摘要:

ISSN 1350-4894 COGSE6 3 (5) 345-446 (1996) ~ Contemporary Organic Synthesis A journal of current developments in Organic Synthesis V O L U M E 3 N U M B E R 5 C O N T E N T S I 'apamycin Synthetic approaches to rapamycin By Mark C. Norley Reviewing the literature published up to August 1995 Synthetic applications of flash vacuum pyrolysis By Hamish McNab Reviewing the literature published between 1990 and 1995 B r $ p r \ Protecting groups By Krzysztof Jarowicki and Philip Kocienski Reviewing the literature published in 1995 0 OH @; ( p 2 Me0 OAc I 0 I. NaH, THF, 55% II. F A . Hfl, 93% 1 fli. ml3. Cr3H6. 66% 0 OH OH q#J- OH 0 OH I (-)-yhodornycinone 345 373 397 The synthesis of quinones By Peter T. Gallagher Reviewing the literature published between 1 January 1991 and 31 December 1995 433Cumulative Contents of Volume 3 Number 1 1 Stoichiometric applications of organotransition metal complexes in organic synthesis ( 2 September 1994 to 30 April 2995) Timothy J.Donohoe 19 Saturated and partially unsaturated carbocycles (January 1994 to April 1995) Christopher D. J. Boden and Gerald Pattenden 41 The enediyne and dienediyne based antiturnour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 1 (up to 25 October 1995) HervC Lhermitte and David S. Grierson 65 Alcohols, ethers and phenols (August 2993 to February 1995) C . S. Hau, Ashley N. Jarvis and Joseph B. Sweeney Number 2 93 The enediyne and dienediyne based antitumour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues.Part 2 (up to 15 November 1995) Hem6 Lhermitte and David S. Grierson 125 The discovery of fluconazole (up to December 1994) Ken Richardson 133 Organic halides (1 July 2994 to 30June 2995) Stephen I? Marsden 151 Aldehydes and ketones (October 1994 to September 1995) Patrick G. Steel Number 3 173 Recent developments in chemical oligosaccharide synthesis (up to October 1995) Geert-Jan Boons 201 Main group organometallics in synthesis (January 1994 to June 1995) Martin Wills 229 Saturated oxygen heterocycles (October 1994 to September 1995) Christopher J. Burns and Donald S. Middleton 243 Carboxylic acids and esters (1 August I994 to 31 July 1995) Tammy Ladduwahetty Number 4 259 Saturated nitrogen heterocycles (1995) Timothy Harrison 277 Catalytic applications of transition metals in organic synthesis ( 1 September 1994 to 31 October 2995) Grabam J. Dawson, Justin F. Bower and Jonathan M. J. Williams 295 Saturated and unsaturated lactones ( 1 August 1994 to 31 Ocfuber 1995) Ian Collins 323 Amines and amides (2995) Michael North Number 5 345 Synthetic approaches to rapamycin (up to August 1995) Mark C . Norley 373 Synthetic applications of flash vacuum pyrolysis (1990 to 1995) Hamish McNab 397 Protecting groups (1995) Krzysztof Jarowicki and Philip Kocienski 433 The synthesis of quinones ( 1 January 1991 to 31 December 1995) Peter T. Gallagher Articles that will appear in forthcoming issues include The intramolecular Heck reaction (up to the end of2995) Susan E. Gibson (nCe Thomas) and Richard J. Middleton Saturated and partially unsaturated carbocycles (May 1995 to April 1996) Kevin I. Booker-Milburn and Andrew S h a r p

ISSN:1350-4894    

DOI:10.1039/CO99603FP017

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S . E. Gibson (nee Thomas), Imperial College of Science, Technology, and Medicine Professor P. J . Kocienski, University of Southampton Professor C. J. Moody, Loughborocigh University uf Technology Professor E. J. Thomas, University qf Manchester International Advisory Board Professor E. J. Corey, Haward University Professor S . Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris XI (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L.E. Overman, University qf California, lrvine Professor L. F. Tietze, University of Giittingen California at San Diego, La Jolla Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently; so too will modern aspects of strategy and computer aided design, biotransformations and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment and new materials, will also be encompassed.Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to Dr Sheila R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK.Deputy Editor: Nicole Brooks. Production Editor: Nicola Coward. Technical Editor: Tony Breen. Tel +44 (0) 1223 420066 Fax +44 (0) 1223 420247 E-mail rsc 1 @rsc.org RSC Server http://chemistry.rsc.org/rsc/ Members of The Royal Society of Chemistry may subscribe to Confemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 1 HN, England. 1996 subscription rates: EEA &185, USA $350, Canada El90 (plus GST), Rest of the World f190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December.Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices. Periodicals postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. $3 The Royal Society of Chemistry, 1996. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording or otherwise, without the prior permission of the publishers.Typeset in Great Britain by Unicus Graphics Ltd, Horsham, West Sussex Printed in Great Britain by Whitstable Litho Ltd, Whitstable, KentContemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (nee Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Haward University Professor S. Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris XI (Paris-Sud) Professor P.D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderahad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Iwine Professor L. F. Tietze, University of Giittingen California at Sun Diego, La Jolla Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently; so too will modern aspects of strategy and computer aided design, biotransformations and protecting group protocols.Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment and new materials, will also be encompassed. Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to Dr Sheila R.Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK. Deputy Editor: Nicole Brooks. Production Editor: Nicola Coward. Technical Editor: Tony Breen. Tel +44 (0) 1223 420066 Fax +44 (0) 1223 420247 E-mail rscl @rsc.org RSC Server http://chemistry.rsc.org/rsc/ Members of The Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 1 HN, England.1996 subscription rates: EEA E185, USA $350, Canada El90 (plus GST), Rest of the World 2190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices. Periodicals postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1996. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording or otherwise, without the prior permission of the publishers. Typeset in Great Britain by Unicus Graphics Ltd, Horsham, West Sussex Printed in Great Britain by Whitstable Litho Ltd, Whitstable, Kent

ISSN:1350-4894    

DOI:10.1039/CO99603FX021

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

280 H. Tani, S. Irie, K. Masumoto and N. Ono, Hetero- 281 S. Dhanalekshmi, C. S. Venkatachalam and K. K. cycles, 1993, 36, 1783. Balasubramian, J. Chem. SOC., Chem. Commun., 1994, 511. Chem. Soc., 1994, 116,6713. 1993,36, 1795. J. Chem. SOC., Perkin Fans. 1, 1995, 2855. 1994,352299. Chem., 1992,45, 1639. 282 W. Adam, M. Ahnveiler and D. Reinhardt, J. Am. 283 B. Alcaide, C. Biurran and J. Plumet, Heterocycles, 284 M. A. Brimble, S. J. Phythian and H. Prabaharan, 285 D. G. Barrett and S.H. Gellman, Tetrahedron Lett., 286 D. B. Clarke, J. R. Guild and R. T. Weavers, Aust. J. Williams: The synthesis of carbocyclic aromatic systems 287 H. R. Sonawane, S. N. Bellur and S. G. Sudrik, Ind. J. 288 E. V. Dehmlow and C. Bollmann, Tetrahedron, 1995, 289 G. P. Shkil and R. S. Sagitullin, Tetrahedron Lett., 290 H.A. Etman, Ind. J. Chem., Sect. B, 1995,34, 285. 291 T. Nakazawa, M. Ishihara, M. Jiguji, M. Yamaguici, Y. Sugihara and I. Murata, Tetrahedron Lett., 1992, 33, 6487. 292 H. Nishino, S. Kajikawa, Y. Hamada and K. Kuro- sawa, Tetrahedron Lett., 1995, 36, 5753. 293 R. F. C. Brown, F. W. Eastwood and J. M. Horvath, Aust. J. Chem., 1995, 48, 1055. Chem., Sect. B, 1992, 31, 606. 51, 3755. 1994,35, 2075. 567280 H. Tani, S. Irie, K. Masumoto and N. Ono, Hetero- 281 S. Dhanalekshmi, C. S. Venkatachalam and K. K. cycles, 1993, 36, 1783. Balasubramian, J. Chem. SOC., Chem. Commun., 1994, 511. Chem. Soc., 1994, 116,6713. 1993,36, 1795. J. Chem. SOC., Perkin Fans. 1, 1995, 2855. 1994,352299. Chem., 1992,45, 1639. 282 W. Adam, M. Ahnveiler and D. Reinhardt, J. Am. 283 B. Alcaide, C. Biurran and J. Plumet, Heterocycles, 284 M. A. Brimble, S. J. Phythian and H. Prabaharan, 285 D. G. Barrett and S.H. Gellman, Tetrahedron Lett., 286 D. B. Clarke, J. R. Guild and R. T. Weavers, Aust. J. Williams: The synthesis of carbocyclic aromatic systems 287 H. R. Sonawane, S. N. Bellur and S. G. Sudrik, Ind. J. 288 E. V. Dehmlow and C. Bollmann, Tetrahedron, 1995, 289 G. P. Shkil and R. S. Sagitullin, Tetrahedron Lett., 290 H. A. Etman, Ind. J. Chem., Sect. B, 1995,34, 285. 291 T. Nakazawa, M. Ishihara, M. Jiguji, M. Yamaguici, Y. Sugihara and I. Murata, Tetrahedron Lett., 1992, 33, 6487. 292 H. Nishino, S. Kajikawa, Y. Hamada and K. Kuro- sawa, Tetrahedron Lett., 1995, 36, 5753. 293 R. F. C. Brown, F. W. Eastwood and J. M. Horvath, Aust. J. Chem., 1995, 48, 1055. Chem., Sect. B, 1992, 31, 606. 51, 3755. 1994,35, 2075. 567

ISSN:1350-4894    

DOI:10.1039/CO99603BX023

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Synthetic approaches to rapamycin MARK C. NORLEY Department of Chemistry, University of Southampton, Southampton SO1 7 lB& UK Present address: Department of Chemistry, University of Nottingham, University Park, Nottingham NG 7 2RD, UK Reviewing the literature published up to August 1995 1 2 2.1 2.2 2.3 2.4 3 3.1 3.2 3.3 3.4 3.5 3.6 3.7 4 5 Introduction The total syntheses The Nicolaou total synthesis The Schreiber total synthesis The Danishefsky total synthesis The Smith total synthesis The fragment syntheses The Ley synthesis of the C22-C42 and C 10-C 17 fragments The Kallmerten synthesis of the C24-C36 fragment The Paterson synthesis of the C24-C32 fragment The Hoveyda synthesis of the C22-C29 fragment The Rama Rao synthesis of the C1-C17 fragment The Pattenden synthesis of the Cl-Cl5 fragment The Mikami synthesis of the C30-C35 and C 10-C 15 fragments Conclusion References 1 Introduction Rapamycin (Scheme 1) is a 31-membered macrocyclic natural product first isolated’” in 1975 from a strain of Streptornyces hygroscopicus found in an Easter Island soil sample.The structure of rapamycin was elucidated by find la^^.^ using a combination of chemical degradation, high field NMR spectroscopy and single-crystal X-ray analysis. In common with the structurally similar macrolide FK-506,5 rapamycin displays potent immuno- suppressive properties. Both compounds have thus attracted intense biological interest due to their potential therapeutic value in organ transplantation and in the treatment of autoimmune Not surprisingly, the biological importance of rapamycin has stimulated much interest in its chemistry.The first total synthesis of rapamycin was published by the Nicolaou group in 1993. This was closely followed by syntheses from Schreiber and Danishefsky, also in 1993, and later from Smith in 1995. A number of syntheses of various fragments have also been reported, as well as several degrada- tion studies.”-I6 In this review the synthetic work towards rapamycin will be summarised. 2 The total syntheses 2.1 The Nicolaou total synthesis Nicolaou’s strategy for the synthesis of rapamycin (Scheme 2)17-’0 identified fully functionalised acyclic precursor 1 and C19-C20 enedistannane 2 as coupling partners in a ‘stitching-cyclisation’ process, whereby the olefinic bridging unit would bring together the two terminal vinyl iodides of 1 in a Abbreviations acac, acetylacetonate; AIBN, 2,2‘-azo(isobutyronitri1e); Aloc, allyloxycarbonyl; 9-BBN, 9-borabicyclo[3.3.1]nonane; BINAP, 2,2’-bis(dipheny1phosphino)-1,l’-binaphthyl; BINOL, l,l’-bi-2-naphthol; Boc, tert-butoxycarbonyl; BOP, benzotriazol-l-yloxytris(dimethy1amino)phosphonium; Bn, benzyl; Bu, butyl; Bz, benzoyl; Cp, cyclopentadienyl; CSA, camphorsulfonic acid; DBU, 1,8-diazabicyclo[5.4.O]undec- 7-ene; DCC, 1,3-dicyclohexylcarbodiimide; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DEIPS, diethylisopropylsilyl; DET, diethyl tartrate; DHP, dihydro- pyran; DIBALH, diisobutylaluminium hydride; DIC, 1,3-diisopropylcarbodiimide; DIPHOS-4, 1,4-bis(diphenyl- phosphino)butane; DIPT, diisopropyl tartrate; DMAP, 4-dimethylaminopyridine; DME, 1,2-dimethoxyethane; DMF, dimethylformamide; DMS, dimethyl sulfide; DMSO, dimethyl sulfoxide; EDC, l-ethyl-3-[3-(dimethyl- amino)propyl]carbodiimide hydrochloride; For, formyl; HCA, hexachloroacetone; HMDS, hexamethyldisilazide; HMPA, hexamethylphosphoramide; HMPT, hexamethyl- phosphorous triamide; HOBT, 1-hydroxybenzotriazole; Ipc, isopinocampheyl; LDA, lithium diisopropylamide; MCPBA, m-chloroperoxybenzoic acid; MOM, methoxy- methyl; Ms, methanesulfonyl; NBD, 2,Snorbornadiene; NBS, N-bromosuccinimide; NCS, N-chlorosuccinimide; NIS, N-iodosuccinimide; NMO, N-methylmorpholine-N- oxide; NPSP, N-(phenylse1eno)phthalimide; PCC, pyridinium chlorochromate; PDC, pyridinium dichromate; Piv, pivaloyl; PMB, p-methoxybenzyl; PMP, p-methoxy- phenyl; PPL, porcine pancreatic lipase; PPTS, pyridinium toluene-p-sulfonate; PTSA, toluene-p-sulfonic acid; TBAF, tetrabutylammonium fluoride; TBDPS, tert-butyldiphenyl- silyl; TBHP, tert-butyl hydroperoxide; TBS, tert-butyl- dimethylsilyl; TDS, thexyldimethylsilyl; TEMPO, 2,2,6,6- tetramethylpiperidin-1-yloxyl; TES, triethylsilyl; Tf, trifluoromethanesulfonyl; TFA, trifluoroacetic acid; THF, tetrahydrofuran; THP, tetrahydropyranyl; TIPS, triiso- propylsilyl; TMS, trimethylsilyl; TPAP, tetrapropyl- ammonium perruthenate; Tr, trityl; Ts, toluene-p-sulfonyl.Norley: Synthetic approaches to rapamycin 345I MeO’ 0 OMe rapam ycin ’OMe FK-506 Scheme 1 Me0 I 21 ; I I rapamycin Stille-type reaction to form the triene and macro- cycle simultaneously. Such a strategy would thus furnish the natural product in a single, final step and would avoid instability problems, deprotection steps, and late stage oxidation state adjustments.Disconnection of 1 at the N7-C8 amide bond reveals two advanced fragments, 3 and 4, of which the more complex 3 may be further dissected to subunits 5-8 as building blocks. The synthesis of cyclohexyl fragment 6 (Scheme 3) began with epoxide 9, prepared from 2-bromo- cyclohexenone by asymmetric reduction, followed by removal of the bromine with Li-Bu‘OH, epoxidation using MCPBA, and benzylation. Regioselective opening of the epoxide with CSA in MeOH followed by standard transformations yielded ketone 10. Enone 11 was then formed from 10 via its TMS enol ether by oxidation with Pd(OAc),. Stereoselective Luche reduction of the enone afforded allylic alcohol 12, which underwent a stereospecific Eschenmoser-Claisen rearrangement upon heating with N , N- dimethylacetamide diniethyl acetal.The resulting amide was reduced to provide primary alcohol 13, which, after hydrogenation of the double bond, was converted to aldehyde 14 via selenoxide formation- elimination and ozonolysis. Condensation of 14 with phosphonate 15 followed by 1,4-reduction of the rrBu3Sn 4 Sn-rrBu3 2 %OH 0 + 5 I / 3 3 Scheme 2 04 Ph 6 I I 8 346 Contemporary Organic SynthesisOBn 0:fJ - a, b, c, d Me0 9 10 11 '""x>, j, k, I, m T B s o a _h,i OH c- MeO Me0 MeO 8 14 n, 0. P 15 TBDPSO.. M e 0 9 "aN?--- Ph 6 13 'OH Yields, Reagents and Conditions: a 90% b 91% C 98% d 92% 0 . 1 f 83% g 95% h .l i 97% i . 1 k 93% I 86% m 88% n 96% 0 . 1 p 75% CSA, MeOH, r.t. TBSOTf, 2,6-lutidine. CH2CI2, 0 "C PdC, H2, EtOH, r.t. 1) LDA, THF, -78 "C; 2) TMSCI, -78 "C + r.t. Pd(OAc),, MeCN, 50 "C LiBH4, CeCI3*7H20, THF-MeOH, -78 "C N,N-dimethylacetamide dimethyl acetal, xylenes, A LiEbBH, THF, 0 "C PdC, H2, EtOH, r.t. @NO2C6H4SeCN, n-Bu3P, THF, r.t. aq. H202, THF, r.t. 1) 03, CH2CI&leOH, -78 "C; 2) DMS, -78 "C + r.t. 1) 15, LEI, CPr2NEt, MeCN, r-t.; 2) 14 1) Rh(PPh3)3Cl, EtsSiH, 50 "C; 2) aq. HF, MeCN, r.t. TBDPSCI, imidazole, DMF, r.t. (COCl)p, DMSO, EtaN, CH2C12, -78 "C + -10 "C 12 Scheme 3 resulting a, P-unsaturated N-acyloxazolidinone then yielded 6. In the synthesis of vinyl iodide 7 (Scheme 4) alcohol 17 was stereoselectively formed by asymmetric crotylboration of aldehyde 16 using Brown's conditions.PMB protection of the alcohol followed by ozonolysis of the terminal double bond and Corey-Fuchs homologation then provided methyl acetylene 18, which was converted to 7 via hydrozirconation and quenching with iodine. The synthesis of aldehyde 8 is depicted in Scheme 5. N-Acyloxazolidinone 19 was obtained from ( + )-P-citronellene beginning with selective cleavage of the trisubstituted double bond (MCPBA, HC104, TBSO 0 TBSO Q3 17 16 Ib, c, d, e TBSO OPMB TBSO OPMB 7 18 Yields, Reagents and Conditions: a b c 2) DMS, -78 "C + r.t. d 100% CBr4, Ph3P, Zn, CH2CI2, r.t. e f 75% (€)-but-e-ene, t-BuOK, n-BuLi, (+)-l&BOMe, BF3.0Et2, 90% NaHMDS, PMBBr, THF-DMF, 0 "C 80% 1) 03, CH2CIfleOH-pyridine, -78 "C; 98% 1) n-BuLi, THF, -78 "C + -20 "C; 2) MeI, -20 "C + 0 "C 85% 1) CpgrHCI, CH2C12, r.t.; 2) I,, 0 "C THF, -78 "C + r.t.Scheme 4 /OTBDPS 22 R = Me 43 8 Yields, Reagents and Conditions: a 73% 1) rrBu2BOTf, Et3N, CH2C12, -78 "C + 0 "C; b 98% LiBH4, H20, Et20, 0 "C + r.t. d 92% LiEt3BH, THF, 0 "C + r.t. e 92% TBAF, THF, r.t. f 97% PMPCH(OMe),, CSA, CH2C12, r.t. g 96% DIBALH, CH2CI2, -78 "C + r.t. h 97% (COCI),, DMSO, Et3N, CH2CI2, -78 "C + r.t. Scheme 5 2) 20, -78 "C + -1 0 "C c 78% TsCI, Et3N, DMAP, CH2C12,O "C NaI04, then Jones oxidation) followed by conversion of the resultant carboxylic acid to a mixed anhydride with pivaloyl chloride. The mixed anhydride was then condensed with the required lithio-oxazolidinone. The other requisite inter- mediate, aldehyde 20, was prepared from Norley: Synthetic approaches to rapamycin 3477 a - 25 6 23 (BOH) + 24 ( A H ) 8 b.c 26 R = "52-- ph 27 R = Me h, 1, i Yields, Reagents and Conditions: a 83% CCI2 (containing 0.1% NiCI2), DMSO, r.t. b 91% Des-Martin periodinane, CHpC12, r.t. d 98% TIPSOTf, 2,6-lutidineI CH2C12, 0 "C e 97% HF*pyridine, THF, r.t. c 85% DIBALH, THF, -78 "C f g 97% 86% (COCl)p, DMSO, EtSN, CHpClp, -78 "C + -10 "C 1) ~FBu~BOT~, EtSN, CHpCIp, -78 "C + 0 "C; 2) 25, -78 "C + -5 "C h 98% LiBH4, H20, Et20, 0 "C + r.t. i 91% TsCI, DMAP, Et3N. CH2CI2, r.t. j 91% LiEt3BH, THF, 0 "C + r.t. k 85% 5, DIC, i-Pr2NEt, 4pyrrolidinopyridine, CHpClp, -20 "C I k Os04, NMO, acetone-H20, r.t. m 75% Pb(OAc)4, Na2C03, benzene, 0 "C + r.t. n 94% CHI3, CrCI2, THFdioxane, r.t. o 98% DDQ, CHCIf120, r.t. p 94% 1) TESOTf, 2,blutidine, CH2C12,O "C; 2) Si02, CH2C12, r.t.I / 3 TBDPSOQ I MeO I 0 3 I Scheme 6 348 Contemporary Organic Synthesisbis(benzy1idene)mannitol by bis-methylation, removal of the benzylidene protecting groups, selective silylation at the primary positions and cleavage of the 1,2-diol. Coupling of 19 and 20 under Evans aldol conditions yielded alcohol 21. The chiral auxiliary-bearing side chain was then converted to the requisite C25 methyl group in 22 via a three-step reduction-tosylation-reduction sequence. Transformation of 22 to 8 then followed standard procedures. The coupling of intermediates 5-8 and their further elaboration to advanced fragment 3 was accomplished as summarised in Scheme 6. Thus, vinyl iodide 7 and aldehyde 8 were coupled by means of a Nozaki-Kishi reaction to afford alcohol 23 along with its C28 epimer 24 in a ratio of ca.2: 1. The undesired minor isomer was converted to 23 via oxidation to the corresponding ketone followed by stereoselective reduction with DIBALH at - 78 "C. Three standard conversions then provided aldehyde 25, which was condensed with the boron enolate of N-acyloxazolidinone 6 to stereoselectively afford aldol product 26. The requisite C35 methyl group in 27 was then generated from the side chain bearing the chiral auxiliary via the three-step procedure as described earlier. Esterification of alcohol 27 with N-Boc-L-pipecolinic acid 5 under standard carbo- diimide conditions followed by cleavage of the terminal double bond and chromium-mediated iodoolefination then furnished vinyl iodide 28, which was finally converted to 3 by exchange of the PMB for TES groups accompanied by concomitant removal of the Boc group.in Scheme 7. Vinyl iodide 29, prepared from 1 -trimethylsilylpropyne by hydrostannylation followed by treatment of the resulting stannane with iodine, was converted to its lithio derivative and coupled with Weinreb amide 30 (readily available from L-ascorbic acid) to afford enone 31. Stereo- selective reduction of 31 according to Suzuki's method yielded alcohol 32 which was converted to epoxide 33 using standard procedures. Regio- selective opening of the epoxide with the mixed cuprate derived from the lithio derivative of primary iodide 34 then afforded alcohol 35. TIPS protection of the alcohol, stereoselective exchange of the TMS group for iodine, liberation of the primary alcohol and oxidation provided aldehyde 36, which was finally condensed with the dianion of methyl glycolate to afford 4 after hydrolysis of the ester.The final stages of Nicolaou's synthesis of rapamycin are shown in Scheme 8. Thus, condensa- tion of amine 3 with carboxylic acid 4 in the presence of HOBT anc' DIC resulted in the formation of amide 37. A series of desilylation steps and oxidation state adjustments then led to bis(viny1 iodide) 1. Finally, exposure of 1 to enedistannane 2 in the presence of (MeCN)2PdC12 and PriNEt in DMF-THF afforded rapamycin in 27% yield. An iodostannane, in which only one vinyl iodide (presumably the less substituted one) had reacted with 2, was also isolated in small amounts; under the The synthesis of advanced fragment 4 is presented I, m Ib 30 33 .IfMB I 32 h, i, j, k - h TMS ?Me 3 .OTIPS; OPMB 35 36 $ OTIPS: ?Me I 4 Yields, Reagents and Conditions: a 70% b 86% c 94% d 93% e . 1 f 64% g 88% h 98% i 97% j 94Y0 k 98% I 1 m 95% 1) t-BuLi, Et20, -78 "C; 2) 30 LiAIH4, LiI, Et20, -100 "C NaH, MeI, DMF, r.t. CSA, MeOH, r.t. K2C03, MeOH, r.t. 1) 34, f-BuLi, Et20, -100 "C; 2) 2-thienylCu(CN)Li, TIPSOTf, 2,6-lutidine, CH2CI2, 0 "C NIS, THF, r.t. DDQ, CH2C12-H20, r.t. 1) methyl glycolate, LDA, THF, -78 "C + 0 "C; LiOH, THF-MeOH-H20, 0 "C MsCI, EtSN, CH&, 0 "C -100 "C + 0 "C; 3) 33, -30 "C 4 0 "C (COC1)2, DMSO, EtSN, CH2CI2, -78 "C + 0 "C 2) 36, THF-HMPA, -78 "C Scheme 7 same Stille reaction conditions as used above, it furnished rapamycin in 70% yield.2.2 The Schreiber total synthesis Schreiber's retrosynthetic analysis of rapamycin is shown in Scheme 9.21-23 Thus, disconnection of the macrocycle at the N7-C8 amide bond identifies amino acid 38 as a fully protected acyclic precursor to macrolactamisation. Disconnection of 38 at the C21 -C22 olefin linkage then reveals advanced fragments 39 and 40, of which the former may be Norley: Synthetic approaches to rapamycin 349I 3 4 1 I I 37 rapamycin 1 Yields, Reagents and Conditions: a 95% HOBT, DIC, CH2C12, 0 OC c 1 HFmpyridine, THF, 0 “C + r.t. d 70% aq. HF, MeCN, r.t. e 27% 2, (MeCN)2PdC12, CPr2NEt, DMF-THF (0.01 M), r.t. b J. (COCl)p, DMSO, Et3N, CH2C12, -78 “C + 0 “C Scheme 8 TIPSO.. Me0 I 38 TIPSO.. I I TIPSO.. 44 Scheme 9 350 Conternporaly Organic Synthesisb Me0'- - Meow- 0 0 45 46 47 48 TIPSO..OH 54 r. s. 1 I TIPSO.. 42 Scheme 10 TIPSO.. MeO P 53 'OH TI PSO.. TIPSO.. MeO x), OH 50 52 Yields, Reagents and Conditions: a 55% Ti(O-kPr),,, (+)-DIPT, TBHP, 4 A molecular sieves, CHzCIp, -20 "C b 94% NaH, PMBBr, mBu4NI, THF, 0 "C + r.t. c & LiMOEt, BF3GEt2, THF, -78 "C d 87% NaH, MeI, THF, 0 "C + r.t. e & HgC12, EtOH, r.t. f 78% DDQ, H20, CH2C12, r.t. g 83% PTSA, 4 A molecular sieves, benzene, r.t. i 4 1) toluene, A; 2) aq. HCI, THF, r.t. j 87% CH2N2, EtpO k 65% 1) BH3*THF, THF, -78 "C + 0 "C; 2) aq. NaOH, aq. H202, 0 "C + r.t. I -1 TIPSOTf, Et3N, CH2C12, 0 "C + r.t. m 87% LiAIH4, THF, 0 "C n 90% I p , Ph3P, imidazole p 71% 1) MCPBA, CH2C12, 0 "C + r.t.; 2) Et2NH, MeOH, r.t.q 88% Ti(O-i.Pr)4, (+)-DET, TBHP, 4 A molecular sieves r 83% Me,AI, hexane, 0 "C s & TsCI, pyridine t 57% K2CO3, MeOH h 4 TBSOTf, Et3N, CH&, -78 "C + 0 "C o 87% 51, THF,-78"C further subdivided into building blocks 41-44 as initial synthetic targets. 42 (Scheme 10) was penta-l,4-dien-3-01 45, which underwent Sharpless asymmetric epoxidation to afford kinetically resolved epoxy alcohol 46. PMB protection of the alcohol, regioselective opening of the epoxide with lithium ethoxyacetylide in the presence of BF,-OEt,, and methylation of the resulting alcohol then afforded alkynyl ether 47. Treatment of 47 with ethanolic HgC12 and removal of the PMB protecting group produced a 6-hydroxy ester, which cyclised to lactone 48 upon treatment with PTSA. Compound 48 was then converted to its silyl ketene acetal, which, after prolonged heating, underwent an Ireland-Claisen rearrangement to afford methyl ester 49 following hydrolysis of the first-formed silyl ester and exposure of the crude acid to diazomethane.Regio- and stereo-selective hydroboration of 49, followed by TIPS protection of the resulting alcohol and reduction of the ester then provided primary alcohol 50, a compound previously employed in Schreiber's total synthesis of FK- 506.24-28 The iodide derived from alcohol 50 was alkylated with lithiated allylic sulfide 51 to regio- selectively afford substituted allylic thioether 52. The starting material for the synthesis of epoxide Oxidation of 52 to the corresponding sulfoxide then resulted in a [2,3]-sigmatropic rearrangement to provide (E)-allylic alcohol 53 after in situ cleavage of the initially formed sulfenate ester.Sharpless asymmetric epoxidation of 53 yielded epoxy alcohol 54, which underwent regioselective epoxide opening with Me-& to introduce the C35 methyl group. The resulting vicinal diol was then converted to 42 using standard procedures. Fragment 43 was constructed as outlined in Scheme 11. Thus, DIBALH reduction of TBS- protected hydroxy ester 55 and Corey-Fuchs homologation of the resulting aldehyde provided methyl acetylene 56. Removal of the TBS protecting group and sulfenylation of the resulting alcohol then yielded compound 57, which underwent a hydrozirconation - brominat ion sequence to afford bromoalkene 43. The synthesis of Weinreb amide 44 (Scheme 12) began with DIBALH reduction of benzyl-protected hydroxy ester 58.Wittig olefination of the resulting aldehyde afforded a, /3-unsaturated ester 59. Reduction of the ester, TBS protection of the resulting alcohol and debenzylation led to homo- allylic alcohol 60, which underwent a hydroxy- directed Rh'-catalysed hydrogenation to provide Norley: Synthetic approaches to rapamyein 35 1I I W a . b . c _ TBSO 0 TBSO 55 56 Id, e I I 43 57 Yields, Reagents and Conditions: a DIBALH, CH2C12, -90 "C b 89% CBr4, Ph3P, Zn, 0 "C -+ r.t. c 95% 1) mBuLi, THF, -78 "C; 2) MeI, -78 "C + r.t. e 72% (PhS)2, rrBu3P, benzene, r.t. f 39% 1) CpgrHCI, toluene, r.t. 3 40 "C; 2) Br2, -78 "C d 3. TFA,THF-H20 Scheme 11 ,OBn ,OH OMe 58 TBSO 59 60 I 63 1 61 OMe I M e " y O TBSO -3 44 Yields, Reagents and Conditions: a J DIBALH, CH2CI,, -90 "C b 80% Ph3P=C(Me)CO2Et, CH2Cl2, r.t.d 1 TBSCI. Et3N, DMAP, CH2C12, r.t. e 94% Na, NH3,-78"C f 90% [Rh(nbd)(diphos-4)]BF4, H2 (1 200 psi), CH2C12, r.t. g J Swern oxidation h 50% 62, mBu2BOTf, CPr2NEt, toluene, -78 "C -+ 0 "C i 63% MeO(Me)NHaHCI, Me3AI, CH2CI2, 0 "C 3 r.t. j 61 Yo PMBOC(=NH)CCI,, TfOH c 100% DIBALH, CH2CI2, -78 "C -+ 0 "C Scheme 12 syn-l,3-dimethyl product 61. Swern oxidation of 61 and Evans aldol condensation of the resulting aldehyde with N-acyloxazolidinone 62 then yielded adduct 63, which was converted to 44 via trans- amination and protection of the secondary alcohol as its PMB ether. The coupling of intermediates 41-44 and their further elaboration to advanced fragment 39 is shown in Scheme 13.Thus, Weinreb amide 44 reacted with the lithio derivative of vinyl bromide 43 to yield enone 64, which underwent a chelation- controlled Zn(BH& reduction to stereoselectively afford alcohol 65. DEIPS protection of the alcohol and oxidation of the sulfide then gave sulfone 66 whose lithio derivative added to epoxide 42 in the presence of BF,*OEt, to afford y-hydroxy sulfone 67. Although metallation of 67 could readily be achieved with n-BuLi, attempted oxidation of this compound with a number of electrophilic oxygen sources was generally unsuccessful; best results were obtained with (TMS0)2, providing ketone 68 in 16% yield. A less direct, but more efficient route to 68 was therefore adopted, whereby olefination of 67 according to the protocol of Julia, Lythgoe and Kocienski, followed by regioselective osmylation and periodate cleavage, provided the ketone in 69% overall yield.An Evans-Tischenko reaction of 68 with N-Boc-L-pipecolinal 41 was then used to introduce the pipecolinate moiety, simultaneously reducing the C32 carbonyl to an (S)-alcohol, to produce coupled product 69 in 95% yield. Four standard conversions then led to 39. Advanced fragment 40 was synthesised as depicted in Scheme 14. Thus, alkylation of methyl acetoacetate 70 with bromide 71 afforded fl-keto ester 72. Catalytic reduction of 72 using Noyori's conditions provided the corresponding p-hydroxy ester, which was converted to Weinreb amide 73. Vinyllithium species 74, obtained (Bu'Li, THF, - 90 "C) from the corresponding vinyl bromide, was then combined with the lithium alkoxide of 73 to yield adduct 75.Removal of the PMB protecting group followed by reduction of the P-hydroxy ketone via the method of Prasad then yielded trio1 76. The C14 and C16 hydroxy groups were distinguished by selective oxidation of the primary alcohol, resulting in the formation of lactol 77. Bis- methylation of 77 followed by treatment with ethane-1 ,2-dithiol-TiC14 subsequently afforded dithiolane 78. Protection of the secondary alcohol in 78 as its TBS ether, removal of the primary TBS protecting group, and transformation of the dithiolane into a dimethyl acetal then provided primary alcohol 79, which underwent allylic oxidation and Wittig elongation to yield dienyl ester 80. Reduction of the ester and conversion of the resulting alcohol to the corresponding chloride, followed by titration with LiPPh2 and exposure of the product to air then yielded 40.rapamycin are shown in Scheme 15. Thus, condensation of aldehyde 39 with the lithium salt of phosphine oxide 40 afforded triene 81. Hydrolysis of The final stages of Schreiber's synthesis of 352 Contemporary Organic SynthesisI 64 I 65 I 66 npso. -.9, '0 42 1 I 41 ,.OPMB - I 39 69 I Yields, Reagents and Conditions: a 78% 1) t-BuLi, THF. -100 "C 2) 44, -78 "C b 90% Zn(BHd2, Et20, -20 "C c 96% DEIPSOTf, 2.blutidine, CH2C12, 0 "C + r.t. d 90% MCPBA, pyridine, -40 "C + r.t. 8 75% 1) rrBuU, -78 " C 2) 42; 3) BF3QEt2 g J 1) OsO,, pyridine; 2) NaHS03 h 69% NaIO,, SO2, Tris-HCI pH 7 buffer i 95% 41, SmITPhCHO (l.l:l), THF, -10 OC j J DW,NaHC03 k 87% AlocCI, 2,&lutMine, pyridine, THF m 96% Swem oxidation f J 1) PBuU, THF.-78 "C; 2) CH~ITE-PM~CI I 71% PPTS-PTSA (4:1), THF-HPO Scheme 13 Norlq: Synthetic approaches to raparnycin 353PMBO PMBO PMBO Li 74 76 70 72 Br 71 n t HO . UlDa 78 OTBS 77 76 Yields, Reagents and Conditions: a 90% 1) NaH, n-BuLi, HMPA, THF, 0 "C; 2) 71 j 94% b 88% RuCI2[(s)-binap]Et& H2 (1100 psi) k 86% d 85% 1) n-BuLi, THF, -78 "C; 2) 74 m & e 93% DDQ, CH2C12, pH 7 buffer n 77% f 98% Et2BOMe, NaBH4, -78 "C o 83% h 78% NaH, MeI, THF, 0 "C + r.t. q 65% i 60% HS(CH2)2SH, TiCI4, -78 "C c 97% MeO(Me)NH.HCI, M M I I 73% g 1 RuCI2(PPhd2, benzene, air P . 1 Scheme 14 the acetal was followed by an aldol reaction of the resulting aldehyde with the lithium enolate of l-ethoxyethyl acetate. Quenching of the reaction with allyl chloroformate, treatment of the crude aldol adduct with TESOTf, and exposure of the resulting silylated material to silica gel then provided amino acid 38.Subjection of 38 to Mukaiyama's macrocyclisation conditions, removal of the three allyl carbonates, Dess-Martin oxidation of the resulting three alcohols and the C9 methylene, and final desilylation-lactolisation of the resulting tetraketone then gave rapamycin. 2.3 The Danishefsky total synthesis Danishefsky has extensively explored ~ y n t h e t i c ~ ~ - ~ ~ as well as degradative'*.14 studies on rapamycin. This work culminated in the total synthe~is,'~ although much of the previously published chemistry was not directly used in the final construction of the natural product. Danishefsky's initial disconnection of the TBSOTf, 2.6-lutiiine HFVyridine, pyridine, THF, r.t.BaMnO,, celite, CH2Cl2 DIBALH HCA, Ph3P, 2,6-di-te&butylpyridine, -40 "C 1) LiPPh2, THF, -78 "C; 2) air (CF&OZ)ZIPh, MeOH PbP=CHC02Et, CH2CI2, 1.t. macrocycle was at the C27-C28 bond, identifying acyclic keto aldehyde 82 as the substrate for a novel macroaldolisation reaction (Scheme 16). Cyclisation of this seco intermediate would thus yield rapamycin after deprotection of the C40 hydroxy group. Disconnection of 82 at the ester linkage reveals fragments 83 and 84 as advanced targets, the latter being available from rapamycin via degradation. The critical step in the synthesis of 83 was an Ireland- Claisen rearrangement of silyl ketene acetal87, to produce carboxylic acid 86.Further manipulations of 86 yielded 83 via a Wittig elongation of aldehyde 85. Ester disconnection of rearrangement precursor 87 identifies cyclohexenol 88 and carboxylic acid 89 as initial targets, whereas further disconnection of advanced fragment 84 reveals subfragments 90-92 as building blocks. The synthesis of cyclohexenol88 (Scheme 17) commenced with carbohydrate derivative 93, whereby methylation of the free hydroxy group, cleavage of the benzylidene acetal with NBS- 354 Contemporary Organic SynthesisTIPSO.- TIPSO., 81 39 40 rapamycin 38 Yields, Reagents and Conditions: a 71% 1) rrBuLi, HMPA, THF, -78 "C; 2) 39 b 56% PPTS, acetone, 43 "C c d 5 1) TESOTf, 2,blutidine, CH2CI2, 0 "C; 2) Si02 e 40% 2-chloro-1 -methylpyridinium iodide, Et3N, CH2Cl2 (O.OOO4 M) g & Dess-Martin periodinane, CH2CI2 h 30% HFVyridine, pyridine, THF & 1) l-ethoxyethyl acetate, LDA, THF, -78 "C; 2) AlocCI, 2,blutidine, -78 "C + r.t.f & Pd(PPhd4, HCONH4, THF Scheme 15 BaC03, and removal of the resulting benzoyl protecting group afforded alcohol 94. Benzyl protection of 94 with concomitant bromide elimination gave compound 95, which underwent a Ferrier transformation when heated with aq. HgC12 to yield alcohol 96. Conversion of 96 to 88 was achieved via enone 97 through p-elimination followed by Luche reduction. titanium-mediated allylation of benzyl-protected hydroxy aldehyde 98 yielded alcohol 99 as an inseparable mixture (7 : 1) with C32 epimer 100. TBS protection of the hydroxy group followed by ozonolysis of the double bond afforded aldehyde 101, which underwent crotylboration to yield alcohol 102 along with C34,C35 epimer 103 (3.5 : 1).Desilylation and chromatography then yielded homogeneous diol, which was subjected to bis- silylation followed by hydroboration to provide primary alcohol 104. Oxidation of 104 (Swern then KMnO,) then gave 89. In the synthesis of carboxylic acid 89 (Scheme 18), The coupling of intermediates 88 and 89 and their further elaboration to advanced fragment 83 is depicted in Scheme 19. Thus, acylation of alcohol 88 with acid 89 was accomplished using EDC-DMAP to provide ester 105, which underwent enolisation- silylation to generate the required silyl ketene acetal 87. Thermolysis of 87 in vigorously refluxing toluene followed by hydrolysis of the resulting silyl ester then yielded carboxylic acid 86 as a single unidentified diastereomer. Treatment of 86 with (COCl),-DMAP afforded lactone 106, thus distinguishing the oxygen functions at C32 and C34.Sulfonhydrazide reduction of the double bond was followed by reduction of the lactone with DIBALH to provide the corresponding lactol, which underwent Suiirez oxidation to yield iodoformate 107. Deiodination, cleavage of the benzyl ethers and regiospecific oxidation of the primary alcohol then provided aldehyde 85, which finally underwent Wittig olefination, TIPS protection of the C40 hydroxy group, reduction of the formate and ethyl Norley: Synthetic approaches to raparnycin 355MeO " O q I TIPSO.* MeO I rapamycin 03 Me0 HoQn : OFor OTBS 85 ymS4' SOpPh 92 OTBS OTBS OBn - Scheme 16 esters, and selective oxidation of the primary allylic alcohol to yield 83. The synthesis of aldehyde 91 (Scheme 20) began with a chelation-controlled Diels-Alder cyclo- addition of (S)-2-(benzyloxy)propanal 108 with diene 109 mediated by MgBr2-OEt2 to provide dihydropyrone 110.Reduction of the carbonyl group was followed by a Ferrier rearrangement (PI-'OH- H+) to yield pseudoglycal 111. Stereoselective hydrogenation of the double bond and removal of the benzyl protecting group then afforded pyranose derivative 112, which was converted to dithianediol 113 by treatment with propane-1,3-dithiol- BF,-OEt,. Cleavage of the diol and Wittig homo- logation of the resulting aldehyde then yielded enoate 114, which was converted to 91 via aldehyde 115 using standard procedures. The starting material selected for the synthesis of sulfone 92 (Scheme 21) was carbohydrate derivative 116, which was converted to compound 117 via stannyl ether formation, benzylation and mesylation.Iodomethoxylation-deiodination of 117 then provided a-methyl-2-deoxyglucoside 118, which was converted to enoate 120 via dithianediol 119 by the 356 Contemporary Organic Synthesis"OMe Me0 'OMe 95 93 94 1. B n O A B n O h J- 0 Me0 MeO OH 88 97 96 Yields, Reagents and Conditions: a 90% NaH, MeI, DMF, 0 "C + r.t. b 93% NBS, BaC03, CCI4, A c 81% NaOMe, MeOH, r.t. d 90% NaH, BnBr, DMF, 0 "C + r.t. e 85% HgClp, acetont+H20, A f 91% MsCI, pyridine, r.t. g 67% CeCI3*7H20, LiBH4, THF-MeOH, -78 "C Scheme 17 I I 0 OlBSOBn 0 OBn 98 99 &OH) + 100 (&OH) 101 Id OH OTBSOBn HO 102 @Me, &OH) 104 + 103 (&Me, W H ) \ h .i '% HO OTBS OTBS OBn 89 Yields, Reagents and Conditions: a 75% Allyl-TMS, TiCI4 b 98% TBSCI, irnidazole, DMF, r.t. c 75% 1) 03, CH2CIdeOH-pyridine, -78 "C; 2) DMS, -78 OC + r.t. d & 1) (-)-DIPT-(€)-crotylboronate, toluene, -78 "C; 2) aq. NaOH, r.t. e 47% TBAF, THF, r.t.; separation f 93% TBSCI, imidazole, DMF, r.t. g 98% 1) g-BBN, THF, r.t.; 2) aq. NaOH, aq. H202, 0 "C h 90% (COC1)2, DMSO, Et3N, -78 "C + r.t. i 99% aq. KMn04, aq. NaH2P04, t-BuOH Scheme 18 BnO.. MeO 105 b 88 89 c, d BnO.. OTBS OTBS OBn C02H OTBS OTBS OBn 87 86 OFor OTBSOBn 106 107 Ht)TBSO 00 83 85 Yields, Reagents and Conditions: a 75% EDC, DMAP, CH2CI2, r.t.i 90% PhSnH, AIBN, toluene, A b - 1) LDA, THF-HMPA, -78 "C; 2) TBSCI, -78 "C + r.t. j 90% Pd(OH)2, H2, EtOAc c - toluene, A k & 4-hydroxy-TEMPO benzoate, Ca(OC1)2, CH2CIflq. NaHC03 d - aq.LiOH,THF I 73% PhP=C(Me)C02Et, toluene, 80 "C 8 70% (COCl)p, DMAP, CH& m 88% TIPSOTf, 2,blutidine, CH2C12, 0 OC f 1) TsNHNH2, DME, 90 "C 2) NaOAc, H20 n 78% DIBALH, toluene, -78 "C g DIBALH, toluene, -78 "C o 90% Mn02,CH2C12 h 85% 12, P~I(OAC)~, cyclohexane, hv Scheme 19 Norley: Synthetic approaches to rapamycin 357OMe 108 109 i-Pq a*** ~ d,e HO BnO : H : : H : I 1 I I 112 If 111 113 I I 114 f OPiV TBDPSO I I 1 91 115 Yields, Reasents and Conditions: a 75% b k c 88% d . 1 0 68% f 96% g 60% i 95% i . 1 k . 1 I 67% m . L n . L 0 1 p 82% h 81% 1j MgBr2.0Et2, THF, r.t.; 2) AcOH, H20 DI BALH I benzene, r.t .PTSA, i-PrOH PdA1203, H2, EtOAC PdC, Ha, EtOAc HS(CH2)3SH, BF3GEt2, CH2Cl2, -78 "C + -20 "C Pb(OAc)d, KOAC, MeCN, -20 "C Ph3P=CHC02Me, CH2CI2, r.t. DIBALH, toluene, -78 "C glyoxylic acid, AcOH, CH2CI2 NaBH4, EtOH PivCI, Et3N, CH2CI2 aq. HF, MeCN Dess-Martin periodinane, CH2CI2 TBDPSCI, EtaN, CH2C12 NCS, AgN03, THF-MeOH Scheme 20 same procedure used for the conversion 112-+114. An Ibuka-Yamamoto (cuprate displacement) reaction was then used to prepare a-methyl ester 121. Reduction of the double bond followed by dithiane cleavage then provided aldehyde 122, which was coupled with vinyl iodide 123 (prepared in five steps from tetrolic acid) by means of a Nozaki- Kishi reaction to provide alcohol 124 as a 1 : 1 epimeric mixture at C16.Oxidation of 124, removal of the benzyl protecting group (with BC13), and reduction of the resulting P-hydroxy ketone via the method of Prasad then afforded syn-1,3-diol 125 as a single diastereomer. Hydrolysis of the ethyl ester followed by lactone formation then served to distinguish the C14 and C16 hydroxy groups, the latter being subsequently methylated (Ag20-MeI) to yield compound 126. A series of four standard transformations then provided 92. further elaboration to advanced fragment 84 is depicted in Scheme 22. Thus, Julia-Lythgoe- Kocienski coupling of aldehyde 91 with sulfone 92, followed by acetylation and P-elimination, yielded vinyl sulfone 127. Reduction of the pivaloate function, reductive desulfonylation, and oxidation of the primary alcohol then afforded aldehyde 128, which was converted to aldehyde 129 in four straightforward steps.Condensation of 129 with the lithio derivative of tert-butyl N-[(phenylsulfinyl)- acetyll-L-pipecolinate then produced adduct 130. Dess-Martin oxidation of 130, followed by desilylation-lactolisation and cleavage of the tert- butyl ester subsequently provided carboxylic acid 131. Conversion of the carboxyl to the corresponding ally1 ester and TMS protection of the tertiary C10 hydroxy group followed by deallylation with Pd(PPh& then afforded 84. The conclusion to Danishefsly's synthesis of rapamycin is shown in Scheme 23. Thus, initial coupling of alcohol 83 and acid 84 using DCC- DMAP at -20 "C was followed by removal of the TBS and TMS protecting groups and oxidation of the C32 hydroxy group to afford C40-silylated seco- rapamycin 82, the substrate for the projected intra- molecular aldolisation.The cyclisation was best carried out using Pr'OTiC13 as the promoter, thus affording a 33% yield of C40-silylated rapamycin 132 in a 1 : 2.3 ratio to an apparent stereoisomer. Rapamycin itself was then obtained in 85% yield by desily la t ion. The coupling of intermediates 90-92 and their 2.4 The Smith total synthesis Smith's retrosynthetic analysis of rapamycin divided the ring into two large fragments encompassing C21-C42 133 and Cl-C20 135 (Scheme 24)."4-36 These fragments were designed to allow flexibility during final assembly of the macrocycle, which could be achieved via intermolecular acylation at C34 followed by intramolecular Pdo-catalysed Stille coupling between C20 and C21, or via initial formation of the triene seco acid followed by macro- lactonisation.In the event the former strategy was used, and this protocol was also applied to the first total synthesis of 27-demethoxyrapamycin (from C21-C42 fragment 134), a compound isolated from the same source as rapamycin whose structure had solely been assigned on the basis of spectral comparisons with the latter. Further disconnection of advanced fragments 133 and 135 identifies building blocks 136-140 as initial synthetic targets. The synthesis of iodide 136 (Scheme 25) began with a Lewis acid catalysed asymmetric Diels-Alder reaction of buta-173-diene with the N-acryloyl derivative 141 of Oppolzer's camphor sultam, to afford adduct 142.Removal of the chiral auxiliary then provided (R)-cyclohex-3-enecarboxylic acid 358 Contemporary Organic Synthesis116 117 118 119 EtO OMS 120 121 OBn OH OH OH I 123 SOpPh 124 125 TESO I Scheme 21 ' S0pPh 92 Yields, Reagents and Conditions: a - rrBu#nO m . 1 b - BnBr, rrBu4NBr n 75% c 99% MsCI, pyridine, 0 "C + r.t. 0 . 1 d 88% NIS, MeOH, MeCN, r.t. P . 1 e 71% rrBu3SnH, AIBN, benzene, A q 71% g 72% Pb(OAc)4, benzene s . 1 f 74% HS(CHZ)~SH, BF3.0Et2, CH2CI2, 0 "C + r.t. r k h 62% Ph3P=CHCOpEf CH&, 0 "C t 86% i 74% MeCu(CN)Li*LiBr, BF@Et2, THF, -78 "C u 3. j 83% (Ph3P)3RhCI, H2, benzene, r.t. v 86% k - dthianecleavage I & 123, CCI2 (containing 0.1% NiC12), DMSO, r.t. 143, which underwent iodolactonisation to yield compound 144.DBU-induced elimination of 144 led to unsaturated lactone 145 which was reduced to the corresponding diol. Conversion of the primary alcohol to a phenyl sulfide, methylation of the secondary alcohol, and oxidation of the sulfide then afforded 3-methoxycyclohexene derivative 146. Regio- and stereo-selective hydroboration of 146 and TIPS protection of the resulting alcohol then yielded sulfone 147 (previously employed in Smith's formal synthesis of FK-50637-39), the lithio derivative of which was added regioselectively to epoxide 148. Reductive desulfonylation then gave alcohol 149 which was converted to epoxide 42 (first used in Schreiber's total synthesis of rapamycin; Section 2.2) through mesylation of the alcohol followed by removal of the TBDPS protecting group with NaH in HMPA.Iodohydrin formation and protection of the resulting secondary alcohol as its PMB ether then furnished 136. The synthesis of dithiane 137 is outlined in Scheme 26. Sulfone 152 was prepared from methyl (R)-3-hydroq-2-methylpropionate 150 via dithiane ' SOPPh 126 Dess-Martin periodinane, CH2Cl2, r.t. Et2BOMe, NaBH4, toluene, -78 "C LiOH, THF-MeOH-H20 0 "C EDC, CH2Clp, r.t. Ag20, MeI, r.t. K2C03, MeOH, r.t. TBSOTf, 2,&Iutidune, 0 "C DIBALH, THF, 0 "C BCIs, CH2C12, -78 "C TESCI, EtSN, CH2C12 151 using standard procedures. The lithio derivative of 152 was then added to aldehyde 153, itself prepared in three steps from L-arabinose. Swern oxidation and desulfonylation of the product afforded ketone 154, which was converted to the corresponding (2)-enolate and trapped with N- phenyltriflimide.The resulting vinyl triflate was then coupled with lithium dimethylcuprate to afford trisubstituted alkene 155. A further six standard conversions provided 137. The preparation of dithiane 138 (Scheme 27) began with the desymmetrisation of meso-dimethyl 2,4-dimethylglutarate 156. Thus, enzymatic hydro- lysis and BH3*DMS reduction of the resulting acid afforded primary alcohol 157 which was converted to 138 via dithiane 158 in seven steps using standard procedures. The coupling of intermediates 136-138 and their further elaboration to advanced fragment 133 is depicted in Scheme 28. Thus, lithiation of dithiane 137, alkylation with iodide 136 and acetal hydrolysis furnished aldehyde 159. Metallation of dithiane 138 and addition to 159 then furnished C27-epimeric Norley: Synthetic approaches to rapamycin 359OPiv TESO OTBS OMe a.b, c OTBS OMe I 92 0- 127 n 0 130 I I I I 131 R=H c 84 R = TMS 0. Pv q Scheme 22 T1pso=n 128 I 1 I 129 Yields, Reagents and Conditions: a 3. 1) LDA, THF, -78 "C; 2) 91 b & AQO, Et3N, DMAP, CH2C12, r.t. c 89% DBU, THF, r.t. d k DIBALH, toluene, 0 "C e 3. Na(Hg), KH2P04, THF-MeOH, -20 "C f 67% Dess-Martin periodinane, pyridine, r.t. g -1 LiCH20Me, Et20, -78 "C h 77% D d a r t i n periodinane, pyridine, CH2Cg, r.t. i & AcOH,THFH20,r.t. j 86% Dess-Martin periodinane, pyridine, CH2C12, r.t. I & Dess-Martin periodinane, pyridine, CH2C12, r.t. m 32% HFopyridine, THF, r.t. n & HC02H, CH2C12, r.t. o 66% K2CO3, allylBr, mBu4NI, DMF, r.t. p 94% TMS-imidazole, DMAP, DMF, r.t.q 70% Pd(PPhg)4, Ph3P, CH2CI2, r.t. k 57% 1) LDA, THF, -78 "C; 2) 129 T1pso*TQ I 83 + I 82 I 84 Yields, Reagents and Conditions: a 85% DCC, DMAP, CH2C12, -20 "C b 50% TBAF, AcOH, THF, 50 "C c 89% Dess-Martin periodinane, pyridine, CH2CI2, r.t. d 10% 1) i-PtOTiC13, CH2C12, -78 "C 2) EhN e 85% HFVyridine, THF, r.t. 132 R = TIPS Scheme 23 rapamycin R=H 360 Contemporaly Organic SynthesisMeO Hoq I I rapamycin (R = OMe) 27demethoxyrapamyan (R = H) TIPSO.. * I 135 n 139 0 140 Scheme 24 133 (R = OMe) 134 (R=H) PMBO CH(OMe)* 136 1 37 I 138 alcohols 160 and 161, with the unwanted diastereo- mer in slight excess (1 : 1.2). Methylation of the alcohol, aldehyde deprotection and Corey-Fuchs homologation then provided terminal alkyne 162 (the unwanted diastereomer from the coupling of 138 with 159 was separated via chromatography of the Corey-Fuchs dibromoalkenes).Removal of the PMB and dithiane protecting groups followed by Pd'-mediated hydrostannylation then completed the preparation of 133. The synthesis of aldehyde 140 (Scheme 29) began with 2-allylcyclopentanone 163, which underwent Baeyer-Villiger oxidation and alkylation to afford lactone 164 as a 1 : 1 mixture of cis/trans isomers. Protection of 164 as the corresponding orthoester with (2R, 3R)-butane-2,3-diol resulted in equilibra- tion of the mixture to a 6 : 1 trans/& ratio, from which the required diastereomer 165 could be separated by HPLC. Ozonolysis of 165 was followed by the addition of vinyllithium species 166, obtained by transmetallation (n-BuLi) of the corresponding silylstannylenyne, itself prepared in two steps from bis(trimethylsilyl)buta-1,3-diyne [MeLi-LiBr/MeI then n-Bu3Sn(Bu)Cu(CN)LiJ&Cl-MeOH]. The resulting C16-epimeric alcohols 167 and 168 were obtained as a 1.1 : 1 mixture in favour of the required diastereomer.Chromatographic separation and methylation, followed by orthoester hydrolysis, silylation, ester reduction and Swern oxidation then yielded 140. Norley: Synthetic approaches to rapamycin 361Scheme 25 141 s TIPSO.. 42 0, P i TIPSO.. 142 149 144 Id 1 47 146 145 I 1 I I a, b, c, d 0 OH S OTBDPS 151 150 Yields, Reagents and Condltiins: a 86% buta-1.3-dieneI EtAIc12, CHzC12, -78 "C b 87% UOH, THF-H20, r.t. c 93% NaHCO3, 12, KI, %O, 0 "C d 96% DBU,THF,A f 70% (PhS)p, rrBuaP, DMF, r.t.h 87% Oxoneb, THFMeOH-Ii20,O "C i j - silyiation k & l)rrBuLi;2)148 I 60% Na(Hg), Na2HP04, MeOH m 90% MsCI, Et3N n 85% NaH.HMPA 8 93% UAIH4,Et@,O0C g 94% CH2b BF@Etz, Et20,O "C 71% 1) BH3*THF, -78 "C -+ r.t.; 2) NaOH, 1-BuOOH o 75% UI, BF3.OEtz p 75% PMBOC(=NH)CCIs, BFaaEt2 Yields, Reagents and Conditions: a 98% TBDPSCI, irnidazole c 3. Swernoxidation e 94% TBAF,THF g 91% NaI, acetone h 91% PhS02Na,DMF i 1 l)rrBuli;2)153 j 4 Swemoxidation b 90% LiBH4, EtzO d 94% HS(CH&SH, BF@Et2 f 95% TsCI, Et3N Scheme 26 k 46% AI(Hg), THF m 70% Me2CuLi, Et20 n 64% CSA,MeOH o 77% PivCI,DMAP p 97% TBSOTf, 2,6lutidine q 99036 DIBALH r 93% Swem oxidation s - acetalisation I 75% 1) LiHMDS, THF-HMPA; 2) Tf2NPh ij 156 I 1 57 I I 168 (MeO)&H 3 138 Yields, Reagents and Condlions: a 88% a-chymotrypsin f 87% HS(CHZ)GH, BF3.OEt2 c 88% TBDPSC1,imidazole h 90% Swemoxidation d 84% DIBALH i - acetalisation e 88Yo Swernoxidation b 100%BH@AS g 95% TBAF Scheme 27 Scheme 30 outlines the' elaboration of aldehyde 140 to advanced fragment 135.Thus, condensation of 140 with the dianion of N-acetyl-L-pipecolinic acid 139, diazomethane esterification of the crude aldol mixture, and Dess-Martin oxidation gave the required tricarbonyl species. Removal of the TBS protecting group then afforded hemiketal 169. 362 Contemporary Organic Synthesis1 59 CH(0Me)Z 1 37 I 162 TIPSO.. 1 h, i, i I I 133 I Scheme 28 Trapping of 169 with TESOTf followed by free radical hydrostannylation, tin-halogen exchange and ester demethylation then completed the synthesis of 135.The conclusion of Smith's synthesis of rapamycin is depicted in Scheme 31. Coupling of alcohol 133 and acid 135 was effected via EDC-induced acylation to afford the seco precursor, which underwent intramolecular Stille coupling with [(2-fu~yl)~P]~PdCl~ in DMF-THF to cleanly generate the macrolide ring. Desilylation then afforded rapamycin. 3 The fragment syntheses 3.1 The Ley synthesis of the C22-C42 and C10-C17 fragments I I 160 (@OH) + 161 @OH) Yields, Reagents and Conditions: a 91% 1) r-BuLi, THF-HMPA; 2) 136 b 70% CI3CCO2H1 acetone c 65% 1) tBuLi, THF-HMPA; 2) 159 d 88% NaH, MeI, 15-crown-5, THF e 97% PTSA,acetone f 4 CBr4, HMPT, THF g 73% nBuLi,THF i 86% (CF3C0z)zIPh, MeOH, H20, THF j 91% rrBu$nHl (Ph3P)2PdC12 h 94% DDQ, CH2C12, H20 171-173) and C10-C17 lactone 174 (Scheme 32).40-42 The key step in the synthesis of epoxide 171 (Scheme 33) involved an intramolecular reaction of an allylsilane with an oxonium ion, generated from an a-alkoxy sulfone, to stereoselectively form a methylene cyclohexane derivative (179-+181).The synthesis began with a Claisen-Johnson rearrange- ment of 2-[(trimethylsilyl)methyl]prop-2-en-l-ol 175 with triethyl orthoacetate to provide ester 176. Condensation of 176 with the anion of methoxy- methyl phenyl sulfone (Bu'Li, DME, -78 "C) afforded P-keto sulfone 177, which was subjected to asymmetric reduction employing BH3.DMS and Corey's oxazaborolidine catalyst 178 to yield P-hydroxy sulfone 179 as a 1 : 2 mixture with C39 epimer 180. The latter could be readily oxidised to 177 for recycling.Following silylation, 179 was The Ley group has published syntheses of C22-C42 fragment 170 (derived by coupling of intermediates treated with SnC& to yield%a& and cis-methylene cyclohexane derivatives 181 and 182 as a 5 : 1 Norley: Synthetic approaches to rapamycin 363'TMS OTBSOMe f, g, h, i,i, 167 ( A H ) + 168 @OH) 140 Yields, Reagents and Conditions: a MCPBA, NaHC03, CH2CI2, r.t. b 55% 1) LDA, THF, -78 OC; 2) Mel, -78 "C + r.t. c 42% (2R,3R)-butane-2,3diol, CSA, benzene, A; separation d 5. ozonolysis e 73% 166,THF,-78"C f - separation; methylation g 86% AcOH,THF h 97% TBSCI, imidazole i 98% DIBALH j 89% Swemoxidation Scheme 29 0 9 OTBSOMe TMS 140 - 139 A 169 135 Yields, Reagents and Conditions: a 79% 1) 139, UHMDS, THF; 2) 140 c 85% Dess-Martin periodinane d l7% aq.HF,MeCN e 85% TESOTf,CH2C12 f 50% mB&SnH, AIBN, 95 "C h 56% LiI, pyridine b 98% CH2N2, Et20 g 97% 12, CH2C!2 Scheme 30 V .. q - I 133 Meo]oH OMe rapamycin Yields, Reagents and Conddions: a 58% EDC, DMAP, DMAPoHCI, CH&I2, r.t. b 74% [(2-f~ryl)~P]~PdC~, CPr2NEt, DMF-THF, r.t. c J TBAF,AcOH,O°C d 61% HFopyridine, pyridine, THF, r.t. Scheme 31 mixture. Hydroboration then provided alcohol 183, at which stage the minor isomer from cyclisation could be separated. Swern oxidation of 183 and crotylboration of the intermediate aldehyde then provided alcohol 184, which underwent epoxidation under standard conditions to provide epoxy alcohols 185 and 186 as a separable 4: 1 mixture of diastereomers. Deoxygenation of 185 via its thionocarbonate derivative by reduction with n- Bu3SnH then afforded 171.Fragment 172 was prepared (Scheme 34) in four steps from methyl (S)-3-hydroxy-2-methyl- propionate-derived alcohol 187 by Swern oxidation, Corey-Fuchs homologation of the intermediate aldehyde, and hydrozirconation-iodination of the resulting methyl acetylene 188. The key step in the synthesis of aldehyde 173 (Scheme 35) involved a selenium-mediated electrophilic cyclisation of an intermediate hemiacetal derived from unsaturated aldehyde 191, to stereoselectively afford acetals 192 and 193. The synthesis began with the desymmetrisation of meso- 2,4-dimethylpentane-1,5-diol 189 by enzymatic monoacyl transfer with methyl acetate. The resulting monoacetate 190 was elaborated to unsaturated 364 Contemporary Organic Synthesis0 e..,.174 170 TBSO.. rapamycin I 171 1 172 1 73 Scheme 32 0 4 b e O f i s c * OEt Me0 S02Ph d o w 177 Me 179 (POMe) + 180 (BOMe) 176 175 u 178 d. c I e.f t . TBSO.. TBSO.. TBSO, . CL g Me0 39 181 (BOMe) + 182 (e0Me) MeO% M e o q o H - 183 184 '1 TBSO.. Me0 Me0 .=wo 185 (ar-0) -+ 186 (PO) --.'u2, 171 Yields, Reagents and Conditions: b 86% MeOCH(Li)SOpPh, DME, -78 "C + r.t. i 70% 1) (-)-Ipc2-(€)-crotylborane, THF-Et20, c 100% BH3mDMS, 178, THF -78 "C; 2) NaOH, H202 d - PDC,CH+ j 90% TBHP, VO(acac),, CH2CI2 e 3. TBSOTf, pyndine, DMAP, CH2C12, 0 "C k 85% mBuLi, THF, -20 "C; 2) CIC(=S)OPh f 60% SnCI4, CH2C12, -78 "C I 80% n-Bu3SnH, AIBN, benzene, A g 80% 1) QBBN, THF, 0 "C -+ r.t.; 2) NaOH, H202 a J (EtO),CMe, EtC02H, 140 "C h 90% (COCI),, DMSO, EtSN, CHZCI, Scheme 33 Norley: Synthetic approaches to rapamycin 365I I I I I I I THPO OH 187 1 aa 172 Yields, Reagents and Conditions: a J (COCl)2, DMSO, Et3N, CH2CI2, -78 "C + r.t.b 77% CBr,, Ph3P, CH2C12, 0 "C c 99% 1) rrButi, THF, -78 "C; 2) Me1 d 85% 1) CpgrHCI, THF, r.t.; 2) I2 Scheme 34 HO f o H ~ Ho\I fOACb,c,d,e 9 Po 191 I f t PhSe 194 192 (pOMe) + 193 (a-OMe) 195 1 73 Yields, Reagents and Conditions: a 55% b . 1 c . 1 e . 1 g 98% i 90% j 88% k 99% I - d 86% f 66% h 83% PPL on celite, MeOAc (COC1)2, DMSO, Et3N, CH2CI2, -78 "C -+ r.t. EtPPhsBr, mBuLi, THF, 0 "C aq. NaOH, nBu4NOH, THF, A (COC1)2, DMSO, Et3N, CH2CI2, -78 "C + r.t. NPSP, MeOH, CH2CI2 1) O,, CH2CI2, -78 "C; 2) Ph3P, -78 "C + r.t. HMMgBr, THF-toluene, -78 "C Zn, MeOH-H20 NaH, Mel, THF 1) O,, CH2C12, -78 "C; 2) Ph3P, -78 "C + r.t.H202, DHP, THF Scheme 35 aldehyde 191 using standard procedures. Treatment of 191 with NPSP and excess MeOH then afforded acetals 192 and 193 as single diastereomers at C26. Selenide oxidation-elimination followed by separation of the anomers and ozonolysis provided aldehyde 194, which underwent stereoselective addition of ethynylmagnesium bromide to yield prop-2-ynyl alcohol 195. Reduction of the triple bond to the corresponding alkene and methylation of the alcohol, followed by ozonolysis then provided 173. Coupling of vinyl iodide 172 with aldehyde 173 was achieved via a Nozaki-Kishi reaction (Scheme 36) to afford alcohol 196 as a 3 : 1 mixture with I L 172 196 @OH) .e 197 (&OH) 1 99 198 TBSO..I 170 Yields, Reagents and Conditions: a 67% CrCI2 (containing 0.5% NiCI2), DMSO c 81% Zn(BH4)2, Et20, 0 "C d 75% NaH, PMBCI, NaI, THF, 0 "C r.t. e 84% Amberlyst-15, MeOH f 85% n-Bu P Nphenylthiosuccinimide, benzene g 93% Oxoied. pH 4 buffer, THF-MeOH h 81% 1) t-BuLi, THF, -78 "C; 2) (MeS)2 i 46% 1) t-BuLi, THF, -78 "C; 2) 171; b 98% TPAP, NMO, CH2CI2 3) BF3.0Et2, -78 "C + r.t. Scheme 36 C28 epimer 197. The minor isomer was converted to 196 via an oxidation-chelation-controlled reduction sequence employing Zn(BHJ2. A series of four standard procedures then provided sulfone 198, which was converted to its a-methylsulfanyl derivative 199. Deprotonation of 199 and addition to epoxide 171 in the presence of BF,-OEt, then afforded coupled product 170 with the ketone function already deprotected (due to the presence of BF-j eOEt2).The synthesis of fragment 174 (Scheme 37) employed n-allyltricarbonyliron chemistry in the key step to generate the lactone ring. Thus, Sharpless asymmetric epoxidation of (2)-4-(benzyloxy)but- 2-en-1-01 200 followed by oxidation of the resulting epoxy alcohol and condensation of the intermediate aldehyde with diethyl phosphonoacetate yielded 366 Contemporary OGanic Synthesis201 H OMe 205 206 204 207 @Me) + 208 (&Me) Yields, Reagents and Conditions: a 75% Ti(O-i.Pr),, (+)-DET, TBHP, CH2CI2, -25 "C b 80% pyridine403, Et3N, DMSO, CH2C12,O "C 3 r.t. c 68% (Et0)2P(0)CH2C02Me, LCI, DBU, MeCN, r.t. e 69% PivCI, pyridine, CH2C12, 0 "C f 94% NaH, MeI, 0 "C h 80% Ti(O-iPr)4, (-)-DET, TBHP, 4 A molecular sieves, CH2CI2, -23 "C i 60% TPAP, NMO, 4 A molecular sieves, CH2C12-MeCN j 83% MePPh3Br, KHMDS, THF, 0 "C + r.t.k 72% Fe2(CO)B, degassed THF I 85% CO (280 atm.), benzene, 70 "C m 82% Pt02, H2, EtOAc, r.t. n 80% 1) LDA, THF, -78 "C; 2) Me1 o 100% Pd(OH)&, H2, EtOAc, r.t. p J Dess-Martin periodinane, t-BuOH, pyridine, CH2CI2 q 5 MeMgBr, Et20, THF, -78 "C r 70% Dess-Martin periodinane, t-BuOH, pyridine, CH2CI2 0 0 d 1 DIBALH, CH&, -78 "C yJO+ g 88% DIBALH, CH&, -78 "C 174 Scheme 37 enoate 201. A further four steps provided allylic alcohol 202, which underwent a second Sharpless epoxidation. Oxidation and Wittig methylenation then furnished alkenyl epoxide 203 as the precursor to the iron carbonyl chemistry. Reaction of 203 with Fe,(CO), in THF gave endo-complex 204 as the predominant product, which was subjected to exhaustive carbonylation to provide unsaturated lactones 205 and 206.Hydrogenation and methyl- ation then produced lactone 207 as a 1 : 1.5 mixture with C11 epimer 208 (the mixture was separable by HPLC and the unwanted major isomer could be recycled to 207 by deprotonation-reprotonation). A further four transformations then afforded 174. 3.2 The Kallmerten synthesis of the C24-C36 fragment Kallmerten's synthesis of C24-C36 fragment 22143 features two [2,3]-Wittig rearrangements as key steps (Scheme 38). The synthesis began with D-glucose-derived compound 209, which was converted to furanosc 210 via benzylation and acid- catalysed isomerisation. A further four steps then yielded aldehyde 211, which, upon chelation- controlled addition of propynylmagnesium bromide and oxidation of the epimeric adducts, afforded ketone 212.A second chelation-controlled Grignard addition followed by reduction of the triple bond then provided (E)-allylic alcohol 213. Alkylation of 213 with chloromethyloxazoline 214 and treatment of the resulting ether 215 with n-BuLi resulted in rapid [2,3]-sigmatropic rearrangement, yielding an inseparable mixture (4.5 : 1) of homoallylic alcohol 216 and its C32 epimer 217. Benzylation and reductive cleavage of the oxazoline group then provided alcohol 218, at which stage the minor isomer from rearrangement could be separated. A further three steps provided prop-2-ynyl ketone 219, which was converted to a-stannyl ether 220 by chelation-controlled reduction of the carbonyl group and Lindlar reduction of the acetylene, followed by alkylation.Upon transmetallation, 220 underwent a second [2,3]-sigmatropic rearrangement to yield 221. 3.3 The Paterson synthesis of the C24-C32 fragment Paterson has reported44 a short synthesis of C24-C32 fragment 225 (Scheme 39) which features a highly n-face-selective boron-mediated anti-aldol reaction as the key step. Thus, Weinreb amide 222 was prepared in two steps from methyl (R)- 3- hydroxy-Zme t hylpropionat e and converted to methoxymethyl ketone 223. Enal 224, prepared from (S)-methyl 3-hydroxy-2-methylpropionate (by TBDPS protection of the alcohol, conversion of the ester to the corresponding aldehyde, Wittig homologation with Ph3P=C(Me)C02Me, DIBALH reduction and Dess-Martin oxidation), was then condensed with the (E)-enol borinate of 223 to afford 225 as the sole product.Norley: Synthetic approaches to rapamycin 367MeO O p 21 9 Me0 O P o B n ' 220 HO I I - MeO O p B n 221 Scheme 38 21 8 P*., MeO 216 (&OH) + 217 @OH) 3.4 The Hoveyda synthesis of the C22-C29 fragment Hoveyda's synthesis45 of C22-CZ9 fragment 231 (Scheme 40) utilises the ability of a siloxane ring to relay asymmetry along an acyclic chain in order to direct a stereoselective osmylation (227 -228). The synthesis began with siloxane 226, prepared by intramolecular Pt-catalysed hydrosilylation of the corresponding (E)-allylic silyloxy hydride. Debenzylation of 226, followed by Swern oxidation Yields, Reagents and Conditions: a & KH,BnBr,DME b 67% HCI,MeOH c & TBSCI, imidazole, THF d 87% MOMCI, CPr2NEt e 99% TBAF,THF g 1 MeCdMgBr, THF, -78 "C i 1 MeMgBr, THF, -78 "C j 81% LiAIH4, THF, 45 "C k 4 KH,214,DME I 70% nBuLi, THF, -78 "C rn & KH,BnBr,DME n J aq.TFA q 1 MeCdMgBr, THF, -78 "C r 64% MnOp, CH2C12 8 1 NaBH4, ZnClp, Et20,O "C t 97% Lindlar catalyst, HP, MeOH u & KH, Me3SnCH21, DME v 44% MeLi,THF,-78"C f 1 (COC1)2, DMSO, EtsN, CH&Iz h 85% (COCI)p, DMSO, EtsN, CH2Ch o 89% LiAlH4 p 1 (COCl)p, DMSO, EtaN, CH2Cl2 k 21 4 21 5 Tritylation of the primary alcohol, methylation of the C27 alcohol and removal of the siloxane afforded hydroxy amide 229, which was converted to enone 230 via reaction with prop-Zenyllithium followed by TBS protection of the alcohol.Chelation-controlled reduction of the carbonyl with Zn(BH,), was followed by a silyl migration to the allylic carbinol induced by NaH in DMSO.The free C26 hydroxy group was then oxidised to the requisite carbonyl to afford 231. 3.5 The Rama Rao synthesis of the C1-C17 fragment and Horner-Emmons olefination of the resulting aldehyde afforded unsaturated Weinreb amide 227. Osmylation of 227 then' stereoselectively afforded siloxane 228 (resulting from rearrangement of the initially formed 1,2-diol), thus differentiating the secondary hydroxy groups at C26 and C27. Rama Rao has fragment 239 beginning with epoxychloride 232 (Scheme 41). Base-induced double elimination of a synthesis of Cl-C17 368 Contemporary Organic SynthesisOMe 0 ~ o T B D p s OH h O B n a * I - I - I //v3Bn 234 OBn Ib.c OTBDPS 233 TBDPSO %OH 222 la I 224 b I OBn 223 OBn 225 I h.i 235 Yields, Reagents and Conditions: a 80% rrBu3SnCH20Me, mBuLi, THF, -78 "C + 0 "C b 94% 1) (cyclohexyl)gBCI, EtSN, Et20, -78 "C + 0 "C; 2) 224, -78 "C + -20 "C n + Scheme 39 237 ?Me M e O N y o OMe BnO Ai' 226 Yields, Reagents and Conditions: a 60% 1) LiNH2-NH3, -33 "C; 2) 233 b 95% Lindlar catalyst, quinoline, MeOH c 60% Ti(O-i-Pr)4, (-)-DIPT, TBHP, 3 A molecular sieves, CHzC12 d 75% Red-At, THF, r.t. e 1 TBAF, THF, r.t. f 1 acetone, PTSA h 70% Zn, BrCH2C02Et, benzene, A i 70% LiOH, DME j 75% 238, pentafluorophenot, DCC, DMAP, CH2Ch k 60% Dess-Martin periodinane, pyridine, CH2CI2 I 70% 0.001 M HCI, MeOH g 80% (COCI)2, DMSO, Et3N, CH2C12, -78 "C 227 HO 228 OMe I Scheme 41 (-..TrO p. T d asymmetric epoxidation of the resulting (2)-alkene to afford epoxyalcohol 235. Regioselective opening of the epoxide with Red-Al followed by a further three transformations led to aldehyde 236, which was subjected to a Reformatsky reaction with Zn- ethyl bromoacetate. Hydrolysis of the resulting /?-hydroxy ester provided acid 237 (as a 1 : 1 mixture of diastereomers) which was coupled with methyl L- pipecolinate 238. Dess-Martin oxidation to the tricarbonyl compound followed by acetonide hydrolysis then led to lactolisation, providing 239 in good yield. 231 230 229 Yields, Reagents and Conditions: a 98% PdlC,H2 b 1 Swemoxidation c 70% Homer-Emmons olefination d 80% Odd, NMO, acetone-H20 e l-tritylpyridinium.BF4, MeCN f 889b NaH, MeI, DMF, 0 "C g 88% TBAF,THF,W"C h 1 H2C=C(Me)Li, Et20, -78 "C i 75% TBSOTf, 2,&1utidine, -78 "C j 90% Zn(BH&-2O0C k 1 NaH, DMSO, r.t.I 80% Swemoxidation 3.6 The Pattenden synthesis of the Cl-Cl5 fragment In Pattenden's synthesis47 of C1-C15 fragment 246 (Scheme 42), a straightfonvard oxidation of acetylenic amide 245 using catalytic Ru04 (generated in situ from RuO, and NaIO,) was used to generate the tricarbonyl unit. The synthesis began with the radical-initiated addition of iodide 240 Scheme 40 232 generated the corresponding prop-2-ynylic alcohol which was coupled in situ with bromide 233 (prepared in six steps from methyl (S)-3-hydroxy- 2-methylpropionate). The resulting product 234 then underwent Lindlar reduction and Sharpless Norley: Synthetic approaches to rapamycin 369P \ 0 a I I 241 242 240 f, g, h 1 ?H 245 6 -*,OH 246 &Me) + 247 (*Me) %OTBS 243 Yields, Reagents and Conditions: a 55% H2C=C(Me)C@Me, rrBu$nCCNaBH4, hv, r.t.b 5. DIBALH,THF c 5. PCC,NaOAc d 76% PhaP=CBr2 e 45% mBuLi, THF, -70 "C f 4 HCI,MeOH g 1 TBSCI, imidazole, DMF h 86% 1) fiBuli, HMPA, -50 "C; 2) CO2 i 86% 244,B0P0PF6 j 35% RuOflal04 k - aq. HF,MeCN O-P(NM+)3 Scheme 42 (derived from the corresponding carbinol) to methyl methacrylate. The resulting 1 : 1 mixture of diastereomeric esters was converted to aldehyde 241 and homologated (Corey-Fuchs) to terminal acetylene 242. Removal of the acetonide and bis- silylation of the resulting diol, followed by metallation and carboxylation of the acetylene, led to acid 243. Coupling of 243 with (S)-2-(methoxy- methy1)piperidine 244 in the presence of BOP.PF6 next produced 245, which, upon exposure to catalytic Ru04, afforded the required amide dione.Bis-desilylation of the product then led to lactolisation, producing 246, which could be cleanly separated from the Cll-epimeric material 247. 3.7 The Mikami synthesis of the C30-C35 and C10-C1S fragments Finally, Mikami has TiC12-catalysed asymmetric carbonyl-ene reaction of (S)- and (R)-homoallylic silyl ethers 248 with methyl that the (S)-BINOL- ;*. HO 0 OTDS 250 b OTDS OTDS 2) TsNHNH~ t Scheme 43 glyoxylate affords 1,4-syn- and 1,4-anti-products 249 respectively with essentially complete diastereoselectivity, independent of reactant chirality (Scheme 43). Further transformations led to 1,4-syn- and 1,4-anti-compounds 250 and 251 respectively, corresponding to the C30-C35 and C10-C15 segments of rapamycin.4 Conclusion The total synthesis of a natural product is not only an intellectual challenge which serves to confirm or refute the initial structural assignment, but also helps to define the scope and limitations of existing synthetic methodology. Furthermore, by minor modifications of a total synthesis, access is provided to virtually unlimited numbers of structurally-related analogues of potential biological value. A natural product of such structural complexity as rapamycin thus presents a challenging synthetic target, and the four total syntheses of this potent immuno- suppressant represent major achievements in this field. Natural product synthesis also provides a stimulus for the development of new synthetic procedures. The new methodology used in the construction of rapamycin and its fragments will undoubtedly find application in other areas of synthesis.5 References 1 V. Vkzina, A. Kudelski and S. N. Sehgal, J. Antibiot., 2 S . N. Sehgal, H. Baker and C. Vezina, J. Antibiot., 3 D. C . N. Swindells, P. S. White and J. A. Findlay, Cun. 1975, 28, 721. 1975, 28, 727. J. Chem., 1978,56, 2491. 370 Contemporary Organic Synthesis4 J. A. Findlay and L. Radics, Can. J. Chem., 1980,58, 579. 5 H. Tanaka, A. Kuroda, H. Marusawa, H. Hatanaka, T. Kino, T. Goto, M. Hashimoto and T. Taga, J. Am. Chem. SOC., 1987,109,5031. 6 S. L. Schreiber, Science, 1991,251,283. 7 S. L. Schreiber, J. Liu, M. W. Albers, M. K. Rosen, R. F. Standaert, T.J. Wandless and P. K. Somers, Tetrahedron, 1992,48,2545. 8 M. K. Rosen and S. L. Schreiber, Angew. Chem., In?. Ed. Engl., 1992, 31, 384. 9 S. L. Schreiber, M. W. Albers and E. J. Brown,Acc. Chem. Res., 1993, 26, 412. 10 P. J. Belshaw, S. D. Meyer, D. D. Johnson, D. Romo, Y. Ikeda, M. Andrus, D. G. Alberg, L. W. Schultz, J. Clardy and S. L. Schreiber, Synlett, 1994, 381. 11 M. T. Goulet and J. Boger, Tetrahedron Lett., 1990,31, 4845. 12 D. Yohannes and S. J. Danishefsky, Tetrahedron Lett., 1992,33,7469. 13 J. Luengo, A. L. Konialian and D. A. Holt, Tetrahedron Lett., 1993,34, 991. 14 D. Yohannes, C. D. Myers and S. J. Danishefsky, Tetrahedron Lett., 1993, 34, 2075. 15 R. J. Steffan, R. M. Kearney, D. C. Hu, A. A. Failli, J. S. Skotnicki, R. A. Schiksnis, J.F. Mattes, K. W. Chan and C. E. Caulfield, Tetrahedron Lett., 1993,34, 3699. Tetrahedron Lett., 1993, 34, 4599. K. Koide, P. Bertinato and K. C. Nicolaou, J. Chem. SOC., Chem. Commun., 1993,617. 18 K. C. Nicolaou, P. Bertinato, A. D. Piscopio, T. K. Chakraborty and N. Minowa, J. Chem. SOC., Chem. Commun., 1993,619. 19 K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa and P. Bertinato, J. Am. Chem. SOC., 1993, 115,4419. Chakraborty, N. Minowa and K. Koide, Chem. Eul: J., 1995, 1, 318. 21 S. D. Meyer, T. Miwa, M. Nakatsuka and S. L. Schreiber, J. 0%. Chem., 1992, 57, 5058. 22 D. Romo, D. D. Johnson, L. Plamondon, T. Miwa and S. L. Schreiber, J. Org. Chem., 1992, 57, 5060. 23 D. Romo, S. D. Meyer, D. D. Johnson and S. L. Schreiber, J. Am. Chem. SOC., 1993, 115, 7906. 24 S. L. Schreiber and D. B. Smith, J. 0%. Chem., 1989, 54, 9. 25 S. L. Schreiber, T. Sammakia and D. E. Uehling, J. Org. Chem., 1989, 54, 15. 26 A. B. Jones, M. Yamaguchi, A. Patten, S. J. 16 J. I. Luengo, L. W. Rozamus and D. A. Holt, 17 A. D. Piscopio, N. Minowa, T. K. Chakraborty, 20 K. C. Nicolaou, A. D. Piscopio, P. Bertinato, T. K. Danishefsky, J. A. Ragan, D. B. Smith and S. L. Schreiber, J. 0%. Chem., 1989, 54, 17. Uehling and S. L. Schreiber,.!. OR. Chem., 1989, 54, 4267. 28 M. Nakatsuka, J. A. Ragan, T. Sammakia, D. B. Smith, D. E. Uehling and S. L. Schreiber, 1. Am. Chem. SOC., 1990,112,5583. 29 M. J. Fisher, C. D. Myers, J. Joglar, S.-H. Chen and S. J. Danishefsky, J. Oig. Chem., 1991,56,5826. 30 S.-H. Chen, R. F. Horvath, J. Joglar, M. J. Fisher and S. J. Danishefsky, J. Oig. Chem., 1991,56,5834. 31 C . M. Hayward, M. J. Fisher, D. Yohannes and S. J. Danishefsky, Tetrahedron Lett., 1993,34, 3989. 32 R. F. Horvath, R. G. Linde 11, C. M. Hayward, J. Joglar, D. Yohannes and S. J. Danishefsky, Tetrahedron Lett., 1993, 34, 3993. J. Am. Chem. SOC., 1993, 115,9345. Leahy, J. L. Leazer Jr. and R. E. Maleczka Jr., Tetrahedron Lett., 1994, 35, 4907. 35 A. B. Smith 111, R. E. Maleczka Jr., J. L. Leazer Jr., J. W. Leahy, J. A. McCauley and S. M. Condon, Tetrahedron Lett., 1994, 35, 4911. 36 A. B. Smith 111, S. M. Condon, J. A. McCauley, J. L. Leazer Jr., J. W. Leahy and R. E. Maleczka Jr., J. Am. Chem. SOC., 1995, 117, 5407. 37 A. B. Smith I11 and K. J. Hale, Tetrahedron Lett., 1989, 30, 1037. 38 A. B. Smith 111, K. J. Hale, L. M. Laakso, K. Chen and A. Rikra, Tetrahedron Lett., 1989,30, 6963. 39 A. B. Smith 111, K. Chen, D. J. Robinson, L. M. Laakso and K. J. Hale, Tetrahedron Lett., 1994,35, 4271. Tetrahedron Lett., 1994, 35, 2087. Tetrahedron Lett., 1994,35, 2091. 1994,35, 2095. 753. 4182. 57, 1643. Lett., 1993, 34, 7111. 34, 2677. 7793. 27 J. A. Ragan, M. Nakatsuka, D. B. Smith, D. E. 33 C. M. Hayward, D. Yohannes and S. J. Danishefsky, 34 A. B. Smith 111, S. M. Condon, J. A. McCauley, J. W. 40 J. C. Anderson, S. V. Ley and S. P. Marsden, 41 C. Kouklovsky, S. V. Ley and S. P. Marsden, 42 S. V. Ley, J. Norman and C. Pinel, Tetrahedron Lett., 43 J. Kallmerten and N. Sin, Tetrahedron Lett., 1993,34, 44 I. Paterson and R. D. Tillyer, J. Org. Chem., 1993, 58, 45 M. R. Hale and A. H. Hoveyda, J. Org. Chem., 1992, 46 A. V. Rama Rao and V. Deshibhatla, Tetrahedron 47 G. Pattenden and M. Tankard, Tetrahedron Lett., 1993, 48 K. Mikami and A. Yoshida, Tetrahedron Lett., 1994,35, Norley: Synthetic approaches to rapamycin 371

ISSN:1350-4894    

DOI:10.1039/CO9960300345

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Synthetic applications of flash vacuum pyrolysis HAMISH McNAB Department of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh EH9 3J4 UK Reviewing the literature published between 1990 and 1995 1 2 3 4 5 6 7 8 9 10 Introduction Apparatus Alkanes Alkenes Alkynes Aromatics Heteroatom-containing functional groups Heterocycles Conclusions References 1 Introduction This review is concerned with the synthetic applications of gas-phase pyrolysis reactions carried out under low pressure flow conditions, a technique commonly known as flash vacuum pyrolysis (FVP) or flash vacuum thermolysis (FVT). In its simplest form, FVP involves vacuum distillation of a substrate through an empty hot tube with the products collected afterwards in a cold trap, and this simple apparatus is increasingly used as an alternative to high boiling solvents or sealed-tube reactions as a means of carrying out preparative pyrolysis chemistry. in that reactive intermediates are generated in the presence of precursor, products and (usually) solvent, so that many unwanted secondary reactions can take place; there are added - often insurmountable - difficulties if the required product is itself thermally unstable.Under FVP conditions, however, the reactive intermediate is generated under unimolecular conditions in the gas phase, and the low pressure flow conditions ensure that individual molecules spend only a short time (of the order of milliseconds) in the reaction zone, so that even thermally unstable products can be quenched without decomposition.The method is therefore ideal for unimolecular reactions but is often inefficient for gas-phase bimolecular reactions. However, reactive molecules which have sufficient lifetime to survive to the cold trap can be trapped chemically in the condensed phase by added reagents, and this can be a useful synthetic procedure. The main problem with condensed-phase methods Work in this field prior to 1980 has been comprehensively surveyed in R.F.C. Brown’s monograph;’ more recent general reviews which emphasise the preparative features of the method include those by Wiers~m,*’~,~ Schaden,’~~ Karpf7 and Brown.8 The well-known application of FVP for the small-scale generation and spectroscopic characterisation of highly reactive species by matrix isolation is specifically excluded from this survey.Other related techniques such as ‘flow’ pyrolysis at atmospheric pressure, vacuum gas-solid reactions (VSGR)9 and ‘microsecond’ FVP” are also excluded. Although almost any organic molecule can be thermally decomposed under FVP conditions if a high enough furnace temperature is used, the most constructive use of the technique for preparative purposes involves the intentional use of a reaction with low activation energy. This can either generate a product directly, or generate a reactive inter- mediate in an appropriate environment for intra- molecular trapping. Such reactions fall into three categories: (i) Pericyclic processes. Because of entropy factors, these are most favourable in the ‘reverse’ direction i.e. retro Diels-Alder reactions, retroene reactions etc.Even intramolecular Diels-Alder reactions in the ‘forward’ direction are relatively rare under FVP conditions because of the precise constraints of the transition state, and similar considerations can often favour radical processes over retroene reactions. (ii) Cleavage of ‘small’ molecules. The driving force behind this mode of reaction is the thermodynamic stability of small molecules such as N2, CO, C02 etc., and consequently can lead to the formation of ‘high-energy’ inter- mediates such as carbenes, nitrenes or diradicals, as well as controlling the direction of fragmentation of heterocyclic systems. (iii) Cleavage of the weakest single bond in the molecule to generate free radicals. Although this is conceptually the simplest FVP mechan- ism, it is by far the least studied, and relatively few useful synthetic methods have emerged. Since these processes are dominated by cleavage mechanisms, it follows that most FVP reactions are oxidative rather than reductive, and often involve the creation of unsaturated centres.This is reflected in the examples quoted in later sections, which are McNab: Synthetic applications of flash vacuum pyrolysis 373arranged according to the functionality which is actually generated in the pyrolysis step. The selection is, of course, a personal one, and is representative of about one third of the relevant articles published during the period. In many examples, the utility of the gas-phase methodology is specifically emphasised by comparison with the results of corresponding solution thermolyses. 2 Apparatus The majority of the reactions described in later sections can be carried out with the simple apparatus shown in Figure 1, versions of which are commercially available.The substrate is contained in the inlet, and is heated under a vacuum of 10-2-10-3 Tom (1 Torr = 133.322 Pa= 1.31 x bar) until it sublimes (or distils) into the furnace tube. The chemistry takes place in the furnace tube, which is generally made from silica, is either empty or packed loosely with silica wool or silica chips, and can be heated electrically up to ca. 1000 "C. The optimum temperature for any reaction is dependent on the tube dimensions, and in practice is determined empirically by small-scale trial reactions. Both temperature and pressure conditions are quoted where possible in the examples given in later sections.Because of the short contact time of the molecules in the hot zone, furnace temperatures are usually outside the normal temperature range of organic chemistry. In our apparatus, most 'useful' reactions take place in the temperature range 450-700 "C, though it must be emphasised that these are 'mild' conditions since most functional groups and chiral centres will survive unchanged. After reaction, the products are quenched in a trap cooled by liquid nitrogen, and can be worked up in the usual way when the pyrolysis is complete. Traps of modified design can be used for rapid quenching of reactive products for subsequent chemical trapping.' Provided the substrate can volatilise without decomposition, FVP can be carried out on an unlimited scale - certainly tens of grams - and for most preparative purposes with standard lab equipment a throughput rate of at least 1-2 grams per hour is typical.3 Alkanes C-C single bonds are not commonly created by FVP methods, though one reaction - the pyrolysis of macrocyclic sulfones - is almost universally employed for C-C bond formation in cyclophane chemistry (see below). Other isolated examples which have been reported recently include the intramolecular ene reaction shown in Scheme 1;" whereas pyrolysis of the precursor in mesitylene led either to no reaction or to decomposition, FVP at 550 "C (0.1 Torr) gave the product as a single diastereoisomer in 80% yield. In contrast, the primary pyrolytic process which occurs on FVP of perfluorohepta-1,6-diene 1 is a formal [2 + 21 cycloaddition leading to its [3.2.0] bicyclic isomer 2, though at high temperatures the final product is the cyclopentene 3 (90%) formed by retro [2 + 21 cleavage of tetrafluoroethylene (Scheme 2).12 The corresponding hydrocarbon displays quite different thermal behaviour, dominated by a retroene reaction.l 2 FVP - H Scheme 1 Scheme 2 The use of sulfone pyrolysis in cyclophane chemistry was first reviewed by Vogtle and Rossa in 1979'" and later in 199213h and is now almost universally employed in this field. The basic strategy involves initial reaction of a dibromo compound Vacwm Nitrogen InlCt I Pressure Inlet Tub8 -Trap Figure 1 374 Contemporary Organic Synthesiswith a dithiol to give a macrocyclic disulfide, which is then oxidised to the disulfone and subjected to FVP (Scheme 3).In the key thermolysis step, loss of SO2 generates a diradical which couples in intramolecular fashion to create the new alkane system. Br ___t Br Scheme 3 The examples which follow have been chosen to illustrate the wide structural diversity which can be accommodated by this strategy, including aromatic, heterocyclic and even aliphatic cyclophanes. Thus the simple orthocyclophane 414 was made from an appropriate bis-sulfone in 56% yield by FVP at 700 "C (0.05 Torr). The synthesis of the more complex 'cuppedophanes' (e.g. 5, 27% at 500 "C and 0.01 Torr) and 'cappedophanes' ( e g 6, 24% under similar conditions) illustrate the applicability of the method to poly~ulfones.'~ 4 5 6 Simple metacyclophanes which have been made include compounds 7 and 8;'6*17 the presence of the functional groups X allows the possibility of elaboration to 'molecular tweezers' which are capable of selectively binding guest molecules.Vogtle's group has also successfully synthesised the tolanophane 9 by this rnethod,l8 though the yield was low owing to the poor volatility of the sulfone, and alternative routes were developed. Mixed orthoparacyclophanes (e.g 10; 75%) and orthometacyclophanes (11; 58%) are also available from disulfones (600 "C, 0.001 Torr).'' Polycyclic aromatic cyclophanes include the anti- metapyrenophanes 12, which are obtained as the exclusive cyclophane products upon pyrolysis BU' X 7 X=NOp 8 X=Br 10 9 11 (480 "C, 0.8 Torr) of either the syn- or the anti- isomer of the disulfone (13 and 14 respectively).20 In the heterocyclic series, the synthesis of [2,](2,3,4,5)thienophane (superthienophane) 15 is a notable achievement.2' The strategy involves two consecutive sulfone pyrolysis steps at 550 "C and 470 "C (0.5-2 Torr) respectively (Scheme 4).Although the overall yield is very low - particularly due to a poor conversion (3%) in the second pyrolysis step - two other potential routes were completely unsuccessful. R' 12 R2 02s+s02 v \ I BU' 14 McNa b: Synthetic applications of flash vacuum pyrolysis 375FVP - FVP - i. NBS ii. Na2S iii. WPBA I 15 Scheme 4 The adamantane unit has been employed as a building block for new cyclophanes - so-called ‘araliphane~’.~~-~~ Pyrolysis conditions of 550-600 “C ( 10-4-10-5 Torr) which lead to both the para- isomer 16 and meta-isomer 17 (50%) are similar to those developed for the aromatic series.In both cases the aromatic rings of the products are severely distorted, showing that even highly strained systems can survive FVP conditions. 16 17 Despite the versatility of the sulfone pyrolysis method exemplified above, Vogtle has recently developed alternative precursors, owing to the poor volatility of complex sulfones and the sensitivity of some thiols and sulfides. The pyrolysis of macro- cyclic dibenzyl ketone derivatives (e.g. 18) proved to be a satisfactory alternati~e~~-~’ which had the added advantage that conditions could be optimised over the range 610-650 “C Torr) to give reasonable yields of successively partially decarbonylated products such as 19-21 (Scheme 5).The precursor ketones are made using TOSMIC methodology, which, unlike the synthesis of sulfones, is compatible with the presence of oxidisable groups in the molecule. phane by FVP of methylenespirocyclohexadienes has been studied in detaiL2’ The synthesis of benzocyclobutene by pyrolysis of a-chloro-o-xylene has been optimised on a 10 g scale and a detailed recipe published.29 The mechanism of the formation of [8]paracyclo- 0 a. \ / FVP - 0 @ \ / 19 @ \ / 0 \ 20 18 21 Scheme 5 4 Alkenes The formation of an alkene unit is a common FVP transformation, which is often accomplished in preparative fashion either by retro heteroene reactions such as acetate or xanthate pyrolysis (which have been reviewed recently) or by retrocycloaddition processes.In this section, the formation of monoenes is considered before that of dienes (and allenes), and the section is completed with a brief consideration of xylylene formation. Heteroene reactions are considered before cycloaddit ion met hods. A comparative study of acetate, xanthate and tosylate pyrolysis has been used to optimise the preparation of 6-chlorohex-1 -ene (Scheme 6)” The main problem here is to avoid secondary elimination of HCl to give hexa-1,5-diene; yields of up to 80% of the required product were obtained from the xanthate 22, which has a lower pyrolysis tempera- ture than the alternative precursors. isoelectronic with that of acetate elimination, and two complementary methods involving sulfoxide pyrolysis at ca.500 “C and 0.1 Torr have been employed to give a-fluoromethyl ketones in around 50% yield (Scheme 7).32*33 Although both methods The mechanism of sulfoxide pyrolysis is 22 R = MeCO, ArS02 or MeSCS Scheme 6 376 Contemporary Organic Synthesis26 25 1 Scheme 7 involve sulfenate elimination, the second has a subsequent fluorine-facilitated Claisen rearrange- ment which extends its scope. The gas-phase procedure is a great improvement over earlier Scheme 9 27 methods as pyrolysis (no products) Or labelled isotopomers in up to 85% yield (Scheme In contrast, cyclopropene-anthracene adducts 29 undergo ring opening of the cyclopropane ring to give bridged alkenes 30 (7147%) under mild FVP conditions (400 "C, 0.05 T~rr).'~' sealed-tube conditions (very low yields due to instability of products and difficulties in separating by-products).decarboxylation of /3-lactones has been reviewed,"4 and the reaction has been applied to the generation of the pyramidalised dodecahedradiene 24 (70%) by pyrolysis of the dilactone 23 at 500 "C (0.01 Torr) (Scheme 8).35 Allenes can also be prepared in this way (see below). The formation of alkenes by stereospecific 28 FVP . I@ Scheme'o 0 wR 23 Scheme 8 Retro Diels-Alder reactions have been employed extensively in alkene formation. Part of the attraction of the method lies in the fact that a sensitive alkene unit can be protected during a synthetic sequence as a Diels-Alder adduct and then released when required under very mild FVP conditions. Owing to its reactivity, cyclopentadiene is the diene component most often used, but dienes which generate aromatic systems on their release such as furan or anthracene often require lower furnace temperatures for this reverse process. Aromatic leaving groups have been used to generate silicon-protected Z-ethene-1,2-diols 25.These could not be released from their anthracene adducts 26 by distillation at 300 "C, but they were successfully generated by FVP at 560 "C (0.01 Torr) and isolated as their dimers 27 (Scheme 9).36 Under the trapping conditions employed, it was not possible to obtain the monomers 25. Methyl cyclopropene-3-carboxylate 28 has a room temperature half-life of 1-2 h but a carefully optimised procedure involving retro Diels-Alder cleavage of dimethyl phthalate at 390-430 "C (0.01 Torr) has been applied to the synthesis of 13C- 29 30 (R = electron withdrawing group) 3,4-Bis(trifluoromethyl)furan 31 is a much better leaving group in retro Diels-Alder reactions than cyclopentadiene, and it has been employed by Warrener and co-workers to give the cyclo- butadiene-l,2-dicarboxylate transfer reagent 32 in 90% yield at 490 "C and 17 Torr (Scheme ll).38 The corresponding endo,exo,exo precursor is much more thermally stable, but pyrolysis at higher tempera- tures leads to undesired electrocyclic ring opening of the cyclobutene function.Three recent examples of FVP mediated retro Diels-Alder reactions in cyclopentenone chemistry may be quoted (Scheme 12). The benzocyclo- pentenone 33 was obtained as shown in quantitative yield en route to methoxsalen 34,39 and a similar route has been employed by the same group to generate the 2,3-double bond of 1,4-anthra- q~inones.~' Both retro Diels-Alder and sulfoxide elimination methodologies were used in a general route to prostanoid precursors 35 (5748% at McNab: Synthetic applications of flash vacuum pyrolysis 37738 F 3 c ~ c F 3 + &C02Me 0 I \ C02Me 0 31 Scheme 11 y p OMe 0 36 Scheme 12 32 c ? OMe 0 33 ii OMe 34 O&OH 35 o*o R' R2 37 350-400 "C and 0.03-0.05 T ~ r r ) .~ ' Closely related anthracene adducts were used to obtain 2-methylene-1,3-dioxygenated cyclopentenes 36 and 37 in 'near-quantitative' yield.42 Application of the retro Diels-Alder cleavage of cyclopentadiene or furan in natural product synthesis has been extensively employed in recent years by Zwanenburg and co-workers.Much of this work has involved the tricyclic cyclopentenone 38 as a key intermediate. This compound is in effect a masked cyclopentadienone, and is available in both homochiral forms by enzymatic resolution of a precursor.43 Chemical transformation of the remaining enone system usually occurs with high regio- and stereo-selectivity, the latter due to Scheme 13 shielding of the concave endo face by the norbornene system (Scheme 13); retro Diels-Alder reaction then yields functionalised cyclopentenones. methodology are shown in Scheme 14. Thus, annelated cyclopentenones 39 have been constructed from the ester 40 via stereospecific conjugate addition of methyllithium (Scheme 14a); FVP at 520 "C (0.01 Torr) gave >90% yields of the products.44 Dihydrosarkomycin esters 41 have been made by a related strategy in which a solution-phase pyrolysis and recombination is a key step (Scheme 14b).45 It is noteworthy that no isomerisation of the double bond to the more stable fully conjugated isomer takes place during the penultimate FVP step, carried out at 510 "C and 0.02 Torr.An enantioselective total synthesis of the natural product (-)-kjellmanianone 42 has been accomplished, again using the ester 40 as the initial starting material (Scheme 1 4 ~ ) . ~ ~ For the epoxides 43, however, careful control of the pyrolysis conditions was required, in order to avoid secondary thermal ring opening to a-pyrones. The use of furan father than cyclopentadiene adducts was crucial in lowering the furnace temperature of the retro Diels-Alder reaction to 300-375 "C, and under these conditions >90% yields of 43 are routinely obtained (Scheme 14d).47 a-Methylene cyclopentenoids have also been made in this way.4x Related epoxides have provided, after reductive ring opening, a stereo- and enantio-selective formal synthesis of clavulone 44 via the key intermediate 45.49750 The work has now been extended to the cyclohexene series and total syntheses of conduritols F and A (46 and 47) have been accomplished (Scheme 15).5' Other examples of this strategy include the generation of the enone 48 (which 'worked beautifully') in 95% yield en route to pilocarpine 49,52 (Scheme 16), and an enantioselective route to indolizidine and pyrrolizidine alkaloidss3 where efficient removal of the controlling cyclopentadiene unit at 450-500 "C (0.1 Torr) is a key step in the overall strategy (e.g.Scheme 17). Diels-Alder component has been elegantly exploited by Bloch and his group. The general strategy again utilises a thermolabile group which can also provide stereocontrol of a variety of reactions. Examples include diastereoselective reduction of the homochiral ketone 50 with lithium A number of related examples based on this The procedure in which furan is used as the retro 378 Contemporary Organic Synthesis40 39 b 41 C H C02Et .b %OH COpMe 40 d 0 43 Scheme 14 I-*- OAc 44 45 Me0 0 42 0 --@$ R' R2 aluminium hydride to give the alcohol 51 and hence the dihydrofuran 52 (82%) by FVP at 500 "C. This compound was used as an intermediate in the synthesis of 53, which is a host specific substance for the ambrosia beetle (Scheme 18).54 Similarly, release of the homochiral 2-alkene 54 is a key step in a total syntheis of (+)-indolizidine 195B 55 (Scheme 19).55 Alder methodology are given in Sections 6 and 8 below.Dienes may be obtained by extension of the methods used for monoenes, or by specific routes such as retrocheletropic processes. Free radical mediated retro [2 + 21 cleavage of fused cyclobutanes at 500-550 "C (0.5 Torr) has been used in the terpene field to give r,w-dienes. Thus, for example, the epoxide 56 of the abundant sesquiterpene caryophyllene gave the P-farnesene epoxide 57 in ca. 45% yield in high chemical and optical purity, though fractional distillation and chromatography was required (Scheme 20).56 current interest.Trahanovsky has employed traditional acetate pyrolysis at 860-900 "C ( Other examples of the application of retro Diels- Cross-conjugated trienes (dendralenes) are of McNab: Svnthetic avvlications of flash vacuum ovrolvsis 379si, 0 0 OAc 11 OH EH , OH OH 47 Scheme 15 oo bH 46 48 49 Scheme 16 Scheme 17 Torr) to give the parent [3]dendralene 58 in ‘relatively high purity’ in > 70% yield (Scheme 21), and its highly reactive cyclic analogue 59 in 45% yield.57 The parent compound 58 can also be made under milder conditions (550 “C, 0.001 Torr, 87%) by cheletropic elimination of SO2 from the sulfone 60 (Scheme 21).58 The closely related dienyne 61 is also best prepared by gas-phase methodology, but the only preparatively useful procedure involves dehydration of the pentynol62 at the rate of 10 g per hour over 5 A molecular sieves at 300 “C (0.001 Torr) (63% isolated yield).” 0 H 50 Me I I 53 Scheme 18 62 54 H 55 Scheme 19 56 57 Scheme 20 \= Ad 58 60 Scheme 21 59 61 62 380 Contemporary Organic SynthesisFVP of halocyclopropenes at 375-650 "C gives up to 85% yields of halogenated allenes generally uncontaminated with the isomeric alkyne (Scheme 22).60 A range of silylated allenes has been obtained in high yield by thermal isomerisation of a series of bicyclic, doubly bridged allenes at 500-600 "C in a nitrogen flow (e.g.Scheme 23).61-63 The reaction is thought to involve a concerted 1,3-shift with inversion at silicon.61 Thermal decarboxylation of a-methylene /3-lactones 63 represents potentially a more general synthetic route to the allene system, but only two examples are reported.@ x3xx4 L RIP <"" xi x2 X2 x4 X'-X4 = H or halogen Scheme 22 Scheme 23 R' No R2 63 FVP of paracyclophane at 650 "C has been used to generate p-xylylene for copolymerisation experi- ments with C60.65 Heterocyclic o-xylylenes represent an important class of reactive diene which are often efficiently made by FVP methods.Recent examples include the extension of the acetate elimination reaction to generate tert-butyl substituted furan- based xylylenes such as 64 (50% at 550 "C and Torr) (Scheme 24), and the effect of the bulky substituent on the dimerisation properties of the ring system has been The method has been extended to the generation and trapping of reactive thiazole, oxazole and imidazole analogues,hR though attempts to make corresponding pyrazole analogues failed. Much of this work depends on the ~ 2 0 c o p h ~ 6 - dimes CH2CMe3 CMe3 64 Scheme 24 discovery of convenient trapping reagents which can compete with inevitable polymerisation reactions; the thiophene xylylene 65, generated by FVP of 2-chloromethyl-3-methylthiophene and quenched at -196 "C, has been found to react smoothly with co- condensed sulfur dioxide on warming, to give the adduct 66 in 62% yield.69 65 66 5 AIkynes Most of the recent work on the generation of the alkyne unit by FVP has centred on the preparation of functionalised (particularly halo-) alkynes, and the use of phosphorus compounds in alkyne synthesis. The pyrolysis of Meldrum's acid (2,2-dimethyl- 1,3-dioxane-4,6-dione) derivatives has been known for some time as a route to alkynes via their methylenecarbene isomers.' A recent application is the preparation of phenylthioacetylene 67 in two steps from readily available starting materials, with the key step being the thermal decomposition of the Meldrum's acid derivative 68 (68%, at 600 "C and 0.001-0.1 Torr) (Scheme 25).70 Routes to haloalkynes include the decomposition of the perffuoro-1,2,3-triazine 69 at 700 "C (0.1 Torr) to give a mixture of difluoroacetylene and cyanogen fluoride, which was fractionated at low temperature to give the acetylene in a pure ~ t a t e .~ ' It has a half- life of ca. 15 min at 300 K and 2 Torr. Fluoroacetylene has been obtained by pyrolysis of the maleic anhydride 70, but was characterised only by matrix isolation.72 Chlorofluoroacetylene and bromofluoroacetylene have been obtained by P-elimination of trimethyltin fluoride at 800 "C from the vinyl derivatives 71 and 72 re~pectively.'~ \SPh 68 67 Scheme 25 A range of aryl and tert-alkyl chloro- and bromo- acetylenes has been made in 37-55% yield by extrusion of triphenylphosphine oxide from the phosphoranes 73 (X = C1 or Br) by FVP at 800 "C (0.001 Torr) (Scheme 26); only traces of the acetylenes were obtained under 'static' pyrolysis condition^.^^ The overwhelming advantages of gas- phase methodology for such extrusions have been emphasised in an extensive series of papers by McNab: Synthetic applications of flash vacuum pyrolysis 381F 0 69 70 71 X=CI 72 X=Br COR 73 Scheme 26 Aitken et aZ.,75-79 wherein a structurally diverse series of phosphoranes has been subjected to FVP at 500-750 "C (0.01 Torr) on a scale of up to 20 g.The method is particularly suitable for alkynes 74 [R' = H, R2 = alkyl or aryl; R' = R2 = alkyl or aryl (59-93% yield),75 or R' = aryl, RZ = C02R (83-92% yield)],76 but yields are more variable for the formation of conjugated diynes (6-68%),77 diacylalkynes (0-67% yield)78 and conjugated enynes (0-85%),79 for which E-2 isomerisation is an added complication. R'+R* 74 A new method of 'solution-spray' flash pyrolysis (SS-FVP) has been developed to overcome disadvantages of involatile substrates in the formation of poly-ynes from cyclobutenedione pyrolyses (Scheme 27).80 The method involves direct introduction of a solution of the compound in benzene as a sprayed aerosol within the quartz pyrolysis tube, which is filled with quartz rings and maintained at a pressure of 1-2 Torr.A range of linear poly-ynes containing from one to six acetylene units has been made using this strategy in yields ranging from 31-99%; these yields are particularly impressive given the high molecular weight and low thermal stability of the precursors, and it is hoped that further applications of this method will be reported in the future. Ox0 R' R2 ss-FVP c Scheme 27 6 Aromatics Although FVP methods are rarely used to make benzene derivatives, there has been much recent interest in fused polycyclic systems, particularly as possible fullerene fragments. In addition, FVP has long been used in generation of cyclic polyenes (non-benzenoid aromatics), many of which are highly sensitive compounds, and a number of these systems are also considered in this section.The Meldrum's acid pyrolysis route to P-naphthols' has been recently applied to the methoxy compound 75 (99% yield at 650 "C and 0.01 Torr), which can be easily transformed to the carboxylic acid 76 which is the intercalating moiety of neocarzinostatin (Scheme 28)." The Brown- Eastwood group have also developed a useful route to 1,2-disubstituted naphthalenes (ca. 70% yield) which involves a Diels-Alder - retro Diels-Alder sequence on pyrolysis of 1 -naphthylmethyl- propynoates 77 at 750 "C (0.02 Torr) (Scheme 29).82 This is a relatively unusual case of a cycloaddition in the forward direction which leads to useful products under FVP conditions.Perchlorotriphenylene 78 has 0 K, 0 I I I 1 . OMe OMe i. [1,5]-H shift ii. electrccyclisation iii. ket-nd tautmerim Me 76 h e 75 Scheme 28 77 1 do Scheme 29 CI Cl 78 382 Contemporary Organic Synthesisproved to be 'unusually e l ~ s i v e ' . ~ ~ ' ~ ~ After a number of failed attempts, the compound was finally obtained in < 1% yield via tetrachlorobenzyne trimerisation, by FVP of tetrachlorophthalic anhydride under relatively high pressure conditions (0.25 Torr) to encourage the intermolecular ~oupling.~'.~~ In the field of polycyclic aromatics, two key reactions have been employed to construct new rings under FVP conditions, both involving pyrolysis of halogen compounds at very high temperatures. The first is exemplified by the reaction shown in Scheme 30B5 in which regiospecific cyclisation with loss of HC1 occurred at 800 "C (0.005 Torr) to give the methyl derivative 79 of the highly tumourogenic benzo[e]acephenanthrylene system in 63% yield.The mechanism probably involves electrocyclic ring closure followed by elimination; a similar mechanism, preceded by well-known thermal E-2 isomerisation has also been proposed to rationalise the formation of phenanthrenes in reasonable yield from o-chlorostilbenes at 950 0C.86 (Dehydrogen- ative cyclisation can also take place, and though the yields are less impressive, the ease of preparing the precursor can be an advantage in more complex Five membered rings can also be formed from o-halopolycyclics, and although temperatures of over 1000 "C are required, the thermodynamic stability of the products allows reasonable yields (38-53%) to be obtained (Scheme 31).88 Fluorene systems can be made by pyrolysis of benzyl bromides at 950 "C Torr) (Scheme 32),89 though in this case the mechanism almost certainly involves homolytic cleavage of the halogen atom followed by free radical cyclisation or hydrogen atom capture.fundamental work by Brown' who showed that under FVP conditions terminal alkynes are in equilibrium with isomeric methylenecarbenes (cf Section 5). This reaction has also been exploited by Dreiding and Karpf in natural product ~ynthesis,~ but its recent use has followed from a concise synthesis of corannulene 80 from the dialkyne 81 discovered by Scott and co-workers (Scheme 33).90 Although the initial yield was low (10% on a 30-50 mg scale), and the pyrolysis conditions were fierce (1000 "C and lop4 Torr) the synthesis was still attractive owing to an easy route to the precursor.It was then found possible to increase the yield to ca. 40% by using the dibromide 82 as precursor, though this mechanism is probably an electrocyclisation- aromatisation sequence as discussed in the previous paragraph. Later work supports this mechanism," since brominated corannulenes can be isolated on variation of the pressure conditions. Corannulene has also been obtained (18%) by FVP of the tetrabromo compound 83 at 1000 0C,92 and by flow pyrolysis at 900 "C of the silylated compound 84 in the presence of hydrogen carrier gas (15%).93 The second key process capitalises on Me Scheme 30 y& \ Scheme 31 Scheme 32 RIP - FVP - FVP L Me 79 \ / Me Scheme 33 In a slight modification of the original approach, a-chlorostyrenes have been employed as thermal precursors to the key alkyne intermediate, and a typical example is shown in Scheme 34 (5% after FVP at 1000 0C).94 Other compounds which have been made by this strategy include the cyclopenta- corannulene 8595 and the C30H12 hydrocarbon 86, albeit in very low yield.96 Five membered rings can McNab: Synthetic applications of flash vacuum pyrolysis 383Scheme 34 85 Scheme 35 N P F w lllc 86 be made efficiently by this r n e t h ~ d ; ~ - ' ~ as shown in Scheme 35 (60% yield after FVP at 1050 "C and 0.01 T ~ r r ) , ~ ~ but the possibility of secondary rearrangement to isomeric, more stable hydrocarbons at the very high temperatures required must not be ignored (eg.ref 100). Although the majority of the activity in synthesis of 'non-benzenoid' aromatics has been in the area of polycyclics, new routes to fulvene"' and hepta- fulvene1O2 derivatives by retro Diels-Alder and phenylcarbene ring expansion routes have been published (Scheme 36). The retro Diels-Alder process takes place at 580 "C (0.006 Torr) to give the fulvenes in 68-99% yield (2 examples), but the carbene ring expansion is less efficient (17% from thep-isomer at 350 "C and lop5 Torr). The preparation of biphenylenes by nitrogen extrusion from fused pyridazines is a well known process.' Recent examples include the perchloro- 1,8-diazabiphenylene 87 ( 14%),'03 and its perfluoro analogue 88 (80%),1"4 obtained by pyrolysis of the appropriate precursor 89 at 850-900 "C (0.03 Torr) (Scheme 37).The polycyclic derivative 90 has also been made as the 'only identifiable product' after 900 "C pyrolysis of 91, though the unstable product could only be isolated in 4% yield after chromatography.'" b CHN2 0 LQ C02Me CH2C0fle Scheme 36 X x 89 Scheme 37 87 X=CI 88 X=F 90 91 There is much current interest in the pentalene system. Griesbeck has reported extensively on a retro Diels-Alder electrocyclisation approach to dihydropentalenes,'06-'m shown in Scheme 38. In the parent case, pyrolysis of the precursor at 520 "C (0.01 Torr) led to the 1,5-dihydro (dendralene-like) isomer 92 in 58% yield on a multi-gram scale, after FVP - I Scheme 38 92 384 Contemporary Organic Synthesisa sequence of 1,5-hydrogen shifts subsequent to the ring closure step.'",107 Methyllo7 and phenylIw analogues have been made by a similar process, which has also been extended to dihydroindenes such as 93 using a cyclopropylpentafulvene precursor 94 (overall yield 90-94% as a mixture of three isomers at 600 "C and 0.08 Torr) (Scheme 39)."' No ring-annelated products were formed from the corresponding epoxide 95, which instead underwent quantitative decarbonyla t ion above 600 "C (0.01 Torr) to vinylcyclopentadienes."' 94 93 Scheme 39 95 The pyrolysis of o-phenyl substituted phthalic anhydrides is a general route to benzannelated pentalenes.82'"0'1'' An early example, shown in Scheme 40, gave a 95% yield of the stable [1,2: 4,5]-dibenzopentalene 96 on FVP of the anhydride 97 at 900 "C (0.04 Torr).82 As shown, the mechanism can be rationalised by ring contraction of an intermediate benzyne, followed by CH insertion of the resulting carbene.82 The correspond- ing reaction of 3-phenylphthalic anhydride and 3-vinylphthalic anhydride under similar conditions gave benzopentalene 98 and pentalene 99 Ph 97 Pp 1 fl 0 96 Scheme 40 McNab: Synthetic applications of flash vacuum pyrolysis 98 99 100 respectively,"' which were isolated as their dimers under normal conditions.The benzopentalene dimer was also obtained by FVP of biphenylene 100 or its precursors at 900 0~.110-112 amlenes have been prepared by Yasunami and c o - ~ o r k e r s , " ~ - ~ ~ ~ in which the key step is the release of the final unit of unsaturation by retro Diels- Alder methodology.This key reaction, shown in Scheme 41,'" has also been applied to the cyclopentazulen-3-one 101"47''5 and the 4-hydroxy compound 1O2.ll6 The yield of this final step is invariably above 80% at pyrolysis temperatures of 400-550 "C (0.1 Torr). A number of potentially unstable fused 1 Fvp Scheme 41 101 102 7 Heteroatom-containing functional groups Surprisingly, FVP methods are not often used to create common heteroatom-containing functional groups, so there is considerable scope here for future development. With the exception of nitrile generation by the isocyanide-cyanide rearrange- ment (see below), most of the activity in this area is focussed on 'unstable' functionalities such as thiones and ketenes where the absence of reagents and convenient low temperature trapping of the pyrolysates are attractive features of the FVP technique.42) has been re~iewed."~ It is in essence a chain The isocyanide-cyanide rearrangement (Scheme FVP R-NC - R-CN Scheme 42 385extension sequence, which, after appropriate functional group transformations, allows the elaboration of an amine into a carboxylic acid containing one more carbon atom. The preparative aspects of the process require suppression of free radical chain side reactions, and this is efficiently accomplished under the dilute conditions of FVP, so that yields can be 'almost quantitative'."' The use of FVP has a number of other advantages for this reaction. Thus, most isocyanides rearrange under standard conditions of 520-550 "C (0.01 Torr), and high throughput rates ( > O S g min-' on a 20 g scale) are possible.Sterically hindered isonitriles react under these standard conditions,"' allyl and propargyl derivatives react without allyl isomerisa- tion"' and homochiral isocyanides rearrange without racernisation.lm used to synthesise unstable isocyanides, notwith- standing the above rearrangement. Examples include the fluorinated compound 103, released from its chromium pentacarbonyl complex 104 by FVP at 240 "C (0.02 Torr),I2' and acetylene isocyanide 105, prepared similarly and identified by photoelectron spectroscopy.*22 FVP of norborna- dienone mine 106 does not give diisocyanogen (CNNC) but rather isocyanogen (CNCN) is obtained, possibly via one isocyanide-cyanide rearrangement; further conversion to cyanogen (NCCN) is found at higher temperature^.'^^ FVP is a classic method for generating unusual ketenes; partly this is due to their distinctive infrared chromophores which render the functional group attractive for matrix isolation, but much useful preparative chemistry can also be accomplished.The Wentrup group is foremost in this area, and an extensive review (203 references) on the preparation and chemistry of a-oxoketenes has recently appeared. 124 An unusually stable a-oxoketene 107 is formed by dimerisation of dipivaloylketene 108 which is itself obtained in 90% yield by FVP (500 "C, lop3 Torr) of the furandione 109 (Scheme 43).'= Dipivaloylketene 108 itself is relatively stable in solution at -20 "C and trapping FVP methods at lower temperatures have been HC,C-NC FHNC FHNC-Cr(CO)s F F F F 103 104 105 106 reactions with heterocumulenes have been investigated.'26 FVP of the diazo compound 111 at 400 "C (lo-' Torr), identified in a matrix, and isolated as its dimer 112 (74%) whose structure was proved by X-ray crystallography (Scheme This structure confirmed that the isomeric ketene 113 was not formed in the carbene ring contraction.Many heterosubstituted methyleneketenes are unusually stable so that they can be isolated at low tempera- tures and trapped with added reagents. The dithia compound 114, for example, prepared by FVP of the Meldrum's acid derivative 115, has a half-life in solution of 20 min at -50 0C,128 and can be trapped by [2 + 21 cycloaddition with The heterocyclic oxoketene 110 has been made by ..\ Me \ Me the 111 110 h e 113 Scheme 44 114 Me 112 oQo u 115 There has been considerable interest in recent years in phosphorus compounds with low coordination numbers. Phosphapropyne 116 can be made in pure form by FVP (700 "C, 0.001 Torr) of either the divinylphosphine 117 or the phosphirane 118, which exist in equilibrium at high temperature (Scheme 45).I3O Remarkably, 116 is stable in solution for at least one week at room temperature. The triaryloxytrioxatriphosphorinane 119 can be cracked to the monomeric aryl phosphenite 120 at 350 "C (lo-' Torr) (Scheme 46) which rapidly dirnerise~.'~' 109 108 107 117 118 116 Scheme 43 Scheme 45 306 Contemporary Organic SynthesisOAr I FVP - ArO-P=O ? o/p.ArO''.OOP\OAr 120 119 [ Ar = Scheme 46 FVP is an ideal method for the synthesis of sensitive thiocarbonyl compounds, and many different routes have been studied.' Recent examples include the pyrolysis of oxidised 1,3-dithiolanes 121 and 122 at 550 "C with loss of SO2 and ethylene to give trifluoromethyl substituted thioketones 123 and sulfines 124 respectively in yields of 5340% (Scheme 47).132 The same type of precursor has been used to generate prop-2-enethial intermediates which can undergo a number of secondary thermal rea~ti0ns.I~~ Diethyl thioxo- malonate S-oxide 125 has been released from its anthracene adduct by retro Diels-Alder reaction at 500 "C Torr) and trapped by reaction with cyclopentadiene ( 47%).134 a 0 0 -\\I/- F3CXS) Fvp_ F3c)=s R S R 121 b ?\ ,P 123 FVP F3c F3c23 - R +=0 I? 0 122 Scheme 47 124 Et02C Et02C +=0 125 A similar strategy has been employed to generate thioaldehydes capable of intramolecular ene reactions. Typical examples are shown in Scheme 48; the yield of the mixture of E and 2 lactones 126 was > 95% from a 600 "C pyrolysis135 whereas the related reaction leading to thialactones (e.g.127) is applicable to 6- 11 membered rings."' a-Oxothiones, including the parent compound 128, have been generated at 850 "C (lo-' Torr) by the unusual retro hetero Diels-Alder process shown in Scheme 49, b FVP Aco2- /- Scheme 48 128 Scheme 49 126 0 0 127 identified by matrix isolation and trapped in 21-53% yield by reaction with a range of diene~.'~'.'~~ generated by FVP. Thus, dichlorothioketene (Cl,C=C=S) was prepared and trapped in quantitative yield by FVP of the dimer 129 at 820 "C (0.001 Torr)."' Allenyl isothiocyanates 13Ol4O and their seleno analogues 13114' are both obtained by FVP of the appropriate cyanate at 350-400 "C (0.01-0.75 Torr) - the former in almost quantitative yield on a daily scale of up to 1 mol (Scheme 50). Both classes of compound are useful substrates for heterocyclisation reactions by treatment with nucleophilic reagents.Sulfur-containing heterocumulenes can also be 129 McNab: Synthetic applications of flash vacuum pyroCysis 387130 x = s 131 X=Se Scheme 50 8 Heterocycles In contrast to the preceding section, FVP reactions provide an increasingly important route to many types of heterocyclic compounds. From the point of view of the heterocyclisation process, gas-phase methods provide the advantages of easily controlled conditions with no necessity for high boiling solvents, and in addition the work-up and isolation of sensitive products is particularly straightforward.In this section, the systems are considered in order of increasing ring size, with subdivisions according to the atomic number of the heteroatom(s) and their number. Annelated compounds are considered directly after the parent ring systems. FVP routes to stable three-membered rings are rare, though annelated heterocyclic four-membered rings can be generated via the appropriate xylylene. Recent examples involve the pyrolysis of ar-mercaptoarylmethanols, which provides the best general route to benzo-annelated t h i e t e ~ .' ~ ~ " ~ ~ Full details have been published of the routes to all three isomeric naphthothietes 132-134,14* which are obtained in yields varying from 50% to almost quantitative from FVP of the appropriate precursors at 750 "C (0.001 Torr) (e.g Scheme 51). The highly reactive bisthiete 135 has been synthesised in 60% yield by a similar strategy.'43 0 K O - Go A A 136 Scheme 52 analogue 139 of the natural product prodigiosin (Scheme 53).14' The indolyl ketene 140 is formed under similar conditions by FVP of the diazo compound 141 (cf Scheme 44); under preparative conditions it is isolated as the tetramer 142 in 75% yield (Scheme 54).'& The novel indeno[ 1,2-b]indole system 143 has been isolated by FVP (800 "C, 0.06 Torr) in 3040% yield using a similar strategy to that employed for the benzopentalenes (Scheme 55; cf Scheme 40).14' 134 Scheme 51 In the five-membered ring series, the amino- methylene Meldrum's acid route to 3-hydroxy- pyrroles'4Q has been extended to unusual N-alkenyl derivatives 136, formed at 600 "C (0.001 Torr) by an unexpectedly facile cleavage of formaldehyde from the initial bicyclic product (Scheme 52).'* The 5-thienyl substituted pyrrol-3(2H)-one 137, available in 70% yield from FVP (600 "C, 0.001 Torr) of the Meldrum's acid 138, has been elaborated to an Q4jo I Me 137 132 133 135 Scheme 53 138 II Et h;le t e 139 FVP is an excellent route to bridgehead nitrogen systems such as pyrrolizin-3-ones and their benzo- analogues.Examples of the former include a short synthesis of the natural product 3,8-didehydrohelio- tridin-5-one 144, in which FVP methods were employed to generate the ring system at two key points in the synthesis (Scheme 56).14* Yields of the pyrolysis steps, carried out at 600 or 650 "C, were 90% and 60% respectively.The related indole derivative 145 yielded the pyrrolo[ 1,2-a]indolone 146 (97%), upon FVP at 750 "C (0.03 T ~ r r ) . ' ~ ~ A route to the pyrrolizidine system has been developed, in which the key step is an intra- molecular 1,3-dipolar cycloaddition of a thermally generated azomethine ylide to an ally1 function (Scheme 57).lW The generation of the ylide 147 388 Contemporary Organic Synthesis0 1 41 140 Scheme 54 Scheme 55 A 148 Scheme 57 1 47 \ C02Et 1 49 1 42 from the oxazolidine 148 further emphasises the propensity for carbonyl compounds to act as thermal leaving groups (cf: Scheme 52), and the pyrrolidine 149, which can be further elaborated to pyrrolizidines, is obtained in 82% yield after in situ cycl~addition.'~~ A simple example of the use of the retro Diels- Alder reaction in heterocyclic chemistry, shown in Scheme 58, is the generation of the 4,5-double bond of 3-vinylisoxazole 150 (99%) from the cyclopenta- diene adduct 151 at 475 "C (0.001 Torr).I5l Pyrolysis of 151 in solution was ineffective.At higher temperatures, the N-0 bond of such compounds may be cleaved, and the FVP reactions of isoxazolones have been studied by Prager and co- workers. These compounds undergo CO, cleavage leading to imino carbene intermediates which can be trapped by adjacent lone pairs rather than \ / '"-9-i 143 COAC 0 0 144 undergoing insertion rea~ti0ns.I~~ A typical example is shown in Scheme 59; the yield of the fused imidazole obtained from a 530 "C (0.01 Torr) pyrolysis is 92%.3-Hydroxythiophenes and thiophen-3(2H)-ones, including the unstable parent compound 152, can be prepared in generally excellent yield via methylene- ketene intermediates by FVP of alkylthiomethylene Meldrum's acid derivatives 153 at 600-625 "C (0.001 Torr) (Scheme 60),'45,'53-'55 and full experimental details are now a~ai1able.l'~ employed in a new synthesis of benzofurans 154,156 in which the ability of the carboxylic ester function Gas-phase free radical chemistry has been Scheme 56 1 50 II 151 145 146 Scheme 58 McNab: Synthetic applications of flash vacuum pyrolysis 389r 1 1 Me Scheme 59 L J I 1 53 (X = 0 or S) Scheme 62 An unusual example of heterolytic reactions taking place in only a short contact time also leads to the benzothiophene system.In this case, the cyclisation of thio acetal 156 is promoted by employ- ing a furnace (200-300 "C, 0.05 Torr) containing a plug of zinc chloride-modified montmorillonite clays; yields were in the range 67-98% for benzo- thiophene and a range of derivatives, but were seldom >50% for the corresponding process in solution (Scheme 63). 159 152 R = H 1 55 Scheme 60 to act as a radical leaving group under FVP conditions is underlined (Scheme 61). Conditions are mild (650 "C and 0.01 Torr), yields are generally in the range 60-90% and the precursors are easily synthesised by Knoevenagel or Wittig methodology.which is also applicable to benzothiophenes involves addition to a pendant alkyne function generated in situ, (Scheme 62), though with the exception of YEt Zn2+ Zn+ An alternative radical approach to benzofurans P P Scheme 63 some specific examples yields are lower and mixtures are often 0btair1ed.I~~ An extension to polycyclics, including the previously unknown benzothieno[3,2-b]benzofuran 155,lS8 has also been reported. 154 Two complementary radical routes to dibenzo- furans and dibenzothiophenes have been developed (Scheme 64).160*'61 In the first, an aryl radical is generated directly by FVP of an ally1 ester 157 at 900 "C (0.001 Torr), but results in only moderate yields (up to 63%) after cyclisation. The same key intermediate is generated indirectly in the alternative method (Scheme 64), which involves pyrolysis of readily available aryl salicylates (or thio salicylates) 158 under more moderate conditions (650 "C, 0.001 Torr).Better yields are usually obtained by this latter route (70-94% for a range of esters derived from p-substituted phenols). Another cyclisation mechanism of methylene- ketene intermediates can give rise to fused bicyclic products of variable ring size (e.g. Scheme 65) in moderate yield,162 by variation of the size of the N- containing ring and the length of the side-chain in the precursor. The method gives rapid entry to ___c C02Me [m Scheme 61 390 Contemporary Organic Synthesis0 f= Y I CO2Et 159 II I Fvp 158 1 57 I Fvp (X = 0 or S) Scheme 64 FVP - Q=*=*=O CI Cl I C02R ' COCl I I Scheme 65 1-azabicyclo[x .y .O]alkane frameworks which are often encountered in the alkaloid field.Surprisingly few FVP reactions have been developed to create monocyclic six-membered heterocycles, though there is considerable interest in fused systems. In one unusual example, (Scheme 66) a fused piperidine ring is created in 83% yield by FVP (270 "C, 3 Torr) of an oxazolidinone unit, with concomitant deprotection of a Boc group.I6' Oxazolidinones are the products from the FVP of N- ethoxycarbonylaziridines 159 under apparently more vigorous conditions (650 "C), though the pressure used (0.001 Torr) is indicative of a much shorter contact time.'64 H Scheme 66 An electrocyclic ring opening is the key step in the route to (+)-&coniceine 160 from the azetine 161 (Scheme 67).'65 Under relatively low pressure conditions for this study (540 "C, 5 Torr), the intermediate azadiene 162 is isolated, which is converted to the bicycle 163 by heating in benzene.Under higher pressure (20-30 Torr) and with a longer contact time, the cycloadduct 163 may be formed directly. 165 In similar fashion, conjugated imino cyclobutenes undergo ring opening, but in this case lead to dihydroisoquinolines 164 by electro- cyclic ring closure and 1,5-H shift at 500-550 "C (lop4 Torr) (Scheme 68). Yields are in the range 50-68%, even in the presence of a sensitive cyclopropyl substituent (e.g. Scheme 68, R = cyclopropyl).166 FVP of conjugated hydrazones such as 165 at 600 "C (0.001 Torr) gave the fused pyridines 166 in ca.50% this cyclisation could not be effected in solution. An electrocyclisation mechanism has been pr~posed,'~' but homolysis of the N-N bond and cyclisation of the resulting intermediate iminyl radical are also possible. 161 162 163 160 Scheme 67 R L A Scheme 68 1 C02Me I R 164 McNab: Synthetic applications of flash vacuum pyrolysis 391NMe2 (X = 0 or S) (X = 0 or S) 165 166 The electrocyclisation of aryl- or heteroaryl- iminoyl ketenes 167 has become a standard route to fused pyridin-4-one structures and some examples are given in references 169-172 (Scheme 69). For preparative purposes, Meldrum's acid derivatives such as 168 are often the most readily accessible precursors, but pyrrole-2,3-diones 169 can also be USed.16%170 Trapping of the ketene by an adjacent lone pair gives rise to the novel betaine structure 170 (50-55% by FVP at 550 "C and 8 x lop5 Torr) whose structure was proved by X-ray crystallography (Scheme 70).17' At higher furnace temperatures this product rearranges to the isomeric structure 171, presumably via regeneration of the ketene.Similarly, pyrimidoquinolinones 172 can be made 'with yields routinely in the range 95-98%' by FVP of the crotonate esters 173 at 530 "C (0.01 Torr), a vast improvement over the corresponding solution thermolysis procedure (Scheme 71).17* An unusual rearangement (Scheme 72) provides a novel entry to this energy I I 168 Ph 169 Scheme 69 ?- Scheme 70 392 Contemporury Oiganic Synthesis 1 70 c H 171 CO2Et L 1 73 CQN 0 1 72 Scheme 71 C02Me kP f y - N N-N r H l L J 0 Scheme 72 An interesting four step pyrolysis sequence (Scheme 73) provides 5-hydroxypyrazolo[ 1,s- alpyridines 174, often in yields of >90%, by FWP of the propynoylpyrazoles 175 at 650 "C (0.03 T ~ r r ) .' ~ ~ Trapping of conjugated ketenes by adjacent 1 75 1 74 Scheme 73carbonyl functions is an important route to R %= lfl-RflO] a-pyrones, and some pyranopyrroles (e.g. Scheme 74) have been made by FVP of Meldrum's acid derivatives at 600-650 "C (0.001 Torr).'" formed 'almost exclusively' by FVP of vinyldiallyl- phosphine 177 at 700 "C (0.001 Torr) via a retroene-electrocyclisation-dehydrogenation mechanism.176 N,O The parent phosphinine (phosphabenzene) 176 is 181 . \ / O%o N I But FVP Scheme 74 7 I BU' 176 177 A number of FVP routes to seven-membered rings have been documented.Stable azepinones may be obtained by the vinylogous cyclisation sequence to that shown in Scheme 53, and FVP of the Meldrum's acid derivative 178 at 600 "C (0.005 Torr) gives the 7-dimethylamino substituted example 179 (90%) which shows unusual cyclo- addition reactions with dienophile~."~ Related 4,5,6,7-tetrahydro( 1 H)-azepin-4-ones 180 are obtained in moderate yield by FVP at 700 "C of the spirocyclobutane isoxazole derivatives 181 (Scheme 75).'78 Application of this strategy to products of other ring sizes has been re~iewed."~ Tsuchiya's group has employed an electrocyclic ring opening strategy to make a number of new benzoheterepine ring systems 182-185 with unusual heteroatoms (Scheme 76).180,'8' Optimum furnace temperatures are 500-550 "C at Torr, and yields can be as high as 85%, whereas no reaction took place under solution pyrolysis conditions.The oxides 182 and 185 can be chemically reduced to the parent systems 186 and 187 respectively. 1 78 179 H 1 80 Scheme 75 Q-"W X 182 X = POPh 183 X=SiMq 184 X-Gem 185 X=AsOP2 186 X=PPh 187 X=AsPh Scheme 76 9 Conclusions It can be readily seen from this survey that FVP methods are no longer the province of specialist thermolysis chemists with interests in mechanisms or unusual intermediates, but are generally useful to the synthetic organic community as a whole. 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Chem. SOC., Perkin Trans. I , 1993,2017. 176 P. Le Floch and F. Mathey, J. Chem. Soc., Chem. Commun., 1993,1295. 177 E. Cartmell, J. E. Mayo, H. McNab and I. H. Sadler, J. Chem. Soc., Chem. Commun., 1993,1417. 178 A. Goti, A. Brandi, F. De Sarlo and A. Guarna, Tetrahedron, 1992,48,5283. 179 A. Brandi, F. M. Cordero, F. De Sarlo, A. Goti and A. Guarna, Synlett, 1993, 1. 180 J. Kurita, S. Shiratori, S. Yasuike and T. Tsuchiya, J. Chem. SOC., Chem. Commun., 1991,1227. 181 J. Kurita, S. Shiratori, S. Yasuike and T. Tsuchiya, Heterocycles, 1993,36, 2677. 182 V. Boekelheide,Acc. Chem. Res., 1980, 13, 65. 170 T. Mosandl, C. 0. Kappe, R. Flammang and 396 Contemporary Organic Synthesis

ISSN:1350-4894    

DOI:10.1039/CO9960300373

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Protecting groups KRZYSZTOF JAROWICKI and PHILIP KOCIENSKI Department of Chemisty, The University, Southampton SOI 7 lBJ, UK Reviewing the literature published in 1995 Continuing the coverage in Contemporary Organic Synthesis, 1995, 2, 315 1 2 2.1 2.2 2.3 2.4 3 4 5 6 7 8 9 10 11 Introduction Hydroxy protecting groups Esters Silyl ethers Alkyl ethers Alkoxyalkyl ethers Thiol protecting groups Diol protecting groups Carboxyl protecting groups Phosphate protecting groups Carbonyl protecting groups Amino protecting groups Miscellaneous protecting groups Reviews References 1 Introduction This review covers new developments in protecting group methodology which appeared in 1995. As with our previous annual review,’ the coverage is a personal selection of methods which we deemed interesting or useful.In addition to examples gleaned from reading the literature, the references were selected through a Science Citation Index search based on the root words ‘block’, ‘protect’ and ‘cleavage’. The review is organised according to the type of functional group protected with emphasis being placed on deprotection conditions. In the accompanying schemes, transformations for which the scale is specified imply that full experimental details were provided in the original reference. Owing to the intense current interest in solid phase synthesis, we have also included recent develop- ments in new linkers. 2 Hydroxy protecting groups 2.1 Esters DMAP increases the rate of acylation of alcohols with acid anhydrides by a factor of lo4. In the case of compound 1, the use of DMAP as a catalyst at room temperature after 5.5 h yielded less than 1% of 2 (Scheme 1).By contrast, Yamamoto and Scheme 1 co-workers2 showed that scandium triflate (1 mol%) accomplished the desired esterification in 94% yield at -20 “C. Scandium triflate is especially useful for large-scale synthesis because as little as 0.1 mol% can be used. derivatives modified with polyethylene glycol (PEG), considerable difficulty was encountered in selectively removing an ester protecting group from the 2’ position (Scheme 2).3 When R =Ac, hydrolysis with NaHCO, was slow and was accompanied by partial hydrolysis of the C13 side chain. The chloroacetyl group was too hydrolytically labile to offer adequate protection. However, the methoxyacetate 3, which hydrolyses ca. 20 times faster than acetate, was cleaved with excess ethanolamine without rupture of the C13 side chain.Relay deprotection is a powerful technique for the selective deprotection of functional groups in a polyfunctionalised sub~trate.~ A good example that emerged this year (Scheme 3) comes from a synthesis of the circulating anodic antigen secreted by the parasite Schistosoma man~oni.~ The two primary alcohol functions in the tetrasaccharide 4 were deprotected selectively in the presence of secondary acetate and p-toluate esters and phthal- imide functions, using hydrazine buffered with During a synthesis of water soluble taxol 0 BzO HOCH2CH NH2. P-prOpBn~l A. 21 h. ~58% R = H PEG = polyethylene glycol Scheme 2 Jarowicki and Kociemki: Protecting groups 397MBzO.. MBzO MBZO R = H 0 Lev= ,+ 0 MBz= k All = ally1 Scheme 3 acetic acid according to the procedure of van Boom and Burgers6 Levulinate esters are useful for the deprotection of alcohols under essentially neutral conditions using hydrazine hydrate.A levulinic acid derivative bearing a trityl alcohol functionality has been developed by Leikauf and Koster (Scheme 4) to OvO BrOCHAH OH AgOTf, coll&i CH&I -30°C - &I% OH serve as a reporter f~nctionality.~ The deprotection is easily assayed colorimetrically by treating the cleavage product 5 with 5% ClzCHCOzH in dichloromethane to give a trityl cation with A,.,,= 513 nm ( E 78500). Another relay deprotection method reported this year for the selective deprotection of ester functions in carbohydrate derivatives8 is illustrated in Scheme 5.The 2-(2-chloroacetoxyethyl)benzoyl group (abbreviated CAEB) functions as a temporary 1,2-trans-directing protecting group for glycosyl donors. It is stable to hydrogenolysis and can be cleaved with thiourea without affecting acetyl, benzoyl, benzyl and benzylidene groups. 2.2 Silyl ethers In the final step of a synthesis of the antitumour antibiotic lankacidin C, Kende and co-worker~~ were faced with the difficult deprotection of the bis-TBS Scheme 4 OYO Scheme 5 398 Contemporay Organic Synthesis8 ("W) 9 ("sickle") 10 ("U") THF-HCO H-H 0 (631) (2 ml) rt, 3h, (0.&3 mmol scale) 7 R = H TBS = telt-butyldimethylsilyl Scheme 8 Scheme 6 ~~ bs x lo4 min-' 8 9 10 R Me 5.6 2.3 0.4 Ts 15.4 4.3 1.3 ether 6 (Scheme 6) without cleavage of the delicate oxanedione ring.Desilylation of 6 failed with all variants of fluoride or HF, but was finally achieved using aqueous formic acid at 20 "C for 3 h to produce in 82% yield the target molecule 7. The solvent dependence of the rate of solvolysis of TBS ethers" has useful implications for selective deprotections. Thus, dilute methanolic HCI in anhydrous THF (<0.5% MeOH, ca. lop2 mol I-') cleaves THP ethers and 1-ethoxyethyl ethers, whereas TBS ethers remain intact even at elevated temperatures (Scheme 7). However both acetal and TBS groups can be cleaved if the amount of MeOH is increased to 50%. HCI MeOH (5.9 (50% mmo~ v h ) r1) T H P O ~ O ~ S THF O"C,2h 90% HCI (13 mmol rl) MeOH (0.4% v/v) THF 67 "C, 4 h 90% I illustrated by three recent examples.First, Johnson and Miller" accomplished the deprotection of the TBS ether 11 in the presence of an acid-labile oxirane ring using fluorosilicic acid in acetonitrile (Scheme 9). Second, a Japanese groupI3 exploited the known lability of TBS ethers towards NBS in the presence of to accomplish selective deprotection of a primary TBS ether in the presence of a secondary TBS ether in P-lactams (Scheme 10). Finally, Lee and co-workers16 reported a new method of selective deprotection of TBS ethers of primary alcohols using sonication (Scheme 11). Under the reaction conditions TBS ethers of phenols as well as secondary and tertiary alcohols remain intact but TBS ethers of primary alcohols can be deprotected in the presence of a primary TBDPS ether.Numerous functionalities are also resistant e.g. -C02R, -OR, -NR2, -Cl, -COR, -CHO and -CONR2. 0 0 Br$) :O H2SiF6* MeCN 74% "Q0 OTBS OH 11 Scheme 9 r Scheme 7 3O0C,12h Scheme 10 The kinetics of the desilylation reactions of a range of sulfonylated and methoxylated norbornyl silyl ethers established a correlation between the geometry of the a-relay and the rate of desilyl- ation. Desilyation rates generally decrease in the order W > sickle-like > U as shown in the table The search for an expanded repertoire of reagents for the cleavage of TBS (TBDMS, tert- butyldimethylsilyl) ethers in sensitive substrates is * @OH MeOKCC14 (1 : 1 vh) ultrasound 40450 "C. 1.5 h 93% -9' OMe OMe TBSO accompanying Scheme 8. TBSO Scheme 11 Jarowicki and Kocienski: Protecting groups 399The removal of a silyl ether protecting group without competing migration of a proximate ester function can be difficult. In a synthesis of zaragozic acid, Carreira and Du Bois17 suppressed formation of the migration product 13 by deprotecting the TBS ether 12 with the HF-pyridine complex in THF buffered with pyridine (Scheme 12).HO DAc HI R = H Scheme 12 13 hydroxy functions were O-benzylated. After replacement of the TDS group with a pivaloyl group, the benzylidene acetal was cleaved reductively to give the desired fragment 15 in only eight steps overall from lactose. butylsilyl ethers makes them more stable than the ubiquitous tert-butyldimethylsilyl ether group toward nucleophilic attack. They are also more difficult to introduce and remove as shown by the transforma- tions depicted in Scheme 14 taken from Nicolaou's synthesis of zaragozic acid." The additional steric bulk in methyldi-tert- ButzMeSiOTf (10 equiv), DMAP (2 equiv) 2,&IutMine (0.65 ml), 70 OC, 8 h 87% (0.467 mmol scale) R = SiMeBut2 1,2-O-Silyl migration is another competing process which is usually considered a nuisance.However, Lassaletta and Schmidt" recently exploited the reaction to good effect in a synthesis previously required a 14-step sequence from lactose (Scheme 13). Thus treatment of 14 (four steps from lactose) with NaH and benzyl bromide in DMF caused 1,2-O-silyl migration of the t hexyldimet hylsilyl (TDS) group thereby protecting the 2-hydroxyl function whilst the remaining free en026 BnO C *ph of the glycosphingolipid precursor 15 which had HO m2Bn 49% HF (0.05 ml) MeNOZ (0.5 ml), 0 "C, 24 h = siMzKl 30% (0.004 mmol scale) R = H Scheme 14 14 Ph 60 0 BnO hB:'+OBn OBn 'OBn a TBAF,THF(Q4% 'J M I , DMAP,p (100%) (c NaBH3CN, H Mt@ (88%) OBn 16 'OBn TDS = thexyldimethylsilyl Scheme 13 tert-Butoxydiphenylsilyl ethers are an inexpensive alternative to tert-butyldiphenylsilyl et hers,20 with comparable stability.Schmittberger and Uguen have shown2' that tert-butoxydiphenylsilyl (DFTBOS) ethers are cleaved slowly using Na2S-9H20 in dry ethanol or methanol at room temperature (rt) - conditions which preserve tert-butyldimethylsilyl (TBS) and tert-butyldiphenylsilyl (TBDPS) ethers (Scheme 15). Control experiments established that the cleavage was not caused by the basic reaction conditions (pH 11.9).Na2wHqO B u'P h2Si0 (1 .o equw) OSiPh20Bu' 700k OH Scheme 15 The Danishefsky research group reported a solid phase synthesis of the Lewis b antigen in which the oligosaccharide was constructed stepwise from a glycal bound to the polymer via a silane linker?2 The linker was prepared by the metallation of 1% divinylbenzene-styrene copolymer 16 followed by reaction with diisopropyldichlorosilane (Scheme 16). 400 Contemporary Organic Synthesis17 16 ROH. Pr'NEt2 C&Cb DMAP Scheme 16 Ph Scheme 18 Nikam and co-workers2' found that Pd-BaS04 is an efficient catalyst for the hydrogenolysis of the 18 benzyl hydroxamate 22 to give the corresponding hydroxamic acid 23 (Scheme 19). With Pd-C, reductive cleavage of the N-0 bond was observed. The resulting chlorosilane 17 was then used to attach the primer glycal unit as a silyl ether 18.The fully developed oligosaccharide was finally cleaved from the polymer with TBAF and HOAc in THF. A very similar strategy has been devised for the solid phase synthesis of 2'-deoxyribose oligonucleotide^.^^ During a monumental synthesis of strychnine, the research group of encountered difficulties with the simple selective protection of the primary alcohol function in the diol 19 as its (triisopropylsilyl) TIPS ether (Scheme 17). The best method involved treatment of the diol 19 with 2 equiv. of TIPSCl and 2.2 equiv. of 1,1,3,3-tetra- methylguanidine at 0 "C in N-met hylpyrollidinone until the diol could no longer be detected by TLC. This treatment provided the readily separable monosilyl ether 20 in 65% yield together with the bis-silyl ether in 33% yield.H (OR tetramelhylguanidine (35 mmol n P s t (a mmot NMP (eo m i 0 "C, S10 h, 65k (14 mmol scale) 19R=H 20 R = TIPS Scheme 17 H (50 psi) N-OBn PM~A~ (lo%, 2.5 g) MeOH (1 I) 73% (0.1 16 mol scale) "Q-OH 0 23 B&H 22 Scheme 19 Two rare methods for cleaving benzyl ethers were reported in 1995. Cleavage of benzyl ethers with P4SI0 does not appear to be a general reaction, but this reagent works well with the carboxylic acid 24 where intramolecular participation is possible (Scheme 20).26 Photochemically induced bromina- tion of a benzyl ether followed by hydrolysis of the resulting bromohydrin derivative27 was used to deprotect the benzyl ether function in furanoside 25 (Scheme 21).28 U 24 Scheme 20 NBS (43.8 mmol) T B D P S O ~ Qco H& (1 (30 37 m1) mmoi) T B D P S O ~ 2.3 Alkyl ethers and Du Bois" found that catalytic hydrogenolysis of During their synthesis of zaragozic acid, Carreira 21 using Pearlman's catalyst [Pd(OH)2] was accom- panied by removal of the TBS groups as well.For reasons which are not clear, the unwanted silyl t (400 mi) hv,rt,Wmrn OBn 70% (31.3 mmd scale) OH 25 deprotection could be suppressed by using Pd on CaC03 together with Pd(OH)2 as the catalyst (Scheme 18). Scheme 21 Jarowicki and Kocienski: Protecting groups 401OMe OMe 26 SMe DW, 4 A molecular sieves, CH&12 MeOTf, 2,WiBu'-dMepyridine 4 A molecular sieves, CCH&H&I, 60% OMe / BnO OBn Scheme 22 The oxidative conditions normally used to deprotect p-methoxybenzyl ethers provide a method for stereodirected glycosylation as illustrated by a synthesis of the pentasaccharide core structure of an asparagine-linked glycoprotein oligosaccharide (Scheme 22).29 The technique involved the generation of a mixed acetal28 on oxidation of the p-methoxybenzyl ether in the trimannoside donor 26 in the presence of chitobiose derivative 27.Activation of the methylthio group in 28 by S- alkylation induced intramolecular creation of the crucial P-mannoside link. The acid lability of p-methoxybenzyl (PMB) groups has long been appreciated but rarely exploited in deprotection chemistry. Scheme 23 shows that PMB ethers can be removed selectively with TFA without detriment to a glycosidic link, and the survival of a trisaccharide under similar conditions suggests that PMB groups may be used in oligosaccharide synthesis."0 During the course of a synthesis in which the removal of an isopropylidene group in the presence of both a PMB ether and a benzyl ether was required, it was discovered3' that iodine in methanol3* cleaved not only the isopropylidene acetal, but also the PMB ether (Scheme 24).The deprotection proceeds with a 1% (w/v) solution of iodine in methanol at reflux. OBn OBn iodine MeOH (1% w h ) reflux. 12-16 h 04% HO OPMB OH Scheme 24 The combined use of TBSOTf (tert-butyldimethyl- silyl trifluoromethanesulfonate) and NEt, readily cleaves p - or o-methoxybenzyl ethers to give directly the corresponding TBS ethers in high yields prepared likewise. * (Scheme 25).33 TES (triethylsilyl) ethers can be TFA (1 0% in CHpC12, 5 ml) rt, 5 min 93% 0 0 +PMB (o.osi mmol scale) PMB = pmethoxybenzyl OH flopMB TBSOTf (2.3 mmol) NEt3 (2.5 mmol) OBn OBn Scheme 23 Scheme 25 402 Contemporary Organic SynthesisFalck and co-workers" recently accomplished the selective protection of the hindered secondary alcohol 29 using p-methoxybenzyl trichloro- acetimidate in the presence of a catalytic amount of trityl tetrafluoroborate as catalyst according to the procedure of Nakajima (Scheme 26).35 H0.,co2Me BOMO " A O T B S OTBS 29R=H PMBOC =NH)CC13 (21.9 mmol) Ph&BF4\0.26 mmol) Et (50 ml), rt, 3 h (8.8 mmol scale) R = PMB Scheme 26 Leonard and Neelima have shown3(' that 1,1,1,3,3,3-hexafluoropropan-2-o1 (pK, 9.3) removes the 4,4'-dimethoxytrityl (DMT) protecting group from the 5'-hydroxyl group of acid-sensitive nucleosides and nucleotides without competing N-glycosyl cleavage (Scheme 27).The reaction is easily followed by the appearance of a bright orange colour (&,,,498 nm) due to the dimethoxytrityl carbocation. NH2 HO Scheme 27 Ugi and co-workers3' have recommended 1 ,l-dianisyl-2,2,2-trichloroethyl ethers (abbreviated DATE) for the protection of alcohols (Scheme 28). DATE ethers are stable to conc. HCl-MeOH- dioxane (1 : 2 : 2), C12CHC02H-CH2C12 (3 : 97), and conc. NH,-dioxane (1 : l), but they are readily Q CI3C-t-Cl + OH t - rt, 12-18 h 92Oh (6 mmol scale) I Zn, ZnBr2 I I OMe HOAc-dioxane (1 :2) rt, 20h cleaved by reduction with a mixture of Zn and ZnBrz in HOAc-dioxane (1 : 2). A new base-labile anchoring group consisting of 9-(hydroxymethyl)fluorene-2-succinic acid coupled to aminoethyl polyethylene glycol (30) was developed for the synthesis of oligosaccharides on polymer supports using 1-(phenylsulfiny1)glycosides as donors.38 The polymer-supported 30 was primed with the first monosaccharide residue 31 as shown in Scheme 29.+ T d OW 31 (2 equiv) Tffl, 2.6-di-Bu1-pyridine CH2Ck. 16 h 0 N H PEG Scheme 29 The 2-( 4-nitropheny1)et hylsulfonyl (Npes) group is a base-labile protecting group for hydroxy functions in nucleoside synthesis (Scheme 30).'9 The Npes group is stable to the acidic conditions used to remove trityl and TBS groups but it is cleaved on treatment with DBU in MeCN at room temperature in 2 h. The Npes group is not removed rapidly by fluoride ions and it is more labile than 2-(4-nitrophenyl)ethyl (Npe) and 2-(4-nitro- pheny1)ethoxycarbonyl (Npeoc) groups.Npes group are introduced by reaction of the alcohol function with 2-(4-nitrophenyl)ethylsulfonyl chloride and pyridine. tert-Butyl and tert-amyl (2-me t hylbut-2-yl) ethers are cleaved by treatment with a catalytic amount of DBU (0.1 M) MeCN rt, 2 h SO20R ROH - 02NCeH&H=CH2 OZN Scheme 28 Scheme 30 Jarowicki and Kocienski: Protecting groups 403Po TBsOTf(O1 uiv) CHS (13) tt,$ h 82% (1.08rnrnd) pho~phorylation.~~ The deprotection is easily accomplished with mercaptoethanol and the course of the deprotection can be monitored by the appearance of the thioether 32 [Amax 341 nm ( E = 12500)l (Scheme 33). NHBoc ~ N H C O R NHBoc Scheme 33 Scheme 31 TBSOTf (Scheme 31).40 When a stoichiometric amount of triflate is used (followed by 2,6-lutidine) the same ethers can be converted directly into the corresponding TBS ethers.Methoxy, allyloxy, lactone, bromo, trimethylsilylalkynyl and alkenyl groups are tolerated. Oliver0 and co-worker~~~ reported that the cationic complex [Ni(bi~y)~](BF~)* is a good catalyst for the electrochemical cleavage of the 0-C (allyl) bond of allyl ethers, affording the parent alcohols or phenols in good yield, under mild conditions (Scheme 32). The electrochemical method is based on the use of a single-compartment cell, fitted with a sacrificial magnesium anode. Reaction is carried out in DMF at a constant current, with 10 mol% of catalyst with respect to the starting allyl ether.The electrochemical set-up is very simple and allows the deprotection on a preparative scale. The method is selective for allyl ethers; homoallyl ethers or enol ethers are not cleaved under these conditions. e-, [Ni(bipy)S)(BF4)2 (10 rnol%) Mg anode DMF (40 ml), rt 86% (3 mrnol scale) OH bipy = 2,2'-bipyridine Scheme 32 The 2,4-dinitrophenyl (Dnp) group is useful for the selective exposure of the aryl hydroxy function of tyrosine without compromising the protecting groups of other tyrosine residues or amino groups in post-assembly peptide modifications such as QH <OH 32 2.4 Alkoxyalkyl ethers In the closing stages of a synthesis of mitomycin derivative FR-900482, the densely functionalised intermediate 33 had to be shorn of its robust MOM (methoxymethyl) protector (Scheme 34).43 The task was accomplished with trityl fluoroborate under conditions devised some years ago by Kishi.44 0 MOM = methoxymethyl Scheme 34 Attempts to deprotect the MEM ether 34 using ZnBr2 in wet CH2C1:5'46 gave the desired primary alcohol 35 (38%) together with the dioxepane derivative 36 (24%) (Scheme 35).19 Fortunately, cleavage of the MEM { [2-(methoxy)ethoxy]methyl} ether with TMSI, generated in situ from reaction of TMSCl with NaI, gave 35 (71%) free of contamina- tion by 36.During a synthesis of the milbemycins, Thomas and co-workers4' required a mild deprotection of SEM ether 37. Magnesium bromide etherate in the presence of butanethiol and K2C03 accomplished the desired deprotection in 90% yield (Scheme 36). acyI-O-di(tert-butyl)silane-3',5'-diyl nucleoside Selective protection of the 2'-hydroxy group of N- 404 Contemporary Organic Synthesis3s A TMSU (46 mmol) NaI (46 mmol) MeCN (300 ml) -3OoC,1.5h c o - ~ o r k e r s ~ ~ had great difficulty protecting the secondary alcohol function in 39 using a selection of the many methods published.Success was finally achieved using bis(trimethylsily1) sulfate5' as catalyst in 1,2-dichloroethane (Scheme 38). The anhydrous, essentially neutral conditions are mild and efficient. Another rare catalyst reported for the tetrahydro- pyranylation of alcohols with 3,4-dihydro-2H-pyran is dicyanoketene ethylene acetaL5' 36 MEM = [2-(methoxy)ethoxy]methyl Scheme 35 36 (24%) 6Me R = H SEM = [2-(trimethylsilyl)ethoxy]methyl Scheme 36 derivatives 38 can be accomplished with 2-[(tri- methylsilyl)ethoxy]methyl chloride (SEMCl) using Bu'MgCI as the base (Scheme 37)." The usual conditions (SEMCl, Hiinig's base) are complicated by N-alkylation. pyranylation of alcohols than entries in Don Giovanni's catalogue. Nevertheless, White and There are probably more methods for tetrahydro- Y ~ B (4 Bu'MgCI (2 equiv) THF, rt, 5 mln (b) SEMCI (2 equiv) Si \O OH Bu4NI (Zequiv) But\ Si But, \O OSEM rt, 20-30 h 38 Scheme 37 7844% + OH dih drop ran (0.26 mmol) (Thyso) & O2 (0.01 mmol) CtCH CH CI CH&I 99% f0.23 mhd safe) OTHP 39 THP = tetrahydropyran-2-yl Scheme 38 A new procedure for oxidative tetrahydro- pyranylation of alcohols involves reaction of tetra- hydropyran (THP) and tetrabutylammonium peroxydisulfate (Scheme 39).5235' Olefins, sulfides and acetals survive intact because the reaction proceeds under nearly neutral conditions. OSO~NBU~ I OSO~NBU~ (1.4 equiv) MP, A, 11 h 85% OTHP OH Scheme 39 For the solid phase synthesis of 2-pyrrolidine methanol ligands, Liu and Ellmad4 required a linker which was stable to Grignard reagents and Red-Al@.The THP group served the purpose and benefitted from easy cleavage from the resin using PPTS (Scheme 40). Reductive cleavage of a THP ether with a combination of boron trifluoride etherate and sodium cyanoborohydride has been reported by Srikrishna and co-~orkers.~' (HIFA) group has been recommended for the protection of 2'-hydroxy functions of nucleosides during automated machine synthesis of RNA 01igorners.~~ As the diester (e.g. 40, Scheme 41), HIFA groups are relatively stable to the acidic conditions used to deprotect dimethoxytrityl groups during chain elongation, but alkaline hydrolysis produces the corresponding diacid 41 which is labile towards dilute HC1.The authors estimate a 42-fold increase in the rate of hydrolysis at pH 1 and 1320-fold increase at pH 3 compared with the diester 40. The four step sequence required to introduce the protecting group is likely to limit its appeal. The 2-hydroxyisophthalate formaldehyde acetal Jarowicki and Kocienski: Protecting groups 405C02Et he Ph ?+kH Me Ph Scheme 40 HO 53 OH 130zC @ HO OH I3 = "eJ y2y NaOH 41 R = H Scheme 41 3 Thiol protecting groups Deprotection of S-benzyl groups using Bu3SnH gives tributylstannyl sulfides57 which are effective thio- glycosidation agents" as illustrated in the synthesis of the thioglycolipid 42 (Scheme 42).During an economical synthesis of ( +)-biotin from L-cysteine, a Belgian groups9 accomplished protection of both an amino group and a thiol as a thiazolidine. The thiazolidine ring was later cleaved very efficiently using dissolving metal reduction as shown in Scheme 43. Protection of a thiol as its MOM derivative can be accomplished by treating the thiol with base and C1CH2Br in MeOH as shown in Scheme 44. Alcohols and carboxylic acids do not react.60 Scheme 42 Scheme 43 CO2H f CO2H NHBoc NHBoc I I Me0 J$ Me0 Scheme 44 .SH KQH (4 mmol) BnNEt GI (0 4 mmol) C I C ~ ~ B ~ ia ml) M e O y MeOH (16 ml) rt. 3 h 90% (2 mmol scale) Me0 Albericio and co-workers6* reported that the phenylacetamidomethyl (Phacm) group can be used to protect the thiol function of cysteine during Boc and Fmoc solid-phase peptide synthesis.The Phacm group can be introduced onto L-cysteine by reaction with N-( hydroxymet hy1)phenylace t amide 43 in the presence of trifluoromethanesulfonic acid (TfOH) (Scheme 45). The crude intermediate is then treated with di-tert-butyl dicarbonate (or Fmoc-succinimide) to give the appropriate fully protected Boc derivative 44 (or corresponding Fmoc derivative). The advantages of using the Phacm group in peptide synthesis stem from the fact that, apart from chemical means (iodine or thallium salts), it can also be removed enzymatically by the action of penicillin amidohydrolase at neutral pH. This makes it orthogonal with the common cysteine protecting groups, such as 4-methylbenzyl, trityl and fluorenylmethyl.An orthogonally protected L-homocysteine has been prepared62 by simple displacement of a bromine from 45 by sodium p-methoxybenzylthiolate as shown in Scheme 46. The S-p-methoxybenzyl group is stable to conditions used for the removal of Boc groups (TFA, room temperature) or NaOH used to hydrolyse benzyl esters but it can be cleaved by boiling TFA63 or Hg(OCOCF3)2 at 0 oC.64 406 Contemporary Organic Synthesisa 0 HCHO (a 35% 5 9 ml 75 mmol) #OH (8.7hmdl) 70 OC 5 min. 25 OC, overnight m- PhANAOH & (74 mmot scale) H 43 b Cl- HSN +ISH COOH Scheme 45 (a) 43 (30.3 mmol). H20 (30 ml) TDH-TFA (1:lg.N ml) 0°C.6h ~~ (b) Boc20 Bu'OH (149 ml), He0 (50 ml) 56% (25 mmol scale) JWMB t THF (25 ml), rt, 10 h 82% (4.88 mmol scale) 45 Scheme 46 4 Diol protecting groups A two-step method for the differential functionaliza- tion of 1,2- and 1,3-diols involves reaction of cyclic acetals with acetyl chloride in the presence of zinc chloride followed by conversion of the resulting chlorornethyl ether into an alkoxyrnethyl ether (Scheme 47).65 When the procedure is applied to the unsymmetrically substituted acetal 46, the product 47 has the acetate at the less hindered centre.By the proper choice of alcohol (methyl or benzyl alcohol) the subsequent step can give rise to a compound with a protected primary 48 or secondary 49 hydroxy group. One of the most useful and widely utilised methods for differentiating the C-4 hydroxy group of sugars involves the reductive regioselective 0-0 L A - (b) ROH (4 equiv) Pr'pNEt (1.2 equiv) Acoa-o'R 46 Et20 (10 ml) R = Me (95%) 0 "C, then rt, 1 h 50 mmol scale R = CH2Ph (75%) R = CH2CH20Me (88%) 47 R=Me MeOH 25ml) K2CO3\m mi of 0.5 M aq.solution) rt, 1.5 h 99% (13.6 mmol scale) 48 49 Scheme 47 H 44 opening of a 4,6-O-benzylidene acetals. DeNinno and co-workers66 reported a new procedure using trifluoroacetic acid and triethylsilane (Scheme 48). Both benzyl and acetate protecting groups are tolerated, although the acetate protected compounds react faster and more cleanly. Reductive cleavage of the p-methoxyphenyl (PMP) methylene acetal50 can be performed with excellent regioselectivity using DIBAL-H at low temperature but the major product 51 is the secondary alcohol rather than the expected primary alcohol (Scheme 49).67 The observed regioselectivity can be attributed to a directing effect by the nitrogen of the vicinal carbamate.A similar result had been previously observed by Takano@ in benzylidene acetals with a vicinal alcohol or ether group. Et $FA SiH (5 (5 equiv) equiv) > B n o T o r : ' - 0 ~ ~ CHpClp (5 ml), 0 "C then rt, 2-4 h 95X (1 37 mmol scale) HO-' OAc Scheme 48 PMP 50 NHBoc /\('OPMB :IBALH OH BOC-N Go+ 'i -0 Bu" bui - 51 PMP = pmethoxyphenyl; PMB = pmethoxybenzyl Scheme 49 Jarowicki and Kocienski: Protecting groups 407During a synthesis of myriocin 52, a Japanese research accomplished the selective reductive cleavage of a PMP methylene acetal with concomitant rearrangement of a 1,3-dioxane to a 1,3-dioxolane (Scheme 50).?H 52 myriocin MOM0 OM0 NaBH&N (0.W mmol) TMSCl(l.92 mmol) MeCN (48 ml) 0 "c + rt, 3 h 86% (0.48 mmd scale) I Q OM0 Scheme 50 In a synthesis of the protein phosphatase inhibitor tautomycin, the Oikawa group7' used the superior hydrolytic lability of the dimethoxybenzylidene acetal in the synthesis of a maleate side chain as shown in Scheme 51. Thus treatment of the 3,4-dimethoxybenzyl ether 53 with DDQ caused oxiditive cyclisation to take place to give the 3,4-dimethoxybenzylidene acetal54. Two further steps converted 54 into the maleate derivative 55 which was then deprotected using PPTS in MeOH. The corresponding p-methoxyphenylmethylene (p-methoxybenzylidene) acetal was labile towards the Wadsworth-Emmons reaction and suffered epimerisation. A Spanish research group7' has thoroughly evaluated DDQ as a reagent for the deprotection of acetals7* and thioacetal~~~ in carbohydrate deriva- tives.The use of 0.1-0.4 equiv. of DDQ in MeCN- H20 (9 : 1) cleaves isopropylidene groups at between room temperature (rt) and 80 "C without affecting tosyl, benzoyl, benzyl or acetate groups, though at elevated temperature some acyl migration may occur. Monosubstituted dioxolanes (e.g. 56, Scheme 52) are more readily hydrolysed than bicyclic, spiro MM (23.3 mmol) pyridine (23.3 mmol) 4 A mdecuiar sieves (2 g) I o*o OH 0' - rt,18h Bub2C& Bub2C& I CH&b (25 ml) 66% (12.9 mmol scale) I OH 53 OH 54 (b) (Eto),P(O)CH(Me)Co& Bu'OK 1 6pk (a) Dess-Martin oxidation MeOJ OH OH Pf'TS (1.92mmol) MeOH (64 ml) - rt, 3.5 h 98%(3.37mmd scale) EQC 55 Scheme 51 56 Scheme 52 HO and disubstituted systems, and 1,3-dioxanes are more labile than 1,3-dioxolanes.Removal of dithioacetals requires 2 equiv. of DDQ at 80 "C. group" required the selective destruction of the benzylidene acetal57 in the presence of an isopropylidene acetal (Scheme 53). The task was accomplished in 89% yield using zinc triflate and ethane-1,2-dithiol with the aid of sonication. During a synthesis of zaragozic acid, the Nicolaou n n 89?h (0.14 mmol scale) 57 Scheme 53 ' " O W H 0 408 Contemporary Organic SynthesisPPTS (cat), MeCN 5065 O C , 1 h (95%) OOC+rt,12h OAll (b) A N , NEtg, DMAP (cat) 58 ACHN' I OAll 59 fi M e B r (2.3 equiv) CH&&, -78 O C , 5 mh All = ally1 TMGN3 = tetramethylguanidinium aide Scheme 54 An efficient strategy for regiocontrolled differentiation of the 4,6-positions of pyranosides has been developed using dimethylboron bromide- mediated cleavage of pht halide or tho ester^.^^ The procedure illustrated in Scheme 54 began with reaction of glycoside 58 with a phthalide orthoester in acetonitrile or DMF in the presence of catalytic PPTS to give the 4,6-O-protected orthoester 59 in excellent yield as a single diastereomer.High selectivity for generation of the C4 benzoate was achieved by employing 2.3 equiv. of dimethylboron bromide. Two important features to be noted are: (i) the reaction proceeds smoothly with no complications from competitive cleavage of the anomeric acetal of the sugar, and hydroxy group is protected over a free primary (C6) hydroxy group. To complete the sequence, selective cleavage of (ii) the sterically demanding secondary (C4) the benzoate moiety in the presence of the three additional acyl functionalities was accomplished using tris (4-methoxypheny1)phosphine in the presence of glacial acetic acid.Presumably this reaction involves intramolecular transacylation of OAll 60 PPh3 (2 WUiv) DlAD (2 equiv) AcSH (2 equiv) 0% -+1t,3h 89% (0.43 mmol scale) f ACHN' AYrsAc OAll hDPS m0,A 1 h 97% (1.63 mmol scale) TBDPS Scheme 55 their p ~ t e n t i a l . ~ ~ Treatment of the diol 61 with benzophenone dimethyl acetal gave the dioxolane derivative 62 which was then elaborated to the fully protected polyol chain 63. Selective unmasking of the terminal 1,2-diol was accomplished by reductive cleavage of the 2,2-diphenyl-l,3-dioxolane with lithium in liquid ammonia - conditions which left the seven remaining hydroxy functions fully the p hosphoranylideneamine 60.protected. During a synthesis of lankacidin C, a selective hydrolysis of an isopropylidene group without harm to a PMB ether was accomplished efficiently using CuC12.2H20 in MeOH at reflux (Scheme 55).9 2,ZDiphenyl- 1,3-dioxolanes are seldom used in synthesis but Scheme 56 gives some indication of Simultaneous protection of the hydroxy group and activation of the C1 carboxyl group of malic acid was accomplished by formation of the dioxolanone 64 by reaction of malic acid with hexafluoroacetone in DMSO (Scheme 57).76 The remaining unprotected carboxyl was transformed into an Jarowicki and Kocienski: Protecting groups 409Ph&(OMe) (26.9 mmol) ph Ph PTSA fm mg) .4 mmd scale) 61 62 I 63 I Li 17.5 mmd), NH (1 4 ml) Et6H (2 ml), -78 &30 min 98% (1.46 mmd scale) I Scheme 56 0 - .2c+0 (CF&C=O (210 mmd) H 0 2 C 7 C 0 2 H 92% DMSO (100 (30 mmol ml), scale) II 0 4 OH 0 It 0 II 0 65 Scheme 57 amino group via Curtius rearrangement. The highly electrophilic dioxolanone 65 was then used to acylate proline tert-butyl ester under mild conditions without the need for further deprotection of the alcohol or activation of the carboxyl function.has reported details of a new method for regio- and enantio-selective differentiation of symmetrical polyols (Scheme 58). Reaction of the enantiopure diene 66 with the 1,5disilylated xylitol 67 in boiling chloroform containing a catalytic amount of CSA gave the protected polyo168 as the only isolated product.The reaction is completely diastereoselective and the product formed is the most thermodynamically stable in which the two side chain methyl groups and the two hydroxylated side chains on the dioxane ring are equatorially orientated, with the spirocentres fully stabilised anomerically. Removal of the dispiroketal moiety can be achieved using 95% aqueous TFA. Similarly protected sugars have been used in a one-pot synthesis of oligosa~charides.~~ The Ley (1.2 equiv) CSA (0.1 mmol) + CHCl (5 ml), A, 25 h TBDPSO, ,OTBDPS 79% (8.7s mmd scale) Me kl TBDPSO TBDPSO HO U O H OH r 68 Me 67 Scheme 58 5 Carboxyl protecting groups At a late stage in the synthesis of the macrodiolide swinholide, Paterson and c o - ~ o r k e r s ~ ~ were faced with the problem of hydrolysing a terminal methyl dienoate ester 69 (Scheme 59) without competing hydrolysis of a similar internal ester. The problem was compounded by the potential elimination of TBSOH and oxene ring scission to generate a highly conjugated system.The desired transformation was eventually achieved in quantitative yield using barium hydroxide hydrate in methanol. The final step of the synthesis of the protein phosphatase in hibit or t automycin 70 involved selective deprotection of the tert-butyl ester of the maleate side chain with concomitant anhydride formation (Scheme 60).*' Protic acids which had worked in model studies failed owing to destruction of the anhydride product 70.However, the reaction proceeded in modest yield using 17.4 equiv. of R - O A O OMe Scheme 59 410 Contemporary Organic SynthesisOMe 70 v* 0 Scheme 60 TESOTf in the presence of 2,6-lutidine. The more reactive TMSOTf gave only decomposition. Carpino and co-workers" have reported two new protecting groups which take advantage of the easy solvolysis of cyclopropylmet hyl systems: the dicyclopropylmethyl (Dcpm) group for carboxyl and the dimethylcyclopropyl (Dmcp) group for amide protection (vide infia). Protection of acids with Dcpm group (prepared by reaction of the acid with dicyclopropylcarbinol and DCC) is especially useful where its selective removal is later necessary in the presence of other acid sensitive groups. Scheme 61 illustrates deblocking of the peptide 71 by TFA to form 72 in which a tert-butyl ether and N-trityl group remained intact.R TFA - 0 &OH Fmoc-Ile-Thr(But)-Arg(Pmc)-GIn(Trt)-Arg(Pmc)-Tyr(Bu')-Q-Dcpm 71 a TFA (1% in CH&). rt, 15 min 92x l i b 1 py, -78°C Fmoc-Ile-Thr(Bu')-Arg(Pmc)-Gln(Trt)-Arg(Pmc)-Tyr(Bu')-OH 72 Scheme 61 As part of a programme aimed at probing the molecular recognition of the immunosuppressant cyclosporin A 73 and its protein receptor, the Schreiber group" required the replacement of the valine group (arrow) in cyclosporin A with a sterically more demanding isoleucine group (Scheme 62). The multistep procedure began with controlled degradation of natural cyclosporin A to the linear peptide 74 in which the amino and carboxyl termini were protected as their Boc and MEM ester derivatives respectively.The MEM (methoxyethoxymethyl) ester, with its favourable metal-binding properties, was essential for the subsequent reduction step (74+75) as all other combinations of common esters and reducing agents failed. Following reduction to the alcohol 75, an acid catalysed N+O shift and N-acylation produced the rearranged ester 76 which could be hydrolysed to give an intermediate from which the ring was reconstructed with incorporation of the desired isoleucine to give the target 77. At a late stage in the synthesis of the potent protein serine-threonine phosphatase inhibitor motuporin (Scheme 63), Valentekovich and Schreiber*2 achieved macrolactamisation of the pentapeptide 78 by a four-step process beginning with reductive removal of the phenacyl ester group followed by pentafluorophenyl ester formation at the C-terminus.N-Terminal Boc group deprotec- tion, followed by dilution and neutralisation with excess Hiinig's base, gave the desired macrocycle 79 in 55% yield. A recent report suggests" that phenacyl esters may also be removed oxidatively as illustrated by the example in Scheme 64. The very mild conditions required to deblock allyl esters continues to attract attention. Thus, a Japanese groupR4 has described the use of Pd(OAc)2 in H20 as a less expensive and more practical alternative to the unstable Pd[PPh3I4 for the deprotection of p-lactam allyl esters (e.g. 80) (Scheme 65). The water is beneficial in promoting reduction of Pd" to Pd". Seitz and Kunzx5 have advanced the art of solid phase synthesis by developing a novel allylic anchor whose virtues were exemplified in a synthesis of protected and unprotected 0-glycosylated Mucin- type glycopeptides. Anchoring through allyl esters not only allows peptide derivatives to be detached without affecting acid- and base-labile structural elements, but also provides orthogonal stability relative to the temporary protecting groups commonly used in solid phase peptide synthesis.In the example shown (Scheme 66) the glycopeptide segment 81 was detached with Pd" catalysis using N-methylaniline as the nucleophile. Benzylic esters activated by electron-donating groups on the aromatic ring are now common Jarowicki and Kocienski: Protecting groups 41 1hydrolysis Me0 phb +-- 76 77 Scheme 62 75 Ph \*.OMe 0 78 79 Scheme 63 CuCleH (55mmol) DM++$'(i :i, 10 mi) 0 , A , 4.5 h 92% 6 mmol scab) 0 + COP, PhC02H (5%).PhCHO (23%) Scheme 64 elements of linkers in solid phase synthesis. Their cleavage can be accomplished under acidic or basic conditions. For example, the peptide H-(Val-His- Leu-Pr~-Pro-Pro)~-OH corresponding to the N- terminal domain of the abundant maize protein 80 R = AII- R = N a c All = ally1 Scheme 65 y-zein has been synthesised by the Giralt group (Scheme 67).86 The protected precursor Fmoc-(Val- His(Trt)-Leu-Pro-Pro-Pro)-OH 82 was synthesised on a solid phase using the highly acid-labile 4- [ 4- (hydroxymet hyl)-3-methoxyphenoxy] butyric acid 412 Contemporary Organic SynthesisOAc Scheme 66 (a 20% piperidine in DMF (b{ 1 X CF 3C02H in CH2Cb Scheme 67 - HO-(Pro)rLeu-His(H)-Val-H b - ( P r&-Le+H is(Trt)-Val- Frnoc H~Pro)~eu-His(Trt)-Val-Fmoc t- 82 - HO-(Pro)&w-His(Trt)-VaI-H (HMPB) of Rinikerx7 as handle.An important feature of this synthetic strategy is the posssibility of obtaining the peptide sequence at different levels of protection by varying the cleavage program. Note the efficient cleavage of the protected segment from the resin by treatment with 1% TFA in dichloro- methane with complete retention of the N-trityl group protecting the imidazole ring in histidine. using p-nitrobenzyl esters, thioethers and carba- mates for side chain protection has been described (Scheme The p-nitrobenzyl side chain- protected amino acids of lysine, cysteine, glutamic acid and aspartic acid were synthesised and incorporated into short peptides by standard Fmoc methodology on polystyrene resin.Deprotection was carried out under mildly acidic reducing conditions using a solution of SnCl,, HOAc and phenol in DMF at room temperature. The deprotection takes advantage of the easy 1,6-elimination of the intermediate p-aminobenzyl ester 83. A solid phase supported peptide synthesis strategy 50% CF&O H CH&I2. rt. 96 rnin 1% CF3CO H CH2Cb. rt. $0 s Scheme 68 .'\#Jy' 0 83 Jarowicki and Kocienski: Protecting groups 4134- { N - [ 1 -( 4,4-Dimet hyl-2,6-dioxocyclo hexy1idene)- 3-methylbutyl]amino}benzyl ester (Dmab) is a new carboxy protecting group that is based on the safety- catch principle and can be used orthogonally with Frnoc-But peptide ~hemistry.'~ It is cleaved with 2% v/v hydrazine-H20-DMF at room temperature within minutes.The key component, 4-{N- [ 1 -( 4,4-dirnethyl-2,6-dioxocyclohexylidene)-3-met hyl- butyllamino} benzyl alcohol 84 was easily prepared as pale yellow crystals (mp 154-157 "C) in cu. 70% 84 (a) Fmoc-Glu(0Bu')-OH HOBT, DCC, DIPEA, CH&12,18 h I (b) 50% CF&02H, CH2C12.2 h 0 85 I i standard automated + Fmoc-But procedures 86 t - ? O Y " H p v H 1 0 Arg( Pmc)-D-Trp-D-Trp-Val+Trp-Tyr(But)-H 87 88 Clt = chlorotrityl HOAt = 1 -hydroxy-ir-azabenzotriazole yield by reaction of 4-aminobenzyl alcohol and 2-(3-methylbutyryl)dimedone in refluxing THF. The value of Dmab is illustrated by a synthesis of a cyclic heptapeptide fragment 88 as shown in Scheme 69. Thus esterification of 84 with Fmoc-Glu(0Bu')-OH using DCC followed by cleavage of the tert-butyl ester with TFA gave the Dmab ester 85.The free carboxyl group was then attached to a 2-chlorotrityl chloride polystyrene resin in preparation for further elaboration to the heptapeptide 86. Removal of the Dmab group by hydrazinolysis then gave a resin- bound heptapeptide 87 which was cyclised. Finally treatment with acid accomplished simultaneous removal the side chain protecting groups and cleavage from the resin to give the target heptapeptide 88. Incorporation of a veratrole moiety into an o-nitrobenzyl component of a solid phase linker enhances its photolability. The method was applied to the synthesis of the eicosarneric 3'-alkyl carboxylic acids 89 (Scheme 70).90 Photocleavage occurred in 92% yield using the band-pass-filtered output of a high pressure Hg-Xe lamp (800 W).The cleavage conditions are mild enough to tolerate phosphodiester and nucleobase protecting groups. I I hv H Me0 0PN02 O T N 0 Scheme 70 0-OH 0 89 n = 1-4 A polymer-bound phenylhydrazide group may be used to protect a C-terminal carboxyl function of a growing peptideP' The phenylhydrazide group serves as a linker which can be easily removed under mild oxidative conditions using Cu" and molecular oxygen (Scheme 71). The phenyl- hydrazide linker is compatible with acid- and base- labile protecting groups. $H NH + Scheme 69 Scheme 71 414 Contemporary Organic Synthesis6 Phosphate protecting groups Some years ago Bannwarth and c o - w o r k e r ~ ~ ~ ~ ~ ~ developed bis( allyloxy)( diisopropy1amino)phosp hine as a phosphinylating agent which could be used for the phosphorylation of hydroxy functions in amino acids after activation by tetrazole followed by oxidation.The allyl protecting groups were later removed with Pdo and Ph3P leading to the phos- phorylated derivatives. Recently N-Boc-O-diallyl- phosphoryl serine and N-Boc-O-diallylphosphoryl threonine were synthesised by the Bannwarth procedure and used to synthesise O-phosphorylated peptides in the Boc mode of solid phase ~ynthesis.~~ The allyl groups were removed with Pd', Ph3P and formic acid. approaches to the solid phase synthesis of peptide- DNA hybrids using the Fmoc strategy for peptide synthesis and the phosphoramidite approach for DNA synthesis. The allyl protecting group used for the phosphate was stable to the DBU used to cleave the Fmoc group but difficulties were experienced optimising allyl cleavage using Pd catalysis, especially when the substrate was bound to a solid support.A useful development is the discovery that allyl phosphates are cleaved with concentrated ammonia under the same conditions used to cleave the oligonucleotide from its solid support as illustrated in Scheme 72. A Hofmann-La Roche group95 investigated [ -0-yo ? ] ov ow I I OH ? H O*N 0 Scheme 72 The hexafluoroisobutyl group [ ( CF3)2CHCH2] has recently been recommended as another base-labile protecting group for phosphate which is compatible with the phosphoramidite protocol.% It is removed under the same conditions as the 2-cyanoethyl group but the phosphoramidite precursors are more stable to heat and therefore easier to purify. Distearoylphosphatidyl-myo-inositol 3,4,5-tris- (dihydrogen phosphate) (PIP3) 92 (Scheme 73) is formed in the plasma membrane and is implicated in cell proliferation and oncogenesis.The Watanabe f Ho 'OCOC17Hs 0 90 (0.83 mmol) tetrazole (1.67 mmol) CH2C12 (2 ml), rt, 25 min MCPBA (1.25 mmol), -78 "C 0 t=J 91 f 92 0 Scheme 73 introduced the three phosphate groups via reaction of trio1 90 with o-xylylene N,N-diethyl- phosphoramidite followed by oxidation. The 3,4,5-tris-O-(o-xylylenedioxyphosphanyloxy)-myo- inositol intermediate 91 was then cleaved by hydrogenolysis in good yield. reagent for cleaving methyl or ethyl phosphonate esters. Salomon and BreuerW found that, in some cases, isopropyl phosphonates cleaved more efficiently when TMSBr was used in excess in dioxane as illustrated in Scheme 74.M ~ K e n n a ~ ~ first introduced TMSBr as a general Jarowicki and Kocienski: Protecting groups 415Scheme 74 Following the precedent set by Chao'" and Sawabe,"' the preparation and cleavage of bis[2-(methyldiphenylsilyl)ethyl] alkyl phosphates and the corresponding bis[2-( trime t hylsily1)et hyl] alkyl phosphates were examined in detail by Freeman and co-workers.'02 Treatment of the triester 93 (Scheme 75) with TBAF or NH4F removes only one 2-(trialkylsily1)ethyl group to give the diester 95, whereas treatment with a solution of HF in MeCN-H20 gives the phosphate monoester 94 (as its ammonium salt) in quantitative yield. Cleavage can also be accomplished with TFA.The rnethyldiphenylsilyl derivative reacted slower than the (trimethylsily1)et hyl analogue. Ph2~SiCH2CH20 I PhfleSiCH2CH20 100% (0.114 mmol scale) MeCKS1&) HF (1.7 mmol) (, ml) 40%.24h PhCH&Hfl-y=O t 93 I NH4F. M H , 60 OC, 72 h or TBAF, DMSO, 70 "C, 2 h 2 NH4' ?- b- PH PhCH2CH20--P=O 94 PhCH2CH20-P=O I P h2MeSiCH2CH20 95 MeNH2. H P 9 o-y=s 7 o=y-s- ow ow OAc OAc 1 I several hours 97 OAc Scheme 76 Me0 98 Scheme 75 Scheme 77 Krotz and co-worker~'~~ have employed P-(trialkylsily1)ethyl phosphorothioates in oligo- nucleotide synthesis. The O,O, 0-trialkyl phosphorothioate 96 could be deprotected with MeNH2-H20 or TBAF as shown in Scheme 76. Removal of the dimethoxytrityl protecting group from 96 was accomplished with 2% C12CHC02H in dichloromethane for 5 min but prolonged exposure to these conditions resulted in a thiono-thiolo rearrangement to give the O,O, S-trialkyl phos- phorothioate 97.The ease of the rearrangement depended on the substitution on silicon: trimethyl- silyl rearranged fastest; methyldiphenylsilyl was slowest. Peptides containing phosphoserine or phospho- threonine can be preparedlW using O[S,S-bis(p- methoxyphenyl)phosphorodithioyl] groups as shown in Scheme 77. Deprotection takes place on treating the phosphopeptide 98 with AgOAc in aqueous pyridine to give the corresponding phospho- monoester 99. 0-Alkylation of phosphates via tributylstannyl salts was applied to dinucleotides such as thymidyl(3'-5')thymidine 100 as shown in Scheme 78. Note the absence of hydroxy group protection.'" Scheme 78 HovTh 0 t)H 100 416 Contemporary Organic SynthesisPh 7 Carbonyl protecting groups Hydrolysis of enol ethers to aldehydes is generally achieved in the presence of strong mineral acids such as aq.HCl, H2S04 and HC104. Yamamoto and co-workers'" reported that combination of a protic acid or Lewis acid with Bu4NF forms milder reagents which are effective for deprotecting acid- labile enol ethers (Scheme 79). For example, treatment of l-methoxybuta-l,3-diene 101 with Bu4NF and BF3.0Etz (or Bu4NF and HCI) gave the corresponding unsaturated aldehyde 102 in 81 % yield whereas the uncomplexed acids BF3-OEt2, HCI or AIC13-OEt2 failed. Scheme 79 The acetal 103 prepared from (2R, 4R)-pentane- 2,4-diol served two useful functions in Wipf's synthesis of the epoxyquinol core of the manumycin antibiotics.'07 First, it afforded diastereocontrol in the epoxidation reaction depicted in Scheme 80.Secondly, the axial methyl group in the acetal ring introduced a beneficial level of strain which enabled the hydrolysis of the acetal to occur without destruction of the product. When both methyl groups in the acetal occupy equatorial positions, the hydrolysis could not be accomplished. 30% H 0 (1 ml, 8.83 mmol) K a 3 (0.02 mmd) THF (5 ml), rt, 6 h 49% (0.18 mmd scale) * O: 0: ij 103 &.-OC I OTBDPS Scheme 80 0 diastereomeric mtio = 4.5:l 4 PPTS 0.08 mmol) acetone (5 ml) H 0 (1 ml) 78% (0.06 mmol scale) T S O d 20 (1.7 mo) 38 "c, b?l OTBDPS The mild conditions used for hydrogenolysis of benzyl ethers have been adapted'" to the deprotection of a 4,5-dip henyl- 1,3-dioxolane as illustrated in Scheme 81.In 1980 Noyori and co-worker~~~~ reported a synthesis of dioxolanes under mild conditions by H (50psi) $d(OH)2 EtOAc 1ooOh --Ph ~ OAc OAc Scheme 81 reaction of a ketone or aldehyde with ethylene glycol bis(trimethylsily1) ether in the presence of TMSOTf. More convenient conditions have been developed"' which generate the bis(trimethylsily1) ether in situ by reaction of the diol (e.g. 104) with a see- or tert-alkoxysilane in the presence of 1 mol% TMSOTf as shown in Scheme 82. Lanthanoid sulfonates have also been found to be good catalysts for acetalisation of aldehydes and ketones with methyl orthoformate. * ' CH& -20 "c, 3 h 85% Ph 104 (1 equiv) (1.2 equiv) Ph Scheme 82 Acetalisation of unsaturated aldehydes can be troublesome because of low yields and side reactions like migration and isomerisation of the double bond.Lu's group'12 examined the influence of the acidic component in the reaction of aldehydes with ethylene glycol and found that the best results are obtained when tartaric acid is used. In the case of compound 105 (Scheme 83), less than 2% of double bond-isomerised acetal was observed; with stronger acids likep-TsOH or succinic acid, 12 and 4% were observed respectively. The presence of magnesium sulfate was also crucial in order to achieve a high yield of the desired products. 105 Scheme 83 u An S,S-acetal has played a key role in the formation of the 2,3,7,8-tetrahydro-6H-oxocine ring in Nicolaou's synthesis of brevetoxin (Scheme 84).lI3 Ag*-assisted cyclisation of the intermediate 106 first generated an 0,s-acetal 107 from which the unwanted ethylthio group was excised under radical Jarowicki and Kocienski: Protecting groups 417H H H '.107X = "-1 p h e H (10 equiv), AlBN (0.1 equiv) Ph e 4 3 h 108X = H 10076 (0.043 mmol scale) Scheme 84 conditions to give the requisite tetrahydrooxocine 108. appeared recently. In the first method (Scheme 85),ll4 aldehydes (e.g. 109) are converted into their 1,3-dithiolanes (e.g. 110) using ceric ammonium nitrate (CAN) and ethane-1 ,Zdithiol. High yields are obtained at room temperature (rt) in the presence of ketones. Alicyclic ketones may be protected at elevated temperature but aromatic and aliphatic ketones remain unaffected. In the second method (Scheme 86),' l5 selective acetalisation of an Two new methods for the formation of S,S-acetals CSH 11 9 109 Scheme 85 wo 0 ? OPMB 110 TBS 111 EtS-TMS, TMSCl 1 A~CIO~, 2 -78 "c aldehyde in the presence of a ketone 111 using Ag'- catalysed thioacetalisation with EtS-TMS and TMSCl was used in a synthesis of a fully functionalised B-ring system of taxol. 8 Amino protecting groups The enhanced electron deficiency of tetrachloro- phthalimides (abbreviated TCP) makes them much easier to cleave than the standard phthalimide function.' l6 For example the te trachloroph t halimide 112 (Scheme 87) was deprotected with four equiv of ethylenediamine in EtOH at 50 "C for 8 h.Under the same conditions the analogous phthalimide survived unscathed. It is noteworthy that the withdrawal of electron density imparted by the four chlorine atoms did not impair the neighbouring group participation of the TCP group in glycosidation reactions.Although the dithiasuccinoyl (Dts) group has been used for the protection of amines for some time, the Meldal group117 was the first to use it in the stereoselective 8-glycosylation of amino sugars. H2N-CH2CH+lH2 (4 eq~iv)**~% EtOH, 284% 50 "c, 8 h BnO c Pent NH* CI CI 112 Scheme 86 Scheme 87 418 Contemporary organic SynthesisACO OAc Cisc(0)cl (1 1.8 mmol) OOC,30min 113 .OEt - CHS (50ml) (1 1.6 mmoi scale) &% ACO OAc "YNYO s-s , 114 0 NHAc \ I s-s (a) NaBH4 (0.485 mmd) 57% (0.485 mmol scale) 12 (3 ml). MeOH (3ml) /OAc ,OBz Aa-O-&&&N, AcO BZO NHAc NHAc 115 Scheme 88 In the example illustrated in Scheme 88, the Dts group in 114 was introduced by reaction of the ethoxythiocarbonyl derivative 113 with chloro- carbonylsulfenyl chloride.Later in the sequence, removal of the Dts group was achieved using sodium borohydride (without affecting the azido group), followed by N-acetylation to give 115. The mild conditions of the cleavage are compatible with most 0- and N-protecting groups. Selective trifluoroacetylation of primary amines in the presence of secondary amines (e.g. 116) can be accomplished by reaction with ethyl trifluoroacetate in THF, MeCN or dioxane at 0 "C to rt (Scheme 89)."s.119 The product is isolated simply by evaporation of the solvent and liberated ethanol. The same conditions accomplish selective monotrifluoroacetylation of secondary diarnines.l2' MeCN rt, 12 (15 h mi) w-l l-4-l H 93% H NHCOCFS NH2 116 Scheme 89 Primary and secondary amines are readily protected as N-pent-4-enoyl derivatives by reaction with pent-4-enoic anhydride.Deprotection is rapidly and efficiently achieved under mild conditions by treatment with three equiv of iodine in aqueous THF for 5-10 min (Scheme 9O).l2l These deprotection conditions do not affect oxidisable funtionalities including p-methoxybenzyl ethers and alkyl sulfides. Aloc groups, however, appear to be incompatible. 0 Scheme 90 The formation of Boc-protected primary amines directly from azides (H2, Pd-C, Boc20) has been known for some time.'22 A ~ o ~ s o ' ~ ~ has now reported a new method which is based on reaction of azides (e.g. 117) with tributylphosphine followed by addition of di-tert-butyl dicarbonate (Scheme 91).The procedure is useful if functional groups are present which are incompatible with catalytic hydrogenat ion conditions. (a) B u p (1.1 equiv.) * F O B n Et@ (4 mi), rt, 1 h -50 'C, 1 h 81X (0.6 mmoi scale) NHBoc OBn (b) -0 (1.1 equiv), Et20 (2 ml) N3 k 117 Scheme 91 Protection of the imidazole ring of histidine with a 2-adamantyloxycarbonyl (2-Adoc) group is accomplished by reaction of N "-protected (Cbz or Boc) histidine derivatives (e.g. 118) with 2-adamantyl chloroformate (Scheme 92).124 The 2-Adoc group in 119 is both stable to Boc- deprotecting conditions, and easily and rapidly removable by anhydrous HF or 1 M trifluoro- methanesulfonic acid and thioanisole in TFA. In addition, the N"-ZAdoc group effectively suppresses racemisation of the histidine residue. The benefits of ""-2-Adoc protection were illustrated in a solid phase synthesis of thyrotropin- releasing hormone.H BocHN 119 Scheme 92 Jarowicki and Kocienski: Protecting groups 419Sajiki has reported that ammonia, pyridine, or ammonium acetate inhibit the Pd-C catalysed hydrogenolysis of benzyl ethers whilst olefins, Cbz groups, benzyl esters and azides are reduced smoothly (Scheme 93).12' 5% P M , H2 ammanla, pyndme or ammonium acetate (0.5 equiv) Cbz H Scheme 93 Matsumura and co-workers126 report that cyclic thioureas (like 120 and 121) efficiently transfer alkoxycarbonyl groups under mild and neutral conditions (Scheme 94). These reagents are reasonably stable to air, moisture and heat - properties which make them much easier to handle than, for instance, benzyl chloroformate and di-tert- butyl dicarbonate.H o s o COOR reflux, 7 h 0.54 mmd scale (0.5 equiv) 121 R = Bu' 120 R = CH2Ph R = CH Ph, 98% R = ButT86% Scheme 94 During a recent synthesis of the antithrombitic cyclic. peptide antagonist 125 of glycoprotein IIbl IIIa, an arginine was protected as the bis-Cbz derivative (Scheme 95).12' The protected arginine was synthesised from the tripeptide 122 by catalytic hydrogenation of the nitrile function to a primary amine. Subsequent reaction with N, N '-bis(benzy1- oxycarbonyl)-S-methylthioisourea128 introduced the protected guanidine function 123 in a single step in good yield. After elaboration to the cyclic derivative 124, the Cbz and benzyl ester functions were removed simultaneously by hydrogenolysis to give the desired target 125 in 90% yield.with the synthesis of highly sensitive peptide conjugates, Waldmann and NagelelZ9 have developed a new urethane protecting group, the p-acetoxybenzyloxycarbonyl (AcOZ) group, which can be cleaved enzymatically under mild conditions using lipases from orange peel, Mucor miehei, or Rhizopus atrhizus. Electric eel acetyl choline esterase can also be used. In all cases the acetyl group is cleaved leading to a phenoxide inter- mediate 126 which fragments spontaneously to a quinone methide intermediate and a carbamate 127. Decarboxylation of the carbamate then returns the deprotected N-terminus of the peptide fragment 128. The value of the methodology was demon- In the search for protecting groups compatible N 122 N-Cbz 123 I I I MeS0&l 1.1 mmd) P 6 c (IW, 150 mg) H (15 PS&, DMF (5 &I), tt.4 h & (1 mmol scale) Scheme 95 strated in a synthesis of the lipohexapeptide C- terminus 129 of the human Ras protein - a protein implicated in growth-factor mediated transduction of extracellular signals across the cell membrane (Scheme 96). The challenge in a synthesis of 129 is the lability of the S-farnesyl group (incompatible with acid conditions used to remove Boc groups) and the S-palmitoyl group (spontaneous hydrolysis at pH 6-7). A novel method for the enzymatic synthesis of sialylglycoconjugates on a polymer support has been described.13o A primer polymer 130 (Scheme 97) having N-acetyl-D-glucosamine residues attached through a phenylalanine-containing linker was elongated with galactosyl and sialyl transferases.The resulting sialo-oligosaccharide was cleaved with a-chymo t rypsin. Three research groups have reported conditions for the transacylation of allyloxycarbonyl (Aloc) groups. Pd-Catalysed deprotection of Aloc groups using Bu,SnH in the presence of carboxylic anhydrides, acid chlorides and activated esters was described by Speckamp and co-workers.131 A useful example is the removal of the Aloc group in the presence of tert-butyl carbonate, which, in essence, amounts to transprotection to a Boc-protected a-amino acid derivative (e.g. 131, Scheme 9th). 420 Contemporary Organic Synthesispacetoxybenzyloxycabnyl (AcOZ) a L 126 J spontaneous fragmentation [.PI + -oyN--q;-Me H 0 I .c +H20 I -- "O*oH H2N-peptlde--OMe 128 129 C-terminal lipohexapeptide fragment of the human N-Ras protein Scheme 96 I rt, 30 rnin I NHAloc 94% NHBoc b 131 NHAloc W(bPh Bu CH,f& SnH (0 14.6 4.6mrnd) 26 mmol ml) ' V O W + rt, 15 min 0 NHFmoc 132 Aloc = allyloxycarbonyl Scheme 98 \ N H - F ~ ~ 133 sily1)trifluoroacetamide has been reported by Guibk and co-~orkers.'~~ The extremely broad functional group tolerance of the Pd-catalysed N-deprotection of the Aloc groups in 134 was a crucial design feature in a synthesis of the epoxyquinol core 135 of the manumycin family of antitumour antibiotics (Scheme 99).'07 The final desilylation step was complicated by the base sensitivity of 135, but HF in MeCN at 0 "C accomplished removal of the TBDPS group where TBAF had failed. Bu SnH (0.50 mmol) AhH (0.75 mrnol) PdC12(PPh3), (0.5 mol%) * 0: CH CI 20ml) 0 -$O& 1 h 0 0: 81% (025 mmol-scale) OTBDPS OTBDPS 134 More importantly, the use of activated N-protected a-amino esters (e.g.132) leads to a dipeptide (eg. 133) as shown in Scheme 98b. This new one-pot method for peptide coupling proceeds under mild conditions in excellent yield and without noticeable racemisation. Beugelmans and co-worker~'~~ have described the use of sodium borohydride as hydride donor in similar transformations. Finally, Pdo- catalysed cleavage or transacylation of ally1 carbamates, carboxylates and phenoxides in the presence of phenylsilane or N-methyl-N-(trimethyl- Scheme 99 I 40% aq HF 2 ml) MeCN (0.5 ml).0 4. 1 h 58% (0.018 mmol scale) 0: -". 0 OH 135 cleave with 0 OH a-chymotrypsin 0 NHAc Ph 130 Scheme 97 Jarowicki and Kocienski: Protecting groups 421The readily prepared Cd-Pb couple cleaves 2,2,2-trichloroethoxycarbonyl (Troc) groups rapidly (30-45 min) and efficiently (90-95%) at pH 7.0 (Scheme loO)."4 5 Equiv. of Cd per Troc group are optimal. Unactivated halogens (including iodine, e.g. as in 136) survive but nitro and azide groups are reduced. Troc esters are deprotected much faster than the corresponding carbamates or carbonates. 10% Cd-Pb (5 mmol) I aNH2 aq NH4OAc (1 M, 4 ml) H ni 89% (1 mmol scale) bI 136 Scheme 100 During a synthesis of the ansamycin antibitoics trienomycin A and F, Smith and co-worker~"~ found that the choice of protecting group for the amide function in intermediate 137 proved to be unexpectedly critical: p-methoxybenzyl and 2-( trimet hylsily1)et hoxymet hyl (SEM) moieties could not be removed without extensive decomposition under oxidative (e.g.DDQ, CAN) or acidic conditions, respectively. However, the 2,2,2-trichloroe t hoxyme t hyl unit, which had previously been deployed for hydroxy group protection by Evans,'36 was successfully cleaved using Na(Hg) (Scheme 101). OTBS 137 Scheme 101 During a large scale synthesis of cetirizine hydrochloride, an antihistamine agent for the treatment of allergic syndromes, Opalka and co-worker~'~~ used HBr and p h e n ~ l ' ~ ~ , ' ~ ~ for the reductive removal of the N-Ts group from 138. However, under these conditions, removal of phenolic by-products complicated workup on a large scale.When 4-hydroxybenzoic acid was used in place of phenol, most of the 4-hydroxybenzoic acid derivatives crystallised out on addition of the crude reaction mixture to water, the remainder being removed by base extraction of the filtrate (Scheme 102). During a synthesis of clavicipitic acid, a Japanese group'4o cleaved an indole N-tosyl group with Mg in Ph c-2 R Scheme 102 138 R = TS R - H J Mg, MeOH rt. 1 h 72% ______) 4hydmxybenzoic acid (16.6 md) 30% HBr-HOAc (8.85 L) rt,2 d,59%(5.M mol scale) Ts N\ \ H Scheme 103 MeOH without racemisation of the a-amino ester (Scheme 103). The reductive cleavage of N-(arylsulfony1)amines with SmI, reported in 1994 requires refluxing THF and DMPU, the latter being added to increase the reduction potential of the Sm.14' However, Hesse and c o - ~ o r k e r s ' ~ ~ * ' ~ ~ have shown that the pyridine- 2-sulfonyl group is cleaved without using DMPU or HMPA because of its lower LUMO energy.Thus the N-(pyridine-2-sulfonyl) group provides a new method for the protection of primary amines, arylamines and amino acid derivatives. The resulting sulfonamides are obtained in good yields and are frequently crystalline, and they can be deprotected under mild conditions by using SmI, in THF at rt or by electrolysis. The N-(pyridine-2-sulfonyl) group was one of five orthogonal amino protecting groups developed for polyamine synthesis as illustrated in Scheme 104 by the selective deprotections of the 1,16-diamino-4,8,13-triazahexadecane 139. The 3-nitropyridine-2-sulfenyl (Npys) group is stable to TFA and 88% formic acid but it is easily removed with: (a) 0.1 M HCl in dioxane, (b) triphenylp hosphine-pent achlorop henol or (c) 2-mer~aptopyridine-N-oxide.'~~ However, Npys groups on a peptide attached to a polymer support are significantly more difficult to cleave than the corresponding solution phase deprotections.Rajagopolan and c o - ~ o r k e r s ' ~ ~ showed that 2-mercaptopyridine-N-oxide in large excess (500 equiv) will cleanly and efficiently cleave the Npys group from lysine residues in polymer-bound peptides 140 (Scheme 105). Genet and co-worker~'~~.'~~ have reported that mono- and di-allylamines can be cleaved using Pd" catalysis and 2-mercaptobenzoic acid as an allyl trapping agent. Tertiary amines like 141 react much faster than secondary amines (as 142) and at room temperature selective deprotection of one allyl group can be achieved (Scheme 106).Removal of 422 Contemporary Organic Synthesis(80%) (0.1 3 rnrnol scale) CF3 (88%) (0.196 mmol scale) I I I I CF3 (60%) (0.104 mrnol scale) CF3 (46%) (0.176 mmol scale) Reagents and conditions: (a) K2CO3, MeOH, rt, 2 h; (b) CF3C02H, CH2CI2, rt, 2.5 h; (c) Pd(PPh),, N,N-dimethylbarbituric acid, CH2CI2, 35 "C, 1.5 h; (d) CICOCHCICH3, CH2CI2, -10 OC, 12 h then MeOH, NEt3, A, 12 h; (e) Sm12, THF, rt, 12 h Scheme 104 SH A- (500 equiv !) ____) CHpCIp, It i"' P h d N e Pd(dba)dPPB (1:l) (5 m o l y 2-mercaptobenzoic acid (1.1 equw) THF, tt, 30 min Ph I 1 40 Pd(dba)TDPPB (1:l) (5 mol%). 2-mercaptobenzoic acld (1.1 equw) THF, 80 "C, 2 h Y Ph d N / H \ Scheme 105 I H the remaining ally1 group in 142 requires a higher temperature (60 "C).Davies and ~o-workers'"~'~~) have extended the range of enantiomerically pure lithium amide bases which undergo conjugate addition to unsaturated esters with a good to excellent diastereomeric ratio dba = dibenzylideneacetone DPPB = 1,4-bis(diphenyIphosphino)butane Scheme 106 Jarowicki and Kocienski: Protecting groups 423(dr). Lithium [a-methylbenzyllamide 143, for example, (Scheme 107) can serve as a differentially protected chiral ammonia equivalent for the asymmetric synthesis of P-amino acids and P-lactams. The allyl group is deprotected first using Rh-catalysed isomerisation-hydrolysis whereas the benzyl group is removed by hydrogenolysis using Pd(OH)2 as the catalyst. I I I I M~CH=CH-CO~BU~ Ph&- THF, -78 "c * PhAN- Li I 92% &C02B"' 143 diastereomeric ratio > 99:l Scheme 107 The reaction of N-benzylindoles (e.g. 144) with lithium diisopropylamide or methyllithium (5 equiv.) results in debenzylation (Scheme 108).The reaction probably occurs via a carbene mechanism. The yields are generally 40-60%. LDA THF. or M L i 4 0 "C, (5 equiv)" 1 h n-0 Y then rt, 12 h 64% H I Bn 1 44 Scheme 108 The formation of aspartimide (cyclic imide) involving aspartic acid residues is one of the most serious side reactions in solid phase peptide synthesis. The reaction is catalysed by base or by strong acid and leads to racemisation and/or isomerisation of the affected residue. Furthermore, although the aspartimide ring is hydrolysed in neutral and alkaline media, attack at both carbonyl groups may occur leading to a mixture of a- and P-aspartyl peptides.In the Fmoc-tert-butyl strategy of synthesis, the problem is especially acute at Asp- Asn and Asp-Gly sequences (146 .+ 145) as illustrated in Scheme 109. In a synthesis of an N-terminal, 20 residue fragment of ferredoxin,"" aspartimide formation was completely suppressed using N-2-hydroxy-4-methoxybenzyl (Hmb) backbone p r o t e ~ t i o n ' ~ ' - ~ ~ ' at the two vulnerable Asp- Gly-Asp-Asn sites 147. Deprotection and cleavage of the completed peptide fragment with 95% TFA- 5% ethanedithiol returned a homogeneous product devoid of aspartimide contaminents. Another approach to the suppression of aspartimide 145 r NH2 acid or base t 146 AspGly-AspAsn OMe OMe 147 I NH2 Scheme 109 formation in solid phase peptide synthesis was reported by Karlstrom and UndCn.'" Protection of the aspartic acid carboxyl as its P-2,4-dimethyl- 3-pentyl ester suppresses aspartimide formation under acidic or basic conditions and it is easier to cleave in TFA (tin 40 h at 4 "C) compared with the corresponding cyclohexyl ester (tllZ 500 h) which is commonly used.The highly coordinated tin hydride Bu2SnC1H in HMPA reduces imines (e.g. 148) to intermediate tin amides 149 whose alkylation with benzyl bromide or allyl bromide affords the corrersponding N-ally1 or N-benzyl tertiary amines (e.g 150, Scheme l10).'54 148 L V 149 Ph, ,Bn N 150 Scheme 110 424 Contemporary Organic SynthesisCarpino and co-workers8" have shown that the enhanced acid lability of the dimethylcyclopropyl- methyl (Dmcp) group compared with the dicyclo- propylmethyl group (vide supra) made it useful for the N-protection of peptide amides (Scheme 111).Previously, peptide amides were obtained via initial assembly of an ester and subsequent ammonolysis. However, Dmcp-protected amides can be intro- duced directly. In the case of pentapeptide 151, treatment with piperidine first removed the Fmoc group and subsequent treatment with TFA deblocked all remaining protecting groups to afford peptide 152 in excellent quality. R 1 NH2 H Fmoc-Asp(O-Bu')-Tyr(Bu')-Ile-Asn(Trt)-Gly-NH(Dmcp) 151 1 t:jkY" H-Asp-Tyr-Ile-Asn-GIy-NH2 1 52 Scheme 11 1 Polyamide (or peptide) nucleic acids (PNAs) are oligomers of nucleobase-derivatised N-( 2-amino- ethy1)glycine which recognise and bind strongly to specific DNA or RNA sequences.PNA oligomers have a number of properties which make them potentially useful as antisense therapeutics and as diagnostic tools. A Hoechst group15' has devised a synthesis of novel monomethoxytrityl (Mmt) protected monomers (e.g. 153) which can be attached sequentially to a supported primer 154. Each cycle is preceded by a mild acid-catalysed deprotection of the Mmt group as shown in Scheme 112. PNAs of mixed base composition have been prepared by this strategy. Whitaker and co-worker~'~~ have given ample testimony to the value of STABASE protection of amino groups in their recent synthesis of (4-amino- pheny1)diphenyl phosphine oxide 155, summarised in Scheme 113.In the search for new variants of the STABASE protecting group for amines which are more stable to hydrolysis and chromatography, Davis and GallagherI5' prepared 1,1,3,3-tetraethyI-l,3-disila- isoindolines (abbreviated TEDI) by the three routes shown in Scheme 114. First the disilane 156 was treated with a primary amine in the presence of CsF (20-30 mol%) in DMPU to give the TEDI 157. Second, the same disilane and primary amine reacted in the presence of PdC12 (5 mol%) after heating in xylene. Finally a two step procedure involving prior formation of bis(bromosi1ane) 158 followed by reaction with the primary amine in the presence of NEt, accomplished the synthesis of TEDI 157. Compound 157 was about 75 times more stable towards water than the corresponding STABASE derivative and it was more stable to column chomatography.However, 157 could be hydrolysed in AcOH-Et20 (1 : 4) with a half-life of 53 minutes. 153 I R = Mmt 154 R = H Mrnt = monomethoxytrityl Scheme 112 Jarowicki and Kocienski: Protecting groups 425t o (a) Buti (4.14 mmol). hexane-Et20 (b) Ph PCI (3.18 mmol). rt, 15 h (3.18 rnmdscek) 0 OOC.1.5h N N u \ I Mesi' 'SiMe Me2Si' 'SiM% Scheme 11 3 156 Br2, CCI4. Br Br, ' . \ /siEt2 or P a l 2 (5 moIO4.) xylene, A, 72 h 0 "C NHp 1 55 9 157 NEts 1 58 Scheme 114 The N-bis(methy1thio)methyleneamine derivative 159 of glycine underwent a highly anti-stereo- selective conjugate addition to ethyl (E)-butenoate to give the adduct 160 (dr 49: l).I5* Hydrolysis of the protecting group resulted in lactamisation (Scheme 115).During a synthesis of pyrrolo[2,3-e]pyrimidine folate analogues, Taylor and Young'59 required protection of the amino and amido groups of the pyrimidinone 161 en route to the intermediate 9-deazaguanine 162 (Scheme 116). The dimethyl- aminomethylene protecting group was introduced first by reaction of 161 with dimethylformamide dimethylacetal. The amido nitrogen was then protected as its pivaloyloxymethyl derivative - a reaction which was accompanied by 15% O-alkylation. The protecting groups were removed simultaneously using aqueous NaOH. Coote and co-workers'60 described the utility of 1,2,4-oxadiazol-5 (4 H)-ones 164 and 5 -benzyloxy- 1,2,4-0xadiazoles 165 as both precursors to, and protecting groups for amidine functionality (Scheme NaOH (450 mmol).H@ (20 ml) CS, (29.8 mmol), Me1 (100 mmol) BnNEtGI (2.2 mmol), PhH (70 ml) 20 "c, 20 min 60% (29.8 mmol scale) I I 0 SMe 159 (€)-Me-CH=CKCO Et (0 97 mmol) NaOH (0.97 mmol), k N ( 1 m9 BnNEtSI (0.097 mmol) rt,2h v SMe f' A SMe >rOrnO" 160 , , Scheme 115 117). The former compounds are stable in basic conditions and can be easy prepared from amidoximes 163. Both protecting groups may be readily removed upon hydrogenation, liberating the parent amidine. A fast conjugate addition occurs when uridines and thymidines (e.8. 166) are treated with methyl propiolate in the presence of DMAP. Scheme 118 shows that N-[ (E)-2-( me t hoxycarbonyl)vinyl]uridine 167 is readily cleaved by nucleophiles such as pyrrolidine or methylamine thereby affording a new N3 protection The adducts are stable to non-aqueous acid but they are hydrolysed by aqueous acid.A model of the BC ring system of the antibiotic sakyomycin required cleavage of a 2,4-dinitrophenyl- amine derivative 168 to release a very sensitive amine 169. The cleavage was achieved slowly under mild conditions using a basic ion exchange resin (IRA-400) in aqueous acetone (Scheme 119).162 from amino acids exploits enaminonitriles as protecting groups for a m i n e ~ . ' ~ ~ The efficiency of the sequence was largely compromised by the modest yields obtained in the final hydrolysis step in the example shown (Scheme 120). The cyano group in the enaminonitrile intermediate 170 was quite robust, withstanding attack by alkyllithiums, Grignard reagents, and borohydride at elevated temperature. A new large scale synthesis of /?-amino alcohols 426 Contemporary Organic Synthesis0 Me2" 1 61 0 0 NaOH (1 M, 6 ml) THF (4 ml) rt, 4 d 48% (0.63 mmd scale) JI H2N Me2" 1 62 (a) NOH (I 1.5 mmol) (b) d H & / ( 2 h 1 2 h ml) DMF 20ml,rt,lh - 6096 (10.4 mmd scale) Me#XHOMe (2ml) DM; (10 I$ r t , 12h 86% (92 mmol scale) I Scheme 116 poc19.PY ______) H reflux, 1 h * dYk0 0 54% C#'XX)El, py reflux, 3 h 75% 164 163 H W - C I 2 0 h &Et, AcOH 91 % + N-0 165 Scheme 117 TO 0 go O x " 166 + C02Me // Scheme 11 8 HCS-CO2Me DMA? rt, 4 0 min ____) pyrrolidine MeCN rt, <2 h 298% - 1 67 0 H O P 0 HO OH aceton6-H20 48h I NO2 168 Scheme 11 9 NHp unstable 169 9 Miscellaneous protecting groups Serotonin 5-HTID receptor agonists are potent antirnigraine drugs.During a synthesis of the 5HTID agonist 172 (Scheme 121), attempts to perform Fischer indole syntheses were complicated by elimination of the rnethylaminosulfonyl group.'" By Jarowicki and Kocienski: Protecting groups 427ONa I BCN 1 NaOH &CN o-"" 1 70 OH Scheme 120 masking the methylaminosulfonyl group (while retaining its pendent methyl group) as a Q-hydroxy- 2-methyl-3( 2H)-isot hiazolone- 1,l -dioxide 171, the requisite Fischer indole synthesis was successful. The protecting group was cleaved in the last step by treatment with 2 M NaOH in EtOH. A key aspect of any solid phase synthesis is the means by which a molecule is linked to the solid support. Perhaps the easiest linkage occurs through a functional group such as an amino group or a carboxyl group which is retained intact or in modified form in the final product after cleavage.Alternatively, a spectator functional group can be appended to the target structure purely for purposes of linkage. However, the spectator group may confer unwanted properties on the cleaved target. An alternative approach would involve linkage through 6 Br 173 6 steps 14% overall - 2 M NaOltEtOH (l:l), rt 62% Me0 I t S02NHMe Scheme 121 a spectator functional group that can be easily replaced by a proton leaving no trace of the solid phase synthesis. Plunkett and Ellman'65 have developed a 'traceless' linker for the solid phase synthesis of benzodiazepine derivatives based on protonolysis of arylsilanes (Scheme 122). The (aminoary1)stannane which serves as a primer group in the synthesis was first attached to a 4-(alkoxy)- phenoxyacetic acid group through a silane linkage and the whole (174) then appended to an (amino- amiMnnethyG polystyrene 174 175 2 Bpoc = P-@biphenylyl)isopropyloxycarbonyl Scheme 122 428 Contemporary Orgpnic Synthesismethy1)polystyrene resin (175).After elaboration of the diazepinone system, cleavage was accomplished with anhydrous HF. Note that the aryl-silicon bond is stable to the trifluoroacetic used to cleave Boc groups owing to the extremely electron-poor nature of the protonated benzodiazepine. The detractions to this route are: (a) the large number of steps required to engineer the arene 173 into a structure 174 which can be attached to the resin and (b) the harsh conditions of anhydrous HF cleavage.Veber and co-workers’66 have reported the synthesis of some arylsilane linkers attached to a polystyrene resin 176 which generate an unsubstituted aryl ring 177 on cleavage with either neat TFA or CsF in hot aqueous DMF (Scheme 123). The authors claim that the cleavage conditions are mild enough to tolerate sensitive substrates. p SiMe, 8 I CHO CF& H (neat) *?O%) CsF DMF-HD 4:l)- il0.C (67%\ 8 CHO 177 176 Scheme 123 Acknowledgement We thank Mr Philip Hall for assistaqnce in the preparation of the manuscript. 10 Reviews 1 ‘Protecting groups 1994’. K. Jarowicki and P. 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ISSN:1350-4894    

DOI:10.1039/CO9960300397

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

The synthesis of quinones PETER T. GALLAGHER Eli Lilly & Co. Ltd., Lilb Research Centre, Windlesharn, Surrey GU20 6PH, UK Reviewing the literature published between 1 January 1991 and 31 December 1995 1 2 2.1 3 3.1 3.2 3.3 4 5 6 Synthesis of benzo-1,4-quinones Synthesis of naphthoquinones Substitution of benzoquinones and naphthoquinones Synthesis of heterocyclic quinones Synthesis of five-membered heteroaromatic quinones Synthesis of six-membered he teroaromat ic quinones Synthesis of saturated heterocyclic quinones Synthesis of anthraquinones and anthracyclinones Synthesis of other polycyclic quinones References 1 Synthesis of benzo-1,4-quinones During the period under review developments in the synthesis of benzoquinones from squaric acid derivatives have occurred. From observations on the thermolysis of 3-alkoxy-4-alkynyl-4-hydroxycyclo- butenones, this reaction has been generalised for the synthesis of a variety of substituted benzo- quinones (Scheme 1).1-3 Cyclobutenones may also be transformed in the presence of tributyltin methoxide to stannylquinones and these in turn undergo palladium-copper co-catalysed cross-coupling to give aryl and hetero- aryl quinones in yields in the range 48-91% (Scheme 2).4 A route for the regioselective synthesis of poly- substituted quinones utilising a benzannulation reaction of alkenyl chromium carbene complexes and l-phenyl-2-trimethylsilylethyne, followed by iodination and then Stille or Suzuki cross-coupling has been developed (Scheme 3).5 Similarly, ferrocenyl acetylene undergoes benz- annulation with aryl and alkenyl chromium carbonyl complexes to produce ferrocenyl quinones.6 Other routes to quinones which have been developed include one to prenylated quinones involving lithiation of dimethylaminophenols and subsequent reaction with alkenals to produce prenyl alcohols which are hydrogenolysed and oxidised with Fremy’s salt (potassium nitrosodisulfonate - ON( give quinones (Scheme 4).’ to Facile double Michael addition induced cyclo- propanation reactions of unsaturated esters have provided easy access to the tricyclo[5. l.0.d5]octane- 2,6-dione.These bis-halocyclopropyl diketones are readily ring opened to give quinones with tributyltin hydride (Scheme MeOxO MeOuO i.TFAA Me0 ~0 Me0 0 PhLi. THE ii. MeOH,M& Ph Me0 Ph OH Buli, THF I Scheme 1 /hI, P&(dba)s, Cur.DMF n / R = pyrid-2-yl 76% R = 4-nitrophenyl 85% R = thien-Pyl 61% Me$ Me dba = dibenzylidene-acetone 0 Scheme 2’ Gallagher: The synthesis of quinones 433i. PhCZCTMS, ii. CAN. 60% THF * w+ph TMS Me 0 El, ccl, WYB / - ? ?+ OH ij Scheme 3 Scheme 6 y e 2 0 I 6- i. BUD. THF, Me&=CHCHO ii. u, NH:, O M 0~~ iii. Fremy's salt OH ij Scheme 4 0 Ph -Co2Et I Buli, CH&b,THF PhQ--Ph H Cl 0 Ph 0 Scheme 5 2 Synthesis of naphthoquinones The synthesis of benzoquinones from cyclobutene- diones (Schemel) is also amenable to the synthesis of naphthoquinones. Thus starting from a cyclobutenedione, consecutive addition of an axyllithium followed by an alkyllithium and then thermal rearrangement at 140 "C produces a bis- 1,4-naphthol which is readily oxidised with 'aqueous ceric ammonium nitrate (Scheme 7).2-Lithiofuran has also be used in this reaction when the products are benzo[b]furandiones.' When a tert-butyl ether is used instead of an isopropyl ether in this type of synthesis, hydroxynaphthoquinones result. These, when subjected to Hooker oxidation (hydrogen peroxide- sodium carbonate-copper sulfate), are oxidatively rearranged to the isomeric hydroxyanthraquinones thereby allowing the synthesis of both hydroxylated regioisomers from the cyclobutenedione route.' ' Pummerer type rearrangement of p-sulfinylphenol derivatives induced with trifluoroacetic anhydride gives a 1 : 1 mixture of of the corresponding 1,4-quinone and the 1,4-dihydroquinone, which when subjected to mild oxidation provide high yields of the 1,4-quinones. A variety of substituents on sulfur are tolerated though low yields of quinone were reported with 4-nitrophenylsulfinylphen01.~ As part of efforts directed towards the synthesis of dynemicin A, Danishefsky utilised a 1,4-quinone to synthesise a quinoline precursor of dynemicin A.This required the synthesis of an appropriately substituted benzopyran, which was subjected to ceric ammonium nitrate (CAN) oxidation to provide a 1,4-quinone (Scheme 6)." Scheme 7 r I 1 L OH J 434 Contemporary Organic SynthesisNaphtho-1 ,dquinones are efficiently synthesised by regioselective reaction between dimet hylpht halide-3-p hosp honates and electron deficient alkenes (Scheme 8). A variety of alkenes may be used in this reaction: as well as fumarate (shown in the Scheme), maleate, acrylamides, vinyl ketones and unsaturated esters have all been successfully annulated.I2 n 0 Scheme 8 A novel oxidative intramolecular cycloaddition of silylene protected dihydroxystyrene derivatives has provided a new route to the ABCD ring system of fredericamycin.The reaction appears quite general and the intermediate acetoxynaphthalene derivatives may also be isolated (Scheme 9).13 Construction of a hydroxynaphthalene prior to oxidation was the route taken to prepare TMS M*SiC12, Et3N, Chbranil [Meov- 1 OMe TMS i. benzene. 150 OC ii. MeOtl iii. AqO. pyridine. n% I iv. H20, TFA (4:l) Me0 OMe Scheme 9 aegyptinones A and B. Thus a photochemical aromatic annulation between diazoacetophenones and silyloxyacetylenes provides the hydroxy- naphthalenes, which were subjected to low temperature oxidation with oxygen to effect quinone formation. l4 The Dotz chromium carbene annulation reaction has been enhanced by the application of ultrasound.Thus chromium carbonyls and alkynes can be transformed in minutes to naphthoquinones and furanoquinones in moderate to good yields (Scheme 1 0 p Me0 i. ultrasound. Bu20 ii. CAN, 69% 0 I Me*ph Ph 0 Scheme 10 Intramolecular benzannulation reactions have also been reported utilising manganese carbene complexes in place of chromium.'6 2.1 Substitution of benzoquinones and napht hoquinones Substitution of quinones with allylic indium reagents has been shown to be a versatile way of introducing allyl, prenyl and geranyl groups to quinones. Reaction proceeds by allylation at the quinone carbonyl followed by facile [3,3]-sigmatropic rearrangement to the 2-allyl-1,4-naphthols which are routinely oxidised to the allylquinones.Direct displacement of chlorine from quinones may also be effected with allylindium sesquiiodide (Scheme 111.l~ Similarly allylation of quinones has been achieved with allyl(trifluoro)silanes and TBAF. Here, as with indium reagents, initial attack is at the quinone carbonyl followed by [3,3]-sigmatropic rearrange- ment; oxidation of the intermediate hydroquinone is with ferric chloride.I8 2-Alkylnaphtho-1,4-quinones may be synthesised by reacting trialkylboranes with unsubstituted naphthoquinones followed by oxidative work-up. Yields are variable and mono- and di-substitution may result." Arylation of quinones is achieved by reacting unsubstituted quinones with arylmercuric chlorides under lithium palladium chloride catalysis.20 benzoquinones by dimethylaminobenzylidene anilines has also been reported. This reaction Displacement of halogen from electron deficient Gallagher: The synthesis of quinones 4350 0 i.2-trhrethylsibxyhrran, MeCN, 51% 1 ii. CAN, MeCN, 77% 0 * CI 0 0 Scheme 11 proceeds via a charge transfer complex and the products from this reaction are either monoanilino- trihalo benzoquinones or bisanilinodihalo benzo- quinones.” Unsubstituted quinones have been directly aminated with 0-benzylhydroxylamine to provide aminoquinones. Alternative hydroxylamines were used but hydroxylamine, O-methylhydroxyl- amine and carboxymethoxylamine were found to be less effective.22 In a novel two step process 2-hydroxynaphtho- quinones have been synthesised by an initial [2+2] cycloaddition reaction between N-sulfinylarylamines (e.g.PhN=S=O) and naphthoquinone. This results in the formation of 2-(N-arylsulfinamoyl)-naphtho- 1,4-quinones which in turn are easily hydrolysed with dilute hydrochloric acid to 2-hydroxynaphtho- quinone.” Titanium catalysed arylation of quinones has been shown to occur with cyclopropylbenzene derivatives. Arylation occurs from the 4-position of the cyclo- propylbenzene to the 2-position of quinones and yields are enhanced by the presence of a trimethyl- silyl substituent on the cyclopropyl ring.24 A general arylation of bromoquinones with arylstannanes under palladium catalysis has been reported to provide aryl quinones in high yields.25 been achieved utilising the facile addition of 2-t rimet hylsiloxyfuran to 2-p henyl t hionap h t ho- quinones to produce intermediate furo[3,2- b]naphtho[2,1-d]furans which are oxidised with CAN to the quinone (Scheme 12).Reductive removal of the sulfur substituent provides the juglinomycin derivative.26 A new synthesis of 5‘-deoxyjuglinomycin A has 3 Synthesis of heterocyclic quinones 3.1 Synthesis of five-membered heteroaromatic quinones The ubiquitous nature of fused heterocyclic quinones, their biological properties and attendant commercial reward has resulted in them becoming 0 Hd Scheme 12 targets for synthesis. Quinones are the active pharmacophore in antitumour agents, antibacterial and antimalarial agents and a rapid two step synthesis of both indoloquinones, and benzo- [b]thienoquinones has been rep~rted.~’ Thus amino- or thio-acetals may be cyclised with PPA in xylene to give 4,7-substituted indoles and benzo[b]thiophenes respectively.These in turn may be oxidised with CAN to give quinones (Scheme 13). to vinylogous carbamates has provided a facile synthesis of pyrroloindoloquinones which was extended to the synthesis of 7-methoxymitosene (Scheme 14).28 A one pot annulation reaction of bromo quinones Me0 Me0 Meb H MeO Scheme 13 0 Br 0 K&Oa CuBq, MeCN + t 61 36 Scheme 14 0 This approach has also proved useful in the sythesis of the ABCD ring system of the originally proposed structure for kinamy~in.~~ The mitosenes and murrayaquinones contain the indolo- 4,7-quinone substructure and a novel approach to this system has been the construction of a 4-formyl- 7-methoxyindole and subsequent oxidative degradation with Fremy’s salt.3o Alternatively as in 436 Contemporary Oeanic Synthesisthe synthesis of the topoisomerase I1 inhibitor BE 10988, a 4-benzyloxyindole may be debenzylated and oxidised with Fremy's salt to provide an indoloquinone.31 direct palladation of anilinobenzoquinones and Carbazoloquinones have also been synthesised by naphthoquinones followed by oxidative cycli~ation.'~-~~ Furanoquinones may be synthesised in an analogous fashion to naphthoquinones from cyclobutenones (cf Section 2).35 They are also accessible from alkynylsulfonium salts by reaction with the enolates of cyclic 1,3-diketones. The first formed dihydrobenzofuranone is firstly dehydro- genated to the phenol and subsequently oxidised with Frerny's salt to the furanoquinone (Scheme 15)." 'i I I H O discorhabdin C OH I Phl(OCOCF&.CF3CH20H. 86% 0 I Me O O H Scheme 15 i. Bu'OK, THF ii. 10% Pd(C), cymene, 200 "C iii. Fremy's salt Me 0 A general synthesis of hydroxynaphthoquinones and the analogous thiophene, pyrrole and furan quinones has been effected by bis-acylation of P-keto esters with oxalyl chloride. The resultant hydroxy esters are then hydrolysed and decarboxylated to give the hydroxy quinones (Scheme 16)"' 0 CO2Et *OH AIC13. !&NO2, (COC1)2 C02Et X = S, 0, NMe 57-85; 0 Scheme 16 The cytotoxic antitumour agent discorhabdin C has proven to be a challenging target but an approach providing a general route to azacarbo- cyclic spirodienes has been developed utilising the hypervalent iodine oxidation of phenol derivatives with bis(trifluoroacetoxy)iodobenzene (Scheme 17)."' Benzo-l,4-quinones bearing electron donating (e.g.amino or thio) substituents undergo dipolar cycloaddition reactions with diazomethane to produce indazoloquinones in moderate yield. Naphthoquinones also undergo this reaction." been reported by base catalysed ring closure of 2-(2-nitrophenacyl)phenylacetic acids, the first formed hydroxynaphthoquinone is reduced with sodium borohydride in isopropanol to give the carbazole (Scheme 18).'" An efficient synthesis of benzo[b]carbazoles has Scheme 17 OMe C02Me NaOH, MeOH, H20. 98% ?Me I OHNo2 Me0 Me0 0 NaBH4. PiOH, W h OMe Scheme 18 Imidazo[4,5-g]quinazolinequinone nucleosides have been studied for their ability to be functionalised into enzyme directed reductive alkylating agents.They are accessible by a chemoselective Fremy's salt oxidation of ribosylated aminoimidazolo[4,5-g]quinazolines (Scheme 19).4' Driven by the need to find alternative quinone functionalised nuclei as acceptors in place of tetracyano-p-quinone dimethane (TCNQ) in charge transfer complexes with tetrathiofulvalene, efficient syntheses of thieno[2,3-b]naphtho-174-quinones were required. Thus microwave assisted cyclisation of several thienoylbenzoic acid derivatives were studied and the most efficient catalyst was found to be Montmorillonite K-l 0 freed of quartz and feldspar." Gallagher: The synthesis of quinones 437Scheme 19 I.BuU, Et20 B r m B r iii. ii. MgBrz Bu'O&OPh * 0-0 iv. TsOH I DW, dioxane 1 Scheme 20 Alternatives to TCNQ were also cited as the reason for the synthesis of t hieno [ 3,241 t hiophene- 2,5-quinone (Scheme 20).43 3.2 Synthesis of six-membered heteroaromatic quinones New 7-aminomethyl-6-chloroquinoline-5,8-quinones have been synthesised by Mannich reaction of 6-chloroquinoline-5,8-quinone and formaldehyde with secondary amines. Yields are moderate (38-80%) and the products possess amoebicidal 6-Chloroquinoline-5,8-quinone is the common precursor for novel oxazolo- and thiazolo- quinolinediones which are formed by reaction of the chloro quinone with amides and thiourea re~pectively.~~ Homophthalic anhydride has been shown to react regiospecifically with 6-bromo-1-chloro- 4-methylisoquinoline-5,8-quinone under basic conditions (sodium hydride, THF) to produce, in 77% yield, 1 -chloro-6-hydroxy-4-me t hylnap ht ho[ 2,3- g]isoquinoline-5,12-quinone, a precursor to antitumour aminonaphthoisoquinolinequinones. The corrresponding unbrominated isoquinoline- 5,8-quinone showed no regio~electivity.~~ Perfragillin B, a cytotoxic isoquinoline quinone isolated from M.pe$-agiZZis, has been synthesised by hetero Diels-Alder reaction of 1,3-bis(tert-butyl- dimethylsi1oxy)-Zazabutadiene and 2,3-bis(methyl- thio)benzoquinone followed by hydrolysis, oxidation and rnethylati~n.~~ During the period under review the first total synthesis of streptonigrone was achieved. Significant steps in the synthesis of this antitumour antibiotic are the room temperature inverse electron demand Diels-Alder reaction of an N-sulfonylazabutadiene with a ketene acetal, chemoselective oxidation of an hydroxyquinoline to a quinone in the presence of a phenol and the introduction of a methoxy group to the quinone with titanium tetraisopropoxide.These last steps are shown in Scheme 21 together with the final steps of the synthesis.49 Br @OH OMe OH OMe Br OMe \ Me 0 H2N Y O M e i. NaN) THF. H20 0~~ < NeBH4, THF, MeOH 111. H2. HBr, CF&H20H Me @ O H OMe OMe streptonigrone Scheme 21 Streptonigrin has also been a target of interest and a new synthesis of the quinolinequinone moiety has been published as has a convergent synthesis of streptonigrin and lavendamycin analogue^.'^*^' An entry into the field of azaanthraquinones is possible by the Diels-Alder reaction between 2-methyl-4-ethyl-5-methoxyoxazole and quino- pimaric The inital adduct may then be cleaved in dimethylformamide dimethyl acetal at elevated temperature to give the azaanthraquinone in 82% yield (Scheme 22).438 Contemporary Organic SynthesisI 0 OMe I 0 OMs H02C‘ \n/. Scheme 22 Ultrasound irradiation has been shown to assist the Diels-Alder reaction of 1-azadienes and quinones which may be converted to azaanthra- q ~ i n o n e s . ~ ~ S-Deazaflavin-6,9-quinones are regarded as hybrids of 5-deazaflavin and coenzyme Q and their synthesis has been achieved by heating 6-alkyl- aminouracils and 2,3-dimethoxybenzaldehyde in DMF. The resultant methoxydeazaflavin is then oxidised in moderate yield with Fremy’s salt to the q ~ i n o n e .~ ~ A series of quinazoline-5,8-diones have been synthesised to evaluate their in vitro cytotoxicity towards L1210 leukaemia cells.55 33 Synthesis of saturated heterocyclic quinones 2,3,4,5-Tetrahydro- 1 H- 1 -benzazepine-2,6,9-trione has been synthesied by the ring expansion of 5-methoxytetralone, demethylation and oxidation with Fremy’s salt. This trione has been used in Diels-Alder and hetero Diels-Alder reactions and when reacted with methacrolein dimethylhydrazone the product is a quinolinotrione (Scheme 23).56-58 A study attempting to find less toxic analogues of the antiturnour agent mitomycin C has been published, wherein a facile removal of a phenyl- seleno group with the soft carbon nucleophile dimedone resulted in easy access to demethylated analogues of mitomycin (Scheme 24).s9,60 4-Hydroxyanisole can be oxidised with copper in the presence of oxygen to a methoxyphenoxy ortho- quinone.Reaction with vinylazetidine displaces 4-methoxyphenol to give a azetidinyl quinone which can then be thermally rearranged ([3,3]-sigmatropic) Me 4v 0 Scheme 23 q/J+gNH2 NAc Meo%N; H H2;PhSe 0 i. dimedone, K&O3, MeOH i. dimedone, EbN, MeCN If. NHs Meotl, MecN NH 0 A 0 Scheme 24 OMe 0 .$ H Me OMe MeCN. rt, 61% OMe 0 toluene. 100 ‘C, 100% Me I OMe Scheme 25 to a tetrahydrobenzazocinequinone, a structure analogous to the natural pigment maesanine (Scheme 25).61 has prompted a search for novel quinolone The appearance of quinolone resistant bacteria Gallagher: The synthesis of quinones 439structures with antibacterial activity.Whilst attempting to synthesise analogues of 3-amino- naphtho-l,4-quinone-2-carboxylic acid a novel photochemical cyclisa tion of 2- hydroxyme t hyl- 3-dialkylaminonaphtho-1,4-quinones was discovered which provides novel dihydro-5,10-dioxo-1 H- naphth[2,3-d][ 1,310xazines in yields in the range 42-70% (Scheme 26).62 0 0 0 0 Me i. CAN, MeCN, rt ii. Hz. Pd(C), EtOAc lii. CH2b, Et@ iv. BBq, CH&12 I v. KOH Scheme 26 Scheme 28 Benzo- and naphtho-pyranquinones have remained targets for synthesis throughout the period of this review, Base catalysed cyclisations of ally1 alcohols to pyran derivatives with potassium tert-butoxide in DMP3 have been applied to the synthesis of both benzopyranquinones,M and to the naphthopyranquinones, ventiloquinones G and E (Scheme 27).65 OH 0 OH 0 i.K&03, MeI, acetone 0 OMe OMe Scheme 27 An alternative approach to the naphthopyran- quinone nucleus has been the addition of 1 -trimethylsiloxyfuran to acylnaphthoquinones to produce furonaphthofurans. These in turn have been oxidatively rearranged with CAN in aqueous acetonitrile to furonaphthopyrans and then converted to the antibiotic deoxyfrenolicin (Scheme 28).h6 Pyranquinones have themselves been used as precursors to anthracycline analogues of idarubicin. Thus acid catalysed cyclisation of hydroxy acetals followed by oxidation provides pyranquinones which on treatment with the lithium enolate of homoph thalic anhydride provides analogues of idarubicin which have antitumour activity (Scheme 29).67 *-1 0 COPH OPNB OPNB Scheme 29 Regioselective photoadditions between hydroxybenzoquinones and methyl vinyl ethers have been shown to produce benzofuran-4,7-diones in moderate yield (Scheme 30).68 between aminonaphthoquinones and methyl vinyl ethers when the products are 2,3-dihydro-l H - benz[ f]indole-4,9-diones in 45-82% yieldseh9 Two independent total synthesis of the potent antibiotics cervinomycins Al and A2 (Figure 1) have been rep~rted.""~ This type of photoaddition has also been reported 440 Contempora y Organic Synthesis0 I! Scheme 30 0 cewinomycin 4 Figure 1 Both syntheses relied on the introduction of ring A in the final steps of the synthesis but differed in their construction of rings B-G.The approaches adopted were, respectively, mild photolytic oxidation to form ring D in the presence of iodine and nucleophilic attack by methyl 4,5-dimethoxy- salicylate on a bromo quinone followed by reduction of the quinone and acylation to form ring F.Both syntheses required oxidative demethylation to produce the quinone ring E. 4 Synthesis of anthraquinones and ant hracyclinones Ant hraquinones and ant hracyclinones remain attractive targets for synthesis primarily because of their biological activity which includes antitumour, antibacterial, anti-HIV, anti-osteoarthritic and anti- Consequently many strategies have been attempted in the synthesis of anthraquinones and of these the most versatile has been the Diels-Alder reaction between halonapht hoquinones and silyl dienol ethers or silyl ketene acetals. Brassard and co-workers have now extended their extensive studies in this area with the reaction of cross- conjugated dienes with halo quinones." Thus at room temperature l-methoxy-3-[methoxy-(trimethyl- si1oxy)met hylene]-2,4-bis( t rimet hylsi1oxy)pent a- 1,4-diene was reacted with 5-acetoxy-2-chloro- naphthoquinone and after acidic hydrolysis produced a (methoxyacety1)anthraquinone in 38% yield (Scheme 31)." Also utilising the Diels-Alder route to anthra- quinones Kelly and co-workers have have taken a styrylanthraquinone and cyclised this under palladium catalysed stannylation conditions to give benzo[a]naphthacenequinone pigments G-2N and G-2A.82 Scheme 31 1.rt. 1 h I. HCI. WF. 38% I A cycloaddition strategy has been used in the synthesis of iminodaunomycinones. Thus acyl derivatives of lO-amino-9-hydroxy-l,4-anthra- quinone have been reacted with 1,3-bistrimethyl- siloxybutadiene in high yield and good regioselectivity. Removal of the acyl protecting groups and hydrolysis of the silyl enol ether adduct followed by addition of ethenyl magnesium bromide and subsequent mercuric sulfate mediated hydrolysis of the alkyne produced the iminodaunomycinones.R" Styrene derivatives have been also been shown to undergo thermal or ultrasound and Lewis acid catalysed cycloaddition reactions to benzoquinones. Thus 2-methylstyrene reacts with 2-methoxy- 3-methybenzoquinone to produce a dimethyl- methoxyphenanthra-l,4-quinone thereby assisting in the identification of naturally occurring phenanthra- quinones of the coleus and plectranthus species.@ The Diels-Alder route to anthraquinones has also found application in the synthesis of rhein (43 -di hydroxyanthraquinone-2-carboxylic acid) the active metabolite of the anti-osteoarthritic drug diacetyl rhein, together with other naturally occurring anthraquinones, e.g..aloe-emodin (Scheme 32) Cycloaddition of 2-hydroxymethylbuta-1,3-diene with a variety of quinones followed by oxidation to anthraquinone aldehydes has been reported. Anthraquinone aldehydes were required for 0 + c'fp C02Et 0 i. EtsN, CH& ii. 140 "c, 99% 1 iv. NaOH. H&, 85% iii. AICl3, CH&b, 85% HO 0 OH 0 Scheme 32 Gallagher: The synthesis of quinones 441incorporation into porphryins as models for the light-initiated charge separation which occurs in photosynthetic reaction centres.86 tumour and antibacterial properties and has as a consequence attracted much synthetic effort.One approach to the anthraquinone framework has been to ortho-lithiate a tetrahydrophenanthridine- carboxamide and to react this with 2,5-dimethoxybenzaldehyde (Scheme 33). The resultant phthalide is reduced to the acid and cyclised to the hydroxylated naphthophenanthridine. This is subsequently oxidised to the quinone with chromium trio~ide.~’ Angucyclines have recently attracted attention due to their biological activity, and a facile one step synthesis from spirocyclic naphthoquinones has been reported. Thus oxidative rearrangement of spirocyclic naphthoquinones with DDQ in benzene Dynemycin, an enediyne anthraquinone, has anti- EQN 9 OMe i.Bu’Li, TMEDA ii. TsOH, toluene, 2,5dimethoxybenzalyde, i. Zn. NaOH, H20, 08% ii. F A , CH&&, 93% I Me0 OH N g p Me0 OMe i. CrO3, H2S04, acetone, 58% ii. CrOs acetic acid, 5 W Me0 0 OMe 111 \. HO 0 0 dynemycin Scheme 33 O A HO 0 0 OH Scheme 34 benz[a]anthraquinones in moderate to good yield (Scheme 34).&? synthesis of anthraquinones Liebeskind and co-workers have reacted 2-trimethylsilyl-3-tributyl- stannylquinones with a range of chlorinated cyclobutenones in good yield (Scheme 35). The reaction is carried out under palladium catalysis and the reaction is presumed to procede via initial reaction between the tin and chlorine residues followed by thermal rearrangement to the benzannulated q ~ i n o n e . ~ ~ In what promises to be a widely applicable TBSO 0 TBSO 0 OTMS Ph 0 Scheme 35 i.NaH, THF, 55% ii. TFA, H20.93% iii. NIB, CsH6. 66% I 0 OH OH * OH 0 OH (-)-y-rhodornycinone Scheme 36 Rhodomycinones (Scheme 36) have become targets for synthesis because of their antitumour properties. A new quinone synthon has been introduced by Fujioka and co-workers who have 442 Contemporary Organic Synthesisexploited the facile addition of homophthalic anhydrides to this quinone. Subsequent rearrange- ment of the first formed tetrahydronaphthacene adduct (5,12- to 6,ll-quinone) and demethylation of the aryl methyl ether provided an economical synthesis of ( - )-y-rhodomycinone. The quinone synthon is formed from 5,8-dimethoxy- 1,2-dioxotetraline 1-[ (2 S , 3 S)-1,4-dimethoxy- 2,3-butylene]acetal by alkylation with ethylmagnesium chloride followed by acid hydrolysis. The resultant ketone is reduced and finally demethylated to produce (5 R,6R)-6-ethyl- 5,6-dihydroxy-5,6,7,8-tetrahydronaphtho- 1,4-quin0ne.~" related to rhodomycinone has been studied.Thus 4-deoxyaklanonic acid has been synthesised and biotransformed with mutant S727 of Streptomyces galileus to anthracyclinones. Homophthalate monoester is reacted with tert-butyl acetoacetate dianion and cyclised with acetic anhydride to produce a coumarin. The dilithio anion of acetyl- acetone produced the anthrone in 72% yieid and this was oxidised and esterified to produce an intermediate propionate, which was in turn rearranged with LDA to produce 4-deoxyaklanonic acid in 70% yield (Scheme 37)."l The biosynthesis of anthracyclinones structurally Y02Bu' u u p n AQO, 16 h, rt.57% ij C02Bu' I i. CuBr2, 02, 87% / ii. MeCHSOCI, DMAP, 82% C02H iii. TFA, 98% I iv. LDA, THF, -70 "C, 70% 0 I I % 0 O H 0 0 4-deoxyaklanonic acid Scheme 37 A rapid entry into the anthracyclinone ring system has been provided by the Diels-Alder reaction of trans-penta-l,3-diene with a benzoylbenzoquinone. Isomerisation of this adduct in pyridine produced the hydroquinone which under mild acid conditions was transformed to the naphthacenedione (Scheme 38).92 The first total synthesis of an angucycline related antibiotic has been published during the period under review. Angucyclines (typified by aquaymycin) n ?I\ 0 0 0 pyridine, 21 h, 94% I n Scheme 38 are a growing class of antibiotics and the synthetic approach to an aromatic analogue of aquaymycin commenced with a cycloaddition between an in situ generated siloxyfuran and an in situ generated benzyne derived from an iodotriflate.Subsequent oxidation with CAN produced a benz[u]anthra- quinone. The antibiotic was synthesised by an ortho glycosylation reaction on the deprotected MOM ether at the hydroquinone oxidation level followed by oxidation (Scheme 39).93 Related precursor aglycones of the angucyclines have been synthesised by cycloaddition between 5-hydroxynaphthoquinone and the silyl ketene acetal derived from ethyl 1 -cycl~hexeneacetate.~~ A similar approach to the construction of the carbon skeleton of angucyclines has been adopted by Krohn and co- workers but introduction of a pentamethyldisilane moiety early in their reaction sequence in the cyclo- hexene ring allowed photolytic conversion of the silane in the presence of oxygen to the tertiary alcohol required in the angucyclinones in the final steps of their One of the lesser known properties of certain anthraquinones is their ability to inhibit the progression of osteoarthritis; thus a synthesis of rhein which has allowed novel analogues of this anti-osteoarthritic has been reported.1,5-Dimeth- oxy-2-naphthaldehyde was converted to a butenoic acid with a novel phosphonate and cyclised to an anthracene ester with acetic anhydride. This was subsequently oxidised and hydrolysed to rhein (Scheme 40).78 been reported starting from phenylsulfonyl- phthalide. This was added to a bicyclic quinone in the presence of lithium terr-butoxide.Subsequent methylation and flash vacuum pyrolysis at 500 "C converted the extended bicyclic quinone to a anthra- 1,4-quinone (Scheme 41).97 A three step synthesis of anthra-1,4-quinones has Gallagher: The synthesis of quinones 443Meo*Me S02Ph s Scheme 39 0 p@--+J OTBDMS .Me + P O T f I MOMO I BuLi lflMe 1 MOMO OTBDMS CAN, MeCN, H20,76% I MOMO &Me \ 0 i. UOSu', -60 O C ii. K@s M e w 4 0 1 OMe 0 OMe 0 Scheme 41 I MgBr i. Etfi, 37% ii. LiAIH4, Etfi, 75% 0 Me0 MeO A@. NaOAc, 140 "c 4 h, 85% I HO 0 OH ii. 48% HBr, 23% C02H CO2Et 0 OMe Scheme 40 5 Synthesis of other polycyclic quinones Extended quinones have latterly been of interest because of their potential as organic semiconductors or as in electron acceptors in xerography." As a consequence of this, extended arrays of quinones have been synthesised.One of these is p-terpheno- Scheme 42 quinone and Boldt and co-workers have recently synthesised the tetra-tert-butyl analogue (Scheme 42). Thus the bis-Grignard derived from 1,4-dibromobenzene is reacted with two equivalents of 2,6-di-te1?-butylbenzoquinone followed by reduction and oxidation. The corresponding tetra- phenyl analogue was too unstable to be isolated.w The other major area of interest with polycyclic quinones is in the synthesis of biomimetic photo- synthetic model compounds. Currently porphyrin quinones are being studied where the quinone nucleus is oriented to allow the quinone access to the porphyrin. Such molecules have been synthesised in very low yield in a three component reaction with benzaldehyde and pyrrole and do display altered cyclic voltammetric properties in the presence of alkali metal ions (Scheme 43).lW A fourfold bridged porphyrin quinone cyclophane has also been constructed which completely capped a single face of a porphyrin." Complex arrays are now being studied with porphyrin monomers, dimers, trimers and tetramers linked to 444 Contemporary Organic Synthesisi.PhCHO, pyrrole, CH2CI2 ii. Chloranil, TFA. 4% 0 0 Scheme 43 q u i n ~ n e s . ' ~ - " ) ~ A range of 1,lO-o-benzeno- [2.2]orthocyclophane-o-quinones have been synthesised to evaluate the intramolecular charge transfer interaction between the donor, a dimethoxybenzene, and the acceptor, an o-benzoquinone. Orthocyclophane-o-quinones are synthesised by [4 + 41 cycloadditions of o-quino- dimethanes with anthracenes.1"6 6 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 L.M. Gayo, M. P. Winters and H. W. 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ISSN:1350-4894    

DOI:10.1039/CO9960300433

出版商:RSC    

年代:1996

数据来源: RSC