Synthesis highlights a review of the literature for 1998 8 Peter Quayle Department of Chemistry University of Manchester Manchester UK M13 9PL 1 Introduction This year saw the 170th anniversary of the .rst and often misrepresented synthesis of an organic compound. In his landmark paper of 1828,Wo� hler reported the serendipitous synthesis of urea from ammonium cyanate a reaction which incidentally takes place in both the solution and solid state. The solid state variant of this transformation —another .rst—has been the subject of much investigation but it is only with the advent of sophisticated X-ray di.raction techniques that a detailed picture of this reaction has come to be unravelled. Since Wo� hler’s investigations the practice of organic synthesis has increased exponentially both in terms of the degree of complexity and structural variation of targets under consideration.Such advances have been made possible by the ready availability of advanced analytical techniques (vide supra) and the realisation by Barton and others, that chemical reactivity with the non d-block elements at least can be correlated with constitutional and stereochemical features of a given molecule. That these principles are self evident is now witnessed by the fact that the interplay between mechanism and stereochemistry provides the cornerstone for most modern texts on the subject. Indeeed it is almost impossible to underestimate the in.uence of Barton on the development of contemporary organic chemistry. Because of the central importance of the principles of conformational analysis exceptions to the often quoted textbook guidelines are continually being searched for.A recent example concerning the identi.cation of ‘‘completely stable axial conformers of monosubstituted cyclohexanes at room temperature’’ appears to be fallacious. The remarkable pace at which the total synthesis of even complex structures can be accomplished has continued this year. In addition the application of combinatorial techniques means that the synthesis of analogues of natural products with potentially interesting biological pro.les can be accomplished relatively rapidly in certain cases. This situation is clearly exempli.ed in the synthesis of structural analogues of the epothilones 1 and derivatives 2 as outlined by Nicolaou. In terms of advances in synthetic methodology the development of a family of catalysts which enable the clean metathesis of functionalised ole.ns has elicited numerous applications the synthesis of ole.ns in this manner has started to rival more conventional methodology such as the Wittig reaction and must rank among one of 235 Annu.Rep. Prog. Chem. Sect. B 1999 95 235—263 O O S S n HO HO N N O O O O O O OH 1 epothilone A OH 2 n = 1 [14]epothilone A n = 2 [15]epothilone A n = 3 epothilone A n = 4 [17]epothilone A n = 5 [18]epothilone A the most important developments of the decade. The observation that readily available yet usually relatively inert aryl chlorides can be coaxed to undergo Heck Stille and Suzuki reactions under mild conditions merely by judicious choice of ligand will serve to widen the use of these reactions further whilst synthetic applications of polymerbound and solid supported reagents and reactions seemingly show no limit. 2 Brevetoxins and related compounds The development of e.cient strategies for the synthesis of medium-ring ethers polyfused ethers and spirocyclic hemiacetals continues to be the focus of much attention.A number of natural products notably toxins of marine origin such as the brevetoxins and ciguatoxins non-terpenoid C -metabolites derived from fatty acid metabolism such as dactoelyne the bryostatins and the spongistatins possess interesting biological pro.les (e.g. modulation of sodium transport or antineoplastic activity) but their low natural abundance precludes a full evaluation of their pharmacology hence the synthesis of the natural products themselves or analogues thereof is pro.ered as a rationale for many of these investigations.Parsons and Ibuka have reported complementary approaches to the synthesis of furanopyrans which utilise di.erent facets of the chemistry of sulfur to e.ect cyclisation. In the .rst example an allenyl sufoxide is used in a tandem intramolecular Michael reaction whilst the second example utilises the redox chemistry of cyclopropyl sul.des to generate a sulfur stabilised cation which su.ers intramolecular capture with a pendent hydroxy moiety (Scheme 1). New approaches to the synthesis of fused polyether motifs—all of which utilise metathesis chemistry—have been disclosed by the groups of Rainier, Hirama and Clark. Rainier’s route employs Danishefsky’s procedure (DMDO) for the stereoselective epoxidation of a suitably functionalised unsaturated sugar derivative followed by regio- and stereospeci.c ring opening with allylmagnesium bromide in THFto a.ord the alcohol 3.Acylation of the free hydroxy group of 3 Takai methylene transfer (CH Br /Zn/TiCl /PbCl ) followed by a ring closure metathesis reaction (RCM) using the molybdenum catalyst 4 a.orded the bicyclic enol ethers in respectable overall yield (ca. 50%) Scheme 2. This procedure can be performed in an iterative sense leading to the synthesis of tricyclic systems in a relatively rapid sequence this 236 Annu.Rep. Prog. Chem. Sect. B 1999 95 235—263 OTBS HO SPh OTBS Ph(O)S O (ii) (i) • O OTBS H OTBS Cl H SPh OMe O OMe OMe (iii) Cl + O OH O OH O H 33% 34% (iv) 51% Scheme 1 Reagents (i) PhSCl Et N Et O (94%); (ii) HF (aq.) CH CN 60 °C (49%); (iii) CAN Me NCl 3Å MS MeOH; (iv) p-TsOH PhH. Scheme 2 Reagents (i) DMDO CH Cl ; (ii) CH ——CHCH MgBr THF; (iii) Ac O; (iv) CH Br Zn TiCl PbCl ; (v) (RO) Mo(—— NAr)——CHCMe Ph (4); (vi) NBS H O—DMF; (vii) KH. study was restricted to the synthesis of pyran systems only. A potential limitation of this variant lies in the initial Takai ole.nation step in that its e.ciency is dependent in an empirical sense upon the precise reaction conditions employed.Hirama’s study clearly indicates that polycyclic ethers can be prepared in a convergent manner where the .nal carbon—carbon forming step is again an RCM reaction whose e.ciency is relatively insensitive to the ring size being generated (seven- to ten-membered rings in yields ranging from 68—94%) Scheme 3. Clark has also demonstrated that function- 237 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 O OBn O O H OBn O O H H (i) 90% O O H H O H H O (ii) (iv) H H H H O O O O O O H H O H H O (iii) 94% (iii) 81% H H H O O O O H H H O H H H O Scheme 3 Reagents (i) (a) CH O H H H O —— CHMgBr THF,78 °C 80%; (b) Et SiH BF ·OEt CH CN 71%; (c) —— CHCH MgBr THF Et O; (b) Et SiH BF ·OEt ; (ii) (a) Li C H THF 91%; (b) (COCl) Et N DMSO CH Cl 78 °C; (c) Ph PMe Br NaHMDS THF 83%; (iii) (PCy ) Cl Ru——CHPh (cat.) PhH 70 °C; (iv) (a) CH Li C H ; (d) (COCl) Et N DMSO CH Cl ; (e) Ph PMeBr NaN(SiMe ) .(i) PCy3 Cl Ru H H CH3 CH3 O PMB O Cl PCy3 Ph PMB steps O O O O 86% H O O H H H CH3 H H Scheme 4 Reagents (i) CH CH3 Cl (0.01 M) 20 °C 12 h. O alised seven- and eight-membered cyclic ethers can be prepared using RCM reactions on highly oxygenated templates Scheme 4.In a somewhat di.erent approach to the synthesis of linearly-fused polytetrahydropyrans Sasaki and Tachibana have shown for example that the carbohydrate-derived vinyl tri.ate 5 undergoes Suzuki coupling with the alkyl borane 6 to a.ord enol ether 7. Oxidation of 7 (hydroboration —Swern sequence) followed by intramolecular hemiacetal formation and then (stereoselective) ionic reduction (Et SiH BF ·OEt ) a.orded the pentacyclic system 8 as a single diastereoisomer in six steps from 5 and 6 Scheme 5. Endocyclisation of enol 238 Annu. Rep. Prog. Chem. Sect. B 1999 95 235&mdash H OTBS O H H O (i) O + 66% B OTf O O H H H H O 6 5 TBS H H H O O O (ii) (iii) O 82% O O O H H H H 7 O O H H OTBS H H H H H H O O O O (iv) (v) OAc O (vi) OAc O O O O 75% O H H H H H H H H 8 Scheme 5 Reagents (i) Cs CO PdCl (dppf) KBr Ph As DMF rt; (ii) (a) ThexylBH THF 0 °C; (b) H O NaOH; (iii) (COCl) DMSO Et N; (iv) CSA CH Cl MeOH; (v) Ac O py rt; (vi) Et SiH BF ·OEt CH Cl ,10 °C. ethers, cobalt-complexed propargylic alcohols and -alkoxy epoxides also gives relatively easy access to a variety of medium-ring ethers Scheme 6 whereas stereoselective 7-exo-trig radical cyclisations have been put to good e.ect in the synthesis of the oxepane ring system present in ciguatoxin, Scheme 7.A crucial step in Yamamoto’s recent synthesis of hemibrevetoxin B requires the installation of the fused oxepane C and D rings which relies upon two sequential stereospeci.c intramolecular alkylation reactions.Remarkably in both cases cyclisation occurs cleanly upon exposure of the respective stannyl-aldehydes to BF ·OEt at 78 °C .nally a.ording the stereochemically homogenous tetracyclic intermediate 9 (94 and 98% isolated yield respectively for cyclisation steps). Mori has also developed an iterative strategy for the introduction of the C and D rings of hemibrevetoxin B. In this rather unusual example oxiranyl anions of the type 10 serve as synthetic equivalents to hypothetical dipole 11 Scheme 8. The coup de gra� ce in the area this year must be Nicolaou’s synthesis of brevetoxin A a molecule possessing 10 rings (from .ve- to nine-membered) and 22 stereogenic centres on a skeleton comprising 44 carbon atoms.This convergent synthesis uses readily available chiral pool materials—.-glucose and .-mannose—as sca.olds for the elaboration of the ABCDE and GHIJ rings respectively. In the crucial union of these two fragments reaction of the anion derived from the phosphine oxide 12 with the aldehyde 13 a.orded a 1 1 mixture of diastereoisomeric adducts which on exposure to KH in DMF produced the Z-ole.n 14 in 72% yield. Ring closure of the alcohol 14 to 15 (80% yield) was accomplished by treatment with Ag followed by ionic reduction Scheme 9. 239 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 OH Br PF6 N 2 74% (i) (i) Br PF6 N OMe 2 31% Co2(CO)6 AcO O 3 OH AcO O 2 O OH H AcO H H OTBS O O HO O OBn H O Scheme 6 Reagents (i)CH O CH 15 h. Cl ; (ii) (a) 4-O NC H CH OH; (b) CH ——CHCH SiMe BF ·OEt ; (c) CF CO Ag H O—MeNO ; (d) Ph PCH OMe; (iii) TFOH Cl 20 °C; (iv) H 5% Rh/C EtOH 60 °C; (v) Eu(fod) toluene 80 °C OH H 3 Bryostatins The bryostatins present another signi.cant challenge to the synthetic chemist both in terms of advancing the art of synthesis itself and producing compounds for biological testing.Bryostatin 1 has entered Phase II clinical trials for the treatment of melanoma non-Hodgkins lymphoma and renal cancer.However it is likely that the development of therapeutic agents from these compounds will only be possible if much simpli.ed and more accessible semi-synthetic or wholly synthetic analogues can be identi.ed. Encouragingly not only was there a total synthesis (Evans et al.) of bryostatin 2 (16) 240 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 OMe OMe O O (ii) 74% Br OH Br OMe O 2 O OH (iv) (iii) H 66% 52% AcO OAc Co(CO)6 OTBDPS (v) H H OTBS O 38% OTBDPS O O H O OBn H O O steps OHC O A B C HO Hemibrevetoxin B Scheme 7 Reagents (i) i-Bu AlSePh toluene,20 °C; (ii) n-Bu SnH (2 equiv.) Et B (catalyst) benzene rt; (iii) BF ·OEt CH Cl 78 °C. H H O O H O OTBPS H H O O H SePh O O H OMOM CO2Me Me OH H H H O D O H H O Me H TIPSO TIPSO TIPSO TIPSO Annu.Rep. Prog. Chem. Sect. B 1999 95 235—263 H (i) 92% O H (ii) 87% O H O H C O H TIPSO 94% H O H C O H TIPSO H H O H C O H TIPSO 98% H O H C O H TIPSO 9 O O H SePh TBPSO OH H H O H O O H H H CO2Me OMOM SnBu3 H O CHO 3 (iii) H H O C OH 3 steps H CHO O C O SnBu3 3 (iii) CH3 H H OH O D C O H 3 241 Me HO H 40 H Me Me O H H O H H O H H H 45 O O I O 30 5 1B0 H 15 H 20 E OH H O H 35 H A O D J H O 2 O H H G O H C O 55 HO OHH 50 F O H H 25 H M HO K H Me L Me OH ciguatoxin (CTX1B) OBn CH3 OTES OTBDPS (i) O + OTf BnO 90% Li SO2Tol O H H OBn OBn H CH3 (ii) O OTES CH3 OTBDPS 90% BnO BnO O O OTBDPS O O H CH3 CH3 O O SO2Tol 10 11 Scheme 8 Reagents (i) THF—HMPA,100 °C; (ii) p-TsOH CHCl 0 °C. Me H Me O B O H A C O Me O H H D H H H O O H OH E F H Me H H O O H H I J G O H O O O H H H brevetoxin A this year but also a report from the Wender group concerning the synthesis of simpli.ed bryostatin analogues which possess signi.cant antitumour activity in vitro.Evans’s synthesis of bryostatin 2 utilises sequential aldol-reduction sequences to set the stereochemistry and oxidation level in the three subunits which comprise the A B C rings. Connection of these fragments was accomplished using Julia—Lythgoe 242 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 (a) Lactonization Me Conjugate addition H Me O Lactonization B H O A C O Me O H H D H Horner-Wittig coupling H H O O H Epoxide opening OH bis- Lactonization E F H Me H H O O H H I J G O H O O O Dithioketal cyclization H H H Epoxide opening OH O Dithioketal cyclization HO OH HO OH D-glucose OH O OH HO Me Me PPh2 OH HO H M e H O H H O B C D O OM e O D-mannose TBDPSO E O O H H H H H TrO + BCDE ring system OHC OTBS 12 H H Me H O O H I J G EtS EtS OTBDPS O O H H H GHIJ ring system (i) 13 72% Scheme 9(a) For reagents see part (b).14 reaction (C16—C17; E:Z95 5) sulfone alkylation (C9—C10) whilst macrolactonisation was achieved in excellent yield (81%) using Yamaguchi’s procedure Scheme 10. Of crucial importance in the synthesis of the bryostatins is the stereocontrolled installation of the exocyclic enoate moieties at C13 and C21. In this approach this problem was tackled relatively late on in the synthesis the enoate moiety at C13 was accomplished in high yield (93%) but with moderate stereoselectivity (Z:E86 14) using a Wittig reaction between ketone 17 and Fuji’s chiral phosphonate 18.The 243 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 Me (b) 12 + 13 H Me TBDPSO B O H (i) 72% C TrO Me O H H D H H O H O H OTBS E EtS H Me H H O O H I J G H EtS OH OTBDPS O O Me H H H 14 H Me TBDPSO B O H (ii) 70% C HO Me O H H D H H H O O H OTBS F H Me H H O O H H I J G O H OTBDPS O O H H H 15 Scheme 9(b) Reagents (i) (a) n-BuLi THF,78 °C; (b) KH DMF; (ii) (a) AgClO ; (b) m-CPBA; (c) Et SiH BF E ·OEt . Me Me HO OR MeO2C O O O OH O OH O H Me Me M e O H O O Pr CO2Me bryostatin 1 R = Ac bryostatin 2 R = H ienoate at C21 was introduced in a two-step aldol dehydration-sequence a.ording the desired product 19 in 54% isolated yield (E:Z12 1).The carbonyl at C20 not only served as a control element for the stereocontrolled introduction of the enoate at C21 but also underwent reagent controlled reduction to a.ord 21 with the correct S 244 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 (a) 7 13 MeO2C O M e M e HO OR7 B A 9 O O 1 O 16 OH O OH O H Me Me C M e M e MeO OPMB B A 9 O 20 1 Me Me O 20 M e O 26 H O Pr CO2Me 16 TBSO 13 16 10 PhO2S (–) B O R3SiO 13 16 H (+) O LG (+) (–) O Me Me C SO2Ph 17 20 Bryostatin retrosynthetic analysis Scheme 10(a) absolute stereochemistry (dr10 1). Completion of the synthesis from this point employed standard deprotection and functional group manipulations.As a corollary to these studies the Wender synthesis of the bryostatin mimic 25 deserves mention. In this investigation extensive molecular modelling studies indicated that the A and B rings of the bryostatin framework could be dispensed with and be replaced with a much simer ‘‘spacer unit’’. Hence the fragment 22 was coupled to the alcohol 23 using the Yamaguchi protocol deprotection of the ketal 24 followed by a rare example of a ‘‘macrotransacetalization’’ followed by deprotection of the C26 hydroxy a.orded the bryostatin analogue 25 in moderate to good yield (56—88% two steps) Scheme 11. Cyclisation in this manner—presumably under conditions of thermodynamic control—a.orded 25 as a single diastereoisomer at C15 in which the side chain adopts an equatorial disposition with respect to the dioxolane ring.4 Acetogenins At this juncture mention should also be made of Marshall’s strategy for the synthesis of bis-tetrahydrofuran acetogenins. In the crucial step of this approach treatment of the aldehyde 26 with the optically pure stannane 27 in the presence of InCl a.orded Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 7 O TBSO O O C Me 26 OPMB M e M e 9 A O OPMB 1 CONHR TBSO OTBS Me 26 OPMB 245 ·SMe . Scheme 10(b) Reagents (i) NaHMDS THF 78 °C then 18; (ii) KHMDS THF 78 °C; then OHCCO Me,78 °C Et NSO NCO Me; (iii) 20 BH the anti-allylic alcohol 28 (86% yield).Conversion of 28 into the aldehyde 29 followed by treatment with the allyl stannane 30 this time in the presence of BF ·OEt a.orded the syn adduct 31 in 92% isolated yield. Double cyclisation of 31 followed by chain extension to 32 using standard methodology completed the synthesis Scheme 12. 5 Altohyrtin (spongistatin 1) A number of complex natural products containing the spiroketal motif have been synthesised this year including calyculin C, oligomycin C, and spongistatin 1 (altohyrtin A). The synthesis of altohyrtin A (spongistatin 1) a potent antitumour agent isolated 246 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 Cl rt; (b) Pd(OH) /C H . Scheme 11 Reagents (i) 2,4,6-(O N) C H COCl Et N PhCH rt; (ii) (a) Amberlyst- 15 CH from marine sponges presents a daunting task.The molecule is made up from a 51-carbon chain which incorporates six pyran rings—four of which are embedded in two isolated spiroketal units a 42-membered lactone ring and a novel chlorodiene moiety. Until this total synthesis was accomplished there was some debate as to a number of stereochemical issues which highlights the (bene.cial) symbiotic relationship between synthetic and natural products chemists alluded to in the introductory section. Approaches to this class of compounds have aroused considerable interest amongst the synthetic community as illustrated by recent publications from the groups of Nakata, Crimmins and Paterson. Nakata’s and Crimmins’ work (Schemes 13 and 14 respectively) is primarily associated with the construction of the spiroketal fragments (C1—C14) from either tri-O-acetyl-.-glucal or readily available pyrone 247 Annu.Rep. Prog. Chem. Sect. B 1999 95 235—263 Scheme 12 Reagents (i) InCl ; (ii) BF ·OEt . intermediates respectively. Paterson describes an aldol strategy for the union of the A/B and C/D spiroketal moieties Scheme 15 which enables the direct introduction of the stereocentres at C15 and C16 in high yield but with modest stereochemical control (84% yield; 67% ds). Kishi’s synthesis of spongistatin 1 is a masterly execution of synthetic planning and utilises a number of reactions which are of growing importance in contemporary organic synthesis Brown allylations for the synthesis of highly versatile allylic alcohols 248 Annu.Rep. Prog. Chem. Sect. B 1999 95 235—263 OAc O OTr OBn 10 steps AcO OAc (iii) Ph O S OTBS O O Me 85% S steps OTBS OPiv OBn O Me OPiv OTBS Me O O HO 1 OMP Scheme 13 Reagents (i) 1,3-Dithiane n-BuLi HMPA 20 °C; (ii) IBX DMSO—THF rt; (iii) (a) n-BuLi HMPA THF; (b) epoxide; (iv) (a) H Pd/C EtOAc rt; (b) CSA CH 1 Me Me O 15 16 14 OR3 OMe 19 C O HO O 33 41 M e M e O F E O OH H OH HO R1 R3 R2 Ac Ac Cl Cl —MeOH (1 1) rt. Me HO B O A D 7 O 23 O R2O 5 O HO OH 50 47 R1 spongistatin 1 Annu. Rep.Prog. Chem. Sect. B 1999 95 235—263 (i) (ii) OTr OBn O S O 96% S OBn OMP Ph OTBSS S O O OBn OH OMP Me (iv) OMP OH OBn 71% Me O 14 OTBS Me O O TESO 1 OMP 249 O O CH3 (ii) (i) 55% 73% OTHP OH O O + OTHP OHC O O H (iii) O O O O 82% OTIPS OTIPS Scheme 14 Reagents (i) LiHMDS THF 78 °C; (ii) (a) TIPSOTf CH Cl ; (b) MeOH PPTS; (c) CF CO H PhH; (iii) CH ——CHMgBr CuBr·Me S. Scheme 15 Reagents (i) LiTMP LiBr THF 78 °C 30 min; (ii) (a) 2 min; (b) AcOH. 250 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 Scheme 16(a) in high ee’s the use of indium reagents and the Nozaki—Kishi reaction for the formation of carbon—carbon bonds in highly complex substrates. His retrosynthesis Scheme 16 splits the target into two fragments C1—C28 33 and C29—C51 34.It was envisaged that coupling of C28 and C29 could be achieved by way of a Z-selective Wittig reaction whilst macrolactonisation installing the O41—C1 bond would be tackled towards the end of the synthesis anticipating that competing cyclization routes e.g. via an unprotected—OH at C-38 would not be observed. Fragment 33 was further disconnected into the vinyl iodide 35 and the aldehyde 36. The 251 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 Scheme 16(b) For reagents see part (c). Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 252 42 + 41 (c) (i) O 28 H O D TBSO MeO 1 MeOCH2CO2 H H O A O AcO B Me OH 43 O H O HO HO (iii) H O H Me H O O AcO Me OH 45 Spongistatin assembly of ABCD fragment Scheme 16(c) Reagents (i) (a) NiCl odinane 83%; (ii) (a) PPTS acetone—H HF—py THF 82%.Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 OMPM OMe TBSO HO 19 (ii) H O Me H O O 15 Me AcO OAc Me OH OMPM OMe HO HO H O H O O A Me B AcO OAc Me OH 1:1 —CrCl THF 86%; (b) Dess-Martin peri- O; (b) Triton-B MeOH—MeOAc 50%; (iii) OMPM 27 O H O OMe 21 19 O O H Me Me OAc 44 OMPM O H O D OMe C O O H Me Me OAc 46 253 OHC OTIPS 47 OTIPS OH 48 steps OTIPS OHC 50 Brown allylation 74% O (iii) O 100% 53 Scheme 17 Reagents (i) ()-Ipc -(Z)-crotyl boronate THF 78 °C; (ii) (a) NMO OsO ; (b) NaIO ; (c) diketene—acetone adduct; (d) ; (iii) DMDO CH Cl .254 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 OH (i) OTIPS 65% OTIPS Me (ii) OTIPS 54% O H OTIPS E O H OTIPS OH 51 OTIPS O O CH3 CH3 O O 54 I Construction of ring E OTIPS Cu(Me)(CN)Li2 Spongistatin construction of ring F steps OTIPS steps OTIPS 49 O OTIPS OTIPS 52 OTIPS H O F OTIPS OH 55 (a) Me Me O O (i) 85% 37 I TIPSO 51 Cl steps 51 Cl Scheme 18(a) Reagents (i) In CH ——C(Cl)CH Cl NaI DMF; (ii) (a) Martin’s sulfurane CH Cl ; (b) HF—py; (c) DMSO CH Cl Et N; (iii) LDA THF HMPA Cl —H O; (b) KF MeOH; (c) Et N 2,4,6-Cl C H COCl 5 °C; (iv) (a) DDQ CH PhMe 50%.OTIPS O OTIPS H OH 55 OTIPS Cl OH 57 Introduction of chlorodiene unit (C48-C51) OTIPS Me 29 O H 59 CHO Me H O H OMPM OMPM 58 78% MeO HO TBSO H 62 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 steps TIPSO OHC OTIPS (ii) 51 89% Cl OTIPS O BrMg OTIPS H HO 38 H O TIPSO H Cl OMPM 61 OTBS Me 29 O P+Ph3I– H H Me O OMPM OMPM OTIPS O OMPM H OMPM 56 CHO O F OMPM OMPM 58 OTIPS 60 OTIPS Me O OTIPS H Me OMPM (iii) 63 40% 255 (b) Cl 50 Cl 256 Annu.Rep. Prog. Chem. Sect. B 1999 95 235—263 62 (iii) 40% OTBS Me MeO HO O H H Me O TBSO H 41 OMPM TBSO 1 OMPM CO2TBDPS H H O O AcO 10 OH Me 63 (iv) OR Me HO HO O 30 H H 40 Me O RO H RO O OH O H H O O AcO 10 OH Me 63 Spongistatin final coupling sequence Scheme 18(b) H O OMe O O H Me Me OAc H O OMe 20 O O H Me Me OAc OH (a) Cl O O 6 2 4 OH HO O O HN X O HN NHMe HN H H O NH NH O O CH2CH(CH3)2 O NH 5 HO2C NH2 7 OH OH HO Oallyl OH O F 6 4 2 HO HO NO O X = Cl vancomycin aglycon X = H eremomycin aglycon 2 HN Cl O HN HN H H O NH O O NMeBoc O NH O O 5 CH2CH(CH3)2 NHDdm MeHN 7 OBn OBn BnO NO Oallyl NH 2 F O 6 6 4 HO X OH HN HN Cl O HN H H NH OH 2 H H O O O NH NH 5 5 HO2C HO2C 7 7 OH OH OH OH HO HO Vancomycin/eremomycin retrosynthetic analysis Scheme 19(a) C1—C12 fragment was prepared from the epoxide 37 using well developed epoxideopening chemistry whilst C13—C17 was prepared from the known alkene 38.These two fragments were joined together by ring opening of the epoxide 39 with the cuprate derived from the iodide 40. Standard functional group manipulations then a.orded the pivotal intermediate 41 which was coupled with the vinyl iodide 42.A key sequence in this synthesis was formation of the C17—C18 bond using the Nozaki—Kishi Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 Oallyl OMs HO 4 O HN NHBoc O 257 (b) X X (X = H Cl) F F 6 6 OH OH O O O2N 2N H NHR O N O i NHR O NH O 65% NH OBn OH NH O MeHN 5 MeHN 5 7 7 OMe MeO OMe OMe OMe MeO 65 66 Biaryl synthesis oxidative coupling sequence BF ·OEt AgBF TFA—CH Cl 0 °C; (b) Scheme 19(b) Reagents (i) (a) VOF NaHB(OAc) . reaction which in this instance a.orded a mixture of diastereoisomeric alcohols (at C17) in 86% yield. Oxidation of this mixture of alcohols to the ketone 43 deprotection of the C23-OH group followed by base-catalysed conjugate addition a.orded the spiroketal fragment 44.It should be pointed out that when cyclization was attempted with a protected hydroxy at C26 then the wrong epimer at C23 was obtained as the sole product (44). However in the case where cyclization was conducted with a free hydroxy group at C26 then a separable 1 1 mixture of spirocycles 45 and 46 was obtained. With theABCD fragment 46 in hand preparation of C29—C51 coupling and cyclisation was attempted. It is tempting as others have done in connection with developing approaches to the spongistatins to prepare the tetrahydropyranyl residues such as the E and F rings from carbohydrate precursors. Oftentimes such a strategy may be cumbersome and a more convergent route from non-carbohydrate precursors should be considered.The key intermediate 48 required for the ring E fragment 34 was in this case available in 64% yield (90% ee) from the aldehyde 47 via two consecutive Brown allylation reactions (Scheme 17). Transformation of 48 to the iodo glucal 49 was accomplished using established chemistry. The precursor 51 to the ring F fragment 55 was also prepared using Brown’s allylation chemistry starting from the aldehyde 50 intermediate 51 was prepared in 74% yield (90%ee) from 50 which then transformed into the glucal 52. Stereospeci.c oxidation of 52 and ring opening with the cuprate 54 a.orded 55 in 70% yield. At this juncture a route to the introduction of the novel chlorodiene fragment (C48—C51) was sought.Conversion of the acetonide 55 to the aldehyde 56 then enabled coupling with the organoindium reagent derived from 2,3-dichloropropene a.ording epimeric alcohols 57 which were dehydrated (Martin’s sulfurane; 85% yield for the two step alkylation dehydration sequence) and converted to the aldehyde 58 Scheme 18. Coupling of 58 with a nucleophilic organometallic reagent derived from the iodide 59 was then investigated an obvious contender (especially from this group) being the the Nozaki—Kishi procedure. Unfortunately although coupling of 58 with 59 using Cr(..)/Ni(..) worked well the undesired epimer was produced as the major product. However treatment of the organomagnesium reagent 258 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 CO DMSO rt; (ii) CsF DMSO rt.Scheme 20 Reagents (i) Na Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 259 Diels-Alder + N N + 70 O N Diels-Alder N NH OMe 72 O (ii) HO 100% CO2Me OAc (iii) 22% HO OCOC6H4NO2-p 75 Scheme 21 Reagents (i) MeOH pH 7.3; (ii) MeOH rt 6 days; (iii) (a) Hg(OTf) CH CN rt; (b) NaCl. 260 Annu. Rep. Prog. Chem. Sect. B 1999 95 235—263 N (i) 0.3% N 71 HN H OMe N N O steps O O NH HNN O 73 MeO2C H H CO2Me O H HO2C H 74 OAc H O HgCl 76 , 60 with the aldehyde 58 under conditions of chelation control a.orded the desired product 61 in 78% yield. Completion of the synthesis involved Wittig coupling of the aldehyde 33 with the phosphorane derived from 62 which a.orded the Z-alkene 63 (40%) which on deprotection followed by macrolactonization using the now standard Yamaguchi’s procedure selectively a.orded the 41-membered ring lactone 64 Scheme 18.Completion of the total synthesis validated the structure put forward by Kitagawa in preference to that pro.ered by Pettit and Fustani. 6 Vancomycin Arguably the notion that natural products such as the erythromycins are derived biogenetically by way of aldol-type chemistry initiated a mammoth e.ort to replicate these reactions in the laboratory. Progress in recent years indeed has been impressive as illustrated by Evans’ synthesis of 6-deoxyerythronolide B and oleanolide which utilises essentially four bond constructs stereoselective aldol reactions diastereoselective epoxidations and reductions.A somewhat di.erent situation regarding stereochemical control is apparent when planning synthetic routes to targets such as vancomycin and erenomycin members of a large family of antibiotics which have an arylglycine heptapeptide core. These antibiotics are of considerable medicinal value due to their e.cacy against Staphylococcus aureus infections. The added complication here is that in the case of vancomycin for example there are three additional elements of atropoisomerism to be considered due to hindered rotation about the two aryl ether moieties (rings 2—4 and 6—4) and the biphenyl residue (rings 5—7). Hence even if the peptide chain was constructed in an enantiomerically pure state the problem which then arises is how to prepare one of the possible eight atropodiastereoisomers.This problem has been addressed by two groups this year, culminating in the total synthesis of the vancomycin and erenomycin aglycons. The strategic bond constructs in these syntheses rely upon relatively standard oxidative and Suzuki biaryl coupling reactions for the union of rings 5—7 and S Ar chemistry to e.ect formation of the aryl ether links between rings 2—4 and 4—6 Scheme 19. In the case of Evans’ synthesis for example whilst the oxidative coupling (VOF ) of 65 to 66 a.orded the unnatural R atropodiastereoisomer (dr95 5) subsequent formation of the ether linkage between rings 4 and 6 (intramolecular S Ar) and atropoisomerization (MeOH; 55 °C; 24 h) a.orded 69 with the desired S biaryl con- .guration.In this particular synthesis a second diastereoselective synthesis (dr5 1; major isomer having natural R con.guration) completed the synthesis of the core structure. Cyclisation at this stage appeared to proceed with no epimerization at the other centres and the major diastereoisomer possessing the correct natural product stereochemistry could be isolated by column chromatography in 80% yield Scheme 20. It is apparent that the stereochemical course of the biaryl and aryl ether coupling reactions is dependent on a subtle interplay between a number of factors including the thermodynamic bias dictated by the global structure as well as those emanating from proximal stereochemical interactions. 261 Annu.Rep. Prog. Chem. Sect. B 1999 95 235—263 7 Potpourri A number of reports concerning ‘‘biomimetic’’ approaches to natural product synthesis have been disclosed this year (Scheme 21). A biomimetic synthesis of keramaphidin B (71) utilising an intramolecular Diels—Alder reaction of 70 has been reported by Baldwin. Although the yield of the key uncatalysed reaction is low (ca. 0.3%) it clearly validates Baldwin’s earlier suggestion concerning the biosynthesis of the manzamines. Along similar lines Williams has developed a synthesis of brevianamide 73 from the indole derivative 72 whilst Whitehead has reported a ‘‘predisposed’’ approach to the manzamenone 74. 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