The enediyne and dienediyne based antiturnour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 2 HERVE LHERMITTE and DAVID S. GRIERSON* Institut de Chimie des Substances Naturelles, F-91198 Gifsur-Yvette, France Reviewing the literature published up to 15 November 1995 Concluding the coverage which commenced in Part 1, Contemporary Organic Synthesis, 1996, 3, 41 1 2 3 4 4.1 4.2 4.3 5 5.1 5.2 5.3 6 7 Introduction Approaches to the total synthesis of the neocarzinostatin chromophore Nine-membered enediynes: kedarcidin and The total synthesis of calicheamicinl esperamicin Central core structure Synthesis of the glycone Total synthesis of ( - )-calicheamicin ylI Dynemicin analogues and the total synthesis of dynemicin A A-ring 'biomimetic' approach Anthraquinone 'platform' assembly Nor-D,E dynemicin analogues: the total synthesis of dynemicin A Conclusion References and notes C- 1027 1 Introduction The discovery and structure elucidation of the highly potent antitumour antibiotics neocarzino- statin 1,' calicheamicin yll 2,* esperamicin Al 33 and dynemicin A 44 (Scheme 1) created a wave of Me I MeO OH MeHN HO neocarzinostatin chrornophore 1 \ ? I HO 2 calicheamicin-y: R' = H, R2 = Et, R3 3 esperamicin-Alb R' = 0, R2 = Pr', R3 = Me M e o y O OH 0 wonder and amazement amongst scientists as to the neverending power of nature to innovate in the constitution of complex multifunctional molecules, and the mechanism through which they exert their biological activity.Antibiotics 1-4 associate with their intracellular target DNA and are converted to high energy diradical species which effect single and/or double strand cleavages through hydrogen abstractions from the deoxyribose ba~kbone.~ These multistep processes are unprecedented.In response to this stimulus, the chemical community quickly set out to demonstrate that modern synthetic methodology and thinking could rise to the C02H OMe OH 0 OH dynernicin A 4 Scheme 1 Lhermitte and Grierson: Enediyne based antitumour antibiotics. Part 2 93challenge that efficient construction of these sensitive and complex molecules represents. In part 1 of this review,6 an overview was given of the research that was initiated to synthesize simpler, more readily accessible enediyne-dienediyne systems and to examine their capacity to undergo Bergman or Myers type cycloaromatization7~R to diradical and polar intermediates.intense efforts to attain the natural products themselves by total synthesis. To date, significant progress has been made to construct the labile core structure of neocarzinostatin 1 and esperamicin 3, and two successful approaches to the aglycone of calicheamicin have been developed. Several routes to the sugar components of 2 and 3 have similarly been devised, and through the coupling of advanced intermediates to both the aryl tetrasaccharide of calicheamicin and its aglycone (calicheamicinone) both Nicolaou and Danishefsky have achieved the total synthesis of natural (-)-2. A considerable body of work has also gone into constructing simplified bioactive analogues of dynemicin A 4, and these efforts have formed a solid basis for the two syntheses of this enediyne antibiotic that have very recently appeared.A description of these ground breaking achievements, in conjunction with many other approaches and strategies that are under development for the total synthesis of the enediyne- dienediyne antitumour antibiotics is given here in Part 2 of this review. Concurrent with these studies, have been equally i. EtMgBr, CH20 ii. - 0 PdO-CuI 0 ~ ~ s - 2 Approaches to the total synthesis of the neocarzinostatin chromophore Wender's group was the first to achieve the construction of the neocarzinostatin chromophore skeleton. In this work they popularized the use of 2-bromocyclopent -2-enone 5 as an A-ring synthon onto which the B-ring propargyl and acetylene units can be conveniently attached (Scheme 2).9,'0 Also central to their strategy is the photochemically induced extrusion of SO, from 6, which effects ring contraction to the strained 9-membered neocarzinostatin intermediate 7.This choice was made in view of the sensitivity of 1 to high pH and certain nucleophiles, as well as to decouple the enthalpic and entropic problems which otherwise combine to make direct closure of the 9-membered ring difficult. The fragile bicyclic dienediyne 8 was obtained by treatment of alcohol 7 with MsCl and DMAP. Elements of this strategy appear in Mikami's ene reaction approach to the construction of 10 from aldehyde 9 (Scheme 3). However, under the thermal conditions employed this intermediate undergoes dehydration and cycloaromatization giving tricycle 11." reaction of an ally1 chromium reagent, generated from 12, as a means to achieve 9-membered ring formation (77-88% yields) (Scheme 4),I2-l4 as well as the 2,3-Wittig ring contraction of the Wender also explored the intramolecular Nozaki iii.TBAF iV.M&I.TEA HO' 5 6 hv 10min,l5% I 7 0 Scheme 2 0 9 10 11 Scheme 3 12-membered ether 13 (R=H) to compound 14.12 However, the yields in the latter study were only moderate, and difficulties were encountered during purification of the mixture of diastereoisomeric products. Krebbs et al. found that the corresponding 0- MEM protected ether 13 (R=MEM) fails to undergo the 2,3-Wittig ring c~ntraction.'~ In contrast, Doi and Takahashi showed that ether 13 (R = TBS) does rearrange efficiently (ButLi, THF, -100 "C, 10 min), and with a high degree of 'cis' selectivity to give the neocarzinostatin derivative 14 (66% yield).16 Further, simple, but delicate transformations gave the dienediyne 15.Takahashi's group have built upon this result to synthesize compound 21 in which the two hydroxy groups are present in the cyclopentene ring with the correct relative stereochemistry (Scheme 5).'7,18 This involved reaction of epoxy ketone 16 with the lithium acetylide 17, followed by dehydration, regioselective Pd(0) catalysed opening of allylic 94 Contemporary Organic SynthesisGOTBS HO R' = Br, R2 = OH R1 = OH, R2 = Br / \ RO . _ _ 12 13 CrC12, THF / 4,5-cis products 77-8770 2,SWittig @OH RO 14 15 Scheme 4 epoxide 18 in the presence of benzoic acid, and elaboration of ketone 19.2,3-Wittig rearrangement of ether 20 produced the neocarzinostatin analogue 21 in greater than 60% yield. Magnus and collaborators have shown that their strategy employing q2-dicobalt hexacarbonyl alkyne complexes can be applied to the synthesis of the bicyclic skeleton of neocarzinostatin 1 (Schemes 6-8).19,20 Their initial plan was to close the C,-& bond in an intramolecular aldol reaction involving the enol (enolate) form 23 of the masked enediyne 22. However, exploratory experiments revealed an unexpected reaction pathway leading to 24 (Scheme 6). This problem could be countered through cyclization of intermediate 25, but in this case, subsequent decomplexation of 26 was accompanied by cycloaromatization of the highly reactive 9-membered enediyne product (Scheme 7).to install the sensitive epoxide trigger of 1 prior to Analysis of the situation led to the audacious plan 16 18 I. PdO, Phcofi ii. TBSCl iii. KSOs MeOH hr. PCC -*. / Br TB TBSO THF, -100 OC 10 min, 62% 20 Scheme 5 21 J 6 R 2 24 Scheme 6 the Lewis acid promoted aldol type cyclization step (Scheme 8). Fortunately, it was found that aldehyde 27, obtained as a mixture of monochiral diastereoisomers, underwent smooth ring closure on treatment with BuzBOTf and Et,N to give 28 in Lhemitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 9525 26 Scheme 7 57% yield. Oxidative decomplexation then gave the desired 9-membered diyne epoxide 29 (69-75% yield), which was a stable product! of the neocarzinostatin chromophore 1 in enantiomerically pure form has been made by Myers et al.(Scheme 9).21,22 They showed that condensation of the chiral epoxy functionalized 1,5-diyne unit 30 with optically pure keto acetal31 led to selective (18:l) formation of the desired 1,Zaddition product 32. Subsequent ring closure of aldehyde 33 to 34 was achieved using LHMDS in the presence of CeC13 (87%). The remarkable aspect of this, and similar ring closures discussed further on, is that the highly strained 9-membered ring is formed via a reaction which is potentially reversible. At this stage it was found that the delicate allylic transposition of 35 to 36 could be effected by brief exposure to trifluoroacetic acid. Hydrolysis of trifluoroacetate 36 was then followed by hydroxy protection and vinylogous elimination of MsOH to give the dienediyne product 37.The most significant progress toward construction E t O & Y B r Br i. -TMS,P$ ii. DlBAL iii. Na(OMe)3BH c bEt I. (-)- DET iL Phrcl Ill. F A 1 V OEt 27 28 29 Scheme 8 rl Snaphth 31 L 32 i. mCPBA iv. TMSOTf i. MeOH, c--- 49% I TMSO HO 0 37 -36 R=H- R=TMS EtSNeHF 35 34 33 Scheme 9 96 Contemporary Organic Synthesis4% o \ NHP C-1027 38 H O M W Me kedarcidin 39 T 0 0 I - Scheme 10 3 Nine-membered enediynes: kedarcidin and C-1027 Recently, Hirama et al. have reported an approach to the 9-membered enediyne core of the enediyne C-1027 3823 and kedarcidin 3924 (Schemes 10 and ll).25926 Fundamental to their strategy is the idea that these highly unstable molecules may exist as nucleophilic addition adducts (Serine-OH) in the apoprotein (Scheme lo), and that liberation of the chromophores is accompanied by enediyne double bond formation.25 antibiotics is unknown, racemic 40 was condensed with optically pure diyne 41 to give 42 (and its C-9 diastereomer as shown in Scheme 11).Both diastereomers were separately carried through to aldehydes 43 and reacted with LHMDS in the presence of CeCI,. Interestingly, ring closure to 43 was succeeded by a facile Cope rearrangement to the bis-allene 44.27 This undesired transformation was suppressed during the corresponding cyclization As the absolute stereochemistry of the two of the enyne intermediate 45 to the point where the target compound 46 could be isolated and characterized (46 can be stored at - 20 "C).was converted to the enediynes 47 and 48 (Scheme 11). Compound 47 underwent rapid cycloaromatization (tg at 20 "C = 11 min), but epoxide 48 could be purified by silica column chromatography. The pronounced dependency of the cycloaromatization rate of 48 on solvent [ti ( CD2C12) = 680 min; ti ( CD2C12/CHD) = 23 min] led to the suggestion that 48 may be virtually in equilibrium with the diradical intermediate 49 due to a very low energy barrier to interconversion, and to a higher barrier to radical neutralization by hydrogen abstraction. Several reports have also appeared concerning preparation of the aromatic and sugar components present in 38 and 39.28,29 By a short sequence of reactions this intermediate 4 The total synthesis of calicheamicin/esperamicin 4.1 Central core structure As with any large molecule, a vast number of retrosynthetic pathways can be envisaged for the preparation of calicheamicidesperamicin. However, in view of the ready availability of enediyne 50,30 the bond disconnection shown in Scheme 12, involving condensation of its dianion across a keto aldehyde platform synthon 51, has attracted particular attention.Given this choice, the problem of constructing the aglycones calicheamicinone 52 and esperamicinone 53 can be reduced to deciding how much of the molecules functionality (and in what form) should be present in the starting platform synthon, and at what moment either direct condensation or stepwise construction of the bridging enediyne system should intervene.Kende achieved the synthesis of the bicyclo[7.3. lltridecane compound 56, possessing the crucial C,-C,, bridgehead double bond of calicheamicinone which prevents cycloaromatization (Scheme 13).31 In this work the aldehyde function in 54 served as a latent ethynyl substituent, and the keto group was elaborated into the a,P-unsaturated aldehyde system found in 55. In the final step the enediyne bridge was successfully buckled together to produce 56 along with its C-8 epimer. Detailed NMR studies of these products permitted reattribution of the stereochemistry initially proposed for the C-8 centre in 2. In the first synthesis of calicheamicinone by Danishefsky et al., the concept of reacting the dianion of enediyne 50 with a fully functionalized platform structure was taken to the letter (Scheme 14).32 Indeed a projected key step was the condensation of 50 with the keto aldehyde synthon 59, obtained by Becker-Alder,, dearomatization of the phenol intermediate 57 and a Dess-Martin periodinane mediated oxidation34 of the resultant alcohol 58.Preliminary studies of this process pointed to the inescapable necessity of having the Lhermitte and Grierson: Enediyne based antitumour antibiotics. Part 2 9740 I 0 Y O ! + LAIH4 iii. TBAF vi. Dess-Martin periodinane 54% periodinane T& 45 TES 42 Y 0 0 MO M = Ce* or ti+ cope rearrangement 72% v H6 h 0 P iii. TBSOTf TBSo' i. MsCl ii. TBAF iv. MsCl v. DBU, 25 O C HO 46 i. TBAF ii. TBSOTf iii. MsCl iv. DBU, 25 OC v TBSO 47 49 44 Scheme 11 MeSSS 51 50 R = H calicheamicinone 52 R = OH esperamicinone 53 PdO-CuI t Scheme 12 98 Contemporaly Organic SynthesisOMe OMe I I 0 54 n 0 55 Scheme 13 Nas 71 96 R-H - R-Ek * n i.HO OH, PPTS ii. OsO,, NMO iii. NaI0, LiHMDS (inverse addition) MF,2O0C * HOW-- H 56 dianion react first with the less reactive keto group in 59. This was achieved by a clever application of the Comins procedure for in situ aldehyde p r ~ t e c t i o n ~ ~ wherein the 1,2-addition product 60 was formed regio- and stereo-selectively. Despite the large distance between the reacting centres in this acyclic intermediate (-6.5 A) ring closure was extraordinarily efficient giving the strained enediyne intermediate 61 with the correct C-8 hydroxy stereochemistry in 60% yield. ether function to the corresponding ketal, elaboration of the C-13 ketone function through epoxide ring opening and oxidative cleavage of the resultant diol, and introduction of azide ion at C-10 in a Michael reaction process.At this stage the exocyclic double bond was stereospecifically introduced into 62 by an intramolecular Wittig reaction, and the azido group was reduced and carbomethoxylated giving lactone 63. The final operations included reductive opening of the lactone ring, and conversion of the derived alcohol to thiol 64, which on treatment with Harpp's disulfide reagent 6536 gave the allylic methyl trisulfide intermediate 66. Selective reaction of 66 with CSA at room temperature touched only the ketal function, completing the synthesis of ( f )-calicheamicinone 52. Scheme 12 are also found in Nicolaou's first synthesis of ( - )-calicheamicinone (Scheme 15).37 Particularly appealing in this work is the idea of capturing in latent form the urethane nitrogen and the C-9 aldehyde function within the Subsequent steps involved conversion of the enol The essential elements of the strategy depicted in L 1 5 0 1 iLTMS0Tf !BR=CH@H 5@R=CHO HO-- 0 L (EtO)Q(O)CHflOCI ii.LiEk iv. (CLJCO)&O v. M H RS 63 I i.DlEAL 61 i. HO(CH&OH, CSA ii. KOAo, AcOH, DMSO hr. Nd04 v. NaN, iii. M a , NH3 56% 6 2 " 3 P'zSSMe 64 R=H 66 R=SSMe Scheme 14 dihydroisoxazole ring of the highly functionalized monochiral intermediate 67. Note also that stereoselective reaction of the keto group in 67 with lithium (trimethylsily1)acetylide to give 68 Lhermitte and Grierson: Enediyne based antitumour antibiotics.Part 2 99n 0 JF HO M*2c--o:L NaOCl (4 : 1 mixture) ii. Naom iii. Jones oxidation c OH i.m/ ii. NaBH4 76 y y W 3 ~ M E M 67 n I OH A OH Dess-Martin I TMS P X 69 x = o Ph"=C:%h 68 70 X=CHC02Me i. K@3, MeOH ii. TESOTI iii. WO-CUI (cat.) n NPhth iv. s i r i ge~ v. AC-p c 97% 78 i. 71, Pdo-CuI ii. DIBAL iii. Dess-Martin iv. CsF TMS 0 I ? Q 73 I KHMDS, -90 "C 72 + 44% i. MsCl ii. silica, py - iil MeNHNH2 74 NHC02Me 75 79 80 ii. M n 4 OH j/ (-)-calicheamicinone 52 Scheme 15 81 Scheme 16 82 R = 83 R = established the chirality at C-1 of the target molecule. In the following steps Swern oxidation of the O-MEM deprotected derivative of 68 effected both oxidation of the liberated secondary alcohol and aromatization of the isoxazole ring giving 69. Reaction of this intermediate with methyl(tripheny1- phosphoranylidene) acetate produced the a,P-unsaturated ester 70 as a single isomer.The enediyne system was then assembled by Pdo-CuI catalysed coupling with cis chloro enyne 71, and the amino aldehyde functionality contained in the 100 Contemporary Organic Synthesisisoxazole ring of 72 was released by N-0 bond cleavage using molybdenum hexacarbonyl. Ring closure of phthalamide derivative 73 to a 9:l mixture of alcohol 74 and lactone 75 (44% combined yield) was achieved through reaction with KHMDS in toluene at - 90 "C. Taking advantage of proximity effects, alcohol 74 possessing the incorrect stereochemistry at C-8 was converted via its mesylate derivative to lactone 75. Reductive ring opening of this lactone, and its elaboration to (-)-calicheamicinone 52 was achieved using the chemistry developed by Danishefsky and Magnus.To gain access to esperamicinone 53 in both its natural (1S,8R)3s and antipodal forms for biological testing,39 Grierson and co-workers employed the two enantiomers of keto ester 77, obtained from the quinic acid derivative 76, as the pivotal intermediate (Scheme 16).4"741 For the natural series, elaboration of seco aldehyde 79 began by stereospecific acetylene addition to (+)-77 using weakly basic dichlorocerium (trimethylsilyl)acetylide, and 0- silylation of the derived alcohol to block intermediate 78 in the conformation having the acetylene function axial. Cyclization of 79 gave the desired bicyclic enediyne product having the correct C-8 stereochemistry ( > 60%).However, to avoid retrocondensation during subsequent operations the cyclized alcohol was converted to its methyl ether 80 before work-up. Introduction of the urethane nitrogen was then achieved by reaction of enone 81 with Ph2S=NH. In this transformation cyclization of 88 Scheme 17 84 TESOTf D the presumed intermediate Michael addition adduct to aziridine 82 is sufficiently rapid that cycloaromatization does not occur. Various conditions can be envisaged to effect ring opening of the N-carbomethoxylated aziridine derivative 83 such that the C9-Clo double bond is reinstalled, and the C-13 centre is activated with respect to construction of the allylic trisulfide system. In a closely related fashion Kadow and Isobe have elaborated the simpler esperamicin intermediates 86 and 87 from keto ester 84 (Scheme 17).42,43 Interesting in Kadow's study is the contrasting dependence of product C-8 stereochemistry on reaction temperature in the ring closure of aldehyde 85, and the analogous cyclization of 90 to 91.Aldehyde 90 was obtained in four steps from Isobe's epoxide 88 (see Scheme 36) by TESOTf induced ring opening to the exocyclic enol ether 89 and regioselective thermal selenoxide cis elimination.44 With respect to the strategy depicted in Scheme 12, Magnus and co-workers approached the problem of synthesizing 52 from almost the opposite viewpoint, i.e. by introducing the functionality onto the 6-membered ring platform after assembly of the bicyclic enediyne skeleton (Scheme 18). In particular, from their work on the preparation of different cobalt complexed bicyclic enediyne structures (see Scheme 12 in Part 1 of this review6), it was observed that the ketone 94 obtained after decomplexation of 93 was sufficiently stable to permit chemical manip~lation.~~-~~ This result is remarkable, in view of the fact that the crucial 0 TBAF ProtO 1 85 86 R' = H, R2 = OTMS 87a R' = OH, R2 = H (25 "C) I 87b R' = H, R2 = OH (0 "C) R3=H 91a R' = H, R2 = OH (20 "C) 91b R'=OH,R2=H R3 = OTES (91-1 b = 1.2:l at -78 "C) t i.PhSeCl ii. mCPBA iii. K2C03 I MeOH - TMS TESO'~ 30% I LHMDS, THF 89 90 Lhermitte and Grierson: Enediyne based antitumour antibiotics. Part 2 101R = Me or H 93 92 R=OMeorH 12. THF, 82% 1 r 1 L -I 95 94 i. DlBAL R=CN 1 ii. MsCl iii. NaSAc iv. LiAIH4 Scheme 18 bridgehead double bond is absent in enediyne 94.The cobalt complexed enediyne 93 was prepared via a ring closure reaction involving reaction of the enol ether system in 92 with a formal carbocation generated by departure of the OMe or OH group under Lewis acid conditions (the Nicholas reaction). conformation in which the C-9 hydrogen is in the plane of the carbonyl system, the enol silyl ether 95 could be generated. This opened the way to a selenium based protocol for creation of the C9-Clo double bond in 96.48949 At this point oxygen functionality can be further introduced at C-11 under SeOz allylic oxidation conditions giving 97, and through a stereocontrolled Wittig-Horner reaction using diethyl cyanomethylphosphonate elaboration of the allylic trisulfide unit in 98 was achieved.48i50 To incorporate the C-8 alcohol function in the molecule the cobalt complexed aldehyde 99 was cyclized through an aldol reaction to 100 (Scheme 19).” Kadow,’* and subsequently R ~ t h ~ ~ and M a g n ~ s , ~ ~ have modified this approach showing that Since 94 adopts preferentially a boat treatment of 101 with PhS-/Ti(OPr’)4 initiates ring closure through a Michael addition-enolate trapping mechanism to give alcohol 102 (Scheme 20).Subsequent oxidative elimination of PhSOH and decomplexation then provides a simple alternative means to access compound 96. At a later stage it was shown that diketone 103 can be converted to the enaminoketone 104 through reaction with either PhZS=NH or the azide ion in DMF (Scheme 21).& Nicolaou’s group turned to synthesizing esperamicinone 53.54 The main emphasis in the approach that was ultimately developed (Scheme 22) was to create the 1,Ztruns-diol system in the late stage intermediate 110 via Sharpless epoxidation of 108 (90% ee) and acid catalysed ring opening of the epoxide unit in acetylene 109.Key operations in the elaboration of allylic alcohol 108 involved nitration of the ketal 105, oxidation of the aromatic ring in 106 to give quinone 107, and ketone to cyanoethylene conversion (65 % overall, Having succeeded in obtaining calicheamicinone, Z : E = 10: 1). 99 loo Scheme 19 i. Pd(OAc), ii. H+ iii. Co2(CO)8 iv. Bu‘OMgBr. ADDP 101 Me2AISPh Ti(OPr’), 1 TBSO A 96 102 Scheme 20 ’& RO-- =. I orNaN3, Ph2S=NH DMF :& 2 2 I 103 Scheme 21 1 04 102 Contemporary Organic Synthesis?Me OMe i.KgO3 K. MsCl MeOH-H@ iii. Dw 55% L n. BUU. -18 "c J),, !i.s2Kfio3 c &HC02Me iii. COCl, then MeOH 56% OH O x 0 TBSo O x 0 II c II 106 i. Ce(NHd2(NO& ii. Silica gel iii. PMBBr OTBS v. TBSCI 111 /$ Ho Me 1 27% HO & . i. BuLi, MeCN ii. TFAA iii. HFQ 4 6 5 4 TBSO o 1 07 108 i. Sharpless epoxidation ii. Dess-Mattin 1 . L 112 Scheme 23 0 0 Scheme 22 4 ,-H@ PMB Schreiber et al. have adopted yet another entirely different strategy for the synthesis of the calicheamicin/esperamicin aglycone based upon an intramolecular Diels-Alder reaction in which the enediyne system acts as a structurally rigid chain connecting the diene and dienophile components (Schemes 23 and 24).55 This approach to the platform ring is astute in that the bridgehead double double bond is created during the Diels-Alder step rendering the cycloadduct thermally stable.Contrary to expectation, compound 111 did not cycloadd via a geometry imposed a o transition state to give the desired product 112 (Scheme 23). However, it was . found that the cycloadduct 114 obtained from Diels-Alder reaction of 113 could be readily converted to the mesylate derivative 115, and that Lewis acid promoted pinacol type rearrangement of this intermediate produces the esperamicin analogue 116 ( > 15 : 1,65%) (Scheme 24). \--I 113 Et*I 65% - 115 4.2 Synthesis of the glycone Sophisticated NMR, molecular modelling, and (bio)chemical studies have revealed much about how the oligosaccharide fragment in calicheamicin, and the trisaccharide and fucosyl anthranilate units in esperamicin, contribute to the interaction of these antibiotics with the minor groove of duplex DNA.56 From this work a detailed picture at the molecular level concerning the differences in site selectivity and capacity of the two compounds to 116 Scheme 24 Lhennitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 103effect single versus double strand breaks in DNA through abstraction of specific hydrogens from the deoxyribose backbone has emerged. In particular, these studies point to the important role played by the hydroxylamino glycoside linkage between the A and B monosaccharide units in preorganizing the oligosaccharide into a conformation that compliments the shape of the minor groove.The development of strategies for the stereocontrolled formation of the /3-N-0 linkage, which joins the anomeric centre in the novel sulfur containing 2-deoxy B-ring sugar and C-4 of the A (or A-E) ring fragment, is therefore a central issue that must be addressed in any effort to construct the A-(E)-B trisaccharide structure common to calicheamicin 2 and esperamicin 3. The discussion will consequently be focused upon the problem of constructing the respective methyl glycosides 117 and 118 (Scheme 25).57-70 B-ring A-ring <Me R1 S .I OH 0 I 0 , OMe I H O W - D-ring '* OH 118 R' = Me, R2 = Pr' Scheme 25 Considering the presence of two 1,Zaminoalcohol systems in the otherwise sparsely functionalized E- ring of 117, Nicolaou, and more recently Roush, chose to construct this sugar from ~ - s e r i n e .~ l - ~ ~ The key step in both routes is the reaction of a serine derived aldehyde intermediate with a chiral ally1 borane reagent. In Nicolaou's synthesis (Scheme 26) this led to formation of compound 119 as a single isomer (75%). Methylation and subsequent ozonolysis gave a methoxy aldehyde intermediate, which was converted to acetal 120 (68% overall yield for the four steps). Cyclization of 120 in dry HCl-MeOH produced a mixture of separable methyl glycosides which were converted to the N- Fmoc (9-fluorenylmethoxycarbonyl) protected glycosyl fluoride 121 by treatment with Fmoc- chloride followed by reaction of the anomeric acetate derivatives with DAST. Coupling of 121 with the methyl D-fucopyranoside derivative 122 followed by deprotection and selective oxidation of the axial C-4 alcohol gave the A-E ketone 123.@ In Kahne's approach to the E-ring the Diels- Alder 124, obtained from reaction of the N-Boc- N, O-isopropylidene derivative of serine aldehyde with Danishefslty's diene, was oxidatively cleaved giving the /3-hydroxy ester 125 in 77% overall yield (Scheme 26).65 Methylation of the secondary alcohol, DIBAL reduction, deprotection under acidic methanolic conditions, and sequential N- acetylation and alkylation then gave 126.Anomeric activation involved OMe +SPh exchange and conversion of the derived thioglycoside to the corresponding sulfoxide 127. Reaction of this sulfoxide with methyl glycoside 128 in the presence of triflic anhydride in pyridine (the Kahne reaction%) gave a disaccharide intermediate which was elaborated to the A-E ring triflate intermediate 129 (64% overall yield).67 The use of glycals both as starting materials and intermediates in the sugar coupling reactions is a key feature of Danishefslty's synthesis of the calicheamicin/esperamicin oligosaccharides.6R~69 This is exemplified by the Theim type coupling (I+C10;)70 of glycal 130 with compound 131, itself derived from D-fucal, to give ultimately the disaccharide intermediate 132 with the 0-4 axial triflate function in 41% overall yield (Scheme 27).In a similar way Beau et al. showed that glycal 133, prepared in six steps from D-arabinal, condenses with the A-ring precursor 134 in a Theim reaction to give the A-E ring intermediate 135 (Scheme 28).71 Three major strategies have evolved to date for the coupling of A-E-ring intermediates to the B- ring via the N-0 bond such that the correct &a- BIQ configuration is obtained. In the initial phase of Nicolaou's synthesis of the calicheamicin glycone the idea was to use the C-2 oxygen substituent in compound 138 to direct selective formation of the P-glycoside 139 (Scheme 29).@~~~ Intermediate 138 was obtained in five steps from glycal 136, the most important operation of which was the stereoselective Zn(B&)2 reduction of ketone 137 from the P-face with concomitant ester migration.As planned, reaction of lactol 138 (a : /I = 8 : 1) with N-hydroxyp ht halamide (Mitsunobu conditions) produced the required /3-anomer 139 as the major product (5 : 1 to 7 : 1; 56% overall).Liberation of the amino group and coupling of the derived hydroxylamine 140 with the A-E ring ketone 123 under acidic conditions proved highly efficient, giving oxime 141 as a single isomer (83%). Conversion of compound 141 to thioniomidazolide 142 then set the stage for a thermal [3,3]-sigmatropic rearrangement to 143. In this step the B-ring C-4 sulfur substituent was introduced stereospecifically, and the C-2 position was deoxygenated. Subsequent condensation of 144 with the acid chloride derivative 145 gave the tetrasaccharide intermediate 146 in 80% yield. In the final steps to the calicheamicin methyl glycoside 117 the B-ring keto group was exposed and reduced, and the remaining protecting groups were removed. Most importantly, the oxime double 104 Contemporary Organic Synthesis20 O y N 7 0 t & O y N 7 0 119 "9 i.A@, Me1 ii. 03, P(0hW3 iii. H*. MeOH iv. NaOH 68% Scheme 26 P h t h N e MeO 130 Scheme 27 124 i. Ru04, NaI04 ii. K2CO3 iii. HCI 125 i. MeOTf, P.&di-teMUtyl- hethylpyridine ii. DIBAL iii. TsOH. ZnCh. MeOH iv. 40, PY v. KOH, Eti 67% OMe I i. HCI -i.LiAIH4 w pq 126 ii. Fm&1, K&03 - iii. AcOH iv. DAST iv. MPBA 65% 55% MeO ii. TFAA iii. PhSH, BF3.Et2O Me0 X=F,R=Fmoc 121 127 X = SOPh, R = COCF3 ii. NaH. HO(CH2)flH iii. Bu2Sn0, Br2, Bu$nOMe 45% 123 OTf - .. w OH i. IClO,, BM~o!&,$P BMPO 131 OH P ii. 41 Ph&H. % AlBN *PhthN ,@ Mi. Tf@, py Me0 132 \ k 6 U 3 0 ii. TsOH OMe Tf20,PY iii. BzCI, TEA, DMAP iv. Tf20, py 64% OSnBu3 ii. TsOH w MeO 129 133 Scheme 28 NIS. MeCN, 4 A molecular sieves 135 134 Lhennitte and Griemon: Enediyne based antiturnour antibiotics.Part 2 105OTBS 138 TBSO %YR2 . OCOAr 139 R =Phth 140 R:=H&~ OTBS 137 ii. TESOTf 83% OTBS 136 TBSO eo;L+ 6COAt' p$ 4N Me0 141 i. DIBAL ii. (Im)&S 79% ____c TBSO ; 142 o K l m S I TEsocg-?c( OTES PhMe, 110 "C 98% I 146 i. TBAF ii. K-Selectride iii. HFpy iv. Et2NH v. NaBH3CN, HCI 19% 117 Scheme 29 bond was reduced selectively such that the required C-N equatorial stereochemistry was obtained (86%; a : /3 = 6 : 1). By essentially the same route the esperamicin trisaccharide 118 was ~ynthesized.~~ The second approach to the calicheamicin aryl tetrasaccharide 117 was developed independently by Danishefsky and Kahne. Here, the B and A-E rings are joined through SN2 displacement of the axial triflate substituent in the A-E fragment by the anion generated from N-acylated B-ring anomeric hydroxyalmine intermediates (Schemes 30 and 31).The N-Teoc derivative 155 employed by ~~~i~h~f~ky68,69,74,75 was prepared by first converting tri-0-acetyl-D-galactal 147 to the a-phenylthio pseudoglycal 148 (82% overall) (Scheme 30). LiAlH4 reduction and mesylation of the remaining hydroxy group then afforded compound 149, which was converted to the disulfide 150. Treatment of 150 with m-CPBA at -40 "C resulted in sulfoxidation of the less hindered anomeric thiophenyl residue only. At room temperature this intermediate underwent clean [ 2,3]-sigmatropic rearrangement giving 151 (76% after 0-silylation). Reaction of this glycal with TMSCH2CH20C(0)NHOH (Teoc-NHOH) in the presence of Ph3P.HBr gave urethane 152 (57%) along with 37% of the undesired N-linked glycoside.The C-4 thiol was then liberated through reaction with EtSH/&CO, giving the B-ring thiol 153 in high yield.76 This intermediate was condensed with acid chloride 154 in the presence of Et,N-DMAP to give the N-Teoc protected B-C-D fragment 155 (85%). In the next step the crucial reaction of the urethane anion of 155 with the A-E ring triflate derivative 132 was effected producing the protected oligosaccharide intermediate 156 in 80% yield. Liberation of the E-ring amino function in 156 106 Contemporary Organic Synthesismb i. a. TEA, DMAP OTES 85% 4 OTBS 155 156 mo-? M* OTBS OMe I How OH oMe 117 Scheme 30 followed by reaction with acetaldehyde and NaBH3CN permitted introduction of the N-ethyl substituent (98%).Final cleavage of the p - methoxybenzyl, silyl and Teoc blocking groups through successive reaction with DDQ and TBAF provided the target glycone 117 in 40% overall yield. By the same sequence of reactions using the S-methyl derivative of thiol 153 the esperamicin glycone 118 was efficiently prepared. 151 TeocNHOH PhpHBr 5796 The requisite B-ring substrate 160 in Kahne's synthesis was prepared in six steps from the readily available D-lyxo-pyranoside 157 (Scheme 31).67 This involved two sequential displacement reactions, and stereoselective formation of the desired p-anomer in the reaction of the sulfoxide derived from 158 with 0-stannyl-N-hydroxyurethane 159 (12 : 1; 39%). N- Alkylation of urethane 160 with the A-E triflate 129 was then effected producing 161 in 81% yield.This Lhemitte and Grierson: Enediyne based antitumour antibiotics. Part 2 107+ i. m CPBA iii. EtO&HN-OSnBu3 . ii. TfzO KHMDS 129 81 % 161 intermediate was fully deprotected by successive treatment with TBAF and NaOMe to give the (A- (E)-B trisaccharide as its disulfide 161. Deprotection at this stage was judicious as the protected aryl tetrasaccharide otherwise obtained proved sensitive to base treatment, undergoing a number of interesting rearrangements. Selective formation of the calicheamicin methyl glycoside 117 from 162 was elegantly achieved by reacting the corresponding thiolate generated in situ (Bu3P) with the phosphate derivative 163 according to Masamune (79% for the two steps).77 Beau et al.showed that BF3 OEt2 assisted cyanoborohydride reduction of the oxime ether double bond in the A-E ring derivative 135 occurs selectively from the /?-face giving the hydroxylamine 164 (74%) (Scheme 32).71778 Preparation of this intermediate for attachment to the B-ring involved isopropylidene hydrolysis and conversion to the N- protected nitrone derivative 165. O-Alkylation of this nitrone, achieved by reaction with trichloroacetimidate 166 in the presence of silver triflate, was accompanied by N,O-acetal formation giving the trisacccharide 167 in 90% yield (/? : a = 5 : 1). After three further deprotection steps the esperamicin methyl glycoside 118 was obtained. In the third strategy for A-(E)-B ring assembly, 1 62 MeO 163 Meo OH t 1 0 \ How MeO OH oMe 117 Scheme 31 4 3 Total synthesis of (-)-calicheamicin ylI To complete the total synthesis of calicheamicin 2 in a convergent fashion required the coupling of an advanced stage optically pure central core intermediate with a suitably protected aryl oligosaccharide component, under conditions where both components and the derived product survive.Further, the coupled product must not be overly sensitive to any subsequent steps of deprotection and functional group elaboration. In particular, provision must be made to avoid the known rearrangement of N-unprotected free glycosides such as 167 to azafuranoses (Scheme 33).60 In Nicolaou’s first synthesis of 2, both the labile trisulfide system in the aglycone and the hydroxylamine system joining the A and B rings of the sugar component were elaborated after the coupling reaction (Scheme 34).79 Important to the success of this approach was the use of the 0-TES and N-Fmoc protected /?-Znitrobenzyl glycoside 168,” which could be converted photolytically to lactols 169 (1:l mixture) and coupled to the calicheamicinone derivative 171 via trichloroacetamide 170 using the exceptionally mild conditions of the Schmidt reaction (76%).’l allylic sulfur atoms was introduced at C-15 in the aglycone.To effect the crucial reduction of the oxime double bond in 173 (NaCNBH3, 4a:4b=2:1; 80% yield) the silyl protecting groups had to be removed. However, temporary reprotection of the sugar hydroxyls subsequently proved necessary in order to elaborate the allylic trisulfide unit. This was achieved through reaction of 174 with TESOTf and With compound 172 in hand, the first of the three 108 Contemporary Organic SynthesisMeS i.HCI, MeOK3120 ii. panisaldehyde, PhMe 135 97x NaBH3CN, BF39Et2 TBAF; THF 0°C I 74% AgOTf, CHzCIz. 90% c-- COCF3 4 A molecular sieves OH ii. KzCO3, MeOH iii. 5 M KOH, rt 32% Me0 118 167 Scheme 32 167 OTBS , 1 HoY Scheme 33 Hunig's base followed by treatment of the crude product mixture with excess HOAc-H20. Reduction of the thioacetate group with DIBAL at - 90 "C then gave the corresponding thiol which was reacted with Harpp's reagent giving 175 in 75% yield. Treatment of this intermediate with HF-pyridine afforded 176 (90%) which was further deprotected 164 165 in the last two steps through sequential treatment with TsOH (70%) and Et2NH (90%), completing the synthesis of (-)-calicheamicin 2.Exploratory studies by Danishefsb of the coupling of the free glycoside derivative of 155 with different forms of the calicheamicin aglycone revealed problems associated with the use of the 0- TBS and N-phthalimide protecting groups, and the potential incompatibility of the allylic trisulfide (and other functionality) during fluoride promoted removal of the N-Teoc hydroxylamine protecting group.69974 In light of these findings and Nicolaou's precedent, they also settled upon use of a 0-TESIN- FMOC substituted oligosaccharide as the glycone precursor to calicheamicin (Scheme 35).82 Coupling of the trichloroacetimidate derivative 178 of lactol 177 with (-)-(S)-acetate 179 under modified Schmidt conditions (AgOTf catalyst) gave the desired P-configured product 180 along with the a-isomer in 58% combined yield.83@ Only four steps were required to convert this coupling product to (-)-2.However, more impressive was the finding that AgOTf catalysed Schmidt coupling of trichloroimidate 178 with the calicheamicinone ketal 181 was possible giving 182 in 34% yield (P-isomer only). From this intermediate ( - )-calicheamicin 2 was obtained by successive treatment with CSA and TBAF. 5 Dynemicin analogues and the total synthesis of dynemicin A Dynemicin A 4 possesses an intriguing hybrid structure composed of a calicheamicin/esperamicin enediyne core structure condensed to an Lhermitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 109Scheme 34 OMe BzO 171 BFNEt2 -40 'C, 76% OR I.DlBAL ii. Ph3P, DEAD, AcSH iii. HFpy 79% 173 R=H,X=SAc I NaBH3CN, BF3.0Et2 -40 oc, 80% T 174 R=H,X=SAc - I i.TESOTf I ii.DlBAL iii. PhthN-SSMe 175 R = TES, X = SSSMe 56% HC'W HO, Mx 18 h. 90% 1 e h N H C 0 2 M e MeSSS 110 Contemporary Organic SynthesisTeoc 0 0 Et(Frnoc)N@ Me0 R 4 2 0 2 M e 181 RrSSSMe ti\\ I HO' 179 R=SAc AgOTf, 4 A molecular CH&12,25 "C i. DIBAL ii. PhthN-SSMe 1 54% (58%) 180 R = SAC (34%) 182 R = SSSMe i. CSA, 25 "C ii. TBAF, 15 min 37% MeSSS EtNH Me0 OH (-)-calicheamicin 2 Scheme 35 anthraquinone unit characteristic of the anthracycline antibiotics. Between these two subunits is the epoxide trigger which is highly susceptible to ring opening in intermediates wherein the anthraquinone system is reduced to the hydroquinone level.Particular care must thus be taken during construction of dynemicin to either maintain the anthraquinone component in a protected form, and/or in the correct oxidation state. The strategies which have evolved for the synthesis of antibiotic 4 include a linear approach in which the pentacyclic 'platform' structure (rings A- E) is elaborated before attempting introduction of the epoxide ring, the enediyne bridge and other functionality onto the A-ring, and a second, more convergent 'biomimetic' approach in which the enediyne core structure is joined to an anthraquinone derivative via formation of the C8-C9 and C2-N1 bonds. However, the approach which has been most extensively developed to access dynemicin and simplified fully functional analogues involves the use of quinoline or phenanthridine derivatives as B-C and A-B-C ring precursors onto which the enediyne/epoxide system can be elaborated, followed by the D-E rings.This later strategy was adapted by Myers and Danishefsky in their respective total syntheses of dynemicin A, and by Schreiber et al. in their synthesis of the di-0- methyl ether-methyl ester of 4. Lhemzitte and Grierson: Enediyne based antitumour antibiotics. Part 2 1115.1 A-ring ‘biomimetic’ approach To access the enediyne core component of dynemicin equipped with the epoxide trigger, Isobe showed that the ketal enone 183 can be converted selectively via 184 to the epoxy diol intermediate 88 (Scheme 36).85 Cyclization of the corresponding aldehyde 185 to the bicyclic dynemicin analogue 186 proved feasible using the LHMDS/CeC13 combination.Note that treatment of the acetate derivative of 186 with TsOH gives 187, providing a convenient link to the calicheamicin series (see Scheme 17). i. TFA*H20 ii. NaBH4 iii. mCPBA * Me0 ii. K2C03. MeOH iii. 71, PdOGuI (cat.) 63% 0 LiHMDS 35% Cecla 183 184 OH 185 oTMS 1 a8 OH HO H.. fJ 0: I I OTMS 186 Scheme 36 AcO’ ! OTMS 1 87 In a more recent study Maier has synthesized the related enediyne 190 in which one of the connections is made to the oxygenated C-ring (Scheme 37).86 The starting ketal enone 189 for this study was prepared in five steps from acid chloride 188. Addressing the problem of making the c&9 connection and closing the B-ring in a biomimetic type synthesis of 4, Isobe showed that palladium based coupling of the more highly functionalized A- ring bromide 191 with the aryl tin derivative 192 OMe 188 Scheme O h R = OH R = CH(0Me)z 180 11 OMe 190 7 0 191 OTBS 1 0- 193 Scheme 38 could be achieved (Scheme 38).87 Treatment of intermediate 193 with TFA in CH2C12 then gave the A-B-C ring synthon 194 in 77% yield.5.2 Anthraquinone ‘platform’ assembly Construction of the anthraquinone portion of dynemicin A has been undertaken by several groups, with the idea in mind either to use this material as a synthetic intermediate on the way to 4, or to evaluate methodology which will subsequently be applied for the elaboration of the D-E rings in late stage intermediates which already contain the 112 Contemporary Organic Synthesisenediyne/epoxide moieties.The possibility that synthetically derived anthraquinones may themselves display antiturnour properties is of further interest. Within the latter synthetic context Schreiber developed a route to the angular anthraquinone 199, involving condensation of the quinoline derived aldehyde 195 with the lithiated benzamide derivative 196, followed by reduction of lactone 197 and intramolecular Friedel-Crafts cyclization to the air sensitive anthracenol 198 (Scheme 39).88 Treatment of this intermediate with DDQ provided 199 in 25% yield. & TsOH ii. PivcI 87% CI CI I I OMe 200 OMe 201 i. HP, Pd/C ii. Bu'Li, TMEDA iii. TsOH 2,5-(Me0)&H3CH0 M m jj.y+EoH iii. Jones o m oxidation OMe I II I Me0 0 OMe U o M e 202 203 OMe 195 Scheme 40 6; OMe 205 LDA, 95% - 199 198 OMe 0 MeO*C' Scheme 39 204 Nicolaou's route to the pentacyclic compound 203 (Scheme 40) began with directed metalation of the phenanthridine intermediate 200 and reaction with diethylcarbamoyl chloride (84%).89 Hydrogenolysis of the C-Cl bond in 201 was then followed by a second metalation reaction with 2,5-dimethoxybenzaldehyde and lactonization.Reduction of lactone 202, ring closure and oxidation with Jones reagent gave 203 (53% overall). Magnus et al. have also devised a synthesis of the B to E rings of dynemicin (Scheme 41) via a seven step sequence in which compound 206 is obtained by conjugate addition of the anion of lactone 205 to the a,P-unsaturated ester 204 followed by aromatization and 0-pivaloate formation (85% ~verall).~' Reaction of 207 with LDA then leads to ethyl ether 208 which is converted to 209 after oxidation (CAN), deprotection and reaction with acetic anhydride.derivative 210, Isobe and co-workers prepared the pentacycle 215 (Scheme 42).9' Remarkably, all efforts to cyclize the conjugated amide intermediate 211 to a 6-membered ring product led instead to spirocycle 212. This situation was countered by effecting a Pd catalysed Heck type reaction of the Starting from the readily available anthraquinone 1 @$ C0,Bu' c--- LDA, 95% bMe kOBu' I 4 207 (J.$ 0 0 i. CAN n. HBr HI. AQO 56% - QJJy OAc 0 OAc OMe &I OEt 208 209 Scheme 41 Lhermitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 113Nicolaou and co-workers, who have focused their activity on the synthesis of dynemicin analogues lacking the D and E ring^.^^-"^ In many respects this effort has been fuelled by the fact that diversely functionalized derivatives of phenanthridines 0 OMe 21 1 t 21 0 0 0 OMe 212 0 c CuBq 64% 0 OMe 21 3 Pd(dba)p, CH,C13 ~(O-TOI)~, P1'2NEt DMF, BSA 67% 1 n 215 I 21 4 21 6 Scheme 42 corresponding p, y-unsaturated amide 213, which proceeds through the preferred ao-trig pathway giving the pentacyclic amide 214 (9 : 1 with double bond isomer). Reaction of this product with NBS- AIBN and base then permitted conversion to pyridone 215.Attempts to close the enediyne bridge across carbons 2 and 7 (dynemicin numbering) in this product through reaction at the amide carbonyl centre failed.92 However, Isobe's group has recently developed Pd catalysis conditions for replacement of the triflate group in 216 by an acetylene function.93 Note the mild conditions of this reaction, plus the fact that no inorganic salt additives are required.5.3 Nor-D,E dynemicin analogues: the total synthesis of dynemicin A An impressive contribution to the chemistry and biological study of dynemicin has been made by 217a-d and 226a,b could readily be obtained as starting substrates'" (Schemes 43 and 44), and by the fact that the derived model compounds retain the capacity to undergo epoxide opening-Bergman cycloaromatization, displaying potent DNA cleaving power. Introduction of oxygen functionality at C-10 in compounds 217a-d was achieved by acetic anhydride promoted rearrangement of their N-oxide derivatives (Scheme 43).94-96,'05 For the next step, Yamaguchi type reaction of compounds 218 with ethynyl magnesium bromide and benzoyl chloride proved to be a very effective means for introduction of the acetylene unit at C-6 in 219 (3 : 1 mixture, 97%).loh Epoxidation of this intermediate occurred uniquely from the face opposite the ethynyl group, giving ketone 220 (after 0-desilylation and PCC oxidation).The acyclic enediyne unit was then constructed through Pdo-CuI catalysed reaction with cis-chloro enyne 71 and TMS cleavage (AgN0,-KCN). Cyclization of compounds 221 to the dynemicin analogues 222a-d was achieved using LDA at -78 "C ( > 60%). It should be emphasized that it was necessary to install the epoxide unit before this ring closure, otherwise a strained product would be formed in which the olefinic double bond is severely distorted.Notice also that, in contrast to studies on calicheamicin, the reactivity of the ketone carbonyl in 21 was sufficient for closure of the enediyne bridge to take place. In a similar manner the synthetic strategy was extended to include benzodiyne analogues of dynemicin in which the central double bond of the enediyne system in 222 was replaced by a phenyl and a naphthalene ring.97j98 Reaction of the ketone derived from 219a with (2R,3R)-butane-2,3-diol also permitted access to enediyne 222a in enantiomerically pure form.99 Further reductive removal of the C-7 hydroxy group in compounds 222 gave the analogues 223. Compound 222a did not display any DNA cleavage activity when incubated with DNA. However, the corresponding free amine caused significant damage to DNA.This observation was pursued and confirmed in tumour culture assays using the base labile N-2-(phenylsulfonyl)- ethoxycarbonyl derivatives 224."'"-'u2 These results indicate that in its free form the amine nitrogen assists epoxide ring opening producing an o-quinone methide type intermediate 225 which picks up a nucleophile and cycloaromatizes. For preparation of the dynemicin analogues 229a,b the synthetic plan had to be modified such that the enediyne system was assembled first, in order to allow for the sensitivity of the epoxide system to the presence of the C-12 oxygen substituent (Scheme 44).'03 In fact the epoxide system in 227 is opened and reformed giving 228 114 Contemporary Organic Synthesis1 mcPBA 218 R 217a R=H b R=We A 219 L 71, PdO-CuI il.&Nos KCN 0:: pm?+Q A 221 I R 225 R = H, OMe, O(CHd20H, 1-i OH X = H, OW, O(CHd20H Scheme 43 prior to cyclization. Compounds 229 were also shown to be mechanism based analogues of dynemicin, their free phenol form 230 rearranging to the p-quinone methide intermediate 231 which reacts with added nucleophiles giving a species which spontaneously cycloaromatizes.'"''~102 226 R I I r"\'. TMS 0:: pho% R 0 227 TBS 22g4b 230 R=OH 3 Scheme 44 231 Wender and Isobe have also been very actively involved in the synthesis of truncated analogues of dynemicin which display potent DNA cleaving power (Scheme 45). Wender's group has developed a synthesis of the enediyne 234 from the readily available quinoline carbinol 232.'07-"0 The Yamaguchi procedure was again employed to introduce the acetylene unit next to nitrogen, and epoxide formation preceded experiments to effect ring closure of aldehyde 233.Isobe's group studied the preparation of the corresponding ketone 236 from quinoline 235 in both racemic and monochiral forms."'-"4 An important innovation by both groups in the enediyne field was the finding that direct condensation of the TMS protected acetylene with the carbonyl function in 233 and 236 could be achieved upon treatment with fluoride ion. Wender further showed that the yield of this transformation could be markedly improved by reacting the cyclized alkoxide intermediate with Ac20 (or other electrophiles) prior to extractive work-up.'" Lhemitte and Grierson: Enediyne based antiturnour antibiotics.Part 2 115232R1=H 235 R' = Me R' F I. M P B A ii. 71, PdO-CuI ill. oxldatbn I 'N iz z: 1 ie } R2 = C02Me 233 R' = H 236 R' = Me Scheme 45 Photochemical cleavage of the o-nitrobenzyl- carbamate protecting group in 238 proved to be a very effective way to generate and study the cycloaromatization chemistry of the derived amine. 109,110 Starting from the TBS ether 239 of 3-hydroxyquinoline, Magnus et al. achieved regioselective introduction of the entire enediyne chain giving 240 after cobalt carbonyl complexation (Scheme 46).I15 Providing nitromethane, a polar cation solvating solvent, was employed in the subsequent cyclization step (a Nicholas reaction), the desired product 241 was obtained in 43% yield. Liberation of the acetylene moiety gave the dynemicin analogue 242, which proved to be remarkably stable to Bergman cyclization compared to 94.In a closely related fashion formation of enediyne 244 from the 6-methoxyquinoline derivative 243 was achieved. However, the difficulty in accessing the starting material for this study led Magnus to conceive an alternative strategy involving epoxidation and selenoxide elimination (245 +246) to introduce the C-3 oxygen substituent (Scheme Two other relevant aspects of the chemistry of these dynemicin systems is the observed isomerization of the bridgehead selenoxide 247 to the corresponding selenite ester 249, via, most probably, the iminium quinomethide 248 (Scheme 48), and the discovery of a nonradical cycloaromatization pathway upon treatment of enediyne 242 with the thiolate ion (2424250, Scheme 49)."6,117 Recently, Takahashi has developed a promising new approach to the dynemicin system in which the 47).239 R' = H 243 R' = OMe A' 242 R' = H 244 R' = OMe Scheme 46 LJ 1 R' R' 241 Ado&, 8" ii. i. Ph2Se2, HP m-CPBA, NaBH4 K2C03 Ad02C&rp - SePh iii. TBSCl / / OMe 245 I OMe 246 m-CPBA, KzC03 (C0)3 1 OTBS N I R"O*C, q R' 240 Scheme 47 2,3-Wittig rearrangement reaction of 251 is employed to generate the tetrahydroquinoline intermediate 252 (Scheme 50)."* Dehydration of this intermediate to diene 253 (a Z,E:Z,Z mixture which is isomerized totally to Z,Z-253 using 12) opened the way to construction of compound 254, 116 Contemporary Organic Synthesisand its conversion to 255 in an intramolecular Diels-Alder reaction.Alternatively, compound 253 was reacted with dimethyl acetylenedicarboxylate in an intermolecular cycloaddition sequence to give the compound 256. Notice that both routes permit control of the C-2,4,7 stereochemistry. In a manner similar to Danishefsky (see Scheme 53), the i. Me02C-C02Me (3:2 mixture), 80% ii. m-CPBA iii. AgN03, NIS 60% AdOzC, p R = Se(0)Ph R 247 R = Se(0)Ph 249 R = OSePh Scheme 48 d= OSePh (pi TBS %OH Me02C, 255 Scheme 50 bis(iodoa1kyne) intermediate 256 was coupled with 2-bis( trimethylstanny1)et hylene to give the dynemicin analogue 257. workers have adapted their Diels-Alder approach in the enediyne field to access di-0-methyl dynemicin methyl ester 271. In the initial phase, In a very elegant fashion, Schreiber and co- 250 242 Scheme 49 TMS TMS I Me02C, T M S e M g B r \ -- ’ \\ CIC02Me (3:l mixture) 95% 251 TBS 252 :BS ii.DBU 67% i. MsCl iii. I2 1 h TMS iii. TsOH 254 68% iBS TBS 253 257 256 Lhermitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 117i. (y-3 TBSO Me Pd’, 85% ii. BtMg SiMeThexyl iii. TBAF c OH Me Br 258 259 i. BrCH=CHC02Me BrCH=CHC02Me PdO4lI (cat.) w Br Me 260 i. Et3SiH I MeAICI2 ii. (COCl)2 iii. TMSOTf iv. D W 51% 261 CI c’v Cocl DMAP, 50% rTpyrmliiino 0s onium exa luorophosphate 51 % B201 1 s’ I OMe i. MeAIC12 ii. Mesityl-SO2NHNHp 4 262 263 R’ = OH, R2 = U-H, R3= ~ O B Z iii. Protect R‘ = H, R2 = &H, R3 = Me ,1 li.”c”A”N 92% I 90% 264 R0 OMe Br 267 AgOTf c ii. K2CO3, Me2S04 57% OMe 266 -0Me 268 OMe 265 i. mCPBA ii. DBU, MeOH iii. CAN - OMe OH OMe OMe OH 0 OMe 0 OH - - 270 269 271 Scheme 51 118 Contemporary Organic Synthesis3-bromo-6-met hoxyquinoline 258 was converted to the acyclic enediyne intermediate 259, which was in turn elaborated to compounds 260 and 261 (Scheme 51).'19 Subjection of these intermediates to conditions aimed at achieving macrocyclization led directly to formation of a common product 262, resulting from an apparent room temperature [4 + 21 cycloaddition.Further experimentation revealed the necessity to epimerize the lactone ring of 262 such that repositioning the double bond to the A-B ring junction position would produce the correct C-4 methyl stereochemistry. Thus, after N-protecting group modification, reaction with DBU and oxidation with CAN gave 263, which was reacted with EtAlCl, at low temperature followed by quenching with mesitylenesulfonylhydrazide. In this way the desired product 265 was produced via a [ 1,5]-sigmatropic rearrangement of the diazene intermediate 264.At this point the A-ring enol ester !i.g;,yg * Me0 # 0Me 04% Tf20 heat. 180°C_ @;:: / NHBoc m -CPBA \ OH 0 0 iii. Pdo, ArB(OH)* 272 273 bR3 274 R2 = OTf; R3 = Me [IIR2=H; R3=TBS S OTBS i. TsOH ii. (Im)&S 65% - OTBS 277 Bu3SnH, AlBN 97% 1 OTBS 278 i. C02, MgBr2. TEA ii. KOBu', MeOTf 49% i. mCPBA ii. TBAF iii. TBSCl iv. Swem oxidation v. KHMDS, CeCI3 rt All0 OMe OH OTBS 276 275 OTBS 0 279 280 PdO 60% (+)-dynemicin A 4 Scheme 52 OTMS 283 OTMS 282 KHMDS 0 281 Lhemitte und Grierson: Enediyne bused antiturnour antibiotics. Part 2 119system of 266 was elaborated by oxidative cleavage of the lactone ring, and the N-protecting group was further modified to enhance its base lability.Under precise conditions, the silver triflate promoted Freidel-Crafts reaction of 266 with 267 produced compounds 268 (1 : 1 mixture) in 57% yield. This intermediate was then converted to the hexacyclic ketol269 (51% overall) exploiting i. @:2 MOMO technology developed for a model system (see Scheme 39). In the final, delicate steps of the synthesis the epoxide unit was introduced, the D-ring nitrogen was deprotected, and the resultant intermediate was oxidized using CAN to give the target molecule 271. It is remarkable that the N- deprotected compound could be converted to the iminoquinone intermediate 270 before total loss of ii.Ph(OTFA)2 i. OsO.,, NMO ii. Ph2(0Me)2 1 M e 3 S n q SnMe3 TIPS ROAN 0 8 0: =OAc *oA&..okph \ ’-0 Ph (.&> OTBS OTBS *‘OAc 0 \ 0 OTBS 288 OTBS 287 COPMOM b Teoc, COZMOM iii. Dess-Mattin periodinane iv Cr2CI v.’C02 hfgBr, TEA vi. MOMCI OMe OMe OTBS OTBS 0 289 290 291 MOMO I (+)-dynemicin A 4 293 Scheme 53 120 Contemporary Organic Synthesisthe molecule occurred through the competing dynemicin cycloaromatization pathway. In their first synthesis of (+)-dynemicin A, Myers et al. settled the problem of the C-4 methyl stereochemistry in the first steps through the use of monochiral diketone 272 as the A-ring precursor (Scheme 52).lZ0 Pdo catalysed condensation of the enol triflate of this intermediate with tert-butyl- 2-borono-4-methoxycarbinolate gave compound 273, which was ring closed and converted to hydroxy ketal274.Introduction of the epoxide unit and enediyne bridge was then undertaken giving 276. Note that the alcohol function and one of the methoxy oxygens played a critical role in directing acetylene addition to the same face of 275 as the methyl substituent. At this juncture ketal deprotection and reaction of cyclic thiocarbonate 277 with tin hydride produced ketone 278. In a very expeditious manner this ketone was converted in two steps (COz, MgBr2, Et,N then KOBu', MeOTf) to the enol methyl ether carboxylic acid 279. Reaction of the desilylated phenol derivative of 279 with iodosobenzene afforded compound 280, which on N-deprotection was transformed to the stable quinone imine 281. To build up the A-B rings of dynemicin a series of different isobenzofurans derivatives were evaluated as Diels-Alder dienophiles. The combination which led to (+)-dynemicin A 4 involved cycloaddition of quinone imine 281 with the tris(trimethylsily1- oxy)isobenzofuran 282 followed by air oxidation and deprotection of the derived Diels-Alder adduct 283.In Danishefsky's total synthesis of ( f )-dynemicin, Diels-Alder chemistry was used in the initial steps to fix the stereochemistry of the C-4 and C-7 centres (Scheme 53).12' This involved Lewis acid mediated intramolecular cycloaddition of compound 284, oxidation of the derived hydroquinone 285 and B- ring closure giving 286. cis-Dihydroxylation of 286 and ketal formation encumbered the lower face of the molecule, thereby directing introduction of the acetylene at C-2 in the required fashion (7 : 1 mixture) to give 287.Seven steps were subsequently needed to construct the C-7 acetylene, modify the hydroxy protection and iodinate both alkyne units giving 288. In a new innovation brought to the dynemicin field, the enediyne bridge was then installed by Pdo coupling of 288 with 2- bis(trimethylstanny1)ethylene producing the enediyne product 289. After subsequent acetate cleavage and removal of the C-5 hydroxy group, the resultant intermediate, the C-5,6 enol ether-ester system of 290 was elaborated. 0-TBS deprotection and treatment with PhI(OAc)2 then produced the key iminoquinone product 291. The D-E rings were built onto this substrate through reaction with the lithium anion of the homophthalic anhydride 292, followed by oxidation of the derived adduct.Exposure of this product to oxygen and light followed by 0-MOM deprotection of quinone 293 completed the synthesis of dynemicin A 4. 6 Conclusion The total synthesis of dynemicin A by Myers and Danishefsky, like the accomplishments in the calicheamicin/esperamicin and neocarzinostatin area, marks just the beginning of what will be a rich harvest of knowledge which synthetic chemists will employ in the construction of the enediyne- and dienediyne-containing molecules that nature still has in waiting. 7 References and notes 1 N. Ishida, K. Miyazaki, K. Kumagai and M. Rikimaru, J. Antibiot., 1965, 18, 68; K. Edo, M. Mizugaki, Y. Koide, H. Seto, K. Furihata, N. Otake and N. Ishida, Tetrahedron Lett., 1985, 26, 331.2 M. D. Lee, T. S. Dunne, M. M. Siegel, C. C. Chang, G. 0. Morton and D. B. Borders, J. Am. Chem. SOC., 1987, 109,3464; M. D. Lee, T. S. Dunne, C. C. Chang, G. A. Ellestad, M. M. Siegel, G. 0. Morton, W. J. McGahren and D. B. Borders, J. Am. Chem. SOC., 1987, 109, 3466. 3 J. Golik, J. Clardy, G. Dubay, G. Groenewold, H. Kawaguchi, M. Konishi, B. Krishnan, H. Ohkuma, K.-I. Saitoh and T. W. Doyle, J. Am. Chem. SOC., 1987, 109, 3461; J. Golik, G. Dubay, G. Groenewold, H. Kawaguchi, M. Konishi, B. Krishnan, H. Ohkuma, K.-I. Saitoh and T. W. Doyle, J. Am. Chem. SOC., 1987, 109,3462. 4 M. Konishi, H. Ohkuma, T. Tsuno, T. Oki, G. D. VanDuyne and J. Clardy, J. Am. Chem. Soc., 1990, 112,3715. 5 G. Pratviel, J. Bernadou and B. Meunier, Angew. Chem., Int.Ed. Engl., 1995, 34, 746; Enediyne Antibiotics as Antitumor Agents, ed. D. B. Broders and T. W. Doyle, Marcel Dekker, New York, 1994. 6 See Part 1 of this review: H. Lhermitte and D. S. Grierson, Contemp. 0%. Synth., 1996,3,41. 7 R. R. Jones and R. G. Bergman, J. Am. Chem. SOC., 1972, 94,660; R. G. Bergman, Acc. Chem. Res., 1973, 6, 25; T. P. Lockhart, P. B. Comita and R. G. Bergman, J. Am. Chem. SOC., 1981, 103, 4082; T. P. Lockhart and R. G. Bergman, J. Am. Chem. SOC., 1981, 103, 4091. 8 A. G. Myers, Tetrahedron Lett., 1987, 28, 4493; I. H. Goldberg,Acc. Chem. Res., 1991, 24, 191. 9 P. A. Wender, M. Harmata, D. Jeffrey, C. Mukai and J. Suffert, Tetrahedron Lett., 1988, 29, 909. review.'j 23. Chem. SOC., 1990, 112,5369. Mah, Tetrahedron Lett., 1990, 31, 6605.J. Am. Chem. SOC., 1977, 99, 3179. Lett., 1990, 31, 3533. 3465. Yamada, T. Shiraki and Y. Sugiura, Angew. Chem., Int. Ed. Engl,, 1993, 32, 1657. 10 See Scheme 36 and reference 74 in Part 1 of this 11 K. Mikami, H. Matsueda and T. Nakai, Synlett, 1993, 12 P. A. Wender, J. A. McKinney and C. Mukai, J. Am. 13 P. A. Wender, J. W. Grissom, U. Hoffmann and R. 14 Y. Okude, S. Hirano, T. Hiyama and H. Nozaki, 15 A. Krebs, T. Wehlage and C.-P. Kramer, Tetrahedron 16 T. Doi and T. Takahashi, J. OR. Chem., 1991,56, 17 T. Takahashi, H. Tanaka, Y. Hirai, T. Doi, H. Lherrnitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 12118 See also: S. Caddick and S. Khan, J. Chem. SOC., Chem. Commun., 1995, 1971. 19 P. Magnus and T. Pitterna, J. Chem. SOC., Chem. Commun., 1991,541.20 P. Magnus and M. Davies, J. Chem. SOC., Chem. Commun., 1991, 1522. 21 A. G. Myers, M. A. M. Fundy and P. A. Lindstrom Jr., Tetrahedron Lett., 1988; 29, 5609; A. G. Myers, M. M. Alauddin, M. A. M. Fuhry, P. S. Dragovich, N. S. Finney and P. M. Harrington, Tetrahedron Lett., 1989,30, 6997; A. G. Myers, P. M. Harrington and E. Y. Kuo, J. Am. Chem. SOC., 1991, 113, 694; A. G. Myers, P. M. Harrington and B.-M. Kwon, J. Am. Chem. SOC., 1992, 114, 1086. 22 See also: N. A. Petasis and K. A. Teets, Tetrahedron Lett., 1993, 34, 805. 23 K.-I. Yoshida, Y. Minami, R. Azuma, M. Saeki and T. Otani, Tetrahedron Lett., 1993, 34, 2637. 24 J. E. Leet, D. R. Schroeder, F. J. Hofstead, J. Golik, K. L. Colson, S. Huang, S. E. Klohr, T. W. Doyle and J. A. Matson, J.Am. Chem. SOC., 1992, 114,4976; J. E. Leet, D. R. Schroeder, D. R. Langley, K. L. Colson, S. Huang, S. E. Klohr, M. S. Lee, J. Golik, S. J. Hofstead, T. W. Doyle and J. A. Matson, J. Am. Chem. SOC., 1993, 115,8432. 116, 10310. 117,8875. Estevez and W.-M. Dai, J, Am. Chem. SOC., 1992, 114, 7360. 28 K.-I. Iida, T. Ishii, M. Hirama, T. Otani, Y. Minami and K.-I. Yoshida, Tetrahedron Lett., 1993, 34, 4079. 29 T. Vuljanic, J. Kihlberg and P. Somfai, Tetrahedron Lett., 1994, 35, 6937. 30 D. Guillerm and G. Linstrumelle, Tetrahedron Lett., 1985,26, 3811; K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975, 4467; K. P. C. Vollhardt and L. S . Winn, Tetrahedron Lett., 1985, 26, 709; S. J. Danishefsky, D. S. Yamashita and N. B. Mantlo, Tetrahedron Lett., 1988, 37, 4681; see also: K.Sonogashira, in Comprehensive Organic Synthesis; ed. B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991,3, pp. 521-549. 31 A. S. Kende and C . A. Smith, Tetrahedron Lett., 1988, 29, 4217. 32 J. N. Haseltine, M. P. Cabal, N. B. Mantlo, N. Iwasawa, D. S. Yamashita, R. S. Coleman, S. J. Danishefsky and G. K. Schulte, J. Am. Chem. SOC., 1991, 113, 3850; J. N. Haseltine and S. J. Danishefsky, J. OF. Chem., 1990, 55, 2576; M. P. Cabal, R. S. Coleman and S. J. Danishefsky, J. Am. Chem. SOC., 1990, 112, 3253; J. N. Haseltine, S. J. Danishefsky and G. K. Schulte, J. Am. Chem. SOC., 1989, 111, 7638; N. B. Mantlo and S. J. Danishefsky, J. Org. Chem., 1989, 54, 2781; S. J. Danishefsky, N. B. Mantlo and D. S . Yamashita, J. Am. Chem. SOC., 1989, 111, 7638; N.B. Mantlo and S. J. Danishefsky, J. 0%. Chem., 1989, 54, 2781; S. J. Danishefsky, N. B. Mantlo and D. S. Yamashita, J. Am. Chem. SOC., 1988, 110, 6890. 33 E. Alder, S. Brasen and H. Miyake, Acta Chem. Scand., 1971,25, 2055; H.-D. Becker, T. Bremholt and E. Alder, Tetrahedron Lett., 1972, 4205. 34 D. B. Dess and J. C. Martin, J. Am. Chem. SOC., 1991, 113, 7277; D. B. Dess and J. C. Martin, J. Org. Chem., 1983,48,4155. 1981, 22,4213. 25 K.-I. Iida and M. Hirama, J. Am. Chem. SOC., 1994, 26 K.-I. Iida and M. Hirama, J. Am. Chem. SOC., 1995, 27 K. C. Nicolaou, G. Zuccarello, C. Riemer, V. A. 35 D. L. Comins and J. D. Brown, Tetrahedron Lett., 36 D. N. Harpp and J. G. Gleason, J. Am. Chem. SOC., 1971,93,2437; D. N. Harpp and D. K. Ash, J. Chem. SOC., Chem.Commun., 1991,541; D. N. Harpp and R. A. Smith, J. Am. Chem. SOC., 1982,104,6045. 37 A. L. Smith, E. N. Pitsinos, C.-K. Hwang, Y. Mizuno, H. Saimoto, G. R. Scariato, T. Suzuki and K. C. Nicolaou, J. Am. Chem. SOC., 1993,115,7612; A. L. Smith, C.-K. Hwang, E. Pitsinos, G. R. Scarlato and K. C. Nicolaou,J. Am. Chem. SOC., 1993,115, 7612; A. L. Smith, C.-K. Hwang, E. Pitsinos, G. R. Scarlato and K. C. Nicolaou, J. Am. Chem. SOC., 1992, 114, 3134. J. Clardy, Tetrahedron Lett., 1992,33, 6049. S. J. Danishefsky and D. M. Crothers,Angew. Chem., Int. Ed. Engl., 1994,33, 855. Grierson, in Recent Progress in the Chemical Synthesis of Antibiotics, ed G. Lukacs, Springer-Verlag, Berlin, 38 J. Golik, B. Krishnan, T. W. Doyle, G. VanDuyne and 39 J. Aiyar, S. A. Hitchcock, D.Denhart, K. K. C. Liu, 40 T. Skrydstrup, H. Audrain, G. Ulibarri and D. S. 1993, VO~. 11, pp. 213-292. 41 G. Ulibarri, T. Skrydstrup, H. Audrain and D. S. 42 J. F. Kadow, D. J. Cook, T. W. Doyle, D. R. Langley, Grierson, J. Org. Chem., 1995, 60, 2753. K. M. Pham, D. M. Vyas and M. D. Wittman, Tetrahedron, 1994, 50, 1519. 43 T. Nishikawa, S. Shibuya and M. Isobe, Synlett, 1994, 482. 44 H. Mastalerz, T. Doyle, J. Kadow, K. hung and D. Vyas, Tetrahedron Lett., 1995,36, 4927. 45 P. Magnus, P. Carter, J. Elliott, R. Lewis, J. Harling, T. Pitterna, W. E. Bauta and S. Fortt, J. Am. Chem. SOC., 1992, 114,2544; P. Magnus, R. T. Lewis and J. C. Huffman, J. Am. Chem. SOC., 1988, 110, 6921; P. Magnus and P. A. Carter, J. Am. Chem. SOC., 1988, 110, 1626. 46 General overviews: P.Magnus, Tetrahedron, 1994,50, 1397; P. Magnus, in Organometallic Reagents in Organic Synthesis, Academic Press, 1994, pp. 1-32. Koga, Tetrahedron Lett., 1989, 30, 851; J. F. Kadow, M. G. Saulnier, M. M. Tun, D. R. Langley and D. M. Vyas, Tetrahedron Lett., 1988,30, 3499. 48 P. Magnus, R. T. Lewis and F. Bennett, J. Am. Chem. SOC., 1992, 114, 2560. 49 P. Magnus and F. Bennett, Tetrahedron Lett., 1989, 30, 3637; P. Magnus and R. T. Lewis, Tetrahedron Lett., 1989,30, 1905. 50 P. Magnus, R. T. Lewis and F. Bennet, J. Chem. SOC., Chem. Commun., 1989,916. 51 P. Magnus, H. Annoura and J. Harling, J. 0%. Chem., 1990, 55, 1709. 52 J. F. Kadow, M. M. Tun, D. M. Vyas, M. D. Wittman and T. W. Doyle, Tetrahedron Lett., 1992,33, 1423. 53 G. P. Roth, D. R. Marshall, J.F. Kadow, S. W. Mamber, W. C. Rose, W. Solomon and N. Zein, Bioorg. Med. Chem. Lett., 1994, 4, 711. 54 D. A. Clark, F. De Riccardis and K. C. Nicolaou, Tetrahedron, 1994,50, 11 391. 55 S. L. Schreiber and L. L. Kiessling, J. Am. Chem. SOC., 1988, 110, 631; S. L. Schreiber and L. L. Kiessling, Tetrahedron Lett., 1989,30, 433; F. J. Schoenen, J. A. Porco Jr, S. L. Schreiber, G. D. VanDuyne and J. Clardy, Tetrahedron Lett., 1989, 30, 3765. 56 S. Walker, J. Murnick and D. Kahne, J. Am. Chem. SOC., 1993, 115, 7954; D. R. Langley, T. W. Doyle and D. L. Beveridge, Tetrahedron, 1994, 50, 1379; D. R. Langley, J. Golik, B. Krishnan, T. W. Doyle and D. L. Beveridge, J. Am. Chem. SOC., 1994, 116, 15; S. Walker, D. Gange, V. Gupta and D. Kahne, J. Am. 47 For related work, see: K.Tomioka, H. Fujita and K. 122 Contemporary Organic SynthesisChem. SOC., 1994, 116,3197; T. Li, Z. Zeng, V. A. Estevez, K. U. Baldenius, K. C. Nicolaou and G. F. Joyce, J. Am. Chem. SOC., 1994,116, 3709; L. G. Paloma, J. A. Smith, W. J. Chazin and K. C. Nicolaou, J. Am. Chem. SOC., 1994, 116, 3697; M. Chatterjee, S. C. Mah, T. D. Tullius and C. A. Townsend, J. Am. Chem. SOC., 1995,117,8074. 57 Syntheses of the C-ring, the D-ring and the C-D ring fragment of calicheamicin 2 include: K. C. Nicolaou, T. Ebata, N. A. Stylianides, R. D. Groneberg and P. J. Carro1,Angew. Chem., Int. Ed. Engl., 1988, 27, 1097; K. V. Laak and H.-D. Scharf, Tetrahedron, 1989, 45,5511; K. V. Laak, H. Rainer and H.-D. Scharf, Etrahedron Lett., 1990,31, 4113; S. H. Olson and S. J.Danishefsky, Tetrahedron Lett., 1994,30, 7901; see also: references 61,69 and 74. 58 Two syntheses of the A-ring sugar equipped with the C-4 hydroxylamine substituent have also been developed: H. Rainer and H.-D. Scharf, Liebigs Ann. Chem., 1993, 117; see also: Golik et al., reference 60. 59 For preparation of the C-D aryl monosaccharide unit in esperamicin 3; see reference 73. 60 In instances where the C-4 hydroxylamine nitrogen and the anomeric centre in ring A are unprotected, very facile rearrangement to a nitrone intermediate occurs: J. Golik, H. Wong, B. Krishnan, D. M. Vyas and T. W. Doyle, Tetrahedron Lett., 1991,32, 1851; see also: reference 69. 61 K. C. Nicolaou, R. D. Groneberg, N. A. Stylianides and T. Miyazaki, J. Chem. SOC., Chem. Commun., 1990, 1275.62 W. R. Roush and J. A. Hunt, J. 0%. Chem., 1995,60, 798. 63 See also: J. Golik, H. Wong, D. M. Vyas and T. W. Doyle, Tetrahedron Lett., 1989,30, 2497. 64 R. D. Groneberg, T. Miyazaki, N. A. Stylianides, T. J. Schultz, W. Stahl, E. P. Schreiner, T. Suzuki, Y. Iwabuchi, A. I. Smith and K. C. Nicolaou, J. Am. Chem. SOC., 1993, 115, 7593; K. C. Nicolaou, R. D. Groneberg, T. MIyazaki, N. A. Stylianides, T. J. Schulze and W. Stahl, J. Am. Chem. SOC., 1990, 112, 8193. 65 D. Kahne, D. Yang and M. D. Lee, Tetrahedron Lett., 1990, 31, 21. 66 D. Kahne, S. Walker, Y. Cheng and D. Van Engen, J. Am. Chem. SOC., 1989, 111,6881. 67 S.-H. Kim, D. Augeri, D. Yang and D. Kahne, J. Am. Chem. SOC., 1994,116, 1766; D. Yang, S.-H. Kim and D. Kahne, J. Am. Chem. SOC., 1991,113,4715. 68 R.L. Halcomb, M. D. Wittman, S. H. Olson and S. J. Danishefsky, J. Am. Chem. SOC., 1991, 113,5080. 69 R. L. Halcomb, S. H. Boyer, M. D. Wittman, S. H. Olson, D. J. Denhart, K. K. C. Liu and S. J. Danishefsky, J. Am. Chem. SOC., 1995, 117,5720. 70 J. Theim, H. Karl and J. Schwentner, Synthesis, 1978, 696; D. Horton, W. Priebe and M. Sznaidman, Carbohyd,: Res., 1990, 205, 71. 71 E. Da Silva, J. Pradi and J.-M. Beau, J. Chem. SOC., Chem. Commun., 1994, 2127, 72 K. C. Nicolaou and R. D. Groneberg, J. Am. Chem. SOC., 1990, 112, 4085. 73 K. C. Nicolaou and D. Clark, Angew. Chem., Int. Ed. Engl., 1992, 31, 855. 74 R. L. Halcomb, S. H. Boyer and S. J. Danishefsky, Angew. Chem., Int. Ed. Engl., 1992, 31, 338. 75 M. D. Wittman, R. L. Halcomb, S. J. Danishefsky, J. Golik and D.Vyas, J. 0%. Chem., 1990, 55, 1979. 76 Other approaches to the B-ring thio sugar include: F.-Y. Dupradeau, S. Allaire, J. Prandi and J.-M. Beau, Tetrahedron Lett., 1993,34,4513; H.-D. Scharf and K. V. Laak, Tetrahedron Lett., 1989,30,4505; A. Classen and H.-D. Scharf, Liebigs Ann. Chem., 1993, 183; J. Golik, T. W. Doyle, G. Van Duyne and J. Clardy, Tetrahedron Lett., 1990,31, 6149. 77 G. 0. Spessard, W. K. Chan and S. Masamune, OF. Synth., 1983, 61, 134. 78 T. Bamhaoud, J.-M. Lancelin and J.-M. Beau, J. Chem. SOC., Chem. Commun., 1992, 1494. 79 K. C. Nicolaou, C. W. Hummel, M. Nakada, S. Shibayama, E. N. Pitsinos, H. Saimoto, Y. Mizuno, K.-U. Baldenius and A. L. Smith, J. Am. Chem. SOC., 1993, 115, 7625; K. C. Nicolaou, C. W. Hummel, E. N. Pitsinos, M.Nakada, A. L. Smith, K. Shibayama and H. Saimoto, J. Am. Chem. SOC., 1992, 114, 10 082. 80 K. C. Nicolaou, E. P. Schreiner and W. Stah1,Angew. Chem., Int. Ed. Engl., 1991, 30, 585; K. C. Nicolaou, E. P. Schreiner, Y. Iwabuchi and T. Suzuki, Angew. Chem., Int. Ed. Engl., 1992, 31, 340. 81 R. R. Schmidt,Angew. Chem., Int. Ed. Engl., 1986, 25, 212. 82 S. A. Hitchcock, S. H. Boyer, M. Y. Chu-Moyer, S. H. Olson and S. J. Danishefsky, Angew. Chem., Int. Ed. Engl., 1994,33, 858; S. A. Hitchcock, M. Y. Chu- Moyer, S. H. Boyer, S. H. Olson and S. J. Danishefsky, J. Am. Chem. SOC., 1995, 117, 5750. 83 For papers on the enzymatic resolution of synthetic intermediates toward calicheamicinone, see: D. S. Yamashita, V. P. Rocco and S. J. Danishefsky, Tetrahedron Lett., 1991,32, 6667; V.P. Rocco, S. J. Danishefsky and G . K. Schulte, Tetrahedron Lett., 1991,32,6671. 84 Concerning the reactivity of compounds related to calicheamicin precursor 180, see also: K. C. Nicolaou, T. Li, M. Nakada, C. W. Hummel, A. Hiatt and W. Wrasidlo,Angew. Chem., Int. Ed. Engl., 1994,33, 183. 85 T. Nishikawa, M. Isobe and T. Goto, Synlett, 1991, 393. 86 M. E. Maier and U. Abel, Synlett, 1994, 38. 87 T. Nishikawa and M. Isobe, Tetrahedron, 1994, 50, 5621. 88 H. Chikashita, J. A. Porco Jr, T. J. Stout, J. Clardy and S. L. Schreiber, J. 0%. Chem., 1991,56, 1692. 89 K. C. Nicolaou, J. L. Gross, M. A. Kerr, R. H. Lemus, K. Ikeda and K. Ohe, Angew. Chem., Int. Ed. Engl., 1994,33, 781. 90 M. Magnus, S. A. Eisenbeis and N. A. Magnus, J. Chem. SOC., Chem. Commun., 1994, 1545. 91 T. Okita and M. Isobe, Tetrahedron, 1994,50, 11 143. 92 M. Isobe, T. Nishikawa, N. Yamamoto, T. Tsukiyama, A. Ino and T. Okita, J. Heterocycl. Chem., 1992, 29, 619. 93 T. Okita and M. Isobe, Synlett, 1994, 589; T. Okita and M. Isobe, Tetrahedron, 1995,51, 3737. 94 K. C. Nicolaou, C.-K. Hwang, A. L. Smith and S. V. Wendeborn, J. Am. Chem. SOC., 1990, 112,7416. 95 K. C. Nicolaou, A. L. Smith, S. V. Wendeborn and C.-K. Hwang, J. Am. Chem. SOC., 1991, 113,3106. 96 K. C. Nicolaou, P. Maligres, T. Suzuki, S. V. Wendeborn, W.-M. Dai and R. K. Chadha, J. Am. Chem. SOC., 1992, 114, 8890. 97 K. C. Nicolaou, Y.-P. Hong, Y. Torisawa, S.-C. Tsay and W.-M. Dai, J. Am. Chem. SOC., 1991, 113,9878. 98 K. C. Nicolaou, W.-M. Dai, Y. P. Hong, S.-C. Tsay, K. K. Baldridge and J. S. Siegel, J. Am. Chem. SOC., 1993, 115, 7944. 99 K. C . Nicolaou, Y. P. Hong, W.-M. Dai, Z.-J. Zeng and W. Wrasidlo, J. Chem. SOC., Chem. Commun., 1992, 1542. Lhermitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 123100 K. C. Nicolaou, W.-M. Dai, S. V. Wendeborn, A. L. Smith, P. Torisawa, P. Maligres and H.-K. Hwang, Angew. Chem., Int. Ed. Engl., 1991,30, 1032. 101 K. C. Nicolaou, W.-M. Dai, S.-C. Tsay and W. Wrasidlo, Bioog. Med. Chem. Lett., 1992, 2, 1155. 102 K. C. Nicolaou, W.-M. Dai, S.-C. Tsay, V. A. Estevez and W. Wrasidlo, Science, 1992, 256, 1172. 103 K. C. Nicolaou and W.-M. Dai, J. Am. Chem. SOC., 1992,114,8908. 104 W.-M. Dai, J. 0%. Chem., 1993,58, 7581. 105 V. Voekelheide and W. J. Linn, J. Am. Chem. SOC., 106 R. Yamaguchi, Y. Nakazono and M. Kawanisi, 107 P. A. Wender and C. K. Zercher, J. Am. Chem. SOC., 108 P. A. Wender, S. Beckham and D. L. Mohler, 109 P. A. Wender, C. K. Zercher, S. Beckham and E.-M. 110 P. A. Wender, S. Beckham and J. G. O’Leary, 11 1 T. Nishikawa, A. Ino, M. Isobe and T. Goto, Chem. 112 T. Nishikawa, M. Yoshikai, K. Obi and M. Isobe, 113 T. Nishikawa, A. Ino and M. Isobe, Tetrahedron, 1994, 114 T. Nishikawa, M. Isobe and T. Goto, Synlett, 1991, 99. 1954,76, 1286. Tetrahedron Lett., 1983, 27, 1801. 1991,113, 2311. Tetrahedron Lett., 1995, 36, 209. Haubold, J. 0%. Chem., 1993, 58,5867. Synthesis, 1994, 1278. Lett., 1991, 1271. Tetrahedron Lett., 1994, 35, 7997. 50, 1449. 115 P. Magnus and S. M. Fortt, J. Chem. SOC., Chem. Commun., 1991,544. 116 P. Magnus, D. Parry, T. Iliadis, S. A. Eisenbeis and A. Fairhurst, J. Chem. SOC., Chem. Commun., 1994, 1543. 117 P. Magnus and S. A. Eisenbeis, J. Am. Chem. SOC., 1993,115, 12627. 118 Y. Sakamoto and T. Takahashi, Synletf, 1995,513; T. Takahashi, Y. Sakamoto, H. Yamada, S. Usui and Y. Fukazawa,Angew. Chem., Int. Ed. Engl., 1995,34, 1345. 119 J. A. Porco Jr, F. J. Schoenen, T. J. Stout, J. Clardy and S. L. Schreiber, J. Am. Chem. SOC., 1990,112, 7410; J. L. Wood, J. A. Porco Jr, J. Taunton, A. Y. Lee, J. Clardy and S. L. Schreiber, J. Am. Chem. SOC., 1992, 114,5898; J. Taunton, J. L. Wood and S. L. Schreiber, J. Am. Chem. SOC., 1993, 115, 10378. 120 A. G. Myers, M. E. Fraley and N. J. Tom, J. Am. Chem. SOC., 1994,116, 11 556; A. G. Myers, M. E. Fraley, N. J. Tom, S. B. Cohen and D. J. Madar, Chem. Biol., 1995, 2, 33. Chem., 1994,59,3755; T. Yoon, M. D. Shair, S. J. Danishefsky and G. E. Shulte, J. 0%. Chem., 1994,59, 3752; M. D. Shair, T. Yoon, T.-C. Chou and S. J. Danishefsky, Angew. Chem., Int. Ed. Engl., 1994,33, 2477; T. Yoon, M. D. Shair and S. J. Danishefsky, Tetrahedron Lett., 1994, 35, 6259; M. D. Shair, T.-Y. Yoon and S. J. Danishefsky, Angew. Chem., Int. Ed. Engl., 19!%, 34, 1721. 121 M. D. Shair, T. Yoon and S. J. Danishefsky, J. 0%. 124 Contemporary Organic Synthesis