~~ The enediyne and dienediyne based antitumour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 1 HERVE LHERMITTE AND DAVID s. GRIERSON* Institut de Chimie des Substances Naturelles, F-91198 Gij-sur-Yvette, France Reviewing the literature published up to 15 October 1995 1 Introduction 2 3 4 Simple yne-ene-allenes and yne-ene-cumulenes 5 Ten-membered ring and higher neocarzinostatin chromophore analogues 6 Conclusion 7 References and notes Enediyne construction and simple monocyclic and bicyclic enediynes Monocyclic and bicyclic enediynes with novel activating devices 1 Introduction In a key contribution to the study of aromatic systems and aromaticity, Bergman and collaborators carried out experiments nearly twenty-five years ago to define the physical existance, structure, bonding properties and reactivity of 1,4-dehydrobenzene 2.' In one particularly elegant experiment the scrambling of the deuterium label in the acyclic enediyne 1 (R = D) provided convincing evidence for the intermediacy of phenylene diradical2 (Scheme 1).This result, further, offered a coherent mechanistic rationale for a number of unexpected transformations, including the tendency of molecules such as the dehydro-azulene 3 and the 1,5-dehydro[ lolannulene 4 to undergo rapid cycloaromatization.27' As important as these studies remain today from a fundamental point of view, the human spirit was a long way at that time from imagining the creative way in which nature has for eons enabled microorganisms to employ this same process in a controlled and lethal manner to assure their proper defence.However, our awareness of this situation changed in the mid 1980s with the structure elucidation of the complex and extraordinary novel antibiotics calicheamicin 5,4 esperamicin 65 and the neocarzinostatin chromophore 9,6 the first three members of a family 3 + r 1 4 & Scheme 1 of naturally occurring and highly potent cytotoxic agents. The most notable features in the common core structure of ( -)-calicheamicin yI1 and (-)-esperamicin Al (Scheme 2) are the presence of a contiguous yne-ene-yne (or 'enediyne') system incorporated into a bicyclo[7.3.l]tridecane framework, an allylic trisulfide unit, and an enone system in which the double bond occupies the bridgehead position.Chemical and biochemical investigations have shown that these entities react in concert to generate the highly reactive 1,4-phenylene diradical intermediate 8 which cause cell destruction through single and double strand Lhemitte and Grierson: Enediyne based antitumour antibiotics. Part 1 41lHfio MesSS MeO 0 Me 5 calicheamicin-yl* R' = H, R2 = Et, R3 = I 1. S 3 M d - ii. Michael addition 7 Scheme 2 Me 8 A? cleavage of duplex DNA.7-9 This is brought about by an unprecedented multistep mechanism involving the aryl oligosaccharide mediated association of the antibiotic with its intracellular target, cleavage (reduction) of the trisulfide bond, and Michael addition of the resulting thiolate anion to the enone double bond to produce the highly strained intermediate 7 lacking the crucial C-9,lO bridgehead double bond.This latter structural modification activates, or unlocks, the molecule with respect to spontaneous Bergman type cycloaromatization to diradical 8. The neocarzinostatin chromophore 9, a very heat-, light- and pH-sensitive 9-membered bicyclic dienediyne, exists in nature in association with an apoprotein." With the knowledge that 9 is activated towards DNA cleavage through reaction with thiols,*-" Myers proposed a mechanism whereby thiol addition at C-12 initiates epoxide ring opening and formation of the yne-ene-cumulene 10 (Scheme 3).11 This strained and very highly reactive intermediate then undergoes a cycloaromatization reaction, analogous to that for the enediynes, giving the diradical 11 which cleaves DNA through hydrogen atom abstraction.In an elegant series of NMR experiments Myers both confirmed the formation of the thioglycolate derivative of 10, measured its stability (ti = 2 h at -38 "C), and deduced the absolute stereochemistry of 9.l27I3 Recently, it has been shown that the alternative pathway, leading to the diradical 13 or its zwitterionic resonance form 14 via cumulene 12, is also operative in aqueous buffered ~olution.'~ In 1990, Konishi and Clardy reported the structure of another enediyne antibiotic, Ar 11 10 12 neocarzinostatin 9 . 13 t L Scheme 3 42 Contemporary Organic Synthesis(+)-dynemicin A 15 (Scheme 4).lS This unique hybrid molecule is essentially composed from an enediyne core as found in calicheamicin/ esperamicin, and an anthraquinone unit typical of the anthracyclines which can associate with DNA through inter~alation.~~~””’” Between these two halves of the molecule is an angular epoxide function which acts as the triggering device.Bioreduction of the paraquinone system of 15 giving 16 activates the molecule toward epoxide opening according to pathway B, or through participation of the electrons on nitrogen (pathway A). As discussed further on, the latter mechanism has, in particular, been exploited to activate simplified analogues of dynemicin A. Reaction of either intermediate with the OH- (Nu-) ion giving 17 alters the shape and strain energy of the D/E rings promoting spontaneous Bergman cyclization to diradical 18. The highly strained nature of dynemicin A is readily apparent from the X-ray crystal structure of its triacetate derivative.” In this molecule the alkyne substituents are bent by up to 20” from linearity, and the distance between the tyo acetylene terminal carbons 23 an< 28 is 3.54 A, i.e.considerably less than the 4.17 A separation observed between the same carbons in 1. Over the past three or four years three new molecules have been added to the list of enediyne based antitumor agents. These include kedarcidin 1918 and C-1027 2OI9 which both possess an enediyne unit within a 9-membered bicyclic framework related to the neocarzinostatin chomophore (Scheme 5). Certain elements are still undetermined concerning the structure of the third and extremely labile molecule named maduropeptin.” However, from the structure of the artifact 21, one perceives a new mechanism of activation involving SN2’ displacement of X- and generation of the central enediyne double bond in 22.discovering new anticancer agents based upon the novel structure and mechanism of action of the enediyne-dienediyne antibiotics, intense efforts have been made to both achieve their total synthesis, and to access simpler and more stable biologically active analogues. Work toward both goals has necessitated the development of new synthetic methodology for the efficient construction of the enynes and enediynes, and for the incorporation of these entities into strained mono- and polycyclic structures under conditions where adventitious cycloaromatization, and/or other undesired rearrangements are avoided. It has similarly required the invention of novel triggering devices, and experiments to establish the different factors which permit Bergman and Myers type electrocyclization of enediyne, yne-ene-allene and yne-ene-cumulene systems to occur at physiological temperatures.These, and many other challenging aspects of the chemistry in this field, are described in this two-part review. In Part 1, synthetic approaches, and the reactivity of simple enediynes and neocarzinostatin analogues are described. In Part 2,20a the discussion In view of the large possibilities of designing and OH 0 OH (+)-dynemicin A 15 IEE OH OH OH 16 C02H OH OH OH OMe OH OH OH OH OH OH 17 Bergman cyclization I COPH OMe OH OH OH 18 Scheme 4 Lhermitte and Grierson: Enediyne based antiturnour antibiotics.Part I 43Me' kedarcidin 19 o \ A0 NH2 C-1027 20 maduropeptin 21 (major artifact) I I h;le Scheme 5 centres more specifically upon the strategies developed for the total synthesis of the neocarzinostatin chromophore, calicheamicin yl', esperamicin Al and dynemicin A. Several earlier reviews have appeared treating the chemistry and/or biological properties of the enediyne-diendiyne antibiotic^.^*^'^'-^* 2 Enediyne construction and simple monocyclic and bicyclic enediynes The seminal investigations by Bergman on the cycloaromatization of simple acyclic enediynes demonstrated that heating to approximately 200 "C is required in order to surmount the activation barrier (AEact = 28-32 kcal mol-') to transformation of 1 to the 174-phenylene diradical 2.1,26,27 In contrast, calicheamicin, dynemicin A and the other enediynes undergo almost instantaneous ambient temperature cycloaromatization upon activation, indicating that incorporation of the enediyne system into a cyclic structure lowers A&,, significantly (21-24 kcal mol-' range).To systematically examine the influence of ring size, and hence the distance rc,d between the acetylene terminal carbon atoms, on cycloaromatization rates, Nicolaou devised a route to the monocyclic enediynes 25 (n = 2-8) starting from the appropriate dibromides 23-28-30 In this approach the key step was the Ramberg-Backlund ring contraction of the sulfone intermediates 24 (Scheme 6).31 These studies showed that for the 10-membered all carbon monocyclic Fnediyne 25 (n = 2), rc,d falls in the range (3.20-3.30 A; MMX calculations) where Bergman cyclization can occur at an appreciable rate at 37 "C (flI2 = 11.8 h).Interestingly, attempts to prepare the 9-membered enediyne 25 (rz = 1) by this route resulted in formation of enediyne 27, presumably by a Cope type rearrangement of 26 and SOz extrusion. Magnus and Snyder further showed that for more highly functionalized cyclic enediynes, AEact is primarily determined by factors influencing the strain energy (i) of the ground state structure and (ii) at the transition state for the cycloaromatization r e a ~ t i o n . ~ ~ , ~ ~ 27 26 Schema 6 44 Contemporary Organic SynthesisOf major impact to all subsequent syntheses of the enediyne and neocarzinostatin type systems has been the existence of modern palladium(0) based coupling methodology permitting assembly of the key ene-yne motif from a wide variety of olefin and acetylene precursors under operationally simple, exceptionally mild, and high yielding conditions.The generality of this approach is nicely illustrated by the construction of the parent 3-ene-1,5-diyne 1 (R = TMS) by V ~ l l h a r d t , ~ ~ ~ ~ ~ and the stable 12-membered ring lactone 30 by Linstrumelle (Scheme 7).35736 In this latter synthesis, described two years prior to the discovery of calicheamicid esperamicin, the species produced by oxidative addition of cis-dichloroethene 28 to Pd(0) reacts with an in situ generated copper acetylide intermediate, and the resulting vinyl-alkynyl palladium derivative undergoes a reductive elimination to liberate the ene-yne product 29 and the Pd(0) catalyst.Various amine bases (Et2NH, Et3N, PriNH2, BuNH2) can be employed in this (Ph3P)4Pdo can be replaced by (Ph3P)2PdC12 when a slight excess of the acetylene component is used to effect reduction of Pd(11).'~ Vinyl and alkynyl tin, zinc and boron reagents can also be employed in these palladium co~plings."~-~* Recently it has been shown that Pd(0) coupling of terminal acetylenes with vinyl bromides, iodides and triflates does not require added CuI when pyrrolidine or piperidine is used as the and, as described by Sonogashira, I"" Pdo-CuI - To" 30 Scheme 7 Following the Linstrumelle strategy the more strained 10-membered monocyclic enediyne 31 has been prepared,@ and by replacing cis-dichloroethene by o-dibromobenzene the related benzodiyne 32 was also These compounds undergo Bergman cyclization at temperatures higher than the parent enediyne 25 (n = 2).Pdo-CuI mediated coupling of aryl iodides with enediyne 1 (R = H) is similarly efficient, and has been used to prepare the novel crown ether 33.46 The reaction threshold for this molecule is apparently lower than for 1 (R = H). However, the 2: 1 sandwich complex with the K+ ion is less reactive. In the search for new enediyne systems which can intercalate with DNA, the acyclic benzodiyne 35 was constructed from the naphthalimide derivative 34 through reaction with two molecules of trimethylsilyl acetylene.47 31 32 : N T 0 &$ CI I 33 i. TMS Pdo-CuI Ill 3s 34 Beau and co-workers have demonstrated the power of the Nozaki-Kishi reaction (CrC12-NiC12) between an acetylenyl iodide and an aldehyde to effect ring closure of 36 to the 10-membered enediyne 37 bearing a prop-2-ynylic alcohol substituent (Scheme 8).48v49 This reaction is similarly a key step in the conceptually interesting synthesis by Fallis of the 'taxamycin' 38 (an enediyne-taxol hybrid):' and the equally novel enediyne-estradiol hybrid 39 by De Clercq." Boger et al.on the other hand, found that the benzodiyne 40 undergoes ring closure to 41 on treatment with lithium amide base, albeit in modest yield (21%).52 This compound was coupled to CDP13, a synthetic non-covalent DNA minor groove binder, and the resulting conjugate 42 was shown to display potent capacity to interact with and cleave supercoiled DNA. has also been used by Nicolaou to effect ring A samarium iodide induced Pinacol type reaction Lhermitte and Grierson: Enediyne based antiturnour antibiotics.Part 1 4560% \OH 36 38 TWO 39 Scheme 0 40 closure of the readily accessible dialdehyde 43 to the 10-membered enediyne 44 (42%) (Scheme 9).53 Working along different lines, Magriotis et al. plan to exploit the facility with which the enediyne antibiotics undergo cycloaromatization to promote tandem Ireland-Claisen rearrangement-Bergman cyclization of the 14-membered lactone 48 to tetrahydronaphthalene systems (Scheme The 43 Scheme 9 Sm12 42% + i. ZnCI? 'Cu(CN)Li '2 44 co&le '- Ro+:ms 47 PdO-CuI ii. desilylation iii. hydrolysis iv. DCC-PPTS 48 Scheme 10 enyne intermediate 46 was prepared by reaction of a stannyl vinyl cuprate with iodoacetylene 45 in the presence of ZnC12, followed by iododestannylation.Subsequent Pdo-CuI mediated coupling of 46 with the acetylene derivative 47 and macrocyclization gave 48. Note the compatibility of this palladium coupling reaction with the presence of the vinyl sulfide unit in the acetylene derivative 47. With the idea of ring contracting larger stable cyclic enediynes to more reactive 10-membered monocyclic forms, Maier and Brandstetter devised a route to compound 51 (Scheme ll).55 The acyclic enediyne intermediate 49 was again obtained in two steps from cis-dichloroethene 28. The key cyclization of 50 was achieved via a Nicholas reaction.56 Under these conditions (Tic&, DABCO) a carbocation species is generated adjacent to the dicobalt hexacarbonyl complexed triple bond which reacts with the electron rich enol ether system at the other extremity of the chain.This ring closure strategy was first introduced to the enediyne field by Magnus and co-workers as part of a systematic study to prepare bicyclic enediynes which have different ring sizes and substituent patterns (Scheme 12).57 As illustrated by the preparation of enediyne 53, the interest in this approach resides in the fact that, compared to the ~ 46 Contemporary Organic Synthesisparent linear enediyne system, the alignment of the reacting centres in the cobalt complex are optimized, and the distance between them is significantly less. This results from the altered 145" bond angles in the masked (complexed) triple bond.In addition, cobalt complexation stabilizes the derived bicyclic product 52, facilitating its isolation and handling. Indeed, on decomplexation of 52 enediyne 53 was observed to cycloaromatize spontaneously. In contrast, the isomeric bicyclic enediyne 54, described in further detail in Scheme 18 of Part 2 of this review,20a was found to be stable. Using Magnus's methodology, compound 58 and yne-ene-allene 59 were prepared by Maier from 5-cycloheptenone 55 (Scheme 13).58 Enediyne 58 cycloaromatizes spontaneously. However, it is remarkable that the yne-ene-allene product 59 - issuing from the cyclization of 56, dyotopic rearrangement of 57 and decomplexation - is stable. completed the synthesis of a 11-membered enediyne possessing a 1,3-trans bicyclic ring junction (Scheme 14).59,60 To obtain ketone 62 the acetylenyl cuprate reagent 61 was added to the cyclohexadienyl iron Schinzer and Kabbara were the first to have i.CO*(CO)& 80% ii. Swern oxidation iii. TBSOTI 1 qTBS 50 TMs\, (4" 0 Q -c Scheme 11 55 i. Ll- li. 28, Pdo-CuI Ui. TBSCI k. - Pdo-Cul OMe 0 i. COdCO), 829L ii. TBSOTf I c i. ii. 56 I 'b' 1. TiCI,, DABCO ii. CAN 1.- 1 TBSO TBSO %> 53 54 59 Scheme 13 Scheme 12 47 Lhermitte and Grierson: Enediyne based antitumour antibiotics. Part 165 Scheme 14 64 complex 60 (98% yield), followed by desilylation and oxidative demetallation. Lewis acid promoted Sakurai of 62 with ally1 silane 63 then proceeded regio- and stereospecifically to produce compound 64. The intramolecular Pdo-CuI coupling of the acetal derived from 64 to give enediyne 65 is remarkable, despite the only moderate yield observed.Mikami has explored a novel approach involving an ene reaction to create the crucial bond between the enediyne containing chain and the 6-membered ring 'platform' component of the calicheamicin/ esperamicin core ~tructure.6~ This involved conversion of the readily accessible alkynyl aldehyde intermediate 66 to the 11-membered bicycle 67 (Scheme 15). A subsequent Nicolaou type r S. I I I I 1 6s 200%,30min PhMe 67 L Scheme 15 Ramberg-Backland ring contraction step could then be exploited to introduce the central double bond. However, at present, the thermal conditions employed (200 "C, 30 min) effect dehydration of the desired product to the enediyne containing compound 68. dynemicin analogue 72 in which the enediyne unit is built across a tetrahydropyridine backbone (Scheme 16)." Thus, reaction of pyridine 69 with ethylchloroformate and ethynylmagnesium bromide (Yamaguchi condition^^^) led to formation of the 1,Zaddition product 70 which was elaborated to the A3.4-piperideine aldehyde 71 (and its A495 isomer; 2: 1 mixture).Reaction of 71 with LHMDS/CeC13 at low temperature produced compound 72 in 35% yield. Brana and co-workers prepared the novel UHMDS -33 I' 35% 72 71 Scheme 16 3 Monocyclic and bicyclic enediynes with novel activating devices Several concepts have been evaluated which have potential application for the in vivo transformation of stable or latent enediyne systems to more reactive forms. One interesting strategy, which in a sense was a prelude to the discovery of mauduropeptin 21, involves introduction of the central enediyne double bond as the triggering step toward cycloaromatization. For instance, Myers and Dragovich envisaged that, by analogy to dynemicin A, bioreduction of anthraquinone 77 would lead to loss of the succinate residue and formation of the 10-membered enediyne 78 (Scheme 17).66 Key synthetic operations in the preparation of 77 include the modified Pedersen pinacolic to convert dialdehyde 73 to a mixture of cis and trans diols 74 (4:l; 40%), and reaction of the derived ketone 75 with the anthracenyllithium reagent 76. Reductive activation of 77 with a flavin-based enzyme system at pH 8.0 proceeded rapidly to give enediyne 78 (75%), which slowly cycloaromatizes at 37 "C in the presence of cyclohexadiene (CHD) (tj = 2 d).48 Contemporary Organic Synthesisd ?3 0' 40% 74 X = H, OH 75X=O J 76 Dess-Martln 1 0 OMe I. Tf,0.2.&lut#Ine 1 li. 8uccI;;hydrlde Q OMe 70 Scheme 17 Taking advantage of the slower cycloaromatiza- tion rate of benzodiynes compared to enediynes, Nicolaou and Semmelhack have independently studied the differential reactivity of hydroquinone based diynes and their corresponding quinone forms ( c j 79 and 80; Scheme 18).68-70 OPiv 0 ?H 79 80 PMP 81 82 PMP = pmethoxyphenyl Scheme 18 Maier has also shown that the enediyne double bond can be introduced via benzylic oxidation in bicyclic 1,5-diyne systems functionalized at the 3 position by a p-methoxyphenyl substituent (81 4 2 ; Scheme 18).71 bicyclic core structure of calicheamicin/esperamicin, Grierson and co-workers constructed the unstrained 13-membered macrocyclic ether 84 by cyclization of 83, and studied its 2,3-Wittig rearrangement to 85 under basic conditions (Scheme 19).72,73 As anticipated from the calculated rc,d distance (3.20 A; MMX calculations) and observations by Magnus on In the course of work on an approach to the 77 the related compound 53, the in situ generated enediyne 86 underwent spontaneous Bergman cycloaromatization. Interestingly, this was accompanied by a 1,5-hydrogen translocation to give the more stable diradical 87, which evolved to a number of products. A similar radical translocation was observed earlier by Wender during studies on neocarzinostatin chromophore analogues.74 Such studies may have relevance to internal radical quenching reactions suspected to occur on cycloaromatization of neocarzinostatin 9 and esperamicin 6.Other strategies through which the central double bond of the enediyne system is generated include the Norrish type I1 photochemical fragmentation of aromatic ketone 88,75 and the Diels-Alder reaction of dienediynes 89.76 Semmelhack has similarly devised methodology for introduction of this double bond based upon the Corey-Winter reaction of thionocarbonate 91 (Scheme 20).77 Note also that the two acetylene functions in 91 were elaborated by reaction of the chlorohydrin derivative 90 with excess LDA. Interestingly, the conjugate 92, formed by joining 37 to a truncated netropsin derivative via a four carbon (crotonate) tether, is 2000 times more effective as a DNA cleaving agent than 37 itself.78 Glycoside bond cleavage, which would convert the sugar derived enediyne 98 to the 10-membered monocycle 99, has also been envisaged as a triggering mechanism for cycloaromatization (Scheme 21).79 To access this bicyclic acetal the ketone 93 (obtained from D-xylose) was reacted with lithium trimethylsilylacetylide in the presence of CeC1,. This preferentially gave the P-substituted product 94, which was converted in three steps to alcohol 95.Attempts to achieve ring closure of aldehyde 96 under strongly basic conditions failed. However, compound 98 was obtained from the corresponding iodoalkyne intermediate 97 under Nozaki-Kishi conditions (CrCl,-NiCl,; 26%).49 Lhermitte and Grierson: Enediyne based antiturnour antibiotics. Part 1 49";o- N \ Et20,O "C 84% (Br K p ___I) hv.PhH pyrex 87% Ph * + Ph L 83 68 TBSO NaH, THF. H& (trace) 1 .OTBS ACi Nio(cat.) * 89 LiTMP 2J-W~i R'O-' rearrangement I 6TBS 84 PhMe, A 1 0 R O K R 0 \\ DBU,CHD r 1 1 Meo" 8 I 6TBS OH MeO' L 86 91 I I 90 OH Products - 37 L A N ? NH2 i d 0 oJ$*o \ q Scheme 19 \ Similarly it was conceived that enol ether hydrolysis of the benzodiyne 103 would give a monocyclic enediyne susceptible to undergo the involved condensation of the ketone 100 (prepared in two steps from 1-tert-butylthio-D-xylopyranoside) with the acetylenyl cerium(m) reagent 101, followed by elaboration of aldehyde 102 and chromium mediated ring closure (95% yield!). an alternative means to destroy the bridgehead double bond in the bicyclic calicheamicid esperamicin system (Scheme 23).81 To obtain analogue 108 the aldehyde 104 was converted to Bergman reaction (Scheme 22).80 Preparation of 103 \ 92 Scheme 20 Enol ether hydrolysis has also been exploited as acetylene 105 by reaction wth ( Me0)2POCHN2,82 and from-there to enediyne 106 by coupling with l-chloro-4-trimethylsilyl-(Z)-but-l-en-3-yne.3s Final cyclization was achieved by treatment of 107 with LiHMDS.The hydrolysis product, ketone 109, is 50 Contemporary Organic SynthesisOMe 98 R = H 97 R = I t H O q o M e OMe 98 Scheme 21 OMe 95 R = H , I 1 J 99 stable enough to be isolated (compare with 53), but does cycloaromatize fairly rapidly [t+ = 35-53 min (R = H, TBS) at 37 "C]. 4 Simple yne-ene-allenes and yne-ene-cumulenes A clear demonstration of the much greater propensity of yne-ene-allenes and yne-ene- cumulenes to cycloaromatize to diradical intermediates compared to enediynes was provided by the simple experiment wherein the 10-membered sulfone 110 was either heated in the presence of cyclohexadiene as the only additive, or treated at room temperature with triethylamine base (Scheme 24).Under the first set of conditions Bergman cyclization occurred progressively (80 "C, 18 h). However, in the presence of Et3N a very rapid cycloaromatization reaction ( < 1 min) was observed via the yne-ene-allene intermediate 11 1 generated by proton rearrangement.83,.84 Koga et al. have attributed the difference in reactivity of these two conjugated systems to less favourable orbital interactions created during enediyne electrocy~lization."~~~ A decrease in the rc,d distance between the reacting centres in yne-ene- allene systems compared to enediynes most probably also contributes to their higher reactivity.In any event, containment of yne-ene-cumulenes in strained rings is not an obligatory requirement for 0 W S B U t O k o 100 OMe i . TBAF Iii. 1,. T i n e OMe 102 Scheme 22 LDA c-- H&O 80% CrClr NiCI, 95% - 1. m CPBA il. BuU OMe 103 these systems to undergo Myers type cycloaromatization at ambient temperatures. For instance, the unstrained acyclic yne-ene-allenes 114 and 115 both cycloaromatize smoothly at 37 "C (t+ = 1.5 to 8 h) and effect cleavage of supercoiled DNA. These compounds were prepared by [2,3]-sigmatropic rearrangement of the in situ formed phosphinite derivatives of enediyne 112 and prop-2-ynylic alcohol 113, respectively (Scheme 25).86-88 As illustrated by the reactivity of 116, substituents on the terminal acetylene carbon C-1 have a considerable influence on the mode of cycloaromatization; i.e. in the presence of cyclohexadiene (CHD) 116 (R = H) cycloaromatizes in the Myers mode (c,-c6 bond formation) to produce 118, whereas 116 (R = tolyl) reacts to give 117 as a consequence of c2-c6 bond formation.89 This may be due to steric hindrance, and/or ground state stabilization of the acetylene moiety.In a more sophisticated experiment compound 119 was constructed, and shown to undergo an intramolecular SN2' reaction giving 120 directly (75% yield) (Scheme 26).90 Lhermitte and Grierson: Enediyne based antitumour antibiotics.Part 1 51108 1 07 109 Scheme 23 Ph2P+ 112 R=H - R=PPh2 0 PhpCl 114 117 (76%) I Scheme 25 110 111 Scheme 24 The parent unsu bs ti tu t ed (2)- 1,2,4- hept a t rien- 6-yne system 124 has been synthesized by either Zn-Cu reduction of mesylate 121,86 or via a sigmatropic rearrangement initiated by oxidation of prop-2-ynylic hydrazine 122 to the unstable diazene 123 at 0 "C (Scheme 27).9',92 Interestingly, these unsubstituted yne-ene-allenes cycloaromatize relatively slowly (ti x 24 h). NMR evidence suggests that this may result from a preference for them to adopt the less hindered s-trans conformation. Saito and co-workers made use of their experience on the [2,3]-sigmatropic rearrangement of prop-2-ynylic phosphinites to prepare phosphine oxide 125 and react it with aldehyde 126 (Scheme 28)?3 This permitted them to construct the acyclic yne-ene-cumulene derivative 127 related to the thiol addition product 10 of the neocarzinostatin chromophore.Alternatively, Wang showed that mesylate 129, obtained by reaction of 126 with lithium acetylide 128, undergoes very mild conversion to 127 on treatment with TBAF.94795 Like the above acyclic allenes this compound could be isolated by flash column chromatography or HPLC and characterized. 115 cy / : ""P(O)Ph2 6 H 118 (57%) Bu'Li R' = Br R' = CHO DMF; -120 % 71% 119 Scheme 26 52 Contemporary Organic SynthesisTwo strategies for the preparation of acyclic yne- ene-ketene analogs of cumulene 10 have also been reported.On the one hand, ketene 131, which cycloaromatizes spontaneously, was generated by heating or photolysing (254 nm) diazoketone 130 (Scheme 29).% In the second study, Moore et al. showed that cyclobutenone 132 fragments on mild heating (CH,CN; 82 "C) to the ketene 133.97 Cyclization of this intermediate to a diradical 122 X = NHNH, 123 zn-cu. 0 'c [2 31 I s-trans 124 S-Ck 124 Scheme 27 Me HO-* Me K O 9-" COzEt 1 30 r Scheme 29 Scheme 28 Lhemitte and Grierson: Enediyne based antitumour antibiotics. Part 1 131 Ph I - Meoxf R 132 1 33 0 TBAF 54% 127 / TMS RO 53'NU-DNA 134 135 R 'R 137 136 Scheme 30 ii.pHa7 1 lHzO DNA cleavage accounts at least partially for the capacity of this intermediate to cleave DNA. sulfones, Nicolaou has suggested that Myers cycloaromatization is not the only route through which these systems can potentially cut DNA (Scheme 30).98 Indeed, on pH dependent conversion of 134 to the corresponding bis(al1enic) sulfone 135, further reaction can occur giving the diradical 136 (pathway A), or through direct reaction with a DNA-nucleophile to give adduct 137 (pathway B).Studies of the reactivity of a series of mono and bis(prop-2-ynylic) sulfones, as well as the novel crown ethers 138 and 139 and compounds 140, has provided convincing evidence for the polar reaction pathway in DNA cleavage (note 138-+141).99-'02 Similarly, it was observed that the 10-membered ring sulfide 143, obtained by dehydration of 142, is converted to the conjugated allene 144 in a basic medium. This intermediate reacts via both polar and radical mechanisms (Scheme 31).Io3 Attachment of aromatic ester residues to these monocycles increased their ability to interact with DNA through intercalation.Somewhat of a surprise, oxidation of sulfide 145 with m-CPBA led to formation of the enyne-allene sulfone 146 as a stable compound.'04 Cycloaromatization of the allene-cumulene 147 Returning to the reactivity of bis(prop-2-ynylic) 0 generated by elimination of HOR from 146 was also split between polar and radical pathways. The Pd(0) coupling and ring closure technology developed during the study of enediyne-dienediyne systems was brought to bear by Myers to construct the fully conjugated 'aromatic' 1,6-didehydro- [lolannulene 151 (Scheme 32).'05 This was achieved by coupling vinyl iodide 148 with a but-3-ynylic alcohol derivative (79%), followed by Wittig olefination, and ring closure of 149 under Nozaki- Kishi conditions to the alcohol 150.Subsequent triflate elimination to give 151 had to be conducted at -90 "C! The half-life for cyclization of 151 at -51 "C is z 25 min, making this the most rapid diradical-forming cycloaroma t iza t ion yet recorded (c.5 10+11; t+ = 2 h at -38 "C). then went on to incorporate the 1,6-didehydro- In a synthetically economic and astute way Myers 138 OMe OMe 141 139 I o=s=o 140n =13,X=CH,N OH [lolannulene system in latent form into the neocarzinostatin analogue 155 (Scheme 33).'06 Compound 155 was prepared starting by reaction of enantiomerically pure 152 with allenylmagnesium 54 Contemporary Organic Synthesis143 R2=H R2 = OCOAr J 144 H+ radical route / k Sm 0 S * H 145 Scheme 31 147 bromide, followed by stannylation of acetylene 153.This product was dimerized under Pd(0) conditions, affording the C2-symmetric alcohol 154 in 34% yield. Mesylation of 154 gave the target molecule 155, which proved to be stable with respect to column purification. However, treatment of this compound with methyl thioglycolate and Et,N led to 148 i.BuUTh4S = (4.3: 1 z : E ) 71% B ii. c&co2H iii. EbN*HF v. Dess-Martin iv. NIS, &NO3 b R 150 151 (stored at 430 "C) Scheme 32 149 152 zl 153 R = H R = SnBuo Scheme 33 Lhermitte and Grierson: Enediyne based antiturnour antibiotics. Part I HSAC02Me EtsN.12 h. 23 "c - TBSO" 154 x 0-0 41% ii. (Ms)&. 70% 1 55cycloaromatized products whose formation may 1.CBr4. P(Phh ii. BuU iii C w e c 37, Suffert showed that upon EtS- addition the -JmS TBSO 83% imply 156 as an intermediate. Applying techniques described later in Scheme benzodienediyne 157 rearranges to a didehydro- [ lolannulene. This intermediate cycloaromatized CHO 159 spontaneously to 158 (Scheme 34)’” in an analogous fashion to the Saito pathwayI4 for the neocarzinostatin chromophore. cow kSA r Ets> SEt 157 € b P / * 156 diradii - 158 Scheme 34 The simple monocycle 163 (Scheme 35) was designed by Toshima et aZ. to undergo cycloaromatization through thiol-acetate addition elimination in a manner closely analogous to neocarzinostatin 9.1m In four steps, D-xylitol was converted to the dialdehyde 159. According to the Corey-Fuchs procedure’0g this compound was elaborated to the diester 160, and from there to the keto-aldehyde 161.An intramolecular Aldol reaction then gave 162, whose conversion to 163 could not be achieved directly under Wittig conditions. neocarzinostatin chromophore skeleton, Wender and Tebbe designed the monocyclic E-configured dienediynes 165 which react as Michael acceptors in the presence of thiols (Scheme 36).74.”0.”’ Although MsOH elimination from 164 produces the less hindered thermodynamic product, the reactive s-cis In conjunction with their pioneering work on the L DIBAL ii. MeMgBr In. De6bMattIn 1 O/ OTBS Scheme 35 conformation can easily be adopted in the tetraene 166. A thorough study of the Myers type cycloaromatization chemistry of 165 was made, which both demonstrated that 166 cyclizes spontaneously and also brought to light an internal radical quenching process involving 1,5-hydrogen transfer (167 + 168).Suffert and Terashima have further defined methodology for stereospecific construction of monocyclic 2- and E-dienediynes from 2- and E- monoenol triflate and dienol triflate precursors (Scheme 37).11271’3 The essential challenge in their work was to establish conditions for controlled preparation of compounds 170 and 171, as well as 172 and 173, from 2-formylcyclopentanone 169. It was found that the 2-enol form of 169 reacts with triflic anhydride and amine base to give the E- configured monoenol triflate 170, whereas reaction of the lithium enolate of 169 with the same reagent gives the 2-monoenol triflate 171. Alternatively, partial conversion of 170 to 171 could be achieved photochemically (254 nm).Similarly, 2-formylcyclopentanone was converted directly to the E-dienol ditriflate 172 (63-71%), and compound 171 was converted to 173 in 47% yield through treatment with LHMDS and PhNTf,. It is interesting that reaction of the lithium enolate of 169 with PhNTf, led to the E- rather than the Z - monoenol triflate, and that there is a-loss of 56 Contemporary Organic SynthesisOTf 3 1 % fi 1 :12 1 y N 9 172 169 0 hv & 0 - LIHMDS PhNTf, JOT, - 4% 254 nm 170 171 173 4 0 165 1 HS-COfle s-co2Me SAC02Me &OTI R1-Z PdO-CuI c gfR' 166 (4: 1 to 12: 1 ratio) 173 I R2-= PdO-CuI r C02Me Me0 I 1 R' \ S*H produds PdO-CuI I C02Me TI 0, TfO, 168 172 Scheme 36 Scheme 37 stereochemistry on treatment of monoenol triflate 171 with Tf20 (171-172).The subsequent Pdo-CuI bis-coupling of dienol ditriflates 172 and 173 with >2 equivalents of diversely substituted terminal acetylenes provided open chain E- and 2-dienediyne systems respectively with common acetylene functions [Z- series: 36-73% yields; E-series: 79-98% yields]. However, sequential addition of two different acetylene units can also be accomplished. As one might expect, for 2-compound 173 there is preferential reaction at the more accessible exocyclic enol triflate function (4:l to 12:l). However, for 22-172 it is the endocyclic position which is substituted first (3:l to 8:l). In this latter instance, the order of introduction of two different acetylene units can be inversed by first coupling with monotriflate 170.A strategy based upon a Pd(0) catalysed insertion-cross coupling sequence has been developed which permits both creation of the cyclopentene ring from an acyclic precursor and introduction of an acetylene appendage with control of the exocyclic C,-& olefin geometry (Scheme 38).'14-"' In the experiment, Pd(0) reacts with dibromo (or diiodo) 174 via n-complexation and selective oxidative addition to the more hindered proximal 2-1-Br bond to give the critical Pd-C a-bonded species 175. In a solvent dependant reaction, this intermediate then undergoes rapid carbometallation of the precoordinated alkyne, resulting in formation of the 2-vinyl organometallic 57 Lhermitte and Grierson: Enediyne based antitumour antibiotics. Part 1ii. BnCl -1 R'=H,Bn 174 - I 175 R'O 176 - 177 Scheme 38 176.Reaction of 176 with the stannylacetylene reagent present in the medium gives the product diene-yne 177. The presence of the vinyl bromide functionality can subsequently serve for introduction of a second acetylene unit. In another Pdo-CuI based approach, reaction of the in situ generated organocopper species 179 with the a-ethynylpalladium species 180 produces the Z - ene-yne product 181 (Scheme 39).'16 This is achieved by slow addition of iodide 180 to a solution of the preformed potassium enolate 178 in the presence of (Ph3P)4Pd and CuI. 178 179 180 181 Scheme 39 Ziegler has shown that the cyclopentenynes such as 185 can be constructed by Bu3SnH induced radical cyclization of either bromo[3]cumulene 182 or the bromoenyne precursor 183, since both systems produce the same delocalized radical intermediate 184 (Scheme 40)."' + ph3p3Br Br- LIHMDS.-70 'C I 182 Bu3SnH AIBN. 80 'C 20 min 1 L 184 \ Bu3SnH AIBN. 80 % 20 min 1 184 I Scheme 40 58 Contemporary Organic Synthesisi. H202 NaOH. H& 1 ii. B u ~ ~ P A OH R * g 9 B r 0 186 R=H 191 R=OTBS \ OTBS 189 iv. BuLi. Bu&nCI R = H 187 R=OTBS R = CH2CH20TES 1 i.i'+L$ R = CH~CO~BU oxidation - OTBS from 193 - OTBS I U 194 195 Scheme 41 5 Ten-membered ring and higher neocarzinostatin chromophore analogues Calculations made by Hirama and collaborators suggest that 10-membered neocarzinostatin chromophore analogues should be more stable than 9 due to reduced ring strain, but at the same time retain the capacity to undergo Myers type cycloaromatization to a diradical intermediate (small difference in the rc,d distance).They thus prepared the conjugated ketone 190 from 2-bromocyclopent-2-enone 186 (Scheme 41) via reaction of the Grignard reagent derived from intermediate 187 with aldehyde 188, followed by Pd(0) catalysed ring closure of the stannane 189 (72%) and Swern ~xidation."**"~ By the same route compound 192 (R = OH, OCOAr) was prepared from monochiral ketone 191.I2O This 10-membered dienediyne ketone cleaves supercoiled DNA with a very marked selectivity for purine bases (G >A). Incorporation of an internal thiol triggering device '0 0 I90 R = H 192 R=OH as in 194 was also achieved starting from the readily available ketone 193.I2l As expected, methanolysis of thioacetate 194 at room temperature resulted in spontaneous thiol addition and Myers type cycloaromatization. Finally, the conjugate 195 was prepared which displayed potent DNA cleaving capacity.122 Krebs et al.have also constructed the cross- conjugated 10-membered dienediyne ketone 198 from acetylene 196 (Scheme 42).'23 The key step in their approach is the Noyori type intramolecular aldol reaction between the acetal and silyl enol ether moieties in the intermediate generated from 197. More recently, Ueda has also described the elaboration of 199 to the isomeric ketone 200, in which a phenyl group replaces the double bond o! to the carbonyl fun~ti0n.I~~ stereoselective introduction of acetylene containing side chains onto 2-formylcyclopentanone derived enol triflates (Scheme 37), Terashima has described In an extension of work on the regio- and Lhermitte and Grierson: Enediyne based antitumour antibiotics.Part 1 59196 R' = MEM, f? = CH(0Et)z 199 R' = THP, f?= TMS 197 lmgn 1. Cr-Ni 1 98 QTp MPO - 0 200 Scheme 42 PivO O f - # PivO **OH Me0 OH the preparation of the two chiral acetylene derivatives 201 and 202, and their coupling to enol triflate 203 (Schemes 43 and 44).1137'25 Further conversion of compound 204 to epoxide 206 provided the possibility of obtaining the 10-membered bicycle 207. However, the 9-membered neocarzinostatin analogue 209 was not accessible from the corresponding epoxide prepared from 205. Similar efforts to prepare this compound by intramolecular acetylide condensation in 208 were also unsuccessful.Interestingly, attempted assembly of the novel 10-membered 1,3-dioxolane 211 through intramolecular transketalization of the polyhydroxylated intermediate 210 led instead to formation of the ll-membered bicycle 212. 6 Conclusion Much of the methodology used to access both the neocarzinostatin analogues and the enediyne systems described so far has either been applied to, or been developed during, efforts to achieve the x:ho HO OH 204 I Q HO'* COpEt 201 202 I 203 I PdO-CuI Scheme 43 60 Contemporary Organic Synthesis 1 206 207 %o 0-.$ OH 209 R=Me 208 R=TBS Scheme 44 21 2total synthesis of the three major enediyne- dienediyne antibiotics: the neocarzinost at in chromophore 9, calicheamicin yl' S/esperamicin A, 6 and dynemicin A 15. 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