Abstract

A stereoselective synthesis of the C1–C13 segment of poecillastrin C has been achieved. The C1–C4 moiety was derived from diallyl l-tartrate, and the amide group at the C3 position was constructed by means of a traceless Staudinger reaction. The C1–C13 segment was submitted to model studies, including esterification with a bulky alcohol at the C1 position and Stille coupling with vinyl iodide at the C13 position. The reactivity of the C1 position was affected by the neighboring C2-protective group. When the C2 hydroxy group was protected as a TBS ether, the C1 carboxylic acid did not undergo esterification with a bulky secondary alcohol, whereas the p-methoxybenzylidene N,O-acetal afforded a 2,4-dimethyl-3-pentyl ester. Stille coupling of the C1–C13 segment with 1-iodohept-1-ene gave the southern part of the poecillastrin C macrolactam attached to simplified eastern and western parts.

The first total synthesis of stoloniferol B and penicitol A has been achieved. Stoloniferol B, which is the common structure of citrinin derivatives, has been constructed by a sequential elaboration that includes a stereoselective vinylogous Mukaiyama aldol reaction, a thermal esterification with methyl acetoacetate, an intramolecular Michael reaction, and a vinylogous Dieckmann cyclization. The enantiomer of the proposed structure of fusaraisochromanone and (S)-7-hydroxy-3-((R)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (the enantiomer of a natural stoloniferol derivative) also have been synthesized. The synthesis revised the structure of fusaraisochromanone to (S)-7-hydroxy-3-((R)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one.

ConspectusThe construction of libraries of acyclic polyketides remains a challenging topic, mostly due to the difficulties associated with finding the right balance between diversity and brevity for the synthetic routes leading to polyketides. Recently, relatively short methods have been developed and applied to the synthesis of natural products. However, these short routes often suffer from limited diversity with respect to the arrangement of functional groups and stereochemistry, as these usually require reactions that direct multiple functional groups simultaneously in one step. Therefore, methods that combine a small number of reaction steps with structural diversity remain an attractive research target for the construction of acyclic polyketide libraries.In 2004, we reported a remote asymmetric induction reaction using chiral vinylketene silyl N,O-acetal 1, which is commensurate to an anti-selective vinylogous Mukaiyama aldol reaction. Ever since, this reaction has been applied to the synthesis of numerous natural products, as this synthetic route is short and efficient on account of the simultaneous introduction of both asymmetric centers and the multiply functionalized carbon chain. Recently, we have developed a variety of this remote asymmetric induction reaction based on the E,E-vinylketene N,O-acetal 1, which includes syn-selective vinylogous Mukaiyama aldol reactions, as well as alkylation, acylation, and bromination reaction. These reactions provide polypropionates in a highly stereoselective manner. The proposed transition states of these reactions are discussed in this Account. Additionally, we have developed a new short synthesis of polypropionates by combining reactions for the remote asymmetric induction and the functionalization of double bonds (wide-range stereocontrol, WRS). The remote asymmetric induction reaction simultaneously constructs the stereogenic centers at the central part of the products and introduces the α,β-unsaturated imide, while the new strategy is based on the initial construction of the central part of the molecule and a subsequent functionalization of the surroundings (WRS). This strategy successfully furnished stereoisomers in a few steps, and the stereodivergent synthesis of 2,4,6-trimethyloctanoic acid derivatives was accomplished. This strategy should also be feasible to construct an acyclic polyketide library. Moreover, we applied this method to the concise synthesis of natural products. In this Account, the development of remote asymmetric induction reactions and the new WRS strategy are described. Applications of the WRS strategy as well as reactions for the stereodivergent synthesis of polypropionates and natural products are also described. The aforementioned acyclic polyketide library should be constructed in the future with the help of the WRS strategy and become a powerful tool in drug discovery.

α,β-Unsaturated imides and α,β-unsaturated esters were found to undergo alcoholysis in the presence of trimethylphosphine. The reaction is initiated by nucleophilic addition of trimethylphosphine to the double bond of the α,β-unsaturated carbonyl compound. Saturated imides also undergo the alcoholysis in the presence of the corresponding α,β-unsaturated imide.

The vinylogous Mukaiyama aldol reaction (VMAR) is a powerful tool of polyketide synthesis, which constructs a large size structure by simultaneous introduction of the stereogenic center(s) and the α,β-unsaturated carbonyl group. A variety of stereocontrolled VMARs have been developed and applied to natural product synthesis. This review is focused on recent development of the vinylogous Mukaiyama aldol reaction using s-trans silyl dienolates.

Stereoselective total synthesis of tabtoxinine-beta-lactam has been achieved. The vinylogous Mukaiyama aldol reaction with vinylketene silyl N,O-acetal and alpha-keto-beta-lactam proceeded to afford the adduct possessing a T beta L-skeleton with a tert-alcohol in high yield and stereoselectivity. Stereoselective introduction of the amino group has been accomplished by azidation at the alpha position of the imide followed by hydrogenolysis. A straightforward method to achieve the potent inhibitor of glutamine synthetase, possessing both alpha-hydroxy-beta-lactam and alpha-amino acid moieties, has been established.

Stereoselective bromination of the E,E-vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved and applied to introduction of heteroatom at gamma-position of alpha,beta-unsaturated imide. The reactions proceeded in high stereoselectivity. Total synthesis of pellasoren A, an antitumor propionate from the myxobacteriun Sorangium cellulosum, has been accomplished in short steps by this methodology and our method of reduced polypropionate synthesis.

Stereoselective vinylogous Mukaiyama aldol reactions using:the Z,E-vinylketene silyl N,O-acetal possessing a chiral auxiliary, derived from (E)-3-pentenoic acid and L-valine, have been achieved. The reaction proceeded smoothly to give a syn adduct in high stereos electivity. Since the products possess structures including delta-alkoxy-gamma-methyl-alpha,beta-unsaturated imide this reaction would be applicable to synthesize polyketides in a short procedure.

Remote asymmetric induction by the vinylogous Mukaiyartia aldol reaction using the acetate-type vinylketene sily N,O-acetal-possessing a chiral auxiliary has been achieved, The silyl N,O-acetal fletived from crotonate and L-valine afforded the O-silylated 5R- and 5S-adducts selectively by treatment with SnCl4 and BF3 center dot OEt2, respectively. The SnCl4-mediated isomerization of silyl dienol ether was found, and the resulting major isomer showed high reactivity to give gamma adduct in high stereoelectivity.

The core structure of cristaxenicin A having trans-fused dihydropyran and nine membered ring has been synthesized and evaluated the antileishmanial activity. The dihydropyran ring was synthesized by [4+2] cycloaddition reaction between an unsaturated aldehyde and a beta-alkoxy-alpha,beta-unsaturated ketone. The nine membered ring possessing alpha,beta-unsaturated aldehyde was constructed by the intramolecular NHK reaction followed by the Mitsunobu rearrangement. The racemic core structure of cristaxenicin A was evaluated the anti-leishmanial activity with an IC50 value of 2.4 mu M. (C) 2016 Elsevier Ltd. All rights reserved.

Two vitamin D-3 derivatives, namely 24,24-difluoro-1 beta,3 beta,25-dihydroxy-19-norvitamin D-3 (6a) and 24,24-difluoro-1 alpha,3 alpha,25-dihydroxy-19-norvitamin D-3 (6b), were synthesized via a convergent route employing Julia-Kocienski olefination as a key step. Compounds 6a and b bound to vitamin D receptor (VDR) with IC50 values of 64.8 and 57.6nm, respectively, exhibiting about 400- and 30-fold greater binding affinity than the corresponding non-fluorinated derivatives 5a and b.

1 beta,3 beta,25-Dihydroxy-19-norvitamin D-3 (4a) and 1 alpha,3 alpha,25-dihydroxy-19-norvitamin D-3 (4b) were synthesized by employing a new A-ring synthon, (1R,3S)-3-((tert-butyldimethylsilyl)oxy)-5-oxocyclohexyl benzoate (19), which was derived from D-(-)-quinic acid in 12 steps. The A-ring was coupled with the circular dichroism (CD) ring by means of Julia Kocienski olefination to construct the diene unit. The structures of the products were confirmed by H-1-NMR and nuclear Overhauser effect (NOE) experiments.

Total synthesis of phthiocerol dimycocerosate A (PDIM A), a virulent factor of Mycobacterium tuberculosis, has been achieved. Phthiocerol, a component of PDIM A, has been synthesized by subsequent epoxide-opening allcylation reactions with arabinose-derived diepoxide. This route is concise and efficient in supplying PDIM A for biological studies.

Stereoselective alkylation of the vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved by using activated alkyl halides including allyl iodides, benzyl iodides, and propargyl iodide with Ag(I) ion in the presence of BF3 center dot OEt2. The reaction proceeded to give reduced polyketides in high stereoselectivity. The synthesis of mycocerosic acid, a component of the cell envelope of Mycobacterium tuberculosis, has been accomplished by this methodology. During the synthetic studies, 2-methylbenzimidazole was found to be a bulky proton source which worked in the presence of liquid ammonia.

The C27-C48 segment of aflastatin A was synthesized by using d-mannoside and l-erythrulose derivatives as chiral building blocks. The aldol reaction of undecan-2-one with mannolactone and a subsequent reduction gave the C37 and C39 stereogenic centers with high selectivity. Another aldol reaction of a tin(II) enolate of a protected erythrulose (C27-C30 segment) with a C31-C48 aldehyde segment gave the C30,C31-syn adduct with the desired stereochemistry. Deprotection of the assembled product proceeded smoothly to give the C27-C48 segment of aflastatin A containing a contiguous polyol moiety.

epi-Cochlioquinone D (1) and its 12-alpha-hydroxyderivative (2) were isolated from Helminthosporium velutinum TS28 based on antifungal screening against Cochliobolus miyabeanus. Relative configurations were established by the NMR analyses except for C5 locating far from the other asymmetric centers. ECD discussions involving spectral comparison with those of other related molecules as well as those based on theoretical calculations disclosed not only the C5 configuration but also the chirality for C12-C22 polycyclic moiety. H. velutinum TS28 also afforded precochlioquinol D (3), just the side chain component, which led us to discuss their biosynthetic pathway. Although 1 and 2 inhibit C miyabeanus effectively, the C-14 epimeric cochlioquinones scarcely inhibited in spite of very close structures. Present study further revealed that C miyabeanus tightly recognizes both the polycyclic moiety and the side chain. In contrast, both cochlioquinones and epi-cochlioquinones exhibited potent cytotoxicity against human colon adenocarcinoma (COLO 201) cells regardless of the C14 configuration as well as type of side chains. (C) 2015 Elsevier Ltd. All rights reserved.

Stereoselective synthesis of the C24-C40 segment of aculeximycin has been achieved by using the Kobayashi aldol reactions and epoxy-opening rearrangement reactions. The C33-C40 segment was synthesized by the Kobayashi aldol reaction followed by epoxidation and Jung rearrangement of epoxide 9, while the C25-C32 segment was constructed by the Kobayashi aldol reaction followed by epoxidation and the epoxy-opening rearrangement reaction of epoxide 13. These segments were connected by the aldol reaction and the sequential dehydration, reduction, and conversion of ethyl ester to ethyl ketone to give the C24-C40 segment 1. All stereogenic centers were constructed by substrate-controlled stereoselective reactions.

A concise synthesis of 6-formylindolo[3,2-b]carbazole (FICZ), a potent ligand of the aryl hydrocarbon receptor (AhR), has been established. The conjugate addition of the enolate derived from indolylacetate 2 to 2-chloro-3-formylindole 3 was accomplished. The following cyclization reaction under the acidic conditions gave the indolo[3,2-b]carbazole skeleton.

Stereoselective acylation of the E,E-vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved by using acid anhydrides and SnCl4. Acid anhydrides having alkyl chains gave the adducts in excellent stereoselectivity. The formal synthesis of khafrefungin has been accomplished by the methodology.

Chemokine (C-C motif) receptor 8 (CCR8), the chemokine receptor for chemokine (C-C motif) ligand 1 (CCL1), is expressed in T-helper type-2 lymphocytes and peritoneal macrophages (PM phi) and is involved in various pathological conditions, including peritoneal adhesions. However, the role of CCR8 in inflammatory responses is not fully elucidated. To investigate the function of CCR8 in macrophages, we compared cytokine secretion from mouse PM phi or bone marrow-derived macrophages (BMM phi) stimulated with various Toll-like receptor (TLR) ligands in CCR8 deficient (CCR8(-/-)) and wild-type (WT) mice. We found that CCR8(-/-) PM phi demonstrated attenuated secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 when stimulated with lipopolysaccharide (LPS). In particular, LPS-induced IL-10 production absolutely required CCR8. CCR8-dependent cytokine secretion was characteristic of PM phi but not BMM phi. To further investigate this result, we selected the small molecule compound R243 from a library of compounds with CCR8-antagonistic effects on CCL1-induced Ca2+ flux and CCL1-driven PM phi aggregation. Similar to CCR8(-/-) PM phi, R243 attenuated secretion of TNF-alpha, IL-6, and most strikingly IL-10 from WT PM phi, but not BMM phi. CCR8(-/-)PM phi and R243-treated WT PM phi both showed suppressed c-jun N-terminal kinase activity and nuclear factor-kappa B signaling after LPS treatment when compared with WT PM phi. A c-Jun signaling pathway inhibitor also produced an inhibitory effect on LPS-induced cytokine secretion that was similar to that of CCR8 deficiency or R243 treatment. As seen in CCR8(-/-) mice, administration of R243 attenuated peritoneal adhesions in vivo. R243 also prevented hapten-induced colitis. These results are indicative of cross talk between signaling pathways downstream of CCR8 and TLR-4 that induces cytokine production by PMQ. Through use of CCR8(-/-) mice and the new CCR8 inhibitor, R243, we identified a novel macrophage innate immune response pathway that involves a chemokine receptor.

The total synthesis of hibarimicinone, a potent v-Src tyrosine kinase inhibitor possessing thirteen stereogenic centers and an axial chirality, has been achieved. The key step to constructing the eight-ring skeleton was the double Michael-Dieckmann-type cyclization (Hauser annulation) using a thiolactone pseudo-dimer. These synthetic studies indicated the efficiency of the thiolactone-employed route to synthesize the multiply functionalized polycyclic compounds. The ABCD-ring moiety including the bridging ether was constructed by a strategy including oxidation of the C-ring hydroquinone and the subsequent transfer of the oxidation stage to the neighboring ring. The atropisomer of hibarimicinone was also synthesized to confirm the structure of the natural product. The total synthesis of hibarimicinone, a potent v-Src tyrosine kinase inhibitor, has been achieved. The key step to constructing the eight-ring skeleton was the double Michael-Dieckmann-type cyclization (Hauser annulation) using a thiolactone pseudo-dimer. The ABCD-ring moiety including the bridging ether was constructed by a strategy including oxidation of the C-ring hydroquinone and the subsequent transfer of the oxidation stage to the neighboring ring. The atropisomer of hibarimicinone was also synthesized to confirm the structure of the natural product. Copyright © 2013 The Chemical Society of Japan and Wiley-VCH Verlag GmbH &amp
Co. KGaA, Weinheim.

The first total synthesis of hibarimicinone has been achieved. The polyhydroxydecalin moieties (AB and GH rings) have been synthesized from sulfonylenone 4 derived from D-arabinose. The chiral biaryl 20 was coupled with two polyhydroxydecalins 11 by Michael-Dieckmann type condensation to give the eight rings system. Aromatization and oxidation with Ag+ gave quinone 24, and the subsequential transannular etheration gave the hibarimicinone skeleton. Deprotection and tautomerization were performed in one pot to give hibarimicinone (1). (C) 2011 Elsevier Ltd. All rights reserved.

K1115 B-1, isolated from the broth of Streptomyces species, was found to be a mixture of stereoisomers. Authors synthesized all stereoisomers of K1115 B-1 by convergent synthesis coupling a rhamnose derivative, an isobenzofuranone, and a chiral tetraol. Comparison of H-1 NMR spectra and optical rotations made it clear that the absolute structures of K1115 B-1 alpha (the major isomer) and K1115 B-1 beta (the minor isomer) were (1R,17S)- and (1R, 17R)-configurations, respectively. The optical rotations of the stereoisomers revealed that alnumycin, reported as the identical structure with K1115 B-1, might be another mixture of stereoisomers. (C) 2010 Elsevier Ltd. All rights reserved.

The first total synthesis of epi-cochlioquinone A has been achieved in a highly convergent manner via [3+3] cycloaddition of catechol 2 and oxadecalin 3 as the key reaction. The synthesis of the catechol segment, possessing the side chain with multi stereogenic centers, features the asymmetric vinylogous Mukaiyama aldol reaction, the stereoselective conjugate addition to the nitroalkene, the stereospecific nitro-Dieckmann condensation, and the transformation of 6-nitrocyclohex-2-enone into catechol 2, using two new methodologies, such as (i) the hydrogen-transfer reaction to o-aminophenol and the subsequent auto-redox-catalysis to catechol and (ii) the direct oxidation of 6-nitrocyclohex-2-enone to o-quinone and the subsequent reduction. The oxadecalin segment was synthesized from a glycosyl cyanide by the [3+3] annulation with a ketone and an acetoacetate. These segments were connected by the [3+3] cyclization, and the resulting tetracyclic compound was subjected to a specific oxidation of the protected hydroquinone to provide epi-cochlioquinone A. (C) 2010 Elsevier Ltd. All rights reserved.

The total synthesis of lactonamycin has been achieved. The synthesis includes sequential intramolecular conjugate addition of alcohols to the acetylenic ester, stereoselective glycosylation of the tertiary alcohol, and Michael-Dieckmann type cyclization with the thioester, by which the highly convergent route has been established. (C) 2010 Elsevier Ltd. All rights reserved.

The first total synthesis and structural determination of TMC-66, an ECE inhibitor, was achieved in short steps by efficient construction of two tricyclic segments and coupling reactions. The oxidative coupling with phenols attaching to electron-withdrawing groups was realized with a novel copper (II) reagent.

The first total synthesis and structural determination of TMC-264 has been accomplished. Regioselective bromination, regioselective methoxymethylation, and nickel(0)-Lewis acid-mediated cyclization afforded multi-functionalized 1-methyl-dibenzo[b,d]-pyran skeleton. (C) 2008 Elsevier Ltd. All rights reserved.

Actinopyrone A, an anti-Helicobacter pylori agent, was synthesized in nine steps from a silyl dienol ether. A vinylogous anti-aldol was stereoselectively synthesized by our developed remote stereoinduction methodology; coupling of this with a sulfone and a phosphonate species led to the construction of a vinylpyrone compound. This was submitted to reductive de-conjugation to give actinopyrone A. The absolute stereochemistry of actinopyrone A was determined to have the configuration 14R,15R.

The first total synthesis and structural determination of (+)-BE-52440A have been achieved by enantiodivergent synthesis. S-Bridging dimerization including S(N)2 epoxy-opening reaction of tetrasubstituted epoxide 2 with sodium sulfide has been achieved in excellent yield with high regioselectivity. The structure of (+)-BE-52440A was determined to be the dimer of kalafungin type pyranonaphthoquinone. (C) 2007 Elsevier Ltd. All rights reserved.

The first total synthesis and structural determination of TMC-66, an ECE inhibitor, was achieved in short steps by efficient construction and coupling of segments. The oxidative coupling with phenols attaching to electron-withdrawing groups was realized with a novel copper(II) reagent. (c) 2007 Elsevier Ltd. All rights reserved.

The first total synthesis and structural determination of YCM1008A, a Ca2+ signaling inhibitor, have been achieved. The N-methoxy pyrano-pyridone moiety was synthesized by successive O- and N-conjugate additions with diketoamide 15. The absolute structure was determined to be (2R,3R,4S,8'R)-configuration. (c) 2007 Elsevier Ltd. All rights reserved.

Vinaxanthone (1) has been biomimetically synthesized from vanillin (2) through an intermolecular Diels-Alder cycloaddition between two molecules of the precursor 11.

Lagunamycin (1) has been synthesized by using our developed remote stereoinduction, Knorr condensation, periodinane oxidation, and diazonation. This enantioselective synthesis determined the absolute configuration of lagunamycin. Existence of rotational conformers was confirmed by NMR studies. (c) 2006 Elsevier Ltd. All rights reserved.

Actinopyrone A (1) has been synthesized by using our developed remote stereoinduction, Kocienski olefination, Horner-Wadsworth-Emmons olefination, and reductive de-conjugation of the vinylpyrone. A concise method of O-methylation to obtain the gamma-pyrone has also been established. (c) 2006 Elsevier Ltd. All rights reserved.

(+)-Tubelactomicin A (1), an antitubercular lactone, has been synthesized from (S)-citronellol (2) and 2-deoxy-l-ribonolactone (18) through intramolecular Diels-Alder reaction, Suzuki-Miyaura coupling, and Shiina macrolactonization. © 2006 Elsevier Ltd. All rights reserved.

The first enantioselective total synthesis of convolutamydines B and E has been achieved using our vinylogous Mukaiyama aldol reaction. The synthesis features highly diastereoselective vinylogous Mukaiyama aldol reaction with isatin instead of aldehydes to construct a chiral center of convolutamydines. Additionally, the absolute configuration of natural convolutamydine B has been determined as R by its CD spectrum.

Vinylketene-N,O-acetals underwent Lewis acid-induced 1,3- or 1,5-rearrangement to afford the corresponding C-alkylated products. 1,5-Rearrangement proceeded predominantly in dichloromethane, and it is quite interesting to achieve an unprecedented high degree of asymmetric induction in such a remote position. Crossover experiments indicated that the reaction proceeded through an ion pair intermediate. (c) 2005 Elsevier Ltd. All rights reserved.

Trichostatin D and 6-epi-trichostatin D have been stereoselectively synthesized through a remote stereoinduction with a chiral vinylketene silyl N,O-acetal and glycosylation of hydroxyimide under Mitsunobu conditions. © 2004 Elsevier Ltd. All rights reserved.

Ketene N,O-acetals were prepared stercoselectively and submitted to a Lewis acid-mediated 1,3-rearrangement to afford C-alkylated products. The reactions proceeded in a stereoselective manner to construct a chiral quaternary carbon in high selectivity. The stereochemistry of the quaternary center was found to be opposite to that obtained by an anionic direct dienolate alkylation. (C) 2003 Elsevier Science Ltd. All rights reserved.

Development of an enantio- and stereoselective construction of 1,2-diols including a quaternary chiral center was achieved by a titanium-mediated aldol reaction of lactates bearing chiral oxazolidine-2-ones. anti-Aldol and syn-aldol were selectively obtained by the choice of a benzyl and TBS protecting group, respectively. Plausible transition states are also shown based on the stereochemistry of the enolate anion. (C) 2002 Elsevier Science Ltd. All rights reserved.

The total synthesis of madindolin A was achieved. Stereoselective construction of the quaternary carbon in the cyclopentenedione moiety was accomplished by alkylation of dienolate bearing a chiral auxiliary. The coupling of sterically hindered aldehyde 17 and acid-sensitive amine 30 was achieved by developing a new reductive amination method using Sn (OTf)₂ and NaBH(OAc)₃. After the reductive coupling, the cyclopentenedione skeleton of madindoline was constructed by intramolecular condensation of triketone 5.

Enantioselective synthesis of the cyclopentenedione moiety of madindolines was achieved. Stereoselective construction of a quaternary carbon was realized by alkylation of an enolate possessing chiral auxiliary. Cyclopentenedione was derived from a triketone precursor by intramolecular condensation. (C) 2000 Elsevier Science Ltd. All rights reserved.

The total synthesis of madindoline A was achieved. The key step of the synthesis is a reductive coupling of an acid-sensitive hydroxyfuroindoline derivative and a sterically hindered aldehyde using Sn(OTf)(2)-NaBH(OAc)(3). After the reductive coupling, the derived trione was subjected to intramolecular condensation to construct a madindoline skeleton. (C) 2000 Elsevier Science Ltd. All rights reserved.

The sarcodictyins A-F and eleutherobin comprise a family of marine-derived diterpenoids with potent cytotoxicities against various tumor cell lines. Investigations have revealed that several of these compounds exert their cytotoxic effects through tubulin binding in a mechanism analogous to that of the clinical anticancer drug Taxol(TM). The biological importance, challenging molecular architecture, and relative scarcity of these natural products have prompted several groups to undertake their total chemical synthesis. In this review we summarize the current synthetic efforts and examine the preliminary structure-activity relationships. which have emerged from early combinatorial libraries.

Three compounds related to the AB fragments of ciguatoxin and gambiertoxin 4b and two diastereomers (at the C-2 position) of the ABC fragment of ciguatoxin have been synthesized in enantiomeric form. The stereochemistry of the C-2 position was introduced selectively from the corresponding pentose derivative. Construction of the A ring with its side chain was completed by Nicholas type cyclization of an acetylene bis(cobalthexacarbonyl) complex followed by reductive decomplexation.

The total synthesis of cytotoxic marine natural products possessing tubulin polymerization and microtubule stabilization properties, sarcodictyins A (7) and B (8), is described. Two related approaches to these target molecules have been developed, both utilizing (+)-carvone (9) as starting material. The first approach involves a stereoselective construction of acetylenic aldehyde 27 (Scheme 2) while the second approach proceeds through a more direct but less selective sequence to the similar intermediate 36 (Scheme 3). Both strategies; involve ring closures of the acetylenic aldehyde precursors to 10-membered rings under basic conditions followed by elaboration and selective reduction of the acetylenic linkage to a cis double bond. This promotes bridging to form the required tricyclic skeleton of the sarcodictyins (27 --> 37 --> 38 --> 39 --> 4, Scheme 4 and 37 --> 44 --> 45 --> 46 --> 47 --> 42, Scheme 5) and (36 --> 48 --> 45, Scheme 6). Installation of the (E)-N(6')-methylurocanic acid residue was achieved by esterification with mixed anhydride 52, while the C-3 ester moieties were installed by standard deprotection, oxidation, and esterification procedures.

The total synthesis of the cytotoxic marine natural products eleutherobin (1) and eleuthosides A (2) and B (3) is described. The strategy involves glycosidation of the (+)-carvone-derived intermediate 7 with the arabinose-derived trichloroacetimidate 9 followed by base-induced ring closure and elaboration to afford the dihydroxy eneynone 19. Selective hydrogenation of 19 led to the generation and intramolecular collapse of dienone 20 furnishing 21 and thence 22 with the required structural framework of the target molecules. Finally, esterification with mixed anhydride 24 followed by deprotection gave eleutherobin (1) which served as a precursor to eleuthosides A (2) and B (3). The a-glycoside anomer of eleutherobin, compound 27, was also synthesized by application of the developed chemistry, demonstrating the flexibility of the sequence in generating designed analogues for biological screening.

The decomplexation of acetylene biscobalthexacarbonyl complexes can usually be achieved under oxidative condition. We had found other reductive conditions with endo-cyclic complexes, and recently other reductive conditions with both endo-and exo-cyclic complexes using either tributyltin hydride or triethylsilane. The original acetylene derivatives were transformed selectively either into the corresponding cis olefins or cis-vinylsilanes. (C) 1998 Elsevier Science Ltd. All rights reserved.