Total syntheses of bengamides B and E

Total syntheses of the cytotoxic marine natural products bengamides B and E are described. Both bengamides are prepared via amide coupling of a protected polyhydroxylated lactone intermediate 9 with a suitably substituted aminocaprolactam intermediate. Lactone 9 is prepared in five steps from commercially available alpha-D-glucoheptonic gamma-lactone. The key reactions are a selective deprotection of a 1,2-acetonide in the presence of a 1,3-acetonide and an (E)-selective olefination of an unstable aldehyde using a gem-dichromium reagent. The bengamide B lactam intermediate 10 is prepared in seven steps from commercially available (5R)-5-hydroxy-L-lysine (12). The desired S-configuration at the gamma-OH lactam position is established using the Mitsunobu reaction.     

Total syntheses of arenamides A,B and C

Total syntheses of the three arenamides A–C, NFκB inhibitors, are described for the first time. The key steps involved in the synthesis are a Crimmin’s aldol, Wittig olefination and a macrolactamization reaction.     

Total syntheses of amythiamicins A, B and C

Total syntheses of the thiopeptide antibiotics amythiamicins A, B and C are reported.     

Total syntheses of the telomerase inhibitors dictyodendrin B, C, and E

Concise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2), C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction to generate an adjacent indole nucleus, and a photochemical 6pi-electrocyclization/aromatization tandem to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal-halogen exchange or cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or -stannanes met with failure.     

Total syntheses of subereamollines A and B

The first total syntheses of (+)- and (-)-subereamollines A and B are reported. The enantiomeric forms of the natural products were obtained by preparative chiral HPLC separation of the corresponding racemates.     

Total syntheses of graphisin A and sydowinin B

Efficient syntheses of the highly substituted benzophenone graphisin A and the xanthone sydowinin B are described. Key steps involve aryl anion addition to substituted benzaldehyde derivatives, subsequent methyl ester installation, and dehydrative cyclization. Oxidation of graphisin A led to a spirodienone derived from a highly substituted benzoquinone intermediate.     

Total syntheses of natural tubelactomicins B, D, and E: establishment of their stereochemistries

Total syntheses of the antimicrobial tricyclic 16-membered macrolides, (+)-tubelactomicin B, (+)-tubelactomicin D, and (+)-tubelactomicin E, have been accomplished for the first time with common synthetic approaches. These total syntheses established the relative and absolute configurations of the three tubelactomicins, for which planar structures had solely been reported. The total synthesis of (+)-tubelactomicin D included a newly developed stereoselective intramolecular Diels-Alder reaction for constructing the highly functionalized octahydronaphthalene substructures.     

Total syntheses of variolin B and deoxyvariolin B

Two alternative synthetic routes have been developed for the preparation of variolin B and deoxyvariolin B. The strategy is based on the preparation of the core tricyclic ring common to all variolins, pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine, followed by a palladium-catalyzed cross-coupling reaction to give the tetracyclic system.     

Total syntheses of (-)-fumiquinazolines A, B, and I

[structure] The first total syntheses of (-)-fumiquinazolines A, B, and I have been accomplished efficiently using the Pd-catalyzed cyclization of an iodoindole carbamate to construct the imidazoindolone moiety and the dehydrative cyclization of a diamide followed by rearrangement through an amidine to construct the quinazolone moiety.     

Total syntheses of schulzeines B and C

Schulzeines B (2) and C (3) were synthesized by a convergent strategy using epimeric tricyclic lactam building blocks, 4 and 5, and the C28 fatty acid side chain 6. Syntheses of tricyclic lactams (4/5) were achieved by Bischler-Napieralski reaction. Sharpless asymmetric dihydroxylation and BINAL-H-mediated asymmetric reduction of an enone was employed to prepare the key fatty acid side chain 6. The spectral as well as analytical data of 2 and 3 were in good agreement with the reported data for the natural products, thus confirming their assigned structures.     

Total syntheses of epothilones B and d

A convergent, total synthesis of epothilones B (2) and D (4) is described. The key steps are Normant coupling to establish the desired (Z)-stereochemistry at C12-C13, Wadsworth-Emmons olefination of methyl ketone 28 with the phosphonate ester 8, diastereoselective aldol condensation of aldehyde 5 with the enolate of keto acid derivatives to form the C6-C7 bond, selective deprotection of acid 52, and macrolactonization.     

Total syntheses of epothilones B and D

Total syntheses of the microtubule stabilizing antitumor drugs epothilone B and D are described, starting from optically pure (S)-malic acid and methyl (R)-3-hydroxy-2-methylpropionate. The synthesis is highly convergent by coupling the three fragments C1-C6 (fragment D), C7-C10 (fragment C), and C11-C21 (fragment B). Key steps are two stereoselective Wittig type olefinations to generate the 12,13- and 16,17-double bonds, an enantioselective Mukaiyama aldol addition to synthesize fragment D, and a sulfone anion allyl iodide alkylation to connect fragments B and C. Finally fragment D was attached to the B + C fragment via aldol addition.     

Total syntheses of isonaamine C and isonaamidine E

The total syntheses of two alkaloids isolated from a marine sponge of the Leucetta sp. have been accomplished in 6 and 7 steps starting from a 4,5-diiodoimidazole derivative. Grignard mediated halogen-metal exchange was used to install the benzyl side chain. C2 substitution was accomplished via lithiation followed by quenching with trisyl azide which provided isonaamine C after hydrogenation. Isonaamidine E was then prepared from isonaamine C via introduction of the hydantoin ring by reaction with an activated parabanic acid derivative.     

Total syntheses of the marine pyrrole alkaloids polycitone A and B

Polycitone B (2) was obtained in four steps from pyrrole dicarboxylic acid 3, including Friedel-Crafts reaction of the corresponding acid chloride with anisole. The conversion of 2 into polycitone A (1) was achieved in two steps via Mitsunobu alkylation of the pyrrolic NH group. The synthesis of polycitone A proceeds in 18% overall yield and offers the possibility of varying the substituents on the pyrrole ring.     

Total syntheses of (-)-fumiquinazolines C, E, and H

[structure: see text] Total syntheses of the heptacyclic fumiquinazolines C and H have been accomplished efficiently using FmocNHCH(CH2SePh)CO2H as the precursor for the requisite dehydrofumiquinazoline.     

Total syntheses of the actin-binding macrolides latrunculin A, B, C, M, S and 16-epi-latrunculin B

The latrunculins are highly selective actin-binding marine natural products and as such play an important role as probe molecules for chemical biology. A short, concise and largely catalysis-based approach to this family of bioactive macrolides is presented. Specifically, the macrocyclic skeletons of the targets were forged by ring-closing alkyne metathesis (RCAM) or enyne-yne metathesis of suitable diyne or enyne-yne precursors, respectively. This transformation was best achieved with the aid of [(tBu)(Me(2)C(6)H(3))N](3)Mo (37) as precatalyst activated in situ with CH(2)Cl(2), as previously described. This catalyst system is strictly chemoselective for the triple bond and does not affect the olefinic sites of the substrates. Moreover, the molybdenum-based catalyst turned out to be broader in scope than the Schrock alkylidyne complex [(tBuO)(3)W[triple chemical bond]CCMe(3)] (38), which afforded cycloalkyne 35 in good yield but failed in closely related cases. The required metathesis precursors were assembled in a highly convergent fashion from three building blocks derived from acetoacetate, cysteine, and (+)-citronellene. The key fragment coupling can either be performed via a titanium aldol reaction or, preferentially, by a sequence involving a Horner-Wadsworth-Emmons olefination followed by a protonation/cyclization/diastereoselective hydration cascade. Iron-catalyzed C--C-bond formations were used to prepare the basic building blocks in an efficient manner. This synthesis blueprint gave access to latrunculin B (2), its naturally occurring 16-epimer 3, as well as the even more potent actin binder latrunculin A (1) in excellent overall yields. Because of the sensitivity of the 1,3-diene motif of the latter, however, the judicious choice of protecting groups and the proper phasing of their cleavage was decisive for the success of the total synthesis. Since latrunculin A and B had previously been converted into latrunculin S, C and M, respectively, formal total syntheses of these congeners have also been achieved. Finally, a previously unknown acid-catalyzed degradation pathway of these bioactive natural products is described. The cysteine-derived ketone 18, the tetrahydropyranyl segment 31 serving as the common synthesis platform for the preparation of all naturally occurring latrunculins, as well as the somewhat strained cycloalkyne 35 formed by the RCAM reaction en route to 2 were characterized by X-ray crystallography.     

Total syntheses of cladoacetals A and B: confirmation of absolute configurations

The first enantioselective syntheses of cladoacetals A (1a, overall yield: 16%) and B (1b, overall yield: 34%) from crotonaldehyde in nine and seven steps, respectively, have been accomplished. Sharpless asymmetric dihydroxylation, Suzuki coupling, and acid-catalyzed intramolecular acetalization were the key steps in the syntheses. The absolute configuration of natural (+)-cladoacetal A was affirmed to be 1S,3S,4R, whereas that of (-)-cladoacetal B was affirmed to be 1R,3S,4S.