Stereoselective synthesis of functionalized trisubstituted olefins via palladium(0)-catalyzed cross-coupling reaction.

[reaction: see text]. A highly flexible and stereoselective protocol for the synthesis of branched (E)- and (Z)-trisubstituted alkenes has been developed. The key steps are hydrozirconation-iodination of (1-alkynyl)trimethylsilane followed by Negishi-type cross-coupling. The resultant (Z)-vinyl silane is iododesilylated and subjected to a second cross-coupling reaction to give the trisubstituted olefin. Model studies aimed at the construction of the C14-C15 (Z)-trisubstituted olefin of discodermolide and the C8-C9 (Z)-trisubstituted olefin of callystatin A and analogues are also described.

Enhanced diastereoselectivity in asymmetric crotylation reactions using propargylic dicobalt hexacarbonyl complexes.

[reaction: see text] Hexacarbonyl dicobalt complexes of propargylic acetals undergo Lewis acid catalyzed crotylation reactions with enhanced levels of diastereoselectivity (dr 6 to >20:1, syn/anti) while efficiently producing stereochemically well-defined homoallylic ethers. These results are in contrast to uncomplexed propargylic acetals, which undergo the crotylation reactions with low selectivity (dr < 2:1, syn/anti). After removal of the cobalt complex, the reactions afford propargylic ethers in high yields.

Formal [4+2]-annulation of chiral crotylsilanes: synthesis of the C19-C28 fragment of phorboxazoles.

A stereoselective synthesis of the C19-C28 fragment of phoborxazole A and B is described. The key step is an enantioselective [4 + 2]-annulation of a crotylsilane 10 with a propargylic aldehyde 11 affording a functionalized dihydropyran 12. A solvent-dependent stereoselective epoxidation of dihydropyrans is also documented.

Total synthesis of rutamycin B and oligomycin C.

The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C (2) is described. The approach relied on the synthesis and coupling of the individual spiroketal fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed the introduction of the stereogenic centers prior to spiroketalization. The present work details the synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41. The requisite polypropionate fragment was assembled in a convergent manner using asymmetric crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A Mukaiyama-type aldol reaction of 35 with the chiral alpha-methyl aldehyde 39 was used for the introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-C17 advanced intermediate 36. A two-carbon homologation completed the construction of the polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was accomplished by the union of two principal fragments that was achieved with an intermolecular palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B and oligomycin C.

An asymmetric aminohydroxylation approach to the azepine core of (-)-balanol.

[reaction: see text]An efficient formal synthesis of the potent protein kinase C inhibitor (-)-balanol that relies on a modified asymmetric aminohydroxylation of the alpha,beta-unsaturated aryl ester (1) is reported. The aryl ester functionality and the dihydroquinyl alkaloid ligand system (DHQ)2-AQN are used to control the regio- and enantioselectivity of the process.

Total synthesis of epothilone A.

[reaction: see text]Epothilones A (1) and B (2) are potent antitumor natural products with a Taxol-like mechanism of action. A total synthesis of epothilone A (1) is reported, which utilized chiral silane-based bond construction methodology to introduce the key C-6 and C-7 stereocenters of fragment 4. The C-15 stereocenter of fragment 5 was established by a lipase-mediated kinetic resolution. The fragments were assembled with a Suzuki coupling reaction and an aldol condensation and cyclized with a Yamaguchi-type macrolactonization reaction.

Palladium-catalyzed cross-coupling of terminal alkynes with 4-trifloyloxazole: studies toward the construction of the C26-C31 subunit of phorboxazole A.

[reaction: see text] A strategy has been developed that successfully takes advantage of transition-metal-catalyzed coupling reactions for the synthesis of highly functionalized oxazoles. Trifloyloxazoles have been used as coupling partners with alkyne-derived vinylmetallic intermediates in Stille- and Negishi-type couplings to assemble the corresponding oxazoles in good isolated yield. The results obtained provide a close analogy and thus good precedent to employ this strategy in the synthesis of the oxazole subunits of phorboxazole A.

Reversal of regioselection in the sharpless asymmetric aminohydroxylation of aryl ester substrates.

[formula: see text] The asymmetric synthesis of beta-hydroxy-alpha-amino acids is reported which relies on the use of alpha,beta-unsaturated aryl ester substrates and the dihydroquinyl alkaloid ligand system (DHQ)2-AQN to control the regio- and enantioselectivity of the asymmetric aminohydroxylation (AA) process. alpha,beta-Unsaturated ester substrates of type 1 have a significant effect on the substrate-ligand recognition event which results in a reversal of regioselectivity in the AA reaction.

Total synthesis of (+)-lactacystin.

A double stereodifferentiating crotylation between aldehyde 1 and silane (S)-2 to afford homoallylic alcohol 3 is the key diastereoselective step (anti:syn >30:1) in an efficient asymmetric synthesis of (+)-lactacystin. This compound is a metabolite isolated from Streptomyces sp. OM-6519 that exhibits significant neurotrophic activity. An additional important step in the synthesis is a catalytic asymmetric aminohydroxylation used as the key step in the synthesis of the (2R,3S)-hydroxyleucine synthon.