Total Synthesis and Structural Elucidation of (−)‐Delactonmycin

Abstract

Dedicated to Professor Albert J. Kascheres on the occasion of his 60th birthdayIn recent years, a number of highly cytotoxic polyketides with similar chemical structures, including the leptomycins, kazusamycins, anguinomycins, and leptolstatins, were isolated as secondary metabolites from Streptomyces strains.[1] In 1997, Wang et al. identified two novel polyketides, named delactonmycin and dilactonmycin, in the extracts from Streptomyces strain A92-308902 with very potent inhibitory activity of the nucleo-cytoplasmic translocation of the HIV-1 regulatory protein Rev.[2] The planar structure of delactonmycin was established by spectroscopic methods, but its relative as well as its absolute configuration remained unknown. In our synthetic studies towards the elucidation of the relative configuration of delactonmycin (1), we were led to presume that it is the same as that of leptomycin B and callystatin Aa structurally related polyketide isolated from the marine sponge Callyspongia truncata [3] -whose relative and absolute configurations were established by spectroscopic methods and total synthesis. [4,5] Our interest in the synthesis of delactonmycin stemmed from its greater structural simplicity relative to that of other members of this class, which renders it an interesting model compound for structure-activity studies.[6] Additionally, the implementation of a successful approach to 1 would pave the way to the total synthesis of other polyketides whose structures have not yet been confirmed by total synthesis. Herein, we disclose our approach and results toward the first total synthesis and structural elucidation of (À)-delactonmycin (1, Scheme 1).The installation of the C4ÀC5 bond through E-selective Wittig olefination between aldehyde 2 and phosphonium bromide 3 was left to a late stage of the synthesis in our retrosynthetic analysis. In turn, 3 could be obtained from a Wittig olefination of aldehyde 4 with ethyl triphenylphosphoranylidene propionate. It was envisaged that aldehyde 4 could be prepared from the syn aldol adduct obtained from the reaction between ethyl ketone 5 and g,d-unsaturated aldehyde 6. The fragments 2, 5, and 6 are available from the methyl (R)-and (S)-3-hydroxy-2-methylpropionates, which we have already used in the total synthesis of the aglycon of the macrolide antibiotic 10-deoxymethymycin. [7] Aldehyde 6 was readily obtained through the sequence shown in Scheme 2. A palladium-catalyzed cross-coupling reaction between the chiral zinc homoenolate 8 [8,9] and cis-2-bromo-2-butene (both commercially available) led to the formation of 11, which was carefully reduced with diisobutylaluminum hydride at À90 8C to afford 6 in 86 % overall yield. Ketone 5 was prepared as described by Paterson et al. [10] in three steps and 57 % overall yield. Conversion of (R)-7 into the Weinreb amide 9 was followed by protection as its p-methoxybenzyl ether 10. Subsequent addition of ethyl magnesium bromide provided ethyl ketone 5. Treatment of 5 with stannous triflate and Et 3 N at À78 8C in CH 2 Cl 2 gene...

Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-organometallics as Reaction Partners

“…In 2007, Crews and coworkers utilized a Negishi cross-coupling to the synthesize the C3-C18 fragment of amphidinolides G and H, where the treatment of compound 227 with alkylzinc 228 in the presence of Pd(PPh 3 ) 4 gave the coupled product 229 in 92% yield (Figure 146d). 524 The same alkylzinc ( 228 ) was used by Pilli and coworkers in the total synthesis of (−)-delactomycin 525…”

Hypervalent iodine reagents in the total synthesis of natural products

“…In the latter case the reaction was performed in the presence of H 2 O (Scheme 10). 213,214 Water has also been used in other total syntheses using DMP in CH 2 Cl 2 , 97,121,122,215 because it accelerates the reaction. 13…”

Total synthesis and structural elucidation of natural products: (–)-Delactonmycin, (+)-plumerinine, and (–)-parvistemoamide

“…In 1997, Wang and coworkers isolated several polyketides from the extracts of Streptomyces strain A92-308902, which displayed nanomolar inhibitory activity against HIV-1 Rev protein during bioassay-guided high-throughput screening [8]. Rev gene is essential for HIV replication, and its protein must be translocated from nucleus to cytoplasm to exert its function and thus could be a potential target for HIV-1 therapy.…”

“…Our bad feelings and apprehension disappeared as we compared the NMR data of the synthetic sample and of natural delactonmycin kindly provided by Dr. Wang, as it left no doubt about the identity of the two samples. The relative configuration of the natural product had thus been established, although the lack of chiroptical data for the natural compound precluded us from confirming its absolute configuration at this point [8].…”

“…Over the years, our interest in synthetic organic chemistry was initially sustained by the unique biological activities of natural compounds such as pheromones [5], polyketides [6], and alkaloids [7] of established chemical structure and steadily evolved to the structural confirmation of the molecular architecture as we stumbled into some examples of structure misassignment in the literature and became interested in applying our knowledge of stereochemical control to the determination of the configuration of some natural products. What follows is an account of our recent results on the structural elucidation of (-)-delactonmycin [8], (+)-plumerinine [9], and (-)-parvistemoamide.…”