Chapter 1 Total synthesis of RK-397

Scott E. Denmark, Shinji Fujimori

Research output: Contribution to journalArticle


RK-397 has been synthesized in a concise manner by employing a highly convergent synthetic strategy that features the use of an eight-carbon building block for 16 carbons in the polyol chain (Figure 11). The coupling of these modules was accomplished by substrate-controlled 1,5-anti-aldol addition and subsequent stereoselective reduction. The synthesis highlights the highly stereoselective vinylogous aldol addition using chiral phosphoramide 56 for the construction of the key intermediate 41. The stereogenic center created by this reaction effectively established 8 out of 10 stereogenic centers in this molecule by substrate control. The use of an alkenylsilane as a masked aldehyde functionality is noteworthy for not only allowing high yields in the key aldol additions, but also forits stability under numerous reaction conditions. The sequential cross-couplings with bis-silyl diene 45 to construct highly conjugated side chain 40 are also highlighted.The efficiency of the synthesis was significantly enhanced by identifying the building block 41. This approach minimized the steps for functional group interconversions and protection/deprotection of the polyol. The longest linear sequence is of 20 steps starting from 3-benzyldimethylsilylpropynol (52) with an overall yield of 4.3%. The previous synthesis by McDonald et al. also took advantage of a modular approach for the construction of the polyol, however, the preparation of the modules seems inefficient (Scheme l).11 The chiral epoxide module 33 is constructed through a hydrolytic kinetic resolution, and the yield for the resolution step is only 42%. In their synthesis, the overall yield for the longest linear sequence was 0.3% (30 steps from isobu-tyraldehyde). The two late-stage reactions are responsible for the low overall yield: the attachment of the triene fragment by Stille coupling (32%) and the macrocyclization by intramolecular olefination (29%).For the coupling of fragments 41 and 42, the Lewis-base-catalyzed aldol addition was employed and successfully provided the aldol product in good yield, however, only marginal 1,5-anti stereoinduction was attained. The compatibility of trichlorosilyl enolates with various functional groups present in 41 and 42 (e.g. benzylidene acetal and p-methoxybenzyloxy ether) was demonstrated. Moreover, the 1,5-syn diastereomer could be obtained in higher selectivity (dr 4/1), which is not possible by the addition of boron enolates. To obtain a better 1,5-anti stereoinduction by addition of the trichlorosilyl enolate, various Lewis bases were surveyed, but chiral phosphoramide 76 was the best catalyst. The selectivity might be improved by changing the protecting group on β-hydroxy group in 41 from benzylidene acetal to TBS group, though this would require additional steps in the synthesis. The selectivity obtained with a trichlorosilyl enolate bearing (β-OTBS group is up to 5.5/1 using phosphoramide 76.36The key intermediate 41 can also be a suitable building block in the synthesis of other polyene macrolides and natural products that possess a poly-acetate structural motif. Analogous intermediates can be prepared using a y-substituted silyl dienol ether that may allow preparation of a polypropi-onate-type structure. Although the alkenylsilane in 41 was oxidized to aldehyde in this synthesis, the benzyldimethylsilyl group can also be used in palladium-catalyzed cross-coupling reaction to form a C-C bond.The modular approach for the synthesis of RK-397 should facilitate preparation of various diastereomers of RK-397 through several modifications of the sequence: (1) by changing the catalyst configuration at thevinylogous aldol addition, (2) by employing the silicon-based aldol to establish 1,5-syn stereoinduction in the key aldol coupling and (3) by changing the reagents for the synlanti carbonyl reduction. These variations may enable preparation of a library of RK-397 isomers to study biological activity of these polyene macrolides.

Original languageEnglish (US)
Pages (from-to)1-34
Number of pages34
JournalStrategies and Tactics in Organic Synthesis
Issue numberC
StatePublished - Dec 1 2008

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry

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