穴田 仁洋

18E-Lyngbyaloside C (1), a 14-membered glycosidic macrolide isolated from the marine cyanobacterium Lyngbya bouilloni, has been shown to exhibit cytotoxicity to HeLa cell lines. We previously reported that Rh_2(S-BPTPI)_4 is a highly effective Lewis acid catalyst for endo- and enantioselective hetero-Diels-Alder (HDA) reactions of a diverse range of aldehydes with Danishefsky-type and Rawal's dienes, in which enantioselectivities up to 99% ee have been achieved. In order to demonstrate the utility of this catalytic process, we embarked on the total synthesis of 1. The synthesis of the C1-C8 fragment 9 was initiated with the HDA reaction between Danishefsky-type diene 3a and benzyloxyacetoaldehyde (14) in the presence of 1 mol% of Rh_2(R-BPTPI)_4 to provide dihydropyranone 13 in 83% yield with 91% ee. The Mukaiyama-Michael addition reaction of silyl ketene acetal derived from ethyl acetate to 13 followed by Ito-Saegusa oxidation gave 2,6-disubstituted dihydropyranone 12, which was converted to tetrahydropyran 19. Removal of the benzyl ether followed by incorporation of the thiotetrazole via the Mitsunobu protocol and oxidation of the derived sulfide furnished sulfone 9. The HDA reaction between Rawal's diene (6) and (R)-3-(4-methoxybenzyloxy)-2-methylpropanal (17b) under catalysis by 1 mol% of Rh_2(R-BPTPI)_4 proceeded cleanly and gave, after treatment with acetyl chloride, the desired dihydropyranone 16b in 82% yield with 95:5 diastereoselectivity. Treatment of 16b with MeLi followed by oxidative rearrangement, stereoselective epoxidation and reduction of epoxylactone provided triol 25, which was uneventfully converted to tosylate 26. Cyanide displacement of the O-tosyl group followed by a sequential reduction with DIBAL-H and NaBH_4 furnished alcohol 27. Protection of the C16 hydroxy group as its MEM ether was followed by oxidative removal of the MPM group and Dess-Martin oxidation to produce the C9-C16 fragment 10. A Julia-Kocienski olefination between the C1-C8 fragment 9 and the C9-C16 fragment 10 afforded E-alkene 8. Sequential catalytic hydrogenation of the double bond and cleavage of the benzylidene protecting group furnished diol 28. Further efforts toward the total synthesis of 1 are currently underway.

Englerin A (1), a group of guaiane sesquiterpene isolated from the stem bark of Phyllanthus engleri collected in east Africa by Beutler and co-workers, have been shown to be a potent and selective inhibitor of the growth of renal cancer cell lines. Recently we reported that Rh_2(S-TCPTTL)_4 (2) is a highly effective catalyst for enantioselective tandem carbonyl ylide formation-cyclization reactions of α-diazo-β-ketoester with phenylacetylene, ethyl ethynyl ether and styrene dipolarophiles, providing cycloadducts in good to high yields and with enantioselectivities of up to 99% ee as well as with perfect exo diastereoselectibity for styrenes. In conjunction with our continuing interest in the carbonyl ylide cycloaddition strategy for the synthesis of natural products, we embarked on a program aimed at total synthesis of englerins. Herein, we describe our efforts toward a synthesis of (-)-englerin A (1). The 1,3-dipolar cycloadditon of carbonyl ylide derived from α-diazo-β-ketoester 11 with 3 equiv of ethyl vinyl ether (12a) using 1 mol % of Rh_2(S-TCPTTL)_4 afforded the exo-cycloadduct 10a in 75% yield with 95% ee. Ito-Saegusa oxidation of silyl enol ether derived from 10a and subsequent addition of organolithium reagent 18b followed by Red-Al^[R!〇] reduction of tert-butyl ester, tosylation of primary alcohol and oxidative rearrangement furnished enone 24, which was converted to ketone 25 in a stereoselective manner. Intramolecular aldol reaction and subsequent Luche reduction gave allyl alcohol 26 in good yield. Hydrogenation of 26 with Pd/C gave diol 27 as a major product, which was transformed to acetate 28. Oxidation of 28 under the Sharpless conditions followed by reduction of 29 with LiBEt_3H gave diol 5 in high yield. Finally, regioselective acylation of the C9-hydroxy group followed by esterification of the C6-hydroxy group with cinnamic acid using Yamaguchi's procedure and desilylation completed the catalytic asymmetric synthesis of (-)-englerin A (1).

The dirhodium(II) complex-catalyzed tandem cyclic carbonyl ylide formation-1,3-dipolar cycloaddition reaction sequence represents one of the most efficient methods for the rapid assembly of complex oxapolycyclic systems. Consequently, the development of a catalytic enantioselective version of this sequence has become a challenging objective. In this context, we previously reported that the tendem formation of keto- or ester-carbonyl ylide from α-diazoketone and intermolecular 1,3-dipolar cycloaddition under the influence of Rh_2(S-BPTV)_4 or Rh_2(S-PTTL)_4, respectively, give cycloadducts with up to 93% ee. Very recently, we also reported high levels of enantioselection (up to 99% ee) for the intermolecular cycloaddition of 2-diazo-3,5-diketoesters-derive dcarbonyl ylides with arylacetylene, alkoxyacetylene and styrene dipolarophiles using Rh_2(S-TCPTTL)_4. In order to demonstrate the synthetic potential of this methodology, we addressed catalytic asymmetric syntheses of oxabicyclic natural products. The 1,3-dipolar cycloaddition of cyclic carbonyl ylide dereved from α-diazoketone 11 with 2 equiv of aromatic aldehyde 12d using 1 mol % of Rh_2(S-BPTV)_4 in benzotrifluoride proceeded smoothly to afford exo-cycloadduct 10d in 67% yield with 87% ee. Peterson olefination of enantiomerically pure 10d followed by DIBAL-H reduction and chlorination afforded the allyl chloride Z-17. S_N2'-Substitution of Z-17 with MeMgI in the presence of CuCN・2LiCl at -40℃ gave the desired product 19 as a major product. Deprotection of silyl protecting group provided psoracorylifol C (7). The 1,3-dipoar cycloaddition of carbonyl ylide derived from α-diazo-β-ketoester 22 with 3 equiv of phenylacetylene 23d using 1 mol % of Rh_2(S-TCPTTL)_4 afforded the 8-oxabicyclo[3.2.1]octan-2-one 24d in 73% yield with 95% ee. Catalytic hydrogenation of the double bond provided 25 in 93% yield with perfect endo diastereoselectivity. Silylation of enantiomerically poure 25 followed by enol triflate formation and reductive elimination of the trifluoromethanesulfonate group furnished alkene 28. Reduction of the ester group in 28 and subsequent silylation gave 29. Allylic oxidation of 29 with SeO_2 followed by oxidation with MnO_2 and subsequent deprotection of two TBDPS groups completed the asymmetric synthesis of 8.

A recent study from our laboratory has shown that Rh₂(S-TCPTTL)₄, characterized by substitution of chlorine atoms for four hydrogen atoms on the phthalimido group in the parent Rh(II) complex, is well suited for enantioselective C–H amidation reation with [(4-nitrophenyl)sulfonylimino]phenyliodinane. As a logical extension of our study in this area, we addressed the enantioselective amidation of silyl enol ethers catalyzed by chiral Rh(II) carboxylates. The Rh(II)-catalyzed aziridination of acyclic silyl enol ethers with [(2-nitrophenyl)sulfonylimino]phenyliodinane followed by treatment with aq. TFA afforded optically active α-amino ketones. The fluorinated catalyst, Rh₂(S-TFPTTL)₄, proved to be the catalyst of choice for this process, exhibiting the highest enantioselectivity of 95% ee. The effectiveness of the present catalytic method has been demonstrated by the enantioselective synthesis of (–)-metazocine.