Novel Approach to the Zaragozic Acids. Enantioselective Total Synthesis of 6,7-Dideoxysqualestatin H5

Abstract

The total synthesis of 6,7-dideoxysqualestatin H5 (3) has been completed by a concise approach that features the stereoselective intramolecular vinylogous aldol reaction of the furoic ester 25a to give 30 or its trimethylsilyl ether derivative 34, which possess the requisite absolute stereochemistry at C(3)-C(5) of 3. Compound 34 was reduced to the saturated bislactone 39, and the C(1) side chain subunit 47 was introduced leading to a mixture of the hemiacetals 48 and the corresponding ketone 49. When this mixture was stirred with methanolic acid, transketalization occurred to give a mixture of 50 and the spirocyclic methyl acetals 51a,b. Oxidation of the primary alcohol group in 50 followed by saponification of the two remaining ester groups gave 3. The longest linear sequence in the synthesis commences with commercially available erythronolactone (26) and requires 17 chemical steps with only 10 isolated intermediates.

The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress

“…In general, 2-substituted cyclohexanones and bicyclic ketones of type A rather elegant, rarely exploited intramolecular VAR involving chiral furoic acid methyl ester 236 was adopted by Martin et al to obtain 6,7-dideoxysqualestatin H5 (235), a member of the natural zaragozic acid family (Scheme 44). 101 Thus, the TiCl 4 -induced cyclization proceeded well, giving the desired spirocyclic adduct 237 with an exquisite level of diastereoselectivity. To stabilize this delicate intermediate, 237 was promptly silylated at the free hydroxyl and then advanced to bicyclic lactone 238.…”

Catalyzed Vinylogous Mukaiyama Aldol Reactions with Controlled Enantio‐ and Diastereoselectivities

“…[8][9][10] We now describe the use of sulfoximine 1 a in copper-catalyzed VMARs between various cyclic dienol silanes and ketonic electrophiles. In contrast to the large number of studies with aldehydes as carbonylic substrates, [11] reports on reactions with ketones are relatively rare, [13] and only a few of those include pyruvates as starting materials.[12b, c, 13] Presumably the additional demand for diastereoselectivity in the simultaneous formation of two stereogenic centers (including one with a fully substituted carbon) in conjunction with the general requirement of top-level regio-and enantioselectivities have posed additional challenges, which have not allowed rapid progress in this area.For the initial adjustment of the reaction conditions, commercially available 2-(trimethylsilyloxy)furan (TMSOF, 3 a) and methyl pyruvate (4 a) were chosen as starting materials (Scheme 1). After a brief optimization, we found that with a catalyst loading of 10 mol %, a CuA C H T U N G T R E N N U N G (OTf) 2 to sulfoximine 1 a ratio of 1:1 and 2,2,2-trifluoroethanol (1.2 equiv) as additive in dry diethyl ether, g-butenolide 5 a could be obtained in 88 % yield after only 5 h at room temperature.…”

Five‐Membered Heterocycles: Furan

“…High syndiastereoselectivity is obtained with bulky a-branched aldehydes [132]. In addition, 2-methoxy, 2-aryloxy and 2-phenylthiofurans also serve as nucleophiles [133].…”