Euonymine (1) and euonyminol octaacetate (2) share the core structure of euonyminol (3), the most hydroxylated member of the dihydro-β-agarofuran family. In 2, eight of the nine hydroxy groups of 3 are acetylated, and 1 has six acetyl groups and a 14-membered bislactone comprising a pyridine dicarboxylic acid with two methyl groups. The different acylation patterns provide distinct biological activities: 1 and 2 display anti-HIV and Pglycoprotein inhibitory effects, respectively. The 11 contiguous stereocenters and 9 oxygen functionalities of the ABC-ring system of 1 and 2 represent a formidable challenge, which is further heightened by the macrocyclic structure of 1. Here we disclose an efficient synthetic strategy for enantioselective total synthesis of 1 and 2. Starting from (R)-glycerol acetonide, we constructed the Bring by an Et 3 N-accelerated Diels−Alder reaction, the C-ring by intramolecular iodoetherification, and the A-ring by ring-closing olefin metathesis. The 10 stereocenters were installed through a series of substrate-controlled stereoselective C−C and C−O bond formations by exploiting the three-dimensional structures of judiciously designed substrates. These newly developed reaction sequences led to protected euonyminol 5, which served as a common intermediate for assembling 1 and 2. Global deprotection of 5 and subsequent acetylation produced 2. Alternatively, the discriminative protective groups of 5 allowed for site-selective bisesterification to generate bislactone. Combining [3 + 2]-cycloaddition and reductive desulfurization introduced the last remaining stereocenters of the two methyl groups on the macrocycle. Finally, deprotection and acetylation gave rise to fully synthetic 1 for the first time.
3β-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene, which has a double bond between C-9 and C-11 and a phenylsulfenyl group on the terminus of the side chain, is a potential synthetic intermediate for steroids with 9,11-unsaturation or 9,11-seco skeletons. We describe here the synthesis of the title compound from 17-ethylenedioxy-3-acetoxyandrosta-3,5-dien-11-one. The introduction of an ethylene unit to 3β-tert-butyldimethylsiloxyandrosta-5,9(11)-dien-17-one by the action of ethyltriphenylphosphonium bromide under basic conditions resulted in an inseparable mixture of two stereoisomeric products (5 : 1). However, in the subsequent step, only the (Z)-isomer was susceptible to the Lewis acid-catalyzed ene reaction with formaldehyde, giving a stereochemically pure product with the desired configuration. Within three steps, the ene-product was derivatized to the title compound, with a total yield of 53% over seven steps. Reductive terminal anion formation by treatment with lithium di-tert-butylbiphenyl (LiDBB) and subsequent nucleophilic attack on a branched aliphatic aldehyde was demonstrated, with an eye toward the introduction of side chains, especially for steroids with oxygen functionality at C-23.
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