Enantioselective Synthesis of (–)-Stemoamide

A kinetic resolution of a diol via etherification catalyzed by a chiral phosphoric acid was developed and applied in the concise total synthesis of (+)-sacidumlignan D, the antipode of natural sacidumlignan D. A zinc-mediated crotylation of a diarylketone and subsequent lactonization quickly established the carbon framework of this class of tetrahydrofuran lignans.Lignans are widely distributed in nature and play important roles as antioxidants by scavenging free radicals that may be involved in some diseases.[1] One of the most important natural anticancer lignans is podophyllotoxin (1), whose derivatives (such as etoposide) were approved in the treatment of severe cancers (Scheme 1).[2] The classical proposed biosynthesis of aryltetralin begins from cinnamyl alcohol derivatives and proceeds through enzymatic coupling, followed by oxidative transformations.[3] Although the mechanism for lignan biosynthesis is not well understood, enzymes appear to participate in some key coupling reactions. Yue and co-workers recently reported an unprecedented skeleton, (À)-sacidumlignan D (2), from the ethanolic extract of the whole plant of Sarcostemma acidum (Roxb.) collected from Hainan Island, China, where local residents apply it as folk medicine to treat chronic cough and postnatal hypogalactia.[4] The preliminary biological assay revealed that only aromatic sacidumlignan A (3) has moderate antimicrobial activities against two Gram-positive bacteria in vitro.Based on the subtypes of classical lignans defined from the carbon skeletal feature of a b-b linkage, [1c] we envisioned that sacidumlignan D may be derived from a skeletal rearrangement of dibenzylbutane via an oxidative cleavage of the C(1) À C(7) bond (Scheme 2).[5] A ring-opening triggered by a hydroxyl group (or H 2 O) would cleave the C(1) À C(7) bond in the spiro structure B, an intermediate generated from acid-catalyzed Friedel-Crafts reaction of quinone methide A. The late oxidation at the C(7') position in C completes the biosynthesis of the tetrahydrofuran ring.[5b] If this is the case, the late-stage biosynthetically derived compound may have intriguing activities in different bioassays. [6] To compensate for the supply problem (0.00048 % yield, 10 mg out of 2.1 kg of the air-dried and powdered whole plant), [4] as well as development of a general and highly enantioselective approach, the concise synthesis of sacidumlignan D was undertaken along with a bio- Scheme 2. Biogenetic proposal for sacidumlignan D (2). Carbon numbering is based on the biogenetic precursor coniferyl or sinapyl alcohol.

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Enantioselective Synthesis of (–)-Stemoamide

Cited by 25 publications

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Kinetic Resolution of Diols via Etherification Catalyzed by a Chiral Phosphoric Acid: Concise Synthesis of (+)‐Sacidumlignan D

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