Chiral pool based approach for the synthesis of bio-active lactones and 1,2-aminoalcohols

Abstract

Synthesis of 10-membered bioactive lactone microcarpalide (I), (2S,3R)-2-aminododecan-3-ol (II), and Xestoaminol C (III) from inexpensive chiral pool sources such as tartaric acid and L-(+)-alanine was described. The ?-hydroxy aldehydes generated from tartaric acid were elaborated to these natural products (Chart 1) with absolute stereocontrol. The key step involved stereoselective reduction of C2-symmetric diketones with L-Selectride with high diastereoselectivity.

Chart 1: Target Molecules

Microcarpalide (I)

(2S,3R)-2-Aminododecan-3-ol (II)

Xestoaminol C (III)

A formal synthesis of microcarpalide from D- & L-tartaric acids and two new synthetic routes to 1,2-aminoalcohols from L-(+)-alanine and L-(+)-tartaric acid were presented.

Synthesis of Microcarpalide

Introduction The term decanolides refers to a relatively small class of naturally occurring 10-membered lactones of polyketide origin. Many of these lactones display pharmacologically interesting features, such as antibacterial, antitumoral, or hypolipidemic properties. Some of these fungal decanolides, including microcarpalide (1), lethaloxin (2), herbarumin I (3), and herbarumin II (4), are shown in Chart 2.

Chart 2: Representative Examples of Decanolides

Microcarpalide (1)

Lethaloxin (2)

Herbarumin I (3)

Herbarumin II (4)

Microcarpalide was isolated by Hemscheidt’s group from the fermentation broths of some unidentified endophytic fungus. It was found to be weakly cytotoxic to mammalian cells and acted as a microfilament-disrupting agent. Since its isolation, several syntheses have been reported.

The first synthesis, reported by Marco et al., involved ring-closing metathesis of diene ester 5 as a key step.

Scheme 1: Synthesis of Microcarpalide by Marco et al.

The precursor acid 6 and alcohol 7 were synthesized from D-tartaric acid and (R)-glycidol, respectively.

Gurjar et al. reported the synthesis of microcarpalide 1 using the same precursor 5, obtained in a multistep sequence from D-mannose.

Kumar and Naidu used Yamaguchi lactonization of acid 9 for constructing microcarpalide (Scheme 2). The acid 9 was synthesized utilizing Sharpless asymmetric dihydroxylation as the key step.

Scheme 2: Synthesis of Microcarpalide by Kumar and Naidu

Ishigami adopted a Julia coupling between fragments 13 and 14 to obtain 12, a precursor for microcarpalide (Scheme 3). Fragments 13 and 14 were synthesized using a Claisen-orthoester rearrangement and Sharpless asymmetric dihydroxylation as pivotal steps.

Scheme 3: Ishigami’s Approach for the Synthesis of Microcarpalide

The synthesis of precursor 5 en route to microcarpalide was also reported by Davoli et al. using Matteson’s boronate ester homologation. Ghosh et al. and Chavan et al. synthesized the same precursor 5 from D-mannitol and but-2-ene-1,4-diol, respectively.

During the preparation of this report, a synthesis of microcarpalide by Cherukupalli and Sharma has also appeared in the literature.