Divergent Asymmetric Total Synthesis of All Four Pestalotin Diastereomers from (R)-Glycidol

Mizuki Moriyama,Tetsuya Fujiwara,Kohei Nakata,Yoo Tanabe

doi:10.3390/molecules25020394

Abstract

All four chiral pestalotin diastereomers were synthesized in a straightforward and divergent manner from common (R)-glycidol. Catalytic asymmetric Mukaiyama aldol reactions of readily-available bis(TMSO)diene (Chan’s diene) with (S)-2-benzyloxyhexanal derived from (R)-glycidol produced a syn-aldol adduct with high diastereoselectivity and enantioselectivity using a Ti(iOPr)4/(S)-BINOL/LiCl catalyst. Diastereoselective Mukaiyama aldol reactions mediated by catalytic achiral Lewis acids directly produced not only a (1′S,6S)-pyrone precursor via the syn-aldol adduct using TiCl4, but also (1′S,6R)-pyrone precursor via the antialdol adduct using ZrCl4, in a stereocomplementary manner. A Hetero-Diels-Alder reaction of similarly available mono(TMSO)diene (Brassard’s diene) with (S)-2-benzyloxyhexanal produced the (1′S,6S)-pyrone precursor promoted by Eu(fod)3 and the (1′S,6R)-pyrone precursor Et2AlCl. Debenzylation of the (1′S,6S)-precursor and the (1′S,6R)-precursor furnished natural (−)-pestalotin (99% ee, 7 steps) and unnatural (+)-epipestalotin (99% ee, 7 steps), respectively. Mitsunobu inversions of the obtained (−)-pestalotin and (+)-epipestalotin successfully produced the unnatural (+)-pestalotin (99% ee, 9 steps) and (−)-epipestalotin (99% ee, 9 steps), respectively, in a divergent manner. All four of the obtained chiral pestalotin diastereomers possessed high chemical and optical purities (optical rotations, 1H-NMR, 13C-NMR, and HPLC measurements).

Highlights

Products possessing the 4-methoxy-5,6-dihydroxy-pyran-2-one structure are distributed in nature [1], including the (i) kavalactone series, such as kavain, methylsitan, dihydrokavain, dihydromethylsitan, etc. [2], and (ii) (−)-pestalotin [3], with the three unnatural diastereomers of (−)-epipestalotin, (+)-pestalotin, and (+)-epipestalotin (Figure 1). (−)-Pestalotin was isolated from
We previously reported asymmetric total syntheses of all these natural products utilizing a catalytic asymmetric Mukaiyama aldol reaction and an asymmetric Ti-Claisen condensation as the crucial steps [22,23]
1 in hand, we investigated a catalytic asymmetric

Summary

Introduction

Products possessing the 4-methoxy-5,6-dihydroxy-pyran-2-one structure are distributed in nature [1], including the (i) kavalactone series, such as kavain, methylsitan, dihydrokavain, dihydromethylsitan, etc. [2], and (ii) (−)-pestalotin [3], with the three unnatural diastereomers of (−)-epipestalotin, (+)-pestalotin, and (+)-epipestalotin (Figure 1). (−)-Pestalotin was isolated fromPesalotia cryptomeriaecola Sawada by Kimura and Tamura’s group; it possesses distinctive bioactivity as a gibberellin synergist [3,4,5]. Products possessing the 4-methoxy-5,6-dihydroxy-pyran-2-one structure are distributed in nature [1], including the (i) kavalactone series, such as kavain, methylsitan, dihydrokavain, dihydromethylsitan, etc. [2], and (ii) (−)-pestalotin [3], with the three unnatural diastereomers of (−)-epipestalotin, (+)-pestalotin, and (+)-epipestalotin (Figure 1). Pesalotia cryptomeriaecola Sawada by Kimura and Tamura’s group; it possesses distinctive bioactivity as a gibberellin synergist [3,4,5]. The same compound was isolated from unidentified penicillium species as a minor component (code number: LLP-880α) by Ellestad’s group [6]. The syntheses are somewhat lengthy [(−)-pestalotin: 8 steps, 4% overall yield; (−)-epipestalotin: 6 steps, 9% overall yield; (+)-pestalotin: 10 steps, 1% overall yield; (+)-epipestalotin: 10 steps, 3% overall yield], and commence with two quite different starting compounds. This work contributed significantly to clarifying the Molecules 2020, 25, 394 stereostructure-activity relationship of these families; 1′S configuration in the side chain was critical for the synergistic mode of action for gibberellin [6,9].

Methods

Discussion

Conclusion