Synthesis of (+)-Cladospolide C

Abstract

(+)-Cladospolide C was synthesized in eight steps with 5% total yield, using methyl acrylate, (3R,4R)-1,5-hexadiene-3,4-diol, and (6R)-6-hepten-2-ol as the starting materials. Two cross-metathesis reactions and Yamaguchi esterification were applied to assemble the three units into (+)-Cladospolide C. Unsuccessful routes using ring-closing metathesis are also discussed.

A Cross‐Metathesis–Conjugate Addition Route to Enantiopure γ‐Butyrolactams and γ‐Lactones from a C2‐Symmetric Precursor

“…[25] In an initial experiment, we applied conditions described by Chou and Hou for a cross-metathesis reaction of the analogous acetonide. [8] The results were rather disappointing, because undesired double cross-metathesis product 2c was the major product, and desired 2b was isolated in only 16 % yield. Due to the pseudo-C 2 symmetry of 2a, mono-Scheme 2.…”

“…[2] Accordingly, (3R,4R)-hexa-1,5-diene-3,4-diol (1), which is available from d-mannitol in a few steps, [3][4][5][6] is a very useful ex-chiral-pool starting material. Diol 1 has been used in target molecule synthesis, [7][8][9][10][11][12][13][14][15][16][17][18][19] as a chiral diene ligand in asymmetric catalysis, [20] and as a probe for catalyst directing effects by hydroxy groups in ring-closing metathesis (RCM) reactions. [6,21,22] The enantiomer, ent-1, has been synthesized by Blechert and co-workers from d-(-)-tartrate and employed in the total synthesis of phomopsolide by using cross metathesis and a subsequent RCM step.…”

“…Recently, Chou and Hou synthesized (+)-cladospolide C by using the cross-metathesis [24] reaction of an acetonide-protected derivative of 1 as the actual desymmetrization step. [8] We became intrigued by the opportunity to monofunctionalize 1 or a protected derivative of 1 by using cross metathesis with an electron-deficient alkene, thereby activating one C-C double bond for a conjugate addition. During this addition, a new stereogenic center would be created and, depending on the nucleophile used, cyclization to oxa-or azacycles may occur (Scheme 1).…”

Practical Preparation of (4R,5R,E)-methyl 5-(tert-butyldimethylsilyloxy)-4-hydroxyhepta-2,6-dienoate

“…They have been applied in natural product synthesis such as (+)-Cladospolide C [2], (+)-Cladospolide D [3], and (−)-Lentiginosine [4]. Previously reported methods to prepare this type of olefin applied crossmetathesis reaction by the addition of phenolic compounds and avoiding the less reactivity of olefins with electron-withdrawing functionality [5].…”

“…As the key intermediate in their research, Lu et al [3] prepared this compound via the metathesis reaction using 5 mol% of the second generation Grubbs' catalyst in the presence of 0.5 equiv of 2,6-di-tert-butyl-4-methylphenol (BHT) (Scheme 1). Chou et al [2] applied the same strategy to prepare similar compound 6 using p-cresol as the additive. Liu et al [4] prepared the aldehyde 8 using the more reactive Hoveyda-Grubbs' catalyst.…”