Formal synthesis of tetrahydrolipstatin and tetrahydroesterastin

A versatile and efficient approach to (3S,5R)-methyl 3-(benzyloxy)-5-(methoxymethoxy)hexadecanoate, a key chiral building block and a common polyol fragment of the anti-tumor and anti-obesity agents tetrahydrolipstatin 3 and tetrahydroesterastin 4 using both hydrolytic kinetic resolution (HKR) and proline catalyzed sequential α-aminoxylation, followed by HWE-olefination reaction is described.

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(R)-Methyl 4-hydroxypentadecanoateC16H32O3[α]D25=+4.8 (c 1.7, CHCl3)Source of chirality: Proline catalyzed α-aminoxylation of aldehydeAbsolute configuration: (4R)

(S)-2-((R)-2-(Methoxymethoxy) tridecyl)oxiraneC17H34O3[α]D25=-7.9 (c 1.04, CHCl3)Source of chirality: Proline catalyzed α-aminoxylation of aldehyde and HKRAbsolute configuration: (2S, 2′R)

(4R,6R)-6-(Methoxymethoxy)heptadec-1-en-4-olC19H38O3[α]D25=-14.35 (c 1.06, CHCl3)Source of chirality: Proline catalyzed α-aminoxylation of aldehyde and HKRAbsolute configuration: (4R,6R)

(3S,5R)-Methyl 3-(benzyloxy)-5-(methoxymethoxy)hexadecanoateC26H44O5[α]D25=-24.4 (c 3.3, CHCl3)Source of chirality: Proline catalyzed α-aminoxylation of aldehyde and HKRAbsolute configuration: (3S,5R)