First stereoselective synthesis of serinol-derived malyngamides and their 1′-epi-isomers

A stereoselective synthesis of 1a {N-[(1R)-2-hydroxy-1-methoxy-methyl ethyl]-(4E,7S)-7-methoxy-4-eicosenamide} has been accomplished in 10 steps from 1-tetradecanol for the first time in 28% overall yield. The key steps involved the coupling reaction of a chiral alkyne with a protected bromide in the presence of t-BuLi, as well as the amidation reaction of (4E,7S)-7-methoxyeicos-4-enoic acid with (R)-methoxyamino alcohol. Acetylation of 1a finished the preparation of 1b {N-[(1S)-2-acetyloxy-1-methoxy-methyl ethyl]-(4E,7S)-7-methoxy-4-eicosenamide}. Their 1′-epi-isomers have also been synthesized with a similar strategy.

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(S)-4-Hydroxy-1-heptadeceneC17H34O[α]D17=-5 (c 1.0, CHCl3)Source of chirality: asymmetric allylationAbsolute configuration: S

(S)-4-Methoxy-1-heptadecyneC18H34O[α]D17=-20 (c 1.0, CHCl3)Source of chirality: asymmetric allylationAbsolute configuration: S

(S)-7-Methoxy-1-tetrahydropyranyloxy-4-icosyneC26H48O3[α]D16=-18 (c 1.0, CHCl3)Source of chirality: asymmetric allylationAbsolute configuration: S

(4E,7S)-7-Methoxyicos-4-enoic acidC21H40O3[α]D16=-10 (c 0.2, CHCl3)Source of chirality: asymmetric allylationAbsolute configuration: S

N-[(1R)-2-Hydroxy-1-methoxy-methyl ethyl]-(4E,7S)-7-methoxy-4-eicosenamideC25H49NO4[α]D16=-4 (c 0.35, CHCl3)Source of chirality: asymmetric allylation and d-serineAbsolute configuration: (7S,1′R)

N-[(1S)-2-Acetyloxy-1-methoxy-methyl ethyl]-(4E,7S)-7-methoxy-4-eicosenamideC27H51NO5[α]D16=-8 (c 0.35, CHCl3)Source of chirality: asymmetric allylation and d-serineAbsolute configuration: (7S,1′S)