First asymmetric synthesis of achaetolide

The first asymmetric synthesis of the 10-membered macrolide achaetolide is reported in this article. The main highlight of the synthetic strategy is the ring-closing metathesis (RCM) of intermediate 19, which in turn can be accessed from coupling between alcohol 11 and acid 18. The synthesis of 11 involves enzymatic kinetic resolution (EKR) coupled with a Mitsunobu inversion strategy, while 18 can be prepared by adopting a metal-enzyme combined dynamic kinetic resolution (DKR) reaction followed by functional group manipulation.

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(R)-(1-Allyl-octyloxy)-tert-butyl-diphenyl-silaneC27H40OSi[α]D29=-0.9 (c 1.5, MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)

(R)-3-(tert-Butyl-diphenyl-silanyloxy)-decanalC26H38O2Si[α]D29=-12.5 (c 1.2, MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (3R)

(Z)-(R)-5-(tert-Butyl-diphenyl-silanyloxy)-dodec-2-enoic acid ethyl esterC30H44O3Si[α]D29=+7.7 (c 1.0, MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (5R)

(2S,3S,5R)-5-(tert-Butyl-diphenyl-silanyloxy)-2,3-dihydroxy-dodecanoic acid ethyl esterC30H46O5Si[α]D29=-5.5 (c 1.75, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S,5R)

(4S,5S)-5-[(R)-2-(tert-Butyl-diphenyl-silanyloxy)-nonyl]-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid ethyl esterC33H50O5Si[α]D29=-6.1 (c 0.3, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,4S,5S)

tert-Butyl-[(R)-1-((4S,5R)-2,2-dimethyl-5-vinyl-[1,3]dioxolan-4-ylmethyl)-octyloxy]-diphenyl-silaneC32H48O3Si[α]D29=-7.8 (c 0.5, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,4S,5R)

(R)-1-((4S,5R)-2,2-Dimethyl-5-vinyl-[1,3]dioxolan-4-yl)-nonan-2-olC16H30O3[α]D29=-3.6 (c 1.0, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,4S,5R)

Acetic acid (S)-1-[2-(4-methoxy-benzyloxy)-ethyl]-allyl esterC15H20O4[α]D29=+8.65 (c 1.0, MeOH)Source of chirality: enzymatic DKRAbsolute configuration: (S)

tert-Butyl-{(S)-1-[2-(4-methoxy-benzyloxy)-ethyl]-allyloxy}-dimethyl-silaneC19H32O3Si[α]D29=-3.5 (c 0.75, MeOH)Source of chirality: enzymatic DKRAbsolute configuration: (S)

(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pent-4-en-1-olC11H24O2Si[α]D29=-5.65 (c 0.5, MeOH)Source of chirality: enzymatic DKRAbsolute configuration: (3S)

(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pent-4-enoic acidC11H22O3Si[α]D29=-3.2 (c 0.5, MeOH)Source of chirality: enzymatic DKRAbsolute configuration: (3S)

(S)-3-Hydroxy-pent-4-enoic acid (R)-1-((2S,3R)-2,3-dihydroxy-pent-4-enyl)-octyl esterC18H32O5[α]D29=-16.3 (c 0.5, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (3R, 4S, 6R, 10S)

(E)-(4S,7R,8S,10R)-10-Heptyl-4,7,8-trihydroxy-3,4,7,8,9,10-hexahydro-oxecin-2-oneC16H28O5[α]D29=-27.8 (c 0.5, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,7R,8S,10R)