Total synthesis of synargentolide B

A simple and efficient stereoselective synthesis of synargentolide B was achieved by using ethyl (S)-2-hydroxypropanoate as a readily available starting material. The key steps involved in the synthesis are Horner–Wadsworth–Emmons olefination, Sharpless asymmetric dihydroxylation, zinc allylation, and Hoveyda–Grubbs IInd generation catalyzed ring closing metathesis.

Figure optionsDownload as PowerPoint slide

(S)-Ethyl 2-(tert-butyldimethylsilyloxy)propanoateC11H24O3Si[α]D25 = −25.1 (c 2.5, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoateAbsolute configuration: (S)

(4R,5S)-Ethyl 5-(tert-butyldimethylsilyloxy)-4-hydroxyhex-2-ynoateC14H26O4Si[α]D25 = +3.4 (c 2.5, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reactionAbsolute configuration: (4R,5S)

(4R,5S)-Ethyl 4,5-bis(tert-butyldimethylsilyloxy)hex-2-ynoateC20H40O4Si2[α]D25 = −9.1 (c 2.3, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reactionAbsolute configuration: (4R,5S)

(6R,7S,E)-Ethyl 6,7-bis(tert-butyldimethylsilyloxy)oct-2-en-4-ynoateC22H42O4Si2[α]D25 = −11.7 (c 3.0, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reactionAbsolute configuration : (6R,7S,E)

(6R,7S,E)-6,7-Bis(tert-butyldimethylsilyloxy)oct-2-en-4-yn-1-olC20H40O3Si2[α]D25 = −14.2 (c 3.2, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reactionAbsolute configuration: (6R,7S,E)

(5R,6S)-5-((E)-5-(4-Methoxybenzyloxy)pent-3-en-1-ynyl)-2,2,3,3,6,8,8,9,9-nonamethyl-4,7-dioxa-3,8-disiladecaneC28H48O4Si2[α]D25 = −10.5 (c 3.4, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reactionAbsolute configuration: (5R,6S,E)

(2R,3R,6R,7S)-6,7-Bis(tert-butyldimethylsilyloxy)-1-(4-methoxybenzyloxy)oct-4-yne-2,3-diolC28H50O6Si2[α]D25 = −19.4 (c 3.4, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reaction, Sharpless asymmetric dihydroxylationAbsolute configuration: (2R,3R,6R,7S)

(5R,6S)-5-((E)-5-(((4R,5R)-5-((4-Methoxybenzyloxy)methyl)-2,2-dimethyl1,3dioxolan-4-yl)ethynyl)-2,2,3,3,6,8,8,9,9-nonamethyl-4,7-dioxa-3,8-disiladecaneC31H54O6Si2[α]D25 = +18.2 (c 1.4, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reaction, Sharpless asymmetric dihydroxylationAbsolute configuration: (5R,6S,E,R,R)

(2S,3R)-5-((4R,5R)-5-((4-Methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)pent-4-yne-2,3-diolC19H26O6[α]D25 = +32.9 (c 1.7, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reaction, Sharpless asymmetric dihydroxylationAbsolute configuration: (2S,3R,R,R)

(2S,3R,E)-5-((4R,5R)-5-((4-Methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)pent-4-ene-2,3-diolC19H28O6[α]D25 = +9.5 (c 1.1, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reaction, Sharpless asymmetric dihydroxylationAbsolute configuration: (2S,3R,E,R,R)

(2S,3R,E)-5-((4R,5R)-5-((4-Methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)pent-4-ene-2,3-diyl diacetateC23H32O8[α]D25 = +3.2 (c 1.3, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reaction, Sharpless asymmetric dihydroxylationAbsolute configuration: (2S,3R,E,R,R)

(2S,3R,E)-5-((4R,5R)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)pent-4-ene-2,3-diyl diacetateC15H24O7[α]D25 = +13.2 (c 0.26, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reaction, Sharpless asymmetric dihydroxylationAbsolute configuration: (2S,3R,E,R,R)

(2S,3R,E)-5-((4R,5R)-5-((R)-1-(Acryloyloxy)but-3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)pent-4-ene-2,3-diyl diacetateC22H32O7[α]D25 = +18.3 (c 0.8, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reaction, Sharpless asymmetric dihydroxylation, zinc allylationAbsolute configuration: (2S,3R,E,R,R,R)

(2S,3R,E)-5-((4R,5R)-2,2-Dimethyl-5-((R)-6-oxo-3,6-dyhydro-2H-pyran-2-yl)-1,3-dioxolan-4-yl)pent-4-ene-2,3-diyl diacetateC19H26O8[α]D25 = +42.2 (c 0.2, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reaction, Sharpless asymmetric dihydroxylation, zinc allylationAbsolute configuration: (2S,3R,E,R,R,R)

(2S,3R,6R,7S,E)-6,7-Dihydroxy-7-((R)-6-oxo-3,6-dyhydro-2H-pyran-2-yl)hept-4-ene-2,3-diyl diacetateC16H22O8[α]D25 = +24.8 (c 0.4, CHCl3)Source of chirality: (S)-ethyl 2-hydroxypropanoate, LiHMDS reaction, Sharpless asymmetric dihydroxylation, zinc allylationAbsolute configuration: (2S,3R,6R,7S,E,R)