Synthesis of C18–C28 ketone fragment of micromonospolide B possessing 1,3-diene and 1,3-anti-diol functionalities

A highly stereocontrolled synthesis of the C18–C28 ketone fragment of the 16-membered plecomacrolide micromonospolide B has been accomplished. The C21–C23 syn–anti stereotriad is secured by the anti-selective aldol condensation of the ephedrine-derived chiral propionate with (E,E)-hexa-2,4-dienal and Sharpless asymmetric allylic epoxidation–regioselective reductive epoxide ring opening, respectively. The overall yield of this 14-step sequence is 18.4% and the target C18–C28 ketone was obtained in enantiomerically pure form.

Figure optionsDownload as PowerPoint slide

(1′R,2′S)-2-[N-Benzyl-N-(2″,4″,6″-trimethylbenzenesulfonyl)]amino-1-phenyl-1-propyl (2R,3R,4E,6E)-3-hydroxy-2-methylocta-4,6-dienoateC34H41NO5SDiastereomer ratio: (2R,3R):(2S,3S) >98:2[α]D20=+39.2 (c 1.05, CHCl3)Source of chirality: anti-selective aldol reactionAbsolute configuration: (1′R,2′S,2R,3R)

(1′R,2′S)-2-[N-Benzyl-N-(2″,4″,6″-trimethylbenzenesulfonyl)]amino-1-phenyl-1-propyl (2R,3R,4E,6E)-3-(triethylsilyl)oxy-2-methylocta-4,6-dienoateC40H55NO5SSiDiastereomer ratio: (2R,3R):(2S,3S) >98:2[α]D20=+45.4 (c 5.50, CHCl3)Source of chirality: anti-selective aldol reactionAbsolute configuration: (1′R,2′S,2R,3R)

(2S,3R,4E,6E)-2-Methyl-3-((triethylsilyl)oxy)octa-4,6-dien-1-olC15H30O2SiDiastereomer ratio: (2S,3R):(2R,3S) >98:2[α]D20=-5.0 (c 1.50, CHCl3)Source of chirality: anti-selective aldol reactionAbsolute configuration: (2S,3R)

(2R,3R,4E,6E)-2-Methyl-3-((triethylsilyl)oxy)octa-4,6-dienalC15H28O2SiDiastereomer ratio: (2R,3R):(2S,3S) >98:2[α]D20=21.0 (c 1.25, CHCl3)Source of chirality: anti-selective aldol reactionAbsolute configuration: (2R,3R)

(2E,4S,5R,6E,8E)-Ethyl 4-methyl-5-((triethylsilyl)oxy)deca-2,6,8-trienoateC19H34O3SiDiastereomer ratio: (4S,5R):(4R,5S) >98:2[α]D20=-4.3 (c 1.30, CHCl3)Source of chirality: anti-selective aldol reactionAbsolute configuration: (4S,5R)

(2E,4S,5R,6E,8E)-4-Methyl-5-((triethylsilyl)oxy)deca-2,6,8-trien-1-olC17H32O2SiDiastereomer ratio: (4S,5R):(4R,5S) >98:2[α]D20=+8.7 (c 1.00, CHCl3)Source of chirality: anti-selective aldol reactionAbsolute configuration: (4S,5R)

(2S,3S,4S,5R,6E,8E)-2,3-Epoxy-4-methyl-5-((triethylsilyl)oxy)deca-6,8-dien-1-olC17H32O3SiDiastereomer ratio: (2S,3S,4S,5R):(2R,3R,4S,5R) >99:1[α]D20=-19.0 (c 0.70, CHCl3)Source of chirality: Sharpless asymmetric allylic epoxidationAbsolute configuration: (2S,3S,4S,5R)

(3R,4R,5R,6E,8E)-4-Methyldeca-6,8-diene-1,3,5-triolC11H20O3Diastereomer ratio: (3R,4R,5R):(3S,4R,5R) >99:1[contaminated with 9% of the 1,2,5-triol][α]D20=+5.5 (c 0.70, CHCl3)Source of chirality: Sharpless asymmetric allylic epoxidationAbsolute configuration: (3R,4R,5R)

(3R,4R,5R,6E,8E)-3,5-Dihydroxy-4-methyldeca-6,8-dien-1-yl trimetylacetateC16H28O4Diastereomer ratio: (3R,4R,5R):(3S,4R,5R) >99:1[α]D20=+27.4 (c 0.45, CHCl3)Source of chirality: Sharpless asymmetric allylic epoxidationAbsolute configuration: (3R,4R,5R)

2-{(4′R,5′S,6′R)-2′,2′-Di-tert-butyl-5′-methyl-6′-[(1″E,3″E)-penta-1″,3″-dienyl]-1′,3′-dioxa-2′-silacyclohex-4′-yl}ethanolC19H36O3SiDiastereomer ratio: (4′R,5′S,6′R):(4′S,5′S,6′R) >99:1[α]D20=+101.3 (c 0.40, CHCl3)Source of chirality: Sharpless asymmetric allylic epoxidationAbsolute configuration: (4′R,5′S,6′R)

2-{(4′R,5′S,6′R)-2′,2′-Di-tert-butyl-5′-methyl-6′-[(1″E,3″E)-penta-1″,3″-dienyl]-1′,3′-dioxa-2′-silacyclohex-4′-yl}acetaldehydeC19H34O3SiDiastereomer ratio: (4′R,5′S,6′R):(4′S,5′S,6′R) >99:1[α]D20=+95.0 (c 0.35, CHCl3)Source of chirality: Sharpless asymmetric allylic epoxidationAbsolute configuration: (4′R,5′S,6′R)

2-{(4′R,5′S,6′R)-2′,2′-Di-tert-butyl-5′-methyl-6′-[(1″E,3″E)-penta-1″,3″-dienyl]-1′,3′-dioxa-2′-silacyclohex-4′-yl}butan-2-oneC21H38O3SiDiastereomer ratio: (4′R,5′S,6′R):(4′S,5′S,6′R) >99:1[α]D20=+97.0 (c 0.35, CHCl3)Source of chirality: Sharpless asymmetric allylic epoxidationAbsolute configuration: (4′R,5′S,6′R)