Efficient synthesis of the core structure of muraymycin and caprazamycin nucleoside antibiotics based on a stereochemically revised sulfur ylide reaction

The reaction of protected uridine 5′-aldehydes with sulfur ylides has been reinvestigated. Further transformation of the resulting epoxide product provided a compound of which a single crystal for X-ray diffraction was obtained. As a consequence from the elucidated structure, the stereochemical configuration of the epoxide furnished by the sulfur ylide reaction was revised. Based on these results, an efficient synthesis of the core structure of the naturally occurring muraymycin and caprazamycin nucleoside antibiotics was developed.

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(2S,3R)-tert-Butyl 3-((2R,3S,4S,5R)-3,4-bis(tert-butyldimethylsilyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-2-yl)oxirane-2-carboxylateC27H48N2O8Si2Ee = 100%De ⩾95%[α]D20=+22.7 (c 1.2, MeOH)Source of chirality: diastereoselective synthesisAbsolute configuration: (1′R,2′S,3′S,4′R,5′R,6′S)

(2S,3R)-tert-Butyl 3-((2R,3S,4S,5R)-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-bis(tert-butyldimethylsilyloxy)-tetrahydrofuran-2-yl)oxirane-2-carboxylateC35H56N2O9Si2Ee = 100%De ⩾95%[α]D20=+31.6 (c 1.3, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (1′R,2′S,3′S,4′R,5′R,6′S)

(2R,3S)-tert-Butyl 3-((2R,3S,4S,5R)-3,4-bis(tert-butyldimethylsilyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-2-yl)-2-(3-((S)-2-(benzyloxycarbonyl)-4-methylpentanamido)propylamino)-3-hydroxypropanoateC44H75N5O11Si2Ee = 100%De ⩾98%[α]D20=+1.9 (c 1.2, MeOH)Source of chirality: diastereoselective synthesisAbsolute configuration: (1′R,2′S,3′S,4′R,5′S,6′R,2″S)

1-((2R,3S,4R,5R)-3,4-Bis(tert-butyldimethylsilyloxy)-5-((2R,3S)-3-(indoline-1-carbonyl)oxiran-2-yl)-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dioneC31H47N3O7Si2Ee = 100%De ⩾95%[α]D20=+42.9 (c 1.1, MeOH)Source of chirality: diastereoselective synthesisAbsolute configuration: (1′R,2′S,3′R,4′R,5′R,6′S)

1-((2R,3S,4R,5R)-3,4-Bis(tert-butyldimethylsilyloxy)-5-((2R,3S)-3-(indoline-1-carbonyl)oxiran-2-yl)-tetrahydrofuran-2-yl)-3-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dioneC39H55N3O8Si2Ee = 100%De ⩾95%[α]D20=+35.5 (c 1.4, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (1′R,2′S,3′R,4′R,5′R,6′S)

1-((2R,3S,4R,5R)-5-((1S,2R)-2-Azido-1-hydroxy-3-(indolin-1-yl)-3-oxopropyl)-3,4-bis(tert-butyldimethylsilyloxy)tetrahydrofuran-2-yl)-3-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dioneC39H56N6O8Si2Ee = 100%De ⩾98%[α]D20=-68.7 (c 0.45, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (1′R,2′S,3′R,4′R,5′S,6′R)

1-((3aS,4R,6R,6aS)-6-((1S,2R)-2-Azido-1-hydroxy-3-(indolin-1-yl)-3-oxopropyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-3-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dioneC30H32N6O8Ee = 100%De ⩾98%[α]D20=-36.5 (c 0.80, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (1′R,2′S,3′S,4′R,5′S,6′R)

1-((2R,3S,4R,5R)-5-((1R,2R)-2-Bromo-1-hydroxy-3-(indolin-1-yl)-3-oxopropyl)-3,4-bis(tert-butyldimethylsilyloxy)tetrahydrofuran-2-yl)-3-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dioneC39H56BrN3O8Si2Ee = 100%De ⩾98%[α]D20=-56.5 (c 1.0, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (1′R,2′S,3′R,4′R,5′R,6′R)

1-((2R,3S,4R,5R)-5-((1S,2S)-2-Azido-1-hydroxy-3-(indolin-1-yl)-3-oxopropyl)-3,4-bis(tert-butyldimethylsilyloxy)tetrahydrofuran-2-yl)-3-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dioneC39H56N6O8Si2Ee = 100%De ⩾98%[α]D20=+69.5 (c 1.2, CHCl3)Source of chirality: diastereoselective synthesisAbsolute configuration: (1′R,2′S,3′R,4′R,5′S,6′S)

1-((2R,3S,4R,5R)-5-((1S,2S)-2-Amino-1-hydroxy-3-(indolin-1-yl)-3-oxopropyl)-3,4-bis(tert-butyldimethylsilyloxy)tetrahydrofuran-2-yl)-3-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dioneC39H58N4O8Si2Ee = 100%De ⩾98%[α]D20=+81.3 (c 1.6, MeOH)Source of chirality: diastereoselective synthesisAbsolute configuration: (1′R,2′S,3′R,4′R,5′S,6′S)