Asymmetric total synthesis of (−)-mangiferaelactone by using an appropriately substituted thiophene as a masked synthon for C-alkyl glycoside

Asymmetric total synthesis of naturally occurring nonenolide (−)-mangiferaelactone was attempted through RCAM (ring closing alkyne metathesis) reaction. As the attempted RCAM reaction failed, the synthesis was finally achieved by successful exploration of a ring closing metathesis (RCM) reaction. 2-Propylthiophene was used as a masked synthon for n-heptyl glycoside, which served as main source for one of the RCM precursors and accessed by reductive desulfurization (Mozingo type reduction) of an appropriately substituted thiophene ribofuranoside. The other RCM precursor was accessed by applying an enzymatic kinetic resolution/Mitsunobu inversion sequence to an alkyne alcohol.

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tert-Butyl(((3aR,4R,6S,6aR)-2,2-dimethyl-6-(5-propylthiophen-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)dimethylsilaneC21H36O4SSi[α]D28 = −38.8 (c 3.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3aR,4R,6S,6aR)

tert-Butyl(((3aR,4R,6R,6aR)-2,2-dimethyl-6-(5-propylthiophen-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)dimethylsilaneC21H36O4SSi[α]D28 = −66.9 (c 0.4, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3aR,4R,6R,6aR)

tert-Butyl(((3aR,4R,6S,6aS)-6-heptyl-2,2dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)dimethylsilaneC21H42O4Si[α]D28 = −25.7 (c 0.8, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3aR,4R,6S,6aS)

((3aR,4R,6S,6aS)-6-Heptyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanolC15H28O4[α]D30 = −3.4 (c 1.6, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3aR,4R,6S,6aS)

(3aS,4S,6S,6aS)-4-(Chloromethyl)-6-heptyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxoleC15H27ClO3[α]D30 = −13.8 (c 2.2, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3aS,4S,6S,6aS)

(S)-1-((4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)octan-1-olC15H26O3[α]D32 = +7.8 (c 2.2, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (1S,4S,5R)

(R)-1-((4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)octan-1-olC15H26O3[α]D30 = +46 (c 1.4, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (1R,4S,5R)

tert-Butyl(((3aR,4R,6R,6aS)-6-heptyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)dimethylsilaneC21H42O4Si[α]D28 = −14.6 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3aR,4R,6R,6aS)

((3aR,4R,6R,6aS)-6-Heptyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanolC15H28O4[α]D30 = −2.3 (c 2.2, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3aR,4R,6R,6aS)

(3aS,4S,6R,6aS)-4-(Chloromethyl)-6-heptyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxoleC15H27ClO3[α]D30 = −11.2 (c 3.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3aS,4S,6R,6aS)

(S)-6-((4-Methoxybenzyl)oxy)hex-1-yn-3-yl acetateC16H20O4[α]D28 = −37.5 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3S)

(R)-6-((4-Methoxybenzyl)oxy)hex-1-yn-3-olC14H18O3[α]D28 = +3.5 (c 1.6, EtOH)Source of chirality: Asymmetric synthesisAbsolute configuration: (3R)

(R)-tert-Butyl((6-((4-methoxybenzyl)oxy)hex-1-yn-3-yl)oxy)dimethylsilaneC20H32O3Si[α]D30 = +27.9 (c 1.8, EtOH)Source of chirality: Asymmetric synthesisAbsolute configuration: (3R)

(R)-4-((tert-Butyldimethylsilyl)oxy)hex-5-yn-1-olC12H24O2Si[α]D28 = +41.6 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3R)

(R)-4-((tert-Butyldimethylsilyl)oxy)hex-5-ynoic acidC12H22O3Si[α]D28 = +28.9 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3R)

(R)-6-((4-Methoxybenzyl)oxy)-1-(trimethylsilyl)hex-1-yn-3-olC17H26O3Si[α]D28 = −0.8 (c 2.6, EtOH)Source of chirality: Asymmetric synthesisAbsolute configuration: (3R)

(S)-1-((4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)octyl (R)-4-((tert-butyldimethylsilyl)oxy)hex-5-ynoateC27H46O5Si[α]D28 = 25.4 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (4S,5R)

(R)-((S)-1-((4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)octyl)4-hydroxyhex-5-ynoateC21H32O5[α]D28 = 21.3 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (4S,5R)

(S)-1-((4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)octyl (R)-4-hydroxyhex-5-enoateC21H36O5[α]D30 = +3.4 (c 1.4, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (4S,5R)

(3aS,4S,9R,11aR,E)-4-Heptyl-9-hydroxy-2,2-dimethyl-7,8,9,11a-tetrahydro-3aH-[1,3]dioxolo[4,5-c]oxecin-6(4H)-oneC19H32O5[α]D30 = −73.4 (c 1.4, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (3aS,4S,9R,11aR,E)

4-(((5R,8R,9R,10S,E)-10-Heptyl-8,9-dihydroxy-2-oxo-3,4,5,8,9,10-hexahydro-2H-oxecin-5-yl)oxy)-4-oxobutanoic acidC20H32O8[α]D30 = −2.3 (c 1.0, MeOH)Source of chirality: Asymmetric synthesisAbsolute configuration: (5R,8R,9R,10S,E)