Stereoselective synthesis of a new trihydroxyindolizidine lactone

A general approach to 1,6,7-trihydroxyindolizidin-8-carboxylates is illustrated through the synthesis of a γ-lactone in an enantiopure form in seven steps starting from (3S)-3-t-butyloxy-1-pyrroline N-oxide and the acetonide of (2E,4S)-4,5-dihydroxy-2-pentenoic acid derived from (S)-malic acid and mannitol, respectively. The process was completely stereoselective and allowed the total control of the relative and absolute configuration of the five contiguous stereocentres of the product.

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Ethyl (3′R,3a′R,4′S)-4′-tert-butoxytetrahydro-3′H-spiro[cyclopropane-1,2′-pyrrolo[1,2-b]isoxazole]-3′-carboxylateC11H16NO3[α]D23=+55.2 (c 0.5, CHCl3)Source of chirality: l-malic acidAbsolute configuration: (3′R,3a′R,4′S)

Ethyl (3′S,3a′R,4′S)-4′-tert-butoxytetrahydro-3′H-spiro[cyclopropane-1,2′-pyrrolo[1,2-b]isoxazole]-3′-carboxylateC11H16NO3[α]D23=+115.0 (c 0.4, CHCl3)Source of chirality: l-malic acidAbsolute configuration: (3′S,3a′R,4′S)

(2aS,3S,6aS,6bS)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-hexahydro-2H-1,4-dioxa-4a-azacyclopenta[cd]pentalen-2-oneC12H17NO5[α]D25=+27.8 (c 1.3, CHCl3)Source of chirality: chiral pool (l-malic acid and mannitol) and diastereoselective 1,3-dipolar cycloadditionAbsolute configuration: (2aS,3S,6aS,6bS); (4S)

(2aS,3S,6aS,6bS)-3-[(1S)-1,2-Dihydroxyethyl]hexahydro-2H-1,4-dioxa-4a-azacyclopenta[cd]pentalen-2-oneC9H13NO5[α]D20=+28.4 (c 0.4, MeOH)Source of chirality: chiral pool (l-malic acid and mannitol) and diastereoselective 1,3-dipolar cycloadditionAbsolute configuration: (2aS,3S,6aS,6bS); (1S)

(2aS,3S,4R,8aS,8bS)-3,4-Dihydroxyoctahydro-2H-furo[4,3,2-hi]-indolizin-2-oneC9H13NO4[α]D20=+5.6 (c 0.2, MeOH)Source of chirality: chiral pool (l-malic acid and mannitol) and diastereoselective 1,3-dipolar cycloadditionAbsolute configuration: (2aS,3S,4R,8aS,8bS)