A cyclopropanol-based approach to synthesis of Unit A of the cryptophycins

A new asymmetric synthesis of Unit A of the cryptophycins has been carried out yielding 13% of the target product over 14 steps. The key steps of the synthesis were diastereoselective hydroboration–oxidation reactions performed on the alkenyl moiety of a 1,3-dioxane derivative 8, which can be easily prepared via the Kulinkovich cyclopropanation of protected diethyl (S)-(−)-malate followed by transformation of the resulting small rings of the product 6 into the functional groups necessary for the synthesis of the target compound.

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(S)-5,5-Dimethyl-7-(prop-1-en-2-yl)-4,6-dioxaspiro[2.5]octaneC11H18O2[α]D20=+44.2 (c 8.3, Et2O)Absolute configuration: (S)Source of chirality: (S)-malic acid (chiral substrate)

(R)-2-((S)-5,5-Dimethyl-4,6-dioxaspiro[2.5]octan-7-yl)propan-1-olC11H20O3[α]D20=+37.1 (c 6.22, CHCl3)Absolute configuration: (2R,7S)Source of chirality: asymmetric synthesis

(S)-5,5-Dimethyl-7-((R,E)-4-phenylbut-3-en-2-yl)-4,6-dioxaspiro[2.5]octaneC18H24O2[α]D20=+58.5 (c 4.70, CHCl3)Absolute configuration: (2R,7S)Source of chirality: asymmetric synthesis

(3S,4R,E)-Methyl 3-hydroxy-4-methyl-6-phenylhex-5-enoateC14H18O3[α]D20=+8.5 (c 11.8, CHCl3)Absolute configuration: (3S,4R)Source of chirality: asymmetric synthesis

(3R,4S,E)-Methyl 3-(tert-butyldimethylsilyloxy)-4-methyl-6-phenylhex-5-enoateC20H32O3Si[α]D20=+18.7 (c 8.00, CHCl3)Absolute configuration: (3R,4S)Source of chirality: asymmetric synthesis

(2E,5S,6R,7E)-Ethyl 5-hydroxy-6-methyl-8-phenylocta-2,7-dienoateC17H22O3[α]D20=+62.8 (c 1.06, CHCl3)Absolute configuration: (5S,6R)Source of chirality: asymmetric synthesis