An enantioselective catalytic approach to syn deoxypropionate units combining asymmetric Cu-catalyzed 1,6- and 1,4-conjugate addition

A novel iterative approach to the synthesis of the naturally ubiquitous syn deoxypropionate motif is reported. The route comprises a new Horner–Wadsworth–Emmons reagent to prepare α,β,γ,δ-bisunsaturated thioesters. Next, two Me-substituents are introduced in high yield, regio- and enantioselectivity using sequential asymmetric Cu-catalyzed 1,6-conjugate addition, base-catalyzed olefin isomerization and Cu-catalyzed enantioselective 1,4-conjugate addition. After reduction to the aldehyde these transformations can be repeated to install three or more Me groups with a syn 1,3-relationship.

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(S,2E,4E)-S-Ethyl 10-(benzyloxy)-7-methyldeca-2,4-dienethioateC20H28O2SSource of chirality: asymmetric catalysis93% ee>95:5 E/Z-ratio[α]D20=+1.2 (c 1.0, CHCl3)Absolute configuration: (S,2E,4E)

(S,E)-S-Ethyl 5-methylnon-3-enethioateC12H22OSSource of chirality: asymmetric catalysis89% ee99:1 regioselectivity (1,6:1,4)[α]D20=+9.0 (c 1.0, CHCl3)Absolute configuration: (S,E)

(S,E)-S-Ethyl 5,7-dimethyloct-3-enethioateC12H22OSSource of chirality: asymmetric catalysis82% ee95:5 regioselectivity (1,6:1,4)[α]D20=+8.3 (c 1.0, CHCl3)Absolute configuration: (S,E)

(S,E)-S-Ethyl 5-methyl-7-phenylhept-3-enethioateC16H22OSSource of chirality: asymmetric catalysis82% ee99:1 regioselectivity (1,6:1,4)[α]D20=+4.1 (c 1.0, CHCl3)Absolute configuration: (S,E)

(S,E)-S-Ethyl 8-(benzyloxy)-5-methyloct-3-enethioateC18H26O2SSource of chirality: asymmetric catalysis86% ee94:6 regioselectivity (1,6:1,4)[α]D20=+5.9 (c 1.0, CHCl3)Absolute configuration: (S,E)

(5S,7S,E)-S-Ethyl 10-(benzyloxy)-5,7-dimethyldec-3-enethioateC21H32O2SSource of chirality: asymmetric catalysis87% syn-product and 13% of anti-product85:15 regioselectivity (1,6:1,4)[α]D20=-0.9 (c 1.0, CHCl3)Absolute configuration: (5S,7S,E)

(5R,7S,E)-S-Ethyl 10-(benzyloxy)-5,7-dimethyldec-3-enethioateC21H32O2SSource of chirality: asymmetric catalysis78% anti-product and 22% of syn-product (13f)87:13 regioselectivity (1,6:1,4)[α]D20=-2.2 (c 1.0, CHCl3)Absolute configuration: (5R,7S,E)

(3S,5S)-S-Ethyl 3,5-dimethylnonanethioateC13H26OSSource of chirality: asymmetric catalysis96% syn-product and 4% of anti-product92% ee[α]D20=-1.3 (c 1.0, CHCl3)Absolute configuration: (3S,5S)

(3R,5S)-S-Ethyl 3,5-dimethylnonanethioateC13H26OSSource of chirality: asymmetric catalysis92% anti-product and 8% of syn-product85% ee[α]D20=+13.9 (c 1.0, CHCl3)Absolute configuration: (3R,5S)

(3S,5S)-S-Ethyl 3,5,7-trimethyloctanethioateC13H26OSSource of chirality: asymmetric catalysis90% syn and 10% anti[α]D20=-9.1 (c 1.0, CH2Cl2)Absolute configuration: (3S,5S)

(3S,5S)-S-Ethyl 3,5-dimethyl-7-phenylheptanethioateC17H26OSSource of chirality: asymmetric catalysis94% syn and 6% of anti[α]D20=-4.8 (c 1.0, CHCl3)Absolute configuration: (3S,5S)

(3S,5S)-S-Ethyl 8-(benzyloxy)-3,5-dimethyloctanethioateC19H30O2SSource of chirality: asymmetric catalysis94% syn and 6% anti[α]D20=-2.8 (c 1.0, CH2Cl2)Absolute configuration: (3S,5S)

(2E,4E,7S,9S)-S-Ethyl 7,9-dimethyltrideca-2,4-dienethioateC17H30OSSource of chirality: asymmetric catalysis>95:5 E/Z-ratio[α]D20=+9.4 (c 1.0, CHCl3)Absolute configuration: (2E,4E,7S,9S)

(5S,7S,9S,E)-S-Ethyl 5,7,9-trimethyltridec-3-enethioateC18H34OSSource of chirality: asymmetric catalysis91% syn- and 9% anti-product90:10 regioselectivity (1,6:1,4)[α]D20=-2.4 (c 1.0, CHCl3)Absolute configuration: (5S,7S,9S,E)

(5R,7S,9S,E)-S-Ethyl 5,7,9-trimethyltridec-3-enethioateC18H34OSSource of chirality: asymmetric catalysis72% anti- and 28% syn-product90:10 regioselectivity (1,6:1,4)[α]D20=+2.5 (c 1.0, CH2Cl2)Absolute configuration: (5R,7S,9S,E)