Lewis acid mediated asymmetric Diels–Alder reactions of chiral 2-phosphonoacrylates

2-Phosphonoacrylates containing four chiral alcohol auxiliaries were efficiently prepared and evaluated in Lewis acid mediated Diels–Alder reactions. Under the activation of SnCl4, all reactions performed in CH2Cl2 at −65 °C exclusively afforded the endo (endo-to-carboxylate) cycloadducts with dr’s ranging from 50:50 to >99:1. The best facial selectivity was obtained from the substrate bearing a (−)-phenylmenthyl group, to give adducts as (dr >99:1) or almost as (dr = 99:1) single diastereomers. Detailed strategies for the structural elucidation of the cycloadducts as well as a rationalization of the observed stereoselectivity are described.

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(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl 2-(diethoxyphosphoryl)-acetateC22H35O5P[α]D20=+14.0 (c 1.1, CHCl3)Absolute configuration: (1R,2S,5R)Source of chirality: (−)-phenylmenthol

(1R,2S,5R)-(Diethoxy-phosphoryl)-acetic acid 2-isopropyl-5-methyl-cyclohexyl esterC16H32O5P[α]D20=-47.3 (c 1.1, CHCl3)Absolute configuration: (1R,2S,5R)Source of chirality: (−)-menthol

(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl (1′R,2′S,4′R)-2-(diethoxyphosphoryl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC28H41O5Pee >99% (from HPLC)[α]D20=+48.5 (c 0.63, CHCl3)Absolute configuration: (1′R,2′S,4′R, 1R,2S,5R)Source of chirality: asymmetric cycloaddition

(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl (1′S,2′S)-1-(diethoxyphosphoryl)-2-methylcyclohex-3-ene carboxylateC28H43O5Pee = 98% (from HPLC)[α]D20=+3.8 (c 1.5, CHCl3)Absolute configuration: (1′S,2′S,1R,2S,5R)Source of chirality: asymmetric cycloaddition

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl (1′R,2′S,4′R)-2-(diethoxyphosphoryl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC22H37O5Pee = 84% (from HPLC)[α]D20=+17.2 (c 0.81, CHCl3)Absolute configuration: (1′R,2′S,4′R,1R,2S,5R)Source of chirality: asymmetric cycloaddition

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl) (1′S,2′S)-1-(diethoxyphosphoryl)-2-methylcyclohex-3-enecarboxylateC22H39O5PEe = 82% (from HPLC)[α]D20=+9.3 (c 1.0, CHCl3)Absolute configuration: (1′S,2′S,1R,2S,5R)Source of chirality: asymmetric cycloaddition

(2R)-2-endo-Hydroxymethyl-5-norborneneC8H12O[α]D20=+70.6 (c 0.6, 95% EtOH)Absolute configuration: (2R)Source of chirality: asymmetric cycloaddition and stereospecific reductive dephosphonylation