Synthesis of novel chiral hydrobenzoin mono-tert-butyl ethers derived from m-hydrobenzoin and their application as chiral auxiliaries in the diastereoselective reduction of α-keto esters

Three m-hydrobenzoin derived chiral hydrobenzoin mono-tert-butyl ethers were synthesized by a new reaction pathway and tested as chiral auxiliaries in the L-selectride® mediated stereoselective reduction of their corresponding phenyl glyoxylates. As a result, improved stereoselectivities of up to a ratio of 92:8 compared to 84:16 with the initially examined analogous benzyl ether were achieved.

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[2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]-2-(2-Benzyloxy-1,2-diphenylethoxy)octahydro-7,8,8-trimethyl-4,7-methanobenzofuranC33H38O3Ee = >98%[α]D20=-54.0 (c 1.10, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]

[2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]-2-[2-(2-Methylpropoxy)-1,2-diphenylethoxy]octahydro-7,8,8-trimethyl-4,7-methanobenzofuranC30H40O3Ee = >98%[α]D20=-66.9 (c 0.98, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]

[2S-(2α(1R*,2S*),3aα,4β,7β,7aα)]-[2-[(Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,2-diphenylethoxy]acetic acid, 1,1-dimethylethyl esterC32H42O5Ee = >98%[α]D20=-59.9 (c 0.96, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1R*,2S*),3aα,4β,7β,7aα)]

[2S-(2α(1R*,2S*),3aα,4β,7β,7aα)]-2-[2-[(Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,2-diphenylethoxy]-2-methylpropionic acid, 1,1-dimethylethyl esterC34H46O5Ee = >98%[α]D20=-57.6 (c 1.66, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]

[2S-(2α(1R*,2S*),3aα,4β,7β,7aα)]-2-[2-[(Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,2-diphenylethoxy]-2-methylpropan-1-olC30H40O4Ee = >98%[α]D20=-49.4 (c 2.28, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1R*,2S*),3aα,4β,7β,7aα)]

[2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]-2-[2-(2-Methoxy-1,1-dimethylethoxy)-1,2-diphenylethoxy]octahydro-7,8,8-trimethyl-4,7-methanobenzofuranC31H42O4Ee = >98%[α]D20=-77.4 (c 1.26, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]

4-Methylbenzene-1-sulfonic acid, [2S-(2α(1R*,2S*),3aα,4β,7β,7aα)]-2-[2-[(octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,2-diphenylethoxy]-2-methylpropyl esterC37H46O6SEe = >98%[α]D20=-66.2 (c 0.84, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1R*,2S*),3aα,4β,7β,7aα)]

Methanesulfonic acid, [2S-(2α(1R*,2S*),3aα,4β,7β,7aα)]-2-[2-[(octahydro-7,8,8-trimethyl-4,7- methanobenzofuran-2-yl)oxy]-1,2-diphenylethoxy]-2-methylpropyl esterC31H42O6SEe = >98%[α]D20=-68.9 (c 1.15, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1R*,2S*),3aα,4β,7β,7aα)]

[2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]-2-[2-(2-Iodo-1,1-dimethylethoxy)-1,2-diphenylethoxy]octahydro-7,8,8-trimethyl-4,7-methanobenzofuranC30H39IO3Ee = >98%[α]D20=-54.6 (c 1.00, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]

[2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]-2-[2-(1,1-Dimethylethoxy)-1,2-diphenylethoxy]octahydro-7,8,8-trimethyl-4,7-methanobenzofuranC30H40O3Ee = >98%[α]D20=-80.5 (c 1.10, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]

[2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]-2-[2-(1,1-Dimethyl-2-phenylethoxy)-1,2-diphenylethoxy]octahydro-7,8,8-trimethyl-4,7-methanobenzofuranC36H44O3Ee = >98%[α]D20=-65.8 (c 1.00, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: [2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]

(1R,2S)-2-Benzyloxy-1,2-diphenylethanolC21H20O2Ee = >98%[α]D20=+31.1 (c 1.00, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

(1R,2S)-2-(2-Methylpropoxy)-1,2-diphenylethanolC18H22O2Ee = >98%[α]D20=+43.7 (c 0.90, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

(1R,2S)-2-(2-Methoxy-1,1-dimethylethoxy)-1,2-diphenylethanolC19H24O3Ee = >98%[α]D20=+123.2 (c 0.56, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

(1R,2S)-2-(1,1-Dimethylethoxy)-1,2-diphenylethanolC18H22O2Ee = >98%[α]D20=+55.8 (c 0.64, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

(1R,2S)-2-(1,1-Dimethyl-2-phenylethoxy)-1,2-diphenylethanolC24H26O2Ee = >98%[α]D20=+1.4 (c 1.00, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

Oxophenylacetic acid, (1R,2S)-2-benzyloxy-1,2-diphenylethyl esterC29H24O4Ee = >98%[α]D20=+55.8 (c 0.64, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

Oxophenylacetic acid, (1R,2S)-2-(2-methylpropoxy)-1,2-diphenylethyl esterC26H26O4Ee = >98%[α]D20=+1.4 (c 1.00, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

Oxophenylacetic acid, (1R,2S)-2-(2-methoxy-1,1-dimethylethoxy)-1,2-diphenylethyl esterC27H28O5Ee = >98%[α]D20=+12.9 (c 1.06, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

Oxophenylacetic acid, (1R,2S)-2-(1,1-dimethylethoxy)-1,2-diphenylethyl esterC26H26O4Ee = >98%[α]D20=+14.1 (c 0.71, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

Oxophenylacetic acid, (1R,2S)-2-(1,1-dimethyl-2-phenylethoxy)-1,2-diphenylethyl esterC32H30O4Ee = >98%[α]D20=+9.8 (c 1.00, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)