Chiral linker. Part 2: Synthesis and evaluation of a novel, reusable solid-supported open chain chiral auxiliary derived from m-hydrobenzoin for the diastereoselective reduction of α-keto esters

Three novel m-hydrobenzoin derived chiral hydrobenzoin mono-alkyl ethers were synthesized and evaluated as open chain chiral auxiliaries in the L-selectrideR/ZnCl2 mediated stereoselective reduction of their corresponding phenyl glyoxylates, resulting in des of up to 91%. The optimized auxiliary structure was immobilized on commercially available Wang-resin by using the ether substituent as a sublinking unit and applied as a reusable solid-supported chiral auxiliary in the same type of reaction with only little loss of stereofacial selectivity.

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[2S-(2α(1R*,2S*),3aα,4β,7β,7aα)]-2-[2-[(Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,2-diphenylethoxy]ethanolC28H36O4Ee = >98%[α]D20=-73.1 (c 1.08, 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]-1,1-diphenylethanolC40H44O4Ee = >98%[α]D20=-77.2 (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(1R*,2S*),3aα,4β,7β,7aα)]

[2S-(2α(1S*,2R*),3aα,4β,7β,7aα)]-2-[2-(2-Methoxyethoxy)-1,2-diphenylethoxy]octahydro-7,8,8-trimethyl-4,7-methanobenzofuranC29H38O4Ee = >98%[α]D20=-67.8 (c 0.90, 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-Methoxy-2,2-diphenylethoxy)-1,2-diphenylethoxy]octahydro-7,8,8-trimethyl-4,7-methanobenzofuranC41H46O4Ee = >98%[α]D20=-42.6 (c 1.23, 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)]-Dimethyl-N-[(2-(octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy-1,2-diphenylethoxy)ethyl]amineC30H41NO3Ee = >98%[α]D20=-82.5 (c 0.79, 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)]

(1R,2S)-2-(2-Dimethylaminoethoxy)-1,2-diphenylethanolC18H23NO2Ee = >98%[α]D20=134.7 (c 0.49, 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-Methoxyethoxy)-1,2-diphenylethanolC17H20O3Ee = >98%[α]D20=22.9 (c 1.04, 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-2,2-diphenylethoxy)-1,2-diphenylethanolC29H28O3Ee = >98%[α]D20=42.6 (c 1.00, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

Oxophenylacetic acid, (1R,2S)-2-(2-dimethylaminoethoxy)-1,2-diphenylethyl esterC26H27NO4Ee = >98%[α]D20=-2.4 (c 0.95, 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-methoxyethoxy)-1,2-diphenylethyl esterC25H24O5Ee = >98%[α]D20=18.6 (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-(2-methoxy-2,2-diphenylethoxy)-1,2-diphenylethyl esterC37H32O5Ee = >98%[α]D20=19.3 (c 1.21, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

3-Oxo-3-phenylpropionic acid, (1R,2S)-2-(2-methoxyethoxy)-1,2-diphenylethyl esterC26H26O5Ee = >98%[α]D20=31.7 (c 0.73, CH2Cl2)Source of chirality: [2R-(2α,3aα,4β,7β,7aα)]-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-olAbsolute configuration: (1R,2S)

(S)-Hydroxyphenylacetic acid, (1R,2S)-2-(2-methoxyethoxy)-1,2-diphenylethyl esterC25H26O5Ee = >98% [De = 91% (S)]Source of chirality: (1R,2S)-2-(2- methoxyethoxy)-1,2-diphenylethanolAbsolute configuration: (S), (1R,2S)

(S)-Hydroxyphenylacetic acid, (1R,2S)-2-(2-methoxy-2,2-diphenylethoxy)-1,2-diphenylethyl esterC37H34O5Ee = >98% [De = 91% (S)]Source of chirality: (1R,2S)-2-(2-methoxy-2,2-diphenylethoxy)-1,2-diphenylethanolAbsolute configuration: (S), (1R,2S)

(S)-Hydroxyphenylacetic acid, (1R,2S)-2-(2-dimethylaminoethoxy)-1,2-diphenylethyl esterC26H29NO4Ee = >98% [De = 81% (S)]Source of chirality: (1R,2S)-2-(2-dimethylaminoethoxy)-1,2-diphenylethanolAbsolute configuration: (S), (1R,2S)

(R)-3-Hydroxy-3-phenylpropionic acid, (1R,2S)-2-(2-methoxyethoxy)-1,2-diphenylethyl esterC26H28O5Ee = >98% [De = 54% (R)]Source of chirality: (1R,2S)-2-(2-methoxyethoxy)-1,2-diphenylethanolAbsolute configuration: (R), (1R,2S)