Enantioselective reduction of ketophosphonates using adducts of chiral natural acids with sodium borohydride

Table 1. Asymmetric reduction of ketophosphonates to hydroxyphosphonates (R'O)2P(O)(CH2)n(CH2)nP(O)(OR')2NaBH4/A Entry Comp-d R R’ n Yield (%) Auxiliary (A) Config of 3,4 ee (%) 1 3a Ph Mnt 0 90 L-Pro S 52.6 2 3b 2-F-C6H4 Mnt 0 90 L-Pro S 79.2 3 3c 2-An Mnt 0 90 L-Pro S 60.6 4 3f Ph Et 0 85 L-Leu - 21 5 3a Ph Mnt 0 95 L-TA R 92.4 6 3a Ph Mnt 0 98 D-TA S 46 7 3b 2-F-C6H4 Mnt 0 97 L-TA S 80.5 8 3c 2-An Mnt 0 96 L-TA S 74 9 3d i-Pr Mnt 0 97.6 L-TA S 68 10 3e Pyperonyl Mnt 0 97 L-TA S 96 11 3f Ph Et 0 95 L-TA S 60 12 3f Ph Et 0 94 D-TA R 60 13 4a CH2Cl Et 1 86 L-TA S 80 14 4a CH2Cl Et 1 82 D-TA R 80 15 4a CH2Cl Et 1 70 Mal - 25 16 4b CH2Cl Mnt 1 94 L-TA S 96 17 4b CH2Cl Mnt 1 80 D-TA R 82 18 4c Ph Et 1 95 D-TA S 44 Table 2. Stereoselectivity of reduction of ketophosphonates Entry Ketophos- phonate R R’ Config TA ee or de of 3 Config of 3 Type of Stereoselectivity 1 1f Et Ph NaBH4 0 - - 2 1f Et Ph R,R-TA 82 S Single 3 1f Et Ph S,S-TA 78 R Single 4 1a Mnt Ph NaBH4 30 R Single 5 1a Mnt Ph R,R-TA 92.5 S Matched double 6 1a Mnt Ph S,S-TA 46 R Unmatched double Insofar as reduction of ketophosphonates with the complex NaBH4/(R,R)-tartaric acid affords (S)-hydroxyphosphonates, it is very probable that P=O group is involved to the transition state leading to formation of hydroxyphosphonates as it shown in Figure 2, and promotes stereofacial attack of carbonyl group by hydride ion from the Si side.