Chiral auxiliary design for the stereoselective addition of alpha-alkoxymethyl carbanions to aldehydes and ketones

A new method has been developed that allows for the stereoselective addition of α-alkoxymethylcarbanions to aldehydes and ketones with the use of a chiral auxiliary on the nucleophile in up to 81% de. Recovery of the chiral auxiliary and the enantiomerically enriched 1,2-diol product was also possible and was demonstrated for the first time. The Sn-Li exchange process was employed to generate the chiral α-alkoxymethylcarbanions. Several chiral auxiliaries with different structural features including carbohydrate derivatives have been synthesized in order to optimize the level of stereoselectivity.; Glucose-derived chiral auxiliaries were able to induce diastereoselectivity in up to 59% de. Additions to electron rich aldehydes provided the highest levels of stereoselectivity, while additions to pentafluorobenzaledehyde resulted in a reversal in the sense of stereoselectivity. The C-glycoside group on the auxiliary was believed to be an important structural feature involved in the stereodifferentiating process. Stereoselectivity was optimized by employing an organotitanium species, however the yield dropped drastically to impractical levels.; A glucosamine-derived chiral auxiliary was unable to induce greater levels of stereoselectivity than glucose-derived chiral auxiliaries. The synthesis of the glucosamine-derived chiral auxiliary was also more difficult due to low yields.; Auxiliaries that were less “sugar like” in structure were also studied such as a 3-methoxytetrahydropyran chiral auxiliary. However addition to 3,4-dimethoxybenzaldehyde resulted in only 31% de. Furthermore a relatively long 12 step synthesis was used to prepare the 3-methoxytetrahydropyran chiral auxiliary derivative.; It was possible to synthesize 5-membered ring auxiliary derivatives in fewer steps; however unprecedented racemization occurred in the final step. Nevertheless the racemic 5-membered ring auxiliaries were unable to induce diastereoselectivity.; Finally, a tetrahydropyran chiral auxiliary without a 3-methoxy substituent was able to induce stereoselective additions in up to 81% de. A transition state structure different from what other auxiliary derivatives experienced was believed to occur. The importance of employing coordination additives in order to achieve higher levels of stereoselectivity was also realized.