STEREOCONTROL BETWEEN REMOTE ATOM CENTERS IN ACYCLIC SUBSTRATES - ANTI ADDITION OF HYDRIDE TO 1,5-HYDROXY KETONE, 1,6-HYDROXY KETONE, AND 1,7-HYDROXY KETONE

For conformationally unconstrained, acyclic organic compounds, the con trol of stereogenic centers at remote positions of a chain, that is, a t a distance of four or more atom centers, remains a challenging probl em in asymmetric synthesis. We report on our studies of 1,5, 1,6, and 1,7 diastereoselectivity in hydride reductions of acyclic hydroxy amin o ketones and related compounds, which were sparked by our discovery o f high 1,5 diastereocontrol (>10:1) with substrates such as 17 and 23. We have been able to achieve both high 1,5- and 1,6-anti diastereocon trol in the reduction of 1,5- and 1,6-hydroxy ketone substrates, respe ctively. However, the level of 1,7-anti diastereocontrol with 1,7-hydr oxy ketones was only moderate. More specifically, reduction of 23 to 2 4 with R-alpine-hydride or Zn(BH4)(2) in CH2Cl2 (predominantly) at -78 degrees C gave high 1,5-anti stereoselectivity (anti/syn = 10:1 or 13 :1, respectively), and reduction of 34 to 35 with R-alpine-hydride (CH 2Cl2) gave high 1,6-anti selectivity (anti/syn = 12:1, respectively), whereas reduction of 46 to 44 with R-alpine-hydride (CH2Cl2) gave only moderate 1,7-anti stereoselectivity (anti/syn = 3:1). Results for red uctions of 1,5- and 1,6-hydroxy ketone substrates having the N-benzyl structural subunit replaced (i.e., 27 --> 28, 29 --> 30, 31 --> 32, 52 --> 53, 54a --> 55a, 54b --> 55b, 54c --> 55c, and 56 --> 57) clearly indicate that the stereoelectronic character of this subunit plays a critical. role in the attainment of high anti asymmetric induction. Th us, while we obtained exceptionally high 1,6-anti stereoselectivity in the reduction of the N-mesitylmethyl substrate, 54c, to 1,6-diols 55c (anti/syn = 22:1) with R-alpine-hydride at -78 degrees C in CH2Cl2, t he N-methyl substrate, 54b, gave a relatively modest anti/syn ratio of 3:1. The diminished anti/syn ratio of 4:1 in the R-alpine-hydride red uction of methoxy amino ketone 50 to 51 also indicates the importance of the free hydroxyl group for attaining high 1,6-anti stereoselectivi ty. To rationalize the high remote anti stereocontrol in such acyclic systems, we discuss a chelation-controlled mechanism, involving extern al hydride addition to a bicyclic metal complex with a coordinated ket one carbonyl (e.g., 33) vs internal hydride addition to a monocyclic m etal complex with an uncoordinated ketone carbonyl (e.g., 58).