The original project was the development of reactions promoted by guanidinium catalysts.� These hydrogen bond catalysts would activate N-acylhydrazone electrophiles for attack by nucleophiles.� Initial studies on this project were unsatisfactory. �Our focus then turned towards a project that was showing promise.� This project involved the kinetic resolution of secondary alcohols which is an important transformation for the preparation of chiral building blocks.� While there are a number of ways to selectively derivatize one alcohol enantiomer over another, the use of a silyl group has been virtually ignored.� Therefore we are working on the asymmetric silylation of secondary alcohols via two different approaches: chiral cation catalysts (Eq. 1) and chiral nucleophilic catalysts (Eq. 2).� Both approaches have shown promising preliminary results in achieving enantioselectivity.�

Chiral Cation Silylations

In the process of investigating a new, asymmetric version of the Mukaiyama aldol reaction we discovered something new.� We determined that the enantioselectivity of the two products (the alcohol and silylated product) arose through enantioselectively silylating the racemic alcohol (Scheme 1), not through the carbon-carbon bond forming step.� Recognizing the value of an enantioselective silylation reaction, we proceeded to target this aspect of the reaction.�

Scheme 1.� General schematic depicting the proposed reaction pathway of (A) the chiral cation mediated reaction and (B) the chiral nucleophile activated pathway.�

The design of the system incorporates the generation of a chiral cation salt between a secondary alkoxide anion and a chiral ammonium cation to facilitate the selective silylation of one of the alkoxides.� The alkoxide is generated in situ and results from the reaction between a silyl ketene acetal and an aldehyde through activation by a Lewis base (an acetate) (Table 1).� Cinchona alkaloids were chosen as the counter ion (Scheme 1).� The catalysts are easily synthesized through nucleophilic substitution on the quinuclidine core. �Figure 1 shows the synthesis of the methyl derivative of cinchonidine. �

The quinidine methyl acetate (QDMeAcO) catalyst was the first catalyst synthesized to screen reactions.� Benzaldehyde and methyl trimethylsilyl dimethylketene acetal were the substrates chosen for the screening.� Solvent was one of the first parameters investigated.� Table 1 shows four of the solvents investigated, showing toluene was the best solvent.� The proposed mechanism of our enantioselective silylation is shown in Scheme 2.� Employing a chiral cation acetate salt in the enantioselective silylation reaction allows for the direct formation and silylation of an alcohol in one pot starting from a silyl ketene acetal and an aldehyde.�

Since we are employing a cinchona alkaloid as the chiral cation for our system, we have four different core structures available for testing.� The four compounds are available in two pairs of diastereomers (Table 2).� We therefore proceeded to derivatize them for investigation in our reaction.� Indeed, the QN/QD diastereomer pair acted as psuedoenantiomers (Table 2) but the cinchonidine structure gave higher enantioselectivity overall.� We also screened other functionalized catalysts, but they did not perform as well as CDMeAcO.� Next we looked at the substrate scope with regards to the aldehyde, incorporating a variety of sterics and electronics.� Table 3 shows the enantioselectivities of 1a-h obtained from the reaction of methyl trimethylsilyl dimethylketene acetal and different aldehydes, showing that sterics and electronics play a role.�

Nucleophilic Enantioselective Silylations.

While our initial asymmetric silylation reaction was quite novel, it was complex, therefore we wanted to develop a system that was more general.� So we began thinking about the mechanism of silylating an alcohol.� It has been postulated that the first step in silylating an alcohol is a pre-equilibrium between the silylating reagent and a nucleophile activator.� Therefore, we reasoned that a chiral nucleophile could be used to selectively silylate one alcohol enantiomer over another (Figure 2).� A series of catalysts were synthesized to protect the secondary alcohol.� For the first round of screening, the derivatizations included: trimethylsilyl, methyl, ethyl, and benzyl (Figure 3).

To test the catalyst substructure, all four of the alkaloids were derivatized with the trimethylsilyl group and 1-indanol was the secondary alcohol chosen for the screening.� Initial reactions were screened in toluene with trimethylsilyl chloride, and triethylamine.� Table 4 shows TMSCD to be the optimal catalyst.�

Initial reaction screenings were performed with triethylamine as the base for neutralization of the HCl generated.� As an initial screen we have also looked at H�nig's base (Table 5).� Surprising, triethylamine still had higher enantioselectivity.� We intend to look at other bases as we continue to optimize our conditions.�

With regards to solvent, we initially screened a few to investigate their affect on the reaction.� Since our reactions are run at low temperatures, we were limited to solvents that did not freeze at -78 �C.� The reactions were screened using the TMSCD catalyst (Table 6) and THF was shown to achieve superior selectivity over other solvents tested.�