A left-handed catcher's mitt is dissymmetric (chiral) and will only fit the left hand of a catcher. Similarly, all biological receptors are chiral, and can distinguish between the two mirror images (enantiomers) of a ligand. For drug development, access to a single enantiomer is becoming increasingly important as the different pharmacological properties of enantiomeric compounds are documented. In spite of this mounting evidence, less than 10% of synthetic drugs on the market (worldwide) are sold as a single enantiomer. Thus, the need for methods of asymmetric synthesis of new drugs will only increase. The field has, in fact, explored in the last two decades. Among the classes of new auxiliary-based methods, the vast majority face-selective addition to a trigonal atom by a nucleophile or an electrophile. During the last several years, another new approach has appeared: the use of chiral nucleophiles. The addition of an organometallic such as RLi or RMgX to a carbonyl has been one of the most widely used methods of organic synthesis of this century. Since the reaction with an aldehyde or unsymmetrical ketone generates a stereocenter, it follows that an enantioface-selective process would be highly desirable. During the period of the proposed fellowship, I will study the dynamics of metalated isoquinolines, which we use as chiral nucleophiles in face- selective additions to aldehydes to give stereochemically homogeneous addition products (100% diastereomeric excess). These addition products are then converted into phthalide isoquinoline and protoberberine alkaloids. A long-range goal is to define the requirements for face selectivity in organolithium and organomagnesium additions, with an eye toward the rational design of chiral catalysts for asymmetric carbonyl additions. In the proposed work, I will use a combination of product stereochemistry (data in hand), cryoscopy and spectroscopy (especially 1H & 13C NMR) to evaluate the dynamics of the organometallic systems and to help formulate a detailed mechanistic rationale for the asymmetric reactions. With the knowledge and expertise obtained, I will continue these types of studies upon returning.
