ABSTRACT
The Merck labs described a process for coupling an asymmetric homologation to an asymmetric homoaldol reaction in a previous communication.
In this tandem asymmetric transformation, chiral amide enolates derived from aminoindanol amides (
I
) were homologated to the zinc homoenolates (
II
), which were subsequently treated with aldehydes following transmetallation to titanium, yielding the homoaldol products (
III
) with two new stereocenters (Scheme 20.1). This case study details the successful development of this complex process as a direct consequence of insights provided by
in situ
infrared (IR) monitoring. In addition,
in situ
IR enabled a more in-depth understanding of the intermediate zincate enolate structures, which was not available via alternative methods, such as lowtemperature nuclear magnetic resonance (NMR). Although we used NMR as a key complement to the IR observations, attempts to use NMR exclusively were not tenable. Many of the intermediates in the process were water, air, and temperature sensitive. In addition, the reaction system consisted of binary and ternary solvent mixtures, further complicating the NMR spectra. When combined with the requirement to conduct the chemistry on very small scale to accommodate NMR tubes, obtaining NMR data proved a very involved process.
