Silyl nitronates facial selectivity

This chapter is divided into four major sections. The first (Section 2.1) will deal with the structure of both alkoxy and silyl nitronates. Specifically, this section will include physical, structural, and spectroscopic properties of nitronates. The next section (Section 2.2) describes the mechanistic aspects of the dipolar cycloaddition including both experimental and theoretical investigations. Also discussed in this section are the regio- and stereochemical features of the process. Finally, the remaining sections will cover the preparation, reaction, and subsequent functionalization of silyl nitronates (Section 2.3) and alkyl nitronates (Section 2.4), respectively. This will include discussion of facial selectivity in the case of chiral nitronates and the application of this process to combinatorial and natural product synthesis. 

Only a few attempts to control the facial selectivity of this [3+2] process are on record, all dealing with the use of chiral, non-racemic dipolarophiles (117). The reactions of a vinyl substituted cephem (121) with the silyl nitronates derived from nitromethane, nitroethane, and nitropropane proceed over 3 days at room temperature to provide a single stereoisomer in moderate yields, Eq. 2.8 (118,119). Approach of the simple nitronate to the dipolarophile is believed to be from the less hindered a-face, however, the configuration of the newly created stereocenter could not be unambiguously assigned. 

In a second report on the use of chiral dipolarophiles, the cycloadditions of silyl nitronates with 123 and 124 provide modest facial selectivity (Table 2.37) (35). Unfortunately, the yields of the cycloadducts are only moderate because of the steric bulk of the dipolarophile. 

A second strategy to control facial selectivity involves the use of chiral sultams and lactams as auxiliaries for the dipolarophile (120-123). Cycloaddition of 132 with a variety of substituted nitronates provides up to 9 1 selectivity of the major diastereomer (Table 2.38). However, substitution at the a-position of the dipolarophile leads to a reduction in stereoselectivity (entry 5). Assuming an s-cis conformation of the dipolarophile, it is proposed that the major isomer arises from an endo approach of the nitronate to the Re face of the dipolarophile (Fig. 2.13). This is supported by X-ray crystallographic analysis of one of the cycloadducts, which resides in a conformation similar to the proposed transition state. However, this analysis assumes that the silyl nitronate is only reacting through the... 

E) configuration. The dipolar cycloaddition of 141 with a silyl nitronate shows a slight increase of facial selectivity over 132 (Eq. 2.9). Because the cycloadducts are converted directly to the corresponding isoxazolines, only the facial selectivity can be determined. It is believed that the cycloaddition proceeds on the Re face of the dipolarophile due to shielding of the Si face by the auxihary. Both chiral auxiliaries can be liberated from the cycloadduct upon reduction with L-Selectride. 

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