Alcohols, 2-nitro diastereomeric mixtures

The synthesis of ephedrine shown in Method H is of commercial interest (316). Condensation of benzaldehyde with nitroethane gives a diastereomeric mixture of nitro alcohols. Reduction yields a separable mixture of ( )-norephedrine and ( )-norpseudoephedrine. Methylation of ( )-norephedrine yields ( )-ephe-drine, which can be resolved into optical antipodes by chemical methods. 

The bone collagen cross-link (+)-deoxypyrrololine has potential clinical utility in the diagnosis of osteoporosis and other metabolic bone diseases. Intrigued by its novel structure and its promise to allow the early discovery of various bone diseases, the research team of M. Adamczyk developed a convergent total synthesis for this 1,3,4-trisubstituted pyrrole amino acid. The key step of the synthesis was the union of the nitroalkane and aldehyde fragments to obtain a diastereomeric mixture of the expected -nitro alcohol in good yield. This new functionality served as a handle to install the pyrrole ring. 

Diastereomeric mixtures of vicinal nitro alcohols obtained by a classical Henry reaction with low dia-stereoselectivity can be easily silylated to give the corresponding mixture of 0-f-butyldimethylsilyl ethers. The latter undergoes an enrichment of the erythro isomer (54 up to >95 5) by treatment with LDA and successive protonation of the corresponding lithium salts (Scheme 8), which occurs with high diastereoselectivity. 

By examining Scheme 1 it is possible to verify the key role of the base as catalyst for the overall process and to justify the lack of stereoselectivity which, in general, has been observed in nitroaldol additions. In fact, the reversibility of the nitroaldol process, as well as the difficulty of a stereoselective protonation of the stereogenic center of the nitronate intermediates, leads to a mixture of diastereomeric 2-nitro alcohols. 

In a typical procedure, diastereomeric a-nitro alcohols 4 are doubly deprotonated then reprotonated by acetic acid at —100 °C. The svn-isomer of 4 is obtained in 90 % yield, provided that protonation is performed in a reaction mixture containing large amounts of hexamethylphosphoric triamide or N,N -dimethyl propylene urea118. 

---