Regioselective Aldol Condensation of Dialdehydes

Significance

Non-symmetric model substrate 2 was designed and synthesized and its intra­molecular aldol condensation studied. Synthesis of dialdehyde 2 was achieved by l-proline-catalyzed nitroso aldol reaction followed by diol formation and NaIO₄-cleavage employing commercial 5α-cholestan-3-one (1) as starting material. Adding small amounts of AcOH improved the yield for the proline-catalyzed nitroso aldol. It was ­observed that the hydroxylation was highly diastereo­selective and took only place from the α-face. Several conditions were screened for the following regioselective aldol condensation. Product 3 was formed predominantly (50:1) when morpholine, octanoic acid and HMPA in Et₂O were used, whereas product 4 was formed in excess (50:1) with conditions using (S)-indoline-2-carboxylic acid in MeCN-CH₂Cl₂. Using d- or l-proline in this case gave diminished yields and selectivity.