Asymmetric hydrogenations for the synthesis of Boc-protected 4-alkylprolinols and prolines.
The utility of 4-substituted prolinols and their corresponding prolines in peptides, peptidomimetics, and natural products has motivated researchers to find new and efficient routes for their preparation. Herein, we report a general approach to the synthesis of Boc-protected 4-alkylprolinols and prolines via a divergent asymmetric hydrogenation strategy. Intermediate exocyclic olefins were prepared by Wittig-type reactions with ketone 6 and subjected to hydroxyl and sterically directed reductions. The Crabtree catalyst (Ir[COD]PyPCy(3)PF(6)) proved to be highly effective in diastereoselective hydrogenations to give trans-substituted pyrrolidines (9). Good facial selectivities were also observed in heterogeneous hydrogenations with Raney-nickel to obtain cis-substituted pyrrolidines (11). Employing this strategy, we describe the synthesis of novel prolinol and proline-based building blocks for incorporation into biologically relevant peptidomimetics.
Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla 92093-0343, USA.
Juan R
JR
Del Valle
Murray
M
Goodman
D000478:Alkylation; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D006865:Hydrogenation; D007202:Indicators and Reagents; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D013237:Stereoisomerism
D007202:Indicators and Reagents; D011392:Proline