Synthesis of Fmoc-protected trans-4-methylproline.
Fmoc-protected trans-4-methylproline was synthesized starting from D-serine. The chiral scaffold of serine in the form of olefinated Garner's aldehyde 3 was used to control the diastereoselective formation of the new stereocenter on the hydrogenation of allylic alcohol 4. The diastereoselectivity (syn/anti ratio) of the process was 86:14, attained with Raney nickel. Hydrogen migration seems not to be the sole factor lowering the diastereoselectivity, as nickel is known not to promote double-bond migration. Instead, the moderate stereocontrol is attributed to the mobility of the side chain of 4, which allows the attack of hydrogen on both faces of the olefin (open transition state). A series of transformations led to ring precursor 8, which after recrystallization afforded the syn diastereoisomer in dr = 95:5. Protected trans-4-methylproline 11 was obtained from 8 in a straightforward fashion.
Nevalainen
M
M
Laboratory of Organic Chemistry, Department of Chemical Technology, Helsinki University of Technology, FIN-02015 HUT, Finland.
Kauppinen
P M
PM
Koskinen
A M
AM
D000596:Amino Acids / Q000737:chemistry*; D005449:Fluorenes / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D013057:Spectrum Analysis
D000596:Amino Acids; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; C427478:N-(9-fluorenylmethoxycarbonyl)-4-methylproline; D011392:Proline