Issue in Honor of Prof. J. Elguero and P. Molina ARKIVOC 2005 (ix) 30-38
was corroborated by chiral chromatography on a Constametric 4100 system equipped with a Chiralcel OD chiral column, a UV–vis detector, hexane/iPrOH/Et2NH (9: 0.9: 0.1) as mobile phase, and the racemic mixture (+)-4/(-)-4 as a reference (see Experimental).
The different stereochemical outcome of the acetylation of compounds (+)-3 to give (±)-4 and (+)-6 to give (+)-4 can be explained by assuming that the presence of an N1-acetyl group in compound (+)-4 hampers the epimerization of the Trp- stereocenter by steric interference in intermediate A, while in the case of the acetylation of compound (+)-3, racemization may take place on intermediate B (Figure 1).
N N O N Ac AcAc OAc (+)-4(+)-6 A
OAc
NH(+)-3
HN Ac
N
O
B
Figure 1. Rationalization of the stereocontrol in the acetylation of compounds (+)-3 and (+)-6.
In agreement with this hypothesis, we observed that the tryptophan stereocenter of (+)-4 did not withstand the basic conditions that were required for its aldol-type condensation with acetaldehyde and, because this reaction proceeds with the anchimeric assistance of the vicinal Nacetyl group leading to its final elimination, compound 7 was obtained as a racemized product (Scheme 2).15
HN NH O O HN 2 eq TMSCl 2 eq Et3N CH2Cl2 rt, 2.5 h N N OTMS OTMS HN 2 eq CH3COCl rt, 16 h N N O O HN 5 Ac AcN N O N Ac AcAc Ac2O, 140 °C, 12 h N N O O N Ac Ac (±)-4 (99%) Ac KF/Al2O3/DMF CH3CHO, 16h N NH O O N AcAc CH3 Ac2O, 140 °C 20 h (+)-3 KF/Al2O3/DMF CH3CHO, 16h O (±)-7 (86%, major isomer) (+)-4 (93%) (+)-6 (70%)
Scheme 2. Reinvestigation of the fate of the Trp-stereocenter in the N-acetylation/aldol- type condensation of cyclo-L-Trp-Gly.
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