N-carbobenzyloxyalanine → HCID 11129651, compound

HRID 1450720Notes

Reaction equation

HRID 1450720 reaction equation
[C:1](NC(=N)O)([CH3:4])([CH3:3])[CH3:2].[NH:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:10]([C:12]([OH:14])=[O:13])[CH3:11]>>[NH:9]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C@H:10]([C:12]([O:14][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH3:11]

Participants

3

Reactant 2

HCID 736104N-carbobenzyloxyalanineHCID 178449238HCID 178449238, compound

Product 1

HCID 11129651HCID 11129651, compound

Procedure

Reaction of 1 at room temperature with 400 mol % of tert-butanol and 1-2 mol % of freshly prepared CuCl gave a quantitative yield of analytically pure tert-butyl isourea 2 (R=But) in less than 1 h. The reaction was monitored using IR by following the disappearance of the carbodiimide absorption at 2130 cm-1 and the appearance of the isourea absorbance at 1660 cm-1. No purification other than evaporation of the excess tert-butanol was necessary to obtain the pure material. Isourea 2 (R=BUt) was then stirred with N-CBZ-Ala (10) in several solvents under a variety of reaction conditions to determine the most effective conditions for tert-butyl ester formation. In general, all the solvents examined gave reasonable yields of N-CBZ-Ala-OBut (15), but warm toluene, overnight, produced the best results. Several other N-BOC protected amino acids were treated with 2 (R=But) and gave good yields of tert-butyl esters under similar conditions. In each example, the yields were comparable if not slightly superior to those obtained using DIC. Esterification of the racemization sensitive CBZ-Ala-Phe (11) with 2 (R=But) gave the tert-butyl ester 20, shown by HPLC analysis to be a single diastereomer. Esterification of 11 using K2CO3 and tert-butyl bromide in DMA (Chevallet et al., Tetrahedron Lett., 34, p. 7409 (1993)) gave 20 with 2.5% racemization to the L,D diastereomer. Other isourea derivatives 2 (R=Bn, Pr1, Et Me) of 1 were synthesized, with results identical to that of 2 (R=But). Each isourea was formed rapidly and quantitatively at room temperature with 1-2 mole % CuCl and only a slight excess of alcohol. The quality of the CuCl catalyst was important, as older samples gave slower reactions and were required in up to 5 mol %. Surprisingly, each isourea, including the But, could be produced quantitatively without the use of catalytic CuCl, although heating and longer reaction times were required. In the case of DIC, no isourea was obtained without catalytic CuCl. All our results indicated that the presence or absence of the CuCl had no effect on esterifications.

Workup

  1. customthe disappearance of the carbodiimide absorption at 2130 cm-1
  2. customNo purification
  3. customother than evaporation of the excess tert-butanol
  4. customto obtain the pure material
  5. customIn general, all the solvents examined gave reasonable

Sources & evidence

ORD record
ord-393c01c9047e40f39207b5a40ca50ffe
Source dataset
uspto-grants-1997_02
Patent number
US05602264

Reaction notes

Loading…