Aldol reactions of pyroglutamates: chiral synthesis of 4.alpha.(S)- and 4.beta.(R)-(arylmethyl)pyroglutamates

Abstract

Scheme I. Optimised Procedures for Obtaining Pure Enantiomers of 2 and 3 5 (286 mg) Recipicstc Solution workup and 4 chromarography (+2: 54 mg (19%) (+)-2: 140 mg (49%) [ a ]~ -134' (84% W ) ID +5OO (31% ee) 1 4 crysrdlization (-1-2: 37 mg (13% overall) (+>2: 62 mg (22% overall) [ a ]~ -1590 (-10046 et) [ a ]~ +158O (--10046 CC) 4 (144 mg) + 5 (143 mg) Recipifatc coupling A Solution workup and 4 chromatography (-)-3 122 mg (43%) (+)-3 121 mg (42%) [a], -540 (46% cc) [a], +540 (46% ee) Crystals: 26%; [ab -3O crystals: 21% [a], +40 Mother liq,: 74%; [ a ]~ -72O (61% ee) Mother liq.: 78%; [a], +73O (62% ee) 4 4 crydlizarion of mother liquors (-)-3 66 mg (23% overall) (+)-3: 68 mg (24% overall) [ a l~ -1170 (2 98% et) [ a ]~ +I 16' (-97% CC) at rt for 20 h under an argon atmosphere. Then concd HCl(5 mL) was added, followed by water (100 mL). The precipitate was filtered off, suspended in acetone with silica gel (20 g), and chromatographed on a silica gel column (40 g) using a light petmleum-ether mixture (1:l) as eluent. The eluate was evaporated to afford 1 (43 mg; 14%): mp 205-207 "C (no depression was observed for a mixture with an authentic sample of enantiome r i d y pure 1); [a]D -No (c 5.0, THF; 100% ee) 0it.U mp 207-209 "C and ["ID -35.5" or -33.4O, respectively, for optically pure compound and [ a ] D +34.3" for the enantiomer.) Analogous workup of the solution furnished 1 (121 mg; 42%): mp 210-214 (B) By Deracemization of (&)-l. To a degassed solution of CuC12.4H20 (200 mg; 1 mmol) in methanol (10 mL) was added a solution of (-)-sparteine (468; 2 mmol) in methanol (10 mL), and the mixture was stirred at rt for 10 min under argon. A solution of (&)-I (286 mg; 1 mmol) in degassed methanol (10 mL) was added, and the mixture was stirred under argon at rt for 20 h. The mixture was then worked up as above to give 1 (267 mg; 94%): mp 212-214 OC; [ a ] D -27.2' (c 5.0, THF; 80% ee). For further resolution, see the text. (S)-(-)-

Directing the Regioselectivity of the Alkylation of Pyroglutamate Carbamates by Formation of a Stable Counter-ion Complex

“…Supplementary proof for the switch in regioselectivity is found in the alkylation using allylbromide as electrophile, since very small amounts of dialkylated products 8 (at the 2-and 4-positions) were isolated. For the small amounts of diallylated products 8, the 13 C values of the C2 and C4 carbons shift to higher values.…”

“…18 To our surprise, we found that the alkylation of 4 occurred at the 2-position of the pyroglutamate and not at the 4-position as expected. This could be deduced from the comparison of 13 C NMR data of the C2 and C4 carbons of the starting material 4 and the alkylated products (Scheme 2, in italic). The value of the C2 carbons in the mono-alkylated products 7c shift from 55 ppm to 65 ppm, whereas the values of the C4 carbons remain around 48 ppm.…”

“…[9][10][11] With one substituent present at the 4-position (described for 10 different types of substituent), the second alkylation also occurs at the 4-position, without any trace of alkylation at the 2-position. 10 Alkylation of Nbenzyl or N-unprotected pyroglutamates 12 or thiopyroglutamates, 13 however, occurs at the 2-position. Thus, using the N-Boc protective group on pyroglutamates leads to alkylation at the 4-position and changing the protective group at nitrogen switches the regioselectivity of the alkylation.…”

Synthesis of N-[3′-(acetylthio)alkanoyl] and N-[3′-mercaptoalkanoyl]-4-α(s)-(phenylmethyl) pyroglutamic acids and prolines as potent ACE inhibitors

“…t-Butyl-2(S)-4-a(S)-(phenylmethyl) pyroglutamate (8), t-butyl-2,4-di(phenylmethyl) pyroglutamate (17), and t-butyl-2(S)-4-a(S)-(phenylmethyl) prolinate (18) Compounds 8, 17, and 18 were synthesized by our already reported procedures (Dikshit and Panday, 1992). (4) 3-(Acetylthio) propionyl chloride 4 was synthesized using reported procedure (Suh et al, 1985) by condensation of acrylic acid 2a with thioacetic acid 1, and 3-(acetylthio) propionic acid 3a thus obtained was converted to its acid chloride 4 by reaction with oxallyl chloride at room temperature.…”

“…Due to reactivity differences between these two carbonyl groups, Li-enolate-derived alkylations/aldol reactions were performed on native pyroglutamates (Dikshit and Panday, 1992), where C-4 alkylation proceeded with complete stereoselectivity; however, in aldol reactions, 4-a-and 4-b-substituted pyroglutamates were obtained in ratio of 4:1.…”