The solid phase synthesis of α,α-disubstituted unnatural amino acids and peptides (di-UPS)

Tetrahedron Letters

Volumn 38, Issue 21, 1997, Pages 3695-3698

  Scott, William L ^a   Zhou, Changyou ^b,c   Fang, Zhiqiang ^b   O'Donnell, Martin J ^b  

^a ELI LILLY AND COMPANY   (United States)

^b INDIANA UNIVERSITY   (United States)

^c MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID SYNTHESIS; ARTICLE; CHIRALITY; IN VITRO STUDY; METHODOLOGY; PEPTIDE SYNTHESIS; REACTION ANALYSIS; STEREOCHEMISTRY;

EID: 0030987839     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(97)00715-6     Document Type: Article

References (53)

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8. Recent studies involving the preparation of α,α-disubstituted α-amino acids: (a) Es-Sayed, M.; Devine, P.; Burgess, L. E.; de Meijere, A.; Meyers, A. I. Chem. Commun. 1995, 141-142;
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38. Fmoc-AA-Wang resins (100-200 mesh, 0.4-0.9 mmol/g) were used as starting materials. Reaction conditions (all at ambient temperature) for 3 to 7 were as follows: a) 3,4-dichlorobenzaldehyde (15 equiv), trimethyl orthoformate (TMOF)/1-methyl-2-pyrrolidinone (NMP) (2:1), 12-15h;
39. 2X (3.0 eq.)/NMP, 12-15 h;
40. 2·HCI/THF (1:2), then diisopropylethyl amine (DIEA)/NMP;
41. 2O, 3 h. Yields are for the unpurified products. Product purity was determined by HPLC using a Vydac Protein and Peptide C18 column (150 x 4.6 mm) with mobile phases consisting of 0.1% (v/v) TFA in water (Solvent A) and 0.085% (v/v) TFA in acetonitrile (Solvent B), a flow rate of 1 mL/min., and a linear gradient from 0-80% solvent B over 20 min. Peaks were detected at 214 nm. Identity was confirmed by LC/MS, and selected products further characterized by HRMS.
42. Early solution-phase studies involving the preparation of α,α-dialkylamino acids by phase-transfer catalyzed (PTC) alkylation of aldimine esters involved use of the 4-chlorobenzaldehyde Schiff bases rather than benzaldehyde imines because the former were often crystalline solids (reference a) and were approximately an order of magnitude more acidic than the latter (reference b). More recently, these aldimine esters have also been used in the catalytic, enantioselective PTC alkylation reactions (reference c). (a) O'Donnell, M. J.; LeClef, B.; Rusterholz, D. B.; Ghosez, L.; Antoine, J. P.; Navarro, M. Tetrahedron Lett 1982, 23, 4259-4262.
43. (b) O'Donnell, M. J.; Bennett, W. D.; Binder, W. A.; Jacobsen, W. N.; Knuth, K.; LeClef, B.; Polt, R. L.; Bordwell, F. G.; Mrozack, S. R.; Cripe, T. A. J. Am. Chem. Soc. 1988, 110, 8520-5.
44. (c) O'Donnell, M. J.; Wu, S. Tetrahedron: Asymmetry 1992, 3, 591-594.
45. (a) For preparation of resin-bound aldimines, see: Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144-154.
46. (b) Asymmetric monoalkylation of a Schiff base ester attached to a resin with pendant chirality has been reported. The substrate is bound to the resin by the imine bond and the reaction is conducted under anhydrous conditions (LDA, THF, -78 °C.). See: Calmes, M; Daunis, J.; Ismaili, H.; Jacquier, R.; Koudou, J.; Nkusi, G.; Zouanate, A. Tetrahedron, 1990, 46, 6021-6032.
47. A simple apparatus is used for manually conducting 24 parallel solid-phase reaction sequences. Reactions are done in fritted glass vials, on a 50-100 umolar scale, typically using 50-100 mg. of resin. The apparatus keeps the 24 separate reactions conveniently arranged for all the steps. It also allows easy cleavage and collection of products in 24 tared vials.
48. 2tBu) provides an interesting example of unique structures available by di-UPS. After alkylation and cleavage, the aspartate side chain spontaneously closed to form the succinimide derivatives 10 and 11 as two separable diastereomers. Products 10 and 11 were separated by preparative HPLC. FORMULA PRESENTED The overall purified yield from starting Fmoc-Phe-Wang resin to the 60:40 mixture of diastereomers was 43% (crude yield = 65%). To verify minimal epimerization during the di-UPS sequence the optical purity of the more readily epimerized Phe residue was determined. Starting material, crude product, and the individual diastereomers were subjected to amino acid hydrolysis conditions and analyzed for optical purity. All three samples gave identical ee's within experimental error (Footnote 11).
49. 2O at ambient temperature gave 96% ee (L/D = 98/2). Phenylalanine from hydrolysis of crude tetrapeptides (13 and 14): 94% ee (L/D = 97/3) and from the purified diastereomeric mixture: 95% ee (L/D = 97.5/2.5).
50. A separate investigation showed that the desired monoalkylated product from Arg(Tos) was obtained in high purity by using shorter reaction times (< 8 h) and less base (BEMP ≤ 1.2 equiv).
51. In contrast to Ser(OtBu), no desired product was obtained starting from Cys(Trt), possibly due to elimination of tritylthiol anion from the corresponding Schiff base enolate.
52. Reaction conditions for 8 to 9: after deprotection (20% piperidine/NMP/30 min) the reaction conditions and analyses were identical to those described in footnote 6.
53. 2)Phe, Met(O) or phenylglycine were introduced as the N-terminal residues of 8, di-UPS again gave the desired α,α-dialkylated products 9 in good yield and purity.