UPS on Weinreb resin: A facile solid-phase route to aldehyde and ketone derivatives of "unnatural" amino acids and peptides

Journal of Combinatorial Chemistry

Volumn 2, Issue 2, 2000, Pages 172-181

  O'Donnell, Martin J ^a   Drew, Mark D ^a,c   Pottorf, Richard S ^a,d   Scott, William L ^b  

^a INDIANA UNIVERSITY   (United States)

^b ELI LILLY AND COMPANY   (United States)

^c ARRAY BIOPHARMA INC   (United States)

^d Provid Research   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALDEHYDE; AMINO ACID; CROSS LINKING REAGENT; DYES, REAGENTS, INDICATORS, MARKERS AND BUFFERS; KETONE; PEPTIDE; PEPTIDE LIBRARY;

ACYLATION; ALKYLATION; ARTICLE; CHEMISTRY; SYNTHESIS;

ACYLATION; ALDEHYDES; ALKYLATION; AMINO ACIDS; CROSS-LINKING REAGENTS; INDICATORS AND REAGENTS; KETONES; PEPTIDE LIBRARY; PEPTIDES;

EID: 0034154193     PISSN: 15204766     EISSN: None     Source Type: Journal    
DOI: 10.1021/cc990071y     Document Type: Article

References (101)

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42. Recent solution-phase syntheses via Weinreb amide substrates to prepare amino aldehydes (c, d, e, f), amino ketones (b, h, i, j), peptide aldehydes (a, g), or peptide ketones (i): (a) Billson, J.; Clark, J.; Conway, S. P.; Hart, T.; Johnson, T.; Langston, S. P.; Ramjee, M.; Quibell, M.; Scott, R. K. The Design and Synthesis of Inhibitors of the Cysteinyl Protease DER P I. Bioorg. Med. Chem. Lett. 1998, 8, 993-998.
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71. (c) O'Donnell, M. J.; Lugar, C. W.; Pottorf, R. S.; Zhou, C.; Scott, W. L.; Cwi, C. L. Solid-Phase Synthesis of Unnatural Amino Acids using Unactivated Alkyl Halides. Tetrahedron Lett. 1997, 38, 7163-7166.
72. (d) Griffith, D. L.; O'Donnell, M. J.; Pottorf, R. S.; Scott, W. L.; Porco, J. A., Jr. Tandem UPS: Sequential Mono- and Dialkylation of Resin-Bound Glycine via Automated Synthesis. Tetrahedron Lett. 1997, 38, 8821-8824.
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74. (f) O'Donnell, M. J.; Delgado, F.; Pottorf, R. S. Enantioselective Solid-Phase Synthesis of α-Amino Acid Derivatives. Tetrahedron 1999, 55, 6347-6362.
75. (g) O'Donnell, M. J.; Delgado, F.; Drew, M. D.; Pottorf, R. S.; Zhou, C.; Scott, W. L. Solid-Phase Synthesis of Unnatural α-Amino Acid Derivatives using a Resin-Bound Glycine Cation Equivalent. Tetrahedron Lett. 1999, 40, 5831-5834.
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81. (e) Dörner, B.; Steinauer, R.; White, P. Solid-Phase Organic Chemistry: Linkers and Functionalized Solid Supports. Chimia 1999, 53, 11 -17.
82. (f) Booth, R. J.; Hodges, J. C. Solid-Supported Reagent Strategies for Rapid Purification of Combinatorial Synthesis Products. Acc. Chem. Res. 1999, 32, 18-26.
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92. (g) Terrent, N. K. Combinatorial Chemistry; Oxford University Press: Oxford, 1998.
93. (h) Bunin, B. A.; Dener, J. M.; Livingston, D. A. Application of Combinatorial and Parallel Synthesis to Medicinal Chemistry. In Annual Reports in Medicinal Chemistry, Vol. 34; Doherty, A. M., Trainor, G. L., Eds.; Academic Press: San Diego, CA, 1999; pp 267-286.
94. BEMP = 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine; BTPP = tert-butylimino-tri(pyrrolidino)-phosphorane.
95. 3CN is 28.4 while in DMSO it has been estimated to be 17.0. See, O'Donnell, M. J.; Delgado, F.; Hostettler, C.; Schwesinger, R. An Efficient Homogeneous Catalytic Enantioselective Synthesis of α-Amino Acid Derivatives. Tetrahedron Lett. 1998, 39, 8775-8778.
96. Compound 12h was obtained in low yield and as a mixture of products when methyllithium was used in place of methylmagnesium chloride.
97. In cases where UPS alkylations are conducted at sites remote to the Weinreb link, normal solid-phase methodology permits introduction of chiral, nonracemic residues at the C-terminal position. The postcleavage lability of this stereocenter is well established (see references 7a and 7b).
98. Phenylalanine for the control was determined by subjecting the starting material benzophenone imine of Gly-Ala-Phe-Wang resin to imine hydrolysis, cleavage from the resin, and then tripeptide hydrolysis to give Phe of 97% ee (L/D = 98.5/1.5). The amounts of L-Phe and D-Phe were determined after the alkylations in the same manner as that for the control. The results were as follows: 2 equiv of BEMP and 4-methylbenzyl bromide, 97% ee (L/D = 98.5/1.5); 2 equiv of BTPP and 4-methylbenzyl bromide, 96% ee (L/D = 98/2); 10 equiv of BEMP and ethyl iodide, 93% ee (L/D = 96.5/3.5); 10 equiv of BTPP and ethyl iodide, 84% ee (L/D = 92/8).
99. 2 is 34-35. See: Bordwell, F. G.; Fried, H. E. Acidities of the H-C Protons in Carboxylic Esters, Amides, and Nitriles. J. Org. Chem. 1981, 46, 4327-4331.
100. To demonstrate that BEMP is as effective as BTPP in normal UPS alkylations of Weinreb resin-bound peptides, starting material 13 was alkylated using standard conditions with EtI and BEMP to give product 15a in quantitative yield (88% HPLC purity). By comparison, the same reaction using BTPP as base gave a 95% yield (91% HPLC purity) of product 15a.
101. This apparatus is described in: Scott, W. L.; Schonegg, R. A.; Cwi, C. L. Vessel Handling System Useful for Combinatorial Chemistry. U.S. Patent 5,785,927, 1998.