Solid-phase synthesis of unnatural amino acids using unactivated alkyl halides

Tetrahedron Letters

Volumn 38, Issue 41, 1997, Pages 7163-7166

  O'Donnell, Martin J ^a   Lugar, Charles W ^a,b   Pottorf, Richard S ^a   Zhou, Changyou ^a,c   Scott, William L ^b   Cwi, Cynthia L ^b  

^a INDIANA UNIVERSITY   (United States)

^b ELI LILLY AND COMPANY   (United States)

^c MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID DERIVATIVE;

ALKYLATION; AMINO ACID SYNTHESIS; ARTICLE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IN VITRO STUDY; MASS SPECTROMETRY; REACTION ANALYSIS;

EID: 0030658103     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(97)01762-0     Document Type: Article

References (12)

1. O'Donnell, M. J.; Zhou, C.; Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070-6072.
2. (a) For background and lead references concerning substitution and elimination reactions, see: March, J., "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," Fourth Edition, John Wiley & Sons, New York, 1992, Chapters 10 and 17.
3. N2 reactions: Dewar, M. J. S.; Yuan, Y.-C. J. Am. Chem. Soc. 1990, 112, 2095-2105.
4. 2 and dried in vacuo at 45°C to afford 22.6 g (0.56 mmol/g.) This resin was stored in an amber glass vial under nitrogen.
5. Initial studies (reference 2) for formation of benzophenone imines of resin-bound amines used 1.5 equiv of benzophenone imine (Merrifield resin) or 1.5 equiv of benzophenone imine and 1.3 equiv of HOAc (Wang resin). We have found the use of the larger excess of reagents guarantees complete conversion to the imine.
6. 3CN (B) with a gradient of 0 - 80 % B in 20 min at a flow rate of 1 mL/min with detection at 220 nm.
7. For lead references concerning phase-transfer alkylations, see: Phase-Transfer Catalysis, Mechanisms and Synthesis, ACS Symposium Series: 659, Halpern, M., Ed., American Chemical Society: Washington, D.C., 1997.
8. 4NI did not improve yields significantly.
9. 4 gave 10% 3 and 59% 4 while MeOTf resulted in 57% 3 and a trace of product 4 together with several impurities.
10. For comparison, alkylation with n-octyl iodide (10 equiv) and BEMP (2 equiv) resulted in complete conversion (0% 3, 90% 4). In contrast, with phenethyl bromide the same amounts of alkyl halide (10 equiv) and BEMP (2 equiv) gave incomplete conversion of starting material and several impurities (7% 3, 57% 4). In the latter case, the base (2 equiv) is likely used up in an elimination reaction with the phenethyl bromide before complete deprotonation of the substrate 1 has occurred.
11. When the alkyl halides, cyclohexyl iodide and 2-iodopropane, were prepared by an in situ Finkelstein reaction on the corresponding bromides yields were lower.
12. For the solid-phase synthesis of α,α-disubstituted unnatural amino acids and peptides (di-UPS), see: Scott, W. L.; Zhou, C.; Fang, Z.; O'Donnell, M. J. Tetrahedron Lett., 1997, 38, 3695-3698.