A practical synthesis of 3(S)-methyl-heptanoic acid from (S)-citronellol

Tetrahedron Asymmetry

Volumn 7, Issue 2, 1996, Pages 435-442

  Breitenbach, Ralph ^a   Chiu, Charles K F ^a   Massett, Stephen S ^a   Meltz, Morgan ^a   Murtiashaw, C William ^a   Pezzullo, Susan L ^a   Staigers, Thomas ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 METHYLHEPTANOIC ACID; ALKANOIC ACID; CARBOXYLIC ACID DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DRUG SYNTHESIS; ENANTIOMER; PRIORITY JOURNAL;

EID: 0030039872     PISSN: 09574166     EISSN: None     Source Type: Journal    
DOI: 10.1016/0957-4166(96)00026-2     Document Type: Article

References (43)

1. Deceased 25th October, 1995.
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21. For syntheses require chiral auxiliaries, see references in 2: (a), (b), (c), (d), (f), (g), (h), (i), (1), (m), (n), (o), (p), (q).
22. For syntheses require organometallic reagents at low temperatures, see references in 2: (a), (c), (e), (h), (n), (o), (p), (q), (r).
23. The commercial naturally derived citronellol is of the (S)-configuration and only ∼60% ee. The optically pure enantiomers are synthetically derived and manufactured by Takasago International Inc. (available in research quantity from Aldrich). For a report of the chemistry, see (a) Tani, K.; Yamagata, T.; Akutagawa, S.; Kumobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S. J. Am. Chem. Soc. 1984, 106, 5208-5217;
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25. (a) At the conclusion of our work, a similar synthesis based on citronellol appeared in the patent literature: Ohno, K.; Hiroshi, N.; Ishikawa, M.; Matsumoto, K.; Nishio, S. U. S. Patent US-4,564,620, 14th Jan., 1986;
26. (b) For a recent synthesis utilizing the chiral 3-methyl group of citronellol, see Kefalas, P.; Ragoussis, N. Synthesis 1995, 644-646.
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30. Enantiomeric excesses were measured by (1) optical rotation, (2) coupling with an optically pure peptide and subsequent high field NMR analysis, and (3) coupling of the acid with D-phenylglycinol followed by HPLC analysis.
31. Our research ozone generator is capable of processing 0.3 mol of substrate in an 8-hour period.
32. 1H-NMR and GC, the epoxide (7) appeared to be a single diastereomer but it was not vigorously verified. Nevertheless, the absolute relative stereochemistry of the epoxide is of no consequence to the synthesis.
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37. The formation of the diol intermediate was observed on tlc as a polar component at the expense of the epoxide, and was subsequently converted to the aldehyde (8).
38. The crude aldehyde (8), although normally of good quality, was purified via its bisulfite addition product. Fieser, L; Fieser, M. Reagents for Organic Synthesis 1967, 1, 1047-1049.
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41. Chiral GC assays (Column: Chiraldex-GTA (Astec), 30 m) were conducted on the methyl ester derivative prepared by heating the 3-methyl-heptanoic acid in methanol with 0.5N HCl at 60°C for 30 min. prior to injection. The GC assays were kindly provided by Mr. D. A. Cole of Analytical R&D, Pfizer Inc. Central Research, Groton.
42. All novel compounds were fully characterized by high field NMR, IR, MS and elemental analysis/high resolution MS.
43. The greater than quantitative yield obtained is due to residual solvent, which is often difficult to remove completely in bulk preparation. Analytical samples were prepared by evacuation under high vacuum to purge residual solvent.