Synthesis 2006(8): 1386-1389  
DOI: 10.1055/s-2006-926419
© Georg Thieme Verlag Stuttgart · New York

Convenient Multigram Synthesis of (R)-Homopipecolic Acid Methyl Ester

Matthias Breuning*, Melanie Steiner
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
Fax: +49(931)8884755; e-Mail: [email protected];
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Received 10 January 2006
10. April 2006 (online)


(R)-Homopipecolic acid methyl ester has been prepared on a multigram scale from 3,4-dihydro-2H-pyran in five steps and 36% overall yield. The stereochemistry was introduced via an asymmetric Michael addition and a fractional crystallization.


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According to a Beilstein search; for some examples see references 2-7.


In the presence of two equivalents of (S)-4 and no additional base, compound 5 was obtained in a slightly improved yield (86%), but with a decreased diastereomeric ratio (67:33).


The analogous cyclization of the tosyloxy derivative of 3 gave comparable results; nevertheless this route was less efficient - the tosyl derivative was prepared in a lower yield (73% from 2).


For a related cyclization of an ω-iodo enoate, see ref. 2.


Mesylate (E)-3 was synthesized from (E)-2, which was accessible by distillation of (E/Z)-2, see ref. 23.


The crude product can also be purified by distillation (bp 75-85 °C, 0.02 mbar) through a Vigreux column (10 cm). Even though the lower boiling fractions were enriched with the minor diastereomer (S,S)-5, satisfactory separation of the two diastereomers was not achieved.


There is just a short filtration through a pad of silica gel prior to the fractional crystallization.


All fractions boiling below 70 °C/0.1 mbar were discarded; fractions boiling at 71-75 °C/0.1 mbar contained mainly (Z)-2, fractions boiling at 92-96 °C/0.1 mbar provided pure (E)-2.