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

Abstract

(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.

Key words

piperidines - stereoselective synthesis - β-amino ester - Michael additions - fractional crystallization

References

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1

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

16

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).

17

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).

18

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

20

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

21

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.

22

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

23

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.