Syntheses of (-)-pelletierine and (-)-homopipecolic acid

Article abstract of DOI:10.1039/c2ob06984a

Enantiomeric syntheses of (-)-homopipecolic acid and (-)-pelletierine have been achieved by chiral resolution of tropanol followed by Baeyer-Villiger oxidation. The methodology provides a practical route for the synthesis of optically pure piperidines. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob06984a

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COMMUNICATION
Syntheses of (−)-pelletierine and (−)-homopipecolic acid†
Wen-Hua Chiou,* Guei-Tang Chen, Chien-Lun Kao and Yu-Kai Gao
Received 25th November 2011, Accepted 27th January 2012
DOI: 10.1039/c2ob06984a
Enantiomeric syntheses of (−)-homopipecolic acid and
(−)-pelletierine have been achieved by chiral resolution of
tropanol followed by Baeyer–Villiger oxidation. The methodo-
logy provides a practical route for the synthesis of optically
pure piperidines.
Substituted piperidine systems are often found in many natural
alkaloids and medicinal compounds with potent biological
activities.1 Enantiopure functionalized piperidines have attracted
much attention from synthetic chemists, resulting in abundant
approaches to their synthesis.2 In recent years, various strategies
for introduction of chirality in piperidines have been developed,
briefly described as follows: (1) Enzymatic resolutions.3 (2)
Organocatalyst-mediated reactions such as aza-1,4-addition,4
aza-Henry reaction,5 aminooxylation,6 addition with lithiopiperi-
dine7 or lithiated N-BOC allylamine derivatives.8 (3) Readily
available chiral amines as nitrogen sources, including phenyl-
Scheme 1 Synthesis of tropanol 2.
ethylamine,9 Betti base,10 phenylglycinol,11 sulfinamide,12
naphthyl-ethylamine,13 SAMP/RAMP hydrazones,14 and
ROPHy/SOPHy oxime ethers.15 (4) Chiral auxiliaries as tem-
plates, including Evans’ oxazolidinone for asymmetric azida-
tion16 and Brown’s IPC-borane for asymmetric allylation.17 (5)
Asymmetric transition-metal catalyzed reactions, e.g. Sharpless
epoxidation,18 ring-opening olefin metathesis,19 Ti-mediated
allylation,20 intramolecular hydroamination,21 hydrogenation of
aromatics,22 aza-Diels–Alder reaction,23 cycloisomerization of
homopropargylic amines.24 (6) Chiral pool derived routes.25
Here, we report enantiomeric syntheses of (R)-homopipecolic
acid and (R)-pelletierine, from optically active 6-tropanol, easily
prepared by Robinson annulation followed by resolution with
(L)-tartaric acid.
aldehyde solution was combined with allylamine, acetone dicar-
boxylic acid in an acetate buffer solution at pH 5.0 overnight to
afford alcohol 1a in 46% yield accompanied by a side product in
15% yield, identified as methyl ether 1b. The formation of
methyl ether 1b could be attributed to the occurrence of
methoxy migration during the hydrolysis. Protonation of 2,5-
dimethoxydihydrofuran followed by loss of a methanol produced
a cation species I as an intermediate for annulation to form
alcohol 1a. However, the methoxy group migration brought the
formation of cation II which was the precursor for the further
reaction to yield methyl ether 1b (Scheme 1). Treatment of tropa-
none derivative 1a, with hydrazine and KOH at an elevated
temperature reduced the ketone group to a methylene group and
removed the allyl group simultaneously, affording 6-tropanol (2)
in 82% yield.
Enantiomerically pure 6-tropanol (2) was achieved by chiral
resolution using (+)-tartaric acid as a resolving agent. Mixing of
racemic 6-tropanol (2) with equal molar amount of (+)-tartaric
acid produced tartrate salts which could be recrystallized in
methanol to afford chirally pure salts as single crystals. The
crystal structure has been elucidated clearly by X-ray crystallo-
graphic analysis as (1R,5S,6R)-tropanol with (+)-tartaric acid
(Fig. 1).
Our synthesis commenced with the preparation of tropanone
derivative 1a, readily available by a modified Robinson tropa-
none synthesis.19 Acidic hydrolysis of commercially available
2,5-dimethoxydihydrofuran in a hydrochloric acid solution at
room temperature gave 2-hydroxybutanedial. The resulting
Department of Chemistry, National Chung Hsing University, Taichung,
Taiwan 402, R.O.C. E-mail: wchiou@dragon.nchu.edu.tw; Fax: +886-4
22862547; Tel: +886-4-22840411-420
†Electronic supplementary information (ESI) available: Experimental
1
procedure, all H, 13C NMR spectra and assignment for all compounds,
and HPLC chromatograms of (+)-3, (+)-6 and (+)-9, and crystallographic
data of (+)-2-tartrate salt in CIF format. CCDC 855622. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ob06984a
After removal of tartaric acid with a basic solution, optically
pure tropanol (+)-2 was reacted with CbzCl in the presence
K2CO3 in THF to give carbamate (+)-3 in 99% yield with 98.4%
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propylene oxide to remove excess hydrogen chloride, giving (R)-
homopipecolic acid (7) in 93% yield. The specific rotation value
of (−)-7, [α]2D5 −24.0° (c: 0.4, H2O) was consistent with the
reported value,9a [α]D25 −23.4° (c: 0.4, H2O) (Scheme 2).
Subsequent transformations to (R)-pelletierine were straight-
forward (Scheme 3): acid (+)-6 was coupled with methoxy-
methylamine using EDC–HOBt activation protocol, yielding
Weinreb amide (+)-8 in 88% yield. Addition of 3.5 equivalents
of MeMgBr in THF at 0 °C yielded Cbz-protected pelletierine
(+)-9 in 86% yield as a colorless oil: [α]2D5 + 12.0° (c: 2.5,
CHCl3) (96.1% ee, (+)-9 tR 10.5 min; (−)-9 tR 11.7 min), (lit.28
[α]2D5 + 10.2° (c: 2.5, CHCl3). Exposure of N-protected pelletier-
ine (+)-9 in a hydrogen atmosphere to palladium on carbon in
ethyl acetate produced free pelletierine (−)-10 in 91% yield. The
specific rotation value of (−)-10, [α]2D5 −19.6° (c: 0.7, EtOH)
was also consistent with the reported value, [α]2D5 −22.1° (c: 4.1,
EtOH).29
Fig. 1 ORTEP drawing of (R,R)-tartrate salt of tropanol (+)-2.
In conclusion, enantiomeric syntheses of (R)-homopipecolic
acids and (R)-pelletierine have been achieved from (+)-6-tropa-
nol, available from Robinson annulation and followed by resol-
ution with (+)-tartaric acid. Baeyer–Villiger oxidation of 6-
tropanone (+)-4 provided lactone (−)-5 as a key intermediate.
The enantiomeric excess values of N-Cbz homopipecolic acid
(+)-6 and N-Cbz pelletierine (+)-9 have been confirmed by chiral
HPLC analysis, as well as their specific rotation values. Sub-
sequent extension of this methodology towards other natural pro-
ducts of interest is currently underway.
Scheme 2 Synthesis of (R)-homopipecolic acid (−)-7.
Acknowledgements
The authors thank the National Science Council, Taiwan
(NSC98-2119-M-005-002-MY3) and the Instrument Center of
National Chung Hsing University for support of this research.
References
Scheme 3 Synthesis of (R)-pelletierine (−)-10.
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