Asymmetric synthesis of erythro- and threo-2-(1-hydroxyalkyl)piperidines via iodocyclocarbamation of 1-acyl-2-alkenyl-1,2,3,6-tetrahydropyridines

Article abstract of DOI:10.1016/S0040-4039(00)00298-7

An iodocyclocarbamation procedure has been developed for the stereoselective preparation of erythro- and threo-2-(1- hydroxyalkyl)piperidines. This methodology was utilized in the asymmetric synthesis of two piperidine alkaloids, (+)-α-conhydrine and (+)-β- conhydrine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00298-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2839–2842
Asymmetric synthesis of erythro- and
threo-2-(1-hydroxyalkyl)piperidines via iodocyclocarbamation
of 1-acyl-2-alkenyl-1,2,3,6-tetrahydropyridines
Daniel L. Comins ∗ and Alfred L. Williams
Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA
Received 14 January 2000; revised 10 February 2000; accepted 11 February 2000
Abstract
An iodocyclocarbamation procedure has been developed for the stereoselective preparation of erythro- and
threo-2-(1-hydroxyalkyl)piperidines. This methodology was utilized in the asymmetric synthesis of two piperidine
alkaloids, (+)-α-conhydrine and (+)-β-conhydrine. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; pyridinium salts; dihydropyridones; alkaloids; iodocyclocarbamation.
Biologically active alkaloids containing a 2-(1-hydroxyalkyl)piperidine unit 1 are abundant in nature.1
The indolizidine alkaloids castanospermine 2, slaframine 3, and swainsonine 4 fall into this category and
have attracted considerable attention from the synthetic community due to their antiviral and antitumor
activities.2 As part of a program directed at exploring the scope of N-acyldihydropyridones as chiral
building blocks,3 strategies for the stereocontrolled preparation of substituted piperidines of the type
1 were investigated. For initial development of an appropriate methodology, the well-characterized
piperidine alkaloids β-conhydrine 5 and α-conhydrine 6 were chosen as targets.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00298-7
tetl 16578

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The iodocyclocarbamation reaction4 was investigated as a method to regio- and stereoselectively
introduce the required oxygen–carbon bond on the C-2 side chain of an appropriate piperidine derivative.
To examine the feasibility of this approach, a racemic substrate was prepared (Scheme 1).
Scheme 1.
The Grignard reagent prepared from cis-bromopropene was added to 4-methoxypyridine and benzyl
chloroformate in THF at −78°C to provide dihydropyridone 7 in high yield.5 Conjugate reduction with
L-Selectride (1 equiv., THF, −78°C, 1 h) gave piperidinone 8, which was subjected to conditions for
iodocyclocarbamation. Anhydrous iodine (1.5 equiv.) and lithium carbonate (5 equiv.) were added to 8
in acetonitrile (0°C, 7 h). After workup and purification, the cyclic carbamate 9 was isolated as a white
solid in 79% yield. The relative stereochemistry of 9 was confirmed by single crystal X-ray analysis.
The relative stereochemistry obtained in the formation of 9 corresponds to that required for β-
conhydrine 5. Based on these results, an asymmetric synthesis of 5 was accomplished as shown in
Scheme 2. A THF solution of cis-propenylmagnesium bromide was added to a mixture of 4-methoxy-
3-(triisopropylsilyl)pyridine6 and the chloroformate of (+)-TCC7 to give N-acyldihydropyridone 10 in
78% yield. Analysis of the crude product revealed that the reaction proceeded in 91% de. One-pot
removal of the chiral auxiliary and TIPS group gave enantiopure dihydropyridone 11 in 80% yield
along with 94% recovery of the chiral auxiliary, (+)-TCC. Treatment of 11 with n-BuLi and benzyl
chloroformate provided the intermediate 12. Conjugate reduction of 12 with L-Selectride followed
by addition of N-(5-chloro-2-pyridyl)triflimide8 afforded vinyl triflate 13, which was subjected to the

2841
iodocyclocabamation reaction conditions used in the preparation of 9. The crude reaction product (≥97%
de) was purified by radial PLC (SiO2, EtOAc/hexanes) to give a 70% yield of cyclic carbamate (+)-14.
Catalytic hydrogenation in the presence of PtO2 reduced 14 to oxazolidinone 15 in 75% yield. Hydrolysis
28
of 15 with KOH afforded a 75% yield of (+)-β-conhydrine 5 ([α] +8.0 (c 0.85, EtOH); lit.9 [α]20 +8.6
D
D
(c 1.0, EtOH)). The 1H and 13C NMR data of 5 were in agreement with literature values.10,11
Scheme 2.
A route to α-conhydrine 6 from the antipode of (+)-14 was investigated. The absolute stereochemistry
at the C-2 stereocenter of α-conhydrine is opposite to that found in β-conhydrine, so (−)-TCC was used
to prepare (−)-14. In order for (−)-14 to be converted to α-conhydrine, the stereocenter at C-1 needed
to be inverted. We were successful in finding a concise solution to this problem as shown in Scheme 3.
Dehydrohalogenation of 14 was carried out with DBU in THF to afford a 99% yield of enol carbamate 16.
Catalytic hydrogenation of 16 occurs from the convex face (22:1) to give the desired oxazolidinone 17,10
28
20
which was hydrolyzed with base to afford (+)-α-conhydrine 6 ([α] + 9.0 (c 0.85, EtOH); lit.10 [α]
D
D
+ 8.9 (EtOH)). Our synthetic material exhibited spectral data in agreement with literature values.12,13
Scheme 3.
In conclusion, a synthetic route has been developed for the preparation of both erythro- and threo-
2-(1-hydroxyalkyl)piperidine derivatives. This methodology was applied to the asymmetric synthe-

2842
sis of (+)-α-conhydrine and (+)-β-conhydrine in overall yields of 18 and 17%, respectively.14 The
strategy should be amenable to the enantioselective synthesis of other alkaloids containing the 2-(1-
hydroxyalkyl)piperidine subunit.
Acknowledgements
We express appreciation to the National Institutes of Health (Grant GM 34442) for financial support
of this research. A.W. also thanks the NIH for a Minority Graduate Research Assistantship. NMR and
mass spectra were obtained at NCSU instrumentation laboratories, which were established by grants from
the North Carolina Biotechnology Center and the National Science Foundation (Grants CHE-9121380,
CH-9509532).
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11. (+)-β-Conhydrine 5: 1H NMR (300 MHz, CDCl3) δ 3.24–3.18 (dt, 1H, J=3.4, 7.9 Hz), 3.08 (d, 1H, J=12.0 Hz), 2.64–2.55
(dt, 1H, J=2.8, 11.9 Hz), 2.41–2.34 (m, 1H), 1.81–1.12 (m, 10H), 0.98 (t, 3H, J=7.4 Hz); 13C NMR (75 MHz, CDCl3) δ
75.4, 61.1, 46.6, 29.1, 26.4, 24.5, 10.2.
12. Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109, and references cited therein.
13. (+)-α-Conhydrine 6: 1H NMR (300 MHz, CDCl3) δ 3.75–3.60 (m, 2H), 3.50 (br s, 1H), 2.03 (br s, 1H), 1.55–1.05 (m, 9H),
0.92–0.85 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 70.5, 54.5, 44.0, 26.9, 25.8, 24.3, 10.5.
14. The structure assigned to each new compound is in accord with its IR and 1H and 13C NMR spectra and elemental analysis
or high-resolution mass spectra.