Highly enantioenriched tetrahydropyridines from chiral organosilanes: Application to the synthesis of quinolizidine alkaloid (-)-217A

Article abstract of DOI:10.1021/ja028937i

The tetrahydropyridine and piperidine subunits are widely found in biologically active molecules and natural products. Alhough considerable synthetic efforts have been made to reach these systems, there are few direct methods available for the preparation of enantionenriched tetrahydropyridines. A Lewis acid-promoted intramolecular imine crotylation is described and results in direct access to enantioenriched 2,6-cis- and 2,6-trans-3-trans-trisubstituted tetrahydropyridines with high diastereoselectivity. An example of the application of this methodology was demonstrated in an expedient total synthesis of (-)-quinolizidine 217A. The absolute stereochemistry of this natural product was established by the total synthesis. Copyright

Full text of DOI:10.1021/ja028937i

Published on Web 12/21/2002
Highly Enantioenriched Tetrahydropyridines from Chiral Organosilanes:
Application to the Synthesis of Quinolizidine Alkaloid (-)-217A
Hongbing Huang,† Thomas F. Spande,‡ and James S. Panek*,†
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment,
590 Commonwealth AVenue, Boston UniVersity, Boston, Massachusetts 02215, and the
Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and DigestiVe and
Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Received October 14, 2002 ; E-mail: Panek@chem.bu.edu
Scheme 1
Functionalized tetrahydropyridine and piperidine ring systems
are widely found in biologically active natural products and
pharmaceuticals.1 While considerable progress has been achieved
in the asymmetric synthesis of substituted piperidines,2 there are
few reports concerning the preparation of tetrahydropyridines with
high levels of enantiopurity.3 Vinylsilane-terminated annulation of
iminium ions is a useful approach to the synthesis of nitrogen-
containing heterocycles.4 However, in cases involving the synthesis
of 2,6-substituted tetrahydropyridines, the use of allyl- and vinyl-
silanes as π-nucleophiles shows limitations as a competitive aza-
Cope rearrangement often compromises reaction diastereoselectiv-
ities.3,5
Scheme 2
In this communication we report a highly stereoselective ap-
proach to both 2,6-cis- and 2,6-trans-3-trans-trisubstituted tetrahy-
dropyridines, which relies on a mild intramolecular imine croty-
lation. This reaction is based on previously reported experiments
leading to [4 + 2] dihydropyran annulation and underscores the
important role of a silicon-bearing center as a dominant stereocon-
trol element leading to highly selective annulations (Scheme 1).6
The utility of this methodology was further demonstrated in the
first asymmetric synthesis of quinolizidine alkaloid (-)-217A.
In considering methods to promote this annulation, we were
initially interested in the use of lanthanide triflates due to their
unique reactivity in the presence of water. On the basis of literature
precedent, we hoped that Yb(OTf)3 could activate imines, generated
in situ, and catalyze an intramolecular crotylation to provide
tetrahydropyridines in a one-pot operation.7 Although the reaction
proceeded under mild conditions, the diastereoselectivity of the
reaction was disappointingly low. After several attempts to increase
the reaction diastereoselectivity, we discovered that the vinylglycine-
like moiety embedded in the annulation product was prone to
epimerization. Moreover, syn-1b was unreactive under the same
reaction conditions.8
Treatment of the preformed imine with a Lewis acid at low
temperature provided the desired product with good-to-excellent
diastereoselectivity.9 Among Lewis acids screened, TiCl4 was
identified as the most general and effective in promoting the
annulation (Scheme 2).10 Thus, complexation of the imine with 2.0
equiv of TiCl4 (CH2Cl2, -78 °C) followed by slow warming to
room temperature and then quenching the reaction mixture at -78
°C (saturated aqueous NaHCO3) provided efficient conversion to
the tetrahydropyridines, which were protected as trifluoroacetamides
before chromatography. The protected tetrahydropyridines could
be isolated as single stereoisomers in 90% purified yield (Table
1).
Table 1. Asymmetric Synthesis of 1,2,5,6-Tetrahydropyridines
chiral
silanes
dr
a
entry
R )
products
yield %
C2,C6-cis/transb
1
2
3
4
5
6
7
i-Pr
m-NO2Ph
2-furyl
(trans)PhCHCH
C6H12
4-BrPh
1a
1a
1a
1a
1b
1b
1b
2a
2b
2c
2d
3a
3b
3c
73
90
89
64
78
82
75
1:13
<1:30
1:12
1:9
10:1
>30:1
2-furyl
8:1
a All yields are based on pure materials isolated by chromatography on
SiO2. b Stereochemistry assigned by NOE experiments. Ratios of diaster-
eomers were determined by 1H NMR (400 MHz) on the crude reaction
mixture before TFA protection.
Results from these experiments demonstrate that the relative
configuration of the silane reagent is the dominant stereocontrol
element and dictates the stereochemical course of the annulation.
The reactivity and selectivity may be attributed to the ability of
silyl group to stabilize the emerging carbocation at the â-position.11
These experiments have shown that aromatic aldehydes were
generally more efficient than aliphatic counterparts. Complete
conversion was achieved within 12 h for aromatic aldehydes, while
longer reaction times were required for aliphatic aldehydes. Both
cis- and trans-2,6-trisubstituted tetrahydropyridines can be prepared
with high diastereoselectivity. More importantly, the annulation
proceeded with complete transfer of chirality from the chiral silane
reagents to the pyridine products. For instance, starting from
enantioenriched chiral silanes (95% ee), tetrahydropyridines were
obtained with high enantiopurity (95 ( 1% ee) for all substrates
studied.12
As an added dimension, the reaction products can be efficiently
converted to isomeric 1,4,5,6-tetrahydropyridines by treating the
† Boston University.
‡ National Institutes of Health.
9
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10.1021/ja028937i CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
column.15 The most highly retained enantiomer coeluted with natural
217A. Assignment of absolute stereochemistry of synthetic (-)-
217A was confirmed when the synthetic material coeluted with the
isolated natural product.17 Thus, it was established that the natural
217A has the same configuration as synthetic (-) - 217A.
In summary, we have described an enantioselective [4 + 2]
annulation, which leads to the assembly of functionalized trisub-
stituted tetrahydropyridines. The methodology has been used as a
key step in a stereocontrolled synthesis of quinolizidine 217A.
Further development and application of this process will be reported
in due course.
Scheme 3. Asymmetric Synthesis of 1,4,5,6-Tetrahydropyridines
Scheme 4 a
Acknowledgment. The work was supported by NIH Grants
CA56304 and P50 GM067041. J.S.P. is grateful to Johnson &
Johnson for a focused giving award. We thank Professor William
Pearson (U. of Michigan) for kindly providing a sample of synthetic
racemic 217A.
Supporting Information Available: General experimental proce-
dures including spectroscopic and analytical data (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Pinder, A. R. Nat. Prod. Rep. 1992, 9, 491-504 and earlier reviews
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over 1200 piperidine entities were in clinical and preclinical research in
a recent 10-year period: Watson, P. S.; Jiang, B.; Scott, B. Org. Lett.
2000, 2, 3679-3681.
a Reaction conditions: (a) i. MgSO4, CH2Cl2; ii. TiCl4, CH2Cl2; iii.
CbzCl, Na2CO3, CH2Cl2, 60% (three steps). b) i. H2, PtO2, MeOH; ii. H2,
Pd/C, K2CO3, MeOH, 90% (two steps). (c) CBr4, NEt3, PPh3, CH2Cl2, rt,
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As an application of this methodology, a concise enantioselective
route to quinolizidine alkaloids has been developed. Using this
approach, quinolizidine ring system (and presumably indolizidine)
can be obtained in enantioenriched form from 1,2,5,6-tetrahydro-
pyridines. While the structures of the inferior homologs 1,9-
disubstituted quinolizadines are well-known, the 1,4-disubstituted
quinolizidines are a relatively new class of alkloids isolated from
amphibians.13 Due to their limited availability from natural sources,
the structure elucidation of this alkaloid class was primarily based
on GC-FTIR and GC-MS analysis. Quinolizidine 217A, isolated
from the Madagascan frog Mantella baroni, is the only 1,4-
disubstituted quinolizidine that has been isolated in sufficient
quantities to allow structure elucidation by 1H NMR spectroscopy.14
To date, a racemic synthesis from the Pearson group has confirmed
the relative stereochemistry.15 To resolve the absolute configuration,
an asymmetric synthesis of quinolizidine 217A was initiated by
reaction of silane 1c and aldehyde 5 to provide Cbz-protected
tetrahydropyridine 6 in 60% yield as a single diastereomer. A short
sequence of functional group conversions (6 f 9) afforded the
intermediate enol-ether, which after conversion to the aldehyde
was subjected to Yamamoto’s olefination to provide enyne 10 in
70-80% yield (Z/E, 5:1).16 Deprotection of the terminal alkyne
provided quinolizidine 217A in quantitative yield (Scheme 4). The
spectroscopic data are in full agreement with those published for
the natural product.14,15 Earlier work has shown synthetic racemic
217A can be resolved into two enantiomers by a chiral GC
(5) Daub, G. W.; Heerding, D. A.; Overman, L. E. Tetrahedron 1988, 44,
3919-3930. Depending on the way iminium ions were generated, partial
racemization was also observed.
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(7) Lanthanide triflate has been used to catalyze the additions of in situ
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(9) Imines are readily prepared as single isomer in quantitative yield by the
condensation of silanes 1 with a variety of aldehydes in the presence of
MgSO4 (CH2Cl2, rt, 0.5 h).
(10) Among Lewis acids that were evaluated, SnCl4, ZnI2, ZrCl4, HfCl4, and
BF3‚Et2O either gave low conversion or were less general in terms of
aldehydes employed.
(11) Lambert, J. B. Tetrahedron 1990, 46, 2677-2689.
(12) Enantiomeric excess (ee) analysis was conducted by chiral HPLC analysis.
The detailed experimental procedure including ee analysis can be found
in the Supporting Information.
(13) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon: New York, 1999;
Vol. 13. Chapter 1, pp 1-161.
(14) (a) Garrafo, H. M. Caceres, J.; Daly, J. W.; Spande, T. F.; Andriamaharavo,
N. R.; Andriantsiferana, M. J. Nat. Prod. 1993, 56, 1016-1038. (b) Jain,
P.; Garrafo, H. M. Yeh, H. J. C.; Spande, T. F.; Daly, J. W.;
Andriamaharavo, N. R.; Andriantsiferana, M. J. Nat. Prod. 1996, 59,
1174-1178. The absolute configuration and optical rotation of 217A are
unknown.
(15) Pearson, W. H.; Suga, H. J. Org. Chem. 1998, 63, 9910-9918.
(16) (a) Yamakado, Y.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Am. Chem.
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(17) See Supporting Information for details.
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