A [3+3] annelation approach to tetrahydropyridines

Article abstract of DOI:10.1021/ol0610789

A stepwise [3+3] annelation sequence to tetrahydropyridines via addition of the Buchi Grignard to aziridines has been developed. These intermediates can be further functionalized with good regio- and stereocontrol and this methodology has been employed in

Full text of DOI:10.1021/ol0610789

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3089-3091
A [3+3] Annelation Approach to
Tetrahydropyridines
Lisa C. Pattenden,† Robert A. J. Wybrow,† Stephen A. Smith,‡ and
Joseph P. A. Harrity*,†
Department of Chemistry, UniVersity of Sheffield, Brook Hill, Sheffield S3 7HF, United
Kingdom, and GlaxoSmithKline Research and DeVelopment, Gunnels Wood Road,
SteVenage, Hertfordshire, SG1 2NY, United Kingdom
j.harrity@sheffield.ac.uk
Received May 3, 2006
ABSTRACT
A stepwise [3
intermediates can be further functionalized with good regio- and stereocontrol and this methodology has been employed in the stereoselective
formal synthesis of ( )-dihydropinidine.
+3] annelation sequence to tetrahydropyridines via addition of the Bu1chi Grignard to aziridines has been developed. These
−
Recent work in our labs has focused on exploiting aziridines
in the stereoselective synthesis of functionalized piperidines
through a [3+3] annelation strategy.1,2 Initial studies centered
on the employment of Trost’s conjunctive reagent in tandem
with a Pd catalyst to deliver a series of enantiopure
2-alkylpiperidines with an exomethylene moiety at C-5.
Additionally, we have also discovered that an allylmagne-
sium based reagent can be used to deliver similar compounds,
generally with greater efficiency. While TMM-based reagents
2 and 3 (Figure 1) have participated in addition to a broad
range of aziridines, the exomethylene unit limited us
somewhat to a single point of functionalization on the
piperidine ring. Accordingly, we anticipated that synthon 4
would allow us to construct piperidines by a similar strategy,
while providing the opportunity to deliver greater function-
alization around the heterocycle. In this context, elegant
studies by Craig and co-workers have shown that a sulfone-
based three-carbon homologating agent can be used to
achieve this goal.3 We report herein that the addition of
propionaldehyde homoenolate equivalent 54 to aziridines
represents a simple and practical alternative to these meth-
ods.5 Furthermore, we demonstrate the employment of this
methodology in target synthesis by the preparation of a
representative cis 2,6-disubstituted piperidine alkaloid.
Pioneering studies by Bu¨chi showed that 1,3-dioxolane
based reagent 6 represented a competent propionaldehyde
homoenolate equivalent, although it was found to decompose
† University of Sheffield.
‡ GlaxoSmithKline.
(1) (a) Hedley, S. J.; Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.;
Harrity, J. P. A. Synlett 2001, 1596. (b) Hedley, S. J.; Moran, W. J.; Price,
D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286. (c) Moran, W. J.;
Goodenough, K. M.; Raubo, P.; Harrity, J. P. A. Org. Lett. 2003, 5, 3427.
(d) Goodenough, K. M.; Moran, W. J.; Raubo, P.; Harrity, J. P. A. J. Org.
Chem. 2005, 70, 207. (e) Goodenough, K. M.; Raubo, P.; Harrity, J. P. A.
Org. Lett. 2005, 7, 2993. (f) Provoost, O. Y.; Hedley, S. J.; Hazelwood, A.
J.; Harrity, J. P. A. Tetrahedron Lett. 2006, 47, 331.
(2) For reviews of alternative [3+3] annelations see: (a) Hsung, R. P.;
Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005, 23. (b) Harrity,
J. P. A.; Provoost, O. Org. Biomol. Chem. 2005, 3, 1333.
Figure 1. [3+3] cycloaddition to piperidines.
10.1021/ol0610789 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/17/2006

at temperatures above 35 °C.6 By way of contrast, the
corresponding 1,3-dioxane 7 has been reported to be more
thermally stable.7 Given that both precursor alkylbromides
are commercially available, we began our investigations by
examining the efficiency of the addition of each Grignard
reagent to readily available Bn-substituted aziridine 8; our
results are outlined in Table 1.
deprotection-cyclization protocol. This process was found
to proceed efficiently with both acetal intermediates 9 and
10 to give the tetrahydropyridine 11, without loss of
enantiopurity over the two steps (Scheme 1).These studies
Scheme 1
Table 1. Optimization of Aziridine Ring Openinga
highlighted that both Grignard reagents were suitable for the
formation of tetrahydropyridines. However, the milder cy-
clization conditions employed in the 1,3-dioxolane system
prompted us to investigate the scope of the annelation
entry
Grignard
additive
yield, %
1
2
3
4
5
6, 1.5 equiv
6, 5.0 equiv
7, 5.0 equiv
7, 5.0 equiv
6, 2.0 equiv
-
-
-
33
80
22a
100
98
Table 2. Stepwise Annelation of Aziridines
20 mol % CuBr‚DMS
20 mol % CuBr‚DMS
a Reaction heated at reflux for 16 h.
Preliminary studies with the dioxolane-based reagent 6
were discouraging: a low yield of product 9 was observed
which could only be improved by the use of a large excess
of Grignard reagent (entries 1 and 2). Surprisingly, the
dioxane-based reagent 7 proved to be inferior and a low yield
of product was obtained even when a large excess of
Grignard was used. Paquette and co-workers have reported
that the dioxane reagent addition to enones can be promoted
by Cu catalysis.8 Indeed, the addition of 20 mol % of CuBr‚
DMS improved the efficiency of the Grignard addition to
the aziridine and provided the desired product in quantitative
yield (entry 4). Pleasingly, these conditions were also
applicable to the dioxolane-based reagent, and further
investigations showed that 9 could be furnished in high yield
when only 2 equiv of Grignard reagent 6 were employed
(entry 5).
We next turned our attention to the piperidine-forming
reaction and opted to perform an in situ acid-catalyzed
(3) (a) Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett
1998, 55. (b) Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V.
Synlett 1998, 58. (c) Adelbrecht, J.-C.; Craig, D.; Dymock, B. W.;
Thorimbert, S. Synlett 2000, 467. (d) Adelbrecht, J.-C.; Craig, D.;
Thorimbert, S. Tetrahedron Lett. 2001, 42, 8369. (e) Adelbrecht, J.-C.; Craig,
D.; Fleming, A. J.; Martin, F. M. Synlett 2005, 2643.
(4) For a review of the chemistry of three-carbon homologating agents
see: Stowell, J. C. Chem. ReV. 1984, 84, 409.
(5) Bu¨chi Grignard reagents have been added to epoxides to prepare
pyrans: (a) Street, S. D. A.; Yeates, C.; Kocienski, P.; Campbell, S. F.
Chem. Commun. 1985, 1386. (b) Rainier, J. D.; Allwein, S. P. Tetrahedron
Lett. 1998, 39, 9601. (c) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson,
H. W. B.; Rainier, J. D. Tetrahedron 2002, 58, 1997.
(6) (a) Bu¨chi, G.; Wu¨est, H. J. Org. Chem. 1969, 34, 1122. (b) Sworin,
M.; Neumann, W. L. Tetrahedron Lett. 1987, 28, 3217. (c) Ponaras, A. A.
Tetrahedron Lett. 1976, 7, 3105.
a Anhydrous HCl (1 M solution in ether) used in these cases.
(7) Stowell, J. C. J. Org. Chem. 1976, 41, 560.
(8) Leone-Bay, A.; Paquette, L. A. J. Org. Chem. 1982, 47, 4173.
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Org. Lett., Vol. 8, No. 14, 2006

sequence with the Bu¨chi Grignard reagent 6, and our results
are highlighted in Table 2. The Grignard addition reaction
was found to proceed in good to excellent yield in all cases
examined. The 2-alkyl- and 2,2′-spiroaziridines underwent
regioselective addition at the methylene unit while the more
hindered bicyclic aziridine participated smoothly in the
addition reaction without any significant drop in yield (entry
5). In addition, we were pleased to find that this technique
was compatible with a SES-protecting group (entry 4).
Finally, the cyclization reactions provided the desired dihy-
dropyridines in high yield, although they were generally
found to be more sluggish in the formation of bicyclic and
spirocyclic products (entries 5-7).
a short synthetic route. Accordingly, we performed the Bu¨chi
Grignard addition-cyclization methodology on aziridine ent-
12 without purification and were delighted to find that
piperidine ent-14 was generated in excellent overall yield.
The TFA-mediated allylation provided product 33 in excel-
lent yield as a single diastereomer. Finally, hydrogenation
provided compound 34, thus completing a formal synthesis
of (-)-dihydropinidine in high overall yield (Scheme 2).11
Scheme 2
Having established the scope of the piperidine-forming
reaction, we decided to perform some representative func-
tionalization reactions. As outlined in eqs 1 and 2, both acid-
mediated allylation and dihydroxylation processes were
highly efficient and proceeded to give 30 and 31, respec-
tively, with good to excellent levels of diastereocontrol.9
Moreover, regioselective substitution of the enamide moiety
in 11 provided bromide 32 in good yield (eq 3).
In conclusion we report a stepwise annelation procedure to
dihydropyridines that is complementary to our previously
reported [3+3] strategies to functionalized piperidines. The
further employment of this technique in target synthesis is
currently ongoing and will be reported in due course.
Acknowledgment. We thank the EPSRC and GSK for
financial support.
Supporting Information Available: Full experimental
details for the syntheses reported are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
Finally, we wished to exploit the enantiospecific piperi-
dine-forming reaction and diastereoselective functionalization
reactions in the synthesis of a piperidine alkaloid. Specifi-
cally, we envisaged that we could access the 2,6-disubstituted
piperidine natural product (-)-dihydropinidine 3410 within
OL0610789
(10) (a) Isolated from the Mexican Bean Beetle, Epilachna VariVestis:
Attygalle, A. B.; Xu, S.-C.; McCormick, K. D.; Meinwald, J.; Blankespoor,
C. L.; Eisner, T. Tetrahedron 1993, 49, 9333. (b) For a recent asymmetric
synthesis see: Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J.
Org. Chem. 2003, 68, 1919.
(9) The stereochemistry of 30 was determined by X-ray crystallography;
please refer to the Supporting Information for details.
(11) Lu, Z.-H.; Zhou, W.-S. J. Chem. Soc., Perkin Trans. 1 1993, 593.
Org. Lett., Vol. 8, No. 14, 2006
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