1,4-Bis(arylsulfonyl)dihydropyridines in synthesis. Enantioselective synthesis of 2,3,6-trisubstituted piperidines

Article abstract of DOI:10.1016/S0022-328X(00)00918-9

A 2-substituted 1,4-bis(4-tolylsulfonyl)-1,2-dihydropyridine is readily accessed from an α-aminoester and 1,1-dimethoxy-3-(4-tolylsulfonyl)propane. This cyclic diene enters into highly selective addition reactions with carbon nucleophiles, and the product

Full text of DOI:10.1016/S0022-328X(00)00918-9

Journal of Organometallic Chemistry 624 (2001) 380–382
www.elsevier.nl/locate/jorganchem
Communication
1,4-Bis(arylsulfonyl)dihydropyridines in synthesis. Enantioselective
synthesis of 2,3,6-trisubstituted piperidines
Santiago Carballares, Donald Craig *
Centre for Chemical Synthesis, Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW 7 2AY, UK
Received 18 October 2000; accepted 28 November 2000
Dedicated with respect and admiration to Professor J.-F. Normant on the occasion of his 65th birthday
Abstract
A 2-substituted 1,4-bis(4-tolylsulfonyl)-1,2-dihydropyridine is readily accessed from an a-aminoester and 1,1-dimethoxy-3-(4-
tolylsulfonyl)propane. This cyclic diene enters into highly selective addition reactions with carbon nucleophiles, and the product
of one of these transformations is converted into a 2,3,6-trisubstituted piperidine via an SN1% reaction. © 2001 Elsevier Science
B.V. All rights reserved.
Keywords: 2,3,6-Trisubstituted piperidines; Enantioselective synthesis; Organolithium
two-step sequence. Heterocycles 2 enter into a variety
of carbon-carbon bond-forming reactions, including
We have been investigating the preparation and use
in nitrogen heterocycle synthesis of 1,4-bis(4-tolylsul-
SN1 [1], SN1% (giving 1) [2], alkylation (giving 4) [2] and
fonyl)-1,2,3,4-tetrahydropyridines (2). These substances
cyclisation reactions [3]. By varying the acidic reagents
are readily assembled from 1,1-dimethoxy-3-(4-tolylsul-
the latter processes could be tuned to give the products
fonyl)propane and N-(4-tolylsulfonyl)aziridines using a
of 1,2- (as in 3) or 1,4- attack (as in 6) on the presumed
iminium intermediates. We have also investigated oxi-
dation reactions of 2, and showed [4] that dihydroxyla-
tion of the enamide double bond took place with
complete selectivity for the a,a-stereoisomer. The ester
derivatives of these products underwent SN1 reactions
giving 5, whose stereoselectivities varied according to
the nature of the substituent at C-2 (Scheme 1).
We rationalised the stereochemical outcomes of the
reactions depicted in Scheme 1 in terms of either axial
attack of the nucleophile on the positively-charged ni-
trogen template, or less hindered facial approach anti-
with respect to the N-tosyl group, which might adopt
conformations in which 1,2-interactions with the C-2
substituent are minimised. Subsequently we have be-
Scheme 1.
come interested in exploiting similarly well-defined con-
formations anticipated for related, more highly
unsaturated systems with a view to gaining access to
more highly substituted piperidines by addition of
* Corresponding author: Tel.: +44-20-75945771; fax: +44-20-
75945868.
E-mail address: d.craig@ic.ac.uk (D. Craig).
0022-328X/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(00)00918-9

S. Carballares, D. Craig / Journal of Organometallic Chemistry 624 (2001) 380–382
381
yield based on the aminoacid derivative. Reduction
with DIBAL-H followed by acetylation gave a mixture
of two diastereomeric b-acetoxysulfones 10 in good
yield. The assignment of R,S- stereochemistry in 10
followed from the anticipated Felkin–Anh sense of
reduction in a non-chelated reactive conformation [7].
Base-induced elimination of the mixture at this stage
using t-BuOK–t-BuOH gave a 3:1 mixture of E- and
Z- vinylic sulfones 11; the major E-isomer underwent
cyclisation on treatment with BF3·OEt2 [8] to provide
dihydropyridine 13. It was subsequently found that
higher overall yields of 13 could be obtained if cyclisa-
tion was carried out prior to the elimination step,
because this obviated the loss of material through for-
mation of Z-11, which was inert towards cyclisation.
Thus, treatment of 10 with BF3·OEt2 and exposure of
the two-component mixture of diastereomeric tetrahy-
dropyridines 12 to a sub-stoichiometric amount of DBU
gave 13 in good overall yield. Material generated using
the latter method was found using chiral HPLC analy-
sis to have an enantiomeric excess of 91%; the use of
increased quantities of DBU in the final step caused
significant lowering of optical purity.
Scheme 2. Reagents and conditions: (i) Add n-BuLi to 7, THF,
−78°C, then add 8 (0.3 equivalents), −78°C“ −30°C, 1.5 h. (ii)
DIBAL-H, CH2Cl2, −78°C, 2 h. (iii) Ac2O, py, r.t., 15 h. (iv)
t-BuOK (2 equivalents), t-BuOH, r.t., 10 min. (v) BF3·OEt2 (15
equivalents), CH2Cl2, −78°C“0°C, 3 h. (vi) BF3·OEt2 (15 equiva-
lents) added to E-11, CH2Cl2, −78°C“0°C, 3 h. (vii) DBU (0.1
equivalents), PhMe, r.t., 70 min.
Attention was turned next to addition reactions of
dihydropyridine 13. A variety of reagents was screened,
in order to define the scope of the reaction in terms of
the degree of basicity and steric demand associated with
the nucleophile. The results are depicted in Scheme 3
and are collected in Table 1.
For all of the organometallic reagents investigated,
successful addition to dihydropyridine 13 was accompa-
nied by the appearance of the deep red colour associ-
ated with the conjugate bases of tetrahydropyridines
[2]. In all cases only 2,3-anti-tetrahydropyridines were
formed, as mixtures of C-4 epimers 14 and 15. We
ascribe this high stereoselectivity to a propensity for
nucleophilic attack to take place at the vinylic sulfone
b-carbon atom on an axial trajectory, anti- with respect
to the C-2 benzyl substituent. The major compound 14a
arising from vinyllithium addition was subjected to
single-crystal X-ray diffraction analysis [9], which
showed clearly the trans-diaxial relationship of the C-2
benzyl and C-3 vinyl groups, and the equatorial dispo-
sition of the C-4 tolylsulfonyl moiety.
Scheme 3.
organometallic reagents to the electrophilic vinylic sul-
fone. This letter reports the results of these
investigations.
Substrate 13 was prepared according to the simple
sequence shown in Scheme 2. Thus, addition of an
excess
fonyl)propane 7 [3,5] to N-(4-tolylsulfonyl)-
lalanine ethyl ester [6] gave the expected
of
lithiated
1,1-dimethoxy-3-(4-tolylsul-
L
-pheny-
8
b-ketosulfone 9 as a diastereomeric mixture in good
Table 1
Addition of nucleophiles to 13
Entry
R
Equivalent RLi
Scale (mmol)
T (°C)
Yield (%)
14:15
a
b
c
d
e
f
H2CꢀCH
CH3
C6H5
CH3(CH2)5CC
C6H5SO2CH2
n-C4H9
2
1.2
4
3
2.5
2
1
−78
−78
−78
−78“−30
−78
95
95
95
17 a
95
95
95
77:23
24:76
30:70
100:0
26:74
17:83
7:93
0.1
0.15
0.5
0.4
0.07
0.24
−78
−78
g
NCCH2
2.5
a 63% of unreacted 13 was recovered.

382
S. Carballares, D. Craig / Journal of Organometallic Chemistry 624 (2001) 380–382
useful addition to existing methods for the preparation
of polysubstituted piperidines [11].
Acknowledgements
We thank the European Commission (Marie Curie
Fellowship to S.C.; contract number HPMF-CT-1999-
00262) for financial support of this research.
Scheme 4. Reagents and conditions: (i) Me3Al (2 equivalents),
CH2Cl2, r.t., 1 h. (ii) (Ph3P)3RhCl (18 mol%), H2 (1 atm), PhMe, r.t.,
10 h. (iii) Na+C10H8− (10 equivalents), DME, −60°C, 45 min.
The final part of this investigation was concerned
with attempting to effect the previously reported SN1
reactions on the more highly substituted tetrahydropy-
ridine substrate 14b/15b. We were particularly keen to
assess whether the presence of the extra substituent
would compromise any part of the sequence used previ-
ously for the generation of fully reduced, unprotected
piperidines. In the event, treatment of a ca. 3:1 mixture
of 14b/15b with trimethylaluminium gave, in 85% over-
all yield from dihydropyridine 13, the trisubstituted
tetrahydropyridine 16 as a single diastereomer. High-
yielding hydrogenation of the double bond was accom-
plished as before using Wilkinson’s catalyst [10].
Finally, desulfonylation occurred efficiently to provide
the piperidine 17 (Scheme 4). Crystallisation of its
hydrochloride gave material which was subjected to
X-ray crystallographic analysis [9]. This clearly demon-
strated the anti- nature of the addition to the vinylic
sulfone moiety in 13 and the syn- nature of the
trimethylaluminium-mediated SN1% reaction with re-
spect to the C-2 substituent.
References
[1] J.C. Adelbrecht, D. Craig, S.Thorimbert, unpublished
observations.
[2] D. Craig, R. McCague, G.A. Potter, M.R.V. Williams, Synlett
(1998) 55.
[3] D. Craig, R. McCague, G.A. Potter, M.R.V. Williams, Synlett
(1998) 58.
[4] J.C. Adelbrecht, D. Craig, B.W. Dymock, S. Thorimbert, Synlett
(2000) 467.
[5] P. Bonete, C. Najera, Tetrahedron 51 (1995) 2763.
[6] Compound 8 was prepared in 99% yield by N-tosylation of
commercially available PheOEt·HCl (Aldrich Chemical Co.) us-
ing TsCl (1.1 equivalents), Et3N (2.2 equivalents) and DMAP
(0.2 equivalents) at 0°C in CH2C12 (0.5M).
[7] Reduction may be considered to be in the Felkin–Anh sense if
the benzyl and tosylamino groups are regarded as medium and
large respectively. For related work on the stereoselectivity of
reduction of a-aminoketones, see: F. Benedetti, S. Miertus, S.
Norbedo, A. Tossi, P. Zlatoidzky, J. Org. Chem. 62 (1997) 9348
and references therein.
[8] After extensive experimentation we have found that BF3·OEt2 is
the reagent of choice for all of these cyclisation–condensation
reactions, giving superior yields to those obtained both with
iodotrimethylsilane and with strong Bro¨nsted acids such as TFA
and H2SO4.
[9] We thank Professor David J. Williams and Dr Andrew J.P.
White of this Department for this determination.
[10] R. Noyori, H. Takaya, in: B.M. Trost (Ed.), Comprehensive
Organic Synthesis, vol. 8, Pergamon, Oxford, 1991, p. 443.
[11] For a review of recent synthetic work on saturated nitrogen
heterocycles including piperidines, and leading references, see: A.
Mitchinson, A. Nadin, J. Chem. Soc. Perkin Trans. I (2000)
2862.
In summary, the results presented herein demonstrate
that a 2-substituted 1,4-bis(4-tolylsulfonyl)-1,2-dihy-
dropyridine enters into efficient and highly stereoselec-
tive addition reactions with carbon nucleophiles, and
that diastereomerically pure trisubstituted piperidines
may easily be accessed from the tetrahydropyridines
produced. The ready availability of the dihydropyridine
substrates is such that the method should prove to be a
.