Asymmetric synthesis of 2-substituted piperidines using a multi-component coupling reaction: Rapid assembly of (S)-coniine from (S)-1-(1-phenylethyl)-2-methyleneaziridine

Article abstract of DOI:10.1039/b106260n

(S)-Coniine is made using a reaction which assembles the piperidine ring by the sequential formation of four new chemical bonds and installs the C-2 stereogenic centre with high levels of diastereocontrol (90% de).

Full text of DOI:10.1039/b106260n

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Asymmetric synthesis of 2-substituted piperidines using a
multi-component coupling reaction: rapid assembly of (S)-coniine
from (S)-1-(1-phenylethyl)-2-methyleneaziridine
Jerome F. Hayes,a Michael Shipman*b and Heather Twinb
a GlaxoSmithKline, Old Powder Mills, Tonbridge, Kent, UK TN11 9AN
b School of Chemistry, University of Exeter, Exeter, Devon, UK EX4 4QD.
E-mail: m.shipman@exeter.ac.uk; Fax: +44 1392 263434; Tel: +44 1392 263469
Received (in Cambridge, UK) 13th July 2001, Accepted 30th July 2001
First published as an Advance Article on the web 21st August 2001
(S)-Coniine is made using a reaction which assembles the
piperidine ring by the sequential formation of four new
chemical bonds and installs the C-2 stereogenic centre with
high levels of diastereocontrol (90% de).
in 42% yield as essentially a single diastereomer (97% de) after
chromatography on neutral alumina (Scheme 2).†‡ Slightly
larger amounts of the (2R)-diastereomer can be detected
{(2S)+(2R) = 95+5} by GC analysis prior to chromatography.
Piperidine 4 (97% de) was obtained in identical yield using
sodium borohydride as the reducing agent, however, the crude
diastereomeric ratio was slightly lower {(2S)+(2R) = 88+12}.
Metalloenamine 2 must be added to a solution of excess
1,3-diiodopropane (5 equiv.) in THF (inverse addition) to obtain
these chemical yields. In this way, additional intermolecular
reactions of imine 3a are suppressed. Using a normal addition
mode, quantities of N-(1-phenylethyl)-4-decylamine (21%)
were produced as a result of displacement of the second iodide
by excess ethylmagnesium chloride present in the reaction
mixture. Further hydrogenolysis of 4 provides (S)-(+)-coniine
hydrochloride in 93% yield whose physical and spectroscopic
data were in good agreement with those reported previously
{mp 212 °C (lit. mp 217 °C6); [a]D25 +8.1 (c 0.6, EtOH) [lit. [a]D28
+ 5.8 (c 0.43, EtOH)]6}. The enantiomeric excess of the
synthetic (S)-coniine was established to be !95% ee by
preparation of the corresponding Mosher amide using (S)-
(+)-a-methoxy-a-(trifluoromethyl)phenylacetic acid chlo-
ride.§
We recently devised a new type of multi-component coupling
reaction using 2-methyleneaziridines.1 Ring opening of this
stable and readily accessible heterocyclic system with a
Grignard reagent in the presence of copper( ) iodide furnishes a
I
metalloenamine in a regiocontrolled fashion by formation of a
carbon–carbon bond. This methodology was originally used to
make simple ketones by further in situ C-alkylation of the
metalloenamine followed by imine hydrolysis. We imagined
that by suitable modification, this multi-component coupling
reaction could be used to assemble 2-substituted piperidines,
important structural motifs in organic chemistry.2 Our basic
approach to these piperidines is depicted in Scheme 1.
Alkylation of the initially generated metalloenamine with a
1,3-difunctionalised electrophile (XCH2CH2CH2X) followed
by reduction of the resultant imine and in situ cyclisation was
anticipated to lead directly to the piperidine ring system by the
sequential formation of two carbon–carbon bonds, one carbon–
nitrogen bond and a carbon–hydrogen bond in a single
transformation. Furthermore, since 2-methyleneaziridines bear-
ing chiral, nonracemic substituents on nitrogen are known,3 we
hoped that control of the absolute stereochemistry at C-2 of the
piperidine ring may be possible by effecting a diastereocon-
trolled reduction of the intermediate imine using an enantiomer-
ically pure 2-methyleneaziridine starting material.4 In this
communication, we report the successful realisation of these
concepts as demonstrated by the enantiocontrolled synthesis of
the hemlock alkaloid (S)-coniine in a very concise fashion.5
We chose to use (S)-1-(1-phenylethyl)-2-methyleneaziridine
1 for this study as it is readily accessible in two steps from (S)-
1-phenylethylamine in good overall yield.3b In addition to
bearing a group suitable for effecting stereocontrolled reduction
of the imine double bond, it possesses the additional attribute
that the PhCHMe group can ultimately be removed by cleavage
of the benzylic C–N bond. Treatment of (S)-1 with EtMgCl and
Interestingly, when 1-iodopropane was used as the electro-
phile in this multi-component coupling reaction, amine 5 was
isolated in 49% yield as a 58:42 mixture of diastereomers after
reduction with NaBH4, indicating that the presence of the
remote iodine atom has a significant influence on the diastereo-
selectivity of the imine reduction. To account for these
differences, we suggest that imine 3a cyclises to iminium ion 6
prior to reduction (Scheme 3). The high level of stereochemical
control seen in favour of the (2S)-diastereomer can be
copper(
I
) iodide, then 1,3-diiodopropane, and finally sodium
triacetoxyborohydride results in the production of piperidine 4
Scheme 1 Planned one-pot piperidine synthesis.
Scheme 2 Asymmetric synthesis of (S)-coniine.
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Chem. Commun., 2001, 1784–1785
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106260n

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mmol) in glacial acetic acid (4 ml) at 10 °C. After 2 hours, water (6 ml) was
slowly added, then 2 M NaOH (4 ml) and EtOAc (4 ml). After 10 min, the
mixture was extracted with EtOAc then washed with aq. NH4Cl (2 3 20
ml), aq. NaHCO3 (2 3 20 ml) and brine (2 3 20 ml). The organic layer was
dried (MgSO4), filtered and the solvent removed in vacuo. Column
chromatography on alumina (0.1% MeOH in CH2Cl2) gave 4 (183 mg,
42%, 97% de) as a pale yellow oil. [a]2D6 +14.0 (c 0.86, CHCl3); nmax (neat)
2929, 2797, 1445 cm21; dH (400 MHz, CDCl3) 7.45–7.19 (5H, m), 4.02
(1H, q, J 6.7 Hz), 2.75–2.73 (1H, m), 2.41–2.36 (1H, m), 2.25–2.17 (1H, m),
1.75–1.25 (10H, m, 5 3 CH2), 1.26 (3H, d, J 6.7 Hz), 0.94 (3H, t, J 7.2 Hz);
dC (100.9 MHz, CDCl3) 146.4 (s), 128.0 (d), 127.5 (d), 126.2 (d), 56.8 (d),
55.7 (d), 45.1 (t), 31.0 (t), 29.6 (t), 25.8 (t), 22.7 (t), 18.9 (t), 14.7 (q), 14.6
(q); Observed: 231.1995 (M+); C16H25N requires 231.1987; Anal. calc. for
C16H25N: C, 83.06; H, 10.89; N, 6.05%. Found: C, 83.15; H, 11.17; N,
5.89%.
Scheme 3 Rationalisation of diastereoselectivity.
rationalised by assuming this iminium cation adopts a con-
formation in which allylic 1,3-strain is minimised by projecting
the hydrogen atom of the benzylic carbon towards the propyl
group, with subsequent hydride addition from the least hindered
Re-face. In contrast, acyclic imine 3b has much greater
conformation freedom and is reduced in a non-selective fashion
to 5.
In conclusion, we have devised a very short and stereo-
selective synthesis of the piperidine alkaloid (S)-coniine by way
of a multi-component coupling reaction. The key step forms
four new chemical bonds ( > 80% efficiency for each) and is
highly stereoselective (90% de). Since we have demonstrated
that a variety of Grignard reagents (alkyl, aryl, benzyl) ring
open 2-methyleneaziridines to metalloenamines,1 this method
should provide a rapid entry to a wide variety of enantiomer-
ically enriched 2-substituted piperidines.
§ rac-Coniine was made and used for comparison purposes.
1 J. F. Hayes, M. Shipman and H. Twin, Chem. Commun., 2000, 1791.
2 For recent reviews, see (a) P. Hammann, Organic Synthesis Highlights II,
ed. H. Waldmannn, VCH, New York, 1995, p. 323; (b) P. D. Bailey, P.
A. Millwood and P. D. Smith, Chem. Commun., 1998, 633; (c) S. Laschat
and T. Dickner, Synthesis, 2000, 1781.
3 (a) A. T. Bottini and V. Dev, J. Org. Chem., 1962, 27, 968; (b) J. Ince, T.
M. Ross, M. Shipman, A. M. Z. Slawin and D. S. Ennis, Tetrahedron,
1996, 52, 7037; (c) J. Ince, T. M. Ross, M. Shipman and D. S. Ennis,
Tetrahedron: Asymmetry, 1996, 7, 3397.
4 Diastereocontrolled [2p + 2p] cycloadditions of 2-methyleneaziridines
have been reported, see T. M. Ross, M. Shipman and A. M. Z. Slawin,
Tetrahedron Lett., 1999, 40, 6091.
5 For recent asymmetric syntheses of coniine, see (a) K. Pachamuthu and
Y. D. Vankar, J. Organomet. Chem., 2001, 624, 359; (b) J. L. Terán, D.
Gnecco, A. Galindo, J. Juárez, S. Bèrnes and R. G. Enríquez,
Tetrahedron: Asymmetry, 2001, 12, 357; (c) M. Eskici and T. Gallagher,
Synlett, 2000, 1360; (d) F. Bois, D. Gardette and J.-C. Gramain,
Tetrahedron Lett., 2000, 41, 8769; (e) T. J. Wilkinson, N. W. Stehle and
P. Beak, Org. Lett., 2000, 2, 155; (f) J. C. A. Hunt, P. Laurent and C. J.
Moody, Chem. Commun., 2000, 1771; (g) M. Shimizu, A. Arai and T.
Fujisawa, Heterocycles, 2000, 52, 137; (h) E. Jo, Y. Na and S. Chang,
Tetrahedron Lett., 1999, 40, 5581; (i) S. B. Davies and M. A. McKervey,
Tetrahedron Lett., 1999, 40, 1229; (j) A. R. Katritzky, G. Qiu, B. Yang
and P. J. Steel, J. Org. Chem., 1998, 63, 6699; (k) M. T. Reding and S. L.
Buchwald, J. Org. Chem., 1998, 63, 6344; (l) F. Sánchez-Sancho and B.
Herradón, Tetrahedron: Asymmetry, 1998, 9, 1951; (m) S. Nazabadioko,
R. J. Pérez, R. Brieva and V. Gotor, Tetrahedron: Asymmetry, 1998, 9,
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50.
We are indebted to EPSRC and GlaxoSmithKline for their
generous financial support of this work. We thank the EPSRC
National Mass Spectrometry Centre for performing some of the
mass spectral measurements and the EPSRC Chemical Data-
base Service at Daresbury.7
Notes and references
† All new compounds have been fully characterised using standard
spectroscopic and analytical methods.
‡ Experimental procedure: To CuI (72 mg, 0.378 mmol) in THF (6 ml) at
230 °C was added EtMgCl (2.0 M in THF, 2.36 ml, 4.72 mmol) dropwise.
After stirring for 10 min, (S)-1 (300 mg, 1.88 mmol) in THF (3 ml) was
added. The reaction mixture was allowed to warm up to room temperature
and stirred for 24 h. This mixture was then added to diiodopropane (1.09
mL, 9.49 mmol) in THF (2 ml) at 0 °C. A reflux condenser was fitted and
the mixture was heated to 40 °C for 18 h. On cooling, the resultant dark
green mixture was added to a solution of sodium borohydride (214 mg, 5.66
6 D. Enders and J. Tiebes, Liebigs Ann. Chem., 1993, 173.
7 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf. Comp. Sci.,
1996, 36, 746.
Chem. Commun., 2001, 1784–1785
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