Diastereoselective access to nonracemic 2-cis-substituted and 2,6-cis-disubstituted piperidines

Article abstract of DOI:10.1021/ol202796w

Access to nonracemic amino ketones via a hydrozirconation/transmetalation/ acylation sequence applied to Boc-protected 1-aminobut-3-enes is presented. This method was applied to the stereoselective synthesis of cyclic imines (or iminiums) which were diastereoselectively converted into 2-cis-substituted and 2,6-cis-disubstituted piperidines. The potential of this approach in the field of alkaloid synthesis was illustrated by the synthesis of (-)-coniine and (-)-indolizidine 209D. Furthermore, access to indolizidines bearing a quaternary center could also be envisioned through this strategy.

Full text of DOI:10.1021/ol202796w

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6292–6295
Diastereoselective Access to Nonracemic
2-cis-Substituted and
2,6-cis-Disubstituted Piperidines
Nicolas Coia, Na¨ıma Mokhtari, Jean-Luc Vasse,* and Jan Szymoniak*
ꢀ
Institut de Chimie Moleculaire de Reims, CNRS (UMR 6229) and Universite de Reims,
51687 Reims Cedex 2, France
ꢀ
jean-luc.vasse@univ-reims.fr; jan.szymoniak@univ-reims.fr
Received October 18, 2011
ABSTRACT
Access to nonracemic amino ketones via a hydrozirconation/transmetalation/acylation sequence applied to Boc-protected 1-aminobut-3-enes is
presented. This method was applied to the stereoselective synthesis of cyclic imines (or iminiums) which were diastereoselectively converted into
2-cis-substituted and 2,6-cis-disubstituted piperidines. The potential of this approach in the field of alkaloid synthesis was illustrated by the
synthesis of (ꢀ)-coniine and (ꢀ)-indolizidine 209D. Furthermore, access to indolizidines bearing a quaternary center could also be envisioned
through this strategy.
Omnipresent in both naturally occurring and biologi-
cally active molecules,1 nitrogen-containing heterocycles
are crucial synthetic targets. Thus, efforts to develop new
methodologies for building this class of molecules are of
continuous interest.2 Classical disconnection implies NꢀC
bond-forming condensation or displacement as the ring-
closure step. Such a strategy typically involves the prerequi-
site generation of an electrophilic site onto substrates bearing
an amine precursor. Emerging from this approach, cross-
metathesis3 and hydroformylation,4 applied to unsaturated
amines, allow a general access to several N-heterocycles.
We have previously described the preparation of 2-
substituted pyrrolidines via hydrozirconation of homoallylic
amines. The resulting zirconocenes I are subsequently
converted into the corresponding iodo intermediates II,
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r
10.1021/ol202796w
Published on Web 11/08/2011
2011 American Chemical Society

which spontaneously cyclize to afford the pyrrolidines
(Scheme 1).5
Although zirconocenes are easily converted into the
corresponding halides, they are inert toward most classical
electrophiles. The transmetalation typically to Al,8 Zn,9 or
Cu10 is a method of choice to readily form more nucleo-
philic organometallic species.11 Therefore, benzoyl chlor-
ide was added in the presence of a transmetalating agent to
perform the acylation.
Scheme 1. Hydrozirconation/Iodination-Mediated Synthesis of
Pyrrolidines
While the use of AlCl3, ZnBr2, or Zn(OTf)2 was un-
successful, both CuI and CuBr SMe2 afforded the ex-
3
pected product. Acylation of alkylzirconocenes is reported
to require a catalytic amount of copper salt, but in our case,
best results were obtained with an equimolar loading of
CuBr SMe2. Several acyl chlorides have been tested in these
3
When considering the aminozirconocene I involved in
the above strategy, one may distinguish a bis-nucleophilic
entity, opening the way to coupling with divalent electro-
philes (Figure 1). Thus, applied to homoallylic amines,
the sequence hydrozirconation/coupling with an acyl
chloride would provide an alternative to the Rh-catalyzed
hydroacylation.6 In turn, such a strategy would allow an
access to substituted piperidines by successive reaction of
the C- and the N-poles of a 4-aminobutylzirconocene
(Figure 1).
optimal conditions, leading to the corresponding amino
ketones 2 (Table 1). Finally, Boc-deprotection under stan-
dard conditions, followed by reductive amination using
NaBH(OAc)3, gave the 2-substituted piperidines 3 with
generally good diastereoselectivities.12
Table 1. Synthesis of Piperidines 3
entry
R
2 (yield, %)
3 (yield, %)a
drb
1
2
3
4
5
Ph
2a (71)
2b (70)
2c (56)
2d (62)
2e (53)
3a (69)
3b (53)
3c (69)
3d (78)
3e (69)
13:1
4:1
2-BrC6H4
n-C3H7
n-C4H9
c-C3H5
12:1
16:1
15:1
Figure 1. Approach toward piperidines.
a Yields refer to the major isomer isolated in the diastereomerically
pure form. b Determined by 1H NMR on the crude mixture.
In this paper, we present a synthetic methodology that
allows the preparation of enantiopure piperidines via a
sequential hydrozirconation/acylation followed by an in-
tramolecular reductive amination.
The feasibility of the approach was first tested starting
from the N-Boc-protected amine 1.7 In that case, a com-
plete hydrozirconation of the substrate was obtained using
1.1 equiv of the Schwartz reagent.
Thus, piperidines 3aꢀe bearing an aryl (entries 1 and 2)
or an alkyl group (entries 3 and 4) at the 2-position were
obtained in good yield. Most compounds were obtained in
a highly diastereoselective manner, except 3b. Neverthe-
less, all compounds could be isolated in diastereomerically
pure form after column chromatography.
Good diastereoselectivity in this reaction was previously
observed13 and postulated to result from an hydride addi-
tion occurring onto the more accessible face of an iminium
(6) Kim, G.; Lee, E.-j Tetrahedron: Asymmetry 2001, 12, 2073–2076.
(7) For the preparation of 1, see the Supporting Information.
(8) (a) Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1977, 99, 638–640.
(b) Zhao, C.; Li, P.; Cao, X.; Xi, Z. Chem.;Eur. J. 2002, 8, 4292–4298.
(9) (a) Wipf, P.; Nunes, R. L. Tetrahedron 2004, 60, 1369–1379. (b)
Wipf, P.; Pierce, J. G. Org. Lett. 2005, 7, 3537–3740. (c) Wipf, P.;
Kendall, C. Chem.;Eur. J. 2002, 8, 1779–1784.
(10) (a) Wipf, P. Synthesis 1993, 537–557. (b) Wipf, P.; Takahashi, H.
J. Chem. Soc., Chem. Commun. 1996, 2675–2676. (c) Yoshifuji, M.;
Loots, M.; Schwartz, J. Tetrahedron Lett. 1997, 15, 1303–1306. (d) Sato,
A.; Ito, H.; Yamaguchi, Y.; Taguchi, T. Tetrahedron Lett. 2000, 41,
10239–10243. (e) Doherty, S.; Knight, J. G.; Robins, E. G.; Scanlan,
T. H.; Champkin, P. A.; Clegg, W. J. Am. Chem. Soc. 2001, 123, 5110–
5111. (f) Sato, A.; Ito, H.; Okada, M.; Nakamura, Y.; Taguchi, T.
Tetrahedron Lett. 2005, 46, 8381–8383.
(11) For zirconocene transmetalation to others metals, see: (a) Wipf,
P.; Jahn, H. Tetrahedron 1996, 52, 12853–12910. (b) Lipshutz, B. H.;
Pfeiffer, S. S.; Noson, K.; Tomioka, T. Titanium and Zirconium in
Organic Synthesis; Wiley: Weinheim, 2002. (c) Wipf, P.; Kendall, C. Topics
in Organometallic Chemistry; Takahashi, T., Ed.; Springer: Berlin, 2004;
Vol. 8, p 1.
(12) The stereochemistry of 3a was assigned by comparison with
known isomers: Fujita, K-I; Fujii, T.; Yamaguchi, R. Org. Lett. 2004, 6,
3525–3528.
(13) Adriaenssens, L. V.; Austin, C. A.; Gibson, M.; Smith, D.;
Hartley, R. C. Eur. J. Org. Chem. 2006, 4998–5001.
(14) Hates, J. F.; Shipman, M.; Twin, H. Chem. Commun. 2001,
1784–1785. (b) Girard, N.; Pouchain, L.; Hurvois, J.-P.; Moinet, C.
Synlett 2006, 1679–1682.
Org. Lett., Vol. 13, No. 23, 2011
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that adopts a conformation minimizing the steric inter-
actions.14
Such an approach constitutes a simple access toward
enantiomerically pure free piperidines as exemplified by
the synthesis of (R)-(ꢀ)-coniine4e,15 obtained by hydro-
genolysis16 of 3c (Scheme 2).
The sequenceappearsasquite general toafforddiversely
cis-2,6-disubstituted piperidines (Table 2).18 Thus, piper-
idines substituted by two aryl groups (entries 2ꢀ5), an aryl
and an aliphatic group (entries 1 and 6ꢀ8), and also two
alkyl groups(entry10) were obtained. Furthermore, access
to each enantiomer of 6g was allowed by inverting the
order of introductionof the substituents R1 and R2 (entry 7
and 8). Piperidine 6i with a vinyl fragment could also be
prepared owing to the selective hydrozirconation of the
less substituted CdC double bond (entry 9).
Scheme 2. Synthesis of (ꢀ)-Coniine
The diastereoselectivity observed in the reduction step
may be rationalized through an axial hydride addition
occurring from a half-chair-like conformation that might
be favored when the R1 substituent is located in a pseu-
doequatorial position (Figure 2).
To extend the potential of the method, we next turned
our attention toward the synthesis of 2,6-disubstituted
piperidines. For that purpose, a series of enantiomerically
pure N-Boc-protected 2-substituted homoallylic amines 4
were prepared according to a known procedure.17
The hydrozirconation/acylation sequence was next applied
to 4 using 2 equiv of the Schwartz reagent, since one is con-
sumed by the NH-carbamate, and 2 equiv of the copper salt.
Figure 2. Plausible origin of the cis-selectivity.
To illustrate the synthetic potential of the method, the
synthesis of indolizidine 209D6,19 was achieved. Thus, 6j
was subjected to hydrogenolysis under acidic conditions to
give the corresponding hydroxy ammonium. The chloro
ammonium was then generated with SOCl2, and cycliza-
tion was promoted by the addition of K2CO3 to provide
the target alkaloid (Scheme 3).
Table 2. Synthesis of Piperidines 6
Scheme 3. Synthesis of Indolizidine 209D
entry
1 a Ph
R1
R2
5 (yield, %) 6b (yield, %) dr
Me
Ph
Ph
5a (69)
5b (45)
5c (70)
6a (72)
6b (73)
6c (77)
6d (87)
6e (81)
6f (88)
6g (73)
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
2 a 2-OMeC6H4
3
4
5
6
Ph
Ph
Ph
Ph
3-ClC6H4 5d (50)
2-BrC6H4 5e (56)
Additionally, an extension toward piperidines bearing a
quaternary center at the 2-position was initiated. Thus, the
c-C3H5
i-Bu
Ph
5f (51%)
5g (72)
5h (63)
5i (56)
5j (47)
7c Ph
8
i-Bu
ent-6g (70) 6.5:1
9
(E)-PhCHdCH Ph
6i (47)
6j (58)
4:1
(17) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.;
Ohfune, Y. J. Org. Chem. 2005, 70, 3464–3471.
10 (CH2)3-OBn
n-C6H13
5.5:1
(18) The cis configuration of 6a was assigned by comparison with the
known compound: Katritzky, A. R.; Qiu, G.; Yang, B.; Steel, P. J.
J. Org. Chem. 1998, 63, 6699–6703. The stereochemistry of all other
compounds was deduced by analogy.
a Racemic material was used as substrate. b Yields refer to the major
isomer isolated in the diastereomerically pure form. c CuI was used as the
transmetalating agent.
˚
(19) For a previous synthesis of indolizidine 209D, see: (a) Ahman, J.;
Somfai, P. Tetrahedron 1995, 51, 9747–9756. (b) Pearson, W. H.;
Walavalkar, R.; Schkeryantz, J. M.; Fang, W. K.; Blickensdorf, J. D.
J. Am. Chem. Soc. 1993, 115, 10183–10194.
(20) The cis configuration was deduced from NOE experiments; see
the Supporting Information.
(15) For recent asymmetric synthesis of coniine see:(a) Passarella, D.;
Barilli, A.; Belinghieri, F.; Fassi, P; Riva, S.; Sacchetti, Silvani, A.;
Danieli, B. Tetrahedron: Asymmetry 2005, 16, 2225–2229. (b) Yamashita,
Y.; Mizuki, Y.; Kobayashi, S. Tetrahedron Lett. 2005, 46, 1803–1806.
(16) (a) Fujita, K-I;Fujii, T.;Komatsubara, A.;Enoki, Y.;Yamaguchi,
R. Heterocycles 2007, 74, 673–682. (b) Fellah, M; Santerem, M; Lhommet,
G.; Mouries-Mansuy, V. J. Org. Chem. 2010, 75, 7803–7808. (c) Miao, L.;
Di Maggio, S. C.; Shu, M.; Trudell, M. L. Org. Lett. 2009, 11, 1579–1582.
(d) Breuning, M.; Steiner, M. Tetrahedron: Asymmetry 2008, 19, 1978–
1983.
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Org. Lett., Vol. 13, No. 23, 2011

addition of allylmagnesium bromide onto the cyclic imine
50c intermediate was tested as a model experiment. In this
case, a high diastereoselectivity was observed, affording
the cis piperidine 7,20 isolated in its pure diastereomeric
form, in 80% yield starting from 5c. Further cyclization
through hydrozirconation/iodination5 provided the indo-
lizidine 8 in 63% yield (Scheme 4).
In summary, applied to protected homoallylic amines,
the hydrozirconation/acylation sequence allows access to
protected amino ketones, ideal precursors of cyclic imines
(or iminiums). The methodology thus consists of the
sequential activation of the C- and N-termini of homo-
allylic amines toward a trivalent electrophile. This ap-
proach was applied to the diastereoselective synthesis of
2-cis-substituted and cis-2,6-disubstituted piperidines,
opening the way to alkaloid synthesis, as illustrated by
the synthesis of (ꢀ)-coniine and (ꢀ)-indolizidine 209D.
Moreover, an access to piperidines bearing a stereocon-
trolled quaternary center is exemplified.
Scheme 4. Synthesis of Piperidines 8
Acknowledgment. We thank Dr. Jean-Bernard Behr
(University of Reims-UMR 6229) for fruiful discussions.
Financialsupport of this work by CNRS and by the Agence
Nationale pour la Recherche is gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 23, 2011
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