N-sulfinyl metalloenamine conjugate additions: Asymmetric synthesis of piperidines

Article abstract of DOI:10.1021/jo051020s

The first examples of conjugate additions of W-tert-butanesulfmyl metalloenamines are reported. Highly stereoselective conjugate additions (97:3 to 99:1 dr) were observed between metalloenamines derived from N-sulfinyl ketimines and α,β-unsaturated ketone

Full text of DOI:10.1021/jo051020s

N-Sulfinyl Metalloenamine Conjugate Additions: Asymmetric
Synthesis of Piperidines
Hillary M. Peltier and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California,
Berkeley, California 94720
jellman@berkeley.edu
Received May 22, 2005
The first examples of conjugate additions of N-tert-butanesulfinyl metalloenamines are reported.
Highly stereoselective conjugate additions (97:3 to 99:1 dr) were observed between metalloenamines
derived from N-sulfinyl ketimines and R,â-unsaturated ketones bearing either alkyl or aryl
substituents. The conjugate addition products could rapidly be converted with high diastereose-
lectivity to 2,4,6-trisubstituted piperidines, which are difficult to access by other methods.
Introduction
additions could provide entry into a variety of function-
alized compounds (eq 1).
N-Sulfinyl metalloenamines have been employed in the
rapid asymmetric syntheses of syn- and anti-1,3-amino
alcohols through highly diastereoselective additions to
aldehydes, followed by subsequent reduction of the N-
sulfinylimino alcohol products.1 Recently, the self-
condensation of N-tert-butanesulfinyl aldimines has also
been reported for the rapid production of biologically
important amine-containing compounds.2 We anticipated
that the scope of the N-sulfinyl metalloenamine additions
could be substantially broadened to include a more
diverse set of electrophiles.3-5 In particular, Michael
Successful Michael additions to R,â-unsaturated ke-
tones 2 would be of particular value because the addition
products 3 could potentially be converted to 2,4,6-
trisubstituted piperidines 4 by stereoselective reduction
and cyclization (Scheme 1). While piperidines are a very
important class of compounds commonly found in natural
products and drugs,6 methods for the asymmetric syn-
thesis of 2,4,6-trialkyl-substituted piperidines have not
previously been reported.7,8
(1) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003,
125, 11276.
(2) Schenkel, L. B.; Ellman, J. A. Org. Lett. 2004, 6, 3621.
(3) For alkylation of N′-tert-butanesulfinyl amidines, see: Kochi, T.;
Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652.
(4) For leading references on applications of tert-butanesulfinyl
imines, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984. (b) Pflum, D. A.; Krishnamurthy, D.; Han, Z. X.;
Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 2002, 43, 923. (c)
Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303. (d) Han,
Z. X.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Pflum, D. A.;
Senanayake, C. H. Tetrahedron Lett. 2003, 44, 4195. (e) Kells, K. W.;
Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666. (f) Cooper, I. R.;
Grigg, R.; Hardie, M. J.; MacLachlan, W. S.; Sridharan, V.; Thomas,
W. A. Tetrahedron Lett. 2003, 44, 2283. (g) Rech, J. C.; Floreancig, P.
E. Org. Lett. 2003, 5, 1495. (h) Jung, P. M. J.; Beaudegnies, R.; De
Mesmaeker, A.; Wendeborn, S. Tetrahedron Lett. 2003, 44, 293. (i)
Chemla, F.; Ferreira, F. Synlett 2004, 983. (j) Kuduk, S. D.; DiPardo,
R. M.; Chang, R. K.; Ng, C.; Bock, M. G. Tetrahedron Lett. 2004, 45,
6641. (k) Jayathilaka, L. P.; Deb, M.; Standaert, R. F. Org. Lett. 2004,
6, 3659. (l) Weix, D. J.; Shi, Y. L.; Ellman, J. A. J. Am. Chem. Soc.
2005, 127, 1092. (m) Zhong, Y.-W.; Izumi, K.; Xu, M.-H.; Lin, G.-Q.
Org. Lett. 2004, 6, 4747.
(5) For a leading reference on applications of arenesulfinyl imines,
see: Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(6) (a) Michael, J. P.Nat. Prod. Rep. 2001, 18, 520. (b) Watson, P.
S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679. (c) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701. (d) O’Hagan, D. Nat. Prod. Rep. 2000,
17, 435. (e) Alkaloids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Wiley: New York, 1985; Vol. 3.
(7) For leading references, see: (a) Glorius, F.; Spielkamp, N.; Holle,
S.; Goddard, R.; Lehmann, C. W. Angew. Chem., Int. Ed. 2004, 43,
2850. (b) Mancheno, O. G.; Arrayas, R. G.; Carretero, J. C. J. Am.
Chem. Soc. 2004, 126, 456. (c) Toure´, B. B.; Hall, D. G. Angew. Chem.,
Int. Ed. 2004, 43, 2001. (d) Comins, D. L.; Zheng, X. L.; Goehring, R.
R. Org. Lett. 2002, 4, 1611. (e) Cassidy, M. P.; Padwa, A. Org. Lett.
2004, 6, 4029. (f) Weintraub, P. M.; Sabol, J. S.; Kane, J. A.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953 and references therein.
10.1021/jo051020s CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/10/2005
7342
J. Org. Chem. 2005, 70, 7342-7345

N-Sulfinyl Metalloenamine Conjugate Additions
SCHEME 1. Planned Route to Piperidines
was further extended from metalloenamines derived from
N-sulfinyl aryl ketimines to those derived from aliphatic
ketimines (entries 3 and 4). Addition of compound 1b to
ketone 2b yielded the desired product 3d in 61% isolated
yield with >99:1 dr, and compound 3e was obtained in
72% yield with >99:1 dr from the addition of 1c to ketone
2b. Use of the metalloenamine formed from the un-
branched ketimine 1d resulted in a complex mixture of
products (entry 5).
Diastereoselective additions of N-sulfinyl metallo-
enamines to nitro olefins were also investigated (Table
3). Deprotonation of 1a with LDA in THF, followed by
addition to commercially available trans-â-nitrostyrene
5a, provided compound 6a in 88% yield with a diaster-
eomeric ratio of 75:25 (entry 1). Imine hydrolysis with
aqueous acetic acid provided the corresponding ketone
in 80% yield, which by comparison with literature data11
defined the major diastereomer as having the (S)-con-
figuration. Previous work had shown that ZnBr2 and
MgBr2 provide increased selectivity for the addition of
1a to aldehydes;1 however, neither the zinc nor magne-
sium metalloenamines enhanced the diastereoselectivity
in this case (entries 2 and 3). Altering the solvent (entry
4) and the base (entry 5) resulted in a reversal in the
sense of induction but did not improve the selectivity.
The scope of the Michael addition was next examined by
evaluating additions to the aliphatic nitroalkene 5b.12
Addition of 1a to 5b without any additive resulted in only
trace amounts of the desired product 6b (entry 6). The
reaction was repeated with ZnBr2 and MgBr2 as additives
to minimize competitive deprotonation of 5b (entries 7
and 8). Although the additions proceeded with dramati-
cally improved yields, only moderate selectivity was
observed.
Asymmetric Synthesis of 2,4,6-Trisubstituted Pi-
peridines. Conversion of the N-sulfinylimino ketones 3
to piperidines began with stereoselective reductions of 3
(Scheme 2). Similar to reductions of â-hydroxy-N-sulfinyl
imines,1 appropriate selection of the reducing agent
allows access to either diastereomeric imine reduction
product from a common intermediate. Treatment of
compounds 3a and 3e with L-Selectride, followed by
selective alcohol oxidation with Dess-Martin periodi-
nane, gave the syn-N-sulfinylamino ketones 7a,b in good
to high yields over the two steps as 97:3 and 96:4
mixtures of diastereomers, respectively. Conversely,
treatment of 3a with NaBH4 and Ti(OEt)4,13 followed by
oxidation with Dess-Martin periodinane, gave the anti-
N-sulfinylamino ketone 7c in 95% yield over the two
steps as a 87:13 mixture of diastereomers.
TABLE 1. Additive Screen of Addition of 1a to 2a
entry
additive
yielda (%)
drb,c
1
2
3
none
MgBr2
ZnBr2
<60
69
84
96:4
97:3
97:3
a Isolated yield. b Determined by LCMS. c The sense of induction
was established by X-ray analysis of the piperidine product 4a
(vida infra).
Results and Discussion
For the initial investigation of conjugate additions of
N-sulfinyl metalloenamines to Michael acceptors, N-
sulfinyl ketimine 1a9 was chosen as a model substrate
because it forms a single metalloenamine upon deproto-
nation, thereby eliminating regioselectivity issues (Table
1). The addition of 1a to ketone 2a, using LDA as a base,
provided product 3a with a 96:4 diastereomeric ratio,
albeit in modest yield (entry 1). Competitive deprotona-
tion of the Michael acceptor has been reported for lithium
enolate conjugate additions10 and was likely responsible
for the modest yield observed in the metalloenamine
addition. It was anticipated that a metal that forms a
more covalent bond might favor conjugate addition over
deprotonation, and therefore, the reaction was repeated
with MgBr2 and ZnBr2 as additives (entries 2 and 3). The
improvement in yield was most dramatic when ZnBr2
was employed (entry 3). Consequently, this additive was
used in all subsequent metalloenamine additions to R,â-
unsaturated ketones.
The N-sulfinylamino ketones 7a-c were then readily
converted to the 2,4,6-trisubstituted piperidines 4a-c
(Scheme 3). Treatment of 7a-c with HCl resulted in
cleavage of the sulfinyl group and cyclization to com-
pounds 8a-c. Subsequent reduction14 with DIBAL-H
provided the desired piperidines 4a-c in moderate to
good yields and with high selectivity. The absolute
configuration of compound 4a was determined by X-ray
To explore the reaction scope for the Michael acceptor,
compound 1a was added to ketones 2b and 2c (Table 2,
entries 1 and 2). Compounds 3b and 3c were obtained
in good yields (82% and 60%) and with high selectivity
(>99:1 dr), demonstrating that this method is general for
both alkyl- and aryl-substituted R,â-unsaturated ketones.
The scope of the additions to R,â-unsaturated ketones
(8) For a leading reference on 4-hydroxy-substituted piperidine
synthesis via methyl acetate addition to arenesulfinyl imines, see:
Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855.
(9) Liu, G. C.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J.
A. J. Org. Chem. 1999, 64, 1278.
(11) Kim, D. Y.; Huh, S. C. Tetrahedron 2001, 57, 8933.
(12) Melton, J.; McMurry, J. E. J. Org. Chem. 1975, 40, 2138.
(13) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999,
40, 6709.
(14) Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane,
S.; Hattori, K.; Yamamoto, H. J. Am.Chem. Soc. 1983, 105, 2831.
(10) Dixon, D. J.; Ley, S. V.; Rodr´ıguez, F. Org. Lett. 2001, 3, 3753.
J. Org. Chem, Vol. 70, No. 18, 2005 7343

Peltier and Ellman
TABLE 2. Generality of Michael Addition to r,â-Unsaturated Ketones
entry
imine
R1
ketone
R2
R3
T (°C)
-78
time (h)
yielda (%)
drb
product
1
2
3
4
5
1a
1a
1b
1c
1d
Ph
Ph
t-Bu
i-Pr
Et
2b
2c
2b
2b
2a
Me
Ph
Me
Me
Me
Ph
Me
Ph
Ph
Me
1.0
22
6.0
4.5
6.0
82
60
61
72
>99:1
>99:1
>99:1
>99:1
n.d.
3bc
3c
3d
3e
3f
-78 to -20
-78
-78
-78
<50
a Isolated yield. b Determined by LCMS. c 85% yield, >99:1 dr obtained without use of ZnBr2.
TABLE 3. Addition of 1a to Nitroalkenes 5
entry
solvent
nitroalkene
R
base
additive
dra
yieldb (%)
product
1
2
3
4
5
6
7
8
THF
THF
THF
Et2O
THF
THF
THF
THF
5a
5a
5a
5a
5a
5b
5b
5b
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
LDA
none
75:25
75:25
75:25
42:58
40:60
n.d.
88
6a
6a
6a
6a
6a
6b
6b
6b
LDA
ZnBr2
MgBr2
none
n.d.
n.d.
n.d.
n.d.
n.d.
70
LDA
LDA
NaHMDS
LDA
LDA
LDA
none
none
ZnBr2
MgBr2
76:24
79:21
92
b
a Determined by LCMS. Isolated yield of analytically pure material.
SCHEME 2. Stereoselective Reduction of
N-Sulfinyl Imines
SCHEME 3. Conversion of N-Sulfinylamino
Ketones to 2,4,6-Trisubstituted Piperidines
synthesis of piperidines in several respects. Importantly,
this methodology installs an alkyl group in the 4-position
of the piperidine ring, which is difficult to accomplish by
other routes. Furthermore, because both the 2,6-cis-4-
trans- and 2,4,6-cis-trisubstituted piperidine isomers can
be accessed depending on the configuration of the sulfi-
namide and selection of the appropriate reductant, four
of the eight possible piperidine diastereomers can poten-
tially be synthesized with high selectivity.
analysis of the corresponding Mosher amide, which also
served to define the sense of induction in the Michael
addition step. The relative stereochemistry for 4b and
4c was established by an observed NOE between the
protons at the 2- and 6-positions of the piperidine rings.
The 1,4-addition methodology described here comple-
ments previously reported methods for the asymmetric
7344 J. Org. Chem., Vol. 70, No. 18, 2005

N-Sulfinyl Metalloenamine Conjugate Additions
Conclusion
method should find wide application in the asymmetric
syntheses of a range of substituted derivatives.
The first examples of the conjugate addition of N-
sulfinyl metalloenamines to Michael acceptors are re-
ported. High yields are observed for additions to both
nitroalkene and R,â-unsaturated ketone acceptors, with
the additions to R,â-unsaturated ketones proceeding with
very high diastereoselectivity (97:3 to 99:1 dr). This
method is general for both alkyl- and aryl-substituted
R,â-unsaturated ketones and metalloenamines derived
from N-sulfinyl ketimines with either aryl or branched
alkyl substituents. The ketone addition products could
then be rapidly converted to 2,4,6-trisubstituted pip-
eridines with good yields and high selectivities. Given
the abundance of natural products and biologically active
compounds that contain the piperidine moiety, this
Acknowledgment. This work was supported by the
National Science Foundation (CHE-0446173). We thank
Dr. Allen G. Oliver and Dr. Frederick J. Hollander for
solving the X-ray crystal structure. The Center for New
Directions in Organic Synthesis is supported by Bristol-
Myers-Squibb as a sponsoring member and Novartis as
a supporting member.
Supporting Information Available: Full experimental
details, spectral data, characterization for all new compounds,
and crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JO051020S
J. Org. Chem, Vol. 70, No. 18, 2005 7345