Stereoselective synthesis of β-substituted β-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines

Article abstract of DOI:10.1021/ol053132b

A highly stereoselective synthesis of β-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines is described. The addition reaction proceeds in good yield (75-99%) and stereoselectivity.

Full text of DOI:10.1021/ol053132b

ORGANIC
LETTERS
2006
Vol. 8, No. 4
789-792
Stereoselective Synthesis of
-Substituted -Amino Sulfones and
Sulfonamides via Addition of Sulfonyl
Anions to Chiral N-Sulfinyl Imines
â
â
Francisco Vela´zquez,* Ashok Arasappan, Kevin Chen, Mousumi Sannigrahi,
Srikanth Venkatraman, Andrew T. McPhail,† Tze-Ming Chan, Neng-Yang Shih, and
F. George Njoroge
Schering-Plough Research Institute, 2015 Galloping Hill Road,
Kenilworth, New Jersey 07033-1300
francisco.Velazquez@spcorp.com
Received December 26, 2005
ABSTRACT
A highly stereoselective synthesis of
â-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines is described.
The addition reaction proceeds in good yield (75−99%) and stereoselectivity.
Optically active â-amino sulfones and â-amino sulfonamides
have been identified as valuable molecules which display
interesting biological properties. â-Amino sulfones in par-
ticular have been identified as HIV protease inhibitors,1
MMP-13 inhibitors for treatment of rheumatoid arthritis,2
and DNA alkylating agents for cancer treatment.3 Addition-
ally, â-amino sulfones are useful synthetic intermediates as
exemplified by their utility in the synthesis of allylic amines.4
Likewise, â-amino sulfonamides are important structural
motifs found in biologically active molecules.5 Synthetic
methodologies for the preparation of racemic â-amino
sulfones and sulfonamides have previously been reported.6
Their asymmetric synthesis has also been achieved via aza-
Michael addition of chiral amines to R,â-unsaturated sulfones
and sulfoxides.7 The same process employing achiral amines
and optically active R,â-unsaturated sulfones and sulfoxides
as reactive partners has also been described.8 However, in
many cases these reactions proceeded with low stereoselec-
tivity and separation of the corresponding diastereomeric
products was laborious.
† Current address: Department of Chemistry, Duke University, Durham,
NC 27708.
(1) Tamamura, H.; Koh, Y.; Ueda, S.; Sasaki, Y.; Yamasaki, T.; Aoki,
M.; Maeda, K.; Watai, Y.; Arikuni, H.; Otaka, A.; Mitsuya, H.; Fujii, N. J.
Med. Chem. 2003, 46, 1768.
(2) Becker, D. P.; Barta, T. E.; Bedell, L.; DeCrescenzo, G.; Freskos,
J.; Getman, D. P.; Hockerman, S. L.; Li, M.; Mehta, P.; Mischke, B.; Munie,
G. E.; Swearingen, C.; Villamil, C. I. Bioorg. Med. Chem. Lett. 2001, 11,
2719.
(3) McIntyre, J. A.; Castaner, J. Drugs Future 2004, 29, 985.
(4) Lehman de Gaeta, L. S.; Czarniecki, M. J. Org. Chem. 1989, 54,
4004.
(5) (a) Wada, C. K.; Holms, J. H.; Curtin, M. L.; Dai, Y.; Florjancic, A.
S.; Garland, R. B.; Guo, Y.; Heyman, H. R.; Stacey, J. R.; Steinman, D.
H.; Albert, D. H.; Bouska, J. J.; Elmore, I. N.; Goodfellow, C. L.; Marcotte,
P. A.; Tapang, P.; Morgan, D. W.; Michaelides, M. R.; Davidsen, S. K. J.
Med. Chem. 2002, 45, 219. (b) Yamaguchi, M.; Nakao, H.; Goto, M.;
Morimoto, M.; Fujioka, S.; Tohnishi, M. PCT Int. Appl. WO 2004018415,
2004. (c) Burrows, J. N.; Tucker, H. PCT Int. Appl. WO 2004006925, 2004.
(6) (a) Naimi-Jamal, M. R.; Ipaktschi, J.; Saidi, M. R. Eur. J. Org. Chem.
2000, 1735. (b) Mladenova, M. Synth. Commun. 1986, 16, 1089.
(7) (a) Enders, D.; Mu¨ller, S. F.; Raabe, G.; Runsink, J. Eur. J. Org.
Chem. 2000, 879. (b) Enders, D.; Mu¨ller, S. F.; Raabe, G. Angew. Chem.,
Int. Ed. 1999, 38, 195.
10.1021/ol053132b CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/19/2006

Herein, we describe an efficient method for the synthesis
of optically active substituted â-amino sulfones and sulfon-
amides via addition of lithiated sulfones/sulfonamides (sul-
fonyl anions) to chiral N-sulfinyl imines. This methodology
represents a new application for chiral N-sulfinyl imines.9
The addition of sulfonyl anions to N-sulfinyl imines for rapid
access to optically active â-amino sulfones and sulfonamides
has not been extensively explored.10 However, addition of
chiral sulfinyl anions to chiral N-sulfinyl imines has been
reported.11 Recently, the addition of lithiated difluoromethyl
phenyl sulfone to N-sulfinyl imines for the synthesis of
R-difluoromethylamines was reported.12
Table 1. Addition of Lithiated Sulfones/Sulfonamides to Chiral
N-Sulfinyl Imines 2-5
sulfone/
sulfonamide
major
product
yield
(%)a
entry
imine
drb
1
2
3
4
5
6
7
8
(S)-2
(S)-2
(S)-3
(S)-3
(S)-4
(S)-4
(R)-5
(R)-5
6a
6b
6a
6b
6a
6b
6a
6b
(2R,4S)-7
(2R,4S)-8
(2R,4S)-9
(2R,4S)-10
(2R,4S)-11
(2R,4S)-12
(2S,4R)-13
(2S,4R)-14
76
75
84
82
81
91
99
80
3:1c
3:1c
3:1c
8:1c
3:1c
3:1c
10:1d
6:1d
N-sulfinyl imines were synthesized for this study from
commercially available (S)-p-tolyl sulfinamide (for imines
2-4) and (R)-p-tolyl sulfinamide (for imine 5) following
reported procedures.13 N-Sulfinyl imines bearing different
R1 groups (Et, Ph, i-Pr, t-Bu) were chosen for this study to
investigate the influence of substitution on the stereochemical
outcome of the addition reactions. First, we investigated the
synthesis of â-substituted â-amino sulfones/sulfonamides.
Addition of sulfonyl anions to the chiral N-sulfinyl imines
was expected to occur with good facial selectivity to form a
new stereogenic center with an adequate level of stereocon-
trol. Initially, addition to imines was explored by reacting
the sulfonyl anion (1.0 equiv) derived from tert-butyl methyl
sulfone (6a) and n-butyllithium with N-sulfinyl imine R-5
at low temperature (-78 °C).14 We observed clean addition
of the lithiated sulfone to give â-aminosulfone 13. However,
unreacted N-sulfinyl imine was observed even after warming
the reaction mixture (0 °C). After some experimentation, we
found that complete and rapid (20 min) addition to the imine
could be achieved by using excess sulfonyl anion to give 13
in excellent (99%) yield as a 10:1 mixture of diastereomers
(entry 7, Table 1). The stereochemistry of the newly created
stereogenic center was determined to be R based on single-
crystal X-ray analysis.15 Furthermore, no difference in yield
and selectivity was observed when using other bases such
as NaHMDS. We then investigated the addition of lithiated
N,N-dimethyl sulfonamide 6b to imine R-5 under the same
conditions. In this reaction, addition occurred cleanly to
afford â-amino sulfonamide 14 in 80% yield albeit with
lower selectivity (entry 8). With the optimized conditions,
a Isolated yield. b Determined by HPLC analysis of crude mixtures.
c Diastereomeric ratio for (2R,4S):(2S,4S) isomers. d Diastereomeric ratio
for (2S,4R):(2R,4R) isomers.
we explored addition of sulfonyl anions derived from 6a and
6b to other N-sulfinyl imines. The results are shown in Table
1.16
Addition of lithiated sulfone 6a to imine S-2 cleanly
delivered â-amino sulfone 7 in moderate yield without
detecting enamine byproducts arising from R-deprotonation
of the imine (entry 1). Likewise, lithiated sulfonamide 6b
added to imine S-2 to give compound 8 with similar yield
and selectivity (entry 2). Then, addition of lithiated sulfone
6a to imine S-3 gave the â-amino sulfone 9 as a 3:1 mixture
of diastereomers (entry 3). In contrast, when lithiated
sulfonamide 6b was reacted with imine S-3 the reaction
proceeded with slightly better selectivity to give an 8:1
mixture of diastereomers (entry 4). Addition of lithiated
sulfone 6a or sulfonamide 6b to imine S-4 gave the
corresponding products 11 and 12 in good yields but poor
diastereoselectivities were observed (entries 5 and 6). The
poor diastereoselectivity observed in the addition of lithiated
sulfone 6a to N-sulfinyl imines S-2, S-3, and S-4 (entries 1,
3, and 5) suggests that similar levels of stereoinduction are
obtained from Et, Ph, or i-Pr groups in the imine.
We then turned our attention to the synthesis of R,â-
substituted â-amino sulfones/sulfonamides. Our interest was
to investigate the stereochemical outcome of addition reac-
tions when using prochiral sulfonyl anions to create two new
stereogenic centers. As mentioned earlier, the stereochemistry
of the â-stereocenter in the product arises from facial
selectivity on the N-sulfinyl imine moiety. However, it was
important to determine the level of stereoinduction that could
be achieved for the R-stereocenter of the addition products.
(8) Ma, D.; Zhu, B.; Xu, H. Tetrahedron Lett. 2002, 43, 8511.
(9) For recent reviews on the chemistry of N-sulfinyl imines see: (a)
Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(b) Zhou, P.; Chen, B.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(10) One example on the addition of lithiated sulfones to chiral N-sulfinyl
imines has been reported: Balasubramanian, T.; Hassner, A. Tetrahedron:
Asymmetry 1998, 9, 2201.
(11) (a) Garc´ıa Ruano, J. L.; Alcudia, A.; del Prado, M.; Barros, D.;
Maestro, M. C.; Ferna´ndez, I. J. Org. Chem. 2000, 65, 2856. (b) Garc´ıa
Ruano, J. L.; Alema´n, J.; Parra, A. J. Am. Chem. Soc. 2005, 127, 13048.
(12) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882.
(13) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278.
(14) See the Supporting Information for detailed experimental procedures
for addition reactions and synthesis of imines and sulfones.
(15) Single-crystal X-ray analysis was performed for â-amino sulfone
16 and the configuration of the rest of the addition products was assigned
by analogy based on the proposed transition state.
(16) A number of addition products were N-deprotected under acidic
conditions. The N-sulfinyl group was readily cleaved by treatment of
methanolic solutions of addition products with 4 M HCl in dioxanes to
give the corresponding amine hydrochloride salts.
790
Org. Lett., Vol. 8, No. 4, 2006

Toward this end, we explored the addition of lithiated tert-
butyl ethyl sulfone 15a to imine R-5. We were delighted to
see that addition occurred with excellent stereocontrol for
both R- and â-stereocenters to afford disubstituted â-amino
sulfone 16 as a single diastereomeric product in 90% yield
(entry 1, Table 2). The absolute stereochemistry for this
Table 2. Synthesis of R,â-Substituted â-Amino Sulfones/
Sulfonamides via Addition of Sulfonyl Anions to Chiral
N-Sulfinyl Imines
Figure 2. Proposed transition state for addition of lithiated sulfone
15a to N-sulfinyl imine R-5.
butyl group in the imine (Figure 2). Similarly, addition of
lithiated adamantyl ethyl sulfone 15b to imine R-5 gave
disubstituted â-amino sulfone 17 as a single diastereomer
in excellent yield (entry 2).
The synthesis of R,â-substituted â-amino sulfonamides
was also investigated. The stereoinduction for the reaction
of lithiated N,N-dimethyl sulfonamide 15c with imine R-5
was also remarkable giving sulfonamide product 18 as a
single diastereomer in good yield (entry 3). Likewise,
addition of lithiated sulfolane (15d) to imine R-5 cleanly
delivered cyclic sulfone 19 in excellent yield (92%) as a
single diastereomer (entry 4). However, when we investigated
the addition of lithiated sulfolane (15d) to imines S-2 and
S-4, a decrease in yield and selectivity was observed (entries
5 and 6). These results are in agreement with the proposed
open transition state whereby smaller R1 substituents in the
imine moiety led to diminished facial selectivity on the imine.
Addition of lithiated N-methyl sultam 15e to imine R-5 gave
a single diastereomeric product 22 in excellent yield (entry
7). Deprotonation of N-PMB sultam 15f with NaHMDS,
followed by treatment with imine S-5 gave addition product
23 as a single diastereomer in nearly quantitative yield (entry
8).
sulfone/
entry imine sulfonamide
major
product
yield
(%)a
drb
1
2
3
4
5
6
7
8e
(R)-5
(R)-5
(R)-5
(R)-5
(S)-2
(S)-4
(R)-5
(S)-5
15a
15b
15c
15d
15d
15d
15e
15f
(1R,2S,4R)-16
(1R,2S,4R)-17
(1R,2S,4R)-18
(1R,2S,4R)-19
(1S,2R,4S)-20
(1S,2R,4S)-21
(1R,2S,4R)-22
(1S,2R,4S)-23
90
92
85
92
76
86
90
91
>99:1c
>99:1c
>99:1c
>99:1c
10:1d
7:1d
>99:1c
>99:1d
a Isolated yield. b Determined by HPLC analysis of crude mixtures.
c Diastereomeric ratio for (1R,2S,4R):(1R,2R,4R) isomers. d Diastereomeric
ratio for (1S,2R,4S):(1S,2S,4S) isomers. e NaHMDS was used for deproto-
nation.
compound was assigned as (1R,2S,4R)-16 by single-crystal
X-ray analysis, Figure 1. The stereochemical outcome of the
The stereochemical outcome of the sultam addition product
23 was established via proton NMR analysis of the resultant
Mosher’s amide.17 Thus, as shown in Scheme 1, removal of
the N-sulfinyl group of 23 followed by basic workup resulted
in amine 24. Treatment of the amine 24 with commercially
available R- or S-Mosher’s acid chloride in the presence of
DIPEA afforded the Mosher’s amide 25a or 25b, respec-
tively. Stereochemical assignment of the R-center (C2) was
determined to be R by comparison of the proton chemical
shift of amides 25a and 25b.17
Further NMR studies (nOe and coupling constant) were
carried out to establish the configuration of the â-center (C1).
Thus, fixing the stereogenic center at C2 (for each of the
amides, 25a and 25b) there were two possible diastereomers,
based on the chirality at C1. For each diastereomer, there
were three possible major conformers around the C1-C2
bond, one conformation in which H1 and H2 were anti and
two in which H1 and H2 were gauche with respect to one
Figure 1. ORTEP diagram for â-amino sulfone 16.
reaction can be explained on the basis of an open transition
state in which the sulfonyl anion attacked the Re-face of the
imine resulting in stereoselective formation of the â-stereo-
center. The R-stereocenter was controlled by the approach
of the sulfonyl anion in such a manner that the methyl group
maintained antiperiplanar orientation with respect to the tert-
(17) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092. (b) Hoye, T. R.; Renner, M. K. J. Org. Chem. 1996,
61, 1, 2056.
Org. Lett., Vol. 8, No. 4, 2006
791

Scheme 1. Synthesis of Mosher’s Amide from Sultam 23
Figure 3. Observed nOe effects in Mosher’s amide 25a.
sulfones and sulfonamides to chiral N-sulfinyl imines and
delivers mono- and disubstituted â-amino sulfones/sulfona-
mides in excellent yields. The reaction proceeded with good
selectivityinthesynthesisofâ-substitutedâ-aminosulfones/sulfon-
amides and gave remarkable stereoselectivity in the synthesis
of R,â-disubstituted â-amino sulfones/sulfonamides. The
described methodology is an important tool that should find
wide application in the synthesis of biologically important
molecules.
another. The observed H1/H2 coupling constant of 4.7 Hz
for 25a was consistent with H1 and H2 in a gauche
relationship. Furthermore, nOe was observed between H1
and H2 confirming the gauche conformation (Figure 3).
Additionally, protons of the tert-butyl group (attached to C2)
exhibited nOe with H1 and H1′. These detailed NMR studies
clearly demonstrated that the configuration at the â-center
(C1) for compound 25a was S.
In summary, we have successfully developed a simple and
effective approach for the stereocontrolled synthesis of
â-amino sulfones and sulfonamides utilizing chiral N-sulfinyl
imines. The presented method involves addition of lithiated
Supporting Information Available: Experimental pro-
cedures, spectral data, crystallographic data, and copies of
spectra for selected compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL053132B
792
Org. Lett., Vol. 8, No. 4, 2006