Highly enantioselective synthesis of sultams via Pd-catalyzed hydrogenation

Article abstract of DOI:10.1021/jo900790k

(Chemical Equation Presented) Using pd(cf₃co₂) ₂/(S,S)-f-Binaphane as the catalyst, an efficient enantioselective synthesis of sultams was developed via asymmetric hydrogenation of the corresponding cyclic imines with high

Full text of DOI:10.1021/jo900790k

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cyclization protocols, including Diels-Alder reactions,3
Highly Enantioselective Synthesis of Sultams via
Pd-Catalyzed Hydrogenation
[3+2] cycloadditions,4 Friedel-Craft,5 and a number of
transition-metal-catalyzed approaches such as Heck re-
actions,6 ring-closing metathesis (RCM),7 and Rh-, Cu-,
and Au-catalyzed selective cyclizations.8 By retrosyn-
thetic analysis, asymmetric hydrogenation of the easily
synthesized cyclic N-sulfonylimines is the most conveni-
ent approach. Oppolzer9 reported the asymmetric hydro-
genation of cyclic N-sulfonylimines with Ru catalyst
systems with up to 99% ee. Baker,10 Ahn,11 Lennon,12
and Deng13 explored Rh- and Ru-catalyzed asymmetric
transfer hydrogenation of cyclic N-sulfonylimines from
saccharin with up to 81%, 93%, 87%, and 98% ee,
respectively. Zhang14 and co-workers described a Pd-
catalyzed asymmetric hydrogenation of cyclic N-sulfony-
limines with 94% ee. However, for the above-reported
hydrogenation methods, in general, only a few examples
derived from saccharin were reported. So, development of
an efficient and general method for synthesis of chiral
sultams is highly desirable.
Chang-Bin Yu, Da-Wei Wang, and Yong-Gui Zhou*
State Key Laboratory of Catalysis, Dalian Institute of
Chemical Physics, Chinese Academy of Sciences, 457
Zhongshan Road, Dalian 116023, China
ygzhou@dicp.ac.cn
Received April 16, 2009
Using pd(cf3co2)2/(S,S)-f-Binaphane as the catalyst, an
efficient enantioselective synthesis of sultams was devel-
oped via asymmetric hydrogenation of the corresponding
cyclic imines with high enantioselectivities. The hydro-
genation products can be conveniently transformed
to chiral homoallylic amines without loss of enantioselec-
tivity.
In 2007, we reported an efficient Pd-catalyzed asymmetric
hydrogenation of cyclic N-sulfonylimines 1 and 3 with 79-
93% ee using Pd(CF3CO2)2/(S)-SegPhos as catalyst.15 Only
moderate enantioselectivities were obtained for the aryl-
substituted substrates 1. This shortcoming prompted us to
seek an efficient asymmetric hydrogenation system for the
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The cyclic sulfonamides, sultams, are of enormous
importance as organic synthetic intermediates, chiral
auxiliaries with considerable success, and privileged
structures in drug discovery due to wide range of bio-
logical activities.1,2 Recently, some efficient methods
have been developed for sultams preparation by classical
*To whom correspondence should be addressed. Phone: +86-411-
84379220.
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DOI: 10.1021/jo900790k
r
Published on Web 06/09/2009
J. Org. Chem. 2009, 74, 5633–5635 5633
2009 American Chemical Society

Yu et al.
JOCNote
TABLE 1. Pd-Catalyzed Asymmetric Hydrogenation of 1a
TABLE 2. Pd-Catalyzed Asymmetric Hydrogenation of 3a
ee (%)b
entry
R of 1
yield (%)
ee (%)b
entry
R of 3
yield (%)
1
2
3
4
Ph (1a)
2-MeC6H4 (1b)
3-MeC6H4 (1c)
4-MeC6H4 (1d)
4-FC6H4(1e))
Me (1f)
99 (2a)
93 (2b)
92 (2c)
92 (2d)
89 (2e)
98 (2f)
98 (2g)
93 (2h)
93 (2i)
91 (2j)
94 (2k)
95 (2l)
90 (2m)
95 (2n)
98 (79)
98
96
97
97
94 (88)
95 (90)
91
95 (92)
94 (92)
94 (91)
95 (93)
91
1
2
3
4
5
6
7
8
9
Me (3a)
n-Bu (3b)
Bn (3c)
Ph (3d)
2-MeC6H4 (3e)
3-MeC6H4 (3f)
4-MeC6H4 (3g)
4-MeOC6H4 (3h)
4-FC6H4 (3i)
3-TBSOCH2C6H4 (3j)
3-HOCH2C6H4 (3k)
97 (4a)
99 (4b)
98 (4c)
99 (4d)
99 (4e)
97 (4f)
97 (4g)
99 (4h)
97 (4i)
95 (4j)
96 (4k)
97 (92)
97 (90)
94 (88)
98
98
98
99
98
94
98
5
6c
7c
8
n-C6H13 (1g)
C6H5CH2 (1h)
9
C6H5OCH2 (1i)
2-MeC6H4OCH2 (1j)
4-MeC6H4OCH2 (1k)
4-CF3C6H4OCH2 (1l)
C6H5CH2OCH2 (1m)
2-nphthylOCH2 (1n)
10
11
12
13
14
10
11
99
a Unless otherwise stated, reactions were performed in TFE on a
0.25 mmol scale: Pd(CF3CO2)2 (2 mol %), (S,S)-f-Binaphane (2.4 mol %),
41 bar of H2, rt, 14 h. b Ee was determined by HPLC analysis; the
numbers in parentheses were obtained by using Pd(CF3CO2)2/(S)-SegPhos
under the identical conditions.
94 (90)
a Unless otherwise stated, reactions were performed in TFE on a
0.25 mmol scale: Pd(CF3CO2)2 (2 mol %), (S,S)-f-Binaphane (2.4 mol %),
41 bar of H2, rt, 14 h. b Ee was determined by HPLC analysis; the
numbers in parentheses were obtained by using Pd(CF3CO2)2/
(S)-SegPhos under identical conditions. c Ee was determined by chiral
HPLC analysis of its N-cinnamyl derivative.
SCHEME 1. Pd-Catalyzed Asymmetric Hydrogenation of
Imine 1a on a Gram-Scale
synthesis of chiral sultams. Very recently, we found that Pd
(CF3CO2)2/(S,S)-f-Binaphane is an efficient catalyst for
asymmetric hydrogenation of prochiral activated imines.16
In our ongoing efforts to develop asymmetric hydrogena-
tion, we envisioned that chiral sultams should be synthesized
via asymmetric hydrogenation of cyclic N-sulfonylimines 1
and 3 by Pd(CF3CO2)2/(S,S)-f-Binaphane. Herein, we report
an efficient method for the enantioselective synthesis of
chiral sultams by asymmetric hydrogenation of the corre-
sponding cyclic imines using Pd(CF3CO2)2/(S,S)-f-Bina-
phane as catalyst with up to 99% ee. The hydrogenation
products can be conveniently transformed to chiral homo-
allylic amines without loss of enantioselectivity.
Cyclic imines 1 and 3 can be conveniently prepared from
commercially available materials according to the known
literature procedure.17 (S,S)-f-Binaphane was synthesized
according to the literature.18
We have previously studied the use of Pd(CF3CO2)2/
(S)-SegPhos in the asymmetric hydrogenation of cyclic
imines 1. To further improve the enantioselectivity, the
effects of ligands on the reactivity and enantioselectivity
were systematically screened by using imine 1a as model
substrate. Interestingly, when a Pd catalyst containing (S,S)-
f-Binaphane ligand was used in the asymmetric hydrogena-
tion of imines 1a, a significant increase in the ee value was
obtained in comparison with the result of using (S)-SegPhos
(entry 1 in Table 1, 79% vs. 98% ee). Inspired by the result, a
series of cyclic N-sulfonylimines 1 were hydrogenated with
high enantioselectives and yields; the results are summarized
in Table 1. For the aryl-substituted imines, the steric and
electronic effects of substituents in aryl have no significant
effect on the ee values and the yields (entries 1-5). Simple
alkyl-substituted imines (entries 6 and 7), bearing methyl and
n-hexyl groups, respectively, showed high enantioselectives
(94% and 95% ee). Benzyl-substituted imine 1h gave 91% ee.
Various aryloxymethyl- and alkoxylmethyl-substituted imi-
nes (entries 8-14) can also be successfully hydrogenated with
high enantioselectivity.
Gratifyingly, the above chiral palladium catalytic system
Pd(CF3CO2)2/(S,S)-f-Binaphane can also be extended to
asymmetric hydrogenation of assorted benzofused imines
3. As summarized in Table 2, a variety of aryl- and alkyl-
substituted cyclic sultams could be obtained in 94-99% ee
values with full conversion. For alkyl-substituted imines,
high enantioselectivities and full conversions were also ob-
tained (94-97% ee, entries 1-3, Table 2). The electronic and
steric characteristics of substituents in the substrates have no
significant influence on the enantioselectivity and reactivity.
Substrates with electron-donating or electron-withdrawing
aryl substituents can be successfully hydrogenated to give the
corresponding cyclic sultams with 94-99% ee (entries 4-11,
Table 2). Notably, the palladium catalytic system can toler-
ate hydroxyl and TBSO groups: for substrates (3j and 3k)
bearing a hydroxyl and TBSO, 98% and 99% ee were
(16) (a) Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.; Zhou,
Y.-G. Org. Lett. 2008, 10, 2071. For recent examples on Pd-catalyzed
asymmetric hydrogenation of imines and ketones, see: (b) Zhou, Y.-G.
Acc. Chem. Res. 2007, 40, 1357. (c) Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G.
Org. Lett. 2005, 7, 3235. (d) Wang, Y.-Q.; Zhou, Y.-G. Synlett. 2006, 1189.
(e) Rubio-Perez, L.; Perez-Flores, F. J.; Sharm, P.; Velasco, L.; Cabrera, A.
Org. Lett. 2009, 11, 265. (f) Suzuki, A.; Mae, M.; Amii, H.; Uneyama, K.
J. Org. Chem. 2004, 69, 5132.
(17) (a) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 31, 2647.
(b) Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379. (c) Freitag, D.; Metz, P.
Tetrahedron 2006, 62, 1799.
(18) Xiao, D.; Zhang, X.-M. Angew. Chem., Int. Ed. 2001, 40, 3425.
5634 J. Org. Chem. Vol. 74, No. 15, 2009

Yu et al.
JOCNote
SCHEME 2. The Synthesis of Chiral Homoallylic Amines from
Hydrogenation Products
The methodology also provides a convenient route to
synthesize chiral sultams with biologically activity. Com-
pound 6 (HIV-1), a chiral sultam with anti-HIV activity,21
can be conveniently synthesized with Pd catalyzed asym-
metric hydrogenation as the key step. N-Methylation of the
4k with methyl iodide gave the target 6 HIV-1 (Scheme 3).
In summary, a general method for the synthesis of chiral
3-substituted cyclic sultam derivatives has been effectively
developed via asymmetric hydrogenation of the correspond-
ing cyclic imines with Pd(CF3CO2)2/(S,S)-f-Binaphane as
catalyst under mild reaction conditions with 91-99% ee. The
hydrogenation products can be conveniently transformed to
chiral homoallylic amines without loss of enantioselectivity.
SCHEME 3. The Enantioselective Synthesis of HIV-1
Experimental Section
Typical Procedure for the Asymmetric Hydrogenation of Cyc-
lic Imine 1a. (S,S)-f-Binaphane (4.8 mg, 0.006 mmol) and Pd-
(CF3CO2)2 (1.7 mg, 0.005 mmol) were placed in a dried Schlenk
tube under nitrogen atmosphere, and degassed anhydrous acet-
one was added. The mixture was stirred at room temperature for
1 h. The solvent was removed under vacuum to give the catalyst.
This catalyst was taken into a glovebox filled with nitrogen and
dissolved in dry TFE (3 mL). The imine 1a (49 mg, 0.25 mmol)
was added to the catalyst solution, and then the mixture
was transferred to an autoclave. The autoclave was stirred
under directed condition for 12 h, then the hydrogen was care-
fully released, the autoclave was opened, and the reaction
mixture was evaporated. Conversion was determined by 1H
NMR analysis. The enantiomeric excess was determined by
HPLC after purification on silica gel with hexane and EtOAc.
3-Phenyl-1,2-thiazolidine 1,1-dioxide (2a):15 yield 99%, 98% ee,
[R]2D4 +39.6 (c 1.42, EtOH); 1H NMR (400 MHz, CDCl3)
δ 2.30-2.44 (m, 1H), 2.76-2.79 (m, 1H), 3.19-3.25 (m, 1H),
3.33-3.36 (m, 1H), 4.55 (br, 1H), 4.71-4.76 (m, 1H), 7.26-7.42
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 32.4, 48.4, 58.4, 126.2,
128.7, 129.2, 140.4. HPLC (OD-H column, iPrOH/hexane
20/80, 0.8 mL min-1, 254 nm) t1 = 19.0 min, t2 = 21.2 min.
obtained, respectively (entries 10 and 11, Table 2). It is also
noteworthy that Pd(CF3CO2)2/(S,S)-f-Binaphane catalytic
system gave higher enantioselecitivity than the Pd
(CF3CO2)2/(S)-SegPhos (entries 1-3, Table 2).
The asymmetric hydrogenation of cyclic N-sulfonylimines
1a on a gram-scale also can be carried out with 1 mol %
palladium catalyst Pd(CF3CO2)2/(S,S)-f-Binaphane in TFE
at room temperature. As illustrated in Scheme 1, the chiral
sultam 2a was obtained in 99% yield with 98% ee by flash
column chromatography.
To explore the potential synthetic utility of this new
method, we attempted its application in the synthesis of
enantiopure homoallylic amine derivatives. As can be seen
in Scheme 2, hydrogenation product 2 reacted with
TMSCH2Cl in the presence of n-BuLi to give the intermedi-
ates in moderate to good yields,19 followed by protection
of nitrogen with toluenesulfonyl chloride. Tandem desilyla-
tion and ring-opening with TBAF in THF afforded chiral
homoallylic amine derivatives without the loss of optical
purity.20
Acknowledgment. We are grateful to the financial support
from National Science Foundation of China (20872140 and
20621063) and the Chinese Academy of Sciences. Dedicated
to Prof. Li-Xin Dai on the occasion of his 85th birthday.
Supporting Information Available: Characterization of pro-
ducts and experimental details. This material is available free
of charge via the Internet at http://pubs.acs.org.
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J. Org. Chem. Vol. 74, No. 15, 2009 5635