Enantioselective synthesis of cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric transfer hydrogenation

Article abstract of DOI:10.1021/ol1017905

Asymmetric transfer hydrogenation (ATH) of cyclic sulfamidate imines 4 and 9, using a HCO₂H/Et₃N mixture as the hydrogen source and well-defined chiral Rh catalysts (S,S)- or (R,R)-2, CpRhCl(TsDPEN), effectively produces the corresponding cyclic sulfamidates with excellent yields and enantioselectivities at room temperature within 0.5 h. ATH of 4,5-disubstituted imines 9, having preexisting stereogenic centers, is shown to take place with dynamic kinetic resolution.

Full text of DOI:10.1021/ol1017905

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4184-4187
Enantioselective Synthesis of Cyclic
Sulfamidates by Using Chiral
Rhodium-Catalyzed Asymmetric Transfer
Hydrogenation
Soyeong Kang,†,‡ Juae Han,†,‡ Eun Sil Lee,† Eun Bok Choi,† and
Hyeon-Kyu Lee*,†,‡
Drug DiscoVery DiVision, Korea Research Institute of Chemical Technology, P.O. Box
107, Yuseong, Daejeon 305-600, Korea, and Medicinal and Pharmaceutical Chemistry
Major, UniVersity of Science and Technology, 113 Gwahango,
Yuseong, Daejeon 305-333, Korea
leehk@krict.re.kr
Received August 1, 2010
ABSTRACT
Asymmetric transfer hydrogenation (ATH) of cyclic sulfamidate imines 4 and 9, using a HCO2H/Et3N mixture as the hydrogen source and
well-defined chiral Rh catalysts (S,S)- or (R,R)-2, Cp*RhCl(TsDPEN), effectively produces the corresponding cyclic sulfamidates with excellent
yields and enantioselectivities at room temperature within 0.5 h. ATH of 4,5-disubstituted imines 9, having preexisting stereogenic centers, is
shown to take place with dynamic kinetic resolution.
Asymmetric transfer hydrogenation (ATH) involves the
reduction of prochiral compounds with a hydrogen source
other than hydrogen gas in the presence of a chiral catalyst.
In general, ATH offers operational simplicity since the
reaction does not involve (high pressure) molecular hydrogen
and can be carried out under areobic conditions. Owing to
its excellent selectivity, wide substrate scope, and operational
simplicity, ATH of ketones is one of the most powerful and
practical methods to access chiral alcohols in both academic
and industrial environments.1 Among the various chiral
catalysts used for ATH, transition metal complexes based
on Ru(II), Rh(III), or Ir(III) with chiral bidentate ligands,
such as N-monosulfonylated 1,2-diamines (e.g., 1-3), have
been used most frequently.1a However, compared to the
reactions of ketones, ATH-promoted conversion of imines
to chiral amines is more challenging owing to the fact that
two additional variables come into play, including the nature
of the nitrogen substituent and stereochemistry about the
CdN double bond (Scheme 1). Generally, ATH of acyclic
imines using catalysts 1-3 provides the corresponding
amines with relatively low enantioselectivities compared to
(1) (a) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300. (b)
Samec, J. S. M.; Backvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc.
ReV. 2006, 35, 237. (c) Gladiali, S.; Alberico, E. Chem. Soc. ReV. 2006,
35, 226. (d) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006,
4, 393. (e) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10,
2045. (f) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (g)
Chao, W.; Xiaofeng, W.; Jianliang, X. Chem. Asian J. 2008, 3, 1750. (h)
Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66, 7931.
† Korea Research Institute of Chemical Technology.
‡ University of Science and Technology.
10.1021/ol1017905  2010 American Chemical Society
Published on Web 08/24/2010

those observed for analogous reaction of ketones.1c,e,2-4 This
is likely a result of the different rates and selectivities of
reduction of the anti and syn isomers.1c,2 However, five- or
six-membered cyclic imines, which lack this stereochemical
issue, undergo ATH induced by catalysts 1-3 with excellent
enantioselectivities.1f,3,5,6 In addition, ATH of acyclic imines
possessing sterically bulky N-substituents, such as N-
(diphenylphosphinoyl) that causes a predominance of the anti
geometry, leads to the corresponding N-(diphenylphosphi-
noyl)amines with high degrees of enantioselectivity.7
steps.10,11 Catalytic asymmetric intramolecular amidation of
prochiral sulfamate esters using chiral Ru(II)-pybox and
valerolactam-derived Rh(II) catalysts has also been employed
to generate chiral cyclic sulfamidates with high enantiose-
lectivities.12 Recently, an efficient enantioselective synthesis
of cyclic sulfamidates (5) employing chiral Pd-catalyzed
asymmetric hydrogenation of corresponding cyclic imines
(4) has been reported.10 Although this method provides cyclic
sulfamidates 5 in high yields and ee’s, it requires the use of
high (600 psi) H2 pressures, only trifluoroethanol as the
solvent, and 2.4 mol % of the expensive chiral (S,S)-f-
binaphane ligand, of which only the (S,S) isomer is com-
mercially available.
Scheme 1
In investigations aimed at the development of new methods
for the preparation of functionalized chiral amines, we have
uncovered a highly efficient and practical ATH-based
procedure for the synthesis of chiral cyclic sulfamidates (5)
starting with the corresponding cyclic imines (4). This
methodology uses a 5:2 mixture of HCO2H and Et3N as the
hydrogen source along with the chiral Rh catalysts (S,S)- or
(R,R)-2, Cp*RhCl(TsDPEN) (Cp* ) pentamethylcyclopen-
tadienyl and TsDPEN ) (1S,2S)- or (1R,2R)-N-p-toluene-
sulfonyl-1,2-diphenylethylenediamine). The cyclic imines
employed in these processes are conveniently prepared from
hydroxyl ketones (6) and sulfamoyl chloride by using
previously described procedures.10
The cyclic imine 4a, (R,R)-2 catalyst (0.5 mol %, S/C )
200), and 5:2 mixture of HCO2H/Et3N (azeotropic mixture)13
in various solvents (EtOAc, CH2Cl2, THF, DMF, MeOH,
toluene, CH3CN) were employed in an effort aimed at
optimizing the ATH reaction conditions. The results (see
Supporting Information) show that in each case 4a is
completely converted to the cyclic sulfamidate (5a) with high
enantioselectivity within 1 h at room temperature. In addition,
ATH of 4a in ethyl acetate takes place completely in 0.5 h
even using 0.1 mol % of catalyst (R,R)-2 (S/C ) 1000), while
the reaction with 0.1 mol % of (R,R)-2 in dichloromethane
solvent requires 3.5 h. Therefore, ethyl acetate was selected
as the solvent for all of the ATH reactions of imines 4.
The preformed chiral Rh(III) complex (R,R)-25 with a 5:2
mixture of HCO2H and Et3N as the hydrogen source was
found to be the best condition for performing the ATH
reactions of the imines 4. The ATH of 4a (0.1 M in ethyl
On the basis of the factors described above, we envisioned
that the cyclic sulfamate imines 4, which are activated by
the electron-withdrawing sulfamidate group and are free of
syn- and anti-isomerism, would be good substrates for highly
enantioselective ATH reactions. Moreover, cyclic sulfami-
dates (5), possessing both a chiral carbon that bears an amine
moiety and a reactive cyclic sulfamidate group, are valuable
precursors in the syntheses of various chiral 1,2-functional-
ized amine derivatives including 1,2-amino alcohols, R-ami-
no acids, and nitrogen-containing heterocycles (Scheme 2).8,9
Typically, cyclic sulfamidates are prepared from chiral amino
alcohols and diols through routes that involve several
(2) Nugent, T. C.; El-Shazly, M. AdV. Synth. Catal. 2010, 352, 753.
(3) Haraguchi, N.; Tsuru, K.; Arakawa, Y.; Itsuno, S. Org. Biomol.
Chem. 2009, 7, 69.
Scheme 2
. 1,2-Functionalized Chiral Amines through ATH of
(4) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 4916.
Cyclic Imines 4 to Form Cyclic Sulfamidate 5
(5) Mao, J.; Baker, D. C. Org. Lett. 1999, 1, 841.
(6) Blackmond, D. G.; Ropic, M.; Stefinovic, M. Org. Process Res. DeV.
2006, 10, 457.
(7) Kwak, S. H.; Lee, S. A.; Lee, K.-I. Tetrahedron: Asymmetry 2010,
21, 800.
(8) Roszkowski, P.; Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.;
Lis, T.; Czarnocki, Z. J. Mol. Catal. A: Chem. 2005, 232, 143.
(9) Bower, J. F.; Rujirawanich, J.; Gallagher, T. Org. Biomol. Chem.
2010, 8, 1505.
(10) Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.; Zhou, Y.-G.
Org. Lett. 2008, 10, 2071.
(11) Melendez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581.
(12) (a) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 9220.
(b) Milczek, E.; Boudet, N.; Blakey, S. Angew. Chem., Int. Ed. Engl. 2008,
47, 6825.
(13) Narita, K.; Sekiya, M. Chem. Pharm. Bull. 1977, 25, 135.
Org. Lett., Vol. 12, No. 18, 2010
4185

complex. ATH of imine 4a, employing the (S,S)-2, produces
the (R)-5a enantiomer with almost the same efficiency and
enantioselectivity as is observed for formation of (S)-5a in
the reaction promoted by (R,R)-2 catalyst (Table 1, entry
2). It should be emphasized that most of the ATH reactions
desribed above take place rapidly (ca. 30 min) under mild
conditions (room temperature, without degassing or drying
of the solvent, and in air (Table 1, entry 18)) and yield
products with high efficiencies and enantioselectivities
(except for the ortho- aryl-substituted imines 4d, 4g, and
4j).
ATH of the alkyl-substituted imine 4o also occurs to
produce the corresponding sulfamidate 5o in high yield
(96%) and enantioselectivity (93% ee) (Table 1, entry 16).
However, the efficienies of reactions of alkyl imines are
sensitive to the steric bulk of the alkyl group, as is
exemplified by the t-butyl-containing imine 4p that is inert
under the ATH reaction conditions even over extended
reaction times (Table 1, entry 17).
To test the practicality of the method described above,
ATH of cyclic imine 4a was carried out on a two gram scale
(10 mmol) using 0.1 mol % of (R,R)-2 catalyst (S/C ) 1000)
at room temperature. After 1.5 h, the cyclic sulfamate (S)-
5a was generated in 99% isolated yield with 98% ee.
To demonstrate the synthetic utility of the current meth-
odology, facile conversion of the cyclic sulfamidate (R)-5a
to the optically active mexiletine analogue (R)-8 was carried
out. Mexiletine (7) is an effective sodium channel blocker
used in its racemic form as an antiarrhythmic and analgesic
oral drug even though (R)-Mexiletine is more active than
its (S)-enantiomer. The results of recent studies revealed that
the optically active mexiletine analogue (R)-8 is 27-fold more
potent than (R)-mexiletine 7 in producing a tonic block and
23-fold more potent under high frequency stimulation
conditions (phasic block).16 Therefore, efficient routes for
the preparation of the enantiomerically pure mexiletine
analogue (R)-8 are highly desirable.16,17
Table 1. Rh-Catalyzed ATH of Cyclic Imines 4a
entry
R
yield(%)b
ee(%)c
configd
1
2
3
4
5
6
7
8
Ph (4a)
Ph (4a)
98
99
98
92
95f
98
99
99
94
99
97
99
91
91
93
96
99
96
99
98
16
99
98
83
98
99
62
99
94
98
98
93g
-
S
Re
S
S
S
S
S
S
S
S
S
S
S
S
S
S
-
S
4-MeOC6H4 (4b)
3-MeOC6H4 (4c)
2-MeOC6H4 (4d)
4-MeC6H4 (4e)
3-MeC6H4 (4f)
2-MeC6H4 (4g)
4-ClC6H4 (4h)
3-ClC6H4 (4i)
2-ClC6H4 (4j)
4-FC6H4 (4k)
4-CNC6H4 (4l)
4-MeO2CC6H4 (4m)
4-NO2C6H4 (4n)
n-C6H13 (4o)
9
10
11
12
13
14
15
16
17
18
h
t-Bu (4p)
-
98
Ph (4a)i
99
a 0.5 mmol scale in 5.0 mL of EtOAc (0.1 M) with 0.5 mL of HCO2H/
Et3N (5:2) mixture and (R,R)-2 catalyst (0.5 mol %) at 25 °C for 0.5 h.
b Isolated yields. c ee was determined by HPLC analysis. d Absolute
configuration was determined by the sign of rotation of the isolated product
for the known compounds (4a, 4c, 4g, 4k, 4o) or by analogy for the
unknown compounds. e (S,S)-2 catalyst was used. f Reaction time 24 h. g ee
of N-cbz derivative of 5o (see Supporting Information). h No reaction was
observed even at an extended reaction time (5 h). i Reaction was conducted
under air.
acetate) is completed in 0.5 h with 0.5 mol % of (R,R)-2
(S/C ) 200) (98% yield, 99% ee). Under essentially the same
reaction conditions, but instead using the chiral Ru(II)
catalyst (R,R)-1,14 ATH of 4a is completed in 12 h (95%
yield, 87% ee). Reaction of 4a promoted by the analogous
Ir(III) catalyst (R,R)-315 also takes place smoothly but with
poor enantioselectivity (2 h, 99% yield, 28% ee).
A variety of imines 4 were subjected to the optimized ATH
reaction conditions (ethyl acetate, room temperature) to
examine the scope and limitations of the process. Most of
these ATH reactions take place completely within 30 min
(Table 1).
Scheme 3
.
Enantioselective Synthesis of Mexiletine Analogue
(R)-8
Cyclic imines 4 bearing meta or para electron-donating
or -withdrawing group substituted aryl substituents are
smoothly converted to the corresponding cyclic sulfamidates
5 in excellent yields and enantioselectivites (91-99% yields
and 94-99% ee) within 30 min. However, imines with ortho-
substituted aryl groups (4d, 4g, 4j) react to afford the
corresponding cyclic sulfamidates with high yields but with
low or even poor enantioselectivity. This observation sug-
gests that through steric or electronic effects ortho-substit-
uentsmightperturbtheformationofthechiralcatalyst-substrate
In the pathway for synthesis of (R)-8, the cyclic sulfami-
date (R)-5a (95% ee) is converted to N-Boc-(R)-5a which is
then reacted with 2-methylphenol in the presence of base at
room temperature for 2 h. After treatment of the reaction
(16) Franchini, C.; Carocci, A.; Catalano, A.; Cavalluzzi, M. M.; Corbo,
F.; Lentini, G.; Scilimati, A.; Tortorella, P.; Camerino, D. C.; Luca, A. D.
J. Med. Chem. 2003, 46, 5238.
(14) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285.
(17) (a) Huang, K.; Ortiz-Marciales, M.; Stepanenko, V.; De Jesus, M.;
Correa, W. J. Org. Chem. 2008, 73, 6928. (b) Koszelewski, D.; Pressnitz,
(15) Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 27, 1199.
D.; Clay, D.; Kroutil, W. Org. Lett. 2009, 11, 4810
.
4186
Org. Lett., Vol. 12, No. 18, 2010

mixture with CF3CO2H, (R)-8 is obtained in high yield (99%)
with almost no loss of the optical purity (94% ee) (Scheme
3).
indicates that the rate of reduction of imine (5R)-9 with
(R,R)-2 proceeds ca. 7 times (87.4:12.6) faster than that
of the (5S)-9 isomer with (R,R)-2 catalyst (Scheme 5).18
Scheme 4.
ATH of Racemic 4,5-Disubstituted Cyclic Imine 9a
Scheme 5
.
Dynamic Kinetic Resolution in ATH of Racemic
4,5-Disubstituted Cyclic Imine 9
a For reaction conditions, see footnote of Table 1.
ATH reaction of the 4,5-disubstituted imines 9, contain-
ing a preexisting stereogenic center, can take place to form
diastereomeic sulfamidates 10 (Scheme 4). In fact, treat-
ment of 9 with the (R,R)-2 catalyst (S/C ) 200) under
the conditions described above produces only a 4,5-cis-
sulfamidate with the major isomer being (4S,5R)-10 (75%
ee, 99% yield, Scheme 4). No 4,5-trans-sulfamidates are
detected by 1H NMR analysis of the crude reaction
mixture. Authentic samples of 4,5-cis- and 4,5-trans-
sulfamidates were independently synthesized by using
known procedures and compared with the ATH products
of 9 (see Supporting Information). The result shows that
hydrogen addition takes place preferentially from the less
hindered face of the cyclic imine 9. In a similar manner,
reduction of the racemic imine 9, using (S,S)-2, yields
only a 4,5-cis-sulfamidate, but in this case, (4R,5S)-10 is
the major isomer produced with 75% ee (99% yield).
These observations suggest that the stereogenic center of
imine 9 is configurationally labile, undergoing rapid
racemization under the ATH reaction conditions. As a
consequence, the absolute stereochemistry of the reduction
products depends on the chirality of the Rh-catalysts used,
representing an example of dynamic kinetic resolution.
In fact, treatment of optically active imine (5S)-9 (89%
ee) with a HCO2H/Et3N (5:2) mixture in the absence of
(R,R)- or (S,S)-2 catalyst (room temperature, 5 min) does
not cause formation of a reduction product, and imine
(5S)-9 is recovered in nearly quantitative yield with a 0.2%
ee, demonstrating that rapid racemization of imine (5S)-9
occurs under the reaction conditions. The stereochemical
results also suggest that reactions of the imine (5R)-9 with
the (R,R)-2 catalyst and imine (5S)-9 with the (S,S)-2
catalyst take place most rapidly. An analysis of stereo-
isomer product distributions generated in these processes
This effort has provided the first example of a reductive
transformation of unsymmetrically disubstituted cyclic imines
to the corresponding optically active cyclic sulfamidates.
In conclusion, the investigation described above has led to
the development of an asymmetric transfer hydrogenation
(ATH) reaction of cyclic sulfamidate imines 4 that uses a
HCO2H/Et3N mixture as the hydrogen source and well-defined
chiral Rh catalysts (S,S)- or (R,R)-2, Cp*RhCl(TsDPEN), and
that occurs at room temperature in ca. 0.5 h. This process
effectively produces the corresponding cyclic sulfamidates
in excellent yields and enantioselectivities. The ATH reaction
of 4-aryl imines 4 is practical, mild, rapid, and enantiose-
lective except in the cases of imines (e.g., 4d, 4 g, 4j) that
have ortho-substituted aryl groups. ATH of 4,5-disubstituted
imines 9, which contain a preexisting stereogenic center, was
found to be accompanied by dynamic kinetic resolution that
causes the stereochemical outcome of the ATH reaction to
be mainly controlled by the stereochemistry of the Rh
catalysts used.
Acknowledgment. We thank the Center for Biological
Modulators of the 21st Century Frontier R&D program
(CBM31-A1200-01-00-00) and the Korea Research Institute
of Chemical Technology for financial support.
Supporting Information Available: Experimental pro-
cedures for the asymmetric transfer hydrogenation and
characterization data for all new compounds including the
1
copies of H and 13C NMR spectra and chromatograms for
the determination of enantiomeric excess of all chiral
compounds on chiral HPLC. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn 1995,
68, 36.
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