Dynamic kinetic resolution in the stereoselective synthesis of 4,5-diaryl cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric transfer hydrogenation

Article abstract of DOI:10.1039/c0cc05289b

The dynamic kinetic resolution of 4,5-diaryl cyclic sulfamidate imines was achieved via asymmetric transfer hydrogenation using a HCO₂H/Et ₃N mixture as the hydrogen source and chiral Rh catalysts (R,R)- or (S,S)-RhCl(TsDPEN)Cp* affo

Full text of DOI:10.1039/c0cc05289b

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COMMUNICATION
Dynamic kinetic resolution in the stereoselective synthesis of 4,5-diaryl
cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric
transfer hydrogenationw
Juae Han,ab Soyeong Kangab and Hyeon-Kyu Lee*ab
Received 30th November 2010, Accepted 31st January 2011
DOI: 10.1039/c0cc05289b
The dynamic kinetic resolution of 4,5-diaryl cyclic sulfamidate
imines was achieved via asymmetric transfer hydrogenation
using a HCO2H/Et3N mixture as the hydrogen source and
chiral Rh catalysts (R,R)- or (S,S)-RhCl(TsDPEN)Cp* affording
the corresponding cyclic sulfamidates in good yields with up to
420 : 1 dr and up to 499% ee.
Dynamic kinetic resolution (DKR), which combines a kinetic
resolution step with an in situ equilibration or racemization of
a configurationally labile substrate, serves as an efficient
method to generate optically pure compounds from racemic
substrates.1
Asymmetric transfer hydrogenation (ATH), using hydrogen
sources other than molecular hydrogen, has proven to be one
of the most powerful general procedures for asymmetric
reduction of ketones or imines, which yields the corresponding
chiral alcohols and amines because of its operational simplicity,
the easy availability of hydrogen sources, and ability to use
readily accessible and less sensitive catalysts.2 In this context,
transition metal-catalyzed asymmetric transfer hydrogenation
of configurationally labile carbonyl compounds via DKR has
emerged as an efficient and powerful technique for controlling
the stereochemistry at two contiguous stereogenic centers
formed in the process. Examples of this application include
ATH of a-substituted b-keto esters,3 b-keto amides,4 b-keto
sulfones,5 2-substituted cycloalkanones,6 1,3-diketones7 and
1,2-diketones.8 However, to our knowledge only one report
exists describing ATH reactions of imines that are accompanied
by DKR.9
Scheme 1 DKR in the Rh-catalyzed ATH reaction of racemic
4,5-disubstituted cyclic imine 4 and 6a.
labile stereogenic center, is accompanied by DKR although
the levels of stereoselectivity were not high (5: 75% ee, 99%
yield, Scheme 1). In considering ways to improve the stereo-
chemical performance of ATH–DKR reactions of cyclic
sulfamidate imines, we envisioned that introduction of aryl
groups at the 5-positon of 4 instead of an alkyl group would
enhance the lability of the hydrogen at the stereogenic center
and that this might lead to more rapid racemization and an
improved level of stereoselectivity.
In this communication, we describe the results of a recent
effort guided by this proposal, which has led to the first
examples of highly efficient and practical ATH-based DKR
reactions of cyclic imines 6 for the synthesis of chiral 4,5-diaryl
substituted cyclic sulfamidates 7. The resulting 4,5-diaryl
cyclic sulfamidates 7 possess both an amine substituted chiral
carbon and a reactive cyclic sulfamidate group, and are
valuable precursors in the synthesis of various chiral 1,2-
functionalized amine derivatives.11 The requisite 4,5-diaryl
cyclic imines 6, probed in this study, are conveniently prepared
from readily available benzoins and sulfamoyl chloride by
using a modification of a previously described procedure.10
Reduction of racemic imine 6a employing a mixture of
HCO2H/Et3N in the presence of the (R,R)-Rh-1 catalyst
(S/C = 200) in EtOAc for 0.5 h at room temperature produces
a mixture of stereoisomeric 4,5-cis-sulfamidates, in which the
(4S,5R)-7a isomer predominates (98% ee, 99% yield,
Scheme 1). No 4,5-trans-sulfamidates were detected in the
crude product mixture by using 1H-NMR analysis. Therefore,
Recently we described a highly efficient procedure for ATH
of prochiral cyclic sulfamidate imines with HCO2H/Et3N as
the hydrogen source and well-defined chiral Rh complexes as
catalysts.10 In this earlier effort, we demonstrated that ATH of
4-phenyl-5-methyl cyclic imine 4, having a configurationally
a Drug Discovery Division, Korea Research Institute of Chemical
Technology, PO Box 107, Yuseong, Daejeon 305-600, Korea
b Medicinal and Pharmaceutical Chemistry Major, University of
Science and Technology, 113 Gwahango, Yuseong, Daejeon 305-333,
Korea. E-mail: leehk@krict.re.kr; Fax: +82 42 8607160;
Tel: +82 42 8607016
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds. CCDC
803456 contains the crystallographic data for (4S,5R)-7a. See DOI:
10.1039/c0cc05289b
c
4004 Chem. Commun., 2011, 47, 4004–4006
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the results show that hydrogen addition occurs only from the
less hindered face of the cyclic imine moiety in 6a.3d
the (R,R)-Rh-1 catalyst (Table 1, entries 1 and 2). These
observations suggest that the stereogenic center of imine 6a
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.14 In addition, the results
in Table 1 show that substituents on the 5-phenyl group of
cyclic imine 6 greatly influence the rate and stereoselectivity of
the ATH–DKR process. Cyclic imines 6 bearing electron-
withdrawing groups, such as chloro (6c, 6d), fluoro (6e), or
trifluoromethyl (6f), at the meta- or para-positions of the
4,5-diaryl moiety are smoothly converted to the corresponding
cyclic sulfamidates 7 in excellent yields and stereoselectivities.
However, imine with the ortho-chloro phenyl (6b) group reacts
to afford the corresponding cyclic sulfamidate (7b) with
high yield but with very low enantioselectivity (22% ee,
Table 1, entry 3).
To optimize the reaction conditions the influence of solvents
on ATH–DKR reaction of 6a was investigated. The cyclic
imine 6a (0.1 M) in the solvents tested (EtOAc, CH2Cl2, THF,
DMF, MeOH, toluene, CH3CN) is completely converted to
the cyclic sulfamidate 7a within 0.5 h at room temperature,
with high levels of stereoselectivity.12 The exception to this
trend is the reaction in MeOH which takes place more slowly
than in the other solvents (2 h, 66% yield). Interestingly, 6a
is completely converted to 7a, employing HCO2H/Et3N
(6a : HCO2H : Et3N = 1 : 2 : 2) as the hydrogen source with
excellent stereoselectivity (97% ee, 89%) even when no solvent
is used. For the sake of experimental convenience, all further
reactions were carried out in EtOAc as solvent. The
ATH–DKR reaction of 6a, promoted by different transition
metal catalysts, was also explored.12 ATH reaction of 6a in
EtOAc (0.1 M) occurs to completion (98% ee, 99%) in 0.5 h
when 0.5 mol% of (R,R)-Rh-1 is used as the catalyst. Under
essentially the same conditions, the chiral Ru(II) catalyst
(R,R)-Ru-3 promotes complete reaction of 6a in 12 h with a
slightly lower enantioselectivity (90% ee, 86% yield). The
Ir(III) catalyst (R,R)-Ir-2 also brings about complete conversion
of 6a, but with a low level of enantioselectivity (2 h, 91% yield,
28% ee). The results show that the preformed (R,R)-Rh-1 is
the best catalyst for the ATH reaction of imine 6a.13
Cyclic imines 6i and 6j bearing electron-donating methyl group
at the meta- or para-positions of the 5-aryl moiety, although
forming the corresponding cyclic sulfamidates 7i and 7j in
excellent yields, display slightly low levels of stereoselectivity.15
Strong electron-donating groups at the para-position of the
5-phenyl group in 6 retard the ATH–DKR reaction. For
example, the 4,5-bis-(4-methoxy-phenyl) substituted cyclic
imine 6h is inert under the ATH reaction conditions even over
extended time periods up to 24 h. In this case, 6h is recovered
nearly quantitatively (Table 1, entry 9). In sharp contrast to
6h, the 4,5-bis-(3-methoxy-phenyl) substituted cyclic imine 6g
is smoothly reduced within 0.5 h to form the corresponding
cyclic sulfamidate 7g in excellent yield but with a slightly lower
enantioselectivity15 (94% ee, Table 1, entry 8).
Under the optimized reaction conditions, ATH reactions
with various imines 6, possessing both electron-donating and
electron-withdrawing substituents on the 4,5-phenyl groups,
were carried out to examine the scope and limitations of the
ATH process and the results are summarized in Table 1.
ATH reaction of 6a employing the (S,S)-Rh-1 catalyst
produced the antipodal sulfamidate (4R,5S)-7a with almost
same efficiency and stereoselectivity (97% ee, 99%) as with
ATH–DKR reactions of cyclic imines having different
aromatic groups at the 4 and 5 positions of imine 6 were also
investigated. ATH reactions of 4-(4-chloro-phenyl)-5-phenyl
Table 1 Rh-catalyzed ATH–DKR reaction of cyclic imines 6a
Entry
Imine
R1
R2
Amine
Yieldb (%)
drc
eed (%)
Config.e
1
2
3
4
5
6
7
8
6a
6a
6b
6c
6d
6e
6f
6g
6h
6i
Ph
Ph
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
4-F-Ph
4-CF3-Ph
3-MeO-Ph
4-MeO-Ph
3-Me-Ph
4-Me-Ph
4-Cl-Ph
4-Cl-Ph
4-Me-Ph
Ph
Ph
7a
7a
7b
7c
7d
7e
7f
7g
7h
7i
99
99
99
99
99
94
99
99g
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
—
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
98
97
22
99
99
99
99
94
—
89
87
97
99
99
4S,5R
4R,5Sf
4S,5R
4S,5R
4S,5R
4S,5R
4S,5R
4S,5R
—
4S,5R
4S,5R
4S,5R
4S,5R
4S,5R
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
4-F-Ph
4-CF3-Ph
3-MeO-Ph
4-MeO-Ph
3-Me-Ph
4-Me-Ph
Ph
h
9
—
10
11
12
13
14
99g
99g,i
98
6j
6k
6l
7j
7k
7l
4-Me-Ph
4-Cl-Ph
99g,i
94
6m
7m
a
b
6 (0.2 mmol), 2.0 mL of EtOAc, 0.2 mL of HCO2H/Et3N (5 : 2) mixture, (R,R)-Rh-1 catalyst (0.5 mol%) at 25 1C for 0.5 h. Isolated
yields. Only a single diastereomer was detected in the 1H-NMR of the crude reaction mixture. ee was determined by using chiral HPLC.
c
d
e
Absolute configuration of 7a was determined by X-ray crystallographic analysis (CCDC 803456w) and those of the others are assigned by analogy
of 7a. (S,S)-Rh-1 catalyst was used. Crude yields. No reaction. Reaction time: 15 min.
f
g
h
i
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4004–4006 4005

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stereogenic centers are produced simultaneously with excellent
levels of diastereoselectivity (420 : 1) and enantioselectivity (as
high as 499% ee). Finally, the absolute configurations of the
stereocenters formed in ATH–DKR reactions of imines 6 are
controlled by the stereochemistry of the Rh-catalysts employed.
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.
Notes and references
1 (a) R. Noyori, M. Tokunaga and M. Kitamura, Bull. Chem. Soc.
Jpn., 1995, 68, 36; (b) H. Pellissier, Tetrahedron, 2008, 64, 1563.
2 (a) T. Ikariya and A. J. Blacker, Acc. Chem. Res., 2007, 40, 1300;
(b) J. S. M. Samec, J.-E. Backvall, P. G. Andersson and P. Brandt,
Chem. Soc. Rev., 2006, 35, 237; (c) S. Gladiali and E. Alberico,
Chem. Soc. Rev., 2006, 35, 226; (d) T. Ikariya, K. Murata and
R. Noyori, Org. Biomol. Chem., 2006, 4, 393; (e) R. Noyori,
M. Yamakawa and S. Hashiguchi, J. Org. Chem., 2001, 66, 7931.
3 (a) D. Cartigny, K. Puntener, T. Ayad, M. Scalone and
V. Ratovelomanana-Vidal, Org. Lett., 2010, 12, 3788;
(b) B. Mohar, A. Valleix, J.-R. Desmurs, M. Felemez,
A. Wagner and C. Mioskowski, Chem. Commun., 2001, 2572;
(c) L. H. Bourdon, D. J. Fairfax, G. S. Martin, C. J. Mathison
and P. Zhichkin, Tetrahedron: Asymmetry, 2004, 15, 3485;
(d) B. Seashore-Ludlow, P. Villo, C. Hacker and P. Somfai, Org.
Lett., 2010, 12, 5274.
Scheme 2 Conversion of cyclic sulfamidates to 1,2-functionalized
amines.
cyclic imine (6k), 4-(4-chloro-phenyl)-5-(4-methyl-phenyl) cyclic
imine (6l) or 4-(4-methyl-phenyl)-5-(4-chloro-phenyl) cyclic
imine (6m) all take place smoothly to generate the corresponding
cyclic sulfamidates 7k, 7l and 7m with excellent yields and
enantioselectivities (Table 1, entries 12–14).
The nature of substituents on the 5-aryl group of the cyclic
imines 6 greatly influences not only the reactivity and stereo-
selectivity of the ATH reaction but also the stability of the
ATH products. For example, cyclic sulfamidates 7g, 7i, 7j
and 7l, having electron donating groups on the meta- or
para-positions of their 5-phenyl moieties, are unstable under
the reaction conditions on the extended reaction time (40.5 h
at rt) or when subjected to silica-gel column chromatographic
purification.15
4 J. Limanto, S. W. Krska, B. T. Dorner, E. Vazquez, N. Yoshikawa
and L. Tan, Org. Lett., 2010, 12, 512.
5 Z. Ding, J. Yang, T. Wang, Z. Shen and Y. Zhang, Chem.
Commun., 2009, 571.
6 (a) R. Fernadez, A. Ros, A. Magriz, H. Dietrich and
J. M. Lassaletta, Tetrahedron, 2007, 63, 6755; (b) A. Ros,
A. Magriz, H. Dietrich, J. M. Lassaletta and R. Fernadez,
Tetrahedron, 2007, 63, 7532; (c) A. Ros, A. Magriz, H. Dietrich,
R. Fernandez, E. Alvarez and J. M. Lassaletta, Org. Lett., 2006, 8,
127; (d) N. J. Alcock, I. Mann, P. Peach and M. Wills,
Tetrahedron: Asymmetry, 2002, 13, 2485.
7 (a) F. Eustache, P. I. Dalko and J. Cossy, Org. Lett., 2002, 4, 1263;
(b) F. Eustache, P. I. Dalko and J. Cossy, Tetrahedron Lett., 2003,
44, 8823; (c) J. Cossy, F. Eustache and P. I. Dalko, Tetrahedron
Lett., 2001, 42, 5005.
The cyclic sulfamidates 7 produced in these reactions are
valuable precursors for the synthesis of various chiral
1,2-functionalized amine derivatives.11 An example of the
usefulness of 7a was shown by the facile conversion of its
N-Boc derivative (4S,5R)-7a (Scheme 2, eqn (1)) to the chiral
aminophosphine 8a, which is a potentially valuable chiral
ligand for transition metal catalyzed asymmetric trans-
formations.16 To further demonstrate the usefulness of the
methodology developed in this effort, the 4,5-differentially
substituted cyclic sulfamidate 7m was transformed into the
corresponding 1,2-differentially substituted diaryl ethylene-
diamine 9m and diaryl aminoethanol 10m, substances that
are difficult to prepare by using alternative routes (Scheme 2,
eqn (2) and (3)).
8 (a) T. Koike, K. Murata and T. Ikariya, Org. Lett., 2000, 2, 3833;
(b) K. Murata, K. Okano, M. Miyagi, H. Iwane, R. Noyori and
T. Ikariya, Org. Lett., 1999, 1, 1119.
9 A. Ros, A. Magriz, H. Dietrich, M. Ford, R. Ferna
J. Lassaletta, Adv. Synth. Catal., 2005, 347, 1917.
´
ndez and
10 S. Kang, J. Han, E. S. Lee, E. B. Choi and H.-K. Lee, Org.Lett.,
2010, 12, 4184.
11 (a) J. F. Bower, J. Rujirawanich and T. Gallagher, Org. Biomol.
Chem., 2010, 8, 1505; (b) R. E. Melendez and W. D. Lubell,
Tetrahedron, 2003, 59, 2581.
In summary, a convenient and highly stereoselective method-
ology for the preparation of 4,5-diaryl cyclic sulfamidates 7
has been developed. This process, involving asymmetric transfer
hydrogenation accompanied by dynamic kinetic resolution
(ATH–DKR), uses HCO2H/Et3N as the hydrogen source
and the well-defined chiral Rh catalysts (S,S)- or (R,R)-Rh-1,
Cp*RhCl(TsDPEN). Most of the 4,5-diaryl cyclic imine
substrates 6 probed undergo highly stereoselective ATH–DKR
reactions rapidly (within 30 min) under mild and experimentally
convenient conditions (room temperature, without the need for
solvent degassing or an inert atmosphere). The exception to this
general rule is imine 6h that has a strong electron-donating
group at the para-position of the 5-phenyl group. Moreover, in
the ATH–DKR reactions of cyclic imines 6, two contiguous
12 See ESIw.
13 The amount of catalyst loading can be reduced to 0.05 mol% (S/C
= 2000) with longer reaction time to complete the reaction without
loss of the optical purity (15 h, 98% ee, 94% yield).
14 Optically active (5S)-6a (85% ee) was prepared and allowed to stir
in an EtOAc solvent in the presence of only Et3N at room
temperature. After 0.5 h, no reduction products were obtained
and racemic 6a (0.4% ee) was recovered quantitatively with almost
complete loss of the optical purity (see ESIw, 6-1 and 6-2).
15 We assume that the relatively lower enantioselectivities of 7g, 7i
and 7j partially come from the instability of 7g, 7i and 7j under the
chiral HPLC column conditions for measurement of ee. In fact, the
ee’s of chromatographically stable N-Boc-7g (98% ee), N-Boc-7i
(91% ee) and N-Boc-7j (93% ee), which were prepared from the
corresponding 7g, 7i and 7j, are higher than those of 7g, 7i and 7j12
.
16 R. Guo, S. Lu, X. Chen, C.-W. Tsang, W. Jia, C. Sui-Seng,
D. Amoroso and K. Abdur-Rashid, J. Org. Chem., 2010, 75, 937.
c
4006 Chem. Commun., 2011, 47, 4004–4006
This journal is The Royal Society of Chemistry 2011