Nonenzymatic kinetic resolution of secondary alcohols: Enantioselective SN2 displacement of hydroxy groups by halogens in the presence of chiral BINAP

Full text of DOI:10.1021/ja010029i

J. Am. Chem. Soc. 2001, 123, 3603-3604
Nonenzymatic Kinetic Resolution of Secondary
3603
Alcohols: Enantioselective SN2 Displacement of
Hydroxy Groups by Halogens in the Presence of
Chiral BINAP
Govindasamy Sekar and Hisao Nishiyama*
School of Materials Science
Toyohashi UniVersity of Technology
Tempaku-cho, Toyohashi, Aichi 441-8580, Japan
ReceiVed January 3, 2001
fast and highly enantioselective (s ) 46 and conversion (C) )
49%). After 6 min, 42% of alkyl chloride (1R,2R)-cis-7 (89%
ee) and 40% of alcohol (1R,2S)-trans-6 (85% ee) were isolated.
BINAP was recovered as BINAP bisoxide 3 in 92% yield without
any racemization (>99.9% ee),7 which can be reused after
reduction.8 In this reaction, the hydroxy group of (1S,2R)-
enantiomer of the racemic alcohol was selectively replaced by
chloride ion through SN2 reaction to produce cis-alkyl chloride.9
A wide-ranging solvent study showed that both the conversion
and enantioselectivity (s) of the NKR of (()-TPCH are highly
dependent on solvent (Table 1). Although we have not yet been
able to correlate enantioselectivity with any single solvent
parameter, it is clear that THF is the solvent of choice as it gave
highest selectivity and conversion (entry 7). Several halogenating
agents such as N,N-dichlorourethane (DCU), N-bromosuccinimide
(NBS), and N-bromoacetamide (NBA) were tested for the kinetic
resolution of (()-TPCH with (S)-BINAP. Although all of the
reactions proceeded smoothly to give corresponding products,
NCS was found to be superior to all in the view of enantiose-
lectivity (Table 1, entries 7-10).
We next studied the effect of the ratio of chiral BINAP and
NCS in the NKR of (()-TPCH at room temperature; the approach
proved to be fruitful. We were surprised to observe that the
selectivity and conversion were highly dependent on the amount
of BINAP and NCS used. Even by only changing the amount of
NCS, the selectivity and conversion of the reaction can be
controlled to some extent. Usage of 2-3-fold excess NCS (with
respect to BINAP) dramatically increased the enantioselectivity.
For example, in the presence of 1 equiv of NCS, 0.3 equiv of
(S)-BINAP gave highest selectivity (s ) 46 and C ) 49%). In
the same way, considerably good selectivity was obtained when
0.4 equiv of (S)-BINAP and 0.9 equiv of NCS were used (s )
35 and C ) 55.1%). When we used more than 0.4 equiv of
BINAP, the reaction proceeded with poor enantioselectivity. For
example, in the presence of 0.5 equiv of BINAP and 1.1 equiv
of NCS the selectivity was dropped to 6 (C ) 76%). In the same
way, s is 12 (C ) 69.7%) when 1.1 equiv of BINAP and NCS
were used.
Enantiopure alcohols are very important structural units for the
synthesis of a wide range of natural products, chiral ligands, and
biologically active compounds1 that can be available by kinetic
resolution of racemic and meso secondary alcohols through
acylation or deacylation catalyzed by enzymes.2 Nonenzymatic
kinetic resolution (NKR) of racemic alcohol is the alternative for
the enzymatic process, which is considered to be a challenging
issue in organic synthesis. Recently, significant progress has been
made in the literature for NKR of racemic and meso secondary
alcohols using chiral or achiral acylating agents.3 However, most
of the methods suffered from the multistep synthesis of chiral
auxiliaries and often provided only moderate enentioselectivities
(s ) selectivity factor4 < 20). In this communication, for the first
time we report high enantioselective nonenzymatic kinetic resolu-
tion of secondary alcohols through SN2 displacement of the
hydroxy group by halogen ions with halogenating agents in the
presence of commercially available chiral diphosphine BINAP
1.5
At the outset, we have chosen commercially available (()-
trans-2-phenylcyclohexan-1-ol 6 (TPCH)6 as a model substrate,
which was subjected to the kinetic resolution with N-chlorosuc-
cinimide (NCS, 1.0 equiv to TPCH) in the presence of (S)-BINAP
(0.3 equiv, stoichiometric amount of phosphorus) in THF at
ambient temperature (eq 1). The reaction was found to be very
(1) For the synthesis and application of enantiopure alcohols, see: (a) Ojima,
I. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-VCH: NewYork, 2000.
(b) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. ComprehensiVe Asymmetric
Catalysis; Springer-Verlag: Berlin, 1999; Vol. 1-3. (c) Whitesell, J. K. Chem.
ReV. 1992, 92, 953.
(2) Reviews: (a) Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic
Organic Chemistry; Pergamon: New York, 1994. (b) Johnson, C. R. Acc.
Chem. Res. 1998, 31, 333.
(3) For selected papers on NKR of alcohols using chiral or achiral acylating
agents, see: (a) Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000,
65, 3154. (b) Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T.
E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629. (c) Kawabata, T.; Nagato,
M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169. (d) Ruble, J. C.;
Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492. (e) Vedejs, E.;
Chen, X. J. Am. Chem. Soc. 1996, 118, 1809. (f) Spivey, A. C.; Maddaford,
A.; Redgrave, A. J. Org. Prep. Proced. Int. 2000, 32, 333 and references
therein.
(4) Selectivity factor (s) ) (rate of fast reacting enantiomer)/(rate of slow
reacting enantiomer). For more information, see: Kagan, H. B.; Fiaud, J. C.
Top. Stereochem. 1988, 18, 249.
(5) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115,
144 and references therein.
(6) For the application of chiral TPCH, see: (a) Schwartz, A.; Madan, P.
B.; Mohasci, E.; O’Brien, J. P.; Todaro, L. J.; Coffen, D. L. J. Org. Chem.
1992, 57, 851. (b) Whitesell, J. K..; Carpenter, J. F. J. Am. Chem. Soc. 1987,
109, 2839. (c) Greene, A. E.; Charbonnier, F.; Luche, M.-J.; Moyano, A. J.
Am. Chem. Soc. 1987, 109, 4752. (d) Whitesell, J. K.; Chen, H.-H.; Lawrence,
R. M. J. Org. Chem. 1985, 50, 4663, and ref 1c.
When the NKR of (()-TPCH was carried out with other
commercially available C2-symmetric chiral diphosphines such
as (+)-DIOP 4 and (+)-Norphos 5 with NCS, the enantioselec-
tivities were dramatically dropped to 1 and 3, respectively (Table
2). These results clearly show that the bulkiness of naphthyl
moiety of BINAP plays an important role in the transition state
to provide very high enantioselectivity. We also found that the
(7) (S)-BINAP bisoxide 3 was quantitatively recovered when the crude
reaction mixture was kept overnight before the column chromatography
purification. The ee of 3 was determined by HPLC analysis with Chiralpak
AD column (hexane/2-propanol ) 75:25).
(8) For the deoxygenation of chiral BINAP bisoxide to BINAP without
loss of enantiomeric excess, see: (a) Takaya, H.; Akutagawa, S.; Noyori, R.
Org. Synth. 1988, 67, 20. (b) Takaya, H.; Mashima, K.; Koyano, K.; Yagi,
M.; Kumobayashi, H.; Taketomi, T.; Akutagawa, S.; Noyori, R. J. Org. Chem.
1986, 51, 629.
(9) trans-Alkyl chloride was not observed in the reaction. The stereochem-
istry of the cis-alkyl chloride was deduced from coupling constant (dt, J )
1
12.6, 3.0 Hz) of peak at 2.89 ppm (CH-Ph) in the H NMR spectrum.
10.1021/ja010029i CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/27/2001

3604 J. Am. Chem. Soc., Vol. 123, No. 15, 2001
Communications to the Editor
Table 1. Effect of Solvents and Various Halogenating Agents in
the NKR of (()-TPCH with (S)-BINAPa
Table 3. NKR of Various â-Aryl- and Alkyl-Substituted
Secondary Alcohols with (S)-BINAP and NCSa
entry
solvent
halogenating agent
time
C (%)b
sb
1
2
3
4
5
6
7
8
9
hexane
CH2Cl2
ether
CH3CN
CHCl3
benzene
THF
THF
THF
THF
NCS
NCS
NCS
NCS
NCS
NCS
NCS
DCUc
NBS
NBA
2.0 h
<10 min
7.5 h
7.0 h
7.0 h
<10 min
<10 min
<10 min
7.0 h
40.0
42.6
38.6
38.8
7.7
31.0
48.2
34.4
38.8
20.2
3
17
9
14
7
7
32
18
14
19
10
<10 min
a Molar ratio of TPCH/BINAP/halogenating agent ) 1.0: 0.8: 0.8
in 2 mL of solvent. b For the calculation of C and s values, see the
Supporting Information. c 0.4 equiv of DCU was used.
Table 2. NKR of (()-TPCH with Various C2-Symmetric
Diphosphine Ligands and NCS, and Effect of Temperaturea
entry
diphosphine
temperature
time
C (%)
s
1
2
3
4
5
1
4
5
1
1
rt
rt
rt
6 min
3.5 h
10 min
12 h
49.0
91.7
46.3
36.7
35.8
46
1b
3b
66
253
a Molar ratio of alcohol/NCS/BINAP ) 1.0:0.9:0.4 unless noted;
room-temperature reactions were stirred for 10 min, and lower-
temperature reactions were allowed to stir overnight. For the reactions
illustrated in this table, the enantiomeric excess of cis cyclic alkyl
chloride ranges from 56-94%. b Calculated from conversion. c Deter-
mined by HPLC analysis using chiral columns unless otherwise noted.
d Determined by comparison of the sign of its optical rotation with
literature values; see Supporting Information for more details. e Ee was
determined by GC analysis using Supelco â-DEX 120 chiral capillary
column. f 1.5 equiv of NCS was used. g Not determined. h Expected to
be (1R,2S) based on the same analogy.
-10 °C-rt
-74 °C-rt
12 h
a Molar ratio of TPCH/diphosphine/NCS ) 1.0: 0.3: 1.0 in THF.
b (1S,2S)-cis-7 and (1S,2R)-trans-6 are the major enantiomers.
enantioselectivity of NKR is highly temperature-dependent. The
enantioselectivity was increased as the temperature decreased. For
example, the selectivity was drastically increased to 66 and 253
from 46 when the reaction temperature was reduced to -10 °C
and -74 °C, respectively (Table 2, entries 1, 4, and 5).
Using the optimized reaction conditions, a wide range of â-aryl-
and alkyl-substituted cyclic secondary alcohols were resolved with
very high enantioselectivities. When the reactions were allowed
for more than 50% conversion, excellent enantiomeric excesses
were obtained for the recovered alcohols (Table 3). All of the
â-aryl-substituted cyclohexanols are recovered in 95-99% enan-
tiomeric excess with excellent enantioselectivities (s ) 13-118,
entries 1-8). (+)-2-Phenylcyclooctan-1-ol was recovered with
88% ee (s ) 13, entry 10). â-Alkyl-substituted cyclohexanol gave
moderate selectivity (s ) 15, entry 9). As expected, acyclic
secondary alcohol gave poor enantioselectivity (s ) 2, entry 11).
This could be because of the less steric hindrance, which occurs
in the transition state. In the same way, excellent enantiomeric
excess were observed for alkyl chlorides when the conversion of
the NKR was controlled to be less than 50%.10 Importantly, to
obtain comparatiVely Very high ee for both the recoVered alcohol
and alkyl chloride (exactly 50% conVersion), the reaction
conditions should be thoroughly optimized for each particular
racemic alcohol.
of monoalkoxide-phosphonium ion intermediate gives BINAP
monoxide 2, which might be immediately getting conversion to
bisoxide 3 through the same alkoxide-phosphonium ion interme-
diate (stepwise mechanism). However, the detailed studies on the
mechanism are under progress.
In conclusion, we have demonstrated highly enantioselective,
novel nonenzymatic kinetic resolution of cyclic secondary alcohols
by using chiral BINAP. To the best of our knowledge, this is the
first report in the literature for kinetic resolution of secondary
alcohols through selective SN2 displacement of hydroxy groups
by halogen ions (s ) up to 253). Further investigations to broaden
the scope and synthetic application of this new enantioselective
NKR and to detail the mechanistic study are under progress. It is
hoped that due to its economic and very high enantioselectivity,
the NKR described herein will enjoy many new applications in
the enantioselective organic synthesis.13
Although at this movement the mechanism of the present
reaction is not very clear, we assume that the reaction proceeds
through an ionic phosphonium-alkoxide intermediate (quaternary
phosphonium salt) in which the chloride ion attacks the alkoxide
in SN2 fashion to provide cis-alkyl chloride and bisoxide 3. This
was supported as 3 was recovered after the reaction. When the
reaction 1 was carried out with monoxide 2,11 the reaction was
much faster than the BINAP-mediated reaction with moderate
enantioselectivity.12 These observation suggests that the formation
Acknowledgment. G.S. thanks Japan Society for the Promotion of
Science (JSPS) for the award of a postdoctoral fellowship. We also thank
Dr. S. Iwasa and Dr. Y. Motoyama of our research group for helpful
discussions.
Supporting Information Available: Experimental procedures, char-
acterization data for new compounds, ee assay data, determination of
absolute stereochemistry, and a table for alkyl chlorides (PDF). This
material is available free of charge via the Internet at http:/pubs.acs.org.
(10) In all the reactions, only cis-alkyl chlorides were selectively obtained
through SN2 displacement with excellent enantioselectivites. See the Table 4
in Supporting Information.
(11) For the synthesis of BINAP monoxide 2, see: Grushin, V. V. J. Am.
Chem. Soc. 1999, 121, 5831.
JA010029I
(12) When the (S)-BINAP mediated reaction 1 was carefully monitored
by TLC, no spot was observed for BINAP monoxide (Rf 0.45, 40% EtOAc in
hexane). This also suggested that the BINAP monoxide 2 should be much
more reactive than BINAP, which might be immediately getting conversion
to 3.
(13) Importantly, the optically active alkyl halides are valuable intermediates
that can be easily converted to variety of useful ligands such as chiral amines
and phosphines. Larock, R. C. ComprehensiVe Organic Transformations;
Wiley-VCH: New York, 1999 and refs 1a, b.