(1R,2S)-(+)-cis-1-amino-2-indanol: An effective ligand for asymmetric catalysis of transfer hydrogenations of ketones

Full text of DOI:10.1021/jo970405a

5
226
J . Org. Chem. 1997, 62, 5226-5228
Sch em e 1a
(
1R,2S)-(+)-cis-1-Am in o-2-in d a n ol: An
Effective Liga n d for Asym m etr ic Ca ta lysis
of Tr a n sfer Hyd r ogen a tion s of Keton es
†
‡
,†
Matthew Palmer, Tim Walsgrove, and Martin Wills*
Department of Chemistry, University of Warwick,
Coventry CV4 7AL, U.K., and SmithKline Beecham
Pharmaceuticals, Old Powder Mills, Nr Leigh,
Tonbridge, Kent TN11 9AN, U.K.
a
Reagents and conditions: (i) 1 mol % of 1, 3, or 4, 0.25 mol %
of [RuCl2(arene)]2, 2.5 mol % of KOH, i-PrOH; see Table 1.
amino alcohol, and in particular, (1R,2S)-(+)-cis-1-amino-
Received March 4, 1997
2
-indanol (1), would be beneficial. Amino alcohol 1,
which is commercially available in both enantiomeric
forms, is an important component of the Merck anti-HIV
compound Indinavir7 and has been used as the basic
component of a valuable series of oxazolidinone chiral
In tr od u ction
Dramatic developments in asymmetric catalysis have
1
been recorded in recent years. In particular, the reduc-
8
auxiliaries and bis-oxazolines for asymmetric catalysis
tion of ketones to enantiomerically enriched alcohols
represents a pivotal transformation due to the combina-
tion of versatility and practical simplicity.2 We have
recently published the results of our ongoing studies of
phosphinamide catalysts for the asymmetric reductions
of ketones by borane.3
of Diels-Alder reactions.9
In a complementary series of investigations, we have
studied the reduction of ketones using chiral transfer
hydrogenation methodology. In principle, this approach
benefits from the use of mild reagents and a requirement
for very low quanitities of an appropriate catalyst. While
many methods have been reported for this transforma-
4
tion, recent years have witnessed a rapid development
5
of the area thanks in particular to the efforts of Noyori
and others.6 Specifically, we were intrigued by the use
of amino alcohols in combination with ruthenium(II)
arene complexes, a technique that provides remarkably
high catalytic activities when even a very small amount
of ligand is employed.5b In order to maximize asymmetric
inductions, we felt that the use of a stereochemically rigid
†
University of Warwick.
SmithKline Beecham Pharmaceuticals.
‡
(
1) For excellent recent surveys see: (a) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; J ohn Wiley and Sons Ltd.: New York,
994. (b) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Press:
Berlin, 1993.
1
(
(
2) Singh, V. K. Synthesis 1992, 605.
3) (a) Burns, B.; Studley, J . R.; Wills, M. Tetrahedron Lett. 1993,
3
4, 7105. (b) Burns, B.; King, N. P.; Studley, J . R.; Tye, H.; Wills, M.
Resu lts a n d Discu ssion
Tetrahedron: Asymmetry 1994, 5, 801. (c) Gamble, M. P.; Studley, J .
R.; Wills, M. Tetrahedron Lett. 1996, 37, 2853. (d) Gamble, M. P.;
Studley, J . R.; Wills, M. Tetrahedron: Asymmetry 1996, 7, 3071. (e)
Burns, B.; Gamble, M. P.; Simm, A. R. C.; Studley, J . R.; Alcock, N.
W.; Wills, M. Tetrahedron: Asymmetry 1997, 8, 73.
In the event, (1R,2S)-(+)-(1) proved to be an excellent
ligand for this application (Scheme 1, Table 1). The use
of 1 mol % in conjunction with 0.25 mol % of the
(
4) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. Rev. 1992, 92,
051.
5) (a) Hashiguchi, S.; Fujii, A.; Takehara, J .; Ikariya, T.; Noyori,
2 2
ruthenium complex [RuCl (p-cymene)] and 2.5 mol % of
1
KOH in propan-2-ol ([ketone] ) 0.1 M) at room temp-
(
erature5b resulted in reduction of acetophenone (2) to (S)-
R. J . Am. Chem. Soc. 1995, 117, 7562. (b) Takehara, J .; Hashiguchi,
S.; Fujii, A.; Inuoe, S.-I.; Ikariya, T.; Noyori, R. J . Chem. Soc., Chem.
Commun. 1996, 233. (c) Gao, J .-X.; Ikariya, T.; Noyori, R. Organome-
tallics 1996, 15, 1087. (d) Fujii, A.; Hashiguchi, S.; Uematsu, N.;
Ikariya, T.; Noyori, R. J . Am. Chem. Soc. 1996, 118, 2521.
1
1
-phenylethanol in 70% isolated yield and 91% ee after
.5 (Table 1, entry 1). The use of other ruthenium arene
complexes gave lower enantiomeric excesses, 69% and
(
6) (a) Puntener, K.; Schwink, L.; Knochel, P. Tetrahedron Lett.
8
2% ee using the benzene- and mesitylene-substituted
1
996, 37, 8165. (b) J iang, Q.; Plew, D. V.; Murtuza, S.; Zhang, X.
Tetrahedron Lett. 1996, 37, 797. (c) Muller, D.; Umbricht, G.; Weber,
B.; Pfaltz, A. Helv. Chim. Acta. 1991, 74, 232. (d) Evans, D. A.; Nelson,
S. G.; Gagne, M. R.; Muci, A. R. J . Am. Chem. Soc. 1993, 115, 9800.
(7) Maligres, P. E.; Upadhyay, V.; Rossen, K.; Cianciosi, S. J .; Purick,
R. M.; Eng, K. K.; Reamer, R. A.; Askin, D.; Volante, R. P.; Reider, P.
J . Tetrahedron Lett. 1995, 36, 2195.
(
6
(
e) Gamez, P.; Fache, F.; Lemaire, M. Tetrahedron: Asymmetry 1995,
, 705. (f) Langer, T.; Helmchen, G. Tetrahedron Lett. 1996, 37, 1381.
g) Brunner, H.; Leitner, W. J . Organomet. Chem. 1990, 387, 209. (h)
(8) Davies, I. W.; Senanayake, C. H.; Castonguay, L.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J . Tetrahedron Lett. 1995, 36, 7619.
(9) (a) Davies, I. W.; Senanayake, C. H.; Larsen, R. D.; Verhoeven,
T. R.; Reider, P. J . Tetrahedron Lett. 1996, 37, 813. (b) Davies, I. W.;
Senanayake, C. H.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J .
Tetrahedron Lett. 1996, 37, 1725. (c) Davies, I. W.; Gerena, L.;
Castonguay, L.; Senanayake, C. H.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J . J . Chem. Soc., Chem. Commun. 1996, 1753. (d) Davies, I.
W.; Gerena, L.; Lu, N.; Larsen, R. D.; Reider, P. J . J . Org. Chem., 1996,
61, 9629. (e) Davies, I. W.; Gerena, I. W.; Cai, D.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J . Tetrahedron Lett. 1997, 38, 1145.
Brunner, H.; Kunz, M. Chem. Ber. 1986, 119, 2868. (i) Wang, G.-Z.;
Backvall, J.-E. J . Chem. Soc., Chem. Commun. 1992, 980. (j) Chowdhury,
R. L.; Backvall, J .-E. J . Chem. Soc., Chem. Commun. 1991, 1063. (k)
Gamez, P; Fache, F.; Lemaire, M. Tetrahedron Lett. 1993, 34, 6897.
(
(
l) Genet, J .-P.; Ratovelomonana-Vidal, V.; Pinel, C. Synlett 1993, 478.
m) Gamez, P.; Dunjic, B.; Fache, F.; Lemaire, M. J . Chem. Soc., Chem.
Commun. 1994, 1417. (n) Gamez, P.; Fache, F.; Lemaire, M. Bull. Soc.
Chim. Fr. 1994, 131, 600. (o) J iang, Y.; J iang, Q.; Zhu, G.; Zhang, X.
Tetrahedron Lett. 1997, 38, 215.
S0022-3263(97)00405-2 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 15, 1997 5227
Ta ble 1
the yield of 49% reflected the incomplete reaction (Table
1, entry 6). No improvement was recorded at -20 °C, at
which temperature an incomplete reaction was observed,
even after a reaction time of 24 h. In an attempt to
improve the yield, a longer reaction time (72 h) was
employed; however, this merely resulted in a further
erosion of the asymmetric induction (Table 1, entries 7
and 8).
Reduction of a series of aromatic ketones under identi-
cal conditions using ligand 1 resulted in reduction to the
corresponding alcohols in good to excellent yields and
enantiomeric excesses (Table 1, entries 9-22). The sense
of the reductions appears to be controlled by steric factors
in each case. In the cases of both 5 and 6 a decrease in
selectivity was observed when prolonged reaction times
were employed. The reduction of 1-tetralone (7) gave the
most remarkable result: up to 98% enantiomeric excess
under the room temperature reduction conditions. Ex-
tended reaction times (Table 1, entry 15) and increased
catalyst loading (Table 1, entry 17) resulted in consider-
able loss of enantioselectivity, although the use of higher
reaction temperatures did not (Table 1, entry 16). High
ee’s in the case of 1-tetralone (7) reduction were achieved,
but at the cost of conversion. Isolated yields of 39-63%
were obtained; however, when account was taken of the
quantity of recovered starting material the mass balance
is generally excellent (see Table 1).
eec
%
entry ketone ligand complexa T/°C
t/h
yield/%b (R/S)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
2
2
2
2
2
2
2
2
5
5
6
6
7
7
7
7
7
1
1
1
3
4
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
A
B
C
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
rt
rt
rt
rt
1.5
1.6
2
70
68
73
95
33
49
47
47
94
89
84
70
40
91 (S)
69 (S)
82 (S)
23 (S)
27 (S)
93 (S)
90 (S)
84 (S)
86 (S)
81 (S)
86 (S)
85 (S)
98 (S)
2
rt 15
0
6.5
-20 24
-20 72
rt
1.7
rt 18
1.5
rt 20
1
1
1
1
1
1
1
1
1
1
2
2
2
rt
rt
4
rt 16
rt 46
39 (85) 98 (S)
60 67 (S)
63 (88) 95 (S)
60 (94) 87 (S)
45
rt
rt
rt
45
4
4
d
d
8
9
10
11
12
1.75 79
1.5
6
94 (S)
84 (S)
81 (S)
56
85
rt 15
52 (90) 43 (S)
63 7 (S)
45
3
a
(
A) arene ) p-cymene, (B) arene ) benzene, (C) arene )
b
mesitylene. Isolated yields: yields corrected for recovered start-
c
ing material in parentheses. Enantiomeric excesses were deter-
mined using chiral HPLC with a Chiralcel OD column. d 4 mol %
of 1, 1 mol % [RuCl2(p-cymeme)]2 used.
analogues, for example (Table 1, entries 2 and 3).
Although purification by flash chromatography was
employed in most cases, the reaction could be worked up
simply by filtration of the reaction mixture through a
plug of silica followed by removal of solvent under
vacuum. In order to determine the importance of the
rigid structure of the ligand, we repeated the reaction
under identical conditions using (R)-phenylglycinol (3).
In this reaction, (S)-phenylethanol was obtained in 95%
yield but only 23% enantiomeric excess (Table 1, entry
In the case of 2-tetralone (10), the asymmetric induc-
tion was somewhat reduced, while for 11 the drop in ee
was greater still. The suggestion that the enantioselec-
tivity of the reaction is driven by the steric difference
between the substituents that flank the ketone is sup-
ported by these results, since the difference in steric
demand between flanking groups is low in each case. The
reduction of the nonaromatic ketone 12 gave a reduction
product with a very low ee, a result that underlies the
key requirement for an aromatic system in the substrate.
In the case of reduction of 10 and 12 it is noteworthy
that reasonable reaction rates and conversions were only
achieved when the hydrogenations were run at 45 °C.
4
), a dramatically inferior result.
Although we have not yet investigated a systematic
series of ligand modifications, the use of the N-methyl
derivative 4 resulted in an inferior asymmetric induction
(
Table 1, entry 5). It therefore appears that a primary
Con clu sion s
amine function in the ligand is essential. The ratio of
ligand to ruthenium(II) is also critical; the use of 0.5 mol
%
identical to those in entry 1 of Table 1 resulted in a
decrease of the ee to 68%.
Concerned that the enantiomeric excesses of the reduc-
tion products might be reduced under extended reaction
times, we studied the progress of the reduction by taking
samples for analysis by chiral HPLC. The results of this
study reveal that over the reaction time studied (typically
We have demonstrated that (1R,2S)-(+)-cis-1-amino-
2-indanol (1) is an excellent ligand for the control of
asymmetric ruthenium-catalyzed transfer hydrogenation
of ketones. The required ligand loading is very low
(typically 1 mol %), and yields and enantiomeric excesses
are generally excellent. We are presently examining the
extension of this methodology to novel substrates and
methods by which the undesirable reaction reversibility
can be prevented.
of [RuCl
2 2
(p-cymene)] with 1 mol % 1 under conditions
2
h), no significant erosion of the ee was observed.
However, further results (see below) suggest that erosion
of enantiomeric excesses does take place over longer
Exp er im en ta l Section
Gen er a l Meth od s. Reactions were run under an atmosphere
of nitrogen in flame- or oven-dried Schlenk flasks. Propan-2-ol
HPLC grade) was degassed prior to use. All ketones were
reaction times. This erosion is presumably a result of
the known reversability of the reaction.5
a,d
The use of
(
formic acid/triethylamine has been reported, for certain
systems,5d to be capable of promoting transfer hydroge-
nation without the associated reversible reaction. In the
case of the ligand 1, however, no reduction was observed
using this hydride source.
Further improvements to the selectivity could be
achieved upon reduction of the reaction temperature,
although the rate was reduced. Hence, using the same
reaction conditions as given above, at 0 °C rather than
room temperature, the selectivity increased to 93% ee but
purified by short path distillation or passing through a plug of
deadened silica. Reactions were monitored by TLC using
aluminum-backed silica gel 60 (F254) plates, visualized using
UV254nm and PMA dip. Flash column chromatography was
carried out routinely using 60 Å silica gel. Proton NMR spectra
were recorded on a 250 MHz instrument. Enantiomeric excesses
were determined by HPLC analysis using a Chiralcel OD
column.
Gen er a l P r oced u r e for Tr a n sfer H yd r ogen a t ion of
Keton es. A solution of (p-cymene)ruthenium(II) chloride dimer
(7.7 mg, 0.0125 mmol) and (1R,2S)-(+)-cis-1-amino-2-indanol (7.5

5
228 J . Org. Chem., Vol. 62, No. 15, 1997
Notes
1
mg, 0.05 mmol) in dry propan-2-ol (4 mL) was heated at 80 °C
for 20 min under nitrogen. After being cooled to room temper-
ature, the light brown solution was transferred via cannula to
a large sealed Schlenk flask. A solution of ketone (5 mmol) in
dry degassed propan-2-ol (45 mL) was added via cannula,
followed by KOH (1.25 mL, 0.1 M in propan-2-ol, 0.125 mmol).
The reaction was run at room temperature and monitored by
TLC until substantially complete (generally 2 h). Workup
consisted of filtering the dark brown solution through a pad of
silica under vacuum (with ethyl acetate washings, 2 × 50 mL).
The combined organic extracts were concentrated in vacuo to
give the crude product, which was purified by flash column
EtOH), 97% ee (S)); H NMR (CDCl
3
, 250 MHz) 7.36-7.23 (m,
5 H), 4.60 (t, J ) 6.60 Hz, 1 H), 1.91-1.69 (m, 2 H), 1.88 (br s,
1 H), 0.92 (t, J ) 7.51 Hz, 3 H).
(S)-1-Tetr a lol: 98% ee (S) by HPLC (Chiralcel OD, propan-
2-ol:hexane ) 2:98 (0.9 mL/min), S isomer 17.4 min, R isomer
1
0d
19.8 min); [R] +34.4° (c 1.01, CHCl ) (lit. [R]D +25.8° (c 3.10,
D
1
3
CHCl ), (S)); H NMR (CDCl , 250 MHz) 7.46-7.41 (m, 1 H),
3
3
7.23-7.17 (m, 2 H), 7.12-7.09 (m, 1 H), 4.79 (br s, 1 H), 2.87-
2.69 (m, 2 H), 1.99-1.60 (m, 5 H).
(
S)-2-Tetr a lol: 81% ee (S) by HPLC of (S)-Mosher ester
Chiralcel OD, propan-2-ol:hexane ) 0.1:99.9 (0.9 mL/min), S
3
isomer 34.4 min, R isomer 38.4 min); [R] -54.4° (c 0.70, CHCl )
(
D
chromatography (SiO
S)-1-P h en yleth a n ol: 91% ee (S) by HPLC (Chiralcel OD,
ethanol:hexane ) 5:95 (0.5 mL/min), S isomer 17.1 min, R isomer
2
, ethyl acetate-petroleum ether).
10e
1
(
lit. [R]
D
3 3
-55.4° (c 0.70, CHCl ), 95.5% ee (S)); H NMR (CDCl ,
(
250 MHz) 7.15-7.07 (m, 4 H), 4.16 (m, 1 H), 3.14-2.72 (m, 4
H), 2.11-2.01 (m, 1 H), 1.90-1.75 (m, 1 H), 1.68 (s, 1 H).
(S)-2-Meth yl-1-p h en ylp r op a n ol: 43% ee (S) by HPLC
(Chiralcel OD, propan-2-ol:hexane ) 2:98 (0.5 mL/min), S isomer
1
0a
1
4.8 min); [R]
D
-48.8° (c 1.0, CH
2
Cl
2
) (lit. [R]
3
D
+48.6° (c 1.0,
1
CH Cl ), 96% ee (R)); H NMR (CDCl
5
6
2
2
, 250 MHz) 7.37-7.25 (m,
H), 4.86 (q, J ) 6.41 Hz, 1 H), 1.92 (br s, 1 H), 1.48 (d, J )
25.4 min, R isomer 28.8 min); [R]D -21.0° (c 1.05, Et O) (lit.10f
2
.41 Hz, 3 H).
1
3
[R]D +34.8° (c 4.90, Et O), 73% ee (R)); H NMR (CDCl , 250
2
(
S)-1-(2′-Na p h th yl)eth a n ol: 86% ee (S) by HPLC (Chiralcel
MHz) 7.37-7.23 (m, 5 H), 4.36 (d, J ) 6.68 Hz, 1 H), 1.96 (dsept,
J ) 6.69, 6.69 Hz, 1 H), 1.83 (br s, 1 H), 1.00 (d, J ) 6.68 Hz, 3
H), 0.80 (d, J ) 6.98 Hz, 3 H).
OD, ethanol:hexane ) 5:95 (0.5 mL/min), S isomer 26.4 min, R
1
0b
isomer 29.3 min); [R]
D
-34.3° (c 1.10, EtOH) (lit. [R]
D
-41.9°
, 250 MHz) 7.86-7.81 (m,
H), 7.53-7.42 (m, 3 H), 5.07 (dq, J ) 3.20, 6.39 Hz, 1 H), 1.94
1
(
c 4.92, EtOH), (S)); H NMR (CDCl
3
(S)-1-(p-Meth oxyp h en yl)eth a n ol: 84% ee (S) by HPLC
(Chiralcel OD, propan-2-ol:hexane ) 10:90 (0.5 mL/min), S
isomer 16.9 min, R isomer 15.9 min); [R] -44.2° (c 1.06, CHCl )
4
(
d, J ) 3.20 Hz, 1 H), 1.59 (d, J ) 6.68 Hz, 3 H).
S)-1-(1′-Na p h th yl)eth a n ol: 94% ee (S) by HPLC (Chiralcel
OD, ethanol:hexane ) 5:95 (0.5 mL/min), S isomer 24.4 min, R
D
3
3
(lit.5d [R]
-51.9° (c 1.04, CHCl
), 97% ee (S)); H NMR (CDCl
1
,
(
D
3
250 MHz) 7.13 (AB, J ) 9.01 Hz, ∆υ ) 105 Hz, 4 H), 4.85 (q, J
) 6.40 Hz, 1 H), 3.81 (s, 3 H), 1.81 (br s, 1 H), 1.48 (d, J ) 6.40
Hz, 3 H).
1
0c
isomer 42.2 min); [R]
D
-79.6° (c 1.02, Et
2
O) (lit. [R]
D
+82.1°
1
(
c 1.0, Et
2
O), 99% ee (R)); H NMR (CDCl , 250 MHz) 8.16-
3
8
.09 (m, 1 H), 7.91-7.84 (m, 1 H), 7.80-7.77 (d, J ) 8.14 Hz, 1
(S)-1-Cycloh exyleth a n ol: 7% ee (S) by HPLC of 4-nitroben-
zoyl ester (Chiralcel OD, propan-2-ol:hexane ) 0.1:99.9 (0.9 mL/
D
H), 7.70-7.67 (d, J ) 7.26 Hz, 1 H), 7.56-7.45 (m, 3 H), 5.68 (q,
J ) 6.39 Hz, 1 H), 1.91 (br s, 1 H), 1.68 (d, J ) 6.39 Hz, 3 H).
min), S isomer 19.5 min, R isomer 21.4 min); [R] +0.3° (c 12.3,
) (lit.1 [R]
0g
1
(
S)-1-P h en ylp r op a n ol: 86% ee (S) by HPLC (Chiralcel OD,
CHCl
3
D
3
-3.4° (c 1.1, CHCl ), 94% ee (R)); H NMR
ethanol:hexane ) 5:95 (0.5 mL/min), S isomer 16.1 min, R isomer
(CDCl , 250 MHz) 3.60-3.50 (m, 1 H), 1.93-1.63 (m, 5 H), 1.50
3
5
d
1
4.2 min); [R]
D
-33.0° (c 5.15, EtOH) (lit. [R]
D
-34.0° (c 5.03,
(br s, 1 H), 1.15 (d, J ) 6.10 Hz, 3 H), 1.34-0.88 (m, 6 H).
Ackn owledgm en t. We thank the EPSRC and Smith-
Kline Beecham (Tonbridge) for generous funding of this
project and Dr. Ian Davies of Merck and Co. (Rahway,
NJ ) for a generous gift of (1S,2R)-(-)-cis-1-amino-2-
indanol and for his advice and assistance.
(
10) (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. Tetrahedron: Asymmetry
1
991, 2, 601. (b) Collyer, T. A.; Kenyon, J . J . Chem. Soc. 1940, 676. (c)
Theisen, P. D.; Heathcock, C. H. J . Org. Chem. 1988, 53, 2374. (d)
Kim, Y. H.; Park, D. H.; Byun, I. S.; Yoon, I. K.; Park, C. S. J . Org.
Chem. 1993, 58, 4511. (e) Martinez, G. R. Tetrahedron: Asymmetry
995, 6, 1491. (f) Niwa, S.; Soai, K. J . Chem. Soc., Perkin Trans. 1
991, 2717. (g) J anssen, A. J . M.; Klunder, A. J . H.; Zwanenburg, B.
1
1
Tetrahedron 1991, 47, 7645.
J O970405A