Enantioselective reduction of prochiral ketones using spiroborate esters as catalysts

Article abstract of DOI:10.1016/j.tetlet.2007.06.086

Novel spiroborate esters derived nonracemic 1,2-aminoalcohols and ethylene glycol are reported as highly effective catalysts for the asymmetric borane reduction of a variety of prochiral ketones with borane-dimethyl sulfide complex at room temperature. Optically active alcohols were obtained in excellent chemical yields using 0.1-10 mol % of catalysts with up to 99% ee.

Full text of DOI:10.1016/j.tetlet.2007.06.086

Tetrahedron Letters 48 (2007) 5799–5802
Enantioselective reduction of prochiral ketones using
spiroborate esters as catalysts
a
a
a
Viatcheslav Stepanenko, Melvin De Jes u´ s, Wildeliz Correa,
a
a
a
Irisbel Guzm a´ n, Cindybeth V a´ zquez, Wilanet de la Cruz,
a,
b
*
Margarita Ortiz-Marciales and Charles L. Barnes
a
Department of Chemistry, University of Puerto Rico—Humacao, CUH Station, Humacao, Puerto Rico 00791, USA
Department of Chemistry, University of Missouri—Columbia, 125 Chemistry Building, Columbia, MO 65211, USA
b
Received 19 May 2007; revised 11 June 2007; accepted 15 June 2007
Available online 22 June 2007
Abstract—Novel spiroborate esters derived nonracemic 1,2-aminoalcohols and ethylene glycol are reported as highly effective cat-
alysts for the asymmetric borane reduction of a variety of prochiral ketones with borane–dimethyl sulfide complex at room temper-
ature. Optically active alcohols were obtained in excellent chemical yields using 0.1–10 mol % of catalysts with up to 99% ee.
ꢀ
2007 Elsevier Ltd. All rights reserved.
The asymmetric synthesis of secondary enantiopure
alcohols from prochiral ketones is a key step in the prep-
aration of a variety of pharmaceutical products.1 To
accomplish this transformation with high enantioselec-
tivity, new methods, such as, asymmetric transfer hydro-
We recently reported the synthesis of a new class of crys-
talline, air- and moisture stable spiroborate esters that
were examined for the reduction of acetophenone as a
model substrate to obtain nonracemic 1-phenyletha-
nol. Catalysts 1–3 (Scheme 1) proved to be the most
valuable due to their outstanding enantioselectivity, fac-
ile synthesis, purity and convenience of handling. We
present here the X-ray crystal structure of catalyst 1, a
correlation study of the catalytic load of 1 with the
enantio-purity of alcohol, and the asymmetric borane
reduction of representative ketones using 1–3 as
catalyst.
,2
1
2
3
4
genation, metal catalyzed hydrogenations, enzymatic
5
6–9
reactions and novel metal hydride reagents, are con-
tinuously being developed as valuable synthetic tools.
7
Chiral boron reagents, in particular oxazaborolidines
derived from nonracemic 1,2-aminoalcohols, are well
known catalysts for the synthesis of highly enantiopure
secondary
alcohols.
Other
oxazaborolidine-like
compounds have been applied for the borane reduction
of prochiral ketones with good to excellent
enantioselectivities.
Spiroborate esters 1 and 2 are readily prepared from
commercially available diphenyl valinol and diphenyl-
8
,9
Borates and boronates have been previously established
1
0
Ph
as effective chirality transfer reagents. Borates accessed
Ph
H
Ph
Ph
Ph
0
O
O
O
Ph
Ph
from nonracemic 1,1 -bi-2-naphtyldiol and complexed
O
O
O
O
B
1
1
B
to anilines reduce acetophenone with up to 64% ee.
Spiroborate esters prepared from nonracemic 1,1 -bi-2-
naphtylborate esters and enantiopure 1,2-aminoalcohols
O
B
N
H
0
NH
NH2
O
2
2
1
3
(
or 2-aminoacids) have been found to catalytically
reduce prochiral aromatic and aliphatic ketones with
8
b,c
modest to high enantioselectivities.
OH
O
0
.1 equiv. Cat.1-3/THF
*
R1
R2
R1
Scheme 1.
R2
o
BH -DMS/ 25 C
3
*
0
Corresponding author. Tel.: +787 852 3222; fax: +787 850 9422;
e-mail: mr_ortiz@webmail.uprh.edu
040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.086

5800
V. Stepanenko et al. / Tetrahedron Letters 48 (2007) 5799–5802
respectively. In addition, catalyst 2 showed excellent
enantioselectivity even with 5 mol % loading (98% ee).
The reduction of representative arylalkyl and aliphatic
ketones was also investigated and the results are shown
1
7
in Table 1. In general, the optical active alcohols were
obtained in excellent chemical yields and outstanding
enantio-purity for ketones with bulky group
differentiation.
It was of interest to study the effect of electronic and
steric factors in the reduction of halogenated aceto-
phenones. Moreover, their enantiopure alcohols are
very important intermediaries in organic synthesis.
Table 1. Electronic and steric effects on asymmetric reduction of
aromatic and aliphatic ketones using spiroborates
a
b
c
Entry
Substrate
Cat.
Yield (%)
ee (%)
d
1
2
3
1
2
3
98
97
99 (R)
Figure 1. Crystal structure of spiroborate 1.
O
d
98 (R)
d
96 (R)
prolinol, respectively, according to the reported proce-
1
3
O
dure. 1,1,2-Triphenyl ethanolamine was synthesized
1
4
e
by established methods. The white crystalline spirobo-
rate complex 1 was found to be particularly stable after
being exposed to moist air for 24 h at 25 ꢁC, as evi-
4
1
90
92 (R)
MeO
O
5
6
2
1
94
96
97 (R)
96 (R)
1
1
1
13
denced by its unchanged B, H and C NMR spectra.
The X-ray diffraction analysis of 1 presented in Figure 1
clearly shows the structure of the amino spiroborate
1
5
O
complex. The observed B1–N1 bond distance at
˚
7
8
1
1
99
81
>99 (R)
1
.665 (2) A is comparable to the bonds of similar boron
1
6
nitrogen coordinated complexes.
O
e
98 (R)
To establish the optimal catalytic load required to
achieve high enantioselectivity, the reduction of ace-
tophenone was studied using different molar equivalents
MeO
O
of catalyst 1 with 0.7 M equiv of BH ÆDMS complex in
3
f
9
1
84
99 (R)
THF at room temperature. As indicated in Figure 2,
1
0 mol % of catalyst 1 afforded (R)-1-phenylethanol
with 99% ee. Moreover, higher enantioselectivities
98% ee) were achieved with as low as 0.5 M % of cata-
O
(
10
11
12
1
1
1
94
90
83
87
lytic load, and even with 0.1 M % of catalyst 1, the enan-
tiomeric excess was high (89%).
O
Spiroborates 2 and 3 were also investigated for the
reduction of acetophenone obtaining (R)-1-phenyletha-
nol with excellent chemical yield and 98% and 96% ee,
72 (R)
61 (R)
O
1
00
0
.5% 1 %
2.5%
5 %
1
0 %
(
99%)
(
98%)
(98%)
(98%)
9
9
8
8
5
0
5
0
O
0
.25 %
(
94%)
1
3
1
98
99 (R)
0.1 %
(
89%)
a
1
equiv ketone, 0.7 equiv BH
3
ÆDMS and 0.1 equiv catalyst in THF at
rt.
b
c
Purified by flash chromatography column or Kugelrohr distillation.
31
Determined by P NMR of derivate with phosphonate (CDA).
d
Determined by GC of alcohol on Chiral Column (CP-Chirasil-
DexCB).
Determined by GC of acetyl derivative on Chiral Column.
Determined by HPLC of acetyl derivative on Chiral Column (Chi-
ralpack ID).
0
1
2
3
4
5
6
7
8
9
10 11 12
%
Catatyst
e
f
Figure 2. Asymmetric reduction of acetophenone in the presence of
catalyst 1.

V. Stepanenko et al. / Tetrahedron Letters 48 (2007) 5799–5802
5801
Table 2. Reduction of representative halogenated aromatic ketones
with spiroborate with 0.1 equiv of catalyst 1
lington, MA, 2004; (b) Challenger, C. A. Chiral Drugs;
John Wiley & Sons: New york, 2001.
a
b
c
2. Ager, D. J. Chiral Chemicals; Marcel Dekker: New York,
Entry
Substrate
Yield (%)
ee (%)
1
999.
3. Morris, D. J.; Hayes, A. M.; Wills, M. J. Org. Chem. 2006,
1, 7035–7044.
O
O
7
d
1
2
98
84
99 (R)
4
. Schiffers, I.; Rantanen, T.; Schmidt, F.; Bergmans, W.;
Zani, L.; Bolm, C. J. Org. Chem. 2006, 71, 2320–2331.
. (a) Bor e´ n, L.; Martin-Matute, B.; Xu, Y.; Cordova, A.;
B a¨ ckvall, J. E. Chem. Eur. J. 2006, 12, 225–232; (b) Zhu,
D.; Hua, L. J.Org. Chem. 2006, 71, 9484–9486; (c) Zhu,
D.; Yang, Y.; Buynak, J. D.; Hua, L. Org. Biomol. Chem.
2006, 4, 2690–2695.
Cl
Br
5
e
98 (R)
O
Cl
Cl
e
3
4
83
88
95 (S)
6
7
. Fang, T.; Xu, J.; Du, D.-M. Synlett. 2006, 1559–1563.
. For reviews see (a) Glushkov, V. A.; Tolstikov, A. G.
Russ. Chem. Rev. 2004, 73, 581–608; (b) Corey, E. J.
Angew. Chem., Int. Ed. 2002, 41, 1650–1667; (c) Fache, F.;
Schulz, E.; Tomamasino, M.; Lemaire, M. Chem. Rev.
F
F
O
98 (S)
2
000, 100, 2159–2231; (d) Corey, E. J.; Helal, C. J. Angew.
F
Chem., Int. Ed. 1998, 37, 1986–2012; (e) Deloux, L.;
Srebik, M. Chem. Rev. 1993, 93, 763–784; (f) Singh, V. K.
Synthesis 1992, 605–617.
O
O
5
6
97
86
82 (S)
94 (R)
CF3
8. (a) Kanth, J. V. B.; Brown, H. C. Tetrahedron 2002, 58,
069–1074; (b) Liu, D.; Shan, Z.; Zhou, Y.; Wu, X.; Qin,
1
J. Helv. Chim. Acta 2004, 87, 2310–2317; (c) Shan, Z.;
Zhou, Y.; Liu, D.; Ha, W. Synth. React. Inorg. Met.-Org.
Nano-Met. Chem. 2005, 35, 275–279; (d) Yang, S.-D.; Shi,
Y.; Sun, Z.-H.; Zhao, Y.-B.; Liang, Y.-M. Tetrahedron:
Asymmetry 2006, 17, 1895–1900.
. (a) Wang, G.; Hu, J.; Zhao, G. Tetrahedron: Asymmetry
2004, 15, 807–810; (b) Gamble, M. P.; Studle, J. R.; Wills,
M. Tetrahedron Lett. 1992, 37, 2853–2856.
10. (a) Cordes, D. B.; Nguyen, T. M.; Kwong, T. J.; Suri, J.
T.; Luibrand, R. T.; Singaram, B. Eur. J. Org. Chem.
2005, 24, 5289–5295; (b) Cordes, D. B.; Kwong, T. J.;
Morgan, K. A.; Singaram, B. Tetrahedron Lett. 2006, 47,
Cl
a
1
equiv ketone, 0.7 equiv BH
3
ÆDMS and 0.1 equiv catalyst in THF at
9
rt.
b
c
Purified by flash chromatography column or Kugelrohr distillation.
Determined by P NMR of derivate with phosphonate (CDA).
Determined by GC of alcohol on Chiral Column (CP-Chirasil-
DexCB).
Determined by GC of acetyl derivative on Chiral Column.
31
d
e
3
49–351.
Several halogenated ketones were reduced with borane–
DMS in the presence of 10 mol % of catalyst 1 providing
their corresponding alcohols with high enantio-
purity (94–99% ee), except for the highly reactive
1
1
1. Thormeier, S.; Carboni, B.; Kaufmann, D. E. J. Organo-
met. Chem. 2002, 657, 136–145.
2. (a) Stepanenko, V.; Ortiz-Marciales, M.; Correa, W.; De-
Jes u´ s, M.; Espinosa, S.; Ortiz, L. Tetrahedron: Asymmetry
2006, 17, 112–115; (b) Ortiz-Marciales, M.; Stepanenko,
V.; Correa, W.; De Jes u´ s, M.; Espinosa, S. U.S. Patent
Application 11/512,599, August 30, 2006.
2
,2,2,-trifluoroacetophenone (82% ee, entry 5), as illus-
trated in Table 2.
1
1
1
3. Huskens, J.; Reetz, M. T. Eur. J. Org. Chem. 1999, 1775–
In conclusion, a facile and efficient method for the
reduction of aralkyl-, aliphatic- and halogenated aro-
matic ketones in the presence of up to 0.5 mol % cata-
lysts 1 with outstanding enantioselectivities has been
established. Catalyst 1 offer an excellent alternative for
asymmetric reduction of ketones similar in enantioselec-
1
786.
4. Berenguer, R.; Garcia, J.; Vilarrrasa, J. Tetrahedron:
Asymmetry 1991, 5, 165–168.
5. The crystal structure has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition
number CCDC 639750. Formula: C H B N O . Unit
1
9
22
1
1
3
tivity to those reported for B-methyl oxazaborolidine
cell parameters: a 8.0330(4), b 9.9264(4), c 20.4313(9),
space group P212121.
7
(
CBS reagent).
1
1
6. Seeger, K.; Heller, G. Z. Kristallogr. 1985, 172, 105–109.
7. Representative procedure. R-(ꢀ)-1-indanol (Table 1, entry
Acknowledgements
5
): To a 100 mL round flask equipped with a septa and
nitrogen flow, 10% of EG-Val borate 1 (0.325 g, 1.0 mmol)
was added. Then, dry THF (30 mL) and BDS complex
(1.0 mL 10 M, 10 mmol) were added to the reaction flask
and the solution was stirred for about 15 min. A solution
of 1-indanone (1.322 g, 10.0 mmol) in dry THF (10 mL)
was added to the reaction mixture for 1 h. The reaction
progress was followed by GC analysis. When the reaction
was complete, the reaction mixture was cooled at 0 ꢁC,
MeOH (20 mL) was added and the mixture was heated in
the rotoevaporator while removing the solvents. The
Financial support by the National Institute of Health
through their MBRS (GM 08216), IMBRE (NC P20
RR-016470) and NSF-ADVANCE (SBE-0123645)
Grants is greatly appreciated. The NIH-IMBRE and
NIH-RISE, NIH-MARC, NSF-AMP undergraduate
student’s support are also gratefully acknowledged.
References and notes
4
concentrated mixture was treated with saturated NH Cl
1
. (a) Silverman, R. B. The Organic Chemistry of Drug
Design and Drug Action; Elsevier Academic Press: Bur-
solution (25 mL) followed by extractions with dichloro-
methane (4 · 20 mL), dried with sodium sulfate and

5802
V. Stepanenko et al. / Tetrahedron Letters 48 (2007) 5799–5802
1
3
concentrated. After vacuum distillation in a Kugelrohr
oven (136 ꢁC/0.6 mmHg), the white solid of 1-indanol was
obtained in a 94% yield (1.264 g). Derivatization by
3
Ar); C NMR (100 MHz, CDCl ): d 29.7; 35.8; 76.3;
124.1; 124.8; 126.6; 128.2; 143.2; 144.9; (Mass, 70 eV, EI):
134.1 (M , 46.83%); 133.1 (100%), 117.2 (75.55%); 105.1
+
1
8
31
20
Alexakis method and analysis by P NMR indicated
(10.08%); ½aꢁD ꢀ29.4 (c 0.033, CHCl
3
); mp: 68–69 ꢁC.
1
9
7.4% ee. H NMR (400 MHz, CDCl
C8-H); 22.05 (s, 1H, OH); 0.41 (m, 1H, C8-H); 2.75 (m,
H, C9-H); 2.99 (m, 1H, C9-H); 5.16 (t, J = 6.2 Hz, 1 H,
C1-H); 7.15–7.19 (m, Ar, 3H); 7.35 (d, J = 5.6 Hz, 1H,
3
): d 1.87 (m, 1H,
18. (a) Alexakis, A.; Frutos, J. C.; Mutti, S.; Mangeney, P. J.
Org. Chem. 1992, 57, 1224–1237; (b) Alexakis, A.; Frutos,
J. C.; Mutti, S.; Mangeney, P. J. Org. Chem 1994, 59,
3326–3334.
1