Enantioselective, organocatalytic reduction of ketones using bifunctional thiourea-amine catalysts

Article abstract of DOI:10.1021/ol100365c

Prochiral ketones are reduced to enantioenriched, secondary alcohols using catecholborane and a family of air-stable, bifunctional thiourea-amine organocatalysts. Asymmetric induction is proposed to arise from the in situ complexation between the borane and chiral thiourea-amine organocatalyst resulting in a stereochemically biased boronate-amine complex. The hydride in the complex is endowed with enhanced nucleophilicity while the thiourea concomitantly embraces and activates the carbonyl.

Full text of DOI:10.1021/ol100365c

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1756-1759
Enantioselective, Organocatalytic
Reduction of Ketones using Bifunctional
Thiourea-Amine Catalysts
De Run Li, Anyu He, and J. R. Falck*
Departments of Biochemistry and Pharmacology, UniVersity of Texas Southwestern
Medical Center, Dallas, Texas 75390
j.falck@utsouthwestern.edu
Received February 11, 2010
ABSTRACT
Prochiral ketones are reduced to enantioenriched, secondary alcohols using catecholborane and a family of air-stable, bifunctional thiourea-amine
organocatalysts. Asymmetric induction is proposed to arise from the in situ complexation between the borane and chiral thiourea-amine
organocatalyst resulting in a stereochemically biased boronate-amine complex. The hydride in the complex is endowed with enhanced
nucleophilicity while the thiourea concomitantly embraces and activates the carbonyl.
The enantioselective reduction of prochiral ketones is a
mainstay in the production of enantioenriched, secondary
alcohols.1 As in other areas of chiral synthetic methodology,
the trend has been away from stoichiometric reductants2
toward more economic and environmentally friendly catalytic
processes3 and, in recent years, has embraced organocataly-
sis.4,5 One of the most prominent and frequently applied
members of this latter category is the Corey-Bakshi-Shibata
(CBS) catalyst, a chiral oxazaborolidine pioneered by Itsuno6
and further developed by Corey7 and other investigators.8
However, the sensitivity of oxazaborolidines to oxygen and
moisture as well as the need in conjunction with a current
project for a highly enantioselective reducing agent compat-
ible with a challenging combination of highly sensitive
functionality, prompted us to explore the utility of urea-/
thiourea-based organocatalysts as an alternative to CBS
oxazaborolidines.9,10
While chiral ureas and thioureas have emerged as
efficacious catalysts for a variety of nucleophilic conjugate
additions11 and 1,2-carbonyl additions, for example,
hydrocyanation,12 Henry reaction,13 and Baylis-Hillman
reaction,14 there are few examples of highly enantiose-
lective hydride additions.15,16 However, the insights gained
developing asymmetric oxy-Michael additions of boronic
(1) Review: (a) Itsuno, S. Org. React. 1998, 52, 395–576. (b) Noyori,
R.; Takeshi, O.; Sandoval, C. A.; Muniz, K. Asymmetric Synth. 2007, 321–
325.
(2) Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C. Principles and Applications
of Asymmetric Synthesis; Wiley-Interscience: New York, 2001; pp
355-367.
(3) (a) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-
VCH Verlag GmbH: Weinheim, Germany, 2005; pp 314-322. (b) Cho,
B. T. Chem. Soc. ReV. 2009, 38, 443–452.
(7) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53,
2861–2863.
(4) Review: Kagan, H. B. In EnantioselectiVe Organocatalysis; Dalko,
P. I., Ed.; Wiley-VCH: Weinheim, Germany, 2007; pp 391-401.
(5) Alternative methodology for enantioselective ketone reductions: (a)
Wu, X.; Xiao, J. J. Chem. Soc., Chem. Commun. 2007, 2449–2466. (b)
Nakamura, K.; Matsuda, T. Curr. Org. Chem. 2006, 10, 1217–1246. (c)
(8) Review Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986–2012.
(9) Li, Derun; Falck, John R., U.S. Pat. Appl. 2009253919, 2009; CAN
151:425227, AN 2009:1231134.
Zhou, L.; Wang, Z.; Wei, S.; Sun, J. Chem. Commun 2007, 2977–2979
(6) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Chem.
Commun. 1983, 8, 469–470.
.
(10) Recent example using borane-amine complex Zhou, Y.; Wang, Y.-
W.; Dou, W.; Zhang, D.; Liu, W.-S. Chirality 2009, 21, 657–662
.
(11) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713–5743.
10.1021/ol100365c  2010 American Chemical Society
Published on Web 03/24/2010

replaced with the simpler (R,R)-trans-N,N′-dimethylcyclo-
hexane-1,2-diamine. The resultant monobasic catalyst B
provided a modest improvement in yield and enantioselec-
tivity, albeit delivering the R-enantiomer of 2 (entry 2). A
survey of commercial boranes showed catecholborane de-
livered the best performance and that toluene was superior
to other common solvents. In concert with the temperature
dependency displayed by CBS catalysts,20 both yield and
optical purity improved using this combination as the
temperature was lowered to around -46 °C (entry 3), but
then declined as the temperature was lowered still further
(entry 4). Primary amine catalyst C (entry 5) was disap-
pointing in all respects and was not further pursued. In
contrast, the corresponding N-benzyl secondary amine cata-
lyst D at -78 °C boosted the stereoselectivity upward to
73% ee, albeit at the expense of yield (entry 6). Mindful of
the preceding temperature dependency, catalyst D was
evaluated over a wider temperature range (see Supporting
Information). At -46 °C, the yield of 2 jumped to 88% and
the enantioselectivity to 98% ee (entry 7); thereafter, the
stereoselectivity slowly declined as the temperature was raised,
for example, 85% ee at -30 °C (entry 8). The biphasic behavior
of the thiourea catalysts might be attributed to the slow
breakdown of the catalyst-product complex below approxi-
mately -46 °C; presumably, the catalyst-product complex is
functionally catalytic, but less enantioselective than the catalyst
alone.20 Catalyst E, which differs from D by having an
N-isobutyl substituent instead of an N-benzyl, showed a
significant loss of enantioselectivity under otherwise identical
reaction conditions (entry 9 vs 7). This might be attributed to
Figure 1. Proposed asymmetric catalysis.
acids with R,ꢀ-unsaturated ketones17 revealed several unique
attributes that we felt could be harnessed for enantioselective
carbonyl reductions. Specifically, we envisioned that the
union between a borane and a chiral thiourea-amine
organocatalyst would result in a stereochemically biased
boronate-amine complex.18 The hydride in the complex is
endowed with enhanced nucleophilicity (the push) while the
thiourea concomitantly embraces and activates the carbonyl
(the pull) (Figure 1). As proof-of-concept, we developed a
family of robust, bifunctional thiourea-amine catalysts and
describe herein their exploitation for the stereodefined
reduction of prochiral ketones to enantioenriched, secondary
alcohols.
Despite its outstanding performance catalyzing the afore-
mentioned oxy-Michael additions,17 thiourea catalyst A19
furnished (S)-(-)-1-phenylethanol (2) in poor yield and low
enantioselectivity at room temperature in THF (Table 1, entry
1) using acetophenone (1) and BH3·THF as the model
substrate and hydride source, respectively. Reasoning that
the cinchona alkaloid moiety might be responsible, it was
Table 1. Influence of Select Reaction Parameters on Yield and Enantioselectivitya
entry
catalyst
borane (equiv)
BH3·THF (0.7)
solvent
temp (°C)
yieldb(%)
eec(%)
config
1
2
3
4
5
6
7
8
9
10
A
B
B
B
C
D
D
D
E
F
THF
THF
23
23
10
40
88
65
25
24
88
88
85
83
5
13
43
27
20
73
98
85
65
96
S
R
R
R
S
S
S
S
S
S
BH3·THF (0.7)
catecholborane (1.6)
catecholborane (1.6)
catecholborane (1.6)
catecholborane (1.6)
catecholborane (1.6)
catecholborane (1.6)
catecholborane (1.6)
catecholborane (1.6)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
-46
-78
-78
-78
-46
-30
-46
-46
a Reaction conditions: catalyst (10 mol %), 24 h, argon atmosphere. b Isolated yield. c Measured by chiral HPLC.
Org. Lett., Vol. 12, No. 8, 2010
1757

Table 2. Enantioselective Reduction of Aryl Ketonesa
Table 3. Enantioselective Reduction of Alkenyl and Alkyl
Ketonesa
a Reaction conditions: catalyst (10 mol %), catecholborane (1.6 equiv),
4 Å molecular sieves, toluene, -46 °C, 24 h. b Isolated yield. c Measured
by chiral HPLC. d Thirty-six hours.
2-acetonaphthone (23, entry 11) and the heterocycle 2-acetylth-
iophene (25, entry 12).
As an extension of our survey of structurally diverse
prochiral carbonyls, R,ꢀ-unsaturated ketones 27, 29, and
31 were transformed in good yields and stereoselectivities
to alcohols 28, 30, and 32, respectively, using catalyst D
(Table 3, entries 1-3). The latter example deserves
comment since it was obtained in appreciably better optical
purity (97% ee) than that reported using the CBS catalyst
(81% ee).21 Unsymmetrical dialkyl ketones, of course,
were more challenging. While alcohol 34 was produced
from ketone 33 in good yield using catalyst D, the chiral
induction was quite modest (entry 4). Drawing inspiration
from the recent work of Zuend and Jacobsen,22 we sought
to improve catalytic performance with the introduction
a Reaction conditions: catalyst D (10 mol %), catecholborane (1.6 equiv),
4 Å molecular sieves, toluene, -46 °C, argon atmosphere. b Isolated yield.
c Measured by chiral HPLC.
just steric differences, although alternative explanations, for
example, π-π bonding between the N-benzyl of D and the
electron-rich catechol of the borane, warrant investigation. A
comparison of catalyst F with D is also instructive. The former
was prepared from a commercial, chiral acyclic-diamine, yet
furnished results comparable to D (entry 10), indicating a wide
latitude in the design of future catalysts.
(12) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901–
4902.
Catalyst D proved useful for the enantioselective reduction
of a wide range of aryl ketones (Table 2). Simple phenyl
alkyl ketones 3 and 5 were smoothly reduced with excellent
stereocontrol to (S)-alcohols 4 (entry 1) and 6 (entry 2),
respectively. Importantly, the presence of an ortho-substituent
did not alter the level of enantioselectivity (entry 3, 7 f 8)
nor did electron-withdrawing (entry 4) or electron-donating
(entry 5) groups, although the latter did require a longer
reaction time. Other functionality was also well tolerated
including p-fluoro (entry 6), p-chloro (entry 7), and p-bromo
(entry 8). The cyclic ketones 1-tetralone (19) and 4-chro-
manone (21) were likewise well behaved and furnished
alcohols 20 (entry 9) and 22 (entry 10) in high yield and
optical purity. Comparable results were obtained using
(13) Shibasaki, M.; Groger, H.; Kanai, M. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
Germany, 2003; Supp. 1, Chapter 29.3.
(14) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007,
46, 4614–4628.
(15) Procuranti, B.; Connon, S. J. J. Chem. Soc., Chem. Commun. 2007,
1421–1423.
(16) Thioureas with metals: (a) Touchard, F.; Fache, M. L. Tetrahedron:
Asymmetry 1997, 8, 3319–3326. (b) Bernard, M.; Delbecq, F.; Fache, F.;
Sautet, P.; Lemaire, M. Eur. J. Org. Chem. 2001, 1589–1596.
(17) Li, D. R.; Murugan, A.; Falck, J. R. J. Am. Chem. Soc. 2008130, 46–
48.
(18) For similar chiral Lewis Base catalyzed silane additions, see: (a)
Kocovsk, P.; Malkov, A. V. In EnantioselectiVe Organocatalysis; Dalko,
P. I., Ed.; Wiley-VCH: Weinheim, Germany, 2007; pp 255-286. (b)
Malkov, A. V.; Stewart-Liddon, A. J. P.; Ramirez-Lopez, P.; Bendova, L.;
Haigh, D.; Kocovsk, P. Angew. Chem., Int. Ed. 2006, 45, 1432–1435. (c)
Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2000, 122, 12021–12022.
1758
Org. Lett., Vol. 12, No. 8, 2010

of an additional chiral center. Indeed, after extensive study
of the structure-activity relationships of the catalyst
scaffold (see Supporting Information for details), catalysts
G and H were found to raise the stereoselectivity for the
reduction of 33 to 63% ee (entry 5) and 79% ee (entry
6), respectively, validating this approach. Yet, catalyst I
was less successful despite having a fourth chiral center.
In the case of cycloalkyl alkyl ketone 35, catalysts D and
H were comparable and furnished 36 with high enanti-
oselectivity (entries 8 and 9).
In summary, we describe a family of air-stable, bifunc-
tional amino-thiourea cataysts for the enantioselective reduc-
tion of prochiral ketones using echolborane. Yields and %
ee using aryl and R,ꢀ-unsaturated ketones rival or exceed
those achievable using extant reagents. Promising results
were also seen using unsymmetrical dialkyl ketones and a
strategy for future catalyst optimization was demonstrated.
Acknowledgment. Financial support provided by the
Robert A. Welch Foundation and NIH (GM31278,
DK38226).
(19) Vakulya, B.; Varga, S.; Csa′mpai, A.; Soos, T. Org. Lett. 2005, 7,
1967–1969.
Supporting Information Available: Synthetic procedures
and analytical data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Stone, G. B. Tetrahedron: Asymmetry 1994, 5, 465–472.
(21) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611–614.
(22) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15872–
15883.
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