Novel dimethoxy(aminoalkoxy)borate derived from (S)-diphenylprolinol as highly efficient catalyst for the enantioselective boron-mediated reduction of prochiral ketones

Article abstract of DOI:10.1016/j.tetlet.2008.12.061

The novel dimethoxyl(aminoalkoxy)borate 1 was isolated as a white crystalline dimer joined by H-bonding as evidenced by X-ray analysis, and demonstrated to be a highly effective catalyst for the asymmetric reduction of representative prochiral ketones with borane-DMS. Optically pure alcohols were obtained using only 1 mol % of catalyst 1 in up to 99% ee.

Full text of DOI:10.1016/j.tetlet.2008.12.061

Tetrahedron Letters 50 (2009) 995–998
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Tetrahedron Letters
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Novel dimethoxy(aminoalkoxy)borate derived from (S)-diphenylprolinol
as highly efficient catalyst for the enantioselective boron-mediated reduction
of prochiral ketones
b
a
Viatcheslav Stepanenko a, Margarita Ortiz-Marciales a, , Charles L. Barnes , Carmelo Garcia
*
a Department of Chemistry, University of Puerto Rico–Humacao, CUH Station, Humacao, PR 00791, USA
b Department of Chemistry, University of Missouri–Columbia, 125 Chemistry Building, Columbia, MO 65211, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The novel dimethoxyl(aminoalkoxy)borate 1 was isolated as a white crystalline dimer joined by H-bond-
ing as evidenced by X-ray analysis, and demonstrated to be a highly effective catalyst for the asymmetric
reduction of representative prochiral ketones with borane–DMS. Optically pure alcohols were obtained
using only 1 mol % of catalyst 1 in up to 99% ee.
Received 31 October 2008
Revised 4 December 2008
Accepted 11 December 2008
Available online 24 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Asymmetric reduction of prochiral ketones is one of the most
efficient methods to introduce chirality when synthesizing non-
racemic biologically active compounds.1 Chiral 1,3,2-oxazaboroli-
dines have been intensely applied as highly effective catalysts for
the asymmetric borane reduction of ketones.2,3 Recently, the de-
sign of more stable and reliable borane catalysts and methods to
improve the enantioselective process for a variety of substrates
have been areas of great interest.4
Previously, we have shown that the spiroaminoborate esters 2
(Scheme 1), derived from chiral amino alcohols and ethylene gly-
col, are valuable catalysts for the asymmetric reduction of prochi-
ral ketones to obtain non-racemic alcohols in high purity.5
trimethyl borate. Moreover, other related B-alkoxy-oxazaboroli-
dines have been suggested as active catalytic species in the reduc-
tion of ketones,6b,9 and in the reaction of addition to aldehydes.8c To
our knowledge, these oxazaborolidines have not been isolated and/
or characterized. Interestingly, when we carried out the reaction of
(S)-diphenylprolinol with trimethyl borate in dry diisopropyl ether
at room temperature, the aminoborate complex 1 was obtained as a
crystalline compound in 68% yield. The product was characterized
by 1H, 13C, 11B NMRs and IR spectroscopic analysis.10
The structure of 1 was conclusively proved by X-ray analysis
(Fig. 1).11 Intriguingly, two molecules in a single unit are packed
together by hydrogen bonding between the N–H and the O–CH3
groups forming a dimeric structure, as illustrated in Figure 1.
The dimethoxyborate 5 (Scheme 2) derived from norephedrine
was also obtained and characterized12 but, unfortunately, the sam-
ple did not provide a good crystal for X-ray analysis.
Furthermore, spiroborate
3 derived from (S)-diphenylprolinol
achieved the best enantioselectivity for a wide variety ketones.5c,d
As part of our new efforts to obtain non-spiro analogues of borate
3, we describe here the synthesis, isolation and characterization of
novel aminoborate esters 1 and 5, (Scheme 2). Additionally, the
enantioselectivity of these borates in the reduction of representa-
tive ketones was studied.
R2
R2
R1
R
R1
Masui and Shiori6a initially attempted to isolate a B-methoxy-
1,3,2-oxazaborolidine from the reaction of (1S,2S,3R,5S)-3-amino-
2-hydroxypinane and trimethyl borate. However, they were not
successful, and they suggested as a reason, the oxazaborolidine
instability. As a result, they used the in situ formation of the
postulated B-methoxy-oxazaborolidine as a simpler and effective
R3
OH
* *
R3
R
* *
B
HO
OH
R4
N
O
O
O
NH
R4
O
O
2
B
+
H
OiPr
B(OiPr)3
H
Ph
Ph
protocol for the borane reduction of acetophenone and a-oxoke-
toxime ethers.6c Also, Masui6a and other groups.7,8a,b studied the
reduction of alkyl arylketones using as catalyst, the in situ gener-
ated oxazaborolidine 4, derived from (S)-diphenylprolinol and
0.1-0.005 equiv Cat. 3
OH
R"
O
THF, BH3-DMS/25oC
O
N
B
H
up to 99%ee
O
O
R'
R'
R"
*
3
* Corresponding author. Tel.: +1 787 850 9469; fax: +1 787 850 9422.
E-mail address: ortiz@quimica.uprh.edu (M. Ortiz-Marciales).
Scheme 1. Synthesis of spiroaminoborate esters for the reduction of ketones.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.061

996
V. Stepanenko et al. / Tetrahedron Letters 50 (2009) 995–998
The theoretical parameters of borate esters 1 and 5, and their
dimmers by DFT B3LYP/6-31G(d) calculations showed that 1 and
decreased slightly when 0.5 mol % of catalyst was loaded (entry
5). Noteworthy, even with 0.25 mol % load of catalyst the selectiv-
ity was still high, 97% ee (entry 6). From the practical point of view,
the optimal amount of catalyst was 1 mol % (entry 4). The effi-
ciency and enantioselectivity of catalyst 1 for the reduction of ace-
tophenone was considerably higher compared with the suggested
B-methoxy-1,3,2-oxazaborolidine 4 formed in situ.6–9
The reduction of acetophenone with 10 mol % of complex 5 un-
der similar reaction conditions provided the 1-phenylethanol in
only 85% ee.
Based on the high reactivity and excellent selectivity of aminob-
orate complex 1 in the reduction of acetophenone, we decided to
apply the methodology for the reduction of representative ketones.
The results are summarized in Table 3. The enantioselectivity in
most cases was very high (up to 99% ee) and comparable with pre-
vious results obtained with the spiroborate ester 3.5 Moreover, in
contrast to the low efficiency of the in situ prepared B-methoxy
oxazaborolidine 4 reported by Xu et al.7 for electron-deficient ke-
tones, the enantioselectivity of 1 was not affected (4–6), obtaining
more than 98% ee with only 1 mol % catalyst.13 Although it seems
5 are thermally favored, with a dimerization free energy (
of ꢀ36.4 kcal/mol and ꢀ10.7 kcal/mol, respectively
Gf/dim ꢀ 2
D
Gdim
)
(
D
Gdim
=
D
DGf/monomer) (Table 1). Although they are both ther-
mally favored, possibly, only compound 1 can dimerize because:
(a) The different substituents (CH3 and Ph) for 5 (Fig. 2, above)
make the orientation of the N–H bonds relative to the O–CH3 group
unsymmetrical inducing extra strain energy. (b) The extra H-atom
in 5 introduces a steric hindrance for its dimer to form, that is, the
monomers never reached the 2.00 Å, the required distance to form
the H-bonds, while in 1, this distance was optimal, as confirmed by
the X-ray experimental values of 1.963 Å.11 (c) The enthalpy for di-
mer 1 is, at least, three times more exothermic than for 5. (d) The
charge distribution in 5 is not as high as in 1. Moreover, the elec-
trostatic potentials in Figure 2, shows that the arrangement of
the most stable dimer 1 induces a larger electrostatic potential be-
tween the NH and the O groups, which, in turn, generates a higher
Coulomb-type interaction between the atom-point charges.
We then examined the aminoborate esters 1 and 5, as pre-
formed catalysts, in the borane-mediated reduction of acetophe-
none. The results of the reaction employing different amount of
catalyst 1 are presented in Table 2. Using 10–1 mol % of aminob-
orate ester 1, the enantioselectivity was 99% (entries 1–4), and
H
Ph
Ph
O
H
H
Ph
Ph
Ph
Ph
O
B(OMe)3
N
vs
NH OH
N
H
B
B
MeO
OMe
Me
OMe
1
4
Ph
Me
Ph
B(OMe)3, EE
-MeOH
H2N
O
B
MeO
OMe
H2N
OH
5
Scheme 2. Formation of aminoborate esters 1 and 5.
Figure 2. Optimized DFT structures of borate esters dimer 1 (below) and 5 (above).
Contours give the electrostatic potentials of each species.
Table 2
Figure 1. X-ray structure of the aminoborate ester dimer 1.
Reduction of acetophenone using different amount of borate 1
Entry
Amount of 1 (%)
Yielda,b (%)
Eec (%)
Table 1
Theoretical parameters of 1 and 5 and their corresponding dimers
1
2
3
4
5
6
10
5
2.5
1
0.5
0.25
83
90
93
91
92
93
99
99
99
99
98
97
Structures
D
Gf (kcal/mol)
Torsion angle HNBO (degrees)
Atomic charge
O
N–H
1
5
ꢀ86,150.3
ꢀ62,189.5
ꢀ172,337.0
ꢀ124,389.7
46.1
ꢀ0.331
ꢀ0.383
ꢀ0.363
ꢀ0.374
0.051
0.036
0.122
0.096
0.53; 7.32a
ꢀ8.8
a
The reduction was carried out with 0.7 equiv of borane–DMS in THF at 25 °C
Dimer-1
Dimer-5
(rt).
6.30; 6.96a
b
Isolated yield after distillation on Kugelrohr apparatus.
Determined by GC of acetate on chiral column.
c
a
The different angles are due to the unsymmetrical dimer.

V. Stepanenko et al. / Tetrahedron Letters 50 (2009) 995–998
997
Table 3
2. Ager, D. J. Handbook of Chiral Compounds; Marcel Dekker: New York, 1999. pp
211–225.
Reduction of representative chiral ketones using 1 mol % of aminoborate ester 1a
3. (a) Corey, E. J.; Helal, C. J. Angew.Chem., Int. Ed. 1998, 37, 1986–2012; (b) Deloux,
L.; Srebnik, M. Chem. Rev. 1993, 93, 763–784.
Entry
1e
Substrate
Yieldb (%)
eec (%)
Configurationd,14
4. (a) Cho, B. T. Tetrahedron 2006, 62, 7621–7643; (b) Glushkov, V. A.; Tolstikov, A.
G. Russ. Chem. Rev. 2004, 73, 581–608.
O
´
5. (a) Stepanenko, V.; Ortız-Marciales, M.; Correa, W.; De Jesús, M.; Espinosa, S.;
93
95
(R)
´
Ortız, L. Tetrahedron: Asymmetry 2006, 17, 112–115; (b) Stepanenko, V.; De
Jesús, M.; Correa, W.; Guzman, I.; Vázquez, C.; De la Cruz, W.; Ortiz-Marciales,
M.; Barnes, C. L. Tetrahedron Lett. 2007, 48, 5799–5802; (c) Stepanenko, V.; De
Jesús, M.; Correa, W.; Guzman, I.; Vázquez, C.; Ortiz, L.; Ortiz-Marciales, M.
Tetrahedron: Asymmetry 2007, 18, 2739–2745; (d) Ortiz-Marciales, M.;
Stepanenko, V.; Correa, W.; De Jesús, M.; Espinosa, S. U.S. Patent Application
11/512,599, August 30, 2006.
N
S
O
O
2
3
91
90
96
96
(R)
(R)
O
6. (a) Masui, M.; Shioiri, T. Synlett 1997, 273–274; (b) Masui, M.; Shioiri, T.
Tetrahedron 1995, 51, 8363–8370; (c) Masui, M.; Shioiri, T. Tetrahedron Lett.
1998, 39, 5195–5198.
7. (a) Xu, J.; Wei, T.; Zhang, Q. J. Org. Chem. 2003, 68, 10146–10151; (b) Xu, J.; Su,
X.; Zhang, Q. Tetrahedron: Asymmetry 2003, 2003, 1781–1786; (c) Xu, J.; Wei, T.;
Zhang, Q. J. Org. Chem. 2004, 69, 6860–6866; (d) Liu, H.; Xu, J. X. J. Mol. Catal. A:
Chem. 2006, 244, 68–72.
8. (a) Garrett, C. E.; Prasad, K.; Repie, O.; Blacklock, T. Tetrahedron: Asymmetry
2002, 13, 1347–1349; (b) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.;
Reamer, R. A.; Mohan, J. J.; Turner Jones, E. T.; Hoogsteen, K.; Baum, M. W.;
Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751–762; (c) Gnanadesikan, V.; Corey,
E. J. Org. Lett. 2006, 8, 4943–4945.
O
S
Cl
4
92
99
(R)
O
5
6
95
88
99
98
(R)
(S)
9. (a) Krzeminski, M. P.; Wojtczak, A. Tetrahedron Lett. 2005, 46, 8299–8302; (b)
Santhi, V.; Rao, J. M. Tetrahedron: Asymmetry 2000, 11, 3553–3560; (c) Ponzo, V.
L.; Kaufman, T. S. Synlett 2002, 1128–1130.
O2N
O
10. Preparation of (ꢀ)-(3aS)-1,1-dimethoxy-3,3-diphenyl-hexahydro-1H-pyrrolo[1,2-
Cl
c][1,3,2]oxazaborol-7-ium-1-uide (1): To a solution of (S)-diphenyl(pyrrolidin-2-
yl)methanol (2.53 g, 10.0 mmol) in dry isopropyl ether (25 mL)
a freshly
redistilled neat dimethyl borate (3 mL, 28.9 mmol) was added drop wise at
room temperature under nitrogen atmosphere. The resulting mixture was left
without stirring over 24 h (after 2 h white crystals started to grow). The
precipitate was filtered, washed with isopropyl ether (4 ꢁ 10 mL) under
nitrogen atmosphere and dried under vacuum at 60 °C over 12 h to give the
F
F
O
7
94
99
(R)
final product as a white solid (2.21 g, 68 % yield). Mp 132–136 °C. IR (m
, cmꢀ1):
3300 (NH), 3059, 2964, 1598, 1390, 1103, 1022; 1H NMR (400 MHz, CDCl3): d
(ppm) 1.42–1.66 (m, 4H, (CH2)2), 2.03–3.23 (m, 8H, B(OMe)2 and NCH2), 4.26–
4.31 (m, 1H, NCH), 6.37 (br d, J = 6.0 Hz, 1H, NH), 7.11–7.28 (m, 6H, CHAr), 7.46–
7.50 (m, 4H, CHAr); 13C NMR (100 MHz, CDCl3): d (ppm) 24.8, 29.0, 46.7, 49.6
(br, 2MeO), 81.4, 126.1, 126.2, 126.3, 126.5, 127.7, 127.8, 146.2, 147.8; 11B NMR
a
The reduction was carried out using 0.7 equiv of borane–DMS in THF at room
temperature.
b
c
Isolated yield after distillation in a Kugelrohr apparatus.
Determined by GC of acetate on chiral column.
Absolute configuration was determined by comparison of optical rotations with
(128 MHz, CDCl3): d 6.7 (s); ½a D23
ꢀ130 (c 1.3, CHCl3).
ꢂ
d
11. The crystal structure has been deposited at the Cambridge Crystallographic
Data Centre and allocated the deposition number CCDC CCDC 704941. Formula:
C19 H24 B N O3; Crystal size 0.55 ꢁ 0.35 ꢁ 0.30 mm. Crystal system, space
group monoclinic, P 21. Unit cell dimensions: a = 9.9641(5) Å alpha = 90 deg;
b = 18.7001(9) Å beta = 107.8240(10)deg; c = 10.1265(5) Å gamma = 90 deg.
Table hydrogen bonds with Hꢃ ꢃ ꢃA < r(A) + 3.200 Å and hDHAh110 deg:
literature values. The configuration of new optical active compounds was assigned
by analogy.
e
The reduction was carried out using 1.7 equiv of borane–DMS.
that the in situ prepared oxazaborolidine methods are more conve-
nient, these methods have been reported to provide less reproduc-
ible results,8a probably due to impurities present in the reaction
mixture and, therefore, require larger amounts of expensive cata-
lysts. Our process is more economical since it uses less diphenyl-
prolinol. Moreover, the less catalytic load permits an easier
purification process that is well suited to large scale syntheses.
In summary, we have prepared new dimethoxy(aminoalk-
oxy)borate catalysts, which were isolated and characterized. Amin-
oborate ester 1 was used for the highly enantioselective and
efficient borane reduction of variety aromatic ketones with only
1 mol % of catalytic loading. Moreover, the versatility of the meth-
od was studied using a variety of heterocyclic and aliphatic ketones
obtaining excellent yields of high enantiomerically enriched sec-
ondary alcohols, which are important in the synthesis of biologi-
cally active compounds.
D–H
d(D–H)
d(Hꢃ ꢃ ꢃA)
1.953
1.963
<DHA
d(Dꢃ ꢃ ꢃA)
2.810
2.858
A
N1A–H1NA
N1B–H1NB
0.882
0.911
163.93
167.05
O2B
O2A
12. Preparation of (it 4S,5R)-2, 2-dimethoxy-4-methyl-5-phenyl-1,3, 2-oxazaborolidin-
3-ium-2-uide (5): To a solution of (1R,2S)-norephedrine (1.51 g, 10.00 mmol) in
dry diethyl ether (25 mL),
a freshly redistilled neat methyl borate (3 mL,
28.88 mmol) was added drop wise over 1 min at 25 °C under a nitrogen
atmosphere. During the addition a white precipitate was formed. The resulting
mixture was stirred over 12 h at 25 °C. The precipitate was filtered, washed with
diethyl ether (5 ꢁ 10 mL) under nitrogen atmosphere and dried under vacuum to
give final product as a white crystalline solid (1.70 g, 76% yield). Mp: 127–130 °C.
IR (m
, cmꢀ1): 3225, 3083, 1607, 1449, 1337, 1196, 1119, 1067; 1H NMR (400 MHz,
DMSO-d6): d (ppm) 1.66 (d, J = 6.8 Hz, 3H, CHMe), 3.21 (s, 6H, 2 OMe), 3.44–3.51
(m, 1H, NCH), 4.90 (d, J = 5.3 Hz, 1H, OCH), 5.46 (br s, 2H, NH2), 7.18–7.39 (m, 5H,
Ph); 13C NMR (100 MHz, DMSO-d 6): d 14.3, 48.6, 51.8, 126.0, 126.3, 127.7, 141.5;
11B-NMR (128 MHz, DMSO-d6): d (ppm) 6.5 (s); ½a 2D3
= ꢀ33° (c 4.3, DMSO). HRMS
ꢂ
m/z: 222.12766 found (calculated for C11H17O3N111B1, (MꢀH)+ requires
222.12960).
13. Reduction of 40-nitroacetophenone using 1 mol % of borate ester 1. Preparation of
(+)-(R)-1-(4-nitrophenyl) ethanol: Borane–SMe2 complex (10 M, 0.7 mL,
7.0 mmol) was added to a solution of catalyst 1 (32.5 mg, 0.10 mmol) in dry
THF (5 mL) at 25 °C and the mixture was stirred for 1 h. A solution of 40-
nitroacetophenone (1.65 g, 10.0 mmol) in THF (5 mL) was added for 1 h using
an infusion pump. The reaction mixture was stirred at rt over 1 h, then cooled
at 0 °C and quenched with methanol (3 mL). The reaction mixture was
concentrated, washed with water (50 mL) and the product was extracted
with dichoromethane (3 ꢁ 20 mL). The extract was dried over Na2SO4 and
concentrated; the residue was distilled in a Kugelrohr apparatus under vacuum
to give the final product as a yellow oil (1.59 g, 95%). 1H NMR (400 MHz, CDCl3):
d (ppm) 1.51 (d, J = 6.8 Hz, 3H, Me), 2.44 (br s, 1H, OH), 5.01 (q, J = 6.5 Hz,
CHMe), 7.52–7.55 (m, 2H, CHAr), 8.16–8.19 (m, 2H, CHAr); 13C NMR (100 MHz,
CDCl3): d(ppm) 25.5, 69.5, 123.7, 126.2, 147.2, 153.2. The enantiomeric excees
Acknowledgements
We thank NIH for the financial support through their MBRS
(GM 08216), INBRE (NC P20 RR-016470) and NSF-ADVANCE
(SBE-0123645).
References and notes
1. (a) Shinkai, I. Pure Appl. Chem. 1997, 69(3), 453–458; (b) Reductions in Organic
Synthesis; Abdel-Magid, A. F., Ed.; American Chemical Society: Washington, DC,
1996; Vol. 641.

998
V. Stepanenko et al. / Tetrahedron Letters 50 (2009) 995–998
was determined by GC analysis of O-acetyl derivative on a CP-Chirasil-DexCB
difluorophenyl)ethanol:
½
a 2D0
ꢂ
=
+43° (c 5, CHCl3), ee 98%; (R)-1-(1-
chiral column as 99% ee (Rt 63.3 min). ½a D23
ꢂ
= +33° (c 2.2, CHCl3).7a
adamantyl)ethanol: ½a D20
ꢂ
=
+1.5° (c 1.6, CHCl3), ee 99%; Lit16: ½a D23
ꢂ
= +1.6°
14. Optical rotation of (R)-1-(3-pyridyl)ethanol: ½a D20
ꢂ
=
+39° (c 2.7, CHCl3), ee 95%;
(c 0.4, CHCl3), ee >98%.
Lit15
[a
]
D
=
+26.7o (c 2, CHCl3), ee 90%; (R)-1-benzofuran-2-yl-ethanol:
15. Fantin, G.; Mogagnolo, F.; Medici, A.; Pedrini, P.; Poli, S. Tetrahedron: Asymmetry
½
a 2D0
ꢂ
=
+18° (c 3, CHCl3), ee 96%; (R)-1-(2-thienyl)ethanol: ½a D20
ꢂ
=
+27° (c
1993, 4, 1607–1612.
2.5, CHCl3), ee 96%; Lit15: ½a D
ꢂ
=
+24.2° (c 5, CHCl3), ee 100%; (R)-6-chloro-
16. Janssen, A. J. M.; Klunder, A. J. H.; Zwanenburg, B. Tetrahedron 1991, 47, 7645–
thiochroman-4-ol: ½a D20
ꢂ
=
+79° (c 2.2, CHCl3), ee 99%; (S)-2-chloro-1-(2,4-
7662.