Spiroborate esters in the borane-mediated asymmetric synthesis of pyridyl and related heterocyclic alcohols

Article abstract of DOI:10.1016/j.tetasy.2007.10.044

The effectiveness of several spiroborate ester catalysts was investigated in the asymmetric borane reduction of 2-, 3-, and 4-acetylpyridines under different reaction conditions. Highly enantiomerically enriched 1-(2-, 3-, and 4-pyridyl)ethanols and 1-(heterocyclic)ethanols were obtained using 1-10% catalytic loads of the spiroborate 5 derived from diphenylprolinol and ethylene glycol.

Full text of DOI:10.1016/j.tetasy.2007.10.044

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2738–2745
Spiroborate esters in the borane-mediated asymmetric synthesis
of pyridyl and related heterocyclic alcohols
Viatcheslav Stepanenko, Melvin De Jes u´ s, Wildeliz Correa, Irisbel Guzm a´ n,
Cindybeth V a´ zquez, Lymaris Ortiz and Margarita Ortiz-Marciales*
Department of Chemistry, University of Puerto Rico-Humacao, CUH Station, Humacao, PR 00791, USA
Received 5 July 2007; accepted 18 October 2007
Abstract—The effectiveness of several spiroborate ester catalysts was investigated in the asymmetric borane reduction of 2-, 3-, and 4-
acetylpyridines under different reaction conditions. Highly enantiomerically enriched 1-(2-, 3-, and 4-pyridyl)ethanols and 1-(hetero-
cyclic)ethanols were obtained using 1–10% catalytic loads of the spiroborate 5 derived from diphenylprolinol and ethylene glycol.
ꢀ
2007 Elsevier Ltd. All rights reserved.
1. Introduction
group significantly increased the enantioselectivity of
non-enolizable diaryl- or pyridylaryl ketones.
1
1
Enantiopure secondary alcohols are key intermediaries in
the synthesis of a large number of pharmaceutical prod-
Recently, we reported the synthesis of a series of stable
spiroborate esters derived from non-racemic 1,2-amino-
alcohols and ethylene glycol. These compounds, shown in
1
,2
ucts. In particular, non-racemic alcohols (or their derived
amines) containing heterocyclic fragments are known for
3
–5
1
13
11
their biological activity. The borane-mediated reduction
of prochiral ketones catalyzed by organoboranes, specifi-
Figure 1, were fully characterized by H, C, and
NMR, HRMS, IR, specific rotation, and mp.
B
All
1
2
6
–8
cally the well-known 1,3,2-oxazaborolidines,
have
exhibited high efficiency and enantioselectivity as cata-
lysts for the borane-mediated asymmetric reduction of
acetophenone.
become the preferred approach to obtain non-racemic
alcohols due to their high enantioselectivity, predictable
absolute stereochemistry, ease of handling and operation,
and low environmental impact. However, ketones contain-
ing a heteroatom can form borane complexes that not only
decrease the borane source but also compete with the enan-
Ph
Ph
Ph
O
O
O
5
tioselective carbonyl reduction. Acetylpyridines were
Ph
O
O
O
Ph
O
O
O
B
reduced with borane employing 20 mol % of B-Me CBS
catalyst, but the process resulted in a low selectivity
B
B
N
H
Ph
N
H
N
H
(
<52% ee). A stoichiometric amount of catalyst increased
9
10
the % ee only modestly. Masui introduced a more reac-
tive oxazaborolidine system generated in situ from 10%
diphenyl prolinol and trimethylborate and successfully
reduced 3- and 4-acetyl heteroaryl ketones with high to
excellent enantioselectivity. However, to achieve good
selectivity for the 2-acetyl analogues, a stoichiometric
amount of the aminoalcohol was required. In related work,
protection of the pyridine nitrogen by a methyl or allylic
1
2
3
Ph
Ph
H
O
B
O
H
N
O
O
O
B
O
N
4
5
*
Corresponding author. Tel.: +1 787 852 3222; fax: +1 787 850 9422;
e-mail: mr_ortiz@webmail.uprh.edu
Figure 1. Chiral spiroborates derived from non-racemic 1,2-amino-
alcohols.
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.044

V. Stepanenko et al. / Tetrahedron: Asymmetry 18 (2007) 2738–2745
2739
Herein, we report a systematic study of the asymmetric
borane-mediated reduction of acetylpyridines and related
heterocyclic ketones using the spiroborate esters 1–5 as
catalysts. These spiroborates are crystalline compounds
that can be stored for long periods of time (>1 y). More-
over, spiroborate 5 was exposed to moist air at 25 ꢁC for
over 24 h, without significant hydrolysis or decomposition
Table 2. Studies on the reduction of 3-acetylpyridine employing different
catalytic loads of 1
c
Entry
Catalyst 1 (mol %)
Yield (%)
ee (%)
a
1
2
3
4
5
6
7
8
20
10
5
2.5
1
0.5
0.25
0.1
84
89
94
95
93
93
96
91
91
91
90
89
87
84
81
65
a
a
a
1
13
11
b
being observed by H, C, and B NMR analysis.
b
b
b
2
. Results and discussion
a
b
c
Purified by column chromatography.
Purified by distillation.
By GC of O-acetyl derivative on a CP-Chiralsil-DexCB column.
Initially, we studied the asymmetric reduction of 3-acetyl-
pyridine 6 using spiroborates 1–5. The reduction was
carried out with BH –SMe (1.6 equiv) and 10 mol % of
3
2
To illustrate the cut-off effect for catalyst 1, the correlation
curve between the amount of catalyst and the enantiopurity
of 1-(3-pyridyl)ethanol is presented in Figure 2.
the catalyst at room temperature. The enantiopure 1-(3-
pyridyl)ethanol 7 was isolated after the reaction mixture
was quenched with methanol at 0 ꢁC, left overnight at
reflux temperature, concentrated under vacuum, and puri-
fied by column chromatography on deactivated aluminum
oxide (method a). The results are summarized in Table 1.
9
9
5
0
Although catalysts 1–4 (entries 1–4) provided good enantio-
selectivities (i.e., >90% ee), spiroborate 5 was particularly
effective, (99% ee) for the reduction of 6 (entry 5).
85
8
7
7
0
5
0
Table 1. Reduction of 3-acetylpyridine with spiroborate esters 1–5 as
catalysts in THF at 25 ꢁC using BH –SMe
3 2
O
OH
*
65
60
Cat. 1-5 (10% mol)
.
0
2.5
5
7.5 10 12.5 15 17.5 20 22.5 25
Catatyst
BH DMS / THF, rt
3
N
N
7
6
%
a
Entry
Cat.
mol %
Yield (%)
ee (%)
Conf.
Figure 2. Amount of catalyst 1 versus % ee of 1-(3-pyridyl)ethanol.
1
2
3
4
5
1
2
3
4
5
10
10
10
10
10
89
85
94
88
80
91
(R)-(+)
(S)-(ꢀ)
(R)-(+)
(S)-(ꢀ)
(R)-(+)
b
96
96
Solvents play a key role in the degree of enantioselectivity
achieved by the oxazaborolidine catalyzed borane-medi-
ated reductions. Therefore, we studied the 3-acetylpyri-
dine reduction in different solvents using only 1 mol % of
spiroborate ester 1 to enhance the differences in enantio-
selectivity. As shown in Table 3 (entry 1), THF was the
most effective solvent in terms of chemical yield and enantio-
selectivity. Less polar solvents such as dichloromethane
and toluene led to a decrease in the enantioselectivity of
the reaction.
c
92
99
6,7
a
b
c
By GC of O-acetyl derivatives on a CP-Chiralsil-DexCB column.
By GC on a chiral column.
By P NMR of phosphonate (CDA).
31
14
Several studies were carried out to determine the minimum
effective catalyst loading, the best reaction temperature and
solvent, as well as borane source. For these studies, we
chose to employ 3-acetylpyridine and spiroborate 1, which
is derived from the inexpensive and commercially available,
norephedrine. The optimal amount of 1 was determined
through the reduction of 3-acetylpyridine with BH –SMe
Table 3. Solvent effects on the reduction of 3-acetylpyridine with 1 mol %
of catalyst 1
a
b
Entry
Solvent
Yield (%)
ee (%)
1
2
3
4
5
THF
Dioxane
t-Butylmethylether
93
87
93
89
65
87
84
71
63
61
3
2
(
2
1.6 equiv) by varying the amount of catalyst from 0.1 to
0 mol % at 25 ꢁC. The results are shown in Table 2. The
2 2
CH Cl
reduction of 3-acetylpyridine with 20 mol % of catalyst 1
afforded the corresponding alcohol in 91% ee and 84% iso-
lated yield (entry 1). Decreasing the catalyst to 1 mol %
slightly decreased the selectivity to 87% ee (entry 5). When
smaller amounts of catalyst (>1 mol %) were used, the iso-
lation process was more convenient by vacuum distillation
in a Kugelrohr apparatus (method b), usually increasing
the chemical yield.
Toluene
a
Isolated yield.
b
By GC of O-acetyl derivative on a CP-Chiralsil-DexCB column.
Temperature and a differing borane source are also critical
factors in the enantioselectivity of carbonyl and oxime
6
,12,13
reductions.
To amplify these changes, the reduction of

2740
V. Stepanenko et al. / Tetrahedron: Asymmetry 18 (2007) 2738–2745
Table 4. Effect of temperature and different borane sources on the
reduction of 3-acetylpyridine in THF with 0.5 mol % of catalyst 1
NMR analysis of the phosphonate derivatives, which were
prepared by the Alexakis method.
14
a
Entry
Reaction conditions
ee (%)
The asymmetric borane reduction of 2-substituted hetero-
aryl ketones is more challenging since borane complexed
to the pyridyl nitrogen can reduce the carbonyl group
through an intramolecular process, thereby decreasing the
enantioselectivity of the reaction. Initially, 2-acetylpyridine
9 was reduced with 0.1 equiv of catalyst 1 and 2 equiv of
1
2
3
4
5
6
BH
BH
BH
BH
BH
BH
3
3
3
3
3
3
–SMe
–SMe
–SMe
–THF, 25 ꢁC
–THF, 25 ꢁC
2
2
2
, 0 ꢁC
, 50 ꢁC
61
71
84
15
65
65
, 25 ꢁC
b
c
–DEA, 25 ꢁC
a
b
c
borane–SMe in THF at room temperature.
Determined by GC of O-acetyl derivatives.
Borane was stabilized with 0.005 M NaBH .
4
Borane was stabilized with <0.005 M N-isopropyl N-methyl-tert-butyl
amine.
2
Quenching the reaction mixture with methanol (procedure
a) for the isolation of 1-(2-pyridyl) ethanol 10 was not effec-
tive, perhaps, due to the formation of the stable alkoxy-
borane complexes. The product was successfully obtained
after acid hydrolysis and continuous extraction from the
aqueous phase for 3 days with diethyl ether. Nevertheless,
the isolated yield was modest. The selectivity was also low,
even when 1 equiv of spiroborate 1 was used (Table 6,
3
1
-acetylpyridine was performed with 0.5 mol % spiroborate
in THF. The results are summarized in Table 4. Optimal
selectivity was achieved at 25 ꢁC in THF using BH –SMe
entry 3, 84% ee). The use of BH –THF stabilized with
3
NaBH (entries 4) resulted in a dramatic decrease in the
enantioselectivity.
3
2
(
4
7
,15
entries 1–3). Several electrophiles, such as TMSCl, BF
3
,
B(OMe) , and BEt , were employed to protect the pyridyl
3
3
nitrogen. The enantioselectivity, however, was not
improved and other side products were observed. The
reduction of 2-acetyl pyridine with 1 equiv of catalyst 5
Further studies were extended to the reduction of the 2-, 3-,
and 4-acetylpyridines with catalyst 5. The results for the 3,
and 4-acetylpyridines are shown in Table 5. Initially, the
solvent dilution effect on the degree of selectivity was deter-
mined for the reduction of 3-acetylpyridine with 1 mol % of
spiroborate ester 5. When the catalyst was diluted ten
times, the enantiomeric excess dropped from 98% to 82%
ee.
and 2 equiv of borane–SMe achieved 93% ee (entry 7).
2
An attempt was made to use the catalyst 5 more efficiently
by adding a second load of 2-acetylpyridine after the initial
asymmetric reduction was performed, before quenching the
reaction. Unfortunately, the enantioselectivity dropped
from an initial 93% ee to 58% ee. Borane–DEA and cata-
lyst 5 afforded 78% ee (entry 8). Surprisingly, when the
Table 5. Enantioselective reduction of 3- and 4-acetylpyridine with
catalyst 5
reducing reagent was BH –DEA, the absolute configura-
3
tion of the product was (S), the opposite compared to that
Ph
obtained with borane–SMe . Since alcohol 10 is water-sol-
H
H
Ph
O
2
uble, the chemical yield was improved by its isolation as its
acetyl ester (entries 6 and 7).
N
B
O
5
OH
O
O
Table 6. Enantioselective reduction of 2-acetylpyridine using spiroborates
1
and 5 as catalysts
.
BH3 DMS / THF
N
N
(
(
R)-1-(3-pyridyl)ethanol 7
R)-1-(4-pyridyl)ethanol 8
O
OH
Cat./THF
BH -X
*
2
a
3
Entry
Cat. 5 (mol %)
Pyridine
Yield (%)
ee (%)
N
N
9
10
1
2
3
4
5
6
7
8
10
5
3-Acetyl
3-Acetyl
3-Acetyl
3-Acetyl
3-Acetyl
4-Acetyl
4-Acetyl
4-Acetyl
80
93
91
96
93
88
95
92
99
99
98
98
94
99
99
99
a
Entry
Catalyst
mol %
Reagent
Yield (%)
% ee ,
2.5
1.0
0.5
10
2.5
1
catalyst
(conf.)
1
2
3
4
5
6
7
1
1
1
5
5
5
5
10
25
100
10
50
100
100
BH
BH
3
–SMe
2
2
2
2
2
2
59
54
58
—
56
8 (R)
16 (R)
40 (R)
10 (R)
58 (R)
93 (R)
78 (S)
3
–SMe
–SMe
–SMe
–SMe
–SMe
BH
BH
BH
BH
BH
3
3
3
3
3
a
By GC of O-acetyl derivatives on a chiral column.
b
82
b
–DEA
79
The reduction of 3-, and 4-acetylpyridines with spiroborate
was successfully performed with less than 5 mol % pro-
viding the enantiopure pyridyl ethanols (>98% ee, Table
, entries 4 and 8) in excellent yield. Remarkably, the
a
By GC on a chiral column (CP-Chiralsil-DexCB) of O-acetate.
The product was isolated as an O-acetate derivative.
5
b
5
reduction of 4-acetyl pyridine at 25 ꢁC in THF using
Other important heteroaryl ketones were reduced with
borane employing the spiroborate 5 catalyst to expand
the scope of the reaction. The results are presented in Table
7. The 5-acetyl-2-methoxypyridine was effectively reduced
with only 1 mol % of catalyst 5 (98% ee, entry 1). The
BH –SMe afforded 99% ee even with 1 mol % of catalyst.
3
2
In addition, using 10% catalyst 3 for the reduction of 3-,
and 4-acetylpyridine, afforded also high enantioselectivity:
3
1
9
7.2% ee and 96.4% ee, respectively, determined by
P

V. Stepanenko et al. / Tetrahedron: Asymmetry 18 (2007) 2738–2745
2741
Table 7. Enantioselective reduction of other heterocyclic ketones using spiroborates 3 and 5 as catalysts
OH
OH
H
N
MeO
N
S
12
11
OH
OH
N
N
N
13
14
a
Entry
Substrate
Catalyst
Prod
mol %
Yield (%)
ee (%)
b
1
2
3
4
5
6
7
31
5-Acetyl-2-methoxy pyridine
2-Acetylphenothiazine
2-Acetylphenothiazine
5
5
5
3
5
5
5
11
12
12
12
13
13
14
1
1
10
10
1
77
94
97
95
85
76
83
98
94
>99
>99
90
92
83
2-Acetylphenothiazine
0
0
4 -(Imidazol-1-yl)acetophenone
4 -(Imidazol-1-yl)acetophenone
10
10
3-Benzoylpyridine
a
14
By P NMR of phosphonate (CDA) derivative.
b
By GC of O-acetyl derivatives on a chiral column.
initial reduction of 2-acetylphenothiazine using 1 mol % of
catalyst 5 afforded 94% ee, but with 10 mol % of catalyst
provided highly enantiopure alcohol 12 (>99% ee). Inter-
estingly, spiroborate ester 3 derived from (S)-diphenyl
valinol also provided 12 with similarly high selectivity. In
tive reagents and solvents were transferred via syringe. All
reagents were obtained commercially unless otherwise
noted. Common solvents were dried and distilled by stan-
dard procedures. Anhydrous borane reagents were pur-
chased from Aldrich and used directly from the sealed
bottle. Chromatographic purification of products was
accomplished using flash chromatography on a Merck
0
the reduction of 4 -(imidazol-1-yl) acetophenone with
1
1
0 mol % of catalyst 5, the enantiomeric excess of alcohol
3 increased slightly to 92%. The solubilities of these large
ꢂ
Silica Gel, Si 60 (200–400 mesh) or Fisher, Activity I,
heterocyclic compounds play a crucial role since they
require more dilute solutions which affects the effectiveness
of the catalyst. The reduction of 3-benzoylpyridine with
60–325 mesh acid alumina oxide deactivated by 3% of
water, 25–30 g; hexane–AcOEt 100:1 to 1:1 using HPLC
grade solvents. Thin layer chromatography (TLC) was per-
formed on Merck Silica Gel plates. Spots were made visible
1
0 mol % of 5 produced (R)-phenyl pyridyl methanol 14
in good yield with 83% ee (entry 7).
with a UV lamp and/or I vapors. Infrared analyses were
2
1
13
performed in a Termo Nicolet 670 FT-IR. H, C, and
1
1
B NMR spectra were recorded on a Bruker Avance
3
. Conclusion
400 MHz spectrometer with standard pulse sequences
operating at 400.152 MHz, 100.627 MHz, 128.384 MHz,
1
13
11
31
Prochiral ketones containing heteroaromatic fragments
undergo asymmetric reduction with a high degree of
enantioselectivity using the novel spiroborates derived
from non-racemic 1,2-amino alcohols. This work demon-
strates that these crystalline spiroborates can be success-
fully used as highly efficient chiral transfer reagents
employing only 1 mol % of the catalyst in some cases.
The synthesis of important enantiopure alcohols with
heterocyclic groups was also achieved in high chemical
yield by a rapid and practical procedure for small and
potentially large-scale industrial use.
and 161.992 MHz for H, C, B, and P, respectively,
in CDCl . Chiral gas chromatography analysis was pro-
3
cessed on a Hewlett Packard GC 5890 equipped with a
Chrompack Chiralsil-Dex-CB column (30 m · 0.25 mm ·
0.25 lm). GC–MS analysis was processed on a Finnigan
Trace GC/Polaris Q Mass detector using a Restek RTX-
5MS column. A Perking Elmer Polarimeter Model 341
was used for optical rotation analysis.
4.1. (± ±-1-(6-Methoxypyridin-3-yl±-ethanol 11
To 1-(6-methoxypyridin-3-yl)ethanone (151 mg, 1 mmol)
in THF (5 mL) and MeOH (1 mL) was added solid sodium
borohydride (38 mg, 1 mmol) at 25 ꢁC. After the reaction
mixture was stirred for 1 h, the solvents were evaporated
and the residue dissolved in water (10 mL). Solid NaCl
was added, followed by ammonia hydroxide solution
4
. Experimental
All reactions were performed in oven-dried glassware
120 ꢁC) under an N atmosphere. Air- and moisture sensi-
(
2

2742
V. Stepanenko et al. / Tetrahedron: Asymmetry 18 (2007) 2738–2745
(
(
30% in water, 1 mL). The product was extracted with ether
78.5 mmol) in dry THF (50 mL) at 25 ꢁC. The mixture
was stirred for 18 h at reflux temperature and cooled to
0 ꢁC. Ethylenediamine (20 mL) was slowly added to the
mixture, followed by a 15% NaOH aqueous solution
(20 mL) over 1 h. The precipitate was removed through a
Celite pad, and the filtrate was concentrated under vac-
uum. The Celite was then extracted overnight with ethyl
ether using a Soxhlet apparatus. The ether solutions were
combined, dried over K CO , filtered, and concentrated.
5 · 10 mL) and dried over Na SO . The solvents were
2
4
removed under vacuum; the residue was distilled in a
Kugelrohr apparatus under vacuum to give the final prod-
uct as a colorless oil (133 mg, 87%).
4.2. General preparation of O-acetyl derivatives for GC-
analysis of pyridyl ethanols
2
3
After vacuum distillation through a 10 cm Vigreux column,
To a solution of the racemic or enantio-enriched alcohol
the colorless diamine 17 was obtained in a 61% yield. Bp
(
20 mg, 0.16 mmol) in dry dichloromethane (1 mL,) in a
1
8
3 ꢁC (20 mmHg); H NMR (400 MHz, CDCl ): d 0.98
2
0
mL vial was added neat triethylamine (0.1 mL,
.72 mmol), acetic anhydride (0.1 mL, 1.06 mmol), and a
3
(
(
(
(
m, 1H, CH); 1.25 (m, 1H, CH); 1.51 (s, 1H, N–H); 1.75
m, 1H, CH); 2.04 (m, 1H, CH); 2.12 (m, 1H, CH); 2.42
C NMR (100 MHz, CDCl ): d 25.0
NHCH ), 30.8, 33.6, 63.2 (NHCH).
small crystal of DMAP (5 mg, 0.04 mmol). The mixture
1
3
s, 3H, CH3);
3
was left at 25 ꢁC for 5 min. After the reaction was complete
(
followed by TLC, hexane/AcOEt, 1:1), the mixture was
3
transferred to a second 10 mL vial with H O (2.5 mL)
2
Me
N
OH
Me
N
and shaken for 5 min. Solid Na CO (2 g) was carefully
2
3
R*
NHMe
NHMe
added by small portions and left for 5 min, shaking from
time to time. Extreme evolution of gas was observed. The
O-acetyl derivative was extracted with diethyl ether
R * R1
R1
PCl3
TEA
P
O
P
Cl
TEA, CDCl3
N
Me
N
Me
17
19
(
4 mL) and the organic phase was transferred with a Pas-
18
teur pipette to another vial and analyzed by chiral GC.
4.3.3.
Chloro-1,3-dimethyl-octahydro-benzo[1,3,2]diaza-
4.3. Synthesis of chiral derivatizing agent (CDA± 18 for
enantiomeric analysis of alcohols by P NMR
phosphole CDA 18. To a solution of chiral diamine 17
(0.50 g, 3.50 mmol) in CH Cl (10 mL) in 25 mL flask
was added triethylamine (2.44 mL, 17.5 mmol), followed
by the addition of PCl (1.22 mL, 14.0 mmol). The mixture
was concentrated under vacuum to eliminate the excess of
PCl . The CDA 18 in CDCl (10 mL) was prepared as a
3
1
14
2
2
4
.3.1. Dicarbamate 16. In a 250 mL round flask, a solu-
3
tion of (R,R)-(ꢀ)-cyclohexane-1,2-diamine 15 (10 g,
8
0
8 mmol) in toluene (130 mL) was stirred and cooled to
ꢁC. Ethyl chloroformate (18.1 mL, 190 mmol) and
3
3
standard solution (0.35 M) for further diastereoisomeric
analyses.
NaOH (7.6 g, 190 mmol) in water (8.3 mL) were added
simultaneously. The temperature should not reach more
than 10 ꢁC during the addition. The mixture was then
stirred overnight and the precipitate was filtered and rinsed
with CH Cl . The solid was continuously extracted in a
4.3.3.1. CDA 18 preparation in a NMR tube. In a dried
NMR tube were placed the chiral alcohol (0.02 g,
2
2
0.141 mmol) and CDCl (0.4 mL). The tube was shaken
3
Soxhlet system overnight with CH Cl (150 mL). The solu-
until complete dissolution. Et N (0.1 mL, 0.717 mmol)
2
2
3
tions were then mixed, dried over MgSO , and concen-
was added with a micro syringe, followed by the addition
4
trated under vacuum. The dicarbamate 17 was obtained
of PCl (0.05 mL, 0.573 mmol). The NMR tube was care-
fully shaken as an exothermic reaction takes place. The
mixture was concentrated under vacuum. The same
3
1
as a white solid (89% yield). H NMR (400 MHz, CDCl ):
3
d 1.23 (m, CH ); 1.72 (d, CH ); 2.0 (d, CH ); 3.33 (m, CH ),
3
2
2
2
1
3
4
.09 (m, CH), 4.97 (N–H); C NMR (100 MHz, CDCl ): d
amounts of CDCl and triethylamine were added again
3
3
1
4.6 (OCH CH ), 24.8, 32.9, 55.4 (NCH), 60.7
to the NMR tube. The in situ solution of CDA 18 was
2
3
3
1
(
OCH CH ), and 157.0 (C@O).
immediately used. A P NMR spectrum was recorded to
2
3
3
1
check the reagent; P NMR (161.992 MHz, CDCl ); d 182.
3
O
C
O
H
N
NH2
NH2
OEt
OEt
3
.3.4. General procedure for derivatization for P NMR
1
Cl
OEt
4
NaOH/Toluene
analysis. To the CDA 18 (0.141 mmol) in a NMR tube
N
H
C
O
was added triethylamine (0.1 mL) and diamine 17 (8–
1
6
31
15
1
0 lL). The solution was shaken and the P NMR spec-
THF
5
LiAlH4
trum was recorded and analyzed. The conversion of 19 to
the corresponding thiophosphoramidates with sulfur (S8)
powder was carried out in the same NMR tube for a sec-
NHMe
3
1
ond P NMR determination in cases where the signals
were not resolved. A racemic sample of each alcohol was
used to identify the relevant signals before each non-race-
mic derivative was analyzed. This was also necessary to
NHMe
1
7
ensure that the alcohol enantiomers react at the same rate
0
31
4
.3.2. (R,R±-N,N -Dimethyl-cyclohexane-1,2-diamine 17.
with the CDA. P NMR (161.992 MHz, CDCl ); d (ppm)
3
To a solution of LiAlH4 (14.89 g, 392.5 mmol) in dry
derivative of (± )-1-(4-pyridyl)ethanol 8, 141.23 and 140.13
THF (300 mL) was slowly added compound 16 (20.29 g,
(Dd = 1.10); (± )-1-(3-pyridyl)ethanol 7, 141.58 and 140.32

V. Stepanenko et al. / Tetrahedron: Asymmetry 18 (2007) 2738–2745
2743
(
(
Dd = 1.26); (± )-1-(2-pyridyl)ethanol 10, 141.11 and 138.23
Dd = 2.88).
removed under vacuum and the residue dissolved in
CH Cl (10 mL). Acetic anhydride (2 mL) and triethyl-
2
2
amine (2 mL) were added followed by DMAP (5 mg). After
stirring at 25 ꢁC for 1 h, the reaction mixture was added to
water (15 mL) and quenched with solid Na CO (10 g). The
4.4. (R±-(+±-1-(3-Pyridyl±-ethanol 7 using 1 mol % of cata-
lyst 5
2
3
organic phase was separated and the product was extracted
A borane–SMe complex (10 M, 1.6 mL, 16.0 mmol) was
with ethyl ether (5 · 10 mL). The combined organic
2
added to a solution of (S)-2-[(1,3,2-dioxaborolan-2-
extracts were dried with MgSO and concentrated in vac-
4
1
2
yloxy)diphenylmethyl]pyrrolidine 5 (32 mg, 0.10 mmol)
in dry THF (5 mL) at 25 ꢁC and the mixture was stirred
for 1 h. A solution of 3-acetylpyridine (1.21 g, 10.0 mmol)
in THF (5 mL) was added for 5 h using an infusion pump.
The reaction mixture was stirred at rt over 1 h, then cooled
at 0 ꢁC and quenched with methanol (10 mL). After reflux-
ing for 12 h, the solvents were removed under vacuum; the
residue was distilled in a Kugelrohr apparatus under vac-
uum. The product was purified by column chromatography
(Al O deactivated by 3% of water, 35 g; hexane and
2
3
hexane–AcOEt 100:1 to 10:1). The main fractions were
concentrated under vacuum and the residue was distilled
in Kugelrohr apparatus under vacuum to give the final
1
product as a colorless oil (338 mg, 82%). H NMR
(400 MHz, CDCl ): d 1.61 (d, J = 6.8 Hz, 3H, CHMe),
3
2.13 (s, 3H, OAc), 5.91 (q, J = 6.8 Hz, 1H, CHMe), 7.20
uum to give the final product as colorless oil (1.18 g,
(m, 1H, CH ), 7.33 (d, J = 8Hz, 1H, CH ), 7.68 (m,
1H, CH ), 8.58 (m, 1H, CH ); C NMR (100 MHz,
Ar Ar
Ar
Ar
1
13
9
6
1
6%). H NMR (400 MHz, CDCl ): d 1.47 (d, J =
.5 Hz, 3H, Me), 4.88 (q, J = 6.5 Hz, CHMe), 6.02 (br s,
3
CDCl ): d 20.7, 21.3, 73.1, 120.5, 122.7, 136.7, 149.4,
3
H, OH), 7.22 (m, 1H, CH ), 8.29 (m, 1H, CH ), 8.41
160.3, 170.3. Chiral GC of O-acetyl derivative indicated
Ar
Ar
1
3
23
D
16
20
(
m, 1H, CHAr); C NMR (100 MHz, CDCl ): d 25.3,
92.9% ee. ½aꢁ ¼ þ90:1 (c 2.5, CHCl ). Lit. ½aꢁD
¼
3
3
6
7.1, 123.6, 133.7, 142.2, 146.9, 147.6. Chiral GC of O-
þ102:3 (c 1.27, CHCl ) for >95% ee.
3
acetyl derivative (t 12.05 min) indicated 98.2% ee.
R
2
D
3
16
20
17
½
aꢁ ¼ þ41:1 (c 3.6, CHCl ). Lit. ½aꢁD ¼ þ52:4 (c 1.40,
4.7. (R±-(+±-1-(6-Methoxy-pyridin-3-yl±-ethanol 11 using
1 mol % of catalyst 5
3
CHCl ) for >95% ee.
3
4.5. (R±-(+±-1-(4-Pyridyl±-ethanol 8 using 1 mol % of cata-
lyst 5
Borane–SMe2 complex (10 M, 0.99 mL, 9.9 mmol) was
added to a solution of (S)-2-[(1,3,2-dioxaborolan-2-
1
2
yloxy)diphenylmethyl]pyrrolidine 5 (19.9 mg, 0.06 mmol)
in dry THF (3 mL) at rt and the mixture was stirred for 1 h.
A solution of 1-(6-methoxypyridin-3-yl)ethanone (930 mg,
6.16 mmol) in THF (5 mL) was added for 5 h using an
infusion pump. The reaction mixture was stirred at 25 ꢁC
over 1 h, then cooled to 0 ꢁC and quenched with methanol
(5 mL). After refluxing for 12 h, the solvents were removed
under vacuum and the product was purified by column
chromatography (Al O deactivated by 3% of water, 25 g;
Borane–SMe2 complex (10 M, 1.6 mL, 16.0 mmol) was
added to a solution of (S)-2-[(1,3,2-dioxaborolan-2-
1
2
yloxy)diphenylmethyl]-pyrrolidine 5 (32 mg, 0.10 mmol)
in dry THF (5 mL) at 25 ꢁC. A solution of 4-acetylpyridine
(
1.21 g, 10.0 mmol) in THF (5 mL) was added for 5 h using
an infusion pump. The reaction mixture was stirred at 25 ꢁC
for 1 h, cooled at 0 ꢁC and quenched with methanol
(
10 mL). After refluxing for 4 h, the mixture was analyzed
2
3
1
1
by B NMR and the N–BH complex signal was observed
hexane–AcOEt 100:1 to 1:1). The main fractions were
concentrated under vacuum and the residue was distilled
in a Kugelrohr apparatus (oven temperature 210 ꢁC) under
vacuum (1 mmHg) to give the final product as a colorless
3
at ꢀ13.28 ppm. More MeOH (10 mL) was added and re-
fluxed for 12 h. The solvents were removed under vacuum
and the residue was distilled in a Kugelrohr apparatus un-
der vacuum to give pure (R)-1-(4-pyridyl)ethanol as a white
ꢀ
1
oil (726 mg, 77%). IR (CaF , film, cm ): 3355 (br, OH),
2
1
1
crystalline material (1.13 g, 92%); (mp: 55–58 ꢁC). H NMR
2974, 2948, 1609, 1496, 1325, 1286, 1253, 1094, 1029. H
(
400 MHz, CDCl ): d 1.39 (d, J = 6.4 Hz, 3H); 4.80 (q,
NMR (400 MHz, CDCl ): d 1.45 (d, J = 6.5 Hz, 3H,
3
3
J = 6.4 Hz, 1H); 5.1 (s, 1H); 7.22 (d, J = 6.0 Hz, 2H); 8.31
CHMe), 3.16 (br s, 1H, OH), 3.89 (s, 3H, OMe), 4.81 (q,
1
3
(
d, J = 5.6Hz, 2H); C NMR (100 MHz, CDCl ): d 25.0
J = 6.5, 1H, CHMe), 6.70 (d, J = 8.6 Hz, 1H, CH ),
3
Ar
1
3
(
CH ); 68.2 (C–H(OH)); 120.6 (CH ); 149.0 (CH );
7.60 (m, 1H, CH ), 8.01 (m, 1H, CH ); C NMR
3
Ar
Ar
Ar Ar
1
56.0. Chiral GC of O-acetyl derivative (t 12.39 min)
(100 MHz, CDCl ): d 24.8, 53.5, 67.6, 110.8, 133.7, 136.5,
R
3
23
16
indicated 99% ee. ½aꢁ ¼ þ49:0 (c 2.5, CHCl ). Lit.
144.1, 163.7. Chiral GC of O-acetyl derivative indicated
D
3
2
0
23
½
aꢁ ¼ þ42:5 (c 1.04, MeOH) for >95% ee.
98.0% ee. ½aꢁD ¼ þ33:7 (c 2.7, CHCl3).
D
4.6. (R±-(+±-1-(2-Pyridyl±-ethanol 10 using 100 mol % cata-
lyst 5
4.8. (R±-(+±-1-(10H-Phenothiazin-2-yl±-ethanol 12 using
10 mol % catalyst 5
Borane–SMe2 complex (10 M, 0.5 mL, 5.00 mmol) was
A borane–SMe complex (10.0 M, 2.0 mL, 20 mmol) was
2
added to a solution of (S)-2-((1,3,2-dioxaborolan-2-
added to a solution of spiroborate 5 (0.323 g, 1.0 mmol) in
dry THF (30 mL) at 25 ꢁC and the mixture was stirred for
about 15 min. A solution of 2-acetyl-1-phenothiazine
(2.413 g, 10.0 mmol) in dry THF (40 mL) was added to
the reaction mixture during for 1 h using an infusion pump.
The mixture was allowed to react overnight. The reaction
was cooled to 0 ꢁC, quenched with MeOH (20 mL), and
1
2
yloxy)diphenylmethyl)pyrrolidine 5 (808 mg, 2.50 mmol)
in dry THF (5 mL) at rt for 4 h. A solution of 2-acetylpyr-
idine (303 mg, 2.50 mmol) in THF (2 mL) was added for
1
h using an infusion pump. The reaction mixture was stir-
red for 1 h at 25 ꢁC, cooled to 0 ꢁC, quenched with metha-
nol (5 mL), and refluxed for 12 h. The solvents were

2744
V. Stepanenko et al. / Tetrahedron: Asymmetry 18 (2007) 2738–2745
1
3
heated at reflux for 2 h. The solvents were removed in vacuo.
The crude product was purified by washing the solid 1-(10H-
phenothiazin-3-yl)ethanol with dichloromethane (50 mL)
several times to remove traces of impurities and dried over-
night under high vacuum obtaining pure (R)-1-(10H-pheno-
thiazin-2-yl)-ethanol (2.375 g, 97.6% yield). Mp 134–
J = 4.4 Hz, 1H); 8.50 (d, J = 2.4 Hz, 1H); C NMR
(100 MHz, CDCl ): d 73.9, 123.5, 126.6, 127.9, 128.7,
134.4, 139.7, 143.2, 148.0, 148.3. Using the in situ CDA
solution a diastereomeric sample was prepared and
analyzed by P NMR (161.992 MHz, CDCl ); the enantio-
3
3
1
3
2
3
20
purity was 83% ee. ½aꢁ ¼ þ12:0 (c 1.6, CHCl ). Lit.
D
3
1
8
ꢀ1
20
1
36 ꢁC. IR (cm ): 3396 (NH), 3314 (OH), 1091 (C–O).
½aꢁ ¼ ꢀ19:0 (c 1.20, CHCl ) for 75% ee (by HPLC).
D
3
1
H NMR (400 MHz, (DMSO)): d 1.27 (d, J = 6.4 Hz, 3H,
CH ); 4.57 (m, 1H, C–HOH); 5.10 (d, J = 4.0 Hz 1H,
3
1
3
–
OH); 6.7–7.0 (m, 7H, Ar); 8.55 (s, 1H, NH). C NMR
(
100 MHz, DMSO): d 26.2, 68.1, 112.0, 114.6, 114.9,
Acknowledgements
1
1
d
17.0, 119.4, 122.1, 126.2, 126.7, 127.9, 142.4, 142.7,
3
1
47.6. P NMR (162 MHz, CDCl ): (racemic derivative):
3
Financial support from the National Institute of
Health through their MBRS (GM 08216), INBRE (NC
P20 RR-016470), and NSF-ADVANCE (SBE-0123645)
Grants is greatly appreciated. Support for under-
graduate scholars from the NIH-INBRE, NIH-RISE,
NIH-MARC, and NSF-AMP programs is also gratefully
acknowledged.
(ppm) 141.02 and 137.91 (Dd = 3.11). (chiral
23
alcohol): d (ppm) 137.91 (>99% ee). ½aꢁ ¼ þ24:0 (c 1.0,
D
MeOH).
0
4
1
.9. (R±-(+±-4 -(Imidozol-1-yl±-phenyl ethanol 13 using
0 mol % catalyst 5
A borane–SMe complex (10 M, 2.0 mL, 20.0 mmol) was
2
added to catalyst 5 (323 mg, 1.0 mmol) in dry THF
0
(
20 mL) at rt. A solution of 4 -(imidazol-1-yl) acetophe-
References
none (1.86 g, 10.0 mmol) in THF (20 mL) was added for
h using an infusion pump. The reaction mixture was stir-
5
1
2
. Shinkai, I. Pure Appl. Chem. 1997, 69, 453–458.
. Silverman, R. B. The Organic Chemistry of Drug Design
and Drug Action; Elsevier Academic Press: Burlington, MA,
red at 25 ꢁC overnight and then cooled to 0 ꢁC and
quenched with methanol (10 mL). After refluxing over-
night, the solvents were removed under vacuum. The crude
product was purified by flash column chromatography on a
silica column (40 g) using ethyl acetate to give pure 13 as a
2
004.
3
. (a) Hull, K. G.; Visnic, M.; Tautz, W.; Sheffron, A. Tetra-
hedron 1997, 53, 12405–12414; (b) Truppo, M. D.; Pollard, D.;
Devine, P. Org. Lett. 2006, 9, 335–338; (c) De Martino, G.; La
Regina, G.; Di Pasquali, A.; Ragno, R.; Bergamini, A.;
Ciaprini, C.; Sinistro, A.; Maga, G.; Crespan, E.; Artico, M.;
Silvestrini, R. J. Med. Chem. 2005, 48, 4378–4388.
4. Challenger, C. A. Chiral Drugs; John Wiley & Sons: New
York, 2001.
5. Tanis, S. P.; Evans, B. R.; Nieman, J. A.; Parker, T. T.;
Taylor, W. D.; Heasley, S. E.; Herrington, P. M.; Perrault,
W. R.; Hohler, R. A.; Dolak, L. A.; Hester, M. R.; Seest, E.
P. Tetrahedron: Asymmetry 2006, 17, 21–54.
white crystalline material (1.40 g, 76%), mp: 118–120 ꢁC;
1
H NMR (400 MHz, CDCl ): d 1.53 (d, J = 6.4Hz, 3H),
3
3
.7 (br s, 1H), 4.96 (q, J = 6.4 Hz, 1H), 7.14 (s, 1H); 7.24
(
s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.8 (d, J = 8.4 Hz, 2H),
.69 (s, 1H); C NMR (100 MHz, CDCl ): d 24.5 (CH );
3 3
1
3
7
6
1
9.3 (C–H(OH)), 118.3, 121.4, 127.0 (CH ), 130.0, 135.5,
Ar
3
1
36.2 (CH ), 146.0. The product was analyzed by
P
Ar
NMR with a small amount of sulfur; the diastereomers
signals at 86.1 ppm (3.5%) and 85.8 ppm (96%) pro-
2
D
3
19
vided 92.5% ee. ½aꢁ ¼ þ31:7 (c 0.40, CHCl ). Lit.
3
6. (a) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V.
J. Am. Chem. Soc. 1988, 110, 1539; (b) Matteson, D. S.
Stereodirected Synthesis with Organoboranes; Springer: Ber-
lin, 1995.
1
D
7
½
aꢁ ¼ ꢀ33 (c 0.48, CHCl ) for >98% (by HPLC) for (S)
3
enantiomer.
7
. (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
986–2012; (b) Glushkov, V. A.; Tolstikov, A. G. Russ.
Chem. Rev. 2004, 73, 581–608.
4.10. (S±-(+±-Phenyl(pyridin-3-yl±methanol 14 with 10 mol %
catalyst 5
1
8
9
. Cho, B. T. Tetrahedron 2006, 62, 7621–7643.
. Quallich, J. G.; Woodall, T. M. Tetrahedron Lett. 1993, 34,
Borane–SMe2 complex (10.0 M, 1.0 mL, 10 mmol) was
added to a solution of spiroborate 5 (0.323 g, 1.0 mmol)
in dry THF (30 mL) at 25 ꢁC and the mixture was stirred
for about 15 min. A solution of 3-benzoylpyridine
7
85–788.
1
1
0. Masui, M. S. T. Synlett 1997, 273–274.
1. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 5675–
(
1.832 g, 10.0 mmol) in dry THF (10 mL) was added to
5678.
the reaction mixture during 1 h. The mixture was allowed
to react overnight. The reaction mixture was cooled to
12. (a) Stepanenko, V.; Ortiz-Marciales, M.; Correa, W.; De
Jes u´ s, M.; Espinosa, S.; Ortiz, L. Tetrahedron: Asymmetry
2
006, 17, 112–115; (b) Ortiz-Marciales, M.; Stepanenko, V.;
0
ꢁC, then MeOH (20 mL) was added and the mixture
Correa, W.; De Jes u´ s, M.; Espinosa, S. U.S. Patent Appli-
cation 11/512,599, August 30, 2006.
was heated at reflux for 8 h. Decomposition of N–BH
3
1
1
complex was confirmed by B NMR and the mixture
was concentrated to colorless oil. The residue was distilled
under high vacuum in the Kugelrohr oven (140 ꢁC/
1
3. (a) Huang, X.; Ortiz-Marciales, M.; Stepanenko, V.; Merced,
F. G.; Ayala, A. M.; De Jes u´ s, M. Org. Lett. 2007, 9, 1793–
1
795; (b) Ortiz-Marciales, M.; Huang, X.; Stepanenko, V.;
0
.7 mmHg) obtaining pure phenyl (pyridin-3-yl)methanol
De Jes u´ s, M.; Merced F. Provisional U.S. Patent Application,
August 30, 2006.
1
(
1.53 g, 83% yield). H NMR (400 MHz, CDCl ): d 4.20
3
(
7
s, 1H, OH); 5.84 (s, 1H, C–H); 7.23 (m, 1H, C–H), 7.27–
.38 (m, 5H); 7.71 (m, J = 7.6 Hz, 1H); 8.36 (dd,
14. (a) Alexakis, A.; Frutos, J. C.; Mutti, S.; Mangeney, P. J.
Org. Chem. 1992, 57, 1224–1237; (b) Alexakis, A.; Frutos, J.

V. Stepanenko et al. / Tetrahedron: Asymmetry 18 (2007) 2738–2745
2745
C.; Mutti, S.; Mangeney, P. J. Org. Chem. 1994, 59, 3326–
334.
17. The absolute configuration was assigned according to the
1
6
3
predicted stereochemical outcome.
1
1
5. Nettles, S. M.; Matos, K.; Burkhardt, E. R.; Rouda, D. R.;
Matos, K.; Burkhardt, E. R.; Rouda, D. R.; Corella, J. A. J.
Org. Chem. 2002, 67, 2970–2976.
18. Massie, S. P.; Cooke, I.; Hills, W. J. Org. Chem. 1956, 21,
1006–1008.
19. Ema, T.; Yoshii, M.; Korenaga, T.; Sakai, T. Tetrahedron:
Asymmetry 2002, 13, 1223–1229.
6. (a) Seemayer, R.; Schneider, M. P. Tetrahedron: Asymmetry
1
992, 3, 827–830; (b) Morris, D. J.; Hayes, A. M.; Wills, M. J.
20. Takemoto, M.; Tanaka, K. J. Mol. Catal. B: Enzym. 2001,
15, 173–176.
Org. Chem. 2006, 71, 7035–7044.