Chiral ligand derived from (1S,2R)-norephedrine as a catalyst for enantioselective prochiral ketone reduction

Article abstract of DOI:10.1016/j.tetasy.2009.03.029

Chiral oxazaborolidines derived from (1S,2R)-(+)-norephedrine and substituted salicylaldehydes were employed in the asymmetric reduction of prochiral ketones using borane dimethyl sulfide as a reducing agent. The secondary alcohols were formed in excellent yields (45-99.8%) with enantioselectivities up to 99.8%. The effect of the substitution in the aromatic ring of the ligand was discussed with the enantioselectivity of the product.

Full text of DOI:10.1016/j.tetasy.2009.03.029

Tetrahedron: Asymmetry 20 (2009) 1150–1153
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Chiral ligand derived from (1S,2R)-norephedrine as a catalyst
for enantioselective prochiral ketone reduction
*
Umesh Balakrishnan, Nallamuthu Ananthi, Sivan Velmathi
Organic and Polymer Synthesis Lab, Department of Chemistry, National Institute of Technology, Tiruchirappalli, Tamil Nadu 620 015, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral oxazaborolidines derived from (1S,2R)-(+)-norephedrine and substituted salicylaldehydes were
employed in the asymmetric reduction of prochiral ketones using borane dimethyl sulfide as a reducing
agent. The secondary alcohols were formed in excellent yields (45–99.8%) with enantioselectivities up to
99.8%. The effect of the substitution in the aromatic ring of the ligand was discussed with the enantiose-
lectivity of the product.
Received 23 February 2009
Accepted 19 March 2009
Available online 4 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
more electron-rich nitrogen atom. Thus directing the borohydride
to specifically approach one of the prochiral faces of the carbonyl
The reduction of ketones to enantiomerically enriched alcohols
is a pivotal transformation in synthetic organic chemistry.1 Since
most drug effects are due to interaction with chiral biological
materials, each enantiomer may have different pharmacological
properties in terms of activity, potency, toxicity, transport mecha-
nism and metabolic route.2 Hence there is an increase in demand
for the synthesis of enantiomerically pure compounds. Among
them prochiral ketone reduction to secondary alcohols plays an
important role as it is the intermediate for many biological trans-
formations. Fiaud and Kagan3 were the first to work on optically
active borane complexes derived from ephedrine alkaloids as a chi-
ral auxiliary for asymmetric reductions, resulting in very low
enantioselectivity. Many chiral diols,4 amino alcohols5 and sulfox-
imines6 have served as chiral ligands in the enantioselective bor-
ane reduction to accelerate the reaction rate and, more
importantly, to provide an asymmetric environment for the react-
ing species. Among them, oxazoborolidines synthesized from chiral
amino alcohols gave excellent ee.7 Hirao et al.8 reported the first
effective stereoselective borane reduction, using stoichiometric
amounts of in situ prepared 1,3,2-oxazaborolidines based on non-
racemic chiral b-amino alcohols which was further improved by
Corey et al.9 This method (CBS reduction) has several advantages
because of easy and efficient recoverability of the chiral catalyst,
high yields, experimental simplicity and economy.
group. However, in the diol ligands, scrambled induction may oc-
cur if both the oxygen atoms have a similar coordinating capability
to the second borane and results in a significant affinity difference
for coordination, possibly offering the second borane an unstable
situation upon coordination with diol-type ligands. Consequently,
lesser enantioselectivity could be expected compared to the oxy-
gen nitrogen-paired ligands. The b-amino alcohol-type ligands de-
rived from ephedra alkaloids are widely used in various
asymmetric reactions such as aldol condensation,10 diethyl zinc
addition to aldehydes,11 Michael addition12 and reduction of pro-
chiral ketones using borane dimethyl sulfide.13
Most of the oxazaborolidines used so far are formed from a
b-amino alcohol moiety introduced by Corey et al.9 and also from
(1R,2S)-ephedrine.14 Generally amino alcohols afford a suitable
and relatively stable complexing site for the first boron involved
in the reduction sequence,15 although diols,16 diamines17 and
amino acid esters18 containing ligands have also been reported to
carry out this function.19
Parrott II20 et al. reported the synthesis and application of a
series of mono N-alkylated ephedrine and norephedrine deriva-
tives in the enantioselective addition of diethylzinc to aldehydes.
In that report, a ligand derived from salicylaldehyde and norephe-
drine was found to give a marginal enantiomeric excess of 54:46.
Herein we report the enantioselective reduction of ketones using
a chiral relay amino alcohol ligand derived from norephedrine
and substituted salicylaldehydes using borane dimethyl sulfide as
a reducing agent. In our case, the enantioselectivity depends on
the electronic effect of the substitution on the salicylaldehyde.
The structure of the chiral amines is shown in Figure 1. To the best
of our knowledge there are no reports on the synthesis of chiral
amines 1a–e derived from (1S,2R)-(+)-norephedrine and substi-
tuted salicylaldehydes and their catalytic activity on enantioselec-
tive ketone reduction.
Among these cases, oxygen and nitrogen are used as the coordi-
nating atoms to boron. In general, the oxygen–nitrogen-paired li-
gands gave a better enantioselectivity than the corresponding
oxygen–oxygen-paired bidendate ligands. This phenomenon can
be rationalized according to the CBS mechanism proposed by Cor-
ey,9 in which a second molecule of borane coordinates with the
* Corresponding author. Tel.: +91 9486067404; fax: +91 431 2500133.
E-mail address: velmathis@nitt.edu (S. Velmathi).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.029

U. Balakrishnan et al. / Tetrahedron: Asymmetry 20 (2009) 1150–1153
1151
OH
OH
R
OH
Cl
OH
HN
HN
CH3
CH3
1a-e
2
R: a = -H, b = -Cl, c = -Br,
d = -NO2, e = -OH
Figure 1.
2. Results and discussion
OH
O
1(a-e) 20mol % BH3.SMe2
THF, 30 min,
The chiral ligands were synthesized from (1S,2R)-(+)-norephe-
drine and substituted salicylaldehyde by reductive amination.20
(1R,2S)-(ꢀ)-norephedrine was also used as a chiral source in order
to show the change in stereoselectivity while changing the stereo-
isomer of norephedrine. The synthesized ligands 1a–e and 2
(Scheme 1) were explored for their catalytic activity in the enantio-
selective reduction of a prochiral ketone (Scheme 2). There are re-
ports showing that halogen containing chiral amino alcohols
shows better enantiomeric excess than the one without halogen.21
Therefore, the reduction of acetophenone was studied in detail
with ligand 1b, and the results are given in Table 1. To 5 mol % of
the chiral ligand taken in dry THF, 1.2 mmol of BMS was added
and refluxed for 30 min. To this 1 mmol of acetophenone was
added and refluxed for another 2 h. After quenching and extrac-
tion, the (S)-isomer of the corresponding secondary alcohol was
obtained in 95% yield and 30% ee (Table 1, entry 1).
The oxazaborolidine formation from the chiral amine and bor-
ane methyl sulfide requires 30 min under refluxing conditions in
dry THF. The structure of oxazaborolidine and the mechanism of
prochiral ketone reduction are shown in Scheme 3. A survey of
the literature reveals that compounds with three coordination sites
around a boron atom will give high ee rather than the one with two
coordination sites22 due to their rigid structure that results in
excellent enantioselectivity. The chosen ligand system is also
tridendate in nature which can be expected to give high ee.
The liberation of three hydrogens during the formation of the
tridentate oxazaborolidine complex between the chiral amine
and borane dimethyl sulfide was cross-checked with the hydrogen
evolution studies. And the second borane will coordinate with the
nitrogen atom from which the hydride transfer occurs.
H
~ 99.8% ee
Scheme 2. Enantioselective prochiral ketone reduction using 1a–e.
Table 1
Enantioselective ketone reduction using BH3ꢁS(CH3)2 as a reducing agent with 1b as
catalyst
Entry
Catalyst amount (%)
Temperature (°C)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
5 mol
5 molc
5 mol
5 mol
5mol
10 mol
15
20
25
30
rt
rt
95
90
97
74
87
99
99
99
30
20
0
ꢀ76
0
0
65
65
65
65
65
65
65
44
60
70
92
88
90
91
100
100
100
10
11
Stoichiometric
a
Isolated yield by column chromatography.
Determined by HPLC analysis using Chiralcel OD-H column.
The reaction was carried out in dry toluene.
b
c
than toluene and dichloromethane.24 So the reduction of different
prochiral ketones was carried out in dry THF.
Then the effect of temperature on the enantioselectivity was
studied with 5 mol % of the chiral catalyst. When the reaction
was performed at lower temperatures of ꢀ76 °C and 0 °C, a racemic
mixture was formed proving that some activation energy is
required to form the oxazaborolidine complex. The enantiose-
lectivity increased with an increase in temperature. At refluxing
temperatures (67 °C), with 5 mol % of the catalyst the enantioselec-
tivity was 44%. Once the reaction temperature was optimized, the
The enantioselectivity of borane reduction may be affected by
reaction conditions such as solvent, temperature and catalyst load-
ing.23 When the reaction was performed with toluene as a solvent,
the enantiomeric excess of 1-phenyl ethanol was decreased to 20%
(entry 2). From the literature survey we found that THF is better
HO
CHO
OH
OH
R
OH
NH2
CH3
1. Ethanol, RT
2. NaBH4, 3h
+
NH
R
CH3
1(a-e)
R: a= -H, b= -Cl, c= -Br,
d= -NO2, e= -OH
Scheme 1. Synthesis of chiral amines.

1152
U. Balakrishnan et al. / Tetrahedron: Asymmetry 20 (2009) 1150–1153
O
B
O
B
O
O
N
N
R
R
RS
RL
H
H
BH2
RS
RL
H
BH2
O
O
1(a-e)
R: a= -H, b= -Cl, c= -Br,
d= -NO2, e= -OH
Scheme 3. Transition state for the oxazaborolidine complex during the prochiral ketone reduction.
Table 3
effect of the catalytic amount on the enantioselectivity was studied
and the results are shown in Table 1. (entries 3–11). Table 1 clearly
explains that up to 20 mol % of the catalyst the enantioselectivity
increases linearly and with 30 mol % of the catalyst, there is no fur-
ther increase in enantiomeric excess. Thus the optimized reaction
conditions were 20 mol % of the catalyst, reaction time of 60 min
and refluxing temperature of THF.
The enantioselectivity of the chiral secondary alcohols using the
chiral amines 1a–e and 2 is given in Table 2. In the case of 1b as a cat-
alyst, (S)-enantiomer was obtained as a major product, and in the
case of 2 we got the (R)-enantiomer as a major product(entry 7 in Ta-
ble 2). Table 2 clearly shows that among the chiral amines 1a–e, 1b
shows the best enantioselectivity. This result is in good agreement
with the reported results of Zong-Xuan Shen et al., which states that
the chloro-containing chiral b-amino alcohol shows better enanti-
oselectivity than the one without chlorine atom.21
Enantioselective reduction of different ketones using chiral ligand 1b and BH3ꢁS(CH3)2
as a reducing agenta
Entry
Ketone
Yieldb (%)
eec (%)
Absolute configurationd
1
2
3
4
5
6
7
8
9
o-Cl Acetophenone
p-OCH3 Acetophenone
p-Br Acetophenone
o-Br Acetophenone
p-NH2 Acetophenone
p-CH3 Actophenone
Ethyl methyl ketone
Isobutyl methyl ketone
p-I Acetophenone
100
100
99
90
50
30
76
62
35
60
99.8
99.8
99
94
60
40
34
30
30
(R)
(S)
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(R)
10
2-Aceto naphthone
18
a
Ratio of ligand/BMS/ketone was 0.2:1.6:1.1.
Isolated yield by column chromatography.
Determined by HPLC analysis using Chiralcel OD-H column.
b
c
d
The absolute configuration was assigned by comparison of the sign of the
To explore the synthetic utility of the chiral ligand 1b, reduction
of different prochiral ketones was studied with the optimized reac-
tion conditions. The results are presented in Table 3.
specific rotation with the literature data.
Table 3 also shows that the aromatic ketones were reduced with bet-
ter enantioselectivity than the aliphatic ketones (entries 7 and 8).
From the above results, the ketones having electron-withdraw-
ing groups were reduced with higher ee and yield than the ketones
having electron-donating groups (entries 1–6) except iodine-
substituted acetophenone and p-methoxy acetophenone. This
may be due to the strong coordination between the second boron
atom and the ketones having electron-donating groups, which
makes the oxazaborolidine complex more rigid than in the case
of ketones having electron-withdrawing groups where the com-
plex is flexible for the hydride transfer.
Among the ketones having halogens, iodine-substituted aceto-
phenone were reduced with a low ee (30%) and yield (35%) com-
pared to chlorine and bromine-substituted acetophenones which
shows that as the size of the halogen increases the enantioselectiv-
ity decreases.
3. Conclusion
In conclusion, we have developed (1S,2R)-(+)-norephedrine-de-
rived chiral amines that are readily synthesized in good yield and
purity, for enantioselective ketone reduction with borane dimethyl
sulfide as a reducing agent. Different prochiral ketones were re-
duced with excellent enantioselectivities of up to 99.8% and in
good yield. By choosing the appropriate stereoisomer of norephe-
drine, corresponding optically active alcohols can be synthesized
with good yield and enantioselectivity.
4. Experimental
ortho-Substituted ketones (entries 1, 4 and 10) gave the (R)-iso-
mer specifically and the para-substituted acetophenones gave the
other isomer. This may be due to the repulsion possible between
the substituents at the ortho-position and the second boron atom,
which may change the approach of the ketones to the boron atom.
4.1. General remarks
1H NMR and 13C spectra were recorded in CDCl3 with a BRUKER
AMX-300 MHz instrument using TMS as an internal standard. Spe-
cific rotation was recorded with a Rudolph Autopol IV polarimeter
(589 nm and CHCl3). Enantiomeric excess was determined with a
Shimadzu2010A HPLC instrument (Chiral column: Chiral Cel OD-
H, Mobile Phase: solvent system 98:2 hexane/i-PrOH) with the
flow rate of 0.5 ml/min at 254 nm. FTIR spectra were recorded with
a Perkin Elmer—DXB spectrometer. Melting points were deter-
mined with a Kherea digital melting point apparatus and are
uncorrected.
Table 2
Enantioselective ketone reduction using BH3ꢁS(CH3)2 as
a reducing agent with
20 mol % of the catalysta
Entry
Catalyst
Yieldb (%)
eec (%)
Absolute configurationd
1
2
3
5
6
7
1a
1b
1c
1d
1e
2
99
99
99
96
70
97
82
97
81
93
60
60
(S)
(S)
(S)
(S)
(S)
(R)
4.2. General procedure for the synthesis of chiral amines
a
Ratio of ligand/BMS/ketone was 0.2:1.6:1.1. 30 min stirring at 65 °C.
Isolated yield by column chromatography.
Determined by HPLC analysis using Chiralcel OD-H column.
The absolute configuration was assigned by comparison of the sign of the
b
c
To an oven-dried, nitrogen-purged flask (1R,2S)-norephedrine
(1.05 g, 6.94 mmol) was added and dissolved in anhydrous ethanol.
To this an equal amount of substituted salicylaldehyde was added
d
specific rotation with the literature data.

U. Balakrishnan et al. / Tetrahedron: Asymmetry 20 (2009) 1150–1153
1153
as an ethanolic solution. The reaction mixture was allowed to stir
at room temperature for 18 h, and then cooled to 0 °C. After cool-
ing, sodium borohydride, (0.53 g, 13.9 mmol) was added and al-
lowed to stir for 2 h. After the completion of the reaction
monitored by TLC, ethanol was removed, and the reaction mixture
was poured into crushed ice. Then the amine was extracted from
aqueous phase using diethyl ether and dried over anhydrous so-
dium sulfate. The solvent was removed under reduced pressure
and the product was recrystallized from diethyl ether and hexane
(1:2). All the other chiral amines 1a–e were synthesized using the
similar procedure.
sphere, borane dimethyl sulfide (0.15 ml, 1.6 mmol) was added
dropwise and refluxed for 30 min. To this mixture acetophenone
(0.12 ml, 1 mmol) was added dropwise and refluxed for 2 h. Then
the reaction mixture was quenched with 2 M HCl and extracted
with chloroform. The chiral alcohol was separated by column chro-
matography with silica gel as an adsorbent and 98:2 (hexane/eth-
ylacetate) as an eluent.
Acknowledgements
The authors thank DST for financial assistance (SR/FTP/CS-142-
2006) in the form of a Fast track sponsored project and Dr. M. Chid-
ambaram, Director, NITT for his constant encouragement, support
and research grant.
4.2.1. Synthesis of 4-chloro-2-(((1S,2R)-1-hydroxy-1-phenyl-
propan-2-ylamino)methyl)phenol 1b
(1S,2R)-Norephedrine and 5-chloro salicylaldehyde were re-
acted to yield compound 1b as a yellow solid in 90% yield. Melting
References
589
point: 52–54 °C. ½
aꢂ
¼ þ11:1 (c 0.2, CHCl3). FTIR (cmꢀ1): 3630 (–
30
OH), 3340 (–NH), 3098 (Ar-CH), 1283(C–O). 1H NMR, CDCl3
d
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117.8, 123.5, 124.2, 126.2, 127.8, 127.9, 128.4, 128.5, 141.2, 157.
Elemental Anal. Calcd: C, 65.86; H, 6.22; N, 4.8. Found: C, 64.38;
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compound 1a as
a yellow colour semi solid in 80% yield.
589
½
aꢂ
¼ þ17:6 (c 0.25, CHCl3). FTIR (cmꢀ1): 3560, 3318, 3045,
30
1260. 1H NMR, CDCl3, d (ppm): 0.9 (d, 3H), 2.85 (q, 1H), 3.82 (dd,
2H), 4.75 (d, 1H), 5.2 (s, 1H), 6.6–6.9 (Ar-H, 3H), 7.15–7.3 (Ar-H,
6H).
4.2.3. Synthesis of 4-bromo-2-(((1S,2R)-1-hydroxy-1-phenylpro-
pan-2-ylamino)methyl)phenol 1c
(1S,2R)-Norephedrine and 5-bromo salicylaldehyde were re-
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589
30
Melting Point: (65–67 °C); ½
a
ꢂ
¼ þ14 (c 0.3,CHCl3). FTIR (cmꢀ1):
3613 (–OH), 3328 (–NH), 3065 (Ar-CH), 1271 (C–O). 1H NMR, CDCl3
d (ppm): 1.08 (d, 3H), 2.98 (m, 1H), 4.03 (dd, 2H), 4.8 (d, 1H), 6.6–
6.7 (Ar-H, 3), 7.2–7.3 (Ar-H, 5H).
4.2.4. Synthesis of 2-(((1S,2R)-1-hydroxy-1-phenylpropan-2-
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589
30
Point: (153–154 °C); ½
aꢂ
¼ þ53 (c 0.2, CHCl3). FTIR (cmꢀ1) 3633
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(ppm): 1.25 (d, 3H), 3.0 (m, 1H), 4.1 (dd, 2H), 4.83 (d, 1H), 6.8–
6.9 (Ar-H, 5H), 7.9–8.2 (Ar-H, 3H).
4.2.5. Synthesis of 4-(((1S,2R)-1-hydroxy-1-phenylpropan-2-
ylamino)methyl)benzene-1,4-diol 1e
(1S,2R)-Norephedrine and 2,5-dihydroxy benzaldehyde were
reacted to yield compound 1e as a yellow colour solid in 78% yield.
589
30
Melting Point: (77–79 °C); ½
aꢂ
¼ þ28 (c 0.2, CHCl3). FTIR (cmꢀ1):
3628 (–OH), 3337 (–NH), 3070 (Ar-CH), 1260 (C–O). 1H NMR, CDCl3
d (ppm): 1.2 (d, 3H), 2.9 (m, 1H), 3.14 (s, 1H), 3.8 (dd, 2H), 4.78 (d,
1H), 6.6–6.8 (Ar-H, 3H), 7.2–7.3 (Ar-H, 5H).
22. Zhang, Y.-X.; Du, D.-M.; Chen, X.; Lü, S.-F.; Hua, W.-T. Tetrahedron: Asymmetry
2004, 15, 177–182.
4.3. General procedure for the prochiral ketone reduction
23. (a) Xu, J.; Wei, T.; Zhang, Q. J. Org. Chem. 2003, 68, 10146–10151; (b) Gilmore,
N. J.; Jones, S.; Muldowney, M. P. Org. Lett. 2004, 6, 2805–2808.
24. Fang, T.; Xu, J.; Du, D.-M. Synlett 2006, 1559–1563.
The reaction was carried out with the molar ratio of ligand/ace-
tophenone/BMS as 0.2:1:1.6. To the chiral ligand 1b (53 mg,
0.2 mmol) dissolved in dry THF (3 ml) under a nitrogen atmo-