Synthesis, resolution, and applications of 3-amino-2,2-dimethyl-1,3- diphenylpropan-1-ol, a conformationally restricted 1,3-aminoalcohol

Article abstract of DOI:10.1016/j.tet.2010.05.001

Efficient synthetic routes to both syn and anti diastereomers of a conformationally restricted 1,3-aminoalcohol were devised. Resolution of the aminoalcohols was accomplished through diastereomeric salt with R-(-)-O-acetyl mandelic acid. These aminoalcoho

Full text of DOI:10.1016/j.tet.2010.05.001

Tetrahedron 66 (2010) 5036e5041
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Synthesis, resolution, and applications of 3-amino-2,2-dimethyl-1,3-
diphenylpropan-1-ol, a conformationally restricted 1,3-aminoalcohol
,
M.N. Patil a, R.G. Gonnade b, N.N. Joshi a
*
a Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
b Centre for Material Characterization, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient synthetic routes to both syn and anti diastereomers of a conformationally restricted 1,3-ami-
noalcohol were devised. Resolution of the aminoalcohols was accomplished through diastereomeric salt
with R-(ꢀ)-O-acetyl mandelic acid. These aminoalcohols were examined as ligands for two standard
reactions, namely, enantioselective addition of Et2Zn to aldehydes and reduction of prochiral ketones
with BH3.
Received 29 March 2010
Received in revised form 27 April 2010
Accepted 1 May 2010
Available online 7 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Aminoalcohol
AldoleTishchenko reaction
Resolution
Diethylzinc
Oxazaborinane
1. Introduction
First and the crucial step of the scheme is an AldoleTishchenko6
reaction between isobutyrophenone and benzaldehyde in the
Aminoalcohols and their derivatives are useful chiral ligands
and auxiliaries for a variety of enantioselective reactions.1 A wide
variety of aminoalcohols, mostly 1,2-aminoalcohols have been
reported in the literature,1c,2 whereas only a few examples for the
use of chiral 1,3-aminoalcohols are known.3,4 Conformational
rigidity is one of the desired features for stereoselective organic
reactions. 1,3-Disubstituted acyclic chiral molecules are therefore
unlikely to prove useful ligand/auxiliary. With the exception of the
ones derived from camphor,4a,f,i,j most 1,3-aminoalcohols posses
flexible backbone and provide poor enantioselectivity.4b,c,g,h,k,l We
conceived the structure 1 and 2, which could be obtained through
a straightforward protocol.5
presence of LiOtBu. The resulting
g-hydroxybenzoate 3 was treated
with thionyl chloride to obtain the anti chlorobenzoate 4 with
retention of configuration. Compound 4 was then converted to
azidobenzoate 5 by treatment with sodium azide in DMF with an
inversion of the configuration. The resulting syn azidobenzoate 5
was first hydrolyzed to azidoalcohol 6, followed by hydrogenation
to obtain syn-1,3-amino alcohol 1 in overall 45% yield. A same
strategy was applied for the preparation of anti-1,3-aminoalcohol 2,
as shown in Scheme 2.
The required syn hydroxylbenzoate 8, which is the key in-
termediate for further transformation, was prepared from the
meso 1,3-diol 7.7 1,3-Diketone8 was reduced using LiBH4/TiCl4 to
obtain 1,3-diol in 92:8 syn/anti ratio. The mixture was converted to
pure syn hydroxybenzoate 8 by treatment with 1 equiv of PhCOCl
followed by crystallization. Treatment of 8 with SOCl2 formed
chlorobenzoate 9 (in 80% yield) with retention of configuration.
The anti azidobenzoate 10 was obtained by reaction of the
compound 9 with sodium azide. Hydrolysis of 10 followed by
hydrogenation provided the corresponding anti-1,3-aminoalcohol
2 in overall 33% yield.
2. Results and discussion
These molecules would offer particular advantage for selectivity
due to conformational rigidity induced by two methyl groups at beta
position. Synthesisof thesynaminoalcohol(1)isdepictedinScheme 1.
3. Resolution
The resolution of amines/aminoalcohols through diastereo-
meric salts with homochiral carboxylic/sulfonic acids is a standard
* Corresponding author. Tel.: þ91 20 25902055; fax: þ91 20 25902629;
e-mail address: nn.joshi@ncl.res.in (N.N. Joshi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.001

M.N. Patil et al. / Tetrahedron 66 (2010) 5036e5041
5037
Scheme 1. Synthesis of compound 1. Reagents and conditions: (a) LiOtBu, THF, 0 ꢁC to rt, 74%; (b) SOCl2, CH2Cl2, rt, 83%; (c) NaN3, DMF, reflux, 83%; (d) KOH, MeOH; (e) H2-Pd/C,
MeOH, 90% (over two steps).
Scheme 2. Synthesis of compound 2. Reagents and conditions: (a) LiBH4, TiCl4, 82%; (b) BzCl, Pyridine, CH2Cl2, rt, 71%; (c) SOCl2, CH2Cl2, rt, 80%; (d) NaN3, DMF, reflux, 78%; (e) KOH,
MeOH; (f) H2-Pd/C, MeOH, 90% (over two steps).
procedure. We examined various mono- as well as dibasic acids for
the resolution of 1 and 2. Unfortunately we could not separate the
diastereomeric salts prepared from almost all commonly used
chiral acids.9 Either the resulting salts were not solid or did not
was stirred with a combination of EtOH/EtOAc (w15:85). The pre-
cipitated solid after basification with aqueous ammonia gave the
enantiopure (þ)-1 while (ꢀ)-1 was recovered from the filtrate. The
same protocol was also applied for the resolution of 2 (Scheme 3).
Scheme 3. Resolution of aminoalcohols.
crystallize with resolution. Finally the resolution could be accom-
plished through preferential precipitation of one of the salts
obtained from R-(ꢀ)-O-acetyl mandelic acid. Unlike the regular
method of crystallization which needs to be repeated at least twice
to obtain complete separation of the mixture, this unusual
procedure provides very high degree of separation in single step.
The mixture of diastereomeric salts was prepared by dissolving the
acid and the aminoalcohol in methanol, and evaporating to dryness
to obtain a powdery mass. Crystallization of the residue from
a mixture of EtOH/EtOAc did not result in the resolution. We then
examined the possibility of preferential precipitation from a mix-
ture of the solvents. Indeed, excellent separation of the two di-
astereomers was obtained when the diastereomeric mixture of salt
Optical purity of all the four stereoisomers of 3-amino-2,2-
dimethyl-1,3-diphenylpropan-1-ol was determined by chiral
HPLC and found to be more than 99%. The absolute configuration
was established by anomalous dispersion effects in X-ray dif-
fraction measurements on the crystal of the hydrobromide salts.
The ORTEP diagram for compound (ꢀ)-1 and (ꢀ)-2 are shown in
Figure 1.10
A standard test for the stereodifferentiating efficacy of an ami-
noalcohol, is in its performance during the addition of diethylzinc
to aldehyde2,11,12 and oxazaborolidine-catalyzed reduction of
ketone.1d,13 We first examined the methyl derivatives of 1 and 2 as
ligands for the addition of Et2Zn. The derivatives 12e15 were
obtained by judicious methylation as shown in Scheme 4.

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M.N. Patil et al. / Tetrahedron 66 (2010) 5036e5041
Figure 1. ORTEPs (A) and (B) of (ꢀ)-1 and (ꢀ)-2, respectively, show the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% and 30% probability level for (ꢀ)-1
and (ꢀ)-2, respectively and H atoms are shown as small spheres of arbitrary radii.
Figure 2. Transition state involving syn-(ꢀ)-14.
Several aromatic and aliphatic aldehydes were also examined
for the reaction with ligand 14 (Table 2). High level of enantiose-
lection were observed in all the cases. The sterically hindered
-napthaldehyde (entry 4) was alkylated with 97:3 er. Even the less
Scheme 4. Synthesis of ligands 12e15.
a
reactive cyclohexanecarboxaldehyde (entry 6), was alkylated
with excellent enantioselectivity and yield (96:4 er, 90% yield).
However hydrocinnamaldehyde an aliphatic aldehyde (entry 7),
provided moderate enantioselectivity although with excellent yield
(88:12 er, 90% yield).
4. Enantioselective addition of Et2Zn to aldehydes
The test reaction involving Et2Zn and benzaldehyde was carried
out in tolueneehexane using 10 mol % of the ligand. The results are
summarized in Table 1.
Table 2
Table 1
Enantioselective addition of Et2Zn to aldehydes catalyzed by (ꢀ)-14a
Enantioselective addition of Et2Zn to benzaldehyde
Entry Aldehyde
Time (h) Yield (%) er
Configuration
1
2
3
4
5
6
7
o-Tolualdehyde
p-Tolualdehyde
p-Chlorobenzaldehyde
1.5
1.5
1
2
2
87
88
86
88
89
84
90
96:4b
95:5b
95:5c
97:3b
98:2b
96:4c
88:12b
s
s
s
s
s
s
s
a
b
-Naphthaldehyde
-Naphthaldehyde
Entry
Ligand
Time (h)
Yielda (%)
erb
Cyclohexanecarboxaldehyde
Hydrocinnamaldehyde
3
2
1
2
3
(ꢀ)-12
(ꢀ)-13
(ꢀ)-14
(ꢀ)-15
(ꢀ)-14
4
4
1
2
2
69
70
90
80
86
92:8
70:30
97:3
80:20
97:3
a
All the reaction were conducted at room temperature using 10 mol % ligand and
1.5 equiv Et2Zn.
b
4
Determined by chiral HPLC analysis.
Determined by chiral GC analysis.
5c
c
a
Isolated yield.
Determined by chiral HPLC analysis.
Reaction carried out at 0 ꢁC.
b
c
5. Reduction of acetophenone
As expected, better enantioselectivity was realized with di-
We also evaluated aminoalcohols (ꢀ)-1, (ꢀ)-2, (ꢀ)-12, and
(ꢀ)-13 as chiral ligands for the enantioselective reduction of
acetophenone with borane. The oxazaborinane catalyst was pre-
pared by treating the aminoalcohol with borane according to the
procedure published by our group earlier.13i Baring aminoalcohol 1
(er 80:20), the results with other derivatives were disappointing
(Scheme 5). However we do believe that optimization of the ligand-
structure would provide better selectivities. It is obvious from the
present work that one can access a wide range of 1,3-aminoalcohols
by varying the substituents on aryl group as well as at the C2
position.
methyl derivative than the monomethyl derivative. The highest
degree of enantioselectivity (97:3 er) was observed with syn
N,N,-dimethyl aminoalcohol (ꢀ)-14 (entry 3). Unexpectedly, the
corresponding anti derivative provided only moderate yield and
moderate enantioselectivity. In the case of the ligand (ꢀ)-14, the
reaction was complete within 1 h at room temperature with 100%
conversion. It was found that lowering the temperature decreased
the reaction rate, but yield and enantioselectivity were comparable
(entries 3 and 5). The 6/4/4 tricyclic transition structure explains
the observed enantioselectivity (Fig. 2).14

M.N. Patil et al. / Tetrahedron 66 (2010) 5036e5041
5039
excess thionyl chloride were evaporated under rotavapour. The
residue was dissolved in CH2Cl2 (50 mL), washed with water, so-
dium bicarbonate, and brine. The solution was dried over Na2SO4
and concentrated under reduced pressure. The residue was purified
by filtration column through
a short column of silica gel
Scheme 5. Enantioselective reduction of acetophenone.
(100e200 mesh) followed by crystallization from ethyl acetate/
petroleum ether (1:9) to obtain 4 as a white solid (6.3 g, 83%),
1
>99:1 dr (by H NMR). Mp 167e168 ꢁC; [Found: C, 75.99; H, 6.30.
6. Conclusion
C24H23ClO2 requires C, 76.08; H, 6.12%]; Rf (10% EtOAc/PE) 0.54; vmax
(CHCl3): 3018, 1722, 1452 cmꢀ1
;
1H NMR (200 MHz, CDCl3)
In conclusion, we have prepared and resolved all the stereo-
isomers of 3-amino-2,2-dimethyl-1,3-diphenylpropan-1-ol. The
synthesis was accomplished in good yields using commercially
available starting materials. Two typical model reactions were ex-
amined for the application in asymmetric catalysis. It was found
that syn-1,3-amino alcohol provides good stereoselectivity for the
addition of diethylzinc to aldehydes and only moderate enantio-
selectivity for reduction of ketone with borane. Other applications
of these conformationally restricted 1,3-aminoalcohols are under
investigation. We are optimistic that these molecules would prove
to be valuable new additions in the repertoire of synthetic chemists.
7.29e8.17 (m, 15H), 6.33 (s, 1H), 5.25 (s, 1H), 0.97 (s, 3H), 0.94 (s,
3H); 13C NMR (50.32 MHz, CDCl3) 164.9, 138.5, 137.7, 133.1, 130.2,
129.5, 129.3, 128.5, 128.0, 127.8, 79.8, 69.1, 43.7, 19.9, 18.4.
7.1.3. syn-(ꢂ)-3-Azido-2,3-dimethyl-1,3-diphenylpropyl benzoate (5).
A mixture of chlorobenzoate 4 (7.58 g, 20 mmol), sodium azide
(5.85 g, 90 mmol), and DMF (90 mL) was stirred under reflux for 3
days. The reaction mixture was cooled to room temperature, poured
into 300 mL of ice water, and extracted with ether (200 mLꢃ3).
Combined organic layer was washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (200e400 mesh) using ethyl
acetate/petroleum ether as the eluent followed by crystallization to
obtain 5 as a white solid (6.4 g, 83%), >99:1 dr (by 1H NMR). Mp
145e146 ꢁC; [Found: C, 74.48; H, 5.77; N, 10.61. C24H23N3O2 requires
C, 74.78; H, 6.01; N, 10.90%]; Rf (10% EtOAc/PE) 0.54; vmax (CHCl3):
7. Experimental section
7.1. General
All the solvents and reagents were purified and dried according
to procedures given in D. D. Perrin’s purification of Laboratory
Chemicals.15 Diethylzinc was purchased from Aldrich. All the alde-
hydes were freshly distilled prior to use. The reactions were moni-
tored by TLC using silica gel 60 F254 precoated plates, and the
products were purified by Column chromatography on silica gel
(100e200 or 230e400 mesh). Melting points were recorded on
Yamaco micro melting point apparatus and are uncorrected. Optical
rotations were measured on BellimheamþStandley ADP220 digital
polarimeter.1H NMR spectrawere recorded at 200 MHz with TMS as
the internal standard. 13C NMR spectra were recorded at 50 MHz
3018, 2104, 1720 cmꢀ1 1H NMR (200 MHz, CDCl3) 7.22e8.12 (m,
;
15H), 5.81 (s, 1H), 4.45 (s, 1H), 1.20 (s, 3H), 0.85 (s, 3H); 13C NMR
(50.32 MHz, CDCl3) 165.0, 137.4, 135.9, 133.1, 130.3, 129.5, 128.8,
128.5, 128.3, 128.0, 127.8, 79.8, 71.7, 42.8, 19.3, 19.1.
7.1.4. syn-(ꢂ)-3-Azido-2,3-dimethyl-1,3-diphenylpropan-1-ol (6). A
mixture of 5 (7.7 g, 20 mmol) and KOH (3.36 g, 60 mmol) was stirred
in methanol (80 mL) for 16 h at room temperature. Methanol was
then removed on a rotary evaporator. Water was added and the
reaction mixture was extracted with ether (30 mLꢃ3). Combined
organic layer was washed with brine, dried over Na2SO4, and con-
centrated under reduced pressure. The residue was purified by flash
chromatography on silica gel (200e400 mesh) using ethyl acetate/
petroleum ether as the eluent followed by crystallization from ethyl
acetate/petroleum ether (1:9) to obtain 6 as a white solid (5.1 g, 90%),
>99:1 dr (by 1H NMR). Mp 145e146 ꢁC; [Found: C, 72.34; H, 6.96; N,
15.29. C17H19N3O requires C, 72.57; H, 6.81; N,14.94%]; Rf (10% EtOAc/
with CDCl3 (
d
¼77) as the reference. Microanalytical data were
obtained using a CarloeErba CHNS-0 EA 1108 elemental analyzer.
Enantiomeric excess was determined using chiral columns on HPLC.
7.1.1. anti-(ꢂ)-3-Hydroxy-2,2-dimethyl-1,3-diphenylpropyl benzoate
(3). A cooled solution of anhydrous tert-butanol (1.9 mL, 20 mmol)
in 10 mL anhydrous THF was treated with nBuLi (20 mmol, 15.4 mL,
1.3 Msolution in cyclohexane) followed byisobutyrophenone(3 mL,
20 mmol). The mixture was allowed to stir for 10 min. Benzaldehyde
(5.1 mL, 50 mmol) dissolved in anhydrous THF (25 mL) was then
added dropwise over a period of 30 min. The mixture was allowed to
stir at room temperature for 16 h. The reaction mixture was
quenched by the addition of 1 N HCl (30 mL) and product was
extracted with ethyl acetate (100 mLꢃ2). Combined organic layer
was washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (200e400 mesh) using ethyl acetate/petroleum ether as
the eluent to obtain 3 as a white solid (5.3 g, 74%), >99:1 dr (by 1H
NMR), mp 138e139 ꢁC; [Found: C, 80.13; H, 6.56. C24H24O3 requires
C, 79.97; H, 6.71%]; Rf (10% EtOAc/PE) 0.32; vmax (CHCl3): 3610,
PE) 0.42; vmax (CHCl3): 3608, 3018, 2104 cmꢀ1 1H NMR (200 MHz,
;
CDCl3) 7.26e7.40 (m, 10H), 4.71 (s, 1H), 4.40 (s, 1H), 1.85 (s, 1H), 1.09
(s, 3H), 0.61 (s, 3H); 13C NMR (50.32 MHz, CDCl3) 141.2, 136.9, 128.9,
128.0, 127.9, 127.7, 127.6, 78.2, 72.7, 43.1, 19.1, 17.7.
7.1.5. syn-(ꢂ)-3-Amino-2,3-dimethyl-1,3-diphenylpropan-1-ol (1).
A solution of 6 (2.81 g, 10 mmol) in methanol (25 mL) was hydro-
genated at room temperature and at 50 psi pressure using 10% Pd/C
(300 mg) for 1 h. Usual work-up provided (ꢂ)-3-amino-2,3-di-
methyl-1,3-diphenylpropan-1-ol (1) as
a white solid (2.56 g,
w100%), >99:1 dr (by 1H NMR). Mp 168e170 ꢁC; [Found: C, 79.95;
H, 8.28; N, 5.27. C17H21NO requires C, 79.96; H, 8.29; N, 5.49%]; Rf
(40% MeOH/EtOAc) 0.45; vmax (CHCl3): 3388, 3018, 1215 cmꢀ1 1H
;
1720 cmꢀ1
;
1H NMR (200 MHz, CDCl3) 7.26e8.17 (m, 15H), 6.37 (s,
NMR (200 MHz, CDCl3) 7.23e7.38 (m, 10H), 4.84 (s, 1H), 4.02 (s, 1H),
0.94 (s, 3H), 0.39 (s, 3H); 13C NMR (50.32 MHz, CDCl3) 143.5, 141.6,
128.4, 128.0, 127.5, 127.3, 127.2, 127.0, 84.9, 66.2, 41.1, 24.8, 11.8.
1H), 4.76 (s, 1H), 2.16 (s, 1H), 0.87 (s, 3H), 0.81 (s, 3H); 13C NMR
(50.32 MHz, CDCl3) 166.0, 141.1, 137.9, 133.2, 130.2, 129.7, 128.5,
128.2, 128.1, 127.8, 127.5, 127.3, 80.0, 76.9, 42.9, 19.2, 17.8.
7.1.5.1. Resolution of (ꢂ)-(1). The aminoalcohol
1 (2.56 g,
7.1.2. anti-(ꢂ)-3-Chloro-2,3-dimethyl-1,3-diphenylpropyl benzoate
(4). Compound 3 (7.2 g, 20 mmol) was dissolved in anhydrous
CH2Cl2 (40 mL) and treated dropwise with thionyl chloride (2.9 mL,
40 mmol). The reaction was monitored by the evolution of gas (HCl
and SO2). After stirring for 24 h at room temperature, CH2Cl2 and
10 mmol) and R-(ꢀ)- O-acetyl mandelic acid (1.94 g, 10 mmol) were
dissolved in methanol (20 mL). The resulting clear solution was
evaporated to dryness under reduced pressure. The salt was dis-
solved in minimum amount of hot ethanol (5 mL) and diluted with
ethyl acetate (30 mL). The resulting solution was stirred at room

5040
M.N. Patil et al. / Tetrahedron 66 (2010) 5036e5041
temperature for 1 h, to obtain one of the diastereomeric salts as
MeOH/EtOAc) 0.45; vmax (CHCl3): 3388, 3018, 1215 cmꢀ1 1H NMR
;
white precipitate. The mixture was filtered to obtain solid salt (2 g,
(200 MHz, CDCl3) 7.24e7.42 (m, 10H), 4.65 (s, 1H), 4.04 (s, 1H), 1.00
(s, 3H), 0.67 (s, 3H); 13C NMR (50.32 MHz, CDCl3) 141.7, 141.1, 128.2,
128.1, 127.6, 127.2, 126.8, 79.5, 65.9, 40.0, 23.6, 20.7.
44%), mp 196e197 ꢁC, [
a
]
D
26 e66 (c¼1, MeOH). The second isomer of
the salt was isolated from mother liquor by evaporation followed by
recrystallization from ethanol: ethyl acetate (1:9), (1.9 g, 42%), mp
160e161 ꢁC, [
a
]
D
ꢀ42 (c 1, MeOH). Basification of the salts was
7.1.10.1. Resolution of (ꢂ)-(2). The same procedure was fol-
lowed as described for the resolution of (ꢂ)-1.
carried out using aqueous NH3 to provide the corresponding opti-
cally pure aminoalcohols. (þ)-1 Isomer of aminoalcohol was
obtained from the precipitated salt while (ꢀ)-1 isomer was isolated
from the salt left in the filtrate.
Precipitated salt 42%yield, mp 175e177 ꢁC, [
Salt from filtrate 39% yield, mp 160e162 ꢁC, [
a
]
26 ꢀ60 (c 1, MeOH).
D
a]
26 ꢀ44 (c 1, MeOH).
D
Basification was carried out as described for above.
(1R,3S)-(þ)-1; 44% yield, mp 169e171 ꢁC, [
a]
26 þ42 (c 1, CHCl3),
(1R,3R)-(þ)-2; 42% yield, mp 142e143 ꢁC, [
a
]
26 þ40 (c 1, CHCl3),
D
D
>99:1 er (Kromasil-5-Amycoat column, 2-propanol/PE/TFA).
>99:1 er (Kromasil-5-Amycoat column, 2-propanol/PE/TFA).
26
(1S,3R)-(ꢀ)-1; 42% yield, mp 170e171 ꢁC, [
a
]
26 ꢀ42 (c 1, CHCl3),
(1S,3S)-(-)-2; 42% yield, mp 141e142 ꢁC, [
a
]
ꢀ40 (c 1, CHCl3),
D
D
>99:1 er (Kromasil-5-Amycoat column, 2-propanol/PE/TFA).
>99:1 er (Kromasil-5-Amycoat column, 2-propanol/PE/TFA).
7.1.6. syn-(ꢂ)-3-Hydroxy-2,2-dimethyl-1,3-diphenylpropyl benzoate
(8). The diol 7 (as a mixture of syn/anti in 92:8, 6.4 g, 25 mmol) was
dissolved in anhydrous CH2Cl2 (75 mL). To the stirred solution,
pyridine (2 mL, 25 mmol) followed by benzoyl chloride (2.9 mL,
25 mmol) were added dropwise. It was then stirred for 16 h at room
temperature. The reaction mixture was diluted with CH2Cl2
(100 mL) and washed with 1 N HCl, water, NaHCO3, water, and
brine, dried over Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by ‘flash chromatography’ on silica
gel (200e400 mesh) using ethyl acetate/petroleum ether as the
eluent followed by crystallization from ethyl acetate/petroleum
ether (1:9) to obtain 8 as a white solid (6.4 g, 71%), >99:1 dr (by 1H
NMR), mp 151e153 ꢁC; [Found: C, 80.26; H, 6.38. C24H24O3 requires
C, 79.97; H, 6.71%]; Rf (10% EtOAc/PE) 0.32; vmax (CHCl3): 3610,
7.2. General procedure for the preparation of N-methyl -1,3-
aminoalcohol
A suspension of 1 (1.28 g, 5 mmol), K2CO3 (1.04 g, 7.5 mmol),
methyl iodide (0.78 g, 5.5 mmol) in acetonitrile (20 mL) was stirred
at room temperature for 16 h. The reaction mixture was filtered and
concentrated under reduced pressure. The residue was purified by
‘flash chromatography’ on silica gel (200e400 mesh) using ethyl
acetate/petroleum ether as the eluent followed by crystallization
from toluene.
7.2.1. (1S,3R)-2,2-Dimethyl-3-(methylamino)-1,3-diphenylpropan-1-ol,
(ꢀ)-12. Yield 75%, mp 118e120 ꢁC; [Found: C, 79.93; H, 8.44; N,
5.23. C18H232N6 O requires C, 80.26; H, 8.61; N, 5.20%]; Rf (20% EtOAc/
1720 cmꢀ1
;
1H NMR (200 MHz, CDCl3) 7.26e8.11 (m, 15H), 6.10 (s,
PE) 0.2; [
a
]
ꢀ80 (c 1, CHCl3); vmax (CHCl3): 3019, 1454 cmꢀ1
;
1H
D
1H), 4.49 (s, 1H), 2.00 (s, 1H), 1.19 (s, 3H), 0.84 (s, 3H); 13C NMR
(50.32 MHz, CDCl3) 165.3, 141.2, 138.1, 132.9, 130.6, 129.6, 128.4,
127.9, 127.8, 127.8, 127.7, 127.7, 127.6, 80.3, 77.8, 43.1, 19.2, 18.0.
NMR (200 MHz, CDCl3) 7.20e7.39 (m, 10H), 4.82 (s, 1H), 3.63 (s, 1H),
2.27 (s, 3H), 0.90 (s, 3H), 0.36 (s, 3H);13C NMR (50.32 MHz, CDCl3)
142.2, 133.0, 131.2, 128.0, 127.6, 127.5, 127.4, 126.8, 84.0, 73.9, 43.6,
42.0, 26.1, 23.9.
7.1.7. syn-(ꢂ)-3-Chloro-2,3-dimethyl-1,3-diphenylpropylbenzoate(9).
The same procedure was followed as described for the compound 4.
Yield 80%, >99:1 dr, mp 136e137 ꢁC; [Found: C, 75.76; H, 6.33.
C24H23ClO2 requires C, 76.08; H, 6.12%]; Rf (10% EtOAc/PE) 0.54; vmax
(CHCl3): 3018,1722,1452 cmꢀ1; 1H NMR (200 MHz, CDCl3) 7.27e8.12
(m, 15H), 5.91 (s, 1H), 4.84 (s, 1H), 1.35 (s, 3H), 0.95 (s, 3H); 13C NMR
(50.32 MHz, CDCl3) 165.0,138.0,137.4,133.2,130.3,129.0,128.5,128.2,
128.1, 128.0, 127.9, 127.8, 79.9, 69.7, 44.4, 19.8, 19.4.
7.2.2. (1S,3S)-2,2-Dimethyl-3-(methylamino)-1,3-diphenylpropan-1-ol,
(ꢀ)-13. Yield 73%, mp 132e134 ꢁC; [Found: C, 80.36; H, 8.77; N,
4.91. C18H23NO requires C, 80.26; H, 8.61; N, 5.20%]; Rf (20% EtOAc/
26
PE) 0.2; [
a
]
ꢀ30 (c 1, CHCl3). vmax (CHCl3): 3000, 1495 cmꢀ1
;
1H
D
NMR (200 MHz, CDCl3) 7.18e7.32 (m, 10H), 4.57 (s, 1H), 3.55 (s, 1H),
2.25 (s, 3H), 0.99 (s, 3H), 0.70 (s, 3H); 13C NMR (50.32 MHz, CDCl3)
141.5, 138.5, 128.4, 128.2, 127.5, 127.3, 127.1, 85.0, 75.4, 41.0, 34.0,
24.9, 12.4.
7.1.8. anti-(ꢂ)-3-Azido-2,3-dimethyl-1,3-diphenylpropyl benzoate (10).
The same procedure was followed as described for the compound 5.
Yield 78%, >99:1 dr, mp 154e155 ꢁC; [Found: C, 75.06; H, 5.76; N,
10.75. C24H23N3O2 requiresC, 74.78;H, 6.01;N,10.90%]; Rf (10%EtOAc/
7.3. General procedure for the preparation of N,N-dimethyl -
1,3-aminoalcohol
PE) 0.54; vmax (CHCl3): 3018, 2104, 1720 cmꢀ1
;
1H NMR (200 MHz,
A suspension of 1 (1.28 g, 5 mmol), K2CO3 (2.08 g, 15 mmol),
methyl iodide (1.78 g, 12.5 mmol) in acetonitrile (25 mL) was stir-
red under reflux temperature for 16 h. The product was isolated
and purified as described above.
CDCl3) 7.26e8.18 (m,15H), 6.2 (s,1H), 4.82 (s,1H), 0.90 (s, 3H), 0.78 (s,
3H); 13C NMR (50.32 MHz, CDCl3) 165.1, 137.7, 136.6, 133.1, 130.3,
129.6,129.0, 128.5,128.1,128.1,128.0,127.9, 79.4, 71.3, 42.2,19.3,18.5.
7.1.9. anti-(ꢂ)-3-Azido-2,3-dimethyl-1,3-diphenylpropan-1-ol (11).
The same procedure was followed as described for the compound 6.
Yield 90%, >99:1 dr, mp 135e136 ꢁC; [Found: C, 72.63; H, 6.80; N,
15.20. C17H19N3O requires C, 72.57; H, 6.81; N,14.94%]; Rf (10% EtOAc/
7.3.1. (1S,3R)-2,2-Dimethyl-3-(dimethylamino)-1,3-diphenylpropan-
1-ol, (ꢀ)-14. Yield 76%, mp 106e107 ꢁC; [Found: C, 80.63; H, 9.15;
N, 4.84. C19H25NO requires C, 80.52; H, 8.89; N, 4.94%]; Rf (20%
EtOAc/PE) 0.24;
[a
]
ꢀ42 (c 1, CHCl3); vmax (CHCl3): 3016,
D
PE) 0.42; vmax (CHCl3): 3608, 3018, 2104 cmꢀ1
;
1H NMR (200 MHz,
1465 cmꢀ1; 1H NMR (200 MHz, CDCl3) 7.26e7.39 (m, 10H), 4.80 (s,
1H), 3.75 (s, 1H), 2.35 (s, 6H), 1.27 (s, 3H), 0.37 (s, 3H); 13C NMR
(50.32 MHz, CDCl3) 141.1,133.0,131.1,128.5,127.9,127.7,127.2,127.0,
85.8, 81.1, 43.7, 42.1, 25.5, 15.3.
CDCl3) 7.26e7.38 (m,10H), 4.97 (s, 1H, eOH), 4.88 (s, 1H),1.92 (s, 1H),
0.72 (s, 3H), 0.68 (s, 3H); 13C NMR (50.32 MHz, CDCl3) 141.4, 137.0,
129.0, 128.0, 128.0, 127.9, 127.6, 127.4, 78.0, 71.7, 42.2, 19.3, 18.9.
7.1.10. anti-(ꢂ)-3-Amino-2,3-dimethyl-1,3-diphenylpropan-1-ol
(2). The same procedure was followed as described for the com-
pound 1.
7.3.2. (1S,3S)-2,2-Dimethyl-3-(dimethylamino)-1,3-diphenylpropan-
1-ol, (ꢀ)-15. Yield 75%, mp 116e118 ꢁC; [Found: C, 80.35; H, 9.00;
N, 4.76. C19H25NO requires C, 80.52; H, 8.89; N, 4.94%]; Rf (20%
Yield w100%, with >99:1 dr, mp 137e139 ꢁC; [Found: 79.84; H,
8.18; N, 5.33. C17H21NO requires C, 79.96; H, 8.29; N, 5.49%]; Rf (40%
EtOAc/PE) 0.24; [
a]
ꢀ102 (c 1, CHCl3); vmax (CHCl3): 3000,
D
1451 cmꢀ1 1H NMR (200 MHz, CDCl3) 7.14e7.43 (m, 10H), 4.67 (s,
;

M.N. Patil et al. / Tetrahedron 66 (2010) 5036e5041
5041
1H), 3.56 (s, 1H), 2.35 (s, 3H), 1.57 (s, 3H), 0.48 (s, 3H);13C NMR
(50.32 MHz, CDCl3) 141.1, 133.1, 131.1, 128.5, 127.8, 127.6, 127.1, 127.0,
86.1, 81.1, 43.7, 42.0, 26.4, 15.2.
4. (a) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29, 5645e5648; (b)
Cicchi, S.; Crea, S.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry 1997, 8, 293e301;
(c) Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron: Asymmetry 1997, 8,
1869e1876; (d) Cho, B. T.; Kim, N. Tetrahedron Lett. 1994, 35, 4115e4118; (e)
Hulst, R.; Heres, H.; Fitzpatrick, K.; Peper, N.; Kellogg, R. M. Tetrahedron:
Asymmetry 1996, 7, 2755e2760; (f) Xingshu, L.; Chi-hung, Y.; Albert, S. C. C.;
Teng-Kuei, Y. Tetrahedron: Asymmetry 1999, 10, 759e763; (g) Panev, S.; Linden,
A.; Dimitrov, V. Tetrahedron: Asymmetry 2001, 12, 1313e1321; (h) Dimitrov, V.;
Dobrikov, G.; Genov, M. Tetrahedron: Asymmetry 2001, 12, 1323e1329; (i) Costa,
V. E. U.; Oliveira, L. F. Tetrahedron: Asymmetry 2004, 15, 2583e2590; (j) Aoyama,
T.; Yoshiyuki, H. Synthesis 2005, 583e587; (k) Martins, J. E. D.; Clarissa, M. M.
Tetrahedron: Asymmetry 2006, 17, 1817e1823; (l) Martinez, A. G.; Enrique, T. V.
Tetrahedron: Asymmetry 2007, 18, 742e749.
7.4. General procedure for the enantioselective addition
of Et2Zn to aldehydes
The addition of Et2Zn to PhCHO in the presence of (ꢀ)-14 was
carried out as described elsewhere4i to obtain (S)-(ꢀ)-1-phenyl-1-
propanol, 87% yield; [
5.15, CHCl3)].
a
]
D ꢀ46.70 (c 5.1, CHCl3) [lit.16
[
a]
D ꢀ45.45 (c
5. Although different molecules, similar structures have been obtained as di-
astereomeric mixtures: Barluenga, J.; Jardon, J.; Gotor, V. J. Chem. Res., Synop.
1986, 464.
7.5. General procedure for the enantioselective reduction
of acetophenone
6. (a) Paul, M. B.; Jared, T. S.; Woerpel, K. A. J. Org. Chem. 1997, 62, 5674e5675; (b)
Cheryl, M. M.; Matthew, O. D.; Shih-Yuan, L.; Morken, J. P. Org. Lett. 1999, 1,
1427e1429; (c) Abu-Hasanayn, F.; Streitwieser, A. J. Org. Chem. 1998, 63,
2954e2960.
7. Maier, G.; Roth, V.; Schmitt, R. K. Chem. Ber. 1985, 118, 704e721.
8. For the preparation of 1,3-dikekone, see: Bhowmick, K. C.; Prasad, K. R. K.; Joshi,
N. N. Tetrahedron: Asymmetry 2002, 13, 851e855.
The reduction of acetophenone with BH3.SMe2 mediated by
(ꢀ)-1 was carried out as described elsewhere.13i to obtain (S)-(ꢀ)-
L-
phenyl ethanol; 86% yield; [
þ44.12 (c 3.0, MeOH)].
a
]
D
ꢀ26.6 (c 3.3, MeOH) [lit.13i
[a]
D
9. Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolution;
Wiley: New York, NY, 1981.
10. The crystallographic data of compound (ꢀ)- 1 and (ꢀ)- 2 has been deposited
with the Cambridge Crystallographic Data Center as deposition No. CCDC
765748 & 765749. Copies of the data can be obtained, free of charge, on ap-
plication to the CCDC, 12 union Road, Cambridge CB2 1EZ, UK [fax: þ44 (1223)
336033; e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
Financial support for this work was provided by Department of
Science and Technology, New Delhi. One of us (M.N.P.) thanks CSIR,
New Delhi, for a research scholarship. We are thankful to Mrs.. S.
Kunte for chiral HPLC analysis.
11. Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823e2824.
12. (a) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.; Hayashi,
M.; Kaneko, T.; Matsuda, Y. J. Organomet. Chem. 1990, 382, 19e37; (b) Noyori, R.;
Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49e69; (c) Soai, K.; Niwa, S.
Chem. Rev. 1992, 92, 833e856; (d) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem. 1997,
62, 3770e3771.
Supplementary data
13. (a) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K.; Hirao, A.; Naka-
hama, S. J. Chem. Soc., Perkin Trans. I 1985, 2039e2044; (b) Nishizawa, M.;
Noyori, R. In Comprehensive organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 8, p 139; (c) Bruner, H.; Zettlmeier, W. Handbook
of Enantioselective Catalysis; VCH: Weinheim, 1993; (d) Singh, V. K. Synthesis
1992, 605e617; (e) Wallabum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3,
1475e1504; (f) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763e784; (g) Corey,
E. J.; Azimioara, M.; Sarshar, S. Tetrahedron Lett. 1992, 33, 3429e3430; (h) Jones,
D. K.; Liotta, D. C.; Shinkai, J.; Mathre, D. J. J. Org. Chem. 1993, 58, 799e801; (i)
Prasad, K. R. K.; Joshi, N. N. Tetrahedron: Asymmetry 1996, 7, 3147e3152.
14. Panda, M.; Puay-Wah, P.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 564e571.
15. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals; Pergamon:
Oxford, New York, NY, 1966.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.05.001.
References and notes
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