A stereocontrolled route to the synthesis of (±)-3-amino-2,2- dimethyl-1,3-diphenylpropan-1-ol

Article abstract of DOI:10.1016/j.tetlet.2010.09.011

Both the diastereomers of (±)-3-amino-2,2-dimethyl-1,3- diphenylpropan-1-ol were synthesized starting from a common intermediate, namely, β-hydroxy oxime 6. Diastereoselective reduction with NaBH ₄/TiCl₄ and H₂-Pd/C provided syn- and anti-isomers, respectively. Good overall yield and selectivity were realized using a simple protocol.

Full text of DOI:10.1016/j.tetlet.2010.09.011

Tetrahedron Letters 51 (2010) 5927–5929
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Tetrahedron Letters
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A stereocontrolled route to the synthesis of
( )-3-amino-2,2-dimethyl-1,3-diphenylpropan-1-ol
⇑
M. N. Patil, K. C. Bhowmick, N. N. Joshi
Division of Organic Chemistry, National Chemical Laboratory, Council of Scientific and Industrial Research, 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:
Received 1 July 2010
Revised 3 September 2010
Accepted 4 September 2010
Available online 15 September 2010
Both the diastereomers of ( )-3-amino-2,2-dimethyl-1,3-diphenylpropan-1-ol were synthesized starting
from a common intermediate, namely, b-hydroxy oxime 6. Diastereoselective reduction with NaBH4/TiCl4
and H2-Pd/C provided syn- and anti-isomers, respectively. Good overall yield and selectivity were realized
using a simple protocol.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Aminoalcohol
Aldol–Tishchenko reaction
b-Hydroxy oxime
Diastereoslective reduction
The design and synthesis of new chiral ligands for asymmetric
synthesis is an important goal in organic synthesis.1 1,3-Aminoalco-
hols and their derivatives have proved to be excellent chiral auxilia-
ries as well as ligands for a variety of enantioselective reactions.2
Various methodologies are described in the literature to prepare
1,3-aminoalcohols. Amongst these, the hydroxyl group-directed
reduction of b-hydroxy oxime or b-hydroxy oximino ether has at-
tracted much attention.3 Narasaka et al.3a first reported the hydroxyl
group-directed reduction of b-hydroxy oximino ether which results
in the formation of syn-1,3-aminoalcohol as a major product. After
this initial report, modifications were reported from various
groups.3b–h In most cases syn-1,3-aminoalcohol was obtained as a
major product. Reductive amination of b-hydroxy ketones was
employed as an alternate approach by Menche et al.4
Diastereoselective reduction of b-hydroxy oxime or oximino
ether would be an ideal approach for the synthesis of syn- and
anti-isomers of 1,3-aminoalcohols. The only report describing such
approach was that by Ellman and co-workers.5 They reported the
preparation of both syn- and anti-1,3-aminoalcohols starting from
a b-hydroxy-N-sulfinyl ketimine. However this method requires ex-
tra steps for the preparation of the starting material.
We recently reported the synthesis and resolution of both syn-
and anti-( )-3-amino-2,2-dimethyl-1,3-diphenylpropan-1-ol,
a
new conformationally restricted 1,3-aminoalcohol 1 and 2.6 These
aminoalcohols were synthesized from the corresponding anti- and
syn-
stitution reactions followed by reduction of azidoalcohol. Though
anti- -hydroxybenzoate can be prepared in a single step through
Aldol–Tishchenko reaction, the synthesis of syn- -hydroxybenzo-
c-hydroxybenzoate, respectively, employing nucleophilic sub-
c
c
ate is quite laborious. Also, the use of sodium azide needs to be
avoided on large scale preparation. We now report herein a short
route for the preparation of 1 and 2 starting from a common inter-
mediate namely, b-hydroxy oxime 6. The retrosynthetic analysis is
shown as follows (Scheme 1).
The required b-hydroxy oxime 6 was prepared from
benzoate 3 in three steps with excellent overall yield (Scheme 2).
The -hydroxybenzoate 3 was prepared employing Aldol–Tish-
chenko6,7 reaction between isobutyrophenone and benzaldehyde
in the presence of LiOtBu. The resulting
-hydroxybenzoate 3
c-hydroxy-
c
c
was then oxidized to the corresponding keto benzoate 4 by chro-
mic acid. We examined various conditions for the hydrolysis of
compound 4 to the corresponding hydroxy ketone. In basic as well
as in acidic conditions, retro aldol reaction took place. Therefore we
first converted 4 into the corresponding oxime 5, which upon
hydrolysis with methanolic KOH gave the b-hydroxy oxime 6.
For the preparation of syn-1,3-aminoalcohol, we attempted
reduction of the oxime 6 with various hydride-reducing agents
known in the literature. LiAlH43c,f in THF and NaBH3CN8 in aqueous
TiCl3 reduced the oxime 6 in moderate yield with low diastereose-
lectivity. The reduction did not proceed at all with NaBH4 in the
presence of NiCl2Á6H2O.3g Finally we were successful in reducing
NH2 OH
NH2 OH
1
2
⇑
Corresponding author. Tel.: +91 20 25902055; fax: +91 20 25902629.
E-mail address: nn.joshi@ncl.res.in (N.N. Joshi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.011

5928
M. N. Patil et al. / Tetrahedron Letters 51 (2010) 5927–5929
HO
NH2 OH
OH
N
OH OCOPh
1 / 2
6
3
Scheme 1. Retrosynthetic analysis.
O
N
OCOPh
OH OCOPh
b
O
a
+
PhCHO
Ph
4
3
c
HO
HO
OCOPh
OH
N
d
5
6
Scheme 2. Synthesis of compound 6. Reagents and conditions: (a) LiOtBu, THF, 0 °C to rt, 73%; (b) K2Cr2O7, dil H2SO4, Et2O, rt, 95%; (c) NH2OHÁHCl, CH3COONa, ethanol, reflux,
90%; (d) KOH, MeOH, rt, 90%.
the oxime 6 with NaBH4 in the presence of TiCl4.9 The reduction
proceeded smoothly with 2 equiv of TiCl4 and excess of NaBH4 at
room temperature. The syn-1,3-aminoalcohol 1 was formed in high
yield (80%) exclusively (Scheme 3).10
However the reduction with NaBH4/TiCl4 is not easy to explain be-
cause the combination can involve several reactive species which
would vary with stoichiometry of the reactants.12 Our preliminary
Table 1
Hydrogenation of 6 proved a little tricky. The reduction did not
take place with hydrogen in the presence of Pd/C in methanol.
Hydrogenation with Raney Ni and HCOONH4-Pd/C in methanol
also failed to yield the reduced product. Hydrogenation in the pres-
ence of 1 equiv acetic acid did give the product, but the reaction
was incomplete. Finally we observed that hydrogenation in the
presence of 1 equiv of hydrochloric acid efficiently reduced the
oxime 6 to 1,3-aminoalcohol in 80% yield with good distereoselec-
tivity (anti:syn = 79:21). The desired anti-isomer 2 was isolated as
its succinate salt by recrystallization (48% yield, >99 de).11
As depicted in Table 1, the observed syn diastereoselectivity in
the present case is similar to that reported by other groups.3,4
Reduction of the b-hydroxy oxime 6
Entry
Reagent
% Yielda
71
dr (syn:anti)b
1
2
3
4
5
6
7
LiAlH4
47:53
55:45
—
>99:1
—
Na(BH3)CN/aq TiCl3
NaBH4/NiCl2Á6H2O
NaBH4/TiCl4
H2, Raney-Ni
HCOONH4, Pd/C
H2, HCl (1 equiv), Pd/C
68
c
80
c
c
—
21:79
78
a
b
c
Isolated combined yield.
Determined by 1H NMR.
Very slow or no reaction.
NH2 OH
NaBH4
TiCl4, DME
RT, 16h
( )-1
80% yield, 100% de
NH2 OH
6
NH2 OH
( )-2
H2-Pd/C
MeOH
HCl. 60psi
RT, 24h
Crystallization
of succinate
salt
79:21 dr (anti:syn)
48% yield, 100% de
Scheme 3. Reduction of b-hydroxy oxime 6.

M. N. Patil et al. / Tetrahedron Letters 51 (2010) 5927–5929
5929
experiments13 rule out Ti (IV)-mediated reduction with NaBH4 as is
the case with reductive amination.4 The anti-selectivity of the
hydrogenation reaction can be explained based on the mechanism
6. Patil, M. N.; Gonnade, R. G.; Joshi, N. N. Tetrahedron 2010, 66, 5036–5041.
7. (a) Paul, M. B.; Jared, T. S.; Woerpel, K. A. J. Org. Chem. 1997, 62, 5674–5675; (b)
Cheryl, M. M.; Matthew, O. D.; Shih-Yuan, L.; Morken, J. P. Org. Lett. 1999, 1,
1427–1429.
proposed for a
-hydroxy ketone.14
8. Spreltzer, H.; Buchbauer, G.; Puringer, Ch. Tetrahedron 1989, 45, 6999–7002.
9. Kano, S.; Tanaka, Y.; Sugino, E.; Hibino, S. Synthesis 1980, 695–697.
10. Preparation of syn-( )-3-amino-2,3-dimethyl-1,3-diphenylpropan-1-ol (1). A
solution of 6 (2.69 g, 10 mmol) in anhydrous 1,2-dimethoxyethane (30 mL)
was added dropwise to an ice-cooled, stirred mixture of TiCl4 (2.2 mL,
20 mmol) and NaBH4 (1.51 g, 40 mmol) in anhydrous 1,2-dimethoxyethane
(30 mL). After the addition, the ice-bath was removed and stirring was
continued at room temperature for 48 h. The reaction mixture was then
quenched by the addition of ice-cold water, followed by 10% aqueous NaOH.
The resulting suspension was filtered and the solid was washed with
dichloromethane. Combined filtrate was transferred to a separating funnel,;
dichloromethane layer was separated, washed with brine, dried over
anhydrous Na2SO4, and evaporated under reduced pressure. The crude
product was purified by crystallization from ethanol to obtain 1 as a white
solid (2.04 g, 80%), >99% de (by 1H NMR). mp 168–170 °C; Rf (40% MeOH/
In conclusion, we have described a short and efficient synthetic
route for the synthesis of both diastereomers of 1,3-aminoalcohol
through the stereoselective reduction of b-hydroxy oxime. The re-
quired b-hydroxy oxime was prepared in excellent yield using eas-
ily accessible materials. The present work will facilitate the
synthetic applications of the homochiral aminoalcohols 1 and 2.
Acknowledgments
The financial support for this work was provided by the Depart-
ment of Science and Technology, New Delhi. One of us (M.N.P.)
thanks CSIR, New Delhi, for a research scholarship.
EtOAc) 0.45; IR (CHCl3): 3388, 3018, 1215 cmÀ1 1H NMR (200 MHz, CDCl3): d
.
0.39 (s, 3H), 0.94 (s, 3H), 4.02 (s, 1H), 4.84 (s, 1H), 7.23–7.38 (m, 10H); 13C NMR
(CDCl3): d 11.8, 24.8, 41.1, 66.2, 84.9, 127.0, 127.2, 127.3, 127.5, 128.0, 128.4,
141.6, 143.5. Anal. Calcd for C17H21NO: C, 79.96; H, 8.29; N, 5.49. Found: C,
79.95; H, 8.28; N, 5.27.
Supplementary data
11. Preparation of anti-( )-3-amino-2,3-dimethyl-1,3-diphenylpropan-1-ol (2). To
a solution of 6 (2.69 g, 10 mmol) in methanol (35 mL) was added concentrated
HCl (1 mL) and the resulting mixture was hydrogenated (60 psi) at room
temperature in the presence of 10% Pd/C (350 mg) for 10 h. The catalyst was
removed by filtration and methanol was evaporated under rotavapour. The
crude salt obtained was dissolved in water, washed with diethyl ether to
remove neutral impurities, and the aqueous solution was basified with
ammonia to obtain the aminoalcohol (2.05 g, 80% yield) as a 79:21 mixture
of anti:syn. This mixture was converted into the corresponding succinate salt,
which was crystallized using ethanol/ethyl acetate (1:9). The salt was treated
as described earlier6 to obtain the desired anti aminoalcohol 2 as a white solid
(1.22 g, 48%), >99% de (by 1H NMR), mp 137–139 °C. Rf (40% MeOH/EtOAc)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.011.
References and notes
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