Enantioselective synthesis of (1S,2R)-ephenamine

Article abstract of DOI:10.1016/j.tetasy.2016.02.013

A short and efficient enantioselective synthesis of (1S,2R)-ephenamine is described employing Sharpless asymmetric dihydroxylation and regioselective nucleophilic opening of a cyclic sulfite as the key steps.

Full text of DOI:10.1016/j.tetasy.2016.02.013

Tetrahedron: Asymmetry 27 (2016) 338–340
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of (1S,2R)-ephenamine
⇑
Ramandeep Kaur, Satyendra Kumar Pandey
School of Chemistry and Biochemistry, Thapar University, Patiala 147001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and efficient enantioselective synthesis of (1S,2R)-ephenamine is described employing Sharpless
asymmetric dihydroxylation and regioselective nucleophilic opening of a cyclic sulfite as the key steps.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 12 February 2016
Accepted 25 February 2016
Available online 22 March 2016
1. Introduction
(1S,2R)-Ephenamine 1, (1S,2S)-pseudoephenamine 2, and their
aminoalcohol analogues (1S,2R)-1,2-diphenyl-2-aminoethanol 3
and (1S,2S)-1,2-diphenyl-2-aminoethanol 4, respectively, have been
used as chiral auxiliaries in diastereoselective alkylation reactions,
providing easy access to enantiomerically pure alcohols, carboxylic
CH3
CH3
N
H
N
H
OH
OH
1
2
acids, a-methyl a
-amino acids,1 and Williams amino acid synthe-
(S,R)-ephenamine
(S,S)-pseudoephenamine
sis.2 The biological activity of ephenamine and pseudoephenamine
analogues significantly varies and depends on the substituents
present at the amino functional group. Therefore, the introduction
of N-substituents in ephenamine and pseudoephenamine analogues
is of great importance for the syntheses of pharmaceuticals and chi-
ral auxiliaries.3 Ephenamine has been used to resolve penicillin and
glycine derivatives,4 and also in a salt form of penicillin G, an antibi-
otic additive used to stimulate growth in livestock and poultry.5
Ephenamine-glutamine salts have been used to provide effective
amounts of glutamine for human consumption6 (Fig. 1).
NH2
NH2
OH
OH
3
4
(S,R)-1,2-diphenyl-2-
(S,S)-1,2-diphenyl-2-
aminoethanol
aminoethanol
Figure 1. Structures of 1,2-diphenyl-2-aminoalcohols.
Various methods for the syntheses of (1S,2R)-ephenamine 1 and
(1S,2R)-3 in their different stereoisomeric forms, mainly based on
chiral pool or auxiliary supported approaches, have been docu-
mented in the literature.7 In continuation of our research program
toward the asymmetric syntheses of bioactive compounds,8 the
Sharpless asymmetric dihydroxylation and cyclic sulfite methodol-
ogy were envisioned as powerful tools for synthetic functional
group transformations. Herein we report a new and short synthesis
of (1S,2R)-ephenamine by employing Sharpless asymmetric dihy-
droxylation as the source of chirality and cyclic sulfite methodol-
ogy as the key steps.
treatment with osmium tetraoxide and potassium ferricyanide as
the co-oxidant, in the presence of (DHQ)2PHAL under Sharpless
asymmetric dihydroxylation conditions9 furnished diol 6 in 97%
yield (99% ee) {[
(c 1.28, C2H5OH)]}.
a] [a]
25 = +95.5 (c 1.28, C2H5OH) [Lit.10 25 = +95.2
D D
With enantiomerically pure (1S,2S)-1,2-diphenylethane-1,2-
diol 6 in hand, we then subjected it to treatment with thionyl chlo-
ride in the presence of Et3N as the base to afford 7, which upon
subsequent treatment with NaN3 furnished azido alcohol deriva-
tive 8 in 89% yield. Concomitant one-pot reduction of the azide
group and Boc protection of the resulting amino alcohol were car-
ried out via hydrogenation in the presence of catalytic amounts of
Pd–C (20%) and Boc2O to afford Boc protected amino alcohol
derivative 9 in excellent yield. The Boc protected derivative via
2. Results and discussion
As outlined in Scheme 1, the synthesis of (1S,2R)-ephenamine 1
began with commercially available trans-stilbene 5, which upon
LAH reduction furnished (1S,2R)-ephenamine
1 as a white
⇑
25 = +32.7 (c 0.5, C2H5OH)
Corresponding author. Tel.: +91 175 239 3832; fax: +91 175 236 4498.
E-mail address: skpandey@thapar.edu (S.K. Pandey).
crystalline solid in 83% yield, {[
a]
D
http://dx.doi.org/10.1016/j.tetasy.2016.02.013
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.

R. Kaur, S. K. Pandey / Tetrahedron: Asymmetry 27 (2016) 338–340
339
[Lit.7b
[a]
25 = +32.8 (c 0.5, C2H5OH)]}. The physical and
4.69 (d, J = 6.88 Hz, 1H), 2.13 (s, 1H); 13C NMR (100 MHz, CDCl3)
d: 139.60, 135.90, 128.67, 128.62, 128.34, 128.25, 128.01, 127.00,
71.19; HRMS (ESI+) m/z calcd for C14H13N3ONa+ ([M+Na]+)
262.1000; Found 262.0951.
D
spectroscopic data were in full agreement with those reported in
the literature.
OH
4.4. tert-Butyl (1R,2S)-2-hydroxy-1,2-diphenylethylcarbamate 9
(b)
(a)
Spectral data of compound 9: White solid, {[
C2H5OH); IR (CH2Cl2) ;
: 3250, 1685, 1172, 738 cmÀ1 1H NMR
a]
25 = +114.1 (c 1,
D
OH
m
5
6
(400 MHz, CDCl3) d: 7.24–7.23 (m, 6H), 7.02–7.05 (m, 4H), 5.29
(s, 1H), 5.04 (s, 1H), 4.98 (br s, 1H), 2.71 (br s, 1H), 1.43 (s, 9H);
13C NMR (100 MHz, CDCl3) d: 155.65, 139.82, 128.09, 127.97,
127.73, 127.66, 127.59, 126.56, 79.94, 60.55, 29.67, 28.28; HRMS
(ESI+) m/z calcd for C19H23NO3Na+ ([M+Na]+) 336.1600; Found
336.1575.
O
S
OH
O
O
(c)
(d)
N3
8
7
4.5. (1S,2R)-2-(Methylamino)-1,2-diphenylethanol 1
Spectral data of compound 1: White crystalline solid, mp
OH
OH
134–136 °C, Lit.7b mp 135–136; {[ 25 = +32.7 (c 0.5, C2H5OH)
a]
D
[Lit.7b = +32.8 (c 0.5, C2H5OH)]; IR (CH2Cl2)
2812, 1441 cmÀ1 1H NMR (400 MHz, DMSO-d6) d: 7.11–7.17 (m,
m
: 3311, 3060, 3043,
(e)
;
NHBoc
HN
CH3
10H), 5.31(br s, 1H), 4.66 (d, J = 5.48 Hz, 1H), 3.62 (d, J = 5.48 Hz,
1H), 2.03 (s, 3H), 1.46 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d:
143.35, 140.79, 127.69, 127.04, 126.93, 76.07, 70.12, 34.08.
9
1
Scheme 1. Reagents and conditions: (a) K3Fe(CN)6, K2CO3, (DHQ)2PHAL, t-BuOH/
H2O 1:1 v/v, OsO4, CH3SO2NH2, 0 °C, 24 h, 97%; (b) SOCl2, Et3N, DCM, 0 °C, 30 min,
85%; (c) NaN3, DMF, 60 °C, 12 h, 89%; (d) H2/Pd–C (20%), (Boc)2O, EtOAc, rt, 12 h,
91%; (e) LiAlH4, THF, reflux, 6 h, 83%.
Acknowledgement
R.K. thanks the Department of Science and Technology (DST),
New Delhi, India for a fellowship. S.K.P. is thankful to DST, New
Delhi, for generous funding of the project (Grant No. SB/FT/CS-
178/2011).
3. Conclusion
In conclusion, a highly enantioselective and short synthesis of
(1S,2R)-ephenamine has been achieved by employing the Sharpless
asymmetric dihydroxylation and cyclic sulfite methodology as the
key steps. The merits of this synthetic approach are high enantios-
electivity with high yielding reaction steps. This synthetic strategy
has significant potential for further extension to other stereoiso-
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4.1. (1S,2S)-1,2-Diphenylethane-1,2-diol 6
Spectral data of compound 6: White solid; {[
C2H5OH) [Lit.9 [ 25 = +95.2 (c 1.28, C2H5OH)]}; IR (CH2Cl2)
m: 3380,
a]
25 = +95.5 (c 1.28,
D
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D
2935, 1510, 937 cmÀ1 1H NMR (400 MHz, CDCl3) d: 7.22–7.24 (m,
;
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4.2. (1S,2S)-1,2-Diphenylethane-1,2-diol cyclic sulfite 7
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C2H5OH)}; IR (CH2Cl2) ;
2935, 1362, 723 cmÀ1 1H NMR
a]
25 = +52.6 (c 1,
D
m
:
(400 MHz, CDCl3) d: 7.24–7.42 (m, 10H), 5.68 (d, J = 9.64 Hz, 1H),
5.22 (d, J = 10.08 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 133.15,
132.07, 129.63, 129.30, 128.93, 128.88, 127.51, 127.16, 91.19,
85.91; HRMS (ESI+) m/z calcd for C14H12O3SNa+ ([M+Na]+)
283.0400; Found 283.0403.
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