A concise synthesis of (+)-deoxoprosophylline via Co(III)(salen)-catalyzed two stereocentered HKR of racemic azido epoxides

Article abstract of DOI:10.1016/j.tetlet.2012.04.067

An efficient synthesis of (+)-deoxoprosophylline has been achieved in high optical purity (99% ee) from readily available cis-2-butene-1,4-diol. The strategy employs Co-catalyzed Hydrolytic Kinetic Resolution (HKR) of two stereocentered racemic azido epoxides and diastereoselective intramolecular reductive cyclization as key reactions.

Full text of DOI:10.1016/j.tetlet.2012.04.067

Tetrahedron Letters 53 (2012) 3213–3215
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A concise synthesis of (+)-deoxoprosophylline via Co(III)(salen)-catalyzed two
stereocentered HKR of racemic azido epoxides
⇑
Dattatray A. Devalankar, Arumugam Sudalai
Chemical Engineering & Process Development Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of (+)-deoxoprosophylline has been achieved in high optical purity (99% ee) from
readily available cis-2-butene-1,4-diol. The strategy employs Co-catalyzed Hydrolytic Kinetic Resolution
(HKR) of two stereocentered racemic azido epoxides and diastereoselective intramolecular reductive
cyclization as key reactions.
Received 14 March 2012
Revised 1 April 2012
Accepted 2 April 2012
Available online 21 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Azido epoxide
Hydrolytic kinetic resolution
Piperidine
Wittig olefination
Alkaloids with multifunctionalized piperidine rings are found
abundantly in nature.1 Prosopis alkaloids containing 2,6-disubsti-
tuted piperidin-3-ols have been isolated from the leaves of an Afri-
can plant, Prosopis africana Taub.2 Typical representatives include
prosophylline (1), deoxoprosophylline (2), and Cassia alkaloids
such as (+)-cassine (3) and carpamic acid (4) (Fig. 1). These natu-
rally occurring piperidine alkaloids and their derivatives are
medicinally important as they possess anesthetic, analgesic, and
antibiotic properties.2,3 Structurally, these compounds possess a
polar head group essentially required for the inhibition of various
glycosidases and lipophilic aliphatic tail that serves to facilitate
transfer across lipid membranes.4,5 These interesting structural
features and therapeutic potential make them attractive synthetic
targets. Although many elegant syntheses of (+)-deoxoprosophyl-
line 2 have been reported,6 several of them suffer from certain lim-
itations such as the use of chiral building blocks, exotic reagents,
involvement of longer reaction sequences, low overall yields, etc.
We have recently reported a flexible method that employs co-Cat-
alyzed Hydrolytic Kinetic Resolution (HKR) of racemic anti-azido
epoxides with two stereocenters to generate the corresponding
diols and epoxides in high optical purity (97–99% ee) in a single
step.7a In this communication, we wish to report a short enantiose-
lective synthesis of (+)-deoxoprosophylline (2) by employing two
stereocentered HKR of racemic azido epoxides (Schemes 1 and 2).
Firstly, our synthesis of (+)-deoxoprosophylline (2) commenced
with commercially available cis-2-butene-1,4-diol (5), which on
treatment with NBS in the presence of sodium azide, gave bromo
azide 6 in 89% yield. The bromo azide 6 was readily transformed
into racemic anti-azido epoxide (84% yield) under basic
7
conditions (NaOH, dry THF, 0 °C). The protection of primary hydro-
xyl group in azido epoxide 7 as benzyl ether (BnBr, NaH, DMF,
ꢀ40 °C) produced a protected racemic azido epoxide 8 in 94% yield.
Compound 8 was then subjected to HKR with (S,S)-salen Co(OAc)
complex7a,b (0.5 mol %) and H2O (0.49 equiv), which produced the
corresponding diol 910 (48%, 99% ee) and chiral epoxide 109,11
(50%, 97% ee) in high optical purity (Scheme 1). The diol 9 was,
however, readily separated from epoxide 10 by a simple flash col-
umn chromatographic purification over silica gel.
We then protected both the free hydroxyl groups in diol 9 as its
disilyl ether derivative 11 (TBSCl, imid., DMF), followed by selective
deprotection (CSA, MeOH, 0 °C) of primary silyl ether that afforded
monosilyl ether 12 in 92% yield. Further, the primary hydroxyl
group in 12 was oxidized using IBX to produce the corresponding
crude aldehyde 13 in 91% yield. The crude aldehyde 13 was then
subjected to Wittig reaction [(EtO)2POCH2COC12H25, prepared from
diethyl-2-oxopropylphosphonate and 1-iodoundecane, i-Pr2NEt,
MeCN, 0 °C]8 to give the corresponding (E)-unsaturated keto azide
14 in 87% yield with exclusive trans selectivity (J = 15.9 Hz). Its char-
acteristic IR frequencies (1717 and 2101 cmꢀ1) due to ketone and
azide functions respectively establish its structure. When, we at-
tempted a one pot catalytic hydrogenation of 14 [1 N HCl, MeOH,
Pd(OH)2, H2 (60 psig)] with the hope of obtaining (+)-deoxopro-
sophylline 2 (azide reduction, hydroxy deprotection, and reductive
cyclization; all occurring in a single step), complex mixtures of
products were obtained. Alternatively, we designed a new route,
wherein we first reduced azide functionality in 14 to amino group
using Staudinger conditions (PPh3, THF/H2O) followed by in situ
⇑
Corresponding author. Tel.: +91 20 25902565; fax: +91 20 25902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.067

3214
D. A. Devalankar, A. Sudalai / Tetrahedron Letters 53 (2012) 3213–3215
HO
HO
HO
R
( )
( )
N
H
N
H
8
n
X
O
3, (+)-cassine (n = 9, R = CH3)
1
2
, (+)-prosophylline (X = O)
4
, (+)-carpamic acid (n = 6, R = OH)
, (+)-deoxoprosophylline (X = H, H)
Figure 1. Some bioactive 2,6-cis-disubstituted piperidin-3-ols.
N3
OH
N3
b
a
RO
HO
OH
O
HO
Br
5
( )-6
( )-7, R = H
c
8
( )- , R = OBn
N3
N3
BnO
BnO
d
OH
O
OH
(-)- (2R, 3R)
(+)-10 (2S, 3S)
50% yield, 97% ee
9
48% yield, 99% ee
Scheme 1. Reagents and conditions: (a) NBS (1.2 equiv), NaN3 (2 equiv), CH3CN/H2O (3:1), 0 °C, 3 h, 89%; (b) NaOH, THF, 0 °C, 3 h, 84%; (c) BnBr, NaH, DMF, ꢀ40 °C, 2 h, 94%;
(d) (S,S)-CoIII(salen) (0.5 mol %), H2O (0.49 equiv), 0–25 °C, 12 h.
N3
N3
N3
H
BnO
b
c
BnO
BnO
OR'
OH
OTBS
O
OTBS
OR
13
9
, R, R' = H
12
a
11, R, R' = TBS
N3
O
NHCbz
OR
O
BnO
d
BnO
e
C12H25
C12H25
OTBS
14
15
, R = TBS
f
16, R = H
HO
RO
g
( )
N
H
8
17
, R = Bn
h
2, R = H
Scheme 2. Reagents and conditions: (a) TBSCl, imid., DMF, 24 h, 98% (b) CSA, MeOH, 0 °C, 5 h, 88%; (c) IBX, EtOAc, reflux, 3 h, 91%; (d) (EtO)2POCH2COC12H25, i-Pr2NEt, CH3CN,
25 °C, 12 h, 87%; (e) PPh3, THF/H2O, 25 °C, 12 h, then aq Na2CO3, CbzCl, 0–25 °C, 12 h, 88%; (f) TBAF, THF, 0 °C, 2 h, 95%; (g) Pd(OH)2, MeOH, H2 (60 psig), 24 h, 94%; (h) Na,
liquid NH3, THF, ꢀ78 °C, 1 h, 97%.
protection of the corresponding amine as its carbamate derivative
15. Deprotection of silyl group in 15 was achieved (TBAF, THF, 0–
25 °C) to give amino ketone 16 in 95% yield. Further, compound
16 was subjected to intramolecular diastereoselective cyclization
under catalytic hydrogenation conditions [Pd(OH)2, MeOH, H2
(60 psig)] that gave 17 as a single diastereomer, without affecting
the OBn group. Finally, O-debenzylation in 17 was carried out by
Birch reduction (Na, liquid NH3, THF, ꢀ78 °C), which furnished (+)

D. A. Devalankar, A. Sudalai / Tetrahedron Letters 53 (2012) 3213–3215
3215
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deoxoprosophylline 2 in quantitative yield. The spectral data and
optical rotation of the synthesized (+)-deoxoprosophylline 2 are in
good agreement with reported values.6,12
In conclusion, we have described a short and efficient enantio-
selective synthesis of (+)-deoxoprosophylline 2 with an overall
yield of 17.5% and high optical purity, that are achieved using
two-stereocentered Co-catalyzed HKR of racemic azido epoxides.
The other operationally simple reaction sequences include Wittig
reaction and diastereoselective intramolecular reductive cycliza-
tion. This strategy is expected to find wide scope for the synthesis
of other similar multifunctionalized piperidine alkaloids.
Acknowledgments
D.A.D. thanks the CSIR, New Delhi for the award of Senior
Research Fellowship. The authors are also thankful to Dr. V.V.
Ranade, Chairman, Chemical Engineering and Process Develop-
ment Division for his constant encouragement and support.
7. (a) Reddy, R. S.; Chouthaiwale, P. V.; Suryavanshi, G.; Chavan, V. B.; Sudalai, A.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
067.
10. Physical and spectral data for (2R,3R)-3-azido-4-(benzyloxy)butane-1,2-diol (9):
Colorless liquid; ½a D25
ꢁ
= ꢀ37.8 (c 1, CHCl3); IR: (CHCl3, cmꢀ1) 1271, 1453, 2099,
2870, 2929, 3384; 1H NMR (200 MHz, CDCl3): d 1.60 (br s, 1H), 2.81 (br s, 1H),
3.59–3.83 (m, 6H), 4.59 (s, 2H), 7.34 (m, 5H); 13C NMR (50 MHz, CDCl3): d
62.02, 63.37, 69.94, 71.36, 73.55, 127.67, 127.94, 128.50, 137.31; Anal. Calcd
for C11H15N3O3 requires C, 55.69; H, 6.37; N, 17.71; Found C, 55.70; H, 6.48; N,
17.65%; Optical purity: 99% ee determined by HPLC analysis (Chiral OD-H
column, n-hexane/2-propanol (90:10), 0.5 mL/min, 254 nm). Retention time:
tmajor = 21.25 and tminor = 24.82 min.
References and notes
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Piperidine Alkaloids: Chemistry and Pharmacology In Alkaloids: Chemical and
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11. Physical and spectral data for (S)-2-((S)-1-azido-2-(benzyloxy)ethyl)oxirane, (10):
Colorless liquid; ½a D25
ꢁ
= +29.3 (c 1, CHCl3) {lit.9 a 3D0
½ ꢁ = -30.2 for its antipode (c 1,
CHCl3)}; IR: (CHCl3, cmꢀ1) 1264, 1453, 2102, 2864; 1H NMR (200 MHz, CDCl3):
d 2.74–2.83 (m, 2H), 3.05–3.11 (m, 1H), 3.44–3.52 (m, 1H), 3.57–3.73 (m, 2H),
4.59 (s, 2H), 7.28–7.39 (m, 5H); 13C NMR (50 MHz, CDCl3): d 45.03, 50.53,
61.70, 69.97, 73.46, 127.57, 127.83, 128.44, 137.41; Anal. Calcd for C11H13N3O2
requires C, 60.26; H, 5.98; N, 19.17; Found C, 60.24; H, 5.90; N, 19.20%; Optical
purity: 99% ee determined by HPLC analysis (Chiral OD-H column, n-hexane/2-
propanol (95:5), 0.5 mL/min, 254 nm) Retention time: tminor = 13.51 and
tmajor = 16.20 min.
12. Physical and spectral data for (+)-deoxoprosophylline (2):Colorless solid, mp
85 °C {lit.6b mp 85–86 °C}; ½a 2D5
ꢁ
+13.5 (c 1, CHCl3) {lit.6b a 2D4
½ ꢁ +13.5 (c 0.3,
CHCl3)}; IR: (CHCl3) 1059, 1467, 2851, 2922, 3169, 3266; 1H NMR (200 MHz,
CDCl3): d 0.88 (t, J = 6.8 Hz, 3H), 1.26 (br s, 24H), 1.71–1.80 (m, 1H), 1.98–2.06
(m, 1H), 2.43–2.60 (m, 2H), 2.77–3.20 (br, 3H), 3.31–3.51 (t, J = 10.6 Hz, 1H),
3.68 (dd, J = 10.9, 5 Hz, 1H), 3.81 (dd, J = 10.9, 4.3 Hz, 1H); 13C NMR (50 MHz,
CDCl3): d 14.16, 22.71, 26.33, 29.40, 29.70, 29.89, 30.87, 31.95, 33.78, 36.44,
56.15, 63.37, 63.46, 69.30; Anal. Calcd for C18H37NO2 requires C, 72.19; H,
12.45, N, 4.68%; Found C, 72.26, H, 12.36, N, 4.70%.
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