Stereoselective synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol

Article abstract of DOI:10.1016/j.tetlet.2011.05.102

A highly stereoselective total synthesis of (+)-(8R,8aR)-perhydro-8- indolizidinol is described. Key steps involved in this synthesis are diastereoselective zinc allylation, azido-olefin cyclization and reductive amination followed by cyclization which effectively constructed the indolizidine ring. This contributes a unique approach to the synthesis of indolizidine alkaloids that offers the advantages of brevity and relatively high overall yields.

Full text of DOI:10.1016/j.tetlet.2011.05.102

Tetrahedron Letters 52 (2011) 4382–4384
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Tetrahedron Letters
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Stereoselective synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol
⇑
R. Sateesh Chandra Kumar, G. Venkateswar Reddy, K. Suresh Babu, J. Madhusudana Rao
Natural Products Laboratory, Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective total synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol is described. Key steps
involved in this synthesis are diastereoselective zinc allylation, azido-olefin cyclization and reductive
amination followed by cyclization which effectively constructed the indolizidine ring. This contributes
a unique approach to the synthesis of indolizidine alkaloids that offers the advantages of brevity and rel-
atively high overall yields.
Received 16 April 2011
Revised 18 May 2011
Accepted 22 May 2011
Available online 30 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indolizidine alkaloids
(+)-(8R,8aR)-Perhydro-8-indolizidinol
Azido-olefin cyclization
Nitrogen-containing heterocycles are widespread in medicinal
chemistry due to the fact that many natural and synthetic biolog-
ically active compounds share this common architectural feature.1
Polyhydroxy indolizidine frame work (Fig. 1) represents one of the
major classes of alkaloids,2 which exhibits intriguing molecular
structures featuring a N-bridgehead bicyclic ring system. These
systems have received much attention in recent years. Many of
the synthetic and natural indolizidines have displayed important
biological activities which can find a variety of applications in
the field of pharmaceuticals and material science.3e–h The struc-
tural diversity and pharmacological activities of these alkaloids,
as well as the limited amounts available from natural sources have
stimulated considerable synthetic effort in this area.3i–r Discovery
and synthesis of new classes of heterocycles, especially if the syn-
thetic methodology is modular and reliable, are always a welcome
addition as they offer routes to new substrates which may possess
advantageous therapeutic activities or chemical reactivity.3a–d
In continuation of our ongoing studies on the synthesis of bio-
active natural products,4 we became interested in various indolizi-
dine alkaloids.
In an earlier study from our laboratory, we had demonstrated
the versatility of allylation (Keck allylation and Marouka allylation)
and Grubb’s cross metathesis reactions for the synthesis of the
putative piperidine alkaloids.4a,c Our retro synthetic strategy for
the present synthesis relies on the azido-olefin cyclization, reduc-
tive amination followed by cyclization starting from the mannitol
diacetonide (Scheme 1).
As shown in Scheme 1, initial disconnection of 4 revealed frag-
ment 6, which could be subjected to reductive amination followed
by cyclization to realize the target molecule. The key step in this
synthesis would utilize one-pot intramolecular hydroboration–
cycloalkylation of the azido-olefin. The brevity of this analysis
along with the structural simplicity of the precursors makes this
route attractive for implementation.
The total synthesis based on the above mentioned plan was ini-
tiated with mannitol diacetonide (13) which can be readily pre-
pared from
D-mannitol. Compound 12 was synthesized from
mannitol diacetonide by following the literature procedure in an
overall yield of 73% in a three step sequence.6 Tosyl ester 12 was
In this Letter, we report a new approach for the stereoselective
synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol 4 as shown in
Scheme 1, which makes use of azido-olefin cyclization and reduc-
tive amination followed by cyclization as key steps in the overall
synthetic sequence. To date only one synthesis is reported on
hydroxyindolizidine 4, which features SmI2 mediated reductive
carbon–nitrogen cleavage reaction as a crucial step for the con-
struction of indolizine ring.5
OH
OH
OH
OH
HO
HO
OH
N
N
2
1
OH
OH
OH
N
N
3
4
⇑
Corresponding author. Tel.: +91 40 27193166; fax: +91 40 27160512.
E-mail address: janaswamy@iict.res.in (J.M. Rao).
Figure 1. Representative examples of indolizidine alkaloids.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.102

R. S. C. Kumar et al. / Tetrahedron Letters 52 (2011) 4382–4384
4383
OH
OH
OH
HO
O
O
N
CbzN
CbzN
N3
9
4
6
11
O
OH
O
O
O
O
O
OH
13
OTs
12
Scheme 1. Retro synthetic analysis of (+)-(8R,8aR)-perhydro-8-indolizidinol.
then converted into its corresponding azide 11 using standard con-
ditions (NaN3, DMF, 70 °C) with 70% yield.7
confirmed epoxide product 7. Treatment of epoxide 7 with allyl
magnesium bromide in the presence of CuI in THF at ꢀ40 °C affor-
ded secondary alcohol 6 in excellent yield. The presence of olefinic
signal at d 5.98–5.59 (m, 1H) confirmed hydroxy pyrrolidine com-
pound 6. Further, ozonolysis of hydroxy compound 6 was smoothly
carried out in dry DCM at ꢀ78 °C to obtain aldehyde (immediately
converted to hemiacetal) without further purification subjected to
reduction with NaBH4 to yield diol 5 in good yield. Diol 5 was con-
verted into monotosylated compound 5a using TsCl, Bu2SnO, DCM
and Et3N.10 Finally, reductive amination followed by cyclization of
compound 5a in hydrogenation conditions to afford hydroxy indo-
lizidine alkaloid 4 in excellent yield with properties consistent
with literature values5 (Scheme 3). All the intermediate com-
pounds were well characterized by IR, NMR and mass spectral
techniques.12
In conclusion, we have developed an efficient stereoselective
protocol for the preparation of hydroxyindolizidine alkaloid 4 by
employing diastereoselective allylation, azido-olefin cyclization
and reductive amination followed by cyclization. This general syn-
thetic route demonstrates its versatility towards the synthesis of
highly functionalized indolizidines and also paves the way for
the structurally related analogues. On the basis of the route de-
scribed herein, further work towards preparation of the library of
hydroxyindolizidine alkaloids for biological analysis is in progress
in our laboratory.
With the chiral azide 11 in hand, our efforts were directed to-
wards the construction of the pyrrolidine ring. For this purpose,
we have used an intramolecular hydroboration–cycloalkylation of
the azido-olefin 11, which has been used for the synthesis of pyr-
rolidinone and piperidine derivatives.8 Thus, chiral azide 11 was
treated with an excess of freshly prepared dicyclohexylborane fol-
lowed by hydrolysis with methanol to afford pyrrolidine interme-
diate 10. This one-pot sequence proceeded by hydroboration of the
double bond of 11 and subsequent formation of a boron nitrogen
bond between the azide and the trialkylborane to afford the cyclic
azide borane complex intermediate I. Finally, migration of the bor-
ane methylene group to N-1 of I proceeds with a ring contraction
and concomitant loss of nitrogen (Scheme 2). Reaction mixture
was diluted with ether and washed with 1 N HCl to yield corre-
sponding hydrochloride salt. Aqueous layer was basified with NaH-
CO3 and treated with Cbz-Cl to yield Cbz-protected amine 10 in
good yield.
Having successfully accomplished the synthesis of key interme-
diate 10, we then shifted our focus to investigate the general appli-
cability of this strategy for the synthesis title compound 4. Thus,
cyclohexylidine group in compound 10 was deprotected with
aqueous TFA to yield diol 9 in moderate yield (62%).9 Selective pro-
tection of diol 9 was achieved with TsCl, Bu2SnO, DCM and Et3N in
3 h to give 8 with 85% yield.10 The formation of monoprotected diol
8 was further determined by the 1H NMR spectrum which showed
the presence of a singlet at d 2.43. Subsequent conversion of 8 to
the corresponding epoxide with NaH, THF at 0 °C in 30 min yielded
7 (94%).11 Absence of tosyl group in 1H NMR and the presence of
epoxide protons (d 2.4–2.52, m, 1H and d 2.57–2.73, m, 1H)
Acknowledgements
The authors gratefully acknowledge keen interest shown by Dr.
J. S. Yadav, Director, IICT, Hyderabad. R.S.C.K and G.V.R. thank CSIR
and UGC, New Delhi for financial support.
OH
O
O
O
O
b
ref. 6
a
O
O
O
O
O
OH
O
CbzN
N3
11
OTs
12
10
13
O
N
N
N
O
B
I
Scheme 2. Synthesis of key intermediate 10. Reagents and conditions: (a) NaN3, DMF, 70 °C, 6 h, 70%; (b) dicyclohexylborane, quenching with methanol, 1 N HCl,
neutralization with NaHCO3, Cbz-Cl, 70%.

4384
R. S. C. Kumar et al. / Tetrahedron Letters 52 (2011) 4382–4384
OH
OH
O
O
c
HO
TsO
d
e
O
CbzN
CbzN
CbzN
CbzN
10
9
8
7
OH
OH
OH
f
g
HO
d
TsO
CbzN
CbzN
CbzN
6
5
5a
OH
h
N
4
Scheme 3. Synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol 4. Reagents and conditions: (c) 90% aqueous TFA, 62%; (d) TsCl, Bu2SnO, DCM, Et3N, 85%; (e) NaH, THF, 0 °C,
30 min, 94%; (f) AllylMgBr, CuI, THF, ꢀ40 °C, 87%; (g) (i) O3, DCM, ꢀ78 °C; (ii) NaBH4, MeOH, 0 °C to rt, 63% (over two steps); (h) Pd/C (10%), H2 (balloon), 70%.
4. (a) Kumar, R. S. C.; Reddy, G. V.; Shankaraiah, G.; Shankaraiah, K. S.; Rao, J. M.
Supplementary data
Tetrahedron Lett. 2010, 51, 1114; (b) Reddy, G. V.; Kumar, R. S. C.; Sreedhar, E.;
Babu, K. S.; Rao, J. M. Tetrahedron Lett. 2010, 51, 1723; (c) Kumar, R. S. C.;
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.102.
Sreedhar, E.; Reddy, G. V.; Babu, K. S.; Rao, J. M. Tetrahedron: Asymmetry 2009,
20, 1160; (d) Reddy, G. V.; Kumar, R. S. C.; Babu, K. S.; Rao, J. M. Tetrahedron Lett.
2009, 50, 4117; (e) Sreedhar, E.; Kumar, R. S. C.; Reddy, G. V.; Robinson, A.;
Babu, K. S.; Rao, J. M. Tetrahedron: Asymmetry 2009, 20, 440.
References and notes
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3. For a recent review article on indolizidine and quinolizidine alkaloids see: (a)
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12. Spectral data of selected compounds: Compound 11: Pale yellow oily liquid;
½
a 2D5
ꢁ
ꢀ10.4 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.88–5.71 (m, 1H),
5.23–5.06 (m, 2H), 4.13–4.02 (m, 1H), 4.02–3.92 (m, 1H), 3.78–3.69 (m, 1H), 3.2
(q, 1H, J = 6.4, 12.6 Hz), 2.29 (t, 2H, J = 6.7 Hz), 1.72–1.48 (m, 10H); 13C NMR
(75 MHz, CDCl3): d 133.9, 118.8, 110.6, 78.0, 66.2, 62.9, 36.5, 35.4, 25.7, 24.4,
24.3; FABMS: m/z 238 [M+1]+. Compound 10: Pale yellow oily liquid; ½a 2D5
ꢁ
+12
(c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.36–7.15 (m, 5H), 5.05 (m, 2H),
4.36–4.13 (m, 1H), 4.12–3.99 (m, 1H), 3.94–3.77 (m, 1H), 3.76–3.64 (m, 1H),
3.63–3.47 (m, 1H), 3.45–3.24 (m, 1H), 2.18–1.67 (m, 6H), 1.64–1.44 (m, 8H);
13C NMR (75 MHz, CDCl3): d 155.9, 141.6, 128.5, 127.4, 127.0, 109.4, 78.0, 65.8,
64.9, 57.9, 47.7, 36.1, 35.2, 25.5, 24.2, 24.1; FABMS: m/z 346 [M+1]+.
Compound 6: Pale yellow oily liquid; ½a D25
ꢁ
+58 (c 1, CHCl3); 1H NMR (300 MHz,
CDCl3): d 7.56–7.17 (m, 5H), 5.98–5.59 (m, 1H), 5.3–4.78 (m, 4H), 3.98–3.74 (m,
1H), 3.7–3.19 (m, 3H), 2.43–1.30 (m, 8H); 13C NMR (75 MHz, CDCl3): d 157.2,
138.5, 136.5, 128.3, 127.9, 114.7, 74.0, 67.1, 63.3, 47.0, 33.7, 29.6, 28.2, 24.1;
FABMS: m/z 290 [M+1]+.