An enantioselective synthesis of (+)-hygroline and (+)-pseudohygroline via Keck allylation and CBS reduction

Article abstract of DOI:10.1016/j.tetlet.2015.06.012

Abstract An enantioselective synthesis of (+)-hygroline and (+)-pseudohygroline has been achieved in high optical purity (98% ee) from readily available 1,4-butanediol. The synthesis strategy employs a Keck allylation, CBS reduction, and Wacker oxidation.

Full text of DOI:10.1016/j.tetlet.2015.06.012

Accepted Manuscript
An enantioselective synthesis of (+)-hygroline and (+)-pseudohygroline via
Keck allylation and CBS reduction
Shubhangi P. Bhoite, Rohit B. Kamble, Gurunath M. Suryavanshi
PII:
S0040-4039(15)00993-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.012
TETL 46404
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 May 2015
1 June 2015
3 June 2015
Please cite this article as: Bhoite, S.P., Kamble, R.B., Suryavanshi, G.M., An enantioselective synthesis of (+)-
hygroline and (+)-pseudohygroline via Keck allylation and CBS reduction, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.06.012
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Graphical Abstract
An enantioselective synthesis of (+)-hygroline
and (+)-pseudohygroline via Keck allylation
and CBS reduction
Leave this area blank for abstract info.
Shubhangi P. Bhoite, Rohit B. Kamble and Gurunath M. Suryavanshi

1
Tetrahedron Letters
journal homepage: www.els evier.com
An enantioselective synthesis of (+)-hygroline and (+)-pseudohygroline via Keck
allylation and CBS reduction
a
Shubhangi P. Bhoite , Rohit B. Kamble and Gurunath M. Suryavanshi ∗
a
a,
a
Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra, India-411008.
ARTICLE INFO
ABSTRACT
Article history:
Received
An enantioselective synthesis of (+)-hygroline and (+)-pseudohygroline have been achieved in
high optical purity (98% ee) from readily available 1,4-butanediol. The synthesis strategy
employs a Keck allylation, CBS reduction and Wacker oxidation.
Received in revised form
Accepted
2
009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Pyrrolidines
Keck allylation
CBS reduction
Wacker oxidation
Introduction
its potent biological activity and fascinating structural features,
several synthesis of (+)-hygroline (1) and (+)-pseudohygroline
Nitrogen containing heterocycles is extensively studied
systems present in natural products and pharmaceutical
intermediates. The pyrrolidine ring is widespread in alkaloid
natural products and is a common subunit found in several drugs
and therapeutic lead compounds. Selected examples include (+)-
hygroline (1) and (+)-pseudohygroline (2) Figure 1.
5
2) have been reported and the majority of these syntheses is
(
initiated from chiral pool resources and its asymmetric synthesis
6
7
is rather rare, involving multistep synthesis. As a part of our
research program aimed at enantioselective synthesis of
1
8
biologically active natural products herein, we report an
enantioselective synthesis of (+)-hygroline (1) and (+)-
pseudohygroline (2) employing Keck allylation and CBS
reductions.
Results and Discussion
Our approach to synthesis of (+)-hygroline (1) commenced
with the preparation of alcohol 8 in 88% yield by the mono
benzyl protection of 1,4-butanediol 7 with benzyl bromide and
sodium hydride in dimethyl formamide (Scheme 1). The terminal
hydroxyl group of alcohol 8 was oxidized using 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) and bis(acetoxy)iodo-
2 2
benzene (BAIB) in CH Cl gave rise to corresponding aldehyde 9
in 93% yield. The aldehyde 9 was then subjected to Keck
9
i
allylation protocol [(R)-BINOL, Ti(O- Pr)
tributyl tin, dichloromethane (CH Cl ), -20 °C] which furnishes
homoallylic alcohol 10 in 86% yield and 98% ee, [α]
(c1, CHCl ). The homo allylic alcohol 10 was converted into its
mesylate 11 using MsCl and NEt in dichloromethane (CH Cl ),
which was further subjected to S 2 displacement with sodium
azide (NaN ) in DMF afforded azide 12. Deprotection of benzyl
ether in 12 with DDQ afforded alcohol 13 which was readily
4
, (5 mol%), allyl
Figure 1. Structures of 2-substituted pyrrolidine
2
2
2
5
D
= -7.4
Often 2-substituted pyrrolidines containing 1,3-amino alcohol
2
units display a wide spectrum of biological activities. Hygroline
and pseudohygroline were isolated from plant extract of Carallia
3
3
2
2
3
brachiata, Erythroxylon coca and Schizanthus hookeri and both
N
4
are biosynthetic precursors for the tropane skeleton. Considering
3
—
——
∗
Corresponding author. Tel.: +91-20-2590-2396; fax: +91-20-2590-2676; e-mail: gm.suryavanshi@ncl.res.in

2
Tetrahedron
converted into its mesylate 14. We next sought to prepared
pyrrolidine core unit for which the azide functionality in 14 was
reduced using Staudinger condition (PPh , THF/H O) to give free
Conclusion
In conclusion a straightforward enantioselective synthesis of
+)-hygroline (1) and (+)-pseudohygroline (2) has been achieved
with good overall yield and high optical purity. The key reaction
employed was asymmetric Keck allylation of aldehyde and
diastereoselective CBS reduction of methyl ketone to introduce
chirality. The synthetic strategy described here has significant
potential for the synthesis of variety of other biologically
important pyrrolidine alkaloids.
3
2
(
amine, which underwent subsequent intramolecular cyclization,
Acknowledgments
We thank SERB-DST (GAP302326), New Delhi for funds.
The authors are also thankful to Dr. V. V. Ranade, Chair,
Chemical Engineering and Process Development Division for
his constant encouragement and support.
References and notes
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3
.
Scheme 1. Reaction conditions: (i) BnBr, NaH, DMF, 0 °C, 2
1
h, 88%; (ii) TEMPO, BAIB, CH
BINOL, Ti(OiPr) , allyltributyltin, 4 A° MS, CH
4 h, 86%; (iv) MsCl, TEA, CH Cl2, 0 ºC, 1 h; (v) NaN
0 °C, 4 h, 74% (over two steps); (vi) DDQ, H O, CH
2
Cl
2
, 0 °C, 1 h, 93%; (iii) (R)-
Cl , -20 °C,
, DMF,
Cl , 25
4
2
2
1
2
8
2
3
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2
2
2
5
.
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°
C, 28 h, 95%; (vii) MsCl, TEA, 0 °C, 1 h, 99.5%; (viii) PPh
THF, H O, 45 °C, 24 h, Cbz-Cl, TEA, CH Cl , 8 h, 63%; (ix)
PdCl (10 mol%), CuCl (10 mol%), DMF:H O, O , 25 °C, 3 h,
6%; (x) (R)-CBS Catalyst, BH .THF, THF, 25 °C, 30 min,
5%; (xi) LiAlH , THF, 60 °C, 8 h, 87%; (xii) (S)-CBS
3
,
1
1
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2
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2
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7
7
3
4
Catalyst, BH3.THF, THF, 25 °C, 30 min, 75%; (xiii) LiAlH
THF, 60 °C, 8 h, 88.8%.
4
,
to give pyrrolidine core unit. Followed by in situ Cbz-protection
of the corresponding cyclic amine to furnishes carbamate
1
0
derivative 15. Wacker oxidation [PdCl
mol%), DMF:H O] of terminal alkene 15 afforded methyl ketone
which was further reduced diastereoselectively using (R)-
2
(5 mol%), CuCl (10
7
8, 11066; (k) Bheemreddy, A.; Reddy, U.V.S.; Reddy, B.V.S.;
2
Reddy, C.S.; Nat. Prod. Comm 2014, 9(5), 633; (l) Lee, J.; Lee,
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1
6
1
1
8
56.
3
CBS reduction [CBS (10 mol%), BH .THF (0.6 mol%), THF]
6
.
(a) Shono, T.; Matsumura, Y.; Tsubata, K.; Uchida, K. J. Org.
Chem. 1986, 51, 2590; (b) Bhat, C.; Tilve, S.G. Tetrahedron
to give secondary alcohol 17 in 75% yield and diastereomeric
excess > 23:1. Finally the conversion of N-Cbz group in 17 to N-
2
013, 69, 6129.
4
methyl group using LiAlH to give a target molecule (+)-
7
8
.
.
Yadav, J. S.; Narasimhulu, G.; Mallikarjuna Reddy, N.; Subba
Reddy, B. V. Tetrahedron Lett. 2010, 51, 1574.
5c
hygroline (1) in 87% yield with overall yield of 15.4% and high
diastereomeric excess in eleven steps (Scheme 1). Similarly
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1
1
distereoselective reduction of ketone 16 with (S)-CBS catalyst
to give alcohol 18 in 75% yield and N-Cbz group of 18 was
converted to N-methyl using LiAlH to afford (+)-
pseudohygroline (2) in 88.8% yield with overall yield 15.7%
4
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5c
1
13
(
(
compound 1 and 2 were in complete agreement with the values
Scheme 1). The H and C NMR and other spectral data of
1
5
j
reported in literature

3
1
1
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Supplementary Material
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