Chemoenzymatic total synthesis of four stereoisomers of centrolobine

Article abstract of DOI:10.1016/j.tetlet.2015.06.084

Abstract Four stereoisomers of centrolobine, (3R,7S)-(-)-centrolobine (1), (3S,7S)-(-)-epi-centrolobine (2), (3S,7R)-(+)-centrolobine (3), and (3R,7R)-(+)-epi-centrolobine (4) have been achieved in an efficient manner in 24-28% overall yield over 9-10 linear steps starting from cheap and commercially available 4-methoxybenzaldehyde following chemoenzymatic protocol. The key features of this synthetic protocol are enzymatic resolution, cross-metathesis (CM), and our own developed tandem isomerization followed by C-O and C-C bond formation reaction.

Full text of DOI:10.1016/j.tetlet.2015.06.084

Tetrahedron Letters 56 (2015) 4916–4918
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemoenzymatic total synthesis of four stereoisomers
of centrolobine
Bollipalli Nagarjuna b, Barla Thirupathi a, Chunduri Venkata Rao b, Debendra K. Mohapatra a,
⇑
a Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 5000 007, India
b Chemistry Department, Sri Venkateswara University, Tirupati, Andhra Pradesh 517502, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Four stereoisomers of centrolobine, (3R,7S)-(À)-centrolobine (1), (3S,7S)-(À)-epi-centrolobine (2),
(3S,7R)-(+)-centrolobine (3), and (3R,7R)-(+)-epi-centrolobine (4) have been achieved in an efficient
manner in 24–28% overall yield over 9–10 linear steps starting from cheap and commercially available
4-methoxybenzaldehyde following chemoenzymatic protocol. The key features of this synthetic protocol
are enzymatic resolution, cross-metathesis (CM), and our own developed tandem isomerization followed
by C–O and C–C bond formation reaction.
Received 22 May 2015
Revised 18 June 2015
Accepted 26 June 2015
Available online 30 June 2015
Keywords:
Centrolobine
Ó 2015 Elsevier Ltd. All rights reserved.
Tetrahydropyran ring
Enzymatic resolution
Cross-metathesis
Tandem isomerization followed by C–O and
C–C bond formation reaction
Centrolobine is a naturally occurring heterocyclic compound,
bearing a six-membered tetrahydropyran ring system usually with
a syn stereochemistry in the alkyl substituents on both carbons
flanking the ether linkage, was (3S,7R)-(+)-centrolobine ((3S,7R)-3)
obtained from the closely related species Centrolobine robustum1
whereas its enantiomer the laevorotatory (3R,7S)-(À)-centrolobine
((3R,7S)-1) isolated from the heartwood of Centrolobium tomento-
sum, mostly found in the amazon rain forest and again from the
stem of Brosimum potabile in 2000.2 It has been shown to be
active against Leishmania amazonensis promastigotes; a parasite
associated with leishmaniasis, a major health problem in Brazil.3
Leishmania is a parasitic disease transmitted by the sand fly, this
parasite attacks the spongiform organs of the body, especially the
liver and spleen. Centrolobines have also been found to exhibit
anti-inflammatory properties.3a,b Although the basic structure
was elucidated in 1964 by total synthesis of the racemic methyl
ether,1a,b its absolute configuration was established by Solladié
and Carreño in 2002 by an enantioselective total syntheis.4 The
excellent bioactivities and relatively simple chemical structure
have attracted considerable attention and several research groups
have accomplished the total synthesis of centrolobine.5,6 In 2009,
Hölter and Schmidt only described the total synthesis of all
stereoisomers of the natural product by using enantioselective
allylation with enantiomerically pure allylsilanes, a tandem ring-
closing metathesis-isomerization reactions.5rAs
part of an
a
ongoing program in exploring tandem isomerization followed by
C–O and C–C bond formation reaction protocol for the synthesis
of pyran ring-containing complex natural products such as
bicyclic core of penostatin B,7a (+)-sorangicin A,7h polyrachi-
tides,7f,b the macrolactone core of leucascandrolide A,7g Z-isomers
of the proposed and revised aspergillide B7d and formal total
synthesis of cladosporin,7e herein, we demonstrated the use of
our above novel strategy for the total synthesis of all possible iso-
mers of centrolobine (see Fig. 1).
According to our retrosynthetic analysis of (3R,7S)-(À)-
centrolobine ((3R,7S)-1) and (3S,7S)-(À)-epi-centrolobine ((3S,7S)-2)
as shown in Scheme 1, both the compounds could be achieved
from ketone intermediates 5, which in turn could be prepared from
trans-2,6-disubstituted dihydropyran 6. Dihydropyran 6 in turn
could be obtained by domino isomerization followed by C–O and
C–C bond formation reaction of d-hydroxy
a,b-unsaturated
aldehyde 7 which could be prepared from homoallyl alcohol 8
by following cross-metathesis reaction. Alcohol 8 could be synthe-
sized from 4-methoxy benzaldehyde (9) through Grignard reaction
and enzymatic resolution of resulting racemic alcohol.
The synthesis of the crucial intermediate 6 was started from
racemic alcohol 10 which was subjected for enzymatic resolution
with Amano lipase PS-C II8 to obtain homoallylic alcohol 8 with
ꢀ99% ee (by HPLC) and acetate derivative 11. Following a modified
Mosher ester method,9 the stereogenic center in compound 15
⇑
Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512.
E-mail address: mohapatra@iict.res.in (D.K. Mohapatra).
http://dx.doi.org/10.1016/j.tetlet.2015.06.084
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

B. Nagarjuna et al. / Tetrahedron Letters 56 (2015) 4916–4918
4917
OH
PS-C(`Amano` II)
enzyme, 4 days
MgBr
CHO
O
O
CuI, THF, -10 o
3 h, 92%
C
H
H
H
H
MTBE, 92%
MeO
MeO
MeO
MeO
OH
MeO
MeO
OH
OH
9
10
OH
1
)
(3R,7S)-(-)-Centrolobine (
2
(3S,7S)-(-)-epi-Centrolobine ( )
OAc
OH
Acrolein
Hoveda-Grubbs
+
12 h, rt, 84%
MeO
O
O
11
8
H
H
seperated by column
chromatography
H
H
MeO
(3R,7R)-(+)-epi-Cetnrolobine (4)
OH
(3S,7R)-(+)-Centrolobine (3)
O
H
SiMe3
Figure 1. Structures of four stereoisomers of centrolobine.
O
I2, 45 min, 91%
H
H
MeO
6
MeO
7
Scheme 2. Synthesis of dihydropyran 6.
O
H
H
2
MeO
MeO
OH
NaIO4, OsO4
2,6-lutidine
5
O
6
O
4
H
H
O
1,4-dioxane–H2O (3:1)
0 °C, 3 h, 87%
H
H
1
3
7
O
MeO
2
MeO
O
O
12
6
H
H
H
H
1
5
OH
MeO
OH
OH
1. 4-OTHPPhMgBr
THF, 0 oC-rt
DMP, CH2Cl2
O
OH
7
O
H
H
0 oC-rt, 4 h, 90%
2. 1N HCl
MeO
O
OH
0 oC-rt
H
O
13
H
H
79% over two steps
6
MeO
MeO
MeO
MeO
H2, PtO2
MeOH
O
OH
CHO
O
H
O
rt, 12 h
89%
H
H
H
MeO
OH
MeO
OH
14
5
8
9
Scheme 3. Synthesis of ketone 5.
Scheme 1. Retrosynthetic analysis of centrolobine.
following a reported protocol5z resulted in the formation of
((3R,7S)-1). Similarly, palladium-
catalyzed reduction of ketone 5 without epimerization furnished
(3S,7S)-(À)-epi-centrolobine (2) (Scheme 4). The spectral and
analytical data for the synthetic compound (3R,7S)-(À)-
centrolobine (1) and (3S,7S)-(À)-epi-centrolobine (2) were in
good agreement with the data reported.5r
After achieving the synthesis of (3R,7S)-(À)-centrolobine (1)
and (3S,7S)-(À)-epi-centrolobine (2), we next focused our research
for the synthesis of other two isomers starting from acetylated
compound 10 obtained through enzymatic resolution.
The acetyl compound 10 was easily saponified by K2CO3 in
methanol to afford homoallyl alcohol 15 in 88% yield, which
became the starting precursor for the synthesis of (3S,7R)-(+)-cen-
trolobine (3) and (3R,7R)-(+)-epi-centrolobine (4). Compound 21
bearing the secondary hydroxyl group was assigned. After having
enantiomerically pure alcohol compound 8, it was then subjected
to cross-metathesis with acrolein in presence of catalytic amount
a,b-unsaturated alde-
hyde 7 in 84% yield. Now, the stage is set to conduct our own
(3R,7S)-(À)-centrolobine
of Hoveyda–Grubbs10 to afford d-hydroxy
developed tandem isomerization followed by C–O and C–C bond
formation reaction.7f Accordingly, d-hydroxy
a,b-unsaturated
aldehyde 7 was treated with allyltrimethylsilane and catalytic
amount (10 mol %) of iodine in THF to furnish trans-2,6-
disubstituted dihydropyran compound 6 in 91% yield as a single
isomer (Scheme 2).
The terminal double bond present in compound 6 was con-
verted to aldehyde via Jin’s one-step dihydroxylation–oxidation
sequence to produce aldehyde 12 in 87% yield (over two steps).11
Aldehyde 12 was subjected to Grignard reaction with THP-pro-
tected 4-hydroxyphenylmagnesium bromide in THF to obtain sec-
ondary alcohol as a 1:1 diastereomeric mixture. An acidic workup
of the reaction mixture resulted in THP deprotection of the pheno-
lic hydroxy function to afford alcohol 13 in 79% yield over two
steps. The secondary hydroxy group present in 13 was oxidized
by Dess–Martin periodinane (DMP),12 which smoothly produced
ketone 14 in 90% yield (Scheme 3).
Compound 14 was then subjected to catalytic hydrogenation
with platinum(IV) oxide to produce compound 5 in 89% yield. At
this stage, we thought of epimerizing trans-pyran to cis-pyran so
that it will produce the natural product (3R,7S)-(À)-centrolobine
((3R,7S)-1). Compound 5 was then subjected to epimerization in
the presence of benzoic acid in CHCl3 under Keinan’s conditions,13
to obtain the cis product in 94% yield and the resulting epimerized
product on treatment with Pd/C under hydrogen atmosphere
O
O
5
H
H
MeO
OH
Pd/C, H2, HCl
EtOH/EtOAc/H2O
(4:1:1), 10 h, 71%
2. Pd/C, H2, HCl
EtOH/EtOAc/H2O
(4:1:1), 10 h, 73%
1. PhCO2H, CHCl3
rt., 2 days
94%
O
O
H
H
H
H
MeO
OH
MeO
OH
1
)
(3R,7S)-Cetrolobine (
2
(3S,7S)-(-)-epi-Centrolobine ( )
Scheme 4. Synthesis of (3R,7S)-(À)-centrolobine (1) and (3S,7S)-(À)-epi-cen-
trolobine (2).

4918
B. Nagarjuna et al. / Tetrahedron Letters 56 (2015) 4916–4918
OH
OAc
Acknowledgments
K2CO3, MeOH
0
oC-rt, 4 h
88%
B.N. and B.T. thank the University Grants Commission (UGC),
MeO
MeO
New Delhi, India for financial assistance in the form of fellowships.
D.K.M. thanks the CSIR, New Delhi, India, for financial support as
part of XII Five Year plan programme under title ORIGIN (CSC-0108).
11
15
OH
O
SiMe3
I2, 45 min, 92%
Acrolein
12 h, rt, 86%
H
16
MeO
Supplementary data
NaIO4, OsO4
2,6-lutidine
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.06.084.
O
O
H
H
H
H
1,4-dioxane–H2O (3:1)
0 °C, 3 h, 86%
17
18
O
MeO
MeO
References and notes
OH
1. 4-OTHPPhMgBr
THF, 0 oC-rt
DMP, CH2Cl2
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O
0 oC-rt, 4 h, 91%
2. 1N HCl
H
H
0
oC-rt
19
MeO
OH
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O
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21
20
MeO
OH
MeO
OH
87%
Scheme 5. Synthesis of ketone 21.
O
O
H
H
21
MeO
OH
Pd/C, H2, HCl
EtOH/EtOAc/H2O
(4:1:1), 10 h, 70%
2. Pd/C, H2, HCl
EtOH/EtOAc/H2O
(4:1:1), 10 h, 72%
1. PhCO2H, CHCl3
rt, 2 days, 95%
O
O
H
H
H
H
MeO
OH
MeO
OH
(3S,7R)-(+)-Centrolobine (3)
(3R,7R)-(+)-epi-Cetnrolobine (4)
Scheme 6. Synthesis of (3S,7R)-(+)-centrolobine (3) and (3R,7R)-(+)-epi-cen-
trolobine (4).
was obtained starting from homoallyl alcohol 15 through the same
sequence of reactions as shown in Schemes 2 and 3 in good overall
yield (Scheme 5).
As earlier mentioned, compound 21 was then subjected to
epimerization in the presence of benzoic acid in CHCl3 under
Keinan’s conditions,13 to obtain the epimerized product in 95%
yield followed by palladium-catalyzed5z reduction of ketone,
resulted in the formation of (3S,7R)-(+)-centrolobine (3).
Similarly, palladium-catalyzed5z reduction of ketone 21 directly
afforded (3R,7R)-(+)-epi-centrolobine (4) (Scheme 6). The
synthesized compounds (3S,7R)-(+)-centrolobine (3) and (3R,7R)-
(+)-epi-centrolobine (4) were characterized by their spectral and
analytical data and were in good agreement with the reported
values.5r
In summary, we have accomplished the synthesis of four
stereoisomers of centrolobine following chemoenzymatic
resolution, domino isomerization followed by C–O and C–C bond
formation reaction, cross-metathesis as key reactions, starting
from 4-methoxy benzaldehyde. Our protocol is highly flexible
and with good overall yield for the synthesis of four stereoisomers
of centrolobine compared to previous reports.
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