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Synthetic Studies towards Stachybotrin C

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Tumma Naresh at Wayne State University
Tumma Naresh
Maïwenn Jacolot at Royal College of Surgeons in Ireland
Maïwenn Jacolot
Mickaël Jean at Université de Rennes 1
Mickaël Jean
Chandrasekhar Srivari at Indian Institute of Chemical Technology
Chandrasekhar Srivari
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Abstract

The preparation of racemic des-hydroxy stachybotrin C is described. Different approaches have been studied. Observations made in the course of the synthesis show the efficiency of the inter-molecular cyclization between the diethyl acetal 19 and phenol 12 leading to the benzopyran moiety 17.
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LETTER ▌2919
letter
Synthetic Studies towards Stachybotrin C
Synthetic Studies towards Stachybotrin C
Naresh Tumma,a,b Maiwenn Jacolot,b Mickael Jean,b Srivari Chandrasekhar,*a Pierre van de Weghe*b
aDivision of Natural Product Chemistry, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500607, India
bUniversité de Rennes 1, UMR 6226, Institut des Sciences Chimiques de Rennes, Equipe PNSCM, UFR des Sciences Biologiques et Pharma-
ceutiques, 2 avenue du Prof Léon Bernard, 35043 Rennes Cedex, France
Fax +33(2)23234425; E-mail: pierre.van-de-weghe@univ-rennes1.fr
Received: 13.09.2012; Accepted after revision: 12.10.2012
Abstract: The preparation of racemic des-hydroxy stachybotrin C
is described. Different approaches have been studied. Observations
made in the course of the synthesis show the efficiency of the inter-
molecular cyclization between the diethyl acetal 19 and phenol 12
leading to the benzopyran moiety 17.
Key words: natural products, pyrano-isoindolinone, spiro com-
pounds, cyclization
Stachybotrin C (1; Figure 1), isolated from culture broths
of Stachybotrys parvispora F4708, has been found to in-
duce significant neurite outgrowth in PC12 cells at levels
of 30 μg/mL and showed protecting effects against neuro-
nal damage.1 Because of its neuritogenic properties,
stachybotrin C, like other small molecules, has been
sought for the treatment of neurodegenerative diseases.2
Stachybotrin C contains a unique pyrano-isoindolinone
ring system with two stereogenic centers (of which only
the relative stereochemistry is known) and is related to
stachybotrins A and B, which were isolated from the fun-
gus Stachybotrys sp.3 Despite efforts described in 2006 by
Inoue and co-workers, to our knowledge, no total synthe-
sis has been reported to date.4
Being aware of the need to develop an efficient and flexi-
ble route to 1 and plausible analogues for medicinal chem-
istry purposes, we disclose in this paper our own efforts in
this research area. First, we wanted to prepare pyrano-
isoindolinone 2, which was expected be a valuable precur-
sor of 1, relying on recent work on the gold-catalyzed in-
tramolecular hydroarylation of alkynes and alkenes.5 The
cyclization could be preceded by the formation of an ether
derivative, which, in turn, could be obtained by the com-
bination of carbonate 4 with phenol 3 (Scheme 1). The ad-
vantage of this approach is that it enables the stereocenter
at the α-position of the ether function to be controlled, and
offers the possibility of developing an asymmetric synthe-
sis of 1.
Our synthesis began with the preparation of the 2,3-di-
hydro-1H-isoindolinone derivative 12 from commercially
Figure 1 Structure of stachybotrin C
N
HO O
O
H
O
H
OMe Me
Me
Me
1
stachybotrin C
Scheme 1 Retrosynthetic approach
1
N
PGO OOPG
O
Me R1Me
Me
Me
R1 =
PG = protecting group
2
N
PGO OOP
G
OH
O OR2
O
R1
Me
3
4
H2N
PGO
OPG
OH
CO2Me
CHO HO
OH
CO2H
5
6
7
SYNLETT 2012, 23, 2919–2922
Advanced online publication: 09.11.2012
0936-5214 143 7-20 96
DOI: 10.1055/s-0032-1317528; Art ID: ST-2012-B0773-L
© Georg Thieme Verlag Stuttgart · New York
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2920 N. Tumma et al. LETTER
Synlett 2012, 23, 2919–2922 © Georg Thieme Verlag Stuttgart · New York
available 3,5-dihydroxybenzoic acid (7) in a short se-
quence of reactions (Scheme 2). Salicylaldehyde 10 was
prepared according to the literature in three steps6 and
then converted into the expected amide 12 after a selective
reductive amination and amide formation with O-protect-
ed tyramine 11.7
Scheme 3 summarizes the synthesis of the advanced pyra-
no-isoindolinone intermediate 17, which was obtained af-
ter thermal intramolecular cyclization. Thus, alkylation of
readily available (E)-geranylacetone 13 (prepared from
geraniol in three steps)7 with ethynylmagnesium bromide
in tetrahydrofuran (THF) proceeded smoothly to afford
carbonate 14 after quenching the reaction mixture with a
slight excess of methyl chloroformate. Coupling optimi-
zation studies on phenol 12 with propargylic carbonate 14
led to the production of ether 15, which was obtained in
good yield by mixing 12 with 14 (2 equiv) in the presence
of K2CO3 (2 equiv), KI (2 equiv), and CuI (0.2 equiv)
upon reflux for 24 hours, followed by an addition of one
more equivalent of carbonate 14 and additional stirring
under reflux for 24 hours to complete the reaction.
Because it is well established that gold complexes possess
high affinity for C–C triple bonds and activate many nu-
cleophilic additions to this kind of unsaturated bond,8 we
thought to use this methodology to form the pyran ring.
Unfortunately, in the presence of a catalytic amount of a
cationic gold(I) complex,5a no formation of the expected
pyran was observed. The desired hydroarylation reaction
failed and only a mixture of phenol 12 and a polycyclized
derivative 16 in a ratio 1:1 was obtained.9 This problem
was, however, solved by performing the reaction under
thermal conditions; thus, heating 15 in xylene at reflux
provided the pyrano-isoindolinone intermediate 17 in
good yield.
Scheme 2 Preparation of the 2,3-dihydro-1H-isoindolinone derivative 12
7
HO CO2Me
OH
SOCl2, MeOH
0 °C to r.t., 2 h
99%
Zn(CN)2, AlCl3, dry HCl
Et2O, 0 °C to r.t., 12 h
40–65%
HO CO2Me
OH
CHO
89
MOMCl, K2CO3
acetone, r.t., 12 h
93%
MOMO CO2Me
OH CHO
10
H2NOMOM
11
NaBH4, MeOH, 0 °C to r.t., 12 h
then AcOH, H2O
80–90%
MOMO
OH
N
OOMOM
12
Scheme 3 Intramolecular cyclization
13
MgBr
THF, 0 °C to r.t., 12 h
then ClCO2Me, r.t., 3 h
14
15
CH2Cl2, r.t., 12 h
PAu
t-Bu
t-Bu NCMe
SbF6
16 + 12
16/12 = 1:1
xylene, BHT
reflux, 6 h
80%
17
12, K2CO3, KI, CuI
acetone, reflux, 2 d
78%
NOMOM
O
MOMO
O
Me
NOMOM
O
MOMO
O
Me
80%
NOMOM
O
MOMO
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
O
Me Me
Me
Me
OCO2Me
Me
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LETTER Synthetic Studies towards Stachybotrin C 2921
© Georg Thieme Verlag Stuttgart · New York Synlett 2012, 23, 2919– 2922
Encouraged by this result, we decided to focus on a
straightforward approach involving an intermolecular cy-
clization, as rationalized by North and co-workers.10 After
conversion of trans,trans-farnesol 18 into diethyl acetal
19 in two efficient steps, heating the latter in xylene under
reflux with phenol 12 and a catalytic amount of 3-picoline
led, after two days, to the pyrano-isoindolinone derivative
17 in 75% yield (Scheme 4).11 The MOM protecting
group was cleanly removed by exposure of 17 to HCl
(generated in situ by adding AcCl to methanol), affording
20 in good yield.12
In conclusion, the preparation of pyrano-isoindolinone
derivative 20 (30% overall yield in 11 steps) from 3,5-di-
hydroxybenzoic acid (7) has been achieved. Compound
20 can be considered as an analogue of stachybotrin C and
its biological activity will be evaluated later. Whereas the
approach involving intramolecular gold-catalyzed hy-
droarylation reaction of alkyne failed, intermolecular cy-
clization to form the benzopyran moiety proved to be
effective. To date, despite our continuous efforts, conver-
sion of intermediate 17 or compound 20 into racemic
stachybotrin C has been unsuccessful. A revised strategy
is in progress and will be reported in due course.
Acknowledgment
This research has been performed as part of the Indo-French ‘Joint
Laboratory for Sustainable Chemistry at Interfaces’. We thank the
CNRS, France, and CSIR, India, for support. We also thank the Mi-
nistère de la Recherche, France, for a fellowship to M.J. and the
PRISM platform for NMR analysis (Université de Rennes 1, UFR
Sciences Biologiques et Pharmaceutiques, 2 avenue du Prof Léon
Bernard, 35043 Rennes Cedex, France).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Supporting InformationSupporting Information
References and Notes
(1) (a) Nozawa, Y.; Yamamoto, K.; Ito, M.; Sakai, N.; Mizoue,
K.; Mizobe, F.; Hanada, K. J. Antibiot. 1997, 50, 635.
(b) Nozawa, Y.; Ito, M.; Sugawara, K.; Hanada, K.; Mizoue,
K. J. Antibiot. 1997, 50, 641.
(2) (a) Wilson, R. M.; Danishefsky, S. J. Acc. Chem. Res. 2006,
39, 53. (b) Joyner, P. M.; Cichewicz, R. H. Nat. Prod. Rep.
2011, 28, 26. (c) Williams, P.; Sorribas, A.; Howes, M.-J. R.
Nat. Prod. Rep. 2011, 28, 48.
(3) Xu, X.; de Guzman, F. S.; Gloer, J. B. J. Org. Chem. 1992,
57, 6700.
(4) Inoue, S.; Kim, R.; Hoshino, Y.; Honda, K. Chem. Commun.
2006, 1974.
(5) (a) Menon, R. S.; Findlay, A. D.; Bissember, A. C.; Banwell,
M. G. J. Org. Chem. 2009, 74, 8901. (b) Jean, M.; van de
Weghe, P. Tetrahedron Lett. 2011, 52, 3509.
(6) Katoh, T.; Ohmori, O.; Iwasaki, K.; Inoue, M. Tetrahedron
2002, 58, 1289; and references cited therein..
(7) For the preparation of 11 and 13, see the Supporting
Information.
(8) For a significant and recent review on gold-catalyzed
additions to C–C multiple bonds, see: Huang, H.; Zhou, Y.;
Liu, H. Beilstein J. Org. Chem. 2011, 7, 897.
(9) The gold-catalyzed biscyclopropanation of dienynes has
been already reported, see: Nieto-Oberhuber, C.; López, S.;
Paz Muñoz, M.; Jiménez-Núñez, E.; Buñuel, E.; Cárdenas,
D. J.; Echavarren, A. M. Chem.–Eur. J. 2006, 12, 1694.
(10) North, J. T.; Kronenthal, D. R.; Pullockaran, A. J.; Real, S.
D.; Chen, H. Y. J. Org. Chem. 1995, 60, 3397.
(11) To a solution of 12 (500 mg, 1.34 mmol, 1.0 equiv) in
anhydrous o-xylene (8 mL), 19 (790 mg, 2.68 mmol,
2.0 equiv) and 3-picoline (33 μL, 0.34 mmol, 0.25 equiv)
were added. The reaction mixture was heated to reflux for
48 h, then the solvent was removed under reduced pressure
and the residue was purified by column chromatography on
silica gel (CH2Cl2–EtOAc, 9:1→4:1) to afford 17 (775 mg,
75%) as a brown oil. 1H NMR (500 MHz, CDCl3): δ = 1.40
(s, 3 H), 1.56 (s, 3 H), 1.59 (s, 3 H), 1.66–1.76 (m, 5 H),
1.92–1.97 (m, 2 H), 2.01–2.15 (m, 4 H), 2.92 (t, J = 7.5 Hz,
2 H), 3.47 (s, 3 H), 3.48 (s, 3 H), 3.74–3.84 (m, 2 H), 4.16 (s,
2 H), 5.05–5.14 (m, 2 H), 5.15 (s, 2 H), 5.22 (s, 2 H), 5.61 (d,
J = 10.2 Hz, 1 H), 6.76 (d, J = 10.2 Hz, 1 H), 6.96 (d, J = 8.7
Hz, 2 H), 7.07 (s, 1 H), 7.16 (d, J = 8.7 Hz, 2 H). 13C NMR
(125 MHz, CDCl3): δ = 15.9, 17.7, 22.5, 25.7, 26.6, 34.0,
39.6, 41.2, 44.3, 47.7, 55.9, 56.3, 78.9, 94.5, 95.0, 101.2,
113.6, 116.4, 117.5, 121.4, 123.6, 124.2, 129.4, 129.7,
131.4, 132.1, 133.9, 135.5, 148.2, 153.2, 155.9, 168.3.
HRMS (ESI): m/z [M + Na]+ calcd for C35H45NO6Na:
598.3139; found: 598.3139.
(12) To a solution of 17 (200 mg, 0.35 mmol, 1.0 equiv) in
anhydrous MeOH (4 mL) was added at 0 °C, acetyl chloride
(100 μL, 1.39 mmol, 4.0 equiv). The solution was stirred at
room temperature for 20 h then concentrated under reduced
Scheme 4 Intermolecular cyclization
1) (COCl)2, DMSO, Et3N
CH2Cl2, –78 °C, 1 h, 99%
2) HC(OEt)3, NH4NO3 (cat.)
EtOH, r.t., 12 h, 99%
18 19
12, 3-picoline (cat.)
xylene, reflux, 24–48 h
75% 17
AcCl, MeOH
r.t., 12 h
82%
N
HO OOH
O
Me Me
Me
Me
20
trans,trans-farnesol Me
MeMe
Me OEt
OEt
Downloaded by: University College Dublin. Copyrighted material.
2922 N. Tumma et al. LETTER
Synlett 2012, 23, 2919–2922 © Georg Thieme Verlag Stuttgart · New York
pressure and the residue was purified by column
chromatography on silica gel (PE–EtOAc, 1:1) to afford 20
(140 mg, 82%) as a pale-yellow oil. 1H NMR (500 MHz,
CDCl3): δ = 1.37 (s, 3 H), 1.56 (s, 3 H), 1.58 (s, 3 H), 1.66
(s, 3 H), 1.66–1.76 (m, 2 H), 1.92–1.97 (m, 2 H), 2.01–2.15
(m, 4 H), 2.85 (t, J = 7.5 Hz, 2 H), 3.70–3.84 (m, 2 H), 4.17
(s, 2 H), 5.05–5.14 (m, 2 H), 5.55 (d, J = 10.2 Hz, 1 H),
6.76–6.79 (m, 3 H), 6.96–7.01 (m, 3 H), 7.46 (br s, 1 H),
8.40 (br s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 15.9, 17.7,
22.5, 25.7, 26.6, 26.6, 33.8, 39.6, 41.2, 44.4, 47.9, 79.0,
102.4, 112.2, 115.6, 117.5, 119.6, 123.7, 124.2, 129.0,
129.7, 130.2, 131.4, 133.2, 135.6, 148.4, 152.7, 154.6,
169.0. HRMS (ESI): m/z [M + Na]+ calcd for C31H37NO4Na:
510.2620; found: 510.2621.
Downloaded by: University College Dublin. Copyrighted material.
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