Reactivity umpolung in intramolecular ring closure of 3,4-disubstituted butenolides: Diastereoselective total synthesis of paeonilide

Article abstract of DOI:10.1021/ol4028804

Remarkable reactivity reversal stratagem in 3,4-disubstituted butenolides under acidic conditions is described. Design of a suitably substituted multifunctional butenolide followed by an acid-catalyzed chemo- and diastereoselective intramolecular ring closure via the reactivity umpolung has been demonstrated to accomplish a concise total synthesis of paeonilide. Overall, the present protocol involves one-pot reduction of an α,β-unsaturated carbon-carbon double bond and intramolecular nucleophilic insertion of oxygen function at the electron-rich γ-position of butenolide. The involved mechanistic aspects have also been discussed.

Full text of DOI:10.1021/ol4028804

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Reactivity Umpolung in Intramolecular
Ring Closure of 3,4-Disubstituted
Butenolides: Diastereoselective Total
Synthesis of Paeonilide
Prashant S. Deore and Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008,
India
np.argade@ncl.res.in
Received October 7, 2013
ABSTRACT
Remarkable reactivity reversal stratagem in 3,4-disubstituted butenolides under acidic conditions is described. Design of a suitably substituted
multifunctional butenolide followed by an acid-catalyzed chemo- and diastereoselective intramolecular ring closure via the reactivity umpolung
has been demonstrated to accomplish a concise total synthesis of paeonilide. Overall, the present protocol involves one-pot reduction of an R,β-
unsaturated carbonꢀcarbon double bond and intramolecular nucleophilic insertion of oxygen function at the electron-rich γ-position of
butenolide. The involved mechanistic aspects have also been discussed.
A large number of the ginkgolide class of natural and
unnatural hydrofurofuran systems have been known in the
literature and have attributed a wide range of biological
activities.1 More specifically, the fused tetrahydrofurofur-
ans and hexahydrofurofurans bearing common acetal/
ketal carbon atom have been imperative targets for stabi-
lity reasons and well-ordered synthetic routes have been
known in the literature (Figure 1).2,3 We have been using
cyclic anhydrides and their derivatives as the potential
precursors for total synthesis of structurally interesting
and biologically important natural products for almost the
past two decades.4 During the course of our studies on
intramolecular oxa-Michael addition reaction of suitably
3,4-disubstituted butenolide, we serendipitously witnessed
an unusual redox neutral process involving nucleophilic
insertion of oxygen function at the γ-position. The normal
reactivity at γ-position of butenolides is nucleophilic
and they undergo facile reactions with an array of elec-
trophiles,5 thus our present observation is orthogonal
to previous reports. In this context, we herein report an
(1) (a) Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade,
A. S.; Thomas, J. B.; Watterson, S. H.; Wagman, A. S. J. Am. Chem. Soc.
2000, 122, 8453. (b) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93,
1897. (c) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617. (d) Corey,
E. J.; Kang, M.-C.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. J. Am.
Chem. Soc. 1988, 110, 649. (e) Corey, E. J.; Su, W.-G. J. Am. Chem. Soc.
1987, 109, 7534.
(2) (a) Liu, J.-K.; Ma, Y.-B.; Wu, D.-G.; Lu, Y.; Shen, Z.-Q.; Zheng,
Q.-T.; Chen, Z.-H. Biosci. Biotechnol. Biochem. 2000, 64, 1511. (b)
Lichtblau, D.; Berger, J. M.; Nakanishi, K. J. Nat. Prod. 2002, 65,
1501. (c) Mayol, L.; Piccialli, V.; Sica, D. J. Nat. Prod. 1986, 49, 823.
(3) (a) Crimmins, M. T.; Jung, D. K.; Gray, J. L. J. Am. Chem. Soc.
1993, 115, 3146. (b) Corey, E. J.; Letavic, M. A. J. Am. Chem. Soc. 1995,
117, 9616.
(4) (a) Mondal, P.; Argade, N. P. J. Org. Chem. 2013, 78, 6802. (b)
Patel, R. M.; Argade, N. P. Org. Lett. 2013, 15, 14. (c) Deore, P. S.;
Argade, N. P. J. Org. Chem. 2012, 77, 739. (d) Kshirsagar, U. A.;
Puranik, V. G.; Argade, N. P. J. Org. Chem. 2010, 75, 2702 and
references cited therein.
Figure 1. Furofuran-based bioactive natural products.
r
10.1021/ol4028804
XXXX American Chemical Society

Scheme 1. Diastereoselective Synthesis of Furofuran Framework of Paeonilide via Reactivity Reversal
Scheme 2. Plausible Mechanism for the Reactivity Umpolung
Figure 2. Plausible product via two consecutive intramolecular
cyclizations of butenolide 7.
interesting instance of reactivity umpolung and its ap-
plication for the total synthesis of (()-paeonilide (1)
(Schemes 1ꢀ5).
Initially, we selected the bioactive natural product
buergerinin from Scrophularia buergeriana6 as a target
compound and started the synthesis of requisite advanced
butenolide intermediate (Scheme 1). Aldol condensation
of O-benzyl-protected aldehyde 27 with relatively more
reactive glyoxalic acid (3) in the presence of morpholine
hydrochloride directly furnished the corresponding maleic
anhydride derivative 4 in 78% yield via a stereoselective
dehydrative cyclization pathway.8 Barbier reaction9 of
propargyl bromide with lactol 4 (masked aldehyde)
provided the corresponding acetylenic derivative 5 in
82% yield following a ring-opening and ring-closing
pathway. Compound 5 upon treatment with sulfuric
acid adsorbed on silica gel underwent smooth hydrolytic
acetylene to ketone transformation and formed the
required product 6 in 86% yield. Chemoselective deben-
zylation of compound 6 with H2/PdꢀC yielded the
essential precursor 3,4-disubstituted butenolide 7 in
Scheme 3. Attempted Intermolecular Nucleophilic Oxygen
Insertions
83% yield. The protection-free multifunctional com-
pound 7 bearing free ketone and alcohol units at ap-
propriate positions can theoretically form an intra-
molecular cyclization product (()-buergerinin G (10)
under acidic conditions via the generation of hemiketal
intermediate 9 followed by a concomitant diastereose-
lective oxa-Michael addition route (Figure 2). Surpris-
ingly, the reaction of compound 7 with p-TSA in
refluxing benzene/toluene followed an alternative novel
intramolecular cyclization pathway in a highly chemo-
and diastereoselective fashion and exclusively delivered
the exotic furofuran system (()-8 in 75% yield.
(5) (a) Yin, L.; Takada, H.; Kumagai, N.; Shibasaki, M. Angew.
Chem., Int. Ed. 2013, 52, 7310. (b) Casiraghi, G.; Battistini, L.; Curti, C.;
Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076 and references cited
therein. (c) Zhou, L.; Lin, L.; Ji, J.; Xie, M.; Liu, X.; Feng, X. Org. Lett.
2011, 13, 3056. (d) Terada, M.; Ando, K. Org. Lett. 2011, 13, 2026. (e)
Cui, H.-L.; Huang, J.-R.; Lei, J.; Wang, Z.-F.; Chen, S.; Wu, L.; Chen,
Y.-C. Org. Lett. 2010, 12, 720.
(6) (a) Lin, S.-J.; Jiang, S.-H.; Li, Y.-M.; Zeng, J.-F.; Zhu, D.-Y.
Tetrahedron Lett. 2000, 41, 1069. (b) Shiina, I.; Iizumi, T.; Yamai, Y.-S.;
Kawakita, Y.-I.; Yokoyama, K.; Yamada, Y.-K. Synthesis 2009, 2915
and references cited therein.
(7) Brimble, M. A.; Haym, I.; Sperry, J.; Furkert, D. P. Org. Lett.
2012, 14, 5820.
(8) Bourguignon, J. J.; Wermuth, C. G. J. Org. Chem. 1981, 46, 4889.
~
€
(9) Jogi, A.; Maeorg, U. Molecules 2001, 6, 964.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 4. Concise Diastereoselective Total Synthesis of (()-Paeonilide via Reactivity Umpolung
The observed addition of oxygen function at the electron-
rich γ-position of butenolide is exceptional. Mechanisti-
cally, the present fact can be attributed to an acid-catalyzed
structural rearrangement encompassing reactivity umpo-
lung depicted in Scheme 2. The butenolide 7 on protona-
tion of lactone carbonyl followed by a conjugate base
induced allylic prototropic shift results in an unusual olefin
isomerization10 to form the labile hydroxyfuran interme-
diate B. The possible driving forces for the present allylic
shift are (i) generation of tetrasubstituted carbonꢀcarbon
double bond between the β- and γ-positions of butenolide
and (ii) formation of an aromatic furan intermediate B.
Intermediate B under acidic conditions selectively trans-
forms into oxocarbenium ion C using relatively more
reactive double bond in furan ring. The synchronized
intramolecular nucleophilic addition of primary alcohol
forms a unique product 8. In transformation of intermedi-
ates A to D, an oxygen function adds to the electron rich
γ-carbon and a proton to the electron deficient β-carbon of
starting butenolide. Hence, the overall reaction pro-
cess becomes viable due to reactivity umpolung11 at the
γ-position of 3,4-disubstituted butenolide 7. As shown in
Scheme 3, the intermolecular reactions of 3,4-disubstituted
butenolide 11/12 with methanol in the presence of p-TSA
in refluxing toluene were unsuccessful to provide the
corresponding desired product 13/14. In both cases, the
starting butenolide was isolated back in quantitative
amount. The above fact clearly reveals that the transfor-
mation of butenolide 7 into the bicyclic product 8 proceeds
smoothly in a forward direction due to overall negative
Gibbs free energy.
a diastereoselctive total synthesis of (()-paeonilide (1).
The (þ)-paeonilide with a novel monoterpenoid skeleton
has been isolated by Liu and co-workers from the roots of
Paeonia delavayi.2a It selectively inhibited platelet aggrega-
tioninducedby the plateletactivating factor(PAF) withan
IC50 value of 8 μg/mL, importantly, without inhibitory
effect on adenoside diphosphate (ADP) or arachidonic
acid (AA)-induced platelet aggregation.2a In the total
synthesis of paeonilide, generation of three contiguous
chiral centers in a enantioselective or diastreoselective
fashion is the challenging task. To date, two racemic12a,b
and two stereoselective12c,d well-organized total synthesis
of paeonilide have been reported in the literature by
employing new carbonꢀcarbon/oxygen bond forming
strategies.12 Specifically, Du’s group reported an efficiant
strategy for the synthesis of racemic paeonilide in five steps
with 59% overall yield.12b
As described in Scheme 4, our synthesis of paeonilide
began with morpholine hydrochloride promoted aldol
condensation of appropriately double O-benzyl-protected
aldehyde 1513 with glyoxalic acid (3). The above stated
stereoselective condensation directly furnished the ex-
pected maleic anhydride derivative 16 in 64% yield follow-
ing a dehydrative cyclization pathway. Barbier reaction of
propargyl bromide with a masked aldehyde 16 in presence
of activated zinc powder provided the corresponding
acetylenic derivative 17 in 82% yield, which on acidic
hydrolysis transformed into the desired ketone 18 in 87%
yield. We systematically studied the selective monobenzyl
and dibenzyl deprotections in compound 18 under various
reaction conditions. The reactions of compound 18 with
H2/PdꢀC in MeOH, HCOOH/PdꢀC in MeOH, LiCl in
DMF, BCl3 in DCM, and BBr3 in DCM resulted in
isolation of staring material and/or decomposition of
reaction mixture. Fortunately, both benzyl groups in
compound 18 were smoothly deprotected in the presence
In the next part of our study, we planned to authenticate
the feasibility of reactivity umpolung conception to design
(10) (a) Wu, Y.; Singh, R. P.; Deng, L. J. Am. Chem. Soc. 2011, 133,
12458. (b) Xue, X.-S.; Li, X.; Yu, A.; Yang, C.; Song, C.; Cheng, J.-P. J.
Am. Chem. Soc. 2013, 135, 7462.
(11) (a) Mahapatra, S.; Carter, R. G. J. Am. Chem. Soc. 2013, 135,
10792. (b) Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K.
J. Am. Chem. Soc. 2011, 133, 15797. (c) Li, Z.; Nakashige, M.; Chain,
W. J. J. Am. Chem. Soc. 2011, 133, 6553. (d) West, S. P.; Bisai, A.; Lim,
A. D.; Narayan, R. R.; Sarpong, R. J. Am. Chem. Soc. 2009, 131, 11187.
(e) Miller, A. K.; Hughes, C. C.; Kennedy-Smith, J. J.; Gradl, S. N.;
Trauner, D. J. Am. Chem. Soc. 2006, 128, 17057 and references cited
therein.
(12) (a) Wang, C.; Liu, J.; Ji, Y.; Zhao, J.; Li, L.; Zhang, H. Org. Lett.
2006, 8, 2479. (b) Du, Y.; Liu, J.; Linhardt, R. J. J. Org. Chem. 2007, 72,
3952. (c) Wang, C.; Zhang, H.; Liu, J.; Ji, Y.; Shao, Z.; Li, L. Synlett
2006, 1051. (d) Harrar, K.; Reiser, O. Chem. Commun. 2012, 48, 3457.
(13) Wang, J.; Hsung, R. P.; Ghosh, S. K. Org. Lett. 2004, 6, 1939.
(14) Varvogli, A.-A. C.; Karagiannis, I. N.; Koumbis, A. E. Tetra-
hedron 2009, 65, 1048.
Org. Lett., Vol. XX, No. XX, XXXX
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of excess of aluminum chloride14 in DCM plus m-xylene
mixture at room temperature and delivered the essential
3,4-disubstituted butenolide 19 in 84% yield. However, the
reaction of compound 19 with p-TSA in refluxing benzene/
toluene furnished a complex mixture of products. We
reasoned that the cause for such decomposition could be
a presence of several oxygen-functions in the starting
material 19, wherein the ratio of number of carbon atoms
to oxygen atoms is 2:1, imparting the instability under
reaction conditions. The controlled reaction of compound
18 with a use of precise amount of AlCl3 (1.50 equiv) in
DCM plus m-xylene mixture at room temperature was
selective and formed the expected monodeprotectedpair of
diastereomers 20 in 81% yield with nearly 1:1 ratio (by 1H
NMR). An attempted flash silica gel column chromato-
graphic separation of the diastereomeric 20 resulted in
their ∼9:1 and ∼1:4 mixtures (by 1H NMR), which were
used as such for the cyclizations. Gratifyingly, the reac-
tions of 1:1 mixture of diasteromers of compound 20 and
their partially purified forms with p-TSA in refluxing
toluene were highly chemo- and diastereoselective result-
ing in the same desired product (()-21 in 73% yield via
structural rearrangement following an intramolecular
cyclization pathway with reactivity umpolung.
Scheme 5. Plausible Mechanism for the Diastereoselective Ring
Closure
The plausible mechanism for involved diastereoselectiv-
ity and reactivity umpolung in the formation of preferred
product (()-21 is represented in Scheme 5. As described
therein, the cause for diastereoselectivity is formation of
the labile hydroxyfuran intermediate (()-E, tentatively
nullifying the chirality at γ-position of both diastereomers
of butenolide 20 to generate a pair of enantiomers. The
cause for reactivity umpolung is generation of oxocarbe-
nium ion intermediate (()-F with a highly diastereoselec-
tive in situ protonation. The intermediate F undergoes
further instantaneous diastereoselective intramolecular
ring closure to yield the desired product 21 as a racemic
mixture. Finally, O-benzyl group in compound (()-21
was deprotected under H2/PdꢀC conditions to form the
known ultimate stage intermediate alcohol (()-22 in 91%
yield. Primary alcohol 22 on treatment with benzoyl
chloride/pyridine in DCM furnished the desired natural
product (()-paeonilide (1) in 99% yield. The analytical
and spectral data obtained for paeonilide (1) was in
complete agreement with the reported data,2,12 and start-
ing from glyoxalic acid it was obtained in seven steps with
24% overall yield.
umpolung process involves insertion of oxygen function at
the electron rich γ-carbon. The enzymatic meso-desymme-
trization of a corresponding diacetate derivative will also
provide access to the corresponding enantiomerically pure
forms of paeonilide. The present convergent access to
fused furofuran systems has a broad scope, and it will be
useful to design several focused minilibraries of their
natural and unnatural analogues and congeners for SAR
studies. We believe that our present redox protocol will
also work equally well to plan the corresponding furopyr-
an based structural architectures. Finally, the present
reactivity umpolung opens a new avenue in the significant
field of butenolide chemistry.
Acknowledgment. P.S.D. thanks CSIR, New Delhi, for
the award of a research fellowship. N.P.A. thanks the
Department of Science and Technology, New Delhi, for
financial support.
Supporting Information Available. Experimental pro-
1
In summary, we have demonstrated a novel reactivity
umpolung in 3,4-disubstituted butenolides and accom-
plished the diastereoselctive total synthesis of paeonilide.
The observed chemo- and diastereoselctivity in the intra-
molecular cyclization leading to a paeonilide is noteworthy
from a basic chemistry point of view. The overall reactivity
cedures, tabulated analytical and spectral data, and H
NMR, 13C NMR, and DEPT spectra of compounds 1,
4ꢀ8, and 16ꢀ22. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX