Nazarov cyclization of divinyl and arylvinyl epoxides: Application in the synthesis of resveratrol-based natural products

Article abstract of DOI:10.1002/chem.201500362

New variation in the Nazarov cyclization has been developed by preparing divinyl and arylvinyl epoxides as pentadienyl cation precursors for the first time. Highly substituted cyclopentadienes, hydrindienes, and indenes were synthesized to demonstrate the compatibility of this reaction with substrates bearing a variety of substitutions and having different types of epoxides. Application of this method in the synthesis of resveratrol-based natural products was also demonstrated.

Full text of DOI:10.1002/chem.201500362

DOI: 10.1002/chem.201500362
Full Paper
&
Organic Chemistry
Nazarov Cyclization of Divinyl and Arylvinyl Epoxides: Application
in the Synthesis of Resveratrol-Based Natural Products
Gangarajula Sudhakar* and Kovela Satish[a]
Abstract: New variation in the Nazarov cyclization has been
developed by preparing divinyl and arylvinyl epoxides as
pentadienyl cation precursors for the first time. Highly sub-
stituted cyclopentadienes, hydrindienes, and indenes were
synthesized to demonstrate the compatibility of this reaction
with substrates bearing a variety of substitutions and having
different types of epoxides. Application of this method in
the synthesis of resveratrol-based natural products was also
demonstrated.
Introduction
The synthesis of cyclopentenones was greatly facilitated by the
several developments in Nazarov cyclization (NC)[1] such as
controlling the placement of the double bond,[2] catalytic,[3]
and asymmetric versions of Nazarov cyclization.[4] Steady ad-
vancements and new variations of this reaction for instance in-
terrupted Nazarov cyclization,[5] and discovery of new penta-
dienyl cation precursors[6] can make Nazarov cyclization further
as a frontline reaction for the assembly of five-membered rings
similar to the Diels–Alder reaction, a primary tool for the syn-
thesis of six membered rings. In the classical Nazarov cycliza-
tion, the divinyl ketone 1 (Figure 1) is activated with Lewis or
Brønsted acid to give pentadienyl cation A, which then under-
goes a 4p-electrocyclic ring closure to furnish oxyallyl cation B,
finally elimination of a proton leads to cyclopentenone C. The
most important fact is, the pentadienyl cation irrespective of
its origin is the requisite in undergoing Nazarov cyclization and
it was mostly generated from conventional precursors, divinyl-
ketones. In view of this searching for alternative pentadienyl
cation precursors can offer a powerful method to synthesize
a diverse array of five-membered rings. In this context, signifi-
cant contributions can be found in the pioneering works of
the West group: cross-conjugated trienes,[7] vinylallenes,[8] alke-
nyldichlorocyclopropanes;[9] Tius group: allenyl vinyl ketones,[10]
a-ketoenones.[11] Divinyl alcohols[7a,12] and transition-metal-cata-
lyzed cycloisomerization approaches[13] were also found to pro-
duce some notable and unconventional pentadienyl cation
precursors. Nevertheless, more flexible and operationally
simple methods with additional functional groups are still
highly desirable.
Figure 1. Classical Nazarov cyclization and proposed Nazarov cyclization’s
pentadienyl cation precursor.
We presumed one such example, divinyl and arylvinyl epox-
ide as a pentadienyl cation precursor which has, surprisingly,
remained largely unexplored. Hampered developments in this
variation might be attributed to difficulties in making suitable
epoxide substrates. But, for this purpose, we considered that
divinyl epoxides may be realized from divinyl ketones and en-
visioned that circumvention of divinyl epoxide 2 could be en-
gaged in the formation of pentadienyl cation D (Figure 1). This
would undergo a Nazarov cyclic intermediate, cyclopenta oxy-
allyl cation E; finally, deprotonation would lead to highly sub-
stituted cyclopentadiene 3.[14] Further, we speculated that the
epoxide, is a surrogate, and plays a similar role as a typical
Nazarov cyclization precursor, wherein the carbonyl oxygen
atom complexes to the acid to form a pentadienyl cation. Ad-
ditionally, the steric effect of the epoxide is expected to render
the steric bulk necessary to enforce the requisite s-trans con-
formation even with a smaller substituent at the a,a’-posi-
tions.[1] Both steric effects and ring strain of susceptible epox-
ides accelerate the reaction and, as a result, it is expected to
work at very mild reaction conditions. Additional substitution
with the hydroxyl functional group on the five-membered ring
features a synthetic handle, which is distinct from the classical
Nazarov cyclization product. To the best of our knowledge,
a generalized approach to divinyl or arylvinyl epoxides as pen-
[a] Dr. G. Sudhakar, K. Satish
Division of CPC (Organic Chemistry-II)
CSIR-Indian Institute of Chemical Technology
Tarnaka, Hyderabad-500007 (India)
E-mail: gsudhakar@iict.res.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500362.
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tadienyl cation precursors has not been reported, except for
a few reports on in situ generation that also only form vinyl al-
lenyl oxides.[15] In particular, it was proposed recently in Fron-
tier’s elegant total synthesis of (Æ)-rocaglamide that the epoxi-
dation of allenol ether generated allene oxide, which under
the acidic reaction conditions unveiled the pentadienyl
cation.[16]
tion with 0.1 equivalents of MeSO3H provided a 76% yield
within 10 min (entries 7–8).
With the optimized reaction conditions in hand, we next
planned to investigate the scope of this new variation of Naza-
rov cyclization. A series of different divinyl epoxides 2a–m
were synthesized from corresponding ketones 1a–m, and em-
ployed to furnish 3a–m, respectively (Table 2). Interestingly,
Herein we report the synthesis of divinyl and arylvinyl epox-
ides, generation of a pentadienyl cation, and consequent Naza-
rov cyclization for the first time. The generality and substrate
scope, including the synthesis of hydrindienes, indenes, and
application of this novel method in a formal synthesis of epi-
caraphenol B and the total synthesis of isoampelopsin D are
described.
Table 2. Substrate scope.
Results and Discussion
At the outset, we developed a very convenient method to
access divinyl epoxide 2a in good yield using a Darzens reac-
tion between divinyl ketone 1a and ethyl bromoacetate.[17] To
establish the feasibility of Nazarov cyclization from divinyl ep-
oxide 2a, various Lewis and Brønsted acids were investigated
using CH2Cl2 as a solvent at À788C to furnish the desired prod-
uct 3a (Table 1). Treatment of 2a with 0.5 equivalents of
Table 1. Preparation of divinylepoxide 2a and optimization of the reac-
tion conditions for the synthesis of 3a from 2a.
[a] Isolated yields in 2 steps. [b] Product obtained as an inseparable regio-
and diastereomeric mixture (3h (2:1, d.r. 1:1), 3i (d.r. 1:1), 3l (2:1, d.r.
1:1)).
Entry[a]
Reagent
Equiv
t [min]
Yield [%][b]
1
2
3
4
5
6
7
8
BF3·OEt2
FeCl3
AlCl3
Cu(OTf)2
Sc(OTf)3
1m TiCl4
TFA
0.5
0.5
0.5
1.0
1.0
0.1
0.5
0.1
10
45
30
8h
90
10
90
10
68
70
72
71[c]
73[c]
84
these divinyl epoxides[18] exhibited higher reactivity as expect-
ed, and very rapidly provided substituted cyclopentadienes 3
in high yields. Inconsistent formation of cyclopentadiene 3 was
noticed during either acidic workup or silica-gel column chro-
matography of epoxide 2. Thus, the crude epoxides 2a–m,
except 2a, 2c, and 2e, were without further purification sub-
jected to Nazarov cyclization after workup. Divinylketone 1b
under Darzens reaction conditions gave the corresponding ep-
oxide and subsequently under the optimized reaction condi-
tions provided the cyclic products 3b in 63% yield. Tetrasubsti-
tuted cyclopentadienes 3c–f as a single regioisomer were ob-
tained in 58–62% yields from divinylketones 1c–f, respectively.
Similarly, trisubstituted cyclopentadiene 3g was also obtained
in a yield of 59% from 1g via 2g. Highly substituted cyclopen-
tadiene 3h was obtained as an inseparable regio- and diaste-
reomeric mixture in 61% yield from the divinylketone 1h. Sym-
metrical substrate, methyls at a,a’- and isopropyls at b,b’-posi-
tions, 2i produced exclusively exo-methylene containing cyclic
product 3i[19] owing to the selective elimination of a proton
from an a-substituted methyl rather than from the b-position.
Additionally, this reaction also worked well for the synthesis of
hydrindienes (3j–l) in yields ranging 58–65% from the corre-
sponding cyclohexene containing divinyl ketones 1j–l. Notably,
70
76
MeSO3H
[a] 0.36 mmol of 2a in CH2Cl2 (0.03m) at À788C was added acid. [b] Iso-
lated yield of 3a. [c] Reaction was run at À788C to room temperature.
TFA=trifluoroacetic acid.
BF3·OEt2 in CH2Cl2 resulted smoothly in the expected cyclopen-
tadiene 3a in 68% yield within 10 min (Table 1, entry 1). With
FeCl3 a slightly improved yield (70%) was obtained but in
45 min (entry 2). Reaction with AlCl3 also resulted in a 72%
yield within 30 min (entry 3). The use of 0.5 equivalents of
Cu(OTf)2 or Sc(OTf)3 produced the product very slowly even
after a longer reaction time. However, using 1 equivalents of
these reagents effectively completed the reaction at À788C to
RT (entries 4–5). The best result (3a in 84% yield and within
10 min) was obtained with 1m TiCl4, even when using only
0.1 equivalent at À788C (entry 6). For protic acids, 0.5 equiva-
lents of trifluoroacetic acid gave a 70% yield, whereas the reac-
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cyclopentadiene 3m with the quaternary carbon atom was
also successfully synthesized in good yield from the ketone
1m.
Table 3. Synthesis of indenes.
After having demonstrated substrate scope, interrupted Naz-
arov cyclization[5] was then planned to ensure a 4p-electrocycli-
zation mechanistic pathway (Scheme 1). Accordingly, the epox-
Scheme 1. Synthesis of 5 from interrupted Nazarov cyclization. DMP=Dess–
Martin periodinane.
ide 2n was prepared from 1n, and subjected to BF3·OEt2 to
give expected interrupted Nazarov cyclic product 4 (d.r. 1:1) in
81% yield (2 steps).[20] To avoid complexity in the NMR spec-
trum of 4 due to the diastereomeric mixture, the allylic hydrox-
yl group in 4 was oxidized to give 5 in 86% yield. It is well-
known that the Nazarov cyclization proceeds in a stereospecific
manner and the olefin geometry of substrate translates to the
two new stereocenters at C1- and C5-positions of the prod-
uct.[21] Thus, based on coupling constants of C1–H at d=
3.74 ppm (d, J=10.8 Hz) and C5–H at d=2.34 ppm (dt, J=
10.8, 3.5 Hz) in 5 an anti relationship is clearly indicated. This
was also further confirmed by nOe interactions between C1–H
with one of the benzyl protons and C5–H with an angular
methyl substituent (Scheme 1). This stereochemical predictabil-
ity is based on the conservation of orbital symmetry, 2n must
be proceeded from conrotatory 4p-electrocyclization of penta-
dienyl cation F to intermediacy of oxyallyl cation G, which was
trapped intramolecularly by a pendant electron-rich aromatic
group to give interrupted Nazarov cyclic product 4 as shown
in Scheme 1.
[a] Isolated yield in 2 steps; [b] Product obtained as an inseparable diaste-
reomeric mixture (3ad (d.r. 1.5:1), 3ae (d.r. 2:1), 3af (d.r. 1.5:1), 3aj (d.r.
4:1)).
tion at b to epoxide was observed when arylvinyl epoxides re-
acted with 1m TiCl4, even though it was the most effective
with divinylepoxides. First, we have selected substrates with
aryl groups bearing electron-donating groups (EDG). Epoxides
2aa–ac were, easily, prepared from 1aa–ac and subjected to
BF3·OEt2 to give 3aa–ac in good yields (Table 3). Highly substi-
tuted indenes 3ad–af were obtained with an inseparable dia-
stereomeric mixture and 76–81% yields from the correspond-
ing ketones via an epoxide without incident. Substrates with
two methoxy groups, one para and the other meta to the reac-
tion site, 1ag, produced 3ag in moderate yield along with
a substituted chromene side product 3’ag. Chromene 3’ag pre-
sumably might have formed from the oxa-Michael addition in
boron coordinated complex H to give oxonium intermediate I.
After having confirmed Nazarov cyclization pathway, further
substrate scope and versatility of this method was intended in
the synthesis of indenes since they are important scaffolds not
only in the bioactive natural products but also in medicinal
and materials chemistry.[22] We observed, arylvinyl epoxides are
more reactive in comparison to divinyl epoxides. In general,
the reaction tolerated a wide range of epoxides 2aa–ao, and
reacting with 0.3 equivalents of BF3·OEt2 afforded indenes in
good to excellent yield (Table 3). Initially, indenes could not be
obtained in satisfactory yields and in some cases chloride addi-
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Table 4. Synthesis of indenyl methanols.
Scheme 2. Plausible reaction pathway for 3’ag from 1ag. LiHMDS=lithium
hexamethyl disilazide.
Subsequently loss of MeOH in I could have given chromene
3’ag as shown in Scheme 2.
Highly electron-rich trimethoxy compounds 1ah–aj fur-
nished the expected indenes 3ah–aj, respectively, in high
yields (Table 3). Monosubstituted reactants, such as 3-methoxy
(para to the reaction site) 1ak, and 4-methoxy (meta to reac-
tion site) 1al, also participated to give 3ak (77%) and 3al
(41%), respectively. The later one was found to be effective
with TiCl4 and the side product by chloride addition at the b-
position to the epoxide accounts for the low yield. Methyl-sub-
stituted products 3am and 3’am were obtained as an insepa-
rable regioisomeric mixture (1:1) from the substrate with
methyl substituted on the aromatic ring para to reaction
center 1am. Remarkably, substrate without any EDGs 1an also
provided 3an in good yield, but with a somewhat longer reac-
tion time (1 h). This clearly indicates the higher reactivity of
this variation. Interestingly, a chloro substituent para to reac-
[a] Based on recovery of starting material. [b] Compound 2au was treated
with TFA.
obtained from 3at, whereas ampelopsin D, isoampelopsin D,
viniferaether B, and caraphenol B could be obtained from
structural skeleton 3au. To perform this, first we have treated
arylvinyl ketones 1aa, 1ai, and 1aj with NaH, (CH3)3S(I), THF/
DMSO, at 08C to RT[23a] to give corresponding epoxides 2ap–
ar, respectively. To our pleasure, epoxides 2ap–ar with BF3·OEt2
provided expected indenyl methanols 3ap–ar, respectively, in
good yields (Table 4). Furthermore, ideally functionalized in-
denyl methanols 3as–au were also realized from ketones 1as,
1ae, and 1af via epoxides 2as–au, respectively. Inseparable
3as and 3’as (9:1) and separable 3au and 3’au (1:1) were ob-
tained in the case of 2as and 2au, respectively. The plausible
reaction pathway for the formation of 3’au has been shown in
Scheme 3. The arylvinyl cation J would give the expected 3au,
whereas its resonance structure K would give 3’au; interesting-
ly, the Nazarov cyclization is the reaction pathway in both
cases. Formation of 3as and 3’as from 2as also could have fol-
lowed the same reaction pathway.
tion center 1ao (bearing
a weakly electron-withdrawing
group) also participated in the reaction to provide the corre-
sponding 3ao along with regioisomer 3’ao (7:3) in a 60% com-
bined yield.
Here, we wondered whether the Corey–Chaykovsky reac-
tion[23] on arylvinyl ketones could be a way to more easily ac-
cessible simple epoxides, and subsequent Nazarov cyclization
could possibly serve as a more straightforward synthetic
handle. Particularly, indenyl methanol frameworks 3as–au
(Table 4) are ideally functionalized key building blocks for the
preparation of a range of biologically important resveratrol-
based natural products which belong to the class of natural
polyphenols.[24] An advanced intermediate which is shown to
possess a similar frame work of resveratrol-based natural prod-
ucts[24] could be obtained from oxidation of indenyl methanol
3as–au followed by the appropriate Grignard reagent addi-
tion.[24d] For instance, gnetulin and gnetuhainin I could be ob-
tained from 3as; quadrangularin A, parthenocissin A, quadran-
fularin B and C, leachianol F and G, and caraphenol C could be
As a prelude of the synthetic utility of this method, we en-
deavored the synthesis of caraphenol B (Scheme 4) from the
oxidation of 3au to the corresponding aldehyde,[24d] which
upon addition of 4-methoxyphenylmagnesium bromide pro-
vided an advanced intermediate 6, which has a similar frame-
work to that present in most of the resveratrol-based natural
products.[24] Finally, the secondary hydroxyl group of 6 was oxi-
dized and subsequently hydrogenated to furnish 7, which is
a formal total synthesis of (Æ)-epi-caraphenol B (originally pro-
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ly, benzofulvene 9 was obtained instead the expected mesyl
derivative, when 6 was treated with methanesulfonyl chloride
in the presence of Et3N. This vinylogous olefination in 6 to 9
can be rationalized by the deprotonation in intermediate L
from the g-position to a mesyl leaving group as shown in
Scheme 4. This opens up a new method and can be extended
to the preparation of benzofulvenes. Substituted indenyl meth-
anols in Tables 3 and 4 and cyclopentadienyl methanols in
Table 2 could be converted to a variety of benzofulvenes and
fulvenes, respectively, which may find some new
applications.[25]
Conclusion
We have developed a new variation of the Nazarov cyclization
from divinyl and arylvinyl epoxides derived from two different
methods (Darzens, and Corey–Chaykovsky). This protocol is
mild and robust and works with a substoichiometric amount
of Lewis acids, which is apparent from the synthesis of various
cyclopentadienes, hydrindienes, indenes, and application to
the total synthesis of resveratrol-based natural products. Addi-
tionally, a polycyclic molecule with three contiguous stereocen-
ters was also achieved from this method of interrupted Naza-
rov cyclization to ensure a 4p-electrocyclization pathway. Fur-
ther pentadienyl cation precursors, dienyl epoxides from other
methods including the asymmetric version, and applications of
this method in various natural product syntheses is in
progress.
Scheme 3. Synthesis of 3au and 3’au from 1af via 2au.
Experimental Section
Method A
TiCl4 (0.1 equiv, 1m in CH2Cl2) was added to a stirred solution of
2a–m (1.0 equiv) in CH2Cl2 (0.03m) at À788C. The reaction mixture
was stirred for 10 min. The reaction was quenched by the addition
of aq. NaHCO3 solution and slowly allowed to warm to RT. The re-
sulting mixture was extracted with EtOAc and the organic layer
was washed with brine and dried over Na2SO4. The solvent was
then evaporated under reduced pressure and the residue was puri-
fied by using silica gel column chromatography (EtOAc/hexanes)
to give cyclopentadienes 3a–m in good yields.
Method B
BF3·OEt2 (0.3 equiv) was added to a stirred solution of 2aa–au
(1.0 equiv) in CH2Cl2 (0.03m) at À788C. After completion of the
starting material, the reaction mixture was quenched with aq.
NaHCO3 solution and slowly allowed to warm to RT. The resulting
mixture was then extracted with EtOAc and the organic layer was
washed with brine and dried over Na2SO4. The solvent was then
evaporated under reduced pressure and the residue was purified
by using silica gel column chromatography (EtOAc/hexanes) to
give indenes 3aa–au in good yields.
Scheme 4. a) 1) DMP, CH2Cl2; 2) 4-methoxyphenylmagnesium bromide, THF;
69% (2 steps); b) 1) DMP, CH2Cl2; 2) H2, Pd/C, Et3N, MeOH/EtOAc (3:1), 67%
(2 steps); c) 1) BF3·OEt2, Et3SiH, CH2Cl2; 2) BBr3, CH2Cl2, À788C–RT, 65%
(2 steps); d) MeSO2Cl, Et3N, CH2Cl2, 08C–RT, 82%.
posed structure of caraphenol B).[24d] Further, removal of the
hydroxyl group of 6 by using BF3·OEt2 and Et3SiH in CH2Cl2 and
subsequent demethylation accomplished the total synthesis of
(Æ)-isoampelopsin D (8) in 65% yield (2 steps).[24e]
Acknowledgements
With the intent to synthesize ampelopsin D from 6 by con-
verting the hydroxyl group in 6 as a leaving group followed by
displacing the double bond with a hydride source. Interesting-
This work was financially supported by the Department of Sci-
ence and Technology (DST), New Delhi, India (Grant No. SR/S1/
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Received: January 28, 2015
Published online on && &&, 0000
&
&
Chem. Eur. J. 2015, 21, 1 – 7
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
Back to vinyl: Divinyl and arylvinyl ep-
oxides have been engaged in the gen-
eration of a pentadienyl cation, and
subsequent Nazarov cyclization pro-
duced various highly substituted cyclo-
pentadienes, hydrindienes, and indenes
with additional functional groups. Appli-
cation of this method in the synthesis
of resveratrol-based natural products
was also demonstrated.
&
Organic Chemistry
G. Sudhakar,* K. Satish
&& – &&
Nazarov Cyclization of Divinyl and
Arylvinyl Epoxides: Application in the
Synthesis of Resveratrol-Based Natural
Products
Chem. Eur. J. 2015, 21, 1 – 7
www.chemeurj.org
7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ