Evidence for Atropisomerism in Polycyclic γ-Butenolides: Synthesis, Scope, and Spectroscopic Studies

Article abstract of DOI:10.1002/chem.202005174

Design and development of a domino cyclative approach for the synthesis of new polycyclic γ-butenolides from β-aryl-Z-enoate propargylic alcohols, through the interception of an intermediate of the Z-enoate-assisted Meyer–Schuster rearrangement, has been reported. A systematic NMR analysis of various derivatives of this class revealed and supported the potential atropisomerism associated with them. These molecules represent first examples of butenolide ring-based atropisomeric compounds in organic chemistry. The synthetic process involves a synchronous construction of both rings with concurrent creation of the potential stereogenic rotational axis.

Full text of DOI:10.1002/chem.202005174

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Organic Chemistry |Hot Paper|
Evidence for Atropisomerism in Polycyclic g-Butenolides:
Synthesis, Scope, and Spectroscopic Studies
Debayan Roy and Beeraiah Baire*[a]
3a and 1,2-diketones 3b. Both unsubstituted (R=H) as well as
Abstract: Design and development of a domino cyclative
approach for the synthesis of new polycyclic g-butenolides
from b-aryl-Z-enoate propargylic alcohols, through the in-
terception of an intermediate of the Z-enoate-assisted
Meyer–Schuster rearrangement, has been reported. A sys-
tematic NMR analysis of various derivatives of this class re-
vealed and supported the potential atropisomerism asso-
ciated with them. These molecules represent first exam-
ples of butenolide ring-based atropisomeric compounds
in organic chemistry. The synthetic process involves a syn-
chronous construction of both rings with concurrent crea-
tion of the potential stereogenic rotational axis.
b-alkyl-substituted Z-enoates have been successfully employed
in this reaction. According to the proposed mechanism, the
possible intermediates are alkoxyfuranyl allene 2 and cyclic or-
thoester 4a. The orthoester 4a upon ring-opening will lead to
the products 3a and 3b.
In continuation of our efforts in exploring this versatile trans-
formation, we aimed to develop an approach for the prototyp-
ical synthesis of potential g-butenolide-based atropisomeric
compounds 5 through the competitive ethanol elimination
from the cyclic orthoester 4b (Scheme 1B) over the usual ring-
opening (Scheme 1A). These structures 5 represent a novel
and unprecedented class of polycyclic butenolides and may
exhibit atropisomerism due to the restricted rotation across
the CÀC bond connecting the butenolide and the bicyclic
system. To promote the elimination of ethanol from 4b over
the competitive ring-opening (as is the case with unsubstitut-
ed as well as b-alkyl-substituted substrates (4a), Scheme 1A),
we proposed to place an aryl substituent on the b-carbon of
the Z-enoate linker of a propargylic alcohol with an intramolec-
ular arene nucleophile such as 1b. According to our design,
the +mesomeric (+M) effect of the b-aryl ring would decline
ring opening of the cyclic orthoester 4b and promote the
elimination of ethanol.
Discovery of new classes of atropisomeric compounds is a hot
area of research as they have tremendous applications.[1] They
are frequently encountered in pharmaceuticals,[2] bioactive nat-
ural products,[3] and as chiral ligands in asymmetric synthesis.[4]
The most explored atropisomeric structures possess six-mem-
bered rings (carbocycles as well as heterocycles).[5] In contrast,
synthesis and study of atropisomeric units possessing at least
one five-membered ring (either carbocyclic or heterocyclic) are
less explored.[6] Therefore, the design and development of syn-
thetic strategies to access the class of five-membered atropiso-
meric structures, especially heterocycle-based ones, are highly
desirable.
To test this hypothesis, we began our investigation with b-
phenyl Z-enoate propargylic alcohol 6a (possessing phenyl as
an intramolecular nucleophile). Treatment of 6a with MsOH
(1.3 equiv) in CH2Cl2 at 08C to RT, gave the expected polycyclic
butenolide 7a in 65% yield after 12 h (entry 1, Table 1). Reac-
tion with pTSA (p-toluenesulfonic acid, entry 2) also gave the
product 7a after 12 h at 558C (at 08C, no reaction was ob-
served) but in poor yield (51%). With TfOH (trflic acid,
1.3 equiv) in CH2Cl2, the reaction was slower (24 h) at 08C to
RT but efficient (70% of 7a) and also gave 7% of 1,4-ketoester
8a (entry 3).[10b] Employing Lewis acids such as BiCl3 and
BF3·Et2O (entries 4 and 5) did not show any improvement in
the reaction outcome. We next screened various solvents (en-
tries 6–9) such as acetonitrile, 1,2-dichloroethane, toluene, and
nitromethane against TfOH (1.3 equiv). Among them, nitrome-
thane (entry 9) was found to be the best to yield the buteno-
lide 7a in 85%, along with 7% of 8a within 3 h at RT. Decreas-
ing the amount of TfOH (entries 10 and 11) resulted in an inef-
ficient process. In almost all experiments with TfOH, the 1,4-ke-
toester 8a was associated in varying amounts. Formation of
7a (path b) and 8a (path a) can be explained via two competi-
tive processes, that is, ethanol elimination versus ring opening,
from the cyclic orthoester intermediate 9a.
The g-butenolides (five-membered cyclic esters) have been
recognized as important structures as they represent the core
framework of many natural products and potential drugs.[7]
They have also been utilized as building blocks for the genera-
tion of structurally diverse complex molecules.[8] However, em-
ploying butenolides as one of the rings in atropisomeric com-
pounds are unprecedented till date.
Recently, we developed a new variant of the classical
Meyer–Schuster (M–S) rearrangement[9] (Scheme 1A), employ-
ing the Z-enoate-attached propargylic alcohol 1a for the nu-
cleophiliation of allene intermediates 2.[10] Various nucleophiles
such as ArÀH, MsOÀ, TsOÀ, ClÀ, and H2O have efficiently been
added for the synthesis of a-functionalized 1,4-enone-esters
[a] D. Roy, Dr. B. Baire
Department of Chemistry, Indian Institute of Technology Madras
Chennai 600036 Tamil Nadu (India)
E-mail: beeru@iitm.ac.in
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202005174.
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Scheme 1. A) Earlier work: the Z-enoate-assisted Meyer–Schuster rearrangement of Z-enoate propargylic alcohols.[10] B) This work: Design for the prototypical
generation of potential g-butenolide based atropisomeric compounds (G1 = H, alkyl, aryl, OH, and OMe; and G2 = H, alkyl, and OMe).
Table 1. Reaction optimization.[a]
conditions (entry 9, Table 1) and afforded the corresponding
products 7b–7p in good yields (70–91%). In case of 6d and
6e, we also isolated minor amounts of the corresponding 1,4-
ketoesters 8d (10%) and 8e (11%), respectively, along with 7d
(75%) and 7e (78%).
Interestingly, 1H NMR spectra of all these tetracyclic com-
pounds 7a–7p exhibited a unique diastereotopic character at
the methylene group present in the butenolide ring. Typical
AB-quartet (3.86, 3.71 ppm, 2H, ABq, J = 22.4 Hz, for 7a) with
a very strong geminal coupling (of 2JHÀH =23.4 Hz) was ob-
served for these two protons in all products (in Figure 2A, the
1H NMR spectrum of compound 7a is depicted). This may be
due to the presence of a chiral axis in these molecules because
of restricted rotation across the CÀC bond connecting the bu-
tenolide and dihydronaphthalene rings. Furthermore, single-
crystal X-ray diffraction analysis of compound 7b (Figure 2B)
unambiguously confirmed the presence of the b-aryl-g-buteno-
lide–dihydronaphthyl framework. This also supported our hy-
pothesis that presence of a chiral rotational axis is due to re-
stricted rotation as the dihedral angle between butenolide and
dihydronaphthalene is close to 908.[11]
Entry Acid
Equiv. Solvent T [8C]
Time [h] Yield[b] 7a [%]
1
2
MsOH
PTSA
1.3
1.3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0 to RT 12
55 12
0 to RT 24
0 to RT
0 to RT
65
51
3
CF3SO3H 1.3
70[c]
60
4
BiCl3
1.3
1.3
4
5
5
BF3OEt2
45
6
7
8
9
10
11
CF3SO3H 1.3
CF3SO3H 1.3
CF3SO3H 1.3
CF3SO3H 1.3
CF3SO3H 0.6
CF3SO3H 0.1
0 to RT 3.5
10
1,2-DCE 0 to RT 12
60[d]
60[e]
85[f]
56[g]
35
toluene 0 to RT
CH3NO2 0 to RT
CH3NO2 0 to RT
7
3
6
CH3NO2 0 to RT 12
Encouraged by the observed atropisomerism in butenolide–
dihydronaphthyl systems, we next synthesized analogous 3-ar-
ylbutenolide-dihydroquinolines (7q–7s) as well as 3-arylbute-
nolide-chromenes (7t, 7u) by changing the linker from
À(CH2)2À to [ÀCH2-N(Ts)À] and [ÀCH2ÀOÀ], respectively
(Figure 3) to understand the influence of heteroatoms on the
atropisomeric behavior. For all these compounds (7q–7u) a
better diastereotopic behavior of butenolide methylene pro-
tons was observed. In case of dihydroquinoline products 7q–
7s, the ‘NÀCH2’protons also exhibited two distinct doublets.
This behavior suggests that these two protons are also in mag-
[a] All reactions were carried out in 0.2 mmol of 6a in 5 mL of solvent.
[b] Yields are after chromatographic purification. [c] 7% of 8a. [d] 11 % of
8a. [e] 15% of 8a. [f] 7% of 8a. [g] 17% of 8a.
Subsequently, we performed a scope study by employing
various b-aryl-Z-enoate propargylic alcohols for the generation
of structurally divergent butenolide-based potential atropiso-
meric compounds (Figure 1). Various intramolecular arene nu-
cleophiles, propargylic alcoholic substituents, and b-aryl
groups were screened. All substrates 6b–6p smoothly under-
went the domino-double cyclization under standard reaction
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Figure 1. Scope study for divergent butanolide-based potential atropisomeric compounds; conditions: TfOH (1.3 equiv), CH3NO2, 08C to RT.
1
Figure 2. A) Observation of possible butyrolactone-based atropisomerism through the analysis of H NMR spectrum of 7a; B) ORTEP diagram for com-
pound 7b.
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Figure 3. Designed dihydroquinoline and naphthopyran substrates to understand the heteroatom effect on the atropisomerism of g-butenolide derivatives.
netically distinct environments, which supports the proposed
atropisomerism. The 1H NMR spectrum of compound 7q exhib-
its diastereotopicity with very broad signals for all protons; this
may be due to the lower rotational barrier compared to more
sterically crowded 7r and 7s. The two naphthopyran–buteno-
lides 7t and 7u that differ in ‘methyl vs. tert-butyl’ on the
pyran ring were also studied. The ÀOCH2À protons of the
methyl-substituted chromene derivative 7t shows only a 2H
singlet at 4.58 ppm and an AB-quartet (diastereotopicity) for
the butenolide methylene (3.85, 3.70 ppm; 2H, ABq, J = 23.5
Hz). On the other hand, the tert-butyl derivative 7u exhibited
two doublets for ÀOCH2À protons (at 4.30 and 5.05 ppm; dia-
stereotopic behavior) as well as AB quartet for the butenolide
methylene protons. This suggests that higher the steric hin-
drance, higher the rotational barrier and hence stronger the
atropisomerism.
erate the corresponding sulfonate 9 in 82% yield. However,
the H NMR spectrum of 9 shows the presence of only a single
1
product instead of a mixture of diastereomers. Furthermore, 9
does not exhibit any atropisomerism as the butenolide–meth-
ylene appears as a singlet at RT instead of AB quartet (compare
i and ii; Figure 4A). It appears that the addition of the sulfonic
acid moiety reduced the barrier for the restricted rotation by
moving away from the phenyl ring on the butenolide in com-
parison to 7g. Single-crystal X-ray diffraction analysis of com-
pound 9 confirmed the distal location of the camphor moiety
and also the structure of 9 (Figure 4B).[13] However, to reinforce
the atropisomeric behavior of 9, we performed a variable-tem-
perature (VT) NMR study (Figure 4A). Accordingly, 1H NMR
spectra were recorded from 0 to À508C with intervals of 108C.
The atropisomeric (diastereotopic) behavior of butenolide–
methylenes began to reappear only at À40 and À508C (vii &
viii; Figure 4A). This supported the proposal of poor rotational
barrier for 9 compared with 7g.
Next, we aimed at the separation of the enantiomers of
these hypothetical atropisomers as corresponding diastereo-
mers by attaching a chiral entity (point chirality) such as chiral
camphor sulfonic acid (Figure 4).[12] Accordingly, the butenolide
7g, which exhibits atropisomeric behavior (see i, Figure 4A),
was treated with (1S,4R)-10-camphorsulfonyl chloride in the
presence of DMAP (4-dimethylaminopyridine) and TEA (trie-
thylamine) in dichloromethane at ice-cold temperature to gen-
In continuation, we have also oxidized few of the dihydro-
naphthalenes 7d, 7e, and 7p to the corresponding naphtha-
lenes 10d, 10e, and 10p by treating with DDQ (2,3-dichloro-
5,6-dicyano-1,4-benzoquinone) in refluxing toluene and ana-
1
lyzed their H-NMR spectra (Scheme 2). Both 10e and 10p ex-
hibited the loss of diastereotopic character, that is, atropiso-
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Figure 4. A) Variable temperature (VT) 1H NMR analysis of compound 9; B) ORTEP diagram for compound 9.
merism, whereas 10d showed a weak AB quartet (see the Sup-
1
porting Information for H NMR spectra). At this stage, we do
not have any other evidence to support the observed atropiso-
merism in our polycyclic g-butenolide frameworks.
Apart from exhibiting prototypical atropisomerism, this new
class of butenolides can also be useful as building block for
the synthesis of various functionalized polycyclic systems
(Scheme 3). Treatment of 7a with NaBH4 in MeOH gave the hy-
droxyketone 11 in 96% yield via a reductive ring opening. Sim-
ilarly, refluxing 7b and tryptamine in acetic acid (AcOH) and
toluene gave the ketoamide 12. On the other hand, reaction
of 7b with salicylaldehyde in the presence of Et3N afforded the
Scheme 2. Aromatization of dihydronaphthalenes.
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Scheme 3. Synthetic transformations of 4-(dihydronaphthyl)-3-arylbutenolides.
polycyclic coumarin 13 in 81% yield through a domino Knoe-
venagel condensation–trans-lactonization reaction sequence.
In conclusion, we have discovered a domino cyclization ap-
proach for the synthesis of a new class of g-butenolide deriva-
tives from b-aryl-Z-enoate propargylic alcohols through the in-
terception of an intermediate of the Z-enoate-assisted Meyer–
Schuster rearrangement. A systematic NMR analysis of various
derivatives of this class of molecules revealed the potential
atropisomerism associated with them. These molecules repre-
sent a first example of atropisomeric compounds consisting of
butenolide ring in organic chemistry. The synthetic process in-
volves a synchronous construction of both rings with the con-
current creation of the potential stereogenic rotational axis.
The synthetic utility of these polycyclic butenolides has also
been demonstrated.
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Acknowledgements
We thank Indian Institute of Technology Madras, Chennai for
infrastructural facility, and SERB-INDIA, for financial support
(CRG/2019/000988). DR thanks IIT Madras for HTRA fellowship.
We also thank Dr. Prabhakararao Tharra for his help during an
initial experimentation.
Conflict of interest
The authors declare no conflict of interest.
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[11] Deposition Number 1881525 contains the supplementary crystallo-
graphic data for this paper. These data are provided free of charge by
Keywords: atropisomerism · butenolides · domino cyclization ·
Meyer–Schuster rearrangement · propargylic alcohols
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the joint Cambridge Crystallographic Data Centre and Fachinforma-
tionszentrum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
the joint Cambridge Crystallographic Data Centre and Fachinforma-
tionszentrum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
[12] We attempted the enantiomeric separation of some of these atropiso-
meric compounds on a chiral-HPLC. But all attempts with a combina-
tion of several solvent mixtures against different chiral columns failed
to provide separation for any of these compounds.
Manuscript received: December 2, 2020
Revised manuscript received: December 22, 2020
Accepted manuscript online: December 30, 2020
Version of record online: January 31, 2021
[13] Deposition Number 2039430 contains the supplementary crystallo-
graphic data for this paper. These data are provided free of charge by
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