An Approach for the Generation of γ-Propenylidene-γ-butenolides and Application to the Total Synthesis of Rubrolides

Article abstract of DOI:10.1021/acs.orglett.1c01529

Design and synthesis of a new class of γ-butenolides, viz. β-aryl-γ-propenylidene-γ-butenolides, have been reported from β-aryl-Z-enoate propargylic alcohols in the presence of acid. Isolation of β-aryl-γ-propenylidene-γ-butenolides and their O18-isomer c

Full text of DOI:10.1021/acs.orglett.1c01529

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Letter
An Approach for the Generation of γ‑Propenylidene-γ-butenolides
and Application to the Total Synthesis of Rubrolides
Debayan Roy, Prabhakararao Tharra, and Beeraiah Baire*
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ABSTRACT: Design and synthesis of a new class of γ-butenolides, viz. β-aryl-γ-propenylidene-γ-butenolides, have been reported
from β-aryl-Z-enoate propargylic alcohols in the presence of acid. Isolation of β-aryl-γ-propenylidene-γ-butenolides and their O18-
isomer confirmed the intermediacy of the allenyl-lactonium ion as well as the cyclic-hemiacetal during the proposed mechanism. By
utilizing the β-aryl-γ-methylenecyclohexenylidene-γ-butenolides as starting materials, a highly stereoselective and efficient approach
has been developed for the syntheses of frameworks of rubrolide natural products. This strategy was further extended for the total
synthesis of rubrolide E.
he allenes (1,2-dienes) are found to be part of many
1
Tbioactive natural products and have also been employed
as important functional groups for the development of many
novel synthetic methodologies.2 These moieties exhibit diverse
bioactivities and they have also been incorporated into the
existing backbone of the biologically active molecules to
further “tune” their biological and pharmacological proper-
ties.1b,c Because of their diverse bioactivities, many synthetic
methodologies have been developed for an efficient synthesis
of structurally diverse allenes.3 One among many such
approaches is the use of propargylic alcohols and their
Figure 1. Representative approaches for allenes from propargylic
alcohols and their derivatives.
1
2
derivatives as starting materials through SN as well as SN ′
mechanisms as depicted in Figure 1.4 Herein, we designed and
developed a Brønsted acid promoted approach for the
generation of γ-propenylidene-γ-butenolides from β-aryl-Z-
enoate propargylic alcohols.
In 2016, our research group developed a new variant of the
classical Meyer−Schuster (M−S) rearrangement5 of prop-
argylic alcohols (Figure 2) possessing a Z-enoate moiety on
their alkyne terminus 1a−c. The Z-enoate helped us to reverse
the electronic properties of the hypothetical allenol inter-
mediate 2 (in classical M−S) from being nucleophilic at the
central sp-carbon to electrophilic as in 3a−c, for the
nucleophilation. Both unsubstituted (R = H; 1a) as well as
β-alkyl (R= alkyl; 1b) substituted Z-enoate linkers have been
successfully employed against various nucleophiles such as Ar-
H, −OMs, −OTs, Cl−, and H2O for the synthesis of 1,4-
ketoesters 4a/b as well as 1,2-diketones 5a/b.6
generate the alkoxyfuran intermediate 6a/b. This 6a/b upon
addition of water gives the cyclic hemiacetal 7a/b, which
further involves a ring opening to generate the products 4a/b
and 5a/b.
Recently,7 we have also employed the β-aryl-Z-enoate
propargylic alcohols 1c for the first synthesis of butenolide-
based potential atropisomeric compounds 8 through the
intramolecular arene trapping. In this reaction, the β-aryl
group on the Z-enoate (due to + mesomeric effect) declined
Received: May 7, 2021
Published: July 14, 2021
According to the working mechanism, the initially formed
allenyl-lactonium ion 3a/b will undergo nucleophilic attack to
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© 2021 American Chemical Society
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Table 1. Discovery and Reaction Optimization for β-Aryl-γ-
propenylidene-γ-butyrenolides
Figure 2. Z-Enoate-assisted Meyer−Schuster rearrangement of Z-
enoate propargylic alcohols (reported work).
the ring-opening from the tetrahedral cyclic hemiacetal
intermediate 7c and promoted the competitive elimination of
EtOH.
Motivated by the distinct reactivity observed with β-aryl-Z-
enoate propargylic alcohols 1c,7 in continuation, we turned our
attention to study β-aryl-Z-enoate propargylic alcohols 9 in the
absence of both intramolecular as well as external nucleophiles
under acidic conditions (Figure 3). According to our
SN2′ reaction to give the product 12a in good yields (65−
90%). In the case of 1.3 equiv of MsOH (entry 7), the reaction
took 2.5 h at 0 °C to rt and gave an excellent yield (90%) of
12a. It is important to mention that none of the above
reactions afforded other competitive products such as the
mesylate trapped product 14a or 4-acylbutenolide 14′a.6d This
again supported the influence of the β-aryl group to induce the
distinct reactivity. An increase in the temperature (55 °C, entry
8) resulted in an unidentified complex mixture. Employing
pTSA (entry 9) resulted in 68% of 12a after 3.5 h. On the
other hand, a relatively weaker Brønsted acid CF3CO2H (entry
10) failed to promote the reaction to give the product 12a.
Various Lewis acids (like, FeCl3, BiCl3, SnCl4, SnCl2, and
AgOTf) failed to give any traces of the product 12a.
After achieving the optimal conditions (entry 7, Table 1), we
sought to explore the substrate scope to understand the
generality of the process and stability of β-aryl-γ-propenyli-
dene-γ-butenolide products (Scheme 1). Various cyclic and
acyclic propargylic alcohols 9b−k were found to smoothly
undergo the reaction to provide the corresponding β-aryl-γ-
propenylidene-γ-butenolides 12b−k in good yields (71−91%)
within 1−7.5 h. The reaction of substrate 9l, with electron-
poor β-aryl (m-NO2-Ph) was found to be very slow and gave
only 46% of the allene 12l with 52% conversion, after 10 h. It is
important to mention that all these allenes were found to have
very short lifetime (5−30 min) at rt (30 °C), whereas they
were stable for 1−3 days when stored at low temperature (<0
°C).8
After learning the reactivity of β-aryl-Z-enoate propargylic
alcohols in the absence of nucleophiles, we planned to
understand the mechanistic insights of this process through
the designed control experiments (Scheme 2). Accordingly, we
performed the reactions with 9a and 9h employing standard
reaction conditions under oxygen atmosphere to see the effect
of the external oxygen (Scheme 2A). But the outcome was very
similar to the one in the absence of oxygen. Next, we
performed an O18-labeling control experiment (Scheme
2B).When 9g was subjected to standard reaction conditions
in the presence of H2O18, an O18 incorporation was observed
(by ESI-HRMS) in the β-aryl-γ-propenylidene-γ-butenolide
Figure 3. Design for the generation of novel γ-propenylidene-γ-
butenolides (present work).
hypothesis, in the absence of nucleophiles, the allenyl-
lactonium ion intermediate 10 can undergo formation of
cyclic hemiacetal 11 followed by EtOH elimination to generate
the β-aryl-γ-propenylidene-γ-butyrolactone 12 (path a). On
the other hand, 10 can be trapped either by the counterion X−
or by water, followed by another molecule of water addition to
generate a new type of cyclic hemiacetal 13 (path b). This 13,
upon EtOH elimination, would give the corresponding 4-
vinylbutenolide 14 (Y = X) or 4-acylbutenolide 14′ (Y = OH).
We began our initial investigation with β-phenyl Z-enoate
propargylic alcohol 9a in the absence of any added
nucleophiles (Table 1). Conducting the reaction of 9a using
0.1 equiv of methanesulfonic acid (MsOH) in different
solvents such as CH2Cl2, DMF, and ethyl acetate at 0 °C to
rt (entries 1−3, Table 1) failed to give any of the expected/
proposed products instead 9a was recovered. To our delight,
increasing the acid amount to 0.2 equiv in CH2Cl2 (entry 4)
gave traces (5%) of a new compound 12a. This was found to
be one of the expected products, β-aryl-γ-propenylidene-γ-
butyrolactone 12a. Further, an increase in the amount of acid
(MsOH) from catalytic to stoichiometric (0.5 to 1.0 to 1.3
equiv, entries 5−7) smoothly promoted the intramolecular
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Subsequently, we envisioned an opportunity to employ these
allenes 12 as building blocks for the synthesis of structurally
novel β-aryl-γ-vinylbutenolides 14′′ by adding the arene
nucleophiles at the allene center (Scheme 3A). Accordingly,
Scheme 1. Scope for β-Aryl-γ-propenylidene-γ-butenolides
Scheme 3. (A) Reactions of β-Aryl-γ-propenylidene-γ-
butenolides with Arene Nucleophiles; (B) NOESY
Correlations of 15f to Support the Z-Configuration; (C)
Rationale for the Observed High Z-Selectivity
Scheme 2. (A) Reaction under Oxygen Atmosphere; (B)
O18-Labeling Experiment to Support the Intermediacy of
the Cyclic Hemiacetal; (C) Possible Mechanism for the
Formation of β-Aryl-γ-propenylidene-γ-butenolides
the allene 12g was treated with MsOH (1.3 equiv) in the
presence of arenes such as anisole, 1,3,5-trimethoxybenzene,
resorcinol and N-Me-indole.6b,e In all cases, the allene 12g was
found to be inert toward the addition of arenes and resulted in
an isomerized Z-triene 15g (with ∼100% Z-stereoselectivity;
89%, 89%, 84% and 87% respective yields) instead of arene
incorporated product 14′′.
12g-O18. The HRMS data shows a (∼1.0:0.75) ratio of 12g
and 12g-O18 (derived from the relative heights of the
corresponding molecular ion peaks).9 Accordingly, the
respective yields of 12g and 12g-O18 were calculated to be
31% and 23% (overall 54% isolated yield). This result
supported the involvement of water and an existence of a
cyclic-hemiacetal intermediate 11 during the reaction. Based
on these observations, we proposed a possible mechanism
(Scheme 2C). The β-aryl-Z-enoate propargylic alcohol 9
initially undergoes an intramolecular SN2′ process to generate
the oxonium ion intermediate 10. In the absence of any
nucleophile, intermediate 10 would undergo an addition of
water to form a cyclic-hemiacetal intermediate 11. A
competitive loss of EtOH from 11 would result in the
formation of the β-aryl-γ-propenylidene-γ-butenolides 12
(Scheme 2C).
This observation suggests that the allenes 12 does not
exhibit any electrophilic character at the central carbon. In the
absence of arene nucleophiles also the reaction of 12g gave the
triene 15g (94%). Further, we treated the allenes 12a, 12e−f
with MsOH in the absence of arenes to see the generality of
this highly stereoselective isomerization process. In all cases,
the corresponding isomerized products 15a, 15e−f (Z-
isomers) were obtained in excellent yields. Further, the
stereochemistry at the alkylidene olefin was confirmed as Z-
configuration through the observed correlations in NOESY-
NMR of the compound 15f (Scheme 3B).10 Interestingly,
these correlations also evidenced the existence of s-trans
conformation of the diene unit consisting of exo-olefin and
cyclic-olefin.
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A possible rationale for the observed stereoselectivity during
the isomerization of allenes is described (Scheme 3C).
Accordingly, the allene 12 upon protonation can give two
rotamers 16a and 16b (across the C−C bond connecting
lactone and olefin). Between them, 16a is highly favored due to
no or less steric interactions, on the other hand 16b is
unfavored because of severe steric repulsions between phenyl
group and cyclohexane hydrogens. Hence 16a is highly
populated at the equilibrium and rapidly undergoes a
deprotonative-isomerization to give the Z-isomer 15-Z as the
exclusive product. The formation E-isomer 15-E is not possible
as 16b converts to 16a.
Since the isomerization of allenes to trienes was found to be
highly feasible process, we envisioned an opportunity to
employ the cyclohexene based trienes such as β-aryl-γ-
methylene-cyclohexenylidene-γ-butenolide 12a, as building
blocks for the total synthesis of rubrolide natural products.
The rubrolides share a common β-aryl-γ-alkylidene-γ-buteno-
lide framework among them (Scheme 4A). Initially, the
DDQ (3 equiv) in refluxing benzene underwent aromatization
to result in the formation of complete framework 20 of
rubrolide natural products in 92% yield (step 3). The
compound 20 represents the dideoxyrubrolide E and deoxy-
didehydroxenofuranones A and B (Scheme 4A). The complete
synthetic scheme involves five steps and provides the
framework 20 in 66% overall yield from commercially available
β-ketoester 17. The same methodology has also been extended
for the synthesis of two other frameworks 21 and 22 from
corresponding alcohols 9b and 9m. In these cases, we have
used the worked up crude mixtures obtained (without
purification and characterization) from each step (steps 1−3;
Scheme 4C) for the subsequent reactions. The rubrolide
frameworks 21 and 22 were obtained with an overall yield of
68% and 70%, respectively (for three steps), directly from the
corresponding Z-enoate propargylic alcohols 9b and 9m.
Subsequently, we extended this methodology for the total
synthesis of rubrolide E (Scheme 5). Many synthetic
Scheme 5. Total Synthesis of Rubrolide E
Scheme 4. Highly Stereoselective and Efficient Approach to
Rubrolide Frameworks
approaches have already been reported for this molecule.13
Accordingly, the β-aryl-β-iodo enoate 23 was prepared from
the reaction of corresponding propynoate 2414 with NaI in
AcOH.15 Next, treatment of the 4-methoxycyclohexanone 2516
with ethynylmagnesium bromide in THF gave an inseparable
(3:1) mixture of anti:syn alcohol 26 (91% yield). The alcohol
26, upon Sonogashira cross coupling with 23 in the presence of
Pd(II) and Cu(I), generated the Z-enoate propargylic alcohol
9d in 94% yield.
Next, we employed the sequential three-step strategy for the
direct conversion of the propargylic alcohol 9d into the (di-O-
methyl)rubrolide E 27, without isolating any of the
intermediates. First, reaction of 9d with MsOH (1.3 equiv)
in CH2Cl2 at 0 °C to rt for 7.5 h followed by treatment of the
worked up crude reaction mixture with 0.3 equiv of MsOH in
CH2Cl2 for 10.5 h was performed. The obtained crude mixture
after the workup was further treated with DDQ (3 equiv) in
benzene to generate the (di-O-methyl)rubrolide E 27 in 69%
overall yield after three steps in a highly stereoselective
manner. The compound 27 upon treatment with BBr3 in
CH2Cl2 underwent the deprotection of two methyl groups and
gave the rubrolide E in 96% yield.17
rubrolides have been isolated from the metabolites of the
colonial tunicate Ritterella rubra as well as the ascidian
Synoicum blochmanni and found to exhibit diverse bioactiv-
ities.11
Initially, development of an approach for the rubrolide
framework was undertaken (Scheme 4B). The β-ketoester 17
upon treatment with Tf2O and aq LiOH gave the vinyltriflate
18.12 Compound 18 upon Sonogashira cross coupling with
propargylic alcohol 19, in the presence of Pd(II) and Cu(I)
catalysts, generated the required Z-enoate propargylic alcohol
9a in 94% yield. Treating this alcohol 9a with MsOH (1.3
equiv) for 2.5 h afforded the allene 12a in 90% yield (entry 7,
Table 1; step 1). Further reaction of the allene 12a with
MsOH (30 mol %) at 0 °C to rt gave the Z-triene 15a in 93%
yield after 9 h (step 2). The triene 15a upon treatment with
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In conclusion, we have discovered and explored an approach
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Experimental procedures, spectroscopic data, and copies
1
of H and 13C NMR spectra for all new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Beeraiah Baire − Department of Chemistry, Indian Institute of
Technology Madras, Chennai 600036 Tamilnadu, India;
orcid.org/0000-0001-8810-1620; Email: beeru@
iitm.ac.in
Authors
Debayan Roy − Department of Chemistry, Indian Institute of
Technology Madras, Chennai 600036 Tamilnadu, India
Prabhakararao Tharra − Department of Chemistry, Indian
Institute of Technology Madras, Chennai 600036
Tamilnadu, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01529
Author Contributions
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(c) Chen, M.; Qian, D.; Sun, J. Organocatalytic enantioconvergent
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carbinols into unsaturated ketones. Ber. Dtsch. Chem. Ges. B 1922, 55,
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Schuster rearrangements. Chem. Rev. 1971, 71, 429−438. (c) Engel,
D. A.; Dudley, G. B. The Meyer−Schuster rearrangement for the
synthesis of α, β-unsaturated carbonyl compounds. Org. Biomol. Chem.
2009, 7, 4149−4158. (d) Zhang, B.; Wang, T. Gold-Catalyzed
Transformations of Propargyl Alcohols and Propargyl Amines. Asian J.
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D.R. performed the majority of the experiments and was
involved in the preparation of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Indian Institute of Technology Madras, Chennai,
for the infrastructural facility and SERB-INDIA for financial
support (CRG/2019/000988). D.R. and P.T. thank IIT
Madras for HTRA fellowships. We thank Ms. Sindoori R.
Nair for her help during the revision of this manuscript.
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