Asymmetric total syntheses of megacerotonic acid and shimobashiric acid A

Article abstract of DOI:10.1021/acs.orglett.5b00140

The asymmetric total syntheses of the α-benzylidene-γ-butyrolactone natural products megacerotonic acid and shimobashiric acid A have been accomplished in nine and 11 steps, respectively, from simple, commercially available starting materials. The key step for each synthesis is the (arene)RuCl(monosulfonamide)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation (DKR-ATH) of racemic α,δ-diketo-β-aryl esters to establish the absolute stereochemistry. Intramolecular diastereoselective Dieckmann cyclization forms the lactone core, and ketone reduction/alcohol elimination installs the α-arylidene.

Full text of DOI:10.1021/acs.orglett.5b00140

Letter
pubs.acs.org/OrgLett
Asymmetric Total Syntheses of Megacerotonic Acid and
Shimobashiric Acid A
Scott W. Krabbe and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
ABSTRACT: The asymmetric total syntheses of the α-
benzylidene-γ-butyrolactone natural products megacerotonic
acid and shimobashiric acid A have been accomplished in nine
and 11 steps, respectively, from simple, commercially available
starting materials. The key step for each synthesis is the
(arene)RuCl(monosulfonamide)-catalyzed dynamic kinetic
resolution-asymmetric transfer hydrogenation (DKR-ATH)
of racemic α,δ-diketo-β-aryl esters to establish the absolute
stereochemistry. Intramolecular diastereoselective Dieckmann cyclization forms the lactone core, and ketone reduction/alcohol
elimination installs the α-arylidene.
atural products containing an α-benzylidene-γ-butyrolac-
activity.7 Although a number of other natural products isolated
from these extracts showed biological activity, the isolation of
1b in a small quantity (1.2 mg) precluded the investigation of
its biological activity.
N
tone1 elicit a wide variety of biological responses,
including antiviral,2 anticancer,3 antifungal,4 and anti-inflamma-
tory activities.5 To date, megacerotonic acid6 1a and
shimobashiric acid A7 1b are the only known members of
this natural product class that contain both C3-aryl and C4-
carboxylic acid substituents (Scheme 1).8 A racemic total
Our laboratory recently reported facile access to enantioen-
riched γ-butyrolactones containing the required C3-aryl and
C4-carboxylate functionality,10 potentially providing rapid entry
to structures 1a and 1b. Approaching the retrosynthetic analysis
of these natural products (Scheme 1), we envisioned Heck
coupling of α-methylene lactone 2 with the appropriate
haloarene (Ar2−X), allowing late-stage installation of a variety
of benzylidene substituents and providing a modular approach
to this class of natural products. Synthetic access to 2 would be
achieved by a known three-step procedure utilizing ruthenium
catalyzed dynamic kinetic resolution asymmetric transfer
hydrogenation (DKR-ATH) of racemic β-aryl-α-keto esters
followed by in situ diastereoselective lactonization.10 Racemic β-
aryl-α-keto esters 3 can be prepared in a single step using a
previously reported glyoxylate Stetter addition.
Initial investigation into this proposed synthetic pathway
focused on the optimization of a route to 1a as we believed the
same pathway would also be applicable to 1b (Scheme 2).
DKR-ATH of β-aryl-α-keto ester 3 with concomitant
lactonization smoothly provided γ-butyrolactone 4 in high
diastereo- and enantioselectivity following a single recrystalliza-
tion. Bromomethylation using dibromomethane followed by
LiCl-promoted Krapcho dealkoxycarbonylation/elimination11
provided α-methylene lactone 2 for investigation of the
projected Heck coupling.
Scheme 1. Retrosynthetic Analysis
synthesis of megacerotonic acid has been reported,9 but its
biological activity has not been investigated. The purpose of
this communication is to report the first asymmetric total
syntheses of megacerotonic acid and shimobashiric acid A via a
route that should be amenable to the preparation of unnatural
congeners.
Megacerotonic acid was isolated by Takeda and co-workers
from Megaceros flagellaris in 1990, and no investigation of its
biological activity data has been reported to date.6 At the time
of its isolation, megacerotonic acid was the only known γ-
butyrolactone natural product to contain the C2-arylidene-C3-
aryl-C4-carboxylic acid substitution pattern. Papin and co-
workers9 carried out a racemic synthesis, unambiguously
establishing its structure. The only other natural γ-butyr-
olactone known with this substituent array, shimobashiric acid
A, was isolated by Murata and co-workers in 2012 from Keiskea
japonica after its extracts showed hyaluronidase inhibitory
Extant methodologies for Heck couplings that deliver
exocyclic alkenes are generally limited to β-unsubstituted- or
β-alkyl-α-methylidene lactones.12 Kim and co-workers reported
Received: January 15, 2015
Published: February 20, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00140
Org. Lett. 2015, 17, 1188−1191

Organic Letters
Letter
Scheme 2. Preliminary Route
Scheme 5. Revised Retrosynthetic Analysis
(monosulfonamide) catalyzed DKR-ATH, providing alcohol
14a in excellent yield with high diastereo- and enantioselectivity
(Scheme 6A).10 Installation of the requisite activated carbonyl
functionality was achieved with 1,1′-carbonyldiimidazole to give
tricarbonyl 15a.18 Selective enolate formation with potassium
bis(trimethylsilyl)amide (KHMDS) led to a diastereoselective
Dieckmann cyclization that delivered 9a. A subsequent ketone
reduction to alcohol 8a was achieved with Pd/C and H2.19
Dehydration to enone 6a (Scheme 6B) was promoted by
polymer supported perfluorosulfonic acid (Nafion SAC-13). In
our hands, the reported ester epimerization and hydrolysis9 of
6a using lithium methoxide/methanol resulted in a number of
undesired byproducts. Switching to sodium tert-butoxide in tert-
amyl alcohol smoothly provided acid 16a as a 14:1 mixture of
chromatographically inseparable diastereomers. Boron tribro-
mide-mediated demethylation and purification by reverse phase
HPLC completed the first asymmetric total synthesis of
megacerotonic acid 1a in nine steps and 11% overall yield
from commercially available materials.
The route to 1b was identical to 1a through the synthesis of
alcohol 8b (Scheme 6A). When 8b was submitted to the
elimination conditions optimized for 8a (Scheme 6B), enone
6b was not formed, and only partial Boc deprotection was
observed, even at elevated temperatures (100 °C). We sought a
solution to this problem that would obviate the necessity of
electron rich arenes and found that the Burgess reagent met
this need, providing enone 6b as well as less electron rich α-
benzylidene-γ-butyrolactones 6c and 6d, prepared via the same
synthetic route (Scheme 7).20
the only example of Heck coupling using β-aryl-α-methylidene
lactones, and formation of the butenolide was heavily favored
over the desired exocyclic alkene.13 In our investigations,
optimization of this coupling protocol provided arylidene 6a in
only 19% yield (Scheme 3).14 Additionally, methylidene 2 was
unreactive toward cross-metathesis with styrenes.15
Scheme 3. Access to 6a via Heck Coupling
Consequently, we turned our attention to an alternative
route from lactone 4, which would allow late stage installation
of different benzylidene substituents (Scheme 4). Krapcho
dealkoxycarbonylation of lactone 4 provided lactone 7 in good
yield.16 Aldol reaction of lactone 7 with p-anisaldehyde
followed by acid catalyzed elimination provided 6a.17
Scheme 4. Krapcho Dealkoxycarbonylation/Aldol/
Elimination Sequence
tert-Butoxycarbonyl removal, epimerization at C4, and
hydrolysis provided 16b in good overall yield as a 14:1 mixture
of chromatographically inseparable diastereomers. Acetal
deprotection and purification by reverse phase HPLC provided
shimobashiric acid A 1b in 11 steps and 5% overall yield from
commercially available material.21
In conclusion, we have reported the first asymmetric total
syntheses of structurally unique α-benzylidene-γ-butyrolactones
megacerotonic acid and shimobashiric acid A via a route
amenable to the synthesis of analogues. This route utilized
DKR-ATH to establish the absolute stereochemistry in
excellent enantio- and diastereoselectivity, and diastereoselec-
tive Dieckmann cyclization formed the lactone core in high
overall yield. Selective ketone reduction and subsequent
elimination formed the α-benzylidene with excellent E:Z
selectivity. Epimerization at C4, hydrolysis, and phenol
deprotection concluded the first asymmetric total syntheses
of megacerotonic acid and shimobashiric acid A. Screening of
the synthesized natural products and analogues thereof for
relevant biological activity is currently underway and will be
reported in due course.
This modified route provided key intermediate 6a in a
disappointing three step overall yield of 20%; however, the
viability of alcohol elimination prompted us to consider a new
retrosynthetic analysis for alcohol 8a (Scheme 5). In this
proposed sequence, access to 8a would be provided by
reduction of β-keto lactone 9, which would arise from (4 +
1)-annulation between a synthetic equivalent of 10 and a
phosgene surrogate (11). DKR-ATH of α,δ-diketo-β-aryl ester
12 would establish the absolute stereochemistry.10
α,δ-Diketo-β-aryl ester 12a was prepared via N-heterocyclic
carbene-catalyzed Stetter reaction of ethyl glyoxylate with
enone 13a10 and was directly submitted to (arene)RuCl-
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DOI: 10.1021/acs.orglett.5b00140
Org. Lett. 2015, 17, 1188−1191

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Letter
Scheme 6. Synthetic Route to Megacerotonic Acid and Shimobashiric Acid A
Scheme 7. Eliminations with the Burgess Reagent
ACKNOWLEDGMENTS
■
The project described was supported by Award No. R01
GM084927 from the National Institute of General Medical
Sciences. S.W.K. acknowledges a National Science Foundation
Graduate Research Fellowship. The authors thank Professor
Marcey Waters, Brendan Peacor, and Nicholas Pinkin (UNC)
for use of and assistance with reverse phase HPLC systems, and
Professor Michael Crimmins (UNC) for helpful discussions. A
natural sample of shimobashiric acid A was generously provided
by Professor Toshihiro Murata (Tohoku Pharmaceutical
University).
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Experimental procedures, characterization, and spectral data for
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jsj@unc.edu.
Notes
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