Total synthesis of (±)-merrilactone A via catalytic Nazarov cyclization

Article abstract of DOI:10.1021/ja068150i

The total synthesis of merrilactone A (a neurotrophic agent) has been achieved. In the approach reported, simultaneous creation of the C-4 and C-5 stereocenters was accomplished stereospecifically using an unprecedented variant of the Nazarov cyclization. Additional studies focused upon this Lewis acid-catalyzed cyclization of a silyloxyfuran-containing intermediate are presented. Copyright

Full text of DOI:10.1021/ja068150i

Published on Web 12/22/2006
Total Synthesis of (()-Merrilactone A via Catalytic Nazarov Cyclization
Wei He, Jie Huang, Xiufeng Sun,† and Alison J. Frontier*
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627
Received November 14, 2006; E-mail: frontier@chem.rochester.edu
Merrilactone A (1, Scheme 1) is a structurally unique pentacyclic
sesquiterpene dilactone isolated in 2000 by Fukuyama and co-
workers from the Illicium merrillianum. It was identified as a potent
nonpeptidal neurotrophic factor that promotes neurite outgrowth
in the culture of fetal rat cortical neurons at a remarkably low
concentration of 0.1 µmol/L.1 In addition to its promising bioac-
tivity, the merrilactone A pentacycle is riddled with synthetic
challenges. The molecule sports seven contiguous chiral centers,
of which three are quaternary, and bears a highly substituted
cyclopentane ring at its core (see ring C, Scheme 1). This densely
functionalized yet compact structure has captured the attention of
a number of synthetic chemists. Danishefsky and Birman achieved
the first total synthesis of (()-merrilactone A, based on a Diels-
Alder cycloaddition.2 A year later, Inoue, Sato, and Hirama reported
a strategy based on the ring contraction of a 1,4-cyclooctenedike-
tone,3 and more recently, Mehta and Singh reported a third synthesis
based on the desymmetrization of 1,4-cyclopentenedione.4 Other
novel approaches to this unique carbocyclic system have also been
disclosed.5,6 In this communication, we report an efficient stereo-
selective synthesis of (()-merrilactone A featuring the Nazarov
cyclization of a silyloxyfuryl enone as the key step.
to a wide range of Lewis acid promoters. However, it was found
that the simpler ketone 5b underwent smooth Nazarov cyclization
catalyzed by the dicationic catalyst [Ir(CO)(Me)(dppe)(DIB)]2+
-
(BArf)- (6)9 to give the enol silane 7 (eq 1). Copper triflate
2
did not catalyze the cyclization of 5b, possibly because it lacks
the electron-withdrawing group important for reactivity in polar-
ized Nazarov cyclizations.7 Triisopropylsilyl triflate also did not
catalyze the cyclization of 5b, underlining how important the strong
Lewis acid character of IrIII complex 6 is to the success of the
cyclization.10
Our laboratory has been involved in developing Nazarov
cyclizations of polarized divinyl ketones.7 This research direction
was spawned by the synthetic strategy targeting merrilactone A
described herein (Scheme 1). Our overall strategy involved elabora-
tion of an intermediate of type 3 into intermediate 2, which Birman
and Danishefsky were able to convert into merrilactone A in two
steps.2 Intermediate 3 would be accessible from cyclization of a
cyclopentanoid derivative of type 4. We imagined that the adjacent
stereocenters at C-4 and C-5 of 4 could arise from the Nazarov
cyclization of an achiral precursor 5. This idea was attractive
because the 4π electrocyclization is expected to follow a conrotatory
pathway,8 which would allow stereospecific creation of both chiral
centers.
To our knowledge, these are the first examples of Nazarov
cyclizations involving a silyloxyfuran component.11 We were also
pleased to note that a quaternary center was formed during the
cyclization of 5b, which was an important prerequisite for applica-
tion to merrilactone A. These results encouraged us to embark upon
the synthesis and cyclization of the fully functionalized silyloxy-
furan 5c.
To this end, known aldehyde 812 was coupled with the lithium
anion of ethyl propiolate to give alcohol 9 (Scheme 2).13 Addition
of a higher order stannylcuprate to the alkynyl ester accompanied
by in situ lactonization gave the vinyltin compound 10 in one
synthetic operation.14 It was then possible to convert 10 to the vinyl
bromide 11 through very slow addition of bromine in dichlo-
romethane. The desired silyloxyfuran 12 was ultimately obtained
in quantitative yield by treatment with triisopropylsilyl triflate under
basic conditions. The lithium anion of 12 was generated using
Scheme 1. General Synthetic Strategy Targeting Merrilactone A
Scheme 2. Synthesis of Silyloxyfuran 5ca
Initial experiments focused on silyloxyfuran 5a, which has an
electron-rich aromatic donor and an electron-poor butenolide accep-
tor. Unfortunately, no cyclization of 5a was observed upon exposure
a Reagents and conditions: (a) ethyl propiolate with n-BuLi, THF,
-78 °C, then 8, 88%; (b) Bu3Sn(Bu)(CN)CuLi2, THF/MeOH, -78 °C, 90%;
(c) Br2, CH2Cl2, rt, 93%; (d) Et3N, triisopropylsilyl triflate, CH2Cl2, -78
to 0 °C, quantitative; (e) t-BuLi, ether, then 13, 82%.
† Present address: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT
06877.
9
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J. AM. CHEM. SOC. 2007, 129, 498-499
10.1021/ja068150i CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Completion of the Synthesisa
Scheme 3. Construction of Rings B, C, and Da
a Reagents and conditions: (a) NaBH4, MeOH, rt, 93% (22a:22b ) 1.2:
1); (b) Dess-Martin periodinane, CH2Cl2, 98%; (c) p-TsOH, benzene,
reflux, 4 h, 92%; (d) m-CPBA, CH2Cl2, rt; (e) p-TsOH, CH2Cl2, rt, 68%
over two steps.
Acknowledgment. We are grateful to the Research Corporation,
the Petroleum Research Fund, NSF (CAREER: CHE-0349045),
and the University of Rochester for generous financial support.
W.H. and A.J.F. thank Prof. Robert K. Boeckman, Jr. (University
of Rochester) for helpful discussions. Prof. Richard Eisenberg and
Dr. Mesfin Janka (University of Rochester) are acknowledged for
providing iridium catalyst 6, and we are grateful to Dr. Alice
Bergmann (University of Buffalo) for carrying out high-resolution
mass spectroscopy.
a Reagents and conditions: (a) 6 (2 mol %), CH2Cl2, 87%; (b) AgNO3,
KCN, THF/EtOH/H2O, 83%; (c) AIBN, Bu3SnH, benzene, reflux, then
p-TsOH, rt, 91%; (d) TBAF, THF, rt, 99%; (e) pyridine, DMAP,
ethylchloroformate, 95%; (f) NaH, THF, rt; (g) p-TsOH, benzene, reflux,
0.5 h, 90% from 18; (h) NaH, CH3I, HMPA, THF, rt, 97%.
t-BuLi, and addition to the R,â-unsaturated Weinreb amide 1315
gave rise to 5c in satisfactory yield.
Supporting Information Available: Experimental procedures and
spectroscopic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
As hoped, Nazarov cyclization of 5c proceeded smoothly with
the dicationic iridium catalyst 6 in dichloromethane to give a single
diastereoisomeric product 14 (Scheme 3). In this event, the
stereocenters at both C-4 and C-5 were created stereospecifically,
setting the stage for the assembly of the multiple fused rings of
target 2 (rings A-D, Scheme 1).
References
(1) (a) Huang, J.-M.; Yokoyama, R.; Yang, C.-S.; Fukuyama, Y. Tetrahedron
Lett. 2000, 41, 6111. (b) Huang, J.-M.; Yang, C.-S.; Tanaka, M.;
Fukuyama, Y. Tetrahedron 2001, 57, 4691.
Approaches involving cyclization of the protected alkyne 14 did
not provide access to ring B. However, removal of the trimethylsilyl
group allowed smooth radical cyclization of the resultant 1,6-enyne
15, and treatment with acid led to protiolysis of the intermediate
vinyl stannane to give the exocyclic olefin (16).16 Fluoride-induced
deprotection of the resultant 16 furnished the hydroxyketone 17,
which was easily converted to the carbonate 18.17 Treatment of 18
with excess NaH in THF triggered intramolecular nucleophilic
lactonization18 to give a 1:1 mixture of desired bislactone 20 and
its open counterpart 19. Treatment of this mixture with p-
toluenesulfonic acid (p-TsOH) under reflux effected cyclization of
19, delivering tetracyclic lactone 20 in 90% overall yield from
carbonate 18.17 R-Methylation of ketone 20 was accomplished with
sodium hydride and iodomethane in the presence of HMPA,
affording 21 in nearly quantitative yield (Scheme 3).19
The necessary adjustments to the carbon skeleton were carried
out as shown in Scheme 4. Reduction of 21 was a bit problematic:
use of either L-Selectride or diisobutylaluminum hydride resulted
in overreduction, and sodium borohydride gave a 1.2:1 ratio of
the desired alcohol 22a and the undesired C-7 epimer 22b.
Fortunately, the yield of the 22a/22b mixture was 93%, and it was
possible to separate the isomers and achieve nearly quantita-
tive oxidation of the undesired 22b (Scheme 4). This recycling
procedure enabled us to regenerate ketone 21 and funnel all material
toward 22a.
(2) (a) Birman, V. B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080.
For an asymmetric version of this strategy, see: (b) Meng, Z.; Danishefsky,
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(3) (a) Inoue, M.; Sato, T.; Hirama, M. J. Am. Chem. Soc. 2003, 125, 10772.
This group recently reported the first enantioselective synthesis of (-)-1;
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(10) Preliminary results suggest that silicon catalysis may also play a role in
the transformation, similar to the behavior observed in Mukaiyama aldol
reactions. See: (a) Carreira, E. M.; Singer, R. A. Tetrahedron Lett. 1994,
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(11) For examples of the analogous Mukaiyama-Michael reactions between
2-trialkylsilyloxyfurans and R,â-unsaturated carbonyl compounds, see: (a)
Barluenga, J.; Prado, A. D.; Santamaria, J.; Tomas, M. Angew. Chem.,
Int. Ed. 2005, 44, 6583 and references therein. (b) Brown, S. P.; Goodwin,
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61, 2699.
(13) For a similar coupling reaction, see: Midland, M. M.; Tramontano, A.;
Cable, J. R. J. Org. Chem. 1980, 45, 28.
(14) A modified procedure was adopted from Reginato, G.; Capperucci, A.;
Degl’Innocenti, A.; Mordini, A.; Pecchi, S. Tetrahedron 1995, 51, 2129.
We found that protection of the secondary alcohol was unnecessary.
(15) Weinreb amide 13 was prepared in three steps from acetol; see the
Supporting Information for experimental details.
Tetracycle 22a was then isomerized into 2 by refluxing with
p-TsOH in benzene. Finally, 2 was converted into merrilactone A
following the known procedures. The spectroscopic data of both
intermediate 2 and our synthetic (()-1 were identical to those
previously reported.2a
Further studies of this new variant of the Nazarov cyclization
are underway, as well as investigation of methods that would allow
asymmetric synthesis of merrilactone A.
(16) Shanmugam, P.; Srinivasan, R.; Rajagopalan, K. Tetrahedron 1997, 53,
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(17) Molander, G. A.; Quirmbach, M. S.; Silva, L. F., Jr.; Spencer, K. C.;
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