Anodic coupling reactions: A sequential cyclization route to the arteannuin ring skeleton

Article abstract of DOI:10.1021/ol702118n

(Chemical Equation Presented) A pair of intramolecular anodic olefin coupling reactions has been used to construct the arteannuin ring skeleton. Both coupling reactions took advantage of a furan ring as one of the coupling partners. In the first, it was found that an enol ether derived from an aldehyde was not an effective initiating group for the reaction. Instead, the cyclization benefited strongly from the use of a N,O-ketene acetal initiating group. In the second cyclization, an endocyclic enol ether was coupled to the furan ring. This second electrolysis reaction generated the key tetrasubstituted carbon at the center of the arteannuin ring skeleton.

Full text of DOI:10.1021/ol702118n

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4599-4602
Anodic Coupling Reactions: A
Sequential Cyclization Route to the
Arteannuin Ring Skeleton
Honghui Wu and Kevin D. Moeller*
Department of Chemistry, Washington UniVersity, St. Louis, Missouri 63130
moeller@wuchem.wustl.edu
Received August 28, 2007
ABSTRACT
A pair of intramolecular anodic olefin coupling reactions has been used to construct the arteannuin ring skeleton. Both coupling reactions
took advantage of a furan ring as one of the coupling partners. In the first, it was found that an enol ether derived from an aldehyde was not
an effective initiating group for the reaction. Instead, the cyclization benefited strongly from the use of a N,O-ketene acetal initiating group.
In the second cyclization, an endocyclic enol ether was coupled to the furan ring. This second electrolysis reaction generated the key
tetrasubstituted carbon at the center of the arteannuin ring skeleton.
The anodic coupling of electron-rich olefins to furan rings
provides an excellent method for synthesizing new ring
skeletons.1-5 It has been used for the synthesis of alliacol
A,3 the cyathin core ring skeleton,4 and the synthesis of
guanacastepene (Scheme 1).5 In each case, the key trans-
formation took advantage of the opportunity oxidation
reactions offer for triggering interesting new umpolong
reactions by coupling the normally nucleophilic carbon R
to a carbonyl to a nucleophilic furan ring. The synthesis of
guanacastepene accomplished by Trauner and co-workers
was particularly noteworthy because of the alternative it
offered to more traditional chemical methods that were not
successful.5
For our part, we have been interested in both demonstrat-
ing the generality of the route used for the alliacol A
synthesis and probing the reactivity of the radical cation
intermediates involved in the cyclizations.6 With this in mind,
the arteannuin family of natural products posed an intriguing
synthetic target.7,8 We envisioned their construction using a
pair of electrolysis reactions as outlined in Scheme 2. The
first cyclization would illustrate the generality of the
electrolysis used in the synthesis of alliacol A. The second
would probe both the compatibility of the cyclization with
(1) For a recent review of the use of electrochemistry in synthesis, see:
Sperry, J. B.; Wright, D. L. Chem. Soc. ReV. 2006, 35, 605.
(2) For general references specifically dealing with oxidative enol ether-
furan coupling reactions, see: (a) Moeller, K. D.; New, D. G. Tetrahedron
Lett. 1994, 35, 2857. (b) Moeller, K. D.; Tesfai, Z. J. Electrochem. Soc.
Jpn. (Denki Kagaku) 1994, 62, 1115. (c) New, D. G.; Tesfai, Z.; Moeller,
K. D. J. Org. Chem. 1996, 61, 1578-1598. (d) Whitehead, C. R.; Sessions,
E. H.; Ghiviriga, I.; Wright D. L. Org. Lett. 2002, 4, 3763. (e) Sperry, J.
B.; Whitehead, C. R.; Ghiviriga, I.; Walczak, R. M.; Wright, D. L. J. Org.
Chem. 2004, 69, 3726. (f) Sperry, J. B.; Wright, D. L. J. Am. Chem. Soc.
2005, 127, 8034. (g) Sperry, J. B.; Cnstanzo, J. R.; Jasinski, J.; Butcher, R.
J.; Wright, D. L. Tetrahedron Lett. 2005, 46, 2789. (h) Sperry, J. B.; Wright,
D. L. Tetrahedron 2006, 62, 6551.
(6) For recent work examining the reactivity of the radical cation
intermediates involved in anodic olefin coupling reactions, see: Huang,
Y.; Moeller, K. D. Tetrahedron 2006, 62, 6536 and references therein.
(7) For initial characterization studies, see: Sy, L.-K.; Borwn, G. D.;
Haynes, R. Tetrahedron 1998, 54, 4345. For more recent structural and
synthetic studies, see: (b) Sy, L.-K.; Cheung, K.-K.; Zhu, N.-Y.; Brown,
G. D. Tetrahedron 2001, 57, 8481. (c) Sy, L.-K.; Zhu, N.-Y.; Brown, G.
D. Tetrahedron 2001, 57, 8495.
(3) (a) Mihelcic, J.; Moeller, K. D. J. Am. Chem. Soc. 2003, 125, 36.
(b) Mihelcic, J.; Moeller, K. D. J. Am. Chem. Soc. 2004, 126, 9106.
(4) Wright, D. L.; Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.; Frey,
D. A. Org. Lett. 1999, 1, 1535.
(5) (a) Hughes, C. C.; Miller, A. K.; Trauner, D. Org. Lett. 2005, 7,
3425. (b) Miller, A. K.; Hughes, C. C.; Kennedy-Smith, J. J.; Gradl, S. N.;
Trauner, D. J. Am. Chem. Soc. 2006, 128, 17057.
10.1021/ol702118n CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/02/2007

Scheme 1
Scheme 3
membered ring? We report here the successful completion
of both cyclizations and the synthesis of the arteannuin ring
skeleton.
One of the strengths of our previous synthesis of alliacol
A was that the absolute stereochemistry of the molecule was
set early with an asymmetric Michael reaction. It was our
hope that the same strategy could be employed for a synthesis
of the arteannuins (Scheme 4). Due to the sensitivity of
electron-rich furans, it was not known whether the best
synthetic approach would be to start with a methylated furan
or, as in the synthesis of alliacol A, add a methyl group to
the five-membered ring derived from the furan late in the
synthesis. For this reason, synthetic routes using both the
methylated and unmethylated furan were pursued. The
syntheses started from bromides 1a and 1b. Metalation with
n-BuLi followed by an alkylation with trimethylene oxide
led to the alcohols 2a and 2b. The alcohols were then
oxidized and submitted to a Horner-Emmons-Wadsworth
reaction to afford substrates for the asymmetric Michael
reaction. The asymmetry of the Michael reactions was
controlled using an oxazolidinone-based chiral auxiliary. In
both cases, the reaction afforded the methylated product in
greater than 98% de. The resulting imide products were
reduced to aldehydes and then converted into the silyl enol
ethers needed for the first anodic cyclization.
endocyclic enol ethers,9 as well as determine whether the
radical cation intermediate involved in the reaction was
reactive enough to overcome the steric barriers associated
with constructing the tetrasubstituted carbon at the core of
the ring skeleton while making a six-membered ring.
This latter question of radical cation reactivity was of
special interest since related radical cyclization reactions
proved to be incapable of this transformation. As illustrated
in Scheme 3, the radical cyclization to form a five-membered
ring product while making the tetrasubstituted carbon and
destroying the furan ring failed. The related radical cation
initiated cyclization was successful.3,10,11 Would the radical
cation cyclization still be successful when challenged with
an endocyclic enol ether and a more difficult to form six-
Anodic oxidation of the nor-methyl substrate proceeded
uneventfully using the same electrolysis conditions employed
in the earlier alliacol A synthesis.3 Namely, substrate 4a was
Scheme 2
(8) For previous synthetic approaches to the arteanniuns and related
molecules, see: (a) Bariault, L.; Deon, D. H. Org. Lett. 2001, 3, 1925. (b)
Sy, L.-K.; Ngo, K.-S.; Brown, G. D. Tetrahedron 1999, 55, 15127. (c)
Nowak, D. M.; Lansbury, P. T. Tetrahedron 1998, 54, 319. (d) Schwaebe,
M.; Little, R. D. J. Org. Chem. 1996, 61, 3240. (e) Jefford, C. W.; Velarde,
J.; Bernardinelli, G. Tetrahedron Lett. 1989, 30, 4485. (f) Zhou, W. S.;
Zhang, L.; Fan, Z. C.; Xu, X. X. Tetrahedron 1986, 42, 4437. (g) Lansbury,
P. T.; Mojica, C. A. Tetrahedron Lett. 1986, 27, 3967. (h) Xu, X.; Zhu, J.;
Huang, D.; Xhou, W. Tetrahedron 1986, 42, 819.
(9) For a previous anodic olefin coupling reaction utilizing an endocyclic
enol ether and a simple olefin trapping group, see: Hudson, C. M.;
Marzabadi, M. R.; Moeller, K. D.; New, D. G. J. Am. Chem. Soc. 1991,
113, 7372.
(10) For related electrochemical cyclizations forming five-membered
rings through the dearomatization of a furan, see: Sperry, J. B.; Ghiviriga,
I.; Wright, D. L. Chem. Commun. 2006, 2, 194.
(11) For radical cyclization reactions involving furan rings, see: (a)
Parsons, P. J.; Penverne, M.; Pinto, I. L. Synlett 1994, 721. (b) Demircan,
A.; Parsons, P. J. Eur. J. Org. Chem. 2003, 1729.
4600
Org. Lett., Vol. 9, No. 22, 2007

reaction conducted by Trauner and co-workers gave a high
yield of cyclized product while employing a very similar
furan ring. However, the cyclization reaction accomplished
by the Trauner group was significantly different in that it
used a ketone enol ether as the coupling partner for the furan
instead of the aldehyde enol ether employed in 4a and 4b.
Recently, we found that the nature of the substituents on a
radical cation intermediate can have a large influence on its
propensity to generate new carbon-carbon bonds.6 In the
cyclization studied by the Trauner group, was the extra
substituent on the enol ether relative to 4b, and hence the
higher electron density of the subsequent radical cation
responsible for the success of the cyclization? If so, then
could the problems arising during the cyclization of 4b be
circumvented with the use of a more electron-rich olefin
coupling partner? While the proposed synthesis of the
arteannuins was not amenable to the use of a ketone enol
ether, it was ideally suited for the use of a more electron-
rich N,O-ketene acetal initiating group. N,O-Ketene acetals
have proven to be outstanding initiating groups for the
formation of carbon-carbon bonds in anodic olefin coupling
reactions and have a significantly lower oxidation potential
(Ep/2 ) +1.15 V vs Ag/AgCl) than either of the furan rings
used in 4a or 4b.6
Scheme 4
oxidized in a three-neck round-bottom flask using a reticu-
lated vitreous carbon (RVC) anode, a carbon rod cathode, a
0.1 M tetraethylammonium tosylate in 20% MeOH/CH2Cl2
electrolyte solution, and a constant current of 20 mA until
2.1 F/mol of charge had been passed. With no further
optimization, the reaction afforded a 60% yield of product
as a mixture of stereoisomers (Scheme 5).
In order to take advantage of a ketene acetal initiating
group, the overall synthetic scheme was modified so that
reduction of the imide product from the Michael reaction
was conducted following the initial electrochemical cycliza-
tion. To this end, the Michael products 3a and 3b were
converted into ketene acetals 6a and 6b as illustrated in
Scheme 6.
Scheme 5
Scheme 6
To our surprise, the anodic cyclization originating from
the methylated substrate (4b) did not proceed well and led
to only a 30% isolated yield of the bicyclic product.
Apparently, the reaction was not compatible with the more
electron-rich furan ring. For comparison, the oxidation
potential (Ep/2) measured for a 3-alkylsubstituted furan such
as the one employed in 4a was +1.64 V vs Ag/AgCl.12 The
oxidation potential (Ep/2) measured for a 3-alkyl-4-methyl-
substituted furan such as the one used in 4b was +1.46 V
vs Ag/AgCl, a value that is competitive with the oxidation
potential of the enol ether initiating group (Ep/2 ) +1.44 V
vs Ag/AgCl).6
Anodic oxidation of both 6a and 6b using the same
reaction conditions employed above led to excellent yields
of the desired bicyclic product. Little difference was observed
between the reactions. An NMR spectrum of each crude
reaction mixture showed that both cyclizations proceeded
in a very clean fashion with yields in the neighborhood of
90% as measured by integration versus an internal standard.
The conclusion that the more electron-rich furan ring was
problematic for the cyclization was surprising since the
(12) CVs were run using a Pt anode and a Ag/AgCl reference electrode
from BAS. All CVs were run with a scan rate of 25 mV/s, a 0.1 M LiClO4
in acetonitrile electrolyte solution, and a 0.025 M concentration of substrate.
Org. Lett., Vol. 9, No. 22, 2007
4601

Clearly, use of the more electron-rich N,O-ketene acetal
solved the problems associated with the additional methyl
group on the furan ring.
Scheme 8
The cyclized products were sensitive to the acid used in
the workup to both wash away the 2,6-lutidine used as a
proton scavenger in the reactions and regenerate the furan
ring from the initially formed methanol trapping product.3,4
Current efforts to optimize the reactions further are focusing
on working-up the reactions while minimizing acid.
Once the bicyclic products were available, they were
converted into substrates for the second anodic cyclization
(Scheme 7). To this end, the imide was reduced to an alcohol,
this case, the cyclizations also benefited from a shift in the
electrolyte used to lithium perchlorate. This change helped
with the isolation of the product because of the greater water
solubility of the perchlorate salt.
Scheme 7
The compatibility of the reactions with the simultaneous
formation of the tetrasubstituted carbon and a six-membered
ring in light of the failure of related radical cyclizations
leading to five-membered rings once again highlighted the
greater reactivity associated with the enol ether radical
cation.14
A comparison of the two routes to the arteannuin skeleton,
one with the methyl substituent on the furan and one without,
suggests that both are feasible and worthy of further attention.
The route including the methyl on the furan removes the
need to add this carbon late in the synthesis. However, the
presence of the methyl group does make the furan more
sensitive and harder to handle. Therefore, it may be best to
add the methyl group after the furan ring has been used to
assemble the tricyclic core of the natural product. Of course,
such a conclusion can be dramatically altered by the success
of the reactions needed to add the carbon to the furanone
late in the synthesis. For the time being, both routes are being
pursued.
and then the alcohol oxidized to an aldehyde. A Horner-
Emmons-Wadsworth reaction was used to construct an
enoate. Selective hydrogenation of the enoate double bond
and conversion of the ester to an enol ether using the Petasis
reagent13 afforded the electrolysis substrates 9a and 9b.
Anodic oxidation of both substrates 9a and 9b led to
excellent yields of the tricyclic product (Scheme 8). In both
cases, an NMR of the crude reaction product showed that
the cyclization afforded the desired product in greater than
80% yield. The methyl group did not appear to make any
difference in the cyclization. Of course, the substrate did
employ the use of a ketone enol ether. Neither the endocyclic
enol ether, formation of the tetrasubstituted carbon, nor the
need to form a six-membered ring presented a problem for
the cyclizations.
Acknowledgment. We thank the National Science Foun-
dation (CHE-9023698) for their generous support of our
work. We also gratefully acknowledge the Washington
University High Resolution NMR facility, partially supported
by NIH Grants RR02004, RR05018, and RR07155, and the
Washington University Mass Spectrometry Resource Center,
partially supported by NIHRR00954, for their assistance.
Supporting Information Available: A sample experi-
mental procedure is included for the oxidation reaction along
with characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Once again, the isolated yields for the product appeared
to be sensitive to the amount of acid used in the workup. In
OL702118N
(13) Petasis, N. A. Transition Metals for Organic Synthesis, 2nd ed.;
Wiley: New York, 2004; Vol. 1, p 427.
(14) Horner, J.; Taxil, E.; Newcomb, M. J. Am. Chem. Soc. 2002, 124,
5402.
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Org. Lett., Vol. 9, No. 22, 2007