Concise total synthesis of (±)-lycopladine A

Article abstract of DOI:10.1021/ol100273p

Chemical Fig Repretation A concise total synthesis of the Lycopodium alkaloid lycopladine A (1) Is described that features sequential conjugate addition and enolate arylatlon reactions to construct the tricyclic core In two steps.

Full text of DOI:10.1021/ol100273p

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1576-1579
Concise Total Synthesis of
(()-Lycopladine A
John E. DeLorbe, Monica D. Lotz, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
sfmartin@mail.utexas.edu
Received February 4, 2010
ABSTRACT
A concise total synthesis of the Lycopodium alkaloid lycopladine A (1) is described that features sequential conjugate addition and enolate
arylation reactions to construct the tricyclic core in two steps.
Lycopladine A (1) is a member of the Lycopodium alkaloid
family that was isolated from the club moss Lycopodium
Scheme 1. Retrosynthetic Analysis of (()-Lycopladine A (1)
complanatum in 2006 by Kobayashi and co-workers.1 It
possesses an unprecedented C16N-type framework consisting
of a pyridyl-fused hydrindanone core, and it shows selective
but modest cytotoxicity toward murine lymphoma L1210
cells (IC50 ) 7 µg/mL).1 Despite its unusual structure and
interesting biological activity, there has been only a single
account of the total synthesis of 1 that was reported by Toste
and co-workers in 2006 and featured a gold(I)-catalyzed
cyclization of a silyl enol ether onto an alkyne to construct
the key quaternary center.2 We now report a facile, alter-
native entry to this alkaloid that involves some novel
chemistry involving the 1,4-addition of a pyridylmethyl
carbanion to a cyclic enone, a reaction that we believe has
general utility.
In our retrosynthetic analysis, we reasoned that the
could be obtained from a diastereoselective conjugate ad-
selective hydroboration/oxidation of 2 would provide the
natural product 1 (Scheme 1). Intermediate 2 would then in
dition of an organometallic derivative of a commercially
available 3-halo-2-methylpyridine 4 (X ) Br, Cl) to an R,ꢀ-
turn be accessed from tricycle 3 via a sequence comprising
unsaturated carbonyl compound 5, followed by an intramo-
of a transesterification using allyl alcohol followed by a
lecular enolate arylation. In fact, our interest in this approach
palladium-catalyzed decarboxylative allylation. Tricycle 3
was stimulated in part by related investigations of enanti-
oselective 1,4-additions.3
(1) Ishiuchi, K.; Kubota, T.; Morita, H.; Kobayashi, J. Tetrahedron Lett.
2006, 47, 3287–3289.
(2) Staben, S. T.; Kennedy-Smith, J.; Huang, D.; Corkey, B. K.;
(3) Smith, A. J.; Abbott, L. K.; Martin, S. F. Org. Lett. 2009, 11, 4200–
4203.
LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991–5994.
10.1021/ol100273p  2010 American Chemical Society
Published on Web 03/02/2010

Although there are a few isolated reports of 1,4-additions
of metalated picoline derivatives to cyclic and acyclic
enones,4 this is not a well-known transformation, and 1,2-
addition may be a significant side reaction,4b,e,5 especially
with allylic and benzylic cuprates.6 Indeed, in preliminary
experiments in which we examined reactions of 1-cyclohex-
2-enone (7) with organocuprates derived from 6, 1,2- and
1,4-addition products 8 and 9 were formed in approximately
equal amounts. We then examined the corresponding reaction
of 7 with the organocopper species generated from 6 using
1 equiv of copper iodide (CuI) and discovered that 1,4-
addition dominated giving a mixture (6:1) of 8 and 9,
respectively (Scheme 2). The nature of the copper(I) salt did
not appear to matter significantly as comparable yields of
the 1,4-adduct were obtained using either CuCN or
CuI·0.75DMS. On the other hand, use of tetrahydrofuran
(THF) as solvent gave better ratios of the 1,4-adduct than
diethyl ether (Et2O).7 When chlorotrimethylsilane (TMSCl)
was not used as an additive,8 a mixture of 8 to 9 (2:1) was
produced. Colder temperatures also seemed to favor 1,4-
addition, but cooling below -78 °C did not have a significant
effect on the ratio of products.
Scheme 3. Conjugate Addition of Pyridyl Anions: Initial Studies
of TMSCl had little beneficial affect upon the ratio of 1,4-
vs 1,2-addition.
The next step of the synthesis required cyclization of 12
to give the tricyclic core of lycopladine A. However,
numerous attempts to effect the palladium-catalyzed cycliza-
tion of the enolate of 12 to give 14 were unsuccessful
(Scheme 4). On the other hand, we found in preliminary
experiments that 13, which was obtained by trapping the
enolate generated from the reaction of 10 with 11 (Scheme
3), afforded an inseparable mixture of 15 and a compound
whose spectral characteristics were consistent with those
expected for 14. The low yield of this reaction coupled with
the concomitant formation of variable amounts of 15
rendered this approach problematic.
Scheme 2. Conjugate Addition of Pyridyl Anions: Model Study
Scheme 4. Enolate Arylation: Initial Attempts
Having established in a simple model the underlying
feasibility of the first stage of our approach to lycopladine
A, we turned our attention to preparing the organocopper
reagent derived from commercially available 10. Accord-
n
ingly, deprotonation of 10 with BuLi in THF at 0 °C
proceeded without detectable metal-halogen exchange, and
transmetalation with CuI at -20 °C generated an organo-
copper intermediate that was allowed to react with racemic
5-methylcyclohex-2-en-1-one (11) to provide an inseparable
epimeric mixture (∼2.5:1) of 12 together with small amounts
of a mixture of 1,2-adducts (Scheme 3). In this case, addition
Because a number of examples involving arylations of
enolates derived from 1,3-dicarbonyl compounds have been
reported,9 we decided to use the unsaturated ꢀ-ketoester 1610
as the conjugate addition partner. In the event, reaction of
the organocopper reagent derived from 10 with 16 proceeded
with a high level of 1,4-selectivity to furnish 17 as a mixture
(∼5.5:1 in CDCl3) of enol and keto tautomers (Scheme 5).
(4) (a) Zhuang, Z.-P.; Zhou, W.-S. Tetrahedron 1985, 41, 3633–3641.
(b) Kraus, G. A.; Vines, D. R.; Malpert, J. H. Tetrahedron 1995, 51, 1337–
1344. (c) Celanire, S.; Salliot-Maire, I.; Ribereau, P.; Godard, A.; Queguiner,
G. Tetrahedron 1999, 55, 9269–9282. (d) Bennasar, M.-L.; Roca, R.;
Monerris, M. J. Org. Chem. 2004, 69, 752–756. (e) Pirnot, M. T.; Taber,
D. F. Thesis, The University of Delaware, Spring 2009.
(5) Sanchez-Sancho, F.; Herradon, B. Heterocycles 2003, 60, 1843–
1854
.
(6) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Smith, R. A. J.
J. Am. Chem. Soc. 1990, 112, 4404–4410.
(9) For a review of Pd-catalyzed R-arylations of carbonyl compounds,
see: Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–245.
(10) Heuschmann, M. Chem. Ber. 1988, 121, 39–49.
(7) House, H. O.; Wilkins, J. M. J. Org. Chem. 1978, 43, 2443–2454.
(8) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019–6022.
Org. Lett., Vol. 12, No. 7, 2010
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Toward this end, we envisioned that the allyl ester 19 would
serve as a useful intermediate. However, initial efforts to
effect the acid-catalyzed transesterification of 3 with allyl
alcohol returned only starting material, whereas use of basic
conditions led to ring cleavage by a retro-Dieckmann
reaction. We eventually discovered that 3 could be smoothly
transformed into 19 in 90% yield by heating with an excess
of allyl alcohol in the presence of the Otera catalyst 18 under
microwave conditions (Scheme 6).15 Central to the success
of this reaction was the rigorous exclusion of water in order
to prevent the formation of the ketone via sequential
hydrolysis of the ester and decarboxylation.
Scheme 5. Conjugate Addition and Enolate Arylation
Scheme 6. Completion of the Synthesis of 1
The diastereoselectivity of this 1,4-addition was judged to
be >20:1 as the epimer was not detected by NMR spectros-
copy.11
Initial attempts to effect the cyclization of 17 using
potassium tert-butoxide (KOtBu) and either Pd(PPh3)4 or
12
Pd(PtBu3)2 as the catalyst were unsuccessful. However,
when 2-(2′,6′-dimethoxybiphenyl)dicyclohexylphosphine (S-
Phos), an electron-rich ligand developed by Buchwald,13 was
used together with tris(dibenzylideneacetone)dipalladium
[Pd2(dba)3], the potassium enolate of 17 underwent facile
cyclization to deliver the requisite tricycle 3 as a single
diastereomer. Although S-Phos had originally been reported
to be effective in promoting Suzuki-Miyaura couplings, it
has also been successfully employed in other enolate
arylations.14 The relative stereochemistry of 3 was confirmed
unequivocally by single-crystal X-ray diffraction (Figure 1).
Subsequent exposure of 19 to catalytic amounts of
Pd(PPh3)4 led to a facile decarboxylation-allylation reaction
to give 2 in 80% yield.16 When 2 was treated with
9-borabicyclo[3.3.1]nonane (9-BBN-H) followed by oxida-
tion of the intermediate organoborane, lycopladine A (1) was
obtained, albeit in only 12% yield. Alternatively, reaction
of 2 with catecholborane in the presence of the Wilkinson
(12) (a) Iwama, T.; Rawal, V. H. Org. Lett. 2006, 8, 5725–5728. (b)
Su, W.; Raders, S.; Verkade, J. G.; Liao, X.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2006, 45, 5852–5855.
Figure 1. X-ray structure of compound 3.
(13) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685–4696.
(14) Chobanian, H. R.; Liu, P.; Chioda, M. D.; Guo, Y.; Lin, L. S.
Tetrahedron Lett. 2007, 48, 1213–1216.
It now remained to elaborate the angular methyl ester in
3 into the 3-propanol side chain found in lycopladine A.
(15) Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307–
5311.
(16) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21,
3199–3202. (b) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T.
J. Am. Chem. Soc. 1980, 102, 6381–6384.
(11) When the tautomeric mixture of 17 was treated with TESCl and
Et3N, a single silyl enol ether was obtained.
1578
Org. Lett., Vol. 12, No. 7, 2010

catalyst [Rh(PPh3)3Cl]17 afforded an intermediate alkyl
boronic ester that was oxidized using aqueous sodium
perborate (NaBO3·4H2O) to deliver lycopladine A in 70%
yield. The spectral data (1H and 13C NMR) of synthetic 1
were consistent with those previously reported.1,2,18 Ad-
ditionally, we observed minor amounts of what appears to
be the isomeric lactol 20, the proportion of which varies with
solvent.
In summary, a concise total synthesis of (()-lycopladine
A (1) has been completed in 21% overall yield by a process
requiring only five steps from the ꢀ-ketoester 16. The
synthesis features a novel sequence of conjugate addition
and enolate arylation to form the tricyclic core in only two
steps. Because 16 can be prepared in enantiomerically pure
form,19 this approach is also amenable to an enantioselective
synthesis of 1.
Acknowledgment. We thank the National Institutes of
General Medical Sciences (GM 25439 and GM 31077) and
The Robert A. Welch Foundation for their generous support
of this work. J.E.D. thanks the Dorothy B. Banks Foundation
and Pfizer, Inc., for graduate research fellowships. We are
also grateful to Prof. F. Dean Toste (University of California,
1
Berkeley) for providing H and 13C NMR data of synthetic
1. We also thank Dr. Vincent Lynch (University of Texas,
Austin) for performing X-ray crystallography.
Supporting Information Available: Experimental pro-
cedures, spectral data, copies of 1H NMR and 13C NMR for
1-3, 8, 9, 12, 13, 17, 19, and 21, and comparison of spectral
data for synthetic and naturally occurring 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992,
114, 6671–6679.
(18) In CD3 OD the lactol 20 comprises about 8% of the total mixture,
whereas in C6D6 the amount of 20 increases to about 20%. When a mixture
of 1 and 20 was treated with TBSCl/imidazole, a single silyl ether 21 was
obtained in 95% yield.
(19) Gruseck, U.; Heuschmann, M. Tetrahedron Lett. 1987, 28, 2681–
2684
.
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