Pyridone annulation via tandem Curtius rearrangement/6π- electrocyclization: Total synthesis of (-)-lyconadin C

Article abstract of DOI:10.1021/ol401954f

A concise, enantioselective total synthesis of the Lycopodium alkaloid (-)-lyconadin C was achieved in 12 steps and high overall yield. Key features include construction of a luciduline congener through Mannich-type cyclization and a one-pot, tandem Curtius rearrangement/6π-electrocyclization to fashion the 2-pyridone system of lyconadin C.

Full text of DOI:10.1021/ol401954f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pyridone Annulation via Tandem Curtius
Rearrangement/6π-Electrocyclization:
Total Synthesis of (ꢀ)-Lyconadin C
Xiayun Cheng and Stephen P. Waters*
Department of Chemistry, The University of Vermont, 82 University Place, Burlington,
Vermont 05405, United States
stephen.waters@uvm.edu
Received July 10, 2013
ABSTRACT
A concise, enantioselective total synthesis of the Lycopodium alkaloid (ꢀ)-lyconadin C was achieved in 12 steps and high overall yield. Key
features include construction of a luciduline congener through Mannich-type cyclization and a one-pot, tandem Curtius rearrangement/6π-
electrocyclization to fashion the 2-pyridone system of lyconadin C.
The synthetic challenges presented by the Lycopodium
alkaloids not only serve as inspiration for target-directed
total synthesis but also provide the motivation for new
advances in synthetic methodology.1 One area of investi-
gation in our research program in heterocyclic chemistry
centers on the synthesis of structurally related Lycopodium
alkaloids, primarily those which we postulate could be ac-
cessible through a common alkaloid precursor. Within this
area, we reported an efficient, three-step total synthesis of
the tricyclic Lycopodium alkaloid luciduline (1, Figure 1).
In turn, this significantly shorter route than those pre-
viously reported2 enabled us to use luciduline as a synthetic
precursor in concise total syntheses of two structurally
related Lycopodium alkaloids, nankakurines A (2) and
B (3), accomplished through making use of the ketone
function in luciduline as a point to install the requisite
spiropiperidine.3 The success of this strategy has prompted
us to identify additional Lycopodium alkaloids which bear
the structural motif present within luciduline.
In 2011, Kobayashi and co-workers disclosed the struc-
tural assignments for lyconadin C (5), a new member of the
lyconadin class of alkaloids obtained from the club moss,
Lycopodium complanatum.4 Spectroscopic studies on lyco-
nadin C revealed a tetracyclic ring system containing a
2-pyridone moiety as found in lyconadin A (4).5 While
elegant total syntheses of lyconadin A have been reported
by Smith,6 Sarpong,7 and Fukuyama,8 to date only one
successful synthesis of lyconadin C has been reported
by Fukuyama using slight modifications of their previous
(1) For recent reviews of the Lycopodium alkaloids, see: (a) Ma, X.;
Gang, D. R. Nat. Prod. Rep. 2004, 21, 752–772. (b) Kobayashi, J.;
Morita, H. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 2005; Vol. 61, p 1. (c) Hirasawa, Y.; Kobayashi, J.; Morita, H.
Heterocycles 2009, 77, 679–729.
(2) For total syntheses of luciduline, see: (a) Scott, W. L.; Evans,
D. A. J. Am. Chem. Soc. 1972, 94, 4779–4780. (b) Oppolzer, W.;
Petrzilka, M. Helv. Chim. Acta 1978, 61, 2755–2762. (c) Szychowsky,
J.; MacLean, D. B. Can. J. Chem. 1979, 57, 1631–1637. (d) Schumann,
D.; Naumann, A. Liebigs Ann. Chem. 1984, 1519–1528. (e) Comins,
D. L.; Brooks, C. A.; Al-awar, R. S.; Goehring, R. R. Org. Lett. 1999, 1,
229–231. (f) Barbe, G.; Fiset, D.; Charette, A. B. J. Org. Chem. 2011, 76,
5354–5362.
(4) Ishiuchi, K.; Kubota, T.; Ishiyama, H.; Hayashi, S.; Shibata, T.;
Kobayashi, J. Tetrahedron Lett. 2011, 52, 289–292.
(5) Kobayashi, J.; Hirasawa, Y.; Yoshida, N.; Morita, H. J. Org.
Chem. 2001, 66, 5901–5904.
(6) (a) Beshore, D. C.; Smith, A. B., III. J. Am. Chem. Soc. 2007, 129,
4148–4149. (b) Smith, A. B., III; Atasoylu, O.; Beshore, D. C. Synlett
2009, 2643–2646.
(7) (a) Bisai, S. P.; West, R.; Sarpong, R. J. Am. Chem. Soc. 2008, 130,
7222–7223. (b) West, S. P.; Bisai, A.; Lim, A. D.; Narayan, R. R.;
Sarpong, R. J. Am. Chem. Soc. 2009, 131, 11187–11194.
(8) Nishimura, T.; Unni, A. K.; Yokoshima, S.; Fukuyama, T. J. Am.
Chem. Soc. 2011, 133, 418–419.
(3) (a) Cheng, X.; Waters, S. P. Org. Lett. 2010, 12, 205–207. (b) For a
previous synthesis, see: (b) Nilsson, B. L.; Overman, L. E.; Read de Alaniz,
J.; Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 11297–11299.
(9) Nishimura, T.; Unni, A. K.; Yokoshima, S.; Fukuyama, T. J. Am.
Chem. Soc. 2013, 135, 3243–3247.
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10.1021/ol401954f
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synthesis of lyconadin A.9 Drawing on the logic employed
in our approach to the nankakurines, the common skeletal
patterns embedded within lyconadin C and luciduline led
us to investigate a synthetic sequence from the luciduline
framework to this new alkaloid. In this Letter, we describe
a concise and enantioselective total synthesis of lyconadin
C that not only passes through a luciduline-like precursor
but also features an efficient method for the construction
of pyridone-containing heterocycles through a tandem
Curtius rearrangement/6π-electrocylization.
of (R)-5-methylcyclohex-2-en-1-one (9)10 and 2-tert-butyl-
dimethylsiloxy-1,3-butadiene (10)11 provided cis-decalone
11, now bearing a silyl enol ether function, with minimal
amounts of its trans-decalone epimer (cis/trans > 20:1).12
Conversion of the ketone in 11 to secondary amine 12,
achieved via reductive amination with benzylamine and
NaBH(OAc)3,13 effectively delivered hydride at the de-
sired, convex face of the decalin system (dr >10:1). Treat-
ment of secondaryamine 12 with aqueous formaldehyde at
rt cleanly effected Mannich-type ring closure,14 delivering
the benzylamine analog of luciduline (13) in 74% yield.
Hydrogenolysis of the benzylamine function in 13 and
installation of a carbamate group provided Cbz-luciduline
(7), which could be prepared in gram-scale quantities in
high overall yield.
Scheme 2. Synthesis of Luciduline Analog 7
Figure 1. Selected Lycopodium alkaloids.
In the early planning stages, we envisioned that the
seven-membered ring within lyconadin C could be fash-
ioned through one-carbon ring expansion of a suitable
luciduline congener (7, Scheme 1). With the ready avail-
ability of luciduline or its analogs, we anticipated that such
a protocol would provide sufficient quantities of a suitably
functionalized cycloheptanone (8), which would in turn
serve as the foundation on which methods toward pyri-
done annulation could be investigated.
Having reached the first checkpoint in the synthesis,
attention was then given to expansion of the cyclohexa-
none ring in 7. While various methods for ring expansions
were explored, we identified the rhodium-catalyzed expan-
sion of R-diazoalcohols to be the most effective protocol.15
Addition of lithiated ethyl diazoacetate onto the ketone
function in 7 gave tertiary alcohol 15 (Scheme 3) as a single
Scheme 1. Strategic Bond Formations toward Lyconadin C
(12) For detailed discussions of similar DielsꢀAlder reactions, see:
(a) Angell, E. C.; Fringuelli, F.; Minuti, L.; Pizzo, F.; Porter, B.;
Taticchi, A.; Wenker, E. J. Org. Chem. 1985, 50, 4686–4690. (b) Organ,
M. G.; Winkle, D. D. J. Org. Chem. 1997, 62, 1881–1885.
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C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849–3862. (b) Abdel-Magid,
A. F.; Mehrman, S. J. Org. Process Res. Dev. 2006, 10, 971–1031.
(14) For examples of Mannich-type reactions in the total synthesis of
Lycopodium alkaloids, see: (a) Heathcock, C. H.; Kleinman, E. F.;
Binkly, E. S. J. Am. Chem. Soc. 1982, 104, 1054–1068. (b) Yang, H.;
Carter, R. G.; Zakharov, L. N J. Am. Chem. Soc. 2008, 130, 9238–9239.
(c) Liau, B. B.; Shair, M. D. J. Am. Chem. Soc. 2010, 132, 9594–9595. (d)
Ramharter, J.; Weinstabl, H.; Mulzer, J. J. Am. Chem. Soc. 2010, 132,
14338–14339. (e) Also see ref 2a.
Our synthesis commenced with a 5-step preparation of
Cbz-luciduline analog 7 (Scheme 2), fashioned through a
sequence similar to our previous 3-step total synthesis of
luciduline (1).3a Lewis acid mediated DielsꢀAlder reaction
(10) (a) Caine, D.; Procter, K.; Cassell, R. A. J. Org. Chem. 1984, 49,
~
2647–2648. (b) Carreno, M. C.; Garcıa Ruano, J. L.; Martın, A. M.;
´ ´
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Pedregal, C.; Rodriguez, J. H.; Rubio, A.; Sanchez, J.; Solladie, G.
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C. Org. Biomol. Chem. 2003, 1, 3989–4004.
(15) For examples of Rh(II)-catalyzed ring expansion reactions of
R-diazoalcohols, see: (a) Nagao, K.; Chiba, M.; Kim, S. Synthesis 1983,
197–199. (b) Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J. Org. Chem. 1990,
55, 4144–4153. (c) Jiang, N.; Ma, Z.; Qu, Z.; Xing, X.; Xie, L.; Wang, J.
J. Org. Chem. 2003, 68, 893–900.
(16) (a) Marchand, A. P.;Arney, B. E.; Gilardi, R.;Flippen-Anderson,
J. L. J. Org. Chem. 1987, 52, 3455–3457. (b) Hashimoto, T.; Naganawa,
Y.; Maruoka, K. J. Am. Chem. Soc. 2009, 131, 6614–6617.
(11) (a) Vedejs, E.; Eberlein, T. H.; Mazur, D. J.; McClure, C. K.;
Perry, D. A.; Ruggeri, R.; Schwartz, E.; Stults, J. S.; Varie, D. L. J. Org.
Chem. 1986, 51, 1556–1562. (b) Kirmse, W.; Mrotzeck, U. Chem. Ber.
1988, 121, 485–492. (c) Yeh, M. P.; Hwu, C. J. Organomet. Chem. 1991,
419, 341–355.
B
Org. Lett., Vol. XX, No. XX, XXXX

diastereomer in 94% yield. Attempts to effect a direct, one-
step TiffeneauꢀDemjanov homologation16 of ketone 7
described the use of vinyl isocyanates for the preparation
of 2-pyridones through a one-pot, two-step annulation
process (Scheme 4c).20 In their strategy, nucleophilic
addition of an enamine (B) onto vinyl isocyanate A
provides a zwitterionic adduct (C), which after tautomer-
ization, cyclization, and elimination of pyrrolidine af-
fords the tetrasubstituted pyridone E.
While the methods of Smith and Fukuyama proved
highly effective in their respective cases, each was unsui-
table for our system due to both the type and the location
of functionality available in β-ketoester 8 or vinyl triflate
16. Moreover, the method of Rigby requires either very
high temperatures or extended reactions times, and is
apparently limited in scope to the formation of pyridones
with multiple ring substituents, presumably due to the
inherent instability of simple, monosubsituted vinyl enam-
ines. Therefore, it became clear to us that methodology
needed to be established that would not only replace the
ester function in 8 or 16 with a nitrogen atom but also
simultaneously incorporate the additional and necessary
functions for subsequent (and ideally, tandem) heterocyc-
lic assembly.
with ethyl diazoacetate and BF3 OEt2 did not give any
3
conversion, while acid-mediated ring expansion17 of dia-
zoalcohol 15 gave rise to complex mixtures. Ultimately,
treatment of diazoalcohol 15 with 1.5 mol % Rh2(OAc)4 at
rt promoted ring expansion within 3 h to yield β-ketoester
8 and its enol tautomer 80. With the intention of using the
ketone function in 8 and 80 for subsequent metal-mediated
cross-coupling, the crude reaction mixture was directly
subjected to enolizing conditions followed by PhNTf2 to
afford vinyl triflate 16 in 82% yield over the two steps.
Scheme 3. Ring Expansion of the Luciduline Skeleton and
Formation of Vinyl Triflate 16
Scheme 4. Previous 2-Pyridone Annulation Tactics in Synthesis
We next directed our investigations toward identify-
ing a suitable pyridone ring annulation protocol that
would complete the framework of lyconadin C. Previous
synthetic efforts toward pyridone-containing Lycopo-
dium alkaloids have utilized several tactics for their
installation.18 In the only reported synthesis of lyco-
nadin C to date, Fukuyama and co-workers employed
a one-pot Michael addition of 2-(phenylsulfinyl)acet-
amide followed by cyclization and sulfoxide elimi-
nation (Scheme 4a), a strategy also utilized in their total
syntheses of lyconadin A (4)8 and huperzine A (6).19
During their pioneering total synthesis of lyconadin
A, Smith and co-workers developed an efficient tan-
dem Michael additionꢀcondensationꢀdecarboxylation
protocol from β-ketoesters and propionamide (Scheme 4b).6
In an earlier series of papers, Rigby and co-workers
Toward the goal of completing the total synthesis, we
wished to investigate a more suitable, intramolecular
cyclization strategy to fashion the disubstituted pyridone
ring in lyconadin C. We postulated that in order to achieve
good reactivity, a system with functional groups in close
proximity with favorable π-orbital overlap would be desir-
able. Cognizant that the requisite pyridone nitrogen in
lyconadin C could well be installed through Curtius re-
arrangement of the corresponding carboxylic acid in ester
16, we further hypothesized that the intermediate isocya-
nate species could be more strategically utilized as one
component of a projected 6π-electrocyclization, thereby
securing the complete pyridone system in a one-pot
ꢀ
(17) (a) Hebrault, D.; Uguen, D.; De Cian, A.; Fischer, J. Tetrahe-
dron Lett. 1998, 39, 6703–6706. (b) Xiao, F.; Wang, J. J. Org. Chem.
2006, 71, 5789–5791.
(18) For reviews of methodologies to construct 2-pyridone rings, see:
(a) Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757–1779.
(b) Heravi, M. M.; Hamidi, H. J. Iran. Chem. Soc. 2013, 10, 265–273.
(19) Koshiba, T.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2009, 11,
5354–5356.
(20) (a) Rigby, J. H.; Balasubramanian, N. J. Org. Chem. 1984, 49,
4569–4571. (b) Rigby, J. H.; Burkhardt, F. J. J. Org. Chem. 1986, 51,
1374–1376. (c) Rigby, J. H.; Balasubramanian, N. J. Org. Chem. 1989,
54, 224–228. (d) Rigby, J. H.; Danca, D. M. Tetrahedron Lett. 1997, 38,
4969–4972. (e) Rigby, J. H. Synlett 2000, 1–12.
Org. Lett., Vol. XX, No. XX, XXXX
C

transformation. A conjugated dienyl isocyanate would
best serve as the optimal substrate due to the planarity
and excellent orbital alignment. This isocyanate would be
accessed via a Curtius rearrangement of the corresponding
dienyl carboxylic acid. Toward this substrate, Pd-cata-
lyzed Stille cross-coupling21 of vinyl triflate 16 (Scheme
5) with tributyl(vinyl)tin afforded diene 17 in 93% yield.
Saponification of the ester in 17 gave the key isocyanate
precursor, carboxylic acid 18, in 90% yield.
Scheme 5. Completion of the Total Synthesis of Lyconadin C
To the best of our knowledge, the 6π-electrocyclization
of nonaryl dienyl isocyanates to pyridones under such mild
conditions has not been previously reported within the
context of alkaloid synthesis. Previously reported electro-
cyclizations of this type are few and mostly limited in scope
to aryl isocyanates, providing pyridones fused to an addi-
tional, adjacent aromatic ring.22 The few other reported
examples employing nonaryl isocyanates23 each require
extended reaction times and high temperatures to achieve
modest yields.
Treatment of acid 18 with 1 equiv of diphenylphosphor-
yl azide (DPPA)24 at rt gave rise to an intermediate acyl
azide. Upon heating the reaction mixture to 80 °C, we
were gratified to observe that Curtius rearrangement to
the corresponding isocyanate was accompanied by
spontaneous 6π-electrocyclization, providing pyridone
20 in 77% overall yield. Removal of the Cbz group in
20 delivered lyconadin C. Spectroscopic data, including
2D COSY, HMQC, and HMBC data, for synthetic
(ꢀ)-lyconadin C as its corresponding TFA salt were in
excellent agreement with those of natural (ꢀ)-lyconadin C
reported by Kobayashi and co-workers.4
represents a further advancement in the chemistry of vinyl
isocyanates, and future applications in total synthesis are
anticipated. In addition, our total synthesis of lyconadin C
further underscores the synthetic versatility of luciduline
and related analogs as intermediates toward more structu-
rally advanced Lycopodium alkaloids. We will report our
extended investigations on the scope of pyridone annula-
tion, aswellasits utilityin alkaloidsynthesis, indue course,
along with further applications of luciduline as a launch
point toward additional Lycopodium alkaloids.
In summary, an enantioselective and concise total synthe-
sis of (ꢀ)-lyconadin C was accomplished in 12 steps and
high overall yield. Our synthesis features the short pre-
paration of a luciduline congener through Mannich-type
cyclization, followed by ring expansion and tandem Cur-
tius rearrangement/6π-electrocyclization to fashion the
pyridone ring. This mild protocol for pyridone formation
Acknowledgment. We gratefully acknowledge the Uni-
versity of Vermont (UVM) for financial support. This
work was also supported by the Vermont Genetics Net-
work through Grant Number 8P20GM103449 from the
INBRE Program of the National Institute of General
Medical Sciences (NIGMS) a component of the National
Institutes of Health (NIH). Its contents are solely the
responsibility of the authors and do not necessarily repre-
sent the official views of NIGMS or NIH. We thank Dr.
Ying Wai Lam and Bruce O’Rourke at UVM for their
assistance in obtaining high-resolution mass spectra and
Prof. Matthias Brewer (UVM) for helpful discussions.
(21) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033–3040.
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J. Org. Chem. 1978, 43, 402–405. (c) Choshi, T.; Yamada, S.; Sugino, E.;
Kuwada, T.; Hibino, S. J. Org. Chem. 1995, 60, 5899–5904. (d) Hayashi,
K.; Choshi, T.; Chikaraishi, K.; Oda, A.; Yoshinaga, R.; Hatae, N.;
Ishikura, M.; Hibino, S. Tetrahedron 2012, 68, 4274–4279.
(23) For selected examples, see: (a) Eloy, F.; Deryckere, A. J.
Heterocycl. Chem. 1970, 7, 1191–1193. (b) MacMillan, J. H.; Wash-
burne, S. S. J. Org. Chem. 1973, 38, 2982–2984. (c) Chuang, T.-H.;
Chang, W.-Y.; Li, C.-F.; Wen, Y.-C.; Tsai, C.-C. J. Org. Chem. 2011, 76,
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Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(24) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc.
1972, 94, 6203–6205. (b) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetra-
hedron 1974, 30, 2151–2157.
The authors declare no competing financial interest.
D
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