Methoxypyridines in the synthesis of lycopodium alkaloids: Total synthesis of (±)-lycoposerramine R

Article abstract of DOI:10.1021/ol100823t

A methoxypyridine serves as a masked pyridone in a concise synthesis of the Lycopodium alkaloid lycoposerramine R, which has been prepared for the first time. The key step of the synthesis is the use of an Eschenmoser Claisen rearrangement to forge a key quaternary carbon center.

Full text of DOI:10.1021/ol100823t

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2551-2553
Methoxypyridines in the Synthesis of
Lycopodium Alkaloids: Total Synthesis
of (()-Lycoposerramine R
Vishnumaya Bisai and Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
rsarpong@berkeley.edu
Received April 10, 2010
ABSTRACT
A methoxypyridine serves as a masked pyridone in a concise synthesis of the Lycopodium alkaloid lycoposerramine R, which has been
prepared for the first time. The key step of the synthesis is the use of an Eschenmoser Claisen rearrangement to forge a key quaternary
carbon center.
The Lycopodium alkaloid family boasts over 200 members,
which possess an array of architecturally complex frame-
works. The construction of these molecules has presented
synthetic challenges that have inspired highly innovative
strategic and tactical solutions.1 The emergence of the
Lycopodium alkaloid huperzine A as a potential treatment
for Alzheimer’s disease has further heightened synthetic
interest in this family of natural products.2 Through detailed
studies that began in 1942 with the work of Manske and, later,
Wiesner, MacLean, Conroy, McMaster and more recently
Kobayashi and Takayama, the biosynthetic connections between
many of these alkaloids continues to be uncovered.3 As a result,
synthetic strategies to the Lycopodium alkaloids that exploit their
structural connections are beginning to offer effective and
concise avenues to a wide array of these natural products.
As a part of a program to exploit methoxypyridines in
the synthesis of various alkaloids, we have reported the
total syntheses of the Lycopodium alkaloid lyconadin A4
and the Galbulimima alkaloid GB 13.5 The methoxypy-
ridine group is uniquely effective as a masked pyridone
because the methoxy group significantly mitigates the
basicity of the pyridine nitrogen via an inductive electron-
withdrawing effect.6 This obviates the need for reversed-
phase chromatographic purification, which is often asso-
ciated with the synthesis of related alkaloids. Building
upon our earlier studies, we have embarked on the
syntheses of the Lycopodium alkaloids lycopladine A (1,
Figure 1),7 lycoposerramine R (2),8 and lannotinidine B
Figure 1. Selected Lycopodium alkaloids.
(3)9 with the intention of accessing all three natural
products from a common intermediate.10
(1) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679–
729.
(2) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752–772.
(3) Hudlicky, T., Reed, J. W. Lycopodium alkaloids. In The Way of
Synthesis, 1st ed.; Wiley-VCH: Weinheim, 2007; pp 573-602.
(4) (a) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008,
130, 7222–7223. (b) West, S. P.; Bisai, A.; Lim, A. D.; Narayan, R.;
Sarpong, R. J. Am. Chem. Soc. 2009, 131, 11187–11194.
10.1021/ol100823t  2010 American Chemical Society
Published on Web 05/04/2010

Key to our unified synthetic strategy is the use of a
common methoxypyridine intermediate (see 4, Scheme 1).
followed by reduction of the vinylogous ester of the adduct
and acidic workup to give 6 in 63% yield over the two steps.
Intramolecular Heck reaction of 6 proceeded without event
to afford tricyclic enone 9 in 79% yield. The R-methylation
of enone 9 and subsequent Luche reduction14 proceeded with
excellent diastereocontrol to give 10 in 92% yield. At this
stage, several variants of the Claisen rearrangement were
explored. Ultimately, the Eschenmoser Claisen rearrange-
ment15 utilizing the dimethyl acetal of N,N-dimethylaceta-
mide (DMA-DMA) proved to be most effective, affording
11 in 94% yield. Iodolactonization of 11 yielded fused
lactone 12 in 78% yield.
Scheme 1. Retrosynthetic Analysis of 2
The structure and relative stereochemistry of iodolactone
12 was confirmed by X-ray analysis of a single crystal (see
ORTEP in Scheme 2). With a robust route to tetracycle 12
Scheme 2. Synthesis of Lactone 12
The methoxy group of the methoxypyridine moiety in 4 may
be removed en route to 1,11 demethylated to unveil the
pyridone in 2, or the methoxypyridine may be unraveled at
a late stage to provide 3. This communication describes our
initial studies toward this overall goal, which has culminated
in a concise first total synthesis of lycoposerramine R.
Retrosynthetically, we envisioned the tetracyclic frame-
work of 2 (Scheme 1) arising from a late-stage reductive
amination of ketoaldehyde 4, which is closely related to 1.
Tricycle 4 could in turn derive from enone 5 by exploiting
a stereospecific pericyclic rearrangement to forge the all-
carbon quaternary center. Enone 5 presented several op-
portunities for the diastereocontrolled intallation of the
potentially challenging quaternary center (e.g., oxy-Cope,
Claisen, or 2,3-Wittig rearrangements). In turn, tricycle 5
could be obtained from 6 via an intramolecular Heck
reaction. The potential Heck precursor 6 could arise from a
union of readily available vinylogous ester 7 and dibromide
812 via a Stork-Danheiser sequence.13
Our synthesis commenced with the coupling of the enolate
of vinylogous ester 7 and picolinyl bromide 8. This was
(5) Larson, K. K.; Sarpong, R. J. Am. Chem. Soc. 2009, 131, 13244–
13245.
secured, we next explored the installation of the piperidine
ring to complete the synthesis of 2. LAH reduction of the
lactone also effected cleavage of the C-I bond leading to
diol 13 (Scheme 3) in 72% yield. Oxidation of 13 under
Swern conditions proceeded without event to yield ketoal-
dehyde 14 in quantitative yield. Two routes for the selective
homologation of the aldehyde group of 14 to afford 4 were
explored (Scheme 4). The first approach entailed selective
Wittig reaction of the aldehyde group using the reagent
derived from methoxymethylene phosphonium chloride,
followed by hydrolysis of the resulting methyl enol ether to
afford 4. Although this reaction worked well on small scale,
the yields proved to be irreproducible on larger scale. After
investigating several alternative homologation strategies, it
(6) This is supported by a comparison of pKa’s of protonated pyridine
and protonated methoxypyridine; see: Joule, J. A.; Mills, K. Heterocyclic
Chemistry, 4th ed.; Blackwell Science Ltd.: Cambridge, 2000; pp 71-
120.
(7) Ishiuchi, K.; Kubota, T.; Morita, H.; Kobayashi, J. Tetrahedron Lett.
2006, 47, 3287–3289.
(8) Katakawa, K.; Kogure, N.; Kitajima, M.; Takayama, H. HelV. Chim.
Acta 2009, 92, 445–452.
(9) Koyama, K.; Morita, H.; Hirasawa, Y.; Yoshinaga, M.; Hoshino,
T.; Obara, Y.; Nakahata, N.; Kobayashi, J. Tetrahedron 2005, 61, 3681–
3690.
(10) Lannotinidine B is especially interesting from a biological perspec-
tive because it has been shown to enhance mRNA expression for nerve
growth factor (NGF) in human glial cells.9
(11) For previous syntheses of 1, see: (a) Staben, S. T.; Kennedy-Smith,
J.; Huang, D.; Corekey, B. K.; LaLonde, R.; Toste, F. D. Angew. Chem.,
Int. Ed. 2006, 45, 5991–5994. (b) DeLorbe, J. E.; Lotz, M. D.; Martin,
S. F. Org. Lett. 2010, 12, 1576–1579.
(12) Kelly, S. A.; Foricher, Y.; Mann, J.; Bentley, J. M. Org. Biomol.
Chem. 2003, 1, 2865–2876.
(14) (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227. (b)
Molander, G. A. Chem. ReV. 1992, 92, 29–68.
(13) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775–1776.
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Org. Lett., Vol. 12, No. 11, 2010

Scheme 3
.
Synthesis of Ketoaldehyde 4
Scheme 5. Completion of the Synthesis of 2
gave spectral data (1H and 13C NMR, IR, MS) fully consistent
with that reported by Takayama et al. following its isola-
tion.17
The synthesis of 2 proceeds in a total of 13 steps (12%
overall yield) from 7 and 8. Key to the completion of the
synthesis is the use of a methoxypyridine as a masked
pyridone as well as an Eschenmoser Claisen reaction to
install a key quaternary carbon center. Our application of
these synthetic studies to the enantioselective synthesis of 2
as well as the related fawcettimine-type alkaloid 3 will be
reported in due course.
Scheme 4. Homologation of Ketoaldehyde 14
Acknowledgment. The authors are grateful to the NIGMS
(RO1 GM086374-01), Amgen, Eli Lilly, Johnson and
Johnson, and AstraZeneca for financial support. Dr. Antonio
DiPasquale (UC Berkeley) is acknowledged for assistance
with X-ray crystallography.
Supporting Information Available: Experimental details
and characterization for all new compounds, including CIF
file. This material is available free of charge via the Internet
at http://pubs.acs.org.
was found that 4 could be obtained in consistently high yields
from 14 using the Ohira-Bestmann reaction to install a triple
bond (see 15) followed by anti-Markovnikov hydration using
the procedure introduced by Grotjahn.16
At this stage, several direct reductive amination possibili-
ties to forge the piperidine ring in 2 were investigated.
However, these were found to be low yielding. Ultimately,
the piperidine moiety was best installed using benzylamine
(Scheme 5) followed by hydrogenolytic cleavage of the
benzyl group. A concluding methyl ether cleavage (NaSEt)
gave lycoposerramine R (2). Synthetic lycoposerramine R
OL100823T
(15) (a) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A HelV. Chim.
Acta 1964, 47, 2425–2429. (b) For a review, see: Castro, A. M. M. Chem.
ReV. 2004, 104, 2939–3002.
(16) Grotjahn, D. B.; Lev, D. A. J. Am. Chem. Soc. 2004, 126, 12232–
12233.
(17) We are grateful to Prof. Hiromitsu Takayama (Chiba University)
1
for copies of H and 13C NMR spectra of 2.
Org. Lett., Vol. 12, No. 11, 2010
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