Toward a unified approach for the lycopodines: Synthesis of 10-hydroxylycopodine, deacetylpaniculine, and paniculine

Article abstract of DOI:10.1021/ol303272w

The enantioselective syntheses of 10-hydroxylycopodine, deacetylpaniculine, and paniculine have been accomplished through use of a common intermediate. Key steps in the synthetic sequence toward these lycopodium alkaloids include formation of the tricyclic core via a conformationally accelerated, intramolecular Mannich cyclization and an organocatalyzed, intramolecular Michael addition to form the C₇-C₁₂ linkage.

Full text of DOI:10.1021/ol303272w

ORGANIC
LETTERS
2013
Vol. 15, No. 4
736–739
Toward a Unified Approach for
the Lycopodines: Synthesis of
10-Hydroxylycopodine,
Deacetylpaniculine, and Paniculine
Mrinmoy Saha and Rich G. Carter*
Department of Chemistry, 153 Gilbert Hall, Oregon State University, Corvallis,
Oregon 97331, United States
rich.carter@oregonstate.edu
Received November 28, 2012
ABSTRACT
The enantioselective syntheses of 10-hydroxylycopodine, deacetylpaniculine, and paniculine have been accomplished through use of a common
intermediate. Key steps in the synthetic sequence toward these lycopodium alkaloids include formation of the tricyclic core via a conformationally
accelerated, intramolecular Mannich cyclization and an organocatalyzed, intramolecular Michael addition to form the C7ÀC12 linkage.
The lycopodium alkaloids represent a sizable collection
of natural products with wide-ranging and significant
biological activity, consisting of over 200 known com-
pounds from four subfamilies (the lycopodines, lycodines,
fawcettimines, and phlegmarines).1 The lycopodine and
lycodine subfamilies have attracted considerable attention
from numerous laboratories2 including our own.3 Inter-
estingly, despite these efforts, there are wide sections of the
lycopodium alkaloids that remain unexplored (e.g., com-
pounds 2À5 in Figure 1). Herein, we disclose the first total
syntheses of three members of the lycopodine subfamily:
10-hydroxylycopodine (2),4 deacetylpaniculine (3),5 and
paniculine (4).5 These natural products 2À4 were isolated
from a Chilean club moss lycopodium confertum.4 In
addition, compounds 3 and 4 were also isolated from
lycopodium paniculatum.4,5
common intermediate strategy using tricycle 7 which
should be accessible from sulfone 6. Sulfone 6 in turn
could be constructed via a combination sulfone migration
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Our unified approach to the synthesis of natural pro-
ducts 2À4 is shown in Scheme 1. We planned to employ a
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r
10.1021/ol303272w
Published on Web 02/05/2013
2013 American Chemical Society

Scheme 1. Retrosynthetic Analysis
Figure 1. Lycopodine-type Lycopodium alkaloids.
followed by intramolecular Mannich cyclization of imine
8, a process first developed for our total synthesis of
lycopodine (1).3b,c The imine 8 would be derived from keto
sulfone 9. The key C7ÀC12 linkage could be accessed via a
diastereoselective intramolecular Michael addition. The
proposed strategy builds on our prior work in the total
synthesis of 1;3b,c however, the presence of the additional
stereochemistry and functionality at C10 complicates the
approach. While natural products 2À4 represent the only
known lycopodiumalkaloids containing oxygenationatthe
Scheme 2. Organocatalyzed Intramolecular Michael Reaction
C10 position, this functionality could provide an important
handle for accessing compounds possessing an additional
CÀC bond at this position (e.g., compound 5).
We commenced our synthesis of the key cyclohexanone
9 with known diol 136 (Scheme 2). Compound 13 is
available in enantioenriched form in three steps from
1-bromo-3-butene via sulfone incorporation, epoxidation,
and Jacobsen hydrolytic kinetic resolution.7 Acetonide
formation under standard conditions followed by sulfone
ester coupling with ester 113b,c cleanly provided the
coupled material 14. Next, cross metathesis with 3-pen-
ten-2-one and HoveydaÀGrubbs second generation cata-
lyst 15 produced the enone 10. Intramolecular Michael
(3) (a) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N. D.;
Carter, R. G. J. Org. Chem. 2008, 73, 5155–5158. (b) Yang, H.; Carter,
R. G.; Zakharov, L. N J. Am. Chem. Soc. 2008, 130, 9238–9239.
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N. D.; Carter, R. G. Org. Lett. 2011, 13, 4144–4147. (e) Veerasamy, N.;
Carlson, E. C.; Carter, R. G. Org. Lett. 2012, 14, 1596–1599.
~
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(b) Morales, G.; Loyola, L. A.; Castillo, M. Phytochemistry 1979, 18,
addition of the keto sulfone 10 was smoothly facilitated by
the acylsulfonamide catalyst 16 developed in our lab3c,8 to
provide cyclohexanone 9 in 85% yield and modest 3:1
diastereoselectivity (51% isolated yield of pure 9 after
crystallization). The stereochemistry of 9 was conclusively
established by X-ray crystallographic analysis. Addtion of
1% EtOH was key to this transformation, as its presence
~
1719–1720. (c) Garland, M. T.; Munoz, O. J. Appl. Crystallogr. 1982, 15,
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von Schnering, H. G.; Peters, K. Acta Crystallogr. 1988, C44, 165–166.
~
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~
(g) Munoz, O. M. Private communication.
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Org. Lett., Vol. 15, No. 4, 2013
737

Scheme 3. Synthesis of the Common Intermediate
Scheme 4. Synthesis of the Tetracycle
19 could easily be recycled by treatment with aqueous acid
to reveal the hemiketal 17. The hemiketal 20 was sequen-
tially silylated with TBSOTf followed by TIPSOTf to reveal
the ketone 21. Aza-Wittig reaction provided the cyclization
precursor 8. Treatment with Zn(OTf)2 provided the unex-
pected tricycle 22 in 57% yield. While compound 22 was a
productive intermediate in the synthetic sequence, we had
anticipated that the rearranged sulfone 6would be the major
product.3b,c We attribute this divergence in the expected and
observed reactivity to the presence of the C10 stereocenter.
This additional stereochemistry likely increases the confor-
mational preference for conformer 8 over comformer 8a (as
compared to the C10 deoxy series) for placement of both the
C12 sulfone and the C7 side arm in the pseudoaxial positions.
This conformationally accelerated intramolecular Mannich
cyclization proceeded significantly faster than the C10 deoxy
series, leading to preferential Mannich cyclization prior to
sulfone rearrangement.3b,c The location of the sulfone moiety
is inconsequential, as desulfurization using sodium/mercury
amalgam provided the key common intermediate 7.
led to a noticeable acceleration in reaction rate. It should
also be noted that, in the absence of catalyst16 or the use of
an alternate base, the conversion and diastereoselectivity
were significantly reduced. In fact, use of our i-Pr2NH,
IPA/CH2Cl2 conditions (which worked smoothly in lyco-
podine synthesis3b,c) resulted in <50% conversion and
low diastereoselectivity (1.5:1 dr). This divergence in re-
activity is related to the presence of the additional func-
tionality at C10 which likely counteracts the directing
influence of the C15 methyl moiety.
With the functionalized cyclohexanone in hand, we
turned our attention to the synthesis of the key common
intermediate (Scheme 3). Acetonide deprotection was
facilitated using aqueous HCl in dioxane to give the
hemiketal 17. Sulfonate activation at C9 followed by azide
displacement provided compound 20 along with the ketal
19. We attribute the formation of 19 to the close confor-
mational proximity of the C13 alcohol and the C9 mesity-
late. In fact, both mesitylate 18 and the azide 20 were prone
to forming the ketal 19 upon prolonged storage. Compound
The synthesis of the tetracyclic core for the lycopodium
alkaloids is shown in Scheme 4. N-Alkylation using
3- iodopropanol provided the primary alcohol 23. The reac-
tion time for this alkylation appeared to be critical, as less
than 10 h provided more recovered starting material and
longer reaction times led to overalkylation. The tandem
Oppenauer oxidation/intramolecular aldol condensation
produced the desired enone 24 in 71% yield. The use of
freshly prepared potassium tert-butoxide and freshly dis-
tilled benzene were necessary to achieve a reproducibly
high yield in this transformation. A small amount of the
retro-Michael product 7 (17%) was also isolated in this
reaction. Hydrogenation using Adams’ catalyst in metha-
nol cleanly yielded the desired product 25.2u,w
With the tetracycle in hand, we shifted our attention to
the completion of the total syntheses of 10-hydroxylyco-
podine (2), deacetylpaniculine (3), and paniculine (4)
(Scheme 5). TAS-F removal of the TIPS protecting group
cleanly provided 10-hydroxylycopodine (2). DIBAL-H
reduction of ketone 25 cleanly proceeded to provide the
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Org. Lett., Vol. 15, No. 4, 2013

absolute configuration by comparison to our reported
synthetic data. We hypothesize that the absolute stereo-
chemistry should be assigned based on analogy to other
lycopodium alkaloids (e.g., 1) for which we have confirmed
synthetically.3b,c For 2, the isolation paper only provided
limited spectroscopic data for comparison.4 From what
data were provided, our synthesized material was in good
agreement with the natural product. To garner additional
confirmation of the original structural assignment of 10-
hydroxylycopodine (2), we sought to link 2 with other
lycopodium alkaloids isolated from the same plant. Synth-
esis of related members of this family (3 and 4) showed
excellent agreement between the synthesized material and
the literature data.5 For 3, the isolation paper5e provided a
tabular listing of the spectral data which shows both H1eq
and H14eq as doublets of doublets at 2.61 ppm; however,
careful analysis of actual 1H NMR spectra provided by the
isolation chemists revealed that these data were tabulated
incorrectly in the isolation paper.
Scheme 5. Total Syntheses of 10-Hydroxylycopodine, Deace-
tylpaniculine, and Paniculine
The first total syntheses of three related members of the
lycopodine subfamily have been accomplished. Key as-
pects to this work include the development of an acylsul-
fonamide-mediated intramolecular Michael reaction to
incorporate the C7 and C12 stereocenters, a conformation-
ally accelerated intramolecular Mannich cyclization to
construct the tricyclic core, and development of a common
intermediate 7 that should provide access to additional
members of this family of alkaloids.
Acknowledgment. Financial support was provided by
the National Institutes of Health (NIH) (GM63723) and
~
Oregon State University). Prof. Orlando Munoz (University
of Chile) is acknowledged for providing a copy of spectral
axial alcohol as a single stereoisomer.9 Acylation using
Ac2O and pyridine in the presenceofDMAP yielded the C5
acetate. Cleavage of the C10 TIPS ether was best accom-
plished using aqueous HCl toproduce the des-silyl product
as its HCl salt. Treatment with pH 10 buffer provided
paniculine (4), and treatment with aqueous sodium hydro-
xide yielded deacetylpaniculine (3).
One important aspect of this work is the clarification of
the structural assignments and spectral data for this sub-
family of natural products. For example, optical rotation
data for these natural products were not provided in the
isolation papers.4,5 Our synthetic material provides a
reference for future isolation chemists to confirm the
data for 3 and 4. The authors are grateful to Prof. Claudia
ꢀ
Maier and Jeff Morre (OSU) for mass spectra data and
Dr. Lev Zakharov (OSU) for X-ray crystallographic analysis
of 9, 17, and 19. Also, Prof. James D. White (OSU), Mr.
Nathan Collett (OSU), and Dr. Roger Hanselmann (Rib-X
Pharmaceuticals) are thanked for their helpful discussions.
Supporting Information Available. Complete experi-
1
mental procedures are provided, including H and 13C
spectra of all new compounds. X-ray crystallographic
data (CIF) for 9, 17 and 19 are also provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) It was imperative that this reaction be quenched with saturated
aqueous Rochelle’s salt for an extended period to fully break up the
aluminium complex. We attribute this reactivity to the presence of the
neighbouring basic nitrogen. In support of this hypothesis, this product
26 readily forms the DCl salt upon standing in CDCl3.
The authors declare no competing financial interest.
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