Synthesis of (+)-complanadine A, an inducer of neurotrophic factor excretion

Article abstract of DOI:10.1021/ja101956x

A total synthesis of the Lycopodium alkaloid (+)-complanadine A is described. Complanadine A has been shown to induce the secretion of neurotrophic factors from 1321N1 cells, promoting the differentiation of PC-12 cells. The use of a simplifying metal mediated [2+2+2] + [2+2+2] sequence using a silyl-substituted diyne and 2 equiv of the corresponding alkyne-nitrile has provided rapid access to the natural product.

Full text of DOI:10.1021/ja101956x

Published on Web 04/13/2010
Synthesis of (+)-Complanadine A, an Inducer of Neurotrophic Factor
Excretion
Changxia Yuan, Chih-Tsung Chang, Abram Axelrod, and Dionicio Siegel*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin, Austin, Texas 78712
Received March 8, 2010; E-mail: dsiegel@cm.utexas.edu
Gene therapy-based approaches to increasing the production of
neurotrophic factors, while promising, have not overcome the
limitations of short-lived effects, undesirable immune responses,
intracranial delivery, and challenges of viral vectors.1 Small
molecules provide an attractive alternative to the biologics-based
strategies to regenerative medicine. Able to mimic neurotrophic
factors, or to induce neurotrophic factor biosynthesis, small
molecules possess the pharmacological advantage.2 The natural
product complanadine A (1) and complanadine B (2) were identified
in a screen of compounds from the club moss Lycopodium
complanatum and reported to induce the secretion of neurotrophic
factors from 1321N1 cells, promoting the differentiation of PC-12
cells.3 While this activity is promising, additional material is needed
to test complanadine A in primary glial cell cultures to discover if
enhanced expression of neurotrophic factors occurs and if so which
are produced.
with 3-iodopropyl acetate (Scheme 1).7 The product was trans-
formed into cyclohexenone 5 through m-CPBA mediated oxidation
of the thioether and a mild sulfoxide elimination (occurring at 23
°C). Treatment of enone 5 with the anion of trimethylsilyl
acetonitrile at -78 °C followed by careful quenching with ethyl
salicylate furnished the Michael adduct as a mixture of diaste-
reomers.5,8,9 Desilylation of the crude mixture with cesium fluoride
facilitated the separation of isomers and provided cyclohexanone
6. Diastereoselective delivery of ethynylmagnesium chloride into
the ketone cleanly provided the corresponding propargyl alcohol 7
as a single isomer. Activation of the propargyl alcohol of 7 as the
corresponding acetate 8 by treatment with neat acetic anhydride
and magnesium perchlorate provided a precursor for a copper
mediated amination reaction.10 Displacement of the tertiary acetate
was examined under a variety of conditions. After optimization,
heating a thoroughly degassed THF solution of diacetate 8 and
benzylamine with a catalytic amount of CuCl provided propargyl
amine 9 in 92% yield.11 Notably, the reaction proceeded with
complete diastereoselectivity. Thorough degassing of the solvent
prevented an otherwise rapid Glaser dimerization. Secondary amine
9 was transformed into the desired alkyne-nitrile 11 in a two-step
sequence initiated by cleavage of the acetate followed by cyclization
using PPh3/CCl4/imidazole, forming alkne-nitrile 11 in a 75% yield
over two steps.12 The structure of 11, determined by NMR, was
corroborated by X-ray crystallography (see Supporting Information).
Figure 1. Structures of complanadine A, complanadine B, and lycodine.
Complanadine A is a member of the large family of lycopodium
alkaloids.4 Aside from their varied and interesting biological
activities, the compounds have attracted the interest of the synthetic
community leading to several creative methods for their laboratory
preparation including the related alkaloid lycodine (3) (Figure 1).5
In addition to our efforts, Sarpong and co-workers have concurrently
completed a synthesis of complanadine A, as well as several
structurally related alkaloids.6
Scheme 1
In Nature, complanadine A is likely synthesized through the
union of two molecules of lycodine (3). In the laboratory setting
the pseudosymmetry of the molecule has allowed the implementa-
tion of a simplifying metal mediated [2+2+2] + [2+2+2] sequence
using a substituted diyne and 2 equiv of the corresponding alkyne-
nitrile (Figure 2).
The first [2+2+2] cycloaddition of alkyne-nitrile 11 and bis(t-
rimethylsilyl)butadiyne proceeded smoothly under thermal condi-
tions using CpCo(CO)2, providing the [2+2+2] cycloadduct 13 as
the major regioisomer (25:1, 13:14, eq 1).13 Unfortunately, even
under the influence of a variety of conditions and catalysts pyridyl-
alkyne 13 proved resistant to undergoing a second [2+2+2]
cycloaddition reaction with alkyne-nitrile 11.
As a result of the low reactivity of pyridyl-alkyne 13, both silicon
groups were removed with TBAF in THF heated to reflux,
generating alkyne 15 (Scheme 2). However, attempts at the second
Figure 2. Synthetic disconnections.
The synthesis of the requisite alkyne-nitrile was initiated by the
alkylation of the thermodynamically favored enolate of thioether 4
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5924 J. AM. CHEM. SOC. 2010, 132, 5924–5925
10.1021/ja101956x  2010 American Chemical Society

C O M M U N I C A T I O N S
acidic methanol solution generated (+)-complanadine A (1), fully
matching with the spectroscopic data reported for the natural
product.3
Scheme 4
[2+2+2] annulation of 15 with the bicycle 11 led only to
decomposition of 15 and recovery of 11. Other transition-metal
catalysts examined, such as Ru(COD)Cl2 and Cp2Zr/NiCl2, were
also ineffective. After routinely noting the unproductive consump-
tion of 15 the reactivity of the alkyne was attenuated by the
reinstallation of the alkynyl trimethylsilyl group providing pyridyl-
alkyne 16. A mixed result was obtained in the cobalt-catalyzed
[2+2+2] annulations of 16 and 11 as the reaction provided a single
compound, symmetric 2,2′-bipyridinyl 17 rather than the desired
2,3′-bipyridinyl isomer (Scheme 2).
The successful synthesis of complanadine A provided several
transformations of utility; the formation of a challenging quaternary
center by Cu(I)-catalyzed amine substitution of propargyl acetate
8 and two late-stage Co(I)-mediated [2+2+2] cycloadditions with
good to excellent regioselectivities. With access to synthetic
complanadine A we are currently examining the effects of the
compound on primary cultures of rat glial cells and examining the
effects on the biosynthesis of neurotrophin mRNAs.
Scheme 2
Acknowledgment. The authors are grateful for the financial
support of the Welch Foundation, Texas Institute for Drug and
Diagnostic Development, and The University of Texas at Austin.
We would also like to thank Prof. Richmond Sarpong at the
University of California, Berkeley for helpful conversations.
Supporting Information Available: Complete references, detailed
experimental procedures, and full spectroscopic characterization data
for all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
After significant experimentation it was discovered that a
remarkable switch in regioselectivity, providing 20 as the major
isomer (1:3, 19/20), was possible by the addition of an excess PPh3
to the reaction using the formyl derivative 18 (Scheme 3).14 The
use of formyl in place of the benzyl group was required as 16 and
11 failed to react in the presence of PPh3. The ability of PPh3 to
change the regioselectivity warrants further study.
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