Total synthesis of (+)-complanadine a using an iridium-catalyzed pyridine C-H functionalization

Article abstract of DOI:10.1021/ja101893b

The total synthesis of the Lycopodium alkaloid complanadine A, which is an unsymmetrical dimer of lycodine, was achieved by exploiting a common tetracyclic precursor. Key to the success of the synthesis was the development of a late-stage site-selective C-H functionalization of a pyridine moiety to arrive at a key boronic ester intermediate.

Full text of DOI:10.1021/ja101893b

Published on Web 04/13/2010
Total Synthesis of (+)-Complanadine A Using an Iridium-Catalyzed Pyridine
C-H Functionalization
Daniel F. Fischer and Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received March 5, 2010; E-mail: rsarpong@berkeley.edu
Scheme 1
The Lycopodium alkaloids are among the most skeletally diverse
families of natural products that have been isolated to date.1 In
addition to their complex architecture, many of the alkaloids in
this family possess potentially useful biological activity, which
includes acetylcholinesterase (AChE) inhibition.2 The utility of
known AChE inhibitors, such as the Lycopodium alkaloid huperzine
A (1, Figure 1),3 to partially address the treatment of Alzheimer’s
disease is supported by the observation of increased memory and
learning in rats upon administration of 1.4 Furthermore, several
AChE inhibitors, including galanthamine5 and Aricept,6 are com-
mercial pharmaceuticals that are used to treat Alzheimer’s disease
indications. However, because AChE inhibition appears to treat only
the symptoms of neurodegenerative diseases, there continues to be
a need to identify other natural products that promote the growth
of new neural networks. In this regard, Lycopodium alkaloids, such
as the lyconadins (e.g., 3)7 and complanadine A (4),8 are especially
interesting because they enhance mRNA expression for nerve
growth factor (NGF) and the production of NGF in human glial
cells.9
literature procedures.13 Aminoketal 12 was used as a direct
precursor to oxygen-sensitive R,ꢀ-unsaturated imine 10.14
As a first step in a program aimed at the biological evaluation
of Lycopodium alkaloids and their analogues as neurotrophic factors,
we have undertaken the synthesis of several of these compounds.
We recently reported the total synthesis of lyconadin A (3).10 In
this manuscript, we present the details of our total synthesis of
complanadine A (4), which is a dimer of the well-known phleg-
marine-derived alkaloid lycodine (5).11 The synthetic challenge
posed by 4 stems primarily from the fact that it is an unsymmetrical
dimer of lycodine (C2-C3′ linkage; see 4) and therefore requires
the introduction of position-control elements prior to merging of
the two halves (see 6 and 7, Scheme 1). A powerful simplification
of the synthesis would entail formation of 6 and 7 from the same
intermediate (e.g., tricyclic enamide 8). Enamide 8 was in turn
envisioned to arise from an acid-promoted formal cycloaddition of
9 and 10 following the precedent of Schumann for the synthesis of
racemic N-desmethyl-R-obscurine (17, Scheme 2).
Enamide 9 was prepared from commercially available 5-keto-
hexanenitrile15 via Zn(II)-catalyzed hydrolysis of the cyano group
and subsequent dehydrative cyclization upon distillation.16 Interest-
ingly, our empirical observations suggest that under the conditions
identified by Schumann for the formation of 17 (Scheme 2) from
9 and 10 (70% HClO4(aq), dioxane, 105 °C, 20 h), enamide 9
undergoes hydrolysis to 13.17 Ketoamide 13 likely forms reactive
enol tautomer 14, which in turn reacts with protonated 10 (generated
in situ from 12) to yield N-desmethyl R-obscurine 17 following a
series of cyclizations (i.e., via 15 and 16).
Scheme 2
The synthesis of complanadine A commenced with the prepara-
tion of ketal 12 (eq 1), which is available from (+)-pulegone using
The synthetic sequence up to this point is easily amenable to
scale-up, which has provided 17 on a multigram scale. At this stage,
we proceeded to address the major challenge of the synthesis, which
was to advance 17 to triflate 7 as well as boronic ester 6. To set
the stage for these tasks, selective Boc protection of 17 (Scheme
3) afforded 8 (65% yield over two steps).18 This was followed by
oxidation of 8 with lead tetraacetate to provide pyridone 18 in 84%
yield. Triflation of the pyridone using triflic anhydride in pyridine
proved optimal, giving 7 in 72% yield.
Figure 1. Selected Lycopodium alkaloids.
9
5926 J. AM. CHEM. SOC. 2010, 132, 5926–5927
10.1021/ja101893b  2010 American Chemical Society

C O M M U N I C A T I O N S
With one of the desired coupling partners in hand, we looked to
address the synthesis of the other (i.e., boronic ester 6).19 The triflate
group in 7 was removed under Pd-catalyzed reducing conditions
to provide Boc-protected lycodine (19).
In summary, we have reported the total synthesis of the
unsymmetrical lycodine dimer complanadine A. Our synthetic
sequence proceeds in eight steps from enamide 9 and acetal 12.
The synthetic strategy also provides potential access to the natural
products lycodine, lycopladine F, and lycopladine G. Highlights
of the complanadine synthesis include a Hartwig-Miyaura Ir(I)-
catalyzed site-selective borylation and a late-stage Suzuki cross-
coupling to form the C2-C3′ bipyridine. The application of the
strategy to the multigram scale production of 4 and congeners, as
well as the synthesis of other Lycopodium alkaloids, is underway
and will be reported in due course.
Scheme 3
Acknowledgment. The authors are grateful to the NIGMS (RO1
GM086374-01), Eli Lilly, Johnson and Johnson, GlaxoSmithKline,
Amgen, and AstraZeneca for financial support. D.F. is thankful for
a DAAD postdoctoral fellowship.
The conversion of 19 to boronic ester 6 was achieved in a single
step, as illustrated in Scheme 4. Our approach to the remarkable
direct C-H functionalization of 19 rested on the uniquely effective
Ir(I)-catalyzed borylation chemistry developed by Hartwig and
Miyaura.20 In the event, treatment of 19 with 4 mol % [Ir(OMe)-
(cod)]2, 8 mol % di-tert-butylbipyridine (dtpy), and diboron
pinacolato ester (0.75 equiv) in THF at 80 °C gave 6 in 75% yield
after 5.5 h. The observed site selectivity is consistent with that noted
by Hartwig for pyridine functionalization and appears to be guided
mainly by steric factors. Suzuki cross-coupling of boronic ester 6
and triflate 7 followed by cleavage of the Boc protecting groups
gave complanadine A (4) in 42% yield over two steps.
Supporting Information Available: Experimental details and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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Scheme 4
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(11) The group of Prof. D. Siegel (UT Austin) has also recently completed a
synthesis of 4 (personal communication).
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For more details, see the Supporting Information.
Synthetic complanadine A gave spectral data (1H and 13C NMR)
consistent with that reported by Kobayashi and co-workers during
its isolation.21
Access to boronic ester 6 should prove highly significant as a
starting point for the synthesis of congeners and analogues of
complanadine A and lycodine. For example, coupling of boronic
ester 6 (Scheme 5) to vinyl bromide 2022 followed by dihydroxy-
lation using the Upjohn method23 and periodate cleavage yields
22, which is a direct precursor to lycopladines G and F.24
(14) For ease of handling, air-sensitive ene-imine 10 was generated in situ
under the reaction conditions for formation of 17.
(15) This reagent may also be prepared according to: Na¨slund, G.; Senning,
A.; Lawesson, S.-O. Acta Chem. Scand. 1962, 16, 1324. For an improved
procedure, see the Supporting Information.
(16) This is an adaptation of a reported procedure: Kopylovich, M. N.;
Kukushikin, V. Y.; Haukka, M.; Frausto da Silva, J. J. R.; Pombiero, A. J. L.
Inorg. Chem. 2002, 41, 4798. For details, see the Supporting Information.
(17) Preliminary results indicated that 13 may be used instead of 9 in the
formation of 17.
(18) Because of its high polarity, 17 was taken directly into the next step without
purification.
(19) Although pyridone 18 may be brominated at the requisite position, attempts
to advance the 3-bromopyridone were unsuccessful.
Scheme 5
(20) (a) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390. (b) For a related reaction,
see: Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R.
Science 2002, 295, 305.
(21) (a) We are grateful to Prof. H. Morita (Hoshi University, Japan) for 1H
and 13C NMR spectra of 4. (b) Complanadine A was obtained along with
small amounts of N-Boc-lycodine (19), which presumably arises from
protodeborylation.
(22) Mori, M.; Washioka, Y.; Urayama, T.; Yoshiura, K.; Chiba, K.; Ban, Y. J.
Org. Chem. 1983, 48, 4058.
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1976, 17, 1973.
(24) Ishiuchi, K.; Kubota, T.; Hayashi, S.; Shibata, T.; Kobayashi, J. Tetrahedron
Lett. 2009, 50, 4221.
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