Rapid access to the heterocyclic core of the calyciphylline a and daphnicyclidin A-type daphniphyllum alkaloids via tandem cyclization of a neutral aminyl radical

Article abstract of DOI:10.1021/ol4034868

A streamlined approach to the tertiary amine-containing core of the calyciphylline A and daphnicyclidin A-type Daphniphyllum alkaloids is presented. A known carvone derivative is converted into the core structure in only four synthetic operations, and it is well poised for further elaboration. The key enabling methodology is a radical cyclization cascade beginning with addition of a secondary, neutral aminyl radical to the β-position of an enone, followed by trapping with a pendant alkyne.

Full text of DOI:10.1021/ol4034868

Letter
pubs.acs.org/OrgLett
Rapid Access to the Heterocyclic Core of the Calyciphylline A and
Daphnicyclidin A‑Type Daphniphyllum Alkaloids via Tandem
Cyclization of a Neutral Aminyl Radical
Ahmad A. Ibrahim, Alexander N. Golonka, Alberto M. Lopez, and Jennifer L. Stockdill*
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
S
* Supporting Information
ABSTRACT: A streamlined approach to the tertiary amine-containing core of the calyciphylline A and daphnicyclidin A-type
Daphniphyllum alkaloids is presented. A known carvone derivative is converted into the core structure in only four synthetic
operations, and it is well poised for further elaboration. The key enabling methodology is a radical cyclization cascade beginning
with addition of a secondary, neutral aminyl radical to the β-position of an enone, followed by trapping with a pendant alkyne.
Scheme 1. Targeted Daphniphyllum Alkaloids
he Daphniphyllum alkaloids are a structurally alluring
Tfamily of plant alkaloids isolated from trees of the genus
Daphniphyllum.1 Biosynthetic proposals from Kobayashi
suggest that they are derived from rearrangements of
secodaphnane,1a which in turn, arises via cyclization and
condensation of squalene.2 Members of this family of alkaloids
exhibit cytotoxicity against murine leukemia (L1210, P-388, and
A-549 cell lines), demonstrate antioxidant activity against PC12
cells, show vasorelaxant effects in the rat aorta, and increase
mRNA expression of nerve growth factor.1a Despite these
promising bioactivities, the biological role of the vast majority
of Daphniphyllum alkaloids has not been determined. The range
of known Daphniphyllum alkaloid bioactivities, their significant
structural diversity, and the sheer number of compounds in this
family of alkaloids demand further investigation of the
therapeutic potential of these compounds and related
structures. Accordingly, the synthetic community has taken
an increased interest in these targets in recent years.1a,3
The combination of fused and bridging ring systems in the
daphnicyclidin A-type (1) and calyciphylline A-type (2)
alkaloids piqued our interest (Scheme 1). Additionally, these
alkaloids pose several other synthetic challenges. The
calyciphylline A subfamily boasts a pair of vicinal all-carbon
quaternary stereocenters, each of which is positioned at the
junction of three rings. Meanwhile, the daphnicyclidin A
subfamily is comprised of two 7-membered rings fused by a
unique fulvene moiety. Both subtypes contain a tertiary
aliphatic amine at the junction of two rings. Importantly, we
felt either subclass of alkaloids could be accessed from a single
core structure such as tricyclic β-amino cyclohexanone 3, which
could be used directly to access the calyciphylline A-type
alkaloids or could furnish the daphnicyclidin A alkaloids upon
ring expansion. We envisioned generation of tricyclic core 3 via
tandem radical cyclization of an N-centered radical, which
could be produced from chloroamine 4. Enone 4 would, in
turn, be generated from known lactone 5, a derivative of
(+)-(S)-carvone (6).
We began our synthetic efforts with bicyclic lactone 5, which
is accessed in three steps from (R)-carvone (Scheme 2).4 This
lactone could be appropriately functionalized to generate the
cyclization substrate in just three synthetic operations. Thus,
DIBAL-H reduction to the lactol was followed by reductive
amination with propargylamine to afford amino alcohol 7 in
86% yield over two steps. Propargylamine derivative 7 was
reacted with NCS in methylene chloride at −78 °C, the
Received: December 3, 2013
Published: February 7, 2014
© 2014 American Chemical Society
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with electron rich olefins, but as nucleophilic radicals with
electron poor olefins.10 On the basis of this reactivity, it is
reasonable to expect that N-centered radicals might exhibit a
similar dichotomy, and the secondary aminyl radicals would
react well with electron poor olefins. However, there are limited
examples of cyclization of any type of NCR with Michael
acceptors, such as enones.8 Guindon and co-workers reported
cyclization of a neutral aminyl radical (derived from 11, Bth =
benzothiazole) onto the β-position of an α,β-unsaturated
carbonyl system to generate pyrrolidine 12 (Scheme 4).8b
Efficient cyclization was observed for benzyl derivatives and
primary tributylstannyl NCRs, with only a small amount of
reduction product 13. However, no cyclization occurred for
dialkyl N-centered radicals.8b In the synthesis of (+)-clividine
by Banwell and co-workers, an arylogous unsaturated lactone
(14) was employed in a radical cyclization, initiated at nitrogen,
to afford pyrrolidine 15 in 83% yield.8c A major byproduct in
the reaction of related structures was the uncyclized N−Cl
reduction product.8c,d In general, neutral aminyl radicals are
particularly prone to nonselective hydrogen atom abstraction
reactions,5 and reduction of the NCR by reaction with
tributyltin hydride often out-competes cyclization.11
Scheme 2. Synthesis of Radical Cyclization Substrate
reaction mixture was warmed to 0 °C, and Dess−Martin
periodinane was added. Finally, the reaction was allowed to
come to ambient temperature. This protocol afforded the
cyclization substrate (ent-4) in 96% yield.
We envisioned that propargyl chloroamine derivative ent-4
would be a viable substrate in a tandem radical cyclization
initiated at nitrogen, directly providing desired core structure
ent-3. As illustrated in Scheme 3, homolytic cleavage of the N−
Cl bond (4) would provide N-centered radical (NCR) 8.
Intramolecular 6-exo addition to the β-position of cyclic enone
would result in the formation of radical 9. We anticipated that
the polarization of the enone would encourage cyclization of
NCR 8 in preference to nonselective hydrogen atom
abstraction.5 Tertiary radical 9 would then be trapped by the
pendant alkyne in a C−C bond-forming event to form vinyl
radical 10. Finally, hydrogen atom abstraction would afford
tricyclic core ent-3.
Scheme 4. Known Cyclizations of Neutral Secondary Aminyl
Radicals onto Polarized Olefins
Scheme 3. Strategy for Facilitating Tandem Cyclization of
Aminyl Radical To Access Core Structure
With these precedents in mind, we were poised to evaluate
the key cyclization reaction. Attempts to induce cyclization of
ent-4 with BEt3 and O2 led to a 52% yield of N−Cl reduction
products.12 Use of neutral CuCl conditions13 provided a low
yield of the vinyl chloride. We were excited to find that reaction
with AIBN and tributyltin hydride at 80 °C in toluene afforded
40−50% yields of tandem cyclization product ent-3 (Table 1).
In an effort to avoid use of tin reagents, a photolytic reaction
was conducted using a sunlamp as the source.14 Unfortunately,
only a 17% yield was observed. The major side products in the
thermally induced cyclization were N−Cl reduction plus
alkenyl radical trapping products, including the alkenyl chloride,
the alkenylstannane, and the benzyl-substituted derivative
arising from •CH2Ph trapping. To avoid the tolyl radical-
derived byproduct, the solvent was changed to trifluorotolue-
ne.8a Surprisingly, this lowered the yield to 27%. Addition of
the AIBN and Bu3SnH over 1 h in toluene resulted in a 61%
yield of the desired product, with the major byproduct being
the alkenyl chloride. In benzene, this protocol afforded only a
21% yield of the tricyclic product. The final hydrogen atom
abstraction seemed to be the limiting factor in improving the
At the outset of our work, there was little known about the
viability of a secondary neutral N-centered radical cyclizing with
a highly polarized olefin such as an enone. Although amidyl,
iminyl, and aminium radicals have been fairly well studied,6
fewer reports have described the cyclization of neutral aminyl
radicals.6b,7,8 Curiously, only one prior example of a 6-exo
cyclizations of a neutral aminyl radical has been reported.9 In
primary aminyl radicals, competitive cyclization between 5-exo
and 6-endo pathways is observed and can be tuned by adjusting
the substituents on the olefin.7b Cyclizations of secondary
neutral aminyl radicals are less common,7a,b,8b−d and this might
be attributable to an increase in their nucleophilicity relative to
primary NCRs. The more nucleophilic NCR would have a
higher SOMO energy, resulting in less favorable overlap with
the HOMO of a neutral or electron-rich olefin. Similar effects
have been observed with alkoxyl radicals, which have
intermediate SOMO energies and react as electrophilic radicals
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yield, and so the reaction was heated to reflux to increase the
rate of the final radical trapping.15 Gratifyingly, this adjustment
led to a 74% yield16 of the cyclization product as a single
diastereomer, with no N−Cl reduction byproducts. Interest-
ingly, we did not observe evidence of [1,5]-hydrogen atom
transfer (to form the amine and an allylic radical) in these
reactions.
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: stockdill@wayne.edu.
Notes
a
The authors declare no competing financial interest.
Table 1. Optimization of the Tandem NCR Cyclization
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (R00-GM097095 to
J.L.S., R25-GM058905 IMSD Fellowship to A.M.L.) and
Wayne State University for generous financial support. We
also gratefully acknowledge the staff of the WSU Lumigen
Instrument Center for spectroscopic support, in particular Dr.
Yuriy Danylyuk and Dr. Bashar Ksebati.
temp (°C)
80
solvent
addition time (h)
% yield (isolated)
40−50
Ph-Me
Ph-Me
Ph-CF3
Ph-Me
Ph-H
0
0
0
1
1
1
21 (sunlamp)
17
DEDICATION
■
80
27
This manuscript is dedicated to Prof. David Y. Gin, in
memoriam, with gratitude for his mentorship and support
during the inception of this strategy.
80
61 (+Cl· transfer pdt.)
21
80
110
Ph−Me
74
a
All reactions were performed using 0.5 equiv of AIBN, 2 equiv of
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■
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NOTE ADDED AFTER ASAP PUBLICATION
■
Schemes 1, 2, 4, and the Supporting Information contained
errors in the version published ASAP on February 7, 2014; the
correct version reposted on February 11, 2014.
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