Synthesis of the core of actinophyllic acid using a transannular acyl radical cyclization

Article abstract of DOI:10.1021/ol300280s

A synthetic study of actinophyllic acid based on an original strategy has been described. A transannular acyl radical cyclization allowed us to obtain a key bicyclo[3.3.2] framework, and construction of a core of the target alkaloid has been accomplished

Full text of DOI:10.1021/ol300280s

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1656–1658
Synthesis of the Core of Actinophyllic
Acid Using a Transannular Acyl Radical
Cyclization
Hisaaki Zaimoku, Tsuyoshi Taniguchi,* and Hiroyuki Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and
Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
tsuyoshi@p.kanazawa-u.ac.jp
Received February 4, 2012
ABSTRACT
A synthetic study of actinophyllic acid based on an original strategy has been described. A transannular acyl radical cyclization allowed us
to obtain a key bicyclo[3.3.2] framework, and construction of a core of the target alkaloid has been accomplished by subsequent introduction of a
C2 unit.
A number of classes of indole alkaloid with unusual
structures and biological activity have recently attracted
the widespread interest of synthetic and medicinal che-
mists.1 One of these, (ꢀ)-actinophyllic acid (1), was iso-
lated by Carroll and co-workers in 2005 from leaves of the
Australian tree Alstonia actinophylla (Scheme 1).2 Actino-
phyllic acid exhibits inhibitory activity in the coupled
enzyme assay of carboxypeptidase U (CPU) /hippuricase
(IC50 = 0.84 μM).2a Since CPU is an inhibitor of the blood
fibrinolysis process, actinophyllic acid might become the
seed of an agent for treatment of thrombotic diseases.
Actinophyllic acid has a unique 2,3,6,7,9,13c-hexahydro-
1H-1,7,8-(methanetriyloxymethano)pyrrolo[10,20:1,2]azo-
cino[4,3-b]indole-8(5H)-carboxylic acid skeleton, and
an elegant total synthesis of this alkaloid based on a
biomimetic aza-Cope/Mannich cascade strategy has re-
cently been reported by Overman and co-workers.3 How-
ever, exploration of new flexible routes to actinophyllic
acid still remains important as long as its derivatives have
the potential tobe medicinal candidates.4 Inthis regard, we
envisaged an alternative approach for the synthesis of
actinophyllic acid that would facilitate the search for
potential derivatives. Herein we report a synthesis of the
core of (()-actinophyllic acid using a well-designed radical
cyclization as a milestone in our synthetic study of this
alkaloid.
Our synthetic strategy for actinophyllic acid is outlined
in Scheme 1. It targeted the corecompound(()-2 (R = H).
The pyrrolidine ring ofcompound (()-2 (R = H) would be
constructed by two alkylations at a nitrogen atom and the
R-position of the ketone in azabicyclo[3.3.2] structure 3.
(1) Reviews:(a) Seigler, D. S. Plant Secondary Metabolism; Springer:
New York, 2001; Chapters 34 and 35, pp 628ꢀ667. (b) Hibino, S.; Choshi,
T. Nat. Prod. Rep. 2002, 19, 148–180.
(2) (a) Carroll, A. R.; Hyde, E.; Smith, J.; Quinn, R. J.; Guymer, G.;
Forster, P. I. J. Org. Chem. 2005, 70, 1096–1099. Recently, absolute
configuration of natural actinophyllic acid was determined by Berova
and co-workers, see: (b) Taniguchi, T.; Martin, C. L.; Monde, K.;
Nakanishi, K.; Berova, N.; Overman, L. E. J. Nat. Prod. 2009, 72,
430–432.
(4) A report of a synthetic study of actinophyllic acid: Vaswani,
R. G.; Day, J. J.; Wood, J. L. Org. Lett. 2009, 11, 4532–4535.
(5) Reviews on acyl radicals: (a) Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991–2070. (b) Schiesser,
C. H.; Wille, U.; Matsubara, H.; Ryu, I. Acc. Chem. Res. 2007, 40, 303–
313. Recent examples of acyl radical cyclizations: (c) Yoshikai, K.;
Hayama, T.; Nishimura, K.; Yamada, K.; Tomioka, K. J. Org. Chem.
2005, 70, 681–683. (d) Grant, W. S.; Zhu, K.; Castle, S. L. Org. Lett.
2006, 8, 1867–1870. (e) Inoue, M.; Ishihara, Y.; Yamashita, S.; Hirama,
M. Org. Lett. 2006, 8, 5801–5804. (f) Roca, T.; Bennasar, M.-L. J. Org.
Chem. 2011, 76, 4213–4218.
(3) (a) Martin, C. L.; Overman, L. E.; Rohde, J. M.
J. Am. Chem. Soc. 2008, 130, 7568–7569. (b) Martin, C. L.; Overman,
L. E.; Rohde, J. M. J. Am. Chem. Soc. 2010, 132, 4894–4906.
r
10.1021/ol300280s
Published on Web 02/28/2012
2012 American Chemical Society

We proposed the transannular acyl radical cyclization of
selenoester 4 to obtain compound 3. Although many
examples of efficient transannular acyl radical cyclizations
for the construction of complex cyclic natural products
have been reported, the synthesis of an azabicyclo[3.3.2]
compound using this methodology has been hardly
investigated.5ꢀ8 A ring-closing metathesis of diene 5 would
be a reliable method for the construction of an eight-
membered ring of radical precursor 4.9
Easily available indole derivative 610 was chosen as a
starting material for our synthesis (Scheme 2). Suzuki-
Miyaura coupling of 2-chloroindole derivative 6 with
potassium vinyltrifluoroborate (1.5 equiv) in the presence
of palladium acetate (1 mol %) and a bidentate phosphine
ligand (1 mol %) gave 2-vinylindole compound 7.11 Sub-
sequently, crude compound 7 was subjected to a Hornerꢀ
WadsworthꢀEmmons reaction to obtain the R,β-unsatu-
rated ester 8 in good overall yield. The 3-butenylamine
moiety of diene 9 was readily introduced by aza-Michael
addition of the corresponding lithium silylamide (2 equiv)
to compound 8.12 After protection of the secondary amine
of compound 9 with a Cbz group, ring-closing metathesis
of compound 10 using Grubbs second-generation catalyst
(2 mol %) afforded eight-membered ring compound 11.
The moderate yield of 11 was due to competitive dimeriza-
tion of compound 10, and improvement in the yield may be
possible by further optimization of the reaction conditions
in the future. Compound 11 was transformed into selenoe-
ster 12 through an ester hydrolysis followed by a selenation
using a combination of diphenyldiselenide and tributyl-
phosphine.13
Scheme 1. Structure and Synthetic Strategy of 1
With selenoester 12 in hand, we examined the key trans-
annular radical cyclization to construct the caged skeleton
of actinophyllic acid. Treatment of compound 12 with
tributyltin hydride (1.5 equiv) and 1,10-azobiscyclohexane-
carbonitrile (ACN) (0.2 equiv) in toluene at reflux caused a
transannular cyclization of an intermediary acyl radical to
give the desired azabicyclo[3.3.2] compound 13 in a per-
fectly regioselective manner (Scheme 3). This result did not
surprise us because the regioselectivity of acyl radical
cyclizations has ostensibly tended to be thermodynamically
controlled.5a Therefore, the exclusive formation of com-
pound 13 via a more stable R-indolyl radical (π-radical)
intermediate would be reasonable in the present cyclization.
Scheme 2. Synthesis of Radical Precursor 12
Scheme 3. Transannular Radical Cyclization of 12
(6) Reviews on transannular cyclizations: (a) Clarke, P. A.; Reeder,
A. T.; Winn, J. Synthesis 2009, 691–709. (b) Bonjoch, J.; Diaba, F.;
Bradshaw, B. Synthesis 2011, 993–1018.
(7) Examples of transannular acyl radical cyclizations: (a) Quirante,
J.; Vila, X.; Escolano, C.; Bonjoch, J. J. Org. Chem. 2002, 67, 2323–2328.
(b) Bennasar, M.-L.; Roca, T.; Garcıa-Dıaz, D. J. Org. Chem. 2008, 73,
´ ´
9033–9039.
(8) Dowd and co-workers have reported the synthesis of a bicyclo-
[3.3.2] compound using a transannular radical reaction: (a) Dowd, P.;
Zhang, W. J. Am. Chem. Soc. 1992, 114, 10084–10085. (b) Dowd, P.;
Zhang, W.; Geib, S. J. Tetrahedron 1995, 51, 3435–3454.
(9) Examples of the similar strategy: (a) Bennasar, M.-L.; Zulaica, E.;
ꢀ
Sole, D.; Roca, T.; Garcıa-Dıaz, D.; Alonso, S. J. Org. Chem. 2009, 74,
´ ´
ꢀ
8359–8368. (b) Bennasar, M.-L.; Sole, D.; Zulaica, E.; Alonso, S. Org.
Lett. 2011, 13, 2042–2045.
Org. Lett., Vol. 14, No. 6, 2012
1657

Scheme 4. Unexpected Formation of 16 from 13
Scheme 5. Synthesis of Actinophyllic Acid Core 20
Next, we focused on constructing the pyrrolidine ring of
the actinophyllic acid core. When compound 13 was
exposed to palladium-catalyzed hydrogenolysis, its Cbz
group was removed and the unexpected tetracyclic com-
pound 16 was obtained (Scheme 4). Probably, deprotec-
tion of the Cbz group set off a ring-opening reaction by
elimination of the hydrogen atom at the R-position of
ketone 14 to give tricyclic intermediate 15 which, following
intramolecular condensation, would afford the corre-
sponding imine 16. Hence, we realized that the ketone
group of compound 13 needed to be masked prior to the
deprotection of the Cbz group.
The ketone group of compound 13 was reduced to
alcohol 17 with sodium borohydride (1 equiv), and we
now succeeded inremovingthe Cbz group of compound 17
by hydrogenolysis and we obtained the secondary amine
18 (Scheme 5). Without isolation of compound 18, it
underwent reductive amination with 2-chloroacetaldehyde
(2 equiv) to give N-alkylated compound 19 in good overall
yield. Finally, oxidation of alcohol 19 with 2-iodoxyben-
zoic acid (IBX) (3 equiv) and subsequent treatment with an
excessive amount of lithium tert-butoxide (5 equiv), in one-
pot, led to the (()-actinophyllic acid core 20 via an in-
tramolecular alkylation.
In conclusion, we have succeeded in synthesizing a core
20 bearing most of the components of (()-actinophyllic
acid. The most remarkable step in our synthetic strategy is
the transannular acyl radical cyclization that provides an
access to the azabicyclo[3.3.2] system 13. We anticipate
that synthesis of an optically active derivative will be pos-
sible by an asymmetric aza-Michael reaction of compound
8.14 Further studies toward the total synthesis of (ꢀ)-
actinophyllic acid using this strategy are currently ongoing
in our laboratory.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology of
Japan.
Supporting Information Available. Expermental detail
and spectroscopic data for new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
ꢀ
(10) Konopelski, J. P.; Hottenroth, J. M.; Oltra, H. M.; Veliz, E. A.;
Yang, Z.-C. Synlett 1995, 609–611. Compound 6 also seems to be
commercially available from some suppliers.
(11) Reviews on Suzuki-Miyaura reaction: (a) Miyaura, N.; Suzuki,
A. Chem. Rev. 1995, 95, 2457–2483. (b) Molander, G. A.; Figueroa, R.
Aldrichim. Acta 2005, 38, 49–56.
(12) Asao, N.; Uyehara, T.; Yamamoto, Y. Tetrahedron 1988, 44,
4173–4180.
(14) Examples of asymmetric aza-Michael reactions: (a) Doi, H.;
Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc.
2003, 125, 2886–2887. (b) Doi, H.; Sakai, T.; Yamada, K.; Tomioka, K.
Chem. Commun. 2004, 1850–1851.
(13) Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W. K.; Bates,
G. S. J. Am. Chem. Soc. 1977, 99, 6756–6758.
The authors declare no competing financial interest.
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