Total synthesis of (±)-actinophyllic acid

Article abstract of DOI:10.1021/ja803158y

The first total synthesis of (±)-actinophyllic acid (1) is reported. Key steps of this synthesis include an intramolecular oxidative coupling of ketone and malonic ester enolates and an aza-Cope-Mannich rearrangement that assembled the core structure of t

Full text of DOI:10.1021/ja803158y

Published on Web 05/21/2008
Total Synthesis of (()-Actinophyllic Acid
Connor L. Martin, Larry E. Overman,* and Jason M. Rohde†
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine, California 92697-2025
Received April 29, 2008; E-mail: leoverma@uci.edu
Scheme 1
During a search for new natural product structures as potential
leads for developing agents for treating cardiovascular disorders,
Quinn, Carroll, and co-workers reported in 2005 the isolation and
relative configuration of actinophyllic acid (1).1 This structurally
unique indole alkaloid was obtained from the leaves of the tree
Alstonia actinophylla collected on the Cape York Peninsula, Far
North Queensland, Australia. It was identified in a coupled CPU/
hippuricase assay as an inhibitor of carboxypeptidase U (CPU), an
endogenous inhibitor of the process the body uses to clear fibrin
clots (fibrinolysis).2 The structure of actinophyllic acid (1) is unique
becausethe1-azabicyclo[4.4.2]dodecaneand1-azabicyclo[4.2.1]nonane
fragments that define its structure are found in no other indole
alkaloid. We report herein the first total synthesis of (()-
actinophyllic acid (1) by a route that is sufficiently concise that it
would be suitable for production of gram quantities of the natural
product.
Our plan for preparing actinophyllic acid (1) is outlined in
retrosynthetic format in Scheme 1. Initial disconnection of the C5
hemiketal and oxidation state adjustments reveals pentacyclic ketone
2, which we envisaged arising from allylic alcohol 5 by aza-
Cope-Mannich rearrangement of formaldiminium ion derivative
4.3 The hexahydro-1,5-methanoazocino[4,3-b]indole ring system
of the ketone precursor of allylic alcohol 5 we saw deriving from
intramolecular oxidative coupling of a dienolate4 generated from
indole-2-malonate precursor 6.
Scheme 2
The synthesis commenced with the preparation of indole di-tert-
butyl malonate 9 using a standard sequence (Scheme 2).5 Reaction
of the magnesium enolate of di-tert-butyl malonate (7) with
2-nitrophenylacetyl chloride, generated in situ from the correspond-
ing acid, gave keto diester 8 in 78% yield. Reduction of the nitro
group and concomitant cyclization delivered indole-2-malonate 9
in 69% yield. After examining several alternate ways to append a
3-piperidone fragment to intermediate 9, we discovered that this
junction was readily accomplished by simply allowing indole 9 to
react at room temperature in N,N-dimethylformamide (DMF) with
the crude bromopiperidone 10,6 generated by bromination of 1-tert-
butoxycarbonyl-3-piperidone.7 In this way, indole 11 was prepared
on multigram scale in 85% yield.
The keto-bridged hexahydroazocino[4,3-b]indole ring system was
constructed in one step by regioselective intramolecular oxidative
coupling of malonate and 3-piperidone enolates. Thus, deprotonation
of 11 with 3.2 equiv of lithium diisopropylamide (LDA) at -78
°C, followed by addition of 3.5 equiv of the Fe(III) oxidant
[Fe(DMF)3Cl2][FeCl4],8 provided tetracyclic ketone 12 in 60-63%
yield. To our knowledge, this is the first example of intramolecular
oxidative coupling of ketone and malonic ester enolates.9,10 It is
noteworthy that this oxidative coupling proceeded in the presence
of an unprotected indole, providing good yields of 12 on scales up
to 10 g.
The elaboration of indole keto diester 12 to (()-actinophyllic
acid is summarized in Scheme 3. tert-Butyl ester substituents had
been incorporated into intermediate 12 with the hope, bolstered
† Current address: Ironwood Pharmaceuticals, Inc., 320 Bent Street, Cambridge,
MA 02141.
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7568 J. AM. CHEM. SOC. 2008, 130, 7568–7569
10.1021/ja803158y CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
installed the tetrahydrofuran ring to provide actinophyllic acid
methyl ester. Acidic hydrolysis then provided (()-actinophyllic acid,
which was most conveniently isolated and characterized as its
hydrochloride salt 17.14
In conclusion, the first total synthesis of (()-actinophyllic acid
(1) was accomplished from di-tert-butyl malonate in an overall yield
of 8% by a concise sequence that proceeds by way of only seven
isolated intermediates. Of the eight stages of the synthesis, all but
one construct C-C or C-N bonds. Key bond formations include
an intramolecular oxidative coupling of ketone and malonate
enolates and an aza-Cope-Mannich rearrangement to construct the
unprecedented actinophyllic acid ring system.
Acknowledgment. This research was supported by the NIH
Neurological Disorders & Stroke Institute (NS-12389). NMR and
mass spectra were obtained at UC Irvine using instrumentation
acquired with the assistance of NSF and NIH Shared Instrumenta-
tion programs. We thank Professor Phil Baran for discussion and
samples of metal salts, and Dr. Joe Ziller for X-ray analyses.
Supporting Information Available: Experimental details for key
1
steps; copies of H and 13C NMR spectra of new compounds (PDF);
CIF file for compound 12. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) Carroll, A. R.; Hyde, E.; Smith, J.; Quinn, R. J.; Guymer, G.; Foster, P. I.
J. Org. Chem. 2005, 70, 1096–1099.
(2) Leurs, J.; Hendriks, D. Thromb. Haemost. 2005, 94, 471–487.
(3) For brief reviews, see: (a) Overman, L. E. Acc. Chem. Res. 1992, 25, 352–
359. (b) Royer, J.; Bonin, M.; Micouin, L. Chem. ReV. 2004, 104, 2311–
2352.
eventually by its X-ray model (see Scheme 2), that these bulky
groups would shield the Si face of the ketone in the addition of a
vinyl nucleophile. This expectation was verified when premixing
of ketone 12 with cerium trichloride,11 followed by reaction with
vinylmagnesium bromide at -78 °C in THF, provided a single
allylic alcohol product, 13, in nearly quantitative yield. Selective
removal of the Boc group from this product, followed by reaction
of the resulting secondary amine with 1 equiv of paraformaldehyde
and a catalytic amount of camphorsulfonic acid (CSA) in benzene
at 70 °C, cleanly promoted aza-Cope-Mannich reorganization to
provide pentacyclic diester 14. Exposure of this crude product to
neat trifluoroacetic acid (TFA) gave amino acid trifluoroacetate salt
15 in 76% overall yield from allylic alcohol 13. Fischer esterification
of 15, followed by counterion exchange, provided ester 16, a 2:1
mixture of R and ꢀ ester epimers, in 92% yield.12
We eventually discovered that the transformation of tetracyclic
allylic alcohol 13 to pentacyclic ester 16 could be carried out
conveniently in a one-pot process by initially exposing 13 to TFA
at room temperature, which cleaved the Boc and tert-butyl esters
and promoted decarboxylation. Removal of TFA in vacuo, dilution
with acetonitrile, and exposure of the resulting amino acid trifluo-
roacetate salt to paraformaldehyde promoted aza-Cope-Mannich
transformation to the carboxylic acid congener of 16, which after
removal of acetonitrile was esterified to provide 16 in 62% yield
as 1:1 mixture of ester epimers.
(4) Ito, Y.; Konoike, T,.; Harada, T.; Saegusa, T. J. Am. Chem. Soc. 1977, 99,
1487–1493.
(5) Mahboobi, S.; Bernauer, K. HelV. Chim. Acta 1988, 71, 2034–2041.
(6) Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc. 1999,
121, 700–709.
(7) Whitlock, C. R.; Cava, M. P. Tetrahedron Lett. 1994, 35, 371–374.
(8) For the use of this oxidant in phenolic couplings, see: (a) Tobinaga, S.;
Kotani, E. J. Am. Chem. Soc. 1972, 94, 309–310. In oxidative dimerization
of ketones, see: (b) Frazier, R. H.; Harlow, R. L. J. Org. Chem. 1980, 45,
5408–5411.
(9) This conversion was initially optimized with the dimethyl ester congener
of 11. These studies showed that yields of the cyclized product were much
lower using 2.0 equiv of LDA and 2.2 equiv of oxidant, or if Fe(acac)3,
FeCl3, Fe(cp)2PF6, or Cu(O2CC5H11) was employed as the oxidant.
2
(10) For examples of intramolecular oxidative coupling of two different ketone
enolates, see: (a) Cohen, T.; McNamara, K.; Kuzemko, M. A.; Ramig, K.;
Landi, J. J., Jr.; Dong, Y. Tetrahedron 1993, 49, 7931–7942. (b) Paquette,
L. A.; Bzowej, E. I.; Branan, B. M.; Stanton, K. J. J. Org. Chem. 1995,
60, 7277–7283. Of ester and amide enolates, see: (c) Baran, P. S.;
Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D.
J. Am. Chem. Soc. 2006, 128, 8678–8693.
(11) Immamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y.
J. Am. Chem. Soc. 1989, 111, 4392–4398.
(12) The constitution and relative configuration of the R epimer was confirmed
by single-crystal X-ray analysis.
(13) Schlosser, M.; Coffinet, D. Synthesis 1971, 380–381.
(14) Final purification of salt 17 by HPLC, as reported for the natural product,1
does not reproducibly give samples of 1 that show identical 1H NMR spectra
nor samples whose spectra precisely match those reported for natural 1 (in
DMSO-d6); we believe such samples are variable mixtures of zwitterionic
1 and salt 17. Addition of incremental amounts of sodium methylsulfinyl-
methylide-d5 to hydrochloride salt 17 in DMSO-d6 revealed incremental
shifts in most resonances. When ca. 1 equiv of base was added, a 1H NMR
spectrum identical to that reported1 for natural 1 was obtained; see the
Supporting Information for details. Unfortunately, a sample of natural
actinophyllic acid is no longer available for direct comparison.
In two additional steps, pentacyclic ester 16 was transformed to
actinophyllic acid (1). Stereoselective aldol reaction of the lithium
enolate derived from ester 16 with monomeric formaldehyde13
JA803158Y
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