Biomimetic total synthesis of angelicoin A and B via a palladium-catalyzed decarboxylative prenylation-aromatization sequence

Article abstract of DOI:10.1021/ol202320m

Five-step total syntheses of angelicoin A and B from 2,2,6-trimethyl-4- dioxinone are reported using late stage biomimetic aromatization reactions via diketo-dioxinones as intermediates. In addition, with angelicoin A, this aromatization was coupled with a palladium-catalyzed decarboxylative prenylation in a one-pot sequence as the key step.

Full text of DOI:10.1021/ol202320m

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5748–5750
Biomimetic Total Synthesis of Angelicoin
A and B via a Palladium-Catalyzed
Decarboxylative Prenylation-
Aromatization Sequence
Katie Anderson, Frederick Calo, Toni Pfaffeneder, Andrew J. P. White,
and Anthony G. M. Barrett*
Department of Chemistry, Imperial College, London, SW7 2AZ, England,
United Kingdom
agm.barrett@imperial.ac.uk
Received August 26, 2011
ABSTRACT
Five-step total syntheses of angelicoin A and B from 2,2,6-trimethyl-4-dioxinone are reported using late stage biomimetic aromatization reactions
via diketo-dioxinones as intermediates. In addition, with angelicoin A, this aromatization was coupled with a palladium-catalyzed decarboxylative
prenylation in a one-pot sequence as the key step.
The rootsof the herbPleurospermum angelicoides, found
in the Himalayan Mountains, are used locally as treat-
ments for typhoid and dysentery and as antipyretic and
diaphoretic agents.1 In 2006, a detailed chemical investiga-
tion of the root extracts was undertaken by Baba et al.,
resulting in the isolation of angelicoin A (1) and B (2)
(Figure 1). Common to both is the presence of a methyl-
substituted resorcylate δ-lactone.2 Resorcylates are com-
mon structural motifs found in a wide range of natural
products, and there are a number of total syntheses of these
important natural products reported.3 However, the majo-
rity of these approaches required multistep sequences with
the need for phenol protection. Inspired by the elegant
work of Harris,4 Hyatt,5 and Boeckmann,6 we have devel-
oped an alternative strategy for the synthesis of resorcylate
natural products employing a late-stage biomimetic aro-
matization of oligo-keto-esters.7À9
(1) Unuyal, S. K.; Awasthi, A.; Rawat, G. S. Curr. Sci. 2005, 82,
1246.
(2) Shibano, M.; Naito, H.; Taniguchi, M.; Wang, N.-H.; Baba, K.
Chem. Pharm. Bull. 2006, 54, 717.
(3) (a) Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 1, 22.
(b) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J.
€
J. Am. Chem. Soc. 2001, 123, 10903. (c) Furstner, A.; Thiel, O. R.;
Kindler, N.; Bartkowska, B. J. Org. Chem. 2000, 65, 7990. (d) Stob, M.;
Baldwin, R. S.; Tuite, J.; Andrews, F. N.; Gillette, K. G. Nature 1962,
196, 1318.
Figure 1. Angelicoin A (1) and B (2) and aigialomycin D (3).
(4) (a) Harris, T. M.; Harris, C. M. Tetrahedron 1977, 11, 2159. For
further information, see:(b) Barrett, A. G. M.; Morris, T. M.; Barton,
D. H. R. J. Chem. Soc., Perkin Trans. 1 1980, 2272. (c) Birch, A J.
Fortschr. Chem. Org. Naturst. 1957, 14, 186. (d) Birch, A. J.; Donovan,
F. W. Austral. J. Chem. 1953, 6, 360.
(5) Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. Org. Chem. 1984, 49,
5105.
r
10.1021/ol202320m
Published on Web 09/21/2011
2011 American Chemical Society

1
Recently, as part of these studies, we reported the total
synthesis of aigialomycin D (3) (Figure 1). Our approach
featured a key Pd(0)-catalyzed deallylation and decarbo-
xylation of allyl ester 5, employing morpholine as a
nucleophilic palladium π-allyl cation scavenger,10 to pro-
vide the ketene precursor 6. Subsequent aromatization
of diketo-dioxinone 6 gave resorcylate 8 as a single regio-
isomer (Scheme 1).11
NOE analysis in the H NMR spectrum.13 Herein we
report for the first time this transformation and further
studies on the total synthesis of resorcylates via diketo-
dioxinones and the application of decarboxylative rear-
rangement of prenyl esters in the total syntheses of angeli-
coins B (2) and A (1).
Scheme 2. Decarboxylation-Allylation
Scheme 1. Synthesis of Aigialomycin D (3)
Application of our dioxinone methodology to the total
synthesis of angelicoin B (2) is shown in Scheme 3.
Acylation of ketoester 129 with acyl chloride 13 provided
diketoester-dioxinone 14. One pot palladium(0)-cata-
lyzed deallyation-decarboxylation-ketene trapping-aro-
matization gave the desired resorcylate 15 in 45% yield
over 3 steps. Deprotection of the silyl ether 15 followed
by acid catalyzed cyclization gave lactone 16 in 60% yield
over 2 steps. Finally, regioselective methylation of phe-
nol 16 provided angelicoin B (2), which had identical
physical and spectroscopic data with those previously
reported.2
Acylation of dioxinone 4 with acyl benzotriazole 17 gave
ketoester 18 in 93% yield.9,14 Subsequent Claisen conden-
sation reaction of ketoester 18 with acid chloride 19,9 in the
presence of magnesium chloride and pyridine, gave dike-
toester 20 in 81% yield. Decarboxylation of diketoester 20
in the presence of Pd(PPh3)4 (10 mol %) gave a separable
mixture of dioxinone 21 and resorcylate 23 in a combined
yield of 60% (Scheme 4). In these transformations, the
linear substituted diketo-dioxinone 22 underwent aroma-
tization faster than its branched isomer 21. Deprotection
of the silyl ether 23 followed by lactonization under basic
conditions provided angelicoin A (1) in an overall yield of
27% over 5 linear steps from dioxinone 4.
During these studies, we observed that reaction of allyl
ester 5 with Pd(PPh3)4 in the absence of morpholine in
CH2CI2 underwent a modified Carroll rearrangement12
affording diketo-dioxinone 9 (Scheme 2). Subsequent ke-
tene trapping with alcohol 7 gave triketoester 10. Aldol
cyclization using cesium acetate followed by acid-mediated
aromatization11 provided resorcylate 11 in 42% yield over
3 steps. The regiochemistry of arene 11 was confirmed by
(6) (a) Boeckman, R. K., Jr.; Pruitt, J. R. J. Am. Chem. Soc. 1989,
111, 8286. (b) Boeckman, R. K., Jr.; Barta, T. E.; Nelson, S. G.
Tetrahderon Lett. 1991, 32, 4091. (c) Boeckman, R. K., Jr.; Weidner,
C. H.; Perni, R. B.; Napier, J. J. J. Am. Chem. Soc. 1989, 111, 8036.
(d) Boeckman, R. K., Jr.; Shao, P.; Wrobleski, S. T.; Boehmler, D. J.;
Heintzelman, G. R.; Barbosa, A. J. J. Am. Chem. Soc. 2006, 128, 10572.
(e) Boeckman, R. K., Jr.; Goldstein, S. W. Total Synth. Nat. Prod. 1988,
7, 1. (f) Boeckman, R. K., Jr.; Perni, R. B. J. Org. Chem. 1986, 51, 5486.
(g) Boeckman, R. K., Jr.; Starrett, J. E., Jr.; Nickell, D. G.; Sum, P. E.
J. Am. Chem. Soc. 1986, 108, 5549. For application of intramolecular
capture of acyl-ketenes in natural product synthesis, see the review by:
(h) Reber, K. P.; Tilley, S. D.; Sorensen, E. J. Chem. Soc. Rev. 2009, 38,
3022.
(7) (a) Basset, J.-F.; Leslier, C.; Hamprecht, D.; White, A. J. P.;
Barrett, A. G. M. Tetrahedron Lett. 2010, 51, 783. (b) Miyatake-
Ondozabal, H.; Barrett, A. G. M. Org. Lett. 2010, 12, 5573.
(c) Mikatake-Ondozobal, H.; Barrett, A. G. M. Tetrahedron 2010, 66, 6331.
(8) The diketo-dioxinones and triketo-compounds exist as ketoÀenol
mixtures. For simplicity, all are drawn in the all keto-form.
(9) Navarro, I.; Basset, J. -F.; Hebbe, S.; Major, S. M.; Werner, T.;
Howsham, C.; Brackow, C. J.; Barrett, A. G. M. J. Am. Chem. Soc. 2008,
130, 10293.
ꢀ
(10) Aubry, N.; Plante, R.; Deziel, R. Tetrahderon Lett. 1990, 31,
6311.
(11) Calo, F.; Richardson, J.; Barrett, A. G. M. Org. Lett. 2009, 11,
4910.
(12) (a) Carroll, M. F. J. Chem. Soc. 1940, 704. (b) Shimizu, L.;
Yamada, T.; Tsuji, J. Tetrahderon Lett. 1980, 21, 3199. (c) Tsuda, T.;
Chujo, Y.; Nishi, S; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980,
102, 6381.
(13) Calo, F. PhD Thesis, Imperial College London, 2010.
(14) Katritzky, A. R.; Wang, Z.; Wang, M.; Hall, C. D.; Suzuki, K.
J. Org. Chem. 2005, 70, 4854.
(15) For X-ray crystal structures, see Supporting Information. Me-
chanistic studies are currently being carried out and will be reported in
due course.
Org. Lett., Vol. 13, No. 21, 2011
5749

phenol 25 in which the prenyl carboxylate ester was re-
tained (Scheme 5). The structures of tricyclic lactone 25
and synthetic angelicoin A (1) were both confirmed by
X-ray crystallographic studies, thereby confirming that the
decarboxylation reaction was accompanied by prenyl
migration.15 This differs from the extensive work of Stoltz
and co-workers, which was based upon the palladium-
catalyzed enantioselective decarboxylative allylic alkyla-
tion reactions of ketone enolates without migration.16 Our
research illustrates that, for these precursors, only migra-
tion of the allyl or prenyl fragment is observed.
Scheme 3. Synthesis of Angelicoin B (2)
Scheme 5. Retention of the Ester Functionality
In summary, we report total syntheses of angelicoin A
(1) and B (2) using biomimetic aromatization reactions
with a highly regioselective decarboxylative prenyl transfer
reaction with the former natural product. We are further
examining oligo-keto-dioxinone aromatization and decar-
boxylation-allyl rearrangement reactions mechanistically,
in the total synthesis of other natural products, and in
medicinal chemistry.
Scheme 4. Synthesis of Angelicoin A (1)
Acknowledgment. We thank GlaxoSmithKline for the
generous Glaxo endownment, the Engineering and Physi-
cal Sciences Research Council (EPSRC) for grant sup-
port, P. R. Haycock and R. N. Sheppard (Imperial College
London) for high-resolution NMR spectroscopy, and Pro-
fessor Kimiye Baba (Osaka University of Pharmaceutical
Sciences) for providing NMR spectra of authentic angel-
icoin A and B.
Supporting Information Available. Experimental pro-
cedures for the synthesis of all new compounds, along with
characterization data and spectra and X-ray structural
data for compounds 1 and 25. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) (a) Sherden, N. H.; Behenna, D. C.; Virgil, S. C.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2009, 48, 6840. (b) Behenna, D. C.; Stoltz, B. M.
J. Am. Chem. Soc. 2004, 126, 15044. (c) Mohr, J. T.; Behenna, D. C.;
Harned, A. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2005, 44, 6924.
(d) Mukherjee, H.; McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Org.
Lett. 2011, 13, 825.
Cyclization of diketoester-dioxinone 20 under basic con-
ditions followed by deprotection of the silyl ether 24 furnished
5750
Org. Lett., Vol. 13, No. 21, 2011