Total synthesis of aigialomycin D using a one-pot ketene generation-trappingaromatization sequence

Article abstract of DOI:10.1021/ol901979x

The total synthesis of aigialomycin D, without the need for phenol protection, was carried out using the C-acylation of a keto-dioxinone dlanlon, a cascade sequence consisting of ketene generation, alcohol trapping and aromatization, and ring-closing meta

Full text of DOI:10.1021/ol901979x

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4910-4913
Total Synthesis of Aigialomycin D using
a One-Pot Ketene Generation-Trapping-
Aromatization Sequence
Frederick Calo,† Jeffery Richardson,‡ and Anthony G. M. Barrett*,†
Department of Chemistry, Imperial College, London SW7 2AZ, England, and Eli Lilly
and Company Limited, Erl Wood Manor, Windlesham, Surrey GU20 6PH, England
agm.barrett@imperial.ac.uk
Received August 26, 2009
ABSTRACT
The total synthesis of aigialomycin D, without the need for phenol protection, was carried out using the C-acylation of a keto-dioxinone
dianion, a cascade sequence consisting of ketene generation, alcohol trapping and aromatization, and ring-closing metathesis.
Aigialomycin D (1), a 14-membered resorcylic macrolide
(Figure 1), isolated in 2002 from the marine mangrove fungus
Aigialus parvus BCC5331, shows potent antitumor (IC50
)
3.0 µg/mL against KB cells) as well as antimalarial activity
(IC50 ) 6.6 µg/mL against Plasmodium falciparum).1
Recently, cyclin-dependent kinase (CDK) and glycogen
synthase kinase 3 (GSK-3) have been identified as its
antitumor targets of action.2 As a result of its interesting
biological properties, several total syntheses of aigialomycin
D (1) have been reported in which the 14-membered ring
was constructed using a Yamaguchi lactonization,3 nickel-
catalyzed ynal-macrocyclization,4 or by ring-closing metath-
esis (RCM).2,5
Figure 1. Structure of aigialomycin D (1).
competitive reaction giving rise to the cyclohexene 4 in
addition to the desired macrocyclization (Figure 2). As a
consequence, the styrene unit was masked at the C2 position
as a phenyl selenide,2 a silyl ether,5a a ketone5b or as a
sulfone5c prior to macrocyclization via RCM and late stage
introduction of ∆1 via elimination.
In all of these total syntheses, the resorcylate phenol groups
were protected. During these studies,2,6 it was shown that
RCM of trienes 2 or 3 were not practical because of a
† Imperial College.
‡ Eli Lilly and Company Limited.
(1) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.;
Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
(2) (a) Barluenga, S.; Dakas, P.-Y.; Meijer, L.; Winssinger, N. Angew.
Chem., Int. Ed. 2006, 45, 3951. (b) Winssinger, N.; Barluenga, S. Chem.
In this paper, we report an alternative strategy to achieve
the total synthesis of aigialomycin D (1), which allows for
macrocyclization via RCM on a triene precursor, does not
require phenol protection, and is sufficiently concise for
analogue synthesis.
Commun. 2007, 22, and references therein
(3) Lu, J.; Ma, J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron:
Asymmetry 2006, 17, 1066
.
.
10.1021/ol901979x CCC: $40.75
Published on Web 10/02/2009
 2009 American Chemical Society

the dioxinones 8 or 9, which in turn should be available from
the C-acylation of dioxinone 10 with Weinreb amides 11 or
12.
Dess-Martin oxidation10 of the known alcohol 13, which
was prepared in three steps from commercially available 2,3-
O-isopropylidene-D-erythronolactone,11 gave the correspond-
ing aldehyde (Scheme 2).
Scheme 2. Synthesis of Weinreb Amides 11 and 12
Figure 2. Formation of byproduct 4 by RCM.
We recently reported the total synthesis of the antifungal
natural products 15G256ι and 15G256ꢀ using diketo-acyl-
ketene generation from a diketo-dioxinone,7 trapping with
an alcohol and aromatization.8 We considered that this mild
procedure should be amenable for the total synthesis of
macrocyclic resorcylates including aigialomycin D (1). Our
retrosynthetic analysis is shown in Scheme 1. Aigialomycin
Scheme 1. Retrosynthetic Analysis
Wittig olefination using either methylenetriphenylphos-
phorane or ethylenetriphenylphosphorane afforded the known
terminal alkene 145b in 71% yield and alkene 1512 as the
Z-isomer in 69% yield over the two steps.
Reduction of the ethyl esters 14 and 15 using DIBAl-H at
-78 °C13 gave the aldehydes, which were immediately
allowed to react with commercially available ylide14 (16) in
dichloromethane at reflux to afford the trans-R,ꢀ-unsaturated
Weinreb amides 11 (78%) and 12 (85%) alongside with small
quantities of the cis-isomers 17 (3%) and 18 (3%).
Keto-dioxinone 10 was synthesized in 55% yield by
acylation of the enolate from dioxinone 19 with acetyl
chloride in THF at -78 °C.
With both Weinreb amides 11 and 12 and the keto-
dioxinone 10 in hand, the crucial acylation step was
investigated (Scheme 3). Solladie´ et al. have previously
Scheme 3. Dianion C-Acylation
D (1) should be available by RCM of the trienes 5 or 6
without phenol protection. We considered that by suitable
choice of the alkene substituent R it should be possible to
direct the RCM away from the formation of cyclohexene 4
to favor macrocyclization.9
Trienes 5 and 6 should be available from a one-pot diketo-
acyl-ketene generation-trapping-aromatization sequence
using commercially available (S)-(+)-4-penten-2-ol (7) and
(4) Chrovian, C. C.; Knapp-Reed, B.; Montgomery, J. Org. Lett. 2008,
10, 811.
(5) (a) Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413. (b) Vu,
N. Q.; Chai, C. L. L.; Lim, K. P.; Chia, S. C.; Chen, A. Tetrahedron 2007,
63, 7053. (c) Baird, L. J.; Timmer, M. S. M.; Teesdale-Spittle, P. H.; Harvey,
J. E. J. Org. Chem. 2009, 74, 2271.
reported the use of trianion C-acylation with the Weinreb
amide of cinnamic acid in their biomimetic synthesis of
Org. Lett., Vol. 11, No. 21, 2009
4911

leridiol.15 Dianion 20, derived from 10, was generated using
lithium di-isopropylamide at -78 °C and allowed to react
with Weinreb amides 11 or 12 at -40 °C to provide the
required diketo-dioxinone 8 (18%) or 9 (20%).16
Scheme 5. Monoanion C-Acylation
Upon heating in toluene, the dioxinones 8 and 9 underwent
a retro-Diels-Alder reaction to generate the ketenes 21 and
22 (Scheme 4), which were trapped with alcohol 7 and
Scheme 4. Synthesis of Resorcylates 5 and 6 via a Ketene
Generation-Trapping-Aromatization Sequence
tion using lithium hydroxide gave the carboxylic acid 26
(92%), which was converted to the acyl chloride 27 with
oxalyl chloride.
Claisen condensation between the enolate derived from
28,7f generated with MgCl2 and pyridine, and crude acyl
chloride 27 gave dioxinone 29 as the only addition product
in 81% yield. Subsequent palladium-catalyzed deallylation
and decarboxylation using tetrakis(triphenylphosphine)-pal-
ladium(0) and morpholine gave the desired diketo-dioxinone
9, which was immediately converted to resorcylate 6 using
the previous reaction conditions (44%). Using this mild and
selective C-acylation approach, the overall yield to synthesize
resorcylate 6 was improved to 35% starting from carboxylic
acid 26.
directly aromatized by reaction with cesium acetate followed
by acetic acid to give, respectively, the resorcylates 5 and 6
in 72% and 74% overall yields. Directly submitting the crude
diketo-dioxinones 8 or 9 to the ketene generation-
trapping-aromatization sequence doubled the overall yields
for 5 (27%) and for 6 (25%) starting from keto-dioxinone
10.17
The key RCM was next investigated (Table 1). Using the
Grubbs-Hoveyda second generation catalyst (15 mol %) at
Table 1. RCM on Trienes 5 and 6
To increase the reactivity and the selectivity toward the
C-acylation only, we decided to examine the mild Claisen
condensation strategy previously used in our group7f
(Scheme 5).
DIBAl-H reduction of ester 15 followed by Wittig olefi-
nation using Ph3PdCHCO2Me gave alkene 25 exclusively
as the E-isomer in 85% yield over the two steps. Saponifica-
concn
ratioc 30:4
(6) Bajwa, N.; Jennings, M. P. Tetrahedron Lett. 2008, 49, 390.
(7) For the first use of dioxinones as precursors for acyl-ketenes, see:
(a) Feldman, P. L.; Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1984, 49,
5105. For the use of dioxinones and acyl-ketenes in complex natural product
total synthesis, see: (b) Boeckman, R. K., Jr.; Weidner, C. H.; Perni, R. B.;
Napier, J. J. J. Am. Chem. Soc. 1989, 111, 8036. (c) Paquette, L. A.;
Macdonald, D.; Anderson, L. G.; Wright, J. J. Am. Chem. Soc. 1989, 111,
8037. (d) Paquette, L. A.; Macdonald, D.; Anderson, L. G. J. Am. Chem.
Soc. 1990, 112, 9292. (e) 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. For the use of diketo-dioxinones in total syntheses, see:
(f) Navarro, I.; Basset, J.-F.; Hebbe, S.; Major, S. M.; Werner, T.; Howsham,
C.; Bra¨ckow, J.; Barrett, A. G. M. J. Am. Chem. Soc. 2008, 130, 10293.
entry triene (10-4 mol L-1
)
methoda (°C) solventb (yield, %)d
1
2
3
4
5
5
6
6
15
6
6
MW (85)
MW (85)
MW (85)
CH2Cl2 1:0.40(50)
CH2Cl2 1:0.21
CH2Cl2 1:0.06(81)
6
thermal (100) PhMe
1:0.06(83)
a Microwave irradiation (MW) or conventional heating (thermal).
b Solvents were degassed with nitrogen. c Ratio of 30:4 determined from
the 1H NMR spectrum of the crude reaction mixture. d Yield of isolated
product 30.
4912
Org. Lett., Vol. 11, No. 21, 2009

a concentration of 15 × 10-4 M and with microwave
irradiation at 80 °C in dichloromethane (entry 1), triene 5
was converted into the trans-macrocycle 30 in 50% isolated
yield. In this case, cyclohexene 4 was also formed (20%).18
By decreasing the concentration to 6 × 10-4 M (entry 2),
the ratio of macrocycle 30 to cyclohexene 4 decreased to
1:0.2.
When subjected to the same conditions, triene 6 gave
the macrocycle 30 (81%) with very little coproduction of
cyclohexene 4 (entry 3). Interestingly, the RCM could also
be performed with conventional heating (entry 4), making
the reaction amendable to larger scale application.
Finally, deprotection of the acetonide moiety was achieved
using 1 M hydrochloric acid in methanol (1:1) giving
aigialomycin D (1) (Scheme 6) (95%), the data of which
were identical to those previously reported.1-5
generation-trapping-aromatization cascade and RCM mac-
rocyclization as the key steps. The synthesis is also note-
worthy in that phenol protection was unnecessary.
Acknowledgment. We thank GlaxoSmithKline for the
generous endowment (to A.G.M.B.), Eli Lilly and Company
and the Engineering and Physical Sciences Research Council
(EPSRC) for grant support (to F. Calo), Peter R. Haycock
and Richard N. Sheppard both at Imperial College London
for high-resolution NMR spectroscopy, and Dr. Isaka Masa-
hiko from the national center for Genetic Engineering and
Biotechnology (BIOTEC) in Thailand for providing copies
1
of the H and 13C NMR spectra of natural aigialomycin D.
Supporting Information Available: Procedures for the
synthesis of new compounds, along with characterization data
and spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL901979X
Scheme 6. Synthesis of Aigialomycin D (1)
(11) Gypser, A.; Peterek, M.; Scharf, H.-F. J. Chem. Soc., Perkin Trans.
1 1997, 1, 1013.
(12) For synthesis of the enantiomer of 15: Batty, D.; Crich, D.
Tetrahedron Lett. 1992, 33, 875.
(13) Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 3, 619.
(14) (a) Zanatta, S. D.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004,
6, 1041. (b) Hanessian, S.; Fu, J.-M.; Chiara, J.-L.; Di Fabio, R. Tetrahedron
Lett. 1993, 34, 4157.
In summary, we report an 11-step total synthesis of
aigialomycin D (1) in 15% overall yield from simple chiral
pool precursors using keto-dioxinone C-acylation, a ketene
(15) Gehrold, N.; Maigna, J.; Solladie´, G. Eur. J. Org. Chem. 1999, 9,
2309.
(16) The low yields resulted from the formation of complex mixtures
containing adducts tentatively assigned as 1,4-addition products and also
from difficulties in the purification of the diketo-dioxinones 8 and 9 on
silica gel chromatography.
(17) By using the crude product, the yields of the C-acylation with the
Weinreb amides were comparable to the yield reported by Solladie´ et al.
(18) 1H NMR of cyclohexene 4 is known: Deruyttere, X.; Dumortier,
L.; Van der Eycken, J.; Vandewalle, M. Synlett 1992, 1, 51.
(8) (a) Harris, C. M.; Harris, T. M. Tetrahedron 1977, 33, 2159. (b)
Hubbard, J. S.; Harris, T. M. J. Org. Chem. 1981, 46, 2566.
(9) (a) Lee, C. W.; Grubbs, R. H. Org. Lett. 2000, 2, 2145. (b) Jeffrey,
C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.; Hoye, T. R. J. Am. Chem.
Soc. 2004, 126, 10210. (c) Gradillas, A.; Pe´rez-Castells, J. Angew. Chem.,
Int. Ed. 2006, 45, 6086.
(10) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
Org. Lett., Vol. 11, No. 21, 2009
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