Total synthesis of TAK-kinase inhibitor LL-Z1640-2 via consecutive macrocyclization and transannular aromatization

Article abstract of DOI:10.1021/ol102468k

The biomimetic total synthesis of LL-Z1640-2 (3) is reported without the use of phenol protection. The aromatic unit was constructed via the transannular aromatization of macrocyclic triketo-ester 2, which in turn was synthesized by macrolactonization usi

Full text of DOI:10.1021/ol102468k

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5573-5575
Total Synthesis of TAK-Kinase Inhibitor
LL-Z1640-2 via Consecutive
Macrocyclization and Transannular
Aromatization†
Hideki Miyatake-Ondozabal and Anthony G. M. Barrett*
Department of Chemistry, Imperial College, London SW7 2AZ, England
agm.barrett@imperial.ac.uk
Received October 12, 2010
ABSTRACT
The biomimetic total synthesis of LL-Z1640-2 (3) is reported without the use of phenol protection. The aromatic unit was constructed via the
transannular aromatization of macrocyclic triketo-ester 2, which in turn was synthesized by macrolactonization using an intramolecular trapping
of a triketo-ketene derived from dioxinone 1.
The macrocyclic nonaketide, LL-Z1640-2 (3) (Figure 1),
was first isolated as an antiprotozoan from an unidentified
fungi by Ellestad et al.1 in 1978 and belongs to a family
of resorcylic acid lactones (RALs). Due to its unique
chemical structure, particularly the cis-enone moiety, it
is known as a potent irreversible, yet selective, inhibitor
of transforming growth factor (TGF)-ꢀ-activated kinase
1 (TAK1, IC50 ) 8.1 nM).2,3 These types of cis-enone RALs
have also been shown to inhibit mammalian cell proliferation
and tumor growth in animals.4 As a result of its useful
biological activities and chemical structure, several total
syntheses have been reported since its isolation.2,5
Figure 1. Structure of LL-Z1640-2 (3) and related resorcylate
lactones.
† This paper is dedicated to Professor Siegfried Blechert on the occasion
of his 65th birthday in March 2011.
(1) Ellestad, F.; Lovell, M. F.; Perkinson, A. N.; Hargreaves, T. R.;
In all the previous syntheses, the 14-membered macrocycle
was constructed by an intramolecular Suzuki coupling
reaction,5b,d Mukaiyama cyclization,5a,c,d or Mitsunobu
macrolactonization,2,5c-e where the phenol groups were
protected throughout the synthesis. An alternative strategy
was also described by Henry et al., which relied on ring-
closing metathesis (RCM) to generate the 14-membered
ring.6
McGahren, J. W. J. Org. Chem. 1978, 43, 2339.
(2) Schirmer, A.; Kennedy, J.; Murli, S.; Reid, R.; Santi, V. D. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 4234
(3) Dakas, P. Y.; Barluenga, S.; Totzke, F.; Zirrgiebel, U.; Winssinger,
N. Angew. Chem., Int. Ed. 2007, 46, 6899
.
.
(4) (a) Camacho, R.; Staruch, M. J.; DaSilva, C.; Koprak, S.; Sewell,
T.; Salituro, G.; Dumont, F. J. Immunopharmacology 1999, 44, 255. (b)
Tanaka, H.; Nishida, K.; Sugita, K.; Yoshida, T. Jpn. J. Cancer Res. 1999,
90, 1139. (c) Williams, D. H.; Wilkinson, S. E.; Purton, T.; Lamont, A.;
Flotow, H.; Murray, E. J. Biochemistry 1998, 37, 9579.
10.1021/ol102468k  2010 American Chemical Society
Published on Web 11/10/2010

Recently, we reported the novel biomimetic syntheses of
bioactive resorcylate natural products 9 utilizing an inter-
molecular ketene trapping and late-stage aromatization7
approach starting from diketo-dioxinone 7 (Scheme 1).8,9
Scheme 2. Retrosynthetic Analysis of LL-Z1640-2 (3)
Scheme 1
.
Use of Diketo-dioxinones 7 as Precursors for the
Synthesis of Resorcylates 9
This methodology was recently extended to intramolecular
ketene trapping and transannular aromatization, replacing the
use of RCM for macrolactonization. The efficacy of this
novel strategy was first demonstrated through the application
for the synthesis of the resorcylic acid lactone, (S)-(-)-
zearalenone (4).10 This ketene trapping macrocyclization
process is an adaption of the excellent methodology intro-
duced by Boeckman and applied by others.11
Herein, we report a novel and efficient biomimetic
synthesis of LL-Z1640-2 (3), without phenol protection,
where macrolactonization and transannular aromatization are
carried out consecutively to build the resorcylic core. It is
noteworthy that this intramolecular ketene trapping-late-stage
aromatization approach should be sufficiently concise for
analogue synthesis such as mitogen-activated protein kinase
(MAPK) inhibitor hypothemycin (5) and MAPK kinase
(MEK) inhibitor LL-783,277 (6).
cylate unit could be constructed by late-stage transannular
aromatization of macrocyclic triketo-ester 2, which may be
prepared by macrolactonization via intramolecular trapping
of the ketene derived from diketo-dioxinone 1. This in turn
could be synthesized by acylation of Weinreb amide 11 with
the dianion derived from keto-dioxinone 12.
Our retrosynthetic analysis is illustrated in Scheme 2. LL-
Z1640-2 (3) should be available following methylation,
acetonide and EOM deprotection, and selective allylic
oxidation of resorcylate 10. We considered that the resor-
Weinreb amide 11 was synthesized in seven steps from
commercially available 2-deoxy-D-ribose (Schemes 3 and 4).
(5) (a) Tatsuta, K.; Takano, S.; Sato, T.; Nakano, S. Chem. Lett. 2001,
172. (b) Selle`s, P.; Lett, R. Tetrahedron Lett. 2002, 43, 4627. (c) Winssinger,
N.; Barluenga, S. Chem. Commun. 2007, 22. (d) Hofmann, T.; Altmann,
H.-K. C. R. Chim. 2008, 11, 1318. (e) Dakas, P. Y.; Jogireddy, R.; Valot,
G.; Barluenga, S.; Winssinger, N. Chem.sEur. J. 2009, 15, 11490.
(6) Henry, N.; Murray, M. N.; Robertson, N.; Marquez, R. Tetrahedron
Lett. 2007, 48, 6088.
Scheme 3. Synthesis of Dioxolane 17
(7) (a) Harris, C. M.; Harris, T. M. Tetrahedron 1977, 33, 2159. (b)
Hubbard, J. S.; Harris, T. M. J. Org. Chem. 1981, 46, 2566.
(8) (a) Navarro, I.; Basset, J.-F.; Hebbe, S.; Major, S. M.; Werner, T.;
Howsham, C.; Brackow, J.; Barrett, A. G. M. J. Am. Chem. Soc. 2008,
130, 10293. (b) Calo, F.; Richardson, J.; Barrett, A. G. M. Org. Lett. 2009,
11, 4910. (c) Basset, J.-F.; Leslie, C.; Hamprecht, D.; White, A. J. P.; Barett,
A. G. M. Tetrahedron Lett. 2010, 51, 783. (d) Navarro, I.; Po¨verlein, C.;
Schlingmann, G.; Barrett, A. G. M. J. Org. Chem. 2009, 74, 8139
(9) The diketo-dioxinones and triketo-compounds exist as keto-enol
mixture. For simplicity, keto-forms are drawn.
.
(10) Miyatake-Ondozabal, H.; Barrett, A. G. M. Tetrahedron 2010, 66,
6331.
(11) Boeckman, R. K. Jr.; Pruitt, J. R. J. Am. Chem. Soc. 1989, 111,
8286. Boeckman, R. K., Jr.; Barta, T. E.; Nelson, S. G. Tetrahedron Lett.
1991, 32, 4091. Boeckman, R. K., Jr.; Weidner, C. H.; Perni, R. B.; Napier,
J. J. J. Am. Chem. Soc. 1989, 111, 8036. Boeckman, R. K., Jr.; Shao, P.;
Wrobleski, S. T.; Boehmler, D. J.; Heintzelman, G. R.; Barbosa, A. J. J. Am.
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Lactol 1312 was subjected to Wittig olefination to give R,ꢀ-
unsaturated ester 14 (80%) with excellent E:Z selectivity.
Following Parikh-Doering oxidation, aldehyde 15 was
obtained, and subsequent treatment with the lithiated alkyne
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Org. Lett., Vol. 12, No. 23, 2010

Scheme 4
.
Synthesis of Weinreb Amide 11 and
Diketo-dioxinone 1
Scheme 5. Synthesis of LL-Z1640-2 (1)
1613 followed by ethoxymethylation of the resulting prop-
argylic alcohol gave alkyne 17 in 58% yield over three steps.
The corresponding Weinreb amide 18 was obtained via
nucleophilic substitution at -25 °C in 80% yield (Scheme
4). Lindlar reduction of alkyne 18 provided exclusively the
Z-alkene 11 (91%). Alkylation of Weinreb amide 11 with
the enolate dianion8b,d derived from keto-dioxinone 12,8b
followed by p-methoxybenzyl deprotection, provided the key
hydroxy-ketene precursor 1 in 48% yield over two steps.
Transmetalation of dilithium enolate using diethylzinc was
essential for minimizing the formation of the Michael
addition adduct and also to achieve complete consumption
of Weinreb amide 11.
oxidation using Dess-Martin periodinane5a,c gave LL-
Z1640-2 (3) in 66% yield over two steps. The synthetic LL-
Z1640-2 (3) displayed physical and spectroscopic data
identical to an authentic sample.15
In summary, we report a 15-step biomimetic total synthesis
of the TAK-kinase inhibitor LL-Z1640-2 (3) from com-
mercially available starting materials. The key steps involved
the use of intramolecular ketene trapping and transannular
aromatization in a one-pot procedure to build the resorcylic
core in high yields.
Thermolysis of diketo-dioxinone 1 resulted in generation
of ketene 1914 which was efficiently trapped intramolecularly
by the alcohol to provide the 18-membered macrocyclic
lactone 2 (Scheme 5).10 Subsequent transannular aromati-
zation, using cesium carbonate, and acidification gave the
desired resorcylate 10 in 55% yield. Regioselective methy-
lation was achieved utilizing methyl iodide in acetone to give
ether 20 (78%). Treatment with polymer-supported sulfonic
acid in methanol resulted in full deprotection,5d,e and allylic
Acknowledgment. We thank GlaxoSmithKline for the
generous endowment (to A.G.M.B.), the Engineering and
Physical Sciences Research Council (EPSRC) for grant
support (to H.M.O.), and P. R. Haycock and R. N. Sheppard
(Imperial College London) for high-resolution NMR spec-
troscopy.
Supporting Information Available: Experimental pro-
cedures for the synthesis of all new compounds, along with
characterization data and spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) Barbat, J.; Gelas, J.; Horton, D. Carbohydr. Res. 1983, 116, 312.
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Acharya, H. P. J. Org. Chem. 2007, 72, 1707. Paquette, L. A.; Hofferberth,
J. E. J. Org. Chem. 2003, 68, 2266.
OL102468K
(14) Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. J. Org. Chem. 1984,
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(15) Commercially available from Aldrich Chemical Co.
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