A chemoenzymatic and enantioselective total synthesis of the resorcylic acid lactone L-783,290, the trans-isomer of L-783,277

Article abstract of DOI:10.1016/j.tetlet.2009.12.067

The structure, 5, assigned to the resorcylic acid lactone L-783,290 has been prepared for the first time and in a modular fashion using a Heck reaction to link the readily available fragments 8 and 14. Chemoenzymatic methods were used to prepare the latte

Full text of DOI:10.1016/j.tetlet.2009.12.067

Tetrahedron Letters 51 (2010) 1044–1047
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Tetrahedron Letters
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A chemoenzymatic and enantioselective total synthesis of the resorcylic
acid lactone L-783,290, the trans-isomer of L-783,277
*
Andrew Lin, Anthony C. Willis, Martin G. Banwell
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The structure, 5, assigned to the resorcylic acid lactone L-783,290 has been prepared for the first time and
in a modular fashion using a Heck reaction to link the readily available fragments 8 and 14. Chemoenzy-
matic methods were used to prepare the latter fragment, in enantiopure form, from chlorobenzene.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 5 November 2009
Accepted 11 December 2009
Available online 21 December 2009
Keywords:
Chemoenzymatic
Heck reaction
Resorcylic acid lactones
Ring-closing metathesis
Synthesis
The mycotoxins known as resorcylic acid lactones (RALs) consti-
tute a significant group of 14-membered and benzannulated mac-
rolides that have been isolated from a wide range of microfungi.1
Representative examples of these types of natural products include
radicicol (1, a HSP-90 inhibitor),2 zearalenone (2, an oestrogen ago-
nist),3 hypothemycin (3, a MAP kinase inhibitor)4 and L-783,277 (4,
a MEK inhibitor).5 The remarkable range of potent biological prop-
erties displayed by such compounds has attracted a great deal of
attention.1 Indeed, a number of RALs are considered important
leads for the development of new therapeutic agents for the treat-
ment of a range of human disease states, particularly cancer.1 This
situation has resulted in extensive efforts to develop economical
and flexible routes to the RALs1,6 and various analogues.7
Herein we describe the first synthesis of the structure, 5,
assigned to L-783,290,5b the trans-isomer and co-metabolite of
the RAL L-783,277 (4).5,8 Both compounds were isolated from a
Phoma spp. (ATCC 74403) by bioassay-guided fractionation using
a kinase screen.5 L-783,277 is a potent and irreversible inhibitor
of MEK, a threonine/tyrosine-specific MAP kinase (IC50 of 4 nM)
and a slightly weaker inhibitor of Lck kinase (IC50 750 nM).
L-783,290 showed an IC50 of 300 nM when tested as an inhibitor
of MEK.
12'
esterification
OH
O
1
3
10'
O
3'
RCM
OH
O
OH
O
1'
7'
MeO
Heck
5
O
5'
O
O
O
HO
HO
coupling
OH
HO
O
O
Cl
5
O
1
2
Our synthesis is a modular one that combines three fragments
corresponding to C1–C6 + C120, C10–C60 and C80–O110 of target 5.
The key bond-forming events are shown in structure 5 and involve,
in order of execution, Heck coupling, esterification and ring-closing
metathesis (RCM) processes. In contrast to the other processes, the
Heck reaction is rarely applied in the synthesis of RALs1a,9 despite
the potential it offers for introducing relevant functionality found
in the C10–C30 region of many of the more biologically active mem-
bers of this class of natural product.
OH
O
OH
O
O
O
MeO
O
MeO
O
HO
HO
OH
OH
3
4
The synthesis of the aromatic fragment corresponding to
* Corresponding author. Tel.: +61 2 6125 8202; fax: +61 2 6125 8114.
E-mail address: mgb@rsc.anu.edu.au (M.G. Banwell).
C1–C6 + C120 of target 5 was straightforward (Scheme 1). Thus,
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.067

A. Lin et al. / Tetrahedron Letters 51 (2010) 1044–1047
1045
hydrogenated in the presence of rhodium on alumina and the
resulting chlorocyclohexene12,13 readily converted, under con-
ventional conditions involving the use of 2,2-dimethoxypropane
(2,2-DMP) and p-TsOH in dichloromethane, into the acetonide
1013 (63%). Subjection of a methanolic solution of compound
10 to ozonolysis at ꢀ78 °C followed by treatment of the interme-
diate ozonide with dimethyl sulfide and in situ reduction of the
ensuing aldehyde with sodium borohydride gave the hydroxy es-
ter 11 in 76% yield. This was readily converted, under conditions
defined by Williams et al.,14 into the Weinreb amide 12 (90%)
which was itself converted into the corresponding o-nitrophenyl-
selenide 13 (89%) using conditions reported by Grieco et al.15 Fi-
nally, treatment of compound 13 with m-chloroperbenzoic acid
(m-CPBA) in CH2Cl2 and exposure of the resulting selenoxides
to diethylamine and oxygen then gave the olefin 14 (93%) re-
quired for the subsequent Heck reaction. The structure of this
pivotal building block was confirmed by a single-crystal X-ray
analysis.16
Extensive experimentation was required to achieve an opera-
tionally useful Heck coupling of aryl iodide 8 and terminal alkene
14 (Scheme 3). Under the best conditions identified thus far,17
heating a DMF solution of a 1:1.5 molar mixture of the substrates
in the presence of Pd(OAc)2, potassium carbonate and tetra-n-
butylammonium bromide (TBAB) at 80 °C for 40 h provided a ca.
8:1 mixture of coupling product 15 and its Z-isomer in 56% com-
bined yield at 80–90% conversion. Pinnick-type oxidation18 of the
chromatographically purified aldehyde 15 gave acid 16 in 75%
yield and the latter compound was hydrogenated in the presence
of 10% palladium on carbon to give the corresponding saturated
system 17 (97%). Subjection of acid 17 to Mitsunobu esterifica-
tion19 with the commercially available and enantiomerically pure
unsaturated alcohol 18 gave the ester/amide 19 (90%) that was
treated with vinyl magnesium bromide and so affording the diene
20 required for the pivotal RCM reaction. When a 1.5 mM solution
of compound 20 in CH2Cl2 was treated with Grubbs’ second-gener-
ation catalyst20 the smooth production of macrolide 21 was ob-
served and this was obtained in 48% overall yield from precursor
19. In the final step of the reaction sequence, compound 21 was
treated with BCl3 in CH2Cl2 at ꢀ78 °C6h and then subjected to aque-
ous work-up. This sequence resulted in simultaneous cleavage of
the C-2 O-methyl ether and hydrolysis of the acetonide unit thus
affording the target macrolide 1 in 60% yield and as a white, crys-
talline solid.
OMe
OMe
(i) NaNO2, H2SO4
–15 ºC, 0.5 h
(ii) KI, H2O
—15 ºC, 3 h
MeO
NH2
MeO
I
6
7
OMe O
DMF, POCl3
100 ºC, 5 h
H
MeO
I
8
Scheme 1.
subjection of the commercially available dimethoxyaniline 6 to a
Sandmeyer reaction using potassium iodide as the nucleophilic
source gave aryl iodide 7 in 71% yield. Reaction of the latter com-
pound with DMF/POCl3 under Vilsmeier–Haack conditions then
afforded, as a crystalline solid, the required and previously re-
ported10 benzaldehyde 8 (63%).
A chemoenzymatic pathway was employed in the enantiose-
lective assembly of the C10–C60 fragment. As shown in Scheme
2, the reaction sequence starts with the enantiomerically pure
and commercially available cis-1,2-dihydrocatechol
9 derived
from the whole-cell biotransformation of chlorobenzene.11 The
non-chlorinated double bond in this diene can be selectively
(i) H2, Rh on Al2O3, MeOH,
OH
OH
18 ºC, 25 min
O
O
(ii) 2,2-DMP, p-TsOH, DCM
0 ºC, 0.5 h
Cl
Cl
9
10
(i) O3, pyr., MeOH
—78 ºC, 12 min;
(ii) DMS, 0 ºC, 2 h
(iii) NaBH4, 0 ºC, 1 h
OMe
O
N
OMe
O
HO
HO
O
O
O19
O
O
C20
O26
i-PrMgCl, (MeO)MeNH•HCl
THF
—15 ºC, 0.5 h
12
11
C3
C1
C4
C17
C14
C18
C13
O2
OMe
O
C16
C15
o-NO2C6H4SeCN
Bu3P, THF
N
C5
o-NO2C6H4Se
18 ºC, 1 h
O
C25
O
C6
C12
C11
O24
C7
C8
13
O21
C10
OMe
N
C9
(i) m-CPBA, DCM
—78 ºC, 0.25 h
O
O
O22
O
O23
(ii) O2, Et2NH
18 ºC, 3 h
14
Figure 1. Structure of compound 5 with labelling of selected atoms. Anisotropic
displacement ellipsoids display 30% probability levels. Hydrogen atoms are drawn
as circles with small radii.
Scheme 2.

1046
A. Lin et al. / Tetrahedron Letters 51 (2010) 1044–1047
OMe O
OMe
Pd(OAc)2, TBAB
K2CO3, DMF, water
80 ºC, 19 h
N
OMe
O
OMe O
X
N
O
H
O
+
MeO
O
O
O
MeO
I
8
14
15 X=H
16 X=OH
Pinnick
oxidation
10% Pd on C
H2 (50 psi)
18 ºC, 48 h
OMe O
OMe O
DIAD, Ph3P, PhMe
0 ºC, 1 h
OMe
O
OMe
O
N
OH
N
+
MeO
MeO
O
HO
O
O
O
O
19
18
17
H2C=CHMgBr, THF
—30 ºC, 6 min
Grubbs' II (5 mole %),
OMe O
O
OH
O
OMe O
DCM
BCl3, DCM
—78 ºC, 1 h
37 ºC, 3 h
O
O
MeO
MeO
MeO
O
O
O
O
O
O
HO
O
OH
20
21
5
Scheme 3.
Altmann, K.-H. C. R. Chim. 2008, 11, 1318; (d) Bräse, S.; Encinas, A.; Keck, J.;
Nising, C. F. Chem. Rev. 2009, 109, 3903.
All the spectral data derived from compound 5 were entirely
consistent with the assigned structure,21 but the final confirma-
tion of this was secured through a single-crystal X-ray analysis
of its chloroform solvate.22 The derived ORTEP is shown in
Figure 1. No spectral data derived from the natural product L-
783,290 have been published and, thus far, our various efforts
to secure these have been unsuccessful. As such, we have been
unable to make relevant comparisons between the two sets of
data.
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The results of the biological evaluation of compound 5 and the
adaptation of the protocols described here to the synthesis of other
RAL’s will be described in due course.
Acknowledgements
6. For representative examples of recent synthetic studies in the area, see: (a)
Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J. Am. Chem.
Soc. 2001, 123, 10903; (b) Tichkowsky, I.; Lett, R. Tetrahedron Lett. 2002, 43,
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Moulin, E.; Lopez, P.; Winssinger, N. Chem. Eur. J. 2005, 11, 4935; (e) Barluenga,
S.; Dakas, P.-Y.; Ferandin, Y.; Meijer, L.; Winssinger, N. Angew. Chem., Int. Ed.
2006, 45, 3951; (f) Lu, J.; Ma, J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron:
Asymmetry 2006, 17, 1066; (g) Vu, N. Q.; Chai, C. L. L.; Lim, K. P.; Chia, S. C.;
Chen, A. Tetrahedron 2007, 63, 7053; (h) Dakas, P.-Y.; Barluenga, S.; Totzke, F.;
Zirrgiebel, U.; Winssinger, N. Angew. Chem., Int. Ed. 2007, 46, 6899; (i) Hofmann,
T.; Altmann, K.-H. Synlett 2008, 1500; (j) Chrovian, C. C.; Knapp-Reed, B.;
Montgomery, J. Org. Lett. 2008, 10, 811; (k) Baird, L. J.; Timmer, M. S. M.;
Teesdale-Spittle, P. H.; Harvey, J. E. J. Org. Chem. 2009, 74, 2271; (l) Calo, F.;
Richardson, J.; Barrett, A. G. M. Org. Lett. 2009, 11, 4910; (m) Dakas, P.-Y.;
Jogireddy, R.; Valot, G.; Barluenga, S.; Winssinger, N. Chem. Eur. J. 2009, 15,
11490.
We thank the Institute of Advanced Studies and the Australian
Research Council for generous financial support.
Supplementary data
Supplementary data (experimental procedures and product
characterization for compounds 5–8, 11–17, 19 and 20, as well as
the X-ray crystal data for compounds 5 and 14, are provided) asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.12.067.
7. For recent examples of analogue studies, see: (a) Yamamoto, K.; Garbaccio, R.
M.; Stachel, S. J.; Solit, D. B.; Chiosis, G.; Rosen, N.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2003, 42, 1280; (b) Moulin, E.; Barluenga, S.; Totzke, F.;
Winssinger, N. Chem. Eur. J. 2006, 12, 8819; (c) Proisy, N.; Sharp, S. Y.; Boxall, K.;
Connelly, S.; Roe, S. M.; Prodromou, C.; Slawin, A. M. Z.; Pearl, L. H.; Workman,
P.; Moody, C. J. Chem. Biol. 2006, 13, 1203; (d) Hearn, B. R.; Sundermann, K.;
References and notes
1. For useful reviews dealing with this class of compound, see: (a) Winssinger, N.;
Barluenga, S. Chem. Commun. 2007, 22; (b) Barluenga, S.; Dakas, P.-Y.; Boulifa,
M.; Moulin, E.; Winssinger, N. C. R. Chim. 2008, 11, 1306; (c) Hofmann, T.;

A. Lin et al. / Tetrahedron Letters 51 (2010) 1044–1047
1047
Cannoy, J.; Santi, D. V. ChemMedChem 2007, 2, 1598; (e) Stevenson, D. E.;
Hansen, R. P.; Loader, J. I.; Jensen, D. J.; Cooney, J. M.; Wilkins, A. L.; Miles, C. O. J.
Agric. Food Chem. 2008, 56, 4032; (f) Rich, J. O.; Budde, C. L.; McConeghey, L. D.;
Cotterill, I. C.; Mozhaev, V. V.; Singh, S. B.; Goetz, M. A.; Zhao, A.; Michels, P. C.;
Khmelnitsky, Y. L. Bioorg. Med. Chem. Lett. 2009, 19, 3059; (g) Day, J. E. H.; Blake,
A. J.; Moody, C. J. Synlett 2009, 1567; (h) Jogireddy, R.; Dakas, P.-Y.; Valot, G.;
Barluenga, S.; Winssinger, N. Chem. Eur. J. 2009, 15, 11498.
14. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.-H.;
Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
15. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485.
16. X-ray crystal data and ORTEPs for compound 14 (CCDC no. 751603) can be
found in the Supplementary data.
17. The conditions employed were essentially those of Jeffery (Jeffery, T.
Tetrahedron 1996, 52, 10113).
18. Conditions defined by Lang and Steglich were employed for this
transformation (Lang, M.; Steglich, W. Synthesis 2005, 1019).
19. Dembinski, R. Eur. J. Org. Chem. 2004, 2763. and references cited therein.
20. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
8. L-783,277 has recently been the subject of two successful total syntheses.6i,m
9. Fürstner has employed the Heck reaction in his total synthesis of (ꢀ)
zearalenone: Fürstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org.
Chem. 2000, 65, 7990.
10. Pailer, M.; Berner, H.; Makleit, S. Monatsh. Chem. 1967, 98, 1603.
11. Compound 9 can be obtained from Questor, Queen’s University of Belfast,
Northern Ireland. Questor Centre Contact Page: http://questor.qub.ac.uk/
newsite/contact.htm (accessed Oct 16, 2009). For reviews on methods for
generating cis-1,2-dihydrocatechols by microbial dihydroxylation of the
corresponding aromatics, as well as the synthetic applications of these
metabolites, see: (a) Hudlicky, T.; Gonzalez, D.; Gibson, D. T. Aldrichim. Acta
1999, 32, 35; (b) Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.; Jolliffe, K. A.;
McLeod, M. D.; McRae, K. J.; Stewart, S. G.; Vögtle, M. Pure Appl. Chem. 2003, 75,
223; (c) Johnson, R. A. Org. React. 2004, 63, 117; (d) Hudlicky, T.; Reed, J. W.
Synlett 2009, 685.
21. Selected spectral data derived from compound 5: mp 127.5–136.5 °C; [
a]D +9.7
(c 0.23, CHCl3); 1H NMR (800 MHz, CD2Cl2) d 11.83 (s, 1H), 7.00 (m, 1H), 6.37
(m, 3H), 5.57 (m, 1H), 4.68 (s, 1H), 3.96 (s, 1H), 3.80 (s, 3H), 3.06 (t, J = 12.8 Hz,
1H), 2.84 (br s, 1H), 2.54 (m, 2H), 1.71 (br s, 2H), 1.62 (s, 1H), 1.45 (d, J = 6.1 Hz,
3H), 1.30 (m, 1H) (signals due to two protons not observed); 13C NMR
(200 MHz, CD2Cl2) d 199.3, 171.4, 166.3, 164.7, 147.7, 143.8, 131.5, 109.5,
104.9, 99.3, 77.4, 73.3, 71.3, 55.7, 38.0, 36.2, 32.8, 26.9, 19.2; IR mmax 3347,
2938, 1695, 1642, 1615, 1353, 1316, 1250, 1202, 1161, 1131, 1111, 1089, 1045,
995 cmꢀ1; MS m/z (EI, 70 eV) 364 (M+Å, 17%), 221 (80), 202 (43), 193 (58), 192
(100), 177 (48), 164 (75); HRMS Found M+Å, 364.1532. C19H24O7 requires M+Å
364.1522.
,
12. Banwell, M. G.; Edwards, A. J.; Loong, D. T. J. ARKIVOC 2004, x, 53.
13. Fonseca, G.; Seoane, G. A. Tetrahedron: Asymmetry 2005, 16, 1393.
22. X-ray crystal data for compound 5 (CCDC no. 751602) can be found in the
Supplementary data.