Highly convergent three component benzyne coupling: The total synthesis of ent-clavilactone B

Article abstract of DOI:10.1021/ja0662671

The first total synthesis of (+)-clavilactone B, a potent antifungal agent and novel tyrosine kinase inhibitor, is described. The absolute configuration of clavilactones has been unambiguously established by using Sharpless asymmetric epoxidation to gener

Full text of DOI:10.1021/ja0662671

Published on Web 10/11/2006
Highly Convergent Three Component Benzyne Coupling: The Total Synthesis
of ent-Clavilactone B
Igor Larrosa,† Marianne I. Da Silva,† Patricio M. Go´mez,† Peter Hannen,† Eunjung Ko,†
Steven R. Lenger,‡ Simon R. Linke,‡ Andrew J. P. White,† Donna Wilton,† and
Anthony G. M. Barrett*,†
Department of Chemistry, Imperial College London, London SW7 2AZ, England, and AstraZeneca,
Process Research and DeVelopment, AVlon Works, SeVern Road, Hallen, Bristol BS10 7ZE, England
Received August 29, 2006; E-mail: agmb@imperial.ac.uk
Clavilactones A, B, and C (1-3), first isolated by Arnone et al.
from a culture of the nontoxigenic fungus Clitocybe claVipes,1 show
antifungal and antibacterial activities.2 Clavilactones A, B, and D
(1, 2, and 4) are potent kinase inhibitors against Ret/ptc1 and
epidermal growth factor receptor (EGF-R) tyrosine kinases. As such
they represent a new structural class of tyrosine kinase inhibitors,3
which are key enzymes modulating the transduction pathway
regulation of essential cellular processes such as growth, differentia-
tion, and apoptosis4,5 (see Figure 1).
Figure 1. Clavilactone family.
Scheme 1. Retrosynthetic Analysis for Clavilactone B (2)
The constitution and relative configuration of the clavilactones
were determined by 1H and 13C NMR spectroscopy studies,
chemical reactions, and single-crystal X-ray analysis of the
dimethoxy derivative of 1.1 Their intriguing structures contain a
constrained ten-membered ring fused to a 2,3-epoxy-γ-lactone and
a benzoquinone or hydroquinone. A concise total synthesis of these
antibiotics would be of considerable interest to further define
structure-activity relationships. Herein, we describe the first total
synthesis of ent-clavilactone B ((+)-2) and the assignment of
absolute stereochemistry.
Our retrosynthetic strategy is outlined in Scheme 1. The trisub-
stituted alkene C11-C12 of clavilactone B (2) should be available
by means of a ring closing metathesis reaction (RCM) from diene
5. Reductive disconnection of the lactone in 5 would lead to diol
6. As part of our ongoing interest in aryne chemistry,6 we considered
that bonds C5-C6 and C13-C14 in 6 could be created in a single
operation using a three-component benzyne coupling strategy.7 This
key process would involve the reaction of benzyne 7 with the
methylallyl organometallic 8 and epoxy-aldehyde 9.
Scheme 2. Asymmetric Synthesis of Epoxy-Aldehyde 9a
Epoxy-aldehyde 9 was synthesized as depicted in Scheme 2. Silyl
protection of propargylic alcohol 10 followed by lithiation and
quenching with ethyl chloroformate gave propargylic ester 11. 1,4-
Cuprate addition to ester 11 yielded exclusively the (Z)-unsaturated
ester 12.8 DIBAl-H reduction of ester 12 followed by Sharpless
epoxidation of the resultant allylic alcohol 13 using L-(+)-diethyl
tartrate gave the (-)-epoxide 14 with excellent yield (89%, two
steps) and enantioselectivity (97% ee).9,10 Finally, Swern oxidation
gave the (+)-epoxy-aldehyde 9 in an overall yield of 77% and 97%
ee after six steps.
After examination of several benzyne precursors we selected
fluorobenzene 15 as the most effective for the three component
coupling reaction.11 Reaction with n-BuLi (1 equiv) gave the
o-fluoroaryllithium, which was allowed to fragment to benzyne in
the presence of methylallyl Grignard (16) at room temperature to
afford the aryl Grignard species 17. Finally, reaction with epoxy-
aldehyde 9 at -78 °C gave the two diastereomeric adducts 18a
(25%) and 18b (40%) (Scheme 3 ).12
a
Conditions: (a) t-BuPh2SiCl, imidazole, CH2Cl2, 96%; (b) n-BuLi;
EtOCOCl, THF, -78 °C, 99%; (c) Mg, 4-bromo-1-butene, THF; CuBr‚SMe2,
THF, -40 °C; 11, THF, -78 °C, 97%; (d) DIBAl-H, PhMe, -78 °C, 96%;
(e) Ti(Oi-Pr)4, L-(+)-DET, t-BuOOH, 4 Å MS, CH2Cl2, -20 °C, 93%, 97%
ee; (f) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 94%.
Unexpectedly, the stereochemical bias of epoxy-aldehyde 9 was
opposite to that reported for similar substrates.13,14 Although the
key three component coupling reaction proceeded with a modest
stereochemical bias favoring the wrong isomer, this was ultimately
irrelevant with the development of a method for the C6 epimer-
ization reaction at a later stage (vide supra).
Deprotection of the silyl ethers 18a and 18b using TBAF in THF
gave the corresponding anti-6 and syn-6-epi-6 diols, respectively,
which were selectively oxidized to yield lactones 5 and 19 (Scheme
4). Interestingly, TPAP oxidation proceeded in superior yield for
the syn lactone 19 (74% yield from the syn-diol 6-epi-6),15 whereas
† Imperial College London.
‡ AstraZeneca.
9
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J. AM. CHEM. SOC. 2006, 128, 14042-14043
10.1021/ja0662671 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Three-Component Benzyne Couplinga
In conclusion, we have developed the first asymmetric synthesis
of clavilactone B (2), a potent antifungal agent and determined its
absolute configuration. Our strategy employs a powerful and
convergent three-component benzyne coupling and an RCM reac-
tion to generate the whole carbon skeleton of the molecule. In
addition, a new mild and selective method for the epimerization of
delicate polyfunctional benzylic lactones has been developed. On
the basis of this approach, the synthesis and bioassay of several
derivatives of clavilactone are underway.
a
Conditions: (a) n-BuLi, THF, -78 °C; CH2dC(Me)CH2MgCl (16),
-78 to 25 °C; (b) 9, -78 to -35 °C, 65% (dr 2:1).
Acknowledgment. We thank GlaxoSmithKline for the generous
endowment (to A.G.M.B.), the Royal Society and the Wolfson
Foundation for a Royal Society Wolfson Research Merit Award
(to A.G.M.B.), the Wolfson Foundation for establishing the Wolfson
Center for Organic Chemistry in Medical Sciences at Imperial
College, the EPSRC, the Ministerio de Educacion y Ciencia (I.L.),
and the Deutscher Akademischer Austausch Dienst (DAAD) (P.H.)
for postdoctoral fellowships. We thank Prof. Gianluca Nasini for
authentic samples of natural 5 and 20.
Scheme 4. Synthesis of (+)-Clavilactone B (2)a
Supporting Information Available: Experimental procedures,
spectroscopic data, and copies of 1H and 13C NMR spectra for all
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
a
Conditions: (a) Bu4NF (TBAF), THF, 87% (6), 86% (6-epi-6); (b)
References
TEMPO (20 mol %), PhI(OAc)2, CH2Cl2, 80%; (c) Pr4NRuO4 (TPAP) (15
mol %), NMO, 4 Å MS, MeCN, 74%; (d) 21 (60 mol %), CH2Cl2, 80%;
(e) Cl2(Cy3P)(sIMes)RudCHPh (40 mol %), tetrafluorobenzoquinone (80
mol %), PhMe, 80 °C, 65%; (f) CAN, MeCN, H2O, 74%.
(1) Arnone, A.; Cardillo, R.; Meille, S. V; Nasini, G.; Tollazi, M. J. Chem.
Soc., Perkin Trans. 1 1994, 2165.
(2) Merlini, L.; Nasini, G.; Scaglioni, L.; Cassinelli, G.; Lanzi, C. Phytochem-
istry 2000, 53, 1039.
(3) Cassinelli, G.; Lanzi, C.; Pensa, T.; Gambetta, R. A.; Nasini, G.; Cuccuru,
G.; Cassinis, M.; Pratesi, G.; Polizzi, D.; Tortoreto, M.; Zunino, F.
Biochem. Pharmacol. 2000, 59, 1539.
(4) Courtneidge, S. A. Semin. Cancer Biol. 1994, 5, 239.
(5) Van der Geer, P.; Hunter, T.; Lindberg, R. A. Annu. ReV. Cell. Biol. 1994,
10, 251.
the use of TEMPO and iodobenzene diacetate was better for the
anti lactone 5 from 6 (80%).16 At this point, we sought to isomerize
lactone 19 into 5 by reversible Lewis acid catalyzed benzylic
C-O bond scission.17 Attempted isomerization of 19 using
TiCln(Oi-Pr)4-n (n ) 0-4) or BX3 (X ) Br, F) led only to
decomposition. In contrast, Yamamoto’s bulky aluminum complex
MeAl(OAr)2 (Ar ) 2,6-t-Bu-4-BrC6H2) mediated the clean, albeit
incomplete, epimerization of 19 into 5 (40% conversion in 3
days).18,19 Gratifyingly, a novel Lewis acid whose structure has been
tentatively assigned as 21 was found to induce complete and clean
conversion of 19 to 5 (80%).20 Conveniently, this sequence of
reactions can be performed on the mixture of diastereoisomers
obtained from the benzyne coupling reaction. Therefore, the crude
mixture of 18a and 18b was deprotected, and the resultant diol
mixture (59%, two steps) directly oxidized to a mixture of 5 and
19 with TEMPO and iodobenzene diacetate (65% yield). The
resultant mixture of lactones 5 and 19 were treated with the
aluminum complex 21 to obtain pure (+)-5 in 80% yield.
RCM reactions to form macrocycles with trisubstituted alkenes,
such as 20, are known to be very difficult.21 Gratifyingly, after
extensive optimization it was found that the slow addition of
Grubbs’ second generation catalyst and tetrafluorobenzoquinone22
to a 0.03 M solution of the diene in toluene at 80 °C, with
concomitant removal of the ethylene formed during the reaction,
gave the clavilactone A dimethyl ether (-)-20, in 65% yield
(Scheme 4). The NMR spectra of the compound obtained were
compared with those of a sample derived from the natural product
and a complete correlation was found. The optical rotation ([R]D
) -105 (c 0.1, MeOH)) was of the same magnitude but opposite
sign to that previously reported ([R]D ) +111 (c 0.1, MeOH)).1
Consequently, the absolute configuration of the natural product was
unambiguously assigned as 6R, 7R, 8R. Finally, oxidative dem-
ethylation of 20 gave (ent)-clavilactone B ((+)-2) (74%).23,12
(6) (a) Morton, G. E.; Barrett, A. G. M. J. Org. Chem. 2005, 70, 3525. (b)
Morton, G. E.; Barrett, A. G. M. Org. Lett. 2006, 8, 2859.
(7) For related three-component benzyne coupling: (a) Pansegrau, P. D.;
Rieker, W. F.; Meyers, A. I. J. Am. Chem. Soc. 1988, 110, 7178. (b)
Yoshida, H.; Fukushima, H.; Oshita, J.; Kunai, A. Angew. Chem., Int.
Ed. 2004, 43, 3935. (c) Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 5334. For a review see (d) Hoffmann, R. W. Dehy-
drobenzene and Cycloalkynes; Academic Press: New York, 1967.
(8) Anderson, R. J.; Corbin, V. L.; Cotterrell, G.; Cox, G. R.; Henrick, C.
A.; Schaub, F.; Siddall, J. B. J. Am. Chem. Soc. 1975, 97, 1197.
(9) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(10) (a) Stoichiometric Sharpless epoxidation was required. (b) Enantiomeric
excess determined by chiral HPLC. See Supporting Information.
(11) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701.
(12) See Supporting Information for details of stereochemical assignments of
all compounds, including 2.
(13) (a) Howe, G. P.; Wang, S.; Procter, G. Tetrahedron Lett. 1987, 28, 2629.
(b) For a review see Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191.
(14) The diastereoselectivity of the 3-component coupling was not affected
by changing the metal, solvent, additives, or the protecting group in 9.
(15) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem.
Soc. 1999, 121, 12208.
(16) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J.
Org. Chem. 1997, 62, 6974.
(17) For an example of such an epimerization. See Barluenga, J.; Viado, A.
L.; Aguilar, E.; Fustero, S.; Olano, B. J. Org. Chem. 1993, 58, 5972.
(18) Saito, S.; Yamamoto, H. Chem. Commun. 1997, 1585.
(19) Attempted isomerization with (2,6-Ph2C6H4O)3Al was unsuccessful.
(20) Studies to determine the actual structure of 21 are underway.
(21) Generally, dimerization of the more reactive monosubstituted olefin occurs
first which may be reversible. In contrast, macrocyclization is usually
irreversible. See (a) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L. Org. Lett.
2001, 3, 449. (b) Crimmins, M. T.; Brown, B. H. J. Am. Chem. Soc. 2004,
126, 10264.
(22) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2005, 127, 17160.
(23) Eskildsen, J.; Reenberg, T.; Christensen, J. B. Eur. J. Org. Chem. 2000,
1637.
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