Total synthesis of (+)-clavilactone A and (-)-clavilactone B by ring-opening/ring-closing metathesis

Article abstract of DOI:10.1021/ol4027842

The enantioselective total synthesis of natural enantiomers of clavilactones A and B has been achieved. A key feature of the synthesis is the use of a ring-opening/ring-closing metathesis, which allows the one-pot transformation of a strained cyclobutenecarboxylate into a γ-butenolide.

Full text of DOI:10.1021/ol4027842

ORGANIC
LETTERS
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Vol. XX, No. XX
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Total Synthesis of (þ)-Clavilactone
A and (ꢀ)-Clavilactone B by
Ring-Opening/Ring-Closing Metathesis
Ken-ichi Takao,* Ryuki Nanamiya, Yuuki Fukushima, Ayumi Namba,
Keisuke Yoshida, and Kin-ichi Tadano
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
takao@applc.keio.ac.jp
Received September 26, 2013
ABSTRACT
The enantioselective total synthesis of natural enantiomers of clavilactones A and B has been achieved. A key feature of the synthesis is the use of
a ring-opening/ring-closing metathesis, which allows the one-pot transformation of a strained cyclobutenecarboxylate into a γ-butenolide.
Clavilactones A 1, B 2, and C were originally isolated
from cultures of the fungus Clitocybe clavipes as antifungal
and antibacterial compounds by Arnone and co-workers
in 1994 (Figure 1).1 Their structures and relative config-
urations were determined by NMR studies and single-
crystal X-ray diffraction analysis of the dimethyl ether
derivative of 1. The clavilactones contain a conformation-
ally rigid 10-membered carbocycle connected to a hydro-
quinone or benzoquinone and an R,β-epoxy-γ-lactone.
Later, clavilactones D 3 and E were also isolated from
the same fungus by using different culture conditions.2
Clavilactones A 1, B 2, and D 3 show potent inhibitory
activity against epidermal growth factor receptor tyrosine
kinases.3 These findings indicate that the clavilactones
represent a novel class oftyrosine kinase inhibitor. Because
they show promise as lead compounds for antitumor
agents, the clavilactones have attracted attention from
synthetic chemists.4,5 In 2006, Barrett and co-workers
reported an elegant total synthesis of (þ)-clavilactone B
(the antipode of 2), thereby establishing the absolute
configuration of natural clavilactone.6 Here we describe
the first total synthesis of the natural enantiomers of clavi-
lactones A 1 and B 2 by a conceptually novel method that
relies on ring-opening/ring-closing metathesis (ROM/RCM).
Olefin metathesis is a powerful synthetic tool in modern
organic chemistry.7 Recently, new methods have been
developed by combining several metathesis steps into a
domino process. For example, ring-rearrangement metathesis
is a highly efficient method for forming carbocycles and
heterocycles.8 A representative ring-rearrangement metathesis
reaction is ROM/RCM, which involves intramolecular
ꢀ
(6) Larrosa, I.; Da Silva, M. I.; Gomez, P. M.; Hannen, P.; Ko, E.;
Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M.
J. Am. Chem. Soc. 2006, 128, 14042–14043.
(7) For recent reviews on the synthetic application of metathesis, see:
(a) Grubbs, R. H.; Wenzel, A. G.; Chatterjee, A. K. In Comprehensive
Organometallic Chemistry III; Mingos, D. M., Crabtree, R. H., Eds.;
Elsevier: Amsterdam, 2007; Vol. 11, pp 179ꢀ205. (b) Mulzer, J.; Ohler,
E.; Gaich, T. In Comprehensive Organometallic Chemistry III; Mingos,
D. M., Crabtree, R. H., Eds.; Elsevier: Amsterdam, 2007; Vol. 11, pp 207ꢀ
269. (c) Mori, M.; Kitamura, T. In Comprehensive Organometallic
Chemistry III; Mingos, D. M., Crabtree, R. H., Eds.; Elsevier: Amsterdam,
2007; Vol. 11, pp 271ꢀ310. (d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4490–4527. (e) Takao, K.; Tadano, K.
Heterocycles 2010, 81, 1603–1629.
(1) Arnone, A.; Cardillo, R.; Meille, S. V.; Nasini, G.; Tolazzi, M.
J. Chem. Soc., Perkin Trans. 1 1994, 2165–2168.
(2) Merlini, L.; Nasini, G.; Scaglioni, L.; Cassinelli, G.; Lanzi, C.
Phytochemistry 2000, 53, 1039–1041.
(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, 1539–1547.
(4) Yasui, H.; Yamamoto, S.; Takao, K.; Tadano, K. Heterocycles
2006, 70, 135–141.
(5) Yoshimitsu, T.; Nojima, S.; Hashimoto, M.; Tsukamoto, K.;
Tanaka, T. Synthesis 2009, 2963–2969.
(8) For a review on ring-rearrangement metathesis, see: Holub, N.;
Blechert, S. Chem.;Asian J. 2007, 2, 1064–1082.
r
10.1021/ol4027842
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undergoes the second catalytic cycle. However, product
(()-5 was obtained in low yield under these conditions,
because complex III also reacts with the terminal alkene in
(()-5 which produces a significant amount of the dimer-
ized product ((()-6). We have now greatly improved the
reaction conditions for the synthesis of 5 and applied this
method to the total synthesis of the clavilactones.
Our retrosynthetic analysis of (þ)-clavilactone A 1 is
shown in Scheme 2. We envisioned the formation of the 10-
memberedcarbocycle by RCM of diene7. The preparation
of 7 would be achieved by epoxidation and a cross-
coupling reaction from γ-butenolide 5. We intended to
construct the γ-butenolide by ROM/RCM of cyclobute-
necarboxylate 4. Substrate 4 for ROM/RCM would be
obtained by condensation of allylic alcohol 8 and cyclobu-
tenecarboxylic acid (9). Acid 9 is a known compound that
can be easily prepared from commercially available cyclo-
butanecarboxylic acid according to a literature procedure.10
At the outset, we investigated the asymmetric synthesis
of allylic alcohol 8, using the enantioselective alkynylation
(Scheme 3). The substrate for alkynylation, aldehyde 11,
Figure 1. Structures of clavilactones A 1, B 2, and D 3.
Scheme 1. ROM/RCM of Cyclobutenecarboxylate (()-4
Scheme 2. Retrosynthetic Analysis of (þ)-Clavilactone A 1
was prepared from 2-bromo-3,6-dihydroxybenzaldehyde
(10)11 by dimethyl etherification.12 Several enantioselective
alkynylations of 2,6-disubstituted benzaldehydes have been
reported,13 and the reaction of 11 with trimethylsilylacetylene
under You’s conditions (BINOL/Et2Zn/N-methylimidazole/
Ti(OiPr)4)14 resulted in a good yield and enantioselectivity
metathesis reactions of alkenyl-substituted carbocyclic
alkenes. These one-pot reactions allow the rapid transfor-
mation of strained carbocyclic alkenes into new carbo-
cycles or heterocycles, resulting in a rearranged ring system
in the product. Previously, we reported the ROM/RCM of
cyclobutenecarboxylate derivatives as a novel method for
concise access to γ-butenolides (Scheme 1).4,9 The exoalk-
ene in substrate (()-4 is thought to react first with the
Grubbs catalyst to form ruthenium carbene complex I,
which is converted to complex III via metallacyclobutane
II. In this transformation, the cyclobutene ring is opened
and the new γ-butenolide ring is formed concomitantly.
Another molecule of substrate (()-4 reacts with complex
III to produce γ-butenolide (()-5 and complex I, which
(10) (a) Campbell, A.; Rydon, H. N. J. Chem. Soc. 1953, 3002–3008.
(b) Dauben, W. G.; Wiseman, J. R. J. Am. Chem. Soc. 1967, 89, 3545–
3549.
(11) Compound 10 was prepared from commercially available 2,5-
dihydroxybenzaldehyde by regioselective bromination: Hu, Y.; Li, C.;
Kulkarni, B. A.; Strobel, G.; Lobkovsky, E.; Torczynski, R. M.; Porco,
J. A., Jr. Org. Lett. 2001, 3, 1649–1652.
(12) For another synthesis of compound 11 from 2,5-dimethoxyben-
zaldehyde in three steps, see: Li, C.; Lobkovsky, E.; Porco, J. A., Jr.
J. Am. Chem. Soc. 2000, 122, 10484–10485.
(13) (a) Liu, L.; Pu, L. Tetrahedron 2004, 60, 7427–7430. (b) Qin, Y.-C.;
Liu, L.; Sabat, M.; Pu, L. Tetrahedron 2006, 62, 9335–9348. (c) Trost,
B. M.; Weiss, A. H.; Jacobi von Wangelin, A. J. Am. Chem. Soc. 2006,
128, 8–9.
(9) As another example of metathesis of cyclobutenecarboxylate, the
synthesis of copolymers of cyclobutenecarboxylates and cyclohexenes
by alternating ROM polymerization has been reported: Song, A.;
Parker, K. A.; Sampson, N. S. J. Am. Chem. Soc. 2009, 131, 3444–3445.
(14) Yang, F.; Xi, P.; Yang, L.; Lan, J.; Xie, R.; You, J. J. Org. Chem.
2007, 72, 5457–5460.
B
Org. Lett., Vol. XX, No. XX, XXXX

(77%, ee = 85%).15 After recrystallization, almost enan-
tiomerically pure alkynylated product 12 was obtained
(ee = >99%). Removal of the trimethylsilyl group from
12 and subsequent Lindlar hydrogenation of the resulting
alkyne 13 provided allylic alcohol 8. The absolute config-
uration of 8 was determined from the Δδ values of the
R-methoxy-R-(trifluoromethyl)phenylacetic acid (MTPA)
ester 14 derived from 8 in their 1H NMR spectra.16
addition of the first-generation Grubbs catalyst improved
the conversion rate, and the addition of benzoquinone 1619
prevented isomerization of the terminal alkene in 5.
Scheme 4. Synthesis of γ-Butenolide 5
Scheme 3. Synthesis of Allylic Alcohol 8
Having established the method for constructing the
γ-butenolide, we turned our attention to forming the
epoxide. However, despite extensive efforts, the corre-
sponding R,β-epoxy-γ-lactone could not be obtained from
γ-butenolide 5.20 To circumvent this problem, γ-buteno-
lide 5 was temporarily reduced with excess DIBALH to
diol 17, which was somewhat unstable, and immediately
protected as silylene acetal 18 (Scheme 5).21 The epoxida-
tion of 18 with m-CPBA proceeded chemo- and stereo-
selectively, giving epoxide 19 as the major product.
With epoxide 19 in hand, we next focused on construct-
ing the 10-membered carbocycle. Stille coupling of 19 and
allylstannane 2022 using CuCl as a promoter provided
diene 21.23 RCM of diene 21 using the second-generation
Grubbs catalyst (20 mol %) initially produced the dimer,
which was slowly converted into cyclized product 22.24 In
this reaction, it was necessary to prolong the reaction time
Treatment of alcohol 8 with LDA and acid anhydride
15, prepared from acid 9 with triphosgene,17 gave cyclo-
butenecarboxylate 4 (Scheme 4). Preliminary studies of the
ROM/RCM of 4 indicated that a large amount of dimer-
ized side product 6 was formed as shown in Scheme 1. To
suppress the dimerization, ROM/RCM of 4 was per-
formed at a much lower concentration (0.001 M) using
the first-generation Grubbs catalyst.18 However, the yield
of γ-butenolide 5 was only 28% and dimer 6 was still
obtained in significant yield. The second-generation
Grubbs catalyst or HoveydaꢀGrubbs catalyst also gave
unsatisfactory results. However, the one-pot ROM/RCM
of 4 in toluene (0.01 M) using the first-generation Grubbs
catalyst (10 mol %), followed by treatment of the resulting
mixture with ethylene (1 atm) and the second-generation
Grubbs catalyst (5 mol %), produced the desired product 5
in good yield (76%). The treatment with ethylene led to
ethenolysis of dimer 6 to product 5. Furthermore, the slow
(20) There have been few successful examples of epoxidation of
γ-aryl-γ-butenolides: Jakubowski, A. A.; Guziec, F. S., Jr.; Sugiura,
M.; Tam, C. C.; Tishler, M.; Omura, S. J. Org. Chem. 1982, 47, 1221–
1228. See also ref 5.
(21) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871–
4874.
(22) Naruta, Y.; Nishigaichi, Y.; Maruyama, K. Org. Synth. 1993, 71,
118–122.
(23) (a) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind,
L. S. J. Org. Chem. 1994, 59, 5905–5911. (b) Han, X.; Stoltz, B. M.;
Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600–7605.
(24) In our preliminary studies, attempted cyclization by the RCM of
compound IV was unsuccessful, and only a dimerized product and/or
naphthalene derivative V were obtained (see ref 4). We conclude that the
epoxy ring is essential for the formation of the 10-membered carbocycle
of clavilactone. Another explanation of our results was suggested by a
referee. It could be that the silylene acetal in 21 is responsible for
inducing a favorable conformation for RCM.
(15) The ee of 12 was determined by chiral HPLC analysis.
(16) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092–4096. (b) Kusumi, T. J. Synth. Org. Chem.
Jpn. 1993, 51, 462–470.
(17) Kocz, R.; Roestamadji, J.; Mobashery, S. J. Org. Chem. 1994,
59, 2913–2914.
(18) Lesma, G.; Crippa, S.; Danieli, B.; Passarella, D.; Sacchetti, A.;
Silvani, A.; Virdis, A. Tetrahedron 2004, 60, 6437–6442.
(19) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160–17161.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Synthesis of 10-Membered Carbocycle 22
Scheme 6. Completion of the Total Synthesis of Clavilactones A
1 and B 2
Treatment of 24 with CAN provided (ꢀ)-clavilactone B 2.6
The reduction of the quinone with NaBH4 finally afforded
(þ)-clavilactone A 1.1 The properties of products 1 and 2
were identical in all respects to those reported for natural
clavilactones A and B.1
In summary, we have achieved the first total synthesis of
the natural enantiomers of clavilactones A 1 and B 2 (1; in
15 steps with 1.6% yield). The key features of the synthesis
are two successful olefin metathesis reactions. First, an ROM/
RCM sequence allowed the one-pot transformation of cyclo-
butenecarboxylate 4 into γ-butenolide 5. Second, the forma-
tion of a 10-membered carbocycle was achieved by RCM of
silylene acetal derivative 21. Furthermore, the three contigu-
ous stereocenters were derived from a single benzylic alcohol,
which was generated asymmetrically through a Ti/BINOL
alkynylation. Extension of this ROM/RCM strategy to the
synthesis of other γ-lactone natural products is underway.
by slow addition of the catalyst. Heating a mixture of 21
and the catalyst (20 mol %) gave only the dimer. 1H NMR
analysis, including NOE experiments, of 22 indicated that
the stereochemistry and conformation were similar to the
natural product 1.25
The final stage of the synthesis required reconstructing
the γ-lactone. Removal of the silylene acetal from 22
provided diol 23, which was oxidized with tetra-n-propy-
lammonium perruthenate (TPAP) and NMO to γ-lactone
24 (Scheme 6).26 The product, compound 24, was identical to
the dimethyl ether derived from natural clavilactone A 1.1,6
Acknowledgment. This work was supported by JSPS
KAKENHI Grant Number 23550060 and Keio Gijuku
Academic Development Funds.
Supporting Information Available. Experimental pro-
cedures, copies of 1H and 13C NMR spectra of new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(25) When the olefinic methyl group was irradiated, signal enhance-
ments were observed for the olefinic proton (5.0%) and Ha (0.7%) but
not for Hb. In addition, no vicinal coupling between Ha and Hb (Ja,b = 0 Hz)
was observed. The absolute configuration of 22 was definitely confirmed by
transformation to compound 24, whose absolute configuration had been
unambiguously determined.1,6
(26) Bloch, R.; Brillet, C. Synlett 1991, 829–830.
The authors declare no competing financial interest.
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