Total Synthesis of Clavilactone B: A Radical Cyclization-Fragmentation Strategy

Article abstract of DOI:10.1021/ol503356m

A new synthetic route to clavilactone B, a naturally occurring inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is disclosed. The route features a sequential samarium-mediated radical cyclization-fragmentation of an indanone derivativ

Full text of DOI:10.1021/ol503356m

Letter
pubs.acs.org/OrgLett
Total Synthesis of Clavilactone B: A Radical Cyclization−
Fragmentation Strategy
Hiroshi Suizu, Daisuke Shigeoka, Hiroshi Aoyama, and Takehiko Yoshimitsu*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: A new synthetic route to clavilactone B, a
naturally occurring inhibitor of epidermal growth factor
receptor (EGFR) tyrosine kinase, is disclosed. The route
features a sequential samarium-mediated radical cyclization−
fragmentation of an indanone derivative, which provides rapid
access to a 10-membered carbocyclic motif fused to an
aromatic ring.
rnone and co-workers identified in 1994 a series of cyclic
bioactive compounds, clavilactones B (1), A (2), and C
(4).6 Our group has also devised a ‘Lariat’ cyclization strategy
that includes sequential iodo-etherification/Friedel−Crafts type
cyclization and reductive olefination, and this strategy has
yielded the core motif of clavilactone D.7 Here, we report a new
synthetic approach to clavilactone B (1), which features a SmI2-
mediated radical cyclization−fragmentation of an indanone
derivative to construct the 10-membered carbocycle of the
target natural product (Scheme 1).
A
(3), as antifungal and antibacterial constituents in a culture of
the nontoxigenic fungus Clitocybe clavipes (Figure 1).1 There-
Scheme 1. Retrosynthesis of Clavilactone B (1)
Figure 1. Structures of clavilactones.
after, Merlini and co-workers reported the isolation of
structurally related clavilactones D (4) and E (5) from the
same fungus grown in a different culture medium although it
has recently been suggested that the originally proposed
structure of clavilactone D (4) needs revision.2 Clavilactones A
(2), B (1), and D (4) have been shown to exhibit potent
inhibitory activity toward epidermal growth factor receptor
(EGFR) tyrosine kinase, which is responsible for cellular
transduction pathways,3 thereby underscoring their relevance to
medicinal applications.
The first total synthesis of clavilactone B (1) was
accomplished by Barrett and co-workers, who devised an
efficient strategy that enabled the rapid construction of a highly
substituted aromatic ring by allylation−alkylation of an aryne
followed by ring-closing metathesis (RCM) to furnish the 10-
membered ring system of clavilactone B (1).4 The second
synthesis of clavilactones B (1) and A (2) was developed by
Takao and co-workers, who employed an elegant sequential
ring-opening/ring-closing olefin metathesis to access the
natural product.5 The most recent synthetic endeavor by Li
and co-workers, who utilized an iron-catalyzed carbonylation−
peroxidation and subsequent RCM, has uncovered a successful
unified approach to clavilactones A (2), B (1), and proposed D
In our retrosynthetic analysis of clavilactone B (1), we
envisioned that functionalized 10-membered ring 7 with the
clavilactone core would be constructed from indanone
derivative 8 by a SmI2-mediated radical cyclization and a
subsequent ring opening of intermediate i bearing a good
leaving group (Scheme 1).8,9 One of the key issues of the
present approach was the stereoselective installation of an aldol
unit suitable for the ionic fragmentation that requires an
antiperiplanar orientation between the leaving group and the
Received: November 19, 2014
Published: December 16, 2014
© 2014 American Chemical Society
126
dx.doi.org/10.1021/ol503356m | Org. Lett. 2015, 17, 126−129

Organic Letters
Letter
internal cleaving C−C bond (8 → i → 7). We expected that
the configuration of key indanone 8 would be available by the
stereoselective aldol reaction of indanone 9. Resultant
compound 7 would be converted by manipulating the γ-keto
ester functionality into γ-lactone 6, which, upon several
oxidative transformations, would produce clavilactone B (1).
The aldolization of indanone 910 was carried out with
aldehyde 1011 using titanium chloride12 in the presence of
triethylamine to provide aldol 11 in 77% yield with excellent
diastereoselectivity (dr >40:1) (Scheme 2). The high
Table 1. Samarium(II)-Mediated Radical Cyclization−
Fragmentation of Mesylate 8
a
product (%)
entry
additive (equiv)
7
15
16
Scheme 2. Total Synthesis of Clavilactone B (1)
1
2
−
21
41
19
15
29
b
Et3N (20)
−
a
Isolated yield after purification by SiO2 column chromatography.
Not detected.
b
production of tetracyclic byproduct 15 suggested the
intervention of intramolecular alkylation of enolate i shown
in Scheme 1. With a view to improving the chemical yield of
desired 7, we envisaged that Lewis bases that likely coordinate
to samarium alkoxide i would weaken the oxygen−samarium
bond to facilitate the fragmentation. After making numerous
attempts to optimize the conditions with such prospects in
mind, we were pleased to find that the use of SmI2 in
combination with triethylamine increased the yield of 7 while
attenuating the production of undesired tetracyclic compound
15 (entry 2). In this particular transformation, neither HMPA
nor water was effective, and both gave complicated undesired
products possibly by over-reduction. It is worth mentioning
that, whereas lactone 16 was generated under the mentioned
conditions,16 it could be converted into advanced intermediate
12 (vide infra) in good overall yield in three steps: its hydrolytic
fragmentation, methyl esterification of resultant γ-keto
carboxylic acid, and reduction of keto ester 17 with DIBAL
(Scheme 3).
Scheme 3. Transformation of Lactone 16 into Diol 12
diastereoselectivity yielded by this process was likely due to
the intermediacy of rigid six-membered transition state ii
generated by a titanium enolate (Figure 2). Resultant aldol 11
Compound 7 was then subjected to reduction with DIBAL
to afford diol 12 (79%) in a diastereomeric ratio of syn/anti =
4:1. The relative stereochemistry of major syn-diol 12 was
unambiguously established by X-ray crystallographic analysis
(Figure 3).17 Regioselective oxidation of the primary hydroxyl
group of diol 12 under TEMPO−NCS conditions18 success-
fully produced lactone 6 in 82% yield. The corresponding anti-
diol (structure not shown) could also be transformed into
lactone 6 by the same TEMPO oxidation protocol through
epimerization of the aldehyde intermediate.19
Further efforts were made with lactone 6 to install an
oxidation state relevant to clavilactone B. Lactone 6 was first
treated with LDA followed by diphenyldiselenide to give an α-
selenylated lactone, which, upon oxidation with NaIO4, gave
butenolide 13 in 81% overall yield. The installation of an
epoxide functionality into butenolide 13 was carried out as
Figure 2. Plausible intermediate ii leading to highly stereocontrolled
aldolization of 9 with 10.
was then converted into mesylate 8 in 94% yield, with which we
examined the key radical cyclization−fragmentation reaction
using samarium reagents.13 Initial attempts to convert mesylate
8 with SmI2 in THF afforded 10-membered motif 7 (21%)
along with tetracyclic compound 15 (19%)14 and lactone 16
(15%)15 as identifiable products (Table 1, entry 1). The
127
dx.doi.org/10.1021/ol503356m | Org. Lett. 2015, 17, 126−129

Organic Letters
Letter
(6) Lv, L.; Shen, B.; Li, Z. Angew. Chem., Int. Ed. 2014, 53, 4164−
4167.
(7) Yoshimitsu, T.; Nojima, S.; Hashimoto, M.; Tsukamoto, K.;
Tanaka, T. Synthesis 2009, 2963−2969.
(8) For recent reviews on fragmentation in natural product synthesis,
see: (a) Drahl, M. A.; Manpadi, M.; Williams, L. J. Angew. Chem., Int.
Ed. 2013, 52, 11222−11251. (b) Prantz, K.; Mulzer, J. Chem. Rev.
2010, 110, 3741−3766.
(9) For a related cyclization−fragmentation strategy for accessing
medium-sized carbocycles using Sm(II)-mediated reactions, see:
Molander, G. A.; Le Huer
66, 4511−4516.
(10) Fillion, E.; Fishlock, D.; Wilsily, A.; Goll, J. M. J. Org. Chem.
2005, 70, 1316−1327.
́
ou, Y.; Brown, G. A. J. Org. Chem. 2001,
Figure 3. X-ray crystallographic structure of syn-diol 12.
reported previously7 by using tert-butylhydroperoxide (TBHP)
under basic conditions to provide epoxide 14 in 61% yield.
Final oxidation of the aryl motif of compound 14 with ceric
ammonium nitrate (CAN) in aqueous MeCN allowed us to
furnish clavilactone B (1). The spectroscopic and analytical
data of synthetic clavilactone B (1) were identical with those
reported in the literature.4−6
In conclusion, we have established a new route to access
clavilactone B, which features a SmI2-mediated radical
cyclization−fragmentation of an indanone derivative. This
approach has allowed for the facile construction of the key
10-membered ring system fused to an aromatic ring. The
approach would provide an alternative to the RCM-based
routes that have been successfully developed so far to
synthesize this class of attractive natural products.
(11) Barnhart, R. W.; Wang, X.; Noheda, P.; Bergens, S. H.; Whelan,
J.; Bosnich, B. J. Am. Chem. Soc. 1994, 116, 1821−1830.
(12) (a) Nerz-Stormes, M.; Thornton, E. R. Tetrahedron Lett. 1986,
27, 897−900. (b) Harrison, C. R. Tetrahedron Lett. 1987, 28, 4135−
4138. (c) Mahrwald, R.; Gundogan, B. J. Am. Chem. Soc. 1998, 120,
̈
413−414.
(13) For selected reviews on samarium(II)-mediated transformations,
see: (a) Szostak, M.; Fazakerley, N. J.; Parmar, D.; Procter, D. J. Chem.
Rev. 2014, 114, 5959−6039. (b) Coote, S. C.; Flowers, R. A.;
Skrydstrup, T.; Procter, D. J. Organic Synthesis Using Samarium
Diiodide. In Encyclopedia of Radicals in Chemistry, Biology and
Materials; Chatgilialoglu, C., Studer, A., Eds.; John Wiley & Sons:
Chichester, U.K., 2012; Vol. 2, pp 849−900. (c) Szostak, M.; Spain,
M.; Parmar, D.; Procter, D. J. Chem. Commun. 2012, 48, 330−346.
(d) Beemelmanns, C.; Reissig, H.-U. Chem. Soc. Rev. 2011, 40, 2199−
2210. (e) Honda, T. Heterocycles 2010, 81, 2719−2747. (f) Dahlen, A.;
Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393−3403. (g) Edmonds,
D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371−3403.
(h) Kagan, H. B. Tetrahedron 2003, 59, 10351−10372. (i) Molander,
G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321−3354. (j) Inanaga, J.
Trends Org. Chem. 1990, 1, 23−30.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) For a review on Sm(II)-mediated synthesis of small carbocycles,
see: Harb, H. Y.; Procter, D. J. Synlett 2012, 23, 6−20.
(15) The structure of compound 16 was unambiguously determined
by X-ray crystallographic analysis. CCDC 1023173 contains the
supplementary X-ray crystallographic data for this compound. These
data are available free of charge from The Cambridge Crystallographic
Data Center via www.ccdc.cam.ac.uk/data_request/cif.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yoshimit@phs.osaka-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge Professor N. Kotoku of Osaka
University for NOE analysis and K. Sawada and S. Nojima
(Osaka University) for their preliminary contribution to this
work. This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas [No. 22136006] from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan (MEXT).
(16) We initially assumed that lactone 16 was formed by protonation
of intermediate i and subsequent cyclization of the resultant ester
during aqueous workup or on silica gel TLC (when monitoring by
TLC). If this is the case, the elongation of reaction time would
increase fragmentation product 7 while decreasing lactone 16.
However, prolonged reaction times did not facilitate the formation
of 7 and led to no further consumption of lactone 16, suggesting that
lactone 16 was generated in situ via rapid protonation of Sm(III)
enolate followed by lactonization. We suspected that intra- or
intermolecular protonation of enolate i by the acidic motifs such as
the methyl substituent of the methanesulfonyl group of the substrate
or intermediate i and the acidic methylene protons of product 7 might
be responsible for such phenomena. Attempted experimentations
where the reaction was quenched by deuterium oxide, however,
REFERENCES
■
(1) Arnone, A.; Cardillo, R.; Meille, S. V.; Nasini, G.; Tollazi, 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. For the discussion on the
necessity of structural revision, see ref 6.
(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) 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.
(5) Takao, K.; Nanamiya, R.; Fukushima, Y.; Namba, A.; Yoshida, K.;
Tadano, K. Org. Lett. 2013, 15, 5582−5585.
128
dx.doi.org/10.1021/ol503356m | Org. Lett. 2015, 17, 126−129

Organic Letters
Letter
showed no deuterium incorporation into the products. In the presence
of t-BuOH (1 equiv) and Et3N (10 equiv), lactone 16 was yielded
(50%) along with fragmented compound 7 (19%), suggesting that the
added proton source accelerated lactone formation. The aforemen-
tioned observations indicate that adventitious moisture in the reaction
mixture might serve as the proton donor. Despite our efforts to adapt
rigorous anhydrous conditions, the formation of lactone 16, however,
could not be suppressed. No further attempts were made to optimize
the conditions.
(17) CCDC 1022864 contains the supplementary X-ray crystallo-
graphic data for this compound. These data are available free of charge
from The Cambridge Crystallographic Data Center via www.ccdc.cam.
ac.uk/data_request/cif. For details, see Supporting Information.
(18) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org. Chem.
1996, 61, 7452−7454.
(19) For details, see the Supporting Information.
129
dx.doi.org/10.1021/ol503356m | Org. Lett. 2015, 17, 126−129