Studies toward the synthesis of maoecrystal v

Article abstract of DOI:10.1021/ol1031238

An approach toward the synthesis of maoecrystal V is described. The synthetic strategy for this approach was designed to address unique challenges posed by the strained tetrahydrofuran ring at the center of the target structure.(Figure Presented)

Full text of DOI:10.1021/ol1031238

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1080–1082
Studies toward the Synthesis of
Maoecrystal V
Zhenhua Gu and Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara,
California 93110, United States
*E-mail: zakarian@chem.ucsb.edu.
Received December 23, 2010
ABSTRACT
An approach toward the synthesis of maoecrystal V is described. The synthetic strategy for this approach was designed to address unique
challenges posed by the strained tetrahydrofuran ring at the center of the target structure.
Maoecrystal V is a densely functionalized C19 diterpe-
noid containing five highly congested rings and seven
stereogenic centers, including two adjacent quaternary
Scheme 1. Synthesis Plan for Maoecrystal V
centers (1, Scheme 1). By far the most modified naturally
occurring ent-kauranoid from Isodon species, it was iso-
lated and characterized by Sun and co-workers in 2004.1
Maoecrystal V exhibits selective cytotoxicity against HeLa
cells (IC50 = 0.02 µg/mL) and virtually no inhibitory
activity against K562, A549, BGC-823, and CNE cells.
While the quaternary sterocenters clearly constitute a
significant challenge associated with the synthesis of maoe-
crystal V, it is the central tetrahydrofuran ring that became
the focus of attention in formulating our strategy. The five-
membered heterocyle is flanked on both sides by trans-
fused six-memberedrings, which createsnotableringstrain
that contributes to difficulties in its construction. As a
testament to this analysis, many research groups provided
(1) Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.; Sun,
H.-D.; Li, M.-L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org. Lett.
quaternary centers, yet the formation of the tetrahydro-
2004, 6, 4327–4330.
successful solutions to the installation of the adjacent
furan ring remained unresolved.2 Recently, Yang and co-
(2) (a) Gong, J.; Lin, G.; Li, C.-C.; Yang, Z. Org. Lett. 2009, 11,
€
4770–4773. (b) Krawczuk, P. J.; Schone, N.; Baran, P. S. Org. Lett. 2009,
workers completed the synthesis of racemic maoecrystal V
by an intramolecular Diels-Alder (IMDA) reaction that
in one event forms the central tetrahydrofuran and the
bicyclo[2.2.2]octane ring systems.3 The IMDA reaction is
preceded by a Wessely oxidative dearomatization, and
11, 4774–4776. (c) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett.
2009, 50, 6586–6587. (d) Nicolaou, K. C.; Dong, L.; Deng, L.; Talbot,
A. C.; Chen., D. Y.-K. Chem. Commun. 2010, 46, 70–72. (e) Lazarski,
K. E.; Hu, D. X.; Stern, C. L.; Thomson, R. J. Org. Lett. 2010, 12, 3010–
3013. (f) Baitinger, I.; Mayer, P.; Trauner, D. Org. Lett. 2010, 12, 5656–
5659.
r
10.1021/ol1031238
Published on Web 01/27/2011
2011 American Chemical Society

Scheme 2
Scheme 3
although it suffers from poor facial selectivity, it does
provide a successful synthetic path to (()-1.
The synthesis plan depicting our approach is outlined in
Scheme 1. This plan features an early installation of the
tetrahydrofuran ring followed by an intramolecular
Diels-Alder reaction with an o-quinone subunit to con-
struct the bicyclo[2.2.2]octane ring system incorporating a
potentially sensitive enol ether.4 The enol ether is intended
to serve as a radical acceptor for the eventual assembly of
the six-memberedlactone.5 The synthesiswillbe concluded
by the formation of the cyclohexenone via intramolecular
aldol cyclization of ketoaldehyde 2.6 Sesamol (6) was
identified as the starting material for synthesis of IMDA
reaction substrate 5. Lability of the enol ether in inter-
mediates such as 3 and 4 was of concern during the design
stages of this investigation.
Alkylation of sesamol with hinderedneopentylic alcohol
77 was carried out under the Mitsunobu conditions in 63%
yield (Scheme 2).8 ortho-Metalation of 8 with n-butyl-
lithium in THF at room temperature followed by trans-
metalation with zinc chloride to the corresposnding
arylzinc chloride reagent and coupling with methyl chlo-
roxoacetate delivered ketoester 9 in 46% yield along with
the recovery of 25% of the starting material.9 The
R-ketoester was advanced to R-diazoester 10 by a two-step
process involving the intermediacy of the tosylhydrazone
generated from 9 and its fragmentation under basic con-
ditions (DBU) in CH2Cl2 at room temperature.10
Diazoester 10 served as a substrate for the formation of
requisite benzofuran 11 by an intramolecular C-H func-
tionalization process. Exposure of 10 to a catalytic amount
of rhodium acetate (1 mol %) in carefully degassed dry
˚
CH2Cl2 in the presence of 4 A molecular sieves resulted in a
clean transformation affording 11 in 86% yield with 10:1
diastereoselectivity.11,12
In order to explore the feasibility of the IMDA process
that forms the basis of our synthesis plan, we chose to
introduce a methyl substituent at the C10 position as a
mimic of the related quaternary center in the natural
product. Thus, for the purposes of this study, the zincate
enolate generated from ester 11 by enolization with LiN-
(SiMe3)2 and addition of diethylzinc was treated with
iodomethane in the presence of DMPU, affording the
alkylation product in quantitative yield as an inseparable
mixture of diastereomers (3:1, Scheme 3).13 Methylation
using a more standard procedure without the addition of
diethylzinc (LiN(SiMe3)2, THF) afforded less than 10%
yield of the desired product and was complicated by
the formation of intractable mixture of products. Upon
(3) Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J. Am. Chem. Soc.
2010, 132, 16745–16746.
(4) For recent examples using masked ortho-quinone as substrates for
Diels-Alder reactions, see:(a) Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Song,
L.-D.; Liao, C.-C. J. Org. Chem. 1999, 64, 4111–4118. (b) Nicolaou,
K. C.; Toh, Q.-Y.; Chen, D. Y.-K. J. Am. Chem. Soc. 2008, 130, 11292–
11293. (c) Singh, V.; Bhalerao, P.; Mobin, S. M. Tetrahedron Lett. 2010,
51, 3337–3339.
(5) (a) Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem. Soc. 2008,
130, 16424–16434. (b) Trost, B. M.; Nguyen, H. M.; Koradin, C.
Tetrahedron Lett. 2010, 51, 6232–6235.
(6) (a) Mahrwald, R. Modern Aldol Reactions, Vol.s 1 and 2, 2004,
Wiley-VCH, Weinheim. Recent applications: (b) Stivala, C. E.; Zakarian, A.
Org. Lett. 2009, 11, 839–842. (c) Qin, Y.; Stivala, C. E.; Zakarian, A.
Angew. Chem., Int. Ed. 2007, 46, 7466–7469. (d) Stivala, C.; Zakarian, A.
J. Am. Chem. Soc. 2008, 130, 3774–3776.
(7) O’Connor, P. D.; Kim, U. B.; Brimble, M. A. Eur. J. Org. Chem.
2009, 4405–4411.
(8) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem. Soc.
Jpn. 1967, 40, 935–939.
(9) Velkov, J.; Mincheva, Z.; Bary, J.; Boireau, G.; Fujier, C. Synth.
(10) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129,
13794–13795.
(11) (a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424.
(b) Koizumi, Y.; Kobayshi, H.; Wakimoto, T.; Furuta, T.; Fukuyama,
T.; Kan, T. J. Am. Chem. Soc. 2008, 130, 16854–16855. (c) Saito, H.;
Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.; Hashimoto, S. Org.
Lett. 2002, 4, 3887–3890.
(12) The assignment of relative stereochemistry is tentative and is
based on literature precedent, see refs.11a-11c
(13) (a) Morita, Y.; Suzuki, M.; Noyori, R. J. Org. Chem. 1989, 54,
1785–1787Recent applications:. (b) Ilardi, E. A.; Isaacman, M. J.; Qin,
Y.-c.; Shelly, S. A.; Zakarian, A. Tetrahedron 2009, 65, 3261–3269. (c)
Iimira, S.; Overman, L. E.; Paulini, R.; Zakarian, A. J. Am. Chem. Soc.
2006, 128, 13095–13101.
Commun. 1997, 27, 375–378.
Org. Lett., Vol. 13, No. 5, 2011
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in the presence of 2,6-di-tert-butyl-2-methylphenol (BHT)
only led to decomposition if any conversion was observed.
In contrast, thermal activation of acrylate 17 (160 °C, o-
DCB) resulted in an efficient cycloaddition affording
lactone 19 in an essentially quantitative yield.18 Notably,
compound 19 containing the enol ether functionality was
stable to silica gel chromatography and showed no decom-
position upon storage at room temperature for several
days, documenting its feasibility for an eventual elabora-
tion to maoecrystal V. Treatment of vinyl sulfonate 18 as a
solution in toluene or o-DCB at ∼90 °C in the presense of
BHT resulted in decomposition, and no cycloaddition
product could be detected. We hypothesized that a trace
amount of acid resulting from exposure of 20 to elevated
temperatures could lead to decomposition of the initially
formed product. This could be prevented by buffering the
reaction medium with a base, and indeed, when 18 was
heated at 90 °C in toluene in the presense of BHT and
i-Pr2NEt, the cycloaddition product was isolated in 60%
yield. As with 19, enol ether 20 displayed excellent stability
to silica gel chromatography and storage.
In conclusion, we reported our progress toward the
synthesis of maoecrystal V. Preparation and stability of
advanced tricyclic enol ether intermediates 19 and 20 was
evaluated. The synthesis features a rhodium-catalyzed
C-H functionalization in the synthesis of dihydrobenzo-
furan 11 and an intramolecular Diels-Alder reaction to
form bicyclo[2.2.2]octane ring system from a masked
o-quinone via an IMDA reaction. The efficient Grignard
reagent-mediated regioselective modification of the cate-
chol methylidene acetal enabled access to the masked
o-quinone intermediate in a concise manner.
Scheme 4
reduction of the ester with lithium aluminum hydride,
the diastereomers could be separated by column chroma-
tography and alcohol 13 was isolated in 63% yield. Initial
attempts at removal of the methylidene group from
the catechol using Pb(OAc)4-AcOH14 or BBr3 were
unproductive;15 however, treatment of 13 with methyl-
magnesium bromide (6 equiv) in benzeneat refluxafforded
the desired monoprotected catechol derivative (14) as a
single regioisomer in a quantitative yield.16 The high
regioselectivity can be attributed to the directing affect of
the primary hydroxyl group in addition to steric effect
considerations.
Oxidative dearomatization of 14 with PhI(O2CCF3)2 in
ethanol readily afforded protected o-quinone 15 that ex-
hibited sufficient stability to be suitable for further studies.17
A set of substrates for the IMDA cyclization study was
prepared as illustrated in Scheme 4. Vinyl carbonate 16,
acrylate 17, and vinylsulfonate 18 were prepared in good
yields by treatment of 15 with vinyl chloroformate, acry-
loyl chloride, and 2-chloroethanesulfonyl chloride, res-
pectively. Heating of vinyl carbonate 16 in 1,2-dichloro-
benzene (o-DCB) at temperatures in the range 130-175 °C
Acknowledgment. We thank Amgen and Eli Lilly for
unrestricted support of our research. This work was
supported by NIGMS (R01 GM077379), NSF (CHE-
0836757), and the University of California Cancer Re-
search Coordinating Committee. We are grateful to Dr.
Hongjun Zhou for assistance with NMR spectroscopy.
Supporting Information Available. Detailed experimen-
1
tal procedures, copies of H and 13C NMR spectra for
compounds described in this letter. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(14) Ikeya, Y.; Taguchi, H.; Yoshioka, I. Chem. Pharm. Bull 1981, 29,
2893–2898.
(15) Tamura, S.; Yoshihira, K.; Tokumaru, M.; Zisheng, X.; Mur-
akami, N. Bioorg. Med. Chem. Lett. 2010, 20, 3872–3875.
(16) Hirao, N. Chem. Abstr. 1931, 25, 5156.
(18) The relative configuration of the product and the corresponding
endo-selectivity of the IMDA reaction are confirmed by NOE studies.
(17) Compound 16 is stable at -20 °C for a few days.
1082
Org. Lett., Vol. 13, No. 5, 2011