Synthesis of functionalized maoecrystal v core structures

Article abstract of DOI:10.1039/b917045f

Two strategies toward the total synthesis of maoecrystal V (1) culminating in the construction of core structures 2 and 3 are described.

Full text of DOI:10.1039/b917045f

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Synthesis of functionalized maoecrystal V core structuresw
K. C. Nicolaou,*abc Lin Dong,a Lujiang Deng,a Adam C. Talbota and David Y.-K. Chen*a
Received (in Cambridge, UK) 18th August 2009, Accepted 8th October 2009
First published as an Advance Article on the web 23rd October 2009
DOI: 10.1039/b917045f
Two strategies toward the total synthesis of maoecrystal V (1)
culminating in the construction of core structures 2 and 3 are
described.
be formed from a bicyclic precursor through an intramolecular
[4 + 2] cycloaddition5 that would introduce two additional
rings, followed by an intramolecular cyclopropanation/
dearomatization/ring opening cascade to forge the final ring
(see Scheme 1). To this end, 2,6-dimethoxy benzoic acid (4)
Maoecrystal V (1, Fig. 1) is a recently reported terpenoid
endowed with potent and selective cytotoxic properties and
novel architectural motifs.1 Isolated from the medicinally used
Chinese herb Isodon eriocalyx, collected from the Jiangchuan
prefecture of Yunnan province, this natural product exhibits
selective cytotoxicity against HeLa cells (IC50 = 0.02 mg mLÀ1) as
compared to three other cell lines tested (K562, A549 and
BGC-823). Its highly unusual structure was finally reported in
2004 after an X-ray crystallographic analysis, although it was
suspected several years earlier on the basis of NMR spectro-
scopic and mass spectrometric experiments.1 By virtue of its
appealing molecular structure and antitumor properties,
maoecrystal V attracted the attention of synthetic organic
chemists and, thus, studies toward its synthesis already began
to emerge.2–4 In this communication, we report our early
forays in this area that culminated in the construction of
functionalized core structures 2 and 3 (Fig. 1) as well as
preliminary biological evaluation of these compounds.
The striking molecular structure of maoecrystal V (1) is
characterized by its compact polycyclic nature, unprecedented
ring framework, and five stereogenic centers (of which three
are quaternary). Our first approach to the pentacyclic frame-
work of this molecule was based on the premise that it could
Fig. 1 Structures of maoecrystal V (1) and functionalized core
structures 2 and 3.
a Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and
Engineering Sciences (ICES), Agency for Science, Technology and
Research (A*STAR), 11 Biopolis Way, The Helios Block #03-08,
Singapore, 138667
Scheme 1 Construction of dienone 2. Reagents and conditions: (a) 5
(1.6 equiv.), Pd(TFA)2 (0.2 equiv.), Ag2CO3 (2.0 equiv.), DMF/DMSO
(20 : 1), 80 1C, 3 h, 89%; (b) BBr3 (1.8 equiv.), CH2Cl2, À15 1C, 2.5 h,
70%; (c) NaH (2.1 equiv.), THF, 0 - 23 1C, 1 h; then 8 (5.0 equiv.)
0 - 23 1C, 16 h; (d) Na2CO3 (5.0 equiv.), MeI (10.0 equiv.), MeOH,
reflux, 2 h, 80% over the two steps; (e) TBSOTf (1.5 equiv.), Et3N
(3.0 equiv.), CH2Cl2, 0 1C, 1.5 h; (f) K2CO3 (4.8 equiv.), hydroquinone
(1.2 equiv.), toluene, reflux, 16 h; then 1.0 N aq. HCl, 1 h, 23 1C, 64%
over the two steps; (g) NaOH (1.0 N aq.)/EtOH (1 : 1), 60 1C, 5 h;
(h) (COCl)2 (5.0 equiv.), DMF (1 drop), CH2Cl2, reflux, 1 h;
(i) TMSCHN2 (5.0 equiv.), THF–CH3CN (1 : 1), 0 1C, 2 h, 79% over
the three steps; (j) Rh2(OAc)4 (0.1 equiv.), CH2Cl2, 23 1C, 1 h, 75%;
(k) 10% Pd/C (0.26 equiv.), H2, EtOAc, 23 1C, 24 h, 87%.
E-mail: kcn@scripps.edu, david_chen@ices.a-star.edu.sg
b Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California, 92037, USA. E-mail: kcn@scripps.edu
c Department of Chemistry and Biochemistry, University of California,
San Diego, 9500 Gilman Drive, La Jolla, California, 92093, USA
w Electronic supplementary information (ESI) available: Experimental
details, X-ray crystallographic analysis and 1H and 13C NMR spectra
of compounds. CCDC 742693, 748550 and 748551. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b917045f
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was reacted with cyclohexenone (5) in the presence of
Pd(OCOCF3)2 catalyst and Ag2CO3 to afford arylated enone
6 through a decarboxylative Heck process,6 in 89% yield.
Mono-demethylation of dimethoxy enone 6 (BBr3, 70% yield)
followed by O-alkylation of the resulting phenol (7) with
bromide 87 resulted in the formation of pyrrolidine derivate 9,
whose conversion to the desired alkenyl methyl ester 10
required quaternization and extrusion of its nitrogen moiety
(Na2CO3–MeI, 80% overall yield from 7). Subsequent
reaction of enone 10 with TBSOTf–Et3N furnished TBS enol
ether 11, which was subjected to the intended intramolecular
[4 + 2] cycloaddition reaction directly and without purification
in the presence of K2CO3 and hydroquinone (toluene, reflux).
Upon exposure of the resulting cycloadducts to aq. HCl, the
exo (major) Diels–Alder product 12 (64% yield from 10) and
its endo isomer (C8-epi-12, not shown, 1.7% yield from 10)
were obtained and chromatographically separated. The
structural identity of 12 (m.p. 200–201 1C, EtOAc/hexanes)
was unambiguously assigned through X-ray crystallographic
analysis8 (see ORTEP, Fig. 2).9 The second of the two
contiguous all carbon quaternary centers was fabricated
through an intramolecular, carbene-mediated cyclopropanation/
fragmentation process inspired by the work of Mander,10 as
shown in Scheme 1. Thus, saponification of the methyl ester
within 12 (1 N aq. NaOH/EtOH 1 : 1, 60 1C), followed by acid
chloride formation [(COCl)2] and exposure to TMSCHN2, led
to a-diazo ketone 13 in 79% overall yield for the three steps.
Treatment of diazo ketone 13 with Rh2(OAc)4 catalyst in
CH2Cl2 at ambient temperature resulted, upon exposure of
the resulting cyclopropane (14) to silica gel, in the formation of
pentacyclic dienone maoecrystal V core 2 in 75% overall yield
from 13. Assigned by NMR spectroscopic and mass spectro-
metric techniques, the structure of 2 was unambiguously
confirmed through X-ray crystallographic analysis of its
fully hydrogenated product [15, H2, Pd–C (cat), 87% yield]
(m.p. 237–238 1C, EtOAc, see ORTEP,11 Fig. 2). Compound 2
holds promise as a possible precursor to maoecrystal V (1).
Our second foray toward maoecrystal V (1) involved the
same type of intramolecular Diels–Alder reaction but a
different dearomatization process to arrive at the even more
advanced intermediate 3, as shown in Scheme 2. Thus,
bis-demethylation of intermediate 6 (BBr3) followed by
mono-protection of the resulting diphenol (16) as a MOM
ether (NaH–MOMCl), afforded phenolic enone 17 in 55%
overall yield. Attachment of the dienophile moiety onto 17 was
carried out through the same sequence as described above
Scheme 2 Construction of pentacyclic lactone 3. Reagents and
conditions: (a) BBr3 (3.5 equiv.), CH2Cl2, À78 - 0 1C, 2 h, 98%;
(b) NaH (1.1 equiv.), MOMCl (1.2 equiv.), THF, 0 1C, 2 h, 56%;
(c) NaH (2.1 equiv.), THF, 0 - 23 1C, 1 h; then 8 (4.0 equiv.), THF,
0 - 23 1C, 8 h; (d) Na2CO3 (2.6 equiv.), MeI (11 equiv.), MeOH,
reflux, 2 h, 57% over the two steps; (e) TBSOTf (1.5 equiv.), Et3N
(3.0 equiv.), CH2Cl2, 0 1C, 2 h; (f) K2CO3 (4.8 equiv.), hydroquinone
(1.2 equiv.), toluene, reflux , 18 h; then 1.0 N aq. HCl, 23 1C, 1 h, 50%
over the two steps; (g) HCl (6.0 N aq.)/EtOH–CHCl3 (1 : 1 : 1), reflux, 3 h,
83%; (h) PIFA (2.0 equiv.), KHCO3 (2.2 equiv.), MeOH, 0 - 23 1C,
0.5 h, 83%; (i) 10% Pd/C (0.33 equiv.), H2, EtOH, 23 1C, 10 h, 23:
66%, 24: 33%; (j) PIFA (2.0 equiv.), KHCO3 (2.2 equiv.), MeOH,
0 - 23 1C, 0.5 h, 70%; (k) 1.0 N aq. NaOH (7.0 equiv.), EtOH, reflux,
5 h; then 1.0 N aq. HCl; (l) ClCH2I (11 equiv.), KOtBu (5.0 equiv.),
18-crown-6 (5.5 equiv.), THF, 23 1C, 3 h, 42% over the two steps.
for 7 - 10 (Scheme 1) (NaH, 8; Na2CO3, MeI),7 leading to
enone alkenyl ester 18 in 57% overall yield. Silyl enol ether
formation within the latter compound (TBSOTf–Et3N) then
provided the desired Diels–Alder substrate 19, which was used
without purification in the following steps as described above
for the related substrate 11. In this instance, heating 19 in
refluxing toluene in the presence of K2CO3 and hydroquinone
Fig. 2 X-ray derived ORTEP of intramolecular Diels–Alder product
12 and triketone 15 with thermal ellipsoids shown at the 50%
probability level.
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Table 1 Cytotoxicity of compounds 2, 3, and 15 against selected
cancer cell lines. (GI50 values in mM)a
Cell line
MCF-7b SF268b
NCI-H460b HeLab
Entry Compound
1
2
3
4
2
3
15
410 410
410
410
3.6 Æ 0.3 5.3 Æ 0.1 5.6 Æ 0.1
6.7 Æ 0.2
410
410
410
410
Doxorubicin 0.089 Æ
0.468 Æ
0.054 Æ
0.965 Æ
0.002
0.011
0.007 Æ
0.003
0.033 Æ
0.000
0.003
0.0065 Æ
0.001
s
5
Taxol
0.008 Æ
Fig. 3 X-ray derived ORTEP of enone lactone 3 with thermal
0.000
0.000
ellipsoids shown at the 50% probability level.
a
Antiproliferative effects of tested compounds against human tumor
cell lines and drug-resistant cell lines in a 48 h growth inhibition assay
using the sulforhodamine B staining methods. Human cancer cell lines:
breast (MCF-7), lung (NCI-H460), CNS (SF268), and cervical
(HeLa). Growth inhibition of 50% (GI50) is calculated as the drug
concentration which caused a 50% reduction in the net protein
increase in control cells during drug incubation.15 GI50 values for
each compound are given in mM and represent the mean of two
provided, upon treatment with 1 N aq. HCl at ambient
temperature, exo Diels–Alder product 20 as a single diastereo-
isomer in 50% overall yield from 18. The desired dearomati-
zation of the benzenoid ring of 20 was performed, this time,
through a sequence involving deprotection of its phenolic
group (6 N aq. HCl/EtOH–CHCl3, 1 : 1 : 1, reflux) and
subsequent treatment of the resulting phenol (21) with
PIFA–KHCO3 in MeOH, furnishing dimethoxy dienone deri-
vative 22 in 69% overall yield for the two steps. Hydrogena-
tion of the latter compound [H2, 10% Pd–C (cat)] afforded a
mixture of the desired diketone 23 (epimeric to 1 at C5) and
aromatized product 24 (24 : 23 ca. 1 : 3 ratio, 99% combined
yield). Chromatographic separation of 24 and 23 allowed
recycling of the former to dienone 22 (PIFA-KHCO3, MeOH,
70% yield), and saponification of the latter to carboxylic acid
25 (aq. NaOH, EtOH, reflux). On exposure to KOtBu and
ClCH2I in the presence of 18-crown-6 at ambient temperature,
diketone carboxylic acid 25 underwent triple alkylation
(two intermolecular and one intramolecular) to afford enone
lactone 3 in 42% overall yield from methyl ester 23. Supported
by NMR spectroscopic and mass spectrometric data,
the structure of 3 (m.p. 173–175 1C, EtOAc/hexanes) was
unambiguously proven by X-ray crystallographic analysis
(see ORTEP,12 Fig. 3). The precise sequence of events in the
cascade leading from 25 to 3 has not been established as yet.
Worthy of note, however, is the failure of chloroester 2613 to
afford 3 (or any other g-lactone product) under the conditions
employed to convert 25 to 3, suggesting that C-alkylation may
precede O-alkylation in this process.14 Containing the entire
ring framework of maoecrystal V (1), core structure 3
(epimeric to 1 at C-5) may prove a viable precursor to this
natural product.
b
independent experiments Æ standard error of the mean. These cell
lines were provided by the National Cancer Institute (NCI), Division
of Cancer Treatment and Diagnosis (DCTD).
(ICES) and Ms Chia Sze Chen (ICES) for X-ray crystallo-
graphic analysis, and Mr Rong-Ji Sum for his assistance in
the biological studies. Financial support for this work was
provided by A*STAR, Singapore.
Notes and references
1 S.-H. Li, J. Wang, X.-M. Niu, Y.-H. Shen, H.-J. Zhang,
H.-D. Sun, M.-L. Li, Q.-E. Tian, Y. Lu, P. Cao and
Q.-T. Zheng, Org. Lett., 2004, 6, 4327–4330.
2 J. Gong, G. Lin, C.-C. Li and Z. Yang, Org. Lett., 2009, DOI:
10.1021/ol9014392.
3 P. J. Krawczuk, N. Schone and P. S. Baran, Org. Lett., DOI:
10.1021/o1901963v.
¨
4 F. Peng, M. Yu and S. J. Danishefsky, Tetrahedron Lett., 2009, 50,
6586–6587.
5 K. C. Nicolaou, S. A. Snyder, T. Montagnon and
G. Vassilikogiannakis, Angew. Chem., Int. Ed., 2002, 41, 1668–1698.
6 D. Tanaka and A. G. Myers, Org. Lett., 2004, 6, 433–436.
7 K. F. W. Hekking, F. L. Van Delft and F. P. J. T. Rutjes,
Tetrahedron, 2003, 59, 6751–6758.
8 CCDC 748550 contains the supplementary crystallographic
data for compound 12. This data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif or in the ESIw.
9 The minor isomer (C8-epi-12) (m.p. 182–183 1C, EtOAc/hexanes)
was also subjected to X-ray crystallographic analysis that
confirmed its structure. CCDC 742701 contains the supplementary
crystallographic data for compound C8-epi-12w.
Compounds 2, 3, and 15 were tested against a panel of
cancer cells, including breast (MCF-7), CNS (SF268), lung
(NCI-H460), and cervical (HeLa), using doxorubicin and
Taxols as standards, and the results are summarized in
Table 1. While compounds 2 and 15 exhibited no significant
cytotoxicity below 10 mM, the more advanced intermediate 3
showed moderate activity (3.6–6.7 mM) against these tumor
cell lines (see Table 1).
10 J. C. Morris, L. N. Mander and D. C. R. Hockless, Synthesis, 1998,
455–467.
11 CCDC 748551 contains the supplementary crystallographic data
for compound 15w.
12 CCDC 742693 contains the supplementary crystallographic data
for compound 3w.
13 Chloroester 26 was prepared from 25 by reaction with K2CO3
(1.0 equiv.) and ClCH2I (11 equiv., DMF, 23 1C, 8 h) in 82% yield.
14 Iodide catalysis in the presence of NaI, or the use of silver salts
were also attempted to effect the g-lactone formation.
15 A. Monks, D. Scudiero, P. Skehan, R. Shoemaker, K. Paull,
D. Vistica, C. Hose, J. Langley, P. Cronise, A. Vaigro-Wolff,
M. Gray-Goodrich, H. Campbell, J. Mayo and M. Boyd,
J. Natl. Cancer Inst., 1991, 83, 757–766.
The described chemistry is expected to facilitate the total
synthesis of maoecrystal V (1) and related compounds for
chemical and biological studies.
We thank Ms Doris Tan (ICES) for high resolution mass
spectrometric (HRMS) assistance, Dr Srinivasulu Aitipamula
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This journal is The Royal Society of Chemistry 2010
72 | Chem. Commun., 2010, 46, 70–72