Synthetic studies toward Maoecrystal V

Article abstract of DOI:10.1016/j.tetlet.2009.09.050

The investigation of an intramolecular Diels-Alder reaction, en route to a projected total synthesis of maoecrystal V, is described.

Full text of DOI:10.1016/j.tetlet.2009.09.050

Tetrahedron Letters 50 (2009) 6586–6587
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Tetrahedron Letters
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Synthetic studies toward Maoecrystal V
Feng Peng a, Maolin Yu a, Samuel J. Danishefsky a,b,
*
a Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
b Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The investigation of an intramolecular Diels–Alder reaction, en route to a projected total synthesis of
maoecrystal V, is described.
Received 1 September 2009
Accepted 10 September 2009
Available online 13 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Our laboratory is devoted to the total synthesis and biological
evaluation of structurally challenging natural products possessing
promising biological activity. In this context, we took note of a re-
cent report by Sun and coworkers of a novel natural product,
termed maoecrystal V (1), which, due to its potent inhibitory activ-
ity against HeLa cells (IC50 = 20 ng/mL), is believed to hold promise
as a lead anticancer agent.1 As shown in Figure 1, maoecrystal V is
a densely functionalized diterpene, possessing an unprecedented
ent-kaurane skeleton, two contiguous quaternary carbon stereo-
centers, and a tertiary alcohol, embedded within a complex ring
system. The structural complexity of 1, coupled with its biological
activity, prompted us to undertake a program directed toward its
total synthesis. We report herein the development of some inter-
esting chemistry en route to a projected total synthesis of maoe-
crystal V (1).
ment, to provide alcohol 2 in 88% yield. It is appreciated that this
bond reorganization establishes the requisite quaternary carbon
center in a highly stereoregulated fashion.
With advanced intermediate 2 in hand, we were now approach-
ing the possibility of examining the feasibility of the key IMDA cycli-
zation. To our surprise, when 2 was subjected to Birch reduction
conditions, the exomethylene group was also reduced, giving rise
to 13 as a 1:3 a/b mixture of methyl epimers (Scheme 3). It seems
not unlikely that electron transfer from Birch reduction intermedi-
ates serves to facilitate reduction of the exomethylene group.
Although the reduction of the undesired exomethylene group
rendered this particular synthetic route toward maoecrystal V
Me
Using the logic of ‘pattern recognition’2 to guide our synthetic
design, we discerned a bicyclo [2.2.2]-octane core in maoecrystal
V (red, 1, Scheme 1) and hypothesized that this motif could be syn-
thesized from an intramolecular Diels–Alder (IMDA) cyclization
(cf. 3?4).3 It was further supposed that following construction of
4, the tetrahydrofuran moiety would be installed (4?5). A series
of functional group transformations providing access to maoecrys-
tal V from 5 seemed to be feasible.
16
O
15
13
O
14
9
2
6
7
10
3
5
4
Me
O
O
20
O
Me
maoecrystal V(1)
Figure 1. Maoecrystal V (1).
As outlined in Scheme 2, the synthesis commenced with a pal-
ladium-catalyzed ketone
tion with TMSCHN2, to provide
a
-arylation of 6,4 followed by etherifica-
PG
O
8
(90% overall yield). This
OH
MOMO
intermediate was subjected to the Stork-Danheiser protocol,5 with
Bu3SnCH2OMOM,6 to afford compound 9 in 75% yield. Following
replacement of the MOM ether with a pivaloate ester, intermediate
10 was in hand. Luche reduction of 10 provided an allylic alcohol,
which was protected as its MOM ether (11). Hydrolysis of 11
served to liberate the hydroxymethyl intermediate, which was
OTBS
IMDA
Me
Me
OMe
PGO
O
O
Me Me
PGO
2
3
O
Me
O
O
O
then alkylated with
a-iodomethyl tributylstannane to furnish the
PGO
Wittig-Still precursor (12).7 Through careful control of the reaction
Me
O
temperature, we were able to achieve the desired [2,3] rearrange-
O
Me
O
O
HO
O
Me
O
O
O
Me
maoecrystal V (1)
Me
O
Me
4
5
* Corresponding author.
E-mail address: s-danishefsky@ski.mskcc.org (S.J. Danishefsky).
Scheme 1. A proposed route to maoecrystal V.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.050

F. Peng et al. / Tetrahedron Letters 50 (2009) 6586–6587
6587
O
OH
OH
MOMO
MeO
MOMO
OMe
c,d
R2
b
a
OMe
+
a,b
2
O
OMe
O
Me
Me
R1
O
Me Me
Br
Me Me
COCl
Me Me
Me Me
MOMO
7
6
8
14α : 14β = 1: 3
13α : 13β = 1: 3
O
O
f,g
c
OMe
OMe
O
MOMO
CO2Me
OTBS
OR
OPiv
IMDA
Me Me
d,e
Me Me
11
MOMO
9
(R = MOM)
from 15c
OTBS
R2
Me
Me Me
10 (R = Piv)
16
Me
Me
R1
O
e
OH
H
MOMO
MOMO
Me
MOMO
O
j
h,i
OTBS
R2
R1
OMe
diene
isomerization
OMe
15a: R1=R2= H
15b: R1= H; R2= Br
15c: R1=H; R2=CO2Me
Me
O
SnBu3
from 15a, 15b
Me
Me Me
Me Me
12
Me
17
2
O
isomers
separable
O
Scheme 2. Synthesis of intermediate 2. Reagents and conditions: (a) Pd(OAc)2, 2-
di-t-butylphosphino-20-methylbiphenyl, K3PO4,
THF, 80 °C, 12 h, 91%; (b)
,
O
O
O
TMSCHN2, Hünig’s base, CH3CN/MeOH = 9:1, 6 h, 100%; (c) Bu3SnCH2OMOM, BuLi,
THF, ꢀ78 °C to ꢀ40 °C, 30 min, 0.5% HCl work-up, 75%; (d) HCl/MeOH, 50 °C, 75%;
(e) PivCl, Py, DCM, 12 h, 96%; (f) NaBH4, CeCl3, MeOH, 0 °C, 2 h, 93%; (g) MOMCl,
Hünig’s base, DCM, 12 h, 95%; (h) DIBAL-H, ꢀ78 °C, DCM, 30 min, 95%; (i) KH, 18-
crown-6, ICH2SnBu3, 0 °C, THF, 6 h, 90%; (j) n-BuLi, ꢀ78 °C to ꢀ20 °C, THF, 6 h, 88%.
O
MOMO
Me
MOMO
CO2Me
CO2Me
H
f
H
H
O
H
16
H
Me
Me Me
O
H
Me
18
Scheme 3. Intramolecular Diels–Alder reaction of 15c. Reagents and conditions: (a)
Li, NH3(l), t-BuOH/THF, ꢀ78 °C, 20 min, ꢀ33 °C, 40 min; (b) 1 N HCl, 0 °C, THF/MeOH
(10:1), 8 h, 2 steps, 78%; (c) acid chloride, Py, DCM, 0 °C. 15a: 70%, 15b: 75%, 15c:
72%; (d) TBSOTf, TEA, DCM, 0 °C, 15 h, 81%; (e) 180 °C, sealed tube, toluene, 12 h; (f)
TBAF, 0 °C, THF, 2 steps, 48%.
MeO2C
MeO2C
TBSO
TBSO
O
O
PO
Me
PO
Me
O
O
Acknowledgments
Me
Me
Me
A (favored)
Me
B (disfavored)
Support was provided by the NIH (HL25848 and CA103823 to
S.J.D.). F.P. thanks Eli Lilly for a graduate fellowship. We thank Pro-
fessor Shengping Zheng (Hunter College) and Dr. Fay Ng for helpful
discussions. Special thanks to Ms. Rebecca Wilson for editorial con-
sultation. We acknowledge Ms. Dana Ryan for assistance with the
preparation of the manuscript.
Figure 2. Transition structures for the Diels–Alder reaction.
problematic, we nevertheless felt that intermediate 13 could serve
as a valuable model substrate, with which to probe the viability of
the key proposed IMDA reaction. Accordingly, acidic hydrolysis of
13 furnished 14, which was then subjected to esterification with
a range of acid chlorides, to provide a series of IMDA precursors,
15a–c (Scheme 3). When compounds 15a and 15b were subjected
to thermal reaction conditions, we observed no cycloadduct, but
only isomerized diene (17). However, it was found that 15c readily
underwent cyclization, under thermal conditions, to furnish the
Diels–Alder cycloadduct 16. Subsequent fluoro-assisted deprotec-
tion afforded 18 in 48% overall yield from 15c. The assignment of
the stereochemistry of the Diels–Alder adduct 18 rests on NMR
analysis. Thus, a key NOESY experiment revealed that the IMDA
cycloaddition had, in fact, proceeded with the opposite sense of fa-
cial selectivity than that required for the plan. To account for the
observed facial selectivity, we postulate the predominance of tran-
sition structure A (Fig. 2), wherein the dienophile approaches the
diene from the back face of the rotamer shown in 15c. The prefer-
ence for this rotamer in a Curtin-Hammet sense8 is not clear. This
IMDA outcome surely complicates its application to a total synthe-
sis of 1. Nonetheless, programs to reach 1 from the general logic
adumbrated above can still be imagined and are being evaluated9.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.050.
References and notes
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