Toward the total synthesis of maoecrystal V: An intramolecular Diels-Alder route to the maoecrystal V pentacyclic core with the appropriate relative stereochemistry

Article abstract of DOI:10.1016/j.tetlet.2010.11.029

A diastereoselective route to the maoecrystal V core compound (6) has been achieved. Key transformations include an intramolecular Diels-Alder cyclization and an exo-glycal epoxide rearrangement sequence.

Full text of DOI:10.1016/j.tetlet.2010.11.029

Tetrahedron Letters 52 (2011) 2104–2106
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Tetrahedron Letters
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Toward the total synthesis of maoecrystal V: an intramolecular Diels–Alder
route to the maoecrystal V pentacyclic core with the appropriate relative
stereochemistry
Feng Peng a, Samuel J. Danishefsky a,b,
⇑
a Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, NY 10027, United States
b Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 2 December 2010
A diastereoselective route to the maoecrystal V core compound (6) has been achieved. Key transforma-
tions include an intramolecular Diels–Alder cyclization and an exo-glycal epoxide rearrangement
sequence.
Ó 2010 Elsevier Ltd. All rights reserved.
The unique and complex structure of maoecrystal V (1, Fig. 1),
first isolated by Sun and co-workers in 2004, serves to render it a
challenging target for total synthesis. Adding to the level of interest
in maoecrystal, is its potent in vitro activity against HeLa cells
(IC50 = 20 ng/ml).1 Particularly noteworthy in this regard is the
apparent specificity of its cytotoxicity against gynecological cells.
Among the defenses which maoecrystal V mounts against those
who would undertake its total synthesis, are two contiguous qua-
ternary carbon stereocenters and a tertiary alcohol, embedded
within a rigid pentacyclic scaffold. Not withstanding the complex-
ity of the problem, a number of groups, including our own,2c have
initiated investigations directed toward the total synthesis of
maoecrystal V.2
In designing our program, we envisioned recourse to an intra-
molecular Diels–Alder (IMDA) cyclization, hoping thereby to gain
access to the bicyclo [2.2.2]-octane core substructure of maoecrys-
tal. In preliminary investigations, the highly functionalized precur-
sor, 2, was indeed found to undergo IMDA cyclization, albeit with
the undesired sense of facial selectivity (Fig. 1).2c We sought to cir-
cumvent this setback through the design of a modified sequence,
featuring IMDA of a less densely functionalized and symmetrical
precursor (cf. 4?5). In devising this new route, we were not insen-
sitive to the potential difficulties inherent in fashioning the requi-
site trans-fused furanoid ring junction3 (6, see ring B and its
junction to ring A). Fortunately, these challenges have now been
met, and a concise synthesis of the maoecrystal V core compound
(6) in the required stereochemical sense has now been accom-
plished for the first time. The manner in which we reached this
important milestone may well have broader implications in the de-
sign of total syntheses.
Our route to the IMDA precursor 4 commenced with a Birch-
type vinylogous acylation between substrates 7 and 8, thus provid-
ing intermediate 9, possessing one of the requisite quaternary
carbon centers (Scheme 1). The latter was subjected to global
DIBAL-H reduction, followed by selective MnO2-mediated reoxida-
tion of the resulting allylic alcohol, to afford 10. A two-step
sequence, involving esterification with acyl chloride 11,4 followed
by formation of the TBS enol ether, provided the target IMDA sub-
strate, 4. In the event, compound 4 readily underwent thermally-
induced IMDA cyclization in reasonable yield to generate the
desired cycloadduct. Upon exposure to TBAF, the TBS group was
hydrolyzed and the phenyl sulfone moiety suffered spontaneous
elimination to afford key intermediate 5 in 62% isolated yield.
We next turned to the stereoselective emplacement of the req-
uisite C10 tertiary alcohol. Initial attempts to accomplish direct
installation of the C10 alcohol through a cascade 1,4-reduction/oxi-
dation sequence resulted in a 1.5:1 diastereomeric mixture of com-
pounds 12a and 12b (Scheme 2).5 Alternatively, we were able to
gain access to 12a as a single diastereomer through a three-step se-
quence. As shown, compound 5 was first treated with basic H2O2 to
provide, with apparent stereospecificity, the desired epoxide 13.
The observed outcome is believed to arise from the presence of
the C16 ketone, which creates a stereoelectronic environment that
promotes epoxidation from the b-face, as shown.6 Upon exposure
to sequential epoxide opening and reduction of the resultant
iodohydrin, epoxide 13 was converted to 12a in good overall yield.
With compound 12a in hand, attentions were directed to installa-
tion of the tetrahydrofuran ring. Efforts to directly achieve etheri-
fication of 12a through activation of the A-ring 5-exo alkene moiety
were unsuccessful. However, a two-step solution was possible.
Thus, upon exposure to m-CPBA, 12a was found to undergo regio-
and stereoselective epoxidation to afford intermediate 14. Follow-
ing treatment with p-TsOH Á H2O, a cyclized product was obtained
in good yield, as a single diastereomer. However, X-ray analysis
⇑
Corresponding author.
E-mail address: s-danishefsky@ski.mskcc.org (S.J. Danishefsky).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.029

F. Peng, S. J. Danishefsky / Tetrahedron Letters 52 (2011) 2104–2106
• Original IMDA-based route to the maoecrystal V core.2c
2105
17
Me
16
O
O
2
O
15
O
13
9
5
O
3
CO2Me
O
H
MOMO
12
MOMO
Me
10
Me
CO2Me
H
11
14
IMDA
18
4
O
8
20
19 Me
OTBS
O
7
O
Me
3
Me
O
Me Me
Me
2
maoecrystal V (1)
undesired facial selectivity
• Modified IMDA-based strategy toward the maoecrystal V core (this work).
O
O
A
O
SO2Ph
E
D
B
O
IMDA
O
C
OTBS
O
O
O
5
O
4
maoecrystal V core (6)
Figure 1.
CO2Me
O
OH
CO2Me
a
b,c
+
Cl
7
9
8
10
O
O
O
O
O
O
SO2Ph
Cl
SO2Ph
11
f
d,e
OTBS
IMDA
O
5
4
O
Scheme 1. Synthesis of intermediate 5. Reagents and conditions: (a) LDA, À78 °C,
THF, 40%; (b) DIBAL-H, À78 °C, DCM, 2 h; (c) MnO2, rt, DCM, 40 min, two steps, 68%;
(d) 11, Py, 0 °C, DCM, 30 min, 86%; (e) TBSOTf, TEA, DCM, À78 °C, 12 h, 91%; (f)
toluene, sealed tube, 166 °C, 1 h, then TBAF, THF, 62%.
revealed the stereochemistry at C5 to be opposite that required for
maoecrystal V (see structure 15, where the A–B rings are cis-fused,
Scheme 2).
Our initial attempt to convert 15 to the requisite [6,5] trans-
fused system through epimerization7 of the C5 stereocenter is
outlined in Scheme 3. Compound 15 was converted to 16 in a
straightforward manner. However, exposure of 16 to the action
of sodium methoxide in methanol afforded a new product, which
was determined to be compound 17. Thus, under these conditions,
compound 16 had undergone an intramolecular aldol reaction,
while the non-natural cis-fusion of the A–B junction persisted.
In order to circumvent the undesired aldol pathway, we sought
to remove the C16 ketone functionality. As shown in Scheme 4,
dithioketal formation, followed by reduction with Raney-Ni and
subsequent oxidation with Dess–Martin reagent furnished the tar-
get monoketone 18 in 70% overall yield. This intermediate served
as a useful model compound in the context of the actual maoecrys-
tal V synthesis. With 18 in hand, we examined its susceptibility to
thermal, base-induced epimerization, hoping to generate at least
some traces of trans-fused epimer. Unfortunately, under standard
conditions (NaOMe, MeOH, 50 °C), no epimerization was observed.
Apparently, the b-face of the A-ring is too congested to allow for
the intermolecular delivery of a proton to the ring junction
position.
Scheme 2. Synthesis of Intermediate 15. Reagents and conditions: (a) PhSiH3,
Mn(dpm)3, O2, DCM/iPrOH, 0 °C, 80%; (b) H2O2, NaOH, MeOH, 0 °C, 95%; (c) MgI2,
DCM, 45 °C, 40 min; (d) Bu3SnH, AIBN, toluene, reflux, two steps, 50%; (e) m-CPBA,
DCM, rt, 18 h, 72%; (f) p-TsOH Á H2O, DCM, rt, 12 h, 90%.
O
O
O
HO
O
HO
c
a,b
5
O
O
aldol
O
15
16
O
17
O
O
O
O
O
Scheme 3. Attempted epimerization of C5. Reagents and conditions: (a) Pd/C, H2,
EtOH, rt, 12 h; (b) DMP, DCM, rt, 12 h, two steps, 75%; (c) NaOCH3, oxygen free,
MeOH, 40 °C, 36 h, 80%.
as a single diastereomer. A two-step dehydration sequence pro-
vided exo-glycal 20 in good yield.9 In the key transformation, exo-
glycal epoxide formation was accomplished through exposure to
DMDO.10 Happily, in situ treatment with BF3 Á OEt2 generated the
rearrangement product, target compound 6. The structure of the re-
duced product 21 was verified by X-ray analysis (Scheme 5).11
In summary, we have accomplished the stereoselective synthe-
sis of the maoecrystal V pentacyclic core structure (6). Key trans-
There occurred to us the possibility of intramolecular transfer of
a strategically placed hydrogen atom to allow for generation of the
required A–B trans-fusion.8 We proceeded as follows (Scheme 4).
Reduction of compound 18 with NaBH4 afforded intermediate 19

2106
F. Peng, S. J. Danishefsky / Tetrahedron Letters 52 (2011) 2104–2106
O
Parkin group (Columbia University) are thanked for their great help
H
O
HO
16
OH
with X-ray diffraction experiments (CHE-0619638 from the NSF).
Special thanks to Ms. Rebecca Wilson for valuable help in editing
the manuscript.
a-c
d
5
e,f
O
O
O
15
19
18
O
O
O
O
O
O
Supplementary data
H
g
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.029.
5
O
O
O
O
O
LA
+
20
6
O
O
O
O
O
O
References and notes
Scheme 4. Epimerization of 15 and synthesis of the maoecrystal
V core (6).
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O
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published in this area. (a) The first total synthesis of maoecrystal has been
accomplished by Yang and co-workers. See: Gong, J.; Lin, G.; Sun, W.; Li, C. -C.;
Yang, Z. J. Am. Chem. Soc. 2010, doi:10.1021/ja108907x; (b) A progress toward
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formations include an IMDA reaction (4?5) and apparently for the
first time, an exo-glycal epoxide rearrangement sequence to install
the rigid tetrahydrofuran moiety. Efforts are underway to apply
these teachings to the total synthesis of maoecrystal V.12
Acknowledgments
These findings are dedicated to a continuing friend and mentor,
Professor Harry H. Wasserman. This work was supported by the
NIH (HL25848 to S.J.D.). F.P. thanks Eli Lilly and Company for a
graduate fellowship. Aaron Sattler and Wesley Sattler from the