A Synthesis of the carbon skeleton of maoecrystal v □

Article abstract of DOI:10.1021/ol901963v

An enantioselective synthesis of the maoecrystal V (1) carbon skeleton Is described. The key transformations Include arylatlon of a 1,3dicarbonyl compound with a triarylbismuth(V) dichloride species, oxidative dearomatlzatlon of a phenol, and a subsequent

Full text of DOI:10.1021/ol901963v

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4774-4776
A Synthesis of the Carbon Skeleton of
Maoecrystal V
Paul J. Krawczuk, Niklas Scho¨ne, and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037
pbaran@scripps.edu
Received August 24, 2009
ABSTRACT
An enantioselective synthesis of the maoecrystal V (1) carbon skeleton is described. The key transformations include arylation of a 1,3-
dicarbonyl compound with a triarylbismuth(V) dichloride species, oxidative dearomatization of a phenol, and a subsequent intramolecular
Diels-Alder reaction.
Maoecrystal V (1, Figure 1) was isolated and characterized
in 2004 by Sun and co-workers from the Chinese medicinal
herb Isodon eriocalyx.1 It possesses an unusual architecture
rendering it the most modified naturally occurring ent-
kauranoid isolated to date.2 The structure was confirmed by
X-ray crystallographic analysis to contain five highly con-
gested rings and seven stereocenters, two of which are
adjacent all carbon quaternary centers located in its interior.
One of these all carbon quaternary centers is also the
bridgehead carbon of the [2.2.2]bicyclooctanone moiety. This
paper reports an early approach to 1 pursued in our laboratory
from November 2007 to May 2008.3
Figure 1. Representations of maoecrystal V.
intramolecular Diels-Alder4 disconnection of the bicyclic
ring system would generate a cyclohexadiene/acrylate con-
jugate 3. It was initially envisioned that silyl enol ether 3
could be used as the diene component in the Diels-Alder
reaction. In order to construct this substrate via the corre-
sponding enone 4, an oxidative coupling of enolates or
related substrates was proposed (i.e., 5 + 6).5
Our initial retrosynthesis, shown in Scheme 1A, began by
disconnecting the tetrahydrofuran ring and simplifying the
enone of the A ring to an olefin leading to 2. Next, an
(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.
2004, 6, 4327–4330.
(2) Sun, H.-D.; Huang, S.-X.; Han, Q.-B. Nat. Prod. Rep. 2006, 23,
673–698.
(4) (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogian-
nakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698. (b) Roush, W. R.
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford,
1991; Vol 5, pp 513-550.
(5) (a) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006,
45, 7083–7086. (b) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem.
Soc. 2008, 130, 11546–11560.
(3) During this period, one of the corresponding authors of the preceding
paper was employed as a postdoctoral associate (C.-C. Li) in this laboratory:
Gong, J.; Lin, G.; Li, C.-C.; Yang, Z. Org. Lett. 2009, DOI: 10.1021/
ol9014392. This work was reported in an NIH proposal (received 8/11/
2008 and reviewed on 10/9/2008 by the BCMB-B study section) and a
final report to the DFG (submitted 7/17/2009).
10.1021/ol901963v CCC: $40.75
Published on Web 10/01/2009
 2009 American Chemical Society

Scheme 1.
Maoecrystal V: (A) Retrosynthetic Analysis, (B) Model Study, and (C) Synthesis of the Complete Carbon Skeletona
a Reagents and conditions: (a) CAN, NaHCO3, MeOH, 0 °C, 46%; (b) Li(t-BuO)3AlH, THF, -78 °C, 53%; (c) acryloyl chloride, Et3N, DMAP, DCM,
0 °C, 36%; (d) TBSOTf, Et3N, DCM, 63%; (e) Pd/C, O2, PhMe, 110 °C, 99%; (f) Pb(OAc)4, AcOH, 59%; (g) 165 °C, o-DCB, ca. 60%; (h) Ar3BiCl2(13),
DBU, PhMe, 67%; (i) Li(t-BuO)3AlH, THF, -78 °C, 72%; (j) acryloyl chloride, DIEPA, DMAP, DCM, -78 °C, 69%; (k) TFA, DCM, 0 °C, 65%; (l)
Pb(OAc)4, AcOH, 81%, dr ) 3:7; (m) 165 °C, o-DCB, BHT 79% for 20, 69% for 21; (n) BF3·OEt2, DCM, 82%; (o) H2, Pd/C, EtOAc, 97% for 23, 99%
for 24; (p) SmI2, MeOH, THF, 0 °C, 76%, dr ) 17:3. CAN ) cerium ammonium nitrate, DMAP ) 4-dimethylaminopyridine, DCM ) dichloromethane,
TBSOTf ) tert-butydimethylsilyl trifluoromethylsulfonate, o-DCB ) o-dichlorobenzene, DIEPA ) diisopropylethylamine, DBU ) 1,8-diazobicylco[5.4.0]undec-
7-ene, TFA ) trifluoroacetic acid, BHT ) 2,6-di-tert-butyl-p-cresol.
Initial studies (Scheme 1B) with a model system using
ꢀ-keto aldehyde 7 and enol ether 8 led to the generation of
the C-10 quaternary center by treatment with cerium am-
monium nitrate.6 Following reduction of the formyl group
and esterification, silylation of the ketone under a variety of
conditions led only to the undesired regioisomeric dienol
ether 9 (presumably due to the sterically hindered R-proton
at C-9). To circumvent this problem, the diene was further
dehydrogenated (Pd/C, O2) and the resulting aromatic moiety
was oxidized using a Wessely oxidation7 (Pb(OAc)4) to
furnish cyclohexadienone 10 in 59% yield. A Diels-Alder
reaction delivered polycycle 11 in ca. 60% yield (3 mg scale)
upon heating to 165 °C.8 X-ray crystallography confirmed
the structure as that corresponding to the undesired regioi-
someric outcome (based on the position of the geminal
dimethyl group relative to the bicyclic portion of the
molecule). Encouraged by the outcome of the intramolecular
(6) Nair, V.; Mathew, J. J. Chem. Soc., Perkin Trans. 1 1995, 187–
188.
(7) (a) Wessely, F.; Sinwel, F. Monatsh. Chem. 1950, 81, 1055–1070.
(b) Barnes-Seeman, D.; Corey, E. J. Org. Lett. 1999, 1, 1503–1504. (c)
Nicolaou, K. C.; Simonsen, K. B.; Vassilikogiannakis, G.; Baran, P. S.;
Vidali, V. P.; Pitsinos, E. N.; Couladouros, E. A. Angew. Chem., Int. Ed.
1999, 38, 3555–3559. (d) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem.
ReV. 2004, 104, 1383–1429.
(8) For recent examples using o-quinols as dienophiles, see: (a) Nicolaou,
K. C.; Toh, Q.-Y.; Chen, D. Y.-K. J. Am. Chem. Soc. 2008, 130, 11292–
11293. (b) Gao, S.-Y.; Chittimalla, S. K.; Chuang, G. J.; Liao, C.-C. J.
Org. Chem. 2009, 74, 1632–1639. (c) Dory, Y. L.; Roy, A.-L.; Soucy, P.;
Deslongchamps, P. Org. Lett. 2009, 11, 1197–1200. (d) Snyder, S. A.;
Kontes, F. J. Am. Chem. Soc. 2009, 131, 1745–1752.
Org. Lett., Vol. 11, No. 21, 2009
4775

Diels-Alder, a revised route was devised to access the
correct carbon framework found in 1 (Scheme 1C).
methanol to give the R-methyl ketone as a mixture of
diastereomers in 76% yield (dr ) 17:3 with 25 as major).12
An X-ray crystal structure of 26 (C-16-epi-25) was obtained
from the minor diasteromer as shown in Scheme 1C,
establishing that the major isomer possesses the proper
orientation of the C-16 methyl group in 1.
Certain elements of the sequential Barton arylation/
Wessely oxidation/Diels-Alder Strategy (i.e., 12f14, 17f18/
19, 18/19f25) reported herein may well find use in an
eventual synthesis of 1.13
The sequence begins with ꢀ-keto aldehyde 12, derived in
three steps from a readily available symmetrical 1,3-
diketone.9 Barton arylation10 of 12 with 139 led to 14 in
67% yield as a 7:3 readily separable mixture of diastereo-
mers. In a fashion similar to that of the model study,
reduction (to afford 15) and acylation led to 16. Removal of
the MOM group with TFA and Wessely oxidation of the
intermediate hemiketal 17 yielded an inconsequential mixture
of diastereomeric acetates 18/19 in 53% yield over two steps.
Dienes 18 and 19 were heated in a microwave reactor in
o-DCB to 165 °C for 1.5 h in the presence of BHT to give
the expected endo-cycloadducts in 79% and 69% yields. The
stereochemistry of the cycloadducts was verified by X-ray
crystallographic analysis.11 Once the structures had been
determined, both adducts were elaborated further toward 1
by hydrogenation of the bicyclic olefin (H2, Pd/C). Next,
the acetate group was excised using SmI2 to give an
intermediate samarium enolate that was protonated by
Acknowledgment. We thank Dr. D.-H. Huang (TSRI) and
Dr. L. Pasternack (TSRI) for NMR spectroscopic assistance
and Dr. G. Siuzdak (TSRI) for assistance with mass
spectroscopy. Dr. Arnold Rheingold (UCSD) and Dr. An-
tonio DiPasquale (UCSD) are acknowledged for X-ray
crystallographic assistance. Financial support for this work
was provided by Bristol-Myers Squibb, the NIH (CA134785),
and the German Research Foundation (DFG) (postdoctoral
fellowship to N.S.).
Supporting Information Available: Detailed experimen-
tal procedures, copies of all spectral data, and full charac-
terization. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) See the Supporting Information for details.
(10) (a) Barton, D. H. R.; Lester, D. J.; Motherwell, W. B.; Papoula,
M. T. B. J. Chem. Soc., Chem. Commun. 1980, 246–247. (b) Barton,
D. H. R.; Blazejewski, J.-C.; Charpiot, B.; Finet, J.-P.; Motherwell, W. B.;
Papoula, M. T. B.; Stanforth, S. P. J. Chem. Soc., Perkin Trans. 1 1985,
2667–2675. (c) Barton, D. H. R.; Finet, J.-P.; Giannotti, C.; Halley, F.
J. Chem. Soc., Perkin Trans. 1 1987, 241–249. (d) Combes, S.; Finet, J.-P.
Tetrahedron 1999, 55, 3377–3386. (e) Fedorov, A. Y.; Finet, J.-P. J. Chem.
Soc., Perkin Trans. 1 2000, 3775–3778. (f) Finet, J.-P.; Fedorov, A. Y. J.
Organomet. Chem. 2006, 691, 2386–2393.
OL901963V
(13) While this paper was in review, two other groups reported progress
toward 1: (a) Peng, F. Yu, M. Danishefsky, S. J. Tetrahedron Lett., 2009,
DOI: 10.1016/j.tetlet.2009.09.050. (b) Nicolaou, K. C.; Dong, L.; Deng,
L.; Talbot, A. C.; Chen, D. Y.-K. Chem. Commun. 2009, in press.
(11) For adduct 21, a crystal was grown directly, whereas adduct 20
was crystallized after removal of the TBS group as alcohol 22.
(12) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135–1138.
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