A synthesis of the carbocyclic core of maoecrystal v

Article abstract of DOI:10.1021/ol101025r

An approach toward the synthesis of the complex polycyclic diterpene maoecrystal V (1) is described. Construction of the advanced tetracyclic core structure (i.e., 19) was achieved in 13 steps from 3,3-dimethylcyclohexanone (6) by employing a stereoselect

Full text of DOI:10.1021/ol101025r

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3010-3013
A Synthesis of the Carbocyclic Core of
Maoecrystal V
Kiel E. Lazarski, Dennis X. Hu, Charlotte L. Stern, and Regan J. Thomson*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208
r-thomson@northwestern.edu
Received May 4, 2010
ABSTRACT
An approach toward the synthesis of the complex polycyclic diterpene maoecrystal V (1) is described. Construction of the advanced tetracyclic
core structure (i.e., 19) was achieved in 13 steps from 3,3-dimethylcyclohexanone (6) by employing a stereoselective Nazarov cyclization
followed by a Diels-Alder reaction to forge the two contiguous quaternary stereocenters.
In 2004, Sun and co-workers reported the structure of
maoecrystal V (1), a topologically complex polycyclic
diterpene that possesses a previously unknown ring system
(Figure 1).1 Apart from its fascinating structure, which
includes vincinal quaternary stereocenters, a rigid [2.2.2]
bicyclooctane core, and a highly strained tetrahydrofuran
ring, maoecrystal V (1) displayed potent and highly selective
activity against HeLa cells (IC50 ) 60 nM). Maoecrystal V
(1) was nontoxic toward several other cancer cell lines
(K562, 0.19 M; A549, 0.8 M).
Figure 1. The structure of maoecrystal V 1.
The underlying logic of our approach toward maoecrystal
V (1) is outlined retrosynthetically in Scheme 1A.3 A number
of retrosynthetic functional group interconversions (FGI’s)
within the natural product led back to pentacyclic compound
2. We chose to mask the six-membered lactone as a
cyclopentanone, reasoning that the lactone could be revealed
by a late-stage oxidative cleavage of the indicated carbon-
carbon bond within 2.
As a consequence of maoecrystal V’s challenging structure
and interesting biological profile, several research groups
have developed approaches toward 1,2 but to date a com-
pleted total synthesis has not been reported. We now describe
our ongoing efforts toward maoecrystal V (1), which have
resulted in a clear strategy for constructing the carbogenic
framework of the natural product.
While it was tempting to install the functionality required
to form the cyclic ether at an early stage in the synthesis,
we elected to pursue a strategy that called for late-stage
introduction to more rapidly simplify subtargets. Thus, we
disconnected the left-hand carbon-oxygen bond within 1,
(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) (a) Gong, J.; Lin, G.; Li, C. C.; Yang, Z. Org. Lett. 2009, 11, 4770–
4773. (b) Krawczuk, P. J.; Scho¨ne, N.; Baran, P. S. Org. Lett. 2009, 11,
4774–4776. (c) Peng, F.; Yu, M. L.; Danishefsky, S. J. Tetrahedron Lett.
2009, 50, 6586–6587. (d) Nicolaou, K. C.; Dong, L.; Deng, L. J.; Talbot,
A. C.; Chen, D. Y. K. Chem. Commun. 2010, 46, 70–72.
(3) Corey, E. J. Angew. Chem., Int. Ed. 1991, 30, 455–465.
10.1021/ol101025r  2010 American Chemical Society
Published on Web 06/03/2010

Scheme 1. Retrosynthetic Analysis of Maoecrystal V (1) and Construction of the Core Rings
leading to tetracyclic compound 2. Our plan to form this
carbon-oxygen bond in the synthetic direction involves
remote functionalization induced by the free alcohol within
2.4 Further retrosynthetic functional group manipulations led
us to [2.2.2] bicyclic structure 3, which we further simplified
to diene 4 by application of a ketene equivalent Diels-Alder
cycloaddition transform.5 The stereoselectivity of the forward
cycloaddition would be controlled by the protected alcohol
within 4, which clearly blocks dienophile approach from the
back face. This Diels-Alder reaction is an alternative
construction to that employed by the groups of Yang,
Danishefsky, Baran, and Nicolaou.2 Recognition of the
cyclopentenone embedded within 4 keyed application of a
Nazarov cyclization transform,6 generating the simplified
precursor 5. In a forward sense, the conversion of enone 5
into the tetracyclic compound 3 would proceed through
maximum use of sequential carbon-skeleton bond-forming
reactions and fashion the congested vicinal quaternary
stereocenters required for the natural product efficiently and
directly.
reb amide in 79% yield and as a single stereoisomer.
Formation of the desired dienone 10 proceeded smoothly in
93% yield following the addition of vinyl anion 9 (generated
from the corresponding bromide) to the Weinreb amide.9
Upon exposure to stoichiometric Fe(III) chloride,10 dienone
10 was transformed into the desired spirocyclic ketone 4 in
good yield and as a single stereoisomer. Reduction of the
carbonyl group proved necessary to facilitate the subsequent
Diels-Alder reaction with nitroethylene11 and reduce byprod-
ucts due to oxidation of the cyclohexadiene ring. Thus, the
[2.2.2] bicyclic ring system (i.e., 11) was produced (44%
over two steps) as a single regioisomer, with only the endo
adduct detected by NMR spectroscopic analysis. Confirma-
tion of the structure of 11 was obtained by single X-ray
structure analysis, which revealed that, as planned, the OTBS
substituent controlled the facial selectivity of both the
Nazarov and Diels-Alder cyclizations.
Attempts to conduct a Nef reaction12 on 11 were met with
minimal success at this juncture, although treatment with
KOH resulted in complete epimerization of the nitro
group;an outcome that facilitated stereoselective installation
of the requisite alcohol (i.e., 13), yet led to some unexpected
chemistry (see below). The desired substrate (i.e., 13) for
our planned remote functionalization to form the ether ring
was prepared by formation of ketone 12 from alcohol 11
(86% yield over three steps), followed by a completely
stereoselective Rubottom oxidation of the thermodynamically
Our synthesis (Scheme 1B) commenced with the regiose-
lective Rubottom oxidation of 3,3-dimethylcyclohexanone
(6),7 followed by conversion of the intermediate secondary
alcohol to its corresponding tert-butyldimethylsilyl (TBS)
ether (7, 70% yield over two steps). A Horner-Wadsworth-
Emmons reaction, using phosphonate 8,8 afforded the Wein-
(4) For a review, see: Heusler, K.; Kalvoda, J. Angew. Chem., Int. Ed.
1964, 3, 525–596.
(8) Nuzillard, J.-M.; Boumendjel, A.; Massiot, G. Tetrahedron Lett.
1989, 30, 3779–3780.
(5) For a review on ketene equivalents for Diels-Alder cycloadditions,
see: Aggarwal, V. K.; Ali, A.; Coogan, M. P. Tetrahedron 1999, 55, 293–
312.
(9) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
(10) Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc. 1982, 104, 2642–
2645.
(6) For recent reviews of the Nazarov cyclization, see: (a) Pellissier, H.
Tetrahedron 2005, 61, 6479–6517. (b) Frontier, A. J.; Collison, C.
Tetrahedron 2005, 61, 7577–7606.
(11) For a relevant example of a closely related Diels-Alder reaction
with nitroethylene, see: Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985,
107, 5574–5576.
(7) (a) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 15, 4319–4322. (b) Hassner, A.; Reuss, R. H.; Pinnick, H. W.
J. Org. Chem. 1975, 40, 3427–3429.
(12) For a review on the Nef reaction see: Ballini, R.; Petrini, M.
Tetrahedron 2004, 60, 1017–1047.
Org. Lett., Vol. 12, No. 13, 2010
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most stable enol silane.13 The structure of 13 was confirmed
by X-ray structural analysis. We next tested a number of
conditions to bring about the desired ring-to-ring function-
alization. Under a variety of conditions,14 such as those
reported by Sua´rez and co-workers for similar transforma-
tions (PhI(OAc)2/I2, hν),14a alcohol 13 was converted to a
compound whose structure initially proved problematic to
assign. Ultimately, X-ray analysis established the product
to be the [2.2.5] bicyclic ring system 14. While this structure
was unexpected, its formation may be rationalized by
formation of the desired oxygen centered radical, which in
turn may undergo a Grob fragmentation due to favorable
alignment of the broken σC-C with σ*C-N of the leaving
group.15
Scheme 3. Generation of the Tetracyclic Core 19 (P ) TBS)
At this juncture we elected to install the lactone before
attempting to form the bridging cyclic ether. Initially, we
attempted to conduct a Baeyer-Villiger reaction16 directly
on ketone 13 (Scheme 2), reasoning that the congested nature
Scheme 2. Baeyer-Villiger Reaction of 13 (P ) TBS)
88% yield.18 Attempted oxidative cleavage of 17 led to
complex reaction mixtures, while reduction of the enone to
generate the saturated ketone proved capricious. Curiously,
under a variety of conditions examined, the major product
was cyclopropane 18, which could be reproducably formed
in 71% yield upon exposure to Pd/C and H2.
The formation of cyclopropane species 18 was completely
unexpected and at this juncture we do not have firm evidence
for a mechanistic rationale of the transformation. We
speculate, however, that the close proximity and alignment
of σ*C-N of the nitro group allows for an intramolecular
alkylation of a presumed palladium enolate intermediate.19
We observed similar reactivity when Pd(OAc)2 was used as
the catalyst, but Pd/C provided the greatest yield. Oxidative
cleavage of 18 proceeded smoothly upon treatment with
methanolic periodic acid, to afford the intermediate enal-
acid, which was reduced with NaBH4. Lactonization occurred
spontaneously under these conditions, providing 19 in 75%
yield from ketone 18 and thus established the key carbocyclic
elements of maoecrystal V (1).
In summary, we have devised a route to access the
challenging core structure (i.e., lactone 19) of maoecrystal
V in 13 steps from 3,3-dimethylcyclohexanone. Systematic
application of powerful carbon-carbon bond forming reac-
tions (i.e., Nazarov and Diels-Alder cyclizations) enabled
rapid assembly of the central quaternary carbon stereocenters
and the complex carbon framework. Continued work toward
maoecrystal V (1) and preliminary biological studies are
underway in our laboratories.
of the structure might favor a conformation of the Criegee
intermediate that would lead to selective migration of the
desired bond.17
Exposure of 13 to trifluoroperoxyacetic acid, however,
afforded lactone 15 in 52% yield. X-ray structure analysis
revealed insertion had occurred on the wrong side of the
carbonyl group, and that under the acidic reaction conditions
the TBS ether had been cleaved thus inducing ketalization.
Attempts to generate the enol silane of ketone 13, as a
prelude to oxidative cleavage, were unsuccessful due to steric
congestion. Likewise, attempted formation of the less
substituted enol silane derived from ketone 12 (see Scheme
1B) led only to formation of the more substituted alkene,
presumably as a consequence of severe steric hindrance. To
avoid these issues, we elected to conduct a Rubottom
oxidation on enone 16 (Scheme 3), which was derived in
two steps from the initial Diels-Alder cycloadduct 11 (see
Scheme 1B). Enol silane formation could be achieved upon
the addition of TMSI and HMDS,13 and thus, following the
addition of m-CPBA, R-hydroxy ketone 17 was accessed in
(13) Miller, R. D.; McKean, D. R. Synthesis 1979, 730–732.
(14) (a) Concepcio´n, J. I.; Francisco, C. G.; Herna´ndez, R.; Salazar,
J. A.; Sua´rez, E. Tetrahedron Lett. 1984, 25, 1953–1956. (b) Dorta, R. L.;
Francisco, C. G.; Freire, R.; Sua´rez, E. Tetrahedron Lett. 1988, 29, 5429–
5432. (c) Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Mlari, B. L.;
Wenkert, E. J. Org. Chem. 1986, 51, 1505–1509.
(16) Baeyer, A.; Villiger, V. Chem. Ber. 1899, 32, 3625–3622.
(17) For an experimental study of the reactive conformations involved
in Baeyer-Villiger reactions, see: Goodman, R. M.; Kishi, Y. J. Am. Chem.
Soc. 1998, 120, 9392–9393.
(18) Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1978, 43, 1599–
1602.
(15) For a recent review of the Grob fragmentation, see: Prantz, K.;
Mulzer, J. Chem. ReV. DOI: 10.1021/cr900386h. Published Online: February
17, 2010. See also: Ho, T.-L. Heterolytic Fragmentation of Organic
Molecules; Wiley: New York, 1993.
(19) For a paper regarding the structure of palladium enolates, see: Veya,
P.; Floriani, C.; Chiesi-Villa, A.; Rizzoli, C. Organometallics 1993, 12,
4899–4907.
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Org. Lett., Vol. 12, No. 13, 2010

Acknowledgment. We gratefully acknowledge support
from Northwestern University, the NIH (training grant
T32AG000260), and the American Cancer Society by way
of an institutional grant (ACS-IRG 93-037-15) to the Robert
H. Lurie Comprehensive Cancer Center at NU. D.X.H. was
the recipient of a NU Undergraduate Research Grant. We
thank Amy A. Sarjeant (NU) for help with X-ray analysis.
Supporting Information Available: Experimental pro-
cedures, spectral data, and crystallographic data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101025R
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