An approach to the core skeleton of lancifodilactone F

Article abstract of DOI:10.1021/ol800111j

Two cycloaddition reactions were utilized for the construction of the 5,6,7-tricyclic skeleton of lancifodilactone F and buxapentalactone. A [2+2] ketene cycloaddition reaction was first used to set their adjacent all-carbon quaternary centers at the 5,6-ring junction. An arene-olefin meta-photocycloaddition reaction was then used to install the 6- and 7-membered rings concurrently.

Full text of DOI:10.1021/ol800111j

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1223-1226
An Approach to the Core Skeleton of
Lancifodilactone F
Qiaoling Wang and Chuo Chen*
Department of Biochemistry, The UniVersity of Texas Southwestern Medical Center,
5323 Harry Hines BouleVard, Dallas, Texas 75390-9038
Chuo.Chen@UTSouthwestern.edu
Received January 16, 2008
ABSTRACT
Two cycloaddition reactions were utilized for the construction of the 5,6,7-tricyclic skeleton of lancifodilactone F and buxapentalactone. A
[2 2] ketene cycloaddition reaction was first used to set their adjacent all-carbon quaternary centers at the 5,6-ring junction. An arene olefin
meta-photocycloaddition reaction was then used to install the 6- and 7-membered rings concurrently.
+
−
Recently, a series of structurally intriguing triterpenoids was
isolated from the Chinese herb Schisandra.1-6 These natural
products bear an usual 5,6,7- or 5,8,7-tricyclic skeleton.
Among them, lancifodilactone F (1)1c particularly attracted
our attention. Unlike other 5,6,7-tricyclic terpenoids7 isolated
from the same sources,1a,2b,5,6 for example, micrandilactone
C (2), it bears two all-carbon quaternary centers at the 5,6-
ring junction (Figure 1). Its structure was proposed based
on NMR experiments and X-ray analysis. It is interesting to
note the structural resemblance of 1 and buxapentalactone
(3),8a which was reported 16 years ago but received little
attention. In contrast to 2, 3, and their biogenic precursor
(2) Isolation of micrandilactones: (a) Li, R.-T.; Zhao, Q.-S.; Li, S.-H.;
Han, Q.-B.; Sun, H.-D.; Lu, Y.; Zhang, L.-L.; Zheng, Q.-T. Org. Lett. 2003,
5, 1023-1026; correction: Org. Lett. 2006, 8, 801. (b) Li, R.-T.; Han, Q.-
B.; Zheng, Y.-T.; Wang, R.-R.; Yang, L.-M.; Lu, Y.; Sang, S.-Q.; Zheng,
Q.-T.; Zhao, Q.-S.; Sun, H.-D. Chem. Commun. 2005, 2936. (c) Li, R.-T.;
Xiao, W.-L.; Shen, Y.-H.; Zhao, Q.-S.; Sun, H.-D. Chem.-Eur. J. 2005,
11, 2989-2996; correction: Chem.-Eur. J. 2005, 11, 6763-6765. Synthetic
studies: (d) Tang, Y.; Zhang, Y.; Dai, M.; Luo, T.; Deng, L.; Chen, J.;
Yang, Z. Org. Lett. 2005, 7, 885-888. (e) Zhang, Y.-D.; Tang, Y.-F.; Luo,
T.-P.; Shen, J.; Chen, J.-H.; Yang, Z. Org. Lett. 2006, 8, 107-110.
(3) Isolation of hendridilactones: Li, R.; Shen, Y.; Xiang, W.; Sun, H.-
D. Eur. J. Org. Chem. 2004, 807-811.
(4) Isolation of sphenadilactones: Xiao, W.-L.; Pu, J.-X.; Chang, Y.;
Li, X.-L.; Huang, S.-X.; Yang, L.-M.; Li, L.-M.; Lu, Y.; Zheng, Y.-T.; Li,
R.-T.; Zheng, Q.-T.; Sun, H.-D. Org. Lett. 2006, 8, 1475-1478; correc-
tion: Org. Lett. 2006, 8, 4669.
(5) Isolation of rubriflordilactones: Xiao, W.-L.; Yang, L.-M.; Gong,
N.-B.; Wu, L.; Wang, R.-R.; Pu, J.-X.; Li, X.-L.; Huang, S.-X.; Zheng,
Y.-T.; Li, R.-T.; Lu, Y.; Zheng, Q.-T.; Sun, H.-D. Org. Lett. 2006, 8, 991-
994.
(1) Isolation of lancifodilactones: (a) Li, R.-T.; Li, S.-H.; Zhao, Q.-S.;
Lin, Z.-W.; Sun, H.-D.; Lu, Y.; Wang, C.; Zheng, Q.-T. Tetrahedron Lett.
2003, 44, 3531-3534. (b) Li, R.-T.; Xiang, W.; Li, S.-H.; Lin, Z.-W.; Sun,
H.-D. J. Nat. Prod. 2004, 67, 94-97. (c) Xiao, W.-L.; Li, R.-T.; Li, S.-H.;
Li, X.-L.; Sun, H.-D.; Zheng, Y.-T.; Wang, R.-R.; Lu, Y.; Wang, C.; Zheng,
Q.-T. Org. Lett. 2005, 7, 1263-1266; correction: Org. Lett. 2006, 8, 801.
(d) Xiao, W.-L.; Zhu, H.-J.; Shen, Y.-H.; Li, R.-T.; Li, S.-H.; Sun, H.-D.;
Zheng, Y.-T.; Wang, R.-R.; Lu, Y.; Wang, C.; Zheng, Q.-T. Org. Lett. 2005,
7, 2145-2148; correction: Org. Lett. 2006, 8, 801. (e) Xiao, W.-L.; Tian,
R.-R.; Pu, J.-X.; Li, X.; Wu, L.; Lu, Y.; Li, S.-H.; Li, R.-T.; Zheng, Y.-T.;
Zheng, Q.-T.; Sun, H.-D. J. Nat. Prod. 2006, 69, 277-279. (f) Xiao, W.-
L.; Huang, S.-X.; Zhang, L.; Tian, R.-R.; Wu, L.; Li, X.-L.; Pu, J.-X.; Zheng,
Y.-T.; Lu, Y.; Li, R.-T.; Zheng, Q.-T.; Sun, H.-D. J. Nat. Prod. 2006, 69,
650-653. Synthetic studies: (g) Fischer, D.; Theodorakis, E. A. Eur. J.
Org. Chem. 2007, 4193-4196. (h) Krishnan, K. S.; Smitha, M.; Suresh,
E.; Radhakrishnan, K. V. Tetrahedron 2006, 62, 12345-12350.
(6) Isolation of wuweizidilactones: Huang, S.-X.; Yang, L.-B.; Xiao,
W.-L.; Lei, C.; Liu, J.-P.; Lu, Y.; Weng, Z.-Y.; Li, L.-M.; Li, R.-T.; Yu,
J.-L.; Zheng, Q.-T.; Sun, H.-D. Chem.-Eur. J. 2007, 13, 4816-4822.
10.1021/ol800111j CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/28/2008

Figure 2. Synthetic strategy for the core Skeleton of 1 and 3.
Figure 1. Structures of triterpenoids 1-4.
reveal the lancifodilactone skeleton 10. We have explored
the arene-alkene meta-photocycloaddition reaction11,12
for this [5+2] strategy owing to its high functional group
compatibility and the accessibility of synthetic precur-
sors.
The arene-olefin meta-photocycloaddition reaction was
discovered more than four decades ago.11 Its synthetic utility
has been clearly demonstrated by Wender and co-workers.13
Although the 4-atom-tethered intramolecular arene-olefin
meta-photocycloaddition was shown to be problematic,14
Wender and DeLong noted that restriction of the tether
conformations improved the efficiency.15 Recently, Russell
and co-workers also found that a fused cyclohexane ring
helped constrain the 4-carbon tether in favorable conforma-
tions and the photocycloaddition adducts were obtained in
good yields despite as a 1:1 mixture of endo/exo isomers.16
Interestingly, we did not observe similar beneficial effects
cycloartenol (4), the C-8 stereogenic center of 1 was
proposed to be (S)-configured based on NMR analyses.
However, this assignment is not supported by the crystal-
lographic data.9
With the uncertainty of the structure of 1 in mind, we
developed a flexible approach that allows not only a facile
construction of its 5,6,7-tricyclic skeleton with the two
adjacent quaternary centers but also access to either config-
uration at the C-8 and C-9 positions (Figure 2). We
envisioned that the 6- and 7-membered rings could be formed
concurrently with an intramolecular [5+2] cycloaddition
reaction.10 In addition, we expected that it would be easier
to introduce the C-13 and C-14 adjacent quaternary centers
during an early stage of the synthesis. We anticipated that
photolysis of 7 would afford the cycloaddition adducts 8 and
9. Selective cleavage of their a and b linkages would then
(7) Cyathane diterpenoids also bear a 5,6,7-tricylic core skeleton. For
examples of their synthesis, see: (a) Snider, B. B.; Vo, N. H.; O’Neil, S.
V.; Foxman, B. M. J. Am. Chem. Soc. 1996, 118, 7644-7645. (b) Trost,
B. M.; Dong, L.; Schroeder, G. M. J. Am. Chem. Soc. 2005, 127, 2844-
2845. (c) Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127,
5334-5335. (d) Waters, S. P.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J.
Am. Chem. Soc. 2005, 127, 13514-13515. (e) Ward, D. E.; Shen, J. Org.
Lett. 2007, 9, 2843-2846. (f) Watanabe, H.; Takano, M.; Umino, A.; Ito,
T.; Ishikawa, H.; Nakada, M. Org. Lett. 2007, 9, 359-362. (g) Piers, E.;
Gilbert, M.; Cook, K. L. Org. Lett. 2000, 2, 1407-1410. (h) Wender, P.
A.; Bi, F. C.; Brodney, M. A.; Gosselin, F. Org. Lett. 2001, 3, 2105-
2108. (i) Magnus, P.; Shen, L. Tetrahedron 1999, 55, 3553-3560. (j)
Dahnke, K. R.; Paquette, L. A. J. Org. Chem. 1994, 59, 885-899.
(8) There has been no report of synthetic studies on buxapentalactone.
For isolation of selected Buxus triterpenoids, see: (a) Atta-ur-Rahman,
Habib, N.; Asif, S. E.; Safdar, A.; Zahida, I.; Choudhary, M. I.; Clardy, J.
Tetrahedron 1992, 48, 3577-3584. (b) Be´ne´chie, M.; Khuong-Huu, F.
Tetrahedron 1976, 32, 701-707. (c) Guilhem, J. Tetrahedron Lett. 1975,
16, 2937-2938.
(11) (a) Wilzbach, K. E.; Kaplan, L. J. Am. Chem. Soc. 1966, 88, 2066-
2067. (b) Bryce-Smith, D.; Gilbert, A.; Orger, B. H. Chem. Commun. 1966,
512-514.
(12) Reviews: (a) Wender, P. A.; Siggel, L.; Nuss, J. M., In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.;
Pergamon Press: Oxford, 1991; Vol. 5, pp 645-673. (b) Keukeleire, D.
D.; He, S. L. Chem. ReV. 1993, 93, 359-380. (c) Cornelisse, J. Chem.
ReV. 1993, 93, 615-669. (d) Hoffmann, N. Synthesis 2004, 481-495. (e)
Mattay, J. Angew. Chem., Int. Ed. 2007, 46, 663-665.
(13) (a) Wender, P. A.; Howbert, J. J. J. Am. Chem. Soc. 1981, 103,
688-690. (b) Wender, P. A.; Dreyer, G. B. Tetrahedron 1981, 37, 4445-
4450. (c) Wender, P. A.; Howbert, J. J. Tetrahedron Lett. 1982, 23, 3983-
3986.
(14) (a) Gilbert, A. Pure Appl. Chem. 1980, 52, 2669-2682. (b) Gilbert,
A.; Taylor, G. N. J. Chem. Soc., Chem. Commun. 1979, 229-230. (c)
Gilbert, A.; Taylor, G. N. J. Chem. Soc., Perkin Trans. 1 1980, 1761-
1768. (d) Ellis-Davies, G. C. R.; Gilbert, A.; Heath, P.; Lane, J. C.;
Warrington, J. V.; Westover, D. L. J. Chem. Soc., Perkin Trans. 2 1984,
1833-1841. There is one exception reported by De Keukeleire and He.
Irradiation of a 3-(benzyloxymethyl)cyclopentene derivative at 254 nm in
cyclohexane-ethyl acetate (5:1) gave the meta-photocycloaddition product
in 42% yield: (e) De Keukeleire, D.; He, S.-L. J. Chem. Soc., Chem.
Commun. 1992, 419-420.
(9) The crystallographic data of 1 published by Sun and co-workers
(CCDC-254747) supports the (9R)-configuration instead. However, the
anisotropic displacement parameters for most atoms are not acceptable,
including 15 of them being non-positive definite. The published data do
not contain suitable information for reinterpretation.
(10) Reviews: (a) Battiste, M. A.; Pelphrey, P. M.; Wright, D. Chem.-
Eur. J. 2006, 12, 3438-3447. (b) Wender, P. A.; Gamber, G. G.; Williams,
T. J. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.;
Wiley-VCH: Weinheim, Germany, 2005; pp 263-299. (c) Wender, P. A.;
Love, J. A. AdV. Cycloaddit. 1999, 5, 1-45. (d) Mascaren˜as, J. L. AdV.
Cycloaddit. 1999, 6, 1-54.
(15) Wender and DeLong have found that photolysis of an oxygen-
bridged arene-olefin system with Hanovia medium-pressure mercury lamp
through Vycor glass in cyclohexane for 2 h provided the desired meta-
photocycloaddition products in 68% yield at 60% conversion based on
recovered starting material. Prolong irradiation led to product decomposition.
DeLong, M. Ph.D. Thesis, Stanford University, 1992.
1224
Org. Lett., Vol. 10, No. 6, 2008

in the systems that bear a fused cyclopentane ring and the
C-13,14 adjacent quaternary centers. Photolysis of a series
of derivatives of 7 resulted only in decomposition under
various conditions.
We examined the photolysis of 19 and 20 under various
conditions. We found that the arene-olefin meta-photo-
cycloaddition reaction proceeded smoothly by irradiating in
dilute cyclohexane at 254 nm through a quartz filter. For
example, photolysis of 19 gave exclusively the exo cyclo-
addition products 21 and 22 in 89% isolated yield (Scheme
2). As chromatographic separation of 21 and 22 was difficult,
To overcome the difficulties encountered in the photolysis
of 7, we introduced a trimethylsiloxyl group to the C-12
position of the tether and a phenol group to the C-1 position
of the arene (19 and 20). We anticipated that the C-12 siloxyl
group and cyclopentane ring would act cooperatively to
constrain the tether conformations. By connecting to the
adjacent C-28 methyl group, the C-1 phenol group would
control both the regioselectivity and endo/exo selectivity of
the photocycloaddition. The C-1 phenol group would further
assist the cleavage of the a and b linkages selectively after
photolysis.
Scheme 2. Establishing the 5,6,7-Tricyclic Skeleton of 1 and 3
We utilized an intramolecular [2+2] ketene cycloaddition
reaction to install the C-13,14 adjacent all-carbon quaternary
centers of 19 and 20 and secure their relative stereochemistry.
The synthesis of 19 and 20 started with addition of the
dianion derived from 11 to ketone 12 to provide 13 after
dehydration (Scheme 1). Alkylation of 13 with chloroacetic
Scheme 1. Establishing the Stereochemistry of the C-13,14
Adjecant All-Carbon Quaternary Centers
and 21 degraded upon exposure to silica gel, the photolysis
products were usually not purified and were used directly
for the subsequent reactions.
The b linkage of 21 and 22 could be cleaved easily by
acid hydrolysis after epoxidation to afford allylic alcohols
23 and 24. Attempts to cleave the b linkage of 21 and 22
under reductive or Lewis/Brønsted acidic conditions were
less efficient and resulted in a complex mixture of products,
presumably due to the overlap of the C-10-C-5 bond with
the olefin π orbital in 21. Upon treating with catalytic
amounts of palladium on carbon under 1 atm atmosphere of
hydrogen, alcohol 24 underwent allylic isomerization to give
ketone 25. The structures of 23 and 25 were confirmed by
X-ray analysis.
Likewise, 20 could be converted to 27, 28, and 29. In fact,
separation of the two diastereomers of 18 was not necessary.
Silylation, photolysis, and cyclopropane ring cleavage could
all be carried out with comparable overall yields using the
mixtures of isomers. It is interesting to note that the
configuration of the siloxyl group does not affect the
stereochemical outcomes of these photocycloaddition reac-
tions. We were surprised to find that, in contrast to the
acid afforded the ketene precursor 14. Treating 14 with oxalyl
chloride followed by triethylamine initiated the [2+2] ketene
cycloaddition reaction to give 15 as the only diastereomer.
A Haller-Bauer reaction17 then opened the cyclobutane ring
of 15. The resulting acid 16 was converted to aldehyde 17.
Allylation of 17 gave a 1:1 diastereomeric mixture of
alcohols 18, which were separated and silylated to give 19
and 20.
(16) Boyd, J. W.; Greaves, N.; Kettle, J.; Russell, A. T.; Steed, J. W.
Angew. Chem., Int. Ed. 2005, 44, 944-946.
(17) Review: Mehta, G.; Venkateswaranb, R. V. Tetrahedron 2000, 56,
1399-1422.
Org. Lett., Vol. 10, No. 6, 2008
1225

chairlike conformation in Russell’s system,16 the olefin tether
of 19 and 20 adopted the boat-like conformations (26) in
the photocycloaddition reaction to give the exo products
exclusively.
The siloxyl group of 19 and 20 is crucial for the successful
implementation of this arene-olefin meta-photocycloaddition
reaction. Photolysis of 18 and 30 under various conditions
resulted in complex mixtures of products. Moving the siloxyl
group from the homoallylic to allylic position also led only
to decomposition. Conformational analysis indicates that the
siloxyl group helps lock the olefin tether in productive
conformations (Figure 3). In particular, the olefin group of
presence of cerium(III) chloride to give tertiary alcohol 31
(Scheme 3). Oxidation of 31 with excess IBX18 afforded
Scheme 3. Manipulating the C-9 Stereogenic Center
enone 32. The C-9 stereocenter is now removed and the
C-1-C-8 bond is activated for cleavage.
In summary, we have utilized two cycloaddition reactions
to construct the 5,6,7-tricyclic skeleton of lancifodilactone
F (1) and buxapentalactone (3). First, a [2+2] ketene
cycloaddition reaction was used to set the C-13,14 adjacent
all-carbon quaternary centers. Next, an arene-olefin meta-
photocycloaddition reaction was used to construct the 6- and
7-membered rings concurrently. Although the relative stereo-
chemistry of 1 is still open to discussion, our strategy allows
flexible installation of both C-8 and C-9 stereocenters in
either configuration. Implementation of this strategy to a
more elaborated system for the synthesis of 1 and 3 is
underway.
Acknowledgment. Financial supports are provided by
Welch Foundation (I-1596), and UT Southwestern. C.C. is
a Southwestern Medical Foundation Scholar in Biomedical
Research. We thank Dr. Radha Akella (UT Southwestern)
for X-ray analysis of 23 (CCDC 659037), 25 (CCDC
659035), 29 (CCDC 659036), and 31a (CCDC 659038) and
Prof. Mitchell DeLong (Duke University) for providing ref
15.
Figure 3. Conformational analysis of 18-20 and 30 (equilibrium
geometry by MMFF/PM3).
18a resides away from arene, and the free hydroxyl group
is buried between the olefin and arene. Silylation helps orient
the olefin group toward the arene. The photocycloaddition
is now the favorable reaction pathway, and decomposition
is suppressed.
After successfully constructing the 5,6,7-tricyclic skeleton
of 1 and 3, we turned our attention to adjusting the C-9
configuration. We intended to use the enone chemistry to
manipulate the C-8 and C-9 configurations. Ketones 25 and
29 reacted smoothly with isopropenyl Grignard in the
Supporting Information Available: Detailed experi-
mental procedures, tabulated spectroscopic data, and crystal-
lographic data for 23, 25, 29, and 31a. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800111J
(18) (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2000, 122, 7596-7597. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.;
Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245-2258.
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