Claisen ring expansion approach toward the CDEF ring system of lancifodilactone G

Article abstract of DOI:10.3987/COM-08-S(D)2

The fused CDEF ring system of lancifodilactone G is assembled via a Nozaki-Hiyama-Kishi cross-coupling reaction and a Petasis-Claisen ring expansion sequence as the key strategic steps.

Full text of DOI:10.3987/COM-08-S(D)2

HETEROCYCLES, Vol. 79, 2009
299
HETEROCYCLES, Vol. 79, 2009, pp. 299 - 302. © The Japan Institute of Heterocyclic Chemistry
Received, 25th June, 2008, Accepted, 28th July, 2008, Published online, 31st July, 2008.
DOI: 10.3987/COM-08-S(D)2
CLAISEN RING EXPANSION APPROACH TOWARD THE CDEF RING
SYSTEM OF LANCIFODILACTONE G‡
Leo A. Paquette* and Kwong Wah Lai
Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210,
USA; e-mail: paquette.1@osu.edu
Abstract – The fused CDEF ring system of lancifodilactone G is assembled via a
Nozaki-Hiyama-Kishi cross-coupling reaction and a Petasis-Claisen ring
expansion sequence as the key strategic steps.
Lancifodilactone G (1, Figure 1) is an architecturally novel, highly oxygenated nortriterpenoid that was
isolated from the medicinal plant Schisandra lancifolia by Sun and co-workers in 2005 (Figure 1).1 Its
structure and relative stereochemistry were determined on the basis of extensive one- and two-
dimensional NMR spectroscopy and mass spectral data, coupled with single-crystal X-ray analysis.2 Its
absolute configuration was recently deduced on the basis of the existing biogenetic connectivity to its
congener micrandilactone B.3 Lancifodilactone G (1) exerts minimal cytotoxicity against C8166 cells
(CC50 > 200 µ/mL) while demonstrating anti-HIV activity with an EC50 = 95.47 ± 14.19 µ/mL and a
selectivity index in the range of 1.82–2.46. For these reasons, we have become engaged in its total
synthesis.4 Herein, we define a route to the fused CDEF ring system of lancifodilactone G (1) based on a
combination of the Nozaki-Hiyama-Kishi (NHK) cross-coupling reaction5 and Petasis-Claisen ring
expansion technology.6
O
O
Me
H
Me
H
F
D
A O
H
O
E
G
Me
B
O
C
H
O
O
OH
HO
O
H
Me
lancifodilactone G (1)
Figure 1. Chemical structure of lancifodilactone G (1).
—————
‡This paper is dedicated to the memory of Dr. John Daly.

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HETEROCYCLES, Vol. 79, 2009
The synthesis commenced with the union of vinyl triflate (2)7 and aldehyde (3)4b as depicted in Scheme 1.
Initial attempts using THF as solvent failed to produce the NHK cross-coupling product at any
appreciable rate due mostly to the poor solubility of the catalysts. To circumvent this issue, recourse was
made to DMF (dried over activated 4Å MS). In this medium, the targeted allylic alcohol (4) was formed
alongside an inseparable mixture of the in situ lactonization products (5). To facilitate structural
characterization, the unpurified reaction mixture was treated directly with excess NaH to generate lactone
(5) as a 1:1 mixture of diastereoisomers with no evidence of epimerization at C14. The next task called
for methylenation of the six-membered lactone (5). To this end, successful reaction of 5 with the Petasis-
Tebbe reagent required vigorous conditions to bring about conversion to the unstable enol ether (6).
Scheme 1
Me
TBSO
Me
OTBS
Me
OHC
H
OTf
Me
OTBS
CrCl2, NiCl2
H
14
H 11
H
+
Me
OP
O
OTBS
DMF, rt, 30 h
MeO2C
OMe
OH
Me
PO
2
(2 equiv)
3 (1 equiv)
(4 : 5 ~ 1 : 1)
4
NaH
THF, rt, 30 min
P = t-BuPh2Si
(47%, 2 steps)
Me
Me
TBSO
Me
TBSO
Me
H
H
Cp2TiMe2
OTBS
OTBS
14
H
H 11
H
O
H
Me
Me
PhMe, 110 °C, 1.5 h
(68%)
OP
OP
O
O
(dr = 1 : 1)
5
6
With the enol ether (6) in hand, its Claisen ring expansion was pursued.6 Preliminary studies of this
process revealed that exposure of 6 to TRIBAL in PhMe at 80 °C gave rise to a complicated mixture of
unwanted products.8 This failure is likely attributable to the acid-sensitivity of the substrate. As a result,
the feasibility of the thermally-induced Claisen rearrangement was examined.6 Thermolysis of 6 in dry p-
cymene solution contained in potassium hydroxide-coated sealed tubes at 140 °C for 6 h resulted in
smooth conversion to the eight-membered ring enone (10) in 48% isolated yield, presumably through the
dual operation of chair-chair and boat-boat transition states 9a and 9b (Scheme 2). The identical
stereochemical outcome of these mechanistic alternatives concisely rationalizes the unique formation of
diastereomer (10) as the product of this 3,3-sigmatropic conversion. The absolute configuration of 10 was
13
deduced with the aid of C NMR, DEPT 135, COSY, NOESY and HMQC experiments.9 In addition, a
minor product tentatively identified as 8 results from competitive 1,3-hydrogen migration within 6 to
form the endo-olefin intermediate (7) and Claisen rearrangement of the latter.

HETEROCYCLES, Vol. 79, 2009
301
Scheme 2
Me
Me
TBSO
Me
Me
TBSO
Me
TBSO
Me
H
H
H
R
OTBS
Me
R
*
sealed tube
H
H
H
11
Me
O
OP
*
O
O
Me
p-cymene (0.03 M)
140 °C, 6 h
8
6 (P = t-BuPh2Si)
8 (~10%)
* undefined
7
not observed
stereochemistry
OTBS
R =
Me
H
OP
OTBS
Me
Me
H
OTBS
8
Me
H
O
O
H
11
Me
(S)
OTBS
(R)
H
8
H
H
Me
H
+
OTB
H
Me
8
H
O
H
S
H
Me
TBDPSO
R
R
9b boat-boat
10 (48%)
9a chair-chair
In summary, we have successfully assembled the fused CDEF framework of lancifodilactone G (1). The
synthetic strategy highlights the utility of the Nozaki-Hiyama-Kishi cross-coupling reaction and Petasis-
Claisen ring expansion technology. Application of these methods to the total synthesis of lancifodilactone
G (1) is in progress.
ACKNOWLEDGMENTS
We thank The Ohio State University for partial financial support.
REFERENCES AND NOTES
1. For the isolation and biological evaluation of lancifodilactone G, see: W.-L. Xiao, H.-J. Zhu, Y.-H.
Shen, R.-T. Li, S.-H. Li, H.-D. Sun, Y.-T. Zheng, R.-R. Wang, Y. Lu, C. Wang, and Q. T. Zheng, Org.
Lett., 2005, 7, 2145.
2. The original structural assignment for lancifodilactone G has been revised, see: W.-L. Xiao, H.-J. Zhu,
Y.-H. Shen, R.-T. Li, S.-H. Li, H.-D. Sun, Y.-T. Zheng, R.-R. Wang, Y. Lu, C. Wang, and Q. T.
Zheng, Org. Lett., 2006, 8, 801.
3. For the absolute configuration of micrandilactone B, see: S.-X. Huang, R.-T. Li, J.-P. Liu, Y. Lu, Y.
Chang, C. Lei, W.-L. Xiao, L.-B. Yang, Q.-T. Zheng, and H.-D. Sun, Org. Lett., 2007, 9, 2079.
4. (a) L. A. Paquette and K. W. Lai, Org. Lett., 2008, 10, 2111. (b) K. W. Lai and L. A. Paquette, Org.
Lett., 2008, 10, 2115.
5. Review of the NHK reaction, see: A. Fürstner, Chem. Rev., 1999, 99, 991.

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HETEROCYCLES, Vol. 79, 2009
6. For previous applications of the Claisen ring expansion for construction of 8-membered ring systems
from our laboratory, see: (a) L. A. Paquette, In Stereocontrolled Organic Synthesis; ed. by B. M. Trost;
Blackwell Scientific Publications: Oxford, England, 1994; pp 313-336. (b) W. A. Kinney, M. J.
Coghlan, and L. A. Paquette, J. Am. Chem. Soc., 1985, 107, 7352. (c) L. A. Paquette and H.-J. Kang,
J. Am. Chem. Soc., 1991, 113, 2610. (d) L. A. Paquette and T. J. Sweeney, Tetrahedron, 1990, 46,
4487. (e) D. Friedrich and L. A. Paquette, J. Org. Chem., 1991, 56, 3831. (f) L. A. Paquette, D.
Friedrich, and R. D. Rogers, J. Org. Chem., 1991, 56, 3841. (g) L. A. Paquette, C. M. G. Philippo,
and N. H. Vo, Can. J. Chem., 1992, 70, 1356. (h) P. Bernardelli, O. M. Moradei, D. Friedrich, J. Yang,
F. Gallou, B. P. Dyck, R. W. Doskotch, T. Lange, and L. A. Paquette, J. Am. Chem. Soc., 2001, 123,
9021.
7. W. D. Wulff, G. A. Peterson, W. E. Bauta, K.-S. Chan, K. L. Faron, S. R. Gilbertson, R. W. Kaesler,
D. C. Yang, and C. K. Murray, J. Org. Chem., 1986, 51, 277.
8. For Tribal-catalyzed Claisen ring expansions, see: (a) L. A. Paquette, L.-Q. Sun, D. Friedrich, and P.
B. Savage, J. Am. Chem. Soc., 1997, 119, 8438. (b) M. Sollogoub, J.-M. Mallet, and P. Sinaÿ, Angew.
Chem. Int. Ed., 2000, 39, 360. (c) Y.-D. Zhang, W.-W. Ren, Y. Lan, Q. Xiao, K.Wang, J. Xu, J.-J.
Chen, and Z. Yang, Org. Lett., 2008, 10, 665.
1
9. For 10: IR (neat) 2924, 1710, 1462, 1256, 1086 cm–1; H NMR (500 MHz, CDCl3) δ 7.74–7.70 (m,
4H), 7.45–7.34 (m, 6H), 5.37 (t, J = 8.5 Hz, 1H), 4.20–4.14 (m, 1H), 3.31 (d, J = 5.0 Hz, 1H), 3.07
(dd, J = 9.5, 5.0 Hz, 1H), 2.95 (dd, J = 9.5, 6.5 Hz, 1H), 2.94–2.86 (m, 1H), 2.79 (d, J = 7.0 Hz, 1H),
2.57–2.33 (m, 4H), 2.10–2.00 (m, 4H), 1.85–1.75 (m, 1H), 1.75–1.61 (m, 3H), 1.53–1.42 (m, 1H),
1.40–1.20 (m, 6H), 1.16 (d, J = 7.0 Hz, 3H), 1.07 (s, 9H), 0.96 (s, 9H), 0.96–0.85 (m, 1H), 0.84 (s,
9H), 0.43 (d, J = 6.5 Hz, 3H), 0.09 (s, 3H), 0.08 (s, 3H), –0.05 (s, 3H), –0.06 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 211.55, 145.23, 136.13, 136.01, 134.91, 134.16, 129.49, 129.30, 127.47, 127.33,
124.28, 90.08, 72.49, 68.46, 62.51, 53.12, 52.65, 49.26, 45.68, 39.16, 38.59, 36.21, 34.91, 33.76,
31.89, 30.40, 30.16, 29.70, 28.62, 27.68, 27.30, 26.06, 25.97, 19.74, 18.29, 18.06, 16.79, –4.03, –4.11,
–5.39.