O. O. Fadeyi et al. / Tetrahedron Letters 50 (2009) 3084–3087
3087
oxide. The ortho-formylation step for 16 proved to be problematic.
The ortho-formylation protocol employed for the synthesis of 11,
Specialized Chemistry Center for Accelerated Probe Development
(1U54MH084659-01).
2
utilizing SnCl and dichloro(methoxy)methane, surprisingly affor-
ded meta-formylation exclusively. Ultimately, hexamethylenetet-
ramine in refluxing TFA provided the desired ortho-formylation
References and notes
1
0
1. Brophy, G.; Mohandas, J.; Slaytor, M.; Sternhell, S.; Watson, T.; Wilson, L.
product 17 in 53% yield. Then, an E-selective Wittig reaction pro-
duced styrenyl phenol 18 in 93% yield, or 35% for the three steps.
Tetrahderon Lett. 1969, 10, 5159–5162.
2
.
Sung, S.; Kim, Y. C. J. Nat. Prod. 2000, 63, 1019–1021.
3. Lindsley, C. W.; Chan, L. K.; Goess, B. C.; Joseph, R.; Shair, M. D. J. Am. Chem. Soc.
000, 122, 422–423.
4
Employing our catalytic Cu(II)/(ꢀ)-sparteine oxidant system pol-
2
emannone C (6) was delivered as a single diastereomer in 90% yield
and once again, NOE measurements confirmed the relative stereo-
chemistry. As with the natural product, our synthetic material was
racemic. Moreover, spectral data for our synthetic polemannone C
were in complete accord with those reported for the natural
4
5
.
.
Daniels, R. N.; Fadeyi, O. O.; Lindsley, C. W. Org. Lett. 2008, 10, 4097–4100.
Jaupovic, J.; Eid, F. Phytochemistry 1987, 26, 2427–2429.
6. Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J. C. J. Am. Chem. Soc. 1971,
3, 6696–6698.
9
7
8
.
.
Matsumoto, M.; Kuroda, K. Tetrahedron Lett. 1981, 22, 4437–4440.
Iyer, M. R.; Trivedi, G. K. Bull. Chem. Soc. Jpn 1992, 65, 1662–1664.
5
,12
product.
9. Baxendale, I. R.; Lee, A. I.; Ley, S. V. Synlett 2001, 9, 1482–1484.
10. Suzuki, Y.; Takahashi, H. Chem. Pharm. Bull. 1983, 31, 1751–1753.
In summary, we have extended the substrate scope of b,b-phe-
nolic coupling/tandem inverse-electron demand Diels-Alder reac-
tion cascade of styrenyl phenols to include ortho-substituted
ethers to afford novel, unnatural benzoxanthenones such as 9 by
11. General experimental for b,b-phenolic coupling: A solution of copper catalyst
(
0.1 equiv), 4 Å molecular sieves and sparteine (0.1 equiv) in MeOH (0.15 M)
was stirred for 15–20 min until no solid copper salt was visible and then cooled
to ꢀ20 °C followed by the addition of phenol (1.0 equiv). The reaction mixture
was stirred at ꢀ20 °C for 24 h with exposure to air. The reaction mixture was
2
application of our novel, catalytic CuCl /(ꢀ)-sparteine oxidation
quenched with saturated NH
4
Cl solution and extracted with CH
2
Cl
2
(3ꢁ). The
system. More importantly, this new catalytic system enabled the
first total synthesis of the highly oxygenated benzoxanthenone li-
gans polemannones B and C from commercial starting materials in
overall yields of 15% and 31.5%, respectively. Extensive NOE work
confirmed the relative stereochemistry of 9 and polemannones B
and C. Biological evaluation of these compounds against large
panels of discrete receptors (GPCRs, ion channels, transporters,
and kinases) is underway, and results will be reported in due
course.
combined organic extracts were washed with 0.5 N HCl, water, and the dried
over MgSO . Filtration and concentration afforded the crude product, which
was purified by flash chromatography (4:1 to 1:1 Hex/EtOAc). Polemannone B:
Yellow solid, R ) d (ppm):
= 0.61 (1:1 Hex/EtOAc); 1H NMR (600.1 MHz, CDCl
.05 (dd, J = 4.9, 1.5 Hz, 1H), 6.51 (s, 1H), 5.89 (d, J = 1.3 Hz, 1H), 5.85 (d,
4
f
3
7
J = 1.3 Hz, 1H), 5.66 (s, 1H), 5.64 (s,1H), 3.96 (s, 1H), 3.93 (s, 1H), 3.26 (dd,
J = 7.5, 2.3 Hz, 1H), 3.17 (dt, J = 7.5, 2.3 Hz, 1H), 2.48 (q, J = 7.2 Hz, 1H), 2.21 (m,
1
H), 1.12 (d, J = 7.2 Hz, 3H), 0.70 (d, J = 7.6 Hz, 3H); 13C NMR (150.9 MHz,
3
CDCl ) d (ppm): 183.2, 151.4, 143.7, 143.0, 137.9, 135.7, 133.6, 131.5, 126.4,
126.4, 116.8, 101.3, 101.1, 100.6, 98.7, 60.2, 59.7, 36.3, 35.6, 35.1, 34.0, 21.4,
+
2
1.1; HRMS (TOF, ES+) C22
H
22
O
8
[M+H] calcd 415.1393, found 415.1383.
= 0.58 (1:1 Hex/EtOAc);
) d (ppm): 6.95 (m, 1H), 6.57 (s, 1H), 4.18 (s, 3H),
3.81 (s, 6H), 3.77 (s, 3H), 3.74 (s, 3H), 3.39 (s, 3H), 3.20 (dd, J = 7.0, 1.8 Hz, 1H),
.07 (m, 1H), 2.53 (q, J = 7.0 Hz, 1H), 2.15 (m, 1H), 1.09 (d, J = 7.2 Hz, 3H), 0.62
d, J = 7.8 Hz, 3H); 13C NMR (150.9 MHz, CDCl
) d (ppm): 183.2, 161.2, 147.3,
41.9, 141.2, 139.0, 138.5, 127.0, 119.1, 106.1, 97.0, 61.2, 60.9, 60.4, 56.2, 53.1,
1
2. Experimental data for poelmanonne C: Yellow solid, R
f
1
H NMR (600.1 MHz, CDCl
3
Acknowledgments
3
(
1
3
3
The authors warmly thank Department of Pharmacology for
support of this research. Vanderbilt is a member of the production
phase of the MLCSN, termed the MLPCN, and houses the Vanderbilt
[M+H]+ calcd
6.3, 35.6, 35.1, 33.7, 21.3, 21.0; HRMS (TOF, ES+) C24
30 8
H O
447.2019, found 447.2019.