P. A. Clarke, J. Winn / Tetrahedron Letters 52 (2011) 1469–1472
1471
O
S
S
CHO
O
OH
PMBO
i
i
O
N
H
O
N
O
PMBO
OH
Bn
OH
17
Bn
O
21
O
20
22
O
O
O
O
14
18
S
O
N
OTBS
O
OTBS
ii
iii
Scheme 6. Reagents and conditions: (i) HBF4ꢁOEt2, Et2O or C6H6, 25 °C, 61%.
O
H
PMBO
PMBO
O
Bn
23
24
H
O
OTBS
O
OTBS
i
ii
O
iv, v
vi, vii
t-BuO2C
HO
t-BuO
OH
HO
OH
O
CO2Me
OH
CO2Me
O
HO
18
19
20
25
26α/26β 1:3
Scheme 7. Reagents and conditions: (i) NaOMe/MeOH, 71%; (ii) SeO2, 1,4-dioxane,
reflux, 76%.
Scheme 3. Reagents and conditions: (i) TiCl4, (ꢀ)-sparteine, CH2Cl2, 0 °C to -78 °C,
60%; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, 25 °C, 99%; (iii) DIBAL-H, CH2Cl2, ꢀ78 °C, 82%;
(iv) SnCl2, t-BuO2CCHN2, CH2Cl2, 25 °C, 67%; (v) DDQ, CH2Cl2/H2O (19:1), 25 °C, 66%;
(vi) NBS, Ph3P, CH2Cl2, ꢀ30 °C; (vii) NaH, THF, ꢀ78 °C to 25 °C, 63% (over two steps).
nucleophiles, such as anisole, cyanide and CO met with failure and
returned only starting material 14.
Lactone 18 was opened with NaOMe to give methyl ester 19 in
71% yield and then functionalized further by treatment with SeO2,
which effected an allylic oxidation and generated aldehyde 20 in
76% yield. The installation of an aldehyde unit at this position pro-
vides a handle to attach other ring systems to the austrodorane
core, such as those found in natural products 3–6 (Scheme 7).
In summary we have constructed a highly functionalized bicy-
clo[4.3.0]nonane core of the austrodorane sesquiterpenoids via a
novel transannular Prins cyclization, and demonstrated that it
may be further functionalized to allow for elaboration into more
complex austrodorane-containing natural products. To our knowl-
edge, this is the first time such a transannular cyclization has been
reported. This route gives access to the austrodorane ring system
containing additional functionality around both rings, which is
non-trivial to install using the alternative methods for the synthe-
sis of these ring systems reported in the literature to-date.
O
O
OTBS
O
i, ii
t-BuO2C
O
14
26α /26β 1:3
Scheme 4. Reagents and conditions: (i) HF (48% aq), MeCN, 25 °C, 100%; (ii) TFA,
CH2Cl2, 25 °C, 56%.
came when we turned to the Brønsted acid HBF4ꢁOEt2, which had
brought success in our investigations into the synthesis of the
pinguisane core.10 When lactone 14 was treated with HBF4ꢁOEt2
in AcOH a new product was formed over a period of 5 h, the struc-
ture of which was determined to be 15 (Scheme 5). A mechanism
for the formation of 15 is given in Scheme 5, where Prins cycliza-
tion of the tetra-substituted double bond onto the protonated car-
bonyl group generated cation 17, which is trapped by the AcOH
solvent to give the functionalized bicyclo[4.3.0]nonane core 15 of
the austrodoranes.
Acknowledgement
We thank the EPSRC (Grant EP/F005970/1) for funding.
References and notes
We repeated the reaction, but this time in the non-nucleophilic
solvents Et2O and benzene. In these cases lactone 14 was smoothly
transformed into 18,13 by loss of a proton from cation 17 (Scheme
6). However, all other attempts to trap carbocation 17, with carbon
1. Gavagnin, M.; Carbone, M.; Mollo, E.; Cimino, G. Tetrahedron Lett. 2003, 44,
1495.
2. Hochlowski, J. E.; Faulkner, D. J.; Matsumoto, G. K.; Clardy, J. J. J. Org. Chem.
1983, 48, 1141.
3. (a) Dumdei, E. J.; de Silva, E. D.; Andersen, R. J. J. Am. Chem. Soc. 1989, 111, 2712;
(b) Morris, S. A.; Dumdei, E. J.; de Silva, E. D.; Andersen, R. J. Can. J. Chem. 1991,
69, 768; (c) Rungprom, W.; Chavasiri, W.; Kokpol, V.; Kotze, A.; Garson, M. J.
Mar. Drugs 2004, 2, 101.
4. (a) Kitagawa, I.; Kobayashi, M. Cancer Chemother. Rep. 1989, 16, 1; (b) Stingl, J.;
Andersen, R. J.; Emerman, J. T. Cancer Chemother. Pharmacol. 1992, 30, 401; (c)
Arno, M.; Betancur-Galvis, L.; Gonzalez, M. A.; Zaragoza, R. J. Bioorg. Med. Chem.
2003, 11, 3171; (d) Keyzers, R. A.; Nothcote, P. T.; Zubkov, O. A. Eur. J. Org. Chem.
2004, 2, 419; (e) Guizzunti, G.; Brady, T. P.; Malhortra, V.; Theodorakis, E. A. J.
Am. Chem. Soc. 2006, 128, 4190.
OAc
i
O
OH
O
O
O
O
14
15
5. (a) Kultcitki, V.; Ungur, N.; Gavagnin, M.; Carbone, M.; Cimino, G. Tetrahedron:
Asymmetry 2004, 15, 423; (b) Kultcitki, V.; Ungur, N.; Gavagnin, M.; Carbone,
M.; Cimino, G. Eur. J. Org. Chem. 2005, 1816.
6. Alvarez-Manzaneda, E.; Chahboun, R.; Barranco, I.; Cabrera, E.; Alvarez, E.; Lara,
A.; Alvarez-Manzaneda, R.; Hmamouchi, M.; Es-Samti, H. Tetrahedron 2007, 63,
11943.
7. Brady, T. P.; Kim, S. H.; Wen, S.; Kim, C.; Theodorakis, E. A. Chem. Eur. J. 2005, 11,
7175.
8. (a) Clarke, P. A.; Black, R. J. G.; Iqbal, M. Synlett 2010, 543; (b) Clarke, P. A.; Grist,
M.; Ebden, M.; Wilson, C. Chem. Commun. 2003, 1560; (c) Clarke, P. A.; Grist, M.;
Ebden, M. Tetrahedron Lett. 2004, 45, 927; (d) Clarke, P. A.; Grist, M.; Ebden, M.;
Wilson, C.; Blake, A. J. Tetrahedron 2005, 61, 353.
AcOH
OAc
O
HO
O
OH
O
OH
O
O
O
15
16
17
Scheme 5. Reagents and conditions: (i) HBF4ꢁOEt2, AcOH, 25 °C, 57%.
9. For a review, see: Clarke, P. A.; Reeder, A. T.; Winn, J. Synthesis 2009, 691.