2090
D. C. Harrowven, M. J. Tyte / Tetrahedron Letters 45 (2004) 2089–2091
OH
Exposure of that mixture to BF3ÆOEt2 induced cyclisa-
CO2Me
OMe
tion to hexahydrophenalene 17 in 57% yield. A minor
component, displaying similar spectral characteristics
and accounting for 9% of the mass balance, was also
given and assigned as pseudopterosin G–J aglycone
dimethyl ether (Scheme 1).
OMe
OMe
a
b, c
72%
O
96%
O
OMe
OH
4
5
6
OMe
The final deprotection of 17 to ( )-pseudopterosin A–F
and K–L aglycone 2 was accomplished with boron
tribromide in the manner described by Buszek and
Bixby.5 In our hands this gave 2 in a pitiful yield of 9%.
Notably, Majdalani and Schmalz have effected the same
conversion in 95% yield by heating 16 with LiSEt in
DMF.6
CHO
OMe
OMe
d
e, 72%
93%
O
OMe
EtO
EtO
O
O
P
O
O
7
9, Z : E ~ 3 : 1
8
In conclusion, a total synthesis of ( )-pseudopterosin
A–F and K–L aglycone 2 has been completed in 14 steps
from 3-methylcatechol using three acid mediated cycli-
sation reactions to construct the hexahydrophenalene
ring system. Work is in progress to adapt the approach
described to address related natural products such as
elisapterosin and colombiasin A.10
OMe
OMe
OMe
OMe
f
g
h
54%
89%
98%
O
O
O
O
10, d.r. ~ 9 : 1
11
OMe
OMe
OMe
OMe
OMe
OMe
References and notes
i
H
H
H
+
91%
1. (a) Look, S. A.; Fenical, W.; Matsumoto, G. K.; Clardy, J.
J. Org. Chem. 1986, 51, 5140–5145; (b) Look, S. A.;
Fenical, W.; Jacobs, R. S.; Clardy, J. Proc. Natl. Acad.
Sci. U.S.A. 1986, 83, 6238–6240; (c) Roussis, V.; Wu, Z.;
Fenical, W.; Strobel, S. A.; VanDuyne, G. D.; Clardy, J.
J. Org. Chem. 1990, 55, 4916–4922; (d) Ata, A.; Kerr, R.
G.; Moya, C. E.; Jacobs, R. S. Tetrahedron 2003, 59,
4215–4222.
CO2H
OH
OH
~ 4 : 5
12, d.r. ~ 5 : 4
13
14
OMe
OR
OMe
OR
H
H
j, k
2. (a) Ettouati, W. S.; Jacobs, R. S. Mol. Pharmacol. 1987,
31, 500–505; (b) Fenical, W. J. Nat. Prod. 1987, 50, 1001–
1008; (c) Potts, B. C. M.; Faulkner, D. J.; Jacobs, R. S. J.
l
57%
62%
PPh3
ꢀ
Nat. Prod. 1992, 55, 1701–1717; (d) Rodrıguez, A. D.
15
Tetrahedron 1995, 51, 4571–4618; (e) Mayer, A. M. S.;
Jacobson, P. B.; Fenical, W.; Jacobs, R. S.; Glaser, K. B.
Life Sci. 1998, 62, 401–407.
16, E:Z ~ 3 : 2
see
text
17, R = Me
( )-2, R = H
3. Rouhi, A. M. Chem. Eng. News 1995, 20, 42.
4. (a) Broka, C. A.; Chan, S.; Peterson, B. J. Org. Chem.
1988, 53, 1584–1586; (b) Corey, E. J.; Carpino, P. J. Am.
Chem. Soc. 1989, 111, 5472–5474; (c) McCombie, S. W.;
Cox, B.; Ganguly, A. K. Tetrahedron Lett. 1991, 32, 2087–
2090; (d) Gill, S.; Kocienski, P.; Kohler, A.; Pontiroli, A.;
Qun, L. J. Chem. Soc., Chem. Commun. 1996, 1743–1744;
(e) LeBrazidec, J.-Y.; Kocienski, P. J.; Connolly, J. D.;
Muir, K. W. J. Chem. Soc., Perkin Trans. 1 1998, 2475–
2477; (f) Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc.
1998, 120, 12777–12782; (g) Chow, R.; Kocienski, P. J.;
Kuhl, A.; LeBrazidec, J.-Y.; Muir, K.; Fish, P. J. Chem.
Soc., Perkin Trans. 1 2001, 2344–2355; (h) Kocienski, P. J.;
Pontiroli, A.; Qun, L. J. Chem. Soc., Perkin Trans. 1 2001,
2356–2366.
5. Buszek, K. R.; Bixby, D. L. Tetrahedron Lett. 1995, 36,
9129–9132.
6. Majdalani, A.; Schmalz, H.-G. Synlett 1997, 1303–1307.
7. Lazerwith, S. E.; Johnson, T. W.; Corey, E. J. Org. Lett.
2000, 2, 2389–2392.
8. (a) Kozikowski, A. P.; Wu, J. P. Synlett 1991, 465–468; (b)
Jung, M. E.; Siedem, C. S. J. Am. Chem. Soc. 1993, 115,
3822–3823; (c) Harrowven, D. C.; Dennison, S. T.; Howes,
P. Tetrahedron Lett. 1994, 35, 4243–4246; (d) Schmalz, H.
Scheme 1. Reagents and conditions: (a) Me2SO4, KOH, acetone, rt,
48 h; (b) H2, PtO2, EtOAc, rt, 2 h; (c) LiAlH4, THF, )78–0 °C, 30 min;
(d) Dess–Martin periodinane, CH2Cl2, 0 °C, 45 min; (e) 8, KOBut,
THF, 0 °C, 45 min then 7, 0 °C, 40 min; (f) TfOH, 77 °C, 15 min;
(g) H2, Pd–C, PtO2, EtOAc, rt, 3 h; (h) Na, NH3, THF, 10 min;
(i) BH3ÆTHF, 0 °C to rt, 16 h; (j) Dess–Martin periodinane, CH2Cl2,
0 °C, 45 min; (k) 15, THF, rt, 2 h; (l) BF3ÆOEt2, CH2Cl2, )78–0 °C, 2 h.
were unable to effect the concomitant hydrogenolysis of
11 to acid 12. To achieve that conversion it was neces-
sary to employ a dissolving metal reduction, with 12
being given as an inseparable 5:4 mixture of diastereo-
isomers. Separation of the diastereoisomers could be
achieved after reduction of these carboxylic acids to
alcohols 13 and 14 with borane–THF complex.
To complete the total synthesis, 14 was oxidised to the
corresponding aldehyde using the Dess–Martin period-
inane reagent. A Wittig olefination with ylide 15 then
installed the final four carbons, providing diene 16 as a
3:2 mixture of (E)- and (Z)-isomers in 63% yield.