1458
H.-Y. Lee et al. / Tetrahedron Letters 46 (2005) 1455–1458
sequence of reactions from the original plan in Scheme 2
1
4. The cyclic b-keto ester was alkylated with a proper alkyl
halide using K CO in DMF and the ketone was trans-
formed into the corresponding olefin using Ph PCH
1
(
Scheme 4). As the direct addition of the methyl anion
to 1 was not fruitful, sterically less demanding cyanide
2
3
3
2
1
2
through Wittig reaction. The remaining ester was con-
verted into the aldehyde and reacted with propargylic or
allylic Grignard reagents to provide the substrates for the
radical reaction.
was added to 1 using Et AlCN and the nitrile was
2
reduced to the desired methyl group. Protection of the
ketone as the acetal with ethylene glycol followed
by reduction of the resulting compound with DIBAL
and deprotection of the acetal with HCl produced
aldehydo-ketone 5. Chemoselective reduction of the
aldehyde of 5 with lithium tris-tert-butoxyalumino-
5
. Stork, G.; Baine, N. H. J. Am. Chem. Soc. 1982, 104,
2
321.
6. Giese, B. Radicals in Organic Synthesis Formation of
Carbon–Carbon Bonds; Pergamon: London, 1986, p 143.
7. (a) Zalkow, L. H.; Harris, R. N., III; Van Derveer, D.
Chem. Commun. 1978, 420; (b) Bohlmann, F.; Zdero, C.;
Bohlmann, R.; King, R. M.; Robinson, H. Phytochemistry
1
3
14
hydride followed by deoxygenation of the alcohol
through the corresponding xantate formation and the
subsequent reduction with tributyl tin hydride provided
1
980, 19, 579; (c) Comey, N.; Grey, A. I.; Hook, I. L.;
6. Since the ozonolysis of the corresponding silyl enol-
ether of 6 produced the desired aldehydoacid along with
the partially oxidized a-hydroxyketones, the reaction
James, P.; Sheridan, H. Phytochemistry 1999, 50, 1057; (d)
Reyes-Trejo, B.; Morales-Rios, M. S.; Alvarez Cisneros,
E. C.; Joseph-Nathan, P. Magn. Reson. Chem. 2003, 41,
mixture was further oxidized with HIO to complete
the cleavage reaction and subsequent esterification fol-
4
1
021; (e) Gauvin, A.; Susperregui, J.; Barth, P.; Louis, R.;
Deleris, G.; Smadja, J. Phytochemistry 2004, 65, 897.
8. (a) Shi, Q. W.; Sauriol, F.; Mamer, O.; Zamir, L. O. Chem.
Commun. 2003, 68; (b) Shi, Q. W.; Sauriol, F.; Lesimple,
A.; Zamir, L. O. Chem. Commun. 2004, 544.
0
lowed by LAH reduction produced 7 and 7 with the
2
.5:1 ratio. The silyl enolether formation from 6 gener-
ated a mixture of regio-isomeric enol ethers with slight
preference toward the desired one with 2.5:1 ratio that
9
. (a) For the total synthesis via radical cyclization: Lee, H.
Y.; Kim, D. I.; Kim, S. Bull. Kor. Chem. Soc. 1999, 20,
0
was transformed into 7 and 7 . Diol 7 was oxidized to
2
7
69; (b) Curran, D. P.; Shen, W. Tetrahedron 1993, 49,
55; (c) Sha, C. K.; Tsong, S. J.; Wang, D. C. Tetrahedron
the corresponding dialdehyde using SwernÕs oxidation
and intramolecular aldol condensation of the dialdehyde
product using piperidino-acetate furnished the mod-
hephene skeleton 8. Finally, the aldehyde of 8 was re-
duced to the corresponding methyl group using the
same protocol as the reduction of the aldehyde of 5 to
yield modhephene with epi-modhephene as the minor
product. Treatment of this mixture with acid produced
Lett. 1990, 31, 3745.
1
0. The epimeric ratio of the cyclization products was
determined by NMR after 4 was converted to 1, since 4
was obtained as a mixture of four isomers not only at the
methyl group but also at the alcohol containing carbon
center, which made it difficult to determine the isomeric
ratio of the reaction at that stage.
1
5
1
1. All the new compounds showed satisfactory spectroscopic
data for the assigned structures. Spectral data of selected
isomerically pure modhephene.
1
compounds; 1, H NMR (400 MHz, CDCl
1
3
) d 5.68 (s,
H), 2.43 (d, J = 16.1, 1H), 2.23 (d, J = 16.1, 1H), 2.00–
In summary, we developed a facile route to propellanes
and demonstrated the versatility of the methodology
through the total synthesis of modhephene.
1
.93 (m, 1H), 1.91 (s, 3H), 1.75–1.60(m, 8H), 1.39–1.28
13
(
m, 1H), 1.25–1.19 (m, 1H), 0.91 (d, J = 6.5, 3H),
NMR (100 MHz, CDCl ) d 199.4, 166.5, 123.3, 57.5, 55.0,
5.1, 41.7, 39.2, 39.0, 34.3, 31.1, 23.9, 21.2, 13.6. IR (neat,
C
3
4
ꢀ
1
Acknowledgements
cm ) 2952, 1670, 1622, 1455, 1378, 1273. HRMS:
calculated for C H O: 204.1514, found: 204.1521. 6,
1
4
20
1
This work was supported by the Center for Molecular
Design & Synthesis (CMDS) and the grant from the
Korea Research Foundation (KRF-2002-070-C-00058).
H NMR (400 MHz, CDCl
d, J = 17.4, 1H), 2.23 (d, J = 17.9, 1H), 2.12–2.02 (m,
H), 1.97 (d, J = 17.4, 1H), 1.58–1.50(m, 4H), 1.37–1.30
m, 6H), 1.00 (s, 3H), 0.91 (s, 3H), 0.83 (d, J = 6.4, 3H),
3
) d 2.41 (d, J = 17.9, 1H), 2.26
(
1
(
1
3
3
C NMR (100 MHz, CDCl ) d 214.1, 56.8, 54.6, 49.6,
4
8
2
1
7.4, 45.1, 37.8, 36.7, 36.5, 35.7, 30.2, 26.7, 25.9, 25.2, 13.0.
References and notes
1
, H NMR (300 MHz, CDCl ) d 9.63 (s, 1H), 6.33 (s, 1H),
3
.02–1.95 (m, 1H), 1.80–1.68 (m, 2H), 1.65–1.53 (m, 4H),
.40–1.24 (m, 4H), 1.12 (d, J = 6.0, 3H), 1.11 (s, 6H).
1
2
3
. (a) Giese, B.; Kopping, B.; Gobel, T.; Dickhout, J.;
Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48,
1
Synthetic modhephene, H NMR (400 MHz, CDCl
4
3
3
) d
3
01; (b) Curran, D. Aldrichim. Acta 2000, 33, 104; (c)
.80(d, J = 1.3, 1H), 2.02–1.99 (m, 1H), 1.74–1.66 (m,
H), 1.58 (d, J = 1.5, 3H), 1.45–0.98 (m, 7H), 0.97 (d,
Banik, B. K. Curr. Org. Chem. 1999, 3, 469; (d) Kim, S.
Chem. Rec. 2001, 1, 415.
. (a) Stork, G.; Mook, R., Jr. J. Am. Chem. Soc. 1987, 109,
J = 6.4, 3H), 0.96 (s, 3H), 0.95 (s, 3H).
1
2. (a) Nagata, W. Org. React. 1977, 25, 255; (b) Patin, A.;
Kanazawa, A.; Philouze, C.; Greene, A. E.; Muri, E.;
Barreiro, E.; Costa, P. C. C. J. Org. Chem. 2003, 68,
2
829; (b) Stork, G.; West, F.; Lee, H. Y.; Isaacs, R. C. A.;
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D. L. J.; Magnuson, S. R.; Manning, H. W. J.; Mayhew,
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. (a) Gomez, A. M.; Company, M. D.; Uriel, C.; Valverde,
S.; Cristobal Lopez, J. Tetrahedron Lett. 2002, 43, 4997;
3
3. Sell, C. S. Aus. J. Chem. 1975, 28, 1383.
831.
1
1
4. Barton, D. H. R.; McCommie, S. W. J. J. Chem. Soc.,
Perkin Trans. 1 1975, 1574.
5. Dvork, C. A.; Rawal, V. H. Chem. Commun. 1997,
(
4
b) Stork, G.; Mook, R., Jr. Tetrahderon Lett. 1986, 27,
529.
1
2
381.