Studies on the total synthesis of (-)-CP-263,114

Article abstract of DOI:10.1021/jo048681u

Alkoxyl radicals have a wide range of applications in organic synthesis due to their remarkable chemical properties in molecular transformation. The present study shows two types of alkoxyl radicals (primary vs tertiary) to selectively undergo dehydrogena

Full text of DOI:10.1021/jo048681u

Studies on the Total Synthesis of (-)-CP-263,114
Takehiko Yoshimitsu,* Shuji Sasaki, Yoshimasa Arano, and Hiroto Nagaoka*
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
takey@my-pharm.ac.jp
Received July 30, 2004
Alkoxyl radicals have a wide range of applications in organic synthesis due to their remarkable
chemical properties in molecular transformation. The present study shows two types of alkoxyl
radicals (primary vs tertiary) to selectively undergo dehydrogenation and â-scission to give rise to
key structural elements of (-)-CP-263,114 (1). By alkoxyl radical transformation followed by
installation of the C19-C25 (CP numbering) side chain and the bridged bisacetal unit, the
functionalized CP precursor 2 was obtained.
Introduction:
(-)-CP-263,114 (phomoidride B) (1), a bioactive fungal
metabolite,1 is of considerable interest to the synthetic
chemical community (Figure 1). Fascination with the CP
molecule stems from the structural uniqueness as well
as the potent inhibitory activity toward ras-farnesyl
transferase and suqualene synthase, both current targets
of medicinal concern. Four successful total syntheses of
12 appear in the literature and new routes to produce
this natural product are avidly being sought.3,4
We previously reported an enantioselective approach
based on alkoxyl radical reactions to a simple core
structure of (-)-CP-263,114 (1).5a,6 In this study, the
synthesis of the advanced CP precursor 2 was conducted
through the following key transformations (Scheme 1):
(1) introduction of the oxygen functionality at C26 via
primary alkoxyl radical-mediated dehydrogenation (10
f 11 f 12), (2) formation of bridgehead double bond via
iodo transfer â-scission of a tertiary alkoxyl radical
intermediate followed by reduction of iodo ether (8 f 7
f 5), and (3) production of the polycyclic caged CP-motif
2 via thioketalization and subsequent bisacetal unit
construction (4 f 3 f 2).
FIGURE 1. Functionalized CP precursor 2.
Results and Discussion
Alkoxyl radicals are widely used in the synthesis of
organic molecules owing to chemical properties that allow
useful reactions such as hydrogen abstraction and â-scis-
sion.7,8 Alkoxyl radical reactions thus serve as means for
key transformation in the synthesis of various natural
products.9-13 The pathways of these reactions generally
depend on the types of alkoxyl radicals generated:
(3) Selected recent papers from other laboratories; (a) Davies, H.
M. L.; Ren, P. D. Tetrahedron Lett. 2000, 41, 9021-9024. (b) Devaux,
J.-F.; O’Neil, S. V.; Guillo, N.; Paquette, L. A. Collect. Czech. Chem.
Commun. 2000, 65, 490-510. (c) Crimmins, M. T.; Hauser, E. B. Org.
Lett. 2000, 2, 281-284. (d) Baldwin, J. E.; Adlington, R. M.; Roussi,
F.; Bulger, P. G.; Marquez, R.; Mayweg, A. V. W. Tetrahedron 2001,
57, 7409-7416. (e) Isakovic, L.; Ashenhurst, J. A.; Gleason, J. L. Org.
Lett. 2001, 3, 4189-4192. (f) Toyota, M.; Majo, V. J.; Ihara, M.
Tetrahedron Lett. 2001, 42, 1555-1558. (g) Ohmori, N. J. Chem. Soc.,
Perkin Trans. 1 2002, 755-767. (h) Matsushita, T.; Ashidas, H.;
Kimachi, T.; Takemoto, Y. Chem. Commun. 2002, 814-815. (i) Su-
likowski, G. A.; Liu, W.; Agnelli, F.; Corbett, R. M.; Luo, Z.; Hersh-
berger, S. J. Org. Lett. 2002, 4, 1451-1454. (j) Armstrong, A.; Critchley,
T. J.; Gourdel-Martin, M.-E.; Kelsey, R. D.; Mortlock, A. A. Tetrahedron
Lett. 2002, 43, 6027-6030. (k) Spiegel, D. A.; Njardarson, J. T.; Wood,
J. L. Tetrahedron 2002, 58, 6545-6554. (l) Bio, M. M.; Leighton, J. L.
J. Org. Chem. 2003, 68, 1693-1700. (m) Banwell, M. G.; Coster, M.
J.; Edwards, A. J.; Voegtle, M. Aust. J. Chem. 2003, 56, 577-583. (n)
Clive, D. L. J.; Sgarbi, P. W. M.; He, X.; Sun, S.; Zhang, J.; Ou, L.
Can. J. Chem. 2003, 81, 811-824.
(4) For reviews, see: (a) Diederichsen, U. Nachr. Chem. Tech. Lab.
1999, 47, 1423-1427. (b) Starr, J. T.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2000, 39, 1415-1412. (c) Hepworth, D. Chem. Ind. (London)
2000, 2, 59-65. (d) Nicolaou, K. C.; Baran, P. S. Angew. Chem., Int.
Ed. 2002, 41, 2678-2720. (e) Spiegel, D. A.; Njardarson, J. T.;
McDonald, I. M.; Wood, J. L. Chem. Rev. 2003, 103, 2691-2727.
(5) (a) Yoshimitsu, T.; Yanagisawa, S.; Nagaoka, H. Org. Lett. 2000,
2, 3751-3754. (b) Yoshimitsu, T.; Yanagiya, M.; Nagaoka, H. Tetra-
hedron Lett. 1999, 40, 5215-5218.
(1) (a) Dabrah, T. T.; Kaneko, T.; Massefski, W., Jr.; Whipple, E. B.
J. Am. Chem. Soc. 1997, 119, 1594-1598. (b) Spencer, P.; Agnelli, F.;
Williams, H. J.; Keller, N. P.; Sulikowski, G. A. J. Am. Chem. Soc.
2000, 122, 420-423. (c) Spencer, P.; Angelli, F.; Sulikowski, G. A. Org.
Lett. 2001, 3, 1443-1445. (d) Sulikowski, G. A.; Angelli, F.; Spencer,
P.; Koomen, J. M.; Russell, D. H. Org. Lett. 2002, 3, 1447-1450.
(2) (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Choi, H.-S.; Yoon,
W. H.; He, Y.; Fong, K. C. Angew. Chem., Int. Ed. 1999, 38, 1669-
1675. (b) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; He,
Y.; Yoon, W. H.; Choi, H.-S. Angew. Chem., Int. Ed. 1999, 38, 1676-
1678. (c) Nicolaou, K. C.; Jung, J.-K.; Yoon, W. H.; He, Y.; Zhong, Y.-
L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 1829-1832. (d)
Nicolaou, K. C.; Jung, J.; Yoon, W. H.; Fong, K. C.; Choi, H.-S.; He, Y.;
Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2002, 124, 2183-2189.
(e) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; Choi, H.-S.
J. Am. Chem. Soc. 2002, 124, 2190-2201. (f) Nicolaou, K. C.; Zhong,
Y.-L.; Baran, P. S.; Jung, J.; Choi, H.-S.; Yoon, W. H. J. Am. Chem.
Soc. 2002, 124, 2202-2211. (g) Tan, Q.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2000, 39, 4509-4511. (h) Chen, C.; Layton, M. E.;
Sheehan, S. M.; Shair, M. D. J. Am. Chem. Soc. 2000, 122, 7424-
7425. (i) Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000,
122, 7825-7826. (j) Hayashi, Y.; Itoh, T.; Fukuyama, T. Org. Lett. 2003,
5, 2235-2238.
10.1021/jo048681u CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/11/2004
9262
J. Org. Chem. 2004, 69, 9262-9268

Studies on the Total Synthesis of (-)-CP-263,114
SCHEME 1. Synthetic Approach Based on Alkoxyl Radical Reactions to (-)-CP-263,114 (1)
SCHEME 2. Pathways of Alkoxyl Radical
Reactions
primary alkoxyl radicals are susceptible to hydrogen
abstraction (i f ii) whereas tertiary radicals favor
â-scission (i f iii + iv) (Scheme 2).
Primary Alkoxyl Radical Dehydrogenation of
10. Primary alcohol 10,5a prepared in 7 steps from
(-)-carvone (13) with an overall yield of 27%, was
subjected to alkoxyl radical-mediated dehydrogenation
(6) Synthetic radical chemistry from this laboratory: novel radical
R-C-H hydroxyalkylation of THF and its application to acetogenin
synthesis: (a) Yoshimitsu, T.; Tsunoda, M.; Nagaoka, H. Chem.
Commun. 1999, 1745-1746. (b) Yoshimitsu, T.; Arano, Y.; Nagaoka,
H. J. Org. Chem. 2003, 68, 625-627. (c) Yoshimitsu, T.; Makino, T.;
Nagaoka, H. J. Org. Chem. 2003, 68, 7548-7550. (d) Yoshimitsu, T.;
Makino, T.; Nagaoka, H. J. Org. Chem. 2004, 69, 1993-1998. Atom
transfer radical annulation approach to paclitaxel: (e) Yoshimitsu, T.;
Nakajima, H.; Nagaoka, H. Tetrahedron Lett. 2002, 43, 8587-8590.
(7) For comprehensive reviews of synthetic radical chemistry, see:
(a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-
Carbon Bonds; Pergamon Press: Oxford, UK, 1986. (b) Motherwell,
W. B.; Crich, D. Free Radical Chain Reactions in Organic Synthesis;
(Scheme 3).14 A mixture of alcohol 10, diacetoxyiodoben-
Academic Press: New York, 1992. (c) Fossey, J.; Lefort, D.; Sorba, J.
zene (DIB),15,16 and iodine in dichloromethane at 0 °C was
Free Radicals in Organic Chemistry; John Wiley & Sons: Paris, France,
1995. (d) Neumann, W. P. Synthesis 1987, 665-683. (e) Curran, D. P.
irradiated with visible light (150 W tungsten lamp) to
produce the desired olefin 11 (29%), iodo ether 14 (21%),
Synthesis. 1988, 417-439 (Part 1), 489-513 (Part 2). (f) Jasperse, C.
P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286. (g)
Togo, H. Chemistry in Organic Free Radicals; Kodansha: Tokyo,
Japan, 2001. (h) Renaud, P.; Sibi, M. P., Eds. Radicals in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2001. (i) McCarroll, A.
J.; Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224-2248.
(8) (a) Boto, A.; Herna´ndez, R.; Sua´rez, E. Tetrahedron Lett. 2002,
43, 1821-1824. (b) Boto, A.; Herna´ndez, D.; Herna´ndez, R.; Sua´rez,
E. J. Org. Chem. 2003, 68, 5310-5319. (c) Antunes, C. S. A.; Bietti,
M.; Lanzalunga, O.; Salamone, M. J. Org. Chem. 2004, 69, 5281-5289.
(9) A recent account of alkoxyl radical reactions: Hartung, J.;
Gottwald, T.; Spehar, K. Synthesis 2002, 1469-1489.
(11) Application of alkoxyl radical â-scission in natural product
synthesis, for recent instances, see: (a) Boto, A.; Herna´ndez, R.;
Montoya, A.; Sua´rez, A. Tetrahedron Lett. 2004, 45, 1559-1563. (b)
Fuhshuku, K.; Tomita, M.; Sugai, T. Tetrahedron Lett. 2004, 45, 1763-
1767. (c) Deng, Y.; Snyder, J. K. J. Org. Chem. 2002, 67, 2864-2873.
(d) Weavers, R. T. J. Org. Chem. 2001, 66, 6453-6461. (e) Wipf, P.;
Li, W. J. Org. Chem. 1999, 64, 4576-4577. (f) Mehta, G.; Mohal, N.
Tetrahedron Lett. 1999, 40, 5791-5794. (g) Rigby, J. H.; Warshakoon,
N. C.; Payen, A. J. J. Am. Chem. Soc. 1999, 121, 8237-8245.
(12) Reviews for alkoxyl radical hydrogen abstraction: (a) Cekovic,
Z. Tetrahedron 2003, 59, 8073-8090. (b) Feray, L.; Kuznetsov, N.;
Renaud, P. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 246-278.
Review containing a brief discussion on this topic: (c) Robertson, J.;
Pillai, J.; Lush, R. K. Chem. Soc. Rev. 2001, 30, 94-103.
(10) Reviews of alkoxyl radical fragmentation: (a) Sua´rez, E.;
Rodriguez, M. S. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 440-
454. (b) Zhang, W. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 234-
245. (c) Yet, L. Tetrahedron 1999, 55, 9349-9403. (d) Nishida, A.;
Nishida, M. Rev. Heteroatom. Chem. 1997, 17, 287-311.
J. Org. Chem, Vol. 69, No. 26, 2004 9263

Yoshimitsu et al.
SCHEME 3. Alkoxyl Radical Dehydrogenation of Primary Alcohol 10
SCHEME 4. Plausible Mechanism of Radical
Dehydrogenation
11. The cyclization of III affords cyclic ether 15. Iodo
ether 14 has been found to be produced from 11 via a
photolytic radical pathway rather than an ionic pathway,
since formation of 14 from 11 is significantly accelerated
by visible light irradiation. This type of radical dehydro-
genation17 may be useful for the regioselective function-
alization of unreactive C-H bonds.18
Synthesis of Bromo Acetal 9. Bromo acetal 9,
required for the construction of the C14 quaternary
center of the CP molecule, was prepared as shown in
Scheme 5. Thus, olefin 11 was first transformed into
trimethylsilylethoxymethyl (SEM) ether 16, which was
subjected to ozonolysis at -78 °C to afford ketone 12 in
83% yield. Reduction of 12 with Zn(BH4)2 in ether at 0
°C proceeded stereoselectively from the concave site to
provide â-alcohol which, by deprotection of the trimeth-
ylsilyl (TMS) group with tetrabutylammonium fluoride
(TBAF) followed by ketalization with 2,2-dimethoxypro-
pane in the presence of PPTS, gave acetonide 17 in 80%
overall yield. Allylation of 17 and subsequent one-carbon
degradation delivered alcohol 19, which then underwent
Grieco olefination19 to provide vinyl lactone 20 in high
yield. Lactone 20 was reduced with LAH in refluxing 1,4-
dioxane to give diol, which was selectively converted to
monosilyl ether 21 in 87% overall yield. Oxidation of the
secondary hydroxyl group in 21 with catalytic TPAP20
in the presence of 4-methylmorpholine N-oxide provided
ketone 22 in 93% yield. Ozonolysis of 22 followed by
stereoselective intramolecular pinacol coupling of the
resulting keto aldehyde efficiently gave diol 23. Diol 23
was then treated with 1,1′-carbonyldiimidazole and
DMAP in THF to afford cyclic carbonate 24 which, by
deprotection of the TBS group with TBAF, gave alcohol
25 in 98% yield. Oxidation of 25 with Dess-Martin
reagent21 resulted in spontaneous â-elimination of the
carbonate group to provide R,â-unsaturated aldehyde 26
in 95% yield. Selective 1,2-reduction of 26 was success-
fully carried out with NaBH4 in the presence of CeCl3‚
7H2O to provide alcohol 27,22 while DIBAL was found
and ether 15 (25%). Reduction of iodo ether 14 with zinc-
acetic acid in methanol provided olefin 11 quantitatively,
thereby producing olefin 11 in ca. 50% overall yield from
10. The six-membered ring structure of iodo ether 14 was
unambiguously determined by NOE analysis.
A plausible mechanism for the radical dehydrogenation
is shown in Scheme 4. A six-membered cyclic transition
state, in which the δ-hydrogen, most accessible from the
primary alkoxyl radical center of I, is abstracted, would
provide carbon-centered radical II. Carbon radical II
subsequently becomes, with oxidation, carbenium ion
intermediate III, deprotonation of which produces olefin
(13) For recent reports of alkoxyl radical hydrogen abstraction in
natural product synthesis, see: (a) Barrero, A. F.; Oltra, J. E.; Alvarez,
M.; Rosales, A. J. Org. Chem. 2002, 67, 5461-5469. (b) Barrero, A. F.;
Oltra, J. E.; Alvarez, M. Tetrahedron Lett. 2000, 41, 7639-7643. (c)
Chatgilialoglu, C.; Gimisis, T.; Spada, G. P. Chem.-Eur. J. 1999, 2866-
2876. (d) Allen, P. A.; Brimble, M. A.; Prabaharan, H. Synlett 1999,
295-298. (e) Petrovic, G.; Saicic, R. N.; Cekovic, Z. Synlett 1999, 635-
637.
(14) A recent impressive instance of alkane functionalization with
diacetoxyiodobenzene-I2, see: Barluenga, J.; Gonza´lez-Bobes, F.; Gonza´-
lez, J. M. Angew. Chem., Int. Ed. 2002, 41, 2556-2558.
(15) Concepcio´n, J. I.; Francisco, C. G.; Herna´ndez, R.; Salazar, J.
A.; Sua´rez, E. Tetrahedron Lett. 1984, 25, 1953-1956. Also, see ref
10a.
(16) Reviews for organohypervalent iodine compounds in radical and
related reactions: (a) Togo, H.; Katohgi, M. Synlett 2001, 565-581.
(b) Ochiai, M. In Chemistry of Hypervalent Compounds; Akiba, K., Ed.;
VCH Publishers: New York, 1999; Chapter 13, pp 359-387. (c)
Zhdankin, V.; Stang, P. J. Chem. Rev. 2002, 102, 2523-2584. (d)
Varvoglis, A. Hypervalent Iodine in Organic Synthesis; Academic
Press: San Diego, CA, 1997. (e) Kitamura, T.; Fujiwara, Y. Org. Prep.
Proced. Int. 1997, 29, 409-458. (f) Wirth, T.; Hirt, U. H. Synthesis
1999, 1271-1287. (g) Hypervalent Iodine Chemistry; Topics in Current
Chemistry 224; Wirth, T., Ed.; Springer-Verlag: Berlin, Germany,
2003.
(17) (a) Breslow, R.; Baldwin, S.; Flechtner, T.; Kalicky, P.; Liu, S.;
Washburn, W. J. Am. Chem. Soc. 1973, 95, 3251-3262. (b) Breslow,
R. Chemtracts 1988, 1, 333-348. (c) Jung, M. E.; Johnson, T. W. J.
Am. Chem. Soc. 1997, 119, 12412-12413. For reviews of the remote
radical functionalization, see: (d) Kalvoda, J.; Heusler, K. Synthesis
1971, 501-526. (e) Majetich, G.; Wheless, K. Tetrahedron 1995, 51,
7095-7129.
(18) Metal-mediated dehydrogenation in natural product synthesis,
for instance, see: (a) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem.
Soc. 2002, 122, 6900-6903. (b) Johnson, J. A.; Sames, D. J. Am. Chem.
Soc. 2000, 122, 6321-6322.
(19) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976,
41, 1485-1486.
(20) (a) Griffith, W. P. Chem Soc. Rev. 1992, 179-185. (b) Griffith,
W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13-19.
9264 J. Org. Chem., Vol. 69, No. 26, 2004

Studies on the Total Synthesis of (-)-CP-263,114
SCHEME 5. Synthesis of Bromo Acetal 9a
SCHEME 6. Synthesis of Tertiary Alcohol 8a
a Reagents and conditions: (a) SEMCl, i-Pr2NEt, CH2Cl2, rt,
86%; (b) O3, CH2Cl2, then Ph3P, -78 °C to rt, 83%; (c) Zn(BH4)2,
Et2O, 0 °C; (d) TBAF, THF, 0 °C; (e) 2,2-dimethoxypropane, PPTS,
acetone, CH2Cl2, rt, 80%, 3 steps; (f) LiHMDS, allylbromide,
HMPA, THF, -78 °C, 85%; (g) O3, CH2Cl2, then Ph3P, -78 °C to
rt; (h) NaBH4, MeOH, rt, 95%, 2 steps; (i) o-O2NC6H4SeCN,
n-Bu3P, THF, -78 to -40 °C, then, H2O2, THF, 0 °C to rt, 88%; (j)
LAH, 1,4-dioxane, reflux; (k) TBSCl, Et3N, DMAP, CH2Cl2, rt, 87%,
2 steps; (l) TPAP, NMO, MeCN, rt, 93%; (m) O3, CH2Cl2, then
Ph3P, -78 °C to rt, 97%; (n) SmI2, HMPA, THF, -40 °C to 0 °C,
91%; (o) 1,1′-carbonyldiimidazole, DMAP, THF, rt, 93%; (p) TBAF,
THF, rt, 98%; (q) Dess-Martin periodinane, CH2Cl2, rt, 95%; (r)
NaBH4, CeCl3‚7H2O, MeOH, 0 °C, 90%; (s) ZnCl2, 2-bromo-1,1-
diethoxyethane, CH2Cl2, 0 °C, 77%.
a Reagents and conditions: (a) (TMS)3SiH, AIBN, benzene,
reflux, 28a (45%), 28b (41%); (b) CsF, DMF, 130 °C, 91% from
28a; (c) Dess-Martin periodinane, CH2Cl2, rt, 91%; (d) Ph3PdCH2,
THF, 0 °C, 92%; (e) dicyclohexylborane, THF, then NaOH, H2O2,
0 °C to rt, 92%; (f) SEMCl, i-Pr2NEt, CH2Cl2, 0 °C, 93%; (g)
Pd(OH)2-C, H2, EtOAc, rt, 98%; (h) Dess-Martin periodinane,
CH2Cl2, rt, 91%; (i) 36, THF, 0 °C to rt, 94%; (j) Pd-C, H2, EtOAc,
rt, 95%.
unsuitable for this reduction owing to concomitant for-
mation of a 1,4-reduction byproduct. Alcohol 27 was then
treated with bromoacetaldehyde diethyl acetal in the
(21) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-
4156. (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287. (c) Ireland, R. E.; Liu, L. J. J. Org. Chem. 1993, 58, 2899-2899.
(d) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552.
(e) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64,
4537-4538.
presence of zinc chloride to give an inseparable diaster-
eomeric mixture of acetal 9 in 77% yield.
Synthesis of Tertiary Alcohol 8. With this bromo
acetal 9, the quaternary stereogenic center at C14 was
(22) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454-
5459.
J. Org. Chem, Vol. 69, No. 26, 2004 9265

Yoshimitsu et al.
SCHEME 7. Alkoxyl Radical â-Scission of Tertiary Alcohol 8 and Olefination of Iodo Ether 6
constructed by radical cyclization (Scheme 6).23 Thus the
treatment of 9 with (TMS)3SiH24,25 and AIBN led to the
formation of cyclized compounds 28a and 28b, which
could be easily separated by silica gel chromatography,
in 86% combined yield (28a:28b ca. 1:1).26 The present
process is superior to that reported earlier,5a which
involves acetalization of 27 with ethylvinyl ether and
NBS followed by radical cyclization with tributyltinhy-
dride, in terms of higher overall yield (66 vs 49%) and
less toxicity of the reagents. For elongation of the side
chains at C9 and C17, SEM ether 28a was first depro-
tected with cesium fluoride in heating DMF27 to provide
alcohol 29 in 91% yield. Dess-Martin oxidation of 29
afforded aldehyde 30, and subsequent Wittig olefination
gave olefin 31 (92%). Hydroboration/oxidation of 31 pro-
vided alcohol 32 whose primary hydroxyl group was
protected as SEM ether to afford 33 in 93% yield. De-
benzylation of 33 under hydrogenation condition followed
by oxidation gave aldehyde 35 in good yield. Wittig
olefination of aldehyde 35 with phosphorane 36 provided
olefin 37 (94%), which was then subjected to catalytic
hydrogenation to furnish alcohol 8 in 95% yield.
SCHEME 8. Alkoxyl Radical â-Scission of Tertiary
Alcohol 40 Possessing Alkenyl Substituent
TABLE 1. Olefination of Iodo Ether 6
entry
conditions
products (%)a
1
2
3
In, AcOH, EtOH, rt
n-BuLi, THF, -78 °C
t-BuLi, THF, -78 °C
38 (38), 8 (50)
38 (43), recovered 6 (53)b
38 (29), recovered 6 (52)b
a Isolated yields. b Accompanied by small amounts of adduct 39
and cyclized 8.
Tertiary Alkoxyl Radical â-Scission and Subse-
quent Bridgehead Olefin Construction. With the
acquisition of the intermediate 8, â-scission of a tertiary
alkoxyl radical and subsequent reductive olefination were
pursued so as to produce the bridgehead double bond, a
characteristic of the CP structure (Scheme 7). Tertiary
alcohol 8 was thus treated with DIB and iodine under
the same conditions as for the radical dehydrogenation
of compound 10 to give the desired keto-iodide 6 as a
single diastereomer in 88% yield. The stereochemistry
associated with C16 in keto iodide 6 was assigned as (S)
on the basis of the coupling constant (JH16-17 ) 12.5 Hz).
It should be noted that a complex mixture was obtained
in the alkoxyl radical â-scission of alcohol 40 possessing
alkenyl substituent probably owing to interference of the
reactive olefin moiety with the reagents (Scheme 8).
The next task was to reduce the iodo ether functional-
ity so as to furnish the bridgehead double bond. Reductive
olefination of 6 with indium metal28 in the presence of
acetic acid in ethanol, however, gave olefin 38 in only
moderate yield (ca. 40%) due to competitive cyclization
leading to the isotwistane compound 8 (50%) (Table 1;
entry 1). The desired olefin 38 could be obtained by using
n-BuLi or t-BuLi as the transmetalation reagent,29 but
careful experimental operations were required to sup-
(23) (a) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara,
M. J. Am. Chem. Soc. 1982, 104, 5564-5566. (b) Stork, G.; Mook, R.,
Jr.; Biller, S. A.; Rychnovsky, S. D. J. Am. Chem. Soc. 1983, 105, 3741-
3742. For more recent instances, see: (c) Clive, D. L. J.; Yu, M.;
Sannigrahi, M. J. Org. Chem. 2004, 69, 4116-4125.
(24) (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-194. (b)
Chatgilialoglu, C.; Ferreri, C.; Gimisis, T. The Chemistry of Organic
Silicon Compounds; John Wiley & Sons: New York, 1998; Vol. 2,
Chapter 25.
(25) For development of silicon reagents for radical reactions, see:
(a) Yamazaki, O.; Yamaguchi, K.; Yokoyama, M.; Togo, H. J. Org.
Chem. 2000, 65, 5440-5442. (b) Sugi, M.; Togo, H. Tetrahedron 2002,
58, 3171-3175 and references therein.
(26) The stereochemistries associated with the ethyl acetal center
in each of compounds 28a and 28b have not been determined but we
have confirmed that common intermediate 3 in Scheme 10 was
similarly obtained from each isomer.
(27) Suzuki, K.; Matsumoto, T.; Tomooka, K.; Matsumoto, K.
Tsuchihashi, G. Chem. Lett. 1987, 113-116.
9266 J. Org. Chem., Vol. 69, No. 26, 2004

Studies on the Total Synthesis of (-)-CP-263,114
SCHEME 9. Olefination of Iodo Ether 7a
a
SCHEME 10 Synthesis of CP-Precursor 2
FIGURE 2. Plausible mechanism of olefination of 7a with
n-BuLi.
press the nucleophilic addition of the alkyllithium re-
agents to the carbonyl group of the substrate (Table 1;
entries 2 and 3): though the reaction was quenched so
that the starting iodo ether 6 remained, detectable
byproducts such as reagent-adduct 39 and cyclized
compound 8 were produced. These undesired reactions
were prevented completely on using alcohol 7a prepared
by reduction of ketone 6 with DIBAL (98% yield, 7a:7b
ca. 4:1) (Scheme 9). Major alcohol 7a30 was thus treated
with n-BuLi in THF at -78 °C to provide the expected
olefin 5 in 87% yield. â-Isomer 7b was converted to
ketone 6, which could be recycled in the reductive
olefination. Although the olefination of 7a takes place via
the poor orbital overlap in the transition state in which
the iodine atom at C16 is situated syn to the oxygen
functionality at C15, the coordination of the acetal oxygen
to lithium cation followed by the butyl anion transfer to
iodine atom may facilitate the efficient olefination of
compound 7a (Figure 2).29a
a Reagents and Conditions: (a) Ac2O, Et3N, DMAP, CH2Cl2, rt,
99%; (b) TBAF, AcOH, THF, rt, 92%; (c) Dess-Martin periodinane,
CH2Cl2, rt, 91%; (d) CrCl2, CH3CHI2, THF, rt, 92%; (e) 1,3-
propanedithiol, concentrated HCl, CH2Cl2, rt, 3 (47%), 44 (38%);
(f) 1,3-propanedithiol, concentrated HCl, CH2Cl2, rt, 73%; (g)
Dess-Martin periodinane, CH2Cl2, rt,; (h) PPTS, MeOH, rt, 74%,
2 steps.
Synthesis of CP-Precursor 2. The stage was now
set for transforming compound 5 into polycyclic CP-motif
(28) Reviews for indium chemistry in organic synthesis: (a) Cintas,
P. Synlett 1995, 1087-1096. (b) Li, C.-J.; Chan, T.-H. Tetrahedron
1999, 55, 11149-11176. (c) Ranu, B. Eur. J. Org. Chem. 2000, 2347-
2356. (d) Chauhan, K. K.; Frost, C. G. J. Chem. Soc., Perkin Trans. 1
2000, 3015-3019. (e) Podlech, J.; Maier, T. C. Synthesis 2003, 633-
655. (f) Miyabe, H.; Naito, T. Org. Biomol. Chem. 2004, 2, 1267-1270.
(g) Ueda, M. Yakugaku Zasshi 2004, 124, 311-319. (h) Nair, V.; Ros.
S.; Jayan, C. N.; Pillai, B. S. Tetrahedron 2004, 60, 1959-1982.
(29) (a) Maeda, K.; Shinokubo, H.; Ohshima, K.; Utimoto, K. J. Org.
Chem. 1996, 61, 2262-2263. (b) Ireland, R. E.; Habich, D.; Norbeck,
D. W. J. Am. Chem. Soc. 1985, 107, 3271-3278. (c) Wender, P. A.;
Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc. 1987, 109, 4390-4392.
(30) We initially assumed the stereochemistry of the newly gener-
ated hydroxyl group of the major alcohol 7a to be â since the hydride
attack seemed most likely to occur from the convex site of ketone 6.
The stereochemistry at C12 in compound 7a, however, was later
found to be R as shown in Figure 3 by NOESY analysis of the final
compound 2.
2 (Scheme 10). Acetylation of 5 followed by deprotection
of the tert-butyldiphenylsilyl (TBDPS) group of 41 with
TBAF produced alcohol 42 in 91% overall yield. Oxidation
of 42 with Dess-Martin periodinane and subsequent
olefination under the Takai condition31 resulted in the
formation of olefin 4 in 84% overall yield.32 Sequential
transformation of 4 into 3, involving cyclic thioketal
formation, SEM deprotection, and intramolecular trans-
acetylation, was found to proceed in one pot: diacetate
4 was treated with propanedithiol in a two-phase mixture
(31) Okazoe, T.; Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109,
951-953. Also, see ref 2g.
(32) A trace of Z-isomer of olefin 4 was also formed.
J. Org. Chem, Vol. 69, No. 26, 2004 9267

Yoshimitsu et al.
FIGURE 3. Selected NOESY and HMBC interactions in compound 2 and TMS derivative 46.
of concentrated hydrochloric acid and dichloromethane
to provide 3 (47%) along with 44 (38%). Isomeric acetate
44 was converted to the desired 3 in good yield under
the same acidic conditions. Dess-Martin oxidation of diol
3 afforded enone 45, which proved somewhat unstable.
Compound 45 was therefore subjected, without purifica-
tion, to methyl acetal formation with PPTS in methanol
to furnish the CP-precursor 2 in 74% overall yield. The
structure of 2 was confirmed by inspection of NOESY
interactions in 2 and HMBC correlations in TMS deriva-
tive 46 (Figure 3).
that enable the introduction of the key structural ele-
ments of the CP molecule and the usefulness of these
radicals in the synthesis of complex molecules. The
alkoxyl radical dehydrogenation is particularly useful
for the regioselective functionalization of unreactive
C-H bonds, and the â-scission used in combination with
the reduction of the resulting iodo ether function-
ality provides a new means for the synthesis of function-
alized olefins. Using the said precursor in possession,
studies toward accomplishing the total synthesis of
(-)-CP-263,114 (1) are presently underway.
In conclusion, fully functionalized polycyclic compound
2, an advanced precursor for the total synthesis of
(-)-CP-263,114 (1), was obtained in optically pure form.33
This study demonstrates the distinct chemical behavior
of primary and tertiary alkoxyl radicals leading to
hydrogen abstraction (10 f 11) and â-scission (8 f 6)
Acknowledgment. This research was supported by
a Grant-in-Aid for Young Scientists (No. 12771369) from
the Japan Society of the Promotion of Science.
Supporting Information Available: Full experimental
details, spectroscopic and analytical data, and 1H/13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(33) The present synthesis consists of a total of 40 steps from lactone
10 with an overall yield of ca. 0.45%. The overall yield was calculated
on the basis of the combined yield of 2 obtained from both 28a and
28b although the route from 28a to 3 appears only in this paper.
JO048681U
9268 J. Org. Chem., Vol. 69, No. 26, 2004