Catalytic diastereoselective polycyclization of homo(polyprenyl)arene analogues bearing terminal siloxyvinyl groups

Article abstract of DOI:10.1021/ol062378t

Highly diastereoselective polycyclization of homo(polyprenyl)arene analogues bearing terminal siloxyvinyl groups was catalyzed by tin(IV) chloride (10 mol %). The cyclizations of tert-butyldiphenylsilyl and triisopropylsilyl polyenol ethers gave 4α(equatorial)- and 4β(axial)-siloxypolycycles as major isomers, respectively. The strong nucleophilicity of pro-C(9), a (6E) geometry, and a bulky silyl group effectively favored the 4α-preference, whereas the weak nucleophilicity of pro-C(9), a (6Z)-geometry, and less steric hindrance of a silyl group favored the 4β-preference.

Full text of DOI:10.1021/ol062378t

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5649-5652
Catalytic Diastereoselective
Polycyclization of
Homo(polyprenyl)arene Analogues
Bearing Terminal Siloxyvinyl Groups
Muhammet Uyanik,† Kazuaki Ishihara,*,† and Hisashi Yamamoto*,‡
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa,
Nagoya 464-8603, Japan, and Department of Chemistry, The UniVersity of Chicago,
5735 South Ellis AVenue, Chicago, Illinois 60637
ishihara@cc.nagoya-u.ac.jp; yamamoto@uchicago.edu
Received September 27, 2006
ABSTRACT
Highly diastereoselective polycyclization of homo(polyprenyl)arene analogues bearing terminal siloxyvinyl groups was catalyzed by tin(IV)
chloride (10 mol %). The cyclizations of tert-butyldiphenylsilyl and triisopropylsilyl polyenol ethers gave 4 (equatorial)- and 4 (axial)-
siloxypolycycles as major isomers, respectively. The strong nucleophilicity of pro-C(9), a (6E) geometry, and a bulky silyl group effectively
favored the 4 -preference, whereas the weak nucleophilicity of pro-C(9), a (6Z)-geometry, and less steric hindrance of a silyl group favored
the 4 -preference.
r
â
r
â
Biomimetic polyene cyclization is an important key step in
the concise total synthesis of polycyclic natural products.1,2
In particular, the Lewis acid promoted diastereoselective
cyclization of polyenic aldehyde acetals to 4â(axial)-alkoxy-
polycycles3 (4â/4R ) ca. 2-17) has been established by
Johnson et al.1 However, excess SnCl4 is often required as
Lewis acid, and there are no methods available for the
synthesis of 4R(equatorial)-alkoxypolycycles. We report here
the SnCl4 (10 mol %)-catalyzed polycyclization of homo-
(polyprenyl)arene analogues bearing terminal siloxyvinyl
groups, which were much more reactive than other initiators
such as acetals, aldehydes, and ketones.4 The R(equatorial)/
â(axial) selectivity of 4-siloxy group3 at polycycles could
be controlled by the nucleophilicity of pro-C(9)3 and the
steric effect of a silyl group.
Initially, we investigated the reactivity and diastereo-
selectivity of the cyclization of (E)-enone 1 in the presence
of 10 mol % of SnCl4 in CH2Cl2 at -78 °C (Scheme 1).
The conversion to trans-tricycles 2 (4â-OH 68% ds) was
18% even after 24 h because of the relatively strong basicity
of the carbonyl oxygen in 1.5 Interestingly, 2R (4R-OH) was
† Nagoya University.
‡ The University of Chicago.
(1) For reviews, see: (a) Johnson, W. S. Tetrahedron 1991, 47, xi-1.
(b) Yoder, R. A.; Johnston, J. N. Chem. ReV. 2005, 105, 4730-4756. To
the best of our knowledge, there are no examples of polycyclization of
ketals.
(4) For Pd(II)-catalyzed polyene cyclizations, see: (a) Koh, J. H.;
Mascarenhas, C.; Gagne´, M. R. Tetrahedron 2004, 60, 7405-7410. For
Hg(II)-catalyzed polyene cyclizations, see: (b) Imagawa, H.; Iyenaga, T.;
Nishizawa, M. Org. Lett. 2005, 7, 451-453.
(5) For an example of the successful cyclization of (E)-9-phenyl-1,1,1-
trifluoronona-5-en-2-one with MeAlCl2 (1.1 equiv) to 4-CF3-trans-10-
methylpodocarpatrienol (90% yield; 4â-OH 100% ds), see: Abouabdellah,
A.; Bonnet-Delpon, D. Tetrahedron 1994, 50, 11921-11932.
(2) For our recent contributions, see: (a) Kumazawa, K.; Ishihara, K.;
Yamamoto, H. Org. Lett. 2004, 6, 2551-2554. (b) Ishibashi, H.; Ishihara,
K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 11122-11123. (c) Uyanik,
M.; Ishibashi, H.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 1601-
1604. (d) Uyanik, M.; Ishihara, K.; Yamamoto, H. Bioorg. Med. Chem.
2005, 13, 5055-5065.
(3) Steroid numbering.
10.1021/ol062378t CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/04/2006

ratio of 4 (entries 3-6). These results suggested that the
cyclization of 4 proceeded via siloxycarbenium ion inter-
mediates. Although similar 4R/4â-selectivities were observed
in CH2Cl2 and toluene (entries 3-6), not only cyclization
but also the subsequent over-reaction from 5R to alkene 6
proceeded more rapidly in CH2Cl2. 4â-Siloxy isomer 5â was
produced as a major isomer from less bulky triisopropylsilyl-
(TIPS) dienol ethers 4, whereas 4R-siloxy isomer 5R was
produced as a major isomer from more bulky tert-butyldi-
methylsilyl(TBDPS) dienol ethers 4. The substituents of the
phenyl group of 4 also influenced the 4R/4â-selectivity:
weaker nucleophilicity at the ortho-position (pro-C(9)3) of
4 increased 4â-selectivity, whereas stronger nucleophilicity
increased 4R-selectivity. Thus, 5aâ was produced from 4a
in 90% yield with >99:1 dr (entry 1). On the other hand,
5fR was produced from 4f in 90% yield with 14:1 dr (entry
9). The R-selectivity of 4f was opposite that of the corre-
sponding ketone 1 (see Scheme 1).
Scheme 1. Cyclization of (E)-Enone 1 to trans-Tricyclic
Alcohols 2
converted to dehydrated alkene 3 under more acidic condi-
tions, but 2â (4â-OH) was stable under the same conditions.
Next, (2E,6E)-, (2Z,6E)-, and (1,6E)-isomeric mixtures of
silyl (6E)-dienol ethers 4 derived from (E)-6-enones were
examined in the presence of 10 mol % of SnCl4 (Table 1).6
Next, (2E,6E)-, (2Z,6E)-, and (1,6E)-isomeric mixtures of
silyl (6E,10E)-trienol ethers 7 derived from (E,E)-6,10-
dienones were examined in the presence of 10 mol % of
SnCl4 (Table 2). Surprisingly, 4R-selective cyclization of 7
Table 2. Cyclization of Silyl (6E,10E)-Trienol Ethers 7 to 8
Table 1. Cyclization of Silyl (6E)-Dienol Ethers 4 to
trans-Tricycles 5
solvent,
time (h)
8 + 9,
yield (%)b
solvent,
time (h)
5,
a
a
entry
7 [R1, SiR2
]
3
(8R:9):8â
entry
4 [R1, SiR2
]
3
yield (%)b
(5R:6):5â
1c
2
3
4
5
6
7
8
9
4a [p-F, TIPS]
4b [H, TIPS]
toluene, 24
toluene, 2
CH2Cl2, 3
toluene, 2
CH2Cl2, 2.5
toluene, 1.5
toluene, 3
5a, 90
5b, 99
5c, 90
5c, 95
5c, 91
5c, 93
5d, 95
5e, 93
5f, 90
(<1:<1):>99
(7:<1):93
(1:10):89
(11:5):84
(9:8):83
(13:2):85
(36:4):60
(63:6):31
(85:9):6
1
2
3
7a [p-Me, TIPS]
7b [m-Me, TIPS]
7c [m-Me, TBDPS] CH2Cl2, 2 8c, 96
toluene, 4 8a + 9a, 92 (58:5):37
toluene, 3 8b + 9b, 91 (57:6):37
4c [p-Me, TIPS]d
4c [p-Me, TIPS]d
4c [p-Me, TIPS]e
4c [p-Me, TIPS]e
4d [m-Me, TIPS]
(91:<1):9
a A (2E)-2-, (2Z)-2-, and 1-enyl mixture of 7. b 8 and 9 were inseparable.
See also ref 7. No detectable amounts of cis-isomers 8 were obtained.
4e [p-Me, TBDPS] CH2Cl2, 3
4f [m-Me, TBDPS] CH2Cl2, 3
to 4-siloxytetracycles 8 proceeded catalytically independent
of the nucleophilicity of the terminal aryl groups (entries 1
and 2). The cyclization of tert-butyldimethylsilyl trienol ether
7c gave 8R with 91:9 dr in 96% yield (entry 3). The
R-preference for 8 could be understood by the relatively
strong nucleophilicity of pro-C(9)3 of 7.8
a A (2E)-2-, (2Z)-2-, and 1-enyl mixture of 4. b Isolated yield. See also
ref 7. No detectable amount of cis-isomer 11 was obtained. c SnCl4 (1 equiv)
was used. d Isomeric ratio of (2E)-2-, (2Z)-2-, 1-enes 4c ) 14:71:15.
e Isomeric ratio of (2E)-2-, (2Z)-2-, 1-enes 4c ) 2:29:69.
For comparison with silyl (6E)-dienol ethers 4, cyclization
of its (6Z)-isomers 10 was also performed under the same
Fortunately, the 4R/4â-selective cyclization of 4 to 4-siloxy-
tricycles 5 proceeded smoothly independent of the isomeric
(7) 4R- and 4â-Hydroxy polycycles could be separated from each other
by column chromatography.
(6) The cyclization of 1 with i-Pr3SiOTf (1 equiv) at -78 °C for 24 h
gave 2 (4â-OH 66% ds) and 3 in respective yields of 18% and 10%.
(8) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-
77.
5650
Org. Lett., Vol. 8, No. 24, 2006

Table 3. Cyclization of Silyl (6Z)-Dienol Ethers 10 to
cis-Tricycles 11
Table 4. Cyclization of (E)-Enals 13 and Their Silyl Dienol
Ethers 14
time
(h)
11,
a
entry
10 [R1, SiR2
]
3
yield (%)b (11R:12):11â
time
(h)
15 or 16,
1
2
3
10a [p-Me, TIPS]
10b [m-Me, TIPS]
10c [m-Me, TBDPS]
24
1
1
11a, 90
11b, 94
11d, 98
(<1:<1):>99
(6:7):87
(62:<1):38
entry
13 or 14 [R1, R2]
yield (%)a
4R:4âb
1c
2c
3
4
5c,e
13a [p-Me, -]
13b [m-Me, -]
14a [p-Me, TIPS]d
14b [m-Me, TIPS]d
14b [m-Me, TIPS]f
0.5
0.5
1
3
12
15a, 87
15b, 89
16a, 97
16b, 97
16b, ca. 80
40:60
55:45
1:99
<1:>99
ca. 25:75
a A (2E)-2-, (2Z)-2-, and 1-enyl mixture of 10. b Isolated yield. See also
ref 7. No detectable amount of cis-isomer 11 was obtained.
a Isolated yield. See also ref 7. No detectable amount of cis-isomer was
obtained. b For 15 or 16. c Yields of 17 or 18 were 11% (entry 1), 10%
(entry 2), and ca. 20% (entry 5). d 1E/1Z ratio of 14 ) <1:>99. e SnCl4
(20 mol %) was used. f 1E/1Z ratio of 14 ) 76:24.
conditions (Table 3). Surprisingly, cis-tricycles 11 were
produced in high yield without any detectable 5. Overall,
the reactivity of 10 was much lower than that of 4 because
the B-ring formation of 11 should occur through the
thermodynamically unfavorable boat-like transition state.
Interestingly, 4â-selectivity of 11 was increased in compari-
son with that of 5. For example, the cyclization of 10a gave
11aâ in 90% yield with >99:1 dr (entry 1), whereas the
cyclization of 4c gave 5câ in 90% yield with 89:1 dr (entry
3, Table 1).
The 4R-selective cyclization would proceed concertedly or
stepwise through antiperiplanar (chair-chair-like) transition
state (TS) 19. On the other hand, the 4â-selective cyclization
would proceed stepwise through synclinal TS-20 or 21
stabilized by Coulomb attractive interaction (minimalization
The cyclization of (E)-5-enals 13 and their silyl (5E)-dienol
ethers 14 was also examined under the same conditions
(Table 4). In the cyclization of 13, A-ring formation occurred
quantitatively with very low 4R/4â-selectivities,9 but mono-
cycles 17 were produced in ca. 10% yield together with
bicycles 15 (entries 1 and 2). In contrast, in the cyclization
of (1Z)-14, 16â was produced in 97% yield with g99:1 dr
regardless of the nucleophilicity of the aryl group of 14
(entries 3 and 4). Although (1E)-14b was much less reactive
than (1Z)-14b, (1E)-14b also give 16bâ as a major isomer
(entry 5). This result suggested that the E/Z-isomerization
of silyl enol ethers derived from aldehydes was relatively
slow and cyclization to 16R was essentially disfavored.
The proposed mechanism is shown in Figure 1. The
regioselective protonation of polyenic silyl enol ethers with
SnCl4‚(H2O)n would induce the subsequent polycyclization.10
Figure 1. Proposed transition-state assemblies 19-21.
of charge separation) between O and pro-C(10).3,11 The
strong nucleophilicity of pro-C(9),3 a (6E)-geometry, and a
bulky silyl group would effectively favor TS-19, whereas
the weak nucleophilicity of pro-C(9),3 a (6Z)-geometry, and
less steric hindrance of a silyl group would favor TS-20 or
21.
(9) For a previous example of the cyclization of a polyenal with SnCl4
(3 equiv) to 4-hydroxypentacycles (49% yield; 4â-OH 84% ds), see: Fish,
P. V.; Johnson, W. S. J. Org. Chem. 1994, 59, 2324-2335.
(10) Although the possibility of the stannylation with SnCl4 cannot be
completely exluded, the subsequent protiodestannation step would be
difficult. In fact, the use of freshly distilled SnCl4 was required to give
polycycles in high yield. Nevertheless, the existence of a trace amount of
water can not be denied. Therefore, SnCl4‚(H2O)n may serve as a Lewis
acid assisted Brønsted acid catalyst. Other Lewis acids such as Sn(OTf)2,
Sc(OTf)3, and Yb(OTf)3 were inert for the present cyclization under the
same conditions as that for SnCl4.
(11) For the synclinal preference by Coulomb attractive interaction,
see: (a) Seebach, D.; Golinski, J. HelV. Chim. Acta 1981, 64, 1413-1423.
(b) Denmark, S. E.; Weber, E. J.; Wilson, T. M.; Wilson, T. M. Tetrahedron
1989, 45, 1053-1065. (c) Yamanaka, M.; Mikami, K. HelV. Chim. Acta
2002, 85, 4264-4271.
Org. Lett., Vol. 8, No. 24, 2006
5651

sized from 4h and 14c with >99% 4R and >99% 4â,
respectively (Scheme 2).7 The anti-herpes active diterpenoid
15c,13 a synthetic intermediate of 24, was also synthesized
with >99:1 dr.
Scheme 2. Total Syntheses of Epimers 22 and 24
Although it was difficult to directly generate silyloxocar-
benium ion intermediates from aldehydes and ketones with
silyl Lewis acids,6 we succeeded in their catalytic generation
with SnCl4 from silyl enol ethers instead of carbonyl
compounds. The main advantage in the catalytic use of SnCl4
is to avoid or to minimize secondary reactions of the
polycyclic products, i.e., elimination of the siloxy groups
(See Scheme 1). The present results demonstrate the synthetic
advantages of using polyprenoid analogues bearing a terminal
siloxyvinyl group as substrates of polyene cyclization with
respect to both the reactivity and 4R/4â-diastereocontrol.5
Acknowledgment. Financial support for this project was
provided by SORST, JST, the Novartis Foundation (Japan)
for the Promotion of Science, and the 21st Century COE
Program of MEXT. We also acknowledge Dr. Manabu
Hatano for the single-crystal X-ray analysis.
Supporting Information Available: Experimental pro-
cedures, full characterization of new compounds, and NMR
spectra of polycyclic compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL062378T
(12) (a) Rowe, J. W.; Nagasampagi, B. A.; Burgstahler, A. W.;
Fitzsimmons, J. W. Phytochemistry 1971, 10, 1647-1651. (b) Lee, C.-K.;
Fang, J.-M.; Cheng, Y.-S. Phytochemistry 1995, 39, 391-394. (c) Dakir,
M.; El Hanbali, F.; Mellouki, F.; Akssira, A.; Benharref, A.; Quilez Del
Moral, J. F.; Barrero, A. F. Nat. Prod. Res. 2005, 19, 719-722.
(13) (a) Akita, H.; Otsuka, Y. Japan Kokai Tokkyo Koho, JP51098258
and JP51098267, 1976. (b) Tagat, J. R.; Nazareno, D. V.; Puar, M. S.;
McCombie, S. W.; Ganguly, A. K. Bioorg. Med. Chem. Lett. 1994, 4, 1101-
1104.
On the basis of the above experimental results, two natural
diterpenoids, 18-norabieta-8,11,13-trien-4-ol (22),12 which
has antibacterial activity, and its epimer 2412 were synthe-
5652
Org. Lett., Vol. 8, No. 24, 2006