The C-ring problem of sterol biosynthesis: TiCl4-induced rearrangement into the anti-markovnikov cation corresponding to the C-ring

Article abstract of DOI:10.1021/ol0057582

(matrix presented) Cation 9, generated by the reaction of diol 8 and BF₃·Et₂O, SnCl₄, Sc(OTf)₃, FeCl₃, TiF₄, or CF₃SO₃H, leads to a hydride shift, providing cation 11,

Full text of DOI:10.1021/ol0057582

ORGANIC
LETTERS
2000
Vol. 2, No. 12
1685-1687
The C-Ring Problem of Sterol
Biosynthesis: TiCl4-Induced
Rearrangement into the
Anti-Markovnikov Cation Corresponding
to the C-Ring
Mugio Nishizawa,* Yoshihiro Iwamoto, Hiroko Takao, Hiroshi Imagawa, and
Takumichi Sugihara
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity,
Yamashiro-cho, Tokushima 770-8514, Japan
mugi@ph.bunri-u.ac.jp
Received March 6, 2000
ABSTRACT
Cation 9, generated by the reaction of diol 8 and BF3‚Et2O, SnCl4, Sc(OTf)3, FeCl3, TiF4, or CF3SO H, leads to a hydride shift, providing cation
3
11, which corresponds to the initiation of backbone rearrangement. On the other hand, TiCl4 selectively induces rearrangement to secondary
cation 13 by ring expansion, which corresponds to the C-ring formation of sterol biosynthesis. AlCl3 and ZrCl4 induce further rearrangement
into six-membered ring tert-cation 16.
On the basis of the idea of the stepwise mechanism of
biomimetic olefin cyclization1,2 and enzymatic cyclization
of oxidosqualene via conformationally flexible cationic
intermediates,3,4 significant attention has been focused on
each step of sterol biosynthesis. Today, the biosyntheses of
phytosterols such as dammaranoid, lupanoid, oleananoid, and
tirucallanoid are explained by the cyclization of oxi-
dosqualene via bicyclic cation 1, tricyclic 6/6/5-cation (pre-C
ring cation) 2, secondary 6/6/6-cation 3, and 6/6/6/5 cation
4 (Scheme 1). In the animal kingdom, steroids are also
constructed through the corresponding boat-form B-ring
(1) (a) Nishizawa, M.; Takenaka, H.; Hayashi, Y. J. Am. Chem. Soc.
1985, 107, 522-523. (b) Nishizawa, M.; Takenaka, H.; Hayashi, Y. J. Org.
Chem. 1986, 51, 806-813.
(2) (a) van Tamelen, E. E. J. Am. Chem. Soc. 1982, 104, 6480-6481.
(b) Dewar, M. J. S.; Reynolds, C. H. J. Am. Chem. Soc. 1984, 106, 1744-
1750.
6
intermediates.5,6 Recently, we have shown that /5 trans
selective cyclization from 1 to 2 does not depend on any
special enzyme effect by achieving a similar Lewis acid-
promoted trans selective cyclization of 5 to 6.7 This may be
due to the steric repulsion between the angular methyl and
C-12 and C-13 methylenes for 6/5 cis cyclization as illustrated
(3) (a) Corey, E. J.; Matsuda, S. P. T.; Bartel, B. Proc. Natl. Acad. Sci.
U.S.A. 1994, 91, 2211-2215. (b) Corey, E. J.; Virgil, S. C.; Cheng, H.;
Baker, C. H.; Matsuda, S. P. T.; Singh, V.; Sarshar, S. J. Am. Chem. Soc.
1995, 117, 11819-11820. (c) Corey, E. J.; Cheng, H. Tetrahedron Lett.
1996, 37, 2709-2712. (d) Corey, E. J.; Cheng, H.; Baker, C. H.; Matsuda,
S. P. T.; Li, D.; Song, X. J. Am. Chem. Soc. 1997, 119, 1277-1288. (e)
Corey, E. J.; Cheng, H.; Baker, C. H.; Matsuda, S. P. T.; Li, D.; Song, X.
J. Am. Chem. Soc. 1997, 119, 1289-1296. (f) Dodd, D. S.; Oehlschlager,
A. C. J. Org. Chem. 1992, 57, 2794-2803. (g) Zheng, Y. F.; Oehlschlager,
A. C.; Georgopapadakou, N. H.; Hartman, P. G.; Scheliga, P. J. Am. Chem.
Soc. 1995, 117, 670-680.
(4) (a) Abe, I.; Rohmer, M.; Prestwich, G. D. Chem. ReV. 1993, 93,
2189-2206. (b) Sato, T.; Abe, T.; Hoshino, T. Chem. Commun. 1998,
2617-2618. (c) Zheng, Y. F.; Abe, I.; Prestwich, G. D. J. Org. Chem.
1998, 63, 4872-4873. (d) Kushiro, T.; Shibuya, M.; Ebizuka, Y. J. Am.
Chem. Soc. 1999, 121, 1208-1216.
(5) (a) Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D. HelV. Chim.
Acta 1955, 38, 1890-1904. (b) Corey, E. J.; Virgil, S. C. J. Am. Chem.
Soc. 1991, 113, 4025-4026. (c) Corey, E. J.; Wood, H. B., Jr. J. Am. Chem.
Soc. 1996, 118, 11982-11983.
(6) Nishizawa, M.; Takenaka, H.; Hirotsu, K.; Higuchi, T.; Hayashi, Y.
J. Am. Chem. Soc. 1984, 106, 6, 4290-4291.
(7) (a) Nishizawa, M.; Takao, H.; Iwamoto, Y.; Yamada, H.; Imagawa,
H. Synlett 1998, 76-78. (b) Nishizawa, M.; Takao, H.; Iwamoto, Y.;
Yamada, H.; Imagawa, H. Synlett 1998, 79-80.
10.1021/ol0057582 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/18/2000

kov cation 13 leading to 14 or 15. Although most of the
Lewis acids afforded only spiro cyclization product 12 via
hydride shift generating cation 11, TiCl4 surprisingly gener-
ated anti-Markovnikov cation 13 selectively. Furthermore,
we found that AlCl3 and ZrCl4 selectively led the rearrange-
ment to the unexpected six-membered ring tert-cation 16 via
13.
Scheme 1
Although diol 8 was inert against BF3‚Et2O (3 equiv) in
CH2Cl2 under 0 °C, rapid reaction took place at room
temperature, affording spirocyclic 12 as the sole product in
82% yield. Reaction of 8 with 3 equiv of SnCl4, Sc(OTf)3,
FeCl3, TiF4, or CF3SO3H in CH2Cl2 at room temperature for
30 min also provided only the spiro ether 12 as shown in
Table 1.
Table 1. Reaction of Diol 8 with Acid and Lewis Acids in
CH2Cl2
product (% yield)
entry
acid
12 14 15 17 18 19 20 21
1
2
3
4
5
6
7
8
9
10
11
12
13
BF3‚Et2O
SnCl4
Sc(OTf)3
FeCl3
FeCl2
CF3SO3H
TiF4
TiCl4
TiCl2(O-i-Pr)2
ZnCl2
Zn(OTf)2
AlCl3
ZrCl4
82
90
51
76
in 7.3c,8 The next problem to be solved was the Markovnikov
wall.3d,9
Transformation of 2 to 3 involves ring expansion of a
tertiary cationic substrate into a secondary cation, namely,
an anti-Markovnikov cation. Although related biomimetic10a,b
as well as chemical10c,d rearrangements have been reported,
the possibility of achieving the transformation of 2 to 3 as a
chemical reaction remained uncertain. We chose diol 8 as
the model compound and investigated the chemical behavior
of the generated cation 9. Three possibilities were suggested
for the further direction of cation 9 (Scheme 2): (1) direct
88
76
1
16
13 26
9
16
7
87
84
However, the reaction of 8 with 3 equiv of TiCl4 in CH2-
Cl2 at room temperature afforded an entirely different result.
Intensive purification of the complicated reaction mixture
provided 6/5 cis-fused ether 14 (16% yield), cis chloro alcohol
17 (13% yield) and trans isomer 18 (26% yield), another 6/5
cis-fused ether (19, 9% yield), another cis chloro alcohol
(20, 16% yield), and another trans chloro alcohol (21,7%
yield) along with 1% of 12 (Scheme 3). Products 19-21
Scheme 2
Scheme 3
cyclization to give oxetane ring 10, (2) hydride shift to 11
and cyclization affording spirocyclic tetrahydrofuran 12, and
(3) biomimetic ring enlargement to generate anti-Markovni-
(8) (a) Berckmoes, K.; De Clercq, P. J. J. Am. Chem. Soc. 1995, 117,
5857-5858. (b) Heinemann, C.; Demuth, M. J. Am. Chem. Soc. 1997, 119,
1129-1130.
(9) Krief, A.; Schauder, J. R.; Guittet, E.; du Penhoat, C. H.; Lallemand,
J. Y. J. Am. Chem. Soc. 1987, 109, 7910-7911.
(10) (a) Corey, E. J.; Nozoe, S. J. Am. Chem. Soc. 1965, 87, 5733-
5735. (b) Ohfune, Y.; Shirahama, H.; Matsumoto, T. Tetrahedron Lett. 1976,
2869-2872. (c) Olah, G. A.; Bollinger, J. M.; Cupas, C. A.; Lukas, J. J.
Am. Chem. Soc. 1967, 89, 2693-2694. (d) Harding, K. E.; Clement, K. S.
J. Org. Chem. 1984, 49, 2049-2050.
should be generated via cation 16 through 1,2-migration of
the side chain from 13. The expected /5 trans-fused ether
15 was not detected in any reaction.
Reaction of 8 with AlCl3 or ZrCl4 under the same
conditions provided another unexpected result. Only double-
6
1686
Org. Lett., Vol. 2, No. 12, 2000

rearrangement and etherification product 19 was obtained
in 87% and 84% yields, respectively. Treatment of 8 with
FeCl2, TiCl2(O-i-Pr)2, ZnCl2, or Zn(OTf)2 did not provide
any reaction product, and most of the starting material was
recovered.
Scheme 5
Structural studies were carried out carefully by preparing
authentic materials as illustrated in Scheme 4.11-13 Stereo-
of 29 and 30 in 87% yield (Scheme 5). Now we can state
that the C-ring formation of steroid biosynthesis may be
altered without an enzyme. The hydride shift observed in
the reactions with most of the Lewis acids is also very
important since it corresponds to the initiation of the
backbone rearrangement.
Scheme 4
It is extremely exciting to consider how the clear selectivity
comes about.14 MM2 calculation of cations 9 using the
CAChe-CONFLEX program elucidated the existence of two
conformers 9a and 9b in 93% and 6% yields, respectively
(Scheme 6).15 The cationic plane of major conformer 9a is
Scheme 6
chemical assignments of 17 and 18 were also achieved by
NOE experiments. Clear NOE cross-peaks between the axial
methyl group and the axial protons in a 1,3 relationship were
detected for 18, whereas 17 did not show any distinctive
NOE cross-peaks between the methyl group and the axial
protons. Stereochemical assignments of 20 and 21 were also
achieved by NOE experiments.
Since only a small amount of five-membered ring product
12 was detected by the reaction of 8 with TiCl4 (entry 8),
we concluded that migration of 9 to anti-Markovnikov cation
13 was controlled with very high selectivity by reflecting
the nature of the counteranion. It is also important to note
that rather than the expected etherification the predominant
reaction path against TiCl4 is chlorination. This should be
due to the tight coordination of TiCl4 into a primary alcohol,
decreasing the nucleophilicity. Accordingly, next we exam-
ined the reaction of acetate 8a. Upon treatment of 8a with
TiCl4 (2 equiv) in CH2Cl2 at room temperature for 1 h, a
very clean reaction took place to give a 3:2 mixture of 17a
and 18a in 86% yield. In sharp contrast, treatment of 8a with
BF3‚Et2O under similar conditions afforded a 2:3 mixture
perpendicular to the marked C-H bond and favorable for
the hydride shift to generate cation 11. On the other hand,
the marked C-C bond of minor conformer 9b is perpen-
dicular to the cationic plane and favorable for C-C bond
migration, affording anti-Markovnikov cation 13. Detection
of the actual conformational change reflecting the nature of
the counteranion is the next target of our research.
Acknowledgment. This study was financially supported
by the Japan Private School Promotion Foundation and by
Grant-in-Aid for Scientific Research 09480146 from the
Ministry of Education, Science, Sports and Culture of the
Japanese Government.
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 10, 12, 14, 15,
17, 18, 19, 20, 21, 22, 23, 24, 25, 27, and 28. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0057582
(14) When oxetane 10 and spiro ether 12 were treated with TiCl4 in
CH2Cl2 at room temperature, an ca. 6:3:1 mixture of 14, 17, and 18 was
formed in nearly quantitative yield. Double rearrangement products such
as 19-21were not detected at all.
(15) Goto, H.; Osawa, E. J. Chem. Soc., Perkin Trans. 2 1993, 187-
198.
(11) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 4713-
4714.
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Commun. 1986, 1568-1569.
(13) Hooz, J.; Gilani, S. S. H. Can. J. Chem. 1968, 46, 86-87.
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