TiCl4 induced anti-Markovnikov rearrangement

Article abstract of DOI:10.1021/ol062337x

(Diagram presented) Stereoisomeric bicyclic tert-alcohols afforded identical ring-expansion products via cationic anti-Markovnikov rearrangement from perpendicular tert-cations into identical six-membered ring secondary cations by the treatment with TiCl<

Full text of DOI:10.1021/ol062337x

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5793-5796
TiCl4 Induced Anti-Markovnikov
Rearrangement
Mugio Nishizawa,* Yumiko Asai, and Hiroshi Imagawa
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity, Yamashiro-cho,
Tokushima 770-8514, Japan
mugi@ph.bunri-u.ac.jp
Received September 22, 2006
ABSTRACT
Stereoisomeric bicyclic tert-alcohols afforded identical ring-expansion products via cationic anti-Markovnikov rearrangement from perpendicular
tert-cations into identical six-membered ring secondary cations by the treatment with TiCl4. These results provide evidence that the reaction
takes place by the cationic stepwise mechanism.
In 1995, Corey and co-workers1,2 confirmed that the bio-
syntheses of sterols involves the tricyclic 6/6/5-cation (pre-
C-ring cation) 1, the 6/6/6-cation 2, and the 6/6/6/5-cation 3
(Scheme 1).3,4 Hydride shift (a) and C-C bond migration
sec-cation, the so-called anti-Markovnikov rearrangement.
The energetic disadvantage of this ring expansion was shown
by Jorgensen through calculation of a model cation.5 Hess
as well as Gao have proposed a concerted mechanism from
(1) (a) Corey, E. J.; Virgil, S. C.; Liu, D. R.; Sarshar, S. J. Am. Chem.
Soc. 1992, 114, 1524-1525. (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.; Matsuda, S. P. T.; Bartel, B. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 2211-2215. (e) T. Sato, T. Abe, T.
Hoshino, Chem. Commun. 1998, 2617-2618.
Scheme 1
(2) (a) Hoshino, T.; Sato, T. Chem. Commun. 2002, 291-301. (b) Wendt,
K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew. Chem., Int. Ed. 2000,
39, 2812-2833. (c) Abe, I.; Rohmer, M.; Prestwich, G. D. Chem. ReV.
1993, 93, 2189-2206.
(3) (a) Woodward, R. B.; Bloch, K. J. Am. Chem. Soc. 1953, 75, 2023-
2024. (b) Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D. HelV. Chim.
Acta 1955, 38, 1890-1904. (c) Stork, G.; Burgstahler, A. W. J. Am. Chem.
Soc. 1955, 77, 5068-5077. (d) Cornforth, J. W.; Cornforth, R. H.;
Donninger, C.; Popjak, G.; Shimizu, Y.; Ichii, S.; Forchielli, E.; Caspi, E.
J. Am. Chem. Soc. 1965, 87, 3224-3228. (e) Corey, E. J.; Russey, W. E.;
Ortiz de Montellano, P. R. J. Am. Chem. Soc. 1966, 88, 4750-4751. (f)
van Tamelen, E. E.; Willett, J. D.; Clayton, R. B.; Load, K. E. J. Am. Chem.
Soc. 1966, 88, 4752-4754. (g) Johnson, W. S. Acc. Chem. Res. 1967, 1,
1-8.
(4) (a) Zheng, Y. F.; Abe, I.; Prestwich, G. D. J. Org. Chem. 1998, 63,
4872-4873. (b) Kushiro, T.; Shibuya, M.; Ebizuka, Y. J. Am. Chem. Soc.
1999, 121, 1208-1216. (c) Abe, I.; Sakano, Y.; Sodeyama, M.: Tanaka,
H.; Noguchi, H.; Shibuya, M.: Ebizuka, Y. J. Am. Chem. Soc. 2004, 126,
6880-6881. (d) Hoshino, T.; Shimizu, K.; Sato, T. Angew. Chem., Int. Ed.
2004, 43, 6700-6703.
(b) from 3 are competing processes leading to tirucallanoids
and tetrahymanoids, respectively. In the animal kingdom,
steroids are also constructed through the corresponding boat-
form B-ring intermediates.1,2,4 The transformation of 1 into
2 involves ring expansion of a tert-cation into an unstable
(5) Jenson, C.; Jorgensen, W. L. J. Am. Chem. Soc. 1997, 119, 10846-
10854.
10.1021/ol062337x CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/16/2006

1 to 2 on the basis of ab initio calculation of model cations
without considering the contribution of counteranions.6
We have also reported the C- and D-ring problem from
an experimental viewpoint by following the fate of model
cation 4.7 When the cation was generated by the reaction of
diol 5 with a variety of Lewis acids, only the spiro product
7 was obtained via a hydride shift to 6 that corresponds to
the conversion a from 3. However, TiCl4 generated the anti-
Markovnikov cation 8 selectively and afforded the six-
membered ring compound 9 along with other related
products, and this result corresponds to the rearrangement
Now we have prepared hydroxy acetate (R)-10 as an
optically active form with 94% ee as seen in chiral GLC
(Figure 1a). Treatment of (R)-10 with 3.0 equiv of TiCl4 in
Scheme 2
Figure 1. GLC analysis using CHROMPACK Cyclodextrine-b-
236M-19 (0.25 × 25 M)
CH2Cl2 at room temperature for 2 h afforded a mixture of
the anti-Markovnikov rearrangement products 11 and 12 in
93% yield in a 3:7 ratio (Scheme 3). Separation of 11 and
Scheme 3
from 1 to 2 and by following path b from 3. This remarkable
selectivity achieved with TiCl4 was explained by the coun-
teranion-controlled conformational changes on the basis of
ab initio calculations.8 We concluded that counteranion
[BF3‚OH]- reinforces the parallel conformation 4-I, from
which the hydride shift is the possible transformation. On
the other hand, counteranion [TiCl4‚OH]- reinforces the
perpendicular conformation 4-II, from which the migration
of C-C bond is the possible transformation. These were, in
fact, the first theoretical calculations of cation conformations
in the presence of counteranions9 and the first example to
overcome the considerable energy barrier (the “big Mark-
ovnikov wall”) in cation chemistry. We have achieved
generalization of this novel anti-Markovnikov rearrangement
by confirming the existence of cationic intermediates.10
12 was achieved by HPLC, and the purified 11 and 12 were
proved to be racemates as seen in chiral GLC analysis (Figure
1b,c). On the other hand, treatment of the alcohol (R)-10
with 2.1 equiv of BF3‚Et2O in CH2Cl2 at room temperature
for 30 min afforded a 1:1 mixture of alkenes 13a and 14 in
93% yield. Separation of 13a and 14 was accomplished by
using HPLC. Since baseline separation of 13a was not
achieved on chiral GLC analysis, the acetyl group was
cleaved by using NaOMe in MeOH to give alcohol 13b, and
the purified 13b was shown to be a racemate by chiral GLC
(Figure 1d). We conclude that the reaction of (R)-10 with
TiCl4 takes place by forming achiral perpendicular cation
15, followed by rearrangement into racemic six-membered
(6) (a) Hess, B. A., Jr. J. Am. Chem. Soc. 2002, 124, 10286-10287. (b)
Rajamani, R.; Gao, J. J. Am. Chem. Soc. 2003, 125, 12768-12781. (c)
Hess, Jr., B. A. Org. Lett. 2003, 5, 165-167. (d) Vrcek, V.; Saunders, M.;
Kronja, O. J. Org. Chem. 2003, 68, 1859-1866. (e) Xiong, Q.; Rocco, F.;
Wilson, W. K.; Xu, R.; Ceruti, M.; Matsuda, S. P. T. J. Org. Chem. 2005,
70, 5362-5375.
(7) Nishizawa, M.; Iwamoto, Y.; Takao, H.; Imagawa, H.; Sugihara, T.
Org. Lett. 2000, 2, 1685-1687.
(8) Nishizawa, M.; Yadav, A.; Imagawa, H.; Sugihara, T. Tetrahedron
Lett. 2003, 44. 3867-3870.
(9) Nishizawa, M.; Yadav, A.; Iwamoto, Y.; Imagawa, H. Tetrahedron
2004, 60, 9223-9234.
(10) Olah, G. A.; Bollinger, J. M.; Cupas, C. A.; Lukas, J. J. Am. Chem.
Soc. 1967, 89, 2692-2694.
5794
Org. Lett., Vol. 8, No. 25, 2006

ring secondary cation 16. The reaction should be terminated
by the chloride attack from â-side as well as R-side to form
(()-117 and (()-12,7 respectively. Conversely, the reaction
with BF3 generates the achiral parallel cation 17, and hydride
shift takes place to give racemic tertiary cyclopentyl cation
18. Subsequent deprotonation provides a mixture of alkenes
(()-137 and 14.7 It is not necessary to consider the reaction
from parallel cation 15′ and perpendicular cation 17′ due to
the significant energy barrier against 15 and 17, respec-
tively.8,9
Scheme 5
Next we designed tert-alcohol 1911 to explore the pos-
sibility of the anti-Markovnikov rearrangement of a simple
isopropyl cation leading to a six-membered ring secondary
cation by using TiCl4. As is the case, the reaction of 19 with
2.0 equiv of TiCl4 at -78 °C for 3 h afforded six-membered
ring product 20 in 71% yield (determined by NMR using
naphthalene as the internal standard) as the sole product
(Scheme 4).12 On the other hand, treatment with BF3‚Et2O
through cis-cation 29 will afford R-chloride 31 via transition
state 30, whereas rearrangement from 28 through trans-cation
32 is expected to lead to â-chloride 34 via transition state
33.
We achieved the reaction of the cis-alcohol 27 with 1.2
equiv of TiCl4 at -78 °C for 12 h and the reaction was
quenched by the addition of NaHCO3 powder after warming
to -20 °C. The reaction cleanly afforded â-chloride 34 in
94% yield as the single product. The 3â equatorial orientation
of chloride was confirmed by the detection of a clean double
doublet at 3.84 ppm with J ) 13.2 and 4.4 Hz. Clear NOE
relationships were observed between 1aH-2âMe, 1aH-4âH,
3RH-1RH, 4âH-2âMe, and 1aH-4aH. The reaction of trans-
alcohol 28 with TiCl4 under the same conditions was also
very clean, and the same product 34 was obtained in 86%
yield as the sole product (Scheme 6). Thus it is evident that
Scheme 4
Scheme 6
(1.2 equiv) in CDCl3 at 0 °C for 15 min afforded only hydride
shift-deprotonation products 21 and 22 in 61% and 29%
NMR yield, respectively.13 The six-membered ring product
20 should be produced through a rearrangement from
perpendicular cation 23 to six-membered ring secondary
cation 24, and the olefinic products 21 and 22 should be
formed via the hydride shift from the parallel cation 25 to
tert-cation 26. Contribution of parallel conformer 23′ as well
as perpendicular conformer 25′ should be negligible due to
their large energy barriers against 23 and 25, respectively.8,9
Finally, we designed a reaction of a pair of stereoisomeric
tert-alcohols 27 and 28 (Scheme 5). If rearrangement takes
place by the concerted mechanism from cation to cation as
proposed by Hess,6a we can expect stereoisomeric rearrange-
ment products, that reflect the stereochemistries of the
starting materials. For example rearrangement from 27
either 27 or 28 generated the same six-membered ring
secondary cation 37 from perpendicular cations 35 or 36 via
C-C bond migration. The contribution of parallel cation 35′
as well as 36′ are negligible due to the high energy barrier
against 35 and 36, respectively.8,9 Stereoselective chloride
attack to 37 from the convex face resulted in selective
formation of 34. We are therefore able to suggest that the
cationic stepwise mechanism for our anti-Markovnikov
rearrangement involves controlling the conformation of
cationic intermediates by the counteranion [TiCl4‚OH]-.10
(11) Mclean, C. D.; Middleton, S. Aust. J. Chem. 1978, 31, 26599-
2667.
(12) Jensen, F. R.; Moder, T. I. J. Am. Chem. Soc. 1975, 98, 2281-
2283.
(13) Apparu, M.; Crandall, J. K. J. Org. Chem. 1984, 49, 2125-2130.
Org. Lett., Vol. 8, No. 25, 2006
5795

We are planning to undertake detailed DFT calculation on
the conformation of our cationic intermediates, and the result
will be described elsewhere.
When 27 and 28 were treated with BF3‚Et2O (1.2 equiv),
tetrasubstituted olefin 38 was obtained as the major product
along with a small amount of 39 (Scheme 7). Parallel cations
induced cyclization of geranylgeranyl acetate.14 Considered
together with the present observations, we propose that the
mechanism of sterol biosynthesis occurs via a totally cationic
stepwise mechanism. At the active site of the enzyme cavity,
the pre-C-ring cation 1 will be reinforced to take a
perpendicular conformation controlled by carboxylates of
aspartic acid residues along with oxygen functionalities of
tyrosine residues, and thereby be rearranged into C-ring
secondary cation 2.15,16 Therefore, we have elucidated that
it is possible to overcome the big Markovnikov wall by cation
chemistry.
Scheme 7
Acknowledgment. We are grateful to Professor Yasufumi
Ohfune of Osaka City University for his kind discussions,
and Dr. Masao Toyota of Tokushima Bunri University for
GC-MS analysis. This study was financially supported by a
Grant-in-Aid from the Ministry of Education, Culture, Sports,
Science, and Technology of the Japanese Government.
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL062337X
(14) (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. (c) Nishizawa, M.; Takao, H.; Kanoh, N.; Asoh,
K.; Hatakeyama, S.; Yamada, H. Tetrahedron Lett. 1994, 35, 5693-5696.
(d) Nishizawa, M.; Takao, H.; Iwamoto, Y.; Yamada, H.; Imagawa, H.
Synlett 1998, 76-78. (e) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Org.
Lett. 2005, 7, 451-453. (f) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Synlett
2005, 703-705.
(15) (a) Lenhart, A.; Weihofen, W. A.; Pleschke, A. E. W.; Schulz, G.
E. Chem. Biol. 2002, 9, 639-646. (b) Lenhart, A.; Reinert, D. J.; Aebi, J.
D.; Dehmlow, H.; Morand, O. H.; Schulz, G. E. J. Med. Chem. 2003, 46,
2083-2092.
(16) The “cationic center” surrounded by the negatively charged amino
acid residues such as D376, D374, D377, Y495, Y609, S307, and Y420 of
SHC15 seems to us the real reacting area of every cyclization-rearrangement
step. The significance of hydrophobic aromatic amino acid residues such
as W169, F601, F605, and F166 is also evident. We envision this area as
an “aromatic tunnel” where the polyene chain of flexible conformation slides
into the cationic center based on the π, π-interactions.15 We wish to call
this a “Catch and Slide mechanism”.
40 and 41 should be formed and following hydride shift into
the common tert-cation 42 should lead to deprotonation to
give 38 and 39. Our earlier Hartree-Fock calculations8,9
predict that there should be a high energy barrier to the
formation of cations 40′ and 41′ from 40 and 41, respectively.
Based on these calculations we presume that it is not
necessary to consider them, though further calculations will
need to be performed to confirm this unambiguously.
In 1985, we reported the first experimental evidence that
olefin cyclization takes place via a stepwise mechanism via
conformationally flexible cationic intermediates by trapping
each cationic intermediate with water during Hg(OTf)2-
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