Tin(IV) chloride-chiral pyrogallol derivatives as new Lewis acid-assisted chiral Bronsted acids for enantioselective polyene cyclization

Article abstract of DOI:10.1021/ol049126h

(Matrix Presented) New Lewis acid-assisted Bronsted acids (LBAs), tin(IV) chloride-2,6-dialkoxyphenols, serve as artificial cyclases for biomimetic polyene cyclization. For example, the enantioselective cyclization of 4-(homogeranyl)toluene using tin(IV) chloride-2,6-di[(1′R,2′R)- trans-2′-(3″,5″-xylyl)cyclohexanoxy]-phenol gave a trans-fused tricyclic compound with 85% ee.

Full text of DOI:10.1021/ol049126h

ORGANIC
LETTERS
2004
Vol. 6, No. 15
2551-2554
Tin(IV) Chloride-Chiral Pyrogallol
Derivatives as New Lewis Acid-Assisted
Chiral Brønsted Acids for
Enantioselective Polyene Cyclization
,†
,‡
Keiko Kumazawa,† 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 S. Ellis AVenue, Chicago, Illinois 60637
ishihara@cc.nagoya-u.ac.jp; yamamoto@uchicago.edu
Received May 12, 2004
ABSTRACT
New Lewis acid-assisted Brønsted acids (LBAs), tin(IV) chloride-2,6-dialkoxyphenols, serve as artificial cyclases for biomimetic polyene cyclization.
For example, the enantioselective cyclization of 4-(homogeranyl)toluene using tin(IV) chloride-2,6-di[(1′R,2′R)-trans-2′-(3′′,5′′-xylyl)cyclohexanoxy]-
phenol gave a trans-fused tricyclic compound with 85% ee.
We recently reported the first example of the enantio-
selective cyclization of polyprenyl alcohols and homo-
(polyprenyl)arenes induced by Lewis acid-assisted chiral
Brønsted acids (chiral LBAs).1,2 Optically pure 2-alkoxy-2′-
hydroxy-1,1′-binaphthyl 1 activated with SnCl4 is effective
for this enantioselective cyclization. The further refinement
of LBAs was required to establish LBA-induced biomimetic
polyene cyclization as a practical synthetic method. However,
we could not design any chiral Brønsted acids that were
superior to 1 by chemical modification of 1. For example,
the introduction of 3,3′-substituents on 1 unexpectedly
decreased not only the activity of the LBA but also the
enantioselectivity of the polyene cyclization. Thus, we
pursued the design of new chiral Brønsted acids, that did
not include a binaphthol skeleton, which were activated with
SnCl4. In this paper, we report a new design for Brønsted
acids that include a pyrogallol skeleton, achiral 2,6-dialkox-
yphenols 2, and optically pure 2,6-di[trans-2′-(3′′,5′′-xylyl)-
cyclohexanoxy]phenol (3c). SnCl4 preferentially chelates
pyrogallol derivatives compared with biphenol and binaph-
thol derivatives (Figure 1).
Our studies began with the diastereoselective cyclization
of 4-(homogeranyl)toluene (4) induced by achiral LBA
prepared in situ from a 1:1 molar mixture of a variety of
phenol derivatives and SnCl4. The reaction was conducted
in the presence of 20 mol % ArOH‚SnCl4 in dichloromethane
at -78 °C. The activity of the Brønsted acid was estimated
by the GC ratio of the crude products. In most cases, the
desired trans-fused AB-ring product 5 was obtained together
† Nagoya University.
‡ The University of Chicago.
(1) For a review, see: Ishibashi, H.; Ishihara, K.; Yamamoto, H. Chem.
Rec. 2002, 2, 177.
(2) (a) Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc.
1999, 121, 4906. (b) Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am.
Chem. Soc. 2000, 122, 8131. (c) Ishihara, K.; Ishibashi, H.; Yamamoto, H.
J. Am. Chem. Soc. 2001, 123, 1505. (d) Ishihara, K.; Ishibashi, H.;
Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 3647.
10.1021/ol049126h CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/01/2004

Scheme 1. Preparation of Optically Active
2,6-Dialkoxyphenols 3 and 13
Figure 1. Chiral and achiral LBAs.
with its cis-fused isomer 6, endo- and exo-isomeric A-ring
products 7, B-ring product 8, chlorinated compound 9,3 and
remaining 4 (Table 1). As a result, 2a-d very effectively
induced the cyclization of 4 to 5 in the presence of SnCl4
(entries 1-4). In particular, 2,6-dimethoxy-4-methylphenol
(2a) gave the best results (entry 1). Not only sterically
hindered 2,6-diisopropoxyphenol (2c) and 2,6-diphenoxy-
phenol (2d) but also 2-methoxyphenol were more effective
than 2-(o-fluorobenzyloxy)-2′-hydoxybiphenyl (entries 3-5
versus entry 6). The activation effect of LBA was caused
by the tight chelation of electron-rich 2-alkoxyphenol deriva-
tives with SnCl4. On the other hand, electron-deficient
phenols were not effectively activated by SnCl4 due to the
relatively weak Lewis basicity of the phenolic oxygen atom.
2,6-Dimethylphenol and 3,5-dimethoxyphenol were almost
inert due to the thermodynamic instability of SnCl4-chelated
complexes.
Table 1. Diastereoselective Cyclization of 4 Induced by
Achiral LBA, ArOH‚SnCl4
a
Next, we sought to design chiral 2,6-dialkoxyphenols that
were chelated with SnCl4 as a new chiral LBA for the
enantioselective polyene cyclization (Scheme 1). C2-sym-
metric chiral 2,6-dialkoxyphenol 3 was prepared from
1-bromo-2,6-difluorobenzene (10) in two steps: the nucleo-
philic substitution reaction of chiral alcohols 11 with 10 to
give chiral 1-bromo-2,6-dialkoxybenzene and its subsequent
oxidation to 3 via the corresponding 2,6-dialkoxybenzenebo-
ronic acid. Asymmetric chiral 2-alkoxy-6-methoxyphenol 13
was prepared from 3-fluorophenol (12) in a similar manner.
Optically active trans-2-arylcycloalkanols 11 were suitable
as chiral alkoxy groups in 3 and 13 because of their
conformational rigidity. Both enantiomers of 11 were
prepared in a facile three-step sequence starting from the
substitution reaction of cycloalkene oxides with arylmagne-
sium bromide in ether in the presence of CuI, subsequent
a All reactions were carried out using SnCl4 (0.02 mmol), aryl alcohol
(0.02 mmol), 4 (0.5 mmol), and dichloromethane (1 mL) at -78 °C under
N2 for the amount of time shown. b See ref 3.
(3) Although 9 was shown to contain a chlorine atom by LRMS analysis
of the crude products, the chemical structure of 9 was not determined.
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Org. Lett., Vol. 6, No. 15, 2004

Scheme 2. Enantioselective Synthesis of Diterpenoid (-)-5
Table 2. Enantioselective Cyclization of 4 Using Chiral
Pyrogallol Derivatives 3 or 13 and SnCl4
Using Chiral and Achiral LBAsa
a Conditions: (a) 3c (2 equiv), SnCl4 (1 equiv), toluene, -78
°C, 1 day; (b) CF3CO2H (10 equiv), SnCl4 (2 equiv), i-PrNO2, -78
°C, 1 day.
this result, the substituent effect on the phenyl group in 3a
was investigated (entries 3-6). When (1′R,2′S)-3c‚SnCl4 was
used, the optical yield of (-)-5 was improved to 77% ee
(entry 4). Furthermore, the enantioselectivity rose to 85%
ee with the use of 2 equiv of 3c and 1 equiv of SnCl4 (entry
5). This result could be explained by the preferential
formation of LBA in equilibrium between the association
and dissociation of 3c and SnCl4. Although the size of
cycloalkane of 2,6-di(2′-xylylcycloalkanoxy)phenol was also
investigated (entries 7 and 8), the use of conformationally
more stable 3c gave the highest ee value. Interestingly, the
use of asymmetric (1′R,2′S)-13c gave (+)-5 with 40% ee
(entry 9). The two contrasting results in entries 4 and 9 led
us to anticipate that the two (1′R,2′S)-2′-xylylcyclohexanoxy
groups in 3c conformationally depend on each other.
Next, diastereoselective cyclization of 7 to 5 was explored
with achiral LBAs to increase the chemical yield of 5
(Scheme 2). A 9:85 molar mixture of (-)-5 and 7, which
were produced by the enantioselective cyclization of 4 under
the conditions shown in entry 5 of Table 2, was treated with
10 equiv of trifluoroacetic acid and 1 equiv of SnCl4 in
2-nitropropane at -78 °C. Thus, (-)-5 was obtained from 4
in 90% yield and 88% trans selectivity without reducing its
optical purity.
a B-ring product 8 was not obtained at all from the reaction in toluene.
b Ee was determined by HPLC analysis (two linear Daicel OD-H columns).
c Optical rotation of 5 is indicated in parentheses. d 3a‚SnCl4 (20 mol %)
was used in CH2Cl2. e 3c (200 mol %) and SnCl4 (100 mol %) were used.
Scheme 3. Enantioselective Cyclization of 2-Geranylphenol
Derivatives Using 3c‚SnCl4
kinetic resolution of (()-11 via acetylation induced by lipase
PS-D “Amano” I (Burkholderia cepacia, Amano), and its
hydrolysis (Scheme 1).4
Chiral pyrogallol derivatives 3 and 13 were examined in
the enantioselective cyclization of 4 in the presence of SnCl4
(Table 2). Although several optically active 2,6-di(acyclic
alkoxy)phenols were examined as Brønsted acids, no asym-
metric induction was induced. On the other hand, 2,6-di(2′-
alkylcycloalkoxy)phenols led to some asymmetric induction.
When 20 mol % (1′R,2′S)-2,6-di(2′-phenylcyclohexanoxy)-
phenol (3a)‚SnCl4 was used in dichloromethane, (-)-5 was
obtained in 60% GC yield with 24% ee (entry 1). Fortunately,
the optical yield of (-)-5 could be improved to 54% ee with
100 mol % 3a‚SnCl4 in toluene (entry 2). On the basis of
(4) (a) Takahashi, M.; Ogasawara, K. Tetrahedron: Asymmetry 1995,
6, 1617. (b) Carpenter, B. E.; Hunt, I. R.; Keay, B. A. Tetrahedron:
Asymmetry 1996, 7, 3107.
To explore the generality and scope of this new chiral
LBA, 3c‚SnCl4, the enantioselective cyclization of 2-gera-
Org. Lett., Vol. 6, No. 15, 2004
2553

Figure 3. Possible explanation for the absolute stereochemistry.
cyclization would be controlled by a linear OH/π interaction
with an initial protonation step. On the basis of the absolute
stereochemistry of product (-)-5,6 the re-face of the terminal
isoprenyl group of 4 would preferentially approach the
activated proton of LBA perpendicular to its H-O bond.
The observed absolute stereopreference is reasonable con-
sidering the steric hindrance around the activated proton.
In summary, pyrogallol derivatives are more effective
Brønsted acids than biphenol derivatives for preparing LBA
with SnCl4. Further investigation of chiral pyrogallol deriva-
tives that are superior to 3c is underway.
Figure 2. ORTEP plot of 3c. Thermal ellipsoids are drawn at the
50% probability level.
nylphenol derivatives 14 and 16 was examined under the
same conditions as in entry 5 of Table 2 (Scheme 3). As
expected, trans-fused tricyclic compounds 15 and 17 were
obtained with 83 and 79% ee, respectively. As in our
previous reports,2c,d the chemical yield and diastereoselec-
tivity of tricyclic compounds strongly depended on the
nucleophilicity of the terminal group of geranyl derivatives.
To understand this absolute stereopreference in the enan-
tioselective cyclization, the crystallization of 3c‚SnCl4 was
attempted. Although we did not succeed in crystallizing the
LBA, a colorless crystal of 3c was obtained. According to
its single-crystal X-ray diffraction analysis, surprisingly, a
phenolic proton was effectively enclosed with two alkoxy
groups (Figure 2).
On the basis the X-ray structure of 3c, the conformational
structure of 3c‚SnCl4 was considered as follows: 3c might
change from a folded conformer to an extended conformer
by chelation of SnCl4, as shown in Figure 3. The H-O bond
in 3c‚SnCl4 would be fixed in the phenoxy plane by chelation
with SnCl4 and hydrogen bonding with the neighboring
ethereal oxygen atom. As in our previous report on the
enantioselective protonation of silyl enol ethers with chiral
LBA,5 the stereochemical course in the enantioselective
Acknowledgment. We thank H. Ishibashi (Nagoya
University) for performing X-ray single-crystal analysis.
Financial support for this project was provided by SORST,
JST, the Kurata Memorial Hitachi Science and Technology
Foundation, and the Tatematsu Foundation.
Supporting Information Available: Experimental pro-
cedures, full characterization of new compounds, and crystal-
lographic data for 3c. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL049126H
(5) Ishihara, K.; Nakashima, D.; Hiraiwa, Y.; Yamamoto, H. J. Am.
Chem. Soc. 2003, 125, 24.
(6) Absolute stereopreference of (1′R,2′S)-3c‚SnCl4 was opposite that
of (R)-1‚SnCl4. Therefore, the absolute configurations of (-)-5 were
determined to be 4aR and 10aR.
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Org. Lett., Vol. 6, No. 15, 2004