Enantioselective Claisen rearrangement of difluorovinyl allyl ethers

Article abstract of DOI:10.1039/a807157h

The enantioselective Claisen rearrangement of difluorovinyl allyl ethers was achieved, for the first time, in moderate to good enantioselectivity using a chiral boron reagent as the Lewis acid.

Full text of DOI:10.1039/a807157h

Enantioselective Claisen rearrangement of difluorovinyl allyl ethers
Hisanaka Ito, Azusa Sato, Tetsuo Kobayashi and Takeo Taguchi*
Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo 192-0392, Japan.
E-mail: taguchi@ps.toyaku.ac.jp
Received (in Cambridge, UK) 29th May 1998, Revised manuscript received 5th October 1998, Accepted 5th
October 1998
The enantioselective Claisen rearrangement of difluorovinyl
allyl ethers was achieved, for the first time, in moderate to
good enantioselectivity using a chiral boron reagent as the
Lewis acid.
and promoting the reaction. Compound 4a was prepared from
the reaction of 2-methoxymethoxyphenylmagnesium bromide
with gaseous trifluoroacetaldehyde generated easily by the
reaction of 2 equiv. of trifluoroacetaldehyde ethyl hemiacetal
with P2O5 at 100 °C, followed by the allylation of the hydroxy
group by using 1.2 equiv. of NaH and 1.5 equiv. of (E)-
1-bromo-3-trimethylsilylprop-2-ene and deprotection under
acidic conditions (Scheme 2). Other compounds 4b–d were also
synthesized by the same procedure (32–57% yield). Compound
4 was converted to 2 via elimination of fluoride by treatment
with 2.5 equiv. of BunLi at 278 to 0 °C in Et2O. After neutral
workup, the vinyl ether 2 was treated with 1.5 equiv. of (S,S)-1
in the presence of 1.5 equiv. of Et3N in CH2Cl2 at 278 °C and
then the mixture was stirred at ambient temperature to give the
rearranged product 3. The results are summarized in Table 1.
In the chiral boron-mediated Claisen rearrangement, the
reaction temperature and enantioselectivity were found to be
affected by the configuration of the olefin (E or Z) and the steric
bulkiness of the substituent R at the g-position. Thus, in the case
of 4a having a TMS substituent, the reaction proceeded at 278
°C to give 3a with high asymmetric induction (entry 1), while in
the reaction of the substrate derived from 4b having an E
primary alkyl substituent, a slightly higher temperature was
required, giving rise to the product 3b with moderate selectivity
(entry 2).7 With the Z substrate derived from 4c, the direction of
asymmetric induction was opposite to that with E substrate 4b
(entry 3).
The development of a preparative method for chiral organo-
fluorine compounds is very important in the field of medicinal
chemistry.1 The Claisen rearrangement of difluorovinyl allyl
ethers is a powerful tool for the synthesis of b-substituted a,a-
difluorocarbonyl compounds.2 Although enantioselective ver-
sions of the Claisen rearrangement have been studied for the
construction of chiral molecules,3 there has been no report
dealing with the reaction of difluorovinyl allyl ethers. We
recently reported the highly enantioselective aromatic Claisen
rearrangement of o-allyloxyphenol derivatives mediated by the
chiral boron reagent 1.4 The efficiency of this system is based
on the s-bond formation of the chiral boron reagent 15 with the
phenolic hydroxy group in the substrate and the subsequent
coordination of the ethereal oxygen to the boron atom to form a
rigid chiral environment in the substrate and to promote the
reaction at low temperature. We report herein the application of
this system to the enantioselective Claisen rearrangement of
difluorovinyl allyl ethers (Scheme 1).
Ph
Ph
O2S
Tol
N
N
SO2
Tol
The absolute stereochemistry of 3d was determined as shown
in Scheme 3. The diastereoselective Claisen rearrangement of 5
B
Br
R
O
OH
O
OH
F
*
(S,S)-1
R
OMOM
TMS
O
OH
F
F
F
i–iii
BrMg
CF3
2
3
Scheme 1
4a
Scheme 2 Reagents and conditions: i, trifluoroacetaldehyde generated from
its hemiacetal with P2O5, THF, 0 °C, 92%; ii, NaH (1.2 equiv.), (E)-
1-bromo-3-trimethylsilylprop-2-ene, THF–DMF, room temp.; iii, 10%
HCl, MeOH, reflux, 31% over 2 steps.
The substrate 2 having a phenolic hydroxy group was
selected, because of the importance of a binding site to the chiral
boron reagent 1 in forming a coordinated cyclic intermediate
R1
R2
O
OH
O
OH
R2
R1
(S,S)-1
BuLi
Et2O
*
CF3
Et3N, CH2Cl2
F
F
3a–e
4a–e
Table 1 The enantioselective Claisen rearrangement of difluorovinyl allyl ethers
Entry
4
R1
R2
T/°C
t/h
3a
Yield (%)b
Ee (%)
1
2
3
4
5
4a
4b
4c
4d
4e
H
H
Pr
Et
TMS
Pr
H
H
H
278
3
5
5
6
3
3a
3b
3c
3d
3e
60
39
55
58
90
d
85c
41d
55d
43d
56d
278?220
278?215
278?215
278?215
c-Hex
a
b
c
Ref. 6. Isolated yield based on 4. Optical purity determined by HPLC using a Chiralcel OD column. Optical purity was determined by HPLC
using a Chiralcel AD column.
Chem. Commun., 1998, 2441–2442
2441

H
H
O
OH
O
OH
O
O
OH
O
OH
O
NOE
O
CF3
O
i,ii
H
O
F
F
O
H
F
F
O
F
F
5
6
6
10
Scheme 4 Reagents and conditions: i, 10% HCl, THF, 60 °C; ii, toluene,
100°C, 63% over 2 steps.
OH OH
O
OH
O
HO
O
F
F
O
the tolylsulfonyl group (A), thus the allylic moiety approaches
preferably from the Re face to avoid steric interaction with A in
the chair like transition state.
F
F
7
8
In conclusion, we have demonstrated for the first time
enantioselective Claisen rearrangement of difluorovinyl allyl
ethers using the chiral boron reagent 1 and the substrate 2
having a phenolic hydroxy group to form an efficient chiral
environment.9
This work was partially supported by a Grant-in-Aid (No.
09672163) from the Ministry of Education, Science, Sports and
Culture, Japan.
O
OMs
O
OH
F
F
F
F
9
3d
From 6 [α]D –24.4 (c 0.50, CHCl3)
From 3d [α]D –13.2 (c 1.64, CHCl3)
Scheme 3 Reagents and conditions: i, BunLi, Et2O; ii, toluene, 70 °C, 47%
over 2 steps (5:1); iii, H2, Pd/C, MeOH, 79%; iv, 10% HCl, THF, 60 °C; v,
MsCl, Et3N, CH2Cl2, vi, NaI, butanone, reflux; vii, Zn, AcOH, H2O–THF,
65% from 7.
Notes and references
1 Biomedicinal Aspects of Fluorine Chemistry, ed. R. Filler and Y.
Kobayashi, Elsevier Biomedical Press and Kodansha Ltd, 1982; J. T.
Welch, Tetrahedron, 1987, 43, 3123; Organofluorine Compounds in
Medicinal Chemistry and Biomedical Applications, ed. R. Filler, Y.
Kobayashi and L. M. Yagupolskii, Elsevier, Amsterdam, 1993.
2 W. B. Metcalf, E. T. Jarvi and J. P. Burkhart, Tetrahedron Lett., 1985, 26,
2861; G.-Q. Shi, Z.-Y. Cao and W.-L. Cai, Tetrahedron, 1995, 51, 5011;
G.-Q. Shi and W.-L. Cai, J. Org. Chem., 1995, 60, 6289; H. Greuter,
R. W. Lang and A. J. Roman, Tetrahedron Lett., 1988, 29, 3291.
3 K. Maruoka, H. Banno and H. Yamamoto, J. Am. Chem. Soc., 1990, 112,
7791; K. Maruoka, H. Banno and H. Yamamoto, Tetrahedron:
Asymmetry, 1991, 2, 647; K. Maruoka and H. Yamamoto, Synlett 1991,
793; K. Maruoka, S. Saito and H. Yamamoto, J. Am. Chem. Soc., 1995,
117, 1165; E. J. Corey and D.-H. Lee, J. Am. Chem. Soc., 1991, 113,
4026; E. J. Corey and R. S. Kania, J. Am. Chem. Soc., 1996, 118, 1229;
U. Kazmaier and A. Krebs, Angew. Chem., Int. Ed. Engl., 1995, 34, 2012;
A. Krebs and U. Kazmaier, Tetrahedron Lett., 1996, 37, 7945.
4 H. Ito, A. Sato and T. Taguchi, Tetrahedron Lett., 1997, 38, 4815.
5 E. J. Corey, R. Imwinkelried, S. Pikul and Y.-B. Xiang, J. Am. Chem.
Soc., 1989, 111, 5493.
6 Optical rotation ([a]D) was measured in CHCl3 at 26 °C. 3a: 41.1; 3b:
18.6; 3c: 218.3; 3d: 28.8; 3e: 220.3.
7 In the absence of Lewis acid, the E isomer 2b smoothly rearranged to 3b
even at room temperature, possibly due to the presence of the phenolic
hydroxy group, to form an intramolecular hydrogen bond between the
ethereal oxygen.
8 The relative stereochemistry of compound 6 was determined via
conversions to 10 and a NOESY experiment, as shown in Scheme 4.
9 Regarding the removal of the hydroxyphenyl moiety, we examined some
conditions, i.e. oxidative degradation of the aromatic ring and cleavage of
the carbon–carbon bond of the aryl ketone moiety (Baeyer–Villiger and
Schmidt rearrangement). In these experiments, although the aromatic
ring was absent from the 1H NMR analysis of the crude mixture, we were
unable to find a clean method for cleavage of the hydroxyphenyl
moiety.
smoothly proceeded to give 6 as a major isomer (47%, 5:1),
which has an R configuration at the newly formed chiral center.8
Hydrogenation of the olefin of 6 (79%) and the subsequent
deprotection of the acetonide group by acid treatment gave
compound 8 as an anomeric mixture. After mesylation of the
primary and phenolic hydroxy groups of 8, the product was
converted to the olefin 9 in 65% yield (four steps). The
enantioselective Claisen rearrangement product 3d was also
converted to 9 by mesylation. Determination of the absolute
stereochemistry of 3d as R configuration could be achieved by
comparison of the specific rotation of each compound.
The observed enantioselectivity is possibly explained as
shown in Fig. 1. The six-membered intermediate is formed by
the attachment of the chiral boron reagent 1 to the phenolic
hydroxy group, and the subsequent coordination of the ethereal
oxygen to the boron atom. In the case of (S,S)-1 and the Z isomer
of 2, the Si face of the difluorovinyl ether moiety is shielded by
Ph
Ph
O
O
O
N
N S
S
A
O
B
O
O
F
F
Fig. 1
Communication 8/07157H
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Chem Commun., 1998, 2441–2442