Highly regio- and stereo-selective alkyl substitution with copper reagents for
the construction of chiral trifluoromethylated quaternary carbon centres
Shuichi Hiraoka, Takashi Yamazaki* and Tomoya Kitazume
Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226, Japan
A new route for the asymmetric construction of quaternary
carbon centres containing a trifluoromethyl group has been
established using a highly regio- and stereo-selective SN2A
reaction of organocopper and organocuprate reagents with
allylic mesylates 4 and 8.
Gilman cuprate Me2CuLi–LiI in Et2O gave the unexpected
diene 6 in 98% yield, rather than either the SN2A product or the
common SN2 type byproduct (Table 1, entry 1). Although the
desired SN2A material 5 was furnished in 35% yield after
changing the solvent to THF, 6 was still the main product (54%
yield, entry 2). Formation of 6 may be rationalized by the
preferential Cu–F elimination because of the relatively poor
reductive elimination ability of the Me ligand on the intermedi-
ary s-copper(iii) adduct (Scheme 2).† One result which
supported this assumption was obtained by the addition of the
electron-donating bidentate amine tetramethylethylenediamine
(TMEDA) to the conditions used in entry 2: TMEDA was
considered to make the ground state more stable than the
corresponding transition state by analogy with HMPA,‡ and the
yield of 6 was significantly increased from 54 to 92% (entry 2
vs. 6).
The above unfavourable pathway giving the difluorinated
diene 6 was avoided by the use of cyanocuprate, known to
undergo a facile reductive elimination,9,10 resulting in complete
SN2A displacement (entry 5). Moreover, it was also found that
addition of BF3 to the Gilman cuprate Me2CuLi–LiI effectively
suppressed the Cu–F elimination irrespective of the solvent
(entries 3 and 4). Treatment of 4 with organocopper reagent,
MeCu–LiI, yielded 5 with high stereoselectivity and complete
g-selectivity (entry 7). On the other hand, in sharp contrast to the
case of the Gilman reagent, significant retardation of the
reaction by BF3 was observed, and this system furnished the
SN2A product 5 in a disappointing 18% yield (entry 8).
Enhancement of biological activity in many natural product
classes by the selective introduction of one, two or three fluorine
atoms is a proven cornerstone strategy for medicinal and
bioorganic chemists.1 We were intrigued by the stereospecific
replacement of either methyl group in the structure 1, as found
R1 R2
(
)
*
OH
R1 = R2 = Me
1
2a R1 = CF3, R2 = Me
2b R1 = Me, R2 = CF3
in Epothilone A2 and antitumour active Shikoccidine deriva-
tives,3 by a trifluoromethyl moiety, which would lead to the
sterically as well as electronically modified structures 2a or 2b
with an additional asymmetric carbon centre. However, as far as
we are aware, the Diels–Alder reaction of 2-(trifluoro-
methyl)acrylate4 is the only reported procedure to access such a
target structure, possibly due to the difficulty of alkyl
substitution at a CF3-attached carbon centre.5 Although in
general the SN2A reaction and 1,4-addition of cuprates are
among the most efficient methods for the synthesis of
quaternary centres,6 such an approach has not yet been
attempted in this context.
Recently we reported a novel strategy for the synthesis of
optically active compounds with variously fluorinated methyl
groups (CH32nFn: n = 1–3) via exo-difluoromethylene com-
pounds synthesised from commercially available d-glucose.7,8
Utilization of the readily accessible allylic alcohol 3 via SN2A
reaction with copper reagents is an attractive way to create
diastereoselectively a quaternary centre. An additional synthetic
advantage of this approach is the possibility of controlling the
alkene stereochemistry as Z, an outcome which is not easily
obtainable otherwise. Here we describe the regio- and stereo-
selective alkyl substitution of allylic mesylates 4 and 8 using
organocopper and organocuprate chemistry.
It is well-known that the use of an organocopper reagent in a
different solvent and/or in the presence (or absence) of ligands
or Lewis acids sometimes leads to the formation of different
species or equilibration mixture, and Table 1 collects the
proposed reactive species in each specific conditions. Lipshutz
et al. claimed that in Et2O solution Me2CuLi exists in the
dimeric form Me4Cu2Li2 (entry 1), while further addition of 2
equiv. of BF3 affords a mixture of Me5Cu3Li2 and MeLi–BF3
(entry 3).11 In THF, Me2CuLi forms an equilibrium mixture of
MeLi, Me3Cu2Li and Me4Cu2Li2 (entry 2), which is converted
to Me3Cu2Li and MeLi–BF3 when such a solution is treated
with BF3 (entry 4).12 It should be noted that the dimeric Gilman
cuprate Me4Cu2Li2 is the reactive species leading to exo-
difluoromethylene compounds 6 (entries 1 and 2). On the basis
of chemical and NMR spectroscopic experiments, Lipshutz also
proposed that MeCu–LiI was in an equilibrium with a MeLi–
13
BF3 complex and I2CuLi in the presence of BF3 and thus,
comparison of entries 7 and 8 suggests only low reactivity of
MeLi–BF3 in this procedure. Consequently, it is concluded that
both Me5Cu3Li2 and Me3Cu2Li should be the ‘true’ reacting
species giving 5 by smooth reductive elimination.
At the initial stages of this investigation, we chose the
substrate 4 depicted in Scheme 1. To our surprise, reaction of
allylic mesylate 4, easily prepared from 3 in three steps, with
Ph
ButMe2SiO
MsO
ButMe2SiO
iv
O
Me
O
O
CF3
Me
reduction-
elimination
CF3
CuIII
F
O
O
β-elimination
i–iii
F
F3C
F3C
F3C
OMe
OMe
OMe
X
Me
3
4
5
X = Me, I, CN
Scheme 1 Reagents and conditions: i, TFA, MeOH–H2O; ii, ButMe2SiCl,
imidazole; iii, MsCl, Et3N; iv, organocopper and organocuprate reagents
Scheme 2
Chem. Commun., 1997
1497
Hiraoka, Shuichi
