Regio- and diastereoselective SN2′ or SN2″ reactions on chiral acetals of cyclic aldehydes promoted by PhCu, BF3

Article abstract of DOI:10.1016/S0957-4166(01)00319-6

The regio- and diastereoselectivity of the addition of PhCu, BF₃ reagent on chiral acetals derived from several mono or dienic aldehydes was studied. It was found that monoethylenic acetals react regio- and diastereoselectively via an overall a

Full text of DOI:10.1016/S0957-4166(01)00319-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1957–1960
Regio- and diastereoselective SN2% or SN2¦ reactions on chiral
acetals of cyclic aldehydes promoted by PhCu, BF3
Fre´de´rique Maze´, Martin Purpura, Fre´de´ric Bernaud, Pierre Mangeney* and Alexandre Alexakis
Laboratoire de Chimie des Organo-Ele´ments associe´ au CNRS, Universite´ P. et M. Curie, 4, Place Jussieu,
F-75252 Paris Cedex 05, France
Received 13 June 2001; accepted 13 July 2001
Abstract—The regio- and diastereoselectivity of the addition of PhCu, BF3 reagent on chiral acetals derived from several mono
or dienic aldehydes was studied. It was found that monoethylenic acetals react regio- and diastereoselectively via an overall anti
SN2% reaction. The regioselectivity observed with the dienic acetals seems to be strongly dependent on the nature of the acetal. In
all cases the SN2¦reaction was the result of an anti process. © 2001 Elsevier Science Ltd. All rights reserved.
Acetals prepared from chiral non-racemic diols with
C2 symmetry have been intensively used in asymmet-
ric synthesis.1 We have already reported regio- and
diastereoselective SN2% and SN2¦ reactions on ethylenic
or dienic acetals derived from acyclic aldehydes, pro-
moted by vinyl or aryl organocopper reagents in the
presence of BF3.2 In this communication, we wish to
report the preliminary results obtained by using
acetals 1a–1b, 2a–2b and 3 derived from cyclic alde-
hydes.
Acetals 1a–1b were obtained, respectively, from 1-
cyclohexene-1-carboxaldehyde 4a or 1-cyclopentene-1-
carboxaldehyde3 4b and the (R,R)-diol 54 (Scheme 1).
From these aldehydes we have also prepared acetals
2a–2b (Scheme 1) using the Bellassoued procedure,5
acetalisation and then transacetalisation. The isomeri-
cally pure acetal 3 was prepared from 2-bromo-cyclo-
hexene-2-one (Scheme 1).
BF3·Et2O was slowly added at −30°C to acetals 1a–1b,
Ph
Ph
1) i
O
Ph
CHO
4a n = 1
O
n( )
2) ii
n( )
i = HC(OEt)3, NH4NO3, ii =
EtOH, 75°C, 6h
HO
OH
Ph
52 %
(R,R)
5
1a n = 1
1b n = 2
A
PPTS, toluene
4b n = 2
ref.5
80%
1) i
O
O
4a,b
n( )
n( )
Ph
CHO
2) ii
58 %
2a n = 1
2b n = 2
Ph
OEt
Br
O
1) tBuLi
THF, -70°C
Li
OEt
HO
1)H+
O
O
Br
Br
Ph
A
2) i
3) ii
88%
2) H2O
THF, -70°C-0°C
90%
Ph
3 (100% Z,E)
95%
Scheme 1.
* Corresponding author. Tel.: 01 44 27 55 68; fax: 01 44 2775 67; e-mail: mangeney@moka.ccr.jussieu.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00319-6

1958
F. Maze´ et al. / Tetrahedron: Asymmetry 12 (2001) 1957–1960
1
2a–2b or 3 in the presence of phenyl copper reagent
(prepared in ether from iodobenzene, 2 equiv. tert-BuLi
and then CuBr·SMe2) to give, after acetylation, the
corresponding enols ethers resulting from SN2% or SN2¦
reactions (Scheme 2). The monoethylenic acetals 1a and
1b yielded to the corresponding SN2% enol ethers 6a and
6b. The (E)-stereochemistry of the double bond was
mined by H NMR (Scheme 2). All enol ethers were
hydrolysed under acidic conditions (HCOOH, pentane)
to give the corresponding aldehydes. Starting from
6a–6b, a mixture of cis- and trans-2-phenylcyclohexane-
(or cyclopentane-) carbaldehydes was obtained. Iso-
merisation according to Scheme 2 yielded trans-alde-
hydes 9a–9b. The hydrolysis of 7a–7b under the same
conditions gave, in both cases, a complex mixture.
Using trifluoroacetic acid on 7a, a quantitative forma-
tion of a 1:1 mixture of cis- and trans-conjugated
aldehydes 10 and non-conjugated aldehyde 11 was
obtained. From 7b, a complex mixture was again
obtained. A mixture of (E)- and (Z)-aldehydes 12 was
obtained from 8 by treatment with formic acid.
1
determined by H NMR (NOE experiments). The ace-
tal 2a yielded regioselectively to the dienic dienol 7
resulting from a SN2¦ reaction. The (E,E)-stereochem-
istry of the double bonds was determined by X-ray
analysis6 of the crystals (73% yield) obtained from the
crude compound. The reaction with acetal 2b was not
regioselective and a 1:1 mixture of enol ethers resulting
from SN2% or SN2¦ reactions was obtained. With the
acetal 3, the reaction was again regioselective to give
the enol ether 8 from SN2¦ reaction. The (E)-stereo-
chemistry of the exocyclic double bound was deter-
Absolute configurations of the aldehydes 9a–9b were
determined by comparison of specific rotation values
with reported data (Scheme 3).7 The absolute configura-
CHO
Ph
1) HCOOH,
Ph
pentane, 2h
O
Ph
n( )
n( )
2) n = 1 DBU, THF, rfx, 3h
n = 2, NaOH, 10%, 15 min.
AcO
H
9a n = 1, 64%
9b n = 2, 73%
Ph
H
O B
n = 1 6a
n = 2 6b
nOe
1a,b
1) PhCu, BF3
Ether, -30°C
2) Ac2O, DMAP
CF3COOH
2 a,b
3
O
n( )
+
CHO
CHO
B
n= 1
Ph
Ph
Ph 10
11
n = 1, 73%
7
n = 2 1/1 mixture SN2’ or SN2’’
H
HCOOH,
Ph
pentane, 2h
Ph
O
CHO
B
H
E (J = 12.6 Hz)
12
8, 60%
Scheme 2.
Ph
Ph
N
Ph
Ph
* *
* *
N
N
N
CHO
S
i
i
Ph
Ph
Ph
S
d.e. = 70%
n =1
d.e. = 92%
n = 2
n( )
Ph
Ph * *
[α]D = +57 (1, benzene)
[α]D = +42 (5, benzene)
9a
9b
i =
NH HN
1) chromatographic
separation9
(R,R) and (S,S)
Ph
N
S
*
d.e. = 72%
2) i
CHO
N
*
Ph
Ph
Ph
H2N
11
Ph
Ph
Ph
Ph
O
NH
HN
Ph
O3, Me2S
NH2
CHO
R
CH2Cl2, -78 °C
Ph
13 [α]D = +17 (1.6, CHCl3)
Ph
12
d.e. = 65%
77%
Scheme 3.

F. Maze´ et al. / Tetrahedron: Asymmetry 12 (2001) 1957–1960
1959
Ph
tion of the new stereogenic centre in 7a was determined
O
from X-ray crytallographic analysis (Fig. 1). The mix-
ture of aldehydes 12 was transformed into the known
3-phenyl cyclohexanone8 13 by ozonolysis (Scheme 3).
The diastereoisomeric excesses of these compounds
were determined according to our previously reported
procedures.9 All values are shown on Scheme 3.
O
PhCu, BF3
PhCu, BF3
Ph
Ph
Ph
n( )
O
n( )
Ph
O
Ph
Ph
6a (E)
1a cisoid
Ph
O
O
O
Ph
n( )
n( )
Ph
1a transoid
O
6a (Z)
From these results, we were able to determine the
stereochemical outcome (anti or syn) of the substitution
reactions. The (Z)- or (E)-stereochemistries of the dou-
ble bonds of the enol ethers reflect the reactive confor-
mation of the starting acetal.1 For example, cisoid or
transoid acetals 1a are, respectively, precursors of (E)-
or (Z)-enol ethers 6a (Scheme 4).
Scheme 4.
In conclusion, acetals derived from cyclohexene or
cyclopentene carboxaldehydes react regio- and
diastereoselectively with PhCu, BF3 via an anti overall
SN2% process. Furthermore the e.e. (92%) obtained with
the six-membered ring 1b is good. The regioselectivity
observed with the dienic acetals seems to be strongly
dependent on the nature of the acetal. Indeed, the
reaction is regioselective (SN2¦) with 2a (n=1) and 3
but not with 2b (n=2). Diastereoselectivities are similar
to those generally obtained for such reactions, but the
stereochemistry is opposite to the one observed with
acetals derived from acyclic aldehydes.2
According to stereochemistries observed for enols
ethers 6a–6b, 7 and 8, conformations of starting acetals
are those shown on Scheme 5. The stereodetermining
step of the reactions is the selective complexation of
BF3 on the oxygene, which is near the pseudo axial
phenyl group.1 Therefore, according to all results
reported in Schemes 2 and 3 (stereochemistries of dou-
ble bonds and absolute configurations of stereogenic
centres) it is clear that all substitution reactions (SN2% or
SN2¦) are anti (Scheme 4).
O
S
O
O
Ph
Ph
7a (after recrystallisation)
Figure 1.
BF3
Ph
CHO
SN2'
O
O
S
Ph
Ph
Ph
O
S
n( )
n( )
ANTI
S
n( )
Ph
AcO
Ph
1a-1b
PhCu
B
BF3
SN2"
O
O
O
Ph
S
B
ANTI
Ph
Ph
2a
PhCu
PhCu
BF3
SN2"
ANTI
O
O
Ph
O
Ph
O
Ph
B
R
Ph
3
Scheme 5.

1960
F. Maze´ et al. / Tetrahedron: Asymmetry 12 (2001) 1957–1960
able. The cyclopentene carboxaldehyde was prepared
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