Tandem enantioselective conjugate addition: Electrophile trapping reactions. Application in the formation of syn or anti aldols [12]

Full text of DOI:10.1021/ja005911n

4358
J. Am. Chem. Soc. 2001, 123, 4358-4359
Scheme 1
Tandem Enantioselective Conjugate Addition:
Electrophile Trapping Reactions. Application in the
Formation of Syn or Anti Aldols
Alexandre Alexakis,* Graham P. Trevitt, and
Ge´rald Bernardinelli
Department of Organic Chemistry, UniVersity of GeneVa
30 quai Ernest Ansermet, Gene`Ve 4, Switzerland CH-1211
ReceiVed December 21, 2000
The 1,4 addition of organometallic reagents to R,â unsaturated
ketones is a powerful method for carbon-carbon bond formation.1
Recent years have seen tremendous advances in the asymmetric
variant of this reaction with ee values greater than 90%, using as
little as 1 mol % of chiral ligand, not uncommon.2
Following on from work within our own group3 we became
interested in trapping the enolate formed during the copper-
catalyzed addition of organozincs to cyclic enones in a subsequent
carbon-carbon bond forming reaction. Herein we outline our
initial findings on the reactivity of these intermediates.
Table 1. Trapping of 2a/b with a Variety of Electrophilesa
b
product
n
electrophile
R1
R2
R3
%
3a
3b
3c
3d
3e
3f
1
1
1
1
2
2
PhCH(OMe)2
MeCH(OEt)2
Me2C(OMe)2
(MeO)3CH
PhCH(OMe)2
(Me)3CH
OMe
OEt
OMe
OMe
OMe
OMe
H
H
Me
OMe
H
Ph
Me
Me
H
Ph
H
62c
62d
54
66
58d
59
OMe
a Reagents and conditions: 1.5 equiv of electrophile, 1.5 equiv of
Lewis acid, 0.5 M in dichloromethane, -20 to 0 °C, 2 h. b Isolated
yield after column chromatography. c 1:1 ratio of diastereomers formed.
d 2:1 ratio of diastereomers formed.
Early work carried out by Noyori indicated that aldehydes are
suitable electrophilic traps for zinc enolates, giving predominately
trans substitution.4 Using the phosphoramidate ligand 1 developed
by Feringa one can generate a homochiral (ee >98%) zinc enolate
following the copper-catalyzed addition of diethyl zinc to cyclo-
hexenone.5 We decided to study the reactivity of this enolate, as
outlined in Scheme 1, and the results are summarized in Table 1.
In addition to aldehydes, it was found that, with Lewis acid
activation, acetals also gave aldol-type products. BF3‚OEt2 and
TMSOTf were found to be suitable Lewis acids for the activation
of benzaldehyde dimethyl acetal with TMSOTf giving a 2:1
excess of one diastereomer of 3a albeit in lower yield. No
reactivity was observed in the absence of Lewis acid. Alkyl acetals
are found to be equally reactive with 3b formed in good yield.
Ketones fail to react in the absence of Lewis acid although
acetone/BF3‚OEt2 gave the enone that would arise following
dehydration of the expected aldol product. However, the ketal
2,2-dimethoxypropane in conjunction with BF3‚OEt2 proved
successful giving the dimethyl-substituted methyl ether product
3c as a single diastereomer. In a similar fashion, methylortho-
formate reacted in good overall yield providing a route to the
differentially protected 1,3 dicarbonyl compound 3d. Again, Lewis
acid activation was found to be essential. The enolate 2b formed
from cycloheptenone gave similar results to 2a with 3e and 3f
formed in good overall yield. To the best of our knowledge, this
is the first time zinc enolates have been used in the cleavage of
acetals.
While we had succeeded in extending the scope of the reactivity
of zinc enolates formed from conjugate addition, we also observed
poor diastereocontrol in cases where a third stereocenter was
generated. On the basis of our findings and those of Noyori,4 it
would appear that electrophiles will react to give trans-substituted
products and it is the center â to the carbonyl group that is formed
in a stereorandom manner. We therefore decided to use a chiral
auxiliary approach to give stereocontrol in the second stage of
the reaction.
Acetals 4a (R ) Ph) and 4b (R ) propenyl) are readily
accessible and known to react with nucleophiles with high
diastereocontrol.6 We were delighted to find that treating 2a with
4a in the presence of TMSOTf gave alcohol 5a as a single
diastereomer, following cleavage of the TMS ether (Table 2). BF3‚
OEt2 gave 5a directly although in slightly lower overall yield.
Scheme 2
Table 2. Enolate Trappings with Chiral Acetalsa
(1) Reviews: Lee, V. J. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming I., Eds.; Pergamon Press: Oxford, 1991; Vol 4, pp 69 and 139.
(2) For a recent reviews see: (a) Tomioka, K.; Nagaoka, Y. In Compre-
hensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer, New York, 2000; p 1105. (b) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033.
(3) (a) Alexakis, A.; Frutos, J.; Mangeney P. Tetrahedron: Asymmetry
1993, 4, 2427. (b) Alexakis, A.; Vastra, J.; Mangeney, P. Tetrahedron Lett.
1997, 38, 7745. (c) Alexakis, A.; Vastra, J.; Burton, J.; Benhaim, C.;
Mangeney, P. Tetrahedron Lett. 1998, 39, 7869. (d) Alexakis, A.; Benhaim,
C. Org. Lett. 2000, 2, 2579. (e) Alexakis, A.; Burton, J.; Vastra, J.; Benhaim,
C.; Fournioux, X.; van den Heuvel, A.; Leveˆque, J.-M.; Maze´, F.; Rosset, S.
Eur. J. Org. Chem. 2000, 4011.
(4) (a) Kitamura, M.; Miki T.; Nakano, K.; Noyori, R. Tetrahedron Lett.
1996, 37, 5141. (b) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Bull.
Chem. Soc. Jpn. 2000, 73, 999.
(5) (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vires, A.
H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620. (b) Feringa, B. L. Acc.
Chem. Res. 2000, 33, 346. (c) For an alternative, highly stereoselective ligand
system see: Kno¨bel, A. K. H.; Escher I. H.; Pfaltz, A. Synlett 1997, 1429.
a Reagents and conditions: (i) 4a/4b (1.5-2.0 equiv), TMSOTf
(1.5-2.0 equiv), -20 to 0 °C, 0.5-2 h; (ii) MeOH, Amberlyst-15, 1
h. b Isolated yield after column chromatography.
X-ray crystallography revealed the stereochemistry of 5a to
be as shown in Figure 1.7 This is in keeping with the expected
stereochemical outcome for reaction with chiral acetals.6
(6) Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry 1990, 1, 477.
10.1021/ja005911n CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/17/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 18, 2001 4359
after removal of the chiral auxiliary (Scheme 4) providing a
method to selectively access both diastereomeric aldol products.
Therefore, a chiral acetal overcomes the directing effect of the
chiral enolate.6 It should be noted that the nature of the Lewis
acid is vital as the use of BF3‚OEt2 gave none of the desired
product. As this was not found to be the case in the formation of
the trans-threo isomer, this would seem to point to a mismatch
effect between the enolate ent-2a and acetal 4a.
Scheme 4a
Figure 1. X-ray structure of 5a.
To incorporate functionalities other than aryl,8 we investigated
the use of acetal 4b. One can envisage using the double bond
contained within the products of these reactions (5b and 5d) as
a chemical handle for a wide range of transformations, thus
dramatically extending the synthetic potential. Reaction with 4b
could afford either the direct opening product or the conjugate
addition adduct. Despite the presence of copper, the products of
direct 1,2 opening were isolated in good yield (Table 2).9
After examining several unsuccessful methods, the chiral
auxiliary was removed using a mild, highly efficient, two-step
procedure as outlined in Scheme 3. Oxidation of the secondary
alcohol 5a gave ketone 6 which, when treated with excess zinc
in aqueous acetic acid, resulted in the elimination of the trans-
threo aldol product 7 in overall quantitative yield.
a Reagents and conditions: (a) (i) 0.5 mol % copper(II) triflate, 1.0
mol % ent-1, CH2Cl2, 0.5 M, -20 °C, 15 min; (ii) 4a (1.5 equiv),
TMSOTf (1.6 equiv), -20 to 0 °C, 2 h; (b) MeOH, Amberlyst-15, 1 h;
(c) PDC (2.0 equiv), CH2Cl2, 3 Å sieves, room temperature, 36 h; (d)
Zn, AcOH/H2O, 1 h; 56% overall yield.
To verify that the chiral ligand plays no role in the reaction
with the chiral acetal a control experiment with triphenylphosphine
as ligand was carried out. This resulted in the formation of a
racemic 3:2 mixture of 5a and 8, indicating that the stereocontrol
at the aldol center arises purely as a result of the chiral auxiliary.
In summary we have extended the reactivity of homochiral
zinc enolates to include trapping with acetals, ketals, and ortho
esters. In the case of chiral acetals, three contiguous stereocenters
and two carbon-carbon bonds can be generated in a tandem, one-
pot reaction with complete control to give syn and anti aldol
products with allyl and aryl substitution.
Scheme 3a
Acknowledgment. We thank the Swiss National Science Foundation
(grant no. 20-53967.98) for financial support.
Note Added after ASAP: There was a spelling error in the title in
the version posted ASAP 04/17/2001. It has been corrected in the print
version posted 05/09/2001.
a Reagents and conditions: (a) PDC (2.0 equiv), 3 Å sieves, CH2Cl2,
room temperature, 36 h; (b) Zn, AcOH/H2O, 1 h; >99% overall yield.
Supporting Information Available: Experimental procedures and
1H and 13C spectra are available for compounds 3a-f, 5a-d, and 6 to 9
plus tables of crystal data, atomic coordinates, bond lengths and angles,
anisotropic displacement parameters and figures for 5a (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
By using the enantiomer of ligand 1 in the conjugate addition
step, trans-erythro aldol 9 was formed as a single diastereomer
(7) Crystal data for 5a: Orthorhombic, space group P212121, colorless
crystal, a ) 8.8471(6) Å, b ) 14.5780(7) Å, c ) 19.1945(10) Å, Z ) 4, 200
K, GOF ) 1.56, R ) 0.033, wR ) 0.034.
(8) For the 1,4 addition of cuprates to 4b see: Mangeney, P.; Alexakis,
A.; Normant, J. F. Tetrahedron Lett. 1986, 27, 3143
JA005911N
(8) The acetal formed by condensation of acetaldehyde and (S,S)-2,4-
pentanediol reacted with 2a with lower selectivity.