Tandem Asymmetric Conjugate Addition-Silylation of Enantiomerically Enriched Zinc Enolates. Synthetic Importance and Mechanistic Implications

Article abstract of DOI:10.1021/ol026644o

(Matrix Presented) The zinc enolates, resulting from the copper-catalyzed enantioselective conjugate addition of dialkyl zinc reagents to cyclic and acyclic enones, could be trapped, quantitatively, as silyl enol ethers with TMSOTf in apolar solvents or w

Full text of DOI:10.1021/ol026644o

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3835-3837
Tandem Asymmetric Conjugate
Addition−Silylation of Enantiomerically
Enriched Zinc Enolates. Synthetic
Importance and Mechanistic Implications
Oliver Knopff and Alexandre Alexakis*
Department of Organic Chemistry, UniVersity of GeneVa, 30, Quai Ernest Ansermet,
1211 GeneVa 4, Switzerland
alexandre.alexakis@chiorg.unige.ch
Received July 31, 2002
ABSTRACT
The zinc enolates, resulting from the copper-catalyzed enantioselective conjugate addition of dialkyl zinc reagents to cyclic and acyclic enones,
could be trapped, quantitatively, as silyl enol ethers with TMSOTf in apolar solvents or with TMSCl and NEt3. These enantiomerically enriched
silyl enol ethers were submitted to four synthetic transformations to show their synthetic utility. The zinc enolates obtained from acyclic
enones were found to be configurationally stable, as shown by the stereochemistry of the silyl enol ethers.
Asymmetric copper-catalyzed conjugate addition has stirred
tremendous interest in the last few years.1 Considerable
progress has been made, using dialkyl zinc reagents as
primary organometallics, with enantioselectivities reaching
>99% on both cyclic and acyclic enones.2 The common
feature of these reactions is the generation of enantiomeri-
cally enriched zinc enolates.
build more complex molecules.3 Despite their low reactivity,
zinc enolates could be made to react with aldehydes,4 with
acetals5 (with BF3‚Et2O as an additive), with allylic acetates6
(with Pd catalysis), and with homopropargylic iodide.7 In
(2) (a) Alexakis, A.; Frutos, J.; Mangeney, P. Tetrahedron: Asymmetry
1993, 4, 2427. (b) Alexakis, A.; Burton, J.; Vastra, J.; Benha¨ım, C.;
Fournioux, X.; van den Heuvel, A.; Leveˆque, J.-M.; Maze´, F.; Rosset, S.
Eur. J. Org. Chem. 2000, 4011. (c) Alexakis, A.; Benha¨ım, C.; Fournioux,
X.; van den Heuvel, A.; Leveˆque, J.-M.; March, S.; Rosset, S. Synlett 1999,
1811. (d) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz,
R.; Feringa, B. L. Tetrahedron, 2000, 56, 2865. (e) Escher, I. H.; Pfaltz, A.
Tetrahedron 2000, 56, 2879. (f) Mizutani, H.; Degrado, S. J.; Hoveyda, A.
H. J. Am. Chem. Soc. 2002, 124, 779.
(3) (a) Taylor, R. J. K. Synthesis 1985, 364. (b) Chapdelaine, M. J.; Hulce,
M. Org. React. 1990, 38, 225.
(4) (a) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron Lett.
1996, 37, 5141. (b) Mandoli, A.; Arnold, L. A.; de Vries, A. H. M.;
Salvadori, P.; Feringa, B. L. Tetrahedron: Asymmetry 2001, 12, 1929.
(5) Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc. 2001,
123, 4358.
Tandem conjugate addition and trapping of the zinc enolate
with an electrophile could be an excellent way to quickly
(1) (a) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 77. (b)
Alexakis, A. In Taylor, R. J. K., Ed. Organocopper Reagents, a Practical
Approach; Oxford University Press: Oxford, 1994; Chapter 8, p 159. (c)
Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York,
1994. (d) Ojima, I. Catalytic Asymmetric Synthesis; Wiley-VCH: Weinheim,
1993. (e) Alexakis, A. in Transition Metal Catalysed Reactions; Murahashi,
S.-I., Davies, S. G., Eds.; IUPAC Blackwell Science: Oxford 1999; p 303.
(f) Tomioka, K.; Nagaoka, Y. ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
2000; p 1105. (g) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
(h) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (i) Ibuka, T.
Organocopper Reagents in Organic Synthesis; Rose Press: Osaka, 2000.
(j) Krause, N. Modern Organocopper Chemistry; VCH: Weinheim, 2002.
(6) (a) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Bull. Chem. Soc.
Jpn. 2000, 73, 999. (b) Naasz, R.; Arnold, L. A.; Pineschi, M.; Keller, E.;
Feringa, B. L. J. Am. Chem. Soc. 2001, 121, 1104.
10.1021/ol026644o CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/04/2002

Scheme 1
Scheme 2
The use of racemic 3 (R ) Me) as a synthon in total synthesis
underlines the synthetic importance of this reaction sequence
to enantiomerically enriched silyl enol ethers.13
view of the versatility of silyl enol ethers,8 it would be
desirable to trap zinc enolates with a silylating agent. The
resulting homochiral silyl enol ethers would then be excellent
substrates for further synthetic elaboration.
Using the phosphoramidate ligands L*,9 one can generate
enantiomerically enriched zinc enolate 1 (ee > 99%). We
made an unexpected observation when we added trimethyl
silyl chloride (TMSCl) as an additive for the copper-catalyzed
addition of diethylzinc to cyclohexenone.
Surprisingly, the O-silylated product 2 was obtained in
82% yield (ds 1:1) if TMSCl was added before the addition
of cyclohexenone to a mixture of diethylzinc, Cu(OTf)2, and
the ligand L* in CH2Cl2. We believe that TMSCl slowed
the rate of the conjugate addition reaction of diethylzinc10
so that the formed zinc enolate intermediate 1 could react
with the starting material. This is in contrast to the known
acceleration effect of TMSCl for the conjugate addition of
cuprates.11 If, however, TMSCl was added after quantitative
formation of the enolate 1, the O-silylated product 3 was
obtained in 83% yield and 99% ee. With TMSOTf, or
TMSCl and NEt3, the corresponding silyl enol ether 3 was
formed in nearly quantitative yield in 1 h at room temperature
(97%). To our knowledge, this is the first O-silylation of
zinc enolates in an apolar solvent (CH2Cl2) in high yield.12
This finding considerably widens the synthetic scope of
the tandem conjugate addition-trapping of electrophile.
Among the many possible reactions of these silyl enol ethers,8
we have performed the reactions to form the following
interesting enantiomerically enriched synthons (Scheme
2).14-17 It should be pointed out, that these transformations
could not be accomplished directly from the zinc enolate.
The easy silylation of zinc enolates may also shed some
light on the mechanism of the conjugate addition on acyclic
enones 4. If the zinc enolate intermediates 5 would be
configurationally stable at the reaction temperature, we could
find out whether the copper-catalyzed conjugate addition
occurs on either the s-trans 4 or the s-cis 4 conformer or at
both.18 On the other hand, it would be interesting to know if
the (E)- and (Z)-zinc enolates 5 ((E)- and (Z)-silyl enol ethers
6) were formed with the same enantiomeric excess. Some
of the results are reported in Table 1.
For the conjugate addition at -30 °C, enones 4 showed
an (E)-selectivity19 in the formation of zinc enolates 5 (entries
1-6). In diethyl ether, higher amounts of the (E)-isomer
(E)-6 were obtained (enties 3 and 6). In all cases, the ee of
the silyl enol ether was determined, after desilylation, and
found to be similar to that of the simple conjugate addition-
hydrolysis process.2c
The question of the configurational stability of zinc enolate
intermediate 5 was addressed as follows. The solvent of the
(7) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755.
(8) Brownbridge, P. Synthesis 1983, 1 and 85.
(9) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (b) Alexakis, A.;
Rosset, S.; Allamand, J.; March, S.; Guillen, F.; Benha¨ım, C. Synlett 2001,
1375. (c) Alexakis, A.; Benha¨ım, C.; Rosset, S.; Humam, M. J. Am. Chem.
Soc. 2002, 124, 5262.
(10) In situ-generated CuCl is not a good catalyst for the conjugate
addition; see Alexakis, A.; Vastra, J.; Mangeney, P. Tetrahedron Lett. 1997,
38, 7745.
(11) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015 and
6019. (b) Alexakis, A.; Berlan, J.; Besace, Y. Tetrahedron Lett. 1986, 27,
1047. (c) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I.
Tetrahedron Lett. 1986, 27, 4029. (d) Marsuzawa, S.; Horiguchi, Y.;
Nakamura, E.; Kuwajima, I. Tetrahedron 1989, 45, 349.
(12) For attempted acceleration of the conjugate addition of diethylzinc
by TMSCl, see: (a) Bolm, C.; Ewald, M.; Felder, M. Chem. Ber. 1992,
125, 1205. (b) Reddy, C. K.; Devasagayaraj, A.; Knochel, P. Tetrahedron
Lett. 1996, 37, 4495. (c) Chataigner, I.; Gennari, C.; Ongeri, S.; Piarulli,
U.; Ceccarelli, S. Chem. Eur. J. 2001, 7, 2628. (d) Schinnerl, M.; Seitz,
M.; Seitz, A.; Kaiser, A.; Reiser, O. Org. Lett. 2001, 3, 4259. For other
examples of silylation of zinc enolates in polar media, see: (e) Nakamura,
E.; Aoki, S.; Sekiya, K.; Oshhino, H.; Kuwajima, I. J. Am. Chem. Soc.
1987, 109, 8056. (f) Kim, S.; Moon Lee, J. Tetrahedron Lett. 1990, 31,
7627. (g) Matsubara, S.; Arioka, D.; Utimoto, K. Synlett 1999, 1253.
(13) Heathcock, C. H.; Tice, C. M.; Germroth, T. C. J. Am. Chem. Soc.
1982, 104, 6081.
(14) Nishitani, K.; Harada, K.; Sano, N.; Sato, K.; Yamakawa, K. Chem.
Pharm. Bull. 1991, 39, 2514.
(15) (a) Danishefsky, S.; Kitahara, T.; McKee, R.; Schuda, P. F. J. Am.
Chem. Soc. 1976, 98, 6715. (b) Piers, E.; Marais, P. C. J. Chem. Soc., Chem.
Commun. 1989, 17, 1222.
(16) Jones, T. K.; Denmark, S. E. J. Org. Chem. 1985, 50, 4037.
(17) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979.
(18) For discussion about the reactive conformer, see: (a) Bo¨rner, C.;
Dennis, M. R.; Sinn, E.; Woodward, S. Eur. J. Org. Chem. 2001, 2435. (b)
Bo¨rner, C.; Ko¨nig, W. A.; Woodward, S. Tetrahedron Lett. 2001, 42, 327.
(19) This is in contrast to the (Z)-selectivity (96:4) observed when the
ketone is reacted with TMSCl and triethylamine. See ref 20.
3836
Org. Lett., Vol. 4, No. 22, 2002

Table 1. Silylation of Acyclic Zinc Enolates
Table 2. Silylation of Acyclic Zinc Enolates
t [h] at room
R2 solvent temperature
(E)-6/(Z)-6
(yield, eea)
(E)-9/(Z)-9
(yield, eea)
entry
R1
entry
R3
solvent
t [h]
1
2
3
4
5
6
Me
Me
Me
hex CH2Cl2
hex toluene
hex Et2O
1 or 24
1 or 24
1 or 24
1
1
1
57/43 (93%, 85% ee)
76/24 (94%, 83% ee)
95/5 (89%, 78% ee)
84/16 (72%, 69% ee)
92/8 (86%, 62% ee)
94/6 (93%, 63% ee)
1
2
3
4
5
6
Me
Me
Me
Ph
Ph
Ph
CH2Cl2
toluene
Et2O
CH2Cl2
toluene
Et2O
1
1
1
1
1
1
43/57 (54%, 76% ee)
30/70 (61%, 83% ee)
69/31 (64%, 84% ee)
14/86 (92%, 69% ee)
5/95 (93%, 61% ee)
3/97 (82%, 59% ee)
pent Me CH2Cl2
pent Me toluene
pent Me Et2O
a ee after desilylation to the corresponding ketone.
a ee after desilylation to the corresponding ketone.
mixtures of zinc enolates (E)-5/(Z)-5 ) 57/43 (CH2Cl2, entry
1) and zinc enolates (E)-5/(Z)-5 ) 95/5 (Et2O, entry 3) was
changed to toluene with removal of CH2Cl2 or Et2O. These
mixtures, which were stirred for 2 h at room temperature in
toluene, showed after silylation the same E/Z ratio. This
suggests that the zinc enolate, once formed, is configuration-
ally stable at room temperature.20
The (E)-selectivity in the formation of the zinc enolates
could be explained by the preference of 4 for the s-trans
conformer (75%).21 Indeed, enones 7, which are known to
prefer the s-cis conformation (65%),22 showed a (Z)-
selectivity in the formation of zinc enolate 8 in apolar
solvents (entries 1, 2, and 4-6, Table 2). Again, in diethyl
ether, higher amounts of the (E)-isomer were formed (entry
3, Table 2).23
clear indication that the ratio of s-trans/s-cis conformers of
enone 7 does not affect the enantiomeric excess of 9. The
silyl enol ethers were obtained in the same enantiomeric
excess when they were formed from addition to both the
s-trans and s-cis conformers. It was also possible to separate
the enantiomers of (Z)-9 (entry 4, Table 2, R3 ) Ph) on a
chiral SFC column. (Z)-9 had the same enantiomeric excess
(69% ee) as the desilylated ketone of the mixture (E)-9/(Z)-9
(69% ee). This proved again that the (E)- and (Z)-silyl enol
ethers were obtained in the same enantiomeric excess.
In summary, we have shown that silyl enol ether could
be obtained from enantiomerically enriched zinc enolates in
apolar solvents in good to high yield, thus considerably
enhancing the synthetic scope of the conjugate addition. We
could also prove that zinc enolates are configurationally
stable at room temperature. The E/Z ratio of the formed zinc
enolate from acyclic R,â-unsaturated ketones is probably
dependent on the ratio of conformers of the substrate in the
reaction mixture. Further findings established that the
obtained enantiomeric excess of silyl enol ethers is not
dependent on the preferred conformation of the acyclic
substrate (s-trans or s-cis).
The results of entries 2 and 3 (Table 2) suggest that the
enantiomeric excess of the silyl enol ethers 9 is not dependent
on the E/Z ratio of zinc enolate intermediates 8. This is a
(20) When the ketone (3-methyl-5-undecanone) was treated with TMSCl
and Et3N, in Et2O, a mixture of four enol ethers was obtained with a (Z)-
selectivity for the minor regioisomers (E)-5/(Z)-5 ) 4/96.
Acknowledgment. The authors thank the Swiss National
Research Foundation No. 20-61891.00 and COST action
D12/0022/99 for financial support.
(21) (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley-Interscience: New York, 1994. (b) Chamberlin, A. R.; Reich, S. H.
J. Am. Chem. Soc. 1985, 107, 1440. (c) Oelichmann, H.-J.; Bougeard, D.;
Schrader, B. Angew. Chem. Suppl. 1982, 1404 and references therein.
(22) Montaudo, G.; Librando, S.; Caccamese, S.; Maravigna, P. J. Am.
Chem. Soc. 1973, 95, 6365.
Supporting Information Available: Experimental details
and spectral data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) This may be due to a change of the confomer ratio in the presence
of ZnX2 in Et2O.
OL026644O
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3837