Highly enantioenriched homoenolate reagents by asymmetric γ-deprotonation of achiral 1-silyl-substituted 1-alkenyl carbamates

Article abstract of DOI:10.1021/ol0364677

1-Trimethylsilyl-1-alkenyl carbamates 1 are deprotonated by n-butyllithium/(-)-sparteine (2) with a high degree of enantiotopic differentiation in the γ-position to form the enantiomerically enriched allyllithium derivatives 3. Trapping these with several

Full text of DOI:10.1021/ol0364677

ORGANIC
LETTERS
2004
Vol. 6, No. 5
783-786
Highly Enantioenriched Homoenolate
Reagents by Asymmetric
γ-Deprotonation of Achiral
1-Silyl-Substituted 1-Alkenyl Carbamates
Jenny Reuber, Roland Fro1hlich,† and Dieter Hoppe*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t Mu¨nster,
Corrensstrasse 40, 48149 Mu¨nster, Germany
dhoppe@uni-muenster.de
Received December 19, 2003
ABSTRACT
1-Trimethylsilyl-1-alkenyl carbamates 1 are deprotonated by n-butyllithium/(−)-sparteine (2) with a high degree of enantiotopic differentiation
in the γ-position to form the enantiomerically enriched allyllithium derivatives 3. Trapping these with several electrophiles proceeds
stereospecifically in an anti-SE′ or syn-SE′ substitution to form products 4 or ent-4, respectively. Compounds 3a (R ) Me) and 3b (R ) Ph)
exhibit toward carbonyl electrophiles opposite senses of almost complete stereospecificity, thus for 3b‚2 the involvement of a η3-complex is
suggested.
Enantioenriched homoenolate reagents are valuable synthetic
building blocks.1 In particular, 1-oxygen-2 and 1-nitrogen-
substituted3 1-metalallyl derivatives proved to be ideal
reagents for enantio- and diastereoselective homoaldol reac-
tions. Quite recently, we found a surprisingly simple ap-
proach to configurationally stable, enantioenriched homoeno-
late reagents by (-)-sparteine-mediated γ-deprotonation of
1-aryl-1-alkenyl carbamates 1 (aryl for Me3Si).4 Here, the
3-pro-R-proton, which is localized in a position remote from
the complexing group, is removed with high selectivity by
the chiral base. Taking into account that an anion-stabilizing
group in position 1 may be required, we now investigated
the 1-trimethylsilyl-1-butenyl carbamate 1a (Scheme 1).5 For
efficient deprotonation in toluene, 3 equiv of n-butyllithium/
(-)-sparteine (2) and a reaction time of 12 h at -78 °C were
required. Under these conditions, the lithium compound 3a
proved to be perfectly configurationally stable, and trapping
it provided the γ-substitution products 4a-c in high yield
and with g95% ee. Acylations of 3a to
* Fax: (+49)251/8336531.
† To whom correspondence regarding X-ray analysis should be addressed.
(1) Reviews: (a) Hoppe, D.; Hense, T. Angew. Chem. 1997, 109, 2376;
Angew. Chem., Int. Ed. Engl. 1997, 36, 2282. (b) Hoppe, D.; Marr, F.;
Bru¨ggemann, M. In Organolithium in EnantioselectiVe Synthesis; Hodgson,
D. M., Ed.; Topics in Organometallic Chemistry; Springer-Verlag: Berlin,
2003; Vol. 5, p 61. (c) Beak, P.; Johnson, T. A.; Kim, D. D.; Lim, S. H. In
Organolithium in EnantioselectiVe Synthesis; Hodgson, D. M., Ed.; Topics
in Organometallic Chemistry; Springer-Verlag: Berlin, 2003; Vol. 5, p 134.
(d) Ahlbrecht, H.; Beyer, U. Synthesis 1999, 365.
(2) (a) Hoppe, D.; Zschage, O. Angew. Chem. 1989, 101, 67; Angew.
Chem., Int. Ed. Engl. 1989, 28, 69. (b) Zschage, O.; Hoppe, D. Tetrahedron
1992, 48, 5657. (c) Hoppe, D.; Kra¨mer, T. Angew. Chem. 1986, 98, 171;
Angew. Chem., Int. Ed. Engl. 1986, 25, 160.
(4) Hoppe, D.; Seppi, M.; Kalkofen, R.; Reupohl, J.; Fro¨hlich, R. Angew.
Chem. 2004, 116, in press.
(5) (E)-1-Trimethylsilyl-1-butenyl N,N-diisopropylcarbamate was pro-
duced from the 2-buten-1-ol in a three-step sequence (see Supporting
Information).
(3) Beak, P.; Weisenburger, G. A. J. Am. Chem. Soc. 1996, 118, 12218.
10.1021/ol0364677 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/13/2004

Scheme 1. Lithiation of 1a and Reaction with Electrophilesa
Scheme 2. Transmetalation and Homoaldol Reactiona
a Reagents and conditions: (a) 3.0 equiv of nBuLi/(-)-sparteine,
toluene, -78 °C, 12 h; (b) (i) 6.0 equiv of EIX, -78 °C, 2 h, (ii)
MeOH, HOAc , (iii) rt.
a Reagents and conditions: 3.5 equiv of ClTi(NEt2)3, toluene,
-78 °C, 6 h; (b) (i) 7.0 equiv of EIX, -25 °C, 2 h, (ii) MeOH,
HOAc, -78 °C, (iii) rt; (c) (i) 7.0 equiv of EIX, -78 °C, 2 h, (ii)
MeOH, HOAc, -89 °C, (iii) rt; (d) 1.5 equiv of PDC, CH2Cl2, rt.
form alkenyl ester 4d and ketone 4e were less efficient
(Scheme 1). We assume that enolate formation by excess of
base is the origin of partial racemization and decomposition.
As will be shown below,6 products 4a-e have (S)-config-
uration, resulting from anti-SE′ attack of the electrophile onto
(R)-3a‚2.
the addition products arising from both pathways. Desily-
lation of (-)-anti-6b led to the known homoaldol product
8b,2 which has the configuration (3S,4R) (Scheme 3). It has
to be assumed that, unlike with the titanium intermediate
5a, the lithium compound (R)-3a‚2 undergoes addition in
an open-chain anti-SE′ process.
The exchange of lithium for tris(diethylamino)titanium7-9
in (R)-3a‚2 generally proceeds with inversion of configura-
tion to form the intermediate (R)-5a, which adds to aldehydes
via a Zimmerman-Traxler transition state10 in a strict syn-
SE′ fashion, leading with complete 1,3-transfer of chirality
to essentially enantiopure homoaldol products anti-6 (Scheme
2 and Table 1). Direct addition of the aldehydes to the
Scheme 3. Desilylation of (-)-anti-6ba
a Reagents and conditions: (a) 1.5 equiv of TBAF, THF, 22 h.
Table 1. Prepared Homoaldol Products 6
c
RCHdO
product
yield
% eea
drb
[R]D
CH3(CH2)2CHdO
(CH3)2CHCHdO
(CH3)3CCHdO
cC6H11CHdO
anti-6a
anti-6b
anti-6c
anti-6d
anti-6e
70
72
80
69
71
g95
g95
g95
g95
89
g95:5
g95:5
g95:5
g95:5
g95:5
-25
-27
-29
-15
-78
In conclusion, the lithium compound (R)-3a‚2 has a very
pronounced tendency for anti-SE′ processes with most
electrophiles exceeding those of the recently investigated
1-aryl derivative.4
(C6H5)CHdO
When we investigated the analogous (E)-3-phenyl-1-
trimethylsilyl-1-propenyl carbamate 1b11 we encountered
some surprises (Scheme 4).
a Determined by 1H NMR shift experiments. b Determined by 1H NMR
and GC. c c ) 0.8-2.8, CHCl3.
(7) Reviews: (a) Reetz, M. T. Organotitanium Reagents in Organic
Synthesis, 1st ed.; Springer-Verlag: Berlin, 1986. (b) Weidmann, B.;
Seebach, D. Angew. Chem. 1983, 95, 12; Angew. Chem., Int. Ed. Engl.
1983, 22, 32. (c) Reetz, M. T. Organotitanium Chemistry. In Organo-
metallics in Synthesis, 2nd ed.; Schlosser, M., Ed.; Wiley: Chichester, 2002;
p 817.
(8) Hoppe, D.; Hanko, R. Angew. Chem. 1982, 94, 378; Angew. Chem.,
Int. Ed. Engl. 1982, 21, 372.
(9) When we used ClTi(OiPr)3 as exchange reagent, diminished yields
(anti-6b 41%; anti-6e 42%) were obtained. This is due to the formation of
radicals, since we isolated an oxidative dimer of 3a ((1E,5E)-[3,4-dimethyl-
1,6-bis(trimethylsilyl)-1,5-hexadien-1,6-diyl] bis[N,N-diisopropylcarbam-
ate]).
lithiated compound (R)-3a‚2 furnishes mixtures of anti- and
syn-6 (approximately 1:1) (Scheme 2).
Samples of the homoallylic alcohols 6d and 6e were
oxidized to ketones (+)-7d ([R]D ) +169 and +168) and
(+)-7e ([R]D ) +158 and +160), respectively, giving
evidence for the identical absolute configuration at C-3 in
(6) Lithiodestannylation of (S)-(+)-4b ([R]D ) +112) with nBuLi/Et2O
at -78 °C and reaction of the formed (S)-3a‚Et2O with Ph3SnCl afforded
(R)-(-)-4c ([R]D ) -66, 48% ee) with 87% yield. Since all known
lithiodestannylations proceed as suprafacial processes, the stereochemical
course of the reverse reaction is (one time more) anti-SE′.
(10) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920.
784
Org. Lett., Vol. 6, No. 5, 2004

Scheme 4. Lithiation of 1b and Reaction with Electrophiles
a Reagents and conditions: (a) 1.2 equiv of nBuLi/(-)-sparteine,
toluene, -78 °C, 1 h; (b) (i) 3.0 equiv of EIX, -78 °C, 2 h, (ii)
MeOH, HOAc, -78 °C, (iii) rt.
Figure 2. X-ray structure of 9c.
As expected, as a result of the attached phenyl residue,
the deprotonation proceeded very smoothly. On trapping the
reaction mixture with silyl and tin chlorides, almost enan-
tiopure products 9a, 9b, or 9c were produced. From 9a and
9c12 X-ray analysis with anomalous diffraction were obtained
(Figures 1 and 2) to reveal the (3R)-configuration arising
Figure 3. X-ray structure of ent-9e.
pure homoaldol products anti-11 (Scheme 5, Table 2). A
second diastereomer could not be detected by 1H NMR and
GC in the crude mixture, and thus the dr is concluded to be
g95:5.
Scheme 5. Transmetalation and Homoaldol Reactiona
Figure 1. X-ray structure of 9a.
from a clean anti-SE′-attack. On the other hand, from
carbonyl electrophiles, without exception, the enantiomers
ent-9d-g were formed. The absolute configuration of ent-
9e12 (Figure 3) could be explored by X-ray analysis; the other
ones were subjected to chemical correlations.
a Reagents and conditions: (a) 1.2 equiv of nBuLi/(-)-sparteine,
toluene, -78 °C, 1 h; (b) 1.5 equiv of ClTi(NEt2)3, -78 °C, 30
min; (c) (i) 3.0 equiv of RCHdO, -78 °C, 2 h, (ii) MeOH, HOAc,
-78 °C, (iii) rt.
After lithium-titanium exchange in (R)-3b‚2, acetone
furnished the enantiomer 9f ([R]D ) -123, 93%, g95%).
Addition of aldehydes to the intermediate titanium compound
10 provides the highly enantioenriched diastereomerically
(11) E)-3-Phenyl-1-trimethylsilyl-1-propenyl N,N-diisopropylcarbamate
was produced from cinnamyl alcohol in a three-step sequence (see
Supporting Information).
It is evident from these results that the lithium-(-)-
sparteine compound (R)-3b‚2 has a high tendency for syn-
Org. Lett., Vol. 6, No. 5, 2004
785

phenyl at C-3, which causes a stabilization of the negative
charge in the anion in position 3. Therefore, we assume that
(R)-3b‚2 has a η3-structure (see Scheme 4) either in the
ground state or its involvement in a rapid equilibration. It
has been demonstrated for the related lithium-(-)-sparteine
complexes 1213 and 1314,15 (Figure 4) that these have a η3-
Table 2. Prepared Homoaldol Products anti-11
c
RCHdO
product
yield
% ee
[R]D
CH3(CH2)2CHdO
(CH3)2CHCHdO
(CH3)3CCHdO
cC6H11CHdO
anti-11a
anti-11b
anti-11c
anti-11d
anti-11e
98
95
98
93
99
91a
94a
-144
-162
-181
-113
-64
95a
97a
4-Br(C6H4)CHdO
g95b
1
a Determined by chiral HPLC. b Determined by H NMR shift experi-
ments. c c ) 0.78-1.8, CHCl3.
addition reactions toward carbonyl compounds, opposite to
compound (R)-3a‚2. What are the reasons? Compound (R)-
3b‚2 differs from (R)-3a‚2 in the exchange of methyl for
Figure 4. Structures of complexes 12 13 and 13,14,15 elucidated by
X-ray analysis.
(12) X-ray crystal structure analysis of 9a: formula C22H39NO2Si2, MW
) 405.72, colorless crystal 0.40 × 0.25 × 0.20 mm3, a ) 21.838(1),
structure (at least in solid state) and that they react with
aldehydes, ketones, and acid chlorides in a strict suprafacial
manner.13,15 Obviously, the lithium cation here has a higher
Lewis acidity toward carbonyl groups than in the appropriate
η1-complexes and, thus, “lures” the carbonyl compound to
enter from the same face of the allylic system.
After desilylation (H for Me3Si in 9, ent-9 or anti-11),
highly enantioenriched products that derive from the homo-
enolate of 3-phenyl-2-propenal are accessible;15 the direct
carbamate-type homoenolate reagent had turned out not to
be configurationally stable.16 Furthermore, in many cases,
both enantiomers can be selectively approached via the same
intermediate 3b‚2 or by utilization of a surrogate, recently
introduced by O’Brien and co-workers.17
b ) 9.844(2), c ) 12.235(1) Å, V ) 2630.2(6) Å3, Fcalc ) 1.025 g cm-3
,
µ ) 13.27 cm-1, empirical absorption correction via ψ scan data (0.619 e
T e 0.777), Z ) 4, orthorhombic, space group Pna21 (No. 33), λ ) 1.54178
Å, T ) 223 K, ω/2θ scans, 2810 reflections collected (-h, -k, -l), [(sin θ)/
λ] ) 0.62 Å-1, 2810 independent and 2370 observed reflections [I g 2σ-
(I)], 254 refined parameters, R ) 0.052, wR2 ) 0.140, Flack parameter
0.01(5), max residual electron density 0.27 (-0.27) e Å-3, hydrogens
calculated and refined as riding atoms. X-ray crystal structure analysis of
9c: formula C37H45NO2SiSn, MW ) 682.52, colorless crystal 0.30 × 0.20
× 0.15 mm3, a ) 9.245(1), b ) 11.945(1), c ) 32.509(1) Å, V ) 3590.0-
(5) Å3, Fcalc ) 1.263 g cm-3, µ ) 7.75 cm-1, empirical absorption correction
(0.801 e T e 0.893), Z ) 4, orthorhombic, space group P212121 (No. 19),
λ ) 0.71073 Å, T ) 198 K, ω and æ scans, 11789 reflections collected
((h, (k, (l), [(sin θ)/λ] ) 0.67 Å-1, 7633 independent (Rint ) 0.031) and
5703 observed reflections [I g 2σ(I)], 386 refined parameters, R ) 0.040,
wR2 ) 0.061, Flack parameter -0.05(2), max. residual electron density
0.48 (-0.46) e Å-3, hydrogens calculated and refined as riding atoms. X-ray
crystal structure analysis of ent-9e: formula C24H39NO3Si, MW ) 417.65,
colourless crystal 0.35 × 0.20 × 0.20 mm3, a ) 9.895(1), b ) 11.670(1),
c ) 22.943(1) Å, V ) 2649.3(4) Å3, Fcalc ) 1.047 g cm-3, µ ) 1.10 cm-1
,
Acknowledgment. Support provided by the Deutsche
Forschungsgemeinschaft, Sonderforschungsbereich 424 and
by the Fonds der Chemischen Industrie is gratefully ac-
knowledged. We thank Mrs. Cornelia Weitkamp for her
outstanding experimental assistance.
empirical absorption correction (0.963 e T e 0.978), Z ) 4, orthorhombic,
space group P212121 (No. 19), λ ) 0.71073 Å, T ) 198 K, ω and æ scans,
20230 reflections collected ((h, (k, (l), [(sin θ)/λ] ) 0.66 Å-1, 6233
independent (Rint ) 0.067) and 4461 observed reflections [I g 2σ(I)], 274
refined parameters, R ) 0.047, wR2 ) 0.105, Flack parameter -0.08(12),
max. residual electron density 0.22 (-0.18) e Å-3, hydrogens calculated
and refined as riding atoms. Data sets were collected with Enraf-Nonius
CAD4 and Nonius KappaCCD diffractometers, the later equipped with a
rotating anode generator Nonius FR591. Programs used: data collection
EXPRESS (Nonius B.V., 1994) and COLLECT (Nonius B. V., 1998), data
reduction MolEN (Fair, K. Enraf-Nonius B.V., 1990) and Denzo-SMN
(Otwinowski, Z.; Minor, W. Methods in Enzymology, 1997, 276, 307-
326), absorption correction for CCD data SORTAV (Blessing, R. H. Acta
Crystallogr. 1995, A51, 33-37; J. Appl. Crystallogr. 1997, 30, 421-426),
structure solution SHELXS-97 (Sheldrick, G. M. Acta Crystallogr. 1990,
A46, 467-473), structure refinement SHELXL-97 (Sheldrick, G. M.
Universita¨t Go¨ttingen, 1997), graphics Diamond (Brandenburg, K. Univer-
sita¨t Bonn, 1997).
Supporting Information Available: Experimental pro-
1
cedures, spectroscopic data, and H and 13C NMR spectra
for 1a, 1b, 4a, anti-6a, ent-9e, anti-11b. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0364677
(15) (a) Beak, P.; Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J. J.
Am. Chem. Soc. 1999, 121, 9522. (b) Beak, P.; Whisler, M. C.; Vaillancourt,
L. Org. Lett. 2000, 2, 2655.
(13) Hoppe, D.; Hoppe, I.; Marsch, M.; Harms, K.; Boche, G. Angew.
Chem. 1995, 107, 2328; Angew. Chem., Int. Ed. Engl. 1995, 34, 2158.
(14) Beak, P.; Pippel, D. J.; Weisenburger, G. A.; Wilson, S. R. Angew.
Chem. 1998, 110, 2600; Angew. Chem., Int. Ed. Engl. 1998, 37, 2522.
(16) Hoppe, D.; Behrens, K.; Fro¨hlich, R.; Meyer, O. Eur. J. Org. Chem.
1998, 2397, 7.
(17) O’Brien, P.; Dearden, M. J.; Firkin, C. R.; Nermet, J.-P. R.; J. Am.
Chem. Soc. 2002, 124, 11870.
786
Org. Lett., Vol. 6, No. 5, 2004