Asymmetric γ-deprotonation and homoaldol reaction of 1,3-dien-2-yl carbamates: Stereo- and regiochemistry

Article abstract of DOI:10.1021/ol061005p

Lithium compounds 7 are configurationally stable intermediates obtained by deprotonation of 1,3-dien-2-yl carbamates 6 with n-butyllithium/(-)-sparteine with a high degree of enantiotopic differentiation at the γ-position. They react with electrophiles regioselectively giving highly enantioenriched products. Starting with different isomers or changing the double-bond geometries in 6 leads to either of the enantiomers.

Full text of DOI:10.1021/ol061005p

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3061-3064
Asymmetric
γ-Deprotonation and
Homoaldol Reaction of 1,3-Dien-2-yl
Carbamates: Stereo- and
Regiochemistry
Roland Bou Chedid, Roland Fro1
hlich,† and Dieter Hoppe*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t Mu¨nster,
Corrensstrasse 40, 48149 Mu¨nster, Germany
dhoppe@uni-muenster.de
Received April 27, 2006
ABSTRACT
Lithium compounds 7 are configurationally stable intermediates obtained by deprotonation of 1,3-dien-2-yl carbamates 6 with n-butyllithium/
)-sparteine with a high degree of enantiotopic differentiation at the -position. They react with electrophiles regioselectively giving highly
enantioenriched products. Starting with different isomers or changing the double-bond geometries in 6 leads to either of the enantiomers.
(
−
γ
The asymmetric homoaldol reaction of 1-metalated 2-alkenyl
carbamates provides a flexible approach to 4-hydroxy-1-
alken-1-yl carbamates,1a which can be transformed into a
manifold of target molecules.1 As we found recently,2 the
deprotonation of (Z)-1-alken-1-yl carbamates 1 by n-butyl-
lithium/(-)-sparteine 2 proceeds smoothly by removal of the
γ-pro-R-H leading to essentially stereohomogeneous five-
membered lithium enolates 3, as long as a slightly carbanion-
stabilizing substituent W (e.g., aryl2a,c or trimethylsilyl2b) is
present in 1 (Scheme 1). Addition of aldehydes or ketones
to form stereohomogeneous adducts 5 is particularly reward-
ing after lithium-titanium exchange.
Scheme 1. Transmetalation and Homoaldol Reaction of 1
* Fax: +49 (0) 251/ 8336531.
† Dr. Roland Fro¨hlich performed the X-ray analyses.
(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. Organolithiums 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
Organolithiums in EnantioselectiVe Synthesis; Hodgson, D. M., Ed.; Topics
in Organometallic Chemistry; Springer-Verlag: Berlin, 2003; Vol. 5, p 134.
(d) Hoppe, D.; Christoph, G. In Chemistry of Organolithium Compounds;
Rappoport, Z., Marek, I., Eds.; John Wiley & Sons Ltd.: Chichester, U.K.,
2004; Vol. 2, p 1055. (e) Ahlbrecht, H.; Beyer, U. Synthesis 1999, 365.
(2) (a) Hoppe, D.; Seppi, M.; Kalkofen, R.; Reupohl, J.; Fro¨hlich, R.
Angew. Chem. 2004, 116, 1447; Angew. Chem., Int. Ed. 2004, 43, 1423.
(b) Hoppe, D.; Reuber, J.; Fro¨hlich, R. Org. Lett. 2004, 6, 783. (c) Hoppe,
D.; Reuber, J.; Fro¨hlich, R. Eur. J. Org. Chem. 2005, 14, 3017. (d) Hoppe,
D.; Kalkofen, R.; Brandau, S.; U¨ naldi, S.; Fro¨hlich, R. Eur. J. Org. Chem.
2005, 21, 4571.
A vinylic group in position R should also be capable of
sufficient kinetic acidification of the γ-protons in diene 6;
however, the lithiated intermediate 7 now exhibits two
positions for γ-attack leading to regioisomers 8 and 9
10.1021/ol061005p CCC: $33.50
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Published on Web 06/08/2006

Scheme 2. Lithiation of 6 and Reaction with Electrophiles
Scheme 4. Stannylation of 6e with Ph3SnCl
(Scheme 2). Further, it is questionable if configurational
stability is still given due to extended conjugation in the
pentadienyl anion of 7.
process,8 the lithium intermediate 7e has the (S)-configura-
tion; this is formed by removal of the encircled proton (pro-R
Dienes 6 are synthesized in a straightforward manner.
After complete isomerization of allyl carbamates3 10 to vinyl
carbamates 11 via lithiation, lithium-titanium exchange,4
and protonation, the (Z)-enol carbamates 6 are obtained after
vinylic lithiation5 of 11, transmetalation to zinc, and Negishi
coupling5c,6 (Scheme 3).
Scheme 3. Synthesis of Dienes 6
Figure 1. X-ray structure of 13.9
in 6e). The structures of the further substitution products are
based on this result, combined with the known or proven
stereochemical courses of the reactions.
The lithium intermediates derived from 6 are configura-
tionally stable under the reaction conditions: after the (-)-
sparteine-mediated deprotonation of 6e (toluene, -78 °C)
and reaction with (CH3)3SiCl, the silane 15 is obtained with
the same enantiomeric purity (er ) 98:2) after a standing
time of 1 h (73%) or in situ trapping (Scheme 5). 15 is
Deprotonation of dienyl carbamate 6e with n-butyllithium/
(-)-sparteine (2) in toluene at -78 °C proceeds smoothly
within 1 h. Trapping with Ph3SnCl provides two separable
regioisomers 13 and 147 in a ratio of 68:32 and an er of
99:1 for 13 (Scheme 4). An X-ray crystal structure analysis
with anomalous diffraction revealed the (5S,1E,3Z) config-
uration of 13 (Figure 1). Because all stannylations of lithiated
2-alkenyl carbamates are known to take place in an anti-SE′
Scheme 5. Configurational Stability of 6
(3) (a) Hoppe, D.; Hanko, R.; Bro¨nneke, A.; Lichtenberg, F.; van Hu¨lsen,
E. Chem. Ber. 1985, 118, 2822. (b) Hoppe, D.; Behrens, K.; Fro¨hlich, R.;
Meyer, O. Eur. J. Org. Chem. 1998, 2397.
(4) 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 Organome-
tallics in Synthesis, 2nd ed.; Schlosser, M., Ed.; Wiley: Chichester, 2002;
p 817.
a c ) 0.76, 1.05 in CHCl3; er ) 98:2.
(5) (a) Hoppe, D.; Paulsen, H. Tetrahedron 1992, 48, 5667. (b) Hoppe,
D.; Peschke, B.; Lu¨ssmann, J.; Dyrbusch, M. Chem. Ber. 1992, 117, 1421.
(c) Sengupta, S.; Snieckus, V. J. Org. Chem. 1990, 55, 5680. (d) Kocienski,
P.; Dixon, N. J. Synlett 1989, 52.
(6) Negishi, E.; Zeng, X.; Tan, Z.; Qian, M.; Hu, Q.; Huang, Z. In Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diedrich,
F., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany,
2004; Vol. 2, p 815.
assigned the (S)-configuration because all silylations of
lithiated 2-alkenyl carbamates are known to take place in
an anti-SE′ process.
(7) 14 decomposes easily not allowing complete analysis.
(8) Paulsen, H.; Graeve, C.; Hoppe, D. Synthesis 1996, 141.
Org. Lett., Vol. 8, No. 14, 2006
3062

Similarly, carbamate 6a was deprotonated and subjected
to a metal exchange with (Et2N)3TiCl, and the titanium
intermediate 16a was intercepted by p-bromobenzaldehyde
to give two regioisomeric homoaldol adducts 17a and 18a
(92%, ratio of 80:20; Scheme 6). Again, the absolute
Scheme 7. Homoaldol Reactions of 6 with Acetone
Scheme 6. Transmetalation and Homoaldol Reaction of 6a
configuration of the major regioisomer 17a (6R,7S,4Z; Figure
2) could be determined by X-ray analysis. Because the
with acetone (Scheme 7). Both enantiomers can be obtained
by applying either 7e or 16e. This also substantiates the syn-
SE′ addition of acetone to 7e.
The sense of enantioselectivity can also be directed by
the used starting regioisomer or the configuration of its
“terminal” double bond (Scheme 7). Asymmetric deproto-
nation of 6c and addition of acetone yield ent-19 (er ) 94:
6, yield 86%). When (1Z)-6d is subjected to the same
reaction conditions, again ent-19 (er ) 96:4, yield 93%) is
produced arising from the Li compound (3S,1Z,4E)-7d. The
latter result again provides clear evidence for a syn-SE′ mode
of ketone addition, which now has to approach from the Si-
face of the styryl moiety. In addition, configurational stability
of the C1-C2 bond against torsion at low temperature must
be concluded.
Concerning the regiochemistry, the following rules are
extracted from the above examples and some more entries
in Table 1 and Scheme 8. The lithium intermediates 7 are
preferentially attacked at the terminus adjacent to the phenyl
residue where the highest electron and charge density are
expected. In the covalently bound titanium compounds 16,
Figure 2. X-ray structure of 17a.9
lithium-titanium exchange of (-)-sparteine allyllithium
complexes proceeds (with no known exception) with inver-
sion of configuration4,10 and the addition step occurs in a
suprafacial manner,11 the lithium intermediate 7a must have
the (S)-configuration; this is formed by removal of the
encircled proton (pro-S in 6a). This is in agreement with
the result extracted from the stannylation reaction.
Table 1. Substitution of 6e with Different Electrophiles via 7e
c
El
product(s)
yield %a
er b
[R]20
D
Me3Si
Me2C(OH)
Me
tBuC(O)
Ph3Sn
15
19
73
88
93
91
85
98:2
99:1
93:7
97:3
99:1
+12
Interesting features were uncovered from the homoaldol
reaction of the lithium (7e) and titanium (16e) intermediates
-174
+266
-150
+7f
9ead,e
9eb:8ebd (98:2)
13:14 (68:32)
(9) Crystal structure data of 13 and 17 are available in the Supporting
Information.
(10) Hoppe, D.; Hanko, R. Angew. Chem. 1982, 94, 378; Angew. Chem.,
Int. Ed. Engl. 1982, 21, 372.
(11) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920.
a Total yield. b Major product determined on chiral HPLC. c c ) 0.65-
1.05, in CHCl3. d Refers to Scheme 2: R1 ) Me, R2 ) Ph. e The absolute
configuration has not been determined yet. f Taken from the major product.
Org. Lett., Vol. 8, No. 14, 2006
3063

position” of the “pentadienyl anion” has ever been found
by us, although this is the preferred center of reactivity in
3-unsubstituted compounds.12
Scheme 8. Homoaldol Reactions of 6e
The alcohol 21a was oxidized to the ketone leading to
ent-9eb (6S,2E,4Z; er ) 99:1; [R]20 ) +154). This
D
substantiates the syn-SE′ addition of pivaloyl chloride to 7e
forming ketone 9eb.
In conclusion, the facile construction of geometrically
defined dienyl carbamates 6, combined with highly stereo-
selective asymmetric deprotonation and substitution reactions,
allows for a flexible synthesis of stereohomogeneous sub-
stituted 1,3-dienes.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Sonderforschungs-
bereich 424) and the Fonds der Chemischen Industrie. R.
Bou Chedid gratefully acknowledges a Doctoral Scholarship
from the NRW International Graduate School of Chemistry.
b
c
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, X-ray crystal analyses of
compounds 13, 17a, and 21a, and 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a Total yield. Major product determined on chiral HPLC. By
1H NMR. dc ) 0.62-0.84, in CHCl3 (major product). eX-ray
structure available in the Supporting Information.
this effect is still seen to a lower extent, but the steric
situation gains in influence by increasing bulkiness of the
attacking carbonyl compound. Surprisingly, no electrophilic
substitution product arising from attack of the “central
OL061005P
(12) Schlosser, M.; Zellner, A. Synlett 2001, 1016.
3064
Org. Lett., Vol. 8, No. 14, 2006