Desymmetization of a meso-allylic acetal by enantioselective conjugate elimination

Article abstract of DOI:10.1021/ol702877j

An unprecedented enantioselective deprotonation/conjugate elimination sequence, which transforms an allylic meso-dioxepane into a chiral diene, is described. The best desymmetrization conditions (ee up to 70%) involve s-BuLi and sparteine at -78 °C in THF.

Full text of DOI:10.1021/ol702877j

ORGANIC
LETTERS
2008
Vol. 10, No. 5
729-732
Desymmetrization of a meso-Allylic
Acetal by Enantioselective Conjugate
Elimination
Ling Xu,†,‡ Thomas Regnier,† Loıc Lemie`gre,†,# Pascal Cardinael,‡
1
Jean-Claude Combret,‡ Jean-Philippe Bouillon,‡ Je´rome Blanchet,§
Jacques Rouden,§ Anne Harrison-Marchand,† and Jacques Maddaluno*,†
Laboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes de l’IRCOF, UMR CNRS
6014, UniVersite´ et INSA de Rouen, 76821 Mont Saint-Aignan Cedex, France, Sciences
et Me´thodes Se´paratiVes de l’IRCOF, EA 3233, UniVersite´ de Rouen, 76821 Mont
Saint-Aignan Cedex, France, and Laboratoire de Chimie Mole´culaire et
Thio-Organique, ENSICAEN, UniVersite´ de Caen Basse-Normandie, UMR CNRS 6507,
6 BouleVard du Mare´chal Juin, 14050 Caen, France
jmaddalu@crihan.fr
Received November 29, 2007
ABSTRACT
An unprecedented enantioselective deprotonation/conjugate elimination sequence, which transforms an allylic meso-dioxepane into a chiral
diene, is described. The best desymmetrization conditions (ee up to 70%) involve s-BuLi and sparteine at 78 C in THF.
−
°
While the asymmetric conjugate addition of organometallic
nucleophiles on activated olefins is the object of extensive
attention,1 the conjugate base-triggered elimination has drawn
much less consideration. Some mechanistic aspects have been
detailed,2 and the application3 of this reaction to the
transformation of unsaturated acetals into 1-oxygenated
dienes are well-known. However, no asymmetric version has
been proposed yet to our knowledge. We3d,4 and others5 have
shown over the last 15 years that this process is also a
synthetic tool to transform, in a simple, mild, and stereose-
lective fashion, unsaturated acetals into 1,4-difunctionalized
dienes (Scheme 1). While the enol ether double bond was
found to be essentially E, the configuration of the other
double bond depended on the nature of the substituent Y
borne by the deprotonation site. The configuration can go
from 90% in favor of the E (Y ) SPh) or of the Z (Y )
OPh) isomer.
† UMR CNRS 6014, IRCOF, Rouen.
‡ EA 3233, IRCOF, Rouen.
§ UMR CNRS 6507, ENSI Caen.
# Present address: Ecole Nationale Supe´rieure de Chimie de Rennes,
UMR CNRS 6226, Av. General Leclerc, 35700 Rennes (France).
(1) Recent results, see for instance: (a) Hu, H.; Snyder, J. P. J. Am.
Chem. Soc. 2007, 129, 7210-7211. (b) Lopez, F.; Minnaard, A. J.; Feringa,
B. L. Acc. Chem. Res. 2007, 40, 179-188. (c) Pena, D.; Lopez, F.;
Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2004,
1836-1837. (d) Arink, A. M.; Braam, T. W.; Keeris, R.; Jastrzebski, J. T.
B. H.; Benhaim, C.; Rosset, S.; Alexakis, A.; van Koten, G. Org. Lett.
2004, 6, 1959-1962.
Scheme 1. Stereoselective Synthesis of (E,E) or (Z,E)
1,4-Disubstituted Dienes by Conjugate Elimination
(2) (a) Cristol, S. Acc. Chem. Res. 1971, 4, 393-400. (b) Moss, R. J.;
Rickborn, B. J. Org. Chem. 1986, 51, 1992-1996. (c) Hill, R. K.; Bock,
M. G. J. Am. Chem. Soc. 1978, 100, 637-639. (d) Handa, S.; Floss, H. G.
J. Chem. Soc., Chem. Commun. 1997, 153-154. (e) Fujita, M.; Matsuchima,
H.; Sugiruma, T.; Tai, A.; Okuyama, T. J. Am. Chem. Soc. 2001, 123, 2946-
2957. (f) Bickelhaupt, F. M.; Buisman, G. J. H.; Koning, L. J.; Nibbering,
N. M. M.; Baerends, E. J. J. Am. Chem. Soc. 1995, 117, 9889-9899.
10.1021/ol702877j CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/07/2008

Scheme 2. Diastereoselectivity of the Intramolecular Cycloaddition of Trienes 2 and 56
When applied to cyclic acetals, this reaction afforded a
the ring fission of 4 triggered by tert-butyllithium, exhibited
a total endo and diastereo control in the final IMDA step
(Scheme 2, bottom). Thus, developing an enantioselective
version required access to an enantiopure triene 5. We
thought that the desymmetrization of the corresponding meso-
dioxepane 4 by a chiral base could solve this problem simply.
This letter presents this enantioselective transformation,
which to our knowledge, has never been described before.
The unsaturated meso-dioxepane 7, analogous to 4 retained
for this study, was prepared from commercially available
1-acetoxy-1,3-butadiene 8 (Scheme 3) following a known
diene prolonged by an hydroxyalkyl chain (Scheme 2).6 We
took advantage of this functional bonus by quenching directly
the intermediate alkoxide with acryloyl chloride for instance.
This set the stage for an intramolecular Diels-Alder (IMDA)
reaction between the diene and the dienophile embedded in
the resulting trienic ester.7 The structure of the tether was
chosen such that it could be easily removed after cycload-
dition.
Substrates 1 and 4 bearing a p-methoxybenzyloxy ether
(PMBO) at one end and a dibenzylic acetal at the other were
selected. Chemically, this choice was dictated by the good
performances of the benzyl groups in the strongly basic
conditions of the elimination, and the ease with which the
PMB group can be removed by a simple hydrogenolytic or
oxidative process. Note that after elimination the dienic
portion of the main isomer of 2 and 5 exhibited a (1Z,3E)
configuration, in accordance with previous results concerning
allylic ethers.3d,4d,g,8 Asymmetry was introduced in the system
through the dioxepane moiety which could be employed
either as a chiral C2 auxiliary (as in 1) or as an achiral meso
entity (as in 4). The first solution afforded modest to good
selectivities in favor of the exo isomers of lactone 3 (Scheme
2, top). In the second case, racemic triene 5, resulting from
Scheme 3. Access to meso Cyclic Acetal 7
(3) See for instance: Mioskowski, C.; Manna, S.; Falck, J. R. Tetrahedron
Lett. 1984, 25, 519-522. (b) Deagostino, A.; Prandi, C.; Venturello, P.
Tetrahedron 1996, 52, 1433-1442. (c) Deagostino, A.; Maddaluno, J.;
Mella, M.; Prandi, C.; Venturello, P. J. Chem. Soc., Perkin Trans. 1 1998,
881-888. (d) Guillam, A.; Toupet, L.; Maddaluno, J. J. Org. Chem. 1998,
63, 5110-5122.
(4) (a) Gaonac’h, O.; Maddaluno, J.; Chauvin, J.; Duhamel, L. J. Org.
Chem. 1991, 56, 4045-4048. (b) Gaonac’h, O.; Maddaluno, J.; Ple´, G.;
Duhamel, L. Tetrahedron Lett. 1992, 33, 2473-2476. (c) Maddaluno, J.;
Gaonac’h, O.; Le Gallic, Y.; Duhamel, L. Tetrahedron Lett. 1995, 36, 8591-
8594. (d) Guillam, A.; Maddaluno, J.; Duhamel, L. J. Chem. Soc., Chem.
Commun. 1996, 1295-1296. (e) Martin, C.; Maddaluno, J.; Duhamel, L.
Tetrahedron Lett. 1996, 37, 8169-8172. (f) Lemie`gre, L.; Regnier, T.;
Combret, J.-C.; Maddaluno, J. Tetrahedron Lett. 2003, 44, 373-377. (g)
Pichon, N.; Harrison-Marchand, A.; Toupet, L.; Maddaluno, J. J. Org. Chem.
2006, 71, 1892-1901.
(5) Tayama, E.; Sugai, S. Tetrahedron Lett. 2007, 48, 6163-6166.
(6) (a) Maddaluno, J.; Gaonac’h, O.; Marcual, A.; Toupet, L.; Giessner-
Prettre, C. J. Org. Chem. 1996, 61, 5290-5306. (b) Lemie`gre, L.; Stevens,
R.; Combret, J.-C.; Maddaluno, J. Org. Biomol. Chem. 2005, 3, 1308-
1318.
(7) Deagostino, A. M.; Maddaluno, J.; Prandi, C.; Venturello, P. J. Org.
Chem. 1996, 61, 7597-7599.
(8) (a) Guillam, A.; Toupet, L.; Maddaluno, J. J. Org. Chem. 1999, 64,
9348-9357. (b) Bataille, C.; Be´gin, G.; Guillam, A.; Lemie`gre, L.; Lys,
C.; Maddaluno, J.; Toupet, L. J. Org. Chem. 2002, 67, 8054-8062.
procedure.9 Thus, reacting 8 and NBS in THF/MeOH led to
bromoacetal 9, which was transformed into 10 by a simple
substitution with potassium p-methoxybenzyloxide. The
transacetalisation of 10 with meso-1,2-bis(1-hydroxyethyl)-
benzene 11 in the presence of camphorsulfonic acid (CSA)
afforded dioxepane 7 in 62% overall yield.10 Note that the
meso-dioxepane 4 bears an acetal which is a pseudoasym-
metric center.11 Thus, two diastereomers were obtained after
transacetalization. The major one was isolated by flash
chromatography and revealed to be syn (Scheme 3). Only
this isomer was considered in the rest of the work.
(9) Deagostino, A.; Balma Tivola, P.; Prandi, C.; Venturello, P. Synlett
1999, 1841-1843.
(10) Diol 11 was prepared according to Lemie`gre, L.; Lesetre, F.;
Combret, J.-C.; Maddaluno, J. Tetrahedron 2004, 60, 415-427.
(11) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley & Sons: New-York, 1994; p 67.
730
Org. Lett., Vol. 10, No. 5, 2008

The enantioselective deprotonation/acetal opening se-
quence was studied next (Scheme 4), varying the nature of
Table 1. Yields and Ee’s of the Enantioselective Conjugate
Elimination of 7 under the Action of Various Bases and Ligands
(base/L*/7 ) 2:2:1)
12 (%)a
ee (%)b
Scheme 4. Enantioselective Transformation of 7 into Alcohol
entry
base
L*
solvent
12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
s-BuLi
t-BuLi
LDA
s-BuLi
s-BuLi
s-BuLi
s-BuLi
LDA
-
-
-
THF
THF
THF
THF
Et2O
DMM
toluene
THF
Et2O
Et2O
Et2O
Et2O
DMM
Et2O
DMM
toluene
Et2O
DMM
78
61
60
81
72
27
54
72
51
34
12
43
57
33
68
31
76
91
-
-
-
13
13
13
13
13
13
14
15
16
16
17
17
17
18e
18e
30 (-)
64 (-)
70 (-)
5 (-)
11 (-)
8 (-)
10 (-)
5 (+)
21 (+)
30 (+)
ndd
LDA
s-BuLi
s-BuLi
s-BuLi
s-BuLi
s-BuLic
s-BuLic
s-BuLic
s-BuLic
s-BuLic
20 (+)
27 (+)
12 (+)
15 (+)
a Isolated yields after preparative thin layer chromatography. b Deter-
mined by HPLC analyses: Chiralpak OD*: 25 cm × 4.6 mm; eluent:
heptane/isopropanol 90:10 (v/v); flow rate: 1.0 mL/min; temperature: 25
°C; monitored by UV at 230 nm. c base/L*/7 ) 4:2:1. d nd ) not
determined. e The species were aggregated at -40 °C, then cooled to -78
°C.
*Employed as 1:1 mixed aggregates of the lithium alkoxide
(17Li) or amide (18Li) and s-BuLi.
the base (alkyllithiums, lithium amide), the solvent (ethereal
and non ethereal), and the chiral ligand (L*). The reaction
was typically carried out under argon atmosphere at
-78 °C for 3 h. The dienol 12 was isolated after hydrolysis
of the reaction mixture. The results obtained are shown in
Table 1.
plummet (compare entries 8 and 4, entries 9 and 5, or entries
7 and 5 and 6). Thus, sec-butyllithium and diethylether or
DMM were retained to evaluate the inductive influence of
other ligands.
Various kinds of bases were screened. sec-Butyllithium
and tert-butyllithium, as well as lithium diisopropylamide
(LDA) proved to be well adapted to this transformation;
alcohol 12 was obtained in satisfying yields (60-78%, Table
1, entries 1-3). Note that the configuration of the diene is
exclusively (1Z,3E) whatever base is employed.
Diamine (-)-sparteine was first considered in the screen-
ing of a chiral ligand for the reaction depicted in Scheme 4
(Table 1, entries 4-9). If 12 was isolated in high yield in
THF, with both sec-butyllythium (entry 4) and LDA (entry
8), the enantioselectivities turned out to be disappointing
(e30%) in this solvent. Actually, THF is a known competi-
tive ligand of sparteine.12 Diethyl ether (entry 5) led to better
results; in the presence of sec-butyllithium, elevated chemical
(72%) yields and good inductions (ee ) 64%) were
measured. The highest 70% ee was obtained with this base
in dimethoxymethane (DMM, entry 6). The kinetics of the
reaction was however altered in these last conditions.
Swapping from sec-butyllithium to LDA or from ethereal
to non-ethereal (toluene, entry 7) solvent caused the ee’s to
Two other diamines, 14 (entry 10) and 15 (entry 11)
derived from 3-aminopyrrolidine and C2-symmetric chiral
piperazine,13 respectively, were considered in this work.
However, in the optimal conditions described above, the ee’s
never exceeded 10%, and varying parameters such as the
temperature, the concentration, the base and the solvent
proved useless. Slightly better results (ee’s up to 20-30%)
were observed in the presence of diphosphine 16 but could
not be improved. In the next step, a chiral mixed aggregate
was used instead of a traditional base/ligand couple. This
was prepared by mixing the lithium alkoxide of (-)-N-
methylephedrine 17 (entries 14-16) or the lithium amide
of 3-(R-methylbenzylamino)pyrrolidine 1814 (entries 17-18)
with 1 equiv of s-BuLi. However, the selectivities associated
to this species, considered as a “chiral unimetal superbase”
remained very low.
The details of the mechanism of the conjugate elimination,
and therefore the induction process occurring in the enan-
tioselective version described here, are unclear at this stage.
Obviously, the enantioselection does not result from a
classical differentiation between the two protons on carbon
(12) (a) Sott, R.; Håkansson, M.; Hilmersson, G. Organometallics 2006,
25, 6047-6053. (b) Hoppe, I.; Marsch, M.; Harms, K.; Boche, G.; Hoppe,
D. Angew. Chem., Int. Ed. Engl. 1995, 34, 2158-2160. (c) Collum, D. B.
Acc. Chem. Res. 1992, 25, 448-454. (d) Lucht, B. L.; Bernstein, M. P.;
Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1996, 118, 10707-10718.
(e) Remenar, J. F.; Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1997,
119, 5567-5572.
(13) Nakamura, D.; Kakiuchi, K.; Koga, K.; Shirai, R. Org. Lett. 2006,
8, 6139-6142.
(14) Harrison-Marchand, A.; Valnot, J.-Y.; Corruble, A.; Duguet, N.;
Oulyadi, H.; Desjardins, S.; Fressigne´, C.; Maddaluno, J. Pure Appl. Chem.
2006, 78, 321-331.
Org. Lett., Vol. 10, No. 5, 2008
731

1 since the latter is to become sp2. Actually, the two oxygens
of the acetals are also enantiotopic, and a specific interaction
between the sparteine-chelated lithium and one of these two
oxygens is probably at the origin of the enantioselective
process. The deracemization can result either from the
deprotonation15 or from the elimination. In the first case, the
theoretical results published by Tonachini and colleagues
about the deprotonation-elimination of a simple acetalic
substrate16 are extremely helpful to understand the process.
In the transition state, the base, its lithium counterion, the
abstracted proton and one oxygen of the acetal lie more or
less in a plane perpendicular to that of the original double
bond (Figure 1, top). This model is compatible with a
Scheme 5. Possible Mechanism of Conjugate Elimination
the deprotonation would first afford 7Li-a which would
quickly transpose into its coordinated3d racemic isomer 7Li-b
(Scheme 5). The sparteine, closely associated to the cation,
could then either favor one of the two enantiomers through
a rapid equilibration process18 of 7Li-b or accelerate the
elimination step (E1cB) for one of those enantiomers
(dynamic kinetic resolution). Note that intermediate 7Li-b
could also be formed along the enantioselective deprotonation
process described above. However, its nonracemic character
depends on the stereospecificity of the allylic transposition
of lithium, which remains to be determined.19
In conclusion, the above results show that, despite the
considerable distance separating the deprotonation and the
elimination sites, an enantioselective 1,4-conjugate elimina-
tion can be achieved. Ee’s up to 70% could be obtained using
sparteine as the chiral ligand of a strong lithiated base such
as s-BuLi. Because sparteine can interact directly with s-BuLi
or with the intermediate allyllithium 7Li, it is difficult to
predict if the enantiodetermining step is the deprotonation
or the elimination itself. Further work will soon be under-
taken in an attempt to clarify this point.
Figure 1. (Top) Transition state computed for the deprotonation
of crotonaldehyde dimethyl acetal by Tonachini et al. (ref 16).
Distances are in Å and charges are between parenthesis. (Bottom)
Schematic adaptation to the deprotonation of 7.
Acknowledgment. L.X. acknowledges the interregional
program Poˆle Universitaire Normand de Chimie Organique
(PUNCHorga) for a financial support. We thank Dr. D.
Harakat (University of Reims) for the HRMS analyses, plus
Dr. G. Ghigo and Prof. G. Tonachini (University of Turin)
for an electronic copy of Figure 1.
concerted process (E2) and can occur indifferently along one
or the other face of the plane containing the unsaturated
acetal. Transposing these results to dioxepane 7, bearing its
syn benzylic methyl groups, and sec-butyllithium/sparteine
(Figure 1, bottom) would allow an enantiofacial differentia-
tion at the origin of the observed ee’s. A similar speculation
was proposed by Alexakis et al. in the related case of a
diastereoselective addition-elimination reaction.17
Supporting Information Available: Detailed experi-
1
mental procedures and H and 13C NMR spectra of the
The second hypothesis assumes that the enantioselection
takes place exclusively at the elimination level. In this case,
synthesized compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) (a) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552-560. (b) Thayumanavan, S.; Basu, A.;
Beak, P. J. Am. Chem. Soc. 1997, 119, 8209-8216. (c) Beak, P.; Anderson,
D. R.; Curtis, M. D.; Laumer, J. M.; Pippel, D. J.; Weisenburger, G. A.
Acc. Chem. Res. 2000, 33, 715-727.
(16) Fossey, J.; Ghigo, G.; Tonachini, G.; Venturello, P. Tetrahedron
1997, 53, 7937-7946.
(17) (a) Alexakis, A.; Mangeney, P.; Normant, J. F. Tetrahedron Lett.
1985, 26, 4197-4200. (b) Alexakis, A.; Mhamdi, F.; Lagasse, F.; Mangeney,
P. Tetrahedron: Asymmetry 1996, 7, 3343-3346.
OL702877J
(18) See for instance: (a) Stratmann, O.; Kaiser, B.; Fro¨hlich, R.; Meyer,
O.; Hoppe, D. Chem. Eur. J. 2001, 7, 423-435.(b) Marr, F.; Fro¨hlich, R.;
Wibbeling, B.; Diedrich, C.; Hoppe, D. Eur. J. Org. Chem. 2002, 2970-
2988. (c) Marr, F.; Hoppe, D. Org. Lett. 2002, 4, 4217-4220.
(19) Basu, A.; Thayumanaval, S. Angew. Chem., Int. Ed. 2002, 41, 716-
738.
732
Org. Lett., Vol. 10, No. 5, 2008