Hetero-diels-alder reactions of cyclic ketone derived enamide. A new and efficient concept for the asymmetric robinson annulation

Article abstract of DOI:10.1021/ol901065e

Chiral enamides, easily prepared in one step from a cyclic ketone and an oxazolidinone, are successfully employed in high-yielding, endo, and facially selective Hetero-Diels-Alder reactions involving activated oxadienes and Siever's reagent as catalyst. F

Full text of DOI:10.1021/ol901065e

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3060-3063
Hetero-Diels-Alder Reactions of Cyclic
Ketone Derived Enamide. A New and
Efficient Concept for the Asymmetric
Robinson Annulation
Florian Gallier,†,‡ Hidayat Hussain,† Arnaud Martel,† Andreas Kirschning,‡ and
Gilles Dujardin*,†
UCO2M UMR 6011 & FR 2575 CNRS, UniVersite´ du Maine, 72085, Le Mans,
France, and Institut fu¨r Organische Chemie der Leibniz UniVersita¨t HannoVer,
Schneiderberg 1B, 30167 HannoVer, Germany
gilles.dujardin@uniV-lemans.fr
Received May 14, 2009
ABSTRACT
Chiral enamides, easily prepared in one step from a cyclic ketone and an oxazolidinone, are successfully employed in high-yielding, endo, and
facially selective Hetero-Diels-Alder reactions involving activated oxadienes and Siever’s reagent as catalyst. From the resulting bicyclic
heteroadducts, a novel and efficient asymmetric modification for the Robinson annulation of cyclic monoketones is described.
Inverse electron demand Hetero-Diels-Alder reactions1 (IED
HDA) between π-electron-deficient oxadienes and electron-
rich dienophiles has been thoroughly studied in the last 40
years. Most of these reactions are based on aldehyde-derived
enol ethers as dienophiles, and impressive asymmetric
extensions have been reported in this area, culminating in
enantioselective catalytic processes using chiral Lewis acid
complexes.2,3 One of the major breakthroughs was the use
of BOX-CuII complexes developed by the Evans and
Jørgensen groups.3b,c These catalysts are also efficient for
the IED HDA reaction of acetophenone silyl enol ethers.3b
However, when other ketone-derived enol ethers are em-
ployed, the results are consistently poor in terms of stereo-
selectivity and/or enantioselectivity. More recently, the first
organocatalytic enantioselective IED HDA reaction between
an enolizable aldehyde and an activated oxadiene in the
presence of a chiral pyrrolidine has been published by
Jørgensen’s group.4 Heteroadduct derivatives were obtained
in good yields and ee’s. However, Tang et al. showed that
under similar conditions cyclic ketones afford bicyclic [3.3.1]
products which are generated by a formal [3 + 3] annulation
process.5 So far no asymmetric version (either catalytic or
stoichiometric) of IED HDA reactions between an oxadiene
† UCO2M, UMR CNRS 6011, Universite´ du Maine.
‡ Institut fu¨r Organische Chemie, Leibniz University Hannover.
(1) (a) Boger, D. L. ComprehensiVe Organic Synthesis; Trost, B. M.,
Flemming, I., Paquette, L. A., Eds.; Pergamon: Oxford, 1991; Vol. 5, chap.
4.1, pp 451-512.
(2) Reviews: (a) Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92, 1007.
(b) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289. (c) Pelissier, H.
Tetrahedron 2009, 65, 2839
.
(3) (a) Wada, E.; Yasuoka, H.; Kanemasa, S. Chem. Lett. 1994, 1637.
(b) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000,
122, 1635. (c) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558. (e)
Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2002,
(4) Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498.
(5) Cao, C.-L.; Sun, X.-L.; Kang, Y.-B.; Tang, Y. Org. Lett. 2007, 9,
4151.
41, 3059
.
10.1021/ol901065e CCC: $40.75
Published on Web 06/19/2009
 2009 American Chemical Society

and a cyclic ketone-derived dienophile has been successfully
reported.6,2c Use of a chiral cyclic ketone-derived dienophile
was investigated in our group. Our previous work on the
Eu(fod)3-catalyzed heterocycloaddition of chiral enol ether
2 and methyl benzylidene-pyruvate 1a showed a very high
endo selectivity but only a moderate facial selectivity7
(Scheme 1), when compared to those obtained under similar
latter can be prepared in two steps from the corresponding
cyclic ketone. We observed that acid-catalyzed azeotropic
distillation of a mixture of cyclohexanone and oxazolidin-
2-one yields the desired product in only one step. These
conditions allow us to synthesize a wide variety of ene-
carbamates more readily. The moderate yield is the result
of the self-condensation of cyclic ketones (Scheme 2), and
the residual oxazolidinone 4 is easily recovered.
Relevant chiral enamides have widely been utilized for
asymmetric transformations in the past few years.12 We
demonstrated the high potential of vinyl oxazolidinones as
new chiral dienophiles in IED HDA reactions.13 More
recently, our group demonstrated that ꢀ-substituted N-viny-
loxazolidin-2-ones allow the high-yielding formation of endo
adducts with a remarkable facial stereodivergency depending
on the Lewis acid used (Eu(fod)3 vs SnCl4).13b However,
SnCl4-catalyzed heterocycloaddition of dienophile 5a with
oxabutadiene 1a only resulted in the cleavage of the enamide
bond, and no adduct was isolated. In contrast, the Eu(fod)3-
catalyzed reaction afforded the desired heteroadduct with
excellent endo and facial selectivity (Scheme 3): one
Scheme 1. HDA Reaction of Chiral Enol Ether 2
conditions with O-vinyl mandelates8 or with the t-butyl
mandelate enol ether derived from 3-pentanone.9
In the late 1980s, Eiden et al. reported that the pyrrolidine
enamine of cyclohexanone undergoes a thermal [4 + 2]
cycloaddition yielding bicyclic [4.4.0] adducts.10 An asym-
metric extension of this method was envisioned, but the lack
of stability of the bicyclic adduct led us to explore other
chiral dienophiles, namely, new N-alkenyloxazolidin-2-ones
5 derived from cyclic ketones (Scheme 2). In this report,
Scheme 3. Hetero-Diels-Alder (HDA) Reaction of Enamide 5a
Scheme 2. Preparation of N-Cycloalkenyloxazolidin-2-ones 5
diastereomer14 was essentially obtained and isolated by
chromatography in high yield (91%).
The endo stereochemistry of adduct 6a was deduced from
1H NMR data, and its absolute configuration was established
by X-ray diffraction (Figure 1).
we wish to highlight a novel one-step procedure to prepare
these new dienophiles and to report their unprecedented use
in asymmetric [4 + 2] heterocycloadditions. We also describe
that the bicyclic heteroadducts thus obtained can be ef-
ficiently involved as key intermediates in the asymmetric
synthesis of octalones.
The most convenient way to access the desired ene-
carbamates 5 involves the copper(I)-catalyzed amination
between oxazolidin-2-one and a (cyclo)alkenyl halide.11 The
(6) Jørgensen, K. A. Eur. J. Org. Chem. 2004, 2093
.
(7) Martel, A. PhD Thesis, Le Mans University, 2001.
(8) (a) Dujardin, G.; Rossignol, S.; Molato, S.; Brown, E. Tetrahedron
1994, 50, 9037. (b) Dujardin, G.; Rossignol, S.; Brown, E. Synthesis 1998,
50, 763.
Figure 1. X-ray structure of adduct endo-6a.
(9) Gong, J.; Bonfand, E.; Brown, E.; Dujardin, G.; Michelet, V.; Geneˆt,
J.-P. Tetrahedon Lett. 2003, 44, 2141.
(10) (a) Eiden, F.; Winkler, W.; Wanner, K. T.; Markhauser, A. Arch.
Pharm. 1985, 318, 648. (b) Eiden, F.; Wu¨nsch, B.; Schu¨nemann, J. Arch.
Pharm. 1990, 323, 481.
The heterocycloaddition of dienophile 5a was then ex-
tended to a range of activated heterodienes 1b-l (Table 1).
Under the same conditions, heteroadducts 6a-i (R ) Ar)
were produced in homogeneous yields (85-91%) with high
(11) (a) Evano, G.; Blanchard, N.; Toumi, M. Chem. ReV. 2008, 108,
3054. (b) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett.
2003, 5, 3667. (c) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809.
Org. Lett., Vol. 11, No. 14, 2009
3061

Table 1. HDA Reactions of Dienophile 5a with Dienes 1a-l
Table 2. HDA Reactions of Dienophile 5b with Dienes 1a-k,m
a Isolated product. b Diastereoselectivities were determined from the 1H
NMR spectra of the purified adduct (vinylic proton). c One minor exo adduct.
d Two minor exo adducts. e Minor endo adduct not detected.
a Isolated product. b Diastereoselectivities were determined from the 1H
NMR spectrum of the purified adduct (vinylic proton). c One minor exo
adduct. d exo adduct not detected. e Minor endo adduct not detected.
in the case of 7f (entry 6). Only little fluctuations of the endo
selectivity were observed when the aryl substituent was
varied (entries 5 and 7-9). Finally, alkyl-substituted het-
erodienes 1j,k afforded adducts in moderate yields but with
a high endo selectivity and complete facial control (entries
10 and 11).
Adduct 6i was then subjected to functional group modi-
fication. After ester reduction with Dibal-H in the presence
of BF3·Et2O,15 the corresponding allylic alcohol was easily
isolated in a pure diastereomeric form and converted into
the iodide 8 in good overall yield. Samarium(III)-induced
reduction of the iodide afforded 9. Hydrolysis of the N,O-
ketal under acidic conditions yielded the 1,5-diketone 11, in
a 2.6:1 diastereomeric ratio (35% yield), in a separable
mixture with the diastereomerically pure octalone 10 (53%
diastereoselectivities, except for trimethoxy-phenyl-substi-
tuted adduct 6i (Table 1, entry 9). In each case, one endo
diastereomer was essentially obtained over the four possible,
and the facial control appeared as complete. The nature of
the ester function (R′) has no effect on the efficiency and a
slight effect on the endo stereoselectivity (Table 1, entries
1-4). Alkyl-substituted heterodienes 1j,k afforded adducts
in moderate yield but with a good endo selectivity and a
complete facial control (Table 1, entries 10 and 11).
Switching from an aryl to an alkoxy substituent (R ) OEt)
led to a dramatic decrease of the endo selectivity, but still
the facial differentiation was very high (Table 1, entry 12).
The common endo geometry and absolute configuration
of the major (or sole) adducts 6b-l was determined from
1
the strong analogies between their H NMR data and those
of adduct (4S,4aR,8aR)-endo-6a.
(12) (a) Aciro, C.; Davies, S. G.; Garner, A. C.; Ishii, Y.; Key, M.-S.;
Ling, K. B.; Prasad, R. S.; Roberts, P. M.; Rodriguez-Solla, H.; O’Leary-
Steele, C.; Russel, A. G.; Sanganee, H. J.; Savory, E. D.; Smith, A. D.;
Thomson, J. E. Tetrahedron 2008, 64, 9320. (b) Lu, T.; Song, Z.; Hsung,
R. P. Org. Lett. 2008, 10, 541, and references cited.
(13) (a) Gaulon, C.; Dhal, R.; Chapin, T.; Maisonneuve, V.; Dujardin,
G. J. Org. Chem. 2004, 69, 4192. (b) Gohier, F.; Bouhadjera, K.; Faye, D.;
Gaulon, C.; Maisonneuve, V.; Dujardin, G.; Dhal, R. Org. Lett. 2007, 9,
211.
We then extended this study to the cyclopentanone-derived
dienophile 5b (Table 2). Again, aryl-substituted heteroad-
ducts 7a-i,m were produced in good yields (82-88%) under
standard conditions with high facial control. In contrast to
the cyclohexenyl series, the endo selectivity proved to be
not total in most cases and notably dependent on the nature
of the ester function beared by the heterodiene (entries 1-6).
Unexpectedly, a high double diastereocontrol was obtained
(14) 95:5:0:0 Ratio of the four possible diastereomers assuming a
concerted mechanism.
(15) Gonda, J.; Helland, A. C.; Ernst, B.; Bellusˇ, D. Synthesis 1993, 7,
729.
3062
Org. Lett., Vol. 11, No. 14, 2009

yield), the latter presumably resulting from the spontaneous
Robinson-type annulation of the former. The (4S,4aR)-
configuration of the octalone 10 was established by 1H NMR
data (Scheme 4).16 The presence of minor amounts of 1,5-
In summary, we have shown that ene-carbamates derived
from cyclanones and oxazolidinone 4 can act as powerful
chiral dienophiles to yield heteroadducts with a range of
activated heterodienes. HDA reactions proceeded in high
yield and endo selectivity as well as facial selectivity under
mild conditions using Siever’s reagent as catalyst. The new
bicyclic heteroadducts served as a starting point for unprec-
edented asymmetric access to a 4-aryl-substituted octalone.
Scheme 4. Enantioselective Octalone Synthesis (I)
In the important field of Robinson annulation products
derived from cyclic monoketones, this novel enantioselective
[4 + 2] route offers new synthetic opportunities due to its
complementarity with the well-established Pfau-d’Angelo’s
method. Indeed, although highly efficient for a range of
R-substituted cyclic monoketones toward alkyl vinyl ketones,
this method based on the Michael addition of a chiral imine-
tautomer is known to suffer from a dramatic decrease of
reactivity when the Michael acceptor is ꢀ-substituted.19
Studies on the scope and limitations of the title HDA reaction
and of the new and promising enantioselective annulation
procedure are currently underway.
Acknowledgment. Dr. K. Adil (LdOF-UMR 6010 CNRS)
is gratefully acknowledged for X-ray structure determination.
F.G. thanks the DAAD for a sandwich scholarship (A/04/
20592). H.H. thanks the Re´gion Pays de la Loire for a
postdoctoral grant.
diketone epi-11 (∼10% yield) appears as a consequence of
an unavoidable acid-mediated epimerization of 11. Fortu-
nately, only the octalone 10 resulting from the aldolisation-
crotonization of the major (S,R)-diketone 11 was observed.
Interestingly, treatment of the residual diastereomeric mixture
of diketone 11 with MeONa in methanol led mainly to the
diastereomerically pure octalone 10,17 thus increasing the
global yield in octalone 10 from dihydropyran 9 up to 74%.18
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL901065E
(17) This reaction afforded as a separable byproduct a ketol (∼25%
yield) that could be the OH-epimer of the precursor aldol of 10.
(18) Enantiopure oxazolidinone 4 was recovered in high global yield
by easy chromatographic separation from the annulation product.
(19) D’Angelo, J.; Desmae¨le, D.; Dumas, F.; Guingant, A. Tetrahedron:
Asymmetry 1992, 3, 459.
(16) NMR data of close octalone (Ar ) Ph, racemic mixture of isomers)
was previously described, but the relative configuration was not assigned:
(a) Wada, E.; Funakoshi, J.; Kanemasa, S. Bull. Chem. Soc. Jpn. 1992, 65,
2456. (b) Aurell, M. J.; Gavina, P.; Mestres, R. Tetrahedron 1994, 50, 2571.
Org. Lett., Vol. 11, No. 14, 2009
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