Enantioselective rare-earth catalyzed quinone Diels-Alder reactions

Article abstract of DOI:10.1021/ja0367602

A highly enantioselective, quinone Diels-Alder reaction catalyzed by chiral samarium and gadolinium pyridyl-bis(oxazoline) (pybox) complexes has been developed. The reaction scope has been extended to include three quinones and five dienes, all of which e

Full text of DOI:10.1021/ja0367602

Published on Web 07/31/2003
Enantioselective Rare-Earth Catalyzed Quinone Diels-Alder Reactions
David A. Evans* and Jimmy Wu
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received June 18, 2003; E-mail: evans@chemistry.harvard.edu
Remarkable progress in the development of enantioselective
Diels-Alder reactions has been achieved through the use of both
chiral auxiliaries1 and chiral Lewis acids.2 However, only a handful
of chiral catalysts effectively mediate selected quinone Diels-Alder
reactions in moderate to good enantioselectivities.3,4 It has even
been suggested that quinone ketals might well be more useful
quinone surrogates in these reactions.5 The purpose of this
communication is to describe a new family of chiral Lewis acid
complexes 1 derived from pyridyl-bis(oxazoline) (pybox) ligands
and samarium and gadolinium triflates that are effective catalysts
in quinone Diels-Alder reactions (eq 1).
A systematic survey of solvents using 10 mol% of 1a-(Sm)
revealed that product enantioselectivity is highly dependent on the
choice of solvent system. Of the solvents that were evaluated (DCM,
THF, and mixtures of ether, THF, and DCM with toluene), the
best results were obtained when the reaction was conducted in a
1:1 mixture of THF and toluene at -78 °C.8 Using the samarium
complex 1a-(Sm), cycloadduct 4a was produced in 97% ee and
87% isolated yield (Table 1, entry 1). The analogous reaction carried
out with 1a-(Gd) afforded comparable results (98% ee, 99% yield).9
From this study, we infer that THF is playing an integral role as a
metal ligand in these reactions.
A number of dienes were then evaluated to determine reaction
scope and catalyst generality (Table 1). A selection of trans-1-
substituted dienes, including 2,4-hexadiene, piperylene, and 2-meth-
yl-1,3-pentadiene (entries 1-6), were effective in the quinone
Diels-Alder reaction with 2. In all cases, only the endo product
was observed, and complete consumption of the quinone occurred
in less than 1 h. We anticipated that trans-1,3-hexadiene (13) would
also undergo facile [4 + 2] cycloaddition; however, its reaction
with 2 was extremely sluggish and displayed only moderate product
enantiomeric excess (63%). Although an ethyl substituent is only
marginally more sterically demanding than its methyl counterpart,
it appears that the additional methylene unit reduces the reaction
rate as a consequence of the increased nonbonding interactions
between the diene and the chelated catalyst-quinone complex A.
From rate data obtained in competition experiments between
piperylene and 1310 catalyzed by both 1a-(Sm) and 1a-(Gd), we
anticipated that the reaction between quinone 2 and dienes
possessing differing alkyl substituents in the 1- and 4-positions
might also be regioselective. Indeed, the reaction of 2 with trans-
2,4-heptadiene (7) and trans-2,4-octadiene (8) afforded a 5:1 and
15:1 mixture of regioisomers in 98% ee for both reactions with
the 1a-(Gd) catalyst (eq 3, 4, entries 7, 8).
We have recently documented the utility of chiral [Sc(Ph-pybox)]-
(OTf)3 and [Sc(Ph-pybox)](Cl2)SbF6 complexes as Lewis acids in
carbonyl addition reactions to glyoxylate esters.6 These results
suggested that trivalent scandium as well as other lanthanide(pybox)
complexes might likewise prove to be effective catalysts for the
illustrated family of quinone Diels-Alder reactions. Accordingly,
the evaluation of a series of metal triflates M(OTf)3: Sc, La, Sm,
Gd, and Yb, as their derived pybox complexes, was carried out in
dichloromethane (DCM, -78 °C) in the catalyzed reaction between
benzoquinone 27 and trans-2,4-hexadiene (3) (eq 2).
During the ligand/metal triflate survey, the reaction was generally
completed in less than 10 min, affording the illustrated cycloadduct
as a single diastereomer. Four complexes emerged from this screen
as promising catalysts: (S,S)-Ph-pybox complexes 1a-(Sc) and 1a-
(Sm) and (2S,3S)-norephedrine-derived gadolinium pybox complex
1b-(Gd). Due to the exceptional yields and absence of byproducts
of the Sm- and Gd-catalyzed reactions, these complexes were
chosen for further study.
Naphthoquinones may also be employed as dienophiles. While
the reaction of naphthoquinone 11 with diene 3 catalyzed by 1a-
(Sm) was slow, affording cycloadduct 12a in low ee (43%), the
more Lewis acidic Gd-complex 1b-(Gd) delivered exceptional
results (91% ee, 99% yield, entry 13).
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10.1021/ja0367602 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Quinone Diels-Alder Reaction Scope
a Absolute stereochemistry was determined by selective Luche reduction of the less sterically hindered ketone, followed by Mosher ester analysis. The
remaining product configurations were assigned by analogy. b Isolated yields of a mixture of regioisomers 5:1 and 15:1 for entries 7 and 8, respectively.c Ee
of major diastereomer was determined after selective Luche reduction of the less sterically hindered ketone.
Supporting Information Available: Experimental details and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org
References
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Evans, D. A.; Johnson J. S. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag:
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Figure 1. Plot of percent ee of 4a vs ee of complex 1a-(Sm).
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Preliminary mechanistic studies with the 1a-(Sm) catalyst indicate
the absence of a nonlinear effect (Figure 1).11 The enantioselec-
tivities of cycloadduct 4a were monitored as a function of catalyst
enantiomeric composition. The illustrated linear relationship be-
tween ee (ligand) and ee (product) suggests that neither catalyst
aggregation nor dimer formation is occurring.
This investigation has highlighted three new lanthanide pybox
complexes, 1a-(Sm), 1a-(Gd), and 1b-(Gd) that might have broader
applications in enantioselective Lewis acid-catalyzed reactions.
(5) Breuning, M.; Corey, E. J. Org. Lett. 2001, 3, 1559-1562.
(6) (a) Evans, D. A.; Masse, C. E.; Wu, J. Org. Lett. 2002, 4, 3375-3378.
(b) Evans, D. A.; Wu, J.; Masse, C. E.; MacMillan, D. W. C. Org. Lett.
2002, 4, 3379-3382. (c) Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow,
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(7) Nakazaki, M.; Naemura, K. J. Org. Chem. 1981, 46, 106-111.
(8) See the Supporting Information for a list of reaction solvent effects.
(9) On the basis of chiral HPLC analysis, it was determined that (S,S)-1a-
(Sm) and (S,S)-1a-(Gd) complexes furnished products possessing the same
(illustrated) absolute stereochemistry.
(10) The rate of reaction using piperylene was at least 7.4 and 10.0 times greater
than with 13 when catalyzed by complexes 1a-(Sm) and 1a-(Gd),
respectively, as determined by chiral HPLC analysis.
Acknowledgment. Support is provided by the NSF (CHE-
9907094) and Merck Research Laboratories. J.W. thanks the ASEE
for a NDSEG predoctoral Fellowship.
(11) (a) Kagan, H. B. AdV. Synth. Catal. 2001, 343, 227-233. (b) Kagan, H.
B. Synlett 2001, 888-899.
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