Chiral oxazaborolidine - Aluminum bromide complexes are unusually powerful and effective catalysts for enantioselective Diels - Alder reactions

Article abstract of DOI:10.1021/ja068637r

Treatment of the chiral oxazaborolidine 1 with AlBr₃ generates the 1:1 complex 3, which is an even more potent Lewis acid catalyst than protonated 1 (i.e., 2) for enantioselective Diels-Alder reactions. Only 4 mol % of catalyst 3 is required to achieve yields and enantiomeric purities of 90% over a broad range of achiral dienes and dienophiles. The ligand from which 3 is derived can be recovered easily and with high efficiency. The method is illustrated by 22 examples. Copyright

Full text of DOI:10.1021/ja068637r

Published on Web 01/19/2007
Chiral Oxazaborolidine-Aluminum Bromide Complexes Are Unusually
Powerful and Effective Catalysts for Enantioselective Diels-Alder Reactions
Duan Liu, Eda Canales, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received December 1, 2006; E-mail: corey@chemistry.harvard.edu
Table 2. Enantioselective Diels-Alder Reactions of
Cyclopentadiene with Various Quinones in the Presence of 4 mol
% of Catalyst 3 in CH2Cl2
The oxazaborolidine 1 is a valuable chiral catalyst for the borane-
mediated enantioselective reduction of achiral unsymmetrical ke-
tones.1 Protonation of 1 with triflic acid generates a chiral oxazaboro-
lidinium cation 2, which is an extraordinarily useful broad-spectrum
catalyst for numerous Diels-Alder reactions.2 It has been applied
to the synthesis of many complex molecules.2e-j Because the oxaza-
borolidine 1 is quite a weak base, its full protonation can only be
achieved using a very strong acid such as triflic acid or triflimide.
Even methanesulfonic and p-toluenesulfonic acids are not efficient
proton donors with 1. In early studies, it was observed that various
Lewis acids did not appear to coordinate to 1 sufficiently to generate
useful catalysts for Diels-Alder reactions. For instance, with BF3
or CH3AlCl2 in CH2Cl2 solution, no useful catalysis was observed.
Recently, we decided to reinvestigate Lewis acid activation despite
Table 1. Enantioselective Diels-Alder Reactions of
Cyclopentadiene with Diverse Dienophiles in the Presence of 4
mol % of Catalyst 3 in CH2Cl2
a Each reaction was carried out at 0.2 M with respect to dienophile and
with 5 equiv of cyclopentadiene. b Toluene was used as solvent.
the unpromising results obtained earlier. Using the very strong
Lewis acid AlBr3, it was found that complete complexation to form
3 occurred with 1 equiv each of 1 and AlBr3 (by 1H NMR analysis),
1
despite the fact that AlBr3 is sterically bulkier than BF3. The H
NMR spectrum of 3 in CD2Cl2 showed downfield shifts for the
pyrrolidine protons and the o-tolyl methyl comparable to those
observed for N-protonation by triflic acid.3 We were surprised not
only by the clean formation of 3 from 1 but also by its strength
and effectiveness as a Diels-Alder catalyst. Excellent Diels-Alder
conversions were routinely observed with only 4 mol % of 3 and
various dienes and dienophiles. The results of experiments with
cyclopentadiene as the test diene and various dienophiles with 4
mol % of 3 as catalyst are summarized in Tables 1 and 2.
Taken together with previous studies on catalyst 2,2a-d the data
shown in Tables 1 and 2 indicate clearly that catalyst 3 is
considerably more efficient than 2 (10-20 mol % generally required
for optimum results). Because of this fact, in most cases, only 4
mol % of catalyst 3 produces excellent results in terms of both
reaction yield and enantioselectivity. The use of catalyst 3 is
especially advantageous for larger scale synthesis not only because
of the low catalyst requirements but also because the chiral ligand
precursor is easily and efficiently recovered.4-6
a Reaction was carried out at 0.5 M concentration with respect to
dienophile and with 5 equiv of cyclopentadiene. b The reaction was carried
out at 2.0 M concentration with respect to dienophile and with 5 equiv of
cyclopentadiene.
The wide applicability of catalyst 3 is also underscored by the
nine examples shown in Table 3 which involve a collection of
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J. AM. CHEM. SOC. 2007, 129, 1498-1499
10.1021/ja068637r CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Enantioselective Diels-Alder Reactions of an
Assortment of Dienes and Dienophiles in the Presence of 4 mol %
of Catalyst 3
Table 4. Enantioselective Diels-Alder Reactions with Furans in
CH2Cl2 with 3 as Catalyst
a The reaction was carried out at 2.0-2.5 M concentration with respect
to dienophile in CH2Cl2 with 5 equiv of furan in the presence of 4 mol %
of catalyst. b 8 mol % of catalyst was used. c Yield based on conversion to
the hydrogenated product.
of Table 4 is transformed into trifluoroethyl (1R)-2,5-dimethylcy-
clohexa-2,4-diene-1-carboxylate at 0 °C for 1 hr (76%).
We were not able to find Lewis acids other than AlBr3 which were
capable of activating 1 to generate useful catalysts for Diels-Alder
reactions. It is perhaps surprising that AlCl3 and GaCl3 were much
inferior to AlBr3 as activators of 1. Although activation was ob-
served with BCl3, the reaction rates and yields were diminished rela-
tive to AlBr3. The greater turnover efficiency of catalyst 3 relative
to 2 may be the result of greater steric screening of the catalytic
boron site by the adjacent AlBr3 subunit and diminished product
inhibition. Weaker Lewis acids were totally unpromising as activa-
tors of 1. In conclusion, our work indicates that the AlBr3-derived
catalyst 3 is both special and highly useful as a chiral catalyst.
Acknowledgment. E.C. is the recipient of a Pfizer postdoctoral
fellowship.
a The reaction was carried out at 0.2 M initial concentration (Co) with
respect to dienophile in CH2Cl2 with 5 equiv of diene. b Co ) 0.5 M with
respect to dienophile in CH2Cl2. c Co ) 1.0 M with respect to dienophile
in CH2Cl2. d The reaction was carried out neat with 3 equiv of diene. e Co
) 0.3 M with respect to dienophile in PhMe with 1.5 equiv of diene. f Two
equivalents of diene was used.
Supporting Information Available: Experimental procedures and
characterization data for all reactions and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109,
5551-5553. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.;
Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925-7926. (c) Corey, E. J.;
Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-2012.
different 1,3-dienes and dienophiles. In each case, including the
first entry with the less reactive diene 1,3-cyclohexadiene, the
reaction proceeds well with just 4 mol % of catalyst 3. In the
examples listed in Table 3, as well as those of Tables 1 and 2, the
absolute configuration of the chiral Diels-Alder adduct obtained
with the (S)-catalyst 3 corresponded to that resulting from the use
of the triflic acid-activated catalyst 2, as determined by comparison
of optical rotation and HPLC or GC analysis using a chiral column.6
We have also briefly examined the catalytic enantioselective
Diels-Alder reaction with two furans as diene component and
trifluoroethyl acrylate and ethyl fumarate as dienophile partner with
the results that are outlined in Table 4.6 Furans are of special interest
as Diels-Alder reactants since the products can be used to prepare
chiral cyclohexane derivatives in which most or even all of the
ring members are functionalized or chiral. The furan adducts are
also useful since they can be deoxygenated by treatment with excess
zinc dust and 3 equiv of TMSBr in CH3CN to form the corre-
sponding 1,3-cyclohexadiene; for example, the adduct in entry 3
(2) (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808-3809. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc.
2002, 124, 9992-9993. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc.
2003, 125, 6388-6390. (d) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am.
Chem. Soc. 2004, 126, 4800-4802. (e) Hu, Q.-Y.; Zhou, G.; Corey, E. J.
J. Am. Chem. Soc. 2004, 126, 13708-13713. (f) Zhou, G.; Hu, Q.-Y.;
Corey, E. J. Org. Lett. 2003, 5, 3979-3982. (g) Snyder, S. A.; Corey, E.
J. J. Am. Chem. Soc. 2006, 128, 740-742. (h) Hong, S.; Corey, E. J. J.
Am. Chem. Soc. 2006, 128, 1346-1352. (i) Yeung, Y.-Y.; Hong, S.; Corey,
E. J. J. Am. Chem. Soc. 2006, 128, 6310-6311. (j) Zhou, G.; Corey, E.
J. J. Am. Chem. Soc. 2005, 127, 11958-11959.
(3) For example, the o-tolyl methyl peak was shifted downfield from (δ) 2.63
in 1 to 2.81 in 3, and the pyrrolidine methine proton was shifted from
4.54 in 1 to 5.26 in 3 (all at 23 °C).
(4) Catalyst 3 was generated by addition of 0.8 equiv of AlBr3 in CH2Br2
solution (Aldrich Co.) to the oxazaborolidine 1.
(5) In large-scale experiments, the chiral ligand diphenylpyrrolidinomethanol
is easily recovered in pure condition for reuse upon workup, being soluble
in aqueous acid and easily extracted from the basified aqueous solution.
This ligand is used industrially and produced on large scale.
(6) Enantioselectivities were determined by either HPLC or gas chromatog-
raphy using chiral columns; for experimental details, see Supporting
Information.
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