A new cationic, chiral catalyst for highly enantioselective Diels-Alder reactions

Article abstract of DOI:10.1021/ol034706k

(Matrix presented) The Diels-Alder reaction of cyclopentadiene and 2-methacrolein is catalyzed by a chiral Lewis acid to form the exo adduct in 96% yield and 96% ee.

Full text of DOI:10.1021/ol034706k

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2465-2467
A New Cationic, Chiral Catalyst for
Highly Enantioselective Diels−Alder
Reactions
Kevin T. Sprott and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received April 28, 2003
ABSTRACT
The Diels−Alder reaction of cyclopentadiene and 2-methacrolein is catalyzed by a chiral Lewis acid to form the exo adduct in 96% yield and
96% ee.
The use of chiral Lewis acids as catalysts for Diels-Alder
reactions has transformed the classical thermal cycloaddition,
already one of the most versatile and useful processes in the
repertoire of synthetic chemistry, into even more powerful
enantioselective versions in recent years.1 The impact of
research in this area has been multifaceted. The use of
catalytic enantioselective Diels-Alder reactions to generate
a chiral adduct from achiral starting materials greatly
facilitates the synthesis of complex molecules.1a In addition,
mechanistic studies have provided a remarkably detailed
understanding of the organizing factors and pre-transition-
state assemblies which give rise to high enantioselectivity.1a,b,2
Further, the understanding of these structural and mechanistic
principles provides a foundation for the prediction of the
absolute stereochemical course of many new reactions and
for the design of new catalysts. In this paper, we describe
the successful design of a new catalytic system and its
application to Diels-Alder reactions of R,â-enals as dieno-
philes. Because of the very high degree of Lewis acidity that
can be achieved through the use of cationic Lewis acids,3
we chose to design this type of catalyst. Specifically, the
chiral bidentate amino phenol 1 was selected as a ligand for
boron in Lewis acid 2. The expectation was that Lewis acid
2 could catalyze enantioselective Diels-Alder additions with
R,â-enals such as 2-methacrolein and direct the addition to
the si face of the dieneophile via the pre-transition-state
assembly 3. The selection of a phenolic subunit in ligand 1
was made in order to preclude heterolytic C-O bond
dissociation in the complex 2. Such cleavage reactions have
been found to limit the thermal stability of strong chiral
Lewis acids.1a,3 The choice of the C2-symmetric pyrrolidine
subunit in 1 was made on the basis of synthetic accessibility
and the presence of a suitably placed π-rich aromatic
neighboring group.1
(1) For recent reviews, see: (a) Corey, E. J. Angew. Chem., Int. Ed.
2002, 41, 1650. (b) Evans, D. A.; Johnson, J. S. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 3, p 1177. (c) Diaz, L. C. J. Braz. Chem. Soc.
1997, 2, 289. (d) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed.
1998, 37, 488. (e) Ishihara, K.; Yamamoto, H. Eur. J. Chem. 1999, 527.
10.1021/ol034706k CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/18/2003

The synthetic route devised for the synthesis of 1 is
outlined in Scheme 1. (E,E)-1,6-Diphenyl-1,5-hexadiene (4)4
triphosgene and Et3N in CH2Cl2. Hydrogenolysis of 6 (1 atm
H2, Raney Ni, 23 °C, EtOH, Me2CO) proceeded smoothly
to form enantiomerically pure (R,R)-1,6-diphenylhexane-2,5-
diol, mp 66-68 °C, [R]22D -12.5 (c ) 2.4, CHCl3). Addition
of methanesulfonyl chloride to this diol and Et3N in CH2Cl2
at -30 °C gave the crystalline bismesylate 7 (mp 99-101
°C) in 95% overall yield from the biscarbonate 6. Reaction
of 7 with 5 equiv of neat benzylamine at 80 °C for 10 h
furnished N-benzyl-(S,S)-2,5-dibenzylpyrrolidine. A small
amount (ca. 5%) of cis-N-benzyl-2,5-dibenzylpyrrolidine was
formed in this reaction which is most conveniently removed
after the next step.8 N-Debenzylation of N-benzyl-(S,S)-2,5-
dibenzylpyrrolidine was accomplished by stirring under 1
atm of H2 with Pd-C catalyst in EtOH at 23 °C to form
(S,S)-2,5-dibenzylpyrrolidine (8) in 90% overall yield from
dimesylate 7. Pure 8 was readily obtained by recrystallization
of the hydrochloride salt from EtOAc. The final step in the
synthesis of ligand 1 was effected in >95% yield by the
reaction of 8 with 2-hydroxybenzyl benzoate in toluene at
reflux for 1 h. This useful procedure involves the base-
catalyzed elimination of benzoic acid from 2-hydroxybenzyl
benzoate to form an intermediate orthoquinone methide
which then serves as a Michael acceptor for 8.
Scheme 1. Synthesis of Ligand 1a
a Reagents: (i) K3Fe(CN)6, K2OsO4‚2H2O, (DHQD)2PHAL,
K2CO3, H2O, t-BuOH, hexanes; (ii) triphosgene, Et3N, CH2Cl2; (iii)
Raney-Ni, H2, EtOH; (iv) MsCl, Et3N, CH2Cl2; (v) BnNH2; (vi)
Pd/C, H2, EtOH; (vii) toluene.
A simple procedure was devised for the synthesis of
1
oxazaborolidine 2 from the chiral aminophenol 1. H and
11B NMR studies demonstrated that boron tribromide does
not coordinate with 2,6-di-tert-butylpyridine in CDCl3 solu-
tion at room temperature or below since mixtures showed
the same spectra as the sum of the component spectra. This
finding led to the following method for generating catalyst
2 from 1 for use in situ. Ligand 1 (dried azeotropically with
benzene or toluene) in CH2Cl2 at 10 °C was treated with 1
equiv of 2,6-di-tert-butylpyridine and subsequently with 1
equiv of boron tribromide to produce a colorless precipitate.
The mixture was allowed to warm to room temperature (23
°C) leading to a colorless, clear solution. After a further 15
min at 23 °C, formation of 2 had proceeded to completion
and the catalyst solution was cooled to -94 °C or -78 °C
for the subsequent Diels-Alder reaction. A number of
Diels-Alder reactions were performed with 2 (10 mol %)
that had been prepared in this way with excellent results
using 2-substituted R,â-enals as dienophiles. These results
and also the result of one test with a quinone as dienophile
are summarized in Table 1 for reactions in CH2Cl2 with
cyclopentadiene (5 equiv) as test diene and catalyst 2 (10
mol %). It is evident from the rapidity of these Diels-Alder
reactions at -78 to -94 °C that catalyst 2 is a powerful
Lewis acid. The absolute configurations of the products were
assigned from comparison of optical rotation with known
values, and ee determinations were made by GC or 1H NMR
(mp 78-80 °C) was synthesized from cinnamyl bromide by
stirring with zinc powder and iodine in ether at -45 °C and
purified to homogeneity on a 60 g scale by recrystallization
from methanol. Enantioselective double bishydroxylation of
4 using the Sharpless catalytic system with the ligand
(DHQD)2PHAL (2 mol %) and K2OsO4 (2 mol %) together
with K2CO3, K3Fe(CN)6, and CH3SO2NH2 in t-BuOH-
H2O-hexanes (1:1:0.6 by volume) at 4 °C for ca. 64 h gave
tetraol 5, mp 123-125 °C, in 97% yield and >99% ee as
determined by HPLC analysis.5-7 This enantiomerically pure
tetraol was converted in >99% yield to the corresponding
bis cyclic carbonate 6, mp 131-133 °C, by reaction with
(2) Corey, E. J.; Lee, T. W. J. Chem. Soc., Chem. Commun. 2001, 1321.
(3) See: (a) Hayashi, Y.; Rohde, J. J.; Corey, E. J. J. Am. Chem. Soc.
1996, 118, 5502. (b) Corey E. J.; Shibata, T.; Lee, T. W. J. Am. Chem.
Soc. 2002, 124, 3808. (c) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem.
Soc. 2002, 124, 9992. (d) Bruin, M. E.; Ku¨ndig, E. P. J. Chem. Soc., Chem.
Commun. 1998, 2635. (e) Ku¨ndig, E. P.; Saudan, C. M.; Bernardinelli, G.
Angew. Chem., Int. Ed. 1999, 38, 1220.
(4) For previous syntheses, see: (a) Clive, D. L. J.; Anderson, P. C.;
Moss, N.; Singh, A. J. Org. Chem. 1982, 47, 1641. (b) De Meijere, A.;
Stecker, B.; Kourdioukov, A.; Williams, C. M. Synthesis 2000, 929. (c)
Doering, W. v. E.; Birladeanu, L.; Sarma, K.; Teles, J. H.; Kla¨rner, F. G.;
Gehrke, J.-S. J. Am. Chem. Soc. 1994, 116, 4289. (d) Ishiyama, T.; Ahiko,
T.-A.; Miyaura, N. Tetrahedron Lett. 1996, 37, 6889. (e) Lutz, R. P.; Berg,
H. A. J. J. Org. Chem. 1980, 45, 3915. (f) Orita, A.; Watanabe, A.; Tsuchiya,
H.; Otera, J. Tetrahedron 1999, 55, 2889. (g) Pasto, D. J.; L’Hermine, G.
Tetrahedron 1993, 49, 3259. (h) Sasaoka, S.; Yamamoto, T.; Kinoshita,
H.; Inomata, K.; Kotake, H. Chem. Lett. 1985, 315. (i) Sjoholm, R.; Rairama,
R.; Ahonen, M. J. Chem. Soc., Chem. Commun. 1994, 1217. (j) Yanagisawa,
A.; Hibino, H.; Habaue, S.; Hisada, Y.; Yasue, K.; Yamamoto, H. Bull.
Chem. Soc. Jpn. 1995, 68, 1263.
(7) The enantiomeric purity of the tetraol 5 was determined by HPLC
analysis at 23 °C using a Chiracel AD column with 1% isopropyl alcohol
in hexanes (retention time for 5 16.7 min; retention times for the
corresponding racemate 18.3 and 16.7 min; retention times for the
corresponding 5,6-diastereomeric racemate 19.9 and 21.7 min).
(5) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(6) The use of hexanes as cosolvent and the addition of a solution of the
substrate 4 in hexanes to the well-stirred reaction mixture are essential to
efficient bis-dihydroxylation.
(8) The formation of cis-N-benzyl-2,5-dibenzylpyrrolidine in small
amounts from the reaction of benzylamine with the bis-mesylate 7 may be
due to π-neighboring group participation by phenyl to form a phenonium
ion which then reacts with benzylamine to give a benzylamino mesylate
with overall retention. Cyclization by an internal SN2 reaction of this amino
mesylate would then lead to cis-N-benzyl-2,5-dibenzylpyrrolidine.
2466
Org. Lett., Vol. 5, No. 14, 2003

at -94 °C) and gave >97% yields of exo adduct, the
enantioselectivities were distinctly lower than for the other
R,â-enals listed in Table 1; 65% ee for bromoacrolein and
71% ee for chloroacrolein. In previous work, ee’s of Diels-
Alder adducts from 2-bromo- and 2-chloroacrolein were
found to be at least as high as with 2-methacrolein.1a,2,3a
Additional research will be required to understand the basis
for the divergent behavior of catalyst 3.
Table 1. Diels-Alder Reactions of R,â-Enals and
Cyclopentadiene with Catalyst 2 (10 mol %)
We believe that there are numerous other useful applica-
tions of the readily available chiral diol 9. For example, it
can be used to prepare the cyclic sulfate 10 and the novel
amino phenol 11 as shown below.
Acknowledgment. This research was supported by a NIH
postdoctoral fellowship to K.T.S. and a grant from Pfizer,
Inc.
analysis of Mosher derivatives as previously described.3a-c,9
The isolation of pure Diels-Alder adducts and recovery of
ligand 1 (>99%) was accomplished simply by flash chro-
matography on silica gel using either ether-pentane or
EtOAc-hexanes for elution. The quantitative recovery of
ligand 1 for reuse together with its synthetic accessibility
and the high enantioselectivities shown in Table 1 combine
to make this new catalytic methodology an attractive option.
The effectiveness of catalyst 2 for the quinone Diels-Alder
subtype indicates a wider potential for catalyst 2 in synthesis.
The simplicity of the methodology can be seen from an
illustrative example.10
The absolute configurations of the adducts listed in Table
1 are in accord with the predictions made on the basis of
the pre-transition-state assembly 3, thus supporting the
general mechanistic model for enantioselective catalytic
Diels-Alder reactions which has been developed.1a,2,3a-c The
results obtained so far indicate that the replacement of the
two phenyl groups in ligand 1 and catalyst 2 by 3,5-di-
methylphenyl could lead to an even more effective catalytic
Diels-Alder system due to the greater π-electron basicity
of the 3,5-dimethylphenyl group as compared to phenyl.1,3a-c
An interesting observation was made on the reaction of
cyclopentadiene and catalyst 2 with 2-bromoacrolein and
2-chloroacrolein. We were surprised to find that, although
these reactions were very fast (complete within ca. 20 min
Supporting Information Available: Experimental pro-
cedures for the synthesis of 4-11 and for the Diels-Alder
reactions summarized in Table 1 and characterization data
for the products shown in Table 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL034706K
(9) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388.
(10) Illustrative Procedure for Catalyst Preparation and Diels-Alder
Reaction. Ligand 1 was dried by azeotropic distillation from toluene or
benzene, and all volatiles were removed under vacuum (<0.5 mm) for 2 h
with magnetic stirring. Ligand 1 (21.2 mg, 0.059 mmol) was dissolved in
CH2Cl2 (1.5 mL) under N2 and cooled to 10 °C, and 2,6-di-tert-butylpyridine
(13.3 µL, 0.059 mmol) was added. Boron tribromide (59 µL, 0.059 mmol,
as a 1.0 M solution in CH2Cl2) was added slowly to the reaction mixture,
and a colorless precipitate formed. The cold bath was removed, and the
reaction mixture was allowed to warm to room temperature over 4-5 min
during which time the precipitate had dissolved. Fifteen minutes after
dissolution of the solid, the colorless, clear reaction mixture was cooled to
-94 °C (liquid N2, hexanes), and methacrolein (49 µL, 0.59 mmol) was
added directly to the stirred reaction mixture. A precooled solution (-94
°C) of 1,3-cyclopentadiene (247 µL, 2.95 mmol, in 494 µL of CH2Cl2)
was added by cannula along the cold flask wall to the reaction mixture
over a 10 min period. The reaction was monitored by TLC, and quenched
with Et3N (ca.. 100 µL) upon completion. The reaction mixture was carefully
concentrated (volatile product) under reduced pressure, and the slurry was
subjected to flash chromatography on silica gel (Et2O-pentane; for less
volatile products, EtOAc-hexanes) to furnish (1S,2R,4S)-bicyclo[2.2.1]hept-
5-ene-2-methyl-2-carboxaldehyde (77.2 mg, 96%) and ligand 1 (21.2 mg,
>99%). Product Rf values were as follows (10% EtOAc-hexanes): 2,6-
di-tert-butylpyridine, Rf ) 0.78. (1S,2R,4S)-bicyclo[2.2.1]hept-5-ene-2-
methyl-2-carboxaldehyde, Rf ) 0.46; ligand 1, Rf ) 0.28.
Org. Lett., Vol. 5, No. 14, 2003
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