J. Am. Chem. Soc.

2000, 122, 4243-4244 4243

New Strategies for Organic Catalysis: The First Scheme 1

Highly Enantioselective Organocatalytic Diels-Alder
Reaction
Kateri A. Ahrendt, Christopher J. Borths, and
David W. C. MacMillan*
Department of Chemistry, UniVersity of California
Berkeley, California 94720
ReceiVed January 7, 2000
Over the past 30 years, enantioselective catalysis has become
one of the most important frontiers in exploratory organic
synthetic research. During this time, remarkable advances have
been made in the development of organometallic asymmetric
catalysts that in turn have provided a wealth of enantioselective
oxidation, reduction, π-bond activation, and Lewis acid-catalyzed
processes.1 Surprisingly, however, relatively few asymmetric
transformations have been reported which employ organic
molecules as reaction catalysts,2 despite the widespread avail- Table 1. Organocatalyzed Diels-Alder Reaction between
ability of organic chemicals in enantiopure form and the accordant Cinnamaldehyde and Cyclopentadiene
potential for academic, industrial, and economic benefit. Herein,
we introduce a new strategy for organocatalysis that we expect
will be amenable to a range of asymmetric transformations. In
this context, we document the first highly enantioselective
organocatalytic Diels-Alder reaction.3 entry catalyst time (h) yield (%) exo:endo exo ee (%)a,b
We recently embarked upon the development of a general 1 (S)-Pro-OMe‚HCl 27 81 2.7:1 48 (2R)
strategy for organocatalytic reactions based upon design features 2 (S)-Abr-OMe‚HCl 10 80 2.3:1 59 (2S)
derived from the arena of Lewis acid catalysis. Specifically, we 3 5 23 92 2.6:1 57 (2R)
reasoned that (i) LUMO-lowering activation and (ii) the kinetic 4 6 84 82 3.6:1 74 (2R)
5 7 8 99 1.3:1 93 (2S)c
lability toward ligand substitution that enables Lewis acid-catalyst
turnover (eq 1) might also be available with a carbogenic system a Product ratios determined by GLC using a Bodman Γ-TA or β-PH

that exists as a rapid equilibrium between an electron-deficient column. b Absolute and relative configurations assigned by chemical
and a relatively electron-rich state. With this in mind, we correlation to a known compound (Supporting Information). c Using 5
hypothesized that the reversible formation of iminium ions from mol % catalyst.
R,β-unsaturated aldehydes and amines (eq 2) might emulate the
equilibrium dynamics and π-orbital electronics that are inherent To test this hypothesis we investigated the capacity of chiral
to Lewis acid catalysis, thereby providing a new platform for the amines to enantioselectively catalyze the Diels-Alder reaction
design of organocatalytic processes. Significantly, this analysis between R,β-unsaturated aldehydes and various dienes.4,5 As
reveals the attractive prospect that chiral amines might function outlined in Scheme 1, we envisioned that condensation of
as enantioselective catalysts for a range of transformations that aldehyde 1 with an enantiopure amine would lead to the formation
traditionally utilize metal salts. of an iminium ion (2) that is sufficiently activated6 to engage a
diene reaction partner. Accordingly, Diels-Alder cycloaddition
would lead to iminium ion 3, which upon hydrolysis would
provide the enantioenriched cycloaddition product (4) while
reconstituting the chiral amine catalyst.
Our enantioselective catalytic Diels-Alder strategy was first
evaluated using cyclopentadiene with (E)-cinnamaldehyde and a
series of chiral secondary amine‚HCl salts. As revealed in Table
1, this LUMO-lowering strategy was successful using only
(1) For leading references, see: (a) ComprehensiVe Asymmetric Catalysis; catalytic quantities of both (S)-proline and (S)-abrine-methyl esters
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds; Springer: Heidelberg, 1999.
(b) Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed; Wiley: New (10 mol %), providing the Diels-Alder adduct in excellent yield
York, 1994. (c) Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993.
(2) For notable examples, see the following. Aldol reaction: (a) Hajos, Z. (4) For recent reviews of enantioselective Diels-Alder reactions involving
G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b) Eder, U.; Sauer, G.; chiral Lewis acids, see: Oppolzer, W. In ComprehensiVe Organic Synthesis;
Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496. (c) Agami, C.; Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 5. (b) Kagan, H.
Meyneir, F.; Puchot, C. Tetrahedron 1984, 40, 1031. (d) List, B.; Lerner, R. B.; Riant, O. Chem. ReV. 1992, 92, 1007. (c) Oh, T.; Reilly, M. Org. Prep.
A.; Barbas, C. F., III. J. Am. Chem. Soc., in press. Phase-transfer catalysis: Proc. Int. 1994, 26, 129. (d) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289.
(e) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, (5) (a) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem.
2353. (f) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287. (g) Corey, E. J.; Soc. 1999, 121, 7559. (b) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka,
Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1999, 120, 13000. (h) Corey, T.; von Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E.
E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. Epoxidation: A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582. (c) Isihara, K.;
(i) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.; Cheung, Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561. (d) Isihara, K.; Kurihara,
K.-K. J. Am. Chem. Soc. 1996, 118, 491. (j) Yang, D.; Wong, M.-K.; Yip, H.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049. (e) Corey, E. J.; Loh,
Y.-C.; Wnag, X.-C.; Tang, M.-W.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem. T. P. J. Am. Chem. Soc. 1991, 113, 8966. (f) Corey, E. J.; Guzman-Perez, A.;
Soc. 1998, 120, 5943. (k) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. Loh, T. P. J. Am. Chem. Soc. 1994, 116, 3611. (g) Bao, J.; Wulff, W. D.;
1996, 118, 9806. (l) Denmark, S. E.; Wu, Z. Synlett 1999, 847. Bayliss-Hillman Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.; Whitcomb, M. C.;
reaction: (m) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Yeung, S.-M.; Ostrander, R. L.; Rheingold, A. L. J. Am. Chem. Soc. 1996,
Am. Chem. Soc. 1999, 120, 10219. 118, 3392.
(3) Asymmetric base-catalyzed Diels-Alder reactions between anthrone (6) It has been established that R,β-unsaturated iminium ions are signifi-
and maleimide have been achieved with moderate selectivity (6-61% ee): cantly more reactive as dienophiles than the corresponding R,β-unsaturated
Riant, O.; Kagan, B. Tetrahedron Lett. 1989, 30, 7403. aldehydes: Baum, J. S.; Viehe, H. G. J. Org. Chem. 1976, 41, 183.

10.1021/ja000092s CCC: $19.00 © 2000 American Chemical Society

Published on Web 04/15/2000
4244 J. Am. Chem. Soc., Vol. 122, No. 17, 2000 Communications to the Editor

Table 2. Organocatalyzed Diels-Alder Cycloadditions between Table 3. Organocatalyzed Diels-Alder Reaction between Acrolein
Cyclopentadiene and Representative Dienophiles or Crotonaldehyde and Representative Dienes

entry R time (h) yield (%) exo:endoa,b exo ee (%) endo ee (%) a,b

1 Me 16 75 1:1 86 (2S) 90 (2S)

2 Pr 14 92 1:1 86 (2S) 90 (2S)
c
3 i-Pr 14 81 1:1 84 (2S) 93 (2S)
4 Ph 21 99 1.3:1 93 (2S) 93 (2S)
5 Furyl 24 89 1:1 91 (2S) 93 (2S)
a Product ratios determined by GLC using a Bodman Γ-TA or β-PH d

column. b Absolute and relative configurations assigned by chemical

correlation to a known compound (Supporting Information).

and moderate stereoselectivity (entries 1 and 2, >80%, 2.3-2.7:1

exo:endo, 48-59% ee). With the C2-symmetric amines 5 and 6,
an increase in enantiocontrol was observed (entries 3 and 4, >82%
yield, 2.6-3.6:1 exo:endo, 57-74% ee). Importantly, control of
iminium ion geometry7 through the use of steric constraints on
the catalyst architecture 7 was found to provide the highest levels
of enantioselectivity (93% ee) while maintaining reaction ef-
ficiency (entry 5, 5 mol %).8-10 Consequently, amine salt 7 was
identified as the optimal catalyst for further exploration.
Experiments that probe the scope of the dienophile reaction
component are summarized in Table 2. Variation in the steric
contribution of the olefin substituent (R1 ) Me, Pr, i-Pr, entries
1-3) is possible without loss in yield or enantioselectivity (>75% a Product ratios determined by GLC using a Bodman Γ-TA or β-PH
yield, endo >90% ee, exo >84% ee). The reaction is also tolerant column. b Absolute and relative configurations assigned by chemical
of aromatic groups on the dienophile component (entries 4 and correlation to a known compound (Supporting Information). c Using
5, 89% yield, endo >93% ee, exo >91% ee). To demonstrate catalyst 5. d Using 5 mol % catalyst.
the preparative utility of this methodology, the addition of model MM3-9.12 Inspection of structure MM3-9 reveals two
cyclopentadiene to cinnamaldehyde was performed on a 50-mmol salient stereocontrol elements: (i) selective formation of the (E)-
scale utilizing catalyst 7 (5 mol %) to afford 12 g of (2S)-8 (99% iminium isomer to avoid nonbonding interactions between the
yield, exo 93% ee). substrate olefin and the geminal methyl substituents, and (ii) the
This amine-catalyzed Diels-Alder cycloaddition is also general benzyl group on the catalyst framework which effectively shields
with respect to diene structure (Table 3). As revealed with 1,3- the re face of the dienophile, leaving the si face exposed to
diphenylisobenzofuran and cyclohexadiene (entries 1 and 2), a cycloaddition. Notably, catalyst 7 achieves high levels of orga-
wide range of diene reactivity can be accommodated without loss
in stereocontrol (entry 1, 75% yield, 35:1 exo:endo, 96% ee; entry
2, 82% yield, 1:14 exo:endo, 94% ee). This methodology allows
access to a number of cyclohexenyl building blocks that incor-
porate acetoxy, alkyl, formyl, and aryl substituents with high levels
of regio- and enantioselectivity (entries 3-6, 72-89% yield, 1:5-
1:11 exo:endo, 83-90% ee). Notably, all of the dienes employed
in this study undergo cycloaddition with excellent diastereose-
lectivity (entries 1, 2, 6, and 7, 5-35:1 endo:exo), with the
exception of cyclopentadiene (Table 1, 1:1-1.3 endo:exo). Finally,
it is noteworthy that the reactions depicted in Tables 2 and 3
were performed under an aerobic atmosphere, using wet solvents
and an inexpensive bench-stable catalyst,11 further illustrating the nizational control with simple aldehydes, presumably due to the
preparative advantages of organocatalysis. geometrical constraints that accompany formation of the iminium
The sense of asymmetric induction observed in all cases ion π-bond. Indeed, we expect that substrate activation by π-bond
involving catalyst 7 is consistent with the calculated iminium ion formation will provide a valuable organizational tool in asym-
metric catalysis.
(7) Molecular modeling calculations suggest that iminium ion stereocontrol In conclusion, we have documented a new strategy for
is essential for attaining high levels of enantiocontrol, as the (E)- and (Z)-
iminium ion isomers are expected to undergo cycloaddition from opposite organocatalysis that has enabled the development of the first
enantiofaces. highly enantioselective amine-catalyzed Diels-Alder reaction.
(8) Although MeOH-H2O was typically employed in this study, other Further studies to address the scope of this new catalytic strategy
solvent combinations were found to be useful (Table 1, entry 5): DMSO- will be forthcoming.
H2O, exo 92% ee; DMF-H2O, exo 90% ee; CH3NO2-H2O, exo 90% ee.
(9) The addition of 5% H2O to the reaction solvent results in increased Acknowledgment. This research has been supported by kind gifts
reaction rates and enantioselectivities. The precise role of H2O in this process from Merck, Roche-Biosciences, and Warner-Lambert.
has not been elucidated; however, we tentatively propose that this addend is
facilitating the iminium ion hydrolysis step in the catalytic cycle. Supporting Information Available: Experimental procedures, spec-
(10) In a representative procedure the dienophile (0.5 mmol) and the diene tral data for all compounds, and stereochemical proofs (PDF). This
(1.5 mmol) were added sequentially to the catalyst (0.025 mmol, 5 mol %) in material is available free of charge via the Internet at http://pubs.acs.org.
the appropriate solvent (0.5 mL). Upon consumption of the aldehyde (3-24
h), the mixture was diluted with Et2O and washed with H2O and brine. The JA000092S
organics were dried (Na2SO4), concentrated, and then purified by flash
chromatography. (12) A Monte Carlo simulation using the MM3 force-field; Macromodel
(11) The estimated cost for the preparation of 50 g of catalyst 7 is $6. V6.5.