New strategies for organic catalysis: The first highly enantioselective organocatalytic diels - Alder reaction [16]

Full text of DOI:10.1021/ja000092s

J. Am. Chem. Soc. 2000, 122, 4243-4244
4243
Scheme 1
New Strategies for Organic Catalysis: The First
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-
ability of organic chemicals in enantiopure form and the accordant
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
We recently embarked upon the development of a general
strategy for organocatalytic reactions based upon design features
derived from the arena of Lewis acid catalysis. Specifically, we
reasoned that (i) LUMO-lowering activation and (ii) the kinetic
lability toward ligand substitution that enables Lewis acid-catalyst
turnover (eq 1) might also be available with a carbogenic system
that exists as a rapid equilibrium between an electron-deficient
and a relatively electron-rich state. With this in mind, we
hypothesized that the reversible formation of iminium ions from
R,â-unsaturated aldehydes and amines (eq 2) might emulate the
equilibrium dynamics and π-orbital electronics that are inherent
to Lewis acid catalysis, thereby providing a new platform for the
design of organocatalytic processes. Significantly, this analysis
reveals the attractive prospect that chiral amines might function
as enantioselective catalysts for a range of transformations that
traditionally utilize metal salts.
Table 1. Organocatalyzed Diels-Alder Reaction between
Cinnamaldehyde and Cyclopentadiene
entry
catalyst
time (h) yield (%) exo:endo exo ee (%)a,b
1
2
3
4
5
(S)-Pro-OMe‚HCl
27
10
23
84
8
81
80
92
82
99
2.7:1
2.3:1
2.6:1
3.6:1
1.3:1
48 (2R)
59 (2S)
57 (2R)
74 (2R)
93 (2S)c
(S)-Abr-OMe‚HCl
5
6
7
a Product ratios determined by GLC using a Bodman Γ-TA or â-PH
column. b Absolute and relative configurations assigned by chemical
correlation to a known compound (Supporting Information). c Using 5
mol % catalyst.
To test this hypothesis we investigated the capacity of chiral
amines to enantioselectively catalyze the Diels-Alder reaction
between R,â-unsaturated aldehydes and various dienes.4,5 As
outlined in Scheme 1, we envisioned that condensation of
aldehyde 1 with an enantiopure amine would lead to the formation
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
catalytic quantities of both (S)-proline and (S)-abrine-methyl esters
(10 mol %), providing the Diels-Alder adduct in excellent yield
(1) For leading references, see: (a) ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds; Springer: Heidelberg, 1999.
(b) Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed; Wiley: New
York, 1994. (c) Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993.
(2) For notable examples, see the following. Aldol reaction: (a) Hajos, Z.
G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b) Eder, U.; Sauer, G.;
Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496. (c) Agami, C.;
Meyneir, F.; Puchot, C. Tetrahedron 1984, 40, 1031. (d) List, B.; Lerner, R.
A.; Barbas, C. F., III. J. Am. Chem. Soc., in press. Phase-transfer catalysis:
(e) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111,
2353. (f) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287. (g) Corey, E. J.;
Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1999, 120, 13000. (h) Corey,
E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. Epoxidation:
(i) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.; Cheung,
K.-K. J. Am. Chem. Soc. 1996, 118, 491. (j) Yang, D.; Wong, M.-K.; Yip,
Y.-C.; Wnag, X.-C.; Tang, M.-W.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem.
Soc. 1998, 120, 5943. (k) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc.
1996, 118, 9806. (l) Denmark, S. E.; Wu, Z. Synlett 1999, 847. Bayliss-Hillman
reaction: (m) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J.
Am. Chem. Soc. 1999, 120, 10219.
(4) For recent reviews of enantioselective Diels-Alder reactions involving
chiral Lewis acids, see: Oppolzer, W. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 5. (b) Kagan, H.
B.; Riant, O. Chem. ReV. 1992, 92, 1007. (c) Oh, T.; Reilly, M. Org. Prep.
Proc. Int. 1994, 26, 129. (d) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289.
(5) (a) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem.
Soc. 1999, 121, 7559. (b) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka,
T.; von Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E.
A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582. (c) Isihara, K.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561. (d) Isihara, K.; Kurihara,
H.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049. (e) Corey, E. J.; Loh,
T. P. J. Am. Chem. Soc. 1991, 113, 8966. (f) Corey, E. J.; Guzman-Perez, A.;
Loh, T. P. J. Am. Chem. Soc. 1994, 116, 3611. (g) Bao, J.; Wulff, W. D.;
Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.; Whitcomb, M. C.;
Yeung, S.-M.; Ostrander, R. L.; Rheingold, A. L. J. Am. Chem. Soc. 1996,
118, 3392.
(3) Asymmetric base-catalyzed Diels-Alder reactions between anthrone
and maleimide have been achieved with moderate selectivity (6-61% ee):
Riant, O.; Kagan, B. Tetrahedron Lett. 1989, 30, 7403.
(6) It has been established that R,â-unsaturated iminium ions are signifi-
cantly more reactive as dienophiles than the corresponding R,â-unsaturated
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
Cyclopentadiene and Representative Dienophiles
Table 3. Organocatalyzed Diels-Alder Reaction between Acrolein
or Crotonaldehyde and Representative Dienes
time (h) yield (%) exo:endoa,b exo ee (%) endo ee (%)
a,b
entry
R
1
2
3
4
5
Me
Pr
i-Pr
Ph
16
14
14
21
24
75
92
81
99
89
1:1
1:1
1:1
1.3:1
1:1
86 (2S)
86 (2S)
84 (2S)
93 (2S)
91 (2S)
90 (2S)
90 (2S)
93 (2S)
93 (2S)
93 (2S)
c
Furyl
d
a Product ratios determined by GLC using a Bodman Γ-TA or â-PH
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%
yield, endo >90% ee, exo >84% ee). The reaction is also tolerant
of aromatic groups on the dienophile component (entries 4 and
5, 89% yield, endo >93% ee, exo >91% ee). To demonstrate
the preparative utility of this methodology, the addition of
cyclopentadiene to cinnamaldehyde was performed on a 50-mmol
scale utilizing catalyst 7 (5 mol %) to afford 12 g of (2S)-8 (99%
yield, exo 93% ee).
This amine-catalyzed Diels-Alder cycloaddition is also general
with respect to diene structure (Table 3). As revealed with 1,3-
diphenylisobenzofuran and cyclohexadiene (entries 1 and 2), a
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
preparative advantages of organocatalysis.
a Product ratios determined by GLC using a Bodman Γ-TA or â-PH
column. b Absolute and relative configurations assigned by chemical
correlation to a known compound (Supporting Information). c Using
catalyst 5. d Using 5 mol % catalyst.
model MM3-9.12 Inspection of structure MM3-9 reveals two
salient stereocontrol elements: (i) selective formation of the (E)-
iminium isomer to avoid nonbonding interactions between the
substrate olefin and the geminal methyl substituents, and (ii) the
benzyl group on the catalyst framework which effectively shields
the re face of the dienophile, leaving the si face exposed to
cycloaddition. Notably, catalyst 7 achieves high levels of orga-
nizational control with simple aldehydes, presumably due to the
geometrical constraints that accompany formation of the iminium
ion π-bond. Indeed, we expect that substrate activation by π-bond
formation will provide a valuable organizational tool in asym-
metric catalysis.
In conclusion, we have documented a new strategy for
organocatalysis that has enabled the development of the first
highly enantioselective amine-catalyzed Diels-Alder reaction.
Further studies to address the scope of this new catalytic strategy
will be forthcoming.
The sense of asymmetric induction observed in all cases
involving catalyst 7 is consistent with the calculated iminium ion
(7) Molecular modeling calculations suggest that iminium ion stereocontrol
is essential for attaining high levels of enantiocontrol, as the (E)- and (Z)-
iminium ion isomers are expected to undergo cycloaddition from opposite
enantiofaces.
(8) Although MeOH-H2O was typically employed in this study, other
solvent combinations were found to be useful (Table 1, entry 5): DMSO-
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
reaction rates and enantioselectivities. The precise role of H2O in this process
has not been elucidated; however, we tentatively propose that this addend is
facilitating the iminium ion hydrolysis step in the catalytic cycle.
(10) In a representative procedure the dienophile (0.5 mmol) and the diene
(1.5 mmol) were added sequentially to the catalyst (0.025 mmol, 5 mol %) in
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
organics were dried (Na2SO4), concentrated, and then purified by flash
chromatography.
Acknowledgment. This research has been supported by kind gifts
from Merck, Roche-Biosciences, and Warner-Lambert.
Supporting Information Available: Experimental procedures, spec-
tral data for all compounds, and stereochemical proofs (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
JA000092S
(12) A Monte Carlo simulation using the MM3 force-field; Macromodel
V6.5.
(11) The estimated cost for the preparation of 50 g of catalyst 7 is $6.