Broadly Effective Enantioselective Diels-Alder Reactions of 1-Amino-substituted-1,3-butadienes

Article abstract of DOI:10.1021/ol0255716

matrix presented A broad range of substituted 1-amino-1,3-butadienes undergo enantioselective Diels-Alder reactions with methacrolein in the presence of 5 mol % of Cr(III)-salen complex 1. The reactions are carried out conveniently, at room temperature, a

Full text of DOI:10.1021/ol0255716

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1163-1166
Broadly Effective Enantioselective
Diels−Alder Reactions of
1-Amino-substituted-1,3-butadienes
Yong Huang, Tetsuo Iwama, and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
Vrawal@uchigao.edu
Received January 16, 2002
ABSTRACT
A broad range of substituted 1-amino-1,3-butadienes undergo enantioselective Diels−Alder reactions with methacrolein in the presence of 5
mol % of Cr(III)-salen complex 1. The reactions are carried out conveniently, at room temperature, and they afford the cycloadducts in high
yields and excellent ee’s.
The clear importance of the Diels-Alder (DA) reaction to
complex molecule synthesis has stimulated considerable
interest in the development of enantioselective catalysts for
this transformation.1 Despite numerous and significant
advances in this area, the overall scope of this reaction
remains limited. Whereas many chiral scaffolds engender
high enantioselectivity in these cycloadditions, a relatively
small range of dienes and dienophiles give useful results.2
Few examples of successful enantioselective DA reactions
of heteroatom-substituted dienes, arguably the most useful
for natural product synthesis applications,3 have been re-
ported, and until recently these had been limited primarily
to mono-alkoxy- or -acyloxy-substituted butadienes.4 Our
recent report on enantioselective DA reactions of 1-amino-
3-siloxy dienes5,6 provided not only the first examples of
the use of doubly heteroatom-substituted dienes in this
process but also one of the earliest examples of amine-
substituted dienes.7-10 As a significant advance of our earlier
report,5 we found that the chiral Lewis acid-catalyzed DA
reactions between a broad range of Oppolzer-Overman11
(4) For reactions involving mono-alkoxy- or -acyloxy-substituted buta-
dienes, see: (a) Marshall, J. A.; Xie, S. J. J. Org. Chem. 1992, 57, 2987-
2989. (b) Corey, E. J.; Guzman-Perez, A.; Loh, T.-P. J. Am. Chem. Soc.
1994, 116, 3611-3612, also see ref 1c.
(5) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122,
7843-7844.
(1) Reviews on catalytic enantioselective Diels-Alder reactions: (a)
Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92, 1007-1019. (b) Dias, L. C.
J. Braz. Chem. Soc. 1997, 8, 289-332. (c) Evans, D. A.; Johnson, J. S. In
ComprehensiVe Asymmetric Catalyst, Vol. III; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; pp 1177-1235.
(2) Of the successful (>90% ee, see ref 1c) DA’s reported, the vast
majority involve the use of cyclopentadiene, butadiene, or their alkyl-
substituted derivatives.
(3) Cf.: (a) Danishefsky, S.; Hershenson, F. M. J. Org. Chem. 1979,
44, 1180-1181. (b) Overman, L. E.; Petty, C. B.; Doedens, R. J. J. Org.
Chem. 1979, 44, 4183-4185. (c) Overman, L. E.; Fukaya, C. J. Am. Chem.
Soc. 1980, 102, 1454-1456. (d) Overman, L. E.; Lesuisse, D.; Hashimoto,
M. J. Am. Chem. Soc. 1983, 105, 5373-5379. (e) Masamune, S.; Reed, L.
A.; Davis, J. T.; Choy, W. J. Org. Chem. 1983, 48, 4441-4444.
(6) Other applications of amino-siloxy dienes: (a) Kozmin, S. A.; Rawal,
V. H. J. Org. Chem. 1997, 62, 5252-5253. (b) Kozmin, S. A.; Rawal, V.
H. J. Am. Chem. Soc. 1997, 119, 7165-7166. (c) Kozmin, S. A.; Rawal,
V. H. J. Am. Chem. Soc. 1998, 120, 13523-13524. (d) Kozmin, S. A.;
Janey, J. M.; Rawal, V. H. J. Org. Chem. 1999, 64, 3039-3052. (e) Kozmin,
S. A.; Green, M. T.; Rawal, V. H. J. Org. Chem. 1999, 64, 8045-8047. (f)
Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1999, 121, 9562-9573.
(g) Janey, J. M.; Iwama, T.; Kozmin, S. A.; Rawal, V. H. J. Org. Chem.
2000, 65, 9059-9068. (h) Kozmin, S. A.; He, S.; Rawal, V. H. Org. Synth.
2000, 78, 160-168. (i)Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321-
3323.
(7) Reviews on Diels-Alder reaction of amino-substituted dienes: (a)
Enders, D.; Meyer, O. Liebigs Ann. 1996, 1023-1035. (b) Barluenga, J.;
Sua´rez-Sobrino, A.; Lo´pez, L. A. Aldrichimica Acta 1999, 32, 4-15.
10.1021/ol0255716 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/07/2002

type 1-carbamate-substituted dienes and R-substituted
acroleins proceed with complete diastereoselectivities, high
enantioselectivities, and good to excellent yields.12
implied that the reaction might not be limited to the specific
diene used in the original study but could be applicable to a
broad range of 1-carbamate-substituted dienes, thereby
greatly expanding the scope and usefulness of the catalyzed
asymmetric DA reaction.
In an initial exploratory study, the Oppolzer-Overman11
type of diene (2a) was allowed to react at room temperature
with 2 equiv of methacrolein (3) and 5 mol % of the
hexafluoroantimonate derivative of Jacobsen’s Cr(III)-salen
catalyst (1) in the presence of 4 Å molecular sieves (Scheme
1). A clean, rapid reaction ensued, affording exclusively the
We had previously reported5 that 1-amino-3-siloxybuta-
dienes undergo DA reactions with a wide range of R-sub-
stituted acroleins catalyzed by Jacobsen’s chiral Cr(III)-salen
catalyst,13-15 to give cycloadducts in excellent yield (>90%)
and up to 97% ee. The primary cycloadducts are readily
hydrolyzed, providing quick entry into synthetically useful
4-substituted or 4,5-disubstituted cyclohexenones.5,6 Upon
further consideration of the early results and the model put
forth to explain the observed enantioselectivity, we hypoth-
esized that although the enol ether moiety may enhance the
reactivity of the diene (by raising the HOMO energy), it is
unlikely to play a role in the enantiodifferentiation (Figure
1). The crucial factor favoring one of the two possible endo
Scheme 1. Eantioselective Diels-Alder Reaction between
1-Aminobutadiene and Methacrolein
Figure 1. Proposed transition states for the facial selectivity.
transition states appeared to be the steric interaction between
the axial hydrogens in the salen diaminocyclohexane and
the alkyl group on the carbamate moiety. This analysis
endo diastereomer (4a) in quantitative yield after 21 h.
Mosher ester analysis of its reduction product (5a) established
that the cycloadduct had formed in 93% enantiomeric excess.
The success of this enantioselective cycloaddition represents
a major advance over our previous work. Unlike the earlier
results, adducts such as 4 are not prone to eliminative
hydrolysis to enones, yet they possess varied functionality
that can be elaborated further for natural products synthesis
applications.
The above chiral salen-catalyzed DA reaction was found
to be remarkably general. We have examined this process
using a variety of dienes and have obtained uniformly good
results, summarized in Table 1. Unlike the low temperature
required for many enantioselective processes, these reactions
(8) The sole example of a Lewis acid-catalyzed enantioselective DA
reaction of a simple amino-substituted diene (i.e., of the Oppolzer-Overman
type) predating our work was that of Evans, who observed high enanti-
oselectivity for the cycloaddition between N-Cbz-amino-1,3-butadiene and
N-acrolyloxazolidinone. The latter is capable of two-point binding to the
chiral catalyst. See: 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, 7582-7594.
(9) After the Evans report, Wipf and Wang reported the same transfor-
mation using Kobayashi’s scandium catalyst: Wipf, P.; Wang, X. Tetra-
hedron Lett. 2000, 41, 8747-8751.
(10) The antibody-catalyzed enantioselective DA reaction of 1-amine-
substituted dienes has been reported: (a) Romesberg, F. E.; Spiller, B.;
Schultz, P. G.; Stevens, R. C. Science 1998, 279, 1929-1933. (b) Heine,
A.; Stura, E. A.; Yli-Kauhaluoma, J. T.; Gao, C.; Deng, Q.; Beno, B. R.;
Houk, K. N.; Janda, K. D.; Wilson, I. A. Science 1998, 279, 1934-1940.
(11) (a) Oppolzer, W.; Fro¨stl, HelV. Chim. Acta 1975, 58, 587-589. (b)
Oppolzer, W.; Fro¨stl, HelV. Chim. Acta 1975, 58, 590-593. (c) Oppolzer,
W.; Fro¨stl, W.; Weber, H. P. HelV. Chim. Acta 1975, 58, 593-595. (d)
Overman, L. E.; Clizbe, L. A. J. Am. Chem. Soc. 1976, 98, 2352-2354.
(e) Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J. Org. Chem.
1978, 43, 2164-2167. (f) Oppolzer, W.; Bieber, L.; Francotte, E.
Tetrahedron Lett. 1979, 4537-4540, and references therein. See also: (g)
Terada, A.; Murata, K. Bull. Chem. Soc. Jpn. 1967, 40, 1644-1649.
(12) The synthetic significance of the present work stems from the paucity
of enantioselective DA reactions of amine-substituted butadienes and the
demonstrated usefulness of 1-aminobutadiene Diels-Alder reactions in
natural product synthesis. See reports cited in ref 3. See also: (a) Chigr,
M.; Fillion, H.; Rougny, A. Tetrahedron Lett. 1987, 28, 4529-4532. (b)
Chigr, M.; Fillion, H.; Rougny, A.; Berlion, M.; Riondel, J.; Beriel, H.
Chem. Pharm. Bull. 1990, 38, 688-691.
(13) For leading references of (salen)Cr(III) catalyst, see: (a) Larkworthy,
L. F.; Nolan, K. B.; O’Brien, P. In ComprehensiVe Coordination Chemistry;
Wilkinson, G., Ed.; Pergamon: Oxford, 1987; Vol. 3, Chapter 35.4.8. (b)
Mart´ınez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am.
Chem. Soc. 1995, 117, 5897-5898. (c) Tokunaga, M.; Larrow, J. F.;
Kakiuchi, F.; Jacobsen, E. N. Science 1997, 227, 936-938. (d) Larrow, J.
F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 7420-
7421 and references cited therein.
(14) Cr(III)-(salen) catalyst was used in enantioselective hetero-Diels-
Alder reactions by Jacobsen: Schaus, S. E.; Brånalt, J.; Jacobsen, E. N. J.
Org. Chem. 1998, 63, 403-405.
(15) Welker has reported the use of Jacobsen’s salen as a stoichiometric
chiral auxiliary for dienes: Chapman, J. J.; Day, C. S.; Welker, M. E. Eur.
J. Org. Chem. 2001, 2273-2282 and references therein.
1164
Org. Lett., Vol. 4, No. 7, 2002

Table 1. Enantioselective Diels-Alder Reaction with Various
1-Aminobutadienes
Table 2. Temperature Effect on Reaction Rate and
Enantioselectivity
entry
diene
temp
time
yielda (%)
ee (%)
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
rt
rt
rt
rt
1 h
2 h
6 h
21 h
26 h
3 d
22 h
3.5 d
24 h
3.5 d
74 (100)
85 (100)
94 (100)
99
94
85 (94)
95
70 (91)
96
87 (91)
93
93
93
93
95
97
89
92
79
85
yield
ee
entrya diene R1
R2
R3 R4 R5 time prod st(%)b (%)d
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Bn
MeO
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
21 h 4a
24 h 4b
22 h 4c
23 h 4d
25 d 4e
22 h 4f
99
95
96
99
93
89
79
92
Alkyl MeO
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
MeO
t-BuO
Me
MeO Me
MeO Ph
MeO
MeO
MeO Me
0 °C
-20 °C
rt
-20 °C
rt
-20 °C
85 (95)c 91
94
93
5 d
15 h 4h
4i
Me 9.5 d 4j
4g
63 (78)c 93
H
H
93
95
Me 4 d
81 (97)c 95
40 (93)c 92
10
10
2j
a Isolated yields. Yields in parentheses are based on recovered starting
materials.
a Reactions were carried out at room temperature in CH2Cl2 (1.0 M)
with 2 equiv of methacrolein, 5 mol % of catalyst 1, and oven-dried 4 Å
sieves (0.8 g/mmol of diene 2). b Isolated yield based on 2. c Yield based
on recovered starting material. d Determined by NMR analysis of a Mosher
ester derivative.
cycloadditions have been consistently good, they can be
improved by carrying out the reactions at a lower temper-
ature. Thus, when the above reaction was carried out at 0
°C, the product was formed with 95% ee (26 h, 94% yield,
entry 5). The ee increased to 97% at -20 °C, but the reaction
did not go to completion, even after 3 days (entry 6). The
same improvement in ee was observed for two other dienes
(entries 7-10).
A final example highlights the capability of the salen-
catalyzed DA reaction. Diene 2a reacted under the standard
conditions with tiglic aldehyde (6), a trisubstituted dienophile,
to afford the expected endo adduct (7) in good yield and
high ee (Scheme 2). The effectiveness of the salen catalyst
were carried out at room temperature. In every case, none
of the exo diastereomer was discernible in the NMR of the
crude reaction mixture. Consistent with our previous obser-
vations, the size of the alkyl group on the nitrogen (R1)
correlated with the enantioselectivity of the product. The
N-allyl and N-methyl dienes (entries 2 and 3) gave cyclo-
adducts with lower ee’s than the N-benzyl diene. The size
of R2 appears not to be important for high enantioselectivity
(entries 4 and 5). Both the tert-butyl carbamate (2d) and the
acetamide (2e) dienes gave the corresponding adducts in high
yields and ee’s. The longer reaction time for the latter is
understandable given the stronger electron withdrawing
ability of the acetyl group compared to the alkoxycarbonyl
group.
Dienes with substituents at the 2-, 3-, or 4-positions were
good substrates for this reaction (entries 6-10). Dienes
possessing a substituent at the 2-position were measurably
less reactive than the other dienes (entries 9 and, 10).
Presumably, 1,3-allylic strain twists the carbamate group out
of planarity with the conjugated diene, rendering it less
electron-rich. Although sluggish, these reactions were clean
and gave high ee’s, and the yields based on recovered starting
material were above 90%. The reduced reactivity of the
phenyl-substituted diene can be attributed to a combination
of steric and electronic effects (entry 7). The rates, and hence
the yields, of several of these reactions could be increased
by slightly raising the reaction temperature.
Scheme 2. Enantioselective Diels-Alder Reaction of
1-Aminobutadiene and Tiglic Aldehyde
in all these reactions is noteworthy since both the diene and
the DA product possess carbamate groups, the carbonyl
oxygens of which are expected to be more Lewis basics
hence better ligandssthan that from the dienophile.
The present study has uncovered the immense potential
of the enantioselective Diels-Alder reaction of 1-amino-
substituted butadienes and R-substituted acroleins catalyzed
by Jacobsen’s chiral Cr(III)-salen complex. The reactions
are conveniently performed, remarkably tolerant of substit-
uents at different positions of the diene framework, and afford
cycloadducts with almost complete endo-selectivity in good
The cycloadditions described here proceed at a good rate
(Table 2). When the reaction between diene 2a and meth-
acrolein was quenched after only 1 h, the product was
obtained in 74% isolated yield, with complete recovery of
the unreacted diene (entry 1). The product yield rose to 85%
after 2 h and to 94% after 6 h (entries 2 and 3). The ee of
the product of each experiment was the same as that obtained
for the 21 h reaction (entry 4). While the ee’s of the
Org. Lett., Vol. 4, No. 7, 2002
1165

yields and high ee’s. This simple process provides ready
access to richly functionalized cyclohexenylamines possess-
ing a quaternary chiral center. The application of this
chemistry to complex targets is currently under investigation.
Research Laboratories and Pfizer Inc. are also gratefully
acknowledged for financial support.
Supporting Information Available: Preparation of Cr-
(III)-salen catalysts, general experimental procedure for
Diels-Alder reactions, and spectroscopic data and specific
rotations of new cycloadducts. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the
National Institutes of Health (R01-GM-55998). Y.H. thanks
Abbott Laboratories for a Graduate Fellowship. Merck
OL0255716
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Org. Lett., Vol. 4, No. 7, 2002