Organocatalytic asymmetric domino Knoevenagel/Diels-Alder reactions: A bioorganic approach to the diastereospecific and enantioselective construction of highly substituted spiro [5,5]undecane-1,5,9-triones

Article abstract of DOI:10.1002/anie.200351916

A practical and environmentally friendly organocatalytic process for the synthesis of optically active highly substituted spiro[5,5]undecane-1,5,9-triones was achieved through the reaction of an aldehyde, an enone, and Meldrum's acid in the presence of a catalytic amount of chiral amino acid (see scheme). The Diels-Alder products were obtained as single diastereomers in excellent yields and enantiomeric excesses.

Full text of DOI:10.1002/anie.200351916

Angewandte
Chemie
Diels–Alder reactions of a,b-unsaturated ketones with nitro
olefins.[5a]
In continuation of our interest in organocatalytic assem-
bly or multicomponent reactions,[2c,d,4c,6e] we herein report the
first organocatalytic diastereospecific and enantioselective
direct asymmetric domino Knoevenagel/Diels–Alder reac-
tions that produce highly substituted spiro[5,5]undecane-
1,5,9-triones 5 from commercially available 4-substituted-3-
buten-2-ones 1a–e, aldehydes 2a–d, and 2,2-dimethyl-1,3-
dioxane-4,6-dione (Meldrum's acid, 3; Scheme 1). Spirocyclic
ketones 5 are attractive intermediates in the synthesis of
natural products and in medicinal chemistry,[7] and are the
starting materials for the synthesis of exotic amino acids
which are used to modify the physical properties and bio-
logical activities of peptides, peptidomimetics, and proteins.[8]
In our reaction we envisioned that an amino acid would
catalyze the domino Knoevenagel condensation[9] of aldehyde
2 with Meldrum's acid 3 to provide the alkylidene derivative
of Meldrum's acid, which would then undergo a concerted
[4+2] cycloaddition with a 2-amino-1,3-butadiene generated
in situ from enone 1 and an amino acid to form substituted
Organocatalytic Domino Reactions
Organocatalytic Asymmetric Domino
Knoevenagel/Diels–Alder Reactions: A
Bioorganic Approach to the Diastereospecific and
Enantioselective Construction of Highly
Substituted Spiro[5,5]undecane-1,5,9-triones**
D. B. Ramachary, Naidu S. Chowdari, and Carlos
F. Barbas III*
One of the ultimate goals in organic chemistry is the catalytic
asymmetric assembly of simple and readily available precur-
sor molecules into stereochemically complex products. In this
regard, the Diels–Alder reaction is one of the most powerful
synthetic methodologies for the construction of cyclic six-
membered rings, and tremendous efforts have been directed
to expand the scope of this cycloaddition reaction with
various combinations of dienes, dienophiles, catalysts, and
reaction conditions.[1] Recently organocatalysis has emerged
spiro[5,5]undecane-1,5,9-triones 5 in a highly enantioselective
and diastereospecific manner.[10] The domino Knoevenagel/
Diels–Alder reaction would then generate a quaternary
center with formation of three new carbon–carbon s bonds
through amino acid catalysis. This proposal was reflective of
the pioneering studies of Tietze and Beifuss[11a,b] and our
recent disclosure of the first direct asymmetric Knoevenagel/
Michael reactions with ketones, aldehydes, and malonates
involving alkylidene malonates generated under organoca-
talysis that subsequently react as electrophiles with ketone-
derived enamines also generated under organocatalysis.[3a] In
contrast to this early study where asymmetric induction was
compromised by the use of the cyclic malonate Meldrum's
acid, the alkylidene derivative of Meldrum's acid proved to be
more efficient in the Diels–Alder reaction than the alkylidene
formed from alkyl malonates.
À
À
as a promising synthetic tool for constructing C C and C N
bonds in aldol,[2] Michael,[3] Mannich,[4] Diels–Alder,[5] and
related reactions[6] with high diastereoselectivity and enan-
tioselectivity. Structurally simple and stable chiral organo-
amines typically facilitate iminium- and enamine-based trans-
formations with carbonyl compounds and may be used as
catalysts in operationally simple, and in some cases environ-
mentally friendly, experimental protocols. Previously we
extended our studies of organoamine-catalyzed aldol,[2a–d]
Michael,[3a,b] Mannich,[4a–f] and related reactions[6c,e] founded
on enamine catalysis, and reported the first direct asymmetric
We were pleased to find that the three-component
reaction of trans-4-phenyl-3-buten-2-one (1a), 4-nitrobenzal-
dehyde (2a), and Meldrum's acid (3) with a catalytic amount
of l-proline in methanol at ambient temperature furnished
the Diels–Alder product 5aa as a single diastereomer in 85%
yield with 60% ee after 48 h (Table 1, entry 6). This product
was accompanied by an unexpected symmetric spirocyclic
ketone 6aa in 7% yield.[12] The stereochemistry of products
5aa and 6aa was established by NMR analysis.
[*] Prof. Dr. C. F. Barbas III, Dr. D. B. Ramachary, Dr. N. S. Chowdari
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2583
E-mail: carlos@scripps.edu
[**] This study was supported in part by the National Institutes of
Health (CA27489) and the Skaggs Institute for Chemical Biology.
We thank Dr. Raj K. Chadha for X-ray structural analysis.
In the asymmetric three-component Diels–Alder
(ATCDA) reaction of 1a, 2a, and 3 catalyzed directly by l-
proline, we found that the solvent (dielectric constant) had a
Supporting information (experimental procedures and analytical
data for all new compounds) for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200351916
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Scheme 1. Amino acid catalyzed asymmetric, three-component Diels–Alder reactions.
Table 1: Effect of solvent on the direct amino acid catalyzed ATCDA reaction of 1a, 2a, an d3.[a]
Entry
Amino acid
Solvent
Dielectric constant [e]
t [h]
Products
Yield [%][b]
Ratio[c] 5aa:6aa
ee for 5aa [%][d]
1
2
3
4
5
6
7
8
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
thiaproline
thiaproline
dl-proline
C6H6
CHCl3
THF
CH2Cl2
C2H5OH
CH3OH
CH3CN
[bmim]BF4
n-C3H7OH
iso-C3H7OH
(S)-CH3CHPhOH
2.3
4.8
7.6
8.9
25
33
38
–
72
72
72
72
48
48
72
24
96
96
96
5aa
5aa
5aa
5aa
5aa, 6aa
5aa, 6aa
5aa
ꢀ10
24
70
35
95
92
65
95
70
65
71
100:0
100:0
100:0
100:0
18:1
nd[e]
71
65
59
38
60
9
12:1
100:0
100:0
20:1
20:1
100:0
5aa
6
9
21.8
18.3
13
5aa, 6aa
5aa, 6aa
5aa
19
39
37
10
11[f]
[a] Experimental conditions: Amino acid (0.1 mmol) was added to a stirred solution of enone (1 mmol), 2a (0.5 mmol), and 3 (0.5 mmol) inthe
solvent (1 mL) at ambient temperature (see Supporting Information). [b] Yield refers to the purified product obtained by column chromatography.
[c] Ratio based on isolated products. [d] Enantiomeric excesses determined by using chiral-phase HPLC. [e] not determined. [f] In this reaction,
0.75 mL of (S)-1-phenylethanol was used.
significant effect on the rates, yields, and ee values (Table 1).
These results indicated that the domino Knoevenagel/Diels–
Alder reaction catalyzed by l-proline produces products 5aa
and 6aa[12] with low yields and good ee values in aprotic
nonpolar solvents (Table 1, entries 2–4) and with excellent
yields and good to moderate ee values in protic solvents
(Table 1, entries 5 and 6). The same reaction in the ionic
liquid [bmim]BF4 (bmim = 1-butyl-3-methylimidazolium)
provided 5aa in 95% yield, albeit with a low ee value of
6% (Table 1, entry 8). The rates of both the Knoevenagel and
Diels–Alder reactions catalyzed by l-proline were faster in
protic/polar solvents than in nonprotic/nonpolar solvents
presumably because of enhanced stabilization of charged
intermediates and more-facile proton-transfer reactions. The
transition state of the bimolecular Diels–Alder reaction is
also effected by protic/polar solvents through hydrogen
bonding.[1d,e]
To understand the role of solvent in this reaction aldehyde
2a, Meldrum's acid (3), and enone 1a were reacted in the
chiral solvent (S)-1-phenylethanol, under dl-proline catalysis.
The expected spiro product 5aa was obtained in 71% yield,
with an ee value of 37% (Table 1, entry 11). Thus, asymmetric
induction can be effected by interactions with a chiral solvent.
This finding supports a potential role of intermolecular
hydrogen bonding, in standard achiral solvents, as a conduit
for both transmission of chiral information from the prolyl-2-
amino-1,3-butadiene and catalysis by lowering the activation
barrier in a diastereotopic bimolecular Diels–Alder transition
state. Intermolecular hydrogen bonding with the solvents
serves these roles in the chiral protic solvent.
Next we probed the structure and reactivity relationships
among a family of 19 pyrrolidine-based catalysts by monitor-
ing the reaction yields and ee values of the ATCDA reaction
of 1a, 2a, and 3 in methanol (Table 2). The structurally simple
amine pyrrolidine catalyzed the ATCDA reaction to produce
5aa in 14% yield and 6aa in 17% yield (Table 2, entry 1). An
imidazoline-type catalyst also catalyzed the ATCDA reaction
(Table 2, entry 15). Among the catalysts screened, 5,5-
dimethyl thiazolidinium-4-carboxylate (DMTC) proved to
be the most efficient catalyst with respect to yield, and
provided 5aa in 88% yield and 86% ee (Table 2, entry 11),
which is significantly better than l-proline in both respects
(Table 2, entry 17). The overall structure/activity relationship
garnered from the catalyst screen of the ATCDA reaction was
similar to that which we reported for the aldol,[2b] with optimal
yield and enantioselectivity being provided by pyrrolidine-
amines substituted at the a-position with an acid functionality,
that is, proline-like catalysts. Notable improvement in the
enantioselectivity of the reaction beyond l-proline catalysis
was found in the ATCDA reactions catalyzed by l-thiapro-
line, L-DMTC, and trans-4-hydroxy-l-proline. These amino
acids catalyze the preferential addition of the in situ gener-
ated benzylidene derivative of Meldrum's acid 8 to the exo
face of the in situ generated 2-amino-1,3-butadiene. It should
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Table 2: Effect of the structure/reactivity of the amino acid on the direct amino acid catalyzed ATCDA reaction of 1a, 2a, an d3 inmethanol at 25 8C.[a]
Entry
Amine
t [h]
Yield [%][b]
ee for 5aa [%][c]
Entry
Amine
t [h]
Yield [%][b]
ee for 5aa [%][c]
5aa
6aa
5aa
6aa
1
48
120
72
14
10
56
17
–
11
12
13
72
84
96
88
65
50
trace
86
89
91
2
8
41
45
trace
4
3[d]
12
4
5
72
96
80
12
13
17
24
68
14
84
96
84
64
trace
14
76
70
15[e]
6
7
8
120
120
96
12
10
23
17
9
65
32
35
16
17
18
19
72
48
84
72
–
–
7
–
85
70
80
60
60
34
trace
trace
trace
9
48
40
7
34
17
40
60
10
120
[a] See Supporting Information. [b] Yield refers to the column purified product. [c] Enantiomeric excesses were determined by using chiral-phase
HPLC. [d] Reactionwas performed inTHF. [e] Reactionperformed at 4 8C.
be noted that l-DMTC was also found to be generally more
efficient than l-proline in aldol reactions involving aromatic
acceptors.[2b]
amino-1,3-butadiene 12, which undergoes a diastereospecific
Diels–Alder reaction with dienophile 8 to furnish the ketone
6aa. Regeneration of acetone and formation of prochiral
ketone 6aa were confirmed by the pyrrolidine-catalyzed
reaction between 2a and 3 in methanol (Scheme 3).
We further explored the scope of the DMTC-catalyzed
ATCDA reaction with various aldehydes 2a–d and enones
1a–e. The spirotriones 5 were obtained as single diastereo-
mers with good yields and excellent ee values together with
the accompanying corresponding acetals 7[13] in low yields.
The reaction of benzaldehyde (2c), piperonal (2d), and
Meldrum's acid (3) with enones 1a and 1b furnished the
prochiral spirotriones 5ac and 5bd, respectively, in excellent
yields (Table 3, entry 1and 2). In the same manner, the
reaction of para-substituted benzaldehydes 2a–b and Mel-
drum's acid (3) with a variety of enones 1a–e in methanol
Formation of the unexpected symmetric triketone 6aa in
the reaction of 1a, 2a, and 3 can be explained as shown in
Scheme 2. Amine-catalyzed Knoevenagel condensation of 2a
with 3 provides the 4-nitrobenzelidene derivative of Mel-
drum's acid 8, which undergoes a Diels–Alder or a double
Michael reaction with the soft nucleophilic 2-amino-1,3-
butadiene generated in situ from enone 1a and an amine to
produce product 5aa. Otherwise the in situ generated hard
nucleophile methoxide (MeOÀ) can react with 8 to regenerate
acetone; the yield of this regeneration will depend on the
basicity of the amine catalyst. Acetone undergoes amine-
catalyzed aldol condensation with aldehyde 2a to furnish
enone 11, which reacts with an amine to form reactive 2-
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furnished the spirotriones 5 as
single diastereomers in good
yields with excellent ee values
together with the corresponding
acetals 7 in low yields (Table 3).
Formation of acetals
7
from
ketones 5 is most likely the result
of acid or base catalysis of the
bifunctional acid/base catalyst
DMTC in methanol. Spirotrione
5bd should be an attractive start-
ing material for the synthesis of
endothelin receptor antagonists.[7d]
The
diastereoselective
ATCDA reaction of a,b-unsatu-
rated ketone 1a and Meldrum's
acid (3) with chiral aldehyde (R)-
2,2-dimethyl-[1,3]dioxolane-4-car-
baldehyde (13) in methanol at
room temperature produced the
expected Diels–Alder product
acetal 14 and ketone 15 as the
major products (Scheme 4). Thus,
optically pure aldehydes can be
used to effect diastereoselective
synthesis of chiral, substituted
cyclohexanones under organoca-
talysis.
The absolute configuration of
product 5aa prepared under
DMTC catalysis was established
by using X-ray crystallography.[14]
Product 5aa was obtained as color-
less, block-shaped crystals from
hexane-chloroform. Crystalliza-
tion enriched the ee value to
99%. On the basis of X-ray struc-
tural analysis and AM1calcula-
tions we propose a transition state
for the DMTC-catalyzed direct
ATCDA reaction (Figures 1and
2).
Scheme 2. Proposed reaction mechanism for the formation of the unexpected product: prochiral
cyclohexanone 6aa.
Scheme 3. Formationof prochiral spirocyclic ketone 6aa from 4-nitrobenzaldehyde (2a) an d
Meldrum's acid (3).
In summary, we have devel-
oped the first direct ATCDA reac-
tion catalyzed by an amino acid.
This experimentally simple and
environmentally friendly approach
can be used to construct highly
Scheme 4. Proline-catalyzed diastereoselective three-component Diels–
Alder reaction of enone 1a and Meldrum's acid (3) with chiral aldehyde 13.
Table 3: Direct DMTC-catalyzed ATCDA reactionof different aldehydes 2a–d and enones 1a–e with
Meldrum's acid (3).[a]
substituted
spiro[5,5]undecane-
1,5,9-triones in a diastereospecific
and enantioselective fashion.
Selective reactions of this type
inspire analogies with enzyme-cat-
alyzed reaction and compliment
traditional Diels–Alder reactions.
As we have suggested previously,
the synthesis of polyfunctionalized
molecules under organocatalysis
Entry
Enone
Aldehyde
t [h]
Products
Yield [%][b]
Ratio 5:7
ee for 5 [%][c]
1[d]
2[d]
3
4
5
1a
1b
1a
1a
1c
1d
1e
2c
2d
2a
2b
2a
2a
2a
96
96
72
96
72
72
72
5ac, 7ac
5bd
5aa, 7aa
5ab, 7ab
5ca
85
99
95
85
93
92
80
16:1
>100:1
13:1
16:1
>100:1
12:1
prochiral
prochiral
86
84
99
88
99
6
7
5da, 7da
5ea, 7ea
15:1
[a] See Supporting Information. [b] Yield of the combined isolated products. [c] Enantiomeric excesses
were determined using chiral-phase HPLC. [d] Reaction catalyzed by l-proline (0.1 mmol).
provides a unique and under-
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Figure 1. Proposed transition state for the DMTC-catalyzed ATCDA
reactionbased onAM1 calculations.
[6] a) Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615; b) U.
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Figure 2. X-ray crystal structure of chiral spiro[5,5]undecane-1,5,9-
trione 5aa.
explored perspective on prebiotic synthesis. Given the
efficiency of the organocatalysis of the Diels–Alder reaction,
consideration should be given to the utilization of these types
of reaction mechanisms in extant biological systems.
[9] a) R. Tanikaga, N. Konya, K. Hamamura, A. Kaji, Bull. Chem.
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(Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, chap.
1.11, p. 341.
Received: May 16, 2003 [Z51916]
[10] For stoichiometric Diels–Alder reactions using iminium acti-
vated dienophiles, see M. E. Jung, W. D. Vaccaro, K. R. Buszek,
Tetrahedron Lett. 1989, 30, 1893; for stoichiometric Diels – Alder
reactions involving chiral 2-amino-1,3-butadienes, see J. Bar-
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4. In both cases, the reaction rates are high but stoichiometric
amounts of chiral amine are required for the additional synthetic
step of preparing the isolable imine or diene.
[11] a) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137; Angew.
Chem. Int. Ed. Engl. 1993, 32, 131; b) L. F. Tietze, Chem. Rev.
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Pharm. Bull. 1982, 30, 3092.
Keywords: amino acids · asymmetric catalysis · cycloaddition ·
domino reactions · enantioselectivity
.
[1] See for example a) D. A. Evans, J. S. Johnson, Comprehensive
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217.
[12] Symmetric ketone 6aa was generated only in alcoholic solvents
and in low yields.
[2] a) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000,
122, 2395; b) K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J.
Am. Chem. Soc. 2001, 123, 5260; c) A. Cordova, W. Notz, C. F.
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Ramachary, A. Cordova, C. F. Barbas III, Tetrahedron Lett.
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Chem. Soc. 2002, 124, 6798.
[3] a) J. M. Betancort, K. Sakthivel, R. Thayumanavan, C. F.
Barbas III, Tetrahedron Lett. 2001, 42, 4441; b) J. M. Betancort,
C. F. Barbas III, Org. Lett. 2001, 3, 3737; c) N. A. Paras, D. W. C.
MacMillan, J. Am. Chem. Soc. 2002, 124, 7894; d) A. Alexakis,
O. Andrey, Org. Lett. 2002, 4, 3611; e) N. Halland, R. G. Hazell,
K. A. Jorgensen, J. Org. Chem. 2002, 67, 8331; f) B. List, C.
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[13] Compounds 7da and 7ea are mixtures of acetal and methyl enol
ethers (see Supporting Information).
[14] Crystal structure data for 5aa: C23H21NO7, Mr = 423.41, mono-
clinic, space group P21/c (No. 14, C2h5), a = 18.571(3), b =
9.6564(16), c = 11.9942(19) Š, a = 90, b = 106.511(3), g = 908,
V= 2062.2(6) Š3, T= 296(2) K, 17946 reflections collected.
CCDC-205429 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
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