The First Organocatalytic Hetero-Domino Knoevenagel-Diels-Alder-Epimerization Reactions: Diastereoselective Synthesis of Highly Substituted Spiro[cyclohexane-1,2′-indan]-1′,3′ ,4-triones

Article abstract of DOI:10.1055/s-2003-41486

L-Proline and pyrrolidine catalyzed the three component hetero-domino Knoevenagel-Diels-Alder-Epimerization reactions of readily available precursors enones 1a-i, arylaldehydes 2a-i and 1,3-indandione 3 to furnish highly substituted prochiral spiro[cycloh

Full text of DOI:10.1055/s-2003-41486

1910
CLUSTER
The First Organocatalytic Hetero-Domino Knoevenagel–Diels–Alder-
Epimerization Reactions: Diastereoselective Synthesis of Highly Substituted
Spiro[cyclohexane-1,2¢-indan]-1¢,3¢,4-triones
The First
O
rganoc
.
a
talytic
HeteB
.venagel–Die
R
ls-Alder–Epimer
a
ization Rea
m
ctions achary, Naidu S. Chowdari, Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California 92037, USA
Fax +1 (858)7842583; E-mail: carlos@scripps.edu
Received 4 June 2003
provide highly substituted prochiral spiro[cyclohexane-
Abstract: L-Proline and pyrrolidine catalyzed the three component
1,2¢-indan]-1¢,3¢,4-triones 5 from commercially available
hetero-domino Knoevenagel–Diels–Alder–Epimerization reactions
4-substituted-3-buten-2-ones 1a–i, aldehydes 2a–i and
1,3-indandione 3 (Scheme 1). Spirocyclic ketones 5 are
of readily available precursors enones 1a–i, arylaldehydes 2a–i and
1,3-indandione 3 to furnish highly substituted prochiral spiro[cyclo-
hexane-1,2¢-indan]-1¢,3¢,4-triones 5a–i in a highly diastereo- attractive intermediates in the synthesis of natural
selective fashion with excellent yields. We demonstrate the first L-
proline and pyrrolidine catalyzed epimerization reactions of trans-
products and in materials chemistry and are the excellent
starting materials for the synthesis of fenestranes, which
spiranes 6a–i to cis-spiranes 5a–i. Prochiral spiranes 5a–i are
could serve as unusual motifs for liquid crystal
excellent starting materials for the synthesis of benzoannelated
engineering and dendrimer chemistry, and for the
centropolyquinanes.
construction of graphite cuttings bearing a saddle-like,
Key words: 2-amino-1,3-butadiene, Diels–Alder reaction, domino
three-dimensionally distorted core.8
reactions, organocatalysis, organic Lewis acid
O
O
One of the ultimate goals in organic chemistry is the
+
+
Ar CHO
Ar
catalytic asymmetric assembly of simple and readily
available precursor molecules into stereochemically com-
plex products. In this regard, the development of domino
and other multicomponent reaction methodologies can
provide expedient access to complex products from
simple starting materials.1 Key to many interesting
variants of these reactions is the incorporation of a Diels–
Alder reaction sequence.2 Recently organocatalysis has
emerged as a promising synthetic tool for constructing
C–C and C–N bonds in aldol,3 Michael,4 Mannich,5
Diels–Alder6 and related reactions7 with high diastereo-
selectivity and enantioselectivity. In these recently
described reactions, structurally simple and stable chiral
organoamines facilitate iminium- and enamine-based
transformations with carbonyl compounds and may be
used as catalysts in operationally simple and in some
cases environmentally friendly experimental protocols.
Extending our studies of organoamine-catalyzed aldol,3a–d
Michael,4a,b Mannich5a–c and related reactions7c,g founded
on enamine catalysis, we reported the first direct asym-
metric Diels–Alder reactions of a,b-unsaturated ketones
with nitro olefins using in situ generated 2-amino-1,3-
butadienes as diene.6a
1
3
2
O
Amino acid (4a)
or
Amine (4b)
Solvent
Ar
Ar
Ar
O
O
O
+
O
O
O
Ar
5
6
Scheme 1 Organocatalytic hetero-domino K–DA-E reaction of
arylidene acetones 1, arylaldehydes 2 and 1,3-indandione 3
In our reaction we envisioned that L-proline (4a) and
pyrrolidine (4b) would catalyze the domino Knoevenagel
condensation of aldehyde 2 with 1,3-indandione 3 to
provide arylidene indandione 8, which would then under-
go a concerted [4+2] cycloaddition with a 2-amino-1,3-
butadiene generated in situ from enone 1 and proline or
pyrrolidine to form substituted spiro[cyclohexane-1,2¢-
indan]-1¢,3¢,4-triones 5 and 6 in a diastereoselective
manner. Epimerization of the minor diastereomer trans-
spirane 6 to the more stable cis-spirane 5 could occur
under the same reaction conditions as shown in Scheme 2.
The domino Knoevenagel–Diels–Alder reaction would
then generate a quaternary center with formation of three
new carbon–carbon s-bonds via organocatalysis. This
proposal was reflective of the pioneering studies of
Tietze1a,b and our recent disclosure of the first direct
asymmetric Knoevenagel–Michael reactions with ke-
tones, aldehydes and malonates involving alkylidene
As part of our program to develop novel organocatalytic
assembly or multicomponent reactions,3c,d,4a,5c,7g herein
we report the first highly diastereoselective
organocatalytic direct hetero-domino Knoevenagel–
Diels–Alder-Epimerization (K–DA-E) reactions that
SYNLETT 2003, No. 12, pp 1910–1914
2
9
.0
9
.2
0
0
3
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41486; Art ID: Y00503ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
The First Organocatalytic Hetero-Domino Knoevenagel–Diels–Alder-Epimerization Reactions
1911
Table 1 Catalyst and Solvent Effect on Organocatalytic Hetero-Domino K–DA-E Reaction of trans-4-Phenyl-3-buten-2-one (1a), Benzalde-
hyde (2a) and 1,3-Indandione (3)a
CO2H
N
H
N
H
H
4a
4b
Entry
Catalyst
Solvent
Temp (°C)
Time (h)
Products
Yield (%)b
Drc
5aa:6aa
1
2
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
CH3OH
CH3OH
CH3OH
[bmim]BF4
[bmim]PF6
CH3OH
CH3OH
THF
24
24
70
24
24
24
70
24
24
24
24
70
24
96
2
5aa, 6aa
5aa
87
96
96
53
55
90
90
85
70
75
80
95
66:33
>100:1
>100:1
33:66
3
5aa
4
24
96
8
5aa, 6aa
5aa, 6aa
5aa
5
33:66
6
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
7
0.75
7
5aa
8
5aa
9
CHCl3
7
5aa
10
11
12d
DMSO
DMF
70
24
1
5aa
5aa
CH3OH
5aa
a Experimental conditions: L-Proline (0.1 mmol) or pyrrolidine (0.15 mmol), benzaldehyde 2a (0.5 mmol) and 1,3-indandione 3 (0.5 mmol) in
the solvent (1 mL) was stirred at ambient temperature for 30 min then enone 1a (1 mmol) was added (see experimental section).
b Yield refers to the purified product obtained by column chromatography.
c Ratio based on NMR analysis of unpurified products.
d Enone 1a, benzaldehyde 2a and 1,3-indandione (3) were all used on a 0.5 mmol scale.
malonates generated under organocatalysis that subse- a significant effect on reaction rates, yields and drs
quently react as electrophiles with ketone derived enam- (Table 1). Our studies revealed that the hetero-domino K–
ines also generated under organocatalysis.4a
DA-E reaction catalyzed by L-proline produces products
5aa and 6aa10 in low yields and poor selectivity in aprotic
nonpolar solvents (results not shown) and with excellent
yields and selectivity in protic/polar solvents (Table 1, en-
tries 1–3). The same reaction in the ionic liquids
[bmim]BF4 and [bmim]PF6 catalyzed by L-proline
provided the kinetic product trans-spirane 6aa as the ma-
jor diastereomer in moderate yield (Table 1, entry 4 and
5).10 Under pyrrolidine catalysis, the hetero-domino K–
DA-E reaction worked well in various solvents and the
optimal conditions involved mixing equimolar amounts
of enone 1a, aldehyde 2a and dione 3 in methanol with
heating to 70 °C for one hour to furnish cis-spirane 5aa as
a single diastereomer in 95% yield.
We were pleased to find that the three-component reaction
of trans-4-phenyl-3-buten-2-one (1a), benzaldehyde 2a
and 1,3-indandione (3) with a catalytic amount of L-
proline in methanol at ambient temperature for 24 hours
furnished Diels–Alder products 5aa and 6aa in 87% yield
with prochiral spirane 5aa as the major isomer (Table 1,
entry 1). The same reaction albeit with an extended
reaction time furnished cis-spirane 5aa as a single
diastereomer in 96% yield (Table 1, entry 2). The minor
diastereomer, trans-spirane 6aa was effectively
epimerized to the thermodynamically stable cis-spirane
5aa under prolonged reaction times via proline catalysis.
Significantly, pyrrolidine also catalyzed the hetero-
domino K–DA-E reaction at ambient temperature to Diastereospecific synthesis of cis-spirane 5aa in the
furnish cis-spirane 5aa as a single diastereomer in 90% reaction of enone 1a, benzaldehyde 2a and 1,3-
yield (Table 1, entry 6). The stereochemistry of products indandione (3) can be explained as illustrated in
5aa and 6aa was established by NMR analysis.9
Scheme 2. Amine-catalyzed Knoevenagel condensation11
of aldehyde 2a with 1,3-indandione (3) provides the
benzylidene-indandione (8a) via imine cation 7a, which is
an excellent organic Lewis acid12 that undergoes a Diels–
Alder or a double Michael reaction with the soft nucleo-
In the three-component hetero-domino K–DA-E reaction
of enone 1a, benzaldehyde 2a and 1,3-indandione (3)
catalyzed directly by L-proline or pyrrolidine, we found
that the solvent (dielectric constant) and temperature had
Synlett 2003, No. 12, 1910–1914 © Thieme Stuttgart · New York

1912
D. B. Ramachary et al.
CLUSTER
O
Epimerization of trans-spirane 6aa to cis-spirane 5aa was
confirmed by the L-proline and pyrrolidine catalyzed re-
action in methanol at ambient temperature (Scheme 4).
The epimerization reaction catalyzed by pyrrolidine was
significantly faster than proline catalysis in methanol. No
epimerization was observed in the absence of catalyst.
H
H+
+
Ar
8
O
O
O
O
Ar
CO2H
1
N
1
H
H2O
Ar
Ph
Ph
O
O
L-Proline
(20 mol%)
3
CO2H
O
O
+
MeOH (0.37 M)
RT, 48 h
∗
∗
N
HO2C
O
O
Ph
99%
Ph
N
H
Ar
9
dr
5aa:6aa = 6:1
dr
5aa:6aa = 2:1
7
HO-
O
O
2
Ph
Ph
O
O
H
Pyrrolidine
(30 mol%)
CO2H
N
H
Ar CHO
Ar
O
O
8
2
Ar
O
O
MeOH (0.1 M)
RT, 0.5 h
99%
∗
∗
O
O
Ph
Ph
O
dr
dr
5aa:6aa = 1:2
5aa:6aa = 10:1
1
2
Knoevenagel Condensation.
Diels-Alder Reaction.
Epimerization.
Ar
Scheme 4 Organocatalytic epimerization of trans-spirane 6aa to
cis-spirane 5aa
3
L-Proline
O
3
Ar
Ar
We further explored the scope of the pyrrolidine catalyzed
hetero-domino K–DA-E reaction with various
arylaldehydes 2b–i and 4-substituted-3-buten-2-ones 1b–
i. Each of the targeted prochiral spirotriones 5 were
obtained as single diastereomers in excellent yields.
Prochiral spiranes 5bb–ii were generated in very good
yields with aromatics bearing either electron withdrawing
or electron donating groups in the para position as shown
in Table 2. The prochiral hetero aromatic cis-spirane 5ii
was also synthesized in good yield under the same
reaction conditions (Table 2, entry 9).
O
O
5
Scheme 2 Proposed catalytic cycle for the L-proline (or pyrrolidine)
catalyzed hetero-domino K–DA–E reactions
phile 2-amino-1,3-butadiene (9a) generated in situ from
enone 1a and the amine catalyst to produce products 5aa
and 6aa. The minor trans-spirane isomer 6aa was epimer-
ized to the thermodynamically stable cis-spirane 5aa via
deprotonation/reprotonation or retro-Michael/Michael
reactions catalyzed by L-proline and pyrrolidine. We fa-
vor the later mechanism, see Scheme 3.
Prochiral cis-spirane 5aa is an excellent starting material
for the synthesis of tetrabenzo[5.5.5.5]fenestrane (fenes-
trindane)8a,h as shown in Scheme 5 and spiranes 5bb–hh
could serve as suitable synthons for the synthesis of
fenestrindanes with fourfold peripheral functionalization.
These functionalized fenestrindanes should provide
materials with a range of physical characteristics.
Ph O
Ph
O
HO2C
L-Proline
O
N
MeOH
RT
In summary, we have developed the first amino acid and
amine catalyzed direct hetero-domino K–DA-E reactions.
This astonishingly simple and atom-economic approach
can be used to construct highly substituted prochiral
spiro[cyclohexane-1,2¢-indan]-1¢,3¢,4-triones 5 in a dias-
tereospecific fashion. A full account detailing asymmetric
variants of this reaction will be forthcoming. Selective
multi-step reactions of this type inspire analogies with
biosynthetic pathways and compliment traditional multi-
component synthetic methodologies. As we have suggest-
ed previously, the synthesis of polyfunctionalized
molecules under organocatalysis provides a unique and
under explored perspective on prebiotic synthesis. A com-
plete understanding of the scope of organocatalysis
should not only empower the synthetic chemist but also
O
Ph
O
Ph
10
6aa
Ph
Ph
O
Ph
Ph
O
HO2C
+ H2O
O
N
O
O
5aa
11
Scheme 3 Proposed mechanism for the L-proline catalyzed epime-
rization of trans-spirane 6aa
Synlett 2003, No. 12, 1910–1914 © Thieme Stuttgart · New York

CLUSTER
The First Organocatalytic Hetero-Domino Knoevenagel–Diels–Alder-Epimerization Reactions
1913
Table 2 Pyrrolidine Catalyzed Hetero-Domino K–DA-E Reactions
of Various trans-4-Aryl-3-buten-2-ones 1a–i, Arylaldehydes 2a–i
and 1,3-Indandione (3) in Methanola
provide a new perspective on the origin of complex mo-
lecular systems.
Entry Ar
1
Products Yield
(%)b
Drc
5:6
Acknowledgment
This study was supported in part by the NIH (CA27489) and the
Skaggs Institute for Chemical Biology.
5aa
93
>100:1
>100:1
References
2
3
5bb
95
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5cc
98
>100:1
NO2
4
5
6
5dd
5ee
5ff
95
95
98
>100:1
>100:1
>100:1
(2) (a) Evans, D. A.; Johnson, J. S. Comprehensive Asymmetric
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OMe
OH
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Cl
O
7
8
5gg
5hh
98
90
>100:1
>100:1
O
N
9
5ii
93
>100:1
S
a Experimental conditions: Pyrrolidine (0.15 mmol), arylaldehydes
2a–i (0.5 mmol) and 1,3-indandione (3) (0.5 mmol) in MeOH (1 mL)
was stirred at ambient temperature for 30 min then arylidene acetones
1a–i (0.5 mmol) was added and heated to 70 °C for 1–2 h (see exper-
imental section).
b Yield refers to the purified product obtained by column chromatog-
raphy.
c Ratio based on NMR analysis of unpurified products.
(5) (a) Notz, W.; Sakthivel, K.; Bui, T.; Barbas, C. F. III
Tetrahedron Lett. 2001, 42, 199. (b) Cordova, A.; Notz, W.;
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O
H
H
H
H
Ref. 8a,h
O
O
5aa
12
all-cis-[5.5.5.5]fenestrane
Scheme 5 Application of cis-spirane 5aa in the synthesis of benzo-
annelated centropolyquinanes
(7) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
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Synlett 2003, No. 12, 1910–1914 © Thieme Stuttgart · New York

1914
D. B. Ramachary et al.
CLUSTER
122.0 (CH), 62.0 (C, C-1 or C-2¢), 48.7 (2 × CH), 43.4
Angew. Chem. Int. Ed. 2002, 41, 1790. (e) List, B. J. Am.
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(2 × CH2). HRMS (MALDI-FTMS): m/z = 381.1492 [M +
H+], calcd for C26H20O3H+ 381.1485. (2b,6a)-2,6-Diphenyl-
spiro[cyclohexane-1,2¢-indan]-1¢,3¢,4-trione(6aa).
C2-Symmetry with twist conformation. 1H NMR (399 MHz,
CDCl3): d = 7.57 (2 H, m), 7.52 (2 H, m), 7.08–6.90 (10 H,
m, 2 × Ph-H), 3.99 (2 H, dd, J = 13.5 and 3.2 Hz, H-2 and 6),
3.62 (2 H, dd, J = 16.3 and 13.5 Hz, H-3b and 5b), 2.78 (2
H, dd, J = 16.7 and 3.2 Hz, H-3a and 5a). 13C NMR (100
MHz, CDCl3): d = 210.0 (C, C=O), 202.8 (2 × C, C=O),
142.0 (2 × C, C-8¢ and 9¢), 137.2 (2 × C), 135.3 (2 × CH,
C-7¢ and 4¢), 128.3 (4 × CH), 128.1 (4 × CH), 127.3
(2 × CH), 122.4 (2 × CH, C-5¢ and 6¢), 61.5 (C, C-1 or 2¢),
43.4 (2 × CH, C-6 and 2), 41.5 (2 × CH2, C-3 and 5). HRMS
(MALDI-FTMS): m/z = 403.1300 [M + Na+], calcd for
C26H20O3Na+ 403.1305.
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(9) General Experimental Procedure for the Preparation of
Prochiral Spiro[cyclohexane-1,2¢-indan]-1¢,3¢,4-triones
by Using L-Proline and Pyrrolidine Catalyzed Hetero-
Domino Knoevenagel–Diels–Alder–Epimerization
Reaction: Method A. In an ordinary glass vial equipped
with a magnetic stirring bar, to 0.5 mmol of the aldehyde and
0.5 mmol of 1,3-indandione was added 1.0 mL of solvent,
and then the catalyst L-proline (0.1 mmol) or pyrrolidine
(0.15 mmol) was added and the reaction mixture was stirred
at ambient temperature for 15–30 min. When the reaction
mixture solidified, more solvent was added, 0.5 mL. Then
0.5 mmol of the enone was added and the reaction stirred at
70 °C for 1–2 h (Table 2). The crude reaction mixture was
treated with saturated aq NH4Cl solution, the layers were
separated, and the organic layer was extracted three to four
times with CH2Cl2 (10 mL), dried with anhyd Na2SO4, and
evaporated. The pure Domino products were obtained by
flash column chromatography (silica gel, mixture of hexane/
EtOAc). Method B. In an ordinary glass vial equipped with
a magnetic stirring bar, to 0.5 mmol of aldehyde, 0.5 mmol
of enone, 0.5 mmol of 1,3-indandione was added 1.0 mL of
solvent, and then the catalyst L-proline (0.1 mmol) or
pyrrolidine (0.15 mmol) was added and the reaction mixture
was heated slowly to 70 °C with stirring for 1–h. the Domino
products were isolated as in Method A. Both methods gave
identical results. (2b,6b)-2,6-Diphenylspiro[cyclohexane-
1,2¢-indan]-1¢,3¢,4-trione(5aa). Plane of symmetry with
chair conformation. 1H NMR (399 MHz, CDCl3): d = 7.64 (1
H, td, J = 7.6 and 1.2 Hz), 7.48 (1 H, m), 7.41 (2 H, m), 7.08–
6.90 (10 H, m, 2 × Ph-H), 3.81 (4 H, m), 2.66 (2 H, ABq,
J = 17.1 Hz). 13C NMR (100 MHz, CDCl3): d = 208.4 (C,
C=O), 203.4 (C, C=O), 201.8 (C, C=O), 142.7 (C, C-8¢),
141.9 (C, C-9¢), 137.3 (2 × C), 135.2 (2 × CH), 128.3
(4 × CH), 128.0 (4 × CH), 127.6 (2 × CH), 122.4 (CH),
(10) Formation of the kinetic product, trans-spirane 6aa as the
major isomer in ionic liquids, as opposed to the cis-spirane
5aa through the endo-transition state in the classical Diels–
Alder route is likely explained by unique solvation in the
ionic liquid of the 2-amino-1,3-butadiene 9a and dienophile
8a in the transition states shown below. Asymmetric
solvation in the ionic liquids may produce a steric hindrance
with the phenyl group on the dienophile, in the endo-
transition state, thereby disfavoring it (Figure 1).
CO2H
N
Ph
O
Endo
Cis-spirane 5aa
Ph
O
H
CO2H
N
Ph
O
Exo
Trans-spirane 6aa
H
O
Ph
= Ionic liquid
Figure 1
(11) (a) Tanikaga, R.; Konya, N.; Hamamura, K.; Kaji, A. Bull.
Chem. Soc. Jpn. 1988, 61, 3211. (b) Tietze, L. F.; Beifuss,
U. The Knoevenagel Reaction, In Comprehensive Organic
Synthesis, Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, Chap. 1.11, 341–392.
(12) (a) Haslinger, E.; Wolschann, P. Bull. Soc. Chim. Belg.
1977, 86, 907. (b) Margaretha, P. Tetrahedron 1972, 28, 83.
Synlett 2003, No. 12, 1910–1914 © Thieme Stuttgart · New York