Direct organocatalytic asymmetric heterodomino reactions: The Knoevenagel/Diels-Alder/epimerization sequence for the highly diastereoselective synthesis of symmetrical and nonsymmetrical synthons of benzoannelated centropolyquinanes

Article abstract of DOI:10.1021/jo049581r

Amino acids and amines have been used to catalyze three component hetero-domino Knoevenagel/Diels-Alder/epimerization reactions of readily available various precursor enones (1a-1), aldehydes (2a-p), and 1,3-indandione (3). The reaction provided excellent

Full text of DOI:10.1021/jo049581r

Dir ect Or ga n oca ta lytic Asym m etr ic Heter od om in o Rea ction s: Th e
Kn oeven a gel/Diels-Ald er /Ep im er iza tion Sequ en ce for th e High ly
Dia ster eoselective Syn th esis of Sym m etr ica l a n d Non sym m etr ica l
Syn th on s of Ben zoa n n ela ted Cen tr op olyqu in a n es
D. B. Ramachary, K. Anebouselvy, Naidu S. Chowdari, and Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La J olla, California 92037
carlos@scripps.edu
Received March 12, 2004
Amino acids and amines have been used to catalyze three component hetero-domino Knoevenagel/
Diels-Alder/epimerization reactions of readily available various precursor enones (1a -l), aldehydes
(2a -p ), and 1,3-indandione (3). The reaction provided excellent yields of highly substituted,
symmetrical and nonsymmetrical spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones (5) in a highly
diastereoselective fashion with low to moderate enantioselectivity. The Knoevenagel condensation
of arylaldehydes (2a -p ) and 1,3-indandione (3) under organocatalysis provided arylidene-1,3-
indandiones (17) in very good yields. We demonstrate for the first time amino acid- and amine-
catalyzed epimerization reactions of trans-spiranes (6) to cis-spiranes (5). The mechanism of
conversion of trans-spiranes (6) to cis-spiranes 5 was shown to proceed through a retro-Michael/
Michael reaction rather than deprotonation/reprotonation by isolation of the morpholine enamine
intermediate of cis-spirane (22). Prochiral cis-spiranes (5a b) and trans-spiranes (6a b) are excellent
starting materials for the synthesis of benzoannelated centropolyquinanes. Under amino acid and
amine catalysis, the topologically interesting dispirane 24 was prepared in moderate yields.
Organocatalysis with pyrrolidine catalyzed a series of four reactions, namely the Michael/retro-
Michael/Diels-Alder/epimerization reaction sequence to furnish cis-spirane 5a b in moderate yield
from enone 1a and 1,3-indandione 3.
In tr od u ction
materials.2 Domino reactions have gained wide accep-
tance because they increase synthetic efficiency by
decreasing the number of laboratory operations required
and the quantities of chemicals and solvents used. Thus,
these reactions can facilitate ecologically and economi-
cally favorable syntheses.
Recently organocatalysis has emerged as a promising
synthetic tool for constructing C-C, C-N, and C-O
bonds in aldol,3 Michael,4 Mannich,5 Diels-Alder,6 and
related reactions7 in highly diastereo- and enantioselec-
tive processes. In these recently described reactions,
structurally simple and stable chiral organoamines fa-
cilitate iminium- and enamine-based transformations
with carbonyl compounds. Often, the organocatalysts can
be used in operationally simple and environmentally
friendly experimental protocols. Because these reactions
Critical objectives in modern synthetic organic chem-
istry include the improvement of reaction efficiency, the
avoidance of toxic reagents, the reduction of waste, and
the responsible utilization of our resources. Domino or
tandem reactions, which consist of several bond-forming
reactions, address many of these objectives. Domino
reactions involve two or more bond-forming transforma-
tions that take place under the same reaction conditions.
Combinations of reactions involving the same mechanism
are classified as homodomino reactions, whereas a se-
quence of reactions with different mechanisms are clas-
sified as heterodomino reactions.1 One of the ultimate
goals in organic synthesis is the catalytic asymmetric
assembly of simple and readily available precursor
molecules into stereochemically complex products, a
process that ultimately mimics biological synthesis. In
this regard, the development of domino and other mul-
ticomponent reaction methodologies can provide expedi-
ent access to complex products from simple starting
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* To whom correspondence should be addressed. Fax: +1-858-784-
2583.
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809.
10.1021/jo049581r CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/06/2004
5838
J . Org. Chem. 2004, 69, 5838-5849

Organocatalytic Heterodomino K-DA-E Reactions
SCHEME 1. Or ga n oca ta lytic Heter od om in o K-DA-E Rea ction of 4-Su bstitu ted 3-Bu ten -2-on es 1a -l,
Ald eh yd es 2a -p , a n d 1,3-In d a n d ion e 3
share common mechanistic features they may be linked
to create one-pot and domino reaction schemes (assembly
reactions). To date, we have described asymmetric as-
sembly reactions involving aldol-aldol,3c,d Michael-
aldol,7d Mannich-cyanation,5d Mannich-allylation,5f am-
ination-aldol,7g and Knoevanagel-Michael4a reactions.
Recently, we reported two interesting domino reactions
founded on Knoevenagel/Diels-Alder reaction sequences.
The first was the direct organocatalytic asymmetric
domino Knoevenagel/Diels-Alder reaction sequence to
accomplish the diastereo- and enantioselective construc-
tion of highly substituted spiro[5.5]undecane-1,5,9-
triones.6a The second was the direct organocatalytic,
hetero-domino, Knoevenagel/Diels-Alder/epimerization
sequence to prepare symmetric prochiral and highly
substituted spiro[cyclohexane-1,2′-indan]-1′,3′,4-triones
(5) in diastereospecific fashion from commercially avail-
able 4-substituted 3-buten-2-ones (1), aldehydes (2), and
1,3-indandione.6b Herein, we report the first direct orga-
nocatalytic asymmetric hetero-domino Knoevenagel/Di-
els-Alder/epimerization (K-DA-E) reaction sequence to
generate highly substituted spiro[cyclohexane-1,2′-in-
dan]-1′,3′,4-triones (5) in a highly diastereoselective and
modestly enantioselective process from commercially
available 4-substituted-3-buten-2-ones (1a -l), aldehydes
(2a -p ), and 1,3-indandione (3) as shown in Scheme 1.
Spirocyclic ketones (5) are attractive intermediates in the
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J . Org. Chem, Vol. 69, No. 18, 2004 5839

Ramachary et al.
CHART 1. Ben zoa n n ela ted Cen tr op olyqu in a n es
synthesis of natural products and in material chemistry
and are the excellent starting materials for the synthesis
of fenestranes8 (centrotriindane and centrotetraindanes),
topologically nonplanar hydrocarbon centrohexaindane,
and other frameworks bearing the [5.5.5.5]fenestrane
core as shown in Chart 1. Fenestrindanes with 8-fold
peripheral functionalization could serve as unusual
motifs for liquid crystal engineering and dendrimer
chemistry and for the construction of graphite cuttings
bearing a saddle-like, three-dimensionally distorted core.8
Resu lts a n d Discu ssion
We envisioned that amino acids 4a -e and simple
amines 4f-j (Chart 2) would act as organocatalysts of
the Knoevenagel condensation of aldehydes 2a -p with
1,3-indandione 3 to provide arylidene indandiones 17a -
p . There is ample precedence for amine-catalyzed Kno-
evenagel reactions.9 2-Arylideneindan-1,3-diones (17) are
attractive compounds in medicinal and material chem-
istry. For example, substituted 2-arylideneindan-1,3-
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5840 J . Org. Chem., Vol. 69, No. 18, 2004

Organocatalytic Heterodomino K-DA-E Reactions
CHART 2. Scr een ed Or ga n oca ta lysts for th e
K-DA-E Rea ction
F IGURE 1. Dienes and dienophiles generated under orga-
nocatalysis.
SCHEME 2. Or ga n oca ta lytic Kn oeven a gel
Con d en sa tion
In these three component organocatalytic K-DA-E
reactions, the Knoevenagel condensation generates reac-
tive dienophiles that can be readily isolated from the
reaction mixture. For example, reaction of 4-nitroben-
zaldehyde 2a and 1,3-indandione 3 in methanol at
ambient temperature under L-proline or pyrrolidine
catalysis furnished the expected 2-(4-nitro-benzylidene)-
indan-1,3-dione 17a in almost quantitative yield as
shown in Scheme 2. Under similar reaction conditions
with different aromatic aldehydes, a wide variety of
2-arylideneindan-1,3-dione dienophiles (17) were syn-
thesized in very good yields.
Am in o Acid -Ca ta lyzed Dir ect Asym m etr ic Het-
er o-Dom in o K-DA-E Rea ction s. We found that the
three-component reaction of trans-4-phenyl-3-buten-2-one
1a , 4-nitrobenzaldehyde 2a , and 1,3-indandione 3 with
a catalytic amount of L-proline (20 mol %) in methanol
at ambient temperature for 24 h furnished the expected
nonsymmetrical Diels-Alder products 5a a and 6a a Ψ in
86% yield with thermodynamically stable cis-spirane 5a a
as the major isomer, dr 24:1 (Table 1, entry 1) (ΨIn all
compounds denoted 5xy and 6xy, x is incorporated from
reactant enones 1 and y is incorporated from the reactant
aldehydes 2.) Unfortunately, the enantiomeric excess (ee)
of the major cis-spirane 5a a was only 5%. Interestingly,
the same reaction with an extended reaction time fur-
nished cis-spirane 5a a as a single diastereomer in 96%
yield, however with 3% ee (Table 1, entry 2). The minor
diastereomer, trans-spirane 6a a , was effectively epimer-
ized to the thermodynamically stable cis-spirane 5a a
under prolonged reaction time via proline catalysis. The
stereochemistry of products 5a a and 6a a was established
by NMR analysis.16
diones 17 derivatives show antibacterial activites,10
nonlinear optical properties,11 electroluminescent de-
vices,12 and are useful as eye lens clarification agents.13
The arylidene indandiones are very good organic Lewis
acids14 (OLA) with low energy LUMO configurations and
are useful as heterodienes and Michael acceptors in
cycloaddition reactions.15 Here, we have utilized arylidene
indandiones 17 as dienophiles in Diels-Alder chemistry.
As dienophiles, 17a -p undergo [4 + 2] cycloaddition
reactions with 2-amino-1,3-butadienes 18a -l generated
in situ from enones 1a -l and amino acids or amines to
generate substituted spiro[cyclohexane-1,2′-indan]-1′,3′,4-
triones 5 and 6 in a diastereoselective manner (Figure
1). Epimerization of the minor diastereomer trans-
spirane 6 to the more stable cis-spirane 5 occurred under
the same reaction conditions. This domino Knoevenagel/
Diels-Alder reaction generates a quaternary carbon
center with formation of three new carbon-carbon σ
bonds via organocatalysis.
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19960412 Heisei. Patent written in J apanese.
In the three-component hetero-domino K-DA-E reac-
tion of enone 1a , 4-nitrobenzaldehyde 2a , and 1,3-
indandione 3 catalyzed directly by L-proline, we found
that the solvent (dielectric constant) and temperature
had a significant effects on reaction rates, yields, dr’s,
and ee’s (Table 1). The hetero-domino K-DA-E reaction
catalyzed by L-proline at ambient temperature in aprotic/
nonpolar solvents produced products 5a a and 6a a in low
(13) Aziz, A. B. M. S. A.; Mohamed, E. S. Eur. Pat. Appl. 1992, 14
pp. CODEN: EPXXDW EP 489991 A1 19920617. Patent written in
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(16) Stereochemistries of the cis- and trans-spiranes were estab-
lished using COSY experiments and were also based on MOPAC
calculations of the thermodynamic equilibration between the two
isomers (see the Supporting Information).
J . Org. Chem, Vol. 69, No. 18, 2004 5841

Ramachary et al.
TABLE 1. Effect of Solven t a n d Am in o Acid on th e Dir ect Am in o Acid Ca ta lyzed Asym m etr ic Heter od om in o K-DA-E
Rea ction of 1a , 2a , or 2b a n d 3a
catalyst
(20 mol %)
solvent
(0.5 M)
drc
(cis/trans)
eed
(cis/trans)
entry
aldehyde
T (°C)
time (h)
products
yieldb (%)
1
2
3
4
5
6
7
8
9
10e
11e
12e
13
14e
15
16e
17
18
19
20
21
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4d
4e
4a
4a
4a
4a
4a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
MeOH
25
25
25
25
25
25
25
25
25
4
25
4
25
4
25
25
25
25
70
25
25
24
96
96
120
120
120
96
96
72
96
96
96
96
96
36
46
24
98
2
5a a , 6a a
5a a
86
98
95
54
63
e5
80
45
62
18
e10
e5
68
40
92
19
87
96
96
53
55
24:1
g99:1
30:1
2.8:1
1:1
5/-
3/-
MeOH
DMSO
THF
CHCl3
C6H6
[bmim]BF4
[bmim]PF6
MeOH
MeOH
THF
5a a , 6a a
5a a , 6a a
5a a , 6a a
5a a , 6a a
5a a , 6a a
5a a , 6a a
5a a , 6a a
5a a , 6a a
5a a , 6a a
5a a , 6a a
5a a
5a a , 6a a
5a a
5a a , 6a a
5a b, 6a b
5a b
1/-
18/15
13/6
34:1
1.5:1
8.5:1
1.3:1
1:1.4
1/-
6/7
17/-
30/3
42/6
THF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
[bmim]BF4
[bmim]PF6
g99:1
1.6:1
g99:1
1:1
9/-
17/4
2/-
14/13
2:1
g99:1
g99:1
1:2
5a b
5a b, 6a b
5a b, 6a b
24
96
1:2
a
Experimental conditions: amino acid (0.1 mmol), 4-nitrobenzaldehyde 2a or benzaldehyde 2b (0.5 mmol), and 1,3-indandione 3 (0.5
mmol) in solvent (1 mL) were stirred at ambient temperature for 30 min then benzylidene acetone 1a (1 mmol) was added (see the
b
Experimental Section). Yield refers to the purified product obtained by column chromatography. c Ratio based on isolated products (1H
d
and 13C NMR analysis). Enantiomeric excesses determined by using chiral-phase HPLC. e 60-80% of unreacted Knoevenagel product
17a was isolated.
to moderate yields with poor diastereoselectivity (Table
1, entries 4-6, 11, and 12). Enantioselectivity improved
in aprotic/nonpolar solvents (Table 1, entries 4-6, 11, and
12). Excellent yields, good diastereoselectivity, and poor
enantioselectivity were observed in protic/polar solvents
(Table 1, entries 1-3). For example, the K-DA-E reaction
in THF furnished spiranes 5a a and 6a a in 54% yield with
dr of 2.8:1 and with ee of 18% for the major cis-spirane
5a a and an ee of 15% for the minor trans-spirane 6a a
(Table 1, entry 4). The same reaction using ionic liquid
[bmim]BF4, a “green solvent”, catalyzed by L-proline at
25 °C furnished the thermodynamically stable product
cis-spirane 5a a as the major diastereomer in 80% yield
with dr of 34:1, albeit with a low ee value of 1% (Table 1,
entry 7). Interestingly, the same reaction under proline
catalysis in ionic liquid [bmim]PF6 at 25 °C furnished
the spiranes 5a a and 6a a in 45% yield with dr of 1.5:1
and with ee of 6% (cis-spirane) and 7% (trans-spirane)
(Table 1, entry 8). In the hetero-domino K-DA-E reaction
under L-proline catalysis, diastereoselectivity was directly
affected by the nature of the solvent (dielectric constant)
as reflected in the epimerization reaction and exo/endo
selectivity. Rates of organocatalytic reactions catalyzed
by amino acids were faster in protic/polar solvents than
in nonprotic/nonpolar solvents presumably due to en-
hanced stabilization of charged intermediates and more
facile proton-transfer reactions. This is especially true
for the epimerization reaction where the dr’s of the
produces obtained using protic/polar solvents were very
high.
asymmetric three-component Diels-Alder (ATCDA) re-
action of 1a , 2a , and Meldrum’s acid.6a Among the
catalysts screened in the ATCDA reaction, the 5,5-
dimethyl thiazolidinium-4-carboxylate (DMTC) proved to
be the most efficient catalyst with respect to yield and
ee. When DMTC was tested in the K-DA-E reaction of
1a , 2a , and 3 in methanol at 25 °C for 72 h, the domino
products 5a a and 6a a were obtained in 62% yield with
dr of 8.5:1 and ee of the major cis-spirane 5a a of 17%
(Table 1, entry 9). The same reaction under DMTC
catalysis at reduced temperature (4 °C) in methanol for
96 h furnished products 5a a and 6a a in 18% yield with
a dr of 1.3:1. Under these conditions, the ee of the major
cis-spirane 5a a was 30% and ee for the minor trans-
spirane 6a a was 3% (Table 1, entry 10). With DMTC
catalysis in THF as solvent at 25 °C, products 5a a and
6a a were obtained in poor yields (e10%) with dr of 1:1.4
and ee for the minor cis-spirane of 42%, while the ee for
the major trans-spirane of 6% (Table 1, entry 11). DMTC-
catalyzed K-DA-E reaction in THF at 4 °C for 96 h
furnished the domino products in very poor yields (Table
1, entry 12). An imidazoline-type catalyst, 4-benzyl-1-
methylimidazolidine-2-carboxylic acid 4c, also catalyzed
the K-DA-E reaction with moderate yield, very good dr,
and low ee at 25 °C and moderate to low yield, and poor
dr with improved ee at 4 °C (Table 1, entries 13 and 14).
trans-3-Hydroxy-L-proline 4d catalyzed the domino K-
DA-E reaction of 1a , 2a , and 3 with very good yield and
excellent diastereoselectivity, but the ee was poor (Table
1, entry 15). trans-4-Hydroxy-L-proline 4e also catalyzed
the domino K-DA-E reaction of 1a , 2a , and 3 but reaction
yield (19%), dr (1:1), and ee (14 and 13) were poor (Table
1, entry 16). While the Knoevenagel product 17a was
formed and consumed in most of the amino acid-catalyzed
heterodomino K-DA-E reactions, in some reactions (Table
Next we probed the structure and reactivity relation-
ships among a family of amino acids and pyrrolidine-
based catalysts by monitoring the reaction yields, dr’s,
and ee values of the hetero-domino K-DA-E reaction and
compared them to the results of the organocatalytic
5842 J . Org. Chem., Vol. 69, No. 18, 2004

Organocatalytic Heterodomino K-DA-E Reactions
Am in e-Ca t a lyzed Dir ect Het er od om in o K-DA-E
Rea ction s. Amines 4f-j can also catalyze the hetero-
domino K-DA-E reaction under different solvent and
temperature conditions. The three-component hetero-
domino K-DA-E reaction of trans-4-phenyl-3-buten-2-one
1a , 4-nitrobenzaldehyde 2a , and 1,3-indandione 3 with
a catalytic amount of chiral diamine, (S)-1-(2-pyrrolidi-
nylmethyl)-pyrrolidine 4f, in methanol at ambient tem-
perature for 24 h furnished the domino product 5a a as a
single diastereomer in 79% yield but with very poor ee
(Table 2, entry 1). The bifunctional acid/base catalyst17
4g, the trifluoroacetic acid salt of diamine 4f, also
catalyzed the heterodomino K-DA-E reaction of 1a , 2a ,
and 3 in DMSO at ambient temperature to furnish the
expected domino products 5a a and 6a a in 71% yield with
dr of 13.5:1, but with poor ee (Table 2, entry 2). Since
enantioselection in these reactions was typically unsat-
isfactory, we studied the simple achiral amine pyrrolidine
4h and found that it furnished cis-spirane 5a b as a single
diastereomer in 90% yield (Table 2, entry 3). Further we
found that pyrrolidine catalysis was not dramatically
affected with respect to reaction rates, yields, or dr’s by
solvent and temperature modification (Table 2). Under
pyrrolidine catalysis, the heterodomino K-DA-E reaction
worked well in a variety of solvents and the optimal
conditions involved mixing equimolar amounts of enone
1a , aldehyde 2b, and 1,3-diketone 3 in methanol with
heating to 70 °C for 1 h to furnish cis-spirane 5a b as a
single diastereomer in 95% yield (Table 2, entry 9).
Interestingly, the six-membered cyclic amines piperidine
(4i) and morpholine (4j) also catalyzed the heterodomino
K-DA-E reaction. Typically, pyrrolidine-based catalysts
are much more effective than six-membered cyclic amines
as organocatalysts and six-membered cyclic amines are
extremely poor catalysts of aldol reactions.3b The reaction
of enone 1a , aldehyde 2b, and 1,3-diketone 3 under
piperidine 4i catalysis in methanol at 70 °C for 4 h
furnished the expected domino products 5a b and 6a b in
71% yield with dr of 43:1 (Table 2, entry 10). Under the
same conditions, morpholine 4j catalyzed formation of
5a b and 6a b in 46% yield with dr of 18.6:1 (Table 2, entry
11). The pyrrolidine-catalyzed heterodomino K-DA-E
reaction was, however, faster.
F IGURE 2. Asymmetric solvation in the ionic liquids.
1, entries 10, 11, 12, 14, and 16) unreacted 17a was
isolated in 60-80% yield. Unreacted 17a was the result
of a very slow rate of the formation of the key intermedi-
ate 2-amino-1,3-butadiene and subsequent Diels-Alder
reaction under these conditions.
The L-proline-catalyzed three-component hetero-dom-
ino K-DA-E reaction of trans-4-phenyl-3-buten-2-one 1a
and 1,3-indandione 3 with a different aldehyde, benz-
aldehyde 2b, furnished products 5a b and 6a b in 87%
yield with dr of 2:1 (Table 1, entry 17). The same reaction,
albeit with an extended reaction time, furnished prochiral
cis-spirane 5a b as a single diastereomer in 96% yield
(Table 1, entry 18). The stereochemistry of products 5a b
and 6a b was established by NMR analysis. The minor
diastereomer, trans-spirane 6a b was effectively epimer-
ized to the thermodynamically stable cis-spirane 5a b
under prolonged reaction time via proline catalysis.
Increasing the reaction temperature to 70 °C facilitated
the epimerization reaction and furnished the expected
domino product 5a b as a single diastereomer in 96% yield
within 2 h. Interestingly the same reaction in the ionic
liquids, [bmim]BF4 and [bmim]PF6, catalyzed by L-proline
at ambient temperature provided the kinetic product
trans-spirane 6a b as the major diastereomer in moderate
yield (Table 1, entries 20 and 21). In these reactions,
enantioselectivity for the minor kinetic product 6a b was
poor. cis-Spirane 5a b has been used as a synthon for the
synthesis of variety of benzoannelated centropolyquinanes
as shown in Chart 1.8
cis-Spirane 5a b is obtained via an endo-transition state
in the classical Diels-Alder route. In ionic liquids,
however, the kinetic product, trans-spirane 6a b, was the
major isomer formed. This is likely due to a unique
organization of the ionic liquid solvent with the 2-amino-
1,3-butadiene 18a and dienophile 17b in the transition
states as shown in Figure 2. Asymmetric solvation in the
ionic liquids then produces a steric hindrance with the
phenyl group on the dienophile in the endo-transition
state, thereby disfavoring it. In the case of dienophile
17a , the high epimerization rate of trans-spirane 6a a
provides cis-spirane 5a a as the major isomer (Table 1,
entries 7 and 8). Ratio of exo/endo products in ionic
liquids or other solvents mainly depend on four factors,
which are (i) substrate effect (electronic factor), (ii) protic
solvent effect (polarization factor), (iii) steric hindrance
induced by ionic solvation, and (iv) basic nature of organo
catalyst.
Or ga n oca ta lytic Ep im er iza tion of tr a n s-Sp ir a n e
6 to cis-Sp ir a n e 5. Epimerization of trans-spirane 6 or
the diastereospecific synthesis of cis-spirane 5 in the
heterodomino K-DA-E reaction of enone 1, aldehyde 2,
and 1,3-indandione 3 can be explained as illustrated in
Scheme 3. Amino acid or amine-catalyzed Knoevenagel
condensation9 of aldehyde 2 with 1,3-indandione 3 pro-
vides the arylidene-indandione 17 via the in situ gener-
ated reactive cationic imine 16. Arylideneindandione 17
then undergoes a concerted [4 + 2] cycloaddition or a
double-Michael reaction with the soft nucleophile, 2-amino-
1,3-butadiene 18 generated in situ from enone 1 and the
amino acid or amine catalyst, to produce products 5 and
6. The energy difference (∆H) between the two isomers
(17) (a) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2003, 5,
4369. (b) Spencer, T. A.; Neel, H. S.; Ward, D. C.; Williamson, K. L. J .
Org. Chem. 1966, 31, 434. (c) Woodward, R. B. Pure Appl. Chem. 1968,
17, 519. (d) Hajos, Z. G.; Parrish, D. R. J . Org. Chem. 1974, 39, 1612.
(e) Greco, M. N.; Maryanoff, B. E. Tetrahedron Lett. 1992, 33, 5009.
(f) Snider, B. B.; Yang, K. J . Org. Chem. 1990, 55, 4392.
J . Org. Chem, Vol. 69, No. 18, 2004 5843

Ramachary et al.
TABLE 2. Effect of Solven t a n d Am in e on th e Dir ect Am in e-Ca ta lyzed Asym m etr ic Heter od om in o K-DA-E Rea ction of
1a , 2a or 2b, a n d 3a
catalyst
(20 mol %)
solvent
(0.5 M)
yieldb
(%)
drc
(cis/trans)
eed
(cis/trans)
entry
aldehyde
T (°C)
time (h)
products
1
2
3
4
5
6
7
8
9e
10
11
4f
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
MeOH
DMSO
MeOH
MeOH
THF
CHCl3
DMSO
DMF
25
25
25
70
25
25
24
25
70
70
70
24
39
8
0.75
7
5a a
5a a , 6a a
5a b
5a b
5a b
5a b
5a b
5a b
5a b
79
71
90
90
85
70
75
80
95
71
46
g99:1
13.5:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
43:1
1
3
4g
4h
4h
4h
4h
4h
4h
4h
4i
7
70
24
1
4
4
MeOH
MeOH
MeOH
5a b, 6a b
5a b, 6a b
4j
18.6:1
a
Experimental conditions: amines 4f,g (0.1 mmol), 4h -j (0.15 mmol), 4-nitrobenzaldehyde 2a or benzaldehyde 2b (0.5 mmol), and
1,3-inandione 3 (0.5 mmol) in solvent (1 mL) were stirred at ambient temperatures for 30 min, then benzyl acetone 1a (1 mmol) was
b
added (see the Experimental Section). Yield refers to the purified product otabined by column chromatography. c Ratio based on isolated
d
products (1H and 13C NMR analysis). Enantiomeric excesses determined by using chiral-phase HPLC. e Enone 1a , benzealdehyde 2b
and 1,3-indandione 3 were used in 0.5 mmol scale.
SCHEME 3. P r op osed Ca ta lytic Cycle for th e
L-P r olin e (or Am in o Acid or Am in e) Ca ta lyzed
Heter od om in o K-DA-E Rea ction s
SCHEME 4. P r op osed Mech a n ism for th e L-P r olin e
(Am in o Acid or Am in e) Ca ta lyzed Ep im er iza tion of
tr a n s-Sp ir a n e 6 to cis-Sp ir a n e 5
thermodynamically more stable cis-isomers 5a a and 5a b,
respectively, at room temperature under mild organo-
catalysis. Epimerization of trans-spiranes 6 to cis-spi-
ranes 5 was favored not only by thermodynamic consid-
erations but also electronic effects.18 The minor kinetic
isomer trans-spirane 6 was epimerized to the thermody-
namically stable cis-spirane 5 via deprotonation/repro-
tonation or retro-Michael/Michael reactions catalyzed by
amino acid or amine. This is in agreement with the
previously proposed retro-Michael/Michael reaction mech-
anism19 at the epimerization step as shown in Scheme
4.
5a a and 6a a is 5.626 kcal/mol based on AM1 and 4.114
kcal/mol based on PM3 calculations. The energy differ-
ence (∆H) between the two isomers of 5a b and 6a b is
6.158 kcal/mol based on AM1 and 5.680 kcal/mol based
on PM3 calculations. Minimized structures of 5a a , 6a a ,
5a b, and 6a b are depicted in the Supporting Information.
Since the differences in ∆H’s between the two isomers
of 5a a /6a a and 5a b/6a b are greater than 5 kcal/mol, the
minor kinetic isomers 6a a and 6a b are epimerized to the
The rate of the epimerization was also related to the
nucleophilic strength of the amino acid or amine catalyst,
(18) Zalukaev, L. P.; Anokhina, I. K.; Aver’yanova, I. A. Dokl. Akad.
Nauk SSSR 1968, 181, 103.
(19) (a) Shternberg, I. Y.; Freimanis, Ya. F. Zh. Org. Khim. 1970,
6, 48. (b) Rowland, A. T.; Filla, S. A.; Coutlangus, M. L.; Winemiller,
M. D.; Chamberlin, M. J .; Czulada, G.; J ohnson, S. D. J . Org. Chem.
1998, 63, 4359.
5844 J . Org. Chem., Vol. 69, No. 18, 2004

Organocatalytic Heterodomino K-DA-E Reactions
SCHEME 5. Or ga n oca ta lytic Ep im er iza tion of
tr a n s-Sp ir a n e 6 to cis-Sp ir a n e 5
significantly faster than that catalyzed by proline. No
epimerization was observed in the absence of catalyst.
To further probe the epimerization mechanism we
sought to study the intermediate enamine of cis-spirane
22. A mixture of cis- and trans-spiranes 5a a and 6a a (1.5:
1) was treated with morpholine in the presence of
catalytic amount of p-TSA under reflux in toluene for 30
min to furnish the enamine of the epimerized cis-spirane
22. NMR analysis of the unpurified mixture showed
features of the enamine (Scheme 6). We studied the
morpholine derived enamine because morpholine en-
amine hydrolysis is slower than that of pyrrolidine or
L-proline enamines.19 Attempted purification of the enam-
ine 22 by flash column chromatography on silica gel
resulted in the formation of the hydrolysis product, cis-
spirane 5a a , in quantitative yield.
Syn th esis of Non sym m etr ica l cis-Sp ir a n es. We
further explored the scope of the L-proline and pyrrolidine
catalyzed hetero-domino K-DA-E reactions with various
arylaldehydes (2a -p ) and 4-substituted-3-buten-2-ones
(1a -l). Each of the targeted spirotriones 5 was obtained
as single diastereomers in excellent yields. In this case,
even though the enantioselectivities are poor, L-proline
was used as catalyst as it is available at reasonable cost.
The L-proline-catalyzed heterodomino K-DA-E reactions
of trans-4-phenyl-3-butene-2-one 1a , various arylalde-
hydes (2a -p ) and 1,3-indandione 3 in methanol at 25
°C for 96 h furnished the expected cis-spiranes in good
yields with high diastereoselectivity as shown in Table
3. None of these nonsymmetrical cis-spiranes were known
in the literature. Various arylaldehydes with different
electron-donating or -withdrawing groups, as well as
heteroaromatic aldehydes furnished the spiranes without
the loss of diastereoselectivity. Interestingly, the hetero-
domino K-DA-E reaction of enone 1a , 4-methoxybenz-
aldehyde 2c, and 1,3-indandione 3 furnished the expected
cis-spirane in 6:1 diastereomeric ratio. In this case, the
epimerization rate of trans-spirane 6a c to cis-spirane 5a c
was slower than with other substrates and so the
diastereoselectivity was poor. Reaction of an arylaldehyde
bearing an electron-donating p-hydroxy substitute fur-
nished cis-spirane 5a f in very good yield and a surpris-
ingly high dr (Table 3, entry 3). Likewise, arylaldehydes
with electron withdrawing substituents such as o-nitro,
p-chloro, p-cyano, and p-methoxycarbonyl also furnished
the cis-spiranes 5a h , 5a g, 5a i, and 5a j with high di-
astereoselectivities. The heterodomino K-DA-E reaction
of heteroaromatic aldehydes, 2-furanaldehyde, and
2-thiophenaldehyde furnished spiranes 5a l and 5a m with
reaction temperature, and nature of the solvent. Epimer-
ization rate of trans-spirane 6 to cis-spirane 5 in protic/
polar solvents under amino acid catalysis was faster than
that in aprotic/nonpolar solvents (Table 1). But under
amine catalysis, the nature of the solvent did not have
much effect on the epimerization rate. In protic/polar
solvents, stabilization of the highly reactive ionic species
generated in the reaction media by hydrogen bonding or
dipolar-dipolar interactions enhanced the reaction rate.
As shown in Scheme 4, the amino acid or amine reacts
with cyclohexanone 6 to generate the enamine 19. The
retro-Michael reaction to form the ring-opened imine/
enolate 20 should be accelerated by hydrogen bonding
with protic/polar solvents. Imine/enolate 20 then under-
goes Michael reaction to form the enamine of the ther-
modynamically stable cis-spirane 21, which undergoes
hydrolysis in situ to furnish cis-spirane 5.
Epimerization of trans-spiranes 6a a and 6a b to cis-
spiranes 5a a and 5a b, respectively, was confirmed in
studies of the L-proline and pyrrolidine-catalyzed reaction
in methanol at ambient temperature (Scheme 5). The
epimerization reaction catalyzed by pyrrolidine was
SCHEME 6
J . Org. Chem, Vol. 69, No. 18, 2004 5845

Ramachary et al.
TABLE 3. L-P r olin e-Ca ta lyzed Heter od om in o K-DA-E Rea ction s of tr a n s-4-P h en yl-3-bu ten -2-on e 1a , Va r iou s Ald eh yd es
2a -o, a n d 1,3-In d a n d ion e 3 in Meth a n ol a t 25 °C for 96 h a
a
Experimental conditions: L-proline (0.1 mmol), aldehyde 2a -o (0.5 mmol), and 1,3-indandione 3 (0.5 mmol) in methanol (1 mL) was
b
stirred at ambient temperature for 30 min, and then benzylidine acetone 1a (1.0 mmol) was added (see the Experimental Section). 20%
of unreacted dienophiles are isolated. c Reaction was performed under pyrrolidine catalysis at 60 °C for 2 h. This product was accompanied
by unexpected product cis-sprirane 5a b (16%) and Knoevenagel product 17n (25%) (see the Experimental Section).
good to moderate yields but with moderate diastereo-
selectivities due to slow epimerization rates. Reaction of
1H-pyrrole-2-carboxyaldehyde 2n with 1a and 3 under
L-proline catalysis did not furnish the expected domino
product, but under pyrrolidine catalysis at 60 °C for 2 h
furnished the domino product 5a n in 30% yield with high
dr. This domino product 5a n was accompanied by an
unexpected product, cis-spirane 5a b, in 16% yield and
unreacted Knoevenagel product 17n in 25% yield. For-
mation of unexpected product 5a b in above reaction will
be considered in the next section. Reaction of R,â-
unsaturated aldehyde, trans-C6H4-CHdCH-CHO 2p
with 1a and 3 under L-proline catalysis also furnished
the expected domino product 5a o in good yields with high
dr.
astereospecifically in very good yields as shown in Table
4. Various trans-4-aryl-3-buten-2-ones and aryl aldehydes
with different substituents on the aromatic ring (ranging
from the electron-donating groups such as p-methoxy,
m,p-methylenedioxy, p-dimethylamino, and p-hydroxy
and electron-withdrawing groups such as p-chloro, p-
nitro, p-cyano, and p-methoxycarbonyl) and also the
heteroaromatic counterparts furnished the expected cis-
spiranes (5) in good yields with high diastereospecificity.
The chloro-, cyano-, and methoxycarbonyl-substituted cis-
spiranes 5gg, 5ii, and 5jj are potentially interesting
intermediates for materials chemistry as they can be
readily manipulated. Thus, numerous arylaldehydes and
various enones are readily reacted under either L-proline
or pyrrolidine catalysis to generate a library of highly
functionalized cis-spiranes (5) (Tables 3 and 4).
Syn th esis of P r och ir a l Sym m etr ica l cis-Sp ir a n es.
Pyrrolidine catalyzed, hetero-domino K-DA-E reactions
of trans-4-aryl-3-butene-2-ones (1a -l), arylaldehydes
(2a -p ), and 1,3-indandione 3 in methanol at 70 °C for
Syn th esis of High ly Su bstitu ted cis-Sp ir a n es. To
prepare highly substituted dispiranes, we used an aryl-
dialdehyde instead of a simple arylaldehyde. Thus, the
heterodomino K-DA-E reaction of terephthalaldehyde 2p ,
1-2
h furnished the expected cis-spiranes 5 di-
5846 J . Org. Chem., Vol. 69, No. 18, 2004

Organocatalytic Heterodomino K-DA-E Reactions
TABLE 4. P yr r olid in e-Ca ta lyzed Heter od om in o K-DA-E Rea ction s of Va r iou s tr a n s-4-Ar yl-3-bu ten -2-on es 1a -l,
Ar yla ld eh yd es 2a -o, a n d 1,3-In a n d ion e 3 in Meth a n ol a t 70 °C for 1-2 h a
a
Experimental conditions: pyrrolidine (0.15 mmol), aldehyde 2a -o (0.5 mmol), and 1,3-inandione 3 (0.5 mmol) in methanol (1 mL)
was stirred at ambient temperature for 30 min, and then arylidene acetone 1a -l (0.5 mmol) was added (see the Experimental Section).
Reaction conversion is 50% only.
b
a dialdehyde, with trans-4-phenyl-3-butene-2-one 1a and
indandione 3 catalyzed by L-proline or pyrrolidine fur-
nished the cis-spiranealdehyde 23 and the dispirane 24
as well as the unexpected product 5a b as shown in Table
5. When L-proline was used as a catalyst, incubation of
the reaction at 25° C for 96 h furnished products 23 and
24 in 16% and 18% yield, respectively (Table 5, entry 1),
while the same reaction performed at 25 °C for 24 h and
40 °C for 48 h resulted in the formation of 23 and 24 in
60% and 18% yield, respectively (Table 5, entry 2). Under
L-proline catalysis, the unexpected product 5a b did not
form. The reaction catalyzed by pyrrolidine at 70 °C for
2 h furnished the dispirane 24 and the unexpected
product 5a b in 15% and 45% yield, respectively (Table
5, entry 3). The identity of dispirane 24 was confirmed
by proton, 13C NMR, and mass analysis. We had previ-
ously observed that the domino product 5a b was also
formed unexpectedly in the hetero-domino K-DA-E reac-
tion of enone 1a , aldehyde 2n and 1,3-indandione 3 under
pyrrolidine catalysis with 16% yield (Table 3, entry 11).
To investigate the formation of the unexpected product
5a b, the reaction was carried out without the aldehyde.
Pyrrolidine catalyzed the reaction of trans-4-phenyl-3-
buten-2-one 1a with 1,3-indandione 3 in methanol at 70
°C for 5 h to furnish the cis-spirane 5a b and the
Knoevenagel product 17b in 28% and 8% yield, respec-
tively, as shown in Scheme 7. The mechanism of forma-
tion of the unexpected product cis-spirane can be ex-
plained as shown in Scheme 7. First, the Michael addition
of indandione 3 to trans-4-phenyl-3-buten-2-one 1a takes
place to generate the adduct 25, which can then undergo
a retro-Michael reaction in one of two ways. The retro-
Michael reaction can either regenerate the starting
materials 3 and 1a or generate acetone and the Knoev-
enagel product 17b. Compound 17b undergoes a Diels-
Alder reaction with trans-4-phenyl-3-buten-2-one 1a to
furnish the mixture of cis- and trans-spiranes 5a b and
6a b as described earlier. Finally, epimerization of the
trans-spirane 6a b takes place to furnish the cis-spirane
5a b. Thus the mechanism of formation of the unexpected
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Ramachary et al.
SCHEME 7. P yr r olid in e-Ca ta lyzed Dir ect Mich a el/Retr o-Mich a el/Diels-Ald er /Ep im er iza tion Rea ction of
En on e 1a a n d 1,3-In d a n d ion e 3 in Meth a n ol a t 70 °C
SCHEME 8. Ap p lica tion of cis-Sp ir a n es 5 in th e Syn th esis of Ben zoa n n ela ted Cen tr op olyqu in a n es
product 5a b involves four steps: a Michael reaction, a
retro-Michael reaction, a Diels-Alder reaction, and
finally an epimerization reaction.
Ap p lica tion of cis-Sp ir a n es 5. Prochiral cis-spiranes
5 are very useful starting materials in the synthesis of
benzoannelated centropolyquinanes. Prochiral cis-spirane
5a b and trans-spirane 6a b have served as useful syn-
thons in the synthesis of fenestranes.8 Kuck and co-
workers have reported the synthesis of a highly strained
centrotetracyclic framework of fenestranes starting from
cis- and trans-spiranes 5a b and 6a b. In their study, the
cis-spirane 5a b was converted to all-cis-[5.5.5.5]fenes-
5848 J . Org. Chem., Vol. 69, No. 18, 2004

Organocatalytic Heterodomino K-DA-E Reactions
TABLE 5. Syn th esis of High ly Su bstitu ted
groups such as chloro, cyano, and methoxycarbonyl
should allow for the development of a rich chemistry by
extension of the peripheral functional groups. Thus,
dendrimers, liquid crystals and poly-condensed ring
systems with saddle-like molecular structures may be
synthesized using the synthons described here.
cis-Sp r ir a n esa
Con clu sion s
The results presented here demonstrate amino acid or
an amine-based organocatalysis of three different reac-
tions in a single pot. This astonishingly simple and atom-
economic approach can be used to construct highly
functionalized symmetric and nonsymmetric spiro[cyclo-
hexane-1,2′-indan]-1′,3′,4-triones (5) in a diastereospecific
fashion. Selective multistep reactions of this type inspire
analogies to biosynthetic pathways and compliment
traditional multicomponent synthetic methodologies. Fur-
ther improvements with respect to the enantioselectivity
of these reactions might be accessible through the
screening or design of novel catalysts. As we have
suggested previously, the synthesis of polyfunctionalized
molecules under organocatalysis provides a unique and
under-explored perspective on prebiotic synthesis. A
complete understanding of the scope of organocatalysis
should not only empower the synthetic chemist but also
provide a new perspective on the origin of complex
molecular systems.
yieldb (%)
catalyst
(30 mol %)
entry
T (°C)
25
25 f 40
70
time (h)
23
24
5a b
1
2
3
4a
4a
4h
96
24 f 48
2
16
60
18
18
15
45
a
Experimental conditions: L-proline 4a or pyrrolidine 4h (0.15
mmol), terephthalaldehyde 2p (0.5 mmol), and 1,3 indandione 3
(1.0 mmol) in methanol (1 mL) were stirred at ambient temper-
ature for 30 min, and then benzylidine acetone 1a (1.0 mmol) was
Ack n ow led gm en t. This study was supported in
part by the NIH (CA27489) and the Skaggs Institute
for Chemical Biology.
b
added (see the Experimental Section). Yield refers to the purified
product obtained by column chromatography.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data (1H NMR, 13C NMR, and mass) for all new compounds
and details of experimental procedures. Copies of 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
trane 7 in nine synthetic steps as depicted in Scheme 8.
The dispirane 24 could serve as a suitable synthon for
the synthesis of topologically interesting difenestranes
26 and 27. Fenestranes containing reactive functional
J O049581R
J . Org. Chem, Vol. 69, No. 18, 2004 5849