Towards organo-click chemistry: Development of organocatalytic multicomponent reactions through combinations of aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen cycloaddition reactions

Article abstract of DOI:10.1002/chem.200400597

Here we report on our studies on combinations of amino acids and copper(I) for catalyzing multicomponent reactions (MCRs). We aimed to prepare both diene and dienophiles simultaneously, under very mild and environmentally friendly conditions, thus giving the constituents for a stereocontrolled Diels-Alder reaction, which in turn yields compounds 4 to 8. A diversity-oriented synthesis of polysubstituted spirotriones 4 to 6 were assembled from simple substrates like 1-(triphenylphosphanylidene)-propan-2-one, two aldehydes, and cyclic-1,3-diketones through Wittig/Knoevenagel/Diels-Alder and aldol/Knoevenagel/Diels-Alder reaction sequences in one pot under stereospecific organocatalysis. Chemical diversity libraries of polysubstituted spirotrione-1,2,3-traizoles 8 were assembled from simple substrates by means of Wittig/Knoevenagel/Diels-Alder/Huisgen cycloaddition reaction sequences in one pot under stereospecific organo/Cu^I catalysis. Functionalized dispirolactones such as 6 are biologically active antioxidants and radical scavengers, and spirotrione-1,2,3-traizoles 8 have found wide applications in chemistry, biology, and materials science. Experimentally simple and environmentally friendly, organocatalytic, asymmetric four-component Diels-Alder (AFCDA) reactions of 1-(triphenylphosphanylidene)-propan-2-one, two different aldehydes, and cyclic-1,3-diketones produced diastereospecific and highly enantioselective substituted spirotriones 4 by means of a Wittig/Knoevenagel/ Diels-Alder reaction sequence in one pot. Additionally we have developed an organocatalytic, asymmetric three-component Michael (ATCM) reaction of 1-(triphenylphosphanylidene)-propan-2-one, aldehyde, and cyclic-1,3-diketones that produced Michael adducts 15, 16 through a Wittig/Michael reaction sequence in a highly enantioselective one-pot process.

Full text of DOI:10.1002/chem.200400597

FULL PAPER
Towards Organo-Click Chemistry: Development of Organocatalytic
Multicomponent Reactions Through Combinations of Aldol,Wittig,
Knoevenagel,Michael,Diels–Alder and Huisgen Cycloaddition Reactions
Dhevalapally B. Ramachary and Carlos F. Barbas III*[a]
Abstract: Here we report on our stud-
ies on combinations of amino acids and
copper(i) for catalyzing multicompo-
nent reactions (MCRs). We aimed to
prepare both diene and dienophiles si-
multaneously, under very mild and en-
vironmentally friendly conditions, thus
giving the constituents for a stereocon-
trolled Diels–Alder reaction, which in
turn yields compounds 4 to 8. A diver-
sity-oriented synthesis of polysubstitut-
ed spirotriones 4 to 6 were assembled
from simple substrates like 1-(triphe-
nylphosphanylidene)-propan-2-one,
Chemical diversity libraries of polysub-
stituted spirotrione-1,2,3-traizoles
and environmentally friendly, organo-
catalytic, asymmetric four-component
Diels–Alder (AFCDA) reactions of 1-
(triphenylphosphanylidene)- propan-2-
one, two different aldehydes, and
cyclic-1,3-diketones produced diaster-
eospecific and highly enantioselective
substituted spirotriones 4 by means of
a Wittig/Knoevenagel/Diels–Alder re-
action sequence in one pot. Additional-
ly we have developed an organocatalyt-
ic, asymmetric three-component Mi-
chael (ATCM) reaction of 1-(triphenyl-
phosphanylidene)-propan-2-one, alde-
hyde, and cyclic-1,3-diketones that
produced Michael adducts 15, 16
through a Wittig/Michael reaction se-
8
were assembled from simple substrates
by means of Wittig/Knoevenagel/
Diels–Alder/Huisgen cycloaddition re-
action sequences in one pot under ster-
eospecific organo/CuI catalysis. Func-
tionalized dispirolactones such as 6 are
biologically active antioxidants and
radical scavengers, and spirotrione-
1,2,3-traizoles 8 have found wide appli-
cations in chemistry, biology, and mate-
rials science. Experimentally simple
two aldehydes, and cyclic-1,3-diketones
Keywords:
cycloaddition
reactions
amino
multicomponent
organocatalysis
organo-click reactions
acids
·
through
Wittig/Knoevenagel/Diels–
·
Alder and aldol/Knoevenagel/Diels–
Alder reaction sequences in one pot
under stereospecific organocatalysis.
·
·
quence in
a highly enantioselective
one-pot process.
Introduction
point of view, ideal reaction strategies for preparation of
structurally complex substances would involve sequences in
which stereocontrolled formation of multiple carbon–carbon
bonds occur in a single step starting from simple, readily
available materials. As a result, great attention has been
given to the development of multicomponent reactions
(MCRs), because of their high degree of atom economy,
their applications in combinatorial chemistry, and diversity-
oriented synthesis.[1] Despite intense interest, there are few
reports of diastereo- or enantioselective MCRs for the syn-
thesis of stereochemically complex polycyclic com-
pounds.[1d–f] A key to many interesting MCRs is the incorpo-
ration of a Diels–Alder and Huisgen cycloaddition reaction
sequences to enable construction of complex polycycles in a
completely stereocontrolled manner.[2]
Many organic reactions and reaction sequences have been
developed for the construction of structurally complex poly-
cyclic natural and non-natural products. More typically,
these reactions and reaction sequences are not as efficient
as enzymatic reactions in terms of selectivity (chemo-, regio-,
diastereo-, and enantioselectivity) or in the ecology and
economy of chemical reactions. From the synthetic chemistꢀs
[a] Dr. D. B. Ramachary, Prof. Dr. C. F. Barbas III
Departments of Chemistry and Molecular Biology and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
Recent studies in our laboratory[3] have led to develop-
ment of novel organocatalytic MCRs or asymmetric assem-
bly reactions of simple substrates in one pot, such as organo-
catalytic asymmetric Michael/aldol,[3i] Knoevenagel/Mi-
chael,[3b] self-aldol,[3c] aldol/aldol,[3d] amination/aldol,[3e]
Knoevenagel/Diels–Alder,[3f] and Knoevenagel/Diels–Alder/
La Jolla, CA 92037 (USA)
Fax :(+1)858-784-2583
E-mail: carlos@scripps.edu
Experimental procedures, compound characterization, and analytical
data (1H NMR, 13C NMR, and HRMS) for all newcompounds
(PDF). This material is available on the WWW under http://www.che-
meurj.org/or from the author.
Chem. Eur. J. 2004, 10, 5323 – 5331
DOI: 10.1002/chem.200400597
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5323

FULL PAPER
epimerization[3g,h] reaction sequences. These reaction condi-
tions use less solvent and less toxic solvents than previously
developed schemes and are thus significantly more environ-
mentally friendly.[3a]
Here we describe the development of a set of powerful,
reliable, and selective MCRꢀs for the rapid synthesis of new
compounds and combinatorial libraries through organo/CuI-
catalyzed [4+2] and [3+2] cycloaddition reactions, an ap-
proach we call “organo-click chemistry”. Recently K. B.
Sharpless and co-workers have provided guidelines for click
chemistry.[4] Ideally, organocatalytic MCRꢀs fulfill all defin-
ing aspects of click chemistry, such as the reaction(s) must
be modular, wide in scope, high yielding, generate only inof-
fensive byproducts, and be stereospecific.
In an extension of our work, we envisaged that asymmet-
ric assembly of simple substrates like acetone or phosphor-
ane, two different aldehydes, and 1,3-cyclic diketones under
organoamine catalysis would provide complex polycyclic
compounds thorugh aldol-condensation/Knoevenagel/Diels–
Alder (A/K/DA), Wittig/Knoevenagel/Diels–Alder (W/K/
DA), Wittig/Michael (W/M) and Knoevenagel/Michael (K/
M) reaction sequences in one pot (Scheme 1). Further we
envisaged that the stereospecific assembly of simple sub-
strates like phosphorane, aldehydes, 1,3-cyclic diketones,
and azides under organo/CuI catalysis would provide com-
plex heterocyclic compounds by means of Wittig/Knoevena-
gel/Diels–Alder/Huisgen cycloaddition (W/K/DA/HC) reac-
tion sequences in one pot (Scheme 1). We aimed to prepare
both diene and dienophiles simultaneously, under very mild
and environmentally friendly conditions, thus giving the con-
stituents for a stereocontrolled Diels–Alder reaction, which
in turn yields compounds 4 to 8 (Scheme 1). In this
article, we describe the results of this investigation that
provide for the organocatalytic stereospecific asymmetric as-
sembly of polysubstituted 1,4-disubstituted 1,2,3-triazoles 8,
dispiro[5.2.5.2]hexadecanes 6, spiro(cyclohexane-1,2’-indan)-
triones 5, spiro[5.5]undecanes 4, and Michael adducts 15 and
16 from simple substrates in one pot. Dispirolactones 6 are
bioactive molecules with antioxidant and radical scavenger
activities[5c] and substituted 1,2,3-triazoles 8 have enabled a
multitude of applications in biology, chemistry, and materi-
als science.[5a,b,f] We have also developed a newmethod for
the synthesis of both optical isomers of spirotriones 4 that
involves a simple change in the order of addition of the re-
actants rather than a change in catalyst.
In our reaction we envisioned that amino acids and
amines would catalyze the domino aldol condensation of an
aldehyde with acetone (or with phosphorane in an uncata-
lyzed Wittig reaction) to provide trans-enone 1 (diene
source). Knoevenagel condensation of an aldehyde with 1,3-
cyclic diketones would provide arylidene–cyclic diketones
(2; dienophile), which would then undergo a concerted
[4+2] cycloaddition with a 2-amino-1,3-butadiene (3) gener-
ated in situ from trans-enone 1 and amino acid or amine to
form substituted spirotriones 4 to 6 in a diastereoselective
manner (Scheme 1). Propargyl substituted spirotriones 4 to
6 would undergo regiospecific [3+2] cycloaddition with
azides to generate 1,2,3-triazoles 8 under CuSO4/Cu catalysis
in one pot. Enones 1 and 2 could also be directed to under-
go asymmetric Michael additions with 1,3-cyclic diketones
or acetone under amino acid or amine catalysis to furnish
compounds 7. The domino A/K/DA or W/K/DA and W/K/
DA/HC reaction would then generate a quaternary center
with formation of four new carbon–carbon s bonds and four
newcarbon–nitrogen s bonds, respectively.
Results and Discussion
Domino aldol/Knoevenagel/Diels–Alder reactions: We were
pleased to find that the three-component reaction of ace-
tone, benzaldehyde, and Meldrumꢀs acid with a catalytic
amount of pyrrolidine in methanol at 408C for 6 h furnished
the Diels–Alder product 4a as single diastereomer in 65%
yield accompanied by the Michael adduct 7a in 20% yield
(Table 1, entry 1). The three-component A/K/DA reaction
of benzaldehyde containing an electron-withdrawing group
(4-NO2) furnished spirotrione 4b as single diastereomer in
66% yield and the Michael adduct 7b in 15% yield
(Table 1, entry 2). Unfortunately, the hetero-domino A/K/
DA reaction of acetone, 4-NO2C6H4CHO, and Meldrumꢀs
Scheme 1. Proposed organo/CuI-catalytic assembly of spirotriones and
spirotrione–triazoles via simultaneously organogenerated diene and dien-
ophiles in aldol (or Wittig)/Knoevenagel/Diels–Alder and Wittig/Knoeve-
nagel/Diels–Alder/Huisgen cycloaddition reaction sequences in one pot.
5324
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Chem. Eur. J. 2004, 10, 5323 – 5331

Organo-Click Chemistry
5323 – 5331
Table 1. Diastereospecific and chemoselective three-component Aldol/
Knoevenagel/Diels–Alder reaction sequence catalyzed by pyrrolidine in
one pot.[a]
but did not generate the alcohols 9 with other aldehydes
(Tables 1 and 2). Pyrrolidine-catalyzed A/K/DA reaction of
benzaldehyde with an electron-donating group (4-MeO) fur-
nished the spirotrione 4c in 72% yield and the Michael
adduct 7c in 20% yield (Table 1, entry 4). Based on these
results, our organocatalytic three-component A/K/DA reac-
tion should find utility in the generation of libraries of spiro-
triones 4 with good to moderate yields in a diastereospecific
manner from simple substrates.
Reaction mechanism: The proposed mechanism of diaster-
eospecific assembly of cis-spiranes (4) and Michael adducts
(7) in the MCRs of acetone, aldehyde, and Meldrumꢀs acid
under pyrrolidine catalysis is illustrated in Scheme 2. First,
reaction of pyrrolidine with aldehyde generates the imine
cation 10, an excellent electrophile that undergoes Mannich
type reactions with enolates or enamines of acetone and
Meldrumꢀs acid to generate Mannich products 11 and 12, re-
spectively. Retro-Mannich or base-induced elimination reac-
tion of amino–ketones 11 and 12 under basic conditions
would furnish trans-enone 1 and benzylidene–Meldrumꢀs
acid 2, respectively. Compound 2 is a reactive dienophile
that undergoes a Diels–Alder or a double Michael reaction
with the soft nucleophile 2-amino-1,3-butadiene 3, generated
in situ from trans-enone 1 and an amine catalyst, to produce
the A/K/DA product 4. Compound 2 can also react with
enolate (or enamine) of acetone to produce domino K/M
product 7. The ratio of domino products 4 and 7 is depend-
ent on the electrophilicity of imine 10, dienophile 2, reaction
temperature, and concentration of acetone in the reaction
media (Table 1, entries 3, 4, and 5). Formation of trans-
enones 1 (diene source) and dienophiles 2 by means of Man-
nich and retro-Mannich reac-
Entry
Ar
Products
Yield[%][b]
d.r.[c]
4
7
1
C6H5
4a,7a
4b,7b
4b,7b
4c,7c
4c,7c
65
66
51
72
57
20
15
5
20
43
>100:1
>100:1
>100:1
>100:1
>100:1
2[d]
3[e]
4
4-NO2C6H4
4-NO2C6H4
4-MeOC6H4
4-MeOC6H4
5[f]
[a] Experimental conditions: pyrrolidine (0.15 mmol), aldehyde
(1.0 mmol), Meldrumꢀs acid (0.5 mmol), and acetone (1 mmol) in metha-
nol (0.5 mL) were stirred at 408C for 6 h (see Experimental Section).
[b] Yield refers to the purified product obtained by column chromatogra-
phy. [c] Ratio based on 1H NMR analysis of unpurified products. [d] Re-
action time 20 h. [e] Reaction was performed at 258C for 72 h. [f] In this
reaction acetone was used as solvent.
acid under l-proline catalysis furnished the spirotrione 4b in
very lowyields. The pyrrolidine-catalyzed three-component
A/K/DA reaction of acetone, 4-nitrobenzaldehyde, and Mel-
drumꢀs acid revealed that yields of this reaction varied with
solvent as shown in Table 2. The highly electrophilic nature
of 4-nitrobenzaldehyde furnished the byproduct alcohol 9b
under pyrrolidine catalysis in the domino A/K/DA reaction,
tions support our hypothesis
Table 2. Effect of solvent on the direct pyrrolidine-catalyzed stereospecific three-component aldol/Knoevena-
gel/Diels–Alder reaction of 4-nitrobenzaldehyde, Meldrumꢀs acid, and acetone in one pot.[a]
that aldol products 9 did not
form in these reactions, with
the exception of reaction with
the highly reactive 4-NO2C6H4-
CHO. This hypothesis is also
supported by the mechanistic
investigation of pyrrolidine-cat-
alyzed enal formation through
aldehyde self-condensation re-
ported by Saito et al.[6]
Entry
Solvent
T
t
Products
Yield[b]
[%]
Ratio[c]
[0.5 m]
[8C]
[h]
[4b:1b:9b]
Domino Wittig/Knoevenagel/
Diels–Alder reactions: To avoid
the formation of byproducts in
the domino A/K/DA reactions,
we developed a new reaction
sequence for the stereospecific
assembly of spirotriones by
means of three-component W/
K/DA reaction in one-pot
1[d]
2[d],[e]
3[f]
4[f]
5[f]
6[f]
7[f]
8[f]
9
MeOH
MeOH
MeOH
EtOH
DMF
THF
CH3CN
CH3C6H5
[bmim]BF4
H2O
258C
258C
72
72
22
72
72
72
72
72
17
72
4b,1b,7b
63
65
80
70
63
65
65
75
50
30
5.3:1:0
5.3:1:1
6:1:1
4:3:1
5:1:0
3.5:5:1
7:3:1
1:2.5:1
30:0:1
2:1:3.5
4b,1b,9b,7b
4b,1b,9b,7b
4b,1b,9b,7b
4b,1b,7b
4b,1b,9b,7b
4b,1b,9b,7b
4b,1b,9b,7b
4b,9b
258C!408C
258C
258C
258C
258C
258C
408C
10
258C!408C
4b,1b,9b
[a] Experimental conditions: pyrrolidine (0.15 mmol), 4-nitrobenzaldehyde (1.0 mmol), and Meldrumꢀs acid
(0.5 mmol) in solvent (0.5 mL) were stirred at ambient temperature for 20 minutes then acetone (1 mmol) was
added (see Experimental Section). [b] Yield refers to the purified product obtained by column chromatogra-
phy. [c] Ratio based on 1H NMR analysis of unpurified products. [d] 5% of domino Knoevenagel/Michael
product 7b was isolated. [e] Acetone was taken in excess (2 mmol). [f] 10–15% of domino Knoevenagel/Mi-
chael product 7b was isolated.
under
organocatalysis.
We
found that the three-component
reaction of 1-(triphenylphos-
phanylidene)-propan-2-one,
benzaldehyde, and Meldrumꢀs
Chem. Eur. J. 2004, 10, 5323 – 5331
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5325

C. F Barbas III and D. B. Ramachary
FULL PAPER
Table 3. Stereospecific assembly of spirotriones through the three-com-
ponent Wittig/Knoevenagel/Diels–Alder reaction sequence in one pot
under l-proline catalysis.
Entry
1,3-Cyclic
diketone
Product
Yield[%]
d.r.
1
2
3
Meldrumꢀs acid
1,3-indandione
spirolactone
spirolactone
dimedone
4a
5a
6a
6a
13a
13a
80
84
91
99
85
95
>100:1
23:1
>100:1
>100:1
–
4[a]
5[b]
6[c]
dimedone
–
[a] Ethanol was used as solvent. [b] Reaction time was 2 h. [c] Reaction
performed at 258C for 5 h.
yl-2-(4-nitro-benzylidene)-cyclohexane-1,3-dione) was gener-
ated. Organocatalytic K/DA reaction of enone 1a, 4-nitro-
benzaldehyde, and dimedone under l-proline catalysis at
room temperature also furnished the 13b in 81% yield with-
out 14b. Organo-generated aldehyde–dimedone adducts,
which are called dimethones, are very useful materials in
medicinal chemistry (anticonvulsant, antidepressant, diuret-
ic, antibacterial, antitumor, or anticarcinogenic activity).[7b–d]
Amino acid catalyzed dimethone formation may also find
application in the analysis of aldehydes in foods.[7a]
Scheme 2. Proposed catalytic cycle for the simultaneous organogenera-
tion of diene and dienophiles in pyrrolidine-catalyzed aldol/Knoevenagel/
Diels–Alder and Knoevenagel/Michael reaction sequences in one pot.
acid with a catalytic amount of l-proline in methanol at
658C for 4 h furnished Diels–Alder product 4a as a single
diastereomer in 80% yield (Table 3, entry 1). Under the
same reaction conditions, different 1,3-cyclic diketones fur-
nished the expected spirotriones 5a and 6a in very good
yields as shown in Table 3. Medicinally important dispirolac-
tone 6a was furnished in 99% yield under optimized condi-
tions (Table 3, entry 4). Chemical diversity libraries of spi-
ranes 4, 5, and 6 could therefore be prepared easily by using
the W/K/DA reaction sequence in a single reaction vessel.
Interestingly, the three-component reaction of 1-(triphe-
nylphosphanylidene)-propan-2-one, benzaldehyde, and di-
medone with a catalytic amount of l-proline in methanol at
658C for 2 h furnished the unexpected product 13a in 85%
yield (Table 3, entry 5) without the expected Diels–Alder
product 14a. The same reaction at room temperature also
furnished 13a in very good yield (Table 3, entry 6). Forma-
tion of 13a in the W/K/DA reaction can be explained due to
more favorable soft–soft interactions of the dienophile (5,5-
dimethyl-2-benzylidene-cyclohexane-1,3-dione) and dime-
done (pKa 11.2, in DMSO at 258C)[7e] as compared to Mel-
drumꢀs acid (pKa 7.3, in DMSO at 258C).[7e] The soft acidic
nature of dimedone was further established in three-compo-
nent Knoevenagel/Diels-Alder (K/DA) reaction as shown in
Scheme 3, in which the less reactive dienophile (5,5-dimeth-
Scheme 3. Formation of unexpected product 13b in organocatalytic
Knoevenagel/Diels–Alder reaction.
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Chem. Eur. J. 2004, 10, 5323 – 5331

Organo-Click Chemistry
5323 – 5331
Effects of solvent, temperature, and amine on the direct
amine-catalyzed stereospecific three-component W/K/DA
reaction of phosphorane, benzaldehyde, and spirolactone in
one pot are shown in Table 4. Domino W/K/DA product 6a
was formed in very good yields under l-proline catalysis,
but dispirolactone 6a was formed in moderate yields under
Effect of amine and solvent on the Wittig reaction: Neither
the type of amino acid or amine catalyst nor the use of
protic solvents (MeOH, EtOH) had an effect on the stereo-
chemistry of the Wittig reaction of aldehydes with phosphor-
ane; these reactions furnished only the trans-enones (1) as
shown in Scheme 4.[9]
Chemical diversity libraries of
Table 4. Effect of solvent and amine on the direct amine-catalyzed stereospecific three-component Wittig/
Knoevenagel/Diels–Alder reaction of phosphorane, benzaldehyde, and spirolactone in one pot.
potential antioxidants: We fur-
ther explored the potential of
the l-proline-catalyzed hetero-
domino W/K/DA reaction for
the synthesis of diverse libraries
of antioxidant dispirolactones
(6) with various arylaldehydes.
Upon simple heating of phos-
phorane, aldehydes, and spiro-
lactone with a catalytic amount
of proline, almost quantitative
conversion to the dispiro-
[5.2.5.2]hexadecanes 6 was ob-
served. The excellent results in
Table 6 establish the scope of
Entry
Catalyst
Solvent1
Solvent2
T [8C]
t [h]
Yield [%][c]
d.r.[d]
1[a]
2[a]
3[b]
4[b]
5[b]
6[b]
7[b]
l-proline
l-proline
l-proline
l-proline
pyrrolidine
pyrrolidine
l-proline
C6H6
C6H6
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
65!25
65!65
25
65
25
1!48
86
99
90
91
62
67
99
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
0.5!12
MeOH
MeOH
MeOH
MeOH
EtOH
48
4
72
2
65
65
4
[a] Experimental conditions: benzaldehyde (0.75 mmol) and 1-(triphenylphosphanylidene)-propan-2-one
(0.25 mmol) in benzene (0.1 mL) were stirred at 658C for 0.5 to 1 h then proline (0.05 mmol), 1,3-cyclic dike- this reaction, which readily ac-
tone (0.25 mmol), and methanol (0.5 mL) was added and stirred (see Experimental Section). [b] All reactants
cepts complex carbohydrate
synthons (see 6r). This proce-
dure is a manifestation of an
mixed at once with same proportions as above in solvent (0.5 mL) and stirred (see Experimental Section).
1
[c] Yield refers to the purified product obtained by column chromatography. [d] Ratio based on H NMR anal-
ysis of purified products.
amine (pyrrolidine) catalysis as shown in Table 4. Interest-
ingly, the primary amino acid glycine also catalyzed the
three-component W/K/DA reaction of phosphorane, alde-
hydes, and spirolactone under physiological conditions to
generate stereospecific spirotriones 6 in one pot as shown in
Table 5. Yields of spirotriones 6 obtained under glycine cat-
Scheme 4. Effect of l-proline and methanol on the stereochemistry of the
Wittig reaction.
Table 5. Glycine-catalyzed stereospecific assembly of spirotriones via
three-component Wittig/Knoevenagel/Diels-Alder reaction sequence in
one pot.[a]
“organo-click chemistry” transformation. Each of the target-
ed prochiral dispirolactones 6 was obtained as a single dia-
stereomer. As the reaction proceeds, the mixture solidifies
as the product is formed.
Antioxidant dispirolactones (6) were generated in good
yields with aromatics bearing hydroxy, propargyl, azide, and
Entry
Ar
Products
Yield [%]
d.r.
glucose moieties in the para-position as shown in Table 6.
Dispirolactone 6r is an analogue of the antioxidative gluco-
side isolated from oregano (Origanum vulgare).[10] Prochiral
cis-spiranes 6a–e, j, k, m are anti-oxidants/free-radical scav-
engers. Generation of molecular diversity around this scaf-
fold may allowfor the identification of more potent species.
The method described here for the synthesis of these antiox-
idants offers significant improvements in synthetic ease and
yields as compared to previous routes.[5c]
1
2
3
C6H5
6a
6b
6c
6a
6c
62
55
73
31
<5
>100:1
>100:1
>100:1
>100:1
>100:1
4-NO2C6H4
4-MeOC6H4
C6H5
4[b]
5[c]
4-MeOC6H4
[a] See Experimental Section. [b] Water (1 mL) was used as solvent.
[c] Reaction performed at 258C for 5 days, enone 1c and Knoevenagel
products were isolated in 90 and 86% yield, respectively.
alysis were, however, typically less than those obtained
under proline catalysis. Glycine catalyzed reactions are sig-
nificant in understanding the reaction-potential of the prebi-
otic world.[8]
Wittig/Knoevenagel/Diels-Alder/Huisgen cycloaddition re-
actions in one pot: Huisgen 1,3-dipolar cycloaddition reac-
tions[2a–c,g] are exergonic fusion processes, and the cycloaddi-
tion of azides and alkynes to give triazoles is arguably the
Chem. Eur. J. 2004, 10, 5323 – 5331
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5327

C. F Barbas III and D. B. Ramachary
FULL PAPER
Table 6. Stereospecific synthesis of chemically diverse libraries of antiox-
idant polysubstituted dispiro[5.2.5.2]hexadecanes by means of Wittig/
Knoevenagel/Diels–Alder reaction sequence in one pot.[a]
Scheme 5. Regiospecific synthesis of 1,4-disubstituted 1,2,3-triazole 8a
catalyzed by CuI ions in the presence of Cu wire.
Table 7. Organo/CuI-catalyzed stereospecific synthesis of polysubstituted
triazoles through Wittig/Knoevenagel/Diels–Alder/Huisgen cycloaddition
reactions in one pot.[a]
[a] All reactions were carried out in EtOH (0.5 M), with 20 mol% of l-
proline at 658C, and complete in 3–12 h. [b] Yield refers to the column
purified product. [c] Reaction time was 20 h. [d] Product obtained from
K/DA reaction.
most useful members of this family. Huisgen cycloaddition
of propargyl-substituted dispiro[5.2.5.2]hexadecane 6u with
benzyl azide under CuSO4/Cu catalysis furnished the regio-
specifically 1,4-disubstituted 1,2,3-triazole 8a in very good
yield as shown in Scheme 5. 1,2,3-Triazoles have found wide
applications in biology, chemistry, and materials science.[5a,b,f]
Therefore, it is important to develop newand more efficient
MCR approaches to diverse arrays of 1,2,3-triazoles in one-
pot. We were pleased to find that the in situ generated dis-
piro[5.2.5.2]hexadecane 6u under proline catalysis further
reacted with benzyl azide in same solvent under CuSO4/Cu-
catalysis to furnish the expected spirotrione-1,2,3-triazole
(8a) in 90% yield with formation of four new carbon–
carbon s bonds and four newcarbon–nitrogen s bonds in
one pot. The scope of this proline/CuI-catalyzed spirotrione–
triazole synthesis is partly revealed by the examples in
Table 7. Variously substituted azides and 1,3-cyclic diketones
readily participate in this one-pot transformation.
[a] See Experimental Section. [b] Yield refers to the column purified
product. [c] Huisgen cycloaddition was slow at 258C (48 h), but at 508C
reaction completed within 5-10 h.
Asymmetric four-component Diels–Alder (AFCDA) reac-
tions: Recently we developed the l-DMTC-catalyzed (l-5,5-
dimethyl thiazolidinium-4-carboxylate) asymmetric three-
5328
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Organo-Click Chemistry
5323 – 5331
component Diels–Alder (ATCDA) reaction of trans-enone,
aldehyde, and Meldrumꢀs acid to produce substituted spi-
ro[5.5]undecanes in very good yields and useful enantiomer-
ic excess (ee). These compounds are useful starting materials
for the synthesis of exotic amino acids.[3f] The versatility of
the ATCDA reaction was improved by optimization as an
asymmetric four-component Diels–Alder (AFCDA) reac-
tion with a L-DMTC-catalyzed W/K/DA reaction sequence
in one pot (Table 8). Reaction of phosphorane, benzalde-
hyde, 4-nitrobenzaldehyde, Meldrumꢀs acid, and l-DMTC in
methanol furnished a single diastereomer, spirane (7R,11S)-
4d in 83% yield and 69% ee (Table 8, entry 1).
Significantly, the antipode of the optical isomer can ob-
tained by simply changing the addition sequence of starting
materials in reaction mixture without changing the catalyst
as shown in Table 8. This technique provides for the synthe-
sis of both optical isomers of a number of spiranes (4) in
good yields and eeꢀs. For example, the optical antipode of
(7R,11S)-4d was obtained in 80% yield and 42% ee by
changing the addition sequence of C6H5CHO and 4-
NO2C6H4CHO. The enantiomeric excess of (7S,11R)-4d was
Scheme 6. Organocatalytic
asymmetric
three-component
Michael
(ATCM) reactions. [a] Literature values from two-component reactions
obtained byK. A. Jorgensen et al.[11]
Table 8. Organocatalytic asymmetric four-component Wittig/Knoevenagel/Diels–Alder reaction sequence used
to generate diastereospecific and enantioselective synthesis of spirolactones in one pot.[a]
yields. The rate of the Michael
reaction in ATCM was fast rel-
ative to the two-component re-
action presumably due to the
basic nature of byproduct tri-
phenylphosphoxide.
Entry
Ar1
Ar2
Yield[%]
d.r.
ee[b]
Absolute[c]
configuration
Conclusion
1[d]
2[d]
3[e]
4[e]
C6H5
4-NO2C6H4
C6H5
4-NO2C6H4
C6H5
4-CNC6H4
C6H5
83
80
85
80
>100:1
>100:1
>100:1
>100:1
69
42
70
42
(7R,11S)-4d
(7S,11R)-4d
(7R,11S)-4e
(7S,11R)-4e
In conclusion, we have demon-
strated for the first time the
organo/CuI-catalyzed enzyme-
like assembly of spirotriones 4,
5, 6, and 8 from readily availa-
ble precursors by means of A/
K/DA, W/K/DA, and W/K/DA/
HC reaction sequences. Combi-
4-CNC6H4
[a] Experimental conditions: aldehyde, Ar1-CHO (0.5 mmol), and 1-(triphenylphosphanylidene)-propan-2-one
(0.5 mmol) in benzene (0.2 mL) were stirred at 658C for 1 h, then l-DMTC (0.1 mmol), aldehyde, Ar2-CHO
(0.5 mmol), Meldrumꢀs acid (0.5 mmol), and methanol (1.0 mL) were added and stirred at 258C (see Experi-
mental Section). [b] Enantiomeric excesses were determined using chiral-phase HPLC. [c] Absolute configura-
tion determined based on HPLC analysis and comparison to earlier reports. [d] Spirotriones 4a and 4b are
formed in 2:1 ratio with 10% yield. [e] Spirotrione 4 f is formed in 10% yield.
nation
of
proline/CuI-ions
proved to be compatible
increased to 90% by recrystalising in 15% isopropanol/
hexane (the mother liquor is enantioenriched). Two addi-
tional examples are shown in Table 8.
organo/metal catalysts for the MCRs in one pot. This simple
one-pot procedure provides direct access to functionalized
dispirolactones (6), shown to be antioxidants and radical
scavengers in biological studies. Glycine was also a function-
al organo catalyst in some systems. Multicomponent reac-
tions catalyzed by glycine may be significant in understand-
ing the potential chemistries available to the prebiotic
world. Significantly, we developed an AFCDA reaction
scheme that yields both optical isomers of 4 simply by
changing the order of reactant addition. Additionally, a
novel organocatalytic ATCM reaction was developed. These
reactions can be performed on a multigram scale under op-
erationally simple and environmentally safe conditions.
These results suggest that the assembly of complex products
from simple starting materials is within the realm of organo-
catalysis involving simple amino acids and amines. Further
Asymmetric three-component Michael (ATCM) reactions:
trans-Enones 1 prepared in situ by means of the Wittig reac-
tion were also studied in the asymmetric Michael reaction
of 1,3-cyclic diketones under organocatalysis as recently re-
ported by Jorgensen et al.[11] As shown in Scheme 6, the
novel asymmetric three-component Michael (ATCM) reac-
tion of phosphorane, benzaldehyde, and diethyl malonate
under imidazolidine catalysis furnished the Michael adduct
15 in 65% yield and 90% ee. The ATCM reaction of phos-
phorane, 2-NO2C6H4CHO, and dibenzyl malonate furnished
the expected product 16 in 84% yield and 91% ee, compara-
ble to the previously disclosed two-component reaction
Chem. Eur. J. 2004, 10, 5323 – 5331
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C. F Barbas III and D. B. Ramachary
FULL PAPER
l-DMTC-catalyzed AFCDA reactions in one pot: A solution of Alde-
hyde, Ar1-CHO (0.5 mmol) and 1-(triphenylphosphanylidene)-propan-2-
one (0.5 mmol) in benzene (0.2 mL) was stirred at 658C for 1 h; then l-
DMTC (0.1 mmol), aldehyde, Ar2-CHO (0.5 mmol), Meldrumꢀs acid
(0.5 mmol), and methanol (1.0 mL) were added and stirred at 258C for
the time indicated in Table 8. The crude reaction mixture was treated
with saturated aqueous ammonium chloride solution, the layers were sep-
arated, and the organic layer was extracted three to four times with di-
chloromethane, dried with anhydrous Na2SO4, and evaporated. The pure
AFCDA products 4d and 4e were obtained by flash column chromatog-
raphy (silica gel, mixture of hexane/ethyl acetate). Enantiomeric excesses
(ee) and NMR spectra of pure AFCDA products were compared with
our previous report of ATCDA products.[3f]
studies aimed at exploring the scope of assembly reactions
of these types are ongoing.
Experimental
General methods: The 1H and 13C NMR spectra were recorded at 400
and 100 MHz, respectively. The chemical shifts are reported in ppm
downfield to TMS (d=0 ppm) for 1H NMR spectra and relative to the
central CDCl3 resonance (d=77.0 ppm) for 13C NMR spectra. Coupling
constants in 1H NMR measurements are given in Hz. In the 13C NMR
spectra, the nature of the carbons (C, CH, CH2, or CH3) was determined
by recording the DEPT-135 experiment, and is given in parentheses.
Flash chromatography (FC) was performed by using silica gel Merck 60
(particle size 0.040–0.063 mm). High-resolution mass spectra were record-
ed on an IonSpec FTMS mass spectrometer with a DHB-matrix. Electro-
spray ionization (ESI) mass spectrometry was performed on an API 100
Perkin–Elmer SCIEX single quadrupole mass spectrometer. The enantio-
meric excess (ee) of the products were determined by HPLC using
Daciel chiralcel OD-H or Daciel chiralpak AS or Daciel chiralpak AD
columns with i-PrOH/hexane as eluent. HPLC was carried out by using a
Hitachi organizer consisting of a D-2500 Chromato-Integrator, an L-4000
UV-Detector, and an L-6200A Intelligent Pump. For thin-layer chroma-
tography (TLC), silica gel plates Merck 60 F254 were used and com-
pounds were visualized by irradiation with UV light and/or by treatment
with a solution of p-anisaldehyde (23 mL), conc. H2SO4 (35 mL), acetic
acid (10 mL), and ethanol (900 mL) followed by heating.
Imidazolidine-catalyzed ATCM reactions in one pot: A solution of alde-
hyde
(0.5 mmol)
and
1-(triphenylphosphanylidene)-propan-2-one
(0.5 mmol) in benzene (0.2 mL) was stirred at 658C for 1 h; then 4-
benzyl-1-methyl-imidazolidine-2-carboxylic acid (0.05 mmol) and diethyl
malonate or dibenzyl malonate (0.5 mL) were added and stirred at 258C
for the time indicated in Scheme 6. The pure ATCM products 15 and 16
were obtained by flash chromatography directly from crude reaction mix-
ture; NMR spectra and eeꢀs of the ATCM products were compared with
literature values, which were obtained from two-component reactions.[11]
Acknowledegments
This study was supported in part by the National Institutes of Health
[CA27489] and the Skaggs Institute for Chemical Biology. We thank Dr.
Derek David Steiner for the preparation of 4-N3C6H4CHO.
Materials: All solvents and commercially available chemicals were used
as received. 1,5-Dioxaspiro[5.5]undecane-2,4-dione and 7-isopropyl-10-
methyl-1,5-dioxaspiro[5.5]undecane-2,4-diones are prepared cyclizing cor-
responding cyclohexanone and (ꢀ)-menthone with malonic acid in acetic
anhydride under catalysis of concentrated H2SO4 or p-TSA at 20 to 508C
for 5–10 h, aqueous work-up and recrystallization with petroleum ether
furnished spiro[5.5]undecane-2,4-diones. Catalyst 4-benzyl-1-methyl-imi-
dazolidine-2-carboxylic acid (d.r.=2:1),[12] 4-N3C6H4CHO,[13] and 4-
[(2,3,4,6-tetra-O-acetyl-d-glucopyranosyl)oxy]benzaldehyde[14] are pre-
pared according to literature procedures.
[1] See for example a) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105,
137; Angew. Chem. Int. Ed. Engl. 1993, 32, 131; b) L. F. Tietze,
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General experimental procedures for organo-click reactions
Pyrrolidine-catalyzed domino A/K/DA and K/M reactions: In an ordina-
ry glass vial equipped with a magnetic stirring bar, solvent (0.5 mL) was
added to the aldehyde (1.0 mmol), Meldrumꢀs acid (0.5 mmol) and ace-
tone (1.0 mmol), followed by the addition of the catalyst pyrrolidine
(0.15 mmol). The reaction mixture was stirred at 408C for the time indi-
cated in Tables 1 and 2. The crude reaction mixture was directly loaded
on silica gel column without aqueous workup and pure domino K/A/DA
and K/M products 4a–c and 7a–c were obtained by flash column chroma-
tography (silica gel, mixture of hexane/ethyl acetate).
[2] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
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Cordova, W. Notz, C. F. Barbas III, J. Org. Chem. 2002, 67, 301;
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N. S. Chowdari, C. F. Barbas III, Angew. Chem. 2003, 115, 4365;
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Amino acid and amine-catalyzed domino W/K/DA reactions: For the
synthesis of antioxidants 6, reactants 1-(triphenylphosphanylidene)-
propan-2-one (0.5 mmol), aldehyde (1.3 mmol), 1,5-dioxa-spiro[5.5]unde-
cane-2,4-dione (0.5 mmol), and l-proline, glycine or pyrrolidine
(0.1 mmol) in ethanol (1.0 mL) were placed in an ordinary glass vial
equipped with a magnetic stirring bar and stirred at 658C for the time in-
dicated in Tables 3–6. The crude reaction mixture was directly loaded on
silica gel column without aqueous workup, and pure domino antioxidant
products 6a–u were obtained by flash column chromatography (silica gel,
mixture of hexane/ethyl acetate).
l-Proline/CuI-catalyzed W/K/DA/HC reactions in one pot: For the syn-
thesis of spirotrione-triazoles 8, reactants 1-(triphenylphosphanylidene)-
propan-2-one (0.25 mmol), 4-prop-2-ynyloxy-benzaldehyde (0.6 mmol),
1,3-cyclic diketone (0.25 mmol) and l-proline (0.05 mmol) in ethanol
(0.5 mL) were placed in an ordinary glass vial equipped with a magnetic
stirring bar and stirred at 658C for the time indicated in Table 7. CuSO4
(0.25 mmol), Cu wire (3 mg), and azide (1.2 mmol) were added to the
crude reaction mixture and stirred at room temperature for the time indi-
cated in Table 7. The crude reaction mixture was directly loaded on silica
gel column without aqueous workup and pure spirotrione–triazole prod-
ucts 8a–f were obtained by flash column chromatography (silica gel, mix-
ture of hexane/ethyl acetate).
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5330
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Received: June 11, 2004
Published online: September 23, 2004
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5331