Direct amino acid-catalyzed cascade biomimetic reductive alkylations: Application to the asymmetric synthesis of Hajos-Parrish ketone analogues

Article abstract of DOI:10.1039/b807999d

A direct amino acid-catalyzed chemo- and enantioselective process for the double cascade synthesis of highly substituted 2-alkyl-cyclopentane-1,3-diones, 2-alkyl-3-methoxy-cyclopent-2-enones and Hajos-Parrish (H-P) ketone analogs is presented via reductive alkylation chemistry. For the first time, we have developed a single-step alkylation of cyclopentane-1,3-dione with aldehydes/ketones and a Hantzsch ester through an organocatalytic reductive alkylation strategy. A direct combination of amino acid-catalyzed cascade olefination-hydrogenation and cascade Robinson annulations of cyclopentane-1,3-dione, aldehydes/ketones, a Hantzsch ester and methyl vinyl ketone furnished the highly functionalized H-P ketone analogues in good to high yields and with excellent enantioselectivities. Many of the reductive alkylation products have shown direct applications in pharmaceutical chemistry.

Full text of DOI:10.1039/b807999d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Direct amino acid-catalyzed cascade biomimetic reductive alkylations:
application to the asymmetric synthesis of Hajos–Parrish ketone analogues†
Dhevalapally B. Ramachary* and Mamillapalli Kishor
Received 12th May 2008, Accepted 11th July 2008
First published as an Advance Article on the web 12th August 2008
DOI: 10.1039/b807999d
A direct amino acid-catalyzed chemo- and enantioselective process for the double cascade synthesis of
highly substituted 2-alkyl-cyclopentane-1,3-diones, 2-alkyl-3-methoxy-cyclopent-2-enones and
Hajos–Parrish (H–P) ketone analogs is presented via reductive alkylation chemistry. For the first time,
we have developed a single-step alkylation of cyclopentane-1,3-dione with aldehydes/ketones and a
Hantzsch ester through an organocatalytic reductive alkylation strategy. A direct combination of amino
acid-catalyzed cascade olefination–hydrogenation and cascade Robinson annulations of
cyclopentane-1,3-dione, aldehydes/ketones, a Hantzsch ester and methyl vinyl ketone furnished the
highly functionalized H–P ketone analogues in good to high yields and with excellent
enantioselectivities. Many of the reductive alkylation products have shown direct applications in
pharmaceutical chemistry.
of attention from chemists and biologists. Amino acid- or amine-
Introduction
catalyzed cascade and multi-component reactions involve two
Cascade and multi-component reactions are processes in which
or more bond-forming transformations that take place under
three or more easily accessible components are combined together
the same reaction conditions from simple starting materials
catalyzed by small molecular units of metal-free proteins.2 Amino
acid/amine-catalyzed reactions have in the past few years emerged
as a powerful synthetic tool for the construction of highly
functionalized, complex and optically active compounds,3 in
particular, amino acid-catalyzed cascade and multi-component
reactions emerging as ideal synthetic strategies for the synthesis of
highly functionalized compounds and drug like small molecules
in one pot, mimicking biological reactions.4
As part of our research program to engineer direct amino
acid/amine-catalyzed cascade, multi-component or organo-click
reactions,4a–i herein we report the first organocatalytic asymmetric
chemo-selective direct cascade olefination–hydrogenation (O–H),
olefination–hydrogenation–Robinson annulation (O–H–RA) and
olefination–hydrogenation–etherfication (O–H–E) reactions that
produce very useful drug synthons, 2-alkyl-cyclopentane-1,3-
diones 7, Hajos–Parrish (H–P) ketone analogs 10 and 2-alkyl-
3-methoxy-cyclopent-2-enones 13 from commercially available
cyclopentane-1,3-dione 1, aldehydes or ketones 2, Hantzsch
ester 3, methyl vinyl ketone 9 and amino acid 4 as shown
in Scheme 1. 2-Alkyl-cyclopentane-1,3-diones 7, H–P ketone
analogues 10 and 2-alkyl-3-methoxy-cyclopent-2-enones 13 are
attractive intermediates in the synthesis of natural products and
in medicinal chemistry,5 whilst 2-alkyl-cyclopentane-1,3-diones 7
and 2-alkyl-3-methoxy-cyclopent-2-enones 13 have broad utility
in pharmaceutical chemistry6 and are excellent starting materials
in natural product synthesis as shown in Chart 1. Hence, their
preparation has continued to attract considerable synthetic inter-
est in developing new methods for their syntheses.7
in a single reaction vessel to produce a functionalized product
displaying features of all inputs; thus, the processes offer greater
possibilities for molecular diversity per step with a minimum of
synthesis time, solvents and effort.1 As cascade reactions are one-
pot reactions, they are easier to carry out than classical multi-
step syntheses. Combined with high-throughput library screening,
this cascade strategy was an important development for drug
discovery in the context of rapid identification and optimization
of biologically active lead compounds. Libraries of small-molecule
organic compounds are perhaps the most desired class of potential
drug candidates. With a small set of starting materials, very large
libraries can be built up within a short time, which can then be used
for research on medicinal substances. In spite of the significant
useful attributes of cascade and multi-component reactions for
modern organic chemistry and their suitability for building up
large compound libraries, these reactions have received limited
interest over the past fifty years. However, in the last decade,
with the introduction of high-throughput biological screening, the
importance of cascade and multi-component reactions for drug
discovery has been recognized and considerable efforts from both
academic and industrial researchers have been focused especially
on the design and development of multi-component procedures for
the generation of libraries of highly functionalized compounds.1
In continuation of the development of novel biomimetic cascade
reactions, recently, amino acid- or amine-catalyzed cascade and
multi-component reactions have attracted a considerable amount
School of Chemistry, University of Hyderabad, Hyderabad-500 046, India.
E-mail: ramsc@uohyd.ernet.in; Fax: +91-40-23012460
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data (1H NMR, 13C NMR and HRMS)
for all new compounds. CCDC reference number 674004. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b807999d
Interestingly, there is no direct methodology for the synthesis
of useful 2-alkyl-cyclopentane-1,3-diones 7 and only two-step
methods are known to prepare them.7 Recently, Paquette et al.
developed the two-step synthesis of 2-alkyl-cyclopentane-1,3-
diones 7 in moderate to good yields via an in situ protection and
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Scheme 1 Direct organocatalytic asymmetric cascade O–H, O–H–RA and O–H–E reactions.
deprotection sequence on 2-alkylidene-1,3-diones 5 with thiophe-
nol and Raney nickel, respectively.7m As shown in Scheme 1, the
well-recognized fact is the inability to arrest olefination reactions
involving cyclopentane-1,3-dione 1 and aliphatic or aromatic
aldehydes 2 at the mono-addition stage.8 Very few adducts such as
5 have been isolated.9 This is because these olefination products
5 are highly reactive Michael acceptors capable of engaging the
unreacted cyclopentane-1,3-dione 1 reagent in kinetically rapid
l,4-addition to give bis-adducts such as 6. Also, there is no report
on the asymmetric synthesis of higher alkyl substituted H–P
ketone analogues 10. This has prompted us to investigate the
cascade synthesis of very useful 2-alkyl-cyclopentane-1,3-diones
7, H–P ketone analogues 10 and 2-alkyl-3-methoxy-cyclopent-2-
enones 13 in a single step through mild amino acid-catalysis.
We consequently set out to develop an amino acid-catalyzed
asymmetric cascade synthesis of higher alkyl analogues of H–P
ketones 10 from simple starting materials, which have not been pre-
pared in the past. In this article, we present the development and
application of the amino acid-catalyzed reductive alkylation of cy-
clopentane-1,3-dione 1 through cascade O–H reaction of reactive
1,3-dione 1, aldehydes or ketones 2 and Hantzsch ester 3. Further-
more, we will present mechanistic insight into the reaction course,
applying a new concept of self-catalysis leading to an understand-
ing of the cascade O–H reaction with utilization of calculations.
We imagine that an amino acid or amine would catalyze the
cascade olefination reaction of 1,3-dione 1 with an aldehyde or
ketone 2 to form substituted 2-alkylidene-cyclopentane-1,3-diones
5, which are very reactive intermediates and further undergo
chemoselective reactions with both 1,3-dione 1 and Hantzsch
ester 3 to produce bis-adducts 6 and hydrogenated 2-alkyl-
cyclopentane-1,3-diones 7, respectively, based on reaction con-
ditions. Amino acid-catalyzed Robinson annulation of products
7 with methyl vinyl ketone 9 furnishes the H–P ketones 10 and
alcohols 11 in good yield with very good enantioselectivity, and
alcohol 11 would be converted into ketone 10 without losing
enantioselectivity as shown Scheme 1.
Results and discussion
Direct amino acid-catalyzed cascade reductive alkylation of
cyclopentane-1,3-dione: reaction optimization
We initiated our preliminary investigation by the in situ reduction
of 2-benzylidene-cyclopentane-1,3-dione 5a‡ with Hantzsch ester
3 as shown in Table 1. The self-catalyzed reaction of cyclopentane-
1,3-dione 1 with 3 equiv of benzaldehyde 2a furnished the
‡ In all compounds denoted 5x, 6x, 7x, 10x, 11x, 12x and 13x, x is
incorporated from reactant aldehydes or ketones 2.
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Chart 1 Natural and non-natural products library generated from 2-alkyl-cyclopentane-1,3-diones.
only unexpected bis-adduct 6a without the expected olefination
product 5a (Table 1, entry 1). The same reaction under proline-
catalysis also furnished the only bis-adduct 6a without product
5a with reduced reaction time (Table 1, entry 2). Interestingly,
self-catalyzed reaction of cyclopentane-1,3-dione 1 and 2 equiv of
benzaldehyde 2a with Hantzsch ester 3 furnished the bis-adduct
6a and expected reductive alkylation product 7a with 80% overall
yield in 1 : 4.3 ratio respectively after 24 h at 25 ◦C (Table 1,
entry 3). The self-catalyzed reductive alkylation reaction with 3
equiv of benzaldehyde 2a furnished the product 7a in 90% yield
after 24 h at 25 ◦C (Table 1, entry 4). Interestingly, the same
reaction under proline-catalysis furnished the expected reductive
alkylation product 7a with 90% yield after 12 h at 25 ◦C in
EtOH as shown in Table 1, entry 5. These preliminary results
prompted us to investigate the solvent and catalyst effect on in situ
trapping of olefination product of cyclopentane-1,3-dione 1 with
benzaldehyde 2a through biomimetic hydrogenation as shown in
Table 2.
After preliminary demonstration of the amino acid-promoted
cascade O–H reactions for the generation of cascade product
7a from 1, 2a and 3, we decided to investigate the solvent and
catalyst effect on cascade O–H reactions. Interestingly, proline-
catalyzed cascade O–H reactions of 1, 2a and 3 are solvent and
catalyst dependent reactions as shown in Table 2. The cascade O–H
reaction of 1, 2a and 3 catalyzed by simple amines like benzylamine
4c, pyrrolidine 4d, piperidine 4e and morpholine 4f in ethanol are
not superior compared to self- and proline-catalysis as shown in
Table 2, entries 1–4. There is a large amount of solvent effect on
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Table 1 Preliminary study for reaction optimizationa
Entry
Catalyst 4a (5 mol%)
Aldehyde 2a (equiv.)
Hantzsch ester 3 (equiv.)
Time/h
Products 6a
Yield (%)b 7a
1
2
3
4
5
—
Proline
—
—
Proline
3.0
3.0
2.0
3.0
3.0
—
—
1.0
1.0
1.0
24
12
24
24
12
75
75
15
10
10
—
—
65
90
90
a Reactions were carried out in ethanol (0.3 M) with 2.0 to 3.0 equiv of 2a and 1.0 equiv of 3 relative to 1 (0.3 mmol) in the presence of 5 mol% of catalyst
4a. b Yield refers to the column purified product.
Table 2 Reaction optimizationa
Entry
Solvent (0.3 M)
Catalyst 4 (5 mol%)
Time/h
Products 6a
Yield (%)b 7a
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
MeOH
H2O
DMSO
DMF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
Benzylamine 4c
Pyrrolidine 4d
Piperidine 4e
Morpholine 4f
Proline 4a
24
24
24
24
3
3
6
6
6
2
6
40
50
50
50
8
71
40
40
10
7
60
50
50
50
88
26
60
60
88
93
80
60
Proline 4a
Proline 4a
Proline 4a
Proline 4a
10
11c
12d
Proline 4a
Proline 4a
20
40
Proline 4a
6
a Reactions were carried out in solvent (0.3 M) with 1.0 to 3.0 equiv of 2a and 1.0 equiv of 3 relative to 1 (0.3 mmol) in the presence of 5 mol% of catalyst
4. b Yield refers to the column purified product. c 2.0 Equiv of 2a was used. d 1.0 Equiv of 2a was used.
the direct proline-catalyzed reductive alkylation or cascade O–H
reaction of 1, 2a and 3 as shown in Table 2. Proline-catalyzed
cascade O–H reactions can be performed in three types of solvents
(protic polar, aprotic polar and aprotic non-polar) with moderate
to good yields as shown in Table 2. Surprisingly, the cascade O–H
reaction of 1, 2a and 3 in H2 O furnished the expected hydrogenated
product 7a in 26% yield accompanied by a 71% yield of bis-
adduct 6a after 3 h at 25 ◦C (Table 2, entry 6). The same cascade
reaction under proline-catalysis in CH2Cl2 furnished the expected
product 7a in 93% yield after 2 h at 25 ◦C (Table 2, entry 10).
We envisioned the optimized conditions to be mixing the 3 equiv
of benzaldehyde 2a with cyclopentane-1,3-dione 1 and Hantzsch
ester 3 at 25 ◦C in CH2Cl2 under 5 mol% of proline-catalysis
to furnish the hydrogenated product 7a in 93% yield (Table 2,
entry 10).
cyclopentane-1,3-dione 1, various aldehydes 2a–v or ketones 2w–x
and Hantzsch ester 3 as shown in Table 3. A series of aromatic and
aliphatic aldehydes 2a–v (3 equiv) were reacted with cyclopentane-
1,3-dione 1 and Hantzsch ester 3 catalyzed by 5 mol% of proline
at 25 ◦C in CH2Cl2 (Table 3). The 2-arylmethyl-cyclopentane-
1,3-diones 7a–i and 2-alkyl-cyclopentane-1,3-diones 7j–v were
obtained as single isomers (tautomer) with excellent yields. The
cascade reaction of cyclopentane-1,3-dione 1 with naphthalene-1-
carbaldehyde 2b and 3 furnished the reductive alkylation product
7b as a single tautomer, in 80% yield after 5 h at 25 ◦C (Table 3).
But the same cascade reaction with naphthalene-2-carbaldehyde
2c and 3 furnished the reductive alkylation product 7c as a
single tautomer, with 93% yield after 1 h at 25 ◦C (Table 3).
Synthesis of 2-arylmethyl-cyclopentane-1,3-diones 7a–i from 1,
2a–i and 3 at 25 ◦C under proline-catalysis has taken longer
reaction times (1–28 h), compared to aliphatic aldehydes 2j–v
as shown in Table 3. Interestingly, proline-catalyzed reductive
alkylation reaction of cyclopentane-1,3-dione 1, a,b-unsaturated
aldehydes 2j–k and Hantzsch ester 3 generated the expected
2-alkyl-cyclopentane-1,3-diones 7j–k in excellent yields with
Diversity-oriented synthesis of reductive alkylation products 7a–x
With the optimized reaction conditions in hand, the scope of the
proline-catalyzed O–H cascade reactions was investigated with
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Table 3 Chemically diverse libraries of cascade O–H products 7a
Fig.
1
Crystal structure of 2-(2-nitro-benzyl)-cyclopentane-1,3-
dione (7i).
Interestingly, many of the 2-alkyl-cyclopentane-1,3-diones 7a–x
exist in the enol form in both the solid state and solution state,
which may be due to the strong intermolecular hydrogen bonding;
also, this characteristic is observed in many other 1,3-diketones.7
The chemical shifts of the C1 and C3 carbon atoms in the isolated,
non-hydrogen-bonded enol forms of 2-alkyl-cyclopentane-1,3-
diones 7a–x can hardly be determined in solution, due to the
rapid keto–enol and enol–enol tautomerism.7n Therefore, in 2-
alkyl-cyclopentane-1,3-dione compounds 7a–x, we observed that
a Yield refers to the column purified product. b A 1 : 2.0 ratio of completely
reduced and 1,4-reduction 7j/k products were formed (see ESI†). c Solvent
CH2Cl2 and ketones 2w/2x were taken in a 1 : 1 ratio.
13
=
C NMR shows two of CH2 carbons a to the carbonyls (C O)
=
including the two carbonyl carbons (2 ¥ CH2 and 2 ¥ C O) are
poor resolution even after 2000 scans on standard sampling. This
same kind of 13C NMR pattern was observed for the other 1,3-
diketones in the literature due to the rapid keto–enol and enol–enol
tautomerism.7
moderate chemoselectivity (Table 3). Completely hydrogenated
products 7j¢/7k¢ and 1,4-reduction products 7j/7k are furnished
in a 1 : 2.0 ratio respectively as shown in Table 3. Interest-
ingly, proline-catalyzed cascade reductive alkylation reaction of
cyclopentane-1,3-dione 1 with chiral aldehydes 2u–v and Hantzsch
ester 3 furnished the expected single enantiomer of 2-alkyl-
cyclopentane-1,3-diones 7u–v in excellent yields with high stereos-
electivity (Table 3). Cascade products (R)-(-)-2-(3,7-dimethyl-oct-
6-enyl)-cyclopentane-1,3-dione 7u and (S)-(+)-2-(3,7-dimethyl-
oct-6-enyl)-cyclopentane-1,3-dione 7v are generated in 90% yields
via cascade O–H reaction. Proline-catalyzed cascade reductive
alkylation of cyclopentane-1,3-dione 1 was further extended with
ketones also as shown in Table 3. Cascade reductive alkylation
reaction of cyclopentane-1,3-dione 1 with acetone 2w or cyclohex-
anone 2x and Hantzsch ester 3 under 5 mol% of proline-catalysis
furnished the expected single isomers of 2-alkyl-cyclopentane-
1,3-diones 7w–x in excellent yields (Table 3). The results in
Table 3 demonstrate the broad scope of this reductive cascade
methodology covering a structurally diverse group of aldehydes
2a–v and ketones 2w–x with many of the yields obtained being
very good, or indeed better, than previously published two-step
alkylation reactions.7 The structure and regiochemistry of 2-alkyl-
cyclopentane-1,3-diones 7a–x were confirmed by X-ray structure
analysis on 7i as shown in Fig. 1.10
Applications of reductive alkylation products
Chemoselective O-alkylation of 2-alkyl-cyclopentane-1,3-diones
Cascade products 2-alkyl-cyclopentane-1,3-diones 7 are read-
ily transformed into substituted 2-alkyl-3-methoxy-cyclopent-2-
enones 13 by treatment with an ethereal solution of diazomethane
in one pot as shown in Scheme 2. The highly functionalized 2-
alkyl-3-methoxy-cyclopent-2-enone unit is a basic building block
for a large number of valuable naturally occurring products.6l–q
Highly functionalized 2-alkyl-3-methoxy-cyclopent-2-enones 13
have gained importance in recent years as starting materials
and intermediates for the synthesis of prostaglandin analogues,
which possess a wide range of physiological and pharmacological
properties.6l–q Long chain 2-alkyl-3-methoxy-cyclopent-2-enones
13 have been successfully utilized as ideal synthons for the
synthesis of prostaglandin analogues, which are used for the
treatment or prevention of cancer.6l–q
Cascade O–H reaction of 1, 2a and 3 under 5 mol% of
proline-catalysis furnished the substituted 2-benzyl-cyclopentane-
1,3-dione 7a in good yield, which on treatment with ethereal
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Scheme 2 Direct organocatalytic one-pot synthesis of 2-alkyl-3-methoxy-cyclopent-2-enones 13.a
diazomethane at 25 ◦C for 0.5 h furnished the chemoselectively
one-pot O–H–E product 2-benzyl-3-methoxy-cyclopent-2-enone
13a in 80% yield through self-catalysis as shown in Scheme 2.
The acidic or highly enolizable nature of 2-alkyl-cyclopentane-
1,3-diones 7 is the main driving force in leading us to observe a
highly chemoselective O-alkylation reaction with diazomethane.
The generality of the proline/self-catalyzed chemoselective one-
pot O–H–E reaction was further confirmed by two more examples
using aliphatic acetaldehyde 2l and acetone 2w to furnish the
expected 2-ethyl-3-methoxy-cyclopent-2-enone 13l in 80% yield
and 2-isopropyl-3-methoxy-cyclopent-2-enone 13w in 85% yield,
respectively as shown in Scheme 2. For pharmaceutical applica-
tions, a diversity-oriented library of enones 13 could be generated
by using our amino acid/self-catalyzed, chemoselective one-pot
O–H–E reaction.
receptor modulators for treating a variety of autoimmune and
inflammatory diseases or conditions (see Chart 2). Interestingly,
to the best of our knowledge, there is no report for the asymmetric
synthesis of useful higher alkyl substituted H–P ketone analogues
10. In this paper, we are presenting the asymmetric synthesis of
H–P ketone analogs 10 with very good ee and yields via amino
acid-catalyzed asymmetric RA of 2-alkyl-cyclopentane-1,3-diones
7 with methyl vinyl ketone 9 as shown in Tables 4–5.
Interestingly, L-proline-catalyzed RA reaction of 2-benzyl-
cyclopentane-1,3-dione 7a with 3 equivalents of freshly distilled
methyl vinyl ketone 9 in CH3CN furnished the expected alcohol
product 11a in 60% yield accompanied by Michael adduct 12a in
26% yield at 25 ◦C for 6 days (Table 4, entry 1). Hydrolysis of
bicyclic-alcohol 11a obtained from L-proline 4a catalysis with 1 N
HClO4 in DMSO at 90 ◦C for 1 h furnished the expected bicyclic-
ketone (+)-10a in 80% yield with 85% ee as shown in Table 4,
entry 1. Solvent screening on the direct L-proline-catalyzed RA
reaction of 7a with 9 revealed that DMSO solvent is suitable to
achieve high yields and ee’s as shown in Table 4. We envisioned the
optimized conditions to be mixing the 2-benzyl-cyclopentane-1,3-
dione 7a and 3 equivalents of freshly distilled methyl vinyl ketone
Amino acid-catalyzed asymmetric Robinson annulations
Higher alkyl substituted H–P ketone analogues 10 are very good
intermediates for the synthesis of natural products like steroids.5
Recently, Ali Amjad et al. reported in their papers11 that higher
alkyl H–P ketone analogues 10 are very good intermediates for
the synthesis of pharmaceutically acceptable salts or hydrates
of heterocycles, which are shown as selective glucocorticoid
◦
9 at 25 C in DMSO under 30 mol% of L-proline to furnish the
alcohol of H–P ketone analogue 11a in 67% yield accompanied
by Michael adduct 12a in 33% yield, which on hydrolysis with
Chart 2 Selective ligand analogues for the human glucocorticoid receptor.
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Table 4 Direct amino acid-catalyzed Robinson annulation of 7a with 9a
Entry
Solvent (0.3 M)
Catalyst 4 (30 mol%)
Yield (%)b 11a
Yield (%)b 12a
Yield (%)b,c 10a
Ee (%)d 10a
1
2
3
4
CH3CN
DMSO
DMF
4a
4a
4a
4b
60
67
58
66
26
33
22
34
80
85
80
96
85
91
91
DMSO
-90
a Reactions were carried out in solvent (0.3 M) with 3.0 equiv of freshly distilled methyl vinyl ketone 9 in the presence of 30 mol% of proline 4. b Yield
refers to the column purified product. c Yield of 10a is based on 11a. d Ee determined by HPLC analysis.
Table 5 Organocatalytic asymmetric synthesis of H–P ketone analogues
10a,b
a See Experimental Section. b Yield refers to the column purified product
and ee determined by HPLC analysis. c Michael adduct 12a were isolated
in 33% yield. d Michael adducts 12m and 12n were isolated in 40–50%
yields respectively.
Fig. 2 Crystal structure of (+)-(R)-7a-benzyl-2,3,7,7a-tetrahydro-6H-
indene-1,5-dione (10a).
1 N HClO4 in DMSO at 90 ◦C for 1 h furnished the expected
bicyclic-ketone (+)-10a in 85% yield with 91% ee as shown in
Table 4, entry 2. D-Proline-catalyzed RA reaction of 7a with 9
Amino acid-catalyzed asymmetric double cascade one-pot
Robinson annulations
followed by hydrolysis furnished the opposite enantiomer of H–P
ketone analogue (-)-10a in 96% yield with 90% ee (Table 4, entry
4). The absolute configuration of product (+)-10a prepared under
L-proline-catalysis was established by using X-ray crystallography
and also by comparison with the proline-catalyzed Hajos–Parrish–
Eder–Sauer–Wiechert reaction.12 The crystal structure of product
(+)-10a is depicted in Fig. 2.10
With an efficient amino acid-catalyzed asymmetric cascade
RA protocol in hand, the scope of the proline-catalyzed cascade
asymmetric RA reactions was investigated with various 2-alkyl-
cyclopentane-1,3-diones 7 and methyl vinyl ketone 9. A series
of 2-alkyl-cyclopentane-1,3-diones 7a–n were reacted with 3.0
equivalents of methyl vinyl ketone 9 catalyzed by 30 mol%
of L-proline at 25 ◦C in DMSO for 6 days (Table 5). All
expected bicyclic-alcohols of H–P ketone analogs 11a–n were
obtained in good yields, which on hydrolysis with 1 N HClO4
in DMSO at 90 ◦C for 0.5–1 h furnished the expected bicyclic-
ketones 10a–n in good yields with 91–94% ee as shown in
Table 5.
After successful demonstration of the amino acid-catalyzed
cascade asymmetric O–H and RA reactions, we decided to
investigate the combination of these two cascade reactions in
one pot. Reaction of three equivalents of benzaldehyde 2a with
cyclopentane-1,3-dione 1 and Hantzsch ester 3 under 5 mol% of
L-proline in CH2Cl2 at 25 ◦C for 2.0 h furnished the expected
2-benzyl-cyclopentane-1,3-dione 7a in good yield. Removing the
solvent CH2Cl2 by vacuum pump and adding DMSO solvent,
30 mol% of L-proline 4a and freshly distilled methyl vinyl ketone 9
to the reaction mixture of cascade asymmetric O–H–RA furnished
the expected bicyclic-alcohol of the H–P ketone analogue 11a in
65% yield accompanied by Michael adduct 12a in 35% yield as
shown in Scheme 3. Hydrolysis of one-pot bicyclic-alcohol 11a
with 1 N HClO4 in DMSO at 90 ◦C for 1 h furnished the expected
bicyclic-ketone (+)-10a in 85% yield with 88% ee as shown in
Scheme 3. Interestingly, in L-proline-catalyzed sequential one-
pot double cascade asymmetric O–H–RA reactions, ee’s were
not effected by reaction by-product 2,6-dimethyl-pyridine-3,5-
dicarboxylic acid diethyl ester 8. Successful combination of two
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Scheme 3 Direct organocatalytic one-pot double cascade asymmetric synthesis of H–P ketone analogues 10.
cascade O–H and RA reactions under L-proline-catalysis was
Mechanistic insights
demonstrated by one more example as shown in Scheme 3.
Even after 6 days at 25 ◦C, the double cascade asymmetric
O–H–RA reaction of 1, 2l, 3 and 9 under 4a-catalysis furnished
the unreacted Michael adduct 12l in 50% yield (see Scheme 3). For
the complete conversion of Michael adduct 12l into chiral bicyclic-
alcohol 11l in the dou◦ble cascade reaction process, we performed
The most possible reaction mechanism for L-proline-catalyzed
regio-, chemo- and enantio-selective synthesis of cascade products
7 and 10 through reaction of cyclopentane-1,3-dione 1, aldehy-
des/ketones 2 and Hantzsch ester 3 is illustrated in Scheme 4. This
catalytic sequential one-pot, double cascade is a four component
reaction comprising a cyclopentane-1,3-dione 1, aldehyde 2,
Hantzsch ester 3, methyl vinyl ketone 9 and a simple chiral amino
acid 4, which is capable of catalyzing each step of this double
cascade reaction. In the first step (Scheme 4), the catalyst (S)-4
activates component 2 by, most likely, iminium ion formation,
which then selectively adds to the cyclopentane-1,3-dione 1 via
a Mannich and retro-Mannich type reaction to generate active
◦
the second step at 25 C for 72 h and at 90 C for 12 h followed
by hydrolysis with 1 N HClO4, furnishing the only expected H–P
ketone analogue 10l in 85–90% overall yield with 86% ee as shown
in Scheme 3. Interestingly, there was only a 4% decrease in ee
compared to the room temperature reaction and this one-pot
double cascade synthetic strategy will have much impact on the
asymmetric synthesis of functionalized small molecules.
Scheme 4 Proposed catalytic cycle for the double cascade reactions.
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olefin 5.4f The following second step is biomimetic hydrogenation
of active olefin 5 by Hantzsch ester 3 to produce 7 through self-
catalysis by decreasing the HOMO–LUMO energy gap between
3 and 5 respectively.4f –i In the subsequent third step, Michael
addition of 7 to methyl vinyl ketone 9 via, most likely, iminium ion
activation leads to the formation of Michael adduct 12.12 In the
fourth step, (S)-4 catalyzed the asymmetric intramolecular aldol
condensation of 12 via enamine catalysis12 and returns the catalyst
(S)-4 for further cycles and releases the desired bicyclic-alcohol of
H–P ketone analogue 11.
Considering the recent applications of amino acid or amine-
catalyzed olefination reactions4a–i and based on our recent dis-
covery of reductive alkylation of CH-acids,4a–i we proposed that
the most likely reaction course for the amino acid-catalyzed direct
addition of cyclopentane-1,3-dione 1 to aldehydes 2 is the one out-
lined through iminium-catalysis as shown in Scheme 4. Formation
of active olefins 5 through proline-catalysis by means of Mannich
and retro-Mannich reactions supports our hypothesis that aldol
products did not form in these reactions. This hypothesis is also
supported by our recent discovery of organo-click reactions4h and
the mechanistic investigation of pyrrolidine-catalyzed enal forma-
tion through aldehyde self-condensation reported by Saito et al.13
Highly chemoselective formation of cascade hydrogenated
products 7 over bis-adduct 6 formation from reactants 1, 3 and
5 can be explained by using HOMO–LUMO energy gaps and
enthalpy differences as shown in Scheme 5. We have chosen 1, 3
and 5a for the model theoretical studies.14 Self-catalyzed Michael
reaction of cyclopentane-1,3-dione 1 with in situ generated active
olefin 5a furnishes the bis-adduct 6a. For the same length of time,
self-catalysis furnishes the hydrogenated product 7a and pyridine
8 from hydride transfer reaction of Hantzsch ester 3 with in situ
generated active olefin 5a. Electronically and thermodynamically,
the self-catalyzed hydride transfer reaction is more favorable than
bis-adduct formation as revealed in Scheme 5.
Michael reaction of cyclopentane-1,3-dione 1 with active olefin
5a, in agreement with the experimental results. Moreover, the
energy gaps between the LUMO of 5a and the HOMO of 1/3
agree with the experimental reactivity order, indicating that the
hydride transfer is the rate-determining step and is a dynamically
fast reaction compared to the Michael reaction. In a second step
to probe the competition between two self-catalyzed reactions
between 1, 3 and 5a, we analyzed the net heat of formations (DDH)
of the two reactions (Scheme 5). The calculated heat of formation
for the hydride transfer reaction is 7.823 kcal mol-1 more than
the bis-adduct formation reaction as revealed in Scheme 5. This
result also strongly suggests that a self-catalyzed hydride transfer
reaction is thermodynamically a more favorable reaction than bis-
adduct formation.
Conclusions
In summary, we have developed the metal-free double cascade syn-
thesis of highly functionalized 2-alkyl-cyclopentane-1,3-diones 7,
chiral H–P ketone analogues 10 and 2-alkyl-3-methoxy-cyclopent-
2-enones 13 from simple starting materials via cascade O–H, RA,
O–H–RA and O–H–E reactions under amino acid-catalysis in one
pot. For the first time, we have reported the reductive alkylation of
highly reactive cyclopentane-1,3-dione 1 with aldehydes/ketones
2 and Hantzsch ester 3 under amino acid-catalysis. The reductive
alkylation strategy, or cascade O–H reaction, proceeds in good
yields with high chemo- and regio-selectivity using only 5 mol%
of amino acid as the catalyst. In this article, we have demonstrated
the concept of self-catalysis by decreasing the HOMO–LUMO
energy gap between in situ generated olefins 5 and Hantzsch ester
3. Furthermore, we have demonstrated the synthetic application
of reductive alkylation products 7. Further work is in progress to
utilize novel O–H, O–H–E and O–H–RA reactions in synthetic
chemistry.
In a first step to probe the competition between two self-
catalyzed reactions between 1, 3 and 5a, we analyzed the energies
of the HOMO and the LUMO for each compound involved in
the reactions (Scheme 5). The calculated energy gaps between
the LUMO of the active olefin 5a and the HOMO of 1 are
greater than the energy gaps between the LUMO of 5a and
the HOMO of the Hantzsch ester 3. This result suggests that
a self-catalyzed hydride transfer reaction proceeds faster than a
Experimental
General methods
1
The H NMR and 13C NMR spectra were recorded at 400 MHz
and 100 MHz, respectively. The chemical shifts are reported in
ppm downfield to TMS (d = 0) for H NMR and relative to the
1
Scheme 5 HOMO–LUMO energy gaps and enthalpy differences for self-catalyzed hydrogenation and bis-adduct formation reactions.
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central CDCl3 resonance (d = 77.0) for 13C NMR. 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. The coupling constants J are given in Hz.
Column chromatography was performed using Acme’s silica gel
(particle size 0.063–0.200 mm). High-resolution mass spectra were
recorded on micromass ESI-TOF MS. GCMS mass spectrometry
was performed on Shimadzu GCMS-QP2010 mass spectrometer.
Elemental analyses were recorded on a Thermo Finnigan Flash
EA 1112 analyzer. LCMS mass spectra were recorded on either
a VG7070 H mass spectrometer using the EI technique or a
Shimadzu-LCMS-2010 A mass spectrometer. IR spectra were
recorded on JASCO FT/IR-5300 and Thermo Nicolet FT/IR-
5700. The X-ray diffraction measurements were carried out at
298 K on an automated Enraf-Nonious MACH 3 diffractometer
Hantzsch ester 3 was added 1.0 mL of dichloromethane, and then
the catalyst amino acid 4 (0.015 mmol, 5 mol%) was added and
the reaction mixture was stirred at 25 ◦C for the time indicated in
Scheme 3. After evaporation of the solvent completely, to the crude
reaction mixture were added 0.9 mmol of methyl vinyl ketone 9,
1.0 mL of DMSO solvent and 0.09 mmol of L-proline 4a and the
reaction mixture was stirred at 25 ◦C for 6 days. The crude reaction
mixture was worked up with aqueous NH4Cl solution, and the
aqueous layer was extracted with dichloromethane (3 ¥ 20 mL).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated. Pure one-pot products 11 and 12 were obtained
by column chromatography (silica gel, mixture of hexane–ethyl
acetate).
General procedure for the direct organocatalytic one-pot synthesis
of 2-alkyl-3-methoxy-cyclopent-2-enones 13. In an ordinary glass
vial equipped with a magnetic stirring bar, to 0.9 mmol of the
aldehyde 2, 0.3 mmol of cyclopentane-1,3-dione 1 and 0.3 mmol
of Hantzsch ester 3 was added 1.0 mL of dichloromethane, and
then the catalyst amino acid 4a (0.015 mmol, 5 mol%) was
added and the reaction mixture was stirred at 25 ◦C for the
time indicated in Scheme 2. After evaporation of the solvent
completely, to the crude reaction mixture was added an excess
ethereal solution of diazomethane and the reaction mixture was
stirred at room temperature for 0.5 h. After evaporation of the
solvent and excess diazomethane completely in a fume hood, the
crude reaction mixture was directly loaded onto a silica gel column
with or without aqueous work-up and pure one-pot products 13
were obtained by column chromatography (silica gel, mixture of
hexane–ethyl acetate).
˚
using graphite monochromated, Mo-Ka (l = 0.71073 A) radiation
with CAD4 software or the X-ray intensity data were measured
at 298 K on a Bruker SMART APEX CCD area detector system
equipped with a graphite monochromator and a Mo-Ka fine-
˚
focus sealed tube (l = 0.71073 A). For thin-layer chromatography
(TLC), silica gel plates Merck 60 F254 were used and compounds
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.
Materials
All solvents and commercially available chemicals were used as
received.
General experimental procedures for the double cascade reactions
General procedure for dehydration of 7a-alkyl-3a-hydroxy-
hexahydro-indene-1,5-diones 11. A solution of alcohol com-
pound 11 (0.2 mmol) and 1 N HClO4 (0.4 mmol) in DMSO
(1.0 ml) was stirred at 90 ◦C for 0.5 to 1 h. After cooling, the
reaction mixture was washed with water and the aqueous layer
was extracted with dichloromethane (3 ¥ 20 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated. Pure
products 10 were obtained by column chromatography (silica gel,
mixture of hexane–ethyl acetate).
Amino acid-catalyzed cascade olefination–hydrogenation reac-
tions with cyclopentane-1,3-dione. In an ordinary glass vial
equipped with a magnetic stirring bar, to 0.9 mmol of the aldehyde
2, 0.3 mmol of cyclopentane-1,3-dione 1 and 0.3mmolof Hantzsch
ester 3 was added 1.0 mL of solvent, and then the catalyst amino
acid 4 (0.015 mmol, 5 mol%) was added and the reaction mixture
was stirred at 25 ◦C for the time indicated in Tables 1–3. The
crude reaction mixture was directly loaded onto a silica gel column
with or without aqueous work-up, and pure cascade products 7
were obtained by column chromatography (silica gel, mixture of
hexane–ethyl acetate).
Acknowledgements
This work was made possible by a grant from the Department
of Science and Technology (DST), New Delhi. MK thanks the
Council of Scientific and Industrial Research (CSIR), New Delhi
for his research fellowship. We thank Prof. M. V. Rajasekharan, Mr
A. R. Biju and Dr P. Raghavaiah for their help in X-ray structural
analysis.
Amino acid-catalyzed Robinson annulation reaction. In an
ordinary glass vial equipped with a magnetic stirring bar, to
0.3 mmol of 2-alkyl-cyclopentane-1,3-diones 7 and 0.9 mmol of
methyl vinyl ketone 9 was added 1.0 mL of DMSO solvent, and
then the catalyst proline 4a (0.09 mmol, 30 mol%) was added and
the reaction mixture was stirred at 25 ◦C for 6 days. The crude
reaction mixture was worked up with aqueous NH4Cl solution,
and the aqueous layer was extracted with dichloromethane (3 ¥
20 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. Pure products 11 and 12 were obtained
by column chromatography (silica gel, mixture of hexane–ethyl
acetate).
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10 CCDC-674004 for 7i and CCDC-674005 for 10a contain the sup-
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