Direct catalytic asymmetric synthesis of highly functionalized tetronic acids/tetrahydro-isobenzofuran-1,5-diones via combination of cascade three-component reductive alkylations and Michael-aldol reactions

Article abstract of DOI:10.1039/c003588b

A practical and sustainable chemical process for the synthesis of highly substituted tetrahydro-isobenzofuran-1,5-diones was achieved for the first time through asymmetric cascade Michael-aldol reaction of 4-hydroxy-3-alkyl-5H-furan- 2-ones with alkyl vinyl ketones in the presence of a catalytic amount of l-proline or 9-amino-9-deoxyepiquinine/TCA. In this article, we discovered for the first time the asymmetric synthesis of privileged bicyclic lactones through kinetic resolution and show the synthetic application to pharmaceuticals and natural products synthesis.

Full text of DOI:10.1039/c003588b

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Direct catalytic asymmetric synthesis of highly functionalized tetronic
acids/tetrahydro-isobenzofuran-1,5-diones via combination of cascade
three-component reductive alkylations and Michael-aldol reactions†
Dhevalapally B. Ramachary* and Mamillapalli Kishor
Received 26th February 2010, Accepted 7th April 2010
First published as an Advance Article on the web 7th May 2010
DOI: 10.1039/c003588b
A practical and sustainable chemical process for the synthesis of highly substituted
tetrahydro-isobenzofuran-1,5-diones was achieved for the first time through asymmetric cascade
Michael-aldol reaction of 4-hydroxy-3-alkyl-5H-furan-2-ones with alkyl vinyl ketones in the presence
of a catalytic amount of L-proline or 9-amino-9-deoxyepiquinine/TCA. In this article, we discovered
for the first time the asymmetric synthesis of privileged bicyclic lactones through kinetic resolution and
show the synthetic application to pharmaceuticals and natural products synthesis.
the synthesis of functionalized tetrahydro-isobenzofuran-1,5-
Introduction
diones, which can serve as good intermediates for the total
Functionalized tetronic acids, 5,6-dihydro-pyran-2-ones, 4-
synthesis of natural and non-natural products as demonstrated
hydroxy-chromen-2-ones and tetrahydro-isobenzofuran-1,5-
in this work. Herein, first time we reported the organocatalytic
diones are an important class of heterocycles, which display very
cascade approach to the asymmetric synthesis of functionalized
large spectrum of biological activities and are widely used as
tetrahydro-isobenzofuran-1,5-diones via “sequential combination
synthetic intermediates, drug intermediates/ingredients in natural
of cascade three-component reductive alkylation (TCRA) and
product synthesis and also in pharmaceuticals (see Chart 1).1
As such, the development of new and more general catalytic
asymmetric methods for their preparation is of significant
interest.2 Interestingly, to the best of our knowledge there
is no report on the direct catalytic asymmetric method for
Michael-aldol (M-A) reactions”.3
Recently Barbas, List and co-workers rediscovered the novel
technology of amino acid-catalyzed intra-/inter-molecular aldol
reactions of ketones/aldehydes with variety of carbonyls to
provide a general route to a variety of aldol products in good
yields with high enantioselectivity, which is known as Barbas-
List aldol (BLA) reaction.4 The advent of amino acid-catalyzed
aldol reaction technology providing a high inspiration to scientific
community to develop cellular type cascade reactions based on
the in situ generated enamine/iminium chemistry.4
However, the amino acid-catalyzed intramolecular aldol re-
action of diketo-lactones 10 is not known and resulting aldol
products 11 and 12 are having a wide range of applications in
natural products and pharmaceutical chemistry (see Chart 1 and
Scheme 1) and also there is no direct asymmetric methodology
available to prepare them by using the classical reaction strategies.
Herein, we have reported a metal-free and novel technology
Chart 1 Natural and non-natural products library containing cascade
TCRA and M-A compounds.
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. See DOI: 10.1039/c003588b
Scheme 1 Direct asymmetric cascade TCRA and M-A reactions.
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Table 1 Optimization for the cascade TCRA reaction of 1a, 2a and 3a
catalysis would lead to bis-adduct 6aa in 75% yield without olefin
5aa formation (Table 1, entry 1). However, when we used one equiv.
of organic hydride 3 in cascade TCRA reaction of 1a and 2a,
bis-adduct 6aa were not detected and instead expected product
7aa were obtained with 80% yield under the standard reaction
conditions (Table 1, entry 2). The optimum conditions involved
the use of 5-mol% catalyst 4a and two equiv. of benzaldehyde 2a
in cascade TCRA reaction of 1a, 2a and 3 in CH2Cl2 at 25 ◦C for
5 h to furnish 7aa in very good yield (Table 1, entry 3). TCRA
product 7aa is important intermediate for the total synthesis of
caspase inhibitor (E) and which is emphasizing the value of this
TCRA approach to the pharmaceuticals.1h This interesting result
represents a novel methodology for the preparation of 3-alkyl-
tetronic acids 7 and a new reactivity for amino acid catalysis.
Products yield (%)b
Aldehyde 2a
(equiv.)
H. ester 3
(equiv.)
Entry
Time/h
6aa
7aa
1
2
3
4
2.0
1.0
2.0
3.0
—
24
24
5
75
—
—
—
—
80
90
90
1.0
1.0
1.0
2
a Reactions were carried out in solvent (0.3 M) with 1–3 equiv. of 2a relative
to the 1a and 3 (0.5 mmol) in the presence of 5-mol% of catalyst 4a. b Yield
refers to the column-purified product.
Asymmetric cascade M-A reaction with 3-benzyl-tetronic acid:
reaction optimization
for the asymmetric synthesis of highly substituted tetrahydro-
isobenzofuran-1,5-diones 11/12 by using the two-step sequen-
tial combination of organocatalytic cascade TCRA and M-A
reactions from commercially available cyclic b-keto-lactones 1,
aldehydes/ketones 2, organic hydride 3, amines/amino acid 4 and
alkyl vinyl ketones 9 (Scheme 1).
Over the last few years, we have been interested in an amino
acid-catalyzed cascade TCRA reactions of CH-acids, aldehy-
des/ketones and organic hydride for the generation of reductive
alkylation products via 1 x C–C/2 x C–H bonds formation in one-
pot.5 During our investigation for new reactive species for such
TCRA processes and also for synthetic applications, we decided
to explore the potential ability of the cyclic b-keto-lactones 1
as CH-acids to participate in an amino acid-catalyzed TCRA
reaction with aldehydes/ketones 2 and organic hydride 3 (see
Scheme 1). Herein, we report our findings regarding these new
TCRA reactions and their synthetic applications.
After successful synthesis of 3-benzyl-tetronic acid 7aa, we
initiated our preliminary studies of the asymmetric cascade
M-A reactions by screening a number of known and novel
organocatalysts for the Michael-aldolization of 7aa with 3 equiv. of
methyl vinyl ketone 9a and some representative results are shown
in Table 2. Interestingly, cascade M-A reaction of 7aa with 3 equiv.
of methyl vinyl ketone 9a in DMSO under 30-mol% of L-proline
4a-catalysis furnished the Michael product (+)-10aaa in 10% yield
with only 23% ee and cascade M-A product (-)-11aaa in 70%
yield with 52% ee, which is enriched to 86% ee with 60–70% yield
after one quick crystallization from isopropanol at 25 ◦C (Table 2,
entry 1). Same reaction in DMSO under 30-mol% of D-proline 4b-
catalysis furnished the opposite enantiomer of Michael product
(-)-10aaa in 10% yield with only 21% ee and cascade M-A product
(+)-11aaa in 50% yield with 53% ee, which is enriched to 92% ee
with 60–70% yield after one quick crystallization from isopropanol
at 25 ◦C (Table 2, entry 2).
To further improvement of ee/yield of cascade products
10aaa/11aaa, we also tested number of primary-/secondary-
amino acids, chiral pyrrolidines and tert-amines based on
cinchona alkaloids like L-phenylalanine 4c, L-tryptophan
4d, OtBu-L-threonine 4e, D-amino-phenyl-acetic acid 4f, 4-
benzyl-1-methyl-imidazolidine-2-carboxylic acid 4g, L-DPP 4h,
L-DPPOTMS 4i, D-DPPOTMS 4j, L-(3,5-Me2)2DPPOTMS 4k,
Results and discussion
Amino acid-catalyzed TCRA reaction with tetronic acid: reaction
optimization
We observed that the reaction of tetronic acid 1a with in situ
generated iminium ion from benzaldehyde 2a under proline-
Table 2 Optimization for the cascade M-A reaction of 7aa and 9aa
Products yield (%)b
Products ee (%)c
Entry
Catalyst 4 (30 mol%)
Solvent (0.3 M)
Time/h
10aaa
11aaa
10aaa
11aaa
1
L-proline 4a
DMSO
DMSO
THF
48
48
8
10
10
60
70
50
40
-23
21
8
-52(-86)
53(92)
55(92)
2
D-proline 4b
3d
Q-NH2/TCA 4u
a Reactions were carried out in solvent (0.3 M) with 3 equiv. of 9a relative to the 7aa (0.5 mmol) in the presence of 30-mol% of catalyst 4. b Yield refers
to the column-purified product. c ee determined by CSP HPLC analysis and values in parenthesis obtained from one quick crystallization of 11aaa from
i-PrOH at 25 ◦C. d Reactions were carried out in solvent (0.1 M) with 3 equiv. of 9a relative to the 7aa (0.5 mmol) in the presence of 10-mol% of 4u and
40-mol% of co-catalyst TCA.
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L-2-benzhydryl-pyrrolidine 4l, quinine (Q) 4m, quinidine (QD)
4n, cinchonine (C) 4o, cinchonidine (CD) 4p, QD-OBn 4q, OH-
QD-OBn 4r, OH-QD 4s, CD-NH2 4t, Q-NH2 4u and DHQ-NH2
4v as catalysts and TCA, TFA or 3,5-DNBA as co-catalysts for
the cascade asymmetric M-A reaction of 7aa with 9a in different
solvents as demonstrated in Chart 2 and Table S1–S4 (see ESI†).
Among these catalysts 4c–v tested for cascade asymmetric M-
A reaction, 10-mol% of 9-amino-9-deoxyepiquinine (Q-NH2) 4u
with 40-mol% of trichloroacetic acid (TCA) showed better results
compared to other catalysts as shown in Table S1–S4 and Table 2,
entry 3.6 Cascade M-A reaction of 7aa and 9a in THF under Q-
NH2/TCA 4u-catalysis furnished the Michael product (-)-10aaa
in 60% yield with only 8% ee and cascade M-A product (+)-11aaa
in 40% yield with 55% ee, which is enriched to 92% ee with 60–
70% yield after one quick crystallization from isopropanol at 25 ◦C
(Table 2, entry 3). We envisioned the optimized condition to be
25 ◦C in DMSO under 30-mol% L-proline 4a-catalysis or at 25 ◦C
in THF under 10-mol% Q-NH2/TCA 4u-catalysis to furnish both
enantiomers of highly substituted M-A product (-)-11aaa and (+)-
11aaa in 70/40% yield with 86–92% ee respectively (Table 2). The
absolute configuration of products (-)-/(+)-11aaa prepared under
L-/D-proline-catalysis was established by comparison with the
proline-catalyzed Hajos-Parrish-Eder-Sauer-Wiechert reaction.4,7
Scheme 2 Observation of kinetic resolution in the cascade M-A reaction
M-A reactions at the ambient conditions. The pronounced kinetic
resolution observed in the aldol reaction inspired us to study the
enantioselective cascade Michael-aldol annulation reaction with
variety of 3-alkyl-tetronic acids.
Diversity-oriented high-yielding synthesis of TCRA products
7aa–7fm
With the optimized reaction conditions in hand, the scope of
the amino acid- and amine/acid-catalyzed cascade TCRA and
asymmetric M-A reactions was investigated. A series of func-
tionalized cyclic b-keto-lactones 1a–f were reacted with 3 equiv.
of aldehydes/ketones 2a–m and 1 equiv. of organic hydride 3
catalyzed by 5-mol% of L-proline 4a at 25 ◦C in CH2Cl2 (Table 3).
TCRA reaction of tetronic acid 1a and 3 with neutral, electron-
withdrawing and electron-donating substituted benzaldehydes
2a–f were generated expected products 7aa–af with excellent yields
(Table 3). Interestingly, TCRA reaction of benzyloxyacetaldehyde
2g with 1a and 3 under 4a-catalysis furnished the 7ag as major
product with 90% yield (Table 3). Fascinatingly, reaction of
tetronic acid 1a with acetone 2h under 4a-catalysis furnished
the 7ah as major single product (Table 3). Interestingly, TCRA
reaction of substituted 4-hydroxy-pyran-2-ones 1b–e with 2a–l
and 3 under 4a-catalysis furnished the expected 3-alkyl-4-hydroxy-
pyran-2-ones 7 with very good yields (Table 3). In continuation,
we also tested 2-hydroxy-[1,4]naphthoquinone 1f as CH-acid
source in TCRA reactions. Reaction of 1f with 2a/2m and
3 under 4a-catalysis furnished the expected 3-alkyl-2-hydroxy-
[1,4]naphthoquinones 7 with good yields as shown in Table 3.
To test the reactivity of enolic OH in cascade TCRA products,
we treated TCRA product 7aa with 15 equiv. of ethereal dia-
zomethane at 25 ◦C for 0.5–1.0 h to furnish the O-methylated
product 8aa in good yields through self-catalysis as shown
in Table 3. Generality of the self-catalyzed chemoselective O-
methylation was further confirmed by one more example using
7fa to furnish the expected 8af in 87% yield.
Chart 2 Library of catalysts screened for the cascade asymmetric M-A
reaction.
Observation of kinetic resolution in the asymmetric cascade
Michael-aldol reactions
Next, we investigated the possibility of kinetic resolution in the
amino acid 4a–b or amine/acid 4u catalyzed cascade asymmetric
M-A reaction of 7aa and 9a at the optimized conditions, because
ee of Michael adduct is not similar as compared to aldol product
from cascade M-A reactions. Treatment of racemic ( )-10aaa
with 30 mol% of (S)-4a in DMSO at 25 ◦C for 1 h furnished
(-)-11aaa in 59% yield with 39% ee. This product was accom-
panied by recovered (+)-10aaa in 22% yield with 16% ee (see
Scheme 2). In a similar manner, treatment of racemic ( )-10aaa
with 10/40 mol% of Q-NH2/TCA 4u in THF at 25 ◦C for 8 h
resulted in the formation of (+)-11aaa in 46% yield with 30%
ee and also recovered (-)-10aaa in 27% yield with 63% ee (see
Scheme 2). Overall notable kinetic resolution was achieved by
means of an amino acid 4a or amine/acid 4u-catalysis in cascade
The results in Table 3 demonstrate the broad scope of this
cascade TCRA methodology covering a structurally diverse group
of cyclic b-keto-lactones 1a–f, aldehydes 2a–m and ketone 2h with
many of the yields obtained being very good, or indeed better,
than previously published two-step alkylation reactions.2
TCRA product 7aa and analogues 7ab–ah are important
compounds for the treating HIV and other retroviruses (D),1g
and also for the synthesis of caspase inhibitor (E)1h and TCRA
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Table 3 High-yielding synthesis of cascade TCRA products 7a
a Reactions were carried out in CH2Cl2 (0.3 M) with 3 equiv. of 2 relative to the 1 and 3 (0.5 mmol) in the presence of 5-mol% of catalyst 4a. Yield refers
to the column-purified product. b Acetone 2h used as solvent and reagent. c TCRA compound 7 were reacted with 15 equiv. of ethereal diazomethane and
stirred at 25 ◦C for 0.5–1 h.
products 7ba–dk are directly useful compounds as HIV-1 and
HIV-2 protease inhibitors, antiviral/antibacterial agents (F),1i–1j
and hepatitis C virus polymerase inhibitor (G).1k TCRA products
7ea/el and analogues are useful as inhibitors of vitamin K epoxide
reductase (H),1l reducing the prothrombin content of the blood
(I)1m and HIV-1 protease inhibitor (J).1n Products 7fa, 7fm and 8fa
are useful compounds as treating Huntington’s disease (M),1q anti-
bacterial, antiviral, and pesticidal compounds (N)1r emphasizing
the value of this novel TCRA approach to the pharmaceuticals
and agrochemicals.
Table 4). Interestingly, Q-NH2/TCA 4u-catalyzed M-A reaction
of 4-hydroxy-3-naphthalen-1-ylmethyl-5H-furan-2-one 7ab with
3 equiv. of freshly distilled methyl vinyl ketone 9a in THF furnished
the expected Michael-alcohol product (+)-11aba in 40% yield with
80% ee and which is accompanying with Michael adduct 10aba
in 60% yield with 13% ee at 25 ◦C for 6 h (Table 4, entry 3). A
series of 4-hydroxy-3-alkyl-5H-furan-2-one 7ac–an were reacted
with 3.0 equiv. of methyl vinyl ketone 9a catalyzed by 30 mol%
of L-proline 4a at 25 ◦C in DMSO for 24–72 h or 10 mol% of Q-
NH2/TCA 4u at 25 ◦C in THF for 6–48 h (Table 4). All expected
bicyclic-alcohols of M-A products 11aca–11ana were obtained in
good yields and ee’s as shown in Table 4. Hydrolysis of bicyclic-
alcohol (+)-11aaa obtained from 4u catalysis with p-TSA in C6H6
at 80 ◦C for 1–2 h furnished the expected bicyclic-ketone (-)-
12aaa in 70% yield with 92% ee as shown in Table 5, entry 1. In a
similar manner, we have prepared two more bicyclic-ketones (-)-
12ana/(+)-12ana in 92% yield with 30–47% ee as shown in Table 5,
entries 2–3.
Applications of TCRA products
Diversity-oriented asymmetric synthesis of cascade M-A products
11aaa–11ana
With natural products synthesis and pharmaceutical applications
in mind, we further extended the utilization of TCRA prod-
ucts in the asymmetric synthesis of functionalized tetrahydro-
isobenzofuran-1,5-diones 11/12 via cascade M-A reactions of
7aa–an and 9a–b under 4a- or 4u-catalysis in one-pot as shown in
Table 4.8 All expected chiral tetrahydro-isobenzofuran-1,5-diones
11/12 were furnished in good yields with good to moderate
ee’s from the reaction of 7 with 9 under 4a or 4u-catalysis (see
Asymmetric synthesis of the key White intermediate for the
synthesis of trisporic acids A–B
Interestingly, L-proline 4a-catalyzed cascade M-A reaction of 4-
hydroxy-3-benzyl-5H-furan-2-one 7aa with 3 equiv. of freshly
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Table 4 Synthesis of chiral cascade M-A products 11a
Scheme 3 Asymmetric synthesis of the key White intermediate and
analogues for the chiral synthesis of trisporic acids A–B.
a Yield refers to the column-purified product. b ee determined by CSP
HPLC analysis and values in paranthesis are obtained from one quick
crystallization of 11 from i-PrOH at 25 ◦C.
10anb in 95% yield with <5% ee, which on further treatment with
30 mol% of L-proline 4a in DMSO at 25 ◦C for 48 h furnished
the cascade M-A product 11anb in 50% yield with 72% ee through
kinetic resolution and which is accompanying with 1 : 1 mixture of
unreacted Michael adduct 10anb and new product 13anb in 18%
yield (see Scheme 3). Unfortunately, we are not able to separate
these two compounds through column chromatography or chiral
HPLC. Hydrolysis of chiral bicyclic-alcohols 11aab/11anb under
p-TSA-catalysis in C6H6 at 80 ◦C for 1–2 h furnished the
expected bicyclic-ketones (+)-12aab/(+)-12anb in 90/95% yield
with 86/72% ee, respectively as shown in Scheme 3.9 The absolute
configuration of products (+)-12aab/(+)-12anb were established
by comparison with the Edmundo A. Ru´veda’s chiral resolution
of the key White intermediate for the synthesis of trisporic acids
B.9b Chiral bicyclic-ketone (+)-12anb and their analogues would be
suitable intermediates for the asymmetric total synthesis of natural
products saudin A, trisporic acids B, anti-ulcerogenic compound
(+)-cassiol and fraxinellonone and its related analogues as shown
in Scheme 3.1a–1e,9
Table 5 Synthesis of chiral bicyclic-ketones 12a
Entry
R1
Products
Yield (%)b
ee (%)c
1
2
3
Ph
H
H
(-)-12aaa
(-)-12ana
(+)-12ana
70
92
92
92
47
30
a Reactions were carried out in benzene (0.1 M) with 10 mol% of p-TSA
as catalyst. b Yield refers to the column purified product. c Ee determined
by CSP HPLC analysis.
Mechanistic insights
distilled ethyl vinyl ketone 9b in DMSO at 25 ◦C for 48 h furnished
the only Michael adduct 10aab in 80% yield with <5% ee, which on
further treatment with 30 mol% of L-proline 4a in DMSO at 25 ◦C
for 48 h furnished the expected cascade M-A product (-)-11aab
in 60% yield with 86% ee through kinetic resolution and which
is accompanying with unreacted Michael adduct 10aab in 10%
yield with 21% ee (see Scheme 3). In a similar manner, L-proline
4a-catalyzed cascade M-A reaction of 4-hydroxy-3-methyl-5H-
furan-2-one 7an with 3 equiv. of freshly distilled ethyl vinyl ketone
9b in DMSO at 25 ◦C for 48 h furnished the Michael adduct
The possible mechanism for L-proline- or Q-NH2/TCA-catalyzed
enantioselective synthesis of cascade products 7, 10 and 11 through
the reaction of tetronic acid 1a, aldehydes/ketones 2, Hantzsch
ester 3 and alkyl vinyl ketone 9 is illustrated in Schemes 4 and 5.
In the first step of cascade TCRA reaction, the catalyst (S)-4a
activates component 2 by most likely iminium ion formation,
which then selectively adds to the tetronic acid 1a via a Mannich
and retro-Mannich type reaction to generate active olefin 5.5
The following second step is hydrogenation of active olefin 5 by
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The observed high enantioselectivity in cascade 11 products
through kinetic resolution can be explained as illustrated in
Scheme 5. L-Proline 4a-catalyzed Michael addition of 7 to alkyl
vinyl ketone 9 furnished the Michael adducts (R)-10 and (S)-10
with <5% ee, which on further reaction of amino acid (S)-4a with
both ketones (R)-10 and (S)-10 generates the enamines with almost
similar rates as shown in Scheme 5. Intramolecular aldol conden-
sation of enamine generated from (R)-10 will be a faster reaction
compared to enamine generated from (S)-10 as shown in TS-1 and
TS-2 based on the strong/weak hydrogen bonding interactions,
respectively (see Scheme 5). In situ hydrolysis of imines generated
from TS-1 and TS-2 with H2O furnished the bicyclic-alcohols
(3aS,7aR)-11 and (3aR,7aS)-11 respectively and observed high
ee of (3aS,7aR)-11 is directly due to the faster reaction rate in
TS-1. In a similar manner, intramolecular aldol condensation of
enamine generated from (S)-10 with Q-NH2/TCA 4u will be a
faster reaction compared to enamine generated from (R)-10 as
shown in TS-3 based on the hydrogen bonding interactions and
steric hindrance, respectively (see Scheme 5). In situ hydrolysis
of imine generated from TS-3 with H2O furnished the bicyclic-
alcohol (3aR,7aS)-11 and observed high ee of (3aR,7aS)-11 is
directly due to the faster reaction rate in TS-3. Stereoselective
hydrogen bonding interactions are main controlling factor than
steric strain control in biomimetic cascade asymmetric M-A
reactions, because ee of M-A product 11 is controlled by co-
catalyst in 4u-catalysis. Presently observed high enantioselectivity
in cascade M-A reactions through kinetic resolution can be easily
understood by rate differences in TS-1 to TS-3, which may needs
to get support from the high level DFT calculations.
Scheme 4 Proposed catalytic cycle for the double cascade reactions.
Conclusions
In summary, this is the first time we have developed the L-proline
4a- or Q-NH2/TCA 4u-catalyzed asymmetric cascade M-A reac-
tion of 4-hydroxy-3-alkyl-5H-furan-2-ones with alkyl vinyl ketone
at the ambient conditions. The asymmetric M-A reaction proceeds
in good yields with high selectivity using L-proline or Q-NH2/TCA
as the catalyst through kinetic resolution. Furthermore, we have
demonstrated the application of TCRA and M-A reactions in
the synthesis of pharmaceutically useful molecules and natural
products. Presently developed combination of cascade TCRA and
M-A reactions will be suitable to synthesize library of 12anb
for the total synthesis of biologically important natural products
and their analogues. Further work is in progress to utilize chiral
bicyclic-alcohols as intermediates for the asymmetric synthesis of
bio-active molecules.
Scheme 5 Proposed transition states for the asymmetric reactions.
Experimental
Hantzsch ester 3 to produce 7 through self-catalysis by decreasing
HOMO–LUMO energy gap between 3 and 5 respectively.5 In
the subsequent third step or first step of cascade M-A reaction,
Michael addition of 7 to alkyl vinyl ketone 9 via most likely
iminium ionactivation leads to the formation ofMichaeladduct 10
with less enantioselective fashion (≤5% ee). In the fourth step, (S)-
4a or Q-NH2/TCA 4u catalyzed the asymmetric intramolecular
aldol condensation of 10 via enamine catalysis and ee’s of
the desired bicyclic-alcohols 11 were obtained through kinetic
resolution.
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
1
ppm downfield to TMS (d = 0) for H NMR and relative to the
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
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(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
VG7070H mass spectrometer using EI technique or Shimadzu-
LCMS-2010A mass spectrometer. IR spectra were recorded on
JASCO FT/IR-5300 and Thermo Nicolet FT/IR-5700. 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.
10 were obtained by column chromatography (silica gel, mixture
of hexane–ethyl acetate).
Preparation of racemic cascade Michael-aldol products 11 with
DL-b-phenylalanine-catalysis
In an ordinary glass vial equipped with a magnetic stirring bar, to
0.3 mmol of 4-hydroxy-3-alkyl-5H-furan-2-one 7 and 0.9 mmol
of methyl vinyl ketone 9a with a catalytic amount of DL-b-
phenylalanine in 1.0 mL of THF solvent and the reaction mixture
◦
was stirred at 25 C for 6–48 h. The crude reaction mixture was
worked up with aqueous NH4Cl solution, and the aqueous layer
was extracted with ethyl acetate (3 ¥ 20 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated.
Pure products 11 were obtained by column chromatography (silica
gel, mixture of hexane–ethyl acetate).
Materials
All solvents and commercially available chemicals were used as
received.
Amino acid-catalyzed asymmetric cascade Michael-aldol reactions
In an ordinary glass vial equipped with a magnetic stirring bar, to
0.3 mmol of 4-hydroxy-3-alkyl-5H-furan-2-one 7 and 0.9 mmol
of methyl vinyl ketone 9a was added 1.0 mL of DMSO solvent,
and then the catalyst L-proline 4a (0.09 mmol) was added, and
the reaction mixture was stirred at 25 ◦C for 2 days. The crude
reaction mixture was worked up with aqueous NH4Cl solution,
and the aqueous layer was extracted with ethyl acetate (3 ¥ 20 mL).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated. Pure cascade M-A products 11 were obtained
by column chromatography (silica gel, mixture of hexane–ethyl
acetate).
General experimental procedures for the cascade
TCRA and M-A reactions
Amino acid-catalyzed cascade three-component reductive
alkylation (TCRA) reactions with cyclic b-keto-lactones
In an ordinary glass vial equipped with a magnetic stirring bar, to
0.6 mmol of the aldehyde 2, 0.3 mmol of CH acid 1, and 0.3 mmol
of Hantzsch ester 3 was added 1.0 mL of solvent, and then the
catalyst amino acid 4a (0.015 mmol) was added, and the reaction
mixture was stirred at 25 ◦C for the time indicated in Table 3. The
crude reaction mixture was directly loaded onto a silica gel column
with or without aqueous workup, and pure cascade products 7aa–
7fm were obtained by column chromatography (silica gel, mixture
of hexane–ethyl acetate).
Q-NH2/TCA-catalyzed asymmetric cascade Michael-aldol
reactions
In an ordinary glass vial equipped with a magnetic stirring bar,
to Q-NH2 4u (0.05 mmol) and TCA (32 mg, 0.2 mmol) in THF
(5.0 mL) were added and stirred at 25 ◦C for 10 min then 0.5 mmol
of 4-hydroxy-3-alkyl-5H-furan-2-one 7 and 1.5 mmol of methyl
vinyl ketone 9a was added, and the reaction mixture was stirred at
25 ◦C for 6–48 h. The crude reaction mixture was worked up with
aqueous NH4Cl solution, and the aqueous layer was extracted with
ethyl acetate (3 ¥ 20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. Pure cascade M-A products
11 were obtained by column chromatography (silica gel, mixture
of hexane–ethyl acetate).
General procedure for the synthesis of 3-benzyl-4-methoxy-5H-
furan-2-one 8aa
In an ordinary glass vial equipped with a magnetic stirring bar, to
1.0 mmol of 4-hydroxy-3-benzyl-5H-furan-2-one 7aa in 1.0 mL of
◦
ether at 0 C added an excess ethereal solution of diazomethane
and the reaction mixture was stirred at room temperature for the
0.5 h. After evaporation of the solvent and excess diazomethane
completely in a fume hood, the crude reaction mixture was directly
loaded on silica gel column without aqueous work-up and pure
products 8aa were obtained by column chromatography (silica gel,
mixture of hexane/ethyl acetate).
General procedure for the hydrolysis of cascade Michael-aldol
products
A solution of bicyclic alcohol compound 11 (0.5 mmol) and p-
TSA (0.05 mmol) in dry benzene (3.0 mL) was stirred at 80 ◦C
for 1 h. After cooling, the reaction mixture washed with aqueous
sodium bicarbonate solution and the aqueous layer was extracted
with dichloromethane (2 ¥ 20 mL). The combined organic layers
were dried (Na2SO4), filtered and concentrated. Pure products 12
were obtained by column chromatography (silica gel, mixture of
hexane–ethyl acetate).
Preparation for racemic Michael products 10 with
triethylamine-catalysis
In an ordinary glass vial equipped with a magnetic stirring bar, to
0.3 mmol of 4-hydroxy-3-alkyl-5H-furan-2-one 7 and 0.9 mmol of
methyl vinyl ketone 9a with a catalytic amount of triethylamine
in 1.0 mL of THF solvent and the reaction mixture was stirred at
25 ◦C for 6–48 h. The crude reaction mixture was worked up with
aqueous NH4Cl solution, and the aqueous layer was extracted
with ethyl acetate (3 ¥ 20 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated. Pure products
Many of the cascade products 7, 8, 10 and 11 are commercially
available, or have been described previously, and their analytical
data match literature values. New compounds were characterized
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1
on the basis of IR, H and 13C NMR and analytical data (see
ESI†).
Int. Ed., 2007, 46, 1570–1581; (g) For the excellent review on iminium-ion
induced cascade reactions, see: A. Erkkila¨, I. Majander and P. M. Pihko,
Chem. Rev., 2007, 107, 5416–5470. For recent papers on organocatalytic
cascade Michael-aldol reactions, see: (h) G. Luo, S. Zhang, W. Duan
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Acknowledgements
This work was made possible by a grant from the Department
of Science and Technology (DST), New Delhi [Grant No.:
DST/SR/S1/OC-65/2008]. MK thanks Council of Scientific and
Industrial Research (CSIR), New Delhi for his SRF fellowship.
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