Direct Organocatalytic Multicomponent Synthesis of Enantiopure γ-Butyrolactones via Tandem Knoevenagel-Michael-Lactonization Sequence

Article abstract of DOI:10.1002/adsc.201701084

An expedient and straightforward protocol is developed for the synthesis of highly enantiopure synthesis of γ-butyrolactones. For the first time, one pot enantioselective organocatalytic multicomponent reaction (OMCR) is explored to construct functionalized butyrolactones without the use of pre-functionalized substrates and expensive transition metals. The protocol is proved to be reproducible on a gram scale. Density functional theory (DFT) calculations strongly support the mechanism and were in close agreement with the observed high stereoselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201701084

Title: Direct Organocatalytic Multicomponent Synthesis of Enantiopure
γ-Butyrolactones via Tandem Knoevenagel-Michael-
Lactonization Sequence
Authors: Tushar M. Khopade, Amol D. Sonawane, Jyotsna S. Arora,
and Ramakrishna Bhat
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701084
Link to VoR: http://dx.doi.org/10.1002/adsc.201701084

10.1002/adsc.201701084
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Direct Organocatalytic Multicomponent Synthesis of
Enantiopure γ-Butyrolactones via Tandem Knoevenagel-
Michael-Lactonization Sequence
Tushar M. Khopade,a Amol D. Sonawane,a Jyotsna S. Aroraa and Ramakrishna G.
Bhata,*
aDepartment of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune, Dr. Homi Bhabha Road,
Pashan, 411008, Pune, Maharashtra, India.
E-mail: rgb@iiserpune.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
(See Fig 1c). Moreover, it is important to note that in other
protocols only aromatic hydroxyketones are proved to be
efficient precursors for the enantioselective synthesis of γ-
butyrolactones and related compounds such as five
membered oxygen heterocycles.[6] However, these
multistep methods are limited to aromatic hydroxyketones
and aromatic Michael acceptors. While the aliphatic
hydroxyketones and aliphatic Michael acceptors did not
react under the reaction conditions[6a] or they were not
explored possibly due to the similar reasons.[6b] However,
organocatalyzed enantiopure synthesis of γ-butyrolactones
that involves easily and commercially available starting
materials, and less reactive simple aliphatic as well as
aromatic hydroxyketones in one step is much more
challenging and demanding to pursue. Some of these
synthetic limitations strongly encouraged us to explore the
synthesis of enantiopure lactones by more convenient and
practical approach. The key challenges are to avoid pre-
functionalized starting materials and expensive transition
metal catalysts. One-pot organocatalytic multicomponent
reactions can prove to be one of the very important
strategies to access the enantiopure γ-butyrolactones in a
cost effective and efficient manner.
Abstract. An expedient and straightforward protocol is
developed for the synthesis of highly enantiopure synthesis
of γ-butyrolactones. For the first time, one pot
enantioselective organocatalytic multicomponent reaction
(OMCR) is explored to construct functionalized
butyrolactones without the use of pre-functionalized
substrates and expensive transition metals. The protocol is
proved to be reproducible on a gram scale. Density
functional theory (DFT) calculations strongly support the
mechanism and were in close agreement with the observed
high stereoselectivity.
Keywords: Multocomponent reactions • Organocatalysis •
γ-Butylrolactones • Enantioselectivity • Hetero-Diels-Alder
reaction
Optically active γ-butyrolactone is one of the most
abundant structural motifs in a wide array of biologically
active natural products.[1] In fact, the γ-butyrolactone core
constitutes about 10% of naturally occurring compounds[2]
and many of these possess a broad range of biological
activities and are known potent anticancer, antibacterial
and antifungal agents.[3] In this regard, several multistep
catalytic approaches have been explored for the racemic
synthesis of γ-butyrolactones.[4] Considering the inevitable
importance of γ-lactone scaffold, conspicuous efforts have
been devoted towards the enantioselective synthesis of a γ-
butyrolactone core with the catalytic approach.[5] Among
these many enantioselective methods, most noteworthy are
asymmetric transfer hydrogenation (Fig 1a),[5a-5c] gold
catalyzed lactonization by Lipshutz (see Fig 1b)[5d] and
chromium catalyzed γ-butyrolactone synthesis by Yun.[5e]
However, some of these methodologies rely on the use of
heavy and expensive transitional metal catalysts (Ir, Ru,
Au, Cr, etc), very expensive ligands and commercially
unavailable pre-functionalized starting materials. Notably,
only countable organocatalyzed protocols such as
asymmetric cross-benzoin/Michael/acetalization by Han,[5f]
cross annulation by Saigo[5g] and Fiksdahl[5h] are limited
only to highly reactive fluorinated ketones as substrates
Figure 1. Enantioselective synthesis of γ-butyrolactones.
1
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10.1002/adsc.201701084
Advanced Synthesis & Catalysis
albeit in poor enantioselectivity at room temperature
(Table 1, entry 1).
Remarkably, to the best of our knowledge, one-pot
enantioselective organocatalytic multicomponent reaction
(OMCR) for the formation of γ-butyrolactone remains an
unmet challenge till date. Keeping all these parameters in
mind, we ventured into developing a novel and more
convenient strategy to synthesize γ-butyrolactone. Herein,
in this paper we report a novel and expedient enantiopure
synthesis of γ-butyrolactones achieved by organocatalytic
enantioselective tandem three component reaction between
Meldrum’s acid, aldehyde and hydroxyketone for the first
time. Recently our laboratory has shown a considerable
interest in Meldrum’s acid related synthesis.[7] In our
continuing efforts, we became interested to evaluate the
scope of Meldrum’s acid with the asymmetric catalysis.
Meldrum’s acid has attracted significant attention as it
offers various valuable products[8] and the usefulness of
which is efficiently demonstrated in complex
entry
Catalyst
(mol%)
Additive
(mol%)
Yieldb d.r.
(%) (trans:
cis) c
ee (%)
(trans/
cis)d
multicomponent
processes.[9]
Undoubtedly,
α,β-
1
2a
3
D-Pro(20)
D-Pro(20)
D-Pro(20)
L-Pro(20)
L-Pro(20)
L-Pro(20)
D-Phg(20)
D-Pip(20)
P (20)
-
-
63
1:2.1
24/26
nd
unsaturated alkylidene Meldrum’s acid derivative 4 acts as
an excellent Michael acceptor in 1,4-addition reaction[10]
and the ensuing intermediates are highly versatile
compounds for various new transformations. By taking
into account of these, we hypothesized a novel three
component chemoselective tandem Knoevenagel-Michael-
lactonization sequence as shown in scheme 1. However,
our proposed multicomponent synthetic scheme has
following daunting chemoselectivity challenges to be met
(Scheme 1). Some of them are:(1) the Knoevenagel
condensation reaction should rapidly lead to alkylidene
Meldrum’s acid product 4 (step 1); (2) very importantly,
1,4-Michael addition (step 2) has to be dominant over aldol
condensation[11] (step 3); (3) by-product, acetone should
barely take part in the reaction to avoid side product 11[9a]
(step 4), i.e. 1,4-Michael addition on intermediate 4; (4)
finally, the lactonization should happen in one pot (step 5)
under ambient temperature. Keeping all these possibilities
in mind, initially we planned to explore the reaction by
using proline as a catalyst as it has widely been used in
aminocatalysis.[12]
trace
64
60
55
50
8
nd
1:2.1
1:2.1
1:2
Q1(20)
Q1(20)
(S)-BINOL(20)
(R)-
nd/24
nd /21
nd /25
nd /25
nd
4
5
6
1:2
7
Q1(20)
-
nd
8
trace
-
nd
nd
9
-
-
10
11
12
13a
14 e
15 e
-
Q1(20)
-
-
-
-
Q2(20)
70
79
trace
78
78
2.5:1
2.5:1
nd
89/
Q2(20)
TFA (40)
TFA (40)
TFA (10)
TFA (20)
91/58
nd
Q2(20)
Q2(5)
2.5:1
2.5:1
91/58
91/58
Q2(10)
Reaction Conditions: Meldrum’s acid 1 (1 equiv.), Benzaldehyde
(1.05 equiv.), Hydroxyacetone (3 equiv.) Catalyst (5-20 mol%),
a
Additive (10-40 mol%), in CHCl3 at rt, 24 h, reactions were
o
carried out at 0 C, bisolated yield after purification by column
c
chromatography, dr was calculated based isolated yileds dee was
e
determined by HPLC, Reactions were stirred for 24 h followed
by heating at 60 oC for 6 h for the decarboxylation.
The structures of both cis and trans diastereomers were
1
confirmed by H, 13C NMR spectral analysis and single-
crystal X-ray diffraction data (see ESI).[13] The low
enantioselectivity of the product 6a may be attributed to
either inadequate steric bulk of proline or less efficient
steric interactions. Initially, we believed that epimerization
of cis-lactone would have resulted in poor
diastereoselective outcome. However, this possibility was
ruled out as we observed no epimerization of cis-lactone of
6a under the similar reaction conditions even after
prolonged reaction time. Subsequently, lowering the
Scheme 1. Proposed one pot synthesis of enantiopure γ-
butyrolactone via Knoevenagel-Michael-lactonization.
o
reaction temperature to 0 C turned out to be extremely
disadvantageous (Table 1, entry 2). This initial exciting
breakthrough for the one pot lactonization encouraged us
to screen some more efficient catalyst systems. Recently, it
has been demonstrated that combining additional
supplemental co-catalyst along with amino acids enhances
the effective stereo interactions.[14] Therefore, we planned
Initially, a model reaction was performed by using
Meldrum’s acid 1, benzaldehyde 2a and hydroxyacetone
3a in presence of catalytic amount of D-proline (20 mol%)
in chloroform. Gratifyingly, the desired lactone 6a was
obtained but as two separable diastereomers (1:2.1 d.r.),
2
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10.1002/adsc.201701084
Advanced Synthesis & Catalysis
to introduce a cinchona based thiourea-amino acid catalytic
assembly with an aim to have high stereocontrol to this
reaction. However, all the modules did not enhance the
enantioselectivity (Table 1, entries 3-7). The lack of
enantioselectivity could be attributed to the unanticipated,
but favorable acid-base interaction between Meldrum’s
acid (pKa 4.9) and thiourea. This might have resulted
proline to catalyze the reaction solely. Surprisingly,
additional amino acid based catalyst (D-pipecolic acid or
P) and thiourea catalyst Q1 were found to be extremely
ineffective in terms of reactivity (Table 1, entry 8-10).
Based on these studies, we surmised that quinine based
bifunctional diamine Q2 may prove to be more potential to
serve as a good catalyst. Chiral cinchona diamines are
believed to invoke favorable stereo interactions due to their
intrinsic ability to simultaneously form enamine and
hydrogen bonding with high degree of conformational
flexibility. To our delight, promising results were obtained
in the presence of quinine based bifunctional primary
amine catalyst Q2 (20 mol%) by affording the desired
product 6a in 70% yield with good stereoselectivity (Table
1, entry 11). It is interesting to note that Knoevenagel
condensation, Michael addition, lactonization and
decarboxylation took place in one pot at room temperature
to afford the desired product 6a. While the two fold
addition of TFA (40 mol%) along with the catalyst Q2(20
enantioselectivity (up to 99% ee). Naphthaldehyde under
the reaction conditions afforded the corresponding lactone
6k in good yield and excellent enantioselectivity (65%,
94% ee).
Table 2. One pot enantiopure synthesis of γ-butyrolactonesa-e
mol%)
marginally
enhanced
the
yield
and
enantioselectivity of desired product 6a (Table 1, entry 12).
Presumably, TFA might have reduced the unanticipated
acid-base interaction between catalyst Q2 and Meldrum’s
acid. Further reduction in catalytic loading (5 and 10 mol%,
entries 14, 15) afforded the desired product 6a along with
the undecarboxylated intermediate 6a’ (detected by
HRMS) at room temperature (see Table 1, entries 14, 15),
unlike in case of higher catalytic loading (20 mol%)
wherein, decarboxylation took place without heating (see
Table 1, entry 12). We observed the incomplete
decarboxylation even after prolonged reaction time (48 h).
Further, in order to decarboxylate the intermediate 6a’, the
reaction mixture was heated at 60 oC for 6 h for the
complete decarboxylation to afford product 6a in 78%
yield without any erosion of enantioselectivity (91% ee).
Based on these results, to avoid higher catalytic loading,
we decided to use 5 mol% of catalyst Q2 followed by
heating for the substrate scope. Encouraged by the initial
results, further we screened various solvents under
optimized reaction condition (Q2 5 mol% followed by
heating, see ESI). Interestingly, THF was found to be the
best solvent for the desired transformation (6a, 78% yield,
94% ee). On the other hand polar solvents such as H2O,
DMSO, DMF, EtOH had a detrimental effect on the
reaction.
aReaction conditions: Meldrum’s acid 1 (1 equiv.), Aldehyde
(1.05 equiv.), Hydroxyketone (3 equiv.) Q2 (5 mol%), TFA as
o
additive (10 mol%), in THF at rt, 24 h then heat at 65 C in one
b
pot; 10 mol% of catalyst Q2 and TFA (20 mol%) were used for
the complete conversion, cisolated yield after purification by
d
column chromatography, d.r. was calculated based on isolated
e
yields ee was determined by HPLC; ee of cis-isomer is given in
parenthesis.
Similarly, heteroaromatic aldehydes such as furfural and
thiophene 2/3-aldehydes afforded the corresponding
lactones 6l, 6m and 6n respectively (up to 94% ee, Table
2). In order to have generality of the method and for the
wider practicability, we planned to explore the reactions of
1-hydroxy-2-pentanone 3b and 2-hydroxyacetophenone 3c.
Under the optimized reaction conditions 3b reacted
smoothly with aldehydes 2a, 2b and Meldrum’s acid 1 to
afford the corresponding lactones 6o and 6p in moderate to
good yields with excellent enantioselectivity (see, Table 2).
Likewise, the reaction of 2-hydroxyacetophenone 3c with
aldehydes 2j and 2h afforded the corresponding products
6q and 6r respectively in moderate to good yield with
good enantioselectivity. Interestingly, it is very significant
to note that the reaction of aliphatic aldehydes such as
isovaleraldehyde 2o and ethyl glyoxalate 2p with 2-
hydroxyacetophenone afforded the corresponding lactones
6s and 6t in good enantioselectivity. We observed that
steric and electronic factors did not have any significant
effect on the efficiency and yield of the reaction. Wide
variety of aldehydes and different functional groups
tolerated the reaction conditions. In order to have some
insight into stereochemical outcome of the transformation
and mechanistic aspects, we carried out few experiments
Having obtained the optimized reaction conditions in hand
(5 mol% Q2, 10 mol% TFA in THF at room temperature
o
for 24 h followed by heating at 65 C for 6 h in one pot),
further the scope of Knoevenagel-Michael-lactonization
was investigated using various aldehydes and
hydroxyketones. It was observed that aromatic aldehydes
containing electron donating as well as withdrawing
functional groups reacted smoothly under the optimized
reaction conditions to afford the corresponding lactones
(6b-6j, Table 2) in good yields with high to excellent
3
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10.1002/adsc.201701084
Advanced Synthesis & Catalysis
on lactone 6b. Esterification followed by oxidation of two
separate diastereomers of 6b (cis and trans) afforded the
corresponding identical enantiomer (see ESI).
This
revealed that only one face of alkylidene Meldrum’s acid 4
interacted with the both re and si face of hydroxyacetone
enamine (ENM). To assign the absolute configuration, the
product 6acis+trans was subjected to Baeyer-Villiger
oxidation followed by reduction of 7a (Scheme 2). By
comparing the specific rotation of product 8a with the
literature value, the absolute configuration of 6a was
assigned as ‘R’ at benzylic position (observed specific
rotation [α]25D = – 41.0 (c 1.0, CHCl3), literature [α]23D = –
27.7 (c 4.0, CHCl3) for ‘R’ configuration).[15]
Scheme 2. Reduction and allylation of butyrolactone 6a.
Scheme 3: Proposed catalytic cycle. a,b,c
aSelected bond distances are in Å. bRelative free energies given in
Further, to make this protocol more practical and to
demonstrate the synthetic utility of the products,
synthetically useful allyl lactone 9a was synthesized
starting from compound 7a in a shorter pathway. Further,
to demonstrate the practical utility of this protocol, lactone
6a was synthesized on a gram scale in good yield (75%)
without the erosion of enantioselectivity (94% ee) (Scheme
2).
To have a better understanding of the mechanism and
stereoselectivity of reaction catalyzed by chiral cinchona
catalyst Q2, we planned to investigate the intermediates
and transition states (TS) that are involved in the catalytic
cycle by Density Functional Theory (DFT) calculations.
The proposed catalytic cycle is outlined in Scheme 3.
Initially protonated primary amine Q2 catalyzes
Knoevenagel condensation to afford the corresponding
heterodiene 4a. Further this reacts with enamine (Z-ENM
and E-ENM as dienophile) via [4+2]-hetero-Diels-Alder
cycloaddition pathway. DFT calculations revealed that Z-
enamine (Z- ENM) is 7.059 kcal.mol-1 more stable than E-
enamine (E-ENM) due to favorable hydrogen bonding. It
is important to note that under experimental conditions, we
obtained only RS and RR lactones selectively.
The optimized structures of all the reactants, TS’s,
intermediates and products are given in ESI. Calculations
were carried out to determine the role of TS’s on the
outcome of stereochemistry of the lactones. This was
further unambiguously supported by single crystal X-ray
analysis and specific rotation. Keeping this in view, we
computationally studied the attack of only Z-ENM (both
re and si faces) to the only si face of heterodiene 4a in
detail for the outcome of RS and RR lactones (see ESI for
data and details). Transition state TS1-SS (si face of 4a and
si face of Z-ENM) is 5.534 kcal.mol-1 more stable than
TS1-SR (si face of 4a and re face of Z-ENM). TS1-SS
leads to more stable major product lactone 6a-RS (10.69
kcal.mol-1 more stable than 6a-RR lactone) through a series
of transition states and intermediates for the stepwise
mechanism (see ESI).
kcal·mol-1;
M06-2X/6-311++G(d,p)/SMD//M06-2X/6-31G(d).
cMost of the H-atoms have been omitted for the sake of clarity.
These DFT calculations strongly support the experimental
results and high stereoselectivity (Theoretical ee = 99% is
in very good agreement with the experimental ee = 94%).
In conclusion, we developed a novel, robust and a
straightforward protocol for the highly enantiopure
synthesis of γ-butyrolactones via one-pot organocatalytic
multicomponent reaction (OMCR) strategy. Potential of
OMCR is explored for the first time for the rapid access of
enantiopure lactone scaffolds starting from commercially
available simple starting materials. Experimental
observation was further supported by the computational
studies. More importantly protocol avoids the use of pre-
functionalized substrates, additional base and, expensive
transition metals. Reaction proved to be highly
enantioselective and reproducible on a gram scale and is
proved to practical to access synthetically useful lactones.
Experimental Section
In a glass vial equipped with a teflon-coated stir bar, 9-
amino(9-deoxy)epiquinine Q2 (0.07 mmol, 22.4 mg, 10
mol%) was dissolved in 1.0 mL of THF. After addition of
TFA (0.14 mmol, 10.6 µL, 20 mol%), the reaction mixture
was stirred for 15 minutes. Then Meldrum’s acid 1 ( 100
mg, 0.7 mmol, 1 equiv.), benzaldehyde (74.3 µL, 0.73
mmol, 1.05 equiv.) and hydroxy acetone (145.6 µL, 2.1
mmol, 3 equiv.) were added subsequently and stirred for
12 h or as indicated in the manuscript. Upon complete
consumption of Meldrum’s acid, the reaction mixture was
o
heated at 65 C for 6 hours to decarboxylate the acid
intermediate. The crude product 6a was purified by
column chromatography on silica gel using petroleum
ether/ethyl acetate as an eluent. Compound 6a was
obtained as solid in 78% yield.
4
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10.1002/adsc.201701084
Advanced Synthesis & Catalysis
Acknowledgements
[13]CCDC-1531212 and CCDC-1531213 contain the
supplementary crystallographic data for 6acis and
6atrans, respectively. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[14] T. Mandal, C.-G. Zhao, Angew. Chem., Int. Ed. 2008, 47,
7714.
R. G. B. thanks DST-SERB (EMR/2015/000909), Govt. of India
for the generous research grant. T. M. K and A. D. S, thank CSIR
for the fellowship. J. S. A. thanks DST for the fellowship. Authors
thank IISER and for the financial assistance.
[15] M. Shevlin, M. R. Friedfeld, H. Sheng, N. A. Pierson, J. M.
Hoyt, L.-C. Campeau, P. J. Chirik, J. Am. Chem. Soc. 2016,
138, 3562.
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5
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10.1002/adsc.201701084
Advanced Synthesis & Catalysis
COMMUNICATION
Direct Organocatalytic Multicomponent Synthesis
of Enantiopure γ-butyrolactones via Tandem
Knoevenagel-Michael-Lactonization Sequence
Adv. Synth. Catal. Year, Volume, Page – Page
Tushar M. Khopade, Amol D. Sonawane, Jyotsna
S. Arora and Ramakrishna G. Bhat*
6
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