Enantioselective Diels-Alder Reactions of Carboxylic Ester Dienophiles Catalysed by Titanium-Based Chiral Lewis Acid

Article abstract of DOI:10.13005/ojc/320217

A new titanium-based chiral Lewis acid 1 has been developed using (1R,2R)-1,2-bis-(2-methoxyphenyl)-ethane-1,2-diol as a chiral vicinal diol ligand. This chiral catalyst was found to exhibit uniformly high enantioselectivity towards carboxylic ester dienophiles in Diels-Alder reactions. The chiral vicinal ligand (1R,2R)-1,2-bis-(2-methoxyphenyl)-ethane-1,2-diol is inexpensive and is easily accessible.

Full text of DOI:10.13005/ojc/320217

ISSN: 0970-020 X
CODEN: OJCHEG
2016, Vol. 32, No. (2):
Pg. 921-926
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Enantioselective Diels-Alder Reactions of Carboxylic Ester
Dienophiles Catalysed by Titanium-Based Chiral Lewis Acid
YOGESH K. CHOUGHULE and ANAND V. PATWARDHAN*
Department of Chemical Engineering, Institute of Chemical Technology,
Matunga, Mumbai 400019, Maharashtra, India.
*Corresponding author E-mail: av.patwardhan@ictmumbai.edu.in
http://dx.doi.org/10.13005/ojc/320217
(Received: March 12, 2016; Accepted: April 05, 2016)
ABSTRACT
A new titanium-based chiral Lewis acid 1 has been developed using (1R,2R)-1,2-bis-(2-
methoxyphenyl)-ethane-1,2-diol as a chiral vicinal diol ligand.This chiral catalyst was found to exhibit
uniformly high enantioselectivity towards carboxylic ester dienophiles in Diels-Alder reactions. The
chiral vicinal ligand (1R,2R)-1,2-bis-(2-methoxyphenyl)-ethane-1,2-diol is inexpensive and is easily
accessible.
Keyword: Chiral Lewis acid, Chiral vicinal ligand, Diels-Alder reaction, Dienophiles, Carboxylic esters.
INTRODUCTION
and which involves introduction of the stereocentre
on the reagent (reagent control).3,4 This involves the
cycloaddition of dienes and dienophiles catalysed
by chiral Lewis acids, and simultaneous induction of
asymmetry into the product.An example of such type
of work, which involve highly reactive oxazolidinone
dienophiles were successfully achieved by Narasaka,
Chapuis, and Corey.4,5 However, the carboxylic ester
dienophiles have shown poor enantioselectivity
under these reagent-controlled conditions because
of their less reactivity. The present work describes
an attempt to develop a chiral Lewis acid for Diels-
Alder reactions which induces asymmetry with ester
dienophiles.
The Diels-Alder reaction is known to be a
popular method in synthetic chemistry.1 The control
of absolute stereochemistry has generated a great
interest recently.2 One successful methodology
developed thus far utilises chiral auxiliaries that
are integrated into the substrate, and eventually
detached from the product by some chemical
means. Here, the stereochemical consequence is
due to the absolute stereocentre of the substrate
(substrate control). There is an alternative method,
which has not yet been as exhaustively explored,

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CHOUGHULE & PATWARDHAN, Orient. J. Chem., Vol. 32(2), 921-926 (2016)
MATERIALS AND METHODS was stirred at 25 °C (carried out at different
General information
temperatures for temperature study: Table 2) for 4
h, and was quenched with 10 mL of 1 N aqueous
Dichloromethane was purified by calcium hydrochloric acid.The aqueous phase was extracted
hydride distillation. Diethyl ether was distilled from (3×20 mL of dichloromethane). The combined
potassium hydroxide and purified by sodium wire. organic phase were dried (using anhydrous sodium
TLC and column chromatography were carried sulphate) and concentrated on rotary evaporator.
out with silica gel. All reactions were conducted Column chromatography of crude oil (silica, 9.5:0.5
under nitrogen atmosphere, and the product was hexane:ethyl acetate) gives enantioenriched Diels-
concentrated under reduced pressure with a rotary Alder product as colourless oil.
evaporator. The purity and characterisation of all
compounds were done using HPLC and NMR Dimethyl-(4S,5S)-1,2-dimethylcyclohexene-4,5-
techniques.
dicarboxylate (2a)
1H NMR (300 MHz, CDCl3; δ, ppm) 1.56 (s,
General procedure for titanium-based chiral 6H), 2.05-2.23 (m, 4H), 2.74-2.78 (m, 2H), 3.63 (s,
Lewis acid formation 1
6H).13C NMR (75 MHz, CDCl3; δ, ppm) 175.2, 123.7,
A 100 mL 3-neck round bottom flask was 51.6, 41.8, 34.0, 18.4.
fitted with calcium guard tube, nitrogen gas inlet, and
rubber septum respectively, to maintain anhydrous Dimethyl-(4S,5S)-l-methylcyclohexene-4,5-
conditions. n-butyllithium (1.68 mL of 2.5 M in dicarboxylate (2b)
hexane, 4.2 mmol) was added to a suspension of
1H NMR (300 MHz, CDCl3; δ, ppm) 1.64
(1R,2R)-1,2-bis-(2-methoxyphenyl)-ethane-1,2-diol (s, 3H), 2.06-2.38 (m, 4H), 2.75 (dt, J = 5.3, 10.8
(0.575 g, 2.1 mmol) in 4 mL of diethyl ether at 0°C. Hz, 1H), 2.85 (dt, J = 5.2, 10.8 Hz, 1H), 3.65 (s, 3H),
The resulting slurry was dissolved in 16 mL of solvent 3.66 (s, 3H), 5.33 (s, 1H). 13C NMR (75 MHz, CDCl3;
(different solvents were used for effect of solvent δ, ppm) 175.3, 175.2, 132.1, 118.9, 52.0, 51.7, 41.6,
experiments see Table 3), and titanium tetrachloride 41.0, 32.4, 27.96, 22.88.
(2.1 mL of 1.0 M solution in Dichloromethane, 2.1
mmol) was added.Lithium Chloride got precipitated. Dimethyl-(4S,5S)-cyclohexene-4,5-dicarboxylate
This mixture was used as such.
(2c)
1H NMR (300 MHz, CDCl3; δ, ppm) 2.12-
2.19 (m, 2H), 2.36-2.43 (m, 2H), 2.81-2.85 (m,
General procedure for Diels-Alder reaction
Dienophile (1.4 mmol) was added to 2H), 3.67 (s, 6H), 5.66 (d, J=2.3Hz, 2H). 13C NMR
a mixture of a Lewis acid (as prepared above), (75 MHz, CDCl3; δ, ppm) 175.2, 124.8, 51.8, 41.1,
followed by diene (7 mmol). The resulting mixture 27.8.
Fig. 1: Diels-Alder reactions catalysed by Lewis acid 1

CHOUGHULE & PATWARDHAN, Orient. J. Chem., Vol. 32(2), 921-926 (2016)
923
Table 1: Enantioselective Diels-Alder reactions catalysed by the
titanium-based chiral Lewis acid 1 (T = 25 °C, 4 h)
Entry
Diene
Dienophile
Major Product
eea%
IsolatedYieldb%
O
O
O
O
O
O
1
94
92
82
80
O
2a
O
O
O
O
O
O
2
O
2b
O
O
O
O
O
3
76-80c
90
55-78c
79
O
O
O
O
2c
O
O
O
O
4
O
O
O
2d
O
O
O
O
5
77
84
O
O
2e
O
O
O
6
71
82
O
2f
O
O
O
7
60-64c
68
58-80c
81
O
2g
O
O
8
O
2h
O
O
O
O
O
9
60
89
O
2i
O
O
10
11
12
55
87
O
2j
O
O
O
45-48c
50
60-84c
85
O
2k
O
O
O
2l
O
aEnantiomeric excess (ee%) was determined by chiral HPLC column CHIRALPAK IA analytical 250×4.6 mm, 5 µm (at
254 nm, methanol)
bIsolated yield by column chromatography (silica gel, 5% ethyl acetate in hexane)
cThe reaction was conducted at –10 °C.

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CHOUGHULE & PATWARDHAN, Orient. J. Chem., Vol. 32(2), 921-926 (2016)
Dimethyl-(2S,3S)-bicyclo[2.2.l]hept-5-ene-2,3- δ, ppm) 176.6, 125.4, 124.0, 51.7, 40.2, 33.8, 31.1,
dicarboxylate (2d)
26.0, 19.1, 18.9.
1H NMR (300 MHz, CDCl3; δ, ppm) 1.46
(dd, J = 1.5 Hz, 8.9 Hz, 1H), 1.62 (d, J = 8.9 Hz 1H), Methyl-(4R)-1-methylcyclohexene-4-carboxylate
2.69 (dd, J = 1.3, 4.1 Hz, 1H), 3.13 (br s, 1H), 3.27 (2j)
(br s, 1H), 3.38 (t, J = 4.0 Hz, 1H), 3.65 (s, 3H), 3.72
1H NMR (300 MHz, CDCl3; δ, ppm) 1.59-
(s, 3H), 6.07 (dd, J = 2.7, 5.5 Hz, 1H), 6.29 (dd, J = 1.62 (m, 2H), 1.65 (s, 3H), 1.98-2.02 (m, 2H), 2.21-
3.2, 5.3 Hz, 1H,). 13C NMR (75 MHz, CDCl3; δ, ppm) 2.23 (m, 2H), 2.45-2.53 (m, 1H), 3.68 (s, 3H), 5.38
174.7, 173.5, 137.4, 135.0, 52.0, 51.7, 47.7, 47.5, (s, 1H). 13C NMR (75 MHz, CDCl3; δ, ppm) 176.5,
47.2, 46.9, 45.5.
133.7 119.2, 51.6, 39.1, 29.3, 27.7, 25.5, 23.5.
Methyl-(1S,6S)-3,4,6-trimethylcyclohex-3-ene-1- Methyl-(1R)-cyclohex-3-ene-1-carboxylate (2k)
carboxylate (2e)
1H NMR (300 MHz, CDCl3; δ, ppm) 1.73–
1H NMR (300 MHz, CDCl3; δ, ppm) 0.81 1.65 (m, 2H, CH2), 2.15–1.99 (m, 2H, CH2), 2.26–
(d, 3H), 1.22 (m, 1H), 1.63 (s, 3H), 1.74 (s, 3H), 2.07- 2.25 (m, 2H, CH2), 2.60–2.55 (m, 1H, CHCO2Me),
2.40 (m, 4H), 2.80-2.84 (m, 1H), 3.70 (s, 3H). 13C 3.70 (s, 3H, CO2CH3), 5.72–5.65 (m, 2H, CH=CH),
NMR (75 MHz, CDCl3; δ, ppm) 175.3, 132.4, 129.7, 13C NMR (75 MHz, CDCl3; δ, ppm) 176.6, 126.9,
51.8, 41.6, 33.0, 32.4, 27.9, 23.1, 22.9, 20.1.
125.4, 51.9, 39.4, 27.7, 25.3, 24.7.
Methyl-(1S,6S)-4,6-dimethylcyclohex-3-ene-1- Methyl bicyclo[2.2.1]hept-5-ene-2-carboxylate
carboxylate (2f)
(2l)
1H NMR (300 MHz, CDCl3; δ, ppm) 0.91 (d,
1H NMR (300 MHz, CDCl3; δ, ppm) 1.26 (m,
3H), 1.25 (m, 1H), 1.66 (s, 3H), 2.10-2.43 (m, 4H), 1H), 1.41 (m, 1H), 1.43 (m, 1H), 1.90 (m, 1H), 2.89
2.82-2.87 (m, 1H), 3.73 (s, 3H), 5.35 (t, 1H).13C NMR (m, 1H), 2.93 (m, 1H), 3.19 (m, 1H), 3.64 (s, 3H), 5.95
(75 MHz, CDCl3; δ, ppm) 179.3, 130.7, 118.0, 52.2, (dd, 1H), 6.16 (dd, 1H). 13C NMR (75 MHz, CDCl3;
45.6, 37.0, 36.1, 31.9, 25.1, 22.1.
δ, ppm) 172.2, 134.0, 128.7, 53.4, 49.0, 42.2, 39.0,
38.8, 26.3.
Methyl-(1S,6S)-6-methylcyclohex-3-ene-1-
carbooxylate (2g)
1H NMR (300 MHz, CDCl3; δ, ppm) 0.88 (d,
3H), 1.23 (m, 1H), 2.11-2.44 (m, 4H), 2.80-2.85 (m,
Table 2: Enantioselective Diels-Alder reactions
catalysed by the titanium-based chiral Lewis
acid 1 carried out at different temperaturea
1H), 3.71 (s, 3H), 5. 33 (m, 1H), 5.63 (m, 1H). 13
C
NMR (75 MHz, CDCl3; δ, ppm) 179.3, 120.7, 118.0,
52.2, 45.6, 37.0, 36.1, 31.9, 22.1.
Entry
Temp.d (°C)
eeb %
Yieldc %
Methyl-(2S)-3-methyl(3S)bicyclo[2.2.1]hept-5-
ene-2-carboxylate (2h)
1
2
3
4
5
–10
0
10
25
30
94
94
94
94
80
70
79
80
82
84
1H NMR (300 MHz, CDCl3; δ, ppm) 1.17 (d,
3H), 1.78 (m, 3H), 2.27 (m, 2H), 2.42 (m, 1H), 3.05
(m, 1H), 3.27 (m, 1H), 3.57 (s, 3H), 5.91 (dd, 1H),
6.18 (dd, 1H). 13C NMR (75 MHz, CDCl3; δ, ppm)
175.2, 138.4, 134.6, 51.5, 47.8, 47.1, 46.8, 45.4,
29.2, 21.1.
aAll experiments were carried out using diene and dienophile
mentioned in (Table 1, entry 1).
bEnantiomeric excess (ee%) was determined by chiral
HPLC column Chiralpak IA analytical 250×4.6 mm, 5µm
(at 254 nm, methanol)
cYield of racemic mixtures were determined by HPLC
dEntries no.1, 2, 3, experiments were carried out for 12, 8,
6 h respectively and entries 4, 5 for 4 h.
Methyl-(1R)-3,4-dimethylcyclohex-3-ene-1-
carboxylate (2i)
1H NMR (300 MHz, CDCl3; δ, ppm) 1.60
(s, 6 H), 1.61-1.69 (m, 1H), 1.90-2.25 (m, 5H), 2.49-
2.58 (m, 1H), 3.67 (s, 3H).13C NMR (75 MHz, CDCl3;

CHOUGHULE & PATWARDHAN, Orient. J. Chem., Vol. 32(2), 921-926 (2016)
925
Table 3: Enantioselective Diels-Alder
reactions catalysed by the titanium-based
chiral Lewis acid 1 carried out using different
solventsa
of products was analyzed by HPLC technique using
a chiral column.The results were certainly promising
for high enantioselectivity towards Diels-Alder
reaction by a titanium-based chiral Lewis acid as
a chiral catalyst (compound-1 in Fig. 1). Results for
the Diels-Alder reaction are summarised in (Table 1).
The configuration of the resulted product (2a-2l) was
confirmed by reported literature.9 In all these cases
the product was conveniently isolated by column
chromatography.It is interesting to note that (1R,2R)-
1,2-bis-(2-methoxyphenyl)-ethane-1,2-diol examined
as ligands and gave reasonable enantiomeric yield.
The results of temperature and solvent experiments
summarized in (table 2) and (table 3) respectively
has been showed optimum enatiomeric and racemic
yield at 25 °C when dichloromethane solvent was
used.
Entry
Solvent
eeb %
Yieldc %
1
2
3
4
5
6
Dichloromethane
1,2-Dichloroethane
Benzene
94
90
60
66
68
26
82
80
84
80
78
88
Toluene
Xylene
n-Hexane
aAll experiments were carried out at 25 °C for 4 h using
diene and dienophile mentioned in (Table 1, entry 1).
bEnantiomeric excess (ee%) was determined by chiral
HPLC column CHIRALPAK IA analytical 250×4.6 mm,
5µm (at 254 nm, methanol)
CONCLUSIONS
cYield of racemic mixtures were determined by HPLC.
In this work, it was found that high
enantioselectivities are possible for Diels-Alder
reaction of carboxylic esters catalysed by titanium-
based chiral Lewis acid. It may be happening
because of availability of the lone pair of electrons
on the oxygen atoms present in the carboxylic ester
group. The lone pair of electrons may be leading
to more steric hindrance in the transition state of
reaction. This resulted in high enantioselectivity of
the product. (1R,2R)-1,2-bis-(2-methoxyphenyl)-
ethane-1,2-diol, a simple and readily available
compound, was effective as the chiral ligand when
titanium metal was used in the Lewis acid. The
titanium is a transition metal element located in the
fourth group of fourth period in the periodic table.
Because of typical electronic structure of transition
elements, they have the ability to adopt multiple
oxidation states to form complexes. They are more
effective catalysts because they have the ability
to make complexes with non-bonding electron
donating groups like carboxylic esters group in the
dienophile (see Dienophile in Table 1).Titanium has
[Ar]3d24s2 electronic configuration having valence
d-orbital which might be responsible to make more
sterically hindered complexes in the transition state
of reaction. The temperature (Table 2) and solvent
(Table 3) studies showed that 25 °C was an optimum
temperature and dichloromethane was found to be
the best solvent for this type of Diels-Alder reaction
when titanium-based chiral Lewis acid 1 was used.
RESULTS AND DISCUSSION
A review of several C2-symmetric diol
ligands employing boron, tin, and titanium Lewis
acids encouraged us to select a titanium-based
Lewis acid of type 1 (Fig.1), in which optically active
(1R,2R)-1,2-bis-(2-methoxyphenyl)-ethane-1,2-diol
was used as the ligand.6 this optically active ligand
was easily synthesised using Sharpless osmylation
method.7 The outcome of the Diels-Alder reactions
as illustrated by (Fig. 1) is compiled in (Table 1).
The chiral Lewis acid 1 was generated
by transformation of (1R,2R)-1,2-bis-(2-methoxy
phenyl)-ethane-1,2-diol to the corresponding
dilithiodialkoxide species upon reaction with
two equivalents of n-butyllithium in diethyl ether.
The resulted mixture was then diluted with
dichloromethane, and titanium tetrachloride was
added.At this point, lithium chloride got precipitated.8
Then the dienophile and diene were added
respectively.The reactions were normally carried out
for 4 h and monitored by TLC and purified by silica
gel column chromatography using 200-400 mesh
particle size of S D Fine-Chem Ltd., Mumbai. The
(1R,2R)-1,2-bis-(2-methoxyphenyl)-ethane-1,2-diol
was readily recovered in near quantitative amounts.A
slight decomposition was observed leading to traces
of 2-methoxy-benzaldehyde. The enantioselectivity

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CHOUGHULE & PATWARDHAN, Orient. J. Chem., Vol. 32(2), 921-926 (2016)
ACKNOWLEDGEMENTS
the award of ‘senior research fellowship’. We are
also thankful to Dr. Sandeep B. Kotwal, Assistant
The author (YKC) is thankful to University Professor, Department of Chemistry, CHM College,
Grants Commission (UGC) – New Delhi, India, for University of Mumbai, for his willing help.
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