Iron catalyzed enantioselective sulfa-Michael addition: A four-step synthesis of the anti-asthma agent Montelukast

Article abstract of DOI:10.1039/c4sc00051j

A salen ligand based on a chiral cis-2,5-diaminobicyclo[2.2.2]octane scaffold forms an iron(iii) complex with ferric chloride which catalyzes asymmetric addition of thiols to α,β-unsaturated ketones under mild conditions. The reaction (sulfa-Michael addition) produces β-thioketones in excellent yield and high enantiomeric excess from a wide range of aliphatic and aromatic thiols using chalcones and other conjugated enones as Michael acceptors. With α-substituted α,β-unsaturated ketones as acceptors, the addition shows strong preference (typically >50:1) for the syn diastereomer over the anti product. An asymmetric synthesis of (R)-Montelukast, the sodium salt of which is the commercial anti-asthma drug Singulair, was devised using conjugate addition of a thiol catalyzed by our iron(iii)-salen complex to an α,β-unsaturated ketone synthesized in a four-component, one-pot tandem Michael-aldol condensation. The reaction sequence to (R)-Montelukast proceeded in 72% overall yield over four steps from commercially available materials. A mechanism for our catalyzed asymmetric sulfa-Michael addition is advanced which coordinates the enone acceptor to the metal centre of the iron-salen complex in an open lower quadrant under the bicyclic scaffold, thereby exposing only the si face of the double bond to attack by the external nucleophilic thiol. Prior internal coordination of the thiol to the metal centre of the complex is proposed based on spectroscopic and chemical evidence and leads to activation of the catalyst through a trans ligand effect. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4sc00051j

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Iron catalyzed enantioselective sulfa-Michael
addition: a four-step synthesis of the anti-asthma
Cite this: Chem. Sci., 2014, 5, 2200
agent Montelukast†
*
James D. White and Subrata Shaw
A salen ligand based on a chiral cis-2,5-diaminobicyclo[2.2.2]octane scaffold forms an iron(III) complex with
ferric chloride which catalyzes asymmetric addition of thiols to a,b-unsaturated ketones under mild
conditions. The reaction (sulfa-Michael addition) produces b-thioketones in excellent yield and high
enantiomeric excess from a wide range of aliphatic and aromatic thiols using chalcones and other
conjugated enones as Michael acceptors. With a-substituted a,b-unsaturated ketones as acceptors, the
addition shows strong preference (typically >50 : 1) for the syn diastereomer over the anti product. An
asymmetric synthesis of (R)-Montelukast, the sodium salt of which is the commercial anti-asthma drug
Singulair®, was devised using conjugate addition of a thiol catalyzed by our iron(III)–salen complex to an
a,b-unsaturated ketone synthesized in a four-component, one-pot tandem Michael-aldol condensation.
The reaction sequence to (R)-Montelukast proceeded in 72% overall yield over four steps from
commercially available materials. A mechanism for our catalyzed asymmetric sulfa-Michael addition is
advanced which coordinates the enone acceptor to the metal centre of the iron–salen complex in an
open lower quadrant under the bicyclic scaffold, thereby exposing only the si face of the double bond to
attack by the external nucleophilic thiol. Prior internal coordination of the thiol to the metal centre of the
complex is proposed based on spectroscopic and chemical evidence and leads to activation of the
catalyst through a trans ligand effect.
Received 6th January 2014
Accepted 10th February 2014
DOI: 10.1039/c4sc00051j
www.rsc.org/chemicalscience
The asymmetric Michael reaction is one of the most powerful chiral salen–metal complexes were found to possess signicant
transformations in synthesis.1 Among reactions of this class, catalytic activity. For example, chromium(III) complex 2c was an
conjugate addition of thiols to unsaturated carbonyl efficient catalyst for the asymmetric hetero-Diels–Alder reaction
compounds (sulfa-Michael addition, SMA) is of special interest and for the asymmetric Nozaki–Hiyama–Kishi reaction9 while
since it provides direct access to enantioenriched suldes.2 the copper(I) complex of the tetrahydrosalen ligand derived
Although a diverse body of research has focused on catalytic from reduction of 1 proved to be an excellent catalyst for the
asymmetric SMA, the Michael acceptors used in these reactions asymmetric Henry reaction.10
have been conned to nitroolens,3 a,b-unsaturated alde-
Our initial studies on asymmetric SMA were carried out with
hydes,4 carboxylic acid derivatives5 and cyclic enones.6 Acyclic metal–salen complexes 2a–f using p-chlorobenzyl thiol (3) and
a,b-unsaturated ketones as Michael acceptors in catalytic trans-chalcone (4) as reactants in solvents of varying polarity.
asymmetric SMA have received only limited attention7 and Results from this investigation indicated that iron(III)–salen
diastereoselectivity associated with thiol addition to a-branched complex (+)-2e was superior to other metal–salen complexes in
enones remains a signicant challenge.8 Thus, an efficient
catalyst for asymmetric SMA of thiols to acyclic enones under
mild conditions which affords adducts with good enantio- and
diastereoselectivity is an important goal.
We have reported a new salen ligand (1) based on the chiral
scaffold cis-2,5-diaminobicyclo[2.2.2]octane and we showed that
the ligand forms stable, well characterized complexes (2a–f)
with a variety of transition metals (Fig. 1).9 Certain of these
Department of Chemistry, Oregon State University, Corvallis, OR, 97330, USA. E-mail:
James.white@oregonstate.edu
Fig. 1 Salen-ligand 1 and metal complexes 2a–f based on a cis-2,5-
diaminobicyclo[2.2.2]octane scaffold.
† Electronic supplementary information (ESI) available: Experimental procedure
and spectral data for all new compounds. See DOI: 10.1039/c4sc00051j
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Table 1 Asymmetric conjugate addition of p-chlorobenzyl thiol (3) to Table 2 Asymmetric sulfa-Michael addition of 3 to 4 catalyzed by
trans-chalcone (4) catalyzed by metal–salen complexes 2a–fa (+)-2e. Effect of catalyst loading and temperaturea
Product 5
Product 5
Catalyst loading
(mol%)
Entry
Temp.
t [h]
Yieldb [%]
eec [%]
Entry
Catalyst
Solvent
t [h]
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
10
10
10
4
15
20
20
12
0
32
47
58
63
49
36
74
84
79
76
82
87
94
59
91
95
96
86
97
98
97
1
2
3
4
5
6
7
8
(+)-2a
(+)-2b
(+)-2c
(+)-2d
(+)-2e
(+)-2f
(+)-2e
(+)-2e
(+)-2e
(+)-2e
(+)-2e
(+)-2e
(+)-2e
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
CHCl3
CH2Cl2
DCE
30
36
52
18
12
6
24
36
24
71
74
59
96
84
46
35
63
52
87
63
68
90
33
22
46
16
36
37
43
46
71
49
75
84
87
7
À5
À5
À5
À5
À15
a
The reaction between trans-chalcone (0.1 mmol) and 4-chlorobenzyl
b
9
thiol (0.12 mmol) was carried out in 1 mL solvent. Yield of isolated
product. c Determined by HPLC using a Chiralcel OD-H column.
10
11
12
13
THF
MeNO2
MeCN
MeOH
31
36
13
a
The reaction between trans-chalcone (0.1 mmol) and 4-chlorobenzyl
indirectly by displacement of a mesylate generated via an
asymmetric ketone reduction.13 We have found that the sulfur
functionality in 9 can be inserted directly with excellent enan-
tioselectivity using conjugated ketone 10 as the substrate in our
asymmetric SMA methodology.
thiol (0.12 mmol) was carried out in 1 mL solvent in the presence of
10 mol% catalyst. Yield of isolated product. Determined by HPLC
using a Chiralcel OD-H column.
b
c
For the synthesis of 10 we devised a one-pot Mannich-aldol
delivering SMA product 5 with good enantioselectivity (Table 1, condensation employing 7-chloroquinaldine (11), 1,3-benzene
entries 5, 7–9). Non-polar chlorinated solvents as the reaction dicarboxaldehyde (12) and methyl 2-acetylbenzoate (13). This
medium gave better results (Table 1, entries 8 and 9) than polar three component reaction catalyzed by p-toluenesulfonamide
solvents (Table 1, entries 10–13). Further screening of reaction gave a,b-unsaturated ketone 10 in high yield (Scheme 1). The
conditions with (+)-2e as catalyst established that optimum reaction sequence is believed to be initiated by addition of
yield and enantioselectivity of 5 was achieved with 20 mol% enamine tautomer 14 of 11 to aldimine 15 and this is followed
catalyst loading at À5 ꢀC in dichloroethane (DCE) as solvent by elimination of p-toluenesulfonamide to generate aldehyde 16
(Table 2, entry 6) although good enantioselectivity was obtained (Scheme 2). The latter condenses with the sulfonamide, forming
with a catalyst loading as low as 4 mol%. Comparison of the a second aldimine 17 which reacts with enol 18 to produce 19.
optical rotation of 5 from this experiment with the literature Final elimination from 19 delivers 10 and regenerates
value7f proved that 5 possessed (R) conguration.
p-toluenesulfonamide.
With optimized reaction conditions for asymmetric SMA of 3
Conjugated ketone 10 underwent smooth SMA with 1-(mer-
and 4 settled, a broad portfolio of thiols 6 was examined in captomethyl)cyclopropyl]acetic acid (20) in the presence of
reaction with a variety of a,b-unsaturated ketones 7 using Fe(III)– catalytic (+)-2e to give b-thioketone 21 in high yield and enan-
salen complex (+)-2e as catalyst (Table 3). In every case, b-thio- tioselectivity. Tosylhydrazone 22 from 21 was reduced with
ketone 8 was obtained in >90% enantiomeric excess and in high NaBH4 in MeOH at room temperature14 to yield sulde 23 and
yield. Thiophenol (Table 3, entry 18) as well as aliphatic thiols addition of methylmagnesium bromide to this ester furnished
and a hydroxyl substituted thiol (Table 3, entry 10) gave good (R)-Montelukast (9) (Scheme 3). The four step route to 9
results, and the reaction was found to tolerate a wide range of proceeds in 72% overall yield based on 11.
aromatic and aliphatic substituents in the unsaturated ketone.
We next tested our asymmetric SMA methodology against
The utility of this enantioselective SMA was demonstrated in a-substituted a,b-unsaturated ketones and found that thiols 6
a synthesis of the leukotriene D4 receptor antagonist (R)-Mon- underwent reaction with conjugated enones 24 in the presence
telukast (9, Scheme 1).11 Singulair® (MK-0476), the sodium salt of (+)-2e as catalyst to give SMA adducts in high yield and with a
of 9, is an orally active drug used for treatment of asthma and syn/anti ratio strongly favoring syn isomer 25 (Table 4). The syn
other respiratory conditions;12 it is currently synthesized in a adduct was produced in high enantiomeric excess from these
multi-step process that introduces the (R) sulfur substituent reactions.
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Table 3 Enantioselective synthesis of b-thioketones 8 from thiols 6 and a,b-unsaturated ketones 7 catalyzed by metal–salen complex (+)-2ea
Entry
R1
R2
R3
t [h]
Product
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Me
iPr
41
36
38
31
31
36
36
36
39
20
49
26
38
49
47
32
31
34
48
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
96
92
89
97
93
98
89
97
98
91
98
98
95
94
96
97
95
89
96
94
97
96
96
97
95
92
98
93
96
96
95
96
97
94
95
93
98
98
C6H5CH2
iPr
C6H5CH2
4-Cl-C6H4CH2
iPr
Ph
3-OMeC6H4
4-OMeC6H4
4-CF3C6H4
4-ClC6H4
4-ClC6H4
2,6-Di-ClC6H3
2,4-Di-NO2C6H3
4-(OH)-3-(OMe)-C6H3
1-Naphthyl
1-Naphthyl
Me
iPr
Cyclohexyl
9
nBu
10
11
12
13
14
15
16
17
18
19
CH2CH2OH
nBu
nBu
Me
iPr
2-Furyl
2-Thiophenyl
Me
Me
Me
iPr
iPr
C6H5CH2
4-Cl-C6H4CH2
Ph
Me
Me
C6H13
Me
C6H5CH2
8s
a
The reaction between trans-enone (0.1 mmol) and thiol (0.12 mmol) was carried out in 1 mL solvent in the presence of 20 mol% catalyst. b Yield of
isolated product. c Determined by HPLC using a Chiralcel OD, AD, OJ, OD-H or AS-H column.
Scheme 1 Asymmetric SMA route to the anti-asthma drug (R)-Mon-
telukast (9).
An attempt to give denition to the role of Fe–salen catalyst
2e in asymmetric SMA led to an experiment in which 1-buta-
nethiol was rst incubated with the catalyst before Michael
acceptor 4 was introduced. Formation of an initial Fe–thiol
complex is supported by the presence of a IR band centered at
ca. 468 cmÀ1 consistent with a Fe–S stretching mode.15 This
precoordinated thiol may play a role in orienting or activating
the enone acceptor within the Fe–salen complex through the
known trans directing effect of sulfur ligands in metal
complexes.16,17
The knowledge that bicyclooctane complex (+)-2e with (R,R)
absolute conguration produces sulfa-Michael adducts 8 of
uniform (R) stereochemistry stipulates that thiol attack at the Scheme 2 One-pot tandem Mannich-aldol sequence to dienone 10.
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Fig. 2 Proposed mechanism for the asymmetric sulfa-Michael addi-
tion of thiols to a,b-unsaturated ketones catalyzed by Fe(III)–salen
complex (+)-2e.
Scheme 3 Synthesis of (R)-Montelukast (9) from enone 10.
b-carbon of the enone occurs from the si face. A pathway
accommodating this nding is proposed in Fig. 2. This mech-
anism places the Fe-coordinated s-trans enone acceptor in the
right front quadrant below the bicyclic scaffold and anti to the
precomplexed thiol. Five coordinated atoms around the central
Fe form a square pyramidal conguration with O1, O2, N2 and S
in the basal plane. Intermolecular approach by thiol to an enone
complexed in this fashion should occur from the more acces-
sible front face leading to si attack.18 Subsequent protonation
from the re face, perhaps assisted by intramolecular delivery
from the free phenol, results in overall syn addition aer
detachment of the product from catalyst. A catalytic cycle that
conforms to this proposed mechanism is shown in Scheme 4.
Scheme 4 Catalytic cycle for the formation of 8 and 25 via asym-
metric SMA in the presence of (+)-2e.
In summary, an iron(III)–salen catalyst 2e based on a bicyclo sulfa-Michael addition of thiols to acyclic conjugated enones.
[2.2.2]octane scaffold has been found to give products in b-Thioketones generated in this manner represent valuable
high enantiomeric excess, diastereomeric ratio and yield in the entry points to important chiral sulfur-containing compounds
Table 4 Diastereoselectivity in asymmetric sulfa-Michael addition of thiols to a-branched enones catalyzed by (+)-2ea
Entry
R1
R2
R3
R4
t (h)
Product
dr syn/antib
Yieldc [%]
eed [%]
1
2
3
4
5
Ph
Me
Me
n-Bu
n-Bu
n-Bu
Me
Me
Ph
Ph
Ph
C6H5CH2
C6H5CH2
Et
(CH3)2CH
(CH3)3C
34
28
46
40
46
25a
25b
25c
25d
25e
>23 : 1
>31 : 1
>50 : 1
>50 : 1
>50 : 1
92
95
92
95
90
98
96
97
96
95
4-ClC6H4
(CH3)2CH
c-C6H11
n-C6H13
6
C6H5CH2
18
25f
>50 : 1
95
98
a
The reaction between enone (0.1 mmol) and thiol (0.12 mmol) was carried out in 1 mL solvent in the presence of 20 mol% catalyst. b Determined
by 1H NMR analysis. c Combined yields of syn and anti isomers. d Determined by HPLC using a Chiralcel OD, AD, OD-H or AS-H column.
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as demonstrated by the synthesis of the drug (R)-Montelukast in
four steps from commercially available materials. A key
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Mannich-aldol sequence that links 11, 12 and 13 in a catalyzed
process leading to Michael acceptor 10. Taken with the fact that
2e is readily available in both enantiomeric forms through
synthesis9 and delivers products in higher enantiomeric excess
than other catalyst systems, the method provides for efficient
asymmetric incorporation of sulfur functions into conjugated
acyclic enones in either absolute conguration.
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Acknowledgements
Support for the Oregon State University NMR facility through
grants from the Murdock Charitable Trust (Grant 2005265) and
from the National Science Foundation (CHE-0722319) is grate-
fully acknowledged.
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2204 | Chem. Sci., 2014, 5, 2200–2204
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