A General Catalytic Route to Enantioenriched Isoindolinones and Phthalides: Application in the Synthesis of (S)-PD 172938

Article abstract of DOI:10.1021/acs.orglett.8b03597

Chiral Br?nsted acid catalyzed enantioselective syntheses of isoindolinones and phthalides have been accomplished via tandem Mannich-lactamization and aldol-lactonization reactions, respectively. A variety of enantioenriched isoindolinones (up to 99% ee) and phthalides (up to 85% ee) containing α-diazoesters were afforded in excellent yields. Furthermore, a concise synthesis of (S)-PD 172938 has been demonstrated by using this protocol.

Full text of DOI:10.1021/acs.orglett.8b03597

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A General Catalytic Route to Enantioenriched Isoindolinones and
Phthalides: Application in the Synthesis of (S)‑PD 172938
Sumit K. Ray,†,§ Milon M. Sadhu,†,§ Rayhan G. Biswas,†,§ Rajshekhar A. Unhale,†
and Vinod K. Singh*,‡
†Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal, MP - 462 066, India
‡Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP - 208 016, India
S
* Supporting Information
ABSTRACT: Chiral Brønsted acid catalyzed enantioselective syntheses of isoindolinones and phthalides have been
accomplished via tandem Mannich-lactamization and aldol-lactonization reactions, respectively. A variety of enantioenriched
isoindolinones (up to 99% ee) and phthalides (up to 85% ee) containing α-diazoesters were afforded in excellent yields.
Furthermore, a concise synthesis of (S)-PD 172938 has been demonstrated by using this protocol.
ptically active isoindolinones are prevalent in many
O
natural and unnatural products of immense synthetic
importance with a myriad of biological activities.1
Many of these synthetic products display important
pharmacological effects (Figure 1, 1a−d). For instance, (S)-
PD 172938 1a is a noted dopamine D4 ligand,2 and
pazinaclone (DN2327) 1b is a sedative and anxiolytic drug.3
Similarly, phthalides or isobenzofuranones are five-mem-
bered benzo-fused γ-butyrolactones frequently distributed in a
wide range of bioactive compounds.4 Their intriguing
pharmaceutical properties are evident from observed anti-
convulsant,5 antibacterial,6 anti-HIV,7 and anticancer8 activities
(Figure 1, 2a−d). Over the past few years, many efforts have
been directed toward the asymmetric synthesis of isoindoli-
nones through various diastereoselective approaches mediated
by a chiral auxiliary.9 Conversely, few direct catalytic
enantioselective syntheses have been reported. These include
Mannich-lactamization,10 aza-Michael addition,11 enantiose-
lective aza-Wacker-type cyclization,12 condensation of 2-
acylbenzaldehydes and anilines through a biomimetic
approach,13 and nucleophilic addition to the in situ generated
ketimine obtained from 3-aryl-3-hydroxy isoindolinones.14 On
the other hand, catalytic asymmetric syntheses of phthalides
have been documented involving transition metal catalyzed
transfer hydrogenation of ortho-keto benzonitrile and ortho-
keto ester,15 bioreduction of 2-acetylbenzonitrile,16 intra-
molecular ketone hydroacylation,17 cycloaddition,18 aldol
reaction,19 addition reaction,20 redox allylation of phthalalde-
hydes,21 and cyclization reaction.22 Despite the presence of
some efficient approaches in the literature, there is no
precedence for the synthesis of these two significant classes
of compounds using a common catalytic approach.
Figure 1. Selected biologically active isoindolinones and phthalides.
α-Diazoesters are an important class of nucleophiles for the
formation of an asymmetric C−C bond in various strategies
with the retention of diazo functionality.23 These have been
Received: November 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03597
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extensively used as nucleophiles in enantioselective aldol
reactions of carbonyl compounds,24 enantioselective Mannich-
type reactions of aldimines25 as well as ketimines,14j,26 and
asymmetric allylic alkylation reactions.27 However, α-diazo-
esters have not been investigated in an asymmetric Mannich-
lactamization and aldol-lactonization reaction for the synthesis
of 3-substituted isoindolinones and phthalides. To address this,
we envisioned the possibility of a common catalytic route for
the synthesis of isoindolinones and phthalides by exploiting the
intrinsic nucleophilic character of α-diazoesters. As outlined in
Scheme 1, it was envisaged that the three-component tandem
Table 1. Catalyst Screening and Selected Entries for the
Optimization of Reaction Conditions
a
Scheme 1. Proposed Tandem Mannich-Lactamization and
Aldol-Lactonization Reactions
b
c
entry
catalyst
solvent
t (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
PA1
PA2
PA3
PA4
PA5
PA6
PA7
PA8
PA7
PA7
PA7
PA7
PA7
PA7
PA7
PA7
PA7
PA7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
toluene
Et2O
xylene
dioxane
DCE
24
20
48
48
48
48
20
48
24
24
20
24
24
24
36
24
36
36
NR
78
trace
36
29
trace
94
trace
82
90
96
90
82
80
90
96
92
88
−
71
ND
50
25
ND
85
ND
83
78
89
77
77
75
83
95
94
91
reaction involving a o-formyl methyl benzoate, an amine, and
diazoester produces 3-substituted isoindolinone under the
influence of a chiral Brønsted acid catalyst via Mannich-type
addition to the in situ generated imine followed by
lactamization.
Additionally, it was also hypothesized that, in the absence of
the amine, o-formyl methyl benzoate should undergo aldol
reaction with α-diazoesters followed by lactonization to form
the phthalide derivatives.
d
9
10
11
12
13
14
15
16
17
18
Initially, optimization of the reaction was conducted by
using 1.0 equiv of 2-formyl methylbenzoate (3a) and p-
anisidine (PMPNH2, 5a) with 1.5 equiv of ethyl diazoacetate
(EDA, 4a) in the presence of 5 mol % (R)-BINOL-derived
phosphoric acid (PA1) in dichloromethane at room temper-
ature. The catalyst PA1 failed to catalyze the reaction (Table 1,
entry 1). It might be due to the poor solubility of the catalyst
(PA1) in dichloromethane. However, when the reaction was
performed in the presence of catalyst PA2 (R =
2,4,6-iPr3C6H2) bearing bulkier substituents, the reaction
worked efficiently and afforded the desired isoindolinone 6a
in 78% yield and 71% enantioselectivity (Table 1, entry 2).
Encouraged by this outcome, a series of chiral phosphoric acids
PA3−PA8 were evaluated for the reaction. Even though the
catalyst PA3 having 9-anthracenyl substituents at the 3,3′-
position was fairly soluble in CH2Cl2, only a trace amount of
the product was detected. The catalyst PA4 bearing 9-
phenanthryl substituents afforded the desired product 6a in
36% yield with 50% ee. Although the precise reason for the
difference in catalytic activity between PA3 and PA4 is unclear
to us, the difference in their reactivity indicates that the size of
the appropriate chiral pocket formed by introduction of the
substituents with different steric hindrance at the 3,3′-position
of the phosphoric acid is crucial. Among all the catalysts
screened, PA7 (H8-TRIP) was found to be the best catalyst to
afford isoindolinone 6a in 94% yield with 85% ee (Table 1,
entry 7). Notably, the presence of 4 Å molecular sieves has a
e
f
DCE
DCE
eg
,
a
Reaction conditions: 3a (0.2 mmol), 4a (0.3 mmol), 5a (0.2 mmol),
4 Å MS (50 mg), PA (0.01 mmol), and solvent (2 mL), unless
specified. Isolated yield of 6a. Determined by HPLC using chiralpak
b
c
d
e
ID column. Without MS. Reaction was conducted at 0 °C.
f
g
Reaction was conducted at −20 °C. 0.004 mmol of PA was used.
ND = Not determined. NR = No reaction.
positive effect on yield as well as enantioselectivity (Table 1,
entry 9). Further, the solvent effect on the enantioselectivity of
the product was evaluated (Table 1, entries 10−15). Among
various solvents screened, 1,2-dichloroethane (DCE) was
found to be the best solvent as the enantioselectivity of 6a
was slightly improved to 89% (Table 1, entry 11). For further
improvement of the enantioselectivity, the reaction was carried
out at 0 °C, affording the product 6a in 96% yield with 95% ee
(Table 1, entry 16). Furthermore, lowering the catalyst loading
and reaction temperature had an adverse effect on the
enantioselectivity as well as reaction rate (Table 1, entries
17−18).
Having identified the best experimental reaction conditions,
the substrate scope for isoindolinone formation was explored.
Initially, a number of α-diazo esters were subjected to the
B
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Scheme 2. Substrate Scope for Isoindolinones
a
Reaction was conducted in 1.5 g sclae of 3a.
reaction under optimized conditions. A variety of isoindoli-
nones having α-diazo ester (6a−g) were obtained in good
yields (up to 96%) with excellent enantioselectivities (up to
96% ee). Notably, bulky diazo ester 4c also partcipated in the
reaction, affording 6c in 90% yield with 90% ee.
partner, the desired isoindolinone 6r was not formed. This
might be due to the sluggish formation of the aldimine derived
from sterically demanding o-anisidine. Furthermore, an
aliphatic amine such as benzylamine was examined for the
tandem reaction, providing corresponding product 6z in 45%
yield with 40% enantioselectivity (Scheme 2). To demonstrate
the practical usefulness of the tandem Mannich-lactamization
process, a gram-scale reaction of methyl 2-formylbenzoate 3a
(9.15 mmol, 1.5 g), 5a (9.15 mmol), and ethyl diazoacetate
(13.72 mmol) was conducted under optimized conditions,
affording 6a in 92% yield with 95% ee.
Having successfully synthesized a broad array of isoindoli-
nones, we next turned our attention toward the synthesis of
biologically interesting phthalides using the same catalytic
system. To this end, we initiated our investigation by the
reaction of methyl 2-formylbenzoate (3a) and EDA (4a) under
the previously identified optimized reaction conditions. 3-
Substituted phthalide 7a was afforded in 78% yield with 70%
ee via tandem aldol-lactonization reaction. Further optimiza-
tion studies were performed to improve the enantioselectivity
(see Supporting Information (SI) for more details). Extensive
optimization studies revealed that 5 mol % of PA7 in
dichloromethane at −20 °C was found to promote the aldol-
lactonization reaction most effectively considering yields and
enantioselectivities.
Among differently substituted benzyl diazoacetates (4d−g)
screened, fluorine-containing benzyl diazoacetate took rela-
tively less time for completion of the reaction and furnished
the isoindolinone 6g in 95% yield with 96% ee. Next, a wide
range of sterically and electronically different o-formyl methyl
benzoates were tested in the three-component reaction. o-
Formyl methyl benzoates having diverse substituents on the
aromatic ring were reacted smoothly and yielded correspond-
ing isoindolinones 6h−p in excellent yields (up to 96%) with
consistently excellent enantioselectivities. Methyl 2-formyl-6-
methylbenzoate required a longer time for completion of the
reaction, furnishing the product 6l in 80% yield with 96% ee.
A series of 4-substituted o-formyl methylbenzoates furnished
isoindolinones 6n−p in 99% enantioselectivities.
Subsequently, to establish the generality of the tandem
reaction, a variety of amines were employed under optimized
reaction conditions. Aromatic amines reacted efficiently and
furnished the desired isoindolinones in 85−90% yields with
90−96% ee. It is noteworthy to mention that the steric factor
has a crucial role in the product formation (6r, 6s, and 6a).
Surprisingly, when o-anisidine was introduced as an amine
C
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Next, the scope of the phthalide formation was explored
with a wide variety of α-diazo esters and 2-formyl methyl
benzoates (Scheme 3). Initially, an array of α-diazo esters with
(up to 85% ee). Significantly, the electronic properties of the
substituent attached to the aromatic ring of the o-formyl
methyl benzoates had negligible effect on the optical yields of
the products.
Phthalide 7l was crystallized from the mixture of diethyl
ether/pentane solvent. The absolute stereochemistry of
compound 7l was unambiguously determined by X-ray crystal
structure analysis (CCDC 1872475). The absolute config-
urations of the other phthalides within series 7 were assigned
by analogy.
Scheme 3. Substrate Scope for Phthalide
To gain some insight into the role of the ester moiety in the
substrates (3), control experiments were conducted. Reaction
of 4a with benzaldehyde (3a′) under optimized conditions did
not yield either the Mannich-product or the aldol-product (see
SI for details). This outcome indicates that the ester moiety in
the substrate plays a crucial role in the product formation.
To rationalize the observed stereochemical outcome, a
plausible transition state model was proposed (Figure 2).25a,e,28
Figure 2. Plausible transition state model.
Chiral phosphoric acid acts as a bifunctional catalyst having
both Brønsted acid and Brønsted basic sites. Initially, imine/
aldehyde and an ester moiety were activated by an acidic
proton through hydrogen bonding and then nucleophilic α-
diazoester attacked the Si- face of the imine/aldehyde.
Subsequently, α-diazoester was deprotonated by the phos-
phoryl oxygen (Brønsted basic site). Finally, lactamization/
lactonization provides the desired product.
To demonstrate the synthetic utility of the protocol, the
enantioenriched isoindolinone 6a was transformed into the
corresponding hydrazone derivative 8 in 87% yield with 93%
ee by NaBH4 reduction. The treatment of 6a with Adams’
catalyst under a hydrogen atmosphere furnished 8 and
compound 9 (by complete removal of diazo group) in 68%
and 15% yields respectively with the retention of enantiose-
lectivities. In addition, the phthalide 7q was successfully
reduced to corresponding hydrazone 10 in 68% yield using a
H2/PtO2 catalytic system with erosion in enantiopurity (71%
ee).29 Subsequently, hydrazone 10 was efficiently converted
into α-keto ester 11 in 70% yield and with retention of
enantioselectivity (Scheme 4).
a
ee after recrystallization in ether−pentane mixture.
delicate functionalities were tested. Phthalides 7a−g were
obtained in good to excellent yields (up to 90%) and
enantioselectivities (up to 85% ee). Among various diazo-
acetates screened, benzyl diazo acetate was best to afford the
corresponding phthalide 7d with 85% ee. Then, we
investigated the scope of the aldol-lactonization tandem
reaction by conducting the reaction of benzyl diazo ester
with a series of methyl 2-formylbenzoates. Interestingly,
enantioenriched phthalides containing diazo ester 7h−p were
afforded in good yields (up to 85%) and enantioselectivities
The title reaction was eventually applied in a concise
synthesis of (S)-PD 172938 (Scheme 5). The synthesis
includes removal of the diazo moiety from enantioenriched
isoindolinone 6a to provide compound 9 in 70% yield and
subsequent removal of the PMP group by using cerium(IV)
D
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Then, 13 was converted to 1a using a procedure described in
literature.11d,30
Scheme 4. Synthetic Transformations
In summary, we have demonstrated a Brønsted acid
catalyzed enantioselective synthesis of isoindolinones and
phthalides via tandem Mannich-lactamization and aldol-
lactonization reactions, respectively, from readily available
precursors. The strategy provides facile access to a variety of N-
and O-heterocycles in excellent yields (up to 96%) and
enantioselectivities (up to 99% ee). The catalytic system is
amenable to gram-scale synthesis of isoindolinones. The
synthetic potential of this methodology has also been
demonstrated by exploiting the reactivity of diazo functionality
in the product. Additionally, a concise total synthesis of (S)-
PD 172938 has been accomplished by using this protocol.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03597.
Experimental details and analytical data (NMR, HPLC,
and ESI-HRMS) (PDF)
Accession Codes
CCDC 1872475 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 5. Synthesis of (S)-PD 172938
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vinodks@iitk.ac.in.
ORCID
Milon M. Sadhu: 0000-0001-5273-1997
Vinod K. Singh: 0000-0003-0928-5543
Author Contributions
§S.K.R., MM.S., and R.G.B. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
V.K.S. thanks the DST India, for the J. C. Bose fellowship.
S.K.R. thanks DST for the INSPIRE Faculty award (DST/
INSPIRE/04/2016001704). M.M.S. thanks DST for an Inspire
fellowship. We are thankful to Dr. Atanu Dey, TIFR
Hyderabad, for assistance with X-ray crystallography.
REFERENCES
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DOI: 10.1021/acs.orglett.8b03597
Org. Lett. XXXX, XXX, XXX−XXX