Asymmetric Syntheses of Medicinally Important Isoindolinones (S)-PD 172938, (R)-JM 1232, and Related Structures

Article abstract of DOI:10.1021/acs.joc.6b00770

A unified approach for the asymmetric syntheses of medicinally important isoindolinones (S)-PD 172938 and (R)-JM 1232 has been accomplished via a Cu(I)-PYBOX-diPh catalyzed highly enantioselective (up to 99% ee) alkynylation/lactamization sequence in a one-pot fashion. The overall sequence involves one C-C and two C-N bond forming events in one pot starting from inexpensive starting material in ambient reaction conditions.

Full text of DOI:10.1021/acs.joc.6b00770

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Article
Asymmetric Syntheses of Medicinally Important Isoindolinones,
(S)-PD 172938, (R)-JM 1232 and Related Structures
Arun Suneja, Vishnumaya Bisai, and Vinod K. Singh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00770 • Publication Date (Web): 05 May 2016
Downloaded from http://pubs.acs.org on May 5, 2016
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Asymmetric Syntheses of Medicinally Important
Isoindolinones, (S)-PD 172938, (R)-JM 1232 and Related
Structures
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†
¶
,†,§
Arun Suneja, Vishnumaya Bisai, and Vinod K. Singh*
†
Department of Chemistry, Indian Institute of Science Education and Research Bhopal,
§
Bhopal Bypass Road, Bhopal, MP - 462 066, India and Indian Institute of Technology
Kanpur, UP – 208 016, India
TOC GRAPHIC
O
O
Ph
Ph
O
O
Ph
Ph
N
NH
H
N Ph
N
N
H
4b
O
O
PMP
H
OMe
N
N
N
1
0 mol % Cu(I)-4b
O
H
CHCl , 0 C - rt
Ar =
3,4-diMePh
+
+
PMPNH2
3
X
N
N
X
Ar
R
Me
JM-1232 (1b)
up to 95%
R
3
5
O
(S) PD172938 (1a)
up to 99% ee
ABSTRACT
A unified approach for the asymmetric syntheses of medicinally important
isoindolinones (S)-PD 172938 and (R)-JM 1232 has been accomplished via a Cu(I)-PYBOX-
diPh catalyzed highly enantioselective (up to 99% ee) alkynylation/lactamization sequence in
one-pot fashion. The overall sequence involves one C-C and two C-N bond forming events in
one-pot starting from inexpensive starting material in ambient reaction conditions.
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INTRODUCTION
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Isoindolinones are heterocyclic compounds (1a-e; Figure 1) having potential
1
2
3
biological activities, such as anti-hypertensive, anti-psychotic, anti-inflammatory, and
4
5
anesthetic. Some members of this class of heterocyclic scaffolds also display anti-ulcer,
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7
8a
8b
vasodilatory, anti-viral, anti-leukemic properties, and platelet aggregation inhibitory
activities. These are also found to induce dose-dependent p53-dependent gene transcription in
9
MDM2-amplified SJSA human sarcoma cell lines. In addition, isoindolinones are useful in
1
0
11
the synthesis of various drugs and complex natural products. Since enantiomers interact
differently with the biological system, therefore, intense research is going on to synthesize
these biologically active isoindolinones in enantioenriched form. In fact, (S)-PD 172938 (1a)
1
2
4
is reported as a potent dopamine D ligand, and (R)-JM 1232 (1b) is a benzodiazepine
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receptor agonists for the treatment of anxiety, whereas 1c is an inhibitor of the β-secretase
14
enzyme for the treatment of Alzheimer’s disease.
Figure 1. Selected enantioenriched isoindolinones.
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Prominent approaches to this class of heterocyclics include Heck cyclization, Diels-
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6
17
Alder approach, domino three-component coupling-lactamization, ring-closure of chiral
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19a-b
19c
hydrazones, reactions of chiral acyliminium ion,
allylation to chiral imines, aza-
2
0a
20b-c
conjugate addition, and chiral appendage mediated carbanion method.
Most of these
syntheses involve a chiral auxiliary mediated diastereoselective approach and face limited
substrate scope. Only a few enantioselective syntheses of isoindolinones are known in
2
1-24
literature.
Towards this, transition-metal catalyzed processes include, Rh(I)-catalyzed
21a
21b
arylation, Cu(I)-catalyzed tandem Michael-Mannich reaction,
Pd(II)-catalyzed aza-
2
1c
Wacker type cyclization
and organocatalytic syntheses include thio-urea catalyzed
2
2
23
malonate addition, our direct organocatalytic Mannich-lactamization, and phase transfer
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catalyzed aza-Michael reactions.
Scheme 1. Our report on domino enantioselective alkynylation/lactamization.
Towards this, we recently reported enantioselective synthesis of isoindolinones (>99%
I i
25
ee) via a Cu - Pr-pybox-diPh 4b catalyzed alkynylation-lactamization cascade (Scheme 1).
We envisioned that one can achieve asymmetric syntheses of 1a-e from a common
enatioenriched isoindolinone 2a via synthetic elaboration (Figure 1). Compound 2a could be
accessed from enantioenriched aryl ketone 2b via a Baeyer-Villiger oxidation, which in turn
could be synthesized from enantioenriched 5 following oxidative reaction (Scheme 2).
Utilizing above strategy, herein, we report first unified approach for the asymmetric syntheses
of medicinally important (S)-PD 172938, and (R)-JM 1232.
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RESULTS AND DISCUSSION
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At the outset, we studied several potential catalysts to ultimately identify the most
efficient catalytic system (Table 1) to realize this transformation. As a model system en route
to isoindolinone derivatives, we carried out Cu-(I)-catalyzed alkynylation/lactamization
cascade with methyl 2-formyl benzoate (3a) in the presence of 10 mol % of Cu(I)-4a-d in
chloroform at room temperature under inert atmosphere. Since p-methoxyphenyl group of
PMPNH can be cleaved under oxidative condition, we decided to us this as amine source.
2
Also, to facilitate Baeyer-Villiger oxidation of compound 2b, we choose p-
methoxyphenylacetylene as terminal alkyne (Table 1).
Table
1.
Optimization
of
domino
Cu(I)-catalyzed
enantioselective
alkynylation/lactamization.
b
entry metal salt
catalyst solvent
Temp
Time
% yield ee
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c
°
C
(h)
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48
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(%)
79
99
92
85
00
94
00
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95
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1
(CuOTf) .PhMe
4a
4b
4c
CHCl3
0 - 25
0 - 25
0 - 25
0 - 25
0 - 25
0 - 25
0 - 25
0 - 25
0 - 25
0 - 25
0 - 25
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92
84
90
00
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(CuOTf)
(CuOTf)
(CuOTf)
CuI
2
2
2
.PhMe
.PhMe
.PhMe
CHCl
CHCl
CHCl
CHCl
CHCl
3
3
3
3
3
4d
4b
4b
4b
4b
4b
4b
4b
Cu(OTf)
CuTC
2
CHCl3
[Cu(CH
3
3
CN)
CN)
4
4
]BF
4
CHCl
CHCl
CHCl
CHCl
3
3
3
3
[Cu(CH
]PF
6
0
(CuOTf)
(CuOTf)
2
2
.PhH
e
11
.PhMe
[
a] Unless otherwise stated all the reactions were performed with 1 equivalent of each
aldehyde and p-anisidine, and 1.2 equivalent of 4-ethynylanisole (ratio of 1:1:1.2) under inert
atmosphere. [b] isolated yields. [c] determined by chiral HPLC analysis. [d] decomposition of
rest of the mass balance. [e] the reaction was carried out on 3.0 mmol scale (~0.5g scale).
Following extensive optimization, it was found that (CuOTf)
2
.PhMe complex of
PYBOX-4a-d afforded isoindolinone 5 in 59%, 92%, 84% and 90% of yields with 79%,
99%, 92% and 85% of ee, respectively (entries 1-4, table 1). Thus, it is quite clear that,
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i
ligands with gem-diphenyl groups 4b-d are superior over 4a. Since Pr-PYBOX-diPh (4b) is
best ligand among all gem-diphenyl groups, further optimization with various Cu-catalysts
were carried out using 4b. Among various Cu(I)-complexes, [Cu(CH CN) ]BF ,
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[
Cu(CH CN) ]PF , and (CuOTf) .PhH afforded 5 in 94%, 93% and 92% ee, respectively,
3 4 6 2
with 83-90% yields (entries 8-10), whereas Cu(I)I and Cu(I)TC-complexes of 4b were found
to be completely inactive catalysts (entries 5 and 7). Gratifyingly, Cu(II)-4b also afforded
isoindolinone 5 in 94% enantioselectivity (entry 6). This method is attractive towards its
utilization in organic synthesis because this catalytic system works without the use of any
additives.
Scheme 2. Synthesis of (S)-PD 172938.
With enough quantity in hand, our effort was thereafter to elaborate compound 5 for
3 2
synthesis of PD 172938 1a (Scheme 2). Towards this, we treated 5 with Hg(OCOCF ) in the
2
6
presence of HgO to affect hydration of alkyne functionality to afford aryl ketone 6 in 54%
yield. The later was then treated with ceric(IV) ammonium nitrate (CAN) to furnish 7 in 84%
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yield, which was then converted to aryl ester 8 in 87% yield via Baeyer-Villiger oxidation.
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Then, ester 8 was reduced with NaBH to get 9 in 82% yield (91% ee), which was followed
by mesylation concomitant with N-alkylations with N-substituted piperazine to complete the
synthesis of (S)-PD 172938 1a in 91% ee (See Supporting Information for HPLC traces).
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In another sequence, we carried out Baeyer-Villiger oxidation of arylketone 6
followed by trans-esterification to afford advanced intermediate for the synthesis of
pazinaclone (DN 2327) 1d (Scheme 3). However, we found that trans-esterification using
K CO /EtOH afforded ethylester 15 in only 69% ee. We speculate that, since pKa of benzylic
2
3
proton is ~21 (essentially vinylogous position: see blue portion of 11), racemization could
takes place via intermediate A. Another alternate racemization pathway would be retro-aza-
Michael process to intermediate B (Scheme 3). A similar case was observed when
2
saponification of 11 was carried out using LiOH.H O to furnish carboxylic acid 13'. When
the later was coupled with 4-piperidone derivative, it afforded amide 14' in 81% ee (See SI
for HPLC traces).
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Scheme 3. Synthesis of advanced intermediate 14'.
Thus, in an alternate strategy, arylester 11 (93% ee) was reduced to primary alcohol
2 and which was re-oxidized to carboxylic acid 13 in 74% overall yield (Scheme 4). Finally,
3 were coupled with 4-piperidone derivative to afford advanced intermediate amide 14
1
1
without the loss of any enantiopurity (Scheme 4).
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Scheme 4. Synthesis of advanced amide intermediate 14.
Next, we targeted for the asymmetric syntheses of (R)-JM 1232 1b (Figure 1).
Towards this, we synthesized o-formyl methylbenzoate 3b from commercially available
acetophenone 16a in 5 steps (Scheme 5). First, 16a was oxidized to benzoic acid 16b in 91%
yield, which was then converted to phthalide 17 by reaction with dibromomethane in the
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presence of Pd(OAc) . The later afforded o-formyl methylbenzoate 3b in 3 steps viz.
2
saponification to form 18, MnO -oxidation to afford 19 followed by reaction with MeI in
2
presence of K CO (Scheme 5).
2
3
Scheme 5. Synthesis of o-formyl methylbenzoate 3b.
Having o-formyl methylbenzoate 3b in hand, we then carried out propargylation using
ligand ent-4b to access isoindolinone 20 with R-stereochemistry (Scheme 6). Gratifyingly,
we could able to use three aromatic amines with different electronic nature, such as aniline,
p-methoxyaniline, and p-fluoroaniline in the presence of 4-ethynylanisole to afford
isoindolinones 20a-c in high yields with excellent enantioselectivities (up to 99% ee).
28
However, all these cases 20 mol % p-fluorobenzoic acid was used as additive.
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Scheme 6. Substrate scope using o-formyl methylbenzoate 3b.
We then synthesized aryl ester 22 from isoindolinone 20a in two steps viz reactions
using Hg(OCOCF ) in presence of HgO, and Baeyer-Villiger oxidation in 44% overall
3
2
4 3
yields (Scheme 7). Aryl ester 22 was reduced with LiBH followed by RuCl -catalyzed
oxidation to afford carboxylic acid 24 (Scheme 7). Finally, amide coupling using N-
methylpiperazine in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride salt (EDCI.HCl) afforded required (R)-JM 1232 (1b) in 94% ee (See
Supporting Information for HPLC traces).
O
Hg(OCOCF3)2
O
O
Ph
Ph
Ph
m-CPBA, Na HPO
LiBH , THF
0 °C - rt, 1 h
N
HgO, THF:H O
2
N
2
4
N
4
H
H
H
CH Cl , rt, 12 h
(20:1), rt, 3.5 h
2
2
86%
51%
92%
O
O
Ar
Ar
OAr
22
94% ee
Ar = p-OMePh 20a
Ar = p-OMePh 21
97% ee
93% ee
O
O
O
Ph
Ph
Ph
H
RuCl .H O, NaIO
N
N
3
2
4
N
H
H
EDCI.HCl, HOBt.H2O
EtOAc/CH CN/H O
3
2
R NH, THF, rt, 16 h
2
rt, 1 h
94% ee
O
8
6%
O
80%
OH
OH
N
R NH =
23
24
2
JM 1232
NMe
N-Methylpiperazine
1b
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Scheme 7. Asymmetric synthesis of JM 1232 (1b).
CONCLUSIONS
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In conclusion, we report asymmetric syntheses of medicinally important
isoindolinones, (S)-PD 172938 (1a), and (R) JM 1232 (1b) via a highly enantioselective one-
pot alkynylation-lactamization cascade. Important features of our strategy include: (1) the
reactions do not require preformed imine equivalents; (2) the method is operationally simple
and inexpensive; (3) excellent enantioselectivity (95% ee) has been achieved even using 0.5 g
scale of 3a. Further application of this strategy is under active investigation in our laboratory.
EXPERIMENTAL SECTION
Materials and Methods
Unless otherwise stated, reactions were performed in oven-dried glassware fitted with
rubber septa and were stirred with Teflon-coated magnetic stirring bars. Liquid reagents and
solvents were transferred via syringe using standard Schlenk techniques. Tetrahydrofuran
(THF), diethyl ether (Et O), benzene and toluene were distilled over sodium/benzophenone
2
2 2 3
ketyl. Dichloromethane (CH Cl ), and chloroform (CHCl ) were distilled over calcium
hydride. All other solvents and reagents were used as received unless otherwise noted.
Reaction temperatures above 25 °C refer to oil bath temperature. Thin layer chromatography
was performed using silica gel 60 F-254 precoated plates (0.25 mm) and visualized by UV
irradiation, 2,4-DNP stain and other stains. Silica gel of particle size 100-200 mesh was used
for column chromatography. Melting points were recorded on a digital melting point
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4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
13
apparatus and are uncorrected. H and C NMR spectra were recorded 400 MHz, 500 MHz,
1
3
and 700 MHz, spectrometers with C operating frequencies of 100 MHz, 125 MHz, and 176
MHz respectively. Chemical shifts (δ) are reported in ppm relative to the residual solvent
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
(
CDCl ) signal (δ = 7.24 ppm for H NMR and δ = 77.0 ppm for C NMR), (DMSO-d )
3
6
1
13
signal (δ = 2.54 ppm for H NMR and δ = 39.9 ppm for C NMR) and (CD
3
OD) signal (δ =
1
13
1
4
.78 and 3.29 ppm for H NMR and δ = 47.6 ppm for C NMR). Data for H NMR spectra
are reported as follows: chemical shift (multiplicity, coupling constants and number of
hydrogen). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), quint
(
quintet), m (multiplet), br (broad), dd (doublet of doublets). IR spectra were recorded on a
-1
FT-IR system and are reported in frequency of absorption (cm ). Only selected IR
absorbances are reported. High-Resolution Mass Spectrometry (HRMS) data was recorded on
TOF-Q-II mass spectrometer using acetonitrile as solvent. Optical rotations were measured
on a commercial automatic polarimeter. Enantiomeric excess was determined by chiral HPLC
analysis using Chiralpak AD-H and Chiralpak IA columns.
2
5
29
Starting materials such as 3a, 10 and 16b were prepared according to the literature known
procedures.
2
5
Procedure for the synthesis of compound (3b):
To a solution of compound 19 (1.5 mmol, 1.0 equiv) in dry DMF (4 mL) was added MeI
3.15 mmol, 2.1 equiv), and K CO (1.5 mmol, 1.0 equiv) at RT. The reaction mixture was
(
2
3
heated at 80 °C for 6 h. Upon completion of the reaction (monitored by TLC), the reaction
mixture was quenched with water (25 mL) and the aqueous layer was extracted with EtOAc
(3 × 40 mL). The combined organic layers were washed with 15 mL of saturated aqueous
Na
2
S
2
O
3
3
solution followed by 15 mL of saturated aqueous NaHCO solution. The organic
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8
9
2 4
layer was then washed with 20 mL of brine solution, dried over anhydrous Na SO ,
concentrated in vacuo, and purified by silica gel column chromatography to afford pure ester
b as a pale yellow solid (275.7 mg, 90%).
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 6-formyl-2,3-dihydro-1H-indene-5-carboxylate (3b): 275.7 mg, 90% Yield of (3b)
1
as pale yellow solid. R = 0.45 (15% EtOAc in hexanes); H-NMR (400 MHz, CDCl ) δ
f
3
1
0.54 (s, 1H), 7.77 (brs, 2H), 3.92 (s, 3H), 2.96 (t, J = 7.5 Hz, 4H), 2.12 (quint, J = 7.5 Hz,
1
3
2H); C-NMR (100 MHz, CDCl ) δ 192.3, 167.2, 150.3, 149.4, 135.8, 130.7, 126.3, 124.2,
3
5
2.6, 32.9, 32.7, 25.2; IR (film) υmax 2953, 2904, 1716, 1688, 1434, 1273, 1119, 1037, 773
-1
+
+
12 3
cm ; HRMS (ESI) m/z 227.0697 [M+Na] ; calculated for [C12H O + Na] : 227.0679; MP
°
3
9-41 C.
2
5
General procedure for Cu(I)-catalyzed Alkynylation-lactamization cascade:
Large Scale:
i
A solution of a ligand 4b (S,S)- Pr-PyBOX-DiPh (0.3 mmol, 10 mol %) and
(CuOTf)
C for 45 min under nitrogen atmosphere. An aldehyde 3a (3.0 mmol) and p-anisidine
3.0mmol) were added and the whole mixture was stirred for additional 45 min followed by
2
.PhMe complex (0.3 mmol, 10 mol %) in dry chloroform (30 mL) was stirred at 0
°
(
addition of 4-ethynylanisole (3.6 mmol) at the same temperature. The reaction mixture was
gradually allowed to warm up to 25 ºC. After completion of the reaction (monitoring by
TLC), the mixture was concentrated in vacuo and purified over silica gel by column
chromatography (EtOAc/hexane) affording product 5 in 986.3 mg, 89% yield and 95% ee.
26
Procedure for the synthesis of compound (6):
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
To a solution of compound 5 (1.5 mmol, 1.0 equiv) in wet THF (60 mL, THF/H O, 20:1, v/v)
was added red HgO (1.2 mmol, 0.8 equiv) and mercuric trifluoroacetate (0.6 mmol, 0.4
equiv). The reaction mixture was stirred for 3.5 h at RT before quenched with saturated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
aqueous Na S solution (25 mL) at 0 °C. After stirring for another 20 minutes, saturated
2
aqueous NaHCO
phase was then extracted with EtOAc (3 × 40 mL). The combined organic layers were
washed with water and brine, dried over anhydrous Na SO , and concentrated in vacuo. The
3
solution (25 mL) was added. After filtration through Celite, the aqueous
2
4
residue was purified by silica gel chromatography to give aryl ketone 6 as orange solid (313.8
mg, 54% yield).
(
)-2-(4-Methoxyphenyl)-3-(2-(4-methoxyphenyl)-2-oxoethyl)isoindolin-1-one (6): 313.8
1
mg, 54% Yield of (6) as orange solid. R = 0.36 (40% EtOAc in hexanes); H-NMR (500
f
MHz, CDCl
3
) δ 7.94-7.96 (m, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.49-7.53 (m, 5H), 6.97 (d, J =
8
3
.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 5.90 (dd, J = 9.6, 3.2 Hz, 1H), 3.86 (s, 3H), 3.83 (s,
1
3
H), 3.45 (dd, J = 17.4, 3.2, 1H), 3.14 (dd, J = 17.4, 9.6 Hz, 1H); C-NMR (125 MHz,
) δ 196.1, 166.9, 163.9, 157.6, 145.4, 132.1, 131.9, 130.4, 129.6, 129.5, 128.6, 125.3,
23.9, 123.2, 114.6, 113.9, 57.6, 55.5, 55.4, 41.5; IR (film) υmax 2933, 1691, 1599, 1512,
CDCl
3
1
1
+
-1
+
250, 1171, 1030, 758 cm ; HRMS (ESI) m/z 388.1551 [M+H] ; calculated for [C H NO
24 21
4
+
°
H] : 388.1543; MP 52-54 C; Enantiomeric excess was determined via HPLC analysis
using a Chiralpak AD-H column; solvent: hexane/2-propanol =65/35; flow rate: 1.0 mL/min;
2
5.0
detection: at 254nm): t
CHCl , for 92% ee).
R
minor = 18.79 min, t
R
major = 33.35 min. [α]
D
= 166.5 (c = 0.4,
3
17b
Procedure for the synthesis of compound (7):
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7
8
9
The compound 6 (0.58 mmol, 1.0 equiv) was dissolved in CH
°C using ice-salt mixture. An aqueous solution of CAN (2.5 equiv, 1.45 mmol dissolved in
.0 mL H O) was added dropwise, and stirred for 10 min at the same temperature. Upon
3
CN (10 mL) and cooled at 10
5
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
completion of the reaction (monitored by TLC), the reaction mixture was quenched with
saturated aqueous solution of NaHCO , and extracted with EtOAc (3 x 20 mL). The organic
3
layers were dried over anhydrous Na SO and concentrated under reduced pressure. The
2
4
crude product was purified by column chromatography using EtOAc/hexane as eluent to
afford compound 7 as brown solid (137.0 mg, 84% yield).
()-3-(2-(4-Methoxyphenyl)-2-oxoethyl)isoindolin-1-one (7): 137.0 mg, 84% Yield of (7)
1
as brown solid. R = 0.31 (60% EtOAc in hexanes); H-NMR (500 MHz, CDCl ) δ 7.94 (d, J
f
3
=
8.9 Hz, 2H), 7.89 (d, J = 7.5 Hz, 1H), 7.61 (td, J = 7.5, 1.1 Hz, 1H), 7.49-7.53 (m, 2H),
6
.99 (brs, 1H), 6.95 (d, J = 8.9 Hz, 2H), 5.15 (dd, J = 10.2, 3.0 Hz, 1H), 3.89 (s, 3H), 3.68
13
(
dd, J = 17.8, 3.3 Hz, 1H), 3.07 (dd, J = 17.8, 10.2 Hz, 1H); C-NMR (125 MHz, CDCl
3
) δ
196.3, 169.9, 164.1, 146.7, 132.0, 131.9, 130.4, 129.2, 128.5, 124.1, 122.4, 113.9, 55.6, 52.6,
-1
4
3.7; IR (film) υmax 3379, 2909, 1694, 1670, 1600, 1360, 1262, 1170, 768 cm ; HRMS (ESI)
+
+
°
m/z 282.1106 [M+H] ; calculated for [C H NO + H] : 282.1125; MP 148-150 C;
1
7
15
3
Enantiomeric excess was determined via HPLC analysis using a Chiralpak AD-H column;
solvent: hexane/2-propanol =50/50; flow rate: 1.0 mL/min; detection: at 254nm): t minor =
R
2
5.0
8
.49 min, t major = 12.18 min. [α]D = 126.7 (c = 0.34, CHCl , for 92% ee).
R
3
26
Procedure for the synthesis of compound (8):
To a solution of compound 7 (0.4 mmol, 1.0 equiv) in CH
4.8 mmol, 12.0 equiv) and m-CPBA (2.4 mmol, 6.0 equiv). The reaction mixture was then
2
2 2 4
Cl (5 mL) was added Na HPO
(
stirred under Ar atmosphere at room temperature for 12 h before it was quenched by 20 mL
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8
9
1
1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of saturated aqueous Na
2 2 3
S O solution. After stirred vigorously for 30 min, 20 mL of
saturated aqueous NaHCO solution was added and extracted with CH Cl (3 × 30 mL). The
3
2
2
2 4
combined organic extracts were washed with brine, dried over anhydrous Na SO , and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
concentrated in vacuo. The residue was purified by column chromatography using
EtOAc/hexane as eluent to afford compound 8 as pale yellow solid (103.5 mg, 87% yield).
4
-Methoxyphenyl ()-2-(3-oxoisoindolin-1-yl)acetate (8): 103.5 mg, 87% Yield of (8) as
1
pale yellow solid. R = 0.38 (60% EtOAc in hexanes); H-NMR (500 MHz, CDCl ) δ 7.91 (d,
f
3
J = 7.6 Hz, 1H), 7.63 (td, J = 7.5, 1.1 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.51 (dd, J = 7.6, 0.8
Hz, 1H), 7.16 (brs, 1H), 7.03-7.07 (m, 2H), 6.91-6.95 (m, 2H), 5.06 (dd, J = 10.1, 3.7 Hz,
1
3
1
H), 3.82 (s, 3H), 3.27 (dd, J = 17.2, 3.8 Hz, 1H), 2.77 (dd, J = 17.2, 10.1 Hz, 1H); C-NMR
125 MHz, CDCl ) δ 170.23, 170.21, 157.6, 145.7, 143.7, 132.2, 131.8, 128.8, 124.2, 122.4,
122.1, 114.6, 55.6, 52.7, 39.7; IR (film) υmax 3244, 2920, 1750, 1697, 1505, 1192, 1140, 752
(
3
-1
+
+
4
cm ; HRMS (ESI) m/z 298.1092 [M+H] ; calculated for [C17H15NO + H] : 298.1074; MP
°
1
38-140 C; Enantiomeric excess was determined via HPLC analysis using a Chiralpak AD-
H column; solvent: hexane/2-propanol =70/30; flow rate: 1.0 mL/min; detection: at 254nm):
25.0
t
R
minor = 11.73 min, t
R
major = 14.18 min. [α]
D
3
= 102.9 (c = 0.58, CHCl , for 92% ee).
31
Procedure for the synthesis of compound (9):
A solution of aryl ester 8 (0.3 mmol, 1.0 equiv) in MeOH (10 mL) was cooled to 0 °C using
ice-water mixture. The reaction mixture was charged with portion wise addition of NaBH
20.0 equiv) at the same temperature. The reaction mixture was then stirred for 1 h at 30 °C.
Upon completion of the reaction (monitored by TLC), the reaction mixture was quenched
with 10 mL of saturated aqueous NH Cl solution and the solvent was removed in vacuo. The
4
(
4
resulting aqueous solution was extracted with EtOAc (5 x 20 mL). The combined organic
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7
8
9
2 4
layers were washed with brine, dried over anhydrous Na SO , and concentrated under
reduced pressure. The residue was purified by small pad of silica gel column chromatography
using MeOH/EtOAc as eluent to afford compound 9 as colorless viscous gel (43.6 mg, 82%
yield).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
)-3-(2-Hydroxyethyl)isoindolin-1-one (9): 43.6 mg, 82% Yield of (9) as colorless viscous
1
gel. R = 0.38 (5% MeOH in EtOAc); H-NMR (400 MHz, DMSO-d ) δ 8.68 (brs, 1H), 7.56-
f
6
7
3
.64 (m, 3H), 7.43-7.49 (m, 1H), 4.69 (t, J = 5.0 Hz, 1H), 4.63 (dd, J = 8.6, 4.0 Hz, 1H),
13
.52-3.63 (m, 2H), 2.00-2.08 (m, 1H), 1.49-1.58 (m, 1H); C-NMR (125 MHz, CDCl
3
) δ
171.3, 147.9, 131.9, 131.6, 128.2, 123.8, 122.4, 60.3, 55.8, 37.1; IR (film) υmax 3279, 2925,
-1
+
1
681, 1418, 1368, 1054, 739 cm ; HRMS (ESI) m/z 178.0889 [M+H] ; calculated for
+
[C
10
H11NO
2
+ H] : 178.0863; Enantiomeric excess was determined via HPLC analysis using
a Chiralpak AD-H column; solvent: hexane/2-propanol =90/10; flow rate: 0.5 mL/min;
25.0
D
detection: at 254nm): t
CHCl , for 91% ee).
R
major = 32.13 min, t
R
minor = 34.14 min. [α]
= 115.3 (c = 0.30,
3
1
2
Procedure for the synthesis of compound (S)-PD 172938 (1a):
Step-I:
2 2
To a solution of alcohol 9 (0.2 mmol, 1.0 equiv) in CH Cl (6 mL) was cooled to 0 °C using
ice-water bath. Et N (0.6 mmol, 3.0 equiv) was added to the reaction mixture followed by
3
dropwise addition of methanesulfonyl chloride (0.24 mmol, 1.2 equiv). The reaction mixture
was stirred for 4 h at room temperature. Once the starting material was completely consumed,
it was diluted with CH
2
Cl
2
. The diluted reaction mixture was washed with 1 N HCl (2 mL).
SO and filtered through Celite to get the
The organic layer was dried over anhydrous Na
2
4
crude product which was used for the next step without further purification.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Step-II:
A DMF (4 mL) solution of the above product (0.2 mmol, 1.0 equiv), 1-(3,4-
dimethylphenyl)piperazine, 10 (0.2 mmol, 1.0 equiv), and N,N-diisopropylethylamine (0.6
mmol, 3.0 equiv) was stirred for 16 h at 80 °C. Once starting material completely consumed
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
monitored by TLC), the volatile component was removed in vacuo. The residue was
partitioned between EtOAc and water, and the organic layer was washed with water and
brine, dried over anhydrous Na SO , filtered, and concentrated in vacuo. The resulting crude
2
4
material was purified by silica gel column chromatography using the solvent system
MeOH/EtOAc/NH OH to afford the title compound 1a as an off-white solid (57.3 mg, 82%
4
over two steps).
()-3-(2-(4-(3,4-Dimethylphenyl)piperazin-1-yl)ethyl)isoindolin-1-one (1a): 57.3 mg, 82%
1
Yield (over 2 steps) of (1a) as off-white solid. R
f
= 0.28 (5% MeOH/CH
2
Cl
2
); H-NMR (700
MHz, CDCl
3
) δ 7.88 (d, J = 7.6 Hz, 1H), 7.59 (td, J = 7.5, 1.0 Hz, 1H), 7.49 (t, J = 7.4 Hz,
1H), 7.50 (dd, J = 7.6, 0.6 Hz, 1H), 7.35 (brs, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 2.4
Hz, 1H), 6.72 (dd, J = 8.2, 2.6 Hz, 1H), 4.66 (dd, J = 10.0, 2.9 Hz, 1H), 3.18-3.24 (m, 4H),
2
3
1
.71-2.75 (m, 3H), 2.64 (dt, J = 12.5, 4.9 Hz, 1H), 2.56-2.59 (m, 2H), 2.26 (s, 3H), 2.21 (s,
1
3
H), 2.15-2.19 (m, 1H), 1.75-1.80 (m, 1H); C-NMR (125 MHz, CDCl
3
) δ 170.1, 149.5,
47.5, 137.1, 132.0, 131.7, 130.1, 128.3, 128.2, 123.9, 122.2, 118.3, 114.0, 57.2, 56.7, 53.4,
49.8, 31.3, 20.2, 18.8; IR (film) υmax 3227, 2923, 2853, 1693, 1614, 1506, 1356, 1139, 1003
-1
+
+
27 3
cm ; HRMS (ESI) m/z 350.2242 [M+H] ; calculated for [C22H N O + H] : 350.2227; MP
°
1
33-135 C; Enantiomeric excess was determined via HPLC analysis using a Chiralpak AD-
H column; solvent: hexane/2-propanol =75/25; flow rate: 1.0 mL/min; detection: at 254nm):
25.0
t
R
minor = 8.98 min, t
R
major = 11.04 min. [α]
D
3
= 44.2 (c = 0.90, CHCl , for 91% ee).
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8
9
4-Methoxyphenyl ()-2-(2-(4-methoxyphenyl)-3-oxoisoindolin-1-yl)acetate (11): 217.8
1
mg, 90% Yield of (11) as pale yellow solid. R
f
= 0.37 (40% EtOAc in hexanes); H-NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
400 MHz, CDCl ) δ 7.93 (d, J = 7.4 Hz, 1H), 7.51-7.60 (m, 3H), 7.44 (d, J = 8.8 Hz, 2H),
3
6.98 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 5.55 (dd, J = 7.4,
.5 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.10 (dd, J = 16.1, 4.4 Hz, 1H), 2.77 (dd, J = 16.1, 7.7
4
13
Hz, 1H); C-NMR (100 MHz, CDCl ) δ 169.2, 166.9, 158.1, 157.5, 143.9, 143.6, 132.2,
3
1
32.1, 129.1, 129.0, 126.3, 124.3, 122.6, 122.0, 114.7, 114.5, 58.2, 55.6, 55.5, 37.7; IR (film)
-1
υ
max 2927, 1751, 1694, 1509, 1388, 1299, 1248, 1192, 1135, 1031, 758 cm ; HRMS (ESI)
+
+
°
m/z 404.1520 [M+H] ; calculated for [C H NO + H] : 404.1492; MP 116-118 C;
2
4
21
5
Enantiomeric excess was determined via HPLC analysis using a Chiralpak AD-H column;
solvent: hexane/2-propanol =65/35; flow rate: 1.0 mL/min; detection: at 254nm): t minor =
R
2
D
5.0
20.75 min, t
R
major = 25.83 min. [α]
3
= 52.4 (c = 0.34, CHCl , for 93% ee).
Procedure for the synthesis of compound (12):
A solution of aryl ester 11 (0.4 mmol, 1.0 equiv) in freshly distilled THF (6 mL) was cooled
to 0 °C using ice-water mixture. The reaction mixture was charged with portion wise addition
of LiBH
stir at room temperature for 1 h. Upon completion of the reaction (monitored by TLC), the
reaction mixture was quenched with 10 mL of saturated aqueous NH Cl solution and the
solvent was removed in vacuo. The resulting aqueous solution was extracted with EtOAc (3 x
0 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO
4
(5.0 equiv) at the same temperature. The reaction mixture was gradually allowed to
4
2
2
4
,
and concentrated under reduced pressure. The residue was purified by short pad of silica gel
column chromatography using EtOAc/hexane as eluent to afford compound 12 as pale yellow
solid (100.8 mg, 89% yield).
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()-3-(2-Hydroxyethyl)-2-(4-methoxyphenyl)isoindolin-1-one (12): 100.8 mg, 89% Yield
1
of (12) as pale yellow solid. R
f
= 0.29 (60% EtOAc in hexanes); H-NMR (500 MHz, CDCl
3
)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
δ 7.93 (d, J = 7.5 Hz, 1H), 7.62 (td, J = 7.6, 1.1 Hz, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.53 (d, J =
7.4 z, 1H), 7.45-7.48 (m, 2H), 6.97-7.00 (m, 2H), 5.31 (dd, J = 6.1, 4.2 Hz, 1H), 3.85 (s, 3H),
13
3
.47-3.56 (m, 2H), 2.20-2.27 (m, 1H), 2.04-2.10 (m, 1H), 1.74 (brs, 1H); C-NMR (125
MHz, CDCl
3
) δ 167.2, 157.6, 144.6, 132.2, 131.9, 129.8, 128.5, 125.5, 124.2, 122.5, 114.5,
-1
5
8.9, 58.0, 55.5, 34.4; IR (film) υmax 3398, 2920, 1670, 1512, 1395, 1247, 1036, 771 cm ;
+
+
3
HRMS (ESI) m/z 284.1282 [M+H] ; calculated for [C17H17NO + H] : 284.1281; MP 137-
°
139 C; Enantiomeric excess was determined via HPLC analysis using a Chiralpak AD-H
column; solvent: hexane/2-propanol =85/15; flow rate: 1.0 mL/min; detection: at 254nm): t
R
2
D
5.0
minor = 31.69 min, t
R
major = 36.81 min. [α]
3
= 25.0 (c = 0.28, CHCl , for 93% ee).
Procedure for the synthesis of compound (13):
32
Method A: Oxidation of primary alcohol
To a solution of alcohol 12 (0.2 mmol, 1.0 equiv) in CH
were added NaIO (0.82 mmol, 4.1 equiv) and RuCl .H O (5 mol %) sequentially. The
3
2
CN/EtOAc/H O (7 mL, 2:2:3, v/v/v)
4
3
2
reaction mixture was then allowed to stir at RT for 1 h. Upon completion of the reaction
monitored by TLC), the reaction mixture was filtered through Celite to remove insoluble
solids. The aqueous layer was then extracted with EtOAc (3 x 20 mL). The combined organic
layers were washed with brine, dried over anhydrous Na SO , and concentrated in vacuo. The
(
2
4
residue was purified by small pad of silica gel column chromatography using MeOH/EtOAc
as eluent to afford compound 13 as white solid (49.4 mg, 83% yield).
33
Method B: Aryl ester hydrolysis using LiOH.H O
2
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The aryl ester 11 (0.2 mmol, 1.0 equiv) was dissolved in THF/H O (4 mL, 1:1, v/v) and
LiOH.H O (1.0 mmol, 5.0 equiv) was added. The reaction mixture was stirred at room
2
temperature for 3 h. Upon completion of the reaction (monitored by TLC), the reaction
mixture was neutralized with 1 N HCl and extracted with EtOAc (3 X 15 mL). The solvent
was removed in vacuo. The residue was purified by short pad of silica gel column
chromatography using MeOH/EtOAc as eluent to afford compound 13 as white solid (47.6
mg, 80% yield).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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(
)-2-(2-(4-Methoxyphenyl)-3-oxoisoindolin-1-yl)acetic acid (13): Method A: 49.4 mg,
1
83% Yield of (13) as white solid. R = 0.28 (10% MeOH in EtOAc); H-NMR (400 MHz,
f
3
CD OD) δ 7.80 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.52 (t,
J = 7.4 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.53 (dd, J = 8.4, 3.7 Hz,
1
3
1H), 3.81 (s, 3H), 2.83 (dd, J = 15.8, 3.6 Hz, 1H), 2.33 (dd, J = 13.9, 9.5 Hz, 1H); C-NMR
125 MHz, CD OD) δ 167.9, 158.4, 145.7, 132.0, 131.3, 128.9, 128.3, 126.4, 123.0, 122.9,
14.1, 59.6, 54.5, 38.4; IR (film) υmax 2920, 1644, 1513, 1394, 1248, 1157, 758 cm ; HRMS
(
3
-1
1
+
+
°
4
(ESI) m/z 298.1077 [M+H] ; calculated for [C17H15NO + H] : 298.1074; MP 175-177 C;
25.0
D
[α]
3
= 25.3 (c = 0.45, CHCl ).
13
Procedure for the synthesis of compound (14):
To a solution of an acid 13 (0.1 mmol, 1.0 equiv), 1,4-dioxa-8-azaspiro[4.5]decane (0.1
mmol, 1.0 equiv), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (0.1
mmol, 1.0 equiv) and 1-hydroxybenzotriazole monohydrate (0.1 mmol, 1.0 equiv) in freshly
distilled THF (5 ml) were allowed to stir at RT for 16 h. The solvent was then concentrated
2
under reduced pressure. The residue was redissolved in EtOAc (15 mL) and H O (10 mL)
and the organic layer was separated. The aqueous layer was extracted thrice with EtOAc (3 x
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
5 mL). The combined organic layers were then washed with brine, dried over anhydrous
Na SO , and concentrated in vacuo. The residue was purified by silica gel column
2
4
chromatography using EtOAc/hexane as eluent to afford compound 14 as white solid (36.8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mg, 87% yield).
(
)-2-(4-Methoxyphenyl)-3-(2-oxo-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-
yl)ethyl)isoindolin-1-one (14): 36.8 mg, 87% Yield of (14) as white solid. R = 0.42 (80%
f
1
EtOAc in hexanes); H-NMR (500 MHz, CDCl
3
) δ 7.92 (d, J = 7.4 Hz, 1H), 7.63 (d, J = 7.5
Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.50-7.53 (m, 3H), 6.99 (d, J = 8.9 Hz, 2H), 5.80 (dd, J =
9.3, 3.5 Hz, 1H), 3.92-3.98 (m, 4H), 3.84 (s, 3H), 3.74-3.79 (m, 1H), 3.67-3.72 (m, 1H), 3.27-
3
2
.36 (m, 2H), 2.89 (dd, J = 15.9, 3.6 Hz, 1H), 2.44 (dd, J = 15.9, 9.4 Hz, 1H), 1.63-1.71 (m,
1
3
H), 1.51 (t, J = 5.7 Hz, 2H); C-NMR (125 MHz, CDCl ) δ 167.9, 166.8, 157.5, 145.3,
3
132.1, 131.8, 129.4, 128.6, 125.1, 123.9, 123.2, 114.5, 106.6, 64.5, 58.4, 55.5, 43.5, 40.0,
-1
3
6.4, 35.4, 34.7; IR (film) υmax 2920, 1750, 1697, 1505, 1192, 1140, 752 cm ; HRMS (ESI)
+
+
°
m/z 423.1919 [M+H] ; calculated for [C24
Enantiomeric excess was determined via HPLC analysis using a Chiralpak AD-H column;
solvent: hexane/2-propanol =65/35; flow rate: 1.0 mL/min; detection: at 254nm): t minor =
26 2 5
H N O + H] : 423.1914; MP 153-155 C;
R
2
D
5.0
14.89 min, t
R
major = 24.68 min. [α]
3
= 97.1 (c = 0.31, CHCl , for 93% ee).
2
6
Procedure for the synthesis of compound (15):
To a solution of aryl ester 11 (0.2 mmol, 1.0 equiv) in EtOH was added K
.0 equiv). The reaction mixture was stirred at room temperature for 4 h. Solvent was
2
3
CO (0.6 mmol,
3
removed and it was purified by silica gel coumn chromatography (hexanes/ethyl acetate as
eluent) to afford ethyl ester 15 as a colorless viscous gel (59.9 mg, 92% yield).
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Ethyl ()-2-(2-(4-methoxyphenyl)-3-oxoisoindolin-1-yl)acetate (15): 59.9 mg, 92% Yield
1
of (15) as colorless viscous gel. R
CDCl
.9 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 5.50 (dd, J = 8.1, 4.4 Hz, 1H), 4.04-4.13 (m, 2H), 3.85
f
= 0.44 (40% EtOAc in hexanes); H-NMR (500 MHz,
3
) δ 7.95 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.53-7.59 (m, 2H), 7.45 (d, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
(s, 3H), 2.90 (dd, J = 16.1, 4.4 Hz, 1H), 2.54 (dd, J = 16.0, 8.2 Hz, 1H), 1.18 (t, J = 7.1 Hz,
13
3
1
1
H); C-NMR (125 MHz, CDCl ) δ 170.4, 166.9, 157.9, 144.3, 132.1, 132.0, 129.2, 128.8,
3
26.1, 124.2, 122.5, 114.6, 61.0, 58.2, 55.5, 37.8, 14.0; IR (film) υmax 2920, 1732, 1693,
-1
+
513, 1389, 1248, 1177, 1034, 758 cm ; HRMS (ESI) m/z 326.1411 [M+H] ; calculated for
+
[C
19
H19NO
4
+ H] : 326.1387; Enantiomeric excess was determined via HPLC analysis using
a Chiralpak AD-H column; solvent: hexane/2-propanol =65/35; flow rate: 1.0 mL/min;
25.0
detection: at 254nm): t minor = 10.61 min, t major = 12.86 min. [α]
D
= 44.5 (c = 0.35,
R
R
3
CHCl , for 69% ee).
27
Procedure for the synthesis of compound (17):
A 50 mL round bottom sealed flask equipped with a magnetic stir bar was charged with
Pd(OAc) (1 mmol, 0.1 equiv) followed by K HPO (30 mmol, 3.0 equiv), 2,3-dihydro-1H-
indene-5-carboxylic acid (10 mmol, 1.0 equiv), and CH Br (25 mL). The reaction tube was
2
2
4
2
2
sealed with a Teflon tube and was stirred at 140 °C for 36 h, after which it was filtered
through a small pad of Celite. The filtrate was concentrated in vacuo and the residue was
purified by silica gel column chromatography (CH
2 2
Cl /hexane as eluent) to give the
corresponding product 17 as a white solid (853.6 mg, 49% yield).
3
,5,6,7-tetrahydro-1H-indeno[5,6-c]furan-1-one (17): 853.6 mg, 49% Yield of (17) as
1
white solid. R
f
= 0.5 (70% CH
2
Cl
2
in hexanes); H-NMR (500 MHz, CDCl
3
) δ 7.71 (s, 1H),
13
7
.30 (s, 1H), 5.25 (s, 2H), 3.00 (q, J = 7.7 Hz, 4H), 2.17 (quint, J = 7.4 Hz, 2H); C-NMR
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5
5
5
5
5
5
5
6
(
125 MHz, CDCl
3
) δ 171.4, 152.3, 146.0, 145.6, 124.1, 121.0, 117.6, 69.4, 33.0, 33.2, 25.8;
-1
IR (film) υmax 2922, 2847, 1746, 1641, 1451, 1012, 771 cm ; HRMS (ESI) m/z 175.0769
+
+
°
10 2
[M+H] ; calculated for [C11H O + H] : 175.0754; MP 116-118 C.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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8
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
0
Procedure for the synthesis of compound (18):
To a solution of compound 17 (3.6 mmol, 1.0 equiv) in an aqueous solution of MeOH (85%,
0 mL) was added KOH pellets (5.4 mmol, 1.5 equiv). The reaction mixture was refluxed for
2
2 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo to
remove MeOH, and the residue was diluted with H O (10 mL). The mixture was then
2
neutralized to pH 4-5 by addition of a solution of KHSO
4
(1 M). The formed solid was
filtrated, and washed with water (3 x 5 mL) to give product 18 as a white solid (657.3 mg,
9
5% yield).
6
-(Hydroxymethyl)-2,3-dihydro-1H-indene-5-carboxylic acid (18): 657.3 mg, 95% Yield
1
of (18) as white solid. R
f
= 0.2 (60% EtOAc in hexanes); H-NMR (500 MHz, DMSO-d
6
) δ
7
.71 (s, 1H), 7.55 (s, 1H), 4.79 (s, 2H), 3.38 (brs, 1H), 2.85-2.91 (m, 4H), 2.03 (quint, J = 7.4
1
3
Hz, 2H); C-NMR (125 MHz, DMSO-d ) δ 169.1, 148.7, 143.3, 142.2, 126.7, 126.4, 123.2,
6
-1
61.8, 33.0, 32.2, 25.4; IR (film) υmax 3292, 2946, 1687, 1413, 1254, 1042, 803 cm ; HRMS
+
+
°
(
12 3
ESI) m/z 215.0670 [M+Na] ; calculated for [C11H O + Na] : 215.0679; MP 134-136 C.
3
0
Procedure for the synthesis of compound (19):
To a solution of compound 18 (3.0 mmol, 1.0 equiv) in dry THF (50 mL) were added Celite
(600 mg), and active MnO (60 mmol, 20.0 equiv) sequentially. The reaction mixture was
2
stirred at room temperature for 12 h. Upon completion of the reaction (monitored by TLC),
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the reaction was filtered through small pad of Celite, and the filtrate was concentrated. The
residue was purified by a silica gel chromatography (EtOAc/Hexane) to give product 19 as a
white solid (325.2 mg, 57% yield).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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32
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3-Hydroxy-3,5,6,7-tetrahydro-1H-indeno[5,6-c]furan-1-one (19): 325.2 mg, 57% Yield of
1
(
19) as white solid. R = 0.5 (50% EtOAc in hexanes); H-NMR (500 MHz, DMSO-d ) δ
f
6
8.04 (s, 1H), 7.61 (s, 1H), 7.47 (s, 1H), 6.57 (s, 1H), 2.92-2.98 (m, 4H), 2.09 (quint, J = 7.5
1
3
Hz, 2H); C-NMR (125 MHz, DMSO-d ) δ 169.0, 152.4, 147.5, 147.0, 125.5, 120.3, 119.7,
6
9
8.2, 32.9, 32.2, 25.8; IR (film) υmax 3362, 2952, 2844, 1744, 1619, 1436, 1152, 1083, 927
-1
+
+
10 3
cm ; HRMS (ESI) m/z 213.0520 [M+Na] ; calculated for [C11H O + Na] : 213.0522; MP
°
1
01-103 C.
Procedure for the synthesis of compounds (20a-c):
i
A solution of a ligand ent-4b (R,R)- Pr-PyBOX-DiPh (0.03 mmol, 10 mol %) and
(
CuOTf)
°C for 20 min under nitrogen atmosphere. An aldehyde 3b (0.3 mmol) and aromatic amine
0.3 mmol) were added and the whole mixture was stirred for additional 30 min followed by
2
.PhMe complex (0.03 mmol, 10 mol %) in dry chloroform (3 mL) was stirred at 0
(
addition of alkyne (0.36 mmol) at the same temperature. The reaction mixture was gradually
allowed to warm up to 25 ºC. After stirring for 12 h, 20 mol % of p-fluorobenzoic acid was
added to the reaction mixture and allowed to stir for another 10-20 h for the completion of
lactamization step. The mixture was concentrated in vacuo and purified over silica gel by
column chromatography (EtOAc/hexane as eluent) affording products 20a-c in upto 95%
yield and upto 99% enantioselectivities.
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2
2
2
2
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3
3
3
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3
3
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(
)-3-((4-Methoxyphenyl)ethynyl)-2-phenyl-3,5,6,7-tetrahydrocyclopenta[f]isoindol-
1(2H)-one (20a): 107.0 mg, 94% Yield of (20a) as white solid. R
f
= 0.3 (15% EtOAc in
) δ 7.85 (d, J = 7.7 Hz, 2H), 7.73 (s, 1H), 7.50 (s, 1H),
.43 (t, J = 8.0 Hz, 2H), 7.17-7.24 (m, 3H), 6.75 (d, J = 8.8 Hz, 2H), 5.92 (s, 1H), 3.75 (s,
1
hexanes); H-NMR (400 MHz, CDCl
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
1
3
3H), 3.00 (dd, J = 16.1, 8.0 Hz, 4H), 2.15 (quint, J = 7.4 Hz, 2H); C-NMR (100 MHz,
CDCl ) δ 167.0, 159.9, 150.3, 145.9, 140.7, 138.0, 133.3, 130.1, 128.9, 124.9, 121.9, 119.7,
3
1
18.7, 114.0, 113.8, 85.8, 82.6, 55.2, 53.0, 33.1, 32.4, 25.7; IR (film) υmax 2924, 2851, 2120,
-1
+
1
700, 1603, 1508, 1448, 1359, 1250, 1031, 772 cm ; HRMS (ESI) m/z 402.1459 [M+Na] ;
+
°
2
calculated for [C26H21NO + Na] : 402.1465; MP 175-177 C; Enantiomeric excess was
determined via HPLC analysis using a Chiralpak IA column; solvent: hexane/2-propanol
=
80/20; flow rate: 1.0 mL/min; detection: at 254nm): t minor = 12.64 min, t major = 19.70
R R
2
D
5.0
min. [α]
3
= 7.8 (c = 0.50, CHCl , for 97% ee).
(
)-2-(4-Methoxyphenyl)-3-((4-methoxyphenyl)ethynyl)-3,5,6,7-
tetrahydrocyclopenta[f]isoindol-1(2H)-one (20b): 116.7 mg, 95% Yield of (20b) as white
1
solid. R
f
= 0.28 (20% EtOAc in hexanes); H-NMR (400 MHz, CDCl
3
) δ 7.71 (s, 1H), 7.67
(
d, J = 9.1 Hz, 2H), 7.48 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.1 Hz, 2H), 6.75 (d, J
=
8.8 Hz, 2H), 5.83 (s, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 2.98 (dd, J = 15.3, 7.6 Hz, 4H), 2.14
13
(quint, J = 7.4 Hz, 2H); C-NMR (100 MHz, CDCl ) δ 166.9, 159.9, 157.3, 150.1, 145.8,
3
140.8, 133.3, 131.0, 130.1, 124.5, 119.6, 118.7, 114.2, 114.1, 133.9, 85.8, 82.8, 55.4, 55.3,
-1
5
3.7, 33.1, 32.5, 25.8; IR (film) υmax 2954, 2095, 1693, 1605, 1510, 1249, 1032, 773 cm ;
+
+
3
HRMS (ESI) m/z 432.1575 [M+Na] ; calculated for [C27H23NO + Na] : 432.1570; MP 168-
°
170 C; Enantiomeric excess was determined via HPLC analysis using a Chiralpak IA
column; solvent: hexane/2-propanol =80/20; flow rate: 1.0 mL/min; detection: at 254nm): t
R
2
D
5.0
minor = 22.09 min, t
R
major = 41.71 min. [α]
3
= 27.4 (c = 0.35, CHCl , for 99% ee).
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()-2-(4-Fluorophenyl)-3-((4-methoxyphenyl)ethynyl)-3,5,6,7-
tetrahydrocyclopenta[f]isoindol-1(2H)-one (20c): 108.5 mg, 91% Yield of (20c) as white
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
solid. R = 0.32 (15% EtOAc in hexanes); H-NMR (400 MHz, CDCl ) δ 7.75-7.79 (m, 2H),
f
3
7.72 (s, 1H), 7.49 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.12 (t, J = 8.7 Hz, 2H), 6.76 (d, J = 8.8
Hz, 2H), 5.87 (s, 1H), 3.76 (s, 3H), 3.00 (dd, J = 16.5, 7.8 Hz, 4H), 2.15 (quint, J = 7.5 Hz,
1
3
2
1
2
H); C-NMR (100 MHz, CDCl ) δ 166.9, 160.0 (d, J = 243.1 Hz), 160.0, 150.5, 146.0,
3
40.7, 134.1 (d, J = 2.8 Hz), 133.3, 129.9, 124.1 (d, J = 8.0 Hz), 119.7, 118.8, 115.6 (d, J =
2.3 Hz), 113.9, 113.8, 86.1, 82.4, 55.3, 53.4, 33.1, 32.4, 25.8; IR (film) υmax 2952, 2101,
-1
+
1688, 1607, 1509, 1365, 1250, 1156 cm ; HRMS (ESI) m/z 420.1351 [M+Na] ; calculated
+
°
for [C26
H20FNO
2
+ Na] : 420.1370; MP 150-152 C; Enantiomeric excess was determined via
HPLC analysis using a Chiralpak IA column; solvent: hexane/2-propanol =80/20; flow rate:
2
D
5.0
1.0 mL/min; detection: at 254nm): t
R
minor = 13.62 min, t
R
major = 27.36 min. [α]
= 8.1
(
3
c = 0.49, CHCl , for 95% ee).
(
)-3-(2-(4-Methoxyphenyl)-2-oxoethyl)-2-phenyl-3,5,6,7-
tetrahydrocyclopenta[f]isoindol-1(2H)-one (21): 141.9 mg, 51% Yield of (21) as yellow
1
solid. R
f
= 0.32 (30% EtOAc in hexanes); H-NMR (400 MHz, CDCl
3
) δ 7.82 (d, J = 8.9 Hz,
2
H), 7.71 (s, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.9 Hz, 2H), 7.29 (s, 1H), 7.16 (t, J =
7.4 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 5.89 (dd, J = 9.6, 2.3 Hz, 1H), 3.81 (s, 3H), 3.43 (d, J =
1
3
1
7.6, 2.7 Hz, 1H), 3.11 (dd, J = 17.6, 9.8 Hz, 1H), 2.81-2.96 (m, 4H), 2.02-2.14 (m, 2H); C-
NMR (125 MHz, CDCl ) δ 196.2, 167.2, 163.9, 149.9, 145.2, 144.2, 137.0, 130.4, 130.2,
129.5, 129.2, 125.2, 122.9, 119.6, 118.9, 113.8, 56.5, 55.5, 41.8, 33.1, 32.4, 25.7; IR (film)
3
-
1
υ
max 2923, 2845, 1696, 1673, 1599, 1494, 1374, 1261, 1169, 758 cm ; HRMS (ESI) m/z
+
+
°
3
3
98.1769 [M+H] ; calculated for [C26H23NO + H] : 398.1751; MP 149-151 C;
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4
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4
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5
5
5
5
5
5
6
Enantiomeric excess was determined via HPLC analysis using a Chiralpak AD-H column;
solvent: hexane/2-propanol =70/30; flow rate: 1.0 mL/min; detection: at 254nm): t major =
R
2
D
5.0
1
6.04 min, t
R
minor = 18.64 min. [α]
3
= 69.7 (c = 0.33, CHCl , for 93% ee).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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0
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0
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9
0
4
-Methoxyphenyl ()-2-(3-oxo-2-phenyl-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindol-1-
f
yl)acetate (22): 106.7 mg, 86% Yield of (22) as white solid. R = 0.35 (30% EtOAc in
1
hexanes); H-NMR (400 MHz, CDCl ) δ 7.75 (s, 1H), 7.59 (d, J = 7.7 Hz, 2H), 7.45 (t, J =
3
7
.9 Hz, 2H), 7.41 (s, 1H), 7.23-7.27 (m, 1H), 6.80-6.86 (m, 4H), 5.60 (dd, J = 8.8, 4.0 Hz,
H), 3.77 (s, 3H), 3.15 (dd, J = 16.2, 4.0 Hz, 1H), 2.98 (t, J = 7.4 Hz, 4H), 2.74 (dd, J = 16.1,
1
1
3
8.2 Hz, 1H), 2.15 (quint, J = 7.4 Hz, 2H); C-NMR (100 MHz, CDCl ) δ 169.5, 167.1,
3
1
1
1
57.5, 150.0, 145.7, 143.7, 142.7, 136.7, 130.5, 129.3, 125.8, 123.9, 122.1, 119.9, 118.4,
14.5, 57.1, 55.6, 38.0, 33.1, 32.4, 25.7; IR (film) υmax 2921, 2851, 1751, 1698, 1504, 1378,
-1
+
4
246, 1192, 1034 cm ; HRMS (ESI) m/z 414.1724 [M+H] ; calculated for [C26H23NO +
+
°
H] : 414.1700; MP 150-152 C; Enantiomeric excess was determined via HPLC analysis
using a Chiralpak IA column; solvent: hexane/2-propanol =80/20; flow rate: 1.0 mL/min;
25.0
detection: at 254nm): t
CHCl , for 94% ee).
R
major = 29.48 min, t
R
minor = 33.18 min. [α]
D
= 51.2 (c = 0.21,
3
(
)-3-(2-Hydroxyethyl)-2-phenyl-3,5,6,7-tetrahydrocyclopenta[f]isoindol-1(2H)-one (23):
1
67.5 mg, 92% Yield of (23) as white solid. R = 0.3 (50% EtOAc in hexanes); H-NMR (700
f
MHz, CDCl
3
) δ 7.74 (s, 1H), 7.57-7.59 (m, 2H), 7.42-7.45 (m, 2H), 7.39 (s, 1H), 7.23 (tt, J =
7
2
.4, 1.0 Hz, 1H), 5.34 (dd, J = 6.2, 3.8 Hz, 1H), 3.45-3.52 (m, 2H), 2.97-3.04 (m, 4H), 2.20-
1
3
.25 (m, 1H), 2.15-2.19 (m, 2H), 2.04-2.09 (m, 1H), 1.84 (brs, 1H); C-NMR (176 MHz,
) δ 167.5, 149.8, 145.2, 143.3, 137.2, 130.5, 129.1, 125.4, 123.4, 119.8, 118.3, 58.1,
7.9, 34.3, 33.1, 32.4, 25.8; IR (film) υmax 3393, 2922, 2851, 1671, 1495, 1388, 1050, 763
CDCl
3
5
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-1
+
+
cm ; HRMS (ESI) m/z 294.1507 [M+H] ; calculated for [C19
H19NO
2
+ H] : 294.1489; MP
°
1
22-124 C; Enantiomeric excess was determined via HPLC analysis using a Chiralpak AD-
H column; solvent: hexane/2-propanol =75/25; flow rate: 1.0 mL/min; detection: at 254nm):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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26
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34
35
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43
44
45
46
47
48
49
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51
52
53
54
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56
57
58
59
60
2
5.0
t
R
minor = 11.63 min, t
R
major = 15.31 min. [α]
D
3
= 24.2 (c = 0.22, CHCl , for 93% ee).
13
(
R)-2-(3-Oxo-2-phenyl-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindol-1-yl)acetic acid (24) :
f
Method A- 49.2 mg, 80% Yield of (24) as white solid. R = 0.34 (10% MeOH in EtOAc);
1
H-NMR (400 MHz, CD
3
OD) δ 7.63 (s, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.44-7.48 (m, 3H),
7
.28 (t, J = 7.4 Hz, 1H), 5.57 (dd, J = 7.6, 3.8 Hz, 1H), 2.99 (dd, J = 13.4, 6.9 Hz, 4H), 2.88
1
3
(dd, J = 16.2, 3.9 Hz, 1H), 2.50 (dd, J = 16.2, 7.7 Hz, 1H), 2.14 (quint, J = 7.4 Hz, 2H); C-
NMR (100 MHz, DMSO-d ) δ 171.5, 166.7, 149.6, 145.2, 143.9, 137.3, 130.6, 129.3, 125.6,
23.9, 119.2, 119.0, 57.0, 36.7, 32.9, 32.3, 25.8; IR (film) υmax 2924, 1677, 1384, 1249,
6
1
-1
+
+
3
1169, 763 cm ; HRMS (ESI) m/z 308.1298 [M+H] ; calculated for [C19H17NO + H] :
°
3
08.1281; MP 198-200 C.
(
)-3-(2-(4-Methylpiperazin-1-yl)-2-oxoethyl)-2-phenyl-3,5,6,7-
1
3
tetrahydrocyclopenta[f]isoindol-1(2H)-one (1b) : 33.5 mg, 86% Yield of (1b) as white
1
solid. R
f
= 0.48 (10% MeOH in CH
2
Cl
2
); H-NMR (500 MHz, CDCl
3
) δ 7.74 (s, 1H), 7.65
(
d, J = 7.8 Hz, 2H), 7.43-7.46 (m, 3H), 7.22 (t, J = 7.4 Hz, 1H), 5.81 (dd, J = 9.2, 3.3 Hz,
1
H), 3.63-3.73 (m, 2H), 3.19-3.30 (m, 2H), 2.99 (t, J = 7.4 Hz, 4H), 2.89 (dd, J = 15.9, 3.4
1
3
Hz, 1H), 2.37-2.45 (m, 3H), 2.27 (s, 3H), 2.22 (t, J = 4.9 Hz, 2H), 2.12-2.18 (m, 2H); C-
NMR (125 MHz, CDCl ) δ 168.3, 167.1, 149.9, 145.3, 144.0, 136.9, 130.1, 129.1, 125.2,
22.9, 119.6, 119.1, 57.4, 54.8, 54.5, 45.9, 45.3, 41.6, 36.6, 33.1, 32.4, 25.7; IR (film) υmax
3
1
2
-1
937, 1694, 1638, 1450, 1376, 1291, 1141, 1001, 849, 758 cm ; HRMS (ESI) m/z 390.2206
+
+
[
27 3 2
M+H] ; calculated for [C24H N O + H] : 390.2176; Enantiomeric excess was determined
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