Efficient access to enantiopure 1,3-disubstituted isoindolines from selective catalytic fragmentation of an original desymmetrized rigid overbred template

Article abstract of DOI:10.1039/c5ob00229j

An efficient and scalable synthesis of various enantiopure 1,3- disubstituted isoindolines is reported. The base catalyzed nucleophilic fragmentation of a rigid overbred template is established with various substrates to afford the corresponding 1,3-disub

Full text of DOI:10.1039/c5ob00229j

Organic &
Biomolecular Chemistry
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Efficient access to enantiopure 1,3-disubstituted
isoindolines from selective catalytic fragmentation
of an original desymmetrized rigid overbred
template†
Cite this: Org. Biomol. Chem., 2015,
3, 4438
1
a
a,b
a
Ganesh Pandey,* Rajesh Varkhedkar and Divya Tiwari
An efficient and scalable synthesis of various enantiopure 1,3- disubstituted isoindolines is reported. The
base catalyzed nucleophilic fragmentation of a rigid overbred template is established with various sub-
strates to afford the corresponding 1,3-disubstituted isoindoline ester, amide, thioate, 1,3-amino alcohol
and isoindolylcarboxylic acid. The crucial rigid overbred template is synthesized in an optically pure form
in multigram scale by asymmetric desymmetrization of the corresponding meso compound.
Received 3rd February 2015,
Accepted 3rd March 2015
DOI: 10.1039/c5ob00229j
www.rsc.org/obc
Introduction
Chiral 1-substituted isoindolinone (1a,2), 1-isoindolyl-
carboxylic acid (1b) and 1,3-disubstituted isoindolines (1c) are
1
constituents of many pharmaceuticals and different natural
2
products (Fig. 1). Studies done in vitro as well as in vivo
have revealed that 1,3-disubstituted isoindoline derivatives if
administered with the cancer drug restore the intracellular
level of drugs and some are found to exhibit antitumor activity
3
in human melanoma cells. Apart from this property, these
molecules are reported to inhibit enzymes such as prolyl
4
dipeptidases DPP8 and DPP9. They are also found to act as
5
N-methyl-D-aspartate antagonists, modulators for endothelin
6
(
3), 5-H2C and 5TH1A receptors and HIV-1 reverse transcrip-
7
Fig. 1 Substituted isoindolines.
tase inhibitors.
Furthermore, disubstituted isoindolines are shown to
8
inhibit amyloid protein aggregation; show antibacterial,
9
11
diuretic activity and antitumor activity (4). They are also dates in organic light emitting diodes. Therefore, it is
identified as potent selective human peroxisome proliferator- imperative to explore a practical and scalable route for the
activated receptor (PPARδ) agonists (5) and lead candidates for asymmetric synthesis of these isoindolines.
1
0a
the treatment of diabetes. The substituted isoindoline carb-
However, to date there are only a few strategies known for
oxylic acid is also a constituent of angiotensin converting the synthesis of 1, 3-disubstituted isoindolines in both
1
0b,c
12
13
enzyme inhibitors and is employed in SAR studies.
More- racemic as well as optically active forms. These are mainly
over, substituted isoindolines are also being explored as candi- chiral auxiliary based approaches since fixing a stereocenter
adjacent to a benzyl moiety is the most challenging task in
their synthesis. More recently, optically active 1,3-disubstituted
a
isoindolines (7) have been obtained either by the 1,2-addition
of a nucleophile onto a bifunctional ε-benzoiminoenoate (6)
followed by intramolecular aza-Michael reaction (route 1,
Molecular Synthesis Laboratory, Centre of Biomedical Research (CBMR), Sanjay
Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road,
Lucknow-226 014, India. E-mail: gp.pandey@cbmr.res.in
b
Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr Homi Bhabha
14
Scheme 1) or (10) by the cycloaddition of the azomethine
Road, Pune-411 008, India
†
1
ylide from imino ester (9) with quinone (8) in the presence of
Electronic supplementary information (ESI) available: Spectroscopic data, H,
C NMR spectra, HPLC data. CCDC 1028992. For ESI and crystallographic data
1
5
1
3
suitable chiral catalysts (route 2, Scheme 1). Although prom-
in CIF or other electronic format see DOI: 10.1039/c5ob00229j
ising, these methods suffer from several drawbacks such as
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Scheme 2 Synthesis of meso-18.
Scheme 1 Approaches towards the asymmetric synthesis of 1,3-disub-
stituted isoindolines.
2
0
(16) with ethynyl phenyl sulfone as shown in Scheme 2.
β-Metalation (n-BuLi, anhydrous THF, −90 °C) of 17 followed
by the addition of benzene sulfonyl fluoride afforded the
desired meso-18 in 60% yield (Scheme 2). The use of expensive
tetrazine for the in situ generation of isoindole and formation
of a large amount of side product 15 led us to abandon this
route and begin exploring another alternative protocol for its
synthesis.
the requirement of expensive catalysts, non-scalability and
inconsistent enantioselectivity. In the context of designing an
entirely new strategy for the synthesis of enantiomerically pure
1
2, we envisaged fixing the stereochemistry of the benzylic
stereocentre in the beginning itself by involving an optically
pure rigid overbred template 11 as a precursor (Scheme 1).
The overbred precursor is the compound which possesses
one or more excess C–C bonds which on cleavage afford the
Subsequently, we evaluated an alternative strategy as shown
in Scheme 3. N-Boc-1,4-epiminonaphthalene (13) was refluxed
21
with benzenesulfenyl chloride in a mixture of hexane–DCM
1
6
(1 : 1) for 1 h and the corresponding addition product on treat-
desired skeleton. This precursor was envisaged owing to the
presence of a considerable distortion in it allowing selective
t
ment with 3 eq. of KO Bu afforded 19 in 95% yield. Repetition
1
7
of the same reaction sequence with 19 afforded 20 in 87%
yield which on oxidation using 4.5 eq. of m-chloroperbenzoic
carbon–carbon/heteroatom bond cleavages.
We would like to report herein our success in this endea-
vour as we prepared an optically pure overbred template 11 (ee
1
8
>
99%) on a multigram scale by asymmetric desymmetriza-
tion of the corresponding meso compound and its successful
transformation to enantiomerically pure (ee = 99%) 12 by
selective catalytic C2–C3 bond cleavage. To the best of our
knowledge, this is the first strategy of synthesizing 12 with con-
sistent enantioselectivity over an entire range of reported
substrates.
Results and discussion
We began our research in this area first by developing a proto-
col for the synthesis of meso-18 by following the sequence
shown in Scheme 2. The reaction of N-Boc-1,4-dihydro-1,4-epi-
1
9
minonaphthalene (13) with N-Boc-pyrrole in the presence of
an equimolar amount of tetrazine (14) and ethynyl phenyl
sulfone in dry DCM afforded 17 in 77% yield. The reaction pre-
sumably involved cycloaddition of in situ generated isoindole Scheme 3 Alternative route for the synthesis of meso-18.
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Table 1 Optimization of reaction conditions for the asymmetric
desymmetrization of meso-18
Yield of
11 (%)
de of a
Yield of
21 (%)
Entry
Solvent
T (°C)
11 (%)
1
2
3
4
THF
THF
THF
THF
25
0
−20
−78
45
35
25
20
30
32
35
49
55
65
75
80
Fig. 2 Plausible reaction mechanism.
a
Determined by HPLC analysis (Atlantis T-3, MeOH–H
.5 mL min ).
2
O = 80 : 20,
−
1
0
acid yielded meso-18 in 92% yield. This approach of obtaining
meso-18 (three step one pot reaction, 76% in overall yield) was
scaled up to 20 g level and thus can be considered as the first
step towards the scalable synthesis of 1,3-disubstituted iso-
indolines (Scheme 3).
Having meso-18 in hand, we proceeded with its desymmetri-
2
2
zation using (S,S)-hydrobenzoin. However, to our disappoint-
ment, diastereoselectivity as well as the yield of the desired 11
was found to be low due to the formation of 21 as the major
product. Our several attempts to optimize the yield and
diastereoselectivity remained unsatisfactory (Table 1). A plaus-
ible mechanism for the formation of 11 and 21 is shown
in Fig. 2.
Poor diastereoselectivity was attributed to the non-selective
approach of the (S,S)-hydrobenzoin anion from both the faces
of meso-18 as depicted by structures A and B whereas the for-
mation of 21 can be explained due to the stabilization of the
anion on to the nitrogen atom of the N-Boc group during
Fig. 3 Plausible explanation for the preferred β-face attack anion of
S,S)-hydrobenzoin.
(
desymmetrization and extended conjugation of the resulting addition will also possibly reduce the formation of
double bond with the aromatic ring (Fig. 3).
undesired 21.
Therefore, we realized that in order to achieve higher
Armed with this proposition, desymmetrization of meso-22
diastereoselectivity, the attack of the anion of (S,S)-hydro- was carried out with the (S,S)-hydrobenzoin anion which
benzoin on the vinylic carbon of meso-18 should be specifically afforded 23 as a single pure diastereomer in 80% yield under
from only one of the β-faces through a least encumbered trajec- optimized experimental conditions (Table 2).
tory in which the phenyl group should be upward and opposite
In order to establish the absolute stereochemistry of 23, its
to the bulky –SO Ph moiety.
2
free –NH moiety was re-protected as N-Boc (Boc anhydride/
Thus, it was envisaged that reducing steric bulk on the DMAP, 82% yield) and recrystallized for single crystal X-ray
2
3
β-face of 22, obtained by deprotection of the N-Boc group, may diffraction analysis (Fig. 4).
possibly favour the β-facial attack of (S,S)-hydrobenzoin anion
With enantiomerically pure 11 in hand, we proceeded with
owing to the situation depicted with structure C in comparison the planned C2–C3 bond cleavage in order to obtain 24.
with the unfavourable situation shown with structure D. Fur- Towards this end, 11 was subjected to catalytic hydrogenolysis
thermore, it was also envisaged that in the case of 22, non- (Pd/C, 10 mol%, 1 atm, H
stabilization of the resulting anion during nucleophilic THF–MeOH (1 : 1) which afforded, to our delight, 24 quantitat-
, NaOMe, 10 mol%, reflux, 5 h) in
2
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Table 2 Optimization of reaction conditions for the asymmetric
desymmetrization of meso-22
Table 3 Optimization of reaction conditions for C2–C3 bond cleavage
Temperature
(°C)
Time
(min)
Yield
(%)
Cis/ b
Entry
Base
trans
a
1
2
3
4
5
NaOMe (1 eq.)
65
65
25
0
10
10
20
45
45
90
95
96
90
92
1 : 1
1 : 3
8 : 2
Only cis
Only cis
a
Entry
Solvent
T (°C)
Time (h)
Yield (%)
de (%)
a
a
a
NaOMe (0.1 eq.)
NaOMe (0.1 eq.)
NaOMe (0.1 eq.)
1
2
3
THF
THF
THF
25
0
−20
1.5
2.5
3
87
85
80
44
82
>99
a
KOtBu (0.1 eq.)
0
a
Sequential addition of MeOH and base after hydrogenolysis.
Isolated yield.
a
Determined by HPLC analysis (Atlantis T-3, MeOH–H
.5 mL min ).
2
O = 80 : 20,
b
−
1
0
2
4
amino acid 36 in 90% yield. Furthermore, treatment of 34
with LiBH in THF produced the corresponding isoindoline
,2-amino alcohol 37 directly in 68% yield.
4
1
Conclusion
In conclusion, we have developed a conceptually new strategy
for the synthesis of both cis- as well as trans-1,3-disubstituted
isoindolines in an optically pure form from a catalytic selective
bond cleavage of a rigid bridged overbred template. An asym-
metric desymmetrization protocol has been developed for the
enantioselective synthesis of a rigid bridged overbred tem-
plate. Furthermore, it has been demonstrated that this strategy
Fig. 4 ORTEP diagram for compound 11.
ively. However, detailed spectroscopic analyses suggested 24 to can be scaled up to the multigram level.
be a mixture of diastereomers. Appropriate controlled experi-
ments (Table 3) suggested that refluxing under this experi-
mental conditions is the root cause for the formation of
diastereomers. Thus, in order to achieve selectivity, first hydro-
genolysis was carried out in THF at reflux temperature followed
by the addition of methanol and base at 0 °C which afforded
Experimental section
Synthesis of tert-butyl 1,4-dihydro-1,4-epiminonaphthalene-
9-carboxylate (13)
the corresponding optically pure (ee > 99%) cis-1,3 disubsti- To a 1000 mL three neck round bottom flask fitted with a con-
tuted isoindoline ester 24 in 95% yield.
denser, magnetic stir bar and dropping funnel, activated mag-
The generality of the protocol was established by studying nesium turning (10.36 g, 0.426 gram atom) was added and the
C2–C3 bond cleavage reaction with various substrates and the flask was flame dried under vacuum. The system was flushed
results are shown in Table 4. It was pleasing to note that the with argon and allowed to cool. N-Boc-pyrrole (64 mL,
enantioselectivity of all the isolated isoindolines remained 370 mmol) in 240 mL of dry THF was introduced into the flask
consistent (ee > 99%).
and heated to gentle reflux. o-Fluorobromobenzene (44.8 mL,
This spectacular success led us to consider the synthesis of 408 mmol) dissolved in 200 mL of dry THF was added drop-
trans-1,3-disubstituted isoindoline 35 as well (Scheme 4). In wise under an argon atmosphere over a period of 30 min and
this context, the cleavage of the C2–C3 bond of 34, obtained by refluxed for 2 h. The initiation of reaction was indicated by the
the hydrogenolysis of 11, was carried out by stirring in MeOH solution turning turbid followed by it turning yellow in colour.
t
for 6 h in the presence of excess of KO Bu (5 eq.) which The solution was cooled and poured into a flask containing
afforded 35 as a major product post epimerization. The trans- 500 mL aqueous solution of ammonium chloride (300 g) and
stereochemistry in 35 was established by detailed NOESY and concentrated ammonium hydroxide (10 mL, 28.0% w/w NH3).
COSY NMR analyses. Similarly, stirring of 34 with LiOH in The aqueous layer was extracted with petroleum ether (3 ×
2
THF–H O (1 : 1) at rt afforded conformationally constrained 400 mL), combined organic layer dried over anhydrous sodium
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Table 4 Synthesis of various 1,3-disubstituted isoindolines
Table 4 (Contd.)
Yield
(%)
Yield
(%)
Entry Substrate
9
1,3-Disubstituted isoindoline
Entry Substrate
1,3-Disubstituted isoindoline
90
1
MeOH
95
2
3
EtOH
92
90
4
83
Scheme 4 C2–C3 bond cleavage of 34.
sulphate and concentrated. The resulting dark oil on column
chromatography (SiO hexane–EtOAc: 95 : 5) followed by
crystallization in hexane afforded 11 as a white crystalline
2
,
5
6
7
8
83
72
65
52
solid (56 g, 60% yield, m.p. 72–73 °C) R = 0.7 (hexane–EtOAc:
f
−
1
9
0 : 10); IR (KBr) ν = 3015, 1693, 1598, 1337, 1081, 751 cm ;
1
3
H NMR (400 MHz, CDCl ) δ 7.27 (m, 2H), 6.99–6.96 (m, 4H),
1
3
5
1
6
.50 (bs, 2H), 1.40 (s, 9H); C NMR (100 MHz, CDCl ) δ
3
55.07, 148.23, 143.43, 142.29, 124.87, 121.02, 120.57, 80.49,
+
6.73, 66.14, 28.08; HRMS (ESI) m/z 266.1151 [(M + Na) ; calcd
+
for (C H NO Na) : 266.1157].
1
5
17
2
Synthesis of (±) tert-butyl 2-(phenylsulfonyl)-1,4-dihydro-
,4-epiminonaphthalene-9-carboxylate (17)
1
To a solution of 13 (5 g, 20.55 mmol) in 210 mL of dry DCM
were added (ethynylsulfonyl)benzene (3.42 g, 20.55 mmol) and
tetrazine 14 (4.85 g, 20.55 mmol). The reaction mixture was
stirred at rt for 18 h, diluted with 100 mL of diethyl ether and
washed with water (3 × 50 mL). The organic phase was dried
over sodium sulphate and the solvent was evaporated under
reduced pressure. The crude product was purified by column
2
chromatography (SiO , hexane–EtOAc: 8 : 2) to give 17 as a
white solid (6.1 g, 77% yield, m.p. 168–169 °C) Rf = 0.4
(
hexane–EtOAc: 80 : 20); IR (KBr) ν = 3057, 1699, 1575, 1365,
154, 1089, 756 cm− ; H NMR (400 MHz, CDCl
1
1
) δ 7.83 (d, J =
1
7
7
5
1
3
.6 Hz, 2H), 7.67 (d, J = 1.3 Hz, 2H), 7.65 (m, 2H), 7.52 (t, J =
.6 Hz, 1H), 7.28 (m, 2H), 6.99 (t, J = 7.34, 1H), 5.7 (bs, 1H),
1
3
3
.53 (s,1H), 1.28 (s, 9H); C NMR (100 MHz, CDCl ) δ 154.35,
46.06, 138.85, 133.82, 131.98, 130.45, 129.49, 129.40, 128.10,
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+
1
25.84, 125.76, 121.78, 121.72, 81.67, 67.6, 66.98, 27.6; m/z 352.1361, 374.1177 [(M + H) (calcd for (C21
H
22NO
2
S) :
+
+
+
HRMS (ESI) m/z 384.1279, 406.1077 [(M
for (C21
+ H) (calcd 352.1371; (M + Na) calcd for (C H NO SNa) : 374.1191].
21 21 2
+
+
H
22NO
4
+
S) : 384.1270; (M
+
Na)
calcd for
Synthesis of tert-butyl 2,3-bis(phenylthio)-1,4-dihydro-1,4-
(C
21
H
21NO
4
SNa) : 406.1089].
epiminonaphthalene-9-carboxylate (20)
The same reaction sequence as described above was repeated
with 19 (10 g, 28.4 mmol) to afford 20 (semi solid, 11.4 g, 87%
Phenylsulfonylation of alkene (17) for the synthesis of
tert-butyl 2,3-bis(phenylsulfonyl)-1,4-dihydro-1,4-
epiminonaphthalene-9-carboxylate (18)
yield). R = 0.6 (hexane–EtOAc: 90 : 10); IR (KBr) ν = 3057, 1699,
f
1
575, 1365, 1154, 1089, 756 cm− ; H NMR (400 MHz, CDCl
δ 7.52 (m, 4H), 7.44 (t, J = 7.3 Hz, 4 H), 7.38 (d, J = 3 Hz, 2H),
.19 (m, 2H), 7.02 (dd, J = 4.9, 2.9 Hz, 2 H), 5.4 (m, 2 H), 1.49
1 1
3
)
To a vacuum dried 250 mL two neck round-bottom flask, 17
(5.0 g, 13.04 mmol) dissolved in anhydrous THF (60 mL) was
7
(
added while stirring. The flask was cooled to −90 °C and
n-BuLi (1.6 M solution in hexane, 8.56 mL, 13.69 mmol) fol-
lowed by benzene sulfonyl fluoride (1.65 mL, 13.69 mmol)
solution in anhydrous THF (5 mL) was introduced dropwise
into the flask. The reaction mixture was allowed to warm to rt
1
3
s, 9H); C NMR (100 MHz, CDCl
3
) δ 154.02, 132. 67, 131.27,
1
6
30.51, 129.21, 127.63, 125.48, 120.54, 120.17, 81.09, 70.46,
+
9.82, 28.11; HRMS (ESI) m/z 482.1229 [(M + Na) calcd for
+
27 2 2
(C H25NO S Na) : 482.1224].
and was quenched slowly with aqueous NH Cl solution
4
Oxidation of bisulfide (20) for the synthesis of tert-butyl 2,3-
bis(phenylsulfonyl)-1,4-dihydro-1,4-epiminonaphthalene-9-
carboxylate (18)
(10 mL). The reaction mixture was extracted with EtOAc (3 ×
1
00 mL), washed with brine, dried over anhydrous Na SO and
2
4
concentrated under reduced pressure. The residue was purified
To a stirring solution of 20 (20 g, 43.51 mmol) in dichloro-
methane (500 mL) was added a solution of m-CPBA (48.76 g,
by column chromatography (SiO , hexane–EtOAc: 7 : 3) to
2
afford 18 (4.1 g, 60% yield, m.p. 185–186 °C) R
f
= 0.3 (hexane–
2
0
17.5 mmol, 77%) in dichloromethane (400 mL) dropwise at
°C. The reaction mixture was allowed to warm to rt and
EtOAc: 7 : 3); IR (KBr) ν = 3043, 2983, 1712, 1324, 1161, 1085,
1
1
7
58, 721 cm− ; H NMR (400 MHz, CDCl ) δ 8.01 (m, 4H), 7.67
3
stirred for an additional 5 h. Aqueous Na
was added and the mixture was washed with H
2
S
2
O
3
(1 M, 300 mL)
O (300 mL) fol-
(
m, 2H), 7.53 (m, 4H), 7.25–6.96 (m, 4H), 5.88 (bs, 2H), 1.27 (s,
1
3
2
9
1
2
H); C NMR (100 MHz, CDCl ) δ 154.07, 138.7, 134.59,
3
lowed by aqueous Na CO (10%, 1000 mL). The organic layer
2
3
29.31, 128.93, 126.38, 126.36, 122.32, 122.07, 82.63, 71.77,
was dried over Na
cation by column chromatography (SiO
gave 18 as a white solid (21 g, 92% yield).
2
SO
4
, concentrated and the residue on purifi-
+
7.74; HRMS (ESI) m/z 546.1016 [(M + Na) calcd for
2
, hexane–EtOAc: 4 : 1)
+
(C H NO S Na) : 546.1021].
2
7
25
6 2
Synthesis of (±) tert-butyl 2-(phenylthio)-1,4-dihydro-1,4-
epiminonaphthalene-9-carboxylate (19)
Synthesis of (−)-(1S,3R,4R,4′S,5′S)-tert-butyl 4′,5′-diphenyl-
3-(phenylsulfonyl)-3,4-dihydro-1H-spiro[1,4-epimino-
naphthalene-2,2′-[1,3]dioxolane]-9-carboxylate (11)
A vacuum dried two neck round bottom flask (2 L), equipped
with a reflux condenser and dropping funnel, was charged To an ice-cold anhydrous THF (10 mL) solution containing
with 13 (12 g, 49 mmol) followed by dry hexane (1000 mL). suspension of NaH (0.33, 8.4 mmol, 60% suspension in
A solution of benzenesulfenyl chloride (6.27 mL, 54.25 mmol) mineral oil) was added a solution of (S,S)-hydrobenzoin (0.9 g,
in dry DCM (300 mL) was introduced to the flask dropwise 4.2) in THF (10 mL) dropwise. After completion of addition,
under an argon atmosphere while refluxing. The reaction the mixture was allowed to warm to rt and allowed to stir for
mixture was allowed to reflux for additional 5 min and the additional one hour and then kept at the desired temperature
solvent was removed under reduced pressure.
(Table 1). A solution of meso-18 (2 g, 3.82 mmol) in 20 mL THF
The crude reaction mixture was dissolved in dry THF was added dropwise and stirred at the same temperature for
(150 mL) and a solution of t-BuOK (1.0 M in 150 mL THF) was another 2 h. After allowing it to warm to rt, MeOH (5 mL) was
added in portions over a period of 15 min. The reaction added. Usual workup afforded a mixture of 11 and 21 that was
mixture was stirred for additional 5 h. The solvent was separated by column chromatography (SiO , hexane–EtOAc:
2
removed under reduced pressure and was diluted with water 60 : 40).
(
200 mL), extracted with hexane (3 × 500 mL), washed with
Data for (−)-(1S,4R,4′S,5′S)-tert-butyl 4′,5′-diphenyl-3-
phenylsulfonyl)-3,4-dihydro-1H-spiro[1,4-epimino-
naphthalene-2,2′-[1,3]dioxolane]-9-carboxylate (11)
5% yield) R = 0.5 (hexane–EtOAc: 95 : 5); IR (KBr) ν = 3057, R = 0.45 (hexane–EtOAc: 70 : 30); (m.p. 180–181 °C); IR (KBr)
brine and dried over Na SO . Removal of hexane followed by
purification of the residue by column chromatography (SiO
hexane–EtOAc: 95 : 5) afforded 19 as a yellowish oil (16.5 g,
9
1
2
4
(
2
,
f
f
−
1
1
−1
699, 1575, 1365, 1154, 1089, 756 cm ; H NMR (400 MHz, ν = 3433, 3064, 3033, 2978, 1706, 1354, 1274, 1146, 756 cm
;
1
CDCl
3
) δ 7.44–7.39 (m, 2H), 7.37–7.27 (m, 3H), 7.25–7.19 (m,
3
H NMR (400 MHz, CDCl ) δ 8.07 (d, J = 7.6 Hz, 2H), 7.60 (m,
2
1
1
1
H), 7.0–6.94 (m, 2H), 6.69 (s, 1H), 5.59 (bs, 1H), 5.23 (bs, 1H) 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.37–7.35 (m, 4H), 7.34–7.29 (m,
1
3
.42 (s, 9H); C NMR (100 MHz, CDCl
3
) δ 154.78, 147.08, 4H), 7.27–7.12 (m, 6H), 5.62 (bd, 1H), 5.27 (bs, 1H), 4.97 (bs,
32.51, 131.85, 129.28, 129.22, 128.96, 127.83, 126.52, 126.20, 1H), 4.71 (d, J = 8.8 Hz, 1H), 3.67 (bs, 1H), 1.31 (s, 9H)
1
3
25.58, 125.50, 124.90, 80.86, 69.02, 67.38, 28.11; HRMS (ESI)
C NMR (100 MHz, CDCl ) δ 157.79, 143.19, 141.94, 138.44,
3
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1
1
8
34.75 133.53, 130.20, 128.55, 128.51, 128.30, 127.94, 127.62, allowed to stir for additional one hour and then cooled to
26.15, 126.05, 123.94, 123.29, 120.43, 119.77, 111.81, 86.40, −20 °C. A solution of meso-22 (50 g, 118 mmol) in 500 mL THF
0.89, 75.74, 69.140, 63.62, 28.05; HRMS (ESI) m/z 618.1920 was added dropwise and stirred at the same temperature for
+
+
[
(M + Na) calcd for (C35
Diastereomeric excess was determined by HPLC with was added. Usual workup followed by column chromatography
an Atlantis T3 5 µm column at 254 nm (MeOH–H O = 80 : 20, (SiO , hexane–EtOAc: 60 : 40) afforded 23 as a yellowish white
flow rate 0.5 mL min ), tmajor = 11.1 min, tminor = 11.8, 13.88, solid (46.8 g, 80%, m.p. 182–184 °C). R = 0.5 (hexane–EtOAc:
4.7 min. 50 : 50); IR (KBr) ν = 3430, 3264, 3035, 1366, 1294, 1240, 1145,
H
33NO
6
SNa) : 618.1926].
another 2 h. After allowing it to warm to rt, MeOH (100 mL)
2
2
−
1
f
1
1
9
−1 1
[α]
D
= −156.11 (c = 0.5, EtOH).
1081, 755, 698 cm ; H NMR (400 MHz, CDCl
8
7
3
) δ 8.05 (d, J =
.3 Hz, 2H),7.70 (m, 1H), 7.62 (m, 2H), 7.40–7.34 (m, 4H),
.30–7.25 (m, 3H), 7.22–7.14 (m, 5H), 7.03–7.01 (m, 2H), 5.02
Data for tert-butyl ((1′S,4S,5S)-4,5-diphenyl-3′-(phenylsulfonyl)-
1
′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-1′-yl)carbamate (21)
(
s, 1H), 4.73 (d, J = 9.1 Hz, 1H), 4.51 (s, 1H), 4.49 (d, J = 9.1 Hz,
13
R
f
= 0.4 (hexane–EtOAc: 70 : 30); IR (KBr) ν = 3468, 2927, 2975, 1H), 3.73 (s, 1H), 1.66 (bs, 1H); C NMR (100 MHz, CDCl
3
) δ
1
7
719, 1620, 1587, 1479, 1451, 1368, 1244, 1148, 1087, 143.72, 141.88, 139.94, 136.06, 134.73, 133.63, 129.19, 128.88,
53 cm− ; H NMR (400 MHz, CDCl
1
1
) δ 8.83 (s, 1H), 8.7–7.96 128.56, 128.48, 128.43, 127.68, 127.32, 127.24, 126.26, 123.23,
3
(
5
5
m, 3H), 7.72–7.59 (m, 5H), 7.52–7.5 (m, 1H) 7.25–7.14 (m, 119.78, 115.86, 86.62, 86.33, 73.06, 69.19, 63.36; HRMS (ESI)
+
+
H), 7.04–7.00 (m, 3H), 6.73–6.56 (m, 2H), 5.6–5.57 (m, 2H), m/z 496.1579, 518.1400 [(M + H) (calcd for (C H NO S) :
30 26 4
1
3
+
+
.60–5.57 (m, 2H), 1.46 (bs, 9H); C NMR (100 MHz, CDCl
3
)
496.1583; (M + Na) calcd for (C30
4
H25NO SNa) : 518.1402].
δ 153.77, 148.27, 141.48, 138.67, 137.49, 137.26, 135.98,
Diastereomeric excess was determined by HPLC with an
1
1
8
33.25, 132.25, 132.04, 130.50, 130.10, 129.83, 129.16, 127.99, Atlantis T3 5 µm column at 254 nm (MeOH–H O = 80 : 20,
2
27.81, 127.53, 127.32, 126.74, 125.87, 125.07, 119.46, 90.01, flow rate 0.5 mL min− ), tmajor = 17.1 min, tminor = 17.9, 19.9,
1
+
0.92, 79.07, 28.118; HRMS (ESI) m/z 618.1918 [(M + Na) calcd 21.8 min, de > 99.
+
22
for (C H NO SNa) : 618.1926].
[α]D = −226.10 (c = 1, EtOH).
3
5
33
6
2
2
[α]
D
= −62.22 (c = 0.1, CH
2 2
Cl ).
Synthesis of (−)-(1S,3R,4R,4′S,5′S)-tert-butyl 4′,5′-diphenyl-3-
(phenylsulfonyl)-3,4-dihydro-1H-spiro[1,4-epimino-
naphthalene-2,2′-[1,3]dioxolane]-9-carboxylate (11)
Synthesis of 2,3-bis(phenylsulfonyl)-1,4-dihydro-
1
,4-epiminonaphthalene (22)
To a solution of 18 (70 g, 133 mmol) in dry DCM (700 mL) was To a solution of anhydrous acetonitrile (800 mL) containing 23
added trifluoroacetic acid (51 mL, 668 mmol) dropwise at 0 °C (40 g, 80.7 mmol) was added catalytic dimethylaminopyridine
and allowed to warm to rt. The reaction mixture was further (0.986 g, 8.07 mmol) and allowed to stir at 0 °C. Di-tert-butyl
stirred at room temperature for 5 h and the progress of the dicarbonate (37 mL, 161.4 mmol) was added dropwise and the
reaction was monitored by TLC. After complete disappearance reaction mixture was allowed to warm to room temperature
of the starting material, the solvent and trifluoroacetic acid while stirring. The progress of the reaction was monitored by
were evaporated off, diluted with EtOAc (500 mL), washed with TLC. After 24 h, the solvent was evaporated off and the residue
aqueous NaHCO3 (10%, 300 mL) and water (500 mL). The was separated by column chromatography (SiO , hexane–
2
2 4
organic layer was dried over Na SO and concentrated to afford EtOAc: 80 : 20) to afford product 11 (42.5 g, 88%, m.p.
a yellowish semi solid 22 (51 g, 90% yield, m.p 146–148 °C) 180–181 °C).
which was processed without further purification. R = 0.3
f
General procedure for nucleophile-assisted anionic
fragmentation (25–33)
(
100% EtOAc); IR (KBr) ν = 3434, 3286, 3063, 2923, 2853, 1622,
1
1
581, 1448, 1334, 1317, 1154, 840 cm−1; H NMR (400 MHz,
CDCl ) δ 7.86 (dd, J = 8.3, 1 Hz, 4H), 7.65 (m, 2H), 7.49 (t, J = To a round bottom flask containing 11 (1 mmol) in THF (1 M)
3
8
2
Hz, 4H), 7.08 (dd, J = 5.3, 2 Hz, 2H), 6.90 (dd, J = 5.3, 2 Hz, was added Pd/C (10 mol%) and hydrogenated at balloon
1
3
H), 5.46 (s, 2H), 2.95 (bs, 1H); C NMR (100 MHz, CDCl
3
)
pressure at reflux for 5 h. After all the starting material was
t
δ 144.52, 138.578, 134.55, 129.37, 128.70, 128.11, 127.83, consumed, and to the same pot were added catalytic KO Bu
1
+
22.27, 71.62; HRMS (ESI) m/z 424.0668, 446.0491 [(M + H)
(0.05 mmol) and the corresponding alcohol or amine
+
+
(
(
calcd for (C22H18NO S ) : 424.0677; (M + Na) calcd for (5 mmol) at room temperature while stirring. The progress of
C H NO S Na) : 446.0497].
4 2
+
the reaction was monitored by TLC. The reaction mixture was
quenched by addition of amberlite weakly acidic cation
exchanger resin until pH 7. The solution was filtered, evapor-
ated and purified by column chromatography.
2
2
17
4 2
Synthesis of (−)-(1S,3R,4R,4′S,5′S)-4′,5′-diphenyl-
-(phenylsulfonyl)-3,4-dihydro-1H-spiro[1,4-epimino-
3
naphthalene-2,2′-[1,3]dioxolane] (23)
(
−)-(1S,3R)-2-tert-Butyl 1-methyl 3-((phenylsulfonyl)methyl)-
isoindoline-1,2-dicarboxylate (25)
= 0.5 (hexane–ethylacetate: 70 : 30); IR
25.3 g, 118 mmol) in THF (250 mL) dropwise. After com- (KBr) ν = 3438, 3067, 2977, 2930, 1752, 1703, 1390, 1309, 1158,
To an ice-cold anhydrous THF (250 mL) solution containing a
suspension of NaH (14.2 g, 354 mmol, 60% suspension in
mineral oil) was added a solution of (S,S)-hydrobenzoin Yield: 95% (0.41 g), R
f
(
pletion of addition, the mixture was allowed to warm to rt and 755 cm− ; H NMR (400 MHz, CDCl ) mixture of rotamers
1
1
25
δ
3
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7
.96 (m, 3H), 7.65 (m, 3H), 7.4 (m, 3H), 5.76 (d, J = 9.6 Hz, 0.5 (−)-(1S,3R)-1-But-3-yn-1-yl 2-tert-butyl 3-((phenylsulfonyl)-
H), 5.67 (d, J = 9.6 Hz, 0.5 H), 5.55 (s, 0.5H), 5.43 (s, 0.5H), 4.27 methyl)isoindoline-1,2-dicarboxylate (28)
(
dd, J = 13.85, 2.27 Hz, 0.5 H), 3.93 (dd, J = 13.85, 1.76 Hz, 0.5
Yield: 83% (0.39 g), R
ν = 3471, 3293, 3067, 2977, 2931, 2254, 1750, 1702, 1390, 1308,
f
= 0.45 (hexane–EtOAc: 70 : 30); IR (KBr)
1
3
H), 3.75 (s, 3H), 3.44 (m, 1H) 1.54, 1.42 (s, 9H); C NMR
100 MHz, CDCl ) mixture of rotamers δ 171.02, 170.95,
(
−1 1
3
1185, 1158, 1002, 755, 688 cm ; H NMR (400 MHz, CDCl
3
)
1
1
1
6
2
52.89, 152.41, 140.62, 140.38, 139.30, 138.70, 134.55, 134.48,
33.84, 133.65, 129.42, 129.24, 129.10, 128.65, 128.61, 127.92,
27.62, 125.45, 125.16, 122.85, 122.61, 81.86, 81.16, 64.59,
4.15, 61.80, 59.79, 57.52, 57.24, 52.71, 52.60, 28.47,
mixture of rotamers δ 8.02 (d, J = 7.3 Hz, 1H), 7.93 (m, 2H),
7
5
2
.62 (m, 3H), 7.51–7.34 (m, 3H), 5.76–5.68 (d, J = 9.06 Hz 1H),
.55–5.44 (s, 1H), 4.31–4.19 (m, 2H), 3.46 (td, J = 14.7, 9.7 Hz,
H), 2.52 (m, 3H), 1.54, 1.43 (s, 9H); C NMR (100 MHz,
13
+
8.18; HRMS (ESI) m/z 454.1298 [(M + Na) ; calcd for
CDCl ) mixture of rotamers 170.29, 170.10, 152.85, 152.33,
3
+
(
C H NO SNa) : 454.1300].
2
2
25
6
1
1
1
6
1
40.65, 140.43, 139.33, 138.76, 134.46, 134.29, 133.84, 133.64,
29.43, 129.23, 129.13, 128.64, 127.90, 127.65, 125.44, 125.12,
23.06, 122.74, 81.86, 81.21, 79.83, 79.60, 70.25, 70.03, 64.58,
4.20, 63.17, 61.82, 59.87, 57.50, 57.21, 28.47, 28.23, 18.95,
HPLC: CHIRALPAK AS-H column at 254 nm (hexane–iso-
−1
propanol = 90 : 10, flow rate 1.5 mL min ), tmajor = 7.9 min,
tminor = 6.9 min.
2
3
[α]
D
= −30.105 (c = 1, EtOH).
+
8.87; HRMS (ESI) m/z 492.1445 [(M + Na) ; calcd for
+
(
C H NO SNa) : 492.1456].
2
5
27
6
(
−)-(1S,3R)-2-tert-Butyl 1-ethyl 3-((phenylsulfonyl)methyl)-
HPLC: CHIRALPAK AS-H column at 254 nm (hexane–isopro-
isoindoline-1,2-dicarboxylate (26)
Yield: 92% (0.42 g), R = 0.4 (hexane–EtOAc: 80 : 20); IR (KBr)
ν = 3472, 3067, 1747, 1703, 1568, 1478, 1390, 1370, 1191, 915,
7
8
panol = 80 : 20, flow rate 1.5 mL min− ), tmajor = 10.8 min,
1
f
tminor = 12.3 min, ee > 99.
23
D
[α]
2 2
= −22.4 (c = 0.5, CH Cl ).
55 cm− ; H NMR (400 MHz, CDCl
1 1
3
) mixture of rotamers δ
(−)-(1S,3R) 2-tert-Butyl 1-(2-hydroxyethyl) 3-((phenylsulfonyl)-
.30–7.88 (m, 3H), 7.68–7.56 (m, 3H), 7.45–7.34 (m, 3H), 5.75
methyl)isoindoline-1,2-dicarboxylate (29)
(
(
(
dd, J = 9.4, 1.5 Hz, 0.5 H), 5.66, (dd J = 9.5, 1.9 Hz, 0.5H), 5.52,
s, 0.5 H), 5.4 (s, 0.5 H), 4.26 (dd, J = 13.9, 2.3 Hz, 0.5H), 4.20
q, J = 7.04 Hz, 2H), 3.93 (dd, 13.9, 2 Hz, 0.5H), 3.44 (m, 1H),
Data: yield: 92% (0.43 g), R = 0.2 (hexane–EtOAc: 60 : 40); IR
f
(
1
KBr) ν = 3470, 2932, 2976, 1747, 1701, 1392, 1307, 1189, 1158,
13
085, 969, 756, 688 cm− ; H NMR (400 MHz, CDCl
1
1
) mixture
1
.54–1.43 (s, 9H), 1.28 (td, J = 7.04, 3 Hz, 3H); C NMR
) mixture of rotamers δ 170.53, 170.42,
3
(100 MHz, CDCl
3
of rotamers δ 8.01–7.86 (m, 3H), 7.60–7.57 (m, 3H), 7.43–7.36
m, 3H), 5.77–5.67 (m, 1H), 5.55, 5.47 (s, 1H) 4.29–4.26 (m,
1
1
1
6
1
52.88, 152.44, 140.69, 140.45, 139.36, 138.74, 134.77, 134.67,
33.81, 133.62, 129.42, 129.23, 129.03, 128.62, 128.59, 127.90,
27.62, 125.45, 125.16, 122.78, 122.56, 81.78, 81.10, 64.70,
4.28, 61.87, 61.72, 61.63, 59.87, 57.52, 57.22, 28.48, 28.21,
(
2
2
1
1
1
1
H), 4.2–4.17 (dd, J = 14, 2.4 Hz, 0.5H), 3.91–3.87 (dd J = 13.7,
.1 Hz, 0.5 H), 3.82 (m, 2H), 3.49 (td, J = 13.2, 9.1 2H), 1.53,
1
3
3
.43 (s, 9H); C NMR (100 MHz, CDCl ) mixture of rotamers δ
+
4.25, 14.09; HRMS (ESI) m/z 468.1452 [(M + Na) ; calcd for
70.85, 170.50, 153.36, 152.57, 140.57, 140.42, 139.22, 138.61,
34.51, 134.16, 134.13, 133.89, 133.71, 133.67, 129.47, 129.25,
29.14, 128.76, 127.86, 127.61, 125.17, 125.01, 122.85, 122.65,
+
(
C
23
H
27NO
6
SNa) : 468.1457].
HPLC: CHIRALPAK AS-H column at 254 nm (hexane–isopro-
−
1
panol = 95 : 5, flow rate 1.5 mL min ), tmajor = 10.8 min, tminor
9.7 min.
82.32, 81.37, 67.16, 64.74, 64.45, 61.67, 60.87, 60.73, 59.62,
7.70, 57.31, 28.45, 28.21; HRMS (ESI) m/z 484.1400 [(M +
=
5
2
2
+
+
[α]
D
= −30.6 (c = 0.5, EtOH).
Na) ; calcd for (C23
H
27NO
7
SNa) : 484.1406].
Cl ).
2
3
[α]
D
= −41.2 (c = 1, CH
2
2
(
−)-(1S,3R)-2-tert-Butyl 1-prop-2-yn-1-yl 3-(phenylsulfonyl)-
methyl)isoindoline-1,2-dicarboxylate (27)
(−)-(1S,3R)-tert-Butyl 1-(diethylcarbamoyl)-3-((phenylsulfonyl)-
methyl)isoindoline-2-carboxylate (30)
Yield: 90% (0.4 g), R = 0.49 (hexane–EtOAc: 70 : 30); IR (KBr) ν
f
=
1
3271, 3067, 2977, 2930, 1757, 1702, 1448, 1389, 1308, 1158, Yield: 72% (0.35 g), R
f
= 0.4 (hexane–EtOAc: 50 : 50); IR (KBr) ν
−
1 1
3
176, 1118, 996, 755, 688, cm ; H NMR (400 MHz, CDCl )
= 3451, 3068, 2978, 2934, 1698, 1650, 1393, 1306, 1157,
mixture of rotamers δ 8.02 (d, J = 7.3 Hz, 1 H), 7.98–7.89 (m, 753 cm−
1
; H NMR (400 MHz, CDCl ) mixture of rotamers
3
1
2
8
1
H), 7.61–7356 (m, 3H), 7.49–7.37 (m, 3H), 5.77, 5.67 (d, J = δ 8.00–7.91 (m, 3H), 7.64–7.50 (m, 3H), 7.41–7.17 (m, 3H),
.5 Hz, 1H), 5.57, 5.47 (s, 1H), 4.81–4.65 (m, 2H), 4.25 (dd, J = 5.88–5.76 (m, 2H), 4.26–3.9 (m, 1H), 3.789–3.62 (m, 3H), 3.52
3.8, 2 Hz, 0.5 H), 3.92 (dd, J = 13.8, 1.8 Hz, 0.5H), 3.44 (ddd, (dq, J = 13.7,7 Hz, 1H), 3.19 (m, 1H), 1.54–1.44 (s, 9H),
1
3
J = 19.9, 13.8, 9.6 Hz, 1H), 2.47, 2.43 (t, J = 2.27 Hz, 1H), 1.54, 1.48–1.39 (m, 3H), 1.13–1.06 (m, 3H); C NMR (100 MHz,
1
3
1
3 3
.44 (s, 9H); C NMR (100 MHz, CDCl ) mixture of rotamers δ CDCl ) mixture of rotamers δ 170.01, 169.58, 152.89, 152.31,
1
1
1
7
69.83, 169.69, 152.84, 152.28, 140.62, 140.39, 139.38, 138.76, 140.73, 140.66, 140.19, 139.60, 136.80, 136.57, 133.58, 133.37,
34.13, 133.97, 133.83, 133.64, 129.42, 129.22, 128.70, 128.68, 129.22, 129.05, 128.60, 128.33, 127.876, 127.62, 125.52, 125.22,
27.89, 127.61, 125.50, 125.17, 122.93, 122.66, 81.97, 81.36, 121.27, 121.16, 81.27, 81.10, 62.26, 61.68, 61.56, 60.25, 57.50,
6.85, 75.51, 64.43, 64.05, 61.81, 59.80, 57.50, 57.20, 53.07, 57.26, 42.60, 42.37, 41.08, 40.90, 28.53, 28.45, 14.99,
+
+
5
2.92, 28.45, 28.16; HRMS (ESI) m/z 478.1294 [(M + Na) ; calcd 14.94; HRMS (ESI) m/z 495.1635 [(M + Na) ; calcd for
+
+
for (C24
H
25NO
6
SNa) : 478.1300].
(C25
H
32
23
N
2
O
5
SNa) : 495.1930].
2
1
[
α] = −29.389 (c = 2 in CH Cl ).
[α]D = −68.7 (c = 0.52, CH Cl ).
D
2
2
2
2
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(
(
−)-(1R,3S)-tert-Butyl 1-((phenylsulfonyl)methyl)-3-
pyrrolidine-1-carbonyl)isoindoline-2-carboxylate (31)
123.10, 122.83, 82.37, 81.94, 71.54, 71.17, 61.93, 60.28, 58.15,
+
57.79, 28.31; HRMS (ESI) m/z 532.1221 [(M + Na) ; calcd for
+
(
C
27
H
27NO
5
S
2
Na) : 532.1228].
Yield: 65% (0.31 g), R
ν = 3451, 2931, 2969, 1699, 1651, 1448, 1387, 1159, 1113,
f
= 0.35 (hexane–EtOAc: 50 : 50); IR (KBr)
2
0
[
α]
D
= −18.887 (c = 2 in CH
2 2
Cl ).
56 cm− ; H NMR (400 MHz, CDCl
1
1
) mixture of rotamers δ
7
7
5
3
2
3
Synthesis of (−)-(1S,3R,4R)-tert-butyl 2-oxo-3-(phenylsulfonyl)-
.95–7.80 (m, 3H), 7.61–7.46 (m, 3H), 7.36–7.121 (3H),
.77–5.63 (m, 2H), 4.23–3.87 (m, 1H), 3.84–3.78 (m, 2H),
.75–3.64 (m, 1H), 3.51–3.44 (m, 1H), 3.42–3.30 (m, 1H),
1,2,3,4-tetrahydro-1,4-epiminonaphthalene-9-carboxylate (34)
To a round bottom flask containing 11 (40 g, 67.15 mmol) in
THF (40 mL) was added Pd/C (8 g) and hydrogenated at
balloon pressure at reflux for 5 h. The reaction mixture was fil-
tered over a bed of celite and the solvent was removed under
reduced pressure. The crude mixture on column chromato-
graphy purification afforded 34 (26.5 g, 98%), yield based on
the recovered starting material; (m.p. 148–150 °C). The remain-
ing starting material (2.4 g) was further recycled.
1
3
.06–2.00 (m, 2H), 1.91–1.84 (m, 2H), 1.51–1.39 (s, 9H);
C
NMR (100 MHz, CDCl ) mixture of rotamers δ 168.83, 168.78,
3
1
1
1
6
2
4
52.68, 151.98, 140.53, 140.44, 139.92, 139.31, 136.48, 136.31,
33.46, 133.25, 129.10, 128.91, 128.43, 128.40, 128.21, 128.19,
27.59, 127.37, 125.30, 124.98, 121.26, 121.23, 81.20, 80.52,
3.40, 63.12, 62.14, 60.03, 57.20, 57.08, 46.93, 46.89, 28.37,
8.13, 26.16, 26.02, 23.97, 23.90; HRMS (ESI) m/z 471.1949,
+
+
f
R = 0.5 (hexane–EtOAc: 70 : 30); IR (KBr) ν = 3425, 3079,
93.1769 [(M + H) = calcd for (C H N O SNa) : 471.1953,
2
5
+
31 2 5
−
1 1
+
2929, 1767, 1711, 1695, 1322, 1154, 1097, 758 cm ; H NMR
400 MHz, CDCl ) δ 7.96, 7.76 (d, J = 7.6 Hz, 2H), 7.65 (m, 1H),
7.56 (m, 2H), 7.47–7.22 (m, 4H), 5.39–5.77 (s, d, 1H), 5.12–5.04
(M + Na) ; calcd for (C25
30 2 5
H N O SNa) : 493.1773].
(
3
HPLC: CHIRALPAK AS-H column at 254 nm (hexane–isopro-
−1
panol = 60 : 40, flow rate 1.5 mL min ), tmajor = 3.4 min, tminor
4.3 min, ee > 99.
1
3
(
s, 1H), 3.64 (s, 1H), 1.41–1.37 (s, 9H); C NMR (100 MHz,
CDCl ) δ 193.00, 192.31, 153.50, 153.6, 144.11, 144.09, 140.96,
38.85, 138.29, 136.05, 134.25, 134.03, 129.24, 129.21, 129.05,
=
2
1
3
[
α] = −118.4 (c = 0.54, CH Cl ).
D
2
2
1
1
8
2
28.94, 128.88, 128.64, 128.56, 124.16, 123.40, 122.68, 121.29,
2.59, 81.39, 69.63, 68.82, 68.20, 68.14, 62.39, 62.12, 29.58,
8.00; HRMS (ESI) m/z 422.1032 [(M + Na) ; calcd for
(−)-(1S,3R)-tert-Butyl 1-((benzo[d][1,3]dioxol-5-ylmethyl)-
carbamoyl)-3-((phenylsulfonyl)methyl)isoindoline-2-
carboxylate (32)
+
+
(
C H NO SNa) : 422.1038].
2
1
21
22
D
5
Yield: 52% (0.29 g), R = 0.3 (hexane–EtOAc: 50 : 50); IR (KBr) ν
=
1
of rotamers δ 8.13 (bs 1H), 7.61–7.57 (m, 3H), 7.45–7.15 (m,
4
4
f
[α]
= −78.5 (c = 1, EtOH).
3432, 2923, 1698, 1670, 1547, 1490, 1446, 1392, 1253, 1158,
Compound 34 was unstable on the HPLC column and
hence its enantiomeric ratio was determined by converting it
either into its corresponding methyl (25) or ethyl ester (26)
−
1 1
3
122, 1038, 927, 752 cm ; H NMR (400 MHz, CDCl ) mixture
H), 7.15–6.7 (m, 4H) 5.88 (s, 2H), 5.54–5.37 (bs, 1H),
.47–4.29 (m, 3H), 3.62–3.47 (m, 1H), 1.56–1.41 (bs, 9H);
(
ee > 99%).
1
3
C
NMR (100 MHz, CDCl ) mixture of rotamers δ 169.98, 154.70, (+)-(1R,3R)-2-tert-Butyl 1-methyl 3-((phenylsulfonyl)methyl)-
3
1
1
1
8
5
5
47.69, 146.69, 140.20, 137.91, 135.93, 133.59, 132.39, 130.10, isoindoline-1,2-dicarboxylate (35)
29.43, 129.13, 128.56, 128.47, 128.29, 128.26, 127.70, 127.51,
26.79, 123.46, 108.80, 108.11, 107.43, 102.55, 102.50, 100.82,
Yield: 70% (0.3 g), R = 0.45 (hexane–EtOAc: 70 : 30); IR (KBr) ν
f
=
1
3435, 2995, 2983, 1750, 1703, 1448, 1391, 1309, 1161, 1086,
1.91, 68.31, 67.46, 60.32, 57.27, 43.00, 28.10; HRMS (ESI) m/z
−1 1
022, 746, 688 cm
3
; H NMR (400 MHz, CDCl ) mixture of
+
+
51.1843, 573.1667 [(M + H) = calcd for (C29
H
31
N
2
O
7
S) :
rotamers δ 7.71–7.56 (m, 2H), 7.58 (m, 1H), 7.5–7.26 (m, 6H),
+
+
51.1852, (M + Na) ; calcd for (C H N O S) : 553.1671].
2
9
31 2 7
5
1
.66–5.6 (m, 1H), 5.36–5.32 (m, 1H), 4.26 (dd J = 14.6, 5.8 Hz,
H), 3.89–3.85 (m, 1H), 3.73–3.71 (s, 3H), 1.51–1.41 (s, 9H);
HPLC: CHIRALPAK AS-H column at 254 nm (hexane–isopro-
13
C
−1
panol = 60 : 40, flow rate 1.5 mL min ), tminor = 8.3 min, tmajor
10.5 min, ee > 99.
NMR (100 MHz, CDCl ) mixture of rotamers δ 170.90, 153.07,
3
=
1
1
40.63, 137.19, 134.74, 133.31, 129.27, 129.06, 129.00, 128.75,
23.92, 122.42, 81.21, 65.79, 59.27, 56.81, 52.41, 28.17; HRMS
2
1
[α]
D
2 2
= −23.5 (c = 0.3, CH Cl ).
+
+
(
ESI) m/z 454.1296 [(M + Na) ; calcd for (C H NO SNa) :
22 25 6
(−)-(1R,3S)-tert-Butyl 1-((phenylsulfonyl)methyl)-3-
4
54.1300].
[α] = +32. 6 (c = 1, CH Cl ).
D 2 2
((phenylthio)carbonyl)isoindoline-2-carboxylate (33)
22
Yield: 90% (0.46 g), R = 0.49 (hexane–EtOAc: 70 : 30); IR (KBr)
f
(
−)-(1S,3R)-2-(tert-Butoxycarbonyl)-3-((phenylsulfonyl)-
ν = 3424, 3064, 2977, 2929, 1706, 1476, 1446, 1372, 1308, 1159,
118, 750, 688 cm−
1 1
methyl)isoindoline-1-carboxylic acid (36)
1
3
; H NMR (400 MHz, CDCl ) mixture of
rotamers δ 8.06–7.95 (m, 3H), 7.69–7.57 (m, 3H), 7.48–7.32 (m, Yield: 90% (0.37 g), R = 0.3 (100% EtOAc); IR (KBr) ν = 3432,
f
8
1
H), 5.85–5.58 (m, 1H), 4.33 (d, J = 13.6 Hz 1H), 3.64 (dd J = 2977, 2926, 1681, 1620, 1416, 1306, 1157, 1131, 1086, 1020,
3.5, 9.4 Hz, 2H), 1.58, 1.51 (s, 9H); C NMR (100 MHz, 754, 689 cm ; H NMR (400 MHz, CDCl ) mixture of rotamers
3
1
3
−1 1
CDCl ) mixture of rotamers δ 197.34, 196.88, 153.24, 152.70, δ 7.92 (d, J = 7.6 Hz, 2H), 7.82–7.74 (m, 2H), 7.65 (dt, J = 13.8,
3
1
1
1
40.59, 140.56, 140.25, 139.22, 138.63, 134.56, 134.48, 134.9, 7.2 Hz, 1H), 7.55 (dt, J = 15.5, 7.6 Hz, 2H), 7.47–7.34 (m, 3H),
33.89, 133.73, 129.64, 129.57, 129.46, 129.40, 129.33, 129.28, 5.72–5.60 (m, 1H), 4.13 (m, 0.6 H), 3.86 (d, J = 13.3 Hz, 0.6 H),
29.21, 128.84, 128.78, 128.02, 127.66, 126.55, 125.38, 125.12, 3.59 (dd, J = 13.6, 9.1 Hz, 0.6 H), 3.46 (dd, J = 13.6, 9.3 Hz,
4446 | Org. Biomol. Chem., 2015, 13, 4438–4448
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1
3
0
.6 H), 1.51–1.42 (s, 9H); C NMR (100 MHz, CDCl
3
) mixture
K. Augustyns and P. Van der Veken, J. Med. Chem., 2011,
54, 5737.
of rotamers δ 174.53, 174.30, 153.37, 152.76, 140.49, 140.14,
1
1
6
38.95, 138.00, 134.01, 133.86, 133.70, 129.44, 129.25, 129.18,
28.75, 127.81, 127.63, 127.89, 123.19, 122.88, 82.37, 81.74,
4.85, 64.18, 61.51, 58.92, 58.01, 57.46, 28.43, 28.13; HRMS
5 A. Müller, G. Höfner, T. Renukappa-Gutke, C. G. Parsons
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5795.
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+
+
(ESI) m/z 440.1138 [(M + Na) ; calcd for (C21
H
23NO
6
SNa) :
4
40.1143].
2
3
[
α] = −44.242 (c = 0.1, CH Cl ).
D
2
2
7
A. Mertens, H. Zilch, B. Koenig, W. Schaefer, T. Poll,
W. Kampe, H. Seidel, U. Leser and H. Leinert, J. Med.
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(−)-(1S,3R)-tert-Butyl 1-(hydroxymethyl)-3-((phenylsulfonyl)-
methyl)isoindoline-2-carboxylate (37)
8
9
C. E. Augelli-Szafran, Y. Lai, A. T. Sakkab and L. C. Walker,
PCT Int. Appl, WO 0076969 A1.2000, 2000.
(a) Y. Minoru, H. Shoichi, K. Hayashi, T. Kazuko,
M. Hiroko, Y. Minako, K. Yonezaw, O. Katsuji, T. Tamotsu
and K. Taya, PCT Int. Appl, EP 1031569 A1, 1999;
Yield: 68% (0.27 g), R = 0.22 (hexane–EtOAc: 60 : 40); IR (KBr)
ν = 3450, 2976, 2828, 1693, 1448, 1394, 1305, 1158, 1117, 1019,
f
1 1
7
56, 565cm− ; H NMR (400 MHz, CDCl
3
) mixture of rotamers
δ 7.93 (d, J = 7.6 Hz, 2H), 7.76–7.56 (m, 4H), 7.35–7.23 (m, 3H),
5
3
9
1
1
6
.72 (d, J = 7.8 Hz, 1H), 5.20 (s, 1H), 4.5 (d, J = 7.6 Hz, 1H),
(
1
b) E. J. Cornish, G. E. Lee and W. R. Wragg, Nature, 1963,
97, 1296; (c) P. P. Mehta, P.-P. Kung, S. Yamazaki,
.91, (bs, 1H), 3.74 (d, J = 12.6 Hz, 1 H), 3.45, (m, 2H), 1.54 (s,
1
3
3
H); C NMR (100 MHz, CDCl ) mixture of rotamers δ 156.56,
M. Walls, A. Shen, L. Nguyen, M. R. Gehring, G. Los,
T. Smeal and M.-J. Yin, Cancer Lett., 2011, 300, 30–39.
40.70, 139.84, 138.52, 137.53, 136.77, 133.83, 129.44, 129.30,
28.53, 127.92, 127.81, 127.61, 124.49, 122.53, 82.10, 67.25,
5.71, 62.31, 57.74, 28.46; HRMS (ESI) m/z 426.1346
1
0 (a) C. A. Luckhurst, L. A. Stein, M. Furber, N. Webb,
M. J. Ratcliffe, G. Allenby, S. Botterell, W. Tomlinson,
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+
+
[(M + Na) ; calcd for (C H NO SNa) : 426.1351].
21 25 5
2
2
[α]
D
2 2
= −19.6 (c = 1, CH Cl ).
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Acknowledgements
We thank DST for financial support under the JC Bose Fellow-
ship scheme. RV and DT are thankful to UGC, New Delhi
for the award of research fellowship. We thank Dr Rajesh
G. Gonnade, Centre for Material Characterization, CSIR-
National Chemical Laboratory, Pune for X-ray crystallographic
analysis.
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S. Van Goethem, V. Matheeussen, J. Joossens, 18 Desymmetrization reaction has been optimized up to 40 g
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scale to afford optically pure overbred template 11.
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4448 | Org. Biomol. Chem., 2015, 13, 4438–4448
This journal is © The Royal Society of Chemistry 2015