Nonenzymatic Dynamic Kinetic Resolution of in situ Generated Hemithioacetals: Access to 1,3-Disubstituted Phthalans

Article abstract of DOI:10.1002/adsc.201701518

The first nonenzymatic DKR reaction of hemithioacetals is developed. Hemithioacetals were formed in situ via thiol addition and subsequently underwent an intramolecular oxa-Michael reaction. The scope of the reaction was quite broad ranging from aliphatic to aromatic substituents and 1,3-disubstituted-1,3-dihyroisobenzofuran products were obtained in good yields with moderate diastereoselectivities and high enantioselectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201701518

Title: Nonenzymatic Dynamic Kinetic Resolution of in situ Generated
Hemithioacetals: Access to 1,3-Disubstituted Phthalans
Authors: Subhas Pan, Utpal Nath, and Deepan Chowdhury
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701518
Link to VoR: http://dx.doi.org/10.1002/adsc.201701518

10.1002/adsc.201701518
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Nonenzymatic Dynamic Kinetic Resolution of in situ Generated
Hemithioacetals: Access to 1,3-Disubstituted Phthalans
Utpal Nath,a Deepan Chowdhurya and Subhas Chandra Pana,*
a
Department of Chemistry, Indian Institute of Technology Guwahati, Assam, India, 781039
Fax: (+91)-361-258-2349; phone: (+91)-361-258-3304; email: span@iitg.ernet.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The first nonenzymatic DKR reaction of
hemithioacetals is developed. Hemithioacetals were formed in
situ via thiol addition and subsequently underwent an
intramolecular oxa-Michael reaction. The scope of the
reaction was quite broad ranging from aliphatic to aromatic
substituents and 1,3-disubstituted-1,3-dihyroisobenzofuran
products were obtained in good yields with moderate
diastereoselectivities and high enantioselectivities.
Keywords: dynamic kinetic resolution; hemithioacetal;
enantioselectivity; organocatalysis; phthalans
Dyanmic kinetic resolution (DKR) is an inherently
efficient and attractive method in which high
enantiomeric excess as well as 100% theoretical yield
of the desired product could be attained.[1] Over the
years, organocatalytic dynamic kinetic resolution
process[2] has established as a powerful approach for
the synthesis of diverse chiral organic molecules
having single or multiple stereocentres. A variety of
substrates including azlactones, α-branched aldehydes,
asymmetric report has hardly been reported and only
Ghorai and co-workers[11] disclosed an synthesis of
(A) Previous works: Enzymatic DKR
O
OAc
enzyme[5a]
HS R2
+
+
R1
H
R1
S
R2
OAc
O
O
OMe
enzyme[5b-d]
O
HS
R
H
1,3-dioxoloane-2,4-diones,
sulfinyl
chlorides,
O
S
R
sulfinate esters, hemiacetals have been employed in
this popular reaction.[3] However, the reports
concerning DKR of hemithioacetals is surprisingly
less despite they could provide valuable sulfur
containing compounds.[4] Though Rayner5a and
Ramström[5b-d] documented few enzyme mediated
DKRs of hemithioacetals (Scheme 1), the chemical
approach for the DKR of hemithioacetals is still not
known.[6] Thus we envisage to develop the first
(B) This work: Chemical DKR
O
O
O
Ar
Ar
Ar
OH
OH
CHO
SR
RSH
+
SR
slow
chiral cat. fast
O
O
Ar
Ar
organocatalytic
DKR
reaction
involving
O
O
hemithioacetal intermediates (Scheme 1).
Challenges: - 1.2 vs 1,4-addition of thiol
- cis vs trans diastereoselectivity
- the reversiblity in thiol addition to
be fast
Chiral 1,3-dihydroisobenzofurans (phthalans) are
important structural motifs that are present in a range
SR
SR
of
natural
products
having
impressive
pharmacological activities such as antidepressive,
antioxidant, antifungal, antibaceterial, antitumor and
cardiovascular disease etc.[7] Besides, few industrial
applications of them are known[8] and they also serve
as important building blocks in organic synthesis.[9]
Some representative 1,3-dihydroisobenzofurans have
been shown in Figure 1. Fascinated by their impressive
activities, a variety of groups are engaged in the
synthesis of 1,3-diyhroisobenzofurans.[10] But
Scheme 1. DKR though hemithioacetal intermediates
1-substituted phthalans. 1,3-Disubstituted-phthalan
system has drawn our attention as they act as extended
scaffold analogous to the more structurally
abbreviated 1,3-disubstituted- 2,5-dihydrofurans such
as 2',3'-benzo-fused didehydronucleoside analogs.[12a]
Herein we embark in a diastereo- and enantioselective
synthesis of 1,3-disubstituted phthalans[12b] by thia-
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701518
Advanced Synthesis & Catalysis
DKR followed by intramolecular oxa-Michael
addition.[13]
mol%) as co-catalyst in toluene at room temperature.
Gratifyingly, after 24 hours, the tandem thiol addition
followed by oxa-Michael addition proceeded
smoothly to deliver 1,3-disubstituted phthalan (3aa) in
70% yield (Table 1, entry 1). The enantioselectivity as
well as diastereoselectivity for cis isomer was slightly
improved using epi-hydroquinine amine II (entry 2).
Since the reaction was quiet fast at rt, the temperature
O
CN
Me
O
N
O
O
H
O
N
OH
H
OH
HO
OH
F
O
O
o
(S)- (+) escitalopram
Pestacin
(+)-egenine
was lowered to 0 C and it proved to be beneficial
(entry 3). Then a quick solvent screening was
performed using catalyst II and delightfully ether
solvents in particular di-nbutylether provided the
product 3aa in good dr (2.5:1) and with high
enantioselectivity (entry 5). Next, cinchonidine
derived bifunctional squramide catalysts III and IV
were employed in the reaction and better
enantioselecitivity (96% ee) was achieved with
catalyst IV (entry 7). Interestingly, the
diastereoselectivity was slightly improved using
molecular sieves 4Å (entry 8). To enhance the
diastereomeric ratio, bifunctional thiourea and urea
catalysts were screened (entries 6-8). Though
enantioselectivity got dropped using thiourea catalyst
V (entry 9), better results were obtained with urea
catalysts VI-VII (entries 10-11). Cinchonidine derived
catalyst VII turned out to be the best catalyst providing
the major product in 75% combined yield with 3:1 dr
and 98% ee (entry 11).
Figure 1. Representative bioactive 1,3-dihydroisobenzo
furans
To materialize these thoughts, the investigation was
initiated by stirring o-formyl chalcone (1a, 0.05 mmol),
benzyl mercaptan (2a, 0.05 mmol), quinine derived
primary amine I (20 mol%) and benzoic acid (20
Table 1. Optimization of the reaction condition
OMe
OMe
H
N
H
N
H
N
NH
N
NH2
NH2
O
NH
Ar
N
N
O
I
II
III
R
OMe
H
N
H
N
H
After fixing the optimized conditions the scope and
generality of the DKR reaction was investigated.
Intially the aryl group on the carbonyl functionality
was varied and it turned out that the reaction outcome
is indifferent to the elctronic nature of the aryl group
(Table 2). At first, different para-substitutions on aryl
group were checked and excellent results were
achieved (entries 2-9). Moderate diastereo- and high
enantioselectivities were achieved for products 3da-
3fa having different 4-halo substitutions (entries 4-6).
However, for enones 1g-1h having 4-cyano and 4-
nitrogroups, the enantioselectivities were moderate for
the corresponding pure products with catalyst VII
(entries 7-8). Delightfully, the enantioselectivities got
enahanced with catalyst IV (the data in parenthesis).
Then ortho- and meta-substituted enones 1j-n were
engaged in the reaction and delightfully here also the
outcome was also very good (entries 10-14). A
heteraromatic furyl conatining enone 1p can also be
employed with excellent results (entry 16). Our
methodology also worked with aliphatic enone 1q and
the corresponding product 3qa was achieved in 51%
combined yield with 88% ee (entry 17). α,β-
Unsaturated ester 1r also participated in the reaction to
provide the corresponding product 3ra in moderate
yield and good enantioselectivity albeit longer reaction
time was required (entry 18). Then the chain length
of the enone part was extended and gratifyingly 2-
N
NH
NH
NH
N
N
Ar
N
Ar
O
NH
tBu
O
N
S
N
H
H
O
IV
V
VI
R = OMe,
VII
R = H,
Ar = 3,5-(CF3)2C6H3
O
O
Ph
Ph
catalyst (5 mol%)
solvent, temp
BnSH
O
+
CHO
SBn
1a
2a
3aa
Entry[a Cata Solven
T
Combin d.r[c] ee
]
(oC) ed yield
(%)[b]
(%)[d]
lyst
t
1[e],[f]
2[e],[f]
3[f],[g]
4[f],[g]
5[f],[g]
6[g]
toluene
toluene
toluene
Et2O
rt
rt
0
0
0
0
0
0
0
0
0
71
70
67
66
68
72
74
73
70
74
75
1:1
70
I
1.6:1 75
1.9:1 81
2.3:1 84
2.5:1 88
1.2:1 90
1.3:1 96
1.4:1 96
1.1:1 81
II
II
II
II
III
IV
IV
V
VI
VII
nBu2O
nBu2O
nBu2O
nBu2O
nBu2O
nBu2O
nBu2O
7[g]
8[g],[h]
9[g],[h]
10[g],[h]
11[g],[h]
3:1
3:1
96
98
[a] Reactions were carried out with 0.05 mmol of 1a and 0.05
mmol of 2a in 0.5 mL solvent. [b] Combined yield of the
(4-oxo-4-phenylbut-2-en-1-yl)
benzaldehyde
1s
isolated product. [c]Determined by H NMR of the crude
1
provided the corresponding isochroman product 3sa in
moderate yield but poor enantiocontrol was observed
(entry 19). The structure of 3sa was determined by 2D
NMR spectroscopy.
reaction mixture. [d] Determined by chiral HPLC and of the
major diastereomer. [e] Reaction time 12 h. [f] PhCO2H as co-
catalyst (5 mol%). [g] Reaction time 24 h. [h] With molecular
sieves 4Å.
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701518
Advanced Synthesis & Catalysis
O
Table 2. Scope of enone with varied ketone substitutents
O
Ph
Ph
+
catalyst VII (5 mol%)
O
X
R
X
BnSH
O
catalyst VII (5 mol%)
n
n
CHO
1t-v
+
BnSH
Mol sieves 4Å
R
O
O
CHO
SBn
O
2a
nBu2O, 0 oC, 24 h
3ta-va
Mol sieves 4Å
nBu2O, 0 oC, 24 h
SBn
3aa-ra, n = 0
3sa, n = 1
2a
O
1a-r
, n = 0
, n = 1
O
1s
Ph
Ph
Me
Ph
O
Entry[a]
R
3
Yield
(%)[b]
d.r[c] ee
O
O
(%)[d]
98
F
SBn
SBn
SBn
F
3ta
57%, 4:1 dr, 92% ee
1
2
3
4
5
6
Ph
77
80
60
63
64
85
3:1
3aa
3ba
3ca
3da
3ea
3fa
3ua
3va
82%, 1.7:1 dr, 94% ee
65%, 1.3:1 dr, 94% ee
4-MeC6H4
4-OMeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
2.2:1 95
2.7:1 95
Scheme 2. Scope of enone with varied olefin
3:1
96
substitutents[a],[b]
2.5:1 96
2.5:1 88
2.1:1 75(8
(1.5: 2)
1)
[a]
Reactions were carried out with 0.1 mmol of 1 and 0.1
7[e][f]
53(52)
3ga
mmol of 2a in 1ml solvent using 5 mol% VII at 0 oC for 1
day.
diastereomers, dr was determined H NMR of isolated
product and ee was measured by chiral HPLC and of the
major diastereomer.
[b]
Yield of the isolated product having mixture of
1
8[f]
4-NO2C6H4
41(40)
2.2:1 74(9
(2:1) 0)
3ha
9
4-PhC6H4
2-MeC6H4
2-FC6H4
3-BrC6H4
3-NO2C6H4
3-CF3C6H4
2-naphthyl
2-furyl
50
48
88
58
39
62
69
70
51
30
3:1
2:1
98
85
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
10
11
12
13[f]
14
15
16
17
18[g]
donating groups were subjected in the reaction
conditions and high enantioselectivities were obtained
(entries 1-3). Similarly, high enantioselectivities were
achieved with 4-halo substituted mercaptans 3ae-3ag
(entries 4-6). Moreover, ortho- and meta-substituted
benzyl mercaptans 2h and 2i also participated in the
reaction delivering products 3ah and 3ai in high
2.5:1 90
3:1
2:1
95
86
2.8:1 95
4:1
5:1
99
96
Methyl
3.2:1 88
1.25: 88
1
OEt
Table 3. Scope of thiols
O
Ph
O
19[h]
Ph, n = 1
45
2:1
42
3sa
[a]
Ph
Reactions were carried out with 0.1 mmol of 1 and 0.1
catalyst VII (5 mol%)
mmol of 2a in 1 ml solvent using 5 mol% VII at 0 oC for 1
+
RSH
O
CHO
[b]
Mol sieves 4Å
nBu2O, 0 oC, 24 h
day.
Unless otherwise mentioned, combined isolated
1a
SR
2b-o
3ab-ao
yield of the mixture of diastereomers. [c] Determined by 1H
NMR of the isolated product. [d] Determined by chiral HPLC
and of the major diastereomer. [e] The data in parenthesis is
with catalyst IV. [f] Yield of pure major diastereomer and d.r.
was determined by 1H NMR of the crude reaction mixture.
[g] Stirred at 60 oC for 10 days. [h] Reaction time 48 h.
Entry[a]
R
3
Yield
(%)[b]
d.r[c]
Ee
(%)[d]
1
2
4-MeC6H4CH2
4-tBuC6H4CH2
53
62
4.2:1
2.7:1
96
96
3ab
3ac
3
4-OMeC6H4
CH2
78
4.7:1
96
3ad
4
5
6
7
8
9
4-FC6H4CH2
4-ClC6H4CH2
4-BrC6H4CH2
2-MeC6H4CH2
3-BrC6H4CH2
2,4-
56
59
62
57
57
59
4.3:1
3:1
3.5:1
3.3:1
3:1
89
94
94
92
93
94
3ae
3af
3ag
3ah
3ai
Then different substitutions on the phenyl group
attached to the aldehyde functionality were screened
and the results are shown in Scheme 2. As can be seen,
the outcome did not change with the substitutions and
excellent results were maintained. For example,
substrate 1t having 4-methyl substitution provided
product 3ta in 57% yield with 4:1 diastereomeric ratio
and a high 92% ee was detected. Similarly excellent
enantioselectivities were obtained for products 3ua
and 3va having 5-F and 6-F substitutions respectively.
Next, the generality of the reaction was further
demonstrated by employing a variety of thiols and the
results are summarized in Table 3. Here also, different
substitutions on the phenyl group of benzyl mercaptan
as well as other thiols were tolerated and excellent
results were achieved. Initially, para-substituted
benzyl mercaptans having electron-neutral and
3.6:1
3aj
Cl2C6H3CH2
2-naphthylCH2
cinnamyl
10
11
62
37
65
21
84
4:1
1.6:1
9:1
1.8:1
3.4:1
98
97
98
91
96
3ak
3al
3am
3an
3ao
12
tbutyl
Ph3CH
13[e]
14
CH3(CH2)6CH2
[a]
Reactions were carried out with 0.1 mmol of 1a and 0.1
o
mmol of 2 in 1 ml solvent using 5 mol% VII at 0 C for 1
[b]
day.
Yield of the isolated product having mixture of
diastereomers. [c] Determined by H NMR of the isolated
1
product. [d] Determined by HPLC. [e] Reaction time 7 days.
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701518
Advanced Synthesis & Catalysis
enantioselectivities (entries 7-8). 2,4-Disubstituted
benzyl mercaptan 2j could also be employed in the
reaction and high enantioselectivity (94% ee) was
detected for product 3aj (entry 9). Excellent
enantioselectivity was also obtained for product 3ak
having 2-naphthylmethylthio group (entry 10). Then
different aromatic and aliphatic thiols were screened
and pleasingly the results were excellent (entries 11-
14).
substituted phthalan 11 was formed in 72% yield with
slight erosion in enantioselectivity.
A scale up reaction was also performed in gram scale
providing the product 3aa in 2.6:1 diastereomeric ratio
and 96% enantiomeric ratio, thus showing the
effectiveness of our reaction in multi-step synthesis.
O
O
Ph
Ph
The scope of the reaction was further demonstrated by
carrying out the reaction of 1a with benzyl alcohol and
thiophenol (Scheme 3). Benzyl alcohol provided the
expected phthalan 4 in moderate diastereomeric ratio
with good enantioselectivity. But for thiophenol
instead of the phthalan derivative, compound 5 having
an indanol moiety was formed by domino
Michael/aldol reaction. The structure of 5 was
determined by 2D NMR spectroscopy. Although the
diastereoselectivity was excellent for this reaction, the
enantioselectivity was found to be moderate.
m-CPBA (3 eq.)
O
O
CH2Cl2, rt, 1 h
96%
SBn
OH
6, 96% ee, 1.5:1 dr
3aa, 98% ee, 3:1 dr
O
O
O
m-CPBA
(5 eq. )
m-CPBA
(3 eq.)
Ar
Ar
Ar
O
O
O
CH2Cl2, rt
1 h
CH2Cl2, rt
SBn
OH
7
O
1 h
9
3ca, 96% ee, 2.7:1 dr
m-CPBA (2 eq.)
Na2HPO4 (2 eq.)
CH2Cl2, rt
m-CPBA (2 eq.)
Na2HPO4 (2 eq.)
CH2Cl2, rt
91%
overall
89%
overall
O
O
O
OAr
O
OAr
O
O
Ph
Ph
catalyst VII (5 mol%)
Ar = 4-OMeC6H4
OH
+
BnOH
O
O
8
10
CHO
93% ee, 1.7:1 dr
63% ee
Mol sieves 4Å
nBu2O, 0 oC, 48 h
1a
OBn
2p
4
O
O
90% ee, 1.8:1 dr
53%
Ph
Et3SiH ( 1.6 eq.)
Ph
TFA ( 5 eq.)
O
O
O
SPh
CH2Cl2, rt
72%
SCPh3
Ph
VII
catalyst
(5 mol%)
Ph
11
, 84% ee
3an, 91% ee, 1.8:1 dr
+
PhSH
CHO
O
Mol sieves 4Å
nBu2O, 0 oC, 24 h
1a
2q
Scheme 4. Synthetic transformations of products 3aa,
3ca and 3an.
5
OH
83%
66% ee, >20:1 dr
In summary, we have developed the first
nonenzymatic organocatalytic DKR of in situ
generated hemithioacetals leading to the synthesis of
1,3-disubstituted-1,3-dihyroisobenzofurans. Cinchon-
idine derived urea was the best catalyst for this
reaction and the dihyroisobenzofuran products were
Scheme 3. Reaction of 1a with benzylalcohol and
thiophenol
The absolute configuration of product 3-(benzylthio)-
1,3-dihydroisobenzofuran-1-yl)-1-(furan-2-yl)ethan
one (3pa) was assigned to be (1R,3S) by X-ray
crystallography.[14] The absolute structure of other
compounds are expected to be same by analogy.
formed
in
good
yields
with
moderate
diastereoselectivities and high enantioselectivities.
Also few synthetic transformations including mono-
substituted dihyroisobenzofuran synthesis has been
demonstrated. Thus our methodology would be useful
for the synthesis of different derivatives of biologically
active 1,3-disubstituted dihyroisobenzofurans.
The synthetic utilities of our reaction were
demonstrated by performing few reactions on the
products (Scheme 4). Initially oxidation of 3aa was
carried out in the presence of 3 equivalents of m-CPBA.
Interestingly, instead of a sulfone product, hemiacetal
6 was formed in 96% yield with 1.5:1 diastereomeric
ratio; and 96% enantiomeric excess of the major
diastereomer was observed. Then compound 3ca was
first converted to hemiacetal 7 by the same method, on
which a Baeyer Villiger oxidation reaction was
performed. This resulted in the formation of ester 8 in
92% overall yield with 93% ee. It was observed that
when 5 equivalents of m-CPBA were employed in the
reaction of 3ca, the phthalide 9 was formed which on
Baeyer Villiger reaction condition provided
compound 10 with loss in enantiopurity. Then
triethylsilane mediated selective removal of trityl
group[15] was envisaged in compound 3an. However,
under the acidic conditions, the complete removal of
triphenylmethanethiol motif was noticed and mono-
Experimental Section
General Information
Chemicals All the reagents used are of commercial grade
and used without purification. Organic solvents that are used
for reactions were dried using standard methods. Reactions
were monitored by silica gel 60 F254 (0.25mm). NMR
spectra were recorded in CDCl3 with tetramethylsilane as
the internal standard for 1H NMR (400 MHz or 500 MHz or
600 MHz) and CDCl3 solvent as the internal standard for 13C
NMR (100 MHz or 125MHz or 150 MHz). Chemical shifts
are reported in ppm tetramethylsilane (CDCl3: δ 7.26 for 1H-
NMR and CDCl3: δ 77.23 for 13C-NMR). For 1H-NMR, data
are reported as follows: chemical shift, multiplicity (s =
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701518
Advanced Synthesis & Catalysis
singlet, d = doublet, dd = double doublet, ddd = doublet of
doublet of doublet, t = triplet, dt = doublet of triplet, q =
quartet, m = multiplet), coupling constants (Hz) and
integration. HRMS spectra were recorded using ESI mode
using a TOF analyzer. HPLC data were recorded using
Dionex (Ultimate 3000) HPLC Instruments.
[4] L. A. Damani, In Sulfur-Conatining Drugs and Related
Organic Compounds: Chemistry, Biochemistry, and
Toxicology, Vol. 1, Ellis Horwood Ltd., Chichester, U.K.,
1989. Part B.
[5] a) S. Brand, M. F. Jones, C. M. Rayner, Tetrahedron
Lett. 1995, 36, 8493; b) M. Sakulsombat, Y. Zhang, O.
Ramström, Chem. Eur. J. 2012, 18, 6129; c) Y. Zhang,
L. Hu, O. Ramström, Chem. Commun. 2013, 49, 1805;
d) Y. Zhang, F. Schaufelberger, M. Sakulsombat, C. Liu,
O. Ramström, Tetrahedron 2014, 70, 3826.
General procedure for organocatalytic asymmetric
hemithio acetalization/oxa-Michael cascade reaction of
ortho-formyl chalcone
[6] For a recent report on DKR of aminothioacetal with
moderate enantioselectivity, see: V. Capaccio, A.
Capobianco, A. Stanzione, G. Pierri, C. Tedesco, A. D.
Mola, A. Massa and L. Palombi, Adv. Synth. Catal. 2017,
359, 2874.
A 5 mL round bottomed flask was charged with ortho-
formyl chalcone 1 (0.1 mmol), catalyst VII (5 mol%) and
100 mg of 4Å molecular sieves. Benzyl mercaptan 2 0.1
mmol) and 1 mL di-n-butyl ether was then added to it. The
reaction vessel was closed by means of a stopper and the
[7] For selected examples and reviews, see: a) R. Karmakar,
P. Pahari, D. Mal, Chem. Rev. 2014, 114, 6213; b) L.
Dorell, M. A. Cohen, S. S. Hupriker, J. M. Gorman, M.
Jones, Psychosomatics 2005, 46, 91; c) J. K. Harper, A.
M. Arif, E. J. Ford, G. A. Strobel, J. A. Porco Jr., D. P.
Tomer, K. L. Oneill, E. M. Heider D. M. Grant,
Tetrahedron 2003, 59, 2471; d) U. Holler, J. B. Gloer,
D. T. Wicklow, J. Nat. Prod. 2002, 65, 876.
o
reaction was stirred at 0 C for 24 hours. The solvent from
the crude reaction mixture was then evaporated and it was
directly subjected to column chromatographic separation
using 3% EtOAc in hexaane as eluent.
Acknowledgements
We gratefully acknowledge the financial support from DST, MPI
and DAE. We also thank CIF, Indian Institute of Technology
Guwahati for the instrument facility.
[8] J. F. DeBernardis, D. L. Arendsen, J. J. Kynel, D. J.
Kerkman, J. Med. Chem. 1987, 30, 178.
[9] For selected examples, see: a) D. Garcia, F. Foubelo, M.
Yus, Tetrahedron, 2008, 64, 4275; b) T.-Y. Yuen, S.-H.
Yang, M. A. Brimble, Angew. Chem. Int. Ed. 2011, 50,
8350; c) S. E. Denmark, C. S. Regens, Y. Kobayashi, J.
Am. Chem. Soc. 2007, 129, 2774.
References
[1] For selected reviews, see: a) Chirality from Dynamic
Kinetic Resolution, 2011, 283-284 ISBN: 978-1-84973-
197-3; b) H. Pellesier, Tetrahedron 2008, 64, 1463; c) H.
Pellesier, Tetrahedron 2003, 59, 8291; d) F. F. Huerta,
A. B. E. Mindis, J.-E. Bäckvall, Chem. Soc. Rev. 2001,
30, 321; e) H. Stecher, K. Faber, Synthesis 1997, 1; f) S.
Caddick and K. Jenkis, Chem. Soc. Rev., 1996, 25, 447;
g) R. S. Ward, Tetrahedron: Asymmetry, 1995, 6, 1475.
[10] M. Ghosh, R. Singha, S. Dhara and J. K. Ray, RSC Adv.
2015, 5, 85911 and referenes cited there in.
[11] B. Ravindra, B. G. Das, P. Ghorai, Org. Lett, 2014, 16,
5580.
[12] a) D. F. Ewing, C. Len, G. Mackenzie, G. Ronco and
P. Villa, Tetrahedron: Asymmetry 2000, 11, 4995. B)
During the preparation of this manuscript, a synthesis
of 1,3-disubstituted phthalan has been reported, S.
[2] For reviews, see: a) H. Pellesier, Tetrahedron 2016, 72,
3133; b) H. Pellesier, Adv. Synth. Catal. 2011, 353, 659.
[3] For selected examples, see: a) L. Tang, L. Deng, J. Am.
Chem. Soc. 2002, 124, 2870; b) J. W. Evans, M. B.
Fierman, S. J. Miller, J. A. Ellmann, J. Am. Chem. Soc.
2004, 126, 8134; c) A. Berkessel, S. Mukerjee, F.
Cleemann, T. N. Müller, J. Lex, Chem. Commun. 2005,
1898; d) N. Shibata, M. Matsunaga, M. Nakagawa, T.
Fukuzumi, S. Nakamura, T. Toru, J. Am. Chem. Soc.
2005, 127, 1374; e) S. Hoffmann, M. Nicoletti, B. List,
J. Am. Chem. Soc. 2006, 128, 13074; f) A. Peschiulli, C.
Quigley, S. Tallon, Y. K. Guńko, S. J. Connon, J. Org.
Chem. 2008, 73, 6409; g) J. Wang, H. Xie, H. Li, L. Zu,
W. Wang, Angew. Chem. Int. Ed. 2008, 47, 4177; h) J.
W. Lee, T. H. Ryu, J. S. Oh, H. Y. Bae, H. B. Jang, C.
E. Song, Chem. Commun. 2009, 7224; i) X. Yang, V. B.
Birman, Angew. Chem. Int. Ed. 2011, 50, 5553; j) S.
Maity, B. Parhi, P. Ghorai, Angew. Chem. Int. Ed. 2016,
55, 7723; k) A. Orue, U. Uria, D. Roca-López, I. Delso,
E. Reyes, L. Carrillo, P. Merino, J. L. Vicario, Chem. Sci.
2017, 8, 2904.
Maity, M. Saha, G. Hazra, P. Ghorai, Org. Lett. 2017
19, 5872.
,
[13] For selected examples on organocatalytic oxa-Michael
additions, see: a) R. R. Reddy, S. S. Gudup, P. Ghorai,
Angew. Chem. Int. Ed. 2016, 55, 15115; b) P. Saha, A.
Biswas, N. Moleleti, V. K. Singh, J. Org. Chem. 2015,
80, 11115; c) Y. Zhu, X. Li, Q. Chen, J. Su, F. Jia, Q.
Qiu, M. Ma, Q. Sun, W. Yan, K. Wang, R. Wang, Org.
Lett. 2015, 17, 3826; d) Z.-C. Geng, S.-Y. Zhang, N.-K.
Li, N. Li, J. Chen, J.; H.-Y. Li, X.-W. Wang, J. Org.
Chem. 2014, 79, 10722; e) T. Azuma, A. Murata, Y.
Kobayashi, T. Inokuma, Y. Takemoto, Org. Lett. 2014,
16, 4256; f) R. Miyaji, K. Asano, S. Matsubara, Org.
Biomol. Chem. 2014, 12, 119; g) Y. Lu, G. Zou, G. Zhao,
ACS Catal. 2013, 3, 1356; h) Y. Kobayashi, Y.
Taniguchi, N. Hayama, T. Inokuma, Y. Takemoto,
Angew. Chem. Int. Ed. 2013, 52, 11114; i) M. T. Corbett
and J. S. Johnson, Chem. Sci. 2013, 4, 2828; j) W. Hou,
B. B. Zheng, J. Chen, Y. Peng, Org. Lett. 2012, 14, 2378;
k) K. Asano, S. Matsubara, J. Am. Chem. Soc. 2011, 133,
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701518
Advanced Synthesis & Catalysis
16711; l) E. M. Phillips, M. Riedrich, K. A. Scheidt, J.
Am. Chem. Soc. 2010, 132, 13179; m) Q. Gu, Z.-Q.
Rong, C. Zheng, S.-L. You, J. Am. Chem. Soc. 2010,
134, 4056; n) C. Liu, X. Zhang, R. Wang, W. Wang, Org.
Lett. 2010, 12, 4948. For reviews on oxa-Michael
reactions, see: o) C. F. Nising, S. Bräse, Chem. Soc. Rev.
2012, 41, 988; p) C. F. Nising, S. Bräse, Chem. Soc. Rev.
2008, 37, 1218.
[14] CCDC 1581645 contains the crystallographic data for
3pa.
[15] W. Guo, B. Wu, X. Zhou, P. Chen, X. Wang, Y.-G.
Zhou, Y. Liu, C. Li, Angew. Chem. Int. Ed. 2015, 54,
4522.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701518
Advanced Synthesis & Catalysis
COMMUNICATION
Nonenzymatic Dynamic Kinetic Resolution of in
situ Generated Hemithioacetals: Access to 1,3-
Disubstituted Phthalans
Adv. Synth. Catal. Year, Volume, Page – Page
Utpal Nath, Deepan Chowdhury, Subhas Chandra
Pan*
7
This article is protected by copyright. All rights reserved.