Asymmetric synthesis of spirooxindoles via nucleophilic epoxidation promoted by bifunctional organocatalysts

Article abstract of DOI:10.3390/molecules23020438

Taking into account the postulated reaction mechanism for the organocatalytic epoxidation of electron-poor olefins developed by our laboratory, we have investigated the key factors able to positively influence the H-bond network installed inside the subst

Full text of DOI:10.3390/molecules23020438

molecules
Article
Asymmetric Synthesis of Spirooxindoles via
Nucleophilic Epoxidation Promoted by
Bifunctional Organocatalysts
Martina Miceli 1, Andrea Mazziotta 1, Chiara Palumbo 1, Elia Roma 1, Eleonora Tosi 1,
Giovanna Longhi 2 ID , Sergio Abbate 2, Paolo Lupattelli 3, Giuseppe Mazzeo 2
ID
and Tecla Gasperi 1,
*
ID
1
Dipartimento di Scienze- Sezione di Nanoscienze e Nanotecnologie, Università degli Studi di Roma Tre,
V.le G. Marconi 446, I-00146 Rome, Italy; martina.miceli@icloud.com (M.M.); adma@kemi.dtu.dk (A.M.);
ch.palumbo@hotmail.it (C.P.); elia.roma@uniroma3.it (E.R.); eleonoratosi93@gmail.com (E.T.)
Dipartimento di Medicina Molecolare e Traslazionale (DMMT), Università di Brescia, viale Europa 11,
25123 Brescia, Italy; giovanna.longhi@unibs.it (G.L.); sergio.abbate@unibs.it (S.A.);
giuseppe.mazzeo@unibs.it (G.M.)
2
3
0
Dipartimento di Scienze, Università degli Studi della Basilicata, via dell Ateneo Lucano 10,
I-85100 Potenza, Italy; paolo.lupattelli@unibas.it
*
Correspondence: tecla.gasperi@uniroma3.it; Tel.: +39-3386711045
Received: 5 February 2018; Accepted: 12 February 2018; Published: 16 February 2018
Abstract: Taking into account the postulated reaction mechanism for the organocatalytic epoxidation
of electron-poor olefins developed by our laboratory, we have investigated the key factors able to
positively influence the H-bond network installed inside the substrate/catalyst/oxidizing agent.
With this aim, we have: (i) tested a few catalysts displaying various effects that noticeably differ in
terms of steric hindrance and electron demand; (ii) employed
different substituents on the aromatic ring (11a ), the exocylic double bond (11h
moiety (11m ). The observed results suggest that the modification of the electron-withdrawing
α
-alkylidene oxindoles decorated with
–g
–l), and the amide
–
v
group (EWG) weakly conditions the overall outcomes, and conversely a strong influence is
unambiguously ascribable to either the N-protected or N-unprotected lactam framework. Specifically,
when the NH free substrates (11m–u) are employed, an inversion of the stereochemical control is
observed, while the introduction of a Boc protecting group affords the desired product 12v in excellent
enantioselectivity (97:3 er).
Keywords: epoxidation; organocatalysis; epoxyoxindole; alkylidenoxindoles; H-bond network;
non-covalent catalysis; chiroptical properties
1. Introduction
“If carbonyl compounds have been said to be virtually the backbone of organic synthesis,
the epoxides correspond to at least one of the main muscles” (Prof. D. Seebach) [1]. As an irreplaceable
muscle, over the years, chiral epoxides have proved to be highly valuable intermediates and
outstanding building blocks in fine organic synthesis. Indeed, the oxirane ring easily undergoes
several stereoselective chemical transformations into a variety of multi-functionalized compounds that
directly led to advanced precursors of both natural products and biologically active molecules [
Among them, spiro-epoxyoxindoles, featured with a spiro-carbon and unstable oxirane motif,
have piqued the interest of a growing number of research groups [ 10]. Such striking allure is
mainly due not only to their recognised medicinal effectiveness [11 17], but also to their role providing
direct access to architecturally complex heterocycles [18 22]. Although various fascinating approaches
have been developed for their preparation, only few are efficient and effective strategies to achieve
2–7].
8–
–
–
Molecules 2018, 23, 438; doi:10.3390/molecules23020438
www.mdpi.com/journal/molecules

Molecules 2018, 23, 438
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this notable framework with high optical purity. For instance, since the seminal work of Brière and
Metzner [23], stereoselective Darzen-type processes have been the object of several investigations.
In 2014 Xiao et al. succeeded in the synthesis of epoxyoxindoles from isatines [8]. Likewise,
Feng and co-workers investigated a Co(acac)2-N,N0-dioxide-catalyzed Darzens reaction to afford
benzyl-substituted trans-spirooxirane-oxindoles [10], while, more recently, Wong has focused his
efforts on the use of (R)-BINOL and Ti(iOPr)4 as catalysts reaching a high level of stereoselectivity
involving chiral sulfur ylides in situ generated from camphor-derived sulfonium salts [24]. Conversely,
less explored have been the stereoselective epoxidation of α-ylidenoxindoles with peroxide, which even
though these furnished the titled products with excellent diastereomeric ratios, provided the
corresponding spiroepoxides only with moderate to good enantioselectivity [25–27].
In the past few years, we have been engaged in the development of the nucleophilic epoxidation of
α
-ylidenoxindoles as well as in the improvement of the corresponding organocatalytic version [25,26],
which mostly relies on the catalyst’s ability to install in the transition state a strong network
with substrate and oxidizing agent (Figure 1A). Pursuing our research and prompted by the
continuous interest concerning spiroepoxy derivatives, we envisaged enhancing the previously
reported procedure by introducing further additional groups capable of installing more H-bonds inside
the substrate/catalyst/oxidant system by modifying both the substrate and the catalyst. Specifically,
since the first step of our nucleophilic epoxidation involved an oxa-Michael addition and, taking
into account the analogous activation process of the enoyl-CoA hydratase in fatty acid metabolism,
we envisaged the possibility of employing a catalyst bearing two hydrogen donor groups that should
increase the α,β-unsaturated bond electrophilicity and make stronger the H-bond network in the
postulated transition state A.
Ph
Ph
N
O
O
H
chiral
H
H
tBu
O
skeleton
Lewis
Acid
O
X
H
N
N
X
H
X
H
Lewis
Acid
R1
H
EtO2C
N
Bronsted
base
Bronsted
base
R3
B
C
R2
A
O
HO
N
Ar
Ar
OH
N
Ph
Ph
H
HN
N
N
N
CO2H
N
H
H
HN N
H
HO
1 Ar = C6H5
5
6
7
2 Ar = 4-NO2-C6H4
3 Ar = 4-MeO-C6H4
4 Ar = 3,5-(tBu)2-C6H3
N
CF3
S
O
OMe
S
N
N
H
N
H
HN
HO
H
NH
N
N
F3C
H
H
N
8
9
10
Figure 1. Postulated transition state (A) of the previously optimized organocatalytic epoxidation that
highlights the substrate/catalyst/oxidant H-bond network. Hypothesized catalyst structures (B,C).
Organocatalysts examined in this study (1–10).

Molecules 2018, 23, 438
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2. Results and Discussion
2.1. Evaluation of the Catalyst Modification
Initially, considering the efficiency of the
α
,
α
-diarylprolinol
1, the catalyst scope was enlarged
to various compounds in which: (i) either the aromatic rings or the pyrrolidine framework were
decorated with substituents different in terms of hindrance- and electron demand ( , Figure 1);
(ii) the Brønsted basic site was preserved, whereas the Lewis acidic site was changed to a tetrazolic
ring ( , Figure 1); (iii) the Brønsted basic site was preserved, while two hydrogen bond donors were
introduced ( and , e.g., an hydroxyl group and an amide moiety, Figure 1); (iv) the Brønsted basic
site was preserved, and linked to a thiourea through a methylene ( , Figure 1); (v) the chiral skeleton
2–5
6
7
8
9
was changed to an epi-quinine, in which the basic site is a tertiary amine and the Lewis acid group is
a thiourea (Soós catalyst 10, Figure 1).
The nucleophilic epoxidation reaction was initially performed using the alkyliden oxindole
11a as model substrate, testing catalysts
(i.e., TBHP as oxidizing agent, hexane as solvent, and room temperature). The observed outcomes
were compared with the simplest -diphenyl prolinol (Table 1). The presence of an electron
withdrawing group (Ar = 4-NO2-C6H4, catalyst , entry 2) on the aromatic moiety dramatically reduce
2–10 and employing previously optimized conditions [25]
α
,
α
1
2
the enantioselectivity as well as the efficiency in terms of time and yield, even though the diastereomeric
ratio was quite favourable to the epoxide trans-12. Conversely, the introduction of an electron donating
moiety (Ar = 4-OMe-C6H4, catalyst
enantiomeric ratio was almost comparable to the reference catalyst. Additionally, the more hindered
catalyst (entry 4) slightly favoured the formation of the cis isomer (25:75) without any significant
3, entry 3), dramatically reduced the diastereoselectivity, while the
4
enhancement in the enantioselectivity, which was completely smoothed over when a second stereogenic
centre was introduced on the five-membered ring (entry 5).
The tetrazolic catalyst
6 (entry 6), featured with an NH function instead of the free hydroxyl
moiety, furnished an interesting high diastereo- (79:21) and enantioselectivity (92:8), but a pronounced
decrease of reactivity was observed in terms of reaction time (240 h) and yield (4%). The use of other
amidic catalysts was subsequently evaluated: pyrrolidine derivative
OH function is sustained by a second NH function, and thioureas and 10 (Figure 1), in which the OH
function is substituted by an NH moiety. Unfortunately, no substantial improvement was observed
and only lower enantioselectivity was detected (entries ). A distinctive issue has to be addressed
7 and 8 (Figure 1), in which the
9
7–9
when compound 10 was employed. Indeed, although the Soós thiourea (10) furnished the desired
products with an optical purity comparable to the model reaction, the low overall yield (36%) and
a reaction time that was too long (144 h) made catalyst 10 unsuitable for further investigations.
Table 1. Effect of selected organocatalyst (
N-methyl -ylidene oxindoles (11a
(EWG) on the exocyclic double bond a,b
1–10, Figure 1) on the asymmetric epoxidation of various
) bearing a carboxylate (CO2Et) as electron-withdrawing group
α
–g
.
trans-12 er e
cis-13 er e
dr d
Entry
Sub
R1
R2
Cat *
Time (h)
Yield (%) c
1
2
3
4
5
6
7
8
a
a
a
a
a
a
a
a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
2
3
4
5
6
7
8
72
168
48
92
56
44
30
36
4
64:36
85:15
55:45
25:75
33:67
79:21
60:40
78:22
91:9
56:44
81:19
69:31
43:57
92:8
60:40
67:33
72:28
80:20
47:53
39:61
56:44
51:49
48
144
240
72
20
33
49:51
53:47
72

Molecules 2018, 23, 438
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Table 1. Cont.
trans-12 er e
cis-13 er e
dr d
Entry
Sub
R1
R2
Cat *
Time (h)
Yield (%) c
9
a
a
H
H
H
H
H
H
Cl
H
H
9
10
1
1
1
1
1
72
144
24
96
33
48
48
10
36
97
90
79
98
72
65:35
40:60
33:67
42:58
37:63
51:49
27:73
67:33
90:10
80:20
89:11
93:7
90:10
85:15
71:29
58:42
66:34
64:36
77:23
62:38
62:38
10
11
12
13
14
15
b f
c g
d g
e h
e h
I
iPr
Cl
OCH3
NO2
EtO2C
g g
1
24
98
51:49
91:9
55:45
O
16
N
CH3
a
Reaction conditions: N-Methyl
α-ylideneoxindole 11 (0.5 mmol), catalyst 1 (0.15 mmol), THBP (0.6 mmol),
b
and high-performance liquid chromatography (HPLC) grade hexane (2.7 mL) at rt. The given stereochemical
assignments are based on the previously reported data for spiroepoxides trans-12a and cis-13a [25]. The yields
c
d
of the isolated products are expressed as the sum of the diastereomers. Determined by proton nuclear magnetic
resonance (1H-NMR) of the crude reaction mixture. Determined by chiral-phase HPLC analysis. For the already
e
f
g
known
α
-ylideneoxyndole 11b see reference [28]. The novel
α
-ylideneoxyndoles 11c
,
11d, and 11g were prepared
-ylideneoxyndoles 11e
h
and fully characterized as reported in the supporting material. For the already known
and 11f, see reference [29]. isopropyl.
α
i
Since the Since the just disclosed results are quite difficult to rationalize and clearly highlight that
the overall domino reaction is not positively affected by either the substitution of the hydroxyl with
other functions, or a change of the catalyst’s scaffold, or the introduction of an additional H-bonding
site, we decided to pursue our investigations employing diarylprolinol 1, the best catalyst so far.
Specifically, the nucleophilic epoxidation was performed on the N-methyl carboxylate
ylideneoxindoles 11b (entries 11–16) that always furnished the easily separable diastereomers
–
g
trans-12b and cis-13b–g, in good to excellent yields and with notable enantioselectivity (up to 93:7 er)
–
g
in favour of the enantiomers (2R0,3R0) and (2S0,3R0), respectively. Noteworthy, the epoxidation of
compounds endowed with two chlorine atoms (entry 13), led to the highest enantioselectivities for
the trans product (93:7 er) together with the highest optical purity for the cis isomer too (77:23 er).
In addition, in few cases (entries 11–13, 15), an inversion of the diastereomeric ratio was observed,
in favour of the products cis-13. Such an effect could be mainly ascribable to some supplementary
interactions between the substituent and the catalyst able to stabilize the transition state that precedes
the cis isomer formation. Furthermore, the steric hindrance as well as the electronic demand on the
aromatic ring due to either a methoxy group (entry 14) or to a naphthyl-derivative (entry 16) do not
strongly affect the overall reactivity.
2.2. Evaluation of the Substrate Scope
In order to explore the effect of the EWG on the developed catalytic system, the reaction
was subsequently performed on
the more hindered phosphonic moiety, which should contribute mostly to an inductive effect (-I)
When phosphonate -ylidenoxindoles 11h (Table 2) were employed as substrates in the optimised
organocatalytic epoxidation, a moderate to good enantioselectivity was observed for the trans isomers
12h , up to 80:20 er); meanwhile, the steric hindrance due to the larger electronwithdrawing group
[PO(OEt)2] enhanced the formation of the cis isomers (13h ), which, as already observed with
α-ylidenoxindole where the carboxylate had been replaced by
α
–l
(
–l
–
l
carboxylic derivatives, became the major diastereomer when a halide (11l) was introduced in position
5 on the aromatic ring.

Molecules 2018, 23, 438
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Table 2. Substrate scope of the organocatalytic epoxidation on
α-ylideneoxindoles 11h–l bearing
a PO(OEt)2 moiety as the EWG group of the exocyclic double bond a.
dr c
Yield (%) b
trans-12 er d
cis-13 er d
Sub
R1
R2
1
2
3
11h e
11i e
11j e
H
H
H
CH3
Ph
Bn
80
95
80
56:44
60:40
56:44
80:20
79:21
74:26
61:39
62:38
55:45
4
11k e
11l f
H
83
65:35
72:28
55:45
5
Cl
CH3
65
40:60
77:23
57:43
a
Reaction conditions: α-ylideneoxindole 11, (0.5 mmol) catalyst 1, (0.15 mmol). THBP (0.6 mmol) and HPLC-grade
b
hexane (2.7 mL) at rt. The yields of the isolated products are expressed as the sum of the diastereomers.
c
d
e
Determined by 1H-NMR of the crude reaction mixture. Determined by chiral-phase HPLC analysis. For the
f
already known
α
-ylideneoxyndole 11h
–k
see reference [26]. The novel
α
-ylideneoxyndole 11l was prepared and
fully characterized as reported in the Supporting Material.
The given stereochemical outcomes are assigned upon a thorough comparison of the reported
experiments, analytical data, and a quantum mechanical ab initio calculation of chiroptical properties.
Specifically, the major diastereomers were identified as the trans products by comparing the
spectroscopic analyses of each isolated compound with the corresponding data already reported
in literature [26], while the (20S,30S) configuration was assigned to the major enantiomer of trans-12h
(see the stereochemistry analysis section below).
The forehead results clearly suggest that the tested substituents on the exocyclic double bond do
not dramatically influence the reagent approach to the electrophilic center (Cβ) which is preferentially
driven toward the less-hindered Re-face of the double bond, although the steric hindrance noticeably
affects the stereoinduction.
Subsequently, the substrate scope was enlarged by evaluating α-ylidenoxindoles 11m–u variously
decorated on the aromatic ring and featured a N-unprotected amide, which should install a further
H-bond between the substrate and the catalyst-oxidant complex (Table 3).
Table 3. Substrate scope of the organocatalytic epoxidation of
N-unprotected amide a.
α
-ylideneoxindoles 11m
–u
featured with
dr c
Yield (%) b
trans-12 er d
cis-13 er d
Sub
R1
R2
Time (h)
1
2
3
4
5
6
7
8
9
11me
11ne
11oe
11pe
11qe
11re
H
F
Cl
I
OCF3
H
H
H
H
H
H
H
F
Cl
Br
Cl
144
43
140
170
96
66
48
86
78
96
97
83
91
76
93
99
87
42
65:35
34:66
40:60
78:22
38:62
23:77
36:64
56:44
35:65
75:25
93:7
73:27
68:32
87:13
92:8
88:12
92:8
83:17
61:39
61:39
59:41
59:41
66:34
70:30
62:38
65:35
86:14
11se
11te
H
Cl
11ue
a
Reaction conditions:
α
-ylideneoxindole 11. (0.5 mmol), catalyst
1
(0.15 mmol). THBP (0.6 mmol) and HPLC-grade
b
hexane (2.7 mL) at rt. The yields of the isolated products are expressed as the sum of the diastereomers.
c
d
e
Determined by 1H-NMR of the crude reaction mixture. Determined by chiral-phase HPLC analysis. For the
already known α-ylideneoxyndole 11m–u, see reference [30].

Molecules 2018, 23, 438
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Comparing the data depicted in Table 3 with the outcomes previously observed [25], it is
undeniable that the reaction was successfully in term of overall yields (up to 99%) without any
loss concerning the diastereomeric ratios (up to 78:22 dr), whereas only a slight decrease in the
enantioselectivity was detected. Nevertheless, a quite surprising result was the outgrowth deriving
from the iodine derivative 11p (entry 4, Table 3), which furnished an inverted diastereomeric ratio
(78:22 in favour of the trans isomer), lower reactivity (170h vs. 24h), and lower optical purity (68:32 vs.
80:20) compared to the corresponding methylated molecule (entry 11, Table 1).
Such observations, taking into account the stereoselectivity previously detected with phosphonate
derivatives 11i–k, which were decorated with different N-substituents (entries 2–4, Table 2), suggest
a special role of the free NH function in the H-bond network existing among substrate/catalyst/oxidant,
a hypothesis which was validated (i) by analysing the configuration of the newly formed stereogenic
centres; as well as (ii) by introducing the tert-butyl carbonyl moiety as nitrogen-protecting group that
should furnish a further coordination site in the epoxidation transition state.
In order to understand how the nucleophilic attack of the oxidizing agent toward the electrophilic
centre (Cβ) on the electron poor olefins 11m–u is stereochemically driven, the experiment depicted in
Scheme 1a was performed. Specifically, the N-methylation of the major diastereomer trans–12m led
to a clean product that, upon spectroscopic and chiral HPLC analysis, resulted to be the enantiomer
(20S,30S)-12a, i.e., the minor enantiomer obtained during the direct organocatalytic epoxidation of the
model substrate 11a (entry 1, Table 1).
Scheme 1. Comparison between N-methyl spiroepoxyoxindoles furnished (
a) by the methylation
of the major diastereomer trans-12m; and (
α-ylidenoxindole 11a.
b) by the organocatalytic epoxidation of the N-methyl
Therefore, the first attack on 11m occurs at the top face of the double bond, i.e., oppositely to
what was observed when N-methyl α-ylideneoxindoles 11a–l were employed.
Additionally, to our delight, the epoxidation reaction carried on the N-Boc protected
α
-ylideneoxindole 11v successfully provided the desired spiroepoxide trans-12v and cis-13v not only
with good diastereomeric excess (66:34 dr), as previously detected, but especially with excellent
enantioselectivity (97:3 er) in the case of the major isomer trans-12v. Actually, in the first trial complete
conversion was accomplished only after 144 h with a quite poor yield of 36%, an outcome that was
remarkably improved (70% of total yield, 24h of reaction time) by using a higher excess of the oxidizing
agent (2.0 equiv. instead of 1.2 equiv.) without any loss in stereoselectivity (66:34 dr, 96:4 er for the
major diastereomer trans-12v) (Scheme 2).

Molecules 2018, 23, 438
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Scheme 2. Organocatalytic epoxidation reaction carried on N-Boc protected α-ylidenoxindole 11v [30]
using 2.0 equivalent of oxidating agent (TBHP).
2.3. Stereochemistry Analysis
To better investigate the stereochemistry of compounds trans-12h and cis-13h, we employed
chiroptical spectroscopies. In particular, we performed electronic and vibrational circular dichroism
(ECD and VCD) and optical rotatory dispersion (ORD) measurements with subsequent analysis by
density functional theory (DFT) and time-dependent DFT (TDDFT) calculations [31–37].
ECD measurement was performed in acetonitrile solution (see experimental details in supporting
material) in the range of 400–180 nm. The ECD spectrum exhibits a weak negative band at ca. 310 nm,
a splitted negative band at ca. 273 nm, and a sequence of intense positive, negative and positive
bands at 250, 224 and about 190 nm, respectively. The negative band at 273 nm and the positive
at 250 nm are both allied to the ultraviolet (UV) band centered at 260 nm which shows multiple
features (Figure 2). ECD/UV calculation was performed at TDDFT/CAM-B3LYP/TZVP level on
the previously optimized most populated conformers at DFT/B3LYP/TZVP level wi0th polarizable
0
continuum model (PCM) [38] approximation (see Figure SM-2 for details) of both the (2 S,3 S) and the
(20S,30R) diastereomers. In Figure 2 a comparison between experimental ECD and UV spectra with
(20S,30S) and (20S,30R) calculated ones is presented.
Despite small differences on relative intensities of the negative and the positive bands at 224
and 190 nm respectively, the calculated spectra of both diastereomers do not clearly discriminate
about 30 carbon AC. On the other hand, unambiguous assignment is provided for 20 carbon as S. Safe
assignment is also supported by considering that all single conformers ECD spectra do not differ each
other (Figure SM-3) showing that the calculation is also quite insensitive to populations and energy
calculation accuracy. All conformers differ by relative orientation of phosphate and ethoxy moieties
(see Figure SM-1) while oxindole chromophore has quite a rigid structure leading to similar ECD
profiles which are driven by the S configuration of 20 carbon.
Interestingly, the calculations of ORD spectra are sensitive to the 30 carbon configuration.
The experimental ORD curve was defined by measuring OR at four wavelengths 589, 546, 435 and
405 nm in chloroform solvent. The experimental ORD trend is negative in sign with specific rotation
values from
−
20 to
−
110. The calculation was performed at CAM-B3LYP/6-311++G(d,p)/PCM(CHCl3)
level at the measured wavelengths. In Figure 3 we report a comparison between experimental and
calculated ORD curves.

Molecules 2018, 23, 438
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Figure 2. Comparison of experimental and computed electronic circular dichroism (ECD) (left) and
ultraviolet (UV) (right) spectra for the different ACs for compounds trans-12h (experimental and
calculated) and cis-13h (calculated).
Figure 3. Comparison of experimental and computed optical rotatory dispersion (ORD) spectra for the
different ACs for compounds trans-12h (experimental and calculated) and cis-13h (calculated).

Molecules 2018, 23, 438
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The experimental ORD curve compares better to the one calculated for (20S,30S) with a specific
rotation values from 54 to
186, while the (20S,30R) calculation provides a positive ORD trend
−
−
and calculated rotation values from +103 to +236. It is worth noting that, like in the ECD case,
the trend in sign of each separated conformer is consistent within each diastereomer calculation:
the (20S,30S) conformer’s distribution presents negative specific rotation values, while the (20S,30R)
diastereomer presents positive values for all conformers (see supporting material Figure SM-3 for
details). These results strongly suggest (20S,30S) is the AC of the experimentally analyzed compound
trans-12h. Figure 4 shows the comparison of experimental and calculated VCD/infrared (IR) spectra
(900–1500 cm−1 range) for the two possible configurations considered for compounds trans-12h
and cis-13h.
Figure 4. Comparison of experimental and computed vibrational circular dichroism (VCD) (left) and
infrared (IR) (right) spectra for the different ACs for compound trans-12h (experimental and calculated)
and cis-13h (calculated). Scaling factor = 0.98 (see Supplementary Materials for details).
Experimental VCD/IR spectra were measured in CCl4 solution while calculations were performed
at the B3LYP/TZVP/PCM(CCl4) level. The VCD/IR case is similar to the ECD/UV: also, from this
0
technique there is no doubt that configuration at 2 is S, while it is difficult to establish the configuration
at 30. In fact, there is not a clear discrimination between the two calculated VCD spectra. Indeed,
some of the experimental features suggest a co-presence of the two diastereomers. In detail, it is
possible to note the experimental peaks 7 and 8 which are well predicted in both IR spectra and they
0
0
are present (even if very weak) in the (2 S,3 S) VCD spectrum. Narrow feature 2 seems to arise from the
0
0
0
0
(2 S,3 R) diastereomer, while experimental band 3a is predicted only in (2 S,3 S). An additional analysis
is possible on the basis of the similarity indices S.I. and Sim_NN of experimental and calculated VCD
spectra. The first index [39] varies between
(right assignment has been made) without intensity sensitivity; the second index [32] is also sensitive
−
1 (reversed AC assignment has been made) and +1
to intensity. Empirically, it is possible to confirm that a good AC assignment is reached when S.I. ≥ 0.5
The largest S.I. and Sim_NN values are found for (20S,30S) with a S.I. = +0.44 and Sim_NN = +0.16;
similarity indices for (20S,30R) are positive but quite smaller (S.I. = +0.34 and Sim_NN = +0.09).
The (20S,30S) AC is slightly favored by vibrational analysis and this agrees with ORD results for the
AC assignment of compound trans-12h.
.
In conclusion, the ECD/UV experimental and computational analysis confirms that the AC of
carbon 20 is no doubt S but is unable to discriminate the AC of the second chiral center on carbon 30

Molecules 2018, 23, 438
10 of 18
since the relevant electronic transitions are farther from 30. ORD analysis suggests (20S,30S) to be the
AC with a well predicted ORD curve in sign and order of magnitude with respect to the experimental
one. VCD/IR analysis confirms the ECD/UV conclusion for center 20, but it does not give a clear
answer for center 30. A co-presence of both (20S,30S) and (20S,30R) diastereomers of trans-12h and
cis-13h cannot be excluded, with a prevalence of (20S,30S) as suggested by similarity indices.
3. Materials and Methods
Solvents and common reagents were purchased from a commercial source and used without
further purification. All the known
α
-ylideneoxindoles (11a
–
b,
11e
–
f,
11h
–
k
, and 11m
–
v) were
synthesised according the literature [26
,
28 30], whereas the unknown substrates (11c
–
,
11d
,
11g 11l)
,
were analogously prepared and fully characterised as reported in the Supplementary Materials.
All reactions were monitored by thin-layer chromatography (TLC) carried out on Merck F-254
silica glass plates and visualized with UV light or by 5% phosphomolibdic acid/ethanol test.
Flash chromatography was performed on Sigma-Aldrich silica gel (60, particle size: 0.040–0.063
1
mm). H-NMR and 13C-NMR were recorded in CDCl3 (99.8% in deuterium) using a Varian Gemini
300 spectrometer (300 MHz, Varian inc., Palo Alto, CA, USA). All chemical shifts are expressed in
parts per million (δ scale) and are referenced to the residual protons of the NMR solvent (CDCl3,
δ
7.24 ppm). Optical rotations were made with the enantioenriched samples on a Jasco DIP-370 digital
polimeter using a Na-lamp. The diastereomeric ratio of the epoxides was determined by 1H-NMR
analysis of the crude reaction mixtures. The enantioselectivities were determined by HPLC analysis on
chiral stationary phase [TSP Spectra Series P200, UV detector at
λ = 254 nm, using a Daicel Chiralpack
IC column and Daicel Chiralpack IA column]. Infrared spectra (FT-IR) were obtained using a Bruker
Vector 22 spectrometer (Bruker, Billerica, MA, USA); data are presented as the frequency of absorption
(cm−1). Melting points were determined with a Mel-Temp. High-resolution mass spectrometry (HRMS)
spectra were recorded with Micromass Q-TOF micro mass spectrometer (Waters Corporations, Milford,
MA, USA) and Micromass LCT (ESI, Waters Corporations, Milford, MA, USA) with Lock-Spray-Injector
(Injection Loop-Modus in a HPLC system, Waters, Alliance 2695).
ORD spectra of trans-12h were recorded with Jasco DIP370 digital polarimeter at four different
wavelengths (589, 546, 435, 405 nm) at a concentration of 0.35 g/100 mL in chloroform solution.
Experimental ECD/UV spectra were obtained by a JASCO 815SE apparatus from 400 nm to 180 nm
under the following experimental conditions: integration time 1 s, scan speed 200 nm/min, bandpass
1 nm, 10 accumulations. Concentration used was 0.00354 M in acetonitrile solution in a 0.1 mm
pathlength quartz cuvette. IR and VCD spectra were collected on a JASCO FVS6000 FTIR (JASCO
Corporation, Easton, ML, USA) equipped with a liquid N2-cooled MCT detector, 5000 accumulations
were averaged in the 850–1500 cm−1 region at 4 cm−1 resolution. The spectra were obtained in CCl4
solutions, in 200 mm pathlength BaF2 cells for a concentration of 0.046 M.
Synthesis and Characterization of Epoxides Trans-12a–v
The synthetic procedures and analytical characterization of the diastereoisomers cis-13a–v are
listed in the Supplementary Materials.
Typical Experimental Procedure for the Synthesis of Epoxides
To a solution of the catalyst 1 (38 mg, 0.15 mmol) and trans-α-ylideneoxindoles 11 (0.5 mmol) in
nHexane for HPLC grade (2.7 mL) was added TBHP (5.5 M in decane solution, 0.6 mmol, 0.11 mL).
◦
The resultant heterogeneous mixture was maintained under stirring at room temperature (25 C) until
reaction completion (TLC nHexane/EtOAc). Afterwards, the crude reaction mixture was purified by
flash chromatography on silica gel (nHexane/EtOAc) to furnish the expected epoxy oxindoles trans-12
and cis-13.

Molecules 2018, 23, 438
11 of 18
(20R,30R)-ethyl 1-methyl-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12a. Following the above general
procedure, trans diastereoisomer 12a was obtained as a whitish solid in 61% yield after purification by
flash chromatography on silica gel (nHexane/EtOAc = 7/3), m.p. 132–134 ◦C. IR (CHCl3): νe = 3033,
1
3010, 2984, 1736, 1709, 1618, 1495, 1473, 1376, 1347 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):
δ (ppm)
1.26 (t, J = 7.2 Hz, 3H, CH3CH2O), 3.25 (s, 3H, CH3N), 4.18 (s, 1H, OCH), 4.24 (dq, J = 10.9 Hz, 7.2 Hz,
1H, CH3CHHO), 4.29 (dq, J = 10.9 Hz, 7.2 Hz, 1H, CH3CHHO), 6.89 (ddd, J = 7.9 Hz, 0.9 Hz, 0.6 Hz,
1H, CHarom), 7.04 (dt, J = 7.7 Hz, 0.9 Hz,1H, CHarom), 7.39 (dt, J = 7.9 Hz, 1.3 Hz, 1H, CHarom),
7.45 (ddd, J = 7.7 Hz, 1.3 Hz, 0.6 Hz, 1H, CHarom). 13C-NMR (CDCl3, 75 MHz, 25 ◦C):
δ (ppm) 14.3,
27.0, 60.0, 60.3, 62.4, 109.1, 119.5, 123.3, 125.0, 131.3, 145.9, 165.9, 170.1. HRMS: exact mass calculated
for (C13H13NNaO4) requires m/z 270.0742, found m/z 270.0741. Chiral-phase HPLC analysis: [Daicel
Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 7/3, flow rate 1.0 mL/min]: Tmajor = 11.91 min,
Tminor = 14.97 min er = 91:9. [α]D = −93 (c = 1.6 g/cm3 inCH2Cl2).
(20R,30R)-ethyl 5-iodo-1-methyl-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12b. Following the above
general procedure, trans diastereoisomer 12b was obtained as a pale yellow solid in 32% yield
after purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3), m.p. 143–145 ◦C.
1
IR (CHCl3): νe◦= 3028, 3017, 3008, 1736, 1727, 1611, 1535, 1486, 1358, 1340 cm−1. H-NMR (CDCl3,
300 MHz, 25 C):
δ (ppm) 1.33 (t, J = 7.1 Hz, 3H, CH3CH2O); 3.24 (s, 3H, NCH3); 3.94–4.41 (m,
3H, CH3CH2O, OCH); 6.69 (t, J = 8.2 Hz, 1H, CHarom); 6.68–6.78 (m, 2H, CHarom). 13C-NMR
(CDCl3, 75 MHz, 25 ◦C): δ (ppm) 14.3, 27.0, 59.6, 60.0, 62.6, 85.6, 111.0, 121.7, 133.6, 140.0, 145.4, 165.5,
169.3. HRMS: exact mass calculated for (C13H12INNaO4) requires m/z 395.9709, found m/z 395.9712.
Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5
1.0 mL/min]: Tmajor = 13.04 min, Tminor = 10.19 min er = 80:20. [
µ
,
λ
= 254 nm, nHexane/EtOH = 70/30, flow rate
α
]
D
=
−
9 (c = 0.0140 g/cm3 in CHCl3).
(20R,30R)-ethyl 5,7-dichloro-1-methyl-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12c. Following the
above general procedure, trans diastereoisomer 12c was obtained as a pale yellow solid in 38% yield
◦
after purification by flash chromatography on silica gel (nHexane/EtOAc = 8/2), m.p. 98–100 C.
IR (CHCl3): νe = 3025, 3011, 2959, 1739, 1727, 1625, 1494, 1471, 1369, 1346 cm−1. H-NMR (CDCl3,
1
300 MHz, 25 ◦C):
δ (ppm) 1.20 (d, J = 6.8 Hz, 6H, (CH3)2CHCarom); 1.29 (t, J = 7.1 Hz, 3H, CH3CH2O);
2.80–2.95 (m, 1H, (CH3)2CHCarom); 3.26 (s, 3H, NCH3); 4.18–4.41 (m, 3H, CH3CH2O, OCH); 6.84 (d,
J = 7.9 Hz, 1H, CHarom); 7.24 (d, J = 7.9 Hz, 1H, CHarom); 7.33 (m, 2H, CHarom). 13C-NMR (CDCl3,
75 MHz, 25 ◦C):
δ
(ppm) 14.3, 24.2 (2
×
C), 26.9, 34.0, 59.9, 60.3, 62.3, 108.9, 119.3, 123.0, 129.0, 143.6,
144.3, 165.9, 170.0. HRMS: exact mass calculated for (C16H19NNaO4) requires m/z 312.1212, found m/z
312.1215. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 70/30,
flow rate 1.0 mL/min]: Tmajor = 14.85 min, Tminor = 8.42 min er = 89:11. [α]D = −79 (c = 0.0220 g/cm3
in CHCl3).
(20R,30R)-ethyl 5,7-dichloro-1-methyl-2-oxospiro[indoline-3,20-oxirane]-30- carboxylate 12d. Following the
above general procedure, trans diastereoisomer 12d was obtained as a pale red solid in 29% yield
after purification by flash chromatography on silica gel (nHexane/EtOAc = 8/2), m.p. 124–126 ◦C.
IR (CHCl3): νe = 3031, 3006, 1740, 1729, 1578, 1463, 1337, 1309 cm−1
.
1H-NMR (CDCl3, 300 MHz,
25 ◦C):
δ (ppm) 1.31 (t, J = 7.1 Hz, 3H, CH3CH2O); 3.62 (s, 3H, NCH3); 4.18–4.40 (m, 3H, CH3CH2O,
◦
OCH); 7.34 (s, 1H, CHarom); 7.40 (s, 1H, CHarom). 13C-NMR (CDCl3, 75 MHz, 25 C):
δ (ppm) 14.3, 30.5,
59.4, 60.6, 62.8, 117.0, 123.6, 124.0, 129.0, 132.9, 140.2, 165.1, 170.1. HRMS: exact mass calculated for
(C13H11Cl2NNaO4) requires m/z 337.9963, found m/z 337.9961. Chiral-phase HPLC analysis: [Daicel
Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH=70/30, flow rate 1.0 mL/min]: Tmajor = 11.74 min,
Tminor = 9.48 min er = 93:7. [α]D = −96 (c = 0.0160 g/cm3 in CHCl3).
(20R,30R)-ethyl 5-methoxy-1-methyl-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12e. Following the
above general procedure, trans diastereoisomer 12e was obtained as a pale yellow solid in 50% yield
after purification by flash chromatography on silica gel (nHexane /EtOAc = 8/2), m.p. 105–107 ◦C.
1
IR (CHCl3): νe = 1735, 1734, 1614, 1492, 1467, 1358, 1260 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):

Molecules 2018, 23, 438
12 of 18
δ (ppm) 1.28 (t, J = 7.1 Hz, 3H, CH3CH2O); 3.23 (s, 3H, NCH3); 3.75 (s, 3H, OCH3); 4.18 (s, 1H, OCH);
4.22–4.25 (m, 2H, CH3CH2O); 6.80 (d, J = 8.5 Hz, 1H, CHarom); 6.92 (d, J = 8.5 Hz, 1H, CHarom);
7.09 (s, 1H, CHarom). 13C-NMR (CDCl3, 75 MHz, 25 ◦C):
δ
(ppm) 14.3, 26.9, 56.0, 59.9, 62.3, 66.1, 109.5,
112.3, 115.9, 120.5, 139.1, 156.3, 165.8, 169.8 ppm. HRMS: exact mass calculated for (C14H15NNaO4)
requires m/z 300.0848, found m/z 300.0844. HPLC analysis: [Daicel Chiralpack IC 5 = 254 nm,
µ, λ
nHeptane/EtOH = 70/30, flow rate 1.0 mL/min]: Tmajor = 16.33 min, Tminor = 11.45 min er = 90:10.
[α]D = −10 (c = 0.0451 g/cm3 in CHCl3).
(20R,30R)-ethyl 1-methyl-5-nitro-2-oxospiro[indoline-3,20-oxirane]-30- carboxylate 12f. Following the above
general procedure, trans diastereoisomer 12f was obtained as a pale yellow◦solid in 19% yield after
purification by flash chromatography on silica gel (DCM 100%), m.p. 170–172 C. IR (CHCl3): νe = 3031,
1
◦
3017, 3009, 1754, 1743, 1617, 1533, 1494, 1340 cm−1. H-NMR (CDCl3, 300 MHz, 25 C):
δ (ppm) 1.34 (t,
J = 7.1 Hz, 3H, CH3CH2O); 3.35 (s, 3H, NCH3); 4.23–4.42 (m, 3H, CH3CH2O, OCH); 7.03 (d, J = 8.9 Hz,
1H, CHarom); 8.37 (d, J = 7.4 Hz, 2H, CHarom). 13C-NMR (CDCl3, 75 MHz, 25 ◦C):
δ (ppm) 14.2, 27.4,
59.4, 60.1, 62.9, 108.9, 120.4, 121.1, 128.0, 143.8, 150.9, 165.1, 170.1. HRMS: exact mass calculated for
(C13H12N2NaO6) requires m/z 315.0593, found m/z 315.0596. Chiral-phase HPLC analysis: [Daicel
Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 70/30, flow rate 1.0 mL/min]: Tmajor = 23.13 min,
Tminor = 22.02 min er = 85:15. [α]D = −29 (c = 0.0180 g/cm3 in CDCl3).
(20R,30R)-ethyl 1-methyl-2-oxo-1,2-dihydrospiro[benzo[g]indole-3,20-oxirane]-30-carboxylate 12g. Following
the above general procedure, trans diastereoisomer 12g was obtained as a pale red solid in 50% yield
after purification by flash chromatography on silica gel (nHexane/EtOAc = 8/2), m.p. 185–187 ◦C.
◦
1H-NMR (CDCl3, 300 MHz, 25 C):
δ
(ppm) 1.26–1.30 (m, 3H, CH3CH2O); 3.88 (s, 3H, NCH3); 4.21–4.31
(m, 3H, OCH, CH3CH2O), 7.50–7.55 (m, 4H, CHarom); 7.86–7.88 (m, 1H, CHarom), 8.40–8.43 (m, 1H,
◦
CHarom). 13C-NMR (CDCl3, 75 MHz, 25 C):
124.7, 126.6, 128.1, 129.2, 142.3, 149.3, 168.6, 170.1. HRMS: exact mass calculated for (C17H15NNaO4)
requires m/z 320.0899, found m/z 320.0896. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5
δ (ppm) 14.3, 28.3, 59.2, 62.5, 63.6, 109.2, 118.5, 122.2, 123.7,
µ,
λ
= 254 nm, nHexane/EtOH = 70/30, flow rate 1.0 mL/min]: Tmajor = 18.48 min, Tminor = 13.56 min
er = 91:9. [α]D = −20.15 (c = 0.0059 g/cm3 in CHCl3).
(20S,30S)-diethyl 1-methyl-2-oxospiro[indoline-3,20-oxiran]-30-yl)phosphonate 12h. Following the above
general procedure, trans diastereoisomer 12h was obtained as a pale yellow solid in 45% yield
after purification by flash chromatography on silica gel (nHexane/EtOAc = 4/6), m.p. 166–168 ◦C.
IR (CHCl3): νe = 1725, 1236 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):
δ (ppm) 1.21 [t, J = 7.0 Hz, 3H,
1
(CH3CH2O)2P], 1.41 [t, J = 7.1 Hz, 3H, (CH3CH2O)2P], 3.26 (s, 3H, NCH3), 3.73 (d, JHP = 27.6 Hz,
1H, OCH), 3.95–4.14 [m, 2H, (CH3CH2O)2P], 4.20–4.37 [m, 2H, (CH3CH2O)2P], 6.90 (d, J = 7.9 Hz,
1H, CHarom), 7.1 (dt, J = 7.7, 1.0 Hz, 1H, CHarom), 7.39 (dt, J = 7.9, 1.3 Hz, 1H, CHarom), 7.99 (d,
J = 7.7 Hz, 1H, CHarom). 13C-NMR (CDCl3, 75 MHz, 25 ◦C):
δ (ppm) 15.9 (d, JCCOP = 5.8 Hz), 16.0 (d,
JCCOP = 5.7 Hz), 26.3, 55.5 (d, JCP = 203.5 Hz), 59.7, 62.7 (d, JCOP = 6.3 Hz), 63.1 (d, JCOP = 6.1 Hz), 108.4,
118.9, 122.6, 126.5, 130.6, 145.3, 170.2. HRMS: exact mass calculated for (C14H18NNaO5P) requires m/z
334.0820, found m/z 334.0824. Chiral-phase HPLC analysis: [Daicel Chiralpack IB 5µ, λ = 254 nm,
nHexane/iPrOH = 9/1, flow rate 1.0 mL/min]: Tmajor = 42.20 min, Tminor = 23.60 min er = 80:20.
[α]D = −2 (c = 0.0101 g/cm3 in CHCl3).
(20S,30S)-diethyl 1-phenyl-2-oxospiro[indoline-3,20-oxiran]-30-yl phosphonate 12i. Following the above
general procedure, trans diastereoisomer 12i was obtained as a pale yellow solid in 57% yield
after purification by flash chromatography on silica gel (nHexane/EtOAc = 1/1), m.p. 197–199 ◦C.
1
IR (CHCl3): νe = 1716, 1265 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):
δ (ppm) 1.18 [t, J = 7.1 Hz, 3H,
(CH3CH2O)2P], 1.34 [t, J =7.1 Hz, 3H, (CH3CH2O)2P], 3.76 (d, JHP = 27.6 Hz, 1H, OCH), 4.00–4.08 [m,
2H, (CH3CH2O)2P], 4.18–4.33 [m, 2H, (CH3CH2O)2P], 6.77 (d, J = 7.6 Hz, 1H, CHarom), 7.05 (t, J = 7.6 Hz,
1H, CHarom), 7.22 (t, J = 7.6 Hz, 1H, CHarom), 7.35–7.46 (m, 5H, CHarom), 7.96 (d, J = 7.6 Hz, 1H, CHarom).
13C-NMR (CDCl3, 75 MHz, 25 ◦C):
δ (ppm) 16.0 (d, JCCOP = 5.7 Hz), 16.2 (d, JCCOP = 5.8 Hz), 58.1 (d,

Molecules 2018, 23, 438
13 of 18
JCP = 203.7 Hz), 60.1, 62.9 (d, JCOP = 6.2 Hz), 63.4 (d, JCOP = 6.1 Hz), 109.8, 118.8, 123.3, 126.1, 126.9,
128.3, 129.5, 130.6, 133.5, 145.5, 169.8 ppm. HRMS: exact mass calculated for (C19H20NNaO5P) requires
m/z 396.0977, found m/z 396.0975. Chiral-phase HPLC analysis: [Daicel Chiralpack IB 5µ, λ = 254 nm,
nHexane/iPrOH = 9/1, flow rate 1.0 mL/min]: Tmajor = 39.90 min, Tminor = 17.50 min er = 79:21.
[α]D = −6.7 (c = 0.0122 g/cm3 in CHCl3).
(20S,30S)-diethyl 1-benzyl-2-oxospiro[indoline-3,20-oxiran]-30-yl phosphonate 12j. Following the above
general procedure, trans diastereoisomer 12j was obtained as a yellow solid in 45% yield after
purification by flash chromatography on silica gel (nHexane/EtOAc = 1/1), m.p. 205–207 ◦C.
1
IR (CHCl3): νe = 1731, 1262 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):
δ (ppm) 1.22 [t, J = 7.1 Hz, 3H,
(CH3CH2O)2P], 1.43 [t, J = 7.1 Hz, 3H, (CH3CH2O)2P], 3.81 (d, JHP = 27.4 Hz, 1H, OCH), 4.02–4.14 [m,
2H, (CH3CH2O)2P], 4.24–4.39 [m, 2H, (CH3CH2O)2P], 4.96 (s, 2H, CH2N), 6.81 (d, J = 7.6 Hz, 1H,
CHarom), 7.07 (t, J = 7.6 Hz, 1H, ◦CHarom), 7.24–7.36 (m, 6H, CHarom), 8.00 (d, J = 7.6 Hz, 1H, CHarom).
13C-NMR (CDCl3, 75 MHz, 25 C):
δ (ppm) 16.2 (d, JCCOP = 5.7 Hz), 16.4 (d, JCCOP = 5.8 Hz), 44.4,
58.1 (d, JCP = 203.1 Hz), 60.2 (d, JCCP = 1.1 Hz), 62.9 (d, JCOP = 6.0 Hz), 63.3 (d, JCOP = 6.0 Hz), 109.3,
119.2, 122.1, 127.3, 127.5, 127.7, 128.7, 131.7, 135.2, 145.5, 170.7 ppm. HRMS: exact mass calculated for
(C20H22NNaO5P) requires m/z 410.1133, found m/z 410.1130. Chiral-phase HPLC analysis: [Daicel
Chiralpack IB 5µ, λ = 254 nm, nHexane/iPrOH = 9/1, flow rate 1.0 mL/min]: Tmajor = 39.90 min,
Tminor = 17.50 min er = 74:26. [α]D = −6.7 (c = 0.0122 g/cm3 in CHCl3).
0
0
0
0
(2 S,3 S)-diethyl 1-(2,4-dichlorobenzyl)-2-oxospiro[indoline-3,2 -oxiran]-3 -yl)phosphonate 12k. Following the
above general procedure, trans diastereoisomer 12k was obtained as a pale yellow solid in 54% yield
after purification by flash chromatography on silica gel (nHexane/EtOAc = 1/1), m.p. 235–237 ◦C.
IR (CHCl3): νe = 1733, 1253 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):
δ (ppm) 1.23 [t, J = 7.1 Hz, 3H,
1
(CH3CH2O)2P], 1.42 [t, J =7.1 Hz, 3H, (CH3CH2O)2P], 3.81 (d, JHP = 27.4 Hz, 1H, OCH), 3.97–4.19 [m,
2H, (CH3CH2O)2P], 4.22–4.39 [m, 2H, (CH3CH2O)2P], 5.03 (s, 2H, CH2N), 6.73 (d, J = 7.9 Hz, 1H,
CHarom), 7.05–7.20 (m, 3H, CHarom), 7.30–7.34 (m, 3H, CHarom), 7.43 (d, J = 1.9 Hz, 1H, CHarom), 8.00 (d,
J = 7.6 Hz, 1H, CHarom). 13C-NMR (CDCl3, 75 MHz, 25 ◦C):
δ (ppm) 15.9 (d, JCCOP = 5.6 Hz), 16.0 (d,
JCCOP = 5.5 Hz), 41.1, 57.9 (d, JCP = 203.0 Hz), 59.7 (d, JCCP = 1.1 Hz), 62.6 (d, JCOP = 6.2 Hz), 63.1 (d,
JCOP = 6.2 Hz), 109.2, 118.9, 123.0, 126.8, 127.2, 128.8, 129.2, 130.6, 130.8, 133.2, 133.8, 144.0, 170.6 ppm.
HRMS: exact mass calculated for (C20H20Cl2NNaO5P) requires m/z 478.0354, found m/z 478.0356.
Chiral-phase HPLC analysis: [Daicel Chiralpack IB 5µ, λ = 254 nm, nHexane/iPrOH = 9/1, flow
rate 1.0 mL/min]: Tmajor = 26.20 min, Tminor = 16.80 min er = 72:28. [α]D = −20.4 (c = 0.0091 g/cm3
in CHCl3).
(20S,30S)-diethyl 5-chloro-1-methyl-2-oxospiro[indoline-3,20-oxiran]-30-yl)phosphonate 12l. Following the
above general procedure, trans diastereoisomer 12l was obtained as a white solid in 38% yield
after purification by flash chromatography on silica gel (nHexane/EtOAc = 1/1), m.p. 211–215 ◦C.
1
IR (CHCl3): νe = 1734, 1260 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):
δ (ppm) 1.26 [t, J = 7.0 Hz, 3H,
(CH3CH2O)2P], 1.42 [t, J =7.0 Hz, 3H, (CH3CH2O)2P], 3.26 (s, 3H, NCH3); 3.73 (d, JHP = 26.6 Hz, 1H,
OCH), 4.05–4.18 [m, 2H, (CH3CH2O)2P], 4.25–4.34 [m, 2H, (CH3CH2O)2P], 6.83 (d, J = 8.3 Hz, 1H,
CHarom), 7.38 (d, J = 8.3 Hz, 1H, CHarom), 8.02 (s, 2H, CHarom). 13C-NMR (CDCl3, 75 MHz, 25 ◦C):
δ
(ppm) 16.4 (d, JCP = 5.9 Hz), 16.6 (d, JCP = 5.6 Hz), 27.1, 58.1 (d, JCP = 203.4 Hz), 59.9, 63.3 (d,
JCP = 6.3 Hz), 63.8 (d, JCP = 6.1 Hz), 109.8, 121.2, 127.5, 128.8, 131.0, 144.3, 170.4. HRMS: exact mass
calculated for (C14H17ClNNaO5P) requires m/z 368.0431, found m/z 368.0433. Chiral-phase HPLC
analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 9/1, flow rate 1.0 mL/min]:
Tmajor = 18.92 min, Tminor = 17.56 min er = 77:23. [α]D = +4 (c = 0.0170 g/cm3 in CHCl3).
(20S,30S)-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12m. Following the above general procedure,
trans diastereoisomer 12m was obtained as a white solid in 62% yield after purification by flash
chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3433, 3035, 3009, 1751,
◦
1726, 1622, 1474, 1340, 1318 cm−1 1H-NMR (CDCl3, 300 MHz, 25 C):
. δ (ppm) 1.29 (t, J = 7.1 Hz,

Molecules 2018, 23, 438
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3H, CH3CH2O); 4.17–4.47 (m, 3H, CH3CH2O, OCH); 6.87–7.17 (m, 2H, CHarom); 7.27–7.51 (m, 2H,
◦
CHarom); 9.38 (s, 1H, NH). 13C-NMR (CDCl3, 75 MHz, 25 C):
123.3, 125.2, 131.3, 143.0, 165.7, 172.6. HRMS: exact mass calculated for (C12H11NNaO4) requires m/z
256.0586, found m/z 256.0582. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5 = 254 nm,
δ (ppm) 14.3, 59.9, 60.5, 62.5, 111.4, 119.6,
µ, λ
nHexane/EtOH = 90/10, flow rate 1.0 mL/min]: Tmajor = 6.28 min, Tminor = 5.51 min er = 75:25.
[α]D = −84.22 (c = 0.0155 g/cm3 in CHCl3).
(20S,30S)-ethyl 5-fluoro-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12n. Following the above general
procedure, trans diastereoisomer 12n was obtained as a white solid in 32% yield after purification
by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3429, 3207, 3031,
1
2979, 1715, 1767, 1752, 1630, 1481, 1319, 1231, 1204 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):
δ (ppm)
1.32 (t, 3H, J = 7.1 Hz, CH3CH2O); 4.19 (s, 1H, OCH); 4.26–4.36 (m, 2H, CH3CH2O); 6.88 (m, 1H,
CHarom); 7.06 (t, 1H, J = 8.4 Hz, CHarom); 7.24 (m, 1H, CHarom); 8.66 (s, 1H, NH). 13C-NMR (CDCl3,
75 MHz, 25 ◦C):
J
δ
(ppm) 14.3, 60.0, 60.5, 62.7, 111.9 (d, JCF = 7.9 Hz), 113.5 (d, JCF = 26.7 Hz), 117.9 (d,
CF = 23.9 Hz), 121.3 (d, JCF = 9.1 Hz), 138.8, 159.3 (d, JCF = 242.2 Hz), 165.4, 172.3. HRMS: exact mass
calculated for (C12H10FNNaO4) requires m/z 274.0492, found m/z 274.0497. Chiral-phase HPLC
analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 90/10, flow rate 1.0 mL/min]:
Tmajor = 10.44 min, Tminor = 9.05 min er = 93:7. [α]D = −132 (c = 0.0155 g/cm3 in CHCl3).
(20S,30S)-ethyl 5-chloro-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12o. Following the above general
procedure, trans diastereoisomer 12o was obtained as a white solid in 33% yield after purification
by flash chromatography on silica gel (nHexane/EtOAc = 1/1). IR (CHCl3): νe◦ = 3433, 3213, 3021,
1764, 1755, 1602, 1441, 1240, 1228, 1213 cm−1 1H-NMR (CDCl3, 300 MHz, 25 C):
. δ (ppm) 1.32 (t,
3H, J = 7.1 Hz, CH3CH2O); 4.19 (s, 1H, OCH); 4.26–4.36 (m, 2H, CH3CH2O); 6.88 (m, 1H, CHarom);
7.06 (t, 1H, J = 8.4 Hz, CHarom); 7.24 (m, 1H, CHarom); 8.66 (s, 1H, NH). 13C-NMR (CDCl3, 75 MHz,
25 ◦C):
δ
(ppm) 14.3, 60.0, 60.5, 62.7, 112.1, 123.3, 125.9, 129.0, 131.3, 140.3, 165.4, 171.8. HRMS: exact
mass calculated for (C12H10ClNNaO4) requires m/z 290.0196, found m/z 290.0198. Chiral-phase
HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 70/30, flow rate 1.0mL/min]:
Tmajor = 5.15 min, Tminor = 4.66 min er = 73:27. [α]D = −43 (c = 0.0108 g/cm3 in CHCl3).
(20S,30S)-ethyl 5-iodo-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12p. Following the above general
procedure, trans diastereoisomer 12p was obtained as a white solid in 71% yield after purification
by flash chromatography on silica gel (nHexane/EtOAc = 1/1). IR (CHCl3): νe = 1765, 1760, 1602,
1
1441, 1240, 1228 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):
δ (ppm) 1.34 (t, 3H, J = 7.0 Hz, CH3CH2O);
4.17–4.40 (m, 3H, CHO, CH3CH2O); 6.76 (d, 1H, J = 8.3 Hz, CHarom);◦7.67 (d, 1H, J = 8.3 Hz, CHarom);
7.76 (s, 1H, CHarom), 8.73 (bs, 1H, NH). 13C-NMR (CDCl3, 75 MHz, 25 C):
δ (ppm) 14.4, 59.8, 60.1, 62.7,
85.6, 113.0, 122.0, 134.2, 140.1, 142.4, 165.4, 171.2. HRMS: exact mass calculated for (C12H10INNaO4)
requires m/z 381.9552, found m/z 381.9555. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5
µ,
λ
= 254 nm, nHexane/EtOH = 90/10, flow rate 1.0 mL/min]: Tmajor = 11.56 min, Tminor = 9.81 min
ee = 68:32. [α]D = −23 (c = 0.0120 g/cm3 in CHCl3).
(20S,30S)-ethyl 2-oxo-5-(trifluoromethoxy)spiro[indoline-3,20-oxirane]-30-carboxylate 12q. Following the
above general procedure, trans diastereoisomer 12q was obtained as a white solid in 29% yield after
purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3433, 3210,
1
◦
3028, 1764, 1724, 1630, 1478, 1371, 1234, 1197 cm−1. H-NMR (CDCl3, 300 MHz, 25 C):
δ (ppm) 1.31 (t,
3H, J = 7.0 Hz, CH3CH2O); 4.20 (s, 1H, OCH); 4.31 (q, 2H, J = 7.0 Hz, CH3CH2O); 6.97 (d, 1H, J = 8.4 Hz,
CHarom); 7.22–7.26 (m, 1H, CHarom); 7.41 (s, 1H, CHarom); 8.41 (bs, 1H, NH). 13C-NMR (CDCl3, 75 MHz,
25 ◦C):
δ
(ppm) 14.2, 60.1, 60.0, 62.7, 111.6, 119.6, 120.6 (q, JCF = 256.0 Hz), 121.3, 124.6, 141.3, 145.1,
165.3, 171.7. HRMS: exact mass calculated for (C13H10F3NNaO5) requires m/z 340.0409, found m/z
340.0410. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 95/5,
flow rate 1.0mL/min]: Tmajor = 12.04 min, Tminor = 9.15 min er = 87:13. [α]D = −56.53 (c = 0.0168 g/cm3
in CHCl3).

Molecules 2018, 23, 438
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(20S,30S)-ethyl 7-fluoro-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12r. Following the above general
procedure, trans diastereoisomer 12r was obtained as a white solid in 21% yield after purification
by flash chromatography on silica gel (nHexane/EtOAc = 8/2). IR (CHCl3): νe = 3433, 3031, 2976,
1
2930, 1752, 1737, 1639, 1493, 1234, 1228 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C): δ (ppm) 1.30 (t, 3H,
J = 7.0 Hz, CH3CH2O); 4.20 (s, 1H, OCH); 4.25–4.30 (m, 2H, CH3CH2O); 7.01–7.05 (m, 1H, CHarom);
7.14 (t, 1H, J ◦= 9.2 Hz, CHarom); 7.28 (d, 1H, J = 9.2 Hz, CHarom); 7.84 (s, 1H, NH). 13C-NMR (CDCl3,
75 MHz, 25 C):
δ (ppm) 14.3, 60.0, 60.1, 62.5, 118.4 (d, JCF = 17 Hz), 121.1 (d, JCF = 3.6 Hz), 122.2,
124.0 (d, JCF = 5.9 Hz), 129.9, 147.4 (d, JCF = 244.7 Hz), 165.3, 170.5. HRMS: exact mass calculated for
(C12H10FNNaO4) requires m/z 274.0492, found m/z 274.0493. Chiral-phase HPLC analysis: [Daicel
Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 8/2, flow rate 1.0 mL/min]: Tmajor = 7.88 min,
Tminor = 8.60 min er = 92:8. [α]D = −63.2 (c = 0.0150 g/cm3 in CHCl3).
(20S,30S)-ethyl 7-chloro-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12s. Following the above general
procedure, trans diastereoisomer 12s was obtained as a white solid in 35% yield after purification
by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3420, 3177, 3009,
1
1764, 1749, 1624, 1478, 1316, 1234, 1189 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):
δ (ppm) 1.29 (t, 3H,
J = 6.8 Hz, CH3CH2O); 4.20–4.31 (m, 2H, CH3CH2O, OCH); 7.01 (t, 1H, J = 8.1 Hz, CHarom); 7.36 (t, 2H,
J = 8.1 Hz, CHarom); 8.14 (s, 1H, NH). 13C-NMR (CDCl3, 75 MHz, 25 ◦C):
116.3, 121.3, 123.6, 124.1, 131.1, 140.4, 165.3, 171.2. HRMS: exact mass calculated for (C12H10ClNNaO4)
requires m/z 290.0196, found m/z 290.0197. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5
δ (ppm) 14.2, 60.1, 60.7, 62.5,
µ,
λ
= 254 nm, nHexane/EtOH = 8/2, flow rate 1.0 mL/min]: Tmajor = 7.72 min, Tminor = 10.00 min
er = 88:12. [α]D = −186.6 (c = 0.0220 g/cm3 in CHCl3).
(20S,30S)-ethyl 7-bromo-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12t. Following the above general
procedure, trans diastereoisomer 12t was obtained as a white solid in 49% yield after purification
by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3414, 3210, 3006,
◦
1742, 1730, 1621, 1444, 1316, 1234 cm−1 1H-NMR (CDCl3, 300 MHz, 25 C):
. δ (ppm) 1.29 (t, 3H,
J = 7.1 Hz, CH3CH2O); 4.20 (s, 1H, OCH); 4.23–4.37 (m, 2H, CH3CH2O); 6.96 (t, 1H, J = 7.9 Hz, CHarom);
7.42 (d, 1H,◦J = 7.9 Hz, CHarom); 7.48 (d, 1H, J = 7.9 Hz, CHarom); 8.06 (s, 1H, NH). 13C-NMR (CDCl3,
75 MHz, 25 C):
δ (ppm) 14.3, 60.1, 61.0, 62.6, 104.1, 121.4, 124.3, 124.5, 133.9, 141.9, 165.3, 170.5. HRMS:
exact mass calculated for (C12H10BrNNaO4) requires m/z 333.9691, found m/z 333.9693. Chiralphase
HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 7/3, flow rate 1.0mL/min]:
Tmajor = 6.14 min, Tminor = 7.18 min er = 92:8. [α]D = −15.85 (c = 0.0132 g/cm3 in CHCl3).
(20S,30S)-ethyl 5,7-dichloro-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12u
. Following the above
general procedure, trans diastereoisomer 12u was obtained as a white solid in 27% yield after
purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3423,
1
◦
3031, 3009, 1757, 1743, 1463, 1323, 1290 cm−1. H-NMR (CDCl3, 300 MHz, 25 C):
δ (ppm) 1.32 (t,
J = 7.0 Hz, 3H, CH3CH2O); 4.18–4.36 (m, 3H, CH3CH2O, OCH); 7.38 (s, 1H, CHarom); 7.42 (s, 1H,
◦
CHarom); 8.09 (s, 1H, NH). 13C-NMR (CDCl3, 75 MHz, 25 C):
122.4, 124.4, 129.3, 130.8, 138.9, 165.1, 170.1. HRMS: exact mass calculated for (C12H9Cl2NNaO4)
requires m/z 323.9806, found m/z 323.9808. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5
= 254 nm, nHexane/EtOH = 7/3, flow rate 1.0 mL/min]: Tmajor = 5.52 min, Tminor = 6.34 min
er = 83:17. [α]D = +137 (c = 0.0090 g/cm3 in CHCl3).
δ (ppm) 14.3, 60.1, 60.4, 62.9, 116.6,
µ,
λ
0
0
0
0
(2R,3 R)-1-(tert-butyl) 3 -ethyl-2-oxospiro[indoline-3,2 -oxirane]-1,3 -dicarboxylate 12v. Following the above
general procedure, trans diastereoisomer 12v was obtained as a white solid in 60% yield after
purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3035,
1
307, 2984, 1736, 1618, 1603, 1495, 1473, 1376, 1347 cm−1. H-NMR (CDCl3, 300 MHz, 25 ◦C):
δ
(ppm)
1.23 (t, J = 5.9 Hz, 3H, CH3CH2O), 1.48 (s, 9H), 4.22 (s, 2H, CH3CH2O), 4.59–4.45 (m, 1H), 7.22 (dtd,
J = 26.3, 7.4, 2.0 Hz, 1H, CHarom), 7.38 (dd, J = 7.3, 2.2 Hz, 2H, CHarom), 7.89 (dd, J = 7.4, 2.1 Hz, 1H,
◦
CHarom). 13C-NMR (CDCl3, 75 MHz, 25 C):
δ (ppm) 14.0, 27.8, 60.5, 61.1, 69.2, 83.4, 114.4, 115.3, 125.2,

Molecules 2018, 23, 438
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125.8, 129.3, 131.3, 150.5, 166.4, 170.8. HRMS: exact mass calculated for (C17H19NNaO6) requires m/z
356,1110, found m/z 356,1112. Chiralphase HPLC analysis: [Daicel Chiralpack IC 5 = 254 nm,
µ, λ
nHexane/EtOH = 9/1, flow rate 1.0 mL/min]: Tmajor = 6.80 min, Tminor = 5.75 min er = 96:4. [α]D = +27
(c = 0.0103 g/cm3 in CHCl3).
4. Conclusions
In summary, we have investigated the organocatalytic epoxidation of α-ylidene oxindoles in
depth, highlighting the strong and weak features of the overall procedure. The above depicted findings
clearly underline the importance of installing a robust H-bond network that mainly involves the
catalyst and the substrate. Specifically, although a few organocatalysts having manifold scaffolds and
diverse substituents have been tested, the simplest α,α-diphenylprolinol 1 results in being the most
suitable structure to successfully perform the devised nucleophilic epoxidation in terms of yield, time
and enantioselectivity.
Additionally, the extension of the substrate scope proves that the nucleophile attack on the
electrophilic center (Cβ) only slightly endures the replacement of the EWG on the exocyclic double
bond, while it is dramatically affected by the substitution pattern on the amidic moiety: (i) noticeable
is the presence of the free NH function that makes the Si-face approach of the oxidizing agent
less-hindered, and therefore preferential; (ii) the effect of the tert–butyloxycarbonyl protecting
group able to induce excellent levels of stereoselectivity is also remarkable. Such unexpected
findings complement our efforts to undertake supplementary mechanistic studies and establish
additional improvements to the developed protocol, which not only should lead to a higher value
of enantioselectivity, but also could furnish the desired spiroepoxyoxindoles bearing a quaternary
stereogenic center with variable stereochemistry by simply modifying the nitrogen-protecting group.
Supplementary Materials: The following are available online.
Acknowledgments: Tecla Gasperi, Martina Miceli, Chiara Palumbo, Andrea Mazziotta, Elia Roma, and
Eleonora Tosi are deeply thankful to Augusto Gambacorta and Maria A. Loreto for their preciuos advice during
every step of their research. Additionally, Tecla Gasperi, Martina Miceli, Elia Roma, and Eleonora Tosi gratefully
acknowledge Dipartimento di Scienze and Sezione di Nanoscienze e Nanotecnologie (Università di Roma Tre,
Roma, Italy) for the financial support.
Author Contributions: Tecla Gasperi, Martina Miceli, Chiara Palumbo, and Andrea Mazziotta conceived,
designed and performed the experiments; Giuseppe Mazzeo, Giovanna Longhi, Sergio Abbate performed the
calculation and analyzed the data for the configuration assignment; Tecla Gasperi mainly wrote the paper with
the help of Elia Roma and Eleonora Tosi; Paolo Lupattelli performed the ORD measurements.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds trans-12a–h, and 12m–u are available from the authors.
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