Rearrangement of Threonine- And Serine-Based N-(3-Phenylprop-2-yn-1-yl) Sulfonamides Yields Chiral Pyrrolidin-3-ones

Article abstract of DOI:10.1021/acs.joc.9b02932

N-(3-Phenylprop-2-yn-1-yl)-sulfonamides derived from serine and threonine were synthesized using solid-phase synthesis and subjected to reaction with trimethylsilyl trifluoromethanesulfonate (TMSOTf). In contrast to the previously reported formation of 1,

Full text of DOI:10.1021/acs.joc.9b02932

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Article
Rearrangement of Threonine and Serine-Based N-(3-
Phenylprop-2-yn-1-yl) Sulfonamides Yields Chiral Pyrrolidin-3-ones
Petra Králová, Michal Malo#, Jiri Pospisil, and Miroslav Soural
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02932 • Publication Date (Web): 06 Dec 2019
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Rearrangement of Threonine and Serine-Based N-(3-Phenylprop-2-yn-1-yl)
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Sulfonamides Yields Chiral Pyrrolidin-3-ones
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Petra Králová,a Michal Maloň,b Jiří Pospíšila,c and Miroslav Sourala,d*
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aDepartment of Organic Chemistry, Faculty of Science, Palacký University, Tr. 17. listopadu 12, 771 46 Olomouc,
Czech Republic
bJEOL (U.K.) Ltd., JEOL House, Silver Court, Watchmead, Welwyn Garden City, Hertfordshire AL7 1LT, United
Kingdom
cLaboratory of Growth Regulators, The Czech Academy of Sciences, Institute of Experimental Botany & Palacký
University, Šlechtitelu 27, 78371 Olomouc, Czech Republic
dInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University,
Hněvotínská 5, 779 00 Olomouc, Czech Republic
*Corresponding author. E-mail: miroslav.soural@upol.cz
TOC
trans
annular
addition
R4
R1 R2
R2 OH
O
OTf
R2
TMSOTf
CH2Cl2
O
HR1
R4
O
R1
N
pinacol
like
rearragement
[1,2]-shift
N
TMS
N
O O2S
R4
O2S
R3
O
R3
O2S
R3
R1 = O, NH
R2 = H, Me
10 examples given
yields 14-71%
R3 = Me, 2/4-NO2Ph, 4-MePh
R4 = H, Me, Ph, 4-MePh, 4-MeOPh, 4-CF3Ph
Keywords: rearrangement, hydroalkoxylation, threonine pyrrolidine
Abstract
N-(3-phenylprop-2-yn-1-yl)-sulfonamides derived from serine and threonine were synthesized
using solid-phase synthesis and subjected to reaction with trimethylsilyl trifluoro-methanesulfonate
(TMSOTf). In contrast to the previously reported formation of 1,4-oxazepanes, this reaction
afforded pyrrolidin-3-ones. A mechanistic explanation for this unexpected outcome is proposed,
and the limitations and scope of the rearrangement are outlined.
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Introduction
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N-Substituted 2/4-nitrobenzenesulfonamides are excellent synthetic intermediates for preparing
diverse nitrogenous heterocycles.1,2 Recently, substantial attention has been paid to N-phenacyl-
2/4-nitrobenzenesulfonamides derived from natural amino acids, especially serine and threonine,
as the cyclization of these compounds stereoselectively yields various chiral morpholine
derivatives.3,4 Based on the synthetic potential of internal alkynols in the field of catalyzed
intramolecular hydroalkoxylations,5–10 we switched from N-phenacyl to N-(3-phenylprop-2-yn-1-yl)
analogues and applied the previously reported reaction11 to potentially synthesize functionalized
1,4-oxazepanes amenable to further diversification (Scheme 1).
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Scheme 1. Different reactivity of N-(3-phenylprop-2-yn-1-yl)sulfonamides
Previous work:
“endo-dig” hydroalkoxylation-reduction to 1,4-oxazepanes
Ph
H
Ph
R2
R1
R2 OH
O
R2
R1
O
TMSOTf
Et3SiH
R1
N
N
N
Ts
Ph
Ts
Ts
This work:
hydroalkoxylation and pinacol-like rearragement to pyrrolidin-3-ones
O
R2
O
R2 OH
TMSOTf
(Et3SiH)
R4
OTf
R4
O
HO
N
N
SO2
O
SO2
R3
R3
H
R4
R4
OTf
R2
TMS
R2
O
R2 OH
O
R4
O
O
O
O
TMS
N
R3
OTf
TMS
N
R3
OTf
.
N
R3
O
O
Scheme 4
For full reaction mechanism see
Surprisingly, completely different reaction outcomes were obtained, and the isolated compounds
were identified as pyrrolidin-3-one derivatives. Inspired by this unusual result and, considering the
limited number of synthetic routes leading to chiral pyrrolidin-3-ones despite their occurrence in
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biologically active compounds,12–17 we decided to explore the limitations and scope of the
rearrangement and provide an insight to reaction mechanism.
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Results and Discussion
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By analogy to previously reported N-phenacyl analogues,3 corresponding phenylalkynol 3a was
prepared using a convenient solid-phase synthesis process. Briefly, Wang resin was acylated with
Fmoc-Thr-(OtBu)-OH, subjected to Fmoc-cleavage, and reacted with 4-nitrobenzenesulfonyl
chloride (4-NsCl). Resulting sulfonamide 1a was alkylated with 3-phenylprop-2-yn-1-ol using a
Mitsunobu alkylation. Cleavage from resin 2a with trifluoroacetic acid (TFA) was followed by
spontaneous cleavage of the t-butyl ether. Intermediate 3a was obtained in excellent crude purity
(≥ 90%, calculated from LC-UV traces) and prior to the final transformation, it was purified by
semipreparative HPLC and fully characterized (Scheme 2). Even with the efficacy of solid-phase
synthesis, consisting particularly in the rapid production of compounds via multi-step reaction
sequences with minimal hands-on-time,18 it should be noted that the corresponding intermediate
3a can also be easily obtained using traditional solution-phase synthesis starting from threonine
with a suitably protected carboxylic group. Intermediate 3a was reacted with TMSOTf and Et3SiH
to obtain 1,4-oxazepane 5a. We applied previously reported conditions11 (i.e., 2 equiv TMSOTf and
1 equiv Et3SiH in anhydrous CH2Cl2) and generated a highly pure compound (≥90%, LC-UV-MS
traces), with a molecular mass corresponding to expected product 5a. However, its 1H and 13C{1H}
NMR spectra were not consistent with the structure of 5a. For example, the 13C{1H} signal at 210.6
ppm indicating a carbonyl group could not be assigned to any carbon atom in 5a. For this reason,
a set of 1D and 2D NMR spectra, including 1H-15N HMBC, was collected and carefully analyzed.
Scheme 2. Synthesis of starting material 3a and its TMSOTf-mediated rearrangement to 4aa
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tBu
tBu
4
5
6
7
O
iv
O
i-iii
OH
O
O
L
L
NH
L
N
See ref. 3
Wang resin
O
1a
4-Ns
O
4-Ns
Ph
2a
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OH
O
O
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v
vi
HO
Ph
O
N
N
O
4-Ns
Ph
4-Ns
4a
3a
(71%)
vi
HOOC
4-Ns
O
Ph
N
5a
aReagents and conditions: (i) Fmoc-Thr(OtBu)OH, 1-hydroxybenzotriazole (HOBt), 4-(dimethylamino)pyridine
(DMAP), diisopropylcarbodiimide (DIC), dimethylformamide (DMF), CH2Cl2, 24 h, rt; (ii) 50% piperidine/DMF, 30
min, rt; (iii) 4-NsCl, 2,6-lutidine, CH2Cl2, 24 h, rt; (iv) 3-phenylprop-2-yn-1-ol, triphenylphosphine (TPP), diisopropyl
azodicarboxylate (DIAD), tetrahydrofurane (THF), 24 h, rt; (v) 50% trifluoroacetic acid (TFA)/CH2Cl2, 1 h, rt; (vi)
TMSOTf/Et3SiH (2:1), anhydrous CH2Cl2, 24 h, 0 °C.
The structure of 4a was determined by means of 1H, 13C{1H}, APT, 1H-1H COSY, 1H-1H NOESY,
1
1
1
1H-13C{1H} HSQC, H-13C{1H} HMQC, H-13C{1H} HMBC and H-15N HMBC. See Supplementary
Information for the complete set of 1D and 2D spectra. Figure 1 summarizes H-13C{1H} and H-
15N long-range correlations. We identified benzoyl, 4-Nosyl, pyrollidin-3-onyl and CH3-CH-O
moieties. 1H-13C{1H} HMBC spectrum provided H13-C14 correlation. At the same time, H13 was also
correlated to C3 and N1 of pyrollidin-3-one moiety. Although, 1H-15N four-bond correlation was not
observed between 4-Nosyl protons and N1, the scaffold structure was confirmed by NOE
1
1
correlations between 4-Nosyl protons and protons H2, Ha , Hb , Ha , Hb5 and H21 (see Supporting
Information for more details). NOE correlations were also observed between benzoyl protons and
protons H2 and H21 (Figure 1).
4
4
5
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21
O
O
O
Me
Me
O
H
H
5
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3
Hb
2
Hb
Ha
13
14
Ph
O
Ph
O
Ha
Hb
H
H
4
1
N
N
9
Hb
5
4-Ns
4-Ns
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Ha
1H-15N{1H} HMBC correlations
Ha
1H-13C{1H} HMBC correlations
Figure 1. Selected correlations for 2D NMR analysis of rearrangement product 4a (all correlations
are displayed in Supporting Information, Figures S48 and S49).
The reaction conditions were further modified to investigate their impact on the reaction outcome
(see Supporting Information for details, Table S3): (i) the same reagents in the same ratio (2 equiv
TMSOTf and 1 equiv Et3SiH) were added in the opposite order and gave the same results; (ii) same
reagents in the opposite ratio (1 equiv TMSOTf and 2 equiv Et3SiH) led only to a mixture of the
corresponding enol triflate and the reduced analogues of compound 3a with double (at room
temperature) or single (at 0 °C) bonds (Scheme 3); (iii) the same reagents in an equimolar ratio (1
equiv TMSOTf and 1 equiv Et3SiH) again yielded a mixture of enol triflate, alkene and alkane
derivatives; (iv) reaction with 2 equiv TMSOTf gave solely compound 4a. The last experiment
shows that Et3SiH is not involved in the conversion of 3a to 4a; thus, it was omitted from the reaction
mixture in further studies. Finally, we tested the reaction of compound 3a with TiCl4 and BF3·OEt2
as the alternative Lewis acids. Treatment with TiCl4 did not provide the rearrangement product
while the reaction with BF3·OEt2 led to the formation of compound 4a; however, the reaction was
slower compared to TMSOTf.
Scheme 3. Outcomes using the conditions (ii) and (iii) (for more details see in the text)
OH
1. TMSOTf
(1 equiv)
2. Et3SiH
(1 or 2 equiv)
HO
N
Ph
Ph
OH
OH
Ph
OTf
O
O
4-Ns
HO
+
HO
N
4-Ns
3a
or
N
O
Ph
OH
O
4-Ns
HO
N
4-Ns
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The structure-reactivity relationship of the rearrangement was further studied using a series of
variously substituted starting materials (Table 1). First, we used different sulfonyl chlorides (2-NsCl,
mesyl chloride and tosyl chloride) to evaluate the effect of the R3 group (intermediates 3a-d).
Similarly, different phenylalkynols bearing electron-donating (Me and OMe) or electron-withdrawing
(CF3) substituents were used, and these reactants resulted in different R4 substituents
(intermediates 3e-g). 2-Butynol (intermediate 3h) and propargyl alcohol (intermediate 3i) were also
included as alternatives to phenylalkynols. Fmoc-Thr(OtBu)-OH was replaced with Fmoc-
Ser(OtBu)-OH to modify the R2 position (intermediate 3j). Finally, Rink amide resin was used
instead of Wang resin, and this afforded carboxamide intermediate 3k. Table 1 shows the observed
scope and limitations of the transformation to products 4.
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Table 1: Rearrangement of 3 to 4: Limitations and scopea-e
R2 XH
R1 R2
X
O
5 steps
TMSOTf (2.0 equiv)
CH2Cl2, time, temp
R1
R4
OH
L
H
N
R3
conditionsa
N
R4
O
Resin
R3
4
3
crude
final
cmpd
time temp
[h] [°C]
yield
[%]c
entry
X
R1
R2
R3
R4
purity
[%]b
96
1
2
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4
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9
4a
4b
4c
4d
4e
4f
4g
4h
4i
O
O
O
O
O
O
O
O
O
O
O
S
O
O
O
O
O
O
O
O
O
O
Me 4-Ns
Me 2-Ns
Me
Me
Me 4-Ns
Me 4-Ns 4-MeOPh
Me 4-Ns 4-CF3Ph
Me 4-Ns
Me 4-Ns
H
Ph
Ph
Ph
Ph
24
24
24
24
24
24
24
72
72
72
72
24
23
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23
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23
40
23
23
23
23
23
71
41
40
50
30
42
18
33
NId
14
14
96
92
80
76
81
56
75
43
Ms
Ts
4-MePh
Me
H
Ph
Ph
Ph
10
11
12
4j
4k
4l
4-Ns
51
60
NH Me 4-Ns
4-Ns
O
H
NPe NPe
aIn analogy with ref. 3 and Scheme 2. For detailed reaction conditions see Supporting Information. bOverall crude
purity determined by HPLC after the entire reaction sequence (6 steps) prior to final purification. cIsolated overall (6
d
steps) yield calculated from the loading of the starting resin. NI = not isolated, compound proved to be unstable
during the HPLC purification process. eNP = not prepared.
It was observed that the reaction times and crude purities depended strongly on the starting
materials. As expected, the electron-withdrawing group substituted arylalkyne 3g (CF3) slowed the
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conversion and a significant amount of the corresponding enol triflate intermediate was detected
after 24 h. In this case, a higher temperature (40 °C) was necessary to push the conversion of the
starting material to the final product 4g. Longer reaction times were required when alkyl (3h) or
hydrogen-bearing (3i) alkynes were used. Similarly, serine-based (3j) rearrangement precursor
yielded the desired product 4j in 48 h and 14% overall yield.19 Replacement of carboxylic acid with
the corresponding amide also led to the slow transformation. Finally, the rearrangement of amide
3k to imidoester 4k (carboxylic acid replaced with the amide) was also rather sluggish and yielded
the desired product in 14% overall yield. Typically, in these cases the corresponding enol triflates
and/or ketones were still detected in the reaction mixtures (9-28%, calculated from their LC-UV-MS
traces). The isolated yields were somewhat compromised in several cases, which was caused by
difficult chromatography and careful removal of impurities with similar retention times to products.
Finally, to further extend applicability of the disclosed reaction sequence, the sulfanyl analogue of
3a was prepared from protected cysteine. However, no traces of the desired pyrrolidinone 4l were
detected.
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As previously reported,11 the reaction of similar intermediates promoted by TMSOTf proceeds
via an intramolecular hydroalkoxylation to the 1,4-oxazepines (Scheme 1), and in the presence of
an external nucleophile (such as Et3SiH), it gives the corresponding 1,4-oxazepanes. In the case
of intermediates 3, we expected the similar reaction course, but the reaction outcome suggested
that at the 1,4-oxazepine stage, the carboxylate/carboxamide as an internal nucleophile added in
a trans-annular manner. Competitive experiments with Et3SiH indicated that the intramolecular
addition is favored over the intermolecular one. The following pinacol-like rearrangement and ring
opening of the cyclic hemiacetal resulted in the formation of the pyrrolidin-3-one scaffold. Although
careful monitoring of the reaction mixture was performed using LC-UV-MS, we were able to detect
only rearranged products 4 along with the corresponding enol triflates as presumed reaction
intermediates. We have tried to support the proposed reaction mechanism by several control
reactions (Scheme 4, Eq. 1 and 2). First, the reaction substrate without the phenylprop-2-yn-1-yl
moiety was treated with TMSOTf (Eq. 2). In this case only intermolecular esterification20 occurred.
Next, an intermediate without the hydroxy group (synthesized from Fmoc-Ala-OH) was reacted with
TMSOTf (Eq. 1). In this case only the enol triflate derivative along with the corresponding ketone
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was produced. These results strongly suggest that both, the hydroxy group and alkynyl moiety are
mandatory to trigger the rearrangement.
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Scheme 4: Control experiments designed to identify essential functional groups of the molecule;
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products determined using LC-UV-MS traces
(Eq. 1)
TMSOTf
(2.0 equiv)
Me
O
Me
Me
OTf
Ph
HO
HO
HO
+
N
Ph
N
N
CH2Cl2, rt
O
4-Ns
O
4-Ns
Ph
O
4-Ns
(Eq. 2)
Me
OH
TMSOTf
OH
Me
O
Me
(2.0 equiv)
HO
O
O
O
OH
4-Ns
NH
CH2Cl2, rt
HN
HN
4-Ns
4-Ns
In addition, reaction shown in Scheme 4, Eq. 1, supports our reaction mechanism since the
hydroxy group is not required to form the enol triflate intermediate C. Our results also suggested
that even though in the case of TMSOTf the reaction proceeds via enol triflate B, the key
intermediate for the cyclization and the subsequent rearrangement is the oxonium intermediate F
(Scheme 5). Our speculation is based on the previously observed BF3·OEt2 promoted
rearrangement of 3a to 4a. Under such conditions, no enol triflate intermediate B can be formed.
Scheme 5: Plausible mechanism of the rearrangement
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O
Me
OH
Lewis acid (2.0 equiv)
CH2Cl2, rt
Ph
O
N
4-Ns
HOOC
N
4-Ns
3a
O
Ph
4a
7
8
9
TMSOTf - promoted
TMS-OTf
Me
Ph
O
TMS
TMS-OTf
O
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H-OTf
O
OH
N
OTf
N
OTf
Ph
I
O
Me
4-Ns
TMS
O 4-Ns
A
H
pinacol-like rearrangement
Ph
Ph
TMS O
Me
O
O
Me
OH
Me
TMS
OTf
O
O
Ph
OTf
O
O
N
N
4-Ns
TMS
N
H
4-Ns
O 4-Ns
B
TMS-OTf
TMS-OTf
H-OTf
Ph
Ph
O
TMS
O
Me
O
Me
O
N
4-Ns
O
G
TMS
TMS
N
OTf
O 4-Ns
C
H
TMS-OTf
TMS
Ph
OTf
Ph
TMS
O
TfO
OTf
Ph
O
O
O
Tf
Me
Me
Me
O
O
O
TMS
N
TMS
N
N
O
O
O
4-Ns
4-Ns
O 4-Ns
H
Tf
F
E
D
Me
OH
BF3.OEt2 - promoted
HOOC
N
H
Ph
4-Ns
Ph
O
Me
3a
H
BF3
O
F3B
N
4-Ns
O
L
Me
O
N
Me
O
H
H
HH
O
O
F3B
F3B
N
O 4-Ns
Ph
O 4-Ns
Ph
K
J
H
TiCl4 - proposed stable intermediate
Expected amide-based intermediate F
Ph
Cl
O
Me
O
Me
Ti
O
OTf
Cl
O
N
TMS
N
M
N
O 4-Ns
Ph
NH
4-Ns
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Taking into account all these observations, we believe that the first step of the TMSOTf-
promoted rearrangement is the reaction between TMSOTf and carboxylic acid of 3a. In situ
generated triflic acid (TfOH) then adds to alkyne to yield the enol triflate intermediate B.21 The
second equivalent of TMSOTf then reacts with the hydroxy group of B to yield the silylated alcohol
C and another equivalent of TfOH. TfOH-mediated enol triflate hydrolysis yields the intermediate D
that further undergoes the intramolecular 7-exo-trig cyclization to yield, upon TMS group release,
the key oxonium intermediate F. Trans-annular cyclization of carboxylic acid to oxonium yields
strained acetal intermediate G that is well organized for Lewis acid promoted C-C bond
fragmentation reaction. Finally, rearranged hemiacetal intermediate H opens up to yield the desired
product 4a.
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Similarly, the oxonium intermediate F can be formed if BF3 is used to trigger the reaction. We
expect that in the first step, the BF3 reacts with the carboxylic acid of 3a.22 Generated intermediate
J then undergoes proton-activated intramolecular 7-endo-dig cyclization of hydroxy group oxygen
to alkyne. Finally, the proton transfer generates the key oxonium intermediate F. Observed
incapacity of TiCl4 to promote the rearrangement of 3a can be rationalized by the intermediate M
formation (hydroxy group is not available for intramolecular cyclization reaction). Proposed reaction
mechanism also rationalizes longer reaction times observed during the formation of compounds
4g-i bearing alkynes substituted with electron-deficient aryl group or with alkyl (lower stabilization
of + Markovnikov addition-type intermediate). Similarly, trans-annular cyclization of the
corresponding TMS-amide intermediate N is slower than in the case of the corresponding acid due
to lower nucleophilicity of the nitrogen atom in N.
Conclusion
To summarize, we have discovered an unexpected rearrangement of N-(3-phenylprop-2-yn-1-
yl) sulfonamides that yielded novel chiral derivatives of pyrrolidin-3-ones. The starting materials are
readily available by either solution-phase or solid-phase synthesis and furnish the target
compounds mostly in good or acceptable crude purities and yields. The reported reaction is broadly
applicable in the case of the pyrrolidine scaffold and therefore can be utilized for the simple
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preparation of diversely substituted products. Its application to more complex compounds and
diverse starting materials can be further studied in the future.
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Experimental section
General Information. Solvents and chemicals were purchased from Sigma-Aldrich (Milwaukee,
WI), Acros Organic (Geel, Belgium) and Fluorochem (Hadfield, United Kingdom). Wang resin (100-
200 mesh, 1% DVB, 1.4 mmol/g) and Rink resin (100-200 mesh, 1% DVB, 0.6 mmol/g) were
obtained from AAPPTec (Louisville, KY). Solid-phase synthesis was carried out in plastic reaction
vessels (syringes, each equipped with a porous disk) using a manually operated synthesizer
(Torviq, Niles, MI). All reactions were carried out at ambient temperature (23 °C) unless stated
otherwise; when the reactions required a heating at higher temperature, the heating was performed
in oil bath at specific temperature (see for each derivative separately below in the text). Synthesis
of N-sulfonamides (1a-l) was performed according to previously reported procedure.3 The LC-MS
analyses were carried out on UHPLC-MS system consisting of UHPLC chromatograph Acquity with
photodiode array detector and single quadrupole mass spectrometer (Waters), using X-Select C18
column with the mobile phase consisting of 10 mM ammonium acetate (AmAc) in H2O and MeCN.
The ESI source operated at discharge current of 5 μA, vaporizer temperature of 350 °C and
º
capillary temperature of 200 C. For the LC/MS analysis, a sample of resin (~5 mg) was treated
with TFA in DCM, the cleavage cocktail was evaporated under a stream of nitrogen, and cleaved
compounds extracted into MeCN (1 mL). Purification was carried out on C18 reverse phase semi
preparative HPLC chromatography with the gradient of 10 mM aqueous AmAc and MeCN, flow
rate 15 mL/min or by normal phase by silica gel chromatography. Residual solvents (H2O and
ammonium acetate buffer) was lyophilized by the ScanVac Coolsafe 110-4 working at -110 °C. All
NMR spectra were performed with using ECA400II or ECX500 spectrometers (JEOL RESONANCE,
Tokyo, Japan) at magnetic field strength of 9.39 T or 11.75 T corresponding to 1H, 13C{1H} and 15
N
resonance frequencies of 399.78 MHz or 500.16 MHz, 100.53 MHz or 125.77 MHz and 50.7 MHz
at 27 ºC. Chemical shifts () are reported in parts per million (ppm) and coupling constants (J) are
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reported in Hertz (Hz). The signals of MeCN-d3, CDCl3 and MeOH-d4 were set at 1.94 ppm, 7.26
1
ppm and 3.31 ppm, respectively, in H NMR spectra and at 118.26 ppm, 77.36 ppm and 49.15
ppm, respectively, in 13C{1H} NMR spectra. 15N chemical shifts were referenced to external 90%
formamide in DMSO-d6 (112.00 ppm).23 The assignment of 1H, 13C{1H} and 15N signals was done
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1
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1
1
1
by 13C{1H} APT, H-1H COSY, H-1H NOESY, H-13C{1H} HSQC, H-13C{1H} HMQC, H-13C{1H}
HMBC and H-15N HMBC. Abbreviations in NMR spectra: br. s – broad singlet, s – singlet, d –
1
doublet, dd – doublet of doublets, ddd – doublet of doublets of doublets, dddd – doublet of doublets
of doublets of doublets, t – triplet, m – multiplet. HRMS analysis was performed using LC-MS
(Dionex Ultimate 3000) with Orbitrap Elite high-resolution mass spectrometer (Thermo Exactive
plus) operating at positive full scan mode (120 000 FWMH) in the range of 100-1000 m/z with
electrospray ionization working at 150 °C and the source voltage of 3.6 kV. The acquired data were
internally calibrated with phthalate as a contaminant in MeOH (m/z 297.15909). IR spectra were
measured by DRIFT (Diffuse Reflectance Infrared Fourier Transform) on a Thermo Nicolet
AVATAR 370 FTIR spectrometer. Absorbance peaks (wavenumbers) are reported in reciprocal
centimeters (cm-1) and transmittances (T) are reported in percentages (%). Specific optical
rotations were measured on Automatic Compact Polarimeter POL-1/2 (ATAGO, Japan) with LED
Light Source and 589 nm interference filter at 24 °C. The length of cuvette was 2 cm and specific
[훼]T
optical rotations are reported as follows: D, concentration (g/ml) and solvent. Melting points were
measured by Boetius stage apparatus (WEB Analytik, Dresden, Germany) and they are reported
in Celsius degrees (°C).
1
1
General method for calculation of yields using H NMR: H NMR spectra of external
standard at three different concentration were measured. In each spectrum, solvent signal was
integrated followed by the integration of selected HAr signal of external standard. Ratios of
solvent/standard signal areas along with known quantity of standard were used to construct a
1
calibration curve. Then, H NMR spectra of studied sample were measured and the ratio of
solvent/sample (selected HAr signal) areas was determined. Using the calibration curve, the
quantity of compound in the sample was calculated.
General procedure for Sonogashira coupling to prepare alkylating agents. Pd(PPh3)2Cl2
and CuI were suspended in degassed TEA under nitrogen. Then aryl iodide was added followed
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by propargyl alcohol and the reaction was stirred intensively for 5-22 h at room temperature for
derivatives II-III or heated at 60 °C in oil bath for 22 h for derivative IV. Then the reaction mixture
was filtrated over Celite, washed with fresh TEA and purified by silica gel chromatography in
EtOAc/hexane.
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3-(p-tolyl)prop-2-yn-1-ol II. According to the general procedure, Pd(PPh3)2Cl2 (483 mg, 0.69
mmol, 1 mol%) and CuI (262 mg, 1.38 mmol, 2 mol%) were suspended in degassed TEA (325
mL) under nitrogen. Then 4-iodotoluene (15.0 g, 68.80 mmol, 1.0 equiv) was added followed by
propargyl alcohol (4.4 mL, 75.68 mmol, 1.1 equiv) and the reaction was stirred intensively for 5 h
at room temperature. Then the reaction mixture was filtrated over Celite, washed with fresh TEA
and purified by silica gel chromatography in EtOAc/hexane (3/7; v/v), Rf = 0.5, yielded pale brown
solid (5.2 g, 35.616 mmol, 51%). HPLC purity 99%. 1H NMR (500 MHz, CDCl3):  = 7.33 (br. d, J =
8.0 Hz, 2H), 7.12 (br. d, J = 8.0 Hz, 2H), 4.49 (s, 2H), 2.35 (s, 3H), 1.79 (br. s, 1H). 13C{1H} NMR
(126 MHz, CDCl3):  = 139.0, 131.9, 129.4, 119.8, 86.9, 86.2, 52.0, 21.8. HRMS (ESI-TOF, pos.):
m/z calcd for C10H11O [M+H]+ 147.0804, found 147.0805. Other spectral and physical properties
(mp 33.0–34.0 °C and IR data) concur with published data.24
3-(4-methoxyphenyl)prop-2-yn-1-ol III. According to the general procedure, Pd(PPh3)2Cl2 (150
mg, 0.21 mmol, 1 mol%) and CuI (81 mg, 0.42 mmol, 2 mol%) were suspended in degassed TEA
(101 mL) under nitrogen. Then 4-iodoanisole (5.0 g, 21.4 mmol, 1.0 equiv) was added followed by
propargyl alcohol (1.4 mL, 23.50 mmol, 1.1 equiv) and the reaction was stirred intensively for 22 h
at room temperature. Then the reaction mixture was filtrated over Celite, washed with fresh TEA
and purified by silica gel chromatography in EtOAc/hexane (3/7; v/v), Rf = 0.4, yielded pale brown
solid (3.1 g, 19.136 mmol, 89%). HPLC purity 99%. 1H NMR (500 MHz, CDCl3):  = 7.37 (br. d, J =
6.9 Hz, 2H), 6.83 (br. d, J = 6.9 Hz, 2H), 4.48 (s, 2H), 3.80 (s, 3H), 1.85 (br. s, 1H). 13C{1H} NMR
(126 MHz, CDCl3):  = 160.1, 133.5, 115.0, 114.3, 86.2, 86.0, 55.6, 52.0. HRMS (ESI-TOF, pos.):
m/z calcd for C10H11O2 [M+H]+ 163.0754, found 163.0755. Other spectral and physical properties
(mp 63.1–63.5 °C and IR data) concur with published data.25
3-(4-trifluoromethyl)phenyl)prop-2-yn-1-ol IV. According to the general procedure, Pd(PPh3)2Cl2
(129 mg, 0.18 mmol, 1 mol%) and CuI (70 mg, 0.36 mmol, 2 mol%) were suspended in degassed
TEA (86.4 mL) under nitrogen. Then 4-iodobenzotrifluoride (2.7 mL, 18.38 mmol, 1.0 equiv) was
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added followed by propargyl alcohol (1.2 mL, 20.21 mmol, 1.1 equiv) and the reaction was stirred
intensively for 22 h at 60 °C in oil bath. Then the reaction mixture was filtrated over Celite, washed
with fresh TEA and purified by silica gel chromatography in EtOAc/hexane (3/7; v/v), Rf = 0.5,
1
yielded waxy yellow solid (3.56 g, 17.800 mmol, 97%). HPLC purity 99%. H NMR (500 MHz,
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CDCl3):  = 7.57 (br. d, J = 8.4 Hz, 2H), 7.53 (br. d, J = 8.4 Hz, 2H), 4.52 (s, 2H), 1.80 (br. s, 1H).
13C{1H} NMR (126 MHz, CDCl3):  = 132.3, 130.6 (q, J = 32.8 Hz), 126.7, 125.6 (q, J = 3.6 Hz),
124.2 (q, J = 271.8 Hz), 90.0, 84.7, 51.9. HRMS (ESI-TOF, neg.): m/z calcd for C10H6F3O [M-H]-
199.0365, found 199.0359. Other spectral and physical properties (mp 40.0–41.1 °C and IR data)
concur with published data.24
General procedure for the Mitsunobu alkylation 2a-l. Resin 1a-l (500 mg) was washed three
times with DCM, anhydrous DMF and anhydrous THF, and solution of alcohol (3.00 mmol) and
triphenylphosphine (TPP, 787 mg, 3.00 mmol) in anhydrous THF (5 mL) was added. The syringe
with resin and reaction solution was connected by a plastic clutch with the second syringe
containing a solution of DIAD (591 μL, 3.00 mmol) in anhydrous THF (5 mL). The syringes were
cooled to -20 °C, their content was mixed together and shaken for 24 h at room temperature. The
resulting resin was washed three times with anhydrous THF and DCM.
Cleavage from the resin and removal of the tBu protecting group 3a-l. The resin 2a-l (500
mg) was shaken in TFA/anhydrous DCM (5 mL, 50%) for 1 h at room temperature. Then the resin
was washed three times with fresh cleavage cocktail (5 mL) and combined washes were
evaporated using a stream of nitrogen. The crude product was purified by reverse-phase
semipreparative HPLC or by silica gel chromatography (see Supporting Information, Table S1).
(-)-N-((4-nitrophenyl)sulfonyl)-N-(3-phenylprop-2-yn-1-yl)-(2S,3R)-2-amino-3-hydroxybutyric
acid 3a. Pale orange amorphous solid (46.8 mg, 0.112 mmol, 82%). The crude product was purified
by silica gel chromatography in DCM/MeOH (9/1; v/v) + 1% HCOOH, Rf = 0.6. HPLC purity 98%.
1
Cleaved from 325 mg of resin 2a (0.420 mmol/g, 0.137 mmol of substrate). H NMR (400 MHz,
MeCN-d3):  = 8.22 (d, J = 9.2 Hz, 2H), 8.12 (d, J = 9.2 Hz, 2H), 7.24-7.34 (m, 5H), 4.58 (s, 2H),
4.44-4.47 (m, 2H), 3.91 (br. s, 1H), 1.24 (d, J = 6.0 Hz, 3H). 13C{1H} NMR (101 MHz, MeCN-d3):
 = 172.6, 151.0, 146.9, 132.3, 130.0, 129.5, 129.4, 124.9, 123.4, 87.0, 84.7, 68.4, 66.8, 38.1, 20.6.
HRMS (ESI-TOF, neg.): m/z calcd for C19H17N2O7S [M-H]- 417.0751, found 417.0756. IR
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푣
(DRIFT): = 3528, 3251, 3106, 2979, 2931, 1724, 1685, 1605, 1528, 1442, 1401, 1344, 1308,
[훼]24
−1
1157, 1088, 854, 822 cm .
= -43.2° (c = 0.00110 g/mL, MeCN).
D
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(-)-N-((2-nitrophenyl)sulfonyl)-N-(3-phenylprop-2-yn-1-yl)-(2S,3R)-2-amino-3-hydroxybutyric
acid 3b. White amorphous solid (29.2 mg, 0.070 mmol, 21%). The crude product was purified by
semipreparative HPLC chromatography. HPLC purity 98%. Cleaved from 622 mg of resin 2b (0.524
mmol/g, 0.326 mmol of substrate). 1H NMR (500 MHz, CDCl3):  = 8.24 (d, J = 8.0 Hz, 1H), 7.46-
7.53 (m, 3H), 7.16-7.25 (m, 5H), 5.84 (br. s, 1H), 4.75 (d, J = 18.6 Hz, 1H), 4.67 (d, J = 18.6 Hz,
1H), 4.57-4.58 (m, 1H), 4.50 (d, J = 4.0 Hz, 1H), 1.33 (d, J = 6.0 Hz, 3H). 13C{1H} NMR (126 MHz,
CDCl3):  = 174.9, 148.2, 134.0, 133.6, 132.1, 132.0, 131.8, 128.8, 128.6, 124.4, 122.6, 86.0, 85.3,
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68.7, 67.0, 38.0, 20.2. HRMS (ESI-TOF, neg.): m/z calcd for C19H17N2O7S [M-H]- 417.0751, found
−1
푣
[훼]24
D
417.0759. IR (DRIFT): = 3209, 2979, 1720, 1541, 1346, 1440, 1159, 1124, 756, 691 cm .
= -21.0° (c = 0.00119 g/mL, MeCN).
(-)-N-(methylsulfonyl)-N-(3-phenylprop-2-yn-1-yl)-(2S,3R)-2-amino-3-hydroxybutyric acid 3c.
White amorphous solid (14.7 mg, 0.047 mmol, 12%). The crude product was purified by
semipreparative HPLC chromatography. HPLC purity 99%. Cleaved from 401 mg of resin 2c (0.524
1
mmol/g, 0.210 mmol of substrate). H NMR (400 MHz, CDCl3):  = 7.31-7.33 (m, 2H), 7.17-7.22
(m, 3H), 4.92 (br. s, 1H), 4.56 (d, J = 18.3 Hz, 1H), 4.48 (d, J = 18.3 Hz, 1H), 4.39-4.46 (m, 1H),
4.32 (d, J = 3.8 Hz, 1H), 3.05 (s, 3H), 1.33 (d, J = 6.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3):  =
174.7, 132.0, 129.1, 128.8, 122.4, 85.4, 85.4, 68.0, 66.2, 41.5, 37.2, 20.2. HRMS (ESI-TOF, neg.):
-
푣
m/z calcd for C14H16NO5S [M-H] 310.0744, found 310.0750. IR (DRIFT): = 3521, 3492, 3005,
[훼]24
−1
2253, 2145, 2000, 1749, 1711, 1361, 1421, 1092 cm .
= -87.5° (c = 0.00012 g/mL, MeCN).
D
(-)-N-((2-nitrophenyl)sulfonyl)-N-(3-phenylprop-2-yn-1-yl)-(2S,3R)-2-amino-3-hydroxybutyric
acid 3d. White amorphous solid, 27.1 mg (31%, 0.112 mmol). The crude product was purified by
semipreparative HPLC chromatography. HPLC purity 99%. Cleaved from 435 mg of resin 2d (0.524
mmol/g, 0.228 mmol of substrate). 1H NMR (400 MHz, CDCl3):  = 7.79 (d, J = 8.2 Hz, 2H), 7.15-
7.26 (m, 7H), 5.16 (br. s, 1H), 4.69 (d, J = 18.9 Hz, 1H), 4.54 (d, J = 18.9 Hz, 1H), 4.45 (m, 2H),
2.28 (s, 3H), 1.24 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3):  = 174.3, 144.0, 137.3,
131.9, 129.8, 128.8, 128.5, 128.2, 122.6, 85.8, 85.0, 77.7, 77.4, 77.0, 68.0, 36.6, 22.3, 21.8, 20.0.
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푣
HRMS (ESI-TOF, neg.): m/z calcd for C20H20NO5S [M-H] 386.1057, found 386.1065. IR (DRIFT):
[훼]2D4
= 3508, 3234, 3055, 2980, 2922, 1915, 1704, 1442, 1327, 1152, 1090, 811, 756 cm−1.
-20.2° (c = 0.00104 g/mL, MeCN).
=
9
(-)-N-((4-nitrophenyl)sulfonyl)-N-(3-(4-trifluoromethyl)phenyl)prop-2-yn-1-yl)-(2S,3R)-2-
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amino-3-hydroxybutyric acid 3g. White amorphous solid (70.0 mg, 0.144 mmol, 69%). The crude
product was purified by semipreparative HPLC chromatography. HPLC purity 99%. Cleaved from
482 mg of resin 2g (0.734 mmol/g, 0.354 mmol of substrate). 1H NMR (400 MHz, MeOH-d4):  =
8.27 (d, J = 8.9 Hz, 2H), 8.17 (d, J = 8.9 Hz, 2H), 7.57 (br. d, J = 7.6 Hz, 2H), 7.43 (br. d, J = 7.6
Hz, 2H), 4.72 (d, J = 18.9 Hz, 1H), 4.63 (d, J = 18.9 Hz, 1H), 4.41-4.54 (m, 2H), 1.35 (d, J = 6.0 Hz,
3H). 13C{1H} NMR (126 MHz, MeOH-d4):  = 173.2, 151.5, 147.5, 133.2, 131.2 (q, J = 32.8 Hz),
130.5, 128.4, 126.4 (d, J = 4.2 Hz), 125.5 (q, J = 271.3 Hz), 125.1, 90.0, 83.7, 68.6, 38.2, 21.0.
HRMS (ESI-TOF, pos.): m/z calcd for C20H18F3N2O7S [M+H]+ 487.0781, found 487.0784. IR
푣
(DRIFT): = 3104, 2983, 2936, 2871, 1925, 1726, 1529, 1404, 1348, 1322, 1159, 1123, 1089,
[훼]24
−1
1066, 1016, 843, 740 cm .
= -44.4° (c = 0.00422 g/mL, MeCN).
D
(-)-N-(but-2-yn-1-yl)-N-((4-nitrophenyl)sulfonyl)-(2S,3R)-2-amino-3-hydroxybutyric acid 3h.
Pale yellow-white amorphous solid (85.2 mg, 0.239 mmol, 73%). The crude product was purified
by semipreparative HPLC chromatography. HPLC purity 99%. Cleaved from 498 mg of resin 2h
(0.656 mmol/g, 0.327 mmol of substrate). 1H NMR (400 MHz, MeOH-d4):  = 8.36 (d, J = 9.1 Hz,
2H), 8.16 (d, J = 9.1 Hz, 2H), 4.39-4.45 (m, 1H), 4.28-4.36 (m, 3H), 3.38-3.24 (1H), 1.66 (s, 3H),
1.26 (d, J = 6.0 Hz, 3H). 13C{1H} NMR (400 MHz, MeOH-d4):  = 174.3, 151.5, 147.8, 130.4, 124.9,
81.2, 76.5, 68.4, 37.4, 20.7, 3.2. HRMS (ESI-TOF, pos.): m/z calcd for C14H17N2O7S [M+H]+
푣
357.0751, found 357.0751. IR (DRIFT): = 3106, 3041, 2980, 2935, 2230, 1706, 1527, 1347, 1309,
[훼]24
−1
1089, 830, 759 cm .
= -74.55° (c = 0.00100 g/mL, MeCN).
D
(-)-N-((4-nitrophenyl)sulfonyl)-N-(prop-2-yn-1-yl)-(2S,3R)-2-amino-3-hydroxybutyric acid 3i.
White amorphous solid (28.1 mg, 0.082 mmol, 33%). The crude product was purified by
semipreparative HPLC chromatography. HPLC purity 99%. Cleaved from 400 mg of resin 2i (0.621
mmol/g, 0.248 mmol of substrate). 1H NMR (500 MHz, MeOH-d4):  = 8.35 (d, J = 9.2 Hz, 2H), 8.15
(d, J = 9.2 Hz, 2H), 4.54 (dd, J = 18.6, 2.5 Hz, 1H), 4.32-4.36 (m, 2H), 4.23 (d, J = 5.2 Hz, 1H), 2.55
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(t, J = 2.5 Hz, 1H), 1.28 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (126 MHz, MeOH-d4):  = 175.0, 151.6,
5
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147.4, 130.4, 125.0, 81.8, 73.6, 69.1, 68.8, 37.2, 20.8. HRMS (ESI-TOF, pos.): m/z calcd for
7
8
+
푣
C13H15N2O7S [M+H] 343.0594, found 343.0594. IR (DRIFT): = 3211, 3105, 2970, 2940, 2231,
9
[훼]2D4
1717, 1528, 1433, 1349, 1309, 1158, 1090, 830, 741 cm−1.
MeCN).
= -88.5° (c = 0.00013 g/mL,
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(-)-N-((4-nitrophenyl)sulfonyl)-N-(3-phenylprop-2-yn-1-yl)-(S)-2-amino-3-hydroxybutyric
acid 3j. White amorphous solid (32.4 mg, 0.080 mmol, 30%). The crude product was purified by
semipreparative HPLC chromatography. HPLC purity 98%. Cleaved from 522 mg of resin 2j (0.515
mmol/g, 0.267 mmol of substrate). 1H NMR (500 MHz, MeOH-d4):  = 8.25 (d, J = 8.8 Hz, 2H), 8.21
(d, J = 8.8 Hz, 2H), 7.20-7.29 (m, 5H), 4.63 (d, J = 18.6 Hz, 1H), 4.57 (dd, J = 7.2, 5.8 Hz, 1H), 4.48
(d, J = 18.6 Hz, 1H), 4.08 (dd, J = 11.4, 5.8 Hz, 1H), 3.91 (dd, J = 11.4, 7.2 Hz, 1H). 13C{1H} NMR
(126 MHz, MeOH-d4):  = 175.1, 151.4, 148.3, 132.7, 130.4, 129.6, 129.5, 125.0, 124.1, 86.5, 85.5,
65.6, 63.1, 36.9. HRMS (ESI-TOF, pos.): m/z calcd for C18H17N2O7S [M+H]+ 405.0751, found
−1
푣
[훼]24
D
405.0751. IR (DRIFT): = 3042, 2240, 1738, 1580, 1532, 1349, 1167, 1156, 1058, 816 cm .
= -29.6° (c = 0.00108 g/mL, MeCN).
(-)-(2S,3R)-3-hydroxy-2-((4-nitro-N-(3-phenylprop-2-yn-1-yl)phenyl)sulfonamido)butanamide
3k. White amorphous solid (32.4 mg, 0.078 mmol, 30%). The crude product was purified by
semipreparative HPLC chromatography. HPLC purity 99%. Cleaved from 715 mg of resin 2k (0.359
mmol/g, 0.257 mmol of substrate). 1H NMR (500 MHz, CDCl3):  = 8.24 (d, J = 8.8 Hz, 2H), 8.17
(d, J = 8.8 Hz, 2H), 7.32-7.35 (m, 1H), 7.26-7.29 (m, 2H), 7.14-7.16 (m, 2H), 6.41 (br. s, 1H), 5.69
(br. s, 1H), 4.83 (d, J = 18.9 Hz, 1H), 4.61 (d, J = 18.9 Hz, 1H), 4.42 (qd, J = 6.4 Hz, 1H), 4.25 (d,
J = 7.4 Hz, 1H), 2.58 (br. s, 1H), 1.22 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3):  =
171.1, 150.5, 145.9, 131.7, 129.7, 129.5, 128.9, 124.3, 121.3, 86.5, 83.6, 66.0, 65.6, 35.6, 19.7.
HRMS (ESI-TOF, pos.): m/z calcd for C19H20N3O6S [M+H]+ 418.1067, found 418.1069. IR
푣
(DRIFT): = 3502, 3486, 3386, 3351, 3189, 3115, 3100, 3078, 3038, 3009, 2980, 2940, 2248,
[훼]24
−1
1932, 1878, 1674, 1606, 1530, 1419, 1344, 1309, 1159, 1089, 1026, 855, 821 cm .
(c = 0.00107 g/mL, MeCN).
= -40.2°
D
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General conditions for rearrangement of 3a-l to pyrrolidin-3-ones 4a-l. (a) TMSOTf –
promoted rearrangement (see Supporting Information, Scheme S1, Table S2-3). For derivative
4a: To a stirred solution of 3a (58 mg, 0.14 mmol, 1.0 equiv) in anhydrous DCM (1.5 mL) cooled to
0 °C, TES was slowly added dropwise (22 μL, 0.14 mmol, 1.0 equiv) followed by addition of TMSOTf
(52 μL mg, 0.28 mmol, 2.0 equiv). After 24 h, the reaction mixture was washed with saturated
solution of NaHCO3/DCM (3×5 mL), dried with anhydrous MgSO4, filtrated and evaporated to
dryness. For derivatives 4a-l: To the crude product 3a-l (cleaved from 500 mg resin), TMSOTf (380
μL, 2.10 mmol, 2.0 equiv) in anhydrous DCM (5 mL) was added and shaken for specific reaction
time and temperature (see later in the text and Supporting Information, Table S2). The reaction
mixture was evaporated under a stream of nitrogen, the residual material was dissolved in
anhydrous DCM (5 mL) and washed three times with saturated solution of NaHCO3. The organic
layer was separated, dried with anhydrous MgSO4, evaporated to dryness and the crude samples
were purified by reverse-phase semi preparative HPLC chromatography. (b) BF3.OEt2 – promoted
rearrangement (see Supporting Information, Scheme S1, Table S3): To the crude product 3a
(cleaved from 100 mg resin), BF3.OEt2 (52 μL, 0.42 mmol, 2.0 equiv) in anhydrous DCM (1 mL)
was added and shaken for 2.5 h, 24 h and 48 h at room temperature. The DCM layer was washed
three times with saturated solution of NaHCO3. dried with anhydrous MgSO4, evaporated to
dryness and analyzed by LC-UV-MS. Conclusion: The observed conversion was 10% after 48
hours calculated from the HPLC-UV traces (205-400 nm). (c) TiCl4 – promoted rearrangement
(see Supporting Information, Scheme S1, Table S3): To the crude product 3a (cleaved from 100
mg resin), TiCl4 (46 μL, 0.42 mmol, 2.0 equiv) in anhydrous DCM (1 mL) was added and shaken
for 2.5 h, 24 h and 48 h at room temperature. The sample for HPLC analysis was obtained by the
same procedure as for BF3.OEt2. Conclusion: The desired product was not detected.
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(+)-(13R)-1-((2S)-1-((4-nitrophenyl)sulfonyl)-3-oxopyrrolidin-2-yl)ether benzoate 4a. Reaction
conditions: 24 h at room temperature. White amorphous solid (40.9 mg, 0.098 mmol, 71%). The
crude product was purified by semipreparative HPLC chromatography. HPLC purity 99%. 1H NMR
(500 MHz, MeCN-d3):  = 8.34 (d, J = 8.9 Hz, 2H, HC8,10), 8.10 (d, J = 8.9 Hz, 2H, HC7,11), 7.93-
7.95 (m, 2H, HC16,20), 7.60-7.63 (m, 1H, HC18), 7.47-7.49 (m, 2H, HC17,19), 5.54 (qd, J = 6.5, 4.0
Hz, 1H, HC13), 4.12 (ddd, J = 4.0, 1.0, 1.0 Hz, 1H, HC2), 4.02 (ddd, J = 12.4, 10.0, 3.3 Hz, 1H,
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HaC5), 3.88 (ddd, J = 12.4, 9.5, 7.7 Hz, 1H, HbC5), 2.31 (dddd, J = 18.8, 7.7, 3.3, 1.0 Hz, 1H, HaC4),
2.04 (dddd, J = 18.8, 10.5, 9.5, 1.0 Hz, 1H, HbC4), 1.47 (d, J = 6.5 Hz, 3H, HC21). 13C{1H} NMR
(126 MHz, MeCN-d3):  = 210.6 (C3), 166.3 (C14), 151.8 (C9), 144.0 (C6), 134.4 (C18), 130.7
(C15), 130.3 (C16,20), 129.8 (C7,11), 129.6 (C17,19), 125.9 (C8,10), 72.1 (C13), 67. (C2), 46.5
(C5), 37.1 (C4), 17.1 (C21). 15N NMR (51 MHz, MeCN-d3):  = 102.7 (N1); 366.9 (N12). See
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Supporting Information for detailed assignments. 1H NMR (500 MHz, CDCl3):  = 8.30 (d, J = 8.9
Hz, 2H), 8.04 (d, J = 8.9 Hz, 2H), 7.89-7.91 (m, 2H), 7.54-7.58 (m, 1H), 7.40-7.43 (m, 2H), 5.57
(qd, J = 6.6, 4.6 Hz, 1H), 4.07 (br. d, J = 4.6 Hz, 1H), 4.00 (ddd, J = 12.2, 9.9, 3.8 Hz, 1H), 3.89
(ddd, J = 12.2, 9.1, 7.8 Hz, 1H), 2.42 (ddd, J = 18.6, 7.8, 3.8 Hz, 1H), 2.24 (ddd, J = 18.6, 9.1, 7.8
Hz, 1H), 1.53 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3):  = 208.8, 165.7, 150.7, 143.9,
133.8, 129.9, 129.8, 128.9, 128.9, 125.0, 77.6, 77.4, 77.1, 70.9, 66.4, 45.7, 36.9, 17.3. HRMS (ESI-
-
푣
TOF, neg.): m/z calcd for C19H17N2O7S [M-H] 417.0751, found 417.0757. IR (DRIFT): = 2874,
[훼]24
−1
1940, 1828, 1763, 1714, 1529, 1452, 1347, 1270, 1222, 1164, 1088, 855, 713 cm .
(c = 0.00165 g/mL, MeCN).
= +61.2°
D
(+)-(R)-1-((S)-1-((2-nitrophenyl)sulfonyl)-3-oxopyrrolidin-2-yl)ethyl benzoate 4b. Reaction
conditions: 24 h at room temperature. Pale yellow amorphous solid (47.6 mg, 0.114 mmol, 41%).
1
The crude product was purified by semipreparative HPLC chromatography. HPLC purity 99%. H
NMR (500 MHz, CDCl3):  = 8.14 (dd, J = 8.3, 1.3 Hz, 1H), 7.92-7.93 (m, 2H), 7.67-7.70 (m, 2H),
7.62-7.64 (m, 1H), 7.56 (td, J = 7.6, 1.3 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 5.56 (qd, J = 6.4, 4.0 Hz,
1H), 4.29 (br. d, J = 4.0 Hz, 1H), 4.23 (ddd, J = 12.3, 9.5, 3.5 Hz, 1H), 3.93 (ddd, J = 12.3, 9.9, 8.0
Hz, 1H), 2.49 (ddd, J = 18.6, 9.5, 9.5 Hz, 1H), 2.42 (ddd, J = 18.6, 8.0, 3.5 Hz, 1H), 1.46 (d, J = 6.4
Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3):  = 209.4, 165.7, 148.5, 134.7, 133.6, 132.7, 132.3, 132.1,
130.0, 129.9, 128.8, 124.9, 71.4, 67.1, 45.8, 37.2, 17.5. HRMS (ESI-TOF, pos.): m/z calcd for
+
푣
C19H19N2O7S [M+H] 419.0907 found 419.0907. IR (DRIFT): = 2979, 2937, 1921, 1765, 1717,
[훼]24
−1
1542, 1450, 1347, 1262, 1225, 1192, 1087, 805, 741, 708 cm .
MeCN).
= +173.3° (c = 0.00118 g/mL,
D
(+)-(R)-1-((S)-1-(mesylsulfonyl)-3-oxopyrrolidin-2-yl)ethyl benzoate 4c. Reaction conditions: 24
h at room temperature. Gray-white amorphous solid (47.1 mg, 0.151 mmol, 40%). The crude product
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was purified by semipreparative HPLC chromatography. HPLC purity 99%. H NMR (500 MHz,
CDCl3):  = 7.95-7.97 (m, 2H, HC10,14), 7.56-7.59 (m, 1H, HC12), 7.43-7.46 (m, 2H, HC11,13), 5.54 (qd,
J = 6.5, 4.0 Hz, 1H, HC7), 4.15 (br. d, J = 4.0 Hz, 1H, HC2), 4.14 (ddd, J = 12.0, 10.0, 2.6 Hz, 1H,
HaC5), 3.81 (ddd, J = 12.0, 10.0, 7.7 Hz, 1H, HbC5), 2.93 (s, 3H, HC6), 2.68 (ddd, J = 18.8, 11.0, 10.0
Hz, 1H, HaC4), 2.50 (ddd, J = 18.8, 7.7, 2.6 Hz, 1H, HbC4), 1.51 (d, J = 6.5 Hz, 3H, HC15). 13C{1H}
NMR (126 MHz, CDCl3):  = 210.3 (C3), 165.7 (C8), 133.7 (C12), 123.0 (C9), 129.9 (C10,14), 128.9
(C11,13), 71.4 (C7), 66.2 (C2), 45.3 (C5), 38.9 (C6), 37.4 (C4), 17.6 (C15). 15N NMR (51 MHz,
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CDCl3):  = 99.2 (N1). See Supporting Information for detailed assignments. HRMS (ESI-TOF, pos.):
+
푣
m/z calcd for C14H18NO5S [M+H] 312.0900 found 312.0899. IR (DRIFT): = 2963, 2934, 1918,
[훼]24
−1
1757, 1716, 1452, 1340, 1265, 1195, 1149, 1086, 1029, 776, 710 cm .
g/mL, MeCN).
= +469.1° (c = 0.00081
D
(+)-(R)-1-((S)-3-oxo-1-tosylpyrrolidin-2-yl)ethyl benzoate 4d. Reaction conditions: 24 h at room
temperature. White amorphous solid (80.4 mg, 0.208 mmol, 50%). The crude product was purified
by semipreparative HPLC chromatography. HPLC purity 99%. 1H NMR (500 MHz, CDCl3):  = 7.92-
7.97 (m, 2H), 7.75 (br. d, J = 8.3 Hz, 2H), 7.53-7.58 (m, 1H), 7.40-7.45 (m, 2H), 7.33 (br. d, J = 8.3
Hz, 2H), 5.63 (qd, J = 6.4, 3.4 Hz, 1H), 4.00 (br. d, J = 3.4 Hz, 1H), 3.96 (ddd, J = 12.7, 9.9, 3.0 Hz,
1H), 3.86 (ddd, J = 12.7, 9.6, 7.7 Hz, 1H), 2.42 (s, 3H), 2.21 (ddd, J = 18.5, 7.7, 3.0 Hz, 1H), 1.94
(ddd, J = 18.5, 9.9, 9.6 Hz, 1H), 1.55 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3):  = 210.7,
165.7, 144.9, 134.9, 133.6, 130.6, 130.1, 129.9, 128.8, 127.8, 71.9, 66.80, 45.8, 36.5, 21.9, 17.3.
+
푣
HRMS (ESI-TOF, pos.): m/z calcd for C20H22NO5S [M+H] 388.1213 found 388.1213. IR (DRIFT):
[훼]24
−1
= 2996, 2939, 2903, 1926, 1763, 1709, 1449, 1164, 1088, 821, 751, 716 cm .
0.00121 g/mL, MeCN).
= +76.4° (c =
D
(+)-(R)-1-((S)-1-((4-nitrophenyl)sulfonyl)-3-oxopyrrolidin-2-yl)ethyl
4-methylbenzoate
4e.
Reaction conditions: 24 h at room temperature. White amorphous solid (24.5 mg, 0.057 mmol, 30%).
1
The crude product was purified by semipreparative HPLC chromatography. HPLC purity 99%. H
NMR (500 MHz, CDCl3):  = 8.27 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 8.6 Hz, 2H), 7.76 (br. d, J = 8.2
Hz, 2H), 7.20 (br. d, J = 8.2 Hz, 2H), 5.53 (qd, J = 6.4, 4.6 Hz, 1H), 4.07 (br. d, J = 4.6 Hz, 1H), 4.03
(ddd, J = 12.0, 9.9, 3.5 Hz, 1H), 3.88 (ddd, J = 12.0, 9.5, 7.6 Hz, 1H), 2.43 (ddd, J = 18.7, 7.6, 3.5
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Hz, 1H), 2.40 (s, 3H), 2.26 (ddd, J = 18.7, 9.9, 9.5 Hz, 1H), 1.51 (d, J = 6.4 Hz, 3H). 13C{1H} NMR
(126 MHz, CDCl3):  = 208.9, 165.8, 150.6, 144.7, 144.1, 129.9, 129.6, 128.8, 127.0, 125.0, 70.6,
66.5, 45.6, 36.9, 22.0, 17.4. HRMS (ESI-TOF, pos.): m/z calcd for C20H21N2O7S [M+H]+ 433.1064
9
푣
found 433.1064. IR (DRIFT): = 2980, 2961, 2874, 1935, 1763, 1707, 1528, 1452, 1346, 1309,
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[훼]24
−1
1266, 1165, 1086, 752, 734 cm .
= +50.0° (c = 0.00131 g/mL, MeCN).
D
(+)-(R)-1-((S)-1-((4-nitrophenyl)sulfonyl)-3-oxopyrrolidin-2-yl)ethyl 4-methoxybenzoate 4f.
Reaction conditions: 24 h at room temperature. Pale yellow amorphous solid (55.0 mg, 0.118 mmol,
42%). The crude product was purified by semipreparative HPLC chromatography. HPLC purity 99%.
1H NMR (500 MHz, CDCl3):  = 8.28 (d, J = 8.9 Hz, 2H), 8.03 (d, J = 8.9 Hz, 2H), 7.83 (br. d, J = 8.9
Hz, 2H), 6.87 (br. d, J = 8.9 Hz, 2H), 5.52 (qd, J = 6.6, 4.6 Hz, 1H), 4.06 (br. d, J = 4.6 Hz, 1H), 4.02
(ddd, J = 12.9, 9.8, 3.4 Hz, 1H), 3.89 (ddd, J = 12.9, 9.3, 7.7 Hz, 1H), 3.85 (s, 3H), 2.42 (ddd, J =
18.6, 7.7, 3.4 Hz, 1H), 2.25 (ddd, J = 18.6, 9.8, 9.3 Hz, 1H), 1.50 (d, J = 6.6 Hz, 3H). 13C{1H} NMR
(126 MHz, CDCl3):  = 208.9, 165.5, 164.1, 150.7, 144.1, 132.0, 128.8, 125.0, 122.1, 114.1, 70.4,
66.5, 55.8, 45.6, 36.9, 17.4. HRMS (ESI-TOF, neg.): m/z calcd for C20H19N2O8S [M-H]- 447.0857
푣
found 447.0846. IR (DRIFT): = 1940, 1766, 1701, 1529, 1510, 1345, 1313, 1255, 1165, 1087,
[훼]24
−1
1026, 854, 735 cm .
= +34.2° (c = 0.00130 g/mL, MeCN).
D
(+)-(R)-1-((S)-1-((4-nitrophenyl)sulfonyl)-3-oxopyrrolidin-2-yl)ethyl
4-(trifluoromethyl)-
benzoate 4g. Reaction conditions: 24 h , heating at 40 °C in oil bath. White amorphous solid (21.7
mg, 0.045 mmol, 18%). The crude product was purified by semipreparative HPLC chromatography.
HPLC purity 98%. 1H NMR (500 MHz, CDCl3):  = 8.37 (d, J = 8.6 Hz, 2H), 8.08 (br. d, J = 8.6 Hz,
4H), 7.70 (br. d, J = 8.2 Hz, 2H), 5.63 (qd, J = 6.5, 4.6 Hz, 1H), 4.01 (br. d, J = 4.6 Hz, 1H), 3.88-
3.91 (m, 2H), 2.42 (ddd, J = 18.6, 7.9, 4.4 Hz, 1H), 2.22 (ddd, J = 18.6, 10.4, 9.2 Hz, 1H), 1.55 (d,
J = 6.5 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3):  = 208.3, 164.7, 150.9, 143.3, 135.3 (q, J = 32.8
Hz), 133.1, 130.4, 129.1, 125.9 (q, J = 3.7 Hz), 123.8 (q, J = 273.0 Hz), 125.1, 71.5, 65.9, 45.6,
36.9, 16.9. HRMS (ESI-TOF, neg.): m/z calcd for C20H16F3N2O7S [M-H]- 485.0625 found 485.0614.
푣
IR (DRIFT): = 2980, 2961, 1943, 1765, 1718, 1530, 1411, 1323, 1269, 1165, 1087, 1016, 856,
[훼]24
−1
757 cm .
= +55.7° (c = 0.00114 g/mL, MeCN).
D
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(+)-(R)-1-((S)-1-((4-nitrophenyl)sulfonyl)-3-oxopyrrolidin-2-yl)ethyl acetate 4h. Reaction
conditions: 72 h at room temperature. Pale yellow amorphous solid (32.1 mg, 0.090 mmol, 33%).
The crude product was purified by semipreparative HPLC chromatography. HPLC purity 98%. 1H
NMR (500 MHz, CDCl3):  = 8.41 (d, J = 8.3 Hz, 2H), 8.08 (d, J = 8.3 Hz, 2H), 5.33 (qd, J = 6.3, 3.7
Hz, 1H), 3.91 (br. d, J = 3.7 Hz, 1H), 3.88 (ddd, J = 18.6, 10.2, 3.7 Hz, 1H), 3.82 (ddd, J = 12.3,
8.6, 7.7 Hz, 1H), 2.35 (ddd, J = 18.6, 7.7, 3.7 Hz, 1H), 2.10 (ddd, J = 18.6, 10.2, 9.1 Hz, 1H), 2.01
(s, 3H), 1.41 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3):  = 209.0, 170.0, 150.9, 143.7,
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129.1, 125.2, 71.2, 66.3, 45.7, 36.8, 21.3, 17.0. HRMS (ESI-TOF, pos.): m/z calcd for C14H17N2O7S
+
푣
[M+H] 357.0751 found 357.0751. IR (DRIFT): = 2982, 2962, 2876, 1815, 1763, 1709, 1532,
[훼]24
−1
1351, 1309, 1238, 1168, 1089, 856 cm .
= +103.2° (c = 0.00109 g/mL, MeCN).
D
(+)-(S)-(1-((4-nitrophenyl)sulfonyl)-3-oxopyrrolidin-2-yl)methyl
benzoate
4j.
Reaction
conditions: 72 h at room temperature. White amorphous solid (15.8 mg, 0.039 mmol, 14%). The
crude product was purified by semipreparative HPLC chromatography. HPLC purity 97%. 1H NMR
(500 MHz, CDCl3):  = 8.21 (d, J = 8.6 Hz, 2H), 7.99 (d, J = 8.6 Hz, 2H), 7.70-7.74 (m, 2H), 7.512-
7.58 (m, 1H), 7.35-7.40 (m, 2H), 4.78 (dd, J = 11.7, 3.4 Hz, 1H), 4.57 (dd, J = 11.7, 2.6 Hz, 1H), 4.15
(dd, J = 3.4, 2.6 Hz, 1H), 3.97 (ddd, J = 10.2, 8.6, 6.3 Hz, 1H), 3.75 (ddd, J = 10.2, 8.0, 8.0 Hz, 1H),
2.66-2.72 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3):  = 207.7, 165.7, 150.5, 144.1, 134.0, 129.6,
129.1, 128.9, 128.6, 124.9, 64.0, 62.3, 44.9, 37.0. HRMS (ESI-TOF, neg.): m/z calcd for
-
푣
C18H15N2O7S [M-H] 403.0594 found 403.0599. IR (DRIFT): =2979, 2959, 2896, 1948, 1762, 1721,
[훼]24
−1
1522, 1344, 1265, 1162, 1147, 1094, 855, 712, 687 cm .
= +56.5° (c = 0.00114 g/mL, MeCN).
D
(+)-N-(R)-1-((S)-1-((4-nitrophenyl)sulfonyl)-3-oxopyrrolidin-2-yl)ethyl benzamide 4k. Reaction
conditions: 72 h at room temperature. Pale white-pink amorphous solid (21.2 mg, 0.051 mmol,
14%). The crude product was purified by semipreparative HPLC chromatography. HPLC purity
99%. 1H NMR (500 MHz, CDCl3):  = 8.30 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.87-7.93
(m, 2H), 7.53-7.59 (m, 1H), 7.38-7.45 (m, 2H), 5.57 (dq, J = 6.3, 3.8 Hz, 1H), 4.07 (br. d, J = 3.8
Hz, 1H), 4.00 (ddd, J = 12.2, 9.9, 3.9 Hz, 1H), 3.90 (ddd, J = 12.2, 9.5, 8.0 Hz, 1H), 2.42 (ddd, J =
18.4, 8.0, 3.9 Hz, 1H), 2.24 (ddd, J = 18.4, 9.9, 9.5 Hz, 1H), 1.53 (d, J = 6.3 Hz, 3H). 13C{1H} NMR
(126 MHz, CDCl3):  = 208.8, 165.8, 143.9, 133.8, 129.9, 129.8, 128.9, 128.9, 125.0, 70.9, 66.4,
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45.7, 36.9, 17.3. HRMS (ESI-TOF, pos.): m/z calcd for C19H20N3O6S [M+H]+ 418.1067 found
5
6
7
8
푣
418.1067. IR (DRIFT): = 2980, 2961, 1935, 1765, 1528, 1451, 1345, 1311, 1265, 1165, 1086,
[훼]24
−1
855, 757, 711 cm .
= +69.4° (c = 0.00142 g/mL, MeCN).
D
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Supporting Information Available
Supporting information contains details of analytical results along with spectroscopic data for the
synthesized compounds. This material is available free of charge via the Internet.
Acknowledgements
This work was supported by an internal grant from Palacký University (IGA_PrF_2019_027)
and the Ministry of Health of the Czech Republic (17-31834A). Jiří Pospíšil is greateful for support
from European Regional Development Fund-Project “Centre for Experimental Plant Biology” (no.
CZ.02.1.01/0.0/0.0/16_019/0000738). Dr. Hiroyuki Koshino, (RIKEN, Japan) is acknowledged for
his confirmation of the final structure 4a using NMR data.
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