Structure-Activity Studies of Truncated Latrunculin Analogues with Antimalarial Activity

Article abstract of DOI:10.1002/cmdc.202000399

Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics renders the parasites unable to effectively establish infection. Therefore, actin presents a potential target for malarial drug discovery, and naturally occurring actin inhibitors such as latrunculins are a promising starting point. However, the limited availability of the natural product and the laborious route for synthesis of latrunculins have hindered their potential development as drug candidates. In this regard, we recently described novel truncated latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core to summarize the SAR for inhibition of malaria motility. This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria.

Full text of DOI:10.1002/cmdc.202000399

Accepted Article
Title: Structure activity studies of truncated latrunculin analogues with
anti-malarial activity
Authors: Swapna Varghese, Raphaël Rahmani, Damien R. Drew,
James G. Beeson, Jake Baum, Brian J. Smith, and Jonathan
Baell
This manuscript has been accepted after peer review and appears as an
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.202000399
Link to VoR: https://doi.org/10.1002/cmdc.202000399
01/2020

10.1002/cmdc.202000399
ChemMedChem
Structure activity studies of truncated latrunculin
analogues with anti-malarial activity
Swapna Varghese,[a] [b] Raphaël Rahmani,[b] Damien R. Drew, [c] James G. Beeson, [c] [d] Jake
Baum,*[e] [f] Brian J. Smith,*[a] and Jonathan B. Baell*[b] [g] [h]
[a]
Dr. S. Varghese, Prof. B. Smith
La Trobe Institute for Molecular Science,
La Trobe University,
Melbourne, Victoria 3086, Australia
E-mail: Brian.Smith@latrobe.edu.au
Dr. S. Varghese, Dr. R. Rahmani, Prof. J. Baell
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences,
Monash University,
[b]
Parkville, Victoria 3052, Australia
E-mail: jonathan.baell@monash.edu
Dr. D. Drew, Prof. J. Beeson
Burnet Institute,
85 Commercial Rd,
[c]
[d]
Melbourne, Victoria 3004, Australia
Prof. J. Beeson
Central Clinical School and Department of Microbiology,
Monash University,
Melbourne, Victoria 3004, Australia
[e] [f] Prof. J. Baum
Walter and Eliza Hall Institute,
1G Royal Parade, Parkville, Victoria 3052, Australia
(and)
Department of Life Sciences,
Imperial College London,
South Kensington SW7 2AZ, United Kingdom
[g] [h] Prof. J. Baell
Australian Translational Medicinal Chemistry Facility (ATMCF),
Monash University,
Parkville, Victoria 3052, Australia
(and)
ARC Centre for Fragment-Based Design,
Monash University,
Parkville, Victoria 3052, Australia
Abstract
Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics
renders the parasites unable to effectively establish infection. Therefore, actin presents a
potential target for malarial drug discovery, and naturally occurring actin inhibitors such as
latrunculins are a promising starting point. However, the limited availability of the natural
product and the laborious route for synthesis of latrunculins have hindered their potential
development as drug candidates. In this regard, we recently described novel truncated
latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin
than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core
to summarize the SAR for inhibition of malaria motility. This study helps further understand
the binding pattern of these analogues in order to develop them as drug candidates for malaria.
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10.1002/cmdc.202000399
ChemMedChem
Keywords: Actin inhibitors, heterocycles, latrunculin analogues, malaria, natural products, P.
falciparum.
Introduction
Malaria is one of the most significant infectious diseases affecting the human population. It is
caused by Plasmodium parasites and transmitted by Anopheles mosquitos. Despite existing
drugs, malaria remains a major health burden.1 The World Health Organisation (WHO)
reported 219 million cases of malaria in 2017 (217 million cases in 2016) with a death toll of
435,000.1 The great majority of disease prevalence and mortality is due to malaria caused by
P. falciparum. The challenge to reducing the burden of malaria is partly due to the growing
resistance of malaria to existing drugs as well as insecticides used for vector control.2, 3 The
current first line therapy for P. falciparum malaria is artemisinin combination therapy, most
commonly artemether with lumefantrine,4-6 however, many parasite strains have developed
resistance to these, with established resistance to other drugs such as chloroquine and
sulfadoxine-pyremethamine.7, 8 The most advanced malaria vaccine RTS,S has low efficacy
(approximately 30% in phase 3 trials) and thus offers only modest protection.9 This
emphasises the need for new drugs with novel modes of action.
Actin is an abundant protein found in eukaryotic cells that reversibly polymerizes between
monomeric (G-actin) and filamentous (F-actin) states. The conversion of G-actin to F-actin,
leads to the hydrolysis of the tightly bound ATP so as to slowly release Pi. Malarial parasites
employ actin dynamics to invade host cells; if actin dynamics is disrupted, the parasites can
no longer glide, invade host cells and establish infection,10-12 making actin inhibitors potential
therapeutics to combat this disease. Many natural products belonging to the macrolide family,
such as the latrunculins (Figure 1, A), jasplakinolide and cytochalasins, are known to bind
actin and thereby disrupt its function.13-15 Latrunculins bind to the G-actin monomer in a 1:1
complex, thereby blocking the ability of actin to polymerize into a growing filament.16
Latrunculins bind above the ATP binding cleft - between subdomains D2 and D4 of the actin
monomer,14 leading to conformational changes within these domains. The actin monomers
can no longer interact with the filament and polymerization is effectively suppressed.17, 18
Computational analysis revealed that sequence similarity between malarial actin and human
actin is sufficient to render homology modelling meaningful, but low enough to allow for
selectivity. Studies on actin polymerization, effect of mutations and chimeric actin have been
investigated by various groups, which contributes towards exploring actin as a drug target
against malaria.19-21
We recently explored truncated latrunculin analogues,22 which demonstrated superior activity
and selectivity compared with naturally occurring latrunculins against Plasmodium parasites.
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10.1002/cmdc.202000399
ChemMedChem
Pursuing these outcomes, we set out to further explore the SAR features around the truncated
latrunculin core C (Figure 1). Our preliminary study highlighted the effect of SAR modifications
at the R1 position;22 here we explore the effects of substitution at the R2, R3 and R4 positions
that further explain the binding interactions of truncated latrunculin analogues in the ATP
binding pocket of actin. We combined key functional group modifications to explore additive
SAR features, and also synthesised a planar equivalent of the THP ring to understand the
importance of chirality and shape in these truncated latrunculin analogues. The activity of the
various R2, R3 and R4 modified analogues were compared with our previous lead compound
B22 (Figure 1) to further understand SAR. Modifications at the different R regions described
herein help establish the binding interaction within the actin binding site and provide further
information for the development of these natural product derived anti-malarial compounds with
superior potency and selectivity.
S
R1
O
O
O
R4
R3
O
O
O
O
N
O
O
R2
OH
O
O
HN
O
PMBN
O
S
S
S
O
A
B
C
: 7 ± 2 µM
EC50
: 44 ± 2 µM
EC50
Fig. 1. Structure of latrunculin B (A), truncated latrunculin analogue22 (B) and truncated
latrunculin core (C).
Results and discussion
R2 modified analogues.
To understand the effect of long chain substitution at the R2 position, a variety of linear alkyl
chain substituents were synthesized while keeping the R1, R3 and R4 substituents consistent
with the analogue B. These molecules were synthesized following the same route as
previously described23 (Figure 2). L-cysteine ethyl ester hydrochloride 1 was successively
converted to the α,β-unsaturated ketone 6a (R3 position with a PMB group) and (but-3-en-1-
yloxy)(tert-butyl)dimethylsilane (10a) was synthesized by TBS protection of but-3-en-1-ol (9a).
Compounds 6a and 10a were then subjected to alkene metathesis followed by deprotection
and simultaneous cyclization to obtain the hemiketal 12a, which was then treated with a
selection of different alcohols to yield the R2 modified intermediates 13(a-c) (Figure 2). These
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10.1002/cmdc.202000399
ChemMedChem
intermediates were then derivatised at the R1 position with a thiophene benzoate ester, to
obtain three R2 modified analogues 14(a-c).
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10.1002/cmdc.202000399
ChemMedChem
O
OEt
R3
O
N
OEt
O
OEt
SH
-Cl, K CO3
cat. N2aI
CDI
R3
HN
O
H2N
DMF
THF
56%
S
S
56-62%
O
3(a-c)
1
2
O
O
N
O
O
N
OH
S
. HCl
TBTU, DIPEA
CH3NHOCH3
1,4 Dioxane,
H
2O
VinylMgBr
R3
N
R3
R3
N
THF
48-95%
KOH
84-90%
DCM
S
O
6(a-c)
S
70-93%
O
4(a-c)
O
5(a-c)
TBSCl
Imidazole
O
OTBS
OH
MgBr
R4
H
R4
10(a-c)
R4
THF
99%
DCM
44-76%
7
8
9(a-c)
O
R4
R3
N
OTBS
O
cat. Hoveyda-Grubbs' II
R3
N
R4
OTBS
DCE, 50°C
23-67%
O
S
O
S
6(a-c)
10(a-c)
11(a-d)
R4
R4
R3
OH
OH
R2
cat. CSA
6 M aq. HCl
R2
O
N
-OH
O
N
OH
O
THF, rt
49-88%
32-69%
R3
S
S
O
O
12(a-d)
13(a-g)
R1
R1
COOH
COOH
DMAP, EDCI.HCl
DMAP, EDCI.HCl
DCM
3-99%
DCM
5%
R1
O
R4
R3
O
R2
O
N
O
S
O
14(a-h, j-l)
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10.1002/cmdc.202000399
ChemMedChem
B
O
HO
OH
O
cat. Pd(dppf)Cl
CO3
2, K2
14h
1,4-Dioxane, Water
O
O
reflux
48%
PMBN
O
14i
S
Fig. 2. General procedure for synthesis of R2 and R3 modified truncated latrunculin analogues.
3-6 (a: PMB, b: benzyl, c: DMB), 7 (a: phenyl, b: pentyl), 9-10 (a: H, b: phenyl, c: pentyl), 11-
12 (a: R3 benzyl, R4 H; b: R3 DMB, R4 H; c: R3 PMB, R4 phenyl; d: R3 PMB, R4 pentyl), 13 (a:
R2 ethyl, R3 DMB, R4 H; b: R2 butyl, R3 PMB, R4 H; c: R2 butoxy, R3 PMB, R4 H; d: R2 methyl,
R3 benzyl, R4 H; e: R2 methyl, R3 DMB, R4 H; f: R2 methyl, R3 PMB, R4 H; g: R2 methyl, R3
DMB, R4 pentyl), 14(a-l).
Potency of these analogues was determined using a standard in vitro growth inhibition assay
against P. falciparum24 (Tables 1-3). The R2 ethoxy analogue 14a (EC50 = 8 µM) demonstrated
comparable activity with the previously reported R2 methoxy analogue B (EC50 = 7 µM),
suggesting the actin binding pocket can accommodate small alkyl chains at this position.
However, longer alkyl substituents led to complete loss of activity (14b and 14c). Inactivity of
both the butoxy analogue (14b) and the 2-methoxyethane analogue (14c) suggests that the
length of the alkyl chain at R2 position plays a greater role in potency than the hydrophobicity
of the alkyl chain at this position. Thus, the R2 position can accommodate small alkyl chains
and leads to potent truncated latrunculins (B, 14a).
Table 1. R2 analogues of truncated latrunculin and their corresponding activity against
Plasmodium parasites.
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10.1002/cmdc.202000399
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EC50 (µM)a
General structure
Compound
R2
CH3
7±2
8±3
B
S
O
14a
O
O
>100
>100
R2
O
14b
14c
PMBN
O
O
S
aData are the mean and standard deviation from a duplicate experiment.
R3 modified analogues.
Previous studies by Sayed et. al. on latrunculin derivatives demonstrated that N-benzyl
substituted latrunculin A was more potent than the canonical latrunculin A in inhibition of actin
polymerization.25 Potency of B (truncated latrunculin with PMB group at the R3 position) also
implies the tolerance of a large bulky substituent at the R3 position. To understand the SAR
around this region, we substituted the thiazolidinone nitrogen with a benzyl group and a 3,4-
dimethoxybenzyl (DMB) group to obtain compounds 13(d-e) (Figure 2). Additive SAR was
also explored by integrating R1 modifications to obtain compounds 14(g-j) (Table 2).
Table 2. R3 analogues of truncated latrunculin and their corresponding activity against
Plasmodium parasites as EC50 values.
I
O
R1
S
General
structure
Compound
EC50 (µM)a
R3
14d22
14e22
14f22
7±0.5 µM
14i
15±2 µM*
17±3 µM#
B22
O
62±1 µM 17±3 µM
7±2 µM
14g
14h
NC
>100 µM 50±3 µM
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10.1002/cmdc.202000399
ChemMedChem
R1
O
O
O
O
O
14j
O
NC
NC
NC
12±2 µM
R3
N
S
O
*Diastereomer A, #Diastereomer B, aData are the mean and standard deviation from a
duplicate experiment. NC- not considered.
P. falciparum growth inhibition assay of R3 substituted analogues showed that PMB was the
most favorable substituent at this position. The R3 PMB analogues favored the naphthyl (14f)
and thiophene (B) substitution at the R1 position, although the furan and iodobenzene
substitutions were also tolerated.22 Benzyl substitution at the R3 position was tolerated but led
to decreased potency when compared with the PMB analogues (3-fold decreased potency
with an iodobenzene (14h) and a 2-fold decreased potency with a naphthyl (14i) substituent
at the R1 position). The two diastereomers of compound 14i were easily separable by column
chromatography (arbitrarily assigned as diastereomer A and diastereomer B) and were
independently assessed for activity. Both diastereomers had comparable activity (15±2 µM
and 17±3 µM, respectively) and hence attempts to configure their exact stereochemistry was
not pursued. The R3 DMB analogue 14j was also found to retain activity against P. falciparum
although PMB remained the most preferred substitution at this position. Thus, all the three R3
substituted analogues were tolerated and gave compounds with superior potency compared
with naturally occurring latrunculin B (EC50 44 µM).
R4 modified analogues.
In order to potentially mimic the macrocycle in the canonical latrunculins, hydrophobic groups
such as a phenyl ring and a pentyl chain, were introduced at the R4 position. The phenyl ring
being cyclic and planar would introduce hydrophobic interactions in a rigid manner whereas
the flexible alkyl chain could possibly assume the most favorable position within the actin
binding site. Phenyl and pentyl aldehydes (7a-b) were used to synthesize analogues 12c,
14(k-l) (Figure 2) and were then tested in growth inhibition assays to determine their potency
(Table 3).
Table 3. R4 analogues of truncated latrunculin and their corresponding activity against
Plasmodium parasites.
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10.1002/cmdc.202000399
ChemMedChem
General
EC50
(µM)a
Compound
12c
R1
R2
R4
structure
OH
H€
29±3
R4
O
S
R1
R2
14k
14l
H€
20±0.6
O
O
O
PMBN
S
O
S
13±3*
20±1#
Me
O
O
*Diastereomer A, #Diastereomer B aData are the mean and standard deviation from a
duplicate experiment. €When the R4 position was a benzyl substituent, the R2 position failed
to undergo methyl substitution under the conditions described.
R4 substituted phenyl hemiketal 12c showed moderate activity against Plasmodium parasites
(29 µM), which upon R1 substitution with a thiophene benzoate group (14k) led to a modest
improvement in activity; this demonstrates the opportunity afforded by R1 modification on
activity of these truncated latrunculins. The pentyl chain analogue 14l (with thiophene
benzoate group at R1 position) also showed moderate activity. The two diastereomers of 14l
were separable by chromatography, and one diastereomer showed slightly greater potency
over the other. Comparison of activity of compound B with compounds 12c and 14(k-l)
suggests that R4 substitution with large lipophilic groups, although well tolerated, leads to less
potent compounds.
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10.1002/cmdc.202000399
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Fig. 3. Model of 14l in the ligand binding site.
A model of 14l in the ligand binding site shows the pentyl R4 group contacts the side chains
of several hydrophobic residues, Ile35, Ile65, Leu68 and Tyr70 (Figure 3). The macrocycle
alkyl chain contacts these residues in the X-ray crystal structure of latrunculin B in complex
with actin (PDB 2q0u).26 Throughout the molecular dynamics simulation the terminal methyl
group of the pentyl group contacts the thiophene of the R1 group; these two groups appear to
form an unconnected surrogate of the latrunculin macrocycle. The hydroxyl of Tyr70 forms a
hydrogen bond with the ring-oxygen in both the X-ray crystal structure of latrunculin B and the
model of B in complex with actin,22 whereas in the model of 14l the tyrosine side chain is
turned away from the ligand; this could help explain the lack of any improvement in affinity by
introduction of the pentyl chain.
Aromatic analogues. To understand the importance of the tetrahydropyran ring and chirality
for actin inhibition, aromatic analogues were synthesized. These analogues were prepared
using standard procedures27 as shown in Figure 4. 1-(3-Hydroxyphenyl)ethan-1-one (15) was
first brominated using copper (II) bromide to yield 16. Compound 16, upon treatment with
potassium thiocyanate under acidic conditions, led to spontaneous ring closure and
dehydroxylation to give 17. Compound 17 served as a building block, which when subjected
to R1 and R4 based modifications gave analogues 18 - 19 as shown in Table 4.
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10.1002/cmdc.202000399
ChemMedChem
OH
OH
OH
CuBr2
1) KSCN, Acetone
EtOAc
reflux
SO
2) aq. H2 4 (50%), Acetic acid
100 °C
O
HN
O
O
Br
S
29% over 3 steps
15
16
17
R1
COOH
DMAP, EDCI.HCl
DCM
45-98%
R1
O
R1
O
O
O
PMBCl, K2CO3
cat. NaI
DMF
70-83%
HN
O
PMBN
S
S
O
19(a-b)
18(a-c)
Fig. 4. Synthesis of aromatic analogues.
Table 4. Aromatic analogues of truncated latrunculin and their corresponding activity against
Plasmodium parasites.
EC50
(µM)a
Compound
18a
Structure
I
O
O
H
N
52±0.22
O
S
S
O
O
18b
>100
H
N
O
O
S
I
O
O
PMB
N
19a
19b
>100
>100
S
S
O
O
PMB
N
O
S
aData are the mean and standard deviation from a duplicate experiment.
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10.1002/cmdc.202000399
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The aromatic analogues when tested against Plasmodium parasites were found to be mostly
inactive. The only weakly active compound identified in this series was compound 18a (Table
4). The inactivity of these analogues emphasizes the influence of the 6-membered ring with
sp3 character over the flat sp2 hybridized aromatic ring. It also suggests that the hydrogen
bond acceptor (oxygen) in the THP ring may be important for activity, potentially engaging in
the receptor binding.
It should be noted that the novel truncated latrunculin analogues described in this work are an
extension of our previous work on R1 modifications, where we established the selectivity of
these analogues for parasite actin over mammalian actin.22 Since the potent compounds
identified in this work are identical in potency with our previous analogues, we did not
endeavour to perform such extensive studies at this stage.
On the basis of the findings and analysis described above, a summary of the SAR of truncated
latrunculin analogues in this study is illustrated in Figure 5.
Bulky substituents
are tolerated but
reduces activity
Lipophilic substituents
enhanced activity
R1
R2
R4
R3
O
N
O
PMB is most preferred,
although benzyl and DMB
substituents are well tolerated
Small alkyl chain substituents
are preferred
S
O
Chirality of core
is crucial for activity
Fig. 5. Summary of the SAR observed with the truncated latrunculin analogues.
Conclusion
With the ongoing increases in the prevalence and geographic spread of P. falciparum to first
line therapeutics and established resistance to other existing drugs, the need for malarial drug
discovery continues to rise. The number of combination therapies available to treat such
resistant strains remains underpopulated thereby increasing the need to explore drugs with
novel modes of action.
Latrunculins are natural products with actin binding properties that can potentially be used to
target various infections including malaria. However, cumbersome synthesis and the lack of
selectivity are the major bottleneck limiting their development as anti-malarials. Here we report
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10.1002/cmdc.202000399
ChemMedChem
the synthesis and biological evaluation of various truncated latrunculin analogues that are not
only synthetically more viable, but also present as a more potent inhibitor of malarial actin.
Further exploration of SAR from our previously reported truncated latrunculin analogues,
helped us to identify additional compounds with greater potency compared with the natural
latrunculins. These novel semi-synthetic natural product analogues highlight interesting
synthetic organic chemistry that we developed en route to our biologically active target
molecules. Our success in improving synthetic ease by removing a macrocycle and two Z–
double bonds from the natural product while improving the activity, encourages further studies
to transform complex natural products to synthetically accessible analogues with improved
biological activity.
The SAR discussed in this paper highlights various favorable and unfavorable features of the
truncated core, and that the tetrahydropyran ring and chirality are crucial. We reference our
SAR interpretation against actin binding and in this context future development of target-
engagement studies would be useful to strengthen the association between phenotypic
readout and target inhibition. These findings will be crucial for the further development of
latrunculin analogues as potential anti-malarial agents.
Experimental section
P. falciparum growth inhibition assay.
The P. falciparum growth inhibition assay was performed as previously reported. 22, 24
Molecular modelling.
A model of 14l in the ligand binding site was created using the YASARA software
(www.yasara.org) using the same approach used earlier;22 all system parameters were the
same as used earlier. The model of B in the ligand binding site was manually converted to 14l,
the geometry minimised and 100 ns of molecular dynamics applied before final energy
minimisation. Figures were created using the CHIMERA program.28
General chemistry experimental.
General. Solvents were of analytical grade or distilled laboratory grade: ethyl acetate (EtOAc);
dichloromethane (DCM); dimethyl formamide (DMF); methanol (MeOH); tetrahydrofuran
(THF). Analytical TLC was performed on silica gel 60/F254 pre-coated aluminium sheets (0.25
mm, Merck). Flash column chromatography was carried out with silica gel 60, 0.63–0.20 mm
1
13
(70–230 mesh, Merck). H and C NMR spectra were recorded at 400 MHz and 100 MHz
respectively. Chemical shifts (δ, ppm) are reported relative to the solvent peak (CDCl3: 7.26
[1H] or 77.16 [13C], DMSO-d6: 2.50 [1H] or 39.52 [13C]). Proton resonances are annotated as:
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10.1002/cmdc.202000399
ChemMedChem
chemical shift (ppm), multiplicity (br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet), coupling constant (J, Hz), and number of protons. Analytical HPLC was acquired
on an Agilent 1260 Infinity analytical HPLC coupled with a G1322A degasser, G1312B binary
pump, G1367E high performance autosampler, G4212B diode array detector. Conditions:
Zorbax Eclipse Plus C18 Rapid resolution column (4.6 × 100 mm) with UV detection at 254
nm and 214 nm, 30°C; sample was eluted using a gradient of 5 – 100% of solvent B in solvent
A where solvent A: 0.1% aq. TFA, and solvent B: 0.1% TFA in CH3CN (5 to 100% B [9 min],
100% B [1 min]; 0.5 mL/min). Low resolution mass spectrometry was performed on an Agilent
6100 Series Single Quad LCMS coupled with an Agilent 1200 Series HPLC, G1311A
quaternary pump, G1329A thermostatted autosampler, and G1314B variable wavelength
detector (214 and 254 nm). High resolution MS was performed on a Waters Autospec
instrument (for compounds 3 - 20) or an Agilent 6224 TOF LCMS coupled to an Agilent 1290
Infinity LC. All data were acquired and reference mass corrected via a dual-spray electrospray
ionization (ESI) source. LC conditions: Agilent Zorbax SB-C18 Rapid Resolution HT (2.1 × 50
mm, 1.8 µm column), 30°C; sample (5 µL) was eluted using a binary gradient (solvent A: 0.1%
aq. HCO2H; solvent B: 0.1% HCO2H in CH3CN; 5 to 100% B [3.5 min], 0.5 mL/min). Purity
was determined by HPLC or 1H NMR analysis and was found to be ≥95% for all compounds.
Exchangeable protons for some compounds were not observed in the NMR spectra.
General procedure A: Ester hydrolysis
To potassium hydroxide (3 eq.) dissolved in water (0.4 M), was successively added 1,4-
dioxane (0.26 M) and the ester (1 eq.). The reaction was allowed to stir for 1 h before being
diluted with 3 M aq. HCl. The aqueous layer was then exacted several times with diethyl ether.
The combined organic layer was washed with brine, dried with magnesium sulphate and
evaporated to dryness to yield the desired product.
General procedure B: Weinreb amide
To the carboxylic acid (1 eq.) dissolved in DCM (0.3 M), was added DIPEA (3 eq.), N,O-
dimethylhydroxylamine hydrochloride (3 eq.) and TBTU (1.5 eq.), and the reaction stirred for
12 h. After the completion of reaction as indicated by TLC analysis, 1 M aq. HCl solution was
added and the aqueous layer extracted with DCM (x 3 times). The organic layer was then
washed with 0.5 M aq. NaOH solution, dried with sodium sulphate and then evaporated to
dryness. Flash chromatography, eluting with 50% EtOAc/petroleum spirits yielded the product.
General procedure C: TBS-protection of alcohol
To the alcohol (1 eq.) dissolved in DMF (0.6 M), tert-butyldimethylsilyl chloride (TBSCl) (1.2
eq.) and imidazole (2 eq.) were added and stirred for 12 h. The reaction mixture was then
diluted with hexane and washed successively with 5% aq. HCl, saturated sodium bicarbonate,
water and brine. Sodium sulphate was used to dry the organic layer and then evaporated to
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10.1002/cmdc.202000399
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dryness. Purification was performed by flash chromatography, eluting with 10%
DCM/petroleum spirits to yield the product.
General Procedure D: TBS-deprotection and spontaneous ring closure
The TBS-protected alcohol (1 eq.) was dissolved in THF (0.05 M) and 1 M aq. HCl (0.35 M)
and stirred for 12 h. The reaction was then quenched with sodium bicarbonate solution and
the aqueous layer washed with DCM. The combined organic layer was washed with brine,
dried with sodium sulphate and evaporated in vacuo. Flash chromatography eluting with 100%
diethyl ether yielded the desired product.
General Procedure E: O-Alkylation
The hemiacetal (1 eq.) was dissolved in the corresponding alcohol (0.05 M) and catalytic CSA
(0.1 eq.) was added. The reaction was stirred for 12 h before being quenched with sodium
bicarbonate solution and extracted repeatedly with DCM. The combined organic layer was
washed with brine and dried with sodium sulphate before evaporating to dryness to yield the
product.
General Procedure F: EDCI coupling
To the alcohol (1 eq.) dissolved in DCM (0.02 M), was added the carboxylic acid (2.8 eq.),
DMAP (3 eq.) and EDCI.HCl (3 eq.). The solution was then stirred at room temperature till the
completion of the reaction, as indicated by the TLC analysis. Saturated ammonium chloride
solution was then added and the aqueous layer extracted with DCM (x 3). The combined
organic layer was then dried with sodium sulphate and evaporated to dryness. Flash
chromatography, eluting with 15% EtOAc/petroleum spirits yielded the product.
General procedure G: Suzuki coupling
To the corresponding halide (1 eq.) dissolved in 4:1 ratio of 1,4-dioxane and water (0.05 M),
was added potassium carbonate (3 eq.). The solution was degassed to remove all the
dissolved oxygen from the solution, before catalytic amount of Pd(dppf)Cl2 (0.05 eq.) was
added and the reaction mixture refluxed for 12 h. The reaction was allowed to cool to room
temperature and then filtered through celite to remove most of the catalyst. The filtrate was
then diluted with EtOAc and washed with brine. The organic layer was dried with sodium
sulphate and evaporated to dryness. Flash chromatography, eluting with 15%
EtOAc/petroleum spirits yielded the desired product.
Ethyl 3-benzyl-2-oxothiazolidine-4-carboxylate (3b)29
To a stirred suspension of (R)-ethyl 2-oxothiazolidine-4-carboxylate (500 mg, 2.85 mmol),
DMF (13 mL), potassium carbonate (591 mg, 4.3 mmol) and catalytic amount of sodium iodide
(21 mg, 0.14 mmol), benzylbromide (0.7 mL, 5.7 mmol) was added drop-wise. The reaction
was stirred overnight at room temperature. After the completion of the reaction, diethyl ether
was added and the suspension washed with brine (x 3). The organic layer was dried with
magnesium sulphate, filtered and evaporated to dryness. Flash chromatography, eluting with
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10.1002/cmdc.202000399
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5% EtOAc/petroleum spirits yielded the product as a clear oil (446 mg, 62%).1H NMR (400
MHz, CDCl3) δ 7.39 – 7.29 (m, 3H), 7.26 – 7.21 (m, 2H), 5.16 (d, J = 15.0 Hz, 1H), 4.24 (q, J
= 7.1 Hz, 2H), 4.14 (dd, J = 8.6, 3.0 Hz, 1H), 4.05 (d, J = 15.0 Hz, 1H), 3.51 (dd, J = 11.4, 8.5
Hz, 1H), 3.35 (dd, J = 11.4, 3.0 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H).
Ethyl 3-(3,4-dimethoxybenzyl)-2-oxothiazolidine-4-carboxylate (3c)
To a stirred suspension of (R)-ethyl 2-oxothiazolidine-4-carboxylate (138 mg, 0.72 mmol),
DMF (3 mL), potassium carbonate (169 mg, 1.2 mmol) and catalytic amount of sodium iodide
(6 mg, 0.036 mmol), 3,4-dimethoxy benzylchloride (220 mg, 1.16 mmol) was added drop-wise.
The reaction was stirred overnight at room temperature. After the completion of the reaction,
diethyl ether was added and the suspension washed with brine (x 3). The organic layer was
dried with magnesium sulphate, filtered and evaporated. Flash chromatography, eluting with
25% EtOAc/petroleum spirits yielded the product as a clear oil (175 mg, 75%). HPLC – rt 6.17
min > 99% purity at 254 nm; HRMS [M+Na]+ 348.0876m/z, found 348.0881 m/z; 1H NMR (400
MHz, CDCl3) δ 6.77 (m, 3H), 5.08 (d, J = 14.7 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.13 (dd, J =
8.5, 3.2 Hz, 1H), 3.99 (d, J = 14.7 Hz, 1H), 3.87 (d, J = 2.9 Hz, 6H), 3.48 (dd, J = 11.4, 8.5 Hz,
13
1H), 3.34 (dd, J = 11.4, 3.2 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl3) δ
171.8, 170.1, 149.5, 149.1, 128.2, 121.1, 111.7, 111.3, 62.3, 59.5, 56.1, 56.1, 47.9, 29.2, 14.3.
3-Benzyl-2-oxothiazolidine-4-carboxylic acid (4b)
Title compound was prepared from ethyl 3-benzyl-2-oxothiazolidine-4-carboxylate (6.8 g, 27
mmol) using General Procedure A as a white solid (5.5 g, 85%). HPLC – rt 5.30 min > 99%
purity at 254 nm; HRMS [M+H]+ 238.0532 m/z, found 238.0531 m/z; 1H NMR (400 MHz, CDCl3)
δ 7.40 – 7.29 (m, 3H), 7.28 – 7.24 (m, 2H), 5.23 (d, J = 15.0 Hz, 1H), 4.21 (dd, J = 8.6, 2.5 Hz,
1H), 4.05 (d, J = 15.0 Hz, 1H), 3.56 (dd, J = 11.5, 8.6 Hz, 1H), 3.42 (dd, J = 11.5, 2.5 Hz, 1H);
13C NMR (101 MHz, CDCl3) δ 173.4, 172.9, 135.5, 129.1, 128.4, 128.3, 59.4, 47.9, 29.3.
3-(3,4-Dimethoxybenzyl)-2-oxothiazolidine-4-carboxylic acid (4c)
Title compound was prepared from ethyl 3-(3,4-dimethoxybenzyl)-2-oxothiazolidine-4-
carboxylate (1.92 g, 5.9 mmol) according to General Procedure A as a yellow oil (1.58 g, 90%).
HPLC – rt 4.65 min > 99% purity at 254 nm; HRMS [M+H]+ 298.0744 m/z, found 298.0758
m/z; 1H NMR (400 MHz, CDCl3) δ 6.85 – 6.75 (m, 3H), 5.13 (d, J = 14.8 Hz, 1H), 4.20 (dd, J
= 8.6, 2.7 Hz, 1H), 4.01 (d, J = 14.8 Hz, 1H), 3.87 (d, J = 1.2 Hz, 6H), 3.53 (dd, J = 11.5, 8.6
Hz, 1H), 3.41 (dd, J = 11.5, 2.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 173.6, 171.9, 149.6,
149.2, 128.0, 121.2, 111.7, 111.3, 58.9, 56.2, 56.1, 47.9, 29.2.
3-Benzyl-N-methoxy-N-methyl-2-oxothiazolidine-4-carboxamide (5b)
Title compound was prepared from 3-benzyl-2-oxothiazolidine-4-carboxylic acid (1 g, 4.2
mmol) according to General Procedure B as a white solid (1.1 g, 93%). HPLC – rt 5.86 min >
99% purity at 254 nm; HRMS [M+H]+ 281.0954 m/z, found 281.0951m/z; 1H NMR (400 MHz,
CDCl3) δ 7.39 – 7.20 (m, 5H), 5.23 (d, J = 14.8 Hz, 1H), 4.40 (dd, J = 8.7, 5.2 Hz, 1H), 3.90
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10.1002/cmdc.202000399
ChemMedChem
(d, J = 14.8 Hz, 1H), 3.47 (dd, J = 11.3, 8.7 Hz, 1H), 3.32 (s, 3H), 3.20 (s, 3H), 3.16 (dd, J =
11.3, 5.2 Hz, 1H; 13C NMR (101 MHz, CDCl3) δ 172.6, 169.2, 135.8, 129.0, 128.8, 128.2, 61.3,
57.6, 47.7, 32.6, 28.2.
3-(3,4-Dimethoxybenzyl)-N-methoxy-N-methyl-2-oxothiazolidine-4-carboxamide
(5c)
Title compound was prepared from 3-(3,4-dimethoxybenzyl)-2-oxothiazolidine-4-carboxylic
acid (1.58 g, 5.3 mmol) according to General Procedure B (1.26 g, 70%). HPLC – rt 5.32 min
1
> 99% purity at 254 nm; HRMS [M+Na]+ 363.0985 m/z, found 363.1002 m/z; H NMR (400
MHz, CDCl3) δ 6.78 – 6.76 (m, 3H), 5.14 (d, J = 14.6 Hz, 1H), 4.39 (dd, J = 8.8, 5.1 Hz, 1H),
3.84 – 3.82 (m, 7H), 3.47 (dd, J = 11.3, 8.8 Hz, 1H), 3.39 (s, 3H), 3.22 (s, 3H), 3.16 (dd, J =
11.3, 5.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 172.5, 171.3, 149.5, 149.0, 128.3, 121.4,
112.0, 111.1, 61.4, 57.7, 56.2, 56.1, 47.6, 32.7, 28.3.
4-Acryloyl-3-benzylthiazolidin-2-one (6b)
To 3-benzyl-N-methoxy-N-methyl-2-oxothiazolidine-4-carboxamide (704 mg, 2.5 mmol) in
THF (8mL) at 0 °C, 1.5 M vinylmagnesium bromide (6.8 mL) was added drop wise and stirred
overnight. After completion of the reaction, 2 M aq. HCl solution was added and then extracted
with DCM (x 3). The combined organic layer was washed with saturated sodium bicarbonate
solution, dried with sodium sulphate and evaporated to dryness. Flash chromatography,
eluting with a gradient from 10% EtOAc/petroleum spirits to 50% EtOAc/petroleum spirits led
to the isolation of the product (589 mg, 95%). HPLC – rt 6.70 min > 92% purity at 254 nm;
1
HRMS [M+H]+ 248.0740 m/z, found 248.0742m/z; H NMR (400 MHz, CDCl3) δ 7.38 – 7.26
(m, 3H), 7.19 (dd, J = 7.3, 1.8 Hz, 2H), 6.48 (dd, J = 17.4, 10.4 Hz, 1H), 6.36 (dd, J = 17.4,
1.3 Hz, 1H), 5.91 (dd, J = 10.4, 1.3 Hz, 1H), 5.16 (d, J = 14.9 Hz, 1H), 4.35 (dd, J = 9.4, 4.3
Hz, 1H), 3.85 (d, J = 14.9 Hz, 1H), 3.53 (dd, J = 11.5, 9.4 Hz, 1H), 3.15 (dd, J = 11.5, 4.3 Hz,
13
1H); C NMR (101 MHz, CDCl3) δ 195.3, 172.1, 135.5, 131.9, 131.4, 129.1, 128.7, 128.3,
63.7, 48.0, 27.9.
4-Acryloyl-3-(3,4-dimethoxybenzyl)thiazolidin-2-one (6c)
To 3-(3,4-dimethoxybenzyl)-N-methoxy-N-methyl-2-oxothiazolidine-4-carboxamide (1.26 g,
3.7 mmol) in THF (25 mL) at -30°C, 1.5 M vinylmagnesium bromide (13 mL) was added drop
wise and stirred overnight. After completion of the reaction, 2 M aq. HCl solution was added
and then extracted with DCM (x 3). The combined organic layer was washed with saturated
sodium bicarbonate solution, dried with sodium sulphate and evaporated to dryness. Flash
chromatography, eluting with a gradient from 20% to 50% EtOAc/petroleum spirits led to the
isolation of the product (530 mg, 48%). HPLC – rt 5.74 min > 99% purity at 254 nm; LRMS
[M+Na]+ 330.1 m/z; 1H NMR (400 MHz, CDCl3) δ 6.82 – 6.65 (m, 3H), 6.47 (dd, J = 17.4, 10.3
Hz, 1H), 6.35 (dd, J = 17.4, 1.3 Hz, 1H), 5.90 (dd, J = 10.3, 1.3 Hz, 1H), 5.05 (d, J = 14.6 Hz,
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10.1002/cmdc.202000399
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1H), 4.34 (dd, J = 9.4, 4.6 Hz, 1H), 3.84 – 3.82 (m, 7H), 3.50 (dd, J = 11.5, 9.4 Hz, 1H), 3.13
13
(dd, J = 11.5, 4.6 Hz, 1H); C NMR (101 MHz, CDCl3) δ 195.3, 172.1, 149.5, 149.1, 131.8,
131.4, 127.8, 121.4, 111.8, 111.2, 63.7, 56.1, 56.1, 47.9, 27.9
Allylmagnesium bromide (8)
Magnesium (321 mg, 13.2 mmol) and catalytic iodine were added to diethyl ether (20 mL).
The reaction mixture was warmed gently before adding allyl bromide (1.04 mL, 6.1 mmol)
dropwise. The reaction turns exothermic and was cooled in an ice bath. After the addition of
1-bromopropane was complete, the reaction was stirred for 1 h to obtain the Grignard reagent.
1-phenylbut-3-en-1-ol (9b)30
To benzaldehyde (0.20 mL, 2 mmol) in THF (20 mL) at 0 °C was added dropwise 0.6 M
allylmagnesium bromide in diethyl ether (4 mmol). The reaction was allowed to slowly warm
up to room temperature and left stirring for 8 h. Saturated ammonium chloride solution was
used to quench the reaction, followed by extraction with diethyl ether (x 3). The organic layer
was then washed with brine, dried with sodium sulphate and evaporated to dryness to obtain
the product (290 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.33 (m, 4H), 7.32 – 7.26 (m,
1H), 5.89 – 5.74 (m, 1H), 5.21 – 5.12 (m, 2H), 4.74 (dd, J = 7.6, 5.3 Hz, 1H), 2.59 – 2.45 (m,
2H), 2.08 (s, 1H).
Non-1-en-4-ol (9c)31
To hexanal (0.25 mL, 2 mmol) in THF (20 mL) at 0 °C was added dropwise 0.6 M
allylmagnesium bromide in diethyl ether (7 mL, 4 mmol). The reaction was allowed to slowly
warm to room temperature and left stirring for 8 h. Saturated ammonium chloride solution was
used to quench the reaction, followed by extraction with diethyl ether (x 3). The organic layer
was then washed with brine and dried with sodium sulphate and evaporated to dryness. Flash
chromatography, eluting with 10% EtOAc/petroleum spirits afforded the product with minor
impurities which was directly used for the next step of TBS-protection.
tert-Butyldimethyl((1-phenylbut-3-en-1-yl)oxy)silane (10b)32
Title compound was prepared from 1-phenylbut-3-en-1-ol (368 mg, 2.48 mmol) according to
the General Procedure C. Flash chromatography, eluting with 100% petroleum spirits afforded
the product (500 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.27 (m, 4H), 7.22 – 7.20 (m,
1H), 5.78 (m, 1H), 5.08 – 4.94 (m, 2H), 4.68 (dd, J = 7.3, 5.2 Hz, 1H), 2.54 – 2.31 (m, 2H),
0.88 (s, 9H), 0.03 (s, 3H), -0.13 (s, 3H).
tert-Butyldimethyl(non-1-en-4-yloxy)silane (10c)33
Title compound was prepared from non-1-en-4-ol (380 mg, 2.4 mmol) according to the General
Procedure C. Flash chromatography, eluting with 100% petroleum spirits afforded the product
(303 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 5.81 (ddt, J = 17.6, 10.4, 7.2 Hz, 1H), 5.09 – 4.94
(m, 2H), 3.67 (q, J = 5.8 Hz, 1H), 2.28 – 2.13 (m, 2H), 1.51 – 1.13 (m, 9H), 0.88 (s, 11H), 0.04
(d, J = 0.8 Hz, 6H).
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(E)-3-Benzyl-4-(5-((tert-butyldimethylsilyl)oxy)pent-2-enoyl)thiazolidin-2-one (11a)
To of 4-acryloyl-3-benzylthiazolidin-2-one (560 mg, 2.26 mmol) dissolved in DCE (12 mL) was
added (but-3-en-1-yloxy)(tert-butyl)dimethylsilane (1.27 g, 6.8 mmol) and catalytic Hoveyda-
Grubbs’ II catalyst (142 mg, 0.23 mmol). The reaction was then heated to 50 °C for 12 h. Upon
completion of the reaction, as indicated by TLC analysis, the reaction mixture was filtered
through celite to remove the catalyst and then subjected to flash chromatography, eluting with
15% EtOAc/petroleum spirits to obtain the product (150 mg, 67%). HPLC – rt 9.46 min > 81%
purity at 254 nm; HRMS [M+H]+ 406.1867m/z, found 406.1856m/z; 1H NMR (400 MHz, CDCl3)
δ 7.35 – 7.27 (m, 3H), 7.22 – 7.15 (m, 2H), 7.00 (dt, J = 15.6, 7.0 Hz, 1H), 6.25 (dt, J = 15.7,
1.5 Hz, 1H), 5.14 (d, J = 15.0 Hz, 1H), 4.29 (dd, J = 9.3, 4.4 Hz, 1H), 3.83 (d, J = 14.9 Hz, 1H),
3.72 (t, J = 6.1 Hz, 2H), 3.49 (dd, J = 11.4, 9.4 Hz, 1H), 3.13 (dd, J = 11.4, 4.4 Hz, 1H), 2.46
– 2.37 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 194.7, 172.2, 148.9,
135.5, 129.0, 128.6, 128.2, 126.3, 63.8, 61.2, 47.9, 36.3, 28.1, 26.0, -5.2.
(E)-4-(5-((tert-Butyldimethylsilyl)oxy)pent-2-enoyl)-3-(3,4-dimethoxybenzyl)thiazolidin-
2-one (11b)
To 4-acryloyl-3-(3,4-dimethoxybenzyl)thiazolidin-2-one (530 mg, 1.7 mmol) dissolved in DCE
(9 mL) was added (but-3-en-1-yloxy)(tert-butyl)dimethylsilane (643 mg, 3.45 mmol) and
catalytic Hoveyda-Grubbs’ II catalyst (53 mg, 0.085 mmol). The reaction was then heated to
50 °C for 12 h. Upon completion of the reaction, as indicated by TLC analysis, the reaction
mixture was filtered through celite to remove the catalyst and then subjected to flash
chromatography, eluting with 15% EtOAc/petroleum spirits to obtain the product (389 mg,
49%). HPLC – rt 8.83 min > 95% purity at 254 nm; HRMS [M+Na]+ 488.1897 m/z, found
1
488.1916 m/z; H NMR (400 MHz, CDCl3) δ 7.03 (dt, J = 15.7, 7.0 Hz, 1H), 6.78 (d, J = 8.1
Hz, 1H), 6.76 – 6.66 (m, 2H), 6.27 (dt, J = 15.7, 1.5 Hz, 1H), 5.07 (d, J = 14.7 Hz, 1H), 4.27
(dd, J = 9.3, 4.7 Hz, 1H), 3.85 (d, J = 5.7 Hz, 6H), 3.80 (d, J = 14.7 Hz, 1H), 3.73 (t, J = 6.1
Hz, 2H), 3.47 (dd, J = 11.4, 9.3 Hz, 1H), 3.13 (dd, J = 11.4, 4.7 Hz, 1H), 2.43 (qd, J = 6.2, 1.4
13
Hz, 2H), 0.87 (s, 9H), 0.04 (d, J = 0.5 Hz, 6H); C NMR (101 MHz, CDCl3) δ 194.9, 172.2,
149.5, 149.1, 148.8, 128.0, 126.3, 121.3, 111.9, 111.2, 64.1, 61.3, 56.1, 56.1, 47.9, 36.4, 28.1,
26.0, -5.2.
(E)-4-(5-((tert-Butyldimethylsilyl)oxy)-5-phenylpent-2-enoyl)-3-(4-
methoxybenzyl)thiazolidin-2-one (11c)
To 4-acryloyl-3-(4-methoxybenzyl)thiazolidin-2-one (743 mg, 3.8 mmol) dissolved in DCE (10
mL) was added tert-butyldimethyl((1-phenylbut-3-en-1-yl)oxy)silane (500 g, 1.9 mmol) and
catalytic Hoveyda-Grubbs’ II catalyst (60 mg, 0.095 mmol). The reaction was then heated to
50 °C for 12 h. Upon completion of the reaction, as indicated by TLC analysis, the reaction
mixture was filtered through celite to remove the catalyst and then subjected to flash
chromatography, eluting with 25% EtOAc/petroleum spirits to obtain the product as a mixture
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10.1002/cmdc.202000399
ChemMedChem
of two diastereomers A and B in 1:1 ratio, respectively (340 mg, 35%).HPLC – rt 4.52 min >
96% purity at 254 nm; HRMS [M+Na]+ 534.2105 m/z, found 534.2114 m/z; 1H NMR (400 MHz,
CDCl3) δ 7.35 – 7.20 (m, 10H), 7.07 – 7.03 (m, 4H), 6.96 – 6.94 (m, 2H), 6.87 – 6.77 (m, 4H),
6.11 – 6.10 (m, 2H), 5.04 – 5.01 (m, 2H), 4.82 – 4.79 (m, 2H), 4.19 – 4.16 (m, 2H), 3.79 (s,
6H), 3.75 – 3.62 (m, 2H), 3.44 – 3.33 (m, 2H), 3.05 – 2.96 (m, 2H), 2.67 – 2.49 (m, 4H), 0.87
(d, J = 3.5 Hz, 18H), 0.01 (d, J = 7.0 Hz, 6H), -0.13 (d, J = 3.3 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 194.8, 194.7, 159.5, 147.8, 147.7, 144.0, 130.1, 128.4, 127.6, 127.6, 127.5, 127.5,
127.1, 127.0, 125. 8, 125.8, 114.3, 73.8, 63.9, 63.8, 55.4, 47.3, 47.3, 44.3, 44.3, 31.1, 28.0,
28.0, 25.9, 25.9, -4.6, -4.9.
(E)-4-(5-((tert-Butyldimethylsilyl)oxy)dec-2-enoyl)-3-(4-methoxybenzyl)thiazolidin-2-
one (11d)
To 4-acryloyl-3-(4-methoxybenzyl)thiazolidin-2-one (484 mg, 2.13 mmol) dissolved in DCE (7
mL) was added tert-butyldimethyl(non-1-en-4-yloxy)silane (303.7 g, 1.18 mmol) and catalytic
Hoveyda-Grubbs’ II catalyst (37 mg, 0.06 mmol). The reaction was then heated to 50 °C for
12 h. Upon completion of the reaction, as indicated by TLC analysis, the reaction mixture was
filtered through celite to remove the catalyst and then subjected to flash chromatography,
eluting with 15% EtOAc/petroleum spirits to obtain the product as a single diastereomer and
a clear oil (139.5 mg, 23%).
HPLC – rt 5.95 min > 99% purity at 214 nm; HRMS [M+H]+ 506.2755 m/z, found 506.2759
m/z; 1H NMR (400 MHz, CDCl3) δ 7.09 (dd, J = 14.4, 5.4 Hz, 2H), 7.04 (dtd, J = 9.7, 7.4, 2.3
Hz, 1H), 6.83 (dd, J = 8.7, 0.8 Hz, 2H), 6.23 (dd, J = 15.6, 1.4 Hz, 1H), 5.08 (d, J = 14.8 Hz,
1H), 4.26 (ddd, J = 9.3, 4.6, 1.8 Hz, 1H), 3.87 – 3.71 (m, 5H), 3.47 (ddd, J = 11.6, 9.3, 2.4 Hz,
1H), 3.11 (ddd, J = 11.4, 4.6, 0.8 Hz, 1H), 2.48 – 2.24 (m, 2H), 1.45 – 1.19 (m, 8H), 0.93 –
0.80 (m, 12H), 0.09 – -0.02 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 194.8, 172.1, 159.6, 149.0,
130.1, 127.5, 126.6, 114.4, 71.2, 63.9, 55.4, 47.4, 40.8, 37.5, 32.0, 28.1, 26.0, 25.1, 22.8, 18.2,
14.2, -4.3.
4-(2,4-Dihydroxytetrahydro-2H-pyran-2-yl)-3-(3,4-dimethoxybenzyl)thiazolidin-2-one
(12b)
Title compound was prepared from (E)-4-(5-((tert-butyldimethylsilyl)oxy)pent-2-enoyl)-3-(3,4-
dimethoxybenzyl)thiazolidin-2-one (389 mg, 0.835 mmol) according to the General Procedure
D. The crude was directly used for the next step of acetal formation.
(4R)-4-((2S)-2,4-Dihydroxy-6-phenyltetrahydro-2H-pyran-2-yl)-3-(4-
methoxybenzyl)thiazolidin-2-one (12c)
Title compound was prepared using (E)-4-(5-((tert-butyldimethylsilyl)oxy)-5-phenylpent-2-
enoyl)-3-(4-methoxybenzyl)thiazolidin-2-one (340 mg, 0.66 mmol) according to the General
Procedure D as a clear oil and a mixture of two diastereomers A and B in 1:1 ratio, respectively
(75 mg, 26%). HPLC – rt (diastereomer A) 6.36 min (46%), (diastereomer B) 6.27 min (38%),
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1
collectively > 84% purity at 254 nm; HRMS [M+H]+ 416.1526 m/z, found 416.1532 m/z; H
NMR (400 MHz, CDCl3) δ 7.42 – 7.27 (m, 10H), 6.98 (dd, J = 8.5, 6.3 Hz, 4H), 6.80 – 6.75 (m,
2H), 6.74 – 6.67 (m, 2H), 5.13 (d, J = 14.5 Hz, 1H), 4.99 – 4.91 (m, 2H), 4.91 – 4.78 (m, 1H),
4.38 (d, J = 12.9 Hz, 1H), 4.34 (d, J = 12.8 Hz, 1H), 4.31 – 4.22 (m, 2H), 3.76 –3.72 (m, 8H),
3.59 (dd, J = 9.4, 1.5 Hz, 1H), 3.41 (dd, J = 11.9, 1.6 Hz, 1H), 3.36 – 3.23 (m, 2H), 3.06 (dd,
J = 40.2, 2.4 Hz, 2H), 2.38 – 2.12 (m, 4H), 1.68 – 1.59 (m, 4H), 1.32 –0.80 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 174.3, 173.2, 159.1, 159.0, 141.1, 140.8, 129.7, 129.5, 128.6, 128.5,
128.1, 128.0, 126.7, 126.3, 114.1, 114.0, 101.4, 100.4, 72.4, 71.8, 64.9, 64.8, 64.6, 64.1, 55.3,
55.3, 48.3, 47.6, 42.7, 41.9, 38.3, 37.1, 27.7, 26.9, 26.5, 22.6.
(4R)-4-(2,4-Dihydroxy-6-pentyltetrahydro-2H-pyran-2-yl)-3-(4-
methoxybenzyl)thiazolidin-2-one (12d)
Title compound was prepared using (E)-4-(5-((tert-butyldimethylsilyl)oxy)dec-2-enoyl)-3-(4-
methoxybenzyl)thiazolidin-2-one (139.5 mg, 0.35 mmol) according to the General Procedure
D as a clear oil which was directly used for the next step of acetal formation.
4-(2-Ethoxy-4-hydroxytetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one
(13a)
Title compound was prepared according to General Procedure E using 4-(2,4-
dihydroxytetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one (100 mg, 0.3 mmol)
and EtOH (2 mL) as a milky oil and a mixture of two diastereomers; A and B in 1:0.44 ratio,
respectively (47.2 mg, 42%). HPLC – rt (diastereomer A) 6.46 min (64%), (diastereomer B)
6.41 min (24%), collectively > 88% purity at 254 nm; HRMS [M+Na]+ 390.1346 m/z, found
390.1341 m/z; 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.18 (m, 2H), 7.10 (d, J = 8.5 Hz, 1H), 6.85
– 6.82 (m, 3H), 5.19 (d, J = 15.6 Hz, 0.5H), 5.01 (d, J = 14.3 Hz, 1H), 4.26 – 4.23 (m, 1.5H),
4.16 – 4.01 (m, 2H), 4.01 – 3.89 (m, 1H), 3.91 – 3.65 (m, 7.5H), 3.65 – 3.55 (m, 1H), 3.55 –
3.03 (m, 6.5H), 2.21 (ddd, J = 12.5, 4.6, 1.8 Hz, 1H), 2.10 (ddd, J = 12.8, 4.7, 1.7 Hz, 0.5H),
1.98 – 1.31 (m, 4.5H), 1.14 (dt, J = 14.1, 7.0 Hz, 4.5H); 13C NMR (101 MHz, CDCl3) δ 173.6,
173.0, 159.2, 159.1, 130.2, 129.9, 129.7, 129.0, 128.8, 128.1, 114.3, 114.2, 114.2, 114.0,
103.3, 102.4, 64.5, 60.4, 60.3, 59.7, 57.6, 55.4, 55.4, 55.2, 54.8, 47.4, 46.7, 38.1, 37.4, 34.8,
34.6, 26.3, 25.5, 15.4, 15.1.
4-(2-Butoxy-4-hydroxytetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one
(13b)
Title compound was prepared according to General Procedure E using 4-(2,4-
dihydroxytetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one (112 mg, 0.33
mmol) and n-butanol (4 mL) as a clear oil and a mixture of two diastereomers; A and B in 1:0.4
ratio respectively (57.3 mg, 44%). HPLC – rt (diastereomer A) 7.45 min (70%), (diastereomer
B) 7.33 (23%), collectively > 93% purity at 254 nm; HRMS [M+H]+ 396.1839 m/z, found
396.1849 m/z; 1H NMR (diastereomers A) (400 MHz, CDCl3) δ 7.22 – 7.18 (m, 2H), 6.85 –
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10.1002/cmdc.202000399
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6.77 (m, 2H), 5.01 (d, J = 14.4 Hz, 1H), 4.29 (d, J = 14.4 Hz, 1H), 4.15 – 4.01 (m, 1H), 3.90 –
3.81 (m, 2H), 3.79 (s, 3H), 3.66 – 3.57 (m, 1H), 3.44 – 3.34 (m, 1H), 3.31 – 3.20 (m, 2H), 3.07
– 3.00 (m, 1H), 2.21 (ddd, J = 12.4, 4.6, 1.8 Hz, 1H), 1.98 – 1.87 (m, 1H), 1.60 – 1.43 (m, 4H),
1
1.43 – 1.23 (m, 2H), 0.91 – 0.88 (m, 3H); H NMR (diastereomers B) (400 MHz, CDCl3) δ
7.10 – 7.02 (m, 2H), 6.85 – 6.77 (m, 2H), 5.20 (d, J = 15.6 Hz, 1H), 4.23 (d, J = 15.6 Hz, 1H),
4.15 – 4.01 (m, 1H), 3.99 (dd, J = 8.0, 5.0 Hz, 1H), 3.82 – 3.73 (m, 4H), 3.57 – 3.48 (m, 1H),
3.44 – 3.34 (m, 2H), 3.31 – 3.20 (m, 1H), 3.07 – 2.96 (m, 1H), 2.10 (ddd, J = 12.7, 4.7, 1.8 Hz,
1H), 1.98 – 1.87 (m, 1H), 1.66 (dd, J = 12.6, 10.9 Hz, 1H), 1.60 – 1.43 (m, 3H), 1.43 – 1.23
(m, 2H), 0.91 – 0.85 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 173.5, 173.0, 159.2, 159.1, 130.2,
130.0, 129.1, 128.8, 128.2, 114.3, 114.0, 103.2, 102.4, 64.5, 60.3, 60.2, 59.7, 59.4, 59.2, 57.4,
55.4, 55.4, 47.5, 46.6, 38.2, 37.5, 34.8, 34.6, 32.0, 26.3, 25.5, 19.7, 19.7, 14.3, 14.1.
4-(4-Hydroxy-2-(2-methoxyethoxy)tetrahydro-2H-pyran-2-yl)-3-(4-
methoxybenzyl)thiazolidin-2-one (13c)
Title compound was prepared according to General Procedure E using 4-(2,4-
dihydroxytetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one (112 mg, 0.329
mmol) and 2-methoxyethanol (10 mL) as a clear oil and a mixture of two diastereomers; A and
B in 1:1 ratio, respectively (43 mg, 32%). HPLC – rt 5.4 min > 87% purity at 254 nm; HRMS
[M+H]+ 398.1632 m/z, found 398.1625m/z; 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.7 Hz,
2H), 7.14 – 7.08 (m, 2H), 6.89 – 6.80 (m, 4H), 5.03 (dd, J = 14.6, 1.9 Hz, 2H), 4.31 – 4.24 (m,
2H), 4.15 – 4.05 (m, 2H), 3.86 (m, 2H), 3.83 – 3.74 (m, 11H), 3.70 – 3.65 (m, 1H), 3.63 – 3.58
(m, 1H), 3.59 – 3.20 (m, 15H), 2.26 (ddd, J = 12.6, 4.6, 2.0 Hz, 1H), 1.95 – 1.88 (m, 2H), 1.67
– 1.58 (m, 1H), 1.56 – 1.40 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 173.0, 130.2, 130.1, 129.0,
127.5, 114.4, 114.3, 114.2, 114.1, 71.8, 64.5, 64.1, 60.9, 60.6, 60.4, 59.7, 59.5, 59.3, 55.5,
55.4, 47.5, 47.5, 37.4, 35.9, 34.7, 28.1, 25.6.
3-Benzyl-4-(4-hydroxy-2-methoxytetrahydro-2H-pyran-2-yl)thiazolidin-2-one (13d)
Title compound was prepared in two steps. In the first step, the starting material, (E)-3-benzyl-
4-(5-((tert-butyldimethylsilyl)oxy)pent-2-enoyl)thiazolidin-2-one (391.6 mg, 0.965 mmol) was
converted to the hemiacetal 3-benzyl-4-(2,4-dihydroxytetrahydro-2H-pyran-2-yl)thiazolidin-2-
one according to General Procedure D (262.7 mg, 88%). The product obtained was treated
with MeOH according to General Procedure E to obtain the title compound as two
diastereomers A and B in 1: 0.6 ratios, respectively (157.3 mg, 57%). 1H NMR (400 MHz,
CDCl3) δ 7.41 – 7.17 (m, 8H), 5.29 (d, J = 15.8 Hz, 0.6H), 5.06 (d, J = 14.5 Hz, 1H), 4.39 (d,
J = 14.6 Hz, 1H), 4.29 (d, J = 15.8 Hz, 0.6H), 4.10 – 3.99 (m, 1.6H), 3.96 (dd, J = 8.8, 4.0 Hz,
0.6H), 3.86 (m, 1.6H), 3.83 – 3.76 (m, 1H), 3.60 (ddd, J = 13.7, 11.4, 2.4 Hz, 1H), 3.56 – 3.48
(m, 0.6H), 3.44 – 3.15 (m, 3.2H), 3.08 (s, 3H), 2.98 (s, 1.8H), 2.21 (ddd, J = 12.5, 4.7, 2.0 Hz,
1H), 2.12 (ddd, J = 12.6, 4.7, 1.9 Hz, 0.6H), 1.98 – 1.86 (m, 1.6H), 1.69 (dd, J = 12.8, 10.9 Hz,
1H), 1.61 – 1.30 (m, 2.2H).
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3-(3,4-dimethoxybenzyl)-4-(4-hydroxy-2-methoxytetrahydro-2H-pyran-2-yl)thiazolidin-
2-one (13e)
Title compound was prepared from 4-(2,4-dihydroxytetrahydro-2H-pyran-2-yl)-3-(3,4-
dimethoxybenzyl)thiazolidin-2-one (531 mg, 1.44 mmol) and MeOH (15 mL) according to
General Procedure E as a pale yellow oil and a mixture of two diastereomers A and B in 1:0.7
ratio, respectively, over 2 steps (138 mg, 43%). HPLC – rt 5.47 min > 90% purity at 254 nm;
HRMS [M+H]+ 384.1475 m/z, found 384.1489 m/z; 1H NMR (400 MHz, CDCl3) δ 6.93 – 6.66
(m, 5.1H), 5.21 (d, J = 15.4 Hz, 0.7H), 5.03 (d, J = 14.3 Hz, 1H), 4.26 (d, J = 14.3 Hz, 1H),
4.19 (d, J = 15.4 Hz, 0.7H), 4.09 – 3.98 (m, 1.7H), 3.96 (dd, J = 7.3, 5.6 Hz, 0.7H), 3.93 – 3.83
(m, 11.9H), 3.83 – 3.74 (m, 1H), 3.62 (ddd, J = 13.4, 11.5, 2.3 Hz, 1H), 3.57 – 3.47 (m, 0.7H),
3.39 – 3.18 (m, 3.4H), 3.09 (s, 3H), 3.02 (s, 2.1H), 2.24 – 2.17 (m, 1H), 2.09 – 1.99 (m, 0.7H),
1.99 – 1.85 (m, 2.4H), 1.80 (d, J = 5.3 Hz, 1H), 1.66 (dd, J = 12.8, 10.9 Hz, 0.7H), 1.59 – 1.38
(m, 2.7H); 13C NMR (101 MHz, CDCl3) δ 149.4, 149.2, 148.7, 129.4, 129.2, 121.4, 119.6, 112.0,
112.0, 111.2, 111.1, 110.5, 103.2, 102.5, 64.5, 64.4, 60.5, 60.3, 59.2, 56.9, 56.0, 56.0, 56.0,
47.8, 47.8, 47.6, 47.1, 37.9, 37.3, 34.7, 34.5, 32.5, 31.6, 26.3, 25.4.
4-(4-Hydroxy-2-methoxy-6-pentyltetrahydro-2H-pyran-2-yl)-3-(4-
methoxybenzyl)thiazolidin-2-one (13g)
Title compound was prepared using (4R)-4-(2,4-dihydroxy-6-pentyltetrahydro-2H-pyran-2-yl)-
3-(4-methoxybenzyl)thiazolidin-2-one (108 mg, 0.26 mmol) and MeOH according to the
General Procedure E as a clear oil as a mixture of two diastereomers A and B in 1:0.8 ratio,
respectively (30.4 mg, 15% over 2 steps). HPLC – rt 7.48 min > 53% purity at 254 nm; HRMS
[M+H]+ 424.2152 m/z, found 424.2157 m/z; 1H NMR (400 MHz, CDCl3) δ 7.20 – 6.80 (m, 7.2H),
5.20 (d, J = 15.4 Hz, 0.8H), 5.10 (d, J = 14.4 Hz, 1H), 4.27 – 4.21 (m, 1H), 4.25 – 4.18 (m,
0.8H), 4.09 – 4.00 (m, 1.8H), 3.93 (dd, J = 8.5, 4.3 Hz, 0.8H), 3.87 – 3.81 (m, 1H), 3.78 – 3.70
(m, 5.4H), 3.62 – 3.46 (m, 1.8H), 3.40 – 3.13 (m, 3.6H), 3.06 (s, 3H), 3.00 (s, 2.4H), 2.46 –
2.37 (m, 1.8H), 2.32 (ddd, J = 14.8, 8.2, 7.0 Hz, 1H), 2.20 (ddd, J = 12.5, 4.7, 1.7 Hz, 0.8H),
2.13 – 2.05 (m, 1.8H), 2.03 – 0.8(m, 23.4H); 13C NMR (101 MHz, CDCl3) δ 159.2, 159.1, 130.0,
128.9, 128.7, 128.6, 114.2, 114.1, 103.1, 102.5, 70.4, 70.2, 64.8, 58.9, 57.0, 55.4, 55.4, 53.6,
47.8, 47.6, 47.2, 46.8, 40.6, 40.2, 37.8, 37.1, 36.3, 35.7, 32.0, 32.0, 26.3, 25.6, 25.4, 25.1,
22.8, 22.7, 14.2, 14.1.
2-Ethoxy-2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)tetrahydro-2H-pyran-4-yl 2-
(thiophen-2-yl)benzoate (14a)
Title compound was prepared using 4-(2-ethoxy-4-hydroxytetrahydro-2H-pyran-2-yl)-3-(4-
methoxybenzyl)thiazolidin-2-one (19.5 mg, 0.053 mmol) and 2-(thiophen-2-yl)benzoic acid (33
mg, 0.16 mmol) according to General Procedure F as a clear oil and a mixture of two
diastereomers; A and B in 1:0.5 ratio respectively (80%). HPLC – rt 9.21 min > 97% purity at
1
254 nm; HRMS [M+Na]+ 576.1485 m/z, found 576.1501 m/z; H NMR (400 MHz, CDCl3) δ
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10.1002/cmdc.202000399
ChemMedChem
7.81 – 7.73 (m, 1.5H), 7.54 – 7.35 (m, 6H), 7.21 (d, J = 8.6 Hz, 2H), 7.09 (ddd, J = 8.7, 8.0,
6.0 Hz, 2.5H), 6.99 (dt, J = 3.5, 1.1 Hz, 1.5H), 6.91 – 6.80 (m, 3H), 5.29 – 5.17 (m, 2H), 5.01
(d, J = 14.4 Hz, 1H), 4.22 (dd, J = 15.0, 9.9 Hz, 1.5H), 3.96 (dd, J = 8.9, 4.0 Hz, 0.5H), 3.86 –
3.69 (m, 7H), 3.68 – 3.59 (m, 1H), 3.58 – 3.49 (m, 0.5H), 3.49 – 3.02 (m, 6H), 2.09 (ddd, J =
12.5, 4.7, 1.7 Hz, 2H), 1.89 (dddd, J = 9.6, 7.2, 4.6, 2.8 Hz, 1H), 1.56 – 1.25 (m, 3H), 1.16 (dt,
J = 15.6, 7.0 Hz, 4.5H); 13C NMR (101 MHz, CDCl3) δ 172.8, 168.1, 168.0, 159.2, 142.2, 134.7,
132.3, 132.2, 131.6, 131.5, 131.2, 131.2, 130.2, 129.8, 129.7, 129.0, 128.8, 128.1, 128.0,
127.3, 126.6, 126.2, 126.0, 114.3, 114.1, 103.2, 102.3, 68.3, 59.9, 59.7, 57.2, 55.4, 55.4, 55.4,
54.9, 47.4, 46.6, 33.7, 33.2, 30.9, 30.8, 27.0, 26.2, 25.3, 15.4, 15.1.
2-Butoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)tetrahydro-2H-pyran-4-yl 2-
(thiophen-2-yl)benzoate (14b)
Title compound was prepared using 4-(2-butoxy-4-hydroxytetrahydro-2H-pyran-2-yl)-3-(4-
methoxybenzyl)thiazolidin-2-one (51.3 mg, 0.13 mmol) and 2-(thiophen-2-yl)benzoic acid (79
mg, 0.39 mmol) according to General Procedure F as a clear oil and a mixture of two
diastereomers; A and B in 1:0.5 ratio, respectively (38.7 mg, 51%). HPLC – rt 9.79 min > 99%
purity at 254 nm; HRMS [M+H]+ 582.1979 m/z, found 582.1991 m/z; 1H NMR (400 MHz, CDCl3)
δ 7.77 (m, 1.5H), 7.54 – 7.37 (m, 6H), 7.21 – 7.19 (m, 2H), 7.13 – 7.06 (m, 2.5H), 6.98 – 6.91
(m, 1.5H), 6.90 – 6.82 (m, 3H), 5.26 – 5.15 (m, 2H), 5.00 (d, J = 14.4 Hz, 1H), 4.24 (d, J =
14.2 Hz, 1H), 4.21 (d, J = 14.9 Hz, 0.5H), 3.98 (dd, J = 8.9, 4.0 Hz, 0.5H), 3.86 – 3.81 (m,
1.5H), 3.79 (s, 4.5H), 3.78 – 3.68 (m, 1H), 3.68 – 3.60 (m, 1H), 3.59 – 3.50 (m, 0.5H), 3.43 –
3.17 (m, 4.5H), 3.12 – 2.98 (m, 1.5H), 2.09 (ddd, J = 12.5, 4.7, 1.7 Hz, 1H), 1.97 – 1.82 (m,
2H), 1.60 – 1.24 (m, 9H), 0.92 – 0.86 (m, 4.5H); 13C NMR (101 MHz, CDCl3) δ 173.2, 172.8,
168.0, 167.9, 159.2, 159.1, 142.2, 134.7, 134.5, 132.3, 132.2, 131.6, 131.5, 131.2, 131.1,
130.2, 129.8, 129.7, 129.0, 128.8, 128.1, 128.0, 127.3, 126.6, 126.1, 126.0, 114.3, 114.0,
103.1, 102.2, 68.3, 59.74, 59.66, 59.56, 59.32, 57.13, 55.40, 55.36, 47.42, 46.50, 33.70, 33.17,
31.95, 30.84, 30.7, 27.0, 26.2, 25.3, 19.7, 19.6, 14.3, 14.0.
2-((R)-3-(4-Methoxybenzyl)-2-oxothiazolidin-4-yl)-2-(2-methoxyethoxy)tetrahydro-2H-
pyran-4-yl 2-(thiophen-2-yl)benzoate (14c)
Title compound was prepared using 4-(4-hydroxy-2-(2-methoxyethoxy)tetrahydro-2H-pyran-
2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one (40 mg, 0.1 mmol) and 2-(thiophen-2-yl)benzoic
acid (62 mg, 0.3 mmol) according to General Procedure F as a clear oil (10.4 mg, 18%). HPLC
– rt 8.82 min > 99% purity at 254 nm; HRMS [M+Na]+ 606.1591 m/z, found 606.1608 m/z; 1H
NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 7.6, 0.9 Hz, 1H), 7.55 – 7.35 (m, 4H), 7.20 (m, 2H),
7.09 (dd, J = 5.1, 3.5 Hz, 1H), 6.98 (dd, J = 3.5, 1.1 Hz, 1H), 6.85 – 6.81 (m, 2H), 5.30 – 5.14
(m, 1H), 5.01 (d, J = 14.4 Hz, 1H), 4.23 (d, J = 14.4 Hz, 1H), 3.80 – 3.75 (m, 5H), 3.77 – 3.67
(m, 1H), 3.57 – 3.50 (m, 1H), 3.49 – 3.41 (m, 2H), 3.33 (s, 3H), 3.31 – 3.20 (m, 3H), 2.13 (ddd,
J = 12.6, 4.7, 1.6 Hz, 1H), 1.89 – 1.85 (m, 1H), 1.50 – 1.28 (m, 2H); 13C NMR (101 MHz,
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10.1002/cmdc.202000399
ChemMedChem
CDCl3) δ 172.9, 167.9, 159.2, 142.2, 134.7, 132.2, 131.6, 131.2, 130.2, 129.9, 129.0, 128.0,
127.4, 126.6, 126.0, 114.1, 103.4, 71.7, 68.2, 59.9, 59.7, 59.7, 59.3, 55.4, 47.5, 33.0, 30.7,
25.4.
2-((R)-3-Benzyl-2-oxothiazolidin-4-yl)-2-methoxytetrahydro-2H-pyran-4-yl furan-2-
carboxylate (14g)
Title compound was prepared from 3-benzyl-4-(4-hydroxy-2-methoxytetrahydro-2H-pyran-2-
yl)thiazolidin-2-one (50 mg, 0.15 mmol) and 2-furoic acid (52 mg, 0.46 mmol) according to the
General Procedure F as a clear oil and a mixture of two diastereomers A and B in 1:0.6 ratio,
respectively (62.5 mg, 99%). HPLC – rt 7.87 min > 95% purity at 254 nm; HRMS [M+H]+
418.1319 m/z, found 418.1325 m/z; 1H NMR (400 MHz, CDCl3) δ 7.54 – 6.40 (m, 12.8H), 5.40
– 5.27 (m, 1.6H), 5.24 – 5.19 (m, 0.6H), 5.06 (d, J = 14.6 Hz, 1H), 4.35 (d, J = 14.5 Hz, 1H),
4.24 (d, J = 15.7 Hz, 0.6H), 3.95 – 3.83 (m, 3.2H), 3.64 – 3.61 (m, 1.6H), 3.37 – 3.26 (m, 3.2H),
3.07 (s, 3H), 2.97 (s, 1.8H), 2.26 – 2.18 (m, 1H), 2.18 – 2.06 (m, 0.6H), 2.04 – 2.01 (m, 1.6H),
1.91 – 1.85 (m, 0.6H), 1.76 – 1.65 (m, 1H), 1.72 – 1.41 (m, 1.6H); 13C NMR (101 MHz, CDCl3)
δ 146.6, 129.0, 128.8, 128.7, 127.8, 127.7, 127.2, 118.4, 118.3, 112.0, 68.1, 68.0, 60.0, 59.9,
59.6, 56.8, 48.3, 47.7, 47.3, 34.3, 33.7, 31.3, 31.2, 26.2, 25.4.
2-(3-Benzyl-2-oxothiazolidin-4-yl)-2-methoxytetrahydro-2H-pyran-4-yl 2-iodobenzoate
(14h)
Title compound was prepared from 3-benzyl-4-(4-hydroxy-2-methoxytetrahydro-2H-pyran-2-
yl)thiazolidin-2-one (100 mg, 0.31 mmol) and 2-iodobenzoic acid (230 mg, 0.93 mmol)
according to the General Procedure F as a clear oil and a mixture of two diastereomers; A and
B in 1:0.7 ratio, respectively (153.6 mg, 89%). HPLC – rt 8.75 min > 99% purity at 254 nm;
HRMS [M+H]+ 554.0493 m/z, found 554.0519 m/z; 1H NMR (400 MHz, CDCl3) δ 7.99 – 7.85
(m, 1.7H), 7.79 – 7.71 (m, 1.7H), 7.42 – 7.35 (m, 1.7H), 7.39 – 7.27 (m, 7.5H), 7.22 – 7.15 (m,
1H), 7.16 – 7.08 (m, 1.7H), 5.43 – 5.33 (m, 1.7H), 5.30 (d, J = 15.9 Hz, 0.7H), 5.08 (d, J = 14.6
Hz, 1H), 4.42 (d, J = 14.6 Hz, 1H), 4.31 (d, J = 15.8 Hz, 0.7H), 4.00 (dd, J = 7.6, 5.2 Hz, 0.7H),
3.96 – 3.82 (m, 2.7H), 3.79 – 3.70 (m, 1H), 3.66 (dd, J = 18.1, 6.5 Hz, 0.7H), 3.46 – 3.23 (m,
3.4H), 3.13 (s, 3H), 3.03 (s, 2.1H), 2.38 (ddd, J = 12.4, 4.8, 1.9 Hz, 1H), 2.28 (ddd, J = 12.6,
4.7, 1.8 Hz, 0.7H), 2.24 – 2.17 (m, 0.7H), 2.17 – 2.08 (m, 1H), 2.00 (dd, J = 12.7, 11.3 Hz,
0.7H), 1.87 – 1.79 (m, 1H), 1.80 – 1.58 (m, 1.7H); 13C NMR (101 MHz, CDCl3) δ 173.2, 166.0,
141.5, 141.4, 137.0, 136.7, 135.0, 132.9, 132.8, 131.2, 131.1, 129.0, 128.8, 128.7, 128.1,
127.8, 127.7, 127.2, 103.3, 102.5, 94.3, 94.2, 69.1, 69.0, 60.1, 59.9, 59.7, 56.9, 48.4, 47.8,
47.7, 47.4, 34.3, 33.7, 31.2, 31.1, 26.3, 25.4.
2-((R)-3-Benzyl-2-oxothiazolidin-4-yl)-2-methoxytetrahydro-2H-pyran-4-yl 2-
(naphthalen-1-yl)benzoate (14i*)
Title compound was prepared from 2-(3-benzyl-2-oxothiazolidin-4-yl)-2-methoxytetrahydro-
2H-pyran-4-yl 2-iodobenzoate (87.3 mg, 0.16 mmol) and 1-naphthalene boronic acid (32.6
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10.1002/cmdc.202000399
ChemMedChem
mg, 0.19 mmol) according to the General Procedure G as a white semisolid as a mixture of
two diastereomers with a combined yield of 50%. Diastereomer A was isolated in 27% yield.
The proton and carbon NMR spectrum show peak splitting due to axial chirality (1:0.76 ratio).
HPLC – rt 4.59 min > 96% purity at 254 nm; HRMS [M+H]+ 554.1996 m/z, found 554.2007
1
m/z; H NMR (400 MHz, CDCl3) δ 8.07 – 8.04 (m, 1.76H), 8.00 – 7.91 (m, 3.52H), 7.63 (m,
1.76H), 7.58 – 7.13 (m, 21.12H), 5.23 (d, J = 14.6 Hz, 1H), 5.19 (d, J = 14.6 Hz, 0.76H), 4.87
– 4.75 (m, 1.76H), 4.15 – 4.02 (m, 1.76H), 3.69 – 3.71 (m, 2.52H), 3.53 – 3.43 (m, 1H), 2.98
– 2.93 (m, 1.76H), 3.22 – 3.16 (m, 3.52H), 2.98 – 2.74 (m, 5.28H), 1.63 – 1.50 (m, 1.76H),
1.49 – 1.40 (m, 1H), 1.37 – 1.23 (m, 0.76H), 0.97 – 0.80 (m, 1.76H), 0.76 – 0.51 (m, 1.76H);
13C NMR (101 MHz, CDCl3) δ 173.5, 173.4, 167.2, 167.2, 141.3, 141.3, 140.2, 140.1, 136.5,
136.5, 133.3, 133.2, 132.5, 132.4, 132.1, 131.9, 131.8, 131.8, 131.7, 130.5, 130.5, 128.9,
128.5, 128.3, 127.8, 127.8, 127.6, 127.6, 127.1, 126.3, 126.1, 126.0, 125.9, 125.9, 125.9,
125.6, 125.4, 125.3, 102.1, 102.0, 67.4, 67.3, 59.7, 59.6, 56.7, 56.6, 47.5, 47.2, 41.0, 32.8,
32.3, 30.4, 29.9, 26.1, 24.0, 22.8, 20.9.
2-((R)-3-Benzyl-2-oxothiazolidin-4-yl)-2-methoxytetrahydro-2H-pyran-4-yl 2-
(naphthalen-1-yl)benzoate (14i#)
Title compound was prepared from 2-(3-benzyl-2-oxothiazolidin-4-yl)-2-methoxytetrahydro-
2H-pyran-4-yl 2-iodobenzoate and 1-naphthalene boronic acid according to the General
Procedure G as a white semisolid in 50% yield as a mixture of two diastereomers.
Diastereomer B was isolated in 21% yield. The proton and carbon NMR spectrum show the
peak splitting due to axial chirality (1:0.76 ratio). HPLC – rt 4.24 min > 99% purity at 254 nm;
HRMS [M+Na]+ 576.1815 m/z, found 576.1824 m/z; 1H NMR (400 MHz, CDCl3) δ 8.11 – 8.04
(m, 1.76H), 8.00 – 7.89 (m, 3.52H), 7.63 – 7.57 (m, 1.76H), 7.58 – 7.19 (m, 21.12H), 5.07 (d,
J = 14.6 Hz, 1H), 4.99 (d, J = 14.6 Hz, 0.76H), 4.87 – 4.75 (m, 1.76H), 4.12 – 4.09 (m, 1.76H),
3.69 – 3.58 (m, 1.76H), 3.65 – 3.57 (m, 0.76H), 3.56 – 3.48 (m, 1H), 3.45 – 3.30 (m, 1.76H),
3.22 – 2.76 (m, 3.52H), 2.95 – 2.93 (m, 5.28H), 1.63 – 1.23 (m, 3.52H), 0.97 – 0.51 (m, 3.52H);
13C NMR (101 MHz, CDCl3) δ 173.0, 172.8, 167.1, 167.0, 141.5, 141.4, 140.2, 140.1, 136.8,
133.3, 133.2, 132.5, 132.4, 132.2, 132.0, 132.0, 131.8, 131.8, 131.7, 131.6, 130.6, 130.4,
128.9, 128.7, 128.7, 128.6, 128.5, 128.4, 128.3, 127.9, 127.8, 127.8, 127.7, 127.7, 127.1,
126.3, 126.1, 126.0, 126.0, 125.9, 125.8, 125.7, 125.7, 125.6, 125.3, 125.1, 102.7, 102.6, 67.3,
67.2, 59.6, 59.6, 59.5, 59.2, 48.0, 47.9, 47.5, 47.5, 32.5, 32.2, 30.26, 29.6, 24.9, 24.9.
2-(3-(3,4-Dimethoxybenzyl)-2-oxothiazolidin-4-yl)-2-methoxytetrahydro-2H-pyran-4-yl
2-(thiophen-2-yl)benzoate (14j)
Title
compound
was
prepared
from
3-(3,4-dimethoxybenzyl)-4-(4-hydroxy-2-
methoxytetrahydro-2H-pyran-2-yl)thiazolidin-2-one (138 mg, 0.36 mmol) and 2-(thiophen-2-
yl)benzoic acid (221 mg, 1.08 mmol) according to the General procedure F as a mixture of
two diastereomers A and B in 1:1 ratio, respectively (5.6 mg, 3%). HPLC – rt (diastereomer A)
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10.1002/cmdc.202000399
ChemMedChem
8.52 min (50%), (diastereomer B) 8.60 min (40%), collectively > 90% purity at 254 nm; HRMS
[M+Na]+ 592.1434 m/z, found 592.1442 m/z; 1H NMR (400 MHz, CDCl3) δ 7.76 (ddd, J = 7.6,
4.0, 1.3 Hz, 2H), 7.54 – 7.31 (m, 8H), 7.11 – 7.02 (m, 2H), 6.98 (dd, J = 3.5, 1.1 Hz, 2H), 6.86
– 6.78 (m, 4H), 6.75 (dd, J = 4.2, 2.3 Hz, 2H), 5.29 – 5.12 (m, 3H), 5.03 (d, J = 14.3 Hz, 1H),
4.20 (d, J = 14.1 Hz, 1H), 4.17 (d, J = 15.1 Hz, 1H), 4.00 – 3.71 (m, 16H), 3.71 – 3.59 (m, 1H),
3.60 – 3.50 (m, 1H), 3.41 – 3.15 (m, 4H), 3.09 (s, 3H), 3.01 (s, 3H), 2.12 – 2.02 (m, 1H), 1.93
– 1.74 (m, 3H), 1.68 – 1.28 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 168.2, 168.1, 149.4, 149.2,
148.7, 148.6, 142.2, 134.6, 134.5, 132.4, 132.2, 131.5, 131.2, 129.8, 129.7, 129.3, 129.2,
128.0, 127.4, 126.6, 126.0, 121.4, 119.6, 112.1, 111.3, 111.1, 110.6, 103.2, 102.4, 68.2, 60.0,
59.9, 59.2, 56.7, 56.1, 56.0, 47.8, 47.7, 47.6, 47.1, 33.5, 33.1, 30.8, 30.7, 26.1, 25.2.
2-Hydroxy-2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-phenyltetrahydro-2H-pyran-
4-yl 2-(thiophen-2-yl)benzoate (14k)
Title compound was prepared using (4R)-4-((2S)-2,4-dihydroxy-6-phenyltetrahydro-2H-pyran-
2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one (50 mg, 0.12 mmol) and 2-(thiophen-2-yl)benzoic
acid (72 mg, 0.35 mmol) according to the General Procedure F as an off-white solid (4.3 mg,
5%). HPLC – rt 8.93 min > 65% purity at 254 nm; HRMS [M+H]+ 602.1666 m/z, found 602.1656
m/z; 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 7.7, 0.9 Hz, 1H), 7.54 – 7.31 (m, 10H), 7.07
(dd, J = 5.1, 3.5 Hz, 1H), 7.01 – 6.93 (m, 3H), 6.72 (dd, J = 9.1, 2.4 Hz, 2H), 5.42 – 5.35 (m,
1H), 5.16 (d, J = 14.5 Hz, 1H), 5.01 (dd, J = 12.0, 1.9 Hz, 1H), 4.29 (d, J = 14.5 Hz, 1H), 3.74
(s, 3H), 3.54 (dd, J = 9.3, 1.8 Hz, 1H), 3.34 – 3.29 (m, 2H), 2.27 – 2.17 (m, 2H), 1.54 – 1.50
(m, 2H); 13C NMR (101 MHz, CDCl3) δ 172.8, 168.1, 159.3, 142.3, 140.4, 134.7, 132.2, 131.6,
131.3, 129.9, 129.8, 128.8, 128.6, 128.4, 128.1, 127.4, 126.8, 126.7, 126.1, 114.2, 101.6,
72.3, 68.5, 64.3, 55.4, 47.7, 37.8, 33.0, 26.8.
2-Methoxy-2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-pentyltetrahydro-2H-pyran-
4-yl 2-(thiophen-2-yl)benzoate (14l*)
Title compound was prepared using 4-(4-hydroxy-2-methoxy-6-pentyltetrahydro-2H-pyran-2-
yl)-3-(4-methoxybenzyl)thiazolidin-2-one (22 mg, 0.05 mmol) and 2-(thiophen-2-yl)benzoic
acid (30 mg, 0.15 mmol) according to the General Procedure F (6.3 mg, 20%). HPLC – rt 7.28
1
min > 74% purity at 254; HRMS [M+H]+ 610.2292 m/z, found 610.2284 m/z; H NMR (400
MHz, CDCl3) δ 7.74 (dd, J = 7.6, 1.1 Hz, 1H), 7.52 – 7.36 (m, 4H), 7.14 – 7.06 (m, 2H), 7.07
(dd, J = 5.1, 3.5 Hz, 1H), 6.98 (dd, J = 3.5, 1.1 Hz, 1H), 6.91 – 6.83 (m, 2H), 5.28 – 5.12 (m,
2H), 4.19 (d, J = 15.5 Hz, 1H), 3.91 (dd, J = 9.6, 3.3 Hz, 1H), 3.80 (s, 3H), 3.53 – 3.49 (m, 1H),
3.38 – 3.21 (m, 2H), 2.98 (s, 3H), 1.97 – 1.88 (m, 1H), 1.87 – 1.77 (m, 1H), 1.52 – 1.15 (m,
10H), 0.86 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.2, 168.2, 159.2, 142.2, 134.5,
132.5, 131.4, 131.1, 129.6, 128.7, 128.6, 128.0, 127.4, 126.6, 126.2, 114.3, 102.4, 69.7, 68.6,
56.7, 55.4, 47.7, 46.7, 36.3, 35.5, 33.4, 31.9, 26.2, 25.0, 22.7, 14.1; [α]D20 = -136.8° (c 0.38,
MeOH).
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10.1002/cmdc.202000399
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2-Methoxy-2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-pentyltetrahydro-2H-pyran-
4-yl 2-(thiophen-2-yl)benzoate (14l#)
Title compound was prepared using 4-(4-hydroxy-2-methoxy-6-pentyltetrahydro-2H-pyran-2-
yl)-3-(4-methoxybenzyl)thiazolidin-2-one (22 mg, 0.05 mmol) and 2-(thiophen-2-yl)benzoic
acid (30 mg, 0.15 mmol) according to the General Procedure F (8.8 mg, 29%). HPLC – rt 8.89
min > 84% purity at 254 nm; HRMS [M+H]+ 610.2292 m/z, found 610.2232 m/z; 1H NMR (400
MHz, CDCl3) δ 7.76 (dd, J = 7.7, 0.9 Hz, 1H), 7.54 – 7.35 (m, 4H), 7.20 – 7.09 (m, 2H), 7.08
(dd, J = 5.1, 3.5 Hz, 1H), 6.98 (dd, J = 3.5, 1.2 Hz, 1H), 6.89 – 6.83 (m, 2H), 5.26 – 5.14 (m,
1H), 5.09 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 14.4 Hz, 1H), 3.80 (s, 3H), 3.79 – 3.68 (m, 1H),
3.66 – 3.55 (m, 1H), 3.29 – 3.15 (m, 2H), 3.06 (s, 3H), 2.10 – 2.03 (m, 1H), 1.98 – 1.89 (m,
1H), 1.57 – 1.21 (m, 10H), 0.93 (t, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.8, 168.1,
159.3, 142.2, 134.6, 132.3, 131.5, 131.2, 130.0, 129.8, 128.8, 128.0, 127.4, 126.6, 126.0,
114.1, 103.0, 70.0, 68.6, 58.9, 55.4, 47.6, 47.2, 36.4, 36.2, 32.9, 32.0, 25.5, 25.3, 22.8, 14.2;
[α]D20 = +47.2° (c 0.53, MeOH).
2-Bromo-1-(3-hydroxyphenyl)ethan-1-one (16)
To 3-hydroxy acetophenone (100 mg, 0.73 mmol) in EtOAc (5 mL) was added copper bromide
(195.7 mg, 0.88 mmol) and refluxed for 12 h. The reaction mixture was then cooled to room
temperature and diluted with EtOAc and washed with brine. The organic layer was then dried
with sodium sulphate and evaporated to dryness. Flash chromatography, eluting with 25%
EtOAc/petroleum spirits gave a mixture of the product and the starting material in 1:0.5 ratio
which was directly used for the next step.
4-(3-hydroxyphenyl)thiazol-2(3H)-one (17)
To potassium thiocyanate (68 mg, 0.7 mmol) in acetone (7 mL), was added 2-bromo-1-(3-
hydroxyphenyl)ethan-1-one (106.5 mg, 0.5 mmol) and stirred for 10 min. The solvent was then
evaporated in vacuo and the residue extracted with EtOAc and brine. The organic layer was
dried with sodium sulphate and evaporated to dryness. The crude thus obtained was dissolved
in acetic acid (3.5 mL) and 50% aq. H2SO4 (0.7 mL). The resulting solution was heated to 100
°C for 12 h. After cooling the solution to room temperature, EtOAc was added. The organic
layer was then washed successively with saturated sodium bicarbonate solution, water and
brine. The organic layer was dried with sodium sulphate before evaporating to dryness. Flash
chromatography, eluting with 25% EtOAc/petroleum spirits gave the product as an off-white
solid (28 mg, 29%). HPLC – rt 4.5 min > 99% purity at 254 nm; HRMS [M+H]+ 194.027 m/z,
found 194.0274 m/z; 1H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.05
(ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.00 (t, J = 2.0 Hz, 1H), 6.77 (ddd, J = 8.1, 2.4, 0.9 Hz, 1H),
6.70 (s, 1H); 13C NMR (101 MHz, DMSO) δ 172.9, 157.7, 134.1, 131.0, 129.9, 115.8, 115.7,
111.8, 97.9.
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10.1002/cmdc.202000399
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3-(2-Oxo-2,3-dihydrothiazol-4-yl)phenyl 2-iodobenzoate (18a)
Title compound was prepared from 4-(3-hydroxyphenyl)thiazol-2(3H)-one (27.9 mg, 0.144
mmol) according to the General Procedure F as a white solid (27.6 mg, 45%). HPLC – rt 7.56
min > 99% purity at 254 nm; HRMS [M+H]+ 423.9499 m/z, found 423.9500 m/z; 1H NMR (400
MHz, DMSO) δ 8.12 (dd, J = 7.9, 0.9 Hz, 1H), 8.03 (dd, J = 7.8, 1.6 Hz, 1H), 7.68 – 7.60 (m,
3H), 7.55 (t, J = 8.0 Hz, 1H), 7.43 – 7.36 (m, 1H), 7.33 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 6.95 (s,
13
1H); C NMR (101 MHz, DMSO) δ 173.3, 165.4, 151.3, 141.5, 134.6, 134.3, 133.3, 131.7,
131.6, 130.7, 129.0, 123.2, 122.4, 118.7, 100.0, 95.6.
3-(2-Oxo-2,3-dihydrothiazol-4-yl)phenyl 2-(thiophen-2-yl)benzoate (18b)
Title compound was prepared from 4-(3-hydroxyphenyl)thiazol-2(3H)-one (20 mg, 0.08 mmol)
and 2-(thiophen-2-yl)benzoic acid (50 mg, 0.24 mmol) according to the General procedure F
(29.8 mg, 98%). HPLC – rt 7.78 min > 99% purity at 254 nm; HRMS [M+H]+ 380.041 m/z,
found 380.0417 m/z; 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 7.94 (dd, J = 7.7, 0.9 Hz, 1H),
7.65 – 7.46 (m, 3H), 7.46 – 7.38 (m, 2H), 7.31 – 7.29 (m, 1H), 7.12 – 7.08 (m, 2H), 7.00 – 6.95
(m, 2H), 6.28 (d, J = 1.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 175.6, 167.0, 151.4, 142.0,
134.9, 133.7, 131.9, 131.7, 131.1, 130.9, 130.4, 130.2, 128.2, 127.6, 127.0, 126.3, 122.4,
122.1, 118.1, 99.1.
3-(2-Oxo-2,3-dihydrothiazol-4-yl)phenyl 3-(thiophen-2-yl)benzoate (18c)
Title compound was prepared from 4-(3-hydroxyphenyl)thiazol-2(3H)-one (50 mg, 0.26 mmol)
and 3-(thiophen-2-yl)benzoic acid (100 mg, 0.77 mmol) according to the General procedure F
(70.8 mg, 72%). HPLC – rt 8.16 min > 99% purity at 254 nm; HRMS [M+H]+ 380.041 m/z,
found 380.0422 m/z; 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.43 – 8.38 (m, 1H), 8.15 –
8.07 (m, 1H), 7.88 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 7.59 – 7.49 (m, 2H), 7.47 – 7.39 (m, 3H),
7.35 (dd, J = 5.1, 1.1 Hz, 1H), 7.30 – 7.24 (m, 1H), 7.13 (dd, J = 5.1, 3.6 Hz, 1H), 6.35 (d, J =
13
1.9 Hz, 1H); C NMR (101 MHz, CDCl3) δ 184.7, 176.2, 151.8, 151.7, 135.3, 133.2, 131.3,
131.2, 130.7, 130.0, 129.5, 129.1, 128.4, 127.6, 125.9, 124.2, 122.5, 122.5, 118.6, 99.4.
3-(3-(4-Methoxybenzyl)-2-oxo-2,3-dihydrothiazol-4-yl)phenyl 2-iodobenzoate (19a)
To a stirred suspension of 3-(2-oxo-2,3-dihydrothiazol-4-yl)phenyl 2-iodobenzoate (32 mg,
0.076 mmol), DMF (0.4 mL), potassium carbonate (18 mg, 0.13 mmol) and catalytic amount
of sodium iodide (0.5 mg, 0.004 mmol), 3-methoxy benzylchloride (12 µL, 0.1 mmol) was
added drop-wise. The reaction was stirred overnight at room temperature. After the completion
of the reaction, diethyl ether was added and the suspension washed with brine (x 3). The
organic layer was dried with magnesium sulphate, filtered and evaporated. Flash
chromatography, eluting with 15% EtOAc/petroleum spirits yielded the product as a clear oil
(34.5 mg, 83% yield). HPLC – rt 8.9 min > 99% purity at 254 nm; LRMS [M-H]- 541.9 m/z; 1H
NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 8.0, 1.0 Hz, 1H), 7.98 (dd, J = 7.8, 1.7 Hz, 1H), 7.48
(td, J = 7.6, 1.2 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.34 – 7.28 (m, 1H), 7.28 – 7.20 (m, 1H),
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