Synthesis and Biological Evaluation of Hoshionolactam-Based Compounds

Article abstract of DOI:10.1002/ejoc.202001588

In search of novel antitrypanosomal agents based on hoshinolactam (IC₅₀=3.9 nM), we disclose the synthesis and biological evaluations of 14 different analogues of the natural product using combinations of different acids and lactams. Antitrypanosomal activity assays revealed that the synthesized analogues were less potent than the parent natural product.

Full text of DOI:10.1002/ejoc.202001588

Full Papers
doi.org/10.1002/ejoc.202001588
Synthesis and Biological Evaluation of Hoshionolactam-
Based Compounds
[
a, c]
[a]
[b, c]
Gorakhnath R. Jachak, Drishya Elizebath, Anurag Shukla,
[b, c]
[a, c, d]
Dhanasekaran Shanmugam,*
and D. Srinivasa Reddy*
In search of novel antitrypanosomal agents based on hoshino-
using combinations of different acids and lactams. Antitrypano-
somal activity assays revealed that the synthesized analogues
were less potent than the parent natural product.
lactam (IC =3.9 nM), we disclose the synthesis and biological
50
evaluations of 14 different analogues of the natural product
Introduction
exiguous and majority of them are associated with side
[8]
effects. In this connection Suenaga et al. isolated hoshinolac-
tam (1) from a marine cyanobacterium and confirmed its gross
structure using spectroscopic techniques, while establishing its
Natural products, thus, have been the major sources of
chemical diversity as starting materials for driving drug
[1]
[9]
discovery over the past century. It is fascinating and intriguing
to note that around 60% of anti-tumor and anti-infectious
drugs that are already marketed or under clinical trials are
natural products or synthetically modified natural product
absolute stereochemistry through total synthesis. Hoshinolac-
tam (1) exhibited very potent antitrypanosomal activity (IC =
50
3.9 nM) without cytotoxicity against human fetal lung fibroblast
MRC-5 cells. Structurally, the natural product possesses a
cyclopropane ring along with a γ-lactam moiety. Despite two
reports on the total synthesis of hoshinolactam have been
[2,3]
derivatives. Interestingly, the potential of natural products as
a source of medicines, especially for treating infectious diseases,
remains largely underutilized. Their broad and unmapped range
of scaffolds, which are difficult to imitate synthetically, hold
immense potential as a source for developing novel drugs and
[9]
documented in the literature by Suenaga and Colobert
[11]
groups
surprisingly, no synthetic report has yet been
documented for analogue synthesis and their biological evalua-
tion around this promising scaffold. Even though Suenaga et al.
have emphasized that structure-activity relationship studies on
synthetic analogues of hoshinolactam may contribute to the
development of new antitrypanosomal drugs. In line with our
interest in the synthesis and evaluation of biologically impor-
[4]
theraputics. Parasitic diseases have enormous health, social
and economic impact and have remained as a serious global
health problem. Infections by protozoan parasites belonging to
the Trypanosomatidae family, such as the Trypanosoma and
Leishmania species that are endemic to tropical regions, affect
[5]
[10]
significant number of people and cause debilitating disease.
tant natural products and their analogues as lead molecules,
In the case of leishmaniasis, which is caused by several species
of Leishmania, about sixteen million people are infected world-
wide, whereas sleeping sickness caused by the Trypanosoma
we have pursued the synthesis of hoshinolactam and its
analogues around the active scaffold. Our main focus was to
study the importance of methyl (CH ) stereocenters in the
3
[6]
brucei affects about three million people in Africa. In addition,
Chagas disease caused by Trypanosoma cruzi, results in the
lactam portion at C2 carbon. Besides, another interesting
moiety which caught our attention was the rare cyclopropane
ring with allylic double bond in the structure (Figure 1).
Thus, we have studied the significance of both the unique
structural features of the natural product and its biological
potency by synthesizing few congeners with/without cyclo-
propane ring, with/without enone double bond and varying the
length of side chain to understand its effect on biological
activity.
[7]
infection of 16–18 million individuals. Currently, the number
of drugs available to treat these parasitic infections are
[
a] Dr. G. R. Jachak, D. Elizebath, Dr. D. S. Reddy
Organic Chemistry Division, CSIR-National Chemical Laboratory,
Dr. Homi Bhabha Road, Pune, 411008, India
E-mail: ds.reddy@ncl.res.in
reddy.ds@iiim.res.in
http://academic.ncl.res.in/ds.reddy
b] Dr. A. Shukla, Dr. D. Shanmugam
[
Biochemical Sciences Division, CSIR-National Chemical Laboratory,
Dr. Homi Bhabha Road, Pune, 411008, India
E-mail: d.shanmugam@ncl.res.in
http://academic.ncl.res.in/d.shanmugam
c] Dr. G. R. Jachak, Dr. A. Shukla, Dr. D. Shanmugam, Dr. D. S. Reddy
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad, New Delhi, 110025, India
[
[
d] Dr. D. S. Reddy
CSIR-Indian Institute of Integrative Medicine,
Canal Road, Jammu 180001, India
Figure 1. Structure of hoshinolactam and planned variations for analogue
synthesis.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001588
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Results and Discussion
repeating the above synthetic sequence with 67% yield over 2
steps (Scheme 3).
Considering the structure of hoshinolactam based analogues
with acid and lactam framework, we conceptually visualized
hoshinolactam and related analogues 2 to be synthesized from
coupling of lactam 3 with various acids. In turn lactam 3 could
be accessed from known L-Leucine aldehyde 4 via lactamiza-
tion, deprotection and Brown’s crotylation/ Evans aldol reaction
sequences. Acids could further be synthesized from commer-
cially available starting materials in one or two steps
After having synthesized lactams (8 and 11), we selected
seven acid fragments among which four were commercially
available (12–15) and the remaining three were synthesized
(21, 23 and 26). Synthesis of acid 21 commenced with allylic
alcohol 18 which on cyclopropanation using Simmons-Smith
reaction resulted in the formation of racemic cyclopropane 19
[15]
in 65% yield.
Cyclopropyl alcohol 19 on oxidation using
Dess- Martin Periodinane (DMP) followed by the Horner-Wads-
worth-Emmons reaction using triethylphophonoacetate in pres-
ence of NaH in THF afforded desired ester 20 with 56% yield
over two steps (Scheme 4).
(Scheme 1).
Accordingly, synthesis of the lactam 8 (2R, 3R, 4S) began
with a diastereoselective Evans aldol addition of the (S)-4-
benzyloxazolidin-2-one (5) with L-Leucine aldehyde (4) in
presence of titanium tetrachloride, which afforded the major
compound 6 with 68% yield. The required compound 6 on
exposure with DMAP in methanol furnished the desired methyl
ester 7 in good yield. In turn, lactam 8 was prepared by
deprotection of the N-Boc group with 20% TFA-CH Cl to afford
Further, ester 20 was subjected to hydrolysis using LiOH.H O
2
under reflux to give desired acid 21 with 93% yield. To
synthesize acid 23, we used alcohol 18 which on oxidation
using DMP followed by a two-carbon homologation and ester
hydrolysis through intermediacy of 22 with 52% yield in three
steps. Furthermore, acid 26 was synthesized by repeating same
synthetic sequence from aldehyde 24 in 62% yield for two
steps (Scheme 4). Next, we focused on synthesis of hoshinolac-
tam (1) which was envisioned using lactam 8 and acid 21.
Accordingly, to a solution of lactam 8 and acid 21 in CH Cl ,
2
2
the TFA salt which was further subjected to cyclization under
basic condition in CH CN leading to the synthesis of lactam 8 at
3
6
4% yield in two steps (Scheme 2).
Subsequently, we focused on synthesis of next lactam 11
2
2
having 2S, 3R, 4S stereochemistry. Accordingly, synthesis of
planned lactam 11 commenced with Brown crotylation reaction
on the known L-Leucine aldehyde (4) using (À )-(E)-B-crotyl
DMAP, 2-methyl-6-nitrobenzoic anhydride (MNBA) and triethyl
amine were added, to afford hoshinolactam (1) in 76% yield
(Scheme 5). Here, the synthesized compound is diastereomeric
mixture (racemic cyclopropane) even though the spectral data
[10a,12]
diisopinocamphenylborane to afford compound 9.
In spite
1
13
of many attempts, we were unable to isolate the alkene 9 in
pure form. Therefore, we proceeded with crude material for
further synthesis. The next step involving transformation of
terminal olefin to methyl ester 9 was carried out using oxidative
ozonolysis (O , 3 N NaOH, CH Cl :CH OH) at À 78°C to obtain
( H and C NMR) are in complete agreement with the reported
[9]
1
13
data. Comparison of the H and C NMR spectra of both the
compounds are provided in the supporting information.
With the desired lactam (8 and 11) as well as acids (12, 13,
14, 15, 21, 23 and 26) in hand, we then used optimized
protocol to achieve the synthesis of analogues 27–39 with
good yields (Figure 2). All the compounds were prepared at
3
2
2
3
[13]
the desired methyl ester 10 with 27% yield in two steps. The
ester 10 was further converted to the desired key lactam 11 by
1
13
more than 30 mg scale. Spectroscopic data (IR, H NMR,
C
NMR and HRMS) of all the synthesized compounds are in
complete agreement with the proposed structures and the
details are available in SI. We evaluated the synthesized
hoshinolactam (diastereomeric mixture) and its analogues
against antitrypanosomal activity to obtain information regard-
ing the SAR of the parent natural product. In addition, we were
also interested in identifying any analogue which may have
similar potency as the parent molecule as novel antitrypanoso-
mal lead molecule. Bioactivity assays were carried out as
Scheme 1. Retrosynthetic analysis of hoshinolactam based analogues.
Scheme 2. Synthesis of lactam with 2R, 3R, 4S stereochemistry.
Scheme 3. Synthesis of lactam with 2S, 3R, 4S stereochemistry.
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Figure 2. Synthesized analogues around hoshinolactam scaffold.
Table 1. Antitrypanosomal activity of hoshinolactam based analogues.
Molecules were tested at 10 μM and oligomycin was tested at 1 μM. All
assays were done in triplicates.
Compounds
Average Growth Inhibition/Standard Deviation
Scheme 4. Synthetic routes for acids.
1
79.02�0.44
(
NDS101324)
2
7
59.01�15.47
82.13�8.61
53.29�13.05
48.24�8.19
47.14�3.26
36.16�9.61
60.45�3.41
48.36�2.02
58.47�7.44
46.51�1.22
38.65�5.63
51.69�1.62
49.02�7.75
101.49+1.83
(
NDS101323)
2
8
(
NDS101322)
2
9
(
NDS101320)
3
0
(
NDS101330)
Scheme 5. Synthesis of hoshinolactam (diastereomeric mixture).
31
(
3
NDS101329)
2
(
3
NDS101327)
3
[9,14]
(NDS101321)
previously reported by Senuga and Co-workers
to monitor
3
4
parasite viability and estimate the % growth inhibition for the
(
NDS101318)
[2]
molecules. The results from the bioactivity assay threw up
some surprising observations (Table 1). It was observed that
synthesized hoshinolactam (diastereomeric mixture) had activ-
ity (IC =5.8�0.77 μM; See supplementary material) which was
35
(
3
NDS101319)
6
(
NDS101328)
37
50
(
3
NDS101325)
8
significantly less active in comparison to the reported value
(
IC =3.9 nM) for parasite killing. In addition, all the synthesized
50
(NDS101326)
39
analogues are less potent than the natural product (Table 1).
(
NDS101331)
Oligomycin
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Conclusion
Synthesis of Ethyl (E)-3-(2-propylcyclopropyl) acrylate (20): DMP
(1.4 g, 3.50 mmol) was added to the stirred solution of alcohol 19
(
0.40 g, 3.50 mmol) in CH Cl (10 mL) at 0°C. The resulting solution
2
2
In short, we have synthesized 14 novel hoshinolactam based
analogues by using various acids and lactams. Biological
evaluation of synthesized analogues towards identification of
novel antitrypanosomal agent suggests that they are less
potent than the natural product. The weaker activity of
analogues from 27–38 could be rationalized due to the absence
of cyclopropane ring. In case of analogue 39 it may be because
of change in stereochemistry on the lactam ring with respect to
natural product. However, poor activity of synthesized hoshino-
lactam (1) is difficult to explain where we expected it be
moderately active considering that it is a mixture of two
diastereomers.
was stirred at 0°C for 1 h further quenched reaction with addition
of aq. NaHCO and extracted with CH Cl (2×25 mL). The organic
3
2
2
layer thus obtained was wash with NaHCO for 2–3 times and dried
3
the organic layer over Na SO , filtered and solvent was removed
2
4
under vaccum. The above obtained crude aldehyde was taken for
next step without further purification. To the stirred solution of NaH
(
118 mg in oil 3.50 mmol) in THF at 0°C, triethylphosphonoacetate
was added (0.862 mL, 3.85 mmol) at same temperature. The
resulting solution was stirred for 30 minutes. To the solution thus
obtained, aldehyde (0.40 g, 3.50 mmol) was added drop wise and
stirred for 1 h at 0°C. After the completion of the reaction saturated
solution of aq. ammonium chloride was added and extracted using
diethyl ether (2×40 mL). The combined organic extracts were
washed with brine (50 mL) and dried over Na SO . The solvent was
2
4
removed under vacuum, and the crude was purified by column
chromatography using ethyl acetate: pet ether (10:90) afforded
compound 20 (56% for two steps). IR υmax(film): 2934, 2841, 1716,
Experimental Section
À 1
1
1
641, 1463, 1352, 1310 cm ; H NMR (200 MHz, CDCl ): δ 6.41 (dd,
3
General Information: All reactions were carried out in oven-dried
glassware under a positive pressure of argon or nitrogen unless
otherwise mentioned with magnetic stirring. Air sensitive reagents
and solutions were transferred via syringe or cannula and were
introduced to the apparatus via rubber septa. All reagents, starting
materials and solvents were obtained from commercial suppliers
and used as such without further purification. Reactions were
monitored by thin layer chromatography (TLC) with 0.25 mm pre-
coated silica gel plates (60 F254). Visualization was accomplished
with either UV light, Iodine adsorbed on silica gel or by immersion
in ethanolic solution of phosphomolybdic acid (PMA), p-anisalde-
J=15.6, 10.1 Hz, 1H), 5.75 (d, J=15.4 Hz, 1H), 4.15–4.04 (m, 2H),
1
0
.39–1.31 (m, 3H), 1.27–1.17 (m, 6H), 0.84 (t, J=7.6 Hz, 3H), 0.78–
.63 (m, 2H).
Synthesis of Ethyl (E)-oct-2-enoate (25): THF was added to a NaH
(669 mg in oil, 0.019 mol) and resulting solution was cooled to 0°C.
To the stirring solution triethylphosphonoacetate (4.048 g,
0.02 mol) was added drop wise at same temperature. The resulting
solution was stirred for 30 minutes at 0°C. Then the aldehyde 24
(1 g, 0.01 mol) was added. The solution was stirred for additional
30 minutes after the completion of the reaction saturated solution
of aq. ammonium chloride was added and extracted using diethyl
ether (2×25 mL). The combined organic extracts were washed with
brine (50 mL) and dried over Na SO . The solvent was removed
hyde, KMnO , Ninhydrin solution followed by heating with a heat
4
gun for ~15 sec. Column chromatography was performed on silica
gel (100–200 or 230–400 mesh size). Deuterated solvents for NMR
2
4
1
13
spectroscopic analyses were used as received. All H NMR, C NMR
spectra were obtained using a 200 MHz, 400 MHz and 500 MHz
spectrometer. Coupling constants were measured in Hertz. All
chemical shifts were quoted in ppm, relative to TMS, using the
residual solvent peak as a reference standard. The following
abbreviations were used to explain the multiplicities: s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. HRMS
under vacuum, and the crude mixture was purified by column
chromatography on silica using ethyl acetate: pet ether (105:95).
The compound 25 was obtained with a yield of 71%. IR υmax(film):
À 1
1
2938, 2841, 1723, 1652, 1469 cm ; H NMR (400 MHz, CDCl ): δ
3
7.01–6.94 (m, 1H), 5.82 (d, J=15.9 Hz, 1H), 4.19 (q, J=6.9 Hz, 2H),
2.20 (q, J=7.3 Hz, 2H), 1.49–1.45 (m, 2H), 1.31–1.28 (m, 7H), 0.90 (t,
1
3
J=6.4 Hz, 3H); C NMR (100 MHz, CDCl ): δ 166.8, 149.5, 121.2, 60.1,
3
(ESI) were recorded on ORBITRAP mass analyzer (Thermo Scientific,
32.1, 31.3, 27.7, 22.4, 14.3, 13.9.
Q Exactive). Mass spectra were measured with ESI ionization in MSQ
LCMS mass spectrometer. Infrared (IR) spectra were recorded on a
FT-IR spectrometer as a thin film. Chemical nomenclature was
generated using Chembiodraw ultra 14.0. Optical rotation values
were recorded on P-2000 polarimeter at 589 nm.
Synthesis of Ethyl (2E,4E)-octa-2,4-dienoate (22): To the stirred
solution of known alcohol (E)-hex-2-en-1-ol (18) (2 g, 0.002 mol) in
CH Cl at 0°C the DMP (9.3 g, 0.002 mol) was added. The resulting
2
2
solution was stirred at 0°C for 1 h. Further reaction was stopped by
addition of aq. NaHCO and extracted with CH Cl (2×20 mL). The
3
2
2
Synthesis of (2-Propylcyclopropyl) methanol (19): To a stirred
obtained organic layer was washed with NaHCO for 2–3 times.
3
solution of CH I (0.895 mL, 2 mmol) in anhydrous CH Cl (25 mL) at
Dried the organic layer over sodium sulphate filtered and
concentrated the reaction mixture. The above obtained aldehyde
was taken for next step without further purification. To the stirred
solution of NaH (712 mg in oil 0.019 mol) in THF at 0°C,
triethylphosphonoacetate was added (4.5 g, 0.02 mol). The resulting
solution was stirred for 30 minutes. To the solution aldehyde (1 g,
0.010 mol) was added drop wise and stirred for 1 h at 0°C. After the
2
2
2
2
À 20°C was added drop wise diethyl zinc (5 mL, 4.99 mmol). The
resulting solution was stirred at that temperature for 15 min (white
precipitate was formed). The solution of (E)-hex-2-en-1-ol (18)
(
500 mg, 4.99 mmol) in anhydrous CH Cl (5 mL) was added drop
2 2
wise followed by TiCl4 (74 μL, 0.74 mmol) addition. After 3 h of
stirring at=20°C, the resulting solution was poured into an
aqueous solution of saturated NH Cl. The layer was washed with
completion of the reaction saturated solution of aq. NH Cl was
4
4
EtOAc (3×50 mL). The combined organic extracts were washed
with brine (50 mL) and dried over Na SO . The solvent was removed
added and extracted using diethyl ether (2×40 mL). The combined
organic extracts were washed with brine (50 mL) and dried over
Na SO . The solvent was removed under vacuum, and the crude
2
4
under vacuum, and the crude mixture was purified on silica gel
2
4
column (100–200 mesh) using ethyl acetate: pet ether (10:90)
was purified by column chromatography using ethyl acetate: pet
1
afforded compound 19 with 65% yield. H NMR (200 MHz, CDCl ): δ
ether (10:90) afforded compound 22 (59%) for two steps. IR
3
À 1
1
3
0
.44 (dd, J=1.8, 7.1 Hz, 2H), 1.43–1.36 (m, 2H), 1.28–1.21 (m, 3H),
.92 (t, J=7 Hz, 3H), 0.90–0.79 (m, 1H), 0.69–0.57 (m, 1H), 0.41–0.32
υmax(film): 2964, 2841, 1967, 1725, 1686, 1424 cm ; H NMR
(400 MHz, CDCl ): δ 7.28 (dd, J=15.0, 10.1 Hz, 1H), 6.19–6.13 (m,
3
(m, 1H).
2H), 5.80 (d, J=15.4 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 2.16 (dd, J=
13.5, 6.8 Hz, 2H), 1.48–1.45 (m, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.94 (t,
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1
3
J=7.3 Hz, 3H); C NMR (100 MHz, CDCl ): δ 167.5, 145.1, 144.5,
1
17 mmol, 2 equiv) was condensed into flask at À 78°C then THF
3
t
28.5, 119.2, 60.1, 35.0, 21.9, 14.3, 13.6. HRMS calculated for
(20 mL) was added followed by addition of KO Bu (2.4 g, 21.5 mmol,
+
C H O [M+H] : 169.1223, found 169.1225.
1.25 equiv) at À 78°C. Next, n-BuLi (13.4 mL, 1.6 M in hexanes,
1
0
17
2
2
1.5 mmol, 1.25 equiv) was added drop wise (maintaining internal
Synthesis of tert-butyl ((2R,3R,4S)-1-((S)-4-benzyl-2-oxooxazolidin-3-
yl)-3-hydroxy-2,6-dimethyl-1-oxoheptan-4-yl) carbamate (6): To a
stirred solution of oxazolidinone derivative 5 (3.5 g, 15.0 mmol) in
CH Cl (70 mL) was added drop wise TiCl (17 mL, 16.5 mmol) and
temperature below À 70°C), after addition the reaction mixture was
warmed to À 50°C for 15 min. The mixture was chilled to À 78°C
once more, and a solution of (À )-B-methoxy diisopinocampheylbor-
ane (25 mL, 1 M in THF, 25 mmol, 1.45 equiv) in THF (30 mL) was
added slowly over 30 min. Then, BF ·Et O (4.1 mL, 29.1 mmol,
2
2
4
DIPEA (3.1 mL, 18.0 mmol) at 0°C. After stirring for 1 h, at 0°C
3
2
aldehyde 4 (3.85 g, 16.5 mmol) in CH Cl (30 mL) was added drop
2
2
1
4
.7 equiv) was added at À 78°C over 10 minutes, finally compound
wise and the solution was allowed to warm slowly to room
temperature and stirred for additional 2 h at room temperature.
The reaction was quenched by the addition of aq. ammonium
(4.3 g, 17.1 mmol) in THF (25 mL) was added drop wise at À 78°C.
The reaction mixture was stirred at À 78°C for 12 h, then warmed to
À 15°C. A mixture of 3 N NaOH (8.3 mL) and 30% hydrogen
peroxide (2.9 mL) was added drop wise to the reaction. After being
heated to reflux for 1 h, the mixture was cooled to 0°C.
Concentrated the reaction mixture, diethyl ether (50 mL) was added
and washed with water (20 mL) and brine (20 mL), dried over
Na SO . The solvent was removed under vacuum, at this stage, we
chloride solution (10 mL) at 0°C and then H O (30 mL) was added
2
to the reaction mixture. The mixture was extracted with CH Cl (3×
2
2
5
0 mL). The combined organic extracts were dried over anhydrous
Na SO , filtered, and concentrated in vacuo. The organic residue
was purified by column chromatography (silica gel 100–200 mesh,
5% ethyl acetate: pet ether) to afford major compound 6. Data for
: IR υmax(film): 3439, 3019, 2980, 1781, 1693, 1502 cm ; H NMR
2
4
2
4
1
6
tried several attempts for purification but we are unable to purify,
so crude crotylation product 9 forwarded for next step.
À 1
1
(
400 MHz, CDCl ): δ 7.34–7.21 (m, 5H), 4.67 (s, 1H), 4.60 (d, J=
3
9
.8 Hz, 1H), 4.19–4.18 (m, 2H), 4.02 (brs, 1H), 3.80–3.74 (m, 1H), 3.32
A solution of crude alkenol 9 in 30 mL of CH Cl and 3 N methanolic
2
2
(
(
d, J=12.8 Hz, 1H), 3.09–3.07 (m, 1H), 2.76–2.70 (m, 1H), 1.70–1.59
m, 2H), 1.49 (s, 9H), 1.27 (d, J=6.7 Hz, 3H), 0.93 (d, J=6.1 Hz, 6H);
NaOH (5 mmol) was stirred at À 78°C as ozone was passed through
the solution after 20–30 min, reaction mixture colour changed to
blue then oxygen was passed in reaction to remove excess of
ozone until reaction mixture was become colourless. The reaction
mixture was allowed to warm up to room temperature, and then
stirred for additional 4 h. The reaction mixture was diluted with
water (30 mL) extracted with CH Cl (50 mL×2). The organic layer
1
3
C NMR (100 MHz, CDCl ): δ 176.8, 155.9, 153.1, 135.2, 129.4, 129.0,
3
1
2
27.4, 79.4, 74.9, 66.2, 55.4, 51.1, 41.2, 39.7, 38.0, 28.3, 24.8, 23.9,
27
1.6, 10.9; [α]D = +29.65 (c 0.80, CHCl ); HRMS calculated for
3
+
C H O N [M+H] : 449.2646, found 449.2650.
2
4
37
6
2
2
2
Synthesis of Methyl (2R,3R,4S)-4-((tert-butoxycarbonyl) amino)-3-
hydroxy-2,6-dimethylheptanoate (7): To a stirred solution of 6
was dried over Na SO , and the solvent was removed under
2
4
reduced pressure. Purification of the crude material on a silica gel
column chromatography (silica gel 230–400 mesh, 15% ethyl
acetate: pet ether) to afford desired olefin ester 10 with 27% yield
for 2 steps. IR υmax(film): 3365, 2941, 2916, 1717, 1681, 1523,
(
3
(
1.29 g, 0.28 mmol) in MeOH (1 mL) was added DMAP (375 mg,
.08 mmol) at room temperature. After completion of reaction
18 h), the mixture was concentrated. The residue was dissolved in
EtOAc (10 mL) and washed with 1 M NaOH (10 mL), brine (5 mL).
The organic layer was dried over anhydrous Na SO and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy (silica gel 230–400 mesh, 10% ethyl acetate: pet ether) to
give methyl ester 7 (79%) as a white solid. IR υmax(film): 3351, 2938,
À 1 1
1
484 cm ; H NMR (400 MHz, CDCl ): δ 4.71 (d, J=9.8 Hz, 1H), 3.82
3
2
4
(
d, J=6.1 Hz, 1H), 3.72 (s, 3H), 3.66 (d, J=8.5 Hz, 1H), 3.33–3.13 (m,
H), 2.69–2.56 (m, 1H), 1.64 (dd, J=6.4, 12.5 Hz, 1H), 1.54 (dd, J=
1
8
.5, 14.0 Hz, 1H), 1.43 (s, 9H), 1.34 (dd, J=7.0, 13.7 Hz, 1H), 1.23 (d,
13
J=7.3 Hz, 3H), 0.93 (t, J=6.1 Hz, 6H); C NMR (100 MHz, CDCl ): δ
À 1
1
3
2
926, 1721, 1696, 1684, 1523, 1436 cm ; H NMR (400 MHz, CDCl ):
3
1
1
3
77.0, 155.9, 79.1, 74.9, 52.0, 49.1, 43.0, 42.3, 28.3, 24.8, 22.9, 22.4,
δ 4.34 (d, J=5.7 Hz, 1H), 3.70 (s, 3H), 2.99 (brs, 1H), 2.88–2.85 (m,
H), 1.76–1.59 (m, 3H), 1.43 (s, 9H), 1.26 (d, J=7.1 Hz, 3H), 0.93 (d,
+
4.1; HRMS calculated for C H O NNa [M+Na] : 326.1938, found
1
5
29
5
1
26.1942.
13
J=6.7 Hz, 6H); C NMR (100 MHz, CDCl ): δ 176.7, 155.9, 79.5, 75.3,
5
0
3
27
1.8, 51.2, 41.6, 40.2, 28.3, 24.7, 23.8, 21.4, 11.9; [α] D =À 32.18 (c
Synthesis of (3S,4R,5S)-4-hydroxy-5-isobutyl-3-methylpyrrolidin-
2-one (11): The compound 11 (454 mg, 71%) was synthesized from
.95, CHCl3).
compound 10 as a white colour solid by following general
Synthesis of (3R,4R,5S)-4-hydroxy-5-isobutyl-3-methylpyrrolidin-
30
procedure for the synthesis of 8. [α]D =À 12.18 (c 0.80, CHCl ); IR
3
2
-one (8): To a stirred solution of methyl ester 7 (400 mg,
À 1
1
υmax(film): 3319, 2953, 1721, 1689, 1598 cm ; H NMR (400 MHz,
1
.32 mmol) in CH Cl (10 mL) was added TFA (1 mL), at 0°C and
2
2
CDCl ) δ 6.18 (brs, 1H), 3.60-3.59 (m, 1H), 3.44–3.39 (m, 1H), 2.39
3
stirred reaction mixture for 40 min. After completion of the
reaction, the solvent was removed completely. The deprotected
compound was used directly in the next step without any further
purification. To a stirred solution of the Boc-deprotected amine in
CH CN (10 mL) was added Et N (1.0 mL) under inert atmospheres.
(
(
pentate, J=7.3 Hz, 1H), 2.05 (brs, 1H), 1.75–1.66 (m, 1H), 1.62–1.55
m, 1H), 1.41–1.33 (m, 1H), 1.24 (d, J=6.7 Hz, 3H), 0.98–0.94 (m, 6H);
13
C NMR (100 MHz, CDCl ) δ 177.2, 81.2, 58.4, 45.3, 43.6, 25.6, 23.2,
3
+
2
2.0, 13.3; HRMS calculated for C H O N [M+H] : 172.1332, found
9 18 2
3
3
172.1334.
The reaction mixture was stirred at same temperature for 20 h and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel 230–400 mesh 10% ethyl acetate: pet
ether) to afford lactam 8 with 2R, 3R, 4S stereochemistry (64% in 2
steps) as a white solid. IR υmax(film): 3258, 2925, 2909, 1711, 1691,
General procedure for synthesis of esters: To a solution of lactam
(1.0 mmol) and crude acid (1.1 mmol) in CH Cl were added DMAP
2
2
(0.5 mmol), followed by MNBA (3.1 mmol) and Et N (10 mmol) at
3
0°C. The resulting solution was stirred at ambient temperature for
À 1
1
1
3
1
5
2
469 cm ; H NMR (400 MHz, CDCl ): δ 6.13 (brs, 1H), 4.21 (s, 1H),
4–5 h. After completion of reaction it was diluted with CH Cl
2
3
2
.65-3.61 (m, 1H), 2.57–2.54 (m, 1H), 2.53 (brs, 1H), 1.69 (qd, J=6.6,
3.1 Hz, 1H), 1.57–1.48 (m, 2H), 1.19 (d, J=7.3 Hz, 3H), 0.96 (t, J=
.8 Hz, 6H); C NMR (100 MHz, CDCl ): δ 178.4, 72.5, 56.1, 43.2, 37.6,
(50 mL) washed with saturated solution of aq. NaHCO (5 mL), brine
3
(5 mL). The organic layer was dried over Na SO and the crude
2
4
1
3
material obtained after removal of the solvent was purified by
column chromatography (silica gel 230–400 mesh, 10% ethyl
acetate: pet ether) to afford corresponding ester.
3
30
D
5.3, 23.0, 22.6, 8.0; [α] =À 22.30 (c 1.10, CHCl ); HRMS calculated
3
+
for C H O N [M+H] : 172.1332, found 172.1334.
9
18
2
Synthesis of Methyl (2S,3R,4S)-4-((tert-butoxycarbonyl) amino)-3-
Synthesis of (2S,3R,4R)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
(2E,4E)-octa-2,4-dienoate (27): The compound 27 (81 mg, 74%)
hydroxy-2,6-dimethylheptanoate
(10):
(E)-2-butene
(3 mL,
Eur. J. Org. Chem. 2021, 2212–2218
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© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202001588
was synthesized from compound 8 and 23 by following general
procedure for the synthesis of ester. IR υmax(film): 3249, 2981, 2925,
2H), 1.67-1.61 (m, 3H), 1.59–1.54 (m, 1H), 1.42 (t, J=7.0 Hz, 2H),
13
1.31–1.27 (m, 7H), 1.10 (d, J=7.3 Hz, 3H), 0.97–0.88 (m, 9H);
C
À 1
1
1
706, 1694 cm ; H NMR (400 MHz, CDCl ): δ 7.31–7.25 (m, 1H),
NMR (100 MHz, CDCl ): δ 177.4, 173.3, 73.1, 54.5, 41.5, 37.9, 34.1,
3
3
6
.49 (brs, 1H), 6.17 (d, J=7.3 Hz, 2H), 5.78 (d, J=15.9 Hz, 1H), 4.85
31.6, 29.1, 28.9, 25.3, 25.0, 23.0, 22.6, 22.4, 14.0, 8.4; HRMS calculated
+
(t, J=4.3 Hz, 1H), 3.59 (td, J=4.7, 8.9 Hz, 1H), 2.52–2.48 (m, 1H),
for C H O NNa [M+Na] : 320.2196, found 320.2198.
1
7
31
3
2
.18–2.13 (m, 2H), 1.52–1.45 (m, 1H), 1.44–1.42 (m, 1H), 1.41–1.38
1
3
Synthesis of (2S,3R,4R)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
cinnamate (33): The compound 33 (69 mg, 76%) was synthesized
from compound 8 and 15 by following general procedure for the
synthesis of ester. IR υmax(film): 3317, 2943, 2928, 1694, 1685.
(
(
m, 3H), 1.30 (d, J=7.3 Hz, 3H), 0.92 (t, J=7.3 Hz, 9H); C NMR
100 MHz, CDCl ): δ 177.2, 166.6, 146.3, 145.7, 128.3, 118.1, 80.4,
3
5
6.7, 44.1, 43.3, 35.0, 25.1, 23.0, 21.8, 21.8, 14.6, 13.6; HRMS
+
calculated for C H O NNa [M+Na] : 316.1883, found 316.1887.
17
27
3
À 1
1
1
503 cm ; H NMR (400 MHz, CDCl ): δ 7.74 (d, J=15.9 Hz, 1H),
3
Synthesis of (2S,3R,4R)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
E)-oct-2-enoate (28): The compound 28 (73 mg, 68%) was
7.56-7.42 (m, 5H), 6.46 (d, J=15.9 Hz, 1H), 6.37 (brs, 1H), 4.95 (t, J=
4.2 Hz, 1H), 3.67 (td, J=4.3, 9.0 Hz, 1H), 2.62–2.55 (m, 1H), 1.70 (td,
J=6.7, 13.4 Hz, 1H), 1.60 (ddd, J=5.8, 7.6, 13.4 Hz, 1H), 1.53–1.45
(
synthesized from compound 8 and 26 by following general
procedure for the synthesis of ester. IR υmax(film): 3189, 2947, 2923,
1
3
(m, 1H), 1.37 (d, J=7.3 Hz, 3H), 0.96 (d, J=8.54, 6H); C NMR
À 1
1
1
705, 1685, 1556, 1264 cm ; H NMR (400 MHz, CDCl ): δ 7.07–6.99
(100 MHz, CDCl ): δ 177.0, 166.4, 145.9, 134.1, 130.6, 128.9, 128.2,
3
3
(
1
m, 1H), 6.45 (brs, 1H), 5.83 (d, J=15.3 Hz, 1H), 4.86 (t, J=4.3 Hz,
H), 3.61 (dd, J=4.6, 8.9 Hz, 1H), 2.55–2.48 (m, 1H), 2.25-2.20 (m,
117.2, 80.7, 56.8, 44.2, 43.3, 25.2, 23.1, 21.8, 14.7; HRMS calculated
+
for C H O NNa [M+Na] : 324.1570, found 324.1575.
1
8
23
3
2
H), 1.68–1.64 (m, 2H), 1.57–1.45 (m, 4H), 1.32 (d, J=6.7 Hz, 6H),
13
Synthesis of (2S,3R,4R)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
2E,4E)-hexa-2,4-dienoate (34): The compound 34 (56 mg, 89%)
0
.96–0.91 (m, 9H); C NMR (100 MHz, CDCl ): δ 177.1, 166.1, 151.1,
3
(
120.4, 80.4, 56.7, 44.1, 43.3, 32.2, 31.3, 27.6, 25.1, 23.0, 22.4, 21.8,
+
was synthesized from compound 8 and 12 by following general
procedure for the synthesis of ester. IR υmax(film): 3257, 2949, 2804,
14.7, 13.9; HRMS calculated for C H O NNa [M+Na] : 318.2040,
17
29
3
found 318.2043.
À 1
1
1
716, 1683 cm ; H NMR (400 MHz, CDCl ): δ 7.33–7.27 (m, 1H),
3
Synthesis of (2S,3R,4R)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
octanoate (29): The compound 29 (81 mg, 73%) was synthesized
from compound 8 and 13 by following general procedure for the
synthesis of ester. IR υmax(film): 3269, 2958, 2931, 2872, 1710, 1698,
6.51 (brs, 1H), 6.19 (d, J=7.3 Hz, 1H), 5.80 (d, J=15.3 Hz, 1H), 4.87
(t, J=4.3 Hz, 1H), 3.63–3.59 (m, 1H), 2.55–2.49 (m, 1H), 2.18–2.15 (m,
1H), 1.72–1.62 (m, 1H), 1.58–1.52 (m, 1H), 1.50–1.43 (m, 3H), 1.32 (d,
1
3
J=7.5 Hz, 3H), 0.94 (t, J=7.4 Hz, 6H); C NMR (100 MHz, CDCl ): δ
3
À 1
1
1
4
2
0
4
439 cm ; H NMR (400 MHz, CDCl ): δ 6.47 (brs, 1H), 4.80 (t, J=
.3 Hz, 1H), 3.58–3.54 (m, 1H), 2.49–2.44 (m, 1H), 2.34 (t, J=7.3 Hz,
177.2, 166.6, 146.2, 145.7, 128.3, 118.1, 80.4, 56.8, 44.1, 43.3, 35.0,
3
25.1, 23.0, 21.8, 14.6, 13.7; HRMS calculated for C H O NNa [M+
1
5
23
3
+
H), 1.70–1.62 (m, 3H), 1.55–1.42 (m, 2H), 1.32–1.26 (m, 12H), 0.95–
Na] : 288.1570, found 288.1573.
13
.87 (m, 9H); C NMR (100 MHz, CDCl ): δ 177.1, 173.3, 80.4, 56.6,
3
Synthesis of (2S,3R,4R)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
nonanoate (35): The compound 35 (48 mg, 69%) was synthesized
from compound 8 and 14 by following general procedure for the
synthesis of ester. IR υmax(film): 3251, 2926, 2918, 1706, 1681,
4.2, 43.3, 34.2, 31.6, 28.9, 28.8, 25.1, 24.9, 23.0, 22.5, 21.8, 14.6, 14.0;
HRMS calculated for C H O NNa [M+Na]+: 320.2198, found
17
31
3
320.2200.
À 1
1
Synthesis of (2S,3R,4S)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
1473 cm ; H NMR (400 MHz, CDCl ): δ 6.41 (brs, 1H), 4.80 (t, J=
3
(
2E,4E)-octa-2,4-dienoate (30): The compound 30 (75 mg, 79%)
4.6 Hz, 1H), 3.55 (td, J=4.5, 8.7 Hz, 1H), 2.50–2.43 (m, 1H), 2.34 (t,
J=7.3 Hz, 2H), 1.65–1.62 (m, 3H), 1.56–1.40 (m, 3H), 1.32–1.28 (m,
was synthesized from compound 11 and 23 by following general
procedure for the synthesis of ester. IR υmax(film): 3275, 2968, 2852,
1
3
12H), 0.96–0.87 (m, 9H); C NMR (100 MHz, CDCl ): δ 176.7, 173.0,
3
À 1
1
1
6
4
1
0
1
8
3
717, 1679 cm ; H NMR (400 MHz, CDCl ): δ 7.34–7.30 (m, 1H),
80.1, 56.3, 43.8, 42.9, 33.9, 31.4, 28.8, 28.8, 28.7, 24.8, 24.5, 22.7, 22.3,
3
+
.20–6.18 (m, 2H), 5.98 (brs, 1H), 5.80 (d, J=15.3 Hz, 1H), 5.64 (t, J=
.3 Hz, 1H), 3.83-3.81 (m, 1H), 2.71–2.68 (m, 1H), 2.18–2.16 (m, 2H),
.57–1.48 (m, 1H), 1.46–1.42 (m, 4H), 1.10 (d, J=6.7 Hz, 3H), 0.95–
21.5, 14.3, 13.7; HRMS calculated for C H O NNa [M+Na] :
1
8
33
3
334.2353, found 334.2355.
13
Synthesis of (2S,3R,4S)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
cinnamate (36): The compound 36 (41 mg, 87%) was synthesized
from compound 11 and 15 by following general procedure for the
synthesis of ester. IR υmax(film): 3368, 2973, 2947, 1705, 1691,
.90 (m, 9H); C NMR (100 MHz, CDCl ): δ 177.5, 166.6, 146.4, 145.7,
3
28.4, 117.9, 73.1, 54.7, 41.7, 37.9, 35.1, 25.3, 23.0, 22.4, 21.9, 13.7,
+
.4; HRMS calculated for C H O NNa [M+Na] : 316.1883, found
17
27
3
16.1884.
À 1
1
1
539 cm ; H NMR (400 MHz, CDCl ): δ 7.74 (d, J=16.5 Hz, 1H),
3
Synthesis of (2S,3R,4S)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
E)-oct-2-enoate (31): The compound 31 (88 mg, 84%) was
7.59–7.47 (m, 2H), 7.41–7.40 (m, 3H), 6.46 (d, J=15.9 Hz, 1H), 6.36
(brs, 1H), 5.72–5.70 (m, 1H), 3.90–3.85 (m, 1H), 2.77–2.74 (m, 1H),
1.61 (dq, J=6.6, 13.1 Hz, 1H), 1.48 (t, J=6.7 Hz, 2H), 1.15 (d, J=
(
synthesized from compound 11 and 26 by following general
procedure for the synthesis of ester. IR υmax(film): 3169, 2954, 2921,
1
3
7.3 Hz, 3H), 0.92 (dd, J=6.1, 16.5 Hz, 6H); C NMR (100 MHz, CDCl3):
δ 177.7, 166.3, 146.0, 134.0, 130.6, 128.9, 128.2, 116.8, 73.4, 54.7,
41.7, 37.9, 25.2, 23.0, 22.4, 8.4; HRMS calculated for C H O NNa [M
À 1
1
1
711, 1658, 1510, 1281 cm ; H NMR (400 MHz, CDCl ): δ 7.27–6.99
3
(
m, 1H), 6.30 (brs, 1H), 5.83 (d, J=15.9 Hz, 1H), 5.63–5.60 (m, 1H),
.84–3.82 (m, 1H), 2.71–2.67 (m, 1H), 2.22 (d, J=7.3 Hz, 2H), 1.57–
1
8
23
3
+
3
1
3
+Na] : 324.1570, found 324.1575.
.53 (m, 1H), 1.48–1.42 (m, 4H), 1.32–1.30 (m, 4H), 1.09 (d, J=7.3 Hz,
13
Synthesis of (2S,3R,4S)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
2E,4E)-hexa-2,4-dienoate (37): The compound 37 (84 mg, 71%)
H), 0.92 (t, J=6.4, 3H), 0.89 (d, J=7.4, 6H); C NMR (100 MHz,
(
CDCl ): δ 177.6, 166.0, 151.2, 120.1, 73.0, 54.7, 41.7, 37.9, 32.3, 31.3,
3
was synthesized from compound 11 and 12 by following general
2
9.7, 27.5, 25.2, 23.0, 22.4, 13.9, 8.4; HRMS calculated for
+
procedure for the synthesis of ester. IR υmax(film): 3249, 2981, 2925,
C H O NNa [M+Na] : 318.2040, found 318.2043.
1
7
29
3
À 1
1
1
706, 1694 cm ; H NMR (400 MHz, CDCl ): δ; 7.33–7.27 (m, 1H),
3
Synthesis of (2S,3R,4S)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
octanoate (32): The compound 32 (43 mg, 82%) was synthesized
from compound 11 and 13 by following general procedure for the
synthesis of ester. IR υmax(film): 3263, 2947, 2926, 1719, 1687,
6.51 (brs, 1H), 6.19 (d, J=7.5 Hz, 1H), 5.80 (d, J=15.4 Hz, 1H), 4.87
(t, J=4.3 Hz, 1H), 3.61 (td, J=4.7, 8.9 Hz, 1H), 2.54–2.49 (m, 1H),
2.18–2.15 (m, 2H), 1.66 (dq, J=6.5, 13.4 Hz, 1H), 1.58–1.42 (m, 4H),
1
3
1.32 (d, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 6H); C NMR (100 MHz,
À 1
1
1
453 cm ; H NMR (400 MHz, CDCl ): δ 5.92 (brs, 1H), 5.59 (t, J=
CDCl ): δ 177.8, 166.5, 146.2, 140.4, 129.6, 117.6, 73.0, 54.8, 41.7,
3
3
4.3 Hz, 1H), 3.84–3.79 (m, 1H), 2.72–2.65 (m, 1H), 2.37 (t, J=7.5 Hz,
Eur. J. Org. Chem. 2021, 2212–2218
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© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202001588
3
+
7.8, 25.1, 23.0, 22.3, 18.7, 8.3; HRMS calculated for C H O NNa [M
Na] : 288.1570, found 288.1574.
Acknowledgements
15
23
3
+
The authors acknowledge CSIR-NCL for providing infrastructure;
CSIR, New Delhi, for providing the research fellowships to G.R.J.;
ICMR, New Delhi, for providing research fellowship to A.S.
Synthesis of (2S,3R,4S)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
nonanoate (38): The compound 38 (34 mg, 75%) was synthesized
from compound 11 and 14 by following general procedure for the
synthesis of ester. IR υmax(film): 3268, 2915, 2903, 1719, 1693,
À 1
1
1
4
2
1
465 cm ; H NMR (400 MHz, CDCl ): δ 6.22 (brs, 1H), 5.58 (t, J=
3
.6 Hz, 1H), 3.84–3.79 (m, 1H), 2.72–2.65 (m, 1H), 2.36 (t, J=7.3 Hz,
H), 1.66–1.53 (m, 4H), 1.42 (t, J=7.0 Hz, 2H), 1.30–1.27 (m, 6H),
Conflict of Interest
13
.10 (d, J=7.3 Hz, 3H), 0.97–0.87 (m, 12H); C NMR (100 MHz,
CDCl ): δ 177.5, 173.2, 73.1, 54.5, 41.5, 37.8, 34.1, 31.8, 29.7, 29.1,
The authors declare no conflict of interest.
3
2
9.1, 25.2, 25.0, 22.9, 22.6, 22.4, 14.1, 8.4; HRMS calculated for
+
C H O NNa [M+Na] : 334.2353, found 334.2356.
1
8
33
3
Keywords: Hoshinolactam · Ozonolysis · Parasitic diseases ·
Trypanosoma
Synthesis of (2S,3R,4S)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
E)-3-(2-propylcyclopropyl) acrylate (39): The compound 39
38 mg, 69%) was synthesized from lactam 11 and 21 by following
general procedure for the synthesis of ester. IR υmax(film): 3216,
(
(
À 1
1
2
968, 2929, 1703, 1613 cm ; H NMR (400 MHz, CDCl ): δ 6.52 (dd,
3
J=10.4, 15.3 Hz, 1H), 6.38 (brs, 1H), 5.85 (d, J=15.3 Hz, 1H), 5.61 (t,
J=4.3 Hz, 1H), 3.84–3.80 (m, 1H), 2.73–2.68 (m, 1H), 1.58 (td, J=6.6,
1
3.0 Hz, 1H), 1.42 (t, J=7.0 Hz, 4H), 1.33–1.28 (m, 4H), 1.09 (d, J=
13
7
.3 Hz, 3H), 0.95–0.90 (m, 9H), 0.87–0.78 (m, 3H); C NMR (100 MHz,
[1] S. M. K. Rates, Toxicon 2001, 39, 603–613.
[2] M. K. Lutz, Nat. Biotechnol. 2003, 21, 602–604.
CDCl ): δ 177.9, 166.1, 155.7, 116.2, 72.8, 54.8, 41.8, 37.8, 35.6, 25.2,
3
[
3] N. Gurnani, D. Mehta, M. Gupta, B. K. Mehta, African J. Basic Appl. Sci.
2014, 6, 171–186.
23.5, 23.0, 22.4, 22.3, 16.3, 13.8, 8.4; HRMS calculated for
+
C H O NNa [M+Na] : 320.2196, found 320.2198.
1
7
31
3
[
[
4] B. Haefner, Drug Discovery Today 2003, 8, 536–544.
5] W. De Souza, T. M. U. Carvalho de, E. S. Barrias, Int. J. of Cell Bio. 2010,
Synthesis of (2S,3R,4R)-2-isobutyl-4-methyl-5-oxopyrrolidin-3-yl
E)-3-(2-propylcyclopropyl) acrylate (1): The compound 1 (45 mg,
6%) was synthesized from lactam 8 and 21 by following general
procedure for the synthesis of ester. IR υmax(film): 3225, 2961, 2947,
2
95394.
6] S. Hoet, F. Opperdoes, R. Brun, J. Quetin-Leclercq, Nat. Prod. Rep. 2004,
1, 353–364.
(
7
[
[
2
7] World Health Organization. WHO report on global surveillance of
epidemic-prone infectious diseases. Geneva: World Health Organization;
2000.
À 1
1
1
1
3
715, 1656 cm ; H NMR (400 MHz, CD OD): δ 6.55 (dd, J=10.1,
3
5.1 Hz, 1H), 5.89 (d, J=15.1 Hz, 1H), 4.79 (dd, J=4.0, 4.8 Hz, 1H),
.61 (ddd, J=3.9, 6.4, 8.0 Hz, 1H), 2.46 (dq, J=5.0, 7.5 Hz, 1H), 1.71
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(td, J=6.7, 13.6 Hz, 1H), 1.54–1.29 (m, 7H), 1.26 (d, J=7.3 Hz, 3H),
1
1
1
.10–1.04 (m, 1H), 0.95–0.91 (m, 9H), 0.87 (ddd, J=4.4, 4.4, 8.9 Hz,
13
H), 0.83–0.79 (m, 1H); C NMR (100 MHz, CD OD): δ 179.3, 167.6,
3
57.1, 117.5, 81.7, 58.3, 45.5, 44.9, 36.6, 25.9, 24.3, 23.4, 23.3, 22.3
[
[
(overlapped), 16.7, 15.1, 14.2; HRMS calculated for C H NO Na [M
18
29
3
+
+
Na] : 330.2040, found 330.2044.
1117–1121; c) S. C. Philkhana, A. K. Verma, G. R. Jachak, B. Hazra, A.
Antitrypanosomal Assay Protocol: Testing of inhibitors was done
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in vitro culture using modified HMI-9 media as described
previously. For determining the antitrypanosomal activity of the
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mycin, a modified protocol as published previously was used. In
the assays carried out in this study, the readout was based on Sybr
Green dye staining of the parasite DNA to estimate the parasite
viability. For the growth inhibition assays, the testing was done in
triplicates. A dose dependent inhibition assay was carried out to
estimate the IC50 values starting with a concentration of 10 μM for
the test compounds and 1 μM for the control inhibitor Oligomycin.
DMSO (1%) was used as vehicle treatment for background
correction.
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[14]
[14]
[
[
Manuscript received: December 6, 2020
Revised manuscript received: March 14, 2021
Accepted manuscript online: March 18, 2021
Eur. J. Org. Chem. 2021, 2212–2218
www.eurjoc.org
2218
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