Natural Product-Derived Chiral Pyrrolidine-2,5-diones, Their Molecular Structures and Conversion to Pharmacologically Important Skeletons

Article abstract of DOI:10.1021/acs.jnatprod.0c00211

The versatility of the natural products (2S,3S)- and (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acids (1 and 2), isolated in large amounts from tropical plant sources, has been demonstrated by the construction of 3-substituted and 3,4-disubstituted chiral pyrrolidine-2,5-diones. The absolute configurations of chiral pyrrolidine-2,5-diones have been ascertained using chiroptical spectroscopic methods and/or single-crystal XRD data. A combination of different reaction strategies delivering a diverse matrix of fused heterocyclic ring systems is presented. The pyrrolo[2,1-a]isoquinoline alkaloid (+)-crispine A possesses a wide range of pharmacological activities including antidepressant, antiplatelet, antileukemic, and anticancer activities. The analogues of indolizino[8,7-b]indole alkaloids (+)- and (-)-harmicine show strong antileishmanial, antinociceptive, PDE5-inhibitory, antimalarial, and antiviral activities. The bicyclic furo[2,3-b]pyrrolo skeleton is present in many natural products. Thus, the uniqueness of relatively cheap, naturally occurring chiral 2-hydroxycitric acid lactones as chirons has been demonstrated by the construction of some important molecular skeletons that are otherwise difficult to synthesize.

Full text of DOI:10.1021/acs.jnatprod.0c00211

pubs.acs.org/jnp
Article
Natural Product-Derived Chiral Pyrrolidine-2,5-diones, Their
Molecular Structures and Conversion to Pharmacologically
Important Skeletons
Deenamma Habel, Divya S. Nair, Zabeera Kallingathodi, Chithra Mohan, Sarath M. Pillai, Rani R. Nair,
Grace Thomas, Simimole Haleema, Chithra Gopinath, Rinshad V. Abdul, Matthew Fritz,
Andrew R. Puente, Jordan L. Johnson, Prasad L. Polavarapu,* and Ibrahim Ibnusaud*
Cite This: https://dx.doi.org/10.1021/acs.jnatprod.0c00211
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The versatility of the natural products (2S,3S)- and
(2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acids (1
and 2), isolated in large amounts from tropical plant sources, has
been demonstrated by the construction of 3-substituted and 3,4-
disubstituted chiral pyrrolidine-2,5-diones. The absolute config-
urations of chiral pyrrolidine-2,5-diones have been ascertained
using chiroptical spectroscopic methods and/or single-crystal XRD
data. A combination of different reaction strategies delivering a
diverse matrix of fused heterocyclic ring systems is presented. The
pyrrolo[2,1-a]isoquinoline alkaloid (+)-crispine A possesses a wide
range of pharmacological activities including antidepressant,
antiplatelet, antileukemic, and anticancer activities. The analogues
of indolizino[8,7-b]indole alkaloids (+)- and (−)-harmicine show
strong antileishmanial, antinociceptive, PDE5-inhibitory, antimalarial, and antiviral activities. The bicyclic furo[2,3-b]pyrrolo
skeleton is present in many natural products. Thus, the uniqueness of relatively cheap, naturally occurring chiral 2-hydroxycitric acid
lactones as chirons has been demonstrated by the construction of some important molecular skeletons that are otherwise difficult to
synthesize.
hiral molecules, either obtained directly from nature or
through chemical modification of the naturally occurring
C
molecules, play a vital role in the pursuit of pharmaceutical and
synthetic organic chemistry. The structure−activity studies
have taken organic synthesis to the domain of enantiopure
synthesis.1 About 80% of small-molecule drugs approved by
the Food and Drug Administration (FDA) are chiral, and 75%
are used as a single enantiomer.2,3 Among various strategies
toward the synthesis of enantiopure compounds, the chiral
pool approach is extremely attractive due to assured optical
purity of the target molecule and economic viability. Several
tropical plants are rich sources of structurally simple chiral 2-
hydroxycitric acids.4 Out of the four possible optical isomers,
the (2S,3S)-diastereomer garcinia acid (1) and the (2S,3R)-
diastereomer hibiscus acid (2) have been isolated as their γ-
lactones in optically pure form in kilogram quantities (Figure
1).5
Figure 1. Structures of diastereomeric garcinia and hibiscus acids.
class of three and four carbon skeletal chiral hydroxy acids,
namely, lactic, malic, mandelic, and tartaric acids. However,
using the molecules having a three- or four-carbon framework,
synthesis of target molecules with a basic skeleton having more
than four carbons inevitably involves lengthy synthetic
sequences.9−11 Therefore, the chiral lactones 1 and 2, bearing
chemically amenable functional groups, could be an ideal
choice for the construction of several bioactive molecules
Received: March 11, 2020
Among these, lactone 1 has been used extensively for the
preparation of antiobesity formulations.6,7 The two stereogenic
centers in these γ-butyrolactones have structural and stereo-
chemical features that relate to several small bioactive
molecules of synthetic or natural origin.8 Accordingly, 1 and
2 are expected to be added to the existing list of the privileged
© XXXX American Chemical Society and
American Society of Pharmacognosy
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX
A

Journal of Natural Products
pubs.acs.org/jnp
Article
Table 1. Representative Biologically Active Molecules Synthetically Related to 1 and 213−24
Scheme 1. Conversion of 1 and 2 into 8, 9, 10, 11, and 12
having six-carbon structural skeletons. Moreover, the intrinsic
stereogenic center steers the stereospecific generation of the
new stereogenic center in the target structures.12 Hence, taking
advantage of the stereochemistry and functional group
flexibility, molecules 1 and 2 serve as ideal choices for the
construction of diverse structural skeletons of a variety of
biologically active molecules of natural and synthetic origin.
Some of the bioactive molecules that can be related to these
skeletal buildups are given in Table 1.
With a goal toward the discovery of novel small molecules
with biological activities, we report the successful and diversity-
oriented construction of chiral skeletons, namely,
tetrahydropyrrolo[2,1-a]isoquinolinones (15 and 17),
hexahydroindolizino[8,7-b]indolones (19 and 21), and furo-
[2,3-b]pyrroles (16 and 18), mostly in just one or two steps
B
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
Scheme 2. Preparation of 3-Substituted Pyrrolidine-2,5-diones 13a−e and 14a−b from Monocyclic Diesters 8a, 8b, and 9
Scheme 3. N-Acyliminium Cyclization Involving Unsymmetrical Pyrrolidine-2,5-dione 13f
using the 3-substituted (13a−e, 14a,b) and 3,4-disubstituted
(23a−e, 24a−f) chiral pyrrolidine-2,5-diones prepared from 1
and 2. These skeletons are related to naturally occurring (R)-
(+)-crispine A (3), (R)-(+)-oleracine E (4), (S)-(−)-trolline
(5), (R)-(+)-harmicine (6), and (+)-madindoline A (7),
respectively (Table 1).
The absolute configurations (ACs) of chiral compounds can
be determined from X-ray structures when good-quality
crystals are available. In situations where this is not possible,
chiroptical spectroscopic methods provide useful approaches
to establish the AC. It is necessary to establish the reliability of
chiroptical spectroscopic methods for determining the ACs of
substituted pyrrolidine-2,5-diones. For this purpose, we have
also undertaken chiroptical spectroscopic measurements and
analyses for two representative pyrrolidine-2,5-diones and
verified the derived AC with those obtained from either
synthetic schemes and/or X-ray structures.
RESULTS AND DISCUSSION
■
For the construction of various structural skeletons (Table 1),
the starting monocyclic diesters 8a, 8b, and 9,5 acyclic triesters
10 and 11, bicyclic anhydride 1225 (Scheme 1), 3-substituted
pyrrolidine-2,5-diones (Scheme 2), and 3,4-disubstituted
pyrrolidine-2,5-diones (Scheme 6) were prepared from 1 and
2. The pyrrolidine-2,5-diones 13a−e are ideal starting
molecules for the construction of tetrahydropyrrolo[2,1-a]
C
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
Scheme 4. Synthesis of Tetrahydropyrrolo[2,1-a]isoquinones 15 and 17 and Furo[2,3-b]pyrroles 16a, 16b,34 and 18
Scheme 5. Synthesis of Hexahydroindolizino[8,7-b]indolones 19 and 21 and Furo[2,3-b] pyrroles 20 and 22
isoquinolinones 15 and 17, furo[2,3-b]pyrroles 16a, 16b, 18,
20, and 22, (−)-hexahydroindolizino[8,7-b]indolones 19 and
21 (Schemes 4 and 5), and pyrroloisoquinolinone 25 (Scheme
6) in one step.
D
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
Scheme 6. Synthesis of 3,4-Disubstituted Pyrrolidine-2,5-diones 23a−e and 24a−f from Bicyclic Anhydride 12
Preparation of the Diastereomeric 3-Substituted
Pyrrolidine-2,5-diones (13 and 14). The diastereomeric
3-substituted pyrrolidine-2,5-diones 13 and 14 were prepared
in promising yield (71% to 90%) (Scheme 2) from 1 and 2 and
are well characterized. These 3-substituted pyrrolidine-2,5-
diones have an inherent appendage of diversity arising from
different substituents attached to the imido nitrogen and
judiciously used for the preparation of various enantiopure
fused poly-heterocyclic ring systems.
Chiroptical Spectroscopic Analysis of Methyl (S)-2-
[(S)-1-Benzyl-3-hydroxy-2,5-dioxopyrrolidin-3-yl]-2-hy-
droxyacetate (13a). As a representative case for the series of
3-substituted pyrrolidine-2,5-diones with (S,S) configuration
(13), vibrational absorption (VA), vibrational circular
dichroism (VCD), electronic absorption (EA), electronic
circular dichroism (ECD), and discrete wavelength optical
rotatory dispersion (ORD) measurements and corresponding
quantum chemical calculations were undertaken for 13a. The
solvent influence was incorporated into the calculations using
the polarizable continuum model (PCM). The four lowest
energy conformers of 13a identified at the B3LYP/aug-cc-
pVDZ/PCM(CH3CN) level are shown in Figure 2.
The VA and VCD spectra are shown in Figure 3. The
experimental VCD spectrum shows negative and positive
bands, associated with corresponding absorption bands, at
1747 and 1716 cm−1, respectively. These two VCD features are
correctly reproduced in the B3LYP/aug-cc-pVDZ/PCM-
(CH3CN) predicted spectra at 1756 and 1719 cm−1. The
VCD bands in the experimental spectrum at 1396, 1315, and
1257 cm−1 are also reproduced in the predicted spectrum at
1412, 1333, and 1267 cm−1.
The EA and ECD spectra are shown in Figure 4. The
experimental electronic spectra show one resolved absorption
band at 203 nm and a broad low-amplitude negative ECD
Cotton effect stretching from 270 to 230 nm, with a peak at
252 nm, followed by a broad positive ECD Cotton effect
stretching from 230 nm and extending beyond 195 nm, with a
peak at 205 nm. The predicted electronic spectra at the
E
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
Figure 2. Four lowest energy conformers of 13a identified at B3LYP/
aug-cc-pVDZ/PCM(CH3CN) level.
Figure 4. Experimental and quantum chemical EA (bottom panel)
and ECD (top panel) spectra of compound 13a.
Figure 5. Experimental and quantum chemical discrete wavelength
ORD spectra of compound 13a.
Figure 3. Experimental and quantum chemical VA (bottom panel)
and VCD (top panel) spectra of compound 13a.
Based on the current data and analysis, it is clear that the
experimental VCD, ECD, and long-wavelength ORD spectra
of 13a have been reproduced very well by the quantum
chemical predictions at the B3LYP/aug-cc-pVDZ/PCM-
(CH3CN) level. Thus, chiroptical spectroscopy provides a
valuable approach for deducing the absolute configurations of
the 3-substituted pyrrolidine-2,5-dione series with (S,S)
configuration.
Chiroptical Spectroscopic Analysis of Methyl (S)-2-
[(R)-1-(3,4-Dimethoxyphenethyl)-3-hydroxy-2,5-dioxo-
pyrrolidin-3-yl]-2-hydroxyacetate (14a). Compounds 13
and 14 have diastereomeric configurations, differing in the AC
of C-3 of the pyrrolidine-2,5-dione ring. We could not measure
the experimental spectroscopic data, but VA, VCD, EA, ECD,
and ORD calculations were undertaken for 14a, to investigate
if the diastereomeric configurations yield sufficiently different
spectroscopic signatures for their identification. The predicted
data for 14a are presented in the Supporting Information. A
comparison of VCD, ECD, and ORD data of 14a with those of
13a reveals that diastereomeric configurations have distinctly
B3LYP/aug-cc-pVDZ/PCM(CH3CN) level indicate an ab-
sorption maximum at 193 nm, a broad negative ECD Cotton
effect stretching from 295 to 235 nm, and a positive ECD
Cotton effect stretching from 235 nm and extending beyond
195 nm.
The ORD data are shown in Figure 5. The experimental
specific rotation (SR) is positive at all six wavelengths
measured, with increasing magnitudes toward shorter wave-
lengths. However, the magnitudes of observed SRs are quite
small. The predicted ORD at the B3LYP/aug-cc-pVDZ/
PCM(CH3CN) level indicates decreasing magnitudes of SR at
shorter wavelengths. Since the reliability of predicted SRs is
generally higher when the magnitudes are larger, the
differences from the trend in experimental SRs at shorter
wavelengths could be attributed to the small magnitudes of
SRs for this molecule.
F
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
different spectroscopic signatures. For 14a, the VCD bands
associated with the CO stretching bands at around 1700
cm−1 are of opposite signs and of different pattern in the
1400−1200 cm−1 region, compared to those for 13a; starting
from long-wavelength side, a positive−negative−positive−
negative ECD spectroscopic pattern predicted for 14a is
different from the negative−positive pattern predicted for 13a;
ORD is negative at all wavelengths for 14a, unlike that for 13a.
These observations enumerate the importance of chiroptical
spectroscopy in discriminating the diastereomeric configura-
tions of 3-substituted pyrrolidine-2,5-diones.
S y n t h e s i s o f T e t r a h y d r o p y r r o l o [ 2 , 1 - a ]-
isoquinolinones 15 and 17, Hexahydroindolizino[8,7-
b]indolones 19 and 21, and Furo[2,3-b]pyrroles 16 and
18. Several molecules with pyrroloisoquinoline18,26−28 and
indolizinoindolone12,13,16,26 ring systems are widely present in
the folk medicines of tropical and subtropical regions.29,30
Given their attractive biological activities, much attention has
been focused on efficient synthetic methods for these N-fused
heterocyclic alkaloids, bearing pyrroloisoquinoline and in-
dolizinoindolone structural frameworks, from simple starting
materials.16,28,31 For the synthesis of these fused heterocyclic
systems, N-acyliminium ion cyclization has become the most
propitious methodology.27,28,32 The synthetic strategy involves
the preparation of the required chiral N-acyliminium ions, via
the reduction of chiral unsymmetrical pyrrolidine-2,5-diones
13c, 13d, 14a, and 14b, which undergo diastereoselective N-
acyliminium cyclization, leading to the formation of
tetrahydropyrrolo[2,1-a]isoquinoline 15 and 17 and
hexahydroindolizino[8,7-b]indolone 19 and 21 ring systems.
The regioselectivity of reduction of unsymmetrical pyrrolidine-
2,5-diones occurs at the more substituted carbonyl.33 It is
known that the N-acyliminium cyclization produces only a
single diastereomer resulting from a diastereospecific attack of
the nucleophilic aryl ring at the least hindered side of the
acyliminium ion (Scheme 3).12
14a,b with excess NaBH4 (10 equiv) followed by quenching
with excess MeOH (path B) resulted in the formation of the
furo[2,3-b]pyrroles 16a, 16b, 18, 20, and 22 diastereospecifi-
cally, via a 5-exo-trig cyclization involving the hydroxy group of
the reduced ester group as the nucleophilic entity. The basic
reaction mixture generated by the excess (10 equiv) of NaBH4
allowed the isolation of furo[2,3-b]pyrroles 16a, 16b, and 18 as
the O−N acetals stable under the isolation conditions.
Accordingly, compound 15, an analogue of naturally
occurring (−)-crispine A (Scheme 4), and 19, an analogue
of naturally occurring (−)-harmicine (Scheme 5), were
synthesized from 13c and 13d, respectively, as single
diastereomers. Similarly, synthesis of compounds 17 and 21,
analogues of (+)-crispine A and (+)-harmicine, respectively,
was achieved using 14a and 14b, the diastereomers of 13c and
13d, respectively. The structure and configurations of these
molecules were established with all spectroscopic data
including single-crystal XRD. The absolute configurations of
the final molecules were defined by relating to the known
absolute configurations of the starting molecules. The
diastereoselective outcome can be explained on the basis of
the favored conformation of intermediate 15a, so that
intramolecular cyclization of 13c leads to 15 via a re-face
attack of the aryl group. Similarly, si-face cyclization of 14a
resulted in the formation of 17. The diastereoselective attack of
the nucleophilic aryl ring occurs at the least hindered side of
the N-acyliminium ion.12,35,36
When the pyrrolidine-2,5-dione 13e was used, a 5-exo-trig
cyclization occurred in the N-acyliminium ion, using 10 equiv
of NaBH4 in EtOH, followed by acidic workup (5 M HCl),
resulting in the exclusive formation of furo[2,3-b]pyrrole
16b.34 However, when the aryl ring bears electron-donating
groups, it competes with the hydroxy group acting as a
nucleophile for the N-acyliminium cyclization. Thus, the
pyrrolidine-2,5-diones 13c and 14a furnished
tetrahydropyrrolo[2,1-a]isoquinolinones 15 and 17 via a 6-
endo-trig Pictet−Spengler cyclization in excellent yield. Thus,
by judiciously tuning the electron density of the aryl ring of the
pyrrolidine-2,5-diones, cyclization can be switched to either
furo[2,3-b]pyrroles or pyrrolo[2,1-a]isoquinolines.
The 3,4-disubstituted pyrrolidine-2,5-diones (23a−e) were
prepared, from the anhydride 12 and using appropriate amines
under refluxing conditions in the presence of acetyl chloride, in
excellent yield (Scheme 6).25 The deacetylation of correspond-
ing pyrrolidine-2,5-diones 23 using acidic EtOH furnished
24a−e in good yield (Scheme 6).
Chiroptical Spectroscopic Analysis of (3aS,6aS)-5-
Benzyl-3a-hydroxydihydro-2H-furo[2,3-c]pyrrole-2,4,6-
(3H,5H)-trione (24f). As a representative case for the series of
3,4-disubstituted pyrrolidine-2,5-diones 23a−e and 24a−f, VA,
VCD, EA, ECD, and discrete wavelength ORD measurements
and corresponding quantum chemical calculations were
undertaken for 24f. The conformers of 24f optimized at the
B3LYP/aug-cc-pVDZ/PCM(CH3CN) level are shown in
Figure 6.
The VA and VCD spectra are shown in Figure 7. The
experimental VCD spectrum shows large negative and positive
bands associated with corresponding absorption bands at 1751
and 1732 cm−1, respectively. These large VCD features are
correctly reproduced in the B3LYP/aug-cc-pVDZ/PCM-
(CH3CN) predicted spectra at 1761 and 1736 cm−1. The
VCD bands in the experimental spectrum at 1801, 1335, 1288,
The tetrahydropyrrolo[2,1-a]isoquinone derivatives 15 and
17, furo[2,3-b]pyrroles 16, 18, 20, and 22, and
hexahydroindolizino[8,7-b]indolones 19 and 21 were prepared
in enantiomerically pure form in good yield from chiral 3-
substituted pyrrolidine-2,5-diones 13 and 14 (Schemes 4 and
5).
Compounds 13 and 14 are N-alkyl imides. It is possible that
the proximal hydroxy groups are directing the regioselective
reductions here. The reduction products of 13 and 14 could be
folded to obtain either five- or six-membered fused
heterocyclic ring systems depending on the conditions of
workup and electronic status of the aromatic ring (Schemes 4
and 5). In continuation of our preliminary work on the
reductive 5-exo-trig cyclization of 3-substituted pyrrolidine-2,5-
diones,34 we have extended the scope of the work to
pyrrolidine-2,5-diones with different electronic characteristics
(Schemes 4 and 5). The pyrrolidine-2,5-diones 13c,d and
14a,b upon reduction with NaBH4 (3 equiv) followed by
workup under acidic conditions (5 M HCl) (path A) furnished
tetrahydropyrrolo[2,1-a]isoquinones 15 and 17 and
hexahydroindolizino[8,7-b]indolones 19 and 21 diastereose-
lectively, via a 6-endo-trig cyclization involving the aromatic
ring as the nucleophilic entity (Schemes 4 and 5). The
chiroptical studies of the (−)-crispine A analogue (1R,10bR)-
1-[(R)-1,2-dihydroxyethyl]-1-hydroxy-8,9-dimethoxy-
1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (15)
was recently reported.29 However, the reduction of 13c−e and
G
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
Figure 6. Two lowest energy conformers of 24f obtained at the
B3LYP/aug-cc-pVDZ/PCM(CH3CN) level.
Figure 8. Experimental and calculated EA (bottom panel) and ECD
(top panel) spectra of 24f.
Figure 7. Experimental and quantum chemical VA (bottom panel)
and VCD (top panel) spectra of 24f.
and 1238 cm−1 are also reproduced in the predicted spectrum
at 1811, 1344, 1295, and 1238 cm−1.
Figure 9. Experimental and quantum chemical discrete wavelength
ORD spectra of 24f.
The EA and ECD spectra are shown in Figure 8. The
experimental electronic spectra show one resolved absorption
band at 205 nm and a broad negative ECD Cotton effect
stretching from 245 to 195 nm, with a peak at 209 nm. The
predicted electronic spectra at the B3LYP/aug-cc-pVDZ/
PCM(CH3CN) level indicate an absorption maximum at 192
nm with an associated negative ECD Cotton effect at 193 nm.
The predicted spectrum also shows a broad negative ECD
Cotton effect around 240 nm, whose corresponding feature
may be hidden in the broad experimental ECD Cotton effect.
Comparison of the experimental and predicted ORD for 24f
is shown in Figure 9. The experimental SR is negative at all six
wavelengths measured, with increasing magnitudes toward
shorter wavelengths. The same pattern is seen in the predicted
ORD at the B3LYP/aug-cc-pVDZ/PCM(CH3CN) level with
predicted magnitudes in much better agreement with the
corresponding experimental magnitudes.
the B3LYP/aug-cc-pVDZ/PCM(CH3CN) level. Thus, chirop-
tical spectroscopy provides a practically useful approach for
deducing the absolute configurations of 3,4-disubstituted
pyrrolidine-2,5-diones.
Synthesis of Pyrroloisoquinolinone 25 from Bicyclic
Anhydride 12. The reaction between 24d and excess NaBH4
(10 equiv), followed by acidic workup,28,33 resulted in the
formation of 2,3-disubstituted pyrrolo[2,1-a]isoquinolinone 25
(Scheme 7). As in the case of pyrrolidine-2,5-diones 13 and
14, the steric crowding at C-312 of 24d directs the reducing
agent to selectively reduce the C-2 carbonyl group. Reduction
of the carbonyl on the more hindered side reduces the overall
steric crowding, whereas there is no such gain if the carbonyl is
reduced at the less hindered side. The resulting N-acyliminium
ion undergoes Pictet−Spengler cyclization to furnish 25
instead of the anticipated 25a. A plausible explanation for
the formation of 25 can be offered on assuming the formation
Based on the current data and analysis, it is clear that the
experimental VCD, ECD, and ORD of 24f have been
reproduced very well by the quantum chemical predictions at
H
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
Scheme 7. Synthesis of Pyrroloisoquinolinone 25 from Bicyclic Anhydride 12
in CD3CN at 1.1 and 3.0 mg/mL using a 100 μm cell with BaF2
windows. EA and ECD spectra were obtained in CH3CN at 1.2 mg/
400 μL and 0.6 mg/400 μL using a 0.1 mm cell. ORD measurements
were made at six discrete wavelengths, 633, 589, 546, 436, 405, and
365 nm, at 1.9 mg/2 mL in CH3CN solvent using a 0.5 dm cell. The
crystal structure was used as the starting point for conformational
searching with the CONFLEX program.39 Ninety-one conformers
were found within a 20 kcal/mol energy window. The first 20
conformers, in the 6 kcal/mol range, were optimized at the B3LYP/6-
31G* level using the Gaussian 09 program.40 The resulting lowest
energy conformers in a 2 kcal/mol energy window were reoptimized
at the B3LYP/aug-cc-pVDZ and B3LYP/aug-cc-pVDZ/PCM-
(CH3CN) levels. ORD, ECD, and VCD calculations were undertaken
for the lowest energy conformations at the B3LYP/6-31G*, B3LYP/
aug-cc-pVDZ, and B3LYP/aug-cc-pVDZ/PCM(CH3CN) levels using
respective optimized geometries. This discussion is restricted to the
results obtained at the B3LYP/aug-cc-pVDZ/PCM(CH3CN) level.
Chiroptical Spectroscopic Predictions for 14a. The details are
provided in the Supporting Information.
Chiroptical Spectroscopic Measurements and Calculations
for 24f. The EA and ECD spectra were measured in CH3CN at 1.66
mg/mL using a 0.1 mm cell, and solvent spectra were subtracted.
ORD measurements at six discrete wavelengths, 633, 589, 546, 436,
405, and 365 nm, were measured at 1.1 mg/mL in CH3CN using a
0.5 dm cell. VCD measurements were made in CD3CN at 1.3 and 4.7
mg/mL using a 100 μm cell with BaF2 windows. A molecular model
of compound 24f was built starting from the structure of acetylated
garcinia acid anhydride. This structure was used as input for
conformational searching with the CONFLEX program.39 Thirteen
conformers were found. These 13 conformations were optimized at
of the epoxide 25c by an intramolecular substitution of the
tertiary hydroxy group of 25b followed by a hydride transfer to
exclusively form 25 (Scheme 7).
The structure of 25 was confirmed on the basis of 1H NMR,
13C NMR, DEPT 90, DEPT 135, and HRMS data. The relative
configuration and structure were established from single-crystal
X-ray crystallography.
EXPERIMENTAL SECTION
■
General Experimental Procedures. All commercial solvents
were distilled prior to use. Dry solvents and reagents were prepared by
following the procedures described in Purification of Laboratory
Chemicals by Perrin, D. D., and Armarego, W. L. F. (3rd ed.,
Pergamon Press, 1988). Melting points were determined on a
“Sunbim” electrically heated melting point apparatus and are
uncorrected. IR spectra were recorded using a Shimadzu IR 470
spectrophotometer as thin films (liquids), PerkinElmer Spectrum-400
FTIR spectrophotometer, and ThermoFisher Is 10 FTIR spectrom-
eter equipped with an ATR unit. Selected characteristic peaks are
reported in cm−1. 1H and 13C NMR were recorded on a Bruker
AVANCE III spectrometer. The chemical shifts are given in parts per
million (ppm) on the δ scale. Data are reported as follows: s = singlet;
d = doublet; t = triplet; q = quartet; p = pentet; dd = doublet of
doublets; dt = doublet of triplets; br = broad. High-resolution mass
spectrometry (HRMS) was recorded on a QTOF mass spectrometer.
Optical rotations were recorded using a Rudolph Autopol IV
polarimeter.
Chiroptical Spectroscopic Measurements and Calcula-
tions37,38 for 13a. VA and VCD measurements were carried out
I
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
the B3LYP/6-31G* level using the Gaussian 09 program.40 The two
lowest energy conformers were found to be within 2 kcal/mol energy.
These two conformers were reoptimized at the B3LYP/aug-cc-pVDZ
and B3LYP/aug-cc-pVDZ/PCM(CH3CN) levels, and ORD, ECD,
and VCD calculations were undertaken using respective optimized
geometries. This discussion is restricted to the results obtained at the
B3LYP/aug-cc-pVDZ/PCM(CH3CN) level.
General Procedure for the Synthesis of 3-Substituted
Pyrrolidine-2,5-diones 13a−e and 14a,b from Monocyclic
Diesters 8a, 8b, and 9. To a stirred solution of 8a (1.0 g, 4.6 mmol,
1 equiv)/8b (1.0 g, 3.64 mmol, 1 equiv)/9 (1.0 g, 4.6 mmol, 1 equiv)
in toluene (10 mL) was added the amine (1 equiv), and the reaction
flask was equipped with a reflux condenser. The resulting mixture was
refluxed. After 5 h, the reaction mixture was concentrated under
reduced pressure and the crude residue was purified by column
chromatography on silica gel 60−120 mesh (20% EtOAc/n-hexane)
to afford pyrrolidine-2,5-diones 13a−e and 14a,b.
Methyl (S)-2-[(S)-1-benzyl-3-hydroxy-2,5-dioxopyrrolidin-3-yl]-2-
hydroxyacetate (13a).34 Colorless needles (CHCl3); mp 106−107
°C; [α]2D5+11 (c 0.1, CHCl3); IR (KBr) νmax 3432, 2949, 1775, 1743,
1695 cm−1; 1H NMR (CDCl3, 400 MHz) 7.34−7.26 (m, 5H), 4.70−
4.62 (m, 2H, CH2), 4.31 (s, 1H), 4.10 (br s, 1H), 3.87 (s, 3H,
OCH3), 3.21 (br s, 1H) 3.16 (d, J = 18.0 Hz, 1H), 2.76 (d, 1H, J =
18.0 Hz); 13C NMR (100 MHz, CDCl3) 176.8 (CO), 173.5 (C
O), 171.8 (COOCH3), 135.1, 128.7, 128.5, 128.0, 76.2, 72.1, 53.8,
42.6, 39.7; HRESIMS m/z 294.0970 [M + H+] (calcd for C14H16NO6
294.0978).
112.1, 111.4, 77.2, 75.4, 72.7, 55.9, 53.3, 40.4, 38.2, 33.0; HRESIMS
m/z 368.1333 [M + H]+ (calcd for C17H22NO8368.1345).
Methyl (S)-2-[(R)-1-(2-(1H-indol-3-yl)ethyl)-3-hydroxy-2,5-dioxo-
pyrrolidin-3-yl]-2-hydroxyacetate (14b). Colorless crystals (CHCl3);
mp 85−86 °C; [α]2D5−37 (c 0.1, CH3OH); IR (KBr) νmax 3405, 2980,
1747, 1670 cm−1; 1H NMR (CDCl3, 400 MHz) 8.01 (s, 1H), 7.68 (d,
J = 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.17 (m, 2H), 7.06 (s, 1H),
4.39 (s, 1H), 3.83 (m, 3H), 3.79 (s, 3H), 3.04 (m, 3H), 2.96 (s, 1H),
2.68 (d, J = 18 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 176.5 (C
O), 173.4 (CO), 171.8 [COOCH(CH3)2], 136.2, 127.4, 122.4,
122.1, 119.6, 118.7, 112.0, 111.2, 75.4, 72.8, 53.3, 39.6, 38.4, 23.3;
HRESIMS m/z 369. 1081 [M
+
Na]+ (calcd for
C17H18N2NaO6369.1063).
General Procedure for the Preparation of Furopyrrolone
Analogues 16, 18, 20, and 22. To a stirred solution of pyrrolidine-
2,5-dione 13c/13d/14a/14b (1 mmol, 1 equiv) in absolute EtOH
(10 mL) precooled to 0 °C was added excess NaBH4 (10 equiv) with
stirring. After 20 h, the reaction was quenched with excess MeOH,
and then a saturated aqueous NaHCO3 solution was added. The
excess MeOH was concentrated under reduced pressure. The aqueous
layer was extracted with CH2Cl2 (3 × 40 mL), and the combined
organic layers were dried over anhydrous MgSO4 and concentrated
under reduced pressure. The resulting crude residue was purified by
column chromatography on silica gel 60−120 mesh (20% n-hexane/
EtOAc) to afford 16a, 18, 20, and 22.
(3R,3aS,6aS)-6-(3,4-Dimethoxyphenethyl)-3,3a-dihydroxytetra-
hydro-2H-furo[2,3-b]pyrrol-5(3H)-one (16a). Yellow oil; [α]2D5 −157
1
(c 0.1, CH3OH); IR (KBr) νmax 3330, 2932, 1662 cm−1; H NMR
Isopropyl (S)-2-hydroxy-2-[(S)-3-hydroxy-1-isopentyl-2,5-dioxo-
(methanol-d4, 400 MHz) 6.87 (m, 2H), 6.78 (d, J = 8.0 Hz,1H), 5.02
(s, 1H), 4.19 (m, 1H), 4.06 (m, 1H), 3.84 (s, 3H, OCH3), 3.81 (s,
3H, OCH3), 3.62 (m, 1H), 3.38 (m, 3H), 3.13 (d, J = 18.0 Hz, 1H),
2.82 (m, 2H), 2.28 (d, J = 18.0 Hz, 1H); 13C NMR (methanol-d4, 100
MHz) 173.5 (CO), 149.1, 147.7, 131.6, 120.8, 112.3, 111.8, 98.6,
81.6, 76.8, 70.6, 55.1, 55.0, 41.6, 37.6, 32.9; HRESIMS m/z 324.1446
[M + H]+ (calcd for C16H22NO6324.1447).
pyrrolidin-3-yl]acetate (13b). Pale yellow oil; [α]2D5 −11 (c 0.3,
1
CHCl3); IR (KBr) νmax3438, 1781, 1700 cm−1; H NMR (CDCl3,
400 MHz) 5.06 (m, 1H), 4.28 (s, 1H), 3.38 (m, 2H), 2.95 (d, J = 18.4
Hz, 1H), 2.59 (d, J = 18.4 Hz, 1H), 1.44 (m, 1H), 1.34 (m, 2H), 1.20
(s, 6H, CH(CH3)2), 0.80 (d, J = 6.4 Hz, 6H, CH(CH3)2); 13C NMR
(CDCl3,100 MHz) 177.0 (CO), 174.3 (CO), 170.4 (COOCH-
(CH3)2), 75.9, 72.5, 71.2, 39.5, 37.4, 36.0, 25.7, 22.2, 22.1, 21.5, 21.4;
(3R,3aR,6aR)-6-[3,4-Dimethoxyphenethyl]-3,3a-dihydroxytetra-
hydro-2H-furo[2,3-b]pyrrol-5(3H)-one (18). Colorless crystals
(CHCl3); mp 114−116 °C; [α]2D5 −45 (c 0.1, acetone); IR (KBr)
HRESIMS m/z 324. 1420 [M
+
Na]+ (calcd for
C14H23NNaO6324.1418).
1
νmax 3387, 2946, 1676 cm−1; H NMR (acetone-d6, 400 MHz) 6.87
Methyl (S)-2-[(S)-1-(3,4-dimethoxyphenethyl)-3-hydroxy-2,5-di-
oxopyrrolidin-3-yl]-2-hydroxyacetate (13c). Colorless needles
(CHCl3); mp 120−122 °C; [α]2D5 +17 (c 0.2, acetone); IR (KBr)
νmax 3466, 2952, 1790, 1739, 1700 cm−1; 1H NMR (CDCl3, 400
MHz) 6.75 (m, 3H), 4.26 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.85 (s,
3H, OCH3), 3.72 (m, 2H), 3.11 (d, J = 18 Hz, 1H), 2.83 (m, 2H),
2.69 (d, J = 18 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 177.1 (C
O), 173.8 (CO), 171.7 (COOCH3), 148.9, 147.8, 130.0, 120.9,
112.1, 111.2, 76.1, 72.1, 55.9, 55.8, 53.7, 40.2, 39.6, 32.8; HRESIMS
m/z 368.1333 [M + H]+ (calcd for C17H22NO8368.1345) (CCDC
1852020).
Isopropyl (S)-2-{(S)-1-[2-(1H-indol-3-yl)ethyl]-3-hydroxy-2,5-di-
oxopyrrolidin-3-yl}-2-hydroxyacetate (13d). Colorless needles
(CHCl3); mp 90−92 °C; [α]2D5 +55 (c 0.1, CH3OH); IR (KBr)
νmax 3465, 2984, 1731, 1690 cm−1; 1H NMR (CDCl3, 400 MHz) 8.09
(s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.18 (m,
2H), 7.02 (s, 1H), 5.27 (m, 1H), 4.14 (s, 1H), 3.81 (m, 2H), 3.11 (s,
1H), 3.05 (m, 3H), 2.68 (d, J = 18.0 Hz, 1H), 1.36 (m, 6H,
CH(CH3)2); 13C NMR (CDCl3, 100 MHz) 177.0 (CO), 174.0
(CO), 170.8 [COOCH(CH3)2], 136.2, 127.4, 122.3, 122.1, 119.6,
118.8, 111.9, 111.1, 76.7, 76.0, 72.2, 72.0, 39.8, 39.5, 23.2, 21.7;
HRESIMS m/z 375.1550 [M + H]+ (calcd for C19H23N2O6375.155)
(CCDC 1852019).
Methyl (S)-2-[(R)-1-(3,4-dimethoxyphenethyl)-3-hydroxy-2,5-di-
oxopyrrolidin-3-yl]-2-hydroxyacetate (14a). Colorless crystal
(CHCl3); mp 133−134 °C; [α]2D5 −38 (c 0.1, acetone); IR (KBr)
νmax 3453, 2933, 1789, 1747, 1703 cm−1; 1H NMR (CDCl3, 400
MHz) 6.75 (m, 3H), 4.42 (d, J = 6.8 Hz, 1H), 3.87 (s, 3H, OCH3),
3.85 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.76 (s, 1H), 3.73 (m, 2H),
3.29 (d, J = 6.8 Hz, 1H), 2.99 (d, J = 18.4 Hz, 1H), 2.82 (m, 2H),
2.66 (d, J = 18.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 176.8 (C
O), 173.4 (CO), 171.6 (COOCH3), 149.0, 147.9, 130.0, 120.9,
(m, 2H), 6.77 (m,1H), 5.04 (s, 1H), 4.93 (br s, 1H), 4.63 (br s, 1H),
3.99 (s, 1H), 3.86 (s, 2H), 3.81 (s, 3H, OCH3), 3.77 (s, 3H, OCH3),
3.58 (m, 1H), 3.36 (m, 1H), 2.81 (m, 2H), 2.60 (d, J = 18.0 Hz, 1H),
2.49 (d, J = 18.0 Hz, 1H); 13C NMR (acetone-d6, 100 MHz) 172.1
(CO), 150.4, 149.0, 132.7, 121.5, 113.6, 113.0, 98.5, 81.3, 76.3,
73.3, 56.1, 56.0, 43.0, 42.7, 34.3; HRESIMS m/z 346.1259 [M + Na]+
(calcd for C16H21NO6Na346.1267) (CCDC 1852023).
(3R,3aS,6aS)-6[(2-(1H-Indol-3-yl)ethyl]-3,3a-dihydroxytetrahy-
dro-2H-furo[2,3-b]pyrrol-5(3H)-one (20). Yellow oil; [α]2D5 −45 (c
0.1, acetone); IR (KBr) νmax 3362, 2934, 1669 cm−1; 1H NMR
(methanol-d4, 400 MHz) 7.61 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz,
1H), 7.10 (m, 2H), 7.02 (m, 1H), 5.08 (s, 1H), 4.19 (dd, J = 14.4 Hz,
6.3 Hz, 1H), 4.08 (dd, J = 6.4 Hz, 2.8 Hz, 1H), 3.69 (m, 1H), 3.51
(m, 1H), 3.39 (m, 1H), 3.18 (d, J = 18.0 Hz, 1H), 3.04 (m, 2H), 2.32
(d, J = 18.0 Hz, 1H); 13C NMR (acetone-d6, 100 MHz) 173.5 (C
O), 136.8, 127.3, 122.0, 120.9, 118.3, 117.8, 111.4, 110.8, 98.7, 81.6,
76.9, 70.5, 40.8, 37.7, 23.1; HRESIMS m/z 303.1351 [M + H]+ (calcd
for C16H19N2O4303.1339).
(3R,3aR,6aR)-6[2-(1H-indol-3-yl)ethyl]-3,3a-dihydroxytetrahy-
dro-2H-furo[2,3-b]pyrrol-5(3H)-one (22). Yellow oil; [α]2D5 +99 (c
0.1, CH3OH); IR (KBr) νmax 3310, 2921, 1651 cm−1; 1H NMR
(methanol-d4, 400 MHz) 7.65 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz,
1H), 7.20 (s, 1H), 7.07 (m, 2H), 5.15 (s, 1H), 4.29 (m, 1H), 4.04
(m,1H), 3.64 (m, 1H), 3.48 (m,1H), 3.39 (m, 1H), 3.15 (m, 1H),
3.04 (m, 2H), 2.25 (m, 1H); 13C NMR (acetone-d6, 100 MHz) 172.4
(CO), 137.7, 128.5, 123.2, 122.1, 119.4, 119.3, 113.1, 112.2, 99.4,
82.7, 78.3, 71.2, 41.6, 38.9, 24.5; HRESIMS m/z 303.1351 [M + H]+
(calcd for C16H19N2O4303.1339).
General Procedure for the Prepara tion of
Tetrahydropyrrolo[2,1-a]isoquinolinones 15 and 17 and
Hexahydroindolizino[8,7-b]indolones 19 and 21. To a stirred
solution of pyrrolidine-2,5-dione 13c/14a/13d/14b (1 mmol) in
J
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
EtOH was added NaBH4 (3 mmol, 3 equiv) at 0 °C. After being
stirred at room temperature for 4 h (13c/14a) and 18 h (13d/14b),
the reaction was quenched with 5 M HCl. The reaction mixture was
concentrated under reduced pressure, and the residue was extracted
with MeOH. The organic layer was concentrated under reduced
pressure, and the crude residue obtained was purified by column
chromatography over silica gel 60−120 mesh (3% MeOH/CHCl3) to
afford 15, 17, 19, and 21.
(CO), 167.4 (CO), 165.4 (OCOCH3), 135.1, 116.4, 84.6, 82.8,
42.3, 38.2, 20.8; HRESIMS m/z 254.0669 [M + H]+ (calcd for
C11H12NO6254.0665).
(3aS,6aS)-5-Heptyl-2,4,6-trioxohexahydro-2H-furo[2,3-c]pyrrol-
3a-yl acetate (23b). Brown liquid; [α]2D5 −65 (c 0.1, CHCl3); IR
1
(KBr) νmax 2930, 1807, 1726 cm−1; H NMR (CDCl3, 400 MHz)
5.25 (s, 1H), 3.57 (m, 2H), 3.20 (d, J = 19.6 Hz, 1H), 3.03 (d, J =
19.6 Hz, 1H), 2.21 (s, 3H), 1.61 (m, 2H), 1.29 (m, 8H), 0.88 (t, J =
6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 171.1 (CO), 170.5
(CO), 170.2 (CO), 167.7 (OCOCH3), 79.6, 79.3, 39.9, 36.1,
31.6, 28.7, 27.0, 26.6, 22.5, 20.2, 14.1; HRESIMS m/z 312.1457 [M +
H]+ (calcd for C15H22NO6312.1447).
(1R,10bR)-1-[(R)-1,2-Dihydroxyethyl]-1-hydroxy-8,9-dimethoxy-
1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (15).8
Colorless crystals (MeOH); mp 99−102 °C; [α]2D5 +157 (c 0.1,
CH3OH); IR (KBr) νmax 3330, 2934, 1661 cm−1 1H NMR
;
(methanol-d4, 400 MHz) 7.42 (s, 1H), 6.71 (s, 1H), 5.06 (s, 1H),
4.28 (m, 1H), 3.95 (dd, J = 6.8, 4.8 Hz, 1H), 3.85 (m, 1H), 3.82 (s,
3H, OCH3), 3.80 (s, 3H, OCH3), 3.72 (m, 1H), 2.85 (m, 3H), 2.63
(d, J = 14.8 Hz, 1H), 2.34 (d, J = 17.2 Hz, 1H); 13C NMR (methanol-
d4, 100 MHz) 173.6 (CO), 149.3, 148.7, 130.1, 125.1, 113.7,
113.3.2, 80.1, 77.4, 66.5, 64.3, 56.5, 56.4, 44.1, 39.0, 29.9; HRESIMS
m/z 346.1256 [M + Na]+ (calcd for C16H21NO6Na346.1267)
(CCDC 1852021).
(3aS,6aS)-5-Nonyl-2,4,6-trioxohexahydro-2H-furo[2,3-c]pyrrol-
3a-yl acetate (23c). Brown liquid; [α]2D5 −113 (c 0.3, CHCl3); IR
1
(KBr) νmax 2926, 2858, 1807, 1727 cm−1; H NMR (CDCl3, 400
MHz) 5.25 (s, 1H), 3.56 (m, 2H), 3.18 (d, J = 19.6 Hz, 1H), 3.05 (d,
J = 19.6 Hz, 1H), 2.20 (s, 3H), 2.05 (s, 1H), 1.84 (m, 1H), 1.61 (m,
2H), 1.28 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100
MHz) 171.1(CO), 170.6(CO), 170.4 (CO), 167.8
(OCOCH3), 79.3, 63.7, 39.9, 36.1, 31.8, 29.4, 29,2, 29.0, 27.0, 26.6,
22.7, 20.2, 14.1; HRESIMS m/z 340.1766 [M + H]+ (calcd for
C17H26NO6340.1760).
(3aS,6aS)-5-Decyl-2,4,6-trioxohexahydro-2H-furo[2,3-c]pyrrol-
3a-yl acetate (23d). Brown liquid; [α]2D5 −113 (c 0.2, CHCl3); IR
(KBr) νmax 2927, 2855, 1811, 1724 cm−1; 1H NMR (CDCl3,400
MHz) 5.25 (s, 1H), 3.57 (m, 2H), 3.20 (d, J = 19.5 Hz, 1H), 3.03 (d,
J = 19.5 Hz, 1H), 2.20 (s, 3H), 1.61 (m, 2H), 1.28 (m, 14H), 0.87 (t,
J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 171.1 (CO), 170.5
(CO), 170.3 (CO), 167.8 (OCOCH3), 79.6, 79.3, 39.9, 36.1,
31.9, 29.5, 29.4, 29.3, 29.0, 27.1, 26.6, 22.7, 20.2, 14.1; HRESIMS m/z
354.1917 [M + H]+ (calcd for C18H28NO6354.1917).
(3aS,3a′S,6aS,6a′S)-Ethane-1,2-diylbis(2,4,6-trioxohexahydro-
3aH-furo[2,3-c]pyrrole-5,3a-diyl) diacetate (23e). To a stirred
solution of 12 (1.07 g, 5 mmol, 1 equiv) in HOAc (5 mL) was
added the diamine (2.5 mmol, 0.5 equiv), and the mixture was
refluxed for 5 h. The reaction mixture was cooled to room
temperature and poured into water. The resulting precipitate was
filtered off by suction and was recrystallized from CHCl3 to afford 23e
as brown crystals; mp 226−230 °C; [α]2D5 −128 (c 0.1, acetone); IR
(KBr) νmax 2999, 1802, 1730 cm−1; 1H NMR (acetone-d6, 400 MHz)
5.54 (s, 2H), 4.02 (d, J = 10.0 Hz, 2H), 3.75 (d, J = 10.0 Hz, 2H),
3.29 (d, J = 19.2 Hz, 2H), 3.21 (d, J = 19.2 Hz, 2H), 2.15 (s, 6H); 13C
NMR (acetone-d6, 100 MHz) 172.3 (CO), 171.9 (CO),
171.7(CO), 169.2 (OCOCH3), 80.8, 79.9, 37.6, 36.0, 20.2;
HRESIMS m/z 475.0613 [M + Na]+ (calcd for C18H16N2O12Na
475.0601).
General Procedure for the Synthesis of Furo[2,3-c]pyrroles
(24a−f) from Bicyclic Anhydride 12. To a stirred solution of 12
(1.0 g, 4.7 mmol, 1 equiv) in dry THF (5 mL) was added the
appropriate amine at 0 °C. After being stirred at room temperature for
5 h, the reaction mixture was concentrated under reduced pressure,
and the residue was refluxed with acetyl chloride (5 mL). After 10 h,
the reaction mixture was concentrated under reduced pressure, and to
a stirred solution of the residue in EtOH (10 mL) was added acetyl
chloride (2 mL) at 0 °C. After 12 h, the reaction mixture was
concentrated under reduced pressure. The crude residue was purified
by column chromatography on silica gel 60−120 mesh (20% EtOAc/
n-hexane) to afford 24a−f.
(1S,10bS)-1-[(R)-1,2-Dihydroxyethyl]-1-hydroxy-8,9-dimethoxy-
1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (17). Col-
orless crystals (MeOH); mp 129−131 °C; [α]2D5 +140 (c 0.1,
CH3OH); IR (KBr) νmax 3264, 2940, 1658 cm−1 1H NMR
;
(methanol-d4, 400 MHz) 6.90 (s, 1H), 6.79 (s, 1H), 5.23 (s, 1H),
4.33 (m, 1H), 4.04 (dd, J = 7.2, 2.7 Hz, 1H), 3.87 (s, 3H, OCH3),
3.84 (s, 3H, OCH3), 3.55 (dd, J = 11.0, 7.6 Hz, 1H), 3.03 (d, J = 16.4
Hz, 1H), 2.85 (m, 2H), 2.67 (m, 1H), 2.15 (d, J = 16.4 Hz, 1H); 13C
NMR (methanol-d4, 100 MHz) 172.7 (CO), 148.1, 147.8, 128.9,
123.1, 112.3, 110.2, 80.0, 71.9, 62.7, 62.1, 55.2, 55.0, 39.6, 37.2, 28.5;
HRESIMS m/z 346.1269 [M + Na]+ (calcd for C16H21NO6Na
346.1267).
(1R,11bR)-1-[(R)-1,2-Dihydroxyethyl]-1-hydroxy-5,6,11,11b-tet-
rahydro-1H-indolizino[8,7-b]indol-3(2H)-one (19). Colorless crys-
tals (MeOH); mp 200−202 °C; [α]2D5 +118 (c 0.1, CH3OH); IR
(KBr) νmax 3465, 2975, 1661 cm−1; 1H NMR (methanol-d4, 400
MHz) 7.44 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.10 (t, J =
7.2 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H) 5.14 (s, 1H), 4.50 (m, 1H), 3.91
(dd, J = 7.0, 4.1 Hz,1H), 3.77 (m, 2H), 3.11−3.04 (m, 1H), 2.93 (s,
1H), 2.87 (m, 2H), 2.41 (d, J = 17.0 Hz, 1H);); 13C NMR (methanol-
d4, 100 MHz) 173.4 (CO), 137.6, 130.1, 128.3, 122.6, 119.8, 118.8,
112.2, 110.6, 78.5, 78.2, 66.2, 63.8, 44.9, 39.0, 21.9; HRESIMS m/z
303.1337 [M + H]+ (calcd for C16H19N2O4303.1345) (CCDC
1852024).
(1S,11bS)-1-[(R)-1,2-Dihydroxyethyl]-1-hydroxy-5,6,11,11b-tetra-
hydro-1H-indolizino[8,7-b]indol-3(2H)-one (21). Colorless crystals
(MeOH); mp 195−197 °C; [α]2D5 +99 (c 0.1, CH3OH); IR (KBr)
νmax 3310, 2921, 1651 cm−1; 1H NMR (methanol-d4, 400 MHz) 7.44
(d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1 Hz), 7.10 (m, 1H), 7.02 (m,
1 H), 5.31 (s, 1H), 4.49 (m, 1H), 4.09 (m, 1H), 3.92 (m, 1H), 3.69
(m, 1H), 3.14 (d, J = 17.0 Hz, 1H), 3.01 (m, 1H), 2.86 (m, 2H), 2.29
(d, J = 17.0 Hz, 1H); 13C NMR (methanol-d4, 100 MHz) 173.8 (C
O), 138.4, 129.9, 128.2, 122.6, 119.9, 118.7, 112.2, 111.1, 79.2, 74.2,
64.0, 62.6, 42.2, 39.0, 22.0; HRESIMS m/z 303.1360 [M + H]+ (calcd
for C16H19N2O4303.1345) (CCDC 1852025).
General Procedure for the Synthesis of Furo[2,3-c]pyrroles
23a−e from Bicyclic Anhydride 12. To a stirred solution of 12
(1.0 g, 4.7 mmol) in dry THF (5 mL) was added the appropriate
amine at 0 °C. After being stirred at room temperature for 5 h, the
mixture was concentrated under reduced pressure, and the residue
was refluxed with acetyl chloride (5 mL). After 10 h, the mixture was
concentrated under reduced pressure. The resulting crude residue was
purified by column chromatography over silica gel 60−120 mesh
(10% EtOAc/n-hexane) to afford crude 23a−e.
(3aS,6aS)-3a-Hydroxy-5-phenethyldihydro-2H-furo[2,3-c]-
pyrrole-2,4,6(5H,6aH)-trione (24a). Colorless crystals (CHCl3); mp
128−130 °C; [α]2D5 −159 (c 0.1, CHCl3); IR (KBr) νmax 3427, 2941,
1816, 1797, 1776, 1726 cm−1; 1H NMR (CDCl3,400 MHz) 7.26 (m,
3H), 7.13 (m, 2H), 4.92 (s, 1H), 3.85 (m, 2H), 3.00 (m, 2H), 2.74
(d, J = 19.2 Hz, 1H), 2.33 (d, J = 19.2 Hz, 1H); 13C NMR (CDCl3,
100 MHz) 174.6 (CO), 171.4 (CO), 168.7 (CO), 136.5,
129.0, 128.9, 127.3, 81.0, 76.8, 40.0, 39.1, 32.5; HRESIMS m/z
276.0882 [M + H]+ (calcd for C14H14NO5276.0872).
(3aS,6aS)-5-Allyl-2,4,6-trioxohexahydro-2H-furo[2,3-c]pyrrol-3a-
yl acetate (23a). White solid; [α]2D5 +160 (c 0.1, acetone); IR (KBr)
νmax 3380, 2937, 1803, 1755, 1735, 1677 cm−1; 1H NMR (acetone-d6,
400 MHz) 5.81 (m, 1H), 5.19 (m, 1H), 5.14 (s, 1H), 5.05 (m, 1H),
3.85 (m, 2H), 3.56 (d, J = 18.0 Hz, 1H), 2.98 (d, J = 18.0 Hz, 1H),
2.13 (s, 3H); 13C NMR (acetone-d6, 100 MHz) 173.1 (CO), 170.3
(3aS,6aS)-3a-Hydroxy-5-(4-methoxybenzyl)dihydro-2H-furo[2,3-
c]pyrrole-2,4,6(5H,6aH)-trione (24b). Colorless crystals (CHCl3);
mp 115−117 °C; [α]D25 −82 (c 0.1, CHCl3); IR (KBr) νmax 3407,
K
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
1
2918, 2849, 1812, 1792, 1771, 1712 cm−1; H NMR (CDCl3,400
MHz) 7.28 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H),5.00 (s, 1H),
4.63 (s, 2H), 3.79 (s, 3H), 2.94 (s, 2H); 13C NMR (CDCl3, 100
MHz) 174.2, 171.2, 168.2, 159.8, 130.4, 126.2, 114.4, 81.2, 76.7, 55.3,
42.8, 39.1; HRESIMS m/z 314.0648 [M + Na]+ (calcd for
C14H13NO6Na 314.0641).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c00211.
■
sı
1H and 13C NMR spectra and HRMS for all new
compounds; single-crystal XRD data of the representa-
tive examples (PDF)
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
(3aS,6aS)-5-Hexadecyl-3a-hydroxydihydro-2H-furo[2,3-c]-
pyrrole-2,4,6(5H,6aH)-trione (24c). Colorless crystals (CHCl3); mp
96−98 °C; [α]2D5 −86 (c 0.2, CHCl3); IR (KBr) νmax 3425, 2917,
1
2846, 1814, 1790, 1773, 1715, 1704 cm−1; H NMR (CDCl3,400
MHz) 5.03 (s, 1H), 3.55 (m, 2H), 3.06 (t, J = 19.2 Hz, 2H), 1.59 (m,
2H), 1.25−1.28 (m, 27H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) 174.8 (CO), 171.5 (CO), 168.7 (CO),
81.3, 76.9, 39.7, 39.2, 31.9, 31.0, 29.7, 29.7, 29.6, 29.5, 29.4, 29.3,
29.0, 27.4, 26.7, 22.7, 14.1; HRESIMS m/z 418.2553 [M + Na]+
(calcd for C22H37NO5Na 418.2569).
(3aS,6aS)-5-(3,4-Dimethoxyphenethyl)-3a-hydroxydihydro-2H-
furo[2,3-c]pyrrole-2,4,6(5H,6aH)-trione (24d). Colorless crystals
(CHCl3); mp 135−137 °C; [α]2D5 −147 (c 0.1, CHCl3); IR (KBr)
νmax 3400, 1815, 1772, 1711 cm−1; 1H NMR (CDCl3, 400 MHz) 6.74
(d, J = 8.0 Hz, 1H), 6.67 (m, 1H), 6.60 (m, 1H), 4.90 (s, 1H), 3.86
(s, 3H), 3.84 (s, 3H), 3.77−3.94 (m, 2H), 2.94 (m, 2H), 2.76 (d, J =
19.2 Hz, 1H), 2.38 (d, J = 19.2 Hz, 1H); 13C NMR (CDCl3, 100
MHz) 174.5 (CO), 171.2 (CO), 168.7 (CO), 149.2, 148.3,
128.8, 121.2, 112.0, 111.4, 81.0, 76.8, 56.0, 55.9, 39.9, 39.1, 32.1;
HRESIMS m/z 358.0907 [M + Na]+ (calcd for C16H17NO7Na
358.0903).
AUTHOR INFORMATION
Corresponding Authors
■
Ibrahim Ibnusaud − Institute for Integrated Programmes and
Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India; Phone: +91 481 2732992;
Email: i.ibnusaud@gmail.com; Fax: +91 481 2732992
Prasad L. Polavarapu − Department of Chemistry, Vanderbilt
University, Nashville, Tennessee 37235, United States;
orcid.org/0000-0001-6458-0508;
(3aS,6aS)-3a-Hydroxy-5-(4-phenylbutyl)dihydro-2H-furo[2,3-c]-
pyrrole-2,4,6(5H,6aH)-trione (24e). Colorless crystals (CHCl3); mp
112−114 °C; [α]2D5 −107 (c 0.1, CHCl3); IR (KBr) νmax 3417, 2934,
1814, 1799, 1789, 1772, 1714 cm−1; 1H NMR (DMSO-d6, 400 MHz)
7.17−7.29 (m, 5H),5.15 (s, 1H), 3.27 (d, J = 18.8 Hz, 1H), 2.74 (d, J
= 18.8 Hz, 1H), 2.51 (m, 4H), 1.53 (m, 4H); 13C NMR (DMSO-d6,
100 MHz) 175.0 (CO), 174.0 (CO), 170.1 (CO), 142.3,
128.8, 128.7, 126.2, 82.3, 77.0, 39.3, 38.8, 35.0, 28.6, 26.9; HRESIMS
m/z 326.1011 [M + Na]+ (calcd for C16H17NO5Na 326.1004).
(3aS,6aS)-5-Benzyl-3a-hydroxydihydro-2H-furo[2,3-c]pyrrole-
2,4,6(3H,5H)-trione (24f).25 Colorless crystals (CHCl3); mp 110−
112 °C; [α]2D5 −133 (c 0.1, CHCl3); IR (KBr) νmax 3382, 1809, 1791,
Email: Prasad.L.Polavarapu@Vanderbilt.Ed
Authors
Deenamma Habel − Institute for Integrated Programmes and
Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India
Divya S. Nair − Institute for Integrated Programmes and
Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India
Zabeera Kallingathodi − Institute for Integrated Programmes
and Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India
Chithra Mohan − Institute for Integrated Programmes and
Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India
Sarath M. Pillai − Institute for Integrated Programmes and
Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India
Rani R. Nair − Institute for Integrated Programmes and
Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India
Grace Thomas − Institute for Integrated Programmes and
Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India
Simimole Haleema − Institute for Integrated Programmes and
Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India
Chithra Gopinath − Institute for Integrated Programmes and
Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India
Rinshad V. Abdul − Institute for Integrated Programmes and
Research in Basic Sciences, Mahatma Gandhi University,
Kottayam 686560, India
Matthew Fritz − Department of Chemistry, Vanderbilt
University, Nashville, Tennessee 37235, United States
Andrew R. Puente − Department of Chemistry, Vanderbilt
University, Nashville, Tennessee 37235, United States
1769, 1714 cm−1; H NMR (400 MHz, CDCl3) 7.26−7.36 (m, 5H)
1
5.04 (s, 1H), 4.71 (s, 2H), 3.56 (s, 1H), 2.97 (s, 2H); 13C NMR
(CDCl3, 100 MHz) 174.3 (CO), 171.3 (CO), 168.3 (CO),
134.1, 129.1, 128.9, 128.7, 81.3, 77.2, 43.3, 39.1; HRESIMS m/z
284.0545 [M + Na]+ (calcd for C13H11NO5Na 284.0535).
Synthesis of Pyrroloisoquinolinone 25 from Bicyclic
Anhydride 12. (1S,2R,10bR)-1-Hydroxy-2-(2-hydroxyethyl)-8,9-di-
methoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one
(25). To a stirred solution of pyrrolidinedione 24d (1.0 g, 2.98 mmol,
1 equiv) in absolute EtOH (10 mL) precooled to 0 °C was added
NaBH4 (1.1 g, 30 mmol, 10 equiv) with stirring. Subsequently over a
3 h period, a 2 M solution of HCl in ethanol (2 mL) was slowly added
via syringe. The resulting solution was acidified to pH 1−3 by the
addition of a 2 M solution of HCl in ethanol over a 15 min period
with stirring. After 20 h, the reaction was quenched with saturated
aqueous NaHCO3 solution, and excess EtOH was concentrated under
reduced pressure. The aqueous layer was extracted with CH2Cl2 (3 ×
40 mL), and the combined organic layers were dried over anhydrous
MgSO4 and concentrated under reduced pressure. The crude residue
was purified by column chromatography on silica gel 60−120 mesh
(20% n-hexane/EtOAc) to afford 25 as colorless crystals (CHCl3):
mp 96−98 °C; [α]2D5 −72 (c 0.1, (CHCl3); IR (KBr) νmax 3500, 3299,
2925, 1688, 1670 cm−1; H NMR (methanol-d4, 400 MHz) 7.09 (s,
1
1H), 6.75 (s, 1H), 4.64 (s, 1H), 4.59 (d, J = 6.0 Hz, 1H), 4.32 (m,
1H), 3.85 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.78 (t, J = 6.6 Hz,
2H), 3.06 (m, 1H), 2.81 (m, 2H), 2.65 (m, 1H), 2.14 (m, 1H), 1.87
(m, 1H); 13C NMR (acetone-d6, 100 MHz) 174.4 (CO),149.4,
149.3, 128.7, 126.8, 113.3, 109.8, 74.7, 63.2, 61.6, 56.2, 56.1, 47.4,
37.4, 28.8, 28.5; HRESIMS m/z 308.1500 [M + H]+ (calcd for
C16H22NO5 308.1498) (CCDC 1852026).
L
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
pubs.acs.org/jnp
Article
(21) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville,
Jordan L. Johnson − Department of Chemistry, Vanderbilt
̀
A.-C.; Coste, H.; Linget, J. M.; Kirilovsky, J.; Hyafil, F.; Labaudiniere,
R. J. Med. Chem. 2003, 46, 4533−4542.
University, Nashville, Tennessee 37235, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jnatprod.0c00211
(22) Davis, R. A.; Duffy, S.; Avery, V. M.; Camp, D.; Hooper, J. N.
A.; Quinn, R. J. Tetrahedron Lett. 2010, 51, 583−585.
(23) Rinehart, K. L.; Kobayashi, J.; Harbour, G. C.; Hughes, R. G.;
Mizsak, S. A.; Scahill, T. A. J. Am. Chem. Soc. 1984, 106, 1524−1526.
(24) Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.; Hayashi,
M.; Komiyama, K.; Omura, S.; Smith, A. B. J. Am. Chem. Soc. 2000,
122, 2122−2123.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(25) Ibnusaud, I.; Thomas, G. Tetrahedron Lett. 2003, 44, 1247−
1249.
The authors acknowledge DST (Government of India) for
financial support via DST Project No. SR/S1/OC-98/2012
dated 14-08-2013. Acknowledgements are due to Prof. Keith
Smith (Cardiff University), Drs. Irishi N. N. Namboothiri (IIT
Bombay), N. G. Ramesh (IIT Delhi), Dr. A. Mohan (IIT
Chennai), and Thomas J. Colacot (Director, Global Technol-
ogy Innovation, Millipore Sigma) for helpful discussions
during manuscript preparation. The authors also acknowledge
the Department of Chemistry, IIT Delhi, for recording the
HRMS data, Department of Physics, M. G. University, and
Department of Chemistry, IIT Madras, for single-crystal XRDs.
P.L.P. acknowledges financial support from the National
Science Foundation (CHE-0804301; CHE-1464874), and
M.F. acknowledges support from the NSF-REU program
(CHE 0850976). This work was conducted in part using the
resources of the Advanced Computing Center for Research
and Education (ACCRE) at Vanderbilt University, Nashville,
TN.
(26) Nanjappa, C.; Hanumanthappa, S. K. T.; Nagendrappa, G.;
Ganapathy, P. S. S.; Shruthi, S. D.; More, S. S.; Jose, G.; Sowmya, H.
B. V; Kulkarni, R. S. Synth. Commun. 2015, 45, 2529−2545.
(27) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M.
Tetrahedron Lett. 1998, 39, 4905−4908.
(28) Allin, S. M.; Gaskell, S. N.; Towler, J. M. R.; Page, P. C. B.;
Saha, B.; McKenzie, M. J.; Martin, W. P. J. Org. Chem. 2007, 72,
8972−8975.
(29) Johnson, L. J.; Nair, S. D.; Pillai, M. S.; Johnson, D.;
Kallingathodi, Z.; Ibnusaud, I.; Polavarapu, P. L. ACS Omega 2019, 4,
6154−6164.
(30) Molina, A.; Pascual-Escudero, A.; Adrio, J.; Carretero, J. C. J.
Org. Chem. 2017, 82, 11238−11246.
(31) Heaney, H.; Taha, M. O. Tetrahedron Lett. 1998, 39, 3341−
3344.
(32) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431−1628.
(33) Wijnberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N.
Tetrahedron 1978, 34, 179−187.
(34) Nair, D. S.; Ibnusaud, I. Tetrahedron Lett. 2014, 55, 5822−
5824.
(35) Singh, K.; Deb, P. K.; Venugopalan, P. Tetrahedron 2001, 57,
7939−7949.
(36) Pulka, K.; Kulis, P.; Tymecka, D.; Frankiewicz, L.; Wilczek, M.;
Kozminski, W.; Misicka, A. Tetrahedron 2008, 64, 1506−1514.
(37) Polavarapu, P. L. Chiroptical Spectroscopy: Fundamentals and
Applications; CRC Press: Boca Raton, FL, 2016.
(38) Berova, N.; Polavarapu, P. L.; Nakanishi, K.; Woody, R. W.
Comprehensive Chiroptical Spectroscopy: Instrumentation, Methodologies,
and Theoretical Simulations; John Wiley & Sons: New York, USA,
2012.
(39) Conflex: High-Performance Conformational Analysis. www.
conflex.net.
(40) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson,
G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A.; Bloino, J.;
Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J.
V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.;
Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson,
T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.;
Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V.
N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell,
A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.;
Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 09,
Revision A.02; Gaussian, Inc.: Wallingford, CT, 2016.
REFERENCES
■
(1) Finefield, J. M.; Sherman, D. H.; Kreitman, M.; Williams, R. M.
Angew. Chem., Int. Ed. 2012, 51, 4802−4836.
(2) Stinson, S. C. Chem. Eng. News 1998, 76, 83−104.
(3) Mori, K. Bioorg. Med. Chem. 2007, 15, 7505−7523.
(4) Lewis, Y. S.; Neelakantan, S. Phytochemistry 1965, 4, 619−625.
(5) Ibnusaud, I.; Thomas, P. T.; Rani, R. N.; Sasi, P. V.; Beena, T.;
Hisham, A. Tetrahedron 2002, 58, 4887−4892.
(6) Heymsfield, S. B.; Allison, D. B.; Vasselli, J. R.; Pietrobelli, A.;
Greenfield, D.; Nunez, C. JAMA 1998, 280, 1596.
(7) Jena, B. S.; Jayaprakasha, G. K.; Singh, R. P.; Sakariah, K. K. J.
Agric. Food Chem. 2002, 50, 10−22.
(8) Prasanth, C. P.; Joseph, E.; Abhijith, A.; Nair, D. S.; Ibnusaud, I.;
Raskatov, J.; Singaram, B. J. Org. Chem. 2018, 83, 1431−1440.
(9) Coppola, G. M.; Schuster, H. F. α-Hydroxy Acids in
Enantioselective Syntheses; Wiley: Weinheim, VCH, 1997.
(10) Gawronski, J.; Gawronska, K. Tartaric and Malic Acids in
Synthesis: A Source Book of Building Blocks, Ligands, Auxiliaries, and
Resolving Agents; Wiley: New York, USA, 1999.
(11) Snyder, S. A. Angew. Chem., Int. Ed. 2014, 53, 3547−3547.
(12) Lee, Y. S.; Kang, D. W.; Lee, S. J.; Park, H. J. Org. Chem. 1995,
60, 7149−7152.
(13) Kawai, N.; Matsuda, M.; Uenishi, J. Tetrahedron 2011, 67,
8648−8653.
(14) Elwan, N. M.; Abdelhadi, H. A.; Abdallah, T. A.; Hassaneen, H.
M. Tetrahedron 1996, 52, 3451−3456.
(15) Kuo, R.; Wu, C.; Chang, F.; Yeh, J.; Chen, I.; Wu, Y. Bioorg.
Med. Chem. Lett. 2003, 13, 821−823.
(16) Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.;
Lebrun, S. Tetrahedron 2004, 60, 6169−6176.
(17) Xiang, L.; Xing, D.; Wang, W.; Wang, R.; Ding, Y.; Du, L.
Phytochemistry 2005, 66, 2595−2601.
́
́
(18) Moreno, L.; Parraga, J.; Galan, A.; Cabedo, N.; Primo, J.;
Cortes, D. Bioorg. Med. Chem. 2012, 20, 6589−6597.
(19) Chakraborty, I.; Jana, S. Synthesis 2013, 45, 3325−3331.
(20) Spindola, H. M.; Vendramini-Costa, D. B.; Rodrigues, M. T.;
Foglio, M. A.; Pilli, R. A.; Carvalho, J. E. Pharmacol., Biochem. Behav.
2012, 102, 133−138.
M
https://dx.doi.org/10.1021/acs.jnatprod.0c00211
J. Nat. Prod. XXXX, XXX, XXX−XXX