Embed Size (px)
Citation preview
Syntheses of Chiral Pyrrolidinediones and related Molecules using (+) and (-) 2-Hydroxycitric acid Lactones
111.1 Introduction
It has been revealed (chapter Il) that chiral pyrrolidines are one of the important
classes of the five membered aza-heterocycles which are very often encountered in
living organisms. Occasionally these compounds have been extracted from plants,
animals and microorganisms, mostly in very minute quantities. 120-1 26 Owing to the
insignificant availability of these nali~rally occurring entities studies on their biological
activity and mechanism of action have been limited. Even then the therapeutic interest
evoked by these molecules is enormous. The ensuing discussion illustrates few cases.
Several molecules having 2-pyrrolidinone moiety are potent neuroactive compounds
due to their interaction with pyrogl~1:amate receptors. 127-129 2,5-Dialkylated pyrrolidines
extracted from venomous ants ancl frog^'^^^'^' (e.g. monomonnes) have shown some
insecticide, hemolytic and anticholinergic activities. 132-133
Well-known ICmethylcarbap~~nem antibiotics having a (3S,5S) cis disubstituted
pyrrolidine ring as the C-2 side chain, such as merpenem, S-4661, and 80-2727. have a
broad antibacterial spectrum cov~i!ring gram-positive and gram-negative bacteria
including Pseudomonas aer~ginoa.' . '~. '~~
Polyhydroxylated pyrrolidine!j have been shown to be potent glycosidase
inhibitors, which are known to posst!ss a variety of beneficial therapeutic effects against
tumor metastasis, metabolic disorder, and viral infection^.'^^^'^^ An optically active
Polyhydroxylated pyrrolidine (206) exhibiting anti HIV property has been reported recently.'44
206 Figure Ill .I
Nonproteinogenic proline derivatives like 207 and 208 have been detected in a
novel cyclic peptide scytonemin A, a metabolite of the cultured cynophyte Scytonema sp.,
which possesses potent calcium antagonistic prope~ties.'~~
_CH3 HC! -CH3
Q C W H I QCOOH I
H H
207 208
Figure 111.2
Yet another example is AG 7352(+) (210) which shows anti-tumor activities equal or
superior to those of cisplatin and etoposide against human breast, ovarian and colon cancers
implanted in The precursor tc~ this new type of anti-tumor agent is the (+)-enantiomer
of 3-methoxy-4-methylaminopyrrolidir e (209).
Me I
M e
HAQ A N" s M e O ~ ~ N H N M~o'.' I
H
21 0 209
Figure 111.3
Few specific examples of 3,L!-disubstituted pyrrolidine based natural products
are shown in Figure 111.4.'~'
H O H 4 ) I'h
Me,
?- Isoanantine kocyanometrine Kainic acid
lsodomoic acid A lsohematinic acid Figure 111.4
lsoanantine or 4-(l-Meth~llC1midazd-5~~31Jnen~methIene2-pynolidimne is the
alkaloid present in the rod bark of Cyncfvet. lujae (leguminosae) and lsocynornebine is present
in the bunk balk of the same plant lsxiornoic a d A or 2-Carboxy-4(5carboxy-l-methyI-I,
4-hexadien9)-3pwdimtic acid is isolated from the red alga Chondria annata. It exhibits
insecticidal activity. lsohematinic acid or 4-methylene-2-5-dioxw3-pyrrolidinepropanoic acid is
an alkaloid from Actinoplanes philippi~tensis. a-Kainic acid is the prototype of a group of
neuroexcitatory amino acids which activate a particular subtype of glutamic acid
receptor^.'^^ These amino acids are important substrates in physiological and
pharmacological studies of the centrat nervous system.14' One of the major obstacles to
overcome the synthesis of a-kair~ic acid is the achievement of the 3.4-cis-
stereochemistry (Scheme l11.1)'~~
R" R', -.
QCOOH I s 04 no- N I HO H
H H HOOC COOH
Scheme 111.1
Consequently facile and effective methods for the enantioselective synthesis of
diversely fundionalized pyrrolidines are worth while synthetic targets. Hydroxy acids like Malic
acid, Tartaric acid etc have been extensively employed for the syntheses of a variety of
pyrrolidine based natural p r~duc ts . '~ " '~~ It has also been seen that (chapter II) all these
synthetic strategies commence with the synthesis of pyrrolidinediones. Majority of the
molecules obtained from these acid:; are pyrrolidines with 2,5-dis~bstitution.~~ In general
preparation of 3 and 3,4-disubstituted chiral pyrrolidines from commonly occurring hydroxy
acids are rare or virtually absent. Stnlctural feature of Garcinia acid [(2S,3S)-tetrahydro-3-
hydroxy-5-0x0-23-furandicarbxylic acid] and Hibiscus acid [(2S,3R)-tetrahydro-3-hydroxy-5-
oxo.2,3-furandicarboxyrc acid], whict- are widely distributed in nature, are ideally suited
for the synthesis of 3 and 3.4-disubsl:ituted pyrrolidines and is expected to be a versatile
entry towards a wide number of nat1.1ral product^.^.' With this background synthesis of
chiral pyrrolidinediones from Garcinia acid and Hibiscus acid have been executed.
111.2 Results and Discussions
2-Hydoxycitric acid contain:, two centres of asymmetry and hence four
stereoisomeric forms are possible. 01.1t of these (2S,3S) and (2S,3R)-hydroxycitric acids
are widely distributed in nature. Due to the presence of a-hydroxyl group, these acids
spontaneously lactonises during isolation and are obtained as lactones namely Garcinia
acid (1) and Hibiscus acid (11).
Figure 111. 5
COOH
Fresh samples of dried rinds of the fruits of Garcinia cambogia and calyxes or leaves
of Hibiscus sabdariffa or leaves of Hibircus furcatus were used for the isolation of Garcinia
and Hibiscus acids following the procedLre developed by lbnusaud and c o - w o r k e r ~ . ~ ~ . ~ ~
111.2.i. Isolation of (2S,3S)-Tetrat1ydro-3-hydmxy-5o~o-2,3furandicarboxyl'i acid (I)
1. The dried fresh rinds of the fruits of Garcinia cambogia was cut into small pieces
and soaked in hot water. The \~ater extract was collected after 10-20 hours. The
extraction was repeated. The combined extract was evaporated to syrup (A).
2. To the syrup (A) sufficient quantity of methanol was added to remove pectin
completely. The filtrate was concentrated to syrup (B).
3. After making syrup (B) alkaline by adding sufficient quantity of alkali at elevated
temperatures, methanol was added to the solution. Separated thick syrup (lower
layer) was washed several tinies with various proportions of aqueous methanol
to get a paste of alkali salt (C).
4. The alkali salt (C) on neutralization with mineral acid followed by evaporation
gave the concentrate (D).
5. The concentrate (D) was trituraled with sufficient quantity of acetone to precipitate the
insolubles. The filtrate on concentration yielded crude 1.
6. The crude acid (1) was purified by recrystallisation and chemical and optical
purity was assured by comparing the I.R, NMR. Mass spectra and [a], values
with that of the reported value:j.
111.2.ii Isolation of (2S,3~Tetrahyd&~hydmxy-50xo-2,3furandicaI1Joxylic acid (1 1)
The fresh calyxes or leaves of (Hibiscus sabdariffa or leaves of Hibiscus furcatus were
extracted with water and was concentrated to a syrup. To this methanol was added to
precipitate inorganic materials. The orljanic layer was concentrated and aqueous alkali was
added to yield the salt of 11. It was then washed several times with alcohol and mineral acid
to regenerate the acid. Affer concentra.:ion the residue was triturated with acetone or methanol
to get crude 11.The final purification of crude 11 was done by repeated extraction or
crystallization from ether. The chemi'::al as well as optical purity of 11 was confirmed by
comparing the I.R, NMR and Mass sp(?ctra with that of the reported values.25
111.2.iii. Syntheses of pyrr~lidinedic~nes (213 and 214) from 1
Pyrrolidinediones are often prepared by simple condensation of Tartaric acid or
Malic acid with appropriate alkyl amine~.~'." Following the same strategy pyrrolidinediones
were synthesized from Garcinia acid. Garcinia acid was refluxed with acetyl chloride for
two hours and concentrated under v;ncuum to get a white solid. The solid obtained was
dissolved in dry THF and benzyl arr~ine was added and stirred at room temperature for
4 hours followed by concentration under vacuum. To this added excess acetyl chloride and
refluxed for 18 hours to complete cyclization. The reaction mixture upon concentration
followed by recrystallisation from ethanol yielded (3aS,GaS)-3a-(acety1oxy)dihydrc-5
(phenylmethyl)-GK-furo[2,5c]pyrrd~-2.4,6(3H,4H)-trione (213a). The IR spectrum
clearly indicates the characteristic absorption bands at v 1790 (S lactone carbonyl) and
1740cm.' (cyclic ~mide carbonyl). The 'H NMR spectrum shows multiplet at a 7.45-7.25
(Ar-H), singlet at 5.31 (5-I-J of lactone), quadret at 4.8 to 4.65 (C6H5-CB2-), and double
\ doublet at 3.9 and 3.2 (diastereotopc /C& ). The I3C shows signals at - a 170.6. 170.4,
\ \
170.l(imide and lactone carbonyls), ,167.3 (-0-sOCH3), 80( CH- ), 79.2 (tertiary -,c- ), /-
43 ( 'N-GIJ, )and at - 6 36 (-CHr, lactone ring), (Figure 111.6).
Scheme 111. 2
The same experiment wijs repeated using methoxybenzyl amine leading to the
formation of (3aS,GaS)-3a-(acelyloxy)dihydr0-~4-methoxyphenylmethyl) 6Hfuro[2,3-c]
pyrrole-2,4,6(3H,4H)-trtone (213b) which was confirmed on the basis of IR, 'HNMR and. 13 CNMR and mass spectra (Figure 111.7).
Following the same procedure methyl-2-(3aS,EaS)-3a-(acetyloxy)-2,4,6-
trioxohexahydro-5H-furo[(2,3-c)pyrol-5-~yl]acetate (213c) was also prepared from Garcinia
acid and Glycinemethylester. Expected I.R. 'HNMR and, ' 3 C N ~ R spectra were obtained.
(Figure 111.8).
Fig. 111.6~ , ,i- ,i -7 - *-.-: . - & - A -7-
MP 3
1 1 1
9, I 2U
I*-&" Fig. 111.6d
-- Fig. 111.7~
Fig. 111.7d
i Fig. 111.8a
-- A ,I 3 - & ! 1 -- * - FF
I I,, I JI 1 1 7 - - 7 1 -
208 1110 160 1.0 L10 100 80 60 a0 lo O W
- - -
Fig. 111.8b
Fig. 111.8~
Isocitrirnide lactone (214) was prepared by retluxing Garcinia acid (1) with 2, (3-4
dimethoxy phenyl) ethylarnine in toluej-te using a dean-stark water separator for four hours.
Usual work up followed by column chromatography (silica gel, hexane-chloroform, 1:l)
furnished crystals of (3aS,6aS)-5[2-1;3,4-dimethoxyphenyl) ethyl]-3a-hydroxy dihydro-2H-
furo[2,3-c]pyrrole-2,4,6[3H,5H]-trione (214) in the optically pure form. The IR spectrum of
214 clearly indicates the charactetistic absorption bands at v3400 (OH, broad), 1790
(2 lactone carbonyl) and 1740 crn' (cyclic irnide carbonyl). The anticipated lHNMR
' 3 ~ ~ ~ ~ and mass spectra were also obtained (Figure 111.9).
214
Scheme 111. 3
It is interesting to note that cyclic imide (214) prepared from 2-(3-4 dirnethoxy
phenyl) ethyl amine is an analogue! of less known mescaline isocitrimide lactone (215), a
psychotropic bioprinciple obtained from Mescal, a cactus which is also classified as an
endangered species. Conspicuously to the best our knowledge except in a review on
Peyote constituents, by Kapadia, G.J. and Fayes, M."' no mention about the
stereostructural features of mescaline isocitrimide lactone is available to date.
Fig. 111.9b
Fig. 111.9~
Fig. 111.9d
111.2.v Mescaline isocitrimide ~ac tone '~ '
Mescaline isocitrimide lactone (Figure 111.6) represents one of the earliest known
hallucinogenic drugs. Closely related chemically to epinephrine, it causes heart palpitations,
diaphoresis, papillary dilation and anxiety. It is identified in the nonbasic constituents of the
colorless oil in the flowering heads of the cactus Lophophora williamsii also called peyote.
This cactus grows wild on the Mexicar1 plateau and in the southwestern United States in dry
places, on cliffs, or on rocky slopes. These regions are very hot and vegetation is subtropical.
Peyote is encountered sometimes singly but more often in clusters. It is barely visible, except
when in flower, since it is mostly covered with earth and looks like a pebble. Peyote, like most
cacti can be grown practically anywhere under glass or in a room. The plant seems to be
capable of standing adverse conditions of drought, heat, and cold. The drug taken in
capsule or dissolved in a drink produces visual hallucinations, as color patterns and special
distoltions but it does not ordinarily induce disorientations. Several Native American nations of
North America used this in religious o-remonies to produce euphoria and a feeling of ecstasy.
Meealine isodt~inide lactone
21 5
Figure 111. 10
111.2.vi Reactions of Hibiscus acid with alkyl amines
As described earlier Hibisc1.1s acid ( I t ) , one of the diastereomer of Garcinia acid (I),
have S and R configuration instead of S and S at C2 and Cg asymmetric centers
respectively. This difference in the configuration makes the orientation of the carboxyl group in
11 different from that of 1 and was revealed from the observation that 11 failed to give any
cyclic imide, which is trans fused, when treated with alkyl amines. (Scheme 111.4)
HO 0
Scheme 111. 4
As the reaction between 11 and alkyl amines failed to give any product, the same
reaction was repeated with Hibiscus acid dimethylester (216) and alkyl amines. Dimethyl
esters (216 and 217) of 1 and 11 have been prepared by diazomethane method following
the procedures developed in this ~abc~ratory.~'
The reaction between 217 and benzyl arnine is expected to give various structures
including pyrrolidinediones (Fig III.ll).
223
Figure Ill. 11
However on refluxing dimethy1(2S,3R)-tetrahydro-3hydroxy-5-oxo-2,3-furandicar-
boxylate (217) and benzyl amine in toluene exclusive formation of a single white solid was
observed.
The possibility of formation of 221 and 223 can be totally ruled out, as trans fusion of
five membered rings is not feasible.
The 1.R spectrum of the produc:t obtained shows characteristic peaks at v 3450 (OH),
1705 (-CONH- or cyclic five membered ring or cyclic six membered ring), 1780m~' (cyclic five
membered ring or 5 lactone carbonyl) 'H NMR shows characteristic peaks at 6 7.4 to 7.2, (Ar-
H), 4.7 (C&I5-C&), 4.4 ( 'CH- ), 3.65i(-OCH3) 3.1 and 2.7(dd, 'C H , lactone ring). The ' 3 ~ - / - 1 -*
\
shows peaks at - 6176.87. 173, and 171 (all due to -m), 77.3 ( 'CH- ), 42 ( ,CH2 , lactone /-
ring) and 53 (-OCH3). With this available data tentatively the formation of all the
products can be justified. To further establish the structure a much more rigorous spectral
analysis is inevitable. This is a typical case for using HMBC as a tool for the
determination of actual structure. Initially by mistake it was concluded as monoamide
(219) based on the following ~ b ~ e ~ a t i ~ n ~ . ' ~ ~
The position of the amide group in (219) can be either at C, or C3 carbon of the
lactone ring. By comparing 13C values of 219 with that of Hibiscus acid (11) and its
dimethyl ester (217) the position of the -CONHR has been assigned at position C2
(Fig.lll.12).
Figure 111. 12
HMBC and 13C spectra of Hibir;cus (11) acid lead to the shifl assignment of C-3 and
C-2 acid carbonyls as 6 172.9 and 167.8 and C-5 lactone carbonyl as 6173.2. Analogy to this
the values assigned for carbonyl carbons of 219 are 6170.8, 166.1 and 172.7 respectively.
Hence based on '3C spectrum, values assigned for carbonyl carbons of 219 are 6 171.3
(C-3, COOCH3). 176.87 (C-2, -CONHF:), and 173.4 (C-5 lactone carbonyl).
Moreover selective reduction of the geminal ester group of the product was carried out
using boranedimethyl sulphide complex in presence of catalflc sodium tetrahydroborate, an
effid~ent and selectiie reducing agent for a-hydmxy esters, which is applicable to the structures
218 and 222 also.153
Scheme 111. 5
An analysis by HMBC (Fig II 14a) clearly indicates the structure to be 218
and the 'H- '~C long-range correlations observed in the HMBC spectrum is
shown in Fig Ill. 14b
Fig Ill. 14b
\
The carbonyl carbon peak at -6 171.302 shows correlations with 6 4.4 ( /CK- proton)
and 6 3.65 (-OCHI,). The carbonyl carbon at 6 173.466 shows correlations with 6 4.4
(&Hs-C&-) and 2.7-3.1 (diastereotopic -C&-). The carbonyl carbon peak at - 6 176.87 \
shows correlations with peaks at 6 4.7 (C6H5-CH2-), 4.4 ( 1 C - H - proton) and diastereotopic -
C&. 20 HMBC spectrum reveals that out of the three carbonyl peaks only one carbonyl
peak (at - 6 171.302) shows correlation with protons of -OC& and >Y- proton (8 4.4).
On the basis of this the anchored ester group has been identified and which is possible
only if the structure is 218. The second and third carbonyl carbon (at - F 173.466 and 6
176.87) show correlation with peaks at 6 4.7 (C6HSCli2) and 2.7-3.1 (diastereotopic -C&-)
and again the third carbonyl carbor~ (at - 6 176.87) shows correlation with peak at 6 4.4
\ ( ,CK- proton). These correlations are possible only if the structure is 218
The reaction was generalized by preparing methyl (2s)-, [2(3R)- 1[(4-methoxybenzyl -3-
hydroxy-2-5-dioxotetrahydro-lH-p{rrol-3-yl]-2-hydroxyethanoate (218b) and methyl (2s).
[2(3R)- 1[2-(3,4-dimethqphenyl) ~thylcarbonyl]-3-hydroxy-2-5-dioxotetrahydro-lH-pyrrol-
3-yl]-2-hydroxyethanoate (218~) using methoxy benzyl amine and 2-(3,4-dimethoxy
phenyl)ethyl amine respectively. Al l the products were characterized by I.R, 'H NMR, 'Ic
and Mass (Fig 111 15816).
Toluene, 'OH reflux
D
Scheme 111. 6
- Fig. 111.15d
,. . -~ ~- p-~
.. 218c
. -L - ~ - - . . ..
-3, - - Fig. 111.16a
--- l n l . I C ,
Fig. 111.16b
Fig. 111.16~
Fig. 111.16d
When dimethyl ester of Garcinia acid (216) was refluxed with benzyl amine in toluene
for 5 hours, it lead to the isolation of Methyl (2.5)-, [2(3S)-1 benzyl-3-hydroxy-2-5-
dioxotetrahydro-lH-pyrrol-3-yl]-2-hydroxyethanoate(225), (Scheme 111.7). 216. the other
diastereomer is a case similar to earlie. 0bse~ation (Figure 111. 17).
Fig 111. 17
The 1.R spectrum shows characteristic: peaks at v 3450 (OH), 1705 (-CONH- or cyclic five
membered ring or cyclic six membered ring), 1775cm.' (cyclic five membered ring or a lactone
carbonyl) 'H NMR shows characteristc peaks at 6 7.4 to 7.2, (Ar-H), 4.7 (C,H,-Cti2-), 4.3
( \cH- ), 3.85 (-OC&) 3.2 and 2.75(dd, l C ~ , lactone ring). The 13c shows peaks at / - / -2
- 6176.87, 173, and 171 (all due to -GO), 77.3 ( 'CH- ), 42 ( 1 ~ ~ 2 , lactone ring) and /-
53 (-OGH3).
1 / Ein III I * =
- ~ Fig. 111.18~ --
,- -
Fig. 111.18d
The possibility of formation of 228 :an be ruled out as the peak corresponding to an - OCH3 is present in 'H and% NbIR. The reaction is identical with that of 216, a
diastereomer of 217 and concludecl the formation of the product (225), a diastereomer
of 218. Though the reactivity of diastereorners can vary no difference was observed in
the course of the reaction as it is proceeding in the same manner which is indicated in
the spectral values. This conclusion has been further established with the help of HMBC
(Fig Ill. 19a) and The 'H-'~c long range correlations observed are shown in Fig Ill. 19b.
Figure Ill. 19a
Fig Ill. 19b
\ The carbonyl carbon peak at -6 171.76 shows correlations with 6 4.3 ( CH- proton)
/ -
and 6 3.85 (-OCH3.). The carbonyl carbon at 6 173.54 shows correlations with 64.3 (CsH,-
Cb-) and 2.75-3.2 (diastereotopic A:&-). The carbonyl carbon peak at - 6 176.9 shows
\ correlations with peaks at 6 4.7 (CbH~-Cli2-), 4.3 ( /CE- proton) and diastereotopic -CHI-.
2D HMBC spectrum reveals that out of the three carbonyl peaks only one carbonyl peak
\ (at - 6 171.76) shows correlation with protons of -OC& and /CH- proton (6 4.3). On
the basis of this here also the anch~xed ester group has been identified and which is
possible only if the structure is 220. The second and third carbonyl carbon (at - 6 173.54
and 6 176.83) shows correlation with peaks at 6 4.7 (C,Hs-C&) and 2.75-3.2
(diastereotopic -C&-) and again the third carbonyl carbon (at - 6 176.83) shows
\ correlation with peak at 6 4.3 ( /CE- proton). These correlations are possible only if the
structure is 220a.
Scheme 111.7
The reaction was generalized by prep;%ing methyl (2s)-, [2(3S)- 1[(4-methoxybenzyl -3-
hydroxy-2-5dioxotetrahydro-lH-pyrrol-3-y~-2-hydroxyethanoate (22513) and methyl (2s)-,
[2(3S)-1[2-(3,4dimethoxyphenyl) ethylcarbonyl]-3-hydroxy-2-5-dioxotetrahydro-1H-pyrrol-
3-yl]-2-hydroxyethanoate (225~) using methoxy benzyl amine and 2-(3,4dimethoxy
phenyl)ethyl amine respectively. All the products were characterized by I.R. 'H NMR, 13C
and Mass (Fig 111 20 & 21).
Fig. 111 20 a +
1
Fig. 111 20 d
--
225 c
.. ,.-, L
wmM"-,~-,, Fig. 111 21 a -. -
- ,. .. ,, .~ . . . . = . . . . ~ . - Fig. Ill 21 b
, .-.- 100 180 laa 140 i x a loo a. t o ,. l o Fig. Ill 21 c
. Fig. Ill 21 d
111.2.vii Reactions of trimethyl esters of Garcinia and Hibiscus acids with alkyl amines
Optically active molecules with two chiral centres, especially 1,2-diols and
related substrates play significant rols as chiral synthons in the synthesis of natural and
biologically active molecule^.'^^ 1,2-diol based ligands have proven their
enantioselective efficiency in several asymmetric catalysis.'55 The extensive use of these
classes of compounds is well established as a large number of 1,2-diol based chiral
molecules are even commercially av;ailab~e.'~~ Pharmacological activity of certain naturally
occurring chiral molecules is attrib~~ted to the presence of vicinal hydroxyl groups3
(Figure 111.22).
Figure 111. 22
The triesters of (-) and (+):?- hydroxycitric acids (231 and 232) also have vicinal
diol moiety.
Me02C C Q M e 2C/.".*~
Me0 HO OH
231 Figure 111. 23
MeOzC_ CQMe MeOzC*H
HO OH
Added to this, these molec~~les possess carbonyls at 1, 4 and 1, 5 position and which
is ideally suited for the formation of pyrrolidinediones (233 and 225) and pipyridinedione
skeleton (234) respectively with all<yl amines. In an earlier observation it was concluded that
monoamide was formed from the c~esters of Garcinia and Hibiscus acids based on the
spectral data excluding HMBC. With !his background the reaction of trimethyl ester of (-) 2-
hydroxycitric acid (231) with benzyl amine was planned anticipating a different behavior
from the triester.
There are three possibilities by whim this reaction could be visualized
1. Condensation of carbmethoxy !groups at C2 and C3 of 231 with benzyl amine leading to
the formation of 233 a 3,4-disu~stituted pyrrolidinedione. (Scheme 111.8.a).
2. Condensation of carbmethoxy group attached to C3 and carbmethoxy group at
C, with benzyl amine to form 225a (obtained from diester) which is a 3-
substituted pyrrolidinedione. (Sicheme 111.8.b).
3. Condensation of ester groups at C2 and Cq of 231 leading to the formation of
pipyridinedione 234 (Scheme 111.8.~).
23 1 234
Scheme 111.8.~
Intrigued by the possibility of f'ormation of 233, 225a and 234 reaction of 231 with
benzyl amine was canied out. Surprisingly it ended up in the isolation of a single product
which was purified by recrystallisati'z~n (chloroform-hexane, 1:l) and was completely
characterized (Figure 111.24).
The 'HNMR shows characteri!;tic peaks at 6 7.3 (arom H), 4.65 (2H, -N-CH2-),
\ 4.3 (IH, /C&- ), 3.8 (3H, -OC!js), 3.2 ((IH, dd, -C&) and 2.8 (lH,dd -C&). ' 3 ~ NMR shows
peaks at -6 176.9, 172.7, 171.7 (-GO peaks), 135.1, 128.7, 128.5.128 (arom), 'CH- at -6 r
77.5, -sH, of the lactone ring at -6 53.6 The 1.R spectrum shows characteristic absorption
peak at v 1740cm.' indicating the presence of 5 membered cyclic imide and hence the
possibility of formation of pipytidinedione (234) is ruled out.These data were insufficient to mark
a structure unambiguously from 233,225a and 234. Ultimately the structure has been identified
with the help of HMBC (Heteronuclear-multiple bond connectivity) spectra. (Figure 111.25~1)
225a r - --- --__
Fig. 111.24a
- MO 110 iY 110 UO 100 80 60 10 20 R. Fig. 111.24~
JAIL- Z O V O . ~ ~ , , , - rn
1
158 ZPB iSB 388 . 1 Fig. 111.24d
Fig. 111.24b
Figure 111.25a 2D HMBC spectrum of 225a
Figure 111,25b Correlation diagram of 225b
The 'H-'~c long range correlations observed in the HMBC spectrum is shown in
Fig 111. 25 b. The carbonyl carbon peak at -6 171.17 shows correlations with 6 4.3
\ ( /CH- proton) and 6 3.8 (-OCH,,). The carbonyl carbon at 6 172.7 shows correlations
with 6 4.65 (C6H~-CHz-) and 2.8-3.2 (diastereotopic XI&-). The carbonyl carbon peak at - 6
\ 176.9 shows correlations with peaks at 6 4.65 (CeH5-CH2-), 4.3 ( ,CY- proton) and
diastereotopic-Gj2-. 2D HMBC spectn~m reveals that out of the three carbonyl peaks only
\ one carbonyl peak (at - 6 171.17) shows correlation with protons of -OW3 and CH-
/ -
proton (6 4.3). On the basis of this the anchored ester group has been identified and
which is possible only if the structurc? is either 225a or 234. Hence the possibility of
formation of 234 can be ruled out. Th? second and third carbonyl carbon (at - 6 172.7
and S 176.9) show correlation with peaks at 6 4.65 (C~HS-CH2) and 2.8-3.2
(diastereotopic -CH2-) and again th,? third carbonyl carbon (at - 6 176.9) shows
\ correlation with peak at 6 4.3 ( CH- proton). These correlations are possible only if the
/ -
structure is 225a. Hence the struct~~re 234 is ruled out. The formation of 233 is
accountable as the structure 225;t is prone to lactonisation easily leading to fused
bicyclic system (214) which is coniparatively less stable than 234. Of the structures
225a and 234 the formation of 225'a can be further justified as the formation of a five
membered ring is entropically more favorable than a six membered ring. To generalize
the synthesis of 225 the reaction vvas repeated with methoxy benzyl amine and 2-(3,4-
dirnethoxy phenyl) eihyiamine and anticipated product was obtained with methoxy benzyl
amine (Fig. 111 26).
Scheme 111. 9
However when the reaction was repeated with 2-(3,4dimethoxy phenyl) ethylamine the
product isolated was 235. This is based on the I.R, 'H and l 3 C NMR and Mass spectrum
(Fig. 111 27).
The molecule 235 itself is not C2 synlmetric. However it is interesting to note that the
envisaged supramolecular dimer is C2 symmetric.
-~ ~ " ... O .. . .",,. ... . , O .~. ." " , _ .j ,,, " ,,, Fig. 111. 27 a
- p~ -.
-- -
I
.: I ,
- 1 =, -t\. pipqs , , ! , , tg ' " I
, , , d , I " ) [
= I , i '
* I i i - 1 - - 7- - - _ _ -_ 4 . R " . s , l o m I I 8 o - . n . M I I . a a ; i
m '
. -. . - . . . .. .. ). .I .. .. ,. ., .. I , I . 1. i. .. I . . 1. -
Fig. 111. 27 a
235
Fig. 111. 27 a
Fig. 111. 27 a
111.2.viii Future Prospects as Supri3molecular species
Molecular recognition phenomena are the basis of any biological process and
extensive effort has been spent to understand the mechanism of such processes and to
discover new examples and applic;ations. Since large part of recognition processes,
particularly those in biological systerns, are based on the formation of hydrogen bonds
between host and guest molecule^,"^^'^' most effort are devoted to the construction of a
host abundant of hydrogen bond donating groups as , aminoacids, carbohydrates units
and s~lfonamides.~ One direction chosen by researcher on the way to build up a
synthetic enzyme, consists of the selection of scaffold onto which easily accessible
optically pure units, containing elements necessary for recognition, are implemented.162
Supramolecular chiron is the minimal homo or hetero chiral molecular unit or
ensemble capable of generating ordered super structures by self assembly through
hydrogen bonding or other covalent forces and leading to topologically distinct enantio
or diastereopure architecture^.'^^ They are characterized both by the special
arrangement of their components, their architecture or superstructure and by the nature
of the intermolecular bonds that holcl these components together. They possess well-
defined structural, conformational, tt~ermodynamic, kinetic and dynamical properties.
Various types of interactions may be distinguished that present different degrees of
strength, directionality, dependence on distance and angles: metal ion coordination,
electrostatic forces, hydrogen bonding wander Waals interactions, donor-acceptor
interactions e t~ . ' '~ Like a molecule a supermolecule may exist in enantiomeric or
diastereomeric forms. Supramolecul3r chirality results both from properties of the
components and from the way in whi::h they associate. Pyrrolidiones 235, 236 etc can
be conveniently converted to C, symmetric or supramolecular dimers. It is envisaged
that these chiral supramolecular or niacromolecules find appl~cation in catalysis, drug
delivery and molecular recognition. Appropriate organization of 235 and 236 is expected
to glve suitable chiral cavity for binding host molecules or self-replicating systems
(Fig. 111. 29).
Figure iii.28
The above reaction was further extended with the trimethyl ester 232 the
diastereorner of (231) and benzyl amir~e leading to the isolation of a white solid. Even
though the TLC is indicative of the formation of two products we could isolate only one
D ~ O ~ U C ~ .
'HNMR of the product show:; characteristic peaks at 6 7.3 ( 2x 5arom ti), 4.65
\ (4H, -N-C!%-), 4.3 (AH, /CK- ), 3.2 (IH, dd, -C&) and 2.8 (1H,dd -C&-). 13C NMR shows
peaks at -6 176.9, 172.7, 171.7 (-GO ~ a k s ) , 135.1, 128.7, 128.5,128 (arom), ,$H- at -6
77.5, -sHr of the lactone ring at -6 43.6. No signal was obtained for -OCli3 in the ' 3 ~ NMR.
Based on these spectroscopic data titntafiely the formation of fobwing products can be
visualized as the M+ is same for all the cases (Fig. 111 31).
Fig. 111. 31 a
-- --~ --...--..-- -., --.-~- . I . . . . l l O C Fig. Ill. 31 b
, , ;d, 1 .L o . .ie ,:I .; ; - Fig. u . 3 1 b
Fig. Ill. 31 d
Hence a thorough analysis was neces:;aly to establish the actual structure and the HMBC of
the molecule solved the actual structure. The 'H-'~C long range correlations observed in
the HMBC spectrum is shown in Fig Ill. 32b
Fig. 111 32 a
Figure 111.32 b
\ The carbonyl carbon peak at -6 170 86 shows correlations with 6 4.48 ( CH- proton)
/ -
and 6 3.8 (-OH,). The carbonyl carbon at 6 173.5 shows correlations with 6 4.48 (CsH,-
Cb-) and 2.6-2.8 (diastereotopic <Hz-). The carbonyl carbon peak at - 6 177.86 shows
correlations with peaks at 6 4.62 (N-CH2-). 4.85 ( 'CH - proton) and diastereotopic <&. 2D / -
HMBC spectrum reveals that out of the three carbonyl peaks only one carbonyl peak (at - \
6 171.17) shows correlation with protons of -OH and CK- proton (64.3). On the basis /
of this and the mass spectrum it has been identified that the anchored ester group has
been converted to amide, which is possible only if the structure, is 236. The second and
third carbonyl carbon (at - 6 173.5 and 6 177.86) show correlation with peaks at 64.48
(C6H5-CH2) and 2.6-2.8 (diastereotopic; -CH,-) and again the third carbonyl carbon (at - \
6 177.86) shows correlation with peak at 6 4.85 ( ,CH- proton). These correlations are
possible only if the structure is 236. The reactions of 231 and 232 with alkyl amines can
be considered as a typical case wher'? the chemical behavior of diastereoisomers can
be differentiated with change in situations.
Me02C .C@hle MeqC+a
HO OH Toluene. ref lux
Scheme 111. 10
Efforts were made to generalize the reaction by preparing other derivatives with
methoxybenzyl arnine and 2, (3-4 dirnethoxy phenyl) ethylarnine however the products
obtained lack consistency.
With rnethoxybenzyl arnine 218b is obtained and with 2, (3-4 dirnethoxy phenyl)
ethylamine 218c is obtained (Fig. 111 33 8 34).
w 232 -- HODS'
Toluene, reflux bz
0
Scheme Ill. 11
Fig. 111. 33 d
1 1 Fig. 111. 34 c
.\hr,,.;,l' = ,,;! 8 , ,; ,I.,
"., C ., ( , r l l \ , , .. -. , , I !
\.~ ,,' >. ,
- ,,. - - - - - - - ,= ,,., .- ,- .- -
" . . . , . , . , ~ -
>bo ,;a 0 1.0 1,. 1.0 .c ro 4 O -
Fig. 111. 34 d
218 c
Fig. 111. 34 a
Fig. 111. 34 b
111.3 General Experimental Details
All commercial solvents were distilled prior to use. Dry solvents and reagents
were prepared by following the prc~cedures described in "Purification of Laboratory
Chemicals" by D. D. Perrin and W. L. F. Armarego (Yd edition, Pergamon Press, 1988).
Dry THF was used as such received from Aldrich. Dried fruit rind of Garcinia cambogia
was procured from a local plantation Leaves or calyxes of Hibiscus subdariffa and the
leaves of Hibiscus furcatus were collected from local area. All reactions which require
anhydrous condition were carried out under a positive flow of dry nitrogen. Anhydrous
sodium sulphate was used to dry organic extracts.
Melting points were determine0 on "Sunbim" make electrically heated melting point
apparatus and are uncorrected. lR spectra were recorded using a Shimadzu IR 470
spectrophotometer as KBr pellets (sc~lids) or thin films (liquids). 'H-NMR spectra were
recorded on a Brucker W M 300 MHz clr Bnrcker Avance 300 or Jeol GSX 400MHz or
Brucker AMX 400MHz NMR system and chemical shift values are reported in parts
per million (ppm) relative to tetrarnethylsilane as internal standard (0.00 ppm).
I3C NMR were recorded on a Brucker WM 300 (75.5 MHz) or jeol GSX 400 (100.6 MHz)
or B ~ c k e r AMX 400 (100.6MHz) NbIR system and chemical shift values are reported
in parts per million (ppm) relative to tetramethylsilane (0.00 ppm). HMBC spectrum
was recorded on Brucker DRX 600 hIMR system. Electron impact mass spectra were
recorded on a Finnigan MAT MS 8231:) or jeol D-300 and FAB MS were recorded on
a jeol SX-1021 DA- 6000 MASS spectro meter. Specific rotations were recorded
using Jasco D I P 370 or Jasco D I 1:' 1000 digital polarimeter or Rudolph Autopol R
II.IIS and Ill digital polarimeter. Elemental analyses were carried out on a Carlo-Erba
CHNS-0-EA 2108 elemental analy:ic.er (CDRI) or Vario EL Ill elementar (M. G.
University).
111.4 Experimental
Dried rinds of the fruits of Gar1:inia cambogia (1 Kg) were cut into small pieces
and soaked in hot water (IL). The extract was collected afler 20 hours and the process
was repeated 4-5 times. The combinti!d extract was concentrated and methanol (2.5L)
was added to precipitate pectin. Uporr filtration the filtrate was concentrated to a syrup.
I t was made alkaline with sufficient quantity of 10 % aqueous sodium hydroxide,
followed by the addition of methanol (IL) till two layers separated. Sodium salt
separated as a paste (lower level) and was washed with 60%aqueous methanol
(5xIOOml). The pure sodium salt was dissolved in sufficient quantity of 2N hydrochloric
acid to regenerate the free acid. It is concentrated and added acetone to precipitate the
impurities. The filtrate on concentration yielded crude crystals of Garcinia acid. Pure
crystals of 1 were obtained upon recrystallisation from acetone-ether mixture.
Yield : 67.59 (6.75% to the dry wt of fruit rinds)
Melting point : 178" C. Reported: 178C
(alks : +102.15"~~nI.O,H20) Reported:+10O0
IR (KBr) : v ,, 3400 (OH,broad), 1790 (8-lactone) and 1741cm~' (carbonyl)
'H NMR (DMSO-d6) : 6 4.80 (s, IH), 3.07(d,.J = 17.4Hz,lH), 2.60 (d.J ~ 1 7 . 4 Hz,
fH) ppm
''C NMR(DMS0-d~) : 6 174.9, 171.9, 169.2, 84.8, 79.0, 39.7 ppm
Mass spednrm (€.I) : nVz 191 (h4+1) (2), 173 (I), 162 (6), 145 (35), 127 (lo), 116 (48), 99
(70). 88(.100), 60 (40) and 55 (20)
Molecular formula : C8HB07
Elemental analysis
Found : C 37.23, H 2.73
Calculated : C37.91 H2.18
Fresh calyxes or leaves (1 Kg) of Hibiscus sabdariffa or leaves of Hibiscus
furcatus were soaked in water r I Lt). After washing with hexane, the concentrated
extract was made alkaline with 8N sodium hydroxide solution (80ml). Methanol was
added to precipitate the sodium salt followed by the addition of 2N hydrochloric acid to
regenerate the acid. Upon ::oncentration followed by the addition of acetone
precipitated the impurities. Th:? residue obtained after concentration was further
extracted with ether which on concentration yielded 10 g of 11 when leaves of Hibiscus
furcatus or 16 g of 11 when fresh ca yxes (1 Kg) of Hibiscus sabdariffa were used.
Melting point : 180°C. Reported : 182-183"C(decomp)
la12 : + I l l o (c l.0,H20) Reported : +11O0
IR (KBr) : v,, 3400 (OH, broad), 1790 (a-1actone)and 1735 cm-' (carbonyl)
'H NMR (acetone-d6) : 6 5.36 (s, ltl),2.8(d,.&17.09Hz.lH), 3.3 (d,J =17.09 IH)ppm
''c NMR (DMSO-d6) : 6 173.2, 1?2.3, 167.1, 82.9, 78.4, 42.2 ppm
Mass spectrum (Ed) : mIz191 (M-1-1) (2), 172 (I), 162 (5), 145 (60), 127 (12), 116 (38), 99
(84), 88(100), 60 (48) and 55 (28)
Molecular formula : C6H607
Elemental analysis
Found : C 37.23, t1 2.73
Calculated : C 37.91, t1 3.18
111.4.iii. (3aS, 6aS)-3a-(acetyloxy) dihydro-5-(phenylmethyI)-6H-furo[2,3-c] pyrrole- 2.4.6 (3H,4H)-trione (2134
A suspension of Garcinia ~ c i d I (Igm, 5mmol.) in acetyl chloride (4ml) was
refluxed for 2hrs. The result~ng mixt~lre was concentrated in vacuum to give a white solid,
which was dissolved in dry THF (5~11). Benzyl amine (0.52gms, 5mmol) was added, the
mixture was stirred at room temp for 4h and thoroughly concentrated in vacuum. Further
acetyl chloride (5ml) was added and the mixture was refluxed for 18h. After concentration in
vacuum, recrystallisation (EtOH) afforded 213a as white crystals.
Yield : 0.8gm (59.4%)
Melting point : 156°C
lalg : +136.24" I C l.O,CHC13)
IR (KBr) : v,,, 1790, 1740, 1250, 1030, 750 cm~'
'H NMR (CDCI3) : 67.45-7.:!5(m,3H);5.31(1H);4.8-4.65(q,2H);3.9(d.lH,J=9.8Hz)
3.2(d,lH. J=9.8Hz);2.2(S,3H)ppm
"C NMR(CDCI3) : 6 170.6,17~3.4,170.1,167.3,134,128.9,128.8,128.5, 128.4, 79.7,
79.8,43.3,:!,5.9,20.1 ppm
Mass spectrum (E.1) : mlz 303(bI') (5.9), 243 (41.72), 199(16.39), 132(28), 11 1(90),
91 (62.58) 83 (14.9). 77(5.9), 57(41.7). 43(100)
Molecular formula : C15H1306F1
Elemental analysis
Found C 58.9, t i 4.2, N 4.5
Calculated C 59.40, H 4.2. N 4.6
The procedure described for 213a is followed with 1 (Igm, 5mmol.) in acetyl
chloride (4ml), and 4-Methoxyber.zyl amine (0.68gms, 5mmol) in THF (5ml).
Recrystallisation (EtOH) afforded 213b as white crystals.
Yield : 0.9gm (54%)
Melting point : 126°C
la1205 -133.84" ( c 1 .O,CHCI3)
'H NMR (CDC13) : i3 2.2 3 2.9(d J=8Hz, IH), 3.2(d J=8Hz, IH),
3.8(s,3H,), 4.5-4.7(m, 2H,), 5.25(s, IH), 6.7-6.8 (d, arom),
7.2-7.3 (d,arom) ppm
l3cNMR(CDCI3) : 6170.9,1'~0.8,,167.7,160.0,130.5,126.59,114.6,80.19,
79.67, 55.6, 43.22, 36.64, 20.5 ppm
M.S. (FAB). : 334 (M+I:i
Molecular formula : Cl~H16N07
Elemental analysis
Found : C 57.49, H 4.91, N 4.31
Calculated : C 57.65, H 4.8, N 4.2.
111.4.~. Glycine methyl ester hydroc:hloride
Thionyl chloride (5.5ml. .i'58ml) was added dropwise with stirring to
dist.methano1 (20ml) at -1O0C, avoidirig the rlse of the temperature above -5°C. Glycine
(5gm,0.66mol) was then added in srglall portions and the mixture was heated at 40°C.
Ten minutes later the solution was clear and a voluminous white precipitate had begun to
appear. After two hours the reaction mixture was cooled to room temperature and the
precipitate was collected and dried in air until the smell disappeared. The methanolic solution
was again concentrated under vacuum and a second portion of Glycine methyl ester
hydrochloride was collected.
Yield : 79 (75%)
IR (nujol) : v,,, 1750cn.i'
'H NMR (D20) : 6 3.72(s,2H:l, 3.70 (s,3H) ppm
111.4.vi. Glycine methyl ester
A stream of dry ammonia w~ils passed through an ice cooled suspension of
Glycine methyl ester hydrochloride (2.79, 21.5ml) in Et20 (30ml) under vigorous stirring
for one hour. The white precipitate of ammonium chloride was removed and the organic
solution was dried on sodium sulphate and concentrated under vacuum until
evaporation of the ammonia. Yield 6596.
'H NMR (D,O) : 6 3.0(s,2H), 3.4 (s.3H) ppm
A titrated solution of glycine methyl esler in methylene chloride was immediately used in
the next step.
A suspension of garcinia acid 1 (Igm, 5mmol.) in acetyl chloride (4ml) was
refluxed for 2hrs. The resulting mixture was concentrated in vacuum to get a white solid,
which was dissolved in methylene c:.hloride (5ml) and then poured into a recently
prepared 1M solution of glycine methyl ester in methylene chloride at 5°C. The solvent
was evaporated, acetyl chloride (5ml:i was added and the mixture was heated under
reflux for 4 hours. The excess of acetic acid and acetyl chloride was removed under
vacuum and the residue was taker1 in methylene chloride, washed with saturated
Na2C03 and the organic layer was cctncentrated and the semisolid obtained is purified
by column chromatography (silica gel, hexane- chloroform, 1:l) to get pure 215.
Yield : 0.74 gm (!j'1.92%)
Melting point : 106°C
IR (KBr) v,,, 3002,2920, 1799, 1740, 1629, 1244 cm-'
'H NMR (CDCI3) : 6 5.2 (s,l H J, 3.1 (d, &9Hz,l H),,3.8 (d,J=9Hz, I H), 2.2(s,6H) ppm
'3CNMR(CDCld : 6171.3,170.7,169,165,162,82.5,79.8,36,34.2,19.1,
18.2 ppm
Molecular formula : CI,H,,NOB
Elemental analysis
Found : C 52.60. H 4..21, N 5.43
Calculated : C 52.58, H 4..3, N 5.5.
To a refluxing solution of 1 (Igrn, 5mmol) in xylene (20ml) was added drop wise
2-(3,4dimethoxy phenyl) ethyl amine (1.675ml 5mmol) and the reaction mixture was
refluxed further for 4 hours using dear -stark water separator. The mixture was cooled to
room temperature and the resulting solid was filtered. The solid substance obtained was
purified by column chromatography (silica gel, hexane- chloroform 1:l).
Yield : I .lgm (65.75%).
Melting point 176°C.
[.I? -33.84" (C 'I .O,CHC13)
IR (KBr) v,,, 3450, 1783, 1740, 1250, 1030,750cm~'
'H NMR (CDCI3) : 66.8-6.5(1n,3H),4.9(s, lH,),3.7-3.9(~,8H),2.9(rn,2H,),
2.8 (d, J=20Hz,lH), 2.4 (d,J=20Hz, 1H)pprn.
MS.( FAB). : 335(M')
Molecular formula : C16H17N07
Elemental analysis
Found : C 57.32, H 5.07 N 4.18.
Calculated : C 57.31, H 5.07 N 4.17.
A solution of 11 (l.Ogm, 525mmol in 25mlether) was treated with excess
diazomethane in ether. The reaction mixture on concentration gave colorless crystals of 217.
Yield : 1.2 gm (11:)0%)
Melting point : 129°C
[.I? : +118.9 (c 0.4952,CHCl3)
IR (KBr) v,,, 3500. 1795, 1745cm-'
'H NMR (CDCI,) : 6 5.31(s.ltl), 3.95(s,3H), 3.84 (s,3H), 3.1 (d, &20.3Hz, IH), 2.87
(d, J=20.3Hz, 1H) ppm
"C NMR (DMSOde) : F 172.74,1'10.80, 166.14,81.96, 77.90, 53.12, 53.03, 40.14ppm
Mass spectrum (€.I) : mlz 219(h11+1) (66), 191 (2), 159(1 OO), 141 (lo), 130(38),
99(1 OO), 74(25)
111.4.~. Methyl (2R)-, [2(3S)-1 benzyl-3-hydroxy-2-5-dioxotetrahydro-lH-pyrrol-3- yl]-2-hydroxyethanoate (21tla)
To a refluxing solution of 217 :Igm, 5rnmol) in toluene (20ml) was added drop
wise benzyl amine (0.52gm, 5mmol) and the reaction mixture was refluxed further for 5
hours. The mixture was cooled to rooni temperature and the resulting solid was filtered.
The solid substance obtained was lurified by column chromatography (silica gel,
hexane- chloroform, 1:l) .
Yield 0.95gn-I (64.8%)
Melting point : 97°C
lali5 : -23.84" (r: 1.O,CHCI3)
IR (KBr) v,, 3445.2954, 1782, 1705, 1435,1346, 1078,762,698 cm-'
'H NMR (CDCI3) : 6 7.4-7.2 (m, 5H), 4.7 (s, 2H.), 4.5(s,lH,), 3.6 (s,3H,), 3.8
(d, J = 20Hz,lH), 2.9 (d,J=2OHz, 1H) ppm
M.S (FAB) : 294(M+1)
Molecular formula : Ci4Hi5061d
Elemental analysis
Found : C.56.61, H.5.1, N.4.6
Calculated : C.57.14, ti1 5.1, N 4.7
The procedure described for 218a was followed using 217 (Igrn, 5rnmol),
toluene (20ml) and 4-methoxy bc!nzyl amine (0.68m1, 5mmol). After column
chromatography (silica gel, hexane-chloroform miturel:l), 218b is isolated as white
crystals.
Yield : 1.28gm (79.2%)
Melting point : 100°C
la12 : -29.84" (c 'I.O,CHCl3)
IR (KBr) v,,, 3442, :;!936, 1814, 1715, 1518, 1026, 749 cm-'
'H NMR (CDC13) : 6 7.3-7.2(d, arorn), 6.7-6.8(d, arorn), 4.7 (s, 2H, >),
4.4(s,lH,), 3.8 (s,3H,), 3.6 (s,3H, ), 3.1 (d,J= 9Hz, IH), 2.7
(d, J= 9Hz. 1H) ppn~
13CNMR(CDC13) : 174.5,172,159,130,129.9,129.2,128.7,77.9,77.7,55,
43,38.4, 30 pprn
MS (FAB) : 324(M+1)
Molecular formula : Ct5H17N07
Elemental analysis
Found : C 55.64, H 5.34, N 4.41
Calculated : C 57.72, H i5.2, N 4.3.
lll.4.Xii. Methyl (2R)-, [2(3S)-1 -[2-(3,4-dimethoxy phenyl)ethyl ]-3-hydroxy-2-5- dioxotetrahydro-lH-pyrr1~1-3-yl]-2-hydroxyethanoate (218c)
The procedure described for 218a was followed using 217 (Igm, 5mmol), toluene
(20ml) and 2-(3,4dimethoxy phenyl)ethyl amine (1.7m1,5mmol). Afler column
chromatography (silica gel, hexane-chloroform mixturel:l), 218c is isolated as white
crystals.
Yield : 1.2 gm (6!5%)
Melting point : 136°C
IR (KBr) v,,, 3451 2941, 1784, 1739, 1704, 1591, 1398, 1023, 766,
700 cm~'
'H NMR (CDCI3) : 66.8-6.7(m,3H),4.4(s, lH,CH),3.7-3.9(s.8H,CH2and
OCH3 x ) 2.9 (m, 2H, CH2), 2.8 (d, J=20Hz, AH), 2.4
(d,J=20Hz, 1H) ppm.
Mass Spectrum (E.1) : 368 (M+ I I
Molecular formula : C16H21N(:)8
Elemental analysis
Found C 52.50, H 5.61, N 3.75
Calculated C 52.31, Y 5.7, N 3.8.
A solution of 1 (l.Ogm, 5mriol) in ether (25ml) was treated with excess
diazomethane in ether. The reaction mixlure upon concentration gave 216 as an yellow oil.
Yield : 1.1 gm (1CO%)
: +65.32." ((: 0.32,CHC13)
IR (film) v,,, 3450, 1795.1740 cm-'
'H NMR (CDCI3) : 6 4.96(s,1 I.{), 3.82(s,3H), 3.78 (s,3H),3.20 (d,J =19.OHz, IH),
2.82(d, J = : 19.OHz,lH)ppm
Mass spectrum (E.1) : mlz 219(b1+1) (I), 191 (3), 159(26), 141(6), 131(25), 99(100),
59(93)
Molecular formula : C16H2,N08
Elemental analysis
Found : C 52.50, H !5.61, N 3.75.
Calculated : C 52.31, .i 5.7, N 3.8.
111.4.xiv. Methyl (2s)-, [2(3S)-1 be~izyl-3-hydroxy-2-5-dioxotetrahydro-I H-pyrrol-3- yl]-2-hydroxyethanoate (225a)
To a refluxing solution of 2113; (Igm, 5mmol) in toluene (20ml) was added drop
wise benzyl amine (0.52gm, 5mrnol) and the reaction mixture was refluxed further for 5
hours. The mixture was cooled to rof:)m temperature and the resulting solid was filtered.
The solid substance obtained was purified by recrystallisation (chloroform-hexane).
Yield : 1.25gm (85%)
Melting point : 82°C
lalg : -12.1" (c 1.OCHCI3)
IR (KBr) : v,,, 3463, 3065, 1775, 1695, 1427, 1342, 1189, 993, 717 cm-'
'H NMR (CDCI3) : 6 7.2-7.3(m,51-1). 4.6 (m,2H), 4.3 (s,lH), 3.12-3.18 (d,J=18,1H),
2.72-2.78 (d,.l=18,1H) ppm
'3~NMR(CDC13 : 6176.85,17~i.54,171.72,135,128.69,128.4,127.9,76.1.72.1,
53.7,42.5, 39.6 ppm
M.S (G.C.M.S) : mlz 294 (M-bl) (5.2), 293 (31.5), 216 (68.4), 204(46.3), 138
(15.7), 132 (Ci2.63)
Molecular formula : CI.IH,,OBN
Elemental analysis
Found : C.56.62, H.Ii.15, N.4.63
Calculated : C.57.14. H 5.1, N 4.7
The procedure described for 225a was followed using 216 (Igm. 5mrnol),
toluene (20ml) and 4-rnethoxy benzyl arnine (0.68rnl. Smmol). After column
chromatography (silica gel, hexanti?-chloroform rnixture1:l). 225b is isolated as white
crystals.
Yield : l . lgm 169.2%)
Melting point : 100°C
la126 : -29.84' (C I.O,CHCI~)
IR (KBr) v,,, 3452,2930, 1784, 1715, 1518, 1026,749 cm"
'H NMR (CDCI3) : 6 7.4-'r.2(d, arom), 6.85-6.7(d, arom), 4.7-4.5 (m, 2H,),
4.3(s,lH,), 3.9 (s,3H,), 3.7 (s,3H, ), 3.2-3.1 (d,J= 9Hz, IH),
2.8-2.7 (d, J= 9Hz. 1H) pprn
13CNMR(CDC13) : 176.7, 173.5, 171.5, 159.4, , 129.9,129.2, 127.7,114, 77.9,
77.7, 55, 53,42,39.6pprn
MS (LCMS) 324(1W+1)
Molecular formula : C15t117N07
Elemental analysis
Found C 5!i1.65, H 5.33, N 4.40
Calculated C 57.72, H 5.2, N 4.3.
111.4.xvi. Methyl (2s)-, [2(3S)-1 -[2-(3,4-dimethoxy phenyl)ethyl ]-3-hydroxy-2-5- dioxotetrahydro-lH-pyrrd-3-yl]-2-hydroxyethanoate (225c)
The procedure described for 225a was followed using 216 (Igm, 5mmol), toluene
(20ml) and 2-(3,4dimethoxy phenyl)ethyl amine (1.7m1,5mmoi). After column
chromatography (silica gel, hexane-c:hloroform mixturel:l), 225c is isolated as white
crystals.
Yield : 0.9gm(51%)
Melting point : 136°C
IR (KBr) v,,, 3491, 2841, 1780, 1719, 1704, 1561, 1388, 1025, 766,
700 cm-'
'H NMR (CDCI3) : 67.1-6.7(m,3H),4.3(s,lH,CH),3.9-3.6(s.8H,CH2and
OCHj 2), 2.8 (m, 2H, CH2), 3.2 (d, J=20Hz, IH), 2.7
(d,J=20H:z, 1 H) ppm.
13CNMR (CDC13) : 6 177,173.7,169.8,148,131.2,130.45120.9,112.2.111.5,
77.3,77, 56.08, ,40.4,40.17, 39.8, 34.9,32.9,29.6 ppm
Mass Spectrum (LCMS): 368 (M+ 1 )
Molecular formula : C16Hz11'(08
Elemental analysis
Found C 52.5'1, H 5.60, N 3.74.
Calculated C 52.3'1, H 5.7, N 3.8.
111.4.xvii. Trimethyl (2S,3S)-1,2-dihydroxy-l,2,3-propanetricarboxylate (231)
To an aqueous solution of 'I (2.0gm IOmmol), sodium hydroxide solution (2N)
was added at about 80°C, to make the reaction mixture alkaline (- pH = 9.0). The
residue obtained after evaporation under reduced pressure, was triturated with dry
methanol and to this suspension 1-hionyl chloride was added. After refluxing for two
hours the reaction mixture was cooled and neutralized with saturated aqueous sodium
bicarbonate. The residue obtained upon concentration under reduced pressure was
extracted with chloroform (3 x 25ml). The combined extract was dried and concentrated
to furnish 231 as yellow oil.
Yield : 0.8gm (45'16)
'H NMR (CDC13) : 6 4.98(s,Itil), 3.84 (s,6H), 3.68 (s,3H), 3.2 (d,J= 18.OHz, IH), 2.8
(d, J = 18.CI Hz, 1 H)pprn
13C NMR (CDCI,) : 6 172.3, 170.7, 166.9, 77.3,74.6, 53.07, 52.9, 51.7,39.25 ppm
Mass spectrum(E.1) : mlz 251 (\A+l) (loo), 219 (23), 191 (32), 159(50), 143 (3), 131
( 4 3 99 ( 1 5), 59 (6), 43 (15)
I11.4.xviii. Methyl (2s)-, [2(3S)-1 benzyl-3-hydroxy-2-5-dioxotetrahydro-lH-pyrrol-3- yl]-2-hydroxyethanoate. (225a)
To a refluxing solution of 2:31(lgm, 4mmol) in toluene (20ml) was added drop
wise benzyl amine (0.45gm, 4mmcml) and the reaction mixture was refluxed further for
4 hours. The mixture was cooled to room temperature and the resulting solid was filtered.
The solid substance obtained was pu1,ified by recrystallisation (chloroform-hexane).
Yield : 1.4grn (100%)
Melting point : 142°C
lalzds : +78.IG (c 1.O,CHCI3)
IR (KBr) : v,,, 3406,2927,1809,1719,1396,1076,964.756 cm-'
'H NMR (CDCI3) : 87.3(m,5H),4.75(m,2H),4.3(s,lH), 3.8(s,3H),3.2-3.1 (d,
J = 20,1kI), 2.7-2.8 (d, J = 20,lH) pprn
13C NMR (CDCI3) : S 176.9, ,173.7, 171.7, 135, 128.4, 128.3, 128, 76.17, 72.3, 53.6,
42.6, 39.1:;. pprn
M.S (FAB) : rnh294(M+l)
Molecular formula : CZSH~Z(:)~N?
Elemental analysis
Found : C 60.47, H 6.21, N 5.42
Calculated : C 60.46, H 3.2, N 5.42.
The procedure described for 225a was followed using 231 (Igm, 4mmol),
toluene (20ml) and 4-methoxy tenzyl amine (0.52m1, 5mmol). After column
chromatography (silica gel, hexane-c:hloroform mixturel:l), 225b is isolated as white
crystals.
Yield : 0.97 (61.2%)
Melting point : 100°C
lal? : 46" (c 1.C',CHCl3)
IR (KBr) v,,, 3436,2947, 1747,1705, 1438, 1076,756 cm~'
'H NMR (CDC13) : 6 7.4-7.2ld, arom), 6.9-6.75(d, arom), 4.7-4.5 (m, 2H),
4.3(s,lH,), 3.85 (s,3H,), 3.75 (s,3H, ), 3.2-3.1 (d,J= 9Hz,
IH), 2.8-2.7 (d, J= 9Hz, 1H) ppm
13CNMR(CDC13) : 176.7, 173.63, 171.54, 159.3, , 129.9,127.5, 114.7, 77.9,
77.7, 55.2, 53.3,42,39.6ppm
MS (HRMS) : 346.0903 iM+Na)
111.4.~~. (2s) - N' - {[(3, 4 dimethoxy phenyl) ethyl] -2- (35)-1-[(3, 4 dimethoxy phenyl) ethyl] -3- hydroxy -2,5 4 0 x 0 tetra hydro -1 H-pyrol -3-yl)-2- hydroxy ethanamide (235)
The procedure described for 2:!5a was followed using 231 (Igm, 4mmol), toluene
(20ml) and 2-(3,4dimethoxy pher>lyl)ethyl amine (0.664,4mmol). After column
chromatography (silica gel, hexane-c~~loroforrn mixturel:3), 225c is isolated as white
crystals.
Yield : 1.00 gm (63%)
Melting point : 136°C
IR (KBr) v,,, 333:!, 2939, 1782, 1708, 1704, 1515, 1261, 1026, 856,
806 cm-'
'H NMR (CDCI,) : 6 6.9-6.7 (m, 3H x 2), 4.8 (s.lH, CH), 3.9 (s,6H, OCH, x 4),
3.7 (m,21.i,CH2 x 2). 3.5(m,2H,CH2 x 2), 3-2.9 (d, J=20Hz,
IH), 2.7-2.6 (d,J=20Hz, 1H) ppm.
13CNMR(CDCl3) : 6 177, 173.7,169.8,148,131.2,130.45120.9.112.2,111.5,
77.3, 77, 56.08, ,40.4,40.17, 39.8, 34.9,32.9,29.6 ppm
Mass Spectrum (LCMS): 517 (M+ 1)
Molecular formula : C6H,7NCb
Elemental analysis
Found : C 37.23. H 2.73
Calculated : C 37.91 H 2.18
111.4.xxi. Trimethyl (2S,3R)-1,2-dihydroxy-l,2,3-propanetricarboxylate (232)
To an aqueous solution of 'I1 (2.0gm IOmmol), sodium hydroxide solution (2N)
was added at about 8092, to make the reaction mixture alkaline (- pH = 9.0). The
residue obtained after evaporatiorr under reduced pressure, was triturated with dry
methanol and to this suspension 1-hionyl chloride was added. After refluxing for two
hours the reaction mixture was cooled and neutralized with saturated aqueous sodium
bicarbonate. The residue obtained upon concentration under reduced pressure was
extracted with chloroform (3 x 25ml). The combined extract was dried and concentrated
to furnish 232 as yellow oil.
Yield : 0.8gm (45%)
lalis : +22.14.1: (c 0.52 ,CHCI3)
IR (KBr) : v,, 3494,3009,2969,1748,1452,1128,1081,1013 cm~'
'H NMR (CDCI3) : 6 4.98(s,lH), 3.84 (s.6H). 3.68 (s,3H), 3.2 (d,J= 18.0Hz, IH), 2.8
(d, J = If'.O Hz, 1H)ppm
13C NMR (CDCI3) : 6 172.3, .70.7, 166.9, 77.3, 74.6, 53.07, 52.9, 51.7, 39.25 ppm
Mass spectrum(E.1) : mlz 251 (h~l+l) (loo), 219 (23), 191 (32), 159(50), 143 (3), 131
(4.5), 99 (15), 59 (6), 43 (15)
111.4.xxii. (2s) -N'-benryl -2-(3R) -4- benzyl -3-hydroxy -2, 5 dioxoterahydro -1 H- pyrrol -3-yl] -2-hydroxy ethanamide (236)
To a refluxing solution of 2:12(lgm, 4mmol) in toluene (201711) was added drop
wise benzyl amine (0.45gm. 4mmol) and the reaction mixture was refluxed further for
4 hours. The mixture was m l e d to room temperature and the resulting solid was filtered.
The solid substance obtained was, purified by repeated recrystallisation (chloroform-
hexane).
Yield : 0.7gm (51%)
Melting point : 142°C
IR (KBr) : v,,, 3444,2950,1781,1701,13266,1099,991,705 wn-'
'H NMR (CDCI3) : 67.4-7.1 (m, 10H),4.75(m.2H),4.9(s,lH),4.4(m,2H),2.9-
2.8(d, J : = 10,1H),2.7-2.6(d, J = 10.1H) ppm
"C NMR (CDCI,) : 6 177.1, 173.7, 170.9, 135, 128.9, 128.6, 128.2, 127.9,127.6, 77.3,
77,43.6, 42.7, 38.1,30.8. ppm
The procedure described lor 235a was followed using 232 (Igm, 4mmol).
toluene (20ml) and 4-methoxy benzyl amine (0.52ml. 5mmol). After column
chromatography (silica gel, hexane-chloroform mixturel:l), 218b is isolated as white
crystals.
Yield : 0.97 (61.2%)
Melting point : 100°C
lalg -29.84" (c 1 .O,CHCI3)
IR (KBr) v,,, 3436, 2947, 1747, 1705, 1438, 1076, 756 cm~'
'H NMR (CDC13) 6 7.4-7.:1!(d, arom), 6.9-6.75(d, arom), 4.7-4.5 (rn, 2H),
4.3(s,lH,), 3.85 (s,3H.), 3.75 (s,3H, ), 3.2-3.1 (d,J= 9Hz,
IH), 2.8-2.7 (d, J= 9Hz, 1 H) ppm
13CNMR(CDC13) : 176.7, 1'73.63, 171.54, 159.3, , 129.9.127.5, 114.7, 77.9,
77.7, 55.:2, 53.3.42,39.6ppm
MS (LCMS) : 324 (M+:s
Molecular formula : C15H171407
Elemental analysis
Found C 55.6!5, H 5.33, N 4.40
Calculated C 57.72, H 5.2, N 4.3.
111.4.xxiv. Methyl (2s)-, [2(3S)-1 -[2-(3,4-dimethoxy phenyl)ethyl J-3-hydroxy-2-5- dioxotetrahydro-I H-pyrrol-3-yl]-2-hydroxyethanoate (218c)
The procedure described for 235a was followed using 232 (Igm, 4rnrnol), toluene
(20ml) and 2-(3,4dimethoxy pt~enyl)ethyl amine (0.664,4rnrnd). After column
chromatography (silica gel, hexane-ctlloroforrn mixture1 :3), 218c is isolated as white solid.
Yield : 1 .OO gm (63%)
Melting point : 136°C
IR (KBr) v,,, 3332, 2939, 1782, 1708, 1704, 1515, 1261, 1026, 856,
806 cm-'
'H NMR (CDCI3) : 66.9-6.;'(m, 3H),4.8(s,lH, CH), 3.9(s,6H,0CH3x 2),3.7
(m,2H,(:.H2), 3.5(m,2H,CH2), 3-2.9 (d, J=20Hz, 1 H), 2.7-2.6
(d,J=201iz, 1 H) ppm.
13CNMR (CDCI3) : 6177,173.7,169.8,148,131.2,130.45120.9,112.2.111.5, 77.3,
77. 56.08, ,40.4.40.17, 39.8, 34.9,32.9,29.6 ppm
Mass Spectrum (LCMS): 368 (M+ " )
Molecular formula : C1,H,,NOt,
Elemental analysis
Found : C 52.51, t-l 5.60, N 3.74.
Calculated : C 52.31, t.1 5.7, N 3.8.
