Chapter III
Synthesis of Analogues of the Quararibea Metabolite Chiral Enolic-γ-Lactones from (2S,3S)- and (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-
furandicarboxylic acids
III. 1 Introduction
There are a large number of biologically active γ–butyrolactone based natural molecules which have matching structure and stereochemistry with that of Garcinia and Hibiscus acids (1 and 2). The ready availability and matching stereochemistry make these molecules ideal choice for the synthesis of several chiral γ-butyrolactone based molecules namely (+) isocitric acid, Quararibea metabolite lactone, (+) avenaciolide, (+) canadensolide, mescaline isocitrimide lactone, cinatrin C2 and C3, cis and trans whisky
lactones, (-) funebrine etc (Figure III.1).
Figure III.1
Chiral butenolides form an important class of compounds which appear as substructures in many natural products and they have been employed as key intermediates for the synthesis of a wide range of bioactive compounds.165 With representation in over 13,000 natural products, these class of synthon have become a valuable architectural platform for the development of new asymmetric methodologies.166 Synthesis of terpenoidal lactone, pheromones; (+) and (-) eldanolide, antileukaemic lignans, (+) trans-burseran, (-) Isostegane, (+) and (-) steganacin (-) verrucarinolactone, prostacycline analogues, chrysanthemic acid, polyoxin J, (-) ranunculin, lasalocid A are few examples. The use of butenolides as synthetic precursors, especially as Diels-Alder dienophiles or Michael acceptors are also frequently encountered.167-172In the interim considerable efforts have been extended on preparing butenolide chirons from chiral and nonchiral sources.173
III.2 Quararibea Metabolite Chiral Enolic-γ--Lactone
Chiral enolic-γ-lactone (126), chiral enamine (127), Funebrine (129) and γ-hydroxy alloisoleucine lactone (amino lactone) (128) are quararibea metabolites isolated from strongly odorous Mexican flowering plant; Quararibea funibris. The strongly odorous flowers of the tree have also been used since pre-Colombian times as a popular local folk medicine for cough, as antipyretic, to control menstrual disorders, psychopathic fears and as a hallucinogen. The chiral enol and enamines are responsible for the characteristic spicy odour which even persists for long in stored herbarium specimens and also used as additives to chocolate drinks from pre-Colombian times. The Zapotec people of Oaxaca, Mexico conducted funeral rites beneath the branches of the tree Quararibea funibris.174,154,157
Figure III.2
Literature shows virtually no synthetic work is ongoing on funebrine other than the synthetic strategy by Le Quesne et al. from β-angelica lactone which have already been discussed in chapter II.157
Very little is known about chiral enolic lactone (126) and related molecule (127). The absolute configuration of these molecules were established using the isolated samples and have not been further confirmed by the enantiopure total synthesis. Though the ethanopharmacological studies of the molecules are limited, certainly these promising molecules warrants further exploration to develop new leads.174
Few examples of butenolide based natural products are given below.
Annonaceous acetogenins are a class of compounds with potential biological properties like cytotoxic, antitumeral, pesticidal and immunosuppressive activities contain butenolide moiety is known to present in the Annonaceae plant species. Tonkinecin (130) is an Annonaceous acetogenin isolated from the roots of Uvaria tonkinesis with potential biological activities.175
Figure III.3
L-Ascorbic acid (131), widely distributed in plant and animal kingdom and the best sources include citrus fruits, hip berries and fresh tea leaves. The acid is known as an antioxidant, radical scavenger and serves as a reductant in some bio-transformations and known to
protect cellular components against oxidative damage.176
Figure III.4
(+) Dysidiolide (132), a novel sesquiterpenoid isolated from Caribbean sponge Dysidea ethria de Laubenfels, exhibits antitumor activity and most importantly it is the first natural product discovered thus far to inhibit protein phosphatase cdc25A.177
Figure III.5
Chiral butenolides can also be used as chirons for the synthesis of several natural products which do not bear any butenolide moiety. B.M. Trost and co-workers have synthesized Afllatoxin B1 (133), a member of a large family of mycotoxins that infect a variety of
agricultural products and animal products, using chiral butenolide (135) (Scheme III.1).178
Scheme III.1
III.2.1 (-) Kainic acid
(-) Kainic acid (136) isolated from the Japanese marine alga Digenea simplex is the parent member of the kainoids that display potent antihelmintic properties and neurotransmitting activities in the mammalian central nervous system. Thus, kainic acid has been widely used as a tool in neuropharmacology for the stimulation of the nerve cells and the mimicry of disease states such as epilepsy, Alzheimer’s disease and Huntington’s chorea. Y. Mortia and co-workers have reported a stereocontrolled total synthesis of 136 by the [3 + 2] cycloaddition of azomethine ylide with chiral butenolide (138) (Scheme III.2).179
Scheme III.2
Optically active unsaturated 4-alkyl γ-lactones (140) were obtained from propargylic carbinols (139) which are obtained by the asymmetric reduction of α-acetylenic carbinols. The butenolide 140 thus obtained is used for the preparation of (+) Tetrahydrocerulenin (141) (Scheme III.3).180
Scheme III.3
T. K. Chakraborthy and S. Chandrasekharan have effectively converted (Z)-2-Butene-1,4-diols (142) to corresponding simple α,β-butenolides (143) using silver carbonate/celite.
Also this methodology had been effectively applied for the synthesis of Eldanolide (144), the wing gland pheromone of the African sugarcane borer, Eldana saccharina (Scheme III.4).181
Scheme III.4
Often chiral butenolides have been obtained either from cabohydrates, γ-keto acids, glutamic acid or from acyclic systems like acetylenic compounds, pyruvic acid derivatives, cyanohydrins of conjugated aldehydes etc; mostly involving multi step synthetic strategies.
Alternatively chiral 5-alkoxy 2(5H)-furanones have obtained by Feringa and co-workers in moderate overall chemical and optical purity by the resolution method. Singlet oxygen photo oxidation of furfural (145) resulted in the formation of 5-hydroxyfuranone (146). 1-menthyloxyfuranones 147 and 148 were obtained via acetalization of 146 using menthol as chiral auxiliary (Scheme III.5).170,1 82,183
Scheme III.5
III.2.2 Syntheses of Chiral Butenolides
Ensuing discussion deals with the known synthesis of chiral butenolides.
Pd(0)/Ag+- co-catalyzed coupling cyclisation reaction of organic halides with allenoicacid resulted in poly substituted optically active butenolides (150) (Scheme III.6).184
Scheme III.6
J.M Concellon and co-workers have synthesized amino γ–butenolides (152) from 3-(1’-amino alkyl)-3,4-epoxy esters (151) (Scheme III.7).185
Scheme III.7
Stobbe condensation of diethyl succinate (153) with ethyl methyl ketone in presence of sodium alkoxide gives itaconic acid derivative (154). Further addition of bromine followed by dehydrobromination gives carboxy butenolide (155) (Scheme III.8). 186
Scheme III.8
α,β-butenolides were synthesized by the oxidation of O-trimethylsilyl cyanohydrin of α,β-unsaturated aldehyde using pyridinium dichromate (PDC) in dimethylformamide (DMF) by E. J. Corey and G. Schimdt. Geraniol (157) undergoes oxidative lactonisation to give 159 and 160 (Scheme III.9).187
Scheme III.9
Some instances of butenolides being used as Diels-Alder dienophiles or Michael acceptors are also available.
Thermal Diel’s–Alder reaction of γ-Menthyloxy butenolide (147) with 2,3-dimethyl butadiene (160) provided enantiomerically pure lactone annulated cyclohexene (161). Enantiomerically pure decalins are particularly attractive targets for asymmetric cycloadditions as numerous natural products and biologically active compounds contains 6,6-ring system. Among these are various classes of steroids, sesquiterpenes of drimane class and diterpenoids of labdane class (Scheme III.10).170,188
Scheme III.10
Intramolecular Diels-Alder reactions (IMDA reactions) are powerful tool in natural product synthesis to construct highly substituted polycyclic carbon skeltons. U. Reiser et al. have described the first IMDA reaction of substituted Feringa-butenolide (162) which contains a methacrylate type dienophile substructure. The butenolide activity is doubly enhanced by the oxidation of the hydroxyl to corresponding ketone (163) (Scheme III.11).167
Scheme III.11
Chiral butenolides have been used as dienophiles in Diels-Alder cycloadditions with
Figure III.16
A comparison of the VCD is made in the carbonyl region to assign the AC without any ambiguity.(Fig.III.17)
Figure III.17
On comparison of the experimental VCD with the calculated ones for the corresponding configurations, only in the case of (2S,3R) as shown in Figure III.17, the spectrum matches the position and phase correctly thereby confirming the AC of 2 as (2S,3R).
cyclopentadiene to generate polyfunctional norbornene derivatives which can be employed to prepare santalene, thromboxine antagonists etc among other interesting compounds (Scheme III.12).189
Scheme III.12
The 4-alkylamine substituted lactones are versatile precursors for the preparation of optically active β-amino acids and β-lactams. B.L. Feringa and co-workers have reported the synthesis of β-lactam using 5-menthyloxy butenolide.1,4-addition of alkyl amine with 5-menthyloxy butenolide (148) gave 4-amine substituted lactone (169). Ring opening with in situ acetylation without epimerization and further ring closure using Mukayama’s procedure resulted in β-lactam 170 (Scheme III.13).170
Scheme III.13
This chapter concerns with the conversion dialkyl esters of 1 and 2 to 2S-Dialkyl 4-methoxy-5-oxo-2,5-dihydro-2,3-furandicarboxylates, analogues of the Quararibea metabolite chiral enolic-γ-lactone (126a) and synthesis of aromatic dialkyl 5-[(methylsulfonyl)oxy]-2,3-furandicarboxylates (209 and 210).
III.3 Result and Discussion
It is clear from the above discussion that the chiral butenolides are important class of chiral synthons and thus enatioselective entry to them is methodologically important. Consequently, many methods dealing with the synthesis of this class of synthons have been published, most of them involve multi-step procedures with very low yield and enantiomeric purity. Structural features of (2S,3S)- and (2S,3R)-Tetrahydro–3-hydroxy-5-oxo-2,3-furandicarboxylic acids (1 and 2) are ideally suited for the synthesis of chiral
butenolides through simple dehydration. Pd/C reduction of the butenolide (171) thus obtained by the dehydration of 1 and 2 is expected to give a very potential natural product namely Isocitric acid (40), a member of Kreb’s tricarboxylic acid cycle. The detailed descriptions of the significance of Isocitric acid have been already discussed in chapter II (Scheme III.14).
Scheme III.14
III.3.1 Isolation of (2S,3S)- and (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids (1 and 2)
The plant materials for the isolation of 1 and 2, have been collected from different regions in South India. Fresh samples of dried rinds of the fruits of Garcinia cambogia and calyxes or leaves of Hibiscus sabdariffa or leaves of Hibiscus furcatus were used for the isolation of 1 and 2 following the procedure developed by Ibnusaud and co-workers. 19-21
III.3.1.1 Isolation of (2S,3S)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (1)
1. The dried fresh rinds of the fruits of Garcinia cambogia were cut into small pieces and soaked in hot water. The water 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 times 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 triturated with sufficient quantity of acetone to precipitate the insoluble. 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 [α]D values with
that of the reported values (Figure III.6 a-d) .
Figure III.6a
Figure III.6b
Figure III.6c
Figure III.6d
III.3.1.2 Isolation of (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3- furandicarboxylic acid (2)
The fresh calyxes or leaves of Hibiscus sabdariffa or leaves of Hibiscus furcatus were extracted with water and was concentrated to syrup. To this methanol was added to precipitate inorganic materials. The organic layer was concentrated and aqueous alkali was added to yield the salt of 2. It was then washed several times with alcohol and mineral acid to regenerate the acid. After concentration the residue was triturated with acetone or methanol to get crude 2.The final purification of crude 2 was done by repeated extraction or crystallization from ether. The chemical as well as optical purity of 2 was confirmed by comparing the I.R, NMR and mass spectra with that of the reported values (Figure.III.7 a-d).
Figure III.7a
Figure III.7b
Figure III.7c
Figure III.7d
III.3.1.3 Determination of Absolute Configuration by Vibrational Circular Dichroism (VCD)
Two important challenges of chirality are the determination of absolute configuration and enantiomeric purity. To understand and fine-tune the mechanism of interaction of medicinal molecules with the corresponding therapeutic targets in the fat metabolism pathway, a determination of absolute configuration of the molecule and its predominant conformation in solution is necessary. Often the asymmetric centers are prone to racemization due to the presence of active hydrogen atoms. Also depending on the nature of the medium or conformation, the molecule attains different absolute configuration and thus functions differently. Hence establishing the absolute configuration of these molecules in solution is a matter of great interest. Vibrational Circular Dichroism (VCD) has emerged as an important tool for the determination of absolute configuration and enantiomeric purity of optically active molecules or entities in the solution state.190-193 A reinvestigation of the absolute configuration of these acids by VCD technique confirms 1 and 2 to be 2S,3S and 2S,3R respectively.
III.3.1.4 Analysis of absolute configuration of (2S,3S)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (1) by Vibrational Circular Dichroism (VCD)
The absolute configuration of 1 and 2 is determined from Hudson lactone rule, Optical
rotatory dispersion curve and calculation of partial molar rotations. To the best of our knowledge no systematic conformational analyses of these molecules in the open form have been carried out. Hence 1 and 2 have been subjected to a systematic VCD analysis.
A three dimensional view of the molecule (1), along with the bond torsions (rotational bonds) and ring torsions (puckering) is shown in Figure III.8 and III.9. These torsions, in turn give rise to a large number of conformers in solution. The ring puckering shown in Figure III.9 gives rise to twist angle of 14.55 deg.
Figure III.8
Figure III.9
Only the first 8 conformers in the above list are used for the analysis as the others are lower in energy than 1k Cal/mole
The alignment of the conformers is shown in the experimental VCD spectrum of 1 in DMSO matrix is shown in Figure III.10. Most of the torsional motions occur in the side chains bearing the carboxylic acid groups.
Figure III.10 Aligned view of the conformers of 1 (2S,3S configuration). The atoms are color coded: Carbon skeleton (grey); Oxygen (red); hydrogen (white). The conformers are generated with MMFF using the default parameters as outlined in the SPARTAN manual.
The experimental VCD spectrum of 1 in DMSO matrix is shown in Figure III.11
Figure III.11 In DMSO, the carbonyl peaks are not well resolved, and only one positive phased signal could be discerned clearly. Hence spectra were measured in acetonitrile (100 % deuterated). As seen, in Figure III.12 all the three carbonyl peaks could be resolved in this solvent and their spectral phases match well with the calculated spectra. Thus the assignment is made as SS.
Figure III.12
In addition, it appears that the C-O stretching (band labeled 4) is blue shifted to 1320 cm-1 and agrees well with the experimental band.
As a control, the spectra for the SR configuration is also generated. However, the band patterns (position, phase and relative intensity distribution) seen in the SR do not match with the experiment (Figure III. 13).
Figure III.13
Thus SR configuration is ruled out for 1 and concluded as SS
III.3.1.5 Analysis of absolute configuration of (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3- furandicarboxylic acid (2) by Vibrational Circular Dichroism (VCD)
The yellow cylinders in Figure III.14 illustrate the torsional degrees of freedom for this molecule. Different conformers arise by rotations about these bonds (see below).
Figure III.14
Recollecting that torsions occur in the acid and hydroxy side chains the 60 conformers were aligned in Fig. III.14. One can see that maximum movements or “torsional noise” occurs in the side chains.
Figure III.15
The lactone ring itself is distorted (and not planar) and for the lowest energy conformer the twist angle (defined as the angle between any two planes in the ring) is 7 deg. The highest energy conformer has a distortion of about 16 deg. (shown below in two views, hydrogens are omitted for clarity). This is the well known ring strain energy that all the cyclic structure exhibit (Figure III.16)
III.3.2 Preparation of Dialkyl (2S,3S)- and (2S,3R)-tetrahydro-3- hydroxy-5-oxo-2,3-furandicarboxylates from 1 and 2
During any functional group transformation of γ-butyrolactone containing target molecule, careful attention should be given to keep the lactone ring intact. The preparation of dimethyl esters of 1 and 2 following the usual procedures for the esterification of carboxylic group resulted in the formation of a mixture of cyclic dimethyl ester (9,13) and acyclic trimethyl ester(17,20) formed by the opening up of the lactone moiety (Scheme III.15).
Scheme III.15
Hence to overcome this difficulty, the diesters were prepared by first converting the lactone to its disodium salt (5 and 6) using aqueous sodium bicarbonate solution (Figure III.18a-b, Figure III. 22a-b). On treating 5 and 6 with thionyl chloride yielded the diacid chloride, which upon treatment with the alcohol gave the corresponding diester exclusively. 5 and 6 can be stored as white crystalline solid. It was suspended in dry methanol and two equivalents of thionyl chloride were added drop wise under ice-cold conditions with stirring. Stirring was continued for two hours and the reaction mixture was neutralized using aqueous sodium bicarbonate solution and the dimethyl esters (9 and 13) were isolated. The experiment was repeated using dry ethyl alcohol to yield the diethyl esters (10 and 172) and using dry isopropyl alcohol yielded the diisopropyl esters (11 and 173) as yellow oil. All the products were characterized using IR, 1H and 13C NMR and mass spectra10 (Scheme III.16) (Figure III.19a-d, FigureIII.20a-d, Figure III.21a-d, Figure III.23a-d, Figure III.24a-d. Figure III.25a-d).
Scheme III.16
The dimethyl esters (9 and 13) can also be prepared exclusively by the treatment of 1 or 2 with diazomethane in ether; hence it requires milder reaction conditions. However this method is limited only to the preparation of methyl esters (Scheme III.17).
Scheme III.17
Figure III.18a
Figure III.18b
Figure III.19a
Figure III.19b
Figure III.19c
Figure II.19d
Figure III.20a
Figure III.20b
Figure III.20c
Figure III.20d
Figure III.21a
Figure III.21b
Figure III.21c
Figure III.21d
Figure III.22a
Figure III.22b
Figure III. 23a
Figure II.23b
Figure II.23c
Figure II.23d
Figure III.24a
Figure III.24b
Figure III.24c
Figure III.24d
Figure III.25a
Figure III.25b
Figure III.25c
Figure III.25d
III.3.2.1 Preparation of Dibenzyl (2S,3S)- and (2S,3R)-tetrahydro-3- hydroxy-5-oxo-2,3-furandicarboxylates from 1 and 2
Dibenzyl esters are not obtained by following the above mentioned procedure since high temperature is required for the formation of benzyl derivatives. However following a
reported procedure refluxing a suspension of 2 in dry benzyl alcohol, p-toluene sulphonicacid monohydrate and toluene for 13 hours at 130 0C and subsequent work-up and recrystallisation and with chloroform–hexane furnished white crystals of dibenzyl esters(12 and 14) (SchemeIII.18) (Figure III.26a-d).
Scheme III.18
Figure III.26a
Figure III.26b
Figure III.26c
Figure III.26d
III.3.3 Preparation of Dialkyl 2S-2(5H) furanone- 4,5-dicarboxylates using Dialkyl (2S,3S)- and (2S,3R)- tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylates.
With the objective of preparing chiral butenolide (171) from 1 and 2, the halogenation of the tertiary hydroxyl group followed by dehydrohalogenation was planned. The following reagents were tried under different condition with out success (Scheme III.19).
1. Tetra butyl ammonium bromide/BF3 :Etherate
2. SOCl2/pyridine
Scheme III.19
3. Dehydration of 9 and 13 using BF3.Etherate was also failed to give the desired
butenolide 171a (Scheme III.20).
Scheme III.20
III.3.4 Dehydroacetylation of Dialkyl (2S,3S)- and (2S,3R)- Tetrahydro-3- actyloxy-5-oxo-2,3- furandicarboxylate.
The tertiary hydroxyl group of dialkylesters of 1 and 2 was protected as acetyl group by the treatment of the compounds with acetyl chloride at room temperature. Even though esters are undergoing complete conversion but could not isolate the acetylated product since they are found to be unstable which results in the sudden decomposition to the dialkyl esters. Acetylated dimethyl and diethyl esters were found to be highly unstable, where as acetylated diisopropyl esters were obtained as stable (SchemeII.21) (Figure III. 27a-d, Figure 28a-d).
.
Scheme III.21
The dehydroacetylation of 177 using DBU was expected to give chiral butenolide 171c. However this reaction failed (Scheme III.22).
Scheme III.22
Figure III.27a
Figure III.27b
Figure III.27c
Figure III.27d
Figure III.28a
Figure III.28b
Figure III.28c
Figure III.28d
105
III.3.5 Phosphorous oxychloride (POCl3) in Functional Group Transformations Phosphorous oxychloride is known to be a strong Lewis acid which is widely
used in various functional group transformations in the broad area of organic
synthesis including Vilsmeier-Haack and Bischler-Napieralski reactions.194
III.3.5.1 Vilsmeier-Haack and Bischler-Napieralski Reactions
The reaction of POCl3 with substituted amides, most often N,N-dimethyl
formamide (DMF) or dimethylacetamide (DMA) lead to the formation of
chloromethyleneammonium salts (182). These salts are highly versatile
intermediates and are involved in reactions like Vilsmeier-Haack and
Bischler-Napieralski reactions (Scheme III.23).194
N
OPOCl3
R1
R2
R3
N
Cl
+R3
R2
R1PO2Cl2
-
181 182
Scheme III.23
The Vilsmeier reagent attacks electron-rich aromatic systems to form aryl
methleneiminium ions which liberate a formylated aromatic compound upon
hydrolysis. Substitution occurs at electron-rich positions. Many heterocycles
are also readily formylated by POCl3/DMF (Scheme III.24).
106
POCl3, DMFOMe OMe
CHO
86%
183 184
POCl3, DMF
75%N
N
CHO
H H185 186
Scheme III.24
A widely used method for cyclization of N-β-phenylethyl amides to form
dihydroisoquinolines and isoquinolines is the Bischler-Napieralski reaction. A
nitrilium ion intermediate has been implicated in this reaction (Scheme III.25).
POCl3
85%NH
O
MeO
MeO
OMe
NO2
MeCN
MeO
MeO N
MeO
NO2
187 188
Scheme III.25
Treatment of tertiary amides with POCl3/DMF results in the formation of
β-dimethylamino α,β-unsaturated amides (Scheme III.26).
107
189190
191
POCl3
N O
Cl
Et
DMF N
Cl
Et
NMe2
Cl
+
N
Et
O
Cl
55%
Scheme III.26
III.3.5.2 Beckmann rearrangement Treatment of ketoximes with POCl3 induces Beckmann rearrangement to
form amides (Scheme III.27).194
192193
POCl3
OH
OH
NOH OH
O
N
DMF
Scheme III.27
Phosphorous oxychloride and zinc (II) chloride are used as catalyst in
Freidel-Crafts reactions (Scheme III. 28).
108
194 195 196
POCl3, ZnCl2OH
COOH
+
OHOH
OH
O
O
OH
OH
60-700C, 2h
47%
Scheme III.28
III.3.5.3 Dehydrating Agent POCl3 is one of the most effective dehydrating agents used in organic
synthesis. The combination of POCl3 and DMF can be used to halogenate
primary, secondary and tertiary aliphatic alcohols (Scheme III. 29).194
POCl3, DMF
90%OH Cl
CHCl3
OOH
CHO OCl
CHO
POCl3, DMF
90%
197 198
199 200
Scheme III.29
Unsubstituted amides undergo dehydration upon treatment with POCl3
(Scheme III.30).
t-Bu
O NH2
t-Bu
CN
+ t-Bu CNPOCl3
201 202 203
Scheme III.30
109
The combination of POCl3 and pyridine is an effective dehydrating agent for
alcohols and cyanohydrins with antielimination (Scheme III.31).194
204205
POCl3, py
OOH
H H
H O
H H
H75%
Scheme III.31
Though optically pure isocitric acid (40) plays a significant role in various
important biological processes like cell respiration, no methods are available
in literature for the enantiopure synthesis of 40 till date. As already
discussed, it is the objective of the present study to dehydrate dialkyl esters
of 1 and 2 using POCl3 in pyridine to get chiral butenolide 171, which upon
simple Pd/C reduction is expected to give optically active Isocitric acids (40a
and 40b).
III.3.6 Dehydration of Dialkyl (2S,3S)- and (2S,3R)- tetrahydro-3- hydroxy-5-oxo-2,3-furandicarboxylate with POCl3.
9 and 13 was dissolved in pyridine and POCl3 was added drop wise at –10 0C and the reaction mixture was stirred at that temperature for two hours.
The reaction was quenched using dil. HCl and the TLC shows the presence
of a highly polar species. The reaction mixture was treated with
diazomethane under the assumption that the ester groups may hydrolyze
under work-up conditions.195 The product formed (206) was isolated using
column chromatography and fully characterized by IR, 1H and 13C NMR and
mass spectra. Unexpectedly the product obtained was the 4-Methoxy
dimethyl 2S-2(5H) furanone-4,5-dicarboxylate (206) which is the analogue of
110
the Quararibea metabolite, methyl ether of chiral enolic-γ-lactone 126b
(Scheme III.32). Formation of these unusual compounds was convincingly
confirmed by further spectral analysis.
OO HCOOR
MeO COOR
1.POCl3pyridine
CH2N2
ether2.
9. R' =-OH, R''=-COOR,R=-CH3
OO H
R'COOR
R''
13. R' =-COOR, R''=-OH,R=-CH3
10. R' =-OH, R''=-COOR,R=-CH2CH3
12. R' =-OH, R''=-COOR,R=-CH2C6H5
172. R' =-COOR, R''=-OH,R=-CH2CH3
174. R' =-COOR, R''=-OH,R=-CH2CH5
R = -CH3
R = -C2H5
R = -CH2C6H5
206.
207.
208.
Scheme III.32
IR spectrum of 2S-Dimethyl-4-methoxy-5-oxo-2,5-dihydro-2,3-furandicarbo-
xylate shows the absence of hydroxyl group and peak at 1750 cm-1 confirms
the presence of lactone moiety; 1H NMR shows the presence of three -OCH3
groups at δ 3.95, 3.89, 3.88 ppm. In 13C NMR signals at δ162.70, 163.30 and
158.37 ppm confirms the three carbonyl groups and signals at δ134 and 127
ppm shows the presence of olefinic carbons. In 13C NMR the signals at δ
84.80 indicates the presence of C2 carbon, signal at δ 58.80 shows the
presence of -OCH3 carbon and signals at δ 52.64 and 53.00 represent
methoxy carbons of the two ester groups(Fig III. 32a-d). In addition to these
DEPT clearly shows the absence of -CH2 and presence of three -CH3 and
one –CH( Figure III.29).
111
Figure III.29
The structure of the unusual product (206) obtained was further confirmed by
recording HMBC (Heteronuclear Multiple Bond Connectivity) spectrum which
further confirms the position of the olefinic bond at the C3-C4 position. The 1H-13C long range correlations observed are shown in figure (FigureIII.30a-c.)
112
Figure III.30a-c
113
The correlation diagram for 5a on the basis of HMBC spectrum can be drawn
as follows (Figure. III.31)
OO H
C OO C
H
H
H
C O
OC
H
H
H
OC
H
H H
3.88
3.953.89
162.3
158.37
163.3
5358.8
52.64
134 127
84.8
Figure III.31
To clearly understand the reaction pathway attempts were made to isolate
the intermediate of the reaction, however not successful as it is a highly polar
species. The reaction of 10 and 172 and 12 and 174 with POCl3 in pyridine at
00C resulted in corresponding 4-Methoxy dialkyl-2S-2(5H)-furanone-4,5-
dicarboxylates (207 and 208). IR, 1H and 13C NMR and mass spectra clearly
confirms the structures of 207 and 208 (Figure III.33a-d, Figure III.34a-d).
114
206
OO H
MeO
CO2CH3
CO2CH3
Figure III.32a
Figure III.32b
115
Figure III.32c
Figure III.32d
116
207CO2C2H5
OO H
MeO
CO2C2H5
Figure III.33a
Figure III.33b
117
Figure III.33c
Figure III.33d
118
208
CO2CH2C6H5
OO H
MeO
CO2CH2C6H5
Figure III.34a
Figure III.34b
119
Figure III.34c
Figure III.34d
120
III.3.7 Dehydration of Diisopropyl (2S, 3R)- tetrahydro-3-hydroxy-5-oxo-2,3-
furandicarboxylate with POCl3.
It is interesting to note that when the diisopropyl (2S,3S)- and (2S,3R)-
tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylates were treated with
POCl3 under the same conditions mentioned for the preparation of 206-208 no significant reaction was observed. But when the reaction was
carried out at room temperature following the usual work-up with dil.
Hydrochloric acid resulted in the isolation of normal dehydration product
(171c) (Scheme III.33).
OO H
R'COOCH(CH3)2
R''
OO HCOOCH(CH3)2
H COOCH(CH3)2
POCl3pyridine
171c11.R'= -OH, R''= -COOCH(CH3)2
173.R'= -COOCH(CH3)2 , R''= -OH
Scheme III.33
IR, 1H and 13C and mass spectra of 209 confirms the structure of the
product. A signal at δ 6.90 indicates the presence of –C=C-H, multiplet at
δ 4.9 0- 5.00 and at 5.10-5.20 are due to the presence of –CH protons of
the isopropyl ester group and multiplet at δ1.20-1.40 stands for methyl
protons of isopropyl ester groups. Signal at δ 4.0 is due to hydrogen on
C2 carbon atom. In the 13C spectrum signals at δ169.3, 165.5 and 164.9
121
are due to the three carbonyl carbons. Signals at δ140.0and 129.1
indicate the presence of two unsaturated carbons (Figure III.35a-d).
It has been seen that the behavior of POCl3 with dialkyl esters were unusual
and interesting. Depending upon the substitution at the alkyl group of the
carboxylic esters different products were formed.
122
OO HCO2CH(CH3)2
H CO2CH(CH3)2171c
Figure III.35a
Figure III.35b
123
Figure III.35c
Figure III.3d
124
III.3.8 Preparation of aromatic Dialkyl-5-[(methylsulfonyl)oxy]-2,3-furandicarboxylates
To have a clear understanding of the observation described for the formation of
206-208, the dehydration of 9 and 13 was effected using another known
dehydrating agent methanesufonyl chloride in triethylamine.196 9 and 13 was
dissolved in dry dichloromethane and 2 mL triethylamine and methanesulfonyl
chloride was added drop wise at 0 0C and the reaction mixture was stirred at
that temperature for two hours. The reaction was quenched using dil.HCl and
extracted in dichloromethane after brine wash. Interestingly, instead of
anticipated dehydration product (171), aromatic dimethyl-5-[(methylsulfonyl)
oxy]-2,3-furandicarboxylate (210) was obtained in quantitative yield. The
reaction was repeated with 11 and 173 resulted in the formation of diisopropyl-
5-[(methylsulfonyl)oxy] -2,3-furandicarboxylate (211) (Scheme III.34).
O COOR
COOR
OCH3SO2
MeSCl,TEA
209. R=-CH3
210. R=-CH(CH3)2
0oC,2hrs
9. R' =-OH, R''=-COOR,R=-CH3
OO H
R'COOR
R''
13. R' =-COOR, R''=-OH,R=-CH311. R' =-OH, R''=-COOR,R=-CH(CH3)2
173. R' =-COOR, R''=-OH,R=-CH(CH3)2
Scheme III.34
The formation of 209 and 210 was confirmed by IR, 1H and 13C NMR, and
mass spectra, for example: 209, the aromatic proton appears at δ 6.4ppm,
ester -CH3 at 5.20 and 5.30 ppm and the -CH3 of methylsulfonyl- at
3.37ppm. Signals at δ 161.0 and157.0ppm in the 13C NMR clearly shows the
presence of only two carbonyls (Figure III.36a-d, Figure III.37a-d).
125
OCH3SO2O COOCH3
COOCH3209
Figure III.36a
Figure III.36b
126
Figure III.36c
Figure III.36d
127
OCH3SO2O COOCH(CH3)2
COOCH(CH3)2210
Figure III.37a
Figure III.37b
128
Figure III.37c
Figure III.37d
129
In view of the formation of 209 and 210 under the condition for normal
dehydration using methanesulfonyl chloride in triethylamine, plausible
mechanism for the formation of 206-208 using POCl3 in pyridine can be
explained.
III.3.9 Plausible mechanism for the formation of Dimethyl 2S-3-methoxy- 2(5H) furanone-4,5-dicarboxylate (206):
Dehydration of 9 and 13 with Methane sulfonyl chloride in triethyl amine
resulted in the formation of aromatic 210 and 211. The structure of 210 and
211 indicates that enolisation of lactone carbonyl is taking place to 9 and 13 in presence of a base. In this view, initially enolisation of lactone carbonyl is
taking place in presence of pyridine (a base) leading to the formation an O-
substituted intermediate 206a. This undergoes a (2,3)-sigmatropic
rearrangement 197(via 5 membered transition state involving six electron
system) gives an α-substituted intermediate 206b. The nucleophilic attack of
C3-hydroxyl group at the phosphorous atom leads to the elimination of
chloride ion which resulted in the formation of a cyclic intermediate 206c.
During work-up using dil. HCl, water molecule attacks the cyclic intermediate
206c leading to the formation of 206d. Finally α-hydroxylated lactone 206e is
formed by the elimination of H3PO3 from 206d. Treatment of diazomethane in
ether with 206e resulted in the final product 206 (Scheme III.35). The (2,3)-
sigmatropic rearrangement is the key step involved in the α-hydroxylation of
9 and 13. This may be the first case where POCl3 is used for the α-
hydroxylation of γ-lactones(dialkyl tetrahydro-3-hydroxy-5-oxo-2,3-
furandicarboxylates).
130
PyridineOO H
OHCOOCH3
COOCH3
OO H
O O HPCl
COOCH3COOCH3
Cl
OO H
O OP
Cl
COOCH3COOCH3H O
H
OO H
OHO
P
H
OHOH
COOCH3
COOCH3
OO H
OH
COOCH3
COOCH3
CH2N2,OO H
MeO
COOCH3
COOCH3
OP
Cl
Cl O H
OH
O COOCH3
COOCH3
-HCl
-H3PO3
H3O+
POCl3
9
206
206a
206b
206c
206d
206e
ether
Scheme III.35: Plausible mechanism for the formation of Dimethyl-2S- 3- methoxy-2(5H)-furanone-4,5-dicarboxylate.
III.3.10 Plausible mechanism for the formation of Dimethy-5-[(methylsulfonyl)oxy] -2,3-furandicarboxylate(209)
On treatment of 9 and 13 with methanesulfonyl chloride in triethyl amine,
enolisation of lactone carbonyl is taking place and hence an O-substituted
intermediate 209a is formed. Since sulfur is reluctant to accommodate 2
electrons no intramolecular sigmatropic rearrangement is involved in the
formation of 209 as in the mechanism of formation of 206. Mesitylation of C3
hydroxyl group followed by elimination of one molecule of MSOH resulted in
the final aromatic product 209 (Scheme III.36).
131
OO H
OHCOOCH3
COOCH3
OH
O
OH
COOCH3
COOCH3
CH3SO2Cl,TEA
OH
OS
CH3O
O
O
COOCH3
COOCH3
SCH3
OO
OCH3SO2O COOCH3
COOCH3
SCH3
O
O
0OC
9 209a
209b
209
-CH3SO3H
Scheme III.36: Plausible mechanism for the formation of Dimethyl-5-[(methylsulfonyl)oxy] -2,3-furandicarboxylate
Though the enolisation of the lactone carbonyl of 9 or 13 is taking place with
both POCl3 and methanesulfonyl chloride; these acid chlorides reacted
differently with 9 and 13. The cyclic intermediate of the type 206c is not
formed in the case of 9 and 13 on reaction with methanesulfonyl chloride. A
(2,3)-sigmatropic rearrangement involved is the key step for the α-
hydroxylation of γ-butyrolactones (dialkyl tetrahydro-3-hydroxy-5-oxo-2,3-
furandicarboxylates). No α-hydroxylation is observed when POCl3 react with
diisopropyl (2S,3S)- and (2S,3R)- tetrahydro-3-hydroxy-5-oxo-2,3-
furandicarboxylates. The bulkiness of the isopropyl group may be the
132
contributing factor for this observation. Reaction of Dialkyl (2S,3S)- and
(2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylates with methane-
sulfonyl chloride in triethyl amine resulted in the formation of aromatic
compounds irrespective of the bulkiness of the alkyl substituent of C2 and C3
carboxylic group.
III.3.11 Applications of 2S- Dimethyl 4-methoxy- 5- oxo - 2, 5- dihydro- 2,3- furan-dicarboxylate (206)
206 is a potential precursor for the synthesis of 126b, 98 and 212 (Scheme
III.37).
OO H
MeO
COOCH3
COOCH3
OO H( )n
OO H
MeO
CH3
CH3
OO H
MeO
COOCH3HCOOCH3
126b
98
211
206
Scheme III.37
III.3.12 Attempted reactions of 2S-Dialkyl-4-methoxy-5-oxo-2,5-dihydro-2,3- furan dicarboxylate
As discussed earlier butenolides are susceptible to Michael type reactions.
Michael addition of benzyl amine with 207 was carried out expecting the
formation of 3-alkylamine substituted lactone 212. 207 was dissolved in
toluene and benzyl amine was added and refluxed the reaction mixture for 4
133
hours with Dean and Stark apparatus, resulted in the formation of substituted
benzyl amide 213 instead of the expected 212 (Scheme III.38).
OO H
COOCH2CH3MeO
COOCH2CH3
OO H
COOCH2CH3MeO
COOCH2CH3
PhCH2NH
OO H
COOCH2CH3MeO
COCONHCH2Ph
212
213
207
Scheme III.38
Butenolides can be used as good dienophiles in Diels-Alder reactions with
cyclopentadiene to generate polyfunctional norbornene derivatives. In this
view Diels-Alder reaction of 206 was carried out with cyclopentadiene
expecting the formation of 215. 206 was dissolved in dry CH2Cl2 and freshly
distilled cyclopentadiene is added drop wise and stirred for 2 hours at room
temperature. TLC showed complete conversion of starting material but the
product formed was not stable and it decomposed back to the starting
material (Scheme III.39).
134
OO H
MeO
COOCH3
COOCH3
+ O
O
HH3COOCH3COOC
MeO
215
206
214
Scheme III.39
III.3.13 Chemoselective Reduction of C2 and C3 Carboxylic Group of 1
Appropriate borane reagents were effectively used for the selective reduction
of carboxylates especially in the case of molecules containing other
functionally identical groups. The preferences for borane reagents like BH3
THF, BH3.SMe2 towards reducing -COOH groups in presence of lactone
carbonyl are well known.
Attempts were made to synthesize 216 from 1. With this objective, reduction
of C2 and C3-COOH of 1 has been attempted using BH3 THF, BH3SMe2, BH3.
THF/Trimethyl Borate and NaBH4/ I2 (Scheme III.40).
OO HCOOH
OHCOOH
OO H OH
OHOH1
216 Scheme III.40
135
217 could be a potential chiral precursor for the syntheses of various natural
products and catalysts (Scheme III.41).
OO H OH
OHOH
216
OO H
OO H OH
O
OO H OH
OH
OO H
O
O
Ti
Cl
Cl
OH
CH3
H
()3
98
217
218
219
220
Scheme III.41
However repeated attempts for the reduction of 1 with the borane reagents
listed above failed to give any desired products. This can be attributed on the
basis of an earlier observation that insoluble polymeric intermediates are
formed during the reaction, which may hinder the completion of the reduction
reactions. The laxity of the reaction could also be due to the formation of
stable acyloxy borane complex (221) (Scheme III.42).
1
OO HCOOH
O
O BO H
OO HCOOH
OHCOOH
BH3
221
Scheme III.42
136
Trimethyl borane is known to facilitate the dissolution of polymers formed
during the reaction using BH3. The alternative procedure developed by
Periasamy et al. by using NaBH4 /I2 was also tried without success.
III.3.14 Efficient Site Selective Reduction Employing BH3SMe2 and Catalytic NaBH4
Saito, S. et al., succeeded in reducing selectively the ester group located
α-to the hydroxyl group in hydroxy esters in presence of another ester group,
using borane-dimethyl sulphide complex and catalytic amount of sodium
borohydride198,199(Scheme III.43).
CO2EtOH
OHEtO2C
OH OH+BH3SMe2 /THF
NaBH4(5 mol %)CO2Et
EtO2C
OH
222 223 224
Scheme III.43
The advantage of this chemoselective reduction had been effectively tried to
reduce C3 COOR group in the case of 9 (Scheme III.44).
OO H
OHCOOCH3
COOCH3
OO H
OHOH
COOCH3BH3SMe2 /THFNaBH4(5 mol %)
9 225
Scheme III.44
With this background attempts were made to reduce triisopropyl ester 19
using borane-dimethyl sulphide complex and catalytic amount of sodium
borohydride expecting the formation of 226 where the selective reduction of
ester groups occurs at C1 and C2 positions of 19. Upon treatment with
PTSA, 226 can undergo cyclization. There are two possible ways of
137
cyclization due to the presence of two –OH group in the γ-position to the
ester group leading to the formation of 216 and 227. The molecule 227 is
also a potential chiral synthon, which can also be effectively used for the
synthesis of several naturally occurring molecules (Scheme III.45).
HOH
OH
COOCH(CH3)2
COOCH(CH3)2
COOCH(CH3)2
19
HOH
OH
CH2OH
CH2OH
COOCH(CH3)2
BH3SMe2. Dry THF
NaBH4
OO
OH
OH
H
OH
OO
OH
OH OHH
PTSA
+
226
216227
Scheme III.45
The selective reduction of 19 was carried out using borane-dimethyl sulphide
complex and catalytic amount of sodium borohydride, expecting the
formation of 226. This has been done by dissolving 19 in dry THF and one
equivalent of borane dimethyl sulphide was added drop wise to the stirred
solution at 25 0C to form the oxyborane intermediate. After one hour 5 mol%
of sodium borohydride was thrown into the reaction mixture and stirring was
continued for two hours. The reaction was quenched using dry methanol and
evaporated to get a colourless oil in quantitative yield. The reaction mixture
has been acetylated to avoid the problem during the isolation of hydroxyl
138
compounds. Acetyl chloride was added drop wise to the reaction mixture
under stirring for overnight. It is clear from the physical data that only two
hydroxyl groups were protected and the product obtained is 230 instead of
expected 228, where cyclization occurs prior to the selective reduction
(Scheme III. 46).
HOH
OH
COOCH(CH3)2
COOCH(CH3)2
COOCH(CH3)2
HOH
OH
CH2OH
CH2OH
COOCH(CH3)2)
BH3SMe2. Dry THF
NaBH4
226
HCOCH3O
COCH3O
CH2OCOCH3
CH2OCOCH3
COOCH(CH3)2
CH3COCl
22819
OO H
OH
COOCH(CH3)2
OH
OO H
OCOCH3
COOCH(CH3)2
OCOCH3229
230
CH3COCl
BH3SMe2. Dry THFNaBH4
Scheme III.46
1H NMR clearly shows the presence of two –COCH3 groups at δ 2.05 and
2.08, one –OCH group at δ 5.11, one –CH2 at 2.90-3.00 and two –CH3 at
1.26 ppm. 13C shows the presence of four carbonyls at δ172.3,169.8,169.6
and166.0 (Figure III. 38a-d).
139
OO H
OCOCH3
COOCH(CH3)2
OCOCH3230
Figure III.38a
Figure III.38b
140
Figure III.38c
Figure III.38d
141
III.4 GENERAL EXPERIMENTAL DETAILS
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 D. D. Perrin and W. L. F. Armarego (3rd edition,
Pergamon Press, 1988). Dry THF was distilled from sodium benzophenone
ketyl just before use. Dried fruit rind of Garcinia cambogia was procured
from a local plantation. Leaves or calyxes of Hibiscus sabdariffa 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 determined on ‘’Sunbim’’ make electrically heated
melting point apparatus and are uncorrected. IR spectra were recorded using
a Shimadzu IR 470 spectrophotometer as KBr pellets (solids) or thin films
(liquids). 1H-NMR spectra were recorded on a Brucker W M 300 MHz or
Brucker 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 tetramethylsilane as internal standard (0.00 ppm). 13C NMR were
recorded on a Brucker WM 300 (75.5 MHz) or jeol GSX 400 (100.6 MHz) or
Brucker AMX 400 (100.6MHz) NMR 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 NMR system. Electron
impact mass spectra were recorded on a Finnigan MAT MS 8230 or jeol D-
300. Specific rotations were recorded using Jasco D I P 370 or Jasco DIP
1000 digital polarimeter. Elemental analyses were carried out on a Carlo-
Erba CHNS-O-EA 1108 elemental analyzer.
142
III.5 EXPERIMENTAL III.5.1 (2S,3S)-Tetrahydro-3hydroxy-5-oxo-2, 3-furandicarboxylic acid (1)
Dried rinds of the fruits of Garcinia cambogia (1 Kg) were cut into
small pieces and soaked in hot water (IL). The extract was collected after 20
hours and the process was repeated 4-5 times. The combined extract was
concentrated and methanol (2.5L) was added to precipitate pectin. Upon
filtration the filtrate was concentrated to a syrup. It 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 (5x100ml).
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 : 67.5g (6.75% to the dry wt of fruit rinds)
Melting point : 178° C. Reported: 178° C
25D][α : +102.15° (c 1.0,H2O) Reported: +100°
IR (KBr) : ν max 3400 (OH, broad), 1790 (γ-lactone) and 1741cm-1 (carbonyl)
1H NMR (DMSO-d6) : δ 4.80 (s, IH), 3.07 (d,.J = 17.4Hz,IH),
2.60 (d,J =17.4 Hz, IH) ppm
13C NMR(DMSO-d6) : δ 174.9, 171.9, 169.2, 84.8, 79.0, 39.7 ppm.
Mass spectrum (E.I) : m/z 191 (M+1) (2), 173 (1), 162 (6), 145 (35), 127 (10), 116 (48), 99 (70), 88(100), 60 (40) and 55 (20)
143
Molecular formula : C6H6O7
Elemental analysis
Found : C 37.23, H 2.73
Calculated : C 37.91, H 2.18
III.5.2 (2S, 3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (2)
Fresh calyxes or leaves (1 Kg) of Hibiscus sabdariffa or leaves of Hibiscus
furcatus were soaked in water (1 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 concentration
followed by the addition of acetone precipitated the impurities. The residue
obtained after concentration was further extracted with ether which on
concentration yielded 10 g of 2 when leaves of Hibiscus furcatus or 16 g of 2
when fresh calyxes (1Kg) of Hibiscus sabdariffa were used.
Melting point : 180°C Reported : 182-183°C (decomp)
25D][α : +111° (c 1.0, H2O) Reported : +110°
IR (KBr) : νmax 3400 (OH, broad), 1790 (γ-lactone) and 1735 cm-1 (carbonyl)
1H NMR (acetone-d6) : δ 5.3 6 (s, 1H), 3.3 (d, J =17.09 IH), 2.8(d, .J
=17.09Hz, 1H), ppm
13C NMR (DMSO-d6) : δ 173.2, 172.3, 167.1, 82.9, 78.4, 42.2 ppm
Mass spectrum (E.I) : m/z191 (M+1) (2), 172 (1), 162 (5), 145 (60), 127 (12), 116 (38), 99 (84), 88(100), 60 (48) and 55 (28)
Molecular formula : C6H6O7
144
Elemental analysis
Found : C 37.23, H 2.73
Calculated : C 37.91, H 3.18
III.5.3 Disodium (2S, 3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (5)
To an aqueous solution of 1 (2.0 g, 10.5 mmol, in 10 ml of water), saturated
aqueous sodium bicarbonate was added till the pH of the reaction mixture
became neutral (ca 15 ml). The residue obtained after evaporation of the
reaction mixture under reduced pressure, was triturated and washed with dry
methanol followed by acetone (5 X 20 ml). The product 5 was finally dried
under vacuum to give a colourless solid.
Yield : 2.0 g (82%)
25D][α : +81.8° (c 1.63, H2O)
IR (KBr) : ν max 3400, 1800, 1600 cm-1
1H NMR (D2O) : 4.84(s, 1H); 3.19(d, 1H), 2.83(d, 1H), 2.27 (s,
1H)
13C NMR (D2O) : 179.4, 177.4, 174.69, 89.1, 81.5, 42.7 ppm;
Mass spectrum (E.I) : 257(M+ 23, 100), 240(58), 195(35.5), 155(20.9)
Molecular formula : C6H4O7Na2
Elemental analysis
Found : C, 30.68, H, 1.70
Calculated : C, 30.76, H, 1.71
145
III.5.4 Dimethyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylate (9)
A solution of 1 (1.0gm, 5mmol) in ether (25ml) was treated with excess
diazomethane in ether. The reaction mixture upon concentration gave diester
9 as yellow oil.
Yield : 1.1 gm (100%)
25D][α : +65.32.° (c 0.32,CHCl3)
IR (film) : νmax 3450, 1795, 1740 cm-1
1H NMR (CDCl3) : δ 4.96(s,1H), 3.82(s,3H), 3.78 (s,3H),
3.20 (d,J =19.0Hz, 1H), 2.82(d, J =
19.0Hz,1H)ppm
13CNMR (CDCl3) : δ 172.5,170.2,166.9,84.2, 79.2, 53.7, 52.9,
39.7ppm
Mass spectrum (E.I) : m/z 219(M+1) (1), 191 (3), 159(26), 141(6),
131(25), 99(100), 59(93)
III.5.5 Diethyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (10)
To a precooled (-5-00C) suspension of 5 (1.0 g, 4.4 mmol) in dry ethanol (10
ml), thionyl chloride (0.7 ml, 10 mmol) was added. The mixture was then
stirred for 48 h at room temperature. After filtration of the reaction mixture, pH
of the filtrate was adjusted to 7.0, by adding saturated aqueous sodium
bicarbonate and was extracted with chloroform (3X10ml). The combined
extract upon drying and evaporation gave the compound (no) as a pale
yellow liquid.
146
Yield : 0.9 g (77%)
25D][α : -81.0° (c 1.0, CHCl3)
IR (liquid film) : ν max 3500, 2990,1800,1740 cm-1
1H NMR (CDCl3) : 4.90(s, 1H), 4.30(m, 4H), 3.10(d, 1H), 2.8(d, 1H),
1.18-1.32 (m, 6H)
13C NMR (CDCl3) : 172.0, 170.5, 170.0, 84.0, 75.0, 62.5, 62.0, 40.0,
15.2, 15.0 ppm;
Mass spectrum (E.I) : 246(M+ 1, 5.5), 218(29.8), 200(5.96), 188(41.7),
172(99.8), 156(17.9), 144(87.9), 127(5.9),
114(67.05), 104(90.9), 99(95.4), 88(20.8), 76(70),
59(5.9), 42(65.6%)
Molecular formula : C10H14O7
Elemental analysis
Found : C, 48.74, H, 5.69
Calculated : C, 48.98, H, 5.71
III.5.6 Diisopropyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (11)
The procedure adopted for 10 was followed with 5 (1.0 g, 4.4 mmol),
isopropyl alcohol (10 ml) and thionyl chloride (0.7 ml, 10 mmol). After work-
up, gave 11 as yellow oil.
Yield : 0.5 g (41%)
25D][α : +32.0° (c 1.0, CHCl3)
IR (liquid film) : ν max 3500, 2980 ,1800,1740 cm-1
147
1H NMR (CDCl3) : 5.10-5.18(m, 1H), 3.96(s, 1H), 2.98(d, 1H),
2.93(d, 1H), 1.18-1.32 (m, 6H)
13C NMR (CDCl3) : 171.5, 170.1, 169.2, 83.9, 74.6, 71.7, 69.8, 40.0,
21.6, 21.5 ppm
Mass spectrum (E.I) : 274(M+, 7.4), 246(60.3), 232(34.2), 216(21.8),
204(37.1), 190(15.8), 174(23), 162(52.3),
144(58.7), 1 32(43.6), 117(12), 98(15), 76(52),
42(100%)
Molecular formula : C12H18O7
Elemental analysis
Found : C, 52.32, H, 6.59
Calculated : C, 52.55, H, 6.57
III.5.7 Dibenzyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (12) To a suspension of 1 (4.0 g, 20.8 mmol) in dry benzyl alcohol (6.4 ml), p-
toluene sulphonic acid monohydrate (50.0 g, 0.26 mmol) and toluene (42.4
ml) were added. The mixture was then refluxed for 13 h at about 1300C. The
mixture was allowed to cool, diluted with chloroform and poured into
saturated aqueous sodium bicarbonate. The organic layer was separated
and the aqueous layer was extracted with chloroform. The combined organic
phase upon drying, evaporation and recrystallisation from chloroform-hexane
gave 12 as colourless crystals.
Yield : 7.0 g (90%)
Mp : 81-830C
25D][α : +34.7° (c 1.0, CHCl3)
148
IR (KBr) : ν max 3500, 3100 ,1820,1700 cm-1
1H NMR (CDCl3) : 7.25-7.34(m, 10H), 5.09-4.92(m, 4H), 4.87(s, 1H),
3.07(d, 1H, J=13.5 Hz), 2.80(d, 1H, 13.5 Hz)
13C NMR (CDCl3) : 171.8, 170.0, 166.2, 134.3, 133.8, 129.1, 128.8,
128.7, 128.6, 84.1, 78.9, 69.0, 67.9, 39.7 ppm;
Mass spectrum (E.I) : m/z 370(M+ 7.0), 280(6.6), 251(3.9), 180(9.4),
107(86.4), 91(100), 65(20.8), 43(4.4%)
Molecular formula : C20H18O7
Elemental analysis
Found : C, 64.55, H, 4.87
Calculated : C, 64.86, H, 4.89.
III.5.8 Disodium (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (6) To an aqueous solution of 2 (2.0 g, 10.5 mmol, in 10 ml of water), saturated
aqueous sodium bicarbonate was added till the pH of the reaction mixture
became neutral (ca 15 ml). The residue obtained after evaporation of the
reaction mixture under reduced pressure, was triturated and washed with dry
methanol followed by acetone (5 X 20 ml). The product 6 was finally dried
under vacuum to give a colourless solid.
Yield : 2g (82%) 25D][α : +56.5o (c 1.02, H2O)
IR (KBr) : ν max 3400, 1800, 1600 cm-1
1H NMR (D2O) : 5.17(s, 1H), 3.21(d, 1H, J=17.8 Hz), 2.24(d, 1H,
J=17.8
Hz), 2.27 (s, 1H) 13C NMR (D2O) : 179.9, 178.1, 173.9, 88.5, 80.5, 43.7 ppm;
149
Mass spectrum (E.I) : m/z 257(M+ 23, 100), 238(41.23), 195(43.59),
168(39.9),142.1(15.96%)
Molecular formula : C6H4O7Na2
Elemental analysis
Found : C, 30.68, H, 1.70
Calculated : C, 30.76, H, 1.
III.5.9 Dimethyl (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylate (13) A solution of 2 (1.0 gm, 5.25 mmol) in 25 ml ether was treated with excess
diazomethane in ether. The reaction mixture on concentration gave 13
colourless crystals of diester.
Yield : 1.13gm (98%)
Melting point : 128°C
25D][α : +116o (c 0.4952,CHCl3)
IR (KBr) : νmax 3500, 1795, 1745cm-1
1H NMR (CDCl3) : δ 5.31(s,1H), 3.95(s,3H), 3.84 (s,3H),
3.1 (d, J=20.3Hz, 1H), 2.87 (d, J=20.3Hz, 1H)
ppm
13C NMR (DMSOd6) : δ 172.74, 170.80, 166.14, 81.96, 77.90, 53.12,
53.03, 40.14ppm
Mass spectrum (E.I) : m/z 219(M+1) (66), 191 (2), 159(100), 141(10),
130(38), 99(100), 74(25%).
III.5.10 Diethyl (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (172) To a precooled (-5-00C) suspension of 6 (1.0 g, 4.4 mmol) in dry ethanol (10
ml), thionyl chloride (0.7 ml, 10 mmol) was added. The mixture was then
150
stirred for 48 h at room temperature. After filtration of the reaction mixture, pH
of the filtrate was adjusted to 7.0, by adding saturated aqueous sodium
bicarbonate and was extracted with chloroform (3X10ml). The combined
extract upon drying and evaporation gave the compound 172 as a pale
yellow liquid.
Yield : 0.8g (68%)
25D][α : +51.4o (c 1.0, CHCl3)
IR (liquid film) : ν max 3500, 2990,1800,1740 cm-1
1H NMR (CDCl3) : 5.10(s, 1H), 4.20(m, 4H), 3.90(d, 1H, J=19.6 Hz),
2.10(d, 1H, J=19.6 Hz), 1.18-1.32 (m, 6H)
13C NMR (CHCl3) : 173.0, 170.5, 170.0, 82.0, 74.0, 62.5, 62.0, 44.0,
15.0 ppm;
Mass spectrum (E.I) : 246(M+ 1, 5.5), 218(30.80),188(27.9), 144(100),
114(27.9), 103(28), 98(57.3), 82(52.9), 75(55.8),
57(5.88), 46(26.4), 42(44.1%)
Molecular formula : C10H14O7
Elemental analysis
Found : C, 48.74, H, 5.69
Calculated : C, 48.98, H, 5.71
III.5.11 Diisopropyl (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (173) The procedure adopted for 172 was followed with 6 (1.0 g, 4.4 mmol),
isopropyl alcohol (10 ml) and thionyl chloride (0.7 ml, 10 mmol). After work-
up, gave 173 as yellow oil.
151
Yield : 0.5g (41%)
25D][α : +41.2(c 1.0, CHCl3)
IR (liquid film) : ν max 3500, 1800,1740 cm-1
1H NMR (CDCl3) : 5.10(m, 1H),4.90(m, 1H), 4.27(s, 1H), 3.10(d,
1H, J=17.3 Hz), 2.80(d, 1H, J=17.3 Hz),
1.10-1.30 (m, 12H)
13C NMR (CDCl3) : 171.7, 170.21, 169.5, 82, 74.6, 70, 68.4, 40.6,
21.5, 20.6 ppm
Mass spectrum (E.I) : 274(M+,2.9), 246(5.9), 232(4.9), 216(5.9),
204(13.4),
190(11.9), 174(20.8), 162(35.8), 144(52.2),
132(47.7),
117(10.4), 98(14.9), 86(4.4), 76(41.7), 42(100%)
Molecular formula : C12H18O7
Elemental analysis
Found : C, 52.32, H, 6.59
Calculated : C, 52.55, H, 6.57
III.5.12 Dibenzyl (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3- furandicarboxylate (14) To a suspension of 1 (4.0 g, 20.8 mmol) in dry benzyl alcohol (6.4 ml),
p-toluene sulphonic acid monohydrate (50.0 g, 0.26 mmol) and toluene (42.4
ml) were added. The mixture was then refluxed for 13 h at about 1300C. The
mixture was allowed to cool, diluted with chloroform and poured into
saturated aqueous sodium bicarbonate. The organic layer was separated
and the aqueous layer was extracted with chloroform. The combined organic
152
phase upon drying, evaporation and recrystallisation from chloroform-hexane
gave 174 as colourless crystals.
Yield : 7.5g (90.9%)
Mp : 900C
25D][α : +26.9 o(c 1.0, CHCl3)
IR (KBr) : ν max 3495, 3100 ,1820,1790, 1750 cm-1
1H NMR (CDCl3) : 7.26-7.38(m, 10H), 5.17-5.35(m, 4H),5.10(s, 1H),
3.03(d, 1H, J=7.47 Hz), 2.83(d, 1H, J=7.47 Hz)
13C NMR (CHCl3) : 171.3, 170.8, 165.2, 134.6, 133.9, 129.2, 128.9,
128.8, 128.7, 85.6, 81.9, 69.5, 67.9, 40.3 ppm;
Mass spectrum (E.I): m/z 370(M+ .4), 268(0.7), 278(10.3), 179(9.7),
145(2.5), 107(78.52), 91(100), 77(11.1),
65(34.07), 51(5.93), 40(7.41%)
Molecular formula : C20H18O7
Elemental analysis
Found : C, 64.55, H, 4.87
Calculated : C, 64.86, H, 4.89.
III.5.13 Diisopropyl (2S,3S)-tetrahydro-3-acetyloxy-3-acetyloxy-5-oxo-2,3-furandicarboxylate (178)
,
Acetyl chloride (4 equ.) was added drop wise to the diester 11
(3.5 mmol) under stirring and the stirring was continued for 12 hours. The
reaction mixture was concentrated under vacuum. 178 obtained as a white solid
153
Yield : 1.036g (85%)
MP : 78 0C
25D][α : +99.85° (c 0.12, CHCl3)
IR (liquid film) : ν max 2989,2939,1800,1755, 1469, 1010, 979, 864
cm-1
1H NMR (CDCl3) : 4.9(m,2H), 3.42-3.55(d, 1H, J=18.44 Hz), 2.82-
2.92(d,1H,J=18.43Hz),2.07(s,3H),1.12-1.259
(m,12H)
13C NMR (CDCl3) : 172, 169.4, 165, 164.7, 83.7, 81, 71.1, 36, 30.7,
21.3, 20.5 ppm
Mass spectrum : 317(M+1)
Molecular formula : C15H22O8
Elemental analysis
Found : C, 53.60, H, 6.11
Calculated : C, 54.55, H, 7.00
III.5.14 Diisopropyl (2S,3R)-tetrahydro-3-acetyloxy-5-oxo-2,3-furandicarboxylate (180)
Acetyl chloride (4 equ.) was added dropwise to the diester 173
(3.5 mmol) under stirring and the stirring was continued for 12 hours. The
reaction mixture was concentrated under vacuum. 180 obtained as colourless
liquid.
Yield : 0.99g (82%)
25D][α : +51.5° (c 0.1, CHCl3)
154
IR (liquid film) : ν max 2989,2939,1800,1755, 1469, 1010, 979, 864
cm-1
1H NMR (CDCl3) : 5.2(m,2H), 5(s, 1H), 3.35-3.6(d, 1H, J=18.13 Hz), 3-
3.2(d, 1H, J=18.13 Hz), 2.58(s,3H), 1.1-1.5(m,12H)
13C NMR (CDCl3) : 171.1, 169, 166.4, 164.7, 80.5, 79.2, 71.3, 40.4, 37,
21.4, 21.2 ppm
Mass spectrum : 317(M+1)
Molecular formula : C15H22O8
Elemental analysis
Found : C, 53.22, 6.09.
Calculated : C, 54.55, H, 7.00
III.5.15 Dimethyl 3-methoxy 2(5H) furanone 4, 5 dicarboxylate (206)
To a solution of 13 or 9 (1g, 4 mmol) in pyridine, POCl3 (4 mmol) was
added at 0oC and stirred for two hours. The reaction mixture was quenched
with 2N hydrochloric acid, extracted with CHCl3 and concentrated. The oil
residue obtained was dissolved in methanol, followed by the addition of
diazomethane in ether. After completion of the reaction (monitored by TLC),
excess diazomethane was removed and concentrated. The residue obtained
was purified by column chromatography (silica gel, hexane – chloroform 8:2).
Yield : 0.4gm (40 %),
Melting point : 71oC
25D][α : -31° (c 1.0, CHCl3)
IR (KBr) : ν max 2970, 1750, 1730, 1420 cm-1
155
UV(CHCl3) λmax : 295nm
1H NMR (CDCl3) : δ 5.60 (s, 1H); 3.95 (s, 3H), 3.89 (s,3H), 3.88
(s,3H) ppm
13C NMR (CDCl3) : δ 162.7, 161.9, 157.7, 133.4, 126.7, 84.4,
58.9, 52.4, 52 ppm
Mass spectrum (E.I) : m/z 230(M+1, 7.1), 217(2.5), 216(13.6),
215(100), 185(3.4), 184(26), 172(21.7),
156(15.1), 141(4.1), 127(8.7%).
Molecular formula : C9H10O7
Elemental analysis
Found : C, 47.01, H, 4.37
Calculated : C, 46.99, H, 4.38
III.5.16 Diethyl 3-methoxy 2(5H) furanone 4, 5 dicarboxylate (207)
The procedure adopted for 206 was followed using 10 or 172. After work-up
the product was isolated as pale yellow oil.
Yield : 0.5g (59%)
25D][α : -14° (c 1.0,CHCl3)
IR (liquid film) : ν max 2990, 1750, 1420 cm-1
1H NMR (CDCl3) : 5.60(s, 1H);4.30(m, 4H), 3.90(s, 3H), 1.50(m,6H)
13C NMR (CDCl3) : 170, 162, 158, 135, 126, 84, 62, 61. 2, 59, 42,
25,15 ppm;
156
Mass spectrum (E.I) : 258(M+, 10.6), 244(20.7), 243(69.6), 214(14.4),
200(23.4), 198(43.5), 186(25), 172(27),
171(100), 169(73.9), 158(34), 144(49.9),
127(32.3), 126(52%).
Molecular formula : C11H14O7
Elemental analysis
Found : C, 51.05, H, 5.32
Calculated : C, 51.17, H, 5.46
III.5.17 Dibenzyl 3-methoxy 2-(5H) furanone 4, 5-dicarboxylate (208)
The procedure adopted for 206 was followed with 12 or 174. After work-up
the product was isolated as pale yellow oil.
Yield : 0.4g(38.5%) 25D][α : -11(0.1o/o, CHCl3);
IR (liquid film ) : ν max 2970,1740,1718,1558,1123, 752, 697 cm-1
1H NMR (CDCl3) : δ 7.30(m, 5H), 5.60(s, 1H), 5.30(q, 2H), 3.90(s,
3H) ppm
13C NMR (CDCl3) : δ 162.2, 162, 157, 135, 128,126, 84.5, 67.2,
66.6, 58.2ppm
Mass spectrum (E.I) : m/z 382 (M+, 3), 366(72.8), 260(12.8), 232(31.5),
214(12.5), 169(49.5), 91(100), 65(20.5%).
Molecular formula : C21H18O7
Elemental analysis
Found : C, 65.13, H, 4.17
Calculated : C, 65.97, H, 4.74
157
III.5.18 Diisopropyl 3-methoxy- 2-(5H) furanone 4, 5- dicarboxylate (171C)
To a solution of 11 or 173 (4 mmol), in pyridine, POCl3 (4 mmol) was added
at 25o C and stirred for two hours. The reaction mixture was quenched with
2N hydrochloric acid, extracted with CHCl3 and concentrated. The residue
obtained was purified by column chromatography (silica gel, hexane –
chloroform 8:2).
Yield : 0.45g (53%)
25D][α : -14° (c 1.0,CHCl3)
IR (liquid film) : ν max 2990, 1750, 1420 cm-1
1H NMR (CDCl3) : 6.90(s, 1H), 5.10(m, 1H), 5.00 (m, 1H), 3.90(s,
1H), 1.50(m, 12H)
13C NMR (CDCl3) : 169.3, 165.5, 164.9, 140, 129.7, 69.4, 68.3, 33,
21.6 ppm;
Mass spectrum (E.I) : 256(M+, 10.6), 244(20.7), 243(69.6), 214(14.4),
200(23.4), 198(43.5), 186(25), 172(27),
171(100), 169(73.9), 158(34), 144(49.9),
127(32.3), 126(52%).
Molecular formula : C12H16O6
Elemental analysis
Found : C, 56.15, H, 6.18
Calculated : C, 56.25, H, 6.29
158
III.5.19 Dimethyl 5-[(methylsulfonyl) oxy] -2,3-furandicarboxylate(209):
To a solution of 9 or 13 (4 mmol), triethyl amine (2ml) in 20 ml
dichloromethane, methanesulfonyl chloride (4 mmol) was added at 0oC and
stirred for two hours. The reaction mixture was quenched with 2N
hydrochloric acid followed by brine wash and extracted with CHCl3. The
residue obtained after concentration was purified by column chromatography
(silica gel, hexane –chloroform 8.5:1.5).
Yield : 0.779g (70%)
IR (liquid film) : ν max 2956, 1733, 1548, 1442, 1386, 1278,
1185, 1065cm-1
UV(CHCl3) λmax : 242nm
1H NMR (CDCl3) : 6.40(s,1H), 3.93(s, 3H), 3.90(s,3H), 3.40(s,3H)
13C NMR (CDCl3) : 161.4, 157.1, 149, 137.9,125.2,81.6, 52.59,
52.56, 39.07 ppm
Mass spectrum (HRMS),
Calculated : 278.1570(M+),
Observed : 278.0037(M+),
III.5.20 Diisopropyl 5-[(methylsulfonyl) oxy] -2,3-furandicarboxylate (210) : To a solution of 11 or 173 (3.64 mmol,), triethyl amine (2ml) in 20 ml
dichloromethane, methanesulfonyl chloride (4 mmol) was added at 0oC and
stirred for two hours. The reaction mixture was quenched with 2N
hydrochloric acid followed by brine wash and extracted with CHCl3. The
residue obtained after concentration was purified by column chromatography
(silica gel, hexane –chloroform 8.5:1.5).
159
Yield : 1.015 g (76%)
IR (liquid film) : ν max 2981, 1735, 1373, 1180, 1103, 1080,
800cm-1;
UV(CHCl3) λmax : 243nm
1H NMR (CDCl3) : 6.87(s,1H), 5.10-4.90(m,2H), 3.90(s,3H), 1.22-
132(m,6H);
13C NMR (CDCl3) : 169.4,165.5,164.9,140.2,129,17,128.7,69.4,
68.5, 33.4,21.7 ppm
Mass spectrum (FAB) : m/z 334 (M+).
III.5.21 Isopropyl (2S,3R)-terahydro-3-acetyloxy-3-acetyloxymethyl-5-oxo-furan-2-carboxylate (230)
To a solution of 19 (4 mmol) in dry tetrahydrofuran, borane dimethyl sulphide
(1.03 equ.) was added drop wise at 20oC under stirring during 10 minutes.
The solution was stirred at that temperature until evolution of hydrogen
ceased. Then the flask was cooled with a water-ice bath (10oC) and stirring
was continued for 10minutes. To the solution was added NaBH4 powder
(5 mol%) in one portion under vigorous stirring at that temperature. After
10minutes, the water bath was removed and the reaction was continued at
room temperature until the disappearance (TLC monitoring) of the starting
molecule. The reaction was quenched using MeOH (3ml) and was stirred for
30min. at room temperature and concentrated to give a clear colourless gum.
This was dissolved in MeOH and again evaporated and this operation was
repeated to eliminate B(OMe)3 as thoroughly as possible. Acetyl chloride
(4 equ.) was added dropwise to the concentrate under stirring and the stirring
was continued for 12 hours. The reaction mixture was concentrated under
vacuum.
160
Yield : 0.589g (65%)
25D][α : +26 (c 1.0, CHCl3)
IR (liquid film) : ν max3494, 3009, 2969, 1780, 1748, 1452,
1128, 1081, 1013 cm-1
1H NMR (CDCl3) : 5.21(s,1H), 5.09(m, 1H), 4.50(s,2H), 2.902-
3.02(dd,2H), 2.12(s,3H), 2.08(s,3H),
1.31(s,6H)
13C NMR (CDCl3) : 172.3, 169.8,169.6, 166.0, 84, 80, 71.1, 69, 37,
21.5, 21.4, 20.3 ppm
Mass spectrum(LCMS) : 303(M+)
Top Related