DIPARTIMENTO DI FARMACIA
Corso di Laurea Magistrale in Chimica e Tecnologia Farmaceutiche
TESI DI LAUREA:
Regio- and stereoselective control of the ring-opening of carbapyranose 1,2-epoxide with α-gluco configuration under chelating conditions.
Relatori: Prof.ssa Valeria Di Bussolo Dr. Vittorio Bordoni
Correlatore: Prof.ssa Cinzia Chiappe Candidata: Silvia Mastrosimone (matricola 479251)
Settore Scientifico Disciplinare: CHIM/06 ANNO ACCADEMICO 2016-2017
I
INDEX
ABSTRACT II
1. INTRODUCTION 1
1.1. Carbohydrates, carbasugars and pseudooligosaccharides 1
1.2. Pseudodisaccharides synthesis 5
1.2.1. Triflate displacement 7
1.2.2. Epoxide opening 10
1.2.3. Other methods for the synthesis of ether-linked
carbadisaccharides 20
1.3. Ionic liquids 22
1.3.1. Glymes 23
1.3.2. Ion complexing 24
1.3.3. Industrial applications 25
1.3.4
Organic chemistry applications
261.3.5. Solvate ionic liquids as reaction media 27
2. STATE OF THE ART 29
3. RESULTS AND DISCUSSION 36
3.1. Purpose of the thesis 36
3.2. Synthesis of carbapyranose 1,2 epoxide with α-gluco configuration 37
3.3. Ring-opening reactions of epoxide 3.14α 42
3.3.1. Ring-opening reactions of epoxide 3.14α under
chelating conditions 47
4. CONCLUSIONS 56
5. EXPERIMENTAL 57
II
ABSTRACT
Carbapyranose 1,2-epoxides have been extensively studied as “glicosyl-donor mimics”, in that the epoxide opening reactions can be used to form ether-linked pseudosaccharides and pseudodisaccharides[1].
Ring-opening reactions of carbapyranose 1,2-epoxides with β-manno configuration had been widely studied because these type of epoxides were opened efficiently with attack at C(1), which is sterically and electronically favoured, to give 1,2-trans-diaxial carba-α-manno derivatives with both O- and N-nucleophiles. Instead carbapyranose 1,2-epoxide with α-gluco configuration didn’t provide good results, because nucleophilic attack was often unregioselective.
Despite of this, carbapyranose 1,2-epoxides with α-gluco configuration turn out to be very useful for the synthesis of pseudosaccharides and pseudodisaccharides with pseudo-gluco configuration on carbapyranose unit.
In my thesis work I have synthesized carbapyranose 1,2-epoxides (2.11) starting from the commercially available tri-O-acetyl-D-glucal (3.3) and I have studied the regiochemical behaviour of this epoxide under different reaction conditions in order to direct the ring-opening process.
3.3 2.11
Synthesis of 1,2-epoxide with α-gluco configuration
I verified that a completely C(1) regio- and stereoselective nucleophilic addition process, with the exclusive formation of the C(1) regioisomer, occurs under methanolysis using LiClO4 as the coordinating agent.
III
On this basis, I have used some ionic liquids as solvent, containing a Li+ cation, in order to
promote the coordination effect and to permit a regio- and stereoselective ring-opening process with different nucleophiles.
G4TFSI[2], synthesized in the laboratory of Prof.ssa Chiappe, turned out to be the most efficient ionic liquid to direct the ring-opening process and to permit the regio- and stereoselective formation of C(1) adducts which correspond to pseuodoglycosides 2.13-Nu with β-gluco configuration.
G4TFSI 2.13-Nu
References:
1. Roscales, S.; Plumet, J. International Journal of Carbohydrate Chemistry 2016, 1 2. Eyckens, D. J.; Champion, M. E.; Fox, B. L.; Yoganantharajah, P.; Gibert, Y.;
1
1. INTRODUCTION
1.1. Carbohydrates, carbasugars and pseudooligosaccharides
Carbohydrates are biomolecules involved in the release of energy and they are constituents of glycoproteins, glycolipids and other compounds. Carbohydrates are also involved in different processes such as signaling, cell-cell communication and molecular and cellular targeting[1]. Therefore they have a key role in different diseases such as cancer,
diabetes or inflammatory processes.
Carbohydrates can be extracted from natural sources or chemically synthesized starting from monosaccharide building blocks. Recent advancements in carbohydrate chemistry gave access to a wide range of synthetic carbohydrates, which can have important application in medicines; indeed, they can be used to make vaccines that are more immunogenic than those based on natural carbohydrates. Furthermore, carbohydrates can be useful chiral auxiliaries for the introduction of functionalities in a wide range of compounds[2].
In order to obtain new carbohydrate derivates with analogous or improved biological and pharmacokinetical properties compared to natural sugars, a number of studies are focused on the preparation of carbohydrate mimetics. In this framework, a wide range of derivates, called carbasugars, have been synthesized .
Carbasugars are compounds in which the ring oxygen of a monosaccharide had been replaced by a methylene group. Enzymes or other biological systems can recognize them instead of the corresponding natural sugars and these synthetic carbohydrates could be also more stable towards degradative enzymes[3].
McCasland’s group synthesized 5a-carba-α-DL-talopyranose[4] (the first reported
carbasugar), 5a-carba-α-DL-galactopyranose[5] and 5a-carba-β-DL glucopyranose[6] (Figure
2
5a-carba-α-DL-talopyranose 5a-carba-α-DL-galactopyranose
5a-carba-β-DL-gulopyranose
Figure 1.1 Racemic carbasugars prepared by McCasland et al. (only D-enantiomers are shown)
They suggested that, in some cases, a carba-sugar might be accepted by enzymes or biological systems in place of a natural sugar and thus might serve to inhibit growth of malignant or pathogenic cells[7]. 7 years later, 5a-carba-α-D-galactopyranose was isolated
as a true natural product from a fermentation broth of Streptomyces sp. MA-4145[8].
In addition to this lots of highly oxygenated cyclohexane and cyclohexene derivates, related to carbasugar, have been isolated from nature. Some compounds, among them, are epoxides such as cyclophellitol, (isolated from Phellinus sp.[9]), cyclohexene derivatives
such as MK7607 (isolated from Curvularia eragrostidis[10]) and other carbonyl compounds (e.g., the important family of Gabosines).
Aminocarbasugar derivates, such as valienamine, validamine, hydroxyvalidamine and valiolamine are also produced by microorganisms[11]. Indeed in 1970 validamycins, a
carba-trisaccharidic antibiotics, was obtained from a fermentation beer of Streptomyces hygroscopicus var. limoneus and validamycin A (Figure 1.2) is the most active component. Validamycins have been widely used in Japan as farming antibiotics.[12]
3
Figure 1.2. Validamicyn A
Validamicin A[13] is a pseudotrisaccharide formed by validoxylamine A and
D-glucopyranose. The core consists of two aminocyclitols, valienamine and validamine, which are connected through a single nitrogen atom.
Another important compound is acarbose (Figure 1.3), which was found screening strains of various Actinomycete genera. Acarbose is used to treat type II insulin-indipendent diabetes and it is formed by a carbatrisaccharides consisting of valienamine, a deoxyhexose, and maltose[14].
Figure 1.3. Acarbose
The valienamine portions of validamycin A and acarbose have been shown to play roles by structural mimicking of the transition state of glucopyranose residues during the hydrolysis of glucosides[15], when it binds to the active sites of enzymes.
Amylostatins were isolated from several strains of Streptomyces diastaticus subsp. Amilostaticus. The chemical structures of amylostatins are very close to that of acarbose analogues containing the acarviosine core[16] (Figure 1.4).
4
Figure 1.4. Amylostatins
Furthermore in the last few years lots of analogues have also been prepared in the search for improved biological activities, such as enzymatic inhibition.
5
1.2. Pseudodisaccharides synthesis
The chemistry used to link a carbasugar to a carbohydrate or another carbasugar is different from the one used to synthesize a glycosidic bond. Nucleophile substitution (SN) reactions have been used for the synthesis of O- and S-pseudodisaccharides, and for the synthesis of N-pseudodisaccharides both SN reactions and reductive ammination have been used.
The bridging bond can be disconnected retrosynthetically to give: a carbasugar C-1 electrophile and a carbohydrate nucleophile a carbasugar C-1 nucleophile and a carbohydrate electrophile The two disconnections are similar but non-equivalent (Figure 1.5).
a
b
6
In the first case (carbasugar used as electrophile) the C1 is flanked by a methylen group (C-5a) and it may be more electrophilic in SN2 reactions than a carbon in a carbohydrate flanked by two carbons each bearing an electron-withdrawing oxygen functionality (disconnection 1 in Figure 1.5 a).
In the second case (carbasugar used as nucleophile, Figure 1.5 a disconnection 2) SN reactions on carbohydrates at carbons other than the anomeric carbon, are difficult because of the presence of electron-withdrawing groups which destabilize potential carbocations. SN1 reactions are very unusual away from the anomeric centre and SN2 reactions are not favored by the presence of electron with-drawing in the β-position to a leaving group (disconnection 2 in Figure 1.5 a and b). However in C5=C5a unsaturated system the C1 position is allylic and it causes an increase of the reactivity in SN reactions. Therefore carbasugar electrophiles (disconnection 1 in Figure 1.5 a) are a better choice than non-carbasugar electrophiles[17].
Stereoelectronic factors are also important, with, for example, the Fürst–Plattner favoured trans diaxial products tending to dominate in epoxide-opening reactions.
7
1.2.1 Triflate displacement
Ether linked pseudodisaccharides have been synthesized by SN2 reaction between carbasugars C1 alcohols and carbohydrate triflates. The alcoxide nucleophile is a strong base and potential competing elimination reactions must be minimized.
Paulsen et al. indentified triflates that can be used to synthesize 6-substituted glucose (1.12-1.14) and 4-substitutes glucose (1.15-1.19) pseudodisaccharides[18]. The
displacement of the primary gluco triflate (1.9) by alkoxides, derived from various carbasugars C(1) alcohols (1.1-1.3), took place in THF at room temperature and it gave the ether-linked (1→6)Glc pseudodisaccharides (1.12-1.14) in excellent yield (Table 1.1, entries 1-3)[18]. NaH was used to generate alkoxides and also tBuOK could be used in
combination with 18-crown-6.
The synthesis of pseudodisaccharides containing 4-substituted glucose was more difficult: the reaction products are sec-sec ethers and the SN2 reaction is more difficult at a secondary carbon. A galactose 4-triflate in the 4C
1 conformation gave only product of
elimination. The conformationally locked (1C
4) 1,6-anhydrogalactose derivative (1.10)
with an equatorial C-4 triflate was used: here the antiperiplanar relationship of H and and OTf is avoided, thus disfavouring a competing elimination pathway. Yields in THF were low but, adding DMF or HMPA as co-solvent, some ether-linked pseudodisaccharides (1.15-1.19) could be synthesized from the corresponding alcohols (1.1 and 1.4-1.7) (Table 1.1, entries 4-8)[18,19].
The synthesis of (1-6)- and (1-4)-linked compounds has high yields and these appears to be independent of the structure of the nucleophile.
However this approach to pseudodisaccharides requires triflates that would not easily undergo 1,2- elimination even under strongly basic conditions, showing thus some limits of applications.
8
Entry Alcohol Triflate Conditions Product
1 1.1 1.9 (1.2 equiv.) NaH, THF, 0°C to rt, 2h 1.12; 84% 2 1.2 1.9 (1.3 equiv.) NaH, THF, 0° to rt, 12h 1.13; 88% 3 1.3 1.9 (1.5 equiv.) NaH, THF, 0°C to rt, 12h 1.14; 86% 4 1.1 1.10 (1.3 equiv.) NaH, HMPA, 0°C to rt, 12h 1.15; 90% 5 1.4 1.10 (2 equiv) NaH, THF, HMPA, 0°C to rt, 24h 1.16; 80%
9
Continued
Entry Alcohol Triflate Conditions Product
6 1.5 1.10 (2 equiv.) i) NaH, HMPA, 0°C to rt, 12h ii) HCl, MeOH 1.17; 88% 7 1.6 1.10 (2 equiv.) NaH, THF, HMPA, 0°C to rt, 12h 1.18; 87% 8 1.7 1.10 (2.7 equiv.) NaH, THF, HMPA, 0°C to rt, 17h 1.19; 89% 9 1.8 1.11 (2 equiv.) NaH, DMF, rt 1.20; 34%
10
1.2.2. Epoxide opening
The coupling reactions of saturated epoxide take place under forcing reaction conditions: elevated temperature (120°C), in alcoholic solvents and in a sealed tube for several days. Carbohydrate amines (1.23-1.29) can open stereospecifically and regiospecifically β-manno-configured 5a-carba-1,2-epoxides (1.21 and 1.22) to give α-manno-configured imino-linked pseudodisaccharides and pseudotrisaccharides in good yields (1.30-1.35; Table 1.2). The reaction is efficient enough for a branched pseudodisaccharide to be formed.[20, 21]
The formation of regioisomeric products from β-manno 1,2-carbasugar epoxides has not been reported. This may be due to the following factors:
Attack at C-1 (to give α-manno-configured carbasugar pseudodisaccharides) results in trans-diaxial opening as favored by the Fürst–Plattner guidelines, so it is stereoelectronically favorable;
C-1 is flanked by an electron-rich methylene group whereas C-2 is flanked by a carbon bearing an electron-withdrawing group, so SN2 is electronically favoured at C-1 over C-2;
the groups flanking C-1 are smaller than those flanking C-2 so attack at C-1 may be favored also from a steric point of view.
11
Entry Epoxide Amine Conditions Product
1 1.21 (1.1 equiv.) 1.23 i) Propan-2-ol, sealed tube, 120°c, 5 days 1.30; 70% 2 1.21 (1.5 equiv.) 1.24 i) Propan-2-ol, sealed tube, 120°c, 6 days 1.31; 61% 3 1.21 (1.5 equiv.) 1.25 i) Propan-2-ol, sealed tube, 120°c, 6 days 1.32; 95%
12
Continued
Entry Epoxide Amine Conditions Product
4 1.21(2.2equiv) 1.26 i) Propan-2-ol, sealed tube, 120°c, 5 days 1.30;72% 5 1.22 1.27 (1.3 equiv.) i) propan-2-ol/ DMF, sealed tube, 120°C, 24h ii) Acetylate 1.33; 59% 6 1.22 1.28 (1.5 equiv.) i) propan-2-ol/ DMF, sealed tube, 120°C, 24h ii) Acetylate 1.34; 56% 7 1.22 1.29 (1.5 equiv.) i) propan-2-ol/ DMF, sealed tube, 120°C, 3 days ii) Acetylate 1.35; 68%
Table 1.2. Synthesis of 1,2-trans α-manno imino-linked pesudodisaccherides and
13
Ogawa et al. have shown that epoxide opening can be used to obtain ether-linked pesudodishaccarides and pseudotrisaccharides. In this reaction it is important to use Lewis acid catalysis to promoted a coupling reaction between a β-manno-configured carbasugar 1,2-epoxide (1.21) and a primary carbohydrate alcohol. However, the same catalyst could not promote the reaction with a secondary carbohydrate alcohol.[22] Basic conditions could
also be used to achieve an efficient coupling: heating the epoxide with the secondary alcohol in DMF in presence of an excess of base gave the products in 35% yield.
Higher yields of the pseudodisaccharide could be obtained by running the reaction in the presence of a crown-ether. Two β-manno configured carbasugar 1,2-epoxides (1.21 and 1.36) were used and they were coupled with primary or secondary carbohydrate alcohols to give the corresponding pseudodisaccharides (1.54-1.56, 1.58 and 1.59a-k) or pseudotrisaccharides (1.57) in good yields and with an excellent regioselectivity for the trans-diaxial-opening products (Table 1.3, entries 12-17).[20, 22-32]
14
The products of these epoxide-opening reactions have the α-manno configuration.
Entry Epoxide Alcohol Cond. Product
1 1.21 (1 equiv) 1.37 BF3OEt2, CH2Cl2, 150°C 1.53; 37% 2 1.21 (2 equiv) 1.38 NaH, DMF, 15-crown-5, 70°C, 2h 1.54; 65% 3 1.21 (1 equiv) 1.39 NaH, DMF, 15-crown-5, 70°C, 4h 1.55; 45% 4 1.21 (2.8 equiv) 1.40 NaH, DMF, 15-crown-5, 70°C, 2h 1.56; 64% 5 1.21 (3 equiv) 1.41 NaH, DMF, 15-crown-5, 70°C, 2 days 1.57;44%
15
Continued
En. Epox. Alcohol Cond. Product
6 1.21 (2.4 equiv) 1.42 NaH, DMF, 15-crown-5, 70°C, 2h 1.58;82% 7 1.36 (3 equiv) 1.43 NaH, DMF, 15-crown-5, 70°C, 3-26h 1.59a; 66% 8 1.36 (3 equiv) 1.44 NaH, DMF, 15-crown-5, 80°C, 3 days 1.59b; 36-48% 9 1.36 (2 equiv) 1.39 NaH, DMF, 15-crown-5, 50°C, Over-night Acetylate 1.59c; 60% 10 1.36 1.45 NaH, DMF, 15-crown-5, 60°C, 6h 1.59d; 52% 11 1.36 (2 equiv) 1.46 NaH, DMF, 15-crown-5, 50°C, Over-night 1.59e; 84%
16
Continued
Ent. Epoxide Alcohol Conditions Product
12 1.36 (2.5 equiv) 1.47 NaH, DMF, 15-crown-5, 70°C, 3h 1.59f; 70% 13 1.36 (2.3 equiv) 1.48 NaH, DMF, 15-crown-5, 70°C, 25h 1.59g; 68% 14 1.36 (1.5 equiv) 1.49 NaH, DMF, 15-crown-5, 60°C, 27h Acetylate 1.59h; 44% 15 1.36 (1.5 equiv) 1.50 NaH, DMF, 15-crown-5, 60°C, 1.59i; 56% 16 1.36 (1.5 equiv) 1.51 NaH, DMF, 15-crown-5, 60°C, 16h 1.59j; 45% 17 1.36 (1.5 equiv) 1.52 NaH, DMF, 15-crown-5, 60°C, 1.59k; 17%
17
Attempts to obtain β-gluco- or β-galacto-configured carbasugar pseudodisaccharides by analogous transdisequatorial opening of the corresponding α-carbasugar epoxides with alcohol nucleophiles failed. When α-gluco and α-galacto 1,2 epoxides were heated with alcohols and base in DMF, only complex mixtures of elimination products were seen. Even octanol, a simple model alcohol, gave the coupling product only in 5% yield.[23,24]
A novel procedure, based on epimerization of C-1 and C-2, was developed in order to obtain ether-linked pseudodisaccharides with configurations other than α-manno.[23-25, 28-32]
Oxidation of free carbasugar gave the C-2 ketone, which could be epimerized at C-1 under basic conditions. The reaction gave a mixture of α- and carbahexuloses in which the β-isomer was the major component.
Reduction of the α-configured C-2 ketone gave the mixtures of gluco- and manno-configured α-linked carbasugar pseudodisaccharides, while reduction of the β-manno-configured C-2 ketone gave mixtures of the gluco- and manno-β-linked carbasugar pseudodisaccharides. Different reduction conditions often gave different diastereoselectivities, as shown in Scheme 1.1. This method, however, requires various steps that lower the yields of the process.
18
1.60 1.61 1.62
1.63 1.64 1.65
Reduction conditions f:A, manno:gluco 1:2 a: C, gluco: 78%;manno: 15% A: NaBH4, CH2Cl2, MeOH, 0°C f: B, gluco: 77% a: D, gluco: 47%;manno: 50%
B: L-selectride, THF g:A, gluco: 66%; manno: 22% b:D, gluco:manno 1:1 C: Borane, THF, O°C h:A, gluco: 43%;manno: 28% c: C, gluco: 69%;manno: 15% D: NaBH4, MeOH, CeCl3 j: A, gluco: 64%; manno: 28% d: C, gluco: 61%
K:A, gluco: 53%; manno: 31% e: C, gluco:52%; manno: 9% f: A, gluco:25%; manno: 42% f: B, manno:67% g: A, gluco: 43%; manno:44% h: D, gluco: 73%; manno:22% i: A, gluco: 39%; manno: 56% j: D, gluco: 50%; manno:43% k: D, gluco:47%; manno: 38%
19
Further protecting group manipulation and inversion of configuration at C-4 by SN2 reaction or oxidation–reduction process gave galacto-configured carbasugars.
Ogawa has suggested that the β-talo-configured 1,2-epoxide (Figure 1.6) could be used to avoid some of the extensive post-processing necessary to achieve α-galacto-configured ether-linked carbasugar pseudodisaccharides, but there are not detailed results of the coupling with this epoxide.[29]
20
1.2.3. Other methods for the synthesis of ether-linked carbadisaccharides
A different approach to carbasugar is the attachment to a carbohydrate component, followed by formation of the pseudodisaccharide.Sinaÿ has developed modifications of the Ferrier II rearrangement where the glycosidic substituent is retained. The reaction has been applied to the synthesis of pseudodisaccharides, and the carbocycles elaborated to give carbadisaccharides. Disaccharides were firstly modified to give exo-glycals and then treated with TIBAL to give pseudodisaccharides[33] (Scheme 1.2).
1.66 a-e 1.67 a-e
Scheme 1.2 Pseudodisaccharide rearrangements
The reaction was diastereoselective and products with an axial C-1 orentation were formed.
C-6 deprotected carbaidopyranosides have been converted to carbaglucopyranosides by an oxidation-epimerisation-reduction sequence. Treatment of the exo-glycal rearrangement precursors with AlMe3 instead of TIBAL gave a rearrangement to cyclohexane products
21
1.68 1.69 75%
Scheme 1.3. Glycoside to pseudodisaccharide rearrangement
Mootoo and co-workers have developed another method. The acyclic compound (1.70), a carbasugar precursor, was coupled to a carbohydrate alcohol by esterification and a Tebbe methylenation gave enol ether (1.71). This was activated with methyl triflate and it gave the carbocyclic enol ether (1.72) by a cyclisation reaction. Finally it was hydrated to give the carbasugar pseudodisaccharide[35] (1.73) (Scheme 1.4).
1.70 1.71
1.73 1.72
Scheme 1.4. Formation of a β-galacto carbasugar pseudodisaccharide by postconjugation
22
This method has only been demonstrated for a single example of an ether-linked carbadisaccharide, but a glycosidically linked compound was also made in the same way starting from a hemiacetal.
1.3 Ionic liquids
In the last decade, ionic liquids have been used as an alternatives to conventional organic solvents because of their advantageous properties such as volatility, non-flammability, high thermal stability, recyclability and their ability to dissolve a wide range of organic and inorganic compounds. They have received considerable attention as environmentally benign reaction media, catalysts, and reagents. Therefore a wide variety of ionic liquids have been synthesized and their applications in organic reactions have been examined[36].
Ionic liquids are molten salts, which are liquid at temperature below 100°C. They are obtained from the combinations of different cations and anions. ILs are divided into four generations depending on their chemical structures and properties: alkylammonium-, dialkylimidazolium-, phosphonium- and N-alkylpyridinium based ILs[37] (Figure 1.7).
Figure 1.7. Alkylammonium, phosphonium, dialkylimidazolium and N-alkylpyridinium
23
1.3.1 Glymes
Glymes, also known as glycol diethers, are saturated non-cyclic polyethers containing no other functional groups. They have both hydrophilic and hydrophobic characteristics and they could solvate alkali cations. They are usually thermally and chemically stable and they have many other properties including being liquid, low viscosity, low vapor pressure and low toxicity[38].
Some glymes have low acute toxicity and they can cause reproductive effects at chronic exposure. The U.S. Environmental Protection Agency (EPA) plans to restrict the use of new glymes, as monoglyme and diglyme have caused reproductive and developmental damage in rodent, while ethyl glymes have also the potential for gene mutation. Since lower molecular weight glymes have shown reproductive toxicity in rats and mice, only higher molecular weight glymes should be used in pharmaceutical applications. For that reason glymes are recommended as solvent for industrial applications and not consumer products[38, 39].
Glymes could be used in laboratory in a wide range of applications such as organic synthesis, electrochemistry, biocatalysis, materials and etc. They are polar aprotic solvents with high chemical stability and they can be used under neutral and basic conditions.
Glymes have high boiling points, are liquid at wide range of temperature (except monoglyme). They are also completely miscible with water and organic solvent such as benzene, ethanol and acetone and they can solvate cations in the same way as crown ethers. Their dipole moments and dielectric constants increase with the increase in ethylene oxide chain length and are generally less polar than methanol and acetone but more polar than THF[38,40].
24
1.3.2 Ion complexing
Glymes contain multiple ethertype oxygen atoms and flexible alkoxy chains and they behave like crown ethers, so they can solvate metal ions through oxygen.
Matsui and Takeyama confirmed that Li+ is coordinated with six oxygen atoms in either
monoglyme or diglyme; however, monoglyme is a bidentate ligand and diglyme is a tridentate ligand[41].
The affinity of glymes in binding lithium increases with increasing ether chain length up to tetraglyme, and a further increase in the affinity for longer glymes is primarily due to the increase in the number of binding sites[42]. However, crown ethers generally have much
higher binding equilibrium constants toward Li+ and Na+, which could be over 100 times
higher than most glymes.
A further study on temperature dependence suggests that the reason for glymes being effective complexing agents of alkali ions is mainly due to a small loss in entropy as compared to solvent separated ion pair formation in THF[43].
The Watanabe group prepared an equimolar complex [Li(glyme)1][TF2N]
bis(trifluoromethane)sulfonimide), which maintains a stable liquid state over a wide temperature range and exhibits high thermal stability and Li+ ionic conductivity, behaving
like a room temperature ionic liquid (IL). The physicochemical of the glyme–Li salt complex can be manipulated by the glyme structure. The same group further observed a higher oxidative stability of glyme molecules when complexing with Li+ cations[44].
Moreover, the ionic association strength of LiX salts was investigated in different aprotic solvents including glymes and the complexing properties of glymes with other metal and organic cations, or even non-ionic molecules have also been studied[45].
25
1.3.3 Industrial applications
Glymes are used in different ways such as cleaning products, inks, batteries and electronics, refrigeration and heat pumps, pharmaceutical formulation etc[46].
Monoglyme (G1) is used to produce active ingredients and as electrolyte solvent for sealed lithium batteries;
diglyme (G2) is used as reaction solvent for organometallic reagents, entrainer for azeotropic distillation, battery electrolyte, solvent in a formulation to improve the bonding of tire cord to rubber, solvent in printing and inkjet inks;
Triglyme (G3) is used as solvent for Teflon etching, high boiling and inert solvent for organic reactions and as solvent in consumer adhesives and paints;
Tetraglyme (G4) is used as solvent for production of binders for paints, for the
formulations of paint strippers and adhesive removers and it is used to extract volatile organic compounds from solid wastes, etc.
The Watanabe[47] group determined the physicochemical properties of triglyme and
tetraglyme solution of Li[Tf2N] and they observed the formation of complexes
Li(glyme)[Tf2N], which can be considered as a ionic liquid in terms of similar iconicity.
Orita et al. demonstrated the potential of Li(tetraglyme)[Tf2N] as replacement of organic
electrolytes in lithium batteries with appropriate electrode-active materials[48].
26
1.3.4 Organic chemistry applications
Glymes are very important in organic synthesis. They are used as solvent in organic reactions, as additives/metal chelators, catalysts and reagents. Glymes, as we previously said, are molten salts at a wide temperature range and they can be used for reactions at low temperatures. Monoglyme, for example, has a freezing point of -69°C and it has been used in low-temperature reaction; moreover it can also be removed easily during the workup.
In addition, glymes have a strong solvating power and can dissolve a variety of compounds, particularly chelating with metal ions. For example, triglyme and tetraglyme are strong chelating agents for Na+ ions[49].
Therefore, glymes (especially monoglyme) have been explored in numerous organic reactions since the 1960s, such as reduction, oxidation, substitution, C–C coupling, borane chemistry, and other reactions. Furthermore glymes can be used as catalysts of many organic reactions. They have both hydrophilic and lipophilic properties and they can be used as direct phase-transfer catalysts. Glymes can form complexes with alkali cations like crown-ethers and have the capacity to stabilize reaction intermediates through hydrogen-bonds[38].
Typically, glymes are chemically inert; however, they could become reactive under certain conditions. Newman and Liang observed that when 3-nitroso-5-methyl-5-tert-butyl-2-oxazolidone was treated with sodium phenoxide, the stereospecific cleavage of monoglyme occurred to form 2-methoxyethyl trans-2,2,3-trimethyl-l-butenyl ether in 46% yield[50].
27
1.3.5 Solvate ionic liquids as reaction media
Solvate ionic liquids are composed by lithium bis(trifluoromethylsulfonyl)imide dissolved in tri- or tetraglyme and they have been already used as a replacement for molecular solvents in electrocyclization reactions. These type of ILs (G3TFSI and G4TFSI) can be simply prepared by dissolving Li(Tf2N) in either tri or tetra-glyme (Figure
1.8).
Figure 1.8.Solvate ILs (G3TFSI and G4TFSI)
G3TFSI or G4TFSI have various properties: they are aprotic;
they remain liquids at low temperatures (e.g. 0 °C) maintaining their high polar nature.
They also have a cation, which has great potential to stabilize polar intermediates or, potentially, participate in Lewis acid activation.
G3TFSI and G4TFSI were compared to an appropriate molecular solvent and also to 5 M lithium perchlorate in diethyl-ether. For this purpose, the reaction between dimethylketene and (E)-cinnamaldehyde, producing alkene, was chosen. (Scheme 1.5)
28
Scheme 1.5. Reaction between dimethylketene and (E)-cinnamaldehyde
The reaction was carried out in G3TFSI and G4TFSI and the final compound was obtained in good yields (Table 1.4).
Entry Solvent t (h) T (°C) Yield
1 CHCl3 6 r.t <5 % 2 5M LPDE 6 r.t 20 % 3 G3TFSI 6 r.t 56 % 4 G4TFSI 6 r.t 41 % 5 G4ClO4 6 r.t 15 % 6[b] G3TFSI 6 r.t 60 % 7 G3TFSI 6[c] 80°C 70 %
[b]Activated molecular sieves (100 mg) were used throughout the reaction. [c] The reaction mixture was heated for the final hour of the specified time.
Table 1.4. Comparison of solvents in the formation of dienes.
Therefore, lithium-derived solvate ionic liquids can be applied to any reactions for which Lewis acid catalysis had been successful, and they can also be used as organic solvents[51].
29
2. STATE OF THE ART
As we previously said, carbapyranose 1,2-epoxides with β-manno configuration (2.1β) can be opened successfully by O- and N-nucleophiles with an excellent regioselectivity. The attack at C(1), that results in trans-diaxial opening, is favoured by the Fürst- Plattner guidelines and it gives 1,2-trans-diaxial carba-α-mannose derivatives. The regioselectivity is due to steric and electronic reasons (Scheme 2.1):
The C(1) is flanked by an electron-rich methylene group, whereas C(2) is flanked by a carbon bearing an electron-withdrawing group; so from an electronic point of view SN2 reaction should be more favourable at C(1) than at C(2).
The C(1) is flanked by a small group, whereas the C(2) is flanked by a bulky ether group; from a steric point of view, the attack at C(1) is favourable.
2.1β α-pseudomanno glycoside
Scheme 2.1. Sterically and electronically favoured nucleophile attack to epoxide 2.1β
On the contrary carbapyranose 1,2-epoxides with α-gluco configuration 2.1α do not give good result: the opening reaction is not regioselective and leads to low yields. In the 2.1α, the attack at C(1) carbon is sterically and electronically favoured (the C(1) carbon is flanked by a small and relativity electron-rich methylene group) and it leads to an unfavourable trans-diequatorial ring-opening (route a). The attack at C(2) at the oxirane carbon, which could lead to a trans-diaxial ring-opening (route b) is sterically hindered and electronically unfavourable (Scheme 2.2).
30
C(2)-adduct 2.1α' 2.1α''
C(1)-adduct
Scheme 2.2. The two regioisomers from nucleophilic attack to epoxide 2.1α
Epoxide 2.1α could reasonably be an effective β-carbaglucosyl donor, which can be used for the synthesis of glycolconjugates bearing a β-carbaglucosidic bond, but it has been so far not useful for this purpose.
Despite of this carbapyranose 1,2-epoxide with α-gluco configuration (such as 2.2) theorically are very useful for the synthesis of pseudosaccharides and pseudodisaccharides (such as 2.3, with pseudo-gluco configuration on carbapyranose unit) (Figure 2.1).
2.2 2.3
Figure 2.1. Carbapyranose 1,2 epoxide (2.2) precursor of pseudosaccharide 2.3
Previous experiments conducted in the group where I performed my thesis work confirmed that carbapyranose 1,2-epoxides with α-gluco configuration react in acidic conditions to give trans-hydroxy adducts with O-nucleophile. In this conditions the oxirane
31
opening yielded a complex mixtures constituted by C(1) and C(2) products (2.5 and 2.6), a bicyclic undesired compound 2.7 and other by products such as 2.8, which is obtained when the acidic catalyst was the weak nucleophile TsOH (Scheme 2.3).
2.4α 2.5 2.6
2.7 2.8
Scheme 2.3. Ring-opening of the 1,2-epoxide 2.4α with MeOH in acid conditions.
Epoxide 2.4α, indeed, exists in two chair conformations characterized by different energies:
Conformer 2.4α' is more stable because of the triequatorial arrangement of the bulky –OBn groups. The nucleophilic attack on this conformer can occur at C(1) oxiran carbon, which is sterically and electronically favoured, through an unfavoured trans-diequatorial ring-opening (route a). However the nucleophilic attack can also occur at the sterically and electronically unfavourable C(2) oxirane carbon, which is flanked by a bulky and electron-withdrawing –OBn group at the C(3). The attack occurs through a favoured trans-diaxial ring-opening (route b).
Conformer 2.4α'' is less stable because of the triaxial arrangement of the hindered –OBn groups. A completely sterically and electronically favoured trans-diaxial ring-opening at the C(1) can occur in this conformer (route c). However, a theoretical interference of an undesired intramolecular trans-diaxial addition can take place at C(1). Indeed an internal nucleophile, the oxygen of the –OBn group in the axial arrangement at C(5), can attack the C(1) position.
32
Following this addition, with supposed elimination of benzyl methyl ether, the formation of the bicyclic compound 2.7 can occur (route d) (Scheme 2.4).
2.4α' 2.4α''
2.6 2.5 2.7
Scheme 2.4. Possible routes for nucleophilic attack in the ring-opening of 1,2-epoxide 2.4α
The bicyclic compound 2.7 can arise from the less stable triaxial conformer 2.4α'' (R=OBn), in which the attack of the –OBn group determines the above undesired addition reaction. This competitive intramolecular addition influences negatively the yield of the typical ring-opening process and structural modifications of the epoxide 2.4α are evaluated in order to eliminate this side reaction.
Therefore the –OBn group at the C(6) was switched firstly with an O-TIPS protective group and then with a O-TBDPS group, but the secondary addition reaction was only reduced. A completely elimination of the undesired reaction, which leads to the compound 2.7, was obtained transforming the hydroxyl functionality on C(6) position present in 2.9 into a methyl group as in compound 2.10 (Scheme 2.5).
33
2.9 2.10 2.11α
Scheme 2.5. The removal of the internal nucleophile in compound 2.10 allows the formation
only of epoxide 2.11α
In this way the undesired compound 2.7 was completely eliminated, but the ring opening reaction was still not regioselective. The methyl-substituted 1,2-epoxide 2.11α commonly reacts through three routes by means of the corresponding triequatorial 2.11α' and triaxial 2.11α'' conformers: both C(1) (2.12) and C(2) (2.13) addition products result from triequatorial conformer 2.11α' (route a and route b). In absence of an internal nucleophile on C(6) position, the small amount of the compound 2.11α'' can undergo only the C(1) product (2.12), by a trans-diaxial ring-opening process (route c) (Scheme 2.6).
2.13 2.11α' 2.11α''
2.12
34
Moreover, observing the ring-opening reaction mechanism, a very interesting possibility to promote the nucleophilic attack at C-1 was identified in the modification, at least partial, of the conformers population toward the triaxial conformer 2.11α'', which leads to the C-1 adduct through the route c illustrated in Scheme 2.6 (vide supra). This result was achieved using strongly coordinating reaction conditions, by means of a chelating metal cation such as Li+ (from LiClO
4) which stabilize the triaxial conformer (2.11α''-Li), in which oxirane
oxygen and –OBn group on C(3) position were appropriately disposed to form a bidentate chelate system with Li+ (Scheme 2.7). Subsequent nucleophilic attack on 2.11α''-Li
necessary occurred at C(1), following a trans-diaxial opening process, with the formation of the desired pseudo-β-O-glycoside 2.13'-Nu
2.11α' 2.11α''
Scheme 2.7. Ring-opening at C(1) by nucleophilic addition to epoxide 2.11α in the presence of Li+
35
In consideration of this important results, the goal the following studies will be optimize the coordinating reaction conditions in order to apply them in a more general and synthetically useful protocol, appropriate for every kind of nucleophiles. Indeed, the described coordinating reaction conditions successfully used, are not easily applicable in reactions with alcohol different from MeOH, because they require the use of an alcohol which acts at the same time as the nucleophile and as solvent. On the contrary, a protocol which allows the use of low amount of nucleophile would be more interesting. For this purpose, the choice of an adequate solvent and reaction conditions represent a crucial point.
36
3. RESULTS AND DISCUSSION
3.1 Purpose of the thesis
As previously discussed, the ring-opening reaction of carbapyranose 1,2-epoxides with α-gluco configuration, such as 2.11α, is unregioselective and allows the formation of both C(1) and C(2) adducts (Scheme 3.1).
2.11α C(1) Adduct C(2) Adduct
Scheme 3.1. Nucleophilic attack on 1,2-epoxide with α-gluco configuration
However, the use of strongly coordinating reaction condition, as previously said, can direct the regiochemistry of the ring-opening process with nucleophiles. Indeed the presence of an ion such as Li+ can modify the equilibrium between the conformers
population towards the triaxial conformer (see Scheme 2.7 Chapter 2).
Therefore, the purpose of my thesis project was to better investigate the nucleophilic addition reactions to carbapyranose 1,2-epoxides with α-gluco configuration, using particular ionic liquids (ILs), containing the Li+ cation, as solvent able to promote the
coordinating process. This way we supposed to direct the ring-opening process through C(1) adducts in order to use them as efficient glycosyl donor mimics for the synthesis of carbasugars.
37
3.2 Synthesis of carbapyranose 1,2 epoxide with α-gluco configuration
The first step of my thesis project was the obtainment of the key intermediate epoxide 2.11α, which was essential for us to better investigate nucleophilic attack conditions leading to a C(1) ring-opening product (Scheme 3.2).2.11α C(1) Adduct
Scheme 3.2. C(1) ring-opening reaction with a generic nucleophile
Among the various approaches available in literature, we chose the one that allows the conversion of the glycal system 3.1 into the carbaglycal system 3.2, as shown in Figure 3.1.
3.1 3.2
Figure 3.1. Conversion of the glycal system 3.1 into the carbaglycal system 3.2
This method was described for the first time by Sudha and Nagarajan[52] and consists in
a Claisen Rearrangement reaction under thermal conditions. The thermal Claisen rearrangement is a [3,3] sigmatropic rearrangement of an allyl vinyl ether, which yields a γ,δ-unsaturated carbonyl. The synthesis of this key intermediate has been reported in Scheme 3.3.
38
3.3 3.4 3.5
3.6 3.7 3.8
3.9 3.10 3.11
Scheme 3.3. Synthesis of carbacyclic system 3.11.
Tri-O-acetyl-D-glucal (+), which is commercially available as pure enantiomer, was
chosen for our purpose.
The synthesis started with the saponification of the tri-O-acetyl-D-glucal (+) 3.3 with MeONa/MeOH. The reaction led to D-glucal 3.4 (˃99% yield), which was protected at the primary hydroxyl functionality with the sterically hindered TBDMS-Cl in a 1:10 mixture of DMF/THF (>99% yield).
The O-TBDMS derivative 3.5 was protected at the secondary hydroxyl functionalities with –OBn protection groups, which were introduced using NaH/BnBr/TBAI (tetrabutylammonium iodide) protocol in THF at 0°C. The reaction mixture was stirred at room temperature for 24 h and none migration of the sylil group was observed (96% yield). To synthesize the allyl vinyl ether 3.9, the C-6 position had to be deprotected. A solution of tetrabutylammonium fluoride (TBAF) in THF was added dropwise to a solution
39
of the sylil ether 3.6 in anhydrous THF at 0°C. The reaction mixture was stirred at room temperature and the primary alcohol 3.7 was obtained (53% yield). Primary alcohol 3.7 was purified by means of flash chromatography (7:3 hexane/AcOEt) and then subjected to oxidation affording the aldehyde 3.8.
The IBX (2-iodoxy benzoic acid), whose synthesis has been recently developed[53], was
chosen as oxidizing agent. The reaction was performed in anhydrous ethyl acetate at 75-80°C using 3.0 equiv. of IBX, and after 24 hours the aldehyde 3.8 was obtained in 99% yield. This compound is not stable and after the work-up process (filtration on Celite® pad
with AcOEt) it should be immediately subject to reaction; otherwise it can be stored in dry ice not more than 24 hours.
Subsequently, the aldehyde was transformed into allyl vinyl ether 3.9 by means of Wittig reaction in anhydrous THF. The necessary phosphorus ylide was obtained in situ by the reaction between methyl-triphenyl phosphonium iodide (Ph3PCH3I) and a strong base,
lithium hexamethyldisilazide (LHMDS). The reaction mixture was filtered on a Celite®
pad, washed in a separatory funnel with saturated aqueous solution of NH4Cl, saturated
aqueous solution of NaHCO3, and saturated aqueous solution of NaCl. The organic layer
was dried with (Na2SO4), concentrated, filtered on a silica gel pad, and then evaporated
leading to the desired olefin 3.9. However the olefin was not completely pure and it was subjected to a flash chromatography (Hexane/AcOEt 95:5).
As previously discussed, the allyl vinyl ether 3.9 was subjected to a thermal Claisen rearrangement in order to convert the glycal system in its carba-analog 3.11.
A solution of olefin (3.9) in 1,3 dichlorobenzene was heated to 240°C for 30 min in a sealed tube, afforded the aldehyde 3.10. This compound is unstable, and consequently it had to be immediately subjected to reduction with NaBH4 in THF/EtOH in 2:1 ratio for 30
minutes giving the primary alcohol 3.11 (64% yield), which is the key precursor for the synthesis of carba 1,2-epoxides.
The following reactions were performed in order to transform the primary hydroxyl functionality into a methyl group and, then to oxidize the carbon-carbon double bond to the desired epoxide 2.11α (Scheme 3.4).
40
3.11 3.12 3.13
2.11α 2.11β
Scheme 3.4. Synthesis of epoxide 2.11
The hydroxyl group was removed by means of a tosylation and a subsequent reduction reaction.
The tosylation was performed in pyridine with tosyl chloride (TsCl) and the reaction mixture was stirred at room temperature for 24 h. After the acidic work-up the–OTs derivative 3.12 was obtained in 70% yield.
The tosylate was then subjected to a reduction of the –CH2OTs functionality to give the
desired methyl group. The reaction was performed in anhydrous Et2O using LiAlH4 for 4 h
at 0°C and, after the work-up, it afforded the methyl-derivative 3.13 (96% yield). This reaction consisted in a nucleophilic substitution where the hydride anion was the nucleophiles and the tosylate the leaving group.
Compound 3.13 was then subjected to epoxidation by means of m-chloroperoxybenzoic acid (MCPBA) in anhydrous dichloromethane. The reaction led to two diastereoisomers, the epoxides 2.11α and 2.11β, characterized by α-gluco and β-manno configuration respectively.
41
The epoxide 2.11α was the main product of the epoxidation and this may be due to the butterfly mechanism of the MCPBA. The latter can attack the olefin functionality both from above and below the molecular plane as illustrated in Scheme 3.5.
Scheme 3.5. Butterfly mechanism for the synthesis of epoxides 2.11
The presence of the benzylic group steric hindrance at C(3) above the molecular plane determines a preference for the below-the-plane-approach over the above-the-plane-approach. Thus the epoxide 2.11α is obtained in a predominant amount.
Epoxides (+)-2.11α and (+)-2.11β were isolated by means of flash chromatography by virtue of their different retention factors (2.11α: Rf = 0.40; 2.11β: Rf = 0.26 in 8:2 Hexane/AcOEt) and the epoxide 2.11α is the subject of the ring-opening reactions that I have studied during this thesis project.
42
3.3 Ring-opening reactions of epoxide 2.11α
After the synthesis of epoxide 2.11α, ring-opening reaction under Lewis acid conditions were performed in order to evaluate its regio- stereochemical behaviour.
Among the possible ring-opening reaction conditions the protocol which uses MeOH/CH2Cl2/Cu(OTf)2 with low amount of nucleophiles, was chosen. This protocol, in
fact, is easily applicable to a wide range of O-nucleophiles.
The treatment of the epoxide 2.11α with MeOH/CH2Cl2/Cu(OTf)2 protocol afforded an
almost 1:1 mixture of the corresponding regioisomeric α-methoxy alcohols 3.14 and 3.15, which were not separable. These compounds were separate by preparative TLC and characterized by means of the corresponding acetates (+)-3.14-Ac and (+)-3.15-Ac (Scheme 3.6).
2.11α 3.14 3.15
3.14-Ac 3.15-Ac
43
The ring-opening reaction was not regioselective (the α-methoxy alcohols 3.14 and 3.15 were obtained in a 1:1 ratio), but, as we previously said, (see the state of the art) the formation of a bycyclic compound 2.7 was not observed.
The unregioselectivity of the ring-opening reaction could indicate that methyl-substituted epoxide 2.11α can react through three independents routes (Scheme 3.7):
Both C(2)- and C(1)-addition products (3.15 and 3.14) arise from triequatorial conformer 2.11α', which is more stable because of the triequatorial arrangement of the hindered –OBn groups.
The nucleophilic attack can occur at C(1), which is sterically and electronically favoured, through an unfavoured trans-diequatorial ring-opening (route a) and can also occur at the sterically and electronically unfavourable C(2), giving a favoured trans-diaxial ring-opening (route b).
The small amount of triaxial conformer 2.11α'', in absence of an internal nucleophiles on C(6) position, can undergo only the attack of the external nucleophiles MeOH to produce, through a favoured trans-diaxial ring-opening process (route c), the C(1)-addition product (3.14).
3.15 2.11α' 2.11α''
3.14
44
In order to study the regio- and stereoselectivity of the ring-opening reactions of carbapyranose 1,2-epoxide with α-gluco configuration, other more hindered nucleophiles were used. The focus was laid on the commercially available or freshly synthesized sugar derivatives in order to evaluate the possibility to obtain pseudodisaccharides by means of the ring-opening reactions.
The first reaction was performed using the commercially available primary alcohol diacetone-D-galactose 3.16 with the CH2Cl2/Cu(OTf)2 protocol (Scheme 3.8). Epoxide
2.11α in anhydrous CH2Cl2 was added dropwise at a solution of diacetone-D-galactose in
CH2Cl2 under argon atmosphere. Cu(OTf)2 (0.4 equiv.) was added to the reaction mixture,
which is kept stirring at room temperature for 64 h. The reaction afforded to two regioisomers 3.17 and 3.18 in a 55:45 ratio (1H NMR), which were purified by means of
preparative TLC [8:2 CH2Cl2/(i-Pr)2O]. The two products were acetylated in order to
45
2.11α 3.16 3.17 3.18
3.17-Ac 3.18-Ac
Scheme 3.8. Ring-opening reaction of epoxide 2.11α with diacetone-D-galactose 3.16 and acetylated products.
Subsequently, the carba-primary alcohol 3.11, synthetic precursor of epoxide 2.11α, was used as O-nucleophile.
A solution of compound 3.11 and Cu(OTf)2 in anhydrous CH2Cl2 was added to a
solution of epoxide 2.11α under argon atmosphere. The crude mixture was subjected to preparative TLC (8:2 hexane/AcOEt) affording the two regioisomers 3.19 and 3.20 in a 54:46 ratio (1H NMR). The two compounds were acetylated in order to evaluate the correct
46
2.11α 3.11 3.19 3.20
3.19-Ac 3.20-Ac
Scheme 3.9. Ring-opening reaction of epoxide 2.11α with primary alcohol 3.11 and acetylation of
the products.
These two adducts represent pseudodisaccharides constituted by two carbasugars moieties and one of them presents an alkene functionality. This functionality could be elaborate in order to obtain more complex pseudodisaccharides.
This result shows that the ring-opening reaction of a carbapyranose 1,2-epoxide, such as 2.11α, can be performed in Lewis acidc conditions, however, the regioselectivity of the reaction is not complete. Thus the possibility to better direct the regiochemistry of the ring-opening reaction was evaluated.
47
3.3.1 Ring-opening reactions of epoxide 2.11α under chelating conditions.
Carbapyranose 1,2-epoxides with α-gluco configuration, such as 2.2, theoretically turn out to be very useful for the synthesis of pseudosaccharides and pseudodisaccharides, such as 2.3, with pseudo-gluco configuration on carbapyranose unit (Figure 3.1). This result can be achieved if the nucleophilc attack selectively occurs at C(1) position.2.2 2.3
Figure 3.1. Carbapyranose 1,2-epoxide precursor of pseudosaccharide 2.3
In consideration of this, I have continued to study the regio- and stereochemical behaviour of epoxide 2.11α previously synthesized, under different reaction conditions and with different nucleophiles in order to direct and to make the ring-opening process synthetically useful.
As previously said, (see the state of the art) it was discovered that using strongly coordinating reaction conditions, by the presence of an ion such as Li+, was possible to
modify the conformers population towards the triaxial conformer 2.11α''. This result could be achieved using LiClO4 as coordinated agent and in this way the nucleophilic attack of
the MeOH would necessary occur at C(1) 3.14 because of the bidentate chelation by the metal cation (2.11α''-Li) (Scheme 3.10).
48
Scheme 3.10. Ring-opening at C(1) in nucleophilic addition of MeOH to epoxide 2.11α in the
presence of LiClO4
In order to confirm this result, the ring-opening reaction of the 1,2-epoxide 2.11α using MeOH as nucleophile and as solvent under chelating condition was repeated.
Epoxide 2.11α was added to a suspension of LiClO4 in methanol, in which MeOH acted
at the same time as nucleophiles and as solvent. The reaction mixture was stirred for 7 days at 80°C and it afforded only the C(1) product, the methoxy alcohol 3.14, which was acetylated 3.14-Ac in order to confirm its exact regiochemistry (1H NMR).
Therefore, in presence of an ion with chelating properties, the ground-state shifted towards the less stable conformation 2.11α'', in which the –OBn group on C(3) and the oxirane oxygen formed a bidentate chelate system with Li+ cation (Figure 3.2).
2.11α' 2.11α''
49
However this coordination reaction conditions are not easily applicable in reactions with alcohols different from MeOH, because in this protocol the use of an alcohol, which acts as nucleophiles and as solvent at the same time, is required.
At this point, it was important to optimize the chelating reaction conditions in order to apply them with different nucleophiles, which were used in controlled quantities (3.0-4.0 equiv.) and with different organic compounds, which acted as solvent and as Lewis acid.
In the framework of a collaboration with the team of Prof.ssa Cinzia Chiappe, we decided to use ionic liquids (ILs), containing a Li+ cation, to promote the coordination
effect and to permit a regio- and stereoselective ring-opening process with different nucleophiles. Ionic liquids, in fact, have been used as solvents in different reactions (see Introduction).
In order to find the most efficient ionic liquid to direct the ring-opening process, in a first phase of my study MeOH, used as model nucleophile, was added to a solution of epoxide 2.11α and an appropriate IL, which acted at the same time as solvent and as chelating agent (Table 3.1). The results, with different ILs, are discussed below.
50
Table 3.1 Ring-opening reaction of the 1,2-epoxide 2.11α using ILs
2.11α 3.14 C(1) adduct 3.15 C(2) adduct
Entry Epoxide Ionic Liquid Conditions C(1) adduct C(2) adduct
1 2.11α 3.21 i) B ii) C; 7 days - - 2 2.11α 3.21 i) A ii) C; 3 days - - 3 2.11α 3.22 i) A ii) C 24h 3.15; 60% 3.16; 40% 4 2.11α 3.22 i) A ii) C; LiTf2N excess, 18h 3.15; 65% 3.16; 35%
51
Continued
Entry Epoxide Ionic Liquid Conditions C(1) adduct C(2) adduct
5 2.11α 3.22 i) A ii) C; LiTf2N excess, 2 days 3.15; 65% 3.16; 35% 6 2.11α 3.23 i) B ii) C; LiTf2N excess, 3 days 3.25; 50% 3.26; 50% 7 2.11α 3.23 i) A ii) C, LiTf2N excess, 6 days 3.15; 65% 3.16; 35% A: IL dried at 70°C for 24 h; B: IL not dried; C: reaction performed at 70°C
The ring-opening reaction of the 1,2-epoxide 2.11α, was performed using the IL G3TFSI 3.21, which is a PEG-based glymes composed by four oxygen atoms which form coordinating bonds with Li+ cation.
The 1,2-epoxide 2.11α was added to a solution of G3TFSI 3.21 (1.2 ml), used without any previously drying, and MeOH (10 equiv.) under argon atmosphere. However the reaction did not afford any products; in fact only the starting material was recovered (1H
NMR).
Considering the fact that it could be important to dry the IL, the reaction, using G3TFSI 3.21, was repeated. Thus, the IL was previously dried for 24 h at 70°C under vacuum and then the epoxide 2.11α was added to a solution of G3TFSI 3.21 (1.2 mL) and MeOH (20 equiv.) under argon atmosphere. However, even in this case, only the starting material was recovered in the crude mixture (1H NMR) (Table 3.1, entries 1-2)
At this point, we decided to use another IL (G4TFSI 3.22), composed by a longer ether chain. G4TFSI 3.22, is a PEG-based glymes, contained five oxygen, instead of G3TFSI 3.21 which was composed by four oxygen atoms. We supposed that the Li+ cation,
52
contained in G4TFSI 3.22, which has a longer ether chain, could be more available to act as Lewis acid and as chelating agent.
Epoxide 2.11α was added to G4TFSI 3.22 (1.2 mL), previously dried, and subsequently MeOH (20.0 equiv.) was added to the reaction mixture, which was stirred at 70°C.
The work-up of this reaction was a crucial point; in fact glymes could be difficulty removed from the reaction mixture. In order to eliminate the residual IL, the crude mixture was diluted with AcOEt and washed with brine. The evaporation of the organic solution afforded a crude mixture in which there was a residual amount of IL, but the 1H NMR
analysis indicated clearly the presence of the two regioisomeric α-methoxy alcohols 3.14 and 3.15 in 60:40 ratio.
This result confirmed our hypothesis: Li+ cation in G4TFSI 3.22 was more available to
act as a chelating agent and as Lewis acid (Table 3.1, entry 3).
Nevertheless, we did not obtain a satisfactory regioselectivity, so that we decided to repeat the reaction with G4TFSI 3.22, which was previously dried, using this time, an excess of a salt containing Li+ (LiTf
2N) in order to increase the amount of Li+ acted as
chelating agent. Epoxide 2.11α was treated with MeOH (20.0 equiv.)/LiTf2N (1.2
equiv.)/G4TFSI 3.22 under the usual protocol. After 18 h the crude mixture was subjected to the work-up; this time, Et2O were used as organic solvent because it was found that
G4TFSI 3.22 was less soluble in Et2O than in AcOEt. However after the work-up a
residual amount of IL was found in the crude mixture, so it was filtered on silica gel pad and the evaporation of the organic solution afforded a crude product consisting of a 65:35 mixture of the two regioisomers 3.14 and 3.15 and a minimum amount of IL (1H NMR)
(Table 3.1, entry 4).
The reaction, even in this case, was not regioselective and the following step was to repeat the reaction, using a greater excess of LiTF2N, in order to increase the availability of
Li+ cation. Epoxide 2.11α was added to a solution of G4TFSI 3.22 and LiTf
2N (1 mL) an
then it was treated with MeOH (9.0 equiv.). After the usual work-up (using Et2O and water
and filtration on silica gel pad), the reaction afforded the two compound 3.14 and 3.15 in 65:35 ratio (1H NMR) (Table 3.1, entry 5).
53
These results were the first case in which we observed an interesting, even if incomplete, regioselectivity in favour of C(1)-adduct, using a nucleophile in controlled quantities and as solvent an IL containing Li+ cation with chelating properties.
In order to compare the behaviour of glymes with that of a classic ionic liquid in presence of an external salt containing Li+, we decided to use another type of IL
[BMIM(Tf2N)], which was already reported as reaction media in literature. Thus, the
ring-opening process of the epoxide 2.11α was also performed using the IL BMIM(Tf2N) 3.23,
used without any further treatment, and using an excess of Li(Tf2N).
Epoxide 2.11α was added to a solution of BMIM(Tf2N) 3.23 and LiTf2N (1.32 mL)
under argon atmosphere and, after the usual work-up, a crude mixture of the two compound 3.24 and 3.25 was obtained in 50:50 ratio (1H NMR) (Table 3.1, entry 6). In this
reaction, the water present in the IL, not preventively dried, acted, instead of the MeOH, as a nucleophile.
The two diols were subjected to a flash chromatography (7:3 hexane/AcOEt) and they were completely characterized by means of the corresponding acetates 3.24-Ac and 3.25-Ac (NMR) (Table 3.1, entry 6).
The ring-opening reaction of epoxide 2.11α was performed, again, using a solution (1.2 mL) of an excess of LiTf2N and BMIM(Tf2N) 3.23, which was previously dried at 70°C
under vacuum. The reaction was very slow and after the usual work-up, it afforded the two α-methoxy alcohols 3.14 and 3.15 in 65:35 ratio (1H NMR) (Table 3.1, entry 7).
In this preliminary study G4TFSI 3.22 turned out to be the most efficient ionic liquid to direct the ring-opening process of the epoxide 2.11α, but the use of an excess of LiTf2N
did not drastically modify the regioselectivity of the addition reaction with MeOH.
Thus, we have identified as the most useful protocol for the ring-opening process of epoxide 2.11α the one in which the reaction was performed at 70°C using G4TFSI 3.22, previously dried, and using the nucleophile in controlled quantities without an excess of LiTf2N.
In order to verify the efficiency of this protocol for the synthesis of pseudodisaccharides, we decide to perform the ring-opening reaction of epoxide 2.11α, using two more hindered O-nucleophiles: a commercially available primary alcohol
