Carbohydrate Chemical Synthesis March 31, 2015 Carbohydrates vs. Protein • Proteins and oligo-/polysaccharides are biomacromolecules assembled from basic building blocks (amino Protein acids and monosaccharides CH3 H respectively). N N • Their modular nature suggests both H O classes of molecules as candidates for stepwise synthetic strategies. • Residues in proteins are linked by Carbohydrate peptide (amide) bonds. CH2OH H O H • Residues in oligo-/polysaccharides H OH H are linked by glycosidic bonds. O O H OH • Unlike proteins which are linear, oligo-/polysaccharides can be branched. O OH 6 5 1 4 3 H CH2OH O H H OH H 2 O H OH Glycosidic Bond • • • • Glycosidic bonds are the backbone linkages connecting the monosaccharide residues in oligo- and polysaccharides. Cyclic monosaccharides are essentially cyclic hemiacetals. Glycosidic bonds are formed when monosaccharides react with other monosaccharides or alcohols under acidic conditions, forming a mixed acetal. Glycosidic bonds can have either α- or β-configurations. H CH2OH O H H OH H H CH2OH O H H OH H O HO H OH OH H OH Maltose: O-α-D-glucopyranosyl(1->4)-D-glucopyranose H CH2OH O H H OH H HO H OH H CH2OH O H H OH H HO OH OH H α-D-Glucopyranose α-D-Glucopyranose Glycosidic Bond • Oligosaccharide synthesis requires: I. A suitable glycosyl donor with an appropriate leaving group on the anomeric carbon. II. Efficient and stereoselective coupling of the glycosyl acceptor. III. Functional groups (-OH) on the glycosyl acceptor and donor must be appropriately protected. R'O 1.) activation of leaving group X O X glycosyl donor 2.) nucleophilic attack by -OH HO O OR glycosyl acceptor R'O O O OH O OR Factors Influencing Glycosidic Bond Formation • Neighboring group parNeighboring Groups: ticipation (stereochemical): O O – Neighboring acyl groups at C2 O O position. – Formation of an acyloxonium Oxocarbenium ion ion intermediate. – Resulting dioxolenium ion promotes 1,2-trans product. • Solvent affect: O O O O Dioxolenium ion O O O Solvent: O Et2O XO O CH3CN O XO OR Axial product O OX O R Orthoester ROH OEt2 – CH3CN favors equatorial product. – Et2O (in combination with halogenated solvent) promotes axial product. 1,2-trans product O OR ROH O ROH XO N CCH 3 OR XO Equatorial product Formation of 1,2-cis product • Participation of acyl groups in on C2 promote 1,2-trans glycosidation. • Preferential formation of 1,2-cis product presents a greater challenge. – A glycosidation reaction employing an SN2 mechanism could be used to form the 1,2-cis product. – β-pyranosyl halides are too unstable for such an approach to be practical. – α-pyranosyl bromides are less reactive than their β- analogs, but when treated with tetraalkyl ammonium bromide, they form the β-anomer (in in situ Anomerization situ). OBn – The β-anomer reacts much faster than the αisomer, which results in preferential formation of the α-glycoside. – This strategy works well with galactose and fructose, but not with glucose or mannose. OBn O BnO BnO BnO Br OBn BnO BnO tight ion pair in α-mode R-OH SN2-type presence of tetraalkylammonium halide O R-OH O Br BnO tight ion pair in β-mode OR BnO 1,2-trans glycoside BnO BnO SN1-type Br OBn BnO BnO BnO Br O BnO OBn OBn BnO BnO O BnO BnO O OBn R-OH BnO SN1-type R-OH SN2-type BnO BnO O BnO OR 1,2-cis glycoside Oxocarbenium Ion O + OH H O H2O Y O HO O Y O O X Glycosidic Bond Oxocarbenium Ion O X • Three preferred synthetic strategies have been developed that allow the synthesis of of most oligosaccharides. 1. Koenigs-Knorr type reactions employing glycosyl halides. 2. Chemistry based on glycosyl trichloroacetimidates. 3. Use of stable glycosides (i.e. thio- and n-pentenyl glycosides)as glycosyl donors. Common Abbreviations and Protecting Groups Me = Methyl H3C tBu = t-Butyl Bn = Benzyl Ac = Acetyl O H3C H3C H3C H3C PMB = p-Methoxybenzyl Phth = Phthalimido O N O Isopropylidine H3C H3C H3CO N-protection O O ketal Koenigs-Knorr Method OAc AcO AcO OAc HBr-HOAc O AcO OAc O AcO AcO OAc ROH Ag2CO3, CH2Cl2 O AcO AcO AcO OR AcO Br • Oldest and most widely used chemistry for the stereospecific formation of glycosidic bonds. (Koenigs & Knorr, 1901). • Utilizes glycosyl halides (Br, Cl or F) as glycosyl donors. • Order of reactivity: I>Br>Cl>F. (Glycosyl iodides are too reactive for general use and glycosyl fluorides require special activation.) • Silver salts serve as promoters to generate oxocarbenium ion. – Insoluble salts: Ag2O and Ag2CO3 – Soluble salts: AgOTf and AgClO3 • Participating protecting groups @C2 position usually results in exclusive formation of the 1,2-trans glycosides. Koenigs-Knorr • Strategies have been developed that utilize mercury salts (HgBr2 and Hg(CN)2) as activators. • Glycosyl bromides and chlorides are readily available from peracetylated sugars or those with free anomeric -OH. • Two major disadvantages associated with KoenigsKnorr chemistry: OAc CH3COCl AcO AcO O AcO AcO Oph AcO Cl O HO HO KOPh AcO OH – The intrinsic lability of glycosyl halides. – Need for heavy metal salts in near equimolar amounts. OAc O OH HO OAc D-glucose CH3COBr OAc O AcO AcO MeOH Ag2CO3 AcO O AcO AcO OMe AcO Br OAc OAc AcO AcO AcO AcO O O BnO OH O AgOTf PhtNH O PhtNH BnO O O O OBn Br OBn N O O n-pentenyl glycoside O SR alkyl thioglycoside Br2 CH2Cl2 Br2/CH2Cl2 or Bu4NBr/CuBr2 O Br Koenigs-Knorr HF/Pyridine (Glycosyl Fluorides) CF3CHFCF2NEt2 O O OH • Glycosyl fluorides can be prepared directly from unprotected anomeric -OH groups. • Can easily prepare β-glycosyl fluorides. • Used more frequently than other glycosyl halides. • Generally more stable to hydrolysis under basic conditions. • Require special promoter chemistry: DEAD/Ph3P/ Et3O+BF4- OAc OBn AcO OBn BnO AcO F AcO OAc OAc O AcO AcO HF OAc AcO AcO Ac2O AcO AcO H3C O O X F X = Lewis acid or combination of Sn and Ag salts O OH NPhth O O OBn OBn OBn Et2NSF3 BnO OBn AcO OBn BnO AcHN O BnO AcO Me F O O AcO NPhth O OBn O(CH2)6CO2tBu NHAc O H3C OBn O O HO OBn OBn OBn O O O O O HO OBn OBn MeO2C OBn OBn AgOTf/HfCp2Cl2, CH2Cl2 4Å molecular sieves BnO OBn AcO OBn BnO AcHN O BnO O AcO Me OBn O O OBn OBn O O O O HO OBn OBn MeO2C O AcO F O O O AcO AcO Br O O AgF OBn MeO2C BnO AcHN OAc O AcO AcO ! Lewis acids: BF3•Et2O, SnCl4, AlMe3, TMSOTf or TiF4. ! Alternatives: SnCl2/AgClO4, SnCl2/TrClO4 or AgOTf BnO F Et2NSF3 (DAST) OBn O O O NPhth AcO H3C OBn O O OBn OBn O(CH2)6CO2tBu NHAc Glycosyl Trichloroacetimidates • The underlying chemistry of forming glycosydic bonds via glycosyl trichloroacetimidates is similar to that of glycosyl halides. • In glycosyl trichloroacetimidates, the anomeric oxygen is derivatized AcOAcO providing a suitable leaving group. • The anomeric -OH of an O– BnO protected reducing sugar is BnO deprotonated by treatment with base (i.e. NaH, K2CO3 or DBU). • The resulting oxyanion adds across the triple bond of trichloroacetonitrile. AcO AcO O K2CO3, CCl3CN AcO O AcO AcO OH AcO O CCl3 NH BnO BnO O BnO BnO NaH, CCl3CN OH BnO O BnO O CCl3 NH Glycosyl Trichloroacetimidates • Glycosyl trichloroacetimidates are Ph activated using catalytic amounts O O O HO of Lewis acid such AcO BnO AcO as BF3•Et2O or O CCl TMSOTf. NH • These activated glycosyl trichloroacetimidates are good glycosyl donors requiring relatively mild reaction conditions. • Normally, the glycosyl donor and acceptor are combined in an inert solvent (i.e. DCM or ACN) and the Lewis acid catalyst is then added. • This chemistry usually results in good yields in both small and large scale reactions. • Donors with ether protecting groups tend to be more reactive than those with ester protecting groups. Ph OBn BF3•Et2O O BnO 3 O O OBn O CH2Cl2 AcO OBn AcO O O BnO BnO OBn BnO OBn BnO OBn O BnO OBn O HO BnO O BnO O O BnO N3 CCl3 OBn NH TMSOTf Et2O, -20°C BnO OBn O BnO BnO OBn OBn O BnO O BnO O BnO O N3 OBn • Thioglycosides are widely used as glycosyl donors in the synthesis of oligosaccharides. • Thioglycosides are versatile glycosyle donors, stable in the absence of thiophilic promoters. • Thioglycoside formation: – Glycosyl halides and acetates can be converted to thioglycosides using thiolate ions) and catalytic Lewis acid. – Tin-mediated thioalkylation (Bu3SnSR) can be used to prepare thioglycosides from glycosyl halides and acetates. – Glycosyl acetates can be converted directly to thioglycosides using an alkyl/aryl thiol and catalytic Lewis acid. – Trimethylsilyl thiothers in and catalytic Lewis acid can be used to form thioglycosides from glycosyl esters. Thioglycosides OAc OAc O AcO AcO OAc X X Bu3SnSR SnCl4 Br – OR – TMSSR BF3•Et2O 1.) MeSH, K, MeOH 2.) Ac2O, NaOAc OAc – OR – TiCl4 EtSH O AcO AcO SR X alkyl/aryl β-D-thioglucopyranoside – OR – RSH BF3•Et2O X = OAc or NHPhTh OAc OAc p-NO2PhSH, NaH O AcO AcO O AcO AcO AcO O AcO AcO HMPA Cl AcO SPhNO2 OAc BF3•Et2O, EtSH O AcO AcO O AcO AcO HMPA AcO AcO SEt OAc Thioglycosides • Thiophilic promoters that can be used to activate thioglycosides include: – Sources of Br+ (Br2/AgOTf, N– bromosuccinimide) – Alkylating agents (i.e. MeOTf). – Sulfenylating agents (i.e. DMTS). O O Br+ SR O R'OH OR' [Me2SSMe]+TfO- SMe O O OBn OAc OAc AcO O AcO AcO AcO O SMe O HO BnO O BnO OBn OAc CuBr2 Et4NBr AgOTf OAc OAc AcO OR' OTf OTf • Glycosidation is believed to occur through formation of oxocarbenium ion. • Selection of reaction conditions and promoter chemistry can be used to control anomeric preferences. DMTS: O R'OH S R OBn O AcO AcO AcO O O O BnO O BnO OBn OAc dimethyl(methylthio)sulfonium triflate Thioglycosides CO2Me • The stability of thioglycosides provides greater flexibility and utility. • Highly specific methods have been developed for activation. • In the absence of thiophilic promoters: OBn O O O BnO O BnO O HO BnO SR BnO NH CCl3 TMSOTf CO2Me OBn – Thioglycosides are stable to activation conditions associated with glycosyl donors such as glycosyl trichloroacetimidates. – Thioglycosides are also stable to OH alkaline conditions associated with the removal acetyl HO protecting groups. – Stability allows removal and replacement of O-protecting OAc groups. O O O O AcO O BnO AcO BnO SR OH 1. DMP, acetone, pTsOH 2. 4,4'-MeOTrCl, pyridine, 70°C O SR 3. NaH, PMB-Cl, DMF 4. HCOOH, CH2Cl2 5. AcCl, pyridine, CH2Cl2 HO O O SR PMBO OBz O SR AcO OAc O O 1. NaOMe/MeOH 2. DMP, pTsOH 3. BzCl, pyridine OAc O SR O NPhth NPhth Thioglycosides OAc • Thioglycosides are exceptionally versatile molecules. • Thioglycosides can be converted to alternative activated glycosyl donors (i.e. halides and trichloroacetimidates). • Thioglycosides can also be used to generate glycosyl acetates. AcO AcO OAc AcO AcO O AcO OAc OAc O AcO OH AcO AcO RSH, R=Ph or Et BF3•Et2O O AcO Br NBS H2O Br2 OAc AcO AcO NIS AcOH O SR AcO alkyl/aryl β-D-thioglucopyranoside NBS DAST OAc OAc AcO AcO R'OH promotor O AcO OAc AcO AcO O AcO OAc AcO AcO O AcO OR' NBS = N-bromosuccinimide DAST = diethylaminosulfur trifluoride NIS = N-iodosuccinimide F Glycals OR OR RO RO OR RO RO E O R'OH E+ E OR O O red. RO RO RO RO OR' O OR OR O O O RO RO OR' ZnCl2 R'OH O RO RO OR' O • The glycal method originally used in the synthesis of 2– deoxyglycosides. • Strategy capitalizes on the electron-rich olefin of the enol ether present in glycals. • A 3-membered onium ion species can be generated by treating the glycal with an elecrophile (E+). (Suitable lectrophiles include: N-iodosuccinimide, phenylselenyl chloride or phenylsulfenyl chloride.) • The onium speices is then glycosidated. (usually results in αconfiguration) • The elcrophile, E, can then be reductively removed to afford the 2-deoxyglycoside. Glycals OR OR RO RO OR RO RO E O R'OH E+ E OR O O red. RO RO RO RO OR' O OR OR O O O RO RO OR' ZnCl2 R'OH O RO RO OR' O • While glycals were originally used in the synthesis of 2deoxyglycosides, Danishefsky and coworkers devised a glycal strategy that afforded 2-hydroxyglycosides. • Glycals are initially treated with dimethyldioxirane which transfers an oxygen bond to the glycal resulting in an epoxide. • The epoxide is then activated using a Lewis acid such as ZnCl2. • The glycosidic bond is then formed by treating the activated epoxide with the desired acceptor. • This strategy usually affords β-glycosides. • Glycosyl epoxides are relatively stable and they can be isolated. Carbohydrate Protecting Groups Selective hydroxyl group protection and deprotection Protecting Groups in Carbohydrate chemistry • Amino acids and proteins have a range of functional group chemistries. • Carbohydrate protecting group chemistry is a matter of differentiating between -OH groups. – – – – – The anomeric -OH 1 vs 2 alcohols Equatorial vs axial diols Vicinal diols Cis- vs trans- diols. OH O HO HO OH OH OH OH O OH HO OH Ethers Acetals Esters O O O R O R O R R Protection at the Anomeric Center Hemiacetal • Due to the reactivity of the anomeric center, it is usually protected before other -OH groups. • Glycoside protection chemistry should be stable to a range of conditions, but must allow for selective deprotection of the anomeric group. • The simplest strategy is to generate the acetal (the glycoside) via acidcatalyzed reaction with an alcohol (Fischer glycosylation). O HO HO OH OH H+ H2O OH OH O HO HO HO O HO HO Oxocarbenium ion HO ROH H+ Glycoside (acetal) OH O HO HO OR OH OH OH Deprotection – Limited to low-boiling alcohols (methanol, ethanol and alllyl alcohol). – Acidic ion-exchange resin is usually used as the acid catalyst. – Yields a mixture of anomers. Usually the most stable product is formed in excess. OH O HO HO O HO HO OR OH OH OH R = ME: strong acidic conditions and high temperature. Allyl: [Pd], p-TsOH and elevated temperature. Benzyl: [Pd], H2, room temperature. Alternative Strategies for Protection of Anomeric OH • For oligosaccharides it is often necessary to resort to protection schemes that allow for selective deprotection of the anomeric OH using mild conditions. • 2-(trimethylsilyl)ethyl (TMSET) glycosides meet this requirement. • Easily formed using standard Koenigs-Knorr glycosylation chemistry and 2-(trimethylsilyl) ethanol. • Compatible with most deprotection and glycosylation reaction conditions. • Can be converted to glycosyl halides, free -OH and 1-O-acyl derivatives. OAc OAc O AcO AcO AcO SiMe3 HO SiMe3 O AcO AcO Ag-salt O AcO Br 1. NaOMe, MeOH 2. "protecting steps" OR SiMe3 O RO RO O RO Cl2CHOCH3 ZnCl2 BF3•Et2O Ac2O OR TFA OR O RO RO RO O RO RO OR Cl O RO RO OH RO OAc RO Alternative Strategies for Protection of Anomeric OH • Silyl ethers are frequently used for the protection of alcohols. • They are stable to conditions involved with removal of Acprotecting groups and thioglycoside chemistry. • TBSOtf is a very reactive reagent for silylation of alcohols. • Can be selectively removed under mild conditions using TBAF (fluoride source). OBn O AcO BnO PhSO2 NH OBn O AcO BnO PhSO2 NH TBSOTf, 2,6-lutidine CH2Cl2 OH OTBS TBAF, AcOH TBSOTf = tert-butyldimethylsilyl triflate TBAF = tetra-N-butylammonium fluoride 2,6-lutidine = OBn N O AcO BnO PhSO2 NH OH Acyl Protecting Groups Ac2O R = Ac • Acyl-based protecting groups are frequently used in carbohydrate chemistry. • Complete acetylation of an unprotected monosaccharide using Ac2O is often an initial synthetic step. (per benzoylation may also be implemented). • Esters are readily cleaved under basic conditions. • Rather than saponification, a transesterification procedure is used (Zemplén procedure). • Benzoates are generally slower to deprotect than acetates. BzCl OH R = Bz OR O HO HO O RO RO OH HO OR RO NaOMe, MeOH O R OH R O N N O O O O O O O O O O Acetate group Benzoylate group O O Pivaloate group Selective Acylation OH OH O HO HO Pyridine, CH2Cl2 -40°C OCH3 BzO BzO O HO HO O BzCl OAc OH OBz OH HO OCH3 ~90% AcCl Pyridine OH O AcO AcO OAc AcO O O OAc HO OH HO O O AcO HO • Regioselective acylation provides route to selective protection patterns. • At lower reaction temperatures, primary and equatorial OH groups are usually benzoylated before axial ones. • Order of reactivity of the -OH groups on a pyranose ring will vary depending on the sugar. • Sterics can play a significant role when acylating oligosaccharides. • Acyl groups can migrate (change position inter and intramolecular). Acetyl groups are most prone to migration. Benzoyl groups to a lesser extent and pivaloyl groups essentially do not migrate. Selective Deacylation • An assortment of methods have been developed for the selective deacylation of the anomeric center. • Generally 1 equivalent of base is used. – Acetyl esters: hydrazine acetate, hydrazine hydrate, piperidine and 2-amino ethanol, or ethylenediamine/ AcOH. – Benzoyl esters: ethanolic dimethylamine in pyridine. • Removal of anomeric benzoyl groups generally takes longer than the removal of acetyl groups. OAc OAc O AcO AcO OAc AcO 1 equiv. base O AcO AcO OH AcO Ether Protecting Groups • Alkyl ethers are generally very stable and resistant to strong base/acid. (making them too stable) • Benzyl and allyl ethers are the ether variants used most frequently. • Ether and ester derivatives combine to provide orthogonality in protection chemistry. • Ethers can be formed using Williamson reaction conditions (NaH or NaOH and an alkyl/aryl halide-Br or Cl). [these conditions may not be suitable for most ester protecting groups.] R= O 1. base (NaH or NaOH) OH O OR 2. R-Hal (Hal = Cl or Br) Benzyl ether (Bn) Ether Protecting Groups • Benzyl ethers: ✽ Removed by catalytic hydrogenation (10% Pd-C). Usually results in quantitative deprotection. ✽ Substituted benzyl ethers occassionally used (i.e. pmethoxybenzyl [pMBn]) ✽ pMBn can be oxidatively removed using CAN or DDQ. (Bn ethers stable to these conditions.) • Allyl ethers: Allyl ether p-Methoxybenzyl ether OAc OBn OAc OBn AcHN O pMBnO O AcO AcO OR O AcO O AcHN O DDQ, CH2Cl2, H2O HO OR O AcO OBn OBn O NC Cl 2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ) NC Cl O Allyl ether OAc OAc O AcO AcO AcO Isomerization O OAc O AcO AcO AcO Mild acid O O AcO AcO OH AcO (2-propenyl ether) ✽ Cleaved under mild conditions and compatible with most protection, deprotection and glycosylation chemistries. ✽ Allyl groups are converted to 2-propenyl ethers (isomerization) by treating with metal catalyst: Pd(0), Rh(I) or Ir(II). ✽ 2-propenyl ether readily hydrolyzed with mild acid. ✽ Alternative: in presence of sensitive groups (isopropylidienes) a mixture of HgO and HgCl2 in aqueous acetone for enol cleavage. Ether Protecting Groups (Trityl ethers) • Trityl ethers: selective for • • • • primary alcohols. Introduced under basic conditions (pyridine) and trityl chloride. Trityl groups can be cleaved under mild acidic conditions (mineral acid in ether). Cleavage conditions may be mild enough to leave isopropylidene groups intact. Substituted trityl groups can be used for even milder deprotection conditions (silica gel or Lewis acid). • Silyl ethers: becoming • • • • • (OTr or OTrt) OH O Ph3CCl DMAP, pyridine O HO HO HO O HO HO HO OCH3 OCH3 Trityl chloride OCH3 Cl OCH3 H3CO Cl Cl Monomethoxytrityl (Mmt) chloride increasingly important as hydroxyl protecting groups. Large number of variations demonstrating a range of reactivities and stability. Generally prepared using appropriate silyl chloride (or triflate) and base (pyridine or imidazole) in DMF. (May also use hexamethyldisilazane in DMF.) t-Butyldimethylsilyl (TBDMS or TBS)group is commonly used in silyl ethers. Silyl ethers can be deprotected under acidic conditions or with fluoride ions (tetrabutylammonium fluoride). Deprotection with fluoride allows removal of silyl ethers in the presence of acid sensitive groups. Dimethoxytrityl (Dmt) chloride Ether Protecting Groups (Silyl ethers) R3Si-Cl OH base O-SiR3 acid or OH fluoride OH TBDMS-Cl O HO HO pyridine HO OCH3 OTBDMs O HO HO HO OTBDMs O HO HO TBDMSO TBDMS-Cl imidazole, DMF OCH3 TBDMS-Cl allows for selective protection of primary OH. Use of imidazole as a catalyst results in 2,6-O-silylated product OCH3 Acetal/Ketal Protecting Groups • Cyclic acetals/ketals allow the simultaneous protection of two hydroxyl groups. • The most common examples are isopropylidene and benzylidene derivatives. • Acetal/ketal formation is generally an acid catalyzed process. • Acetal/ketal protecing groups are stable to nucleophiles and basic conditions, but are acid labile. O H3C O CH3 CH3 CH3 O isopropylidene OH OH O H O O H benzylidene Benzylidene Acetals • Benzylidene acetals mostly form 6membered rings with the phenyl group in an equatorial position. • Generally prepared using free sugar, benzaldehyde and ZnCl2 catalyst. • Generally used for 4,6O-protection in hexopyranosides. • Can form either cis- or trans-fused rings. (trans generally hydrolyze more quickly.) H Ph-CHO ZnCl2 O HO HO trans-fused Ph OH O O O HO HO HO OCH3 OCH3 Ph H OH OH O Ph-CHO ZnCl2 O cis-fused O O HO HO HO HO OCH3 OCH3 OH O HO HO OH HO O O HO OH HO H Ph Ph-CH(OMe)2 O O O OH HO p-TsOH HO O O HO OH HO Benzylidene Removal OH • Benzylidene groups can be removed using acidic conditions or by hydrogenation. • Additional (selective) cleavage chemistries: ✽ Radical oxidative opening (NBS). ✽ Reductive opening with LAH & AlCl3 in ehter. ✽ Reductive regioselective opening of the aetal using sodium cyanoborohydride in HCl-ether. OH O HO O BzO RO RO RO RO OCH3 H2, Pd(OH)2 EtOH OCH3 NBS, CCl4 Δ H Ph O O O RO RO OCH3 NaCNBH3, THF HCl-Et2O LAH, AlCl3 ether OBn OH O HO O BnO RO RO RO RO OCH3 OCH3 Isopropylidine Ketals • Often used in the protection or cis-1,2-diols. • Introduced using dry acetone and an acid or Lewis acid catalyst (ZnCl2). • 5-membered dioxolane rings are generally formed • Can also be introduced via transacetalization and 2,2-dimethyloxypropane. • 2-methyloxypropene can be used, tends to form 1,3dioxane rings. 2,2-dimethyloxypropane O H3C CH3 H3CO OCH3 H3C CH3 2-methyloxypropene OCH3 O Thermodynamic control Kinetic control OCH3 -orO CH3 H3CO OCH3 H3C CH3 CH3 H3C O OH O O OH HO O HO HO CH3 HO [H+] OH HO O H3C CH3 H3C O H3C O OH O O O CH3 CH3 Isopropylidine Ketals • Use of varied Lewis acids with acetone can result in formation of different isopropylidenes. O Acetone 10% H2SO4 H3BO4 O O O O O HO • Acetalization of unprotected pyranoses/ furanoses/ alditols affords useful propylidene protected building blocks with limited numbers of free OH groups. HO OH HO OH OH D-mannitol O O OH Acetone HO ZnCl2 O O Selective Hydrolysis of Isopropylidenes • Isopropylidene groups are removed under acidic conditions (i.e. AcOH, H2SO4 in MeOH or silica gel). • Conditions have to be optimized for specific isopropylidene derivatives. • Optimization of conditions can allow for the selective removal of one or more isopropylidene groups while leaving others intact. • In pyranoses and furanoses, a 1,2O-isopropylidene is generally more stable than are isopropylidenes at other positions. • Five-membered dioxolanes are more stable than 6 membered dioxanes. HO aqueous acid HO O O OH OH O O O O O O 1,2:3,4:5,6-tri-O-isopropylidene D-glucitol HO HO OH acetone HO dry HCl gas OH OH D-mannitol
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