Selective Epimerization Research Articles

General Strategy for the Synthesis of Rare Sugars via Ru(II)-Catalyzed and Boron-Mediated Selective Epimerization of 1,2-trans-Diols to 1,2-cis-Diols.

Human glycans are primarily composed of nine common sugar building blocks. On the other hand, several hundred monosaccharides have been discovered in bacteria and most of them are not readily available. The ability to access these rare sugars and the corresponding glycoconjugates can facilitate the studies of various fundamentally important biological processes in bacteria, including interactions between microbiota and the human host. Many rare sugars also exist in a variety of natural products and pharmaceutical reagents with significant biological activities. Although several methods have been developed for the synthesis of rare monosaccharides, most of them involve lengthy steps. Herein, we report an efficient and general strategy that can provide access to rare sugars from commercially available common monosaccharides via a one-step Ru(II)-catalyzed and boron-mediated selective epimerization of 1,2-trans-diols to 1,2-cis-diols. The formation of boronate esters drives the equilibrium toward 1,2-cis-diol products, which can be immediately used for further selective functionalization and glycosylation. The utility of this strategy was demonstrated by the efficient construction of glycoside skeletons in natural products or bioactive compounds.

Selective Isomerization via Transient Thermodynamic Control: Dynamic Epimerization of trans to cis Diols.

Traditional approaches to stereoselective synthesis require high levels of enantio- and diastereocontrol in every step that forms a new stereocenter. Here, we report an alternative approach, in which the stereochemistry of organic substrates is selectively edited without further structural modification, a strategy with the potential to allow new classes of late-stage stereochemical manipulation and provide access to rare or valuable stereochemical configurations. In this work, we describe a selective epimerization of cyclic diols enabled by hydrogen atom transfer photocatalysis and boronic acid mediated transient thermodynamic control, selectively generating less stable cis products from the otherwise favored trans isomers. A range of substitution patterns and ring sizes are amenable to selective isomerization, including stereochemically complex polyols such as estriol, as well as syn to anti epimerization of acyclic vicinal diols. Moreover, this strategy has enabled the divergent epimerization of saccharide anomers, providing access to distinct sugar isomers from α- or β-configured glycosides.

Two Distinct Hydrogen Atom Transfer Steps Permit Selective Epimerization of Pyranose Frameworks

Key words photoredox catalysis - pyranoses - hydrogen atom transfer - epimerization

Porous Tin-Organic Frameworks as Selective Epimerization Catalysts in Aqueous Solutions

Epimerization of sugars is a carbon-efficient route not only to produce rare carbohydrates but also to extend the product scope for chemical production in future biorefineries. Industrially available catalysts for epimerization are limited mainly to soluble Mo(VI) species as well as substrate-specific epimerases. Here we report highly active and selective tin-organic frameworks (Sn-OF) as solid catalysts for the epimerization of aldoses at the C-2 position, such as the conversion of glucose to mannose. The reaction proceeds via a carbon skeleton rearrangement, that is, through breaking of a C-2/C-3 carbon bond and formation of a C-1/C-3 bond. Partially hydrolyzed Ph3Sn-OH sites were found to be the catalytically active centers. Our results suggest that the high catalytic activity of Sn-OFs for the epimerization is determined by (1) Lewis acidity of tin; (2) free Sn-OH groups; and (3) the high hydrophobicity of organic linkers applied in the aqueous solutions.

A mechanism for the selective epimerization of the glucose mannose pair by Mo-based compounds: towards catalyst optimization

The reducibility of Mo centers of H3PMo12O40 allows the selective C2 epimerization of glucose/mannose through a Mo-assisted 1,2 C-shift.

Synthesis of (2R)- and (2S)-aminooxy analogues of β-O-glucosylserine andN-oxyamide linked glycoconjugates

Glycosyl amino acids are constituents of glycopeptides and glycoproteins playing important roles in various cellular activities and pathogenic processes. We have stereoselectively synthesized both (2R)- and (2S)-aminooxy analogues of β-O-glucosylserine from sn-(3-β-O-glucosyl)glycerol through selective protection, Mitsunobu reaction, oxidation and Lattrell-Dax epimerization reactions. N-oxyamide linked glycopetides and glycolipids have been prepared from the β-O-glucosyl aminooxy acid derivatives. 1H NMR and IR studies suggest the formation of an α N−O turn structure in the glycopeptide 19.

Enantioselective Total Synthesis and Structural Revision of (－)-Isochaetominine

In this paper, the enantioselective total synthesis and structure revision of the proposed structure of isochaetom- inine 8 are described. On the basis of the stereodivergent strategy, a highly efficient five-step synthesis of the proposed struc- ture of isochaetominine 8 and its diastereomer (+)-2,3,14-tri-epi-chaetominine (12) was achieved. The method features the use of L-tryptophan and L-alanine benzyl ester as the starting materials, and a dimethyldioxirane (DMDO)-triggered tandem reac- tion as a key step. A comparison of the physical and spectral data of the natural isochaetominine with those of the diastere- omers obtained during our previous stereodivergent synthesis of chaetominine (1), allowed revising the structure of isochae- tominine as (-)-11-epi-chaetominine (18). The first enantioselective total synthesis of this natural product has been accom- plished previously in our laboratories in five steps, 31.6% overall yield from L-tryptophan. Besides, an investigation on the L-tryptophan and L-valine tert-butyl ester-based synthesis of isochaetominine C resulted in a stereodivergent synthesis of three diastereomers of isochaetominine C. Finally, it was revealed that attempted site selective epimerization at C(14) of 13B led to a bis-epimerization at both C(14) and C(11). Keywords alkaloids; isochaetominine; total synthesis; structural revision; stereodivergent synthesis; epimerization

Degradation and epimerization of ergot alkaloids after baking and in vitro digestion

The degradation and epimerization of ergot alkaloids (EAs) in rye flour were investigated after baking cookies and subsequently subjecting them to an in vitro digestion model. Different steps of digestion were analyzed using salivary, gastric, and duodenal juices. The degradation and bidirectional conversion of the toxicologically relevant (R)-epimers and the biologically inactive (S)-epimers for seven pairs of EAs were determined by a HPLC method coupled with fluorescence detection. Baking cookies resulted in degradation of EAs (2-30 %) and a shift in the epimeric ratio toward the (S)-epimer for all EAs. The applied digestion model led to a selective toxification of ergotamine and ergosine, two ergotamine-type EAs. The initial percentage of the toxic (R)-epimer in relation to the total toxin content was considerably increased after digestion of cookies. Ergotamine and ergosine increased from 32 to 51 % and 35 to 55 %, respectively. In contrast, EAs of the ergotoxine type (ergocornine, α- and β-ergocryptine, and ergocristine) showed an epimeric shift toward their biologically inactive (S)-epimers. Further experiments indicated that the selective epimerization of ergotamine EAs occurs in the duodenal juice only. These results demonstrate that toxification of EAs in the intestinal tract should be taken into consideration.

Sn-Beta zeolites with borate salts catalyse the epimerization of carbohydrates via an intramolecular carbon shift

Carbohydrate epimerization is an essential technology for the widespread production of rare sugars. In contrast to other enzymes, most epimerases are only active on sugars substituted with phosphate or nucleotide groups, thus drastically restricting their use. Here we show that Sn-Beta zeolite in the presence of sodium tetraborate catalyses the selective epimerization of aldoses in aqueous media. Specifically, a 5 wt% aldose (for example, glucose, xylose or arabinose) solution with a 4:1 aldose:sodium tetraborate molar ratio reacted with catalytic amounts of Sn-Beta yields near-equilibrium epimerization product distributions. The reaction proceeds by way of a 1,2 carbon shift wherein the bond between C-2 and C-3 is cleaved and a new bond between C-1 and C-3 is formed, with C-1 moving to the C-2 position with an inverted configuration. This work provides a general method of performing carbohydrate epimerizations that surmounts the main disadvantages of current enzymatic and inorganic processes.

4-(1-Haloalkyl)-3-nitrotetrahydrofurans as versatile scaffolds for the synthesis of diversely functionalized tetrahydrofurans

4-(1-Haloalkyl)-3-nitrotetrahydrofurans, which are accessible by tandem oxidative oxa-Michael addition/radical cyclization/ligand transfer reactions, can be processed to diversely substituted tetrahydrofuran derivatives. Selective epimerization at the nitro function provides tetrahydrofuran diastereomers, which cannot be prepared by the tandem process. Intramolecular alkylations furnish interesting bridgehead nitro oxabicyclo[3.1.0]hexane derivatives in high yields. Intermolecular substitution reactions of the halide functions succeed only with nucleophiles, which are not basic enough to trigger intramolecular alkylations. The aryl substituent in 2-aryl-3-nitrotetrahydrofurans can be selectively oxidatively transformed to carboxylic acid derivatives using catalytic Ru(III) and NaIO 4 without affecting the nitro group. Reduction and hydrogenation reactions provide differently substituted 3-aminotetrahydrofuran derivatives depending on the conditions with moderate to good chemoselectivity.

A New Access to Chiral Phospholanes

AbstractThe hydrogenation of 5‐oxo‐5H‐5λ5‐dibenzophosphol‐5‐ol gives, almost quantitatively, only one geometric isomer of 5‐oxododecahydro‐5λ5‐dibenzophosphol‐5‐ol (2). An X‐ray structure analysis confirmed the formation of a meso isomer with a 4aβ,5aβ,9aβ,9bβ configuration (2a). Another possible way to get 2a is the hydrogenation of (4aβ,5aβ)‐5‐oxo‐2,3,4,4a,5,5a,6,7,8,9‐decahydro‐1H‐5λ5‐dibenzophosphol‐5‐ol (11), which is easily available starting from cyclohexanone. Highly selective epimerization has been achieved using LDA as base at elevated temperature. Resolution of 2e was achieved by salt formation with (R)‐(+)‐ and (S)‐(–)‐N‐benzyl‐α‐methylbenzylamine to give (+)‐ and (–)‐(4aα,5aβ,9aβ,9bβ)‐5‐oxododecahydro‐5λ5‐dibenzophosphol‐5‐ol. The geometry of 2e was confirmed by X‐ray structure analysis. Reduction of (+)‐ or (–)‐2e gave diastereomeric phospholanes (4aα,5R/S,5aβ,9aβ,9bβ)‐dodecahydrodibenzophosphole (1a), which were oxidized to the corresponding secondary phosphane oxides (SPOs) (4aα,5R/S,5aβ,9aβ,9bβ)‐dodecahydrodibenzophosphole 5‐oxide (1b). These phosphanes and phosphane oxides were used as ligands and preligands, respectively, in the Rh‐catalyzed enantioselective hydrogenation of benchmark substrates, where up to 79 % ee have been achieved. B3LYP density functional calculations reveal that among the three possible epimers at the 4aC‐ and 5aC‐positions thechiral isomer (4aα,5aβ,9aβ,9bβ)‐5‐oxododecahydro‐5λ5‐dibenzophosphol‐5‐ol (2e) is 3.52 kcal mol–1 more stable than the related meso isomer 2a in Gibbs free energy. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Highly Substituted Tetrahydropyrones from Hetero-Diels−Alder Reactions of 2-Alkenals with Stereochemical Induction from Chiral Dienes

[reaction: see text] A new method for the stereoselective synthesis of libraries of 2,3,5-trisubstituted tetrahydro-gamma-pyrones and the corresponding tetrahydropyran-4-ols is reported. Dienes with a chiral moiety at position 5 were synthesized starting from (triphenylphosphoranylidene)acetone. In hetero-Diels-Alder (HDA) reactions, especially with alpha,beta-unsaturated aldehydes, they induce diastereomeric ratios from 4:1 to 14:1. Through selective epimerization and reduction, further building blocks are available. These constitute ideal starting points for their use in the total synthesis of complex polyketide macrocycles, especially with the vinyl group available for metathetic coupling.

A Concise Total Synthesis of (+)‐Okaramine C.

The first total synthesis of (+)-okaramine C is described. Our previously described selenocyclisation-oxidative deselenation sequence was used to establish a 3a-hydroxy-pyrrolo[2,3- b]indole core, which was modified by selective epimerisation to the common pyrrolo[2,3- b]indole of the okaramines.

Kinetic resolution of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates for the synthesis of homochiral 3-alkyl-cispentacin and 3-alkyl-transpentacin derivatives

High levels of stereocontrol are observed in the conjugate addition of lithium dibenzylamide to tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn), with addition occurring exclusively anti- to the 3-alkyl substituent. Treatment of a range of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, (i)Pr, (t)Bu) with lithium (RS)-N-benzyl-N-[small alpha]-methylbenzylamide indicates that good enantiorecognition is observed (E > 80) in their mutual kinetic resolution. In these reactions, conjugate addition of the lithium amide occurs exclusively anti- to the 3-alkyl substituent, with subsequent C(1)-protonation occurring preferably anti- to the 2-amino group in the 3-Et, 3-Bn and 3-(i)Pr cases, giving predominantly the corresponding 1,2-syn-2,3-anti-diastereoisomers. Conjugate addition to (RS)-3-tert-butyl cyclopentene-1-carboxylate results in exclusive 2,3-anti -addition and a reversal in C(1)-protonation selectivity, giving predominantly the 1,2-anti-2,3-anti-diastereoisomer. Furthermore, the kinetic resolution of the tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, (i)Pr, (t)Bu) with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds efficiently, giving, at between 47 and 51% conversion, the resolved 3-alkylcyclopentene-1-carboxylates in >85 to >98% ee and the beta-amino ester products of conjugate addition in high de, consistent with E > 80 in each case. Subsequent deprotection of the 1,2-syn-2,3-anti-3-alkyl-beta-amino esters (alkyl = Et, Bn, (i)Pr) by hydrogenolysis and ester hydrolysis gives the corresponding 1,2-syn-2,3-anti-3-alkylcispentacins in >98% de and 98 +/- 1% ee. Selective epimerisation of the 1,2-syn-2,3-anti-3-alkyl-beta-amino esters (alkyl = Et, Bn, (i)Pr, (t)Bu) by treatment with KO(t)Bu in (t)BuOH gives the corresponding 1,2-anti-2,3-anti-3-alkyl-beta-amino esters in quantitative yield and in >98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving the corresponding 1,2-anti-2,3-anti-3-alkylcispentacin hydrochlorides in >98% de.

A concise total synthesis of (+)-okaramine C.

The first total synthesis of (+)-okaramine C is described. Our previously described selenocyclisation-oxidative deselenation sequence was used to establish a 3a-hydroxy-pyrrolo[2,3-b]indole core, which was modified by selective epimerisation to the common pyrrolo[2,3-b]indole of the okaramines.

The first enantioselective synthesis of chiral norbornane-type 1,4-diamine ligand

The asymmetric synthesis of trans-2,3-bis(aminomethyl)norbornane was performed starting with endo-2,3-norbornene dicarboxylate anhydride. Desymmetrization of meso-anhydride 1 and following selective epimerization gave the trans-monoester (+)- 3 with a high enantiomeric excess (98% e.e.). LiAlH 4 reduction of the trans-monoester to the 1,4-diol, which was then treated with phthalimide under Mitsunobu conditions and, following a Gabriel type amine synthesis with hydrazine hydrate, yielded a saturated and unsaturated diamine mixture. Hydrogenation of mixture finally afforded saturated diamine (+)- 8 with a yield of 37%.

Asymmetric synthesis of (1R,2S,3R)-3-methylcispentacin and (1S,2S,3R)-3-methyltranspentacin by kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate.

Conjugate addition of lithium dibenzylamide to tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate occurs with high levels of stereocontrol, with preferential addition of lithium dibenzylamide to the face of the cyclic alpha,beta-unsaturated acceptor anti- to the 3-methyl substituent. High levels of enantiorecognition are observed between tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate and an excess of lithium (+/-)-N-benzyl-N-alpha-methylbenzylamide (10 eq.) (E > 140) in their mutual kinetic resolution, while the kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds to give, at 51% conversion, tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate consistent with E > 130, and in 39% yield and 99 +/- 0.5% de after purification. Subsequent deprotection by hydrogenolysis and ester hydrolysis gives (1R,2S,3R)-3-methylcispentacin in > 98% de and 98 +/- 1% ee. Selective epimerisation of tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate by treatment with KO'Bu in 'BuOH gives tert-butyl (1S,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate in quantitative yield and in > 98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving (1S,2S,3R)-3-methyltranspentacin hydrochloride in > 98% de and 97 +/- 1% ee.

Selective epimerization of l- chiro-inositol to l- muco- and d- chiro-inositol derivatives

In a one step procedure, l-1- O-benzyl-2- O-methyl- chiro-inositol ( 1) was acetalized to the l- muco-inositol derivatives 2, 3 and d-2- O-benzyl-3- O-cyclohexylcarbamoyl-4-deoxy-4-( N, N′-dicyclohexylureido)-1- O-methyl-5,6- O-trichloroethylidene- chiro-inositol ( 4). Complete conversion of l-1- O-benzyl-6- O-cyclohexylcarbamoyl-3- O-formyl-2- O-methyl-4,5- O-trichloroethylidene- muco-inositol ( 3) into l-1- O-benzyl-6- O-cyclohexylcarbamoyl-2- O-methyl-4,5- O-trichloroethylidene- muco-inositol ( 2) is feasible by deformylation in boiling methanolic triethylamine. Furthermore, stepwise deprotection of 2 and 4 is described. Thus, compounds 5, 10, and 7 were obtained by decarbamoylation of 2, 4, and 6, respectively, with boiling methanolic sodium methoxide. The trichloroethylidene group of l-1- O-benzyl-2- O-methyl-4,5- O-trichloroethylidene- muco-inositol ( 5) was removed in a two step procedure (hydrodechlorination–deacetalization) via the ethylidene acetal 7 to give l-1- O-benzyl-2- O-methyl- muco-inositol ( 9). On refluxing d- chiro-inositol derivative 4 with 99% acetic acid, the ureido moiety was cleaved generating d-2- O-benzyl-4-cyclohexylamino-3- O-cyclohexylcarbamoyl-4-deoxy-1- O-methyl-5,6- O-trichloroethylidene- chiro-inositol ( 11). By contrast, cleavage of the ureido moiety of 10 was relatively difficult. The corresponding d-2- O-benzyl-4-cyclohexylamino-4-deoxy-1- O-methyl-5,6- O-trichloroethylidene- chiro-inositol ( 12) was only formed in small amounts. The structures of 1, 3 and 10 were confirmed by X-ray analysis.

Enantioselective syntheses of (+)- and (–)-nephrosteranic acid employing the Nicholas-Schreiber reaction

(+)- and (–)-Nephrosteranic acid (16) have been prepared in an enantioselective fashion from alkyne acid 19 (or ent-19) by a three step sequence involving debenzylation–lactonization, oxidative cleavage, and selective epimerization at C4. Acids 19 and ent-19 were obtained as single enantiomers employing a Nicholas–Schreiber reaction.Key words: paraconic acids, nephrosteranic acid, butyrolactones, Nicholas–Schreiber reaction.

Selective epimerization of rapamycin via a retroaldol/aldol mechanism mediated by titanium tetraisopropoxide.

We describe the efficient and selective epimerization of the immunosuppressant rapamycin to 28-epirapamycin under mild conditions. The mechanism of epimerization involves an equilibrium of the four C28/C29 diastereomers through a two-step retroaldol/aldol (macrocycle ring-opening/ring-closing) sequence. This retroaldol/aldol equilibration is not restricted to rapamycin but is also applicable to acyclic beta-hydroxyketones. A potentially useful extension of the method--the use of beta-hydroxyketones as enolate synthons for effecting inter- or intramolecular aldol reactions under neutral conditions--is demonstrated.