Synthesis of optically active gem-difluorocyclopropanes through a chemo-enzymatic reaction strategy

The synthesis of a chiral difluorocyclopropane building block has been accomplished using lipase-catalyzed reaction; the prochiral diacetate of cis-1,3-bishydroxymethyl-2,2-difluorocyclopropane was converted to the corresponding chiral monoacetate by the Alcaligenes lipase (lipase QL)-catalyzed hydrolysis with >99% enantiomeric excess. Enantiomerically pure trans-1,3-bishydroxymethyl-2,2-difluorocyclopropane was also obtained through the Pseudomonas cepacia SL-25 lipase (lipase SL)-catalyzed reaction. The synthesis of the chiral trans,trans-bis-gem-difluorocyclopropane derivatives has been accomplished using the same lipase technology; trans,trans-1,6-bishydroxymethyl-2,2,5,5-tetrafluorobicyclopropane was obtained in optically active form using the lipase SL-catalyzed hydrolysis of the corresponding diacetate.     

Chemoenzymatic preparation of optically active 4-aryl-5-carboxy-6-methyl-3,4-dihydro-2(1H)-pyridone derivatives

A series of racemic 4-aryl-5-(tert-butoxycarbonyl)-6-methyl-3,4-dihydro-2(1H)-pyridones have been prepared by means of a modified Hantzsch reaction using commercially available starting materials. An easy removal of the tert-butyl group of these pyridones and subsequent reaction with cesium carbonate and chloromethyl 2-methylpropanoate provided us suitable substrates (±)-5 to be used in lipase-catalyzed hydrolysis reactions. Lipase B from Candida antarctica (CAL-B) was the most adequate lipase in the hydrolysis of (±)-5. Despite the low enantioselectivity values obtained (E≤12), several optically active pyridone derivatives were finally isolated with high enantiomeric excesses (ee≥91%) and moderate yields.     

Enzymatic synthesis of N-acylethanolamines: direct method for the aminolysis of esters

Immobilized Candida antarctica (Novozyme 435) catalyzed synthesis of N-acylethanolamines is described. Treatment of methyl esters with lipase and amines yielded the desired amides within 2-24 h with yields ranging from 41% to 98%.     

Rapid access to structured triacylglycerols acylated with n-3 polyunsaturated fatty acids for nutritional applications

In order to better understand the metabolic fate of n-3 polyunsaturated fatty acids (PUFAs), an efficient access to symmetrical and unsymmetrical triacylglycerols (TGs), esterified with PUFAs, with known high purity, is required. In this context, we optimized the esterification of a mixture of glycerols protected as dioxane and dioxolane with PUFAs. The kinetics of this reaction depends on various factors, such as the fatty acid chain length and the stereochemistry of the dioxane. Then, one-pot acetal hydrolysis and esterification of hydroxyl groups led to the desired structured TGs without either double bond isomerization or acyl migration (except when symmetrical TGs are acylated with long-chain saturated fatty acids in external positions). PUFAs location on the glycerol backbone was assayed by NMR, HPLC and pancreatic lipase hydrolysis.     

Biocatalytic enantioselective preparation of phenothiazine-based cyanohydrin acetates: kinetic and dynamic kinetic resolution

Dynamic kinetic resolution is used for the preparation of a series of novel (+)-10-alkyl-phenothiazin-3-ylcyanomethyl acetates. The method exploits a basic resin both for the racemization and formation of phenothiazine-based cyanohydrins and for the decomposition of acetone cyanohydrin in one pot together with Candida antarctica lipase A-catalyzed enantioselective acylation with vinyl acetate in acetonitrile. The Candida antarctica lipase A-catalyzed methanolysis of racemic 10-alkyl-phenothiazin-3-ylcyanomethyl acetates in acetonitrile with E?100 leads to the corresponding (−)-acetates.     

Practical synthesis of (2S,3R)-3-hydroxy-3-methylproline, a constituent of papuamides, using a diastereoselective tandem Michael-aldol reaction

(2S,3R)-3-Hydroxy-3-methylproline, a constituent of cyclodepsipeptides polyoxypeptins A and B, was efficiently synthesized by lithium chloride-induced diastereoselective tandem Michael-aldol reaction using methyl vinyl ketone and N-1-naphthylsulfonylglycine (R)-binaphthyl ester and subsequent hydrolysis of the product in 39% overall yield and five steps.     

Lipase mediated separation of triterpene structural isomers, α- and β-amyrin

Pentacyclic triterpenoids α- and β-amyrin possess a wide range of biological and pharmacological activities. High structural similarity between these two structural isomers makes their chromatographic separation an ineffective and tedious choice. In this study, Candida rugosa lipase catalyzed separation protocol for the isolation of individual isomers has been developed. In the presence of vinyl acetate as the acyl donor, Candida rugosa lipase carried out acetylation of β-amyrin more efficiently as compared to α-amyrin leading to a kinetic separation. The conditions of transesterification reaction were optimized systematically, which was utilized to separate α- and β-amyrin from a mixture obtained from the latex of Plumeria obtusa.     

Stereoselective synthesis of methyl branched chiral deoxypropionate units: a new route for synthesis of insect pheromone (−)-lardolure and (2R,4R,6R,8R) 2,4,6,8-tetramethylundecanoic acid

(−)-Lardolure and (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid have been synthesized via lipase catalyzed desymmetrization strategy to create two methyl chiral centers. Other key steps involved in the synthesis are Wittig reaction, Evan’s asymmetric alkylation, Grignard reaction, Pd-catalyzed isomerization of primary allylic alcohol to corresponding saturated aldehyde, and PhNO/proline catalyzed MacMillan α-hydroxylation.     

Biocatalytic preparation of chiral 3,4-dihydroxypyrrolidines

Enzymatic acylations and alcoxycarbonylations of cis- and trans-3,4-dihydroxypyrrolidines and hydrolysis of their diacylated or dialcoxycarbonylated derivatives have been studied. High enantioselectivity is obtained using Candida antarctica lipase B as catalyst in the hydrolysis of the trans-diacetyl derivative, while for the desymmetrization of the cis-3,4-dihydroxypyrrolidines the best results are obtained in the acylation process catalyzed by C. antarctica lipase A.     

Lipase-mediated kinetic resolution of (RS)-1-bromo-3-[4-(2-methoxy-ethyl)-phenoxy]-propan-2-ol to (R)-1-bromo-3-(4-(2-methoxyethyl) phenoxy) propan-2-yl acetate

A novel biocatalytic method for the enantioselective synthesis of (R)-bromo-3-[4-(2-methoxy-ethyl) phenoxy]-2-propanol [(R)-BMEPP], a precursor for the synthesis of (S)-metoprolol, an anti hypertensive drug is described. We have developed kinetic resolution of rac-BMEPP by transesterification using Candida rugosa lipase and vinyl acetate as the acyl donor affording the product with excellent conversion (49%) and ee (>99%). Various reaction parameters (source of enzyme, reaction media, and concentration of substrate and acylating agent) for the enzymatic kinetic resolution have been reported.     

Enantioselective, chemoenzymatic synthesis, and absolute configuration of the antioxidant (−)-gloeosporiol

The natural antioxidant (−)-gloeosporiol, isolated as a peracetylated derivative from a culture of the fungus Colletotrichum gloeosporioides, has been enantioselectively prepared from 3,4-dihydroxybenzaldehyde by means of a chemoenzymatic synthesis. The key intermediate was obtained by resolution with a lipase from Pseudomonas cepacia. Its stereochemistry, initially assigned as R, according to the Kazlaukas empirical rule for secondary alcohols, was independently confirmed by NMR and chirooptic methods. This, in turn, allowed the assignment of compound (−)-1 as (−)-(2S,3R,4R)-2-(3′,4′dihydroxyphenyl)tetrahydrofuran-3,4-diol.     

Hydrolysis of ammonium oxofluorotungstates: A F, O and W NMR study

Fluorine-19 and natural abundance ¹⁷O and ¹⁸³W NMR spectroscopy were employed for the characterization of aqueous solutions of (NH₄)₂WO₂F₄ and (NH₄)₃WO₃F₃. Dissolution of the (NH₄)₂WO₂F₄ complex is accompanied by its partial acid hydrolysis to give the trans(mer)-dimer, [W₂O₅F₆]⁴⁻, and unreacted cis-[WO₂F₄]²⁻. The cis(fac)-[W₂O₅F₆]⁴⁻ anion is the major soluble product resulting from the alkaline hydrolysis of (NH₄)₂WO₂F₄ along with the isolation of the solid (NH₄)₂WO₃F₂. In addition, the edge-bridging dimer, [W₂O₆F₄]⁴⁻, and the cyclic trimer, [W₃O₉F₆]⁶⁻, are also suggested as hydrolysis products. Decomposition of (NH₄)₃WO₃F₃ occurs in aqueous solution to give NH₄WO₃F.     

An efficient synthetic approach towards trans-β-amino acids and demonstration of their utility in the design of therapeutically important β-peptides and α,β-peptide aldehydes

An efficient synthetic approach towards trans-β^2,3-amino acids involving anti-selective aldol, azidation and controlled hydrolysis as key steps is discussed. Apart from structural elaboration of these building blocks to homo- and hetero-dipeptides, possibility of selective endocyclic cleavage of the chiral auxiliary was advantageously used in the preparation of α,β-hybrid peptide alcohols and corresponding aldehydes, which are promising candidates for biological evaluation against proteases of therapeutic interest.     

E/Z Isomerization of 3,3-disubstituted allylic thioethers

Allylic thioethers of the general structure 1 underwent E/Z isomerization during both basic and acidic hydrolysis of the ester moiety at the remote end of the molecule. The isomerization was dependent on the substitution of the allylic moiety. The presence of a 5-membered heterocycle on the double bond supported the isomerization. However, analogous oxy-ethers were stable.     

Chemoselective hydrolysis of tert-butyl esters in acetonitrile using molecular iodine as a mild and efficient catalyst

A simple, mild and efficient method for the hydrolysis of tert-butyl esters using molecular iodine as a catalyst is described. Acid labile protecting groups, such as N-Boc, OBn, OAc and double bonds, are compatible under the reaction conditions.     

Enzymatic synthesis of optically active 1- and 2-aminoalkanephosphonates

A number of 1- and 2-aminoalkanephosphonates were resolved with high enantioselectivity by Candida antarctica lipase B-catalyzed acetylation. By this method, optically pure aminoalkanephosphonates and amidoalkanephosphonates, the precursors of the corresponding aminoalkanephosphonic acids, were synthesized.     

Highly efficient and selective biocatalytic acylation studies on triazolylsugars

Different acid anhydrides (of C₂ to C₇ aliphatic fatty acids and benzoic acid) have been used to study the selective acylation of primary/secondary hydroxyl groups in 2-phenyl-4-(d-threo-1′,2′,3′-trihydroxypropyl)-2H-1,2,3-triazole, 2-phenyl-4-(d-erythro-1′,2′,3′-trihydroxypropyl)-2H-1,2,3-triazole, 2-phenyl-4-(d-arabino-1′,2′,3′,4′-tetrahydroxybutyl)-2H-1,2,3-triazole and 2-phenyl-4-(d-lyxo-1′,2′,3′,4′-tetrahydroxybutyl)-2H-1,2,3-triazole in the presence of Candida antarctica lipase B in diisopropyl ether. Among the different acid anhydrides, butanoic anhydride was found to be the most efficient acylating agent (for butanoylation); for acetylation, vinyl acetate gave the best results. The reactions with both these acylating agents were highly selective and efficient yielding exclusively the monoacylated products in 95-99% yields in 1-5 h.     

Enzymatic synthesis of optically active α-chloro-δ-hydroxy-β-ketoalkanephosphonates and reactions thereof

A novel and enzymatic approach to α-chloro-δ-hydroxy-β-ketoalkanephosphonates was developed via enantioselective CALB-catalyzed acetylation and CRL-catalyzed hydrolysis. The resultant optically active compounds provide, via Horner-Wadsworth-Emmons (HWE) reaction, chiral α,β-unsaturated ketones that are building block with potential application in organic synthesis.     

Asymmetric synthesis of trans-4,5-dioxygenated cyclopentenone derivatives by organocatalyzed rearrangement of pyranones and enzymatic dynamic kinetic resolution

Dioxygenated cyclopentenones are versatile building blocks for the synthesis of several natural products. Herein we report a direct asymmetric synthesis of trans-4,5-dioxygenated cyclopentenone derivatives through base-catalyzed rearrangement of pyranones followed by dynamic kinetic resolution. Milder conditions than previously reported for this rearrangement have been found regarding amine base catalysis, solvent and temperature effects. All data supports a mechanism involving cyclization of an intermediate formed by electrocyclic ring opening of a pyranone-derived enol. We have developed conditions for asymmetric synthesis of trans-4-tert-butoxy-5-hydroxycyclopent-2-enone, in 81% yield and 95% ee, and analogous dioxygenated cyclopentenones, via a lipase induced dynamic kinetic resolution.     

Chemoenzymatic synthesis of a focused library of enantiopure structured 1-O-alkyl-2,3-diacyl-sn-glycerol type ether lipids

A highly efficient two-step chemoenzymatic synthesis of enantiopure structured ether lipids of the 1-O-alkyl-2,3-diacyl-sn-glycerol type has been developed. Chimyl, batyl and selachyl alcohols possessing pure saturated fatty acid (SFA) attached to the sn-3 position and pure EPA and DHA attached to the sn-2 position were obtained under full regiocontrol. This was offered by mild conditions and a highly efficient lipase that operated at room temperature. High-resolution ¹H NMR spectroscopy was used to monitor the progress of the reactions and to evaluate the full regiocontrol of the reactions involved by keeping track of all prospective adducts involved in these reactions. This was extended to preparation of a focused library of eight monoacyl intermediate adducts for all even-numbered SFA ranging from C₂-C₁₆ and the corresponding EPA and DHA structured diacyl glycerol ethers (DAGE) products for chimyl, batyl and selachyl alcohols, the total of 72 compounds.