Highly efficient biocatalytic resolution of cis- and trans-3-aminoindan-1-ol: syntheses of enantiopure orthogonally protected cis- and trans-indane-1,3-diamine

The efficient chemoenzymatic synthesis of enantiopure 1,3-difunctionalized indane derivatives has been achieved. The corresponding cis and trans N-protected amino alcohols were successfully resolved by acetylation using lipase B, which is a biocatalyst isolated from Candida antarctica. All the possible isomers were obtained in very good chemical yields and ee values (>99 %). The utility of these compounds was subsequently shown by the preparation of orthogonally protected cis- and trans-indane-1,3-diamine using a Mitsunobu reaction. Both enantiomers of the trans isomer and a desymmetrized cis diastereomer were prepared in enantiopure form. Complete inversion of configuration during the Mitsunobu reaction was demonstrated by a combination of NMR techniques and molecular modeling. The utility and versatility of the strategy was also demonstrated by the selective deprotection of each nitrogen atom under mild reaction conditions.     

Highly stereoselective chemoenzymatic synthesis of the 3H-isobenzofuran skeleton. Access to enantiopure 3-methylphthalides

A straightforward synthesis of (S)-3-methylphthalides has been developed, with the key asymmetric step being the bioreduction of 2-acetylbenzonitriles. Enzymatic processes have been found to be highly dependent on the pH value, with acidic conditions being required to avoid undesired side reactions. Baker's yeast was found to be the best biocatalyst acting in a highly stereoselective fashion. The simple treatment of the reaction crudes with aqueous HCl has provided access to enantiopure (S)-3-methylphthalides in moderate to excellent yields.     

Convenient access to new chiral ferroceno-(iso)quinolines

[Chemical reaction: see text] New chiral pyridine derivatives possessing the planar chirality of the ferrocene have been prepared by means of an aldolization-crotonization reaction. This very simple reaction has been applied to the synthesis of isomers 1-4 that differ in the position of the nitrogen atom on the pyridine ring. Following the same procedure, asymmetric synthesis of 1 has been achieved using an enantiopure ferrocenylzinc intermediate. This method has also allowed the preparation of a chiral analogue of 2,2'-bipyridine.     

Lentinus strigellus: a new versatile stereoselective biocatalyst for the bioreduction of prochiral ketones

Growing cells of the basiodiomycete Lentinus strigellus in potato-dextrose broth have been used for the first time as a biocatalyst in the stereoselective reduction of aromatic and aliphatic ketones. Most of the aromatic ketones were converted into the corresponding optically active alcohols in up to >99% enantiomeric excess under very mild reaction conditions. Among the aliphatic ketones tested, 2-octanone was enzymatically reduced by this microorganism to enantiopure (S)-2-octanol with almost complete conversion.     

Highly enantioselective Friedel-Crafts reaction of aromatic amines with ethyl glyoxylate catalyzed by chiral titanium(IV) complexes: practical synthesis of aminomandelic acid derivatives

The asymmetric Friedel-Crafts reaction of a variety of N,N-dialkylanilines with ethyl glyoxylate has been achieved by the catalysis of titanium complexes of BINOL derivatives to give corresponding ethyl esters of p-N,N-dialkylaminomandelic acids in high yields (85-99%) and good to excellent enantioselectivities (80-96.6% ee) under the optimized reaction conditions, which has added a new catalyst for this class of reactions. The reaction could also be carried out at a reduced catalyst loading (1 mol %) in gram scale, which provided a practical synthesis of enantiopure aminomandelic acid derivatives.     

ortho-Metalation of enantiopure aromatic sulfoxides and stereocontrolled addition to imines

Enantiopure aromatic (phenyl, naphthyl) and heteroaromatic (pyridyl, quinolyl, diazinyl) sulfoxides have been synthesized by reaction of (S)-tert-butyl tert-butanethiosulfinate with aryl- or heteroaryllithium derivatives. The ortho-directed metalation of the sulfoxides was performed with lithium bases. Subsequent addition of the lithiated intermediates to N-tosylimines afforded tosylaminoalkyl tert-butylsulfinyl arenes. In most cases a complete asymmetric induction was highlighted in favor of (S,S) isomers. Heating the aminosulfoxides provided an original cyclization to form novel cyclic sulfenamides. A novel enantiopure synthesis of a benzylamine was described. An application of an enantiopure aminosulfoxide as N,S ligand for the asymmetric catalysis of allylic nucleophilic substitution has been successfully tested.     

Synthesis of enantiomerically pure glycidol via a fully enantioselective lipase-catalyzed resolution

The efficient enzymatic synthesis of enantiopure 2,3-epoxypropanol (glycidol) has been achieved. The racemic glycidyl butyrate was successfully resolved by enzymatic hydrolysis using a strategy that combines different immobilization protocols and different experimental reaction conditions. A new enzyme (25 kDa lipase)—which is a lipase-like enzyme purified from the pancreatic porcine lipase (PPL) extract—immobilized on DEAE–Sepharose was selected as the optimal biocatalyst. The optimal results were obtained at pH 7, 25 °C and 10% dioxane using this biocatalyst and a very high enantioselectivity for the enzyme was displayed, obtaining both (R)-(−)-glycidyl butyrate and (R)-(+)-glycidol with enantiomeric excesses >99% (E >100). The hydrolysis of (R)-(−)-glycidyl butyrate produced pure (S)-(−)-glycidol.     

Immobilized Laccase on a New Cryogel Carrier and Kinetics of Two Anthraquinone Derivatives Oxidation

A coordinatively immobilized laccase was prepared using a new cryogel type carrier. The support has a wide-pore texture facilitating diffusion of different substrates to the enzyme reaction center. The biocatalyst proved to be efficient in decolorization of two anthraquinone derivatives, namely Acid Blue 62 and bromaminic acid. After 24 h over 80% of the two substrates have been oxidated. The kinetic data (K (m) and V (max)) for the oxidation of the two anthraquinone derivatives, with the free and immobilized enzyme, have been determined and compared. Other parameters, like k (cat) and the specificity constant have been calculated and analyzed. The influence of substrate properties (hydrophobicity, polarity, etc.) has been discussed.     

Asymmetric Pauson-Khand reactions using camphor-derived chelating thiols as chiral controllers

A convenient procedure for the preparation of enantiopure 10-(R-thio)-2-exo-bornanethiols from (1S)-camphor-10-thiol has been developed. The ethynyl derivatives of these thiols gave excellent diastereoselectivities (up to 98:2) in Pauson-Khand reactions with norbornene and norbornadiene through the intermediacy of a chelated dicobalt pentacarbonyl complex. Thermal reaction conditions starting from the preformed chelated complex gave better results than N-oxide-promoted runs with in situ generation of the chelated intermediate. The corresponding adducts have been elaborated through a protocol consisting of conjugate addition, samarium iodide-promoted cleavage of the chiral auxiliary, and retro-Diels-Alder reaction to afford 4-substituted 2-cyclopentenones in high enantiomeric purity.     

Enantiopure 2-piperidylacetaldehyde as a useful building block in the diversity-oriented synthesis of polycyclic piperidine derivatives

Novel, simple, and convenient strategies for diversely functionalized piperidine derivatives have been developed by using different metal catalyzed reactions starting from enantiopure (R)- and (S)-2-piperidylacetaldehyde.     

Novel N1-C4 beta-lactam bond breakage. Synthesis of enantiopure alpha-alkoxy-gamma-keto acid derivatives

Addition reaction of 2-(trimethylsilyl)thiazole (TMST) to cis- or trans-4-formyl-beta-lactams gave enantiopure alpha-alkoxy-gamma-keto acid derivatives via a novel N1-C4 bond breakage of the beta-lactam nucleus. This is the first time that the cleavage of the N1-C4 bond on the beta-lactam nucleus has been shown to occur in 2-azetidinones lacking an aryl moiety at C4. [reaction--see text]     

Cyclopropanation of enantiopure metal alkenyl carbenes with 2-methoxyfuran: a practical route to carboxycyclopropylglycine precursors

We have examined the reactivity of enantiopure alkenyl Fischer carbene complexes 1, readily available from the chiral pool, with 2-methoxyfuran 4. In this reaction, polyfunctionalised cyclopropylcarbenes 5 are obtained under very mild conditions and with high selectivity, the major stereoisomer being isolated in an enantiopure form. The reaction involves the conjugate nucleophilic addition of 2-methoxyfuran 4 to the carbene complexes 1 followed by ring closure of the resulting zwitterionic intermediate species. The oxidation of the carbene 5 a results in the formation of the enantiopure cyclopropane diester 6. Further elaboration of the cyclopropane 6 allows for an efficient enantioselective access to alcohols or diols 7-9 as well as to cyclopropanecarbaldehydes 10-12. The protocol described herein provides a very simple entry to interesting enantiopure precursors of carboxycyclopropylglycine derivatives from readily available starting materials. In order to test this potential as carboxycyclopropylglycine precursors, the aminocyanation of the cyclopropanecarbaldehyde 10 was undertaken and the alpha-aminocyano derivative 13 was isolated as a single diastereosiomer.     

Organocatalytic ring expansion of beta-lactams to gamma-lactams through a novel N1-C4 bond cleavage. direct synthesis of enantiopure succinimide derivatives

Tetrabutylammonium cyanide (20 mol %) catalyzes ring expansion of 4-(arylimino)methylazetidin-2-ones 2 to 5-aryliminopyrrolidin-2-ones 3 through a novel N1-C4 bond cleavage of the beta-lactam nucleus. New, efficient one-pot protocols to enantiopure succinimide derivatives 3 and 4 from beta-lactam aldehydes 1 have also been developed. [reaction: see text]     

Di-2,2,2-trifluoro-1-(9-anthryl)ethyl fumarate,an easy starting point for the enantioselective preparation of trans-cyclohexene-4,5-dicarboxylate derivatives by Diels–Alder reaction

Di-2,2,2-trifluoro-1-(9-anthryl)ethyl fumarate has been synthesized from fumaric acid and enantiopure Pirkle alcohol. The Diels–Alder reaction with different dienes employing different reaction conditions was assayed, with high diastereomeric excesses obtained. The structure and geometry of the cycloadducts was analyzed by NMR, molecular mechanics and X-ray diffraction. Hydrolysis made it possible to obtain the enantioenriched trans-cyclohexene-4,5-dicarboxylate derivatives and allow us to recover chiral auxiliary.     

Stereoselective diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based polycyclic derivatives

A diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based tricyclic derivatives has been achieved from enantiomerically pure, natural product-like bicyclic scaffold. The solution synthesis of enantiopure bicyclic scaffold was developed by asymmetric hetero Michael reaction. Our approach for the synthesis of polycyclic derivatives utilized regio- and stereoselective hetero Michael reaction and ring-closing metathesis as key steps in solution and on solid phase.     

New polycyclic diamine scaffolds from dimerization of 3-alkyl-1,4-dihydropyridines in acidic medium

[reaction: see text] 3-Alkyl-1,4-dihydropyridines dimerize in acidic medium, at low temperature, to give polycyclic imminium salts derivatives that were reduced to afford new polycyclic diamine scaffolds. The reaction can be extended to enantiopure series starting from R-(+)- or S-(-)-1-phenylethylamine. Long exposure of the polycyclic imminium salt intermediates to air moisture at 20 degrees C resulted in formation of new amide derivatives. This is probably due to the addition of water followed by an intramolecular oxido-reduction process.     

Lewis acid assisted ring-closing metathesis of chiral diallylamines: an efficient approach to enantiopure pyrrolidine derivatives

Lewis acid assisted ring-closing olefin metathesis (RCM) of chiral diallylamines, using the second generation RCM ruthenium-based catalyst, leads to enantiopure pyrrolidine derivatives in 79-93% yields under very mild conditions. The scope of the olefin metathesis has been expanded. [structure: see text]     

Facile and Practical Synthesis of (R)‐6‐Br‐2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl

A new enantiopure 6‐monobromo‐substituted BINAP has been prepared via a one‐step nickel‐catalyzed coupling reaction in moderate yield. It is an important intermediate for asymmetric 2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl (BINAP) derivatives. Its structure was elucidated by NMR spectral and elemental analysis.     

Some new protocols for the assignment of absolute configuration by NMR spectroscopy using chiral solvating agents and CDAs

The utility of enantiopure BINOL (1,10-Bi-2-naphthol), in a ternary ion-pair complex, which is obtained using a carboxylic acid and an organic base, as a versatile chiral solvating agent (CSA) has been demonstrated for chiral analysis and the absolute configuration assignment of hydroxy acids. Another protocol where the utility of NOBIN as a CSA has been developed for discrimination and absolute configuration assignment of acids, hydroxy acids and their derivatives with a distinct strategy where a third ingredient, p-toluenesulfonic acid (p-TsOH) serves as a linker. In addition some three component chiral derivatization protocols have been introduced, such as the use of 2-formylphenylboronic acid and enantiopure mandelic acid or a primary amine for the determination of the configuration of primary amines and hydroxy acids, respectively. A simple, rapid and highly efficient three component chiral derivatizing protocol has also been discussed which was developed for assigning the absolute configuration of chiral α-hydroxy acids and their derivatives, which involves the coupling of 2-formylphenylboronic acid with (R)-[1,1-binaphthalene]-2,2-diamine, and (S)-[1,1-binaphthalene]-2,2-diamine separately. In a few examples, the DFT based theoretical calculations have been carried out to determine the geometry optimized structures of the complexes.     

Chiral pyridin-3-ones and pyridines: syntheses of enantiopure 2,4-disubstituted 6-hydroxy-1,6-dihydro-2H-pyridin-3-ones, 2,3-disubstituted 4-iodopyridines, and enantiopure 2,3-disubstituted 4-pyridinemethanols

The development of an innovative method to access enantiopure 2,4-disubstituted 6-hydroxy-1,6-dihydro-2H-pyridin-3-ones starting from D-glucal via the aza-Achmatowicz transformation has been described. These highly functionalized pyridin-3-ones have been utilized for the synthesis of contiguously substituted pyridines through a rapid and efficient Et(3)N/Ac(2)O promoted cyclo-elimination, aromatization cascade, allowing the facile assembly of important pyridine-based building blocks like 2-substituted 3-acetoxy-4-iodopyridines and enantiopure 2-substituted 3-acetoxy-4-pyridinemethanols possessing benzylic stereogenic centers, whose synthesis otherwise would be tedious. The utilization of commercially available sugars as starting materials, mild reaction conditions, catalytic transfer hydrogen (CTH) of α-furfuryl azide derivatives, transfer of chiral aryl/alkyl methanols from enulosides to pyridin-3-ones and pyridines, high yields, and short reaction times are key features of this method. The utility of the method has been further exemplified by demonstrating the usage of the 2-substituted 3-acetoxy-4-iodopyridine for the construction of biologically significant molecules like 2,7-disubstituted furo[2,3-c]pyridines and 7,7'-disubstituted 2,2'-bifuro[2,3-c]pyridines.