Stereoselective synthesis of unnatural spiroisoxazolinoproline-based amino acids and derivatives

A route to spiroisoxazolinoproline-based amino acid derivatives is reported in which exo-methyleneprolinate 4 (tert-butyl ester) reacts as a dipolarophile with nitrile oxides to generate spiroisoxazolinoprolinates 7/10/11 in good yields (70-75%) and with ca. 1:4 cis:trans diastereoselectivity. tert-Butyl spiroisoxazolinoprolinates were separable by column chromatography and amenable to scale-up leading to single diastereoisomers of N-Boc and N-Fmoc protected spiroisoxazolinoproline amino acids.     

A solid phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsunobu approach

Hydroxyindoline-derived scaffold, 9, was synthesized with the goal of generating a library of indoline-based natural product-like tricyclic derivatives to be utilized as small-molecule chemical probes. The tricyclic ring was obtained by a Mitsunobu reaction of the N-nosyl amino acid conjugate with the primary hydroxyl group. The solid-phase synthesis was achieved by immobilizing scaffold 9 onto the solid support giving a compound, 15. This was then subjected to a series of reactions on solid phase, including the Mitsunobu reaction, leading to the desired indoline-derived tricyclic derivative. The final product has two diversity sites: (i) amino acid as the first diversity and (ii) amidation of the secondary amine for the second diversity. These two diversity sites were utilized in the library generation by IRORI split-and-mix approach.     

A solid-phase, library synthesis of natural-product-like derivatives from an enantiomerically pure tetrahydroquinoline scaffold

With the goal of developing a library synthesis of tetrahydroquinoline-derived natural-product-like small molecules, a practical synthesis of enantiomerically pure tetrahydroquinoline scaffold was achieved. An asymmetric aminohydroxylation reaction was the key step in this strategy. This scaffold was further immobilized onto the solid support for the library generation. The library was obtained from three diversity sites: (i) acylation of the hydroxyl group (R(1)), (ii) coupling of the Fmoc-protected amino acid to the amino group (R(2)), and (iii) amidation of the N-terminal amine group (R(3)).     

Asymmetric synthesis of chiral spiro bis(isoxazoline) and spiro (isoxazole–isoxazoline) ligands

Asymmetric synthesis of novel chiral ligands, bis(isoxazoline) on a spiro[4.4]nonane scaffold and isoxazole–isoxazoline on a spiro[4.5]decane scaffold, has been achieved by utilizing an enantiomerically pure alcohol as the starting material.     

Synthesis of functionalized furopyrazines as restricted dipeptidomimetics

Herein, an efficient synthetic approach to a furopyrazine scaffold with four points of diversity, starting from 2(1H)-pyrazinones, with dipeptomimetic properties, is presented. R-groups corresponding to amino acid side chains were introduced during the 2(1H)-pyrazinone and subsequent furopyrazine formation. The furopyrazine scaffold was further functionalized with an amino- and a carboxy-terminus resulting in a conformationally restricted dipeptidomimetic scaffold. The carboxy-terminus was introduced via a chemoselective vinylation of the 7-position followed by oxidative cleavage, while the amino-terminus was obtained via Buchwald–Hartwig amidation of the 2-position of the scaffold. The versatility of the synthetic method was demonstrated by the synthesis of a small library of diversely substituted furopyrazines having various amino acid side chains on the four points of diversity. Evaluation with an X-ray structure of the scaffold and computational analysis supports the exploitation of the furopyrazine scaffold as a restricted dipeptide mimic, which can mimic the two central residues of a β-turn.     

Tetrahydrofuran-based amino acids as library scaffolds

A furanose sugar amino acid (SAA) has been utilized as a library scaffold for the first time. Two furanose SAA scaffolds were examined to illustrate their potential for derivatization. The resulting 99-member library contained three orthogonal points of diversification that allowed easy access to ethers and carbamates from a hydroxyl moiety, a range of ureas from an azide (via an amine), and a range of amides from a methyl ester. The novel amide formation (by displacement of the methoxide from the methyl ester moiety) was achieved in good yield and purity with high structural confidence. Full characterization of several library intermediates (including a crystal structure) was obtained. The library was submitted for antibacterial screening.     

Synthesis of 5-(thiazol-5-yl)-4,5-dihydroisoxazoles from 3-chloropentane-2,4-dione

Condensation of 3-chloropentane-2,4-dione with thioamides gives 1-(thiazol-5-yl)ethanones and subsequent Wittig olefination, followed by nitrile oxide 1,3-dipolar cycloaddition to the resulting prop-1-en-2-yl moiety, delivers racemic 5-(thiazol-5-yl)-4,5-dihydroisoxazoles. When this thiazole and isoxazoline diheterocyclic scaffold has a carboethoxy substituent at C2 of the thiazole ring, aminolysis provides for effective diversification. A 50-member library of various 5-(thiazol-5-yl)-4,5-dihydroisoxazoles is reported.     

Synthesis and screening of libraries of synthetic tripodal receptor molecules with three different amino acid or peptide arms: identification of iron binders

A novel selectively deprotectable triazacyclophane scaffold was used for the design and split-mix synthesis of two libraries of solid-phase bound tripodal synthetic receptors possessing three different amino acid or peptidic arms. In the synthesis of the first library, the two outer arms consisted of amino acid Ala, Arg, Asp, Gln, Gly, Lys, Phe, Ser, Tyr, or Val and the middle arm consisted of amino acid Asn, Glu, His, Leu, or Pro. The second library contained amino acid and/or (di)peptide arms. The arms were different in all library members. The first outer arm consisted of amino acid(s) Ala, Arg, Gln, Phe, or Ser, the second outer arm consisted of amino acid(s) Asp, Gly, Lys, Tyr, or Val, and the middle arm consisted of amino acid(s) Asn, Glu, His, Leu, or Pro, leading to a 27 000 member library of synthetic tripodal receptor molecules. In on-bead screening experiments, a remarkable selectivity of some library members for Fe(3+) was observed and decoding of their structures by Edman degradation revealed consensus sequences with structural resemblance to non-heme iron proteins.     

Solid-phase synthesis of 7-acylamino-1,4-benzodiazepine-2,5-diones

A method for the synthesis of polymer-bound 7-acylamino-benzodiazepine-2,5-diones is described. The amino group of an alpha-amino acid is linked to polystyrene or TentaGel resin via reductive amination of polymer-bound 4-alkoxy-2,6-dimethoxybenzaldehyde. Acylation with unprotected 5-nitroanthranilic acid is followed by base-catalyzed ring closure. Reduction of the nitro group yields enantiomerically pure 7-aminobenzodiazepin-2,5-dione attached via the N-4 atom to the resin. Acylation of the amino group on the aromatic ring with acid chlorides in N-methylpyrrolidone (no DMF, no base!) followed by cleavage from the resin using TFA/Me(2)S/water (90:5:5) provides the acylated benzodiazepinones in 52-69% (PS resin) and 41-48% (TG resin) yield (based on the theoretical loading) and >70% purity (HPLC, 210 nm). Using Fmoc-protected tyrosine fluoride in NMP gives the amino acid-coupled benzodiazepinones in 24% (PS resin) and 31% (TG resin) yield.     

Asymmetric synthesis of unsaturated, fused bicyclic proline analogues through amino alkylation of cyclic bis(allylsulfoximine)titanium complexes and migratory cyclization of delta-amino alkenyl aminosulfoxonium salts

Described is an asymmetric synthesis of new Delta(3a,4)-unsaturated, fused bicyclic proline analogues from cyclic bis(allylsulfoximine)titanium complexes and N-tert-butylsulfonyl imino ethyl ester. Treatment of the enantiomerically pure five-, six-, seven-, and eight-membered cyclic bis(allylsulfoximine)titanium complexes with the imino ester gave mixtures of the corresponding (E,syn)- and (Z,syn)-configured, delta-sulfoximine substituted, cyclic gamma,delta-unsaturated alpha-amino acid esters with high regio- and diastereoselectivities in good yields. Activation of the N-methyl sulfoximine group of these amino acid derivatives through methylation with Me(3)OBF(4) afforded in nearly quantitative yields the corresponding (dimethylamino)sulfoxonium salts. A novel migratory cyclization of these salts with DBU gave via an isomerization to the corresponding allylic (dimethylamino)sulfoxonium salts and an intramolecular substitution of the (dimethylamino)sulfoxonium group the enantio- and diastereomerically pure, bicyclic, N-tert-butylsulfonyl protected proline analogues having a six- and eight-membered unsaturated carbocyclic ring. Cyclization of the alkenyl (dimethylamino)sulfoxonium salts was independent of the configuration of the double bond. N,N-Dimethylphenylsulfinamide of > or =99% ee was obtained in good yield as a further reaction product. Conversion of the sulfinamide to N,S-dimethyl-S-phenylsulfoximine of > or =99% ee, the starting material for the synthesis of the allylic sulfoximines, had been accomplished previously. Finally, cleavage of the tert-butylsulfonyl protecting group with anhydrous acid furnished the fused bicyclic proline analogue containing an unsaturated six-membered ring in high yield.     

Synthesis of Some Novel Class of Bis(isoxazoline) and Bis(aziridine) Derivatives

Synthesis of some new bis(isoxazoline) derivatives has been described from terepthaldehyde derived bis(nitrones) using microwave irradiation via 1,3‐dipolar cycloaddition reaction. Bis(isoxazoline) derivatives in turn successfully converted into new bis(aziridine) derivatives via Baldwin rearrangement. Simple reaction methodology, non involvement of catalysts, and good to excellent yields are the important features noticed in this synthesis.     

Amphiphilic allylation of arylidene-1,3-oxazol-5(4H)-one using bis-π-allylpalladium complexes: an approach to synthesis of cyclohexyl and cyclohexenyl α-amino acids

An efficient method for synthesis of cyclohexyl and cyclohexenyl α-amino acids via palladium-catalyzed three-component assemblies followed by ring-closing metathesis (RCM) is described. The present catalytic reaction is successfully extended to substituted benzylidene azlactones 2a-j RCH=(1,3-oxazole): R = alkyl or aryl. The amphiphilic bis-allylation of these substrates has been achieved by replacing toxic allylstannanes with allyltrifluoroborate and the reaction proceeded smoothly to afford the corresponding 1,7-diene derivatives 3a-j in acceptable to good yields. RCM of the resulting octadienes using the first generation Grubbs catalyst gave easy access to stereodefined substituted cyclohexene derivatives 7-11 in high yields. Acid hydrolysis of the oxazolone ring of 7-10 gave protected amino acids 12-16. Debenzoylation of 13 and 15 afforded 1-amino-6-aryl-cyclohex-3-enecarboxylic acids 17 and 18 in excellent yields, respectively. Moreover, catalytic reduction of 13 gave the corresponding cyclohexane derivative 19 which could be debenzoylated to give 1-amino-2-phenylcyclohexene-1-carboxylic acid (20). The structures of compounds 9, 12 and 13 were confirmed by X-ray structural analysis. It is an excellent method for creating a wide range of cyclic α,α-disubstituted α-amino acids.     

Solid-phase synthesis of a 4-substituted gamma-lactam library

Pyrrolidin-2-one (gamma-lactam) derivatives have shown a wide range of activities as ligands to diverse receptors, e.g., integrin, CCR5, and CCK. Therefore, we have prepared a large library of these derivatives for high-throughput screening against various protein targets, after developing a synthesis of pyrrolidin-2-ones on solid phase. Exploration of the ring formation was key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-protected amino acids and subsequent deprotection of the Fmoc group were accomplished readily. The resulting resin-bound primary amines were treated with beta-monomethyl itaconate under gentle heat in a mixture of methanol and toluene to yield the desired intermediates. Finally, saponification, amide formation, and cleavage from the resin led to the production of a library of 12,000 pyrrolidin-2-one derivatives. These products were isolated as diastereomeric mixtures of high purity and were obtained in good yields.     

Intramolecular Acylal Cyclisation (IAC) as an Efficient Synthetic Strategy towards the Total Synthesis of Erythrina Alkaloid Derivatives

Compounds that comprise the erythrina alkaloid class of natural products are based on a tetracyclic spiroamine framework and exhibit a range of biological activities on the central nervous system. Herein, we report a new and efficient total synthesis of this multiple‐ring system based on an intramolecular acylal cyclisation (IAC) approach. Using this methodology, the tetracyclic core was rapidly assembled over a two‐step domino process catalysed by a Lewis acid. The effect of heteroatoms, substituents and ring size on the IAC has also been investigated, and the broad application of this procedure is demonstrated by the synthesis of a library of derivatives in good yields with excellent regioselectivity.     

Solid-phase synthesis of urea and amide libraries using the T2 triazene linker

Starting from Merrifield resin, primary amines were immobilized in two steps by triazene linkage (T2-linker). While reaction with isocyanates gave rise to resin-bound urea derivatives, acylation by acid chlorides or anhydrides furnished amides bound to solid support via the nitrogen atom, therefore representing a novel backbone amide linker. Cleavage from the resin was conducted using dilute trimethylsilyl chloride or trifluoroacetic acid, respectively, to yield ureas and amines/amides in a library format (altogether 60 examples; manual synthesis: 17 ureas, 6 mono-alkylated ureas [including dihydroxylation and ozonolysis/Wittig reaction]; automated synthesis: 15 ureas, 15 amides) in high purities and good overall yields. The synthesis of a small library (4 x 4 member) was successfully conducted on a Bohdan Neptune synthesizer.     

Combinatorial synthesis of biheterocyclic benzimidazoles by microwave irradiation

Liquid phasel synthesis of biheterocyclic benzimidazoles by controlled microwave irradiation was investigated. Polymer immobilized o-phenylenediamines was synthesized under microwave irradiation. The resulting PEG bound diamines was N-acylated with 4-fluoro-3-nitrobenzoic acid selectively in primary aromatic amino moiety. Nucleophilic aromatic substitution of amide was performed with various amines then cyclized to form the first benzimidazole scaffold in acidic condition. Successive reduction, cyclization with isothiocyanates yielded 5-(benzimidazol-2-yl)benzimidazoles. The desired products were released from the polymer support to afford the tri-substituted bis-benzimidazoles in good yields and purity.     

Palladium Enolate Umpolung: Cyclative Diacetoxylation of Alkynyl Cyclohexadienones Promoted by a Pd/SPRIX Catalyst

A novel palladium‐catalyzed reaction involving an unusual nucleophilic attack on a palladium enolate was developed using a spiro‐bis(isoxazoline) (SPRIX) ligand. Treatment of alkynyl cyclohexadienone substrates with a Pd/SPRIX catalyst in acetic acid under an oxygen atmosphere furnished diacetoxylated benzofuranone derivatives in good yields. This cyclative diacetoxylation proceeded enantioselectively in the presence of an optically pure SPRIX ligand.     

Synthesis of novel trivalent amino acid glycoconjugates based on the cyclotriveratrylene ('CTV') scaffold

The convenient synthesis of novel trivalent amino acid glycoconjugates based on cyclotriveratrylene ('CTV') is described. These constructs consist of the CTV scaffold, three oligoethylene glycol spacers of variable length connected to a glyco amino acid residue which can also be varied. The resulting library of trivalent glycoconjugates can be used for studying multivalent interactions.     

Total Synthesis of Potent Antitumor Agent (−)‐Lasonolide A: A Cycloaddition‐Based Strategy

A detailed account of the enantioselective total synthesis of (?)‐lasonolide A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an α‐alkoxyacetimide derivative containing an α′ stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3‐dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero‐Diels–Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively.     

Application of divergent multi-component reactions in the synthesis of a library of peptidomimetics based on γ-amino-α,β-cyclopropyl acids

The multi-component condensation of organozirconocene, aldimine and zinc carbenoid was applied to the stereoselective synthesis of cyclopropane amino acid derivatives. These compounds served as scaffolds for the preparation of a 46-member library. The C- and N-termini of the cyclopropane amino acid derivatives were diversified by condensations with ten amines and ten acylating agents, respectively. To improve yields and accelerate library synthesis, most products were prepared under microwave irradiation and purified by polymer-bound scavengers and SPE methodology. All compounds were analyzed by LC-MS and a representative selection was fully characterized.