Solid-phase synthesis of polyfunctional polylysine dendrons using aldehyde linkers

A straightforward method for the solid-phase synthesis of C-terminally modified polylysine dendrons has been developed by applying bisalkoxybenzaldehyde and trisalkoxybenzaldehyde linkers. The method has been used for the synthesis of polylysine dendrons with a variety of C-terminal ‘tail groups’ such as alkyl, propargyl, and dansyl to give dendrons in high crude purity. Furthermore, the method was successful for the synthesis of dendrons with multiple N-terminal pentapeptide groups together with C-terminal alkyl and propargyl tail groups. Finally, the method was shown to be well-suited for automated synthesis.     

Asymmetric synthesis of trifluoromethylated allylic amines using alpha,beta-unsaturated N-tert-butanesulfinimines

[reaction: see text]. The trifluoromethide ion generated in situ from TMSCF(3) and TBAT (tetrabutylammonium triphenyldifluorosilicate), as well as TMAF (tetramethylammonium fluoride), adds to the alpha,beta-unsaturated N-tert-butanesulfinimines exclusively in a 1,2 fashion with high diastereoselectivities, affording the first examples of chiral trifluoromethylated allylic amines.     

Regio- and stereospecific synthesis of allylic tertiary amines

E and Z allylic amines have been synthesised by stereo-specific elimination of Ph₂PO₂^? from pure diastereoisomers (3) and (4).     

Regioselective synthesis of trifluoromethyl group substituted allylic amines via palladium-catalyzed allylic amination

The palladium-catalyzed regioselective allylic amination of α-trifluoromethylated allyl acetate occurred using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)]BF₄/DPPF. The selective formation of the γ-product was attained by Pd(OAc)₂/DPPE, while the α-product was obtained using [Pd(π-allyl)(cod)]BF₄/DPPF.     

Stereoselective and diversity-oriented synthesis of trisubstituted allylic alcohols and amines

Stereoselective and diversity-oriented synthesis of trisubstituted olefins was achieved by using ortho-diphenylphosphanyl benzoate (o-DPPB) as a directing group for allylic substitution. The starting point of this methodology was a set of α-methylene aldehydes derived from Baylis-Hillman adducts. Subsequent addition of different organometallic reagents led to a variety of allylic alcohol substrates. After introduction of the reagent-directing o-DPPB group, copper-mediated allylic substitution with a wide range of Grignard reagents enabled the stereoselective construction of a large number of E-configured trisubstituted allylic alcohols and amines in excellent yields and stereoselectivities. Remarkable is the synthetic flexibility, which allows a wide range of permutations starting from an aldehyde followed by successive introduction of the substituents R(2) and R(3) from organometallic Grignard based reagents. Thus, starting from only a few precursors, a diversity-oriented synthesis of stereodefined trisubstituted allylic alcohols and amines becomes possible.     

Solid-phase synthesis of rigid acylpolyamines using temporary N-4,4'-dimethoxytrityl protection in the presence of trityl linkers

An N-protection protocol employing the 4,4'-dimethoxytrityl (Dmt) group in combination with borane reduction of resin-bound polyamides was shown to be an efficient methodology that enables synthesis of novel analogues of natural acylpolyamine toxins. Thus, three philanthotoxins containing polyamine chains with piperidyl and cyclohexyl structural elements, which introduce conformational rigidity, increased lipophilicity, and altered proteolytic properties, were obtained in 39-44% overall yield.     

Regioselective synthesis of trifluoromethyl group containing allylic amines by palladium-catalyzed allylic amination and sequential isomerization

The palladium-catalyzed regioselective allylic amination of the α-trifluoromethyl group-substituted allyl acetate has been accomplished using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)]BF₄/DPPF as catalysts. The selective formation of the γ-product was attained in the presence of Pd(OAc)₂/DPPE, while the α-product was obtained using [Pd(π-allyl)(cod)]BF₄/DPPF. We also succeeded in the regioselective synthesis of the enantiomerically enriched aminated product from chiral allyl acetate using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)]BF₄/(S)-BINAP. Furthermore, we found that kinetic resolution had occurred during the isomerization step from the γ-type product to the α-type product by the [Pd(π-allyl)(cod)]BF₄/(S)-BINAP catalyst.     

Stereodivergent total asymmetric synthesis of polyhydroxylated pyrrolidines via tandem allylic epoxidation and intramolecular cyclization reactions

Epoxidation of the allylic alcohols 10 and 11 using the VO(acac)₂/t-BuOOH system followed by an intramolecular 5-exo cyclization of the resulting δ-epoxycarbamates 12, 13, 18, and 19 has been shown to provide a general and efficient solution for the asymmetric synthesis of polyhydroxy pyrrolidines. The requisite vicinal amino alcohol functionality was enantio-/regio-selectively installed by the Os-catalyzed asymmetric aminohydroxylation reaction of the designed achiral olefin 6.     

Stereocontrolled synthesis of 2-alkenyl-4-methylene tetrahydropyrans

A variety of 2-alkenyl-4-methylene tetrahydropyrans were synthesized via consecutive transition metal-catalyzed bond forming processes. In this approach, ruthenium-catalyzed coupling of homoallylic carbonates and homopropargylic alcohols generates substrates containing the requisite functionality for a palladium-mediated cyclization, thereby providing concise access to the target structures. The installation of a trisubstituted alkene at the C-2 position was achieved using an olefin cross metathesis process.     

Solid-phase synthesis of aryl, heteroaryl, and sterically hindered alkyl amines using the Curtius rearrangement

An efficient method for the solid-phase synthesis of aryl amines, heteroaryl amines, and sterically hindered alkyl amines has been developed. The key step in this process was the formation of resin-bound carbamates (B) by the Curtius rearrangement of aryl carboxylic acids with Wang resin providing the trapping hydroxyl group. N-Alkylation reactions of B gave secondary amines in good yield. Some biaryl amines, which are found widely in biologically active substances, were also prepared by the Suzuki reaction of resin-bound carbamates of 2-iodoaniline (16) or 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (21). The developed methods can be applied to the preparation of libraries containing aryl, heteroaryl, and sterically hindered alkyl amine structures as the pharmacophores.     

Regioselective synthesis of azetidines or pyrrolidines by selenium-induced cyclization of secondary homoallylic amines

Azetidines or pyrrolidines can be regioselectively obtained by selenocyclization of homoallylic amines, according to the double bond substitution.     

Solid-phase synthesis of 4-biaryl-piperidine-4-carboxamides

A novel solid-phase synthesis of 4-biaryl-piperidine-4-carboxamides has been developed using FDMP resin with a carboxamide as the anchor point. With this approach, three points of diversity were incorporated into a GPCR-directed scaffold. Final products were obtained in good purity and yield.     

Asymmetric carbon-carbon bond formations in conjugate additions of lithiated N-Boc allylic and benzylic amines to nitroalkenes: enantioselective synthesis of substituted piperidines,pyrrolidines, and pyrimidinones

(-)-Sparteine mediated lithiations of N-Boc-allylic and benzylic amines provide configurationally stable intermediates which on conjugate additions to nitroalkenes provide highly enantioenriched enecarbamate products in good yields, and with high diastereoselectivities. Straightforward transformations of these adducts offer general routes to substituted 3,4-substituted piperidines, 3,4-substituted pyrrolidines, and 4,5-substituted pyrimidinones. Diastereoselective substitutions of intermediate lactams followed by reduction provide 3,4,5-substituted piperidines and 3,4-trisubstituted pyrrolidines. Lithiation adjacent to nitrogen of 3,4-substituted piperidines and pyrrolidines followed by diastereoselective substitution opens a route to 2,4,5- and 2,4,5,6-substituted piperidines as well as 2,3,4- and 2,3,4,5-substituted pyrrolidines. The enantiomers of the enecarbamate and 3,4-substituted piperidine products may be accessed by stannylation/transmetalation sequences as well as by further manipulation of 4-substituted piperidones. The methodology is used to synthesize both enantiomers of an aspartic peptidase inhibitor intermediate, 3-hydroxy-4-phenylpiperidine, as well as the antidepressant (+)-femoxetine.     

Novel approach for asymmetric synthesis of fluorinated beta-amino sulfones and allylic amines

[reaction: see text] Enantiomerically pure gamma-fluoroalkyl beta-amino sulfones are readily synthesized in three steps starting from fluorinated imidoyl chlorides and arylmethyl sulfones. A complementary two-step sequence starting from chiral fluorinated beta-amino sulfoxides has also been developed. To illustrate the application of this procedure, a new method for the synthesis of alpha-fluoroalkyl allylic amines in optically pure form involving a Julia methylenation-desulfonylation reaction is presented.     

One-carbon homologation of N-sulfonylaziridines to allylic amines using dimethylsulfonium methylide

[reaction: see text]. Regio- and stereodefined allylic N-sulfonylamines are synthesized in high yields and under experimentally straightforward conditions by reaction of N-sulfonylaziridines with excess dimethylsulfonium methylide.     

Solid-phase oligosaccharide and glycopeptide synthesis using glycosynthases

Enzymatic approaches for the preparation of oligosaccharides are interesting alternatives to traditional chemical synthesis, the main advantage being the regio- and stereoselectivity offered without the need for protecting groups. The use of solid-phase techniques offers easy workup procedures and the prospect of automatability. Here, we report the first application of glycosynthases to solid-phase oligosaccharide synthesis by use of the 51 kDa serine and glycine mutants of Agrobacterium sp. beta-glucosidase, Abg E358S and E358G. Acceptors were linked to PEGA resin through a backbone amide linker (BAL), and using these mutated enzymes, a galactose moiety was transferred from a donor sugar, alpha-D-galactosyl fluoride, with high efficiency (>90%) together with excellent recovery of material. Furthermore, it was demonstrated that a resin-bound model glycopeptide was also an acceptor for the glycosynthase.     

Solid-phase synthesis of 1,2,5-trisubstituted 4-imidazolidinones

An efficient method for the preparation of 1,2,5-trisubstituted 4-imidazolidinones is presented. The synthetic approach is based on the formation of an N-[1-(benzotriazol-1-yl)alkyl] moiety on the amino group of a MBHA resin-bound amino acid. The nucleophilic substitution of the benzotriazole group with an amidic nitrogen results in the formation of a five-membered imidazolidinone ring. The reaction is nonstereospecific and produces diastereomers in ratios that vary depending on the substituents on the ring. A variety of N-alpha-alkylated amino acids were cyclized with aromatic, aliphatic, and heterocyclic aldehydes to determine optimal reaction conditions and to select building blocks for the future preparation of a large, diverse range of individual trisubstituted imidazolidinones as well as a mixture-based combinatorial library.     

Solid-phase synthesis of indolecarboxylates using palladium-catalyzed reactions

Polymer-supported, palladium-catalyzed cyclization reactions effectively synthesized indolecarboxylates. Palladium-catalyzed carbon-carbon bond-forming reactions of immobilized enaminoesters followed by transesterification yielded indole 2- or 3-carboxylates with various functional groups on the benzene ring. Indolecarboxylates were efficiently cyclized via an intramolecular palladium-catalyzed amination reaction of immobilized N-substituted dehydrohalophenylalanines, and immobilized N-acetyl-dehydroalanines were efficiently converted into indolecarboxylates via tandem Heck-amination reactions.     

Solid-phase synthesis of isoquinolinones using Bischler-Napieralski cyclization

Isoquinolinone is a structural unit found in many natural products having various important biological activities. A traceless solid-phase synthetic approach has been developed to prepare isoquinolinone derivatives. This approach enables one to synthesize isoquinolinones having various moieties on benzene nuclei and also can produce derivatives with a proton on the amide nitrogen.