Shortcut access to peptidosteroid conjugates: building blocks for solid-phase bile acid scaffold decoration by convergent ligation

We present three versatile solid-supported scaffold building blocks based on the (deoxy)cholic acid framework and decorated with handles for further derivatization by modern ligation techniques such as click chemistry, Staudinger ligation or native chemical ligation. Straightforward procedures are presented for the synthesis and analysis of the steroid constructs. These building blocks offer a new, facile and shorter access route to bile acid-peptide conjugates on solid-phase with emphasis on heterodipodal conjugates with defined spatial arrangements. As such, we provide versatile new synthons to the toolbox for bile acid decoration.     

Synthesis and antifungal activities of N-glycosylated derivatives of Tunicyclin D,an antifungal octacyclopeptide

A series of glycosylated derivatives of Tunicyclin D were synthesized through a highly efficient and versatile synthetic method. The method is based on solid-phase peptide synthesis using 2-chlorotrityl resin as the solid-phase support and glycosyl amino acids as building blocks. Biological studies of the synthetic Tunicyclin D derivatives showed monosaccharide-containing compounds exhibit improved or similar antifungal activities, whereas the compounds carrying disaccharide glycans, showed much weaker antifungal activities.     

N-to-C solid-phase peptide and peptide trifluoromethylketone synthesis using amino acid tert-butyl esters

Solid-phase peptide synthesis in the N-to-C direction, opposite to the classical C-to-N direction of peptide synthesis, provides the synthetically versatile C-terminal carboxyl group for further modification into C-terminally modified peptide mimetics. These are of general interest as potential bioactive agents, particularly as protease inhibitors. Elaboration of peptide mimetics on the solid-phase would facilitate synthesis of peptide mimetic combinatorial libraries. This report describes an effective strategy for solid-phase inverse peptide synthesis based on readily available amino acid tert-butyl esters. The potential of this approach for peptide mimetic synthesis is demonstrated by the solid-phase synthesis of two peptide trifluoromethylketones.     

Solid-phase synthesis of asymmetrically branched sequence-defined poly/oligo(amidoamines)

We present for the first time the synthesis of asymmetrically branched sequence-defined poly/oligo(amidoamines) (PAAs) using solid-phase synthesis with the capability of introducing diversity at the side chains. We introduce two new versatile (diethylenetriamine) building blocks for solid-phase synthesis bearing Fmoc/Boc and Fmoc/Alloc protecting groups expanding recently used Fmoc/Boc protecting group strategy for linear PAAs to an Fmoc/Alloc/Boc strategy. This allows for orthogonal on-resin cleavage of Fmoc and Alloc protecting groups during solid-phase synthesis of PAAs with backbones differing in chain length and sequence. With these structures we then demonstrate the potential for generating asymmetrical branching by automated multiple on-resin cleavage of Alloc protecting groups as well as the introduction of side chains varying in length and number. Such systems have high potential as nonviral vectors for gene delivery and will allow for more detailed studies on the correlation between the degree of branching of PAAs and their resulting biological properties.     

An efficient synthetic route to glycoamino acid building blocks for glycopeptide synthesis

[reaction: see text] Chemical glycopeptide synthesis requires access to gram quantities of glycosylated amino acid building blocks. Hence, the efficiency of synthesis of such building blocks is of great importance. Here, we report a fast and highly efficient synthetic route to Fmoc-protected asparaginyl glycosides from unprotected sugars in three steps with high yields. The glycosylated amino acids were successfully incorporated into target glycopeptides 7 and 8 by standard Fmoc solid-phase peptide synthesis.     

Homochiral 4-azalysine building blocks: syntheses and applications in solid-phase chemistry

Anomalous amino acids not only play central roles as mimics of natural amino acids but also offer opportunities as unique building blocks for combinatorial chemistry. This paper describes the chiral syntheses and solid-phase applications of a versatile atypical amino acid, 4-azalysine (2,6-diamino-4-azahexanoic acid) 1. The syntheses of differentially protected 4-azalysine derivatives 28a-e have been developed by two efficient and inexpensive routes that start either from Garner's aldehyde 16 or the chiron (S)-N(alpha)-Cbz-2,3-diaminopropionic acid 23. Both approaches employ the convergent modular concept and exploit reductive amination of aldehydes with amines as the key step for the fusion of the two segments. In the first route, the overall process inverts the chirality of the starting material, L-serine, and thus provides an excellent route to the unnatural D-isomers. The alternative route starting from L-asparagine provides a shorter and high-yielding route to orthogonally protected 4-azalysine derivatives. The corresponding N(2)-Fmoc-4-azalysines 31a-e, readily derived from the key intermediate 27, are compatible with the Fmoc-based solid-phase peptide synthesis (SPPS) and solid-phase organic chemistry (SPOC) protocols. Furthermore, the utility and versatility of another key structure, tris-Boc-4-azalysine 2 in the engineering of novel high-loading dendrimeric polystyrene resins 33 and 36, have been demonstrated. Following derivatization with the Rink amide linker 34, the stability and robustness of these resin-bound dendrimers 35 and 37 in the synthesis of small molecules using a range of reaction conditions (e.g., Mitsunobu and Suzuki reactions) have been effectively illustrated.     

Soluble Polymer-Supported Synthesis of α-Amino Acid Derivatives

Due to the central role played by α-amino acid in chemistry and biology, the development of versatile and new methodology for the synthesis of natural and unnatural α-amino acid has emerged as an important and challenging synthetic endeavour for organic chemists.[1] Among the various methodologies reported for α-amino acid synthesis, [2,3] the solid-phase organic synthesis (SPOS) has served as an important approach. [4] However, inherent prob lems on solid supports are reactive site accessibility, site-site interaction and monitoring of the reaction.     

Solid-phase synthesis of 2-aminoquinazolinone derivatives with two- and three-point diversity

A versatile solid-phase method for the synthesis of various substituted 2-amino-4(3H)-quinazolinones with two- and three-point diversity is described. The synthesis commenced with the generation of polymer-bound S-methylisothiourea followed by N-acylation with different substituted o-nitrobenzoic acid. Finally, reduction of the nitro group triggered intramolecular cyclization via formation of guanidine to afford 2-amino-4(3H)-quinazolinone and its derivatives in high yields and purities.     

Synthesis of lipophilic bisanthracene fluorophores: versatile building blocks toward the synthesis of new light-harvesting dendrimers

Lipophilic bisanthracene-based fluorophore and its derivatives were synthesized by the Suzuki-Miyaura cross-coupling reaction of 9-anthrylboronic acid with a substituted dibromobenzene. In addition to desirable fluorescent properties, these molecular systems were demonstrated to serve as versatile building blocks toward the synthesis of two types of new light-harvesting dendrimers due to their chemical stability.     

Solid-phase synthesis of "mixed" peptidomimetics using Fmoc-protected aza-beta3-amino acids and alpha-amino acids

[structure: see text] A solid-phase fluorenylmethyloxycarbonyl (Fmoc)-based synthesis strategy is described for "mixed" aza-beta3-peptides as well as a convenient general approach for their required building blocks, the aza-beta3-amino acid residues (aza-beta3-aa). These monomers allow the synthesis of relatively large quantities of pure mixed aza-beta3-peptides. The required Fmoc-substituted aza-beta3-amino acids are accessible by convenient synthesis, and a number of monomers including those containing side chains with functional groups have been synthesized. The method was applied toward the solid-phase synthesis of aza-beta3-peptide mimetics of a biologically active histone H4 sequence.     

Oligosaccharide synthesis with glycosyl phosphate and dithiophosphate triesters as glycosylating agents

Described is an efficient one-pot synthesis of alpha- and beta-glycosyl phosphate and dithiophosphate triesters from glycals via 1,2-anhydrosugars. Glycosyl phosphates function as versatile glycosylating agents for the synthesis of beta-glucosidic, beta-galactosidic, alpha-fucosidic, alpha-mannosidic, beta-glucuronic acid, and beta-glucosamine linkages upon activation with trimethylsilyl trifluoromethanesulfonate (TMSOTf). In addition to serving as efficient donors for O-glycosylations, glycosyl phosphates are effective in the preparation of S-glycosides and C-glycosides. Furthermore, the acid-catalyzed coupling of glycosyl phosphates with silylated acceptors is also discussed. Glycosyl dithiophosphates are synthesized and are also used as glycosyl donors. This alternate method offers compatibility with acceptors containing glycals to form beta-glycosides. To minimize protecting group manipulations, orthogonal and regioselective glycosylation strategies with glycosyl phosphates are reported. An orthogonal glycosylation method involving the activation of a glycosyl phosphate donor in the presence of a thioglycoside acceptor is described, as is an acceptor-mediated regioselective glycosylation strategy. Additionally, a unique glycosylation strategy exploiting the difference in reactivity of alpha- and beta-glycosyl phosphates is disclosed. The procedures outlined here provide the basis for the assembly of complex oligosaccharides in solution and by automated solid-phase synthesis with glycosyl phosphate building blocks exclusively or in concert with other donors.     

A solid-phase approach to the phallotoxins: total synthesis of [Ala7]-phalloidin

Herein we report a solid-phase synthetic approach to [Ala7]-phalloidin (1). Prior syntheses of phallotoxins were carried out using solution-phase routes that required large scale and preclude library production. The route presented here consists of solution-phase preparation of key orthogonally protected amino acid building blocks, followed by a solid-phase peptide synthesis sequence, featuring two resin-bound macro-cyclization reactions. The final product mixture was composed of two atropisomeric compounds, one designated "natural" (1) and the other designated "non-natural" (1'). The structures of these species were modeled using restrained energy minimization with NMR-derived restraints.     

General inverse solid-phase synthesis method for C-terminally modified peptide mimetics

Peptide mimetics are of considerable interest as bioactive agents and drugs. C-terminally modified peptide mimetics are of particular interest given the synthetic versatility of the carboxyl group and its derivatives. A general approach to C-terminally modified peptide mimetics, based on a urethane attachment strategy and amino acid t-butyl ester-based N-to-C peptide synthesis, is described. This approach is compatible with the reaction conditions generally employed for solution-phase peptide mimetic synthesis. To develop and demonstrate this approach, it was employed for the solid-phase synthesis of peptide trifluoromethyl ketones, peptide boronic acids, and peptide hydroxamic acids. The development of a versatile general approach to C-terminally modified peptides using readily available starting materials provides a basis for the combinatorial and parallel solid-phase synthesis of these peptide mimetic classes for bioactive agent screening and also provides a basis for the further development of solid-phase C-terminal functional group elaboration strategies.     

Light-directed maskless synthesis of peptide arrays using photolabile amino acid monomers

Novel photolabile amino acid monomers for photolithographic solid-phase peptide synthesis has been developed and a method for the maskless synthesis of individually addressable peptide microarrays using new building blocks has been described; these peptide microarrays are suitable for repetitive epitope-binding assays.     

Asymmetric synthesis of beta-amino acid derivatives incorporating a broad range of substitution patterns by enolate additions to tert-butanesulfinyl imines

Addition of Ti(Oi-Pr)(3) ester enolates to tert-butanesulfinyl aldimines and ketimines provided beta-substituted, alpha,beta- and beta,beta-disubstituted, alpha,beta,beta- and alpha,alpha,beta-trisubstituted, and alpha,alpha,beta,beta-tetrasubstituted beta-amino acid derivatives in high yields and with high diastereoselectivites. The N-sulfinyl-beta-amino ester products were further employed as versatile intermediates for both standard solution-phase and solid-phase synthetic transformations, including the synthesis of beta-peptide foldamers.     

Divergent pathway for the solid-phase conversion of aromatic acetylenes to carboxylic acids, alpha-ketocarboxylic acids, and methyl ketones

An efficient divergent pathway for the selective and quantitative solid-phase conversion of aromatic acetylenes to the corresponding carboxylic acids, alpha-keto-carboxylic acids, and methyl ketones is presented. A range of aromatic trimethylsilyl-protected acetylene building blocks was synthesized in excellent yields using a Sonogashira cross-coupling protocol and used in solid-phase synthesis on PEGA resin. Dependent on the selection of conditions, the same solid-supported alkyne could be quantitatively converted to an aromatic carboxylic acid, an aromatic alpha-ketocarboxylic acid, or an aromatic methyl ketone. The conversion to carboxylic acid involved an OsO4/NaIO4/HMTA-mediated oxidative cleavage of the silyl-deprotected alkyne to provide the aromatic carboxylate in excellent yield. The alpha-ketocarboxylic acids were obtained by direct treatment of the trimethylsilyl-protected alkyne with OsO4/NMO/HMTA, while the ketones were obtained by simple acid-mediated hydration of the alkyne using aqueous TFA. In general, all products were obtained in excellent purities, typically above 90%. In addition, it was shown that the alkyne-containing building blocks could easily be incorporated into resin-bound peptides and after chemoselective conversion of the alkyne the new functional groups could be used for further derivatization into peptidomimetic compounds.     

Sulfanyl-methylene-5(4H)-oxazolones and β-sulfanyl-α-nitroacrylates as appealing dienophiles for the synthesis of conformationally constrained cysteine analogues

A new class of masked constrained cysteine derivatives containing the norbornen/ane scaffold were prepared by the way of Diels–Alder cycloaddition reaction by exploitation of two different dienophiles, sulfanyl-methylene-5(4H)-oxazolones and β-sulfanyl-α-nitroacrylates. The new norbornen/ane amino acid derivatives can be considered versatile building blocks due to the presence of the α,α-disubstituted amino acid function, suitable for peptide synthesis, but also by the carbon–carbon norbornene double bond, which could be variously functionalized.     

Stereoselective routes to 3-hydroxy and 3,4-dihydroxy derivatives of 2-aminocyclohexanecarboxylic acid

The Diels-Alder adduct of ethyl (E)-3-nitroacrylate and furan provides a versatile template for the stereoselective synthesis of mono and dihydroxylated derivatives of 2-aminocyclohexanecarboxylic acid (ACHC). The hydroxylated ACHC derivatives can be considered to be useful building blocks for β-peptides.     

Efficient and versatile COMU-mediated solid-phase submonomer synthesis of arylopeptoids (oligomeric N-substituted aminomethyl benzamides)

The development of a highly efficient methodology for solid-phase synthesis of para- and meta-arylopeptoids (oligomeric N-substituted aminomethyl benzamides) with free acids or free amides at the C-terminus is described. The arylopeptoids were synthesised by means of a convenient submonomer protocol in which the arylopeptoid residues were created in an iterative manner on the growing chain using an acylation-substitution cycle. The uronium salt COMU was found to be the most efficient reagent for ensuring fast and clean couplings of the benzoic acid building blocks.     

Synthesis of alpha-(2-->5)Neu5Gc oligomers

A facile synthesis of the sialic acid oligomers alpha-(2-->5)Neu5Gc (1) is presented. Monosaccharides 2-4 with suitable functionality were used as the building blocks. After selective removal of the paired carboxyl and amine protecting groups, the fully protected oligomers were assembled through consecutive coupling of the building blocks by well established peptide coupling techniques. By this approach, fully protected oligomers as large as an octasaccharide were synthesized. Deprotection of these fully protected oligomers was conducted in two steps (LiCl in refluxing pyridine and 0.1 n NaOH) to afford the desired products in high yield. Enzymatic degradation of the octamer with neuraminidase, monitored by capillary electrophoresis (CE), was also accomplished. The stepwise exo-cleavage adducts were all well separated and identified in the CE spectrum. The strategy described here for solution-phase synthesis also provides the basis for future solid-phase synthesis of poly-alpha-(2-->5)Neu5Gc.