First and second generation total synthesis of the teicoplanin aglycon.

Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (>10:1, 76%) without problematic C(2)(3) epimerization provided the basicity of the reaction is minimized.     

A convergent solution-phase synthesis of the macrocycle Ac-Phe-[Orn-Pro-D-Cha-Trp-Arg], a potent new antiinflammatory drug

Relatively few cyclic peptides have reached the pharmaceutical marketplace during the past decade, most produced through fermentation rather than made synthetically. Generally, this class of compounds is synthesized for research purposes on milligram scales by solid-phase methods, but if the potential of macrocyclic peptidomimetics is to be realized, low-cost larger scale solution-phase syntheses need to be devised and optimized to provide sufficient quantities for preclinical, clinical, and commercial uses. Here, we describe a cheap, medium-scale, solution-phase synthesis of the first reported highly potent, selective, and orally active antagonist of the human C5a receptor. This compound, Ac-Phe[Orn-Pro-d-Cha-Trp-Arg], known as 3D53, is a macrocyclic peptidomimetic of the human plasma protein C5a and displays excellent antiinflammatory activity in numerous animal models of human disease. In a convergent approach, two tripeptide fragments Ac-Phe-Orn(Boc)-Pro-OH and H-d-Cha-Trp(For)-Arg-OEt were first prepared by high-yielding solution-phase couplings using a mixed anhydride method before coupling them to give a linear hexapeptide which, after deprotection, was obtained in 38% overall yield from the commercially available amino acids. Cyclization in solution using BOP reagent gave the antagonist in 33% yield (13% overall) after HPLC purification. Significant features of the synthesis were that the Arg side chain was left unprotected throughout, the component Boc-d-Cha-OH was obtained very efficiently via hydrogenation of d-Phe with PtO(2) in TFA/water, the tripeptides were coupled at the Pro-Cha junction to minimize racemization via the oxazolone pathway, and the entire synthesis was carried out without purification of any intermediates. The target cyclic product was purified (>97%) by reversed-phase HPLC. This convergent synthesis with minimal use of protecting groups allowed batches of 50-100 g to be prepared efficiently in high yield using standard laboratory equipment. This type of procedure should be useful for making even larger quantities of this and other macrocyclic peptidomimetic drugs.     

Design and Enantioselective Synthesis of a Peptidomimetic of the Turn in the Helix-Turn-Helix DNA-Binding Protein Motif

A peptidomimetic of the turn in the helix-turn-helix (HTH) motif of DNA-binding proteins was designed and synthesized. Conformational constraint was achieved by an unusual linking of two amino acids with a side chain carbon-carbon bond. A phenyl ring provides the potential for new hydrophobic contacts with the hydrophobic core of the HTH motif. In the mimic, the peptide backbone and the central residue were retained in native form within a 12-membered cyclic tripeptide. The target compound 1b was synthesized by two sequential Horner-Wittig couplings followed by enantioselective hydrogenation with Rh(MeDuPHOS) in eight steps and 35% overall yield. The stereochemical outcome of the key hydrogenation was determined by aromatic ring oxidation with RuO(2)/NaIO(4) to give 2 equiv of Boc-Asp-OMe.     

Synthesis of polyprenylated acylphloroglucinols using bridgehead lithiation: the total synthesis of racemic clusianone and a formal synthesis of racemic garsubellin A

The synthesis of polyprenylated phloroglucinol natural products, including clusianone, nemorosone, and garsubellin A, was pursued by a strategy involving construction of a core bicyclo[3.3.1]nonanetrione structure and subsequent elaboration via organolithium intermediates. Appropriate bridged core structures were obtained through the cyclization of a suitably substituted cyclohexanone enol ether or enol silane with malonyl dichloride. Additional substituents were then introduced by means of regioselective lithiation reactions, including the generation of bridgehead enolates, thus enabling the total synthesis of clusianone and also of an advanced intermediate toward nemorosone. In the case of garsubellin A, an additional THF-like ring was elaborated by a biomimetic 5-exo-tet cyclization of an enol ether (or enol) with a side-chain epoxide. This enabled a formal synthesis of racemic garsubellin A by accessing one of the late intermediates in the Danishefsky synthesis.     

Synthesis of proline-modified analogues of the neuroprotective agent glycyl-l-prolyl-glutamic acid (GPE)

The synthesis of ten proline-modified analogues of the neuroprotective tripeptide GPE is described. Five of the analogues incorporate a proline residue with a hydrophobic group at C-2 and two further analogues have this side chain locked into a spirolactam ring system. The pyrrolidine ring was also modified by replacing the γ-CH₂ group with sulfur and/or incorporation of two methyl groups at C-5.     

A facile synthesis and crystallographic analysis of N-protected β-amino alcohols and short peptaibols

A facile, efficient and racemization-free method for the synthesis of N-protected β-amino alcohols and peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide, tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of β-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III β-turn being observed in the tripeptide alcohol crystals. This method is found to be compatible with Fmoc-, Boc- and other side-chain protecting groups.     

Synthesis of bicyclic tripeptides inspired by the ABC-ring system of vancomycin through ruthenium-based cyclization chemistries

The synthesis of a bicyclic tripeptide that mimics the ABC ring system of vancomycin is described by using a ring closing metathesis (RCM) – peptide coupling – ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) strategy.     

Amino acid derived heterocycles: lewis acid catalyzed and radical cyclizations from peptide acetals

Bicyclization of peptide acetals via nucleophilic attack of a phenyl group on an endocyclic acyliminium ion 4 was explored as a route to novel amino acid derived heterocycles and peptidomimetic scaffolds. In the presence of protic acid, bridged structures such as 6 are formed readily from phenylalanine derivatives, but the fused-ring analogues 5 could not be obtained in good yield. In contrast, radical cyclization of the bromophenyl dihydropyrazinone 7 provides an effective alternative for the synthesis of 5 (n = 0, 1, 2). Additional versatility in this process was demonstrated by efficient synthesis of a different fused ring system, represented by the antihelmintic praziquantel, 8.     

Synthesis and conformation of Gly-Gly dipeptides constrained with phenylalanine-like aminocaproic acid linkers

[structure: see text] The constraint of dipeptides with linkers derived from 6-aminocaproic acid (Aca) is a useful means of constructing a beta-turn peptidomimetic. The extension of this concept to the mimicry of a tripeptide entails the incorporation of a side chain moiety on either end of the Aca chain. The synthesis and conformational analysis of two exemplary compounds is discussed.     

Synthesis of a Novel Thyrotropin Releasing Hormone (TRH) Analog Incorporating a Piperazin‐2‐one Ring

The synthesis of a Thyrotropin Releasing Hormone (TRH) analog incorporating a piperazin‐2‐one ring is described. This conformationally restricted peptidomimetic attempts to retain the key recognition elements of the interaction between TRH and its receptor. The synthesis started from the protected dipeptide 2 and proceeded via the 4‐nitrobenzenesulfonyl‐activated intermediate 3 , which was then cyclized, N‐acylated, and deprotected to yield the target compound 1 .     

Enantioselective synthesis of cyclopropane aminoalcohols containing quaternary stereogenic centers

Some title compounds have been synthesized in enantiomerically pure form starting from d- or l-glyceraldehyde as chiral precursors. A new synthesis of (+)-(Z)-methanohomoserine, one of the key intermediates employed, is also described. The target molecules are densely functionalized. Thus, in addition to one or two hydroxyl groups on a side-chain, an amino group is attached to a quaternary carbon of the cyclopropane ring, and the fourth substituent of such a stereogenic center contains a halogen atom, an alkyl group, or an alcohol, thioether or ester function. Some of these compounds are useful precursors in the synthesis of new cyclopropane nucleosides.     

Synthesis of a novel tricyclic peptidomimetic scaffold

An efficient method to synthesize a novel rigid tricyclic peptidomimetic scaffold through ring-closure of amino-functionalized bicyclic 2-pyridones has been discovered. The scaffold can function as a peptide backbone mimetic (highlighted) with two substituents independently variable to fine-tune biological response. Halogenation of the pyrazolo ring followed by Suzuki couplings made it possible to introduce substituents with variable electronic properties late in the synthetic route, which is preferable in library synthesis.     

RuO4-catalyzed oxidation reactions of isoxazolino-2-azanorbornane derivatives: a short-cut synthesis of tricyclic lactams and peptidomimetic γ-amino acids

A rapid access to peptidomimetic conformationally constrained γ-amino acids has been developed through the efficient RuO₄-mediated oxidation of regioisomeric isoxazolino-2-azanorbornane derivatives. The key intermediates are tricyclic lactams, which are quantitatively hydrolyzed into the desired amino acids. The conformational analysis, conducted by means of DFT calculations, supports the use of these γ-amino acids as β-turn inducers in peptide synthesis.     

o-Hydroxyphenylureas. Intermediates in the urea fusion synthesis of 2-benzoxazolinones

o-Hydroxyphenylureas have been identified as intermediates in the urea fusion synthesis of 2-benzoxazolinones. The pyrolysis of these intermediates represents a new alternate synthesis of the benzoxazolinone ring system.     

Enantioselective total synthesis of Wieland-Gumlich aldehyde and (-)-strychnine

A total synthesis of (-)-strychnine in 15 steps from 1,3-cyclohexanedione in 0.15% overall yield is described. The sequence followed in the assembling of rings is: E-->AE [2-(2-nitrophenyl)-1,3-cyclohexanedione]-->ACE (3a-aryloctahydroindol-4-one)-->ACDE (arylazatricyclic core)-->ABCDE (strychnan skeleton)-->ABCDEF (Wieland-Gumlich aldehyde)-->ABCDEFG (strychnine). The key steps of the synthesis are the enantioselective construction of the 3a-(2-nitrophenyl)-octahydroindol-4-one ring system and the closure of the piperidine ring by a reductive Heck cyclization to generate the pivotal intermediate (-)-14. In contrast, a Lewis acid promoted a-alkoxypropargylic silane-enone cyclization did not lead to synthetically useful azatricyclic ACDE intermediates. The introduction of C-17 and the closure of the indoline ring by reductive amination of the alpha-(2-nitrophenyl) ketone moiety complete the strychnan skeleton from which, via the Wieland-Gumlich aldehyde, the synthesis of (-)-strychnine is achieved.     

Chemoenzymatic Synthesis of Cellular Adhesion Tripeptide RGD Precursor in Organic Media

IntroductionA characteristic tripeptide sequence Arg-Gly-Asp(RGD) that is found within fibronectin and other rela-ted adhesion molecules in extracellular matrices(ECM)has received considerable attention from researcherssince it was proved to be a recognit…     

Solid-phase synthesis and utilization of side-chain reactive unnatural amino acids

Alkylation of the benzophenone imine of glycine Wang resin with α,ω-dihaloalkanes yielded valuable reactive intermediates. These racemic ω-chloro or ω-bromo intermediates were converted to α-amino acids containing diverse side-chain functionalities (e.g. ω-chlorides, nitriles, and thioethers), proline and its ring homologs, and 1-aminocycloalkanecarboxylic acid derivatives.     

Studies directed toward the synthesis of the scabrosins: validation of a tandem enyne metathesis approach

A synthetic approach to the scabrosin family of antibiotics using a ruthenium carbene-catalyzed tandem metathesis and a Pd(II)-catalyzed cyclization is described. The chiral propargyl amino acid is furnished through enantioselective phase-transfer propargylation. The synthesis of the cyclohexadiene ring system is achieved through ring synthesis using tandem enyne metathesis, previously developed in our lab. The complementary methods of methylene-free and 1,5-hexadiene-alkyne metatheses are compared. The indoline heterocycles are formed using a two-step chloroacetoxylation (Bäckvall reaction) with subsequent nucleophilic attack by an amide nucleophile. The indoline subunits were joined and cyclized to furnish the core diketopiperazine ring. The stereochemical assignment of intermediates is also discussed.     

Synthesis of dimethyl heterocyclic‐o‐dicarboxylates using dimethyl acetylenedicarboxylate

Dimethyl acetylenedicarboxylate (DMAD) is a very important and useful reagent for the preparation of dimethyl heterocyclic‐o‐dicarboxylates, which are key intermediates in the synthesis of fused pyridazine derivatives. The synthesis of thiopyranes by the Diels‐Alder reaction of dithiocarboxylate derivatives, synthesis of various cyclazines by [2 + 8] cycloaddition reactions, and synthesis of dimethyl pyrazolo[3,4‐b]pyridine‐5,6‐dicarboxylates and polycyclic heterocycles containing the 1,6‐naphthyridine ring system by the reaction of o‐aminonitrile compounds with DMAD are described here.     

Synthesis of a constrained tricyclic scaffold based on trans-4-hydroxy-l-proline

Drug discovery research has taken advantage of peptidomimetic chemistry in order to achieve new leads possessing structural and functional characteristics of bioactive peptides together with enhanced metabolic resistance towards proteases. Herein is reported the synthesis of a tricyclic peptidomimetic scaffold derived from the combination of trans-4-hydroxy-l-proline and tartaric acid derivatives by means of amidation and acid trans-acetalisation reactions. Further manipulations of the hydroxylic function on the pyrrolidine ring gave access to a new set of amino acid scaffolds possessing high rigidity and a fixed arrangement of the functional groups.