Total synthesis of macrosphelides A, B, and E: first application of ring-closing metathesis for macrosphelide synthesis

A new synthetic route for macrosphelides A, B, and E based on ring-closing metathesis (RCM) was established. The substrates for RCM could be synthesized starting from commercially available chiral materials, methyl (S)-lactate and methyl (S)- or (R)-3-hydroxybutyrate, in good overall yields. In the investigation of the key RCM step, it was found that the steric factor around the reaction site significantly affected the reaction rate of macrocyclization. A detailed account regarding this synthetic study is described herein.     

Investigating the scope of pseudoproline assisted peptide cyclization

The cyclization of linear peptides from six to nine amino acids in length and containing between two and four pseudoproline turn inducers derived from serine or threonine was investigated to determine the effect of peptide length, amino acid composition and spacing between the pseudoproline residues on macrocyclization yield.     

One-pot synthesis of hybrid macrocyclic pentamers with variable functionalizations around the periphery

Rather than four- or six-residue macrocylces, one-pot macrocyclization allows for the highly selective formation of five-residue macrocycles rigidified by intramolecular hydrogen bonds. Variable functionalizations around the pentameric periphery were achieved by reacting monomers with higher oligomers bearing different exterior side chains. The formation of these hybrid pentamers suggests a chain-growth mechanism for the one-pot macrocyclization where the successive addition of monomers onto higher oligomers is faster than those between two monomers or two higher oligomers.     

Simple approach to "locked" chlorins

[reaction: see text] A novel synthetic approach to diversely functionalized "locked" chlorins is described. A suitably substituted 2,5-diformylpyrrole undergoes the macrocyclization reaction with tripyrranes, thereby generating porphyrins. Upon the reaction with 1,3-dipoles these porphyrins regioselectively furnish pyrrolidine-fused chlorins, which cannot oxidize to the corresponding porphyrins. In the process involving just six steps from commercially available and cheap materials we are able to obtain approximately 200 mg of pure stable chlorins (the overall yield is 1.5-2.8%).     

Enzymatic Macrocyclization of 1,2,3‐Triazole Peptide Mimetics

The macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme‐mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4‐substituted 1,2,3‐triazole moieties. The introduction of non‐peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non‐natural triazole‐containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation.     

Synthesis of macrocyclic peptide analogues of proteasome inhibitor TMC-95A

The synthesis of three constrained macrocyclic peptide analogues 1 of TMC-95A as potential proteasome inhibitors is described. The key step involves a Ni(0)-mediated macrocyclization of tripeptides 2 bearing halogenated aromatic side chains for the formation of the biaryl junction. In addition, an enantioselective preparation of l-7-bromotryptophan methyl ester 3 using a Corey-O'Donnell alkylation of the glycine benzophenone imine was achieved in good overall yield with very high ee (>85%) on a multigram scale.     

Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis

Nonribosomal peptides and polyketides have attracted considerable attention in basic and applied research and have given rise to a multitude of therapeutic agents. The biological activity of many of these complex natural products, including for example the peptide antibiotics daptomycin and bacitracin or the polyketide anticancer agents epothilone and geldanamycin, specifically relies on the macrocyclization of linear acyl chains that form the backbone of these highly valuable molecules. The construction of the linear acyl precursors is accomplished by modular protein templates that follow comparable assembly line logic. As an enzymatic key step, macrocyclization is introduced after the consecutive condensation of amino acid or acyl-CoA building blocks by dedicated catalysts, and the mature product is released from the biosynthetic machinery. The diverse chain termination strategies of nonribosomal peptide and polyketide assembly lines, the structures and mechanisms of the versatile macrocyclization catalysts, and chemoenzymatic approaches for the development of new therapeutics are the focus of this review. Further, it is illustrated that macrocyclization is not restricted to secondary metabolites, but represents a commonly found structural motif of other biologically active proteins and peptides.     

Pyranophane transannular diels-alder approach to (+)-chatancin: a biomimetic asymmetric total synthesis

An asymmetric total synthesis of (+)-chatancin was achieved via a transannular Diels-Alder (TADA) reaction of an in situ generated macrocyclic pyranophane pseudobase. The presented route constitutes the second of two proposed biosynthetic pathways that involves a TADA reaction. It links this diterpene biogenetically to the cembranoids. A set of TADA selection rules that rationalize the formation of (+)-chatancin from a dynamic equilibrium of four 2-hydroxy-2H-pyrane bicycles and their 16 potential TADA transition states are also outlined. Beyond the TADA reaction, highlights of the synthetic work include the assembly of a chiral acyclic macrocyclization substrate from (S)-citronellol and an efficient macrocyclization via a beta-ketosulfoxyde/enone Michael addition.     

Selective thioether macrocyclization of peptides having the N-terminal 2-chloroacetyl group and competing two or three cysteine residues in translation

The mode of thioether macrocyclization of peptides containing an N-terminal 2-chloroacetyl group and two or three competing cysteine residues at downstream positions has been extensively studied, leading to a strategy for designated formation of overlapping-bicyclic peptides or dumbbell-type bicyclic peptides.     

Total synthesis of borrelidin

The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is macrocyclization at C11-C12 for the construction of an 18-membered ring after esterification between two segments. A detailed examination of the macrocyclization led us to the samarium(II) iodide-mediated intramolecular Reformatsky-type reaction as the most efficient synthetic approach. The two key segments were synthesized through regioselective methylation, directed hydrogenation, stereoselective Reformatsky-type reaction, and MgBr2.Et2O-mediated chelation-controlled allylation.     

Chiral macrocyclic aliphatic oligoimines derived from trans-1,2-diaminocyclohexane

Aliphatic dialdehydes of rigid structures having a cyclohexane, a bicyclo[2.2.2]octane or a [7]triangulane skeleton, have been condensed with enantiomerically pure trans-1,2-diaminocyclohexane to give [3+3] or [2+2] macrocyclization products. Unlike acyclic aliphatic imines, these macrocyclic oligoimines show enhanced stabilities and their structures in the crystals could be determined by X-ray diffraction analyses. The enantiomerically pure [7]triangulane dialdehyde showed remarkable diastereoselectivity in the condensation with the two enantiomers of trans-1,2-diaminocyclohexane: only one of the enantiomers gave a [2+2] macrocyclization product. Circular dichroism measurements combined with computational analysis show that the lowest energy electronic transition in these cyclic oligoimines is of n-pi* type.     

An in situ approach for nickel-catalyzed cycloaddition

A convenient method for preparing pyridines from air-stable, commercially available catalyst precursors is described. The addition of n-BuLi to Ni(acac)2 and an NHC salt (such as IPr.HCl or SIPr.HCl) rapidly generates an active Ni0/NHC catalyst for the cycloaddition of diynes and nitriles that affords pyridines without a decrease in observed yields. The in situ method also converts diynes and carbon dioxide to the corresponding pyrones.     

A convenient one-pot Negishi coupling of amino-heteroaryl chlorides and alkyl bromides

A simple Ni-catalysed cross-coupling protocol for amino-heteroaryl chlorides with alkylzinc reagents has been developed. The alkylzinc reagents can be commercially available dialkylzincs or alkylzinc halides, or can be conveniently generated in situ from diethylzinc and primary alkyl bromides in the presence of the same inexpensive Ni catalyst used to effect the subsequent coupling reaction.     

ICP emission spectrometer relative response by the branching-ratio method: branching ratios for Fe, Se, Te, Ge and Pd

The relative spectral response of a commercially available inductively coupled argon plasma (ICP) emission spectrometer has been determined over a wide spectral range (approx. 190 to >900 nm) using overlapping sets of radiative branching ratios of several atomic and ionic species. Response curves were determined in two ways. In the first, calibrations were based on Ar II and Ar I lines emitted by Ar-filled hollow-cathode lamps used as line sources instead of the plasma torch. In the second, the ICP emission of selected lines of Ni and Fe was used. Branching ratios determined from the ICP emission of lines of Fe I, Se I, and Te I, using Ar lines for the intensity calibrations, were compared with previously published branching ratios or f-values for these atoms, and good agreement was found. The calibrations based on Ar II and Ni I were used to measure further branching ratios, and application to the measurement of branching ratios from selected levels of Ge I and Pd I is shown.     

Photoisomerizable azobenzene-containing oxacalixarenes

The first examples of photo-responsive azobenzene-containing oxacalixarenes have been synthesized via a 3+1 macrocyclization approach. Introduction of the photoresponsive unit was achieved by using 4-phenylazoresorcinol or (E)-4-(4′-nitrophenylazo)resorcinol as the nucleophilic component in the macrocyclization reaction. These novel macrocycles have been characterized by means of 1D and 2D NMR spectroscopy and DFT calculations (B3LYP/6-31G(d)). According to thermal and photoisomerization studies, tetranitro-oxacalix[4]arenes are less prone to E→Z isomerization than oxacalix[2]arene[2]triazines and, within the two series, p-nitrophenylazo derivatives are more unwilling to isomerize than their phenylazo analogues.     

Fluorescence resonance energy transfer as a probe of peptide cyclization catalyzed by nonribosomal thioesterase domains

Macrocyclization of synthetic peptides by thioesterase (TE) domains excised from nonribosomal peptide synthetases (NRPS) has been limited to peptides that contain TE-specific recognition elements. To alter substrate specificity of these enzymes by evolution efforts, macrocyclization has to be detected under high-throughput conditions. Here we describe a method to selectively detect cyclic peptides by fluorescence resonance energy transfer (FRET). Using this method, picomolar detection limits were easily realized, providing novel entry for kinetic studies of catalyzed macrocyclization. Application of this method also provides an ideal tool to track TE-mediated peptide cyclization in real time. The general utility of FRET-assisted detection of cyclopeptides was demonstrated for two cyclases, namely tyrocidine (Tyc) TE and calcium-dependent antibiotic (CDA) TE. For the latter cyclase, this approach was combined with site-directed affinity labeling, opening the possibility for high-throughput enzymatic screening.     

Asymmetric total syntheses of marine cyclic depsipeptide halipeptins A-D

Halipeptins A-D (1 a-d) are a family of natural cyclic depsipeptides isolated from marine sponges. Total syntheses of these four compounds are detailed in this report. The key elements in this synthesis include the elaboration of the polysubstituted decanoic acid parts by two asymmetric aldol reactions, assembly of the N-methyl-delta-hydroxyisoleucine residue by using either aza-Claisen rearrangement or methylation of aspartates as the key steps, and macrocyclization at the polysubstituted decanoic acid alanine site.     

Application of hitherto unexplored macrocyclization strategies in the epothilone series: novel epothilone analogs by total synthesis

A total synthesis of Epothilone 490 and a synthesis of 11-hydroxy dEpoB utilizing a vinyl-boronate cross-metathesis followed by a Suzuki macrocyclization. A mild route to reach aldehydes from terminal olefins, anticipating Nozaki-Kishi macrocyclization is described.     

Formal total synthesis of oximidine II via a Suzuki-type cross-coupling macrocyclization employing potassium organotrifluoroborates

A formal total synthesis of oximidine II has been achieved, employing a Suzuki-type coupling approach to construct the highly strained, polyunsaturated 12-membered macrolactone. To achieve this goal, benefit was derived from the stability of potassium alkenyltrifluoroborates to establish conditions for the macrocyclization. The stereocontrolled formation of the cis-1,2-diol subunit was accomplished using a diastereoselective, reagent controlled addition to a chiral aldehyde utilizing the Carreira protocol. Advantage was taken of the Snieckus hydroborating reagent to gain access to the key trifluoroborate needed for the macrocyclization.     

Quantitative evaluation of the chloride template effect in the formation of dicationic [1(4)]imidazoliophanes

The formation of macrocycles containing two imidazolium rings such as 1.2X and 2.2X is anion-directed through hydrogen bonding. The template effect exerted by the chloride anion in the ring-closure reaction of the monocationic model intermediate 9+ to yield the [1(4)]imidazoliophane 2(2+) has been evaluated. This effect was quantified following the kinetics of the macrocyclization by using a UV-vis technique. The rate of the ring closure of monocation 9+ is increased up to 10 times, in the presence of Bu4NCl 0.04 M. This finding confirms that the template effect is operative in the macrocyclization leading to dicationic [1(4)]imidazoliophanes.