Prins-type macrocyclizations as an efficient ring-closing strategy in natural product synthesis

Prins-type macrocyclizations have recently emerged as a successful strategy in the synthesis of polyketide-derived natural products. This reaction provides a concise and selective means to form tetrahydropyran-containing macrocyclic rings of varying size. A high degree of functionality within the macrocycle is tolerated and the yields for these transformations are typically good to excellent. Since the initial report of a Prins macrocyclization reaction in 1979, examples of this approach did not re-emerge until 2008. However, the use of this method in natural product synthesis has rapidly gained momentum in the synthetic community, with multiple examples of this macrocyclization tactic reported in the recent literature.     

RCM approach for the total synthesis of cryptophycin-24 (Arenastatin A)

An efficient total synthesis of cryptophycin-24 (arenastatin A) is reported, which features two novel synthetic strategies, the use of a RCM reaction to form the macrocycle, and the introduction of the styrene epoxide moiety prior to the macrocyclization reaction.     

Total synthesis of aigialomycin D: surprising chemoselectivity dependence on alkyne structure in nickel-catalyzed cyclizations

The total synthesis of aigialomycin D was carried out using a nickel-catalyzed ynal macrocyclization as a key step. This key step allowed macrocycle assembly and formation of a disubstituted alkene and a secondary hydroxyl stereocenter in a single step, although the stereocenter was formed unselectively. An interesting side reaction involving five-membered-ring synthesis by an aldehyde/styrene cyclization was observed when macrocyclization of an alkynyl silane was attempted. A mechanistic basis for this surprising process is provided.     

Towards Multi-generation Assemblies with Tetraphenylmethane Subunits

The synthesis of tetra(4-hydroxymethylphenyl)methane is reported. Possessing four benzyl alcohol groups, this molecule is anticipated to undergo self-assembly processes analogous to previously studied benzyl alcohol derived, deep-cavity cavitands (Gibb, C. L. D.; Stevens, E. D.; Gibb, B. C. Chem. Commun. 2000, 363–364). Towards such assembly processes, a bis-protected derivative was synthesized and its ability to undergo a macrocyclization reaction determined. Both the protection strategy employed and the macrocyclization approach are important models for more complex, repetitive self-assembly processes that can be envisaged with these types of molecules.     

Formal total synthesis of the polyketide macrolactone narbonolide

[reaction: see text] An improved synthesis of (3S)-3-dihydronarbonolide is reported that constitutes a formal total synthesis of the 14-membered macrolactone antibiotic narbonolide. The key step was an intramolecular Nozaki-Hiyama-Kishi coupling to accomplish macrocyclization in improved yield. The high level of convergence will also allow us to rapidly synthesize narbonolide analogues for the study of enzymes in the pikromycin biosynthetic pathway.     

Total Synthesis,Stereochemical Reassignment,and Biological Evaluation of (−)‐Lyngbyaloside B

(?)‐Lyngbyaloside B is a 14‐membered macrolide glycoside isolated from the marine cyanobacterium Lyngbya sp. as a cytotoxic substance by Moore and co‐workers. The first total synthesis of (?)‐lyngbyaloside B and the reassignment of its stereostructure is described. The synthesis features an Abiko–Masamune aldol reaction, a vinylogous Mukaiyama aldol reaction, and a macrocyclization involving an acyl ketene intermediate for the construction of the macrocyclic backbone, which contains an acylated tertiary alcohol. The antiproliferative activity of selected compounds against a small panel of human cancer cell lines is also reported.     

Total Synthesis,Stereochemical Reassignment,and Biological Evaluation of (−)‐Lyngbyaloside B

(−)‐Lyngbyaloside B is a 14‐membered macrolide glycoside isolated from the marine cyanobacterium Lyngbya sp. as a cytotoxic substance by Moore and co‐workers. The first total synthesis of (−)‐lyngbyaloside B and the reassignment of its stereostructure is described. The synthesis features an Abiko–Masamune aldol reaction, a vinylogous Mukaiyama aldol reaction, and a macrocyclization involving an acyl ketene intermediate for the construction of the macrocyclic backbone, which contains an acylated tertiary alcohol. The antiproliferative activity of selected compounds against a small panel of human cancer cell lines is also reported.     

Total synthesis of the cyclopeptide alkaloid paliurine E. insights into macrocyclization by ene--enamide RCM

The total synthesis of (-)-paliurine E is described in 14 steps and 11% overall yield. The first successful application of ene--enamide ring-closing metathesis for macrocyclization serves as the foundation for this synthesis and allowed for a straightforward installation of the challenging cyclic enamide together with the macrocycle. In the course of these synthetic studies, we also found that very subtle and minor structural modification of the enamide resulted in dramatic and unexpected changes of their reactivity since a primary amide or an aromatic aldehyde can be obtained after reaction with Grubbs' second-generation catalyst. Further insights on the macrocyclization by ene--enamide RCM are also discussed.     

Total Synthesis of the Protected Aglycon of Fidaxomicin (Tiacumicin B,Lipiarmycin A3)

Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic that is used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have excellent bactericidal activity against multidrug‐resistant Mycobacterium tuberculosis. In spite of its attractive biological activity, no total synthesis has been reported to date. The enantioselective synthesis of the central 18‐membered macrolactone is reported herein. The key reactions include ring‐closing metathesis between a terminal olefin and a dienoate moiety for macrocyclization, a vinylogous Mukaiyama aldol reaction, and a Stille coupling reaction of sterically demanding substrates. The retrosynthesis involves three medium‐sized fragments, thus leading to a flexible yet convergent synthetic route.     

Total synthesis of iejimalide B

Iejimalide B, a structurally unique 24-membered polyene macrolide having a previously underutilized mode of anticancer activity, was synthesized according to a strategy employing Julia-Kocienski olefinations, a palladium-catalyzed Heck reaction, a palladium-catalyzed Marshall propargylation, a Keck-type esterification, and a palladium-catalyzed macrolide-forming, intramolecular Stille coupling of a highly complex cyclization substrate. The overall synthesis is efficient (19.5% overall yield for 15 linear steps) and allows for more practical scaled-up synthesis than previously reported strategies that differed in the order of assembly of key subunits and in the method of macrocyclization. The present synthesis paves the way for efficient preparation of analogues for drug development efforts.     

Palladium‐Catalzyed Atroposelective 16‐Membered Macrocyclization: Total Synthesis of Isoplagiochin D†

Isoplagiochin D is a ring‐strained macrocyclic bisbibenzylis, which showed stable axial chirality in one biaryl structure, and semistable axial chirality in the other biaryl moiety. We reported here an unprecedented example for the catalytically asymmetric synthesis of ring‐strained atropisomers via Pd‐catalyzed macrocyclization between benzyl halides and carbenes. This newly developed Pd‐catalyzed asymmetric macrocyclization protocol enabled us a quick synthesis of isoplagiochin D in a highly enantioselective manner.     

Total synthesis of hirsutellone B via Ullmann-type direct 13-membered macrocyclization

Total synthesis of Hirsutellone B has been achieved by a convergent synthetic strategy. This synthesis features direct construction of the highly strained 13-membered macrocycle of Hirsutellone B utilizing the Ullmann-type reaction. To the best of our knowledge, this is the first application of macrocyclization utilizing an intramolecular Ullmann-type reaction between an aliphatic alcohol and aryl halide.     

Efficient synthesis of meso-substituted corroles in a H2O-MeOH mixture

New and efficient conditions for the synthesis of meso-substituted corroles were developed. The first step, involving the reaction of aldehydes with pyrrole, was carried out in a water-methanol mixture in the presence of HCl. A relatively narrow distribution of aldehyde-pyrrole oligocondensates was obtained through careful control of their solubility in the reaction medium. After thorough optimization of various reaction parameters (cosolvent, reagent, and acid concentration), high yields of bilanes were obtained. Additionally, the bilane derived from 4-cyanobenzaldehyde was isolated, and the oxidative macrocyclization reaction was performed under various reaction conditions (different solvents, different concentrations, and various oxidants). As a result, triphenylcorrole was obtained in the highest yield (32%) reported to date. The scope and limitations studied showed that this method was particularly efficient for moderately reactive aldehydes and those bearing electron-donating groups (yields 14-27%). Using these conditions, corroles bearing strongly electron-donating groups were obtained for the first time. In addition, it was found that the reaction of unhindered dipyrromethanes with aldehydes under analogous conditions afforded trans-A2B-corroles in very high yields (45-56%; 8-fold higher than previously reported) without scrambling. The fact that scrambling was not observed in this reaction despite a very high HCl concentration (0.3 M) is unprecedented. Detailed studies on the oxidation of bilane, derived from sterically hindered dipyrromethane, allowed us to unequivocally establish that the yield of macrocyclization is insensitive to the concentration. It was found the 1H NMR spectra of corroles in deuterated TFA gave very sharp signals.     

Total synthesis of (+)-dactylolide

[reaction: see text] The development of an approach leading to the total synthesis of dactylolide is described. The key features of this route include a catalytic asymmetric allylation, a diastereoselective pyran annulation, and a Horner-Wadsworth-Emmons macrocyclization.     

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.     

Regioselective synthesis of syn disubstituted dibenzo-30-crown-10 ethers

A practical and regioselective synthetic method for the synthesis of syn substituted dibenzo-30-crown-10 ethers is reported. This novel methodology is reported with the syntheses of dibenzo crown ethers bearing nitro, formyl and carbomethoxy groups. The synthesis of macrocyclization precursors was accomplished in three steps and featured an application of para-methoxybenzyl group (PMB) as protecting group of phenol moiety that is orthogonal to NO₂, CHO and COOMe groups. General non-high dilution macrocyclization conditions have been developed that allow for the effective preparation of substituted large crown ethers.     

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.     

A novel synthesis of biaryl-containing macrocycles by a domino Miyaura arylboronate formation: intramolecular Suzuki reaction

[reaction: see text] A novel macrocyclization procedure is developed on the basis of a domino process. Thus, treatment of linear diiodide 11 under defined conditions gave the 15-membered m,m-cyclophane 12 via aryl-aryl bond formation. Two distinct cross-coupling manifolds, Miyaura's arylboronic ester synthesis and intramolecular Suzuki reaction, proceed in an ordered fashion. Concentration is an important factor for the success of this process.     

Tandem Deprotection–Dimerization–Macrocyclization Route to C2 Symmetric cyclo‐Tetrapeptides

Dimerization–macrocyclization has been a long‐standing problem in the cyclization of peptides since, together with the desired cyclic product, many cyclic oligomers and linear polymers may also be formed during the reaction. Therefore, the development of a process that affords the cyclic dimer predominantly is difficult. A novel and versatile strategy for the synthesis of symmetric cyclo‐tetrapeptides by palladium‐promoted tandem deprotection/cyclo‐dimerization from readily available Cbz‐dipeptidoyl benzotriazolides is reported (Cbz=carboxybenzyl).     

Solid-phase based synthesis of jasplakinolide analogs by intramolecular azide-alkyne cycloadditions

The synthesis of a focused library of jasplakinolide analogs with a 1,2,3-triazole in place of an E-configured double bond is described, featuring the Cu(I) catalyzed azide-alkyne cycloaddition reaction as an efficient macrocyclization tool.