胍类化合物的合成进展

胍类化合物是精氨酸残体的一部分，它在具有生物活性的蛋白质、肽中起着重要作用，从天然产物分离得到的胍类化合物大部分具有生理活性，如抗病毒、抗肿瘤、抗艾滋病等。所以，在温和条件下高产率的合成胍类化合物显得非常重要。本文综述了胍类化合物的合成进展。参考文献32篇。     

Total Synthesis of Aculeatins A and B from L‐Malic Acid

An efficient total synthesis of the cytotoxic spiroketal natural products aculeatin A and B is described. The synthesis of the 1,3,5‐triol moiety with appropriate configuration was accomplished from the commercially available L ‐malic acid. The key steps in this synthesis are the Barbier allylation, LiAlH₄/LiI‐mediated syn‐stereoselective 1,3‐asymmetric reduction, and phenyliodine bis(trifluoroacetate) (=[bis(trifluoroacetoxy)iodo]benzene; PIFA) mediated oxidative spirocyclization.     

Synthesis of Histidine‐Containing Oligopeptides via Histidine‐Promoted Peptide Ligation

Histidine‐containing peptides are valuable therapeutic agents for a treatment of neurodegenerative diseases. However, the synthesis of histidine‐containing peptides is not trivial due to the potential of imidazole sidechain of histidine to act as a nucleophile if unprotected. A peptide ligation method utilizing the imidazole sidechain of histidine has been developed. The key imidazolate intermediate that acts as an internal acyl transfer catalyst during ligation is generated by deprotonation. Transesterification with amino acids or peptides tethered with C‐terminal thioester followed by N→N acyl shifts led to the final ligated products. A range of histidine‐containing dipeptides could be synthesized in moderate to good yields via this method without protecting the imidazole sidechain. The protocol was further extended to tripeptide synthesis via a long‐range N→N acyl transfer, and tetrapeptide synthesis.     

Chemoenzymatic Synthesis of Spinosyn A

Following the biosynthesis of polyketide backbones by polyketide synthases (PKSs), post‐PKS modifications result in a significantly elevated level of structural complexity that renders the chemical synthesis of these natural products challenging. We report herein a total synthesis of the widely used polyketide insecticide spinosyn A by exploiting the prowess of both chemical and enzymatic methods. As more polyketide biosynthetic pathways are characterized, this chemoenzymatic approach is expected to become readily adaptable to streamlining the synthesis of other complex polyketides with more elaborate post‐PKS modifications.     

A Rapid Synthesis of 4‐Oxazolidinones: Total Synthesis of Synoxazolidinones A and B

A five‐step total synthesis of the marine natural product synoxazolidinone A was achieved through a diastereoselective imine acylation/cyclization cascade. Synoxazolidinone B and a series of analogues were also prepared to explore the potential of these 4‐oxazolidinone natural products as antimicrobial agents. These studies confirmed the importance of the chlorine substituent for antimicrobial activity and revealed simplified dichloro derivatives that are equally potent against several bacterial strains.     

Machine-Driven Chemoenzymatic Synthesis of Glycopeptide

Historically, researchers have put considerable effort into developing automation systems to prepare natural biopolymers such as peptides and oligonucleotides. The availability of such mature systems has significantly advanced the development of natural science. Over the past twenty years, breakthroughs in automated synthesis of oligosaccharides have also been achieved. A machine-driven platform for glycopeptide synthesis by a reconstructed peptide synthesizer is described. The designed platform is based on the use of an amine-functionalized silica resin to facilitate the chemical synthesis of peptides in organic solvent as well as the enzymatic synthesis of glycan epitopes in the aqueous phase in a single reaction vessel. Both syntheses were performed by a peptide synthesizer in a semiautomated manner.     

Synthesis and Herbicidal Evaluation of 4,6‐Dimethoxyaurone Derivatives

A multi‐step synthesis of 4,6‐dimethoxyaurone derivatives was carried out from phloroglucinol and chloroacetonitrile, and the products were characterized by ¹H NMR, ¹³C NMR, and HRMS. The preliminary bioassays showed that some products exhibited herbicidal activity against dicotyledonous plant Brassica campestris L.     

Stereoselective Synthesis of Highly Substituted Conjugated Dienes via Pd‐Catalyzed Carbonylation of 1,3‐Diynes

The stereoselective synthesis of conjugated dienes was realized for the first time via Pd‐catalyzed alkoxycarbonylation of easily available 1,3‐diynes. Key to success is the utilization of the specific ligand 1,1′‐ferrocenediyl‐bis(tert‐butyl(pyridin‐2‐yl)phosphine) ( L1 ), which allows this novel transformation to proceed at room temperature. A range of 1,2,3,4‐tetrasubstituted conjugated dienes are obtained in this straightforward access in high yields and selectivities. The synthetic utility of the protocol is showcased in the concise synthesis of several important intermediates for construction of natural products rac‐cagayanin, rac‐galbulin, rac‐agastinol, and cannabisin G.     

Synthesis of ‘difficult’ peptides free of aspartimide and related products, using peptoid methodology

We developed an efficient, cost effective strategy for Fmoc-based solid phase synthesis of ‘difficult’ peptides and/or peptides containing Asp/Asn-Gly sequences, free of aspartimide and related products, using a peptoid methodology for the preparation of N-substituted glycines.     

Synthesis of Biaryl‐Bridged Cyclic Peptides via Catalytic Oxidative Cross‐Coupling Reactions

Biaryl‐bridged cyclic peptides comprise an intriguing class of structurally diverse natural products with significant biological activity. Especially noteworthy are the antibiotics arylomycin and its synthetic analogue G0775, which exhibits potent activity against Gram‐negative bacteria. Herein, we present a simple, flexible, and reliable strategy based on activating‐group‐assisted catalytic oxidative coupling for assembling biaryl‐bridged cyclic peptides from natural amino acids. The synthetic approach was utilized for preparing a number of natural and unnatural biaryl‐bridged cyclic peptides, including arylomycin/G0775 and RP 66453 cyclic cores.     

Natural Products Originated from the Oxidative Coupling of Tyrosine and Tryptophan: Biosynthesis and Bioinspired Synthesis

The oxidative coupling of tyrosine and tryptophan units is a pivotal step in the total synthesis of some peptide-derived marine and terrestrial natural products, such as the diazonamides, azonazine and tryptorubin A. This Minireview details the biosynthesis and bioinspired synthesis of natural products with such structures. A special focus is put on the challenges of the synthesis of these natural products and the innovative solutions adopted by synthetic chemists.     

Total Synthesis of Ramonanins A–D

The first total synthesis of the ramonanin family of lignan natural products is described. The short synthesis involves a 2,5‐diaryl‐3,4‐dimethylene tetrahydrofuran intermediate, which participates in an unexpectedly facile Diels–Alder dimerization, generating all four natural products. Insights into the reactivity and stereoselectivity of the key dimerization are provided through computational studies employing B3LYP/6‐31G(d) and M06‐2X/6‐31G(d) model chemistries.     

Synthesis of elaiolide and halichoblelide aglycone

A synthesis of two structurally related macrodiolides representing the aglycone of natural products elaiophylin and halichoblelide is described. The key transformation for both is a Ti(II)-mediated (silyloxy)enyne cyclization, generating a new methyl stereocenter and providing a diene that can be selectively cross metathesized with crotonic acid.     

Flow “Fine” Synthesis: High Yielding and Selective Organic Synthesis by Flow Methods

The concept of flow “fine” synthesis, that is, high yielding and selective organic synthesis by flow methods, is described. Some examples of flow “fine” synthesis of natural products and APIs are discussed. Flow methods have several advantages over batch methods in terms of environmental compatibility, efficiency, and safety. However, synthesis by flow methods is more difficult than synthesis by batch methods. Indeed, it has been considered that synthesis by flow methods can be applicable for the production of simple gasses but that it is difficult to apply to the synthesis of complex molecules such as natural products and APIs. Therefore, organic synthesis of such complex molecules has been conducted by batch methods. On the other hand, syntheses and reactions that attain high yields and high selectivities by flow methods are increasingly reported. Flow methods are leading candidates for the next generation of manufacturing methods that can mitigate environmental concerns toward sustainable society.     

Total Syntheses of Linear Polythiazole/Oxazole Plantazolicin A and Its Biosynthetic Precursor Plantazolicin B

Plantazolicin A, a linear decacyclic natural product, exhibits desirable selective activity against the causative agent of anthrax toxicity. The total synthesis of plantazolicin A and its biosynthetic precursor plantazolicin B was successfully achieved by an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4‐concatenated oxazoles and the mild synthesis of thiazoles from natural amino acids. This report represents the first synthesis of plantazolicin B and includes the first complete characterization data for both natural products.     

Chemoenzymatic Synthesis of Cylindrocyclophanes A and F and Merocyclophanes A and D

Incorporating enzymatic reactions into natural product synthesis can significantly improve synthetic efficiency and selectivity. In contrast to the increasing applications of biocatalytic functional-group interconversions, the use of enzymatic C−C bond formation reactions in natural product synthesis is underexplored. Herein, we report a concise and efficient approach for the synthesis of [7.7]paracyclophane natural products, a family of polyketides with diverse biological activities. By using enzymatic Friedel–Crafts alkylation, cylindrocyclophanes A and F and merocyclophanes A and D were synthesized in six to eight steps in the longest linear sequence. This study demonstrates the power of combining enzymatic reactions with contemporary synthetic methodologies and provides opportunities for the structure–activity relationship studies of [7.7]paracyclophane natural products.     

Biomimetic Total Synthesis of Hyperjapones A–E and Hyperjaponols A and C

Hyperjapones A–E and hyperjaponols A–C are complex natural products of mixed aromatic polyketide and terpene biosynthetic origin that have recently been isolated from Hypericum japonicum. We have synthesized hyperjapones A–E using a biomimetic, oxidative hetero‐Diels–Alder reaction to couple together dearomatized acylphloroglucinol and cyclic terpene natural products. Hyperjapone A is proposed to be the biosynthetic precursor of hyperjaponol C through a sequence of: 1) epoxidation; 2) acid‐catalyzed epoxide ring‐opening; and 3) a concerted, asynchronous alkene cyclization and 1,2‐alkyl shift of a tertiary carbocation. Chemical mimicry of this proposed biosynthetic sequence allowed a concise total synthesis of hyperjaponol C to be completed in which six carbon–carbon bonds, six stereocenters, and three rings were constructed in just four steps.     

Quaternary β2,2‐Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc‐Based Solid‐Phase Peptide Synthesis

β‐Amino acid incorporation has emerged as a promising approach to enhance the stability of parent peptides and to improve their biological activity. Owing to the lack of reliable access to β^2,2‐amino acids in a setting suitable for peptide synthesis, most contemporary research efforts focus on the use of β³‐ and certain β^2,3‐amino acids. Herein, we report the catalytic asymmetric synthesis of β^2,2‐amino acids and their incorporation into peptides by Fmoc‐based solid‐phase peptide synthesis (Fmoc‐SPPS). A quaternary carbon center was constructed by the palladium‐catalyzed decarboxylative allylation of 4‐substituted isoxazolidin‐5‐ones. The N?O bond in the products not only acts as a traceless protecting group for β‐amino acids but also undergoes amide formation with α‐ketoacids derived from Fmoc‐protected α‐amino acids, thus providing expeditious access to α‐β^2,2‐dipeptides ready for Fmoc‐SPPS.     

Synthesis and NMR elucidation of novel pentacycloundecane‐based peptides

The synthesis and NMR elucidation of two novel pentacycloundecane (PCU)‐based peptides are reported. The PCU cage amino acids were synthesised as racemates and the incorporation of the cage amino acid with (S)‐natural amino acids produced diastereomeric peptides. The diastereomeric ‘cage’ peptides were separated using preparative HPLC and the NMR elucidation of these PCU containing peptides are reported for the first time. The ¹H and ¹³C NMR spectra showed series of overlapping signals of the cage skeleton and that of the peptide, making it extremely difficult to resolve the structure using one‐dimensional NMR techniques only. The use of two‐dimensional NMR techniques proved to be a highly effective tool in overcoming this problem. Copyright © 2010 John Wiley & Sons, Ltd.     

Total Synthesis of Resveratrol‐Based Natural Products Using a Palladium‐Catalyzed Decarboxylative Arylation and an Oxidative Heck Reaction

Controlled access to resveratrol‐based natural products is offered by a novel, modular concept. A common building block readily available on a large scale serves as the starting material for the introduction of structurally important aryl groups by a Pd‐catalyzed decarboxylative arylation and an oxidative Heck reaction with good yields and high stereoselectivity. The modular approach is convincingly documented by the successful synthesis of three racemic resveratrol‐based natural products (quadrangularin A, ampelopsin D, and pallidol).