Efficient solid-phase synthesis of cyclic RGD peptides under controlled microwave heating

Cyclic RGD peptides are potent antagonists for the α_vβ₃ integrin receptor. In this Letter, microwave-assisted solid-phase synthesis of cyclic RGD peptides is described. In a coupling reaction between Fmoc-Arg(Pbf)-OH and high-loading H-Gly-Trt(2-Cl) resin, multiple coupling reactions were required for completion under the conventional HBTU activation. We found that the use of COMU, a new coupling reagent, under microwave heating to 50 °C accelerated the reaction even inside the resin. This method was applicable to the synthesis of linear pentapeptides, H-Asp(OtBu)-Xxx-Yyy-Arg(Pbf)-Gly-OH (Xxx = d-Phe(p-Br) or d-Tyr, Yyy = Lys(Boc) or MeVal). Cyclization of these peptides followed by deprotection gave the desired cyclic RGD peptides with high purity.     

Controlled microwave heating in modern organic synthesis

Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of "microwave flash heating" in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.     

Fast synthesis of aryl triflates with controlled microwave heating

[reaction: see text] Synthesis of aryl triflates from phenols using N-phenyltriflimide requires only 6 min for completion when conducted with controlled microwave heating. The methodology was applied to both solution- and solid-phase conditions. Ten different aryl triflates were synthesized and isolated in good yields. Applications in high-throughput chemistry are suggested.     

Fast and selective synthesis of novel cyclic sulfamide HIV-1 protease inhibitors under controlled microwave heating

A novel and highly selective silver-promoted monobenzylation method was developed to promote synthesis of nonsymmetrical sulfamide-based HIV-1 inhibitors. Microwave-accelerated palladium-catalyzed N-amide arylation- and aminocarbonylation reactions were employed for rapid and reliable compound generation. With this class of inhibitory agents, six active inhibitors were identified, the most potent inhibitor possessing a K_i-value of 20 nM.     

A one-pot isomerization-arylation of 2,3-epoxycyclohexanone under controlled microwave heating

A fast one-pot method has been developed for the direct preparation of 3-aryl-1,2-cyclohexanediones from 2,3-epoxycyclohexanone via a microwave-assisted tandem epoxy ketone isomerization-Heck arylation reaction. The preparative microwave-assisted reactions were performed preferentially in 50% aqueous poly(ethylene glycol) utilizing sodium acetate as the base. Within 5-30 min of directed microwave heating, employing less than 0.05 mol % of palladium acetate and no phosphine ligand, up to 72% yield of C3-arylated diketones was isolated in an overall environmentally benign process. On the basis of the chemical reactivity of proposed intermediates, a reaction pathway is proposed where the acetate base promotes the rearrangement of the 2,3-epoxycyclohexanone into the active mono-enol form of 1,2-cyclohexanedione. An alternative classically heated procedure for isomerization-C3-arylation of 2,3-epoxycyclohexanone in DMF is also reported.     

Microwave heating in solid-phase peptide synthesis

The highly refined organic chemistry in solid-phase synthesis has made it the method of choice not only to assemble peptides but also small proteins - mainly on a laboratory scale but increasingly also on an industrial scale. While conductive heating occasionally has been applied to peptide synthesis, precise microwave irradiation to heat the reaction mixture during coupling and N(α)-deprotection has become increasingly popular. It has often provided dramatic reductions in synthesis times, accompanied by an increase in the crude peptide purity. Microwave heating has been proven especially relevant for sequences which might form β-sheet type structures and for sterically difficult couplings. The beneficial effect of microwave heating appears so far to be due to the precise nature of this type of heating, rather than a peptide-specific microwave effect. However, microwave heating as such is not a panacea for all difficulties in peptide syntheses and the conditions may need to be adjusted for the incorporation of Cys, His and Asp in peptides, and for the synthesis of, for example, phosphopeptides, glycopeptides, and N-methylated peptides. Here we provide a comprehensive overview of the advances in microwave heating for peptide synthesis, with a focus on systematic studies and general protocols, as well as important applications. The assembly of β-peptides, peptoids and pseudopeptides are also evaluated in this critical review (254 references).     

A novel DBU-promoted S-N-type Smiles rearrangement reaction under controlled microwave heating

A convenient process for the preparation of pyrido[1,4]thiazinone derivatives is described in the presence of DBU as base under controlled microwave heating. This process allows for efficient construction of thiazinone-fused pyridine by S-N-type Smiles rearrangement methodology.     

An efficient protocol for the solid-phase synthesis of glycopeptides under microwave irradiation

A standardized and smooth protocol for solid-phase glycopeptides synthesis under microwave irradiation was developed. Double activation system was proved to allow for highly efficient coupling of Tn-Ser/Thr and bulky core 2-Ser/Thr derivatives. Versatility and robustness of the present strategy was demonstrated by constructing a Mucine-1 (MUC1) fragment and glycosylated fragments of tau protein. The success of this approach relies on the combination of microwave energy, a resin consisting totally of polyethylene glycol, a low excess of sugar amino acid and the "double activation" method.     

Diversity-oriented synthesis of azaspirocycles

Multicomponent condensation of N-diphenylphosphinoylimines, alkynes, zirconocene hydrochloride, and diiodomethane provides a rapid access to omega-unsaturated dicyclopropylmethylamines. These novel building blocks are converted into heterocyclic 5-azaspiro[2.4]heptanes, 5-azaspiro-[2.5]octanes, and 5-azaspiro[2.6]nonanes by means of selective ring-closing metathesis, epoxide opening, or reductive amination. The resulting functionalized pyrrolidines, piperidines, and azepines are scaffolds of considerable relevance for chemistry-driven drug discovery.     

Rapid and efficient synthesis of 1,2,4-oxadiazoles utilizing polymer-supported reagents under microwave heating

1,2,4-Oxadiazoles can be rapidly and efficiently synthesized from a variety of readily available carboxylic acids and amidoximes using either method A or method B. The use of commercially available polymer-supported reagents combined with microwave heating resulted in high yields and purities of the product 1,2,4-oxadiazoles in an expeditious manner. [structure: see text]     

Colorimetric tools for solid-phase organic synthesis

One of the unresolved problems of solid-phase organic synthesis (SPOS) is the availability of general and rapid methods to monitor the transformation of functional groups present in molecules supported on insoluble supports. Color tests, far from providing the ultimate solution, may help in detection (and sometimes in quantification) of different functional groups. In this short review, we have collected most of the methods available and applied in SPOS with an Experimental Section that describes the procedure we have successfully applied to bead analyses in our laboratories.     

A novel method for the synthesis of polysubstituted diaminobenzonitrile derivatives using controlled microwave heating

A novel, simple and efficient method for the synthesis of polysubstituted diaminobenzonitriles has been developed that involves reaction of 1,1,3-tricyano-2-aminopropionitrile with nitroolefins under controlled microwave irradiation conditions.     

Rapid homogeneous-phase Sonogashira coupling reactions using controlled microwave heating

A microwave-enhanced, rapid and efficient homogeneous-phase version of the Sonogashira reaction is presented. It has been applied to the coupling of aryl iodides, bromides, triflates, and aryl chloride, as well as pyridine and thiophene derivatives with trimethylsilylacetylene. Excellent yields (80-95%) for substrates containing a large variety of substituents in different positions are obtained in 5-25 min.     

Diversity-oriented synthesis of tamoxifen-type tetrasubstituted olefins

A general synthetic scheme for tamoxifen-type tetrasubstituted olefins based on the novel Cu-catalyzed carbomagnesation across alkynyl(2-pyridyl)silane has been developed. A wide array of electronically and structurally diverse tetrasubstituted olefins can be prepared in a regiocontrolled, stereocontrolled, and diversity-oriented manner. Noteworthy features are that (i) the three aryl groups, which are believed to be important (essential) for anti-estrogenic activity, can be varied at will because they all stem from readily available aryl iodides, and (ii) any stereo- and regioisomers can, in principle, be prepared by simply changing the applying order of aryl iodides into the sequence.     

An assessment of the technique of simultaneous cooling in conjunction with microwave heating for organic synthesis

In the light of the controversy in the area and since reports using simultaneous cooling in conjunction with microwave heating are appearing in the literature, we were keen to assess the methodology, looking at temperature measurement issues as well as the use of the technique in three classes of reaction, namely a Heck coupling, a Diels-Alder cycloaddition and a Michael addition. We present our initial findings here.     

Polytetrahydrofuran cross-linked polystyrene resins for solid-phase organic synthesis

Currently, divinylbenzene cross-linked polystyrene (DVB-PS) is the polymer of choice for use in solid-phase organic synthesis (SPOS). While much research has been directed toward the optimization of linker groups for the attachment of compounds to the polymer, the development of new polymers themselves has been relatively neglected. In an attempt to overcome the shortcomings of DVB-PS and to develop new polymers with optimum properties for use in organic synthesis, we have prepared a series of polystyrene polymers that incorporate flexible polytetrahydrofuran (PTHF) based cross-linkers. The objective of incorporating PTHF into the polymers was to slightly increase the overall polarity of the polymer and thus render the resins more organic solvent-like. Since the degree to which a resin swells in and absorbs a particular solvent correlates to how well substrates attached to the polymer are solvated, we compared the swelling of our new resins to commercially available DVB-PS resins. In all cases, we found that our resins swelled to a much greater extent than do DVB-PS resins, and their use should therefore allow for SPOS reaction conditions that more closely mimic homogeneous solution-phase conditions. It was also found that the PTHF chain length of the cross-linker does not affect the level of swelling since all of our cross-linkers afford resins with comparable levels of increased swelling. Furthermore, we have examined the utility of our resins in directed ortho-metalation reactions and found that the increased swelling of our resins allows for isolation of reaction products in yields comparable to what is achieved using standard solution-phase conditions.     

Multicomponent reactions for synthesis of bioactive polyheterocyclic ring systems under controlled microwave irradiation

The multi-component reaction of 1-benzothiopyran-4-ones with heterocyclic amines and dimethylformamide-dimethylacetal (DMFDMA) in DMF at 150 °C under controlled microwave heating afforded novel poly-heterocyclic ring systems. Also, reaction of 3-dimethylaminomethylene-1-benzothiopyran-4-one with activemethylene derivatives was investigated. The structure of all products was established on the bases of spectral data and elemental analyses and alternative synthesis if possible. The prepared compounds were screened for their antitumor activity against HCT-116 “colon” cancer cell line and some derivatives showed promising activity.