Microwave irradiation natural product synthesis

In contrast with the enormous effort directed at natural product synthesis, the application of microwave irradiation in this field is rather scarcely investigated, and a systematic use of this technique for most of the conversions in a (total) synthesis sequence is still a challenging target. We have just reached dawn in the development of microwave-assisted natural product synthesis, although unquestionably, some beautiful examples have already been described. 

The Pictet-Spengler reaction has mainly been investigated as a potential source of polycyclic heterocycles for combinatorial apphcations or in natural product synthesis [149]. Tryptophan or differently substituted tryptamines are the preferred substrates in a cyclocondensation that involves also aldehydes or activated ketones in the presence of an acid catalyst. Several versions of microwave-assisted Pictet-Spengler reactions have been reported in the hter-ature. Microwave irradiation allowed the use of mild Lewis acid catalysts such as Sc(OTf)3 in the reaction of tryptophan methyl esters 234 with different substituted aldehydes (aliphatic or aromatic) [150]. Under these conditions the reaction was carried out in a one-pot process without initial formation of the imine (Scheme 86). 

Abstract An overview of the application of microwave irradiation in natural product synthesis is presented, focusing on the developments in the last 5-10 years. This contribution covers the literature concerning the total synthesis of natural products and their analogues, the synthesis of alkaloids and the construction of building blocks of interest for natural product synthesis. As microwave irradiation appeared on the scene only recently, we are at an early stage of its application in natural product chemistry, even though some nice examples have been communicated recently. The application of dedicated microwave instruments as well as domestic microwave ovens is discussed, giving emphasis to the microwave-enhanced transformations. 

As dedicated microwave instruments appeared rather recently on the market and several interesting applications of microwave irradiation for natural product synthesis were described applying domestic microwave ovens, we decided to include also research performed with domestic ovens, although one could argue that some of these experiments lack reproducibility. On the other hand, the development of safe and reproducible synthetic routes for domestic instruments, which are cheap and at the disposal of every research lab all over the world, is a challenge worth the task as this should tremendously speed up the introduction of microwave irradiation in organic synthesis in general. 

Another interesting example of the use of microwave irradiation in generating interesting building blocks for natural product synthesis, was reported by A.G. Falliset al. [175] regarding the synthesis of the functionalized tricycle [9,3,1,0 ]pentadecene system of Taxanes, the core skeleton that can be found in Taxol (Fig. 8). Taxol has elicited considerable interest [176-178] due... 

Similar processes have been designed and utilized extensively by Barriault and coworkers for efforts in natural product synthesis. An impressive example of this strategy was utilized for the synthesis of the neo-clerodane skeleton of teucrolivin A. Thermal rearrangement of 92 under microwave irradiation results in a tandem sequence featuring an oxy-Cope rearrangement, followed by the Claisen rearrangement and subsequent ene reaction to give 93. 

A solvent-free synthesis of flavones was recently reported by microwave-assisted reaction of phloroglucinol 231 and differently substituted /1-ketoesters 232 [148]. The reaction was simply carried out by mixing the phenol and the ester in an open test tube followed by irradiation for 2-3 min. The internal temperature reached 240 °C and yields were in the range from 68 to 96%. Scheme 85 describes the application of this procedure to the synthesis of the natural product chrysin 233. 

A recent publication by the group of Baran reports the total synthesis of ageli-ferin, an antiviral agent with interesting molecular architecture (Scheme 4.16) [42], Just 1 min of microwave irradiation of sceptrin, another natural product, at 195 °C in water under sealed-vessel conditions provides ageliferin in 40% yield, along with 52% of recovered starting material. Remarkably, if the reaction is performed without... 

Wu and Sun have presented a versatile procedure for the liquid-phase synthesis of 1,2, ,4-tctrahydro-/i-carbolines [77]. After successful esterification of the MeO-PEG-OH utilized with Fmoc-protected tryptophan, one-pot cyclocondensations with various ketones and aldehydes were performed under microwave irradiation (Scheme 7.68). The desired products were released from the soluble support in good yields and high purity. The interest in this particular scaffold is due to the fact that the l,2,3,4-tetrahydro-/f-carboline pharmacophore is known to be an important structural element in several natural alkaloids, and that the template possesses multiple sites for combinatorial modifications. The microwave-assisted liquid-phase protocol furnished purer products than homogeneous protocols and product isolation/ purification was certainly simplified. 

A one-step synthesis of the antifungal and larvicidal natural product methyl 3-(2,4,5-trimethoxyphenyl)propionate was described by J. Tamariz et al. [30] (Scheme 7). Reaction of methyl acrylate with 1,2,4-trimethoxyben-zene catalyzed by AICI3 in 1,1,2,2-tetrachloroethane took 168 h (7 days) at 80 °C, yielding the compound in the low yield of 37%. However, when the reaction was run under microwave irradiation (domestic oven) in a Teflon... 

Concomitant with the tremendously increased application of microwave irradiation in synthesis during the last 5 years, we might expect a rise in interest in its application for natural product chemistry, as more and more natural product chemists are discovering the benefits of this powerful technique. 

Yen and co-workers [54] have reported an efficient one-pot procedure for the synthesis of 4,6-diaryl-2-pyridinones 3 based on a cyclocondensation reaction of iV-ethoxycarbonyl-methylpyridinium chloride or iV-carbamoylmethyl p3Tidinium chloride with an aromatic aldehyde and a substituted acetophenone. The MCR was performed under microwave irradiation (domestic oven) with NTUOAc/AcOH as the reaction medium. The nature of the substituents on the aromatic aldehyde and ketone seem to have little influence on the obtained yields. The highlights of this approach include a convenient and simple experimental procedure with easy product isolation (Scheme 3). 

The spirooxindole system is the core unit of many natural products such as spirotryprostatin A, isopeteropodine, etc. Perumal and co-workers have developed a fast, clean and simple method for the synthesis of spirooxindoles and spiroindenoquinoxaline derivatives catalyzed by silica gel impregnated indium(in) chloride under solvent-free microwave irradiation (Scheme 5.36). 

The quinoline scaffold and derivatives occur in a large number of natural products and drug-like compounds. A method for microwave-assisted synthesis of 2-aminoquinolines has been described by Wilson et al. [62]. The process involves rapid microwave irradiation of secondary amines and aldehydes to form enamines, then addition of 2-azidobenzophenones with subsequent irradiation to produce the 2-aminoquinoline derivatives (Scheme 10.27). Purification of the products was accomplished in a streamlined manner by using solid-phase extraction techniques to produce the desired compounds in high yields and purity. Direct comparison of the reaction under thermal and microwave conditions, using identical stoichiometry and sealed reaction vessels, showed the latter resulted in improved yield. 

The l,2,3,4-tetrahydro-j8-carboline pharmacophore is an important structural element in several tryptophan-derived natural product alkaloids. A soluble polymer supported synthesis of l,2,3,4-tetrahydro-j8-carboline derivatives was reported by Wu and Sung. The one-pot condensation of Fmoc-protected tryptophan anchored to MeO-PEG-OH via an ester linkage has been performed with a variety of aldehydes and ketones under the action of microwave irradiation to provide immobilized l,2,3,4-tetrahydro-yS-carboline derivatives these were liberated from the soluble matrix in good yield and high purity [123]. 

In continuing efforts to develop more general and versatile methods for the synthesis of pyrazoles contained in natural products, and at the same time to use microwave irradiation, instead of conventional heating, particularly the solvent-free technique, because it provides the opportunity to work with open vessels, Yadav et al. [85] prepared a new class of optically pure 4-substituted pyrazoles 128 from 2-formyl glycols 127 and aryl hydrazines (Scheme 12.52). 

---