Azides natural product synthesis

The synthesis of (—)-stemospironine provides another example of the use of aziridinium ions in natural product synthesis <20010L2721>. The Stemona alkaloids are characterized by the l-azabicyclo[5.3.0]decane nucleus. Azide 363 was the key intermediate for the aziridinium-mediated synthesis. Debenzylation at low temperature... 

Ciufolini and co-workers demonstrated the use of 1,3-dipolar azide-olefin cycloaddition reactions in the total synthesis of ( )-FR66979 (52) [25], an antitiunor agent which is structurally related to the mitomycins [26]. Thus, the triazoline 50 was obtained as a single diastereomer by smooth cycloaddition of the activated double bond and the dipole in 49 by heating in toluene. Brief photolysis of 50 provided aziridine 51, which fragmented to 52 (Scheme 8B). Other intramolecular azide-alkene cycloaddition in natural product synthesis is illustrated by a munber of examples [27-32]. 

Curtius rearrangement of these azides leads to ketones via loss of an isocyanic acid (HN=C=0) equivalent, which can be trapped in situ as shown for 49 where benzophenone resulted and addition of aniline to the isocyanic acid gave urea 50. or-Alkoxy- and or-amino acyl azides, meanwhile, are precursors to hemiaminals and hisaminals, respectively. Examples in complex natural product synthesis are shown for 81 and 66 in the Variations and Improvements Section. 

The chiral (salen)Co catalysts have also been applied to cyclization reaction and preparation of intermediates for natural product synthesis [85]. In addition, chiral (salen)Ru catalysts proved to be effective for kinetic resolution of racemic epoxides [86]. Tridentate Schiff base Cr(III) complex (201) derived l-amino-2-indanol acts as a potent catalyst for asymmetric ring-opening reaction of meso-aziridines with trimethylsilyl azide (Scheme 16.60) [87]. The aziridine (200) was readily converted at —30 °C to the corresponding amino-azide in 95% yield with 94% ee. 

The synthesis of triazoles by 1,3-dipolar cycloaddition between azides and alkynes has been extensively studied recently with numerous synthetic applications in the field of click chemistry. However, the Huisgen cycloaddition between azides 39 and alkenes 40 (Scheme 41.9) although less studied offers interesting opportunities for the stereoselective formation of C N bonds in the context of natural products synthesis. The triazolines 41 thus formed are in fact good precursors of aziridines via ring contraction and expulsion of N2. 

Aziridines are important compounds due to their versatility as synthetic intermediates. In addition, aziridine rings are present in innumerable natural products and biologically active compounds. Nitrene addition to alkenes is one of the most well established methods for the synthesis of aziridines. Photolysis or thermolysis of azides are good ways to generate nitrenes. Nitrenes can also be prepared in situ from iodosobenzene diacetate and sulfonamides or the ethoxycarbonylnitrene from the A-sulfonyloxy precursor. 

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

Since the discovery of triazole formation from phenyl azide and dimethyl acetylenedicarboxylate in 1893, synthetic applications of azides as 1,3-dipoles for the construction of heterocychc frameworks and core structures of natural products have progressed steadily. As the 1,3-dipolar cycloaddition of azides was comprehensively reviewed in the 1984 edition of this book (2), in this chapter we recount developments of 1,3-dipolar cycloaddition reactions of azides from 1984 to 2000, with an emphasis on the synthesis of not only heterocycles but also complex natural products, intermediates, and analogues. 

SYNTHESIS OF NATURAL PRODUCTS, INTERMEDIATES, AND THEIR ANALOGUES VIA 1,3-DIPOLAR CYCLOADDITION OF AZIDES... 

The 1,3-dipolar cycloaddition of azides combined with further synthetic transformations is a highly useful reaction for the synthesis of heterocycles and natural products. Even though the chemistry of azide cycloadditions has been known for... 

The first total synthesis of the potent cytotoxic marine natural product makaluvamine F (5) involved the preparation of 2,3-dihydrobenzothiophene 2 <99CC143>. Debenzylation and subsequent acid-catalyzed cyclization of thioether 1 gave 2 which was converted in four steps to 2-azido-2,3-dihydrobenzothiophene 3 using a combination of Phl=0 and McjSiNj for installation of the azide. Reduction of the azide followed by coupling the resultant amine with pyrroloiminoquinone 4 then gave makaluvamine F (5). 

With a range of methods available for the formation of 1,3-dicarbonyl compounds, the dicarbonyl diazomethanes can be readily prepared via a simple diazo transfer reaction with sulfonyl azide. This has made a vast array of dicarbonyl diazomethanes available, which enhances the versatility in organic synthesis. A selection of examples from recent literature to illustrate the versatility of the cyclopropanation using dicarbonyl diazomethane in the construction of natural products as well as other biologically active compounds is described below. 

We have used the reaction extensively to prepare the indole moiety of several natural products. For example, the key step in the synthesis of the bacterial coenzyme methoxatin (36) is the formation of the indole (35) by intramolecular nitrene insertion from the azide (34), readily prepared from commercially available 4-aminosalicyclic acid. The third ring was annelated onto the indole (35) using conventional chemistry to give, after oxidation to the orrho-quinone, the natural product (36). 

Virantmycin is a tetrahydroquinoline alkaloid that has inhibitory activity against DNA and RNA viruses. A total synthesis of virantmycin making use of a key type II aziridine has elucidated the absolute stereochemistry at C-2 and C-3 <1996T10609>. An intramolecular photocyclization of an azide onto a Z-alkene produces type II aziridine 351 in excellent yield. A three-step reduction/selective reoxidation procees yields key aziridine alcohol 352 in 76% overall yield (Scheme 71). The alcohol is methylated and the ester hydrolyzed without harm to the azirdine. A TFA-induced ring opening of the aziridine by chloride provides the natural product virantmycin in good yield. This entire process was also carried out with the -alkene to produce /)(-virantmycin, thus proving the stereochemistry at C-2 and C-3. 

Clathrin-mediated endocytosis can be blocked by several pharmacologic inhibitors, including the antipsychotic drug chlorpromazine (Thorazine), the natural product ikarugamycin, and the antiviral drug amantadine. The metabolic poisons phenylarsine oxide and sodium azide also block CMF but additionally inhibit protein synthesis. Culture of cells under conditions that deplete potassium or calcium, treatment of cells with hypertonic sucrose, or acidification of the cytoplasm by addition of... 

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