Total synthesis aziridines

The aziridination of alkenes catalysed by [CuCl(IPr)] complex 150 was used in a key step of the total synthesis of (+)-agelastatin 152 (Scheme 5.39) [44], The aziridination occurs in presence of 50 mol% of 150 in 52% yield. It is important to note that 150 was the only complex able to promote the aziridination of 149, an electron-deficient cyclopentene. 

The Nagata group also developed a new approach to the construction of bridged aziridines via nitrene intermediates that led to the total synthesis of the indole alkaloids, ibogamine, velbanamine, and coronaridine (1968-1971). 

Cleavage of aziridines has been employed in the asymmetric total synthesis of pancratistatin 57 [47], a compound that is the object of considerable attention thanks to its broad spectrum of antineoplastic activities [48]. The chemistry of vinylaziridines has for the most part been confined to their use in rearrangement sequences resulting in functionalized pyrrolines. Hence, because of the lack of data concerning the ring-opening of vinylaziridines with carbon nucleophiles,... 

The numerous excellent synthetic procedures published by A.C. Richardson also continue to be relied upon by contemporary organic chemists because of their great practicality and reproducibility. Indeed, a recent highly cited enantiospecific total synthesis of the antitumor agent, (—)-agelastatin A, justly testifies to this fact it exploits the remarkably useful Hough-Richardson aziridine as a key synthetic intermediate in the eventual published route to this complex natural product. 

SCHEME 8. Hale and Domostoj s use of die Hough-Richardson aziridine in their 2004 enantiospecific total synthesis of die antitumor alkaloid (—)-agelastatin A. 

Weinreb and co-workers (77) reported a similar protocol in the total synthesis of sarain A. The five-membered ring of the tricyclic central array was constructed via thermolysis of aziridine 244 to furnish the intramolecular [3 + 2]-cycloaddition product 245 in 73% as a single regio- and stereoisomer. Further chemical elaboration to 245 followed by FeCla induced cyclization delivered the advanced synthetic intermediate 247 (Scheme 3.83). 

When the enone 218, possessing a methyl group at the C(2) position, was treated with NaN3 in DMF, aziridine 219 was isolated as the only product (46) (Scheme 9.46). This reaction was adopted for the total synthesis of ( )-desamyl-perhydrohistrionicotoxin (224) from the azido enone 220. 

Fukuyama and Yang (49) developed a highly efficient synthesis of the tetracyclic intermediate 241, used in a total synthesis of mitomycin A (Scheme 9.49). The required azide 240 was produced from 239 in several steps. Upon heating in refluxing toluene, the azide 240 underwent smooth intramolecular cycloaddition with the unsaturated lactone followed by extrusion of nitrogen to give aziridine 241 in 85% yield. 

Molander and Hiersemann (60) reported the preparation of the spirocyclic keto aziridine intermediate 302 in an approach to the total synthesis of (zb)-cephalotax-ine (304) via an intramolecular 1,3-dipolar cycloaddition of an azide with an electron-deficient alkene (Scheme 9.60). The required azide 301 was prepared by coupling the vinyl iodide 299 and the aryl zinc chloride 300 using a Pd(0) catalyst in the presence of fni-2-furylphosphine. Intramolecular 1,3-dipolar cycloaddition of the azido enone 301 in boiling xylene afforded the desired keto aziridine 302 in 76% yield. Hydroxylation of 302 according to Davis s procedure followed by oxidation with Dess-Martin periodinane delivered the compound 303, which was converted to the target molecule (i)-cephalotaxine (304). 

Pancralistatin, [29], The first asymmetric total synthesis of (+)-pancratistatin (94) was reported by Hudlicky 130,26], Thus the bromo olefin 114 (Scheme 15), obtained by a-addition of copper nitrenoid generated from (N-tosyiimino) phenyliodinane to 45, was debrominated to the olefinic aziridine 117. The latter underwent Irons 1,2-ring opening with diarylcyancuprate... 

The Total Synthesis of Diacetyloxodenudatine.—Wiesner and co-workers43 have reported the conversion of (131) into racemic diacetyloxodenudatine (132). This phenol (131) had been prepared previously by the aziridine synthesis 44 (cf. Vol. 4, p. 342). 

An efficient and economical new approach toward the synthesis of 7-aminoaziridinomitosenes, as represented by compound 96, has been developed in less than 15 total operations from commercially available chemicals. Overall our scheme represents the second total synthesis of a fully functionalized aziridinomitosene. At one stage, new insights into the mechanistic details involving the reaction of l,2-epoxypyrrolo[l,2-c]indoles with nucleophiles are provided. Notably, the route presented has the advantage of accessing both the aziridine and 7-amino substituents in deprotected form. Further application of this synthetic approach to additional C-9-substituted mitosenes can be anticipated. 

The intramolecular 1,3-cycloaddition of azidoalkyl cyclohexenones occurred smoothly when the temperature range was between 80-110 °C, however, aziridines were obtained from the intermediate dihydrotriazoles il the correct substitution pattern and regiochemical arrangement were present, cf. formation of 13 and 14 vs. IS131,132. The reaction was applied to the formal total synthesis of ( )-desamylperhydrohistrionicotoxin132. Direct nitrene enone addition can not be ruled out when the reaction is performed in refluxing xylene. 

A dynamic kinetic asymmetric transformation (DYKAT) of racemic vinyl aziridine 347 yielded the enantiopure imidazolidinone 348 (Scheme 90) <20050L823>. This transformation was the initial step in a total synthesis of (+)-pseudodistomin D. 

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. 

The dipolar cycloaddition of an alkyl azide with an alkene to form an aziridine has been exploited in the total synthesis of the alkaloid ( )-aspidospermidine <20050BC213>. Enone 353 was prepared in 11 steps from 3-ethoxycyclohexenone and coupled to 2-iodo nitrobenzene under Ullman cross-coupling conditions. The acetate group of 354 was hydrolyzed and the resulting alcohol converted to an azide using standard conditions in 75% overall yield. The cycloaddition of the azide with the enone was conducted in refluxing benzene for 3 days. The fused-ring aziridine 355 was the only product isolated. None of the initial dipolar cycloadduct triazoline was observed. The... 

The opening of halocyclopropanes to allyl systems according to equation 124 can happen thermally or with the assistance of electrophiles and nucleophiles . Some recent examples include an efficient cyclopentenone synthesis (equation 125) ", an electrocyclic opening/cyclization sequence giving functionalized furan and pyran derivatives (equation 126), an elegant total synthesis of the very fast death factor alkaloid ( ) anatoxin and a nice application of the well known nucleophilic opening to the preparation of crystalline methylene aziridines (equation 127) . 

The asymmetric total synthesis of rauwolfia alkaloids (-)-yohimbane and (-)-alloyohimbane was carried out by S.C. Bergmeier et al. by utilizing a novei aziridine-allylsilane cyclization and the Bischler-Napieralski isoquinoline synthesis as key steps.These alkaloids have a characteristic pentacyclic ring framework and exhibit a wide range of interesting biological activities such as antihypertensive and antipsychotic properties. 

Bergmeier, S. C., Seth, P. P. Aziridine-Allylsilane-Mediated Total Synthesis of (-)-Yohimbane. J, Org, Chem, 1999, 64, 3237-3243. 

An improved method for the total synthesis of ISQ alkaloids, such as 91, via a l-azatricyclo[3.2.1.0 ]octane (89) intermediate aziridine and an indoleacetic anhydride (90) has been described by Nagata and Hirai [94,95] (Scheme 10). 3-Cyclohexane-1-methylamine (88) was converted into aziridine 89 by reaction with lead tetraacetate, which was subsequently reacted with 90 to yield 91. 

Intramolecular 1,3-dipolar cycloaddition of azide (81) proceeds through a triazoline and vinyl-aziridine (82) and results in the formation of tetrahydropyrrolizidine (83) and (84). This represents a formal total synthesis of supinidine. Thermolysis of vinyl aziridine (82) leads to pyrrolizidine (84) probably via azomethine ylides, while the nucleophilic opening leads exclusively to (83) through an intermediate allylic iodide (85). The latter is produced as a mixture of (E) and (Z) isomers but is converted to (83) via an equilibrium and recyclization of the (Z)-isomer (Scheme 30) <85TL3523, 85TL3527). 

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