Macrocyclic allenes

In the area of allenic non-natural product chemistry, the synthesis of the [34]alle-nophane 14 (Scheme 2.4) is particularly noteworthy, with all four of its allenic bridges being formed through subsequent SN2 substitution reactions of propargylic acetates with a methyl magnesium cuprate [14] (see Section 2.5 for an alternative synthesis of macrocyclic allenes). 

This strategy has also been applied to the one-pot double deoxygenation of simple alkyl- and polyether-tethered aromatic dialdehydes to give macrocyclic allenes in high yield without the need for slow-addition techniques. ... 

Craft and Gung developed a paUadium-catalyzed transannular [4+3] cycloaddition route in which all of the rings of cortistatins are prepared in one step from a single macrocyclic precursor (Scheme 19.50) [114]. Exposure of macrocyclic allene 233 to a catalytic amount of palladium (II) acetate in the presence of excess lithium bromide resulted in the formation of 238 as a single isomer in 37% yield. This is the first report of a transannular [4+3] cycloaddition. The proposed mechanism is shown in Scheme 19.50. The formation of allene-palladium complex 234 affords a a-allylpalladium intermediate, which rapidly isomerizes to the 7i-allylpalladium intermediate 235. This can then undergo intramolecular cycloaddilion via an endo (compact) transition strucmre 236 to give bromonium ion 237. The loss of a proton results in the formation of the observed product 238. Cycloadduct 238 was readily converted into the tetracyclic core skeleton of cortistatins 239 by selective reduction of the olefin formed by cycloaddition with furan, followed by reductive debromination. 

Holz, R. C. Allen Chang, C. Horrocks, W. De W. Jr. Spectroscopic characterization of the europium(III) complexes of a series of N.N -bislcarboxymethyl macrocyclic ether bis(lactones). Inorg. Chem. 1991, 30,3270-3275. 

Carbodiimides have chiral structures similar to allenes, i.e., they can exist in optically active forms. Schloegl and Mechtler were the first to report a partial optical separation of N,N"-diferrocenylcarbodiimide into enantiomers by chromatography on acetylated cellulose, but other authors doubt the validity of these results. According to theoretical calculations a separation of carbodiimide enantiomers is not possible. N,N -diferrocenylcarbodiimide was also obtained in optically active form by kinetic resolution in the reaction with (-)-S-6,6"-dinitrodiphenic acid. Cervinka and coworkers isolated both enantiomers of (R,S)-N,N"-bis(o -phenylethyl)carbodiimide, and they found that they undergo racemization at room temperature. A recent study on the racemization mechanism of macrocyclic carbodiimides indicates that the open chain as well as the large ring carbodiimides racemize by nitrogen inversion or tra 5-rotation, while medium size cyclic carbodiimides racemize by cw-rotation. ... 

Review. New synthetic reactions based on the onium salts of aza-arenes have been reviewed (75 references). The reactions discussed involve activation of carboxylic acids or alcohols with 2-haIopyridinium, benzoxazolium, benzothiazolium, and pyridinium salts to afford 2-acyloxy or 2-alkoxy intermediates, which can be transformed into esters, amides, thiol esters, (macrocyclic) lactones, acid fluorides, olefins, allenes, carbodiimides, isocyanates, isothiocyanates, and nitriles under appropriate conditions. 

Scheme 1.21). Transformation of ester 103 into acid chloride 104 then set the stage for the novel macrocyclization step. Deprotonation of 104 induced an intramolecular Wittig condensation followed by immediate loss of HCl to produce allenic lactone 105 in 42% yield. Subsequent [4 + 2] cycloaddition of diene 100 with 105 gave cyclohexene 106 in 55% yield. Aromatization of 106 under basic conditions then afforded a 50% yield of lasiodiplodin (90). 

Later, Dale used the extensive triple-bond migration, which takes place easily in macrocyclic dialkynes (C12-C20) when they are treated with KO-t-Bu in DMSO, to confirm his predictions for the relative stability of cyclic diyne isomers [4 c, 62]. These predictions were based on conformational considerations. Thus, 1,7-cyclotetradecadiyne (119) is almost completely rearranged to the 1,8-isomer 120 because in the latter compound both angle and terminal strain are absent, i.e., an ideal conformation is possible (Scheme 8-11). Dale s predictions, which were made long before the routine use of X-ray crystallography, were summarized in a seminal paper [63] and later confirmed by various X-ray investigations. The triple bond migration in cyclic diynes proceeds via allenic intermediates, which, however, are found only in small quantities in the reaction mixture. 

The reactions in Scheme 38 with allenes as coupling components proceed regioselec-tively with C—C bond formation at the central carbon and carbon-heteroatom bond formation at the more highly substituted terminal carbon atom t i Reactions of this type have recently been performed enantioselectivelyJ " Remarkably, for the macrocyclization in Scheme 39 the carbon-heteroatom bond formation takes place at the unsubstituted terminal carbon atomJ ... 

Ma and Negishi [41] also extended the scope of c do-selective Mizoroki-Heck reactions of allenes to the formation of medium-sized rings and macrocycles. A selection of representative reactions is depicted in Scheme 5.39. Cyclizations of precursors 228a and 228b provided the corresponding eight- and nine-membered rings in 56% and 62% yields... 

The free radical addition of a thiol to carbon-carbon double or triple bonds is a well-established reaction. It represents one of the most useful methods of synthesizing sulfides under mild conditions. Since its discovery [5] and its much later formulation as a free-radical chain reaction (Scheme 1) [6], the anti-Markovnikov addition of thiols to unsaturated compounds has been the subject of many reviews [8, 9]. These reactions were originally initiated by thermal decomposition of peroxides or azocompounds, by UV irradiation or by radiolysis [10]. (An example of addition of 1-thiosugar to alkenes initiated by 2,2 -azobisisobutyronitrile (AIBN) [11] is reported in equation (1)). More recently, organoboranes have been used as initiators and two examples (Et3B and 9-bora-bicyclo [3.3.1.] nonane) are reported in equations (2) and (3) [12,13]. Troyansky and co-workers [14a] achieved the synthesis of macrocycles like 12- and 13-membered sulfur-containing lactones by the double addition of thiyl radical to alkynes. An example is depicted in equation (4). The same approach has also been applied to the construction of 9- and 18-membered crown thioethers [14b]. The radical chain addition of thiyl radicals to differently substituted allenes has been considered in detail by Paste and co-workers [15], who found that preferential attack occurs at the central allenic carbon and gives rise to a resonance-stabilized ally radical. The addition of benzenethiol to allenic esters has been reported and the product formation has been similarly inferred (equation (5)) [16]. 

Linear and macrocyclic butatrienes also undergo cycloaromatization via diradicals, i.e. they undergo DNA cleavage reactions similar to allenes. Strained butatrienes are trapped with dienes to give [4+2] cycloadducts. The ring strains in cyclic butatrienes decrease with ring size. ... 

A synthesis of (+)-( )-lasiodiplodin has been reported which involves the formation of a macrocyclic lactone-allene by intramolecular Wittig reaction on... 

Hydroesterification of the C—C triple bond of a macrocycle has been used as the key step for the total synthesis of several members of the pseudopterane family possessing significant biological activity such as cytotoxicity or anti-inflammatory activity [45]. As any attempts to convert propargylic alcohol 31 directly into butenolide 34 by conventional methods failed, a new route was developed via atmospheric alkoxycarbonylation of mesylate 32 to allenic ester 33. 

---