Stereospecific cyclisation

Optically active co-bromocyanohydrins yield 2-cyano-tetrahydropyrans without racemisation (95CC989) and both the unsaturated alcohol (1) and the diol (2) afford the same tetrahydropyran through stereospecific cyclisation of a common episulfonium ion (95TL1909). 

Much more successful in a pyrrolidine synthesis was the use of a stereochemically defined organolithium 362 formed by tin-lithium exchange from an almost enantiomerically pure stannane 361, itself a product of Beak s sparteine lithiation chemistry. Despite the high temperature (20 °C) required for tin-lithium exchange in hexane-ether, it is nonetheless possible to carry out a stereospecific cyclisation via an organolithium which is configurationally stable, even at 20 °C, on the timescale of the cyclisation.169 The cyclisation proceeds with retention and gives the alkaloid pseudoheliotridane 363 in 87% yield and with no loss of enantiomeric excess. 

A more modern way is the mercury trifluoroacetate-induced cychsation according to Noyori. The starting material is obtainable from a three-component coupling reaction. The stereospecific cyclisation proceeds via a mercurinium ion in what amounts to a 5-exo-di -cyclisation. Critical for the ( /Z)-isomer ratio is the subsequent mercury cleavage. Normally, this reaction proceeds radically with loss of stereochemical integrity. However, if the mercury residue is removed reductively in protic solvents, then the stereochemistry is preserved. 

The application of this procedure to the fused polycyclic compound E, which already has a linear dual and only the last two steps (iii-iv) apply to it, leads to a linear acyclic structure F which may be traced back to the biogenetic cyclisation of squalene to lanosterol via cationic intermediates, as well as to the stereospecific cationic cyclisation of polyolefins studied by Johnson [18]. 

Lemer and Benkovic examined the possibility of performing an intramolecular cyclisation reaction [30]. They chose the formation of a six-membered lactone ring from a hydroxy ester (12) and observed that only one single enantiomer of the 5-lactone (14) in 94% ee was formed from the corresponding 5-hydroxy ester. Moreover, the stereospecific ring closure reaction was accelerated by the antibody -elicited from the transition-state analog 15- by about a factor of 170. 

There is a marked contrast between these rearrangements and two similar classes of reaction. Firstly, anionic cyclisations (see section 7.2) of a-alkoxyorganolithiums such as 32, which proceed with retention.28 Yields in the cyclisation are poor from 33 without the driving force of methoxide elimination, but the methoxy group has no effect on the stereospecificity of the cyclisation. 

Comparable secondary a-alkoxy organolithiums were made from stannanes 313 and 314 and cyclised to tetrahydrofurans during a study of the stereospecificity of the cyclisation reaction with regard to the lithium-bearing centre.153 The stereochemical aspects of these reactions are discussed below. 

Exo cyclisations of vinyllithiums onto phenyl-substituted alkynes 392 and 394 are also syn stereospecific, and give the sort of stereodefined dienes 393 and 395 of value in Diels Alder reactions.180 6-Exo cyclisations are also possible but are much slower, though they still give geometrically pure products (in contrast to 6-exo cyclisations onto silyl alkynes see below). Vinyllithiums cyclise onto alkyl-substituted alkynes (such as 396) only in the presence of TMEDA, and they do so very slowly. Nonetheless, a single geometrical isomer of the product 397 is obtained. 

The intramolecular Friedel-Crafts cyclisation of N-2-naphthylalkylalanines proceeds with retention of configuration and subsequent reduction of the resulting isoquinolinone provides a stereospecific synthesis of the diastereoisomeric 1,2,3,4-tetrahydrobenzo[f]isoquinolin-1-ols (93 and 94) (E. Gellert, N. Kumar and D. Tober,... 

A typical Horner-Wadsworth-Emmons synthesis of a conjugated alkene would involve a phospho-nate ester 92 and an aldehyde and would be extremely E-selective for E-93. This selectivity relies on the reversal of the reaction leading to the major adduct 100, so if we want to make this reaction Z-selective, we have to make the cyclisation of the major adduct faster. The black spot marks where the acceleration is needed. Once the. mi-oxaphosphelane 101 is the major (or only) product, the Z-alkene 102 must be formed as the elimination is stereospecific. 

Finally the remaining alkene is dihydroxylated with catalytic Os04and stoichiometric iV-methyl-morpholine (NMO) as oxidant to give the diol 56 that cyclises to the THF 57 stereospecifically. The aldehyde 58 was used to make (-)-dysiherbane. 

A new, stereospecific synthesis of (+)-isoretronecanol, by a transannular route, has been developed by Leonard et al. Dieckmann cyclisation of NN-bis-(y-ethoxycarbonylpropyl)benzylamine gave ethyl l-benzyl-5-oxo-l-azacyclo-octane-4-carboxylate (20), whose perchlorate was shown to possess a bicyclic structure. Hydrogenation of this perchlorate in ethanol, using palladised charcoal catalyst, afforded ethyl ( )-isoretronecanolate perchlorate (22) as sole product, presumably by stereospecific addition of hydrogen at the less hindered face of the intermediate debenzylated immonium ion (21). Reduction of the free base corresponding to (22), by means of lithium aluminium hydride, gave (+ )-isoretronecanol (23), the stereochemical purity of which was shown by g.l.c. analysis to be >98%. 

Hot on the heels of the recent isolation of sesquicarene (63) five independent syntheses have been reported. In essence, all these syntheses have depended upon an intramolecular carbene-olefin cyclisation, viz. of (64, R = Me), (64, R = H), and (65). Only those syntheses which ensured the trans-A double bond in the precursors were stereospecific. Recently, Corey and Achiwa" have shown that mercuric iodide not only catalyses the diazo decomposition of (65) (i.e. cis,trans) but also isomerises the A double bond of the trans,trans analogue of (65). Thus, sesquicarene can now be obtained from commercially available farnesol trans,trans cis,trans, 1.5 1) in approximately 35%... 

Methanol and propan-2-ol add non-stereospecifically to cholest-4- and -5-ene as do ethylene and tetrafluoroethylene to 3 -acetoxypregna-5,16-dien-20-one although only 16a,17a-addition products were isolated from allene, acetylene, and dichloroethylene the derived 20-anti-oxime isomerises to the syn-isomer on irradiation in THF and cyclises internally in benzene solution. Irradiation of the trans-acid (561) in methanol resulted only in a cis-trans equilibration, although the trans-acid (562) produced the unsaturated lactone (563). 

Finally, we elaborated a highly efficient, structure- and chemoselective, stereospecific one-step method for the synthesis of the racemic drimenol (2) and hydroxy acetate (42) by the superacidic, low temperature cyclisation of E,E-famesol (72) and its acetate (73), respectively [50] (Scheme 10). 

Butenolides may be prepared by the cyclisation of 4,5-epoxyalk-2-enoates, one of the simplest cases being the formation of (.160) (15%). by treatment of (159) with HC104 in aqueous dioxane or aqueous acetone. These simple a,e-butenolides have proved to be convenient synthons for mere complex molecules. The starting material for these cyclisations is obtained via a Wittig reaction of an epoxy-ketone thus (l6l X=0), when condensed with (EtO)2P(0)CH O Et yields a mixture of E and Z (l6lj X=CHC02Et)llt8. The Z isomer forms (162) stereospecifically on hydrolysis. 

Dibutylchlorostannyl)propyl-methacylate co-polymer catalyzes the homolytic cyclisation of the bromo-acetal BrCH2(BuO)CHOCH2CH=CHPr to 2-butoxy-4-butyl-tetrahydrofuran (24)The glycol (25) is oxidized by pyridinium chlorochro-mate to the cis-diol (26) stereospecifically. ... 

Cyclisations of vinyl silanes to oxonium ions, generated by the action of a Lewis acid on an acetal, provides a flexible route into unsaturated oxacycles (Scheme 59 c f. Scheme 55166),17 A high degree (> 99.5%) of stereospecificity was observed but mixtures were obtained in the case of medium-sized rings. Overman has also reviewed the use of vinyl- and alkynylsilane-terminated cyclisations in synthesis.174 Stereochemical aspects of the silicon-directed Nazarov... 

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