Cyclisation reactions intermolecular

As briefly explained in Sect. 1.2.1, the -270 residue TE domain catalyses either a hydrolysis or an intermolecular cyclisation reaction to terminate the biosynthesis of polyketides and fatty acids, releasing the final prodnct from the assembly line. The TE domain exhibits an a/fi-hydrolase fold and is dimeric in modular type I PKS systems. The mechanism of both hydrolytic cleavage and macrolactonisa-tion commences with the transfer of the polyketide chain from the final ACP onto the active site serine of the TE, forming an acyl-TE intermediate. The hydrolytic... 

Due to its marked atom economy, the intramolecular hydroamination of alkenes represents an attractive process for the catalytic synthesis of nitrogen-containing organic compounds. Moreover, the nitrogen heterocycles obtained by hydroamination/cyclisation processes are frequently found in numerous pharmacologically active products. The pioneering work in this area was reported by Marks et al. who have used lanthanocenes to perform hydroamination/cyclisation reactions in 1992. These reactions can be performed in an intermolecular fashion and transition metals are by far the more efficient catalysts for promotion of these transformations via activation of the... 

The synthesis of a tetraphenyl derivative (rubrene, Expt 6.13) of the linearly fused tetracyclic aromatic hydrocarbon naphthacene involves an interesting intermolecular cyclisation process between two molecules of 1-chloro-1,3,3-triphenylpropa-1,2-diene. This substituted allene is formed in situ from 1,1,3-triphenylprop-2-yn-l-ol (Expt 5.41) when the latter is allowed to react with thionyl chloride and the resulting chlorosulphite ester heated with a little quinoline cyclisation occurs spontaneously under these reaction conditions to give rubrene which has an intense red colour. 

The ability of Sml2 to reduce alkyl halides has been exploited in a number of carbon carbon bond-forming reactions. Radicals generated from the reduction of alkyl halides can be trapped by alkenes in cyclisation reactions to form carbocyclic and heterocyclic rings (see Chapter 5, Section 5.3), and the alkyl-samarium intermediates can be used in intermolecular and intramolecular Barbier and Grignard reactions (see Chapter 5, Section 5.4). The reduction of ot-halocarbonyl compounds with Sml2 gives rise to Sm(III) enolates that can be exploited in Reformatsky reactions (Chapter 5, Section 5.5) and are discussed in Section 4.5. 

Enholm reported radical-anionic sequences involving ketyl radical cyclisa-tions that culminate in intermolecular aldol reactions treatment of aldehyde 24 and cyclohexane carboxaldehyde with Sml2 triggers a radical cyclisation-intermolecular aldol sequence to give 25 in good yield (Scheme 6.10).15... 

It is remarkable that in the same year, 1934, two independent approaches, those of Stoll et al. and of Kuhn, led to the definition of two quantities which are conceptually quite similar and can be practically identical in many actual cases. In either case the intramolecular reaction is compared to a corresponding intermolecular process. This is the dimerisation reaction of the bifunctional reactant in the definition of the cyclisation constant C in the case of the effective concentration C ff, must be determined with the aid of an intermolecular model reaction, the choice of which is not always obvious and can possibly lead to conceptual as well as experimental difficulties. It is also worth noting that although these early workers established a firm basis for interpretation of physical as well as of preparative aspects of intramolecular reactions, no extensive use of quantities C and Qff appears to have been made in the chemical literature over more than three decades after their definition. This is in spite of the enormous development of studies in the field of... 

The [Ir(ppy)2bpy] complex photo-catalyses inter- and intramolecular C-H functionalisation reactions of tertiary amines under the visible light irradiation. Oxygen behaves as a chemical switch, triggering different reaction pathways and leading to different products from the same starting material. In anaerobic conditions, the intermolecular addition of iV,iV-dimethyl-anilines to electron-deficient alkenes yields y-amino nitriles. Aerobic conditions, on the other hand, favour a radical addition/ cyclisation reaction, leading to tetrahydroquinoline derivatives. The intramolecular version of the radical addition produces unexpectedly indole-3-carboxaldehyde derivatives. ... 

Far from being limited to cyclisation reactions, Sml2 is also a very powerful reagent for the promotion of reductive intermolecular crosscoupling reactions. The ability to fine-tune the reagent using a range of additives can deliver superb yields and stereoselectivity. 

This early report, while ground breaking, was limited to intramolecular reactions of substrates containing an amino alcohol, as exclusive activation of the alcohol to form an aldehyde with a catalyst is requisite. Advances by the group of Murahashi showed that ruthenium catalysts enabled the intermolecular cyclisation of amino alcohols or diols with primary amines to generate pyrrolidines or piperidines (Scheme 12.42). ... 

Thus, within the approximations on which scheme (1) is based, the yield Y/( 1 + Y) of ring product is solely determined by the value of the initial monomer concentration relative to the kintra/kdim ratio, which Stoll et al. termed the cyclisation constant C. C has units of mol 1 1 and represents the monomer concentration at which intra- and intermolecular processes occur at the same rate. That Stoll et al. disregarded the fact that two monomer units are used up in the intermolecular condensation, as well as that the monomer disappears by reaction with functional groups at the ends of polymer chains was pointed out by Morawetz and Goodman (1970), who proposed an alternative approximate solution to the problem, as based on... 

As we considered above, one of the fundamental problems associated with the preparation of macrocyclic ligands is concerned with the orientation of reactive sites such that they give intramolecular (cyclic) rather than intermolecular (acyclic) products. This is associated with the conformation of the reactants and the reactive sites, and so we might expect that judicious location of donor atoms might allow for metal ion control over such a cyclisation process. This is known as a template synthesis, and the metal ion may be viewed as a template about which the macrocyclic product is formed. This methodology was first developed in the 1960s, and has been very widely investigated since that time. At the present, template reactions usually prove to be the method of choice for the synthesis of many macrocyclic complexes (with the possible exceptions of those of crown ethers and tetraazaalkanes). When the reactions are successful, they provide an extremely convenient method of synthesis. 

The rationale for this approach is that in dilute solutions the formation of a cyclic product by intramolecular reaction (i.e. one end of a molecule bumping into itself) is more likely, and hence faster, than formation of a polymer, which requires a collision between two separate reactants (an intermolecular reaction) (Figure 3.47). If we compare the rates of cyclisation (r<) of a reactant X—Y, rc = A,.- [X—Y], with polymerisation, rp = Ay X—Y]2, we derive the expression ... 

As is usually the case, intramolecular reactions are easier than intermolecular and often do not obey the usual rules. Some do not need the carbonyl group, some show exo rather than endo selectivity, and the cyclisation of 56 gives the meta product 58. The mechanism 57 makes it clear that the expected para product (cf. 42) cannot be formed. This is a particularly impressive example as the product 58 is a bridgehead alkene with a strained geometry.10 The alkene is cis inside the six-membered ring but trans in the outer 10-membered ring. 

This chapter is about the advantage that cyclisations have over intermolecular reactions and therefore about the simplicity of heterocyclic synthesis. We need to look first at some details. It is not true that all cyclisations are favourable. A general cyclic amine synthesis shows that there is a large difference in the rates of formation of rings of different sizes.1 Five-membered rings... 

Though these are the least favourable cyclisations, they do happen and are usually preferred to intermolecular reactions where there is no alternative, i.e. no more favourable ring can be formed. Upjohn s analgesic and anti-depressant tazadoline 31 contains a four-membered cyclic amine, an azetidine. Simple disconnection of C-N bonds gives 32 (where X is a leaving group) and then the enone 33, the aldol product from cyclohexanone 34 and benzaldehyde. 

We have already explained that compounds like 101 are unstable and cyclise rapidly to the lactam. So the workers at Takeda used the lactam 102 as the starting material. Opening the lactam with NaOH gave the anion 103 of 101 that added to 100 to give 99 and hence that aldol product 98 in base. Cyclisation to a seven-membered ring is preferred to intermolecular reactions. 

Only one regioselectivity is possible in the cyclisation of 18 but in intermolecular reactions we need to consider which way round it will go. So the unsymmetrical alkene 24 could add to the very unsymmetrical enone 25 to give 26 or 27. In fact the reaction gives8 virtually 100% of 27 without a trace of 26. 

Cyclisations are easy. In chapters 7 and 21 we saw that the type of control needed to make open chain compounds is often unnecessary for cyclisations as intramolecular reactions usually take precedence over intermolecular. If, therefore, a difficult step needs to be used in a synthesis, it is good strategy to make it a cyclisation. 

H2NCSNH2) and hydrazinedithiocarbonate (H2NNHC(=S)SH)45 The latter reagents cleave the chloroacetyl group by a two-step one-pot reaction. For example, treatment with mercaptoethylamine results in substitution of the chloride followed by intramolecular cyclisation and cleavage (Scheme 2.15b). This reaction exploits the fact that intramolecular reactions are much faster than intermolecular reactions. 

The addition of sp3 or sp2 carbon-centred radicals to unsaturated carbon carbon bonds is yet another class of synthetically useful reactions promoted by the low-valent lanthanide reagent Sml2. Halides and sulfones are the most common functional groups used as precursors to radicals, although other groups have also been successfully employed. Although the intermolecular variant of this reaction has found only limited application, intramolecular variants can be highly successful. In most of these cyclisation events, the... 

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