Cyclisation, intramolecular

Procter has recently shown that radical cyclisation-intramolecular aldol sequences can also be carried out.16 For example, treatment of dialdehydes 26 and 27 with Sml2 results in a sequential cyclisation to give 28 and 29, respectively, as single diastereoisomers in high yield (Scheme 6.11). The diastereo-selectivity of the sequence can be ascribed to the chelation of Sm(III) to intermediates, most notably in controlling the double-bond stereochemistry during the formation of Sm(III) enolate 30.16... 

The outstanding challenge in this area is the synthesis of the natural macrocyclic diester alkaloids. A first step in this direction was taken by Robins and Sakdarat 251), when they managed to reconstruct an 11-membered macrocyclic diester (85) from (+)-retronecine and 3,3-dimethyl-glutaric anhydride. The mixture of 7- and 9-monoesters of retronecine initially produced was cyclised intramolecularly via the corresponding 2-pyridinethiol esters. 

Previous C-labelling studies had indicated that andibenin B (110) was formed by a novel pathway in which a bis-C-methylated tetraketide-derived phenolic precursor is alkylated by farnesyl pyrophosphate to give (109) followed by cyclisation, intramolecular cycloaddition, and oxidative modification. Further... 

The Y-phenylbutyric acid is cyclised to a-tetralone by converting it into the acid chloride with thionyl chloride or phosphorus pentachloride and then an intramolecular Friedel and Crafts reaction is carried out ... 

Esters of dicarboxyUc acids having hydrogen on tbe 8 or e carbon atoms undergo intramolecular cyclisation when heated with sodium or with sodium ethoxide. This cyclisation is known as the Dieckmann reaction. It is essentially an application of the Claiseu (or acetoacetic eater) condensation to the formation of a ring system the condensation occurs internally to produce s... 

If natural rubber is treated with proton donors a product is formed which has the same empirical formula. (CjHjj), and is soluble in hydrocarbon solvents but which has a higher density, is inelastic and whose unsaturation is only 51% that of natural rubber. It is believed that intramolecular ring formation occurs to give products containing the segments shown in Figure 30.5. Known as cyclised rubber it may be prepared by treating rubber, on a mill, in solvent or in a latex with materials such as sulphuric acid or stannic chloride. 

For that reason an intramolecular benzannulation was developed, which incorporates all components for the intramolecular alkoxycarbonylation into the naphthoquinone 105 [65]. Based on that strategy a short and convergent pathway for the synthesis of racemic deoxyfrenolicin 108 was accomplished. Xu et al. replaced the allylacetylene 100 in the reaction sequence for nanaomycin A by alkynoate 106. The benzannulation product 107 was an appropriate precursor for a subsequent tandem oxa-Pictet-Spengler cyclisation/DDQ-induced coupling reaction [66]. Following this strategy the total synthesis of enan-tiomerically pure deoxyfrenolicin could be accomplished (Scheme 48). 

Dialkyl esters of cystine (39) and lanthionine (40) undergo a surprising thermolysis reaction at between 25 C and 80 °C to afford cis and trans methyl 2-methylthiazolidine-2,4-dicarboxylates (43) in protic solvents. A two stage process is proposed for this transformation. An initial i-elimination reaction gives the thiol (41) and the enamine (42). Thiol addition to the imine tautomer of (42) is then followed by loss of ammonia and an intramolecular cyclisation to give (43) <96CC843>. 

Benzo-l,2,3,4-tetrazine 1-lV-oxides 13 can be obtained by intramolecular cyclisation of 2-(r-butylazoxy)phenyldiazonium tetrafluoroborates 11 which leads to 2-(r-butyl)benzo-1,2,3,4-tetrazinium 4-A/ oxides 12 via N to N migration of the r-butyl group followed by... 

The pyrimidines 62 undergo cyclisation on refluxing in dioxane to yield not only the pyrazolopyrimidines 63, but the novel pyrazolo[3, 4 4,5]pyrido[2,3-rflpyrimidines 64 by an intramolecular 1,3-dipolar cycloaddition reaction (Scheme 9)<96JCS(P1)1999>. 

The first examples of intramolecular diene transmissive HDA reactions have been reported. Thus, the divinyl thioketones, derived from the ketones by treatment with Lawesson s reagent, spontaneously cyclise to the thiopyran derivative (27) and react further as shown <96CC811>. 

Cyclopenta[fc]dioxanes (44) are accessible from the reaction of the dioxenylmolybdenum carbene complex (43) with enynes <96JOC159>, whilst an intramolecular and stereoselective cyclisation of (Ti5-dienyl)tricarbonyliron(l+) cations affords chiral frans-2,3-disubstituted 1,4-dioxanes <96JOC1914>. 2,3-Dimethylidene-2,3-dihydro-1,4-benzodioxin is a precursor of the 3,8-dioxa-lff-cyclopropa[i]anthracene, which readily dimerises to dihydrotetraoxaheptacene (45) and the analogous heptaphene <96AJC533>. 

Disubstituted benzo[fo]furans were also prepared by intramolecular cyclisation in the presence of a [Pd(thiourea)4]l2 catalyst (thiourea = H2NCS NH2). No Pd precipitation occurred with this very stable thiourea complex (Scheme 31) [120]. 

The Rh and Ir complexes 85-88 (Fig. 2.14) have been tested for the intramolecular hydroamination/cyclisation of 4-pentyn-l-amine to 2-methyl-1-pyrroline (n = 1). The reactions were carried out at 60°C (1-1.5 mol%) in THF or CDCI3 The analogous rhodium systems were more active. Furthermore, the activity of 87 is higher than 85 under the same conditions, which was attributed to the hemilabihty of the P donor in the former complex, or to differences in the trans-eSects of the phosphine and NHC ligands, which may increase the lability of the coordinated CO in the pre-catalyst [75,76]. 

The pincer complexes 89-90 (Fig. 2.14) catalyse the intramolecular hydroamination/ cyclisation of unactivated alkenes, yielding pyrrolidines and piperidines (n = 1,2, respectively). The reactions can be carried out in benzene or water with high... 

Finally, intramolecular hydroamination/cyclisation of M-alkenyl ureas was catalysed by the well-defined [AuCl(IPr)] complex (Schane 2.16), in the presence of AgOTf (5 mol%, rt, methanol, 22 h). The cationic Au(lPr)+ is presumably the active species [83]. 

The intramolecular hydroarylation/cyclisation of aryl propargylic acetates catalysed by the system [AuCl(IPr)]/AgBF (1 1, 2 mol%, 72-92%, rt, 5 min) was developed as a versatile and efficient method leading to indene derivatives 110 (Scheme 2.20). Analogous catalytic systems, where the IPr was substituted by PPh, gave lower conversions and chemo-Zregio-selectivity. 

Oxidative cyclisations representing intramolecular variant of the Wacker reaction have seen significant developments. The intramolecular oxidative cyclisation of tosylamines was found to be catalysed by the [Pd(TFA)2(IMes)(OH2)] complex (TFA = trifluoroacetate) [42], The presence of a catalytic amount of acetic or benzoic acid leads to improved activity and selectivity (Scheme 10.13). 

The intramolecular asymmetric Stetter reaction of aliphatic aldehydes is generally more difficult to achieve due to the presence of acidic a-protons. Rovis and co-workers have demonstrated that the NHC derived from pre-catalyst 130 promotes the intramolecular Stetter cyclisation with enoate and alkyhdene malonate Michael acceptors 133. Cyclopentanones are generally accessed in excellent yields and enantioselectivities, however cyclohexanones are obtained in significantly lower yields unless very electron-deficient Michael acceptors are employed... 

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... 

In 2003, Livinghouse et al. also reported that chelating bis(thiophosphonic amidates) complexes of lanthanide metals, such as yttrium or neodymium, were able to catalyse intramolecular alkene hydroaminations. These complexes were prepared by attachment of the appropriate ligands to the metals by direct metalation with Ln[N(TMS)2]3- When applied to the cyclisation of 2-amino-5-hexene, these catalysts led to the formation of the corresponding pyrrolidine as a mixture of two diastereomers in almost quantitative yields and diastereos-electivities of up to 88% de (Scheme 10.81). 

The synthesis of a series of chiral organophosphine oxide/sulfide-substituted binaphtholate ligands has recently been reported by Marks and Yu and their corresponding lanthanide complexes characterized. These complexes, generated in situ from Ln[N(TMS)2]3, cleanly catalysed enantioselective intramolecular hydroamination/cyclisation of 1-amino-2,2-dimethyl-4-pentene albeit with a low enantioselectivity of 7% ee (Scheme 10.82). 

An alternative route to anthraquinone, which involves Friedel-Crafts acylation, is illustrated in Scheme 4.3. This route uses benzene and phthalic anhydride as starting materials. In the presence of aluminium(m) chloride, a Lewis acid catalyst, these compounds react to form 2-benzoyl-benzene-1-carboxylic acid, 74. The intermediate 74 is then heated with concentrated sulfuric acid under which conditions cyclisation to anthraquinone 52 takes place. Both stages of this reaction sequence involve Friedel-Crafts acylation reactions. In the first stage the reaction is inter-molecular, while the second step in which cyclisation takes place, involves an intramolecular reaction. In contrast to the oxidation route, the Friedel-Crafts route offers considerable versatility. A range of substituted... 

Finally, aldol reactions can, with suitable dicarbonyl compounds, e.g. (99), be intramolecular, i.e. cyclisations ... 

Crossed Claisen reactions with two different esters, each of which has a-H atoms, are seldom useful synthetically as there are, of course, four possible products. Crossed Claisen reactions are, however, often useful when one of the two esters has no a-H atoms, e.g. HCOzEt, ArC02Et, (C02Et)2, etc., as this can act only as a carbanion acceptor. Such species are in fact good acceptors, and the side reaction of the self-condensation of the other, e.g. RCH2C02Et, ester is not normally a problem. Intramolecular Claisen reactions, where both C02Et groups are part of the same molecule [e.g. (123)], are referred to as Dieckmann cyclisations. These work best, under simple conditions, for the formation of the anions of 5-, 6- or 7-membered cyclic / -ketoesters... 

The 1-methylene compounds 67 with appropriate R4 substituents were useful starting materials for intramolecular cyclisations to C-l to build biologically significant 1,4-bridged derivatives <2001JA5892, 1999TL5429, 20020L1087>. 

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