Strategy cyclisation

Mori et al. have demonstrated the most dramatic uses of lithiated epoxides in natural product synthesis [62]. By employing the chemistry developed by Jackson, and subsequently performing a Lewis acid-catalyzed (BF3 OEt2) cyclisation, tetra-hydrofuran, tetrahydropyran, and oxepane rings are readily accessed this strategy is demonstrated by the synthesis of the marine epoxy lipid 173 (Scheme 5.40) [63]. 

This lithiated epoxysulfone cyclisation strategy has been iteratively applied in the total synthesis of hemibrevitoxin B, a polycyclic ether marine toxin from the red tide organism Gymnodinium breve (Scheme 5.41) [64]. 

The cydopropanation reaction of an unsaturated substrate is one of the most important strategies to access three-membered ring derivatives. The use of Fischer carbene complexes to perform this kind of cyclisation has become an important tool in organic synthesis [4]. In the next few sections the most significant features of this chemistry are briefly described. 

A similar synthetic strategy was applied in the synthesis of menogaril 83, another important anthracycline antitumour antibiotic, and to the synthesis of the tricyclic core of olivin 87, the aglycon of the antitumour antibiotic olivomycin [61,62]. In both cases a tandem benzannulation/Friedel-Crafts cyclisation sequence yielded the tetracyclic and tricyclic carbon core, respectively (Scheme 42). 

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). 

Strategy III Reversal of Polarity, Cyclisation Reactions, Summary of Strategy... 

Either strategy will do for (52) which has been made by route (b) using cyanide (54) instead of an ester (51). Cyclisation of (49) merely needs acid, in contrast to the synthesis of (33). 

Putting this simple strategy into operation demands protection of the aldehyde group in (72) (otherwise it will cyclise) and activation of acetone as (74). The... 

The synthesis of the D-gulonolactam 36 was based on an intramolecular cyclisation /ring enlargement strategy involving reduction of the azido group in 35 followed by intramolecular nucleophilic attack on the lactone moiety to afford 36 in excellent yield <06T7455>. 

Since acetonitrile itself is a poor radical acceptor, strategy B is more suitable for intramolecular cyclisations (Scheme 7.20). 

As we will see, the general strategy for synthesising this pentagonal polycyclic system requires the homolytic disconnection of two vicinal bonds that are exo to the "central" ring, which remains intact (see Schemes 7.21 and 7.22). In the synthetic direction all the cyclisations must be, according to Baldwin s rules, 5-exo. 

From an exhaustive retrosynthetic analysis and from the experimental work performed by Curran [29] [32], it was clear that the synthesis of modhephene required an elaborate strategy. In the first place, the tandem radical cyclisation should be conducted individually rather than just in one step since it allows more flexibility. In the second place, Curran s observation that the precursor of modhephene (54) could be the olefmic exocyclic derivative 55 allows the application of a series of heuristic principles already familiar to us, which greatly simplifies the retrosynthetic analysis and leads to diquinane and, finally, through a second radical retroannulation to the very simple cyclopentanone derivative (Scheme 7.24). 

Strategies based on very particular and specific reactions, such as Diels-Alder addition, either inter- or intramolecular (see also cycloeliminations), cationic cyclisations (important in the "biomimetic synthesis" of steroids), Pauson-... 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

It is worth noting that in this synthesis of Cecropia juvenile hormone a strategy which is the reverse of the one developed by W.S. Johnson [8] for the synthesis of steroids and other fused polycyclic systems bearing cyclohexane rings is used. This method involves a non-enzymatic cyclisation of a polyunsaturated intermediate with the appropriate stereochemistry (all-trans) (Scheme 13.3.6). Such cyclisation occurs with a really amazing stereoselectivity and several new chiral centres with the correct stereochemistry are created in one single step ... 

The general strategy for the synthesis of (-)-swainsonine [5] is to prepare an acyclic key intermediate with the required stereochemistry and proceed then to a double intramolecular cyclisation. 

An alternative strategy towards benzimidazole synthesis relies on the palladium-catalysed cyclisation of (2-bromophenyl)amidines. This chemistry has been reported to take place under aqueous reaction conditions, in the presence of sodium hydroxide in sealed microwave vials. The products were isolated by a catch and release method using a strongly acidic ion exchange resin, thereby avoiding conventional chromatographic purification (Scheme 3.14)23. Selectively, N-functionalised benzimidazoles were conveniently prepared by this method. 

The numerous methods which are available for the synthesis of substituted fi-lactams involve a variety of ring-forming strategies. Two categories only are selected and exemplified below to illustrate some of the interesting chemistry involved Cyclisation reactions and Cycloaddition reactions. 

If the cyclisation is not worked up, the product is the alkynyl-lithium that can be added directly to 55 to give the alcohol 54. In the Merck synthesis of efavirenz, this step is used to make a single enantiomer of 64 and this chemistry is discussed in Strategy and Control.16... 

So we have three promising approaches. But the reactions in the first two are the same they are just done in the reverse order. So the sensible thing is to try one of those so that the starting materials can be used for the other if necessary. Pratt and Raphael found that the 1,5-diCO strategy via enolate 7 was successful. The others may be successful too. Note that the final cyclisation of 2 required only weak acid and weak base. 

There remained the synthesis of 60. An old synthesis7 used essentially the strategy we have outlined via 65 alkylation of MeNH2 with the chloro-acetal 74, conjugate addition of 75 to butenone 76 and cyclisation in acid solution. It was very low yielding. One reason is the poor amine synthesis by alkylation (chapter 8) and another is presumably that the acetal 77 hydrolyses to the aldehyde 65 but control in the cyclisation is poor. 

Rather surprisingly this strategy works.5 It was better to use the diketone 36 (rather than 33), made by acylation of the morpholine enamine 35 of 34 and reductive amination of with 3-aminopropanol to give 37 that is dehydrated in acid to the amine 38. A Mitsunobu-like treatment with Ph3P-Br2 converts the OH to Br whereupon cyclisation of 32 X = Br gives 31. 

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. 

This is the strategy followed in most thiazole syntheses. The regioselectivity issue is which way the reagents combine. There are two possibilities the sulfur could attack either the ketone or the saturated carbon atom as can the nitrogen. But sulfur is excellent at Sn2 reactions while nitrogen is better at addition to carbonyls. So 27 and not 35 is the product. No intermediates are isolated once either the C-S or the C-N bond is formed, cyclisation and aromatisation are fast. This means that aromatic heterocycles are easier to make than the non-aromatic ones. 

After exchange of the protecting group, the Weinreb amide 111 (an alternative to nitriles for the formation of ketones discussed in detail in Strategy and Control) reacted with the aryl Grignard reagent to give, after reduction, 112—the protected version of the alcohol 106 required for cyclisation. 

---