Intramolecular nucleophile delivery

Scheme 10-103 Intramolecular nucleophile delivery provides an efficient route to biologically important corticosteroids.

Scheme 10-lW Synthesis of kainic acid in which Bachi and Melman used intramolecular nucleophile delivery. 

A complex example of activation, aimed at improving ocular delivery, has been reported for prodrugs of pilocarpine (8.87, Fig. 8.6) [123][124], The prodrugs are, in fact, lipophilic diesters of pilocarpic acid (8.86, Fig. 8.6). The first step is enzymatic O-acyl hydrolysis to remove the acyl carrier (Fig. 8.6, Reaction a). In a second step, intramolecular nucleophilic attack leads to loss of the alcohol carrier and ring closure to pilocarpine (Fig. 8.6, Reaction b). 

Negishi and co-workers demonstrated the feasibility of this carbopalladation mode on an allene in an intramolecular approach to medium and large rings [80]. The new C —C bond is fornied at the central carbon atom of the allene moiety to give a jr-allylpalladium complex, which in turn can be trapped by a variety of nucleophiles (arylstannanes to give arylated products, malonates, phenols, amines, etc.) (Scheme 3-27). The yields are remarkably good without using sophisticated nucleophile delivery techniques. 

Recourse has therefore been taken to adopt the strategy successfully used for (3-mannosides, employing intramolecular aglycon delivery, namely, using a tether that forces the nucleophile to approach the oxocarbenium intermediate from the (3... 

The monolithium salt of 4-hydroxy-4-(phenylethynyl)-2.5-cyclohexadienone (12), prepared in situ by the addition of lithium acetylide to /7-benzoquinone, was treated with methylmagnesium chloride in l HF-TMEDA or in THF —DMPU. The syn-, 4-addition adduct 13, derived from intramolecular delivery of the carbon nucleophile by the hydroxy oxygen, as well as the <7s-1,4-diol 14, obtained via intermolecular 1,2-addition, were obtained in varying amounts depending on the conditions. The selectivity on 1,4- to 1,2-addition increased by the addition of cation chelating agents such as DMPU, TMEDA, and 15-crown-5. Although the 1,4 to 1,2... 

Tandem 1,2- and 1,4-additions to quinones.1 The lithium alkoxide formed by 1,2-addition of an alkyllithium to a p-benzoquinone can react as a Michael acceptor with some nucleophiles in the presence of HMPT or DMPU (13, 122). The process involves lithium-metal exchange followed by intramolecular delivery... 

Some nucleophiles (organometallics RM and hydride equivalents, featuring very weak conjugate acids) show a different stereochemical outcome, the attack of the nucleophile taking place at the palladium atom to form a neutral rj3 complex. Reductive elimination—or, in other words, intramolecular delivery of the nucleophile to the allylic framework—occurs with retention of configuration. In short, the reactions with these types of nucleophiles occur with overall inversion (inversion + retention) of configuration. 

On the other hand, protecting groups can be used to thwart heteroatom-assisted delivery. Reaction of the a,f -unsaturated sulfone 51.1 with trimethylsilylethynyl-lithium resulted in intramolecular delivery of the nucleophile to afford adduct 51.2 with a dr = 100 1 [Scheme 1.51].88 When the hydroxy group was protected as its trivnethylsilyl ether, conjugate addition took place from the opposite face to give the diastereoisomeric adduct 51.4, again with a dr = 100 l. 

Intramolecular delivery of the nucleophile can provide a stereoselective entry to bicyclic lactones as demonstrated in equation 22 an isomeric precursor affords the corresponding cis-lactone. ... 

In contrast to the reaction of 1,2-anhydrosugar, C-glycosylation of 1,6-anhydropyranose requires a strong Lewis acid in order to open the anhydro bridge, generating the corresponding oxocarbenium cation (O Eq. 6). Addition of nucleophiles to the cation could be controlled by the stereoelectronic effect, chelation between the nucleophile and the Lewis acid coordinated to the hydroxyl group, or intramolecular delivery of nucleophiles as shown below. 

Regiospecific opening of the epoxide was also achieved by intramolecular delivery of the nucleophile. The alcohol 52 was converted into the reactive intermediate 53 with methyl isocyanate. Cyclisation can occur only to the nearer end of the epoxide (5-exo-tet) to give 54. The stereochemistry is already correct for the SN2 inversion on the epoxide 53. The free OH group is turned into a good leaving group by mesylation without isolation of 54. 

The alternative method of reduction of such hydroxyketones is the a //-selective Evans intramolecular delivery of nucleophilic hydride through a cyclic transition state. In Janda s bryostatin synthesis, the diol monoester 182, produced by kinetic resolution with an immobilised lipase (chapter 29) is reduced to the an//-diol 183 by acetoxy-borohydride. The hydride delivery is intramolecular through a chair transition state 184. This is 1,3-control via a cyclic transition state (chapter 21).30... 

Scheme 10-99 Intramolecular delivery of a nitrogen nucleophile provides the correct stereochemistry at the anomeric position for a synthesis of hydantocidin.

Scheme 10-100 Intramolecular delivery of a nitrogen nucleophile allows stereospecific incorporation of the amino functionality at the sterically hindered C(6) position.

In a new approach to 2 -amino-2 -deoxyuridine (70) and related compounds, involving intramolecular delivery of a nitrogen nucleophile, the anhydronucleo-side 69 was treated as outlined in Scheme 6. The cytidine analogue was also prepared. In a similar way (Scheme 7), 2 -alkoxyamino derivatives could be made from -alkoxyurethanes, and the same type of cyclization was possible with A -alkylurethanes, but required more vigorous conditions. ... 

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