Brominations diastereoselective example

Yaodong Huang, while pursuing the synthesis of ( + )-berkelic acid (69), reported a diastereoselective cycloaddition using method H that leads to another type of 5,6-aryloxy spiroketals (Fig. 4.36).32 For example, addition of three equivalents of t-butyl magnesium bromide to alcohol 70 in the presence of the exocyclic enol ether 71 proceeds in a 72% yield to the spiroketal 72 with a 4.5 1 selectivity favoring the endo approach (Fig. 4.36). Additional experiments suggest the bromine atom decreases the HOMO-LUMO band gap and improves diastereoselectivity. 

In the latter reaction, remarkable examples of diastereoselectivity have been reported. Thus, the treatment of 7,7-dibromonorcarane 22 with n-butyllithium leads to exo-7-bromo-ewdo-7-lithiobicyclo[4.1.0]heptane23 exclusively, as shown by carboxylation (Scheme 8). It turns out that a slight excess of dibromonorcarane 22 relative to butyllithium is prerequisite to that high degree of stereoselectivity. The result is explained as follows the exo-bromine atom in 22 is exchanged first in a kinetically controlled reaction so that the ewrfo-bromo-exo-lithio-isomer 24 is formed. In a second step, an equilibration occurs by means of another bromine-lithium exchange, which takes place between 24 and the dibromonorcarane 22 (still present because used in excess). Thus, the thermodynamically... 

Chelation is another driving force that provides diastereoselective bromine-lithium exchange reactions to give cyclopropyl carbenoids. Thus, the exo-bromine atom in dibro-mocyclopropane 25 is exchanged exclusively due to the methoxy substituent, which encourages the lithium to occupy the cis orientation (equation 16) ° Several representative examples of cyclopropyl bromo lithium carbenoids obtained by bromine-lithium exchange reactions are given in Table 1. 

In the above discussion of stereoselectivity the mechanisms of various reactions have been used to rationalize why some are stereoselective and some are not. Thus the bromination of olefins proceeds via a bridged bromonium ion intermediate and gives only trails addition across the double bond [reactions (6.2) and (6.3)]. In contrast, the addition of HBr across a double bond gives a carboca-tion intermediate that does not maintain the facial integrity of the olefin and is thus much less stereoselective [reaction (6.1)]. In these examples the mechanism of the reaction is used to explain and understand the diastereoselectivity that is observed. There are many other examples (usually in textbooks) where the mechanism of a reaction is used to rationalize the stereoselectivity of the process. To do this requires that the mechanism be known with certainty. 

Of similar nature are chiral halogenations using auxiliary groups. Typical examples are the conversion of esters to enantiomerically pure halohydrins (precursors to chiral epoxides) using camphor-10-sulfonic acid derivatives583 and the chiral synthesis of a-amino acid synthons via diastereoselective bromination of TV-acyl oxazolidone derivatives584. 

Similar terminology is applied to formation of diastereomers. March gave the example of maleic acid (127) and fumaric acid (129) and their reactions with bromine. On addition of bromine to 127, a racemic mixture of 128 was formed. Addition to 129 gave only c.9o-130. In both cases the reaction was diastereo-specific. If 127 gave predominantly 128 with only a trace of the diastereomer (130). the reaction would be diastereoselective rather than diastereospecific. 

The Zambon process also starts from P-naphthol, and affords S-naproxen directly avoiding resolution and recycling. It is one of the few examples of a non-enzymatic, non-fermentation industrial asymmetric synthesis. Clearly, the early stages of the process produce similar waste streams to the Syntex process, with additionally waste from the Friedel-Crafts step. In principle, however, the aluminium salts can be recycled by work-up involving conversion back to aluminium chloride. The key step in this route is the highly diastereoselective (94 6) bromination of the ketal diester, derived from chirality pool 2R, 3R tartaric acid, which is used as an auxiliary. The subsequent acid catalysed 1,2-aryl shift occurs with complete inversion of configuration at the migration terminus [17]. The tartaric acid auxiliary can be efficiently recycled, but clearly there is a... 

A number of processes involving chiral acetals have been examined in the synthesis of pharmaceutically important compounds. In one example, a synthesis of the antiinflammatory drug naproxen (80) includes a diastereoselective bromination reaction to furnish bromide 78 (dr 93 7, Scheme 6.15) [45]. Intramolecular rearrangement gives ester 79 with >99 1 diastereo-selectivity after recrystallization. Subsequent acidic cleavage of the auxiliary followed by reduction (H2 Pd-C) of the bromide that is adventitiously introduced on the naphthyl core afforded naproxen (80). 

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