Functional Group Transformation by Nucleophilic Substitution Reactions

Representative Functional Group Transformations by Nucleophilic Substitution Reactions of Alkyl Halides... 

Functional Group Transformation by Nucleophilic Substitution Reactions... 

This chapter deals with (1) the transformation of the sulfone functionality into other functional groups by nucleophilic substitution reaction, and (2) the addition and elimination reaction of a,/i-unsaturated sulfones. Particular attention will be paid to recent uses of sulfones in organic syntheses1. 

The prominent role of alkyl halides in formation of carbon-carbon bonds by nucleophilic substitution was evident in Chapter 1. The most common precursors for alkyl halides are the corresponding alcohols, and a variety of procedures have been developed for this transformation. The choice of an appropriate reagent is usually dictated by the sensitivity of the alcohol and any other functional groups present in the molecule. Unsubstituted primary alcohols can be converted to bromides with hot concentrated hydrobromic acid.4 Alkyl chlorides can be prepared by reaction of primary alcohols with hydrochloric acid-zinc chloride.5 These reactions proceed by an SN2 mechanism, and elimination and rearrangements are not a problem for primary alcohols. Reactions with tertiary alcohols proceed by an SN1 mechanism so these reactions are preparatively useful only when the carbocation intermediate is unlikely to give rise to rearranged product.6 Because of the harsh conditions, these procedures are only applicable to very acid-stable molecules. 

This chapter has a mechanistic emphasis designed to achieve a practical result. By understanding the mechanisms by which alkyl halides undergo nucleophilic substitution, we can choose experimental conditions best suited to carrying out a particular functional group transformation. The difference between a successful reaction that leads cleanly to a desired product and one that fails is often a subtle one. Mechanistic analysis helps us to appreciate these subtleties and use them to our advantage. 

These heterocyclization reactions provide initial products with a functionality (3 to the heteroatom, except for cases where a proton is the electrophile. Synthetic applications often depend upon further transformation of this functionality. Useful transformations include replacement by hydrogen, elimination to form a ir-bond, nucleophilic substitution, and substitution via radical intermediates. These reactions will be discussed only when understanding the cyclization step requires inclusion of the functional group transformation. 

Danishefsky s synthesis (Scheme 4) [7] started from the readily available Wieland-Mie-scher ketone (19) which, by a series of mainly protection and oxidation reactions, was transformed to the fully functionalized C ring precursor 21. The oxetane moiety was introduced very early on in the synthesis, from a corresponding triol, again by nucleophilic substitution at C5. Noteworthy is the selective protection or modification of primary versus secondary versus tertiary hydroxy groups for this purpose. The benzyl protected enolized form 20 then could be oxidized, cleaved oxidatively and processed to compound 21 which, apart from complete C/D rings, possesses the necessary handles (C2 and C9/10) to bind to the A ring precursor 22 and thus form the B ring. 

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