Steroid substitution reaction

Mechanism On the basis of the available evidence a mechanism has been proposed which envisions rapid formation of the intermediate (25), which may undergo an SNj reaction to form fluoro products with inversion of configuration, as is the case with 3a- and 15a-ols. More frequently this substitution reaction is accompanied by decomposition of (25) to the steroidal cation Sf ", which in turn may undergo rearrangement or elimination as discussed above. 

The oxygen atoms portrayed above can, in principle, be replaced by nitrogen atoms, although this has been verified by experiment only with 20-amino steroids. In view of the difficult access to 8/5-hydroxy steroids, these compounds have not been used for substitution reactions, but they fulfill all requirements for suecessful functionalizations at both C-18 and C-19. 

The substitution reactions of a-bromo-ketones to give a -acetoxy-ketones are generally considered to proceed vih an enol, with allylic (SN2r) substitution in the cis stereochemical sense.62 A new investigation of the reaction between 4/3-bromo-3-oxo-5/3-steroids (29) and acetate ion shows that the initial product is the 2a-acetoxy-ketone (30), which rearranges rapidly under the reaction conditions to give the stable... 

This chapter deals with the most important reactions of steroid alcohols and their derivatives, other than those involving molecular rearrangements. Substitution reactions of halides are included, having many similarities to reactions of the alcohol derivatives. Molecular rearrangements of car-bonium ions originating from steroid alcohols are discussed separately in Chapter 5. 

Neighbouring halogen participation through halonium ions (p. 91) has been postulated to account for features of some substitution reactions. 5a-Bromo-6jS hydroxy steroids (17) are converted by thionyl chloride into the 5a-bromO"6 -chloro derivatives (19) with over-all retention of configuration [124], An intermediate 5a,6a bromonium ion (18) controls the stereochemistry of subsequent introduction of chloride ion. 

When complete product analyses were performed after deamination of the 5a-cholestan 3-yl amines [4, ], the results (Table 28) provided support for the Cohen and Jankowski mechanism, although there is some disagreement between authors as to exact yields of products. The notable features are again higher yields of olefin from the axial amine, predominant retention in substitution products, and only slight sensitivity to solvent composition except for a marked increase in the yield of inverted alcohol in aqueous acetic acid. We may therefore consider the solvated diazonium acetate ion-pair as the key species in the steroid deamination reactions, although further work is needed to estabHsh a complete parallel with the data for decalyl amines. 

Substitution reactions involving 3/S-hydroxy-A -steroids and their derivatives require special mention. Cholesterol reacts with a variety of halogenating agents, including thionyl chloride / StJ, phosphorus pentachioride [81], haHdes of aluminium or titanium [82], 2-chloro-i,i,2 trifluoroethyl di-ethylamine [83] and triphenylphosphine dibromide [55], to... 

Favorskii rearrangements, and other examples are known in the steroid nucleus (see below). Highly polar solvents (methanol or aqueous methanol) were originally used for these reactions the bromoketones may undergo dehydrobromination or substitution reactions in basic media of low polarity, such as pyridine or KOAc/HOAc. Recent work, however, has shown that sodium methoxide in aprotic solvents e.g. 1,2-dimethoxy-ethane) can be used, and tlxat the stereospecificity of various Favorskii reactions using simple alicyclic and aliphatic compounds is markedly dependent upon the nature of the solvent [301],... 

The stereochemical course of nucleophilic substitution reactions is best illustrated by reference to substitution at a saturated carbon atom. The underlying principles of these reactions are fundamental to an understanding of the more complex stereochemistry of iSn reactions on steroids, carbohydrates and vinyl compounds which are considered in detail in the relevant sections below. 

Steroids substituted by spiro-a-methylene-7-lactones [e.g. (431)] have been synthesized as possible antitumour agents by Reformatsky reactions between ethyl 0 -(bromomethyl)acrylate and suitable steroid ketones. 

Substitution reactions using azide ion have become a popular route to nitrogen-containing steroids. The high nucleophilicity of NJ makes it effective even in some cases where Sn2 reactions are normally unfavourable. A notable example is... 

Many stereoselective substitution reactions (Sj 2) were first studied and optimized with steroidal substrates, because this class of compounds provides a large variety of pure enantiomers with just one reactive chiral center. Furthermore, the... 

More sophisticated examples are provided by substitution reactions, which are influenced by a remote double bond. The 3p-hydroxy group of cholesterol, for example, can be substituted by chloride with PClg or, after tosylation, by methoxide. In both cases almost quantitative yields of p-substituted compounds are observed. All 3P-hydroxy steroids with a 5,6-double bond give these reactions. The homoallylic carbonium ion at G3 and its cyclization after neuttaliza-tion at the y carbon atom have thus been established as well as the thermodynamic preference of equatorial substitution in cyclohexane units (Scheme 3.4.2). 

Radiolabeled 4-[ F]fluoropyridine can be synthesized by no-carrier-added nucleophilic aromatic substitution with K[ F]F-K222- In another instance, the nucleophilic substitution reaction was also employed for the synthesis of steroids-containing 4-fluoropyridine motif, and for the synthesis of 4-fluoropyridines annulated with pyrrole (azoindoles).Substantial difference in the reactivity of the pyridinium ring toward nucleophilic substitution in 5-iodo-2,4-difluorpyridine was effectively used for the preparation of 4-fluoropyridines 93 and 94 using difluoropyridine 92 as starting material (Scheme 6.31). 

Polyesters, nylon, and many biological molecules share a common aspect of bond formation during their synthesis. This process is called acyl substitution, and it involves creation of a bond by nucleophilic addition and elimination at a carbonyl group. Acyl substitution reactions occur every moment of every day in our bodies as we biosynthesize proteins, fats, precursors to steroids, and other molecules and as we degrade food molecules to provide energy and biosynthetic raw materials. Acyl substitution reactions are used virtually nonstop in industry as well. Approximately 3 billion pounds of nylon and 4 billion pounds of polyester fibers are made by acyl substitution reactions every year. The molecular graphic above is a portion of a nylon 6,6 polymer. 

Important reactions of free steroids include esterification, where esters and glycosides of steroid compounds are easily hydrolysed. These reactions in food raw materials are catalysed by sterol esterases and glycosidases, respectively. Other important reactions of steroids include elimination and substitution reactions and oxidation. Hydrogenation of steroids is of industrial importance. 

Pyrophosphate derivatives of alcohols participate in the biosynthesis of many molecules, including cholesterol and steroid hormones. The biosynthesis of these molecules begins with a nucleophilic substitution reaction between two frve-carbon isoprenoid pyrophosphates called isopentenyl pyrophosphate and dimethylallyl pyrophosphate. An enzyme-catalyzed reaction interconverts the two isomers. The pyrophosphoryl groups are abbreviated—OPP. 

Androstane Series - A new type of substitution reaction has been described. When the D-homo steroid (l) was treated with a primary amine attack occurred at the 16 position with elimination of dimethylamine at 17a, to yield II.Most probably the key step is a SN2 displacement on the enol by the entering amino groijp. 

The reaction of the steroidal )3-ketoaldehyde (293) with hydroxylamine hydrochloride in acetic acid gave a mixture of the 3- and 5-substituted isoxazoles (294) and (295a). In sodium acetate buffer the reaction provided exclusively the 5-substituted isomer (29Sb) (66JOC3193). 

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