Steroid field

The reagent Is expensive and poisonous, consequently the hydroxylation procedure is employed only for the conversion of rare or expensive alkenes (e.g., in the steroid field) into the glycols. Another method for hydroxylation utilises catalytic amounts of osmium tetroxide rather than the stoichiometric quantity the reagent is hydrogen peroxide in tert.-butyl alcohol This reagent converts, for example, cyc/ohexene into cis 1 2- t/ohexanedlol. 

Under certain conditions surface catalytic deuterations can lead to the exchange of benzylic hydrogens. An example in the steroid field is the exchange of the benzylic hydrogens in estrone methyl ether (42) with deuterium in the presence of palladized charcoal." " According to mass spectrometric analysis, the product (43) contains three deuteriums (83 %), which have been assigned to the 6- and 9a-positions on the basis of NMR evidence." " ... 

While no examples were encountered in the steroid field which utilize this technique, it is well documented in the case of diterpenes. Ferruginol-3-one (79), for example, gives a hexadeuterio product (80) which after back... 

Homogeneous catalytic deuteration of various unsaturated 5a-spirostane derivatives is an excellent method for the preparation of side chain labeled analogs. Thus, saturation of the double bonds at positions 20(21), 23 and 24 provided the corresponding deuterated compounds (144), (145) and (146) in high isotopic purity. The preparation of (146) is a rare example of the saturation of an isolated trisubstituted double bond in the steroid field. 

The most common leaving groups are sulfonate esters and halides. For the sake of convenience, the discussion of certain dehalogenation reactions is also included in this section even though they may not involve 8 2 type displacement. Benzylic alcohols are also known to be displaced by hydrides or deuterides, but there is no evidence for the application of these reactions to the steroid field. 

There are three methods which are commonly used in the steroid field to replace a halogen atom by deuterium. These methods involve treatment of the halides— generally chloride, bromide or iodide—(a) with lithium aluminum deuteride, (b) with deuterium gas and a surface catalyst or (c) with zinc in O-deuterated acids or alcohols. 

Displacement of aromatic halogen in 2,4-diiodo-estradiol with tritiated Raney nickel yields 2,4-ditritiated estradiol. Aromatic halogen can also be replaced by heating the substrate with zinc in acetic acid-OD or by deuteration with palladium-on-charcoal in a mixture of dioxane-deuterium oxide-triethylamine, but examples are lacking for the application of these reactions in the steroid field. Deuteration of the bridge-head position in norbornane is readily accomplished in high isotopic purity by treatment of the... 

The most frequently encountered examples of cyclopropyl ring opening reactions in the steroid field are usually associated with angular or side chain methylation sequences. In fact, isotope labeling of the C-19 angular methyl group is the only reported application of this reaction for deuteration or tritiation pui poses. 

The modification and enhancement of biological activity of drugs and hormones by fluorination represent one of the most fruitful recent developments in medicinal chemistry. Its first successes and most interesting subsequent developments were in the steroid field. Almost every new technique of introducing fluorine into organic compounds has been applied in this area and, as a result of both the gross and subtle chemical differences which steroids display at different locations of the nucleus, has produced a wealth of new chemistry. 

The observation by Yarovenko and Raksha " in 1960 that diethyl (2-chloro-1,1,2-trifluoroethyl) amine (hereafter called fluoroamine ) could replace hydroxyl groups by fluorine was first applied in the steroid field byAyer and Knox and co-workers. These workers found that a methylene... 

The photochemical addition of trifiuoroiodomethane to unsaturated systems has been thoroughly investigated by Haszeldine. Little use has been made of this reaction in the steroid field. Irradiation of the enol ether (64) in trifiuoroiodomethane containing pyridine in a quartz vessel furnishes in 60 %... 

It is hoped that these volumes will be useful not only to the chemist who wishes to carry out synthesis in the steroid field, but also to the broader group of organic chemists who are interested in carrying out selective and stereo-chemically defined reactions, as well as protective chemistry on extraneous functional groups, during a broad range of synthetic applications. The chapter on the introduction of deuterium and by inference tritium into steroids was included because of the importance of this technique in mechanistic and metabolic studies both in the steroid and nonsteroid field. 

The first substance examined in the steroid field was 3j6-hydroxycholest-4-ene (1) and the epimeric 3a-alcohol (3). These compounds react stereospecifically in dry ether with the Simmons-Smith reagent to yield the isomeric cyclopropyl carbinols (2) and (4) in 90 % and 67 % yields, respectively. The rate of this reaction is about one fifth of that observed with simple cyclic car-binols. ... 

The resulting radical and/or cationic species (11) and (12) can then lead to rearrangements which have found interesting applications in the steroid field. 

The first, and to this writing still only case of a ketone a-cleavage-recombi-nation sequence in the steroid field was reported by Butenandt, who found that 17-ketones epimerize at C-13. Ultraviolet irradiation of either stereoisomer produces an equilibrium mixture in which the thermodynamically more favored 13a-compound cf. (15)] with cw-fusion of rings C and D predominates at room temperature. As ultraviolet absorption energies and intensities of the two isomeric ketones are practically identical, the equilibrium composition depends largely on the rate of the competing recombination process from (14). For further examples of the photoisomerization at C-13 of 17-ketosteroids, see ref. 8, 12, 15 and 43. 

A common feature of the reactions in this section is that they serve to introduce functionality at a position remote from functional groups already present. As such, they have proved very useful in synthesizing many compounds, especially in the steroid field (see also 19-2 and 19-14). When N-haloamines in which one alkyl group has a hydrogen in the 4 or 5 position are heated with sulfuric acid, pyrrolidines or piperidines are formed, in a reaction known as the Hofmann-Loffier reaction... 

Other synthetic applications of the Barton reaction in the steroid field follow[Pg.263]

The photochemical cleavage of organic nitrites 224), also known as Barton reaction, has been widely utilized in the steroid field. The mechanistic sequence as described in (2.14) consists of ... 

Ethoxycarbonyl chloride is, by virtue of resonance involving the ester function, less reactive than acetyl chloride, and the reagent has found application for selective O-acylation in the steroid field.34 With this reagent, methyl 4,6-O-benzylidene-a-D-glucopyranoside yielded35 2- and 3-esters in the ratio 24 1, and the related benzyl-thiocarbonyl chloride gave the 2-ester in 58% yield.36... 

Much activity is evident in the application of enzymes in synthetic and natural products chemistry (9-26). Surprisingly, this is not a new field of endeavor, but rather one that was extensively developed for application in solving synthetic chemical problems in the steroid field. The earliest work in this field took place during the early twentieth century, and serious industrial application of biocatalysis began in the late 1940s (8). The successes obtained in steroid chemistry clearly underlined the potential for biocatalysis to contribute in other areas of natural products chemistry including that with the alkaloids. 

Bhacca, NS and DH Williams, Applications of NMR-Sectroscopy in Organic Chemistry, Illustrated from the Steroid Field, San Fransisco, Prentice-Hall, 1964. 

Configurational match/mismatch governs these reactions so that different products may be produced in high yield and selectivity when enantiomeric catalysts are apphed to the same substrate [61, 62], as illustrated by the reaction processes in Scheme 15.8 [61]. Additional examples in the steroidal field have also been reported [66]. In these cases the formation of four-membered ring y9-lactones is common. 

The marked stereoselectivities and clean solid-state reactions of oxiranes were used for synthetic purposes in the steroid field. The stereospecifically obtained trans-chlorohydrins 147 ensue quantitatively from the crystalline 5a,6a-epoxides 146 with gaseous HCl [77]. Similarly, the crystalline 16a,17a-epoxide 148 reacts with gaseous HCl to yield exclusively the traws-chlorohydrin 149 which easily loses HCl to re-form the starting epoxide 148. Therefore, an equilibrium situation is reached in that case [77] (Scheme 16). 

Steroids a) N. S. Bhacca, D. H. Williams, Applications of NMR Spectroscopy in Organic Chemistry. Illustrations from the Steroid Field, Holden-Day, San Francisco 1964. 

In the steroid field, it has been shown that O-trimethylsilyl derivatives may be converted directly into trifluoroacetates,192,193 and the relative merits of these two derivatives for the separation of glycols have been discussed.194... 

To date, the major synthetic achievements in the application of the Barton reaction have been in the steroid field, particularly with compounds involving functionalization of Cw and C19. In principle, Ci can be attacked from an alkoxy radical at C20, C , Cu, or Cu and Cu from an alkoxy radical at Cn, C6, C4, or C2 (six-membered transition-state requirement). 

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