Cholesterol, tosylate

Heteroatoms are not the only groups that will facilitate an SnI reaction when in proximity to the cationic center. Resonance effects in allyl or benzyl carbenium ions stabilize the cationic center and hence facilitate the substitution reaction. Yet, n systems further away from the cationic center can also get involved if their geometry is such that they are oriented toward the carbenium ion s empty p orbital. Consider the solvolysis of cholesterol tosylate in Figure 11.7. Two products are formed, and the solvolysis rate is approximately 100 times... 

The concept of a stable mesomeric cation cannot be inferred solely from kinetic results, but follows from analysis of reaction products, and studies of the reactions of "i-cholesterol and its derivatives. Most important was the demonstration by Winstein [35] that identical product mixtures are produced by the methanolysis of either cholesteryl tosylate or 6 trichloroacetoxy-3a,5a-cyclocholestane (15 X O-COCCls), from which it was argued that these steroids solvolyse through a common cation. Furthermore i-cholesteryl methyl ether (15 X = OMe) is converted by absolute ethanol into a mixture of i-cholesteryl ethyl ether (15 X — OEt) and cholesteryl ethyl ether [36]. i-Cholesteryl acetate (15 ... 

DimethyIcholesteryi tosylate (26 solvolyses [46,48] at a rate intermediate between the 4 a- and4jS-methyl compounds, the products being explained in terms of a cation (27) in which C(4) bears a major part of the change by virtue of its tertiary character. The formation of the A-nor-diene (28) can then proceed by complete rupture of the 4,5-bond, with loss of the C(3)-proton, whilst the major alcoholic product (29) arises from attack of a water molecule on the electron deficient C<4). Although 4,4-dimethyl-i cholesterol was not obtained directly... 

The "symmetrical ion (B), corresponding most nearly to the accepted symmetrical structure of the cyclopropylcarbinyl or bicyclobutonium cation (4) [22], represents delocalisation of the 4,5-bonding electrons as well as the sr-electrons. In its extreme form, 4,5-bond delocalisation is represented by the "unsymmetrical structure (C). Recent work indicates that structures involving 4,5-bond delocalisation may be important. Whitham [43] found that cholesteryl tosylate and 3jS-hy-droxymethyi A-norcholest-5-ene tosylate i8) solvolyse in buffered aqueous acetone to give i-cholesterol and cholesterol... 

Rearrangement during solvolysis of the tosylate ofa 4-hydroxymethyl-4-methyl-3-oxo-steroid is discussed on p. 276. Simultaneous contraction and expansion of adjoining rings affords some curious products when cholesterol reacts with lead tetra-acetate and hydrogen fluoride (p. 258). The 12 ff-hydroxyconanine mesylate... 

Of the activated alcohols described in Section 1.1.2.S.1, alkyl sulfonates ate convenient alkylating re-agents because they can be readily prepared and handled. The correct choice of sulfate-alcoholate combination is often crucial for successful ether synthesis. Thus, for the preparation of cholesteryl ethers from the tosyl derivative of cholesterol and alkoxides, the reaction must be carried out at 110 °C for 2.S h in a sealed tube. Alternatively, the sodium salt of cholesterol can be reacted with an alkyl mesylate at 80 °C for 1 h in DMF to give the corresponding ether in 62-68% yield. ... 

Selective removal of bromine from 3/3,5,6/3-tribromo-5a-cholestane to give 3/3-bromocholest-5-ene was achieved by reaction with [T -C5H5Cr(N02)2]2. The reactions of 11/3-hydroxy-steroids with dialkylaminosulphur trifluorides depend on the substitution at C-9 and involve the formation of intermediate (11) (Scheme 1) (see ref. 232). Selective dehydration with FeCls adsorbed on silica gel allowed the conversion of 5a-cholestane-3/3,5-diol into cholesterol (80%) and 3i3-acetoxy-5a-cholestane-5,25-diol into 3/S-acetoxycholest-5-en-25-ol (72%). Other examples and additionally the hydrolysis of 5,6a-epoxy-5o -cholestan-3/3-ol to the 3/3,5a,6/8-triol (90%) were reported. Chromatographic alumina is reported to effect smooth elimination of sulphonic acids from the esters with less than normal rearrangement. Thus lanosteryl tosylate and cycloartenyl tosylate gave the respective A -compounds in yields of 90% and 45% respec-... 

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). 

A coned, soln. of cholesteryl tosylate in tetrahydrofuran injected under Ng into a stirred soln. of 6 equivalents Na-naphthalene prepared from Na and naphthalene in dry tetrahydrofuran, after a few sec. when the disappearance of the green color indicates completion of the reaction a small amount of water added to convert the alkoxide salt to the alcohol cholesterol. Y 95%. — No epimeriza-... 

Primary tosylates are more prone than bromides to form f-butyl ethers by Sn2 displacement by the f-butoxide anion in DMSO. Sulfonate esters of flexible cyclic and secondary acyclic alcohols give predominately alkenes in the presence of f-BuOK/DMSO. With sulfonate esters of 3-hydroxy steroids, there is competition between /S-elimination and attack of the f-butoxide ion on sulfur to form alcohols mesylates are more prone to this reaction than tosylates. Sulfonate esters of 3a-acetoxy-12a-hydroxycholanate undergo mainly /3-elimination with f-BuOK/DMSO (eq 4). In this case, substitution of various other aprotic solvents for DMSO and DMSO Na+ for f-BuOK was not as effective. Treatment of both the mesylate and the tosylate of cholesterol with f-BuOK/ DMSO gives the conjugated diene, 3,5-cholestadiene, in high yield. ... 

Tosyl cholesteryl acetate (V) (Akhtar and Barton, 1964) was first converted to the corresponding 19-iodide (VI) by treatment with sodium iodide in boiling ethyl methyl ketone. Reduction of the iodide with zinc and acid in the presenee of tritiated water provided cholesteryl acetate-19-H (VII) which was then converted to 7-dehydro-cholesterol-19-H (VIII), presxunably via the N-bromosuccinimide reaction. Ultraviolet irradiation and thermal rearrangement of the provitamin yielded cholecalciferol-9,19-H (IX). 

Tosylation with Retention of Stereochemistry. Although dihydrocholesterol (2) undergoes clean tosylation with inversion in 88% yield using the procedure described above, cholesterol (3a) itself gives an 85% yield of the 33-tosylate (3b). 

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