Steroids, silylation

Corticosteroids. Upjohn chemists have devised a new synthesis of corticoids from 17 5-cyanohydrins (2), readily available from 17-keto steroids. Silylation of the cyanohydrin 2 with 1 provides the silyl ether 3, which on treatment with LDA... 

Ketones cannot be directly fluorinated by (difluoroiodo)arenes however, a-fluoroketones can be prepared by the reaction of silyl enol ethers with difluoroiodotoluene in the presence of BF3 OEt2 and the Et3N-HF complex [22], Some steroidal silyl enol ethers can be converted into the respective a-fluoroketones in a moderate yield [23]. 

In addition, a number of steroidal silyl enol ethers and enol esters have been selectively fluorinated by Selectfluor, as shown below ... 

Iodotoluene difluoride reacts with steroidal silyl enol ethers to give a-fluoro-ketones. Whilst the reaction is slower than with xenon difluoride, the rea nt may find use since the stereochemical outcomes of the reactions differ, suggesting an electrophilic mechanism for the latter reagent, but a nucleophilic mechanism (via an iodonium intermediate) for the iodo-arene derivative. 

Another preparative method for the enone 554 is the reaction of the enol acetate 553 with allyl methyl carbonate using a bimetallic catalyst of Pd and Tin methoxide[354,358]. The enone formation is competitive with the allylation reaction (see Section 2.4.1). MeCN as a solvent and a low Pd to ligand ratio favor enone formation. Two regioisomeric steroidal dienones, 558 and 559, are prepared regioselectively from the respective dienol acetates 556 and 557 formed from the steroidal a, /3-unsaturated ketone 555. Enone formation from both silyl enol ethers and enol acetates proceeds via 7r-allylpalladium enolates as common intermediates. 

The reaLUons of phenyltetrafluorophosphorane with numerous silylated secondary or tertiary a- or (1-hydroxy esters, ketones, nitriles, ethers, nitro, and trichloromethyl derivatives have been investigated, the corresponding a or p fluoro derivatives are obtained in yields varying from reasonable to nearly quantitative [24, 25, 26, 27 The application of phenyltetrafluorophosphorane for fliiorination of silyloxy steroids has also been reported [28]... 

DIRECT SYNTHESIS FROM N-SILYL-PHOSPHORAMINES CARBORANYL DERIVATIVES BIOACTIVE AND BIOERODABLE POLYMERS (STEROIDS, DOPAMINE, PROCAINE, ETC.)... 

Vollhardt118) employed the organocobalt-promoted reaction between Wjftrimethyl-silyl)acetylene (322) and the diyne (338) to construct the steroid estrone 118). 

Most of the more recently described allenic steroids bear an allene group at the 17-position, which was usually formed by an SN2 substitution [106] or reduction [86d] process of a suitable propargylic electrophile. Thus, reduction of the pro-pargylic ether 109 with lithium aluminum hydride followed by deprotection of the silyl ether resulted in the formation of the allenic steroid 110, which irreversibly inhibits the biosynthesis of the insect moulting hormone ecdysone (Scheme 18.35) [107]. 

The addition of (TMS)3SiH in the 3-oxo-l,4-diene steroid-type derivative promoted C(9)—C(10) bond cleavage (Reaction 7.68) [79]. The removal of the silyl group was achieved by treating with dilute aqueous hydrochloric acid at room temperature and the final product was obtained in an 85 % yield. 

Yang L, Luan T, Lan C (2006) Solid-phase microextraction with on-fiber silylation for simultaneous determinations of endocrine dismpting chemicals and steroid hormones by gas chromatography-mass spectrometry. J Chromatogr A 1104 23-32... 

Polyene cyclization in terpene and steroid synthesis is critically dependent on the terminator in order to generate useful functionalities for further modification of the products. Allyl- and propargylsilanes have proven their value in facilitation of the cyclization and generation of an exocyclic methylene and allene, respectively. Thus, a concise approach to albicanyl acetate [126] and the rapid construction of a tetracyclic precursor of steroids [127] are sufficient to demonstrate the concept. Again, a comparison of the substrates with a silyl group with those having a simple alkyl moiety is very enlightening. 

While fluoroxy compounds react well with enol derivatives, fluorine in general does not. However, there are various reports where such reactions are described and in certain cases even with decent yields. In 1982 it was reported that pyruvates with a dominant enolic form react well with fluorine, to give the corresponding fluoro derivatives l.78 Several silyl enol ethers 2 and 379 including ones made from 1,3-dicarbonyl derivatives 480 react quite satisfactorily with fluorine to give the expected a-fluoro ketones. Steroidal 16-enol acetates react with fluorine to form mainly 16a-fluoro-17-oxo steroids e.g. 5.81... 

Fluoropyridinium triflate (la) exhibits high selectivity in fluorinations. In a steroid 8 with two reaction sites, a conjugated and a nonconjugated vinyl acetate moiety, 1-fluoropyridinium triflate (la) reacts at the conjugated site only. On the other hand, steroid 9 with a silyl enol ether and a conjugated acetate moiety affords the product resulting from reaction at the former site only.44,52... 

Treatment of the silyl enol ether 23 with 1-fluoropyridinium triflate (la) gives the 14a- and 14/i-fluoro steroid C/D-ring ketones.61,62... 

F-Teda BF4 (6) is very effective for the fluorination of a wide variety of organic substrates steroidal enol acetates (Table 7)92 and silyl enol ethers, certain carbanions, mildly activated aromatic compounds, and sulfides bearing oc-H atoms.73,75,76,77,84,88 90 The products are obtained with good yields and regioselectivity under very mild reaction conditions (Table 8). 

F-Teda BF4 is effective for the selective addition of fluorine to steroids in good yield, re-gioselectively and, in many cases, stereoselectively at the 6- and 16-positions, under very mild reaction conditions (Table 7).92 Further, 6 will also efficiently fluorinate silyl and alkyl enolates, enamides, carbanions, a-alkenes and actived aromatic compounds (Table 8). As an extension of this method F-Teda BF+ has been used for the electrophilic fluorination of (fluorovinyl)tin compounds affording terminal fluoroalkenes (see Table 9).88... 

Cleavage of t-butyldimethylsilyl ethers.1 The silyl ethers of primary and secondary steroidal alcohols arc converted to the alcohols by LiBF4 in CHjCN-CH2C12 (yields 70-85%). 

An enantioselective synthesis of (+)-estradiol has been accomplished from 1,3-dihy-drobenzo[c]thiophene 2,2-dioxide (306) by successive thermal S02-extrusion and cycloaddition (80HCA1703). Treatment of the optically active iodide (307) with two mole equivalents of the masked quinodimethane (306) in the presence of two mole equivalents of sodium hydride gave (308) as a 1 1 mixture of diastereoisomers. Thermolysis of this alkenic sulfone in 1,2,4-trichlorobenzene furnished the trans-anti-trans steroid (309) in 80% yield. Treatment of (309) with methyllithium gave the methyl ketone, which was subjected to a Baeyer-Villiger oxidation and then silyl ether-acetate cleavage to afford (-l-)-estradiol (310 Scheme 66). 

Removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a silyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. Other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol Besides the aforementioned A-ring aromatic steroids and contraceptive agents, partial synthesis from steroid raw materials has also accounted for the vast majority of industrial-scale steroid synthesis. 

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