Enones protection

S-(Trimethylsilyl)-ketones may be converted into a,j8-unsaturated ketones by bromination and desilylbromination since silyl-lithium reagents add to the /3-position of a,/8-unsaturated enones protection of the enone system can be effected in this manner. ... 

Regiocontrolled q- or / -alkenylation and arylation of cyclic enones are possible without protection of the ketone by applying the coupling reaction of the Q- or /3-halo enones 607 and 608 with aryl and alkenylzinc reagents[468,469]. 

Since this original synthesis, a great number of improvements (191—201) have been made in the stereoselective preparation and derivatization of the CO-chain precursor, in cuprate reagent composition and preparation, in protecting group utilization, and in the preparation and resolution of hydroxycyclopentenones. Illustration of some of the many improvements are seen in a synthesis (202) of enisoprost, a PGE analogue. The improvements consist of a much more efficient route to the enone as well as modifications in the cuprate reactions. Preparation of the racemic enone is as follows ... 

A further improvement in the cuprate-based methodology for producing PGs utilizes a one-pot procedure (203). The CO-chain precursor (67) was first functionalized with zirconocene chloride hydride ia THF. The vinyl zirconium iatermediate was transmetalated direcdy by treatment with two equivalents of / -butyUithium or methyUithium at —30 to —70° C. Sequential addition of copper cyanide and methyUithium eUcited the /V situ generation of the higher order cyanocuprate which was then reacted with the protected enone to give the PG. 

Ethoxy-l,3-dioxolane, pyridinium tosylate (PPTS), benzene, heat, 8 h, 89% yield. In this case protection of an enone proceeds without olefin isomerization. 

This protective group was used to direct the selective cyclopropanation of a variety of enones. Hydrolysis (HCl, MeOH, H2O, it, 94% yield) affords optically active cyclopropyl ketones. 

The 17a-ethynyl compound (59) has been prepared in 88% yield from estr-4-ene-3,17-dione (58) and acetylene, at 2-3 atm pressure in tetrahydro-furan in the presence of potassium t-butoxide. Presumably the A-ring enone system is protected as the enolate anion during the course of the reaction. 

Use of the imonium group for protection of enones was explored. Stability to peracids, lead tetraacetate, bromine, and acetic anhydride was claimed (727). The usual resistance of enamines (but not their salts) to additions of Grignard reagents was used for selective addition to a 3,17-diketosteroid by formation of the usual 3-monoenamine 728). 

Ethyl-2-methyl-l,3-dioxolane/TsOH, reflux, 75% yield."" " These conditions selectively protect a ketone in the presence of an enone. 

The use of enamines as protective groups seems largely to be confined to steroid chemistry, where they serve (in their protonated form) to protect the A-B enone system from bromination and reduction. A large body of literature exists on the preparation and chemistry of enamines, which are easily hydrolyzed with water or aqueous acid. 

This section contains alkylations of ketones and protected ketones, ketone transpositions and annulations, ring expansions and ring openings and dimerizations. Conjugate reductions and Michael alkylations of enone are listed in Section 74 (Alkyls from Alkenes). 

Some insect pheromones are internal ketals. We have already mentioned multistriatin (pp T 2 and 99) and frontalin p 193). Brevicomin (22) is another example. Disconnection of the ketal gives (23) containing a 1,2-diol. Among other syntheses, hydroxy-lation of protected enone (24) by epoxidation and acid catalysed rearrangement gives brevicomin stereo-specifically,... 

Chemo- and stereoselective reduction of (56) to (55) is achieved In highest yield by sodium borohydride in ethanol. The isolated ketone is reduced more rapidly than the enone and (55) is the equatorial alcohol. Protection moves the double bond out of conjugation and even the distant OH group in (54) successfully controls the stereochemistry of the Simmons-Smith reaction. No cyclopropanation occurred unless the OH group was there. Synthesis ... 

Enones and enoates undergo 1,2-reduction [115, 191]. Lipshutz et al. reported the effective protection of carbonyl functions by the triisopropylsilyl acyl silane group (TIPS), which allowed the selective conversion of alkenes or alkynes to the corresponding zirconocene complexes [24]. The aldehyde could subsequently be regenerated by desilylation with TBAF [186]. 

The protection of the hemiacetal hydroxyl in Step B-2 was followed by a purification of the dominant stereoisomer. In Step C-l, the addition of the C(6) methyl group gave predominantly the undesired a-stereoisomer. The enolate was trapped as the trimethylsilyl ether and oxidized to the enone by Pd(OAc)2. The enone from sequence C was then subjected to a Wittig reaction. As in several of the other syntheses, the hydrogenation in Step D-2 was used to establish the configuration at C(4) and C(6). 

Dehydration of cortisone (198) affords the diene 199. This is then converted to ketal 200. The selectivity is due to hindrance about both the 11- and 20-carbonyl groups. The shift of the double bond to the 5,6-position is characteristic of that particular enone. Treatment of protected diene 200 with osmium tetroxide results in selective oxidation of the conjugated double bond at C-16,17 to afford the cis-diol (201). Reduction of the ketone at C-ll (202) followed by hydrolysis of the ketal function gives the intermediate 203. Selenium dioxide has been... 

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