Thioketals synthesis

AHylestrenol (37) is prepared from (32), an intermediate in the synthesis of norethindrone. Treatment of (32) with ethanedithiol and catalytic boron trifluoride provides a thioketal. Reduction with sodium in Hquid ammonia results in the desired reductive elimination of the thioketal along with reduction of the 17-keto group. Oxidation of this alcohol with chromic acid in acetone followed by addition of aHyl magnesium bromide, completes the synthesis... 

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

A eommon approaeh starts with a proteeted 1,4-diearbonyl and unmasks the requisite earbonyl using aeid, thus faeilitating the Paal-Knorr reaetion immediately upon deproteetion. For example, Nagai used sulfurie aeid to eonvert aeetal 77 into 2,4-disubstituted furan 78 albeit in low yield.Molander produeed a different 2,4-disubstituted furan by a similar strategy. Thioketal aeetal 79 was treated with mereury(II) ehloride and furnished furan 80 in 71% yield. Thus this strategy provides a useful approaeh for the synthesis of a variety of 2,4-disubsituted furans. 

Addition to thionolactones cyclic ethers. A wide variety of alkyliithium reagents add to the C=S group of thionolactones. The adducts, after reaction with CH,I, can be isolated in high yield as mixed methyl thioketals. The methylthio group can be removed by reduction with triphenyltin hydride (AIBN) to give cyclic ethers. The reaction is not dependent on the ring size and can be stereoselective, as shown by the synthesis of the ether lauthisan (2) from a thionolactone (1). 

To achieve this synthesis, the methanal first is converted to a thioketal, which then is partially oxidized to give 13. Treatment of13 witha strong base converts it to the carbanion, which can be readily alkylated. By using 1,3-dibromopropane and two equivalents of base, a double displacement forms the cyclic product, 14. The sulfur groups of 14 can be removed easily by acid hydrolysis to give cyclobutanone ... 

This reaction is widely utilised in organic synthesis, when carbonyl groups may be protected as the thioacetals or thioketals. Unlike acetals or ketals, the thio compounds do not undergo acid catalysed hydration, and may be used in acidic reaction conditions. The metal-directed hydrolysis is rationalised in terms of the soft-soft interaction of the sulfur with the metal cation, in contrast to the hard-soft interaction with a proton. Hydrolysis is readily achieved on treatment with aqueous mercury(n) or silver(i) salts. Once again, the... 

The total synthesis of ( + )-Erysotramidine (2) has been described by Ito et al. (137) starting from the amide (174) (Scheme 39). After O-mesylation to 177, base-catalyzed reaction gave the cyclopropane derivative (178) which with zinc in acetic acid was reduced to 179, which was identical to the product (135) of O-methylation of 172. Conversion of 178 to the thioketal (180) was followed by reaction with phenylselenyl chloride. A mixture of two compounds, 181 and 182, was produced the former could be transformed quantitatively to the latter. Finally, treatment of 182 with silver nitrate in methanol gave 183, which was then desulfurized to yield erysotramidine (2). 

In addition to developing a facile route to the synthesis of thioacetals and thioketals, optimization of the reagents residence time within the packed bed enabled the authors to demonstrate the chemoselective protection of aldehydic functionalities in the presence of ketonic moieties (Scheme 34). 

Combination of microbiological chemistry, often yielding scaffolds not easily obtained by purely chemical means, and combinatorial chemistry, enabling rapid and efficient synthesis of analogs, provides a valuable tool for generation of novel test compounds. As an example [24] we describe here the application of our lipoic acid-derived thioketal linker [25] to the solid-phase synthesis of A4-3-keto steroidal ureas from / -sitosterol. 

Other means of improving sulfide yields in the reaction of halides with thiolates are (1) the use of thiols and platinum(II) complex catalysts287, (2) the generation of thiolate anions by electrochemical means288 and (3) the use of phase-transfer conditions237. The first method has been used for the synthesis of thioketals from geminal diiodides and the third has been used for the conversion of gem-dichlorocyclopropanes into cyclopropane thioketals, which are effectively masked cyclopropane moieties. 

Cyclopropanonephenyl thioketals. A typical new one-step synthesis is shown in equation (III). ... 

The reduction of carbonyl compounds to hydrocarbons may be achieved under acidic conditions e.g. the Clemmensen reduction with zinc and concentrated hydrochloric acid), basic conditions (e.g. the Wolff-Kishner reduction of a hydrazone with alkali) or neutral conditions (e.g. the catalytic reduction of thioketals with Raney nickel). The carbonyl group may represent the residue from an earlier step in the synthesis of a compound. 

The use of diphenylcyanomethylphosphine oxide is effective for the synthesis of ( )-a,3-unsaturated nitriles. ° Phosphine oxides can bis used to synthesize a variety of functionalized alkenes, including vinyl ethers (215 equation 51), ° vinyl sulfides (217 equation 52), ° allylic amines (219) and amides (equation 53), " ketene acetals (221 equation 54) and ketene thioketals (223 equation In the examples of a-thio substitution, the alkenes are formed directly. 

West and Naidu found that the diazoketone 358, prepared by alkylating the benzyl ester of L-proline with 5-bromo-l-diazopentan-2-one, cyclized to give a transient spirobicyclic ammonium ylide 359 when heated with coppeifll) acetylacetonate in toluene (Scheme 44) (355,356). This unstable ylide underwent a diastereoselective [1,2]-Stevens rearrangement to give the quinolizidinone 360 and its bridgehead epimer in a ratio of 95 5. However, some racemization (possibly through an achiral diradical intermediate) must have occurred, since 360 had an ee of only 75%. Reduction of the ester and defimctionalization of thioketal 361 with the unusual combination of sodium and hydrazine in hot ethylene glycol completed a synthesis of the unnatural (- )-enantiomer of epilupinine (ent-331). 

The synthesis of verazine [(25S)-22,26-epiminocholesta-5,22(iV)-dien-3/3-ol)] (95) from tomatid-5-en-3/S-ol was described [64-66). Reduction of 86 with sodium borohydride in methanol afforded diol 87 which, when acetylated, furnished the iV,0,C>-fn-acetate (88). Alkaline hydrolysis of 88 yielded the diol 89. Through partial oxidation with one equivalent of chromium trioxide, the A-acetyldiol (89) gave the ketone 90. Treatment of this ketone with ethanedithiol—hydrochloric acid, followed by desulfurization of the resulting thioketal 91 with Raney nickel, yielded 92. 

Verazine (37) has been the subject of a formal total synthesis (Scheme 1) based on the earlier reported versatile syntheses of solanidine and tomatidenol. As in the earlier work, Michael addition of the anion of the configurationally pure nitro-ester (30) to (29) gave the C-22 epimeric mixture (31), from which the individual diastereomers were isolated after acetylation. The (22S)-acetate (32) was converted via thioketal (34) and lactam (35) into the piperidine derivative (36). Base treatment of the N-chloro-derivative of (36) then gave verazine (37). 

The synthesis of the CD segment 532 also started with dithiane 525. One-pot unsymmetric bisalkylation of 525 with 523 and 524 also effectively afforded coupling product 529, after methylation. Deprotection of TBS and acetonide followed by dethioketalization afforded a 2 1 mixture of 530 and 531. Treatment of 530 with HCIO4 effected epimerization to 531. Functional group manipulation converted 531 to iodide 532, which was coupled with thioacetal 533, prepared by Roush asymmetric crotylboration, to give adduct 534. The thioketal 534 was converted into 535 via reduction of ketone (dr = 1 3.5) and introduction of a phenyl-sulfone group. 

For synthesis of the trans N-Boc enantiomer 70, use was made of the chiral ketone 66, which is readily available by enzymatic resolution [91]. The ketone moiety was protected as the thioketal, and selective monohydrolysis then gave the monoacid 68. Curtius rearrangement of 68 with diphenylphosphorylazide (DPPA) and triethylamine (TEA) in tert-butanol gave the Boc-protected amine. Desulfurization with Raney nickel furnished the methyl ester 70 (Scheme 10). The (15,25) trans enantiomer was prepared analogously, starting from the enantiomer of ketone 66 [91]. 

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