Sulfones reductive removal

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

In contrast cyclic y-(rey/-butyldimethylsilyloxy)-a,/ -unsaturated sulfones undergo addition of organometallic reagents to give mainly trans-adducts after reductive removal of the sulfonyl group. 

Several refractory thiophenes, that are often not reductively removable by conventional refining processes, can be oxidized under these conditions, e.g. benzothio-phenes are oxidized to the corresponding sulfoxides and sulfones using ultrasonic and microwave irradiation, respectively, in the presence of NaI04-silica [109]. A noteworthy feature of the procedure is its applicability to long chain fatty sulfides that are insoluble in most solvents and are consequently difficult to oxidize. 

A more recent synthesis of 197 [365] is shown in Fig. 9. Enders introduced the stereogenic centre of (S)-lactic acid into the crucial position 10 in 197. The vinylsulfone B, readily available from lactic acid, was transformed into the planar chiral phenylsulfonyl-substituted (q3-allyl)tetracarbonyliron(+l) tetra-fluoroborate C showing (IR,2S,3 )-configuration. Addition of allyltrimethyl silane yielded the vinyl sulfone D which was hydrogenated to E. Alkylation with the dioxolane-derivative of l-bromoheptan-6-one (readily available from 6-bro-mohexanoic acid) afforded F. Finally, reductive removal of the sulfonyl group and deprotection of the carbonyl group furnished 197. A similar approach was used for the synthesis of 198 [366]. 

A further eight steps were required to convert the cyclopentanone 52 into the sulfone 59 that was deprotonated and treated with an allylic bromide (60) to afford the alkylated sulfone 61 (Scheme 7). The sulfone moiety and the benzyl ether protecting group were reductively removed in a one-pot procedure to afford a mono-protected diol (62). 

The sulfone moiety was reductively removed and the TBS ether was cleaved chemoselectively in the presence of a TPS ether to afford a primary alcohol (Scheme 13). The alcohol was transformed into the corresponding bromide that served as alkylating agent for the deprotonated ethyl 2-(di-ethylphosphono)propionate. Bromination and phosphonate alkylation were performed in a one-pot procedure [33]. The TPS protecting group was removed and the alcohol was then oxidized to afford the aldehyde 68 [42]. An intramolecular HWE reaction under Masamune-Roush conditions provided a macrocycle as a mixture of double bond isomers [43]. The ElZ isomers were separated after the reduction of the a, -unsaturated ester to the allylic alcohol 84. Deprotection of the tertiary alcohol and protection of the prima-... 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolare (29) to the scalemic sulfoxide (30). Direct treatment of the crude Michael adduct with mew-chloroperbeuzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (31) X — a and ftH R = H in over 90% yield. 

Tips In the first step, a sulfone group is reductively removed with the... 

In the previous subsection, it was shown that the Ferrier reaction offers an opportunity to convert glycal derivatives into unsaturated sugar derivatives, which have an isolated double bond between C(2) and C(3). The Tipson-Cohcn reaction is another important reaction for the introduction of isolated double bonds.29 In this procedure, a cis or tram diols are converted into disulfonates (mesylates or tosylates) which are reductively eliminated with sodium iodide and zinc in refluxing DMF (Scheme 3.6a). In this reaction, the C(3) sulfonate is substituted by an iodide, which then is reductively removed by zinc with concomitant elimination of the second sulfonate moiety, introducing a double bond. Stereoelectronic effects make nucleophilic substitutions at C(3) more favourable than similar reactions at C(2) (see Section 3.2.3). Probably, the elimination proceeds through a boat conformation. In this case, the iodide and tosylate are in a syn relation. In most cases, E2 elimination proceeds via a transition state involving an anti orientation. Nevertheless, syn elimination becomes the dominant mode of reaction when structural features prohibit an anti orientation. 

Mulzer (Scheme 8 upper left) obtained the a,/(-unsaturated ester 33 with Z configuration from aldehyde 26a via a Still-Gennari olefination with phosphonate ester 34. Reduction of the ester with DIBAH and application of L-imidazole-PPhj gives allylic iodide 35. This acts as electrophile on the -anion of sulfone 36. After reductive removal of the phenylsulfone, group 28b is obtained [23]. 

Sodium borohydride reduction offers a significant advantage in synthetic applications. The method allows the reductive removal of halides selectively without affecting other functional groups, such as ester, carboxylic acid, nitrile and sulfone. A typical chemoselective dehalogenation is illustrated in Scheme 19. ... 

Desulfonylation. Various sulfonyl groups are reductively removed by Mg/MeOH. These include alkenyl sulfones, alkyl tosylates, and A -Boc-arenesulfonamides (p-toluenesulfonhydrazides, V-tosylaziridines ). But when the V-tosylaziridine contains an electron-withdrawing group, ring cleavage to give p-(V-tosylamino) derivatives takes precedence to detosylation. ... 

The problem is the sulfone. The trisubstituted alkene in 229 is too hindered. Reductive removal of the sulfone and acylation gave a good metathesis substrate 231 and hence the pyrrolidine... 

The first step when using sulfones in the synthesis of natural products consists of the formation of the new C-C bond. This process is normally performed using the sulfone as a nucleophile via the corresponding a-sulfonyl carbanion. Three different strategies are normally employed alkylation of a-sulfonyl carban-ions followed by reductive removal of the sulfonyl group, acylation of a-sulfonyl carbanions followed by reductive removal of the sulfonyl group, and finally, reaction of a-sulfonyl carbanions with activated multiple bonds followed by reductive desulfonylation. 

By far, the most widely used method is the alkylation of an a-sulfonyl carbanion followed by reductive removal of the sulfonyl group. Different electrophiles such as alkyl halides, sulfonates, sulfinates, acetates, oxiranes, and electron-deficient multiple bonds are employed for the formation of the new C-C bond. Palladium-catalyzed it-allylic alkylation with a-sulfonyl carbanions is also a commonly used method. After the C-C bond formation, the conditions for the final desulfonylation reaction with the appropriate reagent will depend on the structure of the sulfone intermediate. 

Difluoromethyl phenyl sulfone is lithiated by LiHMDS at -78°, and the lithio species attacks cyclic sulfates of 1,2-diols and 1,2-amino alcohols to afford a,a-difluoroalkyl sulfones. The benzenesulfonyl group can be reductively removed (Mg, HOAc, NaOAc) or eliminated to provide 1,1-difluoroalkenes with an allylic OH or NH2 group. 

Scheme 7 Ozonization of alcohol (79) followed by treatment of the ozonide with Me2S afforded hydroxy ketones (80), whose acetate derivatives was converted to indenone (83). Hydroxy ketone (84), prepared from (83) was converted to compound (85), whose acetate on oxidation gave diol (87). Its transformation to butenolide (88) was easily carried out. This on oxidation and reduction produced hydroxy phytuberin lactone (89), which was converted to its sulfonyl derivative. Reductive removal of the sulfonate group yielded the cyclopropane derivative (91), which on subjection to reductive cleavage with lithium in liq. NH3 yielded phyberin lactone (92) and deacetyl phytuberin lactone (93)...

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