Sulfones chemoselective

Scheme 4 outlines the synthesis of key intermediate 7 in its correct absolute stereochemical form from readily available (S)-(-)-malic acid (15). Simultaneous protection of the contiguous carboxyl and secondary hydroxyl groups in the form of an acetonide proceeds smoothly with 2,2 -dimethoxypropane and para-toluene-sulfonic acid and provides intermediate 26 as a crystalline solid in 75-85 % yield. Chemoselective reduction of the terminal carboxyl group in 26 with borane-tetrahydrofuran complex (B H3 THF) affords a primary hydroxyl group that attacks the proximal carbonyl group, upon acidification, to give a hydroxybutyrolactone. Treat-... 

It is interesting to note the chemoselectivity of the reaction double and triple bonds, thioketals, epoxides, nitro and sulfone groups and usual functions are not affected. 

Such a methodology is also useful for the chemoselective functionalization of internal voids of dendrimers. This can be accomplished for example by adding 2 equiv. of allyl, propargyl or phosphonate trifluoromethane sulfonate on the dendrimer of generation 1 71-lGj] (Scheme 34). Functionalization occurs on the sulfur atom of the two P=N-P(S) units with the quantitative formation of the... 

T. Akiyama, J. Iwai, Scandium Trifluoromethane-sulfonate-Catalyzed Chemoselective Allylation Reactions of Carbonyl Compounds with Tetraallylgermane in Aqueous Media Tetrahedron Lett. 1997,38, 853-856. 

With both building blocks 103 and 109 in hand, the total synthesis of lb was completed as shown in Scheme 17. Coupling of acid 103 and alcohol 109 under Yamaguchi conditions to give ester 110 and subsequent desilylation followed by chemoselective oxidation provided hydroxy acid 111. Lactonization of the 2-thiopyridyl ester derived from 111 in the presence of cupric bromide produced the macrodiolide 112 in 62% yield, which was finally converted to pamamycin-607 (lb) via one-pot azide reduction/double reductive AT-methylation. In summary, 36 steps were necessary to accomplish the synthesis of lb from alcohols 88 and 104, sulfone 91, ketone 93, and iodide rac-97. 

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-... 

The oxidation of sulfides to sulfoxides (1 eq. of oxidant) and sulfones (2 eq. of oxidant) is possible in the absence of a catalyst by employing the perhydrate prepared from hexafluoroacetone or 2-hydroperoxy-l,l,l-trifluoropropan-2-ol as reported by Ganeshpure and Adam (Scheme 99 f°. The reaction is highly chemoselective and sulfoxidation occurs in the presence of double bonds and amine functions, which were not oxidized. With one equivalent of the a-hydroxyhydroperoxide, diphenyl sulfide was selectively transformed to the sulfoxide in quantitative yield and with two equivalents of oxidant the corresponding sulfone was quantitatively obtained. 2-Hydroperoxy-l,l,l-fluoropropan-2-ol as an electrophilic oxidant oxidizes thianthrene-5-oxide almost exclusively to the corresponding cw-disulfoxide, although low conversions were observed (15%) (Scheme 99). Deprotonation of this oxidant with sodium carbonate in methanol leads to a peroxo anion, which is a nucleophilic oxidant and oxidizes thianthrene-5-oxide preferentially to the sulfone. 

Very recently, Lattanzi and coworkers reported on the use of enantiomericaUy pure camphor derived hydroperoxide 61 for the Ti(OPr-/)4 catalyzed chemoselective asymmetric oxidation of aryl methyl sulfides (equation 59) . The corresponding sulfoxides could be obtained in moderate yields (39-68%) and ee values up to 51%. The sulfoxidation to the sulfoxides is accompanied by further oxidation of the sulfone (kinetic resolution, yields of sulfone up to 9%). This process is stereodivergent with respect to the sulfoxidation step, which was found for the first time. Although the obtained enantioselectivities for the sulfoxides were only moderate, they proved to be among the best reported at that time with the use of enantiopure hydroperoxides as the only asymmetric inductor. The... 

Sulfur compounds with divalent sulfur functionalities are much more prone to dioxirane oxidation on account of their higher nucleophilicity compared to the above-presented oxygen-type nucleophiles. Examples of this type of dioxirane oxidation abound in the literature. Such a case is the oxidation of thiols, which may be quite complex and afford a complex mixture of oxidation products, e.g. sulfinic acids, sulfonic acids, disulfides, thiosulfonates and aldehydes , and is, therefore, hardly useful in synthesis. Nevertheless, the oxidation of some 9i/-purine-6-thiols in the presence of an amine nucleophile produces n >( -nucleoside analogs in useful yields (equation 19). This reaction also displays the general chemoselectivity trend that divalent sulfur functionalities are more reactive than trivalent sp -hybridized nitrogen compounds P. 

One of the main research interests in this area is to find new oxidizing agents having the highest chemoselectivity to obtain the sulfoxide derivatives without overoxidation to sulfones. 1,4-Oxathiane 18 was often used as a model sulfur-containing compound to afford 82 (Table 2) and 17 similarly gave 83. m-2,6-Dimethyl-l,4-dithiane was oxidized to the... 

Oxidation of sulfides to sulfones.[ Sulfides are oxidized chemoselectively to sulfones by KHSOs (3 equivalents) in high yield. Peracids are usually used for this oxidation, but can also oxidize olefinic groups. Oxidation of sulfides to sulfoxides is also possible with 1 equivalent of reagent. 

A recent method for the highly chemoselective oxidation of sulfides to sulfones using Af-methylmorpholine IV-oxide (NMP) and a catalytic perruthenatc was found to be also applicable in the presence of isolated or allylic double bonds [115]. 

E)-3-Arylidenethiochroman-4-oncs possess thioether and oi,[)-unsaturatcd ketone functionalities both of which are susceptible to oxidation by DMD. In fact, chemoselective oxidation at sulfur is observed with a separable mixture of the sulfoxide and sulfone being produced in >5 1 ratio. A similar situation holds for the related thioflavanones. Epoxidation of the alkenic double bond in the thiochromanone 1,1-dioxides alone can be achieved using methyl(trifluoromethyl)-dioxirane (Scheme 65) <1994T13113>. However, reaction of NaOCl with 3-arylidenethioflavanones gives the epoxide and subsequent oxidation with DMD then gives a mixture of the sulfoxide and sulfone <2003MRC193>. 

In principle, the bases Y are also nucleophiles, and, hence, they can react with the same alkyl halides and sulfonates via the SN2 mechanism. The point of reaction is the C atom that bears the leaving group. In order to carry out E2 eliminations chemoselectively, competing Sn2 reactions must be excluded. To understand the outcome of the competition (E2 elimination vs. Sn2 reaction), it is analyzed kinetically with Equations 4.1-4.3. 

Table 4.1 gives the chemoselectivity of E2 eliminations from representative bromides of the type Rprim—Br, Rsec—Br, and Rten—Br. The fraction of E2 product increases in this sequence from 1 to 79 and to 100% and allows for the following generalization E2 eliminations with sterically unhindered bases can be carried out chemoselectively (i.e., without a competing SN2 reaction) only starting from tertiary alkyl halides and sulfonates. To obtain an E2 product from primary alkyl halides and sulfonates at all or to obtain an E2 product from secondary alkyl halides and sulfonates exclusively, one must change the base (see Section 4.4.2). 

Chemoselective E2 eliminations can be carried out with sterically hindered, sufficiently strong bases. Their bulkiness causes them to react with an H atom at the periphery of the molecule rather than at a C atom deep within the molecule. These bases are therefore called nonnucleo-philic bases. The weaker nonnucleophilic bases include the bicyclic amidines DBN (diazabi-cyclononene) and DBU (diazabicycloundecene). These can be used to carry out chemoselective E2 eliminations even starting from primary and secondary alkyl halides and sulfonates (Figure 4.17). 

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