Sulfoxides, allylic alkylation

In the reaction of 88 with /(-phenethyl bromide, l-phenethyl-3-phenylpropyl methyl sulfoxide and bis-3-phenylpropyl sulfoxide, besides 3-phenylpropyl methyl sulfoxide are obtained118. Sulfoxides, bearing a /1-hydrogen to the sulfmyl function, give olefins upon thermolysis. Utilizing this reaction, Trost and Bridges120 alkylated benzyl phenyl sulfoxide, 3,4-methylenedioxybenzyl phenyl sulfoxide, phenylthiomethyl phenyl sulfoxide, phenylsulfinylmethyl phenyl sulfoxide and cyanomethyl phenyl sulfoxide with alkyl, allyl and benzyl halides and subjected these sulfoxides to thermolysis, obtaining olefins in one-pot processes. 

Structural Identification of a Palladium Complex with a Chiral Sulfoxide Ligand Used in Asymmetric Palladium-Catalyzed Allylic Alkylations... 

Allyl halides are also alkylated by zinc cyanocuprates. Allylic bromides, iodides and chlorides react successfully with these reagents, and a number of functional groups in the allylic halide (ester, sulfide, sulfoxide, ether, alkyl halides, acetals) stand up well to the conditions of reaction (equations 29 and 30)41 3. The regiochemistry of attack is predominantly Sn2. 1,3-Dichloroalkenes can be made to undergo two successive coupling reactions to this point, only two identical R group incorporations have been reported (equation 31)44. 

Acyclic stereocontrol remains a challenging problem in synthesis. While enan-tiomerically pure sulfoxides are valuable synthetic intermediates for enantiocon-trolled carbon-carbon bond formation by conjugate addition in cyclic cases, their usefulness for such alkylations in acyclic cases has not been firmly established. Moreover, most sulfoxide directed alkylation protocols utilize the valuable sulfur auxiliary just once, which limits the synthetic versatility of the process. Marino et al. have recently reported SN2 displacements of acyclic allylic mesyloxy vinyl sulfoxides with organocopper reagents (Scheme 10).33 In addition to the excellent observed stereoselectivities, the newly created chiral center is adjacent to a vinyl sulfoxide which should allow for subsequent chirality transfer operations. On treatment with organocopper nucleophiles, both sulfoxide diastereoisomers 40b and 43b underwent SN2 displacements with high Z selectivity to yield products 42b and 45b, respectively (Table 2). The oxidation state on the sulfur was varied... 

Sulfoxides are optically active at the S atom. The natural ( + ) isomers are better substrates than the (—) isomers or the racemic mixture 18, 42). Among saturated alkyl groups, the garlic enzyme is most active on the ethyl derivative 18) while the onion enzyme prefers the propyl derivative (42). The rate differences (at substrate concentration = 0.02M) are caused solely by differences in 42). However, the natural alkenyl sulfoxides (allyl in garlic, 1-propenyl in onion) are the best substrates for the respective enzymes 18,43), and the onion enzyme... 

Madec and Poli recently reported that sulfenate anions can also be used as nucleophiles in catalytic formation of C ryi-S bonds, generating sulfoxides [103]. The sulfenate anions are generated in situ by base-induced elimination of (3-sulfinyles-ters [136]. These groups subsequently developed an enantioselective variant, allowing the asymmetric synthesis of sulfoxides with up to 83% ee (16) [105]. Chiral sulfoxides are present in a variety of pharmaceuticals and are widely used in asymmetric catalysis [137-141]. Likewise, Madec and Poli found that sulfenate anions can be used to generate Csp -S bonds in Pd-catalyzed allylic alkylation [ 142]. o... 

Figure 13.5 Postulated transition states of homogeneous enantioselective reactions which proceed without coordination of one of the substrates to the metal centre allylic alkylation (a), transfer hydrogenation (b) and sulfoxidation (c). Reprinted with permission of Swiss Chemical Society...

Having demonstrated the potential of artificial metalloenzymes for the reduction of V-protected dehydroaminoacids, we turned our attention towards organometallic-catalyzed reactions where the enantiodiscrimination step occurs without coordination of one of the reactants to the metal centre. We anticipated that incorporation of the metal complex within a protein enviromnent may steer the enantioselection without requiring transient coordination to the metal. In this context, we selected the palladium-catalyzed asymmetric allylic alkylation, the ruthenium-catalyzed transfer hydrogenation as well as the vanadyl-catalyzed sulfoxidation reaction. Indeed, these reactions are believed to proceed without prior coordination of the soft nucleophile, the prochiral ketone or the prochiral sulfide respectively. Figure 13.5. 

A new chiral o-(phosphinoamino)phenyl sulfoxide has been demonstrated as an efficient ligand in the Pd-catalyzed asymmetric allylic alkylations of 1 with dimethyl sodiomalonate using [Pd(7r-allyl)Cl]2, affording (5)-2 [45% ee with (5)-36a].f ... 

The first attempt to use chiral /3-phosphino sulfoxides as chiral ligands was successfully accomplished in Pd-catalyzed asymmetric allylic alkylations and aminations.t ... 

Sulfinyl functionality serves as a slightly weaker coordinating element compared with sulfenyl function. Chiral sulfoxide ligands provide rather good enantioselectivity in Pd-catalyzed allylic alkylations. (/ )-o-(Diphenylphosphinoamino)phenyl 2-methoxy-l-naphthyl sulfoxide provided the highest enantioselectivity (97%) among known chiral sulfoxide ligands. 

Chiral 2-(diphenylphosphino)phenyl 2-methoxy-l-naphthyl sulfoxide (6) has been used successfully as a ligand in Pd-catalysed asymmetric allylic alkylation and ami-nation, providing extremely high enantioselectivity. The structure of the intermediate Pd complex chelated by the ligand was determined by X-ray crystallography. 

The Pd-catalyzed allylic alkylation strategy was also applied to the synthesis of allyl sulfoxides 318 by Poli et al. The use of sulfenate anions 319 (Scheme 46.37), generated from 3-sullinylesters 317 by a retro-Michael reaction under biphasic conditions, is noteworthy. 

Maitro G, Prestat G, Madec D, Poli G. Preparation of allyl sulfoxides by palladium-catalyzed allylic alkylation of sulfenate anions. J. Org. Chem. 2006 71 7449-7454. 

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). 

While the chemistry of alkyl and allylic sulfoxide anions is similar to that of phosphine oxides, phosphinates and sulfone stabilized anions (Sections 1.5.2.2.1 -2), the situation is further complicated by the additional stereogenic center at sulfur. Therefore in all cases, asymmetric induction may arise from the stereocenter at sulfur. 

Sulfoxides (R1—SO—R2), which are tricoordinate sulfur compounds, are chiral when R1 and R2 are different, and a-sulfmyl carbanions derived from optically active sulfoxides are known to retain the chirality. Therefore, these chiral carbanions usually give products which are rich in one diastereomer upon treatment with some prochiral reagents. Thus, optically active sulfoxides have been used as versatile reagents for asymmetric syntheses of many naturally occurring products116, since optically active a-sulfinyl carbanions can cause asymmetric induction in the C—C bond formation due to their close vicinity. In the following four subsections various reactions of a-sulfinyl carbanions are described (A) alkylation and acylation, (B) addition to unsaturated bonds such as C=0, C=N or C= N, (C) nucleophilic addition to a, /5-unsaturated sulfoxides, and (D) reactions of allylic sulfoxides. 

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