Asymmetric synthesis of sulfoxides

A new class of chiral sulfinyl transfer reagents, much more reactive towards Grignard reagents than the Andersen menthyl sulfinate ester, have been introduced by Evans [102] and reacted with a wide range of nucleophiles to afford chiral sulfoxides, sulfinate esters or sulfinamides efficiently. These reagents are shown below  

The enantioselective chemical and enzymatic oxidations of sulfides [86, 94] have also received many interesting developments. High e.e. values have been obtained independently by Kagan [103,104] and Modena [105] via modified Sharpless reagents and by Davis s group [106], which used various chiral oxaziridines. 

Oxidation of thioethers derived from the natural chirality pool , the readily available lactic acid and 3-hydroxybutyric acid, has been used in molar-scale preparation of enantiomerically pure sulfoxides methyl (S)-2-(phenylsulfinyl)acrylate and (/ )-isopropenyl p-tolyl sulfoxide [107]. 

Specific cases of enzymatic oxidation give excellent results (see [108] for a comprehensive review and [94] for some more recent references). 

Oxidation of sulfides and sulfoxides, as discussed above, and alkylation of sulfinate salts are the most common methods used to obtain sulfones for synthetic purposes [71, 109-113], A hydrogen peroxide-urea-phthalic anhydride system was recently proposed as a mild convenient reagent for the efficient preparation of sulfones from organic sulfides [114]. 

---

Asymmetric synthesis of sulfoxides can be achieved by biocatalytic oxidation of sulfides and reduction of sulfoxides (Figure 33). i4-27s One example is the reduction of alkyl aryl sulfoxides by intact cells of Rhodobacter sphaeroides f.sp. denitrificans (Figure 33 (a)). 341 In the reduction of methyl -substituted phenyl sulfoxides, ( S )-cnanliomcrs were exclusively deoxygenated while enantiomerically pure (W)-isomcrs were recovered in good yield. For poor substrates such as ethyl phenyl sulfoxide, the repetition of the incubation after removing the toxic product was effective in enhancing the ee of recovered (f )-enantiomers to 100%. 

Chiral cyclic sulfites in asymmetric synthesis of sulfoxides 91PS(58)89. 

Asymmetric synthesis of sulfoxides, sulfinates, and sulfonamides. These sulfiny-lating reagents react with a wide range of nucleophiles with inversion at sulfur.1... 

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... 

Chiral N-sulfonyloxaziridines are useful reagents for the asymmetric synthesis of sulfoxides, selenoxides, and other substrates. Davis and co-workers <97JOC3625> have reported the first example of an e.vtt-camphorylsulfonyloxaziridine 175. prepared by the MCPBA oxidation of camphor inline 174 in the presence of potassium hexamethyldisilazide. This compound was then studied in various asymmetric oxidation applications. 

Many chiral auxiliaries are commercially available, allowing the execution of various types of asymmetric synthesis (ee > 90%) with recovery of the chiral auxiliary. This area has been extensively reviewed and will not be discussed here because lack of place. As recent examples we will develop the case of the asymmetric synthesis of sulfoxides and of ferrocenes with planar chirality. Asymmetric catalysis will be considered in part II of this dbapter. 

Asymmetric synthesis of sulfoxides from chiral sulfite 1 (ref. 28)... 

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). 

When n-BuLi is used instead of t-BuLi, the byproduct after desulfinylation (n-BuS(O)Ph) possesses an acidic proton, which is abstracted by the metalated epoxide. Hence, overall, a stereoselective protodesulfmylation is achieved. This can be used for the asymmetric synthesis of epoxides, such as that of (-)-disparlure from enantiopure sulfoxide 222 (Scheme 5.53) [78]. 

The lithium enolate of ethyl V-methoxyacetimidate (55) was also successfully sulfmy-lated by treatment with sulfinate ester 19 (equation 19)87. Sulfoxide 56 was used in an asymmetric synthesis of some /1-hydroxy esters. 

Kosngi, H., Abe, M., Hatsuda, R., Uda, H., Kato, M. (1997) A Study of Asymmetric Protonation with Chiral fi-Hydroxy Sulfoxides. Asymmetric Synthesis of (—)-Epibatidine. Chemical Communications, 1857-1858. 

We have developed the efficient synthesis of the SERM drug candidate 1 and successfully demonstrated the process on a multiple kilogram scale to support the drug development program. A novel sulfoxide-directed borane reduction of vinyl sulfoxides was discovered. The mechanistic details of this novel reaction were explored and a plausible mechanism proposed. The sequence of asymmetric oxidation of vinyl sulfoxides followed by stereospecific borane reduction to make chiral dihydro-1,4-benzoxathiins was applied to the asymmetric synthesis of a number of other dihydro-1,4-benzoxathiins including the sweetening agent 67. 

Various chiral dipolarophiles have been used in the asymmetric synthesis of hexahydro-isoxazolo[2,3- ]pyridines. Examples include // / -2-methylcnc-l, 3-dithiolane 1,3-dioxide 83 <1998JOC3481>, chiral vinyl sulfoxide 85 <1997TA109>, or chiral dioxolanes <2001TA1747> (Scheme 27). 

Pentitol synthesis An asymmetric synthesis of L-arabinitol involves condensation of the (E)-a,fJ-unsaturated ester (2) with the anion of methyl (R)-p-tolyl sulfoxide (1). The resulting p-keto sulfoxide (3) is reduced stereoselectively by ZnCl2/DIBAH (13, 115-116) to 4. Osmylation of 4 with (CH,)3NO and a catalytic amount of 0s04 (13, 224-225) yields essentially a single triol (5). Finally, a Pum-merer rearrangement of the sulfoxide followed by reduction of an intermediate... 

Peroxidases have been used very frequently during the last ten years as biocatalysts in asymmetric synthesis. The transformation of a broad spectrum of substrates by these enzymes leads to valuable compounds for the asymmetric synthesis of natural products and biologically active molecules. Peroxidases catalyze regioselective hydroxylation of phenols and halogenation of olefins. Furthermore, they catalyze the epoxidation of olefins and the sulfoxidation of alkyl aryl sulfides in high enantioselectivities, as well as the asymmetric reduction of racemic hydroperoxides. The less selective oxidative coupHng of various phenols and aromatic amines by peroxidases provides a convenient access to dimeric, oligomeric and polymeric products for industrial applications. 

This procedure was extended to a method for asymmetric synthesis of optically active epoxides starting from optically active sulfoxides. As the oxiranyUithium 131 reacts with the acidic hydrogen of the n-butyl aryl sulfoxide, the introduction of electrophiles to the reaction mixture was problematic. Therefore, the reaction was performed by addition of 1 equivalent of f-C4H9Li at — 100°C to 130 and the sulfoxide-lithium exchange reaction was found to be extremely rapid (within a few seconds at this temperature). Moreover, as f-butyl aryl sulfoxide 138 has now no more acidic hydrogen, the addition of several electrophiles leads to functionalized epoxides 139 (equation 48). ... 

Starting from optically active 1-chlorovinyl p-tolyl sulfoxide derived from 2-cyclohex-enone, the asymmetric synthesis of cyclopropane derivative (85) was realized (equation 23) . Addition reaction of lithium enolate of tert-butyl acetate to 83 gave the adduct (84) in 96% yield with over 99% ee. Treatment of the latter with i-PrMgCl in a similar way as described above afforded optically pure (15,6/ )-bicyclo[4.1.0]hept-2-ene (85) in 90% yield. 

---