Racemization of allylic sulfoxides

Bickart, P., Carson, F. W., Jacobus, J., Miller, E. G., Mislow, K. Thermal racemization of allylic sulfoxides and interconversion of allylic sulfoxides and sulfenates. Mechanism and stereochemistry. J. Am. Chem. Soc. 1968, 90, 4869-4876. 

To junp forward to a contenporary example, the ready racemization of allylic sulfoxides via reversible [2,3]-sigmatropic rearrangement could enable a dynamic kinetic resolution if one of... 

The addition of the anions of racemic cyclic allylic sulfoxides to various substituted 2-cyclopentenones gives y-l,4-adducts as single diastereomeric products22. The modest yields were due to competing proton-transfer reactions between the anion and enone. The stereochemical sense of these reactions is identical to that for the 1,4-addition reaction of (Z)-l-(/erf-butylsulfinyl)-2-methyl-2-butene to 2-cyclopentenone described earlier. 

The rearrangement of allylic sulfoxides to allylic sulfenates was first studied in connection with the mechanism of racemization of allyl aryl sulfoxides.272 Although the allyl sulfoxide structure is strongly favored at equilibrium, rearrangement through the achiral allyl sulfenate provides a low-energy pathway for racemization. 

Addition of racemic allylic sulfoxide anions to 2(5//)-furanone gives y-1,4-addition adducts1. The simple and induced diastereoselectivities are completely analogous to that of 2-cyclopen-tenone described earlier. 

From studies on the addition of racemic allylic sulfoxide anions of 3-substituted l-(phenyl-sulfinyl)-2-propenes to racemic 4-tcrr-butoxy-2-cyclopentenone, it was found that (El-allylic sulfoxides give. vyw-products, and (Z)-allylic sulfoxides give anti-productsx. 

The observations of the interconversion of allylic sulfenates and sulfoxides made by Braverman and Stabinsky34-38 are confirmed by the work of Mislow and coworkers44-47 who approached the problem from a different angle, namely, enhanced racemization of optically active allylic sulfoxides. 

In order to account for the unusually facile thermal racemization of optically active allyl p-tolyl sulfoxide (15 R = p-Tol) whose rate of racemization is orders of magnitude faster than that of alkyl aryl or diaryl sulfoxides as a result of a comparably drastically reduced AH (22kcalmol- ), Mislow and coworkers44 suggested a cyclic (intramolecular) mechanism in which the chiral sulfoxide is in mobile equilibrium with the corresponding achiral sulfenate (equation 10). 

This type of asymmetric conjugate addition of allylic sulfinyl carbanions to cyclopen-tenones has been applied successfully to total synthesis of some natural products. For example, enantiomerically pure (+ )-hirsutene (29) is prepared (via 28) using as a key step conjugate addition of an allylic sulfinyl carbanion to 2-methyl-2-cyclopentenone (equation 28)65, and (+ )-pentalene (31) is prepared using as a key step kinetically controlled conjugate addition of racemic crotyl sulfinyl carbanion to enantiomerically pure cyclopentenone 30 (equation 29) this kinetic resolution of the crotyl sulfoxide is followed by several chemical transformations leading to (+ )-pentalene (31)68. 

Ohta and coworkers used a bacterium, Corynebacterium equi IFO 3730, rather than a fungus, to oxidize eight alkyl phenyl and p-tolyl sulfides to their respective sulfoxides (119, 120) of configuration R. Virtually all of the sulfur compounds were accounted for as the sum of uncreacted sulfide, sulfoxide and sulfone. The enantiomeric purities of the sulfoxides obtained were quite good and are shown below in parentheses. The formation of the allyl sulfoxides in high optical purity is noteworthy. The authors believe that the sulfoxides were formed by enantioselective oxidation of the sulfides rather than by enantioselective oxidation of racemic sulfoxides, since the yield of sulfoxides was greater than 50% in five of the ten oxidations reported (see also Reference 34). 

The thermal racemization of optically active aryl allyl sulfoxides ArS(0)CHjCH=CH2 is orders of magnitude faster, and has a much lower activation energy, than that of aryl alkyl sulfoxides ArS(0)R (Bickart et ai, 1968). The reason is that the presence of the allyl group permits the sulfoxide to equilibrate with the isomeric, achiral sulfenate ester by a concerted, cyclic process (89) for whichis only about 20 kcal moM.The rates of racemiz-... 

Since allyl sulfoxides may quite easily undergo racemization at the sulfur atom via a reversible [2,3] sigmatropic process, the configurationally more stable chiral allylic phosphine oxides were also investigated.201 Compounds (184) and (185), prepared as a 1 1 mixture from allylphosphonyl dichloride and (-)-ephedrine, were shown to add to cycloalkenones with reasonably high diastereoselectivities. Ozono-lysis of the initially formed 1,4-adducts affords the respective optically active ketoaldehydes (Scheme 67). With a / /-isopropyl-substituted derivative even higher selectivities (88-98% ee) could be obtained. 

Another quite different-looking reaction is the Mi slow rearrangement 1.18 - 1.19, which is invisible because thermodynamically unfavourable but the ease with which it takes place explains why allyl sulfoxides racemize so much more readily than other sulfoxides. Here, one end of the C-S bond moves from the sulfur (S-11) to the oxygen atom (0-21) and the other end moves from C-l to C-3. This is therefore called a [2,3] shift, the bond marked in bold moving two atoms at one end and three at the other. 

Most sulfoxides will retain their configuration at sulfur up to temperatures of about 200 °C—indeed, it is estimated that the half-life for racemization of an enantiomerically pure sulfoxide is about 5000 years at room temperature. However, sulfoxides carrying allyl groups are much less stable—they racemize rapidly at about 50-70 °C. A clue to why this should be is provided by the reaction of an allylic sulfoxide ith trimethyl phosphite, P(OMe)3-... 

The activation parameters of the pyramidal inversion have been determined for various dialkyl, diaryl, and alkyl aryl sulfoxides. They vary between 35 and 42 keal/mol for AH, and -8 and +4 cal/(mol-K) for AS. These values indicate that, in most cases, the thermal stereomutation of sulfoxides occurs at a significant rate only at about 200 °C. There are a few exceptions, such as benzyl and allyl sulfoxides, whose racemization is raised at 130-150 and 50-70 °C, respectively. 

A study of the solvent effects on the rate of thermal racemization of chiral allyl sulfoxides has revealed that polar solvents significantly decelerate the racemization [108], The reaction proceeds by way of a reversible and concerted rearrangement achiral allyl sulfenates are formed as intermediates and an intramolecular a, 7-shift of the allyl group between the sulfoxide oxygen and sulfur termini occurs as shown in Eq. (5-38). 

Alkyl allyl sulfoxides start to racemize significantly only at temperatures above 50°C58-60. For example, ( + )-(S)-ally]-L-cysteine, the progenitor of the odorous part of garlic, did not undergo epimerization at sulfur during isolation and recrystallization61. 

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