Andersen sulfoxide synthesis

The use of sulfoxides as chiral synthons has, over recent years, become a highly dependable protocol in synthetic organic chemistry. To some extent, however, the use of sulfoxides in asymmetric synthesis has been limited by the lack of a reliable and general method for their preparation in optically pure form. In this review we present the development of chiral sulfoxide synthesis via nucleophilic displacement at sulfur from the pioneering work of Andersen in 1962 to more recent methods. Sulfoxides have become associated with many diverse areas of synthetic chemistry indeed, their ability to act as a handle for the stereoselective generation of chirality at proximate centres has attracted much research worldwide. 

The most important and widely used approach to chiral sulfoxides is the method developed by Andersen (5) based on the reaction between the diastereomerically pure (or strongly enriched in one dia-stereomer) menthyl arenesulfinates and Grignard reagents. The first stereospecific synthesis of optically active (+H7 )-ethyl p-tolyl sulfoxide 22 was accomplished in 1962 by Andersen (75) from (-)-(iS)-menthyl p-toluenesulfmate 45 and ethylmagnesium iodide. 

The Andersen synthesis of chiral sulfoxides has also been extended to diastereomerically or enantiomerically pure arenesulfinamides, which on treatment with methyllithium give optically active methyl aryl sulfoxides (83,85). The use of menthyl sulfinates in the synthesis of sulfoxides has been exploited in the preparation of optically active sulfoxides 47 and 48, which are chiral by virtue of isotopic substitution, H- D (86), and (87), respectively. More recent... 

An alternative stereospecific synthesis of chiral sulfimides reported by Nudelman (137) consists of the reaction of the diastereomeric menthyl p-toluenesulfinimidoates 90 with Gri ard reagents giving the optically active sulfimide 91. This reaction, like the Andersen synthesis of chiral sulfoxides, proceeds with inversion of configura-... 

Andersen, K. K., Bujnicki, B., Drabowicz, J., Mikolajczyk, M., and O Brien, J. B. (1984) Synthesis of enantiomerically pure alkyl and aryl methyl sulfoxides from cholesteryl methanesulfinates, J. Org. Chem. 49, 4070-4072. 

The purpose of this article is to present recent developments in the preparation of optically pure sulfoxides using both methods, mainly from 1990 to the present. Emphasis has been given to the bibliographic impact of each method. An application section is included after each route, especially in the case of variation in the Andersen methodology, where important advances have been achieved. It is not the aim of this article to review the chemistry of chiral sulfoxides—several excellent review articles have appeared on this subject, from the seminal review by Solladie19 in 1981 to other recent reviews.20 The literature has been surveyed up to January 1999. The preparation and utilization of chiral sulfoxides in asymmetric synthesis have been the subject of valuable comprehensive as well as specialized accounts which should be consulted for details and considered as complementary to this article. 

In the mid-1960s Mislow started a research program on the mechanism of the thermal racemization of sulfoxides [97-99]. In the course of these efforts he recognized an enormous racemization rate acceleration for (R)-allyl-p-tolyl sulfoxide ((R)-151) as compared to benzyl or, even more pronounced, to alkyl sulfoxides (Scheme 42). For this compound, prepared by Andersen synthesis [100,101], he found a racemization rate exceeding that of the phenyl-substituted sulfoxide by a factor of 560 000. Based on kinetic measurements Mislow et al. determined the activation parameters to be AH = 22 kcal mor ... 

There are several efficient methods available for the synthesis of homochiral sulfoxides [3], such as asymmetric oxidation, optical resolution (chemical or bio-catalytic) and nucleophilic substitution on chiral sulfinates (the Andersen synthesis). The asymmetric oxidation process, in particular, has received much attention recently. The first practical example of asymmetric oxidation based on a modified Sharpless epoxidation reagent was first reported by Kagan [4] and Modena [5] independently. With further improvement on the oxidant and the chiral ligand, chiral sulfoxides of >95% ee can be routinely prepared by these asymmetric oxidation methods. Nonetheless, of these methods, the Andersen synthesis [6] is still one of the most widely used and reliable synthetic route to homochiral sulfoxides. Clean inversion takes place at the stereogenic sulfur center of the sulfinate in the Andersen synthesis. Therefore, the key advantage of the Andersen approach is that the absolute configuration of the resulting sulfoxide is well defined provided the absolute stereochemistry of the sulfinate is known. 

Scheme 8.27. (a) An example of the Andersen synthesis of chiral sulfoxides [119]. (b) Catalytic oxidation of an aromatic sulfide using a chiral titanium complex [118]. fc) Synthesis of a C2-symmetrical fra s-l,3-dithiane-l,3-dioxide and its use as an asymmetric acyl anion equivalent [120,121]. 

The Andersen procedure for the synthesis of ENANTIOMERICALLY ENRICHED, CHIRAL SULFOXIDES 41... 

The Andersen Procedure for the Synthesis of Enantiomerically Enriched, Chiral Sulfoxides... 

Following the pioneering work of Gilman [1], Andersen, in 1962, reported the first synthesis of an optically active sulfoxide of high enantiomeric purity through nucleophilic displacement at sulfur [2]. The key step in Andersen s procedure... 

Andersen later extended this work to include the synthesis of various chiral diaryl sulfoxides via the appropriate arylmagnesium bromide reagents and was also able to provide further evidence to support the proposed inversion of configuration at sulfur as highlighted in Scheme 2.3 [8]. 

Andersen has described the synthesis of enantiomerically pure methyl alkyl and methyl aryl sulfoxides from chlolesteryl methane sulfinates [12]. The reaction of cholesterol and menthanesulfinyl chloride provides the crystalline, epimeric cholesteryl methEme sulfinates in quantitative yields (Scheme 2.5). Pure samples of the (J ) or (S) epimers can be obtained in very low yield (0.7% and 3.5%, respectively) by crystallization. 

This reaction is more stereoselective than the corresponding synthesis of menthyl sulfinate diastereoisomers in the Andersen procedure, allowing for easier fractional crystallization. Optically active (/ )-(+)-methyl phenyl sulfoxide (13) is obtained on reaction of (lf ,2S)-(12) with methyllithium (Scheme 2.14). 

The A -sulfinyloxazolidinones have also been demonstrated to be highly efficient reagents for the synthesis of dialkyl sulfoxides in high yields and with excellent enantioselectivities as discussed, this class of sulfoxide has proved to be inaccessible through the Andersen procedure. Examples are highlighted in Scheme 2.17 and Table 2.6 for A-sulfinyloxazolidinone (16). 

In conclusion, Snyder and Benson s approach allows the synthesis of enantiomerically pure dialkyl and alkyl aryl sulfoxides in good yields and with excellent enantioselectivities. Both enantiomers are accessible by reversing the order of organometallic displacement or by employing the (15,2J )-(+)-ephedrine enantiomer. The only limitations are observed in the synthesis of t-butyl phenyl and aryl phenyl sulfoxides. However aryl phenyl sulfoxides are accessible by the Andersen procedure, and t-butyl phenyl sulfoxides by an approach to chiral sulfoxides developed by Kagan, described below. 

The highly stereoselective synthesis of optically active sulfoxides using the methodology first developed by Andersen in 1962 is still the most important and widespread approach used today [9,10]. The method is based on the reaction of... 

Enantiopure sulfinimines are ammonia imine synthons useful in the asymmetric synthesis of amines and -amino acid derivatives. Sulfinimines unavailable via the Andersen synthesis (R = H) are prepared hy asymmetric oxidation of the sulfenimines, ArS-N=C(R)PhX, with (+)-( ) or (-)-(1) at -20 to 20 °C in CCI4 (eq 8). Crystallization improves the ee to >95%. The sulfoxide chiral recognition model correctly predicts the configuration of the product. 

A discussion of the use of chiral sulfoxides requires a brief introduction of the fundamental approach to their synthesis involving auxiliary displacement the classic method of Andersen [62], This method is based on treat-... 

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