Asymmetric a-sulfenylation

Heterofunctionalisation of carbonyl compounds in the a-position has become an important facet of oiganocatalytic enamine-mediated reactions. In 2005, the Jorgensen group described asymmetric a-sulfenylation of aliphatic aldehydes using TMS-protected prolinol catalysts. The best sulfenylating agent was M-benzylsulfanyl-1,2,4-triazole. Other catalysts, such as proline, prolinol, prolinamide or other secondary amide were less effective. The catalyst with bulkier aromatic groups (C2a) afforded the most enantioselective reaction (Scheme 8.39). 

SCHEME 14.25. Asymmetric a-sulfenylated ketones via nitroso alkene intermediates. 

The asymmetric a-sulfenylation of ketones is a particularly challenging reaction, as demonstrated by the poor success reported in the stereoselective variants via classical enolate/azaenolate reaction with an electrophilic sulfur reagent [71]. An umpolung approach has been devised by Coltart and co-workers [72] to effect the first asymmetric a-sulfenylation of ketones with arene thiols. Nitroso alkene derivatives, in i/tM-generated under basic conditions from a-chloro oximes, reacted with arene thiols in the presence of cinchona thiourea 27, which promoted the conjugate addition of thiophenol (Scheme 14.25). The chiral nonracemic a-sulfenylated oximes were directly hydrolyzed by IBX to ketones in high yield and good enantioselectivity. 

The diarylprolinol silyl ether system was initially applied for the asymmetric a-sulfenylation of aldehydes. Since then, it has proven its usefulness in combination with a large number of heteroatom- and carbon-based electrophiles for asymmetric a-functionalizations of aldehydes (Scheme 2.3) [2, 3, 9]. 

Sobhani S, Fielenbach D, Marigo M, Wabnits TC, Jprgensen AK. Direct organocatalytic asymmetric a-sulfenylation of... 

A noteworthy improvement comes from the use of ligand systems which are themselves optically active." This is die case of the complex (150), shown in Scheme 21, that is prepared from a sulfenylated norephedrine (149). The results reported for the in situ reactions of (150) with various aldehydes (Scheme 21) are summarized in Table 14." Nothing is reported concerning the mechanism of the en-antioselecdve addition, since the absolute configuration of the asymmetrically substituted Ti atom is not known. 

Organolithium-induced deprotonation a to sulfur (Toru, in this volume) and subsequent formation of enantioenriched products in an enantioselective manner has utilised sparteine 2 but, notably, bisoxazolines were found by Toru to be significantly more effective in asymmetric substitution reactions of primary a-sulfenyl carbanions (up to 99% ee) (Scheme 18) [57,58]. 

For example, in 2004, Wang and coworkers reported a series of asymmetric transformations, for example, a-aminoxylahon, Mannich reactions, and a-sulfenylation, under the catalysis of pyrrolidine trifluoromethanesulfonamide 36 the product yields and diastereo- and enanhoselectivities are quite good in most... 

Asymmetric Metal Catalysis The first asymmetric ct-sulfenylation using prochiral substrates under a chiral catalyst was reported by Mukaiyama and co-workers in 1986 (Scheme 46.45). In this pioneering study, the reaction between tin(II) enolates of ketones or 3-acyl-oxazolidin-2-ones and thiosulfonates 394 proceeded with modest-to-high enantioselectivities in the presence of chiral diamine 396. 

Organocatalysis One of the most diHicult aspects in the development of asymmetric sulfenylation methods for carbonyl compounds is to ensure the stability of the resulting a-sulfenylated compounds. Based on the pioneering study by Kuehne of reactions of enamines with arylsulfonyl chloride, the catalytic asymmetric a-sulfe-nylation has been investigated by enamine catalysis. An... 

A subsequent study by Jprgensen et al. also demonstrated the enantioselective a-sulfenylation of (S-dicarbonyl compounds 420 using l-alkylsulfanyl[l,2,4]triazole derivatives 419 in the presence of a catalytic amount of cinchona alkaloid derivative 421. The use of cyclic (S-dicarbonyl compounds ensured the introduction of a quaternary sulfur center however, the observed enantioselectivity was modest in 51-89%. In 2009, Zhu and co-workers reported that a chiral a,a-diaryl prolinol 424 efficiently catalyzed the enantioselective sulfenylation of (S-ketoesters 420 using N-(phenylthio)phthalimide 423 as a sulfur electrophile. The absence of racemizable C—H bonds led to the optically enriched a-sulfenylated products 425 in excellent enantio-selectivities. In 2010, Fu developed a method for catalytic asymmetric 7-sulfenylation of carbonyl compounds using 2,3-allenoates 426 in the presence of a chiral bisphos-phine, TangPhos 427, and a bulky carboxylic acid 428. ... 

Poli G, Belvisi L, Manzoni L, Scolastico C. First asymmetric synthesis of enantiopure a-sulfenyl dithioacetals and a-sulfenyl aldehydes./. Org. Chem. 1993 58 3165-3168. 

Ishimaru T, Ogawa S, Tokunaga E, Nakamura S, Shibata N. Asymmetric synthesis of a-fluoro-a-sulfenyl-p-ketoesters using DBFOC-Ph/Ni(II) complex. J. Fluorine Chem. 2009 130 1049-1053. 

Hatcher JM, Kohler MC, Coltart DM. Catalytic asymmetric addition of thiols to nitrosoalkenes leading to chiral non-racemic a-sulfenyl ketones. Org. Lett. 2011 13 3810-3813. 

In 2007, Hiemstra et al. established a catalytic asymmetric Pictet-Spengler reaction that proceeds via (V-sulfenyliminium ions (Scheme 15) [27], Treatment of iV-sulfenylated tryptamines 42 with aldehydes 40 and BINOL phosphate (R)-3f (5 mol%, R = 3,5-(CF3)2-CgH3) afforded tetrahydro-P-carbohnes. After completion of the cyclization the sulfenyl group was cleaved by the use of HCl. This one-pot... 

The introduction of a-heteroatom functionalization into an aldehyde or ketone is a very useful class of transformation. Performing it directly and asymmetrically, using organocatalysts, has been reviewed for reactions such as amination, oxygenation, halo- genation, and sulfenylation (44 references).260... 

In this chapter, we will outline the application of organocatalysis for the enantio-selective a-heteroatom functionalization of mainly aldehydes and ketones. Attention will be focused on enantioselective animation-, oxygenation-, fluorination-, chlorination-, bromination-, and sulfenylation reactions catalyzed by chiral amines. The scope, potential and application of these organocatalytic asymmetric reactions will be presented as the optically active products obtained are of significant importance, for example in the life-science industries. 

The asymmetric sulfenylation of ketones with chiral sulfenamides is based on the direct reaction of 4-alkylcyclohexanones with optically active sulfenamides in the presence of a catalytic amount of triethylamine hydrochloride37. 

Together with cinchona-PTC-mediated a-alkylations, the asymmetric nucleophilic a-substitution of carbonyl derivatives by using cinchona alkaloids as organocatalysts in nonbiphasic homogeneous conditions also have been extensively studied (e.g., arylation, hydroxylation, amination, hydroxyamination, and sulfenylation). 

More recently, Jacobsen s group [67] developed a similar approach under dual catalysis combining a chiral thiourea and a weak Brpnsted acid for the enantioselective synthesis of A-unsubstituted carboline derivatives. Alternatively, Hiemstra and co-workers [68] considered the use of A-sulfenyliminium ions as intermediates in the asymmetric Pictet-Spengler reaction in the presence of chiral phosphoric acids. Due to the easy acid-mediated removal of the sulfenyl group, this methodology is also powerful for accessing A-unsubstituted products. 

Chiral Lewis acids derived from complexes between copper(I) chloride with phosphino sulfenyl ferrocenes are efficient catalysts for enantioselective aza-Diels-Alder reaction of A-sulfonyl imines with Danishefsky-type dienes (eq 47), and asymmetric conjugate addition of Grignard reagents to cyclic enones (eq 48).136... 

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