A-ketosulfones

Ketones containing sulfur or nitrogen atoms bound to a-carbons suffer carbon-sulfur or carbon-nitrogen bond cleavage under the conditions of the Clemmensen reduction [159, 864 (p. 118). A ketosulfone was reduced to a sulfone-alcohol with zinc in refluxing 80% acetic acid in 70% yield [920]. 

Synthesis A number of synthetic strategies to the COX-2 specific inhibitor etoricoxib have been described (Dube et al. (Merck Frosst), 1998 Davies et al., 2000 Sobera et al., 2001a). In schemes 17-20 the two major routes via a dichloropyridine derivative or a ketosulfone, respectively, as the key intermediates are discussed. 

K. Lorraine, S. King, R. Greasham, and M. Chartrain, Asymmetric bioreduction of a ketosulfone to the corresponding trans-hydroxysulfone by the yeast Rhodotorula rubra MY 2169, Enzyme Microb. Technol. 1996, 39, 250-255. 

Another yeast, Rhodotorula rubra MY 2169, has been shown to reduce a ketosulfone 8 to the corresponding tram-hydroxysulfone 9 (Scheme 19.8). This hydroxysulfone is an intermediate in the drug candidate L-685,393 (10), a carbonic anhydrase inhibitor.81 Results of this biotransformation yielded gram quantities of product with a de of >96%. Studies by Zeneca discuss additional screening experiments aimed at finding microorganisms to reduce a similar ketosulfone.82... 

Chloraniine-T tnhydrate (CT) was obtained commercially Excess chloramine-T is used because we have observed traces of the a-ketosul-tonamide in those cases where the oxyaminated product contains a secondary hydroxyl group We have also observed that these a ketosulfon amides are further oxidized under the reaction conditions in a process which consumes several moles of chloramine-T... 

Enol phosphates of a-ketosulfones provide the key intermediate to alternate schemes leading to acetylenes. Acylation of phenyl sulfones with esters affords the ketone derivatives directly. Alternately, the ketones can be obtained by Moffat oxidation of the condensation products from aldehydes with sulfone anions. Conversion to the enol derivatives followed by treatment with Na/NH or Na(Hg) gives the acetylenes. 

The substrate structure was extended from P-ketoesters not only to similar analogues, such as 1,3-diketones [59], P-alkoxy ketones [60] and a-ketosulfones [61], but also to simple alkanones such as 2-octanone [62],... 

Functional groups present in the molecule that are sensitive to SET, usually multiple bonds, aromatic rings, and nitro and carbonyl groups situated in the a-position to the SO2 group, may play the role of electron acceptor and accelerate the C-SO2 cleavage. This activation has been broadly used, for example, to perform selective desulfonylations of a-ketosulfones (Eq. 11), with... 

Synthesis of (—)-Laulimalide. Different approaches to the (3-hydroxy sulfone moiety needed for the olefination reaction are frequently used in the synthesis of natural products. For instance, a very common strategy consists of carbonyl reduction of the corresponding a-ketosulfone followed by reductive elimination. This sequence is employed in the synthesis of polyhydroxylated indolizidine alkaloids (Eq. 121),207 (+)-dihydromevinolin,268 pleraplysillin-1,269 amphidino-lide B,270 and the novel antitumor agent (—)-laulimalide (Eq. 158).271... 

Similar reaction of 1,2-propanedisulfonyl chloride, however, did not yield a double adduct but gave a low yield (6%) of a product formulated193 as a ketosulfone 102. In the light of the known ease with which 1,2-ethanedisulfonyl chloride is converted to ethenesulfonyl chloride by tertiary amines26, it would seem likely that the reaction may well involve 1-propenesulfonyl chloride and that further experiments are needed for a better understanding of the mechanism of this reaction. 

Anilide 2a catalysed asymmetric intramolecular Michael reaction of formyl enones to chiral cyclic keto-aldehydes in excellent yields with good stereoselectivity (eqn. (1) in Scheme 6.3). The intramolecular Michael addition of a ketosulfone to an unsaturated ketone (eqn. (2) in Scheme 6.3) catalysed by 15e has heen used as a key step in the synthesis of the carbon tricyclic framework of Lycopodine. The same sulfonylprolinamide served as catalyst in the construction of all-carhon substituted quaternary stereocentre via Robinson-type annulation process (eqn. (3) in Scheme 6.3). 

N2O2SC a-Diazosulfones a-Ketosulfone hydrazones Monosulfonylcarbodimides Sulfonylamidines Sulfonic acid amidines 5 N-Sulfonylformamidines 20 N -Sul fony Icyanamides Sulfonylformaldehyde hydrazones Sulfonylhydrazones Thiourea S-dioxides... 

Selective hydrolysis s. 19, 27 a-Ketosulfone hydrazones from a-azo- -ketosulfones Japp-Klingemann cleavage also ring opening s. 19, 28 Garbamyl disulfides from dithioformimidic acid esters s. 16,626... 

Aldol reaction using monoclonal aldolase antibodies, generated against a ketosulfone hapten by reactive immunization, was used to catalyze rapid and highly enantioselective retro-aldol reaction of a thiazole aldol, providing optically pure aldol by kinetic resolution. The product was used for the synthesis of epothilone E (Fig. 10.39(b) and (c)). ... 

Another example of the industrial use of methyl ( )-p-hydroxybutyrate is Zeneca s synthesis of an intermediate for MK-0507 (trade name Trusopt Fig. 7), an antiglaucoma drug developed by Merck [65]. In this synthesis, a ketosulfone derivative is prepared from the tosylate of methyl (/ )-P-hydroxybutyrate, which is as3nnmetrically reduced to a (45,dS)-hydroxysulfone derivative, a key intermediate for MK-0507, by a microorganism. 

Figure 5 Asymmetrical reduction of a ketosulfone to the desired (45,65)-hydroxysulfone, a key intermediate in the synthesis of a drug against glaucoma [40].

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