Sulfoxides chiral intermediates

The large sulfur atom is a preferred reaction site in synthetic intermediates to introduce chirality into a carbon compound. Thermal equilibrations of chiral sulfoxides are slow, and parbanions with lithium or sodium as counterions on a chiral carbon atom adjacent to a sulfoxide group maintain their chirality. The benzylic proton of chiral sulfoxides is removed stereoselectively by strong bases. The largest groups prefer the anti conformation, e.g. phenyl and oxygen in the first example, phenyl and rert-butyl in the second. Deprotonation occurs at the methylene group on the least hindered site adjacent to the unshared electron pair of the sulfur atom (R.R. Fraser, 1972 F. Montanari, 1975). 

Sharpless and Masumune have applied the AE reaction on chiral allylic alcohols to prepare all 8 of the L-hexoses. ° AE reaction on allylic alcohol 52 provides the epoxy alcohol 53 in 92% yield and in >95% ee. Base catalyze Payne rearrangement followed by ring opening with phenyl thiolate provides diol 54. Protection of the diol is followed by oxidation of the sulfide to the sulfoxide via m-CPBA, Pummerer rearrangement to give the gm-acetoxy sulfide intermediate and finally reduction using Dibal to yield the desired aldehyde 56. Homer-Emmons olefination followed by reduction sets up the second substrate for the AE reaction. The AE reaction on optically active 57 is reagent... 

The big difference between the extent of asymmetric induction on the addition to a prostereogenic carbonyl group of simple carbanions a to a chiral sulfoxide on the one hand and enolates of sulfinyl esters on the other, can be attributed to the capacity of the ester function to chelate magnesium in the transition states and intermediates. The results already described for the addition of chiral thioacetal monosulfoxide to aldehydes (see Section 1.3.6.5.) underscore the importance of other functions, e.g., sulfide, for the extent of asymmetric induction. 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

The enantioenriched sulfoxide intermediate 72 (R = CH2OH), obtained by asymmetric 5-oxidation with a chiral oxaziridine (89 11 enantiomeric ratio), has provided a highly enantioselective synthesis of the benzothiepin derivative 71 (4R, 5R). The aldehyde intermediate 72 (R = CHO) was cyclized asymmetrically to 71 (4R, 5R) with >98 2 enantiomeric ratio. Base treatment (f-BuOK, -10°C, THF) of the racemic benzothiepin 73... 

Here an alkynyl sulfoxide 55 is first carbocuprated with an organocopper reagent 56 to provide a vinylcopper intermediate 57, which is then zinc homologated with the primary zinc sp3-carbenoid 58 to yield the allylzinc intermediate 59. This, in a spontaneous syw-/)-climination, gives the corresponding allene 60. This protocol could also be adopted to the preparation of chiral allenes. 

Oae and co-workers (288) were the first to show that nucleophilic displacement at sulfur is accompanied by retention of configuration. They found that chiral 0-labeled alkyl aryl sulfoxides exchange oxygen with dimethylsulfoxide at about 150°C, almost without racemization. To explain the steric course (retention) of this reaction, the formation of a trigonal-bipyramidal intermediate 246 was postulated in which the entering and departing oxygen atoms occupy apical and equatorial positions, respectively. 

It is also possible to intercept the chiral sulfoxide intermediate and convert this species to an a-amino ester. Thus, the Grignard addition to dihydro-l,2-thiazine 1-oxides 131a and 131b followed by NH4CI workup and subsequent ozonolysis of 132a and 132b affords amino ester 133 with excellent retention of the absolute stereochemistry (Scheme 17) <2004JOC7198>. 

Chiral sulfoxides are useful intermediates in asymmetric synthesis. A number of methods can be used for their preparation. For example, enantiomerically pure p-tolylsulfoxides can be obtained by displacing a dimethylphosphonylmethyl moiety, a carbon leaving... 

Asymmetric reactions also occur via oxo metal intermediates 101, 104). Thus, chiral poiphyrin-Fe complexes catalyze oxidation of sulfides with iodosylbenzene in the presence of 1-methylimidazole with high turnover numbers to give optically active sulfoxides in moderate ee (Scheme 45) 105). 

Oxometalloporphyrins were taken as models of intermediates in the catalytic cycle of cytochrome P-450 and peroxidases. The oxygen transfer from iodosyl aromatics to sulfides with metalloporphyrins Fe(III) or Mn(III) as catalysts is very clean, giving sulfoxides, The first examples of asymmetric oxidation of sulfides to sulfoxides with significant enantioselectivity were published in 1990 by Naruta et al, who used chiral twin coronet iron porphyrin 27 as the catalyst (Figure 6C.2) [79], This C2 symmetric complex efficiently catalyzed the oxidation... 

Biooxidation of chiral sulfides was initially investigated in the 1960s, especially through the pioneering work of Henbest et al. [101]. Since then, many developments have been reported and are summarized in reviews [102,103], It would be helpful to reveal some structural or mechanistic details of enzymes involved in theoxidation processes. Biotransformations are also of great current interest for the preparation of chiral sulfoxides, which are useful as synthetic intermediates and chiral auxiliaries. Because extensive review of these transformations is beyond the scope of this chapter, only highlights are discussed in comparison with the abiotic enantioselective oxidations described earlier. Biooxidations by microorganisms and by isolated enzymes are discussed in Sections 6C.12.1. and 6C.12.2. 

An impressive new route to enantiopure syn- and anti- 1,2-diols involves sequential diastereoselective DIBAL reduction of oxalyl-di(/V-iucthyl-/V-methoxyainide) following conversion to a corresponding intermediate / -keto sulfoxide a route that involved control of both reductions by the chiral sulfoxide auxiliary.253 Comparison of / -hydroxy ketone systems with die y-sulfoxide-/ -keto systems used here showed this to be die first example of such asymmetric induction by a y-sulfoxide substituent. 

Chiral sulfoxides are useful both as intermediates and target molecules of synthetic elaboration. The /J-amino-y-hydroxysulfoxidc moiety is one type of chiral sulfoxide which is the intermediate target in the synthesis of (5 )-(+)-sparsomycin. In the key step in this synthesis, the sought after moiety was produced by asymmetric reduction of an oxazoline using DIBAL, in the presence of zinc chloride and at — 78 °C (equation 79)326. 

Steroid synthesis. The sulfoxide (S)-( + )-2 has been used as a chiral synthon for ring D in steroid synthesis. The first step in a synthesis of 11-ketoequilenin (5)3 involves addition of 6-methoxy-2-naphthylmagnesium bromide followed by in situ methylation of the intermediate enolate ion to give 3 in greater than 98% optical purity. This product was converted into optically pure (S, S)-( + )-4, the racemate of which has been converted into( + )-l 1-kctoequilenin. 

The oxidative imination of sulfides and sulfoxides via nitrene transfer processes leads to N-substituted sulfilimines and sulfoximines. This reaction is interesting as chiral sulfoximines are efficient chiral auxiliaries in asymmetric synthesis, a promising class of chiral ligands for asymmetric catalysis and key intermediates in the synthesis of pseudopeptides [169]. However, very few examples of such iron-catalyzed transformations have been described. 

The synthesis of 3 was initiated by reaction of wBuLi with the protected cyclopentenone 2 generating the corresponding vinyllithium reagent by halogen-metal exchange. Subsequent condensation with (S)-(-)-menthyl para-toluenesulfinate (13) provides the enantiodefined sulfoxide substituent in 3.5 Since thermal equilibration of chiral sulfoxides at room temperature is slow, the large sulfur atom is a preferred reaction site in synthetic intermediates to introduce chirality into carbon compounds. 

The enantioselective sulfoxidation of thioanisole for the (R)-isomer by H64D/V68A and H64D/V68S Mbs suggest the sulfoxidation intermediate shown in Scheme 9 could be stabler for (R)-sulfoxide formation over the (S)-isomer. The chiral discrimination for (R)- and ( -intermediates is caused by steric interaction between the transition state and the heme cavity. However, it is... 

Sulopenem (CP-70429 see Tables 1 and 7) has been prepared via this reaction as the key step (G=0/C=S reductive coupling). The total synthesis utilizes L-aspartic acid to generate the chiral precursor 78 of the C-2 side chain, a modified chiron 76 (X = C1) to improve the preparation of the trithiocarbonate intermediate 79, a chemoselective oxalofluoride-based azetidinone N-acylation to give 80 (a procedure that avoids sulfoxide O-acylation), and mild final deprotection conditions of hydroxyl and carboxyl functions. In particular, the chloroallyl ester 81 has been selected, owing to its smooth cleavage by a palladium-mediated transesterification procedure (Scheme 42) <1992JOC4352>. 

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