Oxazolidinone derivatives

In most TiCl2-TADDOLate-catalyzed Diels-Alder and 1,3-dipolar cycloaddition reactions oxazolidinone derivatives are applied as auxiliaries for the alkenoyl moiety in order to obtain the favorable bidentate coordination of the substrate to the catalyst... 

In a more recent study on 1,3-dipolar cycloaddition reactions the use of succi-nimide instead of the oxazolidinone auxiliary was introduced (Scheme 6.19) [58]. The succinimide derivatives 24a,b are more reactive towards the 1,3-dipolar cycloaddition reaction with nitrone la and the reaction proceeds in the absence of a catalyst. In the presence of TiCl2-TADDOLate catalyst 23a (5 mol%) the reaction of la with 24a proceeds at -20 to -10 °C, and after conversion of the unstable succinimide adduct into the amide derivative, the corresponding product 25 was obtained in an endojexo ratio of <5 >95. Additionally, the enantioselectivity of the reaction of 72% ee is also an improvement compared to the analogous reaction of the oxazolidinone derivative 19. Similar improvements were obtained in reactions of other related nitrones with 24a and b. 

The optically active oxazolidinone derivative 3, readily obtainable from serine (see Appendix), is alkylated to give predominantly the cw-product98. The auxiliary is removed by acid hydrolysis to give the 2-amino alcohol. 

We previously described the cyclocoupling of 2-bromoamides onto the carbonyl group of a variety of amides, including 2-bromoamides themselves (ref. 17). The cyclocoupling with DMF affords 2-dimethylamino-oxazolidinone derivatives 12 (ref. 19). Its mechanism has been recently investigated (refs. 14,15b). 

Since 4 has a high inclusion ability for a wide variety of organic compounds 46), it might be useful for various reaction controls. For example, 4 was found to be useful for a selective synthesis of the P-lactam 89 from N,N-diisopropylaeetylformamide (88). Irradiation of 88 in benzene solution and in neat liquid has been reported to give the oxazolidinone derivative 90 exclusively in 86 and 65% yields, respectively, but not any 89 Control of the photocyclization of 88 has been attempted by irradiation... 

The phenylalanine-derived oxazolidinone featured here enjoys three practical advantages over the valine-derived oxazolidinone developed earlier in this laboratory. First, both the intermediate g-amino alcohol and the derived oxazolidinone are crystalline solids which can be purified conveniently by direct crystallization. Second, the oxazolidinone contains a UV chromophore which greatly facilitates TLC or HPLC analysis when it is employed as a chiral auxiliary. Finally, both enantiomers of phenylalanine are readily available, enabling stereocontrol in either sense simply by using the oxazolidinone derived from the appropriate enantiomer. 

Fiuorinated aryl-oxazolidinone derivatives, for example, befloxatone 674... 

Nonbranched amino acids substituted by a fluoroalkyl chain on a carbon distant at least one methylene from the amino acid function have been prepared as racemates by various methods." Under nonracemic form, co-perfluoroalkyl norvaline and norleucine (Rf = C2F5 or more) have been prepared by bromination of an anion of a fluorinated chiral oxazolidinone (derived from RfCH2CH2C02H). Substitution of the bromine atom by an azide and subsequent reduction yield the desired amino acids (Figure 5.10)." ... 

The tandem condensation of isocyanates with an a-ketol in DMF leads to the 2-oxazolidinone derivatives 308 that are dehydrated to the 2(3//)-oxazolones 309 by refluxing in DMSO (Fig. 5.80). ... 

PemoUne is an oxazolidinone derivative that is not structurally similar to amphetamine or methylphenidate. It has fewer stimulating properties than other stimulants and may have less abuse potential. Unlike most other stimulants, pemoline is a Schedule IV agent and does not require a triplicate prescription. However, there are numerous reports of hepatotoxicity in patients taking pemoline (see review by Safer et al. 2001), and it is no longer available in the United States. 

It is a skeletal muscle relaxant, oxazolidinone derivative used in conjunction with other therapeutic agents to treat and discomfort associated with acute mus-... 

As described in Scheme 25, the first method starts with the conversion of an a-amino acid into a p-amino-p-alkyl aldehyde. Then, the chiral aldol condensation between the resulting aldehyde and an oxazolidinone derivative is carried out. In the last step, removal of the oxazolidinone provides the desired product. 

Highly efficient indane-derived C2-symmetric bis(oxazoline)/Cu(OTf)2 complex [36] and transition-metal (Ni, Fe, Co, Cu, Zn, etc.) hydrate complexes of 4,6-dibenzofiirandiyl-2,2 -bis(oxazoline) [37] have been developed for enantioselective Diels-Alder addition of acryloyl oxazolidinone derivatives (Eq. 8A.19). 

With Tartrate-Derived Chiral 1,4-Diol/Ti Complexes A catalytic asymmetric Diels-Alder reaction is promoted by the use of a chiral titanium catalyst prepared in situ from (Pr O TiC and a tartrate-derived (2.R,3.R)-l,l>4,4-tetraphenyl-2,3-0-(l-phenylethylidene)-l,2,3,4-butanetetrol. This chiral titanium catalyst, developed by Narasaka, has been successfully executed with oxazolidinone derivatives of 3-borylpropenoic acids as P-hydroxy acrylic acid equivalents [40] (Eq. 8A.21). The resulting chiral adduct can be utilized for the first asymmetric total synthesis of a highly oxygenated sesquiterpene, (-i-)-Paniculide. 

The enantiomerically pure oxazolidinone derivative 7 (Scheme 4),14,20 was converted into the metathesis precursor 6 by a sequence of carbamate hydrolysis, amide alkylation and protection of the secondary alcohol as the TBDMS ether in a 95% overall yield. Subsequent [Ru-1] catalysed ROM-RCM converted 6 into the desired dihydropyrrole 5. 

The vast majority of successful chiral catalysts to date are based on tartaric acid, BINOL, or oxazolidinone derivatives (Table 26.1). Because derivatives of both of these compounds are commercially available, scale up should not present a problem. If the observed asymmetric induction is found to be low with catalysts based on tartaric acid or oxazolidinones, the sterically hindered titanium BINAP-type complexes should allow for increased selectivity. In addition, nontoxic metal counterions, such as iron and aluminum, do not appear to compromise the asymmetric induction. 

Lead optimization of a series of oxazolidinone derivatives led to the discovery of rivaroxaban l.9 Basic screening tests for this compound demonstrated a highly potent and selective, direct inhibitory action on FXa (IC o = 0.7 nM, Kj = 0.4 nM), excellent in vivo antithrombotic activity and a good pharmacokinetic profile in preliminary studies in animal models (Table 1). The lipophilic chlorothiophene moiety in rivaroxaban is responsible for a decrease in unbound fraction and aqueous solubility and attempts to identify less lipophilic replacements by broad variation were not successful. 

In a broad program of using chiral oxazolidinones in asymmetric synthesis,100 Evans s group published a paper in 1992 on the synthesis and utilization of fV-sulfinyl oxazolidinones as new sulfinylating agent.87 Two chiral auxiliaries were used in the study oxazolidinones derived from (4R, 5S)-norephedrine 74101 and (45)-phenylalanine 75.102 The corresponding fV-sulfinyl oxazolidinones 77 and 78 were obtained either by sulfmylation of the metallated oxazolidinone or by oxidation of the derived N-sulfenamides (Table 15). 

The reaction of the lithiated oxazolidinone derived from (4/f, 5S)-norephedrine 74 and (45)-benzyloxazolidone 75 with arenesulfinyl chloride 76 in THF at -78 °C gave the corresponding Af-sulfinyl oxazolidinones 77 and 78 in modest diastereose-lectivity (32-54% de) in favor of the R diastereomer (Scheme 22). 

Af-(Phenylsulfanylmethyl)oxazolidinones derived from camphor 494 can be lithiated with n-BuLi at —78°C to give the chiral formyllithium equivalent 478683 (Scheme 128). This intermediate added to aldehydes in good yields, but lower stereoselectivity than compound 477, to afford crystalline adducts, which allowed the isolation of the major diastereomer 495. Hydrolysis of these adducts gave a-hydroxy aldehydes, which can be oxidized with PCC to the corresponding a-hydroxy acids. 

The Baeyer-Villiger oxidation of oxazolidinone 202 afforded the previously unknown 5-acyloxyoxazolidin-2-one 203. This intermediate allowed an easy access to several other oxazolidinone derivatives by reaction with different nucleophiles <03SL1903>. 

This coupling procedure with the thioesters proved sensitive to the substitution pattern of both the amino acid and alkene. In contrast, coupling reactions with the M-acyl oxazolidinone derivatives such as 22 proved to be much more effective (Scheme 14) [20]. Mechanistic studies suggested that an alternative pathway was operating in these cases, where reduction of the al-... 

Scheme 14 Alternative acyl-like radical addition reactions with N-acyl oxazolidinone derivatives of amino acids...

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