Intramolecular oxazolidinone

Asymmetric Diels-Alder reactions. Unlike methyl crotonate, which is a weak dienophile, chiral (E)-crotonyl oxazolidinones when activated by a dialkylaluminum chloride (1 equiv.) are highly reactive and diastereoselective dienophiles. For this purpose, the unsaturated imides formed from oxazolidinones (Xp) derived from (S)-phenylalanol show consistently higher diastereoselectivity than those derived from (S)-valinol or (IS, 2R)-norephedrine. The effect of the phenyl group is attributed in part at least to an electronic interaction of the aromatic ring. The reactions of the unsaturated imide 1 shown in equation (I) are typical of reactions of unsaturated N-acyloxazolidinones with cyclic and acyclic dienes. All the Diels-Alder reactions show almost complete endo-selectivity and high diastereoselectivity. Oxazolidinones are useful chiral auxiliaries for intramolecular Diels-Alder... 

N-(2-Hydroxypropyl)carbamates (8.139, Fig. 8.13,b) are prodrugs that resemble the A-(2-hydroxyphenyl)carbamates discussed above. Here, activation yielded the tranquilizer mephenoxalone (8.140, Fig. 8.13,b) and an alcohol or a phenol such as paracetamol. Other active oxazolidinones could be obtained by replacing the MeO group in 8.139 (Fig. 8.13, b) with another substituent. For this series, the mechanism of activation is not an intramolecular nucleophilic attack, but, rather, decomposition of the deprotonated carbamate group as shown in Fig. 8.7,b, Reaction b, with the intermediate isocyanate being trapped to form the oxazolidinone ring. 

Treatment with amines of the type 279 generated the intermediate oxazolidinone 280, which underwent thermal decarboxylative formation of the azomethine yhde. Subsequent in situ intramolecular cycloaddition formed the products 281 and 282 in 63% yield and in a 1 1.2 ratio for n=l. Replacing toluene for acetonitrile, for n = 2, gave comparable yields and an improved ratio of 1 2.1 in favor of 281 (Scheme 3.93). 

Evans has utilized Cu(ll)-bis(oxazoline)-mediated Diels-Alder reactions as the key step in several total syntheses. In 1996, Evans and co-workers used bu-box ligand 3 in the intramolecular Diels-Alder reaction of oxazolidinone 87 to form cycloadduct 88 enantioselectively, as shown in Figure 9.31. Compound 88 was subsequently converted to (-)-isopulo upone 89. 

Chiral Rh(II) oxazolidinones Rh2(BNOX)4 and Rh2(IPOX)4 (25a,b) were not as effective as Rh2(MEPY)4 for enantioselective intramolecular cyclopropanation, even though the steric bulk of their chiral ligand attachments (COOMe versus i-Pr or CH2Ph) are similar. Significantly lower yields and lower enantioselectivides resulted from dinitrogen extrusion from prenyl diazoacetate catalyzed by either Rh2(4.S -lPOX)4 or Rh2(4S-BNOX)4. This difference, and those associated with butenolide formation [91], can be attributed to the ability of the carboxylate substituents to stabilize the carbocation form of the intermediate metal carbene (3b), thus limiting the Rh2(MEPY)4-catalyzed reaction to concerted carbene addition onto both carbon atoms of the C-C double bond. 

Less satisfactory results have been frequently encountered in the related asymmetric cycloaddition of a vinyl epoxide to an isocyanate as in Scheme 8E.30 [160]. The modest enantioselectivities of this process are indicative of the competitive intramolecular nucleophilic addition with enantioface exchange. When the oxazolidinone was generated from an achiral substrate, somewhat higher enantioselectiviites were obtained presumably due to superposition of the enantioselection obtained in the ionization step. 

The final example in this section features a rare instance where the electrophilic center is s -hybridized carbon, as most cyclative cleavages involve the attack of carbonyl derivatives. Oxazolidinones are formed cyclatively18 by the displacement of a sulfonate ester by an acylsulfonamide (Fig. 5). In a variant19 of this cyclization, a quasi-meso bis-sulfonate partitions into a pair of quasi-enantiomeric sulfonates, one resin bound and the other cleaved, depending on the direction of intramolecular cyclization. The resin-bound enantiomer can then be displaced by an external nucleophile. 

Bach and coworkers [88] reported on intramolecular chloroamination reactions with FeCl2 as catalyst starting from 2-alkenyloxycarbonyl azides. TMSC1 was found to be an essential additive for the efficient addition to double and triple bonds. The corresponding oxazolidinones were obtained in moderate to high yields and with high diastereoselectivity (Scheme 3.14). 

Nitrogen nucleophiles also react smoothly. The reaction of optically active propargyl mesylate 198 with aniline without a catalyst gives 200 with inversion. However, the Pd-catalysed reaction affords 199 with retention of stereochemistry [44], The 4-ethenylidene-2-oxazolidinone 202 is obtained by intramolecular reaction of the biscarbamate of the 2-butyn-l,4-diol 201 [45],... 

Schering-Plough uses (S)-4-phenyl-2-oxazolidinone in the large-scale production of their cholesterol absorption inhibitor Zetia (ezetimibe) (11) (Scheme 23.l).40 2 Condensation of the alcohol 12 with imine 13 in the presence of a Lewis acid such as TiCl4 and tertiary amine base yields compound 14. Silylation followed by intramolecular cyclization with tetrabutylammonium fluoride (TBAF) yields the protected ezetimibe 15. Removal of the protecting groups is carried out with weak acid to afford Ezetimibe (11). 

In search for control of absolute stereochemistry, the reaction of thio-chalcones was investigated with unsaturated amides bearing an Evans chiral oxazolidinone [223] and dimenthyl fumarate [224, 225]. For the first time with thiocarbonyl compounds, the efficiency of Lewis acid addition was demonstrated, and reactions could be conducted at room temperature. With EtAlCl2 (Table 4, entry 2) or A1C13 (entry 3), levels of induction up to 92% were attained for the endo isomer. Yb(OTf)3 in DMSO also caused the acceleration of the reaction with chiral acrylamides with p-facial selectivity [226]. This group has also reported [227] an intramolecular hetero Diels-Alder reaction with divinyl thioketones and the double bond of an allyloxy group (Table 4, entry 4). 

This method, employing methylation by Mel, was used to synthesise pheromones such as (S)-sulcatol 416.176 The oxazolidinone protecting group features a safety-catch which is released by treatment with acid intramolecular assistance to hydrolysis of the secondary amide 415 rapidly generates the free alcohol product 416. 

Oxazolidinones are the products of the acid-catalyzed condensation of a-hydroxyamides with aldehydes and ketones (equation 178). Tertiary amides derived from pyruvic acid undergo intramolecular cyclization when irradiated (equation 179) (78JOC419). Treatment of the a-bromo amide (308) with sodium hydride yields inter alia the dimeric oxazolidinone (309), presumably by way of an a-lactam, which adds to the carbonyl group of a second molecule of the amide (equation 180) (80JCS(P1)2249). 

Vinyl-substituted 2-oxazolidinones 208 were synthesised by a catalytic <02JOC974> and also asymmetric intramolecular aminopalladation of readily available derivatives of (Z)-2-buten-l,4-diol 207 <02JA12>. 

The chiral auxiliary approach. Poncas group has worked with chiral sulfur moieties like 10-methylthioisoborneol, Oppolzer s camphorsultam or chiral oxazolidinones which gave excellent results in stereo control and yields [95-100]. Recently they have reported that chiral alkynylthiols like 46 exhibit excellent diastereoselectivities in both inter- and intramolecular PKR, and have used this approach for the synthesis of 47, an intermediate in the synthesis of (+)-15-nor-pentelenene (48) (Scheme 15) [101,102]. 

Another illustration of the role of the conformational mobility on the levels of the observed asymmetric induction is shown by the intramolecular photon cycloaddition of cinnamyl derivatives of vinyl glycine 73 into a mixture of 74 and 75 (Scheme 17). In the sensitized reaction and for steric reasons, the attack of excited styrene on the vinyl oxazolidinone 76 gives mainly 77 [55]. 

The benzo-fused oxazocine 108a smoothly ring-contracted to the rigid [6.5.5]- tricyclic-fused oxazolidinone 164 by an intramolecular SN2 process (Equation 15) <2002TL8025>. 

The inter- and intramolecular Diels-Alder reactions of furans, and their applications to the synthesis of natural products as well as synthetic materials, were reviewed <1997T14179>. HfCU promoted the endo-seXccuve. inter-molecular Diels-Alder cycloadditions of furans with a,/3-unsaturated esters <2002AGE4079>. The cycloaddition between furan and methacrylate was also achieved under these conditions, providing, however the o-isomer as the major cycloadduct. A catalytic enantioselective Diels-Alder reaction between furan and acryloyl oxazolidinone to provide the < 46i-adduct in 97% ee was achieved by using the cationic bis(4-fer7-butyloxazoline)copper(ll) complex 55, as shown in Equation (41) <1997TL57>. 

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