Oxazolidinone auxiliaries

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. 

As with the acyl oxazolidinone auxiliaries, each of these systems permits hydrolytic removal and recovery of the chiral auxiliary. 

In Entry 5, the aldehyde is also chiral and double stereodifferentiation comes into play. Entry 6 illustrates the use of an oxazolidinone auxiliary with another highly substituted aldehyde. Entry 7 employs conditions that were found effective for a-alkoxyacyl oxazolidinones. Entries 8 and 9 are examples of the application of the thiazolidine-2-thione auxiliary and provide the 2,3-syn isomers with diastereofacial control by the chiral auxiliary. 

Enantioselective Reactions of Organocopper Reagents. Several methods have been developed for achieving enantioselectivity with organocopper reagents. Chiral auxiliaries can be used for example, oxazolidinone auxiliaries have been utilized in conjugate additions. The outcome of these reactions can be predicted on the basis of steric control of reactant approach, as for other applications of the oxazolidinone auxiliaries. 

James R. Gage and David A. Evans 83 DIASTEREOSELECTIVE ALDOL CONDENSATION USING A CHIRAL OXAZOLIDINONE AUXILIARY (2S, 3S )-3-HYDR0XY-3-PHENYL-2-METHYLPROPANOIC ACID... 

As already hinted at above, chiral dioxetanes, obtained through the highly stereoselective [2 + 2] cycloaddition of singlet oxygen to the chiral enecarbamate, provide a convenient preparation of optically active 1,2 diols as building blocks for asymmetric synthesis (Scheme 5) . Reduction of the dioxetane 2c by L-methionine, followed by release of the oxazolidinone auxiliary by NaBH4/DBU reduction, affords the enantiomerically pure like-5 diol (for additional cases, see Table 4 in Reference 19e). 

A promising unprecedented application of the chiral enecarbamates Ic in asymmetric synthesis is based on the ship-in-the-bottle strategy, which entails the oxidation of these substrates in zeolite supercages . In this novel concept, presumably dioxetanes intervene as intermediates, as illustrated for the oxidation of the chiral enecarbamate Ic in the NaY zeolite (Scheme 6). By starting with a 50 50 mixture of the diastereomeric enecarbamates (45, 3 R)-lc and (45, 3 5 )-lc, absorbed by the NaY zeolite, its oxidation furnishes the enantiomerically enriched (ee ca 50%) S -methyldesoxybenzoin, whereas the (4R,3 R)-lc and (4R,3 S)-lc diastereomeric mixture affords preferentially (ee ca 47%) the R enantiomer however, racemic methylbenzoin is obtained when the chirality center at the C-4 position in the oxazolidinone is removed. Evidently, appreciable asymmetric induction is mediated by the optically active oxazolidinone auxiliary. 

Unquestionably, the advantage of the present methodology is that the intermediary dioxetane serves as a vehicle to place the chiral inductor (the oxazolidinone auxiliary) and the racemic substrate to be resolved (the methyldesoxybenzoin) in one and the same zeolite supercage. These represent optimal conditions for efficacious asymmetric induction, a novel application of chiral dioxetanes which merits further elaboration. 

The 3-acyl-2(3F/)-oxazolones function as good dienophiles in cycloaddition reactions with cyclic 2,4-dienes such as cyclopentadienes and anthracenes. Thus, the thermal reaction of 3-acetyl-2(37/)-oxazolone with cyclopentadiene and the hexachloro and hexamethyl derivatives gives endo-cycloadducts exclusively. In particular, the chiral cycloadducts 221 and 223 derived from the diastereoselective Diels-Alder reactions of 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazo-lones with hexamethylcyclopentadiene and 9,10-dimethylanthracene, respectively, are highly useful as chiral 2-oxazolidinone auxiliaries. The conformationally rigid roofed structures play a crucial role in affording excellent chiral induction (Fig. 5.54). 

The thermal cycloaddition of 3-acyl-2(3/7)-oxazolones 157 to dialkyl azodicar-boxylates 228 proceeds smoothly under mild conditions (at 80 °C) to give the regiocontrolled cycloadducts 229 exclusively, although two other possible addition modes exist neither diazetidines 230 (1,2-addition) nor isoxazolidines 231 (1,3-addition) are detected. In the case of chiral N-substituents diastereoselectivities of up to 72% de have been obtained. Treatment of the chiral cycloadducts 229 with acidic methanol gives tra i-5-hydrazino-4-methoxy-2-oxazolidmone derivatives 232 that are precursors for a variety of optically active a-amino acids 233 and 2-oxazolidinone auxiliaries 234 (Fig. 5.56 Table 5.10, Fig. 5.57)7 ... 

The alkylation of enolates from some recently developed 2-oxazolidinone auxiliaries will be briefly discussed. The Diels-Alder reaction of the enantiomerically pure 3-(apocamphane-carbonyl)-2(3//)-oxazolone 13 with anthracene gives, diastereoselectively, a 97 3 ratio of diastereomeric adducts63. Recrystallization followed by removal of the apocamphanecarbonyl auxiliary and acylation gives the diastereomerically pure enantiomer 14 in good yield. Subsequent enolate formation and alkylation gives highly diastereoselective reactions and easily purified products due to the fact that the major product is readily crystallized. Thus alkylation... 

Diastereoselective a-azidation via the chiral oxazolidinone auxiliary provides a valuable means of synthesizing highly substituted phenylglycine 46 (Scheme 18).[811... 

Ceric ammonium nitrate Cerate(2-), hexanitrato-, diammonium Cerate(2-), hexakis(nitrato-O)-, diammonium, (OC-6-11) (16774-21-3), 67,141 Cerium(ill) chloride, heptahydrate (18618-55-8), 69, 89 Cesium carbonate Carbonic acid, dicesium salt (534-17-8), 65, 150 CESIUM THIOLATES, 65, 150 Chiral auxiliary, 65, 173, 183, 203, 215 Chiral oxazolidinone auxiliary, from phenylalanine, 68, 77, 83 Chirasil-Val, 66, 153, 154... 

Ytterbium trifluoromethanesulfonate promoted a radical atom-transfer addition of chiral 3-bromoacetyl-2-oxazolidinones to norbornadiene, which afforded the corresponding 5-ex<9-3-bromo-5-nortricycleneacetic acid derivatives in good yields and with high diastereoselectivity (90-96% de, when using the chiral 4-isopropyl- and 4-benzyl-substituted 2-oxazolidinone auxiliaries).133... 

Bio-Mega/Boehringer Ingelheim have used an oxazolidinone auxiliary in the synthesis of renin inhibitors (e.g., 40) for the treatment of hypertension and congestive heart failure.58 A multi-step derivitization of the oxazolidinone 41 from reaction of (6)-4-(l-methylethyl)-2-oxazolidinone and 4-bromo-4-pentenoic acid yielded the desired compound. 

Three types of reactions were possible for the non-destructive removal of the oxazolidinone auxiliary (Scheme 20) ... 

In conclusion, the animation of enolates of N-acyloxazolidinones with dibenzyl or di-r-butylazodicarboxylates presented the following properties (i) diastereomeric excesses in the range 80-98% (ii) good chemical yields (iii) efficient route to both chiral a-hydrazino and a-amino acid derivatives and (iv) non-destructive removal of the chiral oxazolidinone auxiliaries. 

In both cases, only one diastereomer could be detected using high-temperature H NMR spectroscopy. Removal of the oxazolidinone auxiliary from compounds (S,S)-101 and (/ ,R)-101 by treatment with lithium hydroperoxide followed by acidification and treatment with diazomethane generated the corresponding methyl esters (S)-102 and (/ )-102 which have opposite configuration at C2. Amination of either... 

Chiral auxiliaries can be used in plenty of other reactions, and one of the most common types is the alkylation of enolates. Evans s oxazolidinone auxiliaries are particularly appropriate here because they are readily turned into enolizable carboxylic acid derivatives. 

While the sultame and the oxazolidinone auxiliaries represent carboxylate equivalents, which have to be reduced (and sometimes re-oxidized) to the required aldehyde function at C7, the strength of Enders SAMP and RAMP auxiliaries is their direct use as aldehyde and ketone equivalents. However, Nicolaou et al. [13, 16] for the synthesis of the protected building blocks 17a-c had to give up the correct oxidation state in order to allow necessary later manipulations. Considering the necessity of reduction, the cheaper and recoverable Evans-oxazolidinones 18 appear to be the auxiliaries of choice, as demonstrated by Schinzer et al. [21, 22, 36]. A similar methylation is described in an early publication of De Brabander et al. [38] where sultame 21 was methylated and reduced to the a-methylaldehyde 20b in only two steps in good yield and enantiomeric excess. 

Three different methods were used to remove the oxazolidinone auxiliary from 216a ... 

Analogously, after enolization with Ihmds, hypervalent iodine compounds such as PhI(OAc)2 have been used for the stereoselective synthesis of 2,3-disubstituted succinates by using the chiral oxazolidinone auxiliary (45 )-4-(phenylmethyl)-2-oxazolidinone (equation 19) . 

The 4-phenyl-2-oxazolidinone auxiliary has also been employed in the TiCl4-mediated conjugate additions of allylsi-lanes (eq 58). Analogous reactions using the phenylalanine-derived auxiliary with dimethylaluminum chloride afforded lower selectivities. In these reactions the oxazolidinones perform better than the sultams. 

Removal of the Chiral Auxiliary. In each of the following transformations, the oxazolidinone auxiliary is recovered in high yields (eq 62). 

---