Trans-Oxazolines

Amido methanesulfonate 149 was transformed to cfr-oxazoline 150, with a clean inversion of configuration at the a-centre, with K2CO3 in acetone/H20. When 149 was treated with DBU in refluxing CHCI3 the trans-oxazoline 151 was mainly obtained. The trans isomer 151 was more reactive than 150 toward ring-opening reactions . 

The reaction of the p-hydroxy amides with SOCI2 can be solvent sensitive. For example, during the semisynthesis of pachtaxel from baccatin 111, the reaction of hydroxybenzamide 16 with SOCI2 in benzene gave a mixture of isomeric 2-oxo-1,2,3-oxathiazohdines 17a and 17b together with a small amount of the trans-oxazoline 18a. If a polar solvent is used, 18a is formed as the exclusive product. ... 

In their synthesis of the macrocyclic hexapeptide bistratamide D, Meyers and co-workers prepared the tran -oxazoline 70 from the corresponding cw-oxazo-line 69 through several steps, the last of which was cyclization to the oxazoline using Burgess reagent. The net outcome is inversion of the stereocenter at the 5-position of the oxazoline (Scheme 8.25). 

Benzamido allylic acetates 242 and 243 undergo palladium-catalyzed cychza-tion to oxazolines. Excellent yields and very high diastereoselectivity is observed for the conversion of several acyclic primary and secondary benzamido aUyhc acetates to tran -5-vinyl substituted oxazolines 244. The diastereoselectivity of the reaction is determined by the the steric interactions between the R group and the hydrogen of the 7i-allylpalladium complex in the transition state, trans-Oxazolines are obtained since transition state A is favored over transition state B (Scheme 8.66). 

Meyers and Shimano discovered the unusual deprotonation behavior of ethoxy-vinyllithium-HMPA complex (EVL-HMPA) for the deprotonation of the trans-oxazoline 366 and the cw-oxazoline 367. The EVL-HMPA complex is prepared by deprotonation of ethyl vinyl ether with ferf-butyllithium in THE followed by addition of HMPA. Reaction of the frani-oxazoline 366 with both the EVL-HMPA complex and conventional alkyllithium reagents (RLi) resulted in deprotonation at the benzylic 5-position. In contrast, deprotonation of 367 occurred at the 4-position with an alkyllithium reagent RLi, whereas benzylic deprotonation predominated with the EVL-HMPA complex (Scheme 8.117). ° The authors proposed that EVL-HMPA complexes with the 5-phenyl substituent prior to deprotonation. 

The cis-oxazoline 377 (88% ee) was converted to the trans-oxazoline 378 (70% ee) using triethylamine. A two-step sequence then converted 378 to (3-phenylserine 379 thus confirming the cis stereochemistry of 377. 

Pastor and Togni pointed out that the central chirality and the planar chirality in the ferrocenylphosphine ligand 2 are cooperative for stereoselection (the concept of internal cooperativity of chirality) [16,23,24]. As Table 8B1.7 shows, the change of chirality of the stereogenic carbon atom from R to, S results in the formation of the other trans-oxazoline enantiomer with moderate enantiomeric excess. 

A new and simple synthetic approach to substituted 2-oxazolines starts from readily accessible unfunctionalized aromatic/aliphatic olefins and amides, using t-BuOI, prepared in situ from t-BuOCl and Nal. For instance, alkene 129 reacted with p-nitrobenzamide 130 leading to regioisomeric trans-oxazolines 131a,b with retention of the stereochemistry of the starting olefin <07CC3279>. 

Hayashi and Ito have shown that the reaction of methyl isocyanoacetate (MeOCOCH2NC) with aldehydes is catalyzed by gold [339, 408, 752, 1060] or silver [951] complexes. In the presence of ferrocenyl bisphosphines 3.41 (R = CH2CH2NMe2 or CH2CH2N(CH2)5) the reaction is diastereo- and enantio-selective, and provides trans oxazolines 6.131. These oxazolines are precursors of... 

The planar chiral ortho substituted benzaldehyde chromium complexes were also reacted with tosyl methylisocyanide (TosMic) in the presence of K2CO3 in MeOH at 0 °C to give trans-oxazolines with high diastereoselectivity (Eq. 16)... 

The corresponding benzaldehydes without chromium complexation resulted in lower selectivity. Decomplexation and LiAlH4 reduction afforded amino alcohols. Similarly, ethyl isocyanoacetate afforded the corresponding trans-oxazolines with high diastereoselectivity by the reaction with planar chiral benzaldehyde chromium complexes in the presence of LDA in THE at -78 °C (Eq. 17)... 

The reaction conditions using KCN instead of LDA as base (EtOH at room temperature) gave diastereomeric mixture of trans- and cz5-oxazolines. The trans oxazolines obtained from the planar chiral benzaldehyde chromium complexes afforded optically pure a-amino-p-hydroxy acids by decomplexation followed by treatment with acid. 

N-Acylaziridine-2-carboxylates readily rearrange to oxazolines under thennal, acidic, or nucleophilic conditions [91, 123-127]. Treatment of trans-aziridine-2-car-boxylate 176 (Scheme 3.63) with Nal in acetonitrile, for example, resulted in ring-expansion product 177 through the so-called Heine reaction. The reaction involves initial opening of the aziridine ring by iodide and subsequent oxazoline ring-closure by Sn2 displacement of the resultant iodide intermediate [127]. 

A series of chiral phosphinous amides bearing pendant oxazoline rings (50, Ri=H,Tr R2=H,Tr, 51, Ri=H,Tr R2=H,Tr and 54, Ri=H,Tr R2=H,Tr in Scheme 41) have been used as ligands in the copper-catalyzed 1,4-addition of diethylzinc to enones. Two model substrates have been investigated, the cyclic 2-cyclohexenone and the acyclic trans-chalcone. The addition products are obtained quantitatively in up to 67% ee [171]. 

The aza-bis(oxazoline) 14, bearing sterically hindering groups, led to very good results in terms of activity and selectivity, comparable to those obtained from corresponding aza-semicorins or bis(oxazolines). For the enantioselec-tive cyclopropanation of styrene, the trans isomer was obtained in 92% ee... 

Some other groups have studied the opportimity to enhance the diastere-oselectivity of the transformation using the usual copper-bis(oxazohne) catalysts but modifying the carbene source. France et al. [25] observed that the use of (trimethylsilyl)diazomethane associated with a bis(oxazoline) and [Cu(CH3CN)4]PF6 as catalyst precursor allowed the formation of the trans isomer with high yield and selectivity, probably due to the steric bulk of the trimethylsilyl group. 

Rhodium complexes with chelating bis(oxazoline) ligands have been described to a lesser extent for the cyclopropanation of olefins. For example, Bergman, Tilley et al. [32] have prepared a family of bis(oxazoline) complexes of coordinatively unsaturated monomeric rhodium(II) (see 20 in Scheme 13). Interestingly, the use of complex 20 in the cyclopropanation reaction of styrene afforded mainly the cis cyclopropane cis/trans = 63137), with 74% ee and not the thermodynamically favored trans isomer. No mechanistic suggestions are proposed by the authors to explain this unusual selectivity. 

Up to 96% ee were obtained with trans-substituted oxazoline ligands of type 103. 

Entry 9 uses the oxaborazolidine catalysts discussed on p. 505 with 2-bromopropenal as the dienophile. The aldehyde adopts the exo position in each case, which is consistent with the proposed TS model. Entry 10 illustrates the use of a cationic oxaborazolidine catalyst. The chirality is derived from trans-1,2-diaminocyclohcxanc. Entry 12 shows the use of a TADDOL catalyst in the construction of the steroid skeleton. Entry 13 is an intramolecular D-A reaction catalyzed by a Cu-Ws-oxazoline. Entries 14 and 15 show the use of the oxazaborolidinone catalyst with more complex dienes. 

Lowenthal and Masamune (44) investigated the cyclopropanation of trisubsti-tuted alkenes leading to a chrysanthemic acid synthesis. They found that ligand 50c provided poor selectivities in this case (24% de for the trans isomer). Substitution in the 5 position of the oxazolines leads to increased selectivities, with excellent results provided by the BHT ester (94 6, 94% ee), Eq. 32. This ligand proved to be applicable to other trisubstituted and several cis-disubstituted alkenes, providing the corresponding cyclopropanes in ee values of 82-95%. These authors note that catalysts generated from CuOTf, CuOf-Bu, and Cu(II) precursors (with activation) provided similar yields and enantioselectivities. 

Brunner and Berghofer (48) investigated ligands composed of a combination of salicylaldimines and oxazolines. Intriguing effects of the electronic character of the phenol were noted. The electron poor p-nitrophenol 74b provided the trans cyclopropane in 53% ee, compared to 6% ee using the parent phenol ligand 74a. 

The oxidation state of thiazolines and oxazolines can be adjusted by additional tailoring enzymes. For instance, oxidation domains (Ox) composed of approximately 250 amino acids utilize the cofactor FMN (flavin mononucleotide) to form aromatic oxazoles and thiazoles from oxazolines and thiazolines, respectively. Such domains are likely utilized in the biosynthesis of the disorazoles, " diazonimides, bleomycin, and epothiolone. The typical domain organization for a synthetase containing an oxidation domain is Cy-A-PCP-Ox however, in myxothiazol biosynthesis one oxidation domain is incorporated into an A domain. Alternatively, NRPSs can utilize NAD(P)H reductase domains to convert thiazolines and oxazolines into thiazolidines and oxazolidines, respectively. For instance, PchC is a reductase domain from the pyochelin biosynthetic pathway that acts in trans to reduce a thiazolyinyl-Y-PCP-bound intermediate to the corresponding thiazolidynyl-Y-PCP. ... 

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