Oxazoles 2-amino- from

The total synthesis of the peptide derived macrocycle dendroamide A 163 has been accomplished in 19% overall yield from appropriately protected heterocyclic amino acids. The oxazole amino acid 162 resulted from cyclodehydration of P-ketodipeptide 161 with bis(triphenyl)oxodiphosphonium triflate, with notable chemo- and stereoselectivity <03JOC9506>. 

For a closely related method for the synthesis of a-substituted a-amino acids via rearrangement of allyloxy-substituted oxazoles (derived from At-benzoyl-protected a-amino acids) see p 3448. For the synthesis of substituted 2-aminopent-4-enals by Claisen rearrangement of substituted (l-methyl-3-oxahexa-l,5-dienyl)amines see ref 85. 

In the rearrangement of allyl-substituted oxazoles, derived from Ar-benzoyl protected x-amino acids by cyclization with phosgene524, 525 or with triphenylphosphane/carbon tetrachloride502 as dehydrating agent, high selectivity is more of an exception, e.g., for the geranyl derivative 10524. 

Balaban and Frangopol116 observed that the addition of thionyl chloride precludes the formation of oxazolid-4-one and that the yield of 2,5-diphenyloxazole (PPO) is a function of the amount of added thionyl chloride. Some patents20 21 have described the preparation of hitherto unknown 2,5-diaryloxazoles with amino and dialkylamino substituents at the para position of the benzene ring, for use as photoconductive materials for electrophotography. Recently the reaction has been applied for the one-step synthesis of halfordinol (48), an oxazole alkaloid, from p-hydroxymandelonitrile and nicotinaldehyde.117... 

Kawase described a direct and general synthesis of 2,4-disubstituted 5-(trifluoromethyl)oxazoles 500 from reaction of an A -acyl-A-benzyl amino acid 499 with trifluoroacetic anhydride in pyridine (Scheme 1.136). In general, the best... 

Freeman s group ° prepared a series of 5-amino-4-cyano-2-substituted oxazoles 517 from carboxylic acids and aminomalononitrile tosylate (AMNT) (Scheme 1.140). Presumably, AMNT is acylated by a carboxylic acid using DCC, which produces an intermediate A-acylamino nitrile 516 that is cyclized under the reaction conditions to yield 517. The yields of 517 are fair to excellent, and the reaction tolerates a wide variety of functional groups. This further extended the scope of their earlier work. ° Representative examples are shown in Table 1.35. 

Lakhan and Singh ° described the first direct synthesis of 4-amino-2,5-disub-stituted oxazoles 552 from readily available starting materials. They condensed equimolar amounts of an aroyl cyanide 551 and an aldehyde with anhydrous ammonium acetate to afford 552 in 40-65% yield (Scheme 1.151). The reaction works better for aroyl cyanides containing electron-withdrawing groups. The... 

Previously, these authors reported a general synthesis of 2,4,5-trisubstituted oxazoles 561 from 558 (Scheme 1.153). Addition of an alkyUithium reagent to 558 generated a lithium p-bis(trimethylsilyl)amino enolate 559 that was acylated in situ to produce a p-(acyloxy)-A,A-bis-(trimethylsilyl) enamine 560. Cyclization of 560 to 561 was accomplished using FVP or TMSOTf. 

Bromination of substituted oxazoles can yield normal aromatic substitution products or 4,5- and 2,5-addition products, depending on the reaction conditions. For example, Hassner and Fischer " brominated 2,5-diphenyloxazole 111 with bromine in acetic acid and sodium acetate to prepare 4-bromo-2,5-diphenyloxazole 595 (Scheme 1.163). Similarly, Belen kii and co-workers isolated a mixture of 5-bromo-2-phenyloxazole 596 and 4,5-dibromo-2-phenyloxazole 597 from treatment of 2-phenyloxazole 5 with bromine in refluxing benzene. Lawson and VanSant " isolated 2-amino-5-bromo-4-(trifluoromethyl)oxazole 599a and 5-bromo-2-(methylamino)-4-(trifluoromethyl)oxazole 599b from bromination of 2-amino-4-(trifluoromethyl)oxazole 598a and 2-(methylamino)-4-(trifluoromethyl) oxazole 598b, respectively, with bromine in acetic acid and sodium acetate. 

Chattopadhyay and Pattenden first demonstrated the viability of such a synthetic strategy in a model system designed to construct the basic tris-oxazole core. The oxazole amino alcohol 1573 was prepared from Gamer s acid " 1572 in four steps (Scheme 1.401). Serine benzyl ester was the starting material for 2-(acetoxymethyl)-4-oxazolecarbonyl chloride 1574. Acylation of 1573 with 1574 produced the bis-oxazole amide 1575. The differentially functionalized model tris-oxazole 1576 was then prepared from 1575 in two straightforward steps. 

Ohba and co-workers have demonstrated that A -protected a-amino esters are compatible with the Schollkopf oxazole synthesis cf., 38->39). In the case of ammo esters derived from natural amino acids (e.g., 38), the presence of an additional acidic N-H bond in the AABoc ester substrate necessitated the use of an added excess of metalated isocyanide (2.5 equiv was found to be optimal) to obtain maximal yields. Under optimized conditions, oxazoles (39) were obtained in good yield from iV-Boc glycine, alanine, and phenylalanine. Oxazole formation from iV-Boc serine (which possesses an additional acidic site in its hydroxylic side chain) proceeded in good yield (66%) using 3.5 equiv lithiated methyl isocyanide. Notably, no epimerization was detected in the reaction of N-Boc alanine methyl ester with lithiated methyl or ethyl isocyanide under these conditions. Minor epimerization was observed (91-92% ee product) with substrates that lacked a carbamate NH hydrogen e.g., A -Boc proline methyl ester), however. ... 

The first synthesis of dendroamide A106 was achieved by Bertram and Pattenden [153] followed by reports from other research groups [154], The synthetic route was designed based on the disconnection point A (Figure 8.5). The oxazole amino acid 109 was prepared from oxidation of 107, and subsequent cyclization followed by deprotection of the Z group (Scheme 8.8). In parallel, thiazole derivative... 

If wewakazole contains oxazole amino acids, trichamide and venturamides A and B contain two thiazole amino acids. These compounds were isolated from Trichodesmium erythraeum and Oscillatoria sp. (Buenaventura Bay, Panama). Trichamide A is the first natural product to be isolated from T. erythraeum venturamides A and B have antimalarial activities, with IC50 values around 5 xM. 

The application of this technique has shown that, in most cases, thiazole amino acids have the absolute configuration R. If these thiazole amino acids are the result of cyclization/dehydration between an amino acid and a cysteine, oxazole amino acids may be formed from a serine through a similar mechanism. To facilitate the writing of formulas, the symbols Tzl (thiazole), Tzn (thiazoline), Ozl (oxazole) and Ozn (oxazoline) are often used, and, depending on the nature of the alkyl group, we add the symbol of the normal amino acid (o-LeuTzl, o-ValTzl,... 

More recent examples have employed a milder reagent system, triphenyl-phosphine and dibromotetrachloroethane to generate a bromo-oxazoline, which is subsequently dehydrohalogenated. Wipf and Lim utilized their method to transform intermediate 11 into the 2,4-disubstituted system of (+)-Hennoxazole k Subsequently, Morwick and coworkers reported a generalized approach to 2,4-disubstituted oxazoles from amino acids using a similar reagent combination, triphenylphosphine and hexachloroethane. ... 

Some data were obtained from the photochemical isomerization of amino-isoxazoles. 5-Aminoisoxazoles gave the corresponding azirine (Scheme 21) [70JCS(C)1825] when a4-carboethoxy-substituted derivative was used, no azirine was isolated and the oxazole was the only product obtained (Scheme 21) (72CB748). The azirine intermediate was not observed upon irradiating 3-amino derivatives [91H(32)1765]. 

In NRPs and hybrid NRP-PK natural products, the heterocycles oxazole and thiazole are derived from serine and cysteine amino acids respectively. For their creation, a cyclization (or Cy) domain is responsible for nucleophilic attack of the side-chain heteroatom within a dipeptide upon the amide carbonyl joining the amino acids [61]. Once the cyclic moiety is formed, the ring may be further oxidized, to form the oxazoline/thiazoline, or reduced, to form oxazolidine/thiazolidine (Figure 13.20). For substituted oxazoles and thiazoles, such as those... 

The rhodium acetate complex catalyzed the intramolecular C-H insertion of (/ )-diazo-fR)-(phenylsulfonyl)acet-amides 359 derived from (f )-amino acids to afford in high yield the 6-benzenesulfonyl-3,3-dimethyl-7-phenyl-tetrahydro-pyrrolo[l,2-c]oxazol-5-one 360 (Equation 63) <2002JOC6582, 2005TL143>. 

Heterocyclic ring systems are also used to connect two anthraquinone groups. Typical examples include Cl Vat Red 10 (6.106), which is an oxazole derivative obtained from 2-amino-3-hydroxyanthraquinone and the appropriate acyl chloride, the similar thiazole derivative Cl Vat Blue 31 (6.107) and the oxadiazole derivative Cl Vat Blue 64 (6.108). 

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. ... 

From Nocardia strains several closely related compounds (nocobactins, formo-bactin, amamistatins) were isolated that contain three typically Fe " binding sites, two hydroxamate units, and ahydroxyphenyloxazole stmcture (cf. Sect. 3.2 below). The C-terminus is A-hydroxy-cyc/o-Lys bound to a long chain 3-hydroxy fatty acid, whose hydroxy group is esterified by A -acyl-A -hydroxy-Lys, the a-amino group of which is bound to 2-o-hydroxyphenyl-5-methyl-oxazole-4-carboxylic acid (Table 4). For the amamistatins the configuration of the cyclic lysine was determined as L, the open one as d, and that of C-3 of the fatty acid as (S). The involvement in the iron metabolism was not investigated. 

In NRPS, the cyclization domain catalyzes cyclization of the side-chain nucleophile from a dipeptide moiety such as AA-Ser or AA-Cys (AA = amino acids) to form a tetrahedral intermediate, followed by dehydration to form oxazolines and thiazolines (Scheme 7.1) [20]. The synthesis of a 2-methyl oxazoline from threonine follows a similar mechanism. Once a heterocycle is formed, it can be further modified by reductase to form tetrahydro thiazolidine in the case of pyochelin biosynthesis. Conversely, oxidation of the dehydroheterocycles lead to heteroaro-mahc thiazoles or oxazoles as in the case of epothilone D (Figure 7.2) [21]. 

Trimethyloxazole 257 undergoes photochemically induced [2 + 2] cycloaddition with aromatic and aliphatic aldehydes to provide bicyclic oxazolines 258 with excellent regiochemical and stereochemical control. Diastereoselec-tivities from 75-99% can be achieved, which is the first reported example of a Paterno-Biichi reaction involving an oxazole. The oxetane cycloadducts can be hydrolyzed to a-amino-(3-hydroxy ketones. Other oxazoles have not been evaluated to determine if they undergo the photochemical cycloaddition (Scheme 8.71). 

---