Oxazolidine dipeptides

However, it can be difficult to couple to the hindered Hmb-protected amino acids so in cases where the peptide chain contains Ser or Thr, oxazolidine dipeptide derivatives 3 have been employed (Scheme 7). These pseudoproline derivatives induce a turn in the peptide chain disrupting P-sheet formation. 

With peptides that have become aggregated it is frequently not possible to obtain complete reaction, even after carrying out multiple acylation reactions. In such cases it is often necessary to repeat the synthesis, incorporating an Hmb-protected residue (Chapter 5) or an oxazolidine-dipeptide (26-28) two to four residues before the region prone to aggregation. 

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... 

FIGURE 8.9 Synthesis of 2,2-dimethyl-l,3-oxazolidines by reaction of the Fmoc-dipeptide with 2,2-dimethoxypropane (A) giving Fmoc-Xaa-Ser((4 MeMepro)-OH and (B) giving Fmoc-Xaa-Thr(4 MeMepro)-OH. Synthesis of a 2-methyl-1,3-thiazolidine by acylation of the cyclic parent (C) giving Fmoc-Xaa-Cys(YHMepro)-OH. NCA = /V-carboxyanhydridc. 

Symmetrical piperazine-2,5-diones have been obtained in good yields by treating Leuchs anhydrides (l,3-oxazolidine-2,5-diones) with aziridine [70AG(E)162]. The reaction apparently proceeds through the formation of dipeptide aziridides (Scheme 5). 

The resulting product is, however, an N-substituted oxazolidine amino acid, but this can easily be removed by either reductive or oxidative (Fig. 7) procedures. These and similar reactions can be used to prepare y-hydroxy-a-amino acids, arylglycines, a-alkyl-a-amino acids, and a variety of nonproteinogenic dipeptides (Fig. 7). The review by Muzart (58) is an excellent source of further information on the use of Cr compounds in organic synthesis. 

Access to the imino group of oxazolidine-4-carboxylic acid is even more sterically hindered when substitutions are performed at the C2 position. For such cases, the typical procedure is based on the conversion of the desired serine or threonine dipeptides with unprotected hydroxy groups into the oxazolidine rings by reaction with aldehydes or ketones,1139,1691 as described in Vol. E 22a, Section 2.3.2.4. 

Oxazolidine-2,5-diones (276) are the anhydrides of iV-carboxy-a-amino acids. They react with nucleophiles, such as water, alcohols or amines, to give unstable N-carboxy acids, esters or amides which lose carbon dioxide (equation 87). The products (277) are themselves nucleophilic reagents and may react with another molecule of the oxazolidinedione to yield a dipeptide (equation 88). The process may continue, leading to a polypeptide. Chiral oxazolidine-2,5-diones derived from optically active a-amino acids undergo stereospecific polymerization (72C501). 

Heterocydes are common motifs in natural products, which may occur as single, tandem, and multiple moieties within a given molecule (Scheme 8.5) [35-37]. These motifs often provide molecular interaction with nudeotide and protein targets. In the biosynthesis of NRPs, an oxazoline was usually formed from a dipeptide containing serine in the second position upon dehydration (Scheme 8.5) [38]. The syntheses of a thiazoline from cysteine and a 2-methyloxazoline from threonine follow a similar mechanism. These heterocycles can be further custom-made to provide thiazolidines/oxazolidines upon reduction or thiazoles/oxazoles upon oxidation. Enzymatic heterocyclization can be portable, as demonstrated in the synthesis of novel chiral heterocyclic carboxylic adds by hybrid enzymes [39]. 

Muramic acid analogues, e.g. 67, have been synthesized fipom the azide 65 via lactam 66 (Scheme 20). Oxazolidine derivatives reported earlier (Vol.26, Ch.9, ref.37) have been converted into conformationally restricted muramoyl dipeptide analogues. ... 

Mutter and coworkers introduced pseudoprolines, which are Ser or Thr oxazolidines (N and O of the Ser or Thr residue) [60]. They are incorporated as the dipeptides, e.g., Gly-Ser. The oxazoli-dine ring can be opened with TFA-containing cocktails to unprotect the peptides. 

Intramolecular dehydration of 3-hydroxy carboxamides affords the corresponding p-lactams. Side reactions include elimination and formation of aziridines and oxazolidines (eq 29).The efficiency of p-lactam formation is dependent on substrate substituents (including protecting groups for the side-chain amino group) as well as on the choice of azodicarboxylate and P compound. " For example, the dipeptide (33) reacts with DEAD and TPP to give a 2 1 mixture of the p-lactams (34a) and (34b). Control of the labile C-5 stereocenter can be achieved by use oi Triethyl Phosphite instead of TPP (34a) and (34b) are obtained in a >50 1 ratio (eq 30). 3-Hydroxy 0-alkylhydroxamates can also be converted into the corresponding p-lactams (eq 31). ... 

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