Hexapeptide cyclization

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). 

Reimer, K., Meldal, M., Kusumoto, S., Fukase, K., and Bock, K. (1993) Small-scale solid-phase O-glycopeptide synthesis of linear and cyclized hexapeptides from blood-clotting factor IX containing 0-(a-D-Xyl-(l-3)-a-D-Xyl-(l-3)-(3-D-Glc)-L-Ser../. Am. Chem. Soc. Perkin Trans /., 925-932. 

The structure of most of these compounds must be considered as quite well established. Deferrideoxyferrichrome, prepared from the parent compound with Raney nickel and H2 at 50 lbs pressure, is identical to a synthetic cyclic hexapeptide obtained by stepwise addition of three residues of NS-acetyl-L-ornithine to triglycine, followed by cyclization (112). The amino acid sequence in ferrichrome A has been established by degradation (112, 113) and confirmed by crystallography (150). Removal of the a—p unsaturated residue of ferrichrome A, ferrirubin and ferrirho-din followed by re-acylation with acetyl gives, in each case, ferrichrysin (63). All four substances must hence have an identical amino acid sequence and we assume for all of these compounds the configuration shown in Fig. 5. 

P. J. Milburn, Y. Konishi, Y. C. Meinwald, and H. A. Scheraga, J. Am. Chem. Soc., 109, 4486 (1987). Erratum ibid., 109, 8123 (1987). Chain Reversals in Model Peptides Studies of Cystine-Containing Cyclic Peptides. I. Conformational Free Energies of Cyclization of Hexapeptides of Sequence Ac-Cys-X-Pro-Gly-Y-Cys-NHMe. 

Kurokawa and Ohfune [71] employ i DPPA in the synthesis of the hexapeptide echinocandin D 125). As shown in Scheme 42, the cyclization of the Unear peptide 124 was accomplished by DPPA to give 125 in 50% yield. There are more applications of DPPA in the synthesis of macrocycUc natural products [72]. DEPC is relatively less commonly used than DPPA. Kishi and coworkers [73] have successfully achieved the synthesis of the macrocyclic antibiotic rifamycin S using DEPC as a macrolactamization promoter. 

Peptide synthesis. In the synthesis of a cyclic hexapeptide, this water-soluble carbodiimide was used for the dehydrative coupling of two tripeptides and also for the cyclization step. 

Bis-o-phenylene pyrophosphite [1, 60, before references]. The reagent is superior to tlicyclohexylcarbodiimide for cyclization of model penta- and hexapeptides it is less satisfactory in the case of tripeptides.3 3A. W. Miller and P. W. G. Smith. J. Chern. Soc., (C). 2140 (1967)... 

Intramolecular reaction of the organoborane with an azide provides a cyclic amine product. For example, in a synthesis of the cyclic hexapeptide echinocandin D, stereoselective hydroboration of the alkene 19 was followed by cyclization to give the substituted pyrrolidine 20 (5.28). ... 

CVclic Peptides. Polymer supp s aid in the synthesis of cyclic peptides (1.10.131. A recent example is the synthesis of cyc/o-(Gly-His)3 2% crude chromatographic yield in a 1% cross-linked, 0.20 mmol/g aminomethyl resin by a bidirectional method (1401. The actual yield of die cyclization step (Scheme 13) is unknown, because the ovoall yield includes the yields of initial attachrnent, five deprotection-coupling steps, and cleavage from the resin. Most importantly, the cyclic hexapeptide contained no detectable amounts of linear or oligomoic cyclic peptides. 

This work studied the oxidation of A-terminal seiyl and threonyl hexapeptides with periodate and the rate of subsequent cyclization. The first separation baseline resolved the unmodified peptide from the hydrated glyoxylyl peptide from its... 

The bicycUc hexapeptide RA-VII (126), an antitumor agent from mbia plants, has been selectively transformed into the thio-peptide (127). This was then cyclized to an oxazole, which was finally hydrolyzed to form [D-Ala-4]RA-VII (128), the epimer of (126). Another bicyclic hexapeptide (129), which is a potent... 

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