Morpholine-2,5-dione

If mono-hydroxyl functionalized polyethylene glycol), HO-PEG, is added to Ca(NTMS2)2.THF2, then addition of LA affords the diblock PEG-b-PLA (Mn= 15,500, Mn calc = 15,500, Mw/Mn = 1.03).832 Using a similar strategy the reaction of CaFI2 with telechelic diol HO-(PEG)-OH, followed by polymerization of L-LA results in a triblock structure, PLA-b-PEG-b-PLA of narrow polydispersity (1.02-1.08).835 836 Triblock copolymers of morpholine-2,5-diones with PEO have also been prepared in this manner.837... 

Initially PDPs were synthesized by stepwise polycondensation of linear activated depsipeptide [93]. In 1985, Helder, Feijen and coworkers reported the synthesis of PDPs by ROP of a morpholine-2,5-dione derivative (cyclic dimer of ot-hydroxy- and a-amino acid cyclodepsipeptide, cDP) [94, 95]. The ROP method gives an alternative type of PDP by homopolymerization and also allows the copolymerization with other monomers (lactones and cyclic diesters) including LA, GA, and CL to give a wide variety of functional biodegradable materials. The synthesis of PDPs as functional biomaterials has been recently reviewed [17]. 

Feng Y, Klee D, Keul H, Hdcker H (2000) Lipase-catalyzed ring-opening polymerization of morpholine-2,5-dione derivatives a novel route to the synthesis of poly(ester amide)s. Macromol Chem Phys 201 2670-2675... 

Morpholine-2,5-diones have been prepared by intramolecular, nucleophilic cleavage of polystyrene-bound amino acids acylated with a-hydroxy acids (Entry 2, Table... 

This preparation is analogous to the formation of diketopiperazines from dipeptide esters. In a similar approach, morpholine-2,5-diones were obtained by acidolytic cleavage of N-(bromoacety 1)am ino acids from Wang resin (Entry 3, Table... 

Azacyclic monomers containing an endocyclic nitrogen atom which are most commonly subjected to polymerisation in the presence of coordination catalysts include a-aminoacid /V-carboxyanhydrides. However, other monomers of this type, such as morpholine-2,5-dione, have also been subjected to coordination polymerisation. 

Morpholine-2,5-dione (l,4-oxazacyclohexane-2,5-dione) is characterised by the appearance in its molecule of both the <5-lactam and -lactone functions. The coordination polymerisation of this monomer [scheme (22)] has been reported for systems with diethylzinc [178] and tin bis(ethylhexanoate) [150] as catalysts ... 

The polymer formed, poly(morpholine-2,5-dione), is a polydepsipeptide consisting of alternating sequences of a-amino acid and a-hydroxyacid (Table 9.2). 

Morpholine-2,5-dione and its substituted analogue, 6-methylmorpholine-2,5-dione, appeared to undergo copolymerisation with lactide in the presence of the zinc oxide catalyst. The copolymers obtained were characterised by an increased content of a-hydroxyacid units. The copolymerisability of the unsubstituted monomer was comparable with that of lactide. However, the N-methylated monomer was much less susceptible than the unsubstituted one to copolymerisation with lactide [178],... 

Synthesis of Morpholin-2,5-diones via Diastereoselective Halolactonization Mediated by L-Proline Derivatives... 

Poly-p-dioxanone and copolymers Poly-p-dioxanone (PDS) Copolymers of PDS and 1-lactide Copolymers of PDS and glycolide Poly-p-dioxanone-co-morpholine-2,5 dione Copolymers of p-dioxanone and polyethlyene-p-phenylene diglycolate Copolymers of polytrimethylene malonate and p-dioxanone A, B, F, G A, B, G A, B, G A, B, G A, B, G, J A, B, G, H... 

Sn(Oct)2-catalyzed ROP showed that in case of the lipase-catalyzed polymerization, significant amounts of racemization were observed [26]. The lipase-catalyzed ring opening of other 3-alkyl substituted morpholine-2,5-diones was shown as well [27]. 

Polymerization of lactones such as glycolide (G), 1-lactide (LL), dl-lactide (DL-L), p-dioxanone (PD), trimethylene carbonate (TMC), e-caprolactone (CL), 1,5 dioxepan-2-one (DOX), glycosalicylate (GS), morpholine-2,5-dione (MD)... 

PEAs have been synthesized by ring-opening polymerization and polycondensation methods. The first ones were mainly employed to get copolymers of a-hydroxy acids and a-amino acids (i.e., polydepsipeptides) and reported in the literature [4]. Recent works are focused to the use of enzymes (e.g., lipases) as new efficient catalysts for reaction of these morpholine-2,5-diones [5]. It has been demonstrated that the configuration of the a-amino acid moiety did not affect the enzyme-catalyzed polymerization, but in contrast, the configuration of the a-hydroxy acid moiety strongly in-flnenced the polymerization behavior. Unfortunately, ra-cemization of both units was demonstrated to take place dnring polymerization. 

One of the first works applying this approach was Kimura s synthesis of carboxylic acid-functionalized PHAs (mainly PGA) using the functional glycolide (benzyloxy-carbonyl)methyl-l,4-dioxane-2,5-dione [37]. Since then, this regime has been successfully extended to functionalized lactides offering a way of introducing (protected) functional groups such as protected amine, alcohol, and carboxylic acid [38]. In a similar fashion, Feijen has reported on the synthesis of morpholine-2,5-dione derivatives... 

FIGURE 9.3 Functional glycolide, lactide, and morpholine-2,5-dione systems for the synthesis of functional lactide copolymers. 

Z. Pang, et al.. Controllable ring-opening copolymerization of L-lactide and (3S)-benzyloxymethyl-(6S)-methyl-morpholine-2,5-dione initiated by a biogenic compound creatinine acetate. J. Polym. Sci. A Polym. Chem. 50 (2012) 4004-4009, doi 10.1002/ pola.26196. 

Veld, PJ.A., Dijkstra, PJ., Lochem,J.H. and Feijen.J. (1990) Synthesis of alternating polvdepsipeptides by ring-opening polymerization of morpholine-2,5-dione derivatives. Makromol. Chem., 191, 1813-1825. 

S)-Isobutyl morpholine-2,5-dione Porcine pancreatic lipase (10 wt%) M = 9,900, DP = 1.14 using GPC against a polystyrene standard. Reaction time 72 h, conversion 40% atl30°C [58]... 

The enzymatic ROP of six-membered cyclic depsipeptides 3(S)-isopropyl-morpholine-2,5-dione, 3(R)-isopropyl-morpholine-2,5-dione, 3(R,S)-isopropyl-morpholine-2,5-dione, (3S, 6R, S)-3-isopropyl-morpholine-2,5-dione, 3(S)-isobutyl-morpholine-2,5-dione, 3(S)-sec-butyl-morpholine-2,5-dione, 6(S)-methyl-morpholine-2,5-dione and 6(R,S)-methyl-morpholine-2,5-dione has been reported [60]. 

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