Dioxanone derivatives

Dioxanone derivatives.1 The optically active 1,3-dioxanone (acetal lactone) 1 is obtained by reaction of (R)-3-hydroxybutyric acid with pivalaldehyde in the presence of an add catalyst. These derivatives can be used to effect enantio-selective reactions at the 2-, 3-, and 4-positions of (R)-3-hydroxybutyric acid. Thus,... 

Having used their catalytic systems with dienolates derived from unsaturated esters, Denmark performed aldol reactions with the dioxanone-derived dienol ether described above in the context of Carreira s and Campagne s vinylogous aldol reactions (Scheme 21). Here, exclusively, the y product was formed with the nucleophile attacking from the Re face. For all three aldehydes, very good yields (83-92%) and selectivities (74-89% ee) were observed with only 0.01-0.05 mol% of the catalyst. 

A different type of steric shielding method can be used to obtain substituted 6-hydroxy-esters from a dioxanone derived from (R)-3-hydroxybutyric acid and pivalaldehyde (Scheme 14). The... 

Cinchona alkaloid derivatives can also serve as useful Lewis basic catalysts, as very well exemplified by their successful employment in the Morita-Baylis-Hillman (MBH) reaction and its aza variant (aza-MBH), which provide a convenient access to functionalised allylie aleohols and amines. As early as 1999 Hatakeyama and coworkers reported the use of p-isocupreidine (P-ICPD) as a catalyst for the reaction of aliphatic and aromatic aldehydes with 1,1,1,3,3,3-hexafluoroisopropyl acrylate, affording the desired adducts with very high enantioselectivities (Scheme 14.19). The concomitant formation of the dioxanone derivatives lowered the yield in the MBH adducts and caused difficulties in the experimental proeedure. Interestingly, the dioxanone derivatives had the opposite eonfiguration at the alcoholic stereocentre compared to the MBH produet, highlighting an intriguing mechanistic feature of this Lewis-base catalysed reaction. ... 

The diastereoselective indirect alkylation or amination of p-hydroxybutyric acid through 1,3-dioxanones is also known and gives a-aJkylated- or a-hydrazino-P-hydroxy-butyric acid derivatives, respectively. With the 1,3-dioxanone method of alkylation, it is possible to introduce two different alkyl groups diastereoselectively at the a position of P-hydroxybutyric acid. Furthermore, the diastereoselective introduction of alkyl groups at the P position of P-hydroxybutyric acid is also possible via a 1,3-dioxanone derivative. 

At the beginning of investigations on chiral dendrimers in our own group was the question of how to synthesize chiral, non-racemic derivatives of tris(hydroxymethyl)-methane [82], which we wanted to use as dendrimer center pieces. We have developed efficient diastereoselective syntheses of such triols [83-85] from ( R)-3-hydroxybutanoic acid, readily available from the biopolymer PHB [59,60] (cf. Sect. 2.4). To this end, the acid is converted to the dioxanone 52 [86, 87], from which various alkylation products and different aldol adducts of type 53 were obtained selectively, via the enolate (Fig. 20). These compounds have been reduced to give a variety of enantiopure chiral building blocks for dendrimers, such as the core unit 54, triply branching units 55a and 55b or doubly branching unit 56 [1,88]. 

Amination,1 The reaction of the dioxanone 2, derived from (R)-3-hydroxy-butanoic acid, with di-r-butyl azodicarboxylate (14,115-116) provides the derivative 3 in high diastereomeric excess. The same amination of an alkyl (R)-3-hydroxy-... 

Inspired by the biosynthesis of carbohydrates we envisaged a direct de novo synthesis of carbohydrate derivatives by using the DHA-equivalent 4 in a C3+Cn-sirategy. As can be seen from the retrosynthetic analysis, the desired building blocks 5 should be prepared from the dioxanone (4) and an aldehyde component 6 in an organocatalytic aldol reaction... 

Secondly it has been found that a number of trialkylsilyl groups can be added stereoselectively to the /j-position of the C —C double bond in dioxanone 10 (derived from enantiomerically pure 3-hydroxybutanoic acid)23. In this case the presumed silylcuprate is generated from a chlorosilane and a higher-order organocuprate. In the example shown, with addition of phenyldimethylsilyl chloride, a diastereomeric ratio of 91 9 was obtained. Improved ratios were obtained with other groups (e g., 98 2 for trimethylsily 1), but unfortunately none of the latter were susceptible to oxidative cleavage. The first two steps of the procedure produce a mixture of 11 and its silyl enol ether, which is then desilylated to 11 by treatment with tetrabutylammonium fluoride. 

Development of a novel route to the C-7 to C-13 portion e.g. 122) of erythronolides A and B (i.e. 121a and 121b) by Burke makes use of a stereoselective addition of an isopropenyllithium-derived cuprate to homochiral aldehyde (123) as a first, key step (Scheme 20). Formation of allylic alcohol (124) as the major product presumably reflects a 3 chelation controlled pathway vide supra) Subsequent handling of (124), which included as the second critical step a dioxanone to dihydropyran enolate Claisen rearrangement, produces three key subunits, including (122). 

Derivatives of enantiopure a- or p-hydroxyacids are useful reagents. The reactions of (R)- or (5)-3-hydroxybutanoic acid with aldehydes preferentially give c/s-l,3-dioxan-4-ones 1.110. The reactions of the Li enolates of these dioxanones... 

The reaction of A -Fmoc-L-leudnal (139) with l,l,l>3,3>3-hexafluoroisopropyl acrylate (140) proceeded smoothly in the presence of a stoichiometric amount of cinchona alkaloid 141, even at very low temperature, to give a 6 1 mixture of j yw-ester 142 and dioxane derivative 143 (Scheme 1.62). However, the same reaction with N-Fmoc-o-leucinal (ent-139) turned out to be sluggish and only a mixture of dioxanones 143 was obtained in low yield. Thus, it can be concluded that the (/ )-selectivity of the chiral amine catalyst matches well with L-config-uration of the substrate, leading to high yn-selectivity. ... 

Barbas et al. disclosed similar reaction conditions and studied various DHA derivatives. Cyclic analogs tend to give the desired aldols, while TBS- or Bn-protected derivatives are not reactive [73]. A series of proline derivatives, analogs, and dipeptides were screened as catalysts for this transformation [74, 24, 67b]. Overall, the best results were generated by proline itself. The reaction of dioxanone 54 with benzaldehyde (2b) catalyzed by silyloxyprohne can also be performed in the presence of water, giving aldol 53 stereoselectively in 77% yield [75]. 

Absorbable suture materials are catgut (collagen derived from sheep intestinal submucosa), reconstituted collagen, polyglycolide (e.g., Dexon , Dexon II , Dexon S ), poly(glycolide/lactide) random copolymer (e.g.. Vicryl ), antimicrobial-coated Vicryl (Vicryl Plus ), poly-/ -dioxanone (e.g., PDS , PDSII PDS Plus), poly(glycolide/trimethylene carbonate) block copolymer (e.g., Maxon ), poly(glycolide/e-caprolactone) (e.g., Monocryl ,... 

Biodegradable polymers can be classified into three categories according to their origin (i) synthetic polymers, particularly aUphatic polyesters, such as poly (L-lactide) (PLA) [1-3], poly(e-caprolactone) (PCL) [4—6], poly(p-dioxanone) (PPDO) [7-9], and poly(butylene succinate) (PBS) [10-12] (ii) polyesters produced by microorganisms, which mainly correspond to different poly(hydroxyalkanoate)s (e.g., poly(P-hydroxybutyrate) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate)) and (iii) polymers derived from natural resources (e.g., starch, cellulose, chitin, chitosan, lignin, and proteins). 

The following describes the syTnthesis, physical characteristics and in vitro/in vivo properties of poly(p-dioxanone) and its copolymers with other lactone derived absorbable polyesters and related structures, as well as the synthesis of the monomer, p-dioxanone. 

Copolymers of p-dioxanone and alkylene oxides have also been prepared (Bezwada and Shalaby, 1991) (Figure 11). These crystalline copolymers can be either blocky or branched. Diblock (AB) and triblock copohaners (ABA) are derived from monofunctional and difunctional poly(alkylene oxides), respectively, while branched copolymers, are formed from pohdunctional poly(alkylene oxides). Polymerization occurs by reacting p-dioxanone with the desired type and amount of poly(alkylene oxide) in the presence of an organometallic catalyst at elevated temperatures. 

Allograft bone has been very extensively investigated as a commercial bone graft material. One of the first studies on the development of an injectable lysine-derived polyurethane bone graft investigated an LDI-based carrier for demineralized bone matrix [18]. An LDI-poly(p-dioxanone-co-glycolate) prepolymer was mixed with demineralized bone matrix to form a reactive putty. Implantation of the putty in an intramuscular site did not elicit an adverse inflammatory response. Several more recent studies have... 

R-3-hydroxybutyrate (3HB) was reported to be used for the synthesis of carbapenem antibiotics [6]. Other 3-hydroxy acids were also reported to be used as chiral building blocks for the synthesis of macrolides such as pyrenophorin, col-letodiol, grahamimycin A1 and elaiophylidene [6]. The transformation of 3-hydroxyaIkanoates (3HA) to their dioxanone enolates allows the subsequent synthesis of various 3HA derivatives. 3HB dioxanone enolates can be used as intermediates for synthesis of beta-lactones and 2-aIkylated 3HB [6]. 

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