Ester epimerization

Syntheses are facilitated by the stability of boronic esters, which generally behave as ordinary organic compounds and can be isolated and handled by ordinary techniques of organic chemistry. Some a-halo boronic esters epimerize easily and are best used quickly without purification, but the other intermediates may generally be chromatographed, and many are distillable1 - 3. 

The uncatalysed hydrolysis of the 1,3,2-dioxaphosphorinane (70) is slower than that of the ester epimeric at phosphorus because of the generalized anomeric effect, but some antibody preparations are able to reverse this order. ... 

One of the C(15) epimeric thio esters (B) cyclizes more slowly than the other (by a factor of 03. 15) due to steric repulsions involving the methyl group at C(15). After lactonization, the uncyclized diastereomer was recovered and used for the synthesis as following. 

Hiltnnen, J. K., Palosaari, R, and Knnan, W.-H., 1989. Epimerization of 3-hydroxyacyl-CoA esters in rat liver. Journal of Biological Chemistry 264 13535-13540. 

Intramolecular cycloadditions of 4/f-pyrido[l,2-n]pyrimidin-4-ones 235 (R = H, Me Ph) and MeNHOH HCl gave tetracyclic isoxazolo derivatives 237. In the case of 235 (R = Me) a minor epimer 238 was also isolated (00JCR(S)414). Similar reaction of 235 (R = H, Me, Ph) and sarcosine ethyl ester HCl afforded an isomeric mixture of epimeric tetracyclic pyrrolo derivatives 239 and 240. In the reaction of 235 (R = H) and PhCHjNHCHjCOOEt only one product 241 was obtained. 

The use of tetra-n-butylammonium fluoride (54) in an aprotic solvent such as acetonitrile may be more advantageous. Foster and colleagues (19, 37) have effected an SN2 type of reaction using this reagent in the conversion of l,2 5,6-di-0-isopropylidene-3-0-p-tolylsulfonyl-D-allofura-nose into the C-3 epimeric fluorodeoxy derivative. Note that whereas potassium fluoride is ineffective in displacing secondary sulfonate esters in sugars, tetra-n-butylammonium fluoride is capable of effecting a displacement with Walden inversion even in a furanose drivative. 

In its present form, intermediate 12 is not a viable substrate for the crucial Dieckmann condensation it must undergo prior epimerization at C-16. When intermediate 12 is treated with sodium methoxide in hot methanol, enolization at C-16 occurs and an equilibrium is established between 12 and a diastereomeric substance, intermediate 11. Once formed, 11 can either revert back to 12 through the planar enolate form, or it can participate in a productive cyclization reaction to give a new six-membered ring. Under these conditions, the desired transformations take place with exceptional facility to give, after acidification of the reaction medium, enol ester 10. 

When a cold (-78 °C) solution of the lithium enolate derived from amide 6 is treated successively with a,/ -unsaturated ester 7 and homogeranyl iodide 8, intermediate 9 is produced in 87% yield (see Scheme 2). All of the carbon atoms that will constitute the complex pentacyclic framework of 1 are introduced in this one-pot operation. After some careful experimentation, a three-step reaction sequence was found to be necessary to accomplish the conversion of both the amide and methyl ester functions to aldehyde groups. Thus, a complete reduction of the methyl ester with diisobutylalu-minum hydride (Dibal-H) furnishes hydroxy amide 10 which is then hydrolyzed with potassium hydroxide in aqueous ethanol. After acidification of the saponification mixture, a 1 1 mixture of diastereomeric 5-lactones 11 is obtained in quantitative yield. Under the harsh conditions required to achieve the hydrolysis of the amide in 10, the stereogenic center bearing the benzyloxypropyl side chain epimerized. Nevertheless, this seemingly unfortunate circumstance is ultimately of no consequence because this carbon will eventually become part of the planar azadiene. 

Enolates derived from various imino compounds have been sulfinylated in reactions analogous to those shown by equations (14) and (15). Some representative examples are shown in equations 16-18. Here again, these compounds have been utilized in asymmetric syntheses. Addition of sulfinate ester 19 to a THF suspension of a-lithio-N,N-dimethylhydrazones, derived from readily available hydrazones of aldehydes and ketones, leads to a-sulfinylhydrazones in good yield, e.g. 53 and 54 (equations 16 and 17)85,86. Compounds 53 and 54 were obtained in a 95/5 and 75/25 E/Z ratio, respectively. The epimer ratio of compound 53 was 55/45. Five other examples were reported with various E/Z and epimeric ratios. 

Bei Ausbildungeines neuen Chiralitatszentrums werden epimere Hydroxy-carbon-saureester gebildet, deren Verhaltnis von der Art des Losungsmittels abhangt13. Auch nach Meerwein-Ponndorf nicht-reduzierbare Oxo-carbonsaure-ester konnen mit Natriumboranat in Reaktion gebracht werden14. 

Although these Boc derivatives underwent methylation with poor selectivity (compared to 3-amino-N-benzoyl butanoates [106] and Z-protected methyl 4-phen-yl-3-aminobutanoate [107]), epimers were succesfully separated by preparative HPLC or by flash chromatography. However, saponification of the methyl ester caused partial epimerization of the a-stereocenter and a two-step (epimerization free) procedure involving titanate-mediated transesterification to the corresponding benzyl esters and hydrogenation was used instead to recover the required Boc-y9 -amino acids in enantiomerically pure form [104, 105]. N-Boc-protected amino acids 19 and 20 for incorporation into water-soluble /9-peptides were pre-... 

However, upon dissolution, an epimerization of the anions can occur in the presence of acidic counter-ions. This is particularly true for 16a-16d [39]. The nature of the solvent (MeOH, CHCI3) plays a crucial role on the kinetics of epimerization and the position of the resulting equilibrium. For anions made with a 2R, 3R) tartaric backbone, a A configuration is always preferred in MeOH the selectivity, obtained after a slow equilibration, being independent of the nature of the ester alkyl chain (diastereomeric ratio (d.r.) 3 1). However, in chloroform, the A diastereomer is rapidly obtained and the selectivity is best if the ester side chain is sterically demanding (d.r. 2 1 to 9 1 from 16a to 16d) (Scheme 16). 

To obtain this compound the key step consisted in the epimerization of the C-5 in compound 6. This was acomplished by triflation of the alcohol 6 and nucleophilic substitution of the triflate by a large excess of tetrabutylammonium acetate in dichloromethane. A controlled (4 °C, 3 h) basic methanolysis of the enol benzoate led to the keto-ester 11" whose hydroxyl functions at C-4 and C-6 were simultaneously deprotected under acidic conditions to furnish 12. Finally a Zemplen deprotection of the 5-acetoxy group led to 13 obtained in five steps and 11% overall yield from 6 (figure 4). 

As for the synthesis of 5-e/j/-KDG, compound 6 seemed to be a suitable precursor of the methyl ester of 5-deoxy-KDG 20 since only the C-5 hydroxyl was unprotected. In this case the key step was not the epimerization but the removal of that hydroxyl. Our attempts of radicalar deoxygenation of 6 were unsuccessful because the intermediate radical was intramolecularly trappy by the C-2.C-3 double bound. Therefore we first reduced the double bond and then converted the resulting diastereoisomeric alcohols 14 into the corresponding triflates 15 which were submitted to the action of sodium iodide. Finally the iodides 16 Aus obtained were hydrogenolyzed in the presence of diisopropylethylamin to give 17. 

---