3- hydroxyproline esters synthesis

The DL-hycbox]rproline8, synthesized and resolved by Leuchs and coworkers (496,498-500,502) were prepared by the reactions, malonic ester -f epichlorhydrin -> ethyl j-ehloro-y-valerolactone-a-oarboxylate - a-8-dichloro-y-valerolactone -> ,8-diamino-y-valerolactone - hydroxyproline -f- allo-hydroxyproline. Another synthesis through the intermediates, ethyl-y,8-dibromo-o-benzoylamino- -valerate and y-(benzoylhydroj ) proline, has been reported by Hammarsten (367). 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

The easy processibility of hydroxyproline-derived polyesters is in marked contrast to the unfavorable material properties of most conventional poly (amino acids) that cannot usually be processed into shaped objects by conventional polymer-processing techniques (7). Furthermore, since the synthesis of poly(N-acylhydroxyproline esters) does not require the expensive N-carboxyanhydrides as monomeric starting materials, poly(N-acylhydroxyproline esters) should be significantly less expensive than derivatives of conventional poly(hy-droxyproline). 

ENANTIOSELECTIVE SYNTHESIS OF (Z)-N-CARBOBENZYLOXY-3-HYDROXYPROLINE ETHYL ESTER... 

Under the conditions used in peptide synthesis, unprotected aliphatic hydroxy groups can undergo two types of side reactions they can be acylated or dehydrated, the latter leading to dehydroamino acids. The hydroxy group of serine is a primary alcoholic function and therefore exhibits the highest reactivity. The secondary alcoholic functions of threonine, hydroxyproline, (3-phenylserine, hydroxynorvaline, and hydroxynorleucine, as well as of other noncoded amino acids, are less reactive and thus more suited for use in the unprotected form. The aromatic hydroxy group of tyrosine is more acidic than the ahphatic hydroxy groups nevertheless, it can be acylated to form esters. These are active esters which in turn can react with primary amines to form amide bonds. 

Knight and Sibley began their short asymmetric synthesis of (-)-3 very similarly (Scheme 3) (41,42). Baker s yeast reduction of a 3-oxoproline ester and chemical modification of the resulting (2/J,3S)-3-hydroxyprolinate gave aldehyde... 

The racemic tryptophan derivative 207 was condensed with optically pure proline derivatives following the BOP-Cl protocol. For the synthesis of notoamides C (213) and D (215), proline ethyl ester was used as coupling partner (Scheme 41), whereas the synthesis of stephacidin A (225) and notoamide B (227) employed hydroxyproline ethyl ester 219 (Scheme 43). Towards notoamides C (213) and D (215), the diaste-reomeric diketopiperazines 210 and 211 had to be separated by chromatography. The Fmoc can be replaced by a Boc protecting group and BOP-Cl by HATU [172]. 

As illustrated in Scheme 2, the medicinal chemistry synthesis of MK-7009 used an RCM as the key step to constmct the 20-membered macrocycle [4, 5]. Hence, vinyl isoindoline 8 was coupled with hydroxyproline 9 to form prolinol ester 11 after deprotection of the Boc group. Coupling of 11 with the ferf-leucine linker (4)... 

Recently, and co-workers [41] Zhang reported the first highly efficient protocol for the synthesis of a-amino esters with prolinol-derivated catalyst. The (9-pivaloyl 7ra 5-4-hydroxyproline derivative (Cat. 10) achieved best results. Crucial for efficiency was the addition of small quantities of pentanoic acid. Through this approach, a broad range of chiral a-amino esters were synthesized in good yields (up to 97%) and with high levels of enantioselectivity (up to 93%) (Scheme 15.14). 

Synthesis, Hydroxyproline is synthesized by the method of Mcllwain and Richardson (542). a-Acetyl-S-chloro-y-valerolactone, prepared from acetoacetic ester and epichlorohydrin by the method of Leuchs (497), is converted to a-oximino-8-chloro-y-valerolaetone (A) by the action of nitrosyl sulfuric acid. (A) is reduced to a-aniino-8-chIoro-r-valerolactone (B) by shaking it for 3 days with hydrogen and platinum oxide catalyst. (B) is converted to a mixture of the isomeric DL-hydroxy-prolines by treatment for 2 hours with a saturated aqueous solution of ammoma. The copper salts of the two pairs of optical isomers are pre- > see p. 360. 

Steiner, A., Wessig, R, and Polborn, K., Asymmetric synthesis of 3-hydroxyprolines by photocycli-sation of C(l )-substituted N-(2-benzoylethyl)glycine esters, Helv. Chim. Acta, 79, 1843, 1996. 

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