Prolines esters

Based on these studies, it is obvious that poly(N-acylhydroxy-proline esters) are very slowly degrading polymers. These materials may therefore be useful for long-term applications, such as implantable, multiyear contraceptive formulations. For such applications the degradation rates of poly (lactic acid)/poly (glycolic acid) devices would probably be too rapid. 

Compression-molded devices of poly(N-palmitoyl hydroxyproline ester) (side chain length 16 carbons), poly(N-decanoylhydroxy-proline ester) (side chain length 10 carbons), and poly(JN-hexanoyl-hydrox roline ester) (side chain length 6 carbons) were prepared with dye contents of 1,5,10, and 20% of either -nitroaniline or acid orange. Release curves were obtained by placing the loaded devices into phospate buffer (pH 7.4) at 37 C. The amount of released dye was followed spectrophotometrically in the usual fashion. 

At present there is no reason evident why poly(N-acylhydroxy-proline esters) should not be suitable for the formation of microcapsules or microspheres as well. For microencapsulated drug fonmula-tions the longer degradation times of poly(N-acylhydroxyproline esters) as compared to poly (lactic acid) could again be a distinctive advantage for long-term applications. 

Yu, H., and Langer, R., Pseudopoly(amino acids) A study of the synthesis and characterization of poly(acyl-hydroxy-proline esters). Macromolecules. 22, 3250-3255, 1989. 

The naturally-occurring amino acids are good sources of 1,2-dlfunctionalised compounds so that tertiary alcohol (40) can easily be made from proline ester (39). 

Hydroxamic acids constitute an important class of siderophores, which play a major role in iron solubilization and transport. Some of them are important as therapeutic agents. The Michael addition of nitroacetyl proline esters to allyl acrylate followed by Pd(0)-catalyzed intramolecular allyl transfer and subsequent reduction of the nitro group yields a novel class of cyclic hydroxamic acids related to pyroglutamic acid (Scheme 5.9).85... 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Scheme 6. Substrate modulation in enzymatic resolution of a proline ester...

The numerous synthetic approaches relied principally on the formation of a 5-substituted proline ester by reductive amination followed by cyclization of the lactam ring. 

Very recently, Mordini and coworkers" have overcome the problems associated with the long reaction times that are normally required for the synthesis of hydroxamic acids from esters by performing these transformations under MW irradiation. The protective groups are also well tolerated under these reaction conditions, though a partial deprotection of the feri-butoxycarbonyl (Boc) group was observed in the reaction with Boc-proline ester. Amidic bonds and ketals also survive without any detectable decomposition. All the reactions go to completion in about six minutes, except in the case of the conversion of Boc-protected phenylalanine methyl ester, which required longer reaction times (12 min). 

TBDMS=fert-butyl-dimethylsilyl) X=OAc, OTBDMS Fig. 5.9) other A-(Boc-aminoethyl)-4-(/ /S) substituted proline esters were similarly oxidised (X=H, OCOMe, OSO Me) [61],... 

The alkylation of enamines (126a) (Y = OCH3, OC2H5, O-t-QHg) derived from (S)-proline esters was first described by Yamada et al.148). 

In the only application of this method via N-activation, use of an TV-(chloroformyl)-proline ester leads to the AzAla analogue of the powerful antihypertensive agent enalapril with comparable biological activity/36 ... 

The deprotection of t-Boc proline ester 2a is representative of the general procedure employed, tert-Butyl carbamate (0.217 g, 1.0 mmol) and aluminium chloride (0.134 g, 1.0 mmol) doped on a neutral alumina (1.0 g) were mixed thoroughly on a vortex mixer. The reaction mixture was placed in an alumina bath inside an unmodified household microwave oven (operating at frequency 2450 MHz) and irradiated for a period of 1 min. After completion of the reaction (monitored by TLC, EtOAc-hexane, 9 1 v/v), it was neutralized with aqueous sodium bicarbonate solution and the product was extracted into ethyl acetate (2x15 mL). The ethyl acetate layer was separated, dried over magnesium sulfate, filtered, and the crude product thus obtained was purified by column chromatography to afford pure methyl ester 2b in 88% yield. 

Gallimore WA, Galario DL, Lacy C, Zhu Y, Scheuer PJ (2000) Two Complex Proline Esters from the Sea Hare Stylocheilus longicauda. J Nat Prod 63 1022... 

Lim Y, Choi YH, Park J (1999) A self-destroying polycationic polymer biodegradable poly (4-hydroxy-L-proline ester). J Am Chem Soc 121 5633-5639... 

Kurokawa et al81 reported the enzyme-catalyzed kinetic resolution of racemic N-carbamoyl, A-Boc, N-Cbz proline esters and prolinols using protease and Candida antarctica lipase B. The latter was efficient in the enantioselctive hydrolysis of both N-Boc and N-Cbz proline derivatives with E > 100. 

Diphenylprolinol (4) itself is now commercially available at scale, or it can be prepared several ways (Scheme 16.2) Direct addition of an aryl Grignard reagent to a proline ester leads to the diarylprolinol with a low yield in the range of 20-25%.33 A more efficient route is based on an... 

Removal of the sterically more accessible protons at C-5 was required and hence it was reasoned that kinetic deprotonation conditions were required, namely, strong, nonnucleophilic base and low temperature. Model reactions were carried out initially on 4-keto-L-proline ester 47, in the hope of optimizing the triflation conditions before moving to C-3-alkylated derivatives 53 and 54. 

In 1969 Yamada and coworkers reported the first in a series of investigations on the alkylation of chiral enamines, derived from L-proline esters, with methyl acrylate and acrylonitrile170. The enamines were prepared under the usual azeotropic conditions but were not distilled since this resulted in cyclization, by nucleophilic attack of the enamine on the ester function, or partial racemization171. Optical yields were found to be... 

Table 1 Selected adamantanyl derivatives and their corresponding mass spectral data. HPLC data supplied by the author. Cyclopropyl-fused dehydro pyrrolidines were prepared using (C2H5)2Zn, C1CH2I, and A-Boc-4,5-L-proline ester derivatives in CH2C12 according to the method of co-author Robl (1)...

This principle also governs the separation on the commercially available Chirasil-Val [37,38]. In Chirasil-Val , the chiral entity was incorporated in a polysiloxane backbone for higher thermal stability. Some of the compounds separated on Chirasil-Val contained only groups, such as V-TFA-proline esters, that are able to accept hydrogen bonding. To undergo such an interaction, the diamide phase has to have a conformation where both NH groups point toward the selectand in a conformation similar to the a-helix structure of proteins [36]. 

Reduction of C=C Bonds. The reduction of the C=C double bond of isophorone (26) with Pd/C in the presence of (S)-proline yields the saturated ketone (27) with 60% optical purity (eq 10). - With (S)-proline ester/Pd (or Pt) systems the hydrogenation of ethyl pyruvate, an a-keto ester, was investigated, but only insignificant enantioselectivities were reached. ... 

The stereoselective allylation of aldehydes was reported to proceed with allyltrifluorosilanes in the presence of (S)-proline. The reaction involves pentacoordinate silicate intermediates. Optical yields up to 30% are achieved in the copper-catalyzed ally lie ace-toxylation of cyclohexene with (S)-proline as a chiral ligand. The intramolecular asymmetric palladium-catalyzed allylation of aldehydes, including allylating functionality in the molecules, via chiral enamines prepared from (5)-proline esters has been reported (eq 15). The most promising result was reached with the (S)-proline allyl ester derivative (36). Upon treatment with Tetrakis(triphenylphosphine)palladium(0) and PPh3 in THF, the chiral enamine (36) undergoes an intramolecular allylation to afford an a-allyl hemiacetal (37). After an oxidation step the optically active lactones (38) with up to 84% ee were isolated in high chemical yields. The same authors have also reported sucessful palladium-catalyzed asymmetric allylations of chiral allylic (S)-proline ester enamines" and amides with enantiomeric excesses up to 100%. 

Alkylations and Allylations. The asymmetric alkylation of chiral enamines derived from (S)-proline esters has been disclosed. The a-alkylation of cyclohexanone proceeds with an optical purity of 59%. (5)-Proline catalyzes the alkylation of xanthopurpurin (34) by 2-hydroxytetrahydropyran yielding... 

In general, sila-heterocycles are believed to be promising candidates for the development of silicon-based dmgs and agrochemicals. For example, the sila-proline ester 184 was prepared as part of a systematic study of silicon-containing amino acids and proteins <2000JOM19>. 

Control of absolute stereochemistry in ketone alkylation through the use of chirality in the amine component of an enamine represents a nearly ideal case for asymmetric induction where the chiral auxiliary is present in an equimolar amount. The formation of enamines is generally straightforward, cleavage of the product immonium ion is trivial in most cases, and the amine can be readily separated from the prouct for recovery and reuse. Indeed, the first example of such a process was reported by Yamada in 1969 using proline esters as the chiral amine (equation 28). " ... 

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