Bislactim ester ethers

The synthesis of Abu[PO(OH)2]-peptides is also accomplished via the use of Fmoc-Abu-[PO(OAl)2]-OH (22) with the allyl phosphate ester being cleaved by Pd(0)-mediated treatment. Fmoc-Abu[PO(OAl)2]-OH (22)t101] is prepared from Schollkopfs (-)-bislactim ethyl ether 21f102] by a four-step procedure that involves initial treatment of the lithium salt of... 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

Ail extremely useful method for the asymmetric synthesis of substituted amino acids, in particular glutamic acids, is based on optically active bislactim ethers of cyclodipeptides. The lithium etiolates of bislactim ethers (which are prepared easily from amino acids) undergo 1,4-addition to various a,/ -unsaturated esters to give -substituted 2,5-dihydropyrazine-propanoates203-205 with high diastereofacial selectivity, ratio (R/S) > 140-200 1. 

In a further extension of this method, the enolate of the bislactim ether cyclo(L-Val-Gly) or cyclo(L-Val-Ala) were added to methyl (Z)-3-chloro-2-butenoate. The adduct is again a (Z)- ,/l-unsaturated ester and was obtained as a single diastereomer (d.r. > 99 l)207. For further examples see references cited ill the text. 

Treatment of the bislactim ethers with two equivalents of 0.25 N hydrochloric acid at room temperature leads to their hydrolysis to their constituent amino acid esters under these conditions (Scheme 56). The hydrolysis does not proceed via the piperazine-2,5-dione since the products are the esters and not the free amino acids. The rate of hydrolysis depends on the number and nature of the substituents at the 3 and 6 positions (83CJC1397). 

The disadvantage in using such symmetrical bislactim ethers is that half the chiral auxiliary ends up as part of the product molecule thus only half of the auxiliary can be recovered and reused. This drawback is avoided in the mixed bislactim ether prepared from a chiral auxiliary (L-valine) and a racemic amino acid (e.g., DL-alanine). Regiospecific deprotonation followed by diastereoselective alkylation leads to the required a-methyl amino acid ester (193) (83T2085) the de is >95%. In this method, the chiral auxiliary (L-valine) is recovered intact. (Scheme 59). 

An interesting sidelight is that when the methyl group at position 3 of the bislactim ether is replaced by hydrogen, the diastereoselectivity of the alkylation drops to 90-95% (83T2085). The product obtained on acid hydrolysis is an a-unsubstituted amino acid ester (194) (Scheme 60). 

A carbene has been generated at position 3 of the bislactim ether derived from cyclo(L-Val-Gly) via the lithio derivative and the diazo compound. The carbene has been trapped by an acetylene to provide a cyclopropene [88AG(E)433]. Hydrolysis with 0.1 N HC1 leads to the cyclopropene aminoacid esters (Scheme 70). 

A new carbon-carbon bond is formed during the reaction of lactim ethers with compounds containing active methylene groups, such as malonic ester and its derivatives, acetylacetone, barbituric acid, rhodanine, nitromethane, and oxindole.8 9 33 100-102 Examples are the condensation of the lactim ether of tetrahydro-/S-carbolinone with acetoacetic ester103 [Eq. (5)] and the condensation of the bislactim ether of 2,2 -dipyrrolidine-5,5 -dione (48) with butyl cyanoacetate20 [Eq. (6)]. Another instance is the reaction of 2 (R = Me) with 2-phenyloxazolin-5-one, to give 3,4-pentamethyleneimidazoles (49) via the intermediate 4-(homopiperid-2-ylene)oxazolin-5-one (50)104 (Scheme 16). 

Reaction of the Titanated Bislactim Ether. The titanium derivative of the bislactim ether of cyclo(L-Val-Gly) reacts with alkyl aldehydes, aryl aldehydes, and a,(3-unsaturated aldehydes highly diastereoselectively to give almost exclusively the syn addition products (eq 2). Hydrolysis with dilute Trifluo-roacetic Acid affords (2R, 35 )-(3-hydroxy-a-amino acid methyl esters. a-Amino-y-nitro amino acids can be obtained by 1,4-addition of the titanated bislactim ether to nitroalkenes and subsequent hydrolysis of the adduct. ... 

Schollkopf, U., Busse, U., Lonsky, R., and Hinrichs, R., Asymmetric syntheses via heterocyclic intermediates. Part 31. Asymmetric synthesis of various non-proteinogenic amino acid methyl esters (functionalized in the carbon chain) and amino acids by the bislactim ether method, Liebigs Ann. Chem., 2150, 1986. 

Peptide formation with an A-protected, optically pure aminocarboxylic acid is an alternative means of obtaining diastereoisomeric derivatives of chiral aminoalkylphos-phonic acids, the diastereoisomeric products being distinguishable on a quantitative basis by P NMR spectroscopy for example, A-boc-L-alanine was used to distinguish the enantiomers of diethyl (a-aminobenzyl)phosphonate. The reaction between an enan-tiomerically enriched sample of 125 (R = H) and L-leucine methyl ester hydrochloride in the presence of DCC was followed by HPLC separation of the l,l- and D,L-peptides 126 (R = H ratio 95.3 4.7), and essentially the same procedure was applied to an analysis of 125 (R = OCH2Ph), as prepared using the bislactim ether procedure (see Section IV. C.2.b) when the final product consisted of a mixture of R,S and S,S diastereoisomers in the ratio 87.4 12.6 ... 

GC studies) bislactim ethers 2R,5R)-4a, (25,5/ )-4a, (2/f,5/f)-4b, and (2S,5R)-4h were subsequently hydrolyzed with hydrochloric acid at 0°C to jdeld the respective P-(trimethylsilyl)alanine esters (R)-5a and S)-5a and the P-(trimethylgermyl)alanine esters (7 )-5b and (S)-5b. As shown by H-NMR studies using the chiral solvating agent (R>(-)-l-(9-anthryl)-2,2,2-trifluoroethanol, the enantiomeric purities of these esters were >98 % ee. Hydrolysis of the esters (R)-5a, (S)-5a, (R)-5b, and (S -5b in boiling hydrochloric acid and subsequent treatment of the resulting a-amino acid hydrochlorides with propylene oxide yielded the title compounds (R)-la, (S)-la, (R)-lb, and f5)-lb as colorless crystalline solids. 

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