Bislactim ethers synthesis

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. 

The Schollkopf bislactim ether cuprate was also used in the first total synthesis of the antimycotic dipeptide chlorotetaine (equation 19)58. In this case, however, the nucleophilic addition to 4-methylene-2-cyclohexenone did not proceed regioselectively since a 63 37 mixture of the 1,6- and 1,4-adduct was obtained. The 1,6-addition product was converted via several steps into diastereo- and enantioselectively pure chlorotetaine. 

M. Ruiz, T. M. Ruanova, O. Blanco, F. Nunez, C. Pato, and V. Ojea, Diastereoselective synthesis of piperidine imino sugars using aldol additions of metalated bislactim ethers to threose and erythrose acetonides, J. Org. Chem., 73 (2008) 2240-2255. 

Hartwig, W. Mittendorf, J. Enantioselective synthesis of 2,3-diamino acids by the bislactim ether method. Synthesis 1991, 939-941. 

One of the classics is the Schollkopf synthesis via bislactim ethers [7]. Beside efficient methods for the preparation of bislactim ethers [8], a derivative of 1 with R = C02Et has been used for the synthesis of a-alkylated serines [9], and a derivative of 1 with R = H has been used in a... 

Schollkopf-Hartwig bislactim ether reagent for asymmetric synthesis of amino acids by reaction of the metalated reagent with... 

Schdllkopf and cowoikers have pioneered the development of anions of another type of masked carboxylic acid derivative, i.e. bislactim ethers such as (159), derived from (5)-valine and glycine or alanine, for the asymmetric synthesis of amino acids. As shown in Scheme 78, compounds such as... 

Nucleophilic 1,4- and 1.6-additions of cuprates and other organometallic reagents to acceptor-substituted dienes have been utilized extensively in target-oriented stereoselective synthesis - . Schollkopf and coworkers reported the diastereoselective 1,6-addition of a bislactim ether-derived cuprate to 3,5-heptadien-2-one (90% ds equation 17). The corresponding reactions of dienoates were conducted with the lithiated bislactim ether and proceeded with diastereoselectivities of >99% ds (equation 18) the adducts could be converted easily into diastereo- and enantiomerically pure amino acid derivatives. 

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. 

Schollkopf, U., Pettig, D., Busse, U., Egert, E., and Dyrbusch, M., Asymmetric synthesis via heterocyclic intermediates. Part 30. Asymmetric synthesis of glutamic acids and derivatives thereof by the bislactim-ether method. Michael-addition of methyl 2-alkenoates to the hthiated bislactim-ether of cyclo-(L-Val-Gly), Synthesis, 737, 1986. 

Ruiz, M., Ojea, V., Fernandez, M.C., Conde, S., Diaz, A., and Quintela, J.M., Synthesis of 2-amino-2-methyl-4-phosphonobutanoic acids by conjugate addition of lithiated bislactim ether derived from cyclo[Ala-D-Val] to vinylphosphonates, Synlett, 1903, 1999. 

A highly efficient synthesis of a-substituted (A)-a-amino acids has been established using the above route106. Diastereoselective protonation could provide a method of deracemiza-tion 107 of racemic amino acids incorporated in the bislactim ether 1. 

Many other examples of stereoselective fluorinations with glycosides41, benzylic epoxy alcohols42, sterols43, and androstanols44 have been published. Asymmetric synthesis via heterocyclic intermediates is described for the fluorination of the chiral bislactim ether adduct of ketones45. 

Piperazinediones are the keto forms of 2,5-dihydroxy-3,6-dihydropyrazines, and many 2,5-piperazinedione derivatives have been found in nature. Numerous synthetic investigations for these compounds <83H(20)1407, 93AHC(57)186> have been carried out, particularly in an approach to the total synthesis of the antibiotic bicyclomycin <85JA3253> and the synthesis of chiral a-amino acids known as the Schollkopf-Hartwig bislactim ether method. Direct introduction of a substituent on... 

Lactim benzyl ethers. Cyclodipeptides are converted to the bislactim ethers, which are valuable intermediates for stereoselective a-amino acid synthesis. 

O-Alkylation of dioxopiperazines with oxonium salts yields bislactim ethers, e.g. 4, which are used as reagents for the asymmetric synthesis of amino acids (bislactimether method, Schollkopf 1979). The chiral bislactim ether 4 is converted into the 6 r-anion 5 (under kinetic control) by n-butyllithium. Alkylation proceeds with high stereoselectivity (greater than 95%). Acid hydrolysis of the alkylation product 6 leads to (unnatural) (R)-mnno acids 7 and recovery of the chiral auxiliary (5)-valine, from which the starting material dioxopiperazine 3 was derived [160]. 

A further application of the so-called Schoellkopf synthesis has been reported. This employs the lithiated bislactim ether (192) of known chirality (R) this wcis condensed (Scheme 20) with 4-benzyloxy-3-(dimethoxyphosphinoyl)benzaldehyde to form a second centre of chirality (S) in the intermediate (193) further work-up according to the steps in... 

O-Alkylation of chiral dioxopiperazines of type 3 with oxonium salts yields bislactim ethers 4 (cf p. 484), which are used as reagents for the asymmetric synthesis of amino acids (ScHOLLKOPF bislactimether method). 

W. Kambrock, H.-J. Musiol, L. Moroder. Enantioselective synthesis of 5-o-carboranylalanine via methylated bislactim ethers of 2,5-diketopiperazines. Tetrahedron, 1995, 51, 1187-1196. 

Kessels, M. M. Qualmann, B. Facile enantioselective synthesis of (S)-5-(2-methyl-l,2-dicarha-ctoso-dodecaborane(12)-l-yl)-2-aminopentanoic acid (L-MeCBA) using the bislactim ether method, J. Prakt. Chem. 1996, 89. 

Figure 11.80 Use of Schollkopf s bislactim ether for the synthesis of (2S,3R)-[3,4- C2] threonine of high enantiomeric purity...

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... 

---