Bislactim ether

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. 

I.5.2.4.2.2.4. Schollkopf Method Using Chiral Bislactim Ethers... 

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. 

Addition of the tris(diethylamino)titanium and -lithium derivatives of the bislactim ether to nitroalkenes gave a mixture of the four possible stereoisomers29. 

As shown in the two examples described here, formation of the benzene nucleus by trimerization of alkynes is usually catalyzed by a Co-complex. However, Und-heim and coworkers [276] have recently shown that a Ru "-complex can also be used. Reaction of the triyne 6/4-9, which was prepared from SchollkopPs bislactim ether 6/4-8 [277] with Grubbs I catalyst 6/3-13, led to 6/4-10 in an excellent yield of 90%. Hydrolysis of 6/4-10 gave the desired as-indacene-bridged bis(a-amino acid) derivative 6/4-11 (Scheme 6/4.3). 

The titanated bislactim ethers of cyclo(L-Val-Gly-) are added to nitroalkenes with high diastereo-selectivity (Eq. 4.60).SOa Michael addition of lactam bearing (S)-2-( 1-ethyl-1-methoxypropyl) pyrrolidine as auxiliary on the lactam nitrogen to nitroalkenes proceeds with high selectivity (de >96%, ee >96%).80b... 

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 synthesis52-61. Schollkopf and coworkers55 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)56 the adducts could be converted easily into diastereo- and enantiomerically pure amino acid derivatives. 

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. 

Homoallylic coupling (5,/nn) is closely related to allylic coupling in its stereochemical dependence. In cyclic compounds the existence of homoallylic couplings can be used for configurational assignments. For example, tru s-2,5-disubstituted bislactim ethers show a 4 Hz difference in the couplings between H-2 and H-5200. 

Die Synthese von optisch-aktiven, a-substituierten a-Phenyl- und a-Furyl-glycinen aus (JRS.dS jS-Dioxo-S-phenyl- bzw. ( / .(5S)-2,5-Dioxo-3-(2-furyl)-morpholincn5 ist trotz vorhandenen Potentials nicht in Richtung eines allgemeiner anwendbaren Verfahrens entwickelt worden. Die Synthese-Prinzipien entsprechen der Bislactim-ether -Methode mit einem chiralen, nicht-racemischen Enolat als Zwischenstufe6 ... 

Generation of Chiral Cation from the Bislactim Ether and Its Use for... 

Piperazine-2,5-diones, in which both amino acid units are primary, lead to bislactim ethers on O-alkylation with Meerwein s reagents. No selectivity in this reaction has been demonstrated so far. Such bislactim ethers (171) have been prepared and extensively used by Schollkopf and his school [79AG(E)863, and later papers]. During the preparation of these bislactim ethers, neutralization of the initially formed bis-tetrafluoroborate salt is carried out with phosphate buffer to avoid racemization. 

The methine protons at positions 3 and 6 of the bislactim ether (171g) resonate at 4.04 8 (q) in CDC13 solution [79AG(E)863]. 

The 3,6-dioxygenated derivatives of the bislactim ethers have been produced by the reaction of 2,5-diethoxypyrazines with singlet oxygen, followed by sodium borohydride reduction of the endoperoxide [79JCS(P1)1885]. 

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 possibility of selective hydrolysis of one of the imino ether functions in the bislactim ether has been discussed by Schollkopf (88LA1025). This procedure if accomplished regiospecifically would be extremely useful. Treatment of the bislactim ether with one equivalent of hydrogen chloride in ether does give rise to a monolactam monolactim ether however, the state of the art at present does not give control over the regioselectivity. 

Bislactim ethers of the general type (171) react with butyl lithium or LDA in THF or glyme at - 78°C to give the lithium derivative (188) by the abstraction of a proton from position 3. This incorporates a diazapenta-dienyl anion, which was originally represented as an ion pair (83T2085). 

With unsymmetrically substituted bislactim ethers of the type (171b to e), regiospecific deprotonation is feasible. Examples from Schollkopf s work are given below ... 

Structure of the lithio derivatives (84CC853) The crystal structure of a THF solvate of the lithium derivative of racemic bislactim ether (derived from two molecules of alanine) has been determined. In the solid state, the lithium derivative exists as a dimer in which the two lithium atoms are nonequivalent (189). The two organic moieties in each dimer are homo-chiral this means that the crystal contains equal number of enantiomers. The Li Li distance is 2.61 A. In THF solution at - 108°C, the compound seems to exist as an equilibrium mixture of monomer and dimer in the ratio 5 1. It is not clear at the moment whether the reacting species is the monomer or the dimer. 

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). 

The bislactim ether method has also been applied to an intramolecular alkylation (84JOC2286) to generate stereospecifically the /3-tum-inducing element, (LL) 3-amino-2 piperidone-6-carboxylic acid as shown in Scheme 62. The efficiency of chiral induction was in the range 99.5%. It is noteworthy that there is no racemization of the intermediate bromo compound, thus proving the regiospecificity of the deprotonation. 

A similar 3-(2-bromoethyl) derivative has been utilized to synthesize 1-aminocyclopropane-1 -carboxylic acid by an intramolecular base-catalyzed cyclization. This was possible when position 6 was blocked by the presence of two substituents. Some unexpected stereochemical results also came up in this study (85MI2). The starting material was the piperazine-2,5-dione derived from (/ )-(+ )-2-methyl-3-phenylalanine and glycine. The bislactim ether derived from this, on treatment with butyl lithium in THF at -78°C, gave the lithio derivative. Alkylation of this with 2-haloethyl... 

Final hydrolysis of the bislactim ether is best carried out with dilute trifluoroacetic acid (91 LA 1207). 

For 1,4 addition to enones, the cuprates of the bislactim ethers have been found to be very useful [88AG(E)1194]. These are made by reacting the lithio derivatives with CuBr SMe2 in the presence of dimethyl sulfide. 

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). 

Interestingly, another Mg(II)-mediated aldol-type reaction has been investigated by using MgBr2-Et3N with bislactim ethers and aliphatic aldehydes. The aldol products are converted in a-substituted serines (equation 60, Table 6). 

TABLE 6. Diastereoselective aldol-type reaction of bislactim ether with aldehydes... 

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