Bislactim ethers alkylation

The Oppolzer sultam 35-1 (Scheme 35, reaction (101) [84] reacts with even higher stereoselectivies and is easier to remove. The main domains of the Oppolzer sultam are conjugate 1,4-additions or simple double bond additions [Scheme 35, reactions (102) and (103)] [85], which show diastereoselectivities of >95% in most cases. Scheme 36 presents examples of persistent, restorable and selfimmolative auxiliaries which are all based on amino acids or amino alcohols, finders RAMP-SAMP [86] is attached to ketones or aldehydes in form of a hydrazone 36-1 which is used for highly stereoselective electrophilic a-alkyla-tions. After the reaction the auxihary is removed via ozonolysis which generates the nitrosamine 36-2 first. In an ensuing step this is reduced to the original auxiliary. In Schollkopf s bislactim ether alkylations [Scheme 36, reaction (105)]... 

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 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... 

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... 

Najera and coworkers introduced a new class of cyclic alanine templates (227, equation 59), the structure of which was anchored on Schollkopf s bislactim ether . Palladium-catalyzed allylations of the chiral pyrazinone derivative 227 with allylic carbonates (228) as substrates led to the formation of y,i5-unsaturated amino acids (229a-c) under very mild and neutral reaction conditions, whereas the required base for enolate preparation has been generated in situ from the allylic carbonate during jr-allyl complex formation. With this protocol in hand, the alkylated pyrazinones 229 were obtained with excellent regio- and diastereoselectivities (>98% ds). Finally, hydrolysis with 6 N aqueous HCl under relatively drastic conditions (150 °C) led to the free amino acids. 

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. ... 

Reactions of the Bislactim Ether Cuprate. The lithiated bislactim ether can be converted to an azaenolate cuprate by treatment with CuBr SMe2 (see Copper(I) Bromide)fi Conjugate addition of the cuprate to enones (eq 3) and dienones, or alkylation with base labile electrophiles like ethyl 3-bromopropionate, proceeds with high trans diastereoselectivity. Hydrolysis of the Michael... 

A simpler way to restrict the conformation of an enolate is to coniine it in aheterocycle and an important group of chiral enolates come from various derivatives of amino acids. The hrst successful such compounds were Schollkopf s bislactim ethers 41 derived from the diketopiperazines 40 formed when an amino acid such as alanine 39 condenses with itself.4 Treatment of 41 with butyl lithium creates a lithium enolate on one position in the ring the methyl group in the other position keeps the chirality intact. Alkylation occurs selectively on the opposite side to the remaining methyl group 42 and hydrolysis releases a new tertiary amino acid 43 and one of the original alanines. 

On alkylation of anions derived from bislactim ethers of type 1, diastereomeric ratios of... 

Dimethoxy-3,6-dihydropyrazine (109), prepared by methylation of 2,5-piperazinedione with trimethyloxonium tetrafluoroborate, is susceptible to lithiation because the protons at C-3 and C-6 are activated by adjacent imine moieties. The lithium salt of this bislactim ether reacts with the 2-chloro-l-phenylsulfonyl alkene (110) to give the 3-substituted pyrazine (111) (Scheme 25) <89JCS(P1)453>. The bislactim ether from piperazinedione cyclo(L-Val—Gly) is lithiated with butyl-lithium and then treated with ketones, alkyl halides, or others to form, nearly stereospecifically, ran5-3-isopropyl-6-substituted piperazinediones due to the steric influence of the isopropyl group <828866, 838673). Similar stereoselective syntheses have been achieved in reactions starting from cyclo(L-Val—D,L-Ala) <828864, 918939). Acid hydrolysis of these products affords chiral a-amino acids. 

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]. 

Pyrazine derivatives can also be obtained from dioxopiperazines (cf. p. 486) by alkylation with trialkyloxonium salts providing bislactim ethers 27, which are dehydrogenated by 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) to give 2,5-dialkoxypyrazines 28. 

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). 

By deprotonation with nBuli under kinetic control the chiral bislactim ether 4 is converted to the 6it-anion 5, whose alkylation by R-X ( 6) proceeds with high... 

Chronologically, the successful and efficient asymmetric alkylation of enolates was preceded by the development of chiral azaenolates indeed, the meanwhile classic reagents hke Meyers oxazolines [4], Enders hydrazones RAMP and SAMP [5], and Schollkopf s bislactim ethers [6] were the first auxiharies to enable carbon-carbon bond formation with high (overall) enantioselectivity. 

---