Lactim ethers, from

A. Synthesis of Lactim Ethers from Piperazine-2,5-diones. 254... 

Another example of the preparation of lactim ethers from lactams and phosphoryl chloride is the transformation of tetrahydro-/ -carbolin-l-one (19) to l-alkoxy-3,4-dihydro-/3-carboline (20)46,47 (Scheme 3). 

Presumably, the synthesis of lactim ethers from lactams and acylat-ing agents, including phosgene and ethyl chloroformate, proceeds via intermediate imidochlorides5 5 57 (Scheme 4). 

To smoothly prepare the Schollkopf bis-lactim ether from an amino acid, it is important to add 2,6-di-/erf-butylpyridine to the reaction system. It has been reported that the alkylation of the lithiated Schollkopf bis-lactim ether in diethyl ether contains high levels of 7r-facial discrimination, " where the tosylate or halide electrophile is introduced into the opposite side of the bulky group on the bis-lactim ether ring. Such stereochemical outcome for the Schollkopf alkylation is known as the SchoUkopf s rule or Schollkopf s observation. However, this rule is not always obeyed, and the reaction is probably controlled by both... 

The only recorded synthesis of this type from a pyridazine involves the [4 + 2] cycloaddition of the lactim ether (374) with l,2,4,5-tetrazine-3,6-dicarboxylic ester, which proceeds with loss of nitrogen and methanol from the intermediate adduct to give the pyrido[2,3-t/]pyridazine (375) (77AP936). 

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. 

A new route has been developed for the efficient formation of the variably substituted indolo[2,3-a]quinolizine ring system, starting from a properly substituted 2-piperidone (103, 104). For the preparation of octahydroindolo-quinolizine (1), the unsubstituted 2-piperidone 139 was treated with triethox-onium tetrafluoroborate. Then the corresponding lactim ether 140 was alkylated with 3-chloroacetylindole followed by a subsequent two-step reduction process and Bischler-Napieralski ring closure. Finally, reduction of the C=N bond afforded ( )-l (104). 

Bicyclic pyrimidin-4-ones (1100, R = H, n = 0-3 R = Me, n = 1) were also prepared from the appropriate lactim ether and EMME in the presence of ammonia or ammonium acetate [73JAP(K)34897 75MIP1]. Pyrimido[l,2-a]azepine-3-carboxylates (1100, R = H, Ph n = 2) were prepared in the reaction of 7-aminotetrahydro-2//-azepines (R = H, Ph n = 2) and EMME or in the reaction of O-methylcaprolactim and diethyl aminomethylenemalonate in ethanol [73JAP(K)34897 75MIP1]. 

Symmetrical hw-Iactim ethers of type (187) — built up from two identical amino acids — do have one disadvantage, inherent in the system only 50% of the chiral auxiliary — in this case (S)-alanine — is recovered the other 50 % is first racemized via (188) and finally incorporated in the product (189). To avoid this disadvantage Schollkopf et al. have developed methods to synthesize mixed bw-lactim ethers, starting from two different amino acids, e.g. (S)-valine and (R,S)-alanine. Thus, the authors obtained cyclo [(S)-val-(R,S)-ala] and prepared the related h/.s-lactim ether... 

R)-serines starting with the ft/s-lactim ether of cyclo [(S)-val-gly]193). 3,6-Dihydro-3-phenyl-2/f-l,4-oxazin-2-ones (194)194) were synthesized from (R,S)-... 

The earliest report on such lactim ether formation was from Sammes [72JCS(P1)2494], who converted piperazine-2,5-dione to 2,5-diethoxy-3,6-dihydropyrazine (173) with an excess of triethyloxonium fluoroborate. Subsequently, Rajappa and Advani (73T1299) converted proline-based piperazine-2,5-diones into the corresponding monolactim ethers. The starting material was a piperazinedione in which one of the amino acid units was the secondary amino acid proline, and the other a primary amino acid. This naturally led to the regiospecific formation of a monolactim ether (169) (on O-alkylation) from the secondary amide, whereas the tertiary amide remained intact. This was later extended to piperazine-2,5-diones in which the secondary amino acid was sarcosine [74JCS(P 1)2122], leading to the monolactim ethers (170). 

The generation of the anions from the lactim ethers and their reaction with electrophiles is deferred to the next section. 

Decarboxylation of 117 was effected by treatment of 117 with LiCl in hot, aqueous HMPA at 105 °C providing 118 as a mixture of diastereomers that were separated and carried forward individually. Protection of the secondary amide group as the corresponding methyl lactim ether was accomplished by treating 118 with trimethyloxonium tetrafluoroborate in dichloromethane that contained cesium carbonate. Next, the indole nitrogen atom was protected as the corresponding Boc derivative by treatment with dicarbonic acid bis(rm-butyl)ester in the presence of DMAP and the silyl ether was removed with tetrabutylammonium fluoride to provide diol 119 in 52-78% overall yield from 118. Selective conversion of the allylic alcohol to the corresponding... 

Lactim ether formation from 2,3,4,5-tetrahydro-l//-l-benzazepin-2-one on reaction with dimethyl sulfate and triethyloxonium tetrafluoroborate has been described, and reactions of the lactim ether with a number of primary amines were reported <2003CHE344>. 

An alternative stereospecific synthesis of emetine has been accomplished from ethyl trans-5-ethyl-2-oxopiperidine-4-acetate by conversion into the lactim ether (107), which was allowed to react with 3,4-dimethoxyphenacyl bromide to give the ketone (108 R R2 = O). Reduction of this with sodium borohydride, followed by hydrogenolysis of the resulting alcohol, gave (108 R1 = R2 = H), which has previously been converted into emetine.135 The reaction of (107) with 3-benzyloxy-4-methoxyphenacyl bromide and with 4-benzyloxy-3-methoxyphenacyl bromide afforded analogues of (108 RJR2 = O), which were converted into 9-O-desmethylpsychotrine (109 R1 = H, R2 = Me) and 10-0-desmethylpsychotrine (109 R1=Me, R2 = H) respectively.136,137... 

Enantioseleetive Synthesis of a-Unsubstituted Amino Acids from the mixed Bis-lactim Ethers 20b of Cyclo(L-Val-Gly)... 

This article deals with results achieved with the 2,5-dimethoxy-3,6-dihydropyra-zines, the heterocycles of type I. Results obtained with the imidazolinones III are discussed elsewhere 6). At first glance the heterocycles I look rather esoteric. However, the yare nothing but the bis-lactim ethers of the well known 2,5-diketopiperazines, the cyclic dipeptides. — At first, experiments with the symmetrical bis-lactim-ether (6) of cyclo(L-Ala-L-Ala) (5) are described and then results with several mixed bis-lactimethers. Symmetrical bis-lactimethers — i.e. those, build up from two identical amino acids — do have one disadvantage, inherent in the system, namely, only one half of the chiral auxiliary is recovered, the other half is incorporated in the product. But they are easily prepared and, hence, are good models to commence a study. 

Enantioselective Synthesis of a-Methyl Amino Acids from the Bis-lactim Ether (6) of Cyclo(L-Ala-L-Ala) (5)... 

The bis-lactim ether 20b of cyclo(L-Val-Gly) reacts regiospecifically with butyllithium to afford the lithium compound 31. The addition products (32) are formed with alkyl halides in good chemical yields and — depending on R — with 65->95 % de16). They have the (3R)-configuration, as derived either from the H-nmr-spectrum of 32 (Table 4) or, indirectly, from the sign of rotation of the (R)-amino acid methyl ester (34) obtained by hydrolysis. 

Apart from methyl iodide, all alkyl halides react with de >95% with the lithiated bis-lactim ether 35 of cyclo(L-rLeu-Gly) 20d (Table 5). De can be determined either at the stage of the adducts 36 or, indirectly, via ee of the (R)-amino acid methyl esters (type 34) liberated on hydrolysis (2 equivalents 0.1 N HCI, r.t.)18). Although this system works exceedingly well — in fact, it could be the solution to the problem as far as this approach is concerned —, the method has one disadvantage at the tima... 

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