Asymmetric Synthesis of Cyclic α‐Amino Acids by the Bislactim Ether Method

Abstract

guration of the attacking C atom of the alkylating agent.Retention was observed for alkylation with B-phenylalkyl halides: in the first step, intramolecular alkylation with inversion results in the formation of a cyclohexadienylium intermediate, which, in the second step, again with inversion, reacts with the aromatic In the alkylation of benzene with the triflates of the Nphthaloylthreonines l a , b and the N-phthaloylallothreonine methyl esters lc,d, we obtained in every case the Bmethyl-N-phthaloyl phenylalanine methyl esters 2. The overall yields of 2 are between 20 and 40%, because, in addition to the substitution of 1 to give 2, substantial elimination occurs to give a$-(25-30%) and b,y-dehydroamino acid esters (35-40%).Whereas the configuration at C-2-as previously mentioned-is maintained upon the reactions of la-d to give 2, the threonine ( l a , b ) and allothreonine (1c,d) derivatives show diverse behavior upon alkylation with respect t o the stereochemistry at C-3.The threonine derivatives l a , b react largely with retention at C-3, whereas the allothreonine derivatives lc,d afford diastereomeric mixtures in the ratio of 2 : 3. The characterization and structural assignments of the four diastereomers 2a-d were determined by comparison of their optical rotations and 'H-NMR data with literature v a l~e s .~~~ For 2a, we confirmed the configuration by carrying out a n X-ray structure analysis.'61 Furthermore, we were able to show that the product obtained by acid hydrolysis of 2a, removal of the phthaloyl protecting group, and acetylation is identical with the reported (2S,3S)-N-acetyl-p-methylphenylalanine.i71The high stereoselectivity observed in the alkylation of benzene with l a , b and the different behavior of lc, d can be explained in terms of the different conformations of the carbenium ions B and D, which are formed as intermediates in the alkylation.He:H3 E D Alkylation of benzene with (S)and (R)-l-methyl-2phthaloylaminomethyl triflate 3 results in partial retention, whereas with methyl (S)-3-trifluoromethanesulfonyloxybutyrate, (S)-4, complete racemization is observed. We conclude from this that, in the dissociation step, the threonine derivatives l a , b prefer conformation A, whereas the allothreonine derivatives 1c,d prefer conformation C. In the carbenium ion B formed from A, rotation is rendered difficult by the two large neighboring substituents (CH,, CO,CH,); moreover, the aromatic compound can react only from the bottom side with B, because the cationic center is blocked from above by the Nphthaloyl group. This explains the retention observed in the reactions of la,b. For the cationic intermediate D, on the other hand, no or at most only a small hindrance to rotation is expected, which is confirmed by the results of the reactions of lc,d.In analogy to the reactions of benzene, alkyl-and alkoxybenzenes can also undergo reaction with the triflates 1 of the threonine ester. In a one-pot procedure, it is also possible to synthesize phenylalanines and B-methylphenylalanines such as 2 from t...

Synthesis of Silaproline, a New Proline Surrogate

“…Distillation of compound 3 did not induce cyclization into silaproline although this method has been successfully applied by Schöllkopf for the synthesis of cyclic amino acids. [21] Acidic conditions (Scheme 2, pathway a) did not afford the desired cyclic compound, but hydrolyzed the bis-lactim ether. We established that CH 3 CN/ H 2 O/HCO 2 H (49:49:2) were effective conditions to afford the expected silaproline methyl ester 5, in a mixture along with valine methyl ester 6 and dipeptide 8 (Scheme 2, pathway b).…”

Stereoselective Synthesis of Quaternary Proline Analogues

“…Thus, the commercially available bis-lactim ether of cyclo-(-Val-Ala) (158) was alkylated with 1,3-dibromopropane to provide the corresponding di- Scheme 40. alkylated bis-lactim ether 159, which upon cyclization by heating afforded the (R)-2-methylproline precursor 160 (Scheme 40). [85] Later, Undheim et al demonstrated an alternative annulation procedure involving rhodium(II)-catalyzed carbenoid insertions into diazoketone substrates 162. [86] The insertion reactions occurred with complete chemoselectivity at the adjacent annular nitrogen in preference to C-C double bond additions or C-H insertions, and no racemization was observed either in the carbenoid reaction or in the subsequent hydrolysis.…”

Electronically rich N-substituted tetrahydroisoquinoline 3-carboxylic acid esters: concise synthesis and conformational studies

“…The glycine equivalents studied to date include (2 S )–2–isopropyl–3,6–dimethoxy–5–methyl–2,5–dihydropyrazine, 32 (R)– di– tert –butyl 2– tert –butyl–4–oxoimidazolidine–1,3–dicarboxylate, 33 diethyl acetamidomalonate, 34 ethyl acetamidocyano–acetate, 35 ethyl 2–(benzylidene amino)acetate, 36 ( 6R )–6–isopropyl–3–methyl–5–phenyl–3,6–dihydro–2H–1,4–oxazin–2–one, 37 and 1,4–diacetyl piperazine-2,5-dione. 38 An alternative to using dibromo- O -xylenes as electrophiles in the reaction with glycine donors is α-methyl benzyl bromide, which when reacted with ( 2S,5S )–1–benzoyl–2- tert –butyl-3,5-dimethyl–imidazolidin–4–one afforded α,β–dimethyl THIQ3CA after Pictet-Spengler cyclization.…”