Stereoselective Nucleophilic Addition with a New Chiral Template and Its Application to the Synthesis of Optically Active α-Arylglycine Derivatives

Abstract

Mannich-type reaction of phenols with iminolactone 4, readily prepared from commercially available phenylglycine, proceeded with high stereoselectivity to give α-arylglycine derivatives. The reaction was also applicable to other electron-rich aromatic compounds, arylboronic acids and other nucleophiles. Additionally, several Lewis acid-promoted addition reactions with iminolactone 4 were accomplished efficiently. These adducts could be converted readily to the corresponding optically active α-amino acid derivatives.

Mannich-type reaction - iminolactone - phenols - electron-rich aromatics - arylboronic acids - hydroxyphenylglycines - amino acids - α-arylglycines

References

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11b

For preparation of phenols 5b see: ref. 6

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Compound 7 was prepared from 6a by treatment with MsCl and Et₃N in 85% yield. X-ray crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Date Base (Deposition No. 162231). Copies of the data can be obtained free of charge on application to the CCDC 12 Union Road, Cambridge CB21EZ UK [fax [phone]; E-mail: [e-mail]].

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15

Unfortunately the hydroxyphenylglycines 17a-c had no agonist and antagonist activity in mGluR1-5. Detailed experimental procedures and results of the assay will be reported elsewhere.

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17

(S)- or (R)-Phenylglycine methyl ester hydrochloride was purchased from Aldrich Inc. Free methyl ester 1 is easily obtained by treatment with gaseous ammonia in CH₂Cl₂, followed by filtration, and evaporation. Alternatively (S)- or (R)-phenylglycine can be converted to the methyl ester using SOCl₂ in MeOH (see also ref.18).

18 Davies SG, Polywka MEC, and Sanganee HJ. inventors; US  005801249A. Alternatively compound 2 can be prepared from d-phenyl-glycine methyl ester hydrochloride by direct treatment with MeMgI in Et₂O in moderate yield (41% from methyl ester hydrochloride):