Mild and efficient ring opening of monoterpene-fused β -lactam enantiomers. Synthesis of novel β -amino acid derivatives

Both enantiomers of the N -Boc-activated monoterpene-fused β -lactam 3 were readily convertible to N-Boc β -amino acid 4 , β -amino ester 7 , and carboxamide derivatives 9 - 11 via nucleophilic attack on the activated lactam bond. The corresponding β -amino ester 7 was transformed to a novel amino acid 8 .


Results and Discussion
The synthetic route for novel chiral β-amino acid derivatives is presented in Scheme 1.Even though the Schemes depict only compounds prepared from (-)-(1S,5S)-α-pinene, all these reactions were performed by starting from both (-)-(1S,5S)-and (+)-(1R,5R)-α-pinene (see Experimental Section).We have recently described the synthesis of the β-lactam enantiomers 2 from α-pinene enantiomers by regiospecific and stereospecific addition 26,27 of chlorosulfonyl isocyanate (CSI) (Scheme 1).Although the literature includes several well-known methods for the ring opening of azetidinones, 17 transformation of the azetidinone 2 to the amino acid by using aqueous hydrochloric acid solution failed.The synthesis of the amino ester by the refluxing of 2 with ethanolic HCl likewise resulted in the required ethyl ester only in low yield, with many sideproducts. 14The above results suggested that the strongly constrained pinane ring system is broken down under the highly acidic conditions necessary to open the β-lactam ring.Activation of the carboxamide bond of the azetidinone 2 therefore seemed necessary.
Treatment of the β-lactam 2 with di-tert-butyl dicarbonate resulted in the N-Boc β-lactam 3, which was readily openable under mild conditions.The reaction of 3 with aqueous lithium hydroxide in THF gave the N-Boc β-amino acid 4 in good yield (78%). 28,29 Deprotection of 4 resulted in the TFA salt of the corresponding amino acid 8 in only 80% purity.Since the attempted purification of 5 failed, an alternative synthesis pathway was developed to prepare amino acid 8.
Ring opening of the N-Boc β-lactam 3 in the presence of a catalytic amount of NaOMe in dry MeOH gave 6 in excellent yield during a very short reaction time. 30Deprotection of 6 with TFA resulted quantitatively in 7 in high purity.The β-amino ester 7 was transformed to the β-amino acid 8 by refluxing in a dioxane:water = 1:1 mixture for 2 days (Scheme 1). 31he nucleophilic ring opening of the N-Boc β-lactam 3 was also performed with amines such as ammonia, methylamine, resulting in the N-Boc amides 9 and 10 in high yields. 32When benzylamine was applied transamidation process went through only in the presence of potassium cyanide as catalyst, resulting in amide 11 (Scheme 2). 29he enantiomeric purity of the prepared compounds was proved by GC and NMR spectroscopy.There was no sign of the presence of any other diastereomer in the spectra of the prepared compounds.

Conclusions
An efficient method was devised for the ring opening of acid-sensitive monoterpene-fused βlactams.The Boc-activated azetidinone 2 was found to be easily openable under mild conditions by nucleophilic attack.The novel β-amino acid 8 was also prepared.The resulting β-amino acid derivatives may serve as chiral building blocks in the asymmetric synthesis of potential pharmacons, β-amino acid oligomers and modified analogues of natural peptides.They are excellent starting materials for the preparation of potential chiral auxiliaries and catalysts such as 1,3-diamines and 1,3-amino alcohols which could be used in enantioselective syntheses.

Experimental Section
General Procedures. 1 H NMR spectra were recorded on a Bruker Avance DRX 400 spectrometer (400 MHz, δ=0 (TMS) in CDCl 3 , except for compound 8, which was dissolved in CD 3 OD).Chemical shifts are expressed in ppm (δ) relative to TMS as internal reference.J values are given in Hz.FT-IR spectra were recorded on a Perkin-Elmer model 1000 spectrophotometer.Microanalyses were determined on a Perkin-Elmer 2400 elemental analyser.