Synthesis of unsaturated b -amino acid derivatives starting from  the Baylis-Hillman products: a convenient approach to conformationally restricted dipeptides

Alessandra Becci,a Marco Ciclosi,a Roberta Galeazzi,a Mario Orena a* José Sepulveda-Arques b


aDipartimento di Scienze dei Materiali e della Terra - Università di Ancona - Via Brecce Bianche, I-60131 Ancona, Italy
bDepartment of Organic Chemistry, Faculty of Pharmacy - University of Valencia, Avda. Vicent Andrés Estelles s/n, 46100 Burjassot, Valencia, Spain


 

INTRODUCTION

The Baylis–Hillman reaction [1] allows carbon-carbon bond formation leading to compounds 1 starting from activated vinyls and carbonyl compounds.Whereas aldehydes are generally used, N-tosylimines and  activated ketones can be also used as the electrophilic acceptors. [2][3] Thus, the aza version of the reaction, i.e., exchanging the aldehyde reactant for an aldimine and thus forming 2-methylene-3-aminocarbonyl compounds, 2, was also reported and found wide applicability in the synthesis of  lactams, quinolines, and taxol derivatives. [4]
 

Scheme 1

  As part of a programme directed to prepare new, non- proteinogenic amino acids able to induce conformational restrictions in oligopeptides, [5][6][7] we already reported a convenient procedure for the preparation of both unsaturated b-amino acid derivatives, 3 and 4,5 proceeding with high regioselection. [8]
 

Scheme 2

RESULTS AND DISCUSSION

Owing to the difficulty connected with removal of the tosyl group, we devised to obtain both 7 and 8 starting from the corresponding trichloroacetimidates 6 ,  easily prepared in moderate yield by reaction  of the Baylis–Hillman adducts 1 and trichloroacetonitrile in the presence of a catalytic amount (10%) of DBU in DCM. [9]
 
Scheme 3

  Then, by thermal rearrangement of 1 in refluxing toluene, [10] the (E)-trichloroacetylamino esters 7 were exclusively obtained in good yield, whose configuration was assigned by 1H NMR data (Scheme 4).
 

Scheme 4

  On the contrary, treatment of imidates 6 with a catalytic amount of DABCO in DCM at r.t. afforded the trichloroacetylamino esters 8 via a tandem SN2'-SN2' reaction.
 

Scheme 5

  It is worth mentioning, however, that the corresponding DABCO salts 9,  prepared  by reaction of the acetates of Baylis–Hillman  products 1 and DABCO in aqueous THF, failed to give 8 when treated with trichloroacetamide. [11]
 

Scheme 6

This result, together with the apparent behaviour of the trichloroacetylamino moiety as a nucleophile at nitrogen, prompted us to hypothise a concerted pathway, and investigations are currently underway in order to ascertain the reaction mechanism.
Then, we turned our attention towards the synthesis of  conformationally restricted dipeptides and in a preliminary investigation we studied the preparation of the non-natural conformationally restricted dipeptide t-Boc-Gly- b-Ala-Ot-Bu, 15. First, we prepared both the t-butyl acrylate 10 [12] and the acyl isocyanate 11[13] following the literature methods. By reaction in DCM at r.t., the corresponding N-acyl carbamate 12 was obtained in good yield (Scheme 7).
 

Scheme 7

Subsequent treatment of compound 12 with a catalytic (10%) amount of DABCO in DCM at r.t. afforded the corresponding chloroacetamide 13 in high yield.
 
Scheme 8


The nucleophilic displacement carried out with azide ion in DMF starting from 13 gave 14 which, by conversion into the corresponding amino derivative, followed by reaction with (t-Boc)2O, led to the conformationally restricted dipeptide 15 in good yield.

 

Scheme 9

  CONCLUSIONS


In conclusion, we disclosed a divergent approach to either b -amino acid derivatives 7 and 8 simply on changing the reaction conditions. After conversion into the corresponding amino acids, these compounds will be incorporated in oligopeptides, with the aim to induce conformational restrictions. In addition, a simple approach to the non-natural conformationally restricted dipeptide t-Boc-Gly- b-Ala-Ot-Bu, 15 was carried out, and analogue compounds are currently synthesized.

Acknowledgement
We gratefully acknowledge financial support from M.I.U.R. (Rome, Italy - PRIN 2000).

REFERENCES


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