Intramolecular conjugate addition of N-tosyl carbamates: a stereoselective approach to either 4,5-disubstituted oxazolidin-2-ones and unsaturated b-amino esters

Dipartimento di Scienze dei Materiali e della Terra - Università di Ancona, Via Brecce Bianche

I-60131 Ancona, Italy        orena@popcsi.unian.it

José Sepulveda-Arques

Department of Organic Chemistry, Faculty of Pharmacy - University of Valencia, Avda.

Vicent Andrés Estelles s/n, 46100 Burjassot,Valencia, Spain

Department of Chemistry - University Cardenal Herrera - CEU, Edificio Seminario s/n,

46133 Moncada, Valencia, Spain

Received: 20 August 2001 / Uploaded 21 August 2001

Abstract: Starting from allylic alcohols in which the double bond is conjugated with an electron withdrawing group, carbamates 6a-e and 10a-d were prepared. By intramolecular cyclisation, 6a-c gave with total stereoselection 4,5-trans-disubstituted oxazolidin-2-ones, 7a-c, precursors of syn-4-hydroxy-2-amino acids. On the contrary, by cyclisation of carbamates 10a-d, the cyclic compound was not isolated, and unsaturated N-p-toluensulphonylamino esters 11 or 12 were obtained, the reaction outcome depending on the electronic properties of the substituent R group.

Introduction
Results and Discussion
Conclusions
References

Introduction

The intramolecular N-conjugated Michael addition to activated double bonds was scarcely reported and in some cases air-sensitive reagents were employed.^1-9 On the other hand, the N-conjugated Michael addition of N-p-toluenesulphonyl carbamates was already disclosed to give an equimolar diastereomeric mixture of imidazolidin-2-ones starting from a chiral amino ester, with the aim to prepare enantiomerically pure diamino acids.¹⁰

Within a project directed towards the synthesis of non-proteinogenic amino acids,^11-17 we would like to report on the intramolecular conjugate addition of N-p-toluenesulphonyl carbamates prepared starting from hydroxy compounds such as 1 and 2, respectively.

The reactions carried out from compounds 1 were devised in order to synthesize oxazolidin-2-ones which are precursors of the 1-hydroxy-2-amino moiety, a functional pattern which occurs in b-amino-g-hydroxy acids biologically active such as 3^18-20 and in amino alcohols inhibitors of proteases, such as 4.^21,22 Moreover, it is worth mentioning that g-substituted b-amino-g-hydroxy acids with biological activity are components of antibiotic peptides, such as tuberactinomycins A and N,^23,24 or gastroprotective natural products such as Amicocoumacin C and AI-77-B.^25-28

The hydroxy derivatives 5 reacted with p-toluenesulphonyl isocyanate in dichloromethane to give the corresponding N-p-toluenesulphonyl carbamates 6 which were practically pure and were used in the following step without furter purification. By treatment with a catalytic amount of DBU in dichloromethane at room temperature, carbamates 6 underwent intramolecular conjugated addition to the activated double bond, affording oxazolidin-2-ones 7a-e in good yield, the ring size being determined by IR absorption of the carbonyl (1750 cm^-1).^29-32When R was an alkyl or an aryl group, total stereoselection was observed, and 4,5-trans-disubstituted oxazolidin-2-ones 7a-c, were exclusively isolated, whose structure was assigned on the basis of the value of J_4,5 (about 4 Hz) in the ¹H NMR spectrum and n.O.e. experiments.^29-32 These compounds could be precursors of syn-3-amino-4-hydroxy acids after removal of the p-toluenesulphonyl group and cleavage of the heterocyclic ring carried out following literature methods.¹⁰

When R = H, only a regioselective functionalisation was observed, no matter of stereoselection. However, the usefulness of compound 7e was proven by conversion into racemic 3 through simple steps. In fact, simply by treating 7e with Li in liquid NH₃, followed by cleavage of the heterocyclic ring under acidic conditions, racemic 3 was obtained in good yield.

On the other hand, N-p-toluenesulphonyl carbamates 10a-d, prepared from alcohols 9a-d,³³ showed a different behaviour with respect to compounds 6a-e, as it appears from Scheme 5.

In fact, by treating 10a,b with a catalytic amount of DBU or DABCO, first conjugated addition occurred. However, the intermediate oxazin-2-one was not isolated, owing to an immediate elimination reaction which afforded the corresponding N-p-toluenesulphonyl esters 12a,b with total E-stereoselection, as determined by n.O.e. experiments.
 
 

Furthermore, when N-p-toluenesulphonyl carbamates 10c,d were treated under the same conditions, differences in reactivity were observed, which may be due to electronic factors. In fact, starting from 10c, an equimolar mixture of N-p-toluenesulphonyl esters 11c and 12c was recovered, and the structural assignment of 12c was performed by means of ¹H NMR and COSY spectra. On the contrary, starting from 10d, the ester 12d was exclusively obtained in moderate yield.

The formation of esters 12c,d could be explained by a competing elimination reaction initiated by DABCO or DBU, leading to a double bond which then undergoes conjugated addition by the anion of p-toluenesulphonamide (Scheme 7). Since, on increasing the the electron-releasing effect of R group, the amount of 12 increases, the driving force leading to esters 12c,d seems to be the formation of a conjugate electron-rich double bond in the intermediate 13, and theoretical studies are currently underway in order to completely explain the reaction outcome.

In conclusion, N-p-toluenesulphonyl carbamates were disclosed to be useful starting material in order to prepare polyfunctionalised sequences with high stereoselection by intramolecular conjugated addition. Given the mild conditions required for the cyclisation, together with the access to new classes of compounds, the reported strategies should provide valuable intermediates for synthetic applications, and applications are underway in our laboratories.

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