Diastereoselective alkylation of a chiral 1,4-benzodiazepine-2,5-dione containing the α -phenethyl group. Attempted asymmetric synthesis of α , β -diaminopropionic acid

Alkylation of chiral benzodiazepinedione ( S )- 1 with LDA or LHMDS with N -(bromomethyl)- phthalimide (a protected derivative of bromomethylamine), via the lithium enolate of ( S )- 1 in the presence of HMPA as cosolvent was accomplished in moderate yield and good diastereo-selectivity. Hydrolysis of the resultant major diastereomeric product ( S , R )- 4 with 57% HI afforded the desired α , β -diaminopropionic acid 5 in good yield albeit in racemic form, probably due to β -elimination-addition of ammonia under these conditions


Introduction
Several unusual α,β-diamino acids have been identified as constituents of biologically active natural products such as anthramycin (I), 1a bleomycin (II), 1b and capreomycin (III).1c Furthermore, α,β-diamino acids are essential precursors for the preparation of β-lactam antibiotics such as penicillin (IV) and ampicillin (V). 2 Presently, there exists a limited number of methodologies for the enantioselective synthesis of α,β-diamino acids. 3By contrast, a variety of methods is available for the preparation of enantio-enriched α-amino acids, 4 and among them, those employing chiral glycine derivatives have been particularly successful. 5On the other hand, (R)-and (S)-α-phenylethylamines [(R)and (S)-α-PEA] are simple, yet efficient chiral auxiliaries in asymmetric synthesis. 6Indeed, a novel chiral glycine derivative was recently developed by incorporation of (S)-αphenylethylamine into 1,4-benzodiazepine-2,5-dione, (S)-1.The lithium enolate of (S)-1 was alkylated with various electrophiles with high yield and with good diastereoselectivity, and hydrolysis of the main products afforded enantiopure α-amino acids (Scheme1).

I
In the present work, the potential of (S)-1 for the enantioselective synthesis of α,β-diamino propionic acid 5 was investigated.

Scheme 3
The relative configuration of the major diastereomeric carbinol 3 was determined to be unlike, 9 i.e. (S,R)-3, by means of X-ray diffraction crystallography (Figure 1).Salient features in the crystallographic structure are the anticipated boat conformation of the heterocyclic ring 7,11 and the orientation of the phenethyl group.As pointed out in the literature, 12 1,3-strain 13 favors the conformation in which the C-H bond eclipses the adjacent carbonyl group.
Interestingly, (S)-2 exhibits two sets of 1 H and 13 C NMR signals at ambient temperature, in a 84:16 ratio.This observation is ascribed to a dynamic equilibrium between boat conformers M and P (Scheme 4). 14From the inspection of Dreiding models, it is estimated that in conformer P the phenyl ring is in close proximity to one of the vinylic hydrogen atoms, whereas in the M conformer the phenyl ring is far away from the methylidene moiety.Since the predominant conformer in the 1 H NMR spectrum exhibits a signal at significantly high field (δ = 4.48) for one of the vinylic protons, whereas the minor conformer exhibits this proton at a normal δ = 5.40, it is concluded that the equilibrium M -P is displaced to the right; ∆G°2 98 K = -1.0kcal/mol (Scheme 4).

Scheme 4
In order to increase the yield of the desired exocyclic enone (S)-2, the diastereomeric mixture of carbinols 3 was dehydrated by action of p-toluensulfonic acid.This reaction proceeded with 45% yield affording a total of 70% conversion of (S)-1 into (S)-2 (Scheme 3).

B. Lack of reactivity of enone (S)-2 towards the conjugate addition of N-nucleophiles
Scheme 5 summarizes the different conditions under which enone (S)-2 was treated with various N-nucleophiles, in an attempt to achieve a 1,4-addition.

Scheme 5
The failure to accomplish this addition reaction may be explained in terms of structural and electronic limitations present in (S)-2.In particular, the boat conformation of (S)-2 prevents coplanarity between the double bond and the carbonyl group, drastically reducing both conjugation and electrophilic reactivity in this π system.Furthermore, electron donation from either nitrogen will deactivate the enone segment towards nucleophilic addition (Scheme 6).

C. Diastereoselective alkylation of the Li enolate of (S)-1 with N-(bromomethyl)phthalimide
The results of the electrophilic addition of N-(bromomethyl)phthalimide 16 (at -78°C) to the lithium enolate of (S)-1, generated by metallation of the corresponding benzodiazepinedione with LDA or lithium hexamethyldisylazide (LHMDS), are summarized in Scheme 7. Poor diastereoselectivities in the 12-40% range (entries 1 and 3) were found in the absence of additives, as revealed by integration of 1 H and 13 C NMR spectra of the crude product mixtures.Chemicals yields were also poor under these conditions (10-38%).© ARKAT USA, Inc Entry Base Additive (equiv.)(S,R)-4: (S,S)-4 Yield Recently, 7,17 addition of "inert" salts to the reaction media has been found to affect the stereoselectivity of alkylation reactions.Thus, Scheme 7 includes data obtained in the presence of 3 or 6 equivalents of lithium chloride (entries 6 and 7).Disappointingly, diastereoselectivities remained low in the 16-42% range.Nevertheless, it was found that the chemical yields did improve substantially under these conditions (compare entry 3 with entries 6 and 7, Scheme 7).Unexpectedly, the major diastereomeric product in the absence of LiCl corresponds to the unlike configuration, whereas the like diastereomer becomes predominant in the presence of the salt.It is to be expected that seemingly contrasting observations as those reported here will be understood when the knowledge about salt effects on structure and aggregation state of lithium enolates is more advanced. 18n contrast, use of hexamethylphosphoric triamide (HMPA) 19 is known to activate the reactions of organolithium compounds with electrophiles, 20 and to alter regio-and/or stereoselectivity. 7,21In the present study, both yields and diastereoselectivities of the alkylation reaction (cf.entries 1 and 2, and entries 3, 4 and 5, Scheme 7) improved significantly in the presence of HMPA.
Diastereomers (S,R)-4 and (S,S)-4 were separated by flash chromatography.The major product was recrystallized from methanol-dichloromethane (9:1) to afford suitable crystals for X-ray diffraction analysis. 10Figure 2 presents the solid state conformation and that permits the assignment of the relative unlike configuration.In addition, Figure 2 reveals a boat conformation with P helicity, 14 a coplanar orientation of the C-H bond at the phenethyl group and the adjacent carbonyl (as dictated by 1,3 strain 13 ), and a molecular arrangement that allows for π-π stacking between the aromatic rings.

Scheme 8
Hydrolysis of (S,R)-4 goes along with racemization and is presumed to occur via βelimination of ammonia (Scheme 9), as suggested by Rapoport et al. 25 for cysteine derivatives.