Asymmetric synthesis of γ-chloro-α,β-diamino- and β,γ-aziridino-α-aminoacylpyrrolidines and -piperidines via stereoselective Mannich-type additions of N-(diphenylmethylene)glycinamides across α-chloro-N-sulfinylimines

The asymmetric synthesis of new chiral γ-chloro-α,β-diaminocarboxylamide derivatives by highly diastereoselective Mannich-type reactions of N-(diphenylmethylene)glycinamides across chiral α-chloro-N-p-toluenesulfinylaldimines was developed. The resulting (SS,2S,3S)-γ-chloro-α,β-diaminocarboxylamides were formed with the opposite enantiotopic face selectivity as compared to the (SS,2R,3R)-γ-chloro-α,β-diaminocarboxyl esters obtained via Mannich-type addition of analogous N-(diphenylmethylene)glycine esters across a chiral α-chloro-N-p-toluenesulfinylaldimine. Selective deprotection under different acidic reaction conditions and ring closure of the γ-chloro-α,β-diaminocarboxylamides was optimized, which resulted in Nα-deprotected syn-γ-chloro-α,β-diaminocarboxylamides, N-sulfinyl-β,γ-aziridino-α-aminocarboxylamide derivatives, a trans-imidazolidine, and an Nα,Nβ-deprotected syn-γ-chloro-α,β-diaminocarboxylamide.

DPP IVs are proteases that specifically cleave off N-terminal dipeptides and are involved in the degradation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is involved in the regulation of glucose homeostasis through stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. It has been demonstrated that the presence of intravenous GLP-1 increases insulin secretion as a response to elevated glucose levels, and as such, GLP-1 can offer therapeutic benefits for patients with type 2 diabetes. Unfortunately, therapeutic application of GLP-1 is problematic due to the lack of oral activity and the rapid degradation by plasma DPP IV. Therefore, DPP IV inhibitors could offer a solution to this problem, as they can extend the duration of action of GLP-1 and prolong the beneficial effects [10][11][12].
Besides DPP IV, a few related enzymes are present in the family of DPPs, with DPP II, DPP8, DPP9 and FAP being the most important regarding the therapeutic potential, when focusing on the inhibitory potency and selectivity [10][11][12]. In the research focused on DPP II and DPP IV inhibitors, it has been found that the α,γ-diaminoacylpiperidine, (S)-2,4diaminobutanoylpiperidine, is a lead compound in the development of a large series of highly potent and selective DPP II inhibitors [7][8][9] (Figure 1). Next to the α,γ-diaminoacylpyrrolidines and -piperidines, which exhibit a DPP inhibitory effect, some β-aminocarboxylamides, such as sitagliptin, are also known as DPP inhibitors [13]. Sitagliptin is a commercialized oral antihyperglycemic drug of the DPP IV inhibitor class [14].
The results discussed within the present paper demonstrate the synthesis and elaboration of chiral syn-γ-chloro-α,β-diaminocarboxylamide derivatives with excellent diastereoselectivity. In order to develop potential DPP inhibitors, the ring closure and deprotection of the α-amino functionality of the synthesized γ-chloro-α,β-diaminocarboxylamides were explored as well.
The monosubstituted tertiary amide enolates obtained by deprotonation of N-(diphenylmethylene)glycinamides 4 are expected to have the Z-geometry in which A(1,3) interactions are minimized and Li-chelation stabilizes the conformation (Scheme 3), regardless of the base that was used [30,31].
Li-cation, the diphenylmethyleneamino group, and the sulfinylimine nitrogen.
The reversal of the enantiotopic face selectivity in the reaction of the N-sulfinylimines 3 with the glycinamides 4, as compared to the reaction with glycine esters, is attributed to the α-coordinating ability of the chlorine atom with the lithium of the incoming enolate as depicted in transition state TS-6b. The coordinating α-chloro atom in TS-6b overrides the chelation of the sulfinyl oxygen (e.g., TS-6a) and allows the sulfinylimine to react in the conformation wherein the S=O bond and the lone pair of electrons on the nitrogen atom are antiperiplanar [36]. This reversal of stereoselectivity is analogous to results obtained with other N-p-toluenesulfinylimines containing an oxygen atom as α-coordinating group [37][38][39]. The resulting syn-addition products syn-5 were subsequently cyclized to the corresponding N-sulfinyl-β,γ-aziridino-α-aminocarboxylamides 8 upon treatment with K 2 CO 3 in acetone under reflux in a moderate to very good yield (36-90%, Scheme 4).
The conversion of the ring-closure reaction was always complete as determined by TLC analysis, but purification of these N-sulfinyl-β,γ-aziridino-α-aminocarboxylamides 8 by flash chromatography resulted in a considerable loss of product.
In order to extend the potential applicability of the synthesized N-sulfinyl-β,γ-aziridino-α-aminocarboxylamides 8 as building blocks in biomedicinal chemistry, some attempts were made to remove the N-protective groups of diaminocarboxylamides 8 under mild acidic conditions (Scheme 4). In analogy with our recently published results on the corresponding aziridino esters [20], amide 8b was treated with 5 equiv of trifluoroacetic acid in acetone/water (2:1) at rt for 15 min. After a basic workup with NH 4 OH, it was concluded that the conversion towards the N-deprotected syn-β,γ-aziridino-α-aminocarboxylamide 9b was complete based on 1 H NMR and LC-MS analysis of the crude reaction mixture. Unfortunately, all attempted purification techniques (column chromatography, preparative TLC, acid-base extraction) to remove benzophenone and some other minor impurities from the crude reaction mixture, failed to provide the pure N-deprotected syn-β,γ-aziridino-α-aminocarboxylamide 9b.
After a basic workup with NH 4 OH, the α-deprotected syn-γchloro-α,β-diaminocarboxylamides 10 could be purified by crystallization or preparative TLC (21-91% yield). The obtained result was in accordance with the earlier reported selective deprotection of a benzophenone imine functionality, in the presence of an N-p-toluenesulfinyl moiety, of diamino esters with H 3 PO 4 /H 2 O/THF [17,40].
In an initial reaction, syn-γ-chloro-α,β-diaminocarboxylamide syn-5b was treated with 10 equiv of trifluoroacetic acid in ethanol at rt [18]. This resulted in trans-imidazolidine 12b after basic workup with NH 4 OH. It is remarkable that the N-(diphenylmethylene) group was not removed under these reaction conditions but was trapped by the deprotected β-amino group, as the deprotection of analogous anti-substrates under the same reaction conditions led to unprotected anti-α,βdiaminocarboxyl esters [18]. This is possibly due to the fact that solvolysis of the imine functionality with ethanol is not favorable and an acid-catalyzed deprotection of the sulfinyl moiety will occur first [41,42]. The resulting β-amino deprotected synγ-chloro-α,β-diaminocarboxylamide could subsequently ring close further to trans-imidazolidine 12b, which will be less sterically congested than an analogous cis-imidazolidine. In the literature, comparable non-halogenated trans-imidazolidines were already synthesized by 1,3-dipolar cycloaddition of N-benzylidene glycine ester enolates across N-sulfinylaldimines in the presence of a Lewis acid [43]. The transstereochemistry of imidazolidine 12b was ensured by the vicinal coupling constant 3 J H4-H5 = 7.43 Hz and the 1 H NMR chemical shift of H4 (3.85 ppm), which were in the same range as for closely related trans-imidazolidines and trans-oxazolidines [43][44][45]. The trans-imidazolidine 12b is a potential building block for foldamers, as the corresponding trans-oxazolidin-2-ones are already applied as such [46]. trans-Imidazolidine 12b could also be used as a precursor of the corresponding N α ,N β -deprotected α,β-diaminocarboxylamide, by hydrolysis under acidic conditions, in analogy with deprotection reactions of imidazolidines, imidazolines and oxazolines in the literature [16,47,48]. However, in a second reaction, syn-γ-chloro-α,βdiaminocarboxylamide syn-5a was directly converted into the dihydrochloride of the N α ,N β -deprotected syn-γ-chloro-α,βdiaminocarboxylamide 13a, by stirring in 0.5 M (aq) HCl/ EtOAc (2:1) for 30 min at rt, in a yield of 83%. In this reaction, the acid-catalyzed hydrolysis of the benzophenone imine functionality proceeds readily and prevents the formation of the corresponding trans-imidazolidine.

Supporting Information
Supporting Information File 1 General experimental conditions, experimental procedures and data, copies of 1 H NMR and 13 C NMR spectra for compounds 3, syn-5, 8, and 10-13.