Routes to N-glycinamide oxazolidinone derivatives: The reaction of 4-trityloxymethyl-3-oxa-1-azabicyclo[3.1.0]hexan-2-one with active halides

N-Glycinamide oxazolidinones are key intermediates for the synthesis of a new class of peptidomimetics. We report, herein, the synthesis of a series of 3,4,5-trisubstituted oxazolidinones with a glycine residue at N-3 of the oxazolidinone ring. Substituents at C-4 and C-5 contain substitution capabilities which are amenable for the introduction of additional peptide chains. The synthesis of the key N-Glycinamide oxazolidinone is made possible through two reactions; a tandem aziridine ring opening/oxazolidinone alkylation and, subsequently, a fused-lactone ring opening by an amine which leads to the N-Glycinamide oxazolidinones.


Introduction
Peptides continue to be a source of inspiration for the design of therapeutic molecules.2][3] Oxazolidinones and related linkers have been used previously to prepare a variety of peptidomimetics.The use of both the oxazolidin-4-one type rings (1) 4 as well as oxazolidine-2-one rings (2) [5][6][7][8][9] (Figure 1) have been reported.In both cases, the oxazolidinone ring has generally been used to induce formation of secondary structures.In the reported oxazolidine-2-one peptidomimetics, the oxazolidinone ring is acylated with an amino acid or peptide chain, while the 4-position contains a carboxylate group used to acylate the nitrogen of a second peptide chain.We were interested in generating a unique set of oxazolidinone-based peptidomimetics such as 3 in which the nitrogen on the oxazolidinone ring would be alkylated with a peptide chain.A substituted methyl group (X = O, N or halogen) on the 4-position would allow for attachment of an additional peptide chain.The hydroxymethyl group at C-5 would be available to attach additional functionality to aid in solubility or target identification.It was anticipated that 3 could be prepared from an oxazolidinone such as 4 through modification of the C-4 hydroxymethyl group.Oxazolidinone 4 could be available via an aziridine ring opening/alkylation sequence starting with fused ring aziridine 5 (Scheme 1).3][14] We were intrigued with the possibility of an initial reaction of the aziridine of 5 with a reactive alkyl halide that might be followed by aziridine ring opening with a nucleophile to provide 4 or related oxazolidinones.Similar types of reactions have been reported by Pinhas et al. 15 The addition reaction of an N-acylaziridine (e.g., 5) and reactive halides has, however, remained relatively unexplored.Consequently, we propose that reaction of aziridine 5 with a reactive halide should result in the N-alkylation of the oxazolidinone and concomitant ring opening.

Results and Discussion
Based on this hypothesis, the addition reaction of the fused-ring aziridine (5) and an iodoacetate was examined.Reaction of aziridine 5 with t-butyl iodoacetate (6a) in refluxing CH 3 CN provided a moderate yield of the desired oxazolidinone 7a (Scheme 2).Several solvents, additives and temperatures were examined in order to optimize the reaction conditions (Table 1).Using dried CH 3 CN, as opposed to the slightly wet CH 3 CN from the reagent bottle, provided a moderate increase in yield of the reaction.Use of a more polar solvent such as DMF provided a poorer yield of the product (entry 3), while THF provided 7a in a similar yield as wet CH 3 CN.Neither acetone nor dioxane provided any of the expected oxazolidinone 7a.Mechanistically, the reaction could proceed via an initial iodide-mediated aziridine-ring opening leading to intermediate A, which would be followed by an alkylation to provide 7a, as shown in Scheme 3.Alternatively, the alkylation of the aziridine with 6a could occur first to provide the intermediate aziridinium B. [16][17][18] This would be followed by ring opening with iodide to provide 7a.Additional NaI resulted in a significant increase in overall yield of the alkylated oxazolidinone, suggesting that the reaction proceeds via an initial ring opening followed by alkylation.With good reaction conditions in hand, the scope of the reaction was studied with the hope that amide derivatives such as 3 could be directly prepared.Additional esters, such as methyl and ethyl iodoacetates, readily reacted with the fused-ring aziridine to produce the desired oxazolidinone products 7b and 7c in excellent yields (Scheme 4; Table 2).The reactions of the fused-ring aziridine and a series of amides were completely unsuccessful.Neither N,N-dimethyl iodoamide, N-methyl iodoamide or N-benzyl iodoamide provided any of the desired product.Interestingly, the reaction of N,N-dimethyl iodoamide (entry 4) did provide a moderate yield of 4-iodomethyl-5-trityloxymethyl-oxazolidin-2-one (7d), again, suggesting that ring opening of the aziridine by the iodide ion was a key step of the reaction.The α-iodo ketone, iodo-1-phenylethanone, provided product 7g in 54% yield (entry 7).Iodoacetonitrile did not generate any addition product (entry 8).Activated halides, such as benzyl iodide (87%, entry 9), also provided the addition product.
With the success of the reactions of the fused-ring aziridines with the iodides, the reactions with select bromides were also examined.Tert-butylbromoacetate readily underwent reaction with aziridine 5 to provide the oxazolidinone 7j in 74% yield, which was somewhat lower than the reaction with the corresponding iodide.Unlike the reactions with iodides, the addition of NaBr to the reaction did not improve the yield, and, instead, led to decomposition of the starting material.As with the iodoamides, the bromoamide (entry 12) did not provide any of the expected product.The reaction of benzyl bromide with aziridine 5 gave a lower yield of the oxazolidinone product than the corresponding iodide (entry 9 vs. entry 13).The use of α-tosyloxy-methyl acetate was also unsuccessful in providing the alkylated oxazolidinone product (entry 14).Given the lack of success using α-halo amides in the iodide-mediated ring-opening/alkylation sequence, an alternate route to the desired amides (4) was designed.The reaction of an amine with a lactone such as 8 could provide a facile route to a variety of glycinamide substituted oxazolidinones (4).A silver-catalyzed cyclization of the iodomethyl group with the t-butyl ester might be expected to provide the bicyclic lactone (8). 19It was hoped that the t-butyl ester would react with the incipient cation formed by reaction of the iodide and silver salt.This would then release the t-butyl cation and provide 8. Subsequent opening of 8 with an amine would provide the glycine substituted oxazolidinone 4 as shown in Scheme 5.
Multiple attempts to generate the lactone 8 directly from 7a were unsuccessful.Multiple silver salts, solvent, and temperatures were investigated without success.In order to carry out a formation of the lactone 8, an alternate approach from the corresponding carboxylic acid was examined (Scheme 6).Treatment of ester 7b with LiOH in THF/H 2 O at 0 °C provided acid 9 in excellent yield.With the carboxylic acid 9 in hand, the cyclization reaction promoted by different silver salts was studied. 19Silver trifluoroacetate 20 led only to the loss of the trityl group.Adding Na 2 CO 3 to the silver trifluoroacetate to buffer the reaction did not lead to product either.Silver acetate provided lactone 8 in only 17% yield, again with significant loss of the trityl group.Addition of Na 2 CO 3 did not help since none of the expected lactone was obtained under these conditions.Ultimately, silver oxide was found to be the best silver source, with a 78% yield of the product in CH 2 Cl 2 .Upon changing the solvent to CH 3 CN, the yield was increased to 88%. 10 With the key bicyclic lactone 8 in hand, the reactions of the lactone moiety with amines could be examined.Gratifyingly, it was found that the fused-ring lactone moiety 8 could readily react with primary amines to provide the desired products 4 in excellent yields (89%-100%) (Scheme 7; Table 3).
Scheme 7. Reaction of lactone 8 with a series of amines.
Simple primary amines such as methyl, isopropyl, isobutyl, allyl, and benzyl, and 4-methoxybenzylamine all provided amides 4a-4f in excellent yield.Methoxylethyl amine, as well as hydroxyethyl amine, provided amides 4g and 4h, respectively.Glycine derivatives, such as glycine N-methyl amide and glycine methyl ester, both provided the corresponding amide derivatives 4i and 4j in excellent yields.The use of the secondary amine, dibutyl amine, provided none of the expected amide.

Table 3. Results of reactions of lactone 8 with amines
The free alcohol resulting from the amine opening of the lactone was subsequently acylated to demonstrate a route to potential peptidomimetics.It was found that Steglich-esterification conditions worked quite well to provide a small series of ester derivatives from amide 4a (Scheme 8).2-Methyl propanoic acid and 4-Pentynoic acid provided the expected products 10a and 10b in yields of 81 and 85%, respectively.The amino acid Boc-glycine provided 10c in 77% yield.

Conclusions
The synthesis of a novel class of oxazolidinone peptidomimetic has been described.This method uses a new reaction of fused-ring aziridines with activated halides to generate N-alkyl and N-acyl oxazolidinones from a fused-ring aziridine.This ring-opened product has been converted to a bicyclic lactone which readily reacts with primary amines to generate oxazolidinone glycinamides.Further studies on the synthesis of peptidomimetics based on these results will be reported in due course.

Experimental Section
General. 1 H NMR (300 MHz or 500 MHz) and 13 C NMR spectra were measured on a Bruker Avance 300 MHz or 500 MHz NMR spectrometer with TMS used as the internal standard.High Resolution Mass Spectrometry (HRMS) measurements were performed on a Bruker 12 Tesla APEX -Qe FTICR-MS or Q Exactive Plus from Thermo Scientific.CH 2 Cl 2 and THF were dried using a SOLVTEK solvent purification system.CH 3 CN was distilled from CaH 2 and stored over molecular sieves.All amines were purified by distillation prior to use.Aziridine 5 was prepared as previously reported. 10All reactions were conducted under an atmosphere of argon.All other reagents were used as purchased.Chromatography refers to flash chromatography on silica gel according to the method of Still. 21The R*/S* notation is intended to indicate relative stereochemistry. 22neral Procedure A. Reaction of bicyclic lactone (8) with amines: The desired amine (200 mol%) was added to a solution of lactone compound 8 in CH 3 CN (0.05M).The mixture was stirred at room temperature until the reaction was complete as determined by TLC.The solvent was removed and compound 4 was purified via column chromatography (CH 2 Cl 2 :MeOH; 15:1).

Scheme 3 .
Scheme 3. Possible mechanistic rationale for the reaction of 5 with an iodoacetate.

.
Reaction-optimization conditions for the reaction of fused-ring aziridine and iodoacetate a Dried by distillation.