Synthesis of Disubstituted Pyrazino‐Oxazine Derivatives with Controlled Stereochemistry

Abstract

Herein, we report a simple synthesis of disubstituted pyrazino‐oxazines with controlled stereochemistry using readily available building blocks: N‐Fmoc‐protected α‐amino acids and 2‐bromo ketones. The convenient solid‐phase synthesis afforded polymer‐supported derivatives of N‐alkylated N‐acylated tert‐butylserine, which were subjected to spontaneous cyclative cleavage to yield the corresponding pyrazine intermediates. The target 1,7,8,9a‐tetrahydropyrazino[2,1‐c][1,4]oxazine‐6,9‐diones were obtained in two steps by acid‐mediated cleavage of the tert‐butyl group followed by cyclization of the oxazine scaffold.

Use of Triethylsilane for Directed Enantioselective Reduction of Olefines: Synthesis of Pyrazino[2,1‐c][1,4]oxazine‐6,9‐diones with Full Control of the Absolute Configuration

“…For this purpose, Fmoc-D-Ser(tBu)-OH 1 R , 2-bromo-1-(ptolyl)ethan-1-one 2(2) and Fmoc-D-Ala-OH 3 R (2) were used to synthesize intermediate 4 RR (2,2). More specifically, application of the previously reported synthetic method [55] for the reaction of Fmoc-L-Ser(tBu)-OH 1 S , 2-bromo-1-(p-tolyl)ethan-1-one 2(2) and Fmoc-D-Ala-OH 3 R (2) or Fmoc-D-Ser(tBu)-OH 1 R , 2-bromo-1-(p-tolyl)ethan-1-one 2(2) and Fmoc-L-Ala-OH 3 S (1) led to very low conversions rate of intermediates 4, and acylation with Fmoc-D-Ala-OH/Fmoc-L-Ala-OH had to be repeated three times to reach quantitative conversion. By using NMR spectroscopic analysis and the known configuration of C 9 [which originated from Fmoc-D-Ser(tBu)-OH 1 R ] as the reference point, structural elucidation proved the R configuration of the new C 3 stereocenter, to thus give 7 RRR (2,2) as the product.…”

“…By using NMR spectroscopic analysis and the known configuration of C 9 [which originated from Fmoc-D-Ser(tBu)-OH 1 R ] as the reference point, structural elucidation proved the R configuration of the new C 3 stereocenter, to thus give 7 RRR (2,2) as the product. Furthermore, the slow acylation caused increased formation of dealkylated by-products, [55] which significantly decreased crude purities and yields. In contrast, by using a combination of R/S building blocks 1 and 3 in the reaction sequence resulted in unexpected problems during the preparation of intermediates 4.…”

“…Unsaturated tetrahydropyrazino-oxazine-diones 6(R 1 ,R 2 ) were synthesized from either fluorenylmethyloxycarbonyl(Fmoc)-L-Ser(OtBu)-OH 1 S or Fmoc-D-Ser(OtBu)-OH 1 R by using various α-bromoketones 2(R 1 ) and Fmoc-L-amino acids 3 S (R 2 ) or Fmoc-D-Ala-OH 3 R (2) (see Figure 1 for numbering; ChemSet numbering system used) in accordance with the previously reported procedure. [55] Piperazine-2,4-diones 4(R 1 ,R 2 ) were converted into fused intermediates 6(R 1 ,R 2 ) by subsequent tBu protecting group cleavage and TFA-triggered cyclization of the oxazine scaffold (Scheme 1). In the last step, the possible stereoselective formation of fully saturated hexahydropyrazino-oxazine-diones 7 by TES was tested.…”

“…In contrast, by using a combination of R/S building blocks 1 and 3 in the reaction sequence resulted in unexpected problems during the preparation of intermediates 4. More specifically, application of the previously reported synthetic method [55] for the reaction of Fmoc-L-Ser(tBu)-OH 1 S , 2-bromo-1-(p-tolyl)ethan-1-one 2(2) and Fmoc-D-Ala-OH 3 R (2) or Fmoc-D-Ser(tBu)-OH 1 R , 2-bromo-1-(p-tolyl)ethan-1-one 2(2) and Fmoc-L-Ala-OH 3 S (1) led to very low conversions rate of intermediates 4, and acylation with Fmoc-D-Ala-OH/Fmoc-L-Ala-OH had to be repeated three times to reach quantitative conversion. Such behavior can be hypothetically explained by unfavorable spatial orientation of the amino acids side chains that lead to their mutual steric repulsion within the reaction.…”

“…Overall yields were calculated after the entire reaction sequence (ten steps) [55] and HPLC purification. The reaction mixture was concentrated with a stream of nitrogen and the resulting oily residue was dissolved in neat MeCN (5 mL) and purified by semi-preparative HPLC.…”