An Efficient and Highly Stereocontrolled Route to Bulgecinine Hydrochloride

Abstract

(-)-Bulgecinine is a nonproteinogenic amino acid component present in bulgecins A, B, and C, antibiotic glycopeptides derived from Pseudomonas acidophila and Pseudomonas mesoacidophila. In combination with beta-lactam antibiotics, bulgecins exihibit a unique synergistic antibacterial activity against various Gram-negative microorganisms. Utilizing d-serine as a chiral template and employing a highly regio- and stereoselective intramolecular amidomercuration-oxidation protocol in the key pyrrolidine ring forming step, an efficient total synthetic route to enantiopure bulgecinine is reported herein.

Amipurimycin: Total Synthesis of the Proposed Structures and Diastereoisomers

“…To our surprise,none of these four diastereoisomers (1ad)d isplay 1 Ha nd 13 CNMR data that are identical to those reported for natural amipurimycin (see the Supporting Information for ad etailed comparison). The 1 Ha nd 13 CNMR signals from the purine and cyclopentanyl amino acid residues in the synthetic 1a-d all correlate well to the reported ones.The coupling patterns of H1',H2',H4',and H5' at the pyranose rings are also in agreement with those reported for the natural product, thus indicating correctness of the assigned stereochemistry at these four positions.T he biggest discrepancy comes from the chemical shifts of H8', with those from the synthetic 1a-d appearing at d = 4.33-4.37 ppm versus d = 3.96 ppm as reported for the natural amipurimycin. Therefore,i twasl ikely that the stereochemistry at C8',which was previously assigned based on proposed chemical transformations,needed to be corrected.…”

“…Synthesis commenced with the preparation of 5 from larabinose (47 %f or 3s teps) [12] and preparation of the Weinreb amides 6a/6b from d/l-serine (ca. 80 %f or 3 steps) [13] on decagram scale (Scheme 1). Addition of CH 3 Li to aT HF solution of 6a/6b at À78 8 8Cg ave as atisfactory conversion into the methyl ketone 4a/4b (ca.…”

Amipurimycin: Total Synthesis of the Proposed Structures and Diastereoisomers

“…The 1 Ha nd 13 CNMR signals from the purine and cyclopentanyl amino acid residues in the synthetic 1a-d all correlate well to the reported ones.The coupling patterns of H1',H2',H4',and H5' at the pyranose rings are also in agreement with those reported for the natural product, thus indicating correctness of the assigned stereochemistry at these four positions.T he biggest discrepancy comes from the chemical shifts of H8', with those from the synthetic 1a-d appearing at d = 4.33-4.37 ppm versus d = 3.96 ppm as reported for the natural amipurimycin. The 1 Ha nd 13 CNMR signals from the purine and cyclopentanyl amino acid residues in the synthetic 1a-d all correlate well to the reported ones.The coupling patterns of H1',H2',H4',and H5' at the pyranose rings are also in agreement with those reported for the natural product, thus indicating correctness of the assigned stereochemistry at these four positions.T he biggest discrepancy comes from the chemical shifts of H8', with those from the synthetic 1a-d appearing at d = 4.33-4.37 ppm versus d = 3.96 ppm as reported for the natural amipurimycin.…”

Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the β-Lactam Antibiotics

“…37 The value of this methodology for the synthesis of bulgecinine was established by Khalaf and Datta 38 and confirmed by Wang et al 39 In this route, the single stereocenter of the d -serine starting material sets the absolute stereochemistry of the two additional stereogenic carbons of the pyrrolidine. We therefore envisioned 5 as the key intermediate, disassembled retrosynthetically into the known GlcNAc donor 6 and the protected bulgecinine 7 , which in turn would be synthesized from d -serine ( 9 ) through Wang’s trisubstituted pyrrolidine 8 .…”