Regioselective intramolecular ring closure of 2-amino-6-bromo-2,6-dideoxyhexono-1,4-lactones to 5- or 6-membered iminuronic acid analogues: synthesis of 1-deoxymannojirimycin and 2,5-dideoxy-2,5-imino-d-glucitol

Abstract

1-Deoxymannojirimycin (8c) was synthesised from 2-amino-6-bromo-2,6-dideoxy-D-mannono-1,4-lactone (7) by intramolecular direct displacement of the C-6 bromine employing non-aqueous base treatment followed by reduction of the intermediate methyl ester. Likewise, using aqueous base at pH 12, ring closure took place by 5-exo attack on the 5,6-epoxide leading to 2,5-dideoxy-2,5-imino-L-gulonic acid (9b), which was reduced to 2,5-dideoxy-2,5-imino-D-glucitol (9b). The method was further applied to 2-amino-6-bromo-2,6-dideoxy-D-galacto- as well as D-talo-1,4-lactones (14 and 15). However, only the corresponding six-membered ring 1,5-iminuronic acid mimetics, namely (2R,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-galactonic acid, 16) and (2S,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-talonic acid, 17), were obtained. The corresponding enantiomers, L-galacto- as well as L-talo-2-amino-6-bromo-2,6-dideoxy-1,4-lactones ent-14 and ent-15, reacted accordingly to give the D-galacto- and L-altro-1,5-iminuronic acid mimetics, (2S,3S,4R,5S)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-L-galactonic acid, ent-16) and (2R,3S,4R,5S)-3,4,5-trihydroxypipecolic acids (2,6-dideoxy-2,6-imino-L-talonic acid, ent-17), respectively.

Conformational Behaviour of Azasugars Based on Mannuronic Acid

“…The synthesis of DMJ ( 2 ) and its C5 analogues was achieved according to the route devised by Wrodnigg and co‐workers . As depicted in Scheme , methyl mannuronic acid ester azasugar 3 was obtained in four steps from the commercially available calcium d ‐gluconate monohydrate ( 6 ) .…”

“…The residue was purified by column chromatography (EtOAc/EtOH 1:1→100 % EtOH), yielding a pure sample of DMJ ( 2 ) in 29 % yield (105 mg, 0.50 mmol). [α] =−14.0° ( c =0.5, MeOH); 1 H NMR (399 MHz, D 2 O): δ =3.99 (dt, J= 2.9, 1.6 Hz, 1 H; C‐3), 3.76 (dd, J= 12.5, 3.9 Hz, 1 H; C‐7), 3.71 (dd, J= 12.5, 5.5 Hz, 1 H; C‐7a), 3.60 (t, J= 9.7 Hz, 1 H; C‐5), 3.53 (dd, J= 9.6, 3.1 Hz, 1 H; C‐4), 3.03 (dd, J= 14.2, 2.8 Hz, 1 H; C‐2a), 2.80 (dd, J= 14.2, 1.5 Hz, 1 H; C‐2b), 2.57 ppm (ddd, J= 9.7, 4.9, 3.4 Hz, 1 H; C‐6); 13 C NMR (101 MHz, D 2 O): δ =74.4 (C‐4), 67.6 (C‐5), 67.5 (C‐3), 62.4 (C‐6), 59.6 (C‐7), 48.9 ppm (C‐2).…”

Sequential Biocatalytic Aldol Reactions in Multistep Asymmetric Synthesis: Pipecolic Acid, Piperidine and Pyrrolidine (Homo)Iminocyclitol Derivatives from Achiral Building Blocks

“…Compound 13c (178 mg) was dissolved in H 2 O/CH 3 CH 2 OH 1:1 (40 mL) and treated with H 2 (50 psi) in the presence of Pd/C (150 mg) at room temperature during 24 h. After the previously described work‐up, the title compound (96 mg, 99%) was obtained. [α]${{{20\hfill \atop {\rm D}\hfill}}}$ : −29.2 ( c 1.47 in H 2 O) {lit 4c. enantiomer [α]${{{20\hfill \atop {\rm D}\hfill}}}$ : +10.3 ( c 0.57 in H 2 O); lit 4d.…”

“…[α]${{{20\hfill \atop {\rm D}\hfill}}}$ : −16.9 ( c 0.6 in H 2 O); lit 4d. enantiomer [α]${{{18\hfill \atop {\rm D}\hfill}}}$ : +19.5 ( c 0.75 in H 2 O)}; 1 H NMR (400 MHz, D 2 O): δ =4.49 (dd, J =2.8, 1.7 Hz, 1 H), 4.07 (ddd, J =11.3, 9.7, 5.2 Hz, 1 H), 3.90 (d, J =1.5 Hz, 1 H), 3.71 (dd, J =9.7, 3.0 Hz, 1 H), 3.50 (dd, J =12.5, 5.4 Hz, 1 H), 2.87 (dd, J =12.5, 11.3 Hz, 1 H); 13 C NMR (101 MHz, D 2 O): δ =170.7, 73.0, 68.4, 64.2, 61.7, 45.1;4c,d HR‐MS‐ESI: m / z= 178.0713, calcd. for C 6 H 12 NO 5 : 178.0715 [M+H + ].…”

Building Bridges: Biocatalytic C–C-Bond Formation toward Multifunctional Products

“… 26 Furthermore, several benzopyrrolizidine- and cyclohexapyrrolizidine-type cyclitols were readily obtained from a three-step chemoenzymatic synthesis using FucA-F131A variant and an acid phosphate. 27 Due to their strong α-glycosidase inhibitory properties, 28 pharmaceutically relevant pyrrolidine- and piperidine-based iminocyclitols such as 1,4-dideoxy-1,4-imino- d- arabintol (DAB), its corresponding enantiomer LAB, pipecolic acids, or the nutritionally relevant d -fagomine represent attractive target products of multistep chemoenzymatic syntheses involving the powerful DHAP-independent FSA. 29 …”