Concise Synthesis of 1,4-Dideoxy-1,4-imino-l-arabinitol (LAB) from d-Xylose by Intramolecular Stereospecific Substitution of a Hydroxy Group

Abstract

We report a concise and green total synthesis of 1,4-dideoxy-1,4-imino-l-arabinitol hydrochloride from naturally occurring d-xylose. The key step involves a stereospecific substitution of a hydroxy group, without prior derivatization, in which the only byproduct is water. This opens up a novel benign route to iminosugar derivatives with diverse biological activities.

Key words

dideoxyiminoarabitinol - imino sugars - nucleophilic substitution - phosphinic acid - alcohols

Publikationsverlauf

Eingereicht: 29. November 2022

Angenommen nach Revision: 18. Januar 2023

Artikel online veröffentlicht:
15. Februar 2023

• References and Notes

• 1a Dirir AM, Daou M, Yousef AF, Yousef LF. Phytochem. Rev. 2022; 21: 1049
• 1b Papoutsis K, Zhang J, Bowyer MC, Brunton N, Gibney ER, Lyng J. Food Chem. 2021; 338: 128119
• 2 Kong W, Lu C, Ding Y, Meng Y. Eur. J. Pharmacol. 2022; 926: 175023
• 3a Radulescu D, Crisan D, Militaru V, Buzdugan E, Stoicescu L, Grosu A, Vlad C, Grapa C, Radulescu ML. J. Gastrointestin. Liver Dis. 2022; 31: 98
• 3b Lenders M, Brand E. Drugs 2021; 81: 635
• 4a Welter A, Jadot J, Dardenne G, Marlier M, Casimir J. Phytochemistry 1976; 15: 747
• 4b Evans SV, Fellows LE, Shing TK. M, Fleet GW. J. Phytochemistry 1985; 24: 1953
• 5a Nash RJ, Bell EA, Williams JM. Phytochemistry 1985; 24: 1620
• 5b Fleet GW. J, Nicholas SJ, Smith PW, Evans SV, Fellows LE, Nash RJ. Tetrahedron Lett. 1985; 26: 3127
• 6a Concia AL, Gómez L, Bujons J, Parella T, Vilaplana C, Cardona PJ, Joglara J, Clapés P. Org. Biomol. Chem. 2013; 11: 2005
• 6b da Cruz FP, Newberry S, Jenkinson SF, Wormald MR, Butters TD, Alonzi DS, Nakagawa S, Becq F, Norez C, Nash RJ, Kato A, Fleet GW. J. Tetrahedron Lett. 2011; 52: 219
• 7a Huang Y, Dalton DR, Carroll PJ. J. Org. Chem. 1997; 62: 372
• 7b Espelt L, Parella T, Bujons J, Solans C, Joglar J, Delgado A, Clapés P. Chem. Eur. J. 2003; 9: 4887
• 7c Kim J.-Y, Mu Y, Jin X, Park S.-H, Pham V.-T, Song D, Lee K.-Y, Ham W.-H. Tetrahedron 2011; 67: 9426
• 7d Chang Y.-F, Guo C.-W, Chan T.-H, Pan Y.-W, Tsou E.-L, Cheng W.-C. Mol. Diversity 2011; 15: 203
• 7e Ansaria AA, Vankar YD. RSC Adv. 2014; 4: 12555
• 7f Jaszczyk J, Li S, Cocaud C, Nicolas C, Martin OR. Carbohydr. Res. 2019; 486: 107855
• 7g De Angelis M, Primitivo L, Lucarini C, Agostinelli S, Sappino C, Ricelli A, Righi G. Carbohydr. Res. 2020; 492: 108028
• 7h Syal K, Maiti K, Naresh K, Avaji PG, Chatterji D, Jayaraman N. Glycoconjugate J. 2016; 33: 763
• 8a Fleet GW. J, Smith PW. Tetrahedron 1986; 42: 5685
• 8b Kim YJ, Kido M, Bando M, Kitahara T. Tetrahedron 1997; 53: 7501
• 8c Lombardo M, Fabbroni S, Trombini C. J. Org. Chem. 2001; 66: 1264
• 8d Dhavale DD, Kumar KS. A, Chaudhari VD, Sharma T, Sabharwal SG, PrakashaReddy J. Org. Biomol. Chem. 2005; 3: 3720
• 8e Zhou X, Liu W.-J, Ye J.-L, Huang P.-Q. Tetrahedron 2007; 63: 6346
• 8f Upadhyay PK, Kumar P. Synthesis 2010; 3063
• 8g Choi HG, Park D.-S, Lee WK, Sim T. Tetrahedron Lett. 2013; 54: 5775
• 8h Glawar AF. G, Martínez RF, Ayers BJ, Hollas MA, Ngo N, Nakagawa S, Kato A, Butters TD, Fleet GW. J, Jenkinson SF. Org. Biomol. Chem. 2016; 14: 10371
• 8i de Silva EC, Yamakawa NC. G, Dos Santos AA, Coelho F. Synthesis 2017; 49: 4869
• 9 Akkarasamiyo S, Sawadjoon S, Orthaber A, Samec JS. M. Chem. Eur. J. 2018; 24: 3488
• 10 Watile RA, Bunrit A, Margalef J, Akkarasamiyo S, Ayub R, Lagerspets E, Biswas S, Repo T, Samec JS. M. Nat. Commun. 2019; 10: 3826
• 11a Bunrit A, Dahlstrand C, Olsson SK, Srifa P, Huang G, Orthaber A, Sjöberg PJ. R, Biswas S, Himo F, Samec JS. M. J. Am. Chem. Soc. 2015; 137: 4646
• 11b Bunrit A, Srifa P, Rukkijakan T, Dahlstrand C, Huang G, Biswas S, Watile RA, Samec JS. M. ACS Catal. 2020; 10: 1344
• 12 2,3,5-Tri-O-benzyl-1-deoxy-1-[(4-methoxyphenyl)amino]-d-xylitol (12) 4-Methoxyaniline (325 mg, 2.65 mmol) and AcOH (2 drops) were added to a stirred solution of 11 (742 mg, 1.77 mmol) in EtOH (15 mL), and the mixture was heated at 70 °C for 30 min. A solution of NaBH₃CN (222 mg, 3.53 mmol) in EtOH (5 mL) was added, and the mixture was heated at 70 °C for a further 3 h, then cooled to rt. Brine was added and the resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:2)] to give a brown oil; yield: 705 mg (75%), [α]_D ²⁸ –11.6 (c 0.47, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.44–7.24 (m, 15 H, ArH), 6.85–6.80 (m, 2 H, PMP-ArH), 6.66–6.59 (m, 2 H, PMP-ArH), 4.81–4.46 (m, 6 H, OCH₂Ph), 4.10 (td, J = 6.2, 2.3 Hz, 1 H, H-4), 3.95 (q, J = 5.1 Hz, 1 H, H-2), 3.90–3.77 (m, 1 H, H-3), 3.80 (s, 3 H, OCH₃), 3.64–3.49 (m, 2 H, H-5), 3.37 (qd, J = 12.8, 4.8 Hz, 2 H, H-1). ¹³C NMR (100 MHz, CDCl₃): δ = 152.7 (Ar), 141.9 (Ar), 138.1 (3) (Ar), 128.6 (ArH), 128.5 (3) (ArH), 128.1 (ArH), 128.0 (2) (ArH), 127.9 (ArH), 127.8 (ArH), 115.2 (ArH), 114.9 (ArH), 77.7 (C-3), 77.6 (C-2), 74.4 (OCH₂Ph), 73.3 (OCH₂Ph), 72.7 (OCH₂Ph), 71.3 (C-5), 68.9 (C-4), 55.8 (OCH₃), 44.7 (C-1). HRMS (ESI): m/z [M + H]⁺ calcd for C₃₃H₃₈NO₅: 528.2744; found: 528.2777; [M + Na]⁺ calcd for C₃₃H₃₇NNaO₅: 550.2564; found: 550.2557. (2R,3S,4S)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-1-(4-methoxyphenyl)pyrrolidine (13) A 50 wt.% solution of H₃PO₂ in H₂O (13 μL, 0.1 mmol) was added to a stirred solution of amino alcohol 12 (532 mg, 1 mmol) in toluene (5 mL), and the mixture was refluxed for 15 h. When the reaction was complete (TLC), the mixture was cooled to rt and sat. aq NaHCO₃ was added to neutralize the acid. The mixture was then extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine, dried (Na₂SO₄­), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:10)] to give a colorless oil; yield: 379 mg (74%); [α]_D ²⁸ +59.8 (c 0.47, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.21 (m, 15 H, ArH), 6.86 (d, J = 8.9 Hz, 2 H, PMP-ArH), 6.61 (d, J = 8.9 Hz, 2 H, PMP-ArH), 4.72–4.45 (m, 6 H, OCH₂Ph), 4.25 (s, 1 H, H-3), 4.15 (d, J = 4.8 Hz, 1 H, H-2), 3.94 (dd, J = 9.8, 3.8 Hz, 1 H, H-4), 3.79 (s, 3 H, OCH₃), 3.76 (dd, J = 9.5, 3.8 Hz, H-5), 3.63–3.54 (m, 2 H, H-5 and H-1), 3.50 (dd, J = 10.3, 4.9 Hz, 1 H, H-1). ¹³C NMR (100 MHz, CDCl₃): δ = 151.5 (Ar), 142.4 (Ar), 138.4 (Ar), 138.2 (Ar), 138.0 (Ar), 128.6 (ArH), 128.5 (2) (ArH), 127.9 (ArH), 127.8 (3) (ArH), 127.7 (2), 115.0 (ArH), 113.2 (ArH), 83.2 (C-3), 81.6 (C-2), 73.3 (OCH₂Ph), 71.3 (OCH₂Ph), 71.0 (OCH₂Ph), 68.6 (C-5), 64.7 (C-4), 55.9 (OCH₃), 53.7 (C-1). HRMS (ESI): m/z [M + H]⁺ calcd for C₃₃H₃₆NO₄: 510.2663; found: 510.2639; [M + Na]⁺ calcd for C₃₃H₃₅NNaO₄: 532.2458; found: 532.2471.