Synlett 2023; 34(05): 441-444
DOI: 10.1055/s-0041-1738432
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Special Edition Thieme Chemistry Journals Awardees 2022

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

Sunisa Akkarasamiyo∗
a   Department of Chemistry, Special Research Unit for Advanced Magnetic Resonance (AMR), Faculty of Science, Kasetsart University, Chatuchak, Bangkok 10900, Thailand
,
Hatairat Promsaka Na Sakonnakhon
a   Department of Chemistry, Special Research Unit for Advanced Magnetic Resonance (AMR), Faculty of Science, Kasetsart University, Chatuchak, Bangkok 10900, Thailand
,
Punlop Kuntiyong
b   Department of Chemistry, Faculty of Science, Silpakorn University, Sanamchandra Palace Campus, Nakhon Pathom, 73000, Thailand
,
Poonsakdi Ploypradith
c   Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand
d   Program in Chemical Biology, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 906 Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand
,
Joseph S. M. Samec
e   Department of Organic Chemistry, Stockholm University, 106 91 Stockholm, Sweden
› Author AffiliationsS.A. thanks the Department of Chemistry for Chemistry Research Credit (CRC), the Faculty of Science, Kasetsart University for the Pre-Proposal Research Fund (PRF) and the Undergraduate Research Matching Fund (URMF), and Kasetsart University Research and Development Institute (KURDI) for the financial support [FF(KU8.65)]. J.S. thanks the Swedish Research Councils FORMAS and VETENSKAPSRÅDET.
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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0041-1738432.
  • Supporting Information


Publication History

Received: 29 November 2022

Accepted after revision: 18 January 2023

Article published online:
15 February 2023

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  • References and Notes

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  • 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.