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; Hatairat Promsaka Na Sakonnakhon; Punlop Kuntiyong; Poonsakdi Ploypradith; Joseph S. M. Samec

doi:10.1055/s-0041-1738432

Synlett, Table of Contents

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∗

^aDepartment of Chemistry, Special Research Unit for Advanced Magnetic Resonance (AMR), Faculty of Science, Kasetsart University, Chatuchak, Bangkok 10900, Thailand

,

Hatairat Promsaka Na Sakonnakhon

^aDepartment of Chemistry, Special Research Unit for Advanced Magnetic Resonance (AMR), Faculty of Science, Kasetsart University, Chatuchak, Bangkok 10900, Thailand

,

Punlop Kuntiyong

^bDepartment of Chemistry, Faculty of Science, Silpakorn University, Sanamchandra Palace Campus, Nakhon Pathom, 73000, Thailand

,

Poonsakdi Ploypradith

^cLaboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand

^dProgram in Chemical Biology, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 906 Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand

,

Joseph S. M. Samec

^eDepartment of Organic Chemistry, Stockholm University, 106 91 Stockholm, Sweden

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Abstract

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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

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References

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.

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