Length Matters: One Additional Methylene Group in a Reactant is Able to Affect the Reactivity Pattern and Significantly Increase the Product Yield

Abstract

The outcome of the nucleophilic opening of 3-O-benzoyl-β-d-arabinofuranose 1,2,5-orthobenzoate with 4-(ω-chloroalkoxy)phenols (SnCl₄, CH₂Cl₂, –25 °C) unusually strongly depends on the length of the methylene chain of the nucleophile. The presence of one extra methylene group in the molecule of 4-(3-chloropropoxy)phenol [as compared to 4-(2-chloroetoxy)phenol] results in four-fold reduction in the reaction time and five-fold increase in the yield of a selectively protected monosaccharide glycoside with a hydroxy group at C-5, which is a valuable building block for the synthesis of oligoarabinofuranosides related to mycobacterial arabinans. Possible reasons and consequences of this finding are discussed.

Key words

mycobacterial arabinans - oligosaccharides - glycosylation - orthoesters - phenols - reactivity pattern - substituent effects - solution structure

• References and Notes

• 1 New address: University of Zurich, Institute of Physiology, Winterthurerstraße 190, 8057 Zürich, Switzerland.
• 2a World Health Organization Tuberculosis (TB): http://www.who.int/tb/en (01 February 2018).
• 2b World Health Organization Tuberculosis Fact Sheet No. 104: http://www.who.int/mediacentre/factsheets/fs104/en (01 February 2018).
• 3a Tam P.-H. Lowary TL. In Carbohydr. Chem. . Vol. 36. Rauter AP. Lindhorst TK. RSC Publishing; 2010: 36, 38-63
• 3b Lowary TL. Acc. Chem. Res. 2016; 49: 1379
• 3c Islam M. Shinde GP. Hotha S. Chem. Sci. 2017; 8: 2033
• 3d Thadke SA. Mishra B. Islam M. Pasari S. Manmode S. Rao BV. Neralkar M. Shinde GP. Walke G. Hotha S. Nat. Commun. 2017; 8: 14019
• 3e Wu Y. Xiong DC. Chen SC. Wang YS. Ye XS. Nat. Commun. 2017; 8: 14851
• 3f Wang L. Feng S. Wang S. Li H. Guo Z. Gu G. J. Org. Chem. 2017; 82: 12085
• 4 Abronina PI. Podvalnyy NM. Mel'nikova TM. Zinin AI. Fedina KG. Kachala VV. Torgov VI. Kononov LO. Panfertsev EA. Baranova EV. Mochalov VV. Dyatlova VI. Biketov SF. Russ. Chem. Bull. 2010; 59: 2333
• 5 Abronina PI. Zinin AI. Romashin DA. Tereshina VV. Chizhov AO. Kononov LO. Carbohydr. Res. 2018; 464: 28
• 6a Abronina PI. Fedina KG. Podvalnyy NM. Zinin AI. Chizhov AO. Kondakov NN. Torgov VI. Kononov LO. Carbohydr. Res. 2014; 396: 25
• 6b Podvalnyy NM. Abronina PI. Zdorovenko EL. Chizhov AO. Zinin AI. Torgov VI. Kononov LO. Russ. Chem. Bull. 2014; 63: 497
• 6c Kondakov NN. Mel'nikova TM. Zinin AI. Torgov VI. Chizhov AO. Gordeeva EA. Bovin NV. Kononov LO. Russ. Chem. Bull. 2014; 63: 501
• 6d Kondakov NN. Mel'nikova TM. Chekryzhova TV. Mel'nikova MV. Zinin AI. Torgov VI. Chizhov AO. Kononov LO. Russ. Chem. Bull. 2015; 64: 1142
• 6e Abronina PI. Zinin AI. Romashin DA. Malysheva NN. Chizhov AO. Kononov LO. Synlett 2015; 26: 2267
• 6f Podvalnyy NM. Chizhov AO. Zinin AI. Kononov LO. Carbohydr. Res. 2016; 431: 25
• 6g Kononov LO. Fedina KG. Orlova AV. Kondakov NN. Abronina PI. Podvalnyy NM. Chizhov AO. Carbohydr. Res. 2017; 437: 28
• 6h Panova MV. Podvalnyy NM. Okun EL. Abronina PI. Chizhov AO. Kononov LO. Carbohydr. Res. 2018; 456: 35
• 7a Sanchez S. Bamhaoud T. Prandi J. Eur. J. Org. Chem. 2002; 3864
• 7b Podvalnyy NM. Sedinkin SL. Abronina PI. Zinin AI. Fedina KG. Torgov VI. Kononov LO. Carbohydr. Res. 2011; 346: 7
• 7c Podvalnyy NM. Zinin AI. Venkateswara RaoB. Kononov LO. In Carbohydrate Chemistry: Proven Synthetic Methods . Roy R. Vidal S. CRC Press; Boca Raton FL: 2015: 147-154
• 8 Zinin AI. Stepanova EV. Jost U. Kondakov NN. Shpirt AM. Chizhov AO. Torgov VI. Kononov LO. Russ. Chem. Bull. 2017; 66: 304
• 9 Typical Glycosylation Procedure 3-O-Benzoyl-β-d-arabinofuranose 1,2,5-orthobenzoate (1)7b, c(200 mg, 0.588 mmol) and phenol 2a or 2b (2.94 mmol)8 were dried in vacuo, and anhydrous CH₂Cl₂ (4 mL) was added. The reaction mixture was cooled to –25 °C and 1 M solution of SnCl₄ (68 μL, 68 μmol) in CH₂Cl₂ was slowly added to the resulting mixture with a syringe. The reaction mixture was stirred at –25 °C (for 4 h in the case of 2a and for 1 h in the case of 2b) until total consumption of 1 (R_f 0.58, light petroleum/EtOAc 3:1). The reaction mixture was diluted with saturated NaHCO₃ (15 mL), allowed to warm to r.t., and then CH₂Cl₂ (40 mL) was added. The organic layer was separated, washed with 5% NaOH (4×50 mL), dried with Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (light petroleum/EtOAc 3:1 → 1:3) to give monosaccharide glycoside 3a6h (43 mg, 14%) or 3b (237 mg, 77%) along with oligosaccharide glycosides 4a (m ≥ 2, 85%)6b,f or disaccharide derivative 4b (m = 2, 13%), respectively (see Supporting Information for more details). 4-(3-Chloropropoxy)phenyl 2,3-di-O-benzoyl-α-d-arabinofuranoside (3b) Colorless oil, [α]_D ²⁵ +29.7 (c 1.0, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 2.23 (tt~q, 2 H, J = 6.1 Hz, C H ₂CH₂Cl), 3.75 (t, 2 H, J = 6.4 Hz, CH₂Cl), 3.96–4.05 (m, 2 H, H-5), 4.09 (t, 2 H, J = 5.8 Hz, OC H ₂CH₂), 4.50 (ddd~dt, 1 H, J = 3.8, 4.6 Hz, H-4), 5.57 (dd, 1 H, J = 4.6, 1.2 Hz, H-3), 5.80 (d, 1 H, J = 1.2 Hz, H-2), 5.83 (s, 1 H, H-1), 6.87 (d, 2 H, J = 9.1 Hz, OC₆H₄O), 7.06 (d, 2 H, J = 9.1 Hz, OC₆H₄O), 7.40–7.55 (m, 4 H, Bz), 7.56–7.69 (m, 2 H, Bz), 7.99–8.18 (m, 4 H, Bz) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 32.3 ( C H₂CH₂Cl), 41.5 (CH₂Cl), 62.2 (C-5), 64.9 (O C H₂CH₂), 77.6 (C-3), 81.9 (C-2), 84.4 (C-4), 104.9 (C-1), 115.5, 118.4 (OC₆H₄O), 128.5, 128.6, 129.0, 129.1, 129.9, 130.0, 133.62, 133.66 (Bz), 150.2 (C-1 OC₆H₄O), 154.4 (C-4 OC₆H₄O), 165.3, 166.2 (CO) ppm. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₂₇ClO₈Na: 549.1285; found: 549.1287.
• 10 Under the conditions used, 2b is soluble at –25 °C, while 2a forms a suspension even at room temperature.
• 11 One of the reviewers suggested that the relative reactivity of monosaccharide products 3a and 3b towards orthoester 1 could also be important for the success of oligomerization. Clearly, higher reactivity of 3a in comparison with that of 3b might contribute to the observed preferential formation of oligomeric products 4a in the reaction of 1 with 2a. In such a case one has to justify the putative lowered of reactivity of 3b, which is different from 3a by only one methylene group. Note, however, that glycosides 3a and 3b are both readily soluble in CH₂Cl₂ unlike the parent phenols 2a and 2b (see note 10). In our opinion, this high solubility of 3a and 3b makes this scenario hardly possible.
• 12 Kononov LO. RSC Adv. 2015; 5: 46718