Concise Synthesis of (1R,2S,3R,6R)-6-Ethoxy-4-(hydroxymethyl)cyclohex-4-ene-1,2,3-triol, a Key Intermediate for the Synthesis of Uvacalols I and J

Abstract

Uvacalols are novel carbasugars isolated from the genera Uvaria. In this study, we report concise syntheses of (1R,2S,3R,6R)-6-ethoxy-4-(hydroxymethyl)cyclohex-4-ene-1,2,3-triol, a key intermediate for the synthesis of uvacalols I and J, and of its epimer (1R,2S,3S,6R)-6-ethoxy-4-(hydroxymethyl)cyclohex-4-ene-1,2,3-triol, starting from cheap and readily available methyl d-glucopyranoside.

Keywords

uvacalols - carbasugars - methyl glucopyranoside - asymmetric synthesis

Publication History

Received: 24 January 2022

Accepted after revision: 18 February 2022

Article published online:
16 March 2022

• References and Notes

• 1 Takeuchi Y, Shi Q.-W, Sugiyama T, Oritani T. Biosci., Biotechnol., Biochem. 2002; 66: 537
• 2 Suthiphasilp V, Maneerat W, Andersen RJ, Patrick BO, Phukhatmuen P, Pyne SG, Laphookhieo S. Fitoterapia 2019; 138: 104340
• 3a Arjona O, Gómez AM, López JC, Plumet J. Chem. Rev. 2007; 107: 1919 ; and references cited therein
• 3b Plumet J, Gómez AM, López JC. Mini-Rev. Org. Chem. 2007; 4: 201
• 4 Vidyasagar A, Sureshan KM. Org. Biomol. Chem. 2015; 13: 3900
• 5 Fresneda MA, Alibés R, Font J, Bayón P, Figueredo M. J. Org. Chem. 2012; 77: 5030
• 6 Numata A, Iritani M, Yamada T, Minoura K, Matsumura E, Yamori T, Tsuruo T. Tetrahedron Lett. 1997; 38: 8215
• 7 For syntheses of pericosines, see: Biduś, N.; Banachowicz, P.; Buda, B. S. Tetrahedron 2020, 76, 131397; and references cited therein

For a review on the synthesis of percosines, see:
• 8a Usami Y, Ichikawa H, Arimoto M. Int. J. Mol. Sci. 2008; 9: 401 See also
• 8b Usami Y, Horibe Y, Takoaka I, Ichikawa H, Horibe Y, Tomiyama S, Ohtsuka M, Imanishi Y, Arimoto M. J. Org. Chem. 2007; 72: 6127
• 9 Zhou G.-X, Chen R.-Y, Yu D.-Q. J. Asian Nat. Prod. Res. 1999; 1: 227
• 10 Zhou G.-X, Zhang Y.-J, Chen R.-Y, Yu D.-Q. J. Asian Nat. Prod. Res. 2010; 12: 696
• 11 Zhou G.-X, Chen R.-Y, Yu D.-Q. Nat. Prod. Res. 2011; 25: 161
• 12a Pang X.-P, Yu D.-Q. Chin. Chem. Lett. 1995; 6: 305
• 12b Pang X.-P, Yu D.-Q. Phytochemistry 1995; 40: 1709
• 12c Pang X.-P, Yu D.-Q, Lee K.-H. Chin. Chem. Lett. 1996; 7: 241
• 12d Liao Y.-H, Xu L.-Z, Yang S.-L, Dai J, Zhen Y.-S, Zhu M, Sun N.-J. Phytochemistry 1997; 45: 729
• 13 Mondal S, Sureshan KM. Org. Biomol. Chem. 2014; 12: 7279
• 14 https://www.protheragen.com/available-projects/polyoxygenated-cyclohexene-compound (accessed Mar 9, 2022).
• 15a Kumar BS, Mishra GP, Rao BV. Tetrahedron 2016; 72: 1838
• 15b Muniraju C, Rao JP, Rao BV. Tetrahedron: Asymmetry 2012; 23: 86
• 15c Vinaykumar A, Rao BV. Carbohydr. Res. 2021; 509: 108432
• 15d Vinaykumar A, Muniraju C, Rao BV. Tetrahedron Lett. 2017; 58: 1075
• 16 Hirschmann R, Nicolaou KC, Pietranico S, Leahy EM, Salvino J, Arison B, Cichy MA, Spoors PG, Shakespeare WC, Sprengeler PA, Hamley P, Smith AB. III, Reisine T, Raynor K, Maechler L, Donaldson C, Vale W, Freidinger RM, Cascieri MR, Strader CD. J. Am. Chem. Soc. 1993; 115: 12550
• 17a Dechaux E, Savy P, Bouyain S, Monneret C, Florent J.-C. J. Carbohydr. Chem. 2000; 19: 485
• 17b Garegg PJ, Samuelsson B. J. Chem. Soc., Perkin Trans. 1 1980; 2866
• 18a Rao JP, Rao BV. Tetrahedron: Asymmetry 2010; 21: 930
• 18b Surender B, Vinaykumar A, Kumar BS, Vemulapalli SP. B, Rao BV. ChemistrySelect 2018; 3: 9596
• 19 Scholl M, Ding S, Lee CW, Grubbs RH. Org. Lett. 1999; 1: 953
• 20 Luche J. J. Am. Chem. Soc. 1978; 100: 2226
• 21 (1R,2S,3R,6R)-6-Ethoxy-4-(hydroxymethyl)cyclohex-4-ene-1,2,3-triol (16)¹³ Anhyd FeCl₃ (0.036 g, 0.22 mmol) was added to a solution of 24 (0.070 g, 0.14 mmol) in anhyd CH₂Cl₂ (5 mL) at rt, and the resulting mixture was stirred at rt for 3 h until the reaction was complete (TLC). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography [silica gel, EtOAc–MeOH (9:1)] to give a colorless syrup; yield: 0.027 g (75%); [α]_D ²³ –3.3 (c = 0.5, MeOH).IR (neat): 3356, 1674, 1438, 1199, 1142, 771, 723 cm^–1. ¹H NMR (400 MHz, CD₃OD): δ = 5.58 (s, 1 H), 4.11–3.96 (m, 3 H), 3.76 (s, 1 H), 3.66–3.52 (m, 2 H), 3.34–3.22 (m, 2 H,), 1.13 (t, J = 0.9 Hz, 3 H). ¹³C NMR (100 MHz, CD₃OD): δ = 141.36, 122.87, 81.31, 77.71, 75.78, 73.81, 66.27, 62.73, 15.90. MS (ESI): m/z = 227 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₆NaO₅: 227.0895; found: 227.0893.
• 22 (1R,2S,3S,6R)-6-Ethoxy-4-(hydroxymethyl)cyclohex-4-ene-1,2,3-triol (17)Prepared from compound 25 by using a similar procedure to the above to give a syrup; yield: 0.081 g (74%); [α]_D ²³ +1.2 (c = 1.0, MeOH).IR (neat): 3332, 1641, 1433, 1201, 1014, 771 cm^–1. ¹H NMR (400 MHz, CD₃OD): δ = 5.77 (s, 1 H), 4.20–4.06 (m, 3 H), 3.60–3.56 (m, 3 H), 3.36 (s, 2 H,), 1.21 (t, J = 6.9 Hz, 3 H). ¹³C NMR (125 MHz, CD₃OD): δ = 140.69, 125.38, 81.59, 72.87, 72.45, 68.15, 65.97, 63.77, 15.92. MS (ESI): m/z = 227 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₆NaO₅: 227.0895; found: 227.0889.