Preparation of Novel 4′-Spirocyclopropyl Nucleoside Analogues

Abstract

The stereoselective preparation of a novel 4′-spirocyclopropyl nucleoside analogue has been developed by using a semibenzilic Favorskii rearrangement of a 4′-(2-chloro-3-oxocyclobutyl)spirofuranose as a key step. These chiral spirocyclic intermediates, readily obtained on a multigram scale from chiral-pool starting materials, were shown to be highly suitable precursors for achieving full stereoselectivity in the reduction–ring contraction sequence. The downstream introduction of a nucleobase through Vorbrüggen glycosylation successfully resulted in the formation of the corresponding novel 4′-spirocyclic nucleoside analogue in a stereospecific manner.

Key words

cycloaddition - spiro compounds - rearrangement - glycosylation - nucleosides - Favorskii rearrangement

Publication History

Received: 24 January 2020

Accepted after revision: 09 February 2021

Accepted Manuscript online:
09 February 2021

Article published online:
18 February 2021

• References and Notes

• 1a Boriack-Sjodin PA, Swinger KK. Biochemistry 2016; 55: 1557
• 1b Bernstein BE, Meissner A, Lander ES. Cell 2007; 128: 669
• 1c Rodríguez-Paredes M, Esteller M. Nat. Med. 2011; 17: 330
• 1d Ahuja N, Sharma AR, Baylin SB. Annu. Rev. Med. 2016; 67: 73
• 2a Brehmer D, Wu T, Mannens G, Beke L, Vinken P, Gaffney D, Sun W, Pande V, Thuring J.-W, Millar H, Poggesi I, Somers I, Boeckx A, Parade M, Heerde E. v, Nys T, Yanovich C, Herkert B, Verhulst T, Jardin MD, Meerpoel L, Moy C, Diels G, Viellevoye M, Schepens W, Poncelet A, Linders JT, Lawson EC, Edwards JP, Chetty D, Laquerre S, Lorenzi MV. Cancer Res. 2017; 77: DTT02-04
• 2b Wu T, Brehmer D, Beke L, Boeckx A, Diels GS. M, Gilissen RA. H. J, Lawson EC, Pande V, Parade MC. B. C, Schepens WB. G, Thuring JW. J. F, Viellevoye M, Sun W, Meerpoel L. WO 2016070097, 2016
• 2c Wu T, Millar H, Gaffney D, Beke L, Mannens G, Vinken P, Sommers I, Thuring J.-W, Sun W, Moy C, Pande V, Zhou J, Haddish-Berhane N, Salvati M, Laquerre S, Lorenzi MV, Brehmer D. In Proceedings of the American Association for Cancer Research Annual Meeting 2018, Chicago, April 14−18, 2018, Vol.78 (Suppl. 13). American Association of Cancer Research; Philadelphia: 2018.
• 3 Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG, Savona MR, Jongen-Lavrenic M, Altman JK, Thomson B, Blakemore SJ, Daigle SR, Waters NJ, Suttle AB, Clawson A, Pollock R, Krivtsov A, Armstrong SA, DiMartino J, Hedrick E, Löwenberg B, Tallman MS. Blood 2018; 131: 2661
• 4a Maougal M, Escudier J.-M, Len C, Dubreuil D, Lebreton J. In Chemical Synthesis of Nucleoside Analogues . Merino P. Wiley; Hoboken: 2013
• 4b Morquez VE. In Modified Nucleosides in Biochemistry, Biotechnology and Medicine. Herdewijn P. Wiley-VCH; Weinheim: 2008. 305
• 5a Verhoeven J, Verniest GA. F, Thuring JW. J. F, Wu T, Pande V, Meerpoel L, Brehmer D, Sun W, Denmark SE. WO 2019110734, 2019
• 5b Verhoeven J, De Vleeschouwer F, Kong H, Van Hecke K, Pande V, Sun W, Vos A, Wu T, Meerpoel L, Thuring JW, Verniest G. Chem. Eur. J. 2019; 25: 15419
• 6a Boyer SH, Ugarkar BG, Solbach J, Kopcho J, Matelich MC. Ollis K, Gomez-Galeno JE, Mendonca R, Tsuchiya M, Nagahisa A, Nakane M, Wiesner JB, Erion MD. J. Med. Chem. 2005; 48: 6430
• 6b Köllmann C, Wiechert SM, Jones PG, Pietschmann T, Werz DB. Org. Lett. 2019; 21: 6966
• 6c Nowak I, Robins MJ. J. Org. Chem. 2006; 71: 8876
• 6d Lemaire S, Diène C, Gavryushin A, Du Jourdin XM, Paolini L, Jusseau X, Knochel P, Farina V. J. Org. Chem. 2019; 84: 4910
• 6e Xu W, Abboud KA, Ghiviriga I, Dolbier WR. Jr, Rapp M, Wnuk SF. Org. Lett. 2006; 8: 5549
• 6f Jonckers TH. M, Lin T.-I, Buyck C, Lachau-Durand S, Vandyck K, Van Hoof S, Vandekerckhove LA. M, Hu L, Berke JM, Vijgen L, Dillen LL. A, Cummings MD, de Kock H, Nilsson M, Sund C, Rydegård C, Samuelsson B, Rosenquist Å, Fanning G, Van Emelen K, Simmen K, Raboisson P. J. Med. Chem. 2010; 53: 8150
• 6g Liu X, Xia X, Sun C, Lin C, Zhou Y, Hussain M, Tang F, Liu L, Li X, Zhang J. Nucleosides, Nucleotides Nucleic Acids 2016; 35: 479
• 6h Rapp M, Cai X, Xu W, Dolbier WR. Jr, Wnuk SF. J. Fluor. Chem. 2009; 130: 321
• 7a Brand C, Rauch G, Zanoni M, Dittrich B, Werz DB. J. Org. Chem. 2009; 74: 8779
• 7b Ramakrishna B, Sridhar PR. RSC Adv. 2015; 5: 8142
• 8 Belluš D, Ernst B. Angew. Chem. Int. Ed. 1988; 27: 797
• 9a Conia JM, Salaun JR. Acc. Chem. Res. 1972; 5: 33
• 9b Garin DL, Cammack KL. J. Chem. Soc., Chem. Commun. 1972; 333
• 9c Salaun J, Garnier B, Conia JM. Tetrahedron 1973; 29: 2895
• 10 Verniest G, Bombeke F, Kulinkovich OG, De Kimpe N. Tetrahedron Lett. 2002; 43: 599
• 11 The use of methanol as a solvent initially led to the partial (35%) formation of a ring-opened methyl ester byproduct (see Supporting Information); however, this competing side reaction could be avoided by employing THF as the reaction solvent.
• 12a Brook PR, Duke AJ. J. Chem. Soc. D. 1970; 652
• 12b Brook PR. Chem. Commun. 1968; 565
• 13 CCDC 2049503 contains the supplementary crystallographic data for compound 13. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 14a McMurry JE, Bosch GK. Tetrahedron Lett. 1985; 26: 2167
• 14b McMurry JE, Bosch GK. J. Org. Chem. 1987; 52: 4885
• 14c Nakyama Y, Nagase M. J. Org. Chem. 1995; 60: 1878
• 14d Todd MA, Sabat M, Myers WH, Harman WD. J. Am. Chem. Soc. 2007; 129: 11010
• 14e Saitoh H, Sampei T, Kimura T, Kato Y, Ishida N, Satoh T. Tetrahedron Lett. 2012; 53: 3004
• 14f Stadler H. Helv. Chim. Acta 2015; 98: 1189
• 15 (1S,3a'S,6'R,6a'R)-2-Chloro-6'-methoxy-2',2'-dimethyldihydro-6'H-spiro[cyclobutane-1,4'-furo[3,4-d][1,3]dioxol]-3-one (14) Zn (3.06 g, 47.0 mmol, 7.00 equiv) was added to a solution of substrate 10a (2.00 g, 6.72 mmol, 1.00 equiv) in anhyd THF (30 mL), and the mixture was cooled to 0 °C. Glacial HOAc (0.39 mL, 6.7 mmol, 1.00 equiv) was added, and the solution was warmed to rt and stirred for 30 min. The mixture was then filtered through a pad of Celite that was rinsed with EtOAc (200 mL). The filtrate was washed with aq NaHCO₃ (3 × 50 mL) and brine (2 × 50 mL) then dried (MgSO₄), filtered, and concentrated in vacuo to give a pale-yellow oil; yield: 1.77 g (quant); R_f = 0.33 (hexane–EtOAc, 4:1). ¹H NMR (500 MHz, CDCl₃): δ = 5.01 (s, 1 H), 4.98 (d, J = 5.8 Hz, 1 H), 4.83 (dd, J = 4.1, 1.9 Hz, 1 H), 4.68 (d, J = 5.8 Hz, 1 H), 3.52 (dd, J = 18.7, 1.91 Hz, 1 H), 3.42 (dd, J = 18.8, 4.16 Hz, 1 H), 3.41 (s, 3 H), 1.44 (s, 3 H), 1.35 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 197.1, 113.0, 108.7, 85.3, 81.9, 79.5, 69.7, 55.3, 49.9, 26.3, 25.2. [(1R,2S,3a'S,6'R,6a'R)-6'-Methoxy-2',2'-dimethyldihydro-3a'H-spiro[cyclopropane-1,4'-furo[3,4-d][1,3]dioxol]-2-yl]methanol (15) Product 14 (27.0 g, 103 mmol, 1.00 equiv) was dissolved in anhyd THF (270 mL) and cooled to 0 °C. NaBH₄ (19.6 g, 515 mmol, 5.00 equiv) was added in a portionwise manner, and the mixture was stirred at rt for 1 h. 1 M aq NaOH (1080 mL) was added, and stirring was continued for 24 h at 50 °C. The product was extracted with EtOAc (3 × 500 mL) and the combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica gel, heptane–EtOAc (gradient 99:1 to 1:1)]. The fractions containing the product were collected and the solvent was evaporated to afford a colorless oil; yield: 14 g (59%, 60.8 mmol). ¹H NMR (300 MHz, CDCl₃): δ = 4.94 (s, 1 H), 4.68 (d, J = 5.9 Hz, 1 H), 4.60 (d, J = 5.9 Hz, 1 H), 3.93 (dd, J = 11.6, 5.8 Hz, 1 H), 3.34 (s, 3 H), 3.24 (dd, J = 11.6, 9.5 Hz, 1 H), 1.51 (s, 3 H), 1.46–1.39 (m, 1 H), 1.35 (s, 3 H), 1.25 (dd, J = 10.0, 6.9 Hz, 1 H), 0.81 (t, J = 6.9 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 112.5, 107.5, 85.3, 79.9, 69.2, 62.8, 55.0, 26.3, 26.2, 25.3, 9.8. GC/MS (ESI+): m/z [M – CH₃O]⁺ calcd for C₁₀H₁₅O₄: 199.10; found: 199.09: T _r = 6.80 min. (1S,3R,5R,6R,7S)-5-(6-Amino-9H-purin-9-yl)-1-(hydroxymethyl)-4-oxaspiro[2.4]heptane-6,7-diol (17) 6-Chloropurine (3.50 g, 22.6 mmol, 1.10 equiv) was dissolved in MeCN (62.4 mL), and N,O-bis(trimethylsilyl)acetamide (4.19 g, 20.6 mmol, 1.00 equiv) was added dropwise. The mixture was heated to 80 °C for 17 h, then cooled to r.t. A solution of diacetate 16 (7.80 g, 20.6 mmol, 1.00 equiv) in MeCN (54.6 mL) was added, followed by TMSOTf (5.49 g, 24.7 mmol, 1.20 equiv), and the mixture was heated to 80 °C for 2 h then cooled to r.t. The resulting mixture was extracted with EtOAc (×2) and sat. aq NaHCO₃, and the combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified column chromatography [silica gel, CH₂Cl₂–MeOH (gradient 99:1 to 30:1)]. The fractions containing the product were collected, and the solvent was evaporated. The residue (8.0 g, 16 mmol) was dissolved in 1,4-dioxane (80 mL), and 25% aq NH₃ (20 mL) was added. The mixture was heated to 80 °C for 17 h then cooled to r.t. The solvent was removed in vacuo, and the product was dissolved in MeOH (80 mL). NaOMe (0.74 g, 14 mmol, 1.00 equiv) was added, and the mixture was stirred at r.t. for 30 min. It was then stirred with H⁺ exchange resin to pH 7. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography [silica gel, CH₂Cl₂–MeOH (gradient 99:1 to 90:10)]. Fractions containing the product were collected, and the solvent was evaporated to give a white solid; yield: 4.20 g [70% (2 steps), 14.3 mmol]. ¹H NMR (400 MHz, CD₃OD): δ = 8.37 (s, 1 H), 8.21 (s, 1 H), 6.08 (d, J = 5.9 Hz, 1 H), 5.08 (dd, J = 5.9, 5.1 Hz, 1 H), 4.25 (d, J = 5.1 Hz, 1 H), 3.88 (dd, J = 11.7, 5.9 Hz, 1 H), 3.26 (dd, J = 11.4, 9.7 Hz, 1 H), 1.46–1.60 (m, 1 H), 1.05 (dd, J = 10.3, 6.6 Hz, 1 H), 0.89 (t, J = 6.8 Hz, 1 H). ¹³C NMR (75 MHz, CD₃OD): δ = 157.5, 154.0, 150.7, 141.6, 120.6, 89.3, 77.3, 72.9, 72.3, 63.0, 25.9, 12.1. LC-MS (ESI+): m/z [M + H]⁺ calcd for C₁₂H₁₆N₅O₄: 294.11; found: 294.12; T _r = 0.48 min. HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₂H₁₆N₅O₄: 294.1189; found: 294.1195.
• 16 Umbreen S, Linker T. Chem. Eur. J. 2015; 21: 7340