Synlett 2021; 32(09): 892-896
DOI: 10.1055/a-1386-7194
letter

Preparation of Novel 4′-Spirocyclopropyl Nucleoside Analogues

a  Research Group of Organic Chemistry (ORGC), Department of Chemistry and Department of Bio-engineering Sciences, Faculty of Science and Bio-engineering Sciences, Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050 Brussels, Belgium
c  Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium
,
Hanchu Kong
b  Department of Synthetic Chemistry, Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing, 100176, P. R. of China
,
Yongbin Zhao
b  Department of Synthetic Chemistry, Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing, 100176, P. R. of China
,
Wenbin Wang
b  Department of Synthetic Chemistry, Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing, 100176, P. R. of China
,
Vineet Pande
c  Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium
,
Marta Brambilla
c  Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium
,
Kristof Van Hecke
d  XStruct, Department of Chemistry, Ghent University, Krijgslaan 281-S3, 9000 Ghent, Belgium
,
Lieven Meerpoel
c  Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium
,
Jan Willem Thuring
c  Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium
,
Guido Verniest
a  Research Group of Organic Chemistry (ORGC), Department of Chemistry and Department of Bio-engineering Sciences, Faculty of Science and Bio-engineering Sciences, Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050 Brussels, Belgium
c  Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium
› Author Affiliations
We thank VLAIO (formerly IWT) and Janssen Pharmaceutica NV for financial support (project IWT140765). K.V.H. thanks the Research Foundation – Flanders (FWO) (projects AUGE/11/029 and G099319N) for funding.


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.

Supporting Information



Publication History

Received: 24 January 2020

Accepted after revision: 09 February 2021

Publication Date:
09 February 2021 (online)

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
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  • 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); Rf = 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.
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