Preparation to 2'-Deoxy-2'-Spirocyclopropylcytidine via an Alternative

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Preparation to 2’-Deoxy-2’-Spirocyclopropylcytidine via an Alternative Cyclopropanation Reaction Sebastien Lemaire, Coura Diene, Andrei Gavryushin, Xavier Mollat du Jourdin, Léa Paolini, Xavier Jusseau, Paul Knochel, and Vittorio Farina J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 Feb 2019 Downloaded from http://pubs.acs.org on February 5, 2019

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The Journal of Organic Chemistry

Preparation to 2’-Deoxy-2’-Spirocyclopropylcytidine via an Alternative Cyclopropanation Reaction Sébastien Lemaire,a* Coura Diène,b Andrei Gavryushin,b Xavier Mollat Du Jourdin,b Léa Paolini,a Xavier Jusseaua Paul Knochelb and Vittorio Farinaa Janssen Pharmaceutical Companies of Johnson & Johnson, Small Molecule Pharmaceutical Development, Turnhoutseweg 30, 2340 Beerse, Belgium a

Department of Chemistry, Ludwig-Maximilians-Universität, Butenandtstr. 5-13, Building F, D81377 Munich, Germany. b

Email: [email protected] Abstract: Herein we are reporting preparation of 2’-deoxy-2’-spirocyclopropylcytidine via an alternative cyclopropanation reaction starting from -silyl tertiary alcohols. Activation of the hydroxyl function with thionyl chloride in presence of 4-DMAP allows the ring-closing step under mild conditions. Participation of the uracil moiety in the cyclization step is proposed. Keyword: Modified Nucleosides, cyclopropanation Graphical abstract: O

O NH

O O Si O O Si

O

N OH

TMS

NH SOCl2, 4-DMAP THF (75%)

O O Si O O Si

N

O

Recent renewed focus on 2’-deoxy-2’-spirocyclopropane nucleosides as Hepatitis C RNA inhibitors, and especially on 2’-deoxy-2’-spirocyclopropylcytidine (1),1 has triggered our interest in devising a practical, high-yielding and safely scalable synthesis of these potentially valuable chemotherapeutic agents. The medicinal synthesis (Scheme 1) is based on the initial discovery by Robins2 that exomethylene derivatives such as 33 undergo cycloaddition with diazomethane, followed by photolytic extrusion of N2 to yield 2’-spirocyclopropanes. This procedure could be scaled up, with minor modifications, to provide initial quantities of 1 for phase I and toxicological studies.

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However, this process was not considered suitable for eventual commercial production, although diazomethane can be safely generated and handled in specialized facilities, and the photochemical extrusion could be readily carried in a flow set-up using a simple Hg lamp.4 In addition to the need for specialized equipment and stringent safety measures, the synthesis was rather low yielding, especially when chromatographic purification was eliminated and crude reaction products were used for the cycloaddition/fragmentation. It was therefore decided to invest in research toward a new approach to 1. In practice, we targeted key intermediate 6, which could be then transformed into 1 without problems using the published synthesis.1 Classical direct cyclopropanation of 3 with or without 3’-hydroxy protection via SimmonsSmith conditions5,6 was initially examined. Unfortunately, either no reaction or decomposition of the starting substrate ensued. Cyclopropanation using dichlorocarbenes, or opening of epoxides derived from 3 with stabilized phosphonate anions were also unsuccessful.7 O

O NH

O O Si O O Si

N

O

iPr2NEt BzCl, DCM, rt (86%)

2

O O Si O O Si

N O O Si O O Si

5

N

N

Bz

N CH2N2

O

(85%) O

Bz O

O O Si O O Si

ether, rt

3

O

Hg lamp PhMe MeCN Ph2CO

O N

Bz O

N N N

4

NH2

NH NH3, MeOH rt (38%)

O O Si O O Si

N

N

O

6

HO

O

N

O

OH 1

Scheme 1: Discovery approach to key intermediate 6. Finally, a stepwise approach to the cyclopropane core was considered (Scheme 2). We built on literature reports describing cyclopropane formation starting from -stannyl tertiary alcohols.8,9 Although the same authors report the unsuccessful cyclization with the homologous silyl derivatives, we decided to investigate an approach from -silyl tertiary alcohols, because it would avoid using toxic organostannane intermediates. As a back-up approach, we considered protecting the uracil moiety at the N-3 position to limit a possible side reaction where the uracil C-2 carbonyl may attack the incipient carbonium ion at C-2’;10 the cyclization to yield 9 may be irreversible and we envisioned the possibility of avoiding it by reducing the nucleophilicity of the carbonyl.


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O

O

NH

NH O O Si O O Si

O

N

acid O O Si O O Si

OH

N

O

O Si O O Si

O

SiMe3

N O

NH

N vs.

SiMe3

SiMe3

O O Si O O Si

N

O

9

8

7

O

O

6

Scheme 2 : Potential problem with the new approach to 6. In the end, our concerns turned out to be unfounded, and we will describe how the unprotected uracil moiety is actually essential to the success of our approach. We initially attempted formation of 7 by addition of an excess of (trimethylsilyl)ethyl magnesium bromide11 to ketone 103 in the presence of LaCl3.2LiCl12 or ZnCl2 at low temperature (-40°C). This was preceded by deprotonation of the acidic uracil N-H function by addition of MeMgBr. Only low to moderate yields of 7 were obtained (up to 31% yield). The selectivity for the  isomer was complete, but the desired reaction was plagued by the formation of reduction products 1113 (ratio 7:11=60:40). Decreasing the temperature reaction from -40°C to -78°C helped limit formation of 11 (7:11=85:15) but the yield was still too low to be practical (Scheme 3). O NH N O O Si O O O Si

O

O

O

MeMgBr (1 eq), LaCl3.2LiCl (2 eq.) (trimethylsilyl)ethyl)MgBr (1.5 eq.) THF, -40 oC (31%)

NH

NH O O Si O O Si

O

N OH

+

O Si O O Si

N HO O

O

TMS 10

7

11

Scheme 3: Early approach to 7. A much better approach consisted of adding lithium trimethylsilylacetylene14 to 10, followed by reduction of the triple bond (Scheme 4). The alkynyl function was introduced via the addition of a lithiated trimethylsilylacetylene at 0°C in the presence of lanthanum trichloride to limit enolization at 0°C. In the absence of lanthanum trichloride, the yield ranges from 50-78% under cryogenic conditions, achieving high selectivity for the  face addition.14,15,16



O

O Si O O Si

N O

O

O NH

O

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O

(trimethylsilyl)acetylene (2.5 eq.) n-BuLi (2.5 eq.), LaCl3.2LiCl (1 eq.) THF, 0°C (80%)

NH

NH O O Si O O Si

5% w Pd/C

O

N

7

OH

O O Si O O Si

+

10 bar H2 EtOH, rt (88%)

TMS

OH

13

12

10

O

N

Scheme 4: Alternative synthesis of 7.

The -isomer 12 was isolated in good yield as the main product (>95:5 diastereoselectivity by NMR) by flash chromatography. With compound 12 in hand, we investigated its hydrogenation. The best conditions were found to be in ethanol as solvent under 10 bar of hydrogen pressure at 25°C, leading to 7 in high yield, the remainder being the protodesilylated by-product 13. 1H

The cyclization step leading to the cyclopropane 7 was then studied in THF (Scheme 5). Whereas treatment with tetrabutylammonium fluoride led mostly to desilylation product 13, treatment with Lewis acid (e.g. BF3 complexes) led the formation of compound 14 as single isomer with fluoride incorporation and partial hydrolysis of the silylated protecting group. O

O NH

O O Si O O Si

O

N OH

O NH

conditions THF

O O Si O O Si

N

O

NH +

O O Si F O HO Si

TMS 7

O

N OH

TMS 6

14

Scheme 5 : Cyclopropane formation step Table 1 : Cyclopropanation study Entry 1a 2a 3a 4a 5a 6a 7a 8d 9d a

Reagent SOCl2 SOCl2 SOCl2 SOCl2 SOCl2 SOCl2 SOCl2 SOCl2 SOCl2

Base Pyridine DABCO DBU Et3N 2,6-di-tertbutyl-4-methylpyridine 4-DMAP 2,6-lutidine 4-DMAP 2,6-lutidine

Yield of 6 56% 26%b 0%c 19% 11% 75% 73% 73% 55 %e

3 equiv. of SOCl2, 4 equiv. of base; b 8% starting material recovered; c 25% starting material recovered; d 1.5 equiv. of SOCl2, 2 equiv. of base; e 25% starting material recovered


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Eventually, we were delighted to find that thionyl chloride led to fair yields of product when using pyridine as base (Table 1, entry 1). Thionyl chloride seems to be a unique reagent in promoting the desired transformation, as phosgene and oxalyl chloride did not lead to the desired product. The cyclization step was surprisingly dependent on the base used (Table 1). Strong bases were less effective than pyridine and 2,6-lutidine (entries 2-4), whereas the strongly nucleophilic base DMAP was most effective (entries 6 and 8). Varying the stoichiometry of thionyl chloride (1.5-3 eq.). and DMAP (2-4 eq.) did not affect the conversion. Thus, a high-yielding approach to our desired target 7 was developed using a novel thionyl chloride-induced cyclopropanation reaction. Finally, we were curious to see whether a protecting the N-3 of the uracil might further improve the yield by reducing uracil participation in the reaction, which might yield products of cyclization like 9. Surprisingly, the opposite turned out to be the case: N-benzoylated compound 15 was completely inert in the cyclopropanation. This observation is consistent with the idea that a nucleophilic uracil is essential for this reaction to take place. When 15 was spiked at a level of 80% in the cyclization of 7 to yield 6, it was recovered unchanged at the end of the reaction (Scheme 6), whereas 7 cyclized smoothly to 6. O

O

O

NH O O Si O O Si

N

O

N OH

+

O O Si O O Si

SiMe3

7, 20%

O Ph

O

N

N

SOCl2, 4-DMAP. THF

O O Si O O Si

OH

O

O

N

NH

Ph O +

O O Si O O Si

N

O

SiMe3 16, Not detected

15, 80%

6, 20%

Scheme 6 : Failed cyclization of the N-benzoylated material 15. We are therefore led to postulate an intermediate like 17 (Scheme 7) on the pathway to product: participation of the uracil moiety seems indispensable, and the structure of 17 would nicely rationalize such participation. Fragmentation of 17 would be triggered by nucleophilic attack at Si, with subsequent ring closure. More mechanistic work is needed to confirm or disprove the intermediacy of species like 17. O

O N

O O Si O O Si

N

NH O

O S

base O

O O Si O O Si

N

O

SiMe3 Nu 17

6

Scheme 7: Possible rationale to explain results in Scheme 6.



In conclusion, we have developed a simple stepwise approach to spirocyclopropanes like 6, an approach which does not use hazardous reagents and is therefore suitable for scale-up in generic equipment. This cyclization is very specific for the selected substrate and requires the participation of the uracil moiety. Extension to other nucleoside substrates is being investigated.

Experimental part: General experimental information Hydrogen Nuclear Magnetic Resonance spectra (1H NMR) were obtained at 360 MHz, 400 MHz and 600 MHz. Spectra were recorded in CDCl3 or DMSO-d6 solutions. Chemical shifts (δ) are reported in ppm, referenced to the solvent peak of residual CHCl3, DMSO or tetramethylsilane (TMS) as reference. Data are reported as follows: chemical shift (δ), multiplicity, coupling constant (J) in Hertz and integrated intensity. Carbon-13 Nuclear Magnetic Resonance spectra (13C NMR) were obtained at 90, 100 MHz and 151 MHz using broadband 1H decoupling. Fluorine-19 Nuclear Magnetic Resonance spectra (19F NMR) were obtained at 376 MHz using broadband 1H decoupling. Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet), dd (double doublet), t (triplet), td (triple doublet), q (quadruplet), m (multiplet) and bs (broad singlet). Column chromatography was performed using silica gel (230-400 mesh) Thin layer chromatography (TLC) was performed using silica gel GF254, 0.25 mm thickness. For visualization, TLC plates were either placed under ultraviolet light, or phosphomolibdic acid, followed by heating. Air- and moisture-sensitive reactions were conducted in flame-dried or oven dried glassware equipped with tightly fitted rubber septa and under a positive atmosphere of dry argon. Reagents and solvents were handled using standard syringe techniques. 1-((6a'R,8'R,9a'S)-2',2',4',4'-tetraisopropyltetrahydrospiro[cyclopropane-1,9'-furo[3,2f][1,3,5,2,4]trioxadisilocin]-8'-yl)pyrimidine-2,4(1H,3H)-dione (6):1 Under inert atmosphere, in a Schlenk tube were introduced 7 (1 eq., 0.31 mmol, 180 mg) dissolved in THF (5 mL) and 4-DMAP (3.5 eq., 1.07 mmol, 131 mg). The reaction mixture was cooled to 0°C and thionyl chloride (3 eq., 0.92 mmol, 67 µL) was added dropwise. A white precipitate was formed. Complete conversion was obtained after 28.5 hrs of stirring. The solvent was evaporated under reduce pressure to obtain a dried residue. Water (5 mL) and DCM (5 mL) were added. The aqueous layer was extracted with DCM (3 x 3 mL) and the combined organic layers were washed with brine (3 x 3 mL) before being dried on MgSO4. The solvent was evaporated under reduced pressure. The purification was performed by flash chromatography: heptane/EtOAc: 6/4. 6 was obtained as a white foam (75 % yield, 115 mg, purity >95% by H NMR)). 1H NMR (600 MHz, DMSO-d6) δ = 11.35 (br s, 1H), 7.64 (d, J = 7.93 Hz, 1H), 5.79 (s, 1H), 5.63 (d, J = 7.93 Hz, 1H), 4.54 (d, J = 7.93 Hz, 1 H), 4.08 (dd, J = 12.28, 5.10 Hz, 1H), 3.97 (dd, J = 12.46, 2.64 Hz, 1H), 3.78 (ddd, J = 7.84, 5.00, 2.64 Hz, 1H), 0.80 - 1.22 (m, 29H), 0.63 - 0.75 (m, 2H), 0.50 - 0.60 (m, 1H). 13C {1H} NMR (151 MHz, DMSO-d6) δ = 162.9, 150.6, 141.4, 101.9, 88.3, 83.4, 71.2, 61.9, 39.1, 29.2, 17.3, 17.2, 17.0, 16.9, 12.6, 12.4, 12.1, 12.00, 7.81, 6.05. 1-((6aR,8R,9S,9aR)-9-hydroxy-2,2,4,4-tetraisopropyl-9-(2-(trimethylsilyl)ethyl)tetrahydro-6H-furo[3,2f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione (7): In a hydrogenation equipment with overhead stirrer, 500 mg of compound 12 (0.86 mmol) was dissolved in 5 mL of EtOH with 10 mg of 5w% Pd/C. After purging, the reaction mixture was stirred overnight at 25°C under 10 bar hydrogen gas. After


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filtration over decalite and evaporation, 402 mg of desired compound 7 (0.687 mmol) was isolated after silicagel chromatography (heptane/EtOAc 8/2) in 80 % yield. 1H NMR (400 MHz, CDCl3) δ = 8.10 (br s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 5.78 (s, 1H), 5.71 (dd, J = 8.1, 2.2 Hz, 1H), 4.24 (d, J = 9.4 Hz, 1H), 4.15 (dd, , J = 13.3, 1.2 Hz, 1H), 3.99 (dd, J = 13.4, 2.8 Hz, 1H), 3.81 (m, 1H), 2.31 (s, 1H), 2.02 (td, J = 14,3, 4.3 Hz, 1H), 1.61 (td, J = 14.1, 3.8 Hz, 1H), 1.12-1.04 (m, 28H), 0.78 (td, J = 14.0, 3.7 Hz, 1H), 0.61 (td, J = 13.9, 4.4 Hz, 1H), 0.05 (s, 9H). 13C {1H} NMR (100 MHz, CDCl3) δ = 162.1, 151.1, 140.5, 101.4, 87.8, 81.1, 80.4, 73.0, 60.3, 26.6, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0, 16.8, 13.5, 13.1, 12.9,7.7, -1.90. HRMS (ESI)+: [M+H]+ Calcd for C26H51N2O7Si3 587.3004; found 587.3008 1-((6aR,8R,9R,9aR)-9-hydroxy-2,2,4,4-tetraisopropyl-9-((trimethylsilyl)ethynyl)tetrahydro-6H-furo[3,2f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione (12):14 Under inert atmosphere, in a 250 mL Schlenk tube with magnetic stirring was introduced (trimethylsilyl)acetylene (2.5 eq, 150 mmol, 14.73 g) diluted in THF (150 mL). The mixture was cooled to 0°C and n-BuLi (2.5M in heptane, 2.5 eq., 156 mmol, 58.5 mL) was added dropwise to the reaction mixture. The mixture was stirred 1 hr at r.t.. Under inert atmosphere, in a 500 mL RBF equipped with temperature probe and overhead stirrer were introduced 10 (1 eq., 60 mmol, 29.08 g) dissolved in THF (150 mL) and LaCl3.2LiCl (1 eq., 60 mmol, 100 mL). The mixture was cooled to 0°C and the nucleophilic solution was cannulated dropwise to the mixture, the reaction is exothermic at the beginning and spontaneous. At the end of the addition, the mixture was quenched with ammonium chloride (23 w% in water, 88 mL). The desired compound was extracted with EtOAc. The purification was performed by flash chromatography in heptane/EtOAc (7/3), Rf (heptane/EtOAc, 7/3) = 0.25. 12 was obtained as a white solid (70% yield, 24.48g). 1H NMR (360 MHz, CDCl3) δ = 9.10 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 6.06 (s, 1H), 5.71 (d, J = 8.1 Hz, 1H), 4.19-3.95 (m, 4H), 3.49 (s, 1H), 1.11-0.96 (m, 28H), 0.19 (s, 9H). 13C {1H} NMR (90MHz, CDCl3) δ = 163.2, 151.2, 139.8, 101.7, 101.0, 94.4, 88.9, 81.2, 76.4, 73.0, 59.8, 17.5, 17.3, 17.0, 16.8, 16.6, 13.0, 12.9, 12.62, 0.3 1-((6aR,8R,9S,9aR)-9-ethyl-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f] [1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione (13): 1H NMR (400 MHz, CDCl3) δ = 8.44 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 5.82 (s, 1H), 5.7 (dd, J = 8.1 Hz, 1.6 Hz, 1H), 4.21 (d, J = 9.4 Hz 1H), 4.15 (ABX, J = 13.4 Hz, 1.2 Hz, 1H), 3.99 (ABX, J = 13.4 Hz, 2.8 Hz, 1H), 3.80-3.75 (m, 1H), 2.14-2.02 (m, 1H), 1.81-1.68 (m, 1H), 1;17 (t, J = 7.73 Hz), 1.2513-1.01 (m, 28H), 0.93 (t, J = 7.8 Hz, 9H), 0.87-0.60 (m, 2H), 0.54 (q, J = 7.8 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ = 163.5, 151.5, 140.4, 101.5, 87.9, 81.1, 80.3, 73.3, 60.3, 25.7, 17.5, 17.4, 16.8, 13.5, 12.9, 12.4, 6.7. HRMS (ESI)+: [M+H]+ Calcd for C23H43N2O7Si2 515.2609; found 515.2607.

1-((2R,3S,4R,5R)-5-(((fluorodiisopropylsilyl)oxy)methyl)-3-hydroxy-4-((hydroxydiisopropylsilyl)oxy)-3(2-(trimethylsilyl)ethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (14): To a solution of compound 7 (50 mg, 0.085 mmol, 1.0 equiv.) in anhydrous DCM (3.0 mL) under nitrogen at 25°C , a solution of BF3-2AcOH (1.0 M in DCM, 0.26 mL, 3.0 equiv.) was added dropwise and stirred overnight. The reaction mixture was quenched with NaHCO3 aq. 10 wt% then extracted with DCM (5 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The purification was performed by flash chromatography: heptane/EtOAc: 1/1. 14 was obtained as a solid (75 % yield, 38 mg). 1H NMR (400 MHz, CDCl3) δ = 8.68 (s, 1 H), 7.91 (d, J = 8.14 Hz, 1H), 7.28 (s, 1H), 6.03 (s, 1H), 5.67 (dd, J = 8.25, 1.87 Hz,



1H), 4.35 (d, J = 3.08 Hz, 1H), 4.11 (q, J = 2.42 Hz, 1H), 4.02 (dd, J = 11.88, 2.42 Hz, 1H), 3.93 (dd, J = 11.88, 2.20 Hz, 1H), 1.88 (td, J = 14.03, 4.51 Hz, 1H), 1.53 (td, J = 14.03, 3.85 Hz, 1H), 1.20 - 1.37 (m, 2H), 0.83 1.19 (m, 31H), 0.64 (td, J = 13.81, 3.85 Hz, 1H), 0.54 (td, J = 13.86, 4.40 Hz, 1H), 0.0 (s, 9H). . 13C {1H} NMR (100 MHz, CDCl3) δ = 163.6, 150.6, 142.7, 100.7, 87.6, 84.6, 81.6, 77.9, 61.6 (d, J3 = 0.55 Hz, OCH2), 31.8, 29.0, 25.6, 22.7, 17.3, 17.1, 16.6 (d, J3 = 6.5 Hz, 4 CH3), 14.1, 13.4, 13.3, 12.55 (d, J2 = 16.3 Hz, CH), 12.56 (d, J2 = 16.5 Hz, CH), 8.4, -1.9 . 19F {1H} NMR (376 MHz, CDCl3) δ = -148.5. HRMS (ESI)+: [M+H]+ Calcd for C26H52FN2O7Si3 607.3061; found 607.3078 3-benzoyl-1-((6aR,8R,9S,9aR)-9-hydroxy-2,2,4,4-tetraisopropyl-9-(2-(trimethylsilyl)ethyl)tetrahydro6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione (15): In a Schlenk tube, 200 mg of compound 7 (0.341 mmol, 1 equiv.) was dissolved in 10 mL of DCM, 65µL of diisopropylethylamine (0.375 mmol, 1.10 equiv.) and 4 mg of 4-DMAP (0.034 mmol, 0.1 equiv.). After cooling to 0°C, 44µL of benzoyl chloride (0.375 mmol, 1.1 equiv.) was added dropwise. The reaction mixture was stirred overnight, quenched with water, washed once with ammonium chloride. The organic layer was dried over MgSO2 and reduced under reduced pressure. The crude mixture was used directly used for the cyclopropanation step because of the instability of compound 15 during purification by flash chromatography. The conversion was monitor by LCMS leading to a 80:20 ratio in favour of the of compound 15. The crude mixture was submitted to the cyclopropanation conditions as described for compound 6 and monitor by LCMS. Compound 15 can be partially purified on flash chromatography heptane/EtOAc: 8/2. 1H NMR (400 MHz, CDCl3) δ = 8.03 (d, J=8.54 Hz, 1 H), 7.96 (dd, J = 8.3 Hz, 1.4 HZ, 2H), 7.61 - 7.68 (m, 1 H), 7.48 - 7.53 (m, 2 H), 5.83 (d, J = 8.5 Hz, 1H), 5.81 (s, 1 H), 4.30 (d, J = 9.4 Hz, 1 H), 4.19 (dd, J = 13.6, 1.4 Hz, 1 H), 4.03 (dd, J = 2.8, 13.4 Hz, 1 H), 3.82 - 3.88 (m, 1 H), 1.94 - 2.07 (m, 1 H), 1.55 - 1.67 (m, 1 H), 1.28 (bs, 0.6 H), 1.02 1.18 (m, 28 H), 0.66 - 0.76 (m, 1 H), 0.52 - 0.62 (m, 1 H), 0.00 (s, 9 H). 13C {1H} NMR (100 MHz, CDCl3) δ = 168.5, 162.2, 150.2, 140.2, 135.0, 133.4, 131.4, 130.5, 130.0, 129.1, 128.3,101.2, 88.0, 81.3, 80.4, 72.9, 60.4, 26.6, 17.5, 17.4, 17.3, 17.2, 17.0, 16.9, 16.8, 16.7, 13.4, 13.2, 12.9,12.5, 7.2, -2.0. HRMS (ESI)+: [M+H]+ Calcd for C33H55N2O8Si3 691.3266; found 691.3268.

Supporting Information 1H, 13C

and 19F spectra are available for new and for some known compounds. This material is available free of charge via the internet at http://pubs.acs.org

Author Information

*Email: [email protected] ORCID Sébastien Lemaire: 0000-0002-9343-0493 Notes The authors declare no competing financial interest.


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1

Jonckers, T.H.M.; Lin, T.-I.; Buyck, C.; Lachau-Durand, S.; Vandyck, Van Hoof, S.; Vandekerckhove, L. A. M.; Hu, L.; Berke, J. M.; Vijgen, L.; Dillen, L. L. A..; Cummings, M. D.; de Kock, H.; Nilsson, M.; Sund, C.; Rydegard, C.; Samuelsson, B.; Rosenquist, A.; Fanning, G.; Van Emelen, K.; Simmen, K.; Raboisson, P. 2’-Deoxy-2’-Spirocyclopropylcytidine Revisited: A New and Selective Inhibitor of the Hepatitis C Virus NS5B Polymerase J. Med. Chem. 2010, 53, 81508160. 2 Samano, V.; Robins, M.J. Synthesis and Radical-induced Ring-opening Reactions of 2'-Deoxyadenosine-2'Spirocyclopropane and its Uridine Analogs. Mechanistic Probes for Ribonucleotide Reductases J. Am. Chem. Soc. 1992, 114, 4007-4008.

Lemaire, S; Houpis, I. N.; Wechselberger, R.; Langens, J.; Vermeulen, W. A. A.; Smets, N.; Nettekoven, U.; Wang, Y.; Xiao, T.; Qu; H.; Farina, V. Practical Synthesis of (2’R)-2’-Deoxy-2’-C-Methyluridine by Highly Diastereoselective Homogeneous Hydrogenation J. Org. Chem. 2011, 76, 297-300. 4 Proctor, L.D.; Warr, A.J. Development of a Continuous Process for the Industrial Generation of Diazomethane 3

Org. Process Res. Dev. 2002, 6, 884-892; we thank K. Kottsieper (Novasep) for scaling up the synthesis of 4, and J. Rogiers (Tessenderlo Chemie) for scale-up of the photolytic production of 5. 5 Simmons, H.E.; Smith, R. D. A New Synthesis of Cyclopropane from Olefins J. Am. Chem. Soc. 1958, 80, 5323-

5324.

Furukawa, J.; Kawabata, N.; Nishimura, J. A Novel Route to Cyclopropanes from Olefins Tetrahedron Lett., 1966, 7, 3353-3354. 7 Barton, D. H. R.; Crich, D.; Motherwell, W.B. New and Improved Methods for the Radical Decarboxylation of Acids J. Chem. Soc. 1983, 17, 939-941. 8 Fleming, I.; Urch, C. J. Stereospecific Cyclopropane Synthesis From -Stannyl Alcohols J. Organomet. Chem. 1985, 285, 173-191. 9 Murayama, E.; Kikuchi, T.; Sasaki, K.; Sootome, N.; Sato, T. The Reaction of Trimethylstannylmethyllithium with Electrophiles Chem. Lett. 1984, 13, 1897-1900. 10 Sowa, T.; Tsunoda, K. The Convenient Synthesis of Anhydronucleosides via the 2′,3′-O-Sulfinate of Pyrimidine Nucleosides as the Active Intermediates Bull. Chem. Soc. Jpn. 1975, 48, 505507. 11 For preparation of the ((trimethyl)silyl)ethyl) bromide: M. A. Cook, C. Eaborn, D. R. M. Walton The Mechanism of Solvolysis of (2-Bromoethyl)trimethylsilane: Evidence for the Migration of the Trimethylsilyl group J. Organomet. Chem. 1970, 24, 301-306. 12 Krasovskiy, A.; Kopp, F.; Knochel, P. Soluble Lanthanide salts (LnCl3.2LiCl) for the Improved Addition of Organomagnesium Reagents to Carbonyl Compounds Angew. Chem. Int. Ed. 2006, 45, 497-500. 13 Ratio 7:11 defined by LCMS. The reduction may occur from the  face as compared with the NaBD reduction: 4 Wu, J. C.; Bazin, H.; Chattopadhyaya, J. Regiospecific synthesis of 2'-deoxy-2',2"-dideuterio nucleosides Tetrahedron 1987, 43, 2355-2368. 6

14 Bennett, F; Buevich, A. V.; Huang, H.-C.; Girijavallabhan, V.; Kerekes, A. D.; Huang, Y.; Malikzay, A; Smith, E.; Ferrari,

E.; Senior, M.; Osterman, R.; Wang, L.; Wang, J.; Pu, H.; Truong, Q. T.; Tawa, P.; Bogen, S. L.; Davies, I. W.; Weber, A. E. Concise Syntheses and HCV NS5B Polymerase Inhibition of (2′R)-3 and (2′S)-2′-Ethynyluridine-10 and Related Nucleosides Bioorg. Med. Chem. Let. 2017, 27, 5349–5352. 15 Lino T.; Yoshimura, Y.; Matsuda, A. Synthesis of 2’-C-Alkynyl-2’-Deoxy-l-P-D-Arabinofuranosylpyrimidines via Radical Deoxygenation of Tert-Propargyl Alcohols in the Sugar Moiety Tetrahedron 1994, 50, 10397-10406. 16 Blatt, L. M.; Beigelman, L.; Dyatkina, N.; Symons, J. A.; Smith, D. B. Substituted Nucleosides, Nucleotides and analogs thereof, US2015/0366887.


Preparation to 2'-Deoxy-2'-Spirocyclopropylcytidine via an Alternative

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