Syntheses of C-6 Aryl- and Alkynyl-Substituted Thymidines from Thymidine trans-5,6-Bromohydrins

A Journal of

Accepted Article

Title: Syntheses of C6 Aryl and Alkynyl Thymidines from Thymidine

trans-5,6-Bromohydrins

Authors: Pauli Wrigstedt, Vladimir Iashin, Kalle Lagerblom, Juha

Keskiväli, Timo Juhani Repo, and Konstantin Chernichenko

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601219

Link to VoR: http://dx.doi.org/10.1002/ejoc.201601219

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Syntheses of C6 Aryl and Alkynyl Thymidines from Thymidine

trans-5,6-Bromohydrins

Pauli Wrigstedt, Vladimir Iashin, Kalle Lagerblom, Juha Keskiväli, Konstantin Chernichenko and Timo

Repo*

Abstract: C6-substituted thymidines are biochemically important

compounds, whereas thymidine (6-4) photoproduct (5-hydroxy-6-

(thymidine-4-yl) dihydrothymidine) is one of the major DNA damage

caused by the UV component of sunlight. This report describes a

metal-free cis-diastereoselective ring opening of thymidine 5,6-

epoxides using mildly nucleophilic organofluoroborates in the

presence of BF₃∙Et₂O, providing a facile access to (6-4) photoproduct

analogues. A broad range of aryl and alkynylfluoroborates are

compatible with the reaction that also tolerates various protecting

groups. Furthermore, the epoxide addition products undergo thionyl

chloride-pyridine promoted dehydration to the respective

pharmaceutically attractive C6-substituted thymidines in high yields,

thus providing a new and straightforward method for their synthesis.

through trichloropyrimidines,^[10]or lithiation and subsequent

treatment with electrophiles such as aromatic aldehydes.^[11]

Additionally, the latter method allows for the preparation of 6-

iodothymine, which undergoes palladium-catalyzed Sonogashira

cross-coupling.^[12]By contrast, modified thymidine nucleosides

(thymine+deoxyribose) are typically prepared in several steps

involving the separate modification of the thymine base and the

deoxyribose moiety, which are assembled together using various

glycosylation methods.^[13]The direct incorporation of carbon

moiety into the thymidine at the C6 position will be advantageous

in reducing the synthetic steps and avoiding the formation of

undesired N3-deoxyribose^[14]and α-anomer^[13]resulting from the

glycosylation step.

Introduction

Thymine nucleobase and nucleoside analogues are extensively

explored for antimicrobial activity,^[1]treatment of cancer,^[2]as

antiviral agents,^[3]and in studies of DNA repair^[4]and strand

breaking.^[5]Many of the synthetic bioactive pyrimidines possess

a C6 alkyl or aryl core. Illustrative examples are the HIV-active

non-nucleoside transcriptase inhibitors (NNRTIs) emivirine^[6]and

SJ-3366^[7](Figure 1). Although these compounds and their

analogues are structurally rather simple, their syntheses typically

require an extensive chemical work.^[8]

Scheme 1. Strategy towards C6 aryl and alkynyl thymidines.

Figure 1. Examples of bioactive thymine analogues and thymidine (6-4)

photoproduct.

Thymidine (6-4) photoproduct is one of the major DNA damage

triggered by UV irradiation of genomic DNA. This lesion distorts

the DNA helical structure and interferes with DNA replication and

transcription which may lead to mutation and cell death (Figure

1).^[15]We recently developed a synthetic methodology to access

(6-4) photoproduct analogues from readily available thymidine

trans-5,6-bromohydrins through epoxidation and subsequent

ring-opening using various organometallic nucleophiles.^[16]

However, with an easily removable N3-Benzoyl (Bz) protecting

group, the reaction scope was limited to BPh₃and AlPh₃, and did

not tolerate other nucleophiles, such as organozinc,

organomagnesium or AlMe₃reagents (Scheme 1). This was

ascribed to the electron-withdrawing Bz group which decreased

the reactivity of the epoxide and rendered the dihydropyrimidine

N3-C4 bond susceptible to cleaving by strong nucleophiles.

Therefore, organozinc reagents were not reactive, while the use

Existing synthetic approaches to C6-functionalized thymines

involve cycloaddition of ketoesters with thiourea,^[9]reactions

P. Wrigstedt, V. Iashin, K. Lagerblom, J. Keskiväli, K. Chernichenko

and T. Repo

Department of Chemistry

University of Helsinki

P.O. Box 55 (A. I. Virtasen aukio 1), FI-00014 University of Helsinki,

Finland.

E-mail: timo.repo@helsinki.fi

Supporting information for this article is given via a link at the end of

the document.

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of organomagnesium nucleophiles resulted in decomposition

products. Owing to the biological significance of thymidine (6-4)

photoproducts, a straightforward access to their analogues is of

importance since they can be useful in drug development, such

as anticancer and antiviral agents,^{[3c, 17]}in mechanistic studies of

DNA repair^{[4, 17e, 18]}and strand breaking, ^[5]and in the construction

of thymidine fluoro- and chromophores.^[19]

Herein, we report a cis-diastereoselective coupling of various

thymidine epoxides with mildly nucleophilic aryl- and

alkynylfluoroborate salts. Furthermore, we show that the products

can be converted to C6-substituted thymidines through thionyl

chloride-pyridine induced dehydration (Scheme 1).

To test our hypothesis, we prepared trans-bromohydrin 1 (mixture

of 1a and 1b, dr = 5:1, Scheme 2) by treating N-Bz-O,O-TBS

thymidine with N-bromosuccinimide (NBS) in H₂O-THF.^[16]The

formation of the epoxides by exposing 1 to triethylamine (1.2

equiv) in acetone and the subsequent addition of potassium

phenyltrifluoroborate (1.3 equiv) in acetone, in the presence of

BF₃∙OEt₂(1.0 equiv), afforded the products 2a and 2b cis-

diastereoselectively (2a was isolated in 60% yield, no trans-

products observed). The cis diastereochemical arrangement of 2a

(5S, 6R) and 2b (5R,6S, determined from the crude products) was

confirmed by comparing the ¹H and ¹³C NMR spectra to those of

authentic compounds.^[16]Screening of solvents (DCM, THF,

acetone, MeCN, Scheme 2) identified MeCN as optimal, giving 2a

in 83% isolated yield. Lower yields of 20% and 35% of 2a were

obtained using phenylboronic acid as

trifluoroacetic anhydride (TFAA) as promoter in place of BF₃∙OEt₂,

a nucleophile or

Results and Discussion

respectively. Interestingly, in the diastereoselective ring opening

of

benzylic

epoxides

with

potassium

alkenyl

and

Potassium organotrifluoroborates are

a

new class of

phenyltrifluoroborates, TFFA performed notably better than

BF₃∙OEt₂.^[23]

commercially available air-stable, low toxic and mildly nucleophilic

boronic acid derivatives that are important reagents for a vast

array of chemical transformations,^[20]such as Suzuki-Miyaura

cross-coupling,^[21]allylation and crotylation of aldehydes and

ketones,^[22]and ring-opening of benzylic epoxides.^[23]In our

previous work, we demonstrated that N-Bz-O,O-TBS thymidine

epoxide undergoes cis diastereoselective C6-phenylation in the

presence of BPh₃(Scheme 1, TBS = tert-butyldimethylsilyl).^[16]On

this basis, we hypothesized that potassium organotrifluoroborates

would behave equivalently when activated with BF₃∙OEt₂.

Once the satisfactory conditions were determined (1.3 equiv of

RBF₃K and 1.0 equiv of BF₃∙OEt₂, MeCN, 30 min), we explored

the reaction scope with various commercially available aryl and

alkynyltrifluoroborate salts. For analytics and determination of the

yields, only major diastereomers were isolated (cis-products from

1a, yields calculated accordingly) due to the low amount of minor

cis-diastereomers (products from 1b) present in the crude

mixtures, except with 2c, which gave inseparable mixture of cis-

diastereomers. The reaction performed well with electron-rich

aryltrifluoroborates (Ph, o- or m-OMe and p-Me,) even with

sterically demanding 2,5-di-Me substituents, affording the

products 2a-2f in good yields. Slight decrease in the product

yields occurred using aryltrifluoroborates bearing electron-

withdrawing fluorine substituents, particularly at ortho or meta

position (2g-2i). Unfortunately, no reaction occurred using

aryltrifluoroborates

with

strongly

electron-withdrawing

substituents, such as 3,5-CF₃or 2-NO₂, or alkyltrifluoroborates (n-

BuBF₃K). Heteroaryl trifluoroborates 2-thienyl, 3-furanyl and 2-

benzofuranyl reacted nicely with the epoxide and gave the

products 2j, 2k and 2m in good yields. The reaction tolerated

aldehydes as the addition of potassium 5-formyl-2-

furantrifluoroborate generated the desired product 2l in a very

good 82% yield. Additionally, the method was amenable to

potassium propynyl and phenylethynyltrifluoroborates, furnishing

C6-alkynyl alcohols 2n and 2o in high yields. It should be added

that the reaction could also be conducted in one-pot in MeCN by

treating 1 with Et₃N for 15 min prior to the addition of RBF₃K and

BF3∙OEt₂(no isolation of the epoxide and precipitation of

Et₃NHBr). Albeit this resulted in slight decrease in the product

yields (68% with 2f and 72% with 2n), the procedure was

simplified substantially, thereby rendering this approach

applicable.

To expand the substrate scope, we investigated the compatibility

of the reaction with tetramethylammonium trialkynylfluoroborates,

prepared by organometallic-free borylation of alkynes.^[24]These

alkynyltrifluoroborate surrogates were competent nucleophiles in

the allylic substitution of glucals and the synthesis of propargyl

.

Scheme 2. The scope of the reaction.

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ethers. Three different reagents having both electron-releasing

conversion in 30 min with 1.1 equiv of MsCl in the presence of 1.5

equiv of Et₃N, ¹H NMR), the dehydration upon reflux was sluggish

and low yielding, regardless of the base or solvent. Gratifyingly,

the utilization of thionyl chloride (SOCl₂) with an excess of

pyridine^[28]in refluxing CDCl₃afforded 3a in an excellent 92% yield

(tert-Bu,

Ph)

and

electron-withdrawing

(3,5-(CF₃)₂Ph)

substituents attached to the alkynyl moiety were tested in typical

reaction conditions (Scheme 2). Much to our delight, all the

prepared reagents coupled efficiently with the epoxide, generated

from 1, and gave the desired products 2p, 2q and 2o in high yields

using sub-equimolar amount (0.4 equiv) of the reagents. The

electron-rich alkynyls provided the products in higher yields than

the electron deficient ones, in decreasing order of tert-Bu > Ph >

di-CF₃Ph).

The exclusive formation of cis-diastereomers indicates that the

epoxide opens before the nucleophilic attack (Scheme 3),

apparently in a similar manner as the epoxide openings of 2,3-

piperidines with organozinc reagents^[25]and glycals with

organoaluminum compounds.^[26]

after

significantly, but accompanied by inconsistencies in the isolated

products, particularly at temperatures over 90 C. This was

3 h. Utilization of toluene accelerated the reaction

̊

addressed by employing lower-boiling benzene as solvent, which

gave 3a consistently in near quantitative yields in less than 1 h.

The scope of the dehydration was examined with all the prepared

dihydrothymidine alcohols 2a-2q, except with 2l due to the

incompatibility of the aldehyde group with SOCl₂(Scheme 4). All

the alcohols, with the exception 2e and 2h, underwent

dehydration furnishing the corresponding C6-thymidines in high

yields. The reaction performed equally well with a mixture of

diastereomers (2c, dr = 4:1), affording 3c as the sole product in

91% yield. It is worth noting that with 2e and 2h we did not observe

the dehydrated products even after 14 h of refluxing.

Scheme 3. Putative mechanism using RBF₃K with BF₃∙OEt₂.

With the small library of C6-modified dihydrothymidine alcohols in

hand, we undertook efforts to design an efficient C5-dehydration

method to restore the double bond present in thymidine

nucleosides, acknowledging the presence of an acid labile

glycosidic bond (Table 1).

Table 1. Dehydration of 2a to 6-phenylthymidine 3a.^[a]

Reagents^[b]

Base^[b]

Solvent^[c]

Time (h)

Yield (%)

MsCl-Et₃N^[d]

MsCl-Et₃N

SOCl₂

-

CDCl₃

C₆D₆

30

2

27

Pyridine

DBN

40^[e]

44

Scheme 4. The scope of the dehydration.

Pyridine

DBN

8

54

The

selective

N3-debenzoylation

of

C6-substituted

C₆D₆

2

43

dihydrothymidine alcohols can be achieved using primary

alkylamines, such as n-BuNH₂and n-OctNH₂, whereas the use of

smaller nucleophiles, such as aqueous NH₃in MeOH or KOH in

MeOH leads to the dihydrothymidine rearrangement to 2-

oxazolidinones.^[16]As illustrated in Scheme 5, the method was

also applicable to C6-substituted thymidines as the treatment of

3p with n-BuNH₂gave the debenzoylated C6-alkynylthymidine 4

in an excellent 95% yield. Due to the highly ¹⁹F NMR sensitive CF₃

groups, compound 4 could find application in protein chemistry to

monitor various biological processes.^[29]

Pyridine

CDCl₃

C₆D₆

3

92^[e]

95^[e]

SOCl2

1

[a] 10 mg of 2a, reflux, monitored by ¹H NMR [b] 1.1 equiv of MsCl or 1.2

equiv of SOCl2, added at rt. [c] 20 equiv of pyridine, 1.5 equiv of DBN [d] 10

equiv of Et₃N [e] isolated yields.

Initially, we attempted the base catalyzed dehydration of 2a to 6-

phenylthymidine 3a by converting the C5-alcohol to mesylate

using MsCl in the presence of various bases (DBN, pyridine and

Et₃N).^[27]Albeit the mesylation of 2a occurred smoothly (full

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N3-Bz group. Additionally, dehydration of the products using

thionyl chloride and pyridine gave the corresponding

pharmaceutically relevant C6-substituted thymidines in good

overall yields, consequently introducing a new and simple

procedure for their synthesis. Both C6-functionalized

dihydrothymidine alcohols and their dehydrated counterparts find

potential applications in drug development as anticancer and

antiviral agents, in the construction of thymidine fluoro- and

chromophores and in mechanistic studies of DNA repair and

strand breaking.

Scheme 5. N-debenzoylation of 3p with n-BuNH₂.

To evaluate the method using other removable protecting groups

at N3 and sugar moiety, we prepared two bromohydrins: trans N-

Bz-O,O-Ac 5 (dr = 2:1, mixture of diastereomers) and N-PMB-

O,O-Ac 8 (dr = 3:2, major diastereomer, separated by column

chromatography, PMB = p-methoxybenzyl) using NBS in THF-

H₂O (Scheme 6). Both compounds underwent epoxidation when

treated with Et₃N in acetone, albeit 8 required longer reaction time

which was ascribed to the electron donating nature of the N-PMB

Experimental Section

General experimental details:

All manipulations were performed under argon atmosphere unless

otherwise stated using Schlenk technique. All solvents were dried by using

automated solvent purification system, except acetone which was dried

over anhydrous CaSO₄and distilled. All reagents were purchased from

commercial sources and used without further purification unless otherwise

noted. HRMS measurements were carried out using ESI-TOF mass

spectrometer. ¹H NMR and ¹³C NMR spectra were acquired at 27 °C using

300 MHz (300 MHz ¹H-frequency and 75 MHz ¹³C-frequency) or 500 MHz

(500 MHz ¹H-frequency and 125.7 MHz ¹³C-frequency) spectrometer.

Chemical shifts are reported in ppm, and the ppm scale was referenced to

group.

The

subsequent

addition

of

potassium

propynyltrifluoroborate in the presence of BF₃∙OEt₂afforded the

corresponding 6-propynyl dihydrothymidine cis-alcohols 9, 6a and

6b in very good yields. It is noteworthy that the minor

diastereomer 6b, which possess identical configuration (5S,6R)

to that of (6-4) photoproduct (Figure 1), could be isolated in a

reasonable 28% yield. Both N-PMB and O,O-Ac protecting

groups tolerated the dehydration conditions and provided the

corresponding C6-propynyl thymidines 7 and 10 in excellent

yields. The removal of PMB group from 10 by ceric ammonium

nitrate (CAN) in aqueous MeCN^[30]afforded the N-H-6-propynyl

thymidine 11 in 47 % yield.

1

residual solvent peaks (CHCl₃in CDCl₃; 7.26 ppm for H and 77.16 ppm

for ¹³C. Coupling constants are reported in Hz. ¹³C NMR experiments were

performed using APT pulse sequence (¹³C{¹H} proton decoupling). The

following abbreviations were used to describe the multiplicities of

resonances: br s = broad singlet, s = singlet, d = doublet, t = triplet, q =

quartet, m = multiplet. The 2D NMR experiments (HSQC and HMBC) were

used as additional techniques for NMR signal assignments. All NMR

spectra were processed with MestReNova 7.1.2.

General procedure for the coupling of 1a with RBF₃K salts (Scheme

2)

1 (diastereomeric mixture of trans 1a and 1b, dr = 5:1) was prepared using

the method described previously.^[16]Only coupling products from 1a (2a-

2o) were isolated and yields calculated accordingly.

To a solution of 1 (0.12 g, 0.18 mmol, mixture of trans-diastereomers 1a

(100mg, 0.149 mmol) and 1b (20 mg), dr = 5:1) in dry acetone (2.5 mL)

under argon was added triethylamine (31 µL, 0.22 mmol) at room

temperature. The mixture was gently shaken and left standing for 1 h (with

no shaking!) to allow triethylamine hydrobromide precipitation as

transparent needles. The supernatant was then transferred into another

flask under argon using a syringe (Ø 0.6 mm × 25 mm needle). The

remaining precipitate was washed with dry acetone (2×0.7 mL) and the

combined solvents were evaporated in vacuo to afford the mixture of

epoxides as a white solid, which was then dissolved in MeCN (2 mL). To

this solution, desired amount of RBF₃K (0.23 mmol, 1.3 equiv) was added,

followed by the addition of BF₃∙OEt₂(0.18 mmol, 1 equiv) under argon. The

mixture was stirred for 30 min (RBF₃K) and then quenched with sat. aq.

NaHCO₃(3 mL) with vigorous stirring for 5 min. EtOAc (30 mL) and water

(7 mL) were added, the organic layer separated, washed with brine (1×10

mL), dried over NaSO₄, filtered and concentrated in vacuo. The resulting

crude material was purified by column chromatography to afford the title

products 2a-2o.

Scheme 6. Reaction sequence using N-PMB and O,O-Ac protecting groups.

Conclusions

In summary, we have developed a BF₃∙Et₂O-assisted regio- and

diastereoselective

addition

of

various

aryl-

and

alkynylfluoroborates to thymidine 5,6-epoxides that offers a

complementary and broadened substrate scope compared to

current procedures. The presented methodology is compatible

with various protecting groups, particularly with easily removable

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(5S,6R)-3-benzoyl-1-(4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-hydroxy-5-methyl-6-

phenyldihydropyrimidine-2,4(1H,3H)-dione (2a).

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-hydroxy-6-(2-

methoxyphenyl)-5-methyldihydropyrimidine-2,4(1H,3H)-dione (2e).

Potassium

phenyltrifluoroborate

as

a

nucleophile.

Column

Potassium 2-methoxyphenyltrifluoroborate as a nucleophile. Column

chromatography (EtOAc:Hexane 1:5, R_f= 0.2) afforded 2e as a colorless

oil (72 mg, 69%). ¹H NMR (300 MHz, CDCl₃) δ -0.08 (s, 3H), -0.03 (s, 3H),

0.13 (s, 6H), 0.81 (s, 9H), 0.95 (s, 9H), 1.55-1.65 (m, 2H), 1.88 (s, 3H),

3.01 (s, 1H, -OH), 3.55-3.61 (m, 2H), 3.76-3.80 (m, 2H), 3.90 (s, 3H), 4.09-

4.13 (m, 1H), 5.29 (s, 1H), 6.43 (dd, J=7.9, 6.3 Hz, 1H), 6.85 (dd, J=8.2

Hz, 2.2 Hz, 1H), 6.91-6.94 (m, 1H), 6.99-7.04 (m, 1H), 7.30-7.35 (m, 1H),

7.40-7.43 (m, 1H), 7.48-7.53 (m, 2H), 7.62-7.68 (m, 1H), 7.92-7.95 (m, 2H)

ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.1, -4.7, 18.0, 18.6, 25.8, 26.2,

26.4, 36.3, 54.1 (br s, C-6), 56.1, 63.6, 72.0 (C-3’ and C-5), 84.4, 86.2,

111.5, 121.8, 124.9, 127.3, 129.2, 130.2, 130.4, 132.7, 135.0, 137.3, 151.4,

157.5, 169.4, 173.1 ppm;. HRMS (ESI⁺) m/z calcd. for

C₃₆H₅₄N₂NaO₈Si₂[M+Na]⁺721.3311, found 721.3315.

chromatography (EtOAc:Hexane 1:4, R_f= 0.25) afforded 2a as colorless

oil (82 mg, 83%). H NMR (300 MHz, CDCl₃) δ 0.03-0.11 (m, 12H), 0.85

1

(s, 9H), 0.95 (s, 9H), 1.84 (s, 3H), 2.12 – 2.13 (m, 1H), 2.22 – 2.26 (m, 1H),

2.98 (s, 1H), 3.36-3.40 (m, 1H), 3.47-3.50 (m, 1H), 3.76 (br s, 1H), 4.35-

4.36 (m, 1H), 4.80 (s, 1H), 6.17-6.20 (m, 1H), 7.31 – 7.42 (m, 5H), 7.48-

7.51 (m, 2H), 7.63-7.66 (m, 1H), 7.90 – 7.92 (m, 2H) ppm; ¹³C NMR (75

MHz, CDCl₃) δ -5.3, -5.1, -4.7, -4.6, 18.1, 18.6, 25.8, 25.9, 26.2, 38.9, 61.8,

63.6, 71.9, 72.7, 86.9, 87.5, 127.8, 128.5, 128.6, 129.2, 130.4, 132.6,

135.0, 135.7, 150.7, 169.0, 172.9 ppm; HRMS (ESI⁺) m/z calcd. for

C₃₅H₅₂N₂NaO₇Si₂[M+Na]⁺691.3205, found 691.3194.

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(2,6-

dimethylphenyl)-5-hydroxy-5-methyldihydropyrimidine-2,4(1H,3H)-dione

(2c).

(5S,6R)-3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-hydroxy-6-(3-

methoxyphenyl)-5-methyldihydropyrimidine-2,4(1H,3H)-dione (2f).

Potassium 2,6-dimethylphenyltrifluoroborate as a nucleophile. Column

chromatography (EtOAc:Hexane 1:4, R_f= 0.3) afforded 2c as a mixture of

cis-diastereomers as colorless oil (102 mg, 81%).

Potassium 3-methoxyphenyltrifluoroborate as a nucleophile. Column

chromatography (EtOAc:Hexane 1:4, R_f= 0.25) afforded 2f as a colorless

oil (78 mg, 75%). ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s, 3H), 0.05 (s, 3H),

0.09 (s, 3H), 0.10 (s, 3H), 0.85 (s, 9H), 0.94 (s, 9H), 1.83 (s, 3H), 2.11-2.28

(m, 2H), 2.94 (s, 1H, -OH), 3.40-3.54 (m, 2H), 3.76-3.79 (m, 1H), 3.84 (s,

3H), 4.34-4.37 (m, 1H), 4.76 (s, 1H), 6.16 (dd, J=8.2, 5.6 Hz, 1H), 6.85 (dd,

J=8.2 Hz, 2.2 Hz, 1H), 6.97-6.99 (m, 2H), 7.24-7.29 (m, 1H), 7.46-7.52 (m,

2H), 7.62-7.67 (m, 1H), 7.90-7.93 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz,

CDCl₃) δ -5.3, -5.1, -4.7, -4.6, 18.1, 18.6, 25.8, 26.2, 39.0, 55.5, 61.9, 63.6,

71.9, 72.7, 87.0, 87.6, 112.7, 114.6, 120.3, 129.2, 129.5, 130.4, 132.6,

135.0, 137.3, 150.6, 160.0, 169.1, 172.9 ppm;. HRMS (ESI⁺) m/z calcd. for

C₃₆H₅₄N₂NaO₈Si₂[M+Na]⁺721.3311, found 721.3312.

Major diastereomer: ¹H NMR (300 MHz, CDCl₃) δ 0.05-0.07 (m, 12H), 0.88

(s, 9H), 0.92 (s, 9H), 1.59 (s, 3H), 2.00 – 2.24 (m, 2H), 3.14 (s, 1H, -OH),

3.18 – 3.33 (m, 4H), 3.40 (dd, J = 11.0, 3.7 Hz, 1H), 3.73 (ddd, J = 5.3, 3.7,

2.0 Hz, 1H), 4.34 (dt, J = 5.2, 2.3 Hz, 1H), 4.67 (s, 1H), 6.25 (dd, J = 8.3,

5.7 Hz, 1H), 7.02 – 7.16 (m, 2H), 7.18 – 7.35 (m, 3H) ppm; ¹³C{¹H} NMR

(75 MHz, CDCl₃) δ -5.3, -5.2, -4.6, -4.6, 18.1, 18.6, 25.9, 26.2, 26.4, 28.3,

38.6, 61.0, 63.5, 71.3, 72.7, 86.8, 87.2, 127.6, 128.2, 128.3, 136.5, 152.5,

168.7, 173.7 ppm. HRMS (ESI⁺) m/z calcd. for C₃₇H₅₆N₂NaO₇Si₂[M+Na]⁺

719.3518, found 719.3511.

Minor diastereomer: ¹H NMR (300 MHz, CDCl₃) δ-0.08-0.11 (m, 12H),

0.82-0.94 (m, 18H), 1.93-1.95 (m, 4H), 2.35-2.50 (m, 7H), 3.05-3.11 (m,

2H), 3.33-3.41 (m, 1H), 3.65-3.74 (m, 1H), 3.96-3.98 (m, 1H), 5.43 (s, 1H),

6.39-6.44 (m, 1H), 6.99-7.13 (m, 3H), 7.48-7.53 (m, 2H), 7.63-7.68 (m, 1H),

7.93-7.95 (m, 2H) ppm ¹³C {¹H} NMR (75 MHz, CDCl₃) δ δ -5.2, -4.8, -4.6,

18.5, 21.3, 22.4, 25.8, 26.1, 28.2, 36.3, 58.8, 63.3, 70.5, 71.7, 84.8, 85.9,

128.4, 129.0, 129.3, 130.6, 131.7, 132.2, 132.7, 135.0, 136.4, 139.4, 151.3,

168.7, 173.5 ppm HRMS (ESI⁺) m/z calcd. for C₃₇H₅₆N₂NaO₇Si₂[M+Na]⁺

719.3518, found 719.3511.

(5S,6R)-3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(3-fluorophenyl)-5-

hydroxy-5-methyldihydropyrimidine-2,4(1H,3H)-dione (2g).

Potassium 3-fluorophenyltrifluoroborate as

a nucleophile. Column

chromatography (EtOAc:Hexane 1:4, R_f= 0.35) afforded 2g as a foamy oil

(52 mg, 51%). ¹H NMR (300 MHz, CDCl₃) δ 0.04-0.12 (m, 12H), 0.85 (s,

9H), 0.95 (s, 9H), 1.82 (s, 3H), 2.10-2.23 (m, 2H), 3.08 (s, 1H, -OH), 3.40-

3.55 (m, 2H), 3.75-3.78 (m, 1H), 4.34-4.37 (m, 1H), 4.84 (s, 1H), 6.21-6.25

(m, 1H), 7.02-7.05 (m, 1H), 7.11-7.16 (m, 1H), 7.20-7.23 (m, 1H), 7.31-

7.38 (m, 1H), 7.47-7.52 (m, 2H), 7.63-7.68 (m, 1H), 7.88-7.91 (m, 2H) ppm;

¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.3, -5.1, -4.7, -4.6, 18.1, 18.7, 25.8,

26.2, 39.2, 60.6, 63.6, 71.7, 72.7, 86.6, 87.7, 115.4 (d, J (C,F) = 20.9 Hz),

115.6 (d, J (C,F) = 22.6 Hz), 123.0, 129.2, 130.0 (d, J (C,F) = 8.1 Hz),

132.6, 135.1, 138.7 (d, J (C,F) = 6.8 Hz), 150.5, 162.7 (d, J (C,F) = 246

(5S,6R)-3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-hydroxy-5-methyl-6-

(p-tolyl)dihydropyrimidine-2,4(1H,3H)-dione (2d).

Potassium p-tolyltrifluoroborate as a nucleophile. Column chromatography

(EtOAc:Hexane 1:4, R_f= 0.3) afforded 2d as a colorless oil (87 mg, 85%).

¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 3H), 0.05 (s, 3H), 0.09 (s, 3H), 0.10

(s, 3H), 0.85 (s, 9H), 0.94 (s, 9H), 1.82 (s, 3H), 2.10-2.25 (m, 2H), 2.34 (s,

3H), 2.93 (s, 1H, -OH), 3.36-3.52 (m, 2H), 3.74-3.78 (m, 1H), 4.33-4.36 (m,

1H), 4.76 (s, 1H), 6.16 (dd, J=8.1, 5.7 Hz, 1H), 7.16-7.30 (m, 4H), 7.46-

7.51 (m, 2H), 7.62-7.67 (m, 1H) 7.90-7.92 (m, 2H) ppm; ¹³C {¹H} NMR (75

MHz, CDCl₃) δ -5.3, -5.1, -4.7, -4.6, 18.1, 18.7, 21.3, 25.9, 26.2, 39.0, 61.7,

63.6, 71.9, 72.7, 87.0, 87.5, 127.7, 129.2, 129.4, 130.4, 132.7, 135.0,

138.4 150.7, 169.1, 173.0 ppm;. HRMS (ESI⁺) m/z calcd. for

C₃₆H₅₄N₂NaO₇Si₂[M+Na]⁺705.3362, found 705.3340.

Hz),

168.8,

172.8

ppm;

HRMS

(ESI⁺)

m/z calcd. for

C₃₅H₅₁FN₂NaO₇Si₂[M+Na]⁺709.3111, found 709.3093.

(5S,6R)-3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(2,4-difluorophenyl)-

5-hydroxy-5-methyldihydropyrimidine-2,4(1H,3H)-dione (2h).

Potassium 2,4-difluorophenyltrifluoroborate as a nucleophile. Column

chromatography (EtOAc:Hexane 1:6, R_f= 0.25) afforded 2h as a colorless

1

oil (67 mg, 64%). H NMR (300 MHz, CDCl₃) δ 0.04-0.08 (m, 12H), 0.85

(s, 9H), 0.92 (s, 9H), 1.84 (s, 3H), 2.12-2.16 (m, 2H), 3.18 (s, 1H, -OH),

3.38-3.47 (m, 2H), 3.74-3.78 (m, 1H), 4.36 (m, 1H), 5.07 (s, 1H), 6.20-6.24

(m, 1H), 6.76-6.84 (m, 1H), 6.90-6.97 (m, 1H), 7.42-7.54 (m, 3H), 7.65-

10.1002/ejoc.201601219

European Journal of Organic Chemistry

FULL PAPER

7.70 (m, 1H), 7.91-7.93 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -

5.4, -5.2, -4.6, -4.6, 18.1, 18.7, 25.9, 26.1, 26.2, 38.3, 54.6, 63.7, 71.8, 72.9,

86.7, 87.6, 104.0 (t, J (C,F) = 26.1 Hz), 112.1 (dd, J (C,F) = 21.1, 2.5 Hz),

120.6 (d, J (C,F) = 13.5 Hz), 127.9 (m), 129.4, 130.5, 132.4, 135.3, 150.6,

160.3 (dd, J (C,F) = 144.3, 10.8 Hz), 163.6 (dd, J (C,F) = 154.7, 12.5 Hz),

Potassium 5-formyl-2-furantrifluoroborate as a nucleophile. Column

chromatography (EtOAc:Hexane 1:2.5, R_f= 0.3) afforded 2l as a colorless

oil (86 mg, 84%). ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s, 3H), 0.05 (s, 3H),

0.16 (s, 3H), 0.17 (s, 3H), 0.85 (s, 9H), 0.98 (s, 9H), 1.73 (s, 3H), 2.04-2.18

(m, 2H), 3.38 (s, 1H, -OH), 3.69 (d, J=3.2 Hz, 2H), 3.82-3.84 (m, 1H), 4.35-

4.38 (m, 1H), 5.11 (s, 1H), 6.20-6.24 (m, 1H), 6.60 (d, J=3.6 Hz, 1H), 7.22

(d, J=3.6 Hz, 1H), 7.53-7.58 (m, 2H), 7.64-7.69 (m, 1H), 8.08-8.10 (m, 2H),

9.63 (s, 1H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.3, -5.0, -4.7, -4.5,

18.1, 18.7, 25.4, 25.8, 26.2, 39.7, 54.7, 63.6, 70.8, 72.6, 86.1, 87.9, 112.3,

121.9, 129.4, 130.7, 132.4, 135.2, 150.0, 152.7, 157.0, 168.7, 172.7, 177.2

ppm; HRMS (ESI⁺) m/z calcd. for C₃₄H₅₀N₂NaO₉Si₂[M+Na]⁺709.2947,

found 709.2935.

168.9,

172.7

ppm;

HRMS

(ESI⁺)

m/z

calcd.

for

C₃₅H₅₀F₂N₂NaO₇Si₂[M+Na]⁺727.3017, found 727.2991.

(5S,6R)-3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(3-fluorophenyl)-5-

hydroxy-5-methyldihydropyrimidine-2,4(1H,3H)-dione (2i).

Potassium 4-fluorophenyltrifluoroborate as

a nucleophile. Column

(5S,6S)-3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-hydroxy-5-methyl-6-

(thiophen-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (2m).

chromatography (EtOAc:Hexane 1:3.5, R_f= 0.40) afforded 2i as a foamy

oil (82 mg, 80%). ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s, 3H), 0.06 (s, 3H),

0.10 (s, 3H), 0.11 (s, 3H), 0.86 (s, 9H), 0.95 (s, 9H), 1.82 (s, 3H), 2.15-2.20

(m, 2H), 3.06 (s, 1H, -OH), 3.37-3.53 (m, 2H), 3.77 (m, 1H), 4.34-4.36 (m,

1H), 4.81 (s, 1H), 6.22 (dd, J=8.1, 5.8 Hz, 1H), 7.02-7.08 (m, 2H), 7.36-

7.41 (m, 2H), 7.47-7.52 (m, 2H), 7.63-7.68 (m, 1H), 7.87-7.90 (m, 2H) ppm;

¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.3, -5.1, -4.7, -4.6, 18.1, 18.6, 25.8,

26.2, 39.0, 60.7, 63.6, 71.8, 72.6, 86.7, 87.6, 115.4 (d, J (C,F) = 21.5 Hz),

129.2, 129.6 (d, J (C,F) = 7.9 Hz), 130.4, 131.7, 132.5, 135.1, 150.6, 162.8

(d, J (C,F)= 247.3 Hz), 168.9, 172.9 ppm; HRMS (ESI⁺) m/z calcd. for

C₃₅H₅₁FN₂NaO₇Si₂[M+Na]⁺709.3111, found 709.3101.

Potassium thiophene-2-trifluoroborate as

a

nucleophile. Column

chromatography (EtOAc:Hexane 1:4, R_f= 0.3) afforded 2m as a colorless

1

oil (82 mg, 82%). H NMR (300 MHz, CDCl₃) δ 0.05-0.09 (m, 12H), 0.86

(s, 9H), 0.92 (s, 9H), 1.75 (s, 3H), 2.13-2.22 (m, 2H), 3.40 (s, 1H, -OH),

3.61-3.63 (m, 2H), 3.85 (m, 1H), 4.37-4.40 (m, 1H), 5.13 (s, 1H), 6.18-6.23

(m, 1H), 7.02-7.05 (m, 1H), 7.27 (m, 1H), 7.31 (dd, J=5.2, 1.2 Hz, 1H),

7.38-7.43 (m, 2H), 7.57-7.62 (m, 1H), 7.69-7.73 (m, 2H) ppm; ¹³C {¹H}

NMR (75 MHz, CDCl₃) δ -5.4, -5.1, -4.7, -4.5, 18.1, 18.7, 24.9, 25.9, 26.2,

39.8, 57.4, 63.4, 72.2, 72.3, 86.5, 87.5, 126.6, 127.2, 129.1, 130.5, 132.4,

134.9, 138.7, 150.2, 168.6, 173.1 ppm; HRMS (ESI⁺) m/z calcd. for

C₃₃H₅₀N₂NaO₇SSi₂[M+Na]⁺697.2769, found 697.2756.

(5S,6S)-6-(benzofuran-2-yl)-3-benzoyl-1-((2R,4S,5R)-4-((tert-

butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-hydroxy-5-

methyldihydropyrimidine-2,4(1H,3H)-dione (2j).

(5S,6R)-3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-hydroxy-5-methyl-6-

(prop-1-yn-1-yl)dihydropyrimidine-2,4(1H,3H)-dione (2n).

Potassium benzofuran-2-trifluoroborate as

a nucleophile. Column

chromatography (EtOAc:Hexane 1:4, R_f= 0.25) afforded 2j as a colorless

oil (79 mg, 75%). ¹H NMR (300 MHz, CDCl₃) δ 0.05 (s, 3H), 0.06 (s, 3H),

0.16 (s, 3H), 0.17 (s, 3H), 0.85 (s, 9H), 0.98 (s, 9H), 1.77 (s, 3H), 2.15-2.19

(m, 2H), 3.35 (s, 1H, -OH), 3.72 (t, J=3.7 Hz, 2H), 3.82-3.85 (m, 1H), 4.37-

4.40 (m, 1H), 5.14 (s, 1H), 6.16 (t, J=6.7 Hz, 1H), 6.81 (s, 1H), 7.22-7.33

(m, 2H), 7.43-7.50 (m, 3H), 7.56-7.58 (m, 1H), 7.62-7.67 (m, 1H), 8.11-

8.13 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.2, -5.0, -4.7, -4.5,

18.1, 18.7, 25.3, 25.8, 26.3, 39.8, 55.5, 63.5, 70.8, 72.4, 86.4, 87.7, 107.2,

111.3, 121.6, 123.4, 124.9, 128.1, 129.1, 130.6, 132.7, 135.0, 150.3, 152.9,

154.7, 168.7, 173.1 ppm;; HRMS (ESI⁺) m/z calcd. for

C₃₇H₅₂N₂NaO₈Si₂[M+Na]⁺731.3154, found 731.3151.

Potassium propynyltrifluoroborate as

a

nucleophile.

Column

chromatography (EtOAc:Hexane 1:4, R_f= 0.25) afforded 2n as a colorless

oil (83 mg, 88%). ¹H NMR (300 MHz, CDCl₃) δ 0.06 (m, 6H), 0.013 (m, 6H),

0.86 (s, 9H), 0.95 (s, 9H), 1.56 (s, 3H), 1.94 (d, J=2.1 Hz, 3H), 2.00-2.13

(m, 2H), 3.37 (s, 1H, -OH), 3.76-3.78 (m, 2H), 3.91-3.93 (m, 1H), 4.36-4.39

(m, 1H), 4.48-4.50 (m, 1H), 6.19 (dd, J=7.9, 5.9 Hz, 1H), 7.43-7.49 (m, 2H),

7.60-7.64 (m, 1H), 8.06 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -

5.33, -5.25, -4.7, -4.6, 3.9, 18.1, 18.7, 22.5, 25.8, 26.2, 39.6, 50.2, 63.7,

72.2, 72.5, 74.9, 82.6, 85.3, 87.6, 129.2, 130.7, 132.4, 134.9, 150.3, 168.3,

172.8 ppm; HRMS (ESI⁺) m/z calcd. for C₃₂H₅₀N₂NaO₇Si₂[M+Na]⁺

653.3049, found 653.3059.

(5S,6R)-3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(furan-3-yl)-5-

hydroxy-5-methyldihydropyrimidine-2,4(1H,3H)-dione (2k).

(5S,6R)-3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-hydroxy-5-methyl-6-

(phenylethynyl)dihydropyrimidine-2,4(1H,3H)-dione (2o).

Potassium

furan-3-trifluoroborate

as

a

nucleophile.

Column

chromatography (EtOAc:Hexane 1:4, R_f= 0.3) afforded 2k as a colorless

1

oil (82 mg, 84%). H NMR (300 MHz, CDCl₃) δ 0.06-0.07 (m, 12H), 0.87

Potassium (phenylethynyl)trifluoroborate as a nucleophile. Column

(s, 9H), 0.91 (s, 9H), 1.71 (s, 3H), 2.08-2.20 (m, 2H), 3.37 (s, 1H, -OH),

3.60-3.67 (m, 2H), 3.86 (m, 1H), 4.38 (m, 1H), 4.87 (s, 1H), 6.23 (dd, J=8.1,

5.6 Hz, 1H), 6.65 (s, 1H), 7.40-7.43 (m, 3H), 7.58-7.61 (m, 2H), 7.69-7.70

(m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.4, -5.3, -4.7, -4.5, 18.1,

18.6, 24.8, 25.9, 26.2, 39.6, 53.8, 63.5, 72.2, 72.4, 85.8, 87.4, 111.0, 129.1,

130.4, 132.4, 134.9, 141.7, 142.9, 150.5, 168.6, 173.4 ppm;; HRMS (ESI⁺)

m/z calcd. for C₃₃H₅₀N₂NaO₈Si₂[M+Na]⁺681.2998, found 681.2994.

chromatography (EtOAc:Hexane 1:5, R_f= 0.25) afforded 2o as a colorless

oil (86 mg, 83%). ¹H NMR (300 MHz, CDCl₃) δ 0.07-0.08 (m, 6H), 0.16 (m,

6H), 0.88 (s, 9H), 0.97 (s, 9H), 1.64 (s, 3H), 2.03-2.12 (m, 2H), 3.59 (s, 1H,

-OH), 3.77-3.88 (m, 2H), 3.95-3.97 (m, 1H), 4.40-4.43 (m, 1H), 4.90 (s, 1H),

6.31 (dd, J=7.6, 6.2 Hz, 1H), 7.26-7.37 (m, 2H), 7.60-7.63 (m, 1H), 7.86

(m, 3H), 8.00-8.04 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.3, -

4.7, -4.5, 18.1, 18.7, 23.2, 25.8, 26.2, 39.7, 50.0, 63.8, 72.0, 72.6, 82.5,

85.3, 87.8, 88.9, 117.5, 121.1, 122.6, 124.3, 124.7, 128.3, 129.2, 130.5,

131.7, 132.0, 132.2, 132.5, 133.0, 135.2, 150.2, 167.9, 172.6 ppm; HRMS

(ESI⁺) m/z calcd. for C₃₇H₅₂N₂NaO₇Si₂[M+Na]⁺715.3205, found 715.3202.

5-((4S,5S)-1-benzoyl-3-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-

(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-hydroxy-5-

methyl-2,6-dioxohexahydropyrimidin-4-yl)furan-2-carbaldehyde (2l).

10.1002/ejoc.201601219

European Journal of Organic Chemistry

FULL PAPER

Synthesis of Tetramethylammonium trialkynylfluoroborates

[R₃BF][NMe₄] (0.07 mmol, 0.4 equiv) was added, followed by the addition

of BF₃∙OEt₂(0.18 mmol, 22 µL, 1 equiv) under inert atmosphere. The

mixture was stirred for 1 h and then quenched with sat. aq. NaHCO₃(3

mL) with vigorous stirring for 5 min. EtOAc (30 mL) and water (10 mL) were

added, the organic layer separated and washed once with brine (10 mL),

dried over NaSO₄, filtered and concentrated in vacuo. The resulting crude

material was purified by column chromatography to afford the products 2o-

2q.

Tetramethylammonium trialkynylfluoroborates were prepared according to

the procedure described previously.^[24]

Syntheses of Tetramethylammonium fluorotris(phenylethynyl)borate and

Tetramethylammonium tris(3,3-dimethylbut-1-yn-1-yl)fluoroborate

1 equiv of ethynylbenzene or 3,3-dimethylbut-1-yne was mixed with an

equimolar amount of 1,2,2,6,6-pentamethylpiperidine in dry C₆H₆. Then

1.33 eq. of BF₃SMe₂in C₆H₆was added to the solution and the mixture

The

coupling

of

1

with

Tetramethylammonium

fluorotris(phenylethynyl)borate produced 2o in 84% yield. ¹H and ¹³C NMR

spectra of the product were identical to those of obtained above using

potassium phenylethynyltrifluoroborate.

.

was stirred at room temperature under argon atmosphere for 17 h

(ethynylbenzene) and 24 h (3,3-dimethylbut-1-yne). Then the precipitate

of pentamethylpiperidinium tetrafluoroborate was removed by filtration,

and the corresponding amount of tetramethylammonium fluoride in CH₂Cl₂

was added. The mixture was stirred for 4 h (ethynylbenzene) and 16 h

(3,3-dimethylbut-1-yne). The volatiles were then evaporated giving a solid

residue that was dried in vacuum, then washed with benzene giving, after

drying, both compounds as a crystalline solids.

(5S,6R)-3-benzoyl-6-((3,5-bis(trifluoromethyl)phenyl)ethynyl)-1-

((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-hydroxy-5-

methyldihydropyrimidine-2,4(1H,3H)-dione (2p).

Tetramethylammonium

tris((3,5

bis(trifluoromethyl)phenyl)ethynyl)

Tetramethylammonium fluorotris(phenylethynyl)borate. Yield 82%. ¹H

NMR (500 MHz, CD₂Cl₂) δ=7.38 (d, ³J(H,H)=7.2 Hz, 6H), 7.26 (t,

³J(H,H)=7.2 Hz, 6H), 7.21 (t, ³J(H,H)=7.2 Hz, 3H), 3.16 (s, 12H); ¹³C NMR

(75 MHz, CD₂Cl₂) δ 131.6, 128.6, 127.1, 126.2, 107.1 (br), 94.0, 56.4 (t,

¹J(C,N)=3.9 Hz).

fluoroborate as a nucleophile. Column chromatography (EtOAc:Hexane

1:6, R_f= 0.36) afforded 2p as a white solid (95 mg, 77%). H NMR (300

1

MHz, CDCl₃) δ 0.07-0.08 (m, 6H), 0.16 (m, 6H), 0.88 (s, 9H), 0.97 (s, 9H),

1.64 (s, 3H), 2.03-2.12 (m, 2H), 3.59 (s, 1H, -OH), 3.77-3.88 (m, 2H), 3.95-

3.97 (m, 1H), 4.40-4.43 (m, 1H), 4.90 (s, 1H), 6.31 (dd, J=7.6, 6.2 Hz, 1H),

7.26-7.37 (m, 2H), 7.60-7.63 (m, 1H), 7.86 (m, 3H), 8.00-8.04 (m, 2H) ppm;

¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.3, -4.7, -4.5, 18.1, 18.7, 23.2, 25.8,

26.2, 39.7, 50.0, 63.8, 72.0, 72.6, 82.5, 85.3, 87.8, 88.9, 122.6 (br s), 122.9

(q, J (C,F) = 273.1 Hz), 124.3, 128.3, 129.2, 130.5, 131.7, 132.0, 132.2,

132.6, 133.0, 135.2, 150.2, 167.9, 172.6 ppm; HRMS (ESI⁺) m/z calcd. for

Tetramethylammonium tris(3,3-dimethylbut-1-yn-1-yl)fluoroborate. Yield

79%. ¹H NMR (500 MHz, CD₂Cl₂) δ 3.35 (s, 12H), 1.17 (s, 27H); ¹³C NMR

(75 MHz, CD₂Cl₂) δ 101.5 (m), 95.0 (br), 56.9 (t, ¹J(C,N)=3.9 Hz), 32.0,

28.0.

C₃₉H₅₀F₆N₂NaO₇Si₂[M+Na]⁺851.2953, found 851.2951. Mp 53-58

̊C.

Synthesis

of

tetramethylammonium

tris((3,5-

(5S,6R)-3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(3,3-dimethylbut-1-

yn-1-yl)-5-hydroxy-5-methyldihydropyrimidine-2,4(1H,3H)-dione (2q).

bis(trifluoromethyl)phenyl)ethynyl)fluoroborate

168 mg (0.70 mmol, 1 eq.) of 1-ethynyl-3,5-bis(trifluoromethyl)benzene

and 109 mg (0.70 mmol, 1 equiv) of 1,2,2,6,6-pentamethylpiperidine in 4

ml of benzene were mixed with 122 mg (0.94 mmol, 1.33 eq.) of BF₃SMe₂

Tetramethylammonium tris(3,3-dimethylbut-1-yn-1-yl)fluoroborate as

nucleophile. Column chromatography (EtOAc:Hexane 1:6, R_f= 0.20)

afforded 2q as a colorless oil (90 mg, 90%). ¹H NMR (300 MHz, CDCl₃) δ

0.05-0.06 (m, 6H), 0.13 (m, 6H), 0.86 (s, 9H), 0.95 (s, 9H), 1.26 (s, 9H),

1.56 (s, 3H), 2.03-2.06 (m, 2H), 3.26 (s, 1H, -OH), 3.75 (d, J=3.4 Hz, 2H),

3.90-3.93 (m, 1H), 4.35-4.39 (m, 1H), 4.53 (s, 1H), 6.19 (t, J=6.9 Hz, 1H),

7.44-7.49 (m, 2H), 7.60-7.65 (m, 1H), 8.01-8.05 (m, 2H) ppm; ¹³C {¹H}

NMR (75 MHz, CDCl₃) -5.2, -4.7, -4.6, 18.1, 18.7, 22.3, 25.8, 26.2, 27.7,

31.0, 39.3, 50.2, 63.9, 72.0, 72.7, 73.9, 85.4, 87.6, 95.5, 129.1, 130.6,

132.5, 134.8, 150.4, 168.4, 172.8 ppm; HRMS (ESI⁺) m/z calcd. for

C₃₅H₅₆N₂NaO₇Si₂[M+Na]⁺695.3518, found 695.3512.

a

.

in 2 ml of benzene, and the mixture was stirred for 13 h at room

temperature. The produced precipitate was removed by filtration and

washed with 4 ml of benzene. The solution of 46.8 mg (0.50 mmol, 0.72

equiv) of tetramethylammonium fluoride in 4 ml of CH₂Cl₂was added to

the filtrate. The resulting mixture was stirred for additional 14 hours.

Volatiles were evaporated and the residue was washed with benzene. The

filtrate was evaporated, dissolved in 5 ml of CH₂Cl₂, and evaporated to

give the product in 56% yield (107 mg). ¹H NMR (500 MHz, CD₂Cl₂) δ=7.91

(s, 6H), 7.73 (s, 3H), 3.29 (s, 12H). ¹³C NMR (75 MHz, CD₂Cl₂) δ=131.9,

131.9 (q, ²J(C,F)=33.3 Hz), 128.4 (m), 123.7 (q, ¹J(C,F)=272.7 Hz), 120.5

(hept, ³J(C,F)=4.6 Hz), 109.8 (br), 91.5, 56.7 (t, ¹J(C,N)=4.0 Hz).

General procedure for the dehydration of 2a-2q to 3a-3q (Scheme 4)

General procedure for the coupling of 1a with [R₃BF][NMe₄] salts

(Scheme 2)

Thionyl chloride (0.12 mmol, 8.7 µL) was added to a solution of the desired

dihydrothymidine alcohol (0.1 mmol) in benzene (1.5 mL) and stirred for 1

min. Pyridine (2.4 mmol, 193 µL) was added and the solution was refluxed

for 1-3 h depending on substrates. Then, EtOAc (20 mL) and water (7 mL)

were added, the organic layer separated, washed with brine (10 mL) and

dried over NaSO₄. The solvent was evaporated in vacuo to give the crude

product, which was purified by flash column chromatography.

To a solution of 1 (0.12 g, 0.18 mmol, mixture of trans-diastereomers 1a

(100mg, 0.149 mmol) and 1b (20 mg), dr = 5:1) in dry acetone (2.5 mL)

under argon was added triethylamine (31 µL, 0.22 mmol) at room

temperature. The mixture was gently shaken and left standing for 60

minutes (with no shaking!) to allow triethylamine hydrobromide

precipitation as transparent needles. The supernatant was then

transferred into another flask under argon using a syringe (Ø 0.6 mm × 25

mm needle). The remaining precipitate was washed with dry acetone

(2×0.7 mL) and the combined solvent was evaporated in vacuo to afford

the mixture of epoxides as a white solid, which was then dissolved in

MeCN (2mL). To this solution, desired amount of previously prepared

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-methyl-6-

phenylpyrimidine-2,4(1H,3H)-dione (3a).

10.1002/ejoc.201601219

European Journal of Organic Chemistry

FULL PAPER

Reflux for 1h. Column chromatography (EtOAc:Hexane 1:7, R_f= 0.30)

gave 3a as a colorless oil (62 mg, 95%). H NMR (300 MHz, CDCl₃) δ -

MHz, CDCl₃) -5.1, -5.0, -4.7, -4.6, 12.3, 17.3, 18.6, 25.7, 26.1, 38.1, 38.2,

55.5, 55.6, 64.2, 64.3, 72.5, 72.6, 88.1, 88.2, 88.5, 88.6, 109.6, 113.6,

113.8, 115.1, 116.1, 120.1, 120.7, 129.2, 130.6, 130.8, 131.0, 131.9, 133.7,

135.1, 148.8, 151.4, 160.2, 160.4, 162.9, 169.5 ppm; HRMS (ESI⁺) m/z

calcd. for C₃₆H₅₂N₂NaO₇Si₂[M+Na]⁺703.3205, found 703.3210.

1

0.05 (m, 6H), -0.01-0.01 (m, 6H), 0.75 (s, 9H), 0.84 (s, 9H), 1.65 (s, 3H),

1.73-1.82 (m, 1H), 2.86-2.94 (m, 1H), 3.58-3.65 (m, 3H), 4.25-4.31 (m, 1H),

5.40-5.44 (m, 1H), 7.17-7.20 (m, 1H), 7.42-7.45 (m, 1H), 7.49-7.55 (m, 5h),

7.64-7.69 (m, 1H), 7.99-8.03 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃)

-5.1, -5.0, -4.7, -4.6, 12.4, 17.8, 18.6, 25.8, 26.1, 38.1, 64.2, 72.5, 88.1,

88.5, 109.7, 127.9, 128.6, 129.2, 129.4, 129.7, 130.0, 130.8, 131.9, 132.6,

135.1, 148.8, 151.7, 162.9, 169.5 ppm; HRMS (ESI⁺) m/z calcd. for

C₃₅H₅₀N₂NaO₆Si₂[M+Na]⁺673.3100, found 673.3081.

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(3-fluorophenyl)-5-

methylpyrimidine-2,4(1H,3H)-dione (3g).

Reflux for 3h. Column chromatography (EtOAc:Hexane 1:4, R_f= 0.40)

gave 3g as a white solid (63 mg, 94%). As with meta-OMe substituted 3f,

the ¹³C NMR signals of the 3-fluorophenyl moiety appear as duplicates,

thus indicating the presence of conformers. ¹H NMR signals are in

accordance with the product and mass spectroscopic analysis (ESI-TOF)

did not indicate the presence of byproducts. ¹H NMR (300 MHz, CDCl₃)

δ -0.04 (s, 6H), -0.01-0.01 (m, 6H), 0.76 (s,9H), 0.85 (s, 9H), 1.67 (s, 3H),

1.74-1.84 (m, 1H), 2.88-2.96 (m, 1H), 3.62 (m, 3H), 4.26-4.32 (m, 1H),

5.35-5.41 (m, 1H), 6.93-7.01 (m, 1H), 7.19-7.26 (m, 2H), 7.50-7.55 (m, 3H),

7.64-7.70 (m, 1H), 7.99-8.02 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃)

δ -5.1, -5.0, -4.7, -4.6, 12.3, 17.8, 18.5, 25.7, 26.1, 38.0, 64.1, 72.5, 88.2,

88.6, 110.0, 115.3 (d, J (C,F) = 22.5 Hz), 116.1 (d, J (C,F) = 22.5 Hz),

117.2 (d, J (C,F) = 20.6 Hz), 123.8, 124.5, 129.3, 130.8, 131.3 (d, J (C,F)

= 7.6 Hz), 131.7 (d, J (C,F) = 7.8 Hz), 131.8, 134.4 (br s), 135.1, 148.6,

150.1, 162.7, 163.2 (d, J (C,F) = 251.9 Hz), 169.2 ppm; HRMS (ESI⁺) m/z

calcd. for C₃₅H₄₉FN₂NaO₆Si₂[M+Na]⁺691.3005, found 691.2997. Mp 75-

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(2,6-

dimethylphenyl)-5-methylpyrimidine-2,4(1H,3H)-dione (3c).

2c comprised of a mixture of cis-diastereomers (dr = 4:1), which both

dehydrated to 3c. Reflux for 3h. Column chromatography (EtOAc:Hexane

1:7, R_f= 0.40) gave 3c as a colorless oil (62 mg, 91%). ¹H NMR (300 MHz,

CDCl₃) δ -0.05-0.00 (m, 12H), 0.76 (s, 9H), 0.83 (s, 9H), 1.56 (s, 3H), 1.76-

1.82 (m, 1H), 2.16 (s, 3H), 2.32 (s, 3H), 2.84-2.89 (m, 1H), 3.62 (m, 3H),

4.29-4.33 (m, 1H), 5.31-5.34 (m, 1H), 7.15-7.21 (m, 2H), 7.28-7.31 (m, 1H),

7.51-7.54 (m, 2H), 7.65-7.68 (m, 1H), 7.96-7.98 (m, 2H) ppm; ¹³C {¹H}

NMR (75 MHz, CDCl₃) -5.1, -5.0, -4.7, -4.6, 11.1, 17.8, 18.5, 19.6, 19.8,

25.8, 26.1, 38.8, 64.2, 72.4, 88.1, 108.8, 128.2, 128.7, 129.3, 130.0, 130.7,

131.6, 131.8, 134.9, 135.1, 136.1, 148.8, 151.1, 163.0, 169.4 ppm; HRMS

(ESI⁺) m/z calcd. for C₃₇H₅₄N₂NaO₆Si₂[M+Na]⁺701.3413, found 701.3407.

76 ̊C.

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-methyl-6-(p-

tolyl)pyrimidine-2,4(1H,3H)-dione (3d).

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(4-fluorophenyl)-5-

methylpyrimidine-2,4(1H,3H)-dione (3i).

Reflux for 1h. Column chromatography (EtOAc:Hexane 1:7, R_f= 0.30)

gave 3d as a white solid (63 mg, 94%). ¹H NMR (300 MHz, CDCl₃) δ -0.05

(s, 6H), -0.01-0.01 (m, 6H), 0.75 (s, 9H), 0.84 (s, 9H), 1.66 (s, 3H), 1.72-

1.81 (m, 1H), 2.44 (s, 3H), 2.85-2.94 (m, 1H), 3.58-3.65 (m, 3H), 4.25-4.31

(m, 1H), 5.42-5.46 (m, 1H), 7.06 (d, J=7.8 Hz, 1H), 7.30-7.37 (m, 3H), 7.49

(m, 2H), 7.63-7.68 (m, 1H), 7.99-8.02 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz,

CDCl₃) -5.1, -5.0, -4.74, -4.65, 12.4, 17.8, 18.5, 21.5, 25.7, 26.1, 38.0, 64.2,

72.5, 88.1, 88.5, 109.6, 127.8, 128.4, 129.2, 129.6, 130.0, 130.3, 130.8,

131.9, 135.0, 140.1, 148.8, 151.9, 162.9, 169.5 ppm; HRMS (ESI⁺) m/z

calcd. for C₃₆H₅₂N₂NaO₆Si₂[M+Na]⁺687.3256, found 687.3255. Mp 136-

Reflux for 3h. Column chromatography (EtOAc:Hexane 1:4, R_f= 0.40)

gave 3i as a white solid (62 mg, 93%). ¹H NMR (300 MHz, CDCl₃) δ -

0.04-0.01 (m, 12H), 0.76 (s, 9H), 0.85 (s, 9H), 1.66 (s, 3H), 1.73-1.81 (m,

1H), 2.87-2.96 (m, 1H), 3.62 (s, 3H), 4.27-4.32 (m, 1H), 5.36-5.41 (m, 1H),

7.20-7.29 (m, 2H), 7.43-7.55 (m, 4H), 7.64-7.69 (m, 1H), 7.98-8.01 (m, 2H)

ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.1, -5.0, -4.7, -4.6, 12.4, 17.8,

18.5, 25.7, 26.1, 38.0, 64.1, 72.5, 88.1, 88.5, 110.2, 116.6, 116.9 (app t, J

(C,F) = 20.8 Hz), 128.6 (br s), 129.2, 130.1 (d, J (C,F) = 8.0 Hz), 130.8,

131.8, 135.1, 148.7, 150.6, 162.7, 163.5 (d, J (C,F) = 250.8 Hz), 169.3

ppm; ¹⁹F NMR (160 MHz, CDCl₃) -110.21 (m) ppm; HRMS (ESI⁺) m/z calcd.

139 ̊C

for C₃₅H₄₉FN₂NaO₆Si₂[M+Na]⁺691.3005, found 691,3006. Mp 57-58

̊C.

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(3-methoxyphenyl)-

5-methylpyrimidine-2,4(1H,3H)-dione (3f).

6-(benzofuran-2-yl)-3-benzoyl-1-((2R,4S,5R)-4-((tert-

butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-

2,4(1H,3H)-dione (3j).

Reflux for 3h. Column chromatography (EtOAc:Hexane 1:5, R_f= 0.40)

gave 3f as a colorless oil (61 mg, 90%). With 3f, all the carbon peaks of

the deoxyribose and methoxyphenyl moieties in ¹³C NMR spectrum

appear as duplicates. Also, -CH₃of thymine and –OCH₃appear as

duplicates in ¹H NMR spectrum. The same result was achieved by

repeating the reaction. Mass spectroscopic analysis (ESI-TOF) of 3f did

not indicate the presence of any byproduct. However, the ¹H NMR signals

Reflux for 2h. Column chromatography (EtOAc:Hexane 1:6, R_f= 0.35)

gave 3j as a colorless oil (64 mg, 93%). ¹H NMR (300 MHz, CDCl₃) δ -

0.06-(-0.05) (m, 6H), -0.02-0.00 (m, 6H), 0.70 (s, 9H), 0.84 (s, 9H), 1.93 (s,

3H), 1.93-2.02 (m, 1H), 2.94-2.99 (m, 1H), 3.58-3.67 (m, 3H), 4.28-4.31

(m, 1H), 5.40-5.43 (m, 1H), 7.07 (s, 1H), 7.34-7.45 (m, 2H), 7.51-7.59 (m,

3H), 7.65-7.71 (m, 2H), 7.99-8.01 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz,

CDCl₃) δ -5.1, -5.0, -4.8, -4.6, 12.5, 17.8, 18.6, 25.6, 26.1, 38.5, 64.1, 72.5,

88.4, 89.8, 111.3, 112.0, 113.9, 122.2, 124.1, 126.5, 127.3, 129.3, 130.8,

131.7, 135.2, 141.4, 145.0, 148.5, 155.1, 162.5, 168.9 ppm; HRMS (ESI⁺)

m/z calcd. for C₃₇H₅₀N₂NaO₇Si₂[M+Na]⁺713.3049, found 713.3039.

of -OCH₃and -CH₃coalesced at higher temperature (T_c> 52 ̊C in benzene-

d₆, see NMR spectra of 3f), indicating the presence of conformational

isomers (e.g. rotamers or the deoxyribose having other sugar puckering

conformation^[31]). Also, all the ¹³C NMR signals of the sugar moiety were

found coalesced at 70 ̊

C (benzene-d₆). ¹H NMR (300 MHz, CDCl₃) -0.04-

0.01 (m, 12H), 0.76 (s, 9H), 0.84 (s, 9H), 1.67-.168 (m, 3H), 1.75-1.83 (m,

1 H), 2.84-2.95 (m, 1H), 3.62-3.64 (m, 3H), 3.86-3.87 (m, 3H), 4.25-4.32

(m, 1H), 5.41-5.47 (m, 1H), 6.70-6.77 (m, 1H), 6.98-7.04 (m, 2H), 7.40-

7.54 (m, 3H), 7.63-7.69 (m, 1H), 7.99-8.02 (m, 2H) ppm; ¹³C {¹H} NMR (75

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(furan-3-yl)-5-

methylpyrimidine-2,4(1H,3H)-dione (3k).

10.1002/ejoc.201601219

European Journal of Organic Chemistry

FULL PAPER

Reflux for 2h. Column chromatography (EtOAc:Hexane 1:5, R_f= 0.38)

gave 3k as a colorless oil (54 mg, 88%). H NMR (300 MHz, CDCl₃) δ -

(m, 1H), 6.56 (dd, J=7.6, 6.0 Hz, 1H), 7.48-7.53 (m, 2H), 7.64-7.69 (m, 1H),

7.92-7.99 (m, 5H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.13, -5.08, -

4.7, -4.6, 13.3, 17.9, 18.6, 25.8, 26.1, 38.1, 64.1, 72.8, 81.8, 88.6, 89.8,

101.9, 117.4, 120.9, 123.0, 124.0, 124.6, 128.2, 129.3, 130.7, 131.6, 131.8,

132.6, 133.1, 133.4, 135.2, 148.1, 161.8, 168.6 ppm; HRMS (ESI⁺) m/z

calcd. for C₃₉H₄₈F₆N₂NaO₆Si₂[M+Na]⁺833.2847, found 833.2841.

1

0.02-0.02 (m, 12H), 0.80 (s, 9H), 0.85 (s, 9H), 1.82 (s, 3H), 1.85-1.91 (m,

1H), 2.89-2.94 (m, 1H), 3.64-3.68 (m, 3H), 4.31-4.34 (m, 1H), 5.70-5.73

(m, 1H), 6.53 (s, 1H), 7.49-7.52 (m, 2H), 7.61 (s, 2H), 7.64-7.67 (m, 1H),

7.97-7.99 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.1, -5.0, -4.7,

-4.6, 12.7, 17.9, 18.6, 25.8, 26.1, 38.2, 64.2, 72.5, 88.2, 88.4, 110.7, 111.3,

117.1, 129.2, 130.8, 131.8, 135.1, 142.3, 144.1, 144.6, 148.8, 162.6, 169.2

ppm; HRMS (ESI⁺) m/z calcd. for C₃₃H₄₈N₂NaO₇Si₂[M+Na]⁺663.2892,

found 663.2882.

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-6-(3,3-dimethylbut-1-

yn-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (3q).

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-methyl-6-(thiophen-

2-yl)pyrimidine-2,4(1H,3H)-dione (3m).

Reflux for 1h. Column chromatography (EtOAc:Hexane 1:7, R_f= 0.37)

gave 3q as a colorless oil (61 mg, 93%). H NMR (300 MHz, CDCl₃) δ -

1

0.01-0.01 (m, 6H), 0.04-0.04 (m, 6H), 0.84 (s, 9H), 0.85 (s, 9H), 1.38 (s,

9H), 2.00-2.06 (m, 4H), 2.95-3.04 (m, 1H), 3.65-3.68 (m, 2H), 3.82-3.87

(m, 1H), 4.37-4.42 (m, 1H), 6.54-6.58 (m, 1H), 7.45-7.50 (m, 2H), 7.61-

7.66 (m, 1H), 7.89-7.93 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -

5.1, -5.0, -4.63, -4.55, 12.9, 18.0, 18.6, 25.9, 26.1, 29.1, 30.4, 37.8, 64.2,

70.4, 73.0, 88.5, 89.7, 114.6, 117.5, 129.2, 130.7, 131.8, 135.0, 135.3,

148.3, 162.3, 169.0 ppm; HRMS (ESI⁺) m/z calcd. for

C₃₅H₅₄N₂NaO₆Si₂[M+Na]⁺677.3413, found 677.3405.

Reflux for 2h. Column chromatography (EtOAc:Hexane 1:4, R_f= 0.50)

1

gave 3m as a colorless oil (54 mg, 88%). H NMR (300 MHz, CDCl₃) δ -

0.03-0.01 (m, 12H), 0.78 (s, 9H), 0.84 (s, 9H), 1.77 (s, 3H), 1.82-1.88 (m,

1H), 2.89-2.94 (m, 1H), 3.64 (m, 3H), 4.30-4.32 (m, 1H), 5.55-5.58 (m, 1H),

7.16-7.20 (m, 2H), 7.50-7.53 (m, 2H), 7.58 (m, 1H), 7.64-7.67 (m, 1H),

7.99-8.01 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.1, -5.0, -4.7,

-4.6, 12.7, 17.9, 18.6, 25.8, 26.1, 38.2, 64.2, 72.6, 88.3, 88.7, 112.9, 128.0,

129.1, 129.3, 129.8, 130.8, 131.8, 131.9, 135.1, 144.9, 148.6, 162.3, 169.2

ppm; HRMS (ESI⁺) m/z calcd. for C₃₃H₄₈N₂NaO₆SSi₂[M+Na]⁺679.2664,

found 679.2667.

N3-debenzoylation of 3o to 4 (Scheme 5)

To solution of 3p (50 mg, 0.062 mmol) in CHCl₃(1 mL), 20 μL n-

butylamine(0.19 mmol,

3 equiv) was added and stirred at room

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-methyl-6-(prop-1-yn-

1-yl)pyrimidine-2,4(1H,3H)-dione (3n).

temperature for 2 h. Then the solvent was evaporated in vacuo, and the

resulting crude mixture flash column chromatographed through silica gel

(EtOAc:hexane 1:5, R_f= 0.20) to afford 4 as a white solid (41 mg, 95%).

Reflux for 2h. Column chromatography (EtOAc:Hexane 1:5, R_f= 0.30)

gave 3n as a colorless oil (57 mg, 93%). ¹H NMR (300 MHz, CDCl₃) δ

0.00-0.04 (m, 12H), 0.85 (s, 9H), 0.87 (s, 9H), 2.08 (m, 4H), 2.22 (s, 3H),

2.89-2.98 (m, 1H), 3.67-3.69 (m, 2H), 3.81-3.86 (m, 1H), 4.36-4.42 (m, 1H),

6.58-6.63 (m, 1H), 7.45-7.51 (m, 2H), 7.60-7.66 (m, 1H), 7.91-7.93 (m, 2H)

ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.1, -5.0, -4.6, -4.5, 5.2, 12.9, 18.0,

18.6, 25.8, 26.2, 38.2, 64.2, 70.9, 72.7, 88.4, 89.2, 105.3, 115.1, 129.2,

130.7, 131.8, 134.9, 135.0, 148.3, 162.3, 169.0 ppm; HRMS (ESI⁺) m/z

calcd. for C₃₂H₄₈N₂NaO₆Si₂[M+Na]⁺635.2943, found 635.2947.

6-((3,5-bis(trifluoromethyl)phenyl)ethynyl)-1-((2R,4S,5R)-4-((tert-

butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-

2,4(1H,3H)-dione (4).

¹H NMR (300 MHz, CDCl₃) δ 0.06-0.07 (m, 12H), 0.85 (s, 9H), 0.89 (s, 9H),

2.06-2.14 (m, 1H), 2.19 (s, 3H), 3.03-3.12 (m, 1H), 3.74-3.87 (m, 2H), 3.89-

3.92 (m, 1H), 4.49-4.54 (m, 1H), 6.48-6.53 (m, 1H), 7.96 (s, 3H), 8.50 (s,

1H, -NH) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.13, -5.09, -4.7, -4.6,

13.2, 18.0, 18.6, 25.8, 26.1, 37.8, 64.0, 73.0, 82.0, 88.3, 89.5, 101.4, 117.5,

1

122.7 (q, J (C,F) = 273.6 Hz), 123.1, 123.9, 131.8, 132.8 (q, ²J (C,F) =

3-benzoyl-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-methyl-6-

(phenylethynyl)pyrimidine-2,4(1H,3H)-dione (3o).

34.2 Hz), 133.6, 148.8, 162.5 ppm; HRMS (ESI⁺) m/z calcd. for

C₃₂H₄₄F₆N₂NaO₅Si₂[M+Na]⁺729.2585, found 729.2599. Mp 63-67

̊C.

Reflux for 2h. Column chromatography (EtOAc:Hexane 1:6, R_f= 0.40)

gave 3o as a colorless oil (65 mg, 96%). ¹H NMR (300 MHz, CDCl₃) δ

0.00-0.03 (m, 12H), 0.86 (m, 18H), 2.08-2.20 (m, 4H), 2.98-3.07 (m, 1H)

3.68-3.70 (m, 2H), 3.84-3.90 (m, 1H), 4.39-4.44 (m, 1H), 6.69 (dd, J=7.7,

6.2 Hz, 1H), 7.40-7.52 (m, 5H), 7.57-7.67 (m, 3H), 7.93-7.96 (m, 2H) ppm;

¹³C {¹H} NMR (75 MHz, CDCl₃) δ -5.11, -5.05, -4.7, -4.5, 13.1, 18.0, 18.6,

25.9, 26.2, 38.2, 64.2, 72.9, 79.4, 88.4, 89.4, 106.7, 115.7, 120.6, 128.9,

129.2, 130.7, 131.7, 132.1, 134.6, 135.1, 148.3, 162.1, 168.9 ppm;HRMS

(ESI⁺) m/z calcd. for C₃₇H₅₀N₂NaO₆Si₂[M+Na]⁺697.3100, found 697.3095.

Synthesis of 7 (Scheme 6)

O,O-Acetyl protection of Thymidine.

The modified procedure described previously was used.^[32]To a solution

of thymidine (1.0 g, 4.1 mmol) in DMF (10 mL) under argon were added

pyridine (1.3 mL, 16 mmol), 4-dimethylaminopyridine (DMAP, 50 mg, 0.41)

and acetic anhydride (1.1 mL, 12 mmol). The resulting solution was stirred

at rt. for 14 h. Then, sat.aq. NaHCO₃(15 mL) and EtOAc (60 mL) were

added, the organic layer was separated, washed with water (5 × 15 mL),

brine (50 mL) and dried over Na₂SO₄. The solvent was evaporated under

reduced pressure to afford O,O-Ac-thymidine as light yellow oil (1.18 g,

88%), which was used for the next step without further purification. ¹H NMR

(500 MHz, CDCl₃) δ 1.93 (d, J = 1.2 Hz, 3H), 2.10-2.20 (m, 1H), 2.10 (s,

3H), 2.12 (s, 3H), 2.43-2.50 (m, 1H), 4.22-4.25 (m, 1H), 4.33-4.36 (m, 2H),

5.19-5.23 (m, 1H), 6.32 (dd, J = 8.5, 5.6 Hz, 1H), 7.26 (d, J = 1.2 Hz, 1H),

9.28 (br s, 1H, -NH) ppm.

3-benzoyl-6-((3,5-bis(trifluoromethyl)phenyl)ethynyl)-1-((2R,4S,5R)-4-

((tert-butyldimethylsilyl)oxy)-5-(((tert-

butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-

2,4(1H,3H)-dione (3p).

Reflux for 3h. Column chromatography (EtOAc:Hexane 1:6, R_f= 0.38)

1

gave 3p as a colorless oil (76 mg, 94%). H NMR (300 MHz, CDCl₃) δ -

0.01-0.03 (m, 12H), 0.83 (s, 9H), 0.84 (s, 9H), 2.09-2.17 (m, 1H), 2.22 (s,

3H), 3.00-3.08 (m, 1H), 3.67-3.69 (m, 2H), 3.85-3.91 (m, 1H), 4.39-4.44

10.1002/ejoc.201601219

European Journal of Organic Chemistry

FULL PAPER

N-benzoylation of O,O-Ac-thymidine.

(2×1.0 mL) and the combined solvents were evaporated in vacuo to afford

the mixture of epoxides as a white foamy solid, which was then dissolved

The procedure described previously was used.^[16]To a solution of O,O-Ac-

thymidine (1 g, 3.06 mmol) in MeCN (15 mL) under argon were added

triethylamine (0.85 mL, 6.12 mmol), pyridine (0.25 mL, 3.06 mmol) and

benzoyl chloride (0.4 mL, 3.4 mmol). The resulting slurry was heated at

80 °C for 1 h with vigorous stirring. Water (1 mL) was added and stirring

continued while the mixture was cooled down to room temperature. 2 M

NaOH (15 mL) and EtOAc (70 mL) were added and stirred until all the

solids were dissolved. The organic phase was separated, washed with 2

M HCl (2 × 15 mL), 1 M NaOH (2 ×15 mL) and brine (15 mL), and dried

over Na₂SO₄. The solvent was evaporated under reduced pressure to give

the crude N-Bz-O,O-Ac-thymidine as light brown oil (1.24 g, 94 %), which

was used in the next step without further purification. ¹H NMR (500 MHz,

CDCl₃) δ 1.97 (d, J = 1.2 Hz, 3H), 2.08 (s, 3H), 2.14 (s, 3H), 2.17-2.26 (m,

1H), 2.42-2.52 (m, 1H), 4.24-4.27 (m, 1H), 4.33-4.41 (m, 2H), 5.20-5.23

(m, 1H), 6.30 (dd, J = 8.4, 5.7 Hz, 1H), 7.38 (d, J = 1.2 Hz, 1H), 7.46-7.51

(m, 2H), 7.62-7.67 (m, 1H), 7.90-7.92 (m, 2H) ppm.

in MeCN (5 mL).

To this solution was added potassium

propynyltrifluoroborate (89 mg, 0.61 mmol), followed by the addition of

BF₃∙OEt₂(0.47 mmol, 58 µL) under inert atmosphere. The mixture was

stirred for 30 min and then quenched with sat.aqueous NaHCO₃(5 mL)

with vigorous stirring for 5 min. EtOAc (40 mL) and sat. aqueous NaHCO₃

(10 mL) were added, the organic layer separated, washed once with brine

(10 mL), dried over NaSO₄, filtered and concentrated in vacuo. The

resulting crude material was purified by column chromatography (EtOAc-

Hex 1:1) to afford the products 6a (135 mg, 59%, R_f= 0.20 and 6b (64 mg,

28%, R_f= 0.30) as colorless oils.

((2R,3S,5R)-3-acetoxy-5-((5S,6R)-3-benzoyl-5-hydroxy-5-methyl-2,4-

dioxo-6-(prop-1-yn-1-yl)tetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-

yl)methyl acetate (6a).

¹H NMR (300 MHz, CDCl₃) δ 1.59 (s, 3H), 1.92 (d, J=2.1 Hz, 3H), 2.07 (s,

3H), 2.13 (s, 3H), 2.26-2.30 (m, 2H), 3.49 (s, 1H, -OH), 4.17-4.40 (m, 4H),

5.20-5.23 (m, 1H), 6.17 (dd, J=8.1, 6.3 Hz, 1H), 7.44-7.49 (m, 2H), 7.61-

7.66 (m, 1H), 8.02-8.05 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ

3.8, 21.0, 22.8, 35.8, 51.1, 64.2, 72.1, 74.0, 74.5, 81.6, 83.4, 85.4, 129.2,

130.7, 132.1, 135.1, 150.5, 167.9, 170.5, 172.5 ppm; HRMS (ESI⁺) m/z

calcd. for C₂₄H₂₆N₂NaO₉[M+Na]⁺509.1531, found 509.1545.

Synthesis of thymidine trans-bromohydrin 5.

The modified procedure described previously was used.^[16]To a solution

of N-Bz-O,O-Ac-thymidine (1.0 g, 2.32 mmol) in THF (12mL) was added

water (1.2 mL) followed by the addition N-bromosuccinimide (1.65 g, 9.2

mmol). The resulting solution was stirred vigorously at room temperature

for 50 min, whereupon water (10mL) and EtOAc (50 mL) were added, and

the excess bromine was quenched by the addition of solid Na₂S₂O₅in

small portions under vigorous stirring until the solution became colorless.

The organic phase was separated and washed with water (3 × 10 mL),

brine (10 mL) and dried over Na₂SO₄. The solvents were evaporated in

((2R,3S,5R)-3-acetoxy-5-((5R,6S)-3-benzoyl-5-hydroxy-5-methyl-2,4-

dioxo-6-(prop-1-yn-1-yl)tetrahydropyrimidin-1(2H)-yl)tetrahydrofuran-2-

yl)methyl acetate (6b).

¹H NMR (300 MHz, CDCl₃) δ 1.59 (s, 3H), 1.94 (d, J=2.5 Hz, 3H), 2.07 (s,

3H), 2.16 (s, 3H), 2.19-2.29 (m, 1H), 2.51-2.61 (m, 1H), 3.47 (s, 1H, -OH),

4.14-4.17 (m, 1H), 4.26-4.37 (m, 2H), 4.49-4.51 (m, 1H), 5.20-5.23 (m, 1H),

6.25 (dd, J=9.1, 5.5 Hz, 1H), 7.45-7.50 (m, 2H), 7.61-7.66 (m, 1H), 7.97-

8.00 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 3.7, 20.9, 21.0, 22.9,

34.5, 48.9, 64.1, 71.9, 74.2, 74.6, 81.2, 84.1, 84.3, 129.2, 130.5, 132.3,

135.0, 149.9, 168.0, 170.5, 172.7 ppm;HRMS (ESI⁺) m/z calcd. for

C₂₄H₂₆N₂NaO₉[M+Na]⁺509.1531, found 509.1536.

vacuo to give

a crude product, which was purified by column

chromatography (EtOAc:hexane 1:1, R_f= 0.45 for major and 0.40 for minor

diastereomer) to afford a mixture of diastereomers (dr = 2:1, ¹H NMR, 0.80

g, 65%) as colorless oil, wherein (5R,6R) was the major diasteromer.^[33]

Major diastereomer (5R,6R): ¹H NMR (300 MHz, CDCl₃) 2.06 (s, 3H), 2.09

(s, 3H), 2.15 (s, 3H), 2.28-2.61 (m, 2H), 4.07-4-49 (m, 3H), 5.15-5.22 (m,

2H), 5.21 (br s, 1H, -OH), 6.44 (dd, J = 8.7, 6.2 Hz, 1H), 7.45-7.50 (m, 2H),

7.61-7.66 (m, 1H), 7.99-8.02 (m, 2H) ppm.

1.38 (s, 9H), 2.00-2.06 (m,

Dehydration of 6a and 6b to 7.

4H), 2.95-3.04 (m, 1H), 3.65-3.68 (m, 2H), 3.82-3.87 (m, 1H), 4.37-4.42

(m, 1H), 6.54-6.58 (m, 1H), 7.45-7.50 (m, 2H), 7.61-7.66 (m, 1H), 7.89-

7.93 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 20.96, 21.02, 23.1,

35.6, 53.7, 64.0, 73.7, 80.2, 81.6, 84.6, 129.2, 130.5, 132.0, 135.1, 149.9,

165.7, 167.8, 171.2 ppm; HRMS (ESI⁺) m/z calcd. for

C₂₁H₂₃BrN₂NaO₉[M+Na]⁺549.0479, found 549.0459.

Thionyl chloride (0.2 mmol, 14.5 µL) was added to a solution of a mixture

of 6a (40 mg, 0.082 mmol) and 6b (40 mg, 0.082 mmol) in benzene (1.5

mL) and stirred for 1 min. Pyridine (3.3 mmol, 265 µL) was added and the

solution was refluxed for 2h, whereupon EtOAc (30 mL) and water (7 mL)

were added, the organic layer separated, washed with brine (10 mL) and

dried over Na₂SO4. The solvent was evaporated in vacuo to give the crude

product, which was purified by flash column chromatography (EtOAc-Hex,

1:1, R_f= 0.4) to give 7 as a white powder (73 mg, 95%).

Minor diastereomer (5S,6S): ¹H NMR (300 MHz, CDCl₃) 1.99 (s, 3H), 2.07

(s, 3H), 2.11 (s, 3H), 2.28-2.61 (m, 2H), 4.07-4-49 (m, 3H), 4.77 (br s, 1H,

-OH), 5.15-5.22 (m, 2H), 6.07 (dd, J = 8.4, 5.9 Hz, 1H), 7.45-7.50 (m, 2H),

7.61-7.66 (m, 1H), 7.99-8.02 (m, 2H) ppm. ¹³C {¹H} NMR (75 MHz, CDCl₃)

δ 20.96, 21.02, 22.8, 35.0, 53.6, 68.8, 74.5, 80.3, 81.7, 85.7, 129.2, 130.5,

132.2, 135.1, 149.4, 166.3, 168.6, 170.7 ppm; HRMS (ESI⁺) m/z calcd. for

C₂₁H₂₃BrN₂NaO₉[M+Na]⁺549.0479, found 549.0459.

((2R,3S,5R)-3-acetoxy-5-(3-benzoyl-5-methyl-2,4-dioxo-6-(prop-1-yn-1-

yl)-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl acetate (7).

¹H NMR (300 MHz, CDCl₃) δ 1.99 (s, 3H), 2.05 (s, 3H), 2.09 (s, 3H), 2.26-

2.34 (m, 4H), 3.12-3.22 (m, 1H), 4.10-4.18 (m, 2H), 4.38-4.46 (m, 1H),

5.34-5.41 (m, 1H), 6.63 (dd, J=8.7, 4.8 Hz, 1H), 7.46-7.51 (m, 2H), 7.62-

7.67 (m, 1H), 7.90-7.93 (m, 1H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ

5.3, 12.9, 20.9, 36.2, 64.1, 70.8, 74.3, 82.7, 88.6, 105.6, 115.9, 129.3,

130.7, 131.6, 134.1, 135.2, 148.5, 162.0, 168.6, 170.2, 170.8 ppm; HRMS

(ESI⁺) m/z calcd. for C₂₄H₂₄N₂NaO₈[M+Na]⁺491.1425, found 491.1425.

Synthesis of 6a and 6b from 5.

To a solution of 5 (0.25 g, 0.47 mmol, mixture of trans-diastereomers, dr =

2:1) in dry acetone (5 mL) under argon was added triethylamine (80 µL,

0.56 mmol) at room temperature. The mixture was gently shaken and left

standing for 60 minutes (with no shaking!) to allow triethylamine

hydrobromide precipitation as transparent needles. The supernatant was

then transferred into another flask under argon using a syringe (Ø 0.6 mm

× 25 mm needle). The remaining precipitate was washed with dry acetone

Mp 165-168 ̊C.

10.1002/ejoc.201601219

European Journal of Organic Chemistry

FULL PAPER

Synthesis of 10 (Scheme 6)

Synthesis of 9 from 8.

Synthesis of N-PMB-O,O-Ac-Thymidine.

To a solution of 8 (200 mg, 0.37 mmol) in dry acetone (4 mL) under argon

was added triethylamine (103 µL, 0.74 mmol) at room temperature. The

mixture was gently shaken and left standing for 3 h to allow triethylamine

hydrobromide precipitation as transparent needles. The supernatant was

then transferred into another flask containing propynyltrifluoroborate (76

mg, 0.52 mmol) using a syringe (Ø 0.6 mm × 25 mm needle). The

remaining precipitate (Et₃NBr) was washed once with cold dry MeCN (1.0

mL). Then, BF₃∙OEt₂(0.37 mmol, 45 µL) was added and the mixture was

stirred for 30 min, whereupon the reaction was quenched with sat. aq.

NaHCO₃(5 mL) with vigorous stirring for 5 min. EtOAc (30 mL) and water

(10 mL) were added, the organic layer separated, washed once with brine

(10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The

resulting crude material was purified by column chromatography

(EtOAc:CHCl₃1:4, R_f= 0.3) to afford 9 (123 mg, 66%) as a foamy oil.

To a solution of O,O-Ac-thymidine (1 g, 3.06 mmol) in DMF (10 mL) under

argon was added K₂CO₃(0.62 g, 4.5 mmol) and 4-methoxybenzyl chloride

(PMB-Cl, 0.43 mL, 3.2 mmol). The resulting mixture was stirred at room

temperature for 14 h, whereupon EtOH (1.0 mL) was added and stirred for

10 min. Then, water (30 mL) and Et₂O (80 mL) were added, the organic

phase was separated, washed with water (2×20 mL) and brine (20 mL),

and dried over Na₂SO₄. The solvent was evaporated under reduced

pressure to give the crude product, which was purified by column

chromatography (EtOAc:Hex 1:1, R_f= 0.40) to afford N-PMB-O,O-Ac-

1

thymidine as amorphous solid (1.25 g, 91%). H NMR (300 MHz, CDCl₃)

δ 1.94 (s, 3H), 2.09 (s, 3H), 2.10 (s, 3H), 2.06-2.17 (m, 1H), 2.42-2.49 (m,

1H), 3.76 (s, 3H), 4.18-4.27 (m, 1H), 4.32-4.34 (m, 1H), 5.05 (s, 2H), 5.18-

5.21 (m, 1H), 6.34 (dd, J=8.5, 5.6 Hz, 1H), 6.76-6.86 (m, 2H), 7.24 (s, 1H),

7.39-7.49 (m, 2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 13.6, 21.0, 37.7,

44.1, 55.3, 63.9, 74.2, 82.1, 85.6, 110.9, 113.8, 129.2, 130.9, 132.6, 151.0,

159.2, 163.2, 170.2, 170.4 ppm.

((2R,3S,5R)-3-acetoxy-5-((5S,6R)-5-hydroxy-3-(4-methoxybenzyl)-5-

methyl-2,4-dioxo-6-(prop-1-yn-1-yl)tetrahydropyrimidin-1(2H)-

yl)tetrahydrofuran-2-yl)methyl acetate (9).

Synthesis of thymidine trans-bromohydrin 8.

¹H NMR (300 MHz, CDCl₃) δ 1.39 (s, 3H), 1.64 (d, J=2.1 Hz, 3H), 2.07 (s,

3H), 2.09 (s, 3H), 2.15-2.32 (m, 2H), 3.51 (s, 1H, -OH), 3.76 (s, 3H), 4.05-

4.25 (m, 3H), 4.32 (dd, J=12.9, 4.8 Hz, 1H), 4.92 (s, 2H), 5.19 (dt, J=5.2,

2.6 Hz, 1H), 6.21 (dd, J=8.0, 6.4 Hz, 1H), 6.78-6.81 (m, 2H), 7.16-7.38 (m,

2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 3.6, 20.9, 21.0, 23.1, 35.6,

44.4, 50.3, 55.3, 64.2, 71.4, 73.5, 74.6, 81.3, 82.4, 85.7, 113.8, 129.2,

130.0, 152.1, 159.0, 170.4, 170.5, 173.4 ppm; HRMS (ESI⁺) m/z calcd. for

C₂₅H₃₀N₂NaO₉[M+Na]⁺525.1844, found 525.1847.

The modified procedure used with N-Bz-Thymidine was applied to avoid

bromination of the PMB group. To a solution of N-PMB-O,O-Ac-thymidine

(0.5 g, 1.12 mmol) in THF (15mL) was added water (1.5 mL) followed by

the addition N-bromosuccinimide (0.20 g, 1.12 mmol, 1 equiv). The

resulting solution was stirred vigorously at room temperature and

monitored by TLC (EtOAc:hex 1:1). Every 30 min 0.1 equiv of NBS (0.05g

0.11 mmol) was added until the starting material was consumed (TLC).

After 1.5 h the reaction was completed (1.3 equiv of NBS), whereupon

water (10mL) and Et₂O (60 mL) were added, and the excess bromine was

quenched by the addition of solid Na₂S₂O₅in small portions under vigorous

stirring until the solution became colorless. The organic phase was

separated and washed with water (2 × 10 mL), brine (10 mL) and dried

over Na₂SO₄. The solvents were evaporated in vacuo to give the crude

product as a mixture of trans diastereomers (dr = 3:2, ¹H NMR). The

purification by column chromatography (EtOAc:CHCl₃1:4) afforded the

major diastereomer 8 as a white solid (0.265 g, 44%, R_f= 0.40) and the

minor diastereomer as a colorless oil (0.170 g, 28 % R_f= 0.20). Only ¹H

and ¹³C NMR data are reported for the minor diastereomer.

Dehydration of 9 to 10.

Thionyl chloride (0.247 mmol, 18 µL) was added to a solution of 9 (100 mg,

0.206 mmol) in benzene (2.5 mL) and stirred for 1 min. Pyridine (4.1 mmol,

302 µL) was added and the solution was refluxed for 2h, whereupon EtOAc

(30 mL) and water (7 mL) were added, the organic layer separated,

washed with brine (7 mL) and dried over Na₂SO₄. The solvents were

evaporated in vacuo to give the crude product, which was purified by flash

column chromatography (EtOAc-hex, 1:1, R_f= 0.25) to give 10 as a

colorless oil (94 mg, 94%).

((2R,3S,5R)-3-acetoxy-5-(3-(4-methoxybenzyl)-5-methyl-2,4-dioxo-6-

(prop-1-yn-1-yl)-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl

acetate (10).

Major diastereomer 8 (5R,6R): ¹H NMR (300 MHz, CDCl₃) δ 2.03 (s, 3H),

2.09 (s, 3H), 2.12 (s, 3H), 2.17-2.42 (m, 2H), 3.61 (d, J=2.4, 1H), 3.76 (s,

3H), 4.10-4.13 (m, 1H), 4.26 (dd, J=12.1, 3.0 Hz, 1H), 4.40 (dd, J=12.1,

4.9 Hz, 1H), 4.95 (q, J=14.3 Hz, 2H), 5.09 (d, J=2.4 Hz, 1H), 5.14 (dt, J=

6.4, 2.8 Hz, 1H), 6.42-6.59 (m, 1H), 6.69-6.90 (m, 2H), 7.17-7.38 (m, 2H)

ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 21.0, 23.8, 34.8, 44.5, 53.7, 55.3,

64.0, 73.8, 79.6, 81.4, 85.4, 113.9, 129.0, 129.7, 151.3, 159.0, 166.7,

170.6, 171.0 ppm. HRMS (ESI⁺) m/z calcd. for C₂₂H₂₇BrN₂NaO₉[M+Na]⁺

¹H NMR (300 MHz, CDCl₃) δ 2.05 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 2.19

(s, 3H), 2.26 (ddd, J=14.0, 8.7, 5.2 Hz, 1H), 3.12 (ddd, J=13.7, 8.6, 4.8 Hz,

1H), 3.76 (s, 3H), 4.05-4.21 (m, 1H), 4.28 (dd, J=11.5, 7.8 Hz, 1H), 4.50

(dd, J=11.5, 3.8 Hz, 1H), 5.01 (s, 2H), 5.39-5.59 (m, 1H), 6.62 (dd, J=8.7,

4.8 Hz, 1H), 6.74-6.87 (m, 2H), 7.35-7.51 (m, 2H) ppm; ¹³C {¹H} NMR (75

MHz, CDCl₃) δ 5.1, 13.5, 21.0, 21.1, 36.4, 43.9, 55.3, 64.7, 70.9, 74.7, 82.6,

88.8, 103.9, 113.8, 115.4, 129.1, 131.0, 132.2, 150.0, 159.2, 162.5, 170.4,

170.8 ppm; HRMS (ESI⁺) m/z calcd. for C₂₅H₂₈N₂NaO₈[M+Na]⁺507.1738,

found 507.1723.

565.0792, found 565.0802. Mp 132-134 ̊C.

Minor diastereomer (5S,6S): ¹H NMR (300 MHz, CDCl₃) δ 1.98 (s, 3H),

2.08 (s, 3H), 2.09 (s, 3H), 2.33-2.55 (m, 2H), 3.76 (s, 3H), 3.83 (d, J=5.5,

1H), 4.10-4.30 (m, 2H), 4.30-4.48 (m, 1H), 4.74-5.01 (m, 2H), 5.06-5.27

(m, 2H), 6.01 (dd, J=8.1, 6.0 Hz, 1H), 6.65-6.91 (m, 2H), 7.13-7.39 (m,

2H) ppm; ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 21.1, 23.6, 36.1, 44.4, 53.3,

55.4, 64.1, 74.6, 80.4, 81.9, 87.3, 113.9, 128.9, 129.7, 150.7, 159.0, 167.0,

170.8, 171.4 ppm.

Removal of PMB from 10 (Scheme 6)

A procedure described previously was used.^[30]To a solution of 10 (0.21

mmol, 100 mg) in MeCN (3 mL) was added CAN (0.84 mmol, 461 mg) in

H₂O (0.3 mL). The mixture was heated at 70 ̊C for 1.5 h, whereupon water

(10 mL) and EtOAc was added (10 mL). The organic layer was separated

and the water layer was extracted with EtOAc (4×10). The combined

organic layers were washed once with brine (10 mL), dried over Na₂SO_4,

10.1002/ejoc.201601219

European Journal of Organic Chemistry

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and the solvents were evaporated in vacuo to give the crude product,

which was purified by column chromatography (EtOAc-CHCl₃1:4  1:2,

R_f= 0.05 for EtOAc-CHCl₃1:4) to afford 11 as a colorless oil (35 mg, 47%).

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Acknowledgements

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We thank Rocket Wrigstedt and Dr. Jesus E. Perea for their help

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Räisänen is greatly acknowledged for HRMS measurements. V.

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Keywords: Diastereoselectivity • Thymidine photoproduct • DNA

damage • Nucleosides • Borates

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Syntheses of C6 Aryl and Alkynyl

Thymidines from Thymidine trans-

5,6-Bromohydrins

Thymidine derivatization: A metal-free cis-diastereoselective coupling of

thymidine 5,6-epoxides with various aryl- and alkynyltrifluoroborates followed by

near-quantitative dehydration provide C6 aryl and alkynyl thymidines in high overall

yields.

Article Doi

Syntheses of C-6 Aryl- and Alkynyl-Substituted Thymidines from Thymidine trans-5,6-Bromohydrins

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