Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5’-alkynylation

Article abstract of DOI:10.3762/bjoc.13.153

The 5′-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2′,3′-di-O-protecting groups (R¹): O-alkyl groups led to modest diastereoselectivities (65:35) in favor of the 5′R-isomer, whereas O-silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5′S-isomer. A study related to this protecting group effect on the diastereoselectivity is reported.

Full text of DOI:10.3762/bjoc.13.153

Effect of uridine protecting groups on the diastereoselectivity
of uridine-derived aldehyde 5’-alkynylation
Raja Ben Othman‡, Mickaël J. Fer‡, Laurent Le Corre, Sandrine Calvet-Vitale*
and Christine Gravier-Pelletier*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1533–1541.
Laboratoire de Chimie et Biochimie Pharmacologiques et
Toxicologiques, UMR 8601 CNRS, Université Paris Descartes,
Sorbonne Paris Cité (USPC), Centre Interdisciplinaire Chimie
Biologie-Paris (CICB-Paris), 45 rue des Saints Pères, 75270 Paris 06,
France
doi:10.3762/bjoc.13.153
Received: 05 May 2017
Accepted: 20 July 2017
Published: 04 August 2017
Email:
Associate Editor: T. P. Yoon
Sandrine Calvet-Vitale* - sandrine.calvet-vitale@parisdescartes.fr;
Christine Gravier-Pelletier* -
© 2017 Ben Othman et al.; licensee Beilstein-Institut.
License and terms: see end of document.
christine.gravier-pelletier@parisdescartes.fr
*
Corresponding author ‡ Equal contributors
Keywords:
diastereoselective alkynylation; nucleoside; protecting groups; uridine
Abstract
The 5’-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is
significantly influenced by the 2’,3’-di-O-protecting groups (R1): O-alkyl groups led to modest diastereoselectivities (65:35) in
favor of the 5’R-isomer, whereas O-silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5’S-isomer. A
study related to this protecting group effect on the diastereoselectivity is reported.
Introduction
Nucleoside and nucleotide derivatives or analogues are biologi- stereocontrolled formation of a stereogenic center at C-5’, in
cally active compounds of major interest [1,2]. Their wide- spite of its important role for biological activity (Figure 1) [16-
spread applications span from therapeutic agents, such as anti- 19].
bacterial [3-5], antiviral [6] or antitumor [7,8] drugs, to epige-
netic modulators [9] or chemical tools [10,11]. Furthermore, In numerous approaches, this 5′ stereogenic center comes from
they represent central monomers for oligonucleos(t)ide synthe- the chiral pool and the nucleobase is introduced under
sis [12-17]. In the past decades, chemical modifications of these Vorbrüggen conditions [20-26]. It can also be created directly
crucial building blocks have been extensively studied, both on on the nucleoside, either by functionalization of an alkene at
the nucleobase itself and on the sugar moiety [6]. Many of them C-5’ [27-32] or by the diastereoselective addition of a nucleo-
concern the C-2’ and C-3’ sugar positions. However, functio- phile on a carbonyl group. The latter can involve either the
nalization at C-5’ has been much less reported, particularly the reduction of a ketone at C-5’ [12,33-35], or the addition on an
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Beilstein J. Org. Chem. 2017, 13, 1533–1541.
with moderate diastereoselectivity and yield (Table 1)
[
12,35,43-46,48].
In the course of our program devoted to the synthesis of new
MraY inhibitors [49,50], we were interested in developing a
more efficient access to 5’-ethynyluridine, a crucial building
block for the further synthesis of triazole-containing com-
pounds [49]. Intrigued by the moderate diastereomeric ratio re-
ported for the addition or organometallic reagents onto nucleo-
side aldehyde (Table 1), we decided to investigate the influence
of the protecting groups of the uridine aldehyde on the stereo-
chemical outcome of the nucleophilic addition of a Grignard
reagent and we wish to report herein the results of our study.
Results and Discussion
We first prepared primary alcohols 1–5 from uridine and
differing by the nature of R1 protecting groups. The secondary
alcohols at C-2’ and C-3’ were protected either as a cyclic ketal
(
(
[
isopropylidene (1a) [12], isopentylidene (2a), cyclohexylidene
3a)) or as acyclic silyl ethers (4a [15], R1 = TBDMS and 5a
51], R1 = TIPS). Some compounds were also N3-allylated (1b,
Figure 1: C-5’ configuration of nucleoside derivatives and related bio-
logical activity.
4
b and 5b) to evaluate the possible influence of R2 on the dia-
aldehyde of various nucleophiles such as enolates [15,36-38], stereoselectivity of the nucleophilic addition (Scheme 1).
allylborane [39], dialkyl phosphites [40], TMSCN [41] or Grig-
nard reagents [12,17,35,42-47]. Aside from the use of chiral Primary alcohols 1–5 were submitted to an oxidation/Grignard
ligands promoting an excellent facial discrimination of the alde- addition sequence leading to the corresponding propargyl alco-
hyde [34], the addition of Grignard reagents usually proceed hols 11–15 (Scheme 2). The aldehydes 6–10 resulting from oxi-
Table 1: Reported C-5’ diastereoselectivity for the addition of an organometallic reagent on nucleoside aldehydes.
Entry
Basea
Organometallic reagent
Solvent
Temp (°C) dr
C-5’b
Yield (%)c
Ref.
1
2
3
4
5
6
7
8
9
A(Bz)
CH3MgBr
THF
THF
THF
THF
THF
THF
THF
THF
toluene
−78
100
−20
−15
−15
−15
−78
−78
rt
3:2
R
R
R
R
R
R
R
R
S
n.d.
n.d.
44d
21
[35]
[42]
[43]
[12]
[12]
[44]
[45]
[46]
[48]
U
AllylMgBr
16:1
2:1
A
TMSC≡CMgBr
TMSC≡CMgBr
TESC≡CMgBr
TMSC≡CMgBr
AllylMgBr
U
2:1
U
2:1
42
A(Bz)
2:1
40
U
5:1
n.d.
n.d.
47
U
CH2=CHMgBr
5:1
U(MTPM)e
4-phenyl-1-butyne, iPrMgCl,
Zn(OTf2)
1:1.7
aThe nature of the nucleobase protecting group is mentioned in brackets; bC-5’ configuration of the major diastereomer; cisolated yield of the major
diastereomer; dcontaminated with a small amount of the other isomer; eMTPM: monomethoxytetrachlorodiphenylmethoxymethyl.
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Beilstein J. Org. Chem. 2017, 13, 1533–1541.
Scheme 1: Synthesis of alcohols 1–5.
Scheme 2: Synthesis of propargylic alcohols 11–15 and their partial or complete deprotection.
dation with IBX were isolated and directly submitted to Grig- Thus, we prepared compounds (5’R)-11ab [12] and (5’S)-11ab
nard addition without further purification. Grignard reagents [12] from protected uridine 1a and triethylsilylethynylmagne-
were prepared from trimethylsilyl-, triethylsilyl- or triisopropyl- sium chloride. Indeed, Vasella’s group devoted a huge amount
silylacetylene and ethylmagnesium bromide in THF at 0 °C, in of work to the synthesis and characterization of these com-
order to vary the steric hindrance of the silyl group (R3). To un- pounds and notably reported that TES was better than TMS for
ambiguously determine the ratio of diastereomers and the C-5’ efficient separation of both isomers, resulting in an improved
configuration of the major one for the synthesized propargylic 42% yield for the isolated major diastereomer (5’R)-11ab [12].
alcohols 11–15, their partial or complete deprotection was Then, subsequent acidic hydrolysis afforded (5’R)-16 and (5’S)-
carried out to take advantage of an unequivocal 1H NMR com- 16 and alkyne desilylation under basic conditions provided
parison with known compounds, or reliable derivatives.
(5’S)-17 and (5’R)-17 [12] (Scheme 3).
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Beilstein J. Org. Chem. 2017, 13, 1533–1541.
Scheme 3: Synthesis of reference compounds and strategy for assignment of C-5’ configuration.
The differences between 1H NMR data of the related diastereo- after complete deprotection leading to compound (5’R) or (5’S)-
meric compounds (Figure 2 and Figure 3) provided a conclu- 17 (Figure 3). As observed for compound 16, the H-1’ chemi-
sive evidence to unequivocally attribute the absolute configura- cal shift is more shielded for (5’S)-17 isomer (doublet
tion at C-5’ of the synthesized compounds. Thus, for com- (3JH-1’-H-2’ = 6.0 Hz) at 5.98 ppm) than for the (5’R)-17 dia-
pounds 11–15 with R3 = TES, the configuration at C-5’ was de- stereomer (doublet (3JH-1’-H-2’ = 7.0 Hz) at 6.04 ppm). Simi-
termined according to the 1H NMR spectra of (5’R) or (5’S)-16 larly, the H-4’ chemical shift is more shielded for (5’S)-17
derivative (Figure 2). Indeed, in 1H NMR spectrum (500 MHz, isomer (triplet (3JH-4’-H-3’ = 3JH-4’-H-5’ = 3.5 Hz) at 4.03 ppm)
CDCl3), H-1’ appears as a doublet at 6.02 ppm for (5’R)-16 than for the (5’R)-17 diastereomer (triplet (3JH-4’-H-3’ =
(
(
3JH-1’-H-2’ = 7.0 Hz) and as a doublet at 5.98 ppm for (5’S)-16 3JH-4’-H-5’ = 2.5 Hz) at 4.07 ppm). Moreover, chemical shifts
3JH-1’-H-2’ = 6.0 Hz). Furthermore, H-4’ appears as a multiplet for H-3’ (doublet of doublet (3JH3’-H2’ = 5.5 Hz, 3JH3’-H4’ =
at 4.11–4.09 ppm for (5’R)-16 and as a triplet at 4.05 ppm for 2.5 Hz) at 4.30 ppm) and H-2’ (doublet of doublet (3JH2’-H1’ =
5’S)-16 (3JH-4’-H-3’ = 3JH-4’-H-5’ = 3.0 Hz). For compounds 7.0 Hz, 3JH2’-H3’ = 5.5 Hz) at 4.22 ppm) for the (5’R)-17 isomer
(
1
1–15 with R3 ≠ TES, the configuration at C-5’ was attributed are also significantly different from that of the (5’S)-17 isomer
Figure 3: 1H NMR of (5’R)-17 and (5’S)-17 and example of configura-
Figure 2: 1H NMR of (5’R)-16 and (5’S)-16 and of a (5’R)/(5’S)-16 mix-
ture.
tion determination for a pure isolated compound with unknown configu-
ration.
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Beilstein J. Org. Chem. 2017, 13, 1533–1541.
(
triplet (3JH2’-H1’ = 3JH2’-H3’ = 6.0 Hz) at 4.23 ppm for H-2’ dene 2a (Table 2, entry 4) or a cyclohexylidene 3a (Table 2,
and doublet of doublet (3JH3’-H2’ = 6.0 Hz, 3JH3’-H4’ = 3.5 Hz) entry 5) did not modify the observed diastereoselectivity.
at 4.20 ppm for H-3’.
We next turned to the use of acyclic protecting groups. tert-
The results and conditions of assays involving the various syn- Butyldimethylsilyl ether 4a (Table 2, entry 6) led to an im-
thesized substrates 1–5 and Grignard reagents are reported in proved 85:15 ratio. Furthermore, we were delighted to discover
Table 2. The diastereomeric ratio of 11–15 was determined by that, contrary to that which was observed with ketal groups, the
1
H NMR or HPLC analysis of the crude mixture and the C-5’ major diastereomer 4a obtained using tert-butyldimethylsilyl
configuration of the major diastereomer was assigned as ex- ether displayed the 5’S configuration. As was noted for iso-
plained above. To evaluate the effect of the temperature on the propylidene as a protecting group, decreasing the temperature
diastereomeric ratio (Table 2, entries 1 and 2), we first tried to (Table 2, entry 7) or protecting the N-3 nitrogen of uracil
carry out the reaction at lower temperature but it remained close (Table 2, entry 8) did not significantly change the 5’R/5’S ratio.
to 2:1 in favor of the (5’R)-11ab, either with conventional or In both cases, using 3.5 equivalents of Grignard reagent was re-
inverse order of addition. We also tried to increase the reaction quired to complete the reaction.
temperature [52] but, even at 0 °C, the components in the reac-
tion mixture were largely degraded. The protection of uracil In order to improve this reverse diastereoselectivity, we envis-
nitrogen at N-3 position by an allyl group did not significantly aged the use of a more bulky protecting group, such as the tri-
modify the 5’R/5’S ratio (Table 2, entry 3). Increasing the bulki- isopropylsilyl group. The addition of triethylsilylacetylide
ness of the ketal protecting group by introducing an isopentyli- magnesium bromide gave a 5’R /5’S ratio of 5:95 (Table 2,
Table 2: Influence of the protecting groups and conditions on the diastereoselectivity of the alkynyl Grignard addition on uridine derived aldehydes.
Entry
Alcohol
R1
Aldehydea
Grignard
reagent
Temperature
(°C)
Propargyl alcohol
1–5
R2
6–10
R3
equiv
11–15
5’R/5’S
Yield (%)c
ratiob
1
2
3
4
5
6
7
8
9
1a
1a
1b
2a
3a
4a
4a
4b
5a
5a
5a
5a
5a
5a
5b
CMe2
CMe2
CMe2
CEt2
H
H
6a
6a
TES
TES
TES
TES
TES
TES
TES
TES
TES
TES
TMS
TIPS
TIPS
TIPS
TIPS
2.5
2.5
2.5
2.5
2.5
2.5
3.5
3.5
5
−50
−78
−15
−15
−15
−15
−78
−78
−15
−78
−78
−78
−15
−15
−78
11ab
11ab
11bb
12ab
13ab
14ab
14ab
14bb
15ab
15ab
15aa
15ac
15ac
15ac
15bc
65:35d
65:35d
65:35e
65:35
70:30
15:85
15:85
9:91e
5:95
conv: 65%
conv: 65%
52 (24)
54 (15)
65 (18)
64 (48)
51 (38)
59 (39)
64 (53)
65 (32)
66 (36)
61
allyl
H
6b
7a
CcHex
TBDMS
TBDMS
TBDMS
TIPS
H
8a
H
9a
H
9a
allyl
H
9b
10a
10a
10a
10a
10a
10a
10b
10
11
12
13
14
15
TIPS
H
5
5:95
TIPS
H
5
10:90
1:99
TIPS
H
5
TIPS
H
5
2:98
55
TIPS
H
2.5
5
2:98
conv: 85%
43 (27)
TIPS
allyl
10:90e
aNormal addition procedure; bdetermined by 1H NMR and/or HPLC of the crude mixture; cyield of the mixture of diastereomers over two steps from
the corresponding primary alcohol, isolated yield of the major diastereomer is shown in brackets; dan “inverse” order of addition led to the same dia-
stereomeric ratio; e5’-configuration of the major diastereomer was not determined.
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Beilstein J. Org. Chem. 2017, 13, 1533–1541.
entries 9 and 10). To determine if R3 was able to influence this
ratio, we also tested trimethylsilylacetylmagnesium bromide
(
Table 2, entry 11) and triisopropylsilylacetylmagnesium bro-
mide (Table 2, entry 12). When R3 = TMS, the 5’R/5’S ratio
was only 10:90, whereas for R3 = TIPS, an excellent 5’R/5’S
1
:99 ratio was reached, allowing the direct synthesis of (5’S)-
5ac with a substantial 61% isolated yield over two steps.
1
Running this reaction at −15 °C (Table 2, entry 13) slightly
diminished the yield to 55%. The bulkiness of the TIPS groups
required the use of 5 equivalents of Grignard reagent to get a
clean reaction and complete conversion of the starting material
(
Table 2, entry 14). The protection of the N-3 nitrogen with an
allyl group was unfavorable and led to a 5’R/5’S 10:90 ratio
Table 2, entry 15). The three attempts of C-5’ alkynylation of
(
N-3-allylated uridine aldehydes, did not revealed marked influ-
ence on the diastereoselective ratio (Table 2, entries 3, 8, 15).
Figure 4: Hypothetical Cram chelated models.
To explain the diastereoselective outcome of the reaction, we
first considered Cram chelated models (Figure 4).
fying the high selectivity observed for the silyl protected com-
pounds in favor of the 5’S-isomer. However, when ketal groups
A 1,3-chelation of the metal with the carbonyl group and the are used, the 5’R-isomer is predominantly formed with a modest
protecting group oxygen atom at C-3’ would promote an attack diastereoselectivity, meaning that the most stable transition state
of the nucleophile on the Re face of the aldehyde and thus the would involve a 1,3-metal chelation with the carbonyl group
formation of the 5’R diastereoisomers, whereas a 1,2-metal and the protecting group oxygen atom at C-3’ of uridine. Even
chelation with the carbonyl group and the endocyclic oxygen if the later 1,3-chelation can be envisioned, we found this
atom of uridine at C-4’ would explain the formation of the 5’S hypothesis very unlikely due to the large distance between the
diastereoisomer (attack of the nucleophile on the Si face of the two oxygen atoms.
aldehyde, Figure 4). In such a case, the poor chelating ability of
silyl ether groups, along with their bulkiness, would strongly Therefore, the following models would be more consistent with
disfavor the 1,3-chelate and the 5’R-isomer formation, justi- our results (Figure 5).
Figure 5: Proposed stereochemical models.
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Beilstein J. Org. Chem. 2017, 13, 1533–1541.
When R1 is a ketal group (R1 = alkyl, Figure 5 top), on the one General procedure for the oxidation of uridine derivatives
hand, the major formation of the 5’R-isomer would be ex- 1–5. To a suspension of protected uridine derivative 1–5
plained by the Felkin Anh model (Figure 5A top, left) with (1 equiv) in acetonitrile (5 × 10−2 M) was added IBX (3 equiv).
an attack of the nucleophile on the Re face of the aldehyde. On The suspension was refluxed for 45 min–1.5 h until complete
the other hand, the minor formation of the 5’S diastereomer conversion of starting material (TLC). The suspension was
would result from an attack of the nucleophile on the Si face cooled to rt, filtered on a celite® pad and the cake was washed
of the aldehyde on the 1,2-chelated model (Figure 5B top, with EtOAc. The filtrate was then concentrated in vacuo to
right).
afford crude aldehydes 6–10 which were used without other
purification (quantitative yield). Aldehydes have been charac-
When R1 is a trialkylsilyl protecting group (R1 = silyl, Figure 5 terized by 1H and 13C NMR. Since they are quite unstable,
bottom), on the one hand, the 5’S diastereomer formation is in crude aldehydes were used without any further purification and
agreement with an attack on the least hindered face of a 1,2- directly engaged in the alkynylation reaction.
chelated conformer (Figure 5C bottom, right). On the other
hand, the minute formation of the 5’R-isomer that would be ex- General procedure for the 5'-alkynylation of uridine-
plained by the Felkin–Ahn model (Figure 5D bottom, left) is derived aldehydes 6–10. At 0 °C, under Ar, to a solution of tri-
strongly disfavored due to the the bulkiness of the silyl groups alkylsilylacetylene (1.5–2.45 equiv), in THF (0.25 M) was
hampering an approach of the nucleophile on the Re face: the added dropwise a solution of ethylmagnesium bromide (3 M in
bulkier the silyl group, the stronger the effect.
Et2O, 1.5–2.45 equiv). The solution was stirred at 0 °C for
0 min and then at rt for 1 h. Crude aldehydes 6–10 were dis-
solved in THF (0.1 M), transferred into a dropping funnel and
1
Conclusion
In summary, we report a study on the diastereoselective slowly added to the solution of the Grignard reagent at −15 °C.
5
’-alkynylation of uridine aldehydes displaying various The mixture was stirred at −15 °C for 1 h 30 and was allowed to
protecting groups on the secondary alcohols at C-2’ and C-3’ slowly warm to rt for 24 h. The reaction was then quenched by
and at the N-3 position of the uracile. Our results show that addition of a saturated aqueous solution of NH4Cl (40 mL) and
while the N-3 protection has little influence on the alkynylation THF was removed in vacuo. The aqueous phase was extracted
diastereoselectivity, the nature of the diol protecting group with EtOAc and the combined organic layers were dried over
strongly impact the diastereoselective outcome of the reaction. Na2SO4, filtered and concentrated in vacuo. The crude foam
Indeed, whatever the ketal group used, the major 5’R-isomer is was purified by flash chromatography.
obtained with a 2:1 ratio whereas the protection as silyl ethers
leads to an inverse diastereoselectivity in favor of the 5’S-
Supporting Information
isomer. We propose stereochemical models to rationalize the
observed diastereoselectivity. Furthermore by increasing the
Supporting Information File 1
bulkiness of the silyl group both on the diol and the Grignard
reagent, we manage to obtain an excellent diastereoselectivity.
Indeed, by using the most bulky 2’,3’-O-TIPS protecting groups
and TIPS-ethynylmagnesium bromide, the 5’-ethynylation was
achieved in a 99:1 ratio in favor of the 5’S-isomer. The result-
ing building block with a broad potential in nucleos(t)ide deriv-
ative syntheses is obtained in a very satisfactory 61% yield over
two steps.
Description of the materials and methods, and the
preparation and characterization of new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-153-S1.pdf]
Supporting Information File 2
Copies of spectra for final compounds and NMR studies.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-153-S2.pdf]
Experimental
General procedure for N3-allylation of protected uridine de-
rivatives. To a solution of protected uridine derivative (1 equiv) Acknowledgements
in DMF/acetone (1:1, final concentration 0.4 M) was added We thank the “Centre National de la Recherche Scientifique”
K2CO3 (1.8 equiv) and allyl bromide (1.5 equiv). The suspen- and the “Ministère de l′Enseignement Supérieur et de la
sion was stirred at 50 °C for 12 h, filtered and concentrated in Recherche” for financial support of this work and for a Ph.D.
vacuo. The resulting residue was submitted to flash chromatog- grant to M. J. Fer. Assia Hessani (Université Paris Descartes) is
raphy (elution conditions mentioned below) to afford the corre- gratefully acknowledged for mass spectra analyzes and Serge
sponding N-allyl compound.
Turcaud for his expertise and advice in HPLC analysis.
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Beilstein J. Org. Chem. 2017, 13, 1533–1541.
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