Towards new MraY inhibitors: A serine template for uracil and 5-amino-5-deoxyribosyl scaffolding

Article abstract of DOI:10.1002/ejoc.200700527

The bacterial translocase MraY is a good target for the development of new antitbiotics as it is ubiquitous and essential for bacterial growth. The goal of this work was the synthesis of simplified analogues of naturally occurring inhibitors of this enzyme to investigate the essential character of the uridine moiety of these inhibitors with regards to biological activity. Thus, the structure of the targeted enantiomerically pure N-(uracilylpentyl)-β-D-O- (5-amino-5-deoxyribosyl)-L-serine retains uracil and 5-amino-5-deoxyribose parts linked by a serinyl template. The synthetic strategy towards this compound relies on sequential O-glycosylation and N-alkylation by reductive amination of a serine derivative. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700527

FULL PAPER
DOI: 10.1002/ejoc.200700527
Towards New MraY Inhibitors: A Serine Template for Uracil and 5-Amino-
5-deoxyribosyl Scaffolding
Laurent Le Corre,[a] Christine Gravier-Pelletier,*[a] and Yves Le Merrer*[a]
Keywords: Translocase MraY inhibitors / Antibiotics / Glycosylation / Reductive amination / Amino acids
The bacterial translocase MraY is a good target for the devel-
opment of new antitbiotics as it is ubiquitous and essential
for bacterial growth. The goal of this work was the synthesis
of simplified analogues of naturally occurring inhibitors of
this enzyme to investigate the essential character of the urid-
ine moiety of these inhibitors with regards to biological ac-
tivity. Thus, the structure of the targeted enantiomerically
pure N-(uracilylpentyl)-β-D-O-(5-amino-5-deoxyribosyl)-L-
serine retains uracil and 5-amino-5-deoxyribose parts linked
by a serinyl template. The synthetic strategy towards this
compound relies on sequential O-glycosylation and N-alky-
lation by reductive amination of a serine derivative.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
peptidoglycan layer forms part of the bacterial cell wall and
protects the cell from osmotic stress. Indeed, most of the
enzymes involved in its biosynthesis have been demon-
strated to be ubiquitous and essential for bacterial
growth.[2] Owing to its transmembrane localisation,[3] the
translocase MraY has only recently been characterised and
purified to homogeneity[4] and no therapeutic drugs tar-
geting this essential enzyme[5] exist so far. Nevertheless,
The world-wide emergence of bacterial resistance to vari-
ous antibiotics[1] such as β-lactams, vancomycin, methicillin
and other clinically important antibiotics has forced the sci-
entific community to discover novel structures that are able
to treat the resistant bacterial strains. The enzymes involved
in peptidoglycan biosynthesis appear to be the targets of
choice in the development of new antibacterials since the
Figure 1. MraY inhibitors and the target compound 1.
several families of naturally occurring inhibitors have been
identified such as liposidomycins,[6] tunicamycins,[7] murei-
domycins[8] and caprazamycins[9] (Figure 1).
However, although most of these compounds display
high activity in vitro, their antibacterial activity is limited
[a] Laboratoire de Chimie et Biochimie Pharmacologiques et Tox-
icologiques, Université Paris Descartes, CNRS UMR 8601,
45 rue des Saints-Pères, 75270 Paris cedex 06, France
Fax: +33-142868387
E-mail: Christine.Gravier-Pelletier@univ-paris5.fr
Yves.Le-Merrer@univ-paris5.fr
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Towards New MraY Inhibitors
due to their high hydrophilicity or their lack of specificity
leading to toxicity.[10] In an ongoing program directed
towards the inhibition of new targets for fighting antibiotics
resistance, our goal was to develop access to new MraY
inhibitors displaying simplified structures compared with
the natural ones and enhanced biological activity. The de-
scribed approach focuses on the right-hand part of liposi-
domycins and caprazamycins and takes into account the
following motivations: on the one hand, to gain a better
stability of the synthesised inhibitors, and on the other
hand, bearing in mind that the two hydroxy groups at the
2Ј,3Ј positions of the uridine moiety may be unnecessary to
retain biological activity,[11] our plan was to replace the
sugar part of uridine by a C5 acyclic alkyl chain (Figure 1).
Thus, the hypothesis intended to be tested is that only the
uracil template and not the uridine would be crucial to en-
sure possible recognition of the resulting inhibitors by the
enzyme. Thus, uracil, aminoribose and amino acid moieties,
being the three key fragments of the naturally occurring
inhibitors, were retained in the targeted inhibitor 1. It is
evident that, if inhibitory activity was demonstrated for
such a compound, other modifications related to the chemi-
cal linkage between the uracil and serine moieties and that
allow modulations in either its flexibility or polarity would
also be evaluated later on.
Scheme 1. Reagents and conditions: a) Cl3CC(NH)OtBu, cyclohex-
ane, 50 °C (100%); b) DBU, THF, room temp. (100% for 2a); c)
tBuBr, BnEt3NCl, K2CO3, MeCN, 50 °C (88%); d) H2, Pd/C,
EtOAc (100% for 2b); e) i. (Me3Si)2NH, Me3SiCl, 80 °C, ii.
Br(CH2)5Br, DMF, 80 °C (41%); f) BOMCl, DBU, DMF, room
temp. (77%); g) 4, NaI, Cs2CO3, DMF (63% for 5a and 37% for
5b); h) FmocCl, DIPEA, CH2Cl2, room temp. (81% for 6a and
73% for 6b).
On the one hand, esterification with tert-butyl trichlo-
roacetimidate followed by Fmoc deprotection efficiently led
to O-benzyl--serine ester 2a. On the other hand, 3-(benzyl-
oxymethyl)-1-(5Ј-chloropentyl)uracil (4) was prepared in
three steps from uracil. Persilylation of uracil in the pres-
ence of trimethylsilyl chloride and hexamethyldisilazane fol-
lowed by N1-alkylation with 1,5-dibromopentane[12] af-
forded the N1-(bromopentyl)uracil (3).[13] N3-Protection of
3 with benzyloxymethyl chloride (BOMCl)[14] was ac-
companied by simultaneous halogen exchange leading to
N1-(chloropentyl)uracil 4. Then, N-alkylation of O-benzyl-
-serine ester 2a with the uracil derivative 4 was carried out
in the presence of caesium carbonate[15] at 50 °C for 4 d in
DMF to deliver the N-alkylated serine 5a in 63% yield.
Then, further N-protection of 5a as its N-Fmoc derivative
6a cleanly occurred and was followed by attempts to depro-
tect the primary alcohol function prior to glycosylation.
However, all the conditions assayed for this reaction proved
unsuccessful, while concomitant N-Fmoc deprotection was
observed. So we decided to reproduce the same sequence of
reactions, without O-protection, starting from -serine ester
2b, the preparation of which was easily carried out from
commercially available N-(benzyloxycarbonyl)--serine by
esterification with tert-butyl bromide[16] followed by hydro-
genolysis. Then, N-alkylation of 2b with 4 was carried out
under the same conditions as described previously except
Results and Discussion
The retrosynthetic analysis of the target compound 1
(Figure 2) relies on two complementary strategies involving
either N-alkylation of a serinyl derivative followed by O-
glycosylation as the key steps (path a) or, inversely, O-glyco-
sylation and subsequent N-alkylation (path b).
Figure 2. Retrosynthetic pathways: a) O-glycosylation of the N- that completion of the reaction required heating at 80 °C
(uracilylalkyl)serine derivative or b) N-alkylation of the O-(azidori-
bosyl)serine derivative.
for 2 d in DMF to afford the corresponding N-alkylated
serine 5b in a modest 37% yield. All attempts to improve
the yield of this reaction, notably by using other bases (e.g.,
So, in accord with path a, we embarked on the synthesis potassium carbonate, N,NЈ-diisopropylethylamine) and by
of a conveniently protected N-(uracilylpentyl)--serine de- varying the temperature, resulted in lower yields. Finally, N-
rivative (Scheme 1) from commercially available N-Fmoc- protection of 5b as its N-Fmoc derivative 6b cleanly occurred,
O-benzyl--serine.
thus shortening the reaction sequence for its synthesis.
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L. Le Corre, C. Gravier-Pelletier, Y. Le Merrer
FULL PAPER
We next turned to the introduction of the aminoribosyl acid. The O-(5-amino-5-deoxyribosyl)-N-(uracilylpentyl)-
moiety (Scheme 2) onto the (uracilylalkyl)serine template serine derivative 11 was isolated in 44% yield. However,
by O-glycosylation with the 5-azido-5-deoxy-2,3-O-isopen- careful analysis of its NMR spectra revealed both partial
tylidene--ribofuranose (7),[14,17] the use of which was ex- reduction of the uracil double bond (20%) and partial epi-
pected to promote the introduction of the serine derivative merisation at the asymmetric carbon of serine. These by-
onto the β face of the ribose-like molecule due to steric products were respectively attributed to the conditions of
hindrance at its α face.
hydrogenolysis and to the drastic conditions required for N-
alkylation of the serine (80 °C, DMF for 2 d). It has to be
pointed out that this epimerisation was not detected in
compound 9 which was identified as a mixture of atropoiso-
mers resulting from the presence of the Fmoc group and
increasing the complexity of spectra.
This disappointing result prompted us to explore new
routes for the preparation of the target compound 1 and we
decided to not protect the N3 position of the uracil moiety
since its possible participation later in the reaction sequence
had not been ascertained. The alternative preparation of
the N-(uracilylalkyl)serine was carried out following to two
different pathways (Scheme 3).
Scheme 2. Reagents and conditions: a) DAST, CH2Cl2, –30 to
20 °C (β: 66%; α: 22%); b) 6b, BF3·OEt2, –45 to 10 °C (46%); c)
H2, Pd(OH)2, MeOH; d) i. TFA/H2O/THF, 4:3:1; ii. TFA (44%).
The glycosylation reaction involved first the activation of
the anomeric position of the ribose derivative as a fluoride
leading to 8 as a mixture of β/α anomers which could either
be separated by column chromatography [isolated yields:
1
66% for the β anomer (1-H: doublet in H NMR, 2JH1–F
=
61.5 Hz) and 22% for the α anomer (1-H: dd, 2JH1–F = 63.5,
3JH1–H2 = 3.6 Hz)] or used as a mixture. Indeed, condensa-
tion of the N-alkylated -serine 6b in the presence of boron
trifluoride–diethyl ether with either the pure β anomer or a
β/α mixture of anomers of the ribose led to the major for-
mation of the expected β anomer of the O-glycosyl-N-(ura-
cilylalkyl)serine 9 in the same β/α = 9:1 ratio. Thus, the pure
β anomer of 9 (1-H: singlet) could be isolated in 46% yield.
Reduction of the azido group to a primary amine and de-
protection of the N3-BOM of the uracil part were per-
formed by hydrogenolysis in the presence of Pearlman’s cat-
alyst. Surprisingly, these conditions only resulted in the par-
tial deprotection of the N-BOM moiety while deprotection
of the N-Fmoc protecting group occurred, thus affording
Scheme 3. Reagents and conditions: a) i. (Me3Si)2NH, Me3SiCl,
80 °C; ii. Br(CH2)5Br, DMF, 80 °C (41%); b) NaI, acetone, 55 °C
(65%); c) 2b, K2CO3, MeCN, 60 °C (43%); d) TFA, CH2Cl2, room
temp. (83%); e) MsO(CH2)5OTBDPS, Cs2CO3, DMF, 50 °C
(67%); f) HCl, MeOH, room temp. (77%); g) Dess–Martin
periodinane, CH2Cl2, room temp. (77%); h) i. 2b, 4 Å MS, THF;
ii. NaBH(OAc)3 (71%); i) FmocCl, DIPEA, CH2Cl2, room temp.
(71%); j) 8, BF3·OEt2, CH2Cl2, –45 to 10 °C (71%).
First, halogen exchange of the previously obtained N1-
10. Removal of the remaining BOM and isopentylidene (bromopentyl)uracil (3) with sodium iodide afforded the
protecting groups required treatment with a mixture of tri- corresponding more reactive iodo derivative 12 which was
fluoroacetic acid/H2O/THF followed by neat trifluoroacetic then used for N-alkylation of the -serine ester 2b to give
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Towards New MraY Inhibitors
13. However, completion of the reaction required heating α anomers in 71% isolated yield. Unfortunately, irrespective
at 60 °C and thus did not allow the milder conditions de- of the nature of the attempts made to separate these ano-
sired for this reaction. The second pathway proved more mers, it was not possible to obtain the expected pure β an-
promising and involved N-alkylation of -serine ester 2b by omer. Nevertheless, this difficulty could be overcome by in-
reductive amination with N1-formylbutyluracil (17). This verting the sequence of reactions and by carrying out glyco-
latter was prepared in three steps from uracil and involved sylation prior to N-alkylation (Scheme 4).
N1-alkylation with 1-mesyloxy-5-(tert-butyldiphenylsily-
Thus, O-glycosylation of tert-butyl N-Fmoc--serine es-
loxy)pentane readily synthesised from commercially avail- ter (20), obtained by esterification of the commercially
able pentane-1,5-diol by sequential monosilylation and me- available N-Fmoc--serine, with the 1-fluoro--ribofur-
sylation.[18] The chemoselectivity of the uracil alkylation anose derivative 8 led to the expected compound 21 which
was checked by a 2D-NOESY NMR experiment which could be isolated as the pure β anomer in 28% yield. N-
showed spatial coupling between 1-H of the side-chain and Fmoc deprotection with piperidine afforded the primary
6-H of the uracil. The tert-butyldiphenylsilyl protecting amine 22 which was then N-alkylated by reductive amin-
group of the resulting 15 was then removed under acidic ation with the N1-(formylbutyl)uracil (17) to afford the pro-
conditions affording the alcohol 16 which was subsequently tected N-(uracilylpentyl)-O-(azidoribosyl)--serine deriva-
oxidised under Dess–Martin conditions to give the aldehyde tive 23 in 65% yield. To avoid the partial reduction of the
17. Finally, N-alkylation of the -serine ester 2b by re- C5–C6 double bond of the uracil part observed during the
ductive amination with the aldehyde 17 afforded tert-butyl hydrogenolysis of compound 9, reduction of the azido
N-(uracilylpentyl)serine 13 in an improved 71% yield and group of the ribosyl moiety of 23 was carried out under
in the required mild conditions. For further biological Staudinger conditions in the presence of 1,2-bis(diphenyl-
evaluation purposes, acidolysis of the tert-butyl ester in 13 phosphanyl)ethane (84% yield) and was followed by acidic
was carried out and afforded the N-(uracilylpentyl)serine hydrolysis of the isopentylidene protecting group to give the
14. We could then turn to the second key step, the introduc- targeted inhibitor 1 in 48% yield.
tion of the ribosyl-like moiety.
This required N-Fmoc protection of the secondary amine
Conclusions
of 13 (71% yield) and was followed by glycosylation of the
resulting 18 with the 5-azido-5-deoxy-2,3-O-isopentylidene-
1-fluoro--ribofuranose (8) under the same conditions as
described previously and afforded 19 as a 5:1 mixture of β/
In conclusion, enantiomerically pure N-(uracilylpentyl)-
β--O-aminoribosyl--serine has been synthesised by se-
quential O-glycosylation and N-alkylation by reductive am-
ination of a serinyl derivative linker. This structure should
be a promising lead in the development of MraY translo-
case inhibitors. Exploration of its inhibitory activity is cur-
rently in progress and should be reported in due course.
Experimental Section
1H (250 or 500 MHz) and 13C NMR (63 or 126 MHz) spectra were
recorded with a Bruker AM250 spectrometer in CDCl3 at 300 K
(unless indicated otherwise). Chemical shifts (δ) are reported
in ppm and coupling constants are given in Hz. Optical rotations
were measured with a Perkin–Elmer 341 polarimeter equipped with
a sodium (589 nm) or mercury (365 nm) lamp at 20 °C. Mass spec-
tra, chemical ionisation (CI), and high-resolution (HRMS), were
recorded by the Service de Spectrométrie de Masse, ICSN, Gif-
sur-Yvette. All reactions were carried out under argon and were
monitored by thin-layer chromatography with Merck 60F-254 pre-
coated silica (0.2 mm) on glass. Unless indicated, flash chromatog-
raphy was performed with Merck Kieselgel 60 (0.2–0.5 mm) or
Bakerbond C18 (0.04 mm); the solvent systems are given as v/v.
Spectroscopic (1H and 13C NMR, MS) and/or analytical data were
obtained using chromatographically homogeneous samples.[19]
tert-Butyl L-Serine Ester (2b): 10% Pd/C (350 mg) was added to a
solution of tert-butyl N-(benzyloxycarbonyl)--serine ester (1.48 g,
5.01 mmol) in EtOAc (100 mL). Hydrogenation was carried out in
the presence of dihydrogen at room temp. for 90 min. After fil-
tration through a Celite pad and concentration in vacuo, the -
serine ester 2b was isolated as a colourless oil (770 mg, 95%). The
Scheme 4. Reagents and conditions: a) Cl3CC(=NH)OtBu, EtOAc,
C6H12, 20 °C (90%); b) 8, BF3·OEt2, 4 Å MS, CH2Cl2, –45 °C to
room temp. (28%); c) piperidine, DMF, room temp. (93%); d) i. 17,
Na2SO4, THF; ii. NaBH(OAc)3, room temp. (65%); e) (Ph2PCH2)2,
THF, H2O (84%); f) TFA, H2O, THF (48%).
product was used in subsequent steps without purification. [α]D
=
1
–17.5 (c = 1, CH2Cl2). H NMR: δ = 3.74 (dd, J3a–3b = 10.5, J3a–2
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L. Le Corre, C. Gravier-Pelletier, Y. Le Merrer
FULL PAPER
= 4.5 Hz, 1 H, 3a-H), 3.57 (dd, J3b–3a = 10.5, J3b–2 = 6.3 Hz, 1 H,
61.7 (C-2), 50.1 (C-e), 48.4 (C-a), 48.2 (CHFmoc), 48.2 (C-5), 29.4,
3b-H), 3.44 (dd, J2–3b = 6.3, J2–3a = 4.5 Hz, 1 H, 2-H), 2.80 (br. s, 29.3 (C-b, C-d), 28.3 (tBu), 24.4 (c-H) ppm. HRMS (ESI): calcd.
3 H, OH, NH), 1.45 (s, 9 H, tBu) ppm. 13C NMR: δ = 173.1 (C- for C46H51N3O8Na [M + Na]+ 796.3574; found 796.3603.
1), 81.6 (tBu), 64.2 (C-3) 56.6 (C-2), 28.1 (tBu) ppm. HRMS (ESI):
tert-Butyl (S)-2-[5ЈЈ-(3Ј-Benzyloxymethyluracil-1Ј-yl)pentylamino]-
3-hydroxypropanoate (5b): The procedure was similar to that used
calcd. for C7H16NO3 [M + H]+ 162.1130; found 162.1144.
3-(Benzyloxymethyl)-1-(5Ј-chloropentyl)uracil (4): Benzyloxymethyl
chloride (2.14 mL, 9.42 mmol) and DBU (1.4 mL, 9.42 mmol) were
added to a solution of 1-(5-bromopentyl)uracil (3)[12,13] (3.1 g,
11.9 mmol) in DMF (13 mL) and the reaction mixture was stirred
at room temp. for 24 h. The mixture was concentrated in vacuo.
Purification by flash column chromatography (EtOAc/cyclohexane,
6:4) afforded compound 4 as a colourless oil (1.2 g, 77%). Rf = 0.30
for the obtention of 5a and involved -serine ester 2b (63 mg,
0.39 mmol), 3-(benzyloxymethyl)-1-(5Ј-chloropentyl)uracil (4)
(159 mg, 0.47 mmol), caesium carbonate (254 mg, 0.78 mmol) and
NaI (297 mg, 2.34 mmol) in DMF (1.3 mL). The mixture was
heated at 80 °C for 48 h. Flash column chromatography (CH2Cl2/
MeOH, 98:2Ǟ95:5) afforded 5b as a colourless oil (67 mg, 37%).
Rf = 0.17 (CH2Cl2/MeOH, 95:5). [α]D = –9 (c = 1, CH2Cl2). 1H
NMR: δ = 7.45–7.25 (m, 5 H, Harom.), 7.12 (d, J6Ј–5Ј = 7.9 Hz, 1
1
(EtOAc/cyclohexane, 6:4). H NMR: δ = 7.06 (d, J6–5 = 7.9 Hz, 1
H, 6-H), 5.69 (d, J5–6 = 7.9 Hz, 1 H, 5-H), 5.47, 4.69 (2s, 4 H, H, 6Ј-H), 5.72 (d, J5Ј–6Ј = 7.9 Hz, 1 H, 5Ј-H), 5.51, 4.73 (2s, 4 H,
CH2BOM), 3.70 (t, J1Ј–2Ј = 8.3 Hz, 2 H, 1Ј-H), 3.52 (t, J5Ј–4Ј
=
CH2BOM), 3.71 (dd, J3a–3b = 10.7, J3a–2 = 4.5 Hz, 1 H, 3a-H), 3.73
(t, Je–d = 7.5 Hz, 2 H), 3.56 (dd, J3b–3a = 10.7, J3b–2 = 6.6 Hz, 1 H,
6.4 Hz, 2 H, 5Ј-H), 1.90–1.61 (m, 4 H, 2Ј-H, 4Ј-H),1.60–1.40 (m, 2
H, 3Ј-H) ppm. 13C NMR: δ = 162.9 (C-4), 151.3 (C-2), 143.2 (C- 3b-H), 3.27 (dd, J2–3b = 6.6, J2–3a = 4.5 Hz, 1 H, 2-H), 2.82–2.49
6), 137.9 (Carom.), 128.1, 127.5 (CHarom.), 101.3 (C-5), 72.0, 70.3
(m, 2 H, a-H), 2.40 (br. s, 2 H, OH, NH), 1.85–1.35 (m, 15 H, b-
H, c-H, d-H, tBu) ppm. 13C NMR: δ = 172.5 (C-1), 162.9 (C-4Ј),
151.2 (C-2Ј), 143.3 (C-6Ј), 137.7 (Carom.), 128.0, 127.3 (CHarom.),
101.0 (C-5Ј), 81.3 (tBu), 71.8, 70.1 (CH2BOM) 63.2 (C-2), 62.5 (C-
3), 49.3 (C-e), 47.6 (C-a), 29.2 (C-b), 28.3 (C-d), 27.7 (tBu), 23.7
(C-c) ppm. HRMS (ESI): calcd. for C24H36N3O6 [M + H]+
462.2604; found 462.2592.
(CH2BOM), 49.3 (C-1Ј), 44.5 (C-5Ј), 31.7 (C-4Ј), 27.9 (C-2Ј), 23.5
(C-3Ј) ppm. MS (ESI): m/z (%) = 359 (100) [M + Na]+
.
tert-Butyl (S)-3-(Benzyloxy)-2-[5ЈЈ-(3Ј-benzyloxymethyluracil-1Ј-yl)-
pentylamino]propanoate (5a): Caesium carbonate (130 mg,
0.40 mmol) and NaI (160 mg, 1.28 mmol) were added to a solution
of tert-butyl O-benzyl--serine ester (2a)[17] (50 mg, 0.20 mmol)
and 3-(benzyloxymethyl)-1-(5Ј-chloropentyl)uracil (4) (87 mg, tert-Butyl
2-[(S)-N-Fmoc-{5ЈЈ-[3Ј-(benzyloxymethyl)uracil-1Ј-yl]-
0.26 mmol) in DMF (1.3 mL). The reaction mixture was heated at pentylamino}]-3-hydroxypropanoate (6b): DIPEA (0.22 mL,
50 °C for 96 h. The solvent was removed in vacuo. H2O was added
and the aqueous layer was extracted with CH2Cl2. The combined
organic extracts were dried with MgSO4 and concentrated in vacuo.
Flash chromatographic purification (EtOAc, 100%) afforded 5a as
a colourless oil (90 mg, 63%). Rf = 0.22 (EtOAc, 100%). [α]D = –5
1.27 mmol) and FmocCl (214 mg, 0.83 mmol) were added to a
solution of the amine 5b (306 mg, 0.66 mmol) in CH2Cl2 (7 mL)
and the reaction mixture was stirred at room temp. for 2 h. The
solution was concentrated in vacuo. Purification by flash column
chromatography (CH2Cl2/MeOH, 98:2) afforded compound 6b as
a colourless oil (330 mg, 73%). Rf = 0.36 (CH2Cl2/MeOH, 95:5).
1
(c = 1, CH2Cl2). H NMR: δ = 7.36–7.15 (m, 10 H, Harom.), 7.02
(d, J6Ј-5Ј = 7.8 Hz, 1 H, 6Ј-H), 5.62 (d, J5Ј–6Ј = 7.8 Hz, 1 H, 5Ј-H), [α]D = –13 (c = 1, CH2Cl2). 1H NMR (CD3CN, 500 MHz, rotamer
5.43, 4.65 (2s, 4 H, CH2BOM), 4.50, 4.48 (AB, JA–B = 12.1 Hz, 2 H,
mixture): δ = 7.85–7.23 (m, 14 H, 6Ј-H, Harom.), 5.63 (d, J5Ј–6Ј =
CH2 Bn), 3.69–3.53 (m, J3–2 = 5.0 Hz, 4 H, 3-H, e-H), 3.27 (dd, 7.9 Hz, 1 H, 5Ј-H), 5.40 (s, 2 H, CH2BOM), 4.64–4.48 (m, 4 H,
J2–3a = J2–3b = 5.0 Hz, 1 H, H2), 2.70–2.38 (m, 2 H, a-H), 1.93 (br.
s, 1 H, NH), 1.71–1.26 (m, 15 H, b-H, c-H, d-H, tBu) ppm. 13C
NMR: δ = 172.4 (C-1), 163.1 (C-4Ј), 151.5 (C-2Ј), 143.2 (C-6Ј),
CH2BOM, CH2Fmoc), 4.30–4.20 (m, 1 H, CHFmoc), 3.93 (dd, J2–3a
= 7.7, J2–3b = 4.8 Hz, 1 H, 2-H), 3.85–3.54 (m, 4 H, 3-H, e-H), 2.99
(t, J = 3.1 Hz, 1 H, OH), 2.95–2.71 (m, 2 H, a-H), 1.49–1.40 (m, 2
138.1, 138.0 (Carom.), 128.4, 128.3 (CHarom.), 127.7 (CHarom.), 101.6 H, d-H), 1.36 (s, 9 H, tBu), 1.26–1.05 (m, 2 H, b-H), 0.99–0.85 (m,
(C-5Ј), 81.3 (tBu), 73.3 (CH2Bn), 73.3, 70.5 (2 CH2BOM), 71.3 (C-
3), 62.1 (C-2), 49.7 (C-e), 47.9 (C-a), 29.7 (C-b), 28.8 (C-d), 28.2
(tBu), 24.1 (C-c) ppm. HRMS (ESI): calcd. for C31H42N3O6 [M +
H]+ 552.3074; found 552.3074.
2 H, c-H) ppm. 13C NMR (CD3CN, 126 MHz): δ = 169.4 (C-1),
163.1 (C-4Ј), 156.2 (COFmoc), 151.6 (C-2Ј), 143.9, 141.5 138.0
(Carom.), 143.1 (C-6Ј), 128.4, 127.7, 127.2, 124.8, 120.1 (CHarom.),
101.6 (C-5Ј), 82.3 (tBu), 72.3, 70.5 (CH2BOM), 66.8 (CH2Fmoc), 63.3
(C-2), 61.5 (C-3), 49.6 (C-e), 48.8 (C-a), 47.4 (CHFmoc), 28.6 (C-b,
C-d), 28.0 (tBu), 23.6 (c-H) ppm. HRMS (ESI): calcd. for
C39H45N3O8Na [M + Na]+ 706.3104; found 706.3099.
tert-Butyl 3-(Benzyloxy)-2-[(S)-N-Fmoc-{5ЈЈ-[3Ј-(benzyloxymethyl)-
uracil-1Ј-yl]pentylamino}]propanoate (6a): Diisopropylethylamine
(DIPEA) (84 µL, 0.48 mmol) and FmocCl (90 mg, 0.35 mmol) were
added to a solution of the amine 5a (130 mg, 0.24 mmol) in CH2Cl2
(3.5 mL) and the reaction mixture was stirred at room temp. for
3 h. The solution was concentrated in vacuo. Purification by flash
column chromatography (EtOAc/cyclohexane, 1:1) afforded com-
tert-Butyl O-(5Ј-Azido-5Ј-deoxy-2Ј,3Ј-O-isopentylidene-β-
D
-ribos-
-serine
1Ј-yl)-N-Fmoc-N-[5ЈЈ-(N3-benzyloxymethyluracil-1-yl)pentyl]-
L
(9): Molecular sieves (4 Å, 1.3 g) were added to a solution of 6b
(298 mg, 0.50 mmol) and ribosyl fluoride 8[14] (184 mg, 0.75 mmol)
in CH2Cl2 (15 mL). After stirring for 1 h at room temp., boron
pound 6a as a colourless oil (150 mg, 81%). Rf = 0.25 (EtOAc/
1
cyclohexane, 1:1). [α]D = –13 (c = 1, CH2Cl2). H NMR (rotamer trifluoride–diethyl ether (76 µL, 0.6 mmol) was added at –45 °C.
mixture): δ = 7.90–7.22 (m, 19 H, 6Ј-H, Harom.), 5.65 (d, J5Ј–6Ј
7.9 Hz, 1 H, 5Ј-H), 5.41 (s, 2 H, CH2BOM), 4.70–4.53 (m, 4 H,
CH2BOM, CH2Fmoc), 4.47, 4.39 (AB, JA–B = 11.8 Hz, 2 H, CH2 Bn),
=
After allowing to warm to 10 °C over 16 h, the reaction mixture
was diluted with CH2Cl2 (100 mL), filtered through a Celite pad
and washed with a saturated aqueous solution of sodium hydrogen
4.33–4.15 (m, 2 H, 2-H, CHFmoc), 3.84–3.70 (m, 2 H, 3-H), 3.59 (t, carbonate (30 mL). The organic layer was dried with MgSO4 and
Je–d = 7.6 Hz, 2 H, e-H), 3.00–2.69 (m, 2 H, a-H), 1.47–1.01 (m, concentrated in vacuo. Flash column chromatography (cyclohex-
13 H, d-H, b-H, tBu), 1.00–0.80 (m, 2 H, c-H) ppm. 13C NMR
ane/EtOAc, 6:4) afforded a β/α anomer mixture (9:1) of glycosyl-
(CD3CN): δ = 169.5 (C-1), 164.0 (C-4Ј), 156.7 (COFmoc), 152.6 (C- ated product 9 (67%) from which anomer β could be isolated as a
2Ј), 145.2 (C-6Ј, CFmoc), 142.3 (CFmoc), 139.5, 139.3 (Carom.), 129.3, pure compound (220 mg, 46%). Rf = 0.4 (cyclohexane/EtOAc, 1:1).
129.2, 128.6, 128.5, 128.1, 125.5, 121.0 (CHarom.), 101.5 (C-5Ј), 82.1 [α]D = –27 (c = 1, CH2Cl2). 1H NMR (CD3CN, 500 MHz): δ =
(tBu), 73.6 (C-4), 72.5, 71.3 (CH2BOM), 69.3 (C-3), 67.1 (CH2Fmoc), 7.90–7.22 (m, 14 H, 6-H, Harom.), 5.57 (d, J5–6 = 7.8 Hz, 1 H, 5-
5390
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5386–5394

Towards New MraY Inhibitors
H), 5.40 (s, 2 H, CH2 BOM), 5.06 (s, 1 H, 1Ј-H), 4.69–4.46 (m, 7.20 (d, J6Ј–5Ј = 7.8 Hz, 1 H, 6Ј-H), 5.70 (d, J5Ј–6Ј = 7.8 Hz, 1 H,
JCH2–CHFmoc = 5, J2Ј–3Ј = 6 Hz, 6 H, 2Ј-H, 3Ј-H, CH2 Fmoc
CH2 BOM), 4.35–4.21 (m, JCH–CH2 Fmoc = 7.2 Hz, 2 H, 4Ј-H,
,
5Ј-H), 3.78 (dd, J3a–3b = 10.8, J3a–2 = 4.4 Hz, 1 H, 3a-H), 3.73 (t,
Je–d = 7.4 Hz, 2 H, e-H), 3.57 (dd, J3b–3a = 10.8, J3b–2 = 6.4 Hz, 1
CHFmoc), 4.07–4.02 (m, 1 H, 2ЈЈ-H), 3.91 (dd, J3ЈЈa–3ЈЈb = 10.6, H, 3b-H), 3.25 (dd, J2–3b = 6.4, J2–3a = 4.4 Hz, 1 H, 2-H), 2.78–
J3ЈЈa–2ЈЈ = 8.4 Hz, 1 H, 3ЈЈa-H), 3.78 (dd, J3ЈЈb–3ЈЈa = 10.6, J3ЈЈb–2ЈЈ
4.7 Hz, 1 H, 3ЈЈb-H), 3.71–3.55 (m, 2 H, e-H), 3.28 (dd, J5Јa–5Јb
=
=
2.47 (m, 2 H, a-H), 1.80–1.30 (m, 15 H, b-H, c-H, d-H, tBu) ppm.
13C NMR: δ = 172.5 (C-1), 164.6 (C-4Ј), 151.2 (C-2Ј), 144.6 (C-6Ј),
12.5, J5Јa–4Ј = 7.9 Hz, 1 H, 5Јa-H), 3.15 (dd, J5Јb–5Јa = 12.5, J5Јb–4Ј 102.4 (C-5Ј), 82.1 (tBu), 63.5 (C-2), 62.8 (C-3), 48.9 (C-e), 48.0 (C-
= 6.4 Hz, 1 H, 5Јb-H), 2.97–2.70 (m, 2 H, a-H), 1.72–1.42 (m, 6
H, 2 CH2CH3, d-H), 1.38, 1.35, 1.34 (s, 9 H, tBu), 1.18–1.05 (m, 2
H, b-H), 1.02–0.76 (m, 6 H, 2 CH2CH3, c-H) ppm. 13C NMR
(CD3CN, 126 MHz): δ = 169.2 (C-1ЈЈ), 164.0 (C-4), 156.4
(COFmoc), 152.6 (C-2), 145.3 (C-6, Carom.), 142.3, 139.5 (Carom.),
129.2, 128.6, 128.4, 128.1, 125.5, 120.9 (CHarom.), 117.4
[C(CH2CH3)2], 109.4 (C-1Ј), 101.5 (C-5), 86.5 (C-4Ј), 86.3 (C-2Ј),
83.2 (C-3Ј), 82.3 (tBu), 72.5, 71.2 (CH2BOM), 67.4 (CH2Fmoc), 66.4
(C-3ЈЈ), 61.6 (C-2ЈЈ), 54.0 (C-5Ј), 50.1 (C-e), 49.3 (C-a), 48.1
(CHFmoc), 30.0, 29.5 (CH2CH3), 29.3 (C-d), 29.0 (C-b), 28.2 (tBu),
24.3 (C-c), 8.7, 7.7 (CH2CH3) ppm. HRMS (ESI): calcd. for
C49H60N6O11Na [M + Na]+ 931.4218; found 931.4238.
a), 29.7 (C-b), 29.0 (C-d), 28.3 (tBu), 24.1 (C-c) ppm. HRMS (ESI):
calcd. for C16H28N3O5 [M + H]+ 342.2029; found 342.2052.
(S)-3-Hydroxy-2-[5ЈЈ-(uracil-1Ј-yl)pentylamino]pentanoic Acid (14):
TFA (0.3 mL) was added to a solution of the amino acid ester 13
(41 mg, 0.12 mmol) in CH2Cl2 (1.5 mL) and the reaction mixture
was stirred at room temp. for 16 h. The solution was concentrated
in vacuo. After purification by C18 reversed-phase column
chromatography (100% H2O), compound 14 was obtained as a hy-
groscopic white solid (40 mg, 83 %). Rf = 0.4 (100 % H2O). 1H
NMR (CD3OD): δ = 7.58 (d, J6Ј-5Ј = 7.8 Hz, 1 H, 6Ј-H), 5.66 (d,
J5Ј–6Ј = 7.8 Hz, 1 H, 5Ј-H), 4.10–3.90 (m, 3 H, 2-H, 3-H), 3.77 (t,
Je–d = 7.2 Hz, 2 H, e-H), 3.09 (m, 2 H, a-H), 1.85–1.65 (m, 4 H,
b-H, d-H), 1.50–1.30 (m, 2 H, c-H) ppm. 13C NMR (CD3OD): δ
= 170.3 (C-1), 166.7 (C-4Ј), 152.9 (C-2Ј), 147.2 (C-6Ј), 102.3 (C-
5Ј), 63.1 (C-2), 59.8 (C-3), 49.1 (C-e), 47.3 (C-a), 29.3 (C-b), 26.6
(C-d), 24.3 (C-c) ppm.
1-(5Ј-Iodopentyl)uracil (12): A solution of 1-(5Ј-bromopentyl)uracil
(3) (3.1 g, 11.9 mmol) and sodium iodide (8.9 g, 59.3 mmol) in ace-
tone (190 mL) was heated at 55 °C for 3 h. The solvent was then
removed in vacuo. The residue was taken up in EtOAc (100 mL)
and washed with 10% aqueous NaHCO3 (100 mL). The aqueous
layer was extracted with EtOAc (2ϫ100 mL). The combined or-
ganic phases were washed with H2O (100 mL), dried with MgSO4
and concentrated in vacuo. Purification by flash column
chromatography with CH2Cl2/MeOH (95:5) afforded compound 12
as a white solid (2.4 g, 65%). Rf = 0.30 (CH2Cl2/MeOH, 95:5).
1-[5Ј-(tert-Butyldiphenylsilyloxy)pentyl]uracil (15): Uracil (11.05 g,
38.7 mmol) and caesium carbonate (23.3 g, 71.5 mmol) were stirred
in dry DMF (450 mL) at room temp. for 15 min. Then 5-(tert-bu-
tyldiphenylsilyloxy)pentyl methanesulfonate[18] (27.6 g, 65.8 mmol)
in dry DMF (50 mL) was added and the reaction mixture was
heated at 50 °C for 24 h. Water (300 mL) was added and the or-
ganic layer was extracted with EtOAc (3ϫ300 mL) and dried with
MgSO4. After concentration in vacuo and purification by flash col-
umn chromatography with CH2Cl2/MeOH (95:5), compound 15
was obtained as a colourless oil (19.2 g, 67%). Rf = 0.41 (CH2Cl2/
1
M.p. 88–90 °C. H NMR: δ = 8.37 (br. s, 1 H, NH), 7.10 (d, J6–5
= 7.9 Hz, 1 H, 6-H), 5.66 (dd, J5–6 = 7.9, J5–3 = 2.3 Hz, 1 H, 5-H),
3.70 (t, J1Ј–2Ј = 7.3 Hz, 2 H, 1Ј-H), 3.15 (t, J5Ј–4Ј = 6.8 Hz, 2 H, 5Ј-
H), 1.90–1.60 (m, 4 H, 2Ј-H, 4Ј-H), 1.50–1.35 (m, 2 H, 3Ј-H) ppm.
13C NMR: δ = 164.4 (C-4), 151.1 (C-2), 144.6 (C-6), 102.3 (C-5),
48.6 (C-1Ј), 32.7 (C-4Ј), 27.9 (C-2Ј), 27.2 (C-3Ј), 6.5 (C-5Ј) ppm.
HRMS (ESI): calcd. for C9H14N2O2I [M + H]+ 309.0100; found
309.0118.
1
MeOH, 95:5). H NMR: δ = 8.40 (br. s, 1 H, NH), 7.65–7.30 (m,
10 H, Harom.), 7.05 (d, J6–5 = 7.9 Hz, 1 H, 6-H), 5.64 (d, J5–6
=
7.9 Hz, 1 H, 5-H), 3.67 (t, J1Ј–2Ј = 6.6 Hz, 2 H, 1Ј-H), 3.64 (t,
J5Ј–4Ј = 6.1 Hz, 2 H, 5Ј-H), 1.75–1.50 (m, 4 H, 2Ј-H, 4Ј-H), 1.45–
1.30 (m, 2 H, 3Ј-H), 1.02 (s, 9 H, tBu) ppm. 13C NMR: δ = 164.3
(C-4), 151.1 (C-2), 144.6 (C-6), 135.6, 129.7, 127.7 (CHarom.), 134.0
(Carom.), 63.5 (C-5Ј), 48.9 (C-1Ј), 32.0 (C-4Ј), 28.8 (C-2Ј), 26.9
(tBu), 22.8 (C-3Ј), 19.3 (tBu) ppm. HRMS (ESI): calcd. for
C25H32N2O3NaSi [M + Na]+ 459.2080; found 459.2067.
tert-Butyl (S)-3-Hydroxy-2-[5ЈЈ-(uracil-1Ј-yl)pentylamino]propano-
ate (13): From 1-(5Ј-iodopentyl)uracil (12): K2CO3 (52 mg,
0.38 mmol) was added to a solution of -serine ester 2b (54 mg,
0.33 mmol) and 1-(5Ј-iodopentyl)uracil (12) (59 mg, 0.19 mmol) in
CH3CN (1.5 mL). The reaction mixture was heated at 60 °C for
30 h. The solvent was removed in vacuo. H2O was added and the
aqueous layer was extracted with CH2Cl2. The combined organic
extracts were dried with MgSO4 and concentrated in vacuo prior
to flash chromatographic purification (CH2Cl2 /MeOH,
98:2Ǟ95:5) affording 13 as colourless oil (30 mg, 43%).
1-(5Ј-Hydroxypentyl)uracil (16): A 37% solution of HCl (1.65 mL)
was added to a solution of silyl ether 15 (3.7 g, 8.47 mmol) in
MeOH (13 mL) . The reaction mixture was stirred at room temp.
for 4 h. The solvent was concentrated in vacuo and the crude prod-
uct was purified by flash column chromatography with CH2Cl2/
MeOH (95:5). Alcohol 16 was obtained as a white solid (1.3 g,
77%). Rf = 0.18 (CH2Cl2/MeOH, 90:10). M.p. 78–80 °C. 1H NMR:
δ = 9.19 (br. s, 1 H, NH), 7.12 (d, J6–5 = 7.9 Hz, 1 H, 6-H), 5.65
(d, J5–6 = 7.9 Hz, 1 H, 5-H), 3.70 (t, J1Ј–2Ј = 7.1 Hz, 2 H, 1Ј-H),
3.61 (t, J5Ј–4Ј = 6.0 Hz, 2 H, 5Ј-H), 1.80–1.50 (m, 4 H, 2Ј-H, 4Ј-H),
1.45–1.30 (m, 2 H, 3Ј-H) ppm. 13C NMR: δ = 164.6 (C-4), 151.4
(C-2), 145.0 (C-6), 102.1 (C-5), 61.9 (C-5Ј), 48.7 (C-1Ј), 32.0 (C-
4Ј), 28.8 (C-2Ј), 22.6 (C-3Ј) ppm. HRMS (ESI): calcd. for
C9H14N2O3Na [M + Na]+ 221.0902; found 221.0910.
From 5-(Uracil-1Ј-yl)pentanal (17): Serine ester 2b (800 mg,
4.97 mmol) in THF (35 mL) was added to a solution of the alde-
hyde 17 (974 mg, 4.97 mmol) in THF (35 mL) in the presence of
4 Å molecular sieves. The reaction mixture was stirred at room
temp. for 24 h then cooled to 0 °C. Sodium triacetoxyborohydride
(3.16 g, 14.91 mmol) was added and the heterogeneous reaction
mixture was stirred at room temp. for 40 h. After filtration through
a Celite pad, the solvent was removed in vacuo. The residue was
diluted with CH2Cl2/MeOH (95:5, 100 mL) and washed with 10%
aq. Na2CO3 (50 mL). The aqueous layer was extracted with
CH2Cl2/MeOH (95:5, 2ϫ50 mL). The combined organic extracts
were dried with MgSO4 and concentrated in vacuo. Purification by
flash column chromatography with CH2Cl2/MeOH (95:5) as eluent
5-(Uracil-1Ј-yl)pentanal (17): Dess–Martin periodinane (3 g,
7.07 mmol) was added to a solution of 1-(5Ј-hydroxypentyl)uracil
(16) (1.3 g, 6.56 mmol) in CH2Cl2 (140 mL). The resulting hetero-
geneous mixture was stirred at room temp. for 75 min. After di-
lution with CH2Cl2 (200 mL), a saturated aqueous NaHCO3 solu-
afforded compound 13 as a colourless oil (1.2 g, 71%). Rf = 0.22
1
(CH2Cl2/MeOH, 95:5). [α]D = –16 (c = 1, CH2Cl2). H NMR: δ = tion (120 mL) and Na2S2O3 (18.8 g, 118.9 mmol) were added and
Eur. J. Org. Chem. 2007, 5386–5394
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5391

L. Le Corre, C. Gravier-Pelletier, Y. Le Merrer
FULL PAPER
the resulting biphasic solution was stirred at room temp. for
30 min. The organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (5ϫ200 mL). After drying with MgSO4 and
concentrating in vacuo, the product was purified by flash column
chromatography with CH2Cl2/MeOH (95:5) as eluent. The alde-
hyde 17 was obtained as a white solid (1 g, 77 %). Rf = 0.23
(CH2Cl2/MeOH, 90:10). M.p. 82–84 °C. 1H NMR: δ = 9.72 (s, 1
H, 1-H), 9.29 (br. s, 1 H, NH), 7.12 (d, J6Ј–5Ј = 7.8 Hz, 1 H, 6Ј-H),
(ESI): calcd. for C41H52N6O10Na [M + Na]+ 811.3643; found
811.3610.
tert-Butyl N-(Fluorenylmethoxycarbonyl)serine Ester (20): A solu-
tion of tert-butyl trichloroacetimidate (14.5 g) in cyclohexane
(70 mL) was added to a solution of N-Fmoc-serine (5.43 g,
16.6 mol) in ethyl acetate (150 mL) and the mixture was stirred at
room temp. for 24 h. Concentration in vacuo and purification by
column chromatography with cyclohexane/EtOAc (7:3 to 6:4) af-
forded 20 as a white solid (5.76 g, 90%). Rf = 0.27 (cyclohexane/
5.66 (dd, J5Ј–6Ј = 7.8, J5Ј–3Ј = 2.2 Hz, 1 H, 5Ј-H), 3.70 (t, J5–4
=
6.8 Hz, 2 H, 5-H), 2.49 (t, J2–3 = 6.0 Hz, 2 H, 2-H), 1.80–1.50 (m,
4 H, 3-H, 4-H) ppm. 13C NMR: δ = 202.0 (C-1), 164.6 (C-4Ј), 151.3
(C-2Ј), 144.8 (C-6Ј), 102.2 (C-5Ј), 48.4 (C-5), 43.0 (C-2), 28.3 (C-
4), 18.7 (C-3) ppm. HRMS (ESI): calcd. for C9H12N2O3Na [M +
Na]+ 219.0746; found 219.0769.
1
EtOAc, 6:4). [α]D = +2 (c = 1, CH2Cl2). M.p. 130 °C. H NMR: δ
= 7.81–7.21 (m, 8 H, Harom.), 5.78 (d, JNH–2 = 5.7 Hz, 1 H, NH),
4.45 (d, 2 H, JC H 2 – C H F m o c = 6.9 Hz, CH2 F mo c), 4.25 (t,
JCH–CH2Fmoc = 6.9 Hz, 1 H, CHFmoc), 3.98–3.94 (m, 2 H, 3-H),
1.52 (s, 9 H, tBu) ppm. 13C NMR: δ = 170.0 (C-1), 156.8 (COFmoc),
144.1, 141.7 (Carom.), 128.1, 127.5, 125.5, 120.4 (CHarom.), 83.3
(tBu), 67.6 (CH2Fmoc), 64.0 (C-3), 57.1 (C-2), 47.5 (CHFmoc), 28.4
(tBu) ppm. HRMS (ESI+): calcd. for C22H26NO5 [M + H]+
401.2076; found 401.2079.
tert-Butyl (S)-3-Hydroxy-2-{N-Fmoc-[(5ЈЈ-uracil-1Ј-yl)-
pentylamino]}propanoate (18): DIPEA (70 µL, 0.41 mmol) and
FmocCl (97 mg, 0.37 mmol) were added to a solution of the amine
13 (103 mg, 0.3 mmol) in CH2Cl2 (3.5 mL) and the reaction mix-
ture was stirred at room temp. for 2 h. The solution was concen-
trated in vacuo. Purification by flash column chromatography
(CH2Cl2/MeOH, 95:5) afforded compound 18 as a white solid
(121 mg, 71%). Rf = 0.32 (CH2Cl2/MeOH, 95:5). [α]D = –8.4 (c =
1, CH2Cl2). 1H NMR (CD3CN, 350 K): δ = 7.90–7.27 (m, 9 H, 6Ј-
H, Harom.), 5.66 (d, J5Ј–6Ј = 7.8 Hz, 1 H, 5Ј-H), 4.70–4.45 (m, 2 H,
CH2Fmoc), 4.34–4.24 (m, 1 H, CHFmoc), 4.15–4.01 (m, 1 H, 2-H),
3.90 (dd, J3a–3b = 11.3, J3a–2 = 4.3 Hz, 1 H, 3a-H), 3.80–3.68 (m, 1
H, 3b-H), 3.66 (t, Je–d = 6.7 Hz, 2 H, e-H), 3.25–2.75 (m, 2 H, a-
H), 1.65–1.50 (m, 2 H, d-H), 1.44 (s, 9 H, tBu), 1.45–1.30 (m, 2 H,
b-H), 1.20–1.05 (m, 2 H, c-H) ppm. 13C NMR (CD3CN): δ = 170.0
(C-1), 165.1 (C-4Ј), 156.9 (COFmoc), 152.1 (C-2Ј), 146.6 (C-6Ј),
145.3, 142.3 (Carom.), 128.6, 128.1, 125.6, 120.9 (CHarom.), 101.9 (C-
5Ј), 82.1 (tBu), 67.1 (CH2Fmoc), 64.1 (C-2), 61.2 (C-3), 49.1 (C-a, C-
e), 48.2 (CHFmoc), 29.3, 29.1 (C-b, C-d), 28.2 (tBu), 24.3 (c-H) ppm.
HRMS (ESI): calcd. for C31H37N3O7Na [M + Na]+ 586.2529;
found 586.2504.
5-Azido-1-O-(tert-butyl N-fluorenylmethoxycarbonyl-L-serin-3Ј-yl)-
5-deoxy-2,3-O-(isopentylidene)-β- -ribofuranose (21): Molecular si-
D
eves (4 Å, 2 g) were added to a solution of tert-butyl N-Fmoc--
serine ester (20)[17] (318 mg, 0.83 mmol) and ribosyl fluoride 8[14]
(300 mg, 1.22 mmol) in CH2Cl2 (25 mL). After stirring for 2 h at
room temp., boron trifluoride–diethyl ether (125 µL, 0.99 mmol)
was added at –45 °C. After allowing the mixture to warm up to
room temp. over 65 h, the reaction mixture was filtered through
a Celite pad. A saturated aqueous solution of sodium hydrogen
carbonate (20 mL) was then added and the aqueous layer was ex-
tracted with CH2Cl2 (3ϫ40 mL). The organic layer was dried with
MgSO4 and concentrated in vacuo. Purification by flash column
chromatography with cyclohexane/EtOAc (90:10) as eluent af-
forded the glycosylated compound 21 as a white solid (140 mg,
28 %). Rf = 0.29 (cyclohexane/EtOAc, 8:2). [α]D = –8.4 (c = 1,
1
CH2Cl2). H NMR: δ = 7.84–7.31 (m, 8 H, Harom.), 5.58 (d, JNH–
= 8.4 Hz, 1 H, NH), 5.14 (s, 1 H, 1Ј-H), 4.70 (d, J2Ј–3Ј = 5.9 Hz,
2
tert-Butyl O-(5Ј-Azido-5Ј-deoxy-2Ј,3Ј-O-isopentylidene-
D-ribos-1Ј-
1 H, 2Ј-H), 4.61 (d, J3Ј–2Ј = 5.9 Hz, 1 H, 3Ј-H), 4.55–4.41 (m, 3 H,
H2, CH2Fmoc), 4.35 (dd, J4Ј–5Јa = J4Ј–5Јb = 7.5 Hz, 1 H, 4Ј-H), 4.27
(dd, JCH–CH2Fmoc = 7 Hz, 1 H, CHFmoc), 4.13 (dd, J3a–3b = 10.0,
J3a–2 = 3.1 Hz, 1 H, 3a-H), 3.67 (dd, J3b–3a = 10.0, J3b–2 = 3.1 Hz,
1 H, 3b-H), 3.42 (dd, J5Јa–5Јb = 12.5, J5Јa–4Ј = 7.5 Hz, 1 H, 5Јa-H),
3.20 (dd, J5Јb–5Јa = 12.5, J5Јb–4Ј = 7.3 Hz, 1 H, 5Јb-H), 1.80–1.55
(m, 4 H, 2 CH2CH3), 1.46 (m, 9 H, tBu), 1.00–0.80 (m, 6 H, 2
CH2CH3) ppm. 13C NMR: δ = 169.0 (C-1), 156.0 (COFmoc), 144.0,
143.9, 141.4 (Carom.), 127.8, 127.2, 125.3, 120.1 (CHarom.), 117.3
[C(CH2CH3)2], 109.7 (C-1Ј), 85.8 (C-4Ј), 85.5 (C-2Ј), 82.9 (tBu),
82.4 (C-3Ј), 68.6 (C-3), 67.2 (CH2Fmoc), 54.6 (C-2), 53.5 (C-5Ј), 47.3
(CHFmoc), 29.5, 29.0 (2 CH2CH3), 28.2 (tBu), 8.5, 7.5 (2
CH2CH3) ppm. HRMS (ESI): calcd. for C32H40N4O8Na [M +
Na]+ 631.2744; found 631.2759.
yl)-N-Fmoc-N-(5ЈЈ-uracil-1-ylpentyl)- -serine Ester (19): Molecular
L
sieves (4 Å, 280 mg) were added to a solution of 18 (51 mg,
0.11 mmol) and ribosyl fluoride 8[14] (39 mg, 1.22 mmol) in CH2Cl2
(3 mL). After stirring for 2 h at room temp., boron trifluoride–di-
ethyl ether (15 µL, 0.12 mmol) was added at –45 °C. After allowing
the mixture to warm to 10 °C over 18 h, the reaction mixture was
diluted with CH2Cl2 (30 mL), filtered through a Celite pad and
washed with a saturated aqueous solution of sodium hydrogen car-
bonate (10 mL). The organic layer was dried with MgSO4 and con-
centrated in vacuo. Flash column chromatography (CH2Cl2/
MeOH, 99:1) afforded an inseparable (5:1) β/α anomer mixture of
glycosylated product 19 (71%). Rf = 0.17 (CH2Cl2/MeOH, 97:3).
1H NMR (CD3CN, 350 K): δ = 8.79 (br. s, 1 H, NHCO), 7.90–7.22
(m, 9 H, 6-H, Harom.), 5.57 (d, J5–6 = 7.8 Hz, 1 H, 5-H), 5.01 (s, 1
H, 1Ј-H), 4.75–4.45 (m, 4 H, 2Ј-H, 3Ј-H, CH2Fmoc), 4.35–4.21 (m,
5-Azido-1-O-(tert-butyl
L-serin-3Ј-yl)-5-deoxy-2,3-O-(isopentylid-
2 H, 4Ј-H, CHFmoc), 4.14 (m, 1 H, 2ЈЈ-H), 4.01–3.74 (m, 2 H, 3ЈЈ- ene)-β-
D
-ribofuranose (22): Piperidine (0.52 mL, 5.34 mmol) was
H), 3.66 (t, Je–d = 7.2 Hz, 2 H, e-H), 3.35 (dd, J5Јa–5Јb = 12.3,
J5Јa–4Ј = 7.8 Hz, 1 H, 5Јa-H), 3.26 (dd, J5Јb–5Јa = 12.3, J5Јb–4Ј
added to a solution of compound 21 (330 mg, 0.54 mmol) in DMF
(3.5 mL) . After stirring for 2 h at room temp., the reaction mixture
=
7.1 Hz, 1 H, 5Јb-H), 3.18–2.80 (m, 2 H, a-H), 1.79–1.50 (m, 6 H, was concentrated in vacuo. Purification by column chromatography
2 CH2CH3, d-H), 1.49–1.24 (m, 11 H, b-H, tBu), 1.23–1.02 (m, 2
with CH2Cl2/MeOH/NEt3 (97:3:0.001) as eluent afforded the
H, c-H), 1.00–0.82 (m, 6 H, 2 CH2CH3) ppm. 13C NMR: δ = 168.3 amine 22 as a colourless oil (195 mg, 93%). Rf = 0.21 (CH2Cl2/
1
(C-1ЈЈ), 163.9 (C-4), 156.0 (COFmoc), 144.6, 144.5 (Carom.), 144.1
MeOH/NEt3, 97:3:0.001). [α]D = –36 (c = 1, CH2Cl2). H NMR: δ
(C-6), 141.6 (Carom.), 127.9, 127.2, 124.8, 120.1, (CHarom.), 117.4 = 5.14 (s, 1 H, 1Ј-H), 4.67 (d, J2Ј–3Ј = 6.0 Hz, 1 H, 2Ј-H), 4.60 (d,
(tBu), 108.9 (C-1Ј), 102.2 (C-5), 85.7 (C-4Ј), 85.6 (C-2Ј), 82.5 (C- J3Ј–2Ј = 6.0 Hz, 1 H, 3Ј-H), 4.33 (dd, J4Ј–5Јa = 7.1, J4Ј–5Јb = 7.8 Hz,
3Ј), 82.3 (tBu), 67.6 (C-3ЈЈ), 66.9 (CH2Fmoc), 60.8 (C-2ЈЈ), 53.5 (C-
5Ј), 48.8 (C-a, C-e), 47.5 (CHFmoc), 29.6 (CH2CH3, C-d), 29.0 (C-b,
1 H, 4Ј-H), 3.95 (dd, J3a–3b = 9.7, J3a–2 = 5.0 Hz, 1 H, 3a-H), 3.62
(dd, J3b–3a = 9.7, J3b–2 = 4.0 Hz, 1 H, 3b-H), 3.51 (dd, J2–3a = 5.0,
CH2CH3), 28.2 (tBu), 23.7 (C-c), 8.6, 7.6 (2 CH2CH3) ppm. HRMS J2–3b = 4.0 Hz, 1 H, 2-H), 3.45 (dd, J5Јa–5Јb = 12.5, J5Јa–4Ј = 7.7 Hz,
5392
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Eur. J. Org. Chem. 2007, 5386–5394

Towards New MraY Inhibitors
1 H, 5Јa-H), 3.21 (dd, J5Јb–5Јa = 12.5, J5Јb–4Ј = 7.1 Hz, 1 H, 5Јb-H),
(C-1Ј), 102.0 (C-5), 89.9 (C-4Ј), 86.6 (C-2Ј), 83.5 (C-3Ј), 81.8 (tBu),
1.90–1.76 (br. s, 1 H, NH2), 1.69 (q, J = 7.5 Hz, 2 H, CH2CH3), 69.9 (C-3ЈЈ), 62.8 (C-2ЈЈ), 48.9 (C-e), 48.3 (C-a), 45.9 (C-5Ј), 30.3,
1.57 (q, J = 7.5 Hz, 2 H, CH2CH3), 1.47 (m, 9 H, tBu), 0.91 (t, J
= 7.4 Hz, 3 H, CH2CH3), 0.87 (t, J = 7.4 Hz, 3 H, CH2CH3) ppm.
13C NMR: δ = 172.7 (C-1), 117.2 [C(CH2CH3)2], 109.5 (C-1Ј), 85.9
(C-4Ј), 85.5 (C-2Ј), 82.4 (C-3Ј), 81.7 (tBu), 70.5 (C-3), 55.1 (C-2),
53.6 (C-5Ј), 29.5 (2 CH2CH3), 28.9, 28.0 (tBu), 8.4, 7.4 (2
CH2CH3) ppm. HRMS (ESI): calcd. for C17H31N4O6 [M + H]+
387.2244; found 387.2231.
30.0, 29.5, (C-b, C-d, CH2CH3), 28.3 (tBu), 24.6 (C-c), 8.8, 7.7 (2
CH2CH3) ppm. HRMS (ESI): calcd. for C26H44N4O8Na [M +
Na]+ 563.3057; found 563.3063.
O-(5Ј-Amino-5Ј-deoxy-β-D-ribos-1Ј-yl)-N-(5ЈЈ-uracil-1-ylpentyl)-L-
erine (1): ЈTFA (0.3 mL) was added to the amino compound 24
(70 mg, 0.13 mmol) in CH2Cl2 (1.5 mL). After stirring for 24 h at
room temp., the reaction mixture was concentrated in vacuo. The
oily residue was diluted in a 3:1 mixture of THF/H2O (1.5 mL),
TFA (1 mL) was added and the mixture was stirred at room temp.
for 24 h. Concentration in vacuo and purification by C18 reversed-
phase column chromatography (MeOH/H2O, 1:1) afforded the tar-
get compound 1 as a white solid (40 mg, 48%). Rf = 0.18 (MeOH/
H2O, 1:1). [α]365nm = –5 (c = 1, H2O). 1H NMR (CD3OD): δ =
7.59 (d, J6–5 = 7.9 Hz, 1 H, 6-H), 5.67 (d, J5–6 = 7.9 Hz, 1 H, 5-
H), 4.92 (s, 1 H, 1Ј-H), 4.32 (dd, J3ЈЈa–3ЈЈb = 10.7, J3ЈЈa–2ЈЈ = 2.5 Hz,
1 H, 3ЈЈa-H), 4.19–3.95 (m, 3 H, 2Ј-H, 3Ј-H, 4Ј-H), 3.93–3.63 (m,
J3ЈЈb–3ЈЈa = 10.7, J3ЈЈb–2ЈЈ = 2.5, Je–d = 6.9 Hz, 4 H, 3ЈЈb-H, e-H, 2ЈЈ-
H), 3.22 (d, J5Јa–5Јb = 12.1 Hz, 1 H, 5Ј-H), 3.15–2.95 (m, 3 H, 5Јb-
H, a-H), 1.89–1.62 (m, 4 H, b-H, d-H), 1.52–1.33 (m, 2 H, c-
H) ppm. 13C NMR (CD3CN): δ = 171.5 (C-1ЈЈ); 166.7 (C-4), 163.0
(q, 2JC–F = 35 Hz, COCF3), 152.9 (C-2), 147.3 (C-6), 118.2 (q, 1JC–
tert-Butyl O-(5Ј-Azido-5Ј-deoxy-2Ј,3Ј-O-isopentylidene-β-
D-ribos-
1Ј-yl)-N-(5ЈЈ-uracil-1-ylpentyl)- -serine Ester (23): A solution of the
L
amine 22 (114 mg, 0.30 mmol) in THF (2.5 mL) and Na2SO4
(920 mg, 6.48 mmol) were successively added to a solution of the
aldehyde 17 (64 mg, 0.33 mmol) in THF (2.5 mL). After stirring
for 21 h at room temp., sodium triacetoxyborohydride was added
and the heterogeneous mixture was stirred at room temp. over 24 h.
After filtration through a Celite pad and elution with CH2Cl2
(30 mL), the organic layer was washed with a saturated aqueous
solution of sodium carbonate (15 mL). The aqueous layer was ex-
tracted with CH2Cl2 (15 mL). After drying with MgSO4 and con-
centration in vacuo, the oily residue was purified by column
chromatography with CH2Cl2/MeOH/NEt3 (95:5:0.001) as eluent
to afford 23 as a colourless oil (108 mg, 65%). Rf = 0.19 (CH2Cl2/
= 293 Hz, COCF3), 108.6 (C-1Ј), 102.4 (C-5), 80.4 (C-4Ј), 76.0
F
1
MeOH/NEt3, 95:5:0.001). [α]D = –26 (c = 1, CH2Cl2). H NMR: δ
(C-2Ј), 74.1 (C-3Ј), 65.8 (C-3ЈЈ), 62.8 (C-2ЈЈ), 49.1 (C-e), 47.8 (C-
a), 44.2 (C-5Ј), 29.4 (C-d), 26.5 (C-b), 24.4 (C-c) ppm. HRMS
(ESI): calcd. for C17H29N4O8 [M – CF3CO2H + H]+ 417.1985;
found 417.1989.
= 7.14 (d, J6–5 = 7.9 Hz, 1 H, 6-H), 5.67 (d, J5–6 = 7.9 Hz, 1 H, 5-
H), 5.0 (s, 1 H, 1Ј-H), 4.63 (d, J2Ј–3Ј = 6.0 Hz, 1 H, 2Ј-H), 4.57 (d,
J3Ј–2Ј = 6.0 Hz, 1 H, 3Ј-H), 4.30 (dd, J4Ј–5Јa = J4Ј–5Јb = 7.6 Hz, 1 H,
4Ј-H), 3.87 (dd, J3ЈЈa–3ЈЈb = 9.8, J3ЈЈa–2ЈЈ = 4.8 Hz, 1 H, 3ЈЈa-H), 3.70
(t, Je–d = 7.2 Hz, 2 H, e-H), 3.54 (dd, J3ЈЈb–3ЈЈa = 9.8, J3ЈЈb–2ЈЈ
=
5.0 Hz, 1 H, 3ЈЈb-H), 3.44 (dd, J5Јa–5Јb = 12.5, J5Јa–4Ј = 7.8 Hz, 1
H, 5Јa-H), 3.25 (dd, J2ЈЈ–3ЈЈa = 4.8, J2ЈЈ–3ЈЈb = 5.0 Hz, 1 H, 2ЈЈ-H),
3.21 (dd, J5Јb–5Јa = 12.5, J5Јb–4Ј = 7.0 Hz, 1 H, 5Јb-H), 2.72–2.41
(m, 2 H, a-H), 1.77–1.62 (m, 4 H, d-H, CH2CH3), 1.61–1.49 (m, 4
H, b-H, CH2CH3), 1.46 (m, 9 H, tBu), 1.45–1.30 (m, 1 H, c-H),
0.92 (t, J = 7.4 Hz, 3 H, CH2 CH3 ), 0.89 (t, J = 7.6 Hz,
CH2CH3) ppm. 13C NMR (CDCl3, 63 MHz, 300 K): δ = 172.2 (C-
1ЈЈ), 164.1 (C-4), 151.0 (C-2), 144.5 (C-6), 117.2 (C[CH2CH3]2),
109.4 (C-1Ј), 102.2 (C-5), 85.9 (C-4Ј), 85.5 (C-2Ј), 82.4 (C-3Ј), 81.8
(C[CH3]3), 69.3 (C-3ЈЈ), 61.8 (C-2ЈЈ), 53.6 (C-5Ј), 48.8 (C-e), 47.8
(C-a), 29.8 (C-b), 29.5 (C[CH2CH3]2), 29.0 (C-d, C[CH2CH3]2),
28.2 (tBu), 24.1 (C-c), 8.5, 7.5 (2 CH2CH3) ppm. HRMS (ESI):
calcd. for C26H43N6O8 [M + H]+ 567.3142; found 567.3167.
Acknowledgments
We gratefully acknowledge the European Community for financial
support through the Eur-INTAFAR integrated project within the
Sixth Research Framework Programme (contract number LSHM-
CT-2004-512138).
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1Ј-yl)-N-(5ЈЈ-uracil-1-ylpentyl)- -serine Ester (24): 1,2-Bis(diphenyl-
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phosphanyl)ethane (34 mg, 0.09 mmol) was added to the azido de-
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24 as a colourless oil (70 mg, 84%). Rf = 0.21 (CH2Cl2/MeOH/
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H, 3ЈЈa-H), 3.72 (t, Je–d = 7.2 Hz, 2 H, e-H), 3.55 (dd, J3ЈЈb–3ЈЈa
9.7, J3ЈЈb–2ЈЈ = 5.1 Hz, 1 H, 3ЈЈb-H), 3.25 (dd, J2ЈЈ–3ЈЈa = 5.0, J2ЈЈ–3ЈЈb
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=
=
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CH2CH3), 1.61–1.50 (m, 4 H, d-H, CH2CH3), 1.46 (m, 9 H, tBu),
1.45–1.30 (m, 1 H, c-H), 0.90 (t, J = 7.4 Hz, 3 H, CH2CH3), 0.85
(t, J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ = 173.3 (C-1ЈЈ),
165.0 (C-4), 152.2 (C-2), 146.3 (C-6), 116.9 [C(CH2CH3)2], 110.0
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Eur. J. Org. Chem. 2007, 5386–5394
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5393

L. Le Corre, C. Gravier-Pelletier, Y. Le Merrer
FULL PAPER
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Received: June 8, 2007
Published Online: September 7, 2007
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Eur. J. Org. Chem. 2007, 5394