Toward analogues of MraY natural inhibitors: Synthesis of 5′-triazole-substituted-aminoribosyl uridines through a Cu-catalyzed azide-alkyne cycloaddition

Article abstract of DOI:10.1021/jo4014035

A straightforward strategy for the synthesis of triazole-containing MraY inhibitors has been developed. It involves the sequential introduction of a terminal alkyne at the 5′ position of an uridine derivative and O-glycosylation with a protected aminoribose leading to an elaborated alkyne scaffold. An efficient Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) allowed the introduction of chemical diversity toward a small library of inhibitors.

Full text of DOI:10.1021/jo4014035

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Article
Toward Analogs of MraY Natural Inhibitors: Synthesis
of 5’-Triazole-Substituted-Aminoribosyl Uridines
Through a Cu-Catalyzed Azide-Alkyne Cycloaddition
Mickaël Jeremy Fer, Samir Olatunji, Ahmed Bouhss, Sandrine Calvet-Vitale, and Christine Gravier-Pelletier
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4014035 • Publication Date (Web): 17 Sep 2013
Downloaded from http://pubs.acs.org on September 22, 2013
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Toward Analogs of MraY Natural Inhibitors: Synthesis of 5’-Triazole-
Substituted-Aminoribosyl Uridines Through a Cu-Catalyzed Azide-Alkyne
Cycloaddition
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†
‡
‡
,†
Mickaël J. Fer, Samir Olatunji, Ahmed Bouhss, Sandrine Calvet-Vitale,* and Christine
,
†
Gravier-Pelletier*
†
Université Paris Descartes, UMR 8601 CNRS, Laboratoire de Chimie et Biochimie
Pharmacologiques et Toxicologiques, 45 rue des Saints Pères 75006 Paris, France
‡
Université Paris-Sud 11, UMR 8619 CNRS, Laboratoire des Enveloppes Bactériennes et
Antibiotiques, Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Orsay F-91405,
France
christine.gravier-pelletier@parisdescartes.fr; sandrine.calvet-vitale@parisdescartes.fr
TOC Graphic
R
CHEMICAL
DIVERSITY
N
N
N
R
N3
O
O
O
O
N
N
O
O
NH
O
O
NH
H2N
PHN
O
CuAAC
O
HO
OH
PO
OP
HO
OH
PO
OP
1
4 examples
ABSTRACT
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A straightforward strategy for the synthesis of triazole-containing MraY inhibitors has been
developed. It involves the sequential introduction of a terminal alkyne at the 5’ position of an
uridine derivative and O-glycosylation with a protected aminoribose leading to an elaborated
alkyne scaffold. An efficient Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) allowed the
introduction of chemical diversity toward a small library of inhibitors.
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INTRODUCTION
The worldwide emergence of multidrug resistant (MDR) bacteria has become a severe public
health problem which requires the scientific community to discover novel compounds able to
1
,2
fight MDR strains. One way to address antibiotic resistance is to delay this inevitable
phenomenon by focusing on targets which have been little exploited so far such as the
3
bacterial translocase MraY. This transferase involved in the first membrane-associated step
4
of peptidoglycan biosynthesis represents such a challenging target. Indeed, this membrane
protein, which no drug currently used in therapeutics has yet targeted, is an essential enzyme
5,6
of peptidoglycan biosynthesis. The latter is a crosslinked polymer specific to bacteria and is
a major component of their cell wall which protects the cell from osmotic stress. MraY
catalyzes the transfer of the phospho-Mur-N-Ac-pentapeptide moiety from the cytoplasmic
precursor UDP-Mur-N-Ac-pentapeptide to the membrane acceptor undecaprenyl phosphate
(C
55-P) yielding undecaprenyl-pyrophosphoryl-Mur-N-Ac-pentapeptide (lipid I) while
7
releasing uridine monophosphate (UMP).
8,9
MraY is the target of several families of naturally occurring nucleoside antibiotics (Figure
10
11
12
1
)
which notably include FR-900493,
liposidomycins,
caprazamycins
and
1
3
muraymycins. Several elegant synthetic approaches toward these compounds have been
1
4,15
described.
All these natural inhibitors share a common aminoribosyl-O-uridine scaffold
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which has been proven to be essential for biological activity. However, the complexity
displayed by such structures hampers rapid structure-activity relationship studies.
Furthermore, the absence of crystal structure available for the MraY transferase makes the
discovery of new potent inhibitors particularly challenging, not only as regards the
development of new antibacterials but also in a possible contribution to MraY structural
characterization.
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FIGURE 1. Natural inhibitors of MraY
14e,i,15f,m,17
In the context of an ongoing program
directed toward MraY inhibition, our goal was
to develop a straightforward access to a new type of MraY inhibitors (Figure 2) based on the
aminoribosyl-O-uridine skeleton displayed by known natural inhibitors. Structural diversity
was planned to be introduced through a triazole linker at the 5’ position of this scaffold thanks
1
8
to Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Indeed, this robust process seemed
to be particularly relevant at the ultimate key step since it is compatible with a large range of
18,19
functional groups, occurs under mild conditions and is generally high yielding.
Moreover,
the use of a 1,2,3-triazole to connect various fragments to the aminoribosyl-O-uridine
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skeleton appeared to be relevant owing to electronic similarities with the amide bond, a
function present at the same position in some of the above-mentioned natural inhibitors.
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FIGURE 2. Structure of targeted MraY inhibitors
RESULTS AND DISCUSSION
The retrosynthesis we designed (Scheme 1) for the preparation of the targeted inhibitors A
relies on the CuAAC reaction between individual azides (11a-n, Table 1) and 5’-alkynyl-
aminoribosyl uridine B which could be derived from O-glycosylation of the known uridine-
derived propargylic alcohol D, by an anomerically activated and amine protected 5-amino-5-
deoxy-D-ribofuranoside C.
SCHEME 1: Retrosynthetic analysis of targeted inhibitors A
R
N
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HO
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+
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OH
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OP
P = protecting group
LG = leaving group
A
B
C
D
In previous synthetic approaches toward caprazamycins and muraymycins, the 5-
aminoribosyl moiety was introduced by glycosylation with a 5-azidoribosyl derivative as a
1
4d,e,g,i,15c,d,h-m
ribosyl donor.
According to the proposed retrosynthetic analysis, the use of an
azido group to mask the primary amine was excluded to avoid autocondensation during the
CuAAC reaction step. In contrast, the easily cleavable phthalimido group could be suitable for
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our strategy. Accordingly, the 5-phthalimidoribosyl fluoride 8, with pentylidene protection for
the 2,3-dihydroxyl groups, was prepared in four steps (via 5, 6 and 7) from D-ribose in a 47%
overall yield (Scheme 2).
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Initially, ribose was first protected with the acid labile 3-pentylidene group, known to hinder
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the α-face of the ribosyl donor during the glycosylation step. Unfortunately, all attempts to
introduce a phthalimide moiety as a masked primary amine on compounds exhibiting an
unprotected anomeric hydroxyl, either by nucleophilic substitution from mesylate 2 or
2
1
tosylate 3 or by direct Mitsunobu reaction on the alcohol 1, led exclusively to the tricyclic
compound 4.
As a highly effective alternative, direct conversion of D-ribose to β-1-O-allyl-2,3-di-O-
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pentylidene ribofuranoside 5, with concurrent installation of the two useful protecting
groups, was achieved in a single reaction in a 3-pentanone/allylic alcohol mixture in the
presence of sulfuric acid to give 5 as the single β stereoisomer exhibiting a characteristic
singlet for H
1
at 5.13 ppm. The configuration of the hemiketal carbon was also confirmed by
and H (NOESY).
the presence of a nOe between H
1
4
SCHEME 2: Synthesis of the protected 5’-ethynyl-aminoribosyl-O-uridine 10
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The primary alcohol 5 was then converted to the phthalimide 6 by N-alkylation under
Mitsunobu conditions. Various attempts to deprotect the anomeric hydroxyl by using well-
known deallylation conditions proved unsuccessful leading either to unchanged starting
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material (Pd(PPh ) , DMBA, MeOH), or to complex mixtures (Pd(PPh ) , K CO ,
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4
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MeOH). Treatment of compound 6 with nickel chloride and triethylaluminium allowed
allyl deprotection but in modest and unreproductible yields (44%-63%). In contrast, removal
of the allyl protecting group was successfully achieved by oxidative cleavage in the presence
of 4-methylmorpholine-N-oxide, sodium periodate and a catalytic amount of osmium
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tetroxide in a 2/1 dioxane/water mixture affording in 97% yield the anomeric unprotected
ribose 7. The latter was subsequently activated as its fluoride 8 using diethylaminosulfur
trifluoride.
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The known propargyl alcohol 9 was prepared according to a litterature procedure from
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’,3’-O-isopropylidene-uridine by Dess-Martin oxidation of its primary alcohol function
followed by triethylsilylethynylmagnesiumbromide condensation leading to a 2/1 mixture of
the corresponding 5’R/5’S triethylsilylpropargyl alcohols. The separable major 5’R isomer
was then converted into the desired propargyl alcohol 9 in a two step sequence allowing
inversion of the configuration at C5’ under Mitsunobu conditions (PPh
3
, DIAD) leading to the
2,5’S-anhydro-uridine which was subsequently hydrolyzed into the alcohol 9 under basic
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conditions (NaOH, MeOH/H
2
O). The established S configuration in alcohol 9 was further
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confirmed by differentiation from its R diastereoisomer, which is also known and reported.
Next, the propargyl alcohol 9 was submitted to glycosylation with the ribose derivative 8 in
15d
the presence of boron trifluoride etherate at -78 °C to give the alkyne 10 with a high 13/1
β/α selectivity and in an excellent 90% yield, considering the steric hindrance of the ribosyl
acceptor. Assignment of anomers for compound 10 was made according to distinguishing
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characteristic H NMR signals for H1’’, a singlet at 5.31 ppm for the major β anomer and a
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doublet ( JH1’’-H2’’ = 2 Hz) at 5.30 ppm for the minor α anomer.
To introduce chemical diversity in the set of final compounds, we next turned to the synthesis
of second partners for CuAAC, azido building blocks displaying various structures,
complexity and polarity. Thus, several apolar, aliphatic or aromatic, linear or cyclic, azides
such as 11a-11d were selected (Figure 3). In addition, polar azido-alcohols 11e-f, azido
alkylphthalimide 11g, morpholine 11h and imidazole 11i were chosen to potentially mimic
the polar amine moiety present in natural MraY inhibitors. The piperazine-azide 11j, with a
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more polar and complex structure, was also involved in this study. Finally, in order to
determine if compounds containing a benzophenone moiety could inhibit MraY, we also
picked four benzophenone-derived azides 11k-n. Indeed, inhibitors bearing such a
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photoactivable group and exhibiting different spacers between the benzophenone and the
triazole moieties could offer some original opportunities for the mapping of the yet unknown
MraY active site.
FIGURE 3. Structure of azide building blocks 11
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The synthesis of azides 11 (a to n; groups A to E) is depicted in scheme 3. Thus, azides A,
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1a and 11c-f, were synthesized from corresponding bromide or tosyl derivatives. Azides B,
11b and 11i, were prepared by diazotransfer reaction on primary amine 13a and 13b, with
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imidazole-1-sulfonyl azide hydrochloride as a diazo donor. Azides C, 11g (a phthalimide)
and 11h (a morpholine) were prepared through a common intermediate 15 resulting from
activation of pentane-1,5-diol as its dimesylate 14, followed by mono-substitution with
sodium azide. Further substitution by phthalimide or morpholine afforded azides 11g and 11h,
respectively. Finally, azides D, 11k-m, and azide E, 11n, all containing the benzophenone
group, were efficiently prepared from the corresponding dibromo reagent by successive
displacement of bromides, by 4-hydroxybenzophenone and azide anion.
SCHEME 3. Synthesis of azides 11a-n
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With azide partners 11a-n and alkyne 10 in hand, we undertook the synthesis of the targeted
triazole compounds. Accordingly, alkyne scaffold 10 and azide partners 11a-n were submitted
to CuAAC conditions, at room temperature in a 3/1 tert-BuOH/water mixture using catalytic
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CuSO and sodium ascorbate in the presence of DIPEA (Scheme 4).
SCHEME 4: Synthesis of the targeted triazoles 20a-n
The CuAAC reactions resulted in 1,4-triazoles 18a-n, which were isolated in yields of 37 to
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5% (Table 1), which are reasonable considering the bulkiness of the aminoribosyl moiety.
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2
The phthalimide protecting group was then removed under mild conditions by methylamine
to give aminoribosyltriazoles 19a-n. Finally, acidic deprotection of the ketals in a 4/1
trifluoroacetic acid/water mixture provided the desired analogs of MraY natural inhibitors
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0a-n as their trifluoroacetate salts in nearly quantitative yield.
TABLE 1. Yields for the synthesis of 18a-n, 19a-n and 20a-n
1
R -N
3
ꢀ
18ꢀ(yield)ꢀ(%)
a: 61
19ꢀ(yield)ꢀ(%) 20ꢀ(yield)ꢀ(%)
11a
a: 65
b: 63
c: 58
d: 55
e: 47
a: 94
b: 93
c: 89
d: 96
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obtained as a di TFA salt
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j: 86
k: 99
l: 96
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m: 49
n: 37
m: 51
n: 80
m: 99
n: 99
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a
Preliminary in vitro biological evaluation of the synthesized compounds 20k-n, which could
further be exploited as molecular tools for mapping the MraY active site, was carried out on
MraY purified from Bacillus subtilis, as described in the experimental section. The residual
activity of the enzyme was measured in the presence of 1 mM of the tested compounds and
then, the IC50 value was calculated. Commercially available tunicamycin from Streptomyces
sp. was used as a positive control in the tests and resulted in an IC50 value equal to 0.012 µM.
TABLE 2. Inhibitory activity of compounds 20k-n on the MraY enzyme
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Interestingly, all the compounds containing the benzophenone group revealed inhibition of the
MraY enzyme. The biological evaluation of the other synthesized compounds on MraY
enzymatic activity is currently in progress and will be reported elsewhere.
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CONCLUSION
We developed a straightforward synthesis of a highly functionalized alkyne scaffold which
was easily prepared on a multi-gram scale from D-ribose. Subsequent introduction of
chemical diversity achieved with the CuAAC reaction, at a late stage of the synthesis, allowed
rapid access to variously substituted triazole-containing compounds including benzophenone
derivatives. Preliminary biological evaluation of the latter showed interesting inhibition of the
MraY enzyme and these inhibitors will be further exploited as molecular tools for mapping
the MraY active site.
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5
5
5
5
5
6
EXPERIMENTAL SECTION
General Experimental Methods: When needed, reactions were carried out under an argon
atmosphere. They were monitored by thin-layer chromatography with precoated silica on aluminium
foil. Flash chromatography was performed with silica gel 60 (40-63 µm); the solvent systems were
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
given v/v. Spectroscopic H and C NMR, MS and/or analytical data were obtained using
1
13
chromatographically homogeneous samples. H NMR (500 MHz) and C NMR (125 MHz) spectra
were recorded in CDCl unless indicated. Chemical shifts (δ) are reported in ppm and coupling
3
constants are given in Hz. For each compound detailed peak assignments have been made according to
COSY, HSQC and HMBC experiments. The numbering of molecules is indicated in the supporting
information file. Optical rotations were measured with sodium (589 nm) or mercury (365 nm)
lamp at 20 °C. Melting points were measured on a hot bench. IR spectra were recorded on a
-
1
FT-IR spectrophotometer and the wavelengths are reported in cm . Low resolution mass spectra
(LRMS) were recorded with an ion trap mass analyzer under electrospray ionization (ESI) in positive
ionization mode detection or atmospheric pressure chemical ionization (APCI). High resolution
mass sprectra (HRMS) were recorded with a TOF mass analyzer under electrospray ionization (ESI)
in positive ionization mode detection, atmospheric pressure chemical ionization or atmospheric
pressure photoionization (APPI). For MraY activity, the radioactive spots were located and
quantified with a radioactivity scanner (model Multi-Tracemaster LB285).
5-Anhydro-2,3-O-isopentylidene-β-D-ribofuranose (4). Via compound 1 by Mitsunobu
reaction: to a solution of compound 1 (350 mg, 1.6 mmol, 1 equiv), phthalimide (259 mg,
1
.76 mmol, 1.1 equiv) and triphenylphosphine (839 mg, 3.2 mmol, 2 equiv) in anhydrous
toluene (9 mL), diisopropylazodicarboxylate (DIAD) was added dropwise (630 µL, 3.2 mmol,
equiv). The resulting yellow solution was stirred at rt for 16 h and concentrated in vacuo.
2
The crude oil was purified by flash chromatography (Cyclohexane/EtOAc 9/1, then 3/7) to
give tricyclic compound 4 as a colorless oil (210 mg, 66%).
1
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Via the mesylate 2 by nucleophilic substitution: to a solution of compound 1 (350 mg, 1.6
mmol, 1 equiv) in DCM (6 mL), were successively added DMAP (10 mg, 0.08 mmol, 1
equiv), triethylamine (337 µL, 2.41 mmol, 1.5 equiv) and MsCl dropwise (190 µL, 2.41
mmol, 1.5 equiv). The mixture was stirred at rt for 48 h. After addition of EtOAc (30 mL), the
mixture was washed with a 1M HCl aqueous solution (2 × 30 mL). The aqueous layer was
extracted with EtOAc (3 × 30 mL). The combined organic layers were then washed with brine
10
11
12
13
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15
16
17
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46
47
48
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50
51
52
53
54
55
56
57
58
59
60
2 4
(50 mL) and water (50 mL), dried (Na SO ), filtrated and concentrated in vacuo to give the
crude mesylate 2 as a pale yellow oil (470 mg, 99% yield). To a solution of crude mesylate 2
(
470 mg, 1.6 mmol, 1 equiv) in DMF (6 mL) was added in one portion potassium phthalimide
592 mg, 3.2 mmol, 2 equiv). The mixture was stirred at rt for 48 h and then poured into Et
Cl (15 mL), the aqueous phase
O (20 mL). The combined organic layers were dried (Na SO ), filtrated
and concentrated in vacuo. The residue was purified by flash chromatography (DCM/Acetone
9/1) to give tricyclic compound 4 as a colorless oil (181 mg, 57% yield from 1).
(
2
O
(15 mL). After addition of a saturated aqueous solution of NH
was extracted with Et
4
2
2
4
9
Via the tosylate 3 by nucleophilic substitution: at 0 °C, to a solution of compound 1 (2.36 g,
10.8 mmol, 1 equiv) in pyridine (100 mL), was added recrystallized tosyl chloride (3.16 g,
1
6.6 mmol, 1.53 equiv). The mixture was stirred at rt for 48 h and diluted in EtOAc (120 mL).
The resulting solution was transferred into a separatory funnel and washed with a 1M HCl
aqueous solution. The organic layer was washed with brine (2 × 100 mL) and water (100 mL),
2 4
dried (Na SO ), filtrated and concentrated in vacuo to furnish the crude tosylate 3 as a pale
yellow oil (2.89 g, 72% yield). To a solution of crude tosylate 3 (257 mg, 0.69 mmol, 1
equiv), in DMF (20 mL), was added in one portion potassium phthalimide (249 mg, 1.34
mmol, 2 equiv). The mixture was stirred at rt for 48 h and the reaction was quenched at 0 °C
by addition of a saturated aqueous solution of NH
4
Cl (30 mL). The mixture was extracted
SO ), filtrated and
with DCM (4 × 30 mL) and the combined organic layers were dried (Na
2
4
1
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1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
concentrated in vacuo. The residue was purified by flash chromatography (DCM to
DCM/Acetone 95/5) to afford tricyclic compound 4 as a colorless oil (138 mg, 64% yield,
46% from 1). R
f
0.73 (DCM/Acetone 97/3); [α]
D
- 51 (c 1.0, CH
), 4.69 (d, 1H, JH4-H5a = 4.0 Hz, H
), 4.26 (d, 1H, JH3-H2 = 5.5 Hz, H ), 3.39 (dd, 1H, JH5a-H5b = 7.0 Hz,
2
Cl
2
); IR (film) 2976s,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
1
940m, 1350m, 1073s; H NMR δ 5.43 (s, 1H, H
1
4
), 4.31 (d,
H, JH2-H3 = 5.5 Hz, H
2
3
JH5a-H4 = 4.0 Hz, H5a), 3.27 (d, 1H, JH5b-H5a = 7.0 Hz, H5b), 1.69 (q, 2H, JH7-H8 = 7.5 Hz, H
7
),
1
.54 (q, 2H, JH7’-H8’ = 7.5 Hz, H7’), 0.91 (t, 3H, JH8-H7 = 7.5 Hz, H ), 0.86 (t, 3H, JH8’-H7’ = 7.5
8
1
3
Hz, H8’); C NMR δ 116.5 (C
), 29.0 (C7’), 8.5 (C ), 7.8 (C8’); HRMS APCI Calcd for C10
found 201.1123.
1-O-Allyl-2,3-O-isopentylidene-β-D-ribofuranose (5). To a suspension of D-ribose (10.0 g,
6.6 mmol, 1 equiv) in 3-pentanone (40 mL, 377 mmol, 5.7 equiv) was added allyl alcohol
45 mL, 662 mmol, 9.9 equiv) and concentrated sulfuric acid (0.7 mL, 13 mmol, 0.2 equiv).
The suspension was vigorously stirred at 60 °C for 4 h. The resulting pale yellow solution was
cooled down to rt, neutralized by a dropwise addition of Et N (1.88 mL, 13 mmol, 0.2 equiv)
and concentrated in vacuo. After addition of water (200 mL), the residue was extracted with
EtOAc (5 × 200mL). The combined organic layers were dried (Na SO ), filtrated and
6
), 99.9 (C
1
), 81.7 (C
3
), 79.6 (C
2
), 77.8 (C
4
), 63.0 (C
5
), 29.5
+
+
(C
7
8
H
17
O
4
(M + H) 201.1127,
6
(
3
2
4
concentrated in vacuo. The resulting pale yellow oil was purified by flash chromatography
(Cyclohexane/EtOAc 8/2) to give protected ribose 5 as the single β stereoisomer and as a
colorless oil (10.33 g, 60% yield): R
CH Cl
f
D
0.34 (Cyclohexane/EtOAc 8/2); [α] - 73 (c 1.0,
1
2
2
); IR (film) 3469br, 2942w, 1464w, 1097s, 925s; H NMR δ 5.91 (dddd, 1H, JH10-H11’
=
=
),
1
1
7.0 Hz, JH10-H11 = 10.0 Hz, JH10-H9a = 6.0 Hz, JH10-H9b = 6.0 Hz, H10), 5.32 (dd, 1H, JH11’-H10
7.0 Hz, JH11’-H11 = 1.5 Hz, H11’), 5.24 (br d, 1H, JH11-H10 = 10.0 Hz, H11), 5.13 (s, 1H, H
), 4.65 (d, 1H, JH2-H3 = 6.0 Hz, H
), 4.24 (dd, 1H, JH9a-H9b = 12.5 Hz, JH9a-H10 = 6.0 Hz, H9a), 4.07 (dd,
1
4.86 (d, 1H, JH3-H2 = 6.0 Hz, H
Hz, JH4-H5a = 2.5 Hz, H
3
2
), 4.45 (dd, 1H, JH4-H5b = 3.5
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H, JH9b-H9a = 12.5 Hz, JH9b-H10 = 6.0 Hz, H9b), 3.70 (br d, 1H, JH5a-H5b = 12.0 Hz, H5a), 3.63
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
ddd, 1H, JH5b-H5a = 12.0 Hz, JH5b-OH = 9.0 Hz, JH5b-H4 = 3.5 Hz, H5b), 3.19 (br d, 1H, JOH-5b
9.0 Hz, OH), 1.71 (q, 2H, JH7-H8 = 7.0 Hz, H ), 1.59 (q, 2H, JH7’-H8’ = 7.0 Hz, H7’), 0.93 (t, 3H,
H8-H7 = 7.0 Hz, H ), 0.88 (t, 3H, JH8’-H7’ = 7.0 Hz, H8’); C NMR δ 133.3 (C10), 118.5 (C11),
=
7
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
J
8
1
16.7 (C
7’), 8.6, 7.6 (C
59.1545.
1-O-Allyl-5-deoxy-2,3-O-isopentylidene-5-phthalimido-β-D-ribofuranose (6). To
6
), 108.3 (C
1
), 88.9 (C
4
), 86.5 (C
2
), 82.0 (C
3
), 69.2 (C
9
5 7
), 64.3 (C ), 29.5, 29.0 (C ,
+
+
C
8
, C8’); HRMS APCI Calcd for C13
H
23
O
5
(M + H) 259.1545, found
2
a
solution of 5 (9.27 g, 35.9 mmol, 1 equiv), triphenylphosphine (18.8 g, 71.8 mmol, 2 equiv)
and phthalimide (6.34 g, 43.1 mmol, 2 equiv), in anhydrous toluene (203 mL), DIAD was
added dropwise (15.4 mL, 71.8 mmol, 2 equiv). The reaction mixture was stirred at rt for 18 h
and concentrated in vacuo. The residue (55 g) was purified by flash chromatography
(Cyclohexane/ EtOAc 9/1 then 8/2) to give compound 6 as a colorless oil (11.64 g, 84%
yield): R
f
D 2 2
0.44 (Cyclohexane/EtOAc 8/2); [α] - 60 (c 1.0, CH Cl ); IR (film) 2975w, 1774m,
1
1
716s, 1395s, 1034s, 926m; H NMR δ 7.87-7.83 (m, 2H, H14), 7.72-7.70 (m, 2H, H15), 5.91
(dddd, 1H, JH10-H11’ = 17.0 Hz, JH10-H11 = 10.0 Hz, JH10-H9b = 6.5 Hz, JH10-H9a = 5.0 Hz, H10),
.31 (dd, 1H, JH11’-H10 = 17.0 Hz, JH11’-H11 = 1.5 Hz, H11’), 5.19 (br d, 1H, JH11-H10 = 10.0 Hz,
11), 5.14 (s, 1H, H ), 4.82 (d, 1H, JH3-H2 = 6.5 Hz, H ), 4.75 (d, 1H, JH2-H3 = 6.5 Hz, H
(dd, 1H, JH4-H5a = 9.0 Hz, JH4-H5b = 6.0 Hz, H ), 4.27 (dd, 1H, JH9a-H9b = 13.0 Hz, JH9a-H10 = 5.0
5
H
1
3
2
), 4.48
4
Hz, H9a), 3.98 (dd, 1H, JH9b-H9a = 13.0 Hz, JH9b-H10 = 6.5 Hz, H9b), 3.89 (dd, 1H, JH5a-H5b = 14.0
Hz, JH5a-H4 = 9.0 Hz, H5a), 3.83 (dd, 1H, JH5b-H5a = 14.0 Hz, JH5b-H4 = 6.0 Hz, H5b), 1.65 (q, 2H,
J
H7-H8 = 8.0 Hz, H
7
8
), 1.55 (q, 2H, JH7’-H8’ = 8.0 Hz, H7’), 0.87 (t, 3H, JH8-H7 = 8.0 Hz, H ), 0.84
13
(t, 3H, JH8’-H7’ = 8.0 Hz, H8’); C NMR δ 168.4 (C12), 134.3 (C15), 133.9 (C10), 132.2 (C13),
1
6 1 2 4 3 9
23.6 (C14), 117.6 (C11), 116.9 (C ), 107.9 (C ), 86.0 (C ), 84.8 (C ), 82.9 (C ), 68.6 (C ), 41.3
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
+
(
C
5
), 29.7, 29.1 (C
10.1580, found 410.1581.
-Deoxy-2,3-O-isopentylidene-5-phthalimido-β-D-ribofuranose (7). To a solution of 6
7
, C7’), 8.5, 7.5 (C
8
, C8’); HRMS ESI Calcd for C21
H
25NaNO
6
(M + Na)
4
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
5.62 g, 14.5 mmol, 1 equiv), in a 2/1 dioxan/water mixture (100 mL), were successively
added the N-methyl-morpholine-N-oxide in one portion (7.90 g, 47.9 mmol, 3.3 equiv) and an
osmium tetraoxide solution in tert-BuOH dropwise (2.5 % w/v, 0.084 M, 985 µL, cat.).
Sodium periodate was then added in one portion (10.1 g, 47.9 mmol, 3.3 eq). The reaction
mixture was stirred at 70 °C for 18 h and concentrated in vacuo. The aqueous phase was
extracted with DCM (4 × 250 mL). The combined organic layers were dried (Na
filtrated and concentrated in vacuo. The resulting oil was purified by flash chromatography
Cyclohexane/EtOAc 8/2 then 7/3) to give compound 7 as a colorless oil (4.97 g, 97% yield):
2 4
SO ),
(
R
f
0.34, (Cyclohexane/EtOAc 7/3); [α]
D
2 2
- 32 (c 1.0, CH Cl ); IR (film) 3421br, 2974w,
1
2941w, 1773m, 1710s, 1396s, 1082s, 926s; H NMR δ 7.88-7.84 (m, 2H, H11), 7.74-7.71 (m, 2H,
H
12), 5.44 (s, 1H, H
1
), 4.82 (d, 1H, JH3-H2 = 6.0 Hz, H
H4-H5a = 9.0 Hz, JH4-H5b = 6.5 Hz, H ), 3.86 (dd, 1H, JH5a-H5b = 14.0 Hz, JH5a-H4 = 9.0 Hz, H5a), 3.83 (dd,
H, JH5b-H5a = 14.0 Hz, JH5b-H4 = 6.5 Hz, H5b), 2.37-2.12 (br s, 1H, OH), 1.67-1.60 (m, 2H, H
3 2
), 4.76 (d, 1H, JH2-H3 = 6.0 Hz, H ), 4.51 (dd, 1H,
J
4
1
2
7
), 1.53 (q,
1
3
H, JH7-H8 = 7.5 Hz, H
7
), 0.86 (t, 3H, JH8-H7 = 7.5 Hz, H
8
), 0.83 (t, 3H, JH8-H7 = 7.5 Hz, H
8
); C NMR δ
168.1 (C
0.7 (C
9
), 134.1 (C12), 131.9 (C10), 123.5 (C11), 117.0 (C
6
), 104.3 (C ), 85.9 (C ), 84.7 (C
1
2
4
), 82.7 (C
3
),
+
+
+
4
5
), 29.5, 29.0 (C
7
), 8.3, 7.3 (C
8
); HRMS ESI Calcd for C18
H22NO
6
(M + H) 348.1461,
found 348.1462.
1,5-Dideoxy-1-fluoro-2,3-O-isopentylidene-5-phthalimido-D-ribofuranose (8). At -30 °C,
to a solution of compound 7 (4.94 g, 14.2 mmol, 1 equiv) in DCM (173 mL), DAST was
added dropwise (2.8 mL, 21.2 mmol, 1.5 eq). The resulting yellow solution was stirred at -30
°C for 30 min then at rt for 1 h. The reaction was quenched by addition of a saturated aqueous
solution of NaHCO
3
(160 mL) and the aqueous phase was extracted with DCM (4 × 200 mL).
SO ), filtrated and concentrated in vacuo. The
The combined organic layers were dried (Na
2
4
1
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resulting oil was purified by flash chromatography (Cyclohexane/EtOAc 9/1) to give
compound 8 as a β/α mixture (β/α > 9) and as a colorless oil (4.82g, 97%). Compounds 8β
and 8α were isolated and fully characterized: 8β: R
f
D
0.44 (Cyclohexane/EtOAc 8/2); [α] +
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1
2 (c 1.0, CH
.84 (m, 2H, H11), 7.75-7.72 (m, 2H, H12), 5.80 (d, 1H, JH1-F = 61.5 Hz, H
), 4.86 (d, 1H, JH3-H2 = 6.0 Hz, H ), 4.64 (ddd, 1H, JH4-H5b = 9.0
Hz, JH4-H5a = 6.0 Hz, JH4-F = 3.0 Hz, H ), 3.88 (dd, 1H, JH5a-H5b = 14.0 Hz, JH5a-H4 = 6.0 Hz,
5a), 3.81 (dd, 1H, JH5b-H5a = 14.0 Hz, JH5b-H4 = 9.0 Hz, H5b), 1.65 (q, 2H, JH7-H8 = 7.5 Hz, H
2
Cl
2
); IR (film) 2973w, 1773w, 1712s, 1401m, 1130m, 724m; H NMR δ 7.87-
7
1
), 4.90 (dd, 1H, JH2-
H3 = 6.0 Hz, JH2-F = 5.5 Hz, H
2
3
4
H
7
),
1
.56 (q, 2H, JH7’-H8’ = 7.5 Hz, H7’), 0.89 (t, 3H, JH8-H7 = 7.5 Hz, H
8
), 0.87 (t, 3H, JH8’-H7’ = 7.5
1
3
Hz, H8’); C NMR δ 168.2 (C
C1-F = 221 Hz, C ), 86.3 (C
, C7’), 8.5, 7.5 (C , C8’); HRMS ESI Calcd for C18
found 372.1229. 8α: R
9
6
), 134.4 (C12), 133.7 (C10), 123.7 (C11), 117.6 (C ), 115.5 (d,
J
1
4
), 85.6 (d, JC2-F = 41.5 Hz, C
2
), 82.7 (C
3
), 40.6 (C
5
), 29.6, 27.1
+
+
+
(C
7
8
H
20NO
5
FNa (M + Na) 372.1223,
f
D 2 2
0.26 (Cyclohexane/EtOAc 8/2); [α] + 23 (c 1.0, CH Cl ); IR (film)
1
2
976w, 1715s, 1394m, 1105m, 714m; H NMR δ 7.87-7.84 (m, 2H, H11), 7.75-7.72 (m, 2H,
H
=
12), 5.64 (dd, 1H, JH1-F = 63.0 Hz, JH1-H2 = 3.5 Hz, H
7.5 Hz, JH2-H1 = 3.5 Hz, H ), 4.68 (dd, 1H, JH3-H2 = 7.5 Hz, JH3-H4 = 4.0 Hz, H
), 3.93 (d, 2H, JH5a-H4 = JH5b-H4 = 7.0 Hz,
1
), 4.75 (ddd, 1H, JH2-F = 14.5 Hz, JH2-H3
2
3
), 4.62 (dt, 1H,
JH4-H5a = 7.0 Hz, JH4-H5b = 7.0 Hz, JH4-H3 = 4.0 Hz, H
4
H
5
), 1.80 (q, 2H, JH7-H8 = 7.5 Hz, H
.5 Hz, H
33.7 (C10), 123.7 (C11), 121.5 (C
7
), 1.62 (q, 2H, JH7’-H8’ = 7.5 Hz, H7’), 0.94 (t, 3H, JH8-H7 =
13
7
1
7
8
), 0.88 (t, 3H, JH8’-H7’ = 7.5 Hz, H8’); C NMR (CDCl
3
) δ 168.2 (C
9
), 134.4 (C12),
6
), 108.0 (d, JC1-F = 235 Hz, C
1
), 81.5 (C
4
), 81.3 (d, JC2-F =
+
9,5 Hz, C
2
), 81.1 (C
3
), 39.9 (C
5
), 29.9 (C ), 29.4 (C7’), 8.5 (C
7
8
), 8.3 C8’); HRMS ESI Calcd
+
+
for C18
H
20NO
5
FNa (M + Na) 372.1223, found 372.1219.
1’’,5’’-Dideoxy-2’’,3’’-O-isopentylidene-5’’-phthalimido-1’’-[2’,3’-O-isopropylidene-
2
7
5
’(S)-ethynyl-uridinyl]-β-D-ribofuranose (10). The propargylic alcohol 9 (1.1 g, 3.1
mmol, 1 equiv) and the fluoride 8 (1.62 g, 4.65 mmol, 1.5 equiv) were dried together by
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coevaporation with toluene (3 × 10 mL) and dissolved in DCM (86 mL). The flask was
flushed with argon and molecular sieves 4Å (11 g) was added in one portion. The suspension
.
was vigorously stirred at rt for 1 h then cooled to -78 °C. At -78 °C, BF
3
Et
2
O (535 µL, 4.65
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mmol, 1.5 equiv) was dropwise added and the reaction mixture was stirred at this temperature
for 10 min and then at rt for 18 h. The suspension was then diluted in DCM (80 mL) and the
reaction was quenched by addition of a saturated aqueous NaHCO
aqueous phase was extracted with DCM (6 × 150 mL). The combined organic layers were
dried (Na SO ), filtrated and concentrated in vacuo. The resulting white foam was purified by
flash chromatography (Toluene/Acetone 85/15) to give alkyne 10 as a β/α mixture (β/α =
3/1) as a white foam (1.79 g, 90% combined yield). The β anomer was isolated as a white
3
solution (50 mL). The
2
4
1
foam (69% yield): R
CH Cl
f
0.30, Toluene/Acetone 75/25); m.p. 135-137 °C; [α]
D
- 43 (c 1.0,
1
2
2
); IR (film) 3421br, 2974w, 2941w, 1773m, 1710s, 1396s, 1082s, 926s; H NMR δ
8.82 (s, 1H, NH), 7.87-7.85 (m, 2H, H11’’), 7.74-7.73 (m, 2H, H12’’), 7.40 (d, 1H, JH6-H5 = 8.0
Hz, H ), 5.80 (dd, 1H, JH5-H6 = 8.0 Hz, JH5-NH = 2.0 Hz, H ), 5.74 (d, 1H, JH1’-H2’ = 1.5 Hz,
1’), 5.30 (s, 1H, H1’’), 4.92-4.99 (m, 2H, H2’, H3’), 4.81 (d, 1H, JH2’’-H3’’ = 5.5 Hz, H2’’), 4.77
d, 1H, JH3’’-H2’’ = 5.5 Hz, H3’’), 4.67 (dd, 1H, JH5’-H4’ = 6.5 Hz, JH5’-H7’ = 2.0 Hz, H5’), 4.47 (dd,
H, JH4’’-H5’’a = 10.0 Hz, JH4’’-H5’’b = 4.5 Hz, H4’’), 4.34 (dd, 1H, JH4’-H5’ = 6.5 Hz, JH4’-H3’ = 2.5
6
5
H
(
1
Hz, H4’), 3.96 (dd, 1H, JH5’’a-H5’’b = 14.0 Hz, JH5’’a-H4’’ = 10.0 Hz, H5’’a), 3.90 (dd, 1H, JH5’’b-
H5’’a = 14.0 Hz, JH5’’b-H4’’ = 4.5 Hz, H5’’b), 2.60 (d, 1H, JH7’-H5’ = 2.0 Hz, H7’), 1.65-1.61 (m, 2H,
H
7’’), 1.59 (s, 3H, H9’), 1.52 (q, 2H, JH7’’-H8’’ = 7.5 Hz, H7’’), 1.39 (s, 3H, H9’), 0.85 (t, 3H,
1
3
J
H8’’-H7’’ = 7.5 Hz, H8’’), 0.82 (t, 3H, JH8’’-H7’’ = 7.5 Hz, H8’’); C NMR δ 168.3 (C9’’), 162.9
), 134.3 (C12’’), 132.1 (C10’’), 123.6 (C11’’), 117.2 (C6’’), 114.7 (C8’),
), 94.8 (C1’), 88.6 (C4’), 85.9 (C2’’), 84.9 (C4’’), 84.2 (C2’), 82.6 (C3’’),
(C
4
), 150.1 (C
2 6
), 142.1 (C
1
09.4 (C1’’), 102.9 (C
5
81.5 (C3’), 79.7 (C6’), 76.5 (C7’), 68.6 (C5’), 40.7 (C5’’), 29.6, 28.9 (C7’’), 27.2, 25.4 (C9’), 8.4,
-
-
-
7
34 3
.4 (C8’’); HRMS ESI Calcd for C32H N O11 (M - H) 636.2193, found 636.2204.
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General procedure for 4-hydroxy-benzophenone monoalkylation. To a solution of 4-
hydroxy-benzophenone in DMF (0.1 M), was added dibromide derivative (2.46 equiv) and
potassium carbonate (5 equiv). The solution was stirred at rt for 16 h and then diluted in Et
150 mL) and water (150 mL). The aqueous phase was extracted with Et O (2 × 150 mL) and
the combined organic layers were washed with brine (2 × 150 mL) and water (2 × 150 mL),
dried (Na SO ), filtrated and concentrated in vacuo. The residue was purified by flash
2
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
2
2
4
chromatography to give the corresponding building block.
4-O-(3-bromo-propyl)-benzophenone (16a). Compound 16a was synthesized according to
the general procedure for 4-hydroxy-benzophenone monoalkylation from 4-hydroxy-
benzophenone (1.0 g, 5.0 mmol, 1 equiv) and 1,3-dibromopropane (2.5 g, 12.4 mmol, 2.46
equiv). Flash chromatography (Cyclohexane/DCM 2/1 to 1/1) afforded 16a as a colorless oil
(
1.2 g, 75% yield): R
f
0.40 (Cyclohexane/DCM 1/1); IR (film) 3061w, 2928s, 1600s, 1250s;
H NMR δ 7.83 (br d, 2H, JH2-H3 = 9.0 Hz, H ), 7.76 (d, 2H, JH7-H8 = 7.5 Hz, H ), 7.56 (t, 1H,
H9-H8 = 7.5 Hz, H ), 7.47 (t, 2H, JH8-H9 = JH8-H7 = 7.5 Hz, H ), 6.97 (d, 2H, JH3-H2 = 9.0 Hz,
), 4.19 (t, 2H, JHa-Hb = 5.5 Hz, H ), 3.61 (t, 2H, JHc-Hb = 6.5 Hz, H ), 2.35 (tt, 2H, JHb-Hc = 6.5
); C NMR δ 195.6 (C ), 162.4 (C ), 138.4 (C
), 32.3 (C ), 29.8 (C
1
2
7
J
9
8
H
3
a
c
1
3
Hz, JHb-Ha = 5.5 Hz, H
b
5
4
6
), 132.7 (C
2
), 132.6
+
(C
9
), 130.1 (C
1
), 129.8 (C
7
), 128.3 (C
8
), 114.2 (C
3
), 55.7 (C
a
c
b
); MS (ESI
7
9
+
81
+
+
m/z (%)) 319 (M Br + H) (100%), 321 (M Br + H) (100%); HRMS ESI Calcd for
+
+
C
16
H16BrO
2
(M + H) 319.0334, found 319.0324.
4
-O-(5-bromo-pentyl)-benzophenone (16b). Compound 16b was synthesized according to
the general procedure for 4-hydroxy-benzophenone monoalkylation from 4-hydroxy-
benzophenone (1.1 g, 5.05 mmol, 1 equiv) and 1,5-dibromopentane (2.9 g, 12.4 mmol, 2.46
equiv). Flash chromatography (Cyclohexane/DCM 1/1 to 1/3) afforded 16b as a colorless oil
(1.3 g, 72% yield): R
f
0.49 (Cyclohexane/DCM 1/2); IR (film) 2943w, 1650s, 1699s, 1255s;
), 7.76 (d, 2H, JH7-H8 = 7.5 Hz, H ), 7.57 (t, 1H,
1
H NMR δ 7.83 (br d, 2H, JH2-H3 = 9.0 Hz, H
2
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5
5
5
5
5
5
5
6
J
H9-H8 = 7.5 Hz, H
9
), 7.48 (t, 2H, JH8-H9 = JH8-H7 = 7.5 Hz, H
), 3.46 (t, 2H, JHe-Hd= 7.0 Hz, H
), 1.86 (tt, 2H, JHb-Hc = 7.5 Hz, JHb-Ha = 6.5 Hz, H
b
8
), 6.95 (d, 2H, JH3-H2 = 9.0 Hz,
), 1.96 (tt, 2H, JHd-Hc = 7.5
), 1.69-1.63 (m, 2H,
H
3
), 4.06 (t, 2H, JHa-Hb = 6.5 Hz, H
a
e
Hz, JHd-He= 7.0 Hz, H
d
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
H
c
); C NMR δ 195.7 (C
5
), 162.8 (C
4
), 138.5 (C
6
), 132.7 (C
2
), 132.0 (C
9
), 130.3 (C
1
), 129.9
+
(C
7
), 128.4 (C
8
), 114.2 (C
3
), 68.1 (C
a
), 33.6 (C ), 32.6 (C
e
d
), 28.5 (C
b
), 24.9 (C
c
); MS (ESI
7
9
+
81
+
+
m/z (%)) 347 (M Br + H) (100%), 349 (M Br + H) (100%); HRMS ESI Calcd for
+
+
18 2
C H20BrO (M + H) 347.0647, found 347.0651.
4-O-(10-bromo-decanyl)-benzophenone (16c). Compound 16c was synthesized according to
the general procedure for 4-hydroxy-benzophenone monoalkylation from 4-hydroxy-
benzophenone (1.0 g, 5.05 mmol, 1 equiv) and 1,10-dibromodecane (3.72 g, 12.4 mmol, 2.46
equiv). Flash chromatography (Cyclohexane/DCM 2/1 to 1/2) afforded 16c as a white solid
(1.70 g, 80% yield): R
f
0.33 Cyclohexane/DCM 1/1); m.p. 58-60 °C; IR (film) 2919m, 2850m,
), 7.77 (d, 2H, JH7-H8 = 7.5 Hz,
), 7.48 (t, 2H, JH8-H9 = JH8-H7 = 7.5 Hz, H ), 6.96 (d, 2H,
), 4.05 (t, 2H, JHa-Hb = 6.5 Hz, H ), 3.42 (t, 2H, JHj-Hi = 7.0 Hz, H ), 1.89-
1
1
638s, 1254s; H NMR δ 7.83 (br d, 2H, JH2-H3 = 9.0 Hz, H
2
H
7
), 7.57 (t, 1H, JH9-H8 = 7.5 Hz, H
9
8
JH3-H2 = 9.0 Hz, H
3
a
j
1.84 (m, 2H, H
i
) , 1.61 (tt, 2H, JHb-Hc = 8.0 Hz, JHb-Ha = 6.5 Hz, H
b
), 1.51-1.41 (m, 4H, H
c
, H
h
2
),
),
13
1
1
2
.39-1.30 (m, 8H, H
32.0 (C ), 130.2 (C
9.6, 29.5, 29.3 (C
d
, H
), 129.9 (C
, C , C , C
e
, H
f
, H
g
); C NMR δ 195.7 (C
5
), 163.1 (C
), 68.5 (C ), 34.2 (C
), 26.2 (C
4
), 138.6 (C
6
), 132.8 (C
9
1
7
), 128.4 (C
), 28.9 (C
8
), 114.2 (C
3
a
j
i
), 33.0 (C ), 29.7,
+
b
d
e
f
g
), 28.4 (C
h
c
); MS (ESI m/z (%)) 417
79
+
81
+
+
+
2
(M Br + H) (100%), 419 (M Br + H) (100%); HRMS Calcd for C23H29BrO (M + H)
4
17.1429, found 417.1434.
α-Bromo-α’-(4-O-benzophenone)-p-xylene (17). Compound 17 was synthesized according
to the general procedure for 4-hydroxy-benzophenone monoalkylation from 4-hydroxy-
benzophenone (1.0 g, 5.05 mmol, 1 equiv) and α,α’-dibromo-p-xylene (3.27 g, 12.4 mmol,
2
.46 equiv). Flash chromatography (Cyclohexane/DCM 1/1 to 1/2) afforded 17 as a white
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solid (845 mg, 44% yield): R
f
0.16 (Cyclohexane/DCM 1/1); m.p. 122-124 °C; IR (film)
1
3
062w, 2862m, 1641s, 1602s, 1250s; H NMR δ 7.84 (d, 2H, JH2-H3 = 8.5 Hz, H
2
), 7.77 (d,
), 7.48 (t, 2H, JH8-H9 = 7.5
), 5.16 (s, 2H, H ), 4.52 (s,
), 138.0 (C ), 136.8 (C ), 132.7 (C
), 114.6 (C ), 69.9 (C
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
H, JH7-H8 = 7.5 Hz, H
7
), 7.58 (t, 1H, JH9-H8 = JH8-H7 = 7.5 Hz, H
), 7.04 (d, 2H, JH3-H2 = 8.5 Hz, H
), 162.4 (C ), 138.5 (C
), 129.9 (C ), 129.6 (C ), 128.4 (C
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, H
8
), 7.46-7.42 (m, 4H, H
c
, H
d
3
a
1
3
2H, H
f
); C NMR δ 195.6 (C
5
4
6
e
b
2
),
),
1
3
32.1 (C
3.1 (C
9
), 130.8 (C
1
7
d
8
), 128.0 (C
c
3
a
+
79
+
81
+
f
); MS (ESI m/z (%)) 381 (M Br + H) (100%), 383 (M Br + H) (100%); HRMS
+
+
Calcd for C21
2
H18BrO (M + H) 381.0490, found 381.0476.
General procedure for azides synthesis by nucleophilic substitution. Caution: The use of
3
3
azide coumpounds has been shown to be hazardous. In our case and at our scale, no
troubles were noticed. To a solution of bromine or tosyl derivative (1 equiv) in DMF (0.9 M),
was added NaN
and then cooled to rt. The mixture was diluted in a 1/1 Et
DMF). The mixture was transferred into a separatory funnel and the aqueous layer was
extracted with Et O (3 × 4 mL for 1 mL of DMF). The combined organic layers were
successively washed with brine and then water. The organic layer was dried (Na SO ),
3
(2 equiv) and NaI (0.5 equiv). The mixture was stirred at 80 °C overnight
2
O/water mixture (8 mL for 1 mL of
2
2
4
filtrated and concentrated in vacuo. The residue was then purified by flash chromatography to
give the corresponding azide.
1
-azido-decane (11a). Azide 11a was synthesized according to the general procedure for
azides synthesis by nucleophilic substitution from bromo-decane (2 g, 9 mmol). Flash
chromatography (Cyclohexane/DCM 9/1) afforded 11a as a colorless oil (1.53 g, 92% yield):
f
R 0.60 (Cyclohexane/DCM 8/2); IR (film) 2926s, 2855s, 2095s, 1475m. Other spectral data
3
4
were in agreement with literature.
1-azido-3-phenyl-propane (11c). Azide 11c was synthesized according to the general
procedure for azides synthesis by nucleophilic substitution from 1-bromo-3-phenyl-propane
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2
2
2
2
2
2
2
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3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
2g, 10 mmol). Flash chromatography (Cyclohexane/DCM 8/2) afforded 11c as a colorless oil
f
(1.63 g, 99% yield): R 0.50 (Cyclohexane/DCM 8/2). Spectral data were in agreement with
3
5
literature.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
-azido-2-(4-biphenylyl)-ethane (11d). Azide 11d was synthesized according to the general
procedure for azides synthesis by nucleophilic substitution from 2-(4’-biphenylyl)ethyl
3
6
tosylate (1.04 mmol, 368mg); Flash chromatography (Cyclohexane/DCM 9/1) afforded 11d
f
as a white solid (230 mg, 99% yield): R 0.26, (Cyclohexane/DCM 9/1); m.p. 102-104 °C; IR
1
(film) 3031m, 2098s, 1487s; H NMR δ 7.62 (d, 2H, JH8-H9 = 8.0 Hz, H
8
), 7.59 (d, 2H, JH5-H4
=
8
.0 Hz, H
5
), 7.45 (tl, 2H, JH9-H8 = JH9-H10 = 8.0 Hz, H
H4-H5 = 8.1 Hz, H ), 3.58 (t, 2H, JH1-H2 = 7.2 Hz, H
), 140.0 (C ), 137.3 (C ), 129.3 (C
), 52.6 (C ), 35.2 (C ); MS APCI (N
(M) 223.1109, found 223.1102.
-azido-propan-3-ol (11e). Azide 11e was synthesized according to the general procedure for
azides synthesis by nucleophilic substitution from 3-bromopropan-1-ol (1 g, 7.23 mmol).
9
), 7.39-7.36 (m, 1H, H10), 7.33 (d, 2H,
1
3
J
4
1
2
), 2.97 (t, 2H, JH2-H1 = 7.2 Hz, H ); C
NMR δ 141.0 (C
27.3 (C
13 3
Calcd for C14H N
7
6
3
4
), 128.9 (C
9
8
), 127.6 (C ), 127.4 (C10),
+
1
5
1
2
2
) m/z (%): 223 (M) (100%); HRMS APPI
+
+
1
f
Flash chromatography (DCM) afforded 11e as a colorless oil (650 mg, 86% yield): R 0.40
37
(
DCM). Spectral data were in agreement with literature.
1
-azido-pentan-5-ol (11f). Azide 11f was synthesized according to the general procedure for
azides synthesis by nucleophilic substitution from 5-bromopentan-1-ol (800 mg, 4.79 mmol).
Flash chromatography (DCM) afforded 11f as a colorless oil (561 mg, 91% yield): R 0.50
DCM); IR (film) 3375br, 2939m, 2860m, 2096s, 1261m. Other spectral data were in
f
(
3
8
agreement with literature.
4
-(3-azido-propyloxy)-benzophenone (11k). Azide 11k was synthesized according to the
general procedure for azides synthesis by nucleophilic substitution from compound 16a (1.02
g, 3.2 mmol). Flash chromatography (DCM) afforded 11k as a colorless oil (798 mg, 88%
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yield): R
7.84 (br d, 2H, JH2-H3 = 9.0 Hz, H
Hz, H ), 7.48 (t, 2H, JH8-H9 = JH8-H7 = 7.5 Hz, H
H, JHa-Hb = 6.0 Hz, H ), 3.55 (t, 2H, JHc-Hb = 6.5 Hz, H
f
0.42 (Cyclohexane/DCM 1/1); IR (film) 2938br, 2098s, 1600m, 1600s; H NMR δ
), 7.77 (d, 2H, JH7-H8 = 7.5 Hz, H ), 7.58 (t, 1H, JH9-H8 = 7.5
), 6.97 (d, 2H, JH3-H2 = 9.0 Hz, H
2
7
9
8
3
), 4.15 (t,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
a
c
), 2.10 (tt, 2H, JHb-Hc = 6.5 Hz, JHb-Ha
=
),
1
3
6.0 Hz, H
b
); C NMR δ 195.7 (C
5
), 162.5 (C
4
), 138.5 (C
6
), 132.8 (C
2
), 132.1 (C
9
), 130.6 (C
1
+
1
29.9 (C
7
), 128.4 (C
8
), 114.2 (C
3
), 64.9 (C
a
), 48.3 (C
c
), 28.9 (C
b
); MS (ESI m/z (%)) 282 (M
+
+
+
+
+
H) (100%); HRMS ESI Calcd for C16
H
16
N
3
O
2
(M + H) 282.1243, found 282.1245.
4-(5-azido-pentyloxy)-benzophenone (11l). 11l was synthesized according to the general
procedure for azides synthesis by nucleophilic substitution from compound 16b (980 mg, 2.82
mmol). Flash chromatography (DCM) afforded 11l as a colorless oil (835 mg, 96% yield): R
f
1
0
2
.37 (Cyclohexane/DCM 1/1); IR (film) 2117s, 1639s, 1602s, 1252s; H NMR δ 7.83 (br d,
H, JH2-H3 = 9.0 Hz, H
2
), 7.76 (d, 2H, JH7-H8 = 7.5 Hz, H
), 6.95 (d, 2H, JH3-H2 = 9.0 Hz, H
), 3.33 (t, 2H, JHe-Hd = 7.0 Hz, H
.61 (tt, 2H, JHd-Hc = 7.5 Hz, JHd-He = 7.0 Hz, H
7
), 7.57 (t, 1H, JH9-H8 = 7.5 Hz, H
9
),
=
),
7.48 (t, 2H, JH8-H9 = JH8-H7 = 7.5 Hz, H
8
3
), 4.06 (t, 2H, JHa-Hb
6
1
.5 Hz, H
a
e b
), 1.87 (tt, 2H, JHb-Hc = 7.0 Hz, JHb-Ha = 6.5 Hz, H
1
3
d
), 1.62-1.56 (m, 2H, H
c
); C NMR δ 195.7
(
C
5
3
), 162.8 (C
), 68.0 (C
4
), 138.5 (C
6
), 132.7 (C
2
), 132.0 (C
9
), 130.3 (C
1
), 129.9 (C
7
), 128.4 (C
8
), 114.2
+
+
(C
a
), 51.5 (C
e
), 28.9 (C
b
), 28.8 (C
d
c
), 23.5 (C ); MS (ESI m/z (%)) 310 (M + H)
+
+
+
(100%); HRMS ESI Calcd for C18
H
20
N
3
O
2
(M + H) 310.1556, found 310.1549.
4
-(10-azido-decanyloxy)-benzophenone (11m). Azide 11m was synthesized according to the
general procedure for azides synthesis by nucleophilic substitution from compound 16c (1.21
g, 2.9 mmol). Flash chromatography (DCM) afforded 11m as a white solid (980 mg, 90%
yield): R
f
0.49 (Cyclohexane/DCM 1/1); m.p. 46-48 °C; IR (film) 2920m, 2851w, 2118s,
1
1
639s, 1602s, 1252s; H NMR δ 7.83 (br d, 2H, JH2-H3 = 9.0 Hz, H
2
), 7.76 (d, 2H, JH7-H8 = 7.5
), 7.48 (t, 2H, JH8-H9 = JH8-H7 = 7.5 Hz, H ), 6.96 (d,
), 4.05 (t, 2H, JHa-Hb = 6.5 Hz, H ), 3.27 (t, 2H, JHj-Hi = 7.0 Hz, H ), 1.83
Hz, H
7
), 7.57 (t, 1H, JH9-H8 = 7.5 Hz, H
9
8
2
H, JH3-H2 = 9.0 Hz, H
3
a
j
2
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
tt, 2H, JHb-Hc = 7.0 Hz, JHb-Ha = 6.5 Hz, H
b
), 1.61 (tt, 2H, JHi-Hj = JHi-Hh= 7.0 Hz, H
i
), 1.51-1.46
), 163.1 (C ), 138.6
), 114.2 (C ), 68.5 (C ), 51.7
1
3
(m, 2H, H
c
), 1.43-1.30 (m, 10H, H
d
, H
e
, H
f
, H
g
, H
h
); C NMR δ 195.7 (C
5
4
(C
6
), 132.8 (C
2
), 132.0 (C ), 130.2 (C
9
1
), 129.9 (C
7
), 126.1 (C
8
3
a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(C
j
), 29.6, 29.6, 29.5, 29.3 (C
e
, C
f
, C
g
, C
b
, C
d
), 29.1 (C
i
), 26.9 (C
c
), 26.2 (C
h
); MS (ESI m/z
+
+
+
+
(%)) 380 (M + H) (100%), 781 (2M + Na) (50%); HRMS ESI Calcd for C23
H
30
N
3
O
2
(M +
+
H) 380.2338, found 380.2332.
4
-(4-Azidoethyl-benzyloxy)-benzophenone (11n). Azide 11n was synthesized according to
the general procedure for azides synthesis by nucleophilic substitution from compound 17
840 mg, 2.20 mmol). Flash chromatography (Cyclohexane/DCM 1/1 to DCM) afforded 11n
(
as a white solid (601 mg, 80% yield): R
f
0.20 (Cyclohexane/DCM 1/1); m.p. 133-135 °C; IR
1
(film) 3675w, 2988m, 2129s, 1644s, 1600s, 1252s; H NMR δ 7.84 (d, 2H, JH2-H3 = 9.0 Hz,
H
2
), 7.77 (d, 2H, JH7-H8 = 7.5 Hz, H
H8-H7 = 7.5 Hz, H ), 7.48 (d, 2H, JHc-Hd = 7.5 Hz, H
d, 2H, JH3-H2 = 9.0 Hz, H ), 5.17 (s, 2H, H ), 4.38 (s, 2H, H
), 135.7 (C ), 132.8 (C ), 132.1 (C
), 114.6 (C ), 70.0 (C ), 54.7 (C
7
), 7.58 (t, 1H, JH9-H8 = 7.5 Hz, H
9
), 7.48 (t, 2H, JH8-H9
=
J
8
c
), 7.37 (d, 2H, JHd-Hc = 7.5 Hz, H
d
), 7.05
1
3
(
(
3
a
f
); C NMR δ 195.7 (C
5
7
), 162.4
), 128.7
C
4
d
), 138.4 (C
6
), 136.6 (C
e
b
2
9
), 130.7 (C
1
), 129.9 (C
+
(C
), 128.4 (C
8
), 128.1 (C
c
3
a
f
); HRMS ESI Calcd for
+
+
C
21
H
18
N
3
O
2
(M + H) 344.1399, found 344.1393.
1
,5-dimethanesulfonyl-pentane (14). To a solution of pentan-1,5-diol (2.50 g, 24 mmol, 1
equiv) in DCM (120 mL), was added triethylamine (7.68 mL, 55 mmol, 2.3 equiv). At 0 °C,
was then added dropwise methanesulfonyl chloride (4.26 mL, 55 mmol, 2.3 equiv). The
mixture was stirred at 0 °C for 30 minutes then at rt for 2 h. The precipitate was filtrated out
and the filtrate was concentrated in vacuo. The resulting oil was purified by flash
chromatography (Cyclohexane/EtOAc 4/6 then 3/7) to give compound 14 as a colorless oil
1
(5.92 g, 99% yield): R
f
0.47 (Cyclohexane/EtOAc 4/6); IR (film) 2948br, 1347s, 1170s; H
NMR δ 4.25 (t, 4H, JHb-Hc = 6.5 Hz, H
b
a c
), 3.01 (s, 6H, H ), 1.87-1.74 (m, 4H, H ), 1.63-1.50
2
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+
(m, 2H, H
d
b a c d
); C NMR δ 69.6 (C ), 37.6 (C ), 28.7 (C ), 21.8 (C ); MS (ESI m/z (%)) 283 (M
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
+
+
+
Na) (100%); HRMS ESI Calcd for C
7
H
16NaO
6
S
2
(M + Na) 283.0386, found 283.0385.
1-azido-5-methanesulfonyl-pentane (15).To a solution of compound 14 (4.75 g, 18 mmol, 1
equiv) in acetonitrile (95 mL), was added sodium azide (1.18 g, 18.2 mmol, 1 equiv). The
mixture was refluxed for 18 h, cooled to rt and the precipate was filtrated out. The filtrate was
concentrated in vacuo. The resulting oil was purified by flash chromatography
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Cyclohexane/EtOAc 7/3) to furnish compound 15 as a colorless oil (1.77 g, 47% yield, 60%),
and starting material 14 as a colorless oil (625 mg, 13% yield). 15: R
f
0.45
1
(
Cyclohexane/EtOAc 7/3); IR (film) 2099s, 1351s, 1173s; H NMR δ 4.22 (t, 2H, JHb-Hc = 6.5
b f a c
Hz, H ), 3.29 (t, 2H, JHf-He = 6.5 Hz, H ), 3.00 (s, 3H, H ), 1.80-1.66 (m, 2H, H ), 1.69-1.57
1
3
(
m, 2H, H
e
), 1.54-1.46 (m, 2H, H
d
); C NMR δ 69.8 (C
b
), 51.3 (C
f
), 37.5 (C
a
c
), 28.8 (C ), 28.4
+
+
+
(C
e
), 22.9 (C
d
); MS (ESI m/z (%)) 208 (M + H) (100%); HRMS ESI Calcd for
+
+
C
6
H
17
N
4
O
3
S (M + NH
4
) 225.1021, found 225.1015.
1
-azido-5-phthalimido-pentane (11g). To a solution of mesylate 15 (428mg, 2.06 mmol, 1
equiv) in DMF (3 mL), was added potassium phthalimide (1.1 g, 6.2 mmol, 3 equiv). The
suspension was stirred at 80 °C for 12 h, cooled to rt and diluted with ether (15 mL) and water
(
15 mL). The aqueous phase was extracted with Et
layer were washed with brine (2 × 20 mL) and water (20 mL), dried (Na
concentrated in vacuo. The residue was purified by flash chromatography
2
O (3 × 15 mL) and the combined organic
2
SO ), filtrated and
4
(
f
Cyclohexane/EtOAc 8/2) to give azide 11g as a colorless oil (370 mg, 70%): R 0.49
1
(Cyclohexane/EtOAc 8/2); IR (film) 2946m, 2098s, 1773m, 1713s, 1397m; H NMR δ 7.86-
7
7
.83 (m, 2H, H
.2 Hz, H ), 1.75-1.62 (m, 2H, H
), 134.1 (C ), 132.3 (C
8
), 7.73-7.70 (m, 2H, H
), 1.68-1.62 (m, 2H, H
), 123.4 (C ), 51.4 (C
9
), 3.70 (t, 2H, JH5-H4 = 7.5 Hz, H
5
), 3.27 (t, 2H, JH1-H2
=
1
3
1
4
2
), 1.46-1.40 (m, 2H, H
3
); C NMR δ
168.6 (C
6
9
7
8
1
), 37.9 (C
5
), 28.6 (C
2
), 28.3 (C
4
), 24.2
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
+
(
C
3
); MS (ESI m/z (%)) 259 (M + H) (100%) 281 (M + Na) (50%); HRMS APCI Calcd for
+
+
13 15 2 2 2
C H N O (M - N + H) 231.1134, found 231.1133.
1-azido-5-morpholino-pentane (11h). To a solution of mesylate 15 (315 mg, 1.51 mmol, 1
equiv) in dry acetonitrile (4 mL), were successively added morpholine (495 µL, 1.82 mmol,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
.2 equiv) and triethylamine (410 µL, 2.95 mmol, 1.95 equiv). The resulting solution was
refluxed for 12 h, cooled to rt and concentrated in vacuo. The residue was purified by flash
chromatography (DCM/MeOH/Et N 98/2/0.5%) to give azide 11h as a colorless oil (268 mg,
N 95/5/0.5%); IR (film) 2943m, 2861m, 2807m, 2095s,
), 3.23 (t, 2H, JH1-H2 = 7.0 Hz, H ), 2.40-
), 1.51 (qt, 2H, JH2-H1 = JH2-H3 7.0 Hz, H ), 1.51-1.45
), 51.4 (C ),
3
f 3
90%): R 0.40 (DCM/MeOH/Et
1
1
2
121s; H NMR δ 3.66 (t, 4H, JH7-H6 = 5.0 Hz, H
7
1
.38 (m, 4H, H
6
), 2.31-2.26 (m, 2H, H
5
2
1
3
(m, 2H, H
4
), 1.39-1.34 (m, 2H, H
3
); C NMR δ 67.0 (C
7
), 58.9 (C
5
), 53.9 (C
6
1
+
+
2
8.8 (C
2
), 26.2 (C
4
), 24.7 (C
3
); MS (ESI m/z (%)) 199 (M+H) ; HRMS APCI Calcd for
+
+
C
9
H
19
N
4
O (M + H) 199.1559, found 199.1556.
Cycloheptylazide (11b). Caution: this azide is volatile. To a solution of cycloheptylamine
.
(
292 mg, 2.58 mmol, 1 equiv), K
2
CO
3
(713 mg, 5.16 mmol, 2.05 equiv) and CuSO
4
5H
2
O (65
mg, 0.26 mmol, 0.1 equiv), in methanol (20 mL) was added in one portion imidazole-1-
31
sulfonyl-azide-hydrochloride (649 mg, 3.10 mmol, 1.2 equiv). The mixture was stirred at rt
for 18 h. After addition of water (50 mL), the aqueous phase was extracted with Et
mL). The combined organic layer were dried (Na SO ), filtrated and concentrated without
heating in vacuo. The residue was purified by flash chromatography (DCM) to give azide 11b
as a colorless oil (286 mg, 80% yield): R 0.70 (Cyclohexane/DCM = 8/2); IR (film) 2096s,
2
O (3 × 50
2
4
f
3
5b
1
508m, 1231m, 1079m. Other spectral data were in agreement with literature.
1
-(3-azido-propyl)-imidazole (11i). To a solution of 1-(3-amino-propyl)-imidazole (810 mg,
.
6.47 mmol, 1 equiv), K
2
CO
3
(1.83 g, 13.26 mmol, 2.05 equiv) and CuSO
4
5H
2
O (162 mg,
0
.65 mmol, 0.1 equiv), in methanol (20 mL) was added in one portion imidazole-1-sulfonyl-
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azide-hydrochloride (1.6 g, 7.76 mmol, 1.2 equiv). The mixture was stirred at rt for 18 h.
After addition of water (30 mL), the aqueous phase was extracted with DCM (3 × 50 mL).
The combined organic layer were dried (Na
2 4
SO ), filtrated and concentrated in vacuo. The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
residue was purified by flash chromatography (EtOAc/MeOH 98/2) to give azide 11i as a
colorless oil (636 mg, 65% yield): R
f
0.30 (EtOAc/MeOH 98/2); IR (film) 3101w, 2942w,
1
2
900w, 2099s, 1629s, 1508m, 1231m, 1079m; H NMR δ 7.48 (br s, 1H, H
4
), 7.08 (br s, 1H,
), 3.30 (t, 2H, JH1-H2 = 7.0 Hz, H ),
), 47.9
H
5
), 6.91 (br s, 1H, H
6
), 4.06 (t, 2H, JH3-H2 = 7.0 Hz, H
3
1
1
3
2.02 (qt, 2H, JH2-H1 = JH2-H3 = 7.0 Hz, H
2
); C NMR δ 137.3 (C
4
), 129.9 (C
5
), 118.8 (C
6
+
+
+
(
C
3
), 43.8 (C
1
), 30.4 (C
2
); MS (ESI m/z (%)) 152 (M + H) (100%), 303 (2M + H) (100%);
+
+
HRMS APCI Calcd for C
6
10 5
H N (M + H) 152.0936, found 152.0937.
General procedure for Cu(I)-catalyzed azide-alkyne cycloaddition, preparation of
compounds 18a-n. To a solution of alkyne 10 (1 equiv) and azide partner 11a-n (1 to 2 eq) in
2 4
tert-BuOH/H O (1.5 mL/500 µL) were successively added CuSO (0.1 equiv), sodium
ascorbate (0.3 equiv) and N-ethyldiisopropylamine (2.2 equiv). The suspension was sonicated
for 5 min to solubilise all reagents. The mixture was stirred at rt for 18 h and diluted with
DCM (40 mL) and water (15 mL). The aqueous phase was extracted with DCM (6 × 40 mL)
and the combined organic layers were dried (Na
The residue was then purified by flash chromatography to give the corresponding triazole
8a-n.
2 4
SO ), filtrated and concentrated in vacuo.
1
Compound 18a. Triazole 18a was synthesized according to the general procedure for Cu(I)-
catalyzed azide-alkyne from alkyne 10 (230 mg, 0.36 mmol) and azido-decane 11a (132 mg,
0
.72 mmol, 2 equiv). Flash chromatography (Cyclohexane/EtOAc 1/1) afforded 18a as a
white powder (180 mg, 61% yield): R
f
0.17 (Cyclohexane/EtOAc 1/1); m.p. 118-120 °C; [α]
D
1
- 43 (c 1.0, CH Cl
2
2
); IR (film) 2933m, 1714s, 1386m; H NMR δ 7.99 (s, 1H, NH), 7.84-7.82
6
(m, 2H, H11’’), 7.74-7.72 (m, 2H, H12’’), 7.67 (s, 1H, H7’), 7.39 (d, 1H, JH6-H5 = 8.0 Hz, H ),
2
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1
5
.88 (d, 1H, JH1’-H2’ = 2.5 Hz, H1’), 5.80 (dd, 1H, JH5-H6 = 8.0 Hz, JH5-NH = 2.5 Hz, H ), 5.40 (s,
H, H1’’), 5.20 (d, 1H, JH5’-H4’ = 5.5 Hz, H5’), 5.00 (dd, 1H, JH3’-H2’ = 6.0 Hz, JH3’-H4’ = 3.0 Hz,
H
H
H
H
3’), 4.90 (dd, 1H, JH2’-H3’ = 6.0 Hz, JH2’-H1’ = 2.5 Hz, H2’), 4.79 (d, 1H, JH2’’-H3’’ = 5.5 Hz,
2’’), 4.74 (d, 1H, JH3’’-H2’’ = 5.5 Hz, H3’’), 4.50 (dd, 1H, JH4’-H5’ = 5.5 Hz, JH4’-H3’ = 3.0 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4’), 4.36-4.33 (m, 3H, H8’,
5’’a), 3.33 (dd, 1H, JH5’’b-H5’’a = 14.0 Hz, JH5’’b-H4’’ = 3.5 Hz, H5’’b), 1.89-1.86 (m, 2H, H9’),
.63-1.55 (m, 2H, H7’’), 1.56 (s, 3H, H19’), 1.52 (q, 2H, JH7’’-H8’’ = 8.0 Hz, H7’’), 1.32 (s, 3H,
19’), 1.26-1.14 (m, 14H, H10’, H11’, H12’, H13’, H14’, H15’, H16’), 0.88-0.80 (m, 9H, H8’’, H17’);
H4’’), 3.64 (dd, 1H, JH5’’a-H5’’b = 14.0 Hz, JH5’’a-H4’’ = 10.5 Hz,
1
H
1
3
C NMR δ 168.3 (C9’’), 162.7 (C
4
), 150.2 (C
2
), 144.9 (C6’), 141.6 (C
6
), 134.4 (C12’’), 131.9
), 92.9 (C1’), 87.8
(C
10’’), 123.5 (C11’’, C7’), 117.2 (C6’’), 114.8 (C18’), 109.5 (C1’’), 103.0 (C
5
(C4’), 85.9 (C2’’), 84.7 (C4’’), 83.9 (C2’), 82.5 (C3’’), 80.9 (C3’), 72.7 (C5’), 50.6 (C8’), 40.4
(C
5’’), 31.9 (C9’), 30.3 (C7’’), 29.6, 29.5, 29.4, 29.3, 29.0, 27.3, 26.9, 26.5, 25.4, 22.7 (C7’’,
-
C
C
19’, C10’, C11’, C12’, C13’, C14’, C15’ ,C16’), 8.7, 8.4, 7.4 (C8’’, C17’); HRMS ESI Calcd for
-
-
42
55 6
H N O11 (M - H) 819.3929, found 819.3937.
Compound 18b. Triazole 18b was synthesized according to the general procedure for Cu(I)-
catalyzed azide-alkyne cycloaddition from alkyne 10 (210 mg, 0.33 mmol) and azido-
cycloheptane 11b (55 mg, 0.40 mmol, 1.2 equiv). Flash chromatography
(
Cyclohexane/EtOAc 4/6) afforded 18b as a white powder (180 mg, 64% yield): R
f
0.31
(Cyclohexane/EtOAc 3/7); m.p. 143-145 °C; [α] - 30 (c 1.0, CH Cl ); IR (film) 2980m,
D 2 2
1
1
717s, 1697s, 1396m,1086s; H NMR δ 9.70-9.65 (m, 1H, NH), 7.79-7.76 (m, 2H, H11’’), 7.69
(
s, 1H, H7’), 7.69-7.67 (m, 2H, H12’’), 7.31 (d, 1H, JH6-H5 = 8.0 Hz, H
6
), 5.89 (d, 1H, JH1’-H2’
), 5.36 (s, 1H, H1’’), 5.15 (d,
H, JH5’-H4’ = 6.0 Hz, H5’), 5.00 (dd, 1H, JH3’-H2’ = 6.5 Hz, JH3’-H4’ = 4.0 Hz, H3’), 4.85 (dd, 1H,
H2’-H3’ = 6.5 Hz, JH2’-H1’ = 3.0 Hz, H2’), 4.75 (d, 1H, JH2’’-H3’’ = 6.5 Hz, H2’’), 4.70 (d, 1H, JH3’’-
H2’’ = 6.5 Hz, H3’’), 4.64-4.58 (m, 1H, H8’), 4.47 (dd, 1H, JH4’-H5’ = 6.0 Hz, JH4’-H3’ = 4.0 Hz,
=
3
1
.0 Hz, H1’), 5.71 (dd, 1H, JH5-H6 = 8.0 Hz, JH5-NH = 1.5 Hz, H
5
J
2
8
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The Journal of Organic Chemistry
1
2
3
H
4’), 4.27 (dd, 1H, JH4’’-H5’’a = 10.5 Hz, JH4’’-H5’’b = 4.5 Hz, H4’’), 3.58 (dd, 1H, JH5’’a-H5’’b =
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
4.0 Hz, JH5’’a-H4’’ = 10.5 Hz, H5’’a), 3.33 (dd, 1H, JH5’’b-H5’’a = 14.0 Hz, JH5’’b-H4’’ = 4.5 Hz,
H
5’’b), 2.15-2.10 (m, 2H, H9’a), 1.99-1.89 (m, 2H, H9’b), 1.77-1.74 (m, 2H, H10’a), 1.64-1.53
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(m, 8H, H7’’, 11’), 1.52 (s, 3H, H13’), 1.47 (q, 2H, JH7’’-H8’’ = 7.0 Hz, H7’’), 1.29 (s, 3H,
10’b,
H H
1
3
H
13’), 0.78 (t, 3H, JH8’’-H7’’ = 7.0 Hz, H8’’), 0.76 (t, 3H, JH8’’-H7’’ = 7.0 Hz, H8’’); C NMR δ
), 134.2 (C12’’), 131.9 (C10’’), 123.4
11’’), 121.7 (C7’), 117.1 (C6’’), 114.7 (C12’), 109.6 (C1’’), 103.0 (C ), 92.4 (C1’), 87.4 (C4’),
85.9 (C2’’), 84.7 (C4’’), 83.8 (C2’), 82.5 (C3’’), 80.8 (C3’), 72.2 (C5’), 62.6 (C8’), 40.4 (C5’’), 35.6
1
4 2 6
68.1 (C9’’), 163.4 (C ), 150.4 (C ), 144.5 (C6’), 141.3 (C
(C
5
(
C
C
9’), 29.5 (C7’’), 28.9 (C7’’), 27.7 (C11’), 27.2 (C13’), 25.4 (C13’), 24.3 (C10’), 8.3 (C8’’), 7.4
+
+
+
(
49 6
8’’); HRMS ESI Calcd for C39H N O11 (M + H) 777.3459, found 777.3491.
Compound 18c. Triazole 18c was synthesized according to the general procedure for Cu(I)-
catalyzed azide-alkyne cycloaddition from alkyne 10 (200 mg, 0.31 mmol) and 1-azido-3-
phenyl-propane 11c (100 mg, 0.63 mmol,
2
equiv). Flash chromatography
Cyclohexane/EtOAc 3/7) afforded 18c as a white powder (111 mg, 45% yield): Rf 0.54
EtOAc); m.p. 125-127 °C; [α] - 34 (c 1.0, CH Cl ); IR (film) 2940m, 2350m, 1715s, 1390m;
H NMR δ 8.92 (s, 1H, NH), 7.80-7.77 (m, 2H, H11’’), 7.72-7.68 (m, 2H, H12’’), 7.72 (s, 1H,
7’), 7.40 (d, 1H, JH6-H5 = 8.0 Hz, H ), 7.27-7.21 (m, 2H, H12’), 7.16-7.12 (m, 3H, H13’, H14’),
.86 (d, 1H, JH1’-H2’ = 3.0 Hz, H1’), 5.77 (dd, 1H, JH5-H6 = 8.0 Hz, JH5-NH = 2.0 Hz, H ), 5.40 (s,
H, H1’’), 5.23 (d, 1H, JH5’-H4’ = 6.5 Hz, H5’), 4.97 (dd, 1H, JH3’-H2’ = 6.5 Hz, JH3’-H4’ = 4.0 Hz,
(
(
D
2
2
1
H
6
5
1
5
H
H
H
H
3’), 4.92 (dd, 1H, JH2’-H3’ = 6.5 Hz, JH2’-H1’ = 3.0 Hz, H2’), 4.79 (d, 1H, JH2’’-H3’’ = 6.5 Hz,
2’’), 4.73 (d, 1H, JH3’’-H2’’ = 6.5 Hz, H3’’), 4.50 (dd, 1H, JH4’-H5’ = 6.5 Hz, JH4’’-H3’ = 4.0 Hz,
4’), 4.39-4.32 (m, 3H, H8’,
H4’’), 3.65 (dd, 1H, JH5’’a-H5’’b = 14.0 Hz, JH5’’a-H4’’ = 10.0 Hz,
5’’a), 3.37 (dd, 1H, JH5’’b-H5’’a = 14.0 Hz, JH5’’b-H4’’ = 4.5 Hz, H5’’b), 2.62-2.58 (m, 2H, H10’),
2.27-2.21 (m, 2H, H9’), 1.64-1.56 (m, 2H, H7’’), 1.55 (s, 3H, H16’), 1.51 (q, 2H, JH7’’-H8’’ = 7.5
Hz, H7’’), 1.30 (s, 3H, H16’), 0.80 (t, 3H, JH8’’-H7’’ = 7.5 Hz, H8’’), 0.79 (t, 3H, JH8’’-H7’’ = 7.5
2
9
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