De novo synthetic route to a combinatorial library of peptidyl nucleosides

Article abstract of DOI:10.1080/15257770801944394

A stereoselective synthetic route has been developed for the combinatorial synthesis of a structurally unique class of C-4′ side chain modified peptide-linked nucleosides. The synthetic strategy and approach involves initial synthesis of a strategically functionalized amino butenolide template, utilizing L-serine as a chiral starting material. Subsequent transformation of the above lactone to C4′ aminoalkyl substituted nucleosides, followed by the peptidic coupling of the C4′ side chain amine with various amino acids completed the syntheses of the target peptidyl nucleosides. Employing the above route, and utilizing a combination of easily available nucleobases (4) and amino acids (6) as the two diversity elements, synthesis of a 24-member combinatorial library of the title peptide-linked nucleosides has been accomplished. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770801944394

Nucleosides, Nucleotides and Nucleic Acids, 27:389–407, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770801944394
DE NOVO SYNTHETIC ROUTE TO A COMBINATORIAL LIBRARY
OF PEPTIDYL NUCLEOSIDES
Kevin W. C. Poon, Ningning Liang, and Apurba Datta
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas, USA
A stereoselective synthetic route has been developed for the combinatorial synthesis of a
2
structurally unique class of C-4 ꢁ side chain modified peptide-linked nucleosides. The synthetic
strategy and approach involves initial synthesis of a strategically functionalized amino butenolide
template, utilizing L-serine as a chiral starting material. Subsequent transformation of the above
lactone to C4 ꢁ aminoalkyl substituted nucleosides, followed by the peptidic coupling of the C4 ꢁ side
chain amine with various amino acids completed the syntheses of the target peptidyl nucleosides.
Employing the above route, and utilizing a combination of easily available nucleobases (4) and
amino acids (6) as the two diversity elements, synthesis of a 24-member combinatorial library of the
title peptide-linked nucleosides has been accomplished.
Keywords Peptide-nucleoside hybrid; C4 ꢁ-homologation; combinatorial synthesis;
L-serine; chiral aminobutenolide
INTRODUCTION
The design and synthesis of biomimetic molecular entities is an integral
part of contemporary drug discovery endeavors. In this context, con-
struction of multifunctional scaffolds, grafting various biologically relevant
structural units on a common framework, is a highly attractive strategy
for the development of new chemical entities of potential biomedical
application.[1] Amino acids and nucleosides are among the most common
and fundamental building blocks of a vast array of natural macromolecules.
Therefore, creation of designer molecules via a judicious combination of
the above building blocks provides an opportunity to access new and diverse
classes of ‘nature-like’ and yet non-natural organic compounds.[2] Along the
Received 10 October 2007; accepted 20 December 2007.
We thank the National Institute of General Medical Sciences (KU-CMLD, P50 GM-069663) for
financial support, and, Tanvi Parikh for her assistance with some initial experiments.
Address correspondence to Apurba Datta, Department of Medicinal Chemistry, The University of
Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas, 66045-7582, USA. E-mail: adutta@ku.edu
389

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K. W. C. Poon et al.
above lines, and as part of an ongoing program[3] investigating the complex
peptidyl nucleoside families of antifungal antibiotics,[4] we recently initiated
studies exploring the combinatorial synthesis of a new class of structurally
unique amino acid-nucleoside hybrids. Details of the synthesis leading to a
24-member library of peptide-linked nucleosides are reported herein.
In recent times, structurally modified nucleoside building blocks and
oligonucleotides thereof have gained much attention by virtue of their
significant biological profiles, including their use in antisense, antiviral, and
anticancer therapies.[5] This awareness of the potential therapeutic utility of
nucleoside analogs has stimulated an intensive effort in the search for newer
generations of structurally modified analogs, designed to improve their
potency and circumvent the various physical and biological limitations.[6]
Not surprisingly therefore, synthesis of various nucleoside combinatorial
libraries continues to be an active area of research.[7,8] However, almost all
of the nucleoside library construction efforts reported so far are directed
at generating libraries by derivatization of the nucleobase component of
preformed nucleosides. Moreover, the usual approaches in these library
syntheses endeavors employed readily available carbohydrate precursors to
access the central nucleoside scaffold, thereby limiting the opportunities
towards sugar core modification. The above carbohydrate approach in
nucleoside core construction has considerable merit when it can be applied
in an efficient manner, however, when the desired end product incorporates
unusual residues or nonnatural stereochemistry, the relative inflexibility
of the carbohydrate scaffold toward core modifications and the multiple
hydroxyl groups as present in the starting material, often necessitates
lengthy reaction sequence and extensive protection-deprotection protocols.
To circumvent the disadvantages inherent in the carbohydrate approach, an
alternative reaction strategy, involving stereoselective de novo construction
of the nucleoside core of the desired targets, starting from a more simple
non-carbohydrate synthon, is an attractive proposition.[9] Accordingly, em-
ploying an amino acid chiral pool approach, we devised a strategy involving
utilization of easily available L-serine towards initial construction of a
pivotal alkylamino substituted chiral butenolide 1 (Figure 1), its subsequent
conversion to a C4ꢁ homologated and alkylamino substituted enantiopure
nucleoside 2, followed by peptidic coupling of the strategic side chain
amine functionality with various amino acids to form the desired peptidyl
nucleoside scaffold 3.
RESULTS AND DISCUSSION
Following a recently developed protocol from our laboratory,[3b,10] read-
ily available L-serine was converted to the corresponding multifunctional
aminobutenolide 1 (Scheme 1) in 42% overall yield. As evident from its

Peptidyl Nucleosides
391
FIGURE 1 Strategy for combinatorial synthesis of a C4’-homologated peptidyl nucleoside library.
structure, the strategically functionalized lactone 1 already incorporates the
desired dual modifications at C4ꢁ (nucleoside numbering), amine substitu-
tion and homologation of the side chain. Furthermore, the ring olefinic
bond is an ideal precursor for its eventual conversion to a vic-diol function-
ality. Additionally, the enone moiety of 1 also provides an easy handle for
potential structural modifications (epoxidation, nucleophilic/electrophilic
addition, deoxygenation, halogenation, hydrogenation, etc.) at these sites.
Similarly, the lactone carbonyl is well suited for the desired introduction of
nucleobases. Importantly, the chirality of the starting amino acid (L- or D-)
can be easily utilized towards stereoselective formation of various possible
stereoisomers of the lactone 1. The resident chirality of 1 in turn will
dictate the induction and control of asymmetry in the subsequent reactions
(vide infra), thereby providing selective access to various stereoisomeric end
products.
In conformity with our earlier developed protocol, potassium osmate
catalyzed stereoselective dihydroxylation of 1 resulted in the corresponding
diol 4 (Scheme 1) as the only product.[3b] Subsequent partial reduction of
the lactone, followed by treatment of the resulting lactol with an excess of
acetic anhydride provided the triacetate derivative 5 in good overall yield.
The desired nucleobase introduction was performed by reacting 5 with
bis-silylated thymine in the presence of TMSOTf (Vorbru¨ggen protocol),[11]
resulting in a highly regio- (N-1 selective), and stereoselective formation
of the nucleoside derivative 6a. The observed stereoselectivity[3b] in the
nucleobase incorporation can be attributed to the neighboring C2-acetoxy
group-assisted stabilization of the oxonium ion intermediate, resulting
in blocking of the β-face and consequent approach of the nucleobase
exclusively from the α-face. Interestingly, the acidic reaction condition
employed also led to clean cleavage of the side chain N ,O-acetonide
protection. To achieve diversification, the nucleoside forming reaction was
then extended to synthesize the corresponding uridine, 5-fluorouridine,
and cytidine analogs. Accordingly, condensation of 5 with the respective
bis-silylated nucleobases[11] resulted in the expected nucleoside derivatives
in respectable yields. In order to facilitate purification, without isolation, the
free primary hydroxyl containing nucleosides as obtained from the above
reaction were directly subjected to acetylation under standard conditions to
result in the corresponding fully protected nucleoside derivatives 7a–d.

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K. W. C. Poon et al.
SCHEME 1 Synthesis of peptidyl nucleoside library.
The final steps toward library construction involved hydrogenolytic
unmasking of the side chain amine functionality of the above nucleosides,
followed by standard peptidic coupling of the resulting free amine with a
variety of suitably protected amino acids. Employing the above sequence of
reactions, the combination of the four nucleosides 7a–d with six different
amino acids (A–F) resulted in the construction of the 24-member library of
peptidyl nucleosides 8aA–8dF (Scheme 1). It is worth mentioning that, in
the final library-forming step (7 to 8), the two step yields as reported are not
the optimized yields, resulting in the rather large variation (18–91%) in the
product yields.
To demonstrate the feasibility of removal of the protecting groups, two
representative peptidyl nucleosides 8aB and 8bC (Scheme 2) also were
subjected to global deprotection. Thus, following a sequence of initial
alkaline hydrolysis of the acetate groups and subsequent acidic cleavage of
the t-butylcarbamate under standard conditions afforded the fully depro-
tected nucleoside derivatives 9 and 10, respectively, in high overall yields

Peptidyl Nucleosides
393
SCHEME 2 Removal of protecting groups.
(Scheme 2). The above library members are presently being evaluated
against various biological screens.
CONCLUSION
In conclusion, starting from an L-serine derived chiral aminobutenolide
intermediate, de novo synthetic route to a unique class of C4ꢁ homologated
aminoalkyl nucleoside has been developed. Subsequent anchoring of vari-
ous amino acids on the side chain amine functionality of the nucleosides
resulted in a structurally novel nucleoside-peptide hybrid. Utilizing readily
available nucleobases (4) and amino acids (6) as the two diversity elements,
the above method was successfully employed to construct a 24-member
training library of peptidyl nucleosides. In addition to allowing easy access to
a novel structural scaffold of potential biological significance, the other ad-
vantages of the present synthesis are expected to be the inherent flexibility
of the method towards extensive structural modifications, stereocontrolled
reactions, and the presence of multiple functional sites for further derivati-
zation/library construction.
EXPERIMENTAL SECTION
All of the solvents and reagents used were obtained commercially and
used as such unless noted otherwise. Moisture or air sensitive reactions were
conducted under argon atmosphere in oven dried (120◦C) glass apparatus.
Diethyl ether and THF were distilled from sodium benzophenone ketyl,
while dichloromethane was distilled over calcium hydride, prior to use.

394
K. W. C. Poon et al.
Solvents were removed under reduced pressure using standard rotary
evaporators. Flash column chromatography was carried out using Silica gel
60 (230–400 mesh), while thin layer chromatography (TLC) was carried out
on Silica Gel HLF, precoated glass plates. All yields reported refer to isolated
material judged to be homogeneous by TLC and NMR spectroscopy. Proton
and carbon nuclear magnetic resonance spectra were recorded using a
Bruker DRX 400 MHz or Bruker DRX 500 MHz spectrometer (Bruker
Biospin Corp., Billerica, MA, USA). Unless noted otherwise, NMR spectra
were recorded with the chemical shifts (δ) reported in ppm relative to
Me4Si (for 1H) and CDCl3 (for 13C) as internal standards respectively. Mass
spectra were obtained from a ZAB HS mass spectrometer (VG Analytical
Ltd., Manchester, UK) equipped with a 11/250 data system. Fast-atom
bombardment mass spectrometry (FAB-MS) experiments were performed
with a Xenon gun operated at 8 Kev energy and 0.8 mA emission at the
MS laboratory at the University of Kansas. Fast-atom bombardment high
resolution mass spectra (FAB-HRMS) were recorded at 1:10,000 resolution
using linear voltage scans under data system control and collected in a multi-
channel analyzer mode (MCA). A Shimadzu FTIR-8400S spectrophotome-
ter was used to record infrared spectra (Shimadzu Scientific Instruments,
Columbia, MD, USA).
Starting from L-serine, the lactone 1, diol 4, and the triacetate deriva-
tive 5 were prepared following an earlier reported procedure from our
laboratory.[3b] The spectral and analytical data of all of the above com-
pounds were in good agreement with those reported for the corresponding
enantiomeric products reported previously.[3b]
(2S,3S,4S,5R)-2-((S)-1-(Benzyloxycarbonylamino)-2-hydroxyethyl)-5-(5-
methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl
5[3b]
diethanoate (6a). To a solution of the triacetate
(1 g, 2.09 mmol) in
anhydrous (CH2Cl)2 (25 mL) was added bis(trimethylsilyl)thymine (1.41 g,
5.21 mmol; 2.5 equiv), followed by freshly distilled TMSOTf (1.9 mL, 10.43
mmol; 5 equiv). After stirring at room temperature for 2 hours, the reaction
was quenched by the addition of saturated aqueous NaHCO3 solution (10
mL). The organic layer was separated and the aqueous layer was extracted
with CHCl3 (3 × 10 mL). The combined organic extract was washed with
brine (10 mL), dried over Na2SO4, concentrated under vacuum, and the
residue was purified by flash chromatography (EtOAc: hexanes = 3/2 to
25
4/1) to yield pure 6a (842 mg, 80%) as a foamy semisolid: [α]D −4.0 (c 1,
CHCl3); IR (neat) broad 3306, 1751, 1747, 1693 cm−1; 1H NMR (400MHz,
CDCl3) δ 8.37 (s, 1H), 7.46–7.33 (m, 5H), 7.08 (s, 1H), 5.79 (d, J = 5.5 Hz,
1H), 5.63 (br s, 1H), 5.51–5.48 (m, 1H), 5.37–5.34 (m, 1H), 5.14–5.13 (m,
2H), 4.39–4.31 (m, 1H), 4.22–4.05 (m, 1H), 4.0–3.92 (m, 1H), 3.78–3.70
(m, 1H), 2.65 (br s, 1H, exchangeable with D2O), 2.09 (s, 6H), 1.90 (s, 3H).
13C NMR (125.8 MHz, CDCl3) δ 170.5, 170.3, 164.2, 157.1, 151.2, 137.1,
136.6, 128.9, 128.6, 128.5, 112.3, 89.4, 81.9, 72.9, 71.2, 67.5, 61.8, 53.9, 20.9,

Peptidyl Nucleosides
395
20.8, 12.8; HRMS calcd. for C23H28N3O10 m/z (M+H) 506.1775, found
506.1764.
General procedure for the synthesis of the nucleoside triacetates 7a-d.
Following the same procedure as in 6a above, the triacetate 5 was sepa-
rately reacted with the corresponding bis-silylated nucleobases derived from
uracil, 5-fluorouracil, and N 4-acetylcytosine, respectively. After standard
workup of the reaction mixture as above, the crude nucleoside adducts
obtained were subjected to acetylation without any further purification.
After dissolving the above nucleoside adducts (6a-d) in anhydrous
CH2Cl2 (100 mg/mL), the solution was cooled to 0◦C (ice-bath), followed
by sequential addition of pyridine (4 equiv), 4-DMAP (10 mol%), and
acetic anhydride (2 equiv). The cooling bath was removed and stirring
continued at room temperature for 1 hour. The reaction was quenched
by the addition of a saturated solution of aqueous NaHCO3. After stirring
for 15 minutes, the organic layer was separated and the aqueous layer
extracted with CHCl3 (3 times). The combined extract was dried over
anhydrous Na2SO4, concentrated under vacuum, and the crude product
purified by flash chromatography (EtOAc: hexanes = 1/1 to 2/1) to provide
the acetylated nucleoside derivatives 7a-d.
(2S,3S,4S,5R)-2-((S)-1-(Benzyloxycarbonylamino)-2-(ethanoyloxy)ethyl)
-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-
diyl diethanoate (7a): Purified by column chromatography (hexane/ethyl
acetate: 1/2) to obtain the product as a white solid (183 mg, 74%). 1HNMR
(400 MHz, CDCl3): δ 9.12 (s, 1H), 7.35–7.33 (m, 5H), 7.05 (s, 1H), 5.89
(s, 1H), 5.52–5.38 (m, 3H), 5.15–5.08 (m, 2H), 4.27 (m, 3H), 4.12–4.10
(m, 1H), 2.07 (s, 3H), 2.06(s, 3H), 2.04 (s, 3H), 1.91 (s 3H). 13CNMR
(100.6 MHz, CDCl3): δ 170.6, 169.6, 169.5, 163.4, 156.2, 150.4, 135.9, 135.7,
128.6, 128.3, 128.2, 112.1, 88.1, 80.7, 72.1, 70.7, 67.3, 62.9, 51.4, 20.7,
20.4, 12.5. HRMS (ES+) found 548.1875 (M+H) (calc for C25H30N3O11:
548.1880).
(2S,3S,4S,5R)-2-((S)-1-(Benzyloxycarbonylamino)-2-(ethanoyloxy)ethyl)
-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyldieth
anoate (7b). Purified by column chromatography (hexane/ethyl acetate:
1/1 to 1/2) to obtain the product as a white solid (210 mg, 75%). 1HNMR
(400 MHz, CDCl3): δ 9.00 (brs, 1H), 7.35–7.31 (m, 5H), 7.24–7.21 (m, 1H),
5.84 (s, 1H), 5.73 (d, J = 7.6 Hz, 1H), 5.52–5.49 (m, 1H), 5.42–5.38 (m,
2H), 5.11 (s, 2H), 4.24 (s, 3H), 4.14–4.11 (m, 1H), 2.08, 2.06, 2.05 (3s, 9H).
13CNMR (125.8 MHz, CDCl3): δ 170.6, 169.6, 169.5, 162.5, 156.1, 150.1,
140.2, 136.0, 128.6, 128.4, 128.2, 103.5, 88.7, 80.9, 72.2, 70.7, 67.3, 62.9,
51.3, 34.6, 34.5, 31.6, 29.0, 25.3, 22.6, 20.7, 20.4, 14.1, 11.4. HRMS (ES+)
found 534.1725 (M+H) (calc for C24H28N3O11: 534.1724).
(2S,3S,4S,5R)-2-((S)-1-(Benzyloxycarbonylamino)-2-(ethanoyloxy)ethyl)
-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-
diyl diethanoate (7c). Purified by column chromatography (hexane/ethyl

396
K. W. C. Poon et al.
acetate: 1/1 to 1/2) to obtain the product as a white solid (161 mg, 61%).
1HNMR (500 MHz, CDCl3): δ 8.82 (brs, 1H), 7.40–7.31 (m, 6H), 5.87 (brs,
1H), 5.50–5.48 (m, 1H), 5.37–5.34 (m, 2H), 5.16–5.10 (m, 2H), 4.28–4.23
(m, 3H), 4.14–4.11 (m, 1H), 2.08–2.06 (3s, 9H). 13CNMR (125.8 MHz,
CDCl3): δ 170.6, 169.7, 169.5, 156.4, 156.2, 156.1, 148.7, 141.8, 139.9, 135.8,
128.6, 128.4, 128.3, 124.5, 124.2, 88.2, 81.2, 72.1, 70.5, 67.5, 62.9, 51.3,
29.7, 21.1, 20.7, 20.4. HRMS (ES+) found 574.1447 (M+Na) (calc for
C24H26FN3O11Na: 574.1449).
(2S,3S,4S,5R)-2-((S)-1-(Benzyloxycarbonylamino)-2-(ethanoyloxy)ethyl)
-5-(4-ethanamido-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl
diethanoate (7d). Purified by column chromatography (methylene
chloride/methanol: 98/2 to 96/4) to obtain the product as a white solid
1
(174 mg, 75%). HNMR (500 MHz, CDCl3): δ 9.78 (brs, 1H), 7.68 (d, J
= 7.5 Hz, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.34–7.28 (m, 5H), 5.91 (d, J
= 5.0 Hz, 1H), 5.60–5.55 (m, 2H), 5.50 (bs, 1H), 5.10 (s, 2H), 4.29–4.22
(m, 4H), 2.24 (s, 3H), 2.05–2.02 (m, 9H). 13CNMR (125.8 MHz, CDCl3):
δ 170.9, 170.7, 169.5, 169.4, 163.2, 156.2, 154.9, 145.1, 136.2, 128.5, 128.2,
128.1, 97.4, 90.6, 81.0, 73.2, 70.9, 67.2, 62.9, 60.3, 51.4, 34.6, 34.5, 32.5, 29.7,
29.0, 25.3, 24.9, 22.6, 20.7, 20.4, 20.3, 14.2, 14.1, 11.4. HRMS (ES+) found
575.2009 (M+H) (calc for C26H31N4O11: 575.1989).
General procedure for the synthesis of the peptidyl nucleosides 8aA-
8dF. Step 1 (Cbz-deprotection): Each of the side chain N -Cbz protected nu-
cleoside derivatives 7a-d, dissolved separately in ethyl acetate (100 mg/mL)
were treated with 10% palladium on activated carbon (wt. of nucleoside/wt.
of Pd-C = 1/0.1), and the resulting mixture stirred at room temperature
under H2 atmosphere (balloon). After stirring for 2–3 hours (monitored by
TLC), the reaction mixtures were filtered through Celite and the residue
washed thoroughly with ethyl acetate (3×) and methanol (3×). Removal
of solvent under vacuum and drying of the resulting oily residue under
high vacuum provided the corresponding free amino derivatives. The crude
amines thus obtained were used directly for the peptidic coupling reaction
without any further purification.
Step 2 (Peptidic coupling): Each of the the aminoalkyl nucleoside
derivatives as obtained above, were divided into six equal portions, dissolved
in a mixture of anhydrous THF/CH2Cl2 (1:1, 10% solution by wt.), followed
by sequential addition of the different N -Boc amino acids A–F (1.5 equiv)
and EDCI (2 equiv) into the six different reaction flasks. The resulting
mixtures were stirred at room temperature overnight and then quenched
by the addition of water. After separating each of the organic layers, the
aqueous layers were extracted with ethyl acetate (3x), combined extract
dried over anhydrous Na2SO4 and the solvent concentrated under vac-
uum. Purification of the crude residues by flash chromatography (EtOAc:

Peptidyl Nucleosides
397
hexanes = 1/1 to 2/1) provided the pure peptidyl nucleoside derivatives
8aA-8dF (24 compounds).
(2S,3S,4S,5R)-2-((6S,9S)-6-Benzyl-2,2-dimethyl-4,7,12-trioxo-3,11-
dioxa-5,8-diazatridecan-9-yl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)tetrahydrofuran-3,4-diyl diethanoate (8aA). Purified by column
chromatography (hexane/ethyl acetate: 1/1 to 1/2) to obtain the product
1
as a white solid (81 mg, 75%). HNMR (400 MHz, CDCl3, mixture of
rotamers): δ 9.43 (s, 1H), 7.29–7.22 (m, 5H), 7.11 (d, J = 16.8 Hz, 1H), 6.88
& 6.62 (2brs, 1H), 5.90 (brs, 1H), 5.38–5.12 (m, 3H), 4.50–4.35 (m, 2H),
4.30–3.90 (m, 3H), 3.20–3.00 (m, 2H), 2.11–2.03 (m, 9H), 1.96 (s, 3H),
1.39 (s, 9H). 13CNMR (100.6 MHz, CDCl3, mixture of rotamers): δ 171.9,
170.6, 169.7, 169.5, 163.5, 155.3, 150.5, 136.5, 135.7, 129.3, 128.5, 126.8,
112.2, 87.9, 80.4, 71.7, 70.8, 70.6, 62.5, 55.8, 49.1, 38.6, 29.6, 28.1, 20.7, 20.5,
20.4, 12.4. HRMS (ES+) found 661.2729 (M+H) (calc for C31H41N4O12:
661.2721).
(2R,3S,4S,5S)-2-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-5-
((6S,9S)-2,2,6-tri-methyl-4,7,12-trioxo-3,11-dioxa-5,8-diazatridecan-9-
yl)tetrahydrofuran-3,4-diyldiethanoate (8aB). Purified by column
chromatography (hexane/ethyl acetate: 1/2 to 1/4) to obtain the
product as a white solid (90 mg, 81%). 1HNMR (400 MHz, CDCl3, mixture
of rotamers): δ 9.13 (brd, J = 15.2 Hz, 1 H), 7.11 (d, J = 16.8 Hz, 1H), 7.00
(d, J = 8.8 Hz, 1H), 5.93 (brs, 1H), 5.90 (d, J = 6 Hz, 1H), 5.44–5.41 (m,
1H), 5.37 (dd, J = 12, 6 Hz, 1H), 4.48 (brs, 1H), 4.25–4.10 (m, 4H), 2.11
(s, 3H), 2.06 (s, 3H, s, 3H), 1.94 (s, 3H), 1.43 (d, J = 2.4 Hz, 9H), 1.35 (dd,
J = 6.8, 3.2 Hz, 3H). 13CNMR (125.8 MHz, CDCl3, mixture of rotamers): δ
173.3, 170.7, 169.6, 163.2, 155.8, 150.4, 135.8, 112.2, 87.7, 81.2, 80.8, 71.8,
70.7, 70.5, 62.5, 50.2, 49.4, 29.7, 28.3, 20.7, 20.6, 20.4, 12.4. HRMS (ES+)
found 585.2416 (M+H) (calc for C25H37N4O12: 585.2408).
(2S,3S,4S,5R)-2-((S)-1-((S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carbox-
amido)-2-(ethanoyl-oxy)ethyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)tetrahydrofuran-3,4-diyl diethanoate (8aC). Purified by column
chromatography (hexane/ethyl acetate: 1/4) to obtain the product as a
white solid (76 mg, 73%). 1HNMR (500 MHz, CDCl3, mixture of rotamers):
δ 9.34 (brs, 1H), 7.15 (s, 1H), 6.03 (d, J = 7 Hz, 1H), 5.39–5.23 (m, 3H),
4.46 (brs, 1H), 4.27–4.06 (m, 5H), 3.40–3.30 (m, 3H), 2.12–1.99 (m, 11H),
1.93 (d, J = 5.5 Hz, 3H), 1.42 (s, 9H). 13CNMR (125.8 Hz, CDCl3, mixture
of rotamers): δ 170.5, 169.3, 163.5, 150.5, 135.1, 112.4, 86.6, 80.8, 71.4, 70.9,
70.3, 49.1, 49.1, 47.2, 31.6, 29.7, 28.3, 22.6, 20.6, 20.5, 20.3, 12.4. HRMS
(ES+) found 611.2569 (M+H) (calc for C27H39N4O12: 611.2565).
(2S,3S,4S,5R)-2-((6S,9S)-6-(Benzyloxymethyl)-2,2-dimethyl-4,7,12-
trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)-5-(5-methyl-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl diethanoate (8aD).
Purified by column chromatography (hexane/ethyl acetate: 1/2 to 1/4)

398
K. W. C. Poon et al.
1
to obtain the product as a white solid (80 mg, 72%). HNMR (400 MHz,
CDCl3, mixture of rotamers): δ 8.71 (m, 1H), 7.36–7.28 (m, 5H), 7.17–7.07
(m, 2H), 5.92–5.89 (m, 1H), 5.44–5.37 (m, 3H), 4.58–4.47 (m, 3H),
4.38–4.26 (brs, 1H), 4.25–4.16 (m, 2H), 4.11–4.04 (m, 1H), 3.93–3.89 (m,
1H), 3.68–3.57 (m, 1H), 2.09 (s, 3H), 2.07 & 2.04 (2s, 6H), 1.95 & 1.93 (2s,
3H), 1.45 (s, 9H). 13CNMR (125.8 Hz, CDCl3, mixture of rotamers): δ 170.8,
170.6, 169.6, 169.5, 163.1, 155.7, 155.5, 150.2, 137.4, 135.6, 128.5, 128.0,
128.9, 127.7, 127.6, 112.2, 112.1, 87.9, 87.6, 80.9, 80.8, 80.5, 73.4, 73.3,
71.9, 71.8, 70.9, 70.4, 69.7, 69.5, 62.6, 54.1, 49.6, 49.3, 28.3, 20.6, 20.5, 20.4,
12.5, 12.4. HRMS (ES+) found 691.2842 (M+H) (calc for C32H43N4O13:
691.2827).
(2S,3S,4S,5R)-2-((9S,12S)-9-(tert-Butoxycarbonylamino)-3,10,15-trioxo-
1-phenyl-2,14-dioxa -4,11-diazahexadecan-12-yl)-5-(5-methyl-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)tetra-hydrofuran-3,4-diyl diethanoate (8aE).
Purified by column chromatography (hexane/ethyl acetate: 1/2) to obtain
1
the product as a white solid (69 mg, 75%). HNMR (500 MHz, CDCl3,
mixture of rotamers): δ 9.58 & 9.51 (2s, 1H), 7.32–7.28 (m, 6H), 7.15–6.98
(m, 2H), 5.93 & 5.83 (2s, 1H), 5.42–5.29 (m, 3H), 5.18–5.11 (m, 1H), 5.07
(s, 2H), 4.47 (m, 1H), 4.29–4.22 (m, 1H), 4.16–4.02 (m, 4H), 3.17–3.15 (m,
2H), 2.07 (s, 3H), 2.03 (s,6H), 1.92 (s, 3H), 1.88 & 1.77 (m, 1H), 1.64–1.45
(m, 3H), 1.41 (s, 9H). 13CNMR (125.8 Hz, CDCl3, mixture of rotamers):
δ 172.8, 170.7, 169.7, 169.6, 163.7, 156.7, 150.7, 136.6, 135.9, 128.5, 128.1,
112.1, 87.8, 80.8, 80.3, 72.0, 70.7, 66.6, 54.5, 49.5, 40.3, 29.4, 28.3, 22.5,
20.7, 20.5, 20.4, 12.4. HRMS (ES+) found 798.3170 (M+Na) (calc for
C36H49N5O14Na: 798.3174).
(2S,3S,4S,5R)-2-((6S,9S)-6-(2-(1H-Indol-3-yl)ethyl)-2,2-dimethyl-4,7,12-
trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)-5-(5-methyl-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)tetrahydro-furan-3,4-diyl diethanoate (8aF). Purified
by column chromatography (hexane/ethyl acetate: 1/2 to 1/4) to obtain
1
the product as a light yellow solid (52 mg, 71%). HNMR (400 MHz,
CDCl3, mixture of rotamers): δ 9.75 (2 brs, 1H), 8.75 (brs, 1H), 7.68–7.64
(m, 1H), 7.33–7.31 (m, 1H), 7.19–6.98 (m, 4H), 6.82 & 6.34 (2brs, 1H),
5.82–5.76 (m, 1H), 5.33–5.23 (m, 2H), 5.10–5.02 (m, 1H), 4.53–4.20 (m,
2H), 4.19–4.05 (m, 2H), 4.01–3.73 (m, 1H), 3.40–3.14 (m, 2H), 2.10 (s,
3H), 2.05–1.91 (m, 9H), 1.40 (s, 9H). 13CNMR (125.8 Hz, CDCl3, mixture
of rotamers): δ 172.2, 170.6, 170.5, 169.6, 163.5, 155.5, 150.7, 136.2, 136.0,
127.4, 127.3, 123.3, 122.0, 119.5, 119.4, 118.7, 112.3, 112.1, 111.2, 110.2,
88.3, 80.3, 71.8, 71.6, 70.2, 62.4, 62.0, 55.5, 49.0, 28.2, 20.6, 20.4, 12.4.
HRMS (ES+) found 700.2830 (M+H) (calc for C33H42N5O12: 700.2830).
(2S,3S,4S,5R)-2-((6S,9S)-6-Benzyl-2,2-dimethyl-4,7,12-trioxo-3,11-
dioxa-5,8-diazatridecan-9-yl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)tetrahydrofuran-3,4-diyldiethanoate (8bA). Purified by column
chromatography (hexane/ethyl acetate: 1/2) to obtain the product as

Peptidyl Nucleosides
399
a white solid (90 mg, 48%). 1HNMR (400 MHZ, CDCl3, mixture of
rotamers): δ 8.45 (brs, 1H), 7.19–7.32 (m, 5H), 6.68 & 6.37 (2 brs, 1H),
5.80–5.78 (m, 2H), 5.40–5.35 (m, 1H), 5.32–5.29 (m, 1H), 5.12 (brs, 1H),
5.05–4.93 (m, 1H), 4.43–4.32 (m, 2H), 4.24–4.03 (m, 3H), 3.15–3.06 (m,
2H), 2.12–2.09 (m, 9H), 1.40–1.39 (s, 9H). 13CNMR (100.6 Hz, CDCl3,
mixture of rotamers): δ 172.0, 171.8, 170.6, 170.4, 169.7, 169.6, 162.9,
155.4, 150.3, 140.4, 136.5, 129.4, 129.3, 128.6, 128.5, 128.4, 126.9, 126.8,
103.5, 88.3, 80.6, 71.9, 70.8, 70.6, 62.4, 62.2, 55.7, 49.0, 38.7, 31.5, 29.6, 28.1,
22.6, 21.0, 20.7, 20.5, 14.1. HRMS (ES+) found 647.2543 (M+H) (calc for
C30H39N4O12: 647.2565).
(2R,3S,4S,5S)-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-5-((6S,9S)-2,
2,6-trimethyl-4,7, 12-trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)tetrahydrofu-
ran-3,4-diyldiethanoate (8bB). Purified by column chromatography
(hexane/ethyl acetate: 1/3) to obtain the product as a white solid (122 mg,
1
91%). HNMR (500 MHz, CDCl3, mixture of rotamers): δ 8.92 (brs, 1H),
7.34–7.28 (m, 1H), 6.96 (d, J = 7.5 Hz, 1H), 5.91–5.87 (m, 1H), 5.80 (d,
J = 7.5 Hz, 1H), 5.43–5.38 (m, 2H), 5.31–5.26 (m, 0.5H), 5.12–4.99 (m,
1.5H), 4.48 (brs, 1.5H), 4.31–4.10 (m, 5.5H), 2.12 (s, 3H), 2.08 (s, 6H),
1.43 (d, J = 5.0 Hz, 9H). 13CNMR (125.8 Hz, CDCl3, mixture of rotamers):
δ 173.3, 173.2, 170.7, 169.6, 169.3, 162.5, 155.8, 152.9, 150.3, 150.2, 140.3,
103.6, 88.4, 88.2, 85.8, 81.3, 80.9, 80.4, 79.8, 72.0, 71.9, 71.2, 70.7, 70.6, 62.6,
62.5, 50.2, 49.3, 49.2, 30.9, 29.7, 28.3, 28.2, 20.7, 20.6, 20.5, 20.4, 18.1, 17.6.
HRMS (ES+) found 571.2245 (M+H) (calc for C24H35N4O12: 571.2251).
(2S,3S,4S,5R)-2-((S)-1-((S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-
carboxamido)-2-(ethanoyl-oxy)ethyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1
(2H)-yl)tetrahydrofuran-3,4-diyl diethano-ate (8bC). Purified by column
chromatography (hexane/ethyl acetate: 1/2 to 1/4) to obtain the product
1
as a white solid (86 mg, 70%). HNMR (500 MHz, CDCl3, mixture of
rotamers): δ 8.91 & 8.67 (2s, 1H), 7.89–7.53 (m, 1H), 7.42–7.35 (m, 1H),
6.05–6.00 (m, 1H), 5.80 (t, J = 6.5 Hz, 1H), 5.42–5.31 (m, 2H), 4.46 (bs,
1H), 4.30–4.04 (m, 4H), 3.54–3.31 (m, 2H), 2.72–2.32 (m, 1H), 2.12 & 2.11
(2s, 3H), 2.09–2.04 (m, 6H), 1.88 (brs, 3H), 1.45 (s, 9H). 13CNMR (125.8
Hz, CDCl3, mixture of rotamers): δ 172.5, 170.6, 169.7, 169.5, 169.2, 162.4,
162.3, 156.2, 152.8, 150.3, 150.1, 140.0, 139.5, 103.6, 87.1, 80.9, 80.6, 80.5,
71.9, 71.6, 70.8, 70.4, 62.9, 59.9, 49.4, 49.2, 49.1, 47.2, 30.9, 30.8, 29.7, 28.3,
27.7, 24.6, 22.6, 20.7, 20.6, 20.5, 20.4, 13.7. HRMS (ES+) found 597.2397
(M+H) (calc for C26H37N4O12: 597.2408).
(2S,3S,4S,5R)-2-((6S,9S)-6-(Benzyloxymethyl)-2,2-dimethyl-4,7,12-
trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)-5-(2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)tetrahydrofuran-3,4-diyl diethanoate (8bD). Purified by column
chromatography (hexane/ethyl acetate: 1/2 to 1/4) to obtain the product
1
as a white solid (66 mg, 44%). HNMR (500 MHz, CDCl3, mixture of
rotamers): δ 8.65 (brs, 1H), 7.35–7.25 (m, 5H), 7.10–7.00 (m, 1H),

400
K. W. C. Poon et al.
5.89–5.86 (m, 1H), 5.80–5.76 (m, 1H), 5.43–5.35 (m, 2H), 5.33–5.28 (m,
1H), 4.58–4.47 (m, 3H), 4.34–4.10 (m, 4H), 3.97–3.90 (m, 1H), 3.64–3.43
(m, 2H), 2.14–1.94 (m, 9H), 1.45 (s, 9H). 13CNMR (125.8 Hz, CDCl3,
mixture of rotamers): δ 171.0, 170.9, 170.8, 170.6, 169.8, 169.7, 169.6, 169.5,
169.2, 169.1, 162.3, 155.7, 152.8, 150.1, 140.2, 137.4, 128.5, 128.0, 127.9,
127.7, 103.6, 103.5, 88.3, 88.1, 85.8, 85.7, 81.0, 80.9, 79.8, 73.4, 73.3, 72.0,
71.5, 71.1, 70.9, 70.4, 69.7, 69.5, 68.5, 62.5, 54.1, 49.6, 49.5, 49.3, 30.8, 29.7,
28.3, 20.7, 20.6, 20.5, 20.4, 14.1. HRMS (ES+) found 677.2669 (M+H)
(calc for C31H41N4O13: 677.2670).
(2S,3S,4S,5R)-2-((9S,12S)-9-(tert-Butoxycarbonylamino)-3,10,15-
trioxo-1-phenyl-2,14-dioxa-4,11-diazahexadecan-12-yl)-5-(2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)tetrahydro-furan-3,4-diyl diethanoate (8bE).
Purified by column chromatography (hexane/ethyl acetate: 1/2 to 1/4)
1
to obtain the product as a white solid (39 mg, 34%). HNMR (500 MHz,
CDCl3, mixture of rotamers): δ 9.12 & 8.90 (2 brs, 1H), 7.37–7.22 (m, 6H),
7.01–6.86 (m, 1H), 5.88–5.73 (m, 1.5H), 5.48–5.41 (m, 1.5H), 5.34–5.06
(m, 5H), 4.52–4.47 (brs, 1H), 4.32–4.02 (m, 4H), 3.19 (brs, 2H), 2.10–2.04
(m, 9H), 1.88 (brs, 2H), 1.62–1.51 (m, 4H), 1.42 (s, 9H). 13CNMR (125.8
Hz, CDCl3, mixture of rotamers): δ 172.9, 172.7, 170.7, 169.8, 169.3, 162.5,
156.9, 156.8, 156.7, 156.0, 150.3, 140.8, 140.6, 136.6, 136.5, 128.6, 128.1,
103.6, 81.0, 80.9, 80.4, 79.8, 72.4, 72.0, 71.3, 70.6, 70.5, 66.8, 66.7, 62.5,
62.4, 54.5, 49.7, 49.4, 49.2, 40.2, 40.1, 31.6, 31.1, 30.9, 29.7, 29.4, 28.3, 22.7,
22.5, 20.8, 20.7, 20.6, 20.5, 20.4, 14.2. HRMS (ES+) found 762.3201 (M+H)
(calc for C35H48N5O14: 762.3198).
(2S,3S,4S,5R)-2-((6S,9S)-6-(2-(1H-Indol-3-yl)ethyl)-2,2-dimethyl-4,7,12-
trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)-5-(2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)tetrahydrofuran-3,4-diyl diethanoate (8bF). Purified by column
chromatography (hexane/ethyl acetate: 1/2 to 1/4) to obtain the product
1
as a white solid (42 mg, 51%). HNMR (500 MHz, CDCl3 mixture of
rotamers): δ 9.10 (brs, 1H), 8.50 & 8.49 (2s, 1H), 7.67–7.62 (m, 1H),
7.33–7.31 (m, 1H), 7.21–7.12 (m, 4H), 6.62–6.14 (m, 1H), 5.77–5.71 (m,
2H), 5.41–5.06 (m, 3H), 4.10–3.60 (m, 3H), 3.42–3.05 (m, 2H), 2.10–1.97
(m, 9H), 1.42 (s, 9H). 13CNMR (125.8 Hz, CDCl3, mixture of rotamers):
δ 172.2, 172.2, 170.6, 170.5, 169.9, 169.7, 169.6, 169.4, 169.2, 162.5, 155.6,
155.4, 153.0, 150.3, 150.1, 140.5, 140.2, 136.2, 127.4, 127.3, 123.4, 123.3,
122.2, 119.7, 119.6, 118.8, 111.3, 111.2, 110.3, 103.7, 103.5, 89.0, 87.9, 80.4,
80.3, 79.3, 72.0, 71.8, 70.9, 70.7, 70.3, 62.4, 62.0, 55.4, 53.4, 49.2, 49.0, 30.8,
29.7, 28.7, 28.3, 20.7, 20.6, 20.5, 20.4, HRMS (ES+) found 686.2680 (M+H)
(calc for C32H40N5O12: 686.2673).
(2S,3S,4S,5R)-2-((6S,9S)-6-Benzyl-2,2-dimethyl-4,7,12-trioxo-3,11-
dioxa-5,8-diazatridecan-9-yl)-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)tetrahydrofuran-3,4-diyl dietha- noate (8cA). Purified by column
chromatography (hexane/ethyl acetate: 1/1 to 1/2) to obtain the product

Peptidyl Nucleosides
401
as a white solid (67 mg, 53%). 1HNMR (500 MHz, CDCl3, mixture
of rotamers): δ 9.48 (brs, 1H), 7.55–7.44(m, 1H), 7.29–7.20 (m, 5H),
6.02–5.85 (m, 1H), 5.40–5.16 (m, 2H), 5.14–5.02 (m, 1H), 4.48–4.35 (m,
2H), 4.30–4.04 (m, 3H), 3.95–3.61 (m, 1H), 3.19–3.05 (m, 2H), 2.13–2.00
(m, 9H), 1.35 (s, 9H). 13CNMR (125.8 Hz, CDCl3, mixture of rotamers):
δ 172.1, 172.0, 170.6, 170.4, 169.9, 169.7, 169.6, 156.7, 156.5, 155.5, 149.1,
141.9, 140.0, 136.6, 129.3, 128.6, 128.5, 126.9, 124.6, 124.3, 88.1, 81.1,
80.9, 80.6, 71.8, 70.7, 70.5, 62.5, 62.4, 55.9, 49.5, 49.0, 38.6, 29.7, 28.2,
20.7, 20.6, 20.5, 20.3. HRMS (ES+) found 687.2291 (M+Na) (calc for
C30H37FN4O12Na: 687.2290).
(2R,3S,4S,5S)-2-(5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-5-
((6S,9S)-2,2,6-tri-methyl-4,7,12-trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)
tetrahydrofuran-3,4-diyldiethanoate
(8cB).
Purified
by
column
chromatography (hexane/ethyl acetate: 1/1 to 1/2) to obtain the
product as a white solid (50 mg, 64%). 1HNMR (500 MHz, CDCl3, mixture
of rotamers): δ 7.01–6.82 (m, 1H), 5.99–5.88 (m, 1H), 5.38–5.26 (m, 1H),
5.20–5.08 (m, 1H), 5.04–4.94 (m, 1H), 4.51 (brs, 1H), 4.38–4.28 (m, 1H),
4.26–4.10 (m, 3H), 4.03–3.81 (m, 1H), 3.69–3.63 (m, 1H), 2.16–2.02 (m,
9H), 1.45–1.44 (m, 9H), 1.37 (m, 3H). 13CNMR (125.8 Hz, CDCl3, mixture
of rotamers): δ 173.6, 173.5, 173.4, 170.7, 170.0, 169.8, 169.4, 169.6, 165.6,
165.4, 156.9, 156.7, 155.7, 152.0, 149.2, 141.9, 140.0, 124.5, 124.3, 87.5, 85.6,
82.6, 81.4, 81.2, 81.1, 81.0, 80.5, 80.4, 80.2, 71.7, 71.4, 71.2, 70.7, 70.5, 68.7,
62.7, 50.1, 49.6, 49.4, 41.5, 41.3, 29.6, 28.2, 20.7, 20.6, 20.5, 20.4, 20.3, 17.9,
17.5. HRMS (ES+) found 611.1981 (M+Na) (calc for C24H33FN4O12Na:
611.1977).
(2S,3S,4S,5R)-2-((S)-1-((S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-
carboxamido)-2-(ethanoyl-oxy)ethyl)-5-(5-fluoro-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl diethanoate (8cC). Purified by
column chromatography (hexane/ethyl acetate: 1/2) to obtain the product
1
as a white solid (49 mg, 49%). HNMR (500 MHz, CDCl3, mixture of
rotamers): δ 8.79 (brs, 1H), 7.96–7.85 (m, 0.5H), 7.64–7.44 (m, 1.5H), 6.00
(brs, 1H), 5.43–5.32 (m, 2H), 4.48 (brs 1H), 4.31–4.11 (m, 4H), 3.42–3.33
(m, 2H), 2.15–2.05 (m, 9H), 1.89 (brs, 4H), 1.46 (s, 9H). 13CNMR (125.8
Hz, CDCl3, mixture of rotamers): δ 170.6, 170.5, 169.5, 156.5, 156.3, 149.1,
149.0, 141.9, 124.0, 81.2, 80.7, 71.8, 71.5, 70.2, 63.0, 49.3, 47.3, 34.7, 29.7,
28.3, 27.9, 20.6, 20.5, 20.3, 14.1. HRMS (ES+) found 615.2314 (M+H)
(calc for C26H36FN4O12: 615.2314).
(2S,3S,4S,5R)-2-((6S,9S)-6-(Benzyloxymethyl)-2,2-dimethyl-4,7,12-
trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)-5-(5-fluoro-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl diethanoate (8cD).
Purified by column chromatography (hexane/ethyl acetate: 1/1 to 1/2)
1
to obtain the product as a white solid (50 mg, 46%). HNMR (500 MHz,
CDCl3, mixture of rotamers): δ 8.88 (brs, 1H), 7.47–7.41 (m, 1H), 7.36–7.23

402
K. W. C. Poon et al.
(m, 5H), 7.09 (d, J = 9 Hz, 1H), 5.98–5.86 (m, 1H), 5.41–5.34 (m, 2H),
5.33–5.25 (m, 1H), 4.58–4.46 (m, 3H), 4.34–4.31 (m, 1H), 4.25–4.18 (m,
2H), 4.13–4.10 (m, 1H), 3.97–3.91 (m, 1H), 3.66–3.58 (m, 1H), 2.10–1.94
(m, 9H), 1.45 (d, J = 2 Hz, 9H). 13CNMR (125.8 Hz, CDCl3, mixture of
rotamers): δ 171.2, 171.0, 170.6, 169.7, 169.6, 169.5, 156.6, 156.3, 149.0,
141.8, 139.9, 137.4, 128.5, 128.0, 127.9, 127.7, 127.5, 124.5, 124.3, 81.4, 81.2,
80.6, 80.3, 73.4, 73.3, 73.2, 71.9, 71.8, 70.7, 70.3, 69.6, 68.7, 62.7, 62.6, 54.2,
49.8, 49.6, 49.4, 29.7, 28.3, 20.6, 20.5, 20.3. HRMS (ES+) found 695.2573
(M+H) (calc for C31H40FN4O13: 695.2576).
(2S,3S,4S,5R)-2-((9S,12S)-9-(tert-Butoxycarbonylamino)-3,10,15-trioxo-
1-phenyl-2,14-dioxa-4,11-diazahexadecan-12-yl)-5-(5-fluoro-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3,4-diyl diethanoate (8cE).
Purified by column chromatography (hexane/ ethyl acetate: 1/1 to 1/2)
1
to obtain the product as a white solid (65 mg, 47%). HNMR (500 MHz,
CDCl3, mixture of rotamers): δ 9.89 & 9.70 (2brs, 1H), 7.56 & 7.48 (2s, 1H),
7.34–7.28 (m, 5H), 7.13–6.95 (m, 1H), 5.95 & 5.81 (2brs, 1H), 5.41–5.25
(m, 3H), 5.19–5.09 (m, 3H), 4.51–4.50 (brs, 1H), 4.34–3.99 (m, 4H),
3.18–3.17 (m, 2H), 2.16–2.01 (m, 9H), 1.95 (brs, 1H), 1.87 (brs, 1H), 1.70
(brs, 1H), 1.61 (brs, 2H), 1.43–1.42 (m, 10H). 13CNMR (125.8 Hz, CDCl3,
mixture of rotamers): δ 173.0, 170.7, 170.0, 169.7, 156.9, 156.8, 156.7, 155.9,
149.1, 141.8, 139.9, 136.6, 128.5, 128.1, 81.2, 81.0, 80.4, 72.0, 71.8, 71.2,
70.5, 66.6, 62.5, 54.5, 49.4, 49.2, 40.3, 29.7, 29.4, 28.2, 22.5, 20.6, 20.5, 20.4,
20.3. HRMS (ES+) found 797.3386 (M+NH4) (calc for C35H50FN6O14:
797.3370).
(2S,3S,4S,5R)-2-((6S,9S)-6-(2-(1H-indol-3-yl)ethyl)-2,2-dimethyl-
4,7,12-trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)-5-(5-fluoro-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)tetrahydro-furan-3,4-diyl diethanoate (8cF).
Purified by column chromatography (hexane/ethyl acetate: 1/1 to 1/2)
1
to obtain the product as a light yellow solid (33 mg, 27%). HNMR (500
MHz, CDCl3, mixture of rotamers): δ 9.62 (brs, 1H), 8.55 -8.48 (m, 1H),
7.67–7.62 (m, 1H), 7.47–7.43 (m, 2H), 7.18–7.06 (m, 3H), 6.68–6.57 (m,
1H), 5.86–5.72 (m, 1H), 5.42–5.05 (m, 3H), 4.54–4.35 (m, 2H), 4.22–3.58
(m, 3H), 3.36–3.12 (m, 2H), 2.22–1.94 (m, 9H), 1.42 (s, 9H). 13CNMR
(125.8 Hz, CDCl3, mixture of rotamers): δ 172.4, 170.7, 170.5, 170.0, 169.8,
169.7, 156.7, 156.5, 155.5, 149.1, 149.0, 136.3, 136.2, 127.5, 127.3, 123.4,
122.2, 122.1, 119.6, 118.8, 111.3, 111.2, 110.3, 80.7, 80.6, 80.4, 71.9, 71.7,
70.8, 70.3, 62.5, 62.1, 49.2, 49.0, 29.7, 28.3, 22.7, 20.6, 20.5, 20.4, 14.1.
HRMS (ES+) found 704.2592 (M+H) (calc for C32H39FN5O12: 704.2579).
(2S,3S,4S,5R)-2-((6S,9S)-6-Benzyl-2,2-dimethyl-4,7,12-trioxo-3,11-
dioxa-5,8-diazatridecan-9-yl)-5-(4-ethanamido-2-oxopyrimidin-1(2H)-
yl)tetrahydrofuran-3,4-diyl diethanoate (8dA). Purified by column
chromatography (ethyl acetate/methanol: 98/2) to obtain the product as
white solid (55 mg, 51%). 1HNMR (500 MHZ, CDCl3, mixture of rotamers):

Peptidyl Nucleosides
403
δ 9.81 & 9.60 (2s, 1H), 8.18–8.03 (m, 1H), 7.78–7.33 (m, 2H), 7.19–7.18
(brs, 5H), 6.07–5.87 (m, 1H), 5.69–5.37 (m, 2H), 5.31–5.17 (m, 1H),
4.92–4.67 (m, 1H), 4.39–4.10 (m, 4H), 3.12–3.06 (m, 1H), 2.90–2.83 (m,
1H), 2.13 (s, 3H), 2.04–1.98 (m, 9H), 1.36 & 1.33 (2s, 9H). 13CNMR (125.8
Hz, CDCl3, mixture of rotamers): δ 172.4, 172.3, 171.2, 170.8, 170.6, 169.6,
169.3, 169.0, 163.2, 162.9, 155.6, 144.5, 137.1, 136.9, 129.6, 129.5, 128.2,
126.6, 98.0, 97.3, 80.4, 79.6, 73.3, 73.1, 71.5, 62.4, 62.3, 55.1, 49.1, 40.0, 39.5,
29.6, 28.2, 24.9, 24.8, 20.8, 20.6, 20.4, 20.3. HRMS (ES+) found 688.2844
(M+H) (calc for C32H42N5O12: 688.2830).
(2R,3S,4S,5S)-2-(4-Ethanamido-2-oxopyrimidin-1(2H)-yl)-5-((6S,9S)-2,2,
6-trimethyl-4,7,12-trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)tetrahydrofuran-
3,4-diyl diethanoate (8dB). Purified by column chromatography (ethyl
acetate/methanol: 98/2) to obtain the product as white solid (62 mg,
1
45%). HNMR (500 MHz, CDCl3, mixture of rotamers): δ 9.88 & 9.61 (2s,
1H), 8.08–7.30 (m, 3H), 6.04 & 5.85 (2s, 1H), 5.66–5.33 (m, 3H), 4.81 &
4.68 (2s, 1H), 4.55 & 4.47 (2s, 1H), 4.38–4.11 (m, 3H), 2.29–2.23 (2s, 3H),
2.05–2.01 (m, 9H), 1.43 & 1.42 (2s, 9H), 1.33 (brs, 3H). 13CNMR (125.8
Hz, CDCl3, mixture of rotamers): δ 173.8, 173.5, 171.1, 170.8, 170.7, 169.5,
169.4, 169.2, 163.2, 162.9, 155.7, 155.6, 155.5, 155.4, 144.9, 144.8, 97.8, 97.2,
90.4, 90.0, 80.9, 79.8, 73.3, 73.1, 70.9, 69.9, 62.4, 62.3, 49.7, 49.0, 34.6, 31.5,
29.7, 28.3, 25.0, 24.8, 22.6, 20.7, 20.6, 20.4, 19.6, 18.8, 14.1. HRMS (ES+)
found 612.2528 (M+H) (calc for C26H38N5O12: 612.2517).
(2S,3S,4S,5R)-2-((S)-1-((S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-
carboxamido)-2-(ethanoyl-oxy)ethyl)-5-(4-ethanamido-2-oxopyrimidin-1
(2H)-yl)tetrahydrofuran-3,4-diyl diethanoate (8dC). Purified by column
chromatography (ethyl acetate/methanol: 98/2) to obtain the product as
white solid (24 mg, 18%). 1HNMR (500 MHz, CDCl3, mixture of rotamers):
δ 9.60 (bs, 1H), 7.87–7.56 (m, 2H), 7.47 (brs, 1H), 6.09 (brs, 1H), 5.44–5.31
(m, 2H), 4.53 (brs, 1H), 4.33–4.17 (m, 4H), 3.42–3.31 (m, 2H), 2.26 (s,
3H), 2.11–2.03 (m, 9H), 1.87 (brs, 4H), 1.43 (s, 9H). 13CNMR (125.8 Hz,
CDCl3, mixture of rotamers): δ 170.5, 169.5, 163.0, 155.0, 97.5, 81.1, 80.5,
73.1, 70.6, 62.9, 59.9, 49.2, 47.2, 36.6, 34.6, 34.5, 31.5, 29.7, 28.3, 25.2, 24.9,
24.7, 22.6, 20.7, 20.5, 20.4, 14.1. HRMS (ES+) found 638.2665 (M+H)
(calc for C28H40N5O12: 638.2673).
(2S,3S,4S,5R)-2-((6S,9S)-6-(Benzyloxymethyl)-2,2-dimethyl-4,7,12-
trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)-5-(4-ethanamido-2-oxopyrimidin-
1(2H)-yl)tetrahydrofuran-3,4-diyl diethanoate (8dD). Purified by column
chromatography (ethyl acetate/methanol: 98/2) to obtain the product as
white solid (36 mg, 30%). 1HNMR (500 MHz, CDCl3, mixture of rotamers):
δ 9.47 &9.55 (2s, 1H), 7.71–7.58 (m, 2H), 7.49–7.41 (m, 1H), 7.34–7.24 (m,
5H), 6.02 & 5.92 (2s, 1H), 5.66–5.38 (m, 3H), 4.67–4.62 (m, 1H), 4.55–4.46
(m, 3H), 4.28–4.18 (m, 3H), 3.88–3.84 (m, 1H), 3.67–3.62 (m, 1H), 2.22 &
2.21 (2s, 3H), 2.05–1.95 (m, 9H), 1.43 (s, 9H). 13CNMR (125.8 Hz, CDCl3,

404
K. W. C. Poon et al.
mixture of rotamers): δ 170.1, 170.9, 170.6, 169.4, 169.3, 163.1, 163.0, 155.8,
155.3, 155.2, 144.9, 144.7, 137.6, 128.4, 127.8, 127.7, 127.5, 97.6, 97.4, 89.8,
89.5, 73.3, 73.2, 73.0, 70.8, 70.5, 70.4, 70.1, 62.6, 62.4, 54.0, 49.8, 49.4, 29.7,
28.3, 24.9, 20.6, 20.4, 14.1. HRMS (ES+) found 718.2928 (M+H) (calc for
C33H44N5O13: 718.2936).
(2S,3S,4S,5R)-2-((9S,12S)-9-(tert-Butoxycarbonylamino)-3,10,15-
trioxo-1-phenyl-2,14-dioxa-4,11-diazahexadecan-12-yl)-5-(4-ethanamido-
2-oxopyrimidin-1(2H)-yl)tetrahydro-furan-3,4-diyl
diethanoate
(8dE).
Purified by column chromatography (ethyl acetate/methanol: 98/2) to
obtain the product as white solid (37 mg, 26%). 1HNMR (500 MHz, CDCl3,
mixture of rotamers): δ 11.42 & 11.00 (2s, 0.5H), 9.81 & 9.57 (2s, 0.5H),
8.15 &7.87 (2s, 1H), 7.70–7.15 (m, 5H), 5.83–5.03 (m, 8H), 4.68–4.05 (m,
5H), 3.37–3.10 (m, 3H), 2.25–2.18 (m, 3H), 2.13–2.03 (m, 9H), 1.92–1.51
(m, 4H), 1.45 (brs, 11H). 13CNMR (125.8 Hz, CDCl3, mixture of rotamers):
δ 173.5, 173.1, 171.6, 170.6, 170.2, 169.7, 169.4, 164.2, 163.2, 158.3, 156.7,
156.0, 155.7, 155.4, 136.8, 136.6, 128.5, 128.0, 127.7, 97.8, 97.6, 80.6, 79.3,
75.1, 73.3, 69.6, 66.6, 62.0, 60.8, 53.9, 49.9, 40.6, 38.9, 36.6, 32.2, 29.1, 28.3,
24.9, 24.8, 24.7, 24.6, 20.7, 20.6, 20.5, 20.4, 20.2, 14.1. HRMS (ES+) found
803.3471 (M+H) (calc for C37H51N6O14: 803.3464).
(2S,3S,4S,5R)-2-((6S,9S)-6-(2-(1H-Indol-3-yl)ethyl)-2,2-dimethyl-4,7,12-
trioxo-3,11-dioxa-5,8-diazatridecan-9-yl)-5-(4-ethanamido-2-oxopyrimidin-
1(2H)-yl)tetrahydrofuran-3,4-diyl diethanoate (8dF). Purified by column
chromatography (ethyl acetate/methanol: 98/2) to obtain the product as
1
light yellow solid (30 mg, 24%). HNMR (500 MHz, CDCl3, mixture of
rotamers): δ 9.58 (brs, 1H), 8.61 (brs, 1H), 7.60 (brs, 2H), 7.37–7.25 (m,
3H), 7.09–7.02 (m, 3H), 5.79 (brs, 1H), 5.54–5.26 (m, 3H), 4.84–4.73 (m,
1H), 4.63–4.15 (m, 3H), 4.06–4.00 (m, 1H), 3.21–3.13 (m, 2H), 2.16 (s,
3H), 2.05–1.84 (m, 9H), 1.39 (s, 9H). 13CNMR (125.8 Hz, CDCl3, mixture
of rotamers): δ 172.6, 170.8, 170.6, 169.5, 162.9, 155.3, 155.2, 136.1, 127.6,
127.5, 123.4, 121.9, 119.3, 118.7, 111.2, 111.1, 110.6, 97.7, 80.3, 79.8, 73.2,
73.1, 62.5, 62.3, 55.1, 29.7, 28.3, 24.9, 24.8, 20.7, 20.6, 20.4, 20.3. HRMS
(ES+) found 727.2935 (M+H) (calc for C34H43N6O12: 727.2939).
General deprotection procedure to form the free peptidyl nucleosides
9 and 10. Step 1 (Deacetylation): To an ice-cooled solution of the fully
protected peptidyl nucleoside (8aB, or, 8bC) in THF (100 mg / mL) was
added dropwise an aqueous solution of LiOH (5 equiv, 1g/10 mL) with
stirring. After stirring at the same temperature for 2 hours, the reaction
was quenched by addition of saturated aqueous NH4Cl solution till pH 7–8.
After addition of EtOAc (10 mL), the organic layer was separated, aqueous
layer saturated by addition of solid NaCl and the resulting solution extracted
with ethyl acetate (3x). After drying over anhydrous Na2SO4 and removal
of solvent under vacuum, the corresponding deacetylated products were

Peptidyl Nucleosides
405
obtained as white solid, which were taken to the next deprotection step
without any further purification.
Step 2 (Boc-deprotection): The deacetylated nucleoside derivative as
obtained above was added to an ice-cooled solution of CH2Cl2 / TFA (1/9,
10% solution by weight), stirred at the same temperature for 30 minutes
followed by 1 hour at room temperature. Excess solvent was removed
under vacuum and the residue triturated with CH2Cl2 and diethyl ether.
The resulting solid was dried under high vacuum to provide the fully
deprotected peptidyl nucleosides 9 and 10.
(2R,3S,4S,5S)-5-((S)-1-((S)-2-Aminopropanamido)-2-hydroxyethyl)-4-
hydroxy-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydro-
furan-3-yl ethanoate (as the trifluoro-acetate salt) (9). Obtained as a white
1
solid (22 mg, 91%). HNMR (400 MHz, CD3OD, mixture of rotamers): δ
7.45 (d, J = 7.2 Hz, 1H), 5.76 (apparent t, J = 6.8 Hz, 1H), 4.38–4.30 (2 t, J
= 5.6 Hz, 1H), 4.24–4.17 (m, 1H), 4.13 (t, J = 5.6 Hz, 1H), 3.99–3.87 (m,
2H), 3.78–3.68 (m, 2H), 1.90 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H). 13CNMR
(125.8 Hz, CD3OD, mixture of rotamers): δ 171.6, 166.4, 152.7, 139.2,
138.9, 112.2, 92.1, 91.9, 84.2, 83.9, 73.9, 73.6, 72.6, 72.5, 62.1, 61.9, 54.5,
50.6, 30.9, 17.9, 12.4. HRMS (ES+) found 359.1561 (M+H) (calc for free
amine C14H23N4O7: 359.1567).
(S)-N-((S)-1-((2S,3R,4S,5R)-5-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-
yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)-2-hydroxyethyl)pyrrolidine-2-
carboxamide (as the trifluoroacetate salt) (10). Obtained as a white
1
solid (31 mg, 93%). HNMR (400 MHz, CD3OD, mixture of rotamers):
δ 7.62 (dd, J = 8, 2.4 Hz, 1H), 5.75–5.71 (m, 2H), 4.33–4.11 (m, 4H),
3.94–3.71 (m, 4H), 3.43–3.40 (m, 1H), 2.43–2.39 (m, 1H), 2.15–2.01 (m,
3H). 13CNMR (125.8 Hz, CD3OD, mixture of rotamers): δ 170.3, 166.1,
152.4, 143.5, 143.4, 103.3, 92.5, 84.1, 83.7, 74.2, 74.0, 72.8, 72.5, 62.0, 61.9,
61.5, 61.4, 54.8, 47.7, 31.3, 30.9, 30.7, 30.6, 30.3, 25.2. HRMS (ES+) found
371.1584 (M+H) (calc for C15H23N4O7 : 371.1567).
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