Synthesis of functionalized lipids, and their use for a tunable hydrophobization of nucleosides and nucleic acids

Article abstract of DOI:10.1002/hlca.201100410

Two series of functionalized single and double side-chained lipid molecules (Schemes 1 and 2) were prepared. The compounds carry either terminal COOH, OH, or halogen substituents. Moreover, the double side-chained lipid 18 carries an internal alkyne functionality. The latter compound was used to hydrophobize thymidine at N(3) by base-catalyzed alkylation. Additionally, fully protected thymidine, 32, was N(3)-alkylated with the double side-chained alcohol 9 applying Mitsunobu reaction conditions. Copyright

Full text of DOI:10.1002/hlca.201100410

Helvetica Chimica Acta – Vol. 96 (2013)
201
Synthesis of Functionalized Lipids, and Their Use for a Tunable
Hydrophobization of Nucleosides and Nucleic Acids
by Sergei Korneev and Helmut Rosemeyer*
Organic Chemistry I – Bioorganic Chemistry, Institute of Chemistry of New Materials, Fachbereich
Biologie/Chemie, University of Osnabrꢀck, Barbarastrasse 7, D-49076 Osnabrꢀck
(e-mail: helmut.rosemeyer@uos.de)
Dedicated to Prof. Dr. Helmut Vorbrꢀggen, Berlin, in admiration of his outstanding contributions to
organic chemistry
Two series of functionalized single and double side-chained lipid molecules (Schemes 1 and 2) were
prepared. The compounds carry either terminal COOH, OH, or halogen substituents. Moreover, the
double side-chained lipid 18 carries an internal alkyne functionality. The latter compound was used to
hydrophobize thymidine at N(3) by base-catalyzed alkylation. Additionally, fully protected thymidine,
32, was N(3)-alkylated with the double side-chained alcohol 9 applying Mitsunobu reaction conditions.
1. Introduction. – One of the major drawbacks of many chemotherapeutics is their
insufficient penetration through cell membranes as well as the crossing of the
bloodꢀbrain barrier due to their high hydrophilicity. This is particularly true for
antisense and antigene oligonucleotides.
One method to overcome these problems is the introduction of lipophilic residues
to the drug to render them hydrophobic and to improve their pharmacokinetics [1]. In
the case of low-molecular-weight drugs, this kind of chemical modification is heading
for the fulfilment of ꢁLipinskiꢂs Rule of Fiveꢂ [2]. The rule describes molecular
properties important for a drugꢂs pharmacokinetics in the human body, including their
absorption, distribution, metabolism, and excretion, and is important for drug
development where a pharmacologically active lead structure is optimized stepwise
for increased activity and selectivity. One part of the rule is concerned with the drugꢂs
partition coefficient (log P between octan-1-ol and H2O) within the range of ꢀ 0.4 to
þ 5.5. Herein, we describe the synthesis of a series of single and double side-chained
lipids carrying different functional groups. Via these functional groups (halogene,
COOR, COOH, OH, ammonium, and alkyne groups), the lipid residue can be
introduced into chemotherapeutics such as nucleoside antimetabolites and others.
Besides their synthesis, exemplary methods such as alkylation [3] and Mitsunobu
reactions [4] for these introductions are presented.
2. Results and Discussion. – 2.1. Syntheses of Double Side-Chained Lipids. The first
part of the manuscript describes the synthesis of a series of functionalized lipids
carrying two octadecanyl chains. The syntheses are shown in Scheme 1.
ꢃ 2013 Verlag Helvetica Chimica Acta AG, Zꢀrich

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Reaction of dioctadecylamine (1) with methyl 2-bromoacetate (2) in the presence
of dibenzo-[18]-crown-6 gave the pure ester 3 in almost quantitative yield. This was
either saponified to yield the acid 4 or reduced with LiAlH4 to give the alcohol 5. The
latter was submitted to an Appel reaction with CBr4 and Ph3P to afford the bromo
amine 6 in low yield. To extend the spacer between the OH group and the N-atom
carrying the C-chains, the secondary amine 1 was reached with methyl acrylate (7) to
furnish, in almost quantitative yield, the ester 8 which was further reduced with LiAlH4
to give the lipophilic aminopropanol 9. Subsequent Appel bromination to produce the
3-bromopropyl derivative 10, however, was unsuccessful. NMR Spectroscopy revealed
the formation of the quaternization product 11, an N,N-dialkyl-azetidinium bromide1).
This implies that the low yield in case of 6 is also due to the formation of a
quaternization product, namely an N,N-dialkyl aziridinium bromide.
Next, the amine 1 was reacted with succinic anhydride (12) to give the acid 13. This
was converted to the ester 14 by reaction with Me2SO4 in the presence of K2CO3.
Compound 14 was then reduced with LiAlH4 to yield the further extended alcohol 15a,
or with LiAlD4 to give the deuterated lipophilized 4-aminobutanol derivative 16. It
should be noted that this way of labelling of the molecule allows introduction of four
isotope atoms of H in a single synthetic step, which is important for the introduction of
low radioactivity labels, such as tritium (3H1). Moreover, compound 15a was
phosphitylated to the 2-cyanoethyl phosphoramidite 15b ready to be used for a
terminal hydrophobization of nucleic acids.
In a further reaction, the amine 1 was alkylated with 1,4-dichlorobut-2-yne (17) in
the presence of Na2CO3 in benzene to afford, in 61% yield the alkynyl derivative 18,
besides the by-products 19 – 21, each in low yield.
2.2. Syntheses of Single Side-Chained Lipids. Reaction of octadecylamine (22) with
3-bromoprop-1-yne (23) gave, in almost quantitative yield, the tertiary amine 24
(Scheme 2). Reaction of 22 with succinic anhydride (12) afforded the acid 25, which
was further esterified to give 26. Treatment of the latter with LiAlH4 (under the same
conditions as for the reduction of 14 to 15) yielded surprisingly the N-alkylated
pyrrolidine 28 instead of the expected alcohol 27. Reduction of the acid 25 with LiAlH4
in THFat ambient temperature was attempted, however, it led to a reduction of COOH
only, but not of the amide moiety, and gave the hydroxy amide 29 in 82% yield.
Increasing of the reaction temperature to 658 furnished desired amino alcohol 27, but
only in moderate yield of 23%. Fortunately, replacement of THF by Et2O gave
compound 27 in a high yield of 84%. Subsequent reaction of 27 with 23 gave the
alkynylamino alcohol 30 in 61% yield.
2.3. Hydrophobization of Thymidine. The regioselective introduction of lipophilic
hydrocarbon chains in a nucleoside, particularly in a nucleoside with biological activity,
is a difficult synthetic task. Such lipophilic groups can principally positioned either at
the heterocyclic base or at the glyconic moiety, and can be introduced by various
methods, e.g., by base-catalyzed alkylation with alkyl halides; for an overview of such
reactions on purines, see [3] and literature cited therein.
Some exemplary alkylation reactions of thymidine (31) with two of the
functionalized lipids described above, namely with compounds 9 and 18, are outlined
1
)
Spontaneous cyclization to azetidinium salt was also observed earlier [5].

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Scheme 2
in Scheme 3. The reaction of the unprotected thymidine with the alkyne 18 was
performed in DMF/K2CO3 (direct alkylation) and gave the N(3)-alkylated compound
33, which can be further reacted with an azide in a Ru-catalyzed variant of the
azideꢀalkyne cycloaddition (RuAAC; HuisgenꢀSharplessꢀMeldal [3 þ 2] cycloaddi-
tion of azides with internal alkynes). Dimethoxytritylation of 33 afforded the
derivative 34 for further 3’-O-phosphitylation.
Based on the finding that the direct alkylation of thymidine (31) with compound 18
gave only a moderate yield of 33 (46%), the 5’-O-DMT-protected thymidine derivative
37 – prepared from 31 – was subjected to the alkylation with 18 (Scheme 4). However,
the yield of the alkylated product 34 was found to be nearly the same (51%). Therefore,
the totally, orthogonally protected derivative 32 was prepared and subjected to
alkylation. This reaction gave the product 38 in high yield (95%). It was then
deprotected with Bu4NF in THF to provide the desired compound 34 in high yield
(95%). Compound 34 (which was, therefore, prepared in three different ways: from 37,
from 33, and from 38) was then reacted with 2-cyanoethyl N,N-diisopropylchloro-
phosphite in the presence of Hꢀnigꢂs base to form the corresponding phosphoramidite

Helvetica Chimica Acta – Vol. 96 (2013)
205
Scheme 3
39, which is ready to be used for the preparation of oligonucleotides lipophilized at any
position within the sequence.
In a further approach, alkylation of thymidine (31) was performed by a Mitsunobu
reaction [4]. This type of alkylation is somewhat more versatile, because alcohols which
are precursors of halides can be used. However, a protection of the nucleoside OH

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Scheme 4
groups is necessary. For this purpose, we first used also 5’-dimethoxytritylated
thymidine 37 for a Mitsunobu reaction with the alcohol 9, which led, however, to
many by-products. Therefore, we also protected the 3’-OH group of 37 by a (tert-
butyl)(dimethyl)silyl group (! 32). Reaction of compound 32 with the alcohol 9 in the
presence of Ph3P and diisopropyl azodicarboxylate (DIAD) gave in 70% yield the
product 35, which was subsequently desilylated with Bu4NF to give compound 36.
1
All compounds were characterized by H- and 13C-NMR spectroscopy, including
the DEPT-135 pulse technique for assignment of 13C resonances, as well as by
elemental analyses or ESI mass spectrometry. An N-alkylation preferred over an O-
alkylation during the Mitsunobu reaction [4] was established by comparison of the
recorded 13C-NMR chemical shifts with those of corresponding simulated spectra of
both, the N- as well as O-alkylated compounds. However, an O-alkylation as side
reaction is most probable.
In a forthcoming publication, the incorporation of the various phosphoramidites
into oligonucleotides and applications thereof will be reported.
Experimental Part
General. Starting compounds and solvents were purchased from the appropriate suppliers and were
used as obtained. 1,4-Dichlorobut-2-yne (17) was prepared from but-2-yne-1,4-diol and SOCl2 in pyridine
as described in [6]. Reactions were carried out under Ar in a dry Schlenk flask. Column chromatography
(CC): silica gel 60 (SiO2; Merck, Germany). NMR Spectra: AMX-500 spectrometer (Bruker, D-

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Rheinstetten); 1H: 500.14, 13C: 125.76, and 31P: 101.3 MHz; d in ppm rel. to Me4Si as internal standard for
1H and 13C nuclei, and external 85% H3PO4 for 31P; J in Hz. ESI-MS: Bruker Daltronics Esquire HCT
instrument (Bruker Daltronics, D-Leipzig); ionization was performed with a 2% aq. HCOOH soln.
Elemental analyses (C, H, N): VarioMICRO instrument (Fa. Elementar, D-Hanau).
Methyl N,N-(Dioctadecyl)glycinate (3). N,N-Dioctadecylamine (1; 1.90 g, 3.65 mmol), methyl 2-
bromoacetate (2; 1.62 g, 10.6 mmol), dibenzo-[18]-crown-6 (10 mg), and Na2CO3 (1.93 g, 18.3 mmol)
were suspended in benzene (50 ml) at r.t., and the suspension was stirred overnight under reflux (20 h).
A second portion of 2 (0.56 g, 3.65 mmol) was added, and stirring under reflux was continued for further
10 h, until the reaction was complete as monitored by 1H-NMR analysis (amine 1: 2.95 ppm, product 3:
3.34 ppm). The white suspension was filtered through a SiO2 layer (1 cm) to separate the unreacted
amine 1, washed with benzene (2 ꢁ 30 ml), and concentrated in vacuo to give 3 (2.10 g, 97%). Slightly
1
yellow crystalline mass2). TLC (hexane/Et2O 1:1): Rf 0.60. M.p. 60 – 618. H-NMR (CDCl3): 3.71 (s,
MeO); 3.34 (s, CH2COO); 2.58 – 2.55 (m, 2 CH2CH2N); 1.48 – 1.42 (m, 2 CH2CH2N); 1.28 (br. s, 60 H);
0.90 (t, J ¼ 6.9, 2 Me). 13C-NMR (CDCl3): 172.09 (C¼O); 55.05 (NCH2CH2); 54.54 (NCH2CO); 51.20,
51.16 (MeO); 31.90 (CH2CH2Me); 29.68, 29.61, 29.55, 29.31 (CH2(CH2)3N); 27.47 (CH2CH2N); 27.37
(CH2(CH2)2N); 22.65 (MeCH2); 14.04, 14.03 (MeCH2). ESI-MS: 594.7 ([M þ H]þ). Anal. calc. for
C39H79NO2 (594.07): C 78.85, H 13.40, N 2.36; found: C 78.59, H 13.50, N 2.24.
N,N-Dioctadecylglycine (4). Powder of 3 (2.97 g, 5 mmol) was added at once to a freshly prepared
soln. of NaOH (0.40 g, 10 mmol) in H2O (50 ml), and the resulting suspension was stirred at 958
overnight. White precipitate was removed by filtration, washed with Et2O (3 ꢁ 5 ml), suspended in H2O
(20 ml), and carefully made acidic (pH 6) by addition of 5% HCl. The precipitate was collected, washed
with H2O, pressed, and dried in vacuum to furnish 4 (2.84 g, 98%). TLC (CH2Cl2/MeOH 10 :1): Rf 0.43.
M.p. 102 – 1038 ([7]: 102 – 1038). 1H-NMR (CDCl3): 8.63 (br. s, 0.5 H, COOH); 8.15 (br. s, 0.5 H,
COOH); 3.46 (s, CH2CO); 3.06 – 3.03 (m, 2 CH2N); 1.70 – 1.65 (m, 2 CH2CH2N); 1.25 (br. s, 60 H); 0.88
(t, J ¼ 6.8, 2 Me). 13C-NMR (CDCl3): 168.69 (COO); 54.17 (NCH2); 31.94 (MeCH2CH2); 29.77, 29.70,
29.52, 29.38, 27.32 (CH2CH2N); 26.64 (CH2(CH2)2N); 24.89, 22.69 (MeCH2); 14.08 (Me) (1H- and
13C-NMR are in agreement with those reported in [7]).
2-(Dioctadecylamino)ethanol (5). Ester 3 (2.24 g, 3.77 mmol) was dissolved in THF (150 ml), cooled
in an ice-bath, and LiAlH4 (0.57 g, 15 mmol) was added in portions under stirring within 3 min (gas
evolution). The cooling bath was removed, and stirring was continued overnight at r.t. The mixture was
cooled in an ice-bath, and MeOH (2.5 ml) was added dropwise to destroy the excess of LiAlH4. The
mixture obtained was concentrated in vacuo (25 Torr), suspended in CH2Cl2 (100 ml), and carefully
treated with H2O (40 ml) until the formation of a precipitate. The org. layer was separated, washed with
H2O (50 ml), dried (Na2SO4), and concentrated to afford 5 (2.0 g, 94%). Off-white solid2)3). TLC (SiO2,
Et2O): Rf 0.26. M.p. 43 – 448. 1H-NMR (CDCl3): 3.52 (t, J ¼ 5.4, CH2O); 3.1 (br. s, OH); 2.57 (t, J ¼ 5.4,
OCH2CH2N); 2.44 (t, J ¼ 7.2, 2 CH2CH2CH2N); 1.43 (m, CH2CH2CH2N); 1.26 (br. s, 60 H); 0.89 (t, J ¼
6.9, 2 Me). 13C-NMR (CDCl3): 58.28 (CH2O); 55.54 (CH2CH2O); 53.90 (NCH2(CH2)16); 31.93
(MeCH2CH2); 29.70, 29.66, 29.60, 29.36 (CH2(CH2)3N); 27.45 (CH2CH2CH2N); 27.24 (CH2(CH2)2N);
22.68 (MeCH2); 14.08 (Me). ESI-MS: 566.7 ([M þ H]þ).
(2-Bromoethyl)dioctadecylamine (6). PPh3 (8.80 g, 33.6 mmol) was dissolved in a pre-cooled soln. of
5 (3.80 g, 6.71 mmol) in CH2Cl2 (180 ml) at 58, followed by addition of CBr4 (11.15 g, 33.6 mmol) in
portions within 3 min. The resulting orange soln. was stirred at r.t. for 30 h. The mixture was
concentrated, and 6 was isolated by CC (SiO2 (100 g); hexane/CH2Cl2 1:1 to 0 :1) in low yield (0.43 g,
10%). TLC (SiO2; hexane/CH2Cl2 1:1): Rf 0.58. M.p. 69 – 718. 1H-NMR (CDCl3): 3.38 (t, J ¼ 7.5, CH2Br);
2.88 (t, J ¼ 7.5, BrCH2CH2N); 2.50 (t, J ¼ 7.2, 2 (CH2)16CH2N); 1.49 – 1.41 (m, 2 CH2CH2CH2N); 1.27 (br.
s, 60 H); 0.90 (t, J ¼ 6.9, 2 Me). 13C-NMR (CDCl3): 56.16 (BrCH2CH2); 54.48 (NCH2(CH2)16); 31.91
(MeCH2CH2); 29.68, 29.64, 29.61, 29.52 (CH2Br); 29.33, 27.35 (NCH2CH2CH2) 27.21, 22.65 (MeCH2);
14.05 (Me). ESI-MS (calc. 627(79Br)): 548.7 ([M ꢀ HBr þ H]þ), 628.7 ([M(79Br) þ H]þ), 630.6
2
)
The crude product was pure enough to be used in the next step without further purification,
however, it could be purified for anal. purpose by recrystallization from the appropriate solvent or
by chromatography over SiO2.
3
)
The alcohol 5 was only poorly characterized [8].

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([M(81Br) þ H]þ). Anal. calc. for C38H78BrN (628.96): C 72.57, H 12.50, N 2.23; found: C 72.18, H 12.38,
N 2.04.
Methyl N,N-Dioctadecyl-3-aminopropanoate (8). Compound 1 (0.93 g, 1.78 mmol) was added to a
soln. of 7 (1.75 g, 20.3 mmol) in a mixture i-PrOH (14 ml)/CH2Cl2 (6 ml), and the resulting white
suspension was stirred at 458 overnight. The mixture was filtered through a paper filter and concentrated
in vacuo (10 Torr) to afford 8 (1.04 g, 96%). White solid mass2)4). TLC (SiO2, hexane/Et2O 1:1): Rf 0.58.
M.p. 44 – 458. 1H-NMR (CDCl3): 3.67 (s, MeO); 2.78 (t, J ¼ 5.4, CH2CO); 2.47 – 2.36 (m, 3 CH2N); 1.48 –
1.36 (m, 2 CH2CH2CH2N); 1.26 (br. s., 60 H); 0.89 (t, J ¼ 6.9, 2 Me) (in a good agreement with those
reported in [10]). 13C-NMR (CDCl3): 173.35 (C¼O); 54.00 (NCH2(CH2)16); 51.42 (MeO); 49.42
(CH2CH2CO); 32.30 (CH2CO); 31.90 (MeCH2CH2); 29.68, 29.64, 29.60, 29.33 (N(CH2)3CH2); 27.50
(NCH2CH2CH2); 27.19 (N(CH2)2CH2); 22.66 (MeCH2); 14.07 (MeCH2). ESI-MS: 608.7 ([M þ H]þ).
Anal. calc. for C40H81NO2 (608.10): C 79.01, H 13.43, N 2.30; found: C 78.86, H 13.39, N 2.12.
3-(Dioctadecylamino)propanol (9). LiAlH4 (0.26 g, 6.84 mmol) was added in portions within 2 min
to a soln. of 8 (1.04 g, 1.71 mmol) in THF (45 ml), cooled in an ice-bath. The bath was removed, and
stirring was continued overnight. The mixture was carefully treated with a soln. of MeOH (0.6 ml) in
Et2O (2 ml) with cooling in an ice-bath, until the gas evolution ceased. Org. solvents were removed in
vacuo, and the residue was dissolved in CH2Cl2 (70 ml), washed with H2O (3 ꢁ 30 ml), dried (Na2SO4),
and concentrated to give 9 (0.98 g, 98%). White solid mass2)5). TLC (SiO2, Et2O): Rf 0.23. M.p. 48 – 498
1H-NMR (CDCl3): 5.68 (s, OH); 3.79 (t, J ¼ 5.3, CH2OH); 2.63 (t, J ¼ 5.3, CH2CH2CH2OH); 2.38 – 2.43
(m, 2 (CH2)16CH2N); 1.67 (quint., J ¼ 5.3, CH2CH2CH2OH); 1.53 – 1.40 (m, 2 (CH2)15CH2CH2N); 1.26
(br. s, 60 H); 0.89 (t, J ¼ 6.5, 2 Me). 13C-NMR (CDCl3): 64.82 (CH2O); 55.36 (CH2(CH2)2O); 54.22
(NCH2(CH2)16); 31.90 (MeCH2CH2); 29.68, 29.64, 29.60, 29.33, 27.83 (CH2CH2O); 27.51
(NCH2CH2(CH2)15); 26.82 (N(CH2)2CH2(CH2)14); 22.66 (MeCH2); 14.06 (Me). ESI-MS: 580.7 ([M þ
H]þ).
1,1-Dioctadecylazetidinium Bromide (11). Crystals of CBr4 (320 mg, 1 mmol) were added to a pre-
cooled (ice-bath) soln. of 9 (116 mg, 0.2 mmol) and PPh3 (260 mg, 1 mmol) in CH2Cl2 (13 ml), and the
resulting mixture was stirred at the same temp. overnight. The yellow suspension was filtered through a
SiO2 layer (4 cm), and washed consecutively by CH2Cl2 (100 ml) and Et2O (100 ml) to give in the second
fraction light-yellow crystalline 11 (16 mg, 13%). TLC (SiO2; CH2Cl2/Et2O 4 :1): Rf 0.64. 1H-NMR
(CDCl3): 4.52 – 4.49 (m, NCH2); 3.57 – 3.54 (m, NCH2); 3.51 – 3.48 (m, 2 H); 2.87 – 2.79 (m, 2 H); 1.56
(br. s, 2 H); 1.34 – 1.26 (m, 60 H); 1.89 (t, J ¼ 6.8, 2 Me). ESI-MS (calc. 641(79Br)): 562.7 ([M ꢀ HBrþ
H]þ), 642.6 ([M(79Br) þ H]þ), 644.6 ([M(81Br) þ H]þ).
4-(Dioctadecylamino)-4-oxobutanoic Acid (13). Compound 1 (522 mg, 1 mmol) and Et3N (202 mg,
2 mmol) were added consecutively to a stirred soln. of succinic anhydride (12; 150 mg, 1.5 mmol) in
CH2Cl2 (10 ml), and the white suspension formed was stirred at 358 overnight. The resulting clear soln.
was concentrated in vacuo and recrystallized from acetone (3 ml) to give 13 (600 mg, 96%). White
powder. TLC (SiO2; CH2Cl2/AcOEt 1:1): Rf 0.62. M.p. 68 – 698 (acetone; [7]: 63 – 648 (Et2O)). 1H-NMR
(CDCl3): 3.36 – 3.33 (m, NCH2); 3.26 – 3.23 (m, NCH2); 2.70 (s, COCH2CH2CO); 1.62 – 1.52 (m, 2
NCH2CH2); 1.28 (br. s, 60 H); 0.90 (t, J ¼ 6.9, 2 Me). 13C-NMR (CDCl3): 173.88 (COO); 172.55 (CON);
48.42, 46.80 (NCH2); 31.90 (MeCH2CH2); 30.69 (NCOCH2); 29.67, 29.63, 29.59, 29.57, 29.54, 29.52, 29.49,
29.33, 29.28, 28.81, 28.08, 27.61, 26.99, 26.87 (NCH2CH2CH2); 22.65 (MeCH2); 14.06 (Me) (1H- and
13C-NMR are in agreement to those partly reported in [12]). ESI-MS: 622.7 ([M þ H]þ). Anal. calc. for
C40H79NO3 (622.08): C 77.23, H 12.80, N 2.25; found: C 77.12, H 12.89, N 2.08.
Methyl 4-(dioctadecylamino)-4-oxobutanoate (14). Me2SO4 (126 mg, 1 mmol) and K2CO3 (198 mg,
1.43 mmol) were added consecutively to a suspension of 13 (311 mg, 0.5 mmol) in acetone (4 ml), and
the mixture was stirred at 558 overnight. The resulting white suspension was cooled to r.t., the precipitate
was filtered off, washed with acetone (3 ml), and the filtrate was concentrated in vacuo. The residue was
taken up in CH2Cl2 (5 ml), washed with aq. NH3 (2 ml), to destroy the excess of Me2SO4, and H2O (2 ꢁ
3 ml), dried (Na2SO4), and concentrated to yield 14 (291 mg, 91%). Colorless oil, which solidified upon
4
)
Ester 8 was obtained in 42% yield, when the reaction was conducted in only CH2Cl2 according to
[9].
5
)
No spectral data for the propanol 9 were reported in [11].

Helvetica Chimica Acta – Vol. 96 (2013)
209
standing2). TLC (SiO2; hexane/Et2O 1:1): Rf 0.55. M.p. 29 – 308. 1H-NMR (CDCl3): 3.70 (s, MeO);
3.31 – 3.29 (m, NCH2); 3.26 – 3.23 (m, NCH2); 2.70 – 2.67 (m, 2 H, COCH2CH2CO); 2.64 – 2.61 (m, 2 H,
COCH2CH2CO); 1.61 – 1.48 (m, 2 NCH2CH2); 1.27 (br. s, 60 H); 0.90 (t, J ¼ 6.9, 2 Me). 13C-NMR
(CDCl3): 173.72 (COO); 170.49 (CON); 51.62 (MeO); 47.85, 46.18 (NCH2); 31.90, 29.67, 29.63, 29.58,
29.54, 29.42, 29.32, 28.94, 27.99, 27.79, 27.06, 26.92 (NCH2CH2CH2); 22.65 (MeCH2); 14.06 (Me). ESI-MS
(calc. 635): 1294.2 ([2 M þ Na]þ), 658.7 ([M þ Na]þ), 636.7 ([M þ H]þ).
4-(Dioctadecylamino)butan-1-ol (15a). Powdered LiAlH4 (106 mg, 2.8 mmol) was added in portions
during 2 min to a pre-cooled (ice-bath) soln. of 14 (222 mg, 0.35 mmol) in THF (4 ml), and the resulting
suspension was stirred at r.t. overnight. The mixture was cooled on an ice-bath, and MeOH (1 ml) was
added dropwise to destroy the excess of LiAlH4. Stirring was continued, until the gas evolution had
ceased. The precipitate formed was filtered off, washed with Et2O (5 ꢁ 5 ml), the filtrate was
concentrated, and the crude product was purified by chromatography (prep. TLC (CH2Cl2/MeOH 15 :1))
to afford 15a (122 mg, 76%). Colorless solid. TLC (SiO2, CH2Cl2/MeOH 15 :1): Rf 0.30. M.p. 57 – 588.
1H-NMR (CDCl3): 3.56 (br. s, CH2O); 2.49 – 2.43 (m, 6 H, (CH2)2NCH2); 1.68 – 1.64 (m, 4 H); 1.54 – 1.43
(m, 4 H); 1.26 (br. s, 60 H); 0.88 (t, J ¼ 6.9, 2 Me). 13C-NMR (CDCl3): 62.56 (OCH2); 54.58 (NCH2);
53.61 (NCH2(CH2)16); 32.54 (br. s, CH2CH2OH); 31.30 (MeCH2CH2); 29.67, 29.63, 29.60, 29.50, 29.33,
27.62 (NCH2CH2(CH2)15); 26.05 (br. s, NCH2CH2); 25.71 (N(CH2)2CH2(CH2)14); 22.65 (MeCH2); 14.05
(Me). ESI-MS: 522.7 ([M ꢀ C4H8 þ H]þ), 594.8 ([M þ H]þ).
2-Cyanoethyl 4-(Dioctadecylamino)butyl N,N-Diisopropylphosphoramidite (15b). A soln. of 15a
(154 mg, 0.26 mmol) in CH2Cl2 (5 ml) under Ar was treated with Hꢀnigꢂs base (101 mg, 0.78 mmol). The
resulting mixture was cooled in an ice-bath, and (chloro)(2-cyanoethoxy)(diisopropylamino)phosphine
(123 mg, 0.56 mmol) was added, and the mixture was stirred for 20 min with cooling and then for 1 h at
r.t. The resulting colorless clear soln. was diluted with CH2Cl2 (40 ml), washed with an ice-cold aq.
NaHCO3 soln. and brine, and dried (Na2SO4) and concentrated. The resulting oil was chromatographed
(SiO2; eluted with benzene/Et2O/Et3N 80 :10 :1) to give 2 (191 mg, 93%) from the first three fractions
upon evaporation. Colorless oil. 1H-NMR (CDCl3, 500 MHz): 3.91 – 3.79 (m, OCH2); 3.72 – 3.58 (m,
OCH2, 2 NCH); 2.65 (t, J ¼ 6.55, NCCH2); 2.44 – 2.41 (m, NCH2); 2.40 – 2.37 (m, 2 NCH2); 1.65 – 1.60 (m,
OCH2CH2); 1.54 – 1.48 (m, NCH2CH2); 1.45 – 1.39 (m, 2 NCH2CH2); 1.35 – 1.1.27 (m, CH2); 1.27 (br. s,
CH2); 1.20 (d, J ¼ 6.65, CH(Me)2); 1.19 (d, J ¼ 6.65, CH(Me)2); 0.90 (t, J ¼ 6.65, 2 MeCH2). 13C-NMR
2
2
(CDCl3,125 MHz): 117.53 (CꢂN); 63.72 (d, J(C,P) ¼ 17.1, CH2OP); 58.32 (d, J(C,P) ¼ 19.0, CH2OP);
54.25 (2 CH2N); 53.91 (CH2N); 43.51 (d, 2J(C,P) ¼ 12.4, 2 CHNP); 31.90 (2 CH2CH2 Me); 29.68, 29.37,
29.33, 27.66 (2 CH2CH2N); 27.16 (2 CH2(CH2)2N); 24.65 (CHMe); 24.59 (2 CHMe); 24.52 (CHMe);
23.59 (CH2CH2N); 22.66 (2 MeCH2); 20.34 (d, 3J(C,P) ¼ 6.7, CH2CH2OP); 14.06 (2 Me). 31P-NMR
(CDCl3 , 202.5 MHz): 147.42. ESI-MS (calc. 793): 711.7 ([M ꢀ NiPr2 þ OH þ H]þ), 741.8 ([M ꢀ
O(CH2)2CN þ OH þ H]þ), 810.8 ([M þ O þ H]þ).
4-(Dioctadecylamino)[1,1,4,4-2H4]butan-1-ol (16). Powdered LiAlD4 (109 mg, 2.6 mmol) was added
portionwise during 2 min to a pre-cooled (ice-bath) soln. of 14 (206 mg, 0.32 mmol) in THF (4 ml), and
the resulting suspension was stirred at r.t. overnight. The mixture was cooled in an ice-bath, diluted with
Et2O (10 ml), and MeOH (1 ml) was added dropwise to destroy an excess of LiAlD4. Stirring was
continued, until gas evolution had ceased (10 min). The precipitate formed was filtered off, washed with
Et2O (5 ꢁ 5 ml), the filtrate was concentrated, and the crude product was suspended in CH2Cl2. The
resulting precipitate was filtered off and washed with CH2Cl2 (5 ꢁ 1 ml). The filtrate was concentrated
resulting in the formation of 16 (145 mg, 75%). White solid2). TLC (SiO2; CH2Cl2/MeOH 8 :1): Rf 0.60.
M.p. 59 – 608. 1H-NMR (CDCl3): 2.46 – 2.42 (m, (CH2)2NCD2); 1.66 – 1.62 (m, 4 H); 1.51 – 1.46 (m, 4 H);
1.27 (br. s, 60 H); 0.89(t, J ¼ 6.9, 2 Me). 13C-NMR (CDCl3): 61.89 (quint., J(C,D) ¼ 20.5, OCD2); 53.98
(quint., J(C,D) ¼ 21.1, NCD2); 53.71 (NCH2); 32.51 (br. s, CH2CD2OH); 31.90 (MeCH2CH2); 29.67,
29.63, 29.61, 29.53, 29.33, 27.66 (NCH2CH2); 26.13 (br. s, NCD2CH2); 25.93 (N(CH2)2CH2(CH2)14); 22.66
(MeCH2); 14.05 (Me). ESI-MS: 522.7 ([M ꢀ C4H4D4 þ H]þ), 598.8 ([M þ H]þ).
N-(4-Chlorobut-2-yn-1-yl)-N-octadecyloctadecan-1-amine (18). Compound 1 (2.08 g, 4.0 mmol), 1,4-
dichlorobut-2-yne 17, 1.48 g, 12 mmol), and Na2CO3 (1.69 g, 16 mmol) were suspended in benzene
(40 ml) and stirred at 65 – 708 (bath) overnight (16 h), until the reaction was completed (NMR analysis:
amine 1: 2.66 ppm, product 18: 2.44 ppm). The light-brown mixture was concentrated, diluted with Et2O,
inorganic salts and residual starting amine 1 were filtered off and washed with pre-cooled Et2O (þ 58,

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Helvetica Chimica Acta – Vol. 96 (2013)
20 ml). The filtrate was concentrated resulting in the formation of 2.1 g of a beige solid mass. The
product 18 was isolated by CC (SiO2; (100 g); CH2Cl2/Et2O 4 :1; 400 ml) as a light beige mass (1.57 g,
60.5%), followed by other products (in order of their elution from the column): N,N,N’,N’-
tetraoctadecylbut-2-yne-1,4-diamine (19), 4-chlorobut-2-yn-1-ol (20), and bis(4-chlorobut-2-ynyl)diocta-
decylammonium chloride (21).
Data of 18. TLC (SiO2; CH2Cl2): Rf 0.45. M.p. 51 – 528. 1H-NMR (CDCl3): 4.18 (t, J ¼ 1.83, CH2Cl);
3.44 (t, J ¼ 1.83, NCH2Cꢂ); 2.47 – 2.44 (m, 2 CH2CH2N); 1.48 – 1.41 (m, 2 CH2CH2N); 1.28 (br. s, 60 H);
0.90 (t, J ¼ 6.9, 2 Me). 13C-NMR (CDCl3): 82.45 (ClCꢀCꢂ); 79.31 (ClCꢀCꢂC); 53.83 (NCH2CH2); 42.19
(NCH2Cꢂ); 31.92 (CH2CH2 Me); 30.60 (CH2Cl); 29.70, 29.65, 29.56 (CH2CH2CH2 Me); 29.35
(CH2(CH2)3N); 27.52 (CH2CH2N); 27.46 (CH2(CH2)2N); 22.66 (MeCH2); 14.03 (Me). ESI-MS (calc.
607(35Cl)): 608.7 ([M(35Cl) þ H]þ), 609.7, 610.7 ([M(37Cl) þ H]þ), 611.7. Anal. calc. for C40H78ClN
(608.53): C 78.95, H 12.92, N 2.30; found: C 78.73, H 12.97, N 2.15.
1
Data of 19. TLC (SiO2; CH2Cl2): Rf 0.40. M.p. 55 – 568. H-NMR (CDCl3): 3.43 (s, 2 NCH2Cꢂ);
2.47 – 2.44 (m, 4 CH2CH2N); 1.48 – 1.41 (m, 4 CH2CH2N); 1.27 (br. s, 120 H); 0.90 (t, J ¼ 6.9, 4 Me).
13C-NMR (CDCl3): 79.36 (CꢂC); 53.95 (NCH2CH2); 41.97 (NCH2Cꢂ); 31.91 (CH2CH2 Me); 29.70,
29.66, 29.64, 29.34, 27.61, 27.52, 22.66 (MeCH2); 14.06 (Me). ESI-MS (calc. 1092): 548.7 ([M þ 2 H]2þ).
1
Data of 206). TLC (SiO2, CH2Cl2/Et2O 1:1): Rf 0.31. H-NMR (CDCl3): 4.34 (t, J ¼ 1.75, CH2O);
4.19 (t, J ¼ 1.75, CH2Cl).
Data of 21. 1H-NMR (CDCl3): 4.97 (s, 2 ꢂCCH2Nþ); 4.21 (s, 2 CH2Cl); 3.60 – 3.56 (m, 2
CH2CH2Nþ); 1.91 – 1.86 (m, 2 CH2CH2Nþ); 1.27 (br. s, 120 H); 0.90 (t, J ¼ 6.9, 4 Me).
N-Octadecyl-N,N-diprop-2-yn-1-ylamine (¼ N,N-Di(prop-2-yn-1-yl)octadecan-1-amine; 24). 3-Bro-
moprop-1-yne (23; 3.57 g, 30 mmol) and K2CO3 (4.14 g, 30 mmol) were added consecutively to a stirred
suspension of octadecylamine (22; 2.69 g, 10 mmol) in MeOH (20 ml) in a bottle with a screw stopper.
The resulting mixture was stirred at r.t. overnight. The brown suspension was filtered through a SiO2 layer
(1 cm), washed with AcOEt (100 ml), and the filtrate was concentrated to give 24 (3.34 g, 96%). Viscous
mass, which solidified upon standing. The product is pure enough for further reactions, however, it could
be easily purified for anal. purpose by filtration through a SiO2 (5 cm; with hexane/AcOEt 15 :1). TLC
1
(hexane/AcOEt, 2 :2): Rf 0.85. M.p. 43 – 448 (MeOH). H-NMR (CDCl3): 3.45 (d, J ¼ 2.3, NCH2Cꢂ);
2.54 – 2.51 (m, NCH2(CH2)16); 2.22 (t, J ¼ 2.3, CHꢂ); 1.51 – 1.44 (m, 2 H); 1.27 (br. s, 30 H); 0.90 (t, J ¼
6.5, Me). 13C-NMR (CDCl3): 78.91 (CHꢂC); 72.72 (CHꢂ); 53.05 (NCH2(CH2)16); 42.08 (NCH2Cꢂ);
31.90, 29.66, 29.59, 29.55, 29.48, 29.32, 27.45, 27.32, 22.65 (MeCH2); 14.05 (Me). ESI-MS: 384.4 ([M þ
K]þ), 346.4 ([M þ H]þ), 318.3 ([M ꢀ C2H4 þ H]þ), 270.3 ([M ꢀ C6H4 þ H]þ).
4-(Octadecylamino)-4-oxobutanoic acid (25). Powdered 12 (0.440 g, 4.4 mmol) was added in
portions to a stirred soln. of 22 (1.076 g, 4 mmol) in CH2Cl2 (20 ml) at r.t., followed by Et3N (0.808 g,
8 mmol). The resulting white suspension was stirred for 3 h until dissolution of the precipitate. The clear
colorless soln. was concentrated in vacuo, and the residue was crystallized from acetone to afford 25
(1.277 g, 87%). White crystals. Chromatographic separation of the concentrated mother liquid (SiO2
(10 g)); CH2Cl2/MeOH 1:1) gave a further amount of 25 (0.088 g, 6%). TLC (SiO2, CH2Cl2/MeOH
8 :1): Rf 0.64. M.p. 124 – 1258. 1H-NMR (CDCl3): 5.69 (br. s, NH); 3.31 – 3.27 (m, NCH2); 2.73 – 2.71 (m,
NCH2); 2.56 – 2.54 (m, O¼CCH2); 1.56 – 1.51 (m, NCH2CH2(CH2)15); 1.31 (br. s, 2 H); 1.28 (br. s, 28 H);
0.90 (t, J ¼ 6.9, Me). 13C-NMR: 173.02 (COO); 170,90 (CON); 40.05 (NCH2); 31.90 (MeCH2CH2); 30.75,
30.08, 29.66, 29.63, 29.59, 29.54, 29.49, 29.39, 29.32, 29.21, 26.83 (NCH2CH2CH2); 22.65 (MeCH2); 14.05
(Me). ESI-MS: 370.4 ([M þ H]þ).
Methyl 4-(Octadecylamino)-4-oxobutanoate (26). Me2SO4 (0.454 g, 3.6 mmol) and K2CO3 (1.01 g,
7.4 mmol) were added consecutively to a stirred soln. of 25 (0.680 mg, 1.8 mmol) in acetone (4 ml) at r.t.,
and the resulting suspension was heated at 558 overnight. The mixture was cooled to r.t., all solids were
filtered off, washed with acetone (5 ml), the filtrate was concentrated, and the residue was dissolved in
CH2Cl2 (5 ml). The soln. was washed with H2O (2 ꢁ 5 ml), dried (Na2SO4), and concentrated to give 26
(0.502 mg, 72%). Light-cream crystals. TLC (hexane/AcOEt 1 :1): Rf 0.50. M.p. 86 – 878 ([14]: 86.5 –
1
87.58). H-NMR (CDCl3): 5.60 (br. s, 0.8 H, NH); 5.35 (br. s, 0.2 H, NH); 3.69 (s, MeO); 3.23 (q, J ¼
6.75, NCH2); 2.68 (t, J ¼ 6.75, COCH2); 2.46 (t, J ¼ 6.75, COCH2); 1.59 (br. s, 2 H); 1.54 – 1.44 (m,
1
The H- and 13C-NMR spectra are in agreement with those reported [13].
6
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Helvetica Chimica Acta – Vol. 96 (2013)
211
2 H); 1.26 (br. s, 28 H); 0.88 (t, J ¼ 6.8, MeCH2). 13C-NMR (CDCl3): 173.54 (COO); 171.28 (CON); 51.79
(MeO); 39.72 (NCH2); 31.92, 31.14 (NCOCH2); 29.69, 29.65, 29.59, 29.54, 29.48, 29.34, 29.28, 26.88
(NCH2CH2CH2); 22.67 (MeCH2); 14.08 (Me). ESI-MS: 406.3 ([M þ Na]þ), 384.4 ([M þ H]þ).
1-Octadecylpyrrolidine (28). Powdered LiAlH4 (80 mg, 2.08 mmol) was added portionswise to a pre-
cooled (ice-bath) soln. of 26 (100 mg, 0.26 mmol) in THF (3 ml), and the resulting suspension was stirred
at r.t. during 5 h. The resulting grey suspension was cooled on an ice-bath, diluted with Et2O (6 ml), and
MeOH (1 ml) was added dropwise. The resulting mixture was stirred for 30 min until the formation of a
crystalline precipitate was completed. Solids were separated, washed with Et2O (2 ꢁ 5 ml), and the
filtrate was concentrated in vacuo to yield 28 (60 mg, 71%). Yellowish solid mass. TLC (CH2Cl2/MeOH
1
10 :1): Rf 0.46. M.p. 25 – 278 ([15]: 26 – 278). H-NMR (CDCl3): 2.49 (br. s, 2 N(CH2CH2)2); 2.43 – 2.40
(m, NCH2(CH2)16); 1.78 (br. s, N(CH2CH2)2); 1.54 – 1.46 (m, NCH2CH2(CH2)15); 1.30 – 1.26 (m, 30 H);
0.89 (t, J ¼ 6.8, Me). 13C-NMR (CDCl3): 56.72 (NCH2(CH2)16); 54.21 (N(CH2CH2)2); 31.89
(MeCH2CH2); 29.66, 29.59, 29.32, 29.02, 27.72, 23.38 (N(CH2CH2)2); 22.65 (MeCH2); 14.05 (Me).
ESI-MS: 324.4 ([M þ H]þ), 296.3 ([M ꢀ C2H4 þ H]þ).
4-Hydroxy-N-octadecylbutanamide (29). Powdered LiAlH4 (182 mg, 4.8 mmol) was added in
portions during 3 min to a pre-cooled (ice-bath) stirred suspension of 25 (222 mg, 0.6 mmol), dissolved in
THF (10 ml). After 15 min, the cooling bath was removed, and stirring was continued at r.t. for another
5 h. The mixture was cooled on an ice-bath, diluted with Et2O (20 ml), and MeOH (1 ml) and H2O (1 ml)
were added dropwise until the gas evolution had ceased, and the violet suspension turned into a white
precipitate. It was filtered off, washed with Et2O, filtrates were concentrated, and the residue was
separated by prep. TLC (SiO2; CH2Cl2/MeOH 8 :1) to give 29 (175 mg, 82%). Colorless crystals. TLC
1
(CH2Cl2/MeOH 9 :1): Rf 0.42. M.p. 86 – 878 ([16] 86 – 878). H-NMR (CDCl3): 5.73 (br. s, NH); 3.72 –
3.70 (m, CH2O); 3.25 (q, J ¼ 6.7, NCH2); 2.37 – 2.34 (m, CH2C¼O); 1.81 (quint., J ¼ 6.2, CH2CH2C¼O);
1.51 (quint., J ¼ 6.8, NCH2CH2); 1.27 (br. s, 30 H); 0.89 (t, J ¼ 6.8, Me). 13C-NMR (CDCl3): 173.03
(C¼O); 62.37 (COH); 39.71 (NCH2); 34.06 (COCH2); 31.89, 29.66, 29.62, 29.57, 29.52, 29.32, 29.26, 28.17
(NCH2CH2); 26.91 (N(CH2)2CH2); 22.64 (MeCH2); 14.06 (Me). ESI-MS: 356.3 ([M þ H]þ).
4-(Octadecylamino)butan-1-ol (27). Powdered LiAlH4 (340 mg, 8 mmol) was added in portions
during 10 min to a pre-cooled (ice-bath) stirred suspension of 24 (371 mg, 1 mmol) in Et2O (20 ml).
After 5 min, the cooling bath was removed, and stirring was continued at r.t. for another 1 h and then at
358 overnight. The mixture was cooled on an ice-bath, diluted with Et2O (20 ml), and H2O (0.5 ml) was
added dropwise until the gas evolution had ceased; the grey suspension turned into a white precipitate. It
was filtered off and washed with Et2O. The filtrates were concentrated, and the white residue was
separated by prep. TLC (SiO2; CH2Cl2/MeOH 8 :1) to give 27 (288 mg, 84%) as colorless crystals,
1
followed by 29 (22 mg, 6%). TLC (CH2Cl2/Et2O 1:1): Rf 0.42. M.p. 68 – 698 ([17]: 68 – 708). H-NMR
(CDCl3): 3.60 – 3.58 (m, CH2O); 2.67 – 2.65 (m, NCH2); 2.63 – 2.60 (m, NCH2); 1.72 – 1.67 (m, CH2);
1.65 – 1.58 (m, CH2, OH); 1.52 – 1.48 (m, CH2); 1.26 (br. s, 30 H); 0.88 (t, J ¼ 6.8, Me). 13C-NMR (CDCl3):
61.53 (COH); 47.90, 47.80 (NCH2); 31.90 (MeCH2CH2); 29.68, 29.63, 29.60, 29.53, 29.44, 29.33, 29.07,
26.80, 25.96 (NCH2CH2); 23.66 (OCH2CH2CH2); 22.65 (MeCH2); 14.06 (Me). ESI-MS: 270.4
(H3C(CH2)17NH3þ), 314.4 ([M – 28 þ H]þ), 342.7 ([M þ H]þ).
4-[Octadecyl(prop-2-yn-1-yl)amino]butan-1-ol (30). Compound 23 (21 mg, 0.18 mmol) was added
to a stirred suspension of K2CO3 (25 mg, 0.18 mmol) of a soln. of 27 (30 mg, 0.09 mmol) in MeOH (1 ml)
at r.t. The resulting mixture was stirred overnight. The resulting precipitate was filtered off, washed with
AcOEt (3 ml), the filtrate was concentrated in vacuo, and CC (SiO2; CH2Cl2/Et2O 1:1) gave 30 (20 mg,
61%). Colorless crystals. TLC (CH2Cl2/Et2O 1:1): Rf 0.32. M.p. 33 – 348. 1H-NMR (CDCl3): 3.59 (br. s,
CH2O); 3.48 (br. s, CH2Cꢂ); 2.61 – 2.59 (m, NCH2); 2.58 – 2.55 (m, 2 H, NCH2(CH2)15); 2.21 (br. s,
CHꢂ); 1.66 (br. s, CH2CH2CH2O); 1.56 – 1.46 (m, NCH2CH2); 1.26 (br. s, 30 H); 0.88 (t, J ¼ 6.7, Me).
13C-NMR (CDCl3): 73.80 (CHꢂ); 62.63 (CH2OH); 53.87, 53.61 (NCH2); 40.94 (NCH2Cꢂ); 31.90, 30.32
(OCH2CH2); 29.66, 29.62, 29.59, 29.53, 29.43, 29.32, 27.40, 26.83, 25.25 (OCH2CH2CH2); 22.65 (MeCH2);
14.06 (Me). 13C-NMR (C6D6): 78.88 (CHꢂC); 73.97 (CHꢂ); 63.25 (CH2OH); 54.65, 54.49 (NCH2);
41.87 (NCH2Cꢂ); 32.93, 32.76 (OCH2CH2); 32.79, 30.72, 30.58, 30.41, 28.40, 28.29, 26.00, 23.70
(MeCH2); 14.94 (Me). ESI-MS: 308.4 ([M ꢀ C4H8O þ H]þ), 362.4 ([M ꢀ H2O þ H]þ), 380.4 ([M þ
H]þ).

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Helvetica Chimica Acta – Vol. 96 (2013)
5’-O-[Bis(4-methoxyphenyl)(phenyl)methyl]-2’-deoxy-3,4-dihydrothymidine (37). 2’-Deoxythymi-
dine (31; 0.726 g, 3.0 mmol) was added portionwise at r.t. to a yellowish clear soln. of 4,4’-dimethoxytrityl
chloride (1.220 g, 3.6 mmol) in pyridine (15 ml), and the resulting orange mixture was stirred overnight.
It was diluted with AcOEt (80 ml), washed with H2O (3 ꢁ 25 ml), dried (Na2SO4), and concentrated in
vacuo to give an orange viscose mass (2.0 g). The product 37 was isolated by CC (SiO2, 120 g; hexane/
AcOEt 2 :1 to 0 :1; 120 ml) as a light-yellow oil (1.52 g, 93.8%), which solidified on standing at r.t. TLC
1
(SiO2, AcOEt): Rf 0.5. M.p. 123 – 1258 ([18a]: 122 – 1248). H-NMR (CDCl3): 9.67 (br. s, NH); 7.60 (s,
HꢀC(6)); 7.41 (d, J ¼ 7.9, 2 arom. CH); 7.31 – 7.28 (m, 6 H); 7.21 (t, J ¼ 7.2, 1 arom. CH); 6.83 (d, J ¼ 8.7, 4
arom. CH); 6.45 – 6.41 (m, HꢀC(1’)); 4.58 – 4.56 (m, HꢀC(3’)); 4.11 – 4.07 (m, HꢀC(4’)); 3.77 (s, 2 MeO);
3.47 – 3.35 (qAB, d(HA) 3.46, d(HB) 3.37, JAB ¼ꢀ 10.5, JAX ¼ JBX ¼ 2.6, CH2(5’)); 2.47 – 2.43 (m, 1 H of
CH2(2’)); 2.33 – 2.28 (m, 1 H of CH2(2’)); 1.47 (s, Me(7)). 13C-NMR (CDCl3): 164.15 (C(4)); 158.69
(MeOꢀC(arom.)); 150.72 (C(2)); 144.38, 135.78 (C(6)); 135.48, 135.42, 130.08, 128.14, 127.95, 127.08,
113.27, 111.24 (C(5)); 86.88 (CH2OC); 86.37 (C(4’)); 84.85 (C(1’)); 72.38 (C(3’)); 63.67 (C(5’)); 55.21
(MeO); 40.94 (C(2’)); 11.78 (C(7)) (1H- and 13C-NMR spectra are in a good agreement with those
reported in [18]). ESI-MS: 567.3 ([M þ Na]þ), 583.3 ([M þ K]þ), 1111.5 ([2 M þ Na]þ).
5’-O-[Bis(4-methoxyphenyl)(phenyl)methyl]-3’-O-[(tert-butyl)(dimethyl)silyl]-2’-deoxy-3,4-dihy-
drothymidine (32). 1H-Imidazole (0.52 g, 7.6 mmol) was dissolved in a soln. of 5’-O-(4,4’-dimethoxy-
trityl)-2’-deoxythymidine (1.36 g, 2.5 mmol) in DMF (20 ml) at r.t. The resulting mixture was cooled in an
ice-bath, and a soln. of tBuMe2SiCl (0.57 g, 3.8 mmol) in DMF (3 ml) was added dropwise during 5 min.
The cooling bath was removed, and the mixture was stirred at r.t. overnight. MeOH (10 ml) was added to
destroy the excess of tBuMe2SiCl, and the resulting mixture was stirred for 30 min, diluted with AcOEt
(200 ml), washed consecutively with aq. NaHCO3 and H2O, and dried (Na2SO4) and concentrated to give
crude 32 (1.95 g) as a colorless viscous oil2), which was purified by CC (SiO2 (200 g); hexane/AcOEt/
Et3N 15 :15 :1), to give pure 32 (1.45 g, 88%) as a colorless viscose oil, which turned to a solid foam on
drying in high vacuum7). TLC (SiO2; hexane/AcOEt 2 :1): Rf 0.29. M.p. 87 – 888. 1H-NMR (CDCl3): 8.46
(s, NH); 7.64 (s, HꢀC(6)); 7.43 (d, J ¼ 7.9, 2 arom. CH); 7.33 – 7.29 (m, 6 arom. CH); 7.27 – 7.24 (m, 1 arom.
H); 6.85 (d, J ¼ 8.8, arom. CH); 6.37 – 6.34 (m, HꢀC(1’)); 4.54 – 4.52 (m, HꢀC(3’)); 3.98 – 3.95 (m,
HꢀC(4’)); 3.79 (s, 2 MeO); 3.50 – 3.24 (qAB, HA ¼ 3.46, HB ¼ 3.27, JAB ¼ꢀ 10.6, JAX ¼ JBX ¼ 2.8, CH2(5’));
2.37 – 2.32 (m, CH2(2’)); 2.25 – 2.21 (m, CH2(2’)); 1.51 (s, Me(7)); 0.84 (s, SiCMe3); 0.03 (s, SiMe); ꢀ 0.03
(s, SiMe). 13C-NMR (CDCl3): 163.61 (C(4)); 158.76 (MeOC(arom.)); 150.18 (C(2)); 144.35, 135.58
(C(6)); 135.50, 135.46, 130.06, 130.04, 128.14, 127.95, 127.11, 113.28, 113.27, 110.98 (C(5)); 86.84
(CH2OC); 86.80 (C(4’)); 84.90 (C(1’)); 72.11 (C(3’)); 62.94 (C(5’)); 55.23 (MeO); 41.54 (C(2’)); 25.70
(SiCMe); 17.92 (SiC); 11.86 (C(7)); ꢀ 4.69, ꢀ 4.88 (SiMe) (1H- and 13C-NMR spectra are in a good
agreement with those reported in [19]). ESI-MS: 681.4 ([M þ Na]þ), 697.4 ([M þ K]þ).
2’-Deoxy-3-[4-(dioctadecylamino)but-2-yn-1-yl]-3,4-dihydrothymidine (33). Compound 31 (32 mg,
0.132 mmol), DMSO (0.1 ml), and K2CO3 (36 mg, 0.264 mmol) were consecutively added to a stirred
soln. of 18 (80 mg, 0.132 mmol) in THF (0.5 ml) at r.t. in a bottle with a screw stopper, and the mixture
was stirred at 708 during 48 h. The resulting brown mixture was cooled to r.t., treated with H2O (4 ml) and
Et2O (4 ml), the org. phase was separated, and the H2O phase was extracted with Et2O (4 ml). Combined
org. phases were washed with H2O, dried (Na2SO4), concentrated, and prep. TLC (SiO2; AcOEt)
1
afforded 33 (49 mg, 46%). Yellow oil. TLC (AcOEt): Rf 0.33. M.p. 49 – 508. H-NMR (CDCl3): 7.49 (s,
HꢀC(6)); 6.24 (t, J ¼ 6.7, HꢀC(1’)); 4.72 (s, CONCH2Cꢂ); 4.58 – 4.56 (m, HꢀC(3’)); 4.00 – 3.98 (m,
HꢀC(4’)); 3.92 – 3.83 (qAB, d(HA) 3.91, d(HB) 3.84, JAB ¼ꢀ 11.8, JAX ¼ JBX ¼ 2.8, CH2(5’)); 3.33 (s,
CH2NCH2Cꢂ); 2.47 – 2.41 (m, N(CH2)2); 2.34 – 2.32 (m, CH2(2’)); 1.99 (s, Me(7)); 1.44 – 1.40 (m, 4 H);
1.27 (br. s, 60 H); 0.89 (t, J ¼ 6.9, 2 MeCH2). 13C-NMR (CDCl3): 162.36 (C(4)); 150.24 (C(2)); 134.92
(C(6)); 110.30 (C(5)); 87.26 (C(4’)); 86.86 (C(1’)); 71.43 (C(3’)); 62.33 (C(5’)); 53.68 (NCH2(CH2)16);
42.25 (NCH2Cꢂ); 40.25 (CHCH2CH); 31.90 (MeCH2CH2); 30.74 (CONCH2); 29.68, 29.63, 29.55, 29.33,
27.48 (NCH2CH2); 27.07 (N(CH2)2CH2); 22.65 (MeCH2); 14.06 (MeCH2); 13.22 (C(7)). 13C-NMR
(CD3OD): 164.36 (C(4)); 151.64 (C(2)); 136.73 (C(6)); 110.69 (C(5)); 89.06 (C(4’)); 87.28 (C(1’)); 81.09
(Cꢂ); 77.77 (Cꢂ); 72.11 (C(3’)); 62.77 (C(5’)); 54.82 (NCH2(CH2)16); 42.76 (NCH2Cꢂ); 41.49
7
)
The compound 32 is sensitive to acids including SiO2, and addition of Et3N into the elution mixture
improves the isolated yield.

Helvetica Chimica Acta – Vol. 96 (2013)
213
(CHCH2CH); 33.06 (MeCH2CH2); 31.52 (CONCH2); 30.75, 30.66, 30.64, 30.51, 30.44, 28.53
(NCH2CH2); 27.81 (N(CH2)2CH2); 23.71 (MeCH2); 14.41 (MeCH2); 13.13 (C(7)). ESI-MS: 814.7
([M þ H]þ).
5’-O-[Bis(4-methoxyphenyl)(phenyl)methyl]-2’-deoxy-3-[4-(dioctadecylamino)but-2-yn-1-yl]-3,4-
dihydrothymidine (34) from 33. A soln. of 4,4’-dimethoxytrityl chloride (13.4 mg, 0.039 mmol) in
pyridine (0.1 ml) was added to a pre-cooled (ice-bath) soln. of 33 (28 mg, 0.034 mmol), and the resulting
orange soln. was stirred at r.t. 48 h. The mixture was diluted with CH2Cl2 (2 ml), concentrated in vacuum
(0.05 Torr), and the residue was separated by prep. TLC (20 ꢁ 20 cm, SiO2; CH2Cl2/AcOEt/Et3N 40 :9 :1)
to give in the 3rd fraction 34 (28 mg, 73%). Yellowish oil. TLC (SiO2, CH2Cl2/AcOEt/Et3N 40 :9 :1): Rf
0.44. 1H-NMR (CDCl3): 7.55 (s, HꢀC(6)); 7.42 – 7.41 (m, 2 arom. H); 7.32 – 7.30 (m, 6 arom. H); 7.26 – 7.24
(m, 1 arom. H); 6.86 – 6.84 (m, 2 arom. H); 6.43 (t, J ¼ 6.6, HꢀC(1’)); 4.74 (s, CONCH2Cꢂ); 4.58 – 4.55
(m, HꢀC(3’)); 4.05 – 4.03 (m, HꢀC(4’)); 3.81 (s, 2 MeO); 3.52 – 3.39 (qAB, d(HA) 3.45, d(HB) 3.40, JAB
¼
ꢀ 10.5, JAX ¼ 3.3, JBX ¼ 3.1, CH2(5’)); 3.36 (s, CH2NCH2Cꢂ); 2.47 – 2.41 (m, N(CH2)2); 2.34 – 2.29 (m,
NCHCH2); 1.57 (s, Me(7)); 1.46 – 1.40 (m, 4 H); 1.27 (br. s, 60 H); 0.89 (t, J ¼ 6.9, 2 MeCH2). 13C-NMR
(CDCl3): 162.46 (C(4)); 158.78 (COMe); 150.21 (C(2)); 144.32 (OCC(arom.)); 135.40 (OCC(arom.));
133.69 (C(6)); 130.06 (arom. CH); 128.12 (arom. CH); 127.14 (arom. CH); 113.31 (arom. CH); 110.38
(C(5)); 86.99 (OCC(arom.)); 85.84 (C(4’)); 85.30 (C(1’)); 72.36 (C(3’)); 63.43 (C(5’)); 55.23
(NCH2(CH2)16); 53.72 (MeO); 42.35 (NCH2Cꢂ); 41.03 (C(2’)); 31.90 (MeCH2CH2); 30.76 (CONCH2);
29.69, 29.65, 29.60, 29.33, 27.52 (NCH2CH2); 27.41, 22.66 (MeCH2); 14.07 (MeCH2); 12.60 (C(7)).
13C-NMR (C6D6): 161.89 (C4)); 159.03 (COMe); 150.11 (C(2)); 144.88 (OCC(arom.)); 135.63
(OCC(arom.)); 133.40 (C(6)); 130.21 (arom. CH); 128.30 (arom. CH); 126.99 (arom. CH); 113.30
(arom. CH); 109.93 (C(5)); 86.87 (OCC(arom.)); 85.89 (C(4’)); 85.45 (C(1’)); 79.78 (Cꢂ); 77.59 (Cꢂ);
71.90 (C(3’)); 63.64 (C(5’)); 54.48 (NCH2(CH2)16); 53.70 (MeO); 42.12 (NCH2Cꢂ); 40.72 (CHCH2CH);
31.96 (MeCH2CH2); 30.64 (CONCH2); 29.84, 29.75, 29.72, 29.44, 27.75 (NCH2CH2); 27.49, 22.72
(MeCH2); 13.96 (MeCH2); 12.56 (C(7)). ESI-MS: 1116.9 ([M þ H]þ).
5’-O-[Bis(4-methoxyphenyl)(phenyl)methyl]-2’-deoxy-3-[4-(dioctadecylamino)but-2-yn-1-yl]-3,4-
dihydrothymidine (34) from 37. A clear soln. of 37 (72 mg, 0.132 mmol) and 18 (80 mg, 0.132 mmol) in
THF (0.5 ml) was diluted with DMSO (0.2 ml), then K2CO3 (36 mg, 0.264 mmol) was added, and the
resulting mixture was stirred at 708 during 2 d. The resulting brownish mixture was cooled and treated
with H2O (5 ml), extracted with Et2O (2 ꢁ 5 ml), washed with H2O (2 ꢁ 2 ml), dried (Na2SO4), and
evaporated. The crude product was purified by CC (SiO2 60, gradient CH2Cl2/MeOH 500 – 30 :1) to give
34 (75 mg, 51 %) and starting 37 (28 mg, 39%; in order of their elution from the column). TLC (SiO2;
CH2Cl2/AcOEt/Et3N 40 :9 :1): Rf 0.46. 1H-NMR (CDCl3, 500 MHz): 7.55 (s, HꢀC(6)); 7.41 (d, J ¼ 7.65, 2
arom. CH); 7.32 – 7.30 (m, 6 arom. CH); 7.25 (t, J ¼ 7.3, 1 arom. CH); 6.85 (d, J ¼ 8.55, 4 arom. CH); 6.43
(t, J ¼ 6.6, HꢀC(1’)); 4.77 – 4.70 (m, ꢂCCH2); 4.58 – 4.54 (m, HꢀC(3’)); 4.05 – 4.02 (m, HꢀC(4’)); 3.81 (s, 2
MeO); 3.52 – 3.38 (qAB, HA ¼ 3.50, HB ¼ 3.40, JAB ¼ꢀ 10.5, JAX ¼ JBX ¼ 3.3, CH2(5’)); 3.43 (s, OH); 3.36 (s,
ꢂCCH2); 2.47 – 2.40 (m, CH2NCH2, 1 H of CH2(2’)); 2.35 – 2.28 (m, 1 H of CH2(2’)); 1.57 (s, Me(7));
1.47 – 1.40 (m, 2 NCH2CH2(CH2)15); 1.28 (br. s, 60 H); 0.90 (t, J ¼ 6.8, MeCH2).
5’-O-[Bis(4-methoxyphenyl)(phenyl)methyl]-3’-O-[(tert-butyl)(dimethyl)silyl]-2’-deoxy-3-[4-(dio-
ctadecylamino)but-2-yn-1-yl]-3,4-dihydrothymidine (38). A soln. of 32 (329 mg, 0.50 mmol) and 18
(304 mg, 0.50 mmol) in THF (4.0 ml) was diluted with DMF (5 ml); K2CO3 (276 mg, 2.0 mmol) and
dibenzo-[18]-crown-6 (30 mg, 0.08 mmol) were added, and the resulting mixture was stirred at 608 for
2 d. The cooled brown mixture was treated with Et2O (100 ml), washed with H2O (4 ꢁ 15 ml) and brine,
dried (Na2SO4), and concentrated to give 38 (589 mg, 95%). TLC (SiO2; hexane/CH2Cl2/acetone/Et3N
20 :5 :5 :1): Rf 0.75. 1H-NMR (CDCl3, 500 MHz): 7.65 (s, HꢀC(6)); 7.43 (d, J ¼ 7.65, 2 arom. CH); 7.33 –
7.29 (m, 6 arom. CH); 7.25 (t, J ¼ 7.3, 1 arom. CH); 6.85 (d, J ¼ 8.55, 4 arom. CH); 6.40 (t, J ¼ 6.5,
HꢀC(1’)); 4.79 – 4.71 (m, ꢂCCH2); 4.53 – 4.51 (m, HꢀC(3’)); 4.00 – 3.98 (m, HꢀC(4’)); 3.81 (s, 2 MeO);
3.50 – 3.27 (qAB, HA ¼ 3.49, HB ¼ 3.29, JAB ¼ꢀ 10.6, JAX ¼ JBX ¼ 2.6, CH2(5’)); 3.37 (s, ꢂCCH2); 2.45 – 2.42
(m, CH2NCH2); 2.38 – 2.34 (m, 1 H of CH2(2’)); 2.24 – 2.18 (m, 1 H of CH2(2’)); 1.57 (s, Me(7)); 1.45 –
1.39 (m, 2 NCH2CH2(CH2)15); 1.28 (br. s, 60 H); 0.90 (t, J ¼ 6.5, MeCH2); 0.86 (s, SiCMe3); 0.04 (s,
SiMe); – 0.02 (s, SiMe). 13C-NMR (CDCl3, 125 MHz): 162.52 (C(4)); 158.75 (2 OC(arom.)); 150.21
(C(2)); 144.36 (OCC(arom.)); 135.49 (2 OCC(arom.)); 133.73 (C(6)); 130.06, 130.05 (4 arom. CH);
128.14 (2 arom. CH); 127.93 (2 arom. CH); 127.09 (arom. CH); 113.27, 113.26 (4 arom. CH); 110.22

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Helvetica Chimica Acta – Vol. 96 (2013)
(C(5)); 86.83 (OCC(arom.)); 86.74 (C(1’)); 85.58 (C(4’)); 78.94 (ꢂC); 77.56 (ꢂC); 72.06 (C(3’)); 62.92
(C(5’)); 55.22 (2 MeO); 53.74 (CH2NCH2); 42.42 (CH2Cꢂ); 41.64 (C(2’)); 31.91 (CH2Cꢂ); 30.71, 29.69,
29.64, 29.33, 27.52, 25.69 (CMe3); 22.66 (2 MeCH2); 17.90 (SiC); 14.07 (2 MeCH2); 12.62 (C(7)); ꢀ 4.69,
ꢀ 4.89 (2 SiMe). ESI-MS: 1230.9 ([M þ H]þ).
5’-O-[Bis(4-methoxyphenyl)(phenyl)methyl]-2’-deoxy-3-[4-(dioctadecylamino)but-2-yn-1-yl]-3,4-
dihydrothymidine (34) from 38. A soln. of 38 (192 mg, 0.156 mmol) in THF (0.4 ml) was diluted with
H2O (0.05 ml), and a soln. of Bu4NF (0.17ml, 0.156 mmol) in THF was added in one portion. The
resulting clear mixture was stirred at 508 overnight. It was cooled and diluted with CH2Cl2 (10 ml). The
aq. phase was separated, and the soln. was dried (Na2SO4) and concentrated. Pure 34 (135 mg, 78%) was
isolated by CC (SiO2; hexane/CH2Cl2/acetone/Et3N 40 :10 :5 :1). Beige mass TLC (SiO2, hexane/AcOEt
2 :1): Rf 0.69.
5’-O-[Bis(4-methoxyphenyl)(phenyl)methyl]-3’-O-{(2-cyanoethoxy)[N,N-(diisopropyl)amino]phos-
phanyl}-2’-deoxy-3-[4-(dioctadecylamino)but-2-yn-1-yl]-3,4-dihydrothymidine (39). Hꢀnigꢂs base
(47 mg, 0.36 mmol) was added to a soln. of 34 (135 mg, 0.12 mmol) in CH2Cl2 (3 ml) under Ar; the
resulting mixture was cooled in an ice-bath, (chloro)(2-cyanoethoxy)(diisopropylamino)phosphine was
added, and the mixture was stirred for 10 min with cooling, and 1 h at r.t. The resulting light yellow clear
soln. was diluted with CH2Cl2 (30 ml), washed with a cold aq. NaHCO3 soln. and brine, dried (Na2SO4),
and concentrated. The resulting yellowish oil was subjected to CC (SiO2; CH2Cl2/acetone/Et3N 85 :14 :1)
to give, from the first four fractions 39, upon evaporation as a colorless oil (142 mg, 90%) as a mixture of
non-assigned (RP) and (SP) diastereoisomers. 1H-NMR (CDCl3, 500 MHz; mixture of diastereoisomers
X and Y in a ratio of 2.6: 1): 7.64 (s, 0.72 H, HꢀC(6), X); 7.59 (s, 0.28 H, HꢀC(6), Y); 7.43 – 7.41 (m, 2
arom. H, X, Y); 7.33 – 7.28 (m, 6 arom. CH, X, Y); 7.27 – 7.23 (m, 1 arom. H, X, Y); 6.86 – 6.83 (m, 4 arom.
CH, X, Y); 6.48 – 6.46 (m, 0.28 H, HꢀC(1’), X); 6.46 – 6.43 (m, 0.72 H, HꢀC(1’), Y); 4.79 – 4.71 (m, ꢂ
CCH2, X, Y); 4.69 – 4.63 (m, HꢀC(3’), X, Y); 4.20 – 4.18 (m, 0.72 H, HꢀC(4’), X); 4.17 – 4.15 (m,
0.28 H, HꢀC(4’), Y); 3.81 (s, 4.3 H, 2 MeO, X); 3.80 (s, 1.68 H, 2 MeO, Y); 3.69 – 3.55 (m, POCH2, 2
NCH, X, Y); 3.56 – 3.33 (qAB, 0.72 H, d(HA) 3.55, d(HB) 3.34, JAB ¼ꢀ 10.6, JAX ¼ JBX ¼ 2.6, CH2(5’), X);
3.51 – 3.31 (qAB, 0.28 H, d(HA) 3.49, (dHB) 3.33, JAB ¼ 10.6, JAX ¼ JBX ¼ 2.6, CH2(5’), Y); 3.36 (br. s,
ꢂCCH2, X, Y); 2.65 – 2.61 (m, CH2CN, X, Y); 2.60 – 2.55 (m, 0.28 H, CH2(2’), Y); 2.53 – 2.48 (m, 0.72 H,
CH2(2’), X); 2.45 – 2.41 (m, CH2NCH2, X, Y); 2.35 – 2.29 (m, 1 H of CH2(2’), X, Y); 1.51 (s, Me(7), X,
Y); 1.45 – 1.39 (m, 2 NCH2CH2(CH2)15, X, Y); 1.28 (br. s, 60 H); 1.20 – 1.18 (m, 2 CHMe2, X, Y); 0.91 –
0.88 (m, MeCH2, X, Y). 31P-NMR (CDCl3, 202.5 MHz): 149.17, 148.54.
5’-O-[Bis(4-methoxyphenyl)(phenyl)methyl]-3’-O-[(tert-butyl)(dimethyl)silyl]-2’-deoxy-3-[3-(dio-
ctadecylamino)propyl]-3,4-dihydrothymidine (35). Powdered Ph3P (48 mg, 0.182 mmol) was added in
one portion to a stirred clear soln. of 32 (80 mg, 0.121 mmol) and 9 (70 mg, 0.121 mmol) in benzene
(2 ml) at r.t. The mixture was stirred for 5 min until dissolution of all the precipitate. Then, the mixture
was cooled on an ice-bath, and diisopropyl azodicarboxylate (DIAD; 37 mg, 0.182 mmol) in benzene
(0.5 ml) was added dropwise within 1 min. After 5 min, the cooling bath was removed, and the mixture
was stirred at r.t. overnight. The solvent was removed in vacuo, and the light-yellow solid residue was
subjected to CC (SiO2; hexane/AcOEt/Et3N 12 :6 :1) to yield 34 (71 mg, 48%). Viscous yellowish mass.
1
TLC (SiO2; hexane/AcOEt/Et3N 120 :60 :1): Rf 0.53. H-NMR (CDCl3): 7.61 (s, HꢀC(6)); 7.41 (d, J ¼
7.65, 2 arom. CH); 7.32 – 7.29 (m, 6 arom. CH); 7.23 (t, J ¼ 7.3, 1 arom. CH); 6.83 (d, J ¼ 8.55, 4 arom.
CH); 6.39 – 6.37 (m, HꢀC(1’)); 4.51 – 4.49 (m, HꢀC(3’)); 3.97 – 3.92 (m, HꢀC(4’); CONCH2); 3.79 (s, 2
MeO); 3.48 – 3.26 (qAB, d(HA) 3.46, d(HB) 3.27, JAB ¼ꢀ 10.6, JAX ¼ JBX ¼ 2.6, CH2(5’)); 2.54 – 2.51 (m,
NCH2(CH2)2N); 2.42 – 2.39 (m, 2 NCH2(CH2)16); 2.36 – 2.31 (m, 1 H of CH2(2’)); 2.21 – 2.17 (m, 1 H of
CH2(2’)); 1.80 – 1.76 (m, NCH2CH2CH2N); 1.55 (s, Me(7)); 1.45 – 1.39 (m, 2 NCH2CH2(CH2)15); 1.26 (br.
s, 60 H); 0.88 (t, J ¼ 6.5, MeCH2); 0.84 (s, SiCMe3); 0.03 (s, SiMe); ꢀ 0.03 (s, SiMe). 13C-NMR (CDCl3):
163.40 (C(4)); 158.70 (MeOC(arom.)); 150.79 (C(2)); 144.36 (OCC(arom.)); 135.50 (C(6)); 133.34
(OCC(arom.)); 130.03 (OCC¼CH(arom.)); 128.11 (arom. CH); 127.91 (arom. CH); 127.04 (arom. CH);
113.22 (MeOCCH(arom.)); 110.11 (C(5)); 86.76 (C(4’)); 86.62 (C(1’)); 85.41 (CH2OC); 72.03 (C(3’));
62.89 (C(5’)); 55.18 (MeO); 53.83 (NCH2(CH2)16); 51.55 (NCH2(CH2)2N); 41.58 (C(2’)); 40.04
(CONCH2); 31.88 (MeCH2CH2); 29.66 ((CH2)11); 29.31 (N(CH2)3CH2); 27.58 (N(CH2)2CH2CH2);
26.95 (NCH2 CH2(CH2)15); 25.66 (SiCMe); 24.84 (NCH2CH2CH2N); 22.64 (MeCH2); 17.87 (SiC); 14.04
(MeCH2); 12.67 (C(7)); ꢀ 4.72 (SiMe); ꢀ 4.94 (SiMe). ESI-MS: 522.7 ((C18)2NHþ2 ), 1221.1 ([M þ H]þ).

Helvetica Chimica Acta – Vol. 96 (2013)
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5’-O-[Bis(4-methoxyphenyl)(phenyl)methyl]-2’-deoxy-3-[3-(dioctadecylamino)propyl]-3,4-dihydro-
thymidine (36). A soln. of Bu4NF (0.05 ml, 1m in THF) was added to a soln. of 35 (65 mg, 0.05 mmol) and
H2O (20 mg, 1 mmol) in THF (0.1 ml) at r.t., and the resulting mixture was stirred at 508 overnight. The
solvent was removed, the residue was dissolved in CH2Cl2 (1 ml) and filtered through a SiO2 layer (2 cm),
washed consecutively with CH2Cl2 (40 ml), CH2Cl2/AcOEt 10 :1 (40ml), and AcOEt (40 ml) to yield 36
1
(54 mg, 90%) from the 3rd fraction as a colorless glassy mass. TLC (SiO2, AcOEt): Rf 0.4. H-NMR
(CDCl3): 7.55 (s, HꢀC(6)); 7.41 (d, J ¼ 7.65, 2 arom. CH); 7.32 – 7.29 (m, 6 arom. CH); 7.24 (t, J ¼ 7.3, 1
arom. CH); 6.84 (d, J ¼ 8.55, 4 arom. CH); 6.45 – 6.43 (m, HꢀC(1’)); 4.57 – 4.54 (m, HꢀC(3’)); 4.06 – 4.03
(m, HꢀC(4’)); 3.98 – 3.90 (m, CONCH2); 3.80 (s, 2 MeO); 3.50 – 3.37 (qAB, d(HA) ¼ 3.49, d(HB) 3.39,
JAB ¼ ꢀ 10.5, JAX ¼ JBX ¼ 2.9, CH2(5’)); 2.53 – 2.50 (m, NCH2(CH2)2N); 2.44 – 2.39 (m, 5 H, 2
NCH2(CH2)16, CH2(2’)); 2.33 – 2.27 (m, 1 H of CH2(2’)); 1.77 (quint., J ¼ 7.3, NCH2CH2CH2N); 1.54 (s,
Me(7)); 1.45 – 1.39 (m, 2 NCH2CH2(CH2)15); 1.27 (br. s, 60 H); 0.90 (t, J ¼ 6.9, MeCH2). 13C-NMR
(CDCl3): 163.39 (C4)); 158.75 (MeOC(arom.)); 150.84 (C(2)); 144.38 (OCC(arom.)); 135.49 (OC-
C(arom.)); 133.34 (C(6)); 130.07 (OCC¼CH(arom.)); 128.14 (arom. CH); 127.96 (arom. CH); 127.10
(arom. CH); 113.29 (MeOCCH(arom.)); 110.27 (C(5)); 86.92 (CH2OC); 85.91 (C(4’)); 85.25 (C(1’));
72.21 (3’)); 63.52 (C(5’)); 55.21 (MeO); 53.88 (NCH2(CH2)16); 51.61 (NCH2(CH2)2N); 41.06 (C(2’));
40.10 (CONCH2); 31.90 (MeCH2CH2); 29.69 (CH2); 29.64 (CH2); 29.33 (N(CH2)3CH2); 27.62
(N(CH2)2CH2CH2); 26.92 (NCH2CH2(CH2)15); 24.90 (NCH2CH2CH2N); 22.66 (MeCH2); 14.07
(MeCH2); 12.65 (C(7)). ESI-MS: 1106.9 ([M þ H]þ).
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Received October 20, 2011