Synthesis and Self-Assembly of Bolaamphiphiles Based on β-Amino Acids or an Alcohol

Article abstract of DOI:10.1002/hlca.201200060

The synthesis of bolaamphiphiles from unusual β-amino acids or an alcohol and C₁₂ or C₂₀ spacers is described. Unusual β-amino acids such as a sugar amino acid, an AZT-derived amino acid, a norbornene amino acid, and an AZT-derived amino alcohol were coupled with spacers under standard conditions to get the novel bolaamphiphiles 5-8 (Scheme 1), 12 and 13 (Scheme 2), and 17 and 20 (Scheme 3). Some of these compounds, on precipitation from MeOH/H₂O, self-assembled into organized molecular structures. Copyright

Full text of DOI:10.1002/hlca.201200060

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Synthesis and Self-Assembly of Bolaamphiphiles Based on b-Amino Acids or
an Alcohol
by Prathama S. Mainkar, Chirumarry Sridhar, Ambadi Sudhakar, and Srivari Chandrasekhar*
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad –
500007, India (phone: þ 91-40-27193210; fax: þ 91-40-27160512; e-mail: srivaric@iict.res.in)
The synthesis of bolaamphiphiles from unusual b-amino acids or an alcohol and C12 or C20 spacers is
described. Unusual b-amino acids such as a sugar amino acid, an AZT-derived amino acid, a norbornene
amino acid, and an AZT-derived amino alcohol were coupled with spacers under standard conditions to
get the novel bolaamphiphiles 5 – 8 (Scheme 1), 12 and 13 (Scheme 2), and 17 and 20 (Scheme 3). Some
of these compounds, on precipitation from MeOH/H2O, self-assembled into organized molecular
structures.
Introduction. – Bolaamphiphiles are potential monomers for self-assembly and
comprise two hydrophilic groups connected by a hydrophobic chain. The synthetic
bolaamphiphiles try to reproduce the unusual architecture of the monolayered
membrane found in archaebacteria [1]. These molecules tend to self-organize in H2O to
form molecular aggregates, viz., micelles, sheets, vesicles, rings, and fibres [2]. The
parameters which hold the molecules together, other than hydration, include i) length
of the hydrophobic chain, ii) nature of counter ions, iii) chirality, iv) temperature, v)
secondary amide functions, vi) ionic strength, and vii) pH.
Several studies have been carried out towards the synthesis of diverse bolaamphi-
philes. Some of the compounds include d-galactose or lactose as polar head groups [3],
1,w-thymidylic acid appended bolaamphiphiles [4], cholesterol derivatives [5], 1-
glucosamine supramolecular assemblies [6], and 3’-phosphorylated thymidine con-
nected to both ends of an oligomethylene spacer [7]. Amino acids have also been used
to prepare bolaamphiphiles [8]. A recent publication by Bordes and co-workers [9]
signifies the role of an amide bond for self-assembly of surfactants. According to this
report, the amide bond contributed significantly to the hydrophilicity of the surfactant.
This also supported our view that amides would help in self-assembly, and hence we
concentrated on the synthesis of bolaamphiphiles derived from unusual b-amino acids
to check this hypothesis.
Our continued interest in design and synthesis of various b-amino acid monomers in
foldamer research [10] prompted us to explore the possibility of utilizing these b-amino
acids as potential hydrophilic head groups connecting through hydrophobic spacers of
varying lengths. Several reports, over the years, have discussed effects of the length of
the hydrophobic spacer and gelating properties of the molecules. Bozell and co-workers
[11] have used a spacer of 12 C-atoms exhibiting self-assembly compared to spacers of
smaller chain-lengths. Shimizu and co-workers [7] indicated that a C18 spacer formed
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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giant vesicles, and a C20 spacer resulted in robust hydrogels, whereas C15, C14, etc.,
spacers did not show any interesting results. Keeping these results and observations in
mind, we designed compounds containing both C12 and C20 hydrophobic spacers
(hydrocarbon chains). We wish to report herein the synthesis and self-assembling
properties of this new class of molecules having an unusual b-amino acid or an alcohol
motif as head group.
Results and Discussion. – Unusual b-amino acids that are used in the present work
are derived from d-glucose [12], norbornene [13], and AZT (¼ 3’-azido-3’-deoxythy-
midine) [14]. Thus, the methyl esters 1 – 4 [15 – 17] of b-amino acids were prepared
following the protocols published earlier by us. These building blocks were then
converted to the potential bolaamphiphiles 5 – 8 by a standard peptide-coupling
reaction with eicosanedioic acid (9), 2 equiv. of amino ester 1 – 4 and 1-hydroxy-1H-
benzotriazole/1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (HOBt/
EDCI) [18] in CH2Cl2/DMF in good yields (Scheme 1).
Scheme 1. Synthesis of Amide Bolaamphiphiles

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The ester-linked bolaamphiphiles 12 and 13 (Scheme 2) were prepared from Boc-
protected b-amino acids 10 and 11 (Boc ¼ (tert-butoxy)carbonyl). In this instance,
condensation of dodecane-1,12 diol (14) with acid 10 or 11 (2 equiv.) in CH2Cl2 in the
presence of N,N’-dicyclohexylcarbodiimide (DCC) and N,N-dimethylpyridin-4-amine
(DMAP) [19] gave the bolaamphiphiles 12 and 13.
Scheme 2. Synthesis of Ester Bolaamphiphiles
The alcohol-derived bolaamphiphiles 17 (diester-linked) and 20 (alkanediyl-linked)
were prepared from the known antiretroviral drug 3’-azido-3’-deoxythymidine
(¼AZT; 15; Scheme 3). Thus 15 was treated with 10% Pd/C under H2 in MeOH to
give amino derivative 16, which was immediately Boc-protected (!16a). The primary-
alcohol derivative 16a (2.07 equiv.) was treated with eicosanodioic acid (9) and benzoyl
chloride/Et3N/DMAP [20] to furnish bolaamphiphile 17 in 85% yield. AZT (15) was
also treated with tBuMe2SiCl and 1H-imidazole to yield 18. The latter was treated with
1,12-dibromododecane (19), K2CO3, and acetone to give the protected derivative 18a,
followed by reaction with tetrabutylammonium fluoride (Bu4NF) to obtain alkanediyl-
linked bolaamphiphile 20.
After successfully synthesizing the eight bolaamphiphiles 5 – 8, 12, 13, 17, and 20,
these compounds were screened for self-assembly. CD is an excellent method of
determining secondary structures [21]. When the chromophores of the amide groups of
polypeptides are arranged in arrays, their optical transitions are shifted or split into
multiple transitions due to ꢂexcitonꢃ interactions. The result is that different structural
elements have characteristic CD spectra. The CD spectrum of 8 (Fig. 1) showed a
negative band at 195 nm and two positive bands at 215 and 270 nm. Similarly,
compound 13 (Fig. 2) had positive peaks at 200 and 275 nm and a negative one at
230 nm, and compound 17 (Fig. 3) showed positive bands at 210 and 275 nm and two
negative peaks at 220 and 240 nm respectively. The presence of both positive and
negative peaks in these CD spectra confirmed the presence of secondary structures.
Carbohydrate-based bolaamphiphiles and related systems are known to form
noncovalently bonded nanoscale polymers linked through an extensive H-bonding
network established between the carbohydrate head groups during self-assembly [11].
The here synthesized bolaamphiphiles were dispersed in H2O followed by slow
addition of MeOH. The transmission electron microscopy (TEM) images of the

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Scheme 3. Synthesis of AZT-Derived Bolaamphiphiles
Fig. 1. CD Spectrum of bolaamphiphile 8

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Fig. 2. CD Spectrum of bolaamphiphile 13
Fig. 3. CD Spectrum of bolaamphiphile 17
dispersed compounds 5 (Fig. 4) and 8 (Fig. 5) revealed as fibers and vescicles,
respectively, as secondary structures.
Based on the TEM, atomic-force microscopy (AFM), and CD data, compounds 8,
13, and 17 showed the presence of secondary structure. Other compounds failed to self-
aggregate under the conditions that were tried (see Exper. Part).
Conclusions. – We synthesized a set of bolaamphiphiles and analogues with
hydrophobic head groups and studied self-assembly of them. We observed that the
amides 5 and 8 had a selectivity to self-assemble over the alkanediyl-linked derivative
20. Esters 13 and 17 too formed gels which were less prominent when compared to
amides 5 and 8. The presence of a hydrophilic head initiated self-assembly through H-
bonding, whereas hydrophobic heads failed to form any secondary structures (in our
case norbornene derivatives 6 and 7). Therefore, by this study we emphasize that the
basic requirements for self-assembly/secondary-structure formation of a bolaamphi-

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Fig. 4. TEM of bolaamphiphile 5
Fig. 5. TEM of bolaamphiphile 8
phile are the presence of a hydrophilic head which can initiate H-bonding, and the
presence of amide or ester bonds to strengthen the structure, which we demonstrated
by using bolaamphiphiles 8, 13, and 17, derived from a nucleoside-based amino acid.
The authors thank the Council of Scientific and Industrial Research, New Delhi for award of
fellowships to A. S. and C. S., and the Department of Science and Technology (DST), New Delhi, for a
WOS-A fellowship to P. S. M. The authors also thank Dr. B. Jagadeesh, Dr. B. Jagannadh, and Dr. B.
Sreedhar for fruitful discussions and instrumentation.
Experimental Part
1. General. All commercially available reagents and solvents (Fluka, Aldrich, Rankem) were used
without further purification. For reactions requiring anh. conditions, dry solvents were bought
(Rankem). Technical grade AcOEt and petroleum ether used for CC were distilled prior to use. TLC:
silica gel 60 F254 plates (SiO2; Merck); detection with UV light, Molish reagent (H2SO4, EtOH, H2O,
C10H8O), or phosphomolybdic acid (H3PMo12O40, EtOH). Column chromatography (CC): silica gel 60

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(SiO2, 70 – 230 mesh; Merck No. 107734). Optical rotations: Anton paar MCP 200 polarimeter at 258; [a]
values in 10ꢀ1 deg cm2 gꢀ1. IR Spectra: Perkin-Elmer-Paragon Spectrum-400-FTIR/FT-NIR spectrometer;
˜n in cmꢀ1. 1H- and 13C-NMR Spectra: Avance-Bruker-300 and Varian-Innova-500 spectrometer; at 300 or
500 (1H) and 75 and 125 MHz (13C); d(H) in ppm rel. to Me4Si as internal standard, J in Hz; d(C) in ppm
rel. to residual solvent signal (CDCl3, d(C) 77; (D6)DMSO, d(C) 39.51). ESI-Q-MS: Agilent-
Technologies-LC/MSD-Trap-SL instrument; in m/z. HR-ESI-MS: Agilent-Technologies-6510 Q-TOF
LC/MS instrument; in m/z.
2. General Procedure for TEM Studies. In a typical procedure, a compound (5 mg) was mixed with
100 ml of H2O and 30 ml of MeOH at r.t. and heated to 608 to get a clear soln. Upon cooling to r.t., the
bolaamphiphiles 5, 8, 13, and 17 began to precipitate, others remained in soln. The turbid mixture was
subjected to TEM studies. TEM samples were prepared by placing sample-mixture drops directly on the
polymer-coated grids by means of a micropipette. The bolaamphiphiles present in the H2O/MeOH
mixture were allowed to settle, and the extra solvent was subsequently removed by placing the TEM grid
on a neat filter paper and drying at r.t. for half a day. The morphology and size and shape distribution of
the bolaamphiphiles were recorded with the TEM instrument operating at 120 keV. In each image, more
than 150 particles were analyzed with the SIS imaging software to create size-distribution histograms. The
diffraction patterns were recorded at a selected area to determine the crystal structure and phases of
crystals at 660 mm camera length.
3. Amide Bolaamphiphiles: General Procedure. To a stirred soln. of eicosanedioic acid (9; 1.8 mmol)
in dry CH2Cl2/DMF 1:1 (15 ml) was added sequentially HOBt (3.7 mmol) and EDCI (5.2 mmol) at 08
under N2. After 15 min, free amine (3.7 mmol) in dry CH2Cl2/DMF 1:1 (10 ml) was added. The mixture
was allowed to reach r.t. and stirred further for 12 h under N2. After dilution with CH2Cl2, the mixture
was washed with 1n HCl (10 ml), H2O, 5% aq. NaHCO3 soln. (15 ml), and brine, the combined org. layer
dried (Na2SO4) and concentrated, and the residue purified by CC (SiO2 60 – 120, AcOEt/hexane 1:2):
diamide.
(3aR,3’aR,5S,5’S,6R,6’R,6aR,6’aR)-Dimethyl 6,6’-[(1,20-Dioxoeicosane-1,20-diyl)diimino]bis[tetra-
hydro-2,2-dimethylfuro[2,3-d][1,3]dioxole-5-carboxylate] (5): Yield 98 mg (70%). White solid. M.p. 82 –
1
848. [a]2D5 ¼ þ43 (c ¼ 1.2, MeOH). IR (neat): 3307, 2989, 2920, 2850, 1745, 1654, 1080, 1035. H-NMR
(300 MHz, CDCl3): 8.09 (d, J ¼ 9.5, 2 H); 5.94 (d, J ¼ 3.4, 2 H); 4.73 (d, J ¼ 4.1, 2 H); 4.58 (dd, J ¼ 4.2, 9.4,
2 H); 4.42 (d, J ¼ 3.4, 2 H); 3.58 (s, 6 H); 2.04 – 1.99 (m, 4 H); 1.42 (s, 6 H); 1.25 – 1.23 (m, 38 H).
13C-NMR (75 MHz, CDCl3): 172.8; 168.7; 112.7; 104.7; 83.8; 76.7; 56.5; 52.4; 36.4; 29.5; 29.3; 29.2; 29.1;
26.5; 26.0; 25.5. HR-ESI-MS: 763.4363 ([M þ Na]þ, C38H64N2NaO1þ2 ; calc. 763.4351).
(1S,1’S,2S,2’S,3R,3’R,4R,4’R)-Dimethyl
3,3’-[1,20-Dioxoeicosane-1,20-diyl)diimino]bis[bicy-
clo[2.2.1]hept-5-ene-2-carboxylate] (6): Yield 281 mg (72%). White solid. M.p. 120 – 1258. [a]D25
¼
þ110.5 (c ¼ 1, MeOH). IR (neat): 3411, 2978, 1654, 1537, 1365, 1171. 1H-NMR (300 MHz, CDCl3):
6.46 (d, J ¼ 8.8, 2 H); 6.30 – 6.23 (m, 2 H); 6.22 – 6.16 (m, 2 H); 4.22 – 4.11 (m, 2 H); 3.68 (s, 6 H); 2.95 (s,
2 H); 2.71 (s, 2 H); 2.12 (t, J ¼ 7.3, 4 H); 1.95 (d, J ¼ 9.27, 4 H); 1.67 – 1.46 (m, 8 H); 1.6 (br. s, 28 H).
13C-NMR (75 MHz, CDCl3): 174.0; 171.5; 137.3; 136.6; 52.2; 51.0; 48.8; 46.8; 46.0; 44.6; 37.4; 30.2; 30.0;
29.9; 29.7; 26.3. HR-ESI-MS: 663.4343 ([M þ Na]þ, C38H60N2NaO6þ ; calc. 663.4344).
(1S,1’S,2R,2’R,3R,3’R,4R,4’R)-Dimethyl 3,3’-[1,20-Dioxoeicosane-1,20-diyl)diimino]bis[bicy-
clo[2.2.1]hept-5-ene-2-carboxylate] (7): Yield 270 mg (70%). White solid. M.p. 118 – 1208. [a]2D5 ¼ ꢀ62
(c ¼ 1, MeOH). IR (neat): 3411, 2978, 1654, 1537, 1365, 1171. 1H-NMR(300 MHz, CDCl3): 6.19 – 6.16 (m,
2 H); 6.06 – 6.03 (m, 2 H); 5.80 (d, J ¼ 6.3, 2 H); 3.96 (br. s, 2 H); 3.60 (s, 6 H); 3.10 (s, 2 H); 2.80 (s, 2 H);
2.54 (t, J ¼ 3.4, 6.9, 2 H); 2.15 – 2.10 (m, 4 H); 1.62 – 1.52 (m, 8 H); 1.21 (br. s, 28 H). 13C-NMR (75 MHz,
CDCl3): 172.0; 171.7; 135.2; 134.6; 54.1; 52.7; 52.0; 49.0; 47.2; 45.2; 37.2; 30.1; 30.0; 29.9; 29.8; 26.3. HR-
ESI-MS: 663.4343 ([M þ Na]þ, C38H60N2NaO6þ ; calc. 663.4344).
(2S,2’S,3S,3’S,5R,5’R)-Dimethyl 3,3’-[1,20-Dioxoeicosane-1,20-diyl)diimino]bis[5-[3,4-dihydro-5-
methyl-2,4-dioxopyrimidin-1(2H)-yl]tetrahydrofuran-2-carboxylate] (8): Yield 520 mg (72%). White
solid. M.p. 124 – 1268. [a]2D5 ¼ þ37 (c ¼ 0.5, MeOH). IR (neat): 3300, 3071, 2924, 2853, 1748, 1698, 1539,
1469, 1275. 1H-NMR(500 MHz, CDCl3): 11.18 (s, 2 H); 8.41 (d, J ¼ 5.0, 2 H); 7.95 (s, 2 H); 6.4 (t, J ¼ 5.0,
2 H); 4.58 – 4.42 (m, 2 H); 4.28 (d, 2 H); 3.79 (s, 6 H); 2.24 – 1.98 (m, 8 H); 1.83 (s, 6 H); 1.58 – 1.42 (m,
4 H); 1.21 (s, 28 H). 13C-NMR (75 MHz, CDCl3): 172.8; 168.7; 112.7; 104.7; 83.8; 76.7; 56.5; 52.4; 36.4;
29.5; 29.3; 29.2; 29.1; 26.5; 26.0; 25.5. HR-ESI-MS: 845.4661([M þ H]þ, C42H65N6O1þ2 ; calc. 845.4655).

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4. Ester Bolaamphiphiles: General Procedure. To a stirred soln. of acid (0.49 mmol) in anh. CH2Cl2
(10 ml) was added (catalytic) DMAP (3 mg) and dodecane-1,12-diol (14; 0.23 mmol). Then DCC
(0.59 mmol) was added at 08, and the mixture was stirred for 5 min at 08 and 3 h at 208. Precipitated urea
was then filtered off, and the filtrate was evaporated in vacuo. The residue was taken up in CH2Cl2 and
again filtered to remove any further precipitated urea. The CH2Cl2 soln. was washed with 0.5n HCl (2ꢁ)
and sat. NaHCO3 soln., dried (MgSO4), and concentrated and the residue purified by CC (SiO2 60 – 120;
AcOEt/hexane1:3): diester.
(3aR,3’aR,5S,5’S,6R,6’R,6aR,6’aR)-Dodecane-1,12-diyl Bis[6-{[(1,1-Dimethylethoxy)carbonyl]ami-
no}tetrahydro-2,2-dimethylfuro[2,3-d][1,3]dioxole-5-carboxylate] (12): Yield 0.147 g (75%). White solid.
M.p. 75 – 788. [a]2D5 ¼ þ93.5 (c ¼ 1, MeOH). IR (neat): 3411, 3347, 2924, 2850, 1762, 1723, 1247, 1058.
1H-NMR (300 MHz, CDCl3): 5.90 (d, J ¼ 3.3, 2 H); 4.8 (d, J ¼ 8.3, 2 H); 4.75 (d, J ¼ 3.8, 2 H); 4.53 (d, J ¼
3.5, 2 H); 4.4 (dd, J ¼ 3.7, 8.5, 2 H); 4.20 (t, J ¼ 8.3, 4 H); 1.51 (s, 6 H); 1.41 (s, 30 H). 13C-NMR (75 MHz,
CDCl3): 168.2; 154.6; 112.0; 104.0; 84.0; 80.2; 77.1; 65.9; 58.2; 30.2; 30.0; 30.0; 29.7; 29.0; 28.8; 27.2; 26.7;
26.3. HR-ESI-MS: 795.2309 ([M þ Na]þ, C38H64N2NaO1þ4 ; calc. 795.4283).
(2S,2’S,3S,3’S,5R,5’R)-Dodecane-1,12-diyl Bis{5-[3,4-dihydro-5-methyl-2,4-dioxopyrimidin-1(2H)-
yl]}-3-{[(1,1-dimethylethoxy)carbonyl]amino}tetrahydrofuran-2-carboxylate} (13): Yield 83 mg (68%).
White solid. M.p. 160 – 1628. [a]2D5 ¼ þ25.8 (c ¼ 1, MeOH). IR (neat): 3322, 2931, 2853, 1698, 1520, 1473,
1
1273, 1167. H-NMR (500 MHz, (D6)DMSO): 11.19 (s, 2 H); 7.71 (s, 2 H); 7.42 (d, J ¼ 6.3, 2 H); 6.16 –
6.03 (m, 2 H); 4.16 – 3.91 (m, 8 H); 2.19 – 2.01 (m, 4 H); 1.66 (s, 6 H); 1.54 – 1.36 (m, 4 H); 1.26 (s,
9 H); 1.10 (s, 16 H). 13C-NMR (75 MHz, CDCl3): 169.0; 162.1; 153.4; 149.0; 134.8; 108.4; 84.5; 80.8; 77.9;
64.7; 36.0; 29.0; 28.9; 28.7; 28.2; 28.0; 25.3; 12.6. HR-ESI-MS: 877.4560 ([M þ H]þ, C42H65N6O1þ4 ; calc.
877.4553).
5. Alcohol-Derived Bolaamphiphiles 17 and 20. 1,1-Dimethylethyl N-{(2S,3S,5R)-5-[3,4-Dihydro-5-
methyl-2,4-dioxopyrimidin-1(2H)-yl]tetrahydro-2-(hydroxymethyl)furan-3-yl}carbamate (16a). To a
soln. of AZT azide (15; 50 mg, 0.107 mmol) in dry MeOH (5 ml), 20% Pd(OH)2/C (7 mg) was added,
and the mixture was stirred under H2 for 3 h. Then Boc2O (0.029 ml, 0.128 mmol) was added to the
mixture. After 1 h, the mixture was filtered through a pad of Celite, the pad washed with MeOH (20 ml),
the filtrate concentrated, and the residue purified by CC (AcOEt/hexanes 3 :2): 16a (30 mg, 75%). White
solid. M.p. 115 – 1188. Rf (30% AcOEt/hexanes) 0.2. [a]2D5 ¼ þ93.5 (c ¼ 1, MeOH). IR (neat): 3445, 2977,
1652, 1506, 1168. 1H-NMR (300 MHz, CDCl3): 8.65 (s, 1 H); 7.74 (s, 1 H); 6.09 – 6.06 (m, 1 H); 5.07 – 5.05
(br. s, 1 H); 4.23 – 4.05 (m, 2 H); 3.93 – 3.72 (m, 2 H); 2.32 – 2.28 (m, 3 H); 1.91 (s, 3 H); 1.44 (s, 9 H).
13C-NMR (75 MHz, CDCl3): 164.1; 156.1; 150.7; 135.9; 110.9; 85.9; 84.2; 80.5; 61.5; 49.4; 37.7; 28.2; 12.5.
HR-ESI-MS: 342.3219 ([M þ H]þ, C15H24N3O6þ ; calc. 342.3217).
Bis{{(2S,3S,5R)-5-[3,4-dihydro-5-methyl-2,4-dioxopyrimidin-1(2H)-yl]-3-{[(1,1-dimethylethoxy)car-
bonyl]amino}tetrahydrofuran-2-yl}methyl} Eicosanedioate (17). To a soln. of AZT-derived carbamate
16a (100 mg, 0.29 mmol), benzoyl chloride (41 mg, 0.29 mmol), and eicosanedioic acid (9, 50 mg,
0.14 mmol) in dry THF (5 ml), Et3N (0.1 ml, 0.58 mmol) was added slowly, followed by DMAP (9 mg,
25 mol-%). The mixture was stirred until the reaction was complete and then quenched with 10% HCl
soln. (10 ml). The soln. was extracted with AcOEt (2 ꢁ 10 ml), the combined org. phase washed with sat.
NaHCO3 soln. (2 ꢁ 20 ml), dried, and concentrated, and the residue purified by CC (SiO2, AcOEt/
hexane 3 :7): 17 (123 mg, 85%). White solid. M.p. 118 – 1208. [a]2D5 ¼ þ13.7 (c ¼ 1, MeOH). IR (neat):
3338, 2926, 2853, 1772, 1710, 1466. 1H-NMR (300 MHz, CDCl3): 11.4 (s, 2 H); 7.43 (s, 2 H); 7.25 (d, J ¼ 7.5,
2 H); 6.15 (t, J ¼ 6.7, 2 H); 4.30 – 4.01 (m, 6 H); 3.81 – 3.79 (m, 2 H); 2.35 – 2.22 (m, 8 H); 1.79 (s, 6 H);
1.45 (m, 4 H); 1.39 (s, 18 H); 1.22 (br. s, 28 H). 13C-NMR (75 MHz, CDCl3): 173.2; 163.6; 155.4; 150.6;
134.6; 111.4; 84.8; 83.5; 80.2; 64.0; 51.3; 37.7; 34.1; 33.9; 29.5; 29.3; 29.1; 29.0; 28.3; 24.8; 12.5. HR-ESI-
MS: 989.5825 ([M þ H]þ, C50H81N6O1þ4 ; calc. 989.5825).
1-{(2R,4S,5S)-4-Azido-5-{{[(1,1-dimethylethyl)dimethylsilyl]oxy}methyl}tetrahydrofuran-2-yl}-5-
methylpyrimidine-2,4(1H,3H)-dione (18). To a soln. of 15 (7.0 g, 23.4 mmol) in DMF (30 ml) were added
1H-imidazole (2.39 g, 35.1 mmol) and tBuMe2SiCl (4.58 g, 30.4 mmol). After being stirred at r.t. under N2
for 15 h, the mixture was diluted with H2O and extracted with AcOEt (2 ꢁ 100 ml). The combined org.
phase was washed with brine (100 ml), dried (Na2SO4), and concentrated and the residue subjected to
FC (SiO2, hexanes/AcOEt 20 :1): 18 (8.7 g, 90%). White solid. M.p. 99 – 1028. [a]2D5 ¼ þ93.5 (c ¼ 1,
MeOH). IR (neat): 3445, 2977, 1652, 1506, 1168. 1H-NMR (300 MHz, CDCl3): 9.12 (s, 1 H); 7.40 (s, 1 H);

Helvetica Chimica Acta – Vol. 96 (2013)
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6.18 (t, J ¼ 6.7, 1 H); 4.27 – 4.19 (m, 1 H); 4.03 – 3.9 (m, 2 H); 3.86 – 3.79 (m, 1 H); 2.50 – 2.40 (m, 1 H);
2.30 – 2.19 (m, 1 H); 1.93 (s, 3 H); 0.97 (s, 9 H); 0.16 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 150.2; 134;
111.0; 84.4; 84.3; 62.8; 60.4; 37.9; 25.8; 18.3; 12.5; ꢀ 5.3; ꢀ 5.4. HR-ESI-MS: 382.2909 ([M þ H]þ,
C16H28N5O4Siþ; calc. 382.1968).
3,3’-(Dodecane-1,12-diyl)bis[1-{(2R,4S,5S)-4-azido-5-{{[(1,1-dimethylethyl)dimethylsilyl]oxy}me-
thyl}tetrahydrofuran-2-yl}-5-methylpyrimidine-2,4(1H,3H)-dione] (18a). AZT-Derived siyl ether 18
(250 mg, 0.65 mmol), 1,12-dibromododecane (106 mg, 0.32 mmol), and K2CO3 (270 mg, 1.94 mmol)
were added to dry acetone at 208. The mixture was heated to reflux overnight. After completion of the
reaction (TLC minotoring), the mixture was cooled to r.t. and the solvent evaporated. After addition of
H2O, the mixture was extracted with AcOEt (2 ꢁ 20 ml), the org. layer dried (MgSO4) and concentrated,
and the residue purified by CC (SiO2; 60 – 120, AcOEt/hexane 1:5): 18a (198 mg, 65%). White solid. M.
1
p. 56 – 588. [a]2D5 ¼ þ45.5 (c ¼ 1, MeOH). IR (neat): 3445, 2977, 1652, 1506, 1168. H-NMR (300 MHz,
CDCl3): 7.29 (d, J ¼ 1.08, 2 H); 6.14 (t, J ¼ 6.4, 2 H); 4.16 – 4.10 (m, 2 H); 3.88 – 3.79 (m, 8 H); 3.73 – 3.68
(m, 2 H); 2.40 – 2.32 (m, 2 H); 2.18 – 2.11 (m, 2 H); 1.84 (d, J ¼ 0.92, 3 H); 1.53 – 1.43 (m, 2 H); 1.22 – 1.16
(m, 16 H); 0.85 (s, 9 H); 0.04 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 162.2; 149.8; 132.1; 127.6; 109.7; 85.0;
84.2; 62.9; 60.5; 49.8; 38.5; 30.1; 29.8; 28.1; 27.5; 26.5; 19.0; 14.0; ꢀ 4.3; ꢀ 4.5. HR-ESI-MS: 929.5476
([M þ H]þ, C44H77N10O8Siþ2 ; calc. 929.5458).
3,3’-(Dodecane-1,12-diyl)bis[1-[(2R,4S,5S)-4-azidotetra hydro-5-(hydroxymethyl)furan-2-yl]-5-
methylpyrimidine-2,4(1H,3H)-dione] (20). A soln. of 18a (1.4 g, 2.06 mmol) in THF (15 ml) was treated
with 1m Bu4NF in THF (3.09 ml, 3.09 mmol) at 08 and stirred for 2 h at r.t. The mixture was diluted with
H2O and extracted with AcOEt (2 ꢁ 50 ml). The combined org. layer was washed with brine (50 ml),
dried (Na2SO4), and concentrated and the residue purified by CC (SiO2, 40% AcOEt/hexane): 20 (1.1 g,
95%). Semi-solid. Rf (50% AcOEt/hexanes) 0.2. [a]2D5 ¼ þ35.5 (c ¼ 1, MeOH). IR (neat): 3411, 2978,
1
1654, 1537, 1365, 1171. H-NMR (500 MHz, CDCl3): 7.34 (d, J ¼ 1.06, 2 H); 6.16 (t, J ¼ 6.3, 2 H); 4.23 –
4.18 (m, 2 H); 3.96 – 3.76 (m, 6 H); 3.37 (t, J ¼ 6.8, 4 H); 2.47 – 2.39 (m, 2 H); 2.26 – 2.19 (m, 2 H); 1.91
(d, J ¼ 0.87, 6 H); 1.87 – 1.80 (m, 2 H); 1.66 – 1.52 (m, 4 H); 1.36 – 1.24 (m, 16 H). 13C-NMR (75 MHz,
CDCl3): 162.3; 149.7; 133.7; 109.6; 86.4; 84.3; 61.8; 60.8; 50.7; 41.8; 37.9; 30.1; 29.9; 29.7; 28.0; 27.4; 13.9.
HR-ESI-MS: 701.3739 ([M þ H]þ, C32H49N10O8þ ; calc. 701.3729).
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Received February 8, 2012