Synthesis of amphiphilic amino alcohols

Article abstract of DOI:10.1080/00397910802326554

An efficient and general approach for the synthesis of amphiphilic 1,2-amino alcohols is reported. The use of N-benzyl protecting groups is essential for obtaining good yields when opening a long-chain terminal epoxide with an amine. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802326554

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Synthesis of Amphiphilic Amino
Alcohols
Lauri Toom a , Piret Villo a , Ilme Liblikas a & Lauri
Vares a
a University of Tartu , Institute of Technology ,
Tartu, Estonia
Published online: 31 Oct 2008.
To cite this article: Lauri Toom , Piret Villo , Ilme Liblikas & Lauri Vares (2008)
Synthesis of Amphiphilic Amino Alcohols, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:23, 4295-4313,
DOI: 10.1080/00397910802326554
To link to this article: http://dx.doi.org/10.1080/00397910802326554
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Synthetic Communications1, 38: 4295–4313, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802326554
Synthesis of Amphiphilic Amino Alcohols
Lauri Toom, Piret Villo, Ilme Liblikas, and Lauri Vares
University of Tartu, Institute of Technology, Tartu, Estonia
Abstract: An efficient and general approach for the synthesis of amphiphilic 1,2-
amino alcohols is reported. The use of N-benzyl protecting groups is essential for
obtaining good yields when opening a long-chain terminal epoxide with an amine.
Keywords: Amino alcohols, amphiphiles, epoxide opening, N-benzyl protecting
group
INTRODUCTION
The 1,2-amino alcohol moiety is a common structural fragment in many
biologically active natural and synthetic compounds, as well as in auxili-
aries and ligands for asymmetric synthesis.[1] Amphiphilic amino alcohols
are compounds in which the amino alcohol moiety is linked to one or two
aliphatic alkyl chains.[2] In recent decades, this class of compounds have
been extensively studied because of their interesting applications, some
examples being surfactants,[3] antimicrobial agents,[4] and potential iono-
phores.[5] For example, ethambutol 1 is a bacteriostatic antimycobacterial
front-line agent that is recommended by the World Health Organization
for the treatment of tuberculosis (Fig. 1).[6] Several promising analogs of
ethambutol have been synthesized in recent years.[7,8] In this respect,
Tripathi and coworkers synthesized a series of glycosyl amino alcohols
having alkyl chains of varying lengths (e.g., 2a and 2b)[8] and found
that compound 2a is, in vitro, superior to ethambutol.[9] In addition,
similar structural motifs have been used as main structural fragments
Received May 5, 2008.
Address correspondence to Lauri Vares, University of Tartu, Institute of
Technology, 1 Nooruse Street, 50411 Tartu, Estonia. E-mail: lauri.vares@ut.ee
4295

4296
L. Toom et al.
Figure 1. Ethambutol 1 and glycosyl amino alcohols 2a and 2b as antituberculosis
agents: acetogenin solamin and synthetic aza-solamin.
in carbohydrate-based surfactants.[10] Acetogenins, a type of compounds
isolated from the plant family Annonaceae, constitute a novel class of
very promising anticancer agents (e.g., solamin in Fig. 1).[11] Recently a
few studies of acetogenin aza-analogs have been published containing
the amino alcohol structural motif, one example being aza-solamin.[12]
As a part of an ongoing investigation we became interested in amino
alcohols that are structurally related to acetogenins and aza-acetogenins
having the generic structures 3 and 4 (Fig. 2). These compounds have a
polar amino alcohol head group, containing either one or two amine
functionalities, and two lipophilic tail groups. For the preparation of this
type of vicinal amino alcohol moieties, ringopening of epoxides has been
one of the main methods of choice,[13] and this is perhaps a result of the
Figure 2. General synthetic route to amhiphilic amino alcohols.

Synthesis of Amphiphilic Amino Alcohols
4297
plethora of asymmetric methods available for the synthesis of epoxides
from olefins.[14] However, depending on the specific amine and epoxide
that are to be coupled, these ringopening reactions can be sluggish,
requiring dry reaction conditions (in the case of Lewis acid activation)
or afford the product in impractically low yields.[15] The reasons for
the observed low reactivity are not always obvious, making it difficult
to predict the outcome of these reactions. Herein we report a general
synthesis of amphiphilic amino alcohols having the generic structures 3
and 4 via an epoxide opening strategy, thus providing a general solution
to the problem discussed previously.
According to our general synthetic approach, both lipophilic tails are
introduced as epoxides (Fig. 2). Epoxide 5 is first opened with either
ammonia or ethylene-1,2-diamine, yielding amino alcohol 6 or 7, respec-
tively. Epoxide 8 is then opened with intermediate 6 or 7 to yield the
desired product 3 or 4, respectively. The use of enantiomerically pure
epoxides gives an entry to asymmetrically defined products. Epoxides 5
and 8 can be prepared with high enantiomeric purity by a Sharpless
asymmetric dihydroxylation of the corresponding olefin followed by
cyclization, for example.[14]
RESULTS AND DISCUSSION
Epoxide 5a, prepared from 1-dodecene via an asymmetric dihydroxyla-
tion,[16] tosylation,[17] and epoxidation sequence, was conveniently
opened with ammonia to afford amino alcohol 6a[18] in 99% yield
(Scheme 1). Coupling of amine 6a with a second equivalent of epoxide
5a was surprisingly sluggish. Refluxing in 2-PrOH for 1 week afforded
at best only trace amounts of the desired compound 3a (Table 1,
entry 1). Using 1,4-dioxane as solvent and thereby increasing the reaction
temperature did not improve the conversion (entry 2). Attempts to
Scheme 1. (a) Ammonium hydroxide (excess), EtOH, 60 ꢀC, 16 h, 99%; (b) 5b or
9, for reaction conditions, see text and Table 1 (entries 1–6).

4298
L. Toom et al.
Table 1. N-Alkylation of amino alcohols with epoxides
Amino
Entry alcohol Epoxide Product
Reaction conditions
Yield (%)
1
2
3
6a
6a
6a
5a
5a
5a
3a
3a
3a
2-PrOH, reflux, 1 week
1,4-dioxane, reflux, 1 week
cat. CoCl2, MeCN, rt up to
70 ꢀC
cat. FeSO4, MeCN, rt up to
70 ꢀC
cat. CF3SO3H, MeCN, rt up to ncdb
60 ꢀC
0.1 eq K2CO3, 0.1 eq TEBA,
dioxane, 90 ꢀC, 6 days
2-PrOH, reflux, 4 days
0.1 eq K2CO3, 0.1 eq TEBA,
dioxane, 90 ꢀC, 7 days
0.1 eq K2CO3, 0.1 eq TEBA,
dioxane, 90 ꢀC, 10 days
2-PrOH, reflux, 48 h
Traces
Traces
ncdb
4
5
6
6a
6a
6a
5a
5a
5a
3a
3a
3a
ncdb
ncdb
7
8
6b
6b
5b
5b
3b
3b
ncdb
53a
9
6c
5b
3c
54a
10
11
12
6d
7b
7a
5b
5a
5a
3d
4b
4a
87a
2-PrOH, reflux, 24 h
2-PrOH, reflux, one week
74a
ncdb
aIsolated yield.
bNcd—no conversion detected.
activate the epoxide with Lewis acids (CoCl2, FeSO4) or a Brønsted acid
(CF3SO3H) proved fruitless (entries 3–5). We tested solid–liquid phase-
transfer conditions[19] (entry 6) but did not observe any conversion after
6 days at 90 ꢀC. We then prepared iodide 9 from (R)-dodecane-1,2-diol
and attempted to couple it with the left-hand fragment 6a but, however,
once again the coupling failed. We were surprised and puzzled by the low
reactivity of 6a, especially taking into account that the coupling between
5a and ammonia proceeded smoothly.
Compound 6a has a lipophilic tail connected with a polar head
group. We speculated that this might cause a micelle formation, which
in turn slows down the desired coupling reaction. To test our hypothesis,
we reacted propylene oxide with 3 eq. of ethylene-1,2-diamine (Scheme 2).
The intermediate 10 is lacking the lipophilic alkyl chain and its subse-
quent reaction with propylene oxide proceeded smoothly to form 11
(Scheme 2). However, when propylene oxide was reacted with 6a under
the same reaction conditions, no reaction took place.
Consequently, reducing the polarity of the head group in compound
6 should also reduce its propensity for forming micelles and, as a result,

Synthesis of Amphiphilic Amino Alcohols
4299
Scheme 2. (a) MeCN, 65 ꢀC, 24 h, 68%; (b) propylene oxide (3 eq.), MeCN, 65 ꢀC,
24 h, 87%.
increase its reactivity in the subsequent coupling reaction. To test this,
compounds 6b, 6c, and 6d were prepared from tosylamide, nosyl-
amide[20], and benzylamine, respectively (Scheme 3). Epoxides 5a and
5b were used as electrophiles. Epoxide 5b was prepared from 1,13-
tetradecadiene and has a terminal olefin as a handle for further functio-
nalization of 3. When tosylamide 6b and epoxide 5a were refluxed in
2-PrOH, no conversion was detected after 4 days (Table 1, entry 7).
Coupling of 6b with epoxide 5b gave 53% yield of compound 3b after
heating the reaction mixture for 1 week in dioxane at solid–liquid
phase-transfer conditions[19] (Table 1, entry 8). When 6c was used instead,
the coupling with 5b afforded 3c in 54% yield using the same solid–liquid
phase-transfer conditions (Table 1, entry 9). However, when reacting 6d
with 5b, the desired coupling product 3d was obtained in 87% yield after
only 48 h (entry 10), clearly demonstrating the usefulness of this method.
After having identified a suitable protocol for the coupling of the left-
and right-hand fragments with an amine core, we tested the generality of
this strategy by preparing a similar compound having an ethylene-1,2-
diamine core (Scheme 4, and Scheme 5). Epoxide 5a was smoothly
opened with N,N0-dibenzylethylene-1,2-diamine to afford amine 7b.
When 7b was treated with epoxide 5a, the desired product 4b was formed
in 74% yield (Table 1, entry 11). However, as could be predicted, amino
alcohol 7a did not react with epoxide 5a (entry 12). It was also shown that
the benzyl groups in compound 7b could be efficiently removed by using
a standard hydrogenolysis protocol to afford the amphiphilic amino
alcohol 4a.
Scheme 3. (a) N-Alkylation of amino alcohols with epoxides. For reaction condi-
tions, see Table 1.

4300
L. Toom et al.
Scheme 4. (a) 2-PrOH, reflux, 24 h, 99% (7a), 81% (7b); (b) see Table 1, entries 11
and 12; (c) cat. Pd=C, H2 (1 atm), MeOH, 14 h, 82%.
Herein we have demonstrated a simple and convenient method
for the synthesis of amphiphilic 1,2-amino alcohols and showed that
the use of N-benzyl protecting groups is essential for obtaining good
yields when opening a long-chain terminal epoxide with an amphiphilic
amine.
EXPERIMENTAL
All commercially available chemicals were of reagent grade and used
without further purification; solvents used for high-performance liquid
chromatography (HPLC) analysis were of anatytical grade. Epoxides
5a and 5b were prepared according to Scheme 5. Enantiomeric ratio of
15a and 15b was 92:8, determined by chiral gas chromatography (GC)
analyses. Flash-column chromatography was performed on silica gel
(Merck, Kieselgel 60, 230–400 mesh). NMR spectra were obtained on a
l
Bruker Avance-II 400 instrument at 400.1 MHz for H and 100.6 MHz
for 13C. Chemical shifts for 1H and 13C are referenced to TMS via the sol-
vent signals (1H, CHC13 at 7.26 ppm; 13C, CDCl3 at 77.0 ppm). HRMS
spectra were obtained on a Thermo Electron LTQ Orbitrap massspect-
rometer. Analytical chiral HPLC was performed on a Shimadzu Promi-
nence (Chiralpak AD-H 4.6 mm i.d. ꢁ 250 mm L. column, eluted with
hexane=2-PrOH 98:2, at 1.0 mL=min flow rate, column oven at 27 ꢀC).
The IR spectra were measured with the Interspec 2020 Fourier transform
infrared (FTIR) spectrometer. Melting points were determined in open
capillary tubes using a Buchi 535 melting-point apparatus and are uncor-
¨
rected. Chiral GC analyses were performed on a Varian 3900 instrument
using a permethylated b-cyclodextrin column.
Scheme 5. Preparation of epoxides 5a and 5b.

Synthesis of Amphiphilic Amino Alcohols
4301
Preparation of (2R)-Dodecane-1,2-diol (12a)
A typical Sharpless asymmetric dihydroxylation protocol[16] was fol-
lowed. K2OsO2(OH)4 (7.6 mg, 0.021 mmol), 1,4,bis(90-O-dihydroquinidyl)
phthalazine [(DHQD)2PHAL] (82 mg, 0.10 mmol), K2CO3 (4.1 g,
29.7 mmol), and I2 (3.81 g, 15.0 mmol) were dissolved in a 1:1 (v=v) mix-
ture of t-BuOH and H2O (95 mL), cooled to 0 ꢀC. Dodec-1-ene 11a
(1.77 g, 10.5 mmol) was added, and the reaction mixture was stirred at
0 ꢀC for 6 h and then slowly warmed up to ambient temperature. The
crude reaction mixture was extracted with EtOAc, dried over anhydrous
Na2SO4, filtered, and evaporated to dryness. Column chromatographic
purification on silica gel with 5% MeOH in CHCl3 as the eluent afforded
the title product 12a (2.06 g, 10.2 mmol, 97% yield) as white solid. Rf: 0.30
1
(10% MeOH in CHCl3). H NMR (400.1 MHz, CDCl3), d: 3.71 (m, 1H,
CH-O); 3.65 (dd, J ¼ 2.7, 11.2 Hz, 1H, CHa-O); 3.43 (dd, J ¼ 7.8, 11.2 Hz,
1H, CHb-O); 2.69 (bs, 2H, OH); 1.49–1.23 (m, 18H, 9 ꢁ CH2); 0.88 (vt,
3H, CH3). 13C NMR (100.6 MHz, CDCl3), d: 72.3; 66.7; 33.1; 31.9;
29.63; 29.59; 29.58; 29.54; 29.3; 25.5; 22.7; 14.1 (CH3). The 1H NMR data
matched the data of a commercial sample and were also consistent with
previously reported data.[21]
Preparation of (2R)-Tetradec-13-ene-1,2-diol (12b)
K2OsO2(OH)4 (1.8 mg, 5.0 mmol), (DHQD)2PHAL (21 mg, 25 mmol),
K2CO3 (1.04 g, 7.5 mmol), and I2 (0.95 g, 3.8 mmol) were dissolved
in a 1:1 (v=v) mixture of t-BuOH and H2O (25 mL) and cooled to
0 ꢀC. 1,13-Tetradecadiene 11b (0.54 g, 2.50 mmol, ca. 90% purity)
was added as one portion, and the reaction mixture was stirred at
0 ꢀC, monitored with thin-layer chromatography (TLC), and quenched
with Na2SO3 (3.0 g) after 3.5 h when formation of tetradecane-
1,2,13,14-tetrol was detected, although the substrate had not been
fully consumed. Brine (20 mL) was added, and the mixture was
extracted with CH2Cl2 (6 ꢁ 15 mL). The combined organic phases
were dried over anhydrous Na2SO4, filtered, and evaporated to dry-
ness under vacuum. Purification using column chromatography with
5% MeOH in CHCl3 yielded the diol 12b (310 mg, 1.36 mmol, 54%
yield) as white solid. In addition, 240 mg of unreacted 1,13-tetradeca-
diene was recovered. Rf: 0.30 for the diol 12b, and 0.10 for the by-
product tetradecane-1,2,13,14-tetrol (10% MeOH in CHCl3). Mp:
59–60 C. IR (neat) nmax: 3379, 2929, 2857, 1468, 1074, 912 cmꢂ1
.
ꢀ
~
1H NMR (400.1 MHz, CDCl3), d: 5.80 (dddd, J ¼ 6.7, 6.7, 10.1,
16.9 Hz, 1H, CH¼); 4.98 (dm, J ¼ 16.9 Hz, 1H, CHa¼); 4.91 (dm,

4302
L. Toom et al.
J ¼ 10.1 Hz, 1H, CHb¼); 3.67 (m, 1H, CH-OH); 3.61 (dd, J ¼ 2.9,
11.2 Hz, CHa-OH); 3.40 (dd, J ¼ 7.9, 11.2 Hz, CHb–OH); 3.23 (bs,
2H, OH); 2.02 (m, 2H, CH2–CH¼); 1.43–1.22 (m, 18H, 9 ꢁ CH2).
13C NMR (100.6 MHz, CDCl3), d: 139.2 (CH¼); 114.1 (CH2¼); 72.3
(CH–O); 66.7 (CH2-O); 33.8; 33.1 (CH2–CH¼); 29.64; 29.56
(2 ꢁ CH2); 29.54; 29.46; 29.1; 28.9; 25.6. HRMS (m=z) calcd. for
C14H29O2(M þ H)þ 229.2162; found 229.2161.
Preparation of (2R)-2-Hydroxydodecyl 4-Methylbenzenesulfonate (13a)
For selective tosylation of a primary hydroxyl group of a vicinal diol, a
literature procedure[17] was followed.
To a solution of (2R)-dodecane-1,2-diol 12a (2.00 g, 9.89 mmol),
dibutyltin oxide (44 mg, 0.177 mmol), and Et3N (1.00 g, 9.89 mmol) in
CH2Cl2 (28 mL), p-toluenesulfonyl chloride (1.89 g, 9.89 mmol) was
added as a solid in one portion. The reaction was stirred at ambient
temperature for 18 h and then extracted with aqueous saturated
NaHCO3 (20 mL). The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated, giving ca. 3.5 g of white amorphous solid
13a[22] that was used without further purification for the next synthetic
step. An analytical sample was obtained by chromatographic purification
on silica gel (1% MeOH in CHCl3). Rf: 0.50 (5% MeOH in CHCl3). Mp:
59–60 C. IR (neat) nmax: 3554, 2929, 2856, 1352, 1177, 960, 818 cmꢂ1. 1H
ꢀ
~
NMR (400.1 MHz, CDCl3), d: 7.80 (AA0 part of AA0BB0, 2H, CHAr);
7.36 (BB0 part of AA0BB0, 2H, CHAr); 4.04 (dd, J ¼ 2.5, 9.6 Hz, 1H,
CHa-OTs); 3.88 (dd, J ¼ 7.1, 9.6 Hz, 1H, CHb-OTs); 3.83 (m, 1H, CH-
OH); 2.45 (s, 3H, C6H4-CH3); 1.95 (bs, 1H, OH); 1.46–1.20 (m, 18H,
9 ꢁ CH2); 0.87 (vt, 3H, CH3). 13C NMR (100.6 MHz, CDCl3), d: 145.0
(CAr); 132.6 (CAr); 129.9 (CHAr); 127.9 (CHAr); 74.0 (CH2-OTs); 69.5
(CH–OH); 32.6; 31.9; 29.54; 29.50; 29.41; 29.39; 29.27; 25.2; 22.6; 21.6
(C6H4–CH3); 14.1 (CH3). Chiral HPLC analysis showed 91:9 enantio-
meric ratio. HRMS (m=z) calcd. for C19H33O4S (M þ H)þ 357.2094,
found 357.2091.
Preparation of (2R)-2-Hydroxytetradec-13-en-1-yl 4-
Methylbenzenesulfonate (13b)
To a solution of (2R)-tetradec-13-ene-1,2-diol 12b (200 mg, 0.88 mmol),
dibutyltin oxide (4 mg, 0.016 mmol), and Et3N (89 mg, 0.88 mmol) in
CH2Cl2 (10 mL), p-toluenesulfonyl chloride (167 mg, 0.88 mmol) was
added as a solid in one portion. The reaction was stirred at ambient

Synthesis of Amphiphilic Amino Alcohols
4303
temperature for 4 h and then extracted with aqueous saturated NaHCO3
(12 mL). The organic layer was dried over anhydrous Na2SO4, filtered,
and concentrated, giving a solid residue that was used in the next syn-
thetic step without further purifications. Analytical sample of 13b was
obtained by chromatographic purification on silica gel (1.5% MeOH in
ꢀ
~
CHCl3). Rf: 0.50 (5% MeOH in CHCl3). Mp: 59–60 C. IR (neat) nmax
:
3552, 2927, 2854, 1350, 1176, 958, 819 cmꢂ1
.
1H NMR (400.1 MHz,
CDCl3), d: 7.80 (AA0 part of AA0BB0, 2H, CHAr); 7.36 (BB0 part of
AA0BB0, 2H, CHAr); 5.81 (dddd, J ¼ 6.7, 6.7, 10.1, 16.9 Hz, 1H,
CH¼CH2); 4.99 (dm, J ¼ 16.9 Hz, 1H, CH¼CHa); 4.93 (dm, J ¼ 10.1 Hz,
Hz, 1H, CH¼CHb); 4.04 (dd, J ¼ 2.6, 9.6 Hz, 1H, CHa-OTs); 3.88 (dd,
J ¼ 7.1, 9.6 Hz, 1H, CHb-OTs); 3.84 (m, 1H, CH-OH); 2.46 (s, 3H,
C6H4–CH3); 2.04 (m, 2H, CH2–CH¼); 1.45–1.19 (m, 18H, 9 ꢁ CH2).
13C NMR (100.6 MHz, CDCl3), d: 145.0 (CAr); 139.2 (CH¼CH2); 132.7
(CAr); 129.9 (CHAr); 128.0 (CHAr); 114.1 (CH¼CH2); 74.0 (CH2–O);
69.5 (CH–O); 33.8; 32.6; 29.52; 29.49; 29.45; 29.43; 29.41; 29.1; 28.9;
25.2; 21.7 (CH3). HRMS (m=z) calcd. for C21H35O4S (M þ H)þ
383.2251, found 383.2247.
Preparation of (2R)-1,2-Epoxydodecane (5a)
K2CO3 (2.2 g) was added to a solution of crude 13a (3.5 g, ca.
9.8 mmol) in a mixture of MeOH (85 mL) and CH2Cl2 (10 mL). After
stirring at room temperature for 30 min, the solvent was evaporated
under vacuum. The residue was extracted with water (3 ꢁ 15 mL),
and the organic layer was dried over anhydrous Na2SO4, filtered,
and evaporated. Purification with flash-column chromatography on
silica gel (10% EtOAc in petroleum ether as eluent) gave 5a (1.82 g,
9.88 mmol, 99% yield over two steps) as colorless oil. Rf: 0.45
(CHCl3). 1H NMR (400.1 MHz, CDCl3), d: 2.90 (m, 1H, CH–O);
2.74 (dd, J ¼ 4.0, 5.1 Hz, 1H, CHa–O); 2.46 (dd, J ¼ 2.7, 5.1 Hz, 1H,
CHb–O); 1.56–1.23 (m, 18H, 9 ꢁ CH2); 0.88 (vt, 3H, CH3). 13C
NMR (100.6 MHz, CDCl3), d: 52.4 (CH–O); 47.1 (CH2–O); 32.5;
31.9; 29.57; 29.54; 29.4; 29.3; 26.0; 22.7; 14.1 (CH3). The NMR data
matched the data of a commercial sample and were also consistent
with previously reported data.[23]
Preparation of (2R)-1,2-Epoxy-11-tetradecene (5b)
K2CO3 (200 mg, 1.45 mmol) was added to a solution of crude
13b (330 mg, ca. 0.86 mmol) in MeOH (8 mL), stirred for 35 min,

4304
L. Toom et al.
concentrated, extracted with water, dried over Na2SO4, filtered, and
evaporated to dryness under vacuum. Column chromatography with
10% EtOAc in petroleum ether gave 177 mg of 5b as clear oil
(0.84 mmol, 96% yield over two steps). Rf: 0.45 (CHCl3). 1H NMR
(400.1 MHz, CDCl3), d: 5.81 (dddd, J ¼ 6.7, 6.7, 10.1, 16.9 Hz, 1H,
CH¼CH2); 4.98 (dm, J ¼ 16.9 Hz, 1H, CH¼CHa); 4.92 (dm,
J ¼ 10.1 Hz, 1H, CH¼CHb); 2.89 (m, 1H, CH–O); 2.73 (dd, J ¼ 4.0,
5.1 Hz, 1H, CHa–O); 2.45 (dd, J ¼ 2.8, 5.1 Hz, 1H, CHb–O); 2.03
(m, 2H, CH2–CH¼); 1.55–1.24 (m, 18H, 9 ꢁ CH2). 13C NMR
(100.6 MHz, CDCl3), d: 139.2 (CH¼CH2); 114.1 (CH¼CH2); 52.4
(CH–O); 47.1 (CH2–O); 33.8; 32.5; 29.55; 29.53; 29.51; 29.47; 29.43;
29.1; 28.9; 26.0. HRMS (m=z) calcd. for C14H27O (M þ H)þ
211.2056, found 211.2053. NMR data were in agreement with litera-
ture data for the corresponding racemic compound.[24]
Preparation of (R)-1-Aminododecan-2-ol (6a)
Epoxide 5a (58 mg, 0.31 mmol) and 25% aqueous ammonium hydroxide
(2 mL) was heated in EtOH (2 mL) in sealed tube at 60 ꢀC for 16 h. Reac-
tion mixture was concentrated under reduced pressure to afford 63 mg
(>99%) of white amorphous solid, which was used without further pur-
ification. Rf: 0.52 (10:2:0.5 of CHCl3=MeOH=NH4OH). 1H NMR
(400.1 MHz, CD3OD=CDCl3), d: 3.49 (m, 1H, CH–O); 2.67 (dd,
J ¼ 3.2, 13.0 Hz, 1H, CHa–N); 2.49 (dd, J ¼ 8.4, 13.0 Hz, 1H, CHb–N);
1.46–1.19 (m, 18H, 9 ꢁ CH2); 0.85 (vt, 3H, CH3). 13C NMR
(100.6 MHz, CD3OD=CDCl3), d: 72.9 (CH–O); 47.7 (CH2–N); 35.4;
32.4; 30.24; 30.15; 30.14 (2 ꢁ CH2); 29.9; 26.2; 23.2; 14.4 (CH3). NMR
data were consistent with literature data.[4a] HRMS (m=z) calcd. for
C12H28NO (M þ H)þ 202.2165, found 202.2163.
Preparation of N-[(2R)-2-Hydroxydodecyl]-4-
methylbenzenesulfonamide (6b)
(2R)-1,2-Epoxydodecane 5a (369 mg, 2.0 mmol), 4-methylbenzenesulfon-
amide (685 mg, 4.0 mmol), K2CO3 (28 mg, 0.20 mmol), and TEBA
(46 mg, 0.20 mmol) were heated at 90 ꢀC in 1,4-dioxane (1.0 mL) for
20 h. After cooling, the crude product was extracted with brine; the com-
bined organic phases were dried over anhydrous Na2SO4, filtered, and
evaporated to dryness under vacuum. Purifying the residue using column
chromatography with 2.5% of MeOH in CHCl3 gave 6b (570 mg,

Synthesis of Amphiphilic Amino Alcohols
4305
1.60 mmol, 80% yield) as white solid. Rf: 0.30 (5% MeOH in CHCl3). Mp:
55–56 ꢀC. IR (neat) n~max: 3508, 3291, 2928, 2857, 1331, 1163, 1095, 666,
1
555 cmꢂ1. H NMR (400.1 MHz, CDCl3), d: 7.75 (AA0 part of AA0BB0,
2H, CHAr); 7.30 (BB0 part of AA0BB0, 2H, CHAr); 5.23 (dd, J ¼ 5.2,
7.3 Hz, 1H, NH); 3.68 (m, 1H, CH–O); 3.05 (ddd, J ¼ 3.0, 7.3, 12.9 Hz,
1H, CHa–N); 2.76 (ddd, J ¼ 5.2, 8.2, 12.9 Hz, 1H, CHb–N); 2.42 (s,
3H, C6H4–CH3); 2.31 (bs, 1H, OH); 1.41–1.19 (m, 18H, 9 ꢁ CH2); 0.87
(vt, 3H, CH3). 13C NMR (100.6 MHz, CDCl3), d: 143.5 (CAr); 136.6
(CAr); 129.7 (CHAr); 127.1 (CHAr); 70.4 (CH–O); 48.7 (CH2–N); 34.6;
31.9; 29.55; 29.53; 29.47; 29.45; 29.3; 25.3; 22.6; 21.5 (C6H4–CH3); 14.1
(CH3). HRMS (m=z) calcd. for C19H34NO3S (M þ H)þ 356.2254, found
356.2254.
Preparation of N-[(2R)-2-Hydroxydodecyl]-2-nitrobenzenesulfonamide (6c)
(2R)-1,2-Epoxydodecane 5a (369 mg, 2.0 mmol), 2-nitrobenzenesulfon-
amide (809 mg, 4.0 mmol), K2CO3 (28 mg, 0.20 mmol), and TEBA
(46 mg, 0.20 mmol) were heated at 90 ꢀC in 1,4-dioxane (1.0 mL) for
20 h. After cooling, the reaction mixture was diluted with CH2Cl2
(30 mL) and extracted with brine; the combined organic phases were
dried over anhydrous Na2SO4, filtered, and evaporated to dryness
under vacuum. Purifying the residue using column chromatography
with 2.0% of MeOH in CHCl3 gave 6c as white solid (724 mg,
1.87 mmol, 94% yield). Rf: 0.40 (5% MeOH in CHCl3). Mp: 57–
58 ꢀC. IR (neat) n~max
1168 cmꢂ1 1H NMR (400.1 MHz, CDCl3), d: 8.13 (m, 1H, CHAr);
:
3540, 3350, 2930, 2857, 1545, 1367,
.
7.87 (m, 1H, CHAr); 7.74 (m, 2H, 2ꢁCHAr); 5.74 (dd, J ¼ 5.0,
7.1 Hz, 1H, NH); 3.74 (m, 1H, CH–O); 3.24 (ddd, J ¼ 3.2, 7.1,
12.9 Hz, 1H, CHa–N); 2.94 (ddd, J ¼ 5.0, 8.0, 12.9 Hz, 1H, CHb–N);
1.88 (bs, 1H, OH); 1.46–1.20 (m, 18H, 9 ꢁ CH2); 0.88 (vt, 3H,
CH3). 13C NMR (100.6 MHz, CDCl3), d: 148.1 (CAr); 133.60 (CAr);
133.59 (CHAr); 132.7 (CHAr); 131.1 (CHAr); 125.4 (CHAr); 70.4
(CH–O); 49.2 (CH2–N); 34.7; 31.9; 29.56; 29.53; 29.46; 29.44; 29.3;
25.3, 22.7; 14.1 (CH3). HRMS (m=z) calcd. for C18H31N2O5S
(M þ H)þ 387.1948, found 387.1948.
Preparation of (2R)-1-(Benzylamino)dodecan-2-ol (6d)
(2R)-1,2-Epoxydodecane 5a (370 mg, 2.01 mmol) and benzylamine
(655 mg, 6.11 mmol) were refluxed in 2-PrOH (1 mL) for 17 h, fol-
lowed by concentration under vacuum and purification using column

4306
L. Toom et al.
chromatography on silica gel with 2.5% MeOH and 2% Et3N in
CHCl3 as eluent, affording 6d (501 mg, 1.72 mmol, 86% yield) as white
1
solid. Rf: 0.23 (5% MeOH and 2% Et3N in CHCl3). Mp: 59–60 ꢀC. H
NMR (400.1 MHz, CDCl3), d: 7.36–7.24 (m, 5H, CHAr); 3.83 (d,
J ¼ 13.3 Hz, CHa–Ph); 3.77 (d, J ¼ 13.3 Hz, CHb–Ph); 3.61 (m, 1H,
CH–O); 2.76 (dd, J ¼ 3.1, 12.1 Hz, 1H, CH–CHa–N); 2.46 (dd,
J ¼ 9.4, 12.1 Hz, 1H, CH–CHb–N); 1.49–1.16 (m, 18H, 9 ꢁ CH2). 13C
NMR (100.6 MHz, CDCl3), d: 140.1 (Cipso); 128.4 (CHAr); 128.0
(CHAr); 127.1 (CHpara); 69.6 (CH–O); 54.8 (CH2); 53.6 (CH2); 35.0;
1
31.9; 29.7; 29.60; 29.57; 29.3; 25.7; 22.7; 14.1 (CH3). H NMR data
were in an agreement with the corresponding racemic compound.[27]
HRMS (m=z) calcd. for C19H34NO (M þ H)þ 292.2635, found
292.2635.
Preparation of (2R)-1-[(2-Aminoethyl)amino]dodecan-2-ol (7a)
The solution of epoxide 5a (105 mg, 0.568 mmol), ethylene-1,2-diamine
(196 mg, 3.25 mmol) in 10 mL of EtOH was stirred at 50 ꢀC for 4 h until
TLC indicated complete consumption of the starting materials. The reac-
tion mixture was extracted with CH2Cl2 and brine (solid NaOH
was added to brine for better phase separation). The combined organic
phases were filtered and dried, and the filtrate was concentrated in vacuo.
The residue was chromatographed on silica gel (10:2:0.5 of
CHCl3=MeOH=NH4OH) to attain the desired aminated product 7a
(137 mg, 0.562 mmol, 99% yield) as colorless oil. Rf: 0.29 (10:2:0.5 of
~
CHCl3=MeOH=NH4OH). IR (neat) nmax: 3291, 2927, 2856, 1666, 1469,
1099 cmꢂ1 1H NMR (400.1 MHz, CDCl3), d: 3.60 (m, 1H, CH–O);
.
2.82 (m, 2H, CH2–NH2); 2.71 (m, 1H, CH–CHa–N); 2.67 (m, 2H,
NH–CH2); 2.45 (dd, J ¼ 9.2, 12.2 Hz, 1H, CH–CHb–N); 2.01 (bs, 3H,
NH þ OH); 1.47–1.20 (m, 18H, 9 ꢁ CH2); 0.87 (vt, 3H, CH3). 13C
NMR (100.6 MHz, CDCl3), d: 69.6 (CH–O); 55.3; 52.1; 41.7; 35.1;
31.9; 29.7; 29.57; 29.56; 29.3; 25.7; 22.6; 14.1 (CH3). HRMS (m=z) calcd.
for C14H33N2O (M þ H)þ 245.2587, found 245.2587.
Preparation of (2R)-1-{Benzyl[2-(benzylamino)ethyl]amino}dodecan-
2-ol (7b)
(2R)-1,2-Epoxydodecane 5a (398 mg, 2.16 mmol) and N,N0-dibenzylethy-
lene-1,2-diamine (1.5 mL, ca. 6.4 mmol) were refluxed in 2-PrOH
(1.5 mL) for 4 h. After cooling, the solvent was evaporated under
vacuum, and the residue was purified with flash chromatography (1%

Synthesis of Amphiphilic Amino Alcohols
4307
MeOH in CHCl3), giving 7b as slightly yellowish oil (737 mg, 1.74 mmol,
81% yield). Rf: 0.5 (10% MeOH in CHCl3). IR (neat) n~max: 3320, 2928,
1
2856, 1455, 740, 700 cmꢂ1. H NMR (400.1 MHz, CDCl3), d: 7.34–7.21
(m, 10H, CHAr); 3.80 (d, J ¼ 13.5 Hz, 1H, CHa–Ph); 3.70 (s, 2H, CH2–
Ph); 3.50 (d, J ¼ 13.5 Hz, 1H, CHb–Ph); 3.65 (m, 1H, CH–O); 2.74 (m,
2H); 2.64 (m, 1H); 2.55 (m, 1H); 2.51 (dd, J ¼ 3.0, 13.0 Hz, 1H, CH–
CHa–N); 2.41 (dd, J ¼ 9.9, 13.0 Hz, 1H, CH–CHb–N); 1.49–1.17 (m,
18H, 9 ꢁ CH2); 0.89 (vt, 3H, CH3). 13C NMR (100.6 MHz, CDCl3), d:
140.1 (CAr); 139.1 (CAr); 129.0; 128.34; 128.32; 128.0; 127.1; 126.9;
68.3; 60.7; 60.0; 53.5; 46.7; 34.8; 31.9; 29.8; 29.59; 29.58; 29.3; 25.8;
22.7; 14.1 (CH3). HRMS (m=z) calcd. for C28H45N2O (M þ H)þ
425.3526, found 425.3512.
Preparation of (2R)-2-tert-Butyldimethylsilyloxy-1-iodododecane (9)
Imidazole (477 mg, 7.0 mmol) and TBDMSCl (423 mg, 2.8 mmol) were
added to a solution of tosylate 13a (1.0 g, 2.8 mmol) in DMF (3.0 mL).
After stirring at room temperature for 6 h, the reaction mixture was
diluted with brine and extracted with EtOAc (3 ꢁ 15 mL). The organic
layer was dried over anhydrous Na2SO4 and concentrated. Purification
by flash chromatography (gradual elution 0–5% EtOAc=hexanes)
afforded 1.28 g (97%) of colorless oil as (2R)-2-tert-butyldimethyl-
silyloxy-1-(4-methyl-benzenesulfonyloxy)dodecane. Part of this silyl-
protected tosylate (910 mg, 2.23 mmol) was dissolved in acetone (5 mL).
NaI (1.67 g, 11.15 mmol) was added, and the reaction mixture was
refluxed for 20 h. After cooling down, the reaction mixture was diluted
with brine, extracted with EtOAc (3 ꢁ 20 mL), dried over anhydrous
Na2SO4, and concentrated to give 812 mg (85%) of compound 9 as
~
slightly yellowish oil. Rf: 0.70 (CHCl3). IR (neat) nmax: 2932, 2859,
1473, 1257, 1076 cmꢂ1 1H NMR (400.1 MHz, CDCl3), d: 3.54 (ddt,
.
J ¼ 5.1, 6.5, 11.6 Hz, 1H, CH–O); 3.19 (d, J ¼ 5.1 Hz, 2H, CH2–I);
1.64–1.21 (m, 18H, 9 ꢁ CH2); 0.90 [s, 9H, C(CH3]3); 0.88 (vt, 3H, CH2–
CH3); 0.08 (d, J ¼ 11.6 Hz, 6H, Si–CH3). 13C NMR (100.6 MHz, CDCl3),
d: 71.4; 36.9; 31.9; 29.59; 29.56; 29.54; 29.53; 29.3; 25.8; 24.9; 22.7; 18.1;
14.2; 14.1; ꢂ 4.4; ꢂ 4.6. HRMS (m=z) calcd. for C18H40IOSi (M þ H)þ
427.1888, found (M þ H)þ 427.1877.
Preparation of 1-[(2-Aminoethyl)amino]propan-2-ol (10)
Propylene oxide (348 mL, 5.0 mmol), ethylene-1,2-diamine (1.0 mL,
14.9 mmol), and MeCN (0.6 mL) were heated in a sealed tube at 65 ꢀC

4308
L. Toom et al.
for 24 h. After cooling down, the reaction mixture was concentrated to
afford 718 mg of crude product 10 (estimated yield 68%) as slightly yel-
lowish oil. The crude product contains unreacted ethylene-1,2-diamine.
1H NMR (400.1 MHz, CDCl3), d: 3.77 (ddq, J ¼ 3.1, 6.3, 9.2 Hz, 1H,
CH–O); 2.74 (m, 2H); 2.64 (m, 2H); 2.59 (dd, J ¼ 3.1, 12.2 Hz, 1H,
CH–CHa-N); 2.42 (dd, J ¼ 9.2, 12.2 Hz, 1H, CH–CHb–N); 1.10 (d,
J ¼ 6.3 Hz, 3H, CH3). 13C NMR (100.6 MHz, CDCl3), d: 65.6 (CH–O);
1
56.5; 51.2; 40.8; 20.6 (CH3). H NMR and 13C NMR spectra were con-
sistent with literature data.[25] HRMS (m=z) calcd. for C5H15N2O
(M þ H)þ 119.1179, found 119.1177.
Preparation of N,N0-Bis(2-hydroxypropyl)ethylene-1,2-diamine (11)
Propylene oxide (1.0 mL, 14.2 mmol) and MeCN (0.6 mL) were added to
amino alcohol 10 (718 mg, ca. 1:1 mixture of 10 and ethylene-1,2-diamine
13
based on C NMR). The reaction mixture was heated at in at 65 ꢀC for
24 h in a sealed tube. After cooling down, the reaction mixture was con-
centrated to give 993 mg of 11 as an amorphous sticky solid (estimated
yield 87%). The crude product contains unreacted ethylene-1,2-diami-
ne.1H NMR (400.1 MHz, CDCl3), d: 3.78 (ddq, J ¼ 3.1, 6.3, 9.2 Hz,
2H, CH–O); 2.82 (m, 4H, N–CH2–CH2–N); 2.72 (dd, J ¼ 3.1, 12.2 Hz,
2H, CH–CHa–N); 2.42 (dd, J ¼ 9.2, 12.2 Hz, 2H, CH–CHb–N); 1.15 (d,
J ¼ 6.3 Hz, 6H, CH3). 13C NMR (100.6 MHz, CDCl3), d: 65.6 (CH–O);
1
56.7; 52.0; 41.8; 20.4 (CH3). H NMR spectral data are consistent with
literature data.[26] HRMS (m=z) calcd. for C8H21N2O2 (M þ H)þ
177.1598, found 177.1599.
Preparation of N-[(2R)-2-Hydroxytetradec-13-en-1-yl]-N-[(2R)-2-
hydroxydodecyl]-4-methylbenzenesulfonamide (3b)
N-[(2R)-2-Hydroxydodecyl]-4-methylbenzenesulfonamide 6b (345 mg,
0.97 mmol), (2R)-1,2-epoxy-11-tetradecene 5b (170 mg, 0.81 mmol),
K2CO3 (13 mg, 94 mmol), and TEBA (19 mg, 83 mmol) were heated
at 90 ꢀC in 1,4-dioxane (1.0 mL) for 1 week. After cooling, it was
extracted with brine and CHCl3, dried over anhydrous Na2SO4, fil-
tered, and evaporated. Purification by column chromatography using
0.5–3.0% MeOH gradient in CHCl3 afforded unreacted epoxide 5b
(50 mg), unreacted tosylamide 6b, desired products 3b as diastereo-
isomers (combined yield 53%, 241 mg, 0.43 mmol), and a sideproduct
coming from the Hofmann decomposition of TEBA. Spectral data

Synthesis of Amphiphilic Amino Alcohols
4309
given only for the major diastereoisomer of the product. Rf: 0.46 (5%
MeOH in CHCl3). Mp: 65–66.5 ꢀC. IR (neat), n~max: 3312, 2923, 2853,
1
1347, 1157 cmꢂ1. H NMR (400.1 MHz, CDCl3), d: 7.68 (AA0 part of
AA0BB0, 2H, CHAr); 7.31 (BB0 part of AA0BB0, 2H, CHAr); 5.80
(dddd, J ¼ 6.7, 6.7, 10.2, 17.0 Hz, 1H, CH¼); 4.98 (dddd, J ¼ 1.6,
1.6, 2.2, 17.0 Hz, 1H, CHa¼); 4.91 (dddd, J ¼ 1.2, 1.2, 2.2, 10.2 Hz,
1H, CHb¼); 3.90 (m, 2H, CH–O); 3.46 (bs, 2H, OH); 3.01 (m, 4H,
2 ꢁ CH2–N); 2.42 (s, 3H, C6H4–CH3); 2.02 (m, 2H, CH2–CH¼);
1.47–1.20 (m, 36H, 18 ꢁ CH2); 0.87 (vt, 3H, CH2–CH3). 13C NMR
(100.6 MHz, CDCl3), d: 143.5 (CAr); 139.1 (CH¼); 135.1 (CAr);
129.7 (CHAr); 127.4 (CHAr); 114 (CH2¼); 70.1 (CH–O); 56.5 (CH2–
N); 34.6; 33.7 (CH2–CH¼); 31.8; 29.61; 29.60; 29.56; 29.55; 29.53;
29.52; 29.51; 29.4; 29.3; 29.1; 28.9; 25.5; 22.6; 21.4 (C6H4–CH3);
14.1 (CH2–CH3). HRMS (m=z) calcd. for C33H60NO4S (M þ H)þ
566.4238, found 566.4242.
Preparation of N-[(2R)-2-Hydroxytetradec-13-en-1-yl]-N-[(2R)-2-
hydroxydodecyl]-2-nitrobenzenesulfonamide (3c)
N-[(2R)-2-Hydroxydodecyl]-2-nitrobenzenesulfonamide 6c (606 mg,
1.57 mmol), (2R)-1,2-epoxy-11-tetradecene 5b (300 mg, 1.43 mmol),
K2CO3 (22 mg, 0.16 mmol), and TEBA (36 mg, 0.16 mmol) were heated
at 90 ꢀC in 1,4-dioxane (2.0 mL) for 10 days. After cooling, the crude
reaction mixture was diluted with brine, extracted with CH2Cl2, dried
over anhydrous Na2SO4, filtered, and evaporated to dryness under
vacuum. Purification by column chromatography with 1.3% MeOH in
CHCl3 as eluent afforded the unreacted 5b and 6c, together with the
desired product 3c as two diastereoisomers (460 mg, 0.77 mmol, com-
bined yield of the two diastereoisomers 54%). In addition, a similar side
product, coming from the decomposition of TEBA, was observed. Spec-
tral data given only for the major diastereoisomer of the product. Rf: 0.52
(5% MeOH in CHCl3). Mp: 42–43.5 ꢀC. IR (neat) n~max: 3366, 2932, 2858,
1551, 1469, 1375, 1167, 583 cmꢂ1. 1H NMR (400.1 MHz, CDCl3), d: 8.00
(m, 1H, CHAr); 7.70 (m, 2H, CHAr); 7.61 (m, 1H, CHAr); 5.80 (dddd,
J ¼ 6.7, 6.7, 10.1, 16.9 Hz, 1H, CH¼CH2); 4.98 (dm, J ¼ 16.9 Hz, 1H,
CHa¼); 4.91 (dm, J ¼ 10.1 Hz, 1H, CHb¼); 3.89 (m, 2H, CH-O); 3.26
(m, 6H, CH2–N–CH2 þ 2 ꢁ OH); 2.03 (m, 2H, CH2–CH¼); 1.46–1.19
(m, 36H, 18 ꢁ CH2); 0.87 (vt, 3H, CH3). 13C NMR (100.6 MHz, CDCl3),
d: 148.4 (CAr); 139.2 (CH¼); 133.7 (CHAr); 132.0 (CAr); 131.6 (CHAr);
130.9 (CHAr); 124.1 (CHAr); 114.0 (CH2¼); 69.6 (CH–O); 55.6 (CH2–
N); 34.6; 33.8 (CH2–CH¼); 31.9; 29.57; 29.56 (2 ꢁ CH2); 29.54; 29.53;

4310
L. Toom et al.
29.51; 29.50; 29.48; 29.44; 29.3; 29.1; 28.9; 25.4; 22.6; 14.1 (CH3). HRMS
(m=z) calcd. for C32H57N2O6S (M þ H)þ 597.3932, found 597.3935.
Preparation of (2R)-1-[Benzyl((2R)-2-hydroxydodecyl)amino]tetradec-
13-en-2-ol (3d)
(2R)-1-(Benzylamino)dodecan-2-ol 6d (207 mg, 0.71 mmol) and (2R)-2-
(dodec-11-en-1-yl)oxirane 5b (150 mg, 0.71 mmol) were refluxed in 2-
PrOH (5 mL) for 20 h. Purification using column chromatography with
1% MeOH in CHCl3 gave 3d (309.5 mg, 0.617 mmol, 87% yield) as color-
~
less oil. Rf: 0.20 (20% EtOAc in hexanes). IR (neat), nmax: 3411, 2931,
1
2858, 1458, 1080, 911, 743, 701 cmꢂ1. H NMR (400.1 MHz, CDCl3),
d: 7.36–7.24 (m, 5H, CHAr); 5.81 (dddd, J ¼ 6.7, 6.7, 10.1, 16.9 Hz,
1H, CH¼CH2); 4.99 (dm, J ¼ 16.9 Hz, 1H, CH¼CHa); 4.93 (dm,
J ¼ 10.1 Hz, 1H, CH¼CHb); 3.88 (d, J ¼ 13.5 Hz, 1H, CHa-Ph); 3.66
(m, 2H, 2 ꢁ CH–O); 3.47 (d, J ¼ 13.5 Hz, 1H, CHb–Ph); 2.74 (bs, OH);
2.45 (m, 4H, CH2–N–CH2); 2.03 (m, 2H, CH2–CH¼); 1.45–1.18 (m,
36H, 18 ꢁ CH2); 0.88 (vt, 3H, CH3). 13C NMR (100.6 MHz, CDCl3), d:
139.3 (CH¼CH2); 138.4 (Cipso); 129.0 (CHAr); 128.5 (CHAr); 127.4
(CHpara); 114.1 (CH¼CH2); 67.9 (CH–O); 60.6 (CH–CH2–N); 59.7
(CH2–Ph); 34.9; 33.8 (CH2–CH¼); 31.9; 29.7; 29.59; 29.56; 29.55;
29.47; 29.3; 29.1; 28.9; 25.7; 22.7; 14.1 (CH3). HRMS (m=z) calcd. for
C33H60NO2 (M þ H)þ 502.4619, found 502.4601.
Preparation of N,N0-Bis[(2R)-2-hydroxydodecyl]-N,N0-dibenzylethylene-
1,2-diamine (4b)
(2R)-1,2-Epoxydodecane 5a (50 mg, 0.27 mmol) and N,N0-dibenzylethy-
lene-1,2-diamine (33 mL, 0.14 mmol) were refluxed in 2-PrOH (0.5 mL)
for 24 h. Purification with a flash column using 1% MeOH in CHCl3 as
eluent gave the product 4b as oil (61 mg, 0.10 mmol, 74% yield). Rf:
0.75 (10% MeOH in CHCl3). IR (neat) n~max: 3429, 2928, 2857, 1458,
1078 cmꢂ1. 1H NMR (400.1 MHz, CDCl3), d: 7.31–7.16 (m, 10H, CHAr);
4.55 (bs, 2H, OH); 3.73 (d, J ¼ 13.2 Hz, 2H, CHa–Ph); 3.67 (m, 2H, CH–
O); 3.26 (d, J ¼ 13.2 Hz, 2H, CHb–Ph); 2.83 (m, 2H, N–CHa–CHa–N);
2.37 (m, 4H, CH–CH2–N); 2.27 (m, 2H, N–CHb–CHb–N); 1.49–1.17
(m, 36H, 18 ꢁ CH2); 0.89 (vt, 6H, CH3). 13C NMR (100.6 MHz, CDCl3),
d: 138.1 (Cipso); 129.2 (CHAr); 128.3 (CHAr); 127.1 (CHpara); 67.3 (CH–
O); 60.6 (CH–CH2–N); 59.2 (CH2–Ph); 50.8 (N–CH2–CH2–N); 34.8;
31.9; 29.8; 29.60; 29.58; 29.3; 25.7; 22.7; 14.1 (CH3). HRMS (m=z) calcd.
for C40H69N2O2 (M þ H)þ 609.5354, found 609.5355.

Synthesis of Amphiphilic Amino Alcohols
4311
Preparation of N,N0-Bis[(2R)-2-hydroxydodecyl]ethylene-1,2-diamine (4a)
Dibenzyl derivative 4b (51 mg, 0.083 mmol) and 10% palladium on car-
bon (17 mg) was shaken in MeOH (5 mL) under the atmosphere of H2
gas (1 bar) overnight. Filtration and evaporation under vacuum afforded
4a as white powder (29 mg, 82%). Rf: 0.1 (10% MeOH in CHCl3). Mp:
142–144 C. IR (neat), nmax: 3374, 2925, 2855, 1471, 1137 cmꢂ1
.
1H
ꢀ
~
NMR (400.1 MHz, CD3OD=CDCl3), d: 3.72 (m, 2H, 2 ꢁ CH–O); 2.98
(m, 4H, N–CH2–CH2–N); 2.85 (dd, J ¼ 2.9, 12.3 Hz, 2H, CH–CHa–N);
2.66 (dd, J ¼ 9.1, 12.3 Hz, 2H, CH–CHb–N); 1.48–1.21 (m, 36H,
18ꢁCH2); 0.86 (vt, 6H, CH3). 13C NMR (100.6 MHz, CD3OD=CDCl3),
d: 69.3 (CH–O); 54.6 (CH–CH2–N); 46.6 (N–CH2–CH2–N); 35.8; 32.5;
30.27; 30.23; 30.21; 29.9; 26.1; 23.2; 14.3 (CH3). HRMS (m=z) calcd.
for C26H57N2O2 (M þ H)þ 429.4415, found 429.4417.
ACKNOWLEDGMENTS
This work was supported by the Grants Nos. 6520, 7009, 7260, and 7517
from the Estonian Science Foundation, and Estonian Targeted Financing
Grant TLOTI0073. We are grateful to Prof. Peter Somfai for fruitful dis-
cussions and critically reading the manuscript. We thank Lauri Peil for
HRMS analysis. We thank the Estonian State Agency of Medicines
Quality Control Laboratory for giving access to FTIR and melting-point
determination apparatuses.
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