New chiral polyfunctional cyclobutane derivatives from (-)-verbenone: Possible surfactant behaviour

Article abstract of DOI:10.1016/j.tetasy.2013.05.007

New enantiopure cyclobutane derivatives have been synthesized from a chiral precursor derived from (-)-verbenone. The cyclobutane moiety acts as a chiral platform to afford a γ-amino acid function in a branched side-chain containing an additional stereogenic centre as well as additional C₆ or C₁₆-alkyl chains linked to the ring by means of an amine or an amide function. One of these compounds, obtained as a 1:2 mixture with its TFA salt has been investigated, suggesting behaviour as a good surfactant and its critical micellar concentration has been determined.

Full text of DOI:10.1016/j.tetasy.2013.05.007

Tetrahedron: Asymmetry 24 (2013) 713–718
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New chiral polyfunctional cyclobutane derivatives
from (ꢀ)-verbenone: possible surfactant behaviour
a,
Jimena Ospina a, Alessandro Sorrenti a, Ona Illa a, Ramon Pons b, , Rosa M. Ortuño
⇑
⇑
a Departament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
b Departament de Tecnologia Química i de Tensioactius, Institut de Química Avançada de Catalunya, IQACꢀCSIC, c/Jordi Girona 18-26, 08034 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 March 2013
Accepted 14 May 2013
New enantiopure cyclobutane derivatives have been synthesized from a chiral precursor derived from
(ꢀ)-verbenone. The cyclobutane moiety acts as a chiral platform to afford a
c-amino acid function in a
branched side-chain containing an additional stereogenic centre as well as additional C6 or C16-alkyl
chains linked to the ring by means of an amine or an amide function. One of these compounds, obtained
as a 1:2 mixture with its TFA salt has been investigated, suggesting behaviour as a good surfactant and its
critical micellar concentration has been determined.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
of variable length has given rise to a variety of compounds with
an amphiphilic structure and with good surfactant properties.
Surfactants constitute one of the most commonly used groups
of molecules. Their applications range from detergents to cosmet-
ics, drug and food additives, and more recently have been applied
in drug delivery systems. Some of them are useful in industrial pro-
cesses such as those related with petrochemistry, chromatography
and catalysis among others. Research is currently underway in the
fields of high technology such as microelectronics and biotechnol-
ogy, and also in biomedicine.1
Most of the examples use natural a-amino acids.
Another important aspect is chirality in the surfactants. This is-
sue has been exploited especially for their use as templates in the
synthesis of silica materials,4 as deracemization agents5 and in chi-
ral electromigration chromatography techniques6 among others. In
the case of amino acid based surfactants, chirality is directly re-
lated to some of their physicochemical and biological properties.
Our group has experience in the synthesis and structural stud-
ies of enantiopure cyclobutane containing amino acids and pep-
tides, where the cyclobutane ring has a role as an element of
constraint. Starting from chiral pool precursors such as (ꢀ)-verbe-
Surfactants are ‘surface active agents’. This term is used to de-
scribe those molecules that tend to diminish the superficial tension
of an interface, namely water-air or fat-water. Their structure al-
ways implies having differentiated parts of the molecule with
opposite solubility, usually an alkyl chain, which is soluble in
non polar solvents (hydrophobic part), and a functional group that
has a high affinity for polar solvents (hydrophilic part). These mol-
ecules in addition to adsorption also show self-aggregation. Classi-
cally, the maximum adsorption is achieved around the same
concentration at which aggregates form in the bulk solution. The
surface tension, which is related to the amount of adsorbed mate-
rial through the Gibbs adsorption isotherm, tends to level above
the critical micellar concentration because monomer activity tends
to remain constant.
none and (ꢀ)-
prepared and used in the synthesis of several derivatives including
a
-pinene, enantiopure building blocks7 have been
amino ethers with analgesic activity,8 -dehydroamino acids9 and
a
different types of unnatural saturated amino acids.10 From some of
these scaffolds, a wide variety of products have been synthesized
such as: b-peptides,11
c c-lactams and cyclobutyl
-peptides,12
GABA analogues,13 hybrid peptides with cell-uptake properties14
and C3-symmetric dendrimers.15 Some of these compounds aggre-
gate giving vesicles14 or show properties as organogelators.15
Herein we report on the stereoselective synthesis of two types
of chiral cyclobutane containing c-amino acids in which the cyclo-
Amino acid based surfactants are of importance2 due to their
good levels of biodegradability and biocompatibility.3 The
combination of amino acids or peptides with hydrocarbon chains
butane ring is not a part of an amino acid main skeleton but acts as
a chiral platform bearing the appropriate functional groups and
side-chains. These include a C16-alkyl chain that, jointly with the
gem-dimethyl group of the cyclobutane, confers hydrophobicity
to the molecule. Both amino acids differ in that the chain is linked
to the cyclobutane moiety by means of an amine or an amide
function (Chart 1). The physicochemical characterization and
⇑
Corresponding authors. Tel.: +34 93 5811602.
E-mail address: rosa.ortuno@uab.es (R.M. Ortuño).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.007

714
J. Ospina et al. / Tetrahedron: Asymmetry 24 (2013) 713–718
hexadecylamine was coupled with 1 via the formation of an acid
chloride.
Prior to the synthesis of the target molecules, a model system
H
CO2H
NH2
N
H
H
H
with a hydrophobic alkyl chain of only six carbon atoms was syn-
thesized to check the viability of both routes. In order to obtain the
amine substituted model compound 3, a three step sequence was
carried out (Scheme 1). First of all, the carboxylic acid was reduced
to an alcohol by means of BH3 in THF at reflux for 24 h to give 2 in
80% yield. The alcohol in 2 was then converted into a mesylate
using mesyl chloride in CH2Cl2 in the presence of triethylamine.
This mesylate was used directly in the following step without puri-
fication. Next, it was refluxed with hexylamine in acetonitrile to af-
ford diprotected amino acid 3 in 57% yield over two steps. The
same procedure was applied to prepare compound 4, except for
using hexadecylamine instead of hexylamine, although in this case
the yield of the last two steps dropped to 20%. This could be related
to the steric hindrance that the gem-dimethyl substitution in the
cyclobutane ring confers to the molecule. Realizing that the yield
in the target product was very poor and that larger quantities of
material were needed to carry out the surfactant physico-chemical
tests, this synthetic route was not useful for our purposes and,
therefore, we decided to focus our efforts on the synthesis of amide
derivatives 5 and 6.
The route started with compound 1, which was subjected to
carboxylic acid activation as an acyl chloride using oxalyl chloride,
to then couple the resulting intermediate with hexylamine, as a
model reagent, to give compound 5 in 73% yield. When the same
procedure was applied using hexadecylamine instead of the model
amine, product 6 was obtained in 70% yield. As expected, the yields
were higher than in the first synthetic route due to the less severe
steric requirements of the coupling reaction with respect to the
second order substitution process.
H
O
CO2H
NH2
N
H
Chart 1. Types of surfactants envisioned.
properties of this new class of surfactants were investigated and
some results are reported and discussed herein.
2. Results and discussion
2.1. Synthesis
The two types of amino acid derivatives were prepared through
divergent synthetic routes starting from the common chiral
precursor 1, which is a c,e-amino diacid that has previously been
synthesized in our laboratory from (ꢀ)-verbenone12b (Scheme 1).
This compound presents a side-chain containing an orthogonally
protected c-amino acid and bearing an additional stereogenic cen-
tre with a determined absolute configuration at the b-carbonyl po-
sition. Moreover, the carboxyl group can be transformed into a
functional group suitable to introduce the alkyl chain. An amine
and an amide, respectively, were envisioned for this purpose. In
the former case, hexadecylamine was reacted, via an SN2 mecha-
nism, with an appropriate derivative of the primary alcohol result-
ing from the reduction of the carboxylic acid. In the second case,
The model compound 5 was transformed into amphiphile 9 to
check the feasibility of the synthesis. Selective removal of tert-bu-
tyl ester was carried out using trifluoroacetic acid (TFA) in the
presence of triethylsilane in dichloromethane, with acid 7 being
obtained quantitatively. Next, catalytic hydrogenation of the ben-
zyl carbamate in the presence of Pd(OH)2 in MeOH resulted in
compound 9 in 78% yield.
H
ref. 12b
O
CO2tBu
NHCbz
HO
H
O
1
1) (COCl)2, CH2Cl2
The same procedure was applied to the synthesis of amphiphile
10, starting from fully protected amino acid 6. Deprotection of the
carboxyl group was accomplished with TFA to yield 8 in quantita-
tive yield. Next, hydrogenolysis of the benzyl carbamate led to the
BH3, THF
80%
2) RNH2,Et3N
H
CO2tBu
NHCbz
O
CO2tBu
NHCbz
H
formation of what was expected to be exclusively the free c-amino
HO
R NH
acid 10. Nevertheless, high resolution mass spectrometry in posi-
tive and negative mode and elemental analysis of this sample
(see Section 4 for details) revealed the presence of not only 10
but also salt 11 (Scheme 2), which would come from some of the
TFA left in the hydrogenation step of 8. The ratio of 10:11 was cal-
culated to be 0.35:0.65. Attempts to eliminate residual acid after
this step by lyophilization were unsuccessful. It is noteworthy that
the much lower molecular weight of TFA compared with 7 favours
the salt formation even in the presence of a very small amount of
TFA. We attempted to convert the mixture into 11 by stirring it in
dichloromethane in the presence of trifluoroacetic acid, but the
amount of 11 was never increased suggesting that the mixture
composition corresponds to the acid–base equilibrium ratio
(Scheme 2).
H
H
2
R = -(CH2)5CH3, 73%, 5
R = -(CH2)15CH3, 70%, 6
1) MsCl, Et3N
2) RNH2,
AcCN
TFA, Et3SiH
CH2Cl2
H
CO2tBu
NHCbz
H
O
CO2H
R
NH
H
R
NH
NHCbz
H
R = -(CH2)5CH3, 54%, 3
R = -(CH2)15CH3,20%, 4
R = -(CH2)5CH3, quantitative, 7
R = -(CH2)15CH3, quantitative, 8
H2, Pd(OH)2/C
MeOH
2.2. Study of the mixture 10 + 11 as a surfactant
H
H
O
CO2H
NH2
A preliminary test was carried out to evaluate the solubility of
the obtained mixture 10 + 11 in water. The first assays determined
that when an aqueous 2.5 ꢁ 10ꢀ4 M solution was prepared and
shaken, foam appeared. This is a first sign of good behaviour as a
surfactant.
R
NH
R = -(CH2)5CH3, 78%, 9
R = -(CH2)15CH3, 10
Scheme 1.

J. Ospina et al. / Tetrahedron: Asymmetry 24 (2013) 713–718
715
1) H2, Pd(OH)2/C
MeOH
H
H
O
CO2H
NH2
O
CO2H
NH2
+
8
· TFA
R
NH
R
NH
H
H
2) TFA
11
10
R = -(CH2)15CH3
1 : 2
TFA, CH2Cl2
Scheme 2.
11
10
9
70
65
60
55
50
45
40
35
30
25
20
15
10
cmc
8
7
6
5
4
3
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
1E-3
0.01
0.1
1
10
n° mol NaOH x 106
c / mmol Kg-1
Figure 1. Titration of the surfactant mixture 10 + 11 with NaOH.
Figure 2. Plot of surface tension as a function of surfactant concentration for the
10 + 11 mixture in water at 25 °C.
Next, pH measurements were performed to gain more insight
about the sample that contained the mixture 10 + 11. At first,
1.002 g of a 0.0514 wt% solution of the surfactant was titrated with
a 0.0039 wt% NaOH solution (ꢂ1 mM) under a nitrogen atmo-
sphere to avoid carbonation. The inflection point would correspond
to the titration of the carboxylic acid proton of trifluoroacetate salt
11 (6.5 ꢁ 10ꢀ6 mol of NaOH added). Taking into account the differ-
ent molecular weights of the two products and the total mass of
the titrated mixture, the results are in good agreement with the
molar ratio for the two species inferred by the elemental analysis
(Fig. 1).
with zwitterionic surfactants of a similar hydrophobic chain
length. For instance, C14H25N+(CH3)2CH2COO- has a cmc value of
2.2 ꢁ 10ꢀ4 mol kgꢀ1 while C14H25N+(CH3)2CH2SO3ꢀ has a cmc value
of 3.2 ꢁ 10ꢀ4 mol kgꢀ1 19
.
Based on the hydrophobicity of the
hydrocarbon chain and the presence of the cyclobutane group be-
tween the amide and the terminal zwitterionic group, one would
have expected this product to have a lower cmc value; this could
be related to a significant hydration of the amide group.
This mixture also presents the other characteristic to be consid-
ered as a surfactant, that is, self-aggregation. This is shown by the
significant X-ray scattering observed in 19 mmol kgꢀ1 solutions,
well above the cmc as observed from the above results. The exper-
imental scattering pattern obtained at 25 °C is shown in Figure 3 as
a function of scattering vector modulus. There is an apparent in-
crease of intensity at small q and a bump at intermediate q. The fit-
ting of several models did not result in perfect fitting, partly
because of low signal to noise ratio due to the low concentration.
However, a reasonable fitting was obtained using oligolamellar
structures with a repetition distance of 3.7 nm and a few (2.5) cor-
related lamellae and using a core-shell ribbon model with a persis-
tence length longer than 100 nm and width of 40 nm. Both models
give a similar fitting quality, in part because at a local level both
correspond to flat lamellae. Both models result in similar hydro-
phobic thicknesses that would correspond to only 1.2 nm, implying
the strong interdigitation of the hydrophobic chains and an area
per molecule of 1.2 nm2. This value of area per molecule would
be reasonable for the polar head to comprise of not only the zwit-
erionic group, but also the amide group, which is in agreement
with the previous observation of low hydrophobicity introduced
by the cyclobutane group. Whether the observed break in the
surface tension plot corresponds to a monomer to a micelle or
The surface tension (c) of small volumes of the surfactant mix-
ture (10 + 11) was measured using a home-made pendant drop
tensiometer.16 Surface tension was followed as a function of time
until equilibrium was reached (no appreciable variation of
c),
which occurred within 5–6 h from sample preparation. Care was
taken to ensure a saturated humidity atmosphere to prevent evap-
oration; the temperature was maintained at 25.0 0.5 °C. The sur-
face tension of the mixture decreased progressively upon
increasing concentration (Fig. 2) until a break above which it al-
most leveled to a constant value (ꢂ35 mN mꢀ1). The break oc-
curred at a concentration of 2.4 ꢁ 10ꢀ4 mol kgꢀ1, as determined
from the intersection of the two fitting straight lines in the plot
of
c versus logC, which corresponds to the critical micellar concen-
tration (cmc) of the mixture. Concentrations were calculated while
taking into account the weighted average molar mass of the mix-
ture 0.35:0.65 of 10 + 11 (i.e., 526.83 g molꢀ1). This value of cmc
is in good agreement with the value obtained in the preliminary
foaming experiment, where the maximum foaming is usually ob-
served just above the value of cmc.17 This value of cmc,
2.4 ꢁ 10ꢀ4 mol kgꢀ1, is in the expected range of an ionic surfactant
bearing a C16-alkyl chain,18 but appears to be high if it is compared

716
J. Ospina et al. / Tetrahedron: Asymmetry 24 (2013) 713–718
10
1
0.1
0.1
1
q/ nm-1
Figure 3. SAXS intensity corresponding to 19 mmol kgꢀ1 of 10 + 11 mixture in water at 25 °C. The full line corresponds to the best fit result for oligolamellar structures and
the dashed line corresponds to a core-shell ribbon model. From q = 0.5 nmꢀ1 onward the experimental points have been adjacent averaged to reduce noise.
monomer to a vesicle transition cannot be decided with the pres-
ent data and is out of the scope of the present article.
43.9, 44.0, 63.3(CH2OH), 66.5, 80.9, 128.1, 128.4, 136.7, 156.5,
172.4; HRMS Calcd for C23H35NNaO5 (M+Na)+: 428.2407. Found:
428.2418.
3. Conclusion
4.2. (3S)-tert-Butyl-4-benzyloxycarbonylamino-3-((10R,30R)-30-
hexylaminomethyl-20,20-dimethyl-cyclobutyl)butanoate 3
Several new enantiopure cyclobutane derivatives containing a
c-amino acid function in a side-chain and additional C6 or C16-alkyl
chains have been synthesized from a chiral precursor prepared in
turn from (ꢀ)-verbenone. The introduction of alkyl substituents
has been achieved more efficiently by means of amide formation
instead of amine alkylation involving a SN2 process. This result is
explained by the severe steric hindrance imposed by the gem-di-
methyl group on the cyclobutane moiety. The basicity of the pri-
Alcohol 2 (88 mg, 0.22 mmol) was dissolved in anhydrous
CH2Cl2 (2 mL) and the resulting solution was cooled with an ice
bath. Next, triethylamine (45
lL, 0.32 mmol) and mesyl chloride
(22 L, 0.28 mmol) were subsequently added and the reaction
l
was stirred at 0 °C for 1 h. The resultant solution was extracted
with dichloromethane, and the combined extracts were dried over
MgSO4. Solvents were removed at reduced pressure to afford a
crude mesylate (100 mg, 95% yield), which was immediately used
in the next step without purification. To the solution of the mesy-
late (100 mg, 0.21 mmol) in anhydrous CH3CN (4 mL) under a
mary amine in the
c-amino acid function and that of the amide
led to the unexpected formation of a TFA salt obtained jointly with
the free amine in an approximate 2:1 ratio that presumably corre-
sponds to the equilibrium ratio. Studies on this mixture suggest
that it behaves as an efficient surfactant, with the critical micellar
concentration being 2.4 ꢁ 10ꢀ4 mol kgꢀ1. At moderate concentra-
tions, the presence of oligolamellar structures has been observed.
nitrogen atmosphere were added Et3N (40
lL, 0.32 mmol) and hex-
ylamine (60 L, 0.3 mmol). The mixture was stirred at reflux for
l
24 h. The solvent was evaporated under vacuum and diluted with
saturated aqueous NaHCO3 (5 mL). This was extracted with CH2Cl2
(3 ꢁ 5 mL) dried over MgSO4 and evaporated at reduced pressure.
The residue was chromatographed (ethyl acetate/hexane, 1:2 to
4. Experimental
4.1. (3S)-tert-Butyl-4-benzyloxycarbonylamino-3-((10R,30R)-30-
2:1) to afford pure
= ꢀ14.4 (c 1.2, CHCl3); IR (ATR): 2925, 2856, 1719, 1514,
1455, 1366,1245 cmꢀ1 1H NMR (250 MHz, CDCl3): d 0.89 (t,
3 as a yellow oil (58 mg, 57% yield).
½ ꢃ
a 2D2
hydroxymethyl-20,20-dimethylcyclobutyl) butanoate 2
;
J = 71 Hz 3H, CH3), 0.98 (s, 3H), 1.14 (s, 3H), 1.19–1.36 (ca., 10H,
–CH2–), 1.45 (s, 9H, Bu), 1.55–1.76 (m, 1H), 1.82–2.17 (ca., 3H),
To a solution of acid 1 (111 mg, 0.3 mmol) in anhydrous THF
(0.5 mL) was added a 1 M solution of BH3 in THF (0.5 mL, 0.4 mmol,
1.5 equiv). The mixture was heated at reflux under a nitrogen
atmosphere for 24 h. Excess hydride was eliminated by the slow
addition of methanol (1 mL) and water (3 mL). The resultant solu-
tion was extracted with dichloromethane and the combined ex-
tracts were dried over MgSO4. Solvents were removed at reduced
pressure, and the residue was chromatographed (ethyl acetate/
hexane 1:1) to provide alcohol 2 as a colourless oil (85.4 g, 80%
t
2.19–2.33 (m, 1H), 2.38–2.72 (ca., 4H), 2.90–3.07 (m, 1H), 3.16–
3.37 (m, 1H), 5.03–5.26 (ca., 3H, CH2Bn, NH), 7.31–7.43 (ca., 5H,
H
Ar); 13C NMR (90 MHz, CDCl3): 14.2, 16.5, 22.9, 27.4, 28.1, 28.5,
30.1, 31.7, 32.1, 37.5, 40.3, 42.2, 43.1, 44.9, 50.5, 50.7, 66.9, 81.2,
128.5, 128.9, 137.1, 156.9, 172.7; HRMS Calcd for C29H48N2O4
(M+Na)+: 489.3687. Found: 489.3683.
4.3. (3S)-tert-Butyl-4-benzyloxycarbonylamino-3-((10R,30R)-30-
yield). [
a
]
D = ꢀ18.6 (c 1.1, CHCl3); IR (ATR): 3339, 2952, 1789,
1520, 1455, 1367 cmꢀ1
;
1H NMR (250 MHz, CDCl3): d 1.02 (s, 3H,
hexadecylamino-methyl)-20,20-di-methylcyclobutyl)butanoate 4
t
CH3), 1.16 (s, 3H, CH3), 1.44 (s, 9H, Bu), 1.61–1.76 (m, 1H), 1.78–
1.90 (m, 1H), 1.96–2.09 (complex absorption, 4H), 2.19–2.30 (m,
1H), 2.90–3.05 (m, 1H), 3.18–3.31 (m, 1H), 3.49–3.65 (ca., 2H),
5.03–5.29 (ca., 3H, CH2Bn, NH), 7.30–7.41 (ca., 5H, HAr); 13C NMR
(90 MHz, CDCl3): d 16.0, 24.0, 25.37, 28.1, 31.7, 37.3, 39.8, 42.7,
To a solution of mesylate (65 mg, 0.13 mmol) (prepared as ex-
plained in Section 4.2) in anhydrous CH3CN (2 mL) under a nitrogen
atmosphere were added Et3N (30
lL, 0.22 mmol) and hexadecyl-
amine (47 mg, 0.19 mmol). The mixture was stirred at reflux for

J. Ospina et al. / Tetrahedron: Asymmetry 24 (2013) 713–718
717
24 h. The solvent was evaporated under vacuum and diluted with
saturated aqueous NaHCO3 (5 mL). This was extracted with CH2Cl2
(3 ꢁ 5 mL), dried over MgSO4 and evaporated at reduced pressure.
The residue was chromatographed (ethyl acetate/hexane, 1:4 to
2:1) to afford pure 4 as a colourless oil (25 mg, 30% yield). 1H
NMR (250 MHz, CDCl3): d 0.90 (t, J = 6.9 Hz 3H), 1.06 (s, 3H, CH3),
room temperature for 18 h. The solvent was evaporated and the
excess trifluoroacetic acid was removed by lyophilization to afford
acid 7 as a yellow oil (79 mg, quantitative yield). ½a D22
ꢃ
= +15.4 (c 1.3,
CHCl3); IR (ATR): 3322, 2928, 1703, 1638, 1536, 1455, 1371 cmꢀ1
;
1H NMR (250 MHz, CDCl3): d 0.90 (t, J = 6.4 Hz 3H, CH3), 0.99 (s, 3H,
CH3), 1.24 (s, 3H, CH3), 1.29–135 (ca., 6H, –CH2–), 1.38–1.56 (ca.,
2H), 1.59–1.93 (m, 2H), 1.97–2.13 (ca., 2H), 2.17–2.36 (m, 1H),
2.37–2.56 (m, 1H), 2.81–3.43 (ca., 4H), 5.00–5.57 (ca., 4H, CH2Bn,
NH), 7.28–7.54 (ca., 5H, HAr); 13C NMR (90 MHz, CDCl3): 14.4,
17.1, 22.9, 24.1, 26.9, 30.1, 31.6, 31.8, 35.9, 37.6, 39.8, 42.8, 44.0,
47.6, 67.3, 128.7, 128.9, 136.7, 157.4, 172.0, 177.3. HRMS Calcd
for C29H38N2NaO5 (M+Na)+: 469.2673. Found: 469.2674.
t
1.19–1.36 (ca., 27H, –CH2–, 3H, CH3), 1.36–1.54 (ca., 11H, Bu, –
CH2–), 1.88–2.11 (ca., 5H), 2.23–2.36 (ca., 1H), 2.48–2.69 (ca., 5H),
2.77–3.12 (c.a, 2H), 3.18–3.29 (ca., 1H), 4.89–5.38 (ca., 3H, CH2Bn,
NH), 7.31–7.43 (ca., 5H, HAr). LMRS (ESI+, m/z, %) Calcd for
C
38H66N2NaO5 (M+Na)+: 637.5. Found: 637.1.
4.4. (3S)-tert-Butyl-4-benzyloxycarbonylamino-3-((10R,30R)-30-
hexylcarbamoyl-20,20-dimethyl-cyclobutyl)butanoate 5
4.7. (3S)-4-Benzyloxycarbonylamino-3-((10R,30R)-30-hexadec-
ylcarbamoyl-20,20-di-methyl-cyclobutyl)butanoic acid 8
To a solution of acid 1 (370 mg, 0.88 mmol) in anhydrous
CH2Cl2, Et3N (0.15 mL, 1.06 mmol), oxalyl chloride (0.53 mL,
1.06 mmol) and 3 drops of DMF, were subsequently added. The
mixture was stirred at room temperature for 2 h. Next, hexylamine
(0.13 mL, 0.97 mmol) was added and the resultant solution was
stirred at room temperature for 8 h. The solvents were removed
under reduced pressure, the crude of the reaction was extracted
with dichloromethane (4 ꢁ 10 mL) and the organic extracts were
dried over magnesium sulfate. The residue was chromatographed
(ethyl acetate/hexane, 1:2 to 2:1) to afford pure 5 as a colourless
A mixture containing compound 6 (220 mg, 0.34 mmol), triflu-
oroacetic acid (0.34 mL, 4.41 mmol) and triethyl silane (0.14 mL,
0.88 mmol) in anhydrous dichloromethane (4 mL) was stirred at
room temperature for 18 h. The solvent was evaporated and the
excess trifluoroacetic acid was removed by lyophilization to afford
acid 8 as a colourless oil (200 mg, quantitative yield). ½a D22
ꢃ
= +14.2
(c 1.4, CHCl3); IR (ATR): 3320, 2918–2850, 1705, 1636, 1532, 1466,
1160 cmꢀ1; 1H NMR (250 MHz, CDCl3): d 0.90 (t, J = 7.1 Hz 3H, CH3),
0.95 (s, 3H, CH3), 1.25–1.40 (ca., 30H, –CH2–, 3H, CH3), 1.42–1.62
(m, 1H), 1.63–1.94 (m, 1H), 1.95–2.40 (ca., 3H), 2.44–2.67 (m,
1H), 2.84–3.40 (ca., 4H), 5.00–5.48 (ca., 3H, CH2Bn, NH), 5.63–
5.83 (broad, 1H, NH) 7.30–7.47 (ca., 5H, HAr);13C NMR (90 MHz,
CDCl3): 14.5, 17.1, 23.1, 27.3, 29.8, 30.1, 31.5, 32.3, 35.9, 37.7,
40.1, 42.4, 43.1, 47.5, 67.4, 128.5, 128.9, 136.7, 157.5, 172.4,
176.63. HRMS Calcd for C35H58N2NaO5 (M+Na)+: 609.4238. Found:
609.4249.
oil (123 mg, 73% yield). ½a D22
ꢃ
= +5.1 (c 0.9, CHCl3); IR (ATR): 3308,
2928, 1706, 1647, 1528, 1455, 1366 cmꢀ1
;
1H NMR (250 MHz,
CDCl3): d 0.90 (t, J = 7.0 Hz 3H, CH3), 1.01 (s, 3H, CH3), 1.27 (s,
t
3H, CH3), 1.31–1.38 (ca., –CH2–, 5H), 1.45 (s, 9H, Bu), 1.50–1.55
(m, 1H), 1.65–1.84 (m, 2H), 1.88–2.11 (ca., 4H), 2.16–2.31 (m,
1H), 2.38–2.55 (m, 1H), 2.98–3.14 (m, 1H), 3.18–3.38 (ca., 3H),
5.04–5.33 (ca., 3H, CH2Bn, NH), 7.32–7.42 (ca., 5H, HAr); 13C NMR
(90 MHz, CDCl3): d 14.2, 17.0, 22.9, 24.5, 26.8, 28.5, 30.1, 31.7,
31.8, 37.6, 39.7, 42.8, 44.2, 47.6, 53.8, 67.0, 81.2, 128.2, 128.9,
4.8. (3S)-4-Amino-3-((10R,30R)-30-hexylcarbamoyl-20,20-dimeth-
137.1, 156.9, 171.6, 172.5; HRMS Calcd for
C
29H46N2NaO5
ylcyclobutyl)butanoic acid, 9
(M+Na)+: 525.3299. Found: 525.3304.
Compound 7 (44.8 mg, 0.10 mmol) in methanol (5 mL) was
hydrogenated under 5 atmospheres of pressure in the presence
of 30% Pd(OH)2/C (13 mg, 2% Pd in weight) overnight. The reaction
mixture was filtered through Celite and the solvent was removed
under reduced pressure to provide 9 (24.4 mg, 78% yield) as a col-
4.5. (3S)-tert-Butyl-4-benzyloxycarbonylamino-3-((10R,30R)-30-
hexadecylcarbamoyl-20,20-di-methylcyclobutyl)butanoate 6
To a solution of acid 1 (310 mg, 0.74 mmol) in anhydrous
CH2Cl2 (15 mL), Et3N (0.15 mL, 1.08 mmol), oxalyl chloride
(0.44 mL, 0.88 mmol) and 3 drops of DMF, were subsequently
added. The mixture was stirred at room temperature for 2 h. Next,
hexadecylamine (230 mg, 0.95 mmol) was added and the resultant
solution was stirred at room temperature for 8 h. Solvents were re-
moved under reduced pressure, the crude reaction was extracted
with dichloromethane (4 ꢁ 10 mL) and the organic extracts were
dried over MgSO4. The residue was chromatographed (ethyl ace-
tate/hexane, 1:1) to afford pure 6 as a colourless oil (330 mg, 70%
ourless oil. ½a 2D2
ꢃ
= +5.3 (c 1, CH3OH); 1H NMR (250 MHz, CD3OD): d
0.93 (t, J = 6.8 Hz 3H, CH3), 1.00 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.33–
135 (ca., –CH2–, 6H), 1.43–1.61 (ca., 2H), 1.84–2.04 (ca., 3H), 2.11–
2.38 (m, 1H), 2.39–2.65 (m, 1H), 2.66–3.01 (ca., 2H), 3.03–3.27 (ca.,
2H), 3.29–3.34 (m, 1H); 13C NMR (90 MHz, CD3OD):13.4, 16.3, 18.4,
22.6, 22.81, 26.7, 29.5, 30.6, 31.7, 35.9, 39.3, 42.5, 44.2, 46.4, 50.5,
172.7. HRMS Calcd for C17H32N2NaO3 (M+Na)+: 335.2305. Found:
335.2310.
yield). ½a 2D2
ꢃ
= +1.2 (c 1.0, CHCl3); 1H NMR (250 MHz, CDCl3): d
4.9. (3S)-4-Amino-3-((10R,30R)-30-hexadecylcarbamoyl-20,20-di-
methylcyclobutyl) butanoic acid and (3S)-3-carboxy-2-((1R,
3R)-3-hexadecylcarbamoyl-20,20-dimethylcyclobutyl)propan-
1-aminium trifluoroacetate 10 and 11
0.89 (t, J = 7.0 Hz 3H, CH3), 1.00 (s, 3H, CH3), 1.13–1.37 (ca., 28H,
t
–CH2–, 3H, CH3), 1.44 (s, 9H, Bu), 1.68–2.08 (ca., 5H), 2.13–2.33
(m, 1H), 2.38–2.53 (m, 1H), 2.95–3.13 (m, 1H), 3.16–3.44 (ca.,
3H), 5.00–5.58 (ca., 4H, CH2Bn, NH), 7.30–7.41 (ca., 5H, HAr); 13C
NMR (90 MHz, CDCl3): 14.5, 17.0, 23.1, 27.3, 28.5, 29.7, 30.1,
30.2, 31.7, 32.3, 37.6, 39.7, 42.8, 44.6, 67.0, 81.3, 128.5, 128.9,
Compound 8 (200 mg, 0.34 mmol) in methanol (10 mL) was
hydrogenated under 5 atmospheres of pressure in the presence
of 30% Pd(OH)2/C (60 mg, 2% Pd in weight) overnight. The reaction
mixture was filtered through CeliteÒ and the solvent was removed
under reduced pressure to provide amine 10 (180 mg) as a white
solid and its corresponding salt 11. 1H NMR (250 MHz, CDCl3): d
0.90 (t, J = 7.1 Hz 3H, CH3), 0.97 (s, 3H, CH3), 1.06–1.41 (ca., 27H,
–CH2–, 3H, CH3), 1.59 (ca., 2H), 1.95–2.07 (ca., 3H), 2.21–2.66
(ca., 2H), 2.82–3.03 (ca., 2H), 3.10–3.32 (ca., 3H), 4.89–5.21 (broad,
2H, NH); 13C NMR (90 MHz, CD3OD): 13.3, 16.0, 17.72, 18.07, 22.4,
26.7, 29.1, 29.4, 29.5, 30.1, 31.5, 31.8, 39.1, 42.2, 43.1, 45.9, 50.1,
137.1, 156.9, 171.6, 172.4. HRMS Calcd for
C39H66N2NaO5
(M+Na)+: 665.4864. Found: 665.4851.
4.6. (3S)-4-Benzyloxycarbonylamino-3-((10R,30R)-30-hexylcarb-
amoyl-20,20-dimethyl-cyclobutyl)-butanoic acid 7
A mixture containing compound 5 (66.2 mg, 0.13 mmol), triflu-
oroacetic acid (0.13 mL, 1.69 mmol) and triethyl silane (50
lL,
0.31 mmol) in anhydrous dichloromethane (2 mL) was stirred at

718
J. Ospina et al. / Tetrahedron: Asymmetry 24 (2013) 713–718
172.1. 13C NMR (90 MHz, DMSO): 14.4, 17.1, 22.5, 22.9, 26.8, 28.2,
29.2, 29.5, 29.7, 31.2, 31.7, 34.4, 37.9, 38.8, 42.0, 43.0, 46.1, 100.0,
170.4, 173.8. HRMS Calcd for 10: C27H51N2O3 (Mꢀ1)ꢀ: 451.3905.
References
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Found: 451.3900;
C
27H53N2O3 (M+1)+: 453.4051; Found:
453.4060. HRMS Calcd for 11: C29H52F3N2O5 (Mꢀ1)ꢀ: 565.3907.
Found: 565.3839; C27H51N2O3 (MꢀC2F3O2ꢀ2)ꢀ: 451.3905. Found:
451.3900. C27H53N2O3 (MꢀC2F3O2)+: 453.4051; Found: 453.4060.
Anal. calcd for 0.35:0.65 (10 + 11) mixture: C, 64.52; N, 10.07%;
H, 5.32%. Found: C, 64.47; N, 10.58%; H, 5.01%.
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a
detector focussed X-ray beam with
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k = 0.1542 nm Cu K
a-line with more than 97% purity and less than
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4
k
p
h
q ¼
ꢄ sin
2
where, h is the scattering angle. The q values with our setup ranged
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use of a detector focused a small beam (300 ꢁ 400
lm full width
at half maximum), the scattering curves are mainly smeared by
the detector width. This mainly produces a widening of the peaks
without a noticeable effect on the peak position. The scattering
curves for liquid samples have been background subtracted and
put in absolute scale by comparison with
a water sample
scattering.20,21
The instrumentally smeared experimental SAXS curves were fit-
ted to numerically smeared models for beam size and detector
width effects. A least square routine based on the Levenberg–Mar-
quardt scheme was used. A model of core-shell ribbons (high as-
pect ratio ellipsoidal section cylinders22) and a model of bilayers
based on the Modified Caillé Gaussian scheme were used.23,24
Acknowledgments
Imma Carrera is acknowledged for help in the measurement of
surface tensions. Jaume Caelles from the SAXS-WAXS service at
IQAC is acknowledged for the SAXS measurements. The authors
thank financial support from Spanish Ministerio de Ciencia e Inno-
vación (Grant CTQ2010-15408/BQU and CTQ2010-14897) and
Generalitat de Catalunya (Grant 2009SGR-733 and 2009SGR-
1331).
23. Pabst, G.; Rappolt, M.; Amenitsch, H.; Laggner, P. Phys. Rev. E 2000, 62, 4000.
24. Rodriguez, G.; Cocera, M.; Rubio, L.; Alonso, C.; Pons, R.; Sandt, C.; Dumas, P.;
Lopez-Iglesias, C.; de la Maza, A.; Lopez, O. Phys. Chem. Chem. Phys. 2012, 14,
14523.