Design and synthesis of lipids for the fabrication of functional lipidic cubic-phase biomaterials

Article abstract of DOI:10.1021/jo301659c

A series of novel lipids with designed functionalities were synthesized. These lipids are based on conjugation of α-amino acids and their esters, cationic, anionic, neutral, and photochromic moieties to the lipophilic 9-cis octadecenyl chains by amide, ester, thioester, or amine bonds. Because of the plasticity of lipidic cubic phases, it is envisaged that when mixed with monooleoyl-rac-glycerol (monoolein, MO) and water at appropriate proportions, they would assemble to form bicontinuous lipidic cubic phases (LCPs) that exhibit the well-known material properties of LCPs such as phase stability, optical transparency, and chemical permeability. Moreover, due to the nature and position of the functionality at the headgroup region, we envision them to perform as functional materials by design.

Full text of DOI:10.1021/jo301659c

Article
pubs.acs.org/joc
Design and Synthesis of Lipids for the Fabrication of Functional
Lipidic Cubic-Phase Biomaterials
Yazmin M. Osornio, Peter Uebelhart, Silvan Bosshard, Fabian Konrad, Jay S. Siegel,*
and Ehud M. Landau*
Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
S
* Supporting Information
ABSTRACT: A series of novel lipids with designed functionalities
were synthesized. These lipids are based on conjugation of α-
amino acids and their esters, cationic, anionic, neutral, and
photochromic moieties to the lipophilic 9-cis octadecenyl chains by
amide, ester, thioester, or amine bonds. Because of the plasticity of
lipidic cubic phases, it is envisaged that when mixed with
monooleoyl-rac-glycerol (monoolein, MO) and water at appro-
priate proportions, they would assemble to form bicontinuous
lipidic cubic phases (LCPs) that exhibit the well-known material
properties of LCPs such as phase stability, optical transparency,
and chemical permeability. Moreover, due to the nature and
position of the functionality at the headgroup region, we envision
them to perform as functional materials by design.
INTRODUCTION
■
Lipidic cubic phases exhibit a unique combination of material
properties: They are stable, structured, and transparent
hydrogels with a flexible, curved lipid bilayer that spans the
3D space and can coexist stably with any amount of excess
water.1−4 LCPs utilized to date are almost exclusively restricted
to the monoacylglycerol/water binary system at room temper-
ature, with 1-monoolein (1) (1-(cis-9-octadecenoyl)-rac-glycer-
ol, MO) being the most widely used lipid.5 Crystallization of
membrane proteins in LCPs6 has contributed greatly to
Figure 1. Upper panel: structure of monoolein (MO) and of the
membrane biology, culminating with the recent high-resolution
X-ray structures of several G-protein-coupled receptors.7−9
With the notion that the material properties of host−guest
LCPs can be controlled and tuned by molecular design of the
constituent lipids, we have initiated a synthetic approach to
map possible lipid modifications as additives to MO LCPs.
Lipid molecules are composed of three regions: The hydro-
phobic tail, the hydrophilic headgroup, and the linkage region.
In this investigation, all target lipids retain the 9-cis-octadecenyl
hydrophobic tail, while the nature, size, and charge of the
hydrophilic group, as well as the identity of the linkage, have
been systematically modified (Figure 1). Modifications in the
headgroup region include various α-amino acids and their
esters, anionic, cationic, and neutral moieties, as well as
photochromic units such as azobenzene10,11 and o-nitrobenzyl
groups.12 The latter are of special interest because of the optical
transparency of the host LCPs, which can therefore be
envisioned as light-responsive biomaterials that undergo
chemical or structural changes upon photoactivation. More-
over, such materials may provide biocompatible surfaces with
photocleavable or photoswitchable groups.
Pn3m lipidic cubic phase that forms at maximum hydration of MO.
Lower panel: summary of the modifications of the target lipids
(additives).
Previously reported syntheses of similar lipidic compounds
were mostly motivated by their biological activity. Examples
include the synthesis of saturated and unsaturated fatty acid L-
serines, which form gels in water and in organic solvent, and
whose low cytotoxicity was established;13 preparation of a large
synthetic library of endogenous fatty acid amides and their
analogues, in order to assess their inhibitory effects on pro-
inflammatory mediators;14 investigation of the metabolic and
biosynthetic pathways of fatty acyl glycines;15 synthesis of a
series of conjugates of a fatty acids and redox-active amino
acids, which were used to coat colloidal noble-metal nano-
particles;16 synthesis and formation of organogels of fatty N-
acylamino acids and N-acylamino esters;17 and the application
Received: August 20, 2012
© XXXX American Chemical Society
A
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of novel fatty acid amides as anticancer drugs by inducing
apoptosis in tumor cells.18
Table 1. Preparation of α-Amino Acids and Their Esters
Linked to Oleoyl Chain
This paper presents the synthetic pathways of the various
lipidic analogues that are of potential use in functional
biomaterials. Their incorporation into MO-host LCPs, and
the material properties of the resulting biomaterials will be
presented in a following paper.
d
d
yield (%) yield (%)
a
,
b
c
entry
precursor 3
product 4 or 5
of 5
of 4
1
2
3
4
H-Gly-OH, 3a
H-L-Ala-OH, 3b
H-L-Val-OH, 3c
H-L-Phe-OH, 3d
oleoyl-Gly-OH, 4a
oleoyl-L-Ala-OH, 4b
oleoyl-L-Val-OH, 4c
87
76
e
e
45 (19)
40 (25)
oleoyl-L-Phe-OH,
RESULTS AND DISCUSSION
4d
■
I. Synthesis of α-Amino Acids Linked to the Oleoyl
Chain. Initial work focused on the syntheses of lipid derivatives
of the commercially available oleoyl chloride 2 covalently linked
to α-amino acids 3a−d and their esters 3e−m (Scheme 1). The
5
H-L-Phe-OMe, 3e
oleoyl-L-Phe-OH,
91
71
4d
6
7
H-L-Trp-OEt, 3f
H-L-Tyr-OMe, 3g
oleoyl-L-Trp-OH, 4f
92
88
78
93
oleoyl-L-Tyr-OH,
4g
8
9
H-L-Ser-OMe, 3h
oleoyl-L-Ser-OH, 4h
82
90
81
91
Scheme 1. Synthesis of N-Oleoyl-α-amino Acids 4a−m
Tagged to Oleoyl Chloride
H-L-Cys(Bzl)-OEt, oleoyl-L-Cys(Bzl)-
3i
OH, 4i
10
11
12
13
H-L-Glu(OMe)-
oleoyl-L-Glu(OH)-
87
46
73
85
OMe, 3j
OH, 4j
H-L-His-OMe, 3k
oleoyl-L-His-OMe,
5k
(H-L-Cys(OMe))2, (oleoyl-L-
3l
Cys(OMe))2, 5l
f
f
H-Sar-OMe, 3m
oleoyl-Sar-OH, 4m
88
98
a
General conditions for procedure A: amino acid 3a−d (1.0−1.5
equiv), oleoyl chloride (1.0 equiv), 2N NaOH (2.0 mL/mmol), THF
(1.5 mL/mmol), 0 °C to rt, 12 h. General conditions for procedure
b
C: N-oleoyl-α-amino acid 5e−m (1 equiv), LiOH (3 equiv), EtOH/
c
H2O, 0 °C to rt, 12h. General conditions for intermediates 5e−m
(Procedure B): amino acid ester hydrochloride 3e−3m (1.0 equiv),
DIPEA, oleoyl chloride (1.0−1.4 equiv), CH2Cl2 or CH2Cl2/MeOH
d
e
(5 mL/mmol), 0 °C to rt, 2−5 h. Isolated yield. Yield based on a 6−
lipidic derivatives of general structure 4 vary in their amino acid
residue (hydrophobic, anionic or cationic), thereby modifying
fundamental properties such as size, charge, binding, and
diffusivity of the resulting LCPs. The initial approach to prepare
N-oleoyl-α-amino acids 4 was direct acylation between
commercially available L-amino acids and oleoyl chloride 2
(procedure A), using a THF/water mixture under basic
conditions (Scheme 1, Table 1).19 As test substrate, H-Gly-
OH 3a (1.5 equiv, 2.6 mmol scale) was coupled to oleoyl
chloride (1.0 equiv) in a mixture of THF/water (1:2) using
NaOH as a base, followed by neutralization with 1 M HCl to
afford N-oleoyl-Gly-OH 4a in excellent yield (87%, Table 1,
entry 1). On the basis of this result, N-oleoyl-L-Ala-OH 4b
(entry 2), N-oleoyl-L-Val-OH 4c (entry 3), and N-oleoyl-L-Phe-
OH 4d (entry 4) were prepared analogously, resulting in
moderate to good yields. However, when the reaction was
carried out on a 6−8 mmol scale, the reaction yields were
typically less than 30% (entry 3 and 4), possibly due to the
difficulty in handling those compounds during the isolation
process and/or due to the physical state of the final products
being foamy or waxy.
In order to improve the yields, a two-step synthesis was
devised for the preparation N-oleoyl-α-amino acids containing
aromatic, polar, anionic, and cationic side chains (Scheme 1,
procedures B and C). Aromatic amino acids tagged to oleoyl
chloride 2, such as N-oleoyl-L-Phe-OH 4d (Table 1, entry 5),
N-oleoyl-L-Trp-OH 4f (entry 6) and N-oleoyl-L-Tyr 4g (entry
7) were obtained by direct coupling of the corresponding L-
amino acid methyl or ethyl ester hydrochloride 3e, 3f, and 3g,
respectively, with oleoyl chloride 2 using DIPEA as a base in
CH2Cl2, followed by hydrolysis of the ester under basic
conditions (LiOH in a mixture of EtOH/H2O). The acylation
reaction (procedure B), and the hydrolysis reaction (procedure
C) of all these compounds proceeded smoothly, with good to
f
8 mmol scale reaction in parentheses. Rotamers.
excellent yields (71−93%). As shown in Table 1, amino acids
with markedly different steric and electronic properties,
including those with polar (serine 3h and cysteine 3i, entries
8 and 9), anionic (glutamic acid 3j, entry 10), and cationic side
chains (histidine 3k, entry 11), as well as dimeric amino acid
(cystine 3l, entry 12) were acylated in good yields, except for
N-oleoyl-L-His-OMe 5k. In the latter case, in which the
imidazole moiety is not protected, the monoacylated product is
formed in 46% yield along with traces of the bis-acylated
product. The hydrolysis reaction of intermediates 5e−m
proceeded smoothly to afford compounds 4d−m in high yield.
Finally, the oleoyl moiety was also linked to sarcosine (H-
Sar-OMe) 3m (entry 13) to afford compound 5m and 4m in
excellent yield. 1H NMR spectra of these products show clearly
a cis−trans population ratio of 4:1, caused by restricted rotation
about the amide bond.20−22 The correct assignment was
established by NOESY experiment.
II. Synthesis of Oleoyl Derivatives Containing Amide,
Thioester, and Ester Bonds to the Headgroup. With the
aim of modifying the mode of binding between the hydro-
phobic chain and the headgroup, the ester bond of monoolein 1
was replaced with an amide or thioester bond. Initially, N and S
heteroatoms were introduced into the 1-, 3-, or 1,3-position of
the glycerol moiety. In this way, molecules 7, 9, 11 (Scheme 2),
and 13, 14, 15 (Scheme 3) were targeted. Compound 7 was
synthesized from 3-amino-1,2-propanediol 6 in 89% yield using
standard acylation conditions (procedure B).
The rac-3-S-oleoyl-thioglycerol 9 was obtained with some
modifications to a method previously described in the
literature.23,24 Racemic 1,2-O-isopropylidene-3-thio-sn-glycerol
825 was treated with oleoyl chloride in the presence of dry
B
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azide, amine, guanidine, amine having hydroxyethyl, cyanoethyl,
proline, or iminodiacetic groups, were synthesized according to
Schemes 4 and 5.
Scheme 2. Introduction of Heteroatoms into the 3- and 1,3-
Positions of the Glycerol Headgroup
Scheme 4. Synthesis of Cationic Lipids 17, 18, 20, and 21
Scheme 5. Synthesis of the Amide Derivatives 23a−e
Table 2. Preparation of the Amide Derivatives 23a−e
Scheme 3. Introduction of Heteroatoms into the 1-Position
of the Glycerol Headgroup
pyridine in a mixture of hexane/diethyl ether to produce in situ
the rac-1,2-O-isopropylidene-3-S-oleoylthioglycerol, which was
subjected to cleavage conditions using boric acid in 2-
methoxymethanol to afford compound 9. Spectroscopic data
for this compound were identical to those reported, with no
rearrangement of S- to O-acylated compounds observed.23
Preparation of N-(3-amino-2-hydroxypropyl)oleamide 11 was
synthesized in two steps starting from N-monoprotected
diamine 10.26 Upon treatment with oleoyl chloride, the N-
monoprotected diamine 10 underwent smooth acylation.
Removal of the Boc protecting group with 4N HCl in
EtOAc, followed by basification to pH 8 furnished compound
11 in 60% yield (over two steps).
Next, desired compounds 14 and 15 were synthesized from
monoolein 1 as shown in Scheme 3. The primary alcohol of
diol 1 was selectively monoprotected as tosylate by reaction
with 1.2 equiv of p-TsCl in pyridine to afford compound 12 in
78% yield, which was easily separated from the starting material
and the disubstituted side product using silica gel column
chromatography. The resulting monotosylate 12 was converted
into its azide derivative 13 in 73% yield by nucleophilic
displacement with sodium azide in dry DMF, which, in turn,
was reduced into the amine 14 upon refluxing with
triphenylphosphine in a mixture of THF/water. Under these
conditions no isomerization or degradation of the oleoyl moiety
were observed. Nucleophilic displacement of the tosyl group
with the potassium salt of thioacetic acid in dry acetone
proceeded with high conversion (one spot on the TLC plate),
but isolation of thioacetate 15 was not quantitative. Purification
by column chromatography afforded 15 in 26% yield. Low yield
is attributed to the lability of the primary thioacetate group.
In order to expand the library of lipids containing oleoyl
chain covalently bound to various cationic or anionic moieties
in the headgroup region, a series of compounds, which include
a
General conditions for procedures A and B: as described in Table 1.
Isolated yield.
b
The guanidinylated lipid derivative 21 (Scheme 4) was
prepared from the primary azide 17,27 (readily available from 2-
azidoethylamine 16 and oleoyl chloride 2), which was reduced
to the amine derivative 18 under neutral conditions with PPh3
in THF/water in 85% yield. Subsequently, the guanidinylation
reaction of oleamide 18 was performed under mild conditions
using N,N′-di-Boc-N″-triflylguanidine 1928,29 (1.0 equiv) and
Et3N (1 equiv) in CH2Cl2 (0.1 M) to afford the corresponding
N,N′-di-Boc-protected intermediate 20 in high yield (95%).
Removal of the Boc groups using trifluoroacetic acid followed
by ion exchange with the Amberlite IRA-400 (OH) resin,
resulting in the desired guanidine compound 21 in good yield.
Next, various amines having hydroxyethyl groups 22a, 22b,
3,3-iminodipropionitrile 22c, and iminodiacetic acid 22d
moieties were linked to the oleoyl group in good yields
C
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(Scheme 5, Table 2, entries 1−4) using standard acylation
conditions as described above (either procedure A or B). The
free primary amine at C4 of the pyrrolidine ring in 22e30 allows
diverse array of functionalization, such as the tagging of the
oleoyl moiety to N-Boc-cis-4-amine-L-proline amino acid 23e in
82% yield (entry 5).
III. Synthesis of Lipids Containing an Azobenzene
Moiety. In order to incorporate photochromic units into the
LCPs, lipids bearing azobenzene photoactive units in two
positions were designed, either by linking the azobenzene in the
headgroup region (compounds 25, 26, Scheme 6), or by its
incorporation into the alkyl tail (compounds 31−33, Scheme
7).
the common intermediate alkene 27 with the required (Z)-
stereochemistry. Methyl (9Z)-12-(tetrahydro-2′H-pyran-2′-
yloxy)-1-dodec-9-enoate 27 was synthesized in two steps
starting from the commercially available methyl oleate via
ozonolysis31 and Wittig olefination32 as previously described. A
tetrahydropyranyl (THP) group was converted in one-pot into
its corresponding bromide 28 by treatment with PPh3/CBr4,33
which was subsequently alkylated according to similar
procedure34 with 4-phenylazophenol using K2CO3 as a base
in dry acetone to afford compound 29 in 76% yield. Hydrolysis
of the ester group with KOH in MeOH produced acid 30,
which was then coupled with sarcosine methyl ester hydro-
chloride in the presence of DCC and DMAP to yield 31
(procedure D). Methyl ester 31 was converted to correspond-
ing acid 32 by alkaline hydrolysis. The sn-glycerol derivative 33
was obtained by standard DCC-coupling of 30 with solketal
followed by deprotection of acetonide group using boric acid in
2-methoxyethanol.23
Scheme 6. Synthesis of the Azobenzene Derivatives 25 and
26
IV. Synthesis of Lipids Containing an o-Nitrobenzyl
Moiety. In order to control the headgroup charge and identity
by photochemical means, a series of lipids containing o-
nitrobenzyl moieties were synthesized. 4,5-dimethoxy-2-nitro-
benzyl alcohol (NVOC) 34 is commercially available. The 5-
amino-2-nitrobenzyl alcohol 35 was obtained by reduction of
the commercially available 5-amino-2-nitrobenzoic acid with
borane in THF according to a literature procedure,12,35 while
the o-nitrobenzyl alcohol building block 38 was conveniently
obtained from 4-nitro-3-bromomethylbenzoic acid 36 in two
steps (Scheme 8). Hydrolysis of the bromide 3636,37 using
a
Scheme 7. Synthesis of the Azobenzene Derivatives 31−33
Scheme 8. Syntheses of the o-Nitrobenzyl Derivatives 35, 38,
and 39
Na2CO3 in a mixture of water/acetone, followed by
esterification of the free acid with 1 equiv of boron trifluoride
diethyl etherate (BFEE)38 provided compound 38 in 50% yield
(over two steps). An excess of BFEE (3 equiv) resulted in a
significant increase of the yield of 38 to 83%. The photo-
cleavable linker 39 was prepared along similar lines from 3-
nitro-4-bromomethylbenzoic acid 37 (79% over two steps).
2-Nitrobenzyl alcohol 34 was acylated with oleoyl chloride 2
using general procedure B (DIPEA in CH2Cl2) to furnish the
ester 40 in 86% yield (Scheme 9). The synthesis of compound
41 relied on the condensation between N-oleoyl-sarcosine 4m
and the photocleavable linker 34 in a classical DCC-mediated
esterification (procedure D). Compounds 42 and 43 were
prepared in a similar way to compound 41 by coupling oleic
acid or 2,2′-(oleoylimino)diacetic acid 23d to compound 35,
respectively.
a
Reagents and conditions: (i) PPh3, CBr4, CH2Cl2, rt, 20 h, 76%; (ii)
4-phenylazophenol 24, K2CO3, acetone, reflux, 16 h, 76%; (iii) KOH,
MeOH, 40 °C, rt, 87%; (iv) LiOH, EtOH/H2O, 0 °C to rt, 12 h, 92%.
Compound 25 was obtained by direct displacement of
chloride 2 with 4-phenylazophenol 24 in presence of DIPEA in
a mixture of CH2Cl2/MeOH. Compound 26, which has an
additional glycine spacer (linked by an amide bond to the
oleoyl chain and by an ester bond to the azobenzene), was
synthesized in one step starting from compound 4a via amide
condensation using DCC and DMAP in CH2Cl2 (procedure
D).
Target molecules 32 and 33 are based on a C12-alkyl chain
attached at the C1-position to a sarcosine or glycerol residue,
respectively, exhibiting one cis double bond at the C9-position,
and an azobenzene moiety at the C12-position. The syntheses
of compounds 32 and 33 commenced with the preparation of
The o-nitrobenzyl protecting groups 38 and 39 were linked
to the lipidic chain through a carbamate bond, according to
D
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and charge of the hydrophilic group, as well as the identity of
the linkage have been systematically modified. Modifications in
the headgroup region include various α-amino acids and their
esters, anionic, cationic, and neutral moieties, as well as
photochromic units such as and o-nitrobenzyl groups. Linkages
include amide, ester, thioester, or amine bonds. Such designed
lipids, when incorporated as additives to MO-water LCPs,
modify the LCP’s physical and chemical properties. Having
access to this broad array of derivatives opens the door to
controlled structure−activity studies of LCPs as well as to
formation of novel biomaterials with designed functionalities.
Scheme 9. Syntheses of the Lipidic o-Nitrobenzyl Derivatives
40−43
EXPERIMENTAL SECTION
■
General Remarks. Melting points are uncorrected. IR spectra were
recorded on an FT-IR spectrophotometer as films, KBr pills, or via an
ATR sample unit. Nuclear magnetic resonance (NMR) spectra were
recorded under conditions as indicated. Chemical shifts are given in
ppm. Coupling constants J are expressed in Hz. Column
chromatography was performed on silica gel 60 (0.04−0.063 mm,
230−440 mesh or 0.063−0.200 mm, 70−230 mesh). Unless otherwise
stated, starting materials were obtained from commercial suppliers and
used without further purification.
Scheme 10. The carbamate 45 was prepared analogous to
literature procedure39 by the successive mixing of alcohol 38
a
Scheme 10. Syntheses of the Carbamates 45, 46 and 48
General Procedure for the Preparation of Amides 4a−c,
23d,e (Procedure A). A solution of oleoyl chloride (1.0 equiv) in
THF (1.5 mL/mmol) was added dropwise over a period of 15 min to
a stirred solution of the α-amino acid or amine derivative (1.0−1.5
equiv) in 2 N aqueous NaOH (2.0 mL/mmol) at 0 °C under argon.
The resulting mixture was stirred for 30 min at 0 °C and then warmed
to room temperature and stirred until the reaction was judged
complete by TLC analysis. The reaction mixture was diluted with H2O
(10 mL), cooled to 0 °C, and acidified to pH 2 using aqueous HCl (3
N). Subsequently, the mixture was diluted with 100 mL of H2O and
extracted with EtOAc (3 × 30 mL). The combined organic layers were
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by recrystallization or
column chromatography.
N-Oleoylglycine (4a). Prepared according to general procedure A
from glycine (200 mg, 2.66 mmol) and oleoyl chloride (585 μL, 1.77
mmol). Recrystallization of the crude product in EtOH afforded the
title compound (522 mg, 87%) as colorless crystals: mp 92−93 °C; Rf
0.36 (EtOAc/CH2Cl2/MeOH 80:15:5 with 1% AcOH); IR (ATR) ν
(cm−1) 3305, 3001, 2917, 2849, 1698, 1643, 1550, 1407, 1226, 1027,
759, 672; 1H NMR (400 MHz, CDCl3) δ 9.25 (br s, 1H), 6.25 (t, J =
5.2 Hz, 1H), 5.30−5.38 (m, 2H), 4.07 (d, J = 5.2 Hz, 2H), 2.27 (t, J =
7.6 Hz, 2H), 1.98−2.03 (m, 4H), 1.60−1.67 (m, 2H), 1.26−1.34 (m,
20H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.8,
173.0, 130.2, 129.9, 41.7, 36.5, 32.1, 30.0, 29.9, 29.7, 29.54, 29.53,
29.43, 29.39, 29.3, 27.44, 27.39, 25.8, 22.9, 14.3; HRMS (ESI, [M +
H]+) calcd for C20H38N1O3 340.2846, found 340.2847.
a
Reagents and conditions: (i) NaN3, TBAB, CH2Cl2/H2O, 0 °C, 2.5
h; (ii) TFA, CH2Cl2, reflux, 5h, 86% (two steps); (iii) 2 N NaOH,
EtOH, rt, 40 h, 88%; (iv) 39, CDI, CH2Cl2, 0 °C to rt, 12 h, 64%.
with CDI and amine 44. The latter was prepared by
nucleophilic substitution of the oleoyl chloride 2 with sodium
azide, followed by in situ formation of the trifluoroacetamide
(using a modification of the Curtius reaction)40 and subsequent
cleavage with NaOH. Compound 45 was subjected to basic
hydrolysis to produce the corresponding acid 46 in 54% yield.
Following a procedure similar to that described for the
preparation of 45, target molecule 48 was obtained in 64%
yield starting from oleic acid bis(2-aminoethyl)amide 47 and o-
nitrobenzyl alcohol 39. Compound 47 was synthesized in three
steps starting from diethylenetriamine according to known
procedures.41,42
N-Oleoyl-L-alanine (4b). Prepared according to general procedure
A from L-alanine (200 mg, 2.22 mmol) and oleoyl chloride (496 μL,
1.50 mmol). Purification by column chromatography (CH2Cl2/MeOH
95:5 with 0.5% AcOH) afforded the title compound (403 mg, 76%) as
a white solid: mp 58−60 °C; Rf 0.5 (EtOAc/CH2Cl2/MeOH 80:15:5
with 1% AcOH); IR (ATR) ν (cm−1) 3334, 2926, 2856, 1718, 1649,
1
1541, 1456, 1210, 1161; H NMR (400 MHz, CDCl3) δ 6.01 (d, J =
6.8 Hz, 1H), 5.29−5.38 (m, 2H), 4.58 (appears as quin, J = 7.2 Hz,
1H), 2.23 (t, J = 7.6 Hz, 2H), 1.98−2.03 (m, 4H), 1.59−1.67 (m, 2H),
1.46 (d, J = 7.2 Hz, 3H), 1.26−1.30 (m, 20H), 0.88 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 176.2, 174.2, 130.2, 129.9, 48.5,
36.6, 32.1, 30.0, 29.9, 29.7, 29.54, 29.53, 29.43, 29.38, 29.3, 27.44,
27.39, 25.8, 22.9, 18.2, 14.3; HRMS (ESI, [M − H]+) calcd for
C21H38N1O3 352.2857, found 352.2860.
N-Oleoyl-L-valine (4c). Prepared according general procedure A
from L-valine (300 mg, 2.56 mmol) and oleoyl chloride (562 μL, 1.70
mmol). Purification by column chromatography (Et2O/MeOH/
AcOH 96:3:1) afforded the title compound (292 mg, 45%) as a
white waxy solid: mp 71.2−73.9 °C; Rf 0.38 (EtOAc/MeOH/AcOH
CONCLUSIONS
■
In order to expand the scope of lipidic cubic phase biomaterials,
an array of novel lipids with designed functionalities were
synthesized. These are based on the structure of MO, which is
the most widely used lipid that forms LCPs. The target lipids’
hydrophobic tail, responsible for scaffolding of the resulting
LCPs, was retained as MO’s 9-cis octadecenyl. The nature, size,
E
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94:5:1); IR (ATR) ν (cm−1) 3325, 2924, 2854, 1719, 1632, 1540,
1463, 1210, 968, 725; 1H NMR (400 MHz, CDCl3) δ 7.40 (br s, 1H),
6.01 (d, J = 8.8 Hz, 1H), 5.29−5.38 (m, 2H), 4.59 (dd, J = 8.8 Hz, 4.8
Hz, 1H), 2.19−2.32 (m, 3H), 1.98−2.02 (m, 4H), 1.60−1.67 (m, 2H),
1.26−1.30 (m, 20H), 0.98 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz,
3H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.8,
174.1, 130.2, 129.9, 57.2, 36.9, 32.1, 31.2, 30.0, 29.9, 29.7, 29.54, 29.53,
29.44, 29.42, 29.3, 27.44, 27.39, 25.9, 22.9, 19.2, 17.9, 14.3; HRMS
(ESI, [M − H]+) calcd for C23H42N1O3 380.3170, found 380.3169.
3-(Oleamido)diacetic Acid (23d). Prepared according the general
procedure A from iminodiacetic acid 22d (316 mg, 2.37 mmol) and
oleoyl chloride (529 μL, 1.60 mmol). Purification by column
chromatography (Et2O/MeOH 80:20 with 1% AcOH) afforded the
title compound (317 mg, 50%) as colorless foam: Rf 0.41 (Et2O/
MeOH 60:40 with 1% AcOH); IR (neat, cm−1) 3005, 2935, 2854,
1732, 1616, 1466, 1407, 1193, 970, 722; 1H NMR (300 MHz, CDCl3)
δ 9.68 (br s, 2H), 5.32−5.36 (m, 2H), 4.20 (br s, 4H), 2.33 (t, J = 7.5
Hz, 2H), 1.98−2.02 (m, 4H), 1.60−1.62 (m, 2H), 1.27−1.30 (m,
20H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.5,
173.6, 172.2, 130.0, 129.7, 50.9, 49.3, 32.8, 31.9, 29.78, 29.75, 29.6,
29.3 (2C), 29.2, 27.2, 24.8, 22.7, 14.1; HRMS (ESI, [M − H]+) calcd
for C22H38NO5 396.2755, found 396.2752.
1.48 mmol), oleoyl chloride (638 μL, 1.93 mmol), DIPEA (650 μL,
3.72 mmol) in CH2Cl2/MeOH. Purification by column chromatog-
raphy (EtOAc/hexane 20:80) afforded the title compound (680 mg,
92%) as a pale yellow oil: Rf 0.54 (EtOAc/hexane 40:60); IR (neat,
cm−1) 3299, 2926, 2854, 1737, 1652, 1530, 1459, 1377, 1203, 1097,
741; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.54 (d, J = 8.0 Hz,
1H), 7.35 (d, J = 8.0 Hz, 1H), 7.18 (td, J = 7.2 Hz, 1.2 Hz, 1H), 7.11
(td, J = 7.2 Hz, 1.2 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 5.96 (d, J = 7.6
Hz, 1H), 5.30−5.39 (m, 2H), 4.95 (ddd appears as dt, J = 7.6 Hz, 5.4
Hz, 1H), 4.07−4.20 (m, 2H), 3.34 (dd, J = 14.8 Hz, 5.4 Hz, 1H), 3.29
(dd J = 14.8 Hz, 5.0 Hz, 1H), 2.13 (t, J = 7.6 Hz, 2H), 1.97−2.03 (m,
4H), 1.53−1.60 (m, 2H), 1.25−1.30 (m, 20H), 1.22 (t, J = 7.2 Hz,
3H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.0,
172.3, 136.3, 130.2, 130.0, 128.0, 122.9, 122.4, 119.8, 118.9, 111.4,
110.5, 61.6, 53.1, 36.8, 32.1, 30.0, 29.9, 29.7, 29.53, 29.52, 29.44, 29.41,
29.3, 27.9, 27.44, 27.40, 25.7, 22.9, 14.31, 14.29; HRMS (ESI, [M +
H]+) calcd for C31H49N2O3 497.3738, found 497.3739.
N-Oleoyl-L-tyrosine Methyl Ester (5g). Prepared according general
procedure B from L-tyrosine methyl ester hydrochloride (1.0 g, 4.32
mmol), oleoyl chloride (1.57 mL, 4.74 mmol), and DIPEA (1.66 mL,
9.50 mmol) in CH2Cl2. Purification by column chromatography
(EtOAc/hexane 30:70) gave the title compound (1.75 g, 88%) as a
white solid: mp 73−74 °C. Rf 0.44 (EtOAc/hexane 40:60); IR (ATR)
ν (cm−1) 3305, 3006, 2923, 2853, 1740, 1648, 1514, 1443, 1366, 1217,
(4S)-4-(Oleamido)-N-(tert-butoxycarbonyl)-L-proline (23e). Pre-
pared according general procedure A from N-Boc-cis-4-amine-L-proline
22e30 (317 mg, 1.38 mmol) and oleoyl chloride (456 μL, 1.38 mmol).
Purification by column chromatography (Et2O/MeOH 90:10)
afforded the title compound (558 mg, 82%) as a colorless oil: Rf
0.18 (Et2O/MeOH 90:10); IR (neat, cm−1) 3303, 2922, 2854, 1751,
1
829, 721; H NMR (400 MHz, CDCl3) δ 6.92 (d, J = 8.4, 2H), 6.72
(d, J = 8.4, 2H), 6.01 (d, J = 7.6 Hz, 1H), 5.29−5.35 (m, 2H), 4.85−
4.89 (m, 1H), 3.72 (s, 3H), 3.07 (dd, J = 14 Hz, 5.6 Hz, 1H), 2.97 (dd
J = 14.0 Hz, 6.0 Hz, 1H), 2.17 (t, J = 7.6 Hz, 2H), 1.97−2.02 (m, 4H),
1.54−1.61 (m, 2H), 1.26−1.29 (m, 20H), 0.87 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 173.6, 172.6, 155.8, 130.4, 130.2, 129.9,
127.1, 115.8, 53.4, 52.3, 37.5, 36.8, 32.1, 30.0, 29.9, 29.7, 29.52, 29.50,
29.40, 29.35, 29.32, 27.43, 27.38, 25.8, 22.9, 14.3; HRMS (ESI, [M +
H]+) calcd for C28H46N1O4 460.3421, found 460.3421.
1
1650, 1539, 1415, 1254, 1163. H NMR (300 MHz, MeOD) δ 5.40−
5.28 (m, 2H), 4.35 (appears as quin, J = 6.5 Hz, 1H), 4.21 (dd, J = 6.0
Hz, 1H,), 3.72−3.81 (m, 1H), 3.22−3.30 (m, 1H), 2.50−2.62 (m,
1H), 2.16 (t, J = 7.5 Hz, 2H), 1.97−2.08 (m, 4H), 1.86−1.97 (m, 1H),
1.51−1.64 (m, 2H), 1.45 (appears as d, 9H), 1.25−1.37 (m, 20H),
0.90 (t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, MeOD) δ 176.1, 155.7,
130.9, 130.8, 81.8, 59.7, 52.9, 52.1, 37.2, 37.1, 33.1, 30.9 (2C), 30.7,
30.5, 30.4 (2C), 30.3 (2C), 28.7, 28.6, 28.2 (2C), 26.9, 23.8, 14.5;
HRMS (ESI, [M − H]+) calcd for C28H49N2O5 493.3647, found
493.3647.
N-Oleoyl-L-serine Methyl Ester (5h). Prepared according general
procedure B from L-serine methyl ester hydrochloride (1.0 g, 6.43
mmol), oleoyl chloride (2.76 mL, 8.36 mmol), and DIPEA (2.80 mL,
16.07 mmol) in CH2Cl2/MeOH. Purification by column chromatog-
raphy (EtOAc/hexane 60:40) gave the title compound (2.0 g, 82%) as
a white waxy solid: mp 37−39 °C; Rf 0.53 (EtOAc/hexane 85:15); IR
(neat, cm−1) 3296, 2925, 2853, 1738, 1639, 1551, 1468, 1239, 1081,
General Procedure for the Preparation of Amides 5e−m, 7,
11, 17, and 23a−c and the Esters 25 and 40 (Procedure B). A
stirred solution of the α-amino acid ester hydrochloride salt, amine, or
alcohol derivative (1.0 equiv), DIPEA in anhydrous CH2Cl2 (5 mL/
mmol), or in a mixture of anhydrous CH2Cl2/MeOH (5 mL/mmol
2:1) was cooled to 0 °C and treated dropwise with a solution of oleoyl
chloride (1.0−1.4 equiv) in CH2Cl2 (1.0 mL/mmol). The reaction
mixture was allowed to warm to room temperature and stirred until no
more starting material was observed by TLC. The reaction mixture
was poured into brine and extracted three times with CH2Cl2. The
combined organic phases were washed with brine, dried over MgSO4
and concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel.
N-Oleoyl-L-phenylalanine Methyl Ester (5e). Prepared according
general procedure B from L-phenylalanine methyl ester hydrochloride
(1.1 g, 5.10 mmol), oleoyl chloride (2.19 mL, 6.63 mmol), DIPEA
(2.22 mL, 12.74 mmol) in CH2Cl2. Purification by column
chromatography (hexane/EtOAc 85:15) afforded the title compound
(2.05 g, 91%) as a white waxy solid: mp 30−32 °C; Rf 0.44 (hexane/
EtOAc 70:30); IR (ATR) ν (cm−1) 3297, 2923, 2853, 1746, 1647,
1538, 1437, 1211, 1176, 1030, 741, 699; 1H NMR (400 MHz, CDCl3)
δ 7.21−7.30 (m, 3H), 7.07−7.10 (m, 2H), 5.91 (d, J = 7.6 Hz, 1H),
5.30−5.38 (m, 2H), 4.90 (ddd appears as dt, J = 7.6 Hz, 6.0 Hz, 1H),
3.72 (s, 3H), 3.15 (dd, J = 14.0 Hz, 6.0 Hz, 1H), 3.07 (dd J = 14.0 Hz,
5.6 Hz, 1H), 2.16 (t, J = 7.2 Hz, 2H), 1.98−2.03 (m, 4H), 1.54−1.61
(m, 2H), 1.27−1.31 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.9, 172.4, 136.1, 130.2, 129.9, 129.4 (2C),
128.7 (2C), 127.3, 53.1, 52.5, 38.1, 36.7, 32.1, 30.0, 29.9, 29.7, 29.5,
29.42, 29.36, 29.3, 27.41, 27.37, 25.7, 22.9, 14.3; HRMS (ESI, [M +
H]+) calcd for C28H46N1O3 444.3472, found 444.3476.
1
723; H NMR (400 MHz, CDCl3) δ 6.45 (d, J = 6.8 Hz, 1H), 5.29−
5.37 (m, 2H), 4.65−4.68 (m, 1H), 3.96 (dd, J = 11.2 Hz, 4.0 Hz, 1H),
3.90 (dd J = 11.2 Hz, 3.2 Hz, 1H), 3.78 (s, 3H), 2.55 (br s, 1H), 2.25
(t, J = 7.6 Hz, 2H), 1.97−2.02 (m, 4H), 1.60−1.67 (m, 2H), 1.26−
1.30 (m, 20H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 174.0, 171.3, 130.2, 129.9, 63.8, 54.9, 52.9, 36.7, 32.1, 30.0, 29.9,
29.7, 29.52, 29.51, 29.45, 29.41, 29.3, 27.43, 27.38, 25.7, 22.9, 14.3;
HRMS (ESI, [M + H]+) calcd for C22H42N1O4 384.3108, found
384.3110.
N-Oleoyl-S-benzyl-L-cysteine Ethyl Ester (5i). Prepared according
general procedure B from S-benzyl-L-cysteine ethyl ester hydrochloride
(500 mg, 1.81 mmol), oleoyl chloride (780 μL, 2.36 mmol), and
DIPEA (695 μL, 3.98 mmol) in CH2Cl2/MeOH. Purification by
column chromatography (EtOAc/hexane 15:85) afforded the title
compound (821 mg, 90%) as a colorless oil: Rf 0.38 (EtOAc/hexane
20:80); IR (ATR) ν (cm−1) 3294, 2922, 2853, 1740, 1649, 1533, 1455,
1372, 1199, 1028, 700; 1H NMR (400 MHz, CDCl3) δ 7.23−7.34 (m,
5H), 6.11 (d, J = 8.0 Hz, 1H), 5.32−5.37 (m, 2H), 4.79 (ddd appears
as dt, J = 8.0 Hz, 5.4 Hz, 1H), 4.20 (qd, J = 7.8 Hz, 2.8 Hz, 2H), 3.71
(s, 2H), 2.93 (dd, J = 13.6 Hz, 5.0 Hz, 1H), 2.86 (dd J = 13.6 Hz, 5.4
Hz, 1H), 2.19 (t, J = 7.6 Hz, 2H), 1.98−2.03 (m, 4H), 1.60−1.65 (m,
2H), 1.25−1.30 (m, 23H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 173.1, 171.2, 137.9, 130.2, 130.0, 128.8, 127.5, 62.0,
51.7, 36.9, 36.7, 33.9, 32.1, 30.0, 29.9, 29.7, 29.53, 29.52, 29.46, 29.42,
29.35, 27.43, 27.39, 25.7, 22.9, 14.3 (2C); HRMS (ESI, [M + H]+)
calcd for C30H50N1O3S1 504.3506, found 504.3509.
N-Oleoyl-L-glutamic Acid Dimethyl Ester (5j). Prepared according
general procedure B from L-glutamic acid dimethyl ester hydrochloride
(1.0 g, 4.72 mmol), oleoyl chloride (1.72 mL, 5.19 mmol), and DIPEA
(1.81 mL, 10.38 mmol) in CH2Cl2. Purification by column
N-Oleoyl-L-tryptophan Ethyl Ester (5f). Prepared according general
procedure B from L-tryptophan methyl ester hydrochloride (377 mg,
F
dx.doi.org/10.1021/jo301659c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
chromatography (EtOAc/hexane 45:55) afforded the title compound
(1.80 g, 87%) as white waxy solid mp: 33−35 °C. Rf 0.50 (EtOAc/
hexane 70:30); IR (ATR) ν (cm−1) 3295, 2923, 2853, 1740, 1649,
5.46−5.49 (m, 2H), 4.37 (appears as quin, J = 5.6 Hz, 1H), 3.85−4.13
(m, 4H), 2.43 (t, J = 7.5 Hz, 2H), 2.02−2.11 (m, 4H), 1.81 (quin, J =
7.7 Hz, 2H), 1.24−1.39 (m, 20H), 0.86 (t, J = 6.6 Hz, 3H); 13C NMR
(150.9 MHz, d5-pyridine) δ 174.3, 130.2 (2C), 72.2, 65.0, 43.6, 36.7,
32.1, 30.07, 30.04, 29.8, 29.70, 29.65, 29.58, 29.56, 29.45, 27.5 (2C),
26.3, 22.9, 14.3; HRMS (ESI, [M + H]+) calcd for C21H42NO3
356.3159, found 356.3158.
1
1536, 1436, 1374, 1255, 1203, 1171, 986, 722; H NMR (400 MHz,
CDCl3) δ 6.12 (d, J = 7.6 Hz, 1H), 5.29−5.38 (m, 2H), 4.60−4.66 (m,
1H), 3.73 (s, 3H), 3.67 (s, 3H), 2.31−2.47 (m, 2H), 2.16−2.25 (m,
3H), 1.95−2.04 (m, 5H), 1.58−1.66 (m, 2H), 1.26−1.29 (m, 20H),
0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.5, 173.3,
172.7, 130.2, 129.9, 52.7, 52.0, 51.7, 36.7, 32.1, 30.3, 30.0, 29.9, 29.7,
29.49 (2C), 29.42, 29.40, 29.3, 27.6, 27.39, 27.36, 25.7, 22.9, 14.3;
HRMS (ESI, [M + H]+) calcd for C25H46N1O5 440.3370, found
440.3372.
N-(3-Amino-2-hydroxypropyl)oleamide (11). Prepared according
general procedure B from 1-N-Boc-3-aminopropan-2-ol 10 (159 mg,
0.84 mmol), oleoyl chloride (285 μL, 0.86 mmol), and DIPEA (147
μL, 0.84 mmol) in CH2Cl2. Purification by column chromatography
(Et2O/MeOH 50:1) afforded the protected compound NHBoc (307
mg) as a white waxy solid which was dissolved in EtOAc (10 mL) and
treated with a 4N solution of HCl (1 mL) at 0 °C under argon for 10
min. Subsequently, the reaction mixture was stirred overnight at room
temperature and poured into water. The aqueous solution was basified
with 1 M aqueous NaOH until pH ∼8 and extracted three times with
CH2Cl2. The combined organic phases were washed with brine, dried
over MgSO4, filtered and the filtrate was evaporated. The residue was
purified by column chromatography (CH2Cl2/MeOH/concd NH4OH
10:5:1) to yield 11 (179 mg, 60%) as a colorless solid: mp 84.5−85.4
°C; Rf 0.42 (CH2Cl2/MeOH 4:1 with 5% concd NH4OH); IR (KBr,
cm−1) 3350, 3317, 3003, 2920, 2850, 1647, 1555, 1464, 1437, 1384,
N-Oleoyl-L-histidine Methyl Ester (5k). Prepared according general
procedure B from L-histidine methyl ester hydrochloride (1.0 g, 4.13
mmol), oleoyl chloride (1.37 mL, 4.13 mmol), and DIPEA (1.59 mL,
9.08 mmol) in CH2Cl2/MeOH. Purification by column chromatog-
raphy (CH2Cl2/MeOH 98:2) gave the title compound (823 mg, 46%)
as a white solid: mp 87−89 °C. Rf 0.55 (CH2Cl2/MeOH 96:4); IR
(KBr, cm−1) 3419, 3184, 3008, 2923, 2853, 1735, 1645, 1572, 1241,
1
1155, 1042, 1003; H NMR (500 MHz, MeOD) δ 7.58 (s, 1H), 6.86
(s, 1H), 5.31−5.38 (m, 2H), 4.86−4.94 (m, 1H), 4.67 (dd, J = 8.9 Hz,
5.3 Hz, 1H), 4.63 (br s, 1H), 3.70 (s, 3H), 3.10 (dd, J = 14.8 Hz, 5.3
Hz, 1H), 2.97 (dd, J = 14.8 Hz, 8.9 Hz, 1H), 2.19 (t, J = 7.6 Hz, 2H),
1.97−2.02 (m, 4H), 1.52−1.1.59 (m, 2H), 1.22−1.37 (m, 20H), 0.90
(t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, MeOD) δ 176.4, 173.7,
136.5, 131.02, 130.97, 54.1, 52.9, 36.8, 33.2, 31.0 (2C), 30.8, 30.6, 30.5
(2C), 30.4, 30.3, 28.30, 28.28, 27.0, 23.9, 14.6; HRMS (ESI, [M +
H]+) calcd for C25H44N3O3 434.3377, found 434.3369.
N,N′-Bis(oleoyl)-L-cystine (5l). Prepared according general proce-
dure B from L-cystine dimethyl ester dihydrochloride (505 mg, 1.48
mmol), oleoyl chloride (1.26 mL, 3.80 mmol), and DIPEA (1.27 mL,
7.3 mmol) in CH2Cl2. Purification by column chromatography
(EtOAc/hexane 35:65) afforded the title compound (860 mg, 73%)
as a white solid: mp 74−77 °C; Rf 0.38 (EtOAc/hexane 60:40); IR
(ATR) ν (cm−1) 3311, 3005, 2922, 2852, 1747, 1647, 1525, 1435,
1209, 1165, 977, 720; 1H NMR (400 MHz, CDCl3) δ 6.37 (d, J = 7.2
Hz, 2H), 5.30−5.38 (m, 4H), 4.87 (ddd appears as dt, J = 7.2 Hz, 5.2
Hz, 2H), 3.76 (s, 6H), 3.23 (dd, J = 14.4 Hz, 5.2 Hz, 2H), 3.18 (dd J =
14.4 Hz, 5.2 Hz, 2H), 2.25 (t, J = 7.6 Hz, 4H), 1.98−2.03 (m, 8H),
1.60−1.68 (m, 4H), 1.26−1.30 (m, 40H), 0.87 (t, J = 6.8 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 173.2, 171.2, 130.2, 129.9, 52.9, 51.7, 41.0,
36.7, 32.1, 30.0, 29.9, 29.7, 29.53, 29.52, 29.47, 29.45, 29.37, 27.43,
27.40, 25.7, 22.9, 14.3; HRMS (ESI, [M + H]+) calcd for
C44H81N2O6S2 797.5531, found 797.5522.
1
1229, 1119, 994, 718; H NMR (300 MHz, d5-pyridine) δ 8.42 (br s,
1H), 5.23−5.34 (m, 2H), 4.35 (br s, 2H), 3.95−4.03 (m, 1H), 3.55−
3.71 (m, 2H), 2.85−2.99 (m, 2H), 2.23 (t, J = 7.6 Hz, 2H), 1.84−1.94
(m, 4H), 1.57−1.67 (m, 2H), 1.02−1.22 (m, 20H), 0.86 (t, J = 6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 174.2, 130.0, 129.7, 70.5, 44.5,
43.1, 36.7, 31.9, 29.8, 29.7, 29.5, 29.3, 29.23, 29.16, 27.22, 27.18, 25.6,
22.7, 14.1; HRMS (ESI, [M + H]+) calcd for C21H43N2O2 355.3319,
found 355.3316.
N-(2-Azidoethyl)oleamide (17). Prepared according general
procedure B, from 2-azidoethylamine 16 (1.20 g, 13.9 mmol), oleoyl
chloride (5.3 mL, 16 mmol), and DIPEA (5.33 mL, 30.5 mmol) in
CH2Cl2. Purification by column chromatography (hexane/EtOAc
50:50) afforded 17 (3.75 g, 75%) as a white waxy solid: mp 33−35 °C;
Rf 0.28 (hexane/EtOAc 50:50); IR (neat) ν (cm−1) 3297, 2921, 2852,
1
2098, 1644, 1547, 1459, 1347, 1260, 1228, 720; H NMR (400 MHz,
CDCl3) δ 5.73 (br s, 1H, NHCO), 5.30−5.39 (m, 2H), 3.41−3.47 (m,
4H), 2.19 (t, J = 7.6 Hz, 2H), 1.98−2.02 (m, 4H), 1.59−1.65 (m, 2H),
1.27−1.31 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 173.4, 130.0, 129.8, 51.1, 38.9, 36.7, 31.9, 29.8, 29.7, 29.5,
29.34 (2C), 29.26 (2C), 29.1, 27.24, 27.19, 25.6, 22.7, 14.1; HRMS
(ESI, [M + Na]+) calcd for C20H38N4NaO 373.2932, found 373.2933.
2-(Oleamido)propane-1,3-diol (23a). Prepared according general
procedure B from 2-amino-1,3-propanediol 22a (500 mg, 5.48 mmol),
oleoyl chloride (2.17 mL, 6.57 mmol), and Et3N (1.68 mL, 12.06
mmol) in CH2Cl2/MeOH. Purification by column chromatography
(CH2Cl2/MeOH 90:10) afforded the title compound (1.62 g, 83%) as
a white solid: mp 99−100 °C;18 Rf 0.50 (CH2Cl2/MeOH 90:10); IR
(ATR) ν (cm−1) 3396, 2958, 2921, 2851, 1638, 1545, 1466, 1422,
1384, 1246, 1071, 972, 682, 636; 1H NMR (400 MHz, CDCl3) δ 6.29
(d, J = 7.2 Hz, 1H), 5.32−5.38 (m, 2H), 3.91−3.97 (m, 1H), 3.83 (dd,
J = 11.2 Hz, 4.4 Hz, 1H), 3.74 (dd, J = 11.2 Hz, 4.4 Hz, 2H), 2.72 (br
s, 2H), 2.20 (t, J = 7.8 Hz, 2H), 1.97−2.02 (m, 4H), 1.56−1.63 (m,
2H), 1.25−1.29 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 174.7, 130.2, 129.9, 62.5 (2C), 52.7, 36.9, 32.1, 30.0,
29.9, 29.7, 29.52, 29.50, 29.49, 29.47, 29.38, 27.42, 27.38, 26.0, 22.9,
14.3; HRMS (ESI, [M + H]+) calcd for C21H42N1O3 356.3159, found
356.3157.
N-Oleoylsarcosine Methyl Ester (5m). Prepared according general
procedure B from sarcosine methyl ester hydrochloride (420 mg, 3.0
mmol), oleoyl chloride (1.09 mL, 3.3 mmol), and DIPEA (1.40 mL,
8.0 mmol) in CH2Cl2/MeOH. Purification by column chromatog-
raphy (Et2O/MeOH 98:2) afforded the title compound (966 mg,
88%) as a colorless oil: Rf 0.49 (Et2O/MeOH 98:2); IR (neat, cm−1)
3003, 2925, 2854, 1753, 1658, 1464, 1401, 1206, 722. This compound
appears in the 1H NMR spectrum as a distinct pair of cis/trans rotamers in
1
a ratio 4:1; H NMR (500 MHz, CDCl3) δ 5.29−5.39 (m, 2H, cis/
trans), 4.12 (s, 2H, cis), 4.04 (s, 2H, trans), 3.77 (s, 3H, trans), 3.73 (s,
3H, cis), 3.07 (s, 3H, cis), 2.97 (s, 3H, trans), 2.37 (t, J = 7.6 Hz, 2H,
cis), 2.22 (t, J = 7.5 Hz, 2H, trans), 1.98−2.02 (m, 4H, cis/trans), 1.60−
1.67 (m, 2H, cis/trans), 1.27−1.32 (m, 20H, cis/trans), 0.88 (t, J = 6.8
Hz, 3H, cis/trans); 13C NMR (125 MHz, CDCl3) δ 174.0, 173.5,
170.0, 169.6, 130.0, 129.8, 52.4, 52.1, 51.5, 49.3, 36.6, 34.9, 33.2, 33.0,
31.9, 29.8, 29.5, 29.4 (2C), 29.3 (3C), 29.2, 27.22, 27.20, 25.1, 24.9,
22.7, 14.1; HRMS (ESI, [M + H]+) calcd for C22H42NO3 368.3159,
found 368.3164.
2-(Oleamido)-2-(hydroxymethyl)propane-1,3-diol (23b). Pre-
pared according general procedure B from tris(hydroxymethyl)
aminomethane 22b (500 mg, 4.12 mmol), oleoyl chloride (1.63 mL,
4.94 mmol), and Et3N (1.26 mL, 9.08 mmol) in CH2Cl2. Purification
by column chromatography (CH2Cl2/MeOH 90:10) afforded the title
compound (985 mg, 62%) as a white solid: mp 86−88 °C;18 Rf 0.47
(CH2Cl2/MeOH 90:10); IR (ATR) ν (cm−1) 3354, 3286, 3006, 2922,
N-(2,3-Dihydroxypropyl)oleamide (7). Prepared according general
procedure B from 3-amino-1,2-propanediol (218 mg, 2.39 mmol),
oleoyl chloride (861 μL, 2.6 mmol), DIPEA (437 μL, 2.50 mmol) in
CH2Cl2/MeOH. Purification by column chromatography (Et2O/
MeOH 90:10) afforded the title compound (756 mg, 89%) as a white
waxy solid: mp 70−71.5 °C; Rf 0.29 (Et2O/MeOH 90:10); IR (neat,
cm−1) 3305, 3003, 2920, 2850, 1639, 1550, 1467, 1418, 1114, 1055;
1H NMR (600 MHz, d5-pyridine) δ 8.79 (br s, 1H), 6.32 (br s, 2H),
1
2853, 1620, 1530, 1464, 1289, 1131, 1024, 721; H NMR (400 MHz,
CDCl3) δ 6.51 (s, 1H), 5.30−5.38 (m, 2H), 5.25 (br s, 3H), 3.56 (s,
2H), 2.22 (t, J = 7.8 Hz, 2H), 1.98−2.04 (m, 4H), 1.58−1.62 (m, 2H),
G
dx.doi.org/10.1021/jo301659c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1.26−1.30 (m, 20H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.5, 130.2, 129.9, 62.2, 61.2 (2C), 37.2, 32.1, 30.0, 29.9,
29.7, 29.5 (2C), 29.4, 29.33, 29.31, 27.43, 27.38, 26.0, 22.9, 14.3;
HRMS (ESI, [M + H]+) calcd for C22H44N1O4 386.3265, found
386.3264.
(ddd appears as dt, J = 7.6 Hz, 6.0 Hz, 1H), 3.24 (dd, J = 14 Hz, 5.6
Hz, 1H), 3.13 (dd J = 14.0 Hz, 6.0 Hz, 1H), 2.18 (app td, J = 7.6 Hz,
2.8 Hz, 2H), 1.98−2.03 (m, 4H), 1.54−1.57 (m, 2H), 1.25−1.29 (m,
20H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2,
174.1, 135.9, 130.2, 129.9, 129.6, 128.8, 127.4, 53.3, 37.5, 36.7, 32.1,
30.0, 29.9, 29.7, 29.53, 29.52, 29.4, 29.3 (2C), 27.4, 27.4, 25.7, 22.9,
14.3; HRMS (ESI, [M + H]+) calcd for C27H44N1O3 430.3316, found
430.3315.
3-(Oleamido)pentanedinitrile (23c). Prepared according general
procedure B from 3,3-iminodipropionitrile 22c (369 mg, 362 μL, 3.0
mmol), oleoyl chloride (1.09 mL, 3.30 mmol), and DIPEA (1.43 mL,
8.18 mmol) in CH2Cl2. Purification by column chromatography
(Et2O/MeOH 90:10) afforded the title compound (1.12 g, 96%) as a
white solid: mp 40.5−41.2 °C; Rf 0.33 (Et2O/MeOH 90:10); IR (neat,
cm−1) 3004, 2925, 2854, 2249, 1652, 1465, 1455, 1418, 1377, 1196,
1071, 723; 1H NMR (300 MHz, CDCl3) 5.33−5.37 (m, 2H), 3.78 (t, J
= 6.7 Hz, 2H), 3.62 (t, J = 6.2 Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 2.65
(t, J = 6.7 Hz, 2H), 2.36 (t, J = 7.5 Hz, 2H), 2.00−2.02 (m, 4H), 1.65−
1.69 (m, 2H), 1.26−1.28 (m, 20H), 0.88 (t, J = 6.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) 173.5, 130.0, 129.7, 118.4, 116.8, 44.9, 43.4,
33.1, 31.9, 29.8, 29.7, 29.5, 29.33, 29.28, 29.1, 27.23, 27.19, 25.0, 22.7,
18.2, 16.4, 14.1; HRMS (ESI, [M + H]+) calcd for C24H42N3O
388.3322, found 388.3323.
N-Oleoyl-L-tryptophane (4f). Prepared according to general
procedure C from 5f (1.0 g, 2.01 mmol). Column chromatography
of the crude product (CH2Cl2/MeOH 95:5 with 1% AcOH) gave 4f
(736 mg, 78%) as a pale yellow waxy solid: mp 68 °C dec; Rf 0.32
(EtOAc/MeOH/AcOH 94:5:1); IR (KBr, cm−1) 3410, 3309, 3006,
1
2925, 2853, 1723, 1650, 1527, 1457, 1342, 1230, 740; H NMR (400
MHz, CDCl3) δ 9.98 (br s, 1H), 8.35 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H),
7.32 (d, J = 8.0 Hz, 1H), 7.18 (td, J = 7.2 Hz, 0.8 Hz, 1H), 7.10 (td, J =
7.2 Hz, 0.8 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H),
5.30−5.39 (m, 2H), 4.95 (ddd appears as dt, J = 7.6 Hz, 5.6 Hz, 1H),
3.36 (dd, J = 15.0 Hz, 5.2 Hz, 1H), 3.31 (dd J = 15.0 Hz, 5.6 Hz, 1H),
2.09 (t, J = 7.6 Hz, 2H), 1.97−2.03 (m, 4H), 1.48−1.52 (m, 2H),
1.20−1.27 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.5, 174.5, 136.3, 130.2, 130.0, 128.0, 123.4, 122.4, 119.9,
118.6, 111.6, 109.7, 53.6, 36.6, 32.1, 30.0, 29.9, 29.7, 29.54, 29.52, 29.4,
29.3 (2C), 27.5, 27.4, 27.3, 25.6, 22.9, 14.3; HRMS (ESI, [M + H]+)
calcd for C29H45N2O3 469.3425, found 469.3421.
N-Oleoyl-L-tyrosine (4g). Prepared according general procedure C
from 5g (1.0 g, 2.17 mmol). The crude product was precipitated from
cold hexane to afford the title compound (899 mg, 93%) as a white
solid: mp 76−78 °C: Rf 0.28 (EtOAc/MeOH/AcOH 94:5:1); IR
(ATR) ν (cm−1) 3310, 2923, 2853, 1722, 1647, 1614, 1514, 1449,
1365, 1217, 833, 724; 1H NMR (400 MHz, CDCl3) δ 8.53 (br s, 1H),
6.94 (d, J = 8.4, 2H), 6.69 (d, J = 8.4, 2H), 6.26 (d, J = 7.6 Hz, 1H),
5.28−5.37 (m, 2H), 4.83−4.88 (m, 1H), 2.99−3.09 (m, 2H), 2.18 (t, J
= 7.6 Hz, 2H), 1.97−2.02 (m, 4H), 1.54−1.57 (m, 2H), 1.25−1.32 (m,
20H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.1,
174.8, 155.5, 130.6, 130.3, 129.9, 127.1, 115.9, 53.5, 37.0, 36.6, 32.1,
29.98, 29.95, 29.8, 29.6, 29.5, 29.44, 29.37 (2C), 27.5, 27.4, 25.8, 22.9,
14.3; HRMS (ESI, [M + H]+) calcd for C27H44N1O4 446.3265, found
446.3262.
N-Oleoyl-L-serine (4h). Prepared according general procedure C
from 5h (1.0 g, 2.60 mmol). The crude product was precipitated from
cold hexane and recrystallized from EtOH to afford the title
compound (780 mg, 81%) as a white solid: mp 80−82 °C (lit.13
mp 50−60 °C); Rf 0.34 (EtOAc/MeOH 85:15 with 1% AcOH); IR
(ATR) ν (cm−1) 3374, 3337, 3001, 2921, 2852, 1727, 1587, 1537,
1465, 1213, 1033, 788, 648; 1H NMR (400 MHz, CDCl3 + DMSO) δ
6.75 (d, J = 6.8 Hz, 1H), 5.18−5.46 (m, 3H), 4.49−4.51 (m, 1H), 3.90
(dd, J = 11.6 Hz, 3.8 Hz, 1H), 3.77 (dd J = 11.6 Hz, 3.4 Hz, 1H), 2.17
(t, J = 7.6 Hz, 2H), 1.90−1.93 (m, 4H), 1.49−1.59 (m, 2H), 1.18−
1.22 (m, 20H), 0.80 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3
+ DMSO) δ 173.9, 172.6, 130.0, 129.8, 63.1, 54.8, 36.5, 31.9, 29.8,
29.7, 29.5, 29.30 (2C), 29.27 (2C), 29.17, 27.22, 27.20, 25.6, 22.7,
14.1; HRMS (ESI, [M + H]+) calcd for C21H40N1O4 370.2952, found
370.2953.
4-[(E)-Phenyldiazenyl]phenyl Oleoate (25).43 Prepared according
to general procedure B from 4-phenylazophenol 24 (299 mg, 1.51
mmol), oleoyl chloride (648 μL, 1.96 mmol), DIPEA (791 μL, 4.53
mmol) in CH2Cl2/MeOH. Purification by column chromatography
(hexane/EtOAc 97:3) afforded the title compound (475 mg, 68%) as
an orange solid: mp 39−41 °C; Rf 0.25 (hexane/EtOAc 98:2); IR
(ATR) ν (cm−1) 3005, 2922, 2852, 1760, 1749, 1592, 1493, 1466,
1
1200, 1149, 923, 854, 722, 688; H NMR (400 MHz, CDCl3) δ 7.96
(d, J = 8.8 Hz, 2H), 7.91 (d, J = 6.8 Hz, 2H), 7.45−7.54 (m, 3H), 7.24
(d, J = 8.8 Hz, 2H), 5.32−5.40 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H),
2.00−2.04 (m, 4H), 1.74−1.82 (m, 2H), 1.27−1.36 (m, 20H), 0.88 (t,
J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2, 153.0, 152.8,
150.4, 131.3, 130.3, 129.9, 129.3, 124.3, 123.1, 122.4, 34.7, 32.1, 30.0,
29.9, 29.8, 29.6 (2C), 29.4, 29.3 (2C), 27.46, 27.39, 25.1, 22.9, 14.3;
HRMS (ESI, [M + H]+) calcd for C30H43N2O2 463.3319, found
463.3319.
4,5-Dimethoxy-2-nitrobenzyl Oleate (40). Prepared according
general procedure B from 4,5-dimethoxy-2-nitrobenzyl alcohol 34
(300 mg, 1.41 mmol), oleoyl chloride (651 μL, 1.97 mmol), DIPEA
(613 μL, 3.51 mmol), and DMAP (17 mg, 0.14 mmol) in CH2Cl2.
Purification by column chromatography (hexane/EtOAc 80:20)
afforded the title compound (580 mg, 86%) as a yellow solid: mp
36−38 °C; Rf 0.44 (hexane/EtOAc 85:15); IR (KBr, cm−1) 3003,
2922, 2855, 1729, 1616, 1582, 1507, 1470, 1390, 1273, 1069, 974, 796;
1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 6.99 (s, 1H), 5.50 (s,
2H), 5.30−5.36 (m, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 2.41 (t, J = 7.6
Hz, 2H), 1.98−2.02 (m, 4H), 1.63−1.71 (m, 2H), 1.26−1.31 (m,
20H), 0.87 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.3,
153.7, 148.5, 140.3, 130.3, 129.9, 127.4, 110.7, 108.5, 63.3, 56.6, 56.6,
34.5, 32.1, 30.0, 29.9, 29.7, 29.54, 29.53, 29.40, 29.37, 29.3, 27.44,
27.37, 25.2, 22.9, 14.3; HRMS (ESI, [M + H]+) calcd for C27H44N1O6
478.3163, found 478.3163.
General Procedure for the Preparation of the Acids 4d,f−
j,m, 32, and 46 Using LiOH (Procedure C). A mixture of the ester
derivative (1 equiv) in ethanol (15 mL/mmol) and lithium hydroxide
(3 equiv) in H2O (5 mL/mmol) was stirred at room temperature
overnight. The EtOH was evaporated in vacuo at room temperature.
The residue was diluted with H2O (25 mL), acidified to pH 2 using
aqueous HCl (1 N), and extracted with EtOAc (3 × 20 mL). The
combined organic phases were washed with NaHCO3 and brine, dried
over MgSO4, filtered, and evaporated. The crude products were
purified by recrystallization or column chromatography.
N-Oleoyl-L-cysteine (4i). Prepared according general procedure C
from 5i (500 mg, 0.99 mmol). Column chromatography of the crude
product (CH2Cl2/MeOH 95:5 with 1% AcOH) gave 4i (430 mg,
91%) as a white solid: mp 59−62 °C; Rf 0.34 (EtOAc/MeOH 95:5 +
1% AcOH); IR (ATR) ν (cm−1) 3308, 3004, 2922, 2853, 1728, 1625,
1
1524, 1454, 1210, 700; H NMR (400 MHz, CDCl3) δ 9.81 (br s,
1H), 7.22−7.32 (m, 5H), 6.31 (d, J = 7.2 Hz, 1H), 5.30−5.38 (m,
2H), 4.74−4.78 (m, 1H), 3.71 (s, 2H), 2.95 (dd, J = 14.0 Hz, 5.0 Hz,
1H), 2.91 (dd J = 14.0 Hz, 5.8 Hz, 1H), 2.21 (t, J = 7.2 Hz, 2H), 1.98−
2.01 (m, 4H), 1.59−1.62 (m, 2H), 1.27−1.29 (m, 20H), 0.88 (t, J =
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.5, 174.0, 137.9,
130.2, 129.9, 129.1, 128.9, 127.5, 51.8, 36.9, 36.6, 33.3, 32.1, 30.0, 29.9,
29.7, 29.52, 29.51, 29.43, 29.37, 29.35, 27.43, 27.39, 25.7, 22.9, 14.3;
HRMS (ESI, [M + H]+) calcd for C28H46N1O3S 476.3193, found
476.3191.
N-Oleoyl-L-phenylalanine (4d). Prepared following general proce-
dure C from 5e (500 mg, 1.13 mmol). The crude product was
precipitated from cold hexane and recrystallized from EtOH to afford
the title compound (345 mg, 71%) as a white waxy solid: mp 68.5−71
°C; Rf 0.32 (EtOAc/MeOH/AcOH 94:5:1); IR (ATR) ν (cm−1)
1
3309, 3005, 2922, 2853, 1727, 1626, 1536, 1455, 1214, 754, 699; H
NMR (400 MHz, CDCl3) δ 10.27 (br s, 1H), 7.25−7.31 (m, 3H),
7.15−7.17 (m, 2H), 6.01 (d, J = 7.6 Hz, 1H), 5.33−5.37 (m, 2H), 4.90
H
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N-Oleoyl-L-glutamic Acid (4j). Prepared according general
procedure C from 5j (1.0 g, 2.27 mmol). The crude product was
precipitated from cold hexane and recrystallized from EtOH to afford
the title compound (790 mg, 85%) as a white solid: mp 92−93.5 °C;
Rf 0.40 (EtOAc/MeOH 85:15 with 1% AcOH); IR (ATR) ν (cm−1)
3329, 3005, 2922, 2853, 1727, 1642, 1541, 1454, 1411, 1212, 720; 1H
NMR (400 MHz, CDCl3) δ 10.97 (br s, 2H), 6.71 (d, J = 7.6 Hz, 1H),
5.29−5.37 (m, 2H), 4.62−4.67 (m, 1H), 2.43−2.53 (m, 2H), 2.21−
2.27 (m, 3H), 1.97−2.09 (m, 5H), 1.59−1.61 (m, 2H), 1.26−1.29 (m,
20H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 178.1,
175.7, 174.9, 130.2, 129.9, 51.8, 36.6, 32.1, 30.1, 29.98, 29.95, 29.8,
29.54, 29.52, 29.47, 29.43, 29.39, 27.44, 27.41, 27.0, 25.8, 22.9, 14.3;
HRMS (ESI, [M − H]+) calcd for C23H40N1O5 410.2912, found
410.2917.
4-[(E)-Phenyldiazenyl]phenyl (Oleoylamino)acetate (26). Pre-
pared according general procedure D from 4a (100 mg, 0.295
mmol), 4-phenylazophenol 24 (58 mg, 0.295 mmol). Purification by
column chromatography (EtOAc/hexane 30:70) afforded the title
compound (81 mg, 53%) as a yellow solid: mp 117−121 °C; Rf 0.43
(EtOAc/hexane 40:60); IR (ATR) ν (cm−1) 3333, 3002, 2919, 2850,
1
1759, 1650, 1538, 1465, 1236, 1174, 855, 764, 685; H NMR (400
MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 7.6 Hz, 2H),
7.48−7.54 (m, 3H), 7.28 (d, J = 8.8 Hz, 2H), 5.96 (br s, 1H), 5.29−
5.38 (m, 2H), 4.34 (d, J = 5.2 Hz, 2H), 2.29 (t, J = 7.2 Hz, 2H), 1.98−
2.03 (m, 4H), 1.66−1.71 (m, 2H), 1.26−1.31 (m, 20H), 0.87 (t, J =
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.7, 168.8, 152.7,
152.3, 150.7, 131.4, 130.2, 130.0, 129.3, 124.4, 123.1, 122.2, 41.7, 36.6,
32.1, 29.98, 29.92, 29.7, 29.54, 29.53, 29.46, 29.43, 29.3, 27.44, 27.39,
25.8, 22.9, 14.3; HRMS (ESI, [M + Na]+) calcd for C32H45N3NaO3
542.3353, found 542.3349.
N-Oleoylsarcosine (4m). Prepared according general procedure C
from 5m (265 mg, 0.72 mmol). The crude product was purified by
column chromatography (EtOAc/MeOH/AcOH 97:2:1) to afford 4m
(248 mg, 98%) as a colorless oil (lit.44 mp 16.1−17 °C): Rf 0.25
Methyl [[(9Z)-12-[4-[(E)-Phenyldiazenyl]phenoxy]dodec-9-enoyl]-
methylamino]acetate (31). Prepared according general procedure D
from sarcosine methyl ester hydrochloride 3m (21.7 mg, 0.156 mmol)
and acid 30 (61.5 mg, 0.156 mmol). Flash column chromatography of
the crude product (Et2O/hexane 90:10) afforded 31 (71 mg, 95%) as
an orange oil: Rf 0.22 (hexane/Et2O 10:90); IR (neat, cm−1) 3009,
2926, 2853, 1750, 1653, 1600, 1500, 1468, 1402, 1250, 1209, 1142,
1
(EtOAc/MeOH 90:10 + 0.5% AcOH); H NMR (400 MHz, CDCl3,
appears as a 5:1 mixture of cis/trans isomers, assignments in analogy to
5m) δ 8.02 (br s, 1H, cis/trans), 5.30−5.39 (m, 2H, cis/trans), 4.14 (s,
2H, cis), 4.07 (s, 2H, trans), 3.09 (s, 3H, cis), 2.98 (s, 3H, trans), 2.38
(t, J = 7.6 Hz, 2H, cis), 2.24 (t, J = 7.6 Hz, 2H, trans), 1.98−2.02 (m,
4H, cis/trans), 1.62−1.69 (m, 2H, cis/trans), 1.27−1.32 (m, 20H, cis/
trans), 0.88 (t, J = 6.6 Hz, 3H, cis/trans); 13C NMR (100 MHz,
CDCl3) δ 175.1, 173.5, 130.2, 130.0, 50.0, 37.0, 33.4, 32.1, 30.0, 29.9,
29.7, 29.5 (3C), 29.4 (2C), 27.44, 27.41, 25.1, 22.9, 14.3.
1
1023, 840; H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.8 Hz, 2H),
7.87 (d, J = 7.2 Hz, 2H), 7.42−7.51 (m, 3H), 7.01 (d, J = 8.8 Hz, 2H),
5.44−5.58 (m, 2H), 4.12 (s, 2H), 4.05 (t, J = 6.9 Hz, 2H), 3.73 (s,
3H), 3.06 (s, 3H), 2.55−2.60 (m, 2H), 2.36 (t, J = 6.9 Hz, 2H), 2.07−
2.11 (m, 2H), 1.62−1.67 (m, 2H), 1.31−137 (m, 10H); 13C NMR
(100 MHz, CDCl3) δ 174.1, 170.2, 161.7, 153.0, 147.2, 133.2, 130.5,
129.2, 125.0, 124.6, 122.8, 115.0, 68.1, 52.3, 49.5, 36.8, 33.3, 29.8, 29.6
(2C), 29.4, 27.6 (2C), 25.1; HRMS (ESI, [M + Na]+) calcd for
C28H37N3NaO4 502.2676, found 502.2681.
[[(9Z)-12-[4-[(E)-Phenyldiazenyl]phenoxy]dodec-9-enoyl]-
(methyl)amino]acetic Acid (32). Prepared according general
procedure C from 31 (24.0 mg, 0.05 mmol). The crude product
was purified by column chromatography (EtOAc/MeOH 90:10 with
0.5% AcOH) to afford 32 (21.4 mg, 92%) as an orange solid: mp
90.2−92.3 °C; Rf 0.22 (EtOAc/MeOH 10:1); IR (neat, cm−1) 3010,
(9Z)-2,3-Dihydroxypropyl-12-[4-[(E)-phenyldiazenyl]phenoxy]-
dodec-9-enoate (33). Compound 33 was synthesized in two steps.
The first step was prepared according general procedure D from
solketal (13.8 mg, 0.104 mmol), 30 (41 mg, 0.104 mmol), DCC
(21.46 mg, 0.104 mmol), and DMAP (12.70 mg, 0.104 mmol) in dry
CH2Cl2. Purification by preparative layer chromatography (Et2O/
hexane 50:50) afforded the oxirane (46 mg, 86%) as a white solid,
which was used in the next step. To a stirred solution of the oxirane
(30 mg, 0.059 mmol) in 3 mL of 2-methoxyethanol was added boric
acid (742 mg, 12 mmol), and the mixture was heated up to 95 °C and
stirred at this temperature for 20 h. The reaction mixture was allowed
to cool to room temperature and was diluted with water (3 mL) and
CH2Cl2 (5 mL), and the resulting mixture was shaken for some
minutes. The precipitated boric acid was filtered off and washed with
CH2Cl2 and water. The filtrate was extracted with CH2Cl2 (3 × 10
mL), and the combined organic phases were washed with brine and
dried over MgSO4. The solvent was evaporated in vacuo, and the
residue was purified by column chromatography (Et2O/hexane 80:20)
to afford 33 (18.5 mg, 67%) as an orange solid: mp 69.8−71.6 °C; Rf
0.22 (EtOAc/hexane 80:20); IR (neat, cm−1) 3355, 3005, 2920, 2849,
1731, 1603, 1582, 1497, 1298, 1181, 842; 1H NMR (400 MHz,
CDCl3) δ 7.92 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 7.2 Hz, 2H), 7.41−7.52
(m, 3H), 7.00 (d, J = 8.8 Hz, 2H), 5.43−5.59 (m, 2H), 4.13−4.23 (m,
2H), 4.06 (t, J = 6.8 Hz, 2H), 3.87−3.95 (m, 1H), 3.57−3.71 (m, 2H),
2.56−2.61 (m, 2H), 2.35 (t, J = 6.8 Hz, 2H), 2.07−2.12 (m, 2H),
1.58−1.66 (m, 2H), 1.26−1.38 (m, 10H); 13C NMR (100 MHz,
CDCl3) δ 174.3, 161.5, 152.8, 147.0, 132.9, 130.3, 129.0, 124.74,
124.4, 122.5, 114.8, 70.3, 67.9, 65.2, 63.3, 34.1, 29.6, 29.13 (2C), 29.06,
27.40, 27.36, 24.9; HRMS (ESI, [M + Na]+) calcd for C27H36N2NaO5
491.2516, found 491.2523.
1
2927, 2854, 1737, 1602, 1500, 1414, 1298, 1141, 839; H NMR (400
MHz, CDCl3) δ 7.92 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 7.2 Hz, 2H),
7.41−7.51 (m, 3H), 7.00 (d, J = 8.8 Hz, 2H), 5.43−5.58 (m, 2H), 4.10
(s, 2H), 4.04 (t, J = 7.2 Hz, 2H), 3.08 (s, 3H), 2.55−2.60 (m, 2H),
2.36 (t, J = 7.2 Hz, 2H), 2.06−2.11 (m, 2H), 1.62−1.66 (m, 3H),
1.25−1.33 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 175.0, 173.0,
161.7, 153.0, 147.1, 133.2, 130.5, 129.2, 1245.0, 124.6, 122.8, 115.0,
68.1, 50.1, 37.0, 33.3, 29.8, 29.5 (2C), 29.3, 27.6 (2C), 25.0; HRMS
(ESI, [M − H]+) calcd for C27H34N3O4 464.2555, found 464.2555.
3-[[[(8Z)-Heptadec-8-en-1-ylcarbamoyl]oxy]methyl]-4-nitroben-
zoic Acid (46). Prepared according general procedure C from ethyl
benzoate derivative 45 (160 mg, 0.32 mmol). Purification by
preparative layer chromatography (silica gel, CH2Cl2/MeOH 98:2
with 0.5% AcOH) afforded title compound 46 (82 mg, 54%) as a
yellow solid: mp 94−97 °C; Rf 0.37 (EtOAc/hexane 3:2 + 2% AcOH);
IR (neat, cm−1) 3352, 3004, 2921, 2852, 2531, 1703, 1625, 1590, 1538,
1
1480, 1418, 1339, 1306, 1256, 1127, 1046, 923; H NMR (300 MHz,
CDCl3) δ 8.78 (br s, 1H), 8.32 (br d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.2
Hz, 1H), 5.58 (s, 2H), 5.31−5.38 (m, 2H), 4.91 (br s, 1H), 3.18−3.25
(m, 2H), 2.00−2.02 (m, 4H), 1.42−1.51 (m, 1H), 1.26−1.32 (m,
20H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.0,
155.9, 147.5, 139.0, 134.8, 130.4, 130.3, 129.9, 129.1, 126.8, 63.3, 41.5,
32.1, 30.1, 30.0, 29.89, 29.7, 29.5 (2C), 29.4 (2C), 27.42, 27.37, 26.9,
22.9, 14.3; HRMS (ESI, [M − H]+) calcd for C26H39N2O6 475.2814,
found 475.2816.
General Procedure for the Preparation of 26, 31, 33, and
41−43 Using DCC (Procedure D). DCC (1 equiv) and DMAP (1
equiv) were added to a stirred suspension of the carboxylic acid
derivative (1 equiv) in dry CH2Cl2 (20 mL/mmol) at 0 °C under
argon. The reaction mixture was allowed to reach room temperature
and stirred for 1 h. Subsequently, the amine or alcohol derivative (1
equiv) was added to the reaction mixture and stirred overnight. The
dicyclohexylurea was filtered off over Celite, and the filtrate was
diluted with CH2Cl2 (20 mL/mmol) and washed successively with 1 N
HCl, saturated NaHCO3 (aq), H2O and brine. The organic phase was
dried over MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel.
4,5-Dimethoxy-2-nitrobenzyl [Methyl(oleoylamino)]acetate (41).
Prepared according general procedure D from 4,5-dimethoxy-2-
nitrobenzyl alcohol 34 (102 mg, 0.48 mmol) and N-oleoylsarcosine
4m (170 mg, 0.48 mmol). Purification by column chromatography
(EtOAc/hexane 30:70 to 60:40) afforded the title compound (216 mg,
82%) as a pale yellow solid: mp 41.2−42.3 °C. Rf 0.20 (hexane/EtOAc
60:40); IR (neat, cm−1) 2925, 2853, 1752, 1651, 1523, 1462, 1329,
1277, 1179, 873; 1H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 7.05 (s,
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1H), 5.59 (s, 2H), 5.31−5.36 (m, 2H), 4.19 (s, 2H), 4.05 (s, 3H), 3.96
(s, 3H), 3.13 (s, 3H), 2.37 (t, J = 7.5 Hz, 2H), 1.97−2.01 (m, 4H),
1.59−1.64 (m, 2H), 1.26−1.29 (m, 20H), 0.88 (t, J = 6.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 174.0, 169.3, 154.0, 148.2, 139.6, 130.0,
129.7, 127.2, 110.1, 108.2, 63.8, 56.83, 56.4, 49.9, 36.9, 33.1, 31.9, 29.8,
29.7, 29.5, 29.34, 29.32 (2C), 29.2, 27.21, 27.18, 24.9, 22.7, 14.1;
HRMS (ESI, [M + Na]+) calcd for C30H48N2NaO7 571.3354, found
571.3355.
chromatography (Et2O/hexane 60:40) to give 13 (195 mg, 73%) as
a colorless oil: Rf 0.34 (Et2O/hexane 50:50); IR (neat, cm−1) 3455,
3004, 2926, 2855, 2103, 1741, 1457, 1271, 1118; 1H NMR (300 MHz,
CDCl3) δ 5.29−5.40 (m, 2H), 4.13−4.21 (m, 2H), 3.98−4.04 (m,
1H), 3.34−3.46 (m, 2H), 2.45 (br s, 1H), 2.35 (t, J = 7.5 Hz, 2H),
1.98−2.04 (m, 4H), 1.59−1.63 (m, 2H), 1.26−1.31 (m, 20H), 0.88 (t,
J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.0, 130.1, 129.7,
69.2, 65.5, 53.5, 34.1, 31.9, 29.8, 29.7, 29.5, 29.3 (2C), 29.2, 29.1 (2C),
27.23, 27.16, 24.9, 22.7, 14.1; HRMS (ESI, [M + Na]+) calcd for
C21H39N3NaO3 404.2884, found 404.2880.
3-Amino-2-hydroxypropyl Oleate (14). To a solution of azide 13
(108 mg, 0.28 mmol) in THF/H2O 3:2 (5 mL) was added Ph3P (74
mg, 0.28 mmol) and the mixture was heated under reflux for 23 h. The
reaction mixture was allowed to cool to room temperature and
concentrated in vacuo. The residue was purified by column
chromatography (EtOAc/MeOH 95:5) to give 14 (70 mg, 70%) as
a colorless waxy solid: mp 69.8−71.7 °C; Rf 0.27 (EtOAc/MeOH
95:5); IR (neat, cm−1) 3304, 3001, 2919, 2850, 1642, 1556, 1462,
1115, 720; 1H NMR (400 MHz, CDCl3) δ 5.91 (br s, 1H), 5.28−5.40
(m, 2H), 3.72−3.77 (m, 1H), 3.56 (br s, 2H), 3.36−3.47 (m, 2H),
2.99 (br s, 1H), 2.22 (t, J = 7.6 Hz, 2H), 1.99−2.03 (m, 4H), 1.58−
1.65 (m, 2H), 1.27−1.31 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 175.3, 130.1, 129.7, 71.3, 63.5, 42.2, 36.6,
31.9, 29.8, 29.7, 29.5, 29.34, 29.32, 29.25, 29.1, 27.23, 27.16, 25.7, 22.7,
14.1; HRMS (ESI, [M + H]+) calcd for C21H42NO3 356.3159, found
356.3157.
3-(Acetylsulfanyl)-2-hydroxypropyl Oleate (15). A solution of
monotosylate 12 (491 mg, 0.96 mmol) and potassium thioacetate
(142 mg, 1.24 mmol) in dry acetone (7.5 mL) was stirred in a sealed
Schlenk tube at room temperature under argon for 16 h. The mixture
was poured into half saturated brine (70 mL) and extracted with
MTBE (3 × 20). The organic phases were combined and washed with
1 M HCl (20 mL), followed by saturated NaHCO3 (20 mL) and
brine, and dried over MgSO4, and the solvent was evaporated at
reduced pressure. The residue was subjected to column chromatog-
raphy (MTBE/hexane 50:50) to afford 15 (103 mg, 26%) as a
colorless oil: Rf 0.36 (Et2O/hexane 50:50); IR (neat, cm−1) 3386,
2925, 2854, 1745, 1458, 1372, 1231, 1049; 1H NMR (300 MHz,
CDCl3) δ 5.28−5.40 (m, 2H), 5.05−5.08 (m, 1H), 4.35 (dd, J = 12
Hz, 3.9 Hz, 1H), 4.23 (dd, J = 12 Hz, 5.7 Hz, 1H), 2.71−2.77 (m, 2H),
2.32 (t, J = 7.5 Hz, 2H), 2.09 (s, 3H), 1.98−2.04 (m, 4H), 1.54−1.61
(m, 2H), 1.27−1.31 (m, 20H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 196.0, 173.8, 130.0, 129.7, 69.2, 66.6, 34.1, 32.6, 31.9,
30.6, 29.8, 29.7, 29.5, 29.3 (2C), 29.2, 29.1 (2C), 27.22, 27.17, 24.9,
22.7, 14.1; HRMS (ESI, [M + Na]+) calcd for C23H42NaO4S 437.2696,
found 437.2697.
N-(2-Aminoethyl)oleamide (18). To a solution of N-(2-
Azidoethyl)oleamide 17 (1 g, 2.85 mmol) in THF/H2O 3:2 (30
mL) was added triphenylphosphine (748 mg, 2.85 mmol) and the
mixture was heated under reflux for 24 h. The reaction mixture was
allowed to reach room temperature, poured into brine (30 mL) and
extracted with EtOAc (3 × 25 mL). The organic layers were combined
and dried over MgSO4, concentrated under reduced pressure and the
residue was purified by column chromatography (CH2Cl2/MeOH
95:5 with 1% Et3N) to afford 18 (785 mg, 85%) as a colorless solid:
mp 74−76 °C; Rf 0.26 (CH2Cl2/MeOH 95:5 with 1% Et3N); IR
(neat, cm−1) 3293, 2922, 2852, 1643, 1552, 1451, 1252, 1053, 892; 1H
NMR (400 MHz, CDCl3) δ 6.04 (br s, 1H, NHCO), 5.29−5.38 (m,
2H), 3.32 (q, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.18 (t, J = 7.6
Hz, 2H), 1.98−2.01 (m, 4H), 1.93 (br s, 2H, NH2), 1.59−1.64 (m,
2H), 1.26−1.30 (m, 20H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 173.8, 130.2, 130.0, 41.8, 41.6, 37.1, 32.1, 30.0, 29.9,
29.7, 29.53 (2C), 29.50 (2C), 29.4, 27.44, 27.40, 26.0, 22.9, 14.3;
HRMS (ESI, [M + H]+) calcd for C20H41N2O 325.3214, found
325.3214.
5-Amino-2-nitrobenzyl Oleate (42). Prepared according general
procedure D from 5-amino-2-nitrobenzyl alcohol 35 (59 mg, 0.35
mmol) and oleic acid (99 mg, 0.35 mmol). Preparative layer
chromatography of the crude product (Et2O/pentane 70:30) afforded
42 (135 mg, 88%) as a pale yellow solid: mp 57.2−58.4 °C; Rf 0.23
(Et2O/hexane 60:40); IR (neat, cm−1) 3386, 2924, 2853, 1731, 1618,
1
1578, 1420, 1293, 1088; H NMR (400 MHz, CDCl3) δ 8.09 (d, J =
8.9 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 6.57 (dd, J = 8.9 Hz, 2.8 Hz,
1H), 5.52 (s, 2H), 5.30−5.38 (m, 2H), 4.39 (br s, 2H), 2.43 (t, J = 7.6
Hz, 2H), 2.00−2.03 (m, 4H), 1.65−1.72 (m, 2H), 1.26−1.32 (m,
20H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.2,
152.0, 137.8, 136.2, 130.2, 129.9, 128.7, 112.8, 112.6, 63.6, 34.4, 32.0,
29.9, 29.8, 29.7, 29.46, 29.45, 29.33, 29.29, 29.26, 27.4, 27.3, 25.1, 22.8,
14.3; HRMS (ESI, [M + Na]+) calcd for C25H40N2NaO4 455.2880,
found 455.2874.
Bis(5-amino-2-nitrobenzyl)-2,2′-(oleoylimino)diacetate (43). Pre-
pared according general procedure D from 5-amino-2-nitrobenzyl
alcohol 35 (30 mg, 0.18 mmol), 2,2′-(oleoylimino)diacetic acid 23d
(35 mg, 0.088 mmol), DCC (37 mg, 0.18 mmol), and DMAP (22 mg,
0.18 mmol). Purification by preparative layer chromatography (silica
gel, Et2O/MeOH 99:1) afforded the title compound (23 mg, 37%) as
a light yellow oil: Rf 0.27 (Et2O/MeOH 99:1); IR (neat, cm−1) 3365,
3234, 2925, 2854, 1748, 1633, 1582, 1455, 1302, 1260, 1183, 996; 1H
NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 9.2
Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), 6.57 (dd, J
= 9.2 Hz, 2.4 Hz, 1H), 6.51 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 5.58 (s, 2H),
5.56 (s, 2H), 5.31−5.35 (m, 2H), 4.60 (br s, 2H), 4.56 (br s, 2H), 4.33
(s, 2H), 4.32 (s, 2H), 2.37 (t, J = 7.6 Hz, 2H), 1.96−2.00 (m, 4H),
1.62−1.66 (m, 2H), 1.26−1.31 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 174.4, 169.3, 168.5, 152.8, 152.4, 135.6,
134.7, 130.2, 129.9, 128.9, 128.8, 113.04, 112.95, 112.4 (2C), 65.2,
64.7, 50.9, 49.0, 33.0, 32.0, 29.91, 29.85, 29.7, 29.50, 29.47, 29.45, 29.4,
29.3, 27.4, 27.3, 25.1, 22.8, 14.3; HRMS (ESI, [M + Na]+) calcd for
C36H51N5NaO9 720.3579, found 720.3575.
Synthesis of Compounds 12−15, 18, 20, 21, 28−30, 39, 44,
45, and 48. 2-Hydroxy-3(O-tosyl)propyl Oleate (12). To a solution
of monoolein 1 (1.0 g, 2.80 mmol) in absolute pyridine (7.5 mL) was
added p-toluenesulfonyl chloride (642 mg, 3.37 mmol) in small
portions over 30 min at 0 °C. After addition, stirring was continued at
room temperature for 6 h. The reaction mixture was poured into water
and extracted three times with MTBE. The combined organic phases
were washed with half-saturated brine, dried over MgSO4, and
concentrated in vacuo. The residue was subjected to column
chromatography (Et2O/hexane 60:40) to give 12 (1.11 g, 78%) as a
colorless oil: Rf 0.33 (Et2O/hexane 80:20); IR (neat, cm−1) 3462,
1
2926, 2855, 1741, 1599, 1457, 1364, 1190, 1178, 988, 815; H NMR
(400 MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 7.8 Hz,
2H), 5.29−5.38 (m, 2H), 4.03−4.13 (m, 5H), 2.83 (br s, 1H), 2.46 (s,
3H), 2.28 (t, J = 7.2 Hz, 2H), 1.96−2.02 (m, 4H), 1.56−1.61 (m, 2H),
1.25−1.31 (m, 20H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.0, 145.4, 132.6, 130.2, 130.1, 129.9, 128.2, 70.4, 68.0,
64.5, 34.2, 32.1, 29.92, 29.86, 29.7, 29.5 (2C), 29.31, 29.25, 29.2, 27.4,
27.3, 25.0, 22.8, 21.8, 14.3; HRMS (ESI, [M + Na]+) calcd for
C28H46NaO6S 533.2907, found 533.2903.
3-Azido-2-hydroxypropyl Oleate (13). To a solution of mono-
tosylate 12 (0.36 g, 0.7 mmol) in dry DMF (5 mL) was added NaN3
(122 mg, 1.88 mmol) at room temperature under argon. The mixture
was heated to 60 °C for 2.5 h. The reaction mixture was left to cool to
room temperature, poured into water (30 mL) and extracted with
ether (3 × 20 mL). The combined organic phases were washed with
water and brine, dried over MgSO4, and filtered, and the filtrate was
evaporated in vacuo. The residue was purified by column
N-2-[2,3-Di(tert-butoxycarbonyl)guanidino]oleamide (20). N-(2-
Aminoethyl)oleamide 18 (120 mg, 0.37 mmol) in CH2Cl2 (1 mL) was
added in one portion to a solution of N,N′-di-Boc-N′-trifluorometha-
nesulfonylguanidine 19 (131 mg, 0.34 mmol) and Et3N (51.5 μL, 0.37
mmol) in CH2Cl2 (2 mL, filtered over neutral alumina) at 0 °C. The
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reaction was allowed to warm to room temperature and stirred for 3 h.
Then the mixture was diluted with CH2Cl2 (5 mL) and washed with 2
M sodium bisulfate, saturated NaHCO3 aq, and brine. The organic
layer was dried over MgSO4 and concentrated under reduced pressure,
and the residue was purified by column chromatography (hexane/
EtOAc 80:20 to 50:50) to afford 20 (181 mg, 95%) as a white solid:
mp 53−54 °C; Rf 0.25 (hexane/EtOAc 50:50); IR (neat, cm−1) 3322,
2971, 2856, 1724, 1640, 1617, 1559, 1411, 1365, 1228, 1133, 1051,
880, 772; 1H NMR (400 MHz, CDCl3) δ 11.41 (s, 1H, NHBoc), 8.62
(br s, 1H, NH), 7.45 (br s, 1H, NHCO), 5.30−5.37 (m, 2H), 3.54−
3.57 (m, 2H), 3.40−3.43 (m, 2H), 2.17 (t, J = 7.6 Hz, 2H), 1.98−2.02
(m, 4H), 1.60−1.65 (m, 2H), 1.50 (s, 18H), 1.26−1.29 (m, 20H), 0.88
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.6, 163.1,
157.8, 153.3, 130.2, 130.0, 83.8, 79.7, 41.7, 40.5, 37.0, 32.1, 29.99,
29.96, 29.7, 29.56 (2C), 29.54, 29.53 (2C), 29.4, 28.5, 28.3, 27.44,
27.42, 26.0, 22.9, 14.3; HRMS (ESI, [M + Na]+) calcd for
C31H58N4NaO5 589.4299, found 589.4297.
Hz, 2H), 3.66 (s, 3H), 2.54−2.61 (m, 2H), 2.30 (t, J = 6.9 Hz, 2H),
2.05−2.12 (m, 2H), 1.59−1.64 (m, 2H), 1.25−1.40 (m, 10H,); 13C
NMR (75 MHz, CDCl3) δ 174.3, 161.5, 152.8, 147.0, 132.9, 130.3,
129.0, 124.7, 124.4, 122.5, 114.7, 67.8, 51.4, 34.1, 29.5, 29.2, 29.11,
29.09, 27.4 (2C), 24.9; HRMS (ESI, [M + Na]+) calcd for
C25H32N2NaO3 431.2305, found 431.2302.
(9Z)-12-[4-[(E)-Phenyldiazenyl]phenoxy]dodec-9-enoic Acid (30).
A solution of KOH (0.79 g, 14.1 mmol) in MeOH (6.8 mL) was
added dropwise to a stirred solution of 29 (0.70 g, 1.71 mmol) in
MeOH (13 mL) at room temperature under argon. The reaction
mixture was heated at 40 °C for 1 h and stirred overnight at room
temperature. The reaction mixture was poured into water, acidified
with 2 N HCl until pH ∼2, and extracted with Et2O (3 × 30 mL). The
combined organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by recrystalliza-
tion in hexane to afford 30 (588 mg, 87%) as an orange solid: mp
93.5−94 °C; IR (neat, cm−1) 3021, 2920, 2851, 1706, 1599, 1501,
1
1468, 1260, 1209, 1141, 1032, 844; H NMR (300 MHz, CDCl3) δ
N-[2-[(Aminoiminomethyl)amino]butyl]oleamide (21). To a
stirred solution of 20 (150 mg, 0.26 mmol) in CH2Cl2 (2 mL)
cooled at 0 °C under argon was added TFA (2 mL). The mixture was
stirred at 0 °C for 30 min and then at room temperature for 2 h. The
solvent and excess of TFA were removed under reduced pressure and
the residue coevaporated with toluene (3 × 5 mL) to afford the
trifluoroacetate salt in quantitative yield. The salt was dissolved in
H2O, to which Amberlite IRA-402 resin in its OH form was added.
The mixture was stirred for 36 h at room temperature after which the
Amberlite resin was removed by vacuum filtration. The aqueous layer
was washed with CH2Cl2 and concentrated under reduced pressure to
yield 21 (70 mg, 73%) as a white waxy solid: mp 64−66 °C dec; IR
(neat, cm−1) 3275, 2969, 2922, 2853, 1738, 1651, 1540, 1435, 1366,
1228, 1091; 1H NMR (400 MHz, CDCl3) δ 8.16 (br s, 1H, NH), 7.17
(br s, 3H, NH2, NHCO), 5.24−5.44 (m, 2H), 3.14−3.50 (m, 4H),
2.10−2.33 (m, 2H), 1.89−2.08 (m, 4H), 1.48−1.69 (m, 2H), 1.18−
1.38 (m, 20H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 176.3, 158.1, 130.2, 129.9, 40.9, 39.0, 36.5, 32.1, 30.0, 29.9, 29.8,
29.54 (2C), 29.45, 29.42, 29.39, 27.44, 27.41, 25.8, 22.9, 14.3; HRMS
(ESI, [M + H]+) calcd for C21H43N4O 367.3432, found 367.3432.
Methyl (9Z)-12-Bromododec-9-enoate (28). To a solution of
methyl (9Z)-12-(tetrahydro-2′H-pyran-2′-yl-oxy)-1-dodec-9-enoate
27 (1.15 g, 3.95 mmol) in dry CH2Cl2 (20 mL) was added
triphenylphosphine (2.64 g, 10.06 mmol) followed by tetrabromo-
methane (1.58 g, 4.77 mmol) at 0 °C under argon. The reaction
mixture was stirred overnight at room temperature, and then saturated
aqueous NaHCO3 (50 mL) was added to the solution. The mixture
was extracted with CH2Cl2 (3 × 50 mL). The combined organic
phases were washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was subjected to column
chromatography (hexane/Et2O 83:17) to give 28 as a colorless oil
(874 mg, 76%): IR (neat, cm−1) 2929, 2855, 1740, 1437, 1362, 1263,
1172, 1098, 970; 1H NMR (300 MHz, CDCl3) δ 5.51−5.57 (m, 1H),
5.31−5.40 (m, 1H), 3.67 (s, 3H), 3.36 (t, J = 6.9 Hz, 2H), 2.58−2.65
(m, 2H), 2.31 (t, J = 6.9 Hz, 2H), 2.00−2.07 (m, 2H), 1.57−1.64 (m,
2H), 1.31−1.37 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 173.3, 132.0,
124.8, 50.4, 33.1, 31.6, 29.8, 28.4, 28.09, 28.06, 28.02, 26.4, 23.9;
HRMS (ESI, [M + Na]+) calcd for C13H23BrNaO2 313.0773, found
313.0770.
7.91 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 7.2 Hz, 2H), 7.40−7.52 (m, 3H),
7.00 (d, J = 9.0 Hz, 2H), 5.43−5.60 (m, 2H), 4.04 (t, J = 6.9 Hz, 2H),
2.54−2.61 (m, 2H), 2.34 (t, J = 6.9 Hz, 2H), 2.05−2.12 (m, 2H),
1.58−1.66 (m, 2H), 1.25−1.40 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 179.7, 161.5, 152.8, 146.9, 132.9, 130.3, 129.0, 124.7, 124.4,
122.5, 114.7, 67.8, 34.0, 29.5, 29.12, 29.06, 29.00, 27.4 (2C), 24.7;
HRMS (ESI, [M + Na]+) calcd for C24H30N2NaO3 417.2149, found
417.2149.
Ethyl 4-(Hydroxymethyl)-3-nitrobenzoate (39). A 2.6 g (10 mmol)
portion of 3-nitro-4-bromomethylbenzoic acid and 5.3 g (50 mmol) of
Na2CO3 were dissolved in water (40 mL) and acetone (40 mL). The
mixture was placed under reflux overnight, following by evaporation of
the acetone in vacuo. The mixture was washed with diethyl ether (50
mL) and the aqueous phase was acidified until pH ∼2 with a 2 M
solution of HCl. The product was extracted with ethyl acetate (3 × 60
mL) while the pH was kept at 2. The organic layers were combined
and washed with water (100 mL), dried over MgSO4, filtered, and
concentrated in vacuo to afford 1.8 g of the corresponding 4-
(hydroxymethyl)-3-nitrobenzoic acid as an orange solid. The above
crude acid was dissolved in ethanol abs (30 mL), boron trifluoride
diethyl etherate (3.7 mL, 30 mmol) was added at room temperature,
and the reaction mixture was refluxed for 5 h. After the mixture was
cooled to room temperature, the solvent was evaporated in vacuo. To
the residue 50 mL of water was added, the mixture was extracted with
EtOAc (3 × 40 mL), the combined organic layers were dried over
MgSO4, and the solvent was evaporated in vacuo. The residue was
purified by column chromatography (hexane/EtOAc 70:30) to yield
39 (1.77 g, 79%) as a yellow solid: mp 112−114 °C. Rf 0.36 (hexane/
1
EtOAc 70:30); H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 2.0 Hz,
1H), 8.30 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.90 (dd, J = 8.0 Hz, 0.4 Hz,
1H), 5.07 (s, 2H), 4.43 (q, J = 7.2 Hz, 2H), 2.50 (br s, 1H, OH), 1.42
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.6, 147.5,
141.6, 134.7, 131.2, 129.8, 126.2, 62.4, 62.1, 14.5; HRMS (ESI, [M +
Na]+) calcd for C10H11N1NaO5 248.0529, found 248.0528.
(8Z)-Heptadec-8-en-1-amine (44). A solution of sodium azide (4.0
g, 61 mmol) in water (13 mL) was added dropwise to a stirred
solution of oleoyl chloride 2 (15 g, 49.8 mmol) in CH2Cl2 (75 mL)
containing TBAB (50 mg, 0.16 mmol) at 0 °C under argon, and the
resulting two-phase mixture was stirred vigorously for 2 h. The organic
phase was then separated, washed with water (2 × 20 mL), and dried
over MgSO4 for 60 h. Continued evolution of nitrogen as small
bubbles was observed during this period. MgSO4 was filtered off over
Celite, and the resulting crude acid solution was transferred into a two-
neck flask equipped with septum, condenser, and argon inlet and was
used for the next step without further purification. TFA (7.7 g, 5.17
mL, 67 mmol) was added dropwise at room temperature to this
solution, which was thereafter refluxed for 5 h. The reaction mixture
was allowed to cool to room temperature, washed with saturated
aqueous NaHCO3 (2 × 25 mL), dried over MgSO4, filtered, and
concentrated in vacuo. The residue was subjected to column
chromatography (EtOAc/hexane 30:70) to afford the oleic acid
trifluoroacetamide (15.0 g, 86%) as a colorless oil (dried at 40 °C/
Methyl (9Z)-12-[4-[(E)-Phenyldiazenyl]phenoxy]dodec-9-enoate
(29). To a solution of 28 (687 mg, 2.36 mmol) in dry acetone (45
mL) was added 4-phenylazophenol 24 (0.99 g, 5 mmol) followed by
anhydrous potassium carbonate (3.46 g, 25.1 mmol). The reaction
mixture was refluxed for 16 h, cooled to room temperature, poured
into water (300 mL), and extracted with EtOAc (3 × 70 mL). The
combined organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by column
chromatography (Et2O/hexane 10:90 to Et2O 100) to afford 29 (732
mg, 76%) as an orange waxy solid: mp 34.1−34.6 °C; Rf 0.48 (hexane/
Et2O 2:1); IR (neat, cm−1) 3010, 2927, 2854, 1738, 1600, 1582, 1501,
1
1468, 1436, 1250, 1209, 1141, 1024, 833, 689; H NMR (300 MHz,
CDCl3) δ 7.91 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 7.2 Hz, 2H), 7.41−7.53
(m, 3H), 7.00 (d, J = 9.0 Hz, 2H), 5.43−5.60 (m, 2H), 4.05 (t, J = 6.9
K
dx.doi.org/10.1021/jo301659c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2mbar). 6.3 g (18.03 mmol) thereof were cleaved to the amine by
stirring with 15 mL of 2 N aq NaOH in 70 mL of EtOH for 40 h at
room temperature. Subsequently, most of the solvent was evaporated
in vacuo, and the residue was diluted with water (250 mL) and
extracted with Et2O (3 × 70 mL). The combined organic phases were
washed with brine, dried over MgSO4, and evaporated. The crude
product was purified by Kugelrohr distillation at 110 °C/0.05 mbar to
afford 44 (4.2 g, 92%) as a colorless oil: Rf 0.20 (CH2Cl2/MeOH
90:10 with 2% Et3N); IR (neat, cm−1) 3375, 3296, 3005, 2924, 2853,
1619, 1464, 1378, 801; 1H NMR (300 MHz, CDCl3) δ. 5.29−5.40 (m,
2H), 2.67 (t, J = 7.7 Hz, 2H), 2.00−2.04 (m, 4H), 1.19−1.43 (m,
22H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 130.0,
129.8, 42.3, 33.9, 31.9, 29.8, 29.7, 29.5, 29.4, 29.33 (2C), 29.28, 27.20,
27.18, 26.9, 22.7, 14.1; MS (EI) m/z (relative intensity) 253 ([M]+,
32), 154 (49), 140 (85); HRMS (EI, [M + H]+) calcd for C17H36N
254.2842, found 254.2841.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR, 13C NMR, and HRMS spectral data for compounds
4a−d,g−j,m, 5e−m, 7, 11−15, 17, 18, 20, 21, 23a−e, 25, 26,
28−33, 38−46, and 48. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jss@oci.uzh.ch; ehud.landau@oci.uzh.ch.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Debbie Tseng for help with the synthesis.
■
Ethyl 3-[[[(8Z)-Heptadec-8-en-1-ylcarbamoyl]oxy]methyl]-4-ni-
trobenzoate (45). To a stirred suspension of 1,1′-carbonyldiimidazole
(50 mg, 0.31 mmol) in dry CH2Cl2 (1 mL) was added under argon
dropwise a solution of ethyl 3-(hydroxymethyl)-4-nitrobenzoate 38
(70 mg, 0.31 mmol) in dry CH2Cl2 (1 mL) at 0 °C. After the mixture
was stirred for 1 h at room temperature, the (8Z)-8-heptadecen-1-
amine 44 (79 mg, 0.31 mmol) was added and stirring continued
overnight. The reaction mixture was diluted with EtOAc (30 mL) and
washed with aq HCl 10% (2 × 20 mL) and brine (1 × 20 mL). The
organic layer was dried over MgSO4 and filtered, and the solvent was
evaporated in vacuo. Preparative layer chromatography of the crude
product (silica gel, EtOAc/hexane 40:60) afforded 45 (123 mg, 79%)
as a pale yellow waxy solid: mp 62.7−64.5 °C; Rf 0.43 (hexane/EtOAc
60:40); IR (neat, cm−1) 3378, 3344, 3004, 2923, 2852, 1724, 1688,
1527, 1344, 1290, 1269, 1201, 1162, 1138, 1025; 1H NMR (300 MHz,
CDCl3) δ 8.72 (d, J = 1.5 Hz, 1H), 8.28 (dd, J = 1.4 Hz, 8.1 Hz, 1H),
7.68 (d, J = 8.1 Hz, 1H), 5.55 (s, 2H), 5.32−5.37 (m, 2H), 4.86 (br s,
1H), 4.43 (q, J = 7.2 Hz, 2H), 3.17−3.24 (m, 2H), 2.00−2.02 (m,
4H), 1.50−1.54 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H), 1.26−1.31 (m,
20H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.3,
155.5, 147.3, 138.0, 134.1, 131.2, 130.1, 129.7, 128.7, 126.0, 62.9, 61.9,
41.3, 31.9, 29.9, 29.8, 29.7, 29.5, 29.3 (2C), 29.2 (2C), 27.23, 27.16,
26.7, 22.7, 14.3, 14.1; HRMS (ESI, [M + Na]+) calcd for
C28H44N2NaO6 527.3092, found 527.3084.
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solid: mp 72.5−74.0 °C; Rf 0.40 (EtOAc/hexane 80:20); H NMR
(400 MHz, CDCl3) δ 8.70 (d, J = 1.6 Hz), 8.68 (d, J = 1.6 Hz, 1H),
8.26 (dd, J = 8.0 Hz, 1.6 Hz, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.64 (d, J =
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