A practical access to 1,2-diaminophytosphingolipids

Article abstract of DOI:10.1002/ejoc.200800565

A practical approach to the synthesis of phytosphingolipids containing the 1,2-diamino framework is described. The methodology relies on the regioselective ring-opening of phytosphingosine-derived N-nosylaziridines 4 and 6 with primary or secondary amines, acylation and subsequent deprotection steps. For practical purposes, N-substituted benzylamines were used as protected primary amine surrogates to avoid side-reactions in the course of the N-nosyl deprotection step. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800565

FULL PAPER
DOI: 10.1002/ejoc.200800565
A Practical Access to 1,2-Diaminophytosphingolipids
Youssef Harrak,[a] Amadeu Llebaria,[a] and Antonio Delgado*[a,b]
Keywords: Small ring systems / Sphingolipids / Aziridines / Sulfonamides / Heterocycles
A practical approach to the synthesis of phytosphingolipids
containing the 1,2-diamino framework is described. The
methodology relies on the regioselective ring-opening of
phytosphingosine-derived N-nosylaziridines 4 and 6 with
primary or secondary amines, acylation and subsequent de-
zylamines were used as protected primary amine surrogates
to avoid side-reactions in the course of the N-nosyl deprotec-
tion step.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
protection steps. For practical purposes, N-substituted ben- Germany, 2008)
Introduction
The 1,2-diamino moiety is widespread in nature as part
of many biologically active natural products and also as the
key component of a variety of synthetic compounds with
multiple applications in medicinal chemistry as therapeuti-
cally active agents or as pharmacological tools.[1,2] As a re-
sult of our current interest in sphingolipids, we became in-
terested in the exploration of the antifungal properties of a
series of phytosphingolipid analogues encompassing dif-
ferent structural modifications on the sphingoid base skel-
eton. Among them, some 1-amino-1-deoxyphytosphingos-
ines showed promising biological results,[3,4] in agreement
with the hypothesis that the introduction of non-natural
functional groups into a sphingolipid skeleton might alter
the biological profile or the metabolic stability of the re-
sulting analogues.[5] Despite the scarce precedents for the
use of the 1,2-diamino moiety in sphingolipid chemistry,
some important examples have emerged over the last few
years. Thus, phosphoramide A has been reported as a meta-
bolically stable sphingosine-1-phosphate surrogate,[6]
whereas phosphoramide B has been described as a sphingo-
myelinase inhibitor.[7] Other examples of sphingolipid ana-
logues containing the 1,2-diamino framework are found in
the sphingosine kinase inhibitor C[8] and in a series of glu-
cosylceramide synthase inhibitors of general structure D.[9]
(Figure 1).
Figure 1. Phytosphingolipids and some reported sphingolipid ana-
logues containing the 1,2-diamino framework.
As a continuation of this work, in an attempt to widen
the diversity of our previously reported analogues, we wish
to report on a general approach to new phytosphingolipids,
structurally related to phytosphingosine (RЈ = H) or phyto-
ceramide (RЈ = acyl) incorporating a vicinal 1,2-diamino
moiety (Figure 1).
Results and Discussion
Our methodology relies on the regiospecific nucleophilic
ring-opening of N-nosylaziridines 4 or 6, which arise from
mesylate formation from O,O-diprotected 2-azidophytos-
phingosines 1[10] or 2,[11] azide reduction with in situ intra-
molecular cyclization[12] to aziridines 3 or 5 and final sulfo-
nylation with 2-nitrobenezenesulfonyl chloride (nosyl chlo-
ride)[13,14] (Scheme 1).
[a] Research Unit for BioActive Molecules (RUBAM); De-
partament de Química Orgànica Biològica, Institut d’Investiga-
cions Químiques i Ambientals de Barcelona (IIQAB-CSIC),
Jordi Girona 18-26, 08034 Barcelona, Spain
Fax: +34-932-045-904
E-mail: antonio.delgado@cid.csic.es
[b] Universitat de Barcelona, Facultat de Farmàcia, Unitat de
Química Farmacèutica (Unitat Associada al CSIC),
Avgda. Juan XXIII, s/n, 08028 Barcelona, Spain
Eur. J. Org. Chem. 2008, 4647–4654
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4647

Y. Harrak, A. Llebaria, A. Delgado
FULL PAPER
However, attempts to remove the N-nosyl group from
[17]
phytosphingosines 8 and 9 with PhSH/Cs2CO3 met with
limited success as only the anilino (8e, 9e), morpholino (8f,
9f) and pyrrolidino (9g) analogues afforded the expected
phytosphingosines 10e,f and 11e–g as single products in
good yields (see Scheme 3 and Table 2), whereas the nosyl
derivatives 8a–d and 9a–c afforded complex reaction mix-
tures. We hypothesised that a transient amide resulting from
deprotonation of the C(1)NH group by the caesium salt[18]
in the above compounds would be responsible for the ob-
served side-reactions because of an intramolecular amide
displacement of the C(2)N-nosyl group in competition with
the external thiolate.[19] In agreement with this assumption,
no side-reactions were observed with morpholines 8f and
9f, pyrrolidine 9g and tertiary amines 9h and 9i, from which
amide formation is precluded. On the other hand, the lower
nucleophilicity of the caesium amide arising from anilino
derivatives 8e and 9e would not interfere with the external
thiolate in the deprotection step (see Scheme 3 and Table 2).
Scheme 1. Reagents and conditions: (a) MsCl, THF, Et3N; (b)
Ph3P, THF, H2O; (c) ClSO2R, THF, Et3N.
To illustrate the versatility of this synthetic protocol, nos-
ylaziridines 4 and 6 were treated with amines 7a–h in re-
fluxing CH3CN.[15] The reactions took place smoothly un-
der the conditions shown in Scheme 2 to afford 1,2-diami-
nophytosphingosines 8 and 9 in good-to-excellent yields
(Table 1).[16]
Scheme 3. Sequential deprotection of 1,2-diaminophytosphingos-
ines. Reaction conditions: (a) PhSh (4 equiv/mol)/Cs2CO3 (3 equiv/
mol), CH3CN, room temp., 20 h. For compound identification and
yields, see Table 2.
Table 2. Synthesis of the phytosphingosines (see Scheme 3).
Entry Nosylate R1
R2
Amine
(yield [%])
Yield[a,b]
[%]
Scheme 2. Ring-opening of nosylaziridines with amines. Reaction
conditions: amine (2 equiv./mol), CH3CN, reflux, 3 h or room
temp. 24 h. For compound identification and yields, see Table 1.
1
2
3
4
5
6
7
8e
8f
9e
9f
9g
9h
9i
Ph
Ph
H
H
10e (75)
10f (83)
11e (79)
11f (88)
11g (90)
11h (79)
11i (83)
12e
12f
12e
12f
12g
78 (A)
89 (A)
99 (B)
99 (B)
99 (B)
morpholine
morpholine
pyrrolidine
Table 1. Reaction of nosylaziridines 4 and 6 with amines.
2-hydroxyethyl Bn
tBu Bn
12h (R2 = H) 97 (C)
12i (R2 = H) 82 (C)
Entry
Aziridine Amine R1
R2
Ad-
Yield[a] [%]
duct
[a] Isolated yields. [b] A, B, C: deprotection methods (see text).
1
2
3
4
5
6
7
8
4
4
4
4
4
4
6
6
6
6
6
6
6
6
7a
7b
7c
7d
7e
7f
7a
7c
7d
7e
7f
nBu
nOct
2-hydroxyethyl
tBu
Ph
morpholine
nBu
2-hydroxyethyl
tBu
H
H
H
H
H
8a
8b
8c
8d
8e
8f
9a
9c
9d
9e
9f
81
80
89
93
85
89
83
78
95
87
97
99
89
82
Acetal removal under standard acidic conditions af-
forded phytosphingosines 12e–g (Method B, Table 2, en-
tries 3–5). On the other hand, the choice of N-substituted
benzylamines as masked precursors of secondary amines re-
quired the final simultaneous deprotection of the benzyl
and acetal groups in compounds 11h and 11i, which was
easily carried out by catalytic hydrogenation under acidic
conditions to afford phytosphingosines 12h and 12i in excel-
lent yields (Method C, Table 2, entries 6 and 7). Finally,
BCl3-promoted benzyl removal[20] from precursors 10e and
10f afforded phytosphingosines 12e and 12f in acceptable
yields (Method A, Table 2, entries 1 and 2).[21]
H
H
H
H
9
10
11
12
13
14
Ph
morpholine
pyrrolidine
2-hydroxyethyl
tBu
7g
7h
7i
9g
9h
9i
Bn
Bn
[a] Isolated yields. For reaction conditions, see Scheme 2.
4648
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4647–4654

A Practical Access to 1,2-Diaminophytosphingolipids
Scheme 4. Acylation of diamines 11 and simultaneous N- and O-deprotection. Reaction conditions: (a) RCOCl, THF, Et3N; b) H2, 5%
Pd/C, HCl, MeOH.
the next step without further purification. Et(iPr)2N (3.75 mmol)
and Ph3P (3.25 mmol) were added to a solution of the correspond-
ing mesylate (2.5 mmol) in THF/H2O (18:2). The reaction mixture
was heated at 60 °C for 2 h and cooled to room temperature. The
mixture was poured into brine and extracted with Et2O
(3ϫ30 mL). The combined organic layers were dried with Na2SO4
and concentrated under reduced pressure to give a residue, which
was purified by flash chromatography on silica gel (7:3 hexane/ethyl
acetate) to afford the required aziridines.
This protocol was easily adapted to 1,2-diaminophyto-
ceramide derivatives by standard acylation of intermediate
amines 11 and final simultaneous N- and O-deprotection.
An illustrative example is shown in Scheme 4 in which
amine 11i is acylated with two different acyl chlorides and
then deprotected to afford phytoceramides 15a and 15b in
excellent yields and purities (Scheme 4).
Aziridine 3: Oil, yield 960 mg, 80%. [α]D = –23 (c = 1, CDCl3). IR
Conclusions
(neat): ν = 3412, 3018, 2926, 2854, 1454, 1215, 1095, 757, 669 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 7.32 (m, 10 H), 4.72–4.54 (m, 4
H), 3.64 (dt, J = 8.4, 3.6 Hz, 1 H), 3.22 (m, 1 H), 2.16 (m, 1 H),
1.78 (d, J = 5.6 Hz, 1 H), 1.61 (d, J = 3.2 Hz, 1 H), 1.73–1.51 (m,
3 H, NH, 2 CH), 1.30 (m, 24 H), 0.89 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 138.7, 138.4, 128.3–127.5 (10
C), 81.3, 81.0, 72.6, 72.3, 31.9, 30.7, 29.8–29.3 (10 C), 25.9, 23.1,
22.7, 14.1 ppm. HRMS: calcd. for C32H49NO2 [M + H]+ 480.3771;
found 480.3767.
A practical protocol for the simple construction of phy-
tosphingosine analogues bearing a vicinal 1,2-diamino moi-
ety has been developed. The method relies on the regiose-
lective ring-opening of N-nosylaziridines 4 and 6 with suit-
able amines and subsequent N-nosyl removal and deprotec-
tion. N-Acylation of intermediates 11 prior to final O- and
N-deprotection leads to phytoceramide analogues. The ver-
satility and simplicity of the method makes it amenable to
the production of small-to-medium-sized libraries for fur-
ther screening.
Aziridine 5: Oil, yield 690 mg, 82%. [α]D = +7 (c = 1, CDCl3).
1
IR (neat): ν = 3390, 3015, 2911, 2832, 1209, 1055 cm–1. H NMR
˜
(500 MHz, CDCl3): δ = 4.23 (m, 1 H), 3.57 (m, 1 H), 2.09 (m, 1
H), 1.87 (m, 1 H), 1.72 (m, 2 H), 1.58 (m, 2 H), 1.48 (s, 3 H), 1.40
(s, 3 H), 1.31 (m, 24 H), 0.89 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 107.7, 80.3, 77.9, 31.8, 29.8–29.5 (10 C),
28.7, 27.8, 26.6, 25.1, 22.6 (2 C), 14.0 ppm.
Experimental Section
General Methods: All moisture-sensitive reactions were carried out
under argon. All the materials were obtained commercially and
used without further purification. Solvents were distilled prior to
use and dried by standard methods.[22] Thin-layer chromatography
(TLC) was performed on silica gel (Alugram Sil G/UV). Analytical
samples were homogeneous as confirmed by TLC and afforded
spectroscopic results consistent with the assigned structures. Melt-
ing points were determined with an SMP10 melting-point appara-
tus and are uncorrected. Chemical shifts are reported in δ (ppm)
relative to the singlet at δ = 7.24 ppm of CDCl3 and 3.31 ppm of
MeOD for 1H NMR and to the centre line of the triplet at δ =
77.0 ppm of CDCl3 and 49.0 ppm of MeOD for 13C NMR. IR
spectra were measured as films and were recorded with a BOMEM
MB-120 instrument. [α]D values are given in 10–1 degcm2 g–1 and
were measured with a Perkin–Elmer 341 polarimeter. ESI/HRMS
were recorded with a Waters LCT Premier mass spectrometer.
General Procedure for the Preparation of N-(o-Nosyl)aziridines 4
and 6: Et3N (3 mmol) and the sulfonyl chloride derivative (1 mmol,
1 equiv.) in THF (2 mL) was added to a solution of the correspond-
ing aziridine 3 or 5 (1 mmol) in THF (8 mL). The reaction mixture
was stirred at room temperature for 2 h. Then sat. NaHCO3
(15 mL) was added and the mixture was extracted with EtOAc
(3ϫ15 mL). The organic layers were dried with MgSO4 and the
solvents were evaporated at reduced pressure to give the crude azir-
idines, which were purified by column chromatography (5:1 hex-
anes/EtOAc).
N-(o-Nosyl)aziridine (4): Oil, yield 480 mg, 81%. [α]D = –23 (c = 1,
CDCl ). IR (neat): ν = 3012, 2933, 2824, 1412, 1577, 1368, 1189,
˜
3
768 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 8 Hz, 1
H), 7.71 (m, 3 H), 7.30 (m, 10 H), 4.57 (m, 4 H), 3.70 (t, J = 3.6 Hz,
1 H), 3.5 (m, 1 H), 3.27 (m, 1 H), 2.77 (d, J = 7.2 Hz, 1 H), 2.54
(d, J = 4.8 Hz, 1 H), 1.60 (m, 2 H), 1.25 (m, 24 H), 0.87 (t, J =
6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.5, 138.3,
138.0, 134.4, 132.0, 131.6, 131.1, 128.3–127.5 (10 C), 124.3, 80.2,
76.8, 73.4, 72.2, 41.2, 32.7, 31.8, 30.3, 29.7–29.3 (9 C), 25.5, 22.6,
14.1 ppm. HRMS: calcd. for C38H52N2O6S [M + H]+ 665.3654;
found 665.3624.
(S)-2-[(1S,2R)-1,2-Bis(benzyloxy)hexadecyl]aziridine (3) and (S)-2-
[(4S,5R)-2,2-Dimethyl-5-tetradecyl-1,3-dioxolan-4-yl]aziridine (5):
Et3N (7.5 mmol, 3 equiv.) and MsCl (5 mmol) were added to a
solution of azide 1[10] or 2[11] (2.5 mmol) in THF (30 mL) at room
temperature. The reaction mixture was stirred for 3 h, poured into
saturated aqueous NaHCO3 and extracted with EtOAc. The sepa-
rated organic layer was washed with brine, dried with MgSO4 and
concentrated under reduced pressure. The residue was employed in
N-(o-Nosyl)aziridine (6): White solid, yield 377 mg, 82%. [α]D
=
–47 (c = 1, CDCl ); m.p. 112–114 °C. IR (neat): ν = 2924, 2853,
˜
3
Eur. J. Org. Chem. 2008, 4647–4654
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4649

Y. Harrak, A. Llebaria, A. Delgado
FULL PAPER
1547, 1369, 1168, 752 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.21 1 H), 1.66 (m, 2 H), 1.44 (m, 2 H), 1.27 (m, 22 H), 0.89 (t, J =
(d, J = 6.4 Hz, 1 H), 7.70 (m, 3 H), 4.21 (m, J = 6.8 Hz, 1 H), 3.96 7 Hz, 3 H), 0.80 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
(t, J = 6 Hz, 1 H), 3.17 (m, J = 6.8 Hz, 1 H), 2.92 (d, J = 7.2 Hz, 147.8, 138.4, 138.0, 134.4, 133.1, 132.5, 130.8, 128.4 (2 C), 128.3 (2
1 H), 2.52 (d, J = 4.4 Hz, 1 H), 1.60 (m, 2 H), 1.44 (s, 3 H), 1.32
C), 128.1 (2 C), 127.9 (2 C), 127.8, 127.6, 125.0, 81.5, 79.0, 73.9,
(s, 3 H), 1.25 (m, 24 H), 0.87 (t, J = 7 Hz, 3 H) ppm. 13C NMR 71.5, 54.8, 50.0, 41.2, 31.9, 29.9–29.3 (10 C), 28.5 (3 C), 25.2, 22.6,
(100 MHz, CDCl3): δ = 148.4, 134.5, 132.2, 132.0, 131.3, 124.4, 14.1 ppm. HRMS: calcd. for C42H63N3O6S [M + H]+ 738.4555;
108.5, 77.5, 76.9, 39.9, 33.3, 31.9, 29.7–29.3 (10 C), 27.7, 26.7, 25.2,
22.7, 14.1 ppm. HRMS: calcd. for C27H44N2O6S [M + H]+
525.2998; found 525.2997.
found 738.4542.
8e: Oil, yield 347 mg, 85%. [α]D = +53 (c = 1, CDCl3). IR (neat):
ν = 3331, 2914, 1517, 1463, 1127, 814, 724, 668 cm–1. 1H NMR
˜
General Procedure for the Ring-Opening of N-(o-Nosyl)aziridines 4
and 6 with Amines: The corresponding amine (1 mmol) in CH3CN
(1 mL) was added to a stirred solution of the corresponding N-(o-
nosyl)aziridine (0.5 mmol) in dry CH3CN (4 mL). The mixture was
stirred at room temperature for 20 h or at reflux temperature for
2–3 h. Then the solvent was evaporated in vacuo to give a crude,
which was purified by chromatography with 4:1 hexanes/EtOAc.
(400 MHz, CDCl3): δ = 7.89 (dd, J = 7.6, 0.8 Hz, 1 H), 7.62 (dd,
J = 8.4, 1.2 Hz, 1 H), 7.46 (dt, J = 7.6, 1.2 Hz, 1 H), 7.40 (m, 11
H), 6.87 (t, J = 8 Hz, 2 H), 6.56 (t, J = 7.6 Hz, 1 H), 6.15 (d, J =
7.6 Hz, 2 H), 5.96 (d, J = 7.2 Hz, 1 H), 4.74–4.51 (m, 4 H), 4.00
(m, 1 H), 3.98 (br., 1 H), 3.90 (dd, J = 6.4, 2.8 Hz 1 H), 3.67 (mc,
J = 5.6 Hz, 1 H), 3.37 (dd, J = 14, 4 Hz, 1 H), 3.28 (dd, J = 13.6,
7.6 Hz, 1 H), 1.67 (m, 2 H), 1.37 (m, 2 H), 1.27 (m, 22 H), 0.89 (t,
J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.3,
147.0, 138.2, 137.7, 133.8, 133.1, 132.5, 130.6, 128.9 (2 C), 128.5 (2
C), 128.4 (2 C), 128.0 (3 C), 127.7 (2 C), 127.6, 125.2, 117.4, 112.6
(2 C), 82.1, 78.3, 74.1, 71.2, 54.1, 43.3, 31.9, 30.0–29.3 (10 C), 24.7,
22.7, 14.1 ppm. HRMS: calcd. for C44H59N3O6S [M + H]+
758.4271; found 758.4253.
8a: Oil, yield 273 mg, 81%. [α]D = +24 (c = 1, CDCl3). IR (neat):
ν = 3356, 2921, 2849, 1932, 1547, 1469, 1165, 875, 712, 689 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 7.6 Hz, 1 H), 7.80
(d, J = 7.6 Hz, 1 H), 7.65 (t, J = 8 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1
H), 7.32 (m, 10 H), 4.74–4.47 (m, 4 H), 3.80 (t, J = 4.8 Hz, 1 H),
3.70 (m, 1 H), 3.62 (m, 1 H), 2.93 (dd, J = 12.4, 5.2 Hz, 1 H), 2.35
(dd, J = 12.8, 4.4 Hz, 1 H), 2.25 (m, 1 H), 2.17 (m, 1 H), 1.63 (m, 8f: Oil, yield 306 mg, 89%. [α]D = +60 (c = 1, CDCl3). IR (neat):
2 H), 1.37 (m, 2 H), 1.27 (m, 22 H), 1.11 (m, 4 H), 0.89 (t, J = ν = 2913, 2843, 1927, 1554, 1443, 1176, 859, 772, 691 cm–1. 1H
˜
7.2 Hz, 3 H), 0.80 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.6 Hz, 1 H), 7.84 (d,
CDCl3): δ = 147.7, 138.3, 137.9, 134.2, 133.1, 132.5, 131.0, 128.4
(2 C), 128.3 (2 C), 128.2 (2 C), 127.9 (2 C), 127.7, 127.5, 124.9,
81.3, 78.9, 74.0, 71.6, 54.2, 49.4, 48.5, 31.9, 31.6, 29.8–29.3 (10 C),
25.1, 22.6, 20.1, 14.1 ppm. 13.9. HRMS: calcd. for C42H63N3O6S
[M + H]+ 738.4555; found 738.4542.
J = 8 Hz, 1 H), 7.64 (t, J = 7.6 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 1 H),
7.33 (m, 10 H), 4.92–4.40 (m, 4 H), 4.20 (dd, J = 6, 1.2 Hz, 1 H),
3.72 (t, J = 4.4 Hz, 1 H), 3.50 (mc, J = 5.6 Hz, 1 H), 3.33 (m, 2
H), 3.22 (br., 2 H), 2.65 (t, J = 11 Hz, 1 H), 2.40 (dd, J = 13.2,
4 Hz, 1 H), 2.10 (br., 2 H), 1.97 (br., 2 H), 1.65 (m, 2 H), 1.39 (m,
2 H), 1.27 (m, 22 H), 0.89 (t, J = 7 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 147.8, 138.4, 138.2, 133.3, 133.2, 132.4,
131.1, 128.3 (4 C), 127.9 (2 C), 127.7 (2 C), 127.5 (2 C), 125.0, 80.7,
78.3, 74.6, 70.7, 66.3 (2 C), 56.5, 53.5, 52.5 (2 C), 31.9, 30.1–29.3
(10 C), 24.4, 22.6, 14.0 ppm. HRMS: calcd. for C42H61N3O7S [M
+ H]+ 752.4368; found 752.4334.
8b: Oil, yield 270 mg, 80%. [α]D = +42 (c = 1, CDCl3). IR (neat):
ν = 3431, 2917, 2826, 1552, 1447, 814, 711 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 8.03 (d, J = 7.6 Hz, 1 H), 7.82 (d, J =
7.6 Hz, 1 H), 7.65 (t, J = 8 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.32
(m, 10 H), 4.73–4.48 (m, 4 H), 3.80 (t, J = 4.8 Hz, 1 H), 3.63 (m,
2 H), 2.90 (dd, J = 12.4, 5.2 Hz, 1 H), 2.27 (m, 2 H), 2.14 (m, 1
H), 1.64 (m, 2 H), 1.39 (m, 2 H), 1.27 (m, 36 H), 0.89 (m, 6 H) ppm. 9a: Oil, yield 222 mg, 83%. [α]D = +50 (c = 1, CDCl3). IR (neat):
13C NMR (100 MHz, CDCl3): δ = 147.7, 138.4, 138.0, 134.2, 133.1, ν = 3341, 2924, 2853, 1915, 1541, 1465, 1173, 853, 784 cm–1. 1H
˜
132.5, 131.0, 128.4 (2 C), 128.3 (2 C), 128.1 (2 C), 127.8, 127.7 (2
C),127.5, 125.0, 81.2, 78.9, 73.9, 71.4, 54.5, 49.8, 48.3, 31.9, 31.8,
29.8–29.3 (12 C), 27.1, 25.1, 22.6 (2 C), 20.1, 14.0 (2 C) ppm.
HRMS: calcd. for C46H71N3O6S [M + H]+ 794.5215; found
794.5242
NMR (500 MHz, CDCl3): δ = 8.14 (m, 1 H), 7.88 (m, 1 H), 7.72
(m, 2 H), 4.15 (m, 1 H), 4.07 (t, J = 6 Hz 1 H), 3.66 (m, 1 H), 2.88
(dd, J = 12.5, 3.5 Hz, 1 H), 2.38 (m, 1 H), 2.32 (dd, J = 12.5,
3.5 Hz, 1 H), 2.17 (m, 1 H), 1.65–144 (m, 4 H), 1.39 (s, 3 H), 1.29
(s, 3 H), 1.21 (m, 26 H), 0.85 (t, J = 7 Hz, 3 H), 0.83 (t, J = 7 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.7, 135.5, 133.3,
132.9, 130.3, 125.3, 107.8, 77.8, 77.6, 53.9, 49.8, 49.4, 32.1, 31.9,
29.6–29.3 (10 C), 27.5, 26.6, 25.3, 22.7, 20.2, 14.1, 13.9 ppm.
HRMS: calcd. for C31H55N3O6S [M + H]+ 598.3928; found
598.3944.
8c: Oil, yield 301 mg, 89%. [α]D = +35 (c = 1, CDCl3). IR (neat):
ν = 3433, 2918, 1553, 1471, 916, 762 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 8.01 (d, J = 8 Hz, 1 H), 7.80 (d, J = 8 Hz, 1 H), 7.65
(t, J = 8 Hz, 1 H), 7.54 (t, J = 8 Hz, 1 H), 7.33 (m, 10 H), 4.66–
4.47 (m, 4 H), 3.75 (m, 1 H), 3.60 (m, 2 H), 3.36 (t, J = 5.6 Hz, 2
H), 2.94 (br., 1 H, OH), 2.88 (dd, J = 12.4, 5.6 Hz, 1 H), 2.82 (br., 9c: Oil, yield 208 mg, 78%. [α]D = +15 (c = 1, CDCl ). IR (neat): ν
˜
3
1 H, NH), 2.50 (m, 1 H), 2.40 (dd, J = 12.8, 4.4 Hz, 1 H), 2.32 (m,
1 H), 1.60 (m, 2 H), 1.27 (m, 24 H), 0.88 (t, J = 7 Hz, 3 H) ppm.
= 3454, 2931 2833, 1551, 1473, 812, 678 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.13 (m, 1 H), 7.88 (m, 1 H), 7.73 (m, 2 H), 4.13 (m,
13C NMR (100 MHz, CDCl3): δ = 147.7, 138.2, 137.8, 134.2, 133.2, 1 H), 4.04 (t, J = 6 Hz, 1 H), 3.71 (m, 1 H), 3.45 (m, 1 H), 3.40
132.5, 130.8, 128.4 (2 C), 128.3 (2 C), 128.0 (2 C), 127.9, 127.8 (2
C), 127.6, 125.1, 81.3, 78.7, 73.8, 71.5, 61.0, 54.7, 51.1, 48.4, 31.9,
(m, 1 H), 2.98 (br., 3 H), 2.90 (dd, J = 12.8, 4.4 Hz, 1 H), 2.66 (m,
1 H), 2.39 (m, 2 H), 1.59 (m, 2 H), 1.38 (s, 3 H), 1.30 (s, 3 H), 1.35
29.9–29–3 (10 C), 25.2, 22.6, 14.0 ppm. HRMS: calcd. for (m, 24 H), 0.87 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz,
C40H59N3O7S [M + H]+ 586.3492; found 586.3506
CDCl3): δ = 147.7, 135.4, 133.5, 132.9, 132.2, 125.5, 108.0, 77.6 (2
C), 61.0, 53.9, 55.8, 51.3, 49.3, 31.9, 29.6–29–3 (10 C), 27.5, 26.6,
25.3, 22.6, 14.1 ppm. HRMS: calcd. for C29H51N3O7S [M + H]+
586.3580; found 586.3572.
8d: Oil, yield 337 mg, 93%. [α]D = +53 (c = 1, CDCl3). IR (neat):
ν = 3342, 2917, 2843, 1551, 1461, 863, 695 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 8.05 (d, J = 7.6 Hz, 1 H), 7.81 (d, J =
7.6 Hz, 1 H), 7.65 (t, J = 7.6 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 1 H),
7.33 (m, 10 H), 4.75–4.49 (m, 4 H), 3.82 (t, J = 4.4 Hz, 1 H), 3.62
9d: Oil, yield 253 mg, 95%. [α]D = +28 (c = 1, CDCl3). IR (neat):
1
ν = 3361, 2916, 2846, 1549, 1457, 761 cm–1. H NMR (400 MHz,
˜
(m, 2 H), 2.82 (dd, J = 12.4, 4.4 Hz, 1 H), 2.32 (dd, J = 12, 4.4 Hz, CDCl3): δ = 8.12 (dd, J = 7.2, 1.6 Hz, 1 H), 7.83 (dd, J = 6.8,
4650
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4647–4654

A Practical Access to 1,2-Diaminophytosphingolipids
1.2 Hz, 1 H), 7.71 (m, 2 H), 4.10 (m, 2 H), 3.71 (m, 1 H), 2.81 (dd,
J = 12, 3.6 Hz, 1 H), 2.41 (dd, J = 12, 3.6 Hz, 1 H), 1.59 (m, 4 H,
2CH, 2NH), 1.40 (s, 3 H), 1.30 (s, 3 H), 1.25 (m, 24 H), 0.86 (m,
12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.8, 135.6, 133.3,
132.8, 130.2, 125.1, 107.8, 77.8, 77.6, 53.9, 50.3, 42.6, 31.9, 29.7–
29.3 (10 C), 28.5 (3 C), 27.5, 26.6, 25.3, 22.7, 14.1 ppm. HRMS:
calcd. for C31H55N3O6S [M + H]+ 598.3928; found 598.3916.
31.9, 30.2, 29.6–29.3 (9 C), 27.3 (3 C), 26.9, 26.6, 25.1, 22.7,
14.1 ppm. HRMS: calcd. for C38H61N3O6S [M + H]+ 688.4359;
found 688.4347.
(S)-2-Azido-1-[(4S,5R)-2,2-dimethyl-5-tetradecyl-1,3-dioxolan-4-yl]-
N-(o-nosyl)ethanamine (9j): NaN3 (97 mg, 1.5 mmol) was added
portionwise to a stirred solution of the corresponding N-(o-nosyl)-
aziridine 6 (0.15 mmol) in 9:1 MeOH/H2O (10 mL). The mixture
was stirred at reflux temperature for 16 h. Then saturated aqueous
NaHCO3 (30 mL) was added and the aqueous phase was extracted
with EtOAc (3ϫ15 mL). The combined organic extracts were dried
with MgSO4, filtered and the solvents were evaporated under re-
duced pressure. The crude product was purified by chromatography
on 4:1 hexane/EtOAc to give 9j (72 mg, 85%) as a colourless oil:
9e: Oil, yield 241 mg, 87%. [α]D = +13 (c = 1, CDCl3). IR (neat):
ν = 3411, 2919, 2838, 1925, 1557, 1469, 1161, 849, 681 cm–1. 1H
˜
NMR (400 MHz, CDCl3): δ = 8.07 (m, 1 H), 7.74 (m, 1 H), 7.61
(m, 2 H), 7.01 (t, J = 7.6 Hz, 2 H), 6.64 (t, J = 7.6 Hz, 1 H), 6.32
(d, J = 8 Hz, 2 H), 5.88 (d, J = 8.8 Hz, 1 H), 4.17 (m, 2 H), 3.83
(m, 1 H), 3.27 (d, J = 5.2 Hz, 1 H), 1.60 (m, 2 H), 1.45 (s, 3 H),
1.32 (s, 3 H), 1.26 (m, 24 H), 0.88 (t, J = 7 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 147.4 (2 C), 135.0 133.3, 133.0, 130.1, 129.0
(2 C), 125.4, 118.0, 113.0 (2 C), 108.3, 78.5, 77.4, 54.4, 45.0, 31.9,
29.7–29.3 (10 C), 27.3, 26.5, 25.3, 22.7, 14.1 ppm. HRMS: calcd.
for C33H51N3O6S [M + H]+ 618.3629; found 618.3603
[α]D = +11 (c = 1, CDCl ). IR (neat): ν = 3331, 2924, 2853, 2105,
˜
3
1542, 1420, 1355, 1171, 1060, 758 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 8.16 (m, 1 H), 7.95 (m, 1 H), 7.77 (m, 2 H), 5.72 (d,
J = 10 Hz, 1 H), 4.17 (m, 1 H), 4.03 (dd, J = 8, 6 Hz, 1 H), 3.80
(m, 1 H), 3.58 (dd, J = 12.8, 4.4 Hz, 1 H), 3.27 (dd, J = 12.8,
3.2 Hz, 1 H), 1.55 (m, 2 H), 1.40 (s, 3 H), 1.33 (s, 3 H), 1.25 (m,
24 H), 0.87 (t, J = 7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 147.6, 135.5, 133.7, 133.2, 130.1, 125.8, 108.3, 77.4, 76.5, 53.8,
52.6, 31.9, 29.7–29.1 (10 C), 27.7, 26.5, 25.4, 22.7, 14.1 ppm.
HRMS: calcd. for C27H46N5O6S [M + H]+ 568.3169; found
568.3181.
9f: Oil, yield 266 mg, 97%. [α]D = +18 (c = 1, CDCl3). IR (neat):
ν = 2913, 1932, 1557, 1463, 1160, 854, 777 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 8.12 (m, 1 H), 7.93 (m, 1 H), 7.73 (m, 2
H), 4.32 (dd, J = 6.4, 5.2 Hz, 1 H), 4.18 (mc, J = 6.8 Hz, 1 H), 3.60
(m, 1 H), 3.34 (m, 2 H), 3.27 (m, 2 H), 2.59 (dd, J = 13.6, 8.4 Hz,
1 H), 2.36 (dd, J = 14, 3.2 Hz, 1 H), 2.26 (m, 4 H), 1.56 (m, 2 H),
1.40 (s, 3 H), 1.30 (s, 3 H), 1.27 (m, 24 H), 0.87 (t, J = 6.8 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.7, 133.4, 133.3,
132.9, 130.1, 125.4, 107.9, 78.6, 77.1, 66.5 (2 C), 58.7, 54.1, 52.7 (2
C), 31.8, 29.6–29.3 (10 C), 26.9, 26.6, 25.1, 22.6, 14.1 ppm. HRMS:
calcd. for C31H53N3O7S [M + H]+ 612.3782; found 612.3769.
(S)-3-[(4S,5R)-2,2-Dimethyl-5-tetradecyl-1,3-dioxolan-4-yl]-3-[(o-
nosyl)amino]propanenitrile (9k): NaCN (73 mg, 1.5 mmol) was
added portionwise to a stirred solution of N-(o-nosyl)aziridine 6
(0.15 mmol) in CH3CN (10 mL) and the mixture was stirred at re-
flux temperature for 20 h. Saturated aqueous NaHCO3 (30 mL)
was then added and the aqueous phase was extracted with CH2Cl2.
The combined organic layers were dried with MgSO4, filtered and
the solvent evaporated under reduced pressure. The crude product
was purified by silica gel column chromatography (hexane/EtOAc,
5:1) to give 9k (60 mg, 87%) as a colourless oil. [α]D = +9.3 (c =
9g: Oil, yield 263 mg, 99%. [α]D = +19 (c = 1, CDCl3). IR (neat):
ν = 3557, 2949, 2865, 1563, 1313, 1228, 1071 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 8.15 (dd, J = 7, 2 Hz, 1 H), 7.93 (dd, J =
7.5, 2 Hz, 1 H), 7.71 (m, 2 H), 5.08 (br., 1 H, NHSO2), 4.32 (t, J
= 5.5 Hz, 1 H), 4.19 (m, 1 H), 3.52 (m, 1 H), 3.16 (t, J = 6.5 Hz,
2 H), 2.75 (dd, J = 13.5, 9 Hz, 1 H), 2.36 (dd, J = 13.5, 3 Hz, 1
H), 2.19 (m, 4 H), 1.90 (t, J = 6.5 Hz, 2 H), 1.57 (m, 2 H), 1.39 (s,
3 H), 1.31 (s, 3 H), 1.25 (m, 24 H), 0.86 (t, J = 6.5 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 147.1, 135.2, 132.8, 132.6, 130.0,
125.1, 107.5, 78.6, 77.1, 55.9, 54.1, 54.0 (2 C), 44.9, 31.6, 29.4–29.1
(10 C), 26.6, 26.3, 24.9, 24.1, 23.2 (2 C), 13.8 ppm. HRMS: calcd.
for C31H53N3O6S [M + H]+ 596.3677; found 596.3683.
1, CDCl ). IR (neat): ν = 3213, 2917, 2835, 2124, 1536, 1171,
˜
3
916 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.17 (m, 1 H), 7.93
(m, 1 H), 7.77 (m, 2 H), 5.80 (d, J = 8.8 Hz, 1 H), 4.19 (m, 1 H),
4.13 (t, J = 6 Hz, 1 H), 3.94 (m, 1 H), 2.72 (dd, J = 17.2, 5.6 Hz,
1 H), 2.63 (dd, J = 17.2, 4 Hz, 1 H), 1.49 (m, 2 H), 1.40 (s, 3 H),
1.33 (s, 3 H), 1.25 (m, 24 H), 0.87 (t, J = 7 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 147.6, 134.9, 134.0, 133.3, 130.2,
125.8, 116.4, 108.7, 77.7, 77.1, 51.2, 31.9, 29.7–29.1 (10 C), 27.3,
26.6, 25.1, 22.7, 21.9, 14.1 ppm. HRMS: calcd. for C28H45N3O6S
[M + H]+ 552.3107; found 552.3123
9h: Oil, yield 272 mg, 89%. [α]D = –25 (c = 1, CDCl3). IR (neat):
ν = 3427, 2919, 1552, 1437, 837, 698 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 8.12 (m, 1 H), 7.85 (m, 1 H), 7.70 (m, 2 H), 7.29 (m,
5 H), 4.18 (t, J = 5.6 Hz, 1 H), 3.99 (m, 1 H), 3.82 (m, 2 H), 3.57
(m, 3 H), 2.84 (dd, J = 14, 8 Hz, 1 H), 2.68 (m, 2 H), 2.58 (m, 1
H), 1.45 (m, 2 H), 1.33 (s, 3 H), 1.30 (m, 27 H), 0.88 (t, J = 6.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.5, 138.1, 135.4,
133.3, 132.8, 129.9, 128.9 (2 C), 128.3 (2 C), 127.2, 125.2, 107.9,
78.3, 77.2, 59.4, 59.0, 56.1, 55.8, 53.6, 31.8, 29.6–29.3 (10 C), 26.9,
26.4, 25.2, 22.6, 14.0 ppm. HRMS: calcd. for C36H57N3O7S [M +
H]+ 676.3995; found 676.3403
General Procedure for Nosylate Removal: Thiophenol (0.8 mmol)
and Cs2CO3 (0.6 mmol) were successively added to a stirred solu-
tion of the corresponding nosylate (0.2 mmol) in dry CH3CN
(2 mL). After stirring at room temperature for 24 h, saturated aque-
ous NaHCO3 (20 mL) was added and the aqueous phase was ex-
tracted with CH2Cl2. The combined organic extracts were dried
with MgSO4, filtered and the solvents were evaporated under re-
duced pressure. The resulting crudes were purified by column
chromatography (CH2Cl2/MeOH, 99:1).
9i: Oil, yield 255 mg, 82%. [α]D = –7.2 (c = 0.5, CDCl3). IR (neat):
ν = 2917, 1543, 1467, 835, 748 cm–1. 1H NMR (500 MHz, CDCl ): 10e: Oil, yield 86 mg, 75%. [α]D = –5 (c = 1, CDCl ). IR (neat): ν
˜
˜
3
3
δ = 7.98 (dd, J = 7.5, 2 Hz, 1 H), 7.86 (dd, J = 8, 2 Hz, 1 H), 7.67
(m, 2 H), 7.35–7.20 (m, 5 H), 6.02 (br., 1 H, NHSO2), 4.15 (dd, J
= 6.5, 4.5 Hz, 1 H), 3.85 (m, 2 H), 3.69 (d, J = 15.5 Hz, 1 H), 3.34
= 3381, 2920, 2841, 1495, 1043, 769 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 7.36 (m, 10 H), 7.15 (t, J = 7.5 Hz, 2 H), 6.79 (t, J =
7 Hz, 1 H), 6.58 (d, J = 7.6 Hz, 2 H), 4.80–4.59 (m, 4 H), 3.75 (m,
(m, 1 H), 3.01 (dd, J = 14.5, 8.5 Hz, 1 H), 2.74 (dd, J = 14.5, 6 Hz, 1 H), 3.55 (t, J = 4 Hz, 1 H), 3.43 (dd, J = 12.5, 7.5 Hz 1 H), 3.22
1 H), 1.40 (m, 2 H), 1.30 (s, 3 H), 1.28 (m, 24 H), 1.15 (s, 9 H), (m, 1 H), 3.10 (dd, J = 13, 7.5 Hz, 1 H), 1.80–1.44 (m, 5 H, 2 CH,
1.11 (s, 3 H), 0.90 (t, J = 7 Hz, 3 H) ppm. 13C NMR (100 MHz, 3 NH), 1.29 (m, 24 H), 0.90 (t, J = 7 Hz, 3 H) ppm. 13C NMR
CDCl3): δ = 147.7, 141.3, 135.7, 132.9, 132.6, 130.1, 128.4 (2 C), (100 MHz, CDCl3): δ = 148.6, 138.4, 138.3, 128.1 (2 C), 128.4 (2
128.1 (2 C), 126.7, 125.0, 107.3, 77.0, 76.7, 56.0, 55.4, 53.9, 51.1, C), 128.3 (2 C), 128.0 (2 C), 127.8 (2 C), 127.7, 127.6, 117.1, 113.0
Eur. J. Org. Chem. 2008, 4647–4654
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4651

Y. Harrak, A. Llebaria, A. Delgado
FULL PAPER
(2 C), 83.3, 78.5, 73.6, 72.0, 51.7, 47.2, 31.9, 30.5, 29.8–29.3 (9 C), 22.7, 14.1 ppm. HRMS: calcd. for C32H58N2O2 [M + H]+ 503.4491;
25.6, 22.6, 14.1 ppm. HRMS: calcd. for C38H56N2O2 [M + H]+
573.4465; found 573.4439.
found 503.4501.
(S)-2-Azido-1-[(4S,5R)-2,2-dimethyl-5-tetradecyl-1,3-dioxolan-4-yl]-
10f: Oil, yield 94 mg, 83%. [α]D = –14 (c = 1, CDCl ). IR (neat): ν ethanamine (16): NaN3 (325 mg, 5 mmol) was added portionwise
˜
3
= 3395, 2921, 2839, 1499, 1245, 867 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.34 (m, 10 H), 4.78–4.54 (m, 4 H), 3.68 (m, 5 H), (10 mL). The reaction mixture was heated at reflux temperature for
3.50 (m, 1 H), 3.16 (m, 1 H), 2.61 (dd, J = 12.4, 2.8 Hz, 1 H), 2.54 18 h. Then brine (30 mL) was added and the aqueous phase was
to a stirred solution of 5 (179 mg, 0.5 mmol) in 2-ethoxyethanol
(m, 2 H), 2.30 (m, 3 H), 2.02 (br., 2 H), 1.73–1.49 (m, 4 H), 1.26 extracted with EtOAc (3ϫ20 mL). The combined organic extracts
(m, 22 H), 0.89 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, were dried with MgSO4, filtered and the solvents were evaporated
CDCl3): δ = 138.6, 138.5, 128.3 (4 C), 127.9 (2 C), 127.8 (2 C),
under reduced pressure. The residue was purified by chromatog-
127.6, 127.5, 82.8, 79.8, 73.7, 71.8, 67.0 (2 C), 61.8 (2 C), 53.9, 48.8, raphy on hexane/EtOAc (1:1) to give 16 (133 mg, 70%) as a colour-
31.9, 30.5, 29.8–29.3 (9 C), 25.7, 22.6, 14.1 ppm. HRMS: calcd. for
less oil. [α]D = +19 (c = 1, CDCl ). IR (neat): ν = 3421, 2916, 2124,
˜
3
C36H58N2O3 [M + H]+ 567.4550; found 567.4526.
1465, 1172, 961 cm–1. H NMR (400 MHz, CDCl3): δ = 4.16 (m,
1
1 H), 3.84 (dd, J = 9.2, 6 Hz, 1 H), 3.56 (dd, J = 12.4, 2.8 Hz, 1
H), 3.44 (dd, J = 12.4, 6.4 Hz, 1 H), 2.97 (m, 1 H), 1.50 (m, 2 H),
1.40 (s, 3 H), 1.32 (s, 3 H), 1.24 (m, 24 H), 0.87 (t, J = 6.8 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 108.1, 79.0, 77.7, 56.5,
50.3, 31.9, 29.7–29.3 (10 C), 28.2, 26.1, 25.8, 22.7, 14.1 ppm.
11e: Oil, yield 68 mg, 79%. [α]D = +10 (c = 1, CDCl3). IR (neat):
˜
1
ν = 3581, 3386, 2918, 2847, 1499, 1220, 1054, 867 cm–1. H NMR
(500 MHz, CDCl3): δ = 7.20 (t, J = 7.5 Hz, 2 H), 6.71 (m, 3 H),
4.19 (m, 1 H), 3.90 (dd, J = 8, 5.5 Hz, 1 H), 3.50 (m, 1 H), 3.10
(m, 2 H), 1.58 (m, 2 H), 1.48 (s, 3 H), 1.37 (s, 3 H), 1.27 (m, 24
H), 0.90 (t, J = 7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 148.5, 129.2 (2 C), 117.4, 113.1 (2 C), 108.1, 80.9, 77.8, 49.9,
48.5, 31.8, 29.8–29.3 (10 C), 28.3, 26.1, 25.9, 22.7, 14.1 ppm.
HRMS: calcd. for C27H48N2O2 [M + H]+ 433.3725; found
433.3741.
General Procedure for N-Acylation: Et3N (0.3 mmol) and the acid
chloride (0.18 mmol) wad added to a solution of the corresponding
amine (0.15 mmol) in THF (5 mL). The reaction mixture was
stirred at room temperature for 1 h. Then saturated NaHCO3
(10 mL) was added and the mixture was extracted with EtOAc
(3ϫ15 mL). The organic layers were dried with MgSO4 and the
solvents evaporated at reduce pressure to give the crude amides,
which were purified by column chromatography (hexanes/EtOAc,
3:1).
11f: Oil, yield 75 mg, 88%. [α]D = –7 (c = 0.5, CDCl3,). IR (neat):
ν = 3541, 3363, 2915, 2858, 1448, 1368, 1223, 1012 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 4.15 (m, 1 H), 3.79 (m, 1 H), 3.72 (m, 4
H), 3.04 (m, 1 H), 2.62 (m, 3 H), 2.40 (m, 2 H), 2.30 (m, 1 H), 1.98
(br., 2 H, NH2), 1.52 (m, 2 H), 1.41 (s, 3 H), 1.31 (s, 3 H), 1.24 (m,
24 H), 0.87 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 108.1, 81.2, 78.1, 67.3 (2 C), 62.8, 54.3, 47.0 (2 C), 32.1, 30.1–
29.3 (10 C), 28.2, 26.2, 25.8, 22.6, 14.1 ppm. HRMS: calcd. for
C25H50N2O2 [M + H]+ 427.3817; found 427.3825.
13a: Oil, yield 73 mg, 83%. [α]D = +27 (c = 0.5, CDCl3). IR (neat):
1
ν = 3523, 3354, 2926, 2863, 1557, 1451, 1312, 1231, 1009 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 7.26 (m, 5 H), 5.91 (d, J = 6.3 Hz,
1 H), 4.32 (dd, J = 6.6, 5.1 Hz, 1 H), 4.02 (m, 1 H), 3.99 (d, J =
16 Hz, 1 H), 3.54 (d, J = 16 Hz, 1 H), 3.53 (m, 1 H), 3.07 (dd, J =
14.4, 8.7 Hz, 1 H), 2.63 (dd, J = 14.1, 3.9 Hz, 1 H), 1.45 (s, 3 H),
1.40–1.30 (m, 2 H), 1.25 (m, 27 H), 1.14 (s, 9 H), 1.11 (s, 9 H), 0.88
(t, J = 6.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.9,
142.9, 128.2 (2 C), 127.2 (2 C), 126.4, 107.5, 77.6, 77.2, 55.8, 55.6,
50.7, 49.4, 38.6, 31.9, 30.2, 29.6–29.3 (9 C), 27.4 (3 C), 27.3 (3 C),
27.1, 26.5, 25.3, 22.7, 14.1 ppm. HRMS: calcd. for C37H66N2O3 [M
+ H]+ 587.5069; found 587.5073.
11g: Oil, yield 74 mg, 90%. [α]D = +4 (c = 1, CDCl ). IR (neat): ν
˜
3
= 3581, 3377, 2927, 2851, 1450, 1374, 1227, 1054 cm–1. H NMR
1
(500 MHz, CDCl3): δ = 4.14 (m, 1 H), 3.76 (t, J = 7 Hz, 1 H), 3.65
(q, J = 7.5 Hz, 1 H), 2.67 (d, J = 5 Hz, 2 H), 2.59 (d, J = 5 Hz, 2
H), 2.50 (m, 2 H), 1.89 (br., 2 H, NH2), 1.77 (m, 4 H), 1.53 (m, 2
H), 1.41 (s, 3 H), 1.31 (s, 3 H), 1.24 (m, 24 H), 0.88 (t, J = 7 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 107.6, 81.1, 77.9,
60.2, 55.2 (2 C), 48.8, 31.8, 29.7–29.2 (10 C), 28.1, 26.1, 25.8, 23.4
(2 C), 22.6, 14.0 ppm. HRMS: calcd. for C25H50N2O2 [M + H]+
411.3883; found 411.3886.
13b: Oil, yield 77 mg, 82%. [α]D = +21 (c = 0.5, CDCl3). IR (neat):
1
ν = 3527, 3373, 2919, 2849, 1562, 1475, 1221, 987 cm–1. H NMR
˜
(300 MHz, CDCl3): δ = 7.28 (m, 5 H), 5.42 (d, J = 7.2 Hz, 1 H),
4.22 (t, J = 6 Hz, 1 H), 4.01 (m, 1 H), 3.85 (d, J = 15.6 Hz, 1 H),
3.64 (m, 1 H), 3.62 (d, J = 15.6 Hz, 1 H), 2.94 (dd, J = 14.4, 8.7 Hz,
1 H), 2.74 (dd, J = 14.4, 3.9 Hz, 1 H), 1.92 (m, 2 H), 1.66–1.45 (m,
2 H), 1.43 (s, 3 H), 1.25 (m, 37 H), 1.13 (s, 9 H), 0.88 (t, J = 7 Hz,
6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.8, 142.0, 128.3
(2 C), 127.8 (2 C), 126.7, 107.6, 77.6, 77.4, 56.2, 55.8, 50.6, 49.4,
36.7, 31.8, 31.6, 29.7–29.5 (9 C), 29.3, 29.2, 29.0, 27.3, 27.2 (3 C),
26.4, 25.5, 25.3, 22.6 (2 C), 14.1 (2 C) ppm. HRMS: calcd. for
C40H72N2O3 [M + H]+ 629.5549; found 629.5545.
11h: Oil, yield 77 mg, 79%. [α]D = –28 (c = 1, CDCl3). IR (neat):
1
ν = 3573, 3367, 2923, 1494, 1365, 665 cm–1. H NMR (500 MHz,
˜
CDCl3): δ = 7.35 (m, 5 H), 4.12 (m, 1 H), 3.84 (m, 2 H), 3.69 (m,
1 H), 3.63 (m, 2 H), 3.29 (br., 3 H), 3.00 (m, 1 H), 2.81 (m, 2 H),
2.63 (dt, J = 13.5, 3.5 Hz, 1 H), 2.55 (dd, J = 13, 9.5 Hz, 1 H), 1.51
(m, 2 H), 1.40 (s, 3 H), 1.28 (m, 27 H), 0.90 (t, J = 7 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 139.0, 128.9 (2 C), 128.4 (2 C),
127.2, 108.0, 80.3, 77.7, 60.0, 59.8, 57.7, 56.6, 48.7, 31.9, 29.6–29.3
(10 C), 27.9, 26.2, 25.7, 22.6, 14.1 ppm. HRMS: calcd. for
C30H54N2O3 [M + H]+ 491.4143; found 491.4139.
Synthesis of Phytosphingosines and Phytoceramides
11i: Oil, yield 83 mg, 83%. [α]D = +16 (c = 0.5, CDCl3). IR (neat):
˜
CDCl3): δ = 7.26 (m, 5 H), 4.02 (m, 1 H), 3.98 (d, J = 15 Hz, 1
H), 3.65 (dd, J = 8.1, 5.7 Hz, 1 H), 3.46 (d, J = 15 Hz, 1 H), 2.82
Method A: A solution of the corresponding amine (0.1 mmol) in
CH2Cl2 (2 mL) at –78 °C was treated with BCl3 (1 ) in heptane
(2 equiv/mol for each OBn group). The reaction mixture was
warmed to room temp. and stirred for an additional 16 h. The mix-
ν = 3378, 2915, 2843, 1494, 998, 874 cm–1. 1H NMR (300 MHz,
(dd, J = 13, 2.4 Hz, 1 H), 2.59–2.41 (m, 2 H), 1.63 (br., 2 H), 1.45– ture was next cooled to –78 °C and quenched with methanol
1.30 (m, 2 H), 1.39 (s, 3 H), 1.29 (s, 3 H), 1.26 (m, 24 H), 1.16 (s,
9 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 143.2, 128.1 (2 C), 127.9 (2 C), 126.4, 107.6, 81.1, 78.0, 55.8 (2
C), 55.4, 49.0, 31.9, 29.7–29.3 (10 C), 28.2, 27.5 (3 C), 26.1, 25.9,
(2 mL). The solvents were then removed under reduced pressure
and EtOAt (3 mL) was next added to the oily residue. The mixture
was sonicated in an ultrasonic bath for 5 min and the suspended
solid was collected by filtration.
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Eur. J. Org. Chem. 2008, 4647–4654

A Practical Access to 1,2-Diaminophytosphingolipids
Method B: A solution of the corresponding 1-aminophytosphingo-
28.6 (3 C), 28.5, 28.4, 27.6, 26.8 (3 C), 24.4, 15.1 ppm. HRMS:
sine derivative (0.1 mmol) in CH3OH (2 mL) and conc. HCl calcd. for C27H56N2O3 [M + H]+ 457.4301; found 457.4307.
(5 drops) was stirred for 24 h at room temperature. Then the solvent
was evaporated in vacuo to afford the target compounds.
15b: Oil, yield 45 mg, 90%. [α]D = +5 (c = 1, MeOH). IR (neat): ν
˜
= 3521, 2411, 2934, 1428 cm–1. 1H NMR (500 MHz, MeOH,
55 °C): δ = 5.01 (m, 1 H), 3.95 (d, J = 7.5 Hz, 1 H), 3.76 (d, J =
8.5 Hz, 1 H), 3.59 (d, J = 14 Hz, 1 H), 3.33 (m, 2 H), 2.44 (m, 2
H), 1.68–1.30 (m, 51 H), 0.91 (m, 3 H) ppm. 13C NMR (100 MHz,
MeOH): δ = 176.1, 75.1, 73.8, 61.0, 52.5, 42.2, 36.3, 33.7, 33.6,
32.8, 31.5–30.8 (9 C), 26.8 (7 C), 24.4 (2 C), 15.1 (2 C) ppm.
HRMS: calcd. for C30H62N2O3 [M + H]+ 499.4759; found
499.4762.
Method C: A solution of the corresponding 1-aminophytosphingo-
sine derivative (0.1 mmol) in CH3OH (5 mL) and concd. aqueous
HCl (5 drops) was stirred under H2 (2 atm) in the presence of 5%
Pd-C (20 mg) for 24 h. Then the reaction mixture was filtered
through a pad of Celite®, filtered and evaporated in vacuo to afford
the target compounds.
12e: Oil, yield 46 mg, 99% (Method B); 36 mg, 78% (Method A).
[α]D = –20 (c = 1, MeOH). IR (neat): ν = 3365, 2913, 1116,
˜
712 cm–1. 1H NMR (MeOH, 500 MHz): δ = 7.45 (m, 4 H), 7.36
(m, 1 H), 3.84 (m, 1 H), 3.73 (m, 2 H), 3.65 (m, 1 H), 3.56 (dd, J
= 13.5, 4.5 Hz, 1 H), 1.60 (m, 1 H), 1.45 (m, 1 H), 1.18 (m, 24 H),
0.79 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, MeOH): δ =
138.6, 132.3 (2 C), 131.1, 124.0 (2 C), 74.9, 74.7, 52.1, 52.0, 35.5,
33.9, 31.6–31.3 (9 C), 27.5, 24.5, 15.3 ppm. HRMS: calcd. for
C24H44N2O2 [M + H]+ 393.3511; found 393.3491.
Acknowledgments
Partial financial support from the Ministerio de Ciencia y Tecnol-
ogía (Spain) (Project MCYT CTQ2005-00175/BQU), Fondos
Feder (EU), and Generalitat de Catalunya (Project 2005SGR0163)
is acknowledged. Y. H. is grateful to the Spanish Ministerio de Ed-
ucación y Ciencia (MEC) (Juan de la Cierva programme) for a
postdoctoral contract.
12f: Oil, yield 45 mg, 99% (Method B); 40 mg, 89% (Method A).
[α]D = –24 (c = 1, MeOH). IR (neat): ν = 3376, 2922, 2842,
˜
1
1116 cm–1. H NMR (400 MHz, MeOH): δ = 4.10 (m, 1 H), 3.97
(m, 5 H), 3.66 (m, 2 H), 3.56–3.20 (m, 7 H), 1.74 (m, 1 H), 1.55
(m, 1 H), 1.27 (m, 24 H), 0.88 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, MeOH): δ = 75.4, 74.0, 66.0 (2 C), 57.6 (2 C), 50.4, 50.3,
36.0, 33.9, 31.6–31.3 (9 C), 27.2, 24.5, 15.3 ppm. HRMS: calcd. for
C22H46N2O3 [M + H]+ 387.3581; found 387.3587
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
D. Lucet, T. Le Gall, C. Mioskowski, Angew. Chem. Int. Ed.
1998, 37, 2581–2627.
S. R. Kotti, C. Timmons, G. Li, Chem. Biol. Drug Des. 2006,
67, 101–114.
D. Mormeneo, J. Casas, A. Llebaria, A. Delgado, Org. Biomol.
Chem. 2007, 5, 3769–3777.
D. Mormeneo, A. Manresa, J. Casas, A. Llebaria, A. Delgado,
J. Appl. Microbiol. 2008, 104, 1075–1081.
A. Delgado, J. Casas, A. Llebaria, J. L. Abad, G. Fabrias,
ChemMedChem 2007, 2, 580–606.
A. Schick, T. Kolter, A. Giannis, K. Sandhoff, Tetrahedron
1996, 52, 2945–2956.
T. Hakogi, M. Taichi, S. Katsumura, Org. Lett. 2003, 5, 2801–
2804.
J. W. Kim, Y. W. Kim, Y. Inagaki, Y. A. Hwang, S. Mitsutake,
Y. W. Ryu, W. K. Lee, H. J. Ha, C. S. Park, Y. Igarashi, Bioorg.
Med. Chem. 2005, 13, 3475–3485.
12g: Oil, yield 44 mg, 99% (Method B). [α]D = +3 (c = 0.5, MeOH).
1
IR (neat): ν = 3381, 2927, 2825, 1227 cm–1. H NMR (400 MHz,
˜
MeOH): δ = 3.90 (t, J = 3 Hz, 1 H), 3.77 (m, 1 H), 3.67 (m, 2 H),
3.65 (m, 2 H), 3.57 (dd, J = 8.5, 3.5 Hz, 1 H), 3.50 (m, 1 H), 3.42
(dd, J = 14, 7 Hz, 1 H), 3.12 (m, 2 H), 2.11 (m, 2 H), 1.99 (m, 2
H), 1.69 (m, 1 H), 1.48 (m, 1 H), 1.24 (m, 24 H), 0.81 (t, J = 7 Hz,
3 H) ppm. 13C NMR (100 MHz, MeOH): δ = 75.2, 74.0, 57.4, 56.2,
55.3, 52.6, 36.1, 33.9, 31.6–31.3 (9 C), 27.2, 25.0, 24.9, 24.5,
15.3 ppm. HRMS: calcd. for C22H46N2O2 [M + H]+ 371.3564;
found 371.3567
12h: Oil, yield 42 mg, 97% (Method C). [α]D = –6 (c = 1, MeOH).
IR (neat): ν = 3532, 2482, 1970, 1436, 911 cm–1. 1H NMR
˜
(500 MHz, MeOH): δ = 3.85 (br., 1 H), 3.80 (br., 2 H), 3.76 (br., 1
H), 3.67 (br., 1 H), 3.55 (d, J = 9 Hz, 1 H), 3.36 (d, J = 10.5 Hz,
1 H), 3.19 (br., 2 H), 1.63 (m, 1 H), 1.53 (m, 1 H), 1.25 (m, 24 H),
0.86 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, MeOH): δ =
74.8, 74.6, 58.6, 52.5, 51.8, 48.0, 35.5, 33.9, 31.6–31.3 (9 C), 27.5,
24.5, 15.3 ppm. HRMS: calcd. for C20H44N2O3 [M + H]+ 361.3349;
found 361.3346.
[9]
A. Delgado, J. Casas, A. Llebaria, J. L. Abad, G. Fabrias, Bi-
ochim. Biophys. Acta -Biomembranes 2006, 1758, 1957–1977.
C. Xia, J. Schumann, R. Emmanuel, Y. Zhang, W. Chen, W.
Zhang, G. DeLibero, P. G. Wang, J. Med. Chem. 2007, 50,
3489–3496.
Q. H. Fan, N. T. Ni, Q. Li, L. H. Zhang, X. S. Ye, Org. Lett.
2006, 8, 1007–1009.
M. Suzuki, M. Kambe, H. Tokuyama, T. Fukuyama, J. Org.
Chem. 2004, 69, 2831–2843.
For related aziridine derivatives and synthetic equivalents
thereof, see: a) S. Yu, J. Park, S. Chung, Tetrahedron: Asym-
metry 2006, 17, 3030–3036; b) H. Tsunoda, S. Ogawa, Liebigs
Ann. 1995, 267–277; c) C. Sun, R. Bittman, J. Org. Chem. 2004,
69, 7694–7699.
P. E. Maligres, M. M. See, D. Askin, P. J. Reider, Tetrahedron
Lett. 1997, 38, 5253–5256.
[10]
[11]
[12]
[13]
12i: Oil, yield 37 mg, 82% (Method C). [α]D = +10 (c = 1, MeOH).
1
IR (neat): ν = 3412, 2923, 1454, 1041 cm–1. H NMR (500 MHz,
˜
MeOH): δ = 3.84 (br., 1 H), 3.77 (br. d, J = 4.5 Hz, 1 H), 3.68 (br.
m, 1 H), 3.50 (br. d, J = 10 Hz, 1 H), 3.25 (br. d, J = 10 Hz, 1 H),
1.65 (m, 1 H), 1.55 (m, 1 H), 1.42 (s, 9 H), 1.27 (m, 24 H), 0.87 (t,
J = 7 Hz, 3 H) ppm. 13C NMR (100 MHz, MeOH): δ = 74.7 (2 C),
60.2, 52.8, 42.0, 35.6, 33.7, 31.5–31.4 (8 C), 31.1, 27.4, 26.8 (3 C),
24.4, 15.1 ppm. HRMS: calcd. for C22H48N2O2 [M + H]+ 373.3725;
found 373.3733
[14]
[15]
[16]
C. Palomo, J. M. Aizpurua, E. Balentova, A. Jimenez, J. Oyar-
bide, R. M. Fratila, J. I. Miranda, Org. Lett. 2007, 9, 101–104.
15a: Oil, yield 41 mg, 89%. [α]D = +5 (c = 1, MeOH). IR (neat): ν
˜
In addition to the amines shown in Table 1, NaN3 (in refluxing
MeOH/H2O) and NaCN (in refluxing CH3CN) also reacted
with 6 to give the corresponding ring-opened adducts 9j and
9k in 85 and 87% yields, respectively. Interestingly, reaction of
NaN3 with non-activated aziridine 5 in refluxing 2-ethoxye-
thanol afforded amino azide 16 in 70% yield (see Exp. Sect.).
= 3583, 3415, 2921, 2482, 1596, 1461 cm–1. 1H NMR (500 MHz,
MeOH) (mixture of rotamers): δ = 5.01–5.02 (m, 1 H), 4.30–3.83
(m, 1 H), 3.63 (m, 2 H), 3.36 (m, 1 H), 3.09 (m, 1 H), 1.60–1.20
(m, 46 H), 0.90 (m, 3 H) ppm. 13C NMR (100 MHz, MeOH): δ =
183.1, 77.1, 74.7, 59.2, 51.4, 45.2, 40.7, 34.8, 33.8, 31.5–31.1 (9 C),
Eur. J. Org. Chem. 2008, 4647–4654
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4653

Y. Harrak, A. Llebaria, A. Delgado
FULL PAPER
[20] D. R. Williams, D. L. Brown, J. W. Benbow, J. Am. Chem. Soc.
1989, 111, 1923–1925.
[21] Hydrogenolysis of 10e failed. On the other hand, treatment of
the aniline derivative 10e with BCl3/CH2Cl2 afforded 12e, al-
though contaminated with side-products probably as a result
of the reaction of the aniline moiety with the putative benzyl
cation intermediate formed in the course of the deprotection
reaction.
[22] D. D. Perrin, W. L. F. Armarego, Purification of Laboratory
Chemicals, 3rd ed., Pergamon Press, Oxford, 1988.
Received: June 11, 2008
[17] T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995,
36, 6373–6374.
[18] T. Flessner, S. Doye, J. Prakt. Chem. 1999, 341, 186–190.
[19] Treatment of 9a with Cs2CO3 in the absence of PhSH afforded
mainly two different N-(o-nitrophenyl) adducts, one of them
probably arising from C(2)N- to C(1)N-nosyl migration, as
1
judged by the H NMR spectroscopic data of the crude reac-
Published Online: August 27, 2008
tion mixture.
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