A general, efficient and stereospecific route to sphingosine, sphinganines, phytosphingosines and their analogs

Article abstract of DOI:10.1039/b516333a

Sphingosine, sphinganines and phytosphingosines and their analogs were synthesized by an aldol condensation between an iminoglycinate bearing a (+)-(1R,2R,5R)-2-hydroxy-3-pinanone group as chiral auxiliary and an appropriate aldehyde. All condensations proceeded with excellent enantioselectivity to generate the (2S,3R)-d-erythro structures in good yields. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b516333a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A general, efficient and stereospecific route to sphingosine, sphinganines,
phytosphingosines and their analogs
Ye Cai, Chang-Chun Ling and David R. Bundle*
Received 17th November 2005, Accepted 4th January 2006
First published as an Advance Article on the web 26th January 2006
DOI: 10.1039/b516333a
Sphingosine, sphinganines and phytosphingosines and their analogs were synthesized by an aldol
condensation between an iminoglycinate bearing a (+)-(1R,2R,5R)-2-hydroxy-3-pinanone group as
chiral auxiliary and an appropriate aldehyde. All condensations proceeded with excellent
enantioselectivity to generate the (2S,3R)-D-erythro structures in good yields.
This methodology was subsequently used by Li et al. to synthesize
Introduction
the deuterium and tritium labelled sphingosines,12 and by Shioiri
and Irako to prepare sulfobacin A.13 Vo-Hoang et al. recently
ingosines are common long-chain structural constituents of sph-
reported minor modifications for the synthesis of the natural
Sphingosines, sphinganines (dihydrosphingosines) and phytosph-
sphingosine.14 To the best of our knowledge this methodology
has not been used to synthesize other sphingoid derivatives.
We were interested in extending Solladie´-Cavallo’s methodology
as a general route to synthesize other members of the sphingoid
family such as the truncated sphingosine (1),15 sphinganines
(2a–c), phytosphingosine (3) and even its 4-epimer (4) (Fig. 1). This
appeared attractive since the stereo and enantiomeric outcome of
the aldol condensation should be dictated by the (+)-(1R,2R,5R)-
2-hydroxy-3-pinanone auxiliary while the stereochemistry of the
aldehydes should have little effect.
ingolipids. This class of lipid is unusual because they bear a small
positive charge at neutral pH as a consequence of intramolecular
hydrogen bonding.1 This property enables them to cross mem-
branes or move between membranes with ease. The sphingolipids
are essential components of the plasma membrane of eukaryotic
cells, where they are typically found in the outer leaflet. Although
particularly abundant in mammalian cells, they are also present in
bacteria and fungi,2 plants3 and marine organisms.4 In addition to
their structural functions, they are also involved in various biologi-
cal activities and play critical roles in many physiological processes,
including modulation of immune response, signalling and cellular
recognition.5 Sphingosine and sphinganine can both strongly
inhibit protein kinase C6 and their ceramide derivatives are potent
stimulators of the mammalian immune system.7 Phytosphingosine
is a potential heat stress signal in yeast cells,8 and some of its
derivatives exhibit important physiological activities. For example,
KRN7000, an a-galactosylphytosphingosine derivative isolated
from a marine sponge, binds to CD1d protein on antigen
presenting cells and is a powerful immunostimulant of natural
killer T (NKT) cells.9 Recognition of the glycolipid-CD1d complex
by NKT cells results in the production of several cytokines such
as interferon-c (IFN-c) and interleukins (IL)-12 and -4.
Due to their biological significance, as well as the complication
of isolation from natural sources in homogeneous form, a great
deal of effort has been devoted to the synthesis of this class of
compounds.10 Despite their structural diversity, sphingoid bases
share a common (2S,3R)-D-erythro amino alcohol moiety. Of all
the methodologies, strategies based on diastereoselective asym-
metric synthesis are the most challenging. Solladie´-Cavallo and
Koessler11 were the first to achieve the diastereoselective synthesis
of natural sphingosine using an aldol condensation strategy. These
authors employed a titanium enolate derived from an imino-
glycinate bearing a (+)-(1R,2R,5R)-2-hydroxy-3-pinanone group
as chiral auxiliary. When condensing with (E)-2-hexadecenal the
desired (2S,3R)-D-erythro structure was elegantly constructed in
just one step and was found to be the only diastereoisomer isolated.
Fig. 1
Results and discussions
In research that targets ganglioside based cancer vaccines, we have
designed a truncated sphingosine 115 as a versatile aglycone for
the synthesis of glycolipid, tumour-associated antigens.16 Com-
pound 1 conserves the (2S,3R)-D-erythro element found in natu-
ral sphingosine, while permitting flexible carbohydrate epitope–
protein conjugation strategies via either the amino group or the
double bond. In addition, the terminal double bond allows the
transformation of oligosaccharides bearing 1 into the natural
oligosaccharide bearing 18-carbon ceramide through a metathesis
reaction with 1-pentadecene.17,15b,c We have designed a highly
efficient process to prepare 1 on a large scale from 1,2-O-
isopropylidene-a-D-glucofuranose.15a As seen in Scheme 1, com-
pound 1 can be prepared via Solladie´-Cavallo’s route by condens-
ing iminoglycinate 5 with acrolein 6.
The literature reports the preparation of iminoglycinate 5 by
condensation of (+)-(1R,2R,5R)-2-hydroxy-3-pinanone with ethyl
glycinate.18 When the aldol condensation with acrolein was first
carried out using ClTi(OPr-i)3 and NEt3 as reagents, a 1:1 mixture
Alberta Ingenuity Center for Carbohydrate Science, Department of Chem-
istry, University of Alberta, Edmonton, AB T6G 2G2, Canada. E-mail:
dave.bundle@ualberta.ca
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aldehydes (9a–c) in the presence of ClTi(OEt)3 and NEt3, the
corresponding aldol adducts (10a–c) were obtained in yields that
ranged from 83 to 87%. NMR spectroscopy revealed that only one
diastereoisomer was obtained in each case. Imines (10a–c) were
hydrolyzed under acidic conditions to afford intermediate amines
11a–c in high yields (80–85%); and once again, the chiral auxiliary
was recovered. Final reductions using LiAlH4 in refluxing THF
gave the desired sphinganines (2a–c) in 78–85%.
Following the success in the syntheses of truncated sph-
ingosine 1 and sphinganines 2a–c, the D-ribo- and L-lyxo-
phytosphingosines were the logical synthetic targets for exten-
sion of the methodology. Phytosphingosines differ from sphin-
gosines and sphinganines by an additional stereocenter at C-
4. Like sphinganines and sphingosines, the chemical synthesis
of phytosphingosines usually employs carbohydrates22 or amino
acids23 as starting materials, and a few syntheses are based on
asymmetric synthesis.24 In order to prepare phytosphingosine
3 and its 4-epimer 4, aldehydes 14 and 15 are required. We
chose to use the methoxymethyl group (MOM) for protection
of the a-hydroxyl group, because this group is acid-sensitive
and can be easily removed during the hydrolysis of the imine
linkage. The two aldehydes were prepared from 12 and 13 by
Dess–Martin oxidation.25 Both 12 and 13 were synthesized from
the commercially available 1-hexadecene according to known
literature procedures (Scheme 3).24e,26
Scheme 1 Reagents and conditions: (a) ClTi(OEt)3, NEt3, CH2Cl2, 0 ◦C,
72% or ClTi(OPr-i)3, NEt3, CH2Cl2, 0 ◦C, 70%; (b) 1N HCl, THF, 82%;
(c) 2M LiBH4, THF–MeOH, 74%.
of ethyl and isopropyl esters was obtained due to a partial exchange
of the ethoxy group in the glycinate ester with the isopropoxy
group of the reagent. This exchange was also reported in Solladie´-
Cavallo’s original publication.11 However, the desired adducts 7
(R1 = Et, and i-Pr), were obtained in 70% yield and each was
found to be the only diastereoisomer by NMR spectroscopy. To
simplify the analysis, we also performed the reaction using NEt3
and ClTi(OEt)3 (which still contained ∼10% ClTi(OPr-i)3) and as
expected, adduct 7 (R1 = Et) was obtained in 72% yield, as the
major product, as detected by NMR spectroscopy. No 1,4-Michael
addition products were observed in either case (R1 = Et or i-Pr).
The ethyl and isopropyl adducts 7 were both smoothly hydrolyzed
in 1 M HCl in THF to yield 8 in 82% yield. Furthermore, the
chiral auxiliary was recovered and could be recycled to prepare
the iminoglycinate 5. The free amino-ester 8 (Et or i-Pr) was
reduced with LiBH4 in a mixture of methanol and THF at room
temperature to afford the desired truncated sphingosine analogue
1 in 74% yield.
This strategy was applied to the asymmetric syntheses of sph-
inganines (Scheme 2). In the literature, sphinganines are normally
prepared from the hydrogenation of expensive sphingosines,19
carbohydrates,20 or L-serine21 in six or more steps. However,
using the strategy shown in Scheme 2, various sphinganines
with different aliphatic chain lengths were successfully prepared
in a concise manner. Treating the iminoglycinate 5 with three
Scheme
3
Reagents and conditions: (a) Dess–Martin periodinane,
CH2Cl2, Py, RT; (b) ClTi(OEt)3, NEt3, CH2Cl2, 0 ◦C; (c) 1N HCl, THF,
RT; (d) LiAlH4, THF, reflux.
Condensation of the aldehydes 14 and 15 with 5 proceeded
well to give 16 and 17 in excellent yields (83–91%) and high
diastereoselectivity. As predicted, the stereochemistry at the a-
position of the aldehydes did not influence the stereo- and
enantioselectivity of the aldol condensation. Treatment of 16
or 17 with 1N HCl smoothly cleaved both the imine and the
MOM protecting group; intermediates 18 and 19 spontaneously
Scheme 2 Reagents and conditions: (a) ClTi(OEt)3, NEt3, CH2Cl2, 0 ◦C;
(b) 1N HCl, THF; (c) LiAlH4, THF, reflux.
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lactonized to afford 20 and 21, and were isolated as the hy-
drochloride salt in 83 and 79% yield. The stereochemistry of
the lactones was confirmed by comparing the coupling patterns
TLC was performed on Silica Gel 60-F254 (Merck, Darmstadt)
with detection by quenching of fluorescence and/or by charring
with 5% sulfuric acid in water. All commercial reagents were used
as supplied. Ti(OEt)4 was purchased from Aldrich, and contains
∼15% Ti(OPr-i)4. ClTi(OEt)3 (containing ∼10% ClTi(OPr-i)3) was
prepared from Ti(OEt)4 and CH3COCl according to a known
procedure.11 Column chromatography was performed on Silica
Gel 60 (Silicycle, Ontario). 1H NMR spectra were recorded at 300,
500, or 600 MHz. First order proton chemical shifts dH are refer-
enced to either residual CHCl3 (dH 7.24 ppm, CDCl3), CDHCl2 (dH
5.30 ppm, CD2Cl2) or residual CD2HOD (dH 3.30 ppm, CD3OD),
or internal acetone (dH 2.225 ppm, D2O). 13C NMR spectra are
reported to the second decimal; although it is expected that the
reproducibility of chemical shifts will only be accurate to one tenth
of a ppm, the reported data often include resonances separated by
less than 0.1 ppm. Organic solutions were dried with anhydrous
3
and the J2,3 coupling constants with literature data.24e Finally,
both lactones were reduced with LiAlH4 in refluxing THF to give
the desired D-ribo-phytosphingosine (3) and its 4-epimer, L-lyxo-
phytosphingosine (4) in 82 and 80% yields. The overall yield from
1-hexadecene was greater than 45% in both cases.
The stereochemistry of the synthesized sphingoids was deter-
mined by NMR spectroscopy. For example, for compound 1, in
methanol-d4, H-2 appeared as a ddd pattern at 2.77 ppm, with
J1a,2 ∼ 4.5 Hz, J1b,2 ∼ 6.8 Hz and J2,3 ∼ 6.4 Hz. H-3 also appeared
as a ddd pattern, with J3,4 ∼ 6.1 Hz. This is in agreement with
the coupling patterns of the corresponding protons of the natural
sphingosine, as reported in the literature.11 It is also consistent
with a similar compound prepared by another route.15a For
sphinganine derivatives 2a–c, phytosphingosine 3 and its 4-epimer
4, unfortunately, most of the literature NMR data were recorded in
pyridine-d5, DMSO-d6 or chloroform-d. In these solvents, due to
complications resulting from coupling with the attached hydroxyl
protonaswellasaggregationinsomesolvents(suchaschloroform-
d) most of the key protons appear either as broad resonances or
as multiplets. Rarely were coupling constants for these protons
reported. We discovered all these compounds gave well resolved
NMR spectra in methanol-d4. With the suppression of coupling to
the hydroxyl protons, most of the key coupling constants could be
extracted. For example, for sphinganine 2b, the H-2 resonated at
2.70 ppm as a ddd and H-3 at 3.49 as a ddd, with J1a,2 ∼ 4.2 Hz, J1b,2
∼ 7.6 Hz and J2,3 ∼ 5.4 Hz; for phytosphingosine 3, the H-2 ap-
peared as a ddd at 2.94 ppm, H-3 as a dd at 3.33 ppm and H-4 as a
ddd at 3.51 ppm, with J1a,2 ∼ 4.2 Hz, J1b,2 ∼ 6.6 Hz, J2,3 ∼ 5.7 Hz and
J3,4 ∼ 7.8 Hz; in addition, for the phytosphingosine 4-epimer 4, H-2
appeared as a ddd at 2.93 ppm, H-3 as a dd at 3.32 ppm and H-4 as
a ddd at 3.67 ppm, with J1a,2 ∼ 4.2 Hz, J1b,2 ∼ 7.0 Hz, J2,3 ∼ 7.0 Hz
and J3,4 ∼ 2.7 Hz. That the compounds have the same (2S,3R)-D-
erythro configuration is supported by the observation that similar
J2,3 coupling constants (5.4–7.0 Hz) were observed for the newly
formed C2–C3 linkages when comparing to 1 (J2,3 ∼ 6.4 Hz).
Optical rotations were also consistent with literature reports.
◦
Na2SO4 prior to concentration under vacuum at <40 C (bath).
Microanalyses and electrospray mass spectra were performed by
the analytical services of this department.
General procedure A: aldol condensation
To a solution of iminoglycinate 5 (6.0 mmol) in anhydrous CH2Cl2
(4 mL) was added a solution◦ of ClTi(OEt)3 (15.0 mmol) in
anhydrous CH2Cl2 (8 mL) at 0 C under argon; followed by the
addition of Et3N (3.5 mL), a solution of the aldehyde (6.6 mmol)
in anhydrous CH2Cl2 (10 mL) was added dropwise. The reaction
mixture was stirred at 0 ◦C for 5–6 h, and quenched by addition of
brine (30 mL). The mixture was diluted with CH2Cl2 (20 mL) and
the organic phase was separated; the aqueous phase was extracted
with more CH2Cl2 (2 × 50 mL), and organic layers were combined,
dried and concentrated. Chromatography on silica gel (pretreated
with 15% Et3N in eluent) afforded the desired compounds.
For the condensation with acrolein, we also employed ClTi(OPr-
i)3 as reagent in a similar fashion (not shown in the experimental
section). Ethyl and isopropyl esters were obtained as a 1:1 mixture
of single diastereoisomers in 70% yield.
General procedure B: acid hydrolysis of imines
The imines (4.6 mmol) were dissolved in a mixture of 1.0 N HCl
(32 mL) and THF (8 mL) and the mixture was stirred for 3 days
at room temperature. The mixture was extracted with Et2O (2 ×
20 mL), and the organic phase containing mainly the auxiliary
was evaporated. The aqueous phase was neutralized to pH 8 with a
solution of sat. NaHCO3, and extracted with CH2Cl2 until no more
desired compounds could be detected by TLC. The combined
extracts were dried and concentrated. Column chromatography
on silica gel gave the desired amino esters.
Conclusion
We have demonstrated that the (2S,3R)-D-erythro amino alcohol
structures, commonly found in a wide range of sphingoid bases,
can be synthesized in very good yields with high diastereose-
lectivity by an aldol condensation between the titanium enolate
derived from an iminoglycinate that bears the (+)-(1R,2R,5R)-2-
hydroxy-3-pinanone group as chiral auxiliary, and the appropriate
aldehydes. This methodology has been shown to be practical,
highly versatile and amenable to the synthesis of structurally more
elaborate compounds related to sphingolipids.
General procedure C: reduction of the amino esters
Reduction with LiAlH4. To
a solution of amino ester
(1.5 mmol) in anhydrous THF (35 mL) at 0 ◦C, was added LiAlH4
(15 mmol) in small portions under argon; the mixture was heated
at reflux for 3 days. The reaction was cooled and the mixture was
filtered through a thin pad of silica gel using CH2Cl2–MeOH–
NH4OH (100:15:2) as eluent. After concentration, the residue
was purified by column chromatography to provide the desired
sphingoids.
Experimental
General methods
Optical rotations were measured with a Perkin-Elmer 241 po-
larimeter for samples in a 10 cm cell at 22
rotations [a]D are given in units of 10−1 deg cm2 g−1. Analytical
2
◦C. Specific
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Reduction with LiBH4. To a solution of amino ester (2.5 mmol)
in methanol (15 mL) was added dropwise a solution of 2 M LiBH4
in THF (7.5 mL, 15 mmol) at room temperature. The reaction was
continued for 3 days and concentrated. The residue was loaded
onto a thin pad of silica gel and eluted with CH2Cl2–MeOH–
NH4OH (100:15:2) to afford the crude product. After concentra-
tion, the residue was purified by column chromatography to give
the desired sphingoids.
(2S,3R)-2-Aminopent-4-ene-1,3-diol (1). This compound was
prepared according to the general procedure C using LiBH4
as reducing reagent. Compound 1 was obtained as a single
diastereoisomer by chromatography on silica gel (eluent: CH2Cl2–
CH3OH–NH4OH 100:10:1). Yield 74%. [aD25]: +18.5◦ (c 0.75,
1
MeOH). Rf: 0.27 (CH2Cl2–MeOH–NH4OH 100:20:1). H NMR
(CD3OD, 500 MHz): dH 5.90 (ddd, 1H, J = 17.0, 10.5, 6.5 Hz),
5.30 (ddd, 1H, J = 17.0, 1.6, 1.6 Hz), 5.21 (ddd, 1H, J = 10.5, 1.6,
1.6 Hz), 4.03 (dddd, 1H, J = 6.2, 6.1, 1.3, 1.3 Hz), 3.60 (dd, 1H,
J = 10.9, 4.5 Hz), 3.50 (dd, 1H, J = 10.9, 6.9 Hz), 2.77 (ddd, 1H,
J = 6.8, 6.4, 4.5 Hz); 13C NMR (CD3OD, 125 MHz): dC 139.34,
117.08, 75.33, 64.24, 57.80. HRMS m/z calc’d for C5H11NO2Na
(M + Na+): 140.0682; found 140.0680. Anal. calc’d for C5H11NO2:
C, 51.26; H, 9.46; N, 11.96; found: C, 51.28,; H, 9.57; N, 11.36%.
General procedure D: oxidation with Dess–Martin periodinane
(DMP)
To a suspension of DMP (8.0 mmol) in anhydrous CH2Cl2 (45 mL),
was added pyridine (1.5 mL); the resulting slurry was stirred until
all the reagents dissolved. A solution of alcohol (7.9 mmol) in
anhydrous CH2Cl2 (20 ml) was added dropwise and the reaction
was continued at room temperature for 5 h. A solution of sat.
brine (20 ml) and sat. Na2SO3 (20 ml) was added and the organic
phase was separated; the aqueous phase was extracted with more
CH2Cl2 (3 × 50 ml), and the organic extracts were combined,
washed with water (1 × 100 ml) and brine (1 × 40 ml), dried and
evaporated. The desired aldehydes were obtained after column
chromatography.
Ethyl {1R-[1a,2b,3(2R,3R),5a]}-3-hydroxy-2-{(2-hydroxy-2,6,6-
trimethylbicyclo[3,1,1]hept-3-ylidene)amino}hexadecanoate (10a).
This compound was prepared according to the general procedure
A using ClTi(OEt)3 as reagent. Compound 10a (containing trace
amounts of isopropyl ester) was obtained as a single diastereoiso-
mer by chromatography on silica gel (eluent: hexane–EtOAc 6:1).
Yield: 87%. Rf: 0.29 (hexane–EtOAc 4:1). 1H NMR (CDCl3,
600 MHz): dH 4.19 (dq, 2H, J = 7.2, 2.8 Hz), 4.11 (d, 1H, J =
6.3 Hz), 4.07 (m, 1H), 3.01 (br s, 1H), 2.58 (dd, 1H, J = 18.0,
3.0 Hz), 2.53 (ddd, 1H, J = 18.0, 2.5, 2.5 Hz), 2.35 (dddd, 1H, J =
10.7, 6.0, 6.0, 2.3 Hz), 2.09 (dd, 1H, J = 5.9, 5.8 Hz), 2.04 (ddd,
1H, J = 6.0, 5.9, 3.0 Hz), 1.55 (d, 1H, J = 10.7 Hz), 1.50 (s, 3H),
1.33 (s, 3H), 1.25 (t, 3H, J = 7.1 Hz), 1.25–1.50 (m, 24H), 0.88
(t, 3H, J = 7.0 Hz), 0.87 (s, 3H); 13C NMR (CDCl3, 125 MHz):
dC 180.37, 170.59, 76.74, 72.62, 67.07, 61.12, 50.13, 38.64, 38.42,
34.10, 32.78, 31.92, 29.68–29.61 (7C), 29.34, 28.31, 28.03, 27.29,
25.52, 22.80, 22.68, 14.16, 14.10. HRMS m/z calc’d for C28H52NO4
(M + H+): 466.3891; found 466.3893.
Ethyl {1R-[1a,2b,3(2R,3R),5a]}-3-hydroxy-2-[(2-hydroxy-2,6,6-
trimethylbicyclo [3,1,1]hept-3-ylidene)amino]-4-pentenoate (7).
This compound was prepared according to the general procedure
A using ClTi(OEt)3 as reagent. Compound 7 was obtained as a
single diastereoisomer by chromatography on silica gel (eluent:
hexane–EtOAc 4:1) and was found to contain ∼10% isopropyl
ester. Yield 72%. Rf: 0.43 (hexane–EtOAc 1:1). 1H NMR (CDCl3,
600 MHz): dH 5.88 (ddd, 1H, J = 17.0, 10.5, 6.2 Hz), 5.38 (ddd,
1H, J = 17.0, 1.5, 1.5 Hz), 5.22 (ddd, 1H, J = 10.6, 1.5, 1.5 Hz),
4.62 (dd, 1H, J = 6.3, 6.3 Hz), 4.15–4.25 (m, 3H), 3.22 (broad s,
1H), 2.56 (dd, 1H, J = 18.0, 3.0 Hz), 2.53 (ddd, 1H, J = 18.0, 2.6,
2.6 Hz), 2.47 (broad s, 1H), 2.34 (ddd, 1H, J = 10.7, 6, 6, 2.3 Hz),
2.08 (dd, 1H, J = 5.9, 5.9 Hz), 2.03 (ddd, 1H, J = 6.0, 6.0, 3.0 Hz),
1.54 (d, 1H, J = 10.7 Hz), 1.50 (s, 3H), 1.33 (s, 3H), 1.24 (t, 3H,
J = 7.1 Hz), 0.87 (s, 3H); for the isopropyl ester, all signals overlap
with the ethyl ester except the signal at 5.05 (sept, 1H, J = 6.5 Hz).
13C NMR (CDCl3, 100 MHz): dC 180.66, 169.94, 136.50, 116.99,
76.71, 73.77, 67.00, 61.14, 50.22, 38.60, 38.39, 34.15, 28.18, 27.95,
27.26, 22.74, 14.13. HRMS m/z calc’d for C17H28NO4 (M + H+):
310.2018; found 310.2018.
Ethyl {1R-[1a,2b,3(2R,3R),5a]}-3-hydroxy-2-{(2-hydroxy-2,6,6-
trimethylbicyclo[3,1,1]hept-3-ylidene)amino}octadecanoate (10b).
This compound was prepared according to general procedure A
using ClTi(OEt)3 as reagent. Compound 10b (containing trace
amounts of isopropyl ester) was obtained as a single diastereoiso-
mer by chromatography on silica gel (eluent: hexane–EtOAc 6:1).
Yield: 84%. Rf: 0.34 (hexane–EtOAc 4:1). 1H NMR (CDCl3,
600 MHz): dH 4.15 (dq, 2H, J = 7.2, 2.3 Hz), 4.09 (d, 1H, J =
6.0 Hz), 4.04 (m, 1H), 3.22 (br s, 1H), 2.53 (dd, 1H, J = 18.0,
2.5 Hz), 2.49 (ddd, 1H, J = 18.0, 2.5, 2.5 Hz), 2.32 (dddd, 1H, J =
10.8, 6.0, 5.9, 2.3 Hz), 2.06 (dd, 1H, J = 5.9, 5.9 Hz), 2.01 (ddd,
1H, J = 6.0, 5.9, 3.0 Hz), 1.52 (d, 1H, J = 10.7 Hz), 1.48 (s, 3H),
1.30 (s, 3H), 1.24 (t, 3H, J = 7.2 Hz), 1.25–1.50 (m, 28H), 0.85
(t, 3H, J = 6.8 Hz), 0.87 (s, 3H); 13C NMR (CDCl3, 125 MHz):
dC 180.43, 170.54, 76.75, 72.65, 67.09, 61.10, 50.14, 38.64, 38.42,
34.06, 32.78, 31.92, 29.69–29.62 (9C), 29.35, 28.29, 28.02, 27.28,
25.55, 22.79, 22.68, 14.15, 14.10. HRMS m/z calc’d for C30H56NO4
(M + H+): 494.4204; found 494.4202.
Ethyl (2R,3R)-2-amino-3-hydroxy-4-pentenoate (8). This com-
pound was prepared according to the general procedure B.
Compound 8 (containing trace amounts of isopropyl ester)
was obtained by chromatography on silica gel (eluent: CH2Cl2–
CH3OH–NH4OH 100:2.5:1). Yield: 82%. Rf: 0.27 (CH2Cl2–
MeOH–NH4OH 100:5:1). 1H NMR (CD3OD, 500 MHz): dH 5.73
(ddd, 1H, J = 16.7, 10.5, 6.5 Hz), 5.33 (ddd, 1H, J = 17.0, 1.6,
1.6 Hz), 5.21 (ddd, 1H, J = 10.5, 1.5, 1.5 Hz), 4.39 (dddd, 1H, J =
5.2, 5.2, 1.4, 1.4 Hz), 4.19 (dq, 1H, J = 10.8, 7.2 Hz), 4.16 (dq, 1H,
J = 10.8, 7.2 Hz), 3.61 (d, 1H, J = 5.0 Hz), 1.26 (t, 3H, J = 7.0 Hz);
13C NMR (CD3OD, 125 MHz): dC 173.16, 135.57, 117.33, 72.63,
61.18, 58.45 14.178. HRMS m/z calc’d for C7H14NO3 (M + H+):
160.0974; found 160.0974. Anal. calc’d for C7H13NO3: C, 52.82;
H, 8.23; N, 8.80; found: C, 52.92,; H, 8.36; N, 8.31%.
Ethyl {1R-[1a,2b,3(2R,3R),5a]}-3-hydroxy-2-{(2-hydroxy-2,6,6-
trimethylbicyclo[3,1,1]hept-3-ylidene)amino}icosanoate
(10c).
This compound was prepared according to the general procedure
A using ClTi(OEt)3 as reagent. Compound 10c (containing
trace amounts of isopropyl ester) was obtained as a single
diastereoisomer by chromatography on silica gel (eluent: hexane–
1
EtOAc 6:1). Yield: 83%. Rf: 0.34 (hexane–EtOAc 4:1). H NMR
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(CDCl3, 500 MHz): dH 4.17 (dq, 2H, J = 7.1, 2.0 Hz), 4.10 (d,
1H, J = 6.1 Hz), 4.07 (m, 1H), 3.20 (br s, 1H), 2.57 (dd, 1H, J =
18.0, 2.8 Hz), 2.50 (ddd, 1H, J = 18.0, 2.5, 2.5 Hz), 2.33 (dddd,
1H, J = 10.8, 6.0, 5.9, 2.3 Hz), 2.06 (dd, 1H, J = 5.9, 5.9 Hz),
2.02 (ddd, 1H, J = 5.9, 5.8, 2.8 Hz), 1.52 (d, 1H, J = 10.9 Hz),
1.50 (s, 3H), 1.31 (s, 3H), 1.22 (t, 3H, J = 7.2 Hz), 1.25–1.50 (m,
32H), 0.88 (t, 3H, J = 7.0 Hz), 0.87 (s, 3H); 13C NMR (CDCl3,
125 MHz): dC 180.35, 170.55, 76.66, 72.61, 67.05, 61.08, 50.13,
42.90, 38.60, 38.40, 34.07, 32.76, 31.90, 29.33–29.67 (11C), 28.27,
28.03, 27.26, 25.52, 22.77, 22.65, 14.13, 14.08. HRMS m/z calc’d
for C32H60NO4 (M + H+): 522.4517; found 522.4519.
Ethyl (2R,3R)-2-amino-3-hydroxyhexadecanoate (11a). This
compound was prepared according to the general procedure B.
Compound 11a was obtained by chromatography on silica gel
(eluent: Et2O–CH3OH 25:1). Yield: 80%. Rf: 0.31 (Et2O–MeOH
20:1). [a]D25: −7.4 (c 0.50, MeOH). 1H NMR (CD3OD, 600 MHz):
dH 4.33 (dq, 1H, J = 10.8, 7.1 Hz), 4.29 (dq, 1H, J = 10.8, 7.1 Hz),
4.04 (d, 1H, J = 3.3 Hz), 3.99 (ddd, 1H, J = 9.0, 3.7, 3.7 Hz),
1.59 (m, 1H), 1.50 (m, 1H), 1.32 (t, 3H, J = 7.1 Hz), 1.25–1.40 (m,
22H), 0.89 (t, 3H, J = 7.0 Hz); 13C NMR (CD3OD, 125 MHz): dC
168.34, 70.74, 63.54, 58.96, 33.63, 33.07, 30.85, 30.79, 30.77, 30.75,
30.68, 30.57, 30.46, 30.42, 26.91, 23.73, 14.44, 14.43. HRMS m/z
calc’d for C18H38NO3 (M + H+): 316.2846; found 316.2845. Anal.
calc’d for C18H37NO3: C, 61.43; H, 10.88; N, 3.98; found: C, 61.47;
H, 11.07; N, 3.73%.
1H, J = 10.9, 4.2 Hz), 3.50 (ddd, 1H, J = 8.0, 5.5, 3.0 Hz), 3.46
(dd, 1H, J = 10.9, 7.6 Hz), 2.71 (ddd, 1H, J = 7.6, 5.4, 4.2 Hz), 1.52
(m, 2H), 1.25–1.45 (m, 22H), 0.9 (t, 3H, J = 7.0 Hz); 13C NMR
(CD3OD, 125 MHz): dC 74.03, 64.30, 58.15, 34.40, 33.07, 30.82–
30.75 (8C), 27.03, 23.73, 14.42. HRMS m/z calc’d for C16H36NO2
(M + H+): 274.2741; found 274.2743. Anal. calc’d for C16H35NO2:
C, 70.28; H, 12.90; N, 5.12; found: C, 69.65; H, 12.91; N, 5.04%.
(2S,3R)-2-Aminooctadecane-1,3-diol (2b). This compound
was prepared according to the general procedure C using LiAlH4
as reducing reagent. Compound 2b was obtained by chromatog-
raphy on silica gel (eluent: CH2Cl2–CH3OH–NH4OH 100:10:1).
Yield: 78%. [a]D25: +8.1 (c 1.0, MeOH). lit.21 [a]2D5: +1.83 (c 1.0,
pyridine), lit.24e [a]2D5: +5.7 (c 2.74, CHCl3–MeOH 4:1). Rf:
0.41 (CH2Cl2–MeOH–NH4OH 100:20:2). 1H NMR (CD3OD,
600 MHz): dH 3.72 (dd, 1H, J = 10.9, 4.2 Hz), 3.49 (ddd, 1H,
J = 8.0, 5.5, 3.0 Hz), 3.46 (dd, 1H, J = 10.9, 7.6 Hz), 2.70 (ddd,
1H, J = 7.6, 5.4, 4.2 Hz), 1.52 (m, 2H), 1.25–1.45 (m, 26H), 0.9 (t,
3H, J = 7.0 Hz); 13C NMR (CD3OD, 125 MHz): dH 74.07, 64.37,
58.15, 34.41, 33.07, 30.08–30.75 (10C), 27.04, 23.73, 14.43. HRMS
m/z calc’d for C18H40NO2 (M + H+): 302.3054; found 302.3055.
Anal. calc’d for C18H39NO2: C, 71.70; H, 13.04; N, 4.65; found: C,
71.46; H, 12.95; N, 4.58%.
(2S,3R)-2-Aminoicosane-1,3-diol (2c). This compound was
prepared according to the general procedure C using LiAlH4 as
reducing reagent. Compound 2c was obtained by chromatography
on silica gel (eluent: CH2Cl2–CH3OH–NH4OH 100:10:1). Yield:
81%. [a]D25: +6.5 (c 0.9, CHCl3–MeOH 4:1). Rf: 0.19 (CH2Cl2–
MeOH–NH4OH 100:10:2). 1H NMR (CD3OD, 600 MHz): dH
3.72 (dd, 1H, J = 10.9, 4.2 Hz), 3.49 (ddd, 1H, J = 8.0, 5.5,
3.0 Hz), 3.46 (dd, 1H, J = 10.9, 7.6 Hz), 2.70 (ddd, 1H, J = 7.5,
5.4, 4.2 Hz), 1.53 (m, 2H), 1.25–1.44 (m, 30H), 0.9 (t, 3H, J =
7.0 Hz); 13C NMR (CD3OD, 125 MHz): dH 74.11, 64.37, 58.15,
34.41, 33.07, 30.78–30.50 (12C), 27.039, 23.74, 14.43. HRMS m/z
calc’d for C20H44NO2 (M + H+): 330.3366; found 330.3363. Anal.
calc’d for C20H43NO2: C, 72.89; H, 13.15; N, 4.25; found: C, 72.56;
H, 13.04; N, 4.16%.
Ethyl (2R,3R)-2-amino-3-hydroxyoctadecanoate (11b). This
compound was prepared according to the general procedure B.
Compound 11b was obtained by chromatography on silica gel
(eluent: Et2O–CH3OH 25:1). Yield: 84%. Rf: 0.34 (Et2O–MeOH
20:1). [a]D25: −9.6 (c 0.57, MeOH). 1H NMR (CD3OD, 600 MHz):
dH 4.32 (dq, 1H, J = 10.8, 7.2 Hz), 4.28 (dq, 1H, J = 10.8, 7.2 Hz),
4.04 (d, 2H, J = 3.3 Hz), 3.99 (ddd, 1H, J = 8.7, 5.0, 3.3 Hz), 1.59
(m, 1H), 1.50 (m, 1H), 1.32 (t, 3H, J = 7.2 Hz), 1.25–1.40 (m, 26H),
0.89 (t, 3H, J = 7.0 Hz); 13C NMR (CD3OD, 125 MHz): dC 168.32,
70.73, 63.54, 58.95, 33.64, 33.07, 30.79–30.43 (10C), 26.92, 23.72,
14.45 (2C). HRMS m/z calc’d for C20H42NO3: 344.3159 (M + H+);
found 344.3159. Anal. calc’d for C20H41NO3: C, 63.21; H, 11.14;
N, 3.69; found: C, 63.31; H, 11.25; N, 3.48%.
(2R)-2-Methoxymethoxyhexadecanal (14). This compound
was prepared according to the general procedure D. Compound
14 was obtained by chromatography on silica gel (eluent: hexane–
EtOAc 20:1). Yield: 90%. [a]D25: +24.7 (c 1.0, CHCl3). Rf: 0.51
Ethyl (2R,3R)-2-amino-3-hydroxyicosanoate (11c). This com-
pound was prepared according to the general procedure B.
Compound 11c was obtained by chromatography on silica gel
(eluent: Et2O–CH3OH 25:1). Yield: 85%. Rf: 0.35 (Et2O–MeOH
1
(hexane–EtOAc 6:1). H NMR (CD2Cl2, 500 MHz): dH 9.58 (d,
1H, J = 2.0 Hz), 4.70 (d, 1H, J = 7.0 Hz), 4.68 (d, 1H, J = 7.0 Hz),
3.85 (ddd, 1H, J = 6.6, 5.6, 2.0 Hz), 3.39 (s, 3H), 1.64 (m, 2H),
1.41 (m, 2H), 1.20–1.35 (m, 22H), 0.89 (t, 3H, J = 7.0 Hz); 13C
NMR (CD2Cl2, 125 MHz): dC 203.28, 97.15, 82.86, 56.12, 32.32,
30.37, 30.08–29.75 (9C), 25.21, 23.08, 14.26. HRMS m/z calc’d for
C18H36O3Na (M + Na+): 323.2562; found: 323.2564. Anal. calc’d
for C18H36O3: C, 71.95; H, 12.08; found: C, 71.83; H, 12.19%.
1
20:1). [a]D25: −6.8 (c 0.6, MeOH). H NMR (CD3OD, 600 MHz):
dH 4.27 (dq, 1H, J = 10.8, 7.2 Hz), 4.23 (dq, 1H, J = 10.8, 7.2 Hz),
3.87 (ddd, 1H, J = 9.0, 8.9, 3.8 Hz), 3.76 (d, 1H, J = 3.8 Hz), 1.52–
1.60 (m, 2H), 1.30 (t, 3H, J = 7.2 Hz), 1.25–1.40 (m, 30H), 0.89 (t,
3H, J = 7.0 Hz); 13C NMR (CD3OD, 125 MHz): dC 174.37, 74.37,
61.98, 60.37, 33.81, 33.07, 30.90–30.47 (12C), 27.02, 23.74, 14.56,
14.44. HRMS m/z calc’d for C22H46NO3 (M + H+): 372.3472;
found 372.3471. Anal. calc’d for C22H45NO3: C, 64.75; H, 11.36;
N, 3.43; found: C, 64.78; H, 11.43; N, 3.27%.
(2S)-2-Methoxymethoxyhexadecanal (15). This compound
was prepared according to the general procedure D. Compound
15 was obtained by chromatography on silica gel (eluent: hexane–
EtOAc 20:1). Yield: 94%. [a]D25: −24.3 (c 0.9, CHCl3). Rf: 0.50
(2S,3R)-2-Aminohexadecane-1,3-diol (2a). This compound
was prepared according to the general procedure C using LiAlH4
as reducing reagent. Compound 2a was obtained by chromatog-
raphy on silica gel (eluent: CH2Cl2–CH3OH–NH4OH 100:10:1).
Yield: 85%. [a]D25: +8.7 (c 1.0, MeOH). Rf: 0.21 (CH2Cl2–MeOH–
1
(hexane–EtOAc 6:1). H NMR (CD2Cl2, 500 MHz): dH 9.58 (d,
1H, J = 2.0 Hz), 4.70 (d, 1H, J = 7.0 Hz), 4.68 (d, 1H, J = 7.0 Hz),
3.86 (ddd, 1H, J = 7.6, 5.6, 2.2 Hz), 3.39 (s, 3H), 1.62–1.68 (m,
2H), 1.40 (m, 2H), 1.25–1.35 (m, 22H), 0.89 (t, 3H, J = 7.0 Hz); 13
C
1
NH4OH 100:10:2). H NMR (CD3OD, 600 MHz): dH 3.72 (dd,
NMR (CD2Cl2, 125 MHz): dC 203.28, 97.15, 82.84, 56.12, 32.32,
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30.37, 30.08–29.75 (9C), 25.21, 23.08, 14.26. HRMS m/z calc’d for
C18H36O3Na (M + Na+): 323.2562; found: 323.2561. Anal. calc’d
for C18H36O3: C, 71.95; H, 12.08; found: C, 71.62; H, 12.14%.
(2R,3R,4S)-2-Amino-3-hydroxyoctadecane-1,4-lactone hydrochlo-
ride (21). This compound was prepared according to the
general procedure B. Compound 21 was obtained as a single
diastereoisomer by chromatography on silica gel (eluent: CH2Cl2–
CH3OH–NH4OH 100:2.5:1). Yield: 83%. Rf: 0.26 (CH2Cl2–
MeOH–NH4OH 100:5:2). 1H NMR (CD3OD, 600 MHz): dH 4.52
(ddd, 1H, J = 5.2, 2.6, 2.6 Hz), 4.50 (dd, 1H, J = 5.2, 5.0 Hz),
4.43 (d, 1H, J = 5.0 Hz), 1.82 (m, 1H), 1.72 (m, 1H), 1.48 (m, 2H),
1.25–1.40 (m, 22H), 0.89 (t, 3H, J = 7.0 Hz); 13C NMR (CD3OD,
125 MHz): dC 172.91, 84.93, 69.52, 54.40, 33.07, 30.87, 30.84,
30.78, 30.76, 30.72, 30.66, 30.60, 30.57, 30.46, 29.32, 26.33, 23.73,
14.43. HRMS m/z calc’d for C18H36NO3 (M + H+): 314.2690;
found 314.2694. Anal. calc’d for C18H35NO3HCl: C, 61.78; H,
10.37; N, 4.00; found: C, 61.50; H, 10.66; N, 3.74%.
Ethyl {1R-[1a,2b,3(2R,3R,4R),5a]}-3,4-dihydroxy-2-{(2-hydroxy-
2,6,6-trimethylbicyclo[3,1,1] hept-3-ylidene)amino}octadecanoate
(16). This compound was prepared according to the general
procedure A using ClTi(OEt)3 as reagent. Compound 16 (con-
taining trace amounts of isopropyl ester) was obtained as a single
diastereoisomer by chromatography on silica gel (eluent: hexane–
1
EtOAc 6:1). Yield: 91%. Rf: 0.31 (hexane–EtOAc 3:1). H NMR
(CDCl3, 600 MHz): dH 4.78 (d, 1H, J = 6.7 Hz), 4.58 (d, 1H, J =
6.8 Hz), 4.24–4.30 (m, 2H), 4.17 (dt, 2H, J = 7.1, 0.9 Hz), 3.67 (dt,
1H, J = 8.5, 3.2 Hz), 3.41 (s, 3H), 3.23 (br s, 1H), 2.58 (broad s,
2H), 2.32 (ddd, 1H, J = 10.7, 6.0, 5.8 Hz), 2.06 (dd, 1H, J = 6.0,
5.9 Hz), 2.02 (ddd, 1H, J = 6.0, 5.9, 3.0 Hz), 1.58–1.70 (m, 2H),
1.52 (d, 1H, J = 10.7 Hz), 1.47 (s, 3H), 1.33 (s, 3H), 1.25 (t, 3H,
J = 7 Hz), 1.25–1.30 (m, 24H), 0.88 (t, 3H, J = 7.0 Hz), 0.87
(s, 3H); 13C NMR (CDCl3, 125 MHz): dC 180.27, 170.21, 96.45,
78.92, 76.71, 73.82, 64.63, 61.07, 55.81, 50.23, 38.64, 38.43, 34.13,
31.91, 30.23, 29.77–29.35 (7C), 28.26, 28.02, 27.27, 25.36, 22.78,
22.67, 14.16, 14.09. HRMS m/z calc’d for C32H60NO6 (M + H+):
554.4421; found 554.4423.
(2S,3R,4R)-2-Aminooctadecane-1,3,4-triol (D-ribo-phytosphingo-
sine) (3). This compound was prepared according to the general
procedure C using LiAlH4 as reducing reagent. Compound 3
was obtained by chromatography on silica gel (eluent: CH2Cl2–
CH3OH–NH4OH 100:10:1). Yield 82%. [a]D25: +7.6 (c 0.7, pyri-
dine); lit.22i [a]2D4: +8.7 (c 0.8, pyridine); lit.22j [a]2D3: +8.5 (c 0.9,
pyridine). Rf: 0.13 (CH2Cl2–MeOH–NH4OH 100:10:2). 1H NMR
(CD3OD, 500 MHz): dH 3.75 (dd, 1H, J = 10.9, 4.2 Hz), 3.56 (dd,
1H, J = 10.9, 6.6 Hz), 3.51 (ddd, 1H, J = 8.3, 8.0, 3.0 Hz), 3.33
(dd, 1H, J = 7.8, 5.6 Hz), 2.94 (ddd, 1H, J = 6.4, 5.7, 4.2 Hz),
1.73 (m, 1H), 1.55 (m, 1H), 1.25–1.40 (m, 24H), 0.9 (t, 3H, J =
7.0 Hz); 13C NMR (CD3OD, 125 MHz): dC 76.51, 74.51, 64.21,
55.70, 34.78, 33.08, 30.95–30.48 (9C), 26.61, 23.74, 14.44. HRMS
m/z calc’d for C18H40NO3 (M + H+) 318.3002; found 318.3001.
Anal. calc’d for C18H39NO3: C, 68.09; H, 12.38; N, 4.41; found: C,
67.45; H, 12.53; N, 4.29%.
Ethyl {1R-[1a,2b,3(2R,3R,4R),5a]}-3,4-dihydroxy-2-{(2-hydroxy-
2,6,6-trimethylbicyclo[3,1,1] hept-3-ylidene)amino}octadecanoate
(17). This compound was prepared according to the general
procedure A using ClTi(OEt)3 as reagent. Compound 17 (con-
taining trace amounts of isopropyl ester) was obtained as a single
diastereoisomer by chromatography on silica gel (eluent: hexane–
1
EtOAc 6:1). Yield: 83%. Rf: 0.32 (hexane–EtOAc 3:1). H NMR
(CDCl3, 600 MHz): dH 4.66 (d, 1H, J = 6.4 Hz), 4.63 (d, 1H, J =
6.4 Hz), 4.31 (d, 1H, J = 8.2 Hz), 4.20 (quint, 2H, J = 7.0 Hz),
4.12 (quint, 1H, J = 7.1 Hz), 3.57 (ddd, 1H, J = 8, 5.9, 2 Hz),
3.37 (s, 3H), 3.01 (broad s, 1H), 2.66 (dd, 1H, J = 8.2, 2.8 Hz),
2.58 (ddd, 1H, J = 8.1, 2.5, 2.5 Hz), 2.34 (dddd, 1H, J = 10.7,
6.0, 5.8, 2.5 Hz), 2.08 (dd, 1H, J = 5.9, 5.9 Hz), 2.03 (ddd, 1H,
J = 6.0, 5.9, 2.9 Hz), 1.74 (m, 1H), 1.64 (m, 1H), 1.52 (d, 1H, J =
10.7 Hz), 1.48 (s, 3H), 1.32 (s, 3H), 1.24 (t, 3H, J = 7.0 Hz), 1.25–
1.30 (m, 24H), 0.88 (t, 3H, J = 7.0 Hz), 0.85 (s, 3H); 13C NMR
(CDCl3, 125 MHz): dC 180.48, 170.99, 96.55, 77.94, 76.67, 73.43,
64.98, 61.18, 60.37, 55.86, 50.21, 38.62, 38.42, 34.01, 31.91, 31.06,
29.78–29.35 (8C), 28.26, 27.97, 27.28, 25.58, 22.81, 22.68, 14.18,
14.10. HRMS m/z calc’d for C32H59NO6Na (M + Na+): 576.4240;
found 576.4239.
(2S,3R,4S)-2-Aminooctadecane-1,3,4-triol (L-lyxo-phytosphingo-
sine) (4). This compound was prepared according to the general
procedure C using LiAlH4 as reducing reagent. Compound 4
was obtained by chromatography on silica gel (eluent: CH2Cl2–
CH3OH–NH4OH 100:10:1). Yield: 80%. [a]D25: −10.0 (c 1.0,
pyridine); lit.24e [a]2D5: −7.4 (c 0.9, pyridine); lit.22j [a]2D3: −6.2 (c 1.0,
pyridine). Rf: 0.14 (CH2Cl2–MeOH–NH4OH 100:10:2). 1H NMR
(CD3OD, 600 MHz): dH 3.76 (dd, 1H, J = 10.9, 4.2 Hz), 3.67 (ddd,
1H, J = 7.7, 4.8, 2.7 Hz), 3.52 (dd, 1H, J = 10.9, 7.0 Hz), 3.32
(dd, 1H, J = 7.0, 2.7 Hz), 2.93 (ddd, 1H, J = 7.0, 7.0, 4.3 Hz),
1.45–1.59 (m, 2H), 1.25–1.40 (m, 24H), 0.9 (t, 3H, J = 7.0 Hz); 13
C
NMR (CD3OD, 125 MHz): dC 75.31, 72.34, 64.71, 55.65, 34.64,
33.07, 30.86–30.46 (9C), 27.05, 23.73, 14.42. HRMS m/z calc’d
for C18H40NO3 (M + H+): 318.3002; found 318.3002. Anal. calc’d
for C18H39NO3: C, 68.09; H, 12.38; N, 4.41; found: C, 67.70; H,
12.57; N, 4.33%.
(2R,3R,4R)-2-Amino-3-hydroxyoctadecane-1,4-lactone hydrochlo-
ride (20). This compound was prepared according to the
general procedure B. Compound 20 was obtained as a single
diastereoisomer by chromatography on silica gel (eluent: CH2Cl2–
CH3OH–NH4OH 100:2.5:1). Yield: 79%. Rf: 0.27 (CH2Cl2–
MeOH–NH4OH 100:5:2). 1H NMR (CD3OD, 600 MHz): dH 4.47
(d, 1H, J = 6.2 Hz), 4.45 (d, 1H, J = 7.4 Hz), 4.36 (d, 1H, J =
5.3 Hz), 1.8 (quint, 2H, J = 7.5 Hz), 1.24–1.50 (m, 24H), 0.89
(t, 3H, J = 7.0 Hz). 13C NMR (CD3OD, 125 MHz): dC 172.67,
89.78, 70.54, 52.15, 33.07, 32.91, 30.78, 30.77, 30.75, 30.74, 30.67,
30.57, 30.26, 26.60, 23.74, 14.43. HRMS m/z calc’d for C18H36NO3
(M + H+): 314.2690; found 314.2691. Anal. calc’d for C18H35NO3:
C, 68.97; H, 11.25; N, 4.47; found: C, 68.69; H, 11.36; N, 4.43%.
References
1 (a) I. Pascher, Biochim. Biophys. Acta, 1976, 455, 433–451; (b) J. C. M.
Holthuis, T. Pomorski, R. J. Raggers, H. Sprong and G. van Meer,
Physiol. Rev., 2001, 81, 1689–1723.
2 I. Olsen and E. Jantzen, Anaerobe, 2001, 103–112.
3 For a review, see: V. Daniel, D. V. Lynch and T. M. Dunn, New Phytol.,
2004, 161, 677–702.
4 T. F. Molinski, Curr. Med. Chem., 2004, 3, 197–220.
5 (a) A. H. Merrill and C. C. Sweeley, in Biochemistry of Lipids,
Lipoproteins and Membranes, ed. D. E. Vance and J. Vance, Else-
vier, Amersterdam, 1996, vol. 31, pp. 309–339; (b) Y. A. Hannum,
Sphingolipid-Mediated Signal Transduction, R. G. Landes Company,
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Org. Biomol. Chem., 2006, 4, 1140–1146 | 1145
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Austin, 1997; (c) S. A. Porcelli and R. L. Modlin, Annu. Rev. Immunol.,
1999, 17, 297–329; (d) K. C. Nicolaou, J. Li and G. Zenke, Helv.
Chim. Acta, 2000, 83, 1977–2006; (e) V. Costantino, E. Fattorusso,
A. Mangoni, M. Di Rosa and A. Ianaro, J. Am. Chem. Soc., 1997, 119,
12465–12470.
6 C. Rodriguez-Lafrasse, R. Rousson, S. Valla, P. Antignac, P. Louisot
and M. T. Vanvier, Biochem. J., 1997, 325, 787–791.
7 A. Shamshiev, A. Donda, T. I. Prigozy, L. Mori, V. Chigorno, C. A.
Benedict, L. Kappos, S. Sonnino, M. Kronenberg and G. De Libero,
Immunity, 2000, 13, 255–264.
8 (a) R. C. Dickson, E. E. Nagiec, M. Skrzypek, P. Tillman, G. B.
Wells and R. L. Lester, J. Biol. Chem., 1997, 272, 30196–30200; (b) R.
Schneiter, Bioessays, 1999, 21, 1004–1010.
9 (a) T. Kawano, J. Cui, Y. Koezuka, Y. Toura, Y. Kaneko, K. Motoki,
H. Ueno, R. Nakagawa, H. Sato, E. Kondo, H. Koseki and M.
Taniguchi, Science, 1997, 278, 1626–1629; (b) E. Kobayashi, K. Motoki,
Y. Yamaguchi, T. Uchida, H. Fukushima and Y. Koezuka, Bioorg. Med.
Chem., 1996, 4, 615–619; (c) E. Kobayashi, K. Motoki, T. Uchida, H.
Fukushima and Y. Koezuka, Oncol. Res., 1995, 7, 529–534; (d) M.
Morita, K. Motoki, K. Akimoto, T. Natori, T. Sakai, E. Sawa, K.
Yamaji, Y. Koezuka, E. Kobayashi and H. Fukushima, J. Med. Chem.,
1995, 38, 2176–2187.
10 For reviews, see: (a) P. M. Koskinen and A. M. P. Koskinen, Synthesis,
1998, 1075–1091; (b) C. Curfman and D. Liotta, Methods Enzymol.,
1999, 311, 391–457.
11 A. Solladie´-Cavallo and J. L. Koessler, J. Org. Chem., 1994, 59, 3240–
3242.
20 (a) R. Wild and R. R. Schmidt, Liebigs Ann., 1995, 755–764;
(b) E. J. Reist and P. H. Christie, J. Org. Chem., 1970, 35, 3521–
3524.
21 R. C. So, R. Ndonye, D. P. Izmirian, S. K. Richardson, R. L. Guerrera
and A. R. Howell, J. Org. Chem., 2004, 69, 3233–3235, and references
therein.
22 (a) O. Plettenburg, V. Bodmer-Narkevitch and C.-H. Wong, J. Org.
Chem., 2002, 67, 4559–4564; (b) S.-Y. Luo, S. R. Thopate, C.-Y. Hsu
and S.-C. Hung, Tetrahedron Lett., 2002, 43, 4889–4892; (c) S. Figueroa-
Pe´rez and R. R. Schmidt, Carbohydr. Res., 2000, 328, 95–102; (d) A.
Graziani, P. Passacantelli, G. Piancatelli and S. Tani, Tetrahedron:
Asymmetry, 2000, 11, 3921–3937; (e) T. Murakami and K. Taguchi,
Tetrahedron, 1999, 55, 989–1004; (f) Y.-L. Li, X.-H. Mao and Y.-L. Wu,
J. Chem. Soc., Perkin Trans. 1, 1995, 1559–1563; (g) K. Matsumoto, T.
Ebata and H. Matsushita, Carbohydr. Res., 1995, 279, 93–106; (h) R.
Wild and R. R. Schmidt, Tetrahedron: Asymmetry, 1994, 5, 2195–2208;
(i) T. Murakami, H. Minamikawa and M. Hato, Tetrahedron Lett.,
1994, 35, 745–748; (j) R. R. Schmidt and T. Maier, Carbohydr. Res.,
1988, 174, 169–180.
23 (a) A. J. Ndakala, M. Hashemzadeh, R. C. So and A. R. Howell,
Org. Lett., 2002, 4, 1719–1722; (b) H. Azuma, S. Tamagaki and K.
Ogino, J. Org. Chem., 2000, 65, 3538–3541; (c) H. Takikawa, S.-E.
Muto and K. Mori, Tetrahedron, 1998, 54, 3141–3150; (d) R. Imashiro,
O. Sakurai, T. Yamashita and H. Horikawa, Tetrahedron, 1998, 54,
10657–10670; (e) M. Shimizu, I. Wakioka and T. Fujisawa, Tetrahedron
Lett., 1997, 38, 6027–6030; (f) H. Yoda, T. Oguchi and K. Takabe,
Tetrahedron: Asymmetry, 1996, 7, 2113–2116; (g) A. Dondoni, G.
Fantin, M. Fogagnolo and P. Pedrini, J. Org. Chem., 1990, 55, 1439–
1446; (h) S. Sugiyama, M. Honda and T. Komori, Liebigs Ann. Chem.,
1990, 1069–1078.
24 (a) T. Ayad, Y. Ge´nisson, A. Verdu, M. Baltas and L. Gorrichon,
Tetrahedron Lett., 2003, 44, 579–582; (b) H.-K. Lee, E.-K. Kim and
C.-S. Pak, Tetrahedron Lett., 2002, 43, 9641–9644; (c) T. Nakamura
and M. Shiozaki, Tetrahedron, 2001, 57, 9087–9092; (d) C. Martin, W.
Pru¨nck, M. Bortoloussi and R. Bloch, Tetrahedron: Asymmetry, 2000,
11, 1585–1592; (e) L. He, H.-S. Byun and R. Bittman, J. Org. Chem.,
2000, 65, 7618–7626; (f) R. A. Fernandes and P. Kumar, Tetrahedron
Lett., 2000, 41, 10309–10312; (g) O. Shirota, K. Nakanishi and N.
Berova, Tetrahedron, 1999, 55, 13643–13658; (h) T. Nakamura and M.
Shiozaki, Tetrahedron Lett., 1999, 40, 9063–9064; (i) S. Li, J. Pang,
W. K. Wilson and G. J. Schroepfer, Jr., Tetrahedron: Asymmetry, 1999,
10, 1697–1707; (j) A. G. H. Wee and F. Tang, Tetrahedron Lett., 1996,
37, 6677–6680; (k) G.-Q. Lin and Z.-C. Shi, Tetrahedron, 1996, 52,
2187–2192; (l) S. Kobayashi, T. Hayashi and T. Kawasuji, Tetrahedron
Lett., 1994, 35, 9573–9576.
12 S. Li, J. Pang, W. K. Wilson and G. J. Schroepfer, Jr., J. Labelled Compd.
Radiopharm., 1999, 42, 815–826.
13 T. Shioiri and N. Irako, Tetrahedron, 2000, 56, 9129–9142.
14 Y. Vo-Hoang, L. Micouin, C. Ronet, G. Gachelin and M. Bonin,
ChemBioChem, 2003, 4, 27–33.
15 For examples of truncated sphingosine syntheses, see: (a) D. R. Bundle,
C.-C. Ling and P. Zhang, US Patent WO 03/101937; Chem. Abs., 2003,
140, 16928; (b) A. N. Rai and A. Basu, Org. Lett., 2004, 6, 2861–2863;
(c) S. Torssell and P. Somfai, Org. Biomol. Chem., 2004, 2, 1643–1646.
For examples of diastereoisomer syntheses of truncated sphingosine,
see; (d) X. Zhang, W. Ni and W. A. van der Donk, J. Org. Chem., 2005,
70, 6685–6692; (e) H. Razavi and R. Polt, Tetrahedron Lett., 1998, 39,
3371–3374.
16 (a) J. R. Rich and D. R. Bundle, Org. Lett., 2004, 6, 897; (b) S. Jacques,
J. R. Rich, C.-C. Ling and D. R. Bundle, Org. Biomol. Chem., 2006, 4,
142–154; (c) D. R. Bundle, J. R. Rich, S. Jacques, H. N. Yu, M. Nitz
and C.-C. Ling, Angew. Chem., Int. Ed., 2005, 44, 7725–7729; (d) J. R.
Rich and D. R. Bundle, Chem.–Eur. J., 2006, 12, 845–858.
17 C.-C. Ling and D. R. Bundle, unpublished work.
25 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155–
4156.
26 K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung,
K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu and
X.-L. Zhang, J. Org. Chem., 1992, 57, 2768–2771.
18 T. Oguri, N. Kaway and S. Yamada, Chem. Pharm. Bull., 1978, 26, 803.
19 (a) S. Kodato, M. Nakagawa and T. Hino, Tetrahedron, 1989, 45, 7263–
7280; (b) G. N. Nicholas and T. F. Molinski, J. Am. Chem. Soc., 2000,
122, 4011–4019.
1146 | Org. Biomol. Chem., 2006, 4, 1140–1146
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