'Chiron' approach to stereoselective synthesis of sphinganine and unnatural safingol, an antineoplastic and antipsoriatic agent

Article abstract of DOI:10.1039/c5ra27342k

Highly stereoselective total syntheses of sphingoid bases, natural bioactive ceramide sphinganine 1 (with an overall yield of 33%) and unnatural antineoplastic and antipsoriatic drug safingol 17 (with an overall yield of 38%) starting from chirons 3,4,6-tri-O-benzyl-d-galactal and 3,4,6-tri-O-benzyl-d-glucal respectively have been demonstrated. Mitsunobu reaction and late stage olefin cross metathesis are utilized as important steps in order to complete the total synthesis of these sphingoid molecules.

Full text of DOI:10.1039/c5ra27342k

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ARTICLE TYPE
‘Chiron’ approach to stereoselective synthesis of Sphinganine and unnatural Safingol,
an antineoplastic and antipsoriatic agent
Pintu Das, Somireddy Kundooru and Arun K. Shaw*
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
5
DOI: 10.1039/b000000x
a
Division of Medicinal and Process Chemistry, CSIRꢀCentral Drug Research Institute, BSꢀ10/1, Sector 10, Jankipuram Extension, Sitapur Road,
,
Lucknowꢀ226031, India Tel: +91ꢀ9415403775; Eꢀmail: akshaw55@yahoo.com
Highly stereoselective total syntheses of sphingoid bases, natural bioactive ceramide sphinganine 1 (with an overall yield of 33%) and
1
0
unnatural antineoplastic and antipsoriatic drug safingol 17 (with an overall yield of 38%) starting from chirons 3,4,6ꢀtriꢀOꢀbenzylꢀ
galactal and 3,4,6ꢀtriꢀOꢀbenzylꢀ ꢀglucal respectively have been demonstrated. Mitsunobu reaction and late stage olefin cross metathesis
are utilized as important steps in order to complete the total synthesis of these sphingoid molecules.
Dꢀ
D
.
Introduction
Sphinganine and Safingol are sphingoid bases and are composed
of three structural units: a longꢀchain aliphatic 2ꢀaminoꢀ1,3ꢀdiol,
a fatty acid and a polar head group. While the former is a
Sphingolipids possessing long chain 2ꢀaminoꢀ1,3ꢀdiols motif are
unique components of all eukaryotic cells. They are isolated from
mammalian cells, plants, yeast, bacteria, fungi, viruses, marine
1
2
2
5
0
5
3
4
4
5
5
0
5
0
naturally occurring base in
later one is among one of the three unnatural sphingoid bases in
ꢀtheroꢀ(2S,3S)ꢀ configuration known. It has been observed that
Dꢀerythroꢀ(2S,3R)ꢀ configuration, the
1
organisms and in some prokaryotic organisms. Due to
L
intramolecular hydrogen bonding, these Sphingolipids bear a
stereochemistry for both these compounds play a major role in
small positive charge at neutral pH that enables them to cross the
4
their biological activities.
2
membranes or move between membranes easily. Sphingolipids
The variety of biological activities and unique stereostructures of
both sphinganine and safingol substantiate a great deal of interest
to access their economical synthetic route starting from
commercially available precursors. Our group has been actively
working on stereoselective synthesis of various types of
and some of their metabolites play critical roles in various types
of physiological processes that include cell regulation such as cell
proliferation, differentiation, immune response, apoptosis,
3
adhesion and signal transduction. Recent studies have shown
that deviation from sphingolipid metabolism causes several
inherited and most common human diseases including diabetes,
cancer, Alzheimer’s disease, heart and infection by
5
biologically relevant molecules including natural products from
6
7
8,9
microorganisms, plant and marine origin
starting from
10
commercially available chirons . In continuation of our interest
on chiron approach to synthesis of naturally occurring
biomolecules, herein we wish to report on concise syntheses of
title sphingoid bases starting from glycal derived
enantiomerically pure α, βꢀunsaturated δꢀhydroxy aldehydes
3
,4
microorganisms. Some of the representative sphingoid bases
are shown in the figure 1.
11
commonly known as Perlin aldehydes.
With our enduring interest in the syntheses of
3
0
Figure 1. Representative sphingoid bases
biologically active natural products or natural product like
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molecules we are encouraged to undertake the synthesis of the 40 literature reports revealed that highly stereoselective synthetic
bioactive natural products Sphinganine and Safingol from Perlin
aldehydes as a chiral pool material.
approach with less number of steps is still desirable today for
those biologically relevant molecules whose isolation from the
natural sources are either difficult or they are not found in the
nature. Keeping this argument in mind, we designed the highly
5
Synthesis of Sphinganine and Safingol
Synthesis of both the title molecules Sphinganine and Safingol 45 stereoselective synthesis of title natural product 1 based on its
must address two key concerns. First, the stereochemistry at the
,3ꢀamino alcohol unit and second the installation of long chain
retrosynthetic analysis depicted in scheme 2. We envisaged that
sphinganine 1 could be elaborated from the hydrogenolysis of 8.
The long chain sphingoid framework could be readily accessible
from the olefin cross metathesis of Boc protected amine 7 with a
2
unit. In order to synthesize Sphinganine and Safingol, we started
10
our synthetic route from 3,4,6ꢀtriꢀOꢀbenzylꢀDꢀgalactal and 3,4,6ꢀ
triꢀOꢀbenzylꢀDꢀglucal respectively in which the stereochemistry 50 suitable terminal olefin. The C2 amino functionality could be
at 2,3ꢀamino alcohol unit was inherited from the starting
materials. The late stage olefin cross metathesis reaction was
selected to install the long chain unit (Scheme 1).
achieved by Mitsunobu reaction of the terminal olefin 4 with
inversion of stereochemistry. The olefin could be simply obtained
by NaBH reduction of the hydrazone 3 which could in turn be
4
10
prepared from Perlin aldehyde 2 (Scheme 2).
NH2
3R
NHBoc
NHBoc
OH
HO
BnO
C11H23
BnO
BnO
BnO
2
S
C14H29
OH
OBn
8
OBn
7
OBn
4
1
OH
OH
4R
OBn OBn
O
BnO
NHTs
N
5R
O
BnO
3,4,6-tri-O-benzyl-D-galactal
OBn
3
OBn
2
55
15
Scheme 2. Retrosynthesis of Sphinganine 1
Scheme 1. Synthetic plan towards Sphinganine and Safingol
Thus, the synthesis of 1 was started from easily avaiable 3,4,6ꢀtriꢀ
Oꢀbenzylꢀ ꢀgalactal derived Perlin aldehyde which on
Synthesis
of
Sphinganine
1
(
D
-erythro
(2S,3R)
D
2
dihydrosphingosine)
6
0
treatment with 1.5 equiv. of tosylhydrazine at room temperature
20
Sphinganine 1 plays important roles in cell regulation and signal
gave tosylhydrazone 3. It was immediately allowed (without
transduction. It is a biosynthetic intermediate of ceramides,
purification) to react with 10 equiv. of NaBH in AcOH to obtain
4
1
2
sphingomyelin, cerebrosides and gangliosides. It intensely
inhibits protein kinase C6 and its ceramide derivatives are strong
1
6
1
the terminal olefin 4 with 75% yield over two steps. Its H
NMR spectra showing the disappearance of signal for aldehyde
proton and appearance of signals for olefin protons at δ 5.1 and δ
2
stimulators of the mammalian immune system. It is an important
65
25
30
35
part of symbioramide, a new type of bioactive ceramide, which is
5
.9 confirmed the structure . It was then subjected to Mitsunobu
2
+
responsible for increasing sarcoplasmic reticulum Ca ꢀ ATPase
reaction with pthalimide to furnish the pthalimido derivative 5
with 83% yield. The hydrolysis of the pthalimido functionality
was done by treating 5 with methyl amine to produce the required
1
3
activity. Because of its biological activities and the difficulties
associated with the isolation in homogeneous form from natural
sources, various synthetic methods have been reported to access it
and its derivatives during last decades. Its earlier synthetic
strategies were stereoselective by asymmetric routes or chiral
70
free amine 6 whose immediate protection with (Boc) O afforded
2
the protected terminal olefin 7 with 95% yield over two steps.
2
,14
pool material approaches.
But majority of them showed low
levels of stereoselection resulting mixture of diastereoisomers
and enantiomers that need to be separated. Recently, Wulff et al.
demonstrated a general route for a catalytic asymmetric synthesis
of its all four stereoisomers through multicomponent asymmetric
aziridination whereas its total synthesis commencing from
commercial Nꢀtertꢀbutyloxycarbonylꢀ
Lꢀserine methyl ester has
4
,15
been described by Siciliano and coꢀworkers.
Thus, the
Scheme 3. Synthesis of Sphinganine 1.
2
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Reagents and conditions: (a) ref 11; (b) TsNHNH
NaBH , AcOH, 75% (over two steps); (d) Pthalimide, DIAD (Diisopropyl
azodicarboxylate), THF, ꢀ20 °C, 83%; (e) MeNH , DCM; (f) (Boc) O,
Et N, DCM, 95% (over two steps); (g) 1ꢀtetradecene, Grubbs’ second
generation catalyst, DCM, 45 °C, 70%; (h) Pd/C, H , TFA, 87%.
2
, EtOH, 15min; (c)
4
5
and synꢀβꢀamino aldehyde prepared by (R)ꢀproline catalyzes
4
30
reaction between NꢀBocꢀimine and aldehyde.
2
2
Our retrosynthetic analysis envisioned (Scheme 4) for the
3
synthesis of unnatural sphingoid base safingol 17 exhibiting
threoꢀ(2S,3S) configuration was similar to that of natural base
sphinganine 1 occurring in ꢀerythro (2S,3R) configuration
Scheme 2).
Lꢀ
5
2
In order to complete the total synthesis of Sphinganine 1, the long
chain hydrocarbon was installed through the olefin cross
metathesis reaction of 7 with 1ꢀtetradecene in the presence of
Grubbs’ second generation catalyst in dichloromethane at 45 °C
to obtain the unsaturated amine 8 in 70% yield. Finally, its global
50
D
(
1
1
2
2
3
3
4
0
5
0
5
0
5
0
deprotection in the presence of Pd/C, H and TFA provided the
2
natural Sphinganine 1 with 33% overall yield (Scheme 3).
Scheme 4. Retrosynthesis of Safingol 17.
Synthesis of Safingol 17 (L-thero-(2S,3S)-dihydrosphingosine)
Safingol or Lꢀtheroꢀ(2S,3S)ꢀdihydrosphingosine 17 is an
unnatural medicinally important sphingoid base. It is an
5
5
Thus, the tosylhydrazone derivative 11, the key intermediate,
1
7
which was synthesized from 3,4,6ꢀtriꢀOꢀbenzylꢀ
Perlin aldehyde 10 by treating it with 1.5 equiv. of tosylhydrazine
at room temperature on treatment with 10 equiv. of NaBH in
AcOH furnished the terminal olefin 12 with 70% yield over two
Dꢀglucal derived
antineoplastic and antipsoriatic drug and plays significant role
1
2
in cell regulation, signal transduction and inhibits protein
18
4
kinase C. It synergistically increases the toxicity of established
60
chemoꢀ therapeutic agents in several cancer cells in vitro, as well
16
1
19
steps. The structure was established from its H NMR spectra
displaying signals in the olefinic region at δ 5.0 and 5.8 for the
two protons and one proton respectively. Its Mitsunobu reaction
with pthalimide provided the pthalimido derivative 13 with 83%
yield. It was then subjected to undergo hydrolysis with methyl
amine and the immediate protection of the resulting free amine
as in preclinical animal studies and in a phase I clinical trial.
Owing to important biological activities of Safingol, a great deal
of interest has been dedicated towards its total synthesis. The
earlier reports on its syntheses include enantioselective
65
stereoselective reduction of
a
chiral 2ꢀacylaziridine
Pdꢀcatalyzed isomerization of 5ꢀvinyloxazolines
by utilizing hydroboration/Suzuki coupling sequence to elongate
2
0a
intermediate,
with (Boc) O resulted the protected terminal olefin 15 with 96%
2
2
0b
yield over two steps.
the hydrophobic chain,
asymmetric borane reduction of a
2
0c
20d
ketone, nucleophilic addition to a chiral oxazolidinyl ester,
20e
Henry reaction, and multistep total synthesis starting from (Z)ꢀ
2
0f
butꢀ2ꢀeneꢀ1,4ꢀdiol.
during last one decade on its synthesis are based on kinetic
The other literature methods reported
2
1
resolution method,
palladiumꢀcatalyzed transꢀoxazoline
2
2
formation followed by cross metathesis, a diastereoselective
Grignard addition of a suitable alkylmagnesium bromide or
70
Scheme 5. Synthesis of Safingol 17.
lithium
reagent
to
easily
available
utilization of carbohydrate
derived chiral pool material, Sharpless kinetic resolution and
(R)
2
3
cyclohexylideneglyceraldehyde,
Reagents and conditions: (a) ref 11; (b) TsNHNH
NaBH , AcOH, 70% (over two steps); (d) pthalimide, DIAD (Diisopropyl
azodicarboxylate), THF, ꢀ20 °C, 83%; (e) MeNH , (f) (Boc) O, Et N,
2
, EtOH, 15min; (c)
2
4
4
2
5
tethered aminohydroxylation (TA),
chelationꢀcontrolled
2
2
3
75
DCM, 96% (over two steps); (g) 1ꢀtetradecene, Grubbs’ second
generation catalyst, DCM, 45 °C, 76%; (h) Pd/C, H , TFA, 92%.
addition of an organocuprate species to protected αꢀamino
2
6
2
aldehydes, copper (II) catalyzed synꢀ and enantioselective
2
7
Henry Reactions of aliphatic aldehydes, palladiumꢀcatalyzed
After constructing the polar head group (2S,3S 2ꢀamino 1,3 diol)
2
8
intramolecular aminohydroxylation of alkenes,
or from
of title molecule, the long chain hydrocarbon was installed by
29
commercially available ꢀriboꢀ(2S,3S,4R)ꢀphytosphingosine
D
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13
olefin cross metathesis between 1ꢀtetradecene and 15 in the
carbon. For C NMR reference CDCl appeared at 77.40 ppm
3
presence of Grubbs’ second generation catalyst in DCM at 45 °C 45 and CD OD appeared at 48.70 ppm. IR spectra were recorded on
3
to obtain the olefinic compound 16 in 76% yield. Its benzyl
PerkinꢀElmer
Spectrophotometers. Optical rotations were determined on an
Autopol III Polarimeter and DigiPol 781M6U NOVA
Polarimeter using a 1 dm cell at 17 °C–32 °C in chloroform and
881
and
FTIRꢀ8210
PC
Shimadzu
deprotection and reduction of olefin functionality were achieved
5
0
5
0
5
0
5
0
in one pot in the presence of Pd/C, H and TFA resulting in the
a
2
formation of unnatural sphingoid, Safingol 17 with an overall
yield of 38% (Scheme 5). The spectral data of both the title 50 methanol and ethanol as the solvents; concentrations mentioned
natural and unnatural products are in good agreement with those
are in g per 100 mL. Mass spectra were recorded on a JEOL
JMSꢀ600H high resolution spectrometer using EI mode at 70 eV.
ESIꢀHRMS were recorded on a JEOLꢀAccuTOF JMSꢀT100LC
spectrometer. ESIꢀHRMS were recorded on a JEOLꢀAccuTOF
55 JMSꢀT100LC spectrometer.
2
7
reported in the literature. {Sphinganine 1 [α]D +7.8 (c 0.16,
2,15
1
1
2
2
3
3
4
EtOH) Lit : [α] 8.1, c 1.0, CH OH), [α] 7.9, c 1.0, CH OH);
D
3
D
3
27
27
20
Safingol 17 [α]D ꢀ7.5 (c 0.09, EtOH) [Lit : [α]
ꢀ4.0 (c 0.5 in
D
CHCl ), [α] ꢀ11.2 (c 0.10, CHCl :CH OH, 10:1, v/v)]}.
3
D
3
3
Conclusion
Synthesis of compound (2R,3R)-1,3-bis(benzyloxy)hex-5-en-2-ol
(
compound 4)
The Perlin aldehyde 2 (1g, 3.07 mmol) and pꢀtoluenesulfonylhydrazine
856 mg, 4.06mmol) in absolute ethanol (2 ml) were stirred at room
In summary, the highly stereoselective total syntheses of natural
Sphinganine 1 and antineoplastic and antipsoriatic drug Safingol
(
17
1
7
were accomplished starting from chirons 3,4,6ꢀtriꢀOꢀbenzylꢀ
60
temperature until a clear solution resulted (15 min). The solvent was
evaporated after completion of the reaction. To the crude tosylhydrazone
D
ꢀgalactal and 3,4,6ꢀtriꢀOꢀbenzylꢀ ꢀglucal respectively. The
D
stereochemistries at C2 and C3 in Sphinganine (2S,3R) and
Safingol (2S,3S) were directed by the Perlin aldehydes 2 and 10
respectively. The 2S stereochemistry in both the target molecules
3
4
(1.5 g, 3.6 mmol) of glacial acetic acid was added NaBH (1g, 30
mmol) at 0 °C with a precaution that foaming was avoided. The solution
was stirred at room temperature for 2h. The solution was then poured into
was achieved by Mitsunobu reaction and their stereochemistry at 65 crushed ice, treated with aqueous NaOH to make it basic, and extracted
with three portions of diethylether (10mL each). The ether solution was
C3 was conserved from the C4 of their respective unsaturated
dried and concentrated on a rotary evaporator and purified by column
aldehydes 2 and 10. Late stage olefin cross metathesis reaction
chromatography to obtain pure terminal olefin 4 (720 mg, 2.3 mmol) in
was employed to install the long chain hydrocarbon, thus
7
5% yield.
completing the synthesis of title molecules. Our synthetic
strategies for both the molecules were similar and all the reagents
including the starting materials are commercially and easily
available. Thus, it is worth mentioning that both the schemes 3
and 5 are highly cost effective for their commercialization.
7
7
8
0
5
0
Eluent for column chromatography: EtOAc/Hexane (1/9, v/v);
27
1
[
α]
D
ꢀ24.3 (c 0.23, CHCl
3
); R
f
= 0.5 (1/4, EtOAc/Hexane); H NMR (400
3
MHz, CDCl ): δ 2.41ꢀ2.49 (m, 3H), 3.56ꢀ3.57 (m, 2H), 3.63ꢀ3.65 (m,
1H), 3.84ꢀ3.85( dd, J = 5.44, J = 9.93 Hz, 2H), 4.50ꢀ4.56 (m, 3H), 4.68ꢀ
1
2
4.71 (m, 1H), 5.09ꢀ5.17 (m, 2H), 5.85ꢀ5.89 (m, 1H), 7.28ꢀ7.40 (m, 10H);
13
3
C NMR (100 MHz, CDCl ): δ 35.0, 71.1, 71.6, 72.6, 73.5, 78.6, 117.7,
1
27.8, 127.9, 128.0, 128.1, 128.5, 128.7, 134.5, 138.1, 138.3; IR (neat,
Experimental
ꢀ
1
cm ): 668, 698, 770, 1068, 1217, 1403, 1639, 2926, 3017, 3400; ESIꢀ
Organic solvents were dried by standard methods. Analytical
TLC was performed using 2.5 × 5 cm plates coated with a 0.25
mm thickness of silica gel (60Fꢀ254), visualization was done with
CeSO4 and subsequent charring over a hot plate. Silica gel (60–
+
+
HRMS: m/z [M+H] calcd for C20
-((2S,3R)-1,3-bis(benzyloxy)hex-5-en-2-yl)isoindoline-1,3-dione
(compound 5)
25 3
H O 313.1798, measured 313.1798.
2
A solution of phthalimide (458 mg, 3.12 mmol), triphenyl phosphine (817
mg, 3.12 mmol) and the alcohol 4 (650 mg, 2.08 mmol), in dry THF (20
mL) was cooled to −20 ˚C under argon atmosphere. DIAD (0.6 mL, 3.12
mmol) was added drop wise to the above solution. The resulting mixture
1
20 mesh) and silica gel (230–400 mesh) were used in column
chromatography. All the products were characterized by using
1
13
H, C, IR and ESIꢀHRMS. NMR spectra were recorded on a
1
85 was stirred at the same temperature for 2 h and afterward at room
temperature. After overnight stirring, the reaction mixture was evaporated
Bruker Avance 300 MHz spectrometer at 300 MHz ( H) and 75
1
3
1
MHz ( C), 400 MHz spectrometer at 400 MHz ( H) and 100
under reduced pressure to give
a residue which on column
1
3
MHz ( C). Experiments were performed in CDCl and CD OD
3
3
chromatographic purification provided the compound 5 (760 mg, 1.72
at 25 °C. Chemical shifts are given on the δ scale and are
referenced to TMS at 0.00 ppm for a proton and 0.00 ppm for
mmol) in 83 % yield.
4
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27
D
Eluent for column chromatography: EtOAc/Hexane (1/9, v/v); [α]
ꢀ48.4 50 while the stirring was continued. The solution was refluxed for 6 h. The
1
(
c 0.31, CHCl
CDCl
= 10.22 Hz, 1H, ), 4.02ꢀ4.05 (t, J = 9.96 Hz, 1H), 4.14ꢀ4.17 (m, 1H),
4.31ꢀ4.34 (m, 1H), 4.41ꢀ4.45 (m, 2H), 4.56ꢀ4.57 (m, 1H), 4.58ꢀ4.59 (m,
3
); R
f
= 0.6 (1/4, EtOAc/Hexane); H NMR (400 MHz,
temperature of the reaction mixture was cooled slowly to room
temperature. The organic solvent was evaporated under reduced pressure
to give a brown residue, which was directly purified by column
chromatography (230ꢀ400 mesh) to furnish pure compound 8 as a
3
1
): δ 2.15ꢀ2.19 (m, 1H), 2.33ꢀ2.38 (m, 1H), 3.83ꢀ3.86 (dd, J = 4.32,
J
2
5
1
H), 4.88ꢀ4.92 (m, 2H), 5.73ꢀ5.78 (m, 1H), 7.09ꢀ7.17 (m, 5H), 7.19ꢀ7.26 55 colourless oil (97 mg, 0.16 mmol, 70%).
1
3
(
m, 5H), 7.73ꢀ7.74 (m, 2H), 7.74ꢀ7.75 (m, 2H); C NMR (100 MHz,
CDCl ): δ 35.8, 53.5, 67.3, 72.2, 72.7, 76.2, 117.9, 123.4, 123.5, 127.6,
27.7, 127.9, 128.0, 128.4, 128.5, 128.7, 128.8, 132.0, 133.6, 134.0,
Eluent for column chromatography: EtOAc/Hexane (3/97,
27
D
1
3
v/v); [α]
(400 MHz, CDCl
2.02 (m, 2H), 2.31ꢀ2.40 (m, 2H), 3.56ꢀ3.64 (m, 2H), 3.73ꢀ3.76 (m, 1H),
216, 1386, 1639, 1711, 1774, 2926, 3019, 3399; ESIꢀHRMS: m/z 60 3.93 (brs, 1H), 4.46ꢀ4.56 (m, 3H), 4.62ꢀ4.66 (m, 1H), 4.89ꢀ4.91 (m, 1H),
ꢀ7.2 (c 0.16, CHCl
3 f
); R = 0.7 (1/20, EtOAc/Hexane); H NMR
1
3
): δ 0.89ꢀ0.92 (m, 3H), 1.27 (s, 21H), 1.99 (s, 9H), 2.00ꢀ
ꢀ1
1
1
2
2
0
5
0
5
134.1, 138.1, 138.2, 168.7; IR (neat, cm ): 668, 698, 721, 757, 768, 1068,
1
+
+
13
[
M+H] calcd for C28
H
28NO
4
442.2013, measured 442.2010.
3
5.49ꢀ5.53 (m, 2H), 7.31ꢀ7.36 (m, 10H); C NMR (100 MHz, CDCl ): δ
tert-butyl
((2S,3R)-1,3-bis(benzyloxy)hex-5-en-2-yl)carbamate
14.3, 22.8, 28.6, 29.4, 29.5, 29.6, 29.7, 29.8, 29.84, 32.1, 32.9, 34.6, 52.6,
69.2, 72.5, 73.2, 79.0, 125.8, 127.7, 127.8, 128.0, 128.5, 133.8, 138.4,
(
compound 7)
The pthalimide 5 (700 mg, 1.58 mmol) was dissolved in aqueous solution
of MeNH (10 mL, 40 %), and the resulting mixture was stirred in an
ꢀ1
138.7, 155.6; IR (neat, cm ): 763, 1065, 1159, 1217, 1394, 1499, 1641,
+
+
2
65 2925, 3403; ESIꢀHRMS: m/z [M+H] calcd for C37
H58NO
4
580.4360,
open flask for 3 h at 60 °C. The reaction mixture was then concentrated
under reduced pressure, dissolved in water (15 mL) and extracted with
ethyl acetate (4 × 10 mL). The combined organic extracts were washed
measured 580.4357.
(2S,3R)-2-aminooctadecane-1,3-diol (Sphinganine 1)
To a solution of 8 (50 mg, 0.08 mmol) in MeOH (3 mL), trifluoroacetic
acid (0.2 mL, 2.51 mmol) was added and degassed. Next, Pd(OH) /C
The crude was purified by passing it through a filter column. To a stirred 70 (10mg) was added to the reaction mixture and stirred under hydrogen
with brine, dried over Na
2
SO
4
and evaporated under reduced pressure.
2
solution of amine 6 (460 mg, 1.47 mmol) in DCM (20 mL) at 0 ˚C was
added Et N (0.3 mL, 2.2 mmol) and the stirring was continued for 10 min
at the same temperature. After 10 min, Boc O (0.5 mL, 4.7 2.2 mmol)
atmosphere (balloon) for 12 h. After completion of the reaction (TLC), it
was filtered through a short pad of Celite and the Celite pad was washed
3
2
with 1:1 MeOH/CHCl
of the solvent was purified by column chromatography using
75 MeOH/CHCl (1:4) as eluent to furnish the Sphinganine 1 (21 mg, 0.07
mmol) in 81% yield.
3
(10 mL). The residue obtained after concentration
was added dropwise. The resulting reaction mixture was then allowed to
warm to room temperature and stirred for an additional 4 h. Water was
then added to the reaction mixture and the reaction mixture was extracted
with DCM (3 × 10 mL). The combined organic layers were washed with
3
27
D
1
[α]
NMR (400 MHz, CD
(brs, 4H), 3.33 (brs, 1H), 3.69ꢀ3.77 (m, 1H), 3.81ꢀ3.88 (m, 2H); C NMR
+7.9 (c 0.16, EtOH); R
f
= 0.3 (1/4/1, MeOH/CHCl
3
/NH
4
OH);
H
water and brine, dried (Na
2
SO
4
), and evaporated under reduced pressure.
3
OD): δ 0.93ꢀ0.94 (m, 3H), 1.31ꢀ1.33 (m, 24H), 1.51
13
3
3
4
4
0
5
0
5
The crude residue was purified by silica gel column chromatography to
afford olefin 7 (620 mg, 1.50 mmol) in 95 % yield over two steps.
80 (100 MHz, CD
3
OD): δ 13.4, 22.7, 26.0, 29.5, 29.6, 29.8, 32.1, 33.2, 57.5,
2
7
ꢀ1
Eluent for column chromatography: EtOAc/Hexane (3/97, v/v); [α]
D
ꢀ
57.9, 69.3; IR (KBr, cm ): 668, 770, 1067, 1216, 1403, 1638, 2849, 2918,
1
+
+
1
3.0 (c 0.22, CHCl
3
); R
f
= 0.6 (1/19, EtOAc/Hexane); H NMR (400
3019, 3391; ESIꢀHRMS: m/z [M+H] calcd for
C
18
H40NO
2
302.3054,
MHz, CDCl
3
): δ 1.47 (s, 9H), 2.37ꢀ2.45 (m, 2H), 3.57ꢀ3.60 (dd, J
= 9.31 Hz, 1H), 3.66ꢀ3.68 (m, 1H), 3.76ꢀ3.80 (m, 1H), 3.94 (brs, 1H),
.47ꢀ4.65 (m, 4H), 4.91ꢀ4.93 (m, 1H), 5.10ꢀ5.17 (m, 2H), 5.88ꢀ5.99 (m,
1
= 3.63,
measured 302.3054.
J
2
Synthesis of compound (2R,3S)-1,3-bis(benzyloxy)hex-5-en-2-ol
85 (compound 12)
4
1
5
1
13
H), 7.28ꢀ7.30 (m, 10H); C NMR (100 MHz, CDCl
3
): δ 28.5, 35.7.0,
The Perlin aldehyde 10 (1g, 3.07 mmol) and pꢀtoluenesulfonylhydrazine
(856 mg, 4.06mmol) in absolute ethanol (2 ml) were stirred in a RB flask
at room temperature until a clear solution resulted (15 min). After the
completion of the reaction, the solvent was evaporated. To the crude
90 tosylhydrazone 11 (1.5 g, 3.6 mmol) in 15 mL of glacial acetic acid was
2.5, 69.1, 72.4, 73.3, 78.5, 79.4, 117.6, 127.8, 128.0, 128.48, 128.5,
ꢀ1
34.8, 138.3, 138.5, 155.6; IR (neat, cm ): 668, 758, 920, 1028, 1066,
1162, 1215, 1366, 1391, 1499, 1708, 2927, 3018, 3436; ESIꢀHRMS: m/z
+
+
[
M+Na] calcd for C25
tert-butyl ((2S,3R,E)-1,3-bis(benzyloxy)octadec-5-en-2-yl)carbamate
compound 8)
4
H33NaNO 434.2302, measured 434.2300.
4
added NaBH (1g, 30 mmol) at 0°C slowly to avoid foaming. The
(
solution was stirred at room temperature for 2h. Afterward, it was poured
into crushed ice, made basic with aqueous NaOH, and extracted with
three portions of diethylether (10mL each). The ether solution was dried
To a 50 ml two necked oven dried round bottomed flask fitted with reflux
condenser and septum was added Grubbs’ second generation catalyst (10
mg, 0.012 mmol) under argon atmosphere. The olefin 7 (100 mg, 95 and concentrated on a rotary evaporator and purified by column
0
.24mmol) in dry DCM and 1ꢀtetradecene (0.25mL, 0.96mmol) were
chromatography to furnish pure terminal olefin 12 (670 mg, 2.14mmol) in
added simultaneously through a syringe to the above flask. The reaction
mixture was then degassed. The septum was replaced with a glass stopper
70% yield.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

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Page 6 of 9
View Article Online
DOI: 10.1039/C5RA27342K
27
D
Eluent for column chromatography: EtOAc/Hexane (1/9, v/v); [α]
2 4
50 washed with water and brine, dried (Na SO ), and evaporated under
1
+
28.3 (c 0.36, CHCl
MHz, CDCl
.51 (m, 2H), 3.54ꢀ3.58 (m, 1H), 3.75ꢀ3.79 (m, 1H), 4.40ꢀ4.45 (m, 3H),
4.51ꢀ4.54 (m, 1H), 4.98ꢀ5.03 (m, 1H), 5.07ꢀ5.08 (m, 1H), 5.78ꢀ5.85 (m,
3
); R
f
= 0.5 (1/4, EtOAc/Hexane); H NMR (400
reduced pressure. The crude residue was purified by silica gel column
chromatography to afford olefin 15 (620 mg, 1.5 mmol) in 95% yield
over two steps.
3
): δ 2.32ꢀ2.36 (m, 2H), 2.40ꢀ2.41 (d, J= 4.95Hz, 1H), 3.45ꢀ
3
27
5
0
5
0
5
0
5
0
5
Eluent for column chromatography: EtOAc/Hexane (3/97, v/v); [α]
D
1
3
1
1
7
H), 7.18ꢀ7.27 (m, 10H); C NMR (100 MHz, CDCl
3
): δ 34.8, 71.1, 71.6, 55 +33.1 (c 0.24, CHCl
MHz, CDCl
3.42 (m, 2H), 3.68ꢀ3.71 (t, J
1H), 4.32ꢀ4.45 (m, 3H), 4.52ꢀ4.55 (m, 1H), 4.77ꢀ4.79 (d, J=9.54 Hz, 1H),
3
); R
f
= 0.6 (1/19, EtOAc/Hexane); H NMR (400
2.3, 73.5, 79.2, 117.5, 127.8, 128.0, 128.5, 128.6, 134.7, 138.0, 138.4;
3
): δ 1.35 (s, 9H), 2.22ꢀ2.24 (m, 1H), 2.32ꢀ2.39 (m, 1H), 3.37ꢀ
= 5.78, J = 12.04 Hz, 1H), 3.85ꢀ3.91 (m,
ꢀ1
IR (neat, cm ): 667, 698, 756, 917, 1027, 1071, 1216, 1407, 1454, 1496,
1
2
+
+
1
640, 2923, 3013, 3412; ESIꢀHRMS: m/z [M+H] calcd for C20
25 3
H O
1
3
1
1
2
2
3
3
4
4
313.1798, measured 313.1792.
4.99ꢀ5.07 (m, 2H), 5.71ꢀ5.81 (m, 1H), 7.17ꢀ7.27 (m, 10H); C NMR (100
60 MHz, CDCl ): δ 28.5, 36.0, 51.8, 69.5, 72.8, 73.1, 77.0, 79.4, 117.9,
127.7, 127.8, 127.9, 128.1, 128.5, 134.5, 138.3, 138.4, 155.8; IR (neat,
Synthesis of compound 2-((2S,3S)-1,3-bis(benzyloxy)hex-5-en-2-
yl)isoindoline-1,3-dione (compound 13)
3
ꢀ1
A solution of phthalimide (458 mg, 3.12 mmol), triphenyl phosphine (817
mg, 3.12 mmol) and the alcohol 12 (650 mg, 2.08 mmol), in dry THF (20
mL) was cooled to −20 ˚C under argon atmosphere. DIAD (Diisopropyl
cm ): 766, 1062, 1161, 1218, 1406, 1499, 1639, 1704, 3432; ESIꢀHRMS:
+
+
4
m/z [M+H] calcd for C25
H
34NO
412.2482, measured 412.2472.
tert-butyl ((2S,3S,E)-1,3-
Synthesis of compound
azodicarboxylate) (0.6 mL, 3.12 mmol) was added drop wise to the above 65 bis(benzyloxy)octadec-5-en-2-yl)carbamate (compound 16)
solution. The reaction mixture was stirred at the same temperature for 2 h
and then at room temperature. After overnight stirring, the reaction
mixture was evaporated under reduced pressure to give a residue which
on column chromatographic purification provided the compound 13 (760
mg, 1.72 mmol) in 83% yield.
To a 50 ml two necked oven dried round bottomed flask fitted with reflux
condenser and septum was added Grubbs’ second generation catalyst (10
mg, 0.012 mmol) under argon atmosphere. The olefin 15 (100 mg,
0.24mmol) in dry DCM and 1ꢀ tetradecene (0.25mL, 0.96mmol) were
70 added simultaneously through a syringe to the above flask. The reaction
mixture was then degassed. The septum was replaced with a glass stopper
while the stirring was continued. The solution was refluxed for 6 h. The
temperature of the reaction mixture was cooled slowly to room
temperature. The organic solvent was evaporated under reduced pressure
27
Eluent for column chromatography: EtOAc/Hexane (1/9, v/v); [α]
D
1
+
29.5 (c 0.16, CHCl
MHz, CDCl
4.9, J = 10.2 Hz, 1H), 3.96ꢀ4.01 (m, 1H), 4.02ꢀ4.06 (m, 1H), 4.24ꢀ4.27
3
); R
f
= 0.6 (1/4, EtOAc/Hexane); H NMR (400
3
1
): δ 2.16ꢀ2.22 (m, 1H), 2.44ꢀ2.49 (m, 1H), 3.66ꢀ3.70 (dd, J =
2
(
m, 1H), 4.34ꢀ4.37 (m, 1H), 4.41ꢀ4.44 (m, 1H), 4.49ꢀ4.57 (m, 2H), 5.02ꢀ 75 to give a brown residue, which was directly purified by column
5
5
.03 (m, 1H), 5.06 (s, 1H), 5.83ꢀ5.87 (m, 1H), 6.98 (s, 5H), 7.13ꢀ7.17 (m,
chromatography (230ꢀ400 mesh) to furnish pure compound 16 as a
13
H), 7.58ꢀ7.61 (m, 2H), 7.67ꢀ7.69 (m, 2H); C NMR (100 MHz, CDCl
3
):
colourless oil (105 mg, 0.18 mmol, 76%).
27
δ 36.0, 54.1, 66.5, 72.1, 72.8, 76.0, 118.3, 123.2, 123.4, 127.4, 127.7,
Eluent for column chromatography: EtOAc/Hexane (3/97, v/v); [α]
D
1
127.8, 128.2, 128.4, 128.7, 132.1, 133.5, 133.8, 137.9, 138.2, 168.7; IR
+5.1 (c 0.36, CHCl
3
); R
f
= 0.7 (1/20, EtOAc/Hexane); H NMR (400
ꢀ1
(
neat, cm ): 531, 668, 758, 920, 1027, 1073, 1217, 1389, 1639, 1710,
80 MHz, CDCl
3
): δ 0.79ꢀ0.82 (m, 3H), 1.18ꢀ1.23 (m, 19H), 1.35 (s, 9H),
+
+
4
1
4
772, 2926, 3022, 3409; ESIꢀHRMS: m/z [M+H] calcd for C28
H28NO
1.88ꢀ1.99 (m, 2H), 2.14ꢀ2.30 (m, 2H), 3.37ꢀ3.47 (m, 2H), 3.62ꢀ3.87 (m,
2H), 4.19ꢀ4.56 (m, 4H), 4.76ꢀ4.78 (m, 1H), 5.31ꢀ5.46 (m, 2H), 7.18ꢀ7.25
42.2013, measured 442.2007.
1
3
Synthesis of compound tert-butyl ((2S,3S)-1,3-bis(benzyloxy)hex-5-
en-2-yl)carbamate (compound 15)
(m, 10H); C NMR (100 MHz, CDCl
3
): δ 14.3, 22.8, 28.5, 29.4, 29.5,
29.6, 29.7, 29.8, 32.1, 32.5, 32.9, 34.8, 51.9, 69.6, 70.3, 72.9, 73.1, 78.1,
The pthalimido derivative 13 (700 mg, 1.58 mmol) was dissolved in 85 79.3, 125.5, 127.6, 127.8, 127.9, 128.1, 128.5, 133.0, 134.2, 136.2, 138.4,
ꢀ1
aqueous solution of MeNH
2
(10 mL, 40 %), and the resulting mixture was
138.6, 155.8; IR (neat, cm ): 668, 698, 757, 1027, 1068, 1158, 1216,
stirred in an open flask for 3 h at 60 °C. The reaction mixture was then
concentrated under reduced pressure, dissolved in water (15 mL) and
extracted with ethyl acetate (4 × 10 mL). The combined organic extracts
1405, 1454, 1497, 1639, 1706, 2854, 2926, 3017, 3434; ESIꢀHRMS: m/z
+
+
[M+H] calcd for C37
4
H58NO 580.4360, measured 580.4357.
(2S,3S)-2-aminooctadecane-1,3-diol (Safingol 17)
2 4
were washed with brine, dried over Na SO
and evaporated under reduced 90 To a solution of 16 (50 mg, 0.08 mmol) in MeOH (3 mL), trifluoroacetic
pressure. The crude was purified by passing it through a filter column. To
2
acid (0.2 mL, 2.51 mmol) was added and degassed. Next, Pd(OH) /C
a stirred solution of amine 14 (460 mg, 1.47 mmol) in DCM (20 mL) at 0
(10mg) was added to the reaction mixture and stirred under hydrogen
atmosphere (balloon) for 12 h. After completion of the reaction (TLC), it
was filtered through a short pad of Celite and the Celite pad was washed
˚C was added Et
3
N (0.3 mL, 2.2 mmol) and the stirring was continued for
O (0.5 mL, 4.7 2.2
10 min at the same temperature. After 10 min, Boc
2
mmol) was added dropwise. The resulting reaction mixture was then
allowed to warm to room temperature and stirred for an additional 4 h.
Water was then added to the reaction mixture and the reaction mixture
was extracted with DCM (3×10 mL). The combined organic layers were
95 with 1:1 MeOH/CHCl
of the solvent was purified by column chromatography using
MeOH/CHCl (1:4) as eluent to furnish the TFA salt of Safingol 17 salt
3
(10 mL). The residue obtained after concentration
3
(22 mg, 0.07 mmol) in 92 % yield as a white solid. mp 106−111 °C;
6
|
Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

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RSC Advances
View Article Online
DOI: 10.1039/C5RA27342K
2
7
1
[
α]
D
ꢀ7.6 (c 0.09, EtOH); R
f
= 0.3 (1/4/1, MeOH/CHCl
3
/NH
4
OH);
H
P. Ghosal, V. Kumar and A. K. Shaw, Carbohydrate Research, 2010,
50 345, 41ꢀ44.
NMR (400 MHz, CD
3
OD): δ 0.88ꢀ0.91 (m, 3H), 1.29 (s, 25H), 1.54 (brs,
H), 3.03ꢀ 3.08 (m, 1H), 3.63ꢀ3.70 (m, 2H), 3.70ꢀ3.80 (dd, J = 4.04, J
OD): δ 14.4, 23.7, 26.3, 30.4,
3
1
1
2
=
8. (a) S. Kundooru, P. Das, S. Meena, V. Kumar,M. I. Siddiqi, D. Datta
and A. K. Shaw, Org. Biomol. Chem., 2015,13, 8241ꢀ8250; (b) P. Ghosal,
S. Ajay, S. Meena, S. Sinha and A. K. Shaw, Tetrahedron: Asymmetry,
2013, 24, 903ꢀ908; (c) P. Ghosal, D. Sharma, B. Kumar, S. Meena, S.
55 Sinha and A. K. Shaw, Org. Biomol. Chem., 2011, 9, 7372ꢀ7383; (d) P.
Ghosal and A. K. Shaw, Tetrahedron Letters, 2010, 51, 4140ꢀ4142; (e) P.
Ghosal, V. Kumar and A. K. Shaw, Tetrahedron, 2010, 66, 7504ꢀ7509;
1
3
1.7 Hz, 1H); C NMR (100 MHz, CD
3
ꢀ1
5
30.6, 30.8, 33.0, 34.9, 59.1, 60.5, 69.1; IR (KBr, cm ): 669, 770, 1067,
+
1
216, 1403, 1637, 2852, 2922, 3019, 3399; ESIꢀHRMS: m/z [M+H]
+
calcd for C18
H40NO
2
302.3054, measured 302.3051.
Acknowledgements
1
1
2
2
3
3
4
4
0
5
0
5
0
5
0
5
(
f) V. Kumar and A. K. Shaw, J. Org. Chem. 2008, 73, 7526ꢀ7531; (g) L.
We are thankful to Mr. A. K. Pandey for technical assistance and SAIF,
CDRI for providing spectral data. Pintu Das and Somireddy Kundooru
thank CSIR for awarding Senior Research Fellowship and both
contributed to the present work equally. CDRI manuscript no.
315/2015/AKS.
V. R. Reddy, P. V. Reddy and A. K. Shaw, Tetrahedron: Asymmetry,
2007, 18, 542ꢀ546.
6
6
7
7
8
8
9
9
0
5
0
5
0
5
0
5
9
1
1
. A. K. Shaw, Journal of the Indian chemical society, 2013, 90, 1557ꢀ
568.
0. S. Hanessian, Total synthesis of natural Products: The ‘Chiron’
Approach, Pergamon Press Ltd, Oxford, 1983.
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DOI: 10.1039/C5RA27342K
‘Chiron’ approach to stereoselective synthesis of Sphinganine and unnatural
Safingol, an antineoplastic and antipsoriatic agent
Pintu Das, Somireddy Kundooru and Arun K. Shaw*
OH
NPhth
NH2
BnO
(R)
(
R)
O
BnO
(R)
HO
(R)
(
S)
(
S)
C12H25
OBn
OBn
OH
Sphinganine
OBn
BnO
C10H21
conservation of stereochemistry
from starting material-
Chiron Approach
O
late stage installation
of long chain
BnO
Glycal
NH2
NPhth
OH
HO
(S)
(
S)
C12H25
BnO
BnO
(
S)
(S)
(S)
(
R)
O
OH
Safingol
OBn
OBn
Highly stereoselective total syntheses of sphingoid bases, natural bioactive ceramide sphinganine 1 (with an
overall yield of 33%) and unnatural antineoplastic and antipsoriatic drug safingol 17 (with an overall yield of
3
8.2%) starting from chirons 3,4,6-tri-O-benzyl-D-galactal and 3,4,6-tri-O-benzyl-D-glucal respectively have
been demonstrated. Mitsunobu reaction and late stage olefin cross metathesis are utilized as important steps
in order to complete the total synthesis of these sphingoid molecules.