Divergent synthesis of diastereomeric sphingosines from a chiral aziridine

Article abstract of DOI:10.1002/bkcs.10830

All four stereoisomers of sphingosines were synthesized starting from a single intermediate, chiral aziridine (2), which was efficiently prepared by enzymatic desymmetrization in an enatiopure form. Aziridine (2) was converted to 3, which was used for the synthesis of 4. Both the advanced key intermediates, vinylaziridines 3 and 4, were successfully converted to threo-sphingosines 1a and 1b, respectively. Ring-closing metathesis (RCM) using the Grubbs II catalyst was the key reaction in the synthesis. Two erythro-sphingosines 1c and 1d were synthesized by the ring-expansion reactions of vinylaziridines 3 and 4, followed by RCM reactions. The successful divergent synthesis confirmed that chiral vinylaziridine 2 can be used as a key intermediate for the synthesis of sphingosine-related natural products.

Full text of DOI:10.1002/bkcs.10830

Article
DOI: 10.1002/bkcs.10830
BULLETIN OF THE
O.-Y. Kang et al.
KOREAN CHEMICAL SOCIETY
Divergent Synthesis of Diastereomeric Sphingosines from a Chiral
Aziridine
*
On-Yu Kang, Mi-Ri Shin, and Han-Young Kang
Department of Chemistry, Chungbuk National University, Chungbuk 28644, Korea.
E-mail: hykang@chungbuk.ac.kr
*
Received April 7, 2016, Accepted May 9, 2016, Published online July 8, 2016
All four stereoisomers of sphingosines were synthesized starting from a single intermediate, chiral aziri-
dine (2), which was efficiently prepared by enzymatic desymmetrization in an enatiopure form. Aziridine
(
2) was converted to 3, which was used for the synthesis of 4. Both the advanced key intermediates,
vinylaziridines 3 and 4, were successfully converted to threo-sphingosines 1a and 1b, respectively.
Ring-closing metathesis (RCM) using the Grubbs II catalyst was the key reaction in the synthesis. Two
erythro-sphingosines 1c and 1d were synthesized by the ring-expansion reactions of vinylaziridines 3 and
4, followed by RCM reactions. The successful divergent synthesis confirmed that chiral vinylaziridine
2
can be used as a key intermediate for the synthesis of sphingosine-related natural products.
Keywords: Sphingosine, Divergent synthesis, Aziridine, Ring opening, Ring expansion
Introduction
that are easily prepared from cis-2,3-bis(hydroxymethyl)
aziridine for the synthesis of diverse nitrogen-containing
natural products. Here we report the synthesis of all the
possible sphingosines from this chiral vinylaziridine.
Glycosphingolipids (GSLs), a part of the larger family of
sphingolipids, are found in the membranes of all eukaryotic
cells. GSL has a hydrophobic core and hydrophilic extra-
cellular oligosaccharide chain. They are responsible for
diverse biological functions such as cellular communication
and the regulation of cell behavior. The core structure of
GSLs, called ceramide, consists of a long-chain amino alco-
hol, sphingosine, which is linked to a fatty acid (usually a
chain of 18–20 carbon atoms) through an amide bond.
Sphingosine, the backbone of sphingolipids, therefore,
bears a 2-amino-1,3-diol moiety at the one end, and
because of the presence of two stereocenters at these posi-
tions, a total of four isomeric structures are possible, even
though D-erythro-sphingosine is the most abundant form in
nature (Figure 1). Substitution with diverse glycans and
phosphate groups at the hydroxy group present at the end
of the sphingosine base affords structurally diverse
sphingolipids.
Experimental
1
13
H NMR and C NMR spectra were recorded using a Bru-
ker Avance III 400 and a Bruker Avance 500 NMR spec-
trometer (Bruker corporation, Billerica, MA, USA) at
ambient temperature using CDCl as the solvent unless oth-
3
erwise stated. The chemical shifts are reported in ppm
downfield from TMS, and the signal patterns are indicated
as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,
broad. IR spectra were recorded using a Jasco FT/IR-300E
spectrometer (Jasco corporation, Easton, MD, USA). Opti-
cal rotations were measured using a Jasco DIP-1000 digital
polarimeter in solutions in a 1-dm cell. High-resolution
mass spectra (HRMS) were recorded using a maXis 4G
spectrometer (Bruker corporation, Billerica, MA, USA)
using the ESI (electrospray ionization) method. All the
reagents and solvents were of appropriate grade and used
as received unless specified otherwise. Technical-grade
ethyl acetate, hexane, and pentane used for column chroma-
tography were distilled prior to use. Tetrahydrofuran (THF)
and diethyl ether, when used as the solvents for reactions,
were freshly distilled from sodium-benzophenone ketyl.
Dimethylformamide (DMF) was stored over 4-Å molecular
sieves before use. Flash chromatography was carried out
using Merck 60 silica packed in glass columns.
The synthesis of sphingosines and their analogs has been
interesting because of their important biological activities
and unique structural features, leading to better activities
1
,2
and efficient synthetic strategies. Previously, an enantio-
merically pure chiral aziridine (2, Scheme 1) was easily
prepared by enzymatic desymmetrization, and it was suc-
cessfully used as a starting material for the asymmetric syn-
3
thesis of oseltamivir. During this synthetic study,
alkenylaziridines exhibited excellent regio- and stereoselec-
tivity in the ring-opening reactions with various heteroatom
4
nucleophiles, including oxygen and nitrogen nucleo-
(2S,3S)-t-Butyl 3-(acetoxymethyl)-2-vinylaziridine-1-
carboxylate (3). Dess–Martin periodinane (DMP) (3.41 g,
8.04 mmol) was added to a solution of alcohol 2 (987 mg,
5
philes. We have also been intrigued by the potential of
enantiomerically pure cis-3-substituted-2-vinylaziridines
Bull. Korean Chem. Soc. 2016, Vol. 37, 1095–1104
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Article
BULLETIN OF THE
ISSN (Print) 0253-2964 | (Online) 1229-5949
KOREAN CHEMICAL SOCIETY
2
8
[
1
α]D + 50.9 (c 1.44, CHCl ); IR (film) 2979, 1725, 1448,
3
−1
1
370, 1300, 1231, 1160, 1040, 984 cm ; H NMR
(
400 MHz, CDCl ) δ 5.68 (ddd, 1 H, J = 17.0, 10.4,
3
6
.2 Hz, -CHCH ), 5.48 (dd, 1 H, J = 17.0, 1.3 Hz,
2
-
(
CHCHH), 5.32 (bd, 1 H, J = 10.4 Hz, -CHCHH), 4.11
dd, 1 H, J = 12.0, 5.8 Hz, -OCHHCH–), 4.05 (dd, 1 H,
Figure 1. General structure of sphingolipids.
J = 11.8, 6.8 Hz, -OCHHCH–), 3.07 (t, 1 H, J = 6.3 Hz,
-CHCHCH ), 2.84 (q, 1 H, J = 6.6 Hz, -NCHCH –), 2.09
4
.02 mmol) in CH Cl (30 mL), according to the reported
2 2
2
2
3
13
procedure. The resulting solution was stirred at room tem-
perature for 2 h. After the reaction was completed, satu-
rated aqueous NaHCO3 (20 mL) and Na S O (15 mL)
(s, 3 H, −C(O)CH ) 1.46 (s, 9 H, -NC(O)OC(CH ) );
C
3
,
3 3
NMR (125 MHz, CDCl ) δ 170.8, 161.6, 131.1, 120.2,
3
2
2
3
81.6, 62.1, 42.3, 40.5, 28.3, 27.8, 20.8; HRMS (ESI) calcd.
for C H NO + Na 264.1211, found 264.1205.
solutions were added. The mixture was extracted with
12
19
4
CH Cl2 (3 × 20 mL). The organic layer was separated,
(2R,3R)-2-(t-Butoxycarbonylamino)-3-(p-methoxyben-
zyloxy)pent-4-en-1-yl acetate (7). To a solution of vinyla-
ziridine 3 (283 mg, 1.17 mmol) in dry CH Cl (10 mL)
2
dried (MgSO ), and concentrated. Purification by flash
4
chromatography (hexane/EtOAc = 5:1) afforded the desired
aldehyde (586 mg, 2.40 mmol, 60%) as a colorless oil:
2
2
was added p-methoxybenzyl alcohol (728 μL, 5.85 mmol)
2
6
.
ꢀ
[
1
α]D + 48.5 (c 1.25, CHCl ); IR (film): 2979, 2936,
and BF OEt (7.21 μL, 0.0585 mmol) at −20 C. The reac-
3
3
2
−1
1
ꢀ
714, 1516, 1367, 1245, 1167, 1048 cm ; H NMR
tion mixture was stirred at −20 C for 30 min. After the
(
400 MHz, CDCl ) δ 9.37 (d, 1 H, J = 4.9 Hz, -CHCHO),
reaction was completed, a saturated aqueous NaHCO solu-
3
3
4
1
.34 (dd, 1 H, J = 9.8, 4.5 Hz, -OCHHCH–), 4.19 (dd,
H, J = 9.8, 4.5 Hz, -OCHHCH–), 3.11–3.04 (m, 2 H,
tion (10 mL) was added. The mixture was extracted with
CH Cl2 (3 × 10 mL). The organic layer was separated,
2
-
NCHCH -, -CHCHCHO), 2.07 (s, 3 H, −C(O)CH ), 1.46
dried (MgSO ), and concentrated. Purification by flash
chromatography (hexane/EtOAc = 7:1) furnished the
2
3
4
1
3
(s, 9 H, -NC(O)OC(CH ) ); C NMR (100 MHz, CDCl3)
3
3
δ 196.0, 170.3, 159.6, 83.0, 61.1, 44.8, 41.4, 27.7, 20.5;
desired compound 7 (399 mg, 1.05 mmol, 90%) as a color-
25
−1 1
HRMS (ESI) calcd. for C H NO + Na 266.1004, found
less oil: [α]D –19.6 (c 0.60, CHCl ); IR (film) cm ; H
1
1
17
5
3
2
66.1001.
Potassium bis(trimethylsilyl)amide (KHMDS) [10.2 mL
0.7 M in toluene), 7.20 mmol] was added to methyltriphe-
NMR (400 MHz, CDCl ) δ 7.21 (bd, 2 H, J = 8.6 Hz,
3
-OCH Ph–), 6.87 (dd, 2 H, J = 8.6, 2.0 Hz, -OCH Ph–),
2
2
(
5.80 (ddd, 1 H, J = 17.8, 10.3, 7.3 Hz, -CHCH ), 5.35 (bd,
2
nylphosphonium bromide (2.57 g, 7.20 mmol) in THF
1 H, J = 17.8 Hz, -CHCHH), 5.32 (bd, 1 H, J = 10.3 Hz,
ꢀ
(15 mL), and the resulting mixture was stirred at –20 C for
-CHCHH), 4.92–4.79 (m, 1 H, -NHCHCH –), 4.54 (d,
2
3
0 min. A solution of the aldehyde prepared from the pre-
1 H, J = 11.4 Hz, -OCHHPh–), 4.24 (d, 1 H, J = 11.4 Hz,
-OCHHPh–), 4.11 (dd, 1 H, J = 10.8, 7.1 Hz,
-OCHHCH–), 4.06 (dd, 1 H, J = 10.8, 6.2 Hz,
vious procedure (586 mg, 2.40 mmol) in THF (5 mL) was
added dropwise to the above solution using a cannula, and
the reaction mixture was stirred at −20 C for 1 h. After the
ꢀ
-OCHHCH–),
3.97–3.85
(m,
2 H,
-OCHCH-,
reaction was completed, a saturated aqueous NH Cl solu-
tion (15 mL) was added. The mixture was extracted with
-NHCHCH –), 3.81 (s, 3 H, -C(O)CH ) 1.97 (s, 3 H,
−PhOCH ), 1.42 (s, 9 H, -NC(O)OC(CH ) ); C NMR
3 3 3
4
2
3 ,
13
ether (3 × 20 mL). The organic layer was separated, dried
(100 MHz, CDCl ) δ 170.7, 159.3, 155.7, 134.8, 129.9,
3
(
MgSO ), and concentrated. Purification by flash chroma-
129.6, 119.1, 113.8, 79.4, 70.1, 63.5, 60.4, 55.2, 52.6,
28.3, 20.8; HRMS (ESI) calcd. for C H NO + Na
4
tography (hexane/EtOAc = 7:1) provided the desired viny-
20
29
6
laziridine 3 (475 mg, 1.96 mmol, 82%) as a colorless oil:
402.1892, found 402.1887.
Scheme 1. Structures and retrosynthetic analysis of four diastereomers of sphingosines.
Bull. Korean Chem. Soc. 2016, Vol. 37, 1095–1104
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BULLETIN OF THE
Article
Synthesis of Sphingosines
KOREAN CHEMICAL SOCIETY
(
2R,3R)-2-(t-Butoxycarbonylamino)-3-hydroxypent-4-
en-1-yl acetate (8). To a solution of 7 (165 mg,
.434 mmol) in CH Cl /H O (4:1) (10 mL) was added
temperature, and the solution was stirred at room tempera-
ture for 25 min. After the reaction was completed, a satu-
0
rated aqueous NH Cl solution (5 mL) was added. The
2
2
2
4
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 147 mg,
.651 mmol). The reaction mixture was stirred at room
mixture was extracted with ether (3 × 10 mL). The organic
0
layer was separated, dried (MgSO ), and concentrated.
4
temperature for 18 h. After the reaction was completed, a
Purification by flash chromatography (hexane/EtOAc =
6
saturated aqueous NaHCO solution (10 mL) was added.
3:1) afforded the desired product 10 (10 mg, 0.026 mmol,
3
ꢀ
24
The mixture was extracted with CH Cl (3 × 10 mL). The
81%) as a white solid: mp. 56–59 C, [α]D +0.67 (c 0.80,
2
2
organic layer was separated, dried (Na SO ), and concen-
CHCl ; IR (film) 3416, 2924, 2853, 1690, 1504, 1461,
1366, 1248, 1171, 1057, 970 cm ; H NMR (400 MHz,
2
4
3
−
1 1
trated. Purification by flash chromatography (hexane/
EtOAc = 3:1) afforded the desired alcohol 8 (68 mg,
CDCl ) δ 5.75 (dt, 1 H, J = 15.4, 6.6 Hz, -CHCHCH –),
3
2
2
4
0
.262 mmol, 60%) as a colorless oil: [α]D +23.1 (c 0.60,
5.51 (dd, 1 H, J = 15.4, 6.6 Hz, -CHCHOH), 5.24–5.09
(m, 1 H, -CHNHC(O)–), 4.34 (dd, 1 H, J = 6.3, 3.4 Hz,
CHCl ); IR (film) 3443, 3398, 2976, 2925, 2856, 1739,
715, 1510, 1367, 1242, 1168, 1045, 928 cm ; H NMR
3
−1 1
1
-CHCHOH), 3.79 (d, 2 H, J = 4.5 Hz, -CH OH),
2
(
400 MHz, CDCl ) δ 5.86 (ddd, 1 H, J = 17.2, 10.6,
3.68–3.56 (m, 1 H, -NHCHCH–), 2.40–2.21 (b, 2 H,
3
5
.6 Hz, -CHCH ), 5.33 (dd, 1 H, J = 17.2, 1.4 Hz,
-CH OH, -CHCHOH), 2.03 (q, 2 H, J = 6.8 Hz,
2
2
-CHCHH), 5.21 (bd, 1 H, J = 10.6 Hz, -CHCHH),
-CHCHCH –), 1.44 (s, 9 H, -NC(O)OC(CH ) ), 1.39–1.33
2
3 3
5
.01–4.89 (m, 1 H, -NHCHCH –), 4.26–4.23 (m, 1 H,
(m,
2 H,
-CH CH ),
1.31–1.22
(m,
20 H,
2
2
3
1
3
-
4
OCHCH–), 4.22 (dd, 1 H, J = 11.0, 6.8 Hz, -OCHHCH–),
.11 (dd, 1 H, J = 11.3, 6.8 Hz, -OCHHCH–), 3.92–3.79
m, 1 H, -NHCHCH –), 2.81 (bs, 1 H, -CHCHOH), 2.06
-C H CH CH ), 0.88 (t, 3 H, J = 6.6 Hz, -CH CH );
C
1
0
20
2
3
2
3
NMR (100 MHz, CDCl ) δ 156.6, 134.1, 128.9, 79.7, 73.5,
3
(
(
64.4, 55.5, 32.2, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2,
29.0, 28.3, 22.6, 14.1; HRMS (ESI) calcd. for
C H NO + Na 422.3246, found 422.3240.
2
13
s, 3 H, -C(O)CH ) 1.41 (s, 9 H, -NC(O)OC(CH ) );
C
3
,
3 3
NMR (100 MHz, CDCl ) δ 171.2, 156.0, 137.1, 116.7,
3
23 45
4
79.8, 71.2, 63.5, 53.2, 28.2, 20.8; HRMS (ESI) calcd. for
(2R,3R,4E)-D-threo-Sphingosine (1a). Compound 10
C H NO + Na 282.1317, found 282.1311.
(22 mg, 0.055 mmol) was dissolved in CH Cl (1 mL) at
1
2
21
5
2
2
ꢀ
(
2R,3R,4E)-2-(t-Butoxycarbonylamino)-3-hydroxyoc-
tadec-4-en-1-yl acetate (9). To a stirred solution of alcohol
(125 mg, 0.482 mmol) in dry CH Cl (10 mL) at room
0 C. To this solution was added TFA (0.5 mL, mmol), and
the solution was stirred at room temperature for 12 h. After
the reaction was completed, a solution of 33% aqueous
ammonia was added until the pH of the solution reached
8
2
2
temperature were added 1-pentadecene (520 μL,
1
4
.92 mmol) and Grubbs catalyst (second generation,
8–9. The mixture was extracted with CHCl (3 × 5 mL).
3
0 mg, 0.0482 mmol), producing a light brown solution.
The organic layer was separated, dried (MgSO ), and con-
4
ꢀ
This solution was stirred at 40 C for 16 h. After the mix-
centrated. Purification by flash chromatography (CHCl /
3
7
ture was concentrated, purification by flash chromatography
MeOH/NH OH = 135:25:4)
produced pure D-threo-
4
8
(
9
hexane/EtOAc = 4:1) provided the desired alcohol
sphingosine (1a) (14 mg, 0.046 mmol, 87%) as a white
1
ꢀ
28
(114 mg, 0.258 mmol, 53%, E/Z = 12:1, H NMR analy-
solid: mp. 80–83 C, [α]D +2.9 (c 0.8, CHCl ); IR (film)
3
2
3
sis) as a brown oil: [α]D +4.6 (c 0.86, CHCl ); IR (film)
3
1
3350, 3297, 2920, 2849, 1673, 1595, 1463, 1038,
970 cm ; H NMR (500 MHz, CDCl ) δ 5.75 (dt, 1 H,
3
−
1 1
444, 3368, 2924, 2853, 1745, 1720, 1503, 1460, 1366,
3
−1 1
240, 1170, 1045, 971 cm ; H NMR (400 MHz, CDCl )
J = 15.4, 6.6 Hz, -CHCHCH –), 5.45 (dd, 1 H, J = 15.4,
3
2
δ 5.75 (dt, 1 H, J = 15.4, 6.1 Hz, −CHCHCH –), 5.48 (dd,
7.0 Hz, -CHCHOH), 4.02 (bt, 1 H, J = 6.1 Hz,
-CHCHOH), 3.69 (dd, 1 H, J = 10.6, 3.5 Hz, -CHHOH),
3.56 (dd, 1 H, J = 10.7, 6.3 Hz, -CHHOH), 2.87–2.79 (m,
1 H, -CHNH ), 2.52–2.36 (b, 4 H, -CH OH, -CHNH ,
2
1
H, J = 15.4, 6.6 Hz, -CHCHOH), 4.95–4.83 (m, 1 H,
-
-
CHNHC(O)–), 4.22 (dd, 1 H, J = 11.2, 6.4 Hz,
NHCHCHH–), 4.02–4.14 (m, 1 H, -CHCHOH), 4.11 (dd,
2
2
2
1
H, J = 11.1, 6.0 Hz, -NHCHCHH–), 3.89–3.75 (m, 1 H,
-CHOH), 2.04 (q, 2 H, J = 7.0 Hz, -CHCHCH –),
2
-
3
1
NHCHCH–), 2.32–2.22 (b, 1 H, -CHCHOH), 2.08 (s,
1.43–1.33 (m, 2 H, −CH CH ), 1.30–1.24 (m, 20 H,
2
3
13
H, C(O)CH ) 2.03 (q, 2 H, J = 6.9 Hz, -CHCHCH –),
-C H CH CH ), 0.88 (t, 3 H, J = 6.6 Hz, -CH CH );
C
3
,
2
10 20
2
3
2
3
.44 (s, 9 H, -NC(O)OC(CH ) ), 1.37–1.33 (m, 2 H,
NMR (125 MHz, CDCl ) δ 134.1 129.7, 73.8, 64.6, 56.5,
3
3
3
-
3
CH CH ), 1.29–1.23 (m, 20 H, -C H CH CH ), 0.88 (t,
H, J = 6.6 Hz, -CH CH ); C NMR (100 MHz, CDCl3)
2 3
32.3, 31.9, 29.7, 29.6, 29.6, 29.5, 29.3, 29.2, 29.1, 22.7,
14.1; HRMS (ESI) calcd. for C H NO + H 300.2903,
2
3
10 20
2
3
1
3
18 37
2
δ 171.1, 158.9, 134.4, 128.5, 79.7, 71.4, 63.7, 53.5, 32.2,
found 300.2897.
3
2
4
1.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 29.0, 28.3, 22.6,
(2R,3R)-t-Butyl 3-((t-butyldimethylsilyloxy)methyl)-2-
vinylaziridine-1-carboxylate (4). To a solution of methyl-
triphenylphosphonium bromide (2.56 g, 7.17 mmol) in
THF (15 mL) was added potassium bis(trimethylsilyl)
amide (KHMDS) (10.2 mL (0.7 M in toluene),
0.8, 14.1; HRMS (ESI) calcd. for C H NO + H
2
5
47
5
42.3532, found 442.3527.
2R,3R,4E)-2-(t-Butoxycarbonylamino)octadec-4-en-
(
1,3-diol (10). To a solution of alcohol 9 (14 mg,
ꢀ
0
.033 mmol) in methanol (3 mL) was added potassium car-
7.17 mmol). The resulting mixture was stirred at −20 C for
bonate (K CO ) (6.8 mg, 0.050 mmol) at room
30 min. A solution of aldehyde 6 prepared according to the
2
3
Bull. Korean Chem. Soc. 2016, Vol. 37, 1095–1104
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1097

BULLETIN OF THE
Article
Synthesis of Sphingosines
KOREAN CHEMICAL SOCIETY
3
published procedure (756 mg, 2.39 mmol) in THF (5 mL)
was added dropwise to the above solution using a cannula,
(20 mL) solution was added. The mixture was extracted
with CH Cl2 (3 × 20 mL). The organic layer separated,
2
ꢀ
and the reaction mixture was stirred at −20 C for 30 min.
dried (Na SO ), and concentrated. Purification by flash
2
4
After the reaction was completed, a saturated aqueous
chromatography (hexane/EtOAc = 3:1) afforded the desired
NH Cl solution (15 mL) was added. The mixture was
extracted with ether (3 × 20 mL). The organic layer was
allyl alcohol 12 (305 mg, 0.920 mmol, 63%) as a colorless
4
23
oil: [α]D + 4.99 (c 1.02, CHCl ); IR (film) 3402, 3363,
3
separated, dried (MgSO ), and concentrated. Purification by
2976, 2926, 1686, 1511, 1366, 1251, 1168, 1043,
4
−
1 1
flash chromatography (hexane/EtOAc = 7:1) provided the
desired vinylaziridine 4 (608 mg, 1.93 mmol, 81%) as a
923 cm ; H NMR (400 MHz, CDCl ) δ 5.84 (ddd, 1 H,
3
J = 17.1 10.6, 5.4 Hz, −CHCH ), 5.33 (dd, 1 H, J = 17.2,
2
2
1
−1
colorless oil: [α]D –28.8 (c 1.15, CHCl ); IR (film) cm ;
1.6 Hz, −CHCHH), 5.18 (dd, 1 H, J = 10.6, 1.4 Hz,
−CHCHH), 5.15–5.04 (m, 1 H, −CHNHC(O)–), 4.54–4.37
3
1
H NMR (400 MHz, CDCl ) δ 5.68 (ddd, 1 H, J = 17.0,
3
1
0.4, 6.3 Hz, -CHCH ), 5.43 (bd, 1 H, J = 17.1 Hz,
(m, 1 H, −OCHCH–), 3.92–3.77 (m, 2 H, −OCH CH–),
2
2
-
(
CHCHH), 5.28 (bd, 1 H, J = 10.4 Hz, -CHCHH), 3.79
dd, 1 H, J = 11.2, 5.4 Hz, -OCHHCH–), 3.52 (dd, 1 H,
3.68–3.54 (m, 1 H, −NHCHCH2), 3.40 (bs, 1 H,
−CHCHOH), 1.42 (s, 9 H, −NC(O)OC(CH ) ), 0.89 (s,
3
3
J = 11.2, 6.6 Hz, -OCHHCH–), 3.02 (t, 1 H, J = 6.4 Hz,
9 H, −OSi(CH ) C(CH ) ), 0.07 (s, 6 H, −OSi(CH ) C
3 2 3 3 3 2
(CH ) ); C NMR (100 MHz, CDCl ) δ 156.1, 137.4, 116.0,
3 3 3
9.4, 73.5, 65.1, 54.4, 28.3, 25.8, 18.1, −5.6; HRMS (ESI)
13
-
(
(
(
CHCHCH ), 2.84 (q, 1 H, J = 6.5 Hz, -NCHCH –), 1.45
2
2
s, 9 H, -NC(O)OC(CH ) ), 0.89 (s, 9 H, -OSi(CH ) C
3
3
3 2
1
3
CH )), 0.061 (d, 6 H, -OSi(CH ) C(CH ) ); C NMR
calcd. for C H NO Si + H 332.2257, found 332.2251.
3
3 2
3 3
16 33
4
100 MHz, CDCl ) δ 162.1, 131.7, 119.5, 81.2, 61.0, 44.1,
(2S,3S,4E)-1-(t-Butyldimethylsilyloxy)-2-(t-butoxycar-
bonylamino)-3-hydroxyoctadec-4-ene (13). To a stirred
solution of allyl alcohol 12 (87 mg, 0.26 mmol) in dry
3
42.6, 27.9, 25.9, 18.3, −5.2, −5.3; HRMS (ESI) calcd. for
C H NO Si + Na 336.1971, found 336.1965.
1
6
31
3
(3S,4S)-5-(t-Butyldimethylsilyloxy)-4-(t-butoxycarbo-
CH Cl2 (5 mL) at room temperature were added 1-
2
nylamino)-3-(p-methoxybenzyloxy)pent-1-ene (11). To a
solution of vinylaziridine 4 (608 mg, 1.93 mmol) in anhy-
drous CH Cl (20 mL) were added p-methoxybenzyl alco-
pentadecene (280 μL, 1.04 mmol) and Grubbs catalyst
(second generation, 22 mg, 0.026 mmol) producing a light
ꢀ
brown solution. The resulting solution was stirred at 40 C
2
2
.
hol (1.19 mL, 9.65 mmol) and BF OEt
(12 μL,
for 16 h. The mixture was then concentrated. Purification
by flash chromatography (hexane/EtOAc = 4:1) produced
the desired compound 13 (85 mg, 0.165 mmol, 63%, E/
3
2
ꢀ
0
.096 mmol) at –20 C. The reaction mixture was stirred at
ꢀ
−20 C for 1 h. After the reaction was completed, a satu-
1
23
rated aqueous NaHCO solution (15 mL) was added. The
Z = 12:1, H NMR analysis) as a brown oil: [α]D +10.3
3
mixture was extracted with CH Cl (3 × 15 mL). The
(c 1.04, CHCl ); IR (film) 3446, 2925, 2854, 1718, 1696,
1499, 1465, 1365, 1253, 1171, 1106, 968, 837, 778 cm ;
H NMR (400 MHz, CDCl ) δ 5.73 (dt, 1 H, J = 15.4,
2
2
3
−
1
organic layer was separated, dried (MgSO ), and concen-
4
1
trated. Purification by flash chromatography (hexane/
EtOAc = 7:1) afforded the desired alkene 11 (661 mg,
3
6.7 Hz, −CHCHCH –), 5.46 (dd, 1 H, J = 15.4, 6.3 Hz,
2
2
3
1
.46 mmol, 76%) as a colorless oil: [α]
+ 5.23 (c 1.06,
−CHCHOH), 5.17–5.02 (m, 1 H, −CHNHC(O)–),
4.42–4.32 (m, 1 H, −CHCHOH ), 3.83 (dd, 1 H, J = 10.4,
4.0 Hz, −NHCHCHH–), 3.79 (dd, 1 H, J = 10.1, 2.8 Hz,
D
−
1
1
CHCl ); IR (film) cm ; H NMR (400 MHz, CDCl ) δ
3
3
7
.24 (bd, 2 H, J = 8. Hz, -OCH Ph–), 6.87 (bd, 2 H,
2
J = 8.6 Hz, -OCH Ph–), 5.84 (ddd, 1 H, J = 17.5, 10.5,
−NHCHCHH–), 3.68–3.51 (m, 1 H, −NHCHCH –), 3.24
2
2
7
.3 Hz, −CHCH ), 5.31 (bd, 1 H, J = 17.5 Hz, −CHCHH),
(bs, 1 H, −CHCHOH), 2.02 (q, 2 H, J = 6.9 Hz,
2
5.29–5.26 (m, 1 H, −CHCHH), 4.89–4.76 (m, 1 H,
−CHCHCH –), 1.44 (s, 9 H, −NC(O)OC(CH3)3),
2
−CHNHC(O)–), 4.53 (d, 1 H, J = 11.1 Hz, −OCHHPh–),
1.40–1.33 (m, 2 H, −CH CH ), 1.32–1.20 (m, 20 H,
2
3
3
1
1
1
.52 (d, 1 H, J = 11.2 Hz, −OCHHPh–), 4.15–4.07 (m,
−C H CH CH ), 0.90 (s, 9 H, −OSi(CH ) C(CH ) ),
10 20 2 3 3 2 3 3
H, -OCHCH–), 3.80 (s, 3 H, −PhOCH ), 3.75–3.66 (m,
0.86 (t, 3 H, J = 7.0 Hz, −CH CH ), 0.07 (s, 6 H, −OSi
2 3
3
13
H, −NHCHCH –), 3.65–3.57 (m, 2 H, −OCH CH–),
(CH ) C(CH ) ); C NMR (100 MHz, CDCl ) δ 156.2,
3 2 3 3 3
2
2
.42 (s, 9 H, −NC(O)OC(CH ) ), 0.87 (s, 9 H, −OSi
133.4, 128.9, 79.3, 73.6, 65.1, 57.8, 32.3, 31.9, 29.7, 29.6,
29.5, 29.4, 29.3, 29.2, 29.1, 28.4, 25.8, 22.7, 18.1, 14.1,
−5.6; HRMS (ESI) calcd. for C H NO Si + H 514.4292,
3
3
13
(CH ) C(CH ) ), 0.044 (d, 6 H, −OSi(CH ) C(CH ) );
C
3
2
3 3
3 2
3 3
NMR (100 MHz, CDCl ) δ 158.8, 155.4, 135.6, 130.2,
3
29 59
4
1
7
−
29.4, 129.2, 129.0, 128.5, 117.8, 113.5, 113.4, 113.3,
8.7, 70.1, 65.2, 63.4, 61.3, 54.9, 54.9, 28.0, 25.5, 17.8,
found 514.4286.
(2S,3S,4E)-L-threo-Sphingosine (1b). To a solution of
compound 13 (76 mg, 0.15 mmol) was dissolved in EtOH
5.7, −5.8; HRMS (ESI) calcd. for C H NO Si + Na
24 41 5
ꢀ
474.2651, found 474.2646.
(3 mL) at 0 C. A solution of aqueous 2.0 M HCl (2 mL)
(
3S,4S)-5-(t-Butyldimethylsilyloxy)-4-(t-butoxycarbo-
was added. The solution was stirred for 30 min at room
temperature. After the reaction was completed, the solution
was concentrated under reduced pressure. The residue was
diluted with ethyl acetate, and the organic layer was
washed with NaHCO , brine, and dried (MgSO ). The
nylamino)-3-hydroxypent-1-ene (12). To a solution of
alkene 11 (660 mg, 1.46 mmol) in CH Cl /H O (4:1)
20 mL) was added DDQ (497 mg, 2.19 mmol). The reac-
tion mixture was stirred at room temperature for 18 h. After
the reaction was completed, a saturated aqueous NaHCO3
2
2
2
(
3
4
organic solution was concentrated to afford the desired diol
Bull. Korean Chem. Soc. 2016, Vol. 37, 1095–1104
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1098

BULLETIN OF THE
Article
Synthesis of Sphingosines
KOREAN CHEMICAL SOCIETY
as a colorless oil, which was used in the next step without
further purification.
−CHCHH), 5.39–5.28 (bs, 1 H, −C(O)NHCH–), 4.72 (t,
1 H, J = 6.6 Hz, −CHCHCH ), 4.29 (dd, 1 H, J = 11.6,
2
To a solution of crude diol, prepared as described in the
previous procedure, in dry CH Cl (4 mL) was added TFA
4.1 Hz, −OCHHCH–), 4.04 (dd, 1 H, J = 11.6, 6.0 Hz,
−OCHHCH–), 3.79 (td, 1 H, J = 5.9, 4.4 Hz,
2
2
ꢀ
13
(2 mL) at 0 C. The resulting solution was stirred at room
−OCH CH–), 2.11 (s, 3 H, −C(O)CH );
C NMR
2
3
temperature for 12 h. After the reaction was completed, a
solution of 33% aqueous ammonia was added until the pH
of the solution reached to 8–9. The mixture was extracted
(100 MHz, CDCl ) δ 170.6, 157.9, 133.4, 119.6, 79.2,
3
64.2, 56.8, 20.6; HRMS (ESI) calcd. for C H NO + H
8
11
4
186.0766, found 186.0760.
with CHCl (3 × 5 mL). The organic layer was separated,
(4R,5S)-4-(Acetoxymethyl)-5-(pentadec-1-en-1-yl)oxa-
zolidin-2-one (16). To a stirred solution of oxazolidinone
14c (111 mg, 0.599 mmol) in dry CH Cl (15 mL) at room
3
dried (MgSO ), and concentrated. Purification by flash
4
7
chromatography (CHCl /MeOH/NH OH = 135:25:4) pro-
3
4
2
2
8
a,9
vided pure L-threo-sphingosine (1b)
.13 mmol, 88%) as a white solid: mp. 84–86 C, [α]D
2.8 (c 0.82, CHCl ); IR (film) 3400, 3336, 2922, 2853,
(39 mg,
temperature were added 1-pentadecene (644 μL, 2.39 mmol)
and Grubbs catalyst (second generation) (50 mg,
0.0599 mmol), producing a light brown solution. The
ꢀ
24
0
−
1
3
−1
1
ꢀ
675, 1462, 1035, 971 cm ; H NMR (400 MHz, CDCl )
resulting solution was stirred at 40 C for 22 h. The mixture
3
δ 5.74 (dt, 1 H, J = 15.4, 6.7 Hz, −CHCHCH –), 5.44 (dd,
was then concentrated. Purification by flash chromatogra-
2
1
H, J = 15.4, 6.8 Hz, −CHCHOH), 4.01 (bt, 1 H,
J = 5.9 Hz, −CHCHOH), 3.68 (dd, 1 H, J = 10.8, 3.9 Hz,
CHHOH), 3.54 (dd, 1 H, J = 10.1, 6.2 Hz, −CHHOH),
.86–2.73 (m, 1 H, −CHNH2), 2.71–2.49 (b, 4 H,
phy (hexane/EtOAc = 4:1) afforded the desired compound
1
16 (128 mg, 0.348 mmol, 58%, E/Z = 14:1, H NMR anal-
2
3
−
2
−
ysis) as a brown oil: [α]D + 22.5 (c 1.10, CHCl ); IR
3
(film) 3258, 2952, 2913, 284, 1727, 1466, 1380, 1243,
1036, 982, 691 cm ; H NMR (500 MHz, CDCl ) δ 6.42
−
1 1
CH OH, −CHNH , −CHOH), 2.04 (q, 2 H, J = 6.9 Hz,
2
2
3
−
CHCHCH –), 1.43–1.33 (m, 2 H, −CH CH ), 1.32–1.28
(bs, 1 H, −C(O)NHCH–), 5.91 (dt, 1 H, J = 15.2, 6.9 Hz,
2
2
3
(
−
7
2
m, 20 H, −C H CH CH ), 0.88 (t, 3 H, J = 6.5 Hz,
−CHCHCH –), 5.49 (dd, 1 H, J = 15.4, 8.2 Hz,
−CHCHOH), 5.07 (t, 1 H, J = 8.1 Hz, −OCHCH–), 4.18
(dd, 1 H, J = 11.2, 3.7 Hz, −OCHHCH–), 4.02 (td, 1 H,
10
20
2
3
2
13
CH CH ); C NMR (100 MHz, CDCl ) δ 134.2, 129.6,
2
3
3
3.6, 64.4, 56.5, 32.3, 31.9, 29.7, 29.6, 29.6, 29.5, 29.3,
9.2, 29.1, 22.7, 14.1; HRMS (ESI) calcd. for
J = 7.9, 3.7 Hz, −OCH CH–), 3.95 (dd, 1 H, J = 11.2,
2
C H NO + H 300.2903, found 300.2897.
7.6 Hz, −OCHHCH–), 2.11–2.06 (m, 5 H, −C(O)CH3,
−CHCHCH –), 1.41–1.33 (m, 2 H, −CH CH ), 1.29–1.20
1
8
37
2
(4R,5S)-4-(Acetoxymethyl)-5-vinyloxazolidin-2-one
2
2
3
(
0
14c). To a stirred solution of vinylaziridine 3 (197 mg,
(m, 20 H, −C H CH CH ), 0.86 (t, 3 H, J = 6.7 Hz,
10 20 2 3
−CH CH ); C NMR (125 MHz, CDCl ) δ 170.6, 159.1,
2 3 3
.
13
.816 mmol) in CH Cl (10 mL) was added BF Et O
2
2
3
2
(
302 μL, 2.44 mmol) at room temperature. The reaction
139.2, 121.3, 79.1, 63.2, 54.4, 32.2, 31.8, 29.6, 29.6, 29.5,
29.4, 29.3, 29.1, 28.6, 22.6, 20.6, 14.0; HRMS (ESI) calcd.
for C H NO + Na 390.2620, found 390.2614.
mixture was stirred at room temperature for 1 h. After the
reaction was completed, a saturated aqueous Na CO3
2
21 37
4
(
10 mL) solution was added. The mixture was extracted
(4R,5S)-4-(Hydroxymethyl)-5-(pentadec-1-en-1-yl)oxa-
zolidin-2-one (17). To a solution of compound 16 (42 mg,
0.114 mmol) in methanol (5 mL) was added potassium car-
bonate (K CO ) (19 mg, 0.136 mmol) at room temperature.
The resulting solution was stirred at room temperature for
25 min. After the reaction was completed, a saturated aque-
with CH Cl (3 × 10 mL). The organic layer was sepa-
rated, dried (Na SO ), and concentrated. Purification by
flash chromatography (hexane/EtOAc = 3:1) furnished the
desired cis-oxazolidinone 14c (92 mg, 0.496 mmol, 60%)
and trans-oxazolidinone 14t (22 mg, 0.118 mmol, 14%) as
colorless oils: 14c: [α]D +63.7 (c 1.50, CHCl ); IR (film)
3
7
2
2
2
4
2
3
2
3
ous NH Cl solution (5 mL) was added. The mixture was
3
4
281, 2961, 2924, 2855, 1739, 1375, 1260, 1096, 1019,
extracted with ether (3 × 5 mL). The organic layer was
−
1 1
97 cm ; H NMR (400 MHz, CDCl ) δ 6.32 (bs, 1 H,
separated, dried (MgSO ), and concentrated. Purification by
3
4
−
C(O)NHCH–), 5.88 (ddd, 1 H, J = 17.3, 10.5, 6.9 Hz,
flash chromatography (hexane/EtOAc = 1:1) produced the
10
−CHCH ), 5.48 (bd, 1 H, J = 17.2 Hz, −CHCHH), 5.42
desired alcohol 17 (31 mg, 0.095 mmol, 88%) as a white
2
ꢀ
23
(bd, 1 H, J = 10.6 Hz, −CHCHH), 5.13 (t, 1 H,
solid: mp. 98–100 C, [α]D +12.1 (c 0.60, CHCl ); IR
3
J = 7.5 Hz, −CHCHCH ), 4.18 (dd, 1 H, J = 11.3, 4.0 Hz,
(film) 3420, 3326, 2918, 2850, 1740, 1707, 1465, 1241,
1105, 724 cm ; H NMR (400 MHz, CDCl ) δ 6.10 (bs,
2
−
1 1
−
−
−
OCHHCH–), 4.08 (td, 1 H, J = 7.8, 4.1 Hz,
OCH CH–), 3.95 (dd, 1 H, J = 11.3, 7.4 Hz,
OCHHCH–), 2.08 (s, 3 H, −C(O)CH3);
3
1 H, −C(O)NHCH–), 5.83 (dt, 1 H, J = 15.4, 6.7 Hz,
2
1
3
C NMR
−CHCHCH –), 5.37 (dd, 1 H, J = 15.4, 6.8 Hz,
2
(
6
1
100 MHz, CDCl ) δ 170.6, 158.8, 129.7, 120.9, 78.6,
−CHCHOH), 4.38 (dd, 1 H, J = 17.5, 8.8 Hz,
−OCHHCH–), 4.33 (dd, 1 H, J = 8.8, 5.2 Hz,
−OCHHCH–), 4.12 (bt, 1 H, J = 5.2 Hz, −OCHCH–), 3.86
3
3.1, 54.2, 20.6; HRMS (ESI) calcd. for C H NO + H
8 11 4
2
3
86.0766, found 186.0763. 14t: [α]D + 71.5 (c 1.40,
CHCl ); IR (film) 3388, 2924, 2854, 1739, 1644, 1391,
1
(dt, 1 H, J = 8.7, 5.0 Hz, −OCH CH–), 2.94 (bs, 1 H,
3
2
−
1 1
231, 1044, 787 cm ; H NMR (400 MHz, CDCl ) δ 5.92
−CH OH), 2.04 (q, 2 H, J = 6.9 Hz, −CHCHCH –),
3
2
2
(
ddd, 1 H, J = 17.1, 10.4, 6.7 Hz, −CHCH ), 5.47 (bd,
1.40–1.32 (m, 2 H, −CH CH ), 1.30–1.20 (m, 20 H,
2 3
2
1
H, J = 17.1 Hz, −CHCHH), 5.37 (bd, 1 H, J = 10.4 Hz,
−C H CH CH ), 0.87 (t, 3 H, J = 6.7 Hz, −CH CH );
10 20 2 3 2 3
Bull. Korean Chem. Soc. 2016, Vol. 37, 1095–1104
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1099

BULLETIN OF THE
Article
Synthesis of Sphingosines
KOREAN CHEMICAL SOCIETY
1
3
C NMR (100 MHz, CDCl ) δ 160.3, 136.4, 126.4, 73.1,
(film) 3283, 2933, 2895, 2858, 1756, 1466, 1397, 1255,
1221, 1121, 1013, 934, 840, 777 cm ; H NMR
3
−
1
1
6
2
6.3, 56.3, 32.3, 31.9, 29.7, 29.6, 29.6, 29.5, 29.4, 29.3,
9.2, 28.9, 22.7, 14.1; HRMS (ESI) calcd. for
(400 MHz, CDCl ) δ 5.91 (ddd, 1 H, J = 17.0, 10.5,
3
C H NO + Na 348.2514, found 348.2509.
6.4 Hz, −CHCH ), 5.81 (bs, 1 H, −C(O)NHCH–), 5.41
1
9
35
3
2
(
2R,3S,4E)-L-erythro-Sphingosine (1c). To a solution
(dd, 1 H, J = 17.1, 1.1 Hz, −CHCHH), 5.30 (dd, 1 H,
J = 10.4, 1.0 Hz, −CHCHH), 4.73 (td, 1 H, J = 5.6,
1.3 Hz, −CHCHCH ), 3.67–3.58 (m, 3 H, −OCH CH-,
of alcohol 17 (30 mg, 0.092 mmol) in EtOH (1 mL) at
room temperature was added an aqueous 2 M NaOH
2
2
(
8
0.5 mL) solution. The resulting solution was stirred at
0 C for 2 h. After the reaction was completed, the reac-
−OCH CH–), 0.88 (s, 9 H, −OSi(CH ) C(CH ) ), 0.069 (s,
2 3 2 3 3
6 H, OSi(CH ) C(CH ) ); C NMR (100 MHz, CDCl ) δ
3 2 3 3 3
ꢀ
13
tion mixture was cooled to room temperature, diluted with
diethyl ether (10 mL), and washed with 2 M NaOH
158.8, 134.5, 118.3, 79.3, 64.3, 59.3, 25.7, 18.1, −5.5;
HRMS (ESI) calcd. for C H NO Si + H 258.1525, found
12
23
3
(3 × 2 mL). The organic layer was washed with brine,
258.1519.
dried (MgSO ), and concentrated. Purification by flash
(4S,5R)-4-((tert-Butyldimethylsilyloxy)methyl)-5-(pen-
tadec-1-en-1-yl)oxazolidin-2-one (18). To a stirred solu-
tion of oxazolidinone 15c (22 mg, 0.0854 mmol) in dry
4
7
chromatography (CHCl /MeOH/NH OH = 135:25:4) pro-
3
4
8
vided
pure
L-erythro-sphingosine
(1c)
(26 mg,
ꢀ
0
.0868 mmol, 96%) as a white solid: mp. 79–80 C,
CH Cl2 (10 mL) at room temperature were added 1-
2
28
[
α]D +1.9 (c 0.40, CHCl ); IR (film) 3430, 3377, 2921,
pentadecene (92 μL, 0.341 mmol) and Grubbs catalyst
(second generation) (7.2 mg, 0.0085 mmol), producing a
light brown solution. The resulting solution was stirred at
3
−1 1
2852, 1584, 1462, 1096, 971 cm ; H NMR (400 MHz,
CDCl ) δ 5.76 (dt, 1 H, J = 15.3, 6.6 Hz, −CHCHCH –),
3
2
ꢀ
5.46 (dd, 1 H, J = 15.4, 6.4 Hz, −CHCHOH), 4.22–4.06
40 C for 12 h. The mixture was then concentrated. Purifi-
(
3
3
−
m, 1 H, −CHCHOH), 3.80–3.57 (m, 2 H, −CH OH),
cation by flash chromatography (hexane/EtOAc = 4:1)
afforded the desired compound 18 (28 mg, 0.0636 mmol,
2
.31–3.01 (b, 4 H, −CH OH, −CHNH2, −CHOH),
2
1
23
.0–2.85 (brm, 1 H, −CHNH ), 2.04 (q, 2 H, J = 6.8 Hz,
75%, E/Z = 12:1, H NMR analysis) as a brown oil: [α]
2
D
CHCHCH –), 1.40–1.34 (m, 2 H, −CH CH ), 1.31–1.23
–22.6 (c 0.90, MeOH); IR (film) 3481, 3278, 3135, 2923,
2
2
3
(
−
m, 20 H, −C H CH CH ), 0.88 (t, 3 H, J = 6.6 Hz,
2853, 1737, 1465, 1402, 1365, 1254, 1225, 1136, 1102,
1054, 976, 888, 840, 777, 722 cm ; H NMR (400 MHz,
10
20
2
3
13
−1 1
CH CH ); C NMR (125 MHz, CDCl ) δ 134.8, 129.0,
2
3
3
7
2
5.1, 63.7, 56.2, 32.3, 31.9, 29.7, 29.6, 29.6, 29.5, 29.3,
9.2, 29.1, 22.7, 14.1; HRMS (ESI) calcd. for
CDCl ) δ 5.8 (dt, 1 H, J = 15.4, 6.4 Hz, −CHCHCH –),
5.51 (dd, 1 H, J = 15.4, 8.1 Hz, −CHCHOH), 5.22 (bs,
1 H, -C(O)NHCH–), 5.04 (t, 1 H, J = 8.0 Hz, −OCHCH–),
3
2
C H NO + H 300.2903, found 300.2897.
1
8
37
2
(4S,5R)-4-((tert-Butyldimethylsilyloxy)methyl)-5-viny-
3.83 (td, 1 H, J = 7.4, 4.6 Hz, −OCH CH–), 3.61–3.52 (m,
2
loxazolidin-2-one (15c). To a stirred solution of vinylaziri-
dine 4 (75 mg, 0.239 mmol) in CH Cl (5 mL) was added
2 H,
-OCH CH–),
2.08
(q,
2 H,
J = 7.0 Hz,
2
−CHCHCH –), 1.45–1.34 (m, 2 H, −CH CH ), 1.32–1.23
(m, 20 H, −C H CH CH ), 0.92–0.84 (brm, 12 H, −OSi
10 20 2 3
(CH ) C(CH ) , −CH CH ), 0.063 (d, 6 H, −OSi(CH ) C
3 2 3 3 2 3 3 2
2
2
2
2
3
.
BF Et O (88 μL, 0.717 mmol) at room temperature. The
3
2
reaction mixture was stirred at room temperature for 7 h.
After the reaction was completed, a saturated aqueous
13
(CH ) ); C NMR (125 MHz, CDCl ) δ 158.9, 138.4,
3
3
3
Na CO3 (5 mL) solution was added. The mixture was
121.9, 79.2, 62.5, 57.2, 32.2, 31.9, 29.7, 29.6, 29.4, 29.3,
29.1, 28.7, 25.7, 22.7, 18.1, 14.1, −5.5; HRMS (ESI) calcd.
for C H NO Si + Na 462.3379, found 462.3338.
2
extracted with CH Cl (3 × 5 mL). The organic layer was
2
2
separated, dried (Na SO ), and concentrated. Purification
2
4
25 49
3
by flash chromatography (hexane/EtOAc = 2:1) furnished
the desired cis-oxazolidinone 15c (53 mg, 0.205 mmol,
(4S,5R)-4-(Hydroxymethyl)-5-(pentadec-1-en-1-yl)oxa-
zolidin-2-one (19). To a stirred solution of compound 18
(26 mg, 0.0591 mmol) in dry THF (4 mL) at room temper-
ature was added tetrabutylammonium fluoride (TBAF)
[60 μL (1.0 M in THF), 0.0602 mmol]. After 1.5 h, the
reaction mixture was concentrated. Purification by flash
chromatography (hexane/EtOAc = 1:1) offered the desired
alcohol 19 (16 mg, 0.049 mmol, 84%) as a white solid:
5
1
3%) and trans-oxazolidinone 15t (8 mg, 0.0310 mmol,
5%) as colorless oils: 15c: [α]D –57.3 (c 1.00, CHCl3);
2
3
IR (film) 3274, 2929, 2857, 1756, 1466, 1390, 1253, 1222,
−
1
1
1132, 1099, 1057, 1006, 936, 887, 838, 778 cm ;
H
NMR (400 MHz, CDCl ) δ 5.90 (ddd, 1 H, J = 17.3, 10.6,
3
6
.8 Hz, −CHCH ), 5.48 (dd, 1 H, J = 17.2, 1.2 Hz,
2
ꢀ
21
10
−CHCHH), 5.47–5.42 (b, 1 H, −C(O)NHCH–), 5.37 (dd,
mp. 98–100 C, [α]D –11.9 (c 0.53, MeOH) ; IR (film)
1
H, J = 10.5, 1.1 Hz, −CHCHH), 5.09 (t, 1 H,
3285, 2918, 2850, 1700, 1467, 1405, 1094, 1022,
−1
1
J = 7.5 Hz, −CHCHCH ), 3.89 (td, 1 H, J = 7.7, 4.5 Hz,
970, 934, 869, 777, 725 cm ; H NMR 5.92 (dt, 1 H,
2
−
−
−
OCH CH–), 3.58 (dd, 1 H, J = 10.3, 4.5 Hz,
J = 15.2, 6.8 Hz, −CHCHCH –), 5.73 (bs, 1 H, −C(O)
NHCH–), 5.56 (dd, 1 H, J = 15.4, 8.1 Hz, −CHCHOH),
5.08 (t, 1 H, J = 8.1 Hz, −OCHCH–), 3.89 (td, 1 H,
2
2
OCHHCH–), 3.53 (dd, 1 H, J = 10.3, 7.3 Hz,
OCHHCH–), 0.88 (s, 9 H, −OSi(CH ) C(CH ) ), 0.055
3
2
3 3
1
3
(d, 6 H, −OSi(CH ) C(CH ) );
C NMR (100 MHz,
J = 7.4, 3.9 Hz, −OCH CH–), 3.68 (dd, 1 H, J = 11.2,
3
2
3 3
2
CDCl ) δ 158.8, 130.3, 120.1, 78.8, 62.3, 56.9, 25.7, 18.1,
3.9 Hz, −OCHHCH–), 3.63 (dd, 1 H, J = 11.2, 7.1 Hz,
3
−
5.5; HRMS (ESI) calcd. for C H NO Si + H 258.1525,
−OCHHCH–), 2.40–2.15 (b, 1 H, −CH OH), 2.09 (q, 2 H,
1
2
23
3
2
2
1
found 258.1521. 15t: [α]D –65.9 (c 1.40, CHCl ); IR
J = 7.1 Hz, −CHCHCH –), 1.41–1.36 (m, 2 H, −CH CH ),
3
2
2
3
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1
.28–1.24 (m, 20 H, −C H CH CH ), 0.88 (t, 3 H,
1
3
0
20
2
3
1
J = 6.8 Hz, −CH CH ); C NMR (100 MHz, CDCl ) δ
2
3
3
1
2
59.3, 138.9, 121.9, 79.5, 62.1, 56.9, 32.2, 31.9, 29.7,
9.6, 29.5, 29.4, 29.3, 29.1, 28.7, 22.7, 14.1; HRMS (ESI)
calcd. for C H NO + Na 348.2515, found 348.2506.
19
35
3
(2S,3R,4E)-D-erythro-Sphingosine (1d). To a solution
of alcohol 19 (20 mg, 0.061 mmol) in EtOH (1 mL) was
added an aqueous 2 M NaOH (0.5 mL) solution at room
ꢀ
temperature. The resulting solution was stirred at 80 C for
2
h. After the reaction was completed, the reaction mixture
was cooled to room temperature, diluted with diethyl ether
10 mL), and washed with an 2 M NaOH (3 × 2 mL) solu-
tion. The organic layer was washed with brine, dried
MgSO ), and concentrated. Purification by flash chroma-
(
(
4
tography (CHCl /MeOH/NH OH = 135:25:4) furnished
3
4
8
a,b,11
Scheme 2. Preparation of the starting chiral vinylaziridines
pure D-erythro-sphingosine (1d)
(17 mg, 0.056 mmol,
28
3
and 4.
ꢀ
9
2%) as a white solid: mp. 76–77 C, [α]
–1.70 (c 0.41,
D
CHCl ); IR (film) 3400, 3370, 2920, 2850, 1582, 1462,
3
−1 1
1
1
096, 970 cm ; H NMR (400 MHz, CDCl ) δ 5.76 (dt,
3
H, J = 15.4, 6.7 Hz, −CHCHCH –), 5.47 (dd, 1 H,
2
J = 15.4, 7.0 Hz, −CHCHOH), 4.15–4.02 (m, 1 H,
CHCHOH), 3.79–3.55 (m, 2 H, −CH OH), 3.01–2.77
−
2
(
brm, 1 H, −CHNH ), 2.40–2.19 (b, 4 H, −CH OH,
2
2
−
−
CHNH2, −CHOH), 2.05 (q, 2 H, J = 6.8 Hz,
CHCHCH –), 1.41–1.34 (m, 2 H, −CH CH ), 1.29–1.23
2
2
3
(
−
m, 20 H, −C H CH CH ), 0.88 (t, 3 H, J = 6.6 Hz,
10 20 2 3
13
CH CH ); C NMR (125 MHz, CDCl ) δ 134.6, 129.3,
2 3 3
7
2
5.4, 63.9, 56.1, 32.3, 31.9, 29.7, 29.6, 29.6, 29.5, 29.3,
9.2, 29.1, 22.7, 14.1; HRMS (ESI) calcd. for
C H NO + H 300.2903, found 300.2895.
1
8
37
2
Results and Discussion
Synthesis of all four sphingosines started from enantiomeri-
cally pure cis-3-substituted-2-vinylaziridines, i.e., 3 and
Scheme 3. Synthesis of (2R,3R,4E)-D-threo-Sphingosine (1a).
4
, which can be easily prepared from a common chiral
4
aziridine, cis-2-acetoxymethyl-3-hydroxymethylaziridine
As reported previously, the Lewis acid-catalyzed ring
(
(
2) (Scheme 1). (2R,3R,4E)-D-threo-Sphingosine (1a) and
2R,3S,4E)-L-erythro-sphingosine (1c) could be derived
opening of aziridine 3 with p-methoxybenzyl alcohol
(PMBOH) produced 7 in good yield with excellent regio-
and stereoselectivity. Deprotection of the PMB group fol-
lowed by the cross-metathesis reaction of 8 with 1-
pentadecene in the presence of the Grubbs II catalyst suc-
cessfully afforded the protected sphingosine 9 with a good
from chiral vinylaziridine 3. Similarly, (2S,3S,4E)-L-threo-
sphingosine (1b) and (2S,3R,4E)-D-erythro-sphingosine
(1d), in turn, could be prepared from chiral vinylaziridine 4.
Vinylaziridines 3 and 4 became important intermediates
1
for the synthesis of all four possible sphingosines 1a–1d.
Preparation of chiral vinylaziridines 3 and 4 was achieved
using the Wittig reaction of the corresponding aldehydes
E/Z selectivity (12:1, confirmed by H NMR). The target
(2R,3R,4E)-L-threo-sphingosine (1a) was obtained through
a sequential deprotection of the acetyl group (K CO ,
2
3
3,4
(
5
Scheme 2). Enzymatic desymmetrization of meso-diol
provided 2 in an enantiomerically pure form. Oxidation fol-
lowed by the Wittig olefination provided chiral vinylaziridine
. The synthesis of 4 was achieved successfully by conver-
MeOH) in 9 and the Boc group in 10 (TFA, CH Cl ).
2 2
Sphingosine 1a showed identical spectra as those reported
8
in the literature.
3
For the synthesis of the corresponding enantiomeric iso-
mer of sphingosine, i.e., (2S,3S,4E)-D-threo-sphingosine
(1b), it is required to start with aziridine 4 bearing the
opposite stereochemistry to 3 (Scheme 4). The selective
ring opening of aziridine 4 with PMBOH in the presence of
BF .OEt followed by deprotection produced the protected
sion of 2 into aldehyde 6, according to the previously
reported procedure, followed by the Wittig olefination.
First, we investigated the synthesis of (2R,3R,4E)-D-
threo-sphingosine 1a, and the synthetic sequence is sum-
marized in Scheme 3.
3
3
2
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Table 2. Ring-expansion reactions of vinylaziridines 4.
Entry
Lewis acid (equiv)
BF .OEt (0.5)
Sc(OTf) (0.1)
3
Yield (%)
Ratio (15c/15t)
1
2
3
4
68
72
70
70
7:1
2:1
2:1
2:1
3
2
Cu(OTf) (0.1)
2
Sn(OTf) (0.1)
2
investigated using various Lewis-acids. The results are sum-
marized in Tables 1 and 2. In the case of the chiral aziri-
.
dine 3, Lewis acids such as BF OEt , Sc(OTf) , Cu(OTf) ,
3
2
3
2
and Sn(OTf) were tested because these acids had been
2
used for the ring-expansion reactions previously
12b,c,13
(Table 1).
All the Lewis acids examined afforded
Scheme 4. Synthesis of (2S,3S,4E)-D-threo-sphingosine (1b).
mixtures of 4,5-cis (14c) and 4,5-trans (14t) isomers, and
BF .OEt provided the best result. Employing 0.5 equiv of
3
2
this Lewis acid resulted in 75% combined yield with a ratio
of 4:1 (14c/14t). The results of the ring-expansion reaction
of chiral aziridine 4 exhibited a similar trend (Table 2).
allylic alcohol 12. The cross-metathesis reaction provided
the desired sphingosine 13 in a protected form (E/Z selec-
tivity = 12:1 by H NMR). After deprotection of TBS
1
.
BF OEt also produced the best results [0.5 equiv of
3
2
(HCl, EtOH) and Boc (TFA, CH Cl ) groups, the desired
2 2
.
BF OEt , 68% combined yield with a ratio of 7:1 (15c/
3
2
(
2S,3S,4E)-L-threo-sphingosine (1b) was obtained. The
8
15t)]. After the separation, the cis compounds 14c and 15c
were used for the next reactions.
spectra matched with those reported previously.
Next, the synthesis of erythro-sphingosines was investi-
gated. A straight and simple strategy would require the cor-
responding trans isomers of 3 and 4. Because the
corresponding trans isomers in enantiopure forms are not
readily accessible, we searched for another possibility. The
ring expansion of N-Boc-substituted aziridines to the corre-
Having the desired intermediates 14c and 15c in our
hand, we were in the position of pursuing the synthesis of
erythro-sphingosines. The synthesis of one of the erythro-
isomer, i.e., (2R,3S,4E)-L-erythro-sphingosine (1c) is
shown in Scheme 5. Oxazolidinone 14c, obtained from the
1
2,13
sponding oxazolidinones has been well known.
This
ring-expansion reaction occurs regioselectively in the case of
vinylaziridines in an S 1 fashion, providing 2-oxazolidi-
N
nones. The ring-expansion reactions of 3 and 4 were
Table 1. Ring-expansion reactions of vinylaziridines 3.
Entry
Lewis acid (equiv)
BF .OEt (0.5)
Sc(OTf) (0.1)
Yield (%)
Ratio (14c/14t)
1
2
3
4
3
2
75
78
72
79
4:1
2:1
2:1
2:1
3
Cu(OTf)
Sn(OTf)
2
(0.1)
(0.1)
2
Scheme 5. Synthesis of (2R,3S,4E)-L-erythro-sphingosine (1c).
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synthesis of all enantiomers of sphingosine has confirmed
that chiral vinylaziridnes such as 3 and 4 are versatile inter-
mediates for the synthesis of sphingosines and related natu-
ral products.
Acknowledgments. This work was supported by the
research grant of Chungbuk National University in 2014.
This research was also supported by the National Research
Foundation of Korea (NRF) grant funded by the Ministry of
Science, ICT & Future Planning (2012R1A1A2008105) and
Ministry of Education (2015R1D1A3A01020350).
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
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2
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8
those reported in the literatute.
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3
Conclusion
(
Chiral aziridine 2, readily available through the enzymatic
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Bull. Korean Chem. Soc. 2016, Vol. 37, 1095–1104
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1
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