A stereocontrolled route to d-ribo-phytosphingosine and sphinganine from an achiral secondary homoallylic alcohol using Sharpless kinetic resolution

Article abstract of DOI:10.1016/j.tet.2013.03.057

A facile and efficient enantioselective route for the synthesis of d-ribo-phytosphingosine (1a) and sphinganine (1b) has been developed employing commercially available and cheap starting material trans-cinnamaldehyde 2. The synthetic strategy features the Sharpless kinetic resolution, regioselective epoxide opening and Wittig olefination as the key steps.

Full text of DOI:10.1016/j.tet.2013.03.057

Tetrahedron 69 (2013) 3817e3822
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A stereocontrolled route to -ribo-phytosphingosine and
D
sphinganine from an achiral secondary homoallylic alcohol using
Sharpless kinetic resolution
*
Thongam Joymati Devi, Bishwajit Saikia, Nabin C. Barua
Natural Products Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 January 2013
Received in revised form 12 March 2013
Accepted 15 March 2013
Available online 19 March 2013
A facile and efficient enantioselective route for the synthesis of
D-ribo-phytosphingosine (1a) and
sphinganine (1b) has been developed employing commercially available and cheap starting material
trans-cinnamaldehyde 2. The synthetic strategy features the Sharpless kinetic resolution, regioselective
epoxide opening and Wittig olefination as the key steps.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Sphingolipid
Phytosphingosine
Sphinganine
Apoptosis
Regioselective
1. Introduction
An a-galactosylphytosphingosine derivative, KRN7000, isolated from
a marine sponge is a powerful immune stimulant of natural killer T
(NKT) cells.9 Because of their wide spectrum of biological activities,
sphingolipids have been an important class of compounds and a great
dealofeffort hasbeen devoted towards their synthesis. Total synthesis
of sphingolipids is quite challenging because of having more than one
contiguous stereogenic centres. Most synthetic studies have been
focused either starting from the chiral pool materials, particularly
serine10 and carbohydrate,11 or by asymmetric synthesis.12 However,
a practical, short, low cost and high yield synthesis of sphingolipids
and their analogues is still in demand. We have long been engaged in
the synthesis of bioactive natural products having chiral 2-amino al-
cohol moiety.13 Herein we report a general and efficient synthetic
Sphingolipids are ubiquitous components of biological cell mem-
brane of all eukaryotic organisms and in some prokaryotic organisms
and viruses.1 They play diverse important roles in the chemistry of
cellular membranes. In addition to their structural role in biological
membranes, sphingolipids and theirdownstream metabolites are also
involved in various physiological processes, such as cell proliferation,
differentiation, immune response, cell recognition, apoptosis and
signal transduction.2 It has been reported that in human the most
common degenerative diseases, such as cancers,3 Alzheimer’s dis-
ease,4 diabetes,5 heart disease and others neurological syndromes6 are
the results of sphingolipid metabolism defect. Structurally, sphingo-
lipids consist of two structural moietiesda polar head group (sugar
moiety) and a ceramide. The ceramide moiety is composed of
a sphingoid base and a fatty acid, linked by an amide bond. Sphin-
gosine, sphinganine (dihydro-sphingosine) and phytosphingosine are
the three most common naturally occurring sphingoid bases. Sphin-
gosine and sphinganine are known inhibitor of protein kinase C.7
Detail biological studies in Saccharomyces cerevisiae revealed that
phytosphingosine is a potential heat stress signal in yeast cell.8 Some
of theirderivatives show potentantifungal and anticancerproperties.8
route to D
-ribo-phytosphingosine12e and sphinganine12f (Fig. 1) in-
volving Sharpless kinetic resolution,14 regioselective epoxide open-
ing15 and Wittig olefination16 as the key steps.
2. Results and discussion
2.1. Synthetic approach
As shown in Scheme 1, we visualized that the target compounds
would be obtained from the chiral epoxy alcohol 4 in three main
steps via regioselective epoxide opening, Wittig olefination and
oxidative phenyl ring cleavage.17 The stereocenters in 4 could be
* Corresponding author. Tel.: þ91 376 2371283; fax: þ91 376 2370011; e-mail
addresses: ncbarua12@rediffmail.com, ncbarua2000@yahoo.co.in (N.C. Barua).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.057

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T.J. Devi et al. / Tetrahedron 69 (2013) 3817e3822
2.3. Synthesis of sphinganine from azido diol 6
NH2 OH
OH
HO
HO
As shown in Scheme 3, azido diol 6 was acetylated using acetic
anhydride in pyridine in presence of DMAP as catalyst12c to furnish
the diacetylated azido compound 7. This on oxidative cleavage of
the terminal double bond under condition as reported by Yu et al.18
provided the unsaturated aldehyde 8 in 68% yield by losing an
acetic acid molecule. Wittig olefination of 8 with Wittig salt
BrꢀPh3PþCH2C11H23 using n-BuLi in dry THF16 at low temperature
furnished the conjugated (E,Z) diene 9 as single diastereomer.
Catalytic hydrogenation of 9 using 10% Pd/C in EtOAc19 followed by
N-Ac protection (acetic anhydride and pyridine in DCM at room
temperature) provided the protected amino alcohol derivative 10.
Treatment of 10 with RuCl3$3H2O, NaIO4, in CH3CN/CCl4/H2O sol-
vent system,17 underwent oxidative phenyl ring cleavage giving
a crude acid, followed by base catalyzed deprotection of O-Ac using
Et3N in MeOH20a and acid catalyzed deprotection of N-Ac (6 N HCl
in MeOH),20b furnished the crude amino hydroxy acid. Finally,
subsequent borane dimethyl sulphide reduction21 of the acid
functionality of the crude amino hydroxy acid in dry THF at room
temperature provided the desired compound 1b (75% yield, 99% ee)
over four steps.
1a
D-ribo-phytosphingosine (C18
)
NH2
OH
1b
sphinganine (C18
)
Fig. 1. D-ribo-Phytosphingosine (1a) and sphinganine (1b).
introduced by Sharpless kinetic resolution of secondary allylic al-
cohol 3. Finally, 3 would arise from allylation of readily available
trans-cinnamaldehyde 2.
epoxide opening by -N
N3 OP
OP
NH2
Y
OH
HO
O
R
OH
4
7
P = Ac
1a , Y = OH, R = -(CH2)13Me
site for chain extension
11 P = Bn
1b Y = H, R = -(CH2)13Me
OH
trans-cinnamaldehyde
2
3
Scheme 1. Retrosynthesis of D-ribo-phytosphingosine and sphinganine.
2.2. Synthesis of (1S,2S,3R) azido diol intermediate via re-
gioselective epoxide opening
The synthetic sequence leading to azido diol 6 started from
cheap and commercially available trans-cinnamaldehyde. Sec-
ondary homoallylic alcohol 3, prepared by allylation of trans-
cinnamaldehyde with allylmagnesium bromide in THF, was
subjected to Sharpless kinetic resolution14 using Ti(OiPr)4,
(ꢀ)-DET, TBHP in dichloromethane (DCM) to afford the chiral
epoxide 4 (47% yield with 99% ee) as the optically enriched
isomer and chiral allylic alcohol 5 (48% yield with 98% ee).14c
Regioselective epoxide opening of 4 by azide under condition
as reported by our research group15 furnished exclusive benzylic
azidation product 6 with 89% yields with 99% ee after purifica-
tion by flash chromatography as a pale yellow gummy liquid
(Scheme 2).
Scheme 3. Synthesis of sphinganine (dihydrosphingosine). Reagents and conditions:
(i) Ac2O, pyridine, DMAP, 3 h, 96%; (ii) OsO4, 2,6-lutidine, dioxane/H2O (3:1), NaIO4, rt,
6 h, 68%; (iii) BrꢀPh3Pþ(CH2)11Me, n-BuLi, THF, ꢀ15 ꢁCert, 3 h, 92%; (iv) 10% Pd/C, H2,
EtOAc, rt, 4 h; Ac2O, pyridine, DCM, rt, 2 h, 91%; (v) NaIO4, RuCl3$H2O, CCl4/CH3CN/H2O
(2:2:3), 0 ꢁCert, overnight; (vi) Et3N, MeOH, rt, 4 h; 6 N HCl, MeOH, reflux, 2.5 h; (vii)
BH3$Me2S, THF, 0 ꢁCert, 6 h, 75% yield (over four steps), 99% ee.
2.4. Synthesis of
D
-ribo-phytosphingosine
-ribo-phytosphingosine from compound 6 is
The synthesis of
D
illustrated in Scheme 4. First, we performed protection of the diol 6
as TBS ether using tert-butyldimethylsilyl triflate in the presence
2,6-lutidine22 but the reaction was not encouraging as the reaction
did not go to completion (43% conversion). So we decided to change
the protecting group as benzyl ether. Treatment of 6 with benzyl
bromide in dry THF using NaH as base provided benzyl protected
diol 11 in excellent yield.23 Cleavage of the terminal double bond of
11 under condition as reported by Yu et al.18 provided aldehyde, and
this on Wittig olefination with BrꢀPh3PþCH2C11H23 using n-BuLi in
dry THF at low temperature furnished the Z-olefin 12 contaminated
with its E-isomer in the ratio of 12:1 (64% yield over two steps).16
The diastereomeric mixture could easily be separated by column
chromatography. Then the olefins (both cis and trans) were con-
verted to amino diol derivative 13 in a three steps sequence in-
volving (1) catalytic hydrogenation,19 (2) Boc protection of the
resulting amine as carbamate,24 (3) acetylation of the hydroxyl
groups with acetic anhydride in pyridine using DMAP as catalyst12c
(89% yield over three steps). In the next step, phenyl ring was
cleaved to acid on treatment with RuCl3$3H2O, NaIO4, in CH3CN/
CCl4/H2O solvent system17 and this on borane dimethyl sulphide
reduction21 in dry THF for 2 h at 20 ꢁC provided the aminotriol
OH
ii
i
trans-cinnamaldehyde
2
Ph
3
OH
O
OH
Ph
Ph
5 (48%)
(47%)
4
N3 OH
iii
4
Ph
OH
6
Scheme 2. Synthesis of (1S,2S,3R) azido diol via regioselective chiral epoxide opening.
Reagents and conditions: (i) allylmagnesium bromide, THF, 0 ꢁCert, 2 h, 97%; (ii)
ꢁ
ꢀ
ꢀ
Ti(i-PrO)4, (ꢀ)-DET, TBHP, DCM, 3 A MS, ꢀ20 C, 3 h; (iii) NaN3, CH3CN, 4 A MS, rt, 1.5 h,
89% yield, 99% ee.

T.J. Devi et al. / Tetrahedron 69 (2013) 3817e3822
3819
derivative 14. Finally base catalyzed deprotection of two O-Ac of 14
using Et3N in MeOH20a at room temperature followed by acid cat-
alyzed N-Boc deprotection (TFA/DCM at room temperature)24 fur-
nished the target compound 1a (91% yield, 98% ee) over two steps.
The physical and spectroscopic values of 1a and 1b were in accor-
dance with those described in literature.10e12
without further purification. All analytical data were recorded at
Analytical Chemistry Division (CSIR-NEIST, Jorhat-6, Assam, India).
4.1.1. General procedure for the double bond cleavage. To a solution
of olefin (1 equiv) in dioxane/H2O (3:1) (0.1 M) were added 2,6-
lutidine (2 equiv), 0.2% OsO4 solution in isopropanol (0.01 equiv)
and NaIO4 (3.8 equiv) successively. The reaction was stirred at room
temperature for 6 h. After completing the reaction, it was diluted
with DCM/H2O (2:1) and extracted with DCM. The combined or-
ganic extracts were washed with brine and dried over NaSO4. The
solvent was evaporated to give the desired aldehyde residue.
4.1.2. General procedure for the Wittig olefination. To a stirred solu-
tion of Wittig salt (3 equiv) in dry THF (0.06 M) at ꢀ15 ꢁC was added
dropwise a 1.6 M solution of n-BuLi in Hexane (3 equiv) and con-
tinued to stir for 20 min. Then aldehyde (1 equiv) was added and
continued stirring for 15 min at the same temperature. The mixture
was allowed to attain at room temperature and stirred for 3 h. The
reaction was quenched with saturated aqueous NH4Cl solution and
extracted with ether. The combined organic extracts were washed
with water, brine and dried. Evaporation of the solvent gave a resi-
due, which was purified by column chromatography.
Scheme 4. Synthesis of D-ribo-phytosphingosine. Reagents and conditions: (i) BnBr,
NaH, dry THF, 0 ꢁCert, 12 h, 91%; (ii) OsO4, 2,6-lutidine, dioxane/H2O (3:1), NaIO4, rt,
6 h; (iii) n-BuLi, BrꢀPh3PþCH2C11H23, THF, ꢀ40 ꢁCert, 3 h; (iv) 10% Pd/C, H2, EtOAc, rt,
6 h; (v) (Boc)2O, Et3N, DCM, rt, 5 h; (vi) Ac2O, pyridine, DMAP, 3 h; (vii) NaIO4,
RuCl3$H2O, CCl4/CH3CN/H2O (2:2:3), 0 ꢁCert, 8 h; (viii) BH3$Me2S, THF, ꢀ78 ꢁCe20 ꢁC,
2 h; (ix) Et3N, MeOH, rt, 4 h; TFA, rt, 2.5 h, 91% yield (over two steps), 98% ee.
4.1.3. General procedure for the ruthenium catalyzed oxidative
cleavage of phenyl ring. To a solution of phenyl compound (1 equiv)
in CCl4/CH3CN/H2O (2:2:3) (0.08 M) was added NaIO4 (12 equiv)
slowly at 0 ꢁC. After stirring for 30 min at 0 ꢁC, RuCl3$3H2O
(0.05 equiv) was added and the temperature was raised to room
temperature and continued stirring for overnight. The reaction
mixture was filtered and washed the solid with DCM three times.
The combined filtrate was dried and concentrated in vacuo to give
desired carboxylic acid residue.
3. Conclusions
A facile and flexible synthetic route for the synthesis of D-ribo-
phytosphingosine 1a and sphinganine 1b employing simple achiral
starting material has been developed. Chiral epoxide was used for
the regioselective induction of the azido group to the benzylic
position with inversion. The chiral allylic alcohol fraction in the
Sharpless kinetic resolution step would be used for the preparation
of other stereoisomer of phytosphingosine. Wittig olefination was
successfully applied to introduce the long alkyl chain. Our synthetic
approach proved to be efficient as the overall yield of the target
compounds 1a and 1b were found to be 15.6% (thirteen steps) and
16.6% (twelve steps) starting from commercially inexpensive
starting material trans-cinnamaldehyde. Further, the present work
is flexible and would synthesize not only the stereoisomer of
sphingolipid but also the other analogues bearing different alkyl
skeleton backbones.
4.1.4. General procedure for the BDS reduction of carboxylic acid. To
a stirred solution of an organic acid (1 equiv) in dry THF (0.15 M)
was added BH3$Me2S (1.2 equiv) at ꢀ78 ꢁC and continued to stir for
10 min at the same temperature. Then it was allowed to attain at
20 ꢁC (or room temperature) and stirred for 2 h under inert at-
mosphere. The reaction was quenched with methanol and the
resulting mixture was concentrated in vacuo to give residue, which
was purified by flash chromatography.
4.2. Specific chemical procedures and characterization data
4.2.1. 1-Phenyl-hexa-1,5-dien-3-ol (3). To a stirred solution of cin-
namaldehyde (1 g, 7.57 mmol) in THF (13 mL) was added 1 M so-
lution of allylmagnesium bromide in THF (9.08 mL, 9.08 mmol) at
0 ꢁC and continued stirring for 15 min at 0 ꢁC and then for 2.5 h at
room temperature. The reaction was quenched with ice-cooled
NH4Cl solution and extracted with ether. The combined organic
extracts were washed with brine, dried over Na2SO4 and evapo-
rated to dryness. The residue was purified by flash chromatography
(10% EtOAc/Hexane) to give homo allyl alcohol 3 (1.27 g, 7.34 mmol,
97%) as colourless oil; elemental analysis calcd. Found: C, 82.71; H,
8.08; O, 9.21. C12H14O requires C, 82.72; H, 8.10; O, 9.18%; Rf (30%
EtOAc/Hexane) 0.44; IR nmax (film) 3394 (br), 3078, 2906, 1492,
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were recorded using a Bruker DPX-
300 NMR machine. IR spectra were recorded on a PerkineElmer
1640 FT-IR spectrometer. Elemental analysis data were measured on
a PerkineElmer (Model no. AE 2400) CHN analyzer. Optical rotations
were measured using a PerkineElmer 343 polarimeter. Mass spectra
were recorded on WATERS Micro-mass ZQ 4000 (ESI Probe) spec-
trometer. Flash chromatography (CombiFlash) was performed with
Merck silica gel (230e400 mesh), column chromatography was
performed with Merck silica gel (100e200 mesh) and preparative
TLC was carried out on plates prepared with Merck Silica gel G.
Moisture sensitive reactions were conducted under a dry nitrogen
atmosphere. THF was distilled from benzophenone ketyl prior to
use. All solvents were distilled at their boiling point and other
commercially available reagents were used as received, unless oth-
erwise stated. Glassware was oven dried at 120 ꢁC overnight. All the
reagents were used as purchased from commercial suppliers
1448, 966, 916, 748, 694 cmꢀ1; 1H NMR (300 MHz CDCl3)
d 7.40 (5H,
m, Aromatic), 6.63 (1H, d, J¼15.9 Hz, 1CH), 6.28 (1H, dd, J¼15.9,
6.3 Hz, 2CH), 5.87e5.81 (1H, m, 5CH), 5.21e5.15 (2H, m, 6CH2), 4.39
(1H, m, 3CH), 2.47e2.32 (2H, m, 4CH2), 1.88 (1H, s, OH); 13C NMR
(75 MHz, CDCl3) d 136.6,134.0,131.5,130.3, 128.6, 127.6, 126.5,118.5,
71.72, 42.0; MS (ESI, positive ion): m/z (%)¼174.0 (100) [Mþ].
4.2.2. (1R)-1-[(2R,3R)-3-Phenyloxiran-2-yl]-3-buten-1-ol (4) & (3S)-
ꢀ
1-phenyl-hexa-1,5-dien-3-ol (5). Crushed, activated 3 A MS was
added to stirred DCM (30 mL) and the mixture was cooled to

3820
T.J. Devi et al. / Tetrahedron 69 (2013) 3817e3822
ꢀ20 ꢁC. To this were added Ti(i-OPr)4 (1.95 mL, 6.87 mmol),
(ꢀ)-DET (1.4 mL, 8.02 mmol) and the allylic alcohol (1 g, 5.74 mmol)
in DCM (3 mL) successively with stirring. The mixture was stirred
for 15 min at the same temperature and then 5.5 M solution of
TBHP in decane (1.86 mL, 10.31 mmol) was added slowly and
continued stirring for 3 h. The reaction was quenched with 15%
aqueous solution of tartaric acid (20 mL) and continued to stir
vigorously until clear phases were reached. The phases were sep-
arated and the aqueous part was extracted with DCM. The com-
bined organic extracts were concentrated and diluted with ether.
Then it was treated with pre-cooled 10% NaOH aqueous solution
and stirred for 15 min at 0 ꢁC. The aqueous phase was extracted
with ether and the combined organic extracts were washed with
brine and dried. Evaporation of the solvent gave a residue, which
was purified by flash chromatography (5% EtOAc/Hexane) to give
epoxide 4 (511 mg, 2.69 mmol, 47%, 99% ee) and chiral allyl alcohol
5 (479 mg, 2.75 mmol, 48%, 97% ee) both are colourless oil.
compound 7 (261 mg, 0.822 mmol, 96%) as pale yellow oil; ele-
mental analysis calcd. Found: C, 60.51; H, 6.10; N, 13.19. C16H19N3O4
requires C, 60.56; H, 6.03; N, 13.24; O, 20.17; Rf (30% EtOAc/Hexane)
0.51; ½a 2D0
ꢂ
þ67.9 (c 1.12, CHCl3); IR nmax (film) 2926, 2107, 1745, 1372,
1217, 1029 cmꢀ1
;
1H NMR (300 MHz CDCl3)
d
7.39e7.31 (5H, m,
Aromatic), 5.72 (1H, m, 3CH), 5.38e5.33 (2H, m, 4CH2), 5.22 (1H, m,
CHOAc), 5.09 (1H, m, 1CHOAc), 4.70 (1H, m, CHN3), 2.29 (2H, m, CH2),
1.93 (3H, s, COCH3), 1.92 (3H, s, COCH3); 13C NMR (75 MHz, CDCl3)
d
171.0, 170.3, 136.6, 128.6, 128.3, 127.6, 118.5, 81.1, 71.7, 60.4, 42.0,
21.1; MS (ESI, positive ion): m/z (%)¼317.1 (100) [Mþ].
4.2.7. Compound (8). According to the general procedure for olefin
cleavage, compound 7 (100 mg, 0.315 mmol) was converted to a,b-
unsaturated aldehyde 8 (55 mg, 0.214 mmol, 68%) after flash chro-
matography on silica gel (8% EtOAc/Hexane) as colourless oil; ele-
mental analysis calcd. Found: C, 60.26; H, 5.13; N, 16.17. C13H13N3O3
requires C, 60.22; H, 5.05; N, 16.21; O, 18.51; Rf (25% EtOAc/Hexane)
0.56; ½a 2D5
ꢂ
þ12.9 (c 0.85, CHCl3); IR nmax (film) 3032, 2977, 2103, 1741,
4.2.3. Data of 4. Elemental analysis calcd. Found: C, 75.73; H, 7.39;
O, 16.88. C12H14O2 requires C, 75.76; H, 7.42; O, 16.82%; Rf (30%
1697, 1637, 1454, 913 cmꢀ1; 1H NMR (300 MHz CDCl3)
d 9.56 (1H, d,
J¼3 Hz, CHO), 7.42 (5H, m, Aromatic), 6.72 (1H, dd, J¼15.9, 4.8 Hz,
2CH), 6.22 (1H, dd, J¼9.3, 7.8 Hz, 3CH), 5.74 (1H, dd, J¼4.8, 3.3 Hz,
CHOAc), 4.91 (1H, d, J¼5.4 Hz, CHN3), 2.11 (3H, s, CH3CO); 13C NMR
EtOAc/Hexane) 0.41; ½a D20
ꢂ
þ40.9 (c 0.4, CHCl3); IR nmax (film) 3444
1H
7.37 (5H, m, Aromatic), 5.90 (1H, m, 3CH),
(br), 3068, 2976, 2908, 1641, 1494, 1068, 918, 750, 698 cmꢀ1
;
NMR (300 MHz CDCl3)
d
(75 MHz, CDCl3) d 191.0, 170.9, 147.0, 137.1, 132.6, 128.6, 127.6, 126.5,
5.20 (2H, m, 4CH2), 3.99e3.96 (2H, m, CH(O)CH, 1CH), 3.11 (1H, dd,
J¼3.0, 2.4 Hz, CH(O)CH), 2.46e2.33 (2H, m, 2CH2), 1.85 (1H, br s,
74.9, 73.4, 20.6; MS (ESI, positive ion): m/z (%)¼259.0 (100) [Mþ].
OH); 13C NMR (75 MHz, CDCl3)
d
136.8, 133.4, 128.5, 128.2, 125.7,
4.2.8. Compound (9). According to the general procedure for Wittig
olefination, E/Z diene 9 (72 mg, 0.176 mmol, 92%) was obtained after
flash chromatography on silica gel (4% EtOAc/Hexane) as colourless
oil; elemental analysis calcd. Found: C, 72.89; H, 9.10; N, 10.23.
C25H37N3O2 requires C, 72.95; H, 9.06; N,10.21; O, 7.77; Rf (5% EtOAc/
118.4, 68.2, 64.39, 55.1, 37.9; MS (ESI, positive ion): m/z (%)¼190.1
(100) [Mþ].
4.2.4. Data of 5. Elemental analysis calcd. Found: C, 82.70; H, 8.11.
C12H14O requires C, 82.72; H, 8.10; O, 9.18; Rf (30% EtOAc/PE) 0.44;
Hexane) 0.67; ½a D20
þ8.3 (c 0.71, CHCl3); IR nmax (film) 2920, 2850,
ꢂ
½
a 2D0
ꢂ
ꢀ20.4 (c 1.1, CHCl3); IR nmax (film) 3394 (br), 3078, 2906, 1639,
2102, 1743, 1467,1369,1226,1018, 950, 700 cmꢀ1; 1H NMR (300 MHz
1492,1448, 966, 916, 748, 694 cmꢀ1; 1H NMR (300 MHz CDCl3)
d
7.40
CDCl3)
d
7.32 (5H, m, Aromatic), 6.41 (1H, dd, J¼14.1, 11.4 Hz, 3CH),
(5H, m, Aromatic), 6.63 (1H, d, J¼15.9 Hz, 1CH), 6.28 (1H, dd, J¼15.9,
6.3 Hz, 2CH), 5.87e5.81 (1H, m, 5CH), 5.21e5.15 (2H, m, 6CH2), 4.39
(1H, m, 3CH), 2.47e2.32 (2H, m, 4CH2), 1.88 (1H, s, OH); 13C NMR
5.89 (1H, t, J¼11.1 Hz, 4CH), 5.53e5.41 (3H, m, 2CH, 5CH, CHOAc),
4.69 (1H, d, J¼4.8 Hz, CHN3), 2.04 (2H, m, CH2), 1.96 (3H, s, CH3CO),
1.18 (18H, br s, (CH2)9), 0.82 (3H, t, J¼6.3 Hz, 3CH3); 13C NMR
(75 MHz, CDCl3)
d
136.6, 134.0, 131.5, 130.3, 128.6, 127.6, 126.5, 118.5,
(75 MHz, CDCl3) d 171.1, 136.6, 134.0, 131.5, 130.3, 128.6, 128.3, 127.6,
71.72, 42.0; MS (ESI, positive ion): m/z (%)¼174.1 (100) [Mþ].
126.5, 80.9, 60.4, 33.0, 32.9, 32.6, 31.9, 29.7, 29.3, 27.2, 27.0, 25.8, 22.6,
14.1; MS (ESI, positive ion): m/z (%)¼411.2 (100) [Mþ].
4.2.5. (1S,2S,3R)-1-Azido-1-phenyl-hex-5-ene-2,3-diol (6). To a stir-
red solution of epoxy alcohol 4 (500 mg, 2.62 mmol) in CH3CN (8 mL)
4.2.9. Compound (10). To a solution of diene olefin 9 (70 mg,
0.170 mmol) in 3 mL ethylacetate was added 10% Pd/C (10 wt %) and
stirred under hydrogen for 3 h. After completing the reaction, it was
filtered and the filtrate was evaporated to give a residue, which was
used directly in the subsequent N-acetylation reaction without
further purification. To a stirred solution of the above crude amine
in DCM (1 mL) was added pyridine (0.08 mL) and acetic anhydride
(0.04 mL) successively at room temperature and continued to stir
until reaction was completed. Then water was added and extracted
with DCM and dried over Na2SO4. Evaporation of the solvent gave
a residue, which was purified by flash chromatography to give 10
(63 mg, 0.154 mmol, 91%) as colourless oil; elemental analysis calcd.
Found: C, 75.07; H, 10.57; N, 3.18. C27H45NO3 requires C, 75.13; H,
ꢀ
were added NaN3 (337 mg, 5.24 mmol) and 4 A MS (700 mg) suc-
cessively and continued to stirring. Upon completion the reaction
mixture was diluted with CH3CN (20 mL) and filtered. The filtrate
was evaporated to give a residue, which was purified by flash
chromatography (20% EtOAc/Hexane) to give 6 (543 mg, 2.33 mmol,
89%) as pale yellow oil; elemental analysis calcd. Found: C, 61.76; H,
6.43; N, 18.08. C12H15N3O2 requires C, 61.79; H, 6.48; N, 18.01; O,
13.72; Rf (50% EtOAc/Hexane) 0.49; ½a D20
ꢂ
þ14.7 (c 1.03, CHCl3); IR
nmax (film) 3411 (br), 3067, 2916, 2104, 1452, 1251, 1063 cmꢀ1
;
1H
NMR (300 MHz CDCl3) d 7.43e7.32 (5H, m, Aromatic), 5.87e5.75 (1H,
m, 5CH), 5.21e5.11 (2H, m, 6CH2), 4.80 (1H, d, J¼5.7 Hz, 2CH), 3.85
(1H, m, 3CH), 3.50 (1H, m, 1CH), 2.55e2.51 (2H, m, 4CH2), 2.18 (1H, d,
J¼3.9 Hz, OH), 2.04 (1H, d, J¼4.2 Hz, OH); 13C NMR (75 MHz, CDCl3)
10.51; N, 3.24; O, 11.12; Rf (30% EtOAc/Hexane) 0.66; ½a D25
þ2.1 (c
ꢂ
d
135.4, 134.2, 128.8, 128.4, 127.8, 119.1, 75.4, 70.2, 66.8, 37.0; MS (ESI,
1.02, CHCl3); IR nmax (film) 3278, 2963, 2875, 1744, 1655, 1545, 1371,
positive ion): m/z (%)¼233.1 (100) [Mþ].
1244,1224, 702 cmꢀ1; 1H NMR (300 MHz CDCl3)
Aromatic), 6.86 (1H, br s, NH), 5.12 (1H, m, 1CHOAc), 4.74 (1H, d,
d 7.39e7.19 (5H, m,
4.2.6. Compound (7). To a stirred solution of diol 6 (200 mg,
0.857 mmol) in pyridine (3.6 mL) were added DMAP (23 mg) and
acetic anhydride (0.8 mL, 4.28 mmol) successively at room temper-
ature and stirred for 3 h under N2 atmosphere. After completing the
reaction, ice-cooled 6 N HCl solution was added to the reaction
mixture at 0 ꢁC and extracted with ethylacetate. The combined or-
ganic extracts were washed with saturated aqueous NaHCO3 solu-
tion, water and then brine. Then it was dried and evaporated to give
a residue. Then residue was purified by flash chromatography to give
J¼5.1 Hz, CHNHAc), 2.04 (3H, s, CH3CO), 1.60e1.51 (5H, m, CH2
&
CH3CO), 1.31 (26H, br s, (CH2)13), 0.94 (3H, t, J¼9.3 Hz, CH3); 13C
NMR (75 MHz, CDCl3)
d 171.6, 170.1, 138.7, 128.2, 128.1127.7, 125.7,
79.5, 54.2, 30.4, 23.2, 20.9, 20.7, 20.6, 18.5, 14.0; MS (ESI, positive
ion): m/z (%)¼431.3 (100) [Mþ].
4.2.10. Compound (1b).12c To a solution of phenyl compound 10
(60 mg, 0.139 mmol) in CCl4/CH3CN/H2O (2:2:3) (0.08 M) was added
NaIO4 (12 equiv) slowly at 0 ꢁC. After stirring for 30 min at 0 ꢁC,

T.J. Devi et al. / Tetrahedron 69 (2013) 3817e3822
3821
RuCl3$3H2O (0.05 equiv) was added and the temperature was raised
to room temperature and continued stirring for overnight. The re-
action mixture was filtered and washed the solid with DCM three
times. The combined filtrate was dried and concentrated in vacuo to
give desired carboxylic acid residue. The crude acid was dissolved in
methanol (2 mL) and Et3N (70 mg, 0.695 mmol) was added at room
temperature and continued to stir for 3.5 h. Then the solvent was
removed under vacuo to give a residue. To the residue dissolved in
methanol (1.5 mL) was added 6 N aqueous HCl and refluxed for 2.5 h.
The reaction mixture was concentrated under vacuum and the resi-
due was dissolved in methanol followed by evaporation under vac-
uum. This process was repeated until HCl was completely removed.
Then the crude acid was reduced with borane dimethylsulfide
according to the general procedure of borane dimethylsulfide re-
duction to furnish 1b (31 mg, 0.104 mmol, 75% over four steps) after
flash chromatography on silica gel as white solid; elemental analysis
calcd. Found: C, 71.63; H, 13.10; N, 4.59. C18H39NO2 requires C, 71.70;
H, 13.04; N, 4.65; O, 10.61; Rf (MeOH/EtOAc/Hexane, 1:10:10) 0.32;
was filtered and the filtrate was evaporated to give a residue, which
was used directly in the subsequent reaction without further pu-
rification. To the stirred solution of the crude amine in DCM (5 mL)
were added Et3N (1.5 equiv) and di-tert-butyldicarbonate
(0.612 mmol, 1.2 equiv) successively at room temperature and
continued to stir for 5 h. Then the reaction mixture was diluted
with DCM and washed with saturated aqueous NH4Cl and sepa-
rated the organic phase. The organic layer was dried and concen-
trated in vacuo to give the crude product. To the above crude
product in pyridine (3 mL) were added DMAP (catalytic amount)
and acetic anhydride (0.47 mL, 2.55 mmol) successively at room
temperature and stirred for 3 h under N2 atmosphere. After com-
pleting the reaction, ice-cooled 6 N HCl solution was added to the
reaction mixture at 0 ꢁC and extracted with ethylacetate. The
combined organic extracts were washed with saturated aqueous
NaHCO3 solution, water and then brine. Then it was dried and
evaporated to give a residue, which was purified by flash chroma-
tography to compound 13 (248 mg, 0.453 mmol, 89% over three
steps) as colourless oil; elemental analysis calcd. Found: C, 70.19; H,
9.67; N, 2.50. C32H53NO6 requires C, 70.17; H, 9.75; N, 2.56; O, 17.53;
½
a 2D5
ꢂ
þ5.3 (c 1.07, CHCl3/MeOH 9:1); mp 79e83 ꢁC; IR nmax (film)
(KBr) 3627 (br), 3421 (br), 1370 cmꢀ1 1H NMR (300 MHz CD3OD)
;
d
3.68 (2H, m,1CH2), 3.47 (1H, m, 3CH), 2.68 (1H, m, 2CH),1.49 (2H, m,
Rf (5% EtOAc/Hexane) 0.70; ½a D20
þ28.1 (c 1.09, CHCl3); IR nmax (film)
ꢂ
4CH2), 1.25 (26H, m, (CH2)13), 0.89 (3H, t, J¼7.0 Hz, CH3); 13C NMR
3352, 2965, 2935, 2875, 1745, 1713, 1527, 1368, 1221, 1169, 757,
(75 MHz, CD3OD)
d
74.5, 64.4, 55.7, 33.75, 32.0, 30.1, 29.8, 29.7, 26.4,
702 cmꢀ1; 1H NMR (300 MHz CDCl3)
d 7.33e7.22 (5H, m, Aromatic),
23.0, 14.1; MS (ESI, positive ion): m/z (%)¼301.2 (100) [Mþ].
5.36 (2H, m, NH & CHOAc protons), 5.12 (1H, m, CHNHAc), 4.97 (1H,
m, CHOAc), 1.90 (6H, br s, CH3CO), 1.68 (2H, m, CH2), 1.42 (9H, s,
C(CH3)3), 1.26 (24H, br s, (CH2)12), 0.93 (3H, t, J¼7.5 Hz, CH3); 13C
4.2.11. Compound (11). To a stirred solution of diol 6 (230 mg,
0.986 mmol) in dry THF (8 mL) was added slowly 60% dispersion of
NaH (157 mg, 3.94 mmol) at 0 ꢁC. After stirring for 5 min, the reaction
mixture was removed from the ice bath and BnBr (505 mg,
2.95 mmol) was added. The reaction mixture was continued stirring
for overnight under nitrogen atmosphere. The reaction mixture was
then quenched by the slow dropwise addition of saturated aqueous
NH4Cl, diluted with H2O and extracted with ethylacetate. The com-
bined organic layer was dried (Na2SO4) and concentrated in vacuo.
The residue was purified by flash chromatography to give the product
9 (371 mg, 0.897 mmol, 91%) as colourless oil; elemental analysis
calcd. Found: C, 75.50; H, 6.51; N,10.18. C26H27N3O2 requires C, 75.52;
NMR (75 MHz, CDCl3)
d 171.1, 169.9, 154.9, 138.7, 128.4, 127.6, 127.1,
79.9, 74.7, 72.2, 54.3, 32.8, 31.9, 30.6, 29.6, 29.5, 29.4, 29.3, 28.7, 28.3,
28.1, 22.6, 20.8, 20.6, 18.5, 14.1; MS (ESI, positive ion): m/z (%)¼547.1
(100) [Mþ].
4.2.14. Compound (14). Compound 14 was synthesized according
to the general procedure of oxidative phenyl ring cleavage and
BDS reduction in sequence. Colourless oil (74 mg, 0.149 mmol, 82%
over two steps); elemental analysis calcd. Found: C, 64.69; H,
10.20; N, 2.73. C27H51NO7 requires C, 64.64; H, 10.25; N, 2.79; O,
22.32; Rf (40% EtOAc/Hexane) 0.39; ½a D20
þ18.7 (c 1.12, CHCl3); IR
ꢂ
H, 6.58; N, 10.16; O, 7.74; Rf (20% EtOAc/Hexane) 0.56; ½a D20
ꢂ
þ36.7 (c
nmax (film) 3384, 2924, 1746, 1713, 1524, 1368, 1224, 1019,
1.03, CHCl3); IR nmax (film) 3063, 3030, 2923, 2857, 2102, 1454, 1360,
702 cmꢀ1; 1H NMR (300 MHz CDCl3)
d 5.26 (1H, br s, NH), 5.15 (1H,
1094, 735 cmꢀ1
;
1H NMR (300 MHz CDCl3)
d
7.63e7.02 (15H, m,
m, 3CH), 5.06 (1H, m, 4CH), 4.99 (1H, m, 2CH), 3.77 (1H, m, 1CHa),
3.56 (1H, m, 1CHb), 1.97 (6H, s, CH3CO), 1.56 (2H, m, 5CH2), 1.37
(9H, s, C(CH3)3), 1.27 (24H, br s, (CH2)12), 0.87 (3H, t, J¼7.5 Hz, CH3);
Aromatics), 5.91e5.82 (1H, m, 5CH), 5.07 (2H, m, 6CH2), 4.58 (4H, m,
benzyl protons), 4.14 (1H, d, J¼10.5 Hz, CHN3), 3.90 (1H, m, CHOBn),
3.49 (1H, m, CH(OBn)CH2), 2.51 (2H, m, CH2); 13C NMR (75 MHz,
13C NMR (75 MHz, CDCl3)
d 171.2, 169.8, 154.9, 79.9, 74.7, 72.2, 65.3,
CDCl3)
d
140.9,139.0, 136.1,128.4,128.3,128.1, 127.9,125.4,114.3, 79.9,
50.1, 32.8, 31.9, 30.5, 29.7, 29.5, 29.4, 29.1, 28.7, 28.3, 28.1, 22.5,
20.8, 20.6, 18.7, 14.1; MS (ESI, positive ion): m/z (%)¼501.3
(100) [Mþ].
74.7, 72.2, 55.2, 34.0; MS (ESI, positive ion): m/z (%)¼413.1 (100) [Mþ].
4.2.12. Compound (Z-12). According to the general procedure for
olefin cleavage, compound 11 (350 mg, 0.846 mmol) was converted
to aldehyde. This crude aldehyde was used for Wittig olefination
according to the general procedure giving compounds 12 (307 mg,
0.541 mmol, 64% over two steps) after flash chromatography on
silica gel (5% EtOAc/Hexane) as colourless oil; elemental analysis
calcd. Found: C, 78.19; H, 8.66; N, 7.42. C37H49N3O2 requires C, 78.27;
4.2.15. Compound (1a).11c,12c To
a solution of 14 (55 mg,
0.109 mmol) in methanol (1.5 mL) was added Et3N (55 mg,
0.545 mmol) at room temperature and continued to stir for 3.5 h.
Then the solvent was removed under vacuo to give a residue. To the
residue dissolved in DCM (1.5 mL) was added TFA (1.5 mL) at 0 ꢁC
and stirred at room temperature for 45 min. The reaction mixture
was concentrated under vacuum and the residue was dissolved in
methanol followed by evaporation under vacuum. This process was
repeated to remove excess TFA. The crude product was purified by
flash chromatography to furnish 1a (31 mg, 0.099 mmol, 91%) as
white solid; elemental analysis calcd. Found: C, 68.12; H, 12.34; N,
4.39. C18H39NO3 requires C, 68.09; H, 12.38; N, 4.41; O, 15.12; Rf
H, 8.70; N, 7.40; O, 5.64; Rf (5% EtOAc/Hexane) 0.67; ½a D20
þ23.7 (c
ꢂ
1.10, CHCl3); IR nmax (film) 2924, 2853, 2102,1454,1071, 771 cmꢀ1; 1H
NMR (300 MHz CDCl3)
d 7.55e7.14 (15H, m, Aromatics), 5.51e5.48
(2H, m, CH]CH), 4.62e4.56 (4H, m, benzyl protons), 4.33 (1H, d,
J¼10.3 Hz, CHN3), 4.15 (1H, m, 2CH), 3.49 (1H, m, 3CH), 2.13 (1H, m,
4CH), 2.04 (3H, m, 4CH & 7CH2), 1.25 (18H, m, (CH2)9), 0.89 (3H, t,
J¼6.3 Hz, CH3); 13C NMR (75 MHz, CDCl3)
d
139.7, 136.8, 131.1, 129.0,
(MeOH/EtOAc/Hexane, 1:10:10) 0.29; ½a D20
þ7.6 (c 1.08,C5H5N); mp
ꢂ
128.8, 127.4, 125.8, 84.1, 74.5, 73.1, 57.1, 33.2, 30.5, 29.9, 29.8, 29.6,
97e101 ꢁC; IR nmax (film) (KBr) 3319 (br), 2918, 2850, 1470, 1442,
27.1, 23.1, 14.0; MS (ESI, positive ion): m/z (%)¼567.2 (100) [Mþ].
1051 cmꢀ1
;
1H NMR (300 MHz CD3OD)
d
3.76 (1H, dd, J¼10.6,
4.2 Hz, 1CHa), 3.56 (1H, m, 1CHb), 3.50 (1H, m, 4CH), 3.34 (1H, m,
3CH), 3.02e2.95 (1H, m, 2CH), 1.73 (1H, m, 5CHa), 1.61 (1H, m,
5CHb), 1.33e1.51 (24H, m, (CH2)12), 0.91 (3H, t, J¼7.0 Hz, CH3); 13C
4.2.13. Compound (13). To
a solution of E/Z-12 (290 mg,
0.510 mmol) in ethylacetate (6 mL) was added 10% Pd/C (10 wt %)
and stirred under hydrogen for 6 h. After completing the reaction, it
NMR (75 MHz, CD3OD) d 76.3, 74.4, 65.6, 54.9, 33.6, 33.0, 31.1, 30.0,

3822
T.J. Devi et al. / Tetrahedron 69 (2013) 3817e3822
J.; Alonso, J. Chem. Commun. 2002, 426e427; (h) Van den Berg, R. J. B. H. N.;
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Tetrahedron 2011, 67, 9283e9290.
29.9, 29.7, 29.6, 26.1, 23.0, 14.0. MS (ESI, positive ion): m/z (%)¼317.1
(100) [Mþ].
12. (a) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.;
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Acknowledgements
We would like to thank the Director, CSIR-NEIST, Jorhat-785006
for providing necessary facilities to carry out this work. T.J.D. and
B.S. thanks to CSIR-New Delhi for the award of fellowship.
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