Asymmetric synthesis of triacetyl-d-erythro-sphingosine and D-1-deoxyallonojirimycin via Miyashita C2 selective endo-mode azide opening of 2,3-epoxy alcohol

Article abstract of DOI:10.1016/j.tet.2009.10.035

An efficient protocol for the asymmetric synthesis of triacetyl-d-erythro-sphingosine and D-1-deoxyallonojirimycin has been developed starting from commercially available propargyl alcohol. The key steps involved Sharpless asymmetric epoxidation and Miyashita C2 selective endo-mode azide opening of the 2,3-epoxy alcohol.

Full text of DOI:10.1016/j.tet.2009.10.035

Tetrahedron 65 (2009) 10701–10708
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of triacetyl-
D-erythro-sphingosine and D-1-
deoxyallonojirimycin via Miyashita C2 selective endo-mode azide
opening of 2,3-epoxy alcohol
*
R. Sridhar, B. Srinivas, K. Rama Rao
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2009
Received in revised form 7 October 2009
Accepted 11 October 2009
Available online 14 October 2009
An efficient protocol for the asymmetric synthesis of triacetyl-D-erythro-sphingosine and D-1-deoxy-
allonojirimycin has been developed starting from commercially available propargyl alcohol. The key
steps involved Sharpless asymmetric epoxidation and Miyashita C2 selective endo-mode azide opening
of the 2,3-epoxy alcohol.
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Dr. K. Nagarajan on the occa-
sion of his 79th birthday
1. Introduction
erythro-sphingosine and D-1-deoxyallonojirimycin and describe
herein their significance.
Advances in organic synthesis, especially of chiral in-
termediates, have been facilitated by many novel methodologies
developed over the decades. Amongst them, the combination of
Sharpless asymmetric epoxidation and C2 selective endo-mode
nucleophilic substitution reaction of 2,3-epoxy alcohol developed
by Miyashita et al. 1 have acquired significance for the production of
key intermediates in natural product synthesis.2 This type of re-
action proceeds via an intramolecular boron chelate through
a novel endo-mode epoxide opening with extremely high C2
selectivity.1 We have utilised this approach for the asymmetric
Sphingolipids are long chain amino alcohols, which are found in
the plasma membranes of eukaryotic cells. They play important
role in many physiological processes, such as immune response,
cell recognition, adhesion, apoptosis3 and are implicated in a vari-
ety of diseases, such as cancer, Alzheimer’s disease and an array of
neurological syndromes.4
Although a number of structurally related sphingoid base
structures are known, the most frequently encountered sphingoid
base in nature is D-erythro-(2S,3R)-sphingosine 1. D-erythro-sphin-
gosine 1 and its derivatives (Fig. 1) are shown to be promising
synthesis of two biologically important compounds triacetyl-
D-
enzyme inhibitors.5 This has led to growing interest in developing
O
OH
OH
OH
OH
HN
C15H31
C13H27
O
C13H27
OH
C13H27
OH
O
HO
OH NH2
NH2
OH
OH
3
1
2
D-erythro-sphingosine
D-ribo-phytosphingosine
Galcer
Figure 1.
efficient methods for their synthesis.6 Many of these syntheses start
from various chiral pools, such as amino acids7 and carbohydrates.8
Thus, recent interest has increasingly focused on the enantiose-
lective synthesis of
D-erythro-sphingosine and its derivative from
* Corresponding author. Tel.: þ91 40 27193164; fax: þ91 40 27160512.
E-mail address: kakulapatirama@gmail.com (K.R. Rao).
achiral sources.9
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.035

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R. Sridhar et al. / Tetrahedron 65 (2009) 10701–10708
Another important class of biologically important compounds
yield. The E-allylic alcohol 11 was subjected to Sharpless asym-
metric epoxidation18 by using D(–)-diethyl tartrate, Ti(OiPr)4 and
TBHP to afford epoxyalcohol 12 in 79% yield.
are alkaloid sugar mimics with nitrogen in the ring (commonly
known as iminosugars, azasugars, or polyhydroxy piperidines),10
which have become important tools in glycobiology due to their
role as glycosidase inhibitors.11 Glycosidase inhibitors have re-
ceived great deal of attention because of their therapeutic potential
in the treatment of cancer, viral infections including HIV, diabetes
and other metabolic disorders.12 Amongst various polyhydroxy
piperidines, deoxynojirimycin (DNJ 4) and its analogues (Fig. 2)
have acquired significance due to their potential as drugs for
treating a variety of carbohydrate mediated diseases.13 Tradition-
ally enantiopure azasugars were synthesised from the readily
available chiral starting materials like carbohydrates, or aminoacid
derivatives.14 Amongst these azasugars, D-1-deoxyallonojirimycin
7 has become important due to its significant biological activity.15
As a result much synthetic efforts have been directed towards the
stereoselective synthesis D-1-deoxyallonojirimycin 7.16,26
The highly efficient C2 selective azide substitution reaction of 12
was accomplished by using NaN3-(CH3O)3B system developed by
Miyashita et al.1 This reaction proceeds via an intramolecular boron
chelate through a novel endo-mode epoxide opening with ex-
tremely high C2 selectivity (Scheme 2). Under these conditions, the
desired azido diol was produced in good yield and high diaster-
eoselectively (C2/C3 opening, 14:1). The minor 1,2-diol that resul-
ted from C3 opening was removed by treating the mixture with
sodium periodate to give pure 2-azide-1,3-diol 13 in 83% yield.
The resulting 1,3-diol 13 was protected as benzylidene acetal
using benzaldehyde dimethyl acetal19 in the presence of catalytic
amount of PPTS in benzene to give the desired acetal 14 in good
yield (92%). Reduction of azide with Lindlar catalyst19 in methanol
worked efficiently to give the amine, which was taken for the next
OH
OH
OH
OH
HO
OH
OH
HO
OH
OH
HO
OH
OH
HO
OH
OH
N
H
N
H
N
H
N
H
4
5
6
7
1-deoxynojirimycin
1-deoxymannojirimycin
1-deoxygulonojirimycin
1-deoxyallonojirimycin
Figure 2.
We herein, disclose a simple and convenient approach for the
asymmetric synthesis of triacetyl- -erythro-sphingosine 19 and D-
step without purification. It was protected with (Boc)2O in the
presence of
-cyclodextrin20 in water to give 15 in good yield.
D
b
1-deoxyallonojirimycin 7 starting from the commercially available
propargyl alcohol 8.
Deprotection of PMB group using DDQ in DCM/pH 7 buffer gave
alcohol 16 (92%), which upon oxidation under Swern conditions
yielded the aldehyde. The resulting crude aldehyde was subjected
to Wittig methylenation reaction using Ph3PCH3Br and BuOK in
THF at 0 ꢀC to produce the desired olefin 17 in 85% yield.
t
2. Results and discussion
With the key intermediate in hand, we proceeded with the olefin
cross metathesis using 1-pentadecene in the presence of 10 mol % of
Grubbs II generation catalyst, which provided the cross-coupled
product 18 with complete E-stereo selectivity in 94%, yield.9a Finally,
deprotection of 18 with 6 N HCl in MeOH, followed by reaction with
Ac2O in pyridine gave desired product 19 in 92% yield. The spec-
2.1. Synthesis of triacetyl-D-erythro-sphingosine (19)
The retrosynthetic analysis of 19 revealed an intermediate 17,
which can be synthesised conveniently from 2,3-epoxy alcohol 12
and cross-metathesis reaction could be utilised for establishing the
E-double bond of the sphingosine backbone (Fig. 3).
troscopic and analytical data of triacetyl-D-erythro-sphingosine 19
were in good agreement with the literature values.21
Ph
OAc
O
O
cross-metathesis
2.2. Synthesis of D-1-deoxyallonojirimycin (7)
C13H27
C13H27
OAc
+
NHAc
Boc
HN
17
After successful synthesis of 19, we exploited the synthesis of
D-1-deoxyallonojirimycin 7 from the same starting material 8
(Scheme 3). The (ꢁ)-enantiomer of 12 was prepared by using
Sharpless asymmetric epoxidation of 11 by using L(þ)-diethyl tar-
trate, Ti(OiPr)4 and TBHP. The same sequence of reactions (of
Scheme 1) was carried out for the synthesis of (ꢁ)-enantiomer of 15
from 12. Allylation of 15 with allyl bromide using NaH and catalytic
amount of crown ether resulted in 20 (94%). Deprotection of PMB
group using DDQ in DCM/pH 7 buffer gave alcohol 21 (95%), which
upon oxidation under Swern conditions yielded aldehyde. The
resulting crude aldehyde was subjected to olefination under
modified Horner–Wadsworth–Emmons olefination22 using tri-
ethylphosphono acetate and DBU in the presence of Lithium bro-
19
Ph
C2 selective
O
O
epoxide opening
O
PMBO
PMBO
HO
OH
N3
8
14
12
Figure 3. Retrosynthetic analysis of triacetyl-D-erythro-sphingosine 19.
The propargyl alcohol 8 was protected as its PMB ether 9 using
mide to produce the desired
a,b-unsaturated ester 22 in 94% yield.
PMB-Br and NaH in THF with 93% yield. Homologation17 of 9 was
achieved using n-BuLi and formaldehyde resulting in 10 (93%),
which was followed by stereoselective reduction of triple bond
with LiAlH4 in THF to give the desired trans-allylic alcohol 11 in 94%
The useful piperidine intermediate 23 was accomplished by
ring-closing metathesis23 using Grubbs
I generation catalyst
(10 mol %) at 90 ꢀC in good yield (92%). The subsequent diol 24 was
obtained as a single diastereomer in high yield (86%) by the

R. Sridhar et al. / Tetrahedron 65 (2009) 10701–10708
(ii)
10703
(i)
(iii)
HO
PMBO
PMBO
PMBO
PMBO
OH
OH
8
10
11
9
Ph
OH
O
O
(iv)
O
(v)
(vi)
PMBO
PMBO
OH
OH
N3
N3
14
12
13
Ph
Ph
Ph
O
O
O
O
(vii)
O
O
(viii)
(ix)
PMBO
HO
Boc
HN
15
Boc
HN
Boc
HN
17
16
Ph
O
O
OAc
(x)
(xi)
C13H27
C13H27
OAc
NHAc
Boc
HN
18
19
Scheme 1. Synthesis of triacetyl-D-erythro-sphingosine 19. Reagents, conditions and yields: (i) PMBBr, NaH, THF, 0 ꢀC-rt, 12 h, 93%; (ii) n-BuLi, (CH2O)n, THF, ꢁ78 ꢀC-rt, 16 h, 93%;
(iii) LiAlH4, THF, 0 ꢀC-rt, 12 h, 94%; (iv) D(–)-DET, Ti(OiPr)4, TBHP, 4 Å MS, DCM, ꢁ20 ꢀC, 3 h, 79%; (v) (MeO)3B, NaN3, DMF, 50 ꢀC, 3 h, 83%; (vi) PhCH(OMe)2, PPTS, Benzene, reflux,
15 h, 92%; (vii) (a) H2, Lindlar cat, MeOH, rt, 6 h; (b) (Boc)2O, b-CD/H2O, rt, 20 min, 90% for two steps; (viii) DDQ, DCM/pH 7 buffer (5:1), rt, 2 h, 92%; (ix) (a) oxalyl chloride, DMSO,
TEA, DCM, ꢁ78 ꢀC, 1 h; (b) Ph3PCH3Br, tBuOK, THF, 0 ꢀC, 1 h, 85%; (x) 1-pentadecene, Grubbs II generation catalyst (10 mol %), CH2Cl2, reflux, overnight, 94%; (xi) 6 N HCl, MeOH, rt,
overnight; then Ac2O, pyridine, 92% for two steps.
OMe
MeO
B
OH
O
O
2
NaN3-(CH3O)3B
DMF
O
PMBO
PMBO
PMBO
3
OH
OH
N3
13
N3
12
Scheme 2. C2 selective azide substitution reaction.
stereoselective dihydroxylation of the double bond24 of piperidine
23 using cat. OsO4 and 4-methyl morpholine N-oxide at 0 ꢀC. The
formation of single diastereomer 24 can be explained by the ap-
Wadsworth–Emmons olefination, RCM with Grubbs catalyst and
diastereoselective dihydroxylation as the key steps.
proach of OsO4 from the less hindered
a-face of the olefin due to
4. Experimental
4.1. General
steric hindrance on the
b
-face by the bulky N-Boc group.25 The
structure of 24 was also further confirmed by conversion to D-1-
deoxyallonojirimycin 7 of known stereochemical configuration.
Deprotection of 24 with 6 N HCl in MeOH, followed by treatment
with ion-exchange resin DOWEX 50Wx8 yielded 7 in 89%. The
spectroscopic and analytical data of D-1-deoxyallonojirimycin 7
were in good agreement with the literature values.14c
Commercial reagents were used without further purification. All
solvents were purified by standard techniques. Infrared (IR) spectra
were recorded on a Perkin–Elmer 683 spectrometer. Optical rota-
tions were obtained on a Jasco Dip 360 digital polarimeter. Melting
points are uncorrected. NMR spectra were recorded in CDCl3 on
Varian Gemini 200, Bruker 300 or Varian Unity 400 NMR spec-
trometer. Column chromatographic separations were carried out
on silica gel (60–120 mesh). Mass spectra were obtained on Fin-
nigan MAT1020B or micromass VG 70–70H spectrometer operating
at 70 eV using a direct inlet system. All high resolution spectra were
recorded on QSTAR XL hybrid MS/MS system equipped with an ESI
source (IICT, Hyderabad).
3. Conclusion
In summary, we have demonstrated a simple and highly effi-
cient asymmetric synthesis for triacetyl-
D-1-deoxyallonojirimycin. The stereogenic centres in the polar
head group of triacetyl- -erythro-sphingosine were installed by
D-erythro-sphingosine and
D
using Sharpless asymmetric epoxidation, endo-mode C2 selective
azide substitution of 2,3-epoxy alcohol followed by cross-metath-
esis reaction to establish the E-double bond of the sphingosine
backbone, whereas the asymmetric synthesis of D-1-deoxy-
allonojirimycin was obtained utilising Sharpless epoxidation,
endo-mode C2 selective azide substitution of epoxide, Horner–
4.1.1. 1-Methoxy-4-((prop-2-ynyloxy)methyl)benzene (9)26. A round-
bottom flask was charged with 60% dispersion of sodium hydride in
mineral oil (1.66 g, 42.8 mmol) under nitrogen, the oil was removed
by washing with hexane (20 mL), THF (50 mL) was then added and

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R. Sridhar et al. / Tetrahedron 65 (2009) 10701–10708
Ph
O
O
O
(i)
PMBO
PMBO
PMBO
OH
OH
HN Boc
11
(−)12
(−)15
Ph
Ph
Ph
O
O
O
O
O
O
PMBO
EtO
HO
(iv)
(ii)
(iii)
N Boc
O
N Boc
N Boc
21
22
20
Ph
Ph
OH
O
O
O
O
HO
OH
OH
HO
HO
(vi)
(vii)
(v)
N Boc
N Boc
N
H
7
23
24
Scheme 3. Synthesis of D-allo-DNJ 7. Reagents, conditions and yields: (i) L(þ)-DET, Ti(OiPr)4, TBHP, 4 Å MS, DCM, –20 ꢀC, 3 h, 80%; (ii) NaH, allyl bromide, 18-crown-6-ether, THF,
0
ꢀC-rt, 3 h, 94%; (iii) DDQ, DCM/pH 7 buffer (5:1), rt, 2 h, 95%; (iv) (a) oxalyl chloride, DMSO, TEA, DCM, ꢁ78 ꢀC, 1 h; (b) LiBr, triethylphosphonoacetate, DBU, THF, rt, 1 h, 94% for two
steps; (v) Grubbs I generation catalyst, Toluene, 90 ꢀC, 2 h, 92%; (vi) 4% OsO4, NMO, acetone:water, 0 ꢀC, overnight, 86%; (vii) 6 N HCl, MeOH, rt, overnight; DOWEX 50wX8, 89%.
the resulting cloudy white suspension was cooled to 0 ꢀC. A solu-
tion of propargyl alcohol 8 (2 g, 35.7 mmol) in THF (20 mL) was
added via syringe, followed by p-methoxybenzyl bromide (8.6 g,
42.8 mmol). The reaction mixture was stirred at room temperature
for 12 h. It was then carefully quenched with saturated aqueous
NH4Cl (50 mL). The layers were separated and the aqueous layer
was extracted with EtOAc (50 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of crude compound by flash chromatography
(10% EtOAc/hexane) afforded PMB ether 9 (5.8 g, 93%) as yellow
liquid; Rf (5% EtOAc/hexane) 0.42; IR (neat): lmax 3288, 3002, 2940,
(ESIMS): m/z 229 [MþNa]þ; HRMS (ESI): [MþNa]þ, found 229.0937.
C12H14O3Na requires 229.0946.
4.1.3. (E)-4-(4-Methoxybenzyloxy)but-2-en-1-ol (11)26. In a clean
and dry round-bottom flask LiAlH4 (1.29 g, 33.9 mmol) and dry THF
(25 mL) were taken under nitrogen atmosphere and cooled to 0 ꢀC.
To this a solution, alcohol 10 (3.5 g, 16.9 mmol) dissolved in THF
(30 mL) was added via syringe. The reaction mixture was stirred for
12 h at room temperature. It was cooled to 0 ꢀC, then carefully
quenched with saturated aq Na2SO4 (10 mL) and stirred for 3 h.
Then it was filtered through Celite and washed with ethyl acetate
(20 mLꢂ2). The combined organic layers were washed with water
(25 mL), brine (20 mL), dried over Na2SO4 and the solvent was
evaporated in vacuo. The residue obtained was purified by column
chromatography (30% EtOAc/hexane) to give the allylic alcohol 11
(3.3 g, 94%) as yellowish oily liquid; Rf (25% EtOAc/hexane) 0.45; IR
1248, 1078 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d
7.24 (2H, d, J¼8.1 Hz,
Ar-H), 6.84 (2H, d, J¼8.1 Hz, Ar-H), 4.52 (2H, s, benzylic CH2), 4.10
(2H, d, J¼2.2 Hz, CH2OPMB), 3.79 (3H, s, OCH3), 2.4 (1H, t, J¼2.2 Hz,
triple bond CH); 13C NMR (50 MHz, CDCl3):
d 159.2, 129.6, 129.1,
113.7, 79.6, 74.4, 70.9, 56.5, 55.1; MS (ESIMS): m/z 177 [MþH]þ;
HRMS (ESI): [MH]þ, found 177.0822. C11H13O2 requires 177.0837.
(neat): lmax 3400, 2932, 2855, 1611, 1513, 1093 cmꢁ1
(300 MHz, CDCl3):
J¼9.0 Hz, Ar-H), 5.72–5.92 (2H, m, CH]CH), 4.42 (2H, s, benzylic
CH2), 4.12 (2H, d, J¼3.7 Hz, CH2OPMB), 3.96 (2H, d, J¼4.5 Hz,
CH2OH), 3.79 (3H, s, OCH3), 1.49 (1H, s, OH); 13C NMR (50 MHz,
;
1H NMR
d
7.22 (2H, d, J¼8.3 Hz, Ar-H), 6.82 (2H, d,
4.1.2. 4-(4-Methoxybenzyloxy)but-2-yn-1-ol (10)26. To a solution of
alkyne 9 (4 g, 22.7 mmol) in THF (100 mL) was added at ꢁ78 ꢀC
a 1.6 M solution of n-BuLi in hexane (14.2 mL, 22.7 mmol) dropwise
over 10 min under nitrogen atmosphere. The reaction mixture was
stirred at ꢁ78 ꢀC for 40 min, then dry paraformaldehyde (0.98 g,
34 mmol) was added, and the mixture was allowed to warm up to
room temperature and stirred for 16 h. Saturated aqueous NH4Cl
solution (25 mL) was carefully added, the layers were separated,
and the aqueous layer was extracted with EtOAc (50 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was pu-
rified by chromatography (30% EtOAc/hexane) to afford 10 (4.36 g,
93%) as yellow liquid; Rf (15% EtOAc/hexane) 0.44; IR (neat): lmax
CDCl3): d 159.1, 132.2, 130.1, 129.3, 127.7, 113.7, 71.8, 69.7, 62.8, 55.2;
MS (ESIMS): m/z 226 [MþNH4]þ; HRMS (ESI): [MþH]þ, found
209.1137. C13H16O3 requires 209.1146.
4.1.4. ((2R,3R)-3-((4-Methoxybenzyloxy)methyl)oxiran-2-yl)metha-
nol (12). To a cooled (–20 ꢀC) suspension of activated, powdered
4 Å MS (7.5 g) in CH2Cl2 (100 mL) under nitrogen were added D
(ꢁ)-DET (0.68 g, 3.3 mmol), Ti(OiPr)4 (0.87 g, 3 mmol), and TBHP
(4 M in toluene, 3.3 mL, 13.2 mmol). After 20 min, a solution of al-
cohol 11 (2.3 g, 11 mmol) in CH2Cl2 (90 mL) was added at ꢁ20 ꢀC
over a period of 20 min. The resulting mixture was stirred at that
temperature for 3 h, quenched with a cooled solution of ferrous
sulfate and tartaric acid (stoichiometric amount) in distilled water,
stirred vigorously for 30 min, and extracted with ether (50 mLꢂ3).
The combined organic layers were treated with a pre-cooled (0 ꢀC)
3413, 2935, 2860, 1611, 1513, 1248, 1028 cmꢁ1
CDCl3):
7.22 (2H, d, J¼8.6 Hz, Ar-H), 6.81 (2H, d, J¼8.4 Hz, Ar-H),
4.48 (2H, s, benzylic CH2), 4.24 (2H, s, CH2OPMB), 4.12 (2H, s,
CH2OH), 3.77 (3H, s, OCH3); 13C NMR (50 MHz, CDCl3):
159.1,
129.5, 129.1, 128.3, 113.6, 84.8, 81.1, 71.1, 56.8, 55.0, 50.4; MS
;
1H NMR (200 MHz,
d
d

R. Sridhar et al. / Tetrahedron 65 (2009) 10701–10708
10705
solution of 30% NaOH (w/v) in brine and stirred for 1 h at room
temperature. The two layers were separated and the aqueous
layer was extracted with ether (30 mLꢂ3). The combined ether
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was chroma-
68.6, 54.9, 53.2; MS (ESIMS): m/z 378 [MþNa]þ; HRMS (ESI):
[MþNa]þ, found 378.1424. C19H21N3O4Na requires 378.1429.
4.1.7. tert-Butyl (2S,4S,5S)-4-((4-methoxybenzyloxy)methyl)-2-phe-
nyl-1,3-dioxan-5-yl carbamate (15). A solution of azide 14 (700 mg,
1.97 mmol) and Lindlar catalyst (70 mg, 10% by weight) in MeOH
(25 mL) was stirred under H2 atmosphere at room temperature for
6 h. The solution was filtered through Celite and concentrated in
vacuo to give pale yellow oil. The crude amine was used for the
further step without purification.
tographed (40% EtOAc/hexane) to give epoxide 12 (1.95 g, 79%) as
25
white solid; Rf (25% EtOAc/hexane) 0.56; Mp 84 ꢀC; [
a
]
þ14.0 (c
D
1, CHCl3); {[
a
]
25 of compound (ꢁ)12¼ꢁ13.9 (c 1, CHCl3)}; IR (KBr):
D
lmax 3445, 3015, 2928, 1612, 1513, 1060 cmꢁ1 1H NMR (400 MHz,
;
CDCl3):
d
7.21 (2H, d, J¼8.3 Hz, Ar-H), 6.82 (2H, d, J¼9.1 Hz,
Ar-H), 4.47 (2H, dd, J¼11.3, 7.5 Hz, benzylic CH2), 3.85–3.92 (1H, m,
CHaHbOPMB), 3.79 (3H, s, OCH3), 3.56–3.68 (2H, m, CHaHbOPMB
and CHaHbOH), 3.46 (1H, dd, J¼5.3, 11.3 Hz, CHaHbOH), 3.13–3.17
(1H, m, epoxide), 2.99–3.03 (1H, m, epoxide), 1.81 (1H, br s,
To a solution of b-cyclodextrin (220 mg, 0.19 mmol) in distilled
water (5 mL) at room temperature was added crude amine in ace-
tone (1 mL), then (Boc)2O (0.42 mL, 1.97 mmol) was added to the
reaction mixture and stirring was continued for 20 min. The product
was then extracted with ethyl acetate (2ꢂ25 mL) and washed with
brine solution (10 mL). The organic phase was dried over Na2SO4 and
concentrated in vacuo. The crude product thus obtained was purified
by column chromatography (10% EtOAc/hexane) to afford compound
15 (760 mg, 90%) as a white solid. The aqueous layer was cooled to
OH); 13C NMR (CDCl3, 50 MHz):
d 158.9, 129.5, 129.1, 113.4,
72.5, 69.1, 61.04, 55.6, 54.9, 54.1; MS (ESIMS): m/z 247 [MþNa]þ;
HRMS (ESI): [MþNa]þ, found 247.0937. C12H16O4Na requires
247.0946.
4.1.5. (2S,3S)-4-(4-Methoxybenzyloxy)-2-azidobutane-1,3-diol
(13). A mixture of epoxy alcohol 12 (1.6 g, 7.1 mmol), (MeO)3B
(1.6 mL, 14 mmol), and NaN3 (0.91 g, 14 mmol) in DMF (20 mL) was
stirred at 50 ꢀC for 3 h. After cooling to 0 ꢀC, a saturated aqueous
solution of NaHCO3 (5 mL) was added, and the mixture was stirred
for 30 min and the aqueous layer was extracted with ethyl acetate
(2ꢂ20 mL). The combined organic layer was successively washed
with water (10 mL), saturated aqueous solution of NaHCO3 (5 mL),
brine (5 mL), dried over Na2SO4 and concentrated under reduced
pressure to get yellow oil. The residue was dissolved in MeOH (5 mL)
and treated with a solution of NaIO4 (0.45 g, 2.1 mmol) in water
(15 mL). The solution was stirred at room temperature for 20 min
and then extracted with EtOAc (3ꢂ30 mL). The organic fractions
were combined, washed with brine (20 mL), dried over Na2SO4 and
concentrated in vacuo. The crude material was purified by column
5 ꢀC to recover precipitated
b-cyclodextrin by filtration (95%); Rf (5%
25
EtOAc/hexane) 0.41; [
a]
D þ19.4 (c 1, CHCl3); {[
a]
2D5of compound (ꢁ)
15¼ꢁ19.1 (c 1, CHCl3)}; mp 120 ꢀC; IR (KBr): lmax 3345, 2977, 2926,
1680, 1027 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 7.46–7.51 (2H, m, Ar-
H), 7.32–7.39 (3H, m, Ar-H), 7.27 (2H, d, J¼8.6 Hz, Ar-H), 6.86 (2H, d,
J¼8.6 Hz, Ar-H), 5.48 (1H, s, PhCH(O)2), 4.46–4.57 (2H, m, benzylic
CH2), 4.38 (1H, dd, J¼4.3, 6.2 Hz, CHCH2OPMB), 3.8 (3H, s, OCH3),
3.51–3.76 (5H, m, CH2OPMB, CH2CHNH and CHNHBoc), 1.43 (9H, s,
C(CH3)3); 13C NMR (CDCl3, 50 MHz):
d 159.1,155.1,137.5,129.9,129.4,
128.9, 128.1, 126.1, 113.7, 101.1, 80.1, 73.2, 70.5, 69.7, 68.9, 67.8, 55.2,
28.2; MS (ESIMS): m/z 452 [MþNa]þ; HRMS (ESI): [MþNa]þ, found
452.2040. C24H31NO6Na requires 452.2049.
4.1.8. tert-Butyl (2S,4S,5S)-4-(hydroxymethyl)-2-phenyl-1,3-dioxan-
5-ylcarbamate (16). To a solution of 15 (400 mg, 0.93 mmol) in
CH2Cl2 (20 mL) at 0 ꢀC were added aqueous NaH2PO4/Na2HPO4
(pH 7) buffer (4 mL) and DDQ (250 mg, 1.1 mmol). The reaction was
allowed to warm to room temperature. After 2 h the reaction
mixture was filtered through a Celite pad, and layers were sepa-
rated. The aqueous layer was extracted with CH2Cl2 (2ꢂ10 mL), and
the combined organic layer was dried over Na2SO4 and concen-
trated. The residue was purified on silica gel by eluting 15% EtOAc/
chromatography (40% EtOAc/hexane) to give azide 13 (1.58 g, 83%)
25
as a pale yellow oil; Rf (30% EtOAc/hexane) 0.5; [
a]
þ18.1 (c 1,
D
CHCl3); {[
a]
2D5of compound (ꢁ)13¼ꢁ17.9 (c 1, CHCl3)}; IR (neat): lmax
3415, 2932, 2101, 1513,1082 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 7.22
(2H, d, J¼8.0 Hz, Ar-H), 6.85 (2H, d, J¼8.7 Hz, Ar-H), 4.47 (2H, s,
benzylic CH2), 3.81–3.87 (1H, m, CHaHbOPMB), 3.79 (3H, s, OCH3),
3.77–3.78 (2H, m, CHaHbOPMB and CHOH), 3.45–3.61 (3H, m,
CH2OH and CHN3), 2.92 (1H, br s, OH), 2.57 (1H, br s, OH); 13C NMR
hexane to afford alcohol 16 (265 mg, 92%) as a white solid; Rf (10%
25
(CDCl3, 50 MHz):
d
158.9, 129.1, 113.4, 72.6, 70.4, 69.6, 63.7, 61.73,
EtOAc/hexane) 0.45; mp 143 ꢀC; [
a
]
þ8.43 (c 1, CHCl3); IR (KBr):
D
54.7; MS (ESIMS): m/z 290 [MþNa]þ; HRMS (ESI): [MþNa]þ, found
lmax 3369, 3221, 3060, 2923, 1676, 1566 cmꢁ1
;
1H NMR (300 MHz,
290.1110. C12H17N3O4Na requires 290.1116.
CDCl3): 7.42–7.47 (2H, m, Ar-H), 7.29–7.35 (3H, m, Ar-H), 5.42
d
(1H, s, PhCH(O)2), 4.25–4.41 (2H, m, CHCH2OH and CHaHbCHNH),
3.70–3.94 (3H, m, CHaHbCHNH and CH2OH), 3.51–3.57 (2H, m,
CHNHBoc and NH), 1.45 (9H, s, C(CH3)3); 13C NMR (50 MHz, CDCl3):
4.1.6. (2S,4S,5S)-4-((4-Methoxybenzyloxy)methyl)-5-azido-2-phe-
nyl-1,3-dioxane (14). Benzaldehyde dimethyl acetal (0.51 g,
33 mmol) was added in one portion to a solution of diol 13 (0.9 g,
33 mmol) and PPTS (0.053 g, 0.21 mmol) in benzene (30 mL) at
room temperature. The solution was heated at reflux for 15 h, cooled
to room temperature and treated with a saturated aqueous solution
of NaHCO3 (10 mL). The two layers were separated and the aqueous
layer was extracted with EtOAc (3ꢂ30 mL). The organic layers were
combined, washed with brine (20 mL), dried over Na2SO4 and
concentrated in vacuo to give yellow oil. The crude material was
d
155.8, 137.3, 129.1, 128.1, 126.1, 101.2, 81.7, 80.5, 68.9, 62.4, 43.4,
28.1; MS (ESIMS): m/z 332 [MþNa]þ; HRMS (ESI): [MþNa]þ, found
332.1472. C16H23NO5 Na requires 332.1473.
4.1.9. tert-Butyl (2S,4R,5S)-2-phenyl-4-vinyl-1,3-dioxan-5-ylcarba-
mate (17). To a solution of oxalyl chloride (0.114 mL, 1.29 mmol) in
dry DCM (15 mL) at ꢁ78 ꢀC, DMSO (0.136 mL, 1.92 mmol) was
added dropwise with stirring under nitrogen. After stirring for
15 min, alcohol 16 (200 mg, 0.64 mmol) in dry CH2Cl2 (10 mL) was
added to the reaction mixture. After 1 h stirring at ꢁ78 ꢀC, Et3N
(0.53 mL, 3.84 mmol) was added and stirred for another 0.5 h at
ꢁ78 ꢀC and 0.5 h at 0 ꢀC. The reaction mixture was then quenched
with saturated aqueous NH4Cl solution (10 mL) and extracted with
CH2Cl2 (2ꢂ50 mL), brine (25 mL), dried on Na2SO4 and concen-
trated in vacuo. The crude compound was used in the next step
without purification.
purified by column chromatography (10% EtOAc/hexane) to give
25
azide 14 (1.1 g, 92%) as colourless oil; Rf (5% EtOAc/hexane) 0.5; [a]
D
þ17.5 (c 1, CHCl3); {[
a]
2D5of compound (ꢁ)14¼ꢁ17.4 (c 1, CHCl3)}; IR
(neat): lmax 2862, 2108, 1612, 1513, 1098 cmꢁ1; 1H NMR (400 MHz,
CDCl3):
d 7.41–7.46 (2H, m, Ar-H), 7.31–7.37 (3H, m, Ar-H), 7.24 (2H,
d, J¼8.7 Hz, Ar-H), 6.83 (2H, d, J¼8.7 Hz, Ar-H), 5.41 (1H, s,
PhCH(O)2), 4.54 (2H, dd, J¼10.9, 19.0 Hz, benzylic CH2), 4.36 (1H, dd,
J¼5.1,10.9 Hz, CHCH2OPMB), 3.66–3.68 (7H, m, CH2OPMB, OCH3 and
CH2CHN3), 3.60 (1H, m, CHN3); 13C NMR (CDCl3, 50 MHz):
d
159.1,
To methyltriphenylphosphonium iodide (2.58 g, 6.4 mmol) in
dry THF (50 mL) under a nitrogen atmosphere at ꢁ78 ꢀC was added
137.1, 129.7, 129.1, 128.8, 128.0, 125.9, 113.5, 101.1, 79.6, 72.9, 68.9,

10706
R. Sridhar et al. / Tetrahedron 65 (2009) 10701–10708
t-BuOK (0.53 g, 7.3 mmol) and stirred for 30 min at room temper-
ature. Then the orange yellow ylide solution was added to the above
crude aldehyde in dry THF (5 mL) via a cannula and stirring was
continued for 1 h, allowing the temperature to warm to 0 ꢀC. The
reaction mixture was quenched with saturated aqueous NH4Cl
solution (15 mL). The mixture was filtered over a sintered funnel
and the residue was washed with ether (3ꢂ15 mL). The combined
organic filtrates were evaporated after washing with water (25 mL),
drying over anhydrous Na2SO4, and concentrated in vacuo. Purifi-
cation by column chromatography (8% EtOAc in petroleum ether
(CDCl3, 50 MHz): d 171.0, 170.0, 169.6, 137.5, 124.1, 73.8, 62.5, 60.4,
50.6, 32.2, 31.9, 29.7, 29.6, 29.4, 29.3, 29.1, 28.9, 23.3, 22.6, 21.1, 20.7,
14.1; MS (ESIMS): m/z 448 [MþNa]þ; HRMS (ESI): [MþNa]þ, found
448.3032. C24H43NO5Na requires 448.3038.
4.1.12. tert-Butyl (2R,4R,5S)-4-((4-methoxybenzyloxy)methyl)-2-phe-
nyl-1,3-dioxan-5-ylallyl carbamate (20). A round-bottom flask was
charged with a 60% dispersion of sodium hydride in mineral oil
(0.049 g, 1.2 mmol) and THF (10 mL) under nitrogen atmosphere
and the resulting cloudy white suspension was cooled to 0 ꢀC. A
solution of carbamate (-) 15 (0.44 g, 1 mmol) in THF (10 mL) was
added via syringe, followed by allyl bromide(0.1 mL, 1.2 mmol), 18-
crown-6-ether (0.05 g, 0.2 mmol) and the resulting mixture was
stirred at room temperature for 3 h. The mixture was quenched with
saturated NH4Cl (5 mL) and the whole mixture was extracted with
ethyl acetate (3ꢂ25 mL). The combined organic layers were washed
with brine (5 mL), dried over Na2SO4, and concentrated under re-
duced pressure. The residue thus obtained was purified by column
eluent) afforded 17 (167 mg, 85%) as a light yellow solid; Rf (5%
25
EtOAc/hexane) 0.55; [
a]
þ28.1 (c 1, CHCl3); mp 92 ꢀC; IR (KBr):
D
lmax 3353, 2977, 2928, 2858, 1685, 1529 cmꢁ1 1H NMR (300 MHz,
;
CDCl3):
d 7.43–7.49 (2H, m, Ar-H), 7.29–7.36 (3H, m, Ar-H), 5.86–
5.99 (1H, m, CH2]CH), 5.46 (1H, s, PhCH(O)2), 5.4 (1H, d, J¼17.3 Hz,
CHaHb]CH), 5.28 (1H, d, J¼10.1 Hz, CHaHb]CH), 4.21–4.38 (2H, m,
C]CHCH and CHaHbCHNH), 3.93–4.04 (1H, m, CHaHbCHNH), 3.48–
3.72 (2H, m, CHNHBoc and NH), 1.43 (9H, s, C(CH3)3); 13C NMR
(50 MHz, CDCl3):
d
154.9, 137.4, 134.1, 128.9, 128.2, 126.1, 118.9,
chromatography (7% EtOAc/hexane) to give 20 (0.45 g, 94%) as yel-
100.1, 82.1, 69.9, 60.3, 43.1, 28.3; MS (ESIMS): m/z 328 [MþNa]þ;
HRMS (ESI): [MþNa]þ, found 328.1531. C17H23NO4Na requires
328.1524.
low oil; Rf (5% EtOAc/hexane) 0.5; [
a
]
D ꢁ33.5 (c 1, CHCl3); IR (neat):
25
lmax 2973, 2931, 1693, 1612, 1152 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d
7.44 (2H, d, J¼6.5 Hz, Ar-H), 7.28–7.33 (3H, m, Ar-H), 7.21 (2H, d,
J¼8.0 Hz, Ar-H), 6.81 (2H, d, J¼8.0 Hz, Ar-H), 5.67–5.83 (1H, s,
PhCH(O)2), 5.39–5.46 (1H, m, CH]CH2), 5.05–5.21 (2H, m,
CH]CH2), 4.42–4.67 (2H, m, benzylic CH2), 3.87–4.11 (3H, m,
CHCH2O and CH2OPMB), 3.77 (3H, s, OCH3), 3.53–3.69 (5H,
m, CH2CHN, CH2N and CHNBoc), 1.45 (9H, s, C(CH3)3); 13C NMR
4.1.10. tert-Butyl (2S,4R,5S)-4-((E)-pentadec-1-enyl)-2-phenyl-1,3-
dioxan-5-yl carbamate (18). Compound 17 (0.580 mg, 0.26 mmol)
and 1-pentadecene (220 mg, 1.04 mmol) were dissolved in CH2Cl2
(25 mL) at room temperature. Grubbs II generation catalyst
(10 mol %) was added to the solution and then the reaction mixture
was refluxed under nitrogen for 14 h. After cooling the reaction
mixture it was concentrated and purified by column chromatog-
(50 MHz, CDCl3): d 159.1,154.6,134.4,131.6,129.2,128.7,128.1,126.1,
117.1, 113.6, 101.0, 78.2, 73.1, 69.5, 67.87, 67.81, 57.1, 55.4, 55.1, 28.2;
MS (ESIMS): m/z 492 [MþNa]þ; HRMS (ESI): [MþNa]þ, found
492.2355. C27H35NO6Na requires 492.2362.
raphy with hexane:ethyl acetate (4:1) to afford compound 18
25
(120 mg, 94%) as a white solid; Rf (5% EtOAc/hexane) 0.45; [a]
D
þ10.7 (c 1, CHCl3); mp 88 ꢀC; IR (KBr): lmax 3354, 2923, 2853, 1686,
4.1.13. tert-Butylallyl (2R,4R,5S)-4-(hydroxymethyl)-2-phenyl-1,3-di-
oxan- 5-yl carbamate (21). To a solution of 20 (418 mg, 0.89 mmol)
in CH2Cl2 (20 mL) at 0 ꢀC were added aqueous NaH2PO4/Na2HPO4
(pH 7) buffer (4 mL) and DDQ (242 mg, 1 mmol). The reaction was
allowed to warm to room temperature. After 2 h the reaction mix-
ture was filtered through a Celite pad, and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (2ꢂ10 mL), and the
combined organic layer was dried over Na2SO4 and concentrated.
The residue was purified on silica gel by eluting with 15% EtOAc/
1021 cmꢁ1 1H NMR (300 MHz, CDCl3):
; d 7.46–7.53 (2H, m, Ar-H),
7.31–7.41 (3H, m, Ar-H), 5.78–5.91 (1H, m, CH]CH), 5.47–5.61 (2H,
m, PhCH(O)2 and CH]CH), 4.19–4.35 (2H, m, OCHCH and
CHaHbCHNH), 3.91–4.02 (1H, m, CHaHbCHNH), 3.49–3.79 (2H, m,
CHNHBoc and NH), 1.98–2.13 (2H, m, CH2CH]CH), 1.16–1.66 (31H,
m, C(CH3)3 and CH3(CH2)11), 0.87 (3H, t, J¼6.7 Hz, CH2CH3); 13C
NMR (50 MHz, CDCl3): d 154.9, 137.6,136.9,128.9,128.2,126.2,101.1,
82.3, 69.9, 60.3, 47.7, 32.3, 31.8, 29.6, 29.5, 29.4, 29.3, 29.2, 28.8,
28.2, 22.6, 14.1; MS (ESIMS): m/z 510 [MþNa]þ; HRMS (ESI):
[MþNa]þ, found 510.3540. C30H49NO4Na requires 510.3559.
hexane to afford alcohol 21 (295 mg, 95%) as a white solid; Rf (10%
25
EtOAc/hexane) 0.45; [
a]
ꢁ32.1 (c 1, CHCl3); mp 120 ꢀC; IR (KBr):
D
lmax 3519, 2977, 1689, 1132 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
4.1.11. (2S,3R,4E)-1,3-Diacetoxy-2-acetamido-octadec-4-ene [N,O,O-
triacetyl sphingosine] (19). To a solution of 18 (80 mg, 0.16 mmol) in
MeOH (6 mL) was added 6 N HCl. The reaction mixture was stirred
at room temperature for overnight. The solvent was evaporated
under reduced pressure. The residue was dissolved in pyridine
(10 mL) and Ac2O (0.1 mL excess) and DMAP (2 mg) were added
sequentially. The reaction mixture was stirred for 10 h and
quenched with H2O (3 mL). The reaction mixture diluted with H2O
(8 mL) and Et2O (10 mL) and the layers were separated. The aque-
ous layer was extracted with Et2O (2ꢂ10 mL), and the combined
organic layers were washed sequentially with satd aq CuSO4
(2ꢂ5 mL), H2O (10 mL) and brine (5 mL), dried over Na2SO4 and
concentrated. The residue was purified on silica gel by eluting with
15% EtOAc/hexane to afford 19 (64 mg, 92%) as a white solid;Rf (10%
d 7.42–7.47 (2H, m, Ar-H), 7.31–7.37 (3H, m, Ar-H), 5.75–5.89 (1H, s,
PhCH(O)2), 5.43–5.59 (1H, m, CH]CH2), 5.14–5.31 (2H, m, CH]CH2),
4.07–4.49 (3H, m, CHCH2OH and CH2OH), 3.59–3.98 (5H, m, CH2CHN,
CH2N, CHNBoc), 1.47 (9H, s, C(CH3)3); 13C NMR (50 MHz, CDCl3):
d
155.9, 134.5, 129.1, 128.2, 126.1, 117.19, 101.1, 78.2, 73.1, 67.8, 67.2,
62.1, 55.4, 28.2; MS (ESIMS): m/z 372 [MþNa]þ; HRMS (ESI):
[MþNa]þ, found 372.1798. C19H27NO5Na requires 372.1786.
4.1.14. tert-Butyl (2R,4S,5S)-4-((E)-2-(ethoxycarbonyl)vinyl)-2-phe-
nyl-1,3-dioxan-5-ylallyl carbamate (22). To a solution of oxalyl
chloride (0.137 mL,1.54 mmol) in dry DCM (15 mL) at ꢁ78 ꢀC, DMSO
(0.164 mL, 2.32 mmol) was added dropwise with stirring under ni-
trogen. After stirring for 15 min, alcohol 21 (270 mg, 0.77 mmol) in
dry DCM (10 mL) was added to the reaction mixture. After 1 h
stirring at ꢁ78 ꢀC, Et3N (0.64 mL, 4.62 mmol) was added and stirred
for another 0.5 h at ꢁ78 ꢀC and 0.5 h at 0 ꢀC. The reaction mixture
was then quenched with saturated aqueous NH4Cl solution (10 mL)
and extracted with CH2Cl2 (2ꢂ50 mL), brine (25 mL), dried on
Na2SO4 and concentrated in vacuo. The crude compound thus
obtained was used in the next step without further purification.
To a stirred solution of LiBr in dry THF under nitrogen atmo-
sphere, at room temperature, was added triethylphosphonoacetate
25
24
EtOAc/hexane) 0.45; [
a
]
ꢁ12.1 (c1, CHCl3); [lit.21b
[
a
]
ꢁ13.0
D
D
(c1.6 CHCl3)]; mp 99–101 ꢀC; IR (KBr):lmax 3288, 2919, 2850, 1734,
1653, 1548, 1230 cmꢁ1 1H NMR (300 MHz, CDCl3):
; d5.79 (1H,
dd,J¼15.3, 6.6 Hz, C(5)H), 5.65 (1H, d, J¼8.8 Hz, NH), 5.39 (1H, dd,
J¼15.3, 7.9 Hz, C(4)H), 5.25–5.29 (1H, m, C(3)H), 4.39–4.47 (1H, m,
C(2)H), 4.30 (1H, dd, J¼11.7, 5.9 Hz, C(1)Hb), 4.04 (1H, dd, J¼11.7,
4.4 Hz, C(1)Ha), 1.95–2.13 (11H, m, 3X COCH3, C(6)H2), 1.17–1.41
(22H, m, C(7)-C(17)H2), 0.88 (3H, t, J¼6.6 Hz, C(18)H3); 13C NMR

R. Sridhar et al. / Tetrahedron 65 (2009) 10701–10708
10707
(0.184 mL, 0.92 mmol), DBU (117 mg, 0.77 mmol) and finally alde-
hyde dissolved in THF (10 mL). After 1 h stirring saturated NH4Cl
(5 mL) was added and the whole mixture was extracted with ethyl
acetate (3ꢂ25 mL). The combined organic layers were washed with
brine (5 mL), dried over Na2SO4, and concentrated under reduced
pressure. The residue obtained was purified by column chroma-
water and 5% NH4OH as eluent to yield 7 (37 mg, 89%) as a white
25
25
solid; Rf (MeOH) 0.2; mp 163 ꢀC; [
a
]
D þ35.1 (c 1, MeOH), [lit.26
[a]
D
þ36.2 (c 0.83 MeOH)]; IR (neat): lmax 3448, 2924, 2855, 1626, 1379,
1036, 763, 613 cmꢁ1 1H NMR (300 MHz, CDCl3):
; d 4.0 (1H, br s,
NCHCHCH), 3.71 (1H, dd, J¼2.9, 11.7 Hz, NCHCH), 3.52–3.63 (2H, m,
NCH2CH and CHaHbOH), 3.38 (1H, dd, J¼10.3, 2.9 Hz, CHaHbOH),
2.75 (1H, dd, J¼12.5, 5.1 Hz, NCHaHe), 2.55–2.67 (2H, m, NCH,
tography (10% EtOAc/hexane) to give the ester 22 (302 mg, 94%) as
25
a colourless liquid; Rf (5% EtOAc/hexane) 0.47; [
a
]
ꢁ62.1 (c 1,
NCHaHe); 13C NMR (50 MHz, CDCl3):
d 72.3, 69.5, 69.0, 62.2, 55.3,
D
CHCl3); IR (neat): lmax 2977, 2930, 1721, 1694, 1149, 1025 cmꢁ1; 1H
NMR (200 MHz, CDCl3): 7.27–7.48 (5H, m, Ar-H), 6.92 (1H, dd,
44.5; MS (ESIMS): m/z 164 [MþH]þ; HRMS (ESI): [MþH]þ, found
d
164.0925. C6H13NO4 requires 164.0922.
J¼15.8, 10.7 Hz, CH]CHCO), 6.08 (1H, d, J¼15.8 Hz, CH]CHCO),
5.39–5.93 (2H, m, PhCH(O)2 and CH]CH2), 5.11–5.34 (2H, m,
CH]CH2), 4.37–4.51 (1H, m, CH]CHCH), 4.01–4.25 (5H, m,
CH2CHN, CH2N, CHNBoc), 3.57–3.96 (2H, m, OCH2), 1.47 (9H, s,
C(CH3)3), 1.29 (3H, t, J¼6.98 Hz, CH2CH3); 13C NMR (50 MHz, CDCl3):
Acknowledgements
We thank CSIR, New Delhi, India, for fellowships to R.S and B.S.
d
165.9, 154.5, 143.4, 134.1, 128.9, 128.8, 128.2, 125.9, 122.4, 117.6,
100.7, 78.2, 77.4, 68.2, 67.1, 60.4, 55.4, 28.3, 14.1; MS (ESIMS): m/z
440 [MþNa]þ; HRMS (ESI): [MþNa]þ, found 440.2042.
C23H31NO6Na requires 440.2049.
References and notes
1. Sasaki, M.; Tanino, K.; Hirai, A.; Miyashita, M. Org. Lett. 2003, 5, 1789.
2. (a) Tomata, Y.; Sasaki, M.; Tanino, K.; Miyashita, M. Tetrahedron Lett. 2003, 44,
8975; (b) Rogers, E. W.; Molinski, T. F. Org. Lett. 2007, 9, 437.
4.1.15. (2R,4aS,8aS)-tert-Butyl4,4a-dihydro-2-phenyl-6H-[1,3]diox-
3. (a) Riethmuller, J.; Riehle, A.; Grassme, H.; Gulbins, E. Biochim. Biophys. Acta
2006, 1758, 2139; (b) Snook, C. F.; Jones, J. A.; Hannun, Y. A. Biochim. Biophys.
Acta 2006, 1761, 927.
4. (a) Kester, M.; Kolesnick, R. Pharm. Res. 2003, 47, 365; (b) Rosen, H.; Liao, J. Curr.
Opin. Chem. Biol. 2003, 7, 461; (c) Summers, S. A.; Nelson, D. H. Diabetes 2005,
54, 591; (d) Modrak, D. E.; Gold, D. V.; Goldenberg, D. M. Mol. Cancer Ther. 2006,
5, 200; (e) Zhou, S.; Zhou, H.; Walian, P. J.; Jap, B. K. Biochemistry 2007, 46, 2553;
(f) Kolter, T.; Sandhoff, K. Biochim. Biophys. Acta 2006, 1758, 2057.
5. (a) Karlsson, K. A. Trends Pharmacol. Sci. 1991, 12, 265; (b) Hannun, Y.; Bell, R. M.
Science 1989, 243, 500; (c) Hannun, Y. Science 1996, 274, 1855; (d) Kolter, T.;
Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38, 1532; (e) Sawatzki, P.; Kolter, T. Eur.
J. Org. Chem. 2004, 3693.
6. (a) Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998, 1075; (b) Howell, A. R.;
Ndakala, A. J. Curr. Org. Chem. 2002, 6, 365.
ino[5,4–b]pyridine-5
(8aH)-carboxylate
(23). Bis-(tricyclohex-
ylphospine)benzylideneruthenium (IV) chloride (Grubbs’ catalyst)
(5 mg, 10 mol %) was added to a solution of 22 (250 mg, 0.6 mmol)
in toluene (300 mL) and the mixture was stirred for 2 h at 90 ꢀC.
The solvent was evaporated under reduced pressure and the resi-
due obtained was purified by chromatography (20% EtOAc/hexane)
to afford 23 (175 mg, 92%) as a black solid; Rf (15% EtOAc/hexane)
25
0.44; mp 89 ꢀC; [
a]
þ16.5 (c 1, CHCl3); IR (KBr): lmax 3043, 2974,
D
2877, 1704, 1240 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 7.43–7.47 (2H,
m, Ar-H), 7.29–7.35 (3H, m, Ar-H), 5.72–5.85 (2H, m, CH]CH), 5.57
(1H, s, PhCH(O)2), 4.73 (1H, dd, J¼4.8, 6.4 Hz, C]CHCH), 4.49 (1H,
apparent t, J¼11.2, 10.4 Hz, CHaHbCHN), 4.2–4.34 (2H, m, CHaHbCHN
and CHNBoc), 3.68 (1H, dd, J¼2.4, 16.1 Hz, CHaHbN), 3.17–3.25 (1H,
7. (a) Chun, J.; Lee, G.; Byun, H.-P.; Bittman, R. Tetrahedron Lett. 2002, 43, 375; (b)
Yadav, J. S.; Geetha, V.; Raju, A. K.; Gnaneshwar, D.; Chandrasekhar, S. Tetra-
hedron Lett. 2003, 44, 2983; (c) Lombardo, M.; Capdevila, M. G.; Pasi, F.;
Trombini, C. Org. Lett. 2006, 8, 3303; (d) Lee, J.-M.; Lim, H.-S.; Chung, S.-K.
Tetrahedron: Asymmetry 2002, 13, 343.
m, CHaHbN),1.47 (9H, s, C(CH3)3); 13C NMR (50 MHz, CDCl3):
d 154.2,
8. (a) Luo, S.-Y.; Thopate, S. R.; Hsu, C.-Y.; Hung, S.-C. Tetrahedron Lett. 2002, 23,
4889; (b) Chaudhari, V. D.; Kumar, K. S. A.; Dhavale, D. D. Org. Lett. 2005, 7,
5805; (c) Lin, C.-C.; Fan, G.-T.; Fan, J.-M. Tetrahedron Lett. 2003, 44, 5281; (d)
Chiu, H.-Y.; Tzou, D.-L. M.; Patkar, L. N.; Lin, C.-C. J. Org. Chem. 2003, 68, 5788; (e)
Plettenburg, O.; Bodmer-Narkevich, V.; Wong, C.-H. J. Org. Chem. 2002, 67, 4559.
9. (a) Llaveria, J.; Diaz, Y.; Isabel Matheu, M.; Castillon, S. Org. Lett. 2009, 11, 205;
(b) Yoon, H. J.; Kim, Y.-W.; Lee, B. K.; Lee, W. K.; Kim, Y.; Ha, Y.-J. Chem. Commun.
2007, 79; (c) Righi, G.; Ciambrone, S.; D’Achille, C.; Leonelli, A.; Bonini, C. Tet-
rahedron 2006, 62, 11821; (d) Enders, D.; Palecek, J.; Grondal, C. Chem. Commun.
2006, 655; (e) He, L.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2000, 65, 7618; (f)
Cai, Y.; Ling, C.-C.; Bundle, D. R. Org. Biomol. Chem. 2006, 4, 1140.
137.6,128.9,128.2,127.1,126.1, 101.4, 80.6, 75.2, 70.1, 55.1, 45.9, 28.3;
MS (ESIMS): m/z 340 [MþNa]þ; HRMS (ESI): [MþNa]þ, found
340.1529. C18H23NO4Na requires 340.1524.
4.1.16. (2R,4aS,7S,8S,8aR)-tert-Butylhexahydro-7,8-dihydroxy-2-
phenyl-[1,3] dioxino [5,4-b] pyridine-5-carboxylate (24). To a solu-
tion of compound 23 (150 mg, 0.47 mmol) in acetone (2 mL) was
added aqueous 4% OsO4 (65 m
L, 0.01 mmol) solution at 0 ꢀC. After
10. Paulsen, H. Iminosugars as Glycosidase Inhibitors; Wiley-VCH: Germany, 2004; p.1.
11. (a) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497; (b) Legler, G. Adv. Carbohydr.
Chem. Biochem. 1990, 48, 319.
12. (a) Wrodnigg, T. M.; Steiner, A. J.; Ueberbacher, B. J. Anti- Cancer Agents Med.
Chem. 2008, 8, 77; (b) Yoshikuni, Y.; Ezure, Y.; Seto, T.; Mori, K.; Watanabe, M.;
Enomoto, H. Chem. Pharm. Bull. 1989, 37, 106; (c) Kimura, M.; Chen, F.-J.;
Nakashima, N.; Kimura, I.; Asano, N.; Koya, S. J. Trad. Med. 1995, 12, 214; (d)
Robina, I.; Moreno-Vargas, A. J.; Carmona, A. T.; Vogel, P. Curr. Drug Metab. 2004,
5, 329; (e) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100, 4683;
(f) Fan, J.-Q. Trends Pharmacol. Sci. 2003, 24, 355.
13. (a) Bols, M. Acc. Chem. Res. 1998, 31, 1; (b) Iminosugars as Glycosidase Inhibitors.
Nojirimycin and Beyond; Stutz, A. E., Ed.; Wiley-VCH: Weinheim, Germany, 1999.
14. For recent publications see: (a) Racine, E.; Bello, C.; Lemaire, S. G.; Vogel, P.;
Sandrine, P. J. Org. Chem. 2009, 74, 1766; (b) Song, X.; Hollingsworth, R. I. Tet-
rahedron Lett. 2007, 48, 3115; (c) Takahata, H.; Banba, Y.; Sasatani, M.; Nemoto,
H.; Kato, A.; Adachi, I. Tetrahedron 2004, 60, 8199; (d) Saha, N. N.; Desai, V. N.;
Dhavale, D. D. Tetrahedron 2001, 57, 39; (e) Comins, D. L.; Fulp, A. B. Tetrahedron
Lett. 2001, 42, 6839; (f) Yokoyama, H.; Otaya, K.; Kobayashi, H.; Miyazawa, M.;
Yamaguchi, S.; Hirai, Y. Org. Lett. 2000, 2, 2427.
15. Asano, N.; Oseki, K.; Kizu, H.; Matsui, K. J. Med. Chem. 1994, 37, 3701.
16. Previous synthesis of allo-DNJ. (a) Guaragna, A.; D’Errico, S.; D’Alonzo, D.;
Pedatella, S.; Palumbo, G. Org. Lett. 2007, 9, 3473; (b) Hong, B.-C.; Chen, Z.-Y.;
Nagarajan, A.; Kottani, R.; Chavan, V.; Chen, W.-H.; Jiang, Y.-F.; Zhang, S.-C.;
Liao, J.-H.; Sarshar, S. Carbohydr. Res. 2005, 340, 2457; (c) Kato, A.; Kato, N.;
Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamato, T.; Banba, Y.; Ouchi, H.; Takahata,
H.; Asano, N. J. Med. Chem. 2005, 48, 2036; (d) Singh, O. V.; Han, H. Tetrahedron
Lett. 2003, 44, 2387; (e) Asano, K.; Hakogi, T.; Iwama, S.; Katsumura, S. Chem.
Commun. 1999, 41.
10 min, aqueous 50% NMO solution (0.23 mL, 1.41 mmol) was
added and the mixture was stirred overnight at the same temper-
ature. To the reaction mixture Na2SO3 and Na2SO4 were added, it
was filtered through a pad of Celite and the solvent was evaporated.
The residue was purified by column chromatography (50% EtOAc/
hexane) to afford the diol 24 (142 mg, 86%) as a colourless liquid; Rf
25
(40% EtOAc/hexane) 0.52; [
a
;
]
þ4.4 (c 1, CHCl3); IR (neat): lmax
D
3427, 2923, 1694, 1163 cmꢁ1
1H NMR (400 MHz, CDCl3):
d 7.43–
7.47 (2H, m, Ar-H), 7.32–7.37 (3H, m, Ar-H), 5.58 (1H, s, PhCH(O)2),
4.74 (1H, dd, J¼4.3, 7.3 Hz, CHCHN), 4.48 (1H, apparent t, J¼11.7,
10.9 Hz, CHaHbCHN), 4.15 (1H, br s, CHaHbCHN), 4.01 (1H, dd, 5.1,
8.0 Hz, CHNBoc), 3.58–3.67 (2H, m, 2X CHOH), 3.45–3.53 (1H, m,
CHaHbN), 2.88 (1H, t, J¼12.4, 11.7 Hz, CHaHbN), 2.8 (1H, br s, OH),
2.71 (1H, br s, OH), 1.45 (9H, s, C(CH3)3); 13C NMR (50 MHz, CDCl3):
d
154.2, 137.3, 129.1, 128.2, 126.1, 101.3, 80.7, 77.7, 69.8, 69.2, 66.7,
50.1, 46.9, 28.3; MS (ESIMS): m/z 374 [MþNa]þ; HRMS (ESI):
[MþNa]þ, found 374.1576. C18H25NO6Na requires 374.1579.
4.1.17. D-1-Deoxyallonojirimycin (7). To a solution of 24 (90 mg,
0.25 mmol) in MeOH (6 mL) was added 6 N HCl (5 mL) and the
reaction mixture was stirred at room temperature overnight. The
solvent was evaporated under reduced pressure. The residue was
treated with Dowex 50wX8 ion-exchange resin using a sequence of
17. (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. J. Am. Chem. Soc.
1989, 111, 5335; (b) Millar, J. G.; Oehlschlager, A. C. J. Org. Chem. 1984, 49, 2332.

10708
R. Sridhar et al. / Tetrahedron 65 (2009) 10701–10708
18. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974; (b) Pfenninger,
A. Synthesis 1986, 89; (c) Baker, S. R.; Boot, J. R.; Molgan, S. E.; Osborne, D. T.;
Ross, W. J.; Shrubsall, P. R. Tetrahedron Lett. 1983, 24, 4469.
19. Hayes, C. J.; Sherlock, A. E.; Green, M. P.; Wilson, C.; Blake, A. J.; Selby, M. D.;
Prodger, J. C. J. Org. Chem. 2008, 73, 2041.
20. Reddy, M. S.; Narender, M.; Nageswar, Y. V. D.; Rao, K. R. Synlett 2006, 1110.
21. (a) Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith,
A. D. Org. Biomol. Chem. 2008, 6, 1655; (b) Disadee, W.; Ishikawa, T. J. Org. Chem.
2005, 70, 9399; (c) Findeis, M. A.; Whitesides, G. M. J. Org. Chem. 1987, 52, 2838.
22. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush,
W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
23. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413; (b) Furstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3013; (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18; (d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4490; (e) Bhasker, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915.
24. (a) Ghosh, S.; Shashidar, J.; Kumar Dutta, S. Tetrahedron Lett. 2006, 47, 6041; (b)
Cha, J. K.; Kim, N.-S. Chem. Rev. 1995, 95, 1761; (c) Cha, J. K.; Christ, W. J.; Kishi, Y.
Tetrahedron Lett. 1983, 24, 3943.
25. Guaragna, A.; D’Alonzo, D.; Paolella, C.; Palumbo, G. Tetrahedron Lett. 2009, 50,
2045.
26. Takemura, A.; Fujiwara, K.; Shimawaki, K.; Murai, A.; Kawai, H.; Suzuki, T.
Tetrahedron 2005, 61, 7392.