Asymmetric total syntheses of spisulosine, its diastereo- and regio-isomers

Article abstract of DOI:10.1016/j.tet.2010.09.018

Starting from palmityl alcohol, divergent stereoselective syntheses of spisulosine and its diastereo- and regio-isomers have been achieved. In the Sharpless asymmetric dihydroxylation-based approach, the key step is the synthesis of monoprotected diol, whereas Miyashita's boron-directed C-2 regioselective azidolysis of enantiomerically pure epoxy alcohol is the vital step in the Sharpless asymmetric epoxidation-based route. The latter approach involves the first protecting-group-free synthesis of spisulosine.

Full text of DOI:10.1016/j.tet.2010.09.018

Tetrahedron 66 (2010) 9304e9309
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric total syntheses of spisulosine, its diastereo- and regio-isomers
*
Subal Kumar Dinda, Sajal Kumar Das, Gautam Panda
Medicinal and Process Chemistry Division, Central Drug Research Institute (CSIR), M.G. Marg, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 March 2010
Received in revised form 2 September 2010
Accepted 3 September 2010
Available online 22 September 2010
Starting from palmityl alcohol, divergent stereoselective syntheses of spisulosine and its diastereo- and
regio-isomers have been achieved. In the Sharpless asymmetric dihydroxylation-based approach, the key
step is the synthesis of monoprotected diol, whereas Miyashita’s boron-directed C-2 regioselective azi-
dolysis of enantiomerically pure epoxy alcohol is the vital step in the Sharpless asymmetric epoxidation-
based route. The latter approach involves the first protecting-group-free synthesis of spisulosine.
Ó 2010 Published by Elsevier Ltd.
1. Introduction
syn-diastereomer dates back to 1957 when Croatian researchers
synthesized these two molecules for the first time in the de-
Long-chain 2-amino-3-alkanols, which are commonly found in
tunicates and some sponges, comprise an important class of bio-
active molecules. The structures are generally related to the widely
distributed amphiphilic sphingosines and their carbon-chain length
varies from C12 to C30 and their polyunsaturated variants have also
been reported. Ascidians from Pseudodistoma and Clavelina genera
have been prolific in the production of 2-amino-3-alkanols. Exam-
ples are crucigasterins 277, 275, and 225,1 obscuraminols AeF,2
clavaminols AeF,3 and (2S,3R)-2-aminododecan-3-ol.4 Researchers
from PharmaMar reported an initial studies with a molecule known
as ES-285 or spisulosine 1 (Fig. 1), isolated from the marine clam
Spisula polynyma.5 This compound caused a loss of actin stress fi-
termination of absolute configurations of lipid bases with two or
more asymmetric carbon atoms.8a In this context it is important to
mention that in the above synthesis, 1 was known as a purely
synthetic molecule as its isolation as a natural product became
known afterwards.5 In recent time, efficient synthesis of spisulosine
1 and related compounds were achieved by a diastereoselective
addition reaction of appropriate long alkyl chain Grignard reagents
on L
-alanine derived N-protected amino aldehyde derivative.9 Lee
and co-workers reported asymmetric synthesis of N-Boc-spisulo-
sine from an enantiomerically pure 2-acylaziridine derivative.8b
Very recently, Galvez and co-workers reported asymmetric syn-
thesis of the hydrochloride salt of spisulosine from D
-mannitol.8c
bers5 and inhibited cell proliferation with an IC50 of 1
prostate tumor PC-3 and LNCaP cell lines.6
m
M in the
Another recent report of synthesis of 1 involved the stereo-
selective addition of a racemic 3-alkoxy allenylzinc to enantiopure
N-tert-butylsulfinyl imines and a cross-metathesis reaction as the
key steps.8d In this paper, we report a divergent stereoselective and
first protecting group-free syntheses of spisulosine 1 and its dia-
stereo- and regio-isomers employing Sharpless asymmetric dihy-
droxylation and epoxidation reactions as the source of chirality.
OH
n-C15H31
NH2
Spisulosine 1
2. Results and discussion
Fig. 1. Structure of spisulosine.
Our envisioned retrosynthetic analysis for the enantioselective
preparation of spisulosine is depicted in Scheme 1. The target
molecule 1 was anticipated to be accesible from monoprotected
diol 2, which, in turn, could be derived from epoxy alcohol 3. Allylic
chloride 4, which could be derived from alcohol 5.
On the basis of the above retrosynthetic analysis, the first target
for the synthesis of 1 was to synthesize enantiomerically pure ep-
oxy alcohol 3. Our synthesis of 1 started with commercially avail-
able palmityl alcohol 5 (Scheme 2). Swern oxidation of 5 provided
1-hexadecanal, which was used directly in the subsequent Wittig
The promising anticancer agent spisulosine is currently in
clinical trial.7 Consequently, a practical route providing the title
compound should be highly desirable. However, despite its struc-
tural simplicity, spisulosine 1 has been less encountered in terms of
its total synthesis.8,9 The chemistry of 1 and the corresponding
* Corresponding author. E-mail addresses: gautam.panda@gmail.com, gau-
tam_panda@cdri.res.in (G. Panda).
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.09.018

S.K. Dinda et al. / Tetrahedron 66 (2010) 9304e9309
9305
OH
furnished spisulosine 1. The physical and spectral data of 1 were in
agreement with the literature data.9 Thus, spisulosine 1 was syn-
thesized from commercially available palmityl alcohol in 12 steps
and 22.5% overall yield. However, the above synthetic route re-
quired a protecting group.
OP
1
R
Cl
R
R
R
O
2
OH
OH
3
4
R= n-C15H31
5
In an alternative way, we decided to synthesize spisulosine 1
without using any protecting group. Total synthesis of natural or
synthetic biologically important molecules employing a protecting
group-free strategy has been an important challenge in organic
chemistry.13 Our envisioned retrosynthetic analysis for the pro-
tecting group-free enantioselective preparation of spisulosine is
depicted in Scheme 4.
Scheme 1. Retrosynthetic analysis of spisulosine 1.
reaction without further purification to avoid decomposition. Thus,
reaction of the above crude aldehyde with Ph3P]CHCO2Et in dry
CH2Cl2 furnished the desired trans-
yield (80% from 5). Next, DIBAL-H reduction of 6 in dry toluene
furnished the corresponding trans- -unsaturated alcohol 7 in
a,b-unsaturated ester 6 in high
a,b
OH
OH
excellent yield. Compound 7 was then converted into allylic chlo-
ride 4 in 94% yield. Compound 4 was then subjected to Sharpless
OH
R
OH
R
OTs
R
asymmetric dihydroxylation10 with AD mix in tBuOH-H2O (1:1) at
b
N3
12
N3
NH2
0 ꢀC for 24 h furnishing dihydroxyl derivatives 8 in good yield. It is
important to mention that the reaction was carried out under
‘buffered’ conditions (with 3 equiv of NaHCO3) to minimize the
epoxide formation.11,12 Next, treatment of diol 8 with powdered
NaOH in THF at 0 ꢀC afforded the epoxide 3 in good yield.
1
11
OH
CO2Et
R= n-C15H31
R
R
O
13
6
Scheme 4. Protecting group-free retrosynthetic analysis of spisulosine 1.
The target molecule 1 was anticipated to be prepared by one-pot
reduction of azido tosylate 11, which, in turn, could be derived from
azido diol 12. The compound 12 could be obtained from epoxy al-
cohol 13 by the trialkyl borate mediated C-2 selective azidolysis
under Miyashita’s condition.14 Although Miyashita’s pioneering C-2
selective nucleophilic substitution reactions including the azidol-
ysis have been utilized for natural product synthesis,15 it has never
been employed in protecting-group-free synthesis of a target
molecule.
a
CO2Et
OH
b
n-C16H33OH
R
R
e
OH
O
7
6
5
OH
d
c
R
Cl
R
Cl
R
OH
4
8
3
R= n-C15H31
Scheme 2. Reagents and conditions: (a) (i) (COCl)2, DMSO, anhyd. Et3N, CH2Cl2,
ꢁ78 ꢀC, 2 h (ii) Ph3P]CHCO2Et, CH2Cl2, 8 h, 80% (for two steps). (b) DIBAL-H (1 M in
We started by Sharpless asymmetric epoxidation16 of 7 with
toluene), toluene, 0 ꢀC-rt, 1 h, 95%. (c) NCS, PPh3, CH2Cl2, 0 ꢀC-rt, 3 h, 94%. (d) AD mix
b,
D-(ꢁ)-diethyl tartrate to get epoxy alcohol 13 in 85% yield, which
MeSO2NH2, NaHCO3, tBuOH-H2O (1:1), 0 ꢀC, 24 h, 88%. (e) NaOH, THF, 0 ꢀC-rt, 3 h, 92%.
showed >98% ee by 1H NMR analysis of the corresponding Mosher
ester derivative (Scheme 5).
With the enantiomerically pure epoxy alcohol 3 in hand, our
next target was to convert it into 1. Toward that objective, hydroxyl
group of 3 was protected as methoxymethyl ether with MOM-Cl in
CH2Cl2 in the presence of N,N-diisopropylethylamine to give com-
pound 9 in 98% yield (Scheme 3). Next, regioselective reductive ring
opening of 9 with LiAlH4 in THF at 0 ꢀC provided 2 in 95% yield.
Subsequent tosylation of alcohol 2 with tosyl chloride in the pres-
ence of triethylamine and a catalytic amount of DMAP furnished
the corresponding tosylate, which was used for the next step
without further purification. Thus, the above crude tosylate on
refluxing with NaN3 in dry DMF gave the azide 10 in good yield.
OH
N3
a
b or c
R
OH
R
OH +
R
R
OH
OH
O
7
N3
13
OH
14
inseparable mixture
12
d
N3
OH
R
OTs
+
OTs
R
OH
15
N3
11
R = -C15H31
n
separable mixture
e
OMOM
OH
OH
OMOM
b
d
a
OH
NH2
n-C15H31
R
n-C15H31
n-C15H31
3
O
O
-C15H31
n
-C15H31
n
9
R= n-C15H31
2
NH2
11
OH
1
16
OMOM
OH
(from
)
(from 15)
c
n-C15H31
Scheme 5. Reagents and conditions: (a) D-(ꢁ)-DET, Ti(Oi-Pr)4, TBHP, CH2Cl2, ꢁ25 ꢀC,
24 h, 85%.(b) NaN3, (MeO)3B, DMF, 50 ꢀC, 5 h (c) NaN3, NH4Cl, MeOH/H2O(8:1), 80 ꢀC,
18 h (d) TsCl (1.1 equiv), CH2Cl2, anhyd. Et3N, 0 ꢀC, 6 h, 65% (for 11, using reaction
condition ‘b’), 67% (for 15, using reaction condition ‘c’); for combined two steps. (e)
LiAlH4, THF, 0 ꢀC-rt, 5 h, 70% (1), 62% (16).
NH2
N3
1
10
Scheme 3. Reagents and conditions: (a) MOMCl, i-Pr2EtN, CH2Cl2, 0 ꢀC-rt, 12 h, 95%.
(b) LiAlH4, THF, 0 ꢀC-rt, 5 h, 95%. (c) (i) TsCl, CH2Cl2, anhyd. Et3N, DMAP (cat.), 0 ꢀC-rt,
48 h (ii) NaN3, DMF, 90 ꢀC, 5 h, 70% (for two steps). (d) (i) H2, 10% Pd-C, methanol, 6 h,
rt. (ii) conc. HCl, methanol, 80% (for two steps).
Next, C-2 selective azidolysis of enantiomerically pure epoxide
13 by sodium azide in dry DMF in the presence of trimethylborate
furnished mixture of azidodiols 12 (major) and 14 (minor). Un-
fortunately, these two regioisomers did not show any separation
Finally, reduction of the azido group of 10 by hydrogen in the
presence of 10% Pd-C in methanol followed by deprotection of
MOM group of the resulting amine derivative with conc. HCl

9306
S.K. Dinda et al. / Tetrahedron 66 (2010) 9304e9309
on TLC, and an attempt to purify by column chromatography was
also unsuccessful. Miyashita and co-workers isolated the regiose-
lective C-2 substituted products by NaIO4-mediated oxidative
cleavage of the corresponding C-3 substituted minor product (thus,
removing the minor azido diol as one-carbon degraded less polar
aldehydes). However, we were also interested in synthesizing the
regioisomer of 1, in which case compound 14 was needed as an
intermediate. Thus, utilization of the NaIO4-mediated oxidative
cleavage reaction in a mixture of 12 and 14 was not a desired
option for us. We were delighted to see that the corresponding
tosylates 11 and 15, which were obtained by tosylation of a mix-
ture of 12 and 14 with 1.1 equiv of tosyl chloride in dry CH2Cl2 in
the presence of triethylamine at 0 ꢀC, were completely separable
by silica gel column chromatography.
Amounts of isolated 11 and 15 suggested that in the azidolysis
reaction compounds 12 and 14 were formed in 85:15 ratio. Sub-
sequently, compound 11 was treated with LiAlH4 in THF to get
spisulosine 1 in 70% yield. Thus, this synthetic route of spisulosine
did not require any protecting group and involved five fewer steps
as compared to the other one already described in this paper.
Since the above synthetic route allowed to access compound 15
only in minor amount, it was necessary to search for an alternative
route for getting sufficient amount of 15, which could allow the
synthesis of the regioisomer of 1. Toward that objective, epoxide 13
was subjected to the standard azidolysis ring opening reaction17
carried out with NaN3/NH4Cl in an 8:l MeOH and H2O solution to
get 14 (major) and 12 (minor amount), Scheme 5. Next, tosylate 15
was isolated in pure form in the similar way as, that is, described for
11. Treatment of compound 15 with LiAlH4 in THF furnished amino
alcohol 16 in 62% yield.
and various possibilities available for structural modification and
thus it might be considered as a general synthetic strategy to
enantiomerically pure 2-amino-3-alkanols.
4. Experimental
4.1. General methods
All dry reactions were carried out under nitrogen in oven-dried
glassware using standard gas-light syringes, cannulas, and septa.
All reagents and solvents were dried prior to use according to the
standard methods. Commercial reagents were used without further
purification unless otherwise stated. Reactions were monitored on
silica gel TLC plates (coated with TLC grade silica gel, obtained from
Merck). Detecting agents used (for TLC) were iodine vapors and/or
spraying with an aqueous solution of vanillin in 10% sulfuric acid
followed by heating at 150 ꢀC. Column chromatography was per-
formed over silica gel (100e200 mesh) procured from Qualigens
(India) using freshly distilled solvents. Mass spectra were recorded
using electron spray ionization (ESI-MS) on a JEOL SX 102 spec-
trometer using argon/xenon as the FAB gas. Elemental analyses
were done on Varian EL-III C H N analyzer. IR spectra were recorded
on a PerkineElmer FT-IR RXI spectrometer. 1H NMR and 13C NMR
spectra were recorded on Brucker DPX-300 (operating at 300 MHz
for 1H and 75 MHz for 13C) spectrometer using CDCl3. Tetrame-
thylsilane (0.00 ppm) served as an internal standard in 1H NMR and
13
CDCl3 (77.0 ppm) in C NMR. All spectra were recorded at 25 ꢀC.
Coupling constants (J values) are given in hertz (Hz). Chemical
shifts were expressed in parts per million. Optical rotations were
measured at the sodium D-line at ambient temperature with
a PerkineElmer 141 polarimeter.
Next, we turned our attention toward the synthesis of a di-
astereoisomer 23 of spisulosine with the (2S, 3S) configuration.
Toward that objective, the hydroxyl group of epoxide 13 was
mesylated and the resulting epoxy mesylate was then treated with
perchloric acid to afford dihydroxy mesylate 18.18 Treatment of 18
with anhyd. K2CO3 in dry methanol gave epoxy alcohol 19 in 89%
yield. Next, compound 19 was converted into 23 in the similar way
as that has been described for the synthesis of 1 from 3 (Scheme 6).
4.1.1. (2E)-Octadec-2-enoate (6). To a stirring solution of oxalyl
chloride (4.53 g, 35.69 mmol) in dry CH2Cl2 (50 mL) at ꢁ78 ꢀC was
added dropwise dry DMSO (5.6 mL, 71.35 mmol) in CH2Cl2 (20 mL).
After 30 min, alcohol 5 (5.76 g, 23.76 mmol) in CH2Cl2 (20 mL) was
added over 10 min giving copious white precipitate. After stirring
for 1 h at ꢁ78 ꢀC the reaction mixture was brought to ꢁ60 ꢀC and
anhyd. Et3N (13.26 mL, 95.12 mmol) was added slowly and stirred
for 30 min allowing the reaction mixture to warm to rt. The reaction
mixture was then diluted with water (75 mL) and CH2Cl2. The or-
ganic layer was separated and washed with water and brine, dried
(Na2SO4), and passed through short pad of Celite. The filtrate was
concentrated to give the aldehyde as a pale yellow oil, which was
used as such for the next step without purification.
OH
OH
a
b
c
R
OH
OMs
R
R
O
O
13
OH
18
19
OH
OMOM
OMOM
OMOM
d
f
e
To a stirring solution of the above crude aldehyde in dry CH2Cl2
was added (ethoxycarbonylmethylene)-triphenylphosphorane
(9.25 g, 26.54 mmol) and the reaction mixture was stirred for 8 h at
rt. It was then concentrated and purification of the crude product
by silica gel column chromatography (2% ethyl acetate in hexane)
afforded 6 (5.90 g, 80%) as a colorless liquid. Rf: 0.54 (5% ethyl ac-
R
R
R
R
O
NH2
OH
N3
23
22
20
21
R= n-C15H31
Scheme 6. Reagents and conditions: (a) (i) MsCl, Et3N, CH2Cl2, 0 ꢀC; (ii) HClO4, DMSO,
60 ꢀC, 87% (for two steps). (b) K2CO3, MeOH, rt, 89%. (c) MOMCl, i-Pr2EtN, CH2Cl2, 0 ꢀC-
rt, 12 h, 96%. (d) LiAlH4, THF, 0 ꢀC-rt, 5 h, 94%. (e) (i) TsCl, CH2Cl2, anhyd Et3N, DMAP
(cat.), 0 ꢀC-rt, 48 h (ii) NaN3, DMF, 90 ꢀC, 5 h, 71% (for both steps). (f) (i) H2, 10% Pd-C,
methanol, 6 h, rt. (ii) conc. HCl, methanol, 75% (for both steps).
.
etate in hexane). IR (neat): 1716, 1654 cmꢁ1 1H NMR (300 MHz,
CDCl3):
d
7.01e6.91 (m, 1H, H3), 5.80 (d, 1H, J¼15.4, H2), 4.17 (q, 2H,
J¼7.2, CH2), 2.18 (br q, 2H, J¼6.9, H4),1.47e1.26 (m, 29H), 0.87 (t, 3H,
J¼6.5, CH3). MS (ESI): m/z 311 [M]þ. Anal. Calcd for C20H38O2: C,
77.36; H, 12.33. Found: C, 77.51; H, 12.47. The above spectroscopic
data are in consistence with the literature data.19
3. Conclusion
In conclusion, starting from commercially available palmityl
alcohol, new asymmetric total syntheses of spisulosine 1 and its
regio- and diastereomers have been developed. Notable features of
this approach include the use of Sharpless asymmetric dihydroxy-
lation and epoxidation reactions to synthesize the enantiomerically
pure epoxy alcohols and regioselective epoxide azidolysis for the
first protecting-group-free synthesis of 1. The other merits of this
synthesis are high-yielding reaction steps, high enantioselectivity
4.1.2. (2E)-Octadec-2-en-l-o1 (7). To a stirring solution of 3.62 g
(11.66 mmol) of 6 in 40 mL of dry toluene was added dropwise
35 mL (35.0 mmol) of DIBAL-H (1 M in toluene) at 0 ꢀC. The
resulting mixture was allowed to warm to rt over 1 h, then
quenched by adding water (50 mL). The resulting gel was dissolved
by dropwise addition of 6 N HC1. The organic layer was separated,
and the aqueous phase was extracted with ethyl acetate (2ꢂ50 mL).
The combined organic extracts were washed with saturated

S.K. Dinda et al. / Tetrahedron 66 (2010) 9304e9309
9307
aqueous NaHCO3 solution (75 mL), then dried over dried over
anhyd. Na2SO4, filtered, and then concentrated under reduced
pressure. Purification of the crude product by silica gel column
chromatography (8% ethyl acetate in hexane) afforded 7 (2.97 g,
95%) as a colorless solid. Mp: 46e48 ꢀC. Rf: 0.54 (20% ethyl acetate
in hexane). IR (neat): 3420, 2926, 2854, 1637, 1463, 1216, 972,
3.16 mmol) in CH2Cl2 (10 mL) was added MOMCl (0.21 mL,
2.37 mmol) at 0 ꢀC. The mixture was stirred for 12 h at rt. The re-
action was quenched with saturated aqueous NH4Cl (10 mL) and the
mixture was extracted with CH2Cl2 (2ꢂ20 mL). The organic layer
was washed with brine (20 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (10% ethyl acetate in hexane) to
give 9 (0.508 g, 98%) as a colorless oil. Rf: 0.5 (35% ethyl acetate in
766 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 5.75e5.55 (m, 2H, H2,3), 4.08
(d, 2H, J¼4.9, H1), 2.04 (br q, 2H, J¼6.3, H4), 1.48e1.25 (m, 27H), 0.86
(t, 3H, J¼6.5, CH3). 13C NMR (50 MHz, CDCl3):
d
133.5, 128.8, 63.8,
hexane). [
a
]
25 þ25.2 (c 1.5, CHCl3). IR (neat): 2925, 2853, 1467, 1401,
D
32.2, 31.9, 29.7, 29.6, 29.4, 29.3, 29.1, 22.7, 14.1. MS (ESI): m/z 268
[M]þ. Anal. Calcd for C18H36O: C, 80.53; H, 13.52. Found: C, 80.42; H,
13.66. The above spectroscopic data are in consistence with the
literature data.20
1377, 1257, 1216, 1152, 1102, 1036, 920, 721 cmꢁ1. 1H NMR (300 MHz,
CDCl3):
d
4.88 (d, 1H, J¼6.6), 4.66 (d, 1H, J¼6.7), 3.40 (s, 3H),
3.29e3.22 (m, 1H), 3.00e2.96 (m, 1H), 2.78 (t, 1H, J¼4.6), 2.54e2.52
(m, 1H), 1.65e1.25 (m, 28H), 0.88 (t, 3H, J¼6.9). 13C NMR (75 MHz,
CDCl3):
d 95.4, 78.0, 55.5, 54.7, 43.8, 32.3, 31.9, 29.67, 29.63, 29.62,
4.1.3. (2E)-1-Chloro-octadec-2-ene (4). To a stirring solution of al-
cohol 7 (2.5 g, 9.31 mmol), and Ph3P (2.68 g, 10.21 mmol) in 30 mL
of dry CH2Cl2 was added NCS (1.50 g, 11.23 mmol) at 0 ꢀC under
nitrogen. The reaction mixture was stirred at 0 ꢀC for 1 h, then
allowed to warm to rt, and stirred for 2 h. It was then concentrated
and purification of the crude product by silica gel column chro-
matography (2% ethyl acetate in hexane) afforded 4 (2.52 g, 94%) as
a colorless liquid. Rf: 0.58 (5% ethyl acetate in hexane). IR (neat):
3350, 3000, 2950, 2860, 1480, 1200, 1050 cmꢁ1. 1H NMR (300 MHz,
29.56, 29.51, 29.34, 25.4, 22.6, 14.1. MS (ESI): m/z 329 [M]þ. Anal.
Calcd for C20H40O3: C, 73.12; H, 12.27. Found: C, 73.19; H, 12.37.
4.1.7. (2R,3R)-3-Methoxymethoxyoctadecan-2-ol (2). To a stirring
suspension of LiAlH4 (50 mg, 1.33 mmol) in dry THF (8 mL) was
dropwise added a solution of epoxide 9 (0.35 g, 1.06 mmol) in dry
THF (7 mL) at 0 ꢀC. The reaction mixture was allowed to warm to rt,
and stirred for 5 h. The reaction was quenched by the addition of
water (5 mL). The mixture was extracted with ethyl acetate
(3ꢂ15 mL), washed with water (15 mL), brine (15 mL), and dried
over Na2SO4. It was then filtered and concentrated under reduced
pressure. Purification of the crude product by silica gel column
chromatography (15% ethyl acetate in hexane) afforded 2 (332 mg,
CDCl3):
d
5.78e5.68 (m, 2H), 4.01 (d, 2H, J¼6.6), 2.05e2.02 (m, 2H),
1.28e1.43 (m, 26H), 0.89 (t, 3H, J¼6.7). MS (ESI): m/z 289, 287
[M]þ. Anal. Calcd for C18H35Cl: C, 75.35; H, 12.30. Found: C, 75.39;
H, 12.25.
95%) as a colorless liquid. Rf: 0.41 (35% ethyl acetate in hexane).
25
4.1.4. (2R,3R)-1-Chlorooctadecane-2,3-diol (8). To a mixture of AD
[a
]
þ12.7 (c 1.5, CHCl3). IR (neat): 3450, 2925, 2857, 1467, 1400,
D
mix
b
(4.88 g) and NaHCO3 (0.88 g, 10.45 mmol) in tBuOH-H2O (1:1,
1257, 1221, 1159, 1102, 1039, 921, 722 cmꢁ1
.
1H NMR (300 MHz,
35 mL) cooled at 0 ꢀC was added methanesulfonamide (0.33 g,
3.48 mmol). After being stirred for 10 min at 0 ꢀC, allylic chloride 4
(1.0 g, 3.48 mmol) was added in one portion. The reaction mixture
was vigorously stirred at 0 ꢀC for 24 h and then quenched with
solid sodium sulfite (25 g). The stirring was continued for 45 min
and the solution was extracted with ethyl acetate (3ꢂ50 mL). The
combined extracts were dried (Na2SO4) and concentrated under
reduced pressure. Purification of the crude product by silica gel
column chromatography (20% ethyl acetate in hexane) afforded 8
(0.98 g, 88%) as a colorless solid. Mp: 91e93 ꢀC. Rf: 0.45 (30% ethyl
CDCl3): 4.74e4.68 (m, 2H), 3.73e3.65 (m, 1H), 3.42 (s, 3H),
d
3.29e3.23 (m, 1H), 3.04 (br s, 1H), 1.59e1.25 (m, 28H), 1.15 (d, 3H,
J¼6.3), 0.88 (t, 3H, J¼6.3). 13C NMR (75 MHz, CDCl3):
d 97.3, 85.4,
69.2, 55.7, 31.9, 31.1, 29.8, 29.6, 29.3, 25.0, 22.6, 19.0, 14.0. MS (ESI):
m/z 331 [M]þ. Anal. Calcd for C20H42O3: C, 72.67; H, 12.81. Found: C,
72.74; H, 12.89.
4.1.8. (2S,3R)-2-Azido-3-methoxymethoxyoctadecane(10). To an ice-
cooled solution of alcohol 2 (325 mg, 0.98 mmol), anhyd. triethyl-
amine (0.29 mL, 1.96 mmol), and DMAP (10 mg) in dry CH2Cl2
(10 mL) was added TsCl (200 mg, 1.05 mmol). After being stirred for
1 h in an ice bath and then 48 h at rt, the mixture was diluted with
CH2Cl2 (30 mL) and water (20 mL). The organic layer was separated,
washed with brine (15 mL), and dried over Na2SO4. It was then fil-
tered and the filtrate was concentrated under reduced pressure to
get the crude tosylate, which was used for the next step without
further purification.
acetate in hexane). [
a]
25 þ8.7 (c 1.15, MeOH). IR (KBr): 3330, 2928,
D
1230, 563 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 3.99e3.62 (m, 2H),
3.62e3.53 (m, 2H), 2.65 (br s, 1H), 2.25 (br s, 1H), 1.62e1.52 (m,
2H), 1.40e1.15 (m, 26H), 0.90 (t, 3H, J¼7.0). MS (ESI): m/z 323, 321
[M]þ. Anal. Calcd for C18H37ClO2: C, 67.36; H, 11.62. Found: C, 67.49;
H, 11.44.
4.1.5. (2R,3R)-1,2-Epoxyoctadecan-3-ol (3). To a stirring solution of
diol 8 (0.82 g, 2.55 mmol) in THF (15 mL) was added pulverized
NaOH (0.21 g, 5.25 mmol) at 0 ꢀC and reaction mixture was stirred
at rt for 3 h. It was quenched by addition of water (10 mL) and then
extracted with diethyl ether (3ꢂ20 mL). The combined extracts
were dried over Na2SO4, and concentrated under reduced pressure.
Purification of the crude product by silica gel column chromatog-
raphy (10% ethyl acetate in hexane) afforded 3 (0.667 g, 92%) as
To a solution of the above crude tosylate in dry DMF (10 mL) was
added NaN3 (0.34 g, 5.25 mmol). After being stirred for 5 h at 90 ꢀC,
the mixture was diluted with ethyl acetate (20 mL) and water
(10 mL). The organic layer was separated, washed with brine
(15 mL), and dried over Na2SO4. It was then filtered and the filtrate
was concentrated under reduced pressure. Purification of the crude
product by silica gel column chromatography (4% ethyl acetate in
hexane) afforded 10 (243 mg, 70%) as a colorless liquid. Rf: 0.58 (10%
25
a colorless solid. Mp: 62e63 ꢀC. Rf: 0.48 (20% ethyl acetate in
ethyl acetate in hexane). [
a
]
D
þ17.2 (c 1.5, CHCl3). 1H NMR
25
hexane). [
a]
þ0.19 (c 1.76, CHCl3). IR (KBr): 3337, 2959, 2916,
(300 MHz, CDCl3): d 4.73e4.64 (m, 2H), 3.62e3.51 (m, 2H), 3.39 (s,
D
2850, 1466, 1125, 959, 871, 755, 720 cmꢁ1
.
1H NMR (300 MHz,
3H), 1.61e1.19 (m, 31H), 0.86 (t, 3H, J¼6.9). 13C NMR (75 MHz,
CDCl3): 3.47e3.35 (m, 1H), 3.01e2.95 (m, 1H), 2.85e2.80 (m, 1H),
d
CDCl3): d 96.4, 80.3, 59.6, 55.6, 31.8, 30.4, 29.62, 29.60, 29.52, 29.48,
2.73e2.69 (m, 1H), 2.59e2.56 (m, 1H), 1.67e1.27 (m, 28H), 0.88 (t,
29.3, 25.4, 22.6, 14.2, 14.0. MS (ESI): m/z 356 [M]þ, 342 [MꢁN2]þ.
Anal. Calcd for C20H41N3O2: C, 67.56; H, 11.62; N, 11.82. Found: C,
67.51; H, 11.77; N, 11.98.
3H, J¼6.7). 13C NMR (75 MHz, CDCl3):
d 71.7, 55.5, 45.0, 34.1, 31.8,
29.6, 29.4, 29.2, 25.2, 22.6, 14.0. MS (ESI): m/z 285 [M]þ. Anal. Calcd
for C18H36O2: C, 76.00; H, 12.76. Found: C, 6.18; H, 12.64.
4.1.9. (2S,3R)-2-Aminooctadecan-3-ol (1). To a stirred solution of 10
(100 mg, 0.28 mmol) in methanol (10 mL) was added 10% Pd-C
(20 mg). After stirring for 4 h at rt under pressure of a hydrogen
4.1.6. (2R,3R)-1,2-Epoxy-3-methoxymethoxyoctadecane (9). To a stir-
ring solution of alcohol 3 (0.45 g, 1.58 mmol), and i-Pr2EtN (0.53 mL,

9308
S.K. Dinda et al. / Tetrahedron 66 (2010) 9304e9309
balloon, the reaction mixture was filtered through a pad of CeliteÒ
and the filtrate was concentrated under reduced pressure to get the
corresponding amine derivative as a colorless semi-solid, which
was used for the next step without further purification.
of the crude product by silica gel flash column chromatography
(20% EtOAc in n-hexane) afforded 11 (1.43 g, 65%) as a colorless
25
gum. Rf: 0.48 (30% ethyl acetate in hexane). [
a
]
D
ꢁ3.22 (c 2.58,
MeOH). IR (neat): 3431, 3021, 2928, 2364, 1636, 1216, 1102, 765,
To a solution of the above crude amine in methanol (5 mL) was
added two drops of conc. HCl. After being stirred for 12 h at rt, the
mixture was concentrated under reduced pressure. The residue was
redissolved in CHCl3 (10 mL) and the resulting solution was treated
with saturated aqueous NaHCO3 solution (10 mL). The organic layer
was separated, washed with brine (15 mL), and dried over Na2SO4.
It was then filtered and the filtrate was concentrated under reduced
pressure. Purification of the crude product by silica gel column
chromatography (50% methanol in CHCl3) afforded 1 (64 mg, 80%)
669 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
7.82 (d, 2H, J¼8.3, ArH), 7.37
(d, 2H, J¼8.4, ArH), 4.34 (dd, 1H, J1¼3.17, J2¼3.13), 3.64e3.51 (m,
2H), 2.69 (d, 1H, J¼5.18), 2.46 (s, 3H, ArCH3), 1.48e1.23 (m, 28H),
0.88 (t, 3H, J¼6.4, CH3). 13C NMR (75 MHz, CDCl3):
d 145.2, 132.5,
130.0, 128.0, 71.0, 69.0, 64.6, 33.2, 31.9, 29.6, 29.5, 29.4, 29.3, 25.4,
22.7, 21.7, 14.1. MS (ESI): m/z 482 [M]þ. Anal. Calcd for C25H43N3O4S:
C, 62.34; H, 9.00; N, 8.72. Found: C, 62.52; H, 9.21; N, 8.46.
4.1.12. (2S,3S)-3-Azido-2-hydroxyoctadecyl-4-methylbenzenesulfo-
nate (15). A solution of the epoxy alcohol 13 (1.2 g, 4.21 mmol) in
an 8:l MeOH/H2O mixture (18.0 mL) was treated with NaN3 (1.26 g,
19.37 mmol) and NH4Cl (0.45 g, 8.40 mmol) and the resulting re-
action mixture was stirred at 80 ꢀC for 18 h. Dilution with ether and
evaporation of the solution afforded a crude reaction product. This
crude mixture containing regiomeric azidodiols was treated in the
same way as that described for 11. The solvent was removed under
reduced pressure and purification of the crude product by silica gel
flash column chromatography (20% EtOAc in n-hexane) afforded 15
as a white solid. Mp: 67e68 ꢀC. Rf: 0.48 (20% methanol in chloro-
25
form). [
a
]
D
þ21.4 (c 0.5, CHCl3). IR (KBr): 3408 (OH), 3345e3200
(NH), 2922, 2854, 1652, 1468, 1257, 1190, 1070, 1044, 744, 621 cmꢁ1
.
1H NMR (300 MHz, CD3OD):
d
3.68 (m, 1H, CH-3), 3.34e3.22 (m, 1H,
CH-2), 1.49e1.27 (m, 31H), 1.20 (d, 3H, J¼6.7, CH3-1), 0.89 (t, 3H,
J¼6.2, CH3-18). 13C NMR (75 MHz, CDCl3):
d 74.9, 50.5, 32.6, 32.1,
30.1, 29.9, 29.8, 26.4, 22.9,17.1,14.3. MS (ESI): m/z 287 [Mþ1]þ. Anal.
Calcd for C18H39NO: C, 75.72; H, 13.77; N, 4.91. Found: C, 75.79; H,
13.88; N, 5.07. The physical and spectral data were in agreement
with the literature data.9
(1.42 g, 67%) as a colorless gum. Rf: 0.48 (30% ethyl acetate in
25
hexane). [
a
]
D
ꢁ4.53 (c 1.74, MeOH). IR (neat): 3428, 2927, 2366,
4.1.10. {(2R,3R)-3-Pentadecyloxiran-2-yl}methanol
(13). Freshly
1635, 1218, 769 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 7.82 (d, 2H,
distilled Ti(OiPr)4 (3.9 mL, 13.1 mmol) was added to CH2Cl2 and the
J¼8.3, ArH), 7.37 (d, 2H, J¼8.4, ArH), 4.34 (dd, 1H, J1¼3.2, J2¼3.1),
3.64e3.51 (m, 2H), 2.69 (d, 1H, J¼5.18), 2.46 (s, 3H, ArCH3),
1.48e1.23 (m, 28H), 0.88 (t, 3H, J¼6.4, CH3). 13C NMR (75 MHz,
resulting solution was cooled to ꢁ25 ꢀC.
D
-(ꢁ)-DET (3.0 mL,
17.4 mmol) was then added. The resulting mixture was then stirred
for 20 min, and then a solution of 7 (2.92 g, 10.9 mmol) in CH2Cl2
(20 mL) was added. 20 min later TBHP (5.6 M in n-decane, 5.8 mL,
32.7 mmol) was added and then the reaction mixture was stored in
the ꢁ20 ꢀC refrigerator for 24 h. The reaction was then quenched by
addition of Me2S (3.2 mL, 43.6 mmol). The resulting mixture was
stirred for 30 min at ꢁ20 ꢀC and then saturated aqueous Na2SO4
(15 mL) was added. This suspension was allowed to warm to rt,
then filtered through a pad of Celite, washed with diethyl ether, and
purification of the crude product by silica gel column chromatog-
raphy (6% ethyl acetate in hexane) afforded 13 (2.64 g, 85%) as
CDCl3):
d 145.2, 132.5, 130.0, 128.0, 71.0, 69.0, 64.7, 33.2, 31.9, 29.6,
29.5, 29.4, 29.3, 25.4, 22.7, 21.7, 14.1. MS (ESI): m/z 482 [M]þ. Anal.
Calcd for C25H43N3O4S: C, 62.34; H, 9.00; N, 8.72. Found: C, 62.52; H,
9.21; N, 8.46.
4.1.13. (2R,3S)-3-Aminooctadecan-2-ol (16). To a stirring suspen-
sion of LiAlH4 (76 mg, 2.0 mmol) in dry THF (8 mL) was dropwise
added a solution of tosylate 15 (0.12 g, 0.25 mmol) in dry THF (3 mL)
at 0 ꢀC. The reaction mixture was allowed to warm to rt, and stirred
for 8 h. The reaction was quenched by the addition of water (5 mL).
The mixture was extracted with ethyl acetate (3ꢂ10 mL), washed
with water (10 mL), brine (10 mL), and dried over Na2SO4. It was
then filtered and concentrated under reduced pressure. Purification
of the crude product by silica gel column chromatography (50%
a colorless solid. Mp: 67e68 ꢀC. Rf: 0.53 (5% ethyl acetate in hex-
25
ane). [
a
]
þ22.7 (c 0.93, MeOH). IR (neat): 3428, 2923, 1216,
762 cmꢁD1
.
1H NMR (300 MHz, CDCl3):
d
3.95e3.89 (m, 1H, H1a),
3.66e3.58 (m, 1H, H1b), 2.98e2.91 (m, 2H, H2,3), 1.61e1.14 (m, 28H),
0.86 (t, 3H, J¼6.5, CH3). 13C NMR (50 MHz, CDCl3):
d
61.7, 58.4, 56.0,
methanol in CHCl3) afforded 16 (44 mg, 62%) as a white solid. Mp:
25
31.9, 31.5, 29.7, 29.5, 29.4, 25.9, 22.7, 14.1. MS (ESI): m/z 284 [M]þ.
Anal. Calcd for C18H36O2: C, 76.00; H, 12.76. Found: C, 75.96; H,
12.84. The above spectroscopic data are in consistence with the
literature data.20
61e63 ꢀC. Rf: 0.48 (20% methanol in chloroform). [
a
]
D
þ7.3 (c 1.7,
MeOH). IR (KBr): 3408, 3022, 2925, 2855, 1628, 1464, 1257, 1216,
1041, 762, 670 cmꢁ1. 1H NMR (300 MHz, CD3OD):
d
3.78e3.75 (m,
1H, CH-2), 2.81 (m, 1H, CH-3), 1.45e1.26 (m, 28H), 1.10 (d, 3H, J¼6.4,
CH3-1), 0.88 (t, 3H, J¼6.2, CH3-18). 13C NMR (75 MHz, CDCl3):
d 70.2,
4.1.11. (2S,3R)-2-Azido-3-hydroxyoctadecyl-4-methyl benzenesulfo-
nate (11). A solution of the epoxide 13 (1.3 g, 4.57 mmol), (MeO)3B
(1.05 mL, 9.14 mmol), and NaN3 (0.6 g, 9.14 mmol) in DMF was
stirred at 50 ꢀC for 3 h. After cooling to 0 ꢀC, a saturated aqueous
solution of NaHCO3 was added, and the mixture was stirred for
30 min. The mixture was separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic layer was
successively washed with water, a saturated aqueous solution of
NaHCO3, brine, and dried over Na2SO4. Concentration under re-
duced pressure followed by column chromagraphy affored 4.34 g
(95%) of the azido diol as an 84:16 mixture of regioisomers.
To an ice-cooled solution of the above regioisomeric azido diol
in dry CH2Cl2 (10 mL) was added anhyd. Et3N (1.16 mL, 8.31 mmol)
followed by TsCl (0.91 g, 4.75 mmol) and the mixture was kept
overnight at 0 ꢀC. The mixture was diluted with H2O (25 mL) and
extracted with CH2Cl2 (2ꢂ30 mL). The combined organic layers
were washed with H2O (25 mL), brine (25 mL), and dried (Na2SO4).
The solvent was removed under reduced pressure and purification
56.3, 33.3, 32.3, 30.2e29.7 (10ꢂCH2), 26.5, 23.0, 17.2, 14.2. MS (ESI):
m/z 287 [Mþ1]þ. Anal. Calcd for C18H39NO: C, 75.72; H, 13.77; N,
4.91. Found: C, 75.63; H, 13.91; N, 5.02.
Spisulosine 1 was prepared (yield 70%) in the similar way from
tosylate 11.
4.1.14. (2R,3S)-2,3-Dihydroxyoctadecyl methanesulfonate (18). A
solution of 13 (1.82 g, 6.39 mmol) in CH2Cl2 (40 mL) was treated
with MsCl (0.75 mL, 9.6 mmol), and Et3N (1.8 mL, 12.8 mmol) at
0
ꢀC. Upon being stirred for 15 min, the reaction mixture was di-
luted with diethyl ether, washed with saturated NH4Cl, water, and
concentrated. The resulting mixture was dissolved in 60% DMSO
(40 mL) solution, being treated with 70% HClO4 (0.2 mL). After
being stirred for 6 h at 50 ꢀC, the mixture was diluted with EtOAc,
washed with saturated NaHCO3, and water, dried over Na2SO4, and
concentrated. Purification by silica gel column chromatagraphy
(hexane: EtOAc¼7:3 to 1:1) gave 18 (2.12 g, 87%) as a colorless solid.
25
Mp: 91e93 ꢀC. Rf: 0.45 (30% ethyl acetate in hexane). [
a]
þ5.1 (c
D

S.K. Dinda et al. / Tetrahedron 66 (2010) 9304e9309
9309
1.07, MeOH). IR (KBr): 3387, 3322, 2920, 2362, 1339, 1173 cmꢁ1. 1H
NMR (200 MHz, CDCl3): 5.38e5.32 (m, 1H), 4.45e4.29 (m, 2H),
Anal. Calcd for C20H41N3O2: C, 67.56; H, 11.62; N, 11.82. Found: C,
67.71; H, 11.83; N, 12.02.
d
3.83e3.73 (m, 2H), 3.08 (s, 3H), 2.78 (d, 1H, J¼6.7), 1.85e1.13 (m,
28H), 0.88 (t, 3H, J¼6.6). 13C NMR (50 MHz, CDCl3):
d
72.5, 72.2, 71.0,
4.1.19. (2S,3S)-2-Aminooctadecan-3-ol (23). From 22 (95 mg,
0.27 mmol), the title compound was prepared in the same manner
as that described for 1 from 10. Purification of the crude product by
silica gel column chromatography (50% methanol in CHCl3) affor-
37.5, 32.7, 31.9, 31.8, 29.8, 29.6, 29.5, 29.4, 29.3, 29.2, 27.2, 25.7, 22.6,
14.1. MS (ESI): m/z 380 [M]þ, 403 [MþNa]þ. Anal. Calcd for
C19H40O5S: C, 59.96; H, 10.59. Found: C, 59.74; H, 9.87.
ded 23 (58 mg, 75%) as a white solid. Mp: 73e75 ꢀC. Rf: 0.48 (20%
25
4.1.15. (2R,3S)-1,2-Epoxyoctadecan-3-ol (19). A solution of com-
pound 18 (o.80 g, 2.1 mmol) in dry MeOH (30 mL) was treated with
K2CO3 (0.44 g, 3.15 mmol), and the mixture was stirred for 45 min
at rt. After completion of the reaction, the mixture was concen-
trated and extracted with diethyl ether, washed with water, and
brine. The organic layer was dried over Na2SO4 and concentrated.
The residue was purified by silica gel column chromatography (10%
ethyl acetate in hexane) gave 19 (0.53 g, 89%) as a colorless solid.
methanol in chloroform). [
a
]
þ3.4 (c 1.8, MeOH). IR (KBr): 3408,
D
3345e3200, 2922, 2854, 1652, 1468, 1257, 1190, 1070, 1044, 744,
621 cmꢁ1 1H NMR (300 MHz, CD3OD):
.
d
3.68 (m, 1H, CH-3),
3.26e3.22 (m,1H, CH-2),1.49e1.27 (m, 31H),1.20 (d, 3H, J¼6.7, CH3-
1), 0.89 (t, 3H, J¼6.2, CH3-18). 13C NMR (75 MHz, CDCl3):
d 75.0,
50.6, 32.7, 32.2, 30.1, 29.5, 26.3, 22.9, 17.1, 14.2. MS (ESI): m/z 287
[Mþ1]þ. Anal. Calcd for C18H39NO: C, 75.72; H, 13.77; N, 4.91.
Found: C, 75.77; H, 13.92; N, 5.11.
Mp: 69e72 ꢀC. Rf: 0.48 (20% ethyl acetate in hexane). [
a
]
25 þ0.23 (c
D
1.54, MeOH). IR (KBr): 3328, 2963, 2838, 1446, 963, 852, 718 cmꢁ1
.
Acknowledgements
1H NMR (300 MHz, CDCl3):
d 3.39e3.27 (m, 1H), 2.93e2.87 (m, 1H),
2.77e2.72 (m, 1H), 2.65e2.61 (m, 1H), 2.51e2.49 (m, 1H), 1.59e1.19
This research project was partly supported by DST and ICMR,
India. SAIF, CDRIy is acknowledged for analytical data. Subal and
Sajal thank CSIR for fellowships.
(m, 28H), 0.81 (t, 3H, J¼6.5). 13C NMR (75 MHz, CDCl3):
d 71.6, 55.4,
45.0, 34.0, 31.6, 29.6, 29.5, 29.3, 25.1, 22.6, 14.0. MS (ESI): m/z 285
[M]þ. Anal. Calcd for C18H36O2: C, 76.00; H, 12.76. Found: C, 76.09;
H, 12.83.
Supplementary data
4.1.16. (2R,3S)-1,2-Epoxy-3-methoxymethoxyocta-decane (20). From
19 (0.51 g,1.79 mmol), the title compound was prepared in the same
manner as that described for 9. Purification of the crude product by
silica gel column chromatography (10% ethyl acetate in hexane)
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.09.018. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
afforded 20 (0.564 g, 96%) as a colorless oil. Rf: 0.5 (35% ethyl acetate
25
in hexane). [
a
]
þ18.4 (c 1.2, MeOH). IR (neat): 2917, 2843, 1408,
D
References and notes
1369, 1249, 1220, 1141, 1043, 724 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
4.88 (d, 1H, J¼6.6, OCHaHbO), 4.66 (d, 1H, J¼6.7, OCHaHbO), 3.40 (s,
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4579.
0.88 (t, 3H, J¼6.9). 13C NMR (75 MHz, CDCl3):
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(0.540 g, 1.64 mmol), the title compound was prepared in the same
manner as that described for 2. Purification of the crude product by
silica gel column chromatography (15% ethyl acetate in hexane)
afforded 21 (509 mg, 94%) as a colorless liquid. Rf: 0.41 (35% ethyl
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10. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
11. For ‘buffered’ AD reaction of allylic chlorides, see: Vanhessche, K. P. M.; Wang,
Z.-M.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 3469.
acetate in hexane). [
a]
25 þ17.3 (c 1.3, MeOH). IR (neat): 3443, 2913,
D
2839, 1461, 1244, 1204, 1140, 1028, 913, 712 cmꢁ1
.
1H NMR
(300 MHz, CDCl3):
d 4.74e4.68 (m, 2H), 3.73e3.65 (m, 1H), 3.42 (s,
3H), 3.29e3.23 (m, 1H), 3.04 (br s, 1H), 1.59e1.25 (m, 28H), 1.15 (d,
3H, J¼6.3), 0.88 (t, 3H, J¼6.3). 13C NMR (75 MHz, CDCl3):
d 97.3, 85.4,
69.2, 55.7, 31.9, 31.1, 29.8, 29.6, 29.3, 25.0, 22.6, 19.0, 14.0. MS (ESI):
m/z 331 [M]þ. Anal. Calcd for C20H42O3: C, 72.67; H, 12.81. Found: C,
72.81; H, 12.94.
12. Zhang, Z.-B.; Wing, Z.-M.; Wang, Y.-X.; Liu, H.-Q.; Lei, G.-X.; Shi, M. J. Chem. Soc.,
Perkin Trans. 1 2000, 532.
13. For a recent review on protecting group-free total synthesis, see: Young, I. S.;
Baran, P. S. Nat. Chem. 2009, 1, 193.
4.1.18. (2S,3S)-2-Azido-3-methoxymethoxyoctadecane
(22). From
14. Sasaki, M.; Tanino, K.; Hirai, A.; Miyashita, M. Org. Lett. 2003, 5, 1789.
15. (a) Rogers, E. W.; Molinski, T. F. J. Org. Chem. 2009, 74, 7660; (b) Hayes, C. J.;
Sherlock, A. E.; Selby, M. D. Org. Biomol. Chem. 2006, 4, 193.
16. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
17. (a) Caron, M.; Carlier, P. R.; Sharpless, K. B. J. Org. Chem. 1988, 53, 5185; (b)
Behrens, C. H.; Sharpless, K. B. J. Org. Chem. 1985, 50, 5696; (c) Caron, M.;
Sharpless, K. B. J. Org. Chem. 1985, 50, 1557.
18. (a) Calvani, F.; Crotti, P.; Gardelli, C.; Pineschi, M. Tetrahedron 1994, 50, 12999;
(b) Chini, M.; Crotti, P.; Gardelli, C.; Macchia, F. J. Org. Chem. 1994, 59, 4131.
19. He, L.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2000, 65, 7618.
20. Roush, W. R.; Adam, M. A. J. Org. Chem. 1985, 50, 3752.
21 (410 mg, 1.24 mmol), the title compound was prepared in the
same manner as that described for 10. Purification of the crude
product by silica gel column chromatography (4% ethyl acetate in
hexane) afforded 22 (313 mg, 71%) as a colorless liquid. Rf: 0.58 (10%
25
ethyl acetate in hexane). [
(300 MHz, CDCl3):
a
]
þ11.3 (c 1.7, MeOH). 1H NMR
D
d 4.73e4.64 (m, 2H), 3.62e3.51 (m, 2H), 3.39 (s,
3H), 1.61e1.19 (m, 31H), 0.86 (t, 3H, J¼6.9). 13C NMR (75 MHz,
CDCl3): d 96.4, 80.3, 59.6, 55.6, 31.8, 30.4, 29.62, 29.60, 29.52, 29.48,
29.3, 25.4, 22.6, 14.2, 14.0. MS (ESI): m/z 356 [M]þ, 342 [MꢁN2]þ.
y
CDRI communication number 7355.