Total synthesis of (R)-(-)-actisonitrile via O-alkylation of optically active 4-hydroxymethyloxazolidin-2-one derivative

Article abstract of DOI:10.1016/j.tetasy.2011.11.002

The enantioselective synthesis of (R)-(-)-actisonitrile 1 has been achieved via O-alkylation of (4R,αS)-4-hydroxymethyl-3-(α-methylbenzyl) oxazolidin-2-one (αS)-4 with 1-iodohexadecane in the presence of CsOH in DMF. Under these reaction conditions, the O

Full text of DOI:10.1016/j.tetasy.2011.11.002

Tetrahedron: Asymmetry 22 (2011) 1918–1923
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Tetrahedron: Asymmetry
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Total synthesis of (R)-(ꢀ)-actisonitrile via O-alkylation of optically active
4-hydroxymethyloxazolidin-2-one derivative
⇑
⇑
Shigeo Sugiyama , Akihiro Ishida, Moeko Tsuchida, Keitaro Ishii
Department of Life and Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 October 2011
Accepted 4 November 2011
The enantioselective synthesis of (R)-(ꢀ)-actisonitrile 1 has been achieved via O-alkylation of (4R,
aS)-4-
hydroxymethyl-3-(a-methylbenzyl)oxazolidin-2-one (aS)-4 with 1-iodohexadecane in the presence of
CsOH in DMF. Under these reaction conditions, the O-alkylation was much faster than the intramolecular
acyl transfer of ( S)-4.
a
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
to many chemists. Some serinolipids have been synthesized from
the known N-Boc-serinol acetonide,2,10–12 the etherification of
which has been carried out using NaH as a base in DMF or THF
at room temperature.
Some natural products that possess a serinol moiety, for exam-
ple didemniserinolipids A–C,1,2 cyclodidemniserinol trisulfate,3
shishididemniols,4,5 inconspicamide,6,7 and serinol-derived mal-
yngamides8 have been isolated from tunicates, ascidians, marine
sponges, or a blue-green alga as biologically potent marine metab-
olites. Recently, (R)-(ꢀ)-actisonitrile 1 was isolated from an Actino-
cyclidae nudibranch, Actinocyclus papillatus9 (Fig. 1). The structure
has been established as a lipid based structure on a 1,3-propane-
diol ether skeleton by spectroscopic methods, while the absolute
configuration of the stereogenic center was determined by com-
paring the optical properties of natural actisonitrile with those of
(R)-(ꢀ)- and (S)-(+)-synthetic enantiomers, prepared from (S)-
(ꢀ)- and (R)-(+)-glycidyl trityl ethers, respectively. The bioactivity
of both (R)-(ꢀ)- and (S)-(+)-actisonitrile enantiomers has been
tested in a fluorimetric culture cytotoxicity assay on tumor and
nontumor mammalian cells. Both enantiomers exhibited a parallel
concentration-dependent toxic profile, displaying IC50 values with-
in the micromolar range. In particular, (R)-(ꢀ)-1 and (S)-(+)-1
showed moderate cytotoxicity against nontumor H9c2 rat cardiac
On the other hand, we have developed a synthetic method for
4-hydroxymethyloxazolidin-2-one (
benzyl)aminopropane-1,3-diol (R)-2 (Fig. 2) via the asymmetric
desymmetrization process13,14 and from (R)-
-methylbenzyl isocy-
S)-4 has also been also
aR)-3 from (R)-2-(a-methyl-
a
anate and (S)-glycidol.13 Oxazolidinone (
a
synthesized from an optically active aziridine.15 Althoughthese oxa-
zolidinones can be easily synthesized in a few steps, they have not
been used as synthetic intermediates except for the synthesis of
the 3-(2-oxooxazolidin-4-yl)acrylate derivative from (a
S)-4.15 The
benzyl and MOM ethers of 4-hydroxymethyloxazolidin-2-one
derivatives have been synthesized using benzyl bromide16 or benzyl
2,2,2-trichloroacetimidate17 and methoxymethyl chloride,18
respectively, in the presence of Et3N and iPr2EtN; however, the syn-
thesis of the alkyl ethers of the 4-hydroxymethyloxazolidin-2-ones
has not been reported. Strong bases, such as tBuOK and NaH, convert
(aR)-3 to a diastereomeric mixture of (aR)-3 and (aR)-4 via an intra-
molecular acyl transfer.13 In order to investigate the utility of these
oxazolidinones as synthetic intermediates, we began to synthesize
myoblast cells (IC50 23 6 and 23
6 l
M, respectively).9
NC
R2
AcO
O
R2
R1
N
R1 R2
(CH2)15CH3
R1
N
O
O
O
Ph
OH
Ph
OH
HN
Ph
OH
Figure 1. (R)-(ꢀ)-Actisonitrile 1.
(S)
(R)
O
HO
Due to the potent biological activity and the simple structure of
(R)-(ꢀ)-actisonitrile 1, a convenient synthetic method for the
development of enantiomerically pure 1 would be of great interest
(R)-2, R1 = Me
(αR)-3, R1 = Me
(αR)-4, R1 = Me
R2 = H
R2 = H
R2 = H
(S)- , R1 = H,
(αS)- , R1 = H,
(αS)- , R1 = H,
2
3
4
R2 = Me
R2 = Me
R2 = Me
⇑
Corresponding authors.
E-mail address: sugiyama@my-pharm.ac.jp (S. Sugiyama).
Figure 2.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.002

S. Sugiyama et al. / Tetrahedron: Asymmetry 22 (2011) 1918–1923
1919
the serinol derivative 1 from (
develop O-alkylation conditions for (
ular acyl transfer.
a
S)-4. For this purpose we needed to
room temperature for 30 min. In this case, the mixture of (
and (
indicated that the O-alkylation of (
a
R)-4
aS)-4 without the intramolec-
a
R)-3 (63:37) was obtained (Eq. 2). This rapid epimerization
a
S)-4 and ( R)-4 should be fas-
a
We also focused on the dehydration of a formamide to an isoni-
trile, which is the final stage of the synthesis of (R)-(ꢀ)-actisonitrile
1. Mroczkiewicz and Ostaszewski have reported that the synthesis
of enantiomerically pure (2S)-2-isocyano-4-methylpentyl acetate
from (2S)-2-foramide-4-methylpentyl acetate was problem-
atic.19,20 After their examination of several synthetic methods, they
found that reaction conditions using triphenylphosphine, carbon
tetrachloride,21 and triethylamine gave the product possessing
the highest enantiomeric purity. Ichikawa et al. also used an iden-
tical reagent system using carbon tetrabromide22 instead of carbon
tetrachloride for the asymmetric synthesis of (+)-geranyllinaloiso-
cyanide and determined its enantiomeric purity by comparison
with two 1H NMR spectra of urea derived from (+)- and ( )-gera-
ter than their epimerization to prevent the formation of
diastereomer.
a
Next, the O-alkylation of (aS)-4 in DMF was studied, and the re-
sults are summarized in Table 1. O-Alkylation of (aS)-4 in DMF
with 1-iodohexadecane 5a or hexadecanyl tosylate 5b26 in the
presence of DBU, which is an ineffective base for the acyl transfer
of (a
R)-3,13 did not proceed at 100 °C (entries 1 and 2). According
to a reported procedure,24 we attempted the O-alkylation using 1-
bromohexadecane 5c in the presence of tetrabutylammonium io-
dide (TBAI) as the catalyst and CsOHꢁH2O or Cs2CO3 as the base.24
The reaction using Cs2CO3 gave no product (entry 3). The reaction
using CsOHꢁH2O gave the desired ether (
a
S)-6 in 19%; an undesired
ether ( S)-7 was also obtained (entry 4). The formation of (
a
aS)-7
nyllinaloisocyanide and (R)-
a
-methylbenzylamine.23
was due to the rate of O-alkylation, which was not much faster
than the rate of epimerization (Scheme 1, Eq. 1). In order to in-
crease the O-alkylation rate, we next used 1-iodohexadecane 5a in-
stead of bromide 5c. O-Alkylation using 1.0 and 6.0 equiv of 5a
2. Results and discussion
gave ether (
and 6). Since no undesired ether (
a
S)-6 in 48% and 59% yields, respectively (entries 5
After the synthesis of oxazolidinone (
according to the literature,13 we investigated the epimerization
of oxazolidinones ( S)-4 and ( R)-4 via intramolecular acyl trans-
fer and their O-alkylation using CsOH in DMF.24 Treatment of (
S)-
4 with CsOHꢁH2O (1.1 equiv) in DMF (2.5 L/mol) at room tempera-
ture for 30 min gave a diastereomeric mixture of ( S)-4 and ( S)-3
(57:43, determined by 1H NMR analysis) (Scheme 1, Eq. 1). The epi-
merization equilibrated within 4 h to give a mixture of ( S)-4 and
aS)-4 from serinol (S)-2
aS)-7 was formed in these cases,
the O-alkylation was much faster than the epimerization. O-Alkyl-
ation using tosylate 5b was also examined; however, the low sol-
ubility of 5b in DMF at room temperature decreased both the
concentration of the reaction mixture and the yield (entry 7). The
undesired ether (
time (25 h).
a
a
a
a
a
aS)-7 was also obtained during the long reaction
a
The O-alkylation of (
temperature was also investigated using 1.0 and 6.0 equiv of 1-iod-
a
R)-4 using CsOHꢁH2O in DMF at room
(aS)-3 (52:48), and this ratio did not change after 24 h.
ohexadecane 5a and 6.0 equiv of tosylate 5b (Table 2). The O-alkyl-
a
+
(αS)-4
(αS)-4
(αS)-3
(1)
(2)
ation using 6.0 equiv of iodide 5a gave ether (
yield among the three examples and no epimeric ether (
try 2). The yield of ( R)-6 was identical to the yield of the O-alkyl-
ation of ( S)-4 (Table 1, entry 6).
We observed by 1H NMR analysis that the crude mixture in en-
try 6 (Table 1) contained ( S)-6 and 1-hexadecene. In this case, 1-
hexadecene should be converted from 1-iodohexadecane by the
elimination of hydrogen iodide. The molar ratio of ( S)-6 and 1-
hexadecene was 100:86 [59% and 51% based on ( S)-4]. Therefore,
CsOH [1.1 equiv based on ( S)-4] was consumed completely within
30 min from the beginning of the reaction. The starting material
aR)-6 in the best
a
R)-7 (en-
57:43 (30 min)
52:48 (4 h and 24 h)
a
a
a
4
4
+
3
(αR)-
(αR)-
(αR)-
a
63:37 (30 min)
Scheme 1. Epimerization of 4-hydroxymethyloxazolidin-2-ones via intramolecular
acyl transfer.13 Reagents and conditions: (a) CsOHꢁH2O (1.1 equiv), DMF (2.5 L/mol), rt.
a
a
a
Oxazolidinone (a aR)-epimer of (aS)-4,
R)-4,13,25 which was the (
was also treated with CsOHꢁH2O (1.1 equiv) in DMF (2.5 L/mol) at
(aS)-4 was also observed in the crude reaction mixture in 16%
Table 1
O-alkylation of (aS)-4
O
O
O
O
Ph
O(CH2)15CH3
Ph
OH
Ph
X(CH2)15CH3
N
N
N
+
O
O
O(CH2)15CH3
base (1.1 equiv)
MS 4Å
(αS)-4
(αS)-6
(αS)-7
Time (h)
DMF (0.4 mol/L)
Entrya
X(CH2)15CH3
X
Base
Temp (°C)
Yieldb (%)
No.
Equiv
(
aS)-6
(aS)-7
1
2
5a
5b
5c
5c
5a
5a
5b
I
1.0
1.0
2.0
2.0
1.0
6.0
6.0
DBU
DBU
Cs2CO3
CsOHꢁH2O
CsOHꢁH2O
CsOHꢁH2O
CsOHꢁH2O
100
100
rt then 100
rt then 50
14
0
0
0
19
48
59
42
0
0
0
2
0
0
7
TsO
Br
Br
I
14
48 then 5
14 then 2
3c
4c
5
rt
rt
rt
0.5
0.5
25
6
I
7d
OTs
a
The amount of (
aS)-4 was 10 mg except in entries 3, 4, 6 (100 mg), and 7 (50 mg), and 1.5 times the weight of powdered MS 4 Å was used.
b
c
Isolated yield.
TBAI (0.05 equiv) was also used.22
d
The concentration of the mixture was 0.064 mol/L based on (aS)-4.

1920
S. Sugiyama et al. / Tetrahedron: Asymmetry 22 (2011) 1918–1923
Table 2
O-alkylation of (aR)-4
O
O
O
O
O
Ph
O(CH2)15CH3
Ph
OH
Ph
O(CH2)15CH3
X(CH2)15CH3
N
N
N
+
O
CsOH.H2O (1.1 equiv)
MS 4Å
DMF (0.4 mol/L), rt
4
6
7
(αR)-
(αR)-
(αR)-
Entrya
X(CH2)15CH3
X
Time (h)
Yield (%)b
No.
Equiv
(aR)-6
(aR)-7
1
5a
5a
5b
I
I
1.0
6.0
6.0
0.5
0.5
25
19
59
52
0
0
0
2
3c
OTs
a
The amount of (
Isolated yield.
The concentration of the mixture was 0.064 mol/L based on (
a
R)-4 was 10 mg in entries 1 and 2 and 20 mg in entry 3, and 1.5 times the weight of powdered MS 4 Å was used.
R)-4.
b
c
a
recovery, and its epimer (
sumption of CsOH within 30 min. In entry 2 (Table 2) using (
4, the formation of 1-hexadecene was also observed, and (
was not observed in the crude mixture. Thus, the rates of the epi-
merizations of ( S)-4 and ( R)-4 were much slower than the rates
of the O-alkylation of ( S)-4 and ( R)-4 and elimination of hydro-
gen iodide from 1-iodohexadecane.
We found a good method for the O-alkylation of (
R)-4 and continued the total synthesis of 1 using ether (
a
R)-4 was not formed due to the con-
R)-
S)-4
formamide group of 11 was converted to the isonitrile group using
triphenylphosphine and carbon tetrabromide21 to afford (R)-(ꢀ)-
actisonitrile 1 in good yield. The 1H and 13C NMR spectroscopic prop-
a
a
erties of our synthetic material matched those of the reported data.9
31
a
a
The specific rotation [
with the same sign as the reported value [
a
]
values were ½aꢂD ¼ ꢀ15:1 (c 0.3, CHCl3),
D
a
a
a]
D = ꢀ7.0 (c 0.27, CHCl3).9
The enantiomeric purity of 1 was determined after conversion
aS)-4 and
of 1 to isocyanate 12 following the addition of (R)- and (S)-
ylbenzyl amines to give two diastereomers of ureas ( R)-13 and
S)-13. 1H NMR analyses of (
R)-13 and ( S)-13 in C6D6 displayed
a-meth-
(a
aS)-6.
a
Acidic debenzylation using methanesulfonic acid (MsOH)27,28 and
anisole in nitromethane, which is a good solvent for benzyl cationic
reactions,29 gave ether 8 in good yield. After hydrolysis of the oxa-
zolidinone ring of 8, N-formylation of aminoalcohol 9 with ethyl
formate19,20 gave formamide 10; the hydroxy group of 10 was acet-
ylated with acetic anhydride in pyridine. Formamide 10 and acetate
11 have been synthesized9 and the 1H and 13C NMR spectroscopic
data were in good agreement with the reported values. Finally, the
(a
a
a
well-resolved resonances for the individual diastereomers (Fig. 3).
Two different diagnostic methyl groups of the acetyl [singlet; d
1.68 for (
aR)-13, d 1.65 for (
aS)-13] and
a
-methylbenzyl groups
[doublet; d 1.21 for (
a
R)-13, d 1.18 for (
aS)-13] were observed.
No diastereomer existed in each sample in the 1H NMR spectra
(Fig. 3). Thus, actisonitrile 1 was synthesized with excellent enan-
tiomeric purity.
3. Conclusion
In conclusion, the O-alkylation of 4-hydroxymethyloxazolidin-
2-one (
with CsOHꢁH2O in DMF at room temperature (Tables 1 and 2). Un-
der these reaction conditions, O-alkylation from ( S)-3 to ( S)-7
(path C) should also proceed in the same way as the O-alkylation
from ( R)-4 to ( R)-6 did; however, ( S)-7 was not formed from
S)-4 because path B was much faster than path A (the intramolec-
ular acyl transfer). Therefore, ether ( S)-6 was obtained as the sole
aS)-4 was performed efficiently using 1-iodohexadecane
a
a
a
a
a
(a
a
product (Scheme 4). The reaction of the formamide group of 11 to
an isonitrile group using triphenylphosphine and carbon tetrabro-
mide21 was a good method to obtain enantiomerically pure actiso-
nitrile 1 in good yield (Scheme 2). In addition, enantiomeric purity
of 1 was easy to determine after the conversion of 1 to N-
a-meth-
ylbenzyl urea derivatives (
Fig. 3).
aR)-13 and (aS)-13 (Scheme 3 and
4. Experimental
Melting points were measured with Yanaco MP-3 apparatus
and are uncorrected. Optical rotations were determined on a JASCO
DIP-140 polarimeter. NMR spectra were obtained with a JEOL JNM-
LA500 (1H NMR: 500 MHz and 13C NMR: 125 MHz) and a JEOL
JNM-GSX400 (1H NMR: 400 MHz and 13C NMR: 100 MHz) spec-
trometers using tetramethylsilane as the internal standard. IR
spectra were recorded on a JASCO FT/IR-4100 spectrophotometer.
Figure 3. 1H NMR spectra of the two diastereomers (
aR)-13 (red) and (aS)-13
(black) in C6D6 (500 MHz).
Another monoalkyl serinol, (S)-2-amino-3-(dodecyloxy)propan-1-ol, has been
also synthesized from L-Boc-Ser(Bn)-OH, and exhibited anti-inflammatory and
analgesic activities.30
MS and high-resolution MS (HRMS) were taken on
a JEOL
JMS-DX302 spectrometer. Column chromatography was per-

S. Sugiyama et al. / Tetrahedron: Asymmetry 22 (2011) 1918–1923
1921
O
O
4.1.2. (S)-2-(a-Methylbenzyl)amino-1,3-propanediol (S)-2
According to our procedure,13 we synthesized (S)-2 from diethyl
NH
a
-methylbenzyl)aminomalonate ½a D28
¼ ꢀ58:3 (c 0.78, MeOH)
ꢂ
OR1
(S)-(a
6
(αS)-
{for the (R)-enantiomer, ½a D21
ꢂ
¼ þ57:1 (c 1.0, MeOH)}.13
8
b
4.1.3. (4R,
a
S)-4-Hydroxymethyl-3-(
a
-methylbenzyl)-2-oxazo
R1 = (CH2)15CH3
lidinone (
a
S)-4
NH2
According to our procedure,13 we synthesized (
aS)-4 from (S)-2.
HO
OR1
In this case we used Et3N and DMAP instead of pyridine. 2-Chloro-
ethyl chloroformate (3.15 g, 22.0 mmol) was added to a mixture of
serinol (S)-2 (4.30 g, 22.0 mmol), Et3N (2.23 g, 22.0 mmol), and
DMAP (80 mg, 0.66 mmol) in CH2Cl2 (550 mL) at room tempera-
ture. After being stirred for 1 h at room temperature and then
cooled with an ice bath, DBU (10.3 g, 66.1 mmol) was added drop-
wise to the mixture. The resulting mixture was stirred for 15 h with
warming to room temperature. The reaction mixture was washed
twice with 5% hydrochloric acid (52 mL, twice) and once with water
(52 mL). The mixture was then dried over MgSO4, filtered, and con-
centrated in vacuo. The oily residue was chromatographed on silica
gel (hexane/AcOEt, 1:2 to AcOEt) to afford a mixture of oxazolidi-
c
9
NHCHO
OR1
R2O
, R2 = H
10
d
11, R2 = Ac
e
(R)-(−)-actisonitrile 1
Scheme 2. Reagents and conditions: (a) MsOH, anisole, MeNO2, 100 °C, 3 h, 88%. (b)
LiOH, EtOH, H2O, reflux, 1 h, 99%. (c) HCO2Et, reflux, 2 h, 99%. (d) Ac2O, Py, CH2Cl2,
room temp, 2 h, 100%. (e) Ph3P, CBr4, CH2Cl2, ꢀ10 °C, 15 min, 90%.
nones (
which were recrystallized from tert-butyl methyl ether/THF
(47 mL/5 mL) to give pure ( S)-4 as colorless plates (1.55 g) and col-
orless crystalline material from the filtrate [0.87 g, ( S)-4/( S)-3,
aS)-4 and (aR)-3 (2.42 g, 50% yield) as colorless crystals,
a
a
a
93.5:6.5 (0.815 g:0.057 g), 1H NMR analysis13]. Therefore, the ratio
N=C=O
OR
a
of (
a
S)-4/(
a
S)-3 was 97.5:2.5 (2.36 g:0.06 g) ½a D27
¼ ꢀ99:1 (c 1.0,
ꢂ
actisonitrile 1
AcO
CHCl3) {for (
a
R)-3, ½a 2D9
ꢂ
¼ þ102:1 (c 1.0, CHCl3)}.13
R = (CH2)15CH3
12
4.2. O-alkylation of (aS)-4 and (aR)-4
b
b
4.2.1. Typical procedure (Table 1, entry 6)
At first, CsOHꢁH2O (84 mg, 0.50 mmol) was added to a mixture
of oxazolidinone ( R)-4 (100 mg, 0.45 mmol), 1-iodohexadecane
5a (853 L, 2.71 mmol), and powdered molecular sieves 4 Å
O
O
a
l
HN
N
Ph
HN
N
H
Ph
(150 mg) in DMF (1.1 mL),24 and the resulting mixture was stirred
for 30 min at room temperature. The reaction mixture was poured
into H2O and extracted three times with Et2O. The extracts were
combined, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was chromatographed on silica gel (hexane/AcOEt,
H
AcO
OR
AcO
OR
α
13
α
13
( R)-
( S)-
Scheme 3. Synthesis of two diastereomers to determine the enantiomeric purity of
synthetic 1 Reagents and conditions: (a) pyridine N-oxide, I2, MS 4 Å, MeCN, room
7:3) to afford (aS)-6 (118 mg, 59%).
temp, 30 min. (b) (R)- or (S)-
S)-13, 71% from 1].
a-methylbenzylamine, 60 min [(aR)-13, 74% from 1,
4.2.2. (4R,aS)-4-(Hexadecyloxymethyl)-3-(a-methylbenzyl) oxaz
(a
olidin-2-one (
a
S)-6
Rf value, 0.34 (hexane/AcOEt, 7:3). Yellow solid, mp 44–46 °C.
½
a 2D5
ꢂ
¼ ꢀ49:2 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3) d: 7.41
path A
(2H, d, J = 7.3 Hz, Ar), 7.28–7.37 (3H, m, Ar), 5.15 (1H, q,
J = 7.3 Hz, PhCH), 4.30 (1H, t, J = 8.8 Hz, OCHH), 4.12 (1H, dd,
J = 8.8, 5.4 Hz, OCHH), 3.93–3.97 (1H, m, NCH), 3.08 (1H, dt,
J = 9.3, 6.3 Hz, OCHHCH2), 3.02 (1H, dt, J = 9.3, 6.3 Hz, OCHHCH2),
2.96 (1H, dd, J = 9.7, 4.4 Hz, OCHHCHN), 2.91 (1H, dd, J = 9.8,
6.3 Hz, OCHHCHN), 1.70 (3H, d, J = 7.3 Hz, CH3), 1.39 (2H, m,
OCH2CH2), 1.25 (26H, m, C13H26), 0.88 (3H, t, J = 7.3 Hz, CH3). 13C
NMR (CDCl3, 100 MHz) d: 158.4 (C@O), 141.3 (C), 128.4 (CHꢃ2),
127.7 (C), 127.1 (CHꢃ2), 71.4 (CH2O), 70.4 (CH2O), 65.6 (CO2CH2),
53.4 (CH), 51.6 (CH2), 31.9 (CH2), 29.70 (CH2), 29.69 (CH2), 29.7
(CH2), 29.6 (CH2), 29.61 (CH2), 29.57 (CH2), 29.4 (CH2), 29.42
(CH2), 29.38 (CH2), 29.37 (CH2), 26.0 (CH2), 22.7 (CH2), 16.4 (CH),
14.1 (CH3). IR (KBr) cmꢀ1: 2916, 2858, 1733. HR-MS (positive
FAB) m/z: 446.3642 (M+1)+ (Calcd for C28H48NO3: 446.3636). MS
(positive FAB) m/z: 446 [(M+1)+], 342, 190.
(αS)-4
(αS)-6
X
(αS)-3
X
path B
path C
(αS)-7
Scheme 4. The desired O-alkylation from oxazolidinone (aS)-4 to (aS)-6 (path B).
Reagents and conditions; see Table 1 and Section 4.
formed with Kanto Chemical Silica Gel 60 (spherical, 40–50 lm)
otherwise noted. Analytical TLC was performed on plates pre-
coated with 0.25 mm layer of silica gel 60 F254 (Merck).
4.1. Synthesis of (aS)-4
4.1.1. Diethyl (S)-(
a-methylbenzyl)aminomalonate
According to our procedure,13 we synthesized this compound
4.2.3. (4S,
olidin-2-one (
This compound was obtained as the side product from the
O-alkylation of ( S)-4 (Table 1, entries 3 and 7). Rf value, 0.39
a
S)-4-(Hexadecyloxymethyl)-3-(
a-methylbenzyl)oxaz
from diethyl bromomalonate and (S)-(
a
-methylbenzyl)amine.
a
S)-7
½
a 2D8
ꢂ
¼ ꢀ58:0 (c 1.0, CHCl3) {for the (R)-enantiomer, ½a D22
¼ þ61:6
ꢂ
(c 1.1, CHCl3)}.13
a

1922
S. Sugiyama et al. / Tetrahedron: Asymmetry 22 (2011) 1918–1923
(hexane/AcOEt, 7:3). Yellow solid, mp 42–43 °C. ½a D32
ꢂ
¼ þ7:3 (c
(CH2), 29.65 (CH2), 29.62 (CH2), 29.59 (CH2), 29.5 (CH2), 29.3
(CH2), 26.1 (CH2), 22.7 (CH2), 14.1 (CH3). IR (KBr) cmꢀ1: 3343,
3122, 2928, 2853, 1472, 1052. HR-MS (positive FAB, glycerol)) m/
z: 316.3218 (M+1)+ (Calcd for C19H42NO2: 316.3218). MS (positive
FAB, glycerol) m/z: 316 [(M+1)+].
0.16, CHCl3). 1H NMR (500 MHz, CDCl3) d: 7.37 (4H, d-like m, Ar),
7.28–7.32 (1H, m, Ar), 5.18 (1H, q, J = 7.3 Hz, PhCH), 4.18 (1H, d,
J = 8.7 Hz, OCHH), 4.11 (1H, dd, J = 8.7, 3.7 Hz, OCHH), 3.51–3.56
(1H, m, NCH), 3.42 (1H, dd, J = 9.6, 5,5 Hz, OCHH), 3.31–3.38 (3H,
m, OCHH and OCH2), 1.64 (3H, d, J = 7.3 Hz, CH3), 1.51 (2H, m,
CH2), 1.26 (26H, m, CH2ꢃ13), 0.88 (3H, t, J = 7.0 Hz, CH3). 13C
NMR (CDCl3, 125 MHz) d: 158.4 (C@O), 139.2 (C, Ar), 128.7
(CHꢃ2), 127.9 (C), 127.4 (CHꢃ2), 71.8 (CH2O), 71.3 (CH2O), 65.6
(OCH2), 53.8 (CH), 52.7 (CH), 31.9 (CH2), 29.69 (CH2), 29.67 (CH2),
29.65 (CH2), 29.60 (CH2), 29.56 (CH2), 29.46 (CH2), 29.41 (CH2),
29.35 (CH2), 26.1 (CH2), 22.7 (CH2), 18.3 (CH), 14.1 (CH3). IR
4.3.3. (S)-N-(1-(Hexadecyloxy)-3-hydroxypropan-2-yl) form
amide 10
A mixture of aminoalcohol 9 (60.0 mg, 190 lmol) in ethyl for-
mate (1.9 mL) was refluxed for 2 h.19,20 After the reaction mixture
was concentrated in vacuo, the residue was chromatographed on
silica gel (AcOEt) to give formamide 10 as a colorless powder
(KBr) cmꢀ1
:
2912, 2848, 1733. HR-MS (positive FAB) m/z:
(63.9 mg, 98%). Colorless solid, mp 65–67 °C. ½a D29
¼ ꢀ13:4 (c
ꢂ
446.3637 (M+1)+ (Calcd for C28H48NO3: 446.3636). MS (positive
0.62, CHCl3). 1H NMR (500 MHz, CDCl3) d: 8.23 (1H, s, NCHO),
6.27 (1H, br s, NH), 4.14 (1H, septet J = 4.0 Hz, NCH), 3.88 (1H, br
d, J = 11.6 Hz, OCHH), 3.68–3.73 (1H, m, OCHH), 3.66 (1H, dd,
J = 9.8, 4.0 Hz, OCHH), 3.61 (1H, dd, J = 9.8, 5.8 Hz, OCHH), 3.41–
3.48 (2H, m, OCH2), 2.86 (1H, d-like m, OH), 1.54–1.60 (2H, m,
CH2), 1.26 (26H, m, CH2ꢃ13), 0.88 (3H, t, J = J = 7.0 Hz, CH3). 13C
NMR (CDCl3, 125 MHz) d: 161.2 (CHO), 72.0 (CH2O), 71.6 (CH2O),
64.1 (CH2O), 49.5 (NCH), 31.9 (CH2), 29.7 (CH2), 29.65 (CH2),
29.60 (CH2), 29.56 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 26.1
(CH2), 22.7 (CH2), 14.1 (CH3). IR (KBr) cmꢀ1: 3339, 3267, 2919,
2853, 1649. HR-MS (positive FAB) m/z: 344.3160 (M+1)+ (Calcd
for C20H42NO3: 344.3167). MS (positive FAB) m/z: 344 [(M+1)+],
102.
FAB) m/z: 446 [(M+1)+], 342, 190.
4.2.4. (4R,
olidin-2-one (
This compound was obtained as the desired product from the
O-alkylation of ( R)-4 (Table 2). Yellowish solid, mp 43–45 °C.
aR)-4-(Hexadecyloxymethyl)-3-(
a-methylbenzyl)oxaz
aR)-6
a
½
a 2D8
ꢂ
¼ ꢀ10:3 (c 0.43, MeOH). HR-MS (positive FAB) m/z:
446.3637 (M+1)+ (Calcd for C28H48NO3: 446.3636). MS (positive
FAB) m/z: 446 [(M+1)+], 342, 190. 1H NMR (CDCl3), 13C NMR
(CDCl3) and IR (KBr) spectra were identical with those of (
4.3. Total synthesis of (R)-(ꢀ)-actisonitrile 1 from ( S)-6
4.3.1. (R)-4-(Hexadecyloxymethyl)-3-oxazolidin-2-one 8
aS)-7.
a
4.3.4. (R)-2-Formamido-3-(hexadecyloxy)propyl acetate 11
Methanesulfonic acid (582 mg, 6.06 mmol) was added to a mix-
ture of 2-oxazolidinone ( S)-6 (270 mg 606 mol) and anisole
Formamide 10 (49.3 g, 144
(0.28 ml) and treated with acetic anhydride (29 mg, 280 l
l
mol) was dissolved in pyridine
a
l
mol).
(328 mg, 3.03 mmol) in MeNO2 (7.3 mL).27,28 After being stirred
for 3 h at 100 °C (bath temperature), the reaction mixture was
cooled, diluted with AcOEt and washed with saturated aqueous
NaHCO3. The aqueous layer was extracted twice with AcOEt. The
extracts were combined, washed with saturated aqueous NaCl,
dried over MgSO4, and concentrated in vacuo. The residue was
purified with silica gel column chromatography (hexane/AcOEt,
1:1) to give 8 (181 mg, 88%). Colorless solid, mp 62–65 °C.
After being stirred for 2 h at room temperature, the reaction mix-
ture was concentrated in vacuo to give pure 11 as a colorless solid
(53.8 mg, 100%). Colorless solid, mp 61–62 °C. ½a D30
¼ ꢀ4:1 (c 0.65,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3) d: 8.20 (1H, s, CHO), 5.97 (1H, br
d, J = 6.8 Hz, NH), 4.41 (1H, m, NCH), 4.24 (1H, dd, J = 11.2, 6.8 Hz,
OCHH), 4.15 (1H, dd, J = 11.2, 5.9 Hz, OCHH), 3.55 (1H, dd, J = 9.5,
3.2 Hz, OCHH), 3.46 (1H, dd, J = 9.8, 4.9 Hz, OCHH), 3.42 (2H, t,
J = 6.6 Hz, OCH2), 2.07 (3H, s, Ac), 1.54 (2H, m, CH2), 1.41–1.26
(26H, m, C13H26), 0.88 (3H, t, J = 6.8, CH3). 13C NMR (CDCl3,
100 MHz) d: 170.9 (Ac), 160.8 (NHCHO), 71.7 (CH2), 68.9 (CH2),
63.3 (CH2), 46.8 (CH), 31.9 (CH2), 29.7 (CH2), 29.4 (CH2), 26.0
(CH2), 22.7 (CH2), 20.8 (CH3), 14.1 (CH3). IR (KBr) cmꢀ1: 3280,
3066, 2919, 2848, 1732, 1662, 1527, 1463, 1384, 1266, 1115.HR-
MS (positive FAB) m/z: 386.3267 (M+1)+ (Calcd for C22H44NO4:
386.3272). MS (positive FAB) m/z: 386 [(M+1)+]. Anal. Calcd for
½
a 3D0
ꢂ
¼ þ24:7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d: 5.53
(1H, br s, NH), 4.47 (1H, t, J = 8.8 Hz, OCHH), 4.12 (1H, dd, J = 8.8,
4.9 Hz, OCHH), 3.88–4.05 (1H, m, NCH), 3.88–4.05 (1H, m, NCH),
3.44 (4H, m, CH2OCH2), 1.55 (2H, m, CH2), 1.26 (26H, m, C13H26),
0.88 (3H, t, J = 6.6 Hz). 13C NMR (CDCl3, 100 MHz) d: 159.3 (C@O),
72.5 (CH2O), 71.9 (CH2O), 67.1 (CO2CH2), 51.9 (CH2), 31.9 (CH2),
29.67 (CH2), 29.64 (CH2), 29.59 (CH2), 29.56 (CH2), 29.46 (CH2),
29.42 (CH2), 29.33 (CH2), 26.0 (CH2), 22.7 (CH2), 14.1 (CH3). IR
(KBr) cmꢀ1: 3244, 2923, 2848, 1749, 1713. HR-MS (positive FAB)
m/z: 342.3015 (M+1)+ (Calcd for C20H40NO3: 342.3010). MS (posi-
tive FAB) m/z: 342.3 [(M+1)+]. Anal. Calcd for C20H39NO3: C,
70.33; H, 11.51; N, 4.10. Found: C, 70.47; H, 11.65; N, 4.15.
C22H43NO4: C, 68.53; H, 11.24; N, 3.63. Found: C, 68.50; H, 11.31;
N, 3.57.
4.3.5. (R)-Actisonitrile 19
A solution of formamide 10 (49.8 mg, 129
lmol), triphenyl-
phosphine (102 mg, 0.48 mmol), and triethylamine (127
lL,
4.3.2. (S)-2-Amino-3-(hexadecyloxy)propan-1-ol 9
0.92 mmol) dissolved in CH2Cl2 (1.5 mL) was cooled to ꢀ10 °C. A
solution of carbon tetrabromide (173 mg, 0.52 mmol) in CH2Cl2
(0.8 mL) was added to the mixture of 10.22,23 After the reaction
mixture was stirred at –10 °C for 1 h, the reaction was quenched
by the addition of water. The resulting mixture was extracted with
Et2O. The combined organic extracts were washed with 1.0 mol/L
aqueous HCl, saturated aqueous NaHCO3 and brine, and then dried
over MgSO4. Concentration under reduced pressure afforded crude
product which was purified by silica gel chromatography (hexane/
AcOEt, 4:1) to provide 1 (42.5 mg, 90% yield). Yellow gel-like solid.
A mixture of oxazolidinone 8 (165 mg, 483
l
mol) and LiOHꢁH2O
(608 mg, 14.5 mmol) in EtOH (9.7 mL) was refluxed for 1 h. After
cooling, the reaction mixture was diluted with H2O and extracted
three times with AcOEt. The extracts were combined, dried over
MgSO4, and concentrated in vacuo. The residue was chromato-
graphed on neutral silica gel (Kanto Chemical Silica Gel 60 N,
spherical, neutral, 40–50 lm) (CHCl3/MeOH, 9:1) to afford 9 as a
colorless solid (150 mg, 99%). Colorless solid, mp 63–66 °C.
½
a 2D9
ꢂ
¼ þ3:2 (c 1.00, MeOH). 1H NMR (500 MHz, CDCl3) d: 3.64
(1H, dd, J = 11.0, 6.4 Hz, OCHH), 3.52 (1H, dd, J = 11.0, 5.2 Hz,
OCHH), 3.39–3.46 (4H, m, OCH2ꢃ2), 3.09 (1H, quint, J = 5.3 Hz,
NCH), 1.56 (2H, quint, J = 6.9 Hz, CH2), 1.26 (26 H, m, CH2ꢃ13),
0.88 (3H, t, J = 7.0 Hz, CH3). 13C NMR (CDCl3, 125 MHz) d: 73.7
(CH2O), 71.7 (CH2O), 64.9 (CH2O), 52.1 (NCH), 31.9 (CH2), 29.69
½
a 3D1
ꢂ
¼ ꢀ15:1 (c 0.3, CHCl3) {natural product, [ D = ꢀ7.0 (c 0.27,
a
]
CHCl3)}.9 1H NMR (500 MHz, CDCl3) d: 4.40 (1H, dd, J = 11.6,
4.3 Hz, OCHH), 4.20 (1H, dd, J = 11.3, 6.7 Hz, OCHH), 3.95 (1H, m,
NCH), 3.62 (2H, m, OCH2), 3.48 (2H, t, J = 6.7 Hz, OCH2), 2.12 (3H,
s, AcO), 1.56 (2H, m, CH2), 1.34–1.23 (26H, m, C13H26), 0.88 (3H,

S. Sugiyama et al. / Tetrahedron: Asymmetry 22 (2011) 1918–1923
1923
t, J = 7.0 Hz, CH3). 13C NMR (CDCl3, 125 MHz) d: 170.4 (AcO), 158.7
(NC), 72.0 (CH2), 69.1 (CH2), 62.7 (CH2), 53.0 (CH), 31.9 (CH2), 29.64
(CH2), 29.55 (CH2), 26.0 (CH2), 22.7 (CH2), 20.6 (COCH2), 14.1 (CH3).
IR (neat) cmꢀ1: 2930, 2853, 2138, 1749, 1463, 1368, 1229, 1118,
(CH2), 69.8, (CH2), 63.8 (CH2), 50.4 (CH2), 49.0 (CH), 31.9 (CH2),
29.64 (CH2), 29.34 (CH2), 26.1 (CH2), 23.3 (CH3), 22.7 (CH2), 20.8
(CH3), 14.1 (CH3). IR (KBr) cmꢀ1: 3331, 2919, 2853, 1741, 1634,
1239. HR-MS (positive FAB) m/z: 505.4004 (M+1)+ (Calcd for
1047. HR-MS (EI) m/z: 367.3079 (M) (Calcd for
C
22H41NO3:
C
30H52N2O4: 505.4008). MS (positive FAB) m/z: 505 [(M+1)+], 358.
367.3088). MS (EI) m/z: 367 (30%), 324 (60%), 294 (100%).
Acknowledgments
4.4. Synthesis of ureas (
aR)-13 and (aS)-13
The authors wish to thank the staff of the Analysis Center of
Meiji Pharmaceutical University for performing the elemental
analysis (Ms. S. Kubota) and mass spectra (Ms. T. Koseki). This
work was partially supported by a grant from the High-Tech Re-
search Center Project, the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan (S081043).
4.4.1. (R)-3-Hexadecyloxy-(3-(R)-
yl acetate ( R)-13
Urea (
a-methylbenzylureido)prop-2-
a
a
R)-13 was synthesized from 1 according to the reported
procedure.23 Iodine (0.5 mg, 0.004 mmol) was added to a solution
of actisonitrile (1) (15 mg, 0.041 mmol), pyridine N-oxide (11 mg,
0.12 mmol) and powdered molecular sieves 4Å (13 mg) in acetoni-
trile (0.7 ml). The reaction mixture was stirred at room tempera-
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arated aqueous layer was extracted with Et2O, and the combined
organic extracts were washed with saturated aqueous NaHCO3,
brine, and dried over MgSO4. Concentration followed by silica gel
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chromatography (hexane/AcOEt, 1:1) furnished urea
(
aR)-13
(15 mg, 74%). Yellow solid, mp 89–92 °C. ½a D34
ꢂ
¼ ꢀ42:6 (c 0.10,
CHCl3). 1H NMR (500 MHz, C6D6) d: 4.94 (1H, quint, J = 6.9 Hz,
PhCH), 4.28–4.42 (3H, m, NH and OCH2), 4.12–4.15 (2H, m, NH
and NCH), 3.30 (1H, dd, J = 9.5, 3.1 Hz, OCHH), 3.21 (1H, dd,
J = 9.5, 4.6 Hz, OCHH), 3.13–3.18 (2H, m, OCH2), 1.65 (3H, s, Ac),
1.46–1.51 (2H, m, CH2), 1.28–1.34 (26H, m, C13H26), 1.18 (3H, d,
J = 7.0 Hz, CH3), 0.92 (3H, t, J = 7.0 Hz, CH3). 13C NMR (CDCl3,
125 MHz) d: 171.1 (C@O), 156.9 (C@O), 144.1 (C, Ar), 128.7
(CHꢃ2, Ar), 127.3 (CH, Ar), 125.9 (CHꢃ2, Ar), 71.6 (CH2), 69.7
(CH2), 63.9 (CH2), 50.4 (CH2), 49.0 (CH), 31.9 (CH2), 29.64 (CH2),
29.34 (CH2,), 26.0 (CH2), 23.3 (CH3), 22.7 (CH2), 20.8 (CH3), 14.1
(CH3). IR (KBr) cmꢀ1: 3378, 3327, 2919, 2857, 1749, 1638, 1555.
HR-MS (positive FAB) m/z: 505.4007 (M+1)+ (Calcd for
C
30H52N2O4: 505.4008). MS (positive FAB) m/z: 505 [(M+1)+], 358.
4.4.2. (R)-3-Hexadecyloxy-(3-(S)-
yl acetate ( S)-13
Urea ( S)-13 was synthesized from 1 (28 mg, 0.076 mmol)
according to the procedure described in the synthesis of ( R)-13.
(S)- -Methylbenzylamine was used instead of (R)- -methylben-
a-methylbenzylureido)prop-2-
a
a
a
a
a
zylamine to afford (aS)-13 (27.4 mg, 71%). Yellow solid, mp 77–
80 °C. ½a 3D3
ꢂ
¼ ꢀ5:1 (c 0.06, CHCl3). 1H NMR (500 MHz, C6D6) d:
4.99 (1H, quint, J = 6.9 Hz, PhCH), 4.52 (1H, d, J = 7.9 Hz, NH),
4.29–4.37 (3H, m, NH and OCH2), 4.14 (1H, m, NCH), 3.32 (1H,
dd, J = 9.5, 3.6 Hz, OCHH), 3.15–3.26 (3H, m, OCHH and OCH2),
1.68 (3H, s, Ac), 1.46–1.50 (2H, m, CH2), 1.30–1.34 (26H, m,
C13H26), 1.21 (3H, d, J = 6.7 Hz, CH3), 0.92 (3H, t, J = 6.7 Hz, CH3).
13C NMR (CDCl3, 125 MHz) d: 170.9 (C@O), 156.8 (C@O), 144.0
(CH, Ar), 128.7 (CHꢃ2, Ar), 127.3 (CH, Ar), 125.9 (CHꢃ2), 71.6
30. Magrioti, V.; Hadjipavlou-Litina, D.; Constantinou-Kokotou, V. Bioorg. Med.
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