Model studies toward scyphostatin: Synthesis of (S)-4-benzyl-3-(p-toluenesulfonyl)-2-oxazolidinone and its effective transformation to (S)-N-(1-benzyl-2-hydroxyethyl)hexadecanamide

Article abstract of DOI:10.3987/com-01-s(k)55

(S)-4-Benzyl-3-(p-toluenesulfonyl)-2-oxazolidinone (6) was synthesized as a simplified model substrate for the cyclohexenone subunit (2) of scyphostatin (1) starting from L-phenylalanine (3). Transformation of 6 to (S)-N-(1-benzyl-2-hydroxyethyl)hexadecan

Full text of DOI:10.3987/com-01-s(k)55

HETEROCYCLES, Vol. 56, 2002, pp. 553-560, Received, 8th August, 2001
MODEL STUDIES TOWARD SCYPHOSTATIN: SYNTHESIS
OF (S)-4-BENZYL-3-(p-TOLUENESULFONYL)-2-OXAZOLI-
DINONE AND ITS EFFECTIVE TRANSFORMATION TO (S)-
N-(1-BENZYL-2-HYDROXYETHYL)HEXADECANAMIDE‡
Takashi Izuhara,1 Wakako Yokota, Munenori Inoue, and Tadashi Katoh*
Sagami Chemical Research Center, Nishi-Ohnuma, Sagamihara, Kanagawa 229-0012,
Japan
Abstract
–
(S)-4-Benzyl-3-(p-toluenesulfonyl)-2-oxazolidinone (6) was
synthesized as a simplified model substrate for the cyclohexenone subunit (2) of
scyphostatin (1) starting from L-phenylalanine (3). Transformation of 6 to (S)-N-
(1-benzyl-2-hydroxyethyl)hexadecanamide (10) was efficiently achieved to
develop a reliable protocol for the construction of the fatty acid-substituted
aminopropanol side chain moiety present in 1; the method involves hydrolysis of
the cyclic carbamate moiety, N-palmitoylation of the liberated N-Ts-amido
function, and removal of the N-Ts protecting group as the crucial steps.
Scyphostatin (1, Figure 1), a potent inhibitor of neutral sphingomyelinase (IC50=1.0 µM) isolated from
the mycelial extract of Trichopeziza mollissima SANK 13892,2 is anticipated to be a promising
therapeutic agent for inflammation and immunological and neurological disorders.2-4 Structurally, this
natural product possesses a novel, highly oxygenated cyclohexane ring connected with an unsaturated
fatty acid-substituted aminopropanol side chain.2,5,6 Its promising biological profiles as well as unique
Figure 1. Structures of scyphostatin (1) and the cyclohexenone subunit (2)
O
O
OH
OH
O
O
OH
Me Me Me Me
O
O
NH
Me
N
Ts
O
scyphostatin (1)
2
‡ This paper is dedicated to Professor James P. Kutney of the University of British Columbia on the
occasion of his 70th birthday.

structural features make 1 an attractive target for total synthesis, which, however, has not been achieved
to date.7
During the course of our ongoing project directed toward the total synthesis of 1 and analogues,8 we have
recently developed an enantioselective route to the key cyclohexenone subunit (2) bearing the N,O-
protected aminopropanol side chain with the requisite asymmetric carbon centers.9 In order to forward the
projected synthesis to the next phase, we are strongly required to explore a reliable protocol for
constructing the fatty acid-substituted aminopropanol side chain moiety present in 1. Herein we wish to
report a synthesis of (S)-4-benzyl-3-(p-toluenesulfonyl)-2-oxazolidinone (6) starting from L-phenylala-
nine (3) (see, Scheme 1) as well as effective transformation of 6 to (S)-N-(1-benzyl-2-hydroxyethyl)hexa-
decanamide (10) (see, Scheme 2), which represents model studies for the elaboration of the fatty acid-
substituted aminopropanol side chain moiety.
As shown in Scheme 1, we initially pursued the synthesis of (S)-4-benzyl-3-(p-toluenesulfonyl)-2-
oxazolidinone (6) starting with the commercially available L-phenylalanine (3). Thus, treatment of 3 with
gaseous hydrogen chloride in methanol provided L-phenylalanine methyl ester hydrochloride,10 which
was then, without purification, reacted with p-toluenesulfonyl chloride (TsCl) in the presence of
triethylamine, affording the N-Ts protected phenylalanine derivative (4) in 79% yield for the two steps.
After reduction of the methyl ester function in 4 (100%), the resulting phenylalaninol derivative (5) was
allowed to react with phosgene dimer (trichloromethyl chloroformate) in the presence of triethylamine,
resulting in the formation of the desired oxazolidinone (6) in 88% yield.
Scheme 1. Synthesis of (S)-4-benzyl-3-(p-toluenesulfonyl)-2-oxazolidinone (6)
a
b
c
O
O
OMe
O
O
OH
OH
N
NH
NH
NH
2
Ts
Ts
Ts
3
4
5
6
(a) i) HCl, MeOH, reflux ; ii) TsCl, Et N, THF, rt, 79% ( two steps ); (b) NaBH , LiCl,
3
4
EtOH–H O ( 2:1 ), rt, 100 %; (c) Cl COCOCl, Et N, THF, 0 °C, 88%
2
3
3
With the oxazolidinone (6) serving as a model substrate for the cyclohexenone subunit (2) in hand, our
next efforts were devoted to transformation of 6 to a fatty acid-substituted aminopropanol derivative (10)
(Scheme 2). This transformation involves the following three pivotal steps: i) hydrolysis of the cyclic
carbamate moiety (6 → 5), ii) N-palmitoylation of the liberated N-Ts-amide function (7 → 8), and iii)
removal of the N-Ts protecting group (8 → 9). After several experimentations, the carbamate moiety in 6

Scheme 2.
Transformation of (S)-4-benzyl-3-(p-toluenesulfonyl)-2-oxazolidinone (6) to (S)-N-(1-benzyl-
2-hydroxyethyl)hexadecanamide (10)
a
c
OTBDMS
OR
O
O
N
Me
R
N
NH
Ts
Ts
O
6
5
7
:
:
R = H
R = TBDMS
8
9
:
:
R = Ts
R = H
b
d
e
OH
NH
Me
O
10
(a) K CO , MeOH, rt, 100%; (b) TBDMSCl, imidazole, DMF, rt, 100%; (c) NaN(SiMe ) , THF, –78 → –40 °C ;
2
3
3 2
Me(CH ) COCl, –40 → 0 °C, 86%; (d) sodium naphthalenide, DME, –70 °C, 65%; (e) TBAF, THF, rt, 85%
2 14
could be hydrolyzed readily by exposure to potassium carbonate (2.0 equiv) in methanol at room
temperature for 10 min,11 furnishing the N-Ts protected phenylalaninol (5) in quantitative yield.
Protection of the hydroxy group in 5 provided the tert-butyldimethylsilyl (TBDMS) ether (7) in
quantitative yield. Subsequent N-palmitoylation was best achieved by initial treatment of 7 with
NaN(SiMe3)2 (3.0 equiv) in THF at –78 → –40 °C followed by exposure to palmitoyl chloride (2.0
equiv) at –40 → 0 °C, giving rise to the N-palmitoyl-N-Ts-amide (8) in 86% yield. The crucial removal
of the N-Ts protecting group in 8 turned out to be effected by employing sodium naphthalenide in 1,2-
dimethoxyethane (DME) at –70 °C for 5 min,12 which led to the formation of the N-palmitoylamino-
propanol derivative (9) in 65 % yield. Finally, removal of the TBDMS group in 9 by reaction with
tetrabutylammonium fluoride (TBAF) in THF at room temperature, afforded the targeted compound (10) in
85% yield. The 1H NMR spectrum of 10 was identical with that reported13 for its (R)-enantiomer (ent-10).
In summary, we have performed model studies directed toward scyphostatin (1), which involve synthesis
of (S)-4-benzyl-3-(p-toluenesulfonyl)-2-oxazolidinone (6) starting from L-phenylalanine (3) and effective
transformation of 6 to (S)-N-(1-benzyl-2-hydroxyethyl)hexadecanamide (10). The explored protocol for
the transformation of 6 to 10 should hold great promise for constructing the fatty acid-substituted amino-
propanol side chain moiety in 1. On the basis of these model studies, further efforts toward the total
synthesis of 1 and its analogues are currently underway in our laboratories.

EXPERIMENTAL
General
All reactions involving air- and moisture-sensitive reagent were carried out using oven-dried glass ware
and standard syringe-septum cap techniques. Routine monitorings of reaction were carried out using
glass-supported Merck silica gel 60 F254 TLC plates. Flash column chromatography was performed on
Kanto Chemical Silica Gel 60 N (spherical, neutral 40-50μm) with indicated solvents. All solvents and
reagents were used as supplied with the following exceptions. Tetrahydrofuran (THF) and 1,2-
dimethoxyethane (DME) were freshly distilled from sodium/benzophenone under argon. Measurements
of optical rotation were performed with JASCO P-1020 automatic digital polarimeter. Melting points
were taken on Yanaco MP-3 micro melting point apparatus and are uncorrected. 1H and 13C NMR spectra
were measured with a Bruker DRX-500 (500 MHz) spectrometer. Chemical shifts were expressed in ppm
using tetramethylsilane (δ=0) as an internal standard. The following abbreviations are used: singlet (s),
doublet (d), triplet (t), multiplet (m), and broad (br). IR spectral measurements were carried out with a
JASCO FT/IR-5300 spectrophotometer. Low-resolution mass (MS) spectra and high-resolution mass
(HRMS) spectra were measured on a Hitachi M80-B spectrometer.
N-(p-Toluenesulfonyl)-L-phenylalanine methyl ester (4)
Dry hydrogen chloride (HCl) gas was bubbled into a stirred suspension of L-phenylalanine (3) (1.00 g,
6.1 mmol) in methanol (30 mL) at 0 °C. Then, the mixture was refluxed for 4 h. After cooling, the
mixture was concentrated in vacuo to give L-phenylalanine methyl ester hydrochloride as a white solid.
Without purification, the crude product was dissolved in THF (20 mL). Triethylamine (2.52 mL, 18
mmol) and a solution of p-toluenesulfonyl chloride (1.27 g, 6.7 mmol) in THF (10 mL) was added
successively to the above solution at 0 °C under argon. The resulting mixture was stirred for 12 h at rt.
The reaction was quenched with water (10 mL), and the mixture was extracted with Et2O (3 x 80 mL).
The combined extracts were washed with 3% aqueous HCl, saturated aqueous NaHCO3, and brine, then
dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was purified by
column chromatography (hexane–ethyl acetate, 5:2) to give 4 (1.60 g, 79%) as a white solid.
Recrystallization from hexane–dichloromethane (3:1) provided colorless needles, mp 100–101 °C and
20
1
[α]D +11.2° (c 0.97, CHCl3); H NMR (500 MHz, CDCl3) δ 2.40 (3H, s), 3.03 (2H, d, J=6.1 Hz), 3.49
(3H, s), 4.20 (1H, dt, J=6.0, 9.1 Hz), 5.03 (1H, d, J=9.1 Hz), 7.07 (2H, dd, J=2.0, 7.3 Hz), 7.20-7.27 (5H,
m), 7.63 (2H, d, J=8.3 Hz); 13C NMR (125 MHz, CDCl3) δ 21.52, 39.41, 52.36, 56.61, 127.19 (2
carbons), 127.26, 128.58 (2 carbons), 129.41 (2 carbons), 129.61 (2 carbons), 134.93, 136.66, 143.60,
171.22; IR (KBr) 550, 660, 700, 740, 810, 1090, 1160, 1220, 1340, 1440, 1500, 1600, 1740, 2950, 3280
cm-1; CIMS (isobutane) m/z 334 [(M+H)+]; Anal. Calcd for C17H19NO4: C, 61.24; H, 5.74; N, 4.20; S,
9.62. Found: C, 61.05; H, 5.85; N, 4.14; S, 9.49.
(S)-3-Phenyl-2-(N-p-toluenesulfonylamino)-1-propanol (5)
Sodium borohydride (0.37 g, 9.8 mmol) was added to a stirred solution of 4 (1.60 g, 4.8 mmol) and
lithium chloride (0.41 g, 9.7 mmol) in a mixture of ethanol (16 mL) and THF (8 mL) at 0 °C. The mixture

was stirred for 3 h at rt. The reaction was quenched with water (10 mL), and the mixture was extracted
with Et2O (3 x 80 mL). The combined extracts were washed with saturated aqueous NaHCO3 and brine,
and then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane–ethyl acetate, 1:1) to give 5 (1.52 g, 100%) as a colorless syrup:
20
1
[α]D –27.3° (c 1.30, CHCl3); H NMR (500 MHz, CDCl3) δ 2.32 (1H, t, J=5.7 Hz), 2.41 (3H, s), 2.68
(1H, dd, J=7.3, 13.8 Hz), 2.78 (1H, dd, J=7.1, 13.8 Hz), 3.45 (1H, m), 3.53 (1H, m), 3.64 (1H, ddd, J=3.9,
6.1, 11.2 Hz), 5.00 (1H, d, J=7.2 Hz), 6.97 (2H, m), 7.15-7.22 (5H, m), 7.59 (2H, d, J=8.3 Hz); 13C NMR
(125 MHz, CDCl3) δ 21.49, 37.75, 56.61, 64.00, 126.67, 126.99 (2 carbons), 128.63 (2 carbons), 129.13
(2 carbons), 129.66 (2 carbons), 136.71, 136.80, 143.36; IR (neat) 550, 580, 670, 700, 750, 810, 890, 980,
1040, 1090, 1160, 1320, 1450, 1490, 1600, 2880, 2930, 3280, 3500 cm-1; CIMS (isobutane) m/z 306
[(M+H)+]; HREIMS m/z calcd for C15H16NO2S [( M–CH2OH)+], 274.0903, found 274.0900.
(S)-4-Benzyl-3-(p-toluenesulfonyl)-2-oxazolidinone (6)
Trichloromethyl chloroformate (0.39 mL, 2.0 mmol) was added dropwise to a stirred solution of 5 (598
mg, 2.0 mmol) containing triethylamine (1.36 mL, 9.8 mmol) in THF (15 mL) at 0 °C under argon. After
2 h, the reaction was quenched with saturated aqueous NaHCO3 (10 mL), and the mixture was extracted
with Et2O (3 x 70 mL). The combined extracts were washed with 3% aqueous HCl, saturated aqueous
NaHCO3, and brine, then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue,
which was purified by column chromatography (hexane–ethyl acetate, 2:1) to give 6 (572 mg, 88%) as a
white solid. Recrystallization from hexane–dichloromethane (4:1) afforded colorless prisms, mp
20
137–138 °C and [α]D +50.3° (c 0.95, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.46 (3H, s), 2.83 (1H, dd,
J=10.2, 13.4 Hz), 3.53 (1H, dd, J=3.6, 13.4 Hz), 4.09 (1H, dd, J=3.3, 9.0 Hz), 4.15 (1H, t, J=8.4 Hz), 4.67
13
(1H, m), 7.21 (2H, d, J=7.2), 7.25-7.39 (5H, m), 8.01 (2H, d, J=8.4 Hz); C NMR (125 MHz, CDCl3) δ
21.70, 39.74, 57.97, 66.57, 127.53, 128.47 (2 carbons), 129.07 (2 carbons), 129.42 (2 carbons), 129.83 (2
carbons), 134.59, 135.15, 145.67, 152.00; IR (neat) 540, 580, 620, 670, 700, 740, 810, 1090, 1130, 1170,
1370, 1450, 1490, 1600, 1780 cm-1; EIMS m/z 331 (M+); Anal. Calcd for C17H17NO4S: C, 61.61; H, 5.17;
N, 4.23; S, 9.68. Found: C, 61.58; H, 5.26; N, 4.15; S, 9.62.
Hydrolysis of the cyclic carbamate (6) to the phenylalaninol derivative (5)
Potassium bicarbonate (42.0 mg, 0.30 mmol) was added to a stirred solution of 6 (50.0 mg, 0.15 mmol) in
methanol (3 mL) at rt. After 10 min, the mixture was diluted with Et2O (30 mL), and the organic layer
was washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4. Concentration of the
solvent in vacuo afforded a residue, which was purified by column chromatography (hexane–ethyl
acetate, 1:1) to give 5 (46.0 mg, 100%). The 1H NMR spectrum of this material was identical with that of
an authentic sample recorded for the preparation of (S)-3-phenyl-2-(N-p-toluenesulfonylamino)-1-
propanol (5).
(S)-N-[1-Benzyl-2-(tert-butyldimethylsiloxy)ethyl]-p-toluenesulfonamide (7)

tert-Butyldimethylsilyl chloride (285 mg, 1.9 mmol) was added to a stirred solution of 5 (289 mg, 0.95
mmol) and imidazole (193 mg, 2.8 mmol) in DMF (10 mL) at rt. After 12 h, the mixture was diluted with
Et2O (100 mL), and the organic layer was washed with 3% aqueous HCl, saturated aqueous NaHCO3, and
brine, then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was
purified by column chromatography (hexane–ethyl acetate, 7:1) to give 7 (397 mg, 100%) as a colorless
20
syrup: [α]D –11.0° (c 1.22, CHCl3); 1H NMR (500 MHz, CDCl3) δ –0.22 (6H, d, J=11.7 Hz), 0.87 (9H,
s), 2.40 (3H, s), 2.78 (2H, m), 3.34 (1H, dd, J=4.9, 10.1 Hz), 3.41-3.46 (2H, m), 4.75 (1H, d, J=7.9 Hz),
7.04 (2H, dd, J=1.5, 7.7 Hz), 7.16-7.23 (5H, m), 7.64 (2H, d, J=8.3 Hz); 13C NMR (125 MHz, CDCl3) δ
–5.59, –5.54, 18.19, 21.46, 25.83 (3 carbons), 37.93, 56.08, 62.98, 126.49, 126.93 (2 carbons), 128.46 (2
carbons), 129.32 (2 carbons), 129.60 (2 carbons), 137.33, 137.73, 143.15; IR (neat) 550, 590, 670, 700,
740, 780, 810, 840, 970, 1050, 1090, 1160, 1260, 1330, 1420, 1470, 1500, 1600, 2860, 2880, 2930, 2950,
3030, 3060, 3290 cm-1; CIMS (isobutane) m/z 420 [(M+H)+]; HREIMS m/z calcd for C21H30NO3SSi
[(M–Me)+], 404.1717, found 404.1726.
(S)-N-Hexadecanoyl-N-[1-benzyl-2-(tert-butyldimethylsiloxy)ethyl]-p-toluenesulfonamide (8)
Sodium bis(trimethylsilyl)amide in THF (1.0 M solution, 2.91 mL, 2.9 mmol) was added dropwise to a
stirred solution of 7 (408 mg, 0.97 mmol) in THF at –78 °C under argon. The mixture was gradually
warmed up to –40 °C over 1 h, and then a solution of palmitoyl chloride (0.54 mL, 1.8 mmol) in THF (2
mL) was added dropwise to the above mixture at –40 °C. After the resulting mixture was warmed to 0 °C
over 1 h, the stirring was further continued for 1 h at 0 °C. The mixture was diluted with Et2O (100 mL),
and the organic layer was washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography
(hexane–ethyl acetate, 15:1) to give 8 (551 mg, 86%) as a colorless syrup. Since this material contains a
small amount of impurities, further purification of 8 was performed using preparative TLC for obtaining
20
an analytical sample: [α]D –19.2° (c 1.10, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.02 (6H, s) ,0.85 (9H,
s), 0.88 (3H, t, J=6.9 Hz), 1.07-1.34 (24H, br), 1.43 (2H, br), 2.27-2.37 (1H, br), 2.39 (3H, s), 2.46 (1H,
m), 3.17 (1H, dd, J=6.8, 13.8 Hz), 3.29 (1H, dd, J=8.3, 13.8 Hz),3.88 (1H, dd, J=6.1, 10.2 Hz), 4.16 (1H,
13
br), 4.69 (1H, m), 7.13-7.30 (7H, m), 7.51 (2H, d, J=7.2 Hz); C NMR (125MHz, CDCl3) δ –5.44,
–5.41, 14.13, 18.30, 21.56, 22.70, 24.71, 25.89 (3 carbons), 28.91, 29.24, 29.37, 29.42, 29.62 (2 carbons),
29.67 (2 carbons), 29.70 (2 carbons), 29.71 (2 carbons), 31.93, 63.29, 64.82, 126.55, 127.62 (2 carbons),
128.62 (2 carbons), 129.47 (2 carbons), 129.60 (2 carbons), 137.77, 138.80, 144.08, 174.48; IR (neat)
550, 590, 670, 700, 750, 780, 810, 840, 960, 1090, 1160, 1260, 1360, 1470, 1600, 1700, 2850, 2930 cm-1;
CIMS (isobutane) m/z 658 [(M+H)+]; HREIMS m/z calcd for C34H54NO4SSi [(M–tert-Bu)+], 600.3543,
found 600.3555.
(S)-N-[1-Benzyl-2-(tert-butyldimethylsiloxy)ethyl]hexadecanamide (9)
Sodium naphthalenide in 1,2-dimethoxyethane (DME) (0.2 M solution, 3.88 mL, 0.78 mmol) was added
to a stirred solution of 8 (170 mg, 0.26 mmol) in DME (6 mL) at –70 °C under argon. After 5 min, the
reaction was quenched with water (3 mL). The mixture was poured into Et2O (60 mL), and the organic

layer was washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4. Concentration of
the solvent in vacuo afforded a residue, which was purified by column chromatography (hexane–ethyl
20
1
acetate, 5:1) to give 9 (84.0 mg, 65%) as a white amorphous solid; [α]D –20.9° (c 1.12, CHCl3); H
NMR (500 MHz, CDCl3) δ 0.05 (6H, d, J=6.7 Hz), 0.88 (3H, t, J=7.0 Hz), 0.93 (9H, s), 1.22-1.30 (24H,
br), 1.57 (2H, t, J=7.1 Hz), 2.14 (2H, t, J=7.2 Hz), 2.85 (2H, m), 3.51 (2H, d, J=3.0 Hz), 4.21 (1H, m),
13
5.68 (1H, d, J=8.6 Hz), 7.18-7.30 (5H, m); C NMR (125 MHz, CDCl3) δ –5.51, –5.39, 14.13, 18.27,
22.70, 25.74, 25.90 (3 carbons), 29.21, 29.37, 29.48, 29.64, 29.67 (2 carbons), 29.69, 29.70 (2 carbons),
31.93, 37.01, 37.08, 51.23, 62.70, 126.37, 128.39 (2 carbons), 129.40 (2 carbons), 138.19, 172.42; IR
(neat) 510, 700, 740, 780, 840, 1120, 1260, 1380, 1470, 1500, 1550, 1640, 2850, 2930, 3030, 3070, 3290
cm-1; CIMS (isobutane) m/z 504 [(M+H)+]; HREIMS m/z calcd for C27H48NO2Si [(M–tert-Bu)+],
446.3454, found 446.3436.
(S)-N-(1-Benzyl-2-hydroxyetyl)hexadecanamide (10)
Tetrabutylammonium fluoride in THF (1.0 M solution, 0.22 mL, 0.22 mmol) was added dropwise to a
stirred solution of 9 (73.0 mg, 0.15 mmol) in THF (3 mL) at rt. After 2 h, the mixture was concentrated in
vacuo to provide a residue, which was purified by column chromatography (hexane–ethyl acetate, 1:2) to
give 10 (48.0 mg, 85%) as a white solid. Recrystallization from hexane–dichloromethane (3:1) afforded
20
colorless needles, mp 98–99 °C [ lit.,13 mp 100–101 °C for the (R)-enantiomer (ent-10)] and [α]D –15.9°
(c 0.98, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.88 (3H, t, J=7.0 Hz), 1.21-1.32 (24H, br), 1.54 (2H, br),
2.13 (2H, dt, J=3.1, 7.5 Hz), 2.68 (1H, t, J=5.4 Hz), 2.87 (2H, ddd, J=7.6, 13.8, 29.3), 3.61 (1H, dt, J=5.3
11.0 Hz), 3.71 (1H, ddd, J=3.4, 5.6, 11.0 Hz), 4.17 (1H, m), 5.60 (1H, d, J=6.9 Hz), 7.19-7.34 (5H, m);
13C NMR (125 MHz,CDCl3) δ 14.12, 22.70, 25.69, 29.16, 29.33, 29.37, 29.46, 29.62, 29.66 (2 carbons),
29.69, 29.71 (2 carbons), 31.93, 36.85, 37.00, 52.98, 64.81, 126.76, 128.70 (2 carbons), 129.16 (2
carbons), 137.57, 174.02; IR (KBr) 510, 530, 630, 700, 730, 750, 960, 1060, 1090, 1120, 1190, 1220,
1230, 1250, 1270, 1380, 1460, 1470, 1560, 1650, 2850, 2920, 2960, 3030, 3090, 3300 cm-1; EIMS m/z
389 (M+); Anal. Calcd for C25H43NO2: C, 77.07; H, 11.12; N, 3.60. Found: C, 76.72; H, 11.50; N, 3.61.
The 1H NMR spectrum of this material was identical with that reported13 for its (R)-enantiomer (ent-10).
ACKNOWLEDGMENT
We thank Drs. H. Kogen and T. Ogita, Sankyo Co., Ltd., for their constant encouragement and valuable
suggestion. This work was supported in part by Sankyo Co., Ltd.
REFERENCES AND NOTES
1. Graduate student from Department of Electronic Chemistry, Tokyo Institute of Technology,
Nagatsuta, Yokohama 226-8502, Japan.
2. M. Tanaka, F. Nara, K. Suzuki-Konagai, T. Hosoya, and T. Ogita, J. Am. Chem. Soc., 1997, 119,
7871.
3. F. Nara, M. Tanaka, T. Hosoya, K. Suzuki-Konagai, and T. Ogita, J. Antibiotic, 1999, 52, 525.

4. F. Nara, M. Tanaka, S. Masuda-Inoue, Y. Yamamoto, H. Doi-Yoshioka, K. Suzuki-Konagai, S.
Kumakura, and T. Ogita, J. Antibiotic, 1999, 52, 531.
5. Initial structure elucidation2 only determined the relative and absolute stereochemistries of the
cyclohexenone moiety in 1. Recently, Kogen et al. in the Sankyo research group elucidated the
relative and absolute configurations of the three stereocenters within the C-20 unsaturated fatty acid
moiety, see: S. Saito, N. Tanaka, K. Fujimoto, and H. Kogen, Org. Lett., 2000, 2, 505.
6. Subsequently to the Kogen’s report,5 Hoye et al. presented the enantioselective synthesis of the C-20
unsaturated fatty acid moiety in 1, which led to alternative proof of its stereostructure including
absolute configuration, see: T. R. Hoye and M. A. Tennakoon, Org. Lett., 2000, 2, 1481.
7. Recently, a synthetic study toward the cyclohexenone moiety of 1 was reported by Gurjar et al., see:
M. K. Gurjar and S. Hotha, Heterocycles, 2000, 53, 1885.
8. T. Izuhara and T. Katoh, Tetrahedron Lett., 2000, 41, 7651.
9. T. Izuhara and T. Katoh, Org. Lett., 2001, 3, 1653.
10. L-Phenylalanine methyl ester hydrochloride is commercially available from Aldrich; nevertheless,
from the economical point of view, we conducted the preparation of this compound from L-phenyl-
alanine (3) following the reported protocol, see: A. McKillop, R. J. K. Taylor, R. J. Watson, and N.
Lewis, Synthesis, 1994, 31.
11. Alternatively, exposure of the oxazolidinone (6) to tert-BuOK (2.0 equiv) in tert-BuOH–THF (5:1) at
room temperature for 10 min, provided the N-Ts protected aminopropanol derivative (5) in 90 %
yield.
12. For examples for the cleavage of N-Ts-amides by the use of sodium naphthalenide, see: (a) J. M.
McIntosh and L. C. Matassa, J. Org. Chem., 1988, 53, 4452. (b) C. H. Heathcock, T. A. Blumenkopf,
and K. M. Smith, J. Org. Chem., 1989, 54, 1548. (c) Y. Ban, S. Nakajima, K. Yoshida, M. Mori, and
M. Shibasaki, Heterocycles, 1994, 39, 657. (d) T. Katoh, E. Itoh, Y. Yoshino, and S. Terashima,
Tetrahedron, 1997, 53, 10229.
13. The (R)-enantiomer (ent-10) has been previously synthesized by direct acylation of D-alaninol with
palmitic acid in the presence of 1,3-dicyclohexylcarbodiimide (DCC), see: C. Bennion, S. Connolly,
N. P. Gensmantel, C. Hallam, C. G. Jackson, W. U. Primrose, G. C. Roberts, D. H. Robinson, and P.
K. Slaich, J. Med. Chem., 1992, 35, 2939.