Total synthesis of optically active m-phenylene PGl2 derivative: Beraprost

Article abstract of DOI:10.3987/com-00-8868

The optical isomers of m-phenylene PGl₂ derivative, Beraprost, were synthesized in practical scales from optically active carboxy- cyclopenta[b]benzofurans (12 and 13) by Wittig and Wadsworth reactions as key reactions via the intermediate diols (16a and 16b).

Full text of DOI:10.3987/com-00-8868

HETEROCYCLES, Vol. 53, No. 5, 2000, pp. 1085 - 1110, Received, 7th February, 2000
TOTAL SYNTHESIS OF OPTICALLY ACTIVE m-PHENYLENE PGI
2
DERIVATIVE: BERAPROST
a
a
b
Hisanori Wakita, Hideo Yoshiwara, Hisao Nishiyama, and Hiroshi
a
Nagase*
a
Basic Research Laboratories, Toray Industries, Inc., 1111 Tebiro,
Kamakura, Kanagawa, 248-8555 Japan
b
School of Material Science, Toyohashi University of Technology,
Tempakucho, Toyohashi, Aichi, 441-8580 Japan
Abstract-The optical isomers of m-phenylene PGI derivative,
2
Beraprost, were synthesized in practical scales from optically active
carboxy-cyclopenta[b]benzofurans (1 2 and 1 3) by Wittig and
Wadsworth reactions as key reactions via the intermediate diols (16a
and 16b).
PGI , one of natural prostaglandins, has been focused on since its discovery due to
2
1
biological activities such as inhibition of platelet aggregation or vascular vasodilation.
However, it readily decomposes in acidic or even neutral media because of instability of its
enol ether linkage at C5-C6-O. We have been developed a new PGI analogue (1) with m-
2
phenylene skeleton at C5-C6-C7 in order to stabilize the enol ether part in natural PGI
2
2-6
(Figure 1).
We have also developed the stable analogue named Beraprost, whose
5
sodium salt, Beraprost Sodium, is now commercially available as an anti-platelet drug.
With regard to synthesis of Beraprost, synthetic method of its racemic mixture has been
6
already described so far. Synthetic method of optically active form of Beraprost is little
4
described. We synthesized each isomer of Beraprost in order to compare the biological
activity of 4 isomers. In this report we here disclose the results of its study on the synthesis of

CO H
CO H
CO R
2
2
2
4
4
5
5
6
6
O
O
O
H
H
H
7
7
8
8
H
H
H
HO
HO
HO
OH
OH
1 5,6,7-trinor-4,8-inter-
OH
PGI
2 R=H : Beraprost
2
m-phenylene PGI
3 R=Na : Beraprost sodium
2
Figure 1. PGI and its derivatives
2
CO H
2
CO H
2
O
O
H
9
H
8
H
H
16
HO
HO
OH
(8S,9S,16S)-form 5
OH
(8S,9S,16R)-form 6
CO H
CO H
2
2
O
O
H
H
H
H
HO
HO
OH
(8R,9R,16R)-form 7
OH
(8R,9R,16S)-form 8
Figure 2. Beraprost as a mixture of 4 isomers
optically active m-phenylene PGI derivative (5-8) (Figure 2).
2
RESULTS AND DISCUSSION
We have already reported a synthetic method of optically active 3a,8b-cis-dihydro-3H-5-
carboxy-7-bromocyclopenta[b]benzofurans (1 2 and 1 3) in practical scales by optical
7
resolution of 9 with chiral amines (1 0 and 11), respectively (Scheme 1).
We therefore adopted the bromo acids (1 2 and 1 3) as starting compounds for total
synthesis of the Beraprost isomers. In order to introduce α- and ω-side chains to 1 2 and
1 3, Wittig reaction and Prins reaction as key steps were examined to produce two important
intermediates (16a and 16b), respectively (Scheme 2); 1) Prins reaction; 2) hydrolysis; 3)

H
N
Bn
CO H
2
OH
O
H
(+)-cis-amine (10)
Br
CO H
2
H
5
6
4
O
H
12 (l -isomer of 9)
CO H
8a
Br
3a
3
7
8
H
8b
2
2
1
9
H
O
N
H
Br
Bn
OH
H
(-)-cis-amine (11)
13 (d -isomer of 9)
Scheme 1. Optical resolution of carboxylic acid (9)
CO Me
CO Me
2
2
CO Me
CO H
2
2
O
O
a
b
c
H
H
O
O
H
Br
H
3a
H
H
8b
H
OH
H
OH
OTHP
THPO
HO
HO
12: (3aS, 8bS)
13: (3aR, 8bR)
14a: (3aS, 8bS)
14b: (3aR, 8bR)
15a: (3aS, 8bS)
15b: (3aR, 8bR)
16a: (3aS, 8bS)
16b: (3aR, 8bR)
a: 1) trioxane, AcOH, H SO ; 2) 10 N aq. NaOH ; 3) H , 10% Pd/C; 4) MeOH; 5) DHP, p-TsOH; b: 1)
2
+
4
2
-
LAH; 2) MnO ; 3) Ph P CH CH CO H・Br , MeS(=O)CH Na; CH N or MeI; 4) conc. HCl; c: H ,
2
3
2
2
2
2
2
2
2
10% Pd/C
Scheme 2. Synthetic route of optically active diols (16a and 16b) (The structure of this
Scheme indicates the case of (3aS, 8bS)-form.)
hydrogenolysis; 4) methyl esterification; 5) protection of hydroxyl groups by THP; 6) reduc-
tion of ester into alcohol; 7) oxidation of the alcohol to aldehyde; 8) C-3 elongation by using
8
Wittig reaction; 9) deprotection of protective groups; 10) hydrogenation.
Thus obtained diols (16a and 16b) were converted into acetates (23a and 23b) by trityla-
tion of primary hydroxyl group, followed by acetylation of secondary hydroxyl group and
successive deprotection of trityl group (Scheme 3).
At the next step, d-isomer and l-isomer of Wadsworth reagent were necessary as starting
materials of ω-side chain. The d-isomer (1 9) and l-isomer (2 2) of Wadsworth reagent were
derived from (-)-2-methyl-4-hexynic acid (1 7) and (+)-2-methyl-4-hexynic acid (2 0) by met-

CO Me
CO Me
CO Me
2
2
2
c
a
b
O
O
O
H
3a
H
H
9
H
H
H
8b
8
OH
OH
HO
AcO
AcO
16
O
16a: (3aS, 8bS)
16b: (3aR, 8bR)
23a: (3aS, 8bS)
23b: (3aR, 8bR)
24a: (8S, 9S, 16S)
24b: (8S, 9S, 16R)
24c: (8R, 9R, 16R)
24d: (8R, 9R, 16S)
CO H
CO Me
2
2
d
O
O
H
9
H
H
H
8
15
HO
16
OH
HO
X Y
25a: X=OH, Y=H, (8S, 9S, 16S )
25b: X=OH, Y=H, (8S, 9S, 16R )
25c: X=OH, Y=H, (8R, 9R, 16R )
25d: X=OH, Y=H, (8R, 9R, 16S )
5: (8S, 9S, 16S )
6: (8S, 9S, 16R )
7: (8R, 9R, 16R )
8: (8R, 9R, 16S )
26a: X=H, Y=OH, (8S, 9S, 16S )
26b: X=H, Y=OH, (8S, 9S, 16R )
26c: X=H, Y=OH, (8R, 9R, 16R )
26d: X=H, Y=OH, (8R, 9R, 16S )
a: 1) TrCl, Et N; 2) Ac O, Py; 3) HCl; b: 1) DMSO, DCC, TFA, Py; 2) Wadsworth reagent, NaH; c: 1) NaBH ,
3
2
4
CeCl ・7H O; 2) MeONa; d: 2 N aq. NaOH
3
2
Scheme 3. Synthesis of optically active Beraprost (This Scheme indicates the case of (8S,
9S, 16S)-isomer.)
a
b
OMe
P
MeO
MeO
HO C
MeO C
2
2
O
O
17
20
18
21
19
a
b
OMe
P
HO C
MeO C
2
2
O
O
22
a: MeOH, H SO or CH N ; b: MeP(=O)(OMe) , n-BuLi
2
4
2
2
2
Scheme 4. Synthesis of optically active ω-side chain

hyl esterification and successive reaction with anion of dimethyl methylphosphonate,
respectively (Scheme 4).9
The acetate (23a) described above was in turn condensed with chiral Wadsworth reagents
(1 9 and 2 2) to yield 2 isomer forms, that is to say, (8S, 9S, 16S)-form (24a) and (8S, 9S,
16R)-form (24b), respectively (Scheme 3). The acetate (23b) was similarly condensed with
chiral Wadsworth reagents (2 2 and 1 9) to yield 2 isomer forms, that is to say, (8R, 9R, 16R)-
form (24c) and (8R, 9R, 16S)-form (24d), respectively. These isomers were converted into
15α-isomers (25a-d) and 15β-isomers (26a-d) of the corresponding methyl ester by 1,2-
10
reduction using CeCl ・7H O and NaBH in MeOH, followed by methanolysis. The obt-
3
2
4
ained 15β-isomers (26a-d) were respectively converted into 15α-isomers (25a-d) by
oxidation using MnO , followed by reduction (Scheme 5). Each 15α-isomer (25a-d) was
2
hydrolyzed into the carboxylic acid (5-8) (Scheme 3).
CO Me
CO Me
CO Me
2
2
2
O
O
O
b
H
a
H
H
H
H
H
15
HO
HO
HO
OH
26a-26d
O
OH
25a-25d
a: MnO ; b: NaBH , CeCl ・7H O
2
4
3
2
Scheme 5. Conversion of 15β-isomers into 15α-isomers (This Scheme indicates the case
of (8S, 9S, 16S)-isomer.)
Finally, these stereoisomers were assayed for inhibition of platelet aggregation. The effect
was tested in platelet-rich plasma (PRP) obtained from humans and against adenosine dip-
hosphate (ADP, 2.5-10μM)-induced aggregation (Table 1). By this assay, (8S, 9S, 16S)-
isomer (5) was found to be most active isomer.
SUMMARY
The optical isomers of m-phenylene PGI derivative, Beraprost, were synthesized by chiral
2
m-phenylene mother skeleton and chiral Wadsworth reagent. Both of the starting materials

Table 1. Anti platelet activity of 4 isomers
activity ratio compared
with Beraprost sodium
a)
compound
IC (nM)
50
Beraprost sodium
(8S, 9S, 16S)-isomer
(8S, 9S, 16R)-isomer
(8R, 9R, 16R)-isomer
(8R, 9R, 16S)-isomer
5.25
1
4.4
1.19
21.3
0.25
233
0.023
1554
0.0034
a) Each optical isomer was evaluated as its sodium salt.
in condensation were derived from the two chiral carboxylic acids. The C-3 elongation in α-
side chain of chiral m-phenylene mother skeleton was accomplished by using Wittig react-
ion.
ACKNOWLEDGEMENT
We gratefully acknowledge the late Dr. K. Ohno for his leadership and passion. And we
would like to thank Dr. T. Tajima, Ms. M. Kajita, Mr. Y. Hosono, and Mr. R. Hayashi for analy-
tical support.
EXPERIMENTAL
General. 1H NMR spectra of CDCl solution were recorded with JEOL GX-270 spectro-
3
meter at 270 MHz. IR spectra were recorded with Shimazu IR-400 spectrophotometer. MS
spectra were recorded with Hitachi RML 7-M or JEOL JMS D-300 spectrometer. Melting
points were determined on a Yanaco MP-S3 melting point apparatus and are uncorrected.
Analytical TLC was performed with Merck precoated (0.25 mm) silica gel plates. Optical
rotations were recorded with JEOL DIP-140 polarimeter at 20℃. The HPLC purity of 5, 6, 7,
and 8 was determined by measurement of the sample obtained by treatment of their sodium
salt with diazomethane. HPLC condition: chiral HPLC column YMC AK03 (4 mm I.D.×25
cm); EtOH/Hexane/H O = 2/100/0.01; detection by 280 nm; flow rate 1.0 mL/min. The peaks
2
of methyl ester (25a, 25b, 25c, and 25d) were detected at retention time = 47.5 min, 49.9
min, 54.8 min, and 57.0 min, respectively. The purity of each isomer was found to be more

than 98%.
Methyl ester (14a)
7
A mixture of the carboxylic acid (1 2) (l-isomer, 300 g, 1.07 mol, >99.5% e.e.), trioxane (
192.3 g, 2.13 mol), acetic acid (1302 g, 21.7 mol), and concentrated sulfuric acid (98%, 210
g, 2.10 mol) was refluxed at 80℃ for 4.5 h. The mixture was cooled below 50℃ and
neutralized with NaHCO (189 g, 2.25 mol). The acetic acid in the reaction mixture was
3
removed under reduced pressure.
The obtained residue was dissolved in a mixture of MeOH (3 L) and H O (0.5 L) and treated
2
with 10 N NaOH aqueous solution (1068 mL, 10.68 mol). The solution was refluxed for 2 h.
The solution was filtered through celite and the insoluble solid was washed with 70% MeOH
aqueous solution (1 L). The combined filtrates were acidified by addition of concentrated
HCl (1 L) and the organic solvent in the filtrate was evaporated. EtOAc (2 L) was added and
the organic layer was separated. The organic layer was washed with H O 3 times and each
2
aqueous layer was extracted with EtOAc. The combined organic layers were dried over
MgSO and concentrated to give an oil (421 g).
4
The obtained residue was dissolved in MeOH (3.5 L) and treated with 10% Pd/C (60 g). The
mixture was stirred under H atmosphere. After dilution with MeOH (5 L), the reaction mixt-
2
ure was refluxed for 12 h and then neutralized with NaHCO (89.6 g, 1.07 mol). After stirring
3
for 30 min, filtration through celite and concentration of the filtrate gave an oil (373 g). The
obtained residue was dissolved in THF (3 L) and treated with dihydropyran (359.2 g, 4.27
mol) and p-toluenesulfonic acid (10.0 g, 52.6 mmol). The solution was stirred for 2 h and
neutralized with pyridine (4.22 g, 53.4 mmol). The resulting solution was concentrated and
the obtained residue was dissolved in a mixture of EtOAc (2 L) and H O (0.5 L). The organic
2
layer was separated and washed with brine 3 times. Each aqueous layer was extracted with
EtOAc. The combined organic layers were dried over MgSO and evaporated. The same
4
procedure was repeated 2 times by using the carboxylic acid (1 2) (300 g, 1.07 mol).
The combined residues were briefly chromatographed on SiO (5 kg), eluting with a mixture
2
of cyclohexane and EtOAc to yield an oil (646 g). The obtained oil was further chromatogra-
phed on SiO2 (Merck Art 13905, 2 kg), eluting with a mixture of cyclohexane and EtOAc to
1
give pure oily methyl ester (14a) (560 g, 40.2%): H-NMR δ 1.10-1.95 (12H, m), 2.05-2.72

(3H, m), 3.32-4.27 (11H, m), 4.54-4.70, 4.73-5.11 (2H, m), 5.27-5.41, 5.59-5.68 (1H, m), 6.81-
6.92 (1H, m), 7.32-7.47 (1H, m), 7.65-7.78 (1H, m); IR(neat) 2944, 1726, 1714, 1447, 1135,
+
-1
1035 cm ; [α]D= +95.18゜(c 1.0, EtOH); LRMS m/z 432 (M ); HRMS calcd for C H O
24 32 7
432.2148, found 432.2129.
Preparation of triphenyl-2-carboxyethylphosphonium bromide
A solution of 3-bromopropionic acid (61.2 g, 0.400 mol) and triphenylphosphine (110.2 g,
0.420 mol) in MeCN (300 mL) was refluxed for 26 h. To the solution was added ether (400
mL) and the mixture was cooled in a refrigerator for 1 d. The precipitate was filtered out,
washed with MeCN (83 g) and ether (100 g), and dried under reduced pressure to yield
phosphonium salt (149 g, 89.7%). The same procedure was repeated 4 times by using 3-
bromopropionic acid (183.6 g, 1.2 mol) to give phosphonium salt (1660 g, 83.3%).
C-3 Elongation of methyl ester (14a)
The methyl ester (14a) (356.0 g, 0.823 mol) was dissolved in THF (3 L) and 1.5 M LiAlH -
4
THF solution (520 mL, 0.78 mol) was slowly added during 1 h at -20～-10℃. The solution
was treated with brine (50 mL) below 0℃ and then MgSO (150 g) was added to the mixture.
4
The resulting suspension was stirred for 30 min and filtered through celite. The insoluble
solid was washed with THF 5 times and the combined filtrates were concentrated to give an
oil (329.8 g).
A part of the obtained residue (283.8g) was dissolved in CH Cl (1.8 L) and treated with
2
2
MnO (610 g, 7.02 mol). The mixture was stirred at rt for 15 h and filtered through celite. The
2
insoluble solid was washed with EtOAc and the filtrate was evaporated below 40℃ to yield
aldehyde as an oil (274.0 g).
Triphenyl-2-carboxyethylphosphonium bromide (706.8 g, 1.70 mol) was dissolved in DMSO
(2.1 L) and treated with 2.6 M sodium salt of DMSO in DMSO (1309 mL, 3.40 mol) below 10
℃. To the solution was added the aldehyde (274.0 g, ca. 0.68 mol) in THF solution (800 mL)
below 10℃ and the resulting solution was heated at 50℃ for 18 h. The solution was cooled
in an ice bath and treated with iodomethane (500 g, 3.52 mol) below 10℃. The solution was
stirred at rt for 14 h. To the solution were added H O (1.5 L) and oxalic acid (53.6 g, 0.595
2
mol) and the mixture was stirred for 10 min. The solution was extracted with EtOAc 3 times
and each organic layer was washed with brine. The combined organic layers were dried

over MgSO and concentrated to give an oil (323 g). The residue was purified by column
4
chromatography (SiO , 10-25 μm, 2 kg, EtOAc/cyclohexane = 1/6) to give THP-protected
2
butenoate derivative (252.2 g, 75.4%) as an oil.
A solution of THP-protected butenoate derivative (252.0 g, 0.533 mol) in MeOH (1.5 L) was
treated with concentrated HCl (0.5 mL) and heated at 50～60℃ for 1 h. To the solution was
added NaHCO (510 mg, 6.07 mmol) and the mixture was concentrated. The residue was
3
dissolved in MeOH (1.5 L) and the resulting solution was treated with concentrated HCl (0.5
mL). The solution was heated at 50-60℃ for 1 h again. To the mixture was added NaHCO
3
(550 mg, 6.55 mmol) and the suspension was concentrated. To the residue were added
EtOAc (500 mL) and H O (50 mL). The aqueous layer was separated and extracted with
2
EtOAc 3 times. Each organic layer was washed with brine. The combined organic layers
were dried over MgSO and concentrated. The residue was purified by column chromato-
4
graphy (EtOAc/cyclohexane = 1/3 - EtOAc) to give dihydroxybutenoate derivative (15a)
(158.0 g, 97.4%). The pure dihydroxybutenoate derivative (15a) was recrystallized from a
1
mixture of EtOAc and n-hexane to give a white crystal (138.8 g, 85.6%); mp 72.0-74.0℃; H-
NMR δ 1.98-2.25 (3H, m), 2.42 (1H, br s), 2.52-2.68 (1H, m), 3.25 (2H, d, J = 5.4 Hz), 3.38
(1H, t, J = 8.3 Hz), 3.71 (3H, s), 3.70-3.82 (1H, m), 3.85-3.99 (1H, m), 4.02-4.18 (1H, m), 5.08-
5.20 (1H, m), 6.39-6.57 (2H, m), 6.81 (1H, t, J = 7.6 Hz), 7.03 (1H, d, J = 6.4 Hz), 7.15 (1H, d,
-1
J = 7.3 Hz); IR(KBr) 3200, 2930, 1735, 1442, 1230, 1142, 1065, 1030 cm ; [α]D = +93.03゜
+
(c 1.2, EtOH); LRMS m/z 304 (M ); HRMS calcd for C H O 304.1311, found 304.1323.
17 20 5
Dihydroxybutanoate derivative (16a)
A solution of dihydroxybutenoate derivative (15a) (137.8 g, 0.453 mol) in MeOH (1.5 L) was
stirred under H atmosphere in the presence of 10% Pd/C (wet 50%, 22 g) for 3 h. The mix-
2
ture was filtered and the obtained filtrate was evaporated to give an oil (135.3 g). The resid-
ue was recrystallized from a mixture of EtOAc (110 g) and n-hexane (45 g) to yield dihydroxy-
1
butanoate derivative (16a) (119 g, 85.7%): mp 61.0-63.0℃; H-NMR δ 1.58 (2H, br s), 1.72-
2.40 (6H, m), 2.48-2.70 (3H, m), 3.40 (1H, t, J = 7.9 Hz), 3.64 (3H, s), 3.70-3.85 (1H, m), 3.88-
4.03 (1H, m), 4.05-4.19 (1H, m), 5.05-5.18 (1H, m), 6.77 (1H, t, J = 7.4 Hz), 6.94 (1H, d, J =
6.9 Hz), 7.01 (1H, d, J = 7.3 Hz); IR(KBr) 3230, 2950, 1730, 1445, 1348, 1255, 1175, 1060,
+
-1
1030 cm ; [α]D = +25.29゜(c 1.2, EtOH); LRMS m/z 306(M ); HRMS calcd for C H O
17 22 5

306.1467, found 306.1469.
Acetate (23a)
A solution of dihydroxybutanoate derivative (16a) (100 g, 0.326 mol), trityl chloride (137.5 g,
0.493 mol), and triethylamine (137 mL, 0.983 mol) in THF (600 mL) was refluxed for 5.5 h.
The reaction mixture was cooled below 50℃ and treated with acetic anhydride (125 mL,
1.32 mol) and pyridine (107 mL, 1.32 mol). After reflux for 6 h followed by cooling below 10
℃, the resulting mixture was treated with 2.95 N HCl-MeOH solution (700 mL, 2.07 mol) bel-
ow 30℃ and stirred at 30℃ for 2 h. To the solution was added NaHCO (21.6 g, 0.257 mol)
3
and the resulting suspension was concentrated. The obtained residue was dissolved in a
mixture of EtOAc and H O and the organic layer was separated. The aqueous layer was ext-
2
racted with EtOAc 3 times and each organic layer was washed with 1 N HCl (300 mL) and
brine (750 mL). The combined organic layers were dried over MgSO and concentrated.
4
The residue was purified by column chromatography (Merck Art 13905, 2 kg, EtOAc / cyclo-
1
hexane = 2/3) to give acetate (23a) (93.5 g, 82.2%); H-NMR δ 1.80 (3H, s), 1.83-1.99 (2H,
m), 2.12-2.38 (4H, m), 2.47-2.70 (4H, m), 3.66 (3H, s), 3.60-3.76 (3H, m), 5.07 (1H, q, J = 5.5
Hz), 5.13-5.23 (1H, m), 6.77 (1H, t, J = 7.3 Hz), 6.93 (1H, d, J = 7.3 Hz), 7.03 (1H, d, J = 7.3
-1
Hz); IR (neat) 3400, 2955, 1730, 1452, 1365, 1240, 1040 cm ; [α]D = +25.94゜(c 1.2, EtOH);
+
LRMS m/z 348 (M ); HRMS calcd for C H O 348.1572, found 348.1542.
19 24 6
Methyl ester (14b)
7
A mixture of the carboxylic acid (1 3) (d-isomer, 300 g, 1.07 mol, >99.5% e.e.), trioxane (
192.3 g, 2.13 mol), acetic acid (1220 g, 21.3 mol), and concentrated sulfuric acid (98%, 116
mL, 2.13 mol) was refluxed at 80℃ for 7 h. The reaction solution was cooled below 50℃
and neutralized with NaHCO (197 g, 2.34 mol). The acetic acid in the reaction suspension
3
was removed under reduced pressure.
The obtained residue was dissolved in a mixture of MeOH (3 L) and H O (0.5 L) and treated
2
with 10 N NaOH (1120 mL, 11.2 mol). The solution was refluxed for 2 h. The solution was
filtered through celite and the insoluble solid was washed with 70% MeOH aqueous solution
(1 L). The combined filtrates were acidified by addition of concentrated HCl (0.5 L) and the
organic solvent was evaporated. EtOAc (2 L) was added and the organic layer was separat-
ed. The organic layer was washed with H O 3 times and each aqueous layer was extracted
2

with EtOAc. The combined organic layers were dried over MgSO and concentrated to give
4
an oil (473 g).
The obtained residue was dissolved in MeOH (3 L) and treated with 10% Pd/C (60 g). The
mixture was stirred under H atmosphere. After dilution with MeOH (5 L), the reaction mix-
2
ture was refluxed for 15 h and then neutralized with NaHCO (89.6 g, 1.07 mol) After stirring
3
for 30 min, filtration through celite and concentration of the filtrate gave an oil (394 g).
The obtained residue was dissolved in THF (3 L) and treated with dihydropyran (359.2 g,
4.27 mol) and p-toluenesulfonic acid (10.1 g, 53.1 mmol). The solution was stirred for 2 h
and neutralized with pyridine (4.2 g, 53.1 mmol). The resulting solution was concentrated
and the obtained residue was dissolved in a mixture of EtOAc (2 L) and H O (0.5 L). The
2
organic layer was separated and washed with brine 3 times. Each aqueous layer was extra-
cted with EtOAc. The combined organic layers were dried over MgSO and evaporated.
4
The same procedure was repeated 2 times by using the carboxylic acid (1 3) (300 g, 1.07
mol).
The combined residues were briefly chromatographed on SiO (5 kg), eluting with a mixture
2
of cyclohexane and EtOAc to yield an oil (684 g). The obtained oil was further chromatogra-
phed on SiO (Merck Art 13905, 2 kg), eluting with a mixture of cyclohexane and EtOAc to
2
1
give pure oily methyl ester (14b) (604.8 g, 43.6%): H-NMR δ 1.10-1.95 (12H, m), 2.05-2.65
(3H, m), 3.30-4.25 (11H, m), 4.48-4.72 (2H, m), 5.25-5.45 (1H, m), 6.85 (1H, t, J = 7.6 Hz),
7.30-7.49 (1H, m), 7.71 (1H, d, J = 7.9 Hz); IR(neat) 2941, 1728, 1713, 1446, 1292, 1136,
+
-1
1036 cm ; [α]D = -95.83゜(c 1.0, EtOH); LRMS m/z 432 (M ); HRMS calcd for C H O
24 32 7
432.2148, found: 432.2150.
C-3 Elongation of methyl ester (14b)
The methyl ester (14b) (169 g, 0.391 mol) was dissolved in THF (1.5 L) and 1.5 M LiAlH -
4
THF solution (250 mL, 0.375 mol) was slowly added during 1 h at -20～-10℃. The solution
was treated with brine (50 mL) below 0℃ and MgSO (150 g) was added to the mixture. The
4
resulting suspension was stirred for 30 min and filtered through celite. The insoluble solid
was washed with THF 5 times and the combined filtrates were concentrated to give an oil
(160.3 g).
The obtained residue (160.3 g) was dissolved in CH Cl (1.2 L) and treated with MnO
2
2
2

(344.8 g, 3.97 mol). The mixture was stirred at rt for 14 h and filtered through celite. The
insoluble solid was washed with EtOAc and the filtrate was evaporated below 40℃ to yield
aldehyde as an oil (159.2 g).
Triphenyl-2-carboxyethylphosphonium bromide (415.3 g, 1.00 mol) was dissolved in DMSO
(1.2 L) and treated with 2.6 M sodium salt of DMSO in DMSO (720 mL, 1.87 mol) below 10
℃. To the solution was added the aldehyde (159.2 g, ca. 0.39 mol) in THF solution (500 mL)
below 10℃ and the resulting solution was refluxed for 28 h. The solution was washed with
THF / cyclohexane (1/6) 3 times and the aqueous layer was acidified by addition of oxalic
acid (200 g, 2.22 mol). The aqueous layer was extracted with EtOAc (1 L × 4) and each
organic layer was washed with brine. The combined organic layers were dried over MgSO
4
and filtered. The filtrate was treated with 1 M CH N in ether solution in an ice bath. The
2
2
excess CH N was decomposed by addition of AcOH and the solution was concentrated to
2
2
give an oil ( 261.1 g ). The residue was purified by column chromatography (SiO , 10 - 25
2
μm, 2 kg, EtOAc/cyclohexane = 1/5) to give THP-protected butenoate derivative (159.2 g,
86.2%).
A solution of THP-protected butenoate derivative (159.2 g, 0.337 mol) in MeOH (1 L) was
treated with concentrated HCl (0.5 mL) and heated at 50-60℃ for 1 h. To the solution was
added NaHCO (510 mg, 6.07 mmol) and the mixture was concentrated. The residue was
3
dissolved in MeOH (1 L) and the resulting solution was treated with concentrated HCl (0.5
mL). The solution was heated at 50-60℃ for 1 h again. To the mixture was added NaHCO
(550 mg, 6.55 mmol) and the suspension was concentrated. The residue was dissolved in
3
EtOAc (300 mL) and the solution was washed with H O (30 mL). The aqueous layer was
2
extracted with EtOAc 3 times and each organic layer was washed with brine. The combined
organic layers were dried over MgSO and concentrated. The residue (107 g) was purified
4
by column chromatography (EtOAc/cyclohexane = 1/5 - EtOAc) to give dihydroxybutenoate
derivative (15b) (78.2 g, 76.3%). The pure dihydroxybutenoate derivative (15b) was
recrystallized from a mixture of EtOAc and n-hexane to give a white crystal (69.9 g, 68.2%);
1
mp 73.5-74.5℃; H-NMR δ 1.98-2.14 (2H, m), 2.37 (1H, br s), 2.53-2.64 (2H, m), 3.25 (2H,
d, J = 5.5 Hz), 3.37 (1H, t, J = 8.2 Hz), 3.70 (3H, s), 3.70-3.80 (1H, m), 3.82-3.97 (1H, m),
4.00-4.15 (1H, m), 5.08-5.20 (1H, m), 6.38-6.55 (2H, m), 6.80 (1H, t, J = 7.3 Hz), 7.03 (1H, d, J

= 7.3 Hz), 7.15 (1H, d, J = 7.3 Hz); IR(KBr) 3200, 2930, 1738, 1445, 1228, 1142, 1065, 1030
+
-1
cm ; [α]D = -98.69゜(c 1.0, EtOH); LRMS m/z 304 (M ); HRMS calcd for C H O
17 20 5
304.1311, found 304.1317.
Dihydroxybutanoate derivative (16b)
A solution of dihydroxybutenoate derivative (15b) (66.4 g, 0.218 mol) in MeOH (0.7 L) was
stirred under H atmosphere in the presence of 10% Pd/C (wet 50%, 18 g) for 4 h. The mix-
2
ture was filtered and the obtained filtrate was evaporated to give an oil. The residue was
recrystallized from a mixture of EtOAc and n-hexane to yield dihydroxybutanoate derivative
1
(16b) (58.9 g, 88.1%); mp 59.0-61.0℃; H-NMR δ 1.83-2.15 (4H, m), 2.32 (2H, t, J = 7.6
Hz), 2.48-2.70 (4H, m), 2.84 (1H, br s), 3.39 (1H, t, J = 8.2 Hz), 3.64 (3H, s), 3.67-3.78 (1H,
m), 3.83-3.95 (1H, m), 4.01-4.13 (1H, m), 5.04-5.14 (1H, m), 6.77 (1H, t, J = 7.3 Hz), 6.94 (1H,
d, J = 7.3 Hz), 7.01 (1H, d, J = 7.3 Hz); IR(KBr) 3230, 2950, 1733, 1445, 1350, 1255, 1180,
+
-1
1065 cm ; [α]D = -27.23゜(c 1.0, EtOH); LRMS m/z 306 (M ); HRMS calcd for C H O
17 22 5
306.1467, found 306.1489.
Acetate (23b)
A solution of dihydroxybutanoate derivative (16b) (104 g, 0.339 mol), trityl chloride (142.9 g,
0.513 mol), and triethylamine (143 mL, 1.03 mol) in THF (500 mL) was refluxed for 2.5 h.
The reaction mixture was cooled below 50℃ and treated with acetic anhydride (130 mL,
1.38 mol) and pyridine (111 mL, 1.37 mol). The reaction mixture was refluxed for 3 h and
cooled below 10℃. To the mixture was added 3.5 N HCl-MeOH solution (630 mL, 2.21 mol)
below 30℃ and the resulting mixture was stirred at 30℃ for 1 h. To the mixture was added
NaHCO (35 g, 0.42 mol) and the resulting mixture was concentrated. The residue was dis-
3
solved in a mixture of EtOAc and H O and the organic layer was separated. The aqueous
2
layer was extracted with EtOAc 3 times and each organic layer was washed with 1 N HCl
(300 mL) and brine (750 mL). The combined organic layers were dried over MgSO and
4
concentrated. The residue was purified by column chromatography (Merck Art 13905, 2 kg,
EtOAc/cyclohexane = 2/3) to give acetate (23b) (89.5 g, 75.8%) as an oil. The same proce-
dure was repeated by using dihydroxybutanoate derivative (16b) (25 g, 0.082 mol) to yield
1
acetate (23b) (22.3 g, 78 %); H-NMR δ 1.80 (3H, s), 1.83-1.99 (2H, m), 2.12-2.38 (4H, m),
2.47-2.70 (4H, m), 3.66 (3H, s), 3.60-3.76 (3H, m), 5.07 (1H, q, J = 5.9 Hz), 5.13-5.23 (1H, m),

6.77 (1H, t, J = 7.3 Hz), 6.94 (1H, d, J = 7.3 Hz), 7.03 (1H, d, J = 7.3 Hz); IR (neat) 3500, 2960,
+
-1
1730, 1450, 1365, 1240, 1030 cm ; [α]D = -25.94゜(c 1.2, EtOH); LRMS m/z 348 (M );
HRMS calcd for C H O 348.1572, found: 348.1524.
19 24 6
Wadsworth reagent (1 9)
9
To a solution of (-)-2-methylhexynic acid (1 7) (145 g, 1.15 mol, 99.9% e.e.) in MeOH (2.5 L)
was added concentrated sulfuric acid (5 mL) and the solution was refluxed for 24 h. The
solution was allowed to stand at rt and treated with NaHCO (10 g, 0.12 mol). The mixture
3
was concentrated to give residue (155.4 g). To the residue were added EtOAc (700 mL) and
MgSO (5 g). The mixture was filtered and the filtrate was treated with 1 M CH N solution
4
2 2
in ether (50 mL, 50 mmol) in order to esterify the unreacted acid. Distillation gave methyl
ester (1 8) (128.6 g, 79.7%); bp 65-68℃/11-12 mmHg.
Dimethyl methylphosphonate (372.3 g, 3.00 mol) was dissolved in THF (2 L). To the solution
was added 1.56 M BuLi hexane solution (1923 mL, 3.00 mol) during 1.5 h below -50℃. The
solution was stirred for 30 min and cooled below -60℃. To the solution was added a soluti-
on of methyl ester (1 8) (130 g, 0.927 mol) in THF (300 mL) during 45 min. The solution was
stirred for 1 h and the temperature of the solution was raised to -20℃. To the solution were
added EtOAc (180 mL) and H O (400 mL) and the organic layer was separated. The aque-
2
ous layer was extracted with EtOAc 3 times and each organic layer was washed with brine.
The combined organic layers were dried over MgSO and concentrated to give an oil (203
4
g). Distillation gave Wadsworth reagent (1 9) (181.4 g, 84.3%); bp 110-118℃/0.05-0.06
mmHg. The pure 1 9 was analyzed via capillary GC: 3 mm×15 m Dexil 300GC 5wt% Uniport
-1
1
- UH 80-100 mesh, 12.5 mL/min, 150-230℃/10℃min ; t = 8.1 min, GC purity 97.6%. H-
R
NMR δ 1.20 (3H, d, J = 7.3 Hz), 1.76 (3H, t, J = 2.4 Hz), 2.22-2.47 (2H, m), 2.92 (1H, dt, J =
6.7, 6.7 Hz), 3.17 (1H, dd, J = 20.1, 14.0 Hz), 3.25 (1H, dd, J = 20.1, 14.0 Hz), 3.78 (6H, d, J =
-1
21.6 Hz); IR(neat) 2957, 2921, 1713, 1458, 1259, 1183, 1030, 810 cm ; [α]D = +33.4゜(c
+
10.0, EtOH); LRMS m/z 232 (M ); HRMS calcd for C H O P 232.0864, found 232.0887.
10 17 4
Wadsworth reagent (2 2)
9
A solution of (+)-2-methylhexynic acid (2 0) (140 g, 1.11 mol, 99.6% e.e.) in EtOAc (800 mL)
was treated with 1 M CH N ether solution (1.2 L, 1.2 mol) below 10℃. Distillation gave
2
2
methyl ester (2 1) (146 g, 93.8%); bp 63-65℃/10 mmHg.

Dimethyl methylphosphonate (372.3 g, 3.00 mol) was dissolved in THF (2 L). To the solution
was added 1.56 M BuLi hexane solution (1923 mL, 3.00 mol) during 2 h below -50℃. The
solution was stirred for 30 min and cooled below -60℃. To the solution was added a soluti-
on of methyl ester (2 1) (146 g, 1.04 mol) in THF (300 mL) during 45 min. The solution was
stirred for 1 h and the temperature of the solution was raised to -20℃. To the solution were
added EtOAc (180 mL) and H O (450 mL) and the organic layer was separated. The aque-
2
ous layer was extracted with EtOAc 3 times and each organic layer was washed with brine.
The combined organic layers were dried over MgSO and concentrated to give an oil (258
4
g). Distillation gave Wadsworth reagent (2 2) (218.3 g, 90.4%); bp 115-120℃/0.03-0.07
mmHg. The pure 2 2 was analyzed under the condition described above: GC purity 99.0%.
1
H-NMR δ 1.20 (3H, d, J = 6.7 Hz), 1.76 (3H, t, J = 2.4 Hz), 2.22-2.47 (2H, m), 2.92 (1H, dt, J
= 6.7, 6.7 Hz), 3.17 (1H, dd, J = 20.1, 14.0 Hz), 3.25 (1H, dd, J = 20.1, 14.0 Hz), 3.80 (6H, d, J
-1
= 21.6 Hz); IR(neat) 2957, 2922, 1714, 1458, 1259, 1184, 1030, 810 cm ; [α]D = -32.5゜(c
+
10.1, EtOH); LRMS m/z 232 (M ); HRMS calcd for C H O P 232.0864, found 232.0892.
10 17 4
( 8S , 9S ,16S )-Enone (24a)
To a solution of acetate (23a) (60 g, 0.172 mol) and N,N'-dicyclohexylcarbodiimide (42.7 g,
0.207 mol) in THF (300 mL) were added DMSO (184 mL, 2.59 mol), trifluoroacetic acid (2.6
mL, 33.7 mmol), and pyridine (2.8 mL, 34.6 mmol). After stirring at rt for 10 h to give an alde-
hyde, the reaction mixture was cooled in an ice bath.
To a suspension of 60% NaH (8.96 g, 0.224 mol) in THF (200 mL) was added a solution of
Wadsworth reagent (1 9) (53.6 g, 0.231 mol) in THF (100 mL) below 25℃. The solution was
cooled in an ice bath. To the solution of sodium salt of Wadsworth reagent was added the
reaction mixture of the aldehyde below 10℃. The resulting suspension was stirred for 3 h
and treated with AcOH (13.4 mL, 0.234 mol). To the mixture was added cyclohexane (300
mL) and the insoluble solid was filtered off. The filtrate was concentrated and the resulting
residue was dissolved in EtOAc. The organic layer was washed with brine 3 times and each
brine layer was extracted with EtOAc. The combined organic layers were dried over MgSO4
and concentrated. The same procedure was repeated by using acetate (23a) (54 g, 0.155
mol) and the obtained residue was combined with the residue described above. The resid-
ue was purified by column chromatography (EtOAc/cyclohexane = 1/5) to give (8S,9S,16S)-

1
enone (24a) (137.0 g, 92.7%) as an oil; H-NMR δ 1.21 (3H, d, J = 7.0 Hz), 1.72-1.82 (6H,
m), 1.88-2.03 (2H, m), 2.10-2.54 (5H, m), 2.55-2.72 (3H, m), 2.87-3.02 (2H, m), 3.68 (3H, s),
3.60-3.74 (1H, m), 5.01 (1H, q, J = 6.0 Hz), 5.20-5.29 (1H, m), 6.28 (1H, dd, J = 15.8, 1.1 Hz),
6.77 (1H, t, J = 7.3 Hz), 6.83 (1H, dd, J = 15.8, 8.4 Hz), 6.95 (1H, d, J = 7.3 Hz), 6.96 (1H, d, J
-1
= 7.3 Hz); IR(neat) 2950, 1735, 1455, 1370, 1235, 1040 cm ; [α]D = +109.05゜(c 10.0,
+
EtOH); LRMS m/z 452 (M ); HRMS calcd for C H O 452.2196, found 452.2159.
27 32 6
( 8S , 9S ,16S )-Methyl ester (25a)
To a solution of (8S,9S,16S)-enone (24a) (137 g, 0.303 mol) and CeCl ・7H O (67.7 g,
3
2
0.182 mol) in MeOH (2.5 L) was added NaBH (5.75 g, 0.152 mol). To the solution was
4
added saturated NaHCO aqueous solution (150 mL). The mixture was stirred for 1 h and
3
filtered. The obtained filtrate was concentrated and the residue was treated with EtOAc and
brine. The organic layer was separated and the aqueous layer was extracted with EtOAc 3
times. Each organic layer was washed with brine and combined. The organic layer was
dried over MgSO and concentrated to give an oil (134.2 g).
4
The residue was dissolved in MeOH (2 L) and treated with 4.85 M NaOMe (11.8 mL, 57.2
mmol). The solution was stirred at rt for 20 h and neutralized by addition of AcOH (4 mL, 70
mmol). The solution was concentrated and the residue was treated with a mixture of EtOAc
(2 L) and H O (25 mL). The resulting solution was dried over MgSO (50 g) and filtered.
2
4
The filtrate was concentrated to give an oil (120.4 g). The residue was purified by column
chromatography (EtOAc/cyclohexane = 2/3-2/1) to give (8S,9S,16S)-methyl ester (25a)
(37.1 g, 29.7%) as a white crystal, its epimer at C-15 (26a) (48 g, 38%) as a white crystal,
and a mixture of 25a and 26a (8.9 g, 7.1%).
(8S,9S,16S)-methyl ester (25a)
1
mp 83.0-85.0℃ (EtOAc/cyclohexane); H-NMR δ 0.98 (3H, d, J = 6.6 Hz), 1.68-1.82 (4H, m),
1.82-2.02 (3H, m), 2.20-2.28 (2H, m), 2.28-2.42 (3H, m), 2.53-2.72 (3H, m), 3.07 (1H, br s),
3.32-3.50 (2H, m), 3.64 (3H, s), 3.80-3.91 (1H, m), 4.01 (1H, t, J = 7.3 Hz), 5.01-5.10 (1H, m),
5.48-5.70 (2H, m), 6.75 (1H, t, J = 7.5 Hz), 6.86-6.96 (2H, m); IR (KBr) 3580, 3420, 2970,
+
-1
2920, 2880, 1715, 1435, 1250 cm ; [α]D = +115.57゜(c 1.0, EtOH); LRMS m/z 412 (M );
HRMS calcd for C H O 412.2250, found 412.2237.
25 32 5
its epimer at C-15 (26a)

1
mp 120.0-122.5℃ (EtOAc/cyclohexane); H-NMR δ 1.01 (3H, d, J = 7.0 Hz), 1.72-1.85 (4H,
m), 1.85-2.05 (3H, m), 2.05-2.25 (4H, m), 2.32 (2H, t, J = 7.5 Hz), 2.49 (1H, q, J = 7.3 Hz),
2.54-2.68 (3H, m), 3.48 (1H, t, J = 8.4 Hz), 3.65 (3H, s), 3.90-3.98 (1H, m), 4.23 (1H, t, J = 4.2
Hz), 5.05-5.14 (1H, m), 5.59-5.78 (2H, m), 6.76 (1H, t, J = 7.3 Hz), 6.90-6.99 (2H, m); IR (KBr)
-1
3555, 3345, 2950, 2900, 1725, 1440, 1180 cm ; [α]D = +60.76゜(c 1.0, EtOH); LRMS m/z
+
412 (M ); HRMS calcd for C H O 412.2250, found 412.2249.
25 32 5
The obtained epimer at C-15 (26a) (41.8 g, 0.101 mol) was converted into (8S,9S,16S)-
methyl ester (25a) by oxidation using MnO (303.5 g, 3.49 mol) in CH Cl (500 mL),
2
2
2
followed by reduction using CeCl ・7H O (22.8 g, 0.0612 mol) and NaBH (1.91 g, 0.0505
3
2
4
mol) in MeOH (830 mL). The reaction mixture was worked up in the same procedure as
described above and the obtained concentrate was chromatographed together with a
mixture of 25a and 26a above-mentioned. The recycle process was repeated 4 times to
give (8S,9S,16S)-methyl ester (25a) (80.9 g, 64.8%) in total.
( 8S, 9S,16S)-Carboxylic acid (5)
To a solution of (8S,9S,16S)-methyl ester (25a) (71 g, 0.172 mol) in MeOH (1.8 L) was
added 2 N NaOH aqueous solution (260 mL, 0.52 mol) in an ice bath at such a rate that the
temperature of the reaction solution was below 10℃. The solution was stirred at rt for 28 h.
The solution was concentrated below 40℃ and the resulting residue was dissolved in H O
2
(350 mL). The solution was washed with a mixture of ether and cyclohexane (1/1, 500 mL)
and cooled below 10℃. The solution was slowly neutralized with citric acid monohydrate
(43.7 g, 0.208 mol) and extracted with EtOAc 3 times. Each organic layer was washed with
brine and combined. The organic layer was dried over MgSO and concentrated to give 78
4
g. The residue was purified by column chromatography 2 times (1st: EtOAc/cyclohexane =
1/1～EtOAc containing 1% H O, 2nd: 2-propanol/n-hexane = 1/10). The obtained acid was
2
dispersed in a mixture of EtOH (5 mL) and H O (100 mL) and freeze-dried to give
2
1
(8S,9S,16S)-carboxylic acid (5) (32.6 g, 47.6%); mp 59.1-61.0℃; H-NMR δ 0.98 (3H, d, J =
6.7 Hz), 1.68-1.82 (4H, m), 1.82-2.04 (3H, m), 2.19-2.28 (2H, m), 2.28-2.42 (3H, m), 2.51-2.70
(3H, m), 3.38 (1H, t, J = 8.9 Hz), 3.80-3.91 (1H, m), 4.01 (1H, t, J = 7.3 Hz), 5.01-5.10 (1H, m),
5.10-5.48 (3H, br s), 5.48-5.70 (2H, m), 6.74 (1H, t, J = 7.3 Hz), 6.87-6.97 (2H, m); IR(KBr)

-1
3380, 2970, 2920, 2880, 1710, 1440, 1250 cm ; [α]D = +117.37゜(c 1.0, EtOH); LRMS m/z
+
398 (M ); HRMS calcd for C H O 398.2093, found 398.2073.
24 30 5
( 8S, 9S,16R)-Enone (24b)
To a solution of acetate (23a) (53.6 g, 0.154 mol) and N,N'-dicyclohexylcarbodiimide (38.0
g, 0.184 mol) in THF (270 mL) were added DMSO (164 mL, 2.31 mol), trifluoroacetic acid
(2.3 mL, 0.031 mol), and pyridine (2.5 mL, 0.031 mol). After stirring at rt for 10 h to give an
aldehyde, the reaction mixture was cooled in an ice bath.
To a suspension of 60% NaH (8.06 g, 0.202 mol) in THF (180 mL) was added a solution of
Wadsworth reagent (2 2) (48.3 g, 0.208 mol) in THF (100 mL) below 25℃. The solution was
cooled in an ice bath. To the solution of sodium salt of Wadsworth reagent was added the
reaction mixture of the aldehyde below 10℃. The resulting suspension was stirred for 3 h
and treated with AcOH (12.1 mL, 0.211 mol). To the mixture was added cyclohexane (300
mL) and the insoluble solid was filtered off. The filtrate was concentrated and the resulting
residue was dissolved in EtOAc. The organic layer was washed with brine 3 times and each
brine layer was extracted with EtOAc. The combined organic layers were dried over MgSO
4
and concentrated. The residue was purified by column chromatography (EtOAc/cyclohexa-
1
ne = 1/5) to give (8S,9S,16R)-enone (24b) (69.0 g, 98.7%) as an oil; H-NMR δ 1.21 (3H, d,
J = 6.7 Hz), 1.70-1.82 (6H, m), 1.85-2.02 (2H, m), 2.08-2.53 (5H, m), 2.53-2.70 (3H, m), 2.83-
3.04 (2H, m), 3.66(3H, s), 3.60-3.73 (1H, m), 5.00 (1H, q, J = 6.1 Hz), 5.18-5.28 (1H, m), 6.30
(1H, dd, J = 15.9, 1.2 Hz), 6.71-6.90 (2H, m), 6.90-6.97 (2H, m); IR (neat) 2950, 1732, 1450,
+
-1
1365, 1230, 1030 cm ; [α]D = +102.50゜(c 1.0, EtOH); LRMS m/z 452 (M ); HRMS calcd for
C H O 452.2199, found 452.2222.
27 32 6
( 8S , 9S ,16R)-Methyl ester (25b)
To a solution of (8S,9S,16R)-enone (24b) (69 g, 0.152 mol) and CeCl ・7H O (34.1 g, 91.5
3
2
mmol) in MeOH (1.25 L) was added NaBH (2.90 g, 76.7 mmol). To the solution was added
4
saturated NaHCO aqueous solution (75 mL). The mixture was stirred for 1 h and filtered.
3
The obtained filtrate was concentrated and the residue was treated with EtOAc and brine.
The organic layer was separated and the aqueous layer was extracted with EtOAc 3 times.
Each organic layer was washed with brine and combined. The organic layer was dried over

MgSO and concentrated to give an oil (64.2 g).
4
The residue was dissolved in MeOH (1 L) and treated with 4.85 M NaOMe (6.0 mL, 29.1
mmol). The solution was stirred at rt for 20 h and neutralized by addition of AcOH (2 mL, 35
mmol). The solution was concentrated and the residue was treated with a mixture of EtOAc
(900 mL) and H O (15 mL). The resulting solution was dried over MgSO (40 g) and filtered.
2
4
The filtrate was concentrated to give an oil (64.8 g). The residue was purified by column
chromatography (EtOAc/cyclohexane = 2/3-2/1) to give (8S,9S,16R)-methyl ester (25b)
(18.5 g, 29.5%), its epimer at C-15 (26b) (24.7 g, 39.4%), and a mixture of 25b and 26b (5.7
g, 9.1%).
(8S,9S,16R)-methyl ester (25b)
1
mp 101.0-102.5℃ (EtOAc/cyclohexane); H-NMR δ 1.00 (3H, d, J = 6.7 Hz), 1.70-1.83 (4H,
m), 1.83-2.15 (4H, m), 2.18-2.43 (4H, m), 2.52-2.90 (5H, m), 3.47 (1H, t, J = 8.2 Hz), 3.64 (3H,
s), 3.80-3.92 (1H, m), 4.14 (1H, t, J = 5.8 Hz), 5.02-5.12 (1H, m), 5.52-5.70 (2H, m), 6.76 (1H,
t, J = 7.3 Hz), 6.94 (2H, d, J = 7.3 Hz); IR (KBr) 3580, 3420, 2960, 2940, 2880, 1710, 1435,
+
-1
1250 cm ; [α]D = +124.54゜(c 1.0, EtOH); LRMS m/z 412 (M ); HRMS calcd for C H O
25 32 5
412.2250, found 412.2226.
its epimer at C-15 (26b)
1
mp 79.0-81.0℃ (EtOAc/cyclohexane); H-NMR δ 1.02 (3H, d, J = 6.7 Hz), 1.73-1.85 (4H, m),
1.85-2.05 (3H, m), 2.20-2.36 (6H, m), 2.49 (1H, q, J = 7.9 Hz), 2.55-2.68 (3H, m), 3.38 (1H, t, J
= 8.4 Hz), 3.64 (3H, s), 3.89-4.00 (1H, m), 4.09 (1H, t, J = 5.8 Hz), 5.05-5.14 (1H, m), 5.60-
5.78 (2H, m), 6.76 (1H, t, J = 7.3 Hz), 6.92-7.01 (2H, m); IR (KBr) 3550, 3420, 2960, 2930,
+
-1
2880, 1720, 1450, 1240, 1020 cm ; [α]D = +62.87゜(c 1.0, EtOH); LRMS m/z 412 (M );
HRMS calcd for C H O 412.2250, found 412.2256.
25 32 5
The obtained epimer at C-15 (26b) (24.7 g, 0.0599 mol) was converted into (8S,9S,16R)-
methyl ester (25b) by oxidation using MnO , followed by reduction using CeCl ・7H O and
2
3
2
NaBH in MeOH in the same manner as with 26a. The concentrate obtained from the work-
4
up of the reaction was chromatographed together with a mixture of 25b and 26b above-
mentioned. The recycle process was repeated 3 times to give (8S,9S,16R)-methyl ester
(25b) (38.0 g, 60.7%) in total.
( 8S, 9S,16R)-Carboxylic acid (6)

To a solution of (8S,9S,16R)-methyl ester (25b) (28.7 g, 0.0696 mol) in MeOH (0.7 L) was
added 2 N NaOH aqueous solution (125 mL, 0.25 mol) in an ice bath at such a rate that the
temperature of reaction solution was below 10℃. The solution was stirred at rt for 32 h. The
solution was concentrated below 40℃ and the resulting residue was dissolved in H O (150
2
mL). The solution was washed with a mixture of ether and cyclohexane (1/1, 300 mL) and
cooled below 10℃. The solution was slowly neutralized with citric acid monohydrate (17.7
g, 84.2 mmol) and extracted with EtOAc 3 times. Each organic layer was washed with brine
and combined. The organic layer was dried over MgSO and concentrated to give 33 g.
4
The residue was purified by column chromatography 2 times (1st: EtOAc/cyclohexane = 1/1
～EtOAc containing 1% H O, 2nd: 2-propanol/n-hexane = 1/10). The obtained acid was
2
dispersed in a mixture of EtOH (2 mL) and H O (40 mL) and freeze-dried to give (8S,9S,
2
1
16R)-carboxylic acid (6) (13.66 g, 49.3%) as an oil; H-NMR δ 1.02 (3H, d, J = 6.7 Hz), 1.70-
1.85 (4H, m), 1.85-2.15 (4H, m), 2.18-2.45 (4H, m), 2.52-2.71 (3H, m), 3.40 (1H, t, J = 8.4 Hz),
3.82-3.95 (1H, m), 4.08-4.18 (1H, m), 4.60-5.30 (3H, br s), 5.02-5.12 (1H, m), 5.50-5.74 (2H,
m), 6.75 (1H, t, J = 7.3 Hz), 6.94 (2H, d, J = 7.3 Hz); IR(KBr) 3400, 2970, 2930, 2880, 1710,
+
-1
1450, 1250 cm ; [α]D=+115.49゜(c 1.1, EtOH); LRMS m/z 398 (M ); HRMS calcd for
C H O 398.2093, found 398.2090.
24 30 5
( 8R, 9R,16R)-Enone (24c)
To a solution of acetate (23b) (55 g, 0.158 mol) and N,N'-dicyclohexylcarbodiimide (39.0 g,
0.189 mol) in THF (280 mL) were added DMSO (168 mL, 2.37 mol), trifluoroacetic acid (2.3
mL, 0.0299 mol), and pyridine (2.5 mL, 0.0309 mol). After stirring at rt for 10 h to give an
aldehyde, the reaction mixture was cooled in an ice bath.
To a suspension of 60% NaH (8.27 g, 0.207 mol) in THF (180 mL) was added a solution of
Wadsworth reagent (2 2) (49.5 g, 0.213 mol) in THF (100 mL) below 25℃. The solution was
cooled in an ice bath. To the solution of sodium salt of Wadsworth reagent was added the
reaction mixture of the aldehyde below 10℃. The resulting suspension was stirred for 3 h
and treated with AcOH (12.1 mL, 0.211 mol). To the mixture was added cyclohexane (300
mL) and the insoluble solid was filtered off. The filtrate was concentrated and the resulting
residue was dissolved in EtOAc. The organic layer was washed with brine 3 times and each
brine layer was extracted with EtOAc. The combined organic layers were dried over

MgSO and concentrated. The residue was purified by column chromatography (EtOAc /
4
1
cyclohexane = 1/5) to give (8R,9R,16R)-enone (24c) (64.0 g, 89.2%) as an oil; H-NMR δ
1.21 (3H, d, J = 7.3 Hz), 1.70-1.82 (6H, m), 1.87-2.02 (2H, m), 2.08-2.52 (5H, m), 2.53-2.70
(3H, m), 2.87-3.00 (2H, m), 3.66 (3H, s), 3.60-3.73 (1H, m), 5.02 (1H, q, J = 6.1 Hz), 5.18-5.28
(1H, m), 6.29 (1H, d, J = 15.3 Hz), 6.78 (1H, t, J = 7.3 Hz), 6.83 (1H, dd, J = 15.3, 8.2 Hz), 6.95
(1H, d, J = 7.3 Hz), 6.97 (1H, d, J = 7.3 Hz); IR (neat) 2950, 1732, 1442, 1368, 1220, 1030
+
-1
cm ; [α]D = -113.74゜(c 1.0, EtOH); LRMS m/z 452 (M ); HRMS calcd for C H O
27 32 6
452.2199, found 452.2199.
( 8R, 9R,16R)-Methyl ester (25c)
To a solution of (8R,9R,16R)-enone (24c) (64 g, 0.141 mol) and CeCl ・7H O (31.6 g, 84.8
3
2
mmol) in MeOH (1.2 L) was added NaBH (2.685 g, 71.0 mmol). To the solution was added
4
saturated NaHCO aqueous solution (70 mL). The mixture was stirred for 1 h and filtered.
3
The obtained filtrate was concentrated and the residue was treated with EtOAc and brine.
The organic layer was separated and the aqueous layer was extracted with EtOAc 3 times.
Each organic layer was washed with brine and combined. The organic layer was dried over
MgSO and concentrated to give an oil (62.2 g).
4
The residue was dissolved in MeOH (1 L) and treated with 4.85 M NaOMe (5.5 mL, 26.7
mmol). The solution was stirred at rt for 20 h and neutralized by addition of AcOH (1.9 mL,
33 mmol). The solution was concentrated and the residue was treated with a mixture of
EtOAc (800 mL) and H O (10 mL). The resulting mixture was dried over MgSO (30 g) and
2
4
filtered. The filtrate was concentrated to give an oil (62.4 g). The residue was purified by
column chromatography (EtOAc/cyclohexane = 2/3-2/1) to give (8R,9R,16R)-methyl ester
(25c) (19.9 g, 34.2%), its epimer at C-15 (26c) (26.2 g, 45.0%), and a mixture of 25c and
26c (6.1 g, 10.5%).
(8R,9R,16R)-methyl ester (25c)
1
mp 82.0-84.0℃ (EtOAc/cyclohexane); H-NMR δ 0.98 (3H, d, J = 7.3 Hz), 1.68-1.82 (4H, m),
1.82-2.02 (3H, m), 2.20-2.28 (2H, m), 2.28-2.42 (3H, m), 2.53-2.72 (3H, m), 3.10 (2H, br s),
3.39 (1H, t, J = 9.2 Hz), 3.64 (3H, s), 3.80-3.91 (1H, m), 4.01 (1H, t, J = 7.3 Hz), 5.01-5.10 (1H,
m), 5.47-5.72 (2H, m), 6.75 (1H, t, J = 7.3 Hz), 6.86-6.96 (2H, m); IR (KBr) 3580, 3400, 2970,
+
-1
2925, 2880, 1710, 1435, 1240 cm ; [α]D = -115.13゜(c 1.0, EtOH); LRMS m/z 412 (M );

HRMS calcd for C H O 412.2250, found 412.2258.
25 32 5
its epimer at C-15 (26c)
1
mp 121.0-122.5℃ (EtOAc/cyclohexane); H-NMR δ 1.01 (3H, d, J = 7.3 Hz), 1.79 (3H, t, J =
2.4 Hz), 1.80-2.05 (4H, m), 2.05-2.27 (4H, m), 2.32 (2H, t, J = 7.3 Hz), 2.49 (1H, q, J = 7.9 Hz),
2.55-2.70 (3H, m), 3.47 (1H, t, J = 8.5 Hz), 3.65 (3H, s), 3.89-3.98 (1H, m), 4.23 (1H, t, J = 4.6
Hz), 5.05-5.14 (1H, m), 5.59-5.78 (2H, m), 6.76 (1H, t, J = 7.6 Hz), 6.90-6.99 (2H, m); IR (KBr)
-1
3540, 3420, 2970, 2930, 2880, 1715, 1440, 1240, 1020 cm ; [α]D = -65.24゜(c 1.0, EtOH);
+
LRMS m/z 412 (M ); HRMS calcd for C H O 412.2250, found 412.2247.
25 32 5
The obtained epimer at C-15 (26c) (24.7 g, 0.0599 mol) was converted into (8R,9R,16R)-
methyl ester (25c) by oxidation using MnO , followed by reduction using CeCl ・7H O and
2
3
2
NaBH in MeOH in the same manner as with 26a. The concentrate obtained from the work-
4
up of the reaction was chromatographed together with a mixture of 25c and 26c above-
mentioned. The recycle process was repeated 3 times to give (8R,9R,16R)-methyl ester
(25c) (38.2 g, 65.8%) in total.
( 8R, 9R,16R)-Carboxylic acid (7)
To a solution of (8R,9R,16R)-methyl ester (25c) (28.9 g, 0.0701 mol) in MeOH (0.8 L) was
added 2 N NaOH aqueous solution (130 mL, 0.26 mol) in an ice bath at such a rate that the
temperature of reaction solution was below 10℃. The solution was stirred at rt for 30 h. The
solution was concentrated below 40℃ and the resulting residue was dissolved in H O (150
2
mL). The solution was washed with a mixture of ether and cyclohexane (1/1, 300 mL) and
cooled below 10℃. The solution was slowly neutralized with citric acid monohydrate (18.5
g, 0.088 mol) and extracted with EtOAc 3 times. Each organic layer was washed with brine
and combined. The organic layer was dried over MgSO and concentrated to give 33 g.
4
The residue was purified by column chromatography 2 times (1st: EtOAc/cyclohexane = 1/1
～EtOAc containing 1% H O, 2nd: 2-propanol/n-hexane = 1/10). The obtained acid was dis-
2
persed in a mixture of EtOH (2 mL) and H O (35 mL) and freeze-dried to give (8R,9R,16R)-
2
1
carboxylic acid (7) (17.22 g, 61.6%); mp 61.0-63.0℃; H-NMR δ 0.97 (3H, d, J = 6.7 Hz),
1.68-1.82 (4H, m), 1.82-2.04 (3H, m), 2.19-2.28 (2H, m), 2.28-2.42 (3H, m), 2.51-2.70 (3H,
m), 3.37 (1H, t, J = 9.2 Hz), 3.80-3.91 (1H, m), 4.02 (1H, t, J = 7.3 Hz), 5.01-5.10 (1H, m),
5.10-5.48 (3H, br s), 5.48-5.70 (2H, m), 6.74 (1H, t, J = 7.3 Hz), 6.92 (2H, t, J = 7.3 Hz); IR

-1
(KBr) 3380, 2970, 2920, 2880, 1710, 1440, 1250 cm ; [α]D = -115.16゜(c 1.0, EtOH); LRMS
+
m/z 398 (M ); HRMS calcd for C H O 398.2093, found 398.2089.
24 30 5
( 8R, 9R,16S)-Enone (24d)
To a solution of acetate (23b) (55 g, 0.158 mol) and N,N'-dicyclohexylcarbodiimide (39.0 g,
0.189 mol) in THF (280 mL) were added DMSO (168 mL, 2.37 mol), trifluoroacetic acid (2.3
mL, 0.030 mol), and pyridine (2.5 mL, 0.031 mol). After stirring at rt for 10 h to give an alde-
hyde, the reaction mixture was cooled in an ice bath.
To a suspension of 60% NaH (8.27 g, 0.207 mol) in THF (180 mL) was added a solution of
Wadsworth reagent (1 9) (49.5 g, 0.213 mol) in THF (100 mL) below 25℃. The solution was
cooled in an ice bath. To the solution of sodium of Wadsworth reagent was added the reac-
tion mixture of the aldehyde below 10℃. The resulting suspension was stirred for 3 h and
treated with AcOH (12.1 mL, 0.211 mol). To the mixture was added cyclohexane (300 mL)
and the insoluble solid was filtered off. The filtrate was concentrated and the resulting
residue was dissolved in EtOAc. The organic layer was washed with brine 3 times and each
brine layer was extracted with EtOAc. The combined organic layers were dried over MgSO
4
and concentrated. The residue was purified by column chromatography (EtOAc/cyclohexa-
1
ne = 1/5) to give (8R,9R,16S)-enone (24d) (65.0 g, 91.1%) as an oil; H-NMR δ 1.21 (3H, d,
J = 6.7 Hz), 1.70-1.81 (6H, m), 1.85-2.02 (2H, m), 2.08-2.53 (5H, m), 2.53-2.70 (3H, m), 2.83-
3.01 (2H, m), 3.66 (3H, s), 3.60-3.73 (1H, m), 5.00 (1H, q, J = 6.1 Hz), 5.18-5.28 (1H, m), 6.29
(1H, d, J = 15.3 Hz), 6.78 (1H, t, J = 7.3 Hz), 6.83 (1H, dd, J = 15.3, 8.2 Hz), 6.90-6.97 (2H, m);
-1
IR (neat) 2950, 1735, 1450, 1365, 1230, 1030 cm ; [α]D = -103.55゜(c 1.4, EtOH); LRMS
+
m/z 452 (M ); HRMS calcd for C H O 452.2196, found 452.2176.
27 32 6
( 8R, 9R,16S )-Methyl ester (25d)
To a solution of (8R,9R,16S)-enone (24d) (65 g, 0.144 mol) and CeCl ・7H O (32.0 g, 85.9
3
2
mmol) in MeOH (1.2 L) was added NaBH (2.725 g, 72.0 mmol). To the solution was added
4
saturated NaHCO aqueous solution (70 mL). The mixture was stirred for 1 h and filtered.
3
The obtained filtrate was concentrated and the residue was treated with EtOAc and brine.
The organic layer was separated and the aqueous layer was extracted with EtOAc 3 times.
Each organic layer was washed with brine and combined. The organic layer was dried over

MgSO and concentrated to give an oil (61.2 g).
4
The residue was dissolved in MeOH (1 L) and treated with 4.85 M NaOMe (5.5 mL, 26.7
mmol). The solution was stirred at rt for 20 h and neutralized by addition of AcOH (1.9 mL,
33 mmol). The solution was concentrated and the residue was treated with a mixture of
EtOAc (1 L) and H O (15 mL). The resulting mixture was dried over MgSO (40 g) and
2
4
filtered. The filtrate was concentrated to give an oil (62 g). The residue was purified by
column chromatography (EtOAc/cyclohexane = 2/3-2/1) to give (8R,9R,16S)-methyl ester
(25d) (16.4 g, 27.6%), its epimer at C-15 (26d) (25.3 g, 42.6%), and a mixture of 25d and
26d (4.8 g, 8.1%).
(8R,9R,16S)-methyl ester (25d)
1
mp 102.0-104.0℃ (EtOAc/cyclohexane); H-NMR δ 1.02 (3H, d, J = 6.7 Hz), 1.70-1.83 (4H,
m), 1.83-2.15 (4H, m), 2.18-2.43 (4H, m), 2.52-2.90 (5H, m), 3.41 (1H, t, J = 8.9 Hz), 3.65 (3H,
s), 3.80-3.92 (1H, m), 4.14 (1H, t, J = 5.8 Hz), 5.02-5.12 (1H, m), 5.52-5.71 (2H, m), 6.76 (1H,
t, J = 7.3 Hz), 6.94 (2H, d, J = 7.3 Hz); IR (KBr) 3580, 3420, 2960, 2940, 2880, 1710, 1435,
+
-1
1250 cm ; [α]D = -124.02゜(c 1.0, EtOH); LRMS m/z 412 (M ); HRMS calcd for C H O
25 32 5
412.2250, found 412.2246.
its epimer at C-15 (26d)
1
mp 80.0-82.0 (EtOAc/cyclohexane); H-NMR δ 1.00 (3H, d, J = 7.3 Hz), 1.73-1.85 (4H, m),
1.85-2.05 (3H, m), 2.05-2.28 (4H, m), 2.32 (2H, t, J = 7.3 Hz), 2.50 (1H, q, J = 7.3 Hz), 2.55-
2.68 (3H, m), 3.49 (1H, t, J = 8.5 Hz), 3.65 (3H, s), 3.89-4.00 (1H, m), 4.09 (1H, t, J = 6.1 Hz),
5.07-5.16 (1H, m), 5.60-5.79 (2H, m), 6.77 (1H, t, J = 7.6 Hz), 6.92-7.01 (2H, m); IR (KBr)
-1
3550, 3350, 2950, 2930, 2900, 1725, 1440, 1210, 1185, 1000 cm ; [α]D = -59.70゜(c 1.0,
+
EtOH); LRMS m/z 412 (M ); HRMS calcd for C H O 412.2250, found 412.2224.
25 32 5
The obtained epimer at C-15 (26d) (24.3 g, 0.0589 mol) was converted into (8R,9R,16S)-
methyl ester (25d) by oxidation using MnO , followed by reduction using CeCl ・7H O and
2
3
2
NaBH in MeOH in the same manner as with 26a. The concentrate obtained from the work-
4
up of the reaction was chromatographed together with a mixture of 25d and 26d above-
mentioned. The recycle process was repeated 3 times to give (8R,9R,16S)-methyl ester
(25d) (37.4 g, 63.0%) in total.
( 8R, 9R,16S)-Carboxylic acid (8)

To a solution of (8R,9R,16S)-methyl ester (25d) (30.0 g, 0.0727 mol) in MeOH (0.8 L) was
added 2 N NaOH aqueous solution (110 mL, 0.22 mol) in an ice bath at such a rate that the
temperature of reaction solution was below 10℃. The solution was stirred at rt for 38 h. The
solution was concentrated below 40℃ and the resulting residue was dissolved in H O (150
2
mL). The solution was washed with a mixture of ether and cyclohexane (1/1, 300 mL) and
cooled below 10℃. The solution was slowly neutralized with citric acid monohydrate (18.5
g, 0.088 mol) and extracted with EtOAc 3 times. Each organic layer was washed with brine
and combined. The organic layer was dried over MgSO and concentrated to give 33 g.
4
The residue was purified by column chromatography 2 times (1st: EtOAc/cyclohexane = 1/1
～EtOAc containing 1% H O, 2nd: 2-propanol/n-hexane = 1/10). The obtained acid was dis-
2
persed in a mixture of EtOH (2 mL) and H O (40 mL) and freeze-dried to give (8R,9R,16S)-
2
1
carboxylic acid (8) (18.61 g, 64.2%) as an oil; H-NMR δ 1.02 (3H, d, J = 6.7 Hz), 1.70-1.85
(4H, m), 1.85-2.15 (4H, m), 2.18-2.45 (4H, m), 2.52-2.71 (3H, m), 3.39 (1H, t, J = 8.9 Hz),
3.82-3.93 (1H, m), 4.07-4.16 (1H, m), 4.80-5.50 (3H, br s), 5.01-5.10 (1H, m), 5.50-5.70 (2H,
m), 6.75 (1H, t, J = 7.9 Hz), 6.94 (2H, d, J = 7.9 Hz); IR (KBr) 3400, 2920, 1710, 1445, 1250,
+
-1
1190 cm ; [α]D = -118.05゜(c 1.0, EtOH); LRMS m/z 398 (M ); HRMS calcd for C H O
24 30 5
398.2093, found 398.2083.
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W. Bartmann and G. Beck, G. Angew. Chem., Int. Ed. Engl., 1982, 2 1, 751. (c) R. C.
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Org. Chem. Jpn.), 1996, 5 4, 1055.
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8. M. M. Hann, P. G. Sammes, P. D. Kennewell, and J. B. Taylor, J. Chem. Soc., Perkin
Trans. 1, 1982, 307.
9. (a) W. Skuballa, E. Schillinger, C. Sturzebecher, and H. Vorbruggen, J. Med. Chem.,
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obtained the starting materials, (-)- and (+)-2-methylhexynic acids by optical resolution.
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