Synthesis of macrotetrolide α, a designed polynactin analog composed of bishomononactic acids

Article abstract of DOI:10.1016/j.tet.2011.07.012

Macrotetrolide α (1), a designed polynactin analog composed of (+)- and (-)-bishomononactic acids, was synthesized. The monomeric acids were prepared using cis-selective iodoetherification and optical resolution of the corresponding O-acetylmandelates as the key steps. Esterification and macrolactonization of the monomers were performed by Corey-Mukaiyama-Gerlach method. Compound 1 showed no immunosuppressive activity contrary to other natural polynactin congeners.

Full text of DOI:10.1016/j.tet.2011.07.012

Tetrahedron 67 (2011) 7066e7072
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of macrotetrolide
bishomononactic acids
a, a designed polynactin analog composed of
Kentaro Takai y, Tadaatsu Hanadate y, Masaki Abe, Yukie Ono, Teiko Yamada, Shigefumi Kuwahara,
*
Hiromasa Kiyota
Lab of Applied Bioorganic Chemistry, Graduate School of Agricultural Sciences, Tohoku University, 1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Macrotetrolide
a
(1), a designed polynactin analog composed of (þ)- and (ꢀ)-bishomononactic acids, was
Received 30 May 2011
Received in revised form 5 July 2011
Accepted 5 July 2011
synthesized. The monomeric acids were prepared using cis-selective iodoetherification and optical
resolution of the corresponding O-acetylmandelates as the key steps. Esterification and macro-
lactonization of the monomers were performed by CoreyeMukaiyamaeGerlach method. Compound 1
showed no immunosuppressive activity contrary to other natural polynactin congeners.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 14 July 2011
Keywords:
Polynactin
Antibiotics
Bishomononactic acid
Macrotetrolides
Total synthesis
1. Introduction
R2
O
The macrotetrolide ionophore antibiotic ‘polynactin’ family (1),
which has been isolated from various Streptomyces species1,2 is
composed of both enantiomers of nonactic acid (2a), homononactic
acid (2b) or bishomononactic acid (2c) arranged in an alternating
order (Fig.1). The macrolides and monomers showed a wide variety
of biological activities,3 such as antimicrobial, fungicidal, acaricidal,
immunosuppressive4 etc., and a mixture of the parts (1aee) is used
as an acaricide by fermentative production. Their interesting
structures have led many chemists to synthesize these monomers
and tetramers.5,6 Although there is no information about the bi-
ological activities of macrotetrolides BeG (1fei),2 the antimicrobial
and antifungal activities of nonactin (1a), monactin (1b), dinactin
(1c), and trinactin (1d) increase with increasing number of the
ethyl substituent.7 Accordingly, tetranactin (1e) and macro-
tetrolides BeG (1fei) are assumed to exhibit stronger activities. Lee
and Priestley reported that an imaginary analog composed of four
bishomononactate units (1j) was calculated to show stronger Kþ
binding ability,8 which is highly correlated with biological activity.
O
O
O
O
R3
O
(+)
(–)
O
R1
O
O
(–)
O
(+)
O
O
R4
R1
R2
R3
R4
(1a)
(1b)
(1c)
(1d)
(1e)
(1f)
nonactin
monactin
dinactin
trinactin
Me Me Me Me
Me Me Me
Et
Et
Me
Me
Et
Et
Et
Et
Me
Et
Et
tetranactin
Et
Et
macrotetrolide B
Et i-Pr
Et
i-Pr
(1g)
(1h)
(1i)
Et
Et
Et
Me i-Pr i-Pr
C
D
G
Me
Et
i-Pr
Me i-Pr Me
(1j)
macrotetrolide α
macrotetrolide β
i-Pr i-Pr i-Pr i-Pr
(1k) CF3 CF3 CF3 CF3
1l
i-Bu i-Bu i-Bu i-Bu
OH
O
This compound 1j, named macrotetrolide a 9
fluoromethyl analog, macrotetrolide
(1k)10 were synthesized by
, as well as a tri-
HO
R
O
b
R
(+)-nonactic acid
[(+)-2a] Me
[(+)-2b] Et
(+)-homononactic acid
(+)-bishomononactic acid [(+)-2c] i-P
r
* Corresponding author. Tel./fax: þ81 22 717 8785; e-mail address: kiyota@bio-
( )-methyl bishomononactate
(3) i-Pr (Me ester)
chem.tohoku.ac.jp (H. Kiyota).
y
Kentaro Takai and Tadaatsu Hanadate are the co-first authors.
Fig. 1. Polynactin congeners and their monomers.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.012

K. Takai et al. / Tetrahedron 67 (2011) 7066e7072
7067
us. Related analog 1l was reported by Coutable et al.11 Other analogs
were also prepared.12 Especially, Kusche et al. reported that non-
actin analogs with all (þ)- or all (ꢀ)-nonactic acids were bio-
logically inactive.13 In this paper, we describe the synthetic details
and immunosuppressant activity of 1j.
WadswortheEmmons reaction18 giving exclusively (E)-enone
(ꢁ)-9. The iodoetherification proceeded with a complete cis-se-
lectivity [(ꢁ)-10] and the formed iodo group was removed by
treating with Bu3SnH and AIBN to give (ꢁ)-11. The yield of each
eight steps is above 90% (overall 71%). To resolve the racemic (ꢁ)-11,
we first tried asymmetric reduction of the keto group of (ꢁ)-11 [or
(ꢁ)-9] with CBS reagent19 or Baker’s yeast.20 However, both con-
ditions gave products of only up to 46%ee probably due to the bulky
isopropyl group, on the contrary to the superior results of the
corresponding methyl ketones.20
2. Results and discussion
2.1. Synthetic plan
Next we tried the chromatographic separation of diastereomers.
Reduction of the keto group of (ꢁ)-11 with NaBH4 gave the desired
(ꢁ)-12 (40%) and (ꢁ)-8-epi-12 (60%). Although a direct inversion of
8-position of the latter failed,21 oxidation gave the parent (ꢁ)-11 in
a quantitative yield, so (ꢁ)-12 was effectively prepared (>90% yield
after five times recycle). Wang and Metz resolved (S)-mandelate of
(ꢁ)-methyl nonactate using HPLC.20b We applied their method but
used (S)-O-acetylmandelic acid (Scheme 2). In our case, the corre-
sponding esters (þ)-13 and (ꢀ)-14 were easily separated by open
silica gel chromatography (Rf¼0.38 for (þ)-13 and 0.43 for (ꢀ)-14
on silica gel TLC, hexane/EtOAc¼3:1), and the chiral auxiliary was
quantitatively removed to give both enantiomers of bishomono-
nactic acid (2c). To prepare the substrates for macrolactonization,
(þ)-2c was converted to the corresponding benzyl ester (þ)-12.
While the hydroxy group of (ꢀ)-2c was protected with TBS group to
give (ꢀ)-15, or thiol ester (ꢀ)-17 via (ꢀ)-16. The relative configu-
ration of the monomers was determined by a comparison of the 1H
NMR data with those of (þ)-12 and (ꢀ)-15 prepared from
(ꢁ)-methyl bishomononactate (3)9 in a similar manner. The abso-
Our target macrotetrolide
a
(1j) was composed of (þ)- and
(ꢀ)-bishomononactic acids (2c) in alternating order, so 1j could be
synthesized by condensation of these monomers. We had already
achieved the syntheses of (ꢁ)-2c (as its methyl ester)9 and (ꢁ)- and
(þ)-2b,14 by using cis-selective iodoetherification15 as the key step.
Since both enantiomers of 2c were necessary to construct 1j, res-
olution of (ꢁ)-2c or its synthetic intermediates would be effective.
2.2. Preparation of both enantiomers of bishomononactic
acid
In the previous paper, we reported a concise synthesis of
(ꢁ)-methyl bishomononactate (3).6b However, the methyl ester
was found to cause lowering the yield at the later hydrolysis step.16
Thus, we prepared the monomers as benzyl esters (Scheme 1). The
hydroxy group of (ꢁ)-4, our common synthetic intermediate for
polynactins6b and pamamycins,17 was protected as THP ether
[(ꢁ)-5] that was hydrolyzed and esterified again with benzyl group
to give (ꢁ)-6. The THP group was then removed [(ꢁ)-7] and the
resulting hydroxy group was oxidized to afford aldehyde (ꢁ)-8,
which was subjected to Rathke’s modified Hornere
( )-12
a
O
a
O
*
O
O
*
b
d
OR
OR
O
O
O
*
*
MeO
BnO
BnO
c
BnO
O
O
BnO
O
O
( )-4 R = H
( )-5 R = THP
( )-6 R = THP
( )-7 R = H
Ph
OAc
Ph
OAc
O
O
(+)-13
(–)-14
b
b
O
O
O
O
*
e
O
*
*
O
O
*
BnO
f
O
HO
OH
HO
d
OH
O
O
( )-8
( )-9
(+)-2c
(–)-2c
O
g
*
*
c
e
*
BnO
O
O
R
O
( )-10 R = I
( )-11 R = H
BnO
OH HO
OTBS
O
O
O
h
i
(+)-12
(–)-15
h
g
i
O
S
O
O
+
N
OR
*
*
*
*
*
*
BnO
OH
BnO
OH
*
*
O
O
( )-methyl bishomononactate
(–)-16 R = H
( )-12
( )-8-epi-12
(3)
f
(–)-17 R = TBS
Scheme 2. Optical resolution of (ꢁ)-benzyl bishomononactate. (a) i. (S)-O-ace-
tylmandelic acid, EDC, DMAP, CH2Cl2. ii. SiO2 separation [94% for (þ)-13 and quant. for
(ꢀ)-14]. (b) 1 M aq KOH, MeOHeTHF [quant. for (þ)- and (ꢀ)-2c]. (c) BnBr, t-BuOK,
DMF, 65 ꢂC (86%). (d) i. BnBr, t-BuOK, DMF 65 ꢂC (84%). ii. TBSCl, Im, THF (90%). iii. H2,
10% PdeC, MeOH (quant.). (e) (PyS)2, PPh3, THF (74%). (f) TBSOTf, 2,6-lutidine, CH2Cl2
(quant.). (g) i. (S)-(þ)-O-acetylmandelic acid, EDCI, DMAP, CH2Cl2. ii. SiO2 separation.
(h) i. 1 M aq KOH, MeOH, THF. ii. BnBr, t-BuOK, DMF, 65 ꢂC (82% from 3). (i) i. K2CO3,
MeOH. ii. TBSCl, Im, DMF. iii. 1 M aq KOH, MeOH-THF (69% from 3).
Scheme 1. Synthesis of benzyl bishomononactate. (a) DHP, PPTS, CHCl3 (96%). (b) i. 1 M
aq KOH, THFeMeOH. ii. BnBr, t-BuOK, DMF (94%). (c) TsOH, MeOH (90%). (d) Swern
oxidation. (e) (EtO)2P(]O)CH2C(]O)i-Pr, NEt3, LiBr, THF [94% from (ꢁ)-7, E only]. (f) I2
(6 equiv), NaHCO3, CH3CN, 20 ꢂC, 48 h. (g) Bu3SnH, AIBN, toluene. [93% from (ꢁ)-9, cis
only]. (h) NaBH4, MeOH [40% for (ꢁ)-12 and 60% for (ꢁ)-8-epi-12]. (i) DesseMartin
periodinane (quant.).

7068
K. Takai et al. / Tetrahedron 67 (2011) 7066e7072
lute configuration was assumed by the sign of optical rotation of
(þ)-2c with those of (þ)-2a5d and (þ)-2b.5c
O
O
BnO
O
OTBS
b
O
O
2.3. Synthesis of macrotetrolide
a
(+)-18
a
As both components of the macrolide were in hand, we con-
densed (þ)-12 and (ꢀ)-15/(ꢀ)-17 to form a dimeric compound.
Table 1 shows the attempts on the condensation. Condensation
with carbodiimides, such as DCC and EDC only proceeded under
vigorous conditions or by adding HOBt or HOAt (entries 1e7).
BOPCl gave a similar result (entry 8). Yamaguchi lactonization used
by Fleming et al. in the total synthesis of nonactin (1a) also gave
poor yields (entries 9 and 10) due to the large isopropyl substituent.
Although pyridyl thiol ester (ꢀ)-17 could be isolated by Mukaiya-
maeCorey method,22 condensation did not proceed (entry 11).
However, according to Gerlach et al.,5a addition of AgClO4 promoted
and completed the reaction within a few minutes to give desired
(þ)-18 in 86% yield (entry 12). Removal of water from the reaction
O
O
O
BnO
O
OH
O
O
O
(–)-19
O
R
O
OTBS
O
20: R = HO
c
(+)-21: R =
N
S
d
ꢀ
mixture by MS4 A was also important. Unreacted compounds were
O
O
O
recovered as (þ)-12 and (ꢀ)-15.
R1
O
O
O
O
Table 1
Condensation of the monomers
O
O
O
(+)-12
R2O
O
(–)-15
or
(–)-17
O
BnO
O
OTBS
O
O
O
(+)-18
(+)-22: R1 = BnO, R2 = TBS
(+)-23: R1 = BnO, R2 = H
Entry Substrate Conditionsa
Yield (%)
e
f
1
2
3
4
5
6
7
8
(ꢀ)-15
(ꢀ)-15
(ꢀ)-15
(ꢀ)-15
(ꢀ)-15
(ꢀ)-15
(ꢀ)-15
(ꢀ)-15
(ꢀ)-15
(ꢀ)-15
(ꢀ)-17
(ꢀ)-17
DCC (1.2), DMAP (0.2), rt
EDC (2), DMAP (0.2), rt
EDC (2), DMAP (0.2), reflux
EDC (4), DMAP (0.2), reflux
EDC (1), HOBt (1), DMAP (0.1), rt
EDC (1), HOAt (1), DMAP (0.1), rt
EDC (1), HOAt (1), DMAP (0.1), reflux
BOPCl, TEA, CH2Cl2
2,4,6-Cl3(C6H2)COCl, TEA, DMAP, MS4 A, CH2Cl2, rt 16
2,4,6-Cl3(C6H2)COCl, DMAP, THF, toluene, 65 ꢂC
Toluene, reflux
AgClO4, toluene, MS4 A, 0 ꢂC
d
Trace
12
10
17
22
(+)-24: R1 =
, R2 = H
N
S
g
18
20
O
O
ꢀ
9
O
(+)
O
(–)
10
11
12
19
Trace
86
O
O
O
ꢀ
O
(–)
O
(+)
O
a
O
O
Numbers in parenthesis are equivalent.
The dimer (þ)-18 was converted to the counterparts of tetramer,
alcohol (ꢀ)-19 and pyridyl thiol ester (þ)-21 via 20 (Scheme 3).
Both compounds were condensed by Gerlach’s method to afford
acyclic tetramer (þ)-22 in 90% yield. Again the TBS and the benzyl
group of (þ)-22 was successively removed in quantitative yield to
give hydroxy acid (þ)-23 and then (þ)-24. Finally, macro-
macrotetrolide α (1j)
Scheme 3. Synthesis of macrotetrolide
a
. (a) HF, CH3CN, 0 ꢂC (quant.). (b) H2, PdeC,
EtOH (quant.). (c) (PyS)2, Ph3P, toluene (98%). (d) AgClO4, MS4 A, toluene, 0 ꢂC (90%). (e)
ꢀ
i. HF, CH3CN, 0 ꢂC (quant.). (f) i. H2, PdeC, EtOH (88%). ii. (PyS)2, Ph3P, toluene (71%). (g)
AgClO4, MS4 A, toluene, 0 ꢂC (81%).
ꢀ
lactonization by using the same method gave macrotetrolide
a (1j)
in 81% yield. In this step none of octamer was detected. All the
reactions were very clear and all the intermediary compounds were
completely recovered in each step. So the overall yield of the con-
densation steps was nearly quantitative. Overall yield was 22% (42%
brsm) in 25 steps from (ꢁ)-4.
Table 2
Immunosuppressive and cytotoxic activities of macrotetrolide
congeners
a
and polynactin
EL4
Compounds
IC50 (ng/ml)
MLR
Macrotetrolide
Dinactin (1c)
Trinactin (1d)
Tetranactin (1e)
FK506
a
(1j)
63
250
7.8
7.8
7.8
> 5
> 50
2.4. Bioassay
3.9
3.9
3.9
0.2
13
Immunosuppressive activity of macrotetrolide
a (1j) was tested
by MLR (mixed lymphocyte reaction).23 As shown in Table 2, 1j did
not show immunosuppressive (T cell proliferation prepared from
mice of different in MHC antigens, BALB/c and C57BL/6) nor cyto-
toxic (mouse lymphoma EL4) activity compared with other poly-
nactin congeners, such as 1c, 1d, and 1e. This unexpected low
activity of 1j would be due to higher bulkiness or conformational
change of the molecule with four isopropyl substituents. Difference
in mechanism of action, not as an ionophore, would also be
considered.
Cyclosporin A
3. Conclusion
Synthesis of a novel designed polynactin analog, named mac-
rotetrolide , was synthesized in almost quantitative yield by
a

K. Takai et al. / Tetrahedron 67 (2011) 7066e7072
7069
assembly of (þ)- and (ꢀ)-bishomononactic acids. These monomeric
4.4. Benzyl (2RS,3RS)-3-tert-butoxy-6-hydroxy-2-methylhexa-
noate [( )-7]
compounds were prepared by efficient synthesis of the corre-
sponding racemic benzyl ester and optical resolution. Macro-
tetrolide
activity.
a
showed neither immunosuppressive nor cytotoxic
A mixture of (ꢁ)-6 (5.9 g,15 mmol) and TsOH (0.3 g,1.5 mmol) in
water/MeOH (1:1, 150 ml) was stirred at 20 ꢂC for 15 h. Then the
mixture was extracted with ether and the extract was washed with
a saturated aqueous NaHCO3 solution, dried over anhydrous mag-
nesium sulfate and concentrated in vacuo. The residue was chro-
matographed on silica gel (150 g). Elution with hexane/EtOAc (4:1)
4. Experimental
4.1. General
gave (ꢁ)-7 (4.4 g, 14 mmol, 90%) as a colorless oil.
OeH), 2970 (s), 2940 (s), 2870 (w), 1730 (s, C]O), 1190 (s, CeO),
1050 (s, CeO), 755 (s), 700 (s) cmꢀ1
dH (300 MHz) 1.12 (3H, d, J
n (film) 3400 (s,
Optical rotation values were measured by a Horiba Sepa-300
polarimeter. IR spectra were recorded as films by a Jasco Report-
100 spectrometer unless otherwise noted. 1H and 13C NMR spec-
tra were recorded with a Varian Inova 500 (500 MHz for 1H and
125 MHz for 13C), an MR 400 (100 MHz for 13C), and a Gemini 2000
(300 MHz for 1H and 75 MHz for 13C) spectrometers in CDCl3 with
tetramethylsilane as an internal standard. Mass spectra were
recorded with a Jeol JMSe700 spectrometer. Merck silica gel 60
(70e230 mesh) was used for column chromatography. Merck silica
gel 60 F254 (0.50 mm thickness) was used for preparative TLC.
;
7.1 Hz, 2-Me), 1.19 (9H, s, t-Bu), 1.40e1.75 (4H, m), 2.84 (1H, dq, J 7.1,
6.9 Hz, H-2), 3.53e3.62 (2H, m, H-6), 3.94 (1H, m), 5.10 (1H, d, J
12.6 Hz, CHPh), 5.16 (1H, d, J 12.6 Hz, CHPh), 7.32e7.40 (5H, m, Ph);
HRMS (FAB, NOBA): MHþ, found 309.2070. C18H29O4 requires
309.2068.
4.5. Benzyl (2RS,3RS)-3-tert-butoxy-2-methyl-6-oxohexanoate
[( )-8]
To a solution of oxalyl chloride (0.32 ml, 3.5 mmol) in dry THF
(30 ml) was added dropwise a solution of DMSO (0.60 ml, 7.0 mmol)
in dry THF (15 ml) at ꢀ78 ꢂC, and the mixture was stirred for 5 min.
Then a solution of (ꢁ)-7 (1.0 g, 3.2 mmol) in dry THF (15 ml) was
added dropwise and resulting mixture was stirred for 30 min before
Et3N (3.0 ml, 21 mmol) was added dropwise to the mixture. Then the
mixture was stirred for 0.5 h while the temperature was gradually
raised to 20 ꢂC. To the reaction mixture was added water and the
resulting solution was extracted with ether. The extract was washed
with water, dried over anhydrous magnesium sulfate, and concen-
trated in vacuo to give aldehyde (ꢁ)-8 (1.1 g, 3.2 mmol) as a pale
yellow oil. This aldehyde was used in the next step without further
4.2. Methyl (2RS,3RS)-3-tert-butoxy-2-methyl-6-(tetrahydro-
pyran-20-yloxy)hexanoate [( )-5]
To a solution of (ꢁ)-46b,17 (10 g, 43 mmol) and PPTS (1.0 g,
4.0 mmol) in dry CHCl3 (200 ml) was added dropwise 3,4-dihydro-
2H-pyran (DHP, 4.6 ml, 50 mmol) at 0 ꢂC and the mixture was
stirred at 0 ꢂC for 5 h. Then to this was added a saturated aqueous
NaHCO3 solution and extracted with ether. The extract was washed
with brine, dried over anhydrous magnesium sulfate, and concen-
trated in vacuo. The residue was chromatographed on silica gel.
Elution with hexane/EtOAc (5:1) gave (ꢁ)-5 (13 g, 41 mmol, 96%) as
purification.
n
(film) 2720 (m), 1740 (br s, C]O), 1460 (w), 1430 (m),
dH (300 MHz) 1.14 (3H, d, J
a colorless oil.
n
(film) 2960 (s), 2875 (m), 1740 (s, C]O), 1460 (m),
dH (500 MHz) 1.11 (3H, d, J 7.1 Hz, 2-Me), 1.19 (9H, s,
1390 (m),1360 (s),1250 (s),1200 (s) cmꢀ1
;
1360 (m) cmꢀ1
;
7.2 Hz, 2-Me),1.16 (9H, s, t-Bu),1.60e1.81 (2H, m, H-4), 2.42 (2H, dt, J
7.8,1.6 Hz, H-5), 2.79 (1H, dq, J 7.1, 6.9 Hz, H-2), 3.93 (1H, m, H-3), 5.10
(1H, d, J 12.6 Hz, CHPh), 5.16 (1H, d, J 12.6 Hz, CHPh), 7.32e7.40 (5H,
m, Ph), 9.69 (1H, t, J 1.6 Hz, CHO).
t-Bu),1.40e1.75 (9H, m),1.82 (1H, m), 2.74 (1H, dq, J 7.1, 6.8 Hz, H-2),
3.38 (1H, m), 3.51 (1H, m), 3.67 (3H, s, OMe), 3.72 (1H, m),
3.83e3.92 (2H, m), 4.14 (1H, m), 4.58 (1H, m, OCHO); m/z (FAB,
NOBA) 317 (MHþ), 233 (MHeTHPþ); HRMS (FAB, NOBAþPEG):
MHþ, found 317.2323. C17H33O5 requires 317.2326.
4.6. Benzyl (2RS,3RS)-3-tert-butoxy-2,9-dimethyl-8-oxodec-6-
enoate [( )-9]
4.3. Benzyl (2RS,3RS)-3-tert-butoxy-2-methyl-6-(tetrahydro-
pyran-20-yloxy)hexanoate [( )-6]
After a mixture of LiBr$H2O (0.37 g, 3.5 mmol), and dimethyl (3-
methyl-2-oxobutyl)phosphonate (0.68 g, 3.5 mmol) in dry THF
(15 ml) was stirred at 20 ꢂC for 5 min, Et3N (0.50 ml, 3.5 mmol) was
added and mixture was stirred for further 10 min. Then to this was
added (ꢁ)-8 (1.1 g, 3.2 mmol), and the mixture was stirred for 6 h at
20 ꢂC. The mixture was neutralized with a saturated aqueous NH4Cl
solution and extracted with ether. The extract was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
in vacuo. The residue was chromatographed on silica gel (150 g).
Elution with hexane/EtOAc (10:1) gave (ꢁ)-9 [1.1 g, 3.0 mmol, 94%
To a solution of (ꢁ)-5 (5.0 g, 16 mmol) in THF/MeOH (5:2, 70 ml)
was added 1 M aq KOH (30 ml) at 20 ꢂC and the mixture was stirred
for 16 h. Then the reaction mixture was concentrated in vacuo; and
the residue was diluted with water, acidified with 10% citric acid,
and extracted with CHCl3. The extract was washed with brine, dried
over anhydrous magnesium sulfate, and concentrated in vacuo to
give acid (4.8 g, 16 mmol, quant.) as a pale yellow oil. This was used
in the next step without further purification.
To a mixture of the above mentioned acid (4.8 g, 16 mmol) and
KOt-Bu (2.0 g,17 mmol) in dry DMF (250 ml) was added BnBr (2.0 ml,
20 mmol) in oneportion and themixturewasstirredat 65 ꢂC for 16 h.
The mixturewas diluted with ether (150 ml) and washed with water.
The organic layer was dried over anhydrous magnesium sulfate and
concentrated in vacuo to give (ꢁ)-6 (5.9 g, 15 mmol, 94%) as a pale
from (ꢁ)-7] as a pale yellow oil.
1740 (s, C]O),1700 (m, C]C),1680 (s),1635 (s),1200 (m),1070 (m),
710 (m) cmꢀ1
dH (300 MHz) 1.08e1.18 (18H, m), 1.38e1.64 (2H, m),
n (film) 3050 (w, ]CeH), 2970 (s),
;
2.05e2.32 (2H, m), 2.75e2.85 (2H, m), 3.94 (1H, m, H-3), 5.10 (1H,
d, J 12.6, CHPh), 5.17 (1H, d, J 12.6, CHPh), 6.14 (1H, dt, J 15.7, 1.6 Hz,
H-7), 6.81 (1H, m, H-6), 7.35e7.40 (5H, m, Ph); HRMS (FAB, NOBA):
MNaþ, found 397.2363. C23H34O4Na requires 397.2355.
yellowoil.
n
(film) 2970 (s), 2940 (s), 2850 (m),1740 (s, C]O),1190 (s,
dH (500 MHz) 1.13 (3H, d, J
CeO),1035 (s, CeO), 755 (s), 700 (s) cmꢀ1
;
6.9 Hz, 2-Me),1.19 (9H, s, t-Bu),1.38e1.86 (10H, m), 2.79 (1H, dq, J 6.9,
6.6 Hz, H-2), 3.32 (1H, m), 3.50 (1H, m), 3.68 (1H, m), 3.81e3.95 (2H,
m), 4.57 (1H, m, OCHO), 5.11 (1H, d, J 12.8 Hz, CHPh), 5.15 (1H, d, J
12.8 Hz, CHPh), 7.31e7.38 (5H, m, Ph); HRMS (FAB, NOBA): MNaþ,
found 415.2465. C23H36O5Na requires 415.2461.
4.7. Benzyl (2RS,3RS,6SR)-3,6-epoxy-2,9-dimethyl-8-oxodec-
anoate [( )-11]
After a suspension of I2 (1.1 g, 4.2 mmol) and NaHCO3 (1.3 g,
9.4 mmol) in dry CH3CN (15 ml) was stirred at 20 ꢂC for 15 min

7070
K. Takai et al. / Tetrahedron 67 (2011) 7066e7072
under N2, a solution of (ꢁ)-9 (0.50 g, 1.4 mmol) in dry CH3CN (5 ml)
was added dropwise to this mixture, and the resulting mixture was
stirred at 20 ꢂC for 24 h. Then to this was added I2 (1.1 g, 4.2 mmol)
and the mixture was stirred for additional 24 h. The reaction was
quenched with a saturated aqueous Na2S2O3 solution and brine,
and extracted with ether. The extract was washed with brine, dried
over anhydrous magnesium sulfate, and concentrated in vacuo to
give iodide (ꢁ)-10 (0.57 g, 1.3 mmol) as a pale yellow oil, which was
used in the next step without further purification; dH (300 MHz)
1.12 (3H, d, J 6.9 Hz), 1.16 (3H, d, J 7.5 Hz), 1.70 (1H, ddt, J 12.0, 8.7,
6.6 Hz, H-4), 1.85 (1H, ddd, J 14.4, 12.3, 6.3 Hz, H-5), 1.99 (1H, dddd, J
12.0, 7.5, 6.3, 5.7 Hz, H-4), 2.26 (1H, ddt, J 13.2, 8.1, 6.9 Hz, H-5), 2.58
(1H, J 8.4, 7.2 Hz, H-2), 2.91 (1H, sep, J 6.9 Hz, H-9), 4.19 (1H, dd, J 8.1,
6.6 Hz, H-3), 4.23 (1H, dd, J 9.3, 8.4 Hz, H-6), 4.47 (1H, d, J 8.4 Hz,
H-7), 5.09 (1H, d, J 12.6, CHPh), 5.16 (1H, d, J 12.6, CHPh), 7.30e7.40
(5H, m, Ph).
and DMAP (13 mg, 0.1 mmol) in dry CH2Cl2 (20 ml) was stirred at
room temperature for 2 h. To this was added a saturated aqueous
NaHCO3 solution and extracted EtOAc. The extract was washed
with water, brine, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
chromatography. Elution with hexane/EtOAc (10:1) gave (ꢀ)-14
(170 mg, 0.342 mmol, 93.3%) and (þ)-13 (181 mg, 0.364 mmol,
99.4%) as pale yellow oils. (þ)-13: ½a D24
ꢃ
þ20 (c 0.70, CHCl3).
n (KBr)
1735 (br s, C]O), 1495 (m, C]O), 1235 (s), 1060 (s), 760 (s), 700 (s)
cmꢀ1
; dH (300 MHz) 0.55 (3H, d, J 6.9 Hz, gem Me), 0.67 (3H, d, J
6.9 Hz, gem Me), 1.11 (3H, d, J 6.9 Hz, 2-Me), 1.47 (1H, m), 1.55e1.69
(3H, m), 1.76 (1H, ddd, J 14.2, 7.1, 3.9 Hz), 1.86e2.04 (2H, m), 2.20
(3H, s, COMe), 2.56 (1H, dq, J 7.8, 7.1 Hz, 2-H), 3.81 (1H, pseudo
quint, J 5.8 Hz), 4.03 (1H, q, J 8.0 Hz), 4.92 (1H, dt, J 8.8, 4.4 Hz, H-
8), 5.12 (1H, d, J 12.7 Hz, CHHPh), 5.16 (d, J 12.7 Hz, CHHPh), 5.91
(1H, s, CHOAc), 7.30e7.50 (10H, m, Ph); HRMS (FAB, NOBA): MHþ,
A solution of (ꢁ)-10 (0.57 g, 1.3 mmol), Bu3SnH (0.4 ml,
1.4 mmol), and AIBN (10 mg) in dry toluene (15 ml) was stirred at
25 ꢂC for 2 h under N2. Then to this was added KF, and the resulting
suspension was stirred for 3 h before filtration. The filtrate was
chromatographed on silica gel. Elution with hexane/EtOAc (10:1)
found 497.2541. C29H37O7 requires 497.2541. (ꢀ)-14: ½a D24
ꢀ4.1 (c
ꢃ
0.50, CHCl3).
n (KBr) 1750 (s, C]O), 1735 (s, C]O), 1715 (s, C]O),
1495 (m, C]O), 1230 (s), 1210 (s), 1180 (s), 1050 (s), 760 (s), 700 (s)
cmꢀ1
;
dH (300 MHz) 0.87 (3H, d, J 6.9 Hz, gem Me), 0.88 (3H, d, J
6.9 Hz, gem Me), 1.06 (3H, d, J 6.9 Hz, 2-Me), 1.36e1.56 (3H, m),
1.58e1.71 (3H, m), 1.85 (1H, dquint, J 4.9, 6.9 Hz), 2.20 (3H, s, Ac),
2.49 (1H, dq, J 7.7, 7.7 Hz, H-2), 3.23 (1H, m), 3.80 (1H, q, 7.7 Hz),
4.91 (1H, ddd, J 9.3, 4.3, 3.3 Hz, H-8), 5.11 (1H, d, J 12.4 Hz, CHHPh),
5.16 (d, J 12.4 Hz, CHHPh), 5.88 (1H, s, CHOAc), 7.30e7.39 (8H, m,
Ph), 7.44e7.49 (2H, m, Ph); HRMS (FAB, NOBA): MHþ, found
497.2544. C29H37O7 requires 497.2541.
gave (ꢁ)-11 [0.40 g, 1.3 mmol, 93% from (ꢁ)-9] as a pale yellow oil.
(film) 1730 (s, C]O), 1705 (m, C]O), 1250 (s), 1200 (s), 1155 (s),
1060 (s), 750 (m), 740 (m), 710 (s) cmꢀ1
dH (300 MHz) 1.07 (6H, d, J
n
;
6.9 Hz), 1.14 (3H, d, J 7.1 Hz), 1.32e1.69 (2H, m), 1.93e2.17 (2H, m),
2.44e2.65 (2H, m), 2.61 (1H, sep, J 7.2 Hz, H-9), 2.86 (1H, dd, J 8.7,
7.5 Hz, H-7), 4.06 (1H, q, J 6.9 Hz, H-6), 4.22 (1H, quint, J 6.9 Hz, H-3),
5.12 (1H, d, J 12.4, CHPh), 5.17 (1H, d, J 12.4, CHPh), 7.30e7.42 (5H,
m, Ph); dC (125 MHz) 13.4, 17.9, 18.0, 28.5, 31.1, 41.3, 45.4, 46.3, 66.1,
75.7, 8.3, 128.0, 128.1, 128.5, 136.1, 174.5, 199.1, 213.0; HRMS (FAB,
NOBA): MHþ, found 319.1911. C19H25O4 requires 319.1911.
4.10. (L)-Bishomononactic acid [(L)-2c]
A solution of (ꢀ)-14 (498 mg, 1.00 mmol) in 1 M aq KOH/MeOH/
THF (3:2:4, 90 ml) was stirred at 20 ꢂC for 5 h, and it was con-
centrated in vacuo. The residue was acidified with 10% aqueous
citric acid and extracted with EtOAc. The organic layer was washed
with brine, dried over anhydrous magnesium sulfate, and concen-
trated in vacuo. The residue was chromatographed on silica gel.
Elution with CHCl3/MeOH/AcOH¼100:1:0.5 gave (ꢀ)-2c (231 mg,
4.8. Benzyl (2RS,3RS,6SR,8RS)-3,6-epoxy-2,9-dimethyl-8-hydro-
xydecanoate [( )-12] and its 8-epimer [( )-8-epi-12]
To a solution of (ꢁ)-11 (1.6 g, 3.6 mmol) in MeOH (150 ml) was
added NaBH4 (0.40 g, 9.4 mmol) at 0 ꢂC and the mixture was stirred
for 1.5 h. The reaction mixture was quenched with a saturated
aqueous NH4Cl solution and extracted with EtOAc. The extract was
washed with water, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was chromatographed on silica
gel. Elution with hexane/EtOAc (7:1) gave (ꢁ)-12 (0.46 g, 1.4 mmol,
40%) and (ꢁ)-8-epi-12 (0.71 g, 2.2 mmol, 60%) as colorless oils.
1.00 mmol, quant.) as a colorless oil, ½a D21
ꢀ27 (c 0.080, CHCl3); dH
ꢃ
(300 MHz) 0.88e0.92 (3H, d, J 6.9 Hz, 10-H), 0.92e0.95 (3H, d, J
6.6 Hz, 9-Me), 1.16e1.21 (3H, d, J 7.1 Hz, 2-Me), 1.24e1.32 (1H, m),
1.60e1.78 (4H, m), 1.98e2.10 (2H, m), 2.46e2.56 (1H, quint, J 7.1 Hz,
2-H), 3.56e3.62 (1H, m, 8-H), 3.94e4.02 (1H, m, 3-H), 4.20e4.28
(1H, m, 6-H); HRMS (FAB, NOBA): MNaþ, found 253.1415.
C12H22O4Na requires 253.1417.
(ꢁ)-12:
n ; dH
(film) 3450 (br s, OeH), 1740 (s, C]O), 700 (m) cmꢀ1
(300 MHz) 0.87 (3H, d, J 6.9 Hz, gem Me), 0.92 (3H, d, J 6.9 Hz, gem
Me), 1.14 (3H, d, J 7.1 Hz, 2-Me), 1.57e1.72 (5H, m), 1.94e2.05 (2H,
m), 2.48 (1H, d, J 4.6 Hz, OH), 2.60 (1H, dq, J 8.3, 7.1 Hz, H-2), 3.54
(1H, m, H-8), 4.04 (1H, m, H-3), 4.16 (1H, m, H-6), 5.16 (2H, s,
CH2Ph), 7.31e7.40 (5H, m, Ph) ppm; dC (75 MHz) 13.2, 17.7, 18.5,
28.6, 30.5, 33.5, 38.2, 45.3, 66.1, 73.5, 77.4, 80.7, 128.09, 128.12,
128.5, 136.2, 174.7; FABMS (NOBAþPEG): 321 (MHþ), 303
(MHꢀH2Oþ); HRMS (FAB, NOBAþPEG): MHþ, found 321.2068.
C19H29O4 requires 321.2064. (ꢁ)-8-epi-12: dH (300 MHz) 0.87 (3H,
d, J 6.9 Hz, gem Me), 0.90 (3H, d, J 6.9 Hz, gem Me), 1.14 (3H, d, J
6.9 Hz, 2-Me), 1.4e1.75 (5H, m), 1.9e2.1 (2H, m), 2.62 (1H, dq, J 8.1,
7.2 Hz, H-2), 3.45 (1H, br, OH), 3.54 (1H, ddd, J 9.9, 5.1, 1.5 Hz, H-8),
4.04 (1H, dq, J 3.0, 6.9 Hz, H-6), 4.08 (1H, dt, J 8.1, 6.6 Hz, H-3), 5.10
(1H, d, J 12.6 Hz CHPh), 5.18 (1H, d, J 12.6 Hz, CHPh), 7.30e7.40 (5H,
m, Ph).
4.11. (D)-Bishomononactic acid [(D)-2c]
Compound (þ)-2c was prepared from (þ)-13 in the same
manner (quant.) as a colorless oil, ½a D21
þ27 (c 0.090, CHCl3); HRMS
ꢃ
(FAB, NOBA): MNaþ, found 253.1415. C12H22O4Na requires 253.1416.
4.12. Compound (D)-12
A mixture of crude (þ)-2c [ca. 1.00 mmol, prepared from
(þ)-13], KOt-Bu (560 mg, 5.0 mmol), and BnBr (0.57 ml, 0.82 g,
4.8 mmol) in DMF (30 ml) was stirred at 65 ꢂC for 8.5 h. To the
mixture was added a saturated aqueous NH4Cl solution and ether.
The organic layer was separated and washed with water and brine,
dried over anhydrous magnesium sulfate, and concentrated in
vacuo. The residue was chromatographed on silica gel (hexane/
EtOAc¼3:1) to give (þ)-12 [276 mg, 0.861 mmol, 86% from (þ)-13]
4.9. (D)-Benzyl (2S,3S,6R,8S)-8-O-[(S)-O0-acetylmandeloyl]
bishomononactate [(D)-13] and (L)-benzyl (2R,3R,6S,8R)-8-
O-[(S)-O0-acetylmandeloyl]bishomononactate [(L)-14]
as a pale yellow oil, ½a D24
þ3.0 (c 1.0, CHCl3). FABMS (NOBAþPEG):
ꢃ
A
mixture of (ꢁ)-12 (235 mg, 0.733 mmol), (S)-O-ace-
321 (MHþ), 303 (MHꢀH2Oþ); HRMS (FAB, NOBAþPEG): MHþ,
tylmandelic acid (210 mg, 1.10 mmol), EDC (210 mg, 1.10 mmol),
found 321.2068. C19H29O4 requires 321.2064.

K. Takai et al. / Tetrahedron 67 (2011) 7066e7072
7071
4.13. (L)-S-2-Pyridyl (2R,3R,6S,8R)-thiobishomononactate
[(L)-16]
EtOAc. The combined extract was washed with brine, dried over
anhydrous magnesium sulfate and concentrated in vacuo. The
residue was purified by preparative TLC (hexane/EtOAc¼3:1) to
A mixture of (ꢀ)-2c (54 mg, 0.23 mmol), 2,20-dipyridyl disulfide
(130 mg, 0.58 mmol), and PPh3 (100 mg, 0.35 mmol) in dry THF
(5 ml) was stirred at room temperature for 20 h and concentrated in
vacuo. The residue was chromatographed on silica gel. Elution with
hexane/EtOAc¼3:1 gave (ꢀ)-16 (55 mg, 0.17 mmol, 74%) as a pale
give (ꢀ)-19 (24 mg, 0.046 mmol, quant.) as a colorless oil, ½a D23
ꢀ4.1
ꢃ
(c 0.50, CHCl3).
n (film) 3500 (m, OeH), 3050 (w), 3025 (w), 2950
(s), 2875 (m), 1740 (s, C]O), 1460 (m), 1380 (m) cmꢀ1
; dH
(500 MHz) 0.84e0.90 (9H, m), 0.91e0.93 (3H, d, J 6.6 Hz), 1.10 (6H,
dd, J 7.08, 1.46 Hz, 1, 11-Me), 1.40e2.00 (14H, m), 2.47e2.63 (2H, m),
2.62 (1H, m, OH), 3.55 (1H, m, 17-H), 3.86 (1H, m), 3.96e4.06 (2H,
m), 4.10e4.17 (1H, m), 4.88e4.92 (1H, dt, J 8.6, 4.2 Hz, 8-H), 5.15
(2H, s, CH2Ph), 7.28e7.38 (5H, m, Ph); m/z (FAB, NOBA) 555 (MNaþ),
533 (MHþ); HRMS (FAB, NOBAþPEG): MHþ, found 533.3479.
C31H49O7 requires 533.3476.
yellow oil, ½a 2D3
ꢀ40 (c 0.10, CHCl3); dH (300 MHz) 0.88e0.98 (6H, m,
ꢃ
H-10, 9-Me), 1.23 (3H, d, J 7.1 Hz, 2-Me), 1.58e1.82 (4H, m),
1.96e2.08 (2H, m), 2.6 (1H, m, OH), 2.87 (1H, q, J 7.2 Hz, H-2), 3.61
(1H, m, 8-H), 4.04e4.22 (2H, m, H-3, 6), 7.62e7.78 (3H, m, Ar),
8.60e8.64 (1H, m, Ar); m/z (FAB, NOBA) 438 (MHþ); HRMS (FAB,
NOBAþPEG): MHþ, found 324.1638. C19H26O3NS requires 324.1635.
4.17. (D)-S-2-Pyridyl (2S,3S,6R,8S)-[(20R,30R,60S,80R)-80-O0-tert-
buthydimethylsilylbishomononactoyl]thiobishomononactate
[(D)-21]
4.14. (L)-S-2-Pyridyl (2R,3R,6S,8R)-8-O-(tert-butyldimethyl-
silyl)thiobishomononactate [(L)-17]
To a solution of (ꢀ)-16 (55 mg, 0.17 mmol) in CH2Cl2 (5 ml) was
added 2,6-lutidine (0.29 ml, 0.26 mmol), and TBSOTf (0.29 ml,
1.3 mmol) at 0 ꢂC and the mixture was stirred at 0 ꢂC for 40 min. To
the reaction mixture was added water and the aqueous layer was
extracted with EtOAc. The combined extract was dried over anhy-
drous magnesium sulfate and concentrated in vacuo. The residue
was purified by preparative TLC (hexane/EtOAc¼7:1) to give (ꢀ)-17
A suspension of (þ)-18 (30 mg, 0.046 mmol) and 10% PdeC (cat.
amount) in dry EtOH (1 ml) was stirred under hydrogen atmo-
sphere (1 atm) at room temperature for 15 h. The reaction mixture
was filtered through a Celite pad and the filtrate was concentrated
in vacuo to give 20 (25 mg, 0.046 mmol, quant.) as a colorless oil.
n
(film) 3200 (br s), 2950 (s), 2875 (m), 1740 (s, C]O), 1720 (m), 1460
(m), 1380 (m) cmꢀ1. This oil was used in the next step without
further purification.
(74 mg, 0.17 mmol, quant.) as a pale yellow oil, ½a D25
ꢀ19 (c 0.96,
ꢃ
CHCl3); dH (300 MHz) 0.01 (3H, s, MeSi), 0.03 (3H, s, MeSi),
0.82e0.90 (15H, m, t-Bu, H-10, 9-Me), 1.21 (3H, d, J 6.9 Hz, 2-Me),
1.45e1.66 (4H, m), 1.74 (1H, m), 1.94e2.04 (2H, m), 2.83 (1H, dq, J
8.2, 6.6 Hz, H-2), 3.80 (1H, m), 3.94 (1H, m), 4.03 (1H, m), 7.64e7.76
(3H, m, Ar), 8.58e8.64 (1H, m, Ar); m/z (FAB, NOBA) 438 (MHþ);
HRMS (FAB, NOBAþPEG): MHþ, found 438.2495. C23H40O3NSiS
requires 438.2496.
A solution of 20 (25 mg, 0.046 mmol), 2,20-dipyridyl disulfide
(15 mg, 0.068 mmol), and PPh3 (29 mg, 0.068 mmol) in dry tol-
uene (5 ml) was stirred at room temperature for 6 h and then
concentrated in vacuo. The residue was purified by preparative
TLC (hexane/EtOAc¼4:1) to give (þ)-21 (29 mg, 0.045 mmol, 98%)
as a pale yellow oil, ½a D23
ꢃ
þ20 (c 0.20, CHCl3).
n
(film) 2950 (s),
dH
2875 (m), 1740 (s, C]O), 1710 (m), 1460 (m), 1380 (m) cmꢀ1
;
(500 MHz) 0.03 (6H, d, J 6.1 Hz, Me2Si), 0.81e0.86 (6H, dd, J 15.1,
7.1 Hz), 0.87 (9H, s, t-Bu), 0.88e0.92 (6H, dd, J 9.5, 6.8 Hz), 1.11 (3H,
d, J 7.1 Hz), 1.20 (3H, d, J 7.1 Hz), 1.40e2.00 (14H, m), 2.52 (1H,
quint, J 7.1 Hz), 2.85 (1H, quint, J 7.1 Hz), 3.67 (1H, m, H-80),
3.83e3.91 (2H, m), 4.01 (1H, m), 4.10 (1H, m), 4.96 (1H, dt, J 8.6,
4.2 Hz, 8-H), 7.28 (1H, m, Ar), 7.68e7.76 (2H, m, Ar), 8.61 (1H, m,
Ar); m/z (FAB, NOBA) 672 (MNaþ), 650 (MHþ); HRMS (FAB,
NOBAþPEG): MHþ, found 650.3906. C35H60O6NSiS requires
650.3924.
4.15. (D)-Benzyl (2S,3S,6R,8S)-8-O-[(20R,30R,60S,80R)-80-O0-(tert-
buthyldimethylsilyl)bishomononactoyl]bishomononactate
[(D)-18]
To a suspension of (ꢀ)-17 (66 mg, 0.15 mmol), (þ)-12 (50 mg,
ꢀ
0.15 mmol), and MS4 A (50 mg) in dry toluene (10 ml) was
added AgClO4 (35 mg, 0.17 mmol) at 0 ꢂC, and the mixture was
stirred for 5 min. Then to this was added a saturated aqueous
NaHCO3 solution, and extracted with EtOAc. The combined ex-
tract was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated in vacuo. The residue was purified by
preparative TLC (hexane/EtOAc¼10: 1) to give (þ)-18 (84 mg,
4.18. (D)-Benzyl (2S,3S,6R,8S)-8-O-((20R,30R,60S,80R)-80-O0-{(200S,
300S,600R,800S)-800-O00-[(2000R,3000R,6000S,8000R)-8000-O000-tert-buthyldi-
methylsilylbishomononactoyl]bishomononactoyl}bisho-
mononactoyl)bishomononactate [(D)-22]
0.13 mmol, 86%) as a yellow oil, ½a D24
ꢃ
þ7.0 (c 0.70, CHCl3).
n
(film) 3050 (w), 3025 (w), 2950 (s), 2875 (m), 1740 (s, CeO),
1460 (m), 1380 (m) cmꢀ1
; dH (500 MHz) 0.02 (3H, s, MeSi), 0.03
(3H, s, MeSi), 0.80e0.82 (3H, d, J 6.8 Hz, gem Me), 0.83e0.86
(3H, d, J 6.8 Hz, gem Me), 0.88 (9H, s, t-Bu), 1.10 [3H, d, J 7.1 Hz,
2(20)-Me], 1.12 [3H, d, J 7.1 Hz, 20(2)-Me], 1.40e2.00 (14H, m),
2.50 [1H, quint, J 7.3 Hz, 2(20)-H], 2.58 [1H, quint, J 7.3 Hz, 20(2)-
H], 3.67 (1H, dt, J 8.5, 3.7 Hz, 80-H), 3.82e3.89 (2H, m, 3, 30-H),
3.96e4.06 (2H, m, 6, 60-H), 4.90 (1H, dt, J 8.6, 4.2 Hz, 8-H), 5.18
(2H, s, CH2Ph), 7.28e7.38 (5H, m, Ph); m/z (FAB, NOBA) 669
(MNaþ),647 (MHþ); HRMS (FAB, NOBAþPEG): MHþ, found
647.4344. C37H63O7Si requires 647.4340.
To a suspension of (þ)-21 (20 mg, 0.031 mmol), (ꢀ)-19 (21 mg,
ꢀ
0.040 mmol), and MS4 A (20 mg) in dry toluene (5 ml) was added
AgClO4 (9.3 mg, 0.045 mmol) at 0 ꢂC, and the resulting mixture was
stirred for 5 min. To this was added a saturated aqueous NaHCO3
solution and extracted with EtOAc. The combined extract was
washed with brine, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was purified by preparative TLC
(hexane/EtOAc¼10:1) to give (þ)-22 (930 mg, 0.028 mmol, 90%) as
a colorless oil, ½a D22
ꢃ
þ5.3 (c 0.91, CHCl3).
n
(film) 2950 (s), 2875 (m),
dH (500 MHz)
1740 (s, C]O), 1710 (m), 1460 (m), 1380 (m) cmꢀ1
;
4.16. (L)-Benzyl (2S,3S,6R,8S)-8-O-[(20R,30R,60S,80R)-bisho-
mononactoyl]bishomononactate [(L)-19]
0.024 (3H, s, MeSi), 0.036 (3H, s, MeSi), 0.81e0.90 (33H, m),
1.07e1.13 (12H, m), 1.40e2.00 (28H, m), 2.48e2.62 (4H, m, H-2, 11,
20, 29), 3.67 (1H, dt, J 8.5, 3.7 Hz, H-8000), 3.78e3.88 (4H, m),
3.97e4.06 (4H, m), 4.86e4.92 (3H, m, H-8, 80, 800), 5.13 (2H, s,
CH2Ph), 7.28e7.38 (5H, m, Ph); m/z (FAB, NOBA) 1094 (MNaþ), 1072
(MHþ); HRMS (FAB, NOBAþPEG): MNaþ, found 1093.6982.
C61H102O13SiNa requires 1093.6782.
To a solution of (þ)-18 (30 mg, 0.046 mmol) in CH3CN (5 ml) was
added 40% aqueous HF in CH3CN (5:95, 1 ml) at 0 ꢂC and the
mixture was stirred for 3 h at this temperature. Then to this was
added a saturated aqueous NaHCO3 solution and extracted with

7072
K. Takai et al. / Tetrahedron 67 (2011) 7066e7072
4.19. (D)-Benzyl (2S,3S,6R,8S)-8-O-((20R,30R,60S,80R)-80-O0-
{(200S,300S,600R,800S)-800-O00-[(2000R,3000R,6000S,8000R)-bishomonon-
actoyl]bishomononactoyl}bishomononactoyl)bishomonon-
actate [(D)-23]
4.22. Bioassay
Immunosuppressive activity on T cell proliferation (prepared
from mice of different in MHC antigens, BALB/c and C57BL/6) and
cytotoxic activity (mouse lymphoma EL4) of samples were mea-
sured according to the literature.23
To a solution of (þ)-22 (20 mg, 0.019 mmol) in CH3CN (5 ml) was
added 40% aqueous HF in CH3CN (5:95, 1 ml) at 0 ꢂC and the
mixture was stirred for 3 h at this temperature. Then to this was
added a saturated aqueous NaHCO3 solution and extracted with
EtOAc. The combined extract was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated in vacuo. The
residue was purified by preparative TLC (hexane/EtOAc¼3:1) to
Acknowledgements
Financial supports by grant-in-aid from Japan Society for the
Promotion of Science (No. 17580092 and 19580120), The Agricul-
tural Chemical Research Foundation, Intelligent Cosmos Founda-
tion and The Naito Foundation is gratefully acknowledged.
give (þ)-23 (18 mg, 0.019 mmol, quant.) as a colorless oil, ½a D23
þ11
ꢃ
(c 0.33, CHCl3). n (film) 3500 (w), 2950 (s), 2875 (m), 1740 (s, C]O),
1710 (m), 1460 (m), 1380 (m) cmꢀ1
; dH (500 MHz) 0.85e0.94 (24H,
References and notes
m), 1.07e1.13 (12H, m), 1.40e2.00 (28H, m), 2.48e2.62 (4H, m, H-2,
20, 200, 2000), 2.53 (1H, br, OH), 3.56 (1H, m, H-8000), 3.78e3.88 (3H, m),
3.97e4.06 (4H, m), 4.15 (1H, m), 4.86e4.92 (3H, m, H-8, 80, 800), 5.13
(2H, m, CH2Ph), 7.28e7.38 (5H, m, Ph); m/z (FAB, NOBA) 980
(MNaþ), 958 (MHþ); HRMS (FAB, NOBAþPEG): MNaþ, found
979.6116. C55H88O13Na requires 979.5918.
€
1. (a) Corbaz, R.; Ettlinger, L.; Gaumann, E.; Keller-Schierlein, W.; Kradolfer, F.;
€
Neipp, L.; Prelog, V.; Zahner, H. Helv. Chim. Acta 1955, 38, 1445e1448; (b)
Dominguez, J.; Dunitz, J. D.; Gerlach, H.; Prelog, V. Helv. Chim. Acta 1962, 45,
129e138; (c) Beck, J.; Gerlach, H.; Prelog, V.; Voser, V. Helv. Chim. Acta 1962, 45,
620e630; (d) Ando, K.; Oishi, H.; Hirano, S.; Okutomi, T.; Suzuki, K.; Okazaki, H.;
Sawada, M.; Sagawa, T. J. Antibiot. 1971, 24, 347e352; (e) Ando, K.; Murakami, Y.;
Nawata, Y. J. Antibiot. 1971, 24, 418e422.
2. (a) Keller-Schierlein, W.; Gerlach, H.; Seibl, J. Antimicrob. Agents Chemother.
1966, 644e650; (b) Keller-Schierlein, W.; Gerlach, H. Fortschr. Chem. Org. Na-
4.20. (D)-S-2-Pyridyl (2S,3S,6R,8S)-8-O-((20R,30R,60S,80R)-80-O0-
{(200S,300S,600R,800S)-800-O00-[(2000R,3000R,6000S,8000R)-bishomononactoyl]
bishomononactoyl}bishomononactoyl)thiobishomononactate
[(D)-24]
€
turst. 1967, 26, 161e189; (c) Gerlach, H.; Hutter, R.; Keller-Schierlein, W.; Seibl,
€
J.; Zahner, H. Helv. Chim. Acta 1967, 50, 1782e1793.
3. Zizka, Z. Folia Microbiol. 1998, 43, 7e14.
4. (a) Tanouchi, Y.; Shichi, H. Immunology 1988, 63, 471e475; (b) Mori, A.;
Kaminuma, O.; Ogawa, K.; Nakata, A.; Egan, R. W.; Akiyama, K.; Okudaira, H. J.
Allergy Clin. Immunol. 2000, 106, S58eS64.
5. Representative papers are listed: (a) Gerlach, H.; Oertle, K.; Thalmann, A.; Servi,
S. Helv. Chim. Acta 1975, 58, 2036e2043; (b) Gombos, J.; Haslinger, E.; Zak, H.;
Schmidt, U. Tetrahedron Lett. 1975, 3391e3394; (c) Schmidt, U.; Werner, J.
Synthesis 1986, 986e992; (d) Fleming, I.; Ghosh, S. K. J. Chem. Soc., Perkin Trans.
1 1998, 2733e2747; (e) Fleming, I.; Ghosh, S. K. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1996; Vol. 18,
pp 229e268; and references cited therein; (f) Wu, Y.; Sun, Y.-P. Org. Lett. 2006,
8, 2831e2834 and references cited therein; (g) Zhou, Y.; Xu, Q.; Zhai, H.
Tetrahedron Lett. 2008, 49, 5271e5272.
6. Synthesis of (ꢁ)-methyl bishomononactate (3): (a) Walkup, R. D.; Park, G. J. Am.
Chem. Soc. 1990, 112, 1597e1603; (b) Hanadate, T.; Kiyota, H.; Oritani, T. Biosci.
Biotechnol. Biochem. 2001, 65, 2118e2120.
7. Meyers, E.; Pansy, F. E.; Perlmann, D.; Smith, D. A.; Weisenborn, F. L. J. Antibiot.;
Ser. A 1965, 18, 128e129.
8. Lee, J. W.; Priestley, N. D. Bioorg. Med. Chem. Lett. 1998, 8, 1725e1728.
9. (a) Hanadate, T.; Kiyota, H.; Oritani, T. Biosci. Biotechnol. Biochem. 2000, 64,
1671e1674; (b) Biotransformation studies: Hanadate, T.; Takai, K.; Abe, N.; Yamada,
T.; Kuwahara, S.; Kiyota, H. Heterocycl. Commun 2011, doi:10.1515/HC.2011.021
10. Takai, K.; Hanadate, T.; Oi, S.; Kuwahara, S.; Kiyota, H. Tennen Yuki Kagobutsu
Toronkai Koen Yoshishu 2006, 48, 361e366.
A suspension of (þ)-23 (15 mg, 0.016 mmol) and 10% PdeC (cat.
amount) in dry EtOH (1 ml) was stirred under hydrogen atmo-
sphere (1 atm) at room temperature for 15 h. The reaction mixture
was filtered through a Celite pad and the filtrate was concentrated
in vacuo to give acid (12 mg, 0.014 mmol, 88%) as a colorless oil. This
was used in the next step without further purification.
The crude acid (12 mg, 0.014 mmol), 2,20-dipyridyl disulfide
(4.5 mg, 0.021 mmol), and PPh3 (9 mg, 0.021 mmol) in dry tol-
uene (5 ml) was stirred for 6 h at room temperature and con-
centrated in vacuo. The residue was purified by preparative TLC
(hexane/EtOAc¼4:1) to give (þ)-24 (9.8 mg, 0.010 mmol, 71%) as
a 22
a pale yellow oil, ½ ꢃ
þ10 (c 0.35, CHCl3); dH (500 MHz)
0.86e0.94 (24H, m, 4ꢄ DMe2C), 1.06e1.14 (9H, m, 3ꢄ Me), 1.20 (3H,
d, J 6.9 Hz, Me), 1.40e2.05 (24H, m), 2.45e2.60 (3H, m), 2.85 (1H,
quint, J 7.7 Hz), 3.50e3.60 (2H, m), 3.765e3.93 (3H, m), 3.96e4.08
(4H, m), 4.85e5.00 (3H, m), 7.42e7.72 (3H, m), 8.60 (1H, m);
HRMS (FAB, PEG): MHþ, found 960.5874. C53H86O12NS requires
960.5871.
11. (a) Coutable, L.; Adil, K.; Saluzzo, C. Tetrahedron 2008, 64, 11296e11303; (b)
Coutable, L.; Saluzzo, C. Synthesis 2008, 3389e3396.
12. (a) Eng, C.; Simone, J.-M.; Hartenbach, A.; Loiseau, F.; Neier, R. Monatsh. Chem.
2009, 140, 349e354 and references cited therein; (b) Luesse, S. B.; Wells, G.;
Nayek, A.; Smith, A. E.; Kusche, B. R.; Bergmeier, S. C.; McMills, M. C.; Priestley,
N. D.; Wright, D. L. Bioorg. Med. Chem. Lett. 2008, 18, 3946e3949; (c) Loiseau, F.;
Kholod, I.; Nejer, R. Eur. J. Org. Chem. 2010, 4642e4661.
4.21. Macrotetrolide
a (1i)
13. Kusche, B. R.; Smith, A. E.; McGuirl, M. A.; Priestley, N. D. J. Am. Chem. Soc. 2009,
131, 17155e17165.
14. (a) Abe, M.; Kiyota, H.; Adachi, M.; Oritani, T. Synlett 1996, 777e778; (b) Kiyota,
H.; Abe, M.; Ono, Y.; Oritani, T. Synlett 1997, 1093e1095.
ꢀ
To a suspension of (þ)-24 (9.0 mg, 0.0092 mmol) and MS4 A
(10 mg) in dry toluene (5 ml) was added AgClO4 (2 mg,
0.01 mmol) at 0 ꢂC, and the mixture was stirred for 30 min at
15. (a) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103, 3963e3964; (b)
Marek, I.; Lefranc¸ is, J.-M.; Normant, J.-F. Tetrahedron Lett. 1992, 33, 1747e1748.
16. In case of the corresponding methyl esters of (þ)-13 and (ꢀ)-14, simultaneous
hydrolysis of mandelic and methyl esters resulted in low yield and reproducibility.
17. Synthesis of (þ)-4: (a) Furuya, Y.; Kiyota, H.; Oritani, T. Heterocycl. Commun.
2000, 6, 427e430; (b) Kiyota, H.; Furuya, Y.; Kuwahara, S.; Oritani, T. Biosci.
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159e160; (b) Wang, Y.; Metz, P. Tetrahedron: Asymmetry 2000, 11, 3995e3999.
21. The maximum yields under Mitsunobu condition and SN2 reaction via
mesylate were only 14% and 16%, respectively, probably due the bulkiness of
the isopropyl group. Elimination reaction occurred preferentially for the
latter.
0
ꢂC. To this was added a saturated aqueous NaHCO3 solution and
extracted with EtOAc. The combined extract was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
in vacuo. The residue was purified by preparative TLC (hexane/
EtOAc¼10:1) to give 1j (6.4 mg, 0.0075 mmol, 81%) as a colorless
oil, ½a 2D4
ꢁ0 (c 0.02, CHCl3); dH (500 MHz) 0.86e0.91 (24H, m),
ꢃ
1.07e1.13 (12H, m), 1.40e2.08 (28H, m), 2.49 (1H, dq, J 8.6,
6.8 Hz), 2.55e2.62 (2H, m), 2.68 (1H, quint, J 7.1 Hz), 3.77e3.88
(3H, m), 3.95 (1H, m), 4.00e4.08 (3H, m), 3.08e4.15 (1H, m),
4.80e4.96 (4H, m); m/z (FAB, NOBA) 872 (MNaþ), 850 (MHþ); dC
(100 MHz, values were extracted from HMBC and HMQC spectra)
12.9, 17.3, 18.2, 28.2, 29.6, 31.6, 37.2, 46.0, 75.8, 76.6, 79.9, 173.5;
HRMS (FAB, PEG): MNaþ, found 871.5554. C48H80O12Na requires
871.5547.
22. (a) Mukaiyama, T.; Araki, M.; Takei, H. J. Am. Chem. Soc. 1973, 95, 4763e4765; (b)
Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614e5616.
23. Okamoto, M.; Kino, T.; Okuhara, M. Actinomycetologica 1993, 7, 119e127.