Absolute stereochemistries and total synthesis of (+)/(-)-macrosphelides, potent, orally bioavailable inhibitors of cell-cell adhesion

Article abstract of DOI:10.1016/j.tet.2005.02.022

In the current studies, we used the single-crystal X-ray analysis and Kakisawa-Kashman modification of the Mosher NMR method to determine the complete relative and absolute stereochemistries of the (+)-macrosphelides A (+)-1 and B (+)-2. The stereostructure of (+)-2 was determined by chemical comparison with artificial (+)-2 from (+)-1. We also report the convergent total synthesis of (+)-1 and (+)-3, as well as their antipodes, utilizing an asymmetric dihydroxylation for introduction of chirality and Yamaguchi macrocyclization to form the 16-membered trilactone macrolides.

Full text of DOI:10.1016/j.tet.2005.02.022

Tetrahedron 61 (2005) 3789–3803
Absolute stereochemistries and total synthesis of
C)/(K)-macrosphelides, potent, orally bioavailable inhibitors
of cell–cell adhesion
(
a
Toshiaki Sunazuka, Tomoyasu Hirose, Noriko Chikaraishi, Yoshihiro Harigaya,
a
a
a
a
Masahiko Hayashi, Kanki Komiyama, Paul A. Sprengeler, Amos B. Smith, III
a
b
b
a,
¯
and Satoshi Omura
*
a
Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences and School of Pharmaceutical Sciences,
Kitasato University, and the Kitasato Institute, 5-9-1 Shirokane, Minato-Ku, Tokyo 108-8642, Japan
b
Department of Chemistry, Laboratory for Research on the Structure of Matter Monell Chemical Senses Center, University of Pennsylvania,
Pennsylvania, PA 19104, USA
Received 17 December 2004; accepted 1 February 2005
Abstract—In the current studies, we used the single-crystal X-ray analysis and Kakisawa–Kashman modification of the Mosher NMR
method to determine the complete relative and absolute stereochemistries of the (C)-macrosphelides A (C)-1 and B (C)-2. The
stereostructure of (C)-2 was determined by chemical comparison with artificial (C)-2 from (C)-1. We also report the convergent total
synthesis of (C)-1 and (C)-3, as well as their antipodes, utilizing an asymmetric dihydroxylation for introduction of chirality and
Yamaguchi macrocyclization to form the 16-membered trilactone macrolides.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
E-selectin is expressed on activated endothelial cells, which
1
1–13
recognize sialyl Lewis X on the tumor cells.
Several
1
–3
Critical early events in inflammation,
4
the allergic
involve interactions
groups have demonstrated that sialyl Lewis X and E-selectin
molecules perform this important role in tumor cell
–6
7–9
response,
and tumor metastasis
1
4,15
between leukocytes and endothelial cells. In particular,
tumor metastasis is a multi-step process requiring detach-
ment of malignant cells from primary tumor mass,
infiltration and invasion to blood and/or lymph vessels,
adhesion to endothelia of distant organs, and finally
adhesion to endothelial cells.
We previously reported the isolation, determination of
planar structures, and preliminary biological evaluation
of (C)-macrosphelides A and B ((C)-1 and (C)-2) as cell–
cell adhesion inhibitors from Microsphaeropsis sp.
1
0
formation of new tumor colonies. During the early stage
of adhesion between endothelial cells and tumor cells,
1
6
FO-5050 (Fig. 1). We have now extended this study to
Figure 1. Structures of (C)-macrosphelide A, B and E.
Keywords: Kakisawa–Kashman modification; (C)/(K)-Macrosphelides; Cell–cell adhesion.
Corresponding author. E-mail: omura-s@kitasato.or.jp
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.022

3790
T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
the total synthesis and determination of the absolute
stereochemistries of these compounds.
elucidations of (C)-1 and (C)-2. A series of NMR studies
revealed the planar structures of (C)-1 and (C)-2, which
were also supported by FAB-MS, IR data, chemical
characterizations of the derived di- and monoacetates,
1
7
Macrosphelides are the first 16-membered-ring antibiotics
embodying three lactone linkages (i.e., macrotriolides).
The IC50 values of (C)-1 and (C)-2 were 3.5 and 36 mM,
respectively, for the adhesion of human-leukemia HL-60
cells to human-umbilical-vein endothelial cells
1
6
respectively. The relative structure of (C)-1 was con-
to be
2
1
firmed by single-crystal X-ray diffraction
(3S*,8R*,9S*,14R*,15S*) (Fig. 2).
1
6
(
(
HUVEC). Preliminary studies suggest that (C)-1 and
C)-2 prevent cell–cell adhesion by inhibiting the binding
of sialyl Lewis X to E-selectin. (C)-1 also proved to be
The configurations at C(8) and C(14) in (C)-1 were also
22
elucidated using the Kakisawa–Kashman modification of
2
3
Mosher’s method. Thus, (C)-1 was treated with (S)-(K)-
and (R)-(C)-a-methoxy-a-(trifluoromethyl)phenylacetic
acid (MTPA), dicyclohexylcarbodiimide (DCC), and
4-(dimethylamino)pyridine (DMAP) in THF at room
orally active against lung metastasis of B16/BL6 melanoma
18
in mice (50 mg/kg/day) without body weight loss. On the
other hand, Numata and co-workers have found that a strain
of Periconia byssoides isolated from the seahare Aplysia
kurodai, produces novel cytotoxic materials containing
2
2
temperature to provide the 8,14-bis-O-(S)-(K)-MTPA
ester (K)-4 and 8,14-bis-O-(R)-(C)-MTPA ester (C)-5,
respectively (Scheme 1).
1
9
four new macrolides, macrosphelides E–H. Macro-
sphelide E ((C)-3) is identical to (C)-macrosphelide
A ((C)-1), differing only in the stereochemistry at C(3).
Due to their attractive properties and unique structures,
several synthetic approaches to macrosphelides have been
1
The H NMR spectra of (K)-4 and (C)-5 were completely
1
assigned via selective H decoupling. The R configurations
at C(8) and C(14) were confirmed by application of the
2
0
22
1
reported. In conjunction with our continuing investi-
gations into the structure elucidation and synthesis of
important bio-regulatory natural products, we report herein
the determination of the complete relative and absolute
stereochemistries of (C)-macrosphelides A and B ((C)-1
and (C)-2). We also describe the first total synthesis of
these compounds, together with an application of our
synthetic route to the preparation of (C)-3 and some
enantiomers of natural macrosphelides.
Kakisawa–Kashman test to determine the H Dd values
for (K)-4 and (C)-5 (Fig. 3). Thus, the absolute stereo-
chemistry of macrosphelide A is (3S,8R,9S,14R,15S) as
shown in Figure 1. This assignment was also confirmed by
total synthesis.
2
. Results and discussion
2
(
.1. Determination of the absolute stereochemistry of
C)-macrosphelides A and B
Figure 3. d Values for the bis-MTPA ester derivatives of (C)-1 (dZd(K)
K
Initially our attention was directed toward the structure
d
(C)).
Our next aim was to determine the absolute structure of
(
(
C)-2, anticipated to be the a C(14) oxidation product of
C)-1 (Fig. 1). To prepare (C)-2, (C)-1 was treated with
pyridinium dichromate (PDC) in CH Cl at room tempera-
2
2
ture for 3 h (Scheme 2). Initial separation of the reaction
mixture gave three major fractions: (i) a mixture of the 14-
and 8-monoketones, 2 and 6, (ii) pure 8, 14-diketone 7 (16%
yield), and (iii) recovered starting material (C)-1 (45%).
Further purification of the monoketone mixture (2 and 6) by
HPLC then provided pure (C)-2 and 6 in 21 and 18%
yields, respectively. Synthetic (C)-2 derived from (C)-1
was identical with the natural product sample in all respects.
Figure 2. ORTEP plot of (C)-1.
Scheme 1. Synthesis of bis(C)/(K)-MTPA ester. (a) (K)-MTPA, DCC, DMAP, THF, 100% yield; b) (C)-MTPA, DCC, DMAP, THF, 27% yield.

T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
3791
2 2
Scheme 2. PDC oxidation of (C)-1 to provide (C)-2. (a) PDC, CH Cl .
Thus, the absolute stereochemistry of macrosphelide B
(C)-2) is (3S,8R,9S,15S) as shown in Scheme 2.
acid ester) via the common enantio-active precursor 11
(Scheme 3).
(
2
Initially, asymmetric Sharpless dihydroxylation of sorbic
4
2
(
.2. Synthetic strategy for the preparation of
C)-macrosphelide A
2
5
tert-butyl ester 13 using AD-mix-a, (which uses (DHQ)2-
PHAL as a chiral ligand), was employed to afford the
corresponding diol (K)-14 (62%, 85% ee) (Table 1). Three
other chiral ligands were examined for the asymmetric
dihydroxylation. The best result (71%, 88% ee) was
Disconnection of the three esters of (C)-macrosphelide A
(C)-1) reveals two trans-(4R,5S)-4,5-dihydroxyhexenoic
(
acid components and (S)-3-hydroxybutanoic acid (commer-
cially available). Thus, the strategy required the enantio-
selective preparation of trans-(4R,5S)-4,5-dihydroxy-
hexenoic acid, which was prepared by selective asymmetric
dihydroxylation, followed by differential protection for two
hydroxy groups and inversion of allyl alcohol (Scheme 3).
2
6
obtained with Corey-AD-ligand-a without MeI salt (15)
(1,4-bis[(2S,8S,9R)-6 -(4-heptyloxy)-10,11-dihydrocincho-
nan-9-oxylnaphthopyridazine] (Table 1).
0
In order to study the biological structure–activity relation-
ships of macrosphelides, preparation of select derivatives of
their antipodes was desirable. To this end, the antipode of
2
.3. Preparation of building blocks 9 and 10
2
4
(
K)-14 was attempted. Four ligands, (DHQD) PHAL,
2
2
7
26
The starting point of our synthesis required preparation of
the two differentially protected building blocks 9 and 10,
from known (E,E)-hexa-2,4-dienoic acid ester (sorbic
(DHQD) AQN, Corey-AD-ligand-b (18) and Corey-
2
AD-ligand-b without MeI salt (17), were examined for
asymmetric dihydroxylation of 13 (Table 2), with 17 giving
2
6
Scheme 3. Synthetic strategy for the preparation of (C)-1.

3792
T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
Table 1. Asymmetric dihydroxylation of sorbic acid tert-butyl ester using a-ligands
a
b
c
Ligand
Yield of (K)-14
%ee of (K)-14
(
(
1
1
DHQ)
DHQ)
5
6
2
PHAL
AQN
62%
67%
71%
66%
85%
61%
88%
75%
2
a
b
c
Allreactionswerecarriedoutwithligands(0.01 equiv), K
Yields were based on pure materials isolated by chromatography on SiO
3 6 2 3 2 4 2 2
[Fe(CN) ] (3.0 equiv), K CO (3.0 equiv)andK OsO $2H O(0.01 equiv) int-BuOH$H O(1/1v/v).
2
.
The ee of the product was determined by H NMR measurements of the MTPA ester of TBS ether (C)-19.
1
the best result (74%, 98% ee). Interestingly, dihydroxylation
with 18 afforded diol (C)-14 in low yield (5.9%) with large
amounts of tetraol products, as diastereomeric mixtures.
The enantiomeric purities of (K)- and (C)-14 were
solution (0.2 N NaOH MeOH/THF/H O) afforded the first
2
building block (K)-23 (carboxylic acid) in 96% yield
(Scheme 6). The second building block, (K)-24 (secondary
alcohol), was prepared by deprotection of TBS group of
(K)-22 with tetra-n-butylammonium fluoride (TBAF) in
100% yield (Scheme 6).
2
3
determined by Mosher analysis of the silylated alcohol
19).
(
Selective protection of the C(5)–OH group of (K)-14, with
TBSCl, Et N, and DMAP, provided the desired ether (C)-
2
A
.4. Completion of total synthesis of (C)-macrosphelide
3
1
9, together with undesired C(4)–O–TBS ether (C)-20 and
starting material in 56, 11 and 30% yields, respectively,
2
Scheme 4). Mitsunobu inversion of the C(4)–OH group in
8
Condensation of carboxylic acid (K)-23 and alcohol
(
(
(
K)-24, in the presence of DCC, DMAP, and camphorsul-
C)-19 with PPh , DEAD, and formic acid, followed by
3
2
9
fonic acid (CSA) (Keck protocol ) furnished diester (K)-
5 in 92% yield. Subsequent desilylation of (K)-25 was
carried out with TFA to give the alcohol (K)-26 in 99%
hydrolysis of the formyl ester in diluted NH OH/MeOH
4
2
solution afforded (C)-21 in 83% yield. Interestingly, the
TBS protecting group at the C(5)–OH position was found to
migrate to C(4)–OH position, when other carboxylic acids
3
0
yield. The requisite third building block (C)-27 was
prepared by silylation of (S)-3-hydroxybutylic acid, and
coupled by DCC accelerated condensation in the presence
(
e.g. AcOH, BzOH) were used for Mitsunobu inversion.
2
9
of DMAP and CSA (Keck protocol ) with the alcohol (K)-
6 to afford the triester (K)-28 in 96% yield (Scheme 7).
Stereochemistry at the C(4)-position in (C)-21 was
confirmed by the Kakisawa–Kashman modified Mosher’s
2
2
2
2
3
method, after esterification of (C)-21. The (K)- and
C)-MTPA esters of (C)-21 were isolated in 100 and 91%
yield, respectively (Scheme 5 and Fig. 4).
(
Selective, simultaneous removal of the TBS and tert-butyl
groups, to convert (K)-28 to seco acid (K)-29, was
attempted under a variety of acidic conditions. The best
result was obtained by treatment with thioanisole/TFA/
CH
with undesired mono MEM ether 31 in low yield (Table 3).
The other secondary hydroxyl group in TBS ether (C)-21
was protected as b-methoxyethoxymethyl (MEM) ether to
provide (K)-22. Hydrolysis in aqueous sodium hydroxide
3
1
Cl (5:5:1), to give seco acid (K)-29 in 64% yield,
2
2

T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
Table 2. Asymmetric dihydroxylation of sorbic acid tert-butyl ester using b-ligands
3793
a
b
c
Ligand
Yield of (C)-14
%ee of (C)-14
(
(
1
1
DHQD)
DHQD)
7
8
2
PHAL
AQN
68%
61%
74%
5.9%
95%
82%
98%
90%
2
a
b
c
All reactions were carried out with ligands (0.01 equiv), K [Fe(CN)
3
Yields were based on pure materials isolated by chromatography on SiO .
1
The ee of the product was determined by H NMR measurements of the MTPA ester of TBS ether (K)-19.
6
] (3.0 equiv), K CO
2
3
(3.0 equiv) and K OsO
2
$2H O (0.01 equiv) in t-BuOH$H O (1/1 v/v).
4 2 2
2
3 2 2 3 4
Scheme 4. Preparation of (C)-21. (a) TBSCl, Et N, DMAP, CH Cl ; (b) PPh , DEAD, HCOOH; (c) dil. NH OH, 83% yield for two steps.
Scheme 5. Synthesis of (K)/(C)-MTPA ester. (a) (K)-MTPA, DCC,
, 91%
DMAP, CH
yield.
Cl
2 2
, 100% yield; (b) (C)-MTPA, DCC, DMAP, CH Cl
2
2
Figure 4. Stereochemistry identification: d values for the MTPA ester
derivatives of (C)-21.

3794
T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
2 2 2
Scheme 6. Preparation of acid (K)-23 and alcohol (K)-24. (a) MEMCl, i-Pr NEt, CH Cl , 100% yield; (b) 0.2 N NaOH, 96% yield; (c) TBAF, 100% yield.
2
Scheme 7. Synthesis of triester (K)-28. (a) DCC, DMAP, CSA, 92% yield; (b) TFA, THF, H O, 99% yield; (c) (C)-27, DCC, DMAP, CSA, 96% yield.
3
2
Yamaguchi macrolactonization of the seco acid (K)-29
then proceeded in excellent yield (91%) to furnish (K)-32.
Finally, deprotection of (K)-32 in TFA/CH Cl (1:1)
NMR, IR, HR-FABMS, optical rotation, melting point and
mixed melting point, TLC, and HPLC in four solvent
systems) to those of the natural product.
2
2
provided totally synthetic (C)-macrosphelide A ((C)-1)
in 90% yield (Scheme 8). Its spectral properties were
In summary, a highly convergent, stereocontrolled first
total synthesis of (C)-macrosphelide A ((C)-1) has been
1
identical in all respects (400 MHz H and 100 MHz
13
C
Table 3. Deprotection of TBS and t-butyl groups of (K)-28
a
Reaction conditions
Results
TFA$THF$H
HCOOH
AcOH$PrOH$H
2
O (1:8:1)
O (1:4:4)
30 (83%)
(K)-29 (23%)C31 (20%)
(K)-29 (19%)C31 (29%)
(K)-29 (64%)C31 (24%)
2
2 2
TFA$thioanisole$CH Cl (5:5:1)
a
2
Yields were based on pure materials isolated by chromatography on SiO .

T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
3795
Scheme 8. The end game for total synthesis of (C)-macrosphelide A ((C)-1). (a) 2,4,6-trichlorobenzoyl chloride, Et N, DMAP, 91% yield; (b) TFA, 90% yield.
3
Scheme 9. Synthesis of (C)-macrosphelide E ((C)-3). (a) (K)-27, DCC, DMAP, CSA, CH
(c) 2,4,6-trichlorobenzoyl chloride, Et N, DMAP, 66% yield; (d) TFA, 79% yield.
2 2 2 2
Cl , 100% yield; (b) TFA, thioanisole, CH Cl , 51% yield;
3
Scheme 10. Synthesis of (K)-macrosphelides A and E ((K)-1 and (K)-3). (a) TBSCl, Et
3% yield for two steps; (d) MEMCl, i-Pr NEt, CH Cl , 96% yield; (e) 0.2 N NaOH, 85% yield; (f) TBAF, 98% yield; (g) DCC, DMAP, CSA, 62% yield;
h) AcOH, THF, H O, 97% yield; (i) (K)-27, DCC, DMAP, CSA, 77% yield; (j) TFA, thioanisole, CH Cl , 38% yield; (k) 2,4,6-trichlorobenzoyl chloride,
N, DMAP, 86% yield; (l) TFA, 88% yield; (m) (C)-27, DCC, DMAP, CSA, 100% yield; (n) TFA, thioanisole, CH Cl , 41% yield; (o) 2,4,6-
N, DMAP, 85% yield; (p) TFA, 64% yield.
3 2 2 3 4
N, CH Cl , 35% yield; (b) PPh , DEAD, HCOOH; (c) dil NH OH,
7
2
2
2
(
2
2
2
Et
3
2
2
trichlorobenzoyl chloride, Et
3

3796
T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
achieved, in 11 steps, from sorbic acid ester, with a 20%
overall yield. The synthetic scheme includes the use of a
modified Sharpless asymmetric dihydroxylation for the
effective introduction of two stereocenters.
measured on JEOL JNM-EX270 (270 MHz) or Varian
VXR-300 (300 MHz) or Varian XL-400 (400 MHz) or
Varian UNITY-400 (400 MHz). All infrared spectra were
measured on a Horiba FT-210 spectrometer. Melting points
were measured on a Yanagimoto Micro Melting Apparatus.
High- and low-resolution mass spectra were measured on
JEOL JMS-DX300 and JEOL JMS-AX505 HA spectro-
meters. Elemental analysis data were measured on a Yanaco
CHN CORDER MT-5. Single crystal X-ray spectra were
measured on a SMART APEXII diffractometer: AFC-5S.
Liquid chromatographic preparation was conducted on a
Jasco PU-980 with Senshu Pak-PEGASIL ODS.
2
(
.5. Synthesis of (C)-macroshelode E, and
K)-macrosphelides A and E
We next sought to prepare the (C)-macrosphelide E ((C)-
), which was isolated from the gastrointestinal tract of the
3
sea hare Aplysia kurodai. Its absolute structure was
established via a series of NMR studies in conjunction
with HREIMS, UV data, and chemical characterization of
the fragmented 3-hydroxybutyric acid and 4,5-dihydroxy-2-
4.1.1. (5R,6S,11R,12S,16S)-(3E,9E)-5,11-Bis[(S)-a-meth-
oxy-a-trifluoromethylphenyl-acetoxy]-6,12,16-trimethyl-
1,7,13-trioxacyclohexadeca-3,9-diene-2,8,14-trione (K)-
4. At room temperature a solution of (C)-macrosphelide A
(10.0 mg, 29.2 mmol) in dry THF (0.6 mL) was treated with
(S)-(K)-a-methoxy-a-(trifluoromethyl)-phenylacetic acid
(41 mg, 175 mmol), dicyclohexylcarbodiimide (18 mg,
88 mmol), and 4-dimethylaminopyridine (3.6 mg,
29 mmol). A white precipitate formed immediately. The
resultant mixture was stirred for 2 h, quenched with
saturated aqueous NaHCO3 (1 mL), and extracted with
dichloromethane (3!1.5 mL). The combined extracts were
dried over sodium sulfate, filtered and concentrated. To
remove dicyclohexylurea the white solid was taken up in
ether (1 mL) and filtered, the cake was washed with ether
1
9
E-hexenoic acid. Numata and co-workers showed that
C)-macrosphelide E is the C(3) epimer of (C)-macro-
sphelide A. Synthesis of (C)-3 was initiated using a Keck
(
2
9
protocol of the alcohol precursor (K)-26 with building
3
0
block (K)-27 (prepared by silylation of (R)-3-hydroxy-
butylic acid) to give (K)-33 in 100% yield. Removal of the
silyl and tert-butyl moieties from (K)-33, (under the same
3
1
condition as for (K)-28 ) furnished the seco acid (K)-34,
3
2
which was then cyclized by Yamaguchi protocol to give
K)-35 in 66% yield. Finally, acid treatment of (K)-35 to
(
remove MEM protecting groups provided synthetic (C)-3
in 79% yield (Scheme 9), which demonstrated identical,
reported spectral data for the naturally occurring
1
9
compound.
(1 mL), and the combined ethereal solutions were concen-
(
K)-Macrosphelides A and E, which are the antipodes of
the naturally occurring products, were also prepared from
C)-14 following the same procedure as for the syntheses of
C)-macrosphelides A and E (Scheme 10).
trated. Preparative TLC (250 mm!20!20 cm; 2:1 hex-
anes/EtOAc) gave (K)-4 (26.2 mg, 100% yield) as a white
2
0
1
(
(
powder: [a] ZK20 (c 0.86, CHCl ); H NMR (400 MHz,
D 3
CDCl ) d 7.57–7.27 (m, 10H), 6.75 (dd, JZ15.9, 7.1 Hz,
3
1
1
H), 6.69 (dd, JZ15.7, 7.5 Hz, 1H), 5.98 (dd, JZ15.8,
.2 Hz, 2H), 5.38 (m, 1H), 5.32 (m, 1H), 5.30 (m, 1H), 5.12
3
. Conclusion
(m, 1H), 5.10 (m, 1H), 3.53 (s, 3H), 3.50 (s, 3H), 2.53 (m,
H), 2.49 (m, 1H), 1.30 (d, JZ6.5 Hz, 3H), 1.21 (d, JZ
6.5 Hz, 3H), 1.13 (d, JZ6.5 Hz, 3H). C NMR (100 MHz,
1
1
3
As described above, the determination of the absolute
structures of (C)-macrosphelides ((C)-1 and 2) and the
total syntheses of (C)/(K)-macrosphelides A and E were
completed. The longest linear synthetic sequence for the
synthesis of (C)-macrosphelide A comprised of 11 steps,
and proceeded in 20% overall yield (corresponding to an
CDCl ) d 17.1, 17.2, 19.5, 40.6, 55.6 (2 C), 67.7, 69.3, 70.1,
3
75.3, 77.0, 121.7, 124.6, 125.5 (2 C), 125.6 (2 C), 127.1
(4 C) 128.6 (2 C), 129.9 (2 C), 131.5 (2 C), 140.3 (2 C),
140.4 (2 C) 163.4, 163.6, 165.4, 165.7, 169.1; HRMS
C
(FAB, NaI matrix) m/z 797.2053 [(MCNa) ; calcd for
C H O F Na: 797.2009].
8
8% average yield per step). Our synthesis used a modified
3
6 36 12 6
Sharpless-Asymmetric-Dihydroxylation for the introduc-
tion of the two asymmetric carbons. We have also
demonstrated that this synthetic route can be applied to
the preparation of macrosphelide derivatives, including
enantiomers and diastereomers. Studies on the mode of
action and the structure–activity relationships of macro-
sphelides are currently underway.
4.1.2. (5R,6S,11R,12S,16S)-(3E,9E)-5,11-Bis[(R)-a-meth-
oxy-a-trifluoromethylphenyl-acetoxy]-6,12,16-trimethyl-
1,7,13-trioxacyclohexadeca-3,9-diene-2,8,14-trione (C)-
5. Following the procedure described above for the
preparation of (K)-4, (C)-macrosphelide A (10.0 mg,
29.9 mmol) was acylated with (R)-(C)-a-methoxy-a-(tri-
fluoromethyl)phenylacetic acid (41 mg, 175.2 mmol).
Work-up and preparative TLC (250 mm!20!20 cm; 2:1
hexanes/EtOAc) afforded (C)-5 (6.1 mg, 27% yield) as a
4. Experimental
2
0
1
white powder: [a] ZC36 (c 0.43, CHCl ); H NMR
D
3
4
.1. General
(400 MHz, CDCl ) d 7.47–7.28 (m, 10H), 6.70 (dd, JZ15.8,
3
6
.1 Hz, 1H), 6.64 (dd, JZ15.8, 7.0 Hz, 1H), 5.85 (dd, JZ
Dry THF, toluene, ethyl ether, and CH Cl were purchased
2
15.7, 1.2 Hz, 2H), 5.41 (m, 1H), 5.37 (m, 1H), 5.28 (m, 1H),
5.14 (m, 1H), 5.13 (m, 1H), 3.53 (s, 3H), 3.49 (s, 3H), 2.59
(m, 1H), 2.52 (m, 1H), 1.37 (d, JZ6.5 Hz, 3H), 1.30 (d, JZ
2
from Kanto Chemical Co. Precoated silica gel plates with a
fluorescent indicator (Merck 60 F254) were used for
analytical and preparative thin layer chromatography.
Flash column chromatography was carried out with Merk
1
3
6.5 Hz, 3H), 1.27 (d, JZ6.5 Hz, 3H). C NMR (100 MHz,
CDCl ) d 17.4, 17.7, 19.4, 40.6, 55.5, 55.6, 67.7, 69.7, 70.4,
75.2, 76.9, 121.6, 124.5, 124.7 (2 C), 125.2 (2 C), 127.2
3
1
13
silica gel 60 (Art. 1.09385). H and C NMR spectra were

T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
3797
(
1
2 C), 127.3 (2 C), 128.6 (2 C), 129.9 (2 C), 131.3, 131.4,
40.1 (4 C), 163.2, 163.5, 165.7 (2 C), 169.1; HRMS (FAB,
NaI matrix) m/z 797.2000 [(MCNa) ; calcd for
Na SO , warmed to ambient temperature and stirred for
2 3
50 min. The mixture was extracted with 3!8 mL of
CH Cl , dried over Na SO , filtered and concentrated.
C
2
2
2
4
C H O F Na: 797.2009].
36 36 12 6
Flash chromatography (50% EtOAc/hexane) provided
9.9 mg of diol (K)-14 (0.20 mmol, 62%) as a colorless oil.
3
4.1.3. (5R,6S,12S,16S)-(3E,9E)-5-Hydroxy-6,12,16-tri-
methyl-1,7,13-trioxacyclohexa-deca-3,9-diene-2,8,11,14-
Reaction of asymmetric dihydroxylation with Corey AD-
ligand-a non MeI salt (15). To a well-stirred solution of
588 mg (1.8 mmol) of potassium hexacyanoferrate, 247 mg
(1.8 mmol) of potassium carbonate, 2.2 mg (6.0 mmol) of
potassium osmate(VI) dihydrate and 5.9 mg (6.0 mmol) of
Corey AD-ligand-a non MeI salt 15 in 3.2 mL of t-BuOH/
tetraone [macrosphelide B (C)-2]. A mixture of (C)-1
(
10.9 mg, 32 mmol), pyridinium dichromate (72 mg,
92 mmol) in CH Cl (3 mL) was stirred at room tempera-
ture for 3 h, diluted with ether (3 mL), filtered and
1
2
2
concentrated in vacuo. Preparative TLC (250 mm!20!
0 cm; 9:1 chloroform/methanol) gave a mixture of
2
H O (1/1 v/v) was added 57 mg (0.6 mmol) of methansul-
2
monoketones (C)-2 and 5-ketone (6) (5.1 mg) as a colorless
oil, diketone (7) (1.7 mg, 16% yield) as a colorless oil, and
recovered 1 (4.9 mg, 45% yield) as a white solid. Further
purification by HPLC (Senshu Pak, PEGASIL ODS, 20!
fonamide at ambient temperature. The clear yellow solution
was cooled to 0 8C and added 100 mg (0.6 mmol) of
unsaturated ester 13. The solution was stirred vigorously at
0 8C. After stirring for 18.5 h, the reaction was quenched
2
5 cm; 35% CH CN in H O, 0.8 mL/min) afforded pure
3
with 1.0 g of solid Na
and stirred for 50 min. The mixture was extracted with 3!
20 mL of CHCl , dried over Na SO , filtered and concen-
2 3
SO , warmed to ambient temperature
2
(
C)-2 (2.3 mg, 21% yield) and 6 (1.9 mg, 18% yield) as
24
D
colorless oils. (C)-2: [a] ZC10.0 (c 0.39, MeOH) [lit.
3
2
4
C4.1 (c 0.99, MeOH); IR (KBr) 3437 (s), 1736 (s), 1267
H NMR
trated. Flash chromatography (50% EtOAc/hexane) pro-
vided 86 mg of diol (K)-14 (0.42 mmol, 71%) as a colorless
K1
1
(
m), 1190 (m), 1130 (m), 1055 (m) cm
;
2
0
(
400 MHz, CDCl ) d 7.03 (d, JZ15.8 Hz, 1H), 6.92 (dd,
oil: R
CHCl
f
0.18 (1:1 hexane/EtOAc); [a]
); IR (KBr) 3435 (s), 1716 (s), 1369 (m), 1157
3
D
ZK10.3 (c 1.04,
3
JZ15.8, 3.7 Hz, 1H), 6.74 (d, JZ15.8 Hz, 1H), 6.08 (dd,
JZ15.8, 2.1 Hz, 1H), 5.46 (m, 1H), 5.07 (m, 1H), 5.05 (m,
K1
1
(s) cm ; H NMR (270 MHz, CDCl ) d 6.81 (dd, JZ15.8,
3
1
H), 4.32 (br s, 1H), 2.82 (dd, JZ16.3, 11.0 Hz, 1H), 2.62
5.3 Hz, 1H), 6.06 (dd, JZ15.8, 1.7 Hz, 1H), 4.04 (m, 1H),
3.73 (m, 1H), 2.34 (d, JZ4.6 Hz, 1H), 2.11 (d, JZ4.0 Hz,
1H), 1.49 (s, 9H), 1.25 (d, JZ6.3 Hz, 3H); C NMR
(
(
(
dd, JZ16.3, 2.3 Hz, 1H), 1.50 (d, JZ6.9 Hz, 3H), 1.43
d, JZ6.9 Hz, 3H), 1.36 (d, JZ6.4 Hz, 3H); C NMR
100 MHz, CDCl ) d 16.1, 17.9, 19.8, 40.6, 67.7, 74.8, 75.8,
1
3
13
(67.5 MHz, CDCl
145.2, 165.7; HRMS (FAB, NBA matrix) m/z 203.1273
) d 19.1, 28.1, 70.2, 75.7, 80.8, 124.3,
3
3
76.8, 122.6, 132.1, 132.5, 144.2, 164.1, 165.4, 170.3, 196.2;
HRMS (FAB, m-NBA matrix) m/z 341.1212 [(MCH) ;
calcd for C H O : 341.1236].
16 21 8
C
C
[(MCH) ; calcd for C10
C H O : C, 59.39; H, 8.97. Found: C, 59.12; H, 8.88.
10 19 4
H O : 203.1283]. Anal. Calcd for
19 4
1
Compound 6. H NMR (270 MHz, CDCl ) d 7.25 (d, JZ
4.1.7. (4R,5R)-(E)-4,5-Dihydroxyl-2-hexenoic acid
t-butyl ester (C)-14. Following the procedure described
above for the preparation of (K)-14, dihydroxylation of
100 mg (0.60 mmol) of 13 with Corey AD-ligand-b non
3
1
1
5
(
1
5.8 Hz, 1H), 7.02 (dd, JZ15.8, 5.3 Hz, 1H), 6.65 (d, JZ
5.8 Hz, 1H), 6.19 (dd, JZ15.8, 1.3 Hz, 1H), 5.35 (m, 1H),
.20 (q, JZ6.9 Hz, 1H), 4.90 (m, 1H), 4.19 (m, 1H), 2.71
dd, JZ16.2, 10.6 Hz, 1H), 2.57 (dd, JZ16.2, 2.6 Hz, 1H),
.51 (d, JZ7.3 Hz, 3H), 1.39 (d, JZ6.3 Hz, 3H), 1.36
d, JZ6.3, 3H); HRMS (FAB, m-NBA matrix) m/z
2
9
MeI salt (17) afforded 89.3 mg of (C)-14 (74%): [a] Z
D
C12.4 (c 1.56, CHCl ); HRMS (FAB, NBA matrix) m/z
3
C
203.1310 [(MCH) ; calcd for C H O : 203.1283].
(
3
1
0 19 4
C
41.1231 [(MCH) ; calcd for C H O : 341.1236].
16 21 8
4
.1.8. (4S,5S)-(E)-5-(t-Butyldimethylsiloxy)-4-hydroxyl-
1
Compound 7 H NMR (270 MHz, CDCl ) d 7.29 (d, JZ
2-hexenoic acid t-butyl ester (C)-19. To a solution of
1.12 g (5.53 mmol) of diol (K)-14, 34 mg (0.28 mmol) of
4-dimethylaminopyridine and 1.84 g (12.2 mmol) of tert-
butyldimethylsilyl chloride in 11.0 mL of CH Cl at 0 8C
was added 1.85 mL (13.3 mmol) of triethylamine. The
reaction mixture was gradually warmed to ambient
temperature for 5 h. After 7 h 15 min, the solution was
quenched with 5 mL of H O. This mixture was extracted
2
with 3!30 mL of CHCl , washed with 20 mL of saturated
3
NaCl aqueous solution, dried over Na SO , filtered, and
2
3
1
1
1
1
6.2 Hz, 1H), 6.78 (d, JZ15.8 Hz, 1H), 7.09 (d, JZ
5.8 Hz, 1H), 6.56 (d, JZ16.2 Hz, 1H), 5.20 (q, JZ7.3 Hz,
H), 5.12 (q, JZ6.9 Hz, 1H), 5.31 (m, 1H), 2.84 (dd, JZ
6.5, 11.3 Hz, 1H), 2.61 (dd, JZ16.5, 2.1 Hz, 1H), 1.51 (d,
2
2
JZ7.3 Hz, 3H), 1.39 (d, JZ6.9 Hz, 3H), 1.34 (d, JZ
1
.3 Hz, 3H); C NMR (67.5 MHz, CDCl ) d 15.9, 17.0,
3
6
1
1
3
9.5, 40.6, 69.2, 75.5, 76.3, 132.0, 132.2, 132.3, 134.3,
63.1, 163.5, 170.1, 195.6, 197.4; HRMS (FAB, m-NBA
matrix) m/z 339.1075 [(MCH) ; calcd for C H O :
1
C
6
19
8
4
3
39.1080].
concentrated. Chromatography (1.6% EtOAc/hexane) pro-
vided 986 mg of (C)-19 (3.12 mmol, 78% based on
recovered (K)-14, 186 mg of 4-silyl ether (C)-20
(0.59 mmol, 11%) and 316 mg of starting material
4
.1.6. 3.1.4. (4S, 5S)-(E)-4,5-Dihydroxyl-2-hexenoic acid
t-butyl ester (K)-14. Reaction of asymmetric dihydroxyl-
ation with AD-mix-a. To a well-stirred solution of AD-mix-
a (488 mg) in 3.2 mL of t-BuOH/H O (1/1 v/v) was added
(1.56 mmol, 30%). (C)-19: R 0.58 (3:1 hexane/EtOAc);
f
2
4
[a] ZC6.0 (c 1.81, CHCl ); IR (KBr) 3435 (s), 2978 (m),
2
D 3
3
0.4 mg (0.32 mmol) of methansulfonamide at ambient
2931 (m), 2858 (m), 1716 (s), 1369 (m), 1257 (m), 1157 (s),
1097 (m) cm ; H NMR (270 MHz, CDCl ) d 6.79 (dd,
JZ15.8, 4.6 Hz, 1H), 6.02 (dd, JZ15.8, 1.7 Hz, 1H), 3.99
(m, 1H), 3.76 (m, 1H), 2.56 (d, JZ5.9 Hz, 1H), 1.48 (s, 9H),
1.21 (d, JZ6.3 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 3H), 0.06 (s,
K1
1
temperature. The clear yellow solution was cooled to 0 8C
and added 53.8 mg (0.32 mmol) of unsaturated ester 13. The
solution was stirred vigorously at 0 8C. After stirring for
3
2
7 h, the reaction was quenched with 500 mg of solid

3798
T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
1
H); C NMR (67.5 MHz, CDCl ) d K4.9, K4.4, 18.0,
3
3
dicyclohexylcarbodiimide (14 mg, 0.07 mmol), and 4-di-
methylaminopyridine (2.7 mg, 0.02 mmol). A white pre-
cipitate formed immediately. The resultant mixture was
3
2
HRMS (FAB, NaI matrix) m/z 339.1978 [(MCNa) ; calcd
0.1, 25.7, 28.1, 71.1, 75.2, 80.3, 123.8, 146.0, 165.6;
C
for C H O SiNa: 339.1968]. Anal. Calcd for C H O Si:
4
stirred for 15 min, quenched with H O (1 mL), and
2
1
6
32
4
10 32
C, 60.72; H, 10.19. Found: C, 60.88; H, 10.06.
extracted with CHCl (3!4.0 mL). The combined extracts
3
were dried over sodium sulfate, filtered and concentrated.
To remove dicyclohexylurea the white solid was taken up in
ether (1 mL) and filtered, the cake was washed with ether
(1 mL), and the combined ethereal solutions were concen-
trated. Preparative TLC (250 mm!20!20 cm; 6:1
4
2
.1.9. (4R,5R)-(E)-5-(t-Butyldimethylsiloxy)-4-hydroxyl-
-hexenoic acid t-butyl ester (K)-19. Following the
procedure described above for the preparation of (C)-19,
silylation of 78 mg (0.39 mmol) of (C)-14 afforded
8
9.3 mg of (K)-19 (33%, 69% based on recovered (C)-
hexanes/EtOAc) gave (K)-MTPA-21 (11.3 mg, 100%
yield) as a colorless oil: [a] ZK20.5 (c 1.00, CHCl );
D 3
IR (KBr) 2858 (m), 1755 (s), 1720 (s), 1662 (w), 1254 (s),
2
7
27
14): [a] ZK8.2 (c 0.85, CHCl ); HRMS (FAB, NaI
matrix) m/z 339.1968 [(MCNa) ; calcd for C H O SiNa:
3
Found: C, 60.38; H, 10.11.
D
3
C
1
6 32 4
K1 1
39.1968]. Anal. Calcd for C H O Si: C, 60.72; H, 10.19.
1
779 (m), 719 (m) cm ; H NMR (270 MHz, CDCl
(m, 5H), 6.74 (dd, JZ15.8, 6.3 Hz, 1H), 5.91 (dd, JZ15.8,
.3 Hz, 1H), 5.47 (m, 1H), 3.88 (m, 1H), 3.57 (s, 3H), 1.48
(s, 9H), 1.04 (d, JZ6.3 Hz, 3H), 0.84 (s, 9H), K0.01,
3
) d 7.46
0 32 4
1
4
.1.10.
(4R,5S)-(E)-5-(t-Butyldimethylsiloxy)-4-
1
3
hydroxyl-2-hexenoic acid t-butyl ester (C)-19. At room
temperature, to a solution of 836 mg (2.65 mmol) of (C)-21
and 1.39 g (5.29 mmol) of triphenylphosphine in 5.0 mL
of benzene was added a solution of 0.83 mL (5.29 mmol)
of diethyl azodicarboxylate and 0.21 mL (5.56 mmol) of
formic acid in 8.3 mL of benzene over 45 min. The reaction
mixture was stirred for 3.5 h then quenched with 10 mL of
H O. This mixture was extracted with 3!20 mL of CHCl ,
washed with 5.0 mL of saturated NaHCO aqueous solution,
3
dried over Na SO , filtered, and concentrated. This crude
2
product was used directly in the subsequent reaction. To this
product was added 13.0 mL of diluted NH OH solution
K0.04 (s, each 3H); C NMR (67.5 MHz, CDCl ) d K5.2,
3
K4.7, 17.9, 19.2, 25.6, 28.1, 55.6, 69.5, 78.7, 78.7, 80.4,
126.6, 127.5, 128.4, 129.6, 132.1, 139.9, 164.8, 165.7;
HRMS (FAB, m-NBACNaI matrix) m/z 555.2367 [(MC
C
Na) ; calcd for C26H O F SiNa: 555.2366].
39 6 3
4.1.13. (4R,5S)-(E)-5-(t-Butyldimethylsiloxy)-4-(R)-a-
methoxy-a-trifluoromethylphenyl-acetoxy-2-hexenoic
acid t-butyl ester (C)-MTPA-21. At room temperature a
solution of (C)-21 (8.9 mg, 0.03 mmol) in dry THF
(0.6 mL) was treated with (R)-(C)-a-methoxy-a-(trifluoro-
methyl)-phenylacetic acid (40 mg, 0.17 mmol), dicyclo-
hexylcarbodiimide (17 mg, 0.08 mmol), and 4-di-
methylaminopyridine (3.4 mg, 0.03 mmol). A white pre-
cipitate formed immediately. The resultant mixture was
2
3
4
4
(pH 10.0–10.2) in MeOH$H O (3:1), the solution was
2
stirred for 1.5 h at ambient temperature, and then quenched
with 40 mL of saturated NH Cl aqueous solution. This
4
mixture was extracted with 3!50 mL of CHCl , dried over
3
stirred for 20 min, quenched with H O (1 mL), and
2
Na SO , filtered, and concentrated. Chromatography (5%
2
extracted with CHCl (3!4.0 mL). The combined extracts
3
4
EtOAc/hexane) provided 697 mg of (C)-21 (2.21 mmol,
3%) as a colorless oil: R 0.42 (4:1 hexane/EtOAc);
were dried over sodium sulfate, filtered and concentrated.
To remove dicyclohexylurea the white solid was taken up in
ether (1 mL) and filtered, the cake was washed with ether
(1 mL), and the combined ethereal solutions were con-
centrated. Preparative TLC (250 mm!20!20 cm; 6:1
hexanes/EtOAc) gave (C)-MTPA-21 (13.1 mg, 91%
8
f
25
[
(
(
a] ZC17.9 (c 2.58, CHCl ); IR (KBr) 3435 (s), 2931
D 3
m), 2858 (m), 1716 (s), 1369 (m), 1257 (m), 1157 (s), 1097
K1
1
m) cm ; H NMR (270 MHz, CDCl ) d 6.77 (dd, JZ
3
1
1
1
5.8, 5.3 Hz, 1H), 6.00 (dd, JZ15.8, 1.7 Hz, 1H), 4.16 (m,
2
7
H), 3.90 (m, 1H), 2.36 (d, JZ3.6 Hz, 1H), 1.48 (s, 9H),
yield) as a colorless oil: [a] ZC21.7 (c 1.00, CHCl );
D
3
1
3
.09 (d, JZ6.3 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 6H);
C
IR (KBr) 2858 (m), 1755 (s), 1718 (s), 1662 (w), 1255 (s),
779 (m), 719 (m) cm ; H NMR (270 MHz, CDCl ) d 7.51
K1 1
NMR (67.5 MHz, CDCl ) d K5.0, K4.5, 17.8, 18.0, 25.7,
2
3
3
8.1, 70.8, 74.9, 80.4, 123.6, 144.4, 165.6; HRMS
FAB, NaI matrix) m/z 339.1968 [(MCNa) ; calcd for
(m, 5H), 6.65 (dd, JZ15.8, 5.6 Hz, 1H), 5.68 (dd, JZ15.8,
1.7 Hz, 1H), 5.60 (m, 1H), 3.99 (m, 1H), 3.61 (s, 3H), 1.46
(s, 9H), 1.14 (d, JZ6.3 Hz, 3H), 0.86 (s, 9H), 0.07, 0.04 (s,
C
(
C H O SiNa: 339.1968]. Anal. Calcd for C H O Si: C,
1
6
32
4
16 32 4
1
3
6
0.72; H, 10.19. Found: C, 60.88; H, 10.23.
each 3H); C NMR (67.5 MHz, CDCl ) d K5.2, K4.7,
18.0, 18.5, 25.6, 28.0, 55.7, 69.5, 78.4, 78.7, 80.8, 125.5,
127.4, 128.4, 129.6, 132.2, 139.7, 164.8, 165.7; HRMS
3
4
.1.11. (4S,5R)-(E)-5-(t-Butyldimethylsiloxy)-4-
C
(FAB, m-NBACNaI matrix) m/z 555.2370 [(MCNa) ;
hydroxyl-2-hexenoic acid t-butyl ester (K)-21. Following
the procedure described above for the preparation of (C)-
calcd for C26H O F SiNa: 555.2366].
39 6 3
2
1, inversion of 777 mg of (K)-19 afforded 89.3 mg of
28
(
(
K)-21 (73%): [a] ZK20.0 (c 0.70, CHCl ); HRMS
4.1.14. (4R,5S)-(E)-5-(t-Butyldimethylsiloxy)-4-methoxy-
ethoxymethoxy-2-hexenoic acid t-butyl ester (K)-22. At
room temperature, to a solution of 368 mg (1.16 mmol) of
(C)-21 and 2.63 mL (15.08 mmol) of N-ethyldiisopropyl-
amine in 6.0 mL of CH Cl was added 1.32 mL
D
3
C
FAB, NaI matrix) m/z 339.1970 [(MCNa) ; calcd for
C H O SiNa: 339.1968]. Anal. Calcd for C H O Si: C,
1
6
32
4
16 32 4
6
0.72; H, 10.19. Found: C, 60.40; H, 10.22.
2
2
4
.1.12. (4R,5S)-(E)-5-(t-Butyldimethylsiloxy)-4-[(S)-a-
(11.60 mmol) of b-methoxyethoxymethyl chloride, the
reaction mixture was stirred for 66 h, and then quenched
with 5.0 mL of water. This mixture was extracted with 3!
20 mL of CH Cl , washed with 10 mL of saturated NaCl
methoxy-a-trifluoromethylphenyl-acetoxy]-2-hexenoic
acid t-butyl ester (K)-MTPA-21. At room temperature a
solution of (C)-21 (6.9 mg, 0.02 mmol) in dry THF
2
2
(0.4 mL) was treated with (S)-(K)-a-methoxy-a-(trifluoro-
methyl)-phenylacetic acid (31 mg, 0.13 mmol),
solution, dried over Na SO , filtered, and concentrated.
2 4
Chromatography (3.3% EtOAc/hexane) provided 410.4 mg

T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
3799
of (K)-22 (1.02 mmol, 87%) as a colorless oil: R 0.58 (30:1
f
mixture was extracted with 3!20 mL of CHCl , dried over
3
2
6
CHCl /MeOH); [a] ZK28.4 (c 0.62, CHCl ); IR (KBr)
Na SO , filtered, and concentrated. Chromatography (50%
4
3
D
3
2
3
1
435 (s), 2956 (m), 2931 (m), 2889 (m), 2858 (m), 1716 (s),
369 (m), 1254 (m), 1155 (s), 1105 (s) cm ; H NMR
EtOAc/hexane) provided 133 mg of (K)-24 (0.46 mmol,
100%) as a colorless oil: R 0.20 (1:1 hexane/EtOAc);
K1
1
f
2
7
(
(
270 MHz, CDCl ) d 6.72 (dd, JZ15.8, 6.6 Hz, 1H), 5.90
dd, JZ15.8, 1.0 Hz, 1H), 4.72 (s, 2H), 4.02 (dd, JZ11.2,
[a] ZK51.3 (c 1.01, CHCl ); IR (KBr) 3435 (s), 2978
3
D 3
(m), 2933 (m), 2891 (m), 1716 (s), 1367 (m), 1308 (m),
1254 (m), 1155 (s), 1039 (m) cm ; H NMR (270 MHz,
K1
1
6
.9 Hz, 1H), 3.80 (m, 1H), 3.77 (m, 1H), 3.63 (m, 1H), 3.54
(
0
(
m, 2H), 3.38 (s, 3H), 1.47 (s, 9H), 1.17 (d, JZ5.9 Hz, 3H),
CDCl ) d 6.73 (dd, JZ15.8, 6.3 Hz, 1H), 5.96 (dd, JZ15.8,
3
1
3
.86 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); C NMR
1.3 Hz, 1H), 4.75 (dd, JZ15.5, 6.9 Hz, 2H), 4.21 (m, 1H),
3.93 (m, 1H), 3.86 (m, 1H), 3.67 (m, 1H), 3.55 (m, 2H), 3.39
67.5 MHz, CDCl ) d K4.8, K4.6, 18.0, 20.0, 25.8, 27.9,
3
1
3
59.0, 67.1, 70.6, 71.6, 79.9, 80.3, 93.8, 125.4, 144.3, 165.3;
HRMS (FAB, NBA matrix) m/z 405.2658 [(MCH) ; calcd
(s, 3H), 1.48 (s, 9H), 1.14 (d, JZ6.3 Hz, 3H); C NMR
C
(67.5 MHz, CDCl ) d 17.5, 28.1, 59.0, 67.5, 69.0, 71.6, 80.7,
80.8, 94.4, 125.8, 142.3, 165.2; HRMS (FAB, NaI matrix)
m/z 313.1623 [(MCNa) ; calcd for C H O Na:
3
for C H O Si: 405.2672]. Anal. Calcd for C H O Si: C,
2
5
0
41
6
20 41 6
C
9.37; H, 9.96. Found: C, 59.34; H, 10.00.
1
4
26
6
313.1627]. Anal. Calcd for C H O : C, 57.91; H, 9.03.
Found: C, 57.59; H, 8.93.
14 26 6
4
.1.15. (4S,5R)-(E)-5-(t-Butyldimethylsiloxy)-4-methoxy-
ethoxymethoxy-2-hexenoic acid t-butyl ester (C)-22.
Following the procedure described above for the prepa-
ration of (K)-22, MEM protection of 719 mg (2.3 mmol) of
4.1.19. (4S,5R)-(E)-5-hydroxy-4-methoxyethoxy-
methoxy-2-hexenoic acid t-butyl ester (C)-24. Following
2
8
(
K)-21 afforded 884 mg of (C)-22 (96%): [a] ZC29.3 (c
the procedure described above for the preparation of
(K)-24, desilylation of 437 mg (1.1 mmol) of (C)-22
D
0
.15, CHCl ); HRMS (FAB, NaI matrix) m/z 427.2488
3
C
(MCNa) ; calcd for C H O Si Na: 427.2492]. Anal.
31
[
Calcd for C H O Si: C, 59.37; H, 9.96. Found: C, 59.60;
afforded 306 mg of (C)-24 (98%): [a] ZC63.9 (c 0.51,
2
0
40
6
D
CHCl ); HRMS (FAB, NaI matrix) m/z 313.1630 [(MC
2
0
40
6
3
C
Na) ; calcd for C H O Na: 313.1627]. Anal. Calcd for
H, 9.86.
1
4 26 6
C H O : C, 57.91; H, 9.03. Found: C, 57.65; H, 9.06.
14 26 6
4
.1.16. (4R,5S)-(E)-5-(t-Butyldimethylsililoxy)-4-meth-
oxyethoxymethoxy-2-hexenoic acid (K)-23. At room
temperature, 192 mg (0.48 mmol) of (K)-22 was dissolved
in 4.8 mL of 0.2 N NaOH in MeOH$THF$H O (3:1:1)
4.1.20. (4S,5S,10R,11S)-(2E,8E)-11-(tert-Butyldimethyl-
siloxy)-4,10-bis(2-methoxy-ethoxymethoxy)-5-methyl-6-
oxa-1,7-dioxo-2,8-dodecadienoic acid tert-butyl ester
(K)-25. At room temperature, to a solution of 300 mg
(0.86 mmol) of (K)-23, 277 mg (0.78 mmol) of (K)-24,
23 mg (0.19 mmol) of 4-dimethylaminopyridine and 22 mg
(0.093 mmol) of camphorsulfonic acid in 10.0 mL of
CH Cl was added 243 mg (1.18 mmol) of dicyclohexyl-
2
solution, the mixture was stirred for 6 days, and then
quenched with 5.0 mL of 0.2 N HCl aqueous solutin became
neutral solution. This mixture was extracted with 4!15 mL
of CHCl , dried over Na SO , and concentrated. Chroma-
3
2
4
tography (5–9% MeOH/CHCl ) provided 154 mg of (K)-23
3
2
2
(
0.44 mmol, 94%) as a colorless oil: R 0.35 (10:1 CHCl /
f
carbodiimide, the solution was stirred for 18 h 30 min, and
then quenched with 10.0 mL of H O. This mixture was
3
2
2
MeOH); [a] ZK30.0 (c 0.62, CHCl ); IR (KBr) 3435 (s),
D
3
2
2
(
954 (m), 2931 (m), 2891 (m), 2858 (m), 1722 (m), 1703
s), 1255 (m), 1111 (s), 1043 (s) cm ; H NMR (270 MHz,
extracted with 3!10 mL of CHCl , washed with 10.0 mL
3
K1 1
of H O, dried over Na SO , filtered, and concentrated.
2
2
4
CDCl ) d 6.98 (dd, JZ15.8, 6.3 Hz, 1H), 6.02 (dd, JZ15.8,
Chromatography (17–25% EtOAc/hexane) provided
447 mg of (K)-25 (0.71 mmol, 92%) as a colorless oil: R
3
1
(
3
.0 Hz, 1H), 4.74 (dd, JZ10.9, 6.9, 2H), 4.10 (m, 1H), 3.84
m, 1H), 3.76 (m, 1H), 3.66 (m, 1H), 3.54 (m, 2H), 3.38 (s,
H), 1.17 (d, JZ6.3 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03
f
2
3
0.44 (1:1 hexane/EtOAc); [a] ZK40.4 (c 0.50, CHCl );
D 3
IR (KBr) 3435 (s), 2954 (w), 2931 (w), 2889 (w), 1718 (m),
1
3
K1 1
(
s, 3H); C NMR (67.5 MHz, CDCl ) d K4.8, K4.6, 18.0,
1637 (w), 1255 (w), 1157 (m), 1038 (m) cm ; H NMR
(270 MHz, CDCl ) d 6.82 (dd, JZ15.8, 6.6 Hz, 1H), 6.71
3
1
1
9.9, 25.7, 59.0, 67.3, 70.5, 71.6, 79.9, 94.2, 122.4, 148.5,
70.8; HRMS (FAB, NaI matrix) m/z 371.1861 [(MCNa) ;
3
C
(dd, JZ15.8, 6.3 Hz, 1H), 5.98 (dd, JZ15.8, 1.0 Hz, 1H),
5.97 (dd, JZ15.8, 1.3 Hz, 1H), 5.09 (m, 1H), 4.72 (dd, JZ
11.2, 6.9 Hz, 2H), 4.71 (dd, JZ11.2, 6.9 Hz, 2H), 4.34 (m,
calcd for C H O SiNa: 371.1866]. Anal. Calcd for
1
6 32 6
C H O Si: C, 55.14; H, 9.25. Found: C, 54.86; H, 9.18.
16 32 6
1H), 4.05 (m, 1H), 3.74 (m, 1H), 3.65 (m, 2H), 3.60 (m, 2H),
3.52 (m, 4H), 3.37 (s, 3H), 3.36 (s, 3H), 1.47 (s, 9H), 1.22 (d,
4
.1.17. (4S,5R)-(E)-5-(t-Butyldimethylsililoxy)-4-meth-
oxyethoxymethoxy-2-hexenoic acid (C)-23. Following
JZ6.3 Hz, 3H), 1.15 (d, JZ6.4 Hz, 3H), 0.85 (s, 9H), 0.03
1
(s, 3H), 0.01 (s, 3H); C NMR (67.5 MHz, CDCl ) d K4.8,
3
the procedure described above for the preparation of
(
3
K)-23, hydrolysis of 27.1 mg (0.07 mmol) of (C)-22
K4.7, 15.0, 18.0, 19.8, 25.7, 28.0, 59.0, 59.0, 67.1, 67.1,
70.4, 70.5, 71.4, 71.6, 71.6, 79.8, 80.7, 93.7, 93.9, 123.3,
2
8
afforded 19.3 mg of (C)-23 (85%): [a] ZC33.2 (c 0.62,
D
CHCl ); HRMS (FAB, NBA matrix) m/z 347.1888 [(MK
126.2, 141.7, 146.1, 165.0, 165.2; HRMS (FAB, NaI matrix)
m/z 643.3488 [(MCNa) ; calcd for C H O SiNa:
3
K
H) ; calcd for C H O Si: 347.1888]. Anal. Calcd for
C
1
6
31
6
30 56 11
C H O Si: C, 55.14; H, 9.25. Found: C, 54.76; H, 9.31.
1
643.3490]. Anal. Calcd for C H O Si: C, 58.04; H,
30 56 11
6
31
6
9.09. Found: C, 57.99; H, 9.12.
4
.1.18.
(4R,5S)-(E)-5-Hydroxy-4-methoxyethoxy-
methoxy-2-hexenoic acid t-butyl ester (K)-24. At room
temperature, to a solution of 186 mg (0.46 mmol) of silyl
ether (K)-22 in 0.9 mL THF was added 1.4 mL of 1.0 M
tetra-n-butylammonium fluorid in THF, the solution was
4.1.21. (4R,5R,10S,11R)-(2E,8E)-11-(tert-Butyldimethyl-
siloxy)-4,10-bis(2-methoxy-ethoxymethoxy)-5-methyl-6-
oxa-1,7-dioxo-2,8-dodecadienoic acid tert-butyl ester
(C)-25. Following the procedure described above for the
preparation of (K)-25, condensation of 169 mg (0.5 mmol)
stirred for 1 h, and then quenched with 2 mL of H O. This
2

3800
T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
K1
1065 (m), 1039 (s) cm ; H NMR (270 MHz, CDCl ) d
1
of (C)-23 and 169 mg (0.6 mmol) of (C)-24 afforded
3
2
8
1
HRMS (FAB, NaI matrix) m/z 643.3515 [(MCNa) ; calcd
86 mg of (C)-25 (62%): [a] ZC48.5 (c 0.85, CHCl );
6.82 (dd, JZ15.8, 6.3 Hz, 1H), 6.71 (dd, JZ15.8, 6.6 Hz,
1H), 6.05 (dd, JZ15.8, 1.3 Hz, 1H), 5.99 (dd, JZ15.8,
1.3 Hz, 1H), 5.10 (m, 1H), 5.04 (m, 1H), 4.74 (s, 2H), 4.72
(dd, JZ17.5, 6.9 Hz, 2H), 4.36 (m, 2H), 4.24 (m, 1H), 3.77
D
3
C
for C H O SiNa: 643.3490]. Anal. Calcd for
56 11
3
0
C H O Si: C, 58.04; H, 9.09. Found: C, 57.94; H, 8.96.
30 56 11
(m, 2H), 3.63 (m, 2H), 3.53 (m, 4H), 3.37 (s, 6H), 2.48 (dd,
4.1.22. (4S,5S,10R,11S)-(2E,8E)-11-Hydroxy-4,10-bis(2-
methoxyethoxymethoxy)-5-methyl-6-oxa-1,7-dioxo-2,8-
dodecadienoic acid tert-butyl ester (K)-26. 392 mg
JZ14.5, 6.6 Hz, 1H), 2.36 (dd, JZ14.5, 6.3 Hz, 1H), 1.48
(s, 9H), 1.24 (d, JZ6.6 Hz, 3H), 1.20 (d, JZ6.6 Hz, 3H),
1.18 (d, JZ5.9 Hz, 3H), 0.85 (s, 9H), 0.06 (s, 3H), 0.04 (s,
1
3
(
0.63 mmol) of (K)-25 was dissolved in 6.3 mL of
TFA$THF$H O (2:8:1) and the solution was stirred for
3H); C NMR (67.5 MHz, CDCl ) d K4.9, K4.5, 14.9,
3
15.0, 18.0, 23.7, 25.8, 28.1, 44.9, 59.0, 59.0, 65.6, 65.6,
67.2, 67.2, 71.1, 71.6, 71.6, 71.7, 80.8, 80.8, 93.7, 93.8,
124.0, 126.3, 141.7, 143.8, 165.0, 165.0, 170.7; HRMS
2
2
1
2 h at ambient temperature, and then quenched with
5.0 mL of saturated NaHCO3 aqueous solution. This
C
solution was then extracted with 3!40 mL of CHCl3,
washed with 50 mL of saturated NaCl aqueous solution,
dried over Na SO , filtered, and concentrated. Chromatog-
(FAB, NaI matrix) m/z 729.3853 [(MCNa) ; calcd for
H O13Si:
62
C
H
O
C, 57.77; H, 8.84. Found: C, 57.62; H, 8.80.
13SiNa: 729.3857]. Anal. Calcd for C34
34
62
2
4
raphy (6% MeOH/CHCl ) provided 105 mg of (K)-26
3
(
0.21 mmol, 83%) as a colorless oil: R 0.54 (15:1 CHCl /
f 3
4
.1.25. (4S,5R,10S,11R,15R)-(2E,8E)-15-(tert-Butyldi-
2
7
MeOH); [a] ZK58.5 (c 0.66, CHCl ); IR (KBr) 3440 (s),
2
1
D
3
methylsiloxy)-4,10-bis(2-methoxyethoxy-methoxy)-5,11-
dimethyl-6,12-dioxa-1,7,13-trioxo-2,8-hexadeca-dienoic
acid tert-butyl ester (C)-28. Following the procedure
described above for the preparation of (K)-28, conden-
sation of 57.3 mg (0.1 mmol) of (C)-26 and 29.6 mg
980 (w), 2933 (w), 2893 (w), 1716 (s), 1659 (w), 1369 (m),
296 (m), 1255 (m), 1157 (s), 1039 (s) cm ; H NMR
K1
1
(
(
270 MHz, CDCl ) d 6.86 (dd, JZ15.8, 5.9 Hz, 1H), 6.71
3
dd, JZ15.8, 6.3 Hz, 1H), 6.04 (dd, JZ15.8, 1.3 Hz, 1H),
5
2
3
(
1
.97 (dd, JZ15.8, 1.3 Hz, 1H), 5.09 (m, 1H), 4.75 (dd, JZ
0.1, 7.3 Hz, 2H), 4.72 (s, 2H), 4.36 (m, 1H), 4.22 (m, 1H),
.93 (m, 1H), 3.82 (m, 2H), 3.65 (m, 2H), 3.53 (m, 4H), 3.38
(
[
0.1 mmol) of (K)-27 afforded 61.7 mg of (C)-28 (77%):
a] ZC42.9 (c 0.55, CHCl ); HRMS (FAB, NaI matrix)
28
D
3
C
m/z 729.3856 [(MCNa) ; calcd for C H O SiNa:
7
8
3
4 62 13
s, 3H), 3.37 (s, 3H), 2.93 (d, JZ5.9 Hz, 1H), 1.48 (s, 9H),
29.3857]. Anal. Calcd for C H O Si: C, 57.77; H,
34 62 13
.84. Found: C, 57.58; H, 8.97.
1
3
.24 (d, JZ6.6 Hz, 3H), 1.14 (d, JZ6.6 Hz, 3H); C NMR
(
67.5 MHz, CDCl ) d 15.0, 17.7, 28.1, 59.0, 59.0, 67.2, 67.2,
3
6
1
7.5, 67.5, 69.0, 71.6, 71.6, 80.8, 80.9, 93.7, 94.5, 123.6,
26.2, 141.7, 144.3, 165.0, 165.0; HRMS (FAB, NaI matrix)
4.1.26. (4R,5S,10R,11S,15S)-(2E,8E)-15-Hydroxy-4,10-
bis(2-methoxyethoxymethoxy)-5,11-dimethyl-6,12-di-
oxa-1,7,13-trioxo-2,8-hexadecadienoic acid (K)-29. At
C
m/z 529.2632 [(MCNa) ; calcd for C H O Na:
2
529.2625]. Anal. Calcd for C H O : C, 56.90; H, 8.36.
24 42 11
Found: C, 56.53; H, 8.39.
4
42 11
0
0
0
8C, to a solution of 12.7 mg (0.018 mmol) of (K)-28 in
.82 mL of thioanisole and 0.16 mL of CH Cl was added
.82 mL of trifluoroacetic acid with stirring. After stirring
2
2
4
.1.23. (4R,5R,10S,11R)-(2E,8E)-11-Hydroxy-4,10-bis(2-
for 35 min, the reaction mixture was warmed to room
temperature, and the solvent was removed in vacuo.
Chromatography (9% MeOH/CHCl ) provided 6.2 mg of
methoxyethoxymethoxy)-5-methyl-6-oxa-1,7-dioxo-2,8-
dodecadienoic acid tert-butyl ester (C)-26. Following the
procedure described above for the preparation of (K)-26,
desilylation of 178 mg (0.3 mmol) of (C)-25 afforded
3
(
K)-29 (0.012 mmol, 64%) as a colorless oil: R 0.18 (10:1
f
24
2
8
CHCl /MeOH); [a] ZK49.8 (c 0.35, CHCl ); IR (KBr)
3 D 3
1
42 mg of (C)-26 (97%): [a] ZC76.8 (c 0.87, CHCl );
D 3
C
3437 (s), 1718 (s), 1655 (w), 1304 (m), 1180 (m), 1065 (m),
HRMS (FAB, NaI matrix) m/z 529.2616 [(MCNa) ; calcd
K1 1
1
1
039 (s) cm ; H NMR (270 MHz, CDCl ) d 6.92 (dd, JZ
3
for C H O Na: 529.2625]. Anal. Calcd for C H O :
2
C, 56.90; H, 8.36. Found: C, 56.76; H, 8.44.
4
42 11
24 42 11
5.8, 6.3 Hz, 1H), 6.82 (dd, JZ15.8, 6.3 Hz, 1H), 6.09 (dd,
JZ15.8, 1.3 Hz, 1H), 6.05 (dd, JZ15.8, 1.3 Hz, 1H), 5.11
m, 2H), 4.75 (dd, JZ15.5, 6.9 Hz, 2H), 4.73 (dd, JZ15.5,
.9 Hz, 2H), 4.38 (m, 1H), 4.32 (m, 1H), 4.20 (m, 1H), 3.79
m, 2H), 3.66 (m, 2H), 3.53 (m, 4H), 3.39 (s, 3H), 3.38 (s,
H), 2.46 (d, JZ5.6 Hz, 2H), 1.28 (d, JZ6.3 Hz, 3H), 1.24
(
6
(
3
4
.1.24. (4R,5S,10R,11S,15S)-(2E,8E)-15-(tert-Butyldi-
methylsiloxy)-4,10-bis(2-methoxyethoxy-methoxy)-5,11-
dimethyl-6,12-dioxa-1,7,13-trioxo-2,8-hexadeca-dienoic
acid tert-butyl ester (K)-28. At room temperature, to a
solution of 89.7 mg (0.177 mmol) of (K)-26, 50.2 mg
1
3
(
d, JZ6.3 Hz, 6H); C NMR (67.5 MHz, CDCl ) d 15.2,
3
1
7
1
5
5.3, 22.5, 43.2, 59.0, 59.0, 64.4, 64.4, 67.3, 67.3, 71.4,
1.4, 71.5, 71.5, 71.5, 93.7, 93.9, 123.7, 124.2, 143.6, 145.3,
64.8, 169.7, 172.0; HRMS (FAB, NaI matrix) m/z
(
(
0.230 mmol) of (S)-3-tert-butyldimethylsiloxybutylic acid
C)-27, 5.2 mg (0.043 mmol) of 4-dimethylaminopyridine
and 4.9 mg (0.021 mmol) of camphorsulfonic acid in
.0 mL of CH Cl was added 54.9 mg (0.266 mmol) of
dicyclohexylcarbodiimide, the solution was stirred for 14 h,
C
59.2346 [(MCNa) ; calcd for C H O Na: 559.2367].
2
4 40 13
2
2
2
Anal. Calcd for C H O : C, 53.72; H, 7.51. Found: C,
4 40 13
2
5
3.80; H, 7.86.
and then quenched with 1.5 mL of H O. This mixture was
2
extracted with 3!10 mL of CHCl , washed with 8 mL of
3
saturated NaCl solution, dried over Na SO , filtered, and
4
4.1.27. (4S,5R,10S,11R,15R)-(2E,8E)-15-Hydroxy-4,10-
bis(2-methoxyethoxymethoxy)-5,11-dimethyl-6,12-di-
oxa-1,7,13-trioxo-2,8-hexadecadienoic acid (C)-29.
Following the procedure described above for the prepa-
ration of (K)-29, deprotection of 31.3 mg (0.04 mmol) of
2
concentrated. Chromatography (50% EtOAc–hexane) pro-
vided 119.6 mg of (K)-28 (0.169 mmol, 96%) as a colorless
2
D
8
oil: R 0.47 (1:1 hexane/EtOAc); [a] ZK28.3 (c 0.48,
f
CHCl ); IR (KBr) 3435 (s), 2931 (w), 2895 (w), 1718 (s),
654 (w), 1369 (w), 1304 (m), 1255 (m), 1155 (s), 1088 (m),
3
2
9
1
(C)-28 afforded 8.9 mg of (C)-29 (38%): [a] ZC57.8 (c
D

T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
3801
0
.18, CHCl ); HRMS (FAB, NaI matrix) m/z 559.2333
3
8.5 Hz, 1H), 2.56 (dd, JZ15.5, 3.5 Hz, 1H), 1.45 (d, JZ
6.6 Hz, 3H), 1.37 (d, JZ6.6 Hz, 3H), 1.33 (d, JZ6.6 Hz,
C
[
(MCNa) ; calcd for C H O Na: 559.2367].
24 40 13
1
3
H); C NMR (100 MHz, CDCl ) d 17.8, 18.0, 19.7, 41.0,
3
67.7, 73.2, 74.1, 74.8, 75.0, 122.3, 122.8, 145.0, 146.0,
3
4.1.28. (5R,6S,11R,12S,16S)-(3E,9E)-5,11-Bis(2-methoxy-
ethoxymethoxy)-6,12,16-trimethyl-1,7,13-trioxacyclo-
hexadeca-3,9-diene-2,8,14-trione (K)-32. To a solution of
164.5, 165.7, 170.1; HRMS (FAB, NaI matrix) m/z
C
365.1219 [(MCNa) ; calcd for C16H O Na: 365.1212].
22 8
2
(
4
5.4 mg (0.047 mmol) of (K)-29 was added 570 ml
0.284 mmol) of 0.5 M triethylamine in toluene and
70 ml (0.237 mmol) of 0.5 M 2,4,6-trichlorobenzoyl chlor-
4.1.31. (K)-Macrosphelide A (K)-1. Following the
procedure described above for the preparation of (C)-1,
deprotection of 4.3 mg (0.008 mmol) of (C)-32 afforded
ide in toluene at room temperature, and the solution was
stirred for 1 h. This solution was diluted with 12.3 mL of
toluene and added to a solution of 145 mg (1.18 mmol) of 4-
dimethylaminopyridine in 4.7 mL of toluene at 80 8C over
2
5
2.5 mg of (K)-1 (88%): [a] ZK80.0 (c 0.07, MeOH);
D
C
HRMS (FAB, NaI matrix) m/z 365.1219 [(MCNa) ; calcd
for C H O Na: 365.1212].
16 22 8
2
h. The anhydride flask was washed with 6.2 mL of toluene
and the washing added to the mixture over 30 mim. The
reaction was then heated at 80 8C for a total of 3.5 h. After
cooling, the white suspension was diluted with 16 mL of
4.1.32. (4R,5S,10R,11S,15R)-(2E,8E)-15-(tert-Butyldi-
methylsiloxy)-4,10-bis(2-methoxyethoxy-methoxy)-5,11-
dimethyl-6,12-dioxa-1,7,13-trioxo-2,8-hexadeca-dienoic
acid tert-butyl eter (K)-33. To a solution of 123 mg
(0.24 mmol) of (K)-26, 63 mg (0.29 mmol) of (K)-27,
7 mg (0.06 mmol) of 4-dimethylaminopyridine and 7 mg
(0.03 mmol) of camphorsulfonic acid in 2.0 mL of CH Cl
saturated NaHCO aqueous solution became clear. The two
3
layers were separated and aqueous layer was extracted with
3!25 mL of EtOAc. The combined organic layers were
dried over Na SO , filtered, and concentrated. Chromato-
2
4
2
2
graphy (9% MeOH/CHCl ) provided 22.3 mg of (K)-32
3
was added 75 mg (0.36 mmol) of dicyclohexylcarbodiimide
at room temperature. The reaction mixture was stirred for
22 h, and then quenched with 2.0 mL of H O. The mixture
(
0.043 mmol, 91%) as a colorless oil: R 0.61 (10:1 CHCl /
f 3
2
7
MeOH); [a] ZK86.5 (c 0.68, CHCl ); IR (KBr) 1724 (s),
D
3
2
K1
252 (m), 1188 (s), 1138 (m), 1109 (m), 1055 (s) cm ; H
1
1
was extracted with 3!20 mL of CHCl , the combined
3
NMR (270 MHz, CDCl ) d 6.71 (dd, JZ15.8, 7.3 Hz, 1H),
organic layers were washed with 15 mL of saturated NaCl
solution, dried over Na SO , filtered, and concentrated.
Chromatography (50% EtOAc/hexane) provided 171 mg of
3
6
1
1
2
3
1
6
.69 (dd, JZ15.8, 6.9 Hz, 1H), 5.96 (dd, JZ15.8, 1.0 Hz,
H), 5.89 (dd, JZ15.8, 1.0 Hz, 1H), 5.29 (m, 1H), 5.02 (m,
H), 4.92 (m, 1H), 4.70 (dd, JZ8.6, 4.6 Hz, 2H), 4.67 (s,
H), 4.08 (m, 2H), 3.76 (m, 2H), 3.62 (m, 2H), 3.53 (m, 4H),
.37 (s, 6H), 2.58 (dd, JZ14.8, 3.0 Hz, 1H), 2.47 (dd, JZ
4.8, 8.3 Hz, 1H), 1.39 (d, JZ6.3 Hz, 3H), 1.30 (d, JZ
2
4
(K)-33 (0.24 mmol, 100%) as a colorless oil: R 0.47 (1:1
f
2
D
8
hexane/EtOAc); [a] ZK54.0 (c 0.49, CHCl ); IR (KBr)
3
3431 (s), 2931 (w), 2895 (w), 1720 (s), 1659 (w), 1369 (w),
1298 (m), 1255 (m), 1153 (s), 1038 (s) cm ; H NMR
K1
1
1
3
.3 Hz, 3H), 1.28 (d, JZ6.3 Hz, 3H); C NMR (67.5 MHz,
(270 MHz, CDCl ) d 6.78 (dd, JZ15.8, 6.3 Hz, 1H), 6.68
3
CDCl ) d 18.1, 18.3, 20.0, 41.3, 59.5, 59.5, 67.7, 67.7, 67.9,
(dd, JZ15.8, 6.3 Hz, 1H), 6.02 (dd, JZ15.8, 1.3 Hz, 1H),
5.95 (dd, JZ15.8, 1.3 Hz, 1H), 5.06 (m, 1H), 5.00 (m, 1H),
4.71 (s, 2H), 4.69 (dd, JZ17.8, 6.9 Hz, 2H), 4.31 (m, 2H),
4.22 (m, 1H), 3.74 (m, 2H), 3.61 (m, 2H), 3.49 (m, 4H), 3.34
(s, 6H), 2.45 (dd, JZ14.9, 7.3 Hz, 1H), 2.31 (dd, JZ14.9,
5.6 Hz, 1H), 1.45 (s, 9H), 1.21 (d, JZ6.6 Hz, 3H), 1.17 (d,
JZ6.6 Hz, 3H), 1.09 (d, JZ6.6 Hz, 3H), 0.82 (s, 9H), 0.02
3
7
1
1.0, 72.0, 72.0, 72.1, 79.1, 79.1, 93.7, 94.3, 124.9, 125.0,
44.4, 145.5, 164.7, 164.8, 170.0; HRMS (FAB, NaI matrix)
C
m/z 541.2272 [(MCNa) ; calcd for C H O Na:
4
2
38 12
541.2261]. Anal. Calcd for C H O : C, 55.59; H, 7.39.
24 38 12
Found: C, 55.83; H, 7.49.
1
3
4
.1.29. (5S,6R,11S,12R,16R)-(3E,9E)-5,11-Bis(2-methoxy-
(s, 3H), 0.00 (s, 3H); C NMR (67.5 MHz, CDCl ) d K4.9,
3
ethoxymethoxy)-6,12,16-trimethyl-1,7,13-trioxacyclo-
hexadeca-3,9-diene-2,8,14-trione (C)-32. Following the
procedure described above for the preparation of (K)-32,
lactonization of 11.6 mg (0.02 mmol) of (C)-29 afforded
K4.6, 14.9(2C), 17.8, 23.7, 25.7(3C), 28.0(3C), 44.7,
58.9(2C), 65.6, 67.2(2C), 71.1, 71.6(2C), 71.8, 76.5,
80.7(2C), 93.6, 93.7, 124.0, 126.2, 141.6, 143.8,
164.9(2C), 170.8; HRMS (FAB, NaI matrix) m/z 729.3855
2
9
C
9
HRMS (FAB, NaI matrix) m/z 541.2247 [(MCNa) ; calcd
.8 mg of (C)-32 (86%): [a] ZC94.5 (c 0.22, CHCl );
[(MCNa) ; calcd for C34H O13SiNa: 729.3857].
62
D
3
C
for C H O Na: 541.2261].
4.1.33. (4S,5R,10S,11R,15S)-(2E,8E)-15-(tert-Butyldi-
methylsiloxy)-4,10-bis(2-methoxyethoxy-methoxy)-5,11-
dimethyl-6,12-dioxa-1,7,13-trioxo-2,8-hexadeca-dienoic
acid tert-butyl ester (C)-33. Following the procedure
described above for the preparation of (K)-33, conden-
sation of 53.8 mg (0.1 mmol) of (C)-26 and 30.1 mg
(0.1 mmol) of (C)-27 afforded 81.6 mg of (C)-33 (100%):
24 38 12
4
2
.1.30. (C)-Macrosphelide A (C)-1. To a solution of
.7 mg (5.2 mmol) of (K)-32 in 0.29 mL of CH Cl was
2
2
added 0.29 mL of trifluoroacetic acid. After stirring for
.5 h at ambiemt temperature, the reaction mixture was
concentrated in vacuo, and chromatographed (10% MeOH/
7
2
7
CHCl ) to provide 1.6 mg (4.7 mmol, 90%) of (C)-1 as
3
[a] ZC70.2 (c 0.45, CHCl ); HRMS (FAB, NaI matrix)
D 3
C
colorless solid: R 0.43 (10:1 CHCl /MeOH); mp 146–
3
m/z 729.3881 [(MCNa) ; calcd for C34H O13SiNa:
62
f
2
D
7
1
MeOH) [lit. C84.1 (c 0.59, MeOH)]; IR (KBr) 3437 (s),
47 8C (MeOH) (lit. 141–142 8C); [a] ZC82.0 (c 0.10,
729.3857].
K1
713 (s), 1284 (m), 1190 (m), 1051 (m) cm ; H NMR
1
1
4.1.34. (4R,5S,10R,11S,15R)-(2E,8E)-15-Hydroxy-4,10-
bis(2-methoxyethoxymethoxy)-5,11-dimethyl-6,12-di-
oxa-1,7,13-trioxo-2,8-hexadecadienoic acid (K)-34. To
a solution of 29 mg (0.042 mmol) of (K)-33 in 2.0 mL of
thioanisole and 0.4 mL of CH Cl was added 2.0 mL of
(
(
400 MHz, CDCl ) d 6.87 (dd, JZ15.8, 5.8 Hz, 1H), 6.86
dd, JZ15.8, 5.8 Hz, 1H), 6.05 (dd, JZ15.8, 1.7 Hz, 1H),
3
6
4
.03 (dd, JZ15.8, 1.7 Hz, 1H), 5.38 (m, 1H), 4.95 (m, 1H),
.86 (m, 1H), 4.22 (m, 1H), 4.14 (m, 1H), 2.62 (dd, JZ15.5,
2
2

3802
T. Sunazuka et al. / Tetrahedron 61 (2005) 3789–3803
trifluoroacetic acid dropwise at 0 8C. After stirring for
0 min, the reaction was concentrated in vacuo. Chroma-
tography (9% MeOH/CHCl ) provided 12 mg of (K)-34
4.1.37. (5S,6R,11S,12R,16S)-(3E,9E)-5,11-Bis(2-methoxy-
ethoxymethoxy)-6,12,16-trimethyl-1,7,13-trioxacyclo-
hexadeca-3,9-diene-2,8,14-trione (C)-35. Following the
procedure described above for the preparation of (K)-35,
lactonization of 11.8 mg (0.02 mmol) of (C)-34 afforded
3
3
(
0.021 mmol, 51%) as a colorless oil: R 0.18 (10:1 CHCl /
f 3
2
8
MeOH); [a] ZK68.8 (c 0.25, CHCl ); IR (KBr) 3437 (s),
1
D
3
K1
720 (s), 1660 (w), 1300 (m), 1180 (m), 1039 (s) cm ; 1H
25
9.7 mg of (C)-35 (85%): [a] ZC37.3 (c 0.22, CHCl );
D
3
C
HRMS (FAB, NaI matrix) m/z 541.2261 [(MCNa) ; calcd
NMR (270 MHz, CDCl ) d 6.92 (dd, JZ15.8, 6.3 Hz, 1H),
3
6
1
.82 (dd, JZ15.8, 6.3 Hz, 1H), 6.07 (dd, JZ15.8, 1.3 Hz,
H), 6.05 (dd, JZ15.8, 1.3 Hz, 1H), 5.12 (m, 2H), 4.76 (dd,
for C H O Na: 541.2261].
4 38 12
2
JZ15.5, 6.8 Hz, 2H), 4.72 (dd, JZ15.5, 6.8 Hz, 2H), 4.38
m, 1H), 4.34 (m, 1H), 4.21 (m, 1H), 3.78 (m, 2H), 3.65 (m,
4
1
.1.38. (C)-Macrosphelide E (C)-3. To a solution of
1 mg (0.02 mmol) of (K)-35 in 0.15 mL of CH Cl was
(
2
2
2
1
3
H), 3.53 (m, 4H), 3.38 (s, 6H), 2.51 (dd, JZ15.8, 8.6 Hz,
H), 2.43 (dd, JZ15.8, 4.0 Hz, 1H), 1.27 (d, JZ6.6 Hz,
H), 1.22 (d, JZ6.6 Hz, 6H); C NMR (67.5 MHz, CDCl3)
added 0.45 mL of trifluoroacetic acid. After being stirred at
ambiemt temperature for 2 h, the reaction mixture was
concentrated in vacuo, and chromatographed (10% MeOH/
1
3
d 15.3, 15.4, 22.4, 43.3, 59.0(2C), 64.3(2C), 67.3(2C),
CHCl ) to provide 5.8 mg (0.017 mmol, 79%) of (C)-3 as
3
7
1
1.6(3C), 76.5(2C), 93.8, 93.9, 124.3(2C), 143.5, 145.4,
64.9(2C), 171.8; HRMS (FAB, NaI matrix) m/z 559.2352
28
colorless solid: R 0.43 (10:1 CHCl /MeOH); [a] ZC21.5
f
3
D
(
1
c 0.31, MeOH); IR (KBr) 3433 (s), 1716 (s), 1665 (w),
K1 1
645 (w), 1280 (m), 1192 (m), 1053 (m) cm ; H NMR
C
[
(MCNa) ; calcd for C H O Na: 559.2367].
24 40 13
(
(
6
4
1
400 MHz, CDCl ) d 7.02 (dd, JZ16.0, 4.0 Hz, 1H), 6.80
dd, JZ16.0, 5.0 Hz, 1H), 6.13 (dd, JZ16.0, 1.8 Hz, 1H),
.06 (dd, JZ16.0, 1.8 Hz, 1H), 5.32 (m, 1H), 5.12 (m, 1H),
.97 (m, 1H), 4.37 (br s, 1H), 4.18 (br s, 1H), 2.73 (dd, JZ
6.0, 3.0 Hz, 1H), 2.60 (dd, JZ16.0, 7.3 Hz, 1H), 1.42 (d,
3
4
.1.35. (4S,5R,10S,11R,15S)-(2E,8E)-15-Hydroxy-4,10-
bis(2-methoxyethoxymethoxy)-5,11-dimethyl-6,12-di-
oxa-1,7,13-trioxo-2,8-hexadecadienoic acid (C)-34.
Following the procedure described above for the prepa-
ration of (K)-34, deprotection of 29.6 mg (0.04 mmol) of
JZ6.7 Hz, 3H), 1.39 (d, JZ6.7 Hz, 3H), 1.31 (d, JZ
2
5
1
6.7 Hz, 3H); C NMR (100 MHz, CDCl ) d 17.3, 17.8,
3
(
C)-33 afforded 9.2 mg of (C)-34 (41%): [a] ZC70.0 (c
D
3
0
.12, CHCl ); HRMS (FAB, NaI matrix) m/z 559.2363
3
19.6, 40.5, 66.6, 73.8, 75.2, 75.4, 76.0, 122.3, 123.0, 145.0,
145.3, 165.3, 166.7, 170.8; HRMS (FAB, NBA matrix) m/z
3
C
[
(MCNa) ; calcd for C H O Na: 559.2367].
24 40 13
C
43.1381 [(MCH) ; calcd for C H O : 343.1393].
16 23 8
4.1.36. (5R,6S,11R,12S,16R)-(3E,9E)-5,11-Bis(2-methoxy-
ethoxymethoxy)-6,12,16-trimethyl-1,7,13-trioxacyclo-
4.1.39. (K)-Macrosphelide E (K)-3. Following the
procedure described above for the preparation of (C)-3,
deprotection of 5.9 mg (0.01 mmol) of (C)-35 afforded
hexadeca-3,9-diene-2,8,14-trione (K)-35. To a solution of
3
2.0 mg (0.060 mmol) of (K)-34 was added 720 ml
0.36 mmol) of 0.5 M triethylamine in toluene and 600 ml
0.30 mmol) of 0.5 M 2,4,6-trichlorobenzoyl chloride in
(
(
28
2
.4 mg of (K)-3 (64%): [a] ZK25.0 (c 0.20, MeOH);
D
C
HRMS (FAB, NBA matrix) m/z 343.1394 [(MCH) ; calcd
toluene at room temperature, and stirred for 1 h. The
solution was then diluted with 15.0 mL of toluene and added
to a solution of 180 mg (1.48 mmol) of 4-dimethylamino-
pyridine in 5.9 mL of toluene at 80 8C over 2 h. The
anhydride flask was washed with 8.0 mL of toluene and the
washing added to the mixture over 30 mim. The reaction
was then heated at 80 8C for a total of 3.5 h. After cooling,
the white suspension was diluted with 20 mL of saturated
for C H O : 343.1393].
16 23 8
Acknowledgements
This work was supported by the Grant of the 21st Century
COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT), The Japan Science and
Technology Corporation (JST), a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports
and Culture, Japan and Japan Keirin Association. We also
thank BRUKER axa K.K. for the X-ray analyses.
NaHCO aqueous solution became clear. The two layers
3
were separated and aqueous layer was extracted with 3!
2
5 mL of EtOAc. The combined organic layers were dried
over Na SO , filtered, and concentrated. Chromatography
2
4
(
(
9% MeOH/CHCl ) provided 20.0 mg of (K)-35
3
0.039 mmol, 66%) as a colorless oil: R 0.61 (10:1
f
2
D
8
CHCl /MeOH); [a] ZK30.0 (c 0.52, CHCl ); IR (KBr)
1
3
3
K1 1
722 (s), 1191 (m), 1134 (m), 1111 (m), 1035 (m) cm ; H
NMR (270 MHz, CDCl ) d 6.81 (dd, JZ15.8, 5.9 Hz, 1H),
3
6
1
2
1
3
1
6
.78 (dd, JZ15.8, 6.9 Hz, 1H), 6.12 (dd, JZ15.8, 1.0 Hz,
H), 5.94 (dd, JZ15.8, 1.0 Hz, 1H), 5.22 (m, 1H), 5.10 (m,
H), 4.72 (dd, JZ15.5, 6.9 Hz, 2H), 4.72 (s, 2H), 4.31 (m,
H), 4.12 (m, 1H), 3.75 (m, 2H), 3.62 (m, 2H), 3.53 (m, 4H),
.37 (s, 6H), 2.75 (dd, JZ14.9, 3.0 Hz, 1H), 2.53 (dd, JZ
4.9, 6.6 Hz, 1H), 1.39 (d, JZ6.6 Hz, 3H), 1.35 (d, JZ
References and notes
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