Systematic strategy for the synthesis of cyanobacterin and its stereoisomers. 2. Asymmetric total synthesis of the 2- and 3-epimers of dechloro-cyanobacterin

Article abstract of DOI:10.1271/bbb.67.2215

Stereocontrolled total syntheses of the (2S,3R)- and (2R,3S)-isomers of the non-chlorinated analog of cyanobacterin, a potent photosynthesis inhibitor, were achieved. Since both the (2R,3R)- and (2S,3S)-isomers of this compound had been previously synthes

Full text of DOI:10.1271/bbb.67.2215

This article was downloaded by: [North Dakota State University]
On: 02 November 2014, At: 18:30
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Bioscience, Biotechnology, and Biochemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/tbbb20
Systematic Strategy for the Synthesis of
Cyanobacterin and Its Stereoisomers. 2. Asymmetric
Total Synthesis of the 2- and 3-Epimers of Dechloro-
cyanobacterin
Yasushi HAGAa, Momotoshi OKAZAKIa & Yoshihiro SHUTOa
a The United Graduate School of Agricultural Science, Ehime UniversityTarumi 3-5-7,
Matsuyama 790-8566, Japan
Published online: 22 May 2014.
To cite this article: Yasushi HAGA, Momotoshi OKAZAKI & Yoshihiro SHUTO (2003) Systematic Strategy for the Synthesis of
Cyanobacterin and Its Stereoisomers. 2. Asymmetric Total Synthesis of the 2- and 3-Epimers of Dechloro-cyanobacterin,
Bioscience, Biotechnology, and Biochemistry, 67:10, 2215-2223, DOI: 10.1271/bbb.67.2215
To link to this article: http://dx.doi.org/10.1271/bbb.67.2215
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Biosci. Biotechnol. Biochem., 67 (10), 2215–2223, 2003
Systematic Strategy for the Synthesis of Cyanobacterin and Its Stereoisomers. 2.
Asymmetric Total Synthesis of the 2- and 3-Epimers of Dechloro-cyanobacterin
Yasushi HAGA,† Momotoshi OKAZAKI, and Yoshihiro SHUTO
The United Graduate School of Agricultural Science, Ehime University, Tarumi 3-5-7,
Matsuyama 790-8566, Japan
Received May 22, 2003; Accepted June 27, 2003
Stereocontrolled total syntheses of the (2
,3 )-isomers of the non-chlorinated analog of
cyanobacterin, a potent photosynthesis inhibitor, were
achieved. Since both the (2 ,3 )- and (2 ,3 )-isomers
S,3R)- and
(2
R S
R
R
S S
of this compound had been previously synthesized from
the same starting material, a systematic strategy for the
synthesis of all stereoisomers could be established.
Key words: cyanobacterin; natural photosynthesis
inhibitor; synthesis of stereoisomers;
Evans and non-Evans aldol condensation;
diastereoselective alkynylation
Fig. 1. Structures of Cyanobacterin 1 and Its Dechlorinated
Analogs (2–5).
Cyanobacterin (1 in Fig. 1) has been isolated from
the cyanobacterium, Scytonema hofmanni, as a po-
tent photosynthesis inhibitor.1) Its eŠect against both
algae and angiosperms is known to act by inhibiting
photosynthetic electron transport in the oxygen-
evolving system of photosynthesis (photosystem
material and basic plan for the synthesis of 4 and 5
were required to be similar to those in the previous
report.7) The retrosynthetic analysis of 4 is shown in
Scheme 1. The stereochemistry at the C-3 position
2,3)
4)

).
Racemic 1 synthesized by Jong et al
.
and
of
4 was achieved by chelation-controlled di-
some less-active analogs have been assayed.5,6)
However, the investigation has not given satisfactory
knowledge to explain the structure-activity relation-
ship, especially concerning the stereochemistry at
both asymmetric carbons. These features of this
compound prompted us to develop a new and
e‹cient synthetic route to 1 and its all stereoisomers.
In the previous paper,7) we have described the
stereoselective total synthesis of dechloro derivative 2
as a model compound of 1 and its enantiomer 3. Both
compounds were prepared from the same starting
material 7 by using an asymmetric aldol reaction in
the presence or absence of TiCl4, respectively produc-
ing non-Evans-type and Evans-type products as the
key step. We thought that the synthetic procedure
utilized would be suitable for preparing the two
diastereomers of 2, enabling all four stereoisomers to
be able obtained and examined for their biological
activity.
astereoselective alkynylation of b-hydroxy ketone 6
before exposing to Ag＋-catalyzed exo-cyclization.
Intermediate 6 was obtained stereoselectively by the
Evans aldol reaction between 7 and 8. 3-Epimer 5
could be synthesized by applying the non-Evans aldol
reaction instead of the Evans type.
Results and Discussion
Acylated oxazolidinone 7 was subjected to the
Evans aldol reaction8,9) with commercially available
isobutyraldehyde 8 to provide a single isomer of
Evans syn aldol adduct 9 in an 81.4
2). On the other hand, in the presence of TiCl4 (
condensation between 7 and 8 gave a mixture of the
two non-Evans aldol adducts, anti-(10-a) and syn
(10-b), in an 88.2 yield. The reaction was di-
z
yield (Scheme

),10)
-
z
astereoselective, and 10-a was predominantly pro-
duced (80.2:19.8), contrary to the syn selective
reaction of 7 with 4-methoxyphenylpropynal de-
scribed in the previous paper.7) Although Walker and
Heathcock9) have discussed the selectivity from the
The most important aspect of our study is the de-
velopment of a systematic strategy for the synthesis
of 1 and all its stereoisomers. Therefore, the starting
†
To whom correspondence should be addressed. Fax:
81-89-943-5242; E-mail: haga agr.ehime-u.ac.jp
＋ ＠

2216
Y. HAGA et al
.
viewpoint of steric bulk and the addition rate of
Lewis acid, the stereochemistry at the C-3 position of
10 was not signiˆcant in this step of our strategy.
Resulting 9 and 10, which had an inverse conˆgu-
ration at the C-2 position, were readily reduced
with lithium tetrahydroborate in aqueous Et2O.
Regioselective protection of the primary hydroxyl
groups in 11 and 12 as the tert-butyldimethylsilyl
(TBS) ether and subsequent Swern oxidation of the
secondary hydroxyl groups of resulting 13 and 14
almost exclusively provided 15 and 16. The TBS
protecting groups in these compounds were removed
in an acidic medium to aŠord 6 and 17 in 64.9
68.1 yields, respectively, in 4 steps.
z and
z
In the next diastereoselective alkynylation step, the
stereochemistry at the C-3 position of 1,3-diol 18 was
constructed. The chelation-controlled neucleophilic
attack of metal acetylide to 6 led to 18 and its isomer
19. The former had the desired conˆguration and the
latter was thought to have been produced by applica-
tion of the Felkin-Anh model.11) These two reactions
were probably competitive and would favorably act
depending on the reagent and condition used.
Indeed, as shown in Table 1, when lithium was used
as a counter cation, the latter reaction predominantly
proceeded and selectively provided 19. As a second
trial, the use of cuprate instead of the lithium cation
resulted in an improved ratio of objective 18.
Furthermore, the addition of Lewis acid under this
condition led to a reverse in the selectivity. The
addition of TiCl4 (
68.0 yield with moderate selectivity (81.7:18.3, de-
termined by 1H-NMR). Similarly, (2
)-isomer 17
aŠorded 20 along with its isomer 21 in a yield of
58.5 with similar selectivity (78.9:21.1). According
to the HPLC analysis performed with a Chiralcel OF

) gave the desired compound in a
z
S
z
Scheme 1. Retrosynthetic Analysis of 4.
Scheme 2. Synthesis of 1,3-Diols 18 and 20.
Reagents and conditions: (a) isobutyraldehyde (8), nBu2BOTf, iPr2NEt, CH2Cl2,
78
9
z
C— 15
(11), 90.8 (12-b); (d)
(14-b); (e) DMSO, (COCl)2, Et3N, CH2Cl2, 789C, 90.8z (15), 90.9
9
C, 81.4
z
; (b) 8, nBu2BOTf,
－
－
i
－
＝
Pr2NEt, TiCl4, CH2Cl2, 78
9C—0
9
C, 88.2
z
(10-a:10-b 80.2:19.8); (c) LiBH4, Et2O, 91.2
z
(12-a), 89.0
－
z
TBS-Cl, Et3N, DMAP, DMF, 98.3
z
z
(13), 99.7
z
(6), 82.8
(14-a), 98.2
z
(16); (f) AcOH
789C—r.t., 58.5z (20:21 78.9:21.1).
W
THF
W
H2O (2:1:1), 79.7
z
z
(17); (g) see Table 1; (h) 4-methoxyphenylacetylene, nBuLi, CuI, TiCl4, Et2O,
－
＝

Total Synthesis of the 2- and 3-Epimers of Dechloro-cyanobacterin
2217
×
column (4.6 250 mm, Daicel Chemical Industries),
both these compounds was almost the same value
＋
－
it was found that the enantiomeric excess values for
18 and 20 were 98.1
with the opposite sign ( 46.1 and 46.7, respec-
tively), and their melting point (mp), and IR, 1H- and
13C-NMR spectral data were identical. Although
further eŠorts to improve the yield in last step and
the diastereoselectivity in the alkynylation reaction
would be necessary for this synthetic procedure, both
4 and 5 were obtained with high optical purity.
In conclusion, we accomplished the stereoselective
total synthesis of the 2- and 3-epimers (4 and 5) of
dechloro-cyanobacterin 2 in 12 steps with overall
z z
and 99.1 , respectively. Each
major product in this reaction (18 and 20) was identi-
cal with the minor isomer described in our previous
report.7) Similarly, each minor product, (19 and 21),
corresponded to the objective compound in the previ-
ous paper. The IR, H- and 13C-NMR spectral date
1
and speciˆc rotation of the corresponding com-
pounds were identical with each other. Accordingly,
it was conˆrmed that our synthetic strategy enabled
the preparation of all four stereoisomers of the 1,3-
diol (18–21) which were the important intermediates
of the desired product.
yields of 7.9
z and 7.0z, respectively. Since we have
previously reported the synthesis of 2 and 3, we could
establish a systematic strategy for the synthesis of all
four stereoisomers of this model compound from the
same starting material. This strategy will enable us to
synthesize natural occurring product 1 and all its
stereoisomers.
The next step was the oxidation of each primary
hydroxyl group in 18 and 20 to carboxylic acid and
exo-cyclization to construct a g-ylidene-g-butyrolac-
tone framework. As shown in Scheme 3, their oxida-
tion could be achieved with two kinds of oxidant.
The combination of tetrapropylammonium per-
Experimental
ruthenate (TPAP) and
N-methylmorpholine-N-oxide
(NMO) followed by sodium chlorite in the presence
All melting point (mp) data are uncorrected. IR
spectra were recorded by a Shimadzu FTIR-8100
spectrometer. 1H- and 13C-NMR spectra were
measured with a JEOL JNM-EX400 spectrometer at
400 MHz and 100 MHz, respectively. Chemical shifts
are reported relative to internal tetramethylsilane
of 2-methyl-2-butene gave desired carboxylic acids 22
and 23 in 68.4
z and 67.6z yields, respectively.
Finally, Ag＋-catalyzed annulation12) of 22 and 23
furnished exo-cyclic products 4 and 5 in 43.8 and
40.3 yields, respectively. The speciˆc rotation of
z
z
(TMS, 0.00 ppm) or chloroform-
d (CDCl3, 7.26
1
ppm) for H and relative to CDCl3 (77.00 ppm) or
acetone-d6 (30.30 ppm) for 13C. Optical rotation
values were determined with a Horiba SEPA-200
Table 1. Diastereoselective Alkynylation of 6
Reagents and conditionsa
Yield (
z)
Ratio (18:20)b
polarimeter. Silica gel 60 (100–210 mm) was obtained
from Kanto Chemical Co. TLC and preparative TLC
were respectively carried out by using Merck silica gel
60 F254 precoated plastic plates of 0.2 mm in thickness
and Merck silica gel 60 F254 precoated glass plates of
0.5 mm in thickness.
Ar Li, THF, 78


－
9
－
C
78
65.4
39.5
68.0
29.8:70.2
46.1:54.9
81.7:18.3
(Ar
(Ar

2


)
)
CuLi, Et2O,
9
C
2

CuLi, TiCl4, Et2O,
－
78 C–r.t.
9
a
b
Ar 4-methoxyphenyl,
Determined by 1H-NMR.
＝
Scheme 3. Synthesis of the 2-Epimer (4) and 3-Epimer (5).
Reagents and conditions: (a) (1) TPAP, NMO, MS-4A, CH2Cl2; (2) NaClO2, 2-methyl-2-butene, NaH2PO4, tBuOH
68.4 (22), 67.6 (23); (b) AgNO3, MeOH, 43.8 (4), 40.3 (5).
W
H2O (4:1), 09C,
z
z
z
z

2218
Y. HAGA et al.
(4S )-4-Benzyl-[(2S,3R)-3-hydroxy-4-methyl-2-
(3,4-methylenedioxybenzyl)valeryl]-2-oxazolidinone
). To a stirred solution of 7 (2.08 g, 5.89 mmol)
in CH2Cl2 (30 ml) was added dibutylboron tri‰ate
11.5 mmol) and then
(2.39 ml, 13.7 mmol) at
N, N-diisopropylethylamine
－
209C under an N2 at-
(
9
mosphere. The reaction mixture was allowed to
warm to 0 C and stirred for 2 h, before cooling to
9
78 C. In another ‰ask, to a solution of TiCl4 ( )

9
(5.7 ml of a 1.0
M
solution in CH2Cl2, 5.7 mmol) and
-diisopropylethylamine (1.28 ml, 7.35 mmol) at
C under an N2 atmosphere. The reaction mix-
C and stirred for 2 h,
C. A solution of 8 (0.58 ml,
－
N
,
N
(2.65 ml, 24.2 mmol) in CH2Cl2 (50 ml) was added
－
20
9
dropwise a solution of 8 (1.10 ml, 12.1 mmol) in
－
9
CH2Cl2 (2 ml) at 78 C under an N2 atmosphere,
ture was allowed to warm to 0
before cooling to 78
9
－
9
and the mixture stirred for 15 min. To the reaction
mixture was added the above-mentioned solution of
the boron enolate via a cannula under N2 pressure.
The resulting solution was stirred for 1 h at the same
6.39 mmol) in CH2Cl2 (1 ml) was added to this mix-
ture, and the resulting solution was stirred for 1 h at
the same temperature before being allowed to warm
－
to 15
9
C. After stirring for 3 h, the reaction mixture
9
temperature, before being allowed to warm to 0 C
was quenched by adding the mixed solvent of a phos-
phate buŠer solution (pH 6.86, 25 ml) and CH3OH
and stirred for another 4 h. The mixture was
quenched by adding of a mixed solvent of a phos-
phate buŠer solution (pH 6.86, 30 ml) and CH3OH
(25 ml) and then 30
z
H2O2 (25 ml) and CH3OH
C, the
(25 ml). After stirring vigorously for 1 h at 0
9
(30 ml), and then 30
ml). After stirring vigorously for 1 h at 0
ganic layer was separated, and the aqueous layer was
extracted with Et2O (2 20 ml). The combined or-
z
H2O2 (30 ml) and CH3OH (30
organic layer was separated, and the aqueous phase
9
C, the or-
×
was extracted with Et2O (2 20 ml). The combined
organic layer was successively washed with sat.
NaHCO3 and brine. After drying (Na2SO4) and
concentration, the residue was puriˆed by column
chromatography on silica gel (hexane-EtOAc, 3:1 to
3:2). After removing the solvent in vacuo, the result-
ing residue was recrystallized from hexane-2-
propanol (2:1) to give 9 as white crystals. The mother
liquor was evaporated, and the residue was puriˆed
by column chromatography on silica gel (hexane-
EtOAc, 2:1) to provide 9 as a second crop (total
×
ganic phase was successively washed with sat.
NaHCO3 and brine. After drying (Na2SO4) and con-
centrating, the residue was puriˆed by column chro-
matography on silica gel (toluene-EtOAc, 15:1) to
provide an anti-adduct (10-a) and syn-adduct (10-b)
separately. After removing the solvent, 10-a was
i
recrystallized from Pr2O. After concentrating the
mother liquor, the residue was puriˆed by column
chromatography on silica gel (hexane-EtOAc, 3:2)
to provide a second crop of 10-a (total yield 4.12 g,
2.04 g, 81.4
z
), Rf 0.31 (hexane-EtOAc, 3:2), mp
D
3.87, CHCl3); 1H-NMR
z
88.2 ).
25
＋
64–65
(CDCl3)
d, 6.8 Hz, C
2.32 (1H, dd,
br, –O ), 2.93 (1H, dd,
9
C, [
: 1.01 (3H, d,
3), 1.78–1.86
a
]
3.4
9
(
c
＝
d
J
6.8 Hz, C
1H, m, (CH3)2C
9.3, 13.7Hz, Ph–C 2), 2.54 (1H,
H
3), 1.05 (3H,
10-a: Rf 0.37 (toluene-EtOAc, 12:1), mp 85–86
9
C,
25
D
1
J
＝
H
s
H
t
,
[
a
]
＋
108 (c 2.40, CHCl3); H-NMR (CDCl3) d:
9
＝
＝
＝
6.8
J
H
0.94 (3H, d,
J
6.8 Hz, C
H
3), 1.02 (3H, d,
J
H
J
＝
2.9, 13.3 Hz,
Hz, C 3), 1.73–2.02
H
s
1H, m, (CH3)2C
H
t
, 2.72 (1H,
＝
＝
s
＝
＝
＝
＝
Ar1–C
Ar1–C
H
H
2CHC O), 2.96 (1H, dd,
J
4.9, 13.3Hz,
dd,
13.2 Hz, Ar1–C
13.2 Hz, Ar1–C
10.3 Hz, –O ), 3.27 (1H, dd,
Ph–C 2), 3.38 1H, ddd, 4.4, 6.3, 10.3 Hz,
(OH) 3.89 (1H, dd,
2O), 4.08 (1H, dd,
2O), 4.39 (1H, ddd,
J
9.8, 13.2 Hz, Ph–C
H
2), 2.92 (1H, dd,
J
J
7.3,
8.3,
＝
＝
H2CHC O), 2.97 (1H, dd,
2CHC O), 3.09 (1H, dd,
1H, dd,
J
11.2, 13.7 Hz,
Ph–C
H
2), 3.53
J
＝
3.4, 7.8 Hz, C
2.7, 9.0 Hz, NCHC
8.3, 9.0 Hz, NCHC 2O), 4.59–4.66 (2H, m,
O, and NC CH2O), 5.84 (1H, d,
H
t
(OH) ,
H
2CHC
＝
O), 3.09 (1H, d,
J
＝
＝
＝
3.4, 13.2 Hz,
4.02 (1H, dd,
J
H
2O), 4.10 (1H,
H
J
dd,
J
＝
＝
H
H
H
s
J
＝
＝
＝
8.3, 9.0 Hz,
C
H
C
H
J
1.5 Hz,
1.5 Hz, O–C 2–O),
), 6.98 (2H, d, 7.8 Hz,
), 7.16–7.29 (3H, m, Ph–
); 13C-NMR
(CDCl3) : 19.71, 19.75, 32.02, 32.46, 38.05, 47.45,
C
H
t
,
J
J
＝
＝
O–C
2–O), 5.90 (1H, d,
J
H
NCHC
NCHC
H
H
2.2, 9.0 Hz,
4.4, 7.3, 8.3 Hz,
CH2O), 5.90
2–O), 6.70–6.75 (3H, m, Ar1– ), 7.21
), 7.27–7.34 (3H, m,
: 17.87, 19.53, 32.44,
6.70–6.78 (3H, m, Ar1–
Ph–
H
J
＝
J
＝
＝
H
H
C
H
C
O), 4.49–4.52 (1H, m, NC
H
d
(2H, s, O–C
H
H
＝
6.8 Hz, Ph–H
55.69, 66.32, 77.83, 101.52, 108.85, 110.68, 123.10,
128.01, 129.61, 129.98, 132.23, 135.77, 146.81,
148.26, 153.52, 176.64; IR nmax (CHCl3) cm－1: 1786,
1683, 1508, 1491, 1457, 1393, 1358, 1247, 1217, 1196,
1115, 1046, 940, 816, 777, 760, 739, 709. Anal.
(2H, d,
J
Ph–
H
); 13C-NMR (CDCl3)
d
36.26, 37.95, 46.70, 55.47, 66.01, 77.74, 100.89,
108.15, 109.60, 122.19, 127.42, 128.99, 129.45,
131.94, 135.15, 146.20, 147.57, 153.12, 176.65; IR
nmax (CHCl3) cm－1: 1790, 1679, 1611, 1512, 1495,
1452, 1388, 1358, 1256, 1217, 1200, 1115, 1051, 940,
816, 777, 764, 739, 709. Anal. Found: C, 67.68; H,
Found: C, 67.58; H, 6.40; N, 3.12
z
. Calcd. for
C24H27NO6: C, 67.75; H, 6.40; N, 3.29
z.
(4S)-4-Benzyl-[(2R,3R S)-3-hydroxy-4-methyl-2-
6.77; N, 3.08
z. Calcd. for C24 H27NO6: C, 67.75; H,
W
(3,4-methylenedioxybenzyl)valeryl]-2-oxazolidinone
6.40; N, 3.29
z.
(
10-a) and (10-b). To a stirred solution of 7 (3.88 g,
10-b: Rf 0.29 (toluene-EtOAc, 12:1), colorless oil,
25
D
1
＋
11.0 mmol) in CH2Cl2 (40 ml) was added dibutyl-
boron tri‰ate (11.5 ml of a 1.0 solution in CH2Cl2,
[a
]
113
9
(c
0.87, CHCl3); H-NMR (CDCl3)
d
:
M
1.03 (3H, d, J 6.8 Hz, CH3), 1.07 (3H, d, J 6.8
＝ ＝

Total Synthesis of the 2- and 3-Epimers of Dechloro-cyanobacterin
2219
Hz, C
H
3), 1.76–1.86
s
1H, m, (CH3)2C
H
t
, 2.53 (1H,
＝
9.3, 12.7 Hz,
80.95, 100.78, 108.19, 109.48, 121.91, 134.55,
145.92, 147.74; IR nmax (CHCl3) cm－1: 1722, 1658,
1564, 1546, 1512, 1495, 1448, 1252, 1222, 1196, 1046,
940, 820, 781, 764, 756, 743. Anal. Found: C, 66.37;
＝
d,
Ph–C
O), 3.20 (1H, dd,
3.9, 4.1, 7.3 Hz, C
J
4.1 Hz, –O
H ), 2.70 (1H, dd, J
＝
＝
H
2), 2.97 (2H, d,
J
7.9 Hz, Ar1–C
H
2CHC
＝
J
3.4, 12.7 Hz, Ph–C
H
2), 3.65
1H, ddd,
J
＝
H
(OH) , 3.77 (1H,
t
H, 8.04 . Calcd. for C H O : C, 66.65; H, 7.99
z
z
.
s
14
20
4
＝
＝
dd,
2.4, 9.0 Hz, NCHC
NC
J
8.2, 9.0 Hz, NCHC
H
2O), 4.01 (1H, dd,
J
(2S,3R)-4-Methyl-2-(3,4-methylenedioxyphe-
H
2O), 4.38–4.44 (1H, m,
nyl)methyl-1,3-pentanediol (12-a
)
: 90.8
z yield from
H
CH2O), 4.50 (1H, ddd,
J
3.9, 7.8, 8.1 Hz,
10-a, colorless oil, [
a
]
13.7 (c
9
2.49, CHCl3); 1H-
25
＝
＋
D
＝
＝
6.8 Hz, C
C
H
C
O), 5.88 (2H, s, O–C
m, Ar1– ), 7.18 (2H, d,
7.26–7.34 (3H, m, Ph–
); 13C-NMR (CDCl3)
H
2–O), 6.62–6.70 (3H,
6.8 Hz, Ph– ),
NMR (CDCl3)
d
: 0.88 (3H, d,
6.8 Hz, 3), 1.84–1.95
and (CH3)2C , 2.37 (1H, dd,
2), 2.69–2.73
), D2O exchange; 2.73 (1H, dd,
13.9 Hz, Ar1–CH2 , 3.28–3.36 (1H, m, C
D2O exchange; 3.32 (1H, dd, 5.4, 7.1 Hz,
＝
J
H
3), 1.00
H
J
＝
H
d
(3H, d,
J
＝
C
H
s
2H, m,
＝
9.5,
H
:
Ar1–CH2C
H
H
t
J
18.58, 19.14, 31.36, 32.54, 38.06, 46.87, 55.30,
66.00, 76.67, 100.83, 108.09, 109.56, 121.93, 127.37,
128.92, 129.38, 132.55, 135.13, 146.21, 147.55,
153.07, 175.88; IR nmax (CHCl3) cm－1: 1790, 1679,
1512, 1495, 1452, 1393, 1358, 1252, 1217, 1200, 1115,
1046, 940, 816, 781, 764, 743, 709. Anal. Found: C,
13.9 Hz, Ar1–C
H
s(2H, m, Ar1–CH2
＝
and O
H
J
5.6,
)
t
s
H
OH),
J
＝
C
H
OD
t
, 3.67 (1H, dd,
J
6.8, 10.8 Hz, C
2OH and O , D2O exchange;
4.4, 10.8 Hz, C 2OD) , 5.93 (2H,
); 13C-NMR
H2OH),
3.87–3.92
s
2H, m, C
H
H
＝
67.48; H, 6.56; N, 3.18
67.75; H, 6.40; N, 3.29
z
. Calcd. for C24H27NO6: C,
3.89 (1H, dd,
s, O–C
(CDCl3)
J
H
t
z.
H
2–O), 6.63–6.74 (3H, m, Ar1–
H
d
: 16.11, 19.46, 30.54, 34.85, 43.27, 64.63,
Procedure for reductive cleavage of the chiral aux-
iliary. Lithium tetrahydroborate (1.5 eq) was added
to the solution of 9 (7.90 mmol) or 10 (7.17 mmol) in
80.35, 100.93, 108.27, 109.12, 121.80, 132.50,
146.13, 147.87; IR nmax (CHCl3) cm－1: 1722, 1658,
1564, 1516, 1495, 1448, 1252, 1222, 1192, 1042, 944,
820, 777, 764, 756, 743. Anal. Found: C, 66.46; H,
Et O (7 ml mmol) at 0
9
C. The reaction mixture was
allowed to warm to room temperature and stirred for
6 h, before slowly adding 2 -HCl at 0 C. After
W
2
7.98
z z
. Calcd. for C14H20O4: C, 66.65; H, 7.99 .
M
9
(2S,3S)-4-Methyl-2-(3,4-methylenedioxyphenyl)-
decomposing the excess reducing agent, the ethereal
layer was separated. The aqueous phase was extract-
methyl-1,3-pentanediol (12-b
)
: 89.0
z yield from
25
10-b, mp 108–110
1H-NMR (acetone-d6
3), 0.98 (3H, d,
m, (CH3)2C and Ar1–CH2C
10.8, 13.7 Hz, Ar1–C
Hz, Ar1–C
m, C 2OH and C
dd, 3.9, 7.3 Hz, C
10.5 Hz, C 2OD) , 3.51–3.58
D2O exchange; 3.53 (1H, dd,
OD) , 3.70 (1H, ddd,
5.92 (2H, s, O–C 2–O), 6.68–6.75 (3H, m, Ar1–
13C-NMR (CDCl3)
9
C, [
a
]
－
34.8
9
(
c
2.01, CHCl3);
D
×
＝
ed with EtOAc (2 10 ml), and the combined organic
)
d
: 0.91 (3H, d,
J
6.8 Hz,
layer was successively washed with sat. NaHCO3 and
brine. After drying (Na2SO4) and concentrating, the
residue was puriˆed by column chromatography on
silica gel (hexane-EtOAc, 2:1) to provide the
products.
C
H
J
＝
6.3 Hz, C
H
3), 1.78–1.88
＝
, 2.58 (1H, dd, J
s
2H,
H
H
t
＝
H
2), 2.76 (1H, dd,
J
3.9, 13.7
(2H,
H
2), 2.78 (1H, s, –O
H
), 3.45–3.50
s
H
H
OH), D2O exchange; 3.49 (1H,
(2R,3R)-4-Methyl-2-(3,4-methylenedioxyphenyl)-
J
＝
H
OD), 3.50 (1H, dd,
(1H, m, C
J
＝
3.9,
methyl-1,3-pentanediol (11
)
: 91.2
z
yield, mp 113
9
C,
H
t
s
H
2OH),
25
1
－
＝
[
a
]
31.0
: 0.91 (3H, d,
3), 1.79–1.89
, 2.59 (1H, dd,
9(c
1.42, CHCl3); H-NMR (acetone-d6
)
J
5.9, 10.5 Hz,
D
d
J
＝
6.8 Hz, C
H
3), 0.99 (3H, d,
J
＝
6.4
C
H
t
J
＝
4.9, 9.0, 9.5 Hz, –O
H
H
),
);
Hz, C
H
s
2H, m, (CH3)2C
H
and
H
Ar–CH2C
Ar1–C 2), 2.78 (1H, dd,
2.79 (1H, br, –O ), 3.46–3.51
and C
7.9 Hz, C
2OD) , 3.52–3.59
change; 3.56 (1H, dd,
H
t
J
＝
10.5, 13.9 Hz,
d
:19.17, 19.25, 29.27, 31.07,
＝
H
J
3.7, 13.9 Hz, Ar1–C
(2H, m, C 2OH
3.9,
3.9, 10.7 Hz,
2OH), D2O ex-
H
2),
43.46, 64.56, 80.93, 100.78, 108.19, 109.48, 121.98,
134.55, 145.72, 147.63; IR nmax (CHCl3) cm－1: 1722,
1658, 1564, 1512, 1495, 1448, 1256, 1222, 1196, 1046,
940, 820, 781, 764, 756, 743. Anal. Found: C, 66.23;
H
s
H
H
OH), D2O exchange; 3.50 (1H, dd,
J
＝
＝
H
H
OD), 3.51 (1H, dd,
(1H, m, C
J
C
H
t
s
z z
H, 8.13 . Calcd. for C14H20O4: C, 66.65; H, 7.99 .
＝
J
5.9, 10.7 Hz, C
H
2OD)
t,
＝
3.70 (1H, ddd,
J
4.4, 8.5, 9.3 Hz, –O
H
), 5.93 (2H,
Procedure for regioselective silylation. To a stirred
solution of 11 (6.54 mmol) or 12 (6.35 mmol) in
1
s, O–C
H
2–O), 6.69–6.76 (3H, m, Ar1–
: 0.94 (3H, d,
H
); H-NMR
3), 1.05 (3H,
＝
(CDCl3)
d
J
6.3 Hz, C
H
DMF (2 ml mmol) was added imidazole (2.50 eq), a
W
＝
d,
J
6.3 Hz, C
H
3), 1.82–1.90
s
2H, m, (CH3)2C
H
catalytic amount of DMAP, and TBS-Cl (1.05 eq) at
and Ar–CH2C
H
t
, 2.14 (1H, br, –O
H
), 2.52 (1H, br,
2), 3.55 (1H,
2OH
2–O), 6.67–6.74 (3H,
); 13C-NMR (acetone-d6
: 19.57, 20.44,
9
0 C. The reaction mixture was allowed to warm to
＝
H
–O
dd,
and C
m, Ar1–
H
), 2.72 (1H, d,
J
7.8 Hz, Ar1–C
2OH), 3.65 (2H, m, C
H
room temperature and stirred for 18 h before
quenching with sat. NH4Cl (20 ml). After stirring for
5 min, the organic layer was separated, and the aque-
J
＝
H
2.7, 8.8 Hz, C
H
OH), 5.92 (2H, s, O–CH
×
H
)
d
ous phase was extracted with Et2O (2 5 ml). The
31.69, 31.99, 46.12, 63.58, 79.17, 102.10, 109.14,
combined organic layer was successively washed with
sat. NaHCO3 and brine. After drying and concentrat-
ing, the residue was puriˆed by column chro-
110.81, 123.32, 136.96, 146.95, 148.93; 13C-NMR
(CDCl3) d: 19.17, 19.23, 29.67, 31.08, 43.47, 64.58,

2220
Y. HAGA et al
.
matography on silica gel (hexane-EtOAc, 9:1) to
provide a silyloxy alcohol.
1149, 1081, 1051, 995, 944, 845, 790, 777, 764, 739,
692. Anal. Found: C, 65.40; H, 9.42
z. Calcd. for
(2R,3R)-1-tert-Butyldimethylsilyloxy-4-methyl-2-
z
C20H34O4Si: C, 65.53; H, 9.35 .
(3,4-methylenedioxyphenyl)methyl-3-pentanol
(
13
)
:
25
98.3
z
yield, colorless oil, [
a
]
－
21.5
9
(
c
4.23,
Procedure for Swern oxidation. Four equivalents
D
1
CHCl3); H-NMR (CDCl3)
d
: 0.02 (3H, s, Si–C
H
H
J
3),
of dimethyl sulfoxide (DMSO) was added to a stirred
＝
0.04 (3H, s, Si–C
0.92 9H, s, (CH3
6.8 Hz, C 3), 1.79–1.90
Ar1–CH2C , 2.72 (2H, d,
3.50 (1H, s, ), 3.52
(OH) , 3.63 (2H, d,
(2H, s, O–C 2–O), 6.61–6.73 (3H, m, Ar1–
NMR (CDCl3)
H
3), 0.91 (3H, d,
J
6.3 Hz, C
3),
solution of oxalyl chloride (2.0 eq) in CH Cl (10 ml
W
2
2
×
＝
－
mmol) at 78
s
)
3
t,
1.06 (3H, d,
2H, m, (CH3)2C
7.8 Hz, Ar1–C
9
C under an N2 atmosphere. The
H
s
H
and
2),
resulting solution was stirred for 15 min before add-
ing a solution of 13 (3.60 mmol) or 14 (3.49 mmol) in
CH2Cl2 (10 ml). After stirring for 2 h, triethylamine
(6.0 eq) was added to the solvent, and the resulting
H
t
J
＝
s1H, d,
H
＝
O
H
J
8.8 Hz,
＝
C
H
t
J
2.9 Hz, C
H
2OSi), 5.92
H
H
); 13C-
5.75, 5.70, 18.05, 19.20, 19.45,
9
mixture was allowed to warm to 0 C over 30 min. To
－
－
d
:
the mixture was then added sat. NH4Cl (50 ml), and
this was allowed to warm to room temperature. The
organic layer was separated and the aqueous phase
25.86, 29.18, 30.82, 43.26, 65.37, 81.20, 100.76,
108.04, 109.45, 122.00, 134.86, 145.62, 147.56; IR
nmax (CHCl3) cm－1: 3495, 2983, 2876, 1512, 1495,
1478, 1393, 1367, 1252, 1196, 1149, 1081, 1046, 995,
940, 841, 781, 769, 750, 739, 692. Anal. Found: C,
×
was extracted with Et2O (2 10 ml). The combined
organic layer was successively washed with sat.
NaHCO3 and brine. After drying and concentrating,
the residue was puriˆed by column chromatography
on silica gel (hexane-EtOAc, 7:1) to provide a
silyloxy ketone.
65.26; H, 9.53
H, 9.35
z
. Calcd. for C20H34O4Si: C, 65.53;
z
.
(2S,3R)-1-tert-Butyldimethylsilyloxy-4-methyl-2-
(3,4-methylenedioxyphenyl)methyl-3-pentanol
(2R)-1-tert-Butyldimethylsilyloxy-4-methyl-2-(3,4-
25
(
14-a
)
: 99.7
z
yield from 12-a; colorless oil, [
a
]
methylenedioxyphenyl)methyl-3-pentanone
(
15
)
:
D
1
25
＋
9.0
(
c
3.65, CHCl3); H-NMR (CDCl3)
3), 0.05 (3H, s, Si–C 3), 0.85 (3H, d,
6.3 Hz, CH3), 0.90 9H, s, (CH3
6.8 Hz, C 3), 1.75–1.85
, 2.69 (1H, dd,
2), 2.78 (1H, dd,
d
: 0.04
90.8
yield, colorless oil, [
a
]
＋
11.2
0.86,
9
z
9
(c
D
1
(3H, s, Si–C
＝
H
H
J
CHCl3); H-NMR (CDCl3)
d
: 0.01 (3H, s, Si–C
H
H
6.8 Hz,
3),
3),
×
＝
6.8 Hz, C
s
)
3
t
, 1.02 (3H,
0.02 (3H, s, Si–C
0.87 9H, s, (CH3
3), 2.37–2.48 1H, m, (CH3)2C
6.4, 13.7 Hz, Ar–C 2), 2.70 (1H, dd,
13.7 Hz, Ar1–C 2), 3.13–3.20 (1H, m, Ar1–CH2
, 3.61 (1H, dd,
(1H, dd, 8.3, 9.5 Hz, C
O–C 2–O), 6.55–6.70 (3H, m, Ar1–
(CDCl3) 5.64, 5.57, 17.12, 17.20, 18.18,
H
3), 0.81 (3H, d,
, 0.99 (3H, d,
, 2.59 (1H, dd,
8.8,
J
d,
J
＝
H
t
s
2H, m, (CH3)2C
H
s
)
×
3
t
J
＝
＝
and Ar1CH2C
H
J
8.8, 13.7 Hz,
C
H
s
H t
Ar–C
H
J
＝
6.8, 13.7 Hz, Ar1–C
H
2),
J
＝
H
J
＝
＝
3.18
s
1H, ddd,
J
4.3, 7.3, 8.0 Hz, C
7.3 Hz, –O ), 3.58 (1H, dd,
2OSi), 3.87 (1H, dd, 3.2, 10.0 Hz,
2OSi), 5.91 (2H, s, O–C 2–O), 6.31–6.73 (3H, m,
Ar1– 5.76, 5.69, 18.02,
); 13C-NMR (CDCl3)
H
(OH)
t
J
, 3.29
H
＝
H
＝
＝
J
(1H, d,
J
H
3.7,
C
H
t
5.0 , 9.5 Hz, C
2OSi), 5.92 (2H, s,
); 13C-NMR
H2OSi), 3.74
10.2 Hz, C
J
＝
J
＝
H
C
H
H
d
H
H
H
:
－
－
d
:
－
－
18.59, 19.44, 25.79, 25.83, 32.00, 35.26, 42.96,
63.20, 79.56, 100.71, 108.01, 109.41, 121.99, 134.43,
145.65, 147.53; IR nmax (CHCl3) cm－1: 2983, 2876,
1512, 1495, 1478, 1448, 1393, 1367, 1256, 1200, 1149,
1085, 1046, 999, 940, 841, 781, 773, 751, 739, 692.
25.80, 34.71, 42.09, 55.01, 64.72, 100.79, 108.15,
109.32, 121.87, 133.25, 145.93, 147.56, 216.57; IR
nmax (CHCl3) cm－1: 2940, 2876, 1713, 1512, 1495,
1474, 1448, 1367, 1256, 1222, 1196, 1098, 1046, 1012,
944, 841, 820, 790, 756, 739. Anal. Found: C, 65.45;
Anal. Found: C, 65.27; H, 9.36
z
. Calcd. for
H, 9.15
8.85
(2S)-1-tert-Butyldimethylsilyloxy-4-methyl-2-(3,4-
z
. Calcd. for C20H32O4Si: C, 65.89; H,
C20H34O4Si: C, 65.53; H, 9.35
z
.
z.
(2S,3S)-1-tert-Butyldimethylsilyloxy-4-methyl-2-
(3,4-methylenedioxyphenyl)methyl-3-pentanol
methylenedioxyphenyl)methyl-3-pentanone
(
16
)
:
25
25
(
14-b
)
: 98.2
17.3
(3H, s, Si–C
z
yield from 12-b, colorless oil, [
a
]
90.9
z
yiel,; colorless oil, [
a
]
－
16.6
9
(c
1.67,
D
D
1
1
＋
9
(
c
1.91, CHCl3); H-NMR (CDCl3)
H
d
: 0.02
CHCl3); H-NMR (CDCl3)
d
: 0.00 (3H, s, Si–C
H
H
6.8 Hz,
3),
3),
＝
6.8 Hz, C
3), 0.03 (3H, s, Si–C
H
3), 0.91 (3H, d,
J
0.01 (3H, s, Si–C
H
3), 079 3H, d,
J
＝
6.3Hz, CH3), 0.92 9H, s, (CH3
＝
)
×
3 , 1.06 (3H, d,
0.86 9H, s, (CH3
)
×
t
3 , 0.98 (3H, d,
J
＝
s
t
s
J
6.3 Hz, C
Ar1–CH2C
3.48–3.53 (2H, m, C
H
t
3), 1.79–1.90
s
2H, m, (CH3)2C
H
and
2),
C
H
3), 2.36–2.47
s
1H, m, (CH3)2C
H
t, 2.58 (1H, dd,
＝
＝
＝
J 8.8,
H
, 2.72 (2H, d,
J
7.3 Hz, Ar1–C
H
J
5.9, 13.4 Hz, Ar1–C
13.4 Hz, Ar1–C
, 3.60 (1H, dd,
(1H, dd, 8.3, 9.5 Hz, C
O–C 2–O), 6.56 (1H, d,
(1H, s, Ar1– ), 6.68 (1H, d,
NMR (CDCl3)
H
2), 2.69 (1H, dd,
H
(OH) and –O
H
), 3.63 (2H, d,
H2), 3.12–3.19 (1H, m, Ar–CH2
＝
＝
J
3.4 Hz,
6.62–6.66 (2H, m, Ar1–
Ar1–
); 13C-NMR (CDCl3)
C
H
2OSi), 5.92 (2H, s, O–C
H
2–O),
7.8 Hz,
5.75, 5.70, 18.05,
C
H
t
J
5.1, 9.5 Hz, C
H2OSi), 3.74
H
), 6.72 (1H, d,
J
＝
J
＝
H
2OSi), 5.90 (2H, s,
－
－
＝
J 7.8 Hz, Ar–
H
d
:
H
H
), 6.61
); 13C-
5.64, 5.58, 17.12, 17.18, 18.17,
＝
7.8 Hz, Ar–H
19.20, 19.46, 25.87, 29.16, 30.82, 43.24, 65.37,
81.22, 100.76, 108.05, 109.45, 122.01, 134.85,
145.62, 147.56; IR nmax (CHCl3) cm－1: 3495, 2983,
2876, 1508, 1495, 1478, 1448, 1393, 1367, 1256, 1200,
H
J
－
:
－
d
25.80, 34.70, 42.07, 55.00, 64.71, 100.78, 108.16,
109.31, 121.86, 133.24, 145.92, 147.56, 216.54; IR

Total Synthesis of the 2- and 3-Epimers of Dechloro-cyanobacterin
2221
nmax (CHCl3) cm－1: 2940, 2876, 1713, 1512, 1495,
1478, 1452, 1367, 1256, 1217, 1196, 1098, 1046, 1012,
948, 841, 820, 786, 751, 739. Anal. Found: C, 65.82;
eq) in Et2O (20 ml) was added dropwise
n
-BuLi (a
－
solution in hexane, 5.00 eq) at 789C under
1.58
M
an N2 atmosphere. After stirring for 30 min, the
resulting solution was added to a suspension of CuI
(95 purity, 2.30 eq) in Et2O (30 ml) at the same
z
H, 9.06
8.85
z. Calcd. for C20H32O4Si: C, 65.89; H,
z
.
temperature, and the reaction mixture was stirred for
30 min. In another ‰ask, to a stirred Et2O solution
Procedure for cleavage of the silyl ether. Acetic
acid (12 ml) was added to solution of 15

a
(40 ml) was added TiCl4 ( ) (2.20 eq) followed by a
(3.54 mmol) or 16 (3.12 mmol) in THF (6 ml) and
H2O (6 ml) at room temperature. The reaction
mixture was stirred for 16 h and diluted with EtOAc
(10 ml) and H2O (10 ml). The organic layer was
separated, and the aqueous phase was extracted with
EtOAc (5 ml). The combined organic layer was
successively washed with sat. NaHCO3 and brine.
After drying and concentrating, the residue was puri-
ˆed by column chromatography on silica gel (hexane-
EtOAc, 2:1) to provide a hydroxy ketone.
solution of 6 (3.05 mmol) or 17 (3.20 mmol) in Et2O
(10 ml) at
－
78 C under an N2 atmosphere. The
9
mixture was aged for 15 min before adding of the
above-mentioned cuprate solution via a cannula
under N2 pressure. The resulting solution was al-
lowed to warm to room temperature and stirred for
12 h before quenching with sat. NH4Cl (100 ml).
After removing the resulting precipitate by suction
×
ˆltration, the ˆltrate was extracted with Et2O (2
15ml). The combined organic layer was successively
washed with sat. NaHCO3 and brine. After drying
and concentrating the residue was puriˆed by column
chromatography on silica gel (toluene-EtOAc, 7:1) to
provide crude 18 or 20, together with minor isomer
19 or 21, respectively. The resulting crystals of 18 or
20 were recrystallized from hexane-EtOAc (5:1) to
give white crystals. The mother liquor was evaporat-
ed, and the residue was puriˆed by column chro-
matography on silica gel (hexane-EtOAc, 3:1) to
provide a second crop of crystals.
(2R)-1-Hydroxy-4-methyl-2-(3,4-methylenediox-
yphenyl)methyl-3-pentanone (
6
)
: 79.7
z
yield, yellow
25
1
＋
oil, [
a
]
72.3
9
(
c
3.63, CHCl3); H-NMR (CDCl3)
D
＝
＝
J
d
: 0.92 (3H, d,
J
6.8 Hz, CH3), 1.05 (3H, d,
3), 2.21 (1H, br, O ), 2.47–2.57 1H, m,
2.69 (1H, dd, 7.5, 13.6 Hz,
2), 2.81 (1H, dd, 7.8, 13.6 Hz, Ar1–C
4.1, 7.8, 13.9 Hz, Ar–CH2C
6.8 Hz, C
H
H
s
＝
J
(CH3)2C
Ar1–C
3.09 (1H, ddd,
3.67 (1H, dd,
dd,
O–C
(CDCl3)
H
t,
H
J
＝
H
H
2),
＝
J
t
,
＝
J
4.1, 11.1 Hz, C
6.4, 11.1 Hz, 2OH), 5.92 (2H, s,
2–O), 6.59–6.73 (3H, m, Ar1–
); 13C-NMR
: 17.13, 17.89, 34.51, 41.37, 53.77, 62.81,
H2OH), 3.74 (1H,
J
＝
CH
H
H
(2R,3R)-5-(4-Methoxyphenyl)-2-(3,4-methylene-
dioxybenzyl)-3-(1-methylethyl)-4-pentyne-1,3-diol
d
100.87, 108.26, 109.22, 121.86, 132.57, 146.12,
147.69, 218.10; IR nmax (CHCl3) cm－1: 3474, 2983,
2897, 1709, 1512, 1495, 1470, 1452, 1393, 1367, 1252,
1217, 1196, 1157, 1119, 1085, 1046, 940, 867, 820,
781, 756, 743, 696. Anal. Found: C, 67.04; H,
(
18
)
: 68.0
z
yield, mp 103–104
9
C, Rf 0.50 (hexane-
25
1
－
EtOAc, 3:2), [
a
]
8.7
9(c
1.72, CHCl3); H-NMR
6.4 Hz, C 3), 1.19
3), 1.97–2.01 (1H, m,
1H, m, (CH3)2C , 2.19
2), 3.66
2OH), 3.81 (4H, s, OCH3
11.2 Hz, C 2OH), 5.93
), 6.83
8.8 Hz,
: 17.22, 18.00, 29.43,
D
(CDCl3)
(1H, d,
Ar–CH2C
(1H, br, –O
(1H, d,
and –O
(2H, s, O–C
(2H, d, 8.8 Hz, Ar2–
Ar2–
); 13C-NMR (CDCl3)
d
: 1.09 (1H, d,
J
＝
H
＝
J
H
6.4 Hz, CH
), 2.20–2.30
s
H
t
7.23
z
. Calcd. for C14H18O4: C, 67.18; H, 7.25
z
.
H
), 2.85–2.90 (2H, m, Ar–CH
＝
(2S )-1-Hydroxy-4-methyl-2-(3,4-methylenediox-
J
H
11.2 Hz, C
), 4.38 (1H, d,
H
yphenyl)methyl-3-pentanone (17
low oil, [
(CDCl3)
)
: 82.8
z
yield, yel-
J
＝
H
a
]
77.3
9
(
c
4.09, CHCl3); 1H-NMR
H
2–O), 6.70–6.76 (3H, m, Ar1–
H
＝
25
－
D
d
: 0.93 (3H, d,
6.8 Hz, C
J
＝
6.8 Hz, C
H
3), 1.06 (3H,
J
＝
H
), 7.36 (2H, d, J
＝
d,
J
H
H
3), 2.10 (1H, br, –O
H
＝
), 2.47–2.57
H
d
s
1H, m, (CH3)2C
Ar1–C 2), 2.81 (1H, dd,
3.10 (1H, ddd,
t
, 2.69 (1H, dd,
J
7.3, 13.7 Hz,
34.53, 46.80, 55.29, 62.73, 79.08, 86.30, 88.51,
100.82, 108.25, 109.55, 113.91, 114.82, 122.02,
133.09, 134.19, 145.83, 147.66, 159.62; IR nmax
(CHCl3) cm－1: 3473, 2983, 1615, 1517, 1495, 1452,
1299, 1256, 1222, 1179, 1110, 1046, 940, 841, 794,
H
J
＝
7.6, 13.7 Hz, Ar1–C
4.1, 7.6, 14.2 Hz, Ar–CH2C
4.1, 10.9 Hz, C
6.8, 10.9 Hz, 2OH), 5.92 (2H, s,
2–O), 6.56 (1H, d,
), 6.68 (1H, d,
: 17.15, 17.96, 34.53, 41.36,
H
H
2),
＝
J
t,
3.68 (1H, dd,
J
＝
H2OH), 3.74 (1H,
＝
dd,
J
CH
＝
O–C
H
J
7.8 Hz, Ar1–
H
), 6.61
);
764, 739, 713. Anal. Found: C, 72.24; H, 6.99
Calcd. for C23H26O5: C, 72.23; H, 6.85
(2R,3S)-isomer 19: 15.2 yield, yellow oil, Rf 0.45
z.
(1H, s, Ar1–
H
J
＝
7.8 Hz, Ar1–
H
z
.
13C-NMR (CDCl3)
d
z
25
＋
53.73, 62.81, 100.90, 108.30, 109.25, 121.90, 132.57,
146.16, 147.73, 218.14; IR nmax (CHCl3) cm－1: 3474,
2983, 2897, 1705, 1508, 1491, 1470, 1448, 1388, 1367,
1252, 1217, 1199, 1157, 1115, 1085, 1042, 935, 867,
816, 781, 756, 743, 696. Anal. Found: C, 66.86; H,
(hexane-EtOAc, 3:2); [
a
]
32.8
9
(
c
0.37, CHCl3);
D
1H-NMR (CDCl3)
d
:
1.13 (3H, d,
J
6.4 Hz,
＝
－
＝
－
CH
s
C
H
3), 1.16 (3H, d,
(1H, m, Ar1CH2C
, 2.65 (1H, dd,
2.82 (1H, s, –O ), 3.05 (1H, dd,
Ar1C 2), 3.21 (1H, br, –O ), 3.82 (5H, br, –OCH3
and C 2OH), 5.92 (2H, s, O–C 2–O), 6.68–6.75
(3H, m, Ar1– ), 6.86 (2H, d, 8.8 Hz, Ar2– ),
J
6.8 Hz,
3), 2.10–2.17
1H, m, (CH3)2
11.5, 13.9 Hz, Ar1C 2),
3.2, 13.9 Hz,
H
), 2.18–2.24
＝
C
H
t
J
H
＝
J
7.40
z. Calcd. for C14H18O4: C, 67.18; H, 7.25
z.
H
H
H
Procedure for diastereoselective alkynylation. To a
stirred solution of 4-methoxyphenylacetylene (4.75
H
H
H
J
＝
H

2222
Y. HAGA et al.
＝
7.40 (2H, d,
J
8.8 Hz, Ar2–
H
); 13C-NMR (CDCl3)
without further puriˆcation.
t
d
: 16.42, 18.09, 33.16, 35.35, 47.53, 55.32, 62.00,
To a stirred solution of this aldehyde in BuOH
and H2O (4:1) were added NaH2PO4 (2.7 eq) and 2-
methyl-2-butene (10 eq) at room temperature. The
79.24, 86.35, 88.37, 100.83, 108.20, 109.46, 113.98,
114.73, 122.07, 133.19, 134.19, 145.86, 147.67,
159.74.
solution was aged for 10 min and cooled to 0
before treating with NaClO2 (80 purity, 1.1 eq).
9
C,
(2S,3S )-5-(4-Methoxyphenyl)-2-(3,4-methylene-
dioxybenzyl)-3-(1-methylethyl)-4-pentyne-1,3-diol
z
The resulting mixture was stirred for 1.5 h at the
same temperature, and then EtOAc (5 ml) and H2O
(5 ml) were added. The organic layer was separated,
and the aqueous phase was extracted with EtOAc
(
20
)
: 58.5
z
yield, mp 103–104
9
C, Rf 0.50 (hexane-
EtOAc, 3:2); [
a
]
12.99(c
2.58, CHCl3); 1H-NMR
25
＋
D
(CDCl3)
d
: 1.08 (3H, d,
J
＝
6.4 Hz, C
3), 1.95–2.00 (1H, m, Ar1CH2C
, 2.45 (1H, br, OH),
H
3), 1.18 (3H,
＝
×
d,
J
6.4 Hz, C
H
H
),
(2 5 ml). The combined organic layer was washed
2.19–2.29
s
1H, m, (CH3)2C
H
t
H
with brine. After drying and concentrating, the
residue was puriˆed by column chromatography on
silica gel (hexane-EtOAc, 2:1 to 1:2) to provide the
desired acid.
＝
＝
J
2.85 (2H, d,
J
13.6 Hz, ArC
2OH), 3.79 (3H, s, –OC
), 4.38 (1H, dd, 3.6, 11.2 Hz,
2OH), 5.92 (2H, s, O–C 2–O), 6.69–6.75 (3H, m,
9.3 Hz, Ar2– ), 7.36 (2H,
); 13C-NMR (CDCl3)
: 17.22,
2), 3.65 (1H, dd,
4.9, 11.2 Hz, C
H
H
3), 3.85
(1H, br, –O
H
J
＝
C
H
H
(2S,3R)-3-Hydroxy-5-(4-methoxyphenyl)-2-(3,4-
＝
Ar1–
H
), 6.81 (2H, d,
J
H
methylenedioxybenzyl)-3-(1-methylethyl)-4-pen-
25
＝
d,
J
9.3 Hz, Ar2–
H
d
tynoic acid (22): 68.4 yield, yellow oil, [a]
z
D
1
－
17.98, 29.41, 34.50, 46.76, 55.26, 62.64, 79.08,
86.25, 88.49, 100.77, 108.22, 109.54, 113.88, 114.84,
122.01, 133.07, 134.21, 145.77, 147.63, 159.57; IR
nmax (CHCl3) cm－1: 3474, 2983, 1615, 1517, 1495,
1448, 1299, 1256, 1226, 1179, 1106, 1046, 940, 841,
790, 767, 739, 713. Anal. Found: C, 72.37; H,
38.8
(3H, d,
3), 1.26 (1H, s, O
(CH3)2C , 2.93–3.00 (2H, m, Ar1C
Ar1CH2C
Ar1C 2CH), 3.76 (3H, s, OC
O–C 2–O), 6.62–6.70 (3H, m, Ar1–
9
J
(
c
0.98, CHCl3); H-NMR (CDCl3)
6.8 Hz, C 3), 1.20 (3H, d,
), 2.09–2.19
d
: 1.06
6.8 Hz,
1H, m,
2CH and
4.9, 10.3 Hz,
3), 5.91 (2H, s,
), 6.74 (2H, d,
＝
H
J
＝
C
H
H
s
H
t
H
＝
), 3.13 (1H, dd, J
H
H
H
7.04
z
. Calcd. for C23H26 O5: C, 72.23; H, 6.85
yield, yellow oil, f 0.44
2.61, CHCl3);
1.13 (3H, d, 6.4 Hz,
3), 2.10–2.15
1H, m,
11.7, 13.7 Hz,
z
.
H
H
＝
＝
8.8 Hz, Ar2–
(2S,3R)-isomer 21: 15.6
z
R
J
8.8 Hz, Ar2–
H
), 7.26 (2H, d,
J
H );
13C-NMR (CDCl3)
d
: 17.45, 17.79, 32.02, 33.88,
25
－
(hexane-EtOAc, 3:2), [
a
]
36.8
9(
c
D
1H-NMR (CDCl3)
d:
J
J
＝
54.88, 55.22, 74.92, 86.45, 86.78, 100.91, 108.36,
109.18, 113.84, 114.38, 121.81, 131.92, 133.20,
146.30, 147.73, 159.69, 179.99.
－
＝
－
CH
C
H
3), 1.15 (3H, d,
6.8 Hz,
(1H, m, Ar1–CH2C
H
), 2.16–2.25
s
＝
(CH3)2C
Ar1–C
13.7 Hz, Ar1–C
H
t,
2.65 (1H, dd,
J
(2R,3S)-3-Hydroxy-5-(4-methoxyphenyl)-2-(3,4-
＝
H
2), 2.82 (1H, s, –O
H
), 3.04 (1H, dd,
J
3.3,
methylenedioxybenzyl)-3-(1-methylethyl)-4-pen-
25
H
2), 3.34 (1H, br, –O
H
), 3.80 (1H,
tynoic acid (23): 67.6 yield, yellow oil, [a]
z
D
1
＝
＋
dd,
–OCH3 and C
6.68–6.74 (3H, m, Ar1–
J
8.3, 10.3 Hz, C
H
2OH), 3.81–3.85 (4H, m,
2–O),
35.5
(3H, d,
3), 1.25 (1H, s, O
(CH3)2C
Ar1C 2CH), 2.97 (1H, dd,
ArCH2C ), 3.13 (1H, dd,
Ar1C 2CH), 3.76 (3H, s, –OC
O–C
9
(
c
0.84, CHCl3); H-NMR (CDCl3)
d
: 1.06
6.4 Hz,
1H, m,
H
2OH), 5.91 (2H, s, O–C
H
J 6.4 Hz, CH3), 1.20 (3H, d, J
＝ ＝
＝
H
), 6.85 (2H, d,
8.8 Hz, Ar2–
J
8.8 Hz,
); 13C-NMR
: 16.41, 18.09, 33.15, 35.34, 47.47, 55.30,
C
H
H
), 2.09–2.19
s
＝
＝
Ar2–
H
), 7.40 (2H, d,
J
H
H
t,
2.93 (1H, dd,
J
10.5, 15.3 Hz,
(CDCl3)
d
H
J
＝
＝
5.1, 15.3 Hz,
61.96, 79.21, 86.30, 88.38, 100.80, 108.17, 109.45,
113.96, 114.73, 122.00, 133.17, 134.19, 145.84,
147.65, 159.71. Anal. Found: C, 71.90; H, 7.02
Calcd. for C23H26O5: C, 72.23; H, 6.85
H
J
5.1, 10.5 Hz,
H
H
3), 5.92 (2H, s,
z
.
H
2–O), 6.62–6.70 (3H, m, Ar1–
8.8 Hz, Ar2–
H
), 6.75 (2H, d,
＝
＝
8.8 Hz, Ar2–
z.
J
H
), 7.26 (2H, d,
J
H );
13C-NMR (CDCl3)
d
: 17.45, 17.79, 32.04, 33.89,
Procedure for oxidation. To a stirred solution of
18 (0.95 mmol) or 20 (1.25 mmol) in CH Cl (10 ml
54.77, 55.24, 74.93, 86.44, 86.79, 100.92, 108.36,
109.20, 113.86, 114.38, 121.82, 131.93, 133.21,
146.31, 147.74, 159.71, 179.99.
W
2
2
mmol) were added NMO (1.5 eq) and crushed
molecular sieves at room temperature under an N2
atmosphere. The reaction mixture was stirred for
5 min before adding a catalytic amount of TPAP.
After stirring for 12 h, H2O (10 ml) was added to the
mixture, and resulting biphasic solution was stirred
for 5 min before passing through a Celite ˆlter. The
Procedure for lactonization. To a stirred solution
of carboxylic acid 22 (0.51 mmol) or 23 (0.24 mmol)
in CH OH (12 ml mmol) was added 0.1 -AgNO3
M
W
3
(1.2 ml mmol) at room temperature. The reaction
W
mixture was stirred for 2 days in the dark. After con-
centrating the solvent in vacuo, the residue was puri-
ˆed by column chromatography on silica gel (CCl4-
EtOAc, 12:1), and the resulting crystals were
recrystallized from CH2Cl2-petroleum ether (1:2) to
give 4 or 5. The mother liquor was concentrated, and
the residue was puriˆed by column chromatography
ˆltrate was extracted with Et2O (2
×
10 ml), and the
combined organic layer was successively washed with
sat. NaHCO3 and brine. After drying and concentrat-
ing, the residue was puriˆed by column chro-
matography on silica gel (hexane-EtOAc, 3:1) to
provide an aldehyde which was used in next step

Total Synthesis of the 2- and 3-Epimers of Dechloro-cyanobacterin
2223
on silica gel (CCl4-EtOAc, 9:1) to provide a second
crop of crystals.
104.47, 108.31, 109.43, 113.89, 122.04, 125.93,
130.06, 131.51, 146.44, 147.83, 151.43, 158.75,
174.37; IR nmax (CHCl3) cm－1: 3025, 1803, 1735,
1687, 1611, 1512, 1491, 1448, 1294, 1252, 1213, 1179,
1102, 1042, 995, 940, 863, 786, 769, 751, 739. Anal.
(2S,3R,4Z )-3-Hydroxy-5-(4-methoxyphenyl)-(3,4-
methylenedioxybenzyl)-3-(1-methylethyl)-4-penten-
25
4-olide (
4
)
: 43.8
z
yield, mp 129–130
9
C, [
a
]
D
1
＋
46.1
9(
c
0.98, CHCl3); H-NMR (CDCl3)
d
: 0.95
Found: C, 69.66; H, 6.10z. Calcd. for C23H24O6: C,
＝
＝
2.9 Hz,
(3H, d,
J
2.9 Hz, C
1H, m, (CH3)C
), 2.86–2.92 (2H, m, Ar1–C
Ar1–CH2C ), 3.13 (1H, dd, 8.3, 17.3 Hz,
2), 3.82 (3H, s, OC 3), 5.68 (1H, s,
), 5.86 (1H, s, O–C 2–O), 5.90 (1H, s,
), 6.78 (1H, s,
8.8 Hz, Ar2– ), 7.51 (2H,
); H-NMR (acetone-d6 : 0.85
H
3), 0.96 (3H, d,
, 2.03 (1H, s,
2CH and
J
69.68; H, 6.10z.
C
H
3), 1.88–2.02
s
H t
–O
H
H
References
H
J
＝
1) Mason, C., Edwards, K., Carlson, R., Pignatello, J.,
Gleason, F., and Wood, J., Isolation of chlorine-con-
taining antibiotic from the freshwater cyanobacteri-
Ar1–C
Ar2–C
H
H
H
H
O–C
H
H
2–O), 6.72 (2H, s, Ar1–H
um Scytonema hofmanni
. Science, 215, 400–402
＝
Ar1–
), 6.87 (2H, d,
J
H
(1982).
1
d,
J
＝
8.8 Hz, Ar2–
H
) d
2) Gleason, F., and Case, D., Activity of the natural
algicide, cyanobacterin, on angiosperms. Plant Phys-
iol., 80, 834–837 (1986).
3) Gleason, F., Case, D., Sipprell, K., and Magnuson,
T., EŠect of the natural algicide, cyanobacterin, on a
herbicide-resistant mutant of Anacystis nidulans R2.
Plant Science, 46, 5–10 (1986).
4) Jong, T., Williard, P., and Porwoll, J., Total synthe-
sis and X-ray structure determination of cyanobacte-
rin. J. Org. Chem., 49, 735–736 (1984).
5) Gleason, F., and Paulson, L., Site of action of the
natural algicide, cyanobacterin, in the blue-green
＝
＝
4.4 Hz,
(3H, d,
J
4.4 Hz, C
H
3), 0.86 (3H, d,
J
C
H
3), 1.92–2.01
s
1H, m, (CH3)C
H
t
, 2.85 (1H, dd,
＝
＝
＝
J
8.3, 14.2 Hz, Ar1–C
8.3 Hz, Ar1–CH2C
14.2 Hz, Ar1–C 2), 4.71 (1H, s, –O
Ar2–C ), 5.92 (1H, s, O–C 2–O), 5.93 (1H, s,
O–C 2–O), 6.72–6.80 (2H, m, Ar1– ), 6.89–6.91
(1H, m, Ar1– 8.8 Hz, Ar2– ),
); 13C-NMR (CDCl3)
: 16.44, 16.86, 32.93, 38.19, 47.24, 55.29, 81.30,
H
2), 2.97 (1H, dd,
J
J
5.4,
H
), 3.17 (1H, dd,
5.4,
H
H ), 5.81 (1H, s,
H
H
H
H
＝
H
), 6.92 (2H, d,
J
H
＝
8.8 Hz, Ar2–H
7.51 (2H, d,
d
J
100.99, 104.51, 108.36, 109.43, 113.91, 122.06,
125.94, 130.09, 131.49, 146.50, 147.89, 151.44,
158.79, 174.34; IR nmax (CHCl3) cm－1: 3025, 1803,
1735, 1687, 1611, 1516, 1491, 1448, 1294, 1256, 1213,
1179, 1106, 1042, 995, 944, 863, 786, 769, 751, 739.
(2R,3S,4Z )-3-Hydroxy-5-(4-methoxyphenyl)-(3,4-
alga, Synechococcus sp. Arch. Microbiol.
273–277 (1984).
, 138,
6) Gleason, F. K., Thoma, W. J., and Carlson, J. L.,
Cyanobacterin and analogs: structure and activity
relationships of a natural herbicide. In ``Progress in
Photosynthesis Research'' vol. 3, ed. Biggins, J.,
Martinius NijhoŠ, The Hague, pp. 11763–11766
(1987).
7) Haga, Y., Okazaki, M., and Shuto, Y., Systematic
strategy for the synthesis of cyanobacterin and its
stereoisomers. 1. Asymmetric total synthesis of
dechloro-cyanobacterin and its enantiomer. Biosci.
Biotechnol. Biochem., 67, 2183–2193 (2003).
8) Evans, D. A., Bartroli, J., and Shih, T. L., Enan-
tioselective aldol condensations. 2. Erythro-selective
chiral aldol condensation via boron enolates. J. Am.
Chem. Soc., 103, 2127–2129 (1981).
9) Evans, D. A., Nelson, J. V., Vogel, E., and Taber, T.
R., Steroselective aldol condensation via boron
enolates. J. Am. Chem. Soc., 103, 3099–3111 (1981).
10) Walker, M. A., and Heathcock, C. H., Extending the
scope of the Evans aldol reactions: preparation of
anti and ``non-Evans'' syn aldols. J. Org. Chem., 56,
5747–5750 (1991).
11) Ho, T.-L., Conformations. In ``Stereoselectivity in
Synthesis'', John Wiley & Sons, Inc., New York, pp.
3–6 (1999).
methylenedioxybenzyl)-3-(1-methylethyl)-4-penten-
25
4-olide (
5
)
: 40.3
z
yield, mp 130
9
d
C, [
a
]
－
46.7
9
J
D
1
(
c
3.45, CHCl3); H-NMR (CDCl3)
2.0 Hz, C 3), 0.95 (3H, d,
1.93–2.01 1H, m, (CH3)C , 2.13 (1H, s, –O
2.85–2.93 (2H, m, Ar1–CH2C and Ar1–C 2CH),
3.12 (1H, dd, 8.8, 16.9 Hz, Ar1–C 2), 3.81 (3H,
s, OC ), 5.85 (1H, s,
: 0.94 (3H, d,
＝
H
J
＝
2.4 Hz, C
H
3),
s
H
t
H
H ),
H
J
＝
H
H
3), 5.68 (1H, s, Ar2–C
H
O–C
H
H
2–O), 5.89 (1H, s, O–C
), 6.78 (1H, s, Ar1–
), 7.50 (2H, d,
1H-NMR (acetone-d6
: 0.85 (3H, d,
H
2–O), 6.71 (2H, s,
＝
H
Ar1–
H
), 6.86 (2H, d,
J
＝
8.8 Hz, Ar2–
H
J
8.8 Hz, Ar2–
);
4.4 Hz,
3), 2.05–2.14 1H,
)
＝
d
J
＝
C
H
3), 0.86 (3H, d,
m, (CH3)C , 2.85 (1H, dd,
Ar1–C 2), 2.97 (1H, dd,
Ar1–CH2C ), 3.17 (1H, dd,
Ar1–C 2), 4.71 (1H, s, –O
5.92 (1H, s, O–C 2–O), 5.93 (1H, s, O–C
6.72–6.80 (2H, m, Ar1– ), 6.89–6.91 (1H, m,
8.8 Hz, Ar2– ), 7.51 (2H,
); 13C-NMR (CDCl3)
: 16.41,
16.85, 32.85, 38.14, 47.22, 55.26, 81.23, 100.95,
J
4.4 Hz, C
H
s
H
t
J
＝
＝
J
＝
J
8.1, 14.2 Hz,
5.9, 8.1 Hz,
5.9, 14.2 Hz,
H
H
H
H
), 5.81 (1H, s, Ar2–C
H ),
2–O),
H
H
H
＝
Ar1–
H
), 6.92 (2H, d,
8.8 Hz, Ar2–
J
H
12) Belil, C., Pascual, J., and Serratosa, F., Intramolecu-
lar cyclization of alkylpropargylidenemalonic acids.
Tetrahedron Lett., 2701–2708 (1964).
＝
d,
J
H
d