Synthesis of the ABC-ring models of goniodomin A: preference for the unnatural configuration at C11 of the BC-ring in a non-macrocyclic model system

Article abstract of DOI:10.1016/j.tetlet.2008.03.082

To confirm the natural relative stereochemistry of the ABC-ring of goniodomin A (1), the corresponding three stereoisomeric compounds, (2R,5S,6S,7S,9S,11R,15S)-, (2R,5S,6S,7R,9R,11S,15R)-, and (2R,5S,6S,7R,9R,11R,15S)-isomers (2, 3, and 5, respectively),

Full text of DOI:10.1016/j.tetlet.2008.03.082

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3242–3247
Synthesis of the ABC-ring models of goniodomin A:
preference for the unnatural configuration at C11 of
the BC-ring in a non-macrocyclic model system
a
a,
*
Takahiro Katagiri , Kenshu Fujiwara , Hidetoshi Kawai a,b, Takanori Suzuki a
a Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
b PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
Received 27 February 2008; revised 14 March 2008; accepted 18 March 2008
Available online 20 March 2008
Abstract
To confirm the natural relative stereochemistry of the ABC-ring of goniodomin A (1), the corresponding three stereoisomeric
compounds, (2R,5S,6S,7S,9S,11R,15S)-, (2R,5S,6S,7R,9R,11S,15R)-, and (2R,5S,6S,7R,9R,11R,15S)-isomers (2, 3, and 5, respectively),
were stereoselectively synthesized using
a Nozaki–Hiyama–Kishi reaction as a key step. It was also found that a
(2R,5S,6S,7R,9R,11S,15S)-isomer (4), corresponding to the absolute configuration of 1 recently proposed by Sasaki, was not detected
during the formation of 5 from a common ketodiol substrate under acid-catalyzed spiroacetalization conditions. This would be
attributable to the absence of a macrocyclic framework.
Ó 2008 Elsevier Ltd. All rights reserved.
Goniodomin A (1, Fig. 1) is a unique bioactive metabo-
lite from dinoflagellates Alexandrium hiranoi and monila-
tium.1–3 Its planar structure was elucidated by
Murakami’s detailed NMR analysis, but its stereochemis-
try was unknown for a long time.1 We previously studied
the absolute configuration of goniodomin A by model syn-
thesis and NMR comparison between 1 and the models,
thereby confirming the natural relative configurations of
the A- and F-rings and predicting that of the DE-ring.4
We then turned our attention to the determination of the
configuration of the ABC-ring, and planned to synthesize
model compounds 2–4 for NMR comparison. During the
course of our studies, Sasaki elucidated the absolute config-
uration of 1 from intensive NMR analysis of the natural
product and chemical synthesis of its degradation product.5
It was also revealed from Sasaki’s results that model 4 pos-
sessed the natural configuration. In this Letter, we describe
the stereoselective synthesis of model compounds 2, 3, and
5, the C11-epimer of 4, based on the Nozaki–Hiyama–
Kishi (NHK) reaction,6 as well as the notable finding of
little production of 4 during the formation of 5 from a
common ketodiol substrate under acid-catalyzed spiro-
acetalization conditions. This would be attributable to
the absence of a macrocyclic framework.
Initially, the possible relative configurations of the ABC-
ring of 1 were deduced based on our previous results with
the A-ring (6 in Fig. 2) and the NMR data on the BC-ring
reported by Murakami.1 The tentative stereochemistry of
the BC-ring (7) was derived as follows: (i) the chair confor-
mation of the C-ring with equatorial C16 (R3) was
presumed from a large JH14a–H15 (9.1 Hz), showing a
trans-diaxial relationship of H14a and H15, even though
JH14b–H15 had a somewhat puzzling intermediate value
(6.7 Hz), which is out of the typical range of an equato-
rial–axial relationship (2–3 Hz); (ii) the NOE correlation
of H7/H15, indicating the close proximity of these protons,
implied the double anomeric spirocyclic acetal of the BC-
ring; (iii) the NOE enhancement of C9–CH3/H15 denoted
that the methyl group would be at an axial position and
cis to H7, although it was rather confusing that both
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706 4924.
E-mail address: fjwkn@sci.hokudai.ac.jp (K. Fujiwara).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.082

T. Katagiri et al. / Tetrahedron Letters 49 (2008) 3242–3247
3243
21
20
OH
OPMB
TBSO
15
E
D
16
OH
2
(S)
O
24
2
26
O
27
TBSO
OTBS
12
O
2
7 H
O
Me
I
8
OH1C1
H
5
15
C
HO
11O
O
Me
O
H
A
O
6
1
31
Me
O
(S)-8
9
7
B
OH
Me
H
32
O
9
RO
TBSO
OH7C
O
33
F
I
Me
JH6-H7 = 8.6 Hz
11
2
(S)
36
34
Me
O
O
Me
8
Goniodomin A (1)
H
H
O
Me
Me
(S)-10a: R = PMB
11
OPMB
HO
OPMB
HO
15
11
15
H
O
H
O
TBSO
TBSO
5
5
H
H
2
6
2
6
O
O
2
(R)
7
11
O
O
TBSO
2
7
7
(R)-10b:
O
O
Me
(R)-8
OHC
O
3
7 H
H
H
H
H
O
Me
ODMB
TBDPSO
13
O
Me
O
Me
R = NAP
8
OH1C1
H
Me
9
9
O
Me
(2-naphthyl-
methyl)
Me
Me
Me
12
(2R,5S,6S,7S,9S,11R,15S)
(2R,5S,6S,7R,9R,11S,15R)
3
2
Scheme 1.
OPMB
OPMB
15
15
H
O
H
O
HO
H
HO
H
5
5
2
6
2
6
O
O
iodide (S)-8 or (R)-8, respectively, and (iii) acid-catalyzed
stereoselective spiroacetalization. Model 5 was also synthe-
sized from (S)-8 and 12 in a similar manner.
11
11
O
O
7
7
O
Me
O
Me
H
H
H
H
O
Me
O
Me
9
9
Me
Me
(2R,5S,6S,7R,9R,11S,15S)
(2R,5S,6S,7R,9R,11R,15S)
Iodide (S)-8 was prepared from (S)-glycidyl ether 14 by
the following four steps: (i) reaction of 14 with propargyl-
magnesium bromide/CuCN, (ii) TBS protection to form
167 (89%, 2 steps), (iii) regioselective stannylcupration
(72%),8 and (iv) iodination (90%) (Scheme 2). Iodide (R)-
8 was similarly derived from the (R)-enantiomer of 14.
Iodide (S)-10a was synthesized from a known chiral alco-
hol 189 by a process including Dess–Martin oxidation10
of 18, Corey–Fuchs acetylene formation to produce 19
(60%, 3 steps),11 regioselective stannylation,8 and iodin-
ation (72%, 2 steps). The preparation of (R)-10b was per-
formed in the same way from a NAP ether with (R)-
configuration corresponding to 19.12
5
4
Fig. 1.
NOE
R3
R3
15
Hb
15
H
Ha14
H
O
HO
C
H
H
7
O
11O
R4
5
A
Me
2
6
OR2
7
R4
B
R1
O
O
Ha
9
9
H
H
10
H
O
Me
Hb
6
7
JH9-H10a = 6.8 Hz
JH9-H10b = 6.8 Hz
JH14a-H15 = 9.1 Hz
JH14b-H15 = 6.7 Hz
A-ring of 1
BC-ring of 1
deduced from
reported
The synthesis of 2 began from known 214a (Scheme 3).
The removal of TBDPS from 21 (52%), followed by TPAP
oxidation,13 produced aldehyde 11, which was reacted with
(S)-10a under NHK conditions6 to give 23 as a single
from our
previous work
1H NMR data1a
Fig. 2.
JH9–H10a and JH9–H10b showed the same intermediate values
(6.8 Hz), which deviated from the normal 3J values
(2–3 Hz) of equatorial–axial or equatorial–equatorial pro-
tons. Hence, at this stage, the ABC-ring of 1 was thought
OR
OTBS
OPMB
17: R = SnBu3
(S)-8: R = I
O
a
c
OPMB
X
OPMB
14
15: R = H
b
d
*
*
*
*
*
*
*
to have either (2R ,5S ,6S ,7S ,9S ,11R ,15S )-configu-
16: R = TBS
*
*
*
ration, corresponding to model 2, or (2R ,5S ,6S ,
OPMB
OPMB
OPMB
X
*
*
*
*
7R ,9R ,11S ,15R )-configuration, corresponding to
model 3.
OH e, f, g
h
Next, models 2 and 3 were synthesized to establish the
relative stereochemistry of the ABC-ring of 1 by the com-
parison of the NMR data of 1 and models 2 and 3. The
synthetic routes to 2 and 3 (Scheme 1), established after
exhaustive investigations, strongly relied on the following
steps: (i) diastereoselective NHK reaction,6 which created
the (7S)-configuration of 9 with substrates (S)-10a and 11
and the (7R)-configuration of 12 with (R)-10b and 13, (ii)
the second NHK reaction6 of aldehydes 9 and 12 with
Me
18
Me
19
Me
20: X = SnBu3
(S)-10a: X = I
i
Scheme 2. Reagents and conditions: (a) propargylmagnesium bromide,
CuCN, Et2O, À20 °C; (b) TBSOTf, 2,6-lutidine, CH2Cl2, 23 °C, 89% (2
steps); (c) Bu3SnH, LDA, CuCN, THF, À78 °C, then MeOH, 23 °C, 72%;
(d) I2, THF, 23 °C, 90%; (e) DMPI, CH2Cl2, 23 °C; (f) CBr4, PPh3,
CH2Cl2, 0 °C, 71% (2 steps); (g) BuLi, THF, À78 °C, 85%; (h) Bu3Sn-
AlEt2, CuCN (cat.), THF, À30 °C; (i) I2, THF, 23 °C, 72% (2 steps).

3244
T. Katagiri et al. / Tetrahedron Letters 49 (2008) 3242–3247
JH14a–H15 and JH14b–H15 could not be measured due to
the chemical shift equivalence of H14a and H14b.
TBSO
TBSO
b
c
f
R2O
7
9
11
RO
Model 3 was synthesized from known 2816 (Scheme 4).
The protection of 28 as a TBS ether (99%), followed by
modified Wacker oxidation,17 afforded 30 (93%), which
was converted to 31 (87%, 2 steps) through enol triflate
formation and the subsequent Sonogashira reaction18 with
propargyl alcohol. Enyne 31 was transformed to 33 (88%, 2
steps) via reduction and protection with TBDPSCl. The
removal of the acetonide of 33 (77%) and stepwise selective
DMB protection (79%, 2 steps) produced 34, which was
oxidized with TPAP/NMO to afford 13.13 NHK coupling
of 13 with (R)-10b efficiently furnished 35 (78%) along with
a small amount of its diastereomer (5%).6 The stereochem-
istry at C7 of 35 was determined by the NMR analysis of
44 derived from 35, in which large values of JH5–H6 and
JH6–H7 (both showed 11.2 Hz) and an NOE enhancement
between 1,3-diaxial protons H5 and H7 were observed
(Fig. 3). Thus, the stereocenter C7 of 35 was successfully
constructed by a substrate-control in the NHK reaction
step. Alcohol 35 was converted to 38 via TBS protection
(85%), TBDPS deprotection (88%),19 and Katsuki–Sharp-
less asymmetric epoxidation (96%).20 The treatment of 38
with Et2OÁBF3 successfully constructed the A-ring, and
the resulting diol 39 was protected as an isopropylidene
acetal to give 40 (80%, 2 steps). After the removal of the
NAP group of 40 (98%), the resulting 41 was oxidized to
12. Iodide (R)-8 was successfully coupled with 12 under
NHK conditions6 to give 42, which was oxidized to 43
(68% from 41). The removal of the TBS group from 43
and the subsequent treatment with CSA furnished 3 as a
single isomer (94%, 2 steps).
O
O
O
O
(S)-10a
H
H
H
H
O
Me
O
Me
Me
Me
R1O Me
23: R1 = PMB, R2 = H
21: R = TBDPS
22: R = H
d
e
a
24: R1 = PMB, R2 = TBS
25: R1 = H, R2= TBS
PMBO
OPMB
OTBS
H HO
OTBS
X
15
g
i, j
O
H
6O 2
OTBS
O
11
11
O
O
7
O
Me
(S)-8
H
H
H
9
H
O
O
Me
Me
Me
Me
Me
26: X = H, OH
27: X = O
2
h
NOE
PMBO
15
PMBO
15
HO
H
H
H
H
Hb
14
H
H
H
6
O
O
O
7
7
Ha
Ha
Hb
O
O
CH3
Ha
13
10
9
10
Hb
H
9
Ha
H
H
J6-7
=
1.7 Hz
J9-10a = 11.7 Hz
J9-10b 4.3 Hz
Hb
H
CH3
H
H
2a
=
2b
in C6D6
Scheme 3. Reagents and conditions: (a) 10% NaOH–MeOH (1:1), 23 °C,
52%; (b) TPAP, NMO, CH2Cl2, 23 °C; (c) (S)-10a, CrCl2, NiCl2, DMSO,
23 °C, 81% (2 steps); (d) TBSOTf, 2,6-lutidine, CH2Cl2, 23 °C, ꢀ100%; (e)
DDQ, CH2Cl2–H2O (10:1), 23 °C, 92%; (f) DMPI, CH2Cl2, 23 °C; (g) (S)-
8, CrCl2, NiCl2, DMSO, 23 °C; (h) DMPI, CH2Cl2, 23 °C, 67% (3 steps
from 25); (i) TASF, DMF, 23 °C; (j) CSA, CH2Cl2, 0 °C, 50% (2 steps).
isomer (81%, 2 steps).14,15 Alcohol 23 was converted to 25
(92%) via protection with TBSOTf and removal of the
PMB group. After the oxidation of 25 with DMPI,10 the
resulting 9 was subjected to NHK reaction with (S)-8 to
smoothly furnish 26,6which was oxidized to 27 (67% from
25). The removal of the TBS groups of 27, followed by
treatment with CSA, produced 2 as a single isomer (50%,
2 steps).
The stereochemistry of 3 was confirmed by NMR anal-
ysis. The NOE enhancement of H2/H6, showing the cis-
relationship of H2 and H6, verified the C2-configuration
on the basis of the known C6 stereochemistry. The NOE
correlations of H7/H15, C12@CH/H10b, and C12@CH/
H9 also established the double anomeric spiroacetal struc-
ture of the BC-ring with (11S)-configuration. The presence
of a chair–boat interconversion equilibrium in the B-ring
was suggested from the coexistence of the NOE correl-
ations of C9–Me/H7 and C12@CH/H9, which indicated
a 1,3-diaxial relationship of C9–Me and H7 and a close
proximity of C12@CH and H9 in a boat conformation,
respectively, as well as the deviations of the coupling con-
stants JH9–H10a (7.4 Hz) and JH9–H10b (5.9 Hz) from the
The stereochemistry of 2 was confirmed by NMR anal-
ysis. The double anomeric spiroacetal structure of the BC-
ring with (11R)-configuration was determined by the NOE
correlations of H7/H15, C12@CH/H10b, and C12@CH/
H9. Moreover, the coexistence of NOEs of H7/C9-CH3
and H7/H10a suggested not only the cis-relationship of
all of H7, C9-CH3, and H10a, but also the presence of a
conformational equilibrium between the boat and chair
forms of the B-ring (2a and 2b, respectively). The devia-
tions of the coupling constants JH9–H10a (11.7 Hz) and
3
normal J values (2–3 Hz) of equatorial–axial or equato-
rial–equatorial protons. The large JH14a–H15 (10.6 Hz) and
small JH14b–H15 (3.9 Hz) indicated the chair conformation
of the C-ring of 3.
The chemical shifts of 1 significantly deviated from
those of both 2 and 3, partly due to the difference of sub-
stituents at C2 and C15 of 1 from those of either model.
Therefore, the structural similarity of 1 to 2 or 3 was
assessed from the similarity of the NOE correlations and
the coupling constants. The reported NOE correlation of
H7/H15 in 1 was also observed in each model. Although
3
JH9–H10b (4.3 Hz) from the normal J values (2–3 Hz) of
equatorial–axial or equatorial–equatorial protons in a
chair conformer would also be attributed to the chair–boat
interconversion equilibrium in the B-ring. The chair con-
formation of the C-ring of 2 was also confirmed by the
NOE correlation of H15/H13a, which indicated a 1,3-di-
axial relationship of these protons, though the size of

T. Katagiri et al. / Tetrahedron Letters 49 (2008) 3242–3247
3245
Me
O
Me
O
OR
TBSO Me
TBSO
NOE
ONAP
Me
b
e
c, d
H
H
JH5-H6 = 11.2 Hz
JH6-H7 = 11.2 Hz
O
O
Me
O
O
6
O
O
O
5
Me
Me
7
Me
Me
Me
HO
k
ODMB TBDPSO
44
28: R = H
30
31
a
29: R = TBS
Fig. 3.
OTBS
TBSO
HO
j
g, h, i
O
13
the NOE enhancement of H15/C9–CH3 was absent in both
models in contrast to its presence in 1, the intermediate val-
ues of JH9–H10a and JH9–H10b of 1 (both 6.8 Hz) were more
similar to those of 3 (JH9–H10a = 7.4 Hz, JH9–H10b = 5.9 Hz)
than those of 2 (JH9–H10a = 11.7 Hz, JH9–H10b = 4.3 Hz).
The value of JH6–H7 of 1 (8.6 Hz, Fig. 1) was also similar
to that of 3 (7.7 Hz) and quite different from that of 2
(1.7 Hz). Therefore, the stereochemical relationship
between the A- and B-rings of 1 was presumed to be the
same as that of 3.21 Although the value of JH14a–H15 of 1
(9.1 Hz) was similar to that of 3 (10.6 Hz), JH14b–H15 of 1
(6.7 Hz) clearly deviated from that of 3 (3.9 Hz). Therefore,
it was suspected that the stereochemistry at C15 of 1 was
different from that of 3. Hence, we next attempted to syn-
thesize model 4, the C15-epimer of 3, for the confirmation
of the above possibility.
Although we applied the above established route to the
synthesis of 4, the produced spiroacetal was 5, the (11R)-
epimer of 4 (Scheme 5). Aldehyde 12, prepared from 41
by Dess–Martin oxidation,10 was successfully reacted with
iodide (S)-8 under NHK conditions6 to give 45, which was
oxidized to 46 (85% 3 steps from 41). The removal of the
TBS from 46, followed by the treatment with CSA,
furnished 5 as a single isomer (68%, 2 steps).
O
Me
RO
(R)-10b
Me
DMBO
TBDPSO
32: R = H
34
f
33: R = TBDPS
TBSO
Me
ONAP
Me OR
OTBS
O
n
o
ODMB
OTBS
R1O
OH
ONAP
ODMB
35: R = H, R1 = TBDPS
36: R = TBS, R1 = TBDPS
37: R = TBS, R1 = H
38
l
m
TBSO
Me
TBSO
p
r
12
O
OTBS
O
O
OH
H
H
H
OTBS
39
H
O
Me
OR
Me
ONAP
OH
Me
40: R = NAP
41: R = H
q
PMBO
OPMB
H HO
OTBS
15
OTBS
X
s
u, v
O
H
6O 2
OTBS
O
11
O
O
(R)-8
7
O
Me
H
H
9
H
H
O
O
Me
Me
Me
Me
Me
H
42: X = H, OH
43: X = O
3
t
The stereochemistry of 5 was confirmed by NMR anal-
ysis. The chair B-ring with equatorial C9–Me and axial C6
was determined by a large JH9–H10a (12.6 Hz), a small
JH9–H10b (4.7 Hz), and the NOE enhancement of H6/H9.
NOE
H
H
H
H
Ha
Hb
CH3
Hb
10
JH9-H10a = 7.4 Hz
JH9-H10b = 5.9 Hz
H
9
9
10
12
Ha
12
Ha
H3C
Ha
O
O
15
H
O
7
O
15
7
14
Hb
14
H
H
Hb
H
PMBO
H
OPMB
O
6
H
5
OPMB
15
HO
OTBS
O
H
O
OPMB
HO
OTBS
2
5
H
a
c, d
H
X
3a
3b
OTBS
2
6
O
12
(S)-8
11
O
O
7
JH5-H6 = 8.0 Hz
JH6-H7 = 7.7 Hz
JH14a-H15 = 10.6 Hz
JH14b-H15 3.9 Hz
O
Me
H
H
H
H
O
Me
O
in C6D6
=
Me
9
Me
Me
Me
45: X = H, OH
46: X = O
5
Scheme 4. Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2,
23 °C, 99%; (b) PdCl2, Cu(OAc)2, O2, AcNMe2–H2O (7:1), 23 °C, 93%; (c)
PhNTf2, KHMDS, THF, À78 °C, 87%; (d) propargyl alcohol,
PdCl2(PPh3)2, CuI, BuNH2, PhMe, 23 °C, ꢀ100%; (e) Red-Al, Et2O,
À20 °C, 90%; (f) TBDPSCl, imidazole, CH2Cl2, 23 °C, 98%; (g) AcOH–
THF–H2O (3:1:1), 55 °C, 77%; (h) 3,4-dimethoxybenzaldehyde, CSA,
reflux, 90%; (i) DIBAH, Et2O, À78 °C, 88%; (j) TPAP, NMO, MS4A,
CH2Cl2, 23 °C; (k) (R)-10b, CrCl2, NiCl2, DMSO, 23 °C, 78% (2 steps); (l)
TBSOTf, 2,6-lutidine, DMAP, CH2Cl2, 23 °C, 85%; (m) TBAF, AcOH,
THF, 23 °C, 88%; (n) (+)-DET, TBHP, Ti(iOPr)4, MS4A, CH2Cl2,
À20 °C, 96%; (o) BF3ÁOEt2, CH2Cl2, À78 °C; (p) 2,2-dimethoxypropane,
PTSÁH2O, 0 °C, 80% (2 steps); (q) DDQ, wet CH2Cl2, 23 °C, 98%; (r)
DMPI, CH2Cl2, 23 °C; (s) (R)-8, CrCl2, NiCl2, DMSO, 23 °C; (t) DMPI,
CH2Cl2, 23 °C, 68% (3 steps from 41); (u) TASF, DMF, 23 °C; (v) CSA,
CH2Cl2, 0 °C, 94% (2 steps).
b
Ha
NOE
Me
H
Hb
10
9
H
JH6-H7
=
8.0 Hz
H
H
JH9-H10a = 12.6 Hz
13
O
JH9-H10b
JH14a-H15 = 10.8 Hz
JH14b-H15 3.8 Hz
= 4.7 Hz
7
Hb
Ha
6
O
O
Ha
15
2
H
H
HO
14
Hb
=
H
H
5
OPMB
5a
in C6D6
Scheme 5. Reagents and conditions: (a) (S)-8, CrCl2, NiCl2, DMSO–THF
(3:1), 23 °C; (b) DMPI, CH2Cl2, 23 °C, 85% (3 steps from 41); (c) TASF,
DMF, 23 °C; (d) CSA, CH2Cl2, 0 °C, 68% (2 steps).

3246
T. Katagiri et al. / Tetrahedron Letters 49 (2008) 3242–3247
20 21
OH
Acknowledgments
E
D
24
OH
O
16
15
O
26
HH
27
H
H
We are grateful to Prof. Makoto Sasaki and Prof. Masa-
H HO 5
H 6
O
to Oikawa (Graduate School of Life Sciences, Tohoku
University) for sending us a preprint prior to publication
and for helpful discussions. We also thank Mr. Kenji
Watanabe and Dr. Eri Fukushi (GC–MS and NMR
Laboratory, Graduate School of Agriculture, Hokkaido
University) for measurements of mass spectra, and Dr.
Yasuhiro Kumaki (High-Resolution NMR Laboratory,
Graduate School of Science, Hokkaido University) for
measurements of NMR spectra. This work was supported
by a Global COE Program (B01) and a Grant-in-Aid for
Scientific Research from the Ministry of Education, Cul-
ture, Sports, Science, and Technology of Japanese
Government.
C
A
O
O
2
1
31
O
11
7
B
OH
H
H
32
O
Me
9
O
33
F
Me
36
34 Me
Fig. 4. Absolute configuration of 1 proposed by Sasaki.
The NOE interaction of H7/H10a may suggest distortion
of the chair conformer at C7 or some contribution of a
boat-conformer with C7 prow and C10 stern due to the
1,3-diaxial repulsion between C6 and an axial oxygen at
C11. The chair C-ring was also confirmed by a large
JH14a–H15 (10.8 Hz), a small JH14b–H15 (3.8 Hz), and the
NOE enhancement of H13a/H15. The NOE correlations
of H6/H15 and C12@CH/H10a established the double
anomeric structure of the BC-ring with (11R)-configura-
tion. Because these NMR data disagreed with those of
1,1 the relative configuration of the BC-ring of 1 must
Supplementary data
Supplementary data (spectral data of compounds 2, 3,
and 5) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2008.03.082.
*
*
*
*
*
not be 6S ,7R ,9R ,11R ,15S . Interestingly, the JH6–H7
value of 5 (8.0 Hz) was quite similar to those of 3 and 1
(7.7 Hz and 8.6 Hz).
References and notes
1. Murakami, M.; Makabe, K.; Yamaguchi, K.; Konosu, S.; Wa¨lchli,
M. R. Tetrahedron Lett. 1988, 29, 1149.
We found that model 4 was not detected during the for-
mation of 5 from a common ketodiol substrate, derived
from 46, under acid-catalyzed spiroacetalization condi-
tions. Sasaki, however, proposed the absolute configura-
tion of 1 (Fig. 4),5 in which the ABC-ring possessed the
same stereochemistry as 4. It is notable that the BC-ring
of 1 exists in a form that has been proven to be thermody-
namically unstable in a non-macrocyclic system. The pres-
ence of the macrocyclic framework of 1 would make the
(11R)-isomer of the BC-ring (corresponding to 5) more
constrained than the (11S)-isomer (corresponding to 4),
and this constraint would invert the relative stability of
the (11R)- and (11S)-isomers. In this study, we could not
prove the true stereochemistry of the ABC-ring by model
synthesis, but the above finding would be important for
designing a synthesis of 1 and suggests that the stereoselec-
tive construction of the BC-ring would be successful in the
presence of the macrolactone framework.
2. Hsia, M. H.; Morton, S. L.; Smith, L. L.; Beauchesne, K. R.; Huncik,
K. M.; Moeller, P. D. R. Harmful Algae 2006, 5, 290.
3. For bioactivity of 1: Abe, M.; Inoue, D.; Matsunaga, K.; Ohizumi,
Y.; Ueda, H.; Asano, T.; Murakami, M.; Sato, Y. J. Cell. Physiol.
2002, 190, 109 and references cited therein.
4. (a) Fujiwara, K.; Naka, J.; Katagiri, T.; Sato, D.; Kawai, H.; Suzuki,
T. Bull. Chem. Soc. Jpn. 2007, 80, 1173; (b) Katagiri, T.; Fujiwara, K.;
Kawai, H.; Suzuki, T. Tetrahedron Lett. 2008, 49, 233.
5. Takeda, Y.; Shi, J.; Oikawa, M.; Sasaki, M. Org. Lett. 2008, 10, 1013.
6. (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc.
1977, 99, 3179; (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.;
Nozaki, H. Tetrahedron Lett. 1983, 24, 5281; (c) Jin, H.; Uenishi, J.;
Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644.
7. Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Wei,
H.-X.; Weyershausen, B. Angew. Chem., Int. Ed 2001, 40, 3849.
8. Sharma, S.; Oehlschlager, A. C. J. Org. Chem. 1989, 54, 5064.
9. Murakami, N.; Sugimoto, M.; Nakajima, T.; Kawanishi, M.; Tsutsui,
Y.; Kobayashi, M. Bioorg. Med. Chem. 2000, 8, 2651.
10. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
11. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
12. Oka, T.; Murai, A. Tetrahedron 1998, 54, 1.
In conclusion, three stereoisomeric model compounds,
(2R,5S,6S,7S,9S,11R,15S)-, (2R,5S,6S,7R,9R,11S,15R)-,
and (2R,5S,6S,7R,9R,11R,15S)-isomers (2, 3, and 5,
respectively), for the ABC-ring of 1 were stereoselectively
synthesized by using a Nozaki–Hiyama–Kishi reaction as
a key step. It was also found that a (2R,5S,6S,7R,
9R,11S,15S)-isomer (4), corresponding to the absolute
configuration of 1 recently proposed by Sasaki, was not
detected during the formation of 5 from a common
ketodiol substrate under acid-catalyzed spiroacetalization
conditions. This would be attributable to the absence of a
macrocyclic framework. Further studies toward the total
synthesis of 1 are in progress in our laboratory.
13. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
14. The stereochemistry at C7 of 23 was determined to be S by modified
Mosher’s method: Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J. Am. Chem. Soc. 1991, 113, 4092.
15. Origin of the stereoselectivity is unclear: cf.: Heathcock, C. H.;
McLaughlin, M.; Medina, J.; Hubbs, J. L.; Wallace, G. A.; Scott, R.;
Claffey, M. M.; Hayes, C. J.; Ott, G. R. J. Am. Chem. Soc. 2003, 125,
12844.
16. Miranda, L. S. M.; Meireles, B. A.; Costa, J. S.; Pereira, V. L. P.;
Vasconcellos, M. L. A. A. Synlett 2005, 869.
17. Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998,
39, 876.
18. Sonogashira, K.; Tohda, Y.; Hagiwara, N. Tetrahedron Lett. 1975,
50, 4467.

T. Katagiri et al. / Tetrahedron Letters 49 (2008) 3242–3247
3247
19. Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.; Shiraha-
ma, H.; Nakata, M. Synlett 2000, 1306.
and C8@CH2 and show different NMR behavior than the B-rings of
non-macrocyclic models 2 and 3. However, natural compound 1, in
fact, displays quite similar values of JH9–H10a and JH9–H10b to 3, which
suggests the B-ring of 1 does not have a distorted conformation.
Therefore, it was thought that 1 possesses the same stereochemical
relationship between the A- and B-rings as 3 even within the
macrolide framework. This conclusion is now supported by the
absolute stereochemistry of 1 proposed by Sasaki.
20. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
21. We justified the comparison of macrocyclic 1 to non-macrocyclic
models 2 and 3 as follows. If 1 assumes the same stereochemical
relationship between the A- and B-rings as 2 with an anti-relationship
between H6 and H7 in the macrolide framework, the B-ring should
transform itself to relieve the severe steric repulsion between C5–OH