Stereoselective synthesis of the C1-C16 fragment of goniodomin A

Article abstract of DOI:10.1246/bcsj.20120152

Stereoselective synthesis of the C1-C16 fragment of the antifungal marine polyether macrolide goniodomin A is described. A Stille-type coupling of organostannanes and thioesters was exploited as the key carbon-carbon bondforming process, namely for the fo

Full text of DOI:10.1246/bcsj.20120152

948
Bull. Chem. Soc. Jpn. Vol. 85, No. 9, 948-956 (2012)
© 2012 The Chemical Society of Japan
Selected Papers
Stereoselective Synthesis of the C1-C16 Fragment of Goniodomin A
Motohiro Nakajima, Haruhiko Fuwa,* and Makoto Sasaki*
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577
Received May 29, 2012; E-mail: hfuwa@bios.tohoku.ac.jp; masasaki@bios.tohoku.ac.jp
Stereoselective synthesis of the C1-C16 fragment of the antifungal marine polyether macrolide goniodomin A is
described. A Stille-type coupling of organostannanes and thioesters was exploited as the key carbon-carbon bond-
forming process, namely for the formation of the C7-C8 and C11-C12 bonds. Construction of the spiroacetal domain via
acid-catalyzed acetalization of a triol-enone 30 unexpectedly provided a mixture of natural 11S spiroacetal 2, unnatural
11R spiroacetal 32, and constitutional isomer 33. Fortunately, it was eventually found that protection of the C5 hydroxy
group as its acetate facilitated the isolation of natural 11S isomer 47 via acid-catalyzed equilibration of unnatural 11R
isomer 48 and avoided the formation of a constitutional isomer, thereby increasing the efficacy of the spiroacetalization
process.
Goniodomin A (1, Figure 1) was isolated as a potent anti-
an intriguing target molecule for the synthetic community.
Fujiwara and co-workers have reported the synthesis and
stereochemical analysis of the A/BC- and F-ring fragments8a,8b
and a D/E-ring model compound.8c Our group has independ-
ently embarked on studies toward the total synthesis of 1 and
completed the synthesis of the C15-C36 fragment.9,10 Herein,
we report in detail our stereoselective synthesis of the A/BC-
ring fragment encompassing the C1-C16 carbon backbone of
1, by exploiting the Stille-type coupling of organostannanes
and thioesters.11
fungal agent from the dinoflagellate Alexandrium hiranoi (for-
merly Goniodoma pseudogoniaulax) collected by Murakami
et al. from a rock pool in Jogashima, Japan.1 More recently, it
was reported that 1 was also isolated from the dinoflagellate
Alexandrium monilatum by Moeller et al.2 Recently, we as-
signed the absolute configuration of 1 based on extensive 2D
NMR studies, degradation/derivatization experiments, and the
synthesis and NMR spectroscopic analysis of suitably designed
model compounds.3 It has been shown that 1 exhibits a range
of interesting biological activities, including antifungal activ-
ity,1 antiangiogenesis activity,4 and modulation of actomyosin
ATPase activity.5-7 Ohizumi and co-workers found that 1 alters
the conformation of actin through binding to F-actin, which
leads to expression of actomyosin ATPase activity. It was also
reported that 1 induces differential modulation of actomyosin
ATPase activity between the ventricular and atrial muscles, and
it appears to be highly sensitive to the troponin/tropomyosin
complex.
Results and Discussion
Initial Synthetic Plan toward the C1-C16 Model of
Goniodomin A. Our initial plan for a convergent synthesis of
the C1-C16 fragment 2 is illustrated in Scheme 1 (Tol: p-tolyl).
We envisioned that 2 would be synthesized from enone 3 via
desilylation and spiroacetalization. Enone 3 could be con-
structed by means of a Stille-type coupling12 between vinyl-
stannane 4 and thioester 5. The latter would be accessible via
Stille-type coupling of thioester 6 with vinylstannane 7.
Synthesis of the C1-C7 Thioester 6. The synthesis of
the C1-C7 thioester 6 began with the known alcohol 813
(Scheme 2). Ozonolysis of the double bond followed by
a reductive workup with NaBH4 afforded diol 9 in 93%
yield. Selective silylation of the primary alcohol within 9
[triisopropylsilyl chloride (TIPSCl), imidazole] gave alcohol
10 in 98% yield. Oxidation with tetra-n-propylammonium
perruthenate (TPAP) in the presence of N-methylmorpholine
N-oxide (NMO)14 provided ketone 11 (96%), which was
methylenated to afford olefin 12 (91%). The silyl group was
removed with tetra-n-butylammonium fluoride (TBAF) (99%),
and the liberated hydroxy group was benzylated to provide
benzyl ether 13 (100%). Deprotection of the benzylidene acetal
under acidic conditions gave diol 14 in 90% yield. Bis-
silylation (97%) followed by selective liberation of the primary
Because of its highly complex molecular architecture and
characteristic biological activities, goniodomin A (1) represents
Figure 1. Structure of goniodomin A (1).
Published on the web September 8, 2012; doi:10.1246/bcsj.20120152

M. Nakajima et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
949
OBn
HO
H
16
H
H
Ph
O
OH
Ph
Ph
O
O
OH
c
a
O
O
O
O
O
O
O
1
H
H
O
H
11
OPG
OBn
8
9: PG = H
10: PG = TIPS
b
2
Me
H
O
H
H
Ph
X
g
e,f
O
O
O
H
H
H
OBn
OBn
TBSO
OTIPS
OTBS
13
11: X = O
12: X = CH2
d
TBSO
O
OBn
TBSO
HO
HO
j-l
h,i
O
Me
3
HO
O
O
OBn
OBn
14
15
OBn
OTBS
16
TBSO
TBSO
TolS
O
11
+
TolS
1
O
O
12
OBn
6
O
Me OTBS
OBn
4
SnBu3
5
Scheme 2. Synthesis of thioester 6. Reagents and conditions:
(a) O3, MeOH/CH2Cl2, ¹78 °C; then NaBH4, ¹78 to 0 °C,
93%; (b) TIPSCl, imidazole, THF/CH2Cl2, 0 °C to room
temperature, 98%; (c) TPAP, NMO, 4 ¡ molecular sieves,
¹
CH2Cl2, room temperature, 96%; (d) Ph3P+CH3Br , n-
TBSO
BuLi, THF, 0 °C to room temperature, 91%; (e) TBAF,
THF, room temperature, 99%; (f) BnBr, NaH, DMF, 0 °C
to room temperature, 100%; (g) CSA, MeOH/CH2Cl2,
room temperature, 90%; (h) TBSCl, imidazole, DMF,
50 °C, 97%; (i) CSA, MeOH/CH2Cl2, 0 °C, 87%; (j) SO3¢
pyridine, Et3N, DMSO/CH2Cl2, 0 °C; (k) NaClO2, NaH2-
PO4, 2-methyl-2-butene, t-BuOH/H2O, 0 °C to room tem-
perature; (l) p-toluenethiol, DCC, DMAP, CH2Cl2, 0 °C to
room temperature, 85% (three steps).
PMBO
8
7
+
TolS
SnMe3
1
11
O
Me
O
OBn
7
6
Scheme 1. Initial synthetic plan for the C1-C16 fragment.
alcohol under acidic conditions afforded primary alcohol 15
(87%). Oxidation of 15 to the corresponding carboxylic acid
and subsequent esterification with p-toluenethiol under Steglich
conditions [N,N¤-dicyclohexylcarbodiimide (DCC), 4-(N,N-
dimethylamino)pyridine (DMAP)]15 afforded thioester 6 in
85% yield for the three steps.
Synthesis of the C8-C11 Vinylstannane 7. The synthesis
of the C8-C11 vinylstannane 7 commenced with the known
carboxylic acid 1616 (Scheme 3). Condensation of 16 with (R)-
4-benzyloxazolidin-2-one (17) gave imide 18 in 89% yield.17
Diastereoselective methylation of 18 was performed using
Evans conditions [sodium hexamethyldisilazide (NaHMDS),
MeI, THF, ¹78 to ¹40 °C]18 to give methylated product 19
in 95% yield as a single diastereomer (judged by 600 MHz
1H NMR analysis). Removal of the chiral auxiliary with LiOH
triisopropylbenzenesulfonyl hydrazide (TrisNHNH2) to give
hydrazone 22. Exposure of 22 to t-BuLi effected lithiation to
deliver olefin 23, which confirmed that the corresponding vinyl
anion could be generated. However, we were unable to trap the
vinyl anion with n-Bu3SnCl. Moreover, we found that signifi-
cant racemization of the C9 stereogenic center occurred during
the transformation from 21, as chiral HPLC analysis of 23
showed that the optical purity of the material was only 12% ee.
The C9 racemization problem was totally unexpected, since
Smith and co-workers have reported a closely related trans-
formation.22 Accordingly, we resorted to Stille reaction for the
preparation of 7. Conversion of 21 into the corresponding enol
triflate with potassium hexamethyldisilazide (KHMDS) and N-
phenyl bis(trifluoromethanesulfonyl)imide (PhNTf2) followed
by Stille coupling with (Me3Sn)2 in the presence of [Pd(PPh3)4]
and LiCl23,24 afforded vinylstannane 7 in 71% yield (two steps).
The optical purity of this material was confirmed to be 96% ee
by chiral HPLC analysis of the protodestannylated product 23.
19
and aqueous H2O2 (98%) followed by condensation with
N,O-dimethylhydroxylamine via a mixed anhydride yielded
Weinreb amide 20 (73%). Treatment of 20 with MeMgBr20 gave
methyl ketone 21 in 96% yield (96% ee by chiral HPLC
analysis). We first attempted to synthesize 7 by means of
Shapiro reaction.21 Methyl ketone 21 was reacted with 2,4,6-

950
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
Synthetic Studies on Goniodomin A
PMBO
PMBO
CO2H
PMBO
PMBO Me
OMe
O
O
O
O
O
N
O
a
c,d
b
+
16
N
N
HN
Bn
O
O
O
Me
Bn
Me
Bn
18
19
20
17
NHTris
Me
PMBO
PMBO
PMBO
O
N
e
f
g
9
Me
21
22
23
Me
h,i
Me
Me
12% ee
PMBO
PMBO
j
SnMe3
23
7
Me
Me
96% ee
Scheme 3. Synthesis of vinylstannane 7. Reagents and conditions: (a) PivCl, Et3N, THF, ¹20 °C; then 17, LiCl, ¹20 °C to room
temperature, 89%; (b) NaHMDS, THF, ¹78 °C; then MeI, ¹78 to ¹40 °C, 95% (d.r. >20:1); (c) LiOH, aqueous H2O2, THF/H2O,
0 °C to room temperature, 98%; (d) ClCO2i-Bu, N-methylpiperidine, MeONHMe¢HCl, CH2Cl2, ¹15 °C, 73%; (e) MeMgBr, THF,
0 °C, 96%; (f) TrisNHNH2, THF, 0 °C to room temperature; (g) t-BuLi, THF, ¹78 to 0 °C, 38% (two steps); (h) KHMDS, PhNTf2,
THF, ¹78 °C; (i) (Me3Sn)2, [Pd(PPh3)4], LiCl, THF, 70 °C, 71% (two steps); (j) n-BuLi, THF, ¹78 °C.
alkyne 26 in 95% yield (two steps). Regioselective hydro-
stannylation26 of 26 with (n-Bu3Sn)2Cu(CN)Li2 furnished
vinylstannane 4 in 84% yield.
OBn
OBn
OH
OTBS
CHO
a
O
b,c
BnO
Optimization Studies on Stille-Type Coupling. The use
of thioesters as electrophiles in palladium-catalyzed coupling
has recently emerged as a powerful means to synthesize various
carbonyl compounds.27 Liebeskind and co-workers pioneered
the “thioester variant” of Stille coupling, which proceeds in the
presence of a palladium(0) catalyst with a weakly coordinating
phosphine ligand and stoichiometric amounts of a copper(I) salt
under mild reaction conditions.12 Nonetheless, the Liebeskind-
modified Stille-type coupling has scarcely been applied to the
synthesis of complex natural products,9,28 and the versatility of
the reaction has not been fully verified.
benzyl (S)-
24
glycidyl ether
25
OBn
d,e
OBn
OTBS
OTBS
f
26
4
SnBu3
We studied Stille-type coupling of thioester 6 with vinyl-
stannane 7 under various conditions (Table 1). A slight excess
of vinylstannane 7 (1.1 equiv) was used relative to thioester 6.
On the basis of our previous experience,9b the reaction was
initially conducted under the influence of tris(dibenzylidene-
acetone)dipalladium(0) [Pd2(dba)3]/(EtO)3P catalyst system
and copper(I) diphenylphosphinate (CuDPP) in degassed THF
at room temperature, which gave enone 27 in 66% yield. How-
ever, the reaction did not reach completion, and a significant
amount of 6 (32%) was recovered (Entry 1). To improve the
material throughput, efforts were made to optimize the reaction
conditions. By changing the ratio of Pd/(EtO)3P from 1/2 to
1/4, the product yield increased to 76% (Entry 2). Changing
the catalyst system from [Pd2(dba)3]/(EtO)3P to [Pd2(dba)3]¢
CHCl3/(EtO)3P turned out to be detrimental for the present
reaction (Entry 3). It was eventually determined that the use
of Ph3As as a ligand29 was beneficial for increasing both the
Scheme 4. Synthesis of vinylstannane 4. Reagents and
conditions: (a) allylMgBr, CuI, THF, ¹40 to ¹25 °C;
(b) TBSCl, imidazole, DMF, room temperature; (c) O3,
CH2Cl2, ¹78 °C; then Ph3P, ¹78 °C to room temperature,
69% (three steps); (d) CBr4, Ph3P, Et3N, CH2Cl2, 0 °C;
(e) n-BuLi, THF, ¹78 °C, 95% (two steps); (f) (n-Bu3Sn)2,
n-BuLi, CuCN, THF, ¹78 °C, 84%.
Synthesis of the C12-C16 Vinylstannane 4. Our synthesis
of the C12-C16 vinylstannane 4 started with commercially
available benzyl (S)-glycidyl ether and is shown in Scheme 4.
Regioselective epoxide opening with allylmagnesium bro-
mide/CuI gave alcohol 24. Silylation using t-butyldimethyl-
silyl chloride (TBSCl)/imidazole followed by ozonolysis of
the double bond led to aldehyde 25 (69% overall yield). A
Corey-Fuchs alkyne synthesis25 via a dibromoolefin delivered

M. Nakajima et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
951
product yield and conversion (Entries 4 and 5). The best result
was obtained when the reaction was carried out under the
influence of [Pd2(dba)3]¢CHCl3/Ph3As, giving enone 27 in
92% yield with complete consumption of thioester 6 within
1.5 h at room temperature (Entry 5). Thus, we showed the
beneficial role of Ph3As in Stille-type coupling of organo-
stannanes and thioesters.
(28:7-epi-28 = 3:1-1:2).30 Eventually, we found that reduction
of 27 with Zn(BH4)2 through chelate-control31 led to the forma-
tion of allylic alcohol 28 in 63% yield with a 5:1 diastereo-
selectivity. The diastereomers could be separated by flash
column chromatography on silica gel. The stereochemistry of
the newly generated C7 stereogenic center was established on
3
the basis of the JH,H analysis of acetonide 31, which was
Synthesis of the Cyclization Precursor 30. The synthesis
of the cyclization precursor 30 is summarized in Scheme 5.
Reduction of 27 was investigated under a variety of conditions.
Our attempts involved the use of NaBH4/CeCl3, diisobutyl-
aluminum hydride (DIBALH), and sodium bis(2-methoxy-
ethoxy)aluminum hydride (Red-Alμ), but these reducing agents
provided a mixture of allylic alcohol 28 and its C7 epimer
(i.e., 7-epi-28) with disappointingly low diastereoselectivity
derived from 28 in two steps (Scheme 6). Silylation of the
resultant alcohol 28 gave a bis-silyl ether (100%), from which
the p-methoxybenzyl (PMB) group was removed with 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) to deliver alcohol
29 (99%). A two-stage oxidation followed by esterification
with p-toluenethiol provided thioester 5 in 82% yield for the
three steps. Stille-type coupling of thioester 5 with vinyl-
stannane 4 under the optimized conditions described above
afforded enone 3 in 86% yield. Removal of all of the silyl
groups using tris(dimethylamino)sulfonium difluorotrimethyl-
silicate (TASF)32 led to triol-enone 30 in 98% yield. We found
that the addition of H2O was critically important for obtaining
30 in high yield with good reproducibility.32b,33,34 On the
other hand, attempts at cleavage of the silyl groups and in situ
spiroacetalization by using HF¢pyridine or 46% aqueous HF
solution/CH3CN resulted in complete degradation of the mate-
rial. Thus, these deprotection experiments demonstrated that 30
is susceptible to acid and base, presumably due to the presence
of the highly reactive ¡,¢-unsaturated carbonyl group.
Table 1. Screening of the Reaction Conditions for the Stille-
Type Coupling of 6 and 7a)
Spiroacetalization of Triol-Enone 30. The spiroacetaliza-
tion of 30 was then investigated, as summarized in Table 2.
First, treatment of 30 under acidic conditions [(«)-10-cam-
phorsulfonic acid (CSA), CH2Cl2, 0 °C to room temperature]
delivered a mixture of (11S)-spiroacetal 2 (19%), (11R)-
spiroacetal 32 (30%), and fused acetal 33 (27%), which were
separable with flash column chromatography on silica gel
and reverse-phase HPLC (Entry 1). The use of a milder acid,
pyridinium p-toluenesulfonate (PPTS), under the same reaction
conditions gave a similar result (Entry 2). While monitoring
the course of the reaction by TLC analysis, it was found that
spiroacetals 2 and 32 initially appeared and then gradually
isomerized to the fused acetal 33. Therefore, it was surmised
Yield/%
Entry
Pd catalyst
Ligand (equiv)
27
6
1b)
2b)
3c)
4b)
5c)
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]¢CHCl3
[Pd2(dba)3]
[Pd2(dba)3]¢CHCl3
(EtO)3P (0.2)
(EtO)3P (0.4)
(EtO)3P (0.4)
Ph3As (0.4)
Ph3As (0.4)
66
76
52
87
92
32
23
38
11
0
a) All reactions were performed using vinylstannane 7 (1.1
equiv), palladium catalyst (5 mol %), ligand (0.2-0.4 equiv),
and CuDPP (2.0 equiv) in degassed THF at room temperature.
b) Reaction time: 2 h. c) Reaction time: 1.5 h.
HO
TBSO
PMBO
TBSO
PMBO
TBSO
a
d-f
b,c
7
O
O
O
Me OTBS
OBn
Me
O
OBn
Me OH
OBn
28
29
27
BnO
TBSO
OPG PGO
PGO
4
3: PG = TBS
30: PG = H
TolS
h
O
O
g
O
Me OTBS
OBn
OBn
5
O
Me
Scheme 5. Synthesis of triol-enone 30. Reagents and conditions: (a) Zn(BH4)2, Et2O, ¹40 °C, 63% (dr 5:1); (b) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 °C, 100%; (c) DDQ, pH 7 buffer, CH2Cl2, 0 °C to room temperature, 99%; (d) SO3¢pyridine, Et3N, DMSO,
CH2Cl2, 0 °C; (e) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O, 0 °C to room temperature; (f) p-toluenethiol, DCC,
DMAP, CH2Cl2, 0 °C to room temperature, 82% (three steps); (g) [Pd2(dba)3]¢CHCl3, Ph3As, CuDPP, THF, room temperature,
86%; (h) TASF, H2O, DMF, 0 °C to room temperature, 98%.

952
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
Synthetic Studies on Goniodomin A
PMBO
TBSO
O
Me OH
a,b
OBn
28
Me
O
5
Me
6
O
O
7
PMBO
OBn
31
Me
H
OBn
5
O
6
O
O
Me
7
H
Me
H
J5,6 = 9.5 Hz
J6,7 = 10.0 Hz
Figure 2. Structures of 2, 32, and 33. The double-headed
blue arrows indicate important NOEs. For clarity, the
benzyloxy groups are omitted. The structure of the 3D
model was generated by conformational searches using the
MMFF94s force field followed by geometry optimization
(HF6-31G*// PM3 level of theory).
Scheme 6. Confirmation of the C7 stereogenic center.
Reagents and conditions: (a) TBAF, THF, room temper-
ature, 96%; (b) Me2C(OMe)2, PPTS, CH2Cl2, room tem-
perature, 81%.
Table 2. Spiroacetalization of Triol-Enone 30a)
BnO
OBn
HO
OBn
HO
HO
acid
O
O
O
O
O
30
11
O
+
+
O
CH2Cl2
O
11
O
OBn
OBn
Me
2
32
11R unnatural
OBn
Me
Me
11S natural
33
Yield/%
Entry
Acid
Solvent
Temperature
Time
2
32
33
1
2
3
4
5b)
CSA
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
0 °C to r.t.
0 °C to r.t.
0 °C
0 °C to r.t.
0 °C to r.t.
24 h
23 h
31 h
36 h
5 d
19
23
36
19
6
30
28
46
34
14
27
28
15
30
32
PPTS
PPTS
PPTS
PPTS
CH3CN/H2O (4:1)
a) All reactions were performed using CSA (0.1 equiv) or PPTS (1.5 equiv) at the indicated temperature
(r.t.: room temperature). The products were separated by reverse-phase HPLC. b) The reaction did not
complete even after five days. The starting material was recovered in 47% yield.
that the spiroacetals 2 and 32 are the kinetic products. Indeed,
running the reaction at 0 °C was beneficial for suppressing the
formation of the undesired fused acetal 33, and returned a
mixture of 2 (36%), 32 (46%), and 33 (15%) (Entry 3). The
product selectivity was not affected upon changing the solvent
to CH3CN (Entry 4). The use of CH3CN/H2O (4:1) as solvent
considerably slowed down the reaction and provided the
undesired 33 as the major product (Entry 5). The structures of
2, 32, and 33 were established on the basis of the observed
NOESY correlations, as shown in Figure 2.

M. Nakajima et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
953
OBn
HO
O
O
O
OBn
2
Me
OBn
5
OTBS AcO
TBSO
O
Scheme 7. Spiroacetalization of a triol-enone delivered from
enone 34.8b Reagents and conditions: (a) TASF, DMF, room
temperature; (b) CSA, CH2Cl2, 0 °C, 68% (two steps).
OBn
36
O
Me
The present spiroacetalization favors the unnatural (11R)-
spiroacetal 32 over the natural (11S)-spiroacetal 2 because the
former benefits from a double anomeric effect. These results are
different from those obtained by Fujiwara et al.8b The authors
reported that, in their study, acid-catalyzed spiroacetalization
of a triol-enone derived from tris-TBS ether 34 by desilylation
with TASF, delivered (11R)-spiroacetal 35 as a sole isolable
product (Scheme 7). However, in the current study, it was con-
firmed that each of the products 2, 32, and 33 gave an approxi-
mately 2:1:1 mixture of 32, 2, and 33 upon treatment with
CSA (CH2Cl2, 0 °C), indicating that the products were in
equilibration under these conditions. This result suggests that
the 11S configuration of the natural product might be attributed
to the constraint originating from the macrocyclic skeleton.
Although the synthesis of the targeted C1-C16 fragment
2 was completed, our inability to control the course of the
spiroacetalization of triol-enone 30 remained an unsolved
problem. We took it seriously because it might be difficult to
forge the macrocyclic skeleton with unnatural R configura-
tion at the C11 stereogenic center. Indeed, in contrast to 2 and
32, our previous derivatization studies on 1 showed that the
natural product did not isomerize into the corresponding (11R)-
isomer upon treatment with PPTS,3 implying that the unnatural
11R configuration might be prohibited by the presence of the
macrocyclic backbone. Based on this premise, we envisioned
that it would be necessary to devise a practical means to set the
C11 stereogenic center in its correct configuration prior to the
formation of the macrolactone ring.35
Revised Synthetic Plan toward the C1-C16 Fragment of
Goniodomin A. Our revised synthetic strategy toward the
C1-C16 fragment 2 is outlined in Scheme 8. It was considered
that the temporary masking of the C5 hydroxy group of enone
36 with an acetyl group would be a feasible way to suppress
the formation of the undesired fused acetal 33 during acid-
catalyzed spiroacetalization. Furthermore, the acetyl group
would be easily removed under basic conditions without
touching the spiroacetal domain. We envisioned that enone
36 would be accessible via a two-fold use of the Stille-type
coupling in a manner similar to the synthesis of 3. Thus, enone
36 could be retrosynthetically divided into thioester 38 and
vinylstannanes 4 and 7.
OBn
AcO
OTBS
+
TolS
O
O
+
Me OTBS
OBn
SnBu3
37
4
TESO
PMBO
TolS
SnMe3
O
Me
O
OBn
38
7
Scheme 8. Revised synthesis plan toward the C1-C16
fragment 2.
Synthesis of Protected Enone 36. The synthesis of enone
36 commenced with the previously elaborated diol 14
(Scheme 9). Protection of 14 with triethylsilyl chloride
(TESCl)/imidazole and subsequent selective unmasking of
the primary alcohol under acidic conditions delivered alcohol
39 in 90% yield (two steps). Parikh-Doering oxidation36
followed by Pinnick oxidation37 and condensation of the
resultant carboxylic acid with p-toluenethiol led to thioester 38
in 52% yield (three steps). Since the remainder of the material
lost its TES group, the hydroxy group of 40 was reprotected as
its TES ether to give additional amounts of thioester 38 in
88% yield. Thioester 38 was then coupled with vinylstannane
7 under the optimized conditions to afford enone 41 in 85%
31
yield. Chelate-controlled reduction of 41 using Zn(BH4)2
delivered a 5:1 separable mixture of allylic alcohol 42 and its
diastereomer in 59% combined yield. Protection of 42 with
t-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf)/2,6-
lutidine, removal of the TES group, and acylation led to acetate
43 (88%, three steps), from which the PMB group was cleaved
with DDQ to give alcohol 44 (95%). Oxidation of 44 to the
corresponding carboxylic acid [(i) Dess-Martin periodinane38
then (ii) NaClO2] followed by esterification with p-toluenethiol

954
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
Synthetic Studies on Goniodomin A
HO
PGO
TolS
PMBO
TESO
TESO
7
a,b
c-e
HO
HO
O
O
g
O
O
OBn
O
OBn
Me
O
OBn
OBn
14
39
38: PG = TES
40: PG = H
41
f
PMBO
TESO
PGO
AcO
AcO
m-o
h
i-k
TolS
O
O
O
Me OH
OBn
Me OTBS
OBn
O
Me OTBS
OBn
43: PG = PMB
44: PG = H
37
42
l
BnO
OTBS AcO
TBSO
4
O
p
OBn
O
Me
36
Scheme 9. Synthesis of enone 36. Reagents and conditions: (a) TESCl, imidazole, DMF, 50 °C; (b) PPTS, MeOH, CH2Cl2, ¹10 °C,
90% (two steps); (c) SO3¢pyridine, Et3N, DMSO, CH2Cl2, 0 °C; (d) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O,
0 °C to room temperature; (e) p-toluenethiol, DCC, DMAP, CH2Cl2, 0 °C to room temperature, 38: 52% (three steps), 40: 46%
(three steps); (f) TESCl, imidazole, DMF, 50 °C, 88%; (g) [Pd2(dba)3]¢CHCl3, Ph3As, CuDPP, THF, room temperature, 85%;
(h) Zn(BH4)2, Et2O, ¹40 °C, 59% (dr 5:1); (i) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to room temperature, 99%; (j) PPTS, CH2Cl2,
MeOH, 0 °C to room temperature, 89%; (k) Ac2O, pyridine, DMAP, THF, 0 °C to room temperature, 100%; (l) DDQ, pH 7 buffer,
CH2Cl2, 0 °C to room temperature, 95%; (m) DMP, CH2Cl2, 0 °C to room temperature; (n) NaClO2, NaH2PO4, 2-methyl-2-butene,
t-BuOH/H2O, 0 °C to room temperature; (o) p-toluenethiol, DCC, DMAP, CH2Cl2, 0 °C to room temperature, 92% (three steps);
(p) [Pd2(dba)3]¢CHCl3, Ph3As, CuDPP, THF, room temperature, 87%.
furnished thioester 37 in 92% yield for the three steps. Stille-
type coupling of 37 with vinylstannane 4 proceeded cleanly to
furnish enone 36 in 87% yield.
(K2CO3, MeOH, 0 °C to room temperature) proceeded without
incident to furnish the C1-C16 fragment 2 in 86% yield.
Conclusion
Completion of the Synthesis of the C1-C16 Fragment 2.
Unexpectedly, desilylation of 36 with TASF32 (H2O, DMF,
room temperature) delivered a mixture of diol 45 and its
constitutional isomer 46 (Scheme 10). Cleavage of the silyl
ethers under neutral conditions by using a mixture of aqueous
HF/TBAF39 also resulted in a 1:2 mixture of 45 and 46 in 85%
combined yield. We considered that the basicity of the fluoride
ion would have caused the acyl migration. We also examined
the deprotection of the silyl groups with aqueous HF solution
in CH3CN, but in this case we only obtained a complex mixture
of products. However, we were delighted to find that the acyl
migration observed during the desilylation with aqueous HF/
TBAF was inconsequential to the subsequent spiroacetaliza-
tion. Thus, treatment of a 1:2 mixture of diols 45 and 46 with
PPTS in CH2Cl2 at 0 °C to room temperature delivered a
mixture of (11S)-spiroacetal 47 (31%) and (11R)-spiroacetal 48
(60%), which could be readily separated by flash column chro-
matography on silica gel. This result indicated that the C7 acetyl
group of 46 remigrated to the C5 hydroxy group under the reac-
tion conditions. In addition, acid treatment of unnatural (11R)-
spiroacetal 48 (PPTS, CH2Cl2, 0 °C to room temperature) gave
natural (11S)-spiroacetal 47 (33%) together with recovered 48
(58%), demonstrating that the unnatural 48 could be converted
to natural 47. Finally, deprotection of 47 under basic conditions
We have accomplished a stereoselective synthesis of the
C1-C16 fragment 2 by exploiting the Stille-type coupling of
thioesters with vinylstannanes and acid-catalyzed spiroacetali-
zation. We found that the Stille-type coupling of thioesters with
vinylstannanes was best performed by using the [Pd2(dba)3]¢
CHCl3/Ph3As catalyst system and CuDPP. The acid-catalyzed
spiroacetalization of triol-enone 30 proved to be a significant
challenge because of the difficulties associated with selective
synthesis of (11S)-spiroacetal 2 over unnatural (11R)-spiroacetal
32 and fused acetal 33. We eventually found that protection
of the C5 hydroxy group of the spiroacetalization precursor as
its acetate (i.e., 45) greatly facilitated the isolation of natural
spiroacetal 47 and isomerization of unnatural 48 to natural
47. Studies toward the completion of the total synthesis of
goniodomin A are currently underway in our laboratory and
will be reported in due course.
We thank Drs. Yoshiyuki Takeda, Tomoyuki Saito, and
Ms. Jinglu Shi (Graduate School of Life Sciences, Tohoku
University) for their contribution to the initial stage of this
work. This work was supported in part by a Grant-in-Aid for
Scientific Research (A) (No. 21241050) from Japan Society for
the Promotion of Science (JSPS).

M. Nakajima et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
955
BnO
6
K. Matsunaga, K. Nakatani, M. Murakami, K. Yamaguchi,
Y. Ohizumi, J. Pharmacol. Exp. Ther. 1999, 291, 1121.
M. Yasuda, K. Nakatani, K. Matsunaga, M. Murakami, K.
Momose, Y. Ohizumi, Eur. J. Pharmacol. 1998, 346, 119.
a) K. Fujiwara, J. Naka, T. Katagiri, D. Sato, H. Kawai, T.
OTBS AcO
TBSO
7
O
8
OBn
Suzuki, Bull. Chem. Soc. Jpn. 2007, 80, 1173. b) T. Katagiri, K.
Fujiwara, H. Kawai, T. Suzuki, Tetrahedron Lett. 2008, 49, 233.
c) T. Katagiri, K. Fujiwara, H. Kawai, T. Suzuki, Tetrahedron Lett.
2008, 49, 3242.
36
O
a
Me
9
a) T. Saito, H. Fuwa, M. Sasaki, Org. Lett. 2009, 11, 5274.
b) T. Saito, H. Fuwa, M. Sasaki, Tetrahedron 2011, 67, 429.
10 The carbon numbering throughout this paper corresponds to
that of the natural product.
11 A part of this work has been communicated: H. Fuwa, M.
Nakajima, J. Shi, Y. Takeda, T. Saito, M. Sasaki, Org. Lett. 2011,
13, 1106.
BnO
OH
XO
YO
5
O
7
OBn
12 a) R. Wittenberg, J. Srogl, M. Egi, L. S. Liebeskind, Org.
Lett. 2003, 5, 3033. b) H. Li, H. Yang, L. S. Liebeskind, Org. Lett.
2008, 10, 4375.
13 H. Fuwa, M. Sasaki, K. Tachibana, Tetrahedron 2001, 57,
3019.
O
Me
45: X = Ac, Y = H
46: X = H, Y = Ac
14 a) W. P. Griffith, S. V. Ley, G. P. Whitcombe, A. D. White,
J. Chem. Soc., Chem. Commun. 1987, 1625. b) S. V. Ley, J.
Norman, W. P. Griffith, S. P. Marsden, Synthesis 1994, 639.
15 B. Neises, W. Steglich, Angew. Chem., Int. Ed. Engl. 1978,
17, 522.
b
OBn
PGO
OBn
AcO
16 K. Hirai, H. Ooi, T. Esumi, Y. Iwabuchi, S. Hatakeyama,
Org. Lett. 2003, 5, 857.
17 T. K. Chakraborty, V. R. Suresh, Tetrahedron Lett. 1998,
39, 7775.
O
O
O
O
+
O
O
11
11
OBn
OBn
48
18 D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc.
1982, 104, 1737.
19 D. A. Evans, T. C. Britton, J. A. Ellman, Tetrahedron Lett.
1987, 28, 6141.
Me 11S natural
Me
11R unnatural
47: PG = Ac
2: PG = H
d
c
20 S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815.
21 a) R. H. Shapiro, M. J. Heath, J. Am. Chem. Soc. 1967, 89,
5734. b) R. H. Shapiro, Org. React. 1976, 23, 405.
22 A. B. Smith, III, C. Sfouggatakis, C. A. Risatti, J. B. Sperry,
W. Zhu, V. A. Doughty, T. Tomioka, D. B. Gotchev, C. S. Bennett,
S. Sakamoto, O. Atasoylu, S. Shirakami, D. Bauer, M. Takeuchi, J.
Koyanagi, Y. Sakamoto, Tetrahedron 2009, 65, 6489.
23 W. D. Wulff, G. A. Peterson, W. E. Bauta, K.-S. Chan,
K. L. Faron, S. R. Gilbertson, R. W. Kaesler, D. C. Yang, C. K.
Murray, J. Org. Chem. 1986, 51, 277.
Scheme 10. Completion of the synthesis of the C1-C16
fragment 2. Reagents and conditions: (a) 46% aq HF/
TBAF, THF, 0 °C, 85% (45:46 = 1:2); (b) PPTS, CH2Cl2,
0 °C to room temperature, 47: 31%; 48: 60%; (c) PPTS,
CH2Cl2, 0 °C to room temperature, 33% (recovered 48:
58%); (d) K2CO3, MeOH, 0 °C to room temperature, 86%.
Supporting Information
24 Here, we used (Me3Sn)2 as a nucleophile because it is
known that Stille coupling of (Me3Sn)2 with enol triflates works
more efficiently than that of (Bu3Sn)2. See ref. 23. Furthermore, we
envisaged that the reactivity of trimethylvinylstannane 7 in Stille-
type coupling would be higher than that of the corresponding
tributylvinylstannane due to its sterically less hindered character.
25 E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769.
26 S. Sharma, A. C. Oehlschlager, J. Org. Chem. 1989, 54,
5064.
27 a) T. Fukuyama, H. Tokuyama, Aldrichimica Acta 2004,
37, 87. b) H. Prokopcová, C. O. Kappe, Angew. Chem., Int. Ed.
2009, 48, 2276.
28 a) A. Morita, S. Kuwahara, Org. Lett. 2006, 8, 1613.
b) Although not a typical Stille-type coupling, Movassaghi et al.
have applied copper(I)-catalyzed coupling of thioesters and
organostannanes to their total synthesis of (¹)-agelastatins. See:
M. Movassaghi, D. S. Siegel, S. Han, Chem. Sci. 2010, 1, 561.
29 V. Farina, B. Krishnan, J. Am. Chem. Soc. 1991, 113, 9585.
The experimental procedure and spectroscopic data of newly
synthesized compounds are included in the Supporting Infor-
mation. This material is available free of charge on the Web
at: http://www.csj.jp/journals/bcsj/.
References
1
M. Murakami, K. Makabe, K. Yamaguchi, S. Konosu,
M. R. Wälchli, Tetrahedron Lett. 1988, 29, 1149.
M. H. Hsia, S. L. Morton, L. L. Smith, K. R. Beauchesne,
K. M. Huncik, P. D. R. Moeller, Harmful Algae 2006, 5, 290.
Y. Takeda, J. Shi, M. Oikawa, M. Sasaki, Org. Lett. 2008,
10, 1013.
2
3
4
M. Abe, D. Inoue, K. Matsunaga, Y. Ohizumi, H. Ueda, T.
Asano, M. Murakami, Y. Sato, J. Cell. Physiol. 2002, 190, 109.
5
K. Furukawa, K. Sakai, S. Watanabe, K. Maruyama, M.
Murakami, K. Yamaguchi, Y. Ohizumi, J. Biol. Chem. 1993, 268,
26026.

956
Bull. Chem. Soc. Jpn. Vol. 85, No. 9 (2012)
Synthetic Studies on Goniodomin A
30 We have also examined the following reagents and
conditions for the reduction of 27: (1) NaBH4, CeCl3¢7H2O,
MeOH, ¹40 °C, 100% (28:7-epi-28 = 1:1); (2) DIBALH, CH2Cl2,
¹78 °C, 68% (28:7-epi-28 = 3:1); (3) DIBALH, hexanes, ¹78 °C,
80% (28:7-epi-28 = 1:2); (4) Red-Alμ, toluene, 0 °C, 66% (28:
7-epi-28 = 2:1).
31 a) T. Takahashi, M. Miyazawa, J. Tsuji, Tetrahedron Lett.
1985, 26, 5139. b) T. Oishi, T. Nakata, Acc. Chem. Res. 1984, 17,
338.
34 During desilylation of 3 using TASF, concomitant spiroa-
cetalization of 30 was observed neither in the presence nor absence
of H2O.
35 A late-stage formation of the BC-ring spiroacetal consti-
tutes another possible synthetic strategy toward 1. However, we
think it impractical because the “open-chain” form of the BC-ring
domain (i.e., C7-C15) reveals a highly reactive ¡,¢-unsaturated
ketone at C11, which would be quite difficult to manage during the
course of multistep transformations.
32 a) R. Noyori, I. Nishida, J. Sakata, M. Nishizawa, J. Am.
Chem. Soc. 1980, 102, 1223. b) K. A. Scheidt, H. Chen, B. C.
Follows, S. R. Chemler, D. S. Coffey, W. R. Roush, J. Org. Chem.
1998, 63, 6436.
36 J. R. Parikh, W. v. E. Doering, J. Am. Chem. Soc. 1967, 89,
5505.
37 B. S. Bal, W. E. Childers, Jr., H. W. Pinnick, Tetrahedron
1981, 37, 2091.
33 Under anhydrous conditions, the reaction occasionally gave
a complex mixture of unidentified products, suggesting that triol-
enone 30 is sensitive under basic conditions.
38 D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
39 M. Enomoto, T. Nakahara, S. Kuwahara, Tetrahedron 2006,
62, 1102.