Concise asymmetric total synthesis of scyphostatin, a potent inhibitor of neutral sphingomyelinase

Article abstract of DOI:10.1002/chem.200700871

The concise asymmetric total synthesis of scyphostatin has been achieved by condensation of the optically active cyclohexane unit, prepared from the commercially available 1,4-cyclohexadiene by our own method, and the side chain, prepared by the method developed by Hoye and Tennakoon (T. R. Hoye, M. A. Tennakoon, Org. Lett. 2000, 2, 1481-1483). The modification of the epoxy cyclohexenone unit was achieved in a late stage of the total synthesis, and deprotection of the primary alcohol was conducted in the final step. During the synthesis several key reactions were attained: 1) intramolecular bromoetherification of the cyclohexadiene acetal; 2) stereoselective introduction of the tertiary alcohol, 3) deprotection of the acetal function to the aldehyde by combination with silyl triflate/2,4,6-collidine and the one-pot synthesis of the disilyl aldehyde compounds, with different types of silyl groups, from the dihydroxy acetal compounds; and 4) facile deprotection of the 2,4-dimethoxyphenylmethyl (^2,4DMPM) protecting group of the primary alcohol.

Full text of DOI:10.1002/chem.200700871

FULL PAPER
DOI: 10.1002/chem.200700871
Concise Asymmetric Total Synthesis of Scyphostatin, a Potent Inhibitor of
Neutral Sphingomyelinase
Hiromichi Fujioka,* Yoshinari Sawama, Naoyuki Kotoku, Takuya Ohnaka,
Takashi Okitsu, Nobutaka Murata, Ozora Kubo, Ruichuan Li, and Yasuyuki Kita*[a]
Abstract: The concise asymmetric total
synthesis of scyphostatin has been
achieved by condensation of the opti-
synthesis, and deprotection of the pri-
mary alcohol was conducted in the
final step. During the synthesis several
key reactions were attained: 1) intra-
molecular bromoetherification of the
cyclohexadiene acetal; 2) stereoselec-
tive introduction of the tertiary alco-
hol, 3) deprotection of the acetal func-
tion to the aldehyde by combination
with silyl triflate/2,4,6-collidine and the
one-pot synthesis of the disilyl alde-
hyde compounds, with different types
of silyl groups, from the dihydroxy
acetal compounds; and 4) facile depro-
tection of the 2,4-dimethoxyphenyl-
methyl (2,4DMPM) protecting group of
the primary alcohol.
cally active cyclohexane unit, prepared
from the commercially available 1,4-cy-
clohexadiene by our own method, and
the side chain, prepared by the method
developed by Hoye and Tennakoon
(T. R. Hoye, M. A. Tennakoon, Org.
Lett. 2000, 2, 1481–1483). The modifi-
cation of the epoxy cyclohexenone unit
was achieved in a late stage of the total
Keywords: asymmetric synthesis ·
bromoetherification
·
cyclic
compounds
scyphostatin
·
natural products
·
Introduction
Scyphostatin (1)[1] was isolated from Dasyscyphus mollissi-
mus SANK-13892 in 1997 and showed the most potent ac-
tivity (IC50 =1.0 mm) toward a neutral sphingomyelinase (N-
SMase) among the large number of already reported N-
SMase inhibitors.[2] N-SMase is the enzyme that accelerates
the conversion of sphingomyelin into ceramide. Since the
ceramide is believed to be an intracellular lipid second mes-
senger and to play vital roles in the regulation of cell prolif-
eration, modulation of the inflammatory process, and apop-
tosis,[3] 1 is recognized as a lead compound for the treatment
of inflammation and autoimmune diseases. This molecule
consists of an epoxy cyclohexenone unit with an amino alco-
hol moiety and an unsaturated fatty acid side chain, so that
1 is a challenging target compound for many organic chem-
ists in view of not only its biological activity but also its
unique structure. Although several synthetic studies toward
1 have already been reported,[4,5] to the best of our knowl-
edge only two total asymmetric syntheses of 1 have, quite
recently, been reported by Katoh and co-workers from d-
arabinose derivatives in 22 steps[6] and by Takagi et al.
through a spirolactone derivative from tyrosine in 18 steps.[7]
We now present our study on the total asymmetric synthe-
sis of 1. For the optically active epoxy cyclohexenone unit of
1, we recently succeeded in the synthesis of model com-
pound 5, which has the same epoxy cyclohexenone unit of
1.[8] Thus the intramolecular bromoetherification of the
diene acetal 2 gave a cyclohexene eight-membered acetal 3
in a stereoselective manner.[9] Compound 3 was transformed
into the allyl alcohol 4, which was further modified to 5. In
the beginning, we attempted to convert the dimethyl acetal
function of 5 into an aldehyde function, which would be
used for the further construction of the amino alcohol
moiety and the introduction of the fatty acid side chain.
However, the conversion of 5 into 6 was unsuccessful, possi-
[a] Dr. H. Fujioka, Y. Sawama, N. Kotoku, T. Ohnaka, T. Okitsu,
N. Murata, O. Kubo, R. Li, Prof. Dr. Y. Kita
Graduate School of Pharmaceutical Sciences
Osaka University, 1–6 Yamada-oka
Suita, Osaka, 565-0871 (Japan)
Fax : (+81)6-6879-8229
E-mail: fujioka@phs.osaka-u.ac.jp
kita@phs.osaka-u.ac.jp
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bly as a result of the instability of the epoxy cyclohexenone
unit (Scheme 1). We then decided to develop an alternative
way to synthesize 1. As another synthetic plan, we had to
consider the instability of 1, as it is a very unstable com-
of the synthetic route to an epoxy cyclohexenone unit with
an amino alcohol moiety using cyclohexene eight-membered
acetal 4 are described. In a previous study,[9] the cyclohexa-
diene acetal 2 was prepared by the transacetalization of di-
ethylacetal 8, obtained from benzoic acid by using a four-
step sequence according to a previously reported proce-
dure[10] with (R,R)-hydrobenzoin. We then succeeded in syn-
thesizing 8 in only one step. Thus, lithiation of commercially
available 1,4-cyclohexadiene (7) and successive reaction
with bromoacetaldehyde diethyl acetal afforded 8 in a one-
pot operation in 75% yield. The transformation of 8 into di-
methyl acetal 10 was carried out by our previously reported
procedure:[8] 1) Transacetalization of 8 with (R,R)-hydroben-
zoin, 2) intramolecular bromoetherification of 2 with NBS
in the presence of MeOH, 3) radical reduction of 3, 4) ste-
reoselective oxidation of 9 by using SeO2, and 5) acidic
treatment of 4 in MeOH (Scheme 3).
Scheme 1. Attempted conversion of 5 into 6. NBS=N-bromosuccinimide.
pound under acidic and basic conditions. For example, the
epoxy cyclohexenone unit of 1 has many reactive functional
groups, such as the enone, unstable under basic conditions,
and the epoxide, unstable under acidic conditions. The pri-
mary alcohol of 1 causes an intramolecular nucleophilic
attack on the ketone under basic conditions. Furthermore,
the trienamide unit of the side chain causes decomposition
even under neutral conditions.[1b]
A summary of our total synthesis is depicted in Scheme 2.
We first condensed the optically active cyclohexane unit,
prepared by our own method, and the side chain prepared
by the method developed by Hoye and Tennakoon.[5a] Then
modification of the epoxy cyclohexenone unit was achieved
in a late stage of the total synthesis, and deprotection of the
primary alcohol was conducted in the final step. We then
completed the first generation asymmetric total synthesis of
1. We next improved two reactions, thus giving a more effi-
cient second generation asymmetric total synthesis of 1 in a
total of 17 steps.
Scheme 3. Synthesis of cyclohexene dimethyl acetal 10. i) sec-BuLi,
TMEDA, THF, À788C, then BrCH2CH
C
We then examined the construction of the amino alcohol
moiety. First, we prepared the p-methoxyphenylmethyl
(MPM) ether 14a from 10 by using a three-step sequence
(Scheme 4, a series): 1) Methylation of the benzyl alcohol,
2) acid hydrolysis of the acetal, and 3) nucleophilic addition
of 4-methoxyphenylmethyloxymethyl lithium from the stan-
nyl compound 13.[11] The stereochemistry of the secondary
alcohols 14a and 14a’ was determined by using a modified
Mosherꢁs method (see the Experimental Section).[12] In this
case, the undesired S alcohol 14a’ was obtained as a major
product. Our study using 14a is shown in Scheme 5. The
Mitsunobu reaction[13] of the secondary alcohol 14a using
DPPA for introduction of the azide group with inversion
was unsuccessful and gave a diastereomeric mixture of the
allylic azide 15 because of the presence of the reactive allyl-
ic tertiary alcohol. We then attempted to first convert the
olefin and then introduce a nitrogen atom. In this case, the
Scheme 2. Summary of the synthesis of scyphostatin (1).
Results and Discussion
stereoselective epoxidation[14] of 14a with [VO
(acac)2]) and
A
TBHP proceeded well without any problems to give the
epoxy alcohol 16. However, the following Mitsunobu reac-
tion afforded a low yield of the desired azide 17 accompa-
Examination of the synthetic route to an epoxy cyclohexe-
none unit with an amino alcohol moiety: Herein, the studies
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Total Synthesis of Scyphostatin
FULL PAPER
Since the presence of the naked tertiary alcohol caused
unfavorable side reactions, as shown in Scheme 5 (a series),
we next examined a route using the triethylsilyl (TES) ether
14b, in which the tertiary alcohol was protected as a silyl
ether. Compound 14b was prepared from 10 almost in the
same procedure as 14a shown in Scheme 4. Thus, the depro-
tection of the acetal function and silylation of the tertiary al-
cohol of 11 by using our recently developed method,[15]
a
combination of TESOTf and 2,6-lutidine followed by a
work-up with water gave the TES ether aldehyde 12b in ex-
cellent yield. The subsequent nucleophilic addition of the
lithiated 13 gave the diastereomixture of 14b and 14b’. The
stereochemistries of the secondary alcohols were also deter-
mined by the modified Mosherꢁs method.[12] To our delight,
the ratio of the two alcohols 14b and 14b’ was reversed
compared to the ratio of 14a and 14a’, and the desired alco-
hol 14b was obtained as the major product. This outcome
shows that the silylation of the tertiary alcohol increases the
ratio of the desired alcohol.
Scheme 4. Syntheses of MPM ethers 14a and 14b. i) MeI, NaH, THF/
DMF (1:1), 08C; ii) HCO2H (10%), CH3CN (90% aq.), RT for 12a or
TESOTf, 2,6-lutidine, CH2Cl2, 08C for 12b; iii) MPMOCH2SnBu3 (13), n-
BuLi, THF, À788C. DMF=N,N-dimethylformamide, TESOTf=triethyl-
silyl trifluoromethanesulfonate.
Introduction of a nitrogen atom and its conversion are
shown in Scheme 6. The Mitsunobu reaction of 14b gave
the azide 19 in good yield. Formation of an undesirable al-
lylic azide, such as 15, was not observed. For examination of
the synthetic route available for the synthesis of 1, a benzoyl
group was introduced in place of the unsaturated fatty acid
side chain. The reduction of 19 using LiAlH4 followed by N-
acylation gave the benzoate 20. Deprotection of the MPM
and TES ethers gave the diol 21 in two steps. Protection of
the primary alcohol with a tert-butyldimethylsilyl (TBS),
tert-butyldiphenylsilyl (TBDPS), or acetyl (Ac) group, re-
spectively, and stereoselective epoxidation of each com-
pound gave the epoxy alcohols 22a–c. However, the reac-
tions to remove the hydrobenzoin unit of 22a–c caused sev-
eral side reactions, such as opening of the oxirane ring,
cleavage of the amide bond, deprotection of the primary al-
cohol, and so on, thus the yields of the desired compounds
23a–c were low. These results showed that the removal of
the hydrobenzoin unit is necessary at an early stage.
Scheme 5. Introduction of a nitrogen atom into 14a. i) DPPA, PPh3,
DEAD, THF, RT; ii) TBHP, [VO(acac)2], toluene, 08C; iii) DPPA, PPh3,
A
DEAD, THF, RT; iv) MsCl, Et3N, CH2Cl2, 08C; v) NaN3 or TMSN3.
DEAD=diethyl azodicarboxylate, DPPA=diphenylphosphorylazide,
Ms=methanesulfonyl, TBHP=tert-butylhydroperoxide, TMS=trimeth-
ylsilyl.
nied by the allylic azide 18,
which was obtained by b-elimi-
nation of the tertiary alcohol
17. In another trial using 14a
and 16, the selective mesyl-
A
followed by nucleophilic sub-
stitution resulted in low yields
of the mixture of the epimeric
azide isomers C and D to our
disappointment. Furthermore,
the reduction of the azide
group of 17 did not afford the
desired amino compound pos-
sibly as a result of the presence
of the tertiary alcohol.
Scheme 6. Introduction of a nitrogen atom into 14b. i) DPPA, PPh3, DEAD, THF, RT; ii) LiAlH4, THF, 08C;
iii) BzCl, Et3N, CH2Cl2, RT; iv) DDQ, CH2Cl2, RT; v) TBAF, THF, RT; vi) TBSCl, imidazole, DMF, RT for
22a; TBDPSCl, imidazole, DMF, RT for 22b; Ac2O, pyridine, RT for 22c; vii) TBHP, [VO
RT; viii) 1. [Pd
chloro-5,6-dicyano-1,4-benzoquinone, TBAF=tetra-n-butylammonium fluoride, TBDPSCl=tert-butyldiphe-
nylsilyl chloride, TBSCl=tert-butyldimethylsilyl chloride.
N
A
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H. Fujioka, Y. Kita et al.
Asymmetric total synthesis of 1; first generation: Based
on the results described above, we decided to remove the
hydrobenzoin unit before constructing the oxirane ring,
forming the amide bond, and deprotecting the primary alco-
hol. Since the epoxy cyclohexenone unit is considered to be
unstable, in other words, very reactive under various reac-
tion conditions, its construction was carried out at a late
stage of the total synthesis. Our first generation asymmetric
synthesis of 1 is shown in Scheme 7. Birch reduction of the
hydrobenzoin unit of 10, prepared from 1,4-cyclohexadiene
(7) in six steps (Scheme 2), gave the diol 24, which was
treated with TBSCl/imidazole to afford the hydroxy silyl
ether 25. Deprotection of the acetal function of 25 by our
recently developed method[15] gave the disilylated aldehyde
26a in high yield. Nucleophilic addition of 4-methoxyphe-
nylmethyloxymethyl lithium from the stannyl compound 13
to 26a gave the two alcohols (R)-27a and (S)-27a’ in a ratio
of 2.2:1 and 81% total yield. The stereochemistry of the two
alcohols was determined by the modified Mosherꢁs
method[12] (see the Experimental Section). The desired
R isomer 27a was converted into amine 29a through azide
28a by the Mitsunobu reaction[13] in 69% yield followed by
reduction using LiAlH4. Condensation of the amine 29a and
side chain acid 30, prepared by the method developed by
Hoye and Tennakoon,[5a] gave amide 31a, which was desilyl-
AHCTREUNG
AHCTREUNG
gave cis-epoxy alcohol 33a in 69% yield as a single isomer.
Oxidation of the secondary alcohol of 33a using TPAP/
NMO[16] gave the ketone 34a in 49% yield (88% based on
the consumed 33a). The treatment of 34a with LDA and
the reaction with N-tert-butylphenylsulfinimidoyl chloride
gave enone 35a in 37% yield (51% based on consumed
34a).[17] The addition of [15]crown-5 to the reaction mixture
improved the yield. Deprotection of the MPM ether to give
the alcohol was successfully done using trityl tetrafluorobo-
À
rate (Ph3C+BF4 ) to afford scyphostatin (1) in 32% yield,[18]
whereas CAN and DDQ, usually used for the deprotection
of the MPM ether,[19] gave a complex mixture as a result of
the reaction at the trienamide unit (the same results were
obtained in our model study of 35a with a trienamide unit,
as described later in Table 2). The spectroscopic data of syn-
thetic 1 are identical with those previously reported.[1a] As
stated above, our first generation synthesis of 1 was attained
in 18 steps from the commercially available 1,4-cyclohexa-
diene (7).
Studies of the improvements
of the first generation asym-
metric synthesis: In the first
generation asymmetric synthe-
sis described above, some steps
(i.e., the conversion of 24 into
26a and the low-yielding trans-
formation of 35a to 1) could
be improved by extending our
method and searching for
more
efficient
protecting
groups and deprotecting condi-
tions.
One-pot conversion of dihy-
droxy acetal 24 into disilyl al-
dehydes 26a–e: For the first
generation asymmetric synthe-
sis outlined above, the secon-
dary alcohol of 24 was protect-
ed as a TBS ether to give 25,
and then our deprotection
method using acetal groups af-
forded aldehyde 26a, both hy-
droxy groups of which were
protected as silyl ethers. Since
the second step of the reaction
mentioned above, that is, the
use of TESOTf/2,4,6-collidine
followed by a work-up with
water, uses reagents and condi-
tions employed for the silyl-
Scheme 7. First generation asymmetric total synthesis of scyphostatin (1). i) Ca, EtOH, liq. NH3, À408C;
ii) TBSCl, imidazole, DMF, RT; iii) TESOTf, 2,4,6-collidine, CH2Cl2, 08C, then H2O; iv) Bu3SnCH2OMPM
(13), nBuLi, THF, À788C; v) DPPA, PPh3, DEAD, CH2Cl2, RT; vi) LiAlH4, THF, RT; vii) 30, DCC, DMAP,
CH2Cl2, 08C; viii) TBAF, THF, 08C; ix) TBHP, [VO(acac)2], toluene, 08C; x) TPAP, NMO, CH2Cl2, 08C;
N
j) LDA, [15]crown-5, Ph(Cl)S=NtBu, THF, À788C; xii) Ph3C+BF4À, CH2Cl2, 08C. DCC=N,N’-dicyclohexylcar-
bodiimide, DMAP=dimethylaminopyridine, LDA=lithium diisopropylamide, NMO=N-methylmorpholine-
N-oxide, TPAP=tetra-n-propylammonium perruthenate.
A
next examined obtaining disilyl
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Total Synthesis of Scyphostatin
FULL PAPER
aldehyde 26 directly from 24 in one step by applying our
method. However, the treatment of 24 with TESOTf/2,4,6-
collidine gave the lactol derivative 36, in which the tertiary
alcohol was protected as a TES ether, in 63% yield
(Scheme 8). We already found that the addition of alcohols
to the pyridinium-type salt intermediates prepared by the
reaction of the acetal groups with the TESOTf/base combi-
nation gave mixed acetals in high yields.[15b]
TESOTf (2.0 equiv) was added to the resulting solution fol-
lowed by a work-up with water to give the bis(TES) ether
A
aldehyde 26b in 65% yield from a one-pot operation.
The results shown in Scheme 10 encouraged our efforts
toward the one-pot synthesis of the disilyl aldehyde, al-
though the yield of 26b was moderate. We then studied this
conversion in detail (Table 1). At first, the tert-butyldime-
Table 1. One-pot synthesis of disilyl aldehyde 26.[a]
Scheme 8. Treatment of 24 with TESOTf/2,4,6-collidine.
Entry
1
T
[8C]
Reagent (equiv)
R2
Product
Yield [%]
R1
R3
0
TBS (2)
TES (4)
26a
26c
26c
26a
26d
26e
TES
TBS
TBS
TES
TMS
TES
85
13
89
98
94
90
The formation of lactol 36 was rationalized by the intra-
molecular attack of the naked secondary alcohol on the
N,O-acetal carbon atom of the intermediate. This result sug-
gests that the secondary alcohol moiety must be protected
before deacetalization. For our deacetalization method, the
order of the addition of the reagents and substrates is very
important. When the silyl triflate, such as TESOTf or
TMSOTf, is added to the mixture of an acetal and 2,4,6-col-
lidine, we can obtain an aldehyde (Method A in
Scheme 9).[15] On the other hand, when an acetal is added to
2
3
4
5
0
À78
À78
0
TBS (4)
TBS (2)
TBS (2)
TIPS (2)
TES (2)
TES (4)
TMS (4)
TES (4)
[a] TIPS=triisopropylsilyl.
thylsilylation of the secondary alcohol of 24 was performed
with the proper amount of TBSOTf and an excess of 2,4,6-
collidine (8.0 equiv). Thereafter TESOTf or TMSOTf were
added to the reaction mixture and a work-up with water af-
forded disilyl aldehydes 26. The reactions in entries 1 and 2
were carried out at 08C. The use of 2.0 equivalents of
TBSOTf as the first silyl triflate and TESOTf as the second
silyl triflate gave the desired 26a along with bis(TBS) ether
G
26c (Table 1, entry 1). The use of more TBSOTf (4.0 equiv)
gave only 26c (Table 1, entry 2). We then studied the reac-
tion using 2.0 equivalents of TBSOTf and 4.0 equivalents of
TESOTf at À788C, which produced of 26a in 98% yield
(Table 1, entry 3). The reaction using TMSOTf instead of
TESOTf afforded the TMS ether 26d in 94% yield (Table 1,
entry 4). The use of triisopropylsilyl trifluoromethanesulfo-
nate (TIPSOTf) instead of TBSOTf at 08C gave TIPS ether
26e in 90% yield (Table 1, entry 5). Based on these results,
we developed a one-pot synthesis of different disilyl alde-
hydes 26a–e by controlling the amount of silyl triflate, the
order of the addition of the reagents, and the reaction tem-
perature.
Study of the protection and deprotection of the primary
alcohol: In the final step of the first generation asymmetric
synthesis, the conversion of 35a into 1 resulted in a low
yield (32%; Scheme 7). Especially, reagents such as DDQ
or CAN,[19] which are recognized as good reagents for the
deprotection of MPM ethers, resulted in decomposition of
the compound. We therefore examined the protecting group
and deprotection conditions for the primary alcohol of 1
using the MPM-type protecting group (Table 2). We used
Scheme 9. Reactivity of the silyl triflate/2,4,6-collidine combination.
the mixture of the silyl triflate and base, no deacetalization
is observed (Method B in Scheme 9). However, the combi-
nation of the silyl triflate and 2,4,6-collidine is employed for
the silylation of alcohols.[19] We then utilized this different
reactivity with 24 for the one-pot synthesis of disilyl alde-
hyde 26b (Scheme 10). Thus 24 was added to a solution of
TESOTf (4.0 equiv) and 2,4,6-collidine (8.0 equiv) in CH2Cl2
to give disilyl acetal 37 as an intermediate. Additional
Scheme 10. One-pot synthesis of disilyl aldehyde from dihydroxy acetal
24.
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H. Fujioka, Y. Kita et al.
Table 2. Examination of protecting group (PG) and deprotection condi-
tions.
asymmetric synthesis of 1 in a total
of 17 steps with a higher total yield
via 29b, which has TMS and
2,4DMPM protecting groups. As the
silyl group for the protection of the
tertiary alcohol, the TMS group was
chosen for the higher yield in every
Entry
PG
Reagent
Time
Yield [%]
step for the synthesis of 1 (compare Scheme 11 (second gen-
eration synthesis) to Scheme 7 (first generation synthesis)).
Aldehyde 26d was obtained from commercially available
1,4-cyclohexadiene (7) in eight steps (Schemes 3 and 7 and
Table 1, entry 4). Nucleophilic addition of the lithium re-
agent derived from the 2,4-dimethoxyphenylmethyloxymeth-
yl stannyl compound 40, which was easily prepared by using
the procedure developed by Still,[11] to the aldehyde 26d af-
forded alcohol (R)-27b in 56% yield accompanied by its ste-
reoisomeric alcohol (S)-27b’ in 36% yield. The stereochem-
istry of the two alcohols was determined by the modified
Mosherꢁs method[12] (see the Experimental Section). The
1
2
3
4
5
6
7
8
9
MPM
MPM
MPM
MPM
MPM
MPM
MPM
DDQ
5 min
5 min
5 min
5 min
6 h
2 h
3 h
2 h
<5 min
30 min
decomp
decomp
decomp
decomp
67
trace
56
9 0
DDQ[a]
CAN
[b]
MgBr·OEt2
Ph3C+BF4À
À
Ph3C+PF5
À
Ph3C+SnCl5
À
3,4DMPM
2,4DMPM
2,4DMPM
Ph3C+BF4À
Ph3C+BF4
HPF4
93
quant.
10
[a] NaHCO3 was added as an additive. [b] Me2S was added as an additive.
PG=protecting group.
trienamide alcohol 39 as
model compound that has an
amino alcohol unit with
highly reactive trienamide
component. Treatment of
MPM ether 38a with DDQ,
a
a
[20]
CAN, or MgBr2·OEt2
also
resulted in decomposition
(Table 2, entries 1–4). Howev-
er, the use of trityl tetrafluoro-
À
borate (Ph3C+BF4 )[18] gave
the desired product 39 in 67%
yield in 6 hours (Table 2,
entry 5). The other trityl re-
agent, trityl pentafluorophos-
À
phate (Ph3C+PF5 ) produced a
Scheme 11. Second generation asymmetric total synthesis of scyphostatin (1). i) 2,4DMPMOCH2SnBu3 (40);
nBuLi, THF, À788C (56%); ii) DPPA, PPh3, DEAD, THF, RT (75%); iii) LiAlH4, THF, 08C to RT; iv) 30,
trace amount of 39 (Table 2,
entry 6), whereas the trityl
pentachlorostannane (Ph3C+
DCC, DMAP, CH2Cl2, RT; v) TBAF, THF, RT (59% from azide 28b); vi) TBHP, [VO(acac)2], toluene, 08C
G
(73%); vii) DMP, CH2Cl2, 408C (69%, 78% based on the consumed 33b); viii) Ph(Cl)S=NtBu, LDA,
[15]crown-5, THF, À788C (35%, 82% based on the consumed 34b); ix) Ph3C+BF4À, CH2Cl2, 08C (66%).
À
SnCl5 ) afforded 39 in 56%
yield (Table 2, entry 7). The
use of the 3,4-dimethoxyphe-
À
nylmethyl (3,4DMPM) group and Ph3C+BF4 increased the
yield to 90% and shortened the reaction time to 2 hours
(Table 2, entry 8). The use of the 2,4-dimethoxyphenylmeth-
Mitsunobu reaction of 27b with DPPA[13] afforded azide(S)-
28b in 75% yield, which was reduced by LiAlH4 to afford
amino alcohol 29b. Condensation of the amino group of
29b with the side chain acid 30,[5a] followed by desilylation
gave dihydroxyamide 32b in 59% yield from azide 28b. The
stereo- and chemoselective epoxidation of 32b with [VO-
À
yl (2,4DMPM) group and Ph3C+BF4 gave better results:
<5 minutes and 93% yield of 39 (Table 2, entry 9). Al-
though HBF4 also afforded 39 in a quantitative yield, the
conditions were strongly acidic (Table 2, entry 10). We then
A
À
chose 2,4DMPM and Ph3C+BF4 for the most efficient total
which was oxidized using Dess–Martin periodinane
(DMP)[21] to afford epoxy ketone 34b in 69% yield (78%
based on consumed 33b). The treatment of 34b with LDA
and reaction with N-tert-butylphenylsulfinimidoyl chloride[17]
gave enone 35b in 35% yield (82% based on consumed
synthesis of 1.
Asymmetric total synthesis of 1: second generation: Since
the improvement of some of the drawbacks in the first gen-
eration asymmetric synthesis of 1 was carried out, we tried
to utilize these results and achieved the second generation
34b). Finally, deprotection of 2,4DMPM ether 35b was suc-
À[18]
cessfully carried out by Ph3C+BF4
to afford 1 in 66%
10230
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 10225 – 10238

Total Synthesis of Scyphostatin
FULL PAPER
ing mixture was allowed to warm to room temperature over 6 h with stir-
ring. After saturated NaHCO3 (aq.) was added, The reaction mixture was
extracted with Et2O. The organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel using hexane/EtOAc (15:1) as the eluent to
give 3 (0.27 g, 0.63 mmol, 64%) as a colorless oil. [a]2D4 =À156.0 (c=1.62,
yield. The spectroscopic data of synthetic 1 were identical
with those of the authentic compound.
Conclusion
CHCl3); IR (KBr): n˜ =3031, 1495, 1454, 1125 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d=2.01 (2H, dd, J=5.6, 6.3 Hz), 2.5–2.6 (1H, m), 2.8–3.0 (1H,
m), 3.29(3H, s), 3.3–3.5 (1H, m), 4.04 (1H, dd, J=5.3, 8.9Hz), 4.31 (1H,
dt, J=7.9, 5.9 Hz), 4.41 (1H, d, J=9.1 Hz), 4.47 (1H, d, J=9.1 Hz), 5.24
(1H, dd, J=5.0, 6.3 Hz), 5.5–5.7 (2H, m), 6.9–7.4 ppm (10H, m);
13C NMR (75 MHz, CDCl3): d=35.3, 35.4, 37.7, 47.7, 54.9, 81.9, 88.0,
88.5, 105.1, 124.4, 127.3, 127.4, 127.5, 127.7, 127.8, 129.1, 137.9,
138.1 ppm; FAB-MS m/z: 451 [M++Na]; HR-FAB-MS: calcd for
C23H25O3BrNa [M++Na]: 451.0885; found 451.0873.
The concise asymmetric total synthesis of scyphostatin (1)
was achieved from commercially available 1,4-cyclohexa-
diene in a total of 17 steps. The characteristic points of our
synthesis are that 1) the chiral acetal from the optically pure
hydrobenzoin works not only as a discrimination tool for
two olefins, a source of oxygen atoms, and a protecting
group for the alcohol unit, but also as the template for ste-
reoselective oxidation using SeO2;[8] 2) the silyl triflate/2,4,6-
collidine combination works not only for the deprotection
of the acetal, but also for the silylation of hydroxy functions
to give disilyl aldehyde compounds with different kinds of
silyl groups in a one-pot operation; 3) the use of the
2,4DMPM protecting group would be very useful for the syn-
theses of other unstable compounds; and 4) the asymmetric
centers are constructed step-by-step, which allows the syn-
theses of many stereoisomeric analogues.
(1R,3R,4R,6R,8S)-6-Methoxy-3,4-diphenyl-2,5-dioxabicyclo
A
9-ene (9): mixture of (0.91 g, 2.1 mmol), Bu3SnH (0.86 mL,
A
3
3.2 mmol), and a catalytic amount of azobisisobutyronitrile (AIBN) in
toluene (21 mL) was refluxed for 1 h under N2. After being cooled to
room temperature, saturated KF (aq.) was added to the mixture. The re-
action mixture was extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel using hexane/
EtOAc (10:1) as the eluent to give 9 (0.66 g, 1.9mmol, 89%) as colorless
crystals. M.p. 162–1648C (hexane/EtOAc); [a]2D6 =À101.2 (c=1.23,
1
CHCl3); IR (KBr): n˜ =3029, 1096, 994 cmÀ1; H NMR (300 MHz, CDCl3):
d=1.7–2.2 (6H, m), 3.2–3.3 (1H, m), 3.29(3H, s), 3.84 (1H, dt, J=4.5,
11.4 Hz), 4.42 (1H, d, J=9.0 Hz), 4.49 (1H, d, J=9.0 Hz), 5.39 (1H, dd,
J=5.1, 8.1 Hz), 5.63 (2H, d, J=2.7 Hz), 6.9–7.3 ppm (10H, m); 13C NMR
(75 MHz, CDCl3): d=24.6, 25.7, 35.4, 37.3, 54.8, 79.6, 87.4, 88.7, 105.3,
126.9, 127.3, 127.6, 127.7, 127.9, 129.1, 138.3, 139.5 ppm; elemental analy-
sis (%) calcd for C23H26O3: C 78.83, H 7.48; found: C 78.86, H 7.47.
Experimental Section
General: All melting points are uncorrected. 1H NMR spectra were re-
corded at 270 or 300 MHz and 13C NMR spectra were recorded at 67.8 or
75 MHz with CDCl3 as the solvent and SiMe4 as the internal standard. In-
frared (IR) absorption spectra (cmÀ1) were recorded as KBr pellets.
(1S,3R,5R,6R,8S)-3-Methoxy-5,6-diphenyl-4,7-dioxabicyclo[6.4.0]dodec-
E
11-en-1-ol (4): A mixture of 9 (71 mg, 0.202 mmol), pyridine (32.6 mL,
0.404 mmol), and SeO2 (11.4 mg, 0.102 mmol) in 1,4-dioxane (4 mL) was
stirred for 1 h at 808C under N2. After being cooled to room tempera-
ture, saturated NaHCO3 (aq.) was added to the mixture. The reaction
mixture was extracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4, and concentrated in vacuo. The residue was pu-
rified by column chromatography on silica gel using hexane/EtOAc (7:1)
as the eluent to give 4 (30.6 mg, 0.084 mmol, 41%) and recovered 9
1-(2,2-Diethoxyethyl)-2,5-cyclohexadiene (8): sec-BuLi (0.98m in n-
hexane/cyclohexane, 3.2 mL, 3.1 mmol) was added slowly to a stirred so-
lution of 7 (0.30 mL, 3.2 mmol) in THF (5 mL) at À788C under N2. After
being stirred for 5 min at the same temperature, TMEDA (0.50 mL,
3.3 mmol) was added. The resulting mixture was stirred for an additional
1 h. Bromoacetoaldehyde diethyl acetal (0.40 mL, 2.7 mmol) was added
to the reaction mixture. After being stirred for 2 h, the reaction mixture
was quenched by addition of saturated NaHCO3. The reaction mixture
was extracted with Et2O. The organic layer was washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel using hexane/Et2O (10:1) as the
eluent to give 8 (0.39g, 2.0 mmol, 75%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): d=1.17–1.25 (6H, m), 1.72 (2H, t, J=5.7 Hz), 2.61–
2.66 (2H, m), 2.83–2.94 (1H, m), 3.45–3.71 (4H, m), 4.65 (1H, t, J=
5.7 Hz), 5.65–5.74 ppm (4H, m).
(20.6 mg, 29%). 4: White crystals; M.p. 159–1628C (hexane); [a]D26
=
À34.3 (c=1.21, CHCl3); IR (KBr): n˜ =3438, 3033, 1096, 994 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=1.7–1.8 (1H, m), 1.9–2.0 (1H, m), 2.0–
2.2 (2H, m), 2.07 (1H, dd, J=7.2, 15.2 Hz), 2.44 (1H, dd, J=4.5,
15.2 Hz), 3.32 (3H, s), 4.08 (1H, dd, J=3.3, 10.8 Hz), 4.51 (1H, d, J=
9.0 Hz), 5.01 (1H, d, J=9.0 Hz), 5.47 (1H, m), 5.50 (1H, s), 5.73 (1H, dt,
J=3.5, 9.9 Hz), 6.9–7.3 ppm (10H, m); 13C NMR (75 MHz, CDCl3): d=
24.2, 27.3, 41.5, 55.0, 75.7, 84.0, 87.2, 89.0, 106.5, 127.1, 127.5, 127.6, 127.7,
127.9, 128.0, 128.1, 132.5, 137.3, 139.5 ppm; elemental analysis calcd (%)
for C23H26O4: C 75.38, H 7.15; found: C 75.43, H 7.12.
A
TsOH (0.1 mmol) was added slowly to a stirred solution of 8 (0.31 g,
1.6 mmol) and (R,R)-hydrobenzoin (0.34 g, 1.6 mmol) in toluene (10 mL)
under N2. The resulting mixture was stirred for 2 h at 708C. After being
cooled to room temperature, saturated NaHCO3 (aq.) was added to the
mixture. The reaction mixture was extracted with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by column chromatography on silica gel
using hexane/EtOAc (25:1) as the eluent to give 2 (0.51 g, 1.6 mmol,
100%) as a colorless oil. [a]D25 =+31.0 (c=1.00, CHCl3); IR (KBr): n˜ =
C
3022, 1605, 1497, 1456 cmÀ1 1H NMR (300 MHz, CDCl3): d=2.02 (2H,
;
dd, J=4.8, 6.7 Hz), 2.6–2.7 (2H, m), 3.1–3.2 (1H, m), 4.77 (2H, s), 5.63
(1H, t, J=4.8 Hz), 5.7–5.9(4H, m), 7.2–7.4 ppm (10H, m); elemental
analysis (%) calcd for C22H22O2: C 82.99, H 6.96; found: C 82.93, H 7.04.
(1R,3R,4R,6R,8R,12R)-12-Bromo-6-methoxy-3,4-diphenyl-2,5-
dioxabicyclo[6.4.0]dodec-9-ene (3): NBS (0.21 g, 1.2 mmol) was added
A
portionwise to a stirred solution of 2 (0.32 g, 1.0 mmol) and MeOH
(0.20 mL, 5.0 mmol) in CH3CN (10 mL) at À408C under N2. The result-
Chem. Eur. J. 2007, 13, 10225 – 10238
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10231

H. Fujioka, Y. Kita et al.
emental analysis (%) calcd for C24H30O5: C 72.34, H 7.59; found: C
72.39, H 7.61.
0.86–0.94 (15H, m), 1.29(6H, m), 1.49(6H, m), 3.71 (2H, s), 3.78 (3H,
s), 4.34 (2H, s), 6.86 (2H, d, J=8.7 Hz), 7.22 ppm (2H, d, J=8.7 Hz);
13C NMR (75 MHz, CDCl3): d=8.9, 13.7, 27.3, 29.1, 55.1, 61.0, 77.4,
113.5, 129.0, 130.9, 158.9 ppm.
A
1.23 mmol) was added to liquid NH3 (3.0 mL) at À788C under N2. The
reaction mixture was allowed to warm to À408C to give a clear-blue solu-
(2R)-1-[(1S,6S)-1-Triethylsiloxy-6-tert-butyldimethylsiloxycyclohex-2-en-
1-yl]-3-[(4-methoxyphenyl)methyloxy]propan-2-ol (27a) and (2S)-1-
[(1S,6S)-1-triethylsiloxy-6-tert-butyldimethylsiloxy cyclohex-2-en-1-yl]-3-
[(4-methoxyphenyl)methyloxy]propan-2-ol (27a’): nBuLi (1.56m in
hexane, 0.22 mL) was added dropwise to a solution of MPMOCH2SnBu3
(13; 155.4 mg, 0.352 mmol) in dry THF (1.0 mL) at À788C under N2.
After being stirred for 15 min, a solution of 26a (33.8 mg, 0.088 mmol) in
THF (1.0 mL) was added to the reaction mixture. After being stirred for
5 min, the reaction mixture was quenched with water and extracted with
EtOAc. The organic layer was washed with brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by column chroma-
tography using hexane/EtOAc (7:1) as the eluent to give 27a (26.4 mg,
56%) and 27a’ (12 mg, 25%).
tion.
A solution of 10 (49.0 mg, 0.123 mmol) and EtOH (0.06 mL,
1.23 mmol) in Et2O (0.5 mL) was added to dropwise to the blue solution
at À408C under N2. After being stirred for 30 min, the reaction mixture
was quenched with saturated NH4Cl (aq.) After NH3 was removed by
distillation at atmospheric pressure, The reaction mixture was extracted
with EtOAc. The organic layer was dried over Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography on silica
gel using hexane/EtOAc (1:2) as the eluent to give 24 (22.2 mg,
0.110 mmol, 91%) as a colorless oil. [a]2D8 =À28.3 (c=2.10, CHCl3): IR
(KBr): n˜ =3340, 1724, 1380, 1274 cmÀ1 1H NMR (300 MHz, CDCl3): d=
;
1.66–1.83 (2H, m), 1.92–2.04 (1H, m), 2.13–2.21 (3H, m), 3.36 (3H, s),
3.44 (3H, s), 3.54 (1H, s), 3.81 (1H, dd, J=3.9, 7.5 Hz), 3.85 (1H, s), 4.76
(1H, dd, J=3.9, 7.5 Hz), 5.51 (1H, dt, J=10.0, 2.1 Hz), 5.74 ppm (1H, dt,
J=10.0, 3.6 Hz); 13C NMR (75 MHz, CDCl3): d=22.7, 25.4, 38.2, 51.8,
53.6, 71.5, 72.4, 102.1, 127.9, 130.8 ppm; FAB-MS m/z: 225 [M++Na];
HR-FAB-MS: calcd for C10H18O4Na [M+ +Na]: 225.1103; found
225.1095.
27a: Colorless oil; [a]2D5 =+33.0 (c=1.25, CHCl3); IR (KBr): n˜ =3482,
2945, 1612, 1514, 1461 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.08 (3H,
;
s), 0.09(3H, s), 0.62 (6H, q, J=7.8 Hz), 0.83 (9H, s), 0.94 (9H, t, J=
7.8 Hz), 1.58–2.19(6H, m), 3.30–3.40 (2H, m), 3.80 (3H, s), 3.97 (1H, d,
J=5.4 Hz), 4.05 (1H, s), 4.11–4.20 (1H, m), 4.46 (1H, d, J=11.7 Hz),
4.53 (1H, d, J=11.7 Hz), 5.53 (1H, d, J=10.2 Hz), 5.78 (1H, dt, J=10.2,
3.6 Hz), 6.86 (2H, d, J=8.4 Hz), 7.26 ppm (2H, d, J=8.4 Hz); 13C NMR
(75 MHz, CDCl3): d=À4.9, À4.0, 6.6, 7.0, 17.9, 22.2, 25.7, 26.3, 40.8, 55.1,
67.3, 72.8, 74.5, 76.2, 113.5, 129.1, 129.8, 130.5, 131.0, 159.0 pm; elemental
analysis (%) calcd for C29H52O5Si2: C 64.88, H 9.76; found: C 64.74, H
9.79.
A
G
A
a
(30.4 mg, 0.154 mmol) in DMF (1.5 mL) at room temperature under N2,
and the mixture was stirred for 12 h. The reaction mixture was quenched
with addition of water and extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel using
hexane/EtOAc (7:1) as the eluent to give 25 (46 mg, 0.14 mmol, 98%) as
a colorless oil. [a]2D5 =À15.5 (c=1.29, CHCl3); IR (KBr): n˜ =3487, 2952,
27a’: Colorless oil; [a]2D6 =À12.5 (c=1.39, CHCl3); IR (KBr): n˜ =3482,
2931, 1612, 1514, 1463 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.11 (3H,
;
s), 0.14 (3H, s), 0.62 (6H, q, J=7.2 Hz), 0.91 (9H, s), 0.93 (9H, t, J=
7.2 Hz), 1.62–1.77 (3H, m), 1.98 (1H, dd, J=9.0, 14.7 Hz), 2.07–2.13 (2H,
m), 3.35–3.46 (2H, m), 3.80 (3H, s), 3.84 (1H, dd, J=4.2, 10.8 Hz), 4.11–
4.18 (1H, m), 4.18 (1H, s), 4.50 (2H, s), 5.62–5.64 (2H, m), 6.86 (2H, d,
J=8.7 Hz), 7.26 ppm (2H, d, J=8.7 Hz); 13C NMR (75 MHz, CDCl3):
d=À4.6, À4.4, 6.6, 6.8, 7.0, 7.1, 18.0, 24.5, 25.7, 25.8, 28.8, 41.8, 55.1, 66.0,
72.7, 74.5, 77.0, 113.5, 127.7, 129.1, 130.6, 133.0, 158.9 ppm; FAB-MS m/z:
559[ M++Na]; HR-FAB-MS: calcd for C29H52O5Si2Na [M++Na]:
559.3251; found 559.3265.
1471, 1253 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.10 (6H, s), 0.91 (9H,
;
s), 1.56–1.65 (1H, m), 1.77–1.84 (2H, m), 2.09–2.16 (3H, m), 3.35 (3H, s),
3.38 (3H, s), 3.64 (1H, s), 3.77 (1H, dd, J=3.3, 9.6 Hz), 4.78 (1H, dd, J=
5.2, 6.8 Hz), 5.52 (1H, dt, J=10.0, 1.8 Hz), 5.67 ppm (1H, dt, J=10.0,
3.3 Hz); 13C NMR (75 MHz, CDCl3): d=À4.8, 18.0, 23.5, 27.6, 37.7, 52.2,
53.0, 71.9, 74.7, 102.3, 127.6, 131.2 ppm; elemental analysis (%) calcd for
C16H32O4Si: C 60.72, H 10.19; found: C 60.64, H 10.00.
ACHTREUNG
Determination of the absolute configurations of the secondary alcohols
of 27a and 27a’: The absolute configurations of the secondary alcohols of
27a and 27a’ were determined by a modified Mosherꢁs method.[12]
a
0.0787 mmol) in dry CH2Cl2 (0.78 mL) at 08C under N2. After being
stirred at the same temperature for 5 min, the reaction mixture was
quenched with water and extracted with CH2Cl2. The organic layer was
washed with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography using hexane/EtOAc
(25:1) as the eluent to give 26a (28.1 mg, 0.073 mmol, 93%) as a color-
less oil. [a]2D5 =+36.9( c=1.60, CHCl3); IR (KBr): n˜ =2954, 1720, 1461,
1253 cmÀ1; H NMR (300 MHz, CDCl3): d=0.08 (6H, s), 0.62 (6H, q, J=
1
7.8 Hz), 0.88 (9H, s), 0.94 (9H, t, J=7.8 Hz), 1.54–1.64 (1H, m), 1.82–
1.92 (1H, m), 2.03–2.19 (2H, m), 2.31 (1H, dd, J=2.7, 15.9Hz), 2.63
(1H, dd, J=3.2, 15.9Hz), 3.89 (1H, dd, J=2.0, 14.5 Hz), 5.57 (1H, dt,
J=10.0, 1.8 Hz), 5.76 (1H, dt, J=10.0, 3.6 Hz), 9.82 ppm (1H, dd, J=2.7,
3.2 Hz); 13C NMR (75 MHz, CDCl3): d=À4.0, 7.2, 18.0, 23.1, 25.9, 28.2,
51.4, 75.8, 129.5, 130.9, 202.6; elemental analysis (%) calcd for
C20H40O3Si2: C 62.44, H 10.48; found: C 62.55, H 10.38 ppm.
Preparation of MPMOCH2SnBu3 (13):[11] A mixture of 4-methoxybenzyl
alcohol (3.8 mL, 30.4 mmol) and NaH (1.4 g, 60% in oil, 35.1 mmol) in
THF (120 mL) was stirred at room temperature under N2. After being
stirred for 1 h,
a solution of tri-n-butylstannylmethyl iodide (10.1 g,
23.4 mL) in THF (30 mL) was added slowly to the solution. The resulting
mixture was stirred for three days. The reaction mixture was quenched
by addition of MeOH. The solution was diluted with Et2O. The organic
layer was washed with water two times. The organic layer was dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography on silica gel using hexane/Et2O (30:1) as the eluent to
give 13 (8.8 g, 85%) as a colorless oil. 1H NMR (300 MHz, CDCl3): d=
General procedure for the preparation of an MTPA ester: DCC
(3.3 mmol),
a-methoxy-a-(trifluoromethyl)phenylacetyl
chloride
(MTPACl) (4.3 mmol), and DMAP (3.3 mmol) were added successively
to a stirred solution of secondary alcohol 27a or 27a’ (1.0 mmol) in
10232
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 10225 – 10238

Total Synthesis of Scyphostatin
FULL PAPER
CH2Cl2 (10.0 mL) at room temperature. After being stirred for 30 min,
the solvent was removed in vacuo. The residue was purified by column
chromatography using hexane/EtOAc (20:1) as the eluent.
(c=0.77, CHCl3); IR (KBr): n˜ =2952, 2104, 1612, 1514, 1461 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=0.08 (3H, s), 0.11 (3H, s), 0.58 (6H, q,
J=7.8 Hz), 0.88 (9H, s), 0.92 (9H, t, J=7.8 Hz), 1.50–1.65 (3H, m), 1.84–
1.92 (3H, m), 1.98–2.12 (1H, m), 3.41 (1H, dd, J=8.4, 9.9 Hz), 3.66 (1H,
dd, J=3.3, 9.9 Hz), 3.81 (3H, s), 3.86 (1H, dd, J=2.8, 8.4 Hz), 4.42 (2H,
s), 5.48 (1H, d, J=10.1 Hz), 5.74 (1H, dt, J=10.1, 3.7 Hz), 6.88 (2H, d,
J=8.6 Hz), 7.28 ppm (2H, d, J=8.6 Hz); 13C NMR (75 MHz, CDCl3):
d=À4.1, À4.0, 6.9, 7.0, 14.1, 18.0, 22.5, 25.8, 27.2, 38.9, 55.1, 58.2, 72.7,
73.6, 74.0, 74.5, 113.6, 113.7, 128.9, 129.0, 129.2, 129.6, 130.1, 131.3,
159.1 ppm; FAB-MS m/z: 584 (M+ +Na); HR-FAB-MS: calcd for
C29H51N3O4Si2Na [M++Na]: 584.3316; found 584.3322.
(2R)-1-[(1S,6S)-1-Triethylsiloxy-6-tert-butyldimethylsiloxycyclohex-2-en-
1-yl]-3-[(4-methoxyphenyl)methyloxy]propan-2-
yl (2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropa-
noate (27a; (S)-MTPA): Colorless oil; 1H NMR
(300 MHz, CDCl3): d=0.07 (6H, s), 0.62 (6H, q,
J=7.8 Hz), 0.87 (9H, s), 0.94 (9H, t, J=7.8 Hz),
1.37–2.08 (5H, m), 2.15 (1H, dd, J=4.8,
15.0 Hz), 3.44 (1H, d, J=10.8 Hz), 3.49(3H, s),
3.56 (1H, dd, J=2.1, 10.8 Hz), 3.76 (1H, dd, J=
3.6, 11.1 Hz), 3.80 (3H, s), 3.99–4.07 (1H, m),
4.32 (1H, d, J=11.4 Hz), 4.41 (1H, d, J=
11.4 Hz), 5.62 (1H, d, J=10.0 Hz), 5.69(1H, d, J=10.0 Hz), 6.83 (2H, d,
J=8.4 Hz), 7.16 (2H, d, J=8.4 Hz), 7.27–7.35 (3H, m), 7.57 ppm (2H, d,
J=7.5 Hz).
A
(8R,10S,14R)-8,10,12,14-(tetramethyl)hexadeca-2,4,6,12-tetraenoylami-
no]propyl}-2-cyclohexene-1,6-diol (32a): A solution of 28a (138.8 mg,
0.247 mmol) in dry THF (2.4 mL) was added to a solution of LiAlH4
(93.7 mg, 2.47 mmol) in THF (2.4 mL) at 08C under Ar. After being
stirred for 1.5 h at room temperature, the reaction mixture was quenched
with water and 15% NaOH (aq.), then the precipitate was filtered
through a Celite pad. The filtrate was evaporated in vacuo to give crude
29a. Side-chain carboxylic acid 30 (86.0 mg, 0.296 mmol), DCC
(203.9 mg, 0.988 mmol), and DMAP (120.7 mg, 0.988 mmol) were added
to a solution of crude 29a in CH2Cl2 (2.5 mL) at room temperature
under Ar. After being stirred for 1 h, the reaction mixture was quenched
with water and extracted with CH2Cl2. The organic layer was washed
with brine, dried over Na2SO4, and evaporated in vacuo to give crude
coupled product 31a. TBAF (2.47 mL, 1.0m in THF, 2.47 mmol) was
added to crude 31a in THF (1.2 mL) at room temperature under Ar.
After being stirred at room temperature for 10 h, the reaction mixture
was quenched with water and extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, and evaporated in vacuo. The
residue was purified by column chromatography using hexane/EtOAc
(2R)-1-{(1S,6S)-1-Triethylsiloxy-6-[tert-butyldimethylsiloxycyclohex-2-en-
1-yl]}-3-[(4-methoxyphenyl)methyloxy]propan-2-yl (2R)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate (27a; (R)-MTPA): Colorless oil; 1H NMR
(300 MHz, CDCl3): d=0.05 (6H, s), 0.61 (6H, q,
J=7.8 Hz), 0.85 (9H, s), 0.94 (9H, t, J=7.8 Hz),
1.42–1.72 (3H, m), 1.96–2.00 (2H, m), 2.11 (1H,
dd, J=5.1, 15.3 Hz), 3.52 (1H, d, J=10.8 Hz),
3.56 (3H, s), 3.65 (1H, dd, J=2.7, 11.0 Hz), 3.72
(1H, dd, J=3.6, 11.0 Hz), 3.81 (3H, s), 4.41 (1H,
d, J=11.4 Hz), 4.53 (1H, d, J=11.4 Hz), 5.44
(1H, dt, J=10.2, 3.0 Hz), 5.58 (1H, d, J=
10.2 Hz), 5.63–5.73 (1H, m), 6.85 (2H, d, J=
8.7 Hz), 7.23 (2H, d, J=8.7 Hz), 7.28–7.37 (3H,
m), 7.59ppm (2H, d, J=7.5 Hz).
(1:2) as the eluent to give 32a (97.6 mg, 66%) as a yellow oil. [a]D24
+3.13 (c=1.53, CHCl3); IR (KBr): n˜ =3307, 2923, 1651, 1608, 1514,
1456 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.79(3H, d, J=6.4 Hz), 0.84
=
(2S)-1-{(1S,6S)-1-Triethylsiloxy-6-[tert-butyldimethylsiloxycyclohex-2-en-
1-yl]}-3-[(4-methoxyphenyl)methyloxy]propan-2-yl (2S)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate (27a’; (S)-MTPA):
Colorless oil; 1H NMR (300 MHz, CDCl3): d=
0.04 (3H, s), 0.07 (3H, s), 0.57 (6H, q, J=
7.8 Hz), 0.85 (9H, s), 0.91 (9H, t, J=7.8 Hz),
1.50–1.98 (5H, m), 2.03 (1H, dd, J=4.5,
10.5 Hz), 3.52–3.54 (1H, m), 3.55 (3H, s), 3.70
(1H, dd, J=3.6, 9.6 Hz), 3.79 (1H, dd, J=2.4,
11.4 Hz), 3.80 (3H, s), 4.38 (1H, d, J=11.4 Hz),
4.52 (1H, d, J=11.4 Hz), 5.40 (1H, d, J=
10.0 Hz), 5.61 (1H, dt, J=10.0, 3.6 Hz), 5.70–
5.75 (1H, m), 6.84 (2H, d, J=8.7 Hz), 7.22 (2H, d, J=8.7 Hz), 7.27–7.41
(3H, m), 7.59ppm (2H, d, J=7.2 Hz).
;
(3H, t, J=7.3 Hz), 0.90 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz), 1.03
(1H, m), 1.16–1.34 (3H, m), 1.52 (3H, d, J=1.3 Hz), 1.55 (1H, m), 1.72–
1.80 (2H, m), 1.83–1.92 (3H, m), 1.98–2.09 (2H, m), 2.17 (1H, m), 2.23
(1H, m), 2.32 (1H, m), 3.60 (1H, d, J=4.2 Hz), 3.81 (3H, s), 3.92 (1H,
dd, J=2.9, 8.3 Hz), 4.26 (1H, m), 4.42 (1H, d, J=11.5 Hz), 4.50 (1H, d,
J=11.5 Hz), 4.84 (1H, d, J=9.4 Hz), 5.51 (1H, d, J=10.0 Hz), 5.67–5.72
(2H, m), 5.76 (1H, d, J=14.9Hz), 6.07 (1H, dd, J=10.9, 14.9 Hz), 6.16
(1H, dd, J=11.4, 14.7 Hz), 6.27 (1H, d, J=6.0 Hz), 6.48 (1H, dd, J=
10.9, 14.7 Hz), 6.89 (2H, d, J=9.0 Hz), 7.22 (1H, dd, J=11.4, 14.9Hz),
7.26 ppm (2H, d, J=9.0 Hz); 13C NMR (125 MHz, CDCl3): d=12.1, 16.2,
19.5, 21.1, 21.4, 22.9, 25.7, 28.3, 30.6, 34.1, 34.9, 39.1, 44.0, 45.9, 48.3, 55.3,
72.0, 72.3, 72.6, 72.9, 113.9, 121.9, 127.7, 128.3, 129.2, 129.6, 129.8, 131.3,
132.1, 133.1, 140.7, 141.9, 145.7, 159.4, 166.9 ppm; FAB-MS m/z: 59 4 [M+
+H]; HR-FAB-MS: calcd for C37H56NO5 [M++H]: 594.4158; found
594.4153.
(2S)-1-{(1S,6S)-1-Triethylsiloxy-6-[tert-butyldimethylsiloxycyclohex-2-en-
1-yl]}-3-[(4-methoxyphenyl)methyloxy]propan-2-yl (2R)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate (27a’; (R)-MTPA):
Colorless oil; 1H NMR (300 MHz, CDCl3): d=
0.07 (3H, s), 0.09(3H, s), 0.58 (6H, q, J=
7.5 Hz), 0.86 (9H, s), 0.91 (9H, t, J=7.5 Hz),
1.53–1.94 (5H, m), 2.09 (1H, dd, J=4.2,
14.4 Hz), 3.45 (1H, dd, J=8.1, 11.4 Hz), 3.51
(3H, s), 3.72 (1H, dd, J=2.4, 11.4 Hz), 3.78 (3H,
s), 3.84 (1H, dd, J=3.3, 9.6 Hz), 4.31 (1H, d, J=
11.7 Hz), 4.42 (1H, d, J=11.7 Hz), 5.49(1H, d,
(1R,2S,3S,6S)-1,6-Dihydroxy-2,3-epoxy-1-{(2S)-3-[(4-methoxyphenyl)me-
thyloxy]-2-[(2E,4E,6E,12E)-(8R,10S,14R)-8,10,12,14-(tetramethyl)hexa-
deca-2,4,6,12-tetraenoylamino]propyl}cyclohexane (33a): A solution of
aqueous TBHP (18 mL, 0.147 mmol) in toluene (0.2 mL) was dried with
molecular sieves (4 Š) at room temperature under Ar. After being
stirred for 20 min, a solution of 32a (8.7 mg, 0.0147 mmol) and [VO-
A
above mixture at 08C. After being stirred for 30 min, the reaction mix-
ture was quenched with saturated Na2S2O3 (aq.) and extracted with Et2O.
The organic layer was washed with brine, dried over Na2SO4, and evapo-
rated in vacuo. The residue was purified by column chromatography
using hexane/EtOAc (3:2) as the eluent to give 33a (6.1 mg, 69%) as a
yellow oil. [a]2D4 =+10.2 (c=1.10, CHCl3); IR (KBr): n˜ =3305, 2956,
J=10.2 Hz), 5.67 (1H, dt, J=10.2, 3.9Hz), 5.71–
5.77 (1H, m), 6.82 (2H, d, J=8.7 Hz), 7.16 (2H, d, J=8.7 Hz), 7.25–7.42
(3H, m), 7.56 ppm (2H, d, J=7.5 Hz).
(2S)-2-Azido-1-{(1S,6S)-1-triethylsiloxy-6-[tert-butyldimethylsiloxycyclo-
hex-2-en-1-yl]}-3-[(4-methoxyphenyl)methyloxy]propane (28a): PPh3
(194.0 mg, 0.738 mmol), DEAD (0.33 mL; 40% in toluene, 0.738 mmol),
and DPPA (95 mL, 0.442 mmol) were added successively to a stirred solu-
tion of 27a (207.4 mg, 0.369mmol) in THF (3.7 mL) at room tempera-
ture under Ar. The reaction mixture was stirred at the same temperature
for 30 min. After removal of the solvent in vacuo, the residue was puri-
fied by column chromatography using hexane/EtOAc (20:1) as the eluent
to give 28a (138.8 mg, 0.247 mmol, 67%) as a colorless oil. [a]2D5 =+19.7
1651, 1606, 1514, 1454 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.79(3H,
;
d, J=6.6 Hz), 0.83 (3H, t, J=7.1 Hz), 0.90 (3H, d, J=6.8 Hz), 0.99 (3H,
d, J=6.6 Hz), 1.12–1.32 (4H, m), 1.52 (3H, s), 1.53–1.67 (4H, m), 1.71–
1.78 (1H, m), 1.84–2.08 (4H, m), 2.23 (1H, m), 2.33 (1H, m), 2.81 (1H,
d, J=3.5 Hz), 3.40 (1H, d, J=3.5 Hz), 3.72–3.81 (3H, m), 3.82 (3H, s),
4.21 (1H, m), 4.50 (2H, s), 4.83 (1H, d, J=9.3 Hz), 5.70 (1H, dd, J=8.4,
14.7 Hz), 5.74 (1H, d, J=14.8 Hz), 6.08 (1H, dd, J=10.8, 14.7 Hz), 6.16
Chem. Eur. J. 2007, 13, 10225 – 10238
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10233

H. Fujioka, Y. Kita et al.
(1H, dd, J=11.4, 14.6 Hz), 6.23 (1H, d, J=6.5 Hz), 6.47 (1H, dd, J=
10.8, 14.6 Hz), 6.90 (2H, d, J=8.6 Hz), 7.22 (1H, dd, J=11.4, 14.8 Hz),
7.28 ppm (2H, d, J=8.6 Hz); 13C NMR (125 MHz, CDCl3): d=12.1, 15.9,
18.6, 19.9, 21.1, 21.4, 28.3, 30.5, 32.3, 34.1, 34.9, 38.4, 43.9, 46.1, 48.2, 55.3,
56.1, 57.8, 67.0, 69.9, 71.4, 73.0, 113.9, 121.6, 127.6, 128.3, 129.6, 129.9,
132.1, 133.1, 140.8, 142.2, 145.9, 159.6, 166.9 ppm; FAB-MS m/z: 610 [M+
+H]; HR-FAB-MS: calcd for C37H56NO6 [M++H]: 610.4108; found
610.4092.
ACHTREUNG
À
no]propyl}-2-cyclohexen-1-one (scyphostatin (1)): Ph3C+BF4 (6.6 mg,
0.0200 mmol) was added to a solution of 35a (10.1 mg, 0.0167 mmol) in
CH2Cl2 (0.2 mL) at 08C under Ar. After being stirred for 5 min, the reac-
tion mixture was quenched with saturated NaHCO3 (aq.) and extracted
with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by column
chromatography using EtOAc/acetone (4:1) as the eluent to give scy-
phostatin (1) (2.67 mg, 32%) as a yellow oil. [a]2D5 =+60.5 (c=0.20,
MeOH); IR (KBr): n˜ =3292, 2956, 2923, 1697, 1651, 1606, 1512,
ACHTREUNG
ACHTREUNG
2,4,6,12-tetraenoylamino]propyl}cyclohexan-1-one (34a): TPAP (1.1 mg,
0,0030 mmol) and NMO (4.6 mL, 0.0224 mmol) were added to a stirred
solution of 33a (9.1 mg, 0.0149 mmol) in CH2Cl2 (0.15 mL) at 08C under
Ar. After being stirred for 30 min, the reaction mixture was quenched
with saturated NaHCO3 (aq.) and extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, and evaporated in
vacuo. The residue was purified by column chromatography using
hexane/EtOAc (1:1) as the eluent to give 34a (4.4 mg, 49%) as a yellow
oil, and the substrate 33a (4.0 mg, 44%) was recovered. [a]2D6 =À7.5 (c=
1.04, CHCl3); IR (KBr): n˜ =3290, 2923, 1722, 1651, 1610, 1514,
1454 cmÀ1 1H NMR (500 MHz, CD3OD): d=0.83–0.86 (6H, m), 0.91
;
(3H, d, J=6.7 Hz), 1.00 (3H, d, J=6.8 Hz), 1.04 (1H, m), 1.19(1H, m),
1.27–1.41 (2H, m), 1.54 (3H, s), 1.58 (1H, m), 1.78 (1H, m), 1.86 (1H,
m), 1.88 (1H, m), 2.08 (1H, dd, J=3.7, 14.7 Hz), 2.27 (1H, m), 2.35 (1H,
m), 3.46 (1H, dd, J=5.5, 11.0 Hz), 3.52 (1H, dd, J=4.9, 11.0 Hz), 3.59
(1H, m), 3.66 (1H, d, J=3.7 Hz), 4.04 (1H, m), 4.86 (1H, m), 5.71 (1H,
m), 5.89(1H, d, J=15.3 Hz), 6.07 (1H, dd, J=1.3, 9.8 Hz), 6.15 (1H, dd,
J=11.6, 14.6 Hz), 6.26 (1H, dd, J=11.0, 15.3 Hz), 6.54 (1H, dd, J=11.0,
14.6 Hz), 7.09–7.18 ppm (2H, m); 13C NMR (125 MHz, CD3OD): d=
12.9, 16.9, 20.5, 22.0, 22.5, 30.1, 32.2, 36.0, 36.7, 40.3, 46.0, 48.5, 49.8, 50.1,
58.8, 65.9, 78.0, 124.2, 129.9, 130.4, 132.6, 134.5, 134.7, 141.8, 142.9, 146.4,
146.8, 169.0, 200.4 ppm; FAB-MS m/z: 486 [M++H]; HR-FAB-MS: calcd
for C29H44NO5 [M++H]: 486.3219; found 486.3199. The 1H and 13C NMR,
IR, and HR-FAB-MS spectra showed good agreement with those of au-
thentic sample (see the Acknowledgements).
1
1461 cmÀ1; H NMR (300 MHz, CDCl3): d=0.77–0.86 (6H, m), 0.90 (3H,
d, J=6.8 Hz), 0.99 (3H, d, J=6.3 Hz), 1.10–1.40 (4H, m), 1.52 (3H, s),
1.55 (1H, m), 1.76 (1H, m), 1.87 (1H, m), 2.14 (1H, d, J=2.9Hz), 2.16
(1H, d, J=2.9Hz), 2.21 (1H, m), 2.30–2.46 (4H, m), 2.79(1H, m), 3.36
(1H, d, J=4.1 Hz), 3.39(1H, m), 3.45 (1H, dd, J=5.3, 9.4 Hz), 3.65 (1H,
dd, J=4.4, 9.4 Hz), 3.81 (3H, s), 4.06 (1H, m), 4.13 (1H, brs), 4.38 (1H,
d, J=11.2 Hz), 4.43 (1H, d, J=11.2 Hz), 4.84 (1H, d, J=9.8 Hz), 5.69
(1H, dd, J=8.5, 15.2 Hz), 5.71 (1H, d, J=14.9Hz), 6.06 (1H, d, J=
8.5 Hz), 6.08 (1H, dd, J=11.0, 15.2 Hz), 6.16 (1H, dd, J=11.2, 14.9Hz),
6.48 (1H, dd, J=11.0, 14.9Hz), 6.78 (2H, d, J=8.5 Hz), 7.19(1H, dd,
J=11.2, 14.9Hz), 7.24 ppm (2H, d, J=8.5 Hz); 13C NMR (125 MHz,
CDCl3): d=12.1, 16.2, 19.5, 21.1, 22.3, 24.9, 25.6, 28.3, 29.7, 30.5, 31.6,
33.9, 35.1, 46.3, 49.2, 53.0, 60.7, 70.9, 72.9, 77.8, 113.9, 122.2, 127.7, 128.3,
129.6, 129.9, 132.1, 133.1, 140.5, 141.6, 145.6, 159.4, 166.1, 209.9 ppm;
FAB-MS m/z: 608 [M++H]; HR-FAB-MS: calcd for C37H54NO6 [M+
+H]: 608.3951; found 608.3937.
Experiment in Scheme 8: 2,4,6-Collidine (0.18 mL, 1.38 mmol) and
TESOTf (0.21 mL, 0.920 mmol) were successively added to a solution of
24 (46.1 mg, 0.230 mmol) in dry CH2Cl2 (2.3 mL) at 08C under N2. After
being stirred at the same temperature for 5 min, the reaction mixture was
quenched with water and extracted with CH2Cl2. The organic layer was
washed with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography using hexane/EtOAc
(25:1) as the eluent to give 36 (41.1 mg, 0.146 mmol, 63%) as a colorless
oil. [a]2D2 =+136.5 (c=0.64, CHCl3); IR (KBr): n˜ =2875, 1445, 1238 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=0.57 (6H, q, J=7.9Hz), 0.93 (9H, t, J=
7.9Hz), 1.80–1.88 (2H, m), 1.95–2.12 (3H, m), 2.33–2.48 (1H, m), 3.35
(3H, s), 4.04 (1H, t, 5.4 Hz), 5.09(1H, dd, J=3.2, 6.3 Hz), 5.70–5.83 ppm
(2H, m); 13C NMR (75 MHz, CDCl3): d=6.4, 6.9, 21.2, 26.1, 47.8, 55.4,
77.2, 83.4, 104.7, 128.2, 130.6 ppm; FAB-MS m/z: 307 [M++Na]; HR-
FAB-MS: calcd for C15H28O3SiNa [M++Na]: 307.1701; found 307.1736.
ACHTREUNG
ACHTREUNG
2,4,6,12-tetraenoylamino]propyl}2-cyclohexen-1-one (35a): LDA in THF
(0.25m) was prepared as follows: nBuLi (1.56m in hexane, 0.78 mL) was
added to a solution of diisopropylamine (70.3 mL, 0.5 mmol) in dry THF
(1.15 mL) at À788C for 30 min under Ar. LDA (0.25m in THF, 0.10 mL)
and [15]crown-5 (20 mL, 0.10 mmol) were added to a solution of 34a
(6.1 mg, 0.010 mmol) in THF (0.1 mL) at À788C under Ar. After being
stirred for 10 min, a solution of N-tert-butylbenzenesulfinimidoyl chloride
(22.0 mg, 0.10 mmol) in THF (0.1 mL) was added to the reaction mixture.
After being stirred for 30 min, the reaction mixture was quenched with
water and extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue was puri-
fied by column chromatography using Et2O as the eluent to give 35a
(2.3 mg, 0.0037 mmol, 38%) as a yellow oil, and the substrate 34a
(1.6 mg, 26%) was recovered. [a]2D5 =+22.3 (c=0.32, CHCl3); IR (KBr):
General procedure for the one-pot synthesis of disilyl aldehydes: Silyl tri-
flate (R1OTf) was added to a solution of 2,4,6-collidine in dry CH2Cl2 at
0 or À788C under N2. After being stirred at the same temperature for
30 min, a solution of 24 in dry CH2Cl2 was added to the reaction mixture
at the same temperature. After being stirred at the same temperature for
5–10 min, silyl triflate (R2OTf) was added to the reaction mixture at the
same temperature. After being stirred at the same temperature for 5 min,
the reaction mixture was quenched with water and extracted with
CH2Cl2. The organic layer was washed with brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by column chroma-
tography using hexane/EtOAc (25:1) as the eluent to give 26 in the yield
shown in Table 1.
n˜ =3320, 2922, 1693, 1651, 1612, 1514, 1454 cmÀ1 1H NMR (500 MHz,
;
AHCTREUNG
CDCl3): d=0.71–0.91 (9H, m), 0.99 (3H, d, J=7.0 Hz), 1.20–1.30 (4H,
m), 1.52 (3H, s), 1.55 (1H, m), 1.85–2.05 (4H, m), 2.20 (1H, m), 2.31
(1H, m), 3.46 (1H, dd, J=4.0, 9.0 Hz), 3.53 (1H, m), 3.58 (1H, dd, J=
3.5, 9.0 Hz), 3.69 (1H, d, J=4.0 Hz), 3.81 (3H, s), 4.14 (1H, brs), 4.22
(1H, m), 4.42 (2H, s), 4.84 (1H, d, J=9.0 Hz), 5.69 (1H, m) 5.70 (1H, d,
J=15.0 Hz), 5.91 (1H, d, J=8.7 Hz), 6.08 (1H, dd, J=11.0, 15.5 Hz),
6.16 (1H, dd, J=10.5, 14.0 Hz), 6.17 (1H, d, J=10.5 Hz), 6.48 (1H, dd,
J=11.0, 14.0 Hz), 6.88 (2H, d, J=8.7 Hz), 7.08 (1H, dd, J=3.5, 8.7 Hz),
7.22 (1H, m), 7.23 ppm (2H, d, J=8.7 Hz); 13C NMR (125 MHz, CDCl3):
d=11.9, 14.0, 15.9, 21.0, 22.6, 28.2, 29.2, 29.7, 32.1, 33.5, 34.9, 38.3, 44.9,
47.1, 55.3, 58.9, 65.5, 71.4, 72.9, 106.8, 109.1, 113.9, 121.8, 127.2, 128.0,
128.5, 129.5, 130.3, 132.9, 140.0, 141.9, 143.9, 158.9, 165.6, 197.3 ppm;
FAB-MS m/z: 606 [M++H]; HR-FAB-MS: calcd for C37H52NO6 [M+
+H]: 606.3795; found 606.3796.
;
0.94 (9H, t, J=7.9Hz), 0.95 (9H, t, J=7.9Hz), 1.57–1.67 (1H, m), 1.84–
1.94 (1H, m), 1.99–2.19 (2H, m), 2.33 (1H, dd, J=2.4, 15.9Hz), 2.59
(1H, dd, J=3.0, 15.9Hz), 3.90 (1H, dd, J=3.2, 9.2 Hz), 5.59 (1H, dt, J=
10.1, 1.8 Hz), 5.78 (1H, dt, J=10.1, 3.6 Hz), 9.79 ppm (1H, t, J=3.0 Hz);
13C NMR (75 MHz, CDCl3): d=4.9, 6.7, 6.8, 7.1, 23.1, 28.3, 51.7, 75.5,
75.7, 129.6, 131.0, 202.3 ppm; FAB-MS m/z: 407 [M++Na]; HR-FAB-
MS: calcd for C20H40O3Si2Na [M++Na]: 407.2414; found 407.2433.
(1S,6S)-1,6-Di(tert-butyldimethylsiloxy)cyclohex-2-en-1-yl acetaldehyde
(26c): Colorless oil; [a]2D5 =+64.4 (c=0.70, CHCl3); IR (KBr): n˜ =2955,
1717, 1471, 1256 cmÀ1; H NMR (300 MHz, CDCl3): d=0.07 (3H, s), 0.08
1
(3H, s), 0.09(3H, s), 0.11 (3H, s), 0.86 (18H, s), 1.58–1.69(1H, m), 1.89–
2.06 (2H, m), 2.12–2.21 (1H, m), 2.35 (1H, dd, J=2.7, 15.9Hz), 2.67
10234
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Chem. Eur. J. 2007, 13, 10225 – 10238

Total Synthesis of Scyphostatin
FULL PAPER
(1H, dd, J=2.7, 15.9Hz), 3.92 (1H, dd, J=2.4, 7.5 Hz), 5.56 (1H, d, J=
10.1 Hz), 5.83 (1H, dt, J=10.1, 3.6 Hz), 9.83 ppm (1H, t, J=2.7 Hz);
13C NMR (75 MHz, CDCl3): d=À4.7, À4.2, À2.3, À1.9, 18.0, 18.2, 22.2,
25.8, 25.9, 27.1, 51.7, 74.5, 74.8, 130.2, 130.4, 202.7 ppm; FAB-MS m/z:
407 [M++Na]; HR-FAB-MS: calcd for C20H40O3Si2Na [M++Na]:
407.2414; found 407.2415.
103.6, 103.7, 118.6, 122.9, 127.7, 129.6, 130.2, 130.3, 139.1, 139.4, 140.5,
158.3, 160.4, 165.3 ppm; FAB-MS m/z: 540 [M++H]; HR-FAB-MS: calcd
for C34H54NO4 [M++H]: 540.4053; found 540.4058.
General procedure for the deprotection of MPM-type ethers with Ph3C+
BF4À: Ph3C+BF4À (1.1 mmol) was added to a solution of MPM-type ether
38 (1 mmol) in CH2Cl2 (10 mL) at 08C under Ar. After completion of
the reaction (TLC check), the reaction mixture was quenched by the ad-
dition of saturated NaHCO3 (aq.), and the reaction mixture was extract-
ed with CH2Cl2. The organic layer was dried over Na2SO4 and concen-
trated in vacuo. The residue was purified by column chromatography on
silica gel using hexane/EtOAc (10:1) as the eluent to give 39 in the yield
shown in Table 2.
ACHTREUNG
;
0.07 (6H, s), 0.12 (9H, s), 0.86 (9H, s), 1.59 (1H, m), 1.84 (1H, m) 1.96–
2.17 (2H, m), 2.30 (1H, dd, J=2.6, 15.7 Hz), 2.65 (1H, dd, J=3.0,
15.7 Hz), 3.86 (1H, dd, J=3.3, 9.5 Hz), 5.61 (1H, dt, J=10.0, 1.8 Hz),
5.77 (1H, dt, J=10.0, 3.5 Hz), 9.81 ppm (1H, t, J=3.0 Hz); 13C NMR
(75 MHz, CDCl3): d=À4.6, À4.5, 2.4, 18.0, 23.3, 25.8, 28.2, 51.2, 75.4,
76.3, 129.6, 130.7, 202.9 ppm; FAB-MS m/z: 365 [M++Na], HR-FAB-MS
m/z: calcd for C17H34O3Si2Na [M++Na]: 365.1944; found 365.1949.
Alcohol (39): White crystals; m.p. 84–868C; IR (KBr): n˜ =3280, 2923,
1
1651, 1608, 1539, 1463 cmÀ1; H NMR (300 MHz, CDCl3): d=0.88 (3H, t,
J=7.0 Hz), 0.87–1.00 (2H, m), 1.11–1.32 (17H, m), 1.34–1.44 (2H, m),
1.58–1.83 (6H, m), 2.12 (2H, dd, J=6.8, 14.3 Hz), 3.01 (1H, brs), 3.56
(1H, dd, J=6.2, 10.9Hz), 3.72 (1H, dd, J=3.1, 10.9Hz), 4.15 (1H, m),
5.51 (1H, d, J=7.5 Hz), 5.81–5.95 (2H, m), 6.07–6.22 (2H, m), 6.51 (1H,
dd, J=10.6, 14.3 Hz), 7.25 ppm (1H, dd, J=10.5, 14.9Hz); 13C NMR
(75 MHz, CDCl3): d=14.1, 22.6, 26.0, 26.2, 26.4, 28.9, 29.2, 29.3, 29.5,
31.8, 32.8, 32.9, 33.7, 34.3, 38.8, 49.8, 67.0, 76.6, 121.9, 127.5, 129.7, 140.2,
140.6, 141.9, 167.2 ppm; FAB-MS m/z: 39 0 [M++H]; HR-FAB-MS: calcd
for C25H44NO2 [M++H]: 390.3372; found 390.3390.
ACHTREUNG
;
q, J=7.8 Hz), 0.94 (9H, t, J=7.8 Hz), 1.08 (18H, s), 0.88–1.15 (3H, m),
1.58–1.69(1H, m), 1.87–1.96 (1H, m), 2.02–2.18 (2H, m), 2.34 (1H, dd,
J=2.4, 15.8 Hz), 2.69(1H, dd, J=3.4, 15.8 Hz), 4.06 (1H, dd, J=3.3,
10.5 Hz), 5.60 (1H, dt, J=9.8, 1.7 Hz), 5.74 (1H, dt, J=9.8, 3.7 Hz),
9.91 ppm (1H, dd, J=2.4, 3.4 Hz); 13C NMR (75 MHz, CDCl3): d=6.8,
7.1, 12.9, 18.15, 18.23, 24.1, 29.4, 51.2, 77.1, 77.2, 128.9, 131.6, 203.1 ppm;
FAB-MS m/z: 449[ M++Na]; HR-FAB-MS: calcd for C23H46O3Si2Na
[M++Na]: 449.2844; found 449.2880.
Preparation of 2,4DMPMOCH2SnBu3 (40):[11] A mixture of 2,4-methoxy-
benzyl alcohol (2.54 g, 15.1 mmol) and NaH (0.70 g, 60% in oil,
17.4 mmol) in THF (40 mL) was stirred at room temperature under N2.
After being stirred for 1 h at the same temperature, a solution of tri-n-bu-
tylstannylmethyl iodide (5.0 g, 11.6 mmol) in THF (8 mL) was added
slowly to the solution. The resulting mixture was stirred for three days.
The reaction mixture was quenched by addition of MeOH, and the solu-
tion was diluted with Et2O. The organic layer was washed with water two
times, dried over Na2SO4, and concentrated in vacuo. The residue was pu-
rified by column chromatography on silica gel using hexane/Et2O (30:1)
as the eluent to give 40 (3.7 g, 68%) as a colorless oil. IR (KBr): n˜ =
Experiments in Table 2: Compounds 38a–c were prepared from cyclo-
hexylacetoaldehyde and the corresponding stannyl compound with 4-me-
thoxyphenylmethyloxymethyl (for 38a), 3,4-dimethoxyphenylmethyloxy-
methyl (for 38b), or 2,4-dimethoxyphenylmethyloxymethyl (for 38c)
groups in the same way as compounds 31a and 31b (see Schemes 7 and
11, respectively).
MPM ether (38a): White crystals; m.p. 110–1128C; IR (KBr): n˜ =3273,
2954, 1614, 1506, 1463 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.85–0.94
;
2923, 1651, 1612, 1514, 1448 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.88
;
(15H, m), 1.28 (6H, m), 1.51 (6H, m), 3.72 (2H, s), 3.87 (3H, s), 3.88
(3H, s), 4.35 (2H, s), 6.83–6.87 ppm (3H, m); 13C NMR (75 MHz,
CDCl3) d: 9.0, 13.7, 27.3, 29.1, 55.3, 61.4, 71.5, 98.3, 103.7, 119.7, 129.7,
158.2, 160.2 ppm.
(3H, t, J=6.2 Hz), 0.85–0.98 (2H, m), 1.08–1.32 (15H, m), 1.35–1.49
(2H, m), 1.52–1.71 (7H, m), 1.74–1.83 (1H, m), 2.12 (2H, dd, J=6.8,
14.3 Hz), 3.47 (2H, t, J=3.1 Hz), 3.81 (3H, s), 4.27 (1H, m), 4.40 (1H, d,
J=11.8 Hz), 4.47 (1H, d, J=11.8 Hz), 5.56 (1H, d, J=9.3 Hz), 5.75 (1H,
d, J=14.9Hz), 5.88 (1H, m), 6.07–6.22 (2H, m), 6.49 (1H, dd, J=10.6,
14.9Hz), 6.68 (2H, d, J=8.7 Hz), 7.22 (1H, m), 7.24 ppm (2H, d, J=
8.7 Hz); 13C NMR (75 MHz, CDCl3): d=14.1, 22.6, 26.1, 26.2, 26.5, 29.0,
29.2, 29.3, 29.4, 29.5, 31.8, 33.0, 33.6, 34.3, 39.5, 46.5, 55.3, 71.8, 72.9, 76.5,
113.8, 122.8, 127.8, 129.3, 129.8, 130.2, 139.6, 139.9, 141.0, 159.2,
165.5 ppm; FAB-MS m/z: 510 [M++H]; HR-FAB-MS: calcd for
C33H52NO3 [M++H]: 510.3947; found 510.3946.
(2R)-1-[(1S,6S)-1-Trimethylsiloxy-6-(tert-butyldimethylsiloxy)cyclohex-2-
en-1-yl]-3-[(2,4-dimethoxyphenyl)methyloxy]propan-2-ol (27b) and (2S)-
1-[(1S,6S)-1-Trimethylsiloxy-6-(tert-butyldimethylsiloxy)cyclohex-2-en-1-
yl]-3-[(2,4-dimethoxyphenyl)methyloxy]propan-2-ol (27b’): nBuLi (1.58m
in hexane, 0.24 mL) was added dropwise to
a
solution of
2,4DMPMOCH2SnBu3 (40; 177.2 mg, 0.376 mmol) in dry THF (0.9mL) at
À788C under N2. After being stirred for 15 min, a solution of 26d
(36.1 mg, 0.105 mmol) in THF (0.9mL) was added to the reaction mix-
ture. After being stirred for 5 min, the reaction mixture was quenched
with water and extracted with EtOAc. The organic layer was washed
with brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography using hexane/EtOAc (10:1) as
the eluent to give 27b (30.8 mg, 0.0588 mmol, 56%) and 27b’ (12 mg,
0.0378 mmol, 25%).
3,4DMPM ether (38b): White crystals; m.p.74–758C; IR (KBr): n˜ =3284,
2923, 1651, 1608, 1514, 1448 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.88
;
(3H, t, J=7.0 Hz), 0.88–0.99 (2H, m), 1.11–1.32 (15H, m), 1.35–1.46
(3H, m), 1.57–1.70 (6H, m), 1.74–1.83 (1H, m), 2.11 (2H, dd, J=6.9,
14.1 Hz), 3.46 (2H, d, J=4.0 Hz), 3.80 (6H, s), 4.29(1H, m), 4.39(1H, d,
J=11.5 Hz), 4.47 (1H, d, J=11.5 Hz), 5.57 (1H, d, J=8.8 Hz), 5.76 (1H,
d, J=14.7 Hz), 5.83–5.92 (1H, m), 6.06–6.21 (2H, m), 6.48 (1H, dd, J=
10.6, 14.5 Hz), 6.80–6.85 (3H, m), 7.22 ppm (1H, dd, J=11.2, 14.7 Hz);
13C NMR (75 MHz, CDCl3): d=14.0, 22.6, 26.1, 26.4, 28.9, 29.1, 29.2,
29.3, 29.4, 31.8, 32.9, 33.5, 34.2, 39.5, 46.5, 55.7, 55.8, 71.8, 73.0, 73.1,
110.7, 110.8, 110.9, 120.2, 122.7, 127.6, 129.7, 130.6, 139.5, 139.9, 141.0,
148.5, 148.9, 165.5 ppm; FAB-MS m/z: 540 [M++H]; HR-FAB-MS: calcd
for C34H54NO4 [M++H]: 540.4053; found 540.4039.
27b: Colorless oil; [a]2D5 =+26.0 (c=0.67, CHCl3): IR (KBr): n˜ =3498,
2945, 1614, 1504, 1454 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.11 (3H,
;
s), 0.12 (3H, s), 0.16 (9H, s), 0.88 (9H, s), 1.62 (1H, dd, J=9.5, 14.3 Hz),
0.74 (1H, m), 1.84–1.97 (2H, m), 2.04 (1H, m), 2.14 (1H, m), 3.45 (2H,
d, J=5.3 Hz), 3.83 (6H, s), 3.89(1H, brs), 3.95 (1H, dd, J=2.2, 7.5 Hz),
4.22 (1H, m), 4.57 (2H, s), 5.68 (1H, d, J=10.1 Hz), 5.81 (1H, dt, J=
10.1, 3.1 Hz), 6.47 (1H, s), 6.49(1H, d, J=7.9Hz), 7.29ppm (1H, d, J=
7.9Hz); 13C NMR (75 MHz, CDCl3): d=À4.8, À4.1, 2.3, 17.9, 22.5, 25.7,
26.6, 40.6, 55.2, 67.2, 67.8, 73.5, 74.9, 98.3, 103.8, 119.3, 129.6, 130.2, 131.1,
158.4, 160.4 ppm; FAB-MS m/z: 547 [M++Na]; HR-FAB-MS: calcd for
C27H48O6Si2Na [M++Na]: 547.2887; found 547.2890.
2,4DMPM ether (38c): White crystals; m.p.67–688C; IR (KBr): n˜ =3284,
2923, 1651, 1612, 1510, 1454 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.88
;
(3H, t, J=7.1 Hz), 0.85–0.99 (2H, m), 1.11–1.30 (15H, m), 1.38–1.45
(3H, m), 1.57–1.71 (6H, m), 1.74–1.84 (1H, m), 2.12 (2H, dd, J=6.9,
14.1 Hz), 3.49(2H, d, J=3.3 Hz), 3.79(6H, s), 4.27 (1H, m), 4.40 (1H, d,
J=11.7 Hz), 4.50 (1H, d, J=11.7 Hz), 5.78 (1H, d, J=14.8 Hz), 5.88
(2H, m), 6.06–6.21 (2H, m), 6.42–6.50 (3H, m), 7.17–7.22 ppm (2H, m);
13C NMR (75 MHz, CDCl3): d=13.9, 22.4, 26.0, 26.3, 28.8, 28.9, 29.0,
29.2, 29.3, 31.6, 32.7, 33.3, 34.0, 39.3, 46.3, 55.0, 67.7, 71.5, 98.2, 98.3,
27b’: Colorless oil; [a]2D6 =À8.4 (c=0.64, CHCl3): IR (KBr): n˜ =3512,
2931, 1614, 1508, 1463 cmÀ1 1H NMR (300 MHz, CDCl3): d=0.07 (3H,
;
s), 0.08 (3H, s), 0.11 (9H, s), 0.90 (9H, s), 1.63 (1H, dd, J=2.4, 14.9Hz),
1.63–1.83 (2H, m), 2.01 (1H, dd, J=9.2, 14.9 Hz), 2.05–2.12 (2H, m),
Chem. Eur. J. 2007, 13, 10225 – 10238
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10235

H. Fujioka, Y. Kita et al.
3.42 (1H, dd, J=5.5, 9.7 Hz), 3.47 (1H, dd, J=6.0, 9.7 Hz), 3.78 (3H, s),
3.79(3H, s), 3.83 (1H, dd, J=3.7, 10.4 Hz), 4.02 (1H, brs), 4.13 (1H, m),
4.52 (2H, s), 5.65 (2H, dt, J=10.1, 2.9Hz), 6.43 (1H, s), 6.45 (1H, m),
7.25 ppm (1H, d, J=8.3 Hz); 13C NMR (75 MHz, CDCl3): d=À4.6, À4.4,
2.5, 24.2, 25.8, 28.6, 41.1, 55.3, 66.4, 67.8, 74.9, 76.6, 78.1, 98.3, 103.8,
119.3, 127.9, 130.2, 132.1, 158.4, 160.4 ppm; FAB-MS m/z: 547 [M++Na];
HR-FAB-MS: calcd for C27H48O6Si2Na [M++Na]: 547.2887; found
547.2889.
7.0, 14.8 Hz), 1.89–2.06 (2H, m), 2.10 (1H, dd, J=5.0, 14.8 Hz), 3.56 (3H,
s), 3.55–3.64 (2H, m), 3.75 (3H, s), 3.77 (1H, dd, J=2.7, 8.4 Hz), 3.80
(3H, s), 5.46 (1H, d, J=11.9Hz), 5.49(1H, d, J=10.0 Hz), 5.54 (1H, d,
J=11.9Hz), 5.65 (1H, dt, J=10.0, 3.5 Hz), 5.73 (1H, m), 6.42 (1H, s),
6.44 (1H, m), 7.22–7.35 (4H, m), 7.59ppm (2H, d, J=7.3 Hz).
(2S)-1-[(1S,6S)-1-Trimethylsiloxy-6-tert-butyldimethylsiloxycyclohex-2-
en-1-yl]-3-[(2,4-dimethoxyphenyl)methyloxy]-propan-2-yl (2R)-3,3,3-tri-
fluoro-2-methoxy-2-phenylpropanoate (27b’; (R)-MTPA): Colorless oil;
[a]2D5 =+35.2 (c=1.10, CHCl3); IR (KBr): n˜ =
Determination of the absolute configurations of the secondary alcohols
of 27b and 27b’: The absolute configurations of the secondary alcohols
of 27b and 27b’ were determined by the modified Mosherꢁs method.[12]
Each MTPA ester was synthesized in the same way as 27a and 27b.
2935, 1745, 1614, 1508, 1463 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=0.07 (6H, s), 0.12
(9H, s), 0.90 (9H, s), 1.64 (1H, m), 1.78 (1H,
m), 1.80 (1H, dd, J=7.0, 14.6 Hz), 1.95–2.15
(2H, m), 2.21 (1H, dd, J=4.2, 14.6 Hz), 3.52
(1H, dd, J=8.0, 11.2 Hz), 3.54 (3H, s), 3.67
(1H, dd, J=3.0, 11.2 Hz), 3.76 (3H, s), 3.80
(3H, s), 3.83 (1H, dd, J=3.3, 9.7 Hz), 4.39 (1H, d, J=12.0 Hz), 4.45 (1H,
d, J=12.0 Hz), 5.63 (1H, d, J=10.2 Hz), 5.71 (1H, dt, J=10.2, 3.3 Hz),
5.76 (1H, m), 6.41 (1H, s), 6.43 (1H, m), 7.17–7.47 (4H, m), 7.57 ppm
(2H, d, J=7.3 Hz).
(2S)-2-Azido-1-[(1S,6S)-1-trimethylsiloxy-6-tert-butyldimethylsiloxycyclo-
hex-2-en-1-yl]-3-[(2,4-dimethoxyphenyl)methyloxy]propane (28b): PPh3
(122.0 mg, 0.465 mmol), DEAD (0.21 mL, 40% in toluene, 0.465 mmol),
and DPPA (50 mL, 0.223 mmol) were added successively to a stirred solu-
tion of 27b (81.4 mg, 0.155 mmol) in THF (1.6 mL) at room temperature
under Ar. The reaction mixture was stirred at the same temperature for
30 min. After removal of the solvent in vacuo, the residue was purified
by column chromatography using hexane/EtOAc (17:1) as the eluent to
give 28b (64.0 mg, 0.116 mmol, 75%) as a colorless oil. [a]2D5 =+18.8 (c=
General procedure for the preparation of an MTPA ester: DCC
(3.3 mmol), MTPA (4.3 mmol), and DMAP (3.3 mmol) were added suc-
cessively to
a stirred solution of secondary alcohol 27b or 27b’
(1.0 mmol) in CH2Cl2 (10.0 mL) at room temperature. After being stirred
for 30 min, the solvent was removed in vacuo. The residue was purified
by column chromatography using hexane/EtOAc (20:1) as the eluent.
0.77, CHCl3): IR (KBr): n˜ =2933, 2108, 1614, 1508, 1463 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=0.08 (6H, s), 0.10 (9H, s), 0.88 (9H, s), 1.56 (1H,
dd, J=5.5, 14.6 Hz), 1.63 (1H, m), 1.83 (1H, m), 2.01 (1H, dd, J=6.8,
14.6 Hz), 2.02 (1H, m), 2.12 (1H, m), 3.48 (1H, dd, J=7.9, 9.9 Hz), 3.66
(1H, dd, J=3.7, 9.9 Hz), 3.75 (1H, m), 3.79 (3H, s), 3.80 (3H, s), 3.83
(1H, dd, J=2.8, 8.4 Hz), 4.53 (2H, s), 5.57 (1H, d, J=10.1 Hz), 5.76 (1H,
dt, J=10.1, 3.7 Hz), 6.43–6.50 (2H, m), 7.28 ppm (1H, d, J=8.0 Hz);
13C NMR (75 MHz, CDCl3): d=À4.7, À4.2, 2.4, 2.6, 18.1, 22.8, 25.9, 27.3,
38.4, 55.4, 57.7, 67.7, 73.9, 75.1, 98.3, 103.9, 118.9, 129.8, 129.9, 130.8,
158.3, 160.5 ppm; FAB-MS m/z: 572 [M++Na]; HR-FAB-MS: calcd for
C27H47N3O5Si2Na [M++Na]: 572.2952; found 572.2939.
(2R)-1-[(1S,6S)-1-Trimethylsiloxy-6-tert-butyldimethylsiloxycyclohex-2-
en-1-yl]-3-[(2,4-dimethoxyphenyl)methyloxy]-propan-2-yl (2S)-3,3,3-tri-
fluoro-2-methoxy-2-phenylpropanoate (27b; (S)-MTPA): Colorless oil;
[a]2D6 =À27.5 (c=1.03, CHCl3); IR (KBr): n˜ =
2935, 1745, 1614, 1508, 1463 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=0.07 (6H, s), 0.13
(9H, s), 0.87 (9H, s), 1.57 (1H, m), 1.72 (1H,
m), 1.74 (1H, dd, J=4.7, 15.2 Hz), 2.07 (2H,
m), 2.14 (1H, dd, J=5.7, 15.2 Hz), 3.49(3H,
s), 3.51 (1H, m), 3.63 (1H, dd, J=2.4,
(1S,6S)-1-{(2S)-3-[(2,4-Dimethoxyphenyl)methyloxy]-2-[(2E,4E,6E,12E)-
10.6 Hz), 3.73 (1H, m), 3.76 (3H, s), 3.80
(8R,10S,14R)-8,10,12,14-(tetramethyl)hexadeca-2,4,6,12-tetraenoylami-
no]propyl}-2-cyclohexene-1,6-diol (32b): A solution of 28b (275.8 mg,
0.50 mmol) in dry THF (5.0 mL) was added to a solution of LiAlH4
(190.0 mg, 5.0 mmol) in THF (5.0 mL) at 08C under Ar. After being
stirred for 1.5 h at room temperature, the reaction mixture was quenched
with water and 15% NaOH (aq.), then the precipitate was filtered
through a Celite pad. The filtrate was evaporated in vacuo to give crude
29b. Side-chain carboxylic acid 30 (168.0 mg, 0.58 mmol), DCC
(412.7 mg, 2.0 mmol), and DMAP (244.3 mg, 2.0 mmol) were added to a
solution of crude 29b in CH2Cl2 (2.5 mL) at room temperature under Ar.
After being stirred for 1 h, the reaction mixture was quenched with water
and extracted with CH2Cl2. The organic layer was washed with brine,
dried over Na2SO4, and evaporated in vacuo to give crude coupled prod-
uct. TBAF (5.0 mL, 1.0m in THF, 5.0 mmol) was added to the crude cou-
pled product in THF (5.0 mL) at room temperature under Ar. After
being stirred for 10 h, the reaction mixture was quenched with water and
extracted with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, and evaporated in vacuo. The residue was purified by
column chromatography using hexane/EtOAc (1:2) as the eluent to give
32b (183.3 mg, 0.295 mmol, 66%) as a yellow oil. [a]2D4 =+9.81 (c=2.38,
(3H, s), 4.40 (1H, d, J=12.1 Hz), 4.46 (1H, d, J=12.1 Hz), 5.69(1H, m),
5.72 (1H, m), 5.79(1H, d, J=10.1 Hz), 6.42 (2H, m), 7.17 (1H, d, J=
8.8 Hz), 7.24–7.43 (3H, m), 7.58 ppm (2H, d, J=7.5 Hz).
(2R)-1-[(1S,6S)-1-Trimethylsiloxy-6-tert-butyldimethylsiloxycyclohex-2-
en-1-yl]-3-[(2,4-dimethoxyphenyl)methyloxy]-propan-2-yl (2R)-3,3,3-tri-
fluoro-2-methoxy-2-phenylpropanoate (27b; (R)-MTPA): Colorless oil;
[a]2D4 =À8.4 (c=0.91, CHCl3); IR (KBr): n˜ =
2935, 1745, 1614, 1508, 1463 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=0.04 (6H, s), 0.13
(9H, s), 0.84 (9H, s), 1.50 (1H, m), 1.59 (1H,
dd, J=4.9, 15.2 Hz), 1.71 (1H, dd, J=4.0,
13.2 Hz), 1.97–2.06 (2H, m), 2.07 (1H, dd,
J=5.5, 15.2 Hz), 3.56 (1H, m), 3.57 (3H, m),
3.70 (1H, dt, J=10.8, 3.7 Hz), 3.76 (1H, m),
3.77 (3H, s), 3.80 (3H, s), 4.48 (1H, d, J=11.7 Hz), 4.55 (1H, d, J=
11.7 Hz), 5.48 (1H, dt, J=10.0, 2.9Hz), 5.69 (1H, d, J=10.0 Hz), 5.70
(1H, m), 6.43 (1H, s), 6.44 (1H, d, J=7.0 Hz), 7.21–7.37 (4H, m),
7.59ppm (2H, d, J=7.5 Hz).
(2S)-1-[(1S,6S)-1-Trimethylsiloxy-6-tert-butyldimethylsiloxycyclohex-2-
en-1-yl]-3-[(2,4-dimethoxyphenyl)methyloxy]-propan-2-yl (2S)-3,3,3-tri-
fluoro-2-methoxy-2-phenylpropanoate (27b’;
CHCl3); IR (KBr): n˜ =3305, 2923, 1591, 1504, 1454 cmÀ1 1H NMR
;
(500 MHz, CDCl3): d=0.80 (3H, d, J=6.1 Hz), 0.84 (3H, t, J=7.4 Hz),
0.90 (3H, d, J=6.7 Hz), 0.99 (3H, d, J=6.1 Hz), 1.02 (1H, m), 1.20 (1H,
m), 1.27–1.38 (2H, m), 1.52 (3H, s), 1.56 (1H, m), 1.70–1.76 (2H, m),
1.81 (1H, dd, J=6.7, 14.7 Hz), 1.85–1.93 (2H, m), 2.01 (1H, dd, J=3.7,
15.3 Hz), 2.07 (1H, m), 2.17 (1H, m), 2.23 (1H, m), 2.32 (1H, m), 3.55
(1H, brs), 3.62 (2H, d, J=4.3 Hz), 3.81 (3H, s), 3.82 (3H, s), 3.92 (1H,
(S)-MTPA): Colorless oil; [a]2D5 =+1.8 (c=
1.30, CHCl3); IR (KBr): n˜ =2933, 1747, 1614,
1508, 1463 cmÀ1; 1H NMR (300 MHz, CDCl3):
d=0.07 (6H, s), 0.12 (9H, s), 0.90 (9H, s),
1.49(1H, m), 1.70 (1H, m), 1.74 (1H, dd, J=
10236
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 10225 – 10238

Total Synthesis of Scyphostatin
FULL PAPER
d, J=6.7 Hz), 4.10 (1H, brs), 4.25 (1H, m), 4.47 (1H, d, J=11.3 Hz),
4.52 (1H, d, J=11.3 Hz), 4.83 (1H, d, J=9.2 Hz), 5.51 (1H, d, J=
9.8 Hz), 5.65–5.72 (2H, m), 5.75 (1H, d, J=14.0 Hz), 6.07 (1H, dd, J=
11.0, 15.3 Hz), 6.16 (1H, dd, J=11.0, 14.6 Hz), 6.39(1H, d, J=6.1 Hz),
6.43–6.50 (3H, m), 7.18–7.24 ppm (2H, m); 13C NMR (125 MHz, CDCl3):
d=12.1, 16.2, 19.5, 21.1, 21.4, 22.9, 25.6, 28.3, 30.5, 34.1, 34.9, 39.2, 44.0,
45.9, 48.3, 49.1, 55.5, 66.1, 72.1, 72.2, 72.4, 98.7, 104.0, 118.5, 122.1, 127.8,
128.2, 129.0, 130.9, 131.5, 132.2, 133.1, 140.5, 141.7, 145.6, 158.8, 161.0,
166.8 ppm; FAB-MS m/z: 624 [M++H]; HR-FAB-MS: calcd for
C38H58NO6 [M++H]: 624.4264; found 624.4250.
ACHTREUNG
AHCTREUNG
2,4,6,12-tetraenoylamino]propyl}-2-cyclohexen-1-one (35b): LDA in THF
(0.25m) was prepared as follows: nBuLi (1.56m in hexane, 0.78 mL) was
added to a solution of diisopropylamine (70.3 mL, 0.5 mmol) in dry THF
(1.15 mL) at À788C for 30 min. under Ar. LDA (0.25m in THF, 0.35 mL)
and [15]crown-5 (69 mL, 0.348 mmol) were added to a solution of 34b
(7.4 mg, 0.0116 mmol) in THF (0.3 mL) at À788C under Ar. After being
stirred for 10 min, a solution of N-tert-butylbenzenesulfinimidoyl chloride
(75.1 mg, 0.348 mmol) in THF (0.3 mL) was added to the reaction mix-
ture. After being stirred for 15 min, the reaction mixture was quenched
with water and extracted with EtOAc. The organic layer was washed
with brine, dried over Na2SO4, and evaporated in vacuo. The residue was
purified by column chromatography using Et2O as the eluent to give 35b
(2.6 mg, 0.0058 mmol, 35%) as a yellow oil, and the substrate 34b
(4.3 mg, 58%) was recovered. [a]2D3 =+24.8 (c=0.30, CHCl3); IR (KBr):
(1R,2S,3S,6S)-1,6-Dihydroxy-2,3-epoxy-1-{(2S)-3-[(2,4-dimethoxyphenyl)-
methyloxy]-2-[(2E,4E,6E,12E)-(8R,10S,14R)-8,10,12,14-(tetramethyl)hex-
adeca-2,4,6,12-tetraenoylamino]propyl}cyclohexane (33b): A solution of
aqueous TBHP (0.46 mL, 3.69mmol) in toluene (3.0 mL) was dried with
molecular sieves (4 Š) at room temperature under Ar. After being
stirred for 20 min, a solution of 32b (230.0 mg, 0.369mmol) and [VO-
n˜ =3271, 2958, 1697, 1651, 1612, 1514, 1461 cmÀ1 1H NMR (500 MHz,
;
A
CDCl3): d=0.80 (3H, d, J=6.1 Hz), 0.81 (3H, m), 0.90 (3H, d, J=
6.7 Hz), 0.99 (3H, d, J=6.7 Hz), 1.02 (1H, m), 1.16–1.33 (3H, m), 1.61
(3H, s), 1.74 (1H, m), 1.88 (1H, dd, J=6.7, 12.8 Hz), 2.01 (2H, m), 2.20
(1H, m), 2.32 (1H, m), 3.50 (1H, dd, J=4.9, 9.5 Hz), 3.52 (1H, m), 3.61
(1H, dd, J=3.7, 9.5 Hz), 3.69 (1H, d, J=3.7 Hz), 3.80 (3H, s), 3.81 (3H,
s), 4.22 (1H, m), 4.45 (2H, s), 4.84 (1H, d, J=9.2 Hz), 5.68 (1H, dd, J=
9.8, 14.7 Hz), 5.69 (1H, d, J=14.7 Hz), 5.97 (1H, d, J=9.0 Hz), 6.04–6.21
(3H, m), 6.41–6.49(3H, m), 7.07 (1H, dd, J=4.3, 9.0 Hz), 7.17 (1H, d,
J=9.2 Hz), 7.21 ppm (1H, dd, J=11.6, 14.7 Hz); 13C NMR (125 MHz,
CDCl3): d=12.1, 19.5, 21.1, 21.4, 28.3, 29.7, 30.5, 31.6, 34.1, 35.0, 38.3,
44.0, 45.5, 47.9, 48.3, 53.0, 55.5, 56.3, 68.3, 71.8, 98.6, 114.0, 118.5, 122.2,
127.8, 128.3, 130.5, 130.8, 132.1, 133.1, 140.5, 144.1, 144.6, 145.6, 158.9,
160.9, 165.9, 197.7 ppm; FAB-MS m/z: 636 [M++H]; HR-FAB-MS: calcd
for C38H54NO7 [M++H]: 636.3900; found 636.3876.
above mixture at 08C. After being stirred for 30 min, the reaction mix-
ture was quenched with saturated Na2S2O3 (aq.) and extracted with Et2O.
The organic layer was washed with brine, dried over Na2SO4, and evapo-
rated in vacuo. The residue was purified by column chromatography
using hexane/EtOAc (3:2) as the eluent to give 33b (172.9mg,
0.269mmol, 69%) as a yellow oil. [ a]2D4 =+19.1 (c=0.73, CHCl3); IR
(KBr): n˜ =3330, 2923, 1651, 1591, 1504, 1454 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d=0.80 (3H, d, J=6.7 Hz), 0.83 (3H, t, J=7.4 Hz), 0.90 (3H, d,
J=6.7 Hz), 0.99 (3H, d, J=8.6 Hz), 1.02 (1H, m), 1.20 (1H, m), 1.28–
1.35 (2H, m), 1.52 (3H, s), 1.52–1.62 (2H, m), 1.74 (1H, m), 1.84–1.97
(4H, m), 2.05 (1H, d, J=14.7 Hz), 2.17 (1H, m), 2.23 (1H, m), 2.32 (1H,
m), 2.64 (1H, brs), 2.80 (1H, d, J=3.1 Hz), 3.39(1H, m), 3.75–3.80 (3H,
m), 3.81 (3H, s), 3.83 (3H, s), 4.21 (1H, m), 4.51 (1H, d, J=11.3 Hz),
4.54 (1H, d, J=11.3 Hz), 4.84 (1H, d, J=9.2 Hz), 5.70 (1H, dd, J=8.5,
15.3 Hz), 5.74 (1H, d, J=14.7 Hz), 6.08 (1H, dd, J=11.0, 15.3 Hz), 6.16
(1H, dd, J=11.6, 14.7 Hz), 6.43 (1H, d, J=6.7 Hz), 6.44–6.51 (3H, m),
7.19–7.24 ppm (2H, m); 13C NMR (125 MHz, CDCl3): d=12.1, 16.2, 18.7,
19.5, 19.9, 21.0, 21.4, 28.3, 30.5, 34.1, 35.0, 38.3, 44.0, 46.1, 48.3, 49.1, 55.4,
56.0, 57.9, 67.6, 68.3, 69.9, 71.4, 98.7, 103.9, 118.6, 121.8, 127.7, 128.2,
131.0, 133.1, 135.5, 140.7, 141.9, 145.7, 158.8, 161.0, 166.9 ppm; FAB-MS
m/z: 640 [M++H]; HR-FAB-MS: calcd for C38H58NO7 [M++ H]:
640.4213; found 640.4220.
A
(8R,10S,14R)-8,10,12,14-(tetramethyl)hexadeca-2,4,6,12-tetraenoylami-
À
no]propyl}-2-cyclohexen-1-one (scyphostatin (1)): Ph3C+BF4 (1.8 mg,
0.00564 mmol) was added to a solution of 35b (3.0 mg, 0.0047 mmol) in
CH2Cl2 (0.2 mL) at 08C under Ar. After being stirred for 5 min, the reac-
tion mixture was quenched with saturated NaHCO3 (aq.) and extracted
with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by column
chromatography using EtOAc/acetone (4:1) as the eluent to give scy-
phostatin (1; 1.5 mg, 0.00312 mmol, 66%). [a]2D5 =+60.5 (c=0.20,
MeOH); IR (KBr): n˜ =3292, 2956, 2923, 1697, 1651, 1606, 1512,
ACHTREUNG
ACHTREUNG
1454 cmÀ1 1H NMR (500 MHz, CD3OD): d=0.83–0.86 (6H, m), 0.91
;
2,4,6,12-tetraenoylamino]propyl}cyclohexan-1-one (34b): Dess–Martin
periodinane (120.5 mg, 0.284 mmol) was added to a stirred solution of
33b (90.8 mg, 0.142 mmol) in CH2Cl2 (7.0 mL) under N2. After being
stirred at 408C for 10 min, the reaction mixture was quenched with satu-
rated NaHCO3 (aq.) and extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and evaporated in vacuo. The resi-
due was purified by column chromatography using hexane/EtOAc (1:1)
as the eluent to give 34b (62.5 mg, 0.098 mmol, 69%) as a yellow oil, and
the substrate 33b (10.9mg, 12%) was recovered. [ a]2D5 =À6.2 (c=2.52,
(3H, d, J=6.7 Hz), 1.00 (3H, d, J=6.8 Hz), 1.04 (1H, m), 1.19(1H, m),
1.27–1.41 (2H, m), 1.54 (3H, s), 1.58 (1H, m), 1.78 (1H, m), 1.86 (1H,
m), 1.88 (1H, m), 2.08 (1H, dd, J=3.7, 14.7 Hz), 2.27 (1H, m), 2.35 (1H,
m), 3.46 (1H, dd, J=5.5, 11.0 Hz), 3.52 (1H, dd, J=4.9, 11.0 Hz), 3.59
(1H, m), 3.66 (1H, d, J=3.7 Hz), 4.04 (1H, m), 4.86 (1H, m), 5.71 (1H,
m), 5.89(1H, d, J=15.3 Hz), 6.07 (1H, dd, J=1.3, 9.8 Hz), 6.15 (1H, dd,
J=11.6, 14.6 Hz), 6.26 (1H, dd, J=11.0, 15.3 Hz), 6.54 (1H, dd, J=11.0,
14.6 Hz), 7.09–7.18 ppm (2H, m); 13C NMR (125 MHz, CD3OD): d=
12.9, 16.9, 20.5, 22.0, 22.5, 30.1, 32.2, 36.0, 36.7, 40.3, 46.0, 48.5, 49.8, 50.1,
58.8, 65.9, 78.0, 124.2, 129.9, 130.4, 132.6, 134.5, 134.7, 141.8, 142.9, 146.4,
146.8, 169.0, 200.4 ppm; FAB-MS m/z: 486 [M++H]; HR-FAB-MS m/z:
486.3199 (calcd for C29H43NO5H: 486.3219); the 1H and 13C NMR, IR,
and HR-FAB-MS spectra showed good agreement with those of the au-
thentic sample.
CHCl3); IR (KBr): n˜ =3290, 2923, 1720, 1651, 1612, 1508, 1454 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=0.80 (3H, d, J=6.7 Hz), 0.83 (3H, t, J=
7.4 Hz), 0.90 (3H, d, J=6.7 Hz), 0.99 (3H, d, J=6.7 Hz), 1.02 (1H, m),
1.20 (1H, m), 1.25–1.36 (2H, m), 1.52 (3H, s), 1.55 (1H, m), 1.75 (1H,
m), 1.88 (1H, m), 2.10 (1H, dd, J=6.1, 15.0 Hz), 2.17 (1H, dd, J=6.7,
15.0 Hz), 2.24 (1H, m), 2.32 (1H, m), 2.35–2.42 (3H, m), 2.80 (1H, m),
3.49(1H, dd, J=4.9, 9.5 Hz), 3.66 (1H, dd, J=4.3, 9.5 Hz), 3.80 (3H, s),
3.81 (3H, s), 4.05 (1H, m), 4.24 (1H, brs), 4.45 (2H, s), 4.84 (1H, d, J=
9.2 Hz), 5.68 (1H, dd, J=8.5, 15.0 Hz), 5.71 (1H, d, J=15.0 Hz), 6.07
(1H, dd, J=11.0, 15.0 Hz), 6.16 (1H, dd, J=11.3, 14.6 Hz), 6.21 (1H, d,
J=7.3 Hz), 6.43–6.49(3H, m), 7.18 (1H, d, J=8.6 Hz), 7.19ppm (1H,
dd, J=11.3, 15.0 Hz); 13C NMR (125 MHz, CDCl3): d=12.1, 16.2, 19.5,
21.1, 21.4, 22.3, 28.3, 29.7, 30.5, 31.7, 34.1, 34.9, 42.5, 44.0, 46.2, 48.3, 53.0,
55.4, 60.7, 68.1, 71.0, 76.8, 98.6, 104.0, 118.5, 122.4, 127.8, 128.2, 130.9,
132.1, 133.1, 140.4, 141.4, 145.5, 158.7, 160.9, 166.1, 209.8 ppm; FAB-MS
m/z: 638 [M++H]; HR-FAB-MS: calcd for C38H56NO7 [M++H]:
638.4057; found 638.4065.
Acknowledgements
We are grateful to Dr. Toshio Takatsu at Sankyo Co. for his generous gift
1
of the H and 13C NMR and IR spectra of 1. This study was supported by
a Grant-in-Aid for Scientific Research (S) and a Grant-in-Aid for Scien-
tific Research for Exploratory Research from the Japan Society for the
Promotion of Science and by a Grant-in-Aid for Scientific Research on
Priority Areas (17035047) from the Ministry of Education, Culture,
Chem. Eur. J. 2007, 13, 10225 – 10238
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10237

H. Fujioka, Y. Kita et al.
Sports, Science, and Technology, Japan and the Shorai Foundation for
Science and Technology.
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Received: June 8, 2007
Published online: September 28, 2007
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