Enantioselective total synthesis of (+)-scyphostatin, a potent and specific inhibitor of neutral sphingomyelinase

Article abstract of DOI:10.1055/s-2007-965893

The total synthesis of (+)-scyphostatin, a specific and potent neutral sphingomyelinase inhibitor from a microorganism, was accomplished for the first time starting from D-arabinose and both enantiomers of methyl 3-hydroxy-2-methylpropionate. The method i

Full text of DOI:10.1055/s-2007-965893

622
FEATURE ARTICLE
Enantioselective Total Synthesis of (+)-Scyphostatin, a Potent and Specific
Inhibitor of Neutral Sphingomyelinase
Enantioselective Total
uSynthesis of
n
(
+)-Scyphos
e
tatin nori Inoue,a Wakako Yokota,a Tadashi Katoh*b
a
Sagami Chemical Research Center, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558,
b
Japan
Fax +81(22)7270135; E-mail: katoh@tohoku-pharm.ac.jp
Received 4 August 2006; revised 31 October 2006
genic states such as AIDS,6 inflammation,7 and immuno-
logical and neurological disorders.8
Abstract: The total synthesis of (+)-scyphostatin, a specific and po-
tent neutral sphingomyelinase inhibitor from a microorganism, was
accomplished for the first time starting from D-arabinose and both
enantiomers of methyl 3-hydroxy-2-methylpropionate. The method
involves (a) stereoselective aldol coupling of a methyl 1,3-diox-
olane-4-carboxylate with the Garner aldehyde to establish the
asymmetric quaternary carbon center at C4, (b) ring-closing meta-
thesis of the resultant diene to construct the cyclohexene ring, (c)
Negishi coupling of a vinyl iodide and an alkyl iodide to form the
requisite trisubstituted E-alkene, (d) formation of an amide from the
cyclohexene segment and the trisubstituted E-alkene fatty acid seg-
ment, and (e) stereospecific formation of an epoxide ring from the
mesylate of the amide formed from the two segments.
The gross structure of scyphostatin (1) was revealed by
extensive spectroscopic analyses and derivatization stud-
ies.1 It consists of a novel, highly oxygenated cyclohex-
enone ring attached to an aminopropanol side chain
substituted with a 20-carbon unsaturated fatty acid. This
initial structure elucidation only established the relative
and absolute stereochemistry of the cyclohexenone por-
tion of 1. Subsequently, Kogen et al. determined the rela-
tive and absolute configurations of the three stereogenic
centers at C8¢, C10¢, and C14¢ in the fatty acid side chain.9
At almost the same time, Hoye et al. achieved an enantio-
selective synthesis of the 20-carbon unsaturated fatty acid
moiety for the first time, and provided alternative proof of
its stereostructure, including the absolute configuration.10
Key words: scyphostatin, sphingomyelinase, inhibitors, total syn-
thesis, aldol reaction, Negishi coupling
Introduction
8
O
9
7
6
Scyphostatin (1, Figure 1), isolated from the mycelia ex-
tract Trichopeziza mollissima SANK 13892 by Ogita et al.
in 1997, has been shown to be a powerful and specific in-
hibitor of membrane-bound neutral sphingomyelinase (N-
SMase).1,2 It has been reported that 1 inhibits N-SMase
and acidic SMase (A-SMase) with IC50 values of 1.0 mM
and 49.3 mM, respectively.1,2 Remarkably, of the many
low-molecular-weight N-SMase inhibitors of natural3 or
synthetic4 origin, this natural product is the most potent
and specific one known to date.
OH
4
1
5
2
O
3
OH
Me
14’
Me
Me
10’
Me
8’
12’
NH
Me
13’
O
(+)-scyphostatin (1)
Figure 1 Structure of (+)-scyphostatin (1)
The remarkable biological properties and unique structur-
al features have made 1 an exceptionally intriguing and
timely target for total synthesis. So far, many synthetic ef-
forts toward scyphostatin (1) have been reported.11 We
have already reported our own preliminary results con-
cerning the enantioselective synthesis of the epoxycyclo-
hexenone substructure.12 Subsequently, we have also
disclosed an efficient method for the introduction of a fat-
ty acid side chain at the aminopropanol moiety.13 More re-
cently, we have communicated the first total synthesis of
(+)-scyphostatin (1) in an enantiomerically pure form.14 In
this article, we wish to describe the full details of our suc-
cessful total synthesis of (+)-1.
SMase is the enzyme that specifically cleaves the phos-
phoester linkage of sphingomyelin (SM) to generate phos-
phocholine and ceramide. The SM-derived ceramide has
been known as an intracellular lipid second messenger in
mammalian cell membranes and plays important roles in
the cellular signal transmission pathway, in particular, as
a signal transduction factor in cell differentiation and ap-
optosis induction.5 Consequently, SMase inhibitors are
considered as valuable chemical tools to explore the bio-
logical function of the enzyme and the catabolite ceramide
in signal transduction. Additionally, potent and selective
SMase inhibitors are highly anticipated to be promising
candidates for the treatment of ceramide-mediated patho-
SYNTHESIS 2007, No. 4, pp 0622–0637
x
x
.
x
x
.2
0
0
7
Advanced online publication: 18.01.2007
DOI: 10.1055/s-2007-965893; Art ID: F12106SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Enantioselective Total Synthesis of (+)-Scyphostatin
623
enolate of 5, leading to establishment of the requisite
asymmetric quaternary carbon center at the C4-position
(scyphostatin numbering). This type of coupling reaction
is considerably challenging at the synthetic chemistry lev-
el, because substrate 5 possesses unusual trihydroxy func-
tionalities at the C4-, C5-, and C6-positions. Ester 5, in
turn, could be accessible from D-arabinose (7) that has the
correct stereochemistries for 5.
Results and Discussion
Synthetic Plan for (+)-Scyphostatin (1)
Our synthetic plan for (+)-scyphostatin (1), outlined in
Scheme 1, is based on our intensive model studies.12
Since the highly oxygenated cyclohexenone system in 1
was expected to be fairly labile under acidic and/or basic
conditions,1,2 we planned the construction of the epoxycy-
clohexenone system to be at a late stage of the synthesis.
The target molecule 1 would be produced from the cyclo-
hexenone segment 2 and the 20-carbon fatty acid segment
3 via an amide coupling of these segments, followed by
enone and epoxide-ring formations.
On the other hand, segment 3 could be derived from the
Hoye intermediate 810 through Horner–Wadsworth–
Emmons (HWE) olefination. The key feature of our syn-
thesis of 8 is Negishi coupling between vinyl iodide 9 and
alkyl iodide 10 to generate the requisite trisubstituted E-
olefin 8. Intermediates 9 and 10 could be accessed from
the two commercially available isomers methyl (R)-3-hy-
droxy-2-methylpropionate (11) and its S-isomer ent-11,
respectively.
The segment 2 would be derived from diene 4 through
ring-closing metathesis (RCM). The RCM substrate 4
would be prepared through aldol coupling of ester 5 with
the Garner aldehyde (6),15 where we envisioned that 6 ap-
proaches exclusively from the less hindered a-face of the
Biographical Sketches
Munenori Inoue was born versity, he joined the group associate professor at the
in 1971 in Hiroshima, Ja- of Prof. Tadashi Katoh at Tokyo Institute of Technol-
pan. He received his PhD in Sagami Chemical Research ogy. His current research in-
1999 from the University of Center as a research fellow terests include the synthesis
Tokyo under the direction of (2001–2004). In 2004 he be- of biologically active com-
Prof. Takeshi Kitahara. Af- came a junior research fel- pounds, especially natural
ter spending a postdoctoral low and started his own products, and the develop-
year (1999–2001) with Prof. research at the same insti- ment of new chemical reac-
John L. Wood at Yale Uni- tute. He is also a visiting tions.
Wakako Yokota was born Shishido. In 2001 she joined where she was engaged in
in 1975 in Kochi, Japan. She the group of Prof. Tadashi the synthesis of new agro-
studied pharmaceutical sci- Katoh at Sagami Chemical chemicals
(2003–2006).
ence at Tokushima Univer- Research Center as a re- Currently she works as a
sity and obtained her BS search fellow (2001–2003). pharmacist at Kitasato Phar-
degree in 1999 and MS de- In 2003 she was transferred macy in Kanagawa, Japan.
gree in 2001 under the guid- to the group of Dr. Kenji
ance of Prof. Kozo Hirai at the same institute,
Tadashi Katoh received his Chemical Research Center a Pfizer Award (1999) in
PhD in 1988 from Hoshi as a research fellow in 1989, synthetic organic chemistry
University under the direc- where he enjoyed working in Japan. In 2004 he moved
tion of Prof. Toshio Honda with Dr. Shiro Terashima to Tohoku Pharmaceutical
and the late Prof. Tetsuji (1989–1998). In 1998 he University as full professor.
Kametani. After spending a was appointed as a visiting His research interests in-
postdoctoral year (1988– professor at the Tokyo Insti- clude development of new
1989) with Prof. Philip D. tute of Technology, and synthetic methodologies for
Magnus at Indiana Univer- started his independent re- structurally unique and bio-
sity and the University of search career. He received a logically significant natural
Texas, he joined Sagami Progress Award (1998) and products.
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

624
M. Inoue et al.
FEATURE ARTICLE
O
OH
4
O
OH
Me
Me
Me
Me
NH
Me
O
(+)-scyphostatin (1)
OTBS
Me
Me
Me
Me
Me
Cl
+
OH
HO
O
NH
Boc
O
O
3
2
HWE olefination
Me Me
ring-closing metathesis
Me
Me
TsO
OTBDPS
OH
8
4
O
PMBO
O
Negishi coupling
N
O
Boc
Me Me
Me
Me
4
OHC
+
BnO
I
OTBDPS
O
I
N
Boc
aldol coupling
CO2Me
9
10
6
HO
HO
O
5
6
4
Me
6
Me
4
5
PMBO
O
OH
HO
OH
CO2Me
MeO2C
O
OH
D-arabinose (7)
5
methyl (R)-3-hydroxy-2-methylpropionate (11)
ent-11
Scheme 1 Synthetic plan for (+)-scyphostatin (1)
lithium hexamethyldisilazide proved to be problematic:
the reaction rate was very slow and the yield of the cou-
pling product 18 was low (ca. 30%). After several experi-
ments, we were delighted to find that the use of a sodium
base such as sodium hexamethyldisilazide was fairly ef-
fective for this coupling reaction. Thus, treatment of 5
with sodium hexamethyldisilazide (1.2 equiv) in tetrahy-
drofuran at –78 °C, followed by reaction with the Garner
aldehyde (6) (1.1 equiv) at the same temperature for four
hours provided the desired coupling product 18 in 69%
yield as a single diastereomer. The newly formed C4 ste-
reochemistry of the product 18 was completely controlled,
as we expected; the assignment was later confirmed by an
NOESY experiment of the transformed compound 19.
The C3 stereochemistry in 18 was tentatively assigned on
the basis of the well-known Felkin–Anh model. As shown
in intermediate 17 (Scheme 3), the electrophile 6 (E+)
would be accessed exclusively from the less hindered a-
face of the sodium enolate under the influence of the ad-
jacent C5 stereocenter, leading to establishment of the
requisite asymmetric quaternary carbon center at C4 in
18.
Synthesis of Methyl Ester 5
At first, we pursued the synthesis of methyl ester 5
(Scheme 2), the substrate for the crucial aldol coupling re-
action, starting from the known compound 12,16 readily
derived from D-arabinose (7) by O-benzylglycosylation
and acetonide formation. After p-methoxybenzyl protec-
tion of the hydroxy group in 12 (70% yield), the benzyl
protecting group of the resulting ether 13 was removed by
hydrogenolysis to furnish hemiacetal 14 (2:1 mixture of
a-and b-anomers) in 86% yield. Wittig olefination of 14
afforded alcohol 15 (86% yield), which was further con-
verted into substrate 5 in 74% overall yield over a three-
step sequence involving Swern oxidation, oxidation with
sodium chlorite, and methyl esterification with diazo-
methane.
Synthesis of Diene 4
Having obtained intermediate 5, we next carried out the
synthesis of diene 4, the substrate for the key RCM reac-
tion, as shown in Scheme 3. Initial attempts to achieve the
aldol coupling between 5 and the Garner aldehyde (6)15
with a lithium base such as lithium diisopropylamide or
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Total Synthesis of (+)-Scyphostatin
625
HO
HO
E +
O
BnO
O
BnO
HO
O
ref. 16
a
MeO
CO2Me
O
O
a
OH
PMBO
O
O
4
5
(2 steps)
Na
PMBO
O
OH
O
PMBO
O
O
O
D-arabinose (7)
12
13
5
17
HO
O
OH
c
b
d
CO2Me
3
4
CO2Me
OH
3
b, c
PMBO
O
PMBO
4
O
5
O
PMBO
O
H
O
O
O
PMBO
O
N
H
O
N
O
14
15
Boc
Boc
NOE
18
19
CHO
CO2Me
O
e, f
PMBO
PMBO
O
CHO
O
9
OH
O
O
d
e
O
PMBO
O
16
5
PMBO
N
O
O
N
O
Boc
Scheme 2 Synthesis of intermediate 5. Reagents and conditions: (a)
PMBCl, NaH, DMSO, r.t., 70%; (b) H2, Raney Ni, EtOH, r.t., 86%;
(c) Ph3MeP+Br–, t-BuOK, benzene, reflux, 86%; (d) DMSO, (COCl)2,
CH2Cl2, –78 °C, then i-Pr2NEt, –78 to 0 °C, 95%; (e) NaClO2,
NaH2PO4, DMSO–H2O (4:1), r.t.; (f) CH2N2, Et2O, MeOH, 0 °C,
78% (2 steps).
Boc
20
4
Scheme 3 Synthesis of intermediate 4. Reagents and conditions: (a)
NaHMDS, THF, –78 °C, then Garner aldehyde (6), THF, –78 °C,
69%; (b) NaHMDS, THF, 0 °C, then CS2, then MeI, 0 °C to r.t.;
(c) n-Bu3SnH, AIBN, toluene, reflux, 53% (2 steps) (92% based on
recovery of 18); (d) DIBAL-H, CH2Cl2, –100 °C, 88%; (e)
H2C=CH2MgBr, THF, 0 °C, 93%.
The secondary hydroxy group in 18 was eliminated by use
of the Barton–McCombie protocol,17 to give the deoxy-
genated product 19 in 53% overall yield (92% yield based
on recovery of 18). At this stage, the C4 stereochemistry
could be unambiguously confirmed by 500-MHz 1H
NMR NOESY experiments of 19, in which a clear NOE
interaction between C3-H and C5-H was observed.
recovery of 22). At this stage, the C9 configuration of the
Grignard reaction product 4 (cf. Scheme 3) was deter-
mined to be R by an NOESY experiment of 2; the selected
NOE correlation is depicted in the formula 2A
(Scheme 4): clear NOE interactions between a C3-H and
C5-H, a C3-H and C9-H, an -OSiMe group and an isopro-
pylidene Me group, and an -OSiMe group and C6-H are
observed; this revealed an R-configuration at C9.
To continue the synthesis, methyl ester 19 was reduced
with diisobutylaluminum hydride in dichloromethane at
–100 °C, providing the corresponding aldehyde 20 in 88%
yield. Subsequent Grignard reaction of 20 with vinylmag-
nesium bromide in tetrahydrofuran at 0 °C furnished
diene 4 in 93% yield as the single diastereomer. This re-
action proceeded presumably through the usual Felkin–
Anh model. The C9 stereochemistry of 4 was later con-
firmed by a NOESY experiment of the transformed com-
pound 2 (see below).
OR
9
OH
a
O
PMBO
O
O
PMBO
O
N
O
N
O
Boc
Boc
21: R = H
4
b
22: R = TBS
Synthesis of Cyclohexenone Segment 2
t-Bu
Me
We next conducted the synthesis of the cyclohexene seg-
ment 2 as shown in Scheme 4. The critical RCM
reaction18 of diene 4 proceeded smoothly and cleanly in
refluxing dichloromethane in the presence of the first-
generation Grubbs catalyst [RuCl2(=CHPh)(PCy3)2]19 (10
mol%) for 12 hours, and the desired cyclohexene 21 was
produced in 96% yield. After protection of the secondary
hydroxy group in 21 (93% yield), the N,O-isopropylidene
group of the resulting tert-butyldimethylsilyl ether 22 was
selectively cleaved by treatment with pyridinium p-tolu-
enesulfonate in ethanol at 60 °C; this gave the requisite
cyclohexene segment 2 in 57% yield (84% yield based on
NOEs
Si
Me
Me
O
Me
9
OTBS
3
H
6
O
c
O
6
9
OH
PMBO
5
O
H
5
NH
Boc
PMBO
O
3
H
H
OH
NHBoc
H
2
2A
Scheme 4 Synthesis of intermediate 2. Reagents and conditions: (a)
[RuCl2(=CHPh)(PCy3)2] (10 mol%), CH2Cl2, reflux, 96%; (b)
TBSOTf, 2,6-lutidine, CH2Cl2, r.t., 93%; (c) PPTS, EtOH, 60 °C,
57% (84% based on recovery of 22).
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

626
M. Inoue et al.
FEATURE ARTICLE
tempts to realize the crucial Negishi coupling reaction of
10 and 9 under the original conditions24,25 [e.g., t-BuLi
(2.0 equiv), ZnCl2 (1.0 equiv), THF or Et2O, –78 °C to r.t.
for preparation of the zinc reagent of 10; Pd(PPh3)4, THF
or Et2O, r.t. to 50 °C for the coupling reaction with 9] re-
sulted in failure; the coupling product 28 was not ob-
tained. The preparation of the zinc reagent of 10 with
activated zinc, Rieke zinc, and a zinc–copper couple was
also unsuccessful. After several experiments, to our de-
light, we found that the use of the modified conditions de-
veloped by Smith et al.26 gave satisfactory results. Thus, a
mixture of 10 and one equivalent of zinc(II) chloride in di-
ethyl ether was treated with three equivalents of tert-
butyllithium to generate the putative mixed zinc reagent
27,26 which was allowed to react with vinyl iodide 9 in the
presence of tetrakis(triphenylphosphine)palladium (10
mol%) in tetrahydrofuran at room temperature for 13
hours, leading to the desired coupling product 28 in 84%
yield. In this reaction, the minor inseparable 3-iodo regio-
isomer of 9, as we expected, did not give the correspond-
ing coupling product and was recovered unchanged.
Syntheses of Vinyl Iodide 9 and Alkyl Iodide 10
Having established the synthetic pathway to the cyclohex-
ene segment 2 possessing the requisite multifunctional
groups and all the correct stereochemistries, we next un-
dertook the syntheses of vinyl iodide 9 and alkyl iodide
10, both key intermediates for the synthesis of the 20-car-
bon fatty acid segment 3. As shown in Scheme 5, vinyl io-
dide 9 was prepared from the known aldehyde 23,20 easily
derived from commercially available methyl (R)-3-hy-
droxy-2-methylpropionate (11). Thus, aldehyde 23 was
subjected to Corey–Fuchs acetylene formation–
methylation21 to afford methylacetylene 24 in 94% yield.
Subsequent hydrozirconation–iodination22 (Cp2ZrHCl,
benzene, 40 °C; I2, r.t.) of 24 produced the desired vinyl
iodide 9 in 70% yield as a mixture of 2- and 3-iodo regio-
1
isomers (2-I/3-I, 87:17 by 500-MHz H NMR) that were
very difficult to separate.
ref. 20
Me
Me
a, b
HO
BnO
BnO
CO2Me
CHO
(2 steps)
In the next stage, we examined the conversion of the cou-
pling product 28 into the Hoye intermediate 8 (Scheme 6).
Initial attempts to remove the benzyl protecting group
from 28 under Birch conditions [Li (20 equiv), NH3(l),
tetrahydrofuran, –30 °C] turned out to be fruitless; unex-
pectedly, the benzene rings of the tert-butyldiphenylsilyl
group were predominantly reduced to form the corre-
sponding cyclohexa-1,4-diene rings. After several trials,
we were pleased to find that lithium 4,4¢-di-tert-butylbi-
phenylide (LiDBB)27 was quite effective for this purpose;
the desired alcohol 29 was obtained in 90% yield. Subse-
quent tosylation of 29 under standard conditions delivered
the Hoye intermediate 8.10
11
23
Me
Me Me
c
BnO
2
3
I
Me
24
9
ref. 23
Me
Me
Me
d
OTBDPS
OH
MeO2C
(5 steps)
25
ent-11
Me
Me
Me
Me
e, f
Further transformation of tosylate 8 into aldehyde 32
(Scheme 6) proceeded via intermediates 30 and 31 by se-
quential methylation with Me2CuLi (97% yield), depro-
tection of the tert-butyldiphenylsilyl group in 30 with
tetrabutylammonium fluoride (91% yield), and oxidation
of 31 with n-Pr4NRuO4.28 Aldehyde 32 was then subjected
to the HWE reaction with the known dimethyl phospho-
nate 3329 to provide methyl ester 34 (46% yield from 31)
and its 6¢Z-isomer (17% yield from 31); these products
were separated by HPLC. Spectral data (1H NMR and 13C
NMR, MS) of 34 were in good agreement with those re-
ported by Kogen et al.9 Finally, the desired acid chloride
3 was synthesized from 34 via carboxylic acid 35 by alkali
hydrolysis of 34 with two molar potassium hydroxide fol-
lowed by reaction with oxalyl chloride in the presence of
N,N-dimethylformamide.
HO
OTBDPS
I
OTBDPS
26
10
Scheme 5 Synthesis of intermediates 9 and 10. Reagents and con-
ditions: (a) PPh3, CBr4, CH2Cl2, 0 °C; (b) n-BuLi, THF, –78 °C, then
MeI, 0 °C, 94% (2 steps); (c) Cp2ZrHCl, benzene, 40 °C, then I2, r.t.,
70%; (d) O3, CH2Cl2–MeOH (3:1), –78 °C, then NaBH4, r.t., 84%; (e)
MsCl, Et3N, CH2Cl2, r.t.; (f) NaI, acetone, reflux, 95% (2 steps).
Alkyl iodide 10, the coupling partner of 9, was prepared
from the known olefin 2523 that was accessed from the
commercially available S-isomer of 11 (ent-11)
(Scheme 5). Thus, ozonolysis of 25 followed by reductive
workup with sodium borohydride provided the corre-
sponding alcohol 26 in 84% yield. Compound 26 was then
converted into alkyl iodide 10 in 95% overall yield in a
two-step sequence involving conventional mesylation and
iodination.
Completion of the Total Synthesis of
(+)-Scyphostatin (1)
Synthesis of the C-20 Fatty Acid Segment 3
The final route that led to completion of the total synthesis
of (+)-scyphostatin (1) is summarized in Scheme 7. At
first, we investigated the coupling reaction between the
cyclohexene segment 2 and the fatty acid segment 3.
With both vinyl iodide 9 and alkyl iodide 10 in hand, our
next efforts were devoted to the synthesis of the 20-carbon
fatty acid segment 3, as shown in Scheme 6. Our initial at-
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Total Synthesis of (+)-Scyphostatin
627
Me
Me
Me
Me
a
Zn
OTBDPS
I
OTBDPS
t-Bu
Me
27
10
Me
Me
Me
d
OTBDPS
RO
28: R = Bn
29: R = H
8: R = Ts
b
c
Me
Me
Me
Me
Me
Me
Me
Me
f
OR
Me
Me
CHO
30: R = TBDPS
31: R = H
32
e
g
Me
Me
Me
Me
6’
Me
COR
MeO
MeO
P
CO2Me
34: R = OMe
35: R = OH
3: R = Cl
h
i
O
33
Scheme 6 Synthesis of the intermediate 3. Reagents and conditions: (a) t-BuLi, ZnCl2, Et2O, –78 to 0 °C, then 9, Pd(PPh3)4, THF, r.t., 81%;
(b) LiDBB, THF, –78 °C, 90%; (c) TsCl, Et3N, DMAP, CH2Cl2, r.t.; (d) Me2CuLi, Et2O, –40 °C, 97% (2 steps); (e) TBAF, THF, r.t., 91%; (f)
n-Pr4NRuO4, NMO, MS, CH2Cl2, r.t.; (g) 33, LDA, THF, –78 to –30 °C, 46% (2 steps); (h) 2 M aq KOH, MeOH–THF, r.t.; (i) (COCl)2, CH2Cl2,
DMF, r.t.
Thus, the tert-butoxycarbonyl and p-methoxybenzyl pro- ride–silica gel, and acetic acid turned out to be ineffective;
tecting groups of 2 were simultaneously removed by treat- the corresponding diol was not obtained and the starting
ment with trimethylsilyl triflate30 in the presence of 2,6- material 40 was recovered unchanged. Eventually, we
lutidine to produce amine 36, wherein the two hydroxy overcame this problem by using aqueous trichloroacetic
groups were partially protected as the trimethylsilyl acid; this, followed by treatment with two molar sodium
ethers. The liberated amine 36 was immediately treated hydroxide at ambient temperature, produced the desired
with acid chloride 3 in the presence of triethylamine to epoxide 41 in 45% overall yield (82% yield based on re-
give the amide coupling product 37 (73% yield from 2) covery of 40) without appreciable isomerization of the
upon treatment with aqueous acetic acid. Amide 37 was C12¢–C13¢ double bond (Scheme 7).
further converted into mesylate 39 in 67% overall yield by
The final step was deprotection of the acetyl group in 41.
selective acetylation of the primary hydroxy group and
Initial attempts to achieve this under conventional condi-
subsequent mesylation of the secondary hydroxy group in
tions (e.g., K2CO3, NaOMe, KOH in MeOH, aq KOH in
the resulting acetate 38. Deprotection of the tert-bu-
THF or CH2Cl2, DBU or NH3 in THF) resulted in failure;
disappearance of the starting material 41 could be ascer-
tained by TLC analysis, while unidentified decomposition
products were generated in the reaction mixture. We rea-
tyldimethylsilyl group in 39 followed by Dess–Martin
oxidation31 furnished enone 40 in 98% yield for the two
steps.
The remaining task to complete the projected synthesis soned that this failure was due to the sensitivity of the ep-
was cleavage of the N,O-isopropylidene moiety in 40 fol- oxyenone moiety to these basic conditions. Therefore, we
lowed by epoxide-ring formation and final deprotection of decided to attempt the acetyl deprotection by an enzymat-
the acetyl group. In our preliminary model studies,12 the ic method in the hope that the sensitive epoxyenone sys-
epoxide-ring formation was successfully achieved by hy- tem would remain intact under such relatively mild
drolysis of an N,O-isopropylidene moiety with aqueous conditions. After the screening of several enzymes such as
trifluoroacetic acid followed by treatment with one molar lipases PS, AY-30G, and F-AP15, we were pleased to find
sodium hydroxide at 0 °C. Upon applying these condi- that the desired acetyl deprotection was best achieved by
tions to 40, however, partial isomerization of the C12¢– the use of lipase PS. Thus, exposure of 41 to lipase PS in
C13¢ double bond in the side chain was observed; this is phosphate buffer–acetone at room temperature for ten
presumably due to the use of a strong acid such as trifluo- hours provided (+)-scyphostatin (1) in 60% yield
1
roacetic acid. Less strong acids such as p-toluenesulfonic (Scheme 7); the spectroscopic properties (IR, H NMR
acid, pyridinium p-toluenesulfonate, hydrogen chloride, and 13C NMR, and MS) of this product were identical with
boron trifluoride–diethyl ether complex, iron(III) chlo- those of natural 1. The optical rotation of a synthetic sam-
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

628
M. Inoue et al.
FEATURE ARTICLE
the cyclohexene segment 2 and the fatty acid segment 3;
and (e) stereospecific epoxide-ring formation of mesylate
40 to deliver the fully functionalized cyclohexene 2. Im-
portantly, the explored synthetic route has the potential
for producing scyphostatin analogues possessing a variety
of fatty acid side chains in enantiomerically pure forms.
These efforts are currently underway.
OTBS
OTBS
OH
PMBO
OH(TMS)
O
(TMS)HO
O
a
NH
NH2
O
O
Boc
2
36
OTBS
Routine monitoring of reactions was carried out on glass-supported
Merck silica gel 60 F254 TLC plates. Flash column chromatography
was performed on Kanto Chemical Silica Gel 60N (spherical, neu-
tral 40–50 mm) with the solvents indicated at the pertinent proce-
dures. All solvents and reagents were used as supplied, with the
following exceptions. THF and Et2O were freshly distilled from Na/
benzophenone under argon. Toluene was distilled from Na under
argon. CH2Cl2, DMSO, DMF, and benzene were distilled from
CaH2 under argon. Optical rotations were measured on a JASCO P-
1020 automatic digital polarimeter. Melting points were determined
on a Yanaco MP-3 micro melting point apparatus and are uncorrect-
ed. 1H NMR and 13C NMR spectra were obtained on a Bruker DRX-
500 (500 MHz) spectrometer. Chemical shifts are expressed in ppm
relative to TMS (d = 0) as internal standard. IR spectra were mea-
sured on a JASCO FT/IR-5300 spectrometer. HRMS spectra were
obtained on a JEOL MStation JMS-700 mass spectrometer.
R2O
b
O
OR1
Me
Me
Me
Me
O
NH
Me
O
37: R1 = R2 = H
c
38: R1 = Ac, R2 = H
39: R1 = Ac, R2 = Ms
d
O
e, f
MsO
O
OAc
NH
Me
Me
Me
Me
O
Me
O
40
Benzyl 3,4-O-Isopropylidene-2-O-(4-methoxybenzyl)-b-D-ara-
binoside (13)
O
A soln of 1216 (5.00 g, 18 mmol) in anhyd DMSO (10 mL) was add-
ed dropwise to a stirred suspension of NaH (60% dispersion in min-
eral oil; 1.00 g, 25 mmol) in anhyd DMSO (15 mL) at 0 °C under
argon. After the mixture had stirred for 1 h at r.t., PMBCl (3.10 mL,
23 mmol) was added, and stirring was continued for 15 h at r.t. The
reaction was quenched with sat. aq NH4Cl (10 mL) at 0 °C, and the
resulting mixture was extracted with Et2O (2 × 50 mL). The com-
bined extracts were washed with sat. aq NaHCO3 (2 × 30 mL) and
brine (30 mL), and then dried (MgSO4). Concentration of the soln
in vacuo afforded a residue, which was purified by column chroma-
tography (hexane–EtOAc, 3:1) to give a white solid; yield: 5.00 g
(70%).
OH
g
O
OR
NH
Me
Me
Me
Me
12’
Me
13’
O
41: R = Ac
1: R = H [ (+)-scyphostatin ]
h
Scheme 7 Synthesis of (+)-scyphostatin (1). Reagents and condi-
tions: (a) TMSOTf, 2,6-lutidine, CH2Cl2, r.t., then MeOH; (b) 3, Et3N,
CH2Cl2, r.t., then aq AcOH, 73% (2 steps); (c) Ac2O, py, DMAP,
CH2Cl2, r.t., 72%; (d) MsCl, Et3N, CH2Cl2, r.t., 93%; (e) TBAF, THF,
r.t.; (f) DMP, CH2Cl2, r.t., 98% (2 steps); (g) Cl3CCO2H, H2O,
CH2Cl2, reflux, then 2 M NaOH, r.t., 45% (82% based on recovery of
40); (h) lipase PS, pH 7 phosphate buffer, acetone, r.t., 60%.
White powder (recrystallization, hexane–CHCl3, 3:1); mp 52.0–
53.0 °C; [a]D20 –160.6 (c 1.04, CHCl3).
IR (KBr): 744, 1030, 1091, 1178, 1255, 1383, 1516, 1612, 2926,
2951, 3024 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.35 (s, 3 H), 1.43 (s, 3 H), 3.52
(dd, J = 3.4, 7.8 Hz, 1 H), 3.79 (s, 3 H), 3.92 (dd, J = 0.7, 3.3 Hz, 1
H), 3.97 (dd, J = 2.7, 3.3 Hz, 1 H), 4.22 (m, 1 H), 4.36 (dd, J = 5.7,
7.8 Hz, 1 H), 4.52 (d, J = 12.4 Hz, 1 H), 4.56 (d, J = 12.1 Hz, 1 H),
4.65 (d, J = 12.1 Hz, 1 H), 4.72 (d, J = 12.4 Hz, 1 H), 4.81 (d,
J = 3.4 Hz, 1 H), 6.83 (d, J = 8.7 Hz, 2 H), 7.23 (d, J = 8.7 Hz, 2 H),
7.28–7.40 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 26.3, 28.2, 55.3, 58.9, 69.2, 71.8,
73.5, 75.4, 76.4, 95.8, 108.8, 113.7 (2 C), 127.8, 127.9 (2 C), 128.4
(2 C), 129.4 (2 C), 130.4, 137.3, 159.2.
25
ple of 1 {[a]D +61.0 (c 0.04, MeOH)} was identical to
that of natural 1 {[a]D25 +66.4 (c 0.09, MeOH)}.
Conclusion
We have accomplished the first total, enantioselective
synthesis of naturally occurring (+)-scyphostatin (1),
starting from D-arabinose derivative 12 in 22 steps (linear
sequence of reactions). The key steps of the synthesis
were (a) a stereoselective aldol-type coupling reaction of
ester 5, derived from D-arabinose (7), with Garner alde-
hyde (6) to establish the requisite asymmetric quaternary
carbon center at C4; (b) RCM reaction of diene 4 to con-
struct the cyclohexene ring 21; (c) Negishi coupling be-
tween alkyl iodide 10 and vinyl iodide 9 to give
trisubstituted E-olefin 28; (d) amide formation to connect
Anal. Calcd for C23H28O6: C, 68.98; H, 7.05. Found C, 68.87; H,
7.18.
3,4-O-Isopropylidene-2-O-(4-methoxybenzyl)-D-arabinose (14)
A mixture of 13 (5.00 g, 12.5 mmol) and Raney Ni (W-2, 5.00 g) in
EtOH (50 mL) was stirred for 12 h under H2 (1 atm) at r.t. The mix-
ture was diluted with EtOAc (50 mL), and then the catalyst was re-
moved by filtration of the mixture through a small pad of Celite.
Concentration of the filtrate in vacuo afforded a residue, which was
purified by column chromatography (hexane–EtOAc, 2:1 to 1:1);
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Total Synthesis of (+)-Scyphostatin
629
this gave a mixture of a- and b-anomers 14 (a/b, 1:2) as a white
semisolid.
(2S,3S,4R)-2,3-O-Isopropylidenedioxy-4-(4-methoxybenzyl-
oxy)hex-5-enal (16)
DMSO (2.52 mL, 36 mmol) was added dropwise to a stirred soln of
oxalyl chloride (2.33 mL, 27 mmol) in CH2Cl2 (80 mL) at –78 °C
under argon. After 20 min, a soln of 15 (2.74 g, 8.9 mmol) in CH2Cl2
(40 mL) was added at –78 °C, and stirring was continued for 30 min
at the same temperature. After addition of i-Pr2NEt (12.0 mL, 69
mmol) at –78 °C, the mixture was gradually warmed to 0 °C over 1
h. The reaction was quenched with H2O (20 mL) at 0 °C, and the
mixture was extracted with Et2O (2 × 80 mL). The combined ex-
tracts were washed successively with 3% aq HCl (2 × 50 mL), sat.
aq NaHCO3 (2 × 40 mL), and brine (50 mL), and then dried
(MgSO4). Concentration of the soln in vacuo afforded a residue,
which was purified by column chromatography (hexane–EtOAc,
5:1).
Yield: 2.50 g (86%); [a]D20 –47.0 (c 1.00, CHCl3).
Recrystallization of the anomeric mixtures (hexane–CHCl3, 3:1)
gave pure b-anomer 14 as white needles.
Mp 115.5–116.5 °C; [a]D20 –49.4 (c 1.00, CHCl3).
IR (KBr): 778, 1035, 1066, 1177, 1244, 1377, 1510, 1612, 2932,
2959, 3013, 3323 cm–1.
1H NMR (500 MHz, CDCl3): d (a-anomer) = 1.36 (s, 3 H), 1.48 (s,
3 H), 3.45 (d, J = 6.7 Hz, 1 H), 3.47 (m, 1 H), 3.80 (s, 3 H), 3.80
(ddd, J = 0.8, 3.4, 13.1 Hz, 1 H), 4.06 (dd, J = 2.1, 13.0 Hz, 1 H),
4.20–4.24 (m, 2 H), 4.69 (d, J = 11.4 Hz, 1 H), 4.71 (m, 1 H), 4.72
(d, J = 11.4 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2 H), 7.31 (dd, J = 8.6 Hz,
2 H).
13C NMR (125 MHz, CDCl3): d (a-anomer) = 25.8, 27.6, 55.3, 62.5,
72.70, 72.71, 77.2, 78.8, 95.5, 109.9, 113.8 (2 C), 129.7 (2 C),
130.0, 159.4.
1H NMR (500 MHz, CDCl3): d (b-anomer) = 1.36 (s, 3 H), 1.46 (s,
3 H), 3.09 (d, J = 5.7 Hz, 1 H), 3.60 (dd, J = 3.4, 5.9 Hz, 1 H), 3.80
(s, 3 H), 3.83 (dd, J = 2.0, 13.0 Hz, 1 H), 4.12 (dd, J = 3.0, 13.0 Hz,
1 H), 4.23 (m, 1 H), 4.37 (t, J = 6.0 Hz, 1 H), 4.61 (d, J = 11.7 Hz,
1 H), 4.74 (d, J = 11.7 Hz, 1 H), 5.11 (dd, J = 3.4, 5.7 Hz, 1 H), 6.88
(d, J = 8.6 Hz, 2 H), 7.27 (dd, J = 8.6 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d (b-anomer) = 25.9, 27.7, 55.3, 60.0,
72.4, 72.6, 74.4, 75.6, 90.9, 109.2, 113.9 (2 C), 129.71 (2 C),
129.73, 159.5.
Yield: 2.59 g (95%); colorless oil; [a]D20 –75.2 (c 1.00, CHCl3).
IR (neat): 831, 1033, 1072, 1250, 1381, 1516, 1614, 1724, 2868,
2988, 3076 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.37 (s, 3 H), 1.57 (s, 3 H), 3.78
(dd, J = 2.4, 8.2 Hz, 1 H), 3.80 (s, 3 H), 4.01 (d, J = 10.9 Hz, 1 H),
4.37 (dd, J = 2.0, 8.2 Hz, 1 H), 4.39 (d, J = 10.9 Hz, 1 H), 4.49 (dd,
J = 2.4, 8.1 Hz, 1 H), 5.35 (d, J = 17.3 Hz, 1 H), 5.38 (d, J = 10.3
Hz, 1 H), 5.94 (ddd, J = 8.1, 10.3, 17.3 Hz, 1 H), 6.85 (d, J = 8.7 Hz,
2 H), 7.22 (d, J = 8.7 Hz, 2 H), 9.56 (d, J = 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 25.1, 26.5, 55.2, 69.5, 77.6, 80.5,
82.9, 111.2, 113.6 (2 C), 119.9, 129.2 (2 C), 129.9, 134.3, 159.1,
201.3.
HRMS–FAB: m/z [M + H]+ calcd for C17H23O5: 307.1546; found:
307.1559.
HRMS–FAB: m/z [M + H]+ calcd for C16H23O6: 311.1495; found:
311.1509.
Methyl (2S,3S,4R)-2,3-O-Isopropylidenedioxy-4-(4-methoxy-
benzyloxy)hex-5-enoate (5)
(2R,3S,4R)-2,3-O-Isopropylidene-4-(4-methoxybenzyloxy)hex-
5-ene-1,2,3-triol (15)
NaClO2 (4.52 g, 50 mmol) was added in small portions to a stirred
soln of 16 (3.04 g, 9.9 mmol) and NaH2PO4 (7.76 g, 50 mmol) in
DMSO–H2O (4:1, 100 mL) at r.t. After 1 h, the reaction was
quenched with 15% aq Na2S2O3 (30 mL) at 0 °C, and the mixture
was extracted with EtOAc (3 × 70 mL). The organic layer was
washed with brine (2 × 50 mL), and then dried (MgSO4). Concen-
tration of the soln in vacuo afforded the corresponding carboxylic
acid (2.80 g), which was directly, without further purification, used
for the next reaction.
t-BuOK (3.10 g, 28 mmol) was added to a stirred suspension of
Ph3MeP+Br– (10.4 g, 29 mmol) in anhyd benzene (80 mL), and the
resulting mixture was heated at reflux for 3 h under argon. A soln of
14 (1.75 g, 5.6 mmol) in anhyd THF (40 mL) was added to the phos-
phorane soln, and the resulting mixture was heated at reflux for 1 h.
After cooling, the reaction mixture was quenched with sat. aq
NH4Cl (40 mL) at 0 °C, and then extracted with Et2O (2 × 60 mL).
The organic layer was washed successively with sat. aq NaHCO3
(2 × 40 mL) and brine (40 mL), and then dried (MgSO4). Concen-
tration of the soln in vacuo afforded a residue, which was purified
by column chromatography (hexane–EtOAc, 4:1).
A 0.5 M soln of CH2N2 in Et2O (24.0 mL, 12 mmol) was added
dropwise to a stirred soln of the crude carboxylic acid (2.80 g) in
MeOH (20 mL) at 0 °C, and stirring was continued for 30 min at r.t.
The reaction was quenched with AcOH (2.0 mL) at 0 °C, and the re-
sulting mixture was diluted with Et2O (100 mL). The organic layer
was washed with sat. aq NaHCO3 (3 × 30 mL) and brine (30 mL),
and then dried (MgSO4). Concentration of the soln in vacuo afford-
ed a residue, which was purified by column chromatography (hex-
ane–EtOAc, 3:1); this gave 5 as a colorless oil.
Yield: 1.50 g (86%); colorless oil; [a]D20 –19.4 (c 1.04, CHCl3).
IR (neat): 756, 933, 1037, 1248, 1379, 1514, 1612, 2839, 2986,
3076, 3474 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.37 (s, 3 H), 1.50 (s, 3 H), 2.60
(dd, J = 5.3, 7.9 Hz, 1 H), 3.66 (dt, J = 11.8, 5.6 Hz, 1 H), 3.72 (ddd,
J = 4.9, 7.9, 11.8 Hz, 1 H), 3.80 (s, 3 H), 3.96 (dd, J = 5.3, 7.9 Hz,
1 H), 4.18 (dt, J = 5.1, 6.0 Hz, 1 H), 4.24 (dd, J = 5.4, 6.2 Hz, 1 H),
4.38 (d, J = 11.5 Hz, 1 H), 4.61 (d, J = 11.5 Hz, 1 H), 5.36 (d,
J = 17.3 Hz, 1 H), 5.40 (d, J = 10.3 Hz, 1 H), 5.91 (ddd, J = 8.0,
10.3, 17.3 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 2 H), 7.26 (d, J = 8.7 Hz, 2
H).
Yield: 2.61 g (78%, over 2 steps); [a]D20 –34.2 (c 1.01, CHCl3).
IR (neat): 823, 1076, 1248, 1381, 1514, 1614, 1730, 1761, 2839,
2988, 3076 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.39 (s, 3 H), 1.60 (s, 3 H), 3.53
(s, 3 H), 3.79 (s, 3 H), 4.01 (dd, J = 4.0, 8.0 Hz, 1 H), 4.20 (d,
J = 11.5 Hz, 1 H), 4.43 (dd, J = 4.0, 7.3 Hz, 1 H), 4.51 (d, J = 11.5
Hz, 1 H), 4.67 (d, J = 7.3 Hz, 1 H), 5.34 (d, J = 17.3 Hz, 1 H), 5.36
(d, J = 10.4 Hz, 1 H), 5.90 (ddd, J = 8.0, 10.4, 17.3 Hz, 1 H), 6.85
(d, J = 8.6 Hz, 2 H), 7.23 (d, J = 8.6 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 25.4, 27.2, 55.2, 61.2, 70.1, 77.7,
78.0, 78.8, 108.7, 113.8 (2 C), 120.3, 129.5, 129.6 (2 C), 134.8,
159.3.
HRMS–FAB: m/z [M + H]+ calcd for C17H25O5: 309.1702; found:
309.1700.
13C NMR (125 MHz, CDCl3): d = 25.5, 26.6, 51.8, 55.2, 69.7, 75.3,
78.4, 80.4, 110.8, 113.5 (2 C), 119.7, 128.5 (2 C), 130.4, 134.8,
158.8, 170.2.
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

630
M. Inoue et al.
FEATURE ARTICLE
HRMS–FAB: m/z [M + H]+ calcd for C18H25O6: 337.1651; found:
337.1668.
mers in the tert-butyl carbamate group resulted in extensive line
1
broadening, and, in some instances, doubling of signals in the H
NMR and 13C NMR spectra.)
Methyl (2S,3S,4R)-2-{[(4R)-3-tert-Butoxycarbonyl-2,2-dimeth-
yloxazolidin-4-yl]hydroxymethyl}-2,3-O-isopropylidenedioxy-
4-(4-methoxybenzyloxy)hex-5-enoate (18)
Yield: 475 mg [53%, or 92% based on recovery of starting material
18 (389 mg, 42%)]; [a]D20 –10.4 (c 0.72, CHCl3).
IR (neat): 770, 852, 1088, 1249, 1389, 1516, 1615, 1698, 1732,
2937, 2982, 3080 cm–1.
A 1.0 M soln of NaHMDS in THF (2.96 mL, 3.0 mmol) was added
dropwise to a stirred soln of 5 (796 mg, 2.4 mmol) in anhyd THF
(25 mL) at 0 °C under argon. After 20 min, a soln of the Garner al-
dehyde (6; 598 mg, 2.6 mmol) in anhyd THF (10 mL) was added at
–78 °C, and the resulting soln was stirred for 4 h at the same tem-
perature. The reaction was quenched with sat. aq NH4Cl (20 mL) at
–78 °C, and the mixture was extracted with Et2O (2 × 50 mL). The
combined extracts were washed with sat. aq NaHCO3 (2 × 30 mL)
and brine (30 mL), and then dried (MgSO4). Concentration of the
soln in vacuo afforded a residue, which was purified by column
chromatography (hexane–EtOAc, 8:1 to 5:1); this gave 18 as a
white solid; yield: 930 mg (69%). (Note that the presence of rota-
mers in the tert-butyl carbamate group resulted in extensive line
1H NMR (500 MHz, CDCl3): d = 1.45 (s, 6 H), 1.47 (s, 9 H), 1.56
(br s, 3 H), 1.59 (s, 3 H), 1.82 (br s, 1 H), 2.45 (br s, 0.5 H), 2.65 (br
s, 0.5 H), 3.51 (s, 3 H), 3.78 (s, 3 H), 3.79 (br, 1 H), 3.85 (br, 1 H),
4.03 (d, J = 2.8 Hz, 1 H), 4.08 (br, 1 H), 4.19 (d, J = 11.4 Hz, 1 H),
4.25 (br, 1 H), 4.48 (br, 1 H), 5.31–5.41 (m, 2 H), 5.95 (ddd, J = 7.8,
10.3, 17.7 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 2 H), 7.22 (d, J = 8.6 Hz, 2
H).
13C NMR (125 MHz, CDCl3): d = 27.0 (2 C), 27.7 (3 C), 28.5 (2 C),
41.4, 52.0, 54.8, 55.2, 67.1, 69.8, 78.0, 79.9, 84.0, 87.8, 93.1, 111.4,
113.5 (2 C), 119.4, 128.4 (2 C), 130.5, 134.9, 151.6, 158.8, 171.6.
HRMS–FAB: m/z [M + H]+ calcd for C29H44NO9: 550.3016; found:
550.3039.
1
broadening, and, in some instances, doubling of signals in the H
NMR and 13C NMR spectra.)
Colorless needles (recrystallization, hexane–CH2Cl2, 4:1); mp
(2S,3S,4R)-2-{[(4S)-3-tert-Butoxycarbonyl-2,2-dimethyloxazoli-
din-4-yl]methyl}-2,3-O-isopropylidenedioxy-4-(4-methoxyben-
zyloxy)hex-5-enal (20)
86.5–88.0 °C; [a]D20 –13.1 (c 1.08, CHCl3).
IR (KBr): 772, 843, 1067, 1251, 1370, 1399, 1518, 1614, 1688,
1724, 2939, 2982, 3090, 3489 cm–1.
A 1.0 M soln of DIBAL-H in toluene (0.11 mL, 0.11 mmol) was
added dropwise to a stirred soln of 19 (54.0 mg, 0.10 mmol) in an-
hyd CH2Cl2 (2 mL) at –100 °C under argon. After 1 h, the reaction
was quenched with MeOH (1 mL) at –100 °C. A 15% aq soln of
Rochelle salt (5 mL) was added to the mixture at 0 °C, and stirring
was continued for 1 h at r.t. The resulting mixture was extracted
with Et2O (3 × 20 mL). The combined extracts were washed with
brine (2 × 20 mL), and then dried (MgSO4). Concentration of the
soln in vacuo afforded a residue, which was purified by column
chromatography (hexane–EtOAc, 5:1); this gave 20 as a colorless
oil. (Note that the presence of rotamers in the tert-butyl carbamate
group resulted in extensive line broadening, and, in some instances,
doubling of signals in the 1H NMR and 13C NMR spectra.)
1H NMR (500 MHz, CDCl3): d = 1.46 (br s, 3 H), 1.49 (br s, 3 H),
1.50 (br s, 9 H), 1.62 (s, 6 H), 2.52 (br s, 0.5 H), 2.93 (br s, 0.5 H),
3.46 (s, 3 H), 3.78 (s, 3 H), 3.85 (dd, J = 6.5, 9.6 Hz, 1 H), 3.90–4.10
(m, 2 H), 4.14 (d, J = 11.4 Hz, 1 H), 4.23–4.38 (m, 2 H), 4.50 (d,
J = 11.4 Hz, 1 H), 4.59 (br s, 1 H), 5.31–5.40 (m, 2 H), 5.96 (ddd,
J = 8.0, 10.3, 17.6 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 2 H), 7.21 (d,
J = 8.6 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 27.0 (4 C), 28.5 (3 C), 52.0, 55.2,
58.9, 63.7, 69.7, 71.8, 77.3, 80.5, 83.7, 86.2, 93.5, 111.7, 113.5 (2
C), 119.2, 128.4 (2 C), 130.6, 135.5, 152.3, 158.8, 171.3.
HRMS–FAB: m/z [M + H]+ calcd for C29H44NO10: 566.2965;
found: 566.2938.
Yield: 45.0 mg (88%); [a]D20 –30.5 (c 0.63, CHCl3).
IR (neat): 770, 849, 1092, 1250, 1389, 1516, 1614, 1698, 1730,
2935, 2982, 3070 cm–1.
Methyl (2S,3S,4R)-2-{[(4S)-3-tert-Butoxycarbonyl-2,2-dimethyl-
oxazolidin-4-yl]methyl}-2,3-O-isopropylidenedioxy-4-(4-meth-
oxybenzyloxy)hex-5-enoate (19)
1H NMR (500 MHz, CDCl3): d = 1.47 (s, 6 H), 1.49 (s, 9 H), 1.55
(s, 3 H), 1.57 (br s, 3 H), 1.75 (br, 1 H), 2.41 (br s, 0.5 H), 2.65 (br
s, 0.5 H), 3.75 (br, 1 H), 3.79 (s, 3 H), 3.82–3.90 (br, 2 H), 4.02 (d,
J = 2.9 Hz, 1 H), 4.05–4.20 (br, 2 H), 4.44 (br, 1 H), 5.33–5.43 (m,
2 H), 5.91 (ddd, J = 8.0, 10.3, 17.3 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 2
H), 7.22 (d, J = 8.6 Hz, 2 H), 9.52 (br s, 1 H).
13C NMR (125 MHz, CDCl3): d = 27.6 (4 C), 28.5 (3 C), 39.2, 54.3,
55.2, 67.7, 69.9, 77.2, 80.1, 87.3, 89.0, 93.3, 111.7, 113.7 (2 C),
119.9, 129.6 (3 C), 134.4, 151.7 159.2, 200.6.
A 1.0 M soln of NaHMDS in THF (4.00 mL, 4.0 mmol) was added
dropwise to a stirred soln of 18 (924 mg, 1.6 mmol) in anhyd THF
(35 mL) at 0 °C under argon. After 20 min, CS2 (0.90 mL, 15 mmol)
was added dropwise to the above soln at 0 °C, and stirring was con-
tinued for 20 min at the same temperature. MeI (1.00 mL, 16 mmol)
was then added dropwise to the stirred soln at 0 °C, and then the re-
sulting soln was allowed to warm to r.t. over 30 min. The reaction
was quenched with sat. aq NH4Cl (10 mL) at 0 °C, and the mixture
was extracted with Et2O (3 × 40 mL). The organic layer was washed
with sat. aq NaHCO3 (2 × 30 mL) and brine (30 mL), and then dried
(MgSO4). Concentration of the soln in vacuo afforded a residue,
which was immediately passed through silica gel (hexane–EtOAc,
2:1); this gave the corresponding methyl xanthate (1.35 g) as a col-
orless oil, which was directly used for the next reaction without fur-
ther purification.
HRMS–FAB: m/z [M + H]+ calcd for C28H42NO8: 520.2910; found:
520.2883.
(3R,4R,5S,6R)-4-{[(4S)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-
oxazolidin-4-yl]methyl}-4,5-O-isopropylidene-6-(4-methoxy-
benzyloxy)octa-1,7-diene-3,4,5-triol (4)
A 0.97 M soln of H2C=CH2MgBr in THF (0.50 mL, 0.49 mmol)
was added dropwise to a stirred soln of 20 (58.0 mg, 0.11 mmol) in
anhyd THF (2.5 mL) at 0 °C under argon. After 1 h, the reaction was
quenched with sat. aq NH4Cl (5 mL) at 0 °C, and the mixture was
extracted with Et2O (3 × 20 mL). The combined extracts were
washed with sat. aq NaHCO3 (2 × 20 mL) and brine (20 mL), and
dried (MgSO4). Concentration of the soln in vacuo afforded a resi-
due, which was purified by column chromatography (hexane–
EtOAc, 6:1); this gave 4 as a colorless oil. (Note that the presence
n-Bu3SnH (1.20 mL, 4.5 mmol) and AIBN (66.0 mg, 0.40 mmol)
were added successively to a soln of the crude methyl xanthate (1.35
g) in toluene (40 mL). For the deaeration of the reaction mixture, it
was frozen in liquid N2, and the reaction vessel was evacuated in
vacuo for 30 min before being filled with dry argon. The mixture
was heated at reflux for 1 h under argon. After cooling, the reaction
mixture was concentrated in vacuo; this afforded a residue, which
was purified by column chromatography (hexane–EtOAc, 10:1 to
3:1); this gave 19 as a colorless oil. (Note that the presence of rota-
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Total Synthesis of (+)-Scyphostatin
631
of rotamers in the tert-butyl carbamate group resulted in extensive
line broadening, and, in some instances, doubling of signals in the
1H NMR and 13C NMR spectra.)
Yield: 57 mg (93%); [a]D20 +17.5 (c 1.21, CHCl3).
fied by column chromatography (hexane–EtOAc, 10:1); this gave
22 as a colorless oil. (Note that the presence of rotamers in the tert-
butyl carbamate group resulted in extensive line broadening, and, in
some instances, doubling of signals in the 1H NMR and 13C NMR
spectra.)
IR (neat): 770, 855, 1107, 1248, 1393, 1514, 1615, 1670, 1700,
2935, 2982, 3090, 3423 cm–1.
Yield: 250 mg (93%); [a]D20 –42.2 (c 0.88, CHCl3).
IR (neat): 775, 835, 1094, 1250, 1391, 1514, 1615, 1692, 2932,
2982, 3045 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.37 (s, 6 H), 1.40 (s, 3 H), 1.46
(s, 9 H), 1.51 (s, 3 H), 1.58 (m, 0.7 H), 1.73 (br, 0.3 H), 2.18 (br, 0.3
H), 2.29 (br d, 0.7 H, J = 14.5 Hz), 3.10 (br, 0.3 H), 3.73 (d, J = 6.0
Hz, 1 H), 3.79 (s, 3 H), 3.80–4.00 (m, 1.7 H), 4.00–4.20 (br, 1 H),
4.25–4.38 (br, 2 H), 4.44 (br, 1 H), 4.47 (br d, J = 11.4 Hz, 1 H),
4.60 (br d, J = 11.4 Hz, 1 H), 5.21 (dt, J = 10.8, 2.0 Hz, 1 H), 5.29–
5.51 (m, 3 H), 5.98 (m, 0.7 H), 6.15 (m, 0.6 H), 6.38 (m, 0.7 H), 6.85
(d, J = 7.7 Hz, 2 H), 7.28 (d, J = 7.7 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 24.3, 26.6, 27.6, 28.0, 28.3 (3 C),
39.7, 53.8, 55.2, 68.7, 70.2, 72.0, 80.5, 84.1, 84.5, 87.1, 92.7, 107.9,
113.7 (2 C), 114.7, 119.2, 129.4 (2 C), 130.5, 135.6, 139.0, 152.4,
159.1.
1H NMR (500 MHz, DMSO-d6): d = 0.04 (s, 6 H), 0.83 (s, 9 H), 1.36
(s, 3 H), 1.38 (s, 15 H), 1.45 (s, 3 H), 1.78–1.90 (br, 2 H), 3.74 (s, 3
H), 3.80–4.45 (m, 6 H), 4.49 (d, J = 11.4 Hz, 1 H), 4.54 (d, J = 11.4
Hz, 1 H), 5.93 (br, 1 H), 6.05 (ddd, J = 1.6, 4.7, 9.7 Hz, 1 H), 6.97
(d, J = 8.6 Hz, 2 H), 7.25 (d, J = 8.6 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): d = –4.4, –4.2, 17.7, 25.7 (6 C),
27.0 (2 C), 28.8 (2 C), 43.2, 53.7, 54.9, 66.9, 67.7, 69.8, 74.5, 78.9,
82.7, 83.9, 92.2, 109.0, 113.5 (2 C), 129.2 (2 C), 130.0, 130.6,
132.4, 150.7, 158.6.
HRMS–FAB: m/z [M + H]+ calcd for C34H56NO8Si: 634.3775;
found: 634. 3781.
HRMS–FAB: m/z [M + H]+ calcd for C30H46NO8: 548.3223; found:
548.3203.
(1S,2S,3R,6R)-1-[(2S)-2-(tert-Butoxycarbonylamino)-3-hydroxy-
propyl]-6-(tert-butyldimethylsiloxy)-1,2-O-isopropylidene-3-
(4-methoxybenzyloxy)cyclohex-4-ene-1,2-diol (2)
(1S,2R,3R,6R)-2-{[(4S)-3-tert-Butoxycarbonyl-2,2-dimethyl-
oxazolidin-4-yl]methyl}-1,2-O-isopropylidene-6-(4-methoxy-
benzyloxy)cyclohex-4-ene-1,2,3-triol (21)
A soln of 22 (212 mg, 0.34 mmol) and PPTS (50.0 mg, 0.20 mmol)
in EtOH (8 mL) was heated at 60 °C for 3 h. After cooling, the re-
action mixture was diluted with Et2O (50 mL). The organic layer
was washed with 1 M NaOH (15 mL) and brine (15 mL), and then
dried (MgSO4). Concentration of the soln in vacuo afforded a resi-
due, which was purified by column chromatography (hexane–
EtOAc, 6:1); this gave 2 as a white solid; yield: 113 mg [57%, or
84% based on recovered 22 (68 mg, 32%)].
[RuCl2(=CHPh)(PCy3)2] (24.0 mg, 29 mmol) was added to a soln of
4 (160 mg, 0.29 mmol) in anhyd CH2Cl2 (200 mL). For the deaera-
tion of the reaction mixture, it was frozen in liquid N2, and the reac-
tion vessel was evacuated in vacuo for 30 min before being filled
with dry argon. The mixture was then heated at reflux for 12 h. After
cooling, the reaction mixture was stirred for 3 h at r.t. under air.
Evaporation of the soln in vacuo afforded a residue, which was pu-
rified by column chromatography (hexane–EtOAc, 8:1); this gave
21 as a colorless oil. (Note that the presence of rotamers in the tert-
butyl carbamate group resulted in extensive line broadening, and, in
some instances, doubling of signals in the 1H NMR and 13C NMR
spectra.)
White needles (recrystallization, hexane–CHCl3, 5:1); mp 112.5–
113.5 °C; [a]D20 –61.5 (c 1.03, CHCl3).
IR (KBr): 777, 842, 1080, 1250, 1370, 1518, 1535, 1616, 1672,
2934, 2957, 3045, 3290, 3449, 3557 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.03 (s, 3 H), 0.05 (s, 3 H), 0.84
(s, 9 H), 1.42 (s, 9 H), 1.44 (s, 3 H), 1.49 (s, 3 H), 1.68 (dd, J = 8.0,
14.8 Hz, 1 H), 1.87 (dd, J = 6.0, 14.8 Hz, 1 H), 2.87 (br, 1 H), 3.63
(m, 1 H), 3.72–3.80 (m, 2 H), 3.80 (s, 3 H), 3.96 (d, J = 4.3 Hz, 1
H), 4.23 (d, J = 5.6 Hz, 1 H), 4.48 (m, 1 H), 4.57 (d, J = 11.3 Hz, 1
H), 4.67 (d, J = 11.3 Hz, 1 H), 4.82 (br, 1 H), 5.92 (dd, J = 2.2, 9.7
Hz, 1 H), 6.08 (m, 1 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.29 (d, J = 8.6
Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = –4.6, –4.1, 18.1, 26.0 (3 C), 27.2,
27.3, 28.4 (3 C), 42.1, 49.3, 55.3, 65.6, 67.3, 71.2, 77.3, 79.6, 83.5,
85.7, 110.3, 113.8 (2 C), 129.6 (2 C), 130.3, 131.3, 132.8, 155.5,
159.2.
Yield: 146 mg (96%); [a]D20 –48.9 (c 1.20, CHCl3).
IR (neat): 772, 850, 1078, 1252, 1391, 1514, 1612, 1696, 2936,
2982, 3040, 3524 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.33 (s, 3 H), 1.35 (s, 6 H), 1.44
(s, 3 H), 1.47 (s, 6 H), 1.60 (s, 3 H), 1.95 (dd, J = 11.3, 13.5 Hz, 1
H), 2.08 (dd, J = 10.6, 11.9 Hz, 1 H), 2.83 (d, J = 9.9 Hz, 1 H), 3.79
(s, 3 H), 3.91 (dd, J = 6.1, 8.3 Hz, 1 H), 4.02–4.30 (m, 4 H), 4.35
(m, 1 H), 4.43 (d, J = 11.3 Hz, 1 H), 4.52 (d, J = 11.3 Hz, 1 H), 5.96
(ddd, J = 1.8, 5.1, 9.9 Hz, 1 H), 6.04 (br d, J = 9.9 Hz, 1 H), 6.85 (d,
J = 8.6 Hz, 2 H), 7.22 (d, J = 8.6 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 23.2, 26.9, 27.0, 27.3, 28.3 (3 C),
45.3, 54.0, 55.3, 67.8, 67.9, 70.6, 70.7, 79.6, 81.6, 82.4, 93.1, 109.4,
113.8 (2 C), 126.1, 129.5 (2 C), 130.3, 137.2, 151.5, 159.4.
HRMS–FAB: m/z [M + H]+ calcd for C31H52NO8Si: 594.3462;
found: 594.3435.
HRMS–FAB: m/z [M + H]+ calcd for C28H42NO8: 520.2910; found:
520.2887.
(4S)-5-(Benzyloxy)-4-methylpent-2-yne (24)
CBr4 (1.92 g, 5.8 mmol) was added to a stirred soln of (R)-2320 (344
mg, 1.9 mmol) and PPh3 (3.04 g, 12 mmol) in anhyd CH2Cl2 (40
mL) at 0 °C. After 10 min, the mixture was quenched with sat. aq
NaHCO3 (15 mL), and extracted with CH2Cl2 (2 × 50 mL). The
combined extracts were washed with brine (2 × 30 mL), and then
dried (MgSO4). Concentration of the soln in vacuo afforded a resi-
due, which was purified by column chromatography (hexane–
EtOAc, 1:0 to 10:1); this gave the corresponding dibromoalkene
(645 mg) as a colorless oil. A 1.58 M soln of n-BuLi in hexane (2.46
mL, 3.9 mmol) was added dropwise to a stirred soln of the dibro-
moalkene (645 mg, 1.9 mmol) in anhyd THF (20 mL) at –78 °C un-
der argon. After 1 h, the reaction mixture was allowed to warm to
(1S,2S,3R,6R)-1-{[(4S)-3-tert-Butoxycarbonyl-2,2-dimethyl-
oxazolidin-4-yl]methyl}-6-(tert-butyldimethylsiloxy)-1,2-O-iso-
propylidene-3-(4-methoxybenzyloxy)cyclohex-4-ene-1,2-diol
(22)
TBSOTf (0.20 mL, 0.86 mmol) was added dropwise to a stirred soln
of 21 (221 mg, 0.43 mmol) in anhyd CH2Cl2 (12 mL) containing
2,6-lutidine (0.14 mL, 1.2 mmol) at 0 °C under argon. After 30 min
at r.t., the reaction was quenched with H2O (5 mL) at 0 °C, and the
mixture was extracted with EtOAc (2 × 30 mL). The organic layer
was washed with brine (2 × 20 mL), and then dried (MgSO4). Con-
centration of the soln in vacuo afforded a residue, which was puri-
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

632
M. Inoue et al.
FEATURE ARTICLE
0 °C, and MeI (0.14 mL, 2.3 mmol) was added. The resulting soln
was further stirred for 1 h at 0 °C. The reaction was quenched with
sat. aq NH4Cl (10 mL) at 0 °C, and the mixture was extracted with
Et2O (2 × 40 mL). The combined extracts were washed with sat. aq
NaHCO3 (2 × 20 mL) and brine (20 mL), and then dried (MgSO4).
Concentration of the soln in vacuo afforded a residue, which was
purified by column chromatography (hexane–EtOAc, 50:1).
13C NMR (125 MHz, CDCl3): d = 17.4, 17.9, 19.3, 26.8 (3 C),
33.12, 33.13, 37.1, 68.3, 68.7, 127.58 (2 C), 127.59 (2 C), 129.5 (2
C), 133.94, 133.95, 135.62 (2 C), 135.63 (2 C).
HRMS–FAB: m/z [M + H]+ calcd for C23H35O2Si: 371.2406; found:
371.2432.
(2R,4S)-1-(tert-Butyldiphenylsiloxy)-5-iodo-2,4-dimethylpen-
tane (10)
20
Yield: 342 mg (94%, 2 steps); colorless oil; [a]D –3.0 (c 1.59,
CHCl3).
MsCl (0.13 mL, 1.7 mmol) was added dropwise to a stirred soln of
26 (417 mg, 1.1 mmol) in anhyd CH2Cl2 (6 mL) containing Et3N
(0.31 mL, 2.2 mmol) at r.t. After 1 h, the reaction was quenched
with sat. aq NaHCO3 (5 mL) at 0 °C, and the mixture was extracted
with CH2Cl2 (2 × 25 mL). The combined extracts were washed suc-
cessively with 3% aq HCl (15 mL), sat. aq NaHCO3 (15 mL), and
brine (15 mL), and then dried (MgSO4). Concentration of the soln
in vacuo afforded the corresponding mesylate (515 mg) as a color-
less oil, which was used for the next reaction without further purifi-
cation.
IR (neat): 610, 698, 735, 1028, 1097, 1204, 1360, 1454, 1497, 1605,
2859, 2971, 3030 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.17 (d, J = 6.9 Hz, 3 H), 1.80 (d,
J = 2.4 Hz, 3 H), 2.70 (m, 1 H), 3.32 (dd, J = 7.5, 9.0 Hz, 1 H), 3.48
(dd, J = 6.1, 9.0 Hz, 1 H), 4.56 (dd, J = 12.2, 16.2 Hz, 2 H), 7.27–
7.37 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 3.5, 18.1, 26.7, 72.9, 74.3, 76.4,
81.1, 127.5, 127.6 (2 C), 128.3 (2 C), 138.3.
A mixture of the crude mesylate (515 mg) and NaI (1.01 g, 6.7
mmol) in acetone (10 mL) was heated at reflux for 6 h. After cool-
ing, the mixture was diluted with H2O (5 mL), and extracted with
Et2O (3 × 30 mL). The combined extracts were washed with sat. aq
Na2S2O3 (20 mL) and brine (20 mL), and then dried (MgSO4). Con-
centration of the soln in vacuo afforded a residue, which was puri-
fied by column chromatography (hexane–EtOAc, 20:1).
(2E,4S)-5-(Benzyloxy)-2-iodo-4-methylpent-2-ene (9)
A soln of 24 (101 mg, 0.54 mmol) and Cp2ZrHCl (348 mg, 1.4
mmol) in anhyd benzene (3 mL) was heated at 40 °C for 30 min. Af-
ter cooling of the mixture, a soln of I2 (274 mg, 1.1 mmol) in anhyd
benzene (2 mL) was added at r.t. After 30 min, the reaction was
quenched with sat. Na2S2O3 (2 mL) at 0 °C, and the mixture was ex-
tracted with CH2Cl2 (3 × 20 mL). The combined extracts were
washed successively with 3% aq HCl (15 mL), sat. aq NaHCO3 (15
mL), and brine (15 mL), and then dried (MgSO4). Concentration of
the soln in vacuo afforded a residue, which was purified by column
chromatography (hexane–EtOAc, 100:1); this gave 9, containing an
inseparable regioisomer, as a pale yellow oil.
20
Yield: 513 mg (95%, 2 steps); colorless oil; [a]D +7.3 (c 1.42,
CHCl3).
IR (neat): 503, 615, 702, 739, 824, 1111, 1194, 1262, 1389, 1427,
1460, 1589, 2859, 2930, 2959, 3071 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.93 (d, J = 6.3 Hz, 3 H), 0.94 (d,
J = 6.7 Hz, 3 H), 1.00 (m, 1 H), 1.06 (s, 9 H), 1.47 (m, 2 H), 1.70
(m, 1 H), 3.07 (dd, J = 5.9, 9.6 Hz, 1 H), 3.23 (dd, J = 3.6, 9.5 Hz,
1 H), 3.43 (dd, J = 6.1, 9.9 Hz, 1 H), 3.49 (dd, J = 5.5, 9.9 Hz, 1 H),
7.35–7.45 (m, 6 H), 7.66 (dd, J = 0.9, 6.5 Hz, 4 H).
13C NMR (125 MHz, CDCl3): d = 17.3, 18.0, 19.3, 21.4, 26.9 (3 C),
31.8, 33.1, 40.4, 68.8, 127.6 (4 C), 129.6 (2 C), 133.9 (2 C), 135.6
(4 C).
20
Yield: 118 mg (70%, 13% regioisomer); [a]D –12.3 (c 1.25,
CHCl3).
IR (neat): 610, 698, 735, 853, 1049, 1098, 1204, 1375, 1453, 1495,
1638, 2855, 2926, 2963, 3030 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.00 (d, J = 6.8 Hz, 3 H), 2.40 (s,
3 H), 2.77 (m, 1 H), 3.29 (dd, J = 3.4, 6.7 Hz, 2 H), 4.52 (s, 2 H),
6.00 (dd, J = 1.5, 9.5 Hz, 1 H), 7.25–7.37 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 17.0, 27.9, 36.1, 73.0, 74.2, 94.5,
127.5, 127.6, 127.6, 128.3, 138.4, 143.8.
HRMS–FAB: m/z [M + H]+ calcd for C23H34IOSi: 481.1424; found:
481.1407.
HRMS–FAB: m/z [M + H]+ calcd for C13H17IO: 317.0402; found:
317.0422.
(2S,3E,6S,8R)-1-(Benzyloxy)-9-(tert-butyldiphenylsiloxy)-
2,4,6,8-tetramethylnon-3-ene (28)
A 1.0 M soln of ZnCl2 in Et2O (0.58 mL, 0.58 mmol) was added to
a stirred soln of 10 (279 mg, 0.58 mmol) in anhyd Et2O (2 mL) at
r.t. For the deaeration of the reaction mixture, it was frozen in liquid
N2, and the reaction vessel was evacuated in vacuo for 30 min be-
fore being filled with dry argon (freeze–vacuum deaeration tech-
nique). A 1.41 M soln of t-BuLi in pentane (1.24 mL, 1.8 mmol)
was added to a stirred soln of the above mixture at –78 °C over 10
min under argon. The resulting soln was gradually warmed to –40
°C and stirred for 30 min at the same temperature. The mixture was
allowed to warm to r.t., and stirring was continued for 1 h. A soln of
9 (160 mg, 0.51 mmol, including 13% of an inseparable 3-iodo re-
gioisomer) in anhyd THF (2 mL) and Pd(PPh3)4 (58.0 mg, 51 mmol)
in anhyd THF (2 mL) [degassed by freeze–vacuum deaeration tech-
nique for 30 min] were added successively to the above cloudy sus-
pension of alkylzinc reagent, and the resulting mixture was stirred
for 13 h at r.t. while shielded from light. The reaction was quenched
with H2O (10 mL) at 0 °C, and the mixture was extracted with Et2O
(3 × 20 mL). The organic layer was washed with sat. aq NaHCO3
(20 mL) and brine (20 mL), and then dried (MgSO4). Concentration
of the soln in vacuo afforded a residue, which was purified by col-
umn chromatography (hexane–CH2Cl2, 4:1).
(2S,4R)-5-(tert-Butyldiphenylsiloxy)-2,4-dimethylpentan-1-ol
(26)
An O3 stream was bubbled through a soln of 2523 (369 mg, 1.0
mmol) in CH2Cl2–MeOH (3:1, 20 mL) at –78 °C until the color of
the soln had changed to blue. The mixture was purged with argon,
and then NaBH4 (304 mg, 8.1 mmol) in EtOH–H2O (1:1, 15 mL)
was added at –78 °C. The mixture was allowed to warm to r.t. over
1 h. The reaction was quenched with 3% aq HCl (10 mL) at 0 °C,
and the mixture was extracted with CH2Cl2 (2 × 40 mL). The com-
bined extracts were washed with sat. aq NaHCO3 (2 × 20 mL) and
brine (20 mL), and then dried (MgSO4). Concentration of the soln
in vacuo afforded a residue, which was purified by column chroma-
tography (hexane–EtOAc, 1:0 to 20:1).
Yield: 315 mg (84%); colorless oil; [a]D20 +1.74 (c 1.45, CHCl3).
IR (neat): 505, 613, 702, 740, 1362, 1389, 1427, 1472, 1589, 1892,
1960, 2859, 2930, 2957, 3052, 3071, 3355 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.88 (d, J = 6.7 Hz, 3 H), 0.93 (m,
1 H), 0.95 (d, J = 6.7 Hz, 3 H), 1.05 (s, 9 H), 1.26 (br, 1 H), 1.46 (m,
1 H), 1.64 (m, 1 H), 1.74 (m, 1 H), 3.35 (dd, J = 6.7, 10.5 Hz, 1 H),
3.41 (dd, J = 6.3, 9.9 Hz, 1 H), 3.46 (dd, J = 5.1, 10.6 Hz, 1 H), 3.52
(dd, J = 5.4, 9.9 Hz, 1 H), 7.35–7.45 (m, 6 H), 7.63–7.69 (m, 4 H).
Yield: 188 mg (81%); colorless oil; [a]D20 +11.8 (c 1.00, CHCl3).
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Total Synthesis of (+)-Scyphostatin
633
IR (neat): 503, 569, 613, 700, 739, 1109, 1262, 1387, 1427, 1456,
1589, 1740, 2857, 2928, 2959, 3071 cm–1.
brine (2 × 10 mL), and then dried (MgSO4). Concentration of the
soln in vacuo afforded a residue, which was purified by column
chromatography (hexane).
Yield: 49.2 mg (97%, 2 steps); pale yellow oil; [a]D20 –5.22 (c 1.18,
1H NMR (500 MHz, CDCl3): d = 0.74 (d, J = 6.1 Hz, 3 H), 0.92 (d,
J = 6.7 Hz, 3 H), 0.97 (d, J = 6.7 Hz, 3 H), 1.05 (s, 9 H), 1.20–1.35
(m, 2 H), 1.56 (d, J = 1.2 Hz, 3 H), 1.58–1.65 (m, 2 H), 1.75 (m, 1
H), 2.00 (m, 1 H), 2.71 (m, 1 H), 3.22 (dd, J = 7.6, 9.1 Hz, 1 H), 3.32
(dd, J = 6.1, 9.1 Hz, 1 H), 3.40 (dd, J = 6.6, 9.8 Hz, 1 H), 3.50 (dd,
J = 5.2, 9.8 Hz, 1 H), 4.52 (d, J = 12.1 Hz, 1 H), 4.47 (d, J = 12.1
Hz, 1 H), 4.90 (d, J = 9.0 Hz, 1 H), 7.26–7.45 (m, 11 H), 7.67 (dd,
J = 1.4, 7.9 Hz, 4 H).
13C NMR (125 MHz, CDCl3): d = 16.2, 17.8, 18.0, 19.3, 19.8, 26.9
(3 C), 28.1, 33.0, 33.2, 41.4, 47.7, 69.0, 72.9, 75.5, 127.4, 127.5 (2
C), 127.6 (4 C), 128.3 (2 C), 128.9, 129.5 (2 C), 134.12, 134.13,
134.5, 135.62 (2 C), 135.64 (2 C), 138.8.
CHCl3).
IR (neat): 503, 615, 702, 738, 822, 1111, 1262, 1385, 1427, 1460,
2859, 2928, 2959 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.75 (d, J = 6.1 Hz, 3 H), 0.81 (t,
J = 7.4 Hz, 3 H), 0.89 (d, J = 6.7 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H),
1.05 (s, 9 H), 1.13–1.23 (m, 2 H), 1.27–1.39 (m, 2 H), 1.52 (d,
J = 1.3 Hz, 3 H), 1.56–1.65 (m, 2 H), 1.75 (m, 1 H), 1.97 (dd,
J = 9.3, 16.8 Hz, 1 H), 2.22 (m, 1 H), 3.40 (dd, J = 6.6, 9.8 Hz, 1 H),
3.56 (dd, J = 5.1, 9.8 Hz, 1 H), 4.83 (d, J = 9.3 Hz, 1 H), 7.34–7.44
(m, 6 H), 7.66 (dd, J = 1.3, 7.7 Hz, 4 H).
13C NMR (125 MHz, CDCl3): d = 12.0, 16.2, 17.9, 19.3, 20.0, 21.0,
26.9 (3 C), 28.2, 30.5, 33.2, 34.1, 41.3, 47.9, 69.0, 127.6 (4 C),
129.46, 129.47, 132.3, 132.9, 134.14, 134.16, 135.63 (2 C), 135.65
(2 C).
HRMS–FAB: m/z [M + H]+ calcd for C36H51O2Si: 543.3658; found:
543.3640.
(2S,3E,6S,8R)-9-(tert-Butyldiphenylsiloxy)-2,4,6,8-tetramethyl-
non-3-en-1-ol (29)
HRMS–FAB: m/z [M + H]+ calcd for C30H47OSi: 451.3396; found:
451.3412.
A 0.26 M soln of LiDBB in THF (4.0 mL, 1.1 mmol) [prepared
from Li (8.7 mg, 1.3 mmol) and DTBB (346 mg, 1.3 mmol)] was
added dropwise to a stirred soln of 28 (40.0 mg, 70 mmol) in anhyd
THF (1.5 mL) at –78 °C. After 5 min, the reaction was quenched
with brine (5 mL) at 0 °C, and the resulting mixture was extracted
with EtOAc (2 × 20 mL). The combined extracts were washed with
brine (2 × 10 mL), and then dried (MgSO4). Concentration of the
soln in vacuo afforded a residue, which was purified by column
chromatography (hexane–EtOAc, 10:1).
(2R,4S,6E,8R)-2,4,6,8-Tetramethyldec-6-en-1-ol (31)
A 1.0 M soln of TBAF in THF (0.61 mL, 0.61 mmol) was added to
a stirred soln of 30 (91.7 mg, 0.20 mmol) in THF (1.5 mL) at r.t. Af-
ter 24 h, the reaction mixture was diluted with Et2O (30 mL), and
the organic layer was washed with sat. aq NaHCO3 (10 mL) and
brine (10 mL), and then dried (MgSO4). Concentration of the soln
in vacuo afforded a residue, which was purified by column chroma-
tography (hexane–EtOAc, 20:1).
Yield: 30.0 mg (90%); pale yellow oil; [a]D20 –7.73 (c 1.00, CHCl3).
IR (neat): 505, 615, 702, 741, 824, 939, 1032, 1111, 1188, 1260,
1387, 1427, 1460, 1589, 2859, 2928, 2957, 3362 cm–1.
Yield: 39.5 mg (91%); colorless oil; [a]D20 –9.23 (c 1.20, CHCl3).
IR (neat): 511, 608, 702, 818, 880, 1036, 1111, 1260, 1377, 1458,
1547, 1669, 1725, 2276, 2870, 2922, 2957, 3353 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.76 (d, J = 6.0 Hz, 3 H), 0.92 (d,
J = 6.7 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H), 1.05 (s, 9 H), 1.32 (m, 2
H), 1.53 (s, 1 H), 1.58 (d, J = 1.2 Hz, 3 H), 1.60–1.68 (m, 2 H), 1.77
(m, 1 H), 2.04 (dd, J = 9.7, 17.3 Hz, 1 H), 2.60 (m, 1 H), 3.25–3.55
(m, 4 H), 4.85 (d, J = 9.4 Hz, 1 H), 7.35–7.45 (m, 6 H), 7.67 (dd,
J = 1.4, 7.9 Hz, 4 H).
13C NMR (125 MHz, CDCl3): d = 16.4, 17.1, 17.8, 19.3, 19.8, 26.9
(3 C), 28.1, 33.2, 35.5, 41.5, 47.8, 68.0, 69.0, 127.6 (4 C), 128.5,
129.5 (2 C), 134.09, 134.10, 135.6 (4 C), 136.8.
1H NMR (500 MHz, CDCl3): d = 0.82 (d, J = 7.5 Hz, 3 H), 0.84 (t,
J = 7.4 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H),
1.15–1.25 (m, 2 H), 1.25–1.38 (m, 3 H), 1.56 (d, J = 1.4 Hz, 3 H),
1.64–1.70 (m, 2 H), 1.75 (m, 1 H), 2.00 (dd, J = 9.4, 17.1 Hz, 1 H),
2.24 (m, 1 H), 3.37 (dd, J = 6.9, 10.4 Hz, 1 H), 3.53 (dd, J = 5.0,
10.5 Hz, 1 H), 4.86 (d, J = 9.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 12.0, 16.2, 17.5, 20.2, 21.0, 28.2,
30.5, 33.2, 34.1, 40.9, 47.7, 68.3, 132.2, 133.1.
HRMS–FAB: m/z [M]+ calcd for C14H28O: 212.2140; found:
212.2131.
HRMS–FAB: m/z [M + H]+ calcd for C29H45O2Si: 453.3189; found:
453.3189.
(3R,4E,7S,9R)-10-(tert-Butyldiphenylsiloxy)-3,5,7,9-tetra-
methyldec-4-ene (30)
Methyl (2E,4E,6E,8R,10S,12E,14R)-8,10,12,14-Tetramethyl-
hexadeca-2,4,6,12-tetraenoate (34)
TsCl (63.0 mg, 0.33 mmol) was added to a stirred soln of 29 (51.0
mg, 0.11 mmol) in anhyd CH2Cl2 (0.9 mL) containing Et3N (0.14
mL, 0.99 mmol) and DMAP (1.3 mg, 11 mmol) at r.t. After 3 h, the
reaction mixture was diluted with CH2Cl2 (30 mL), and the organic
layer was washed successively with 3% aq HCl (2 × 10 mL), sat. aq
NaHCO3 (2 × 10 mL), and brine (10 mL), and then dried (MgSO4).
Concentration of the soln in vacuo afforded the corresponding
tosylate 8 (80 mg) as a pale yellow oil, which was used for the next
reaction without further purification.
A mixture of 31 (39.5 mg, 0.19 mmol), 3-Å MS (33 mg), and NMO
(76.0 mg, 0.65 mmol) in CH2Cl2 (2.8 mL) was stirred for 10 min at
r.t. n-Pr4NRuO4 (13.0 mg, 37 mmol) was added to the above mixture
at r.t. After 10 min, the mixture was filtered through a short pad of
silica gel, and the filtrate was concentrated in vacuo (water bath
< 25°C); this gave aldehyde 32 (26.1 mg) as a colorless oil, which
was used immediately for the next reaction.
A soln of 3329 (76.0 mg, 0.32 mmol) in anhyd THF (0.7 mL) was
added dropwise to a stirred soln of LDA in anhyd THF [prepared
from i-Pr2NH (50.0 mL, 0.32 mmol) and 1.58 M n-BuLi in n-hexane
(0.20 mL, 0.32 mmol) in THF (0.34 mL)] at –78 °C. After 30 min,
a soln of the crude aldehyde 32 (26.1 mg) in anhyd THF (0.7 mL)
was added slowly to the above soln, and the resulting mixture was
stirred for 30 min at –78 °C and for 30 min at –30 °C. The reaction
was quenched with sat. aq NH4Cl (5 mL) at –30 °C, and the result-
ing mixture was extracted with Et2O (2 × 30 mL). The combined
extracts were washed with brine (2 × 15 mL), and then dried
(MgSO4). Concentration of the soln in vacuo afforded a residue,
A 1.2 M soln of MeLi in Et2O (5.50 mL, 6.6 mmol) was added drop-
wise to a stirred suspension of CuI (628 mg, 3.3 mmol) in anhyd
Et2O (3 mL) at –10 °C under argon. After 30 min, a soln of the crude
tosylate 8 (80 mg) in anhyd Et2O (5 mL) was added to the above
mixture at –40 °C. The resulting mixture was allowed to warm to
r.t., and stirring was continued for 13 h. The reaction was quenched
with 25% NH4OH (3 mL) and sat. aq NH4Cl (3 mL) at 0 °C, and
then the resulting mixture was stirred under air until the color of the
soln had changed to bright blue. The mixture was extracted with
Et2O (2 × 20 mL), and the combined extracts were washed with
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

634
M. Inoue et al.
FEATURE ARTICLE
which was purified by column chromatography (hexane–EtOAc,
100:1); this gave a mixture of 34 and its 6¢Z-isomer (49.2 mg, 82%;
ratio 73:27, by 500-MHz 1H NMR). A pure sample of 34 was iso-
lated from this mixture by HPLC [DAICEL CHIRALPAK AD-H,
i.d. 10 × 250 mm; hexane–i-PrOH, 200:1, 1.0 mL·min–1; UV detec-
tion: 254 nm absorbance; tR (34): 12.5 min, tR (6¢Z-isomer): 10.8
min].
washed with sat. aq NaHCO3 (30 mL) and brine (30 mL), and then
dried (MgSO4). Concentration of the soln in vacuo afforded a resi-
due of 37, which was purified by column chromatography (hexane–
EtOAc, 2:1 to 1:1).
Yield: 26.0 mg (73%); colorless oil; [a]D20 –33.7 (c 0.97, CHCl3).
IR (neat): 777, 837, 1062, 1251, 1375, 1460, 1543, 1609, 1649,
2928, 2957, 3040, 3285 cm–1.
20
Yield: 27.2 mg (46%, 2 steps); colorless oil; [a]D –1.57 (c 1.45,
1H NMR (500 MHz, CDCl3): d = 0.07 (s, 6 H), 0.80 (d, J = 6.5 Hz,
3 H), 0.84 (t, J = 7.4 Hz, 3 H), 0.88 (s, 9 H), 0.90 (d, J = 6.7 Hz, 3
H), 0.99 (d, J = 6.6 Hz, 3 H), 1.03 (m, 1 H), 1.20 (dt, J = 13.4, 7.7
Hz, 1 H), 1.27–1.36 (m, 2 H), 1.44 (s, 3 H), 1.48 (s, 3 H), 1.52 (s, 3
H), 1.56 (m, 1 H), 1.76 (dd, J = 7.4, 15.0 Hz, 1 H), 1.81–1.91 (m, 2
H), 1.93 (dd, J = 6.3, 15.0 Hz, 1 H), 2.23 (m, 1 H), 2.33 (m, 1 H),
2.41 (br, 1 H), 3.06 (br, 1 H), 3.68 (br d, J = 9.0 Hz, 1 H), 3.85 (dd,
J = 4.0, 11.4 Hz, 1 H), 3.90 (d, J = 4.4 Hz, 1 H), 4.17 (m, 1 H), 4.31
(d, J = 5.2 Hz, 1 H), 4.72 (m, 1 H), 4.84 (br d, J = 9.3 Hz, 1 H), 5.70
(dd, J = 8.4, 15.2 Hz, 1 H), 5.77 (d, J = 14.9 Hz, 1 H), 5.87–5.94 (m,
2 H), 6.05–6.13 (m, 2 H), 6.18 (dd, J = 11.3, 14.8 Hz, 1 H), 6.49 (dd,
J = 10.7. 14.8 Hz, 1 H), 7.23 (dd, J = 11.3, 14.8 Hz, 1 H).
CHCl3).
IR (neat): 505, 613, 702, 740, 1362, 1389, 1427, 1472, 1589, 1892,
1960, 2859, 2930, 2957, 3052, 3071, 3355 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.80 (d, J = 6.5 Hz, 3 H), 0.84 (d,
J = 7.4 Hz, 3 H), 0.90 (d, J = 6.7 Hz, 3 H), 1.00 (d, J = 6.7 Hz, 3 H),
1.02 (m, 1 H), 1.19 (m, 1 H), 1.27–1.39 (m, 2 H), 1.52 (d, J = 1.2
Hz, 3 H), 1.56 (m, 1 H), 1.76 (dd, J = 7.3, 13.2 Hz, 1 H), 1.88 (dd,
J = 6.8, 13.1 Hz, 1 H), 2.23 (m, 1 H), 2.34 (m, 1 H), 3.74 (s, 3 H),
4.85 (d, J = 9.4 Hz, 1 H), 5.73 (dd, J = 8.5, 15.2 Hz, 1 H), 5.84 (d,
J = 15.3 Hz, 1 H), 6.10 (dd, J = 10.7, 15.2 Hz, 1 H), 6.22 (dd,
J = 11.3, 14.9 Hz, 1 H), 6.52 (dd, J = 10.7, 14.9 Hz, 1 H), 7.31 (dd,
J = 11.3, 15.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = –4.5, –4.1, 12.1, 16.2, 18.2, 19.5,
21.1, 21.4, 26.0 (3 C), 27.5 (2 C), 28.3, 30.5, 34.1, 35.0, 41.9, 44.0,
48.3, 48.6, 65.5, 67.4, 70.7, 83.9, 86.9, 110.7, 122.1, 127.7, 128.3,
131.9, 132.1, 133.1, 133.7, 140.6, 141.8, 145.7, 166.1.
13C NMR (125 MHz, CDCl3): d = 12.1, 16.2, 19.5, 21.1, 21.4, 28.4,
30.6, 34.1, 35.0, 44.0, 48.3, 51.5, 119.5, 127.8, 128.2, 132.1, 133.1,
141.5, 145.1, 146.5, 167.7.
HRMS–FAB: m/z [M + H]+ calcd for C21H34O2: 319.2637; found:
HRMS–FAB: m/z [M + H]+ calcd for C38H66NO6Si: 660.4659;
319.2623.
found: 660.4642.
(2E,4E,6E,8R,10S,12E,14R)-8,10,12,14-Tetramethylhexadeca-
2,4,6,12-tetraenoyl Chloride (3)
(2E,4E,6E,8R,10S,12E,14R)-N-{(1S)-1-(Acetoxymethyl)-2-
[(3aS,4R,7R,7aS)-4-(tert-butyldimethylsiloxy)-7-hydroxy-2,2-
dimethyl-7,7a-dihydro-1,3-benzodioxol-3a(4H)-yl]ethyl}-
8,10,12,14-tetramethylhexadeca-2,4,6,12-tetraenamide (38)
A soln of Ac2O (5.4 mL, 52 mmol) in CH2Cl2 (0.2 mL) was added to
a stirred soln of 37 (34.0 mg, 52 mmol) in CH2Cl2 (1.6 mL) contain-
ing py (20 mL, 0.24 mmol) and DMAP (0.4 mg, 3.2 mmol) at r.t. Af-
ter 20 min, the mixture was diluted with H2O (5 mL), and extracted
with Et2O (3 × 20 mL). The combined extracts were washed with
sat. aq NaHCO3 (2 × 15 mL) and brine (15 mL), and then dried
(MgSO4). Concentration of the soln in vacuo afforded a residue,
which was purified by column chromatography (hexane–EtOAc,
5:1).
A soln of 34 (26.2 mg, 82 mmol) in 2 M aq KOH–THF–MeOH
(3:3:1, 2 mL) was stirred for 12 h at r.t. The reaction mixture was
acidified with 1 M HCl (2 mL) at 0 °C and extracted with Et2O
(3 × 15 mL). The combined organic extracts were dried (MgSO4).
Concentration of the soln in vacuo afforded carboxylic acid 35 (26.0
mg), which was used for the following reaction without further pu-
rification.
Oxalyl chloride (21.0 mL, 0.24 mmol) was added to a stirred soln of
the crude carboxylic acid 35 (26.0 mg) in CH2Cl2 (2 mL) containing
DMF (6.0 mL, 82 mmol) at r.t. After 1 h, the solvent was removed in
vacuo; this afforded acid chloride 3 (26.0 mg) as a colorless oil,
which was used immediately, without further purification, for the
next reaction.
Yield: 26.0 mg [72%, or 81% based on recovered 37 (4.0 mg,
12%)]; colorless oil; [a]D20 –26.5 (c 0.96, CHCl3).
IR (neat): 777, 837, 1061, 1250, 1371, 1460, 1539, 1610, 1649,
1744, 2928, 2957, 3055, 3281 cm–1.
(2E,4E,6E,8R,10S,12E,14R)-N-{(1S)-2-[(3aS,4R,7R,7aS)-4-
(tert-Butyldimethylsiloxy)-7-hydroxy-2,2-dimethyl-7,7a-di-
hydro-1,3-benzodioxol-3a(4H)-yl]-1-(hydroxymethyl)ethyl}-
8,10,12,14-tetramethylhexadeca-2,4,6,12-tetraenamide (37)
TMSOTf (0.26 mL, 1.4 mmol) was added dropwise to a stirred soln
of 2 (32.0 mg, 54 mmol) in anhyd CH2Cl2 (2 mL) containing 2,6-lu-
tidine (0.28 mL, 2.4 mmol) at 0 °C. The soln was stirred for 3 h at
r.t. MeOH (2 mL) was added, and stirring was continued for 1 h at
r.t. The mixture was diluted with H2O (5 mL), and extracted with
Et2O (5 × 30 mL). The combined extracts were washed with sat. aq
NaHCO3 (30 mL) and brine (30 mL), and then dried (Na2SO4). Con-
centration of the soln in vacuo afforded amino alcohol 36 (80 mg,
containing a small amount of 2,6-lutidine), which was used for the
next reaction without further purification.
1H NMR (500 MHz, CDCl3): d = 0.09 (s, 6 H), 0.80 (d, J = 6.5 Hz,
3 H), 0.84 (t, J = 7.4 Hz, 3 H), 0.88 (s, 9 H), 0.90 (d, J = 6.7 Hz, 3
H), 0.99 (d, J = 6.6 Hz, 3 H), 1.02 (m, 1 H), 1.19 (dt, J = 13.4, 7.8
Hz, 1 H), 1.27–1.35 (m, 2 H), 1.38 (s, 3 H), 1.44 (s, 3 H), 1.52 (d,
J = 1.2 Hz, 3 H), 1.56 (m, 1 H), 1.73–1.81 (m, 2 H), 1.85–1.91 (m,
2 H), 2.07 (s, 3 H), 2.23 (m, 1 H), 2.33 (m, 1 H), 2.41 (m, 1 H), 3.87
(d, J = 4.6 Hz, 1 H), 4.21 (d, J = 3.8, 11.3 Hz, 1 H), 4.33 (dd,
J = 6.0, 11.3 Hz, 1 H), 4.41–4.49 (m, 2 H), 4.68 (br s, 1 H), 4.84 (d,
J = 9.4 Hz, 1 H), 5.65–5.80 (m, 2 H), 5.75 (d, J = 14.9 Hz, 1 H),
5.87 (dd, J = 2.7, 9.6 Hz, 1 H), 6.04–6.12 (m, 2 H), 6.18 (dd,
J = 11.3, 14.8 Hz, 1 H), 6.49 (dd, J = 10.7, 14.8 Hz, 1 H), 7.23 (dd,
J = 11.3, 14.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = –4.5, –4.1, 12.1, 16.2, 18.2, 19.5,
20.9, 21.1, 21.4, 26.0 (3 C), 27.5, 27.6, 28.3, 30.5, 34.1, 35.0, 42.6,
44.0, 46.1, 48.3, 66.6, 67.3, 70.7, 84.0, 87.1, 110.6, 122.0, 127.7,
128.3, 132.1, 132.6, 133.1, 133.1, 140.7, 141.9, 145.8, 165.6, 171.4.
HRMS–FAB: m/z [M + H]+ calcd for C40H68NO7Si: 702.4765;
found: 702.4748.
A soln of crude acid chloride 3 (26.0 mg, ca. 80 mmol) in anhyd
CH2Cl2 (2 mL) was added dropwise to a stirred soln of the crude
amino alcohol 36 (80.0 mg, containing a small amount of 2,6-luti-
dine) in anhyd CH2Cl2 (2 mL) containing Et3N (80 mL, 0.58 mmol)
at r.t. After 1 h, 60% aq AcOH (1.0 mL) was added, and the soln was
stirred for 6 h at r.t. The mixture was diluted with H2O (15 mL) and
then extracted with Et2O (2 × 50 mL). The combined extracts were
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Total Synthesis of (+)-Scyphostatin
635
(2E,4E,6E,8R,10S,12E,14R)-N-{(1S)-1-(Acetoxymethyl)-2-
[(3aS,4R,7R,7aS)-4-(tert-butyldimethylsiloxy)-7-mesyloxy-2,2-
dimethyl-7,7a-dihydro-1,3-benzodioxol-3a(4H)-yl]ethyl}-
8,10,12,14-tetramethylhexadeca-2,4,6,12-tetraenamide (39)
MsCl (8.0 mL, 0.1 mmol) was added to a stirred soln of 38 (31.0 mg,
38 mmol) in CH2Cl2 (2 mL) containing Et3N (82.0 mL, 0.60 mmol)
at r.t. After 1 h, the reaction was quenched with H2O (2 mL), and the
mixture was extracted with Et2O (3 × 20 mL). The combined ex-
tracts were washed with 1 M HCl (2 × 10 mL), sat. aq NaHCO3
(2 × 10 mL), and brine (10 mL), and then dried (MgSO4). Concen-
tration of the soln in vacuo afforded a residue, which was purified
by column chromatography (hexane–EtOAc, 6:1).
1.76 (dd, J = 7.4, 13.1 Hz, 1 H), 1.85–1.94 (m, 2 H), 2.06 (s, 3 H),
2.20 (dd, J = 9.2, 15.6 Hz, 1 H), 2.23 (m, 1 H), 2.33 (m, 1 H), 3.22
(s, 3 H), 4.10 (dd, J = 4.8, 11.3 Hz, 1 H), 4.23 (dd, J = 5.1, 11.3 Hz,
1 H), 4.42–4.50 (m, 2 H), 4.84 (d, J = 9.5 Hz, 1 H), 5.52 (dd, J = 1.7,
3.8 Hz, 1 H), 5.71 (dd, J = 8.4, 15.2 Hz, 1 H), 5.75 (d, J = 15.0 Hz,
1 H), 5.84 (d, J = 7.6 Hz, 1 H), 6.08 (dd, J = 10.8, 15.0 Hz, 1 H),
6.18 (dd, J = 11.3, 14.9 Hz, 1 H), 6.26 (d, J = 10.1 Hz, 1 H), 6.48
(dd, J = 10.7, 14.8 Hz, 1 H), 6.83 (ddd, J = 1.9, 4.8, 10.1 Hz, 1 H),
7.21 (dd, J = 11.3, 14.9 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 12.1, 16.2, 19.5, 20.8, 21.1, 21.4,
26.7, 27.1, 28.4, 29.7, 30.5, 34.1, 35.0, 39.0, 44.0, 45.4, 48.3, 66.1,
70.6, 77.7, 81.1, 110.0, 122.0, 127.6, 128.2, 130.5, 132.1, 133.1,
138.9, 140.8, 141.9, 145.9, 165.7, 171.0, 197.2.
Yield: 32.0 mg (93%); colorless oil; [a]D20 –31.2 (c 1.07, CHCl3).
IR (neat): 777, 841, 1078, 1177, 1250, 1364, 1460, 1539, 1611,
1649, 1744, 2928, 2957, 3045, 3271 cm–1.
HRMS–FAB: m/z [M + H]+ calcd for C35H54NO9S: 664.3519;
found: 664.3544.
1H NMR (500 MHz, CDCl3): d = 0.09 (s, 3 H), 0.10 (s, 3 H), 0.80
(d, J = 6.5 Hz, 3 H), 0.84 (t, J = 7.4 Hz, 3 H), 0.89 (s, 9 H), 0.90 (d,
J = 6.7 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.02 (m, 1 H), 1.19 (dt,
J = 13.4, 7.8 Hz, 1 H), 1.27–1.35 (m, 2 H), 1.38 (s, 3 H), 1.47 (s, 3
H), 1.52 (d, J = 1.0 Hz, 3 H), 1.56 (m, 1 H), 1.73–1.81 (m, 2 H),
1.81–1.91 (m, 2 H), 2.08 (s, 3 H), 2.23 (m, 1 H), 2.33 (m, 1 H), 3.10
(s, 3 H), 3.99 (d, J = 4.9 Hz, 1 H), 4.22 (dd, J = 3.7, 11.3 Hz, 1 H),
4.34 (dd, J = 5.8, 11.3 Hz, 1 H), 4.43 (m, 1 H), 4.50 (d, J = 5.4 Hz,
1 H), 4.84 (d, J = 9.3 Hz, 1 H), 5.52 (m, 1 H), 5.65–5.75 (m, 2 H),
5.75 (d, J = 15.1 Hz, 1 H), 5.93 (dd, J = 2.4, 9.7 Hz, 1 H), 6.08 (dd,
J = 10.7, 15.1 Hz, 1 H), 6.17 (dd, J = 11.3, 14.8 Hz, 1 H), 6.25 (m,
1 H), 6.49 (dd, J = 10.7. 14.8 Hz, 1 H), 7.21 (dd, J = 11.3, 14.8 Hz,
1 H).
(2E,4E,6E,8R,10S,12E,14R)-N-[(1S)-2-Acetoxy-1-{[(1S,2S,3S)-
2,3-epoxy-1-hydroxy-6-oxocyclohex-4-enyl]methyl}ethyl]-
8,10,12,14-tetramethylhexadeca-2,4,6,12-tetraenamide (41)
A soln of 40 (6.6 mg, 6.9 mmol) and Cl3CCO2H (66.0 mg, 0.42
mmol) in CH2Cl2 (0.36 mL) containing H2O (18 mL) was heated at
reflux for 3 h. The mixture was basified with 2 M NaOH (0.22 mL)
at 0 °C, and the resulting mixture was stirred for 10 min at r.t. The
mixture was diluted with H2O (8 mL), and extracted with Et2O
(3 × 30 mL). The combined extracts were washed with brine (2 × 20
mL) and dried (MgSO4). Concentration of the soln in vacuo afford-
ed a residue, which was purified by column chromatography (hex-
ane–EtOAc, 2:1 to 1:3).
Yield: 2.4 mg [45%, or 82% based on recovered 40 (3.0 mg, 45%)];
colorless oil; [a]D20 +46.9 (c 0.12, CHCl3).
13C NMR (125 MHz, CDCl3): d = –4.6, –4.2, 12.1, 16.2, 18.2, 19.5,
20.9, 21.1, 21.4, 26.0 (3 C), 27.4, 27.6, 28.3, 30.6, 34.1, 35.0, 38.4,
42.5, 44.0, 46.1, 48.3, 66.4, 66.8, 80.8, 83.8, 84.1, 111.5, 121.9,
127.6, 128.3, 129.2, 132.1, 133.1, 134.7, 140.7, 141.9, 145.8, 165.5,
171.3.
HRMS–FAB: m/z [M + H]+ calcd for C41H70NO9SSi: 780.4541;
found: 780.4541.
IR (neat): 736, 837, 1006, 1238, 1373, 1456, 1539, 1609, 1651,
1682, 1732, 2924, 2959, 3353 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.80 (d, J = 6.5 Hz, 3 H), 0.84 (t,
J = 7.4 Hz, 3 H), 0.90 (d, J = 6.7 Hz, 3 H), 0.99 (d, J = 6.7 Hz, 3 H),
1.02 (m, 1 H), 1.19 (m, 1 H), 1.27–1.35 (m, 2 H), 1.52 (d, J = 1.3
Hz, 3 H), 1.76 (dd, J = 7.3, 13.0 Hz, 1 H), 1.87 (dd, J = 7.1, 13.0 Hz,
1 H), 1.96–2.10 (m, 3 H), 2.07 (s, 3 H), 2.23 (m, 1 H), 2.33 (m, 1 H),
3.58 (dt, J = 1.6, 3.9 Hz, 1 H), 3.72 (d, J = 3.8 Hz, 1 H), 4.02 (m, 1
H), 4.14 (m, 1 H), 4.22–4.32 (m, 2 H), 4.83 (d, J = 9.4 Hz, 1 H), 5.71
(dd, J = 8.4, 15.4 Hz, 1 H), 5.73 (d, J = 15.0 Hz, 1 H), 5.86 (d,
J = 7.1 Hz, 1 H), 6.08 (dd, J = 10.8, 15.1 Hz, 1 H), 6.17 (dd,
J = 11.3, 15.0 Hz, 1 H), 6.23 (dd, J = 1.6, 9.9 Hz, 1 H), 6.49 (dd,
J = 10.6. 14.8 Hz, 1 H), 7.13 (dd, J = 3.9, 9.9 Hz, 1 H), 7.23 (dd,
J = 11.4, 14.9 Hz, 1 H).
[(2E,4E,6E,8R,10S,12E,14R)-N-{(1S)-1-(Acetoxymethyl)-2-
[(3aS,7R,7aS)-7-mesyloxy-2,2-dimethyl-4-oxo-7,7a-dihydro-
1,3-benzodioxol-3a(4H)-yl]ethyl}-8,10,12,14-tetramethylhexa-
deca-2,4,6,12-tetraenamide (40)
A 1 M soln of TBAF in THF (30.0 mL, 30 mmol) was added to a
stirred soln of 39 (24.0 mg, 30 mmol) in THF (1.5 mL) at r.t. After
30 min, additional 1 M TBAF in THF (20.0 mL, 20 mmol) was add-
ed. After 20 min, the mixture was diluted with Et2O (30 mL), and
the organic layer was washed with 1 M NaOH (8 mL) and brine (8
mL), and then dried (MgSO4). Concentration of the soln in vacuo
afforded the corresponding alcohol (22.0 mg) as a colorless oil,
which was used for the next reaction without further purification.
13C NMR (125 MHz, CDCl3): d = 12.1, 16.2, 19.5, 20.8, 21.1, 21.4,
28.3, 30.5, 34.1, 35.0, 37.6, 44.0, 45.6, 48.0, 48.3, 55.8, 65.9, 76.6,
121.7, 127.1, 128.3, 130.1, 132.1, 133.1, 140.9, 142.1, 144.7, 145.9,
166.1, 171.1, 197.6.
DMP (48.0 mg, 0.11 mmol) was added to a stirred soln of the crude
alcohol (22.0 mg) in CH2Cl2 (2 mL) at r.t. After 20 min, the reaction
was quenched with 15% aq Na2S2O3 (2 mL) at 0 °C, and the mixture
was extracted with Et2O (3 × 20 mL). The combined extracts were
washed with 1 M NaOH (10 mL) and brine (10 mL), and then dried
(MgSO4). Concentration of the soln in vacuo afforded a residue,
which was purified by column chromatography (hexane–EtOAc,
6:1 to 2:1).
HRMS–FAB: m/z [M + H]+ calcd for C31H46NO6: 528.3325; found:
528.3333.
(2E,4E,6E,8R,10S,12E,14R)-N-[(1S)-1-{[(1S,2S,3S)-2,3-Epoxy-
1-hydroxy-6-oxocyclohex-4-enyl]methyl}-2-hydroxyethyl]-
8,10,12,14-tetramethylhexadeca-2,4,6,12-tetraenamide [(+)-
scyphostatin; 1]
A mixture of 41 (3.2 mg, 6.0 mmol) and lipase PS (16 mg) in acetone
(0.16 mL) containing phosphate buffer (pH 7) (0.16 mL) was stirred
for 10 h at r.t. The reaction mixture was diluted with Et2O (50 mL),
and the resulting mixture was filtered through a small pad of Celite.
The filtrate was washed with sat. aq NaHCO3 (10 mL) and brine (10
mL), and then dried (MgSO4). Concentration of the soln in vacuo
afforded a residue, which was purified by column chromatography
(acetone–EtOAc, 1:4). The 1H NMR and 13C NMR, IR, and
HRMS–FAB spectra (see below) are compatible with those of nat-
ural (+)-scyphostatin (1).
20
Yield: 20.0 mg (98%, 2 steps); colorless oil; [a]D –21.8 (c 0.98,
CHCl3).
IR (neat): 794, 858, 1071, 1177, 1237, 1368, 1457, 1534, 1611,
1653, 1696, 1741, 2926, 2959, 3378 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.80 (d, J = 6.5 Hz, 3 H), 0.84 (t,
J = 7.4 Hz, 3 H), 0.90 (d, J = 6.7 Hz, 3 H), 1.00 (d, J = 6.7 Hz, 3 H),
1.02 (m, 1 H), 1.19 (dt, J = 13.4, 7.8 Hz, 1 H), 1.26 (s, 3 H), 1.27–
1.35 (m, 2 H), 1.33 (s, 3 H), 1.52 (d, J = 1.0 Hz, 3 H), 1.56 (m, 1 H),
Synthesis 2007, No. 4, 622–637 © Thieme Stuttgart · New York

636
M. Inoue et al.
FEATURE ARTICLE
Yield: 1.8 mg (60%); colorless amorphous powder; [a]D25 +61.0 (c
0.08, MeOH) [lit.1 [a]D25 +66.4 (c 0.09, MeOH)].
Couladouros, E. A.; Giannis, A. ChemBioChem 2003, 4,
1223. (f) Lindsey, C. C.; Gómez-Díza, C.; Villalba, J. M.;
Pettus, T. R. R. Tetrahedron 2002, 58, 4559. (g) Hakogi,
T.; Monden, Y.; Taichi, M.; Iwama, S.; Fujii, S.; Ikeda, K.;
Katsumura, S. J. Org. Chem. 2002, 67, 4839.
IR (neat): 802, 1039, 1261, 1377, 1460, 1543, 1609, 1651, 1703,
1738, 2924, 2957, 3346 cm–1.
1H NMR (500 MHz, CD3OD) d = 0.83 (d, J = 6.5 Hz, 3 H), 0.86 (t,
J = 7.4 Hz, 3 H), 0.91 (d, J = 6.9 Hz, 3 H), 1.00 (d, J = 6.7 Hz, 3 H),
1.03 (m, 1 H), 1.19 (m, 1 H), 1.33–1.38 (m, 2 H), 1.59 (d, J = 1.3
Hz, 3 H), 1.59 (m, 1 H), 1.79 (m, 1 H), 1.85–1.91 (m, 2 H), 2.08 (dd,
J = 3.4, 14.7 Hz, 1 H), 2.27 (m, 1 H), 2.35 (m, 1 H), 3.46 (dd,
J = 5.7, 10.9 Hz, 1 H), 3.52 (dd, J = 5.1, 10.9 Hz, 1 H), 3.59 (dt,
J = 1.6, 3.9 Hz, 1 H), 3.67 (d, J = 3.9 Hz, 1 H), 4.06 (m, 1 H), 4.85
(m, 1 H), 5.70 (dd, J = 8.7, 15.1 Hz, 1 H), 5.90 (d, J = 15.0 Hz, 1 H),
6.07 (dd, J = 1.6, 9.9 Hz, 1 H), 6.15 (dd, J = 10.7, 15.1 Hz, 1 H),
6.25 (dd, J = 11.1, 14.9 Hz, 1 H), 6.53 (dd, J = 10.6, 14.7 Hz, 1 H),
7.12–7.17 (m, 2 H).
13C NMR (125 MHz, CD3OD) d = 13.0, 16.9, 20.4, 22.0, 22.4, 30.0,
32.2, 35.9, 36.8, 40.3, 45.7, 48.5, 49.8, 50.1, 58.7, 66.1, 78.0, 124.2,
129.9, 130.4, 132.5, 134.0, 134.7, 141.9, 142.9, 146.3, 146.7, 169.1,
200.1.
HRMS–FAB: m/z [M + H]+ calcd for C29H44NO5: 486.3220; found:
486.3194.
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Acknowledgment
We greatly thank Dr. H. Kogen, Dr. T. Ogita, and Dr. T. Akiyama
(Sankyo Co., Ltd.) for fruitful discussions and the generous gift of
natural (+)-scyphostatin (1). We also thank Dr. N. Sugimoto and Dr.
N. Kawahara (National Institute of Health Sciences) for HRMS–
FAB measurements and assistance with NMR spectroscopy experi-
ments. This work was supported in part by Grants-in-Aid for Scien-
tific Research on Priority Areas (17035073) and for High
Technology Research Program from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
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