Stereoselective synthesis of the hydrophobic side chain of scyphostatin

Article abstract of DOI:10.1071/CH03298

The hydrophobic side chain of scyphostatin was synthesized by a convergent synthetic pathway. The key reactions were the enzymatic asymmetric acetylation of a meso-diol, construction of the C12′-C13′ trisubstituted E-olefin moiety by Negishi coupling, and

Full text of DOI:10.1071/CH03298

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 439–447
Stereoselective Synthesis of the Hydrophobic Side Chain of Scyphostatin
Ryukichi Takagi,A Shinjiro Tsuyumine,A Hiroko Nishitani,A Wataru Miyanaga,A
and Katsuo OhkataA,B
A Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama,
Higashi-Hiroshima 739-8526, Japan.
B Author to whom correspondence should be addressed (e-mail: ohkata@sci.hiroshima-u.ac.jp).
The hydrophobic side chain of scyphostatin was synthesized by a convergent synthetic pathway. The key reactions
were the enzymatic asymmetric acetylation of a meso-diol, construction of the C12ꢀ–C13ꢀ trisubstituted E-olefin
moiety by Negishi coupling, and construction of the (2ꢀE,4ꢀE,6ꢀE)-triene moiety by Horner–Wadsworth–Emmons
olefination.
Manuscript received: 21 November 2003.
Final version: 28 January 2004.
Introduction
E-olefin moiety (C12ꢀ–C13ꢀ), and a (2ꢀE,4ꢀE,6ꢀE)-triene
moiety. When we commenced this project, the relative
and absolute stereochemistry of the three stereocentres had
yet not been established, and were later determined to be
(8ꢀR,10ꢀS,14ꢀR) in the form of either an ester or an amide by
Kogen et al.[6] and Hoye et al.,[4h] independently. The report
by Hoye et al. also describes the first stereoselective synthesis
of the side chain.
In this paper, the stereoselective synthesis of the hydro-
phobic side chain up to the previously unreported free acid
2 is described. The difference in optical rotation values
of the geometric isomers (2ꢀE,4ꢀE,6ꢀE)-, (2ꢀZ,4ꢀE,6ꢀE)-,
(2ꢀE,4ꢀZ,6ꢀE)-, and (2ꢀE,4ꢀE,6ꢀZ)-30 is also described.
Scyphostatin 1 was isolated as a potent inhibitor of
neutral sphingomyerinase (N-SMase) from the mycelial
extract of Dasyscyphus mollissima by Ogita et al. (Sankyo
Co.) in 1997 (Scheme 1).[1] Scyphostatin 1 consists of
a hydrophobic side chain 2 and a hydrophilic 4,5-epoxy-
cyclohex-2-en-1-one moiety 3. Our interest in such biphilic
natural products[2,3] has inspired us to carry out synthetic
studies on scyphostatin 1. Other groups have also reported
their synthetic efforts.[4] Recently, Katoh et al. reported the
total synthesis of scyphostatin 1 from d-arabinose.[5]
We planned a convergent strategy for the synthesis of
Scyphostatin 1, namely, to synthesize the hydrophobic car-
boxylic acid 2 and the hydrophilic cyclohexenone 3 moieties
separately and combine them at the final stage of the total syn-
thesis.The structural features of the hydrophobic moiety 2 are
three stereogenic centres (C8ꢀ, C10ꢀ, C14ꢀ), a trisubstituted
Results and Discussion
Our initial synthetic strategy was based on the use of two
Horner–Wadsworth–Emmons (HWE) olefinations to attach
the three fragments as depicted in Scheme 2.[7] For the mid-
dle part 4, we envisioned that it could be stereoselectivity
constructed from diol 6. Incidentally, the use of diol 6 and
the HWE reagent 5 were found to be the same reagents as
those used in the method of Hoye et al.[4h]
O
O
HO
OH
NH
The absolute stereochemistry of (8ꢀR,10ꢀS) was intro-
ducedbyasymmetricacetylationofmeso-diol6usingporcine
pancreatic lipase (PPL; Scheme 3).[8] Thus, the chiral alcohol
7 was obtained by the PPL-catalyzed asymmetric acetylation
of the meso-diol 6 (62%, 99% e.e.).[9] Protection of the chi-
ral alcohol 7 with tert-butyldimethylsilyl chloride (TBSCl)
followed by reduction with LiAlH4 gave alcohol 9 (80%,
two steps). Halogenation of the alcohol 9 with PPh3–I2
afforded iodide 10, which was subsequently converted into
phosphonate 4 (70%, two steps).
O
1
Scyphostatin
O
O
OH
HO
OH
O
NH2
hydrophilic moiety
2
hydrophobic side chain moiety
3
We shifted our focus to the formation of the C12ꢀ–
C13ꢀ double bond by HWE olefination (Scheme 4). To
Scheme 1.
© CSIRO 2004
10.1071/CH03298
0004-9425/04/050439

440
R. Takagi et al.
HWE olefination
Horner–Wadsworth–Emmons olefination
12؅
6؅
20ꢀ
19ꢀ
11ꢀ
18ꢀ
9ꢀ
17ꢀ
8ꢀ
OH
O
1ꢀ OH
16ꢀ 15ꢀ
5ꢀ
3ꢀ
11؅
7؅
14ꢀ
10ꢀ
6ꢀ
4ꢀ
2ꢀ
13ꢀ 12ꢀ
7ꢀ
Negishi coupling
O
2
hydrophobic moiety
2 hydrophobic moiety
CO2Et
OTBS
CHO
(EtO)2P(O)
ButZn
OTBS
PivO
I
4
12
10؅
(EtO)2P(O)
CO2Et
O
5
(EtO)2P(O)
OEt
Scheme 2. Synthetic strategy via two WHE olefinations.
5
(a)
(b)
Scheme 5. Synthetic strategy via Negishi coupling reaction and HWE
olefination.
HO
R1
OH
R2
AcO
OH
6
7
91%
(d)
CO2Et
OTBS
OH
R
(e)
MeO2C
4 steps
OTBS
13
14
R ꢁ CN
Methyl (2S)-3-hydroxy-
2-methylpropinonate
(EtO)2P(O)
(a)
(b)
(c)
4
R1 ꢁ OAc, R2 ꢁ OTBS
R1 ꢁ OH, R2 ꢁ OTBS
R1 ꢁ I, R2 ꢁ OTBS
R ꢁ CHO
8
(c)
9
15
R ꢁ CH2OH
(d)
10
16 R ꢁ CH2OPMB
Scheme 3. Reagents and conditions: (a) PPL on Celite, vinyl acetate,
Et2O, 25◦C (62%, 99% e.e.); (b) TBSCl, Et3N, DMAP, THF, 25◦C
(99%); (c) LiAlH4, THF, 0◦C (81%); (d) PPh3, I2, imidazole, benzene,
25◦C (99%); (e) (EtO)2P(O)CH2CO2Et, NaH, DMSO, 25◦C, then 10,
25◦C (71%).
(g)
(h)
PMBO
R
PMBO
17 R ꢁ CH2OH
20
(e)
(f)
18
19
R ꢁ CHO
R ꢁ CH ꢁ CBr2
CO2Et
19؅
OTBS
ꢂ
CHO
(EtO)2P(O)
R2
R1O
14؅
4
(2S)-2-methylbutanal
21 R1 ꢁ PMB, R2 ꢁ SiMe2Ph
22 R1 ꢁ H, R2 ꢁ SiMe2Ph
(i)
NaH
THF, 0 to 25ºC
(j)
23 R1 ꢁ Piv, R2 ꢁ SiMe2Ph
(k)
CO2Et
CO2Et
R1 ꢁ Piv, R2 ꢁ I
12
OTBS
ꢂ
OTBS
Scheme 6. Reagents and conditions: (a) DIBAL, CH2Cl2, −78◦C,
then H+, −78 to 25◦C; (b) NaBH4, MeOH, 0–25◦C (89%, two steps);
(c) PMBOC(NH)CCl3, PPTS, CH2Cl2, 25◦C (99%); (d) TBAF, THF,
25◦C (99%); (e) (COCl)2, DMSO, Et3N, CH2Cl2, 25◦C; (f) PPh3,
CBr4, THF, 0–25◦C (100%, two steps); (g) BunLi, THF, 0◦C, then
MeI, 0–25◦C (89%); (h) (PhMe2Si)2CuLi · LiCN, THF, −40◦C (99%);
(i) DDQ, H2O, CH2Cl2, 0◦C (81%); (j) PivCl, pyridine, 25◦C (82%);
(k) NIS, CH3CN, THF, 25◦C (96%).
14؅
E-11
Z-11
66%
E :Z ꢁ 27:73
diastereomer ratio of Z-11 4:1
Scheme 4.
establish a synthetic route, (2S)-2-methylbutanal (easily pre-
pared from the commercially available alcohol) was used
for the HWE olefination. Treatment of phosphonate 4 with
(2S)-2-methylbutanal using NaH as a base gave a mixture of
E- and Z-11 (E-to-Z ratio 27 : 73, 66%).[10] Unfortunately,
epimerization at C14ꢀ was observed (diastereomeric ratio of
Z-11 4 : 1), and improvements could not be achieved under
milder conditions [LiCl, 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and LiCl, diisopropylethylamine (DIPEA)].[11,12]
Therefore, we decided to make a few adjustments to our
original strategy. The site of one of the bond formations was
changed from C12ꢀ–C13ꢀ to C11ꢀ–C12ꢀ. We anticipated that
the use of the Negishi coupling reaction[13] between organo-
zinc compound 10ꢀ, which could be generated from 10, and
vinyl iodide 12 would serve this purpose (Scheme 5).
The absolute configuration at C14ꢀ in the hydropho-
bic side chain 2 was introduced from commercially avail-
able methyl (2S)-3-hydroxy-2-methylpropionate (Scheme 6).
The nitrile 13 was obtained from methyl (2S)-3-hydroxy-
2-methylpropionate in four steps (91%).[14] Treatment of

Stereoselective Synthesis of a Side Chain of Scyphostatin
441
nitrile 13 with diisobutylaluminum hydride (DIBAL) gave
aldehyde 14. Alcohol 17 was obtained by a sequence of
reduction with NaBH4, protection with a p-methoxybenzyl
(PMB) group, and deprotection of the TBS group (87%,
four steps). Aldehyde 18, which was generated by Swern
oxidation of 17, was elaborated to acetylene 20 by Corey
and Fuchs’ procedure (89%, three steps).[15] Hydrosilyla-
tion of acetylene 20 with (PhMe2Si)2CuLi · LiCN afforded
vinyl silane 21 in 99% yield.[16] Although hydrostannylations
of 20 with PdCl2(PPh3)2/Bu3SnH or (Bu3Sn)CuCNLi were
also examined, the reactions were unsatisfactory in terms
of both yield and regioselectivity (67% yield, 11 : 1; 10%
yield, 30 : 1, respectively). The PMB group of 21 had to be
replaced by a pivaloyl (Piv) group (66%, two steps), because
the PMB group could not withstand the iododesilylation con-
ditions.Treatment of vinyl silane 23 with N-iodosuccinimide
(NIS)[17] afforded vinyl iodide 12 in 96% yield. The geo-
metry of vinyl iodide 12 was confirmed by differential NOE
(dif-NOE) experiments: When the H14ꢀ methine proton was
irradiated, the intensity of the H19ꢀ methyl proton signal was
enhanced by 1.6%. HPLC analysis using a chiral column indi-
cated that the optical purity of vinyl iodide 12 was 95% e.e.
(the racemate of 12 was used as a control).
ButLi, ZnCl2
ButZn
OTBS
I
OTBS
Et2O, ꢃ78ºC
10
10؅
19؅
11؅
OTBS
OPiv
I
PivO
PivO
14؅
PivO
13؅
24
ꢂ
Pd(PPh3)4
12؅
temp.
24 : 12؅
25ºC 67% : 32%
0ºC 85% : 7%
Scheme 7.
(d)
OTBS
R
R
24 R ꢁ OPiv
25 R ꢁ OH
28 R ꢁ CH2OH
(a)
(b)
(c)
(e)
29
R ꢁ CHO
26
27
R ꢁ OMs
R ꢁ H
Subsequently, we focussed our attention on the construc-
tion of the C12ꢀ–C13ꢀ trisubstituted E-olefin moiety using the
Negishi coupling reaction (Scheme 7). Treatment of iodide
10 in ether with ButLi in the presence of ZnCl2 at −78◦C
afforded organozinc compound 10ꢀ in situ. Complete con-
sumption of iodide 10 required 3 equivalents of ButLi.[18] The
reaction mixture was then warmed to 25◦C. To the reaction
mixture was added Pd(PPh3)4 (0.05 equiv) and vinyl iodide
12. Efficient conversion of vinyl iodide 12 required 2 equiv-
alents of the organozinc compound. The reaction mixture
was stirred at 25◦C. After workup, 24 and a homo-coupling
product 12ꢀ were obtained in 67 and 32% yields, respec-
tively. When the coupling reaction was carried out at 0◦C,
the homo-coupling reaction of 12ꢀ was slightly suppressed
(24, 85%; homo-coupling product 12ꢀ, 7%). The geometry
of 24 was confirmed by dif-NOE: When the H14ꢀ methine
proton was irradiated, the intensity of the H19ꢀ methyl proton
signal was enhanced by 2.7%. Moreover, NOE enhancement
at H11ꢀ (1.1%) was observed when vinyl proton H13ꢀ was
irradiated.
Synthesis of the hydrophobic side chain 2 was com-
pleted as follows (Scheme 8). Reduction of 24 with LiAlH4
afforded alcohol 25 (97%). Dehydroxylation of the hydroxy
group at C16ꢀ was achieved by mesylation of alcohol 25,
followed by reduction of mesylate 26 with LiAlH4, and 27
was obtained in 97% yield over two steps. Treatment of 27
with tetrabutyl ammonium fluoride (TBAF) gave alcohol 28
(99%). Alcohol 28 was oxidized to aldehyde 29 under Swern
oxidation conditions, and HWE olefination of aldehyde 29
with phosphonate 5[19] gave a mixture of four geomet-
ric isomers: (2ꢀE,4ꢀE,6ꢀE)-, (2ꢀZ,4ꢀE,6ꢀE)-, (2ꢀE,4ꢀZ,6ꢀE)-,
and (2ꢀE,4ꢀE,6ꢀZ)-30 [85%, ratio of (2ꢀE,4ꢀE,6ꢀE) to
(2ꢀZ,4ꢀE,6ꢀE) to (2ꢀE,4ꢀZ,6ꢀE) to (2ꢀE,4ꢀE,6ꢀZ) is approx-
imately 10 : 1 : 1 : 1]. The four isomers were separated
by high-performance liquid chromatography (HPLC). The
(f)
R
30
R ꢁ CO2Et
(g)
2 R ꢁ CO2H
Scheme 8. Reagents and conditions: (a) LiAlH4, THF, 0◦C (97%);
(b) MsCl, Et3N, THF, 0◦C (98%); (c) LiAlH4, THF, 0–25◦C (99%); (d)
TBAF, THF, 25◦C (99%); (e) (COCl)2, DMSO, Et3N, CH2Cl2, −78◦C;
(f) 5, LDA, THF, −78◦C, then 16, 0◦C (85%); (g) 5 M LiOH, THF,
25◦C (100%).
geometry of the (2ꢀ,4ꢀ,6ꢀ)-triene moiety was confirmed
by coupling constants in the 1H NMR spectrum: for
(2ꢀE,ꢀE,6ꢀE)-30, JH2 ,H3 15.3, JH4 ,H5 14.7, JH6 H7 15.1 Hz;
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
for (2ꢀZ,4ꢀE,6ꢀE)-30, JH2 ,H3 11.4, JH4 ,H5 15.1, JH6 H7
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
14.9 Hz; for (2ꢀE,4ꢀZ,6ꢀE)-30, JH2 ,H3 15.0, JH4 ,H5 11.4,
ꢀ
ꢀ
ꢀ
ꢀ
JH6 H7 14.9 Hz; for (2ꢀE,4ꢀE,6ꢀZ)-30, JH2 ,H3 15.5, JH4 ,H5
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
14.5, JH6 H7 11.0 Hz. We noticed that the optical rotation
value of (2ꢀE,4ꢀE,6ꢀE)-30 is negative and small, while those
of (2ꢀE,4ꢀZ,6ꢀE)- and (2ꢀE,4ꢀE,6ꢀZ)-30 are large and posi-
tive (Scheme 9). We consider that the difference of the optical
rotation values results from a distorted confomer of the triene
moiety caused by allylic strain. Spectroscopic data (1H and
13C NMR) and the optical rotation value of our synthetic
ethyl tetraenate (2ꢀE,4ꢀE,6ꢀE)-30 were compared with those
of Hoye’s four synthetic diastereomers.[4h] Although the C10ꢀ
signals in the 13C NMR spectrum appeared at δ 29.9, which
was slightly shifted toward the reported value (δ 31.3), the
other data were identical to those of the (8ꢀR,10ꢀS,14ꢀR)-
diastereomer. Hydrolysis of ethyl ester of (2ꢀE,4ꢀE,6ꢀE)-30
was performed by using 5 M LiOH, and hydrophobic car-
boxylic acid 2 was obtained without isomerization of the
triene moiety (100%). The geometry of the carboxylic acid
1
2 was confirmed by the coupling constants in the H NMR
spectrum: JH2 ,H3 14.5, JH4 ,H5 14.3, JH6 ,H7 14.9 Hz.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ

442
R. Takagi et al.
(2R,4S)-5-Acetoxy-2,4-dimethylpentyl Benzoate
CO2Et
To a mixture of 7 (16.9 mg, 0.10 mmol) in THF (1.0 mL) were added
Et3N (0.02 mL, 0.14 mmol) and BzCl (0.02 mL, 0.17 mmol) at 0◦C.
The mixture was stirred at 25◦C for 3 h. The mixture was quenched
with saturated NH4Cl and the aqueous layer was extracted with Et2O.
The organic layer was washed with H2O and brine, dried over anhydrous
MgSO4, filtered, and evaporated. The resulting residue was purified by
PTLC (EtOAc/hexane, 1 : 5) to give the benzoate of 7 (24.9 mg, 92%)
as a colourless oil, RF (EtOAc/hexane, 1 : 5) 0.48, [α]22 −1.57 (c 1.51,
CHCl3). δH (500 MHz, CDCl3) 0.94 (3 H, d, J 6.7, 4-DCH3), 1.06 (3 H,
d, J 6.7, 2-CH3), 1.52–1.59 (2 H, m, H3), 1.92–2.11 (2 H, m, H2, H4),
2.02 (3 H, s, COCH3), 3.88 (1 H, dd, J 6.4, 10.7, H5), 3.96 (1 H, dd,
J 5.5, 10.7, H5), 4.12 (1 H, dd, J 6.4, 10.7, H1), 4.21 (1 H, dd, J 5.5,
10.7, H1), 7.43–7.58 (3 H, m, Ph), 8.03–8.06 (2 H, m, Ph). Found: m/z
278.1513. M+ requires 278.1518.
(2ꢀE,4ꢀE,6ꢀE)-30
[a]2D2 ꢃ1.57 (c 0.19, CHCl3)
CO2Et
(2ꢀZ,4ꢀE,6ꢀE)-30
[a]2D2 ꢃ0.42 (c 0.21, CHCl3)
CO2Et
(2ꢀE,4ꢀZ,6ꢀE)-30
[a]2D2 ꢂ21.5 (c 0.15, CHCl3)
(2S,4R)-5-(tert-Butyldimethylsilyloxy)-2,4-dimethylpentyl
Acetate 8[21]
CO2Et
To a mixture of monoacetate 7 (419 mg, 2.40 mmol) in THF (5.0 mL)
were added Et3N (0.45 mL, 3.2 mmol), 4-dimethylaminopyridine
(DMAP, 30.0 mg, 0.31 mmol), and TBSCl (424 mg, 2.81 mmol) at 0◦C.
The mixture was stirred at 25◦C for 3 h. The mixture was quenched
with saturated NH4Cl and the aqueous layer was extracted with Et2O.
The organic layer was washed with H2O and brine, dried over MgSO4,
filtered, and evaporated. The resulting residue was purified by bulb-to-
bulb distillation (120–130◦C/1 mmHg) to give 8 (683 mg, 99%) as a
colourless oil, RF (EtOAc/hexane, 1 : 2) 0.72. vmax (film)/cm−1 2954,
2931, 2888, 1743, 1469, 1388, 1365, 1238, 1095. δH (500 MHz, CDCl3)
−0.03 (6 H, s, SiCH3), 0.89 (9 H, s, SiC(CH3)3), 0.88–0.91 (3 H, m,
4-CH3), 0.94 (3 H, d, J 6.7, 2-CH3), 1.24–1.33 (1 H, m, H3), 1.42–1.50
(1 H, m, H3), 1.65–1.73 (1 H, m, H4), 1.84–1.94 (1 H, m, H2), 2.04 (3
H, s, OCH3), 3.36 (1 H, dd, J 6.1, 9.7, H5), 3.42 (1 H, dd, J 6.1, 9.7,
H5), 3.82 (1 H, dd, J 6.7, 10.7, H1), 3.95 (1 H, dd, J 5.2, 10.7, H1).
δC (125 MHz, CDCl3) −5.5 (2 C, SiCH3), 17.4 (4-CH3), 17.7 (2-CH3),
18.2 (SiC(CH3)3), 20.8 (C3), 25.8 (3 C, SiC(CH3)3), 30.0 (COCH3),
33.0 (C4), 37.4 (C2), 67.9 (C5), 69.3 (C1), 171.0 (COCH3). Found: m/z
231.1417. M+ − But requires 231.1416.
(2ꢀE,4ꢀE,6ꢀZ)-30
[a]2D2 ꢂ59.8 (c 0.24, CHCl3)
Scheme 9. Optical rotation values of (2ꢀE,4ꢀE,6ꢀE)-, (2ꢀZ,4ꢀE,6ꢀE)-,
(2ꢀE,4ꢀZ,6ꢀE)-, and (2ꢀE,4ꢀE,6ꢀZ)-30.
Conclusion
The stereoselective synthesis of the hydrophobic carboxylic
acid 2 of scyphostatin 1 was accomplished by a conver-
gent synthetic pathway. The key reactions were enzymatic
asymmetric acetylation of a meso-diol, construction of the
C12ꢀ–C13ꢀ trisubstituted E-olefin moiety by Negishi cou-
pling, and construction of the (2ꢀE,4ꢀE,6ꢀE)-triene moiety
by Horner–Wadsworth–Emmons olefination.
(2S,4R)-5-(tert-Butyldimethylsilyloxy)-2,4-dimethylpentan-1-ol 9[21]
To a mixture of LiAlH4 (210 mg, 5.53 mmol) inTHF (5.0 mL) was added
acetate 8 (692 mg, 2.40 mmol) in THF (5.0 mL) at 0◦C. The mixture
was stirred for 4 h at 0–25◦C. The mixture was quenched with H2O,
dilute HCl was added, and the aqueous layer was extracted with Et2O.
The organic layer was washed with H2O and brine, dried over MgSO4,
filtered, and evaporated. The resulting residue was purified by column
chromatography (SiO2; EtOAc/hexane, 1 : 5) to give 9 (464 mg, 79%)
as a colourless oil, RF (EtOAc/hexane, 1 : 2) 0.61, [α]2D2 −1.12 (c 2.03,
CHCl3) [lit.[22] −1.2 (c 1.4, CHCl3]. vmax (film)/cm−1 3351, 2954,
2927, 2857, 1469, 1388, 1361, 1253. δH (500 MHz, CDCl3) 0.04 (6 H,
s, SiCH3), 0.90 (9 H, s, SiC(CH3)3), 0.91 (3 H, d, J 4.0, 4-CH3), 0.94 (3
H, d, J 6.7, 2-CH3), 1.40–1.56 (2 H, m, H3), 1.67–1.78 (2 H, m, H2, H4),
3.35–3.54 (4 H, m, H1, H5). δC (125 MHz, CDCl3) −5.5 (2 C, SiCH3),
17.6 (4-CH3), 17.7 (2-CH3), 18.3 (SiC(CH3)3), 25.6 (C3), 25.9 (3 C,
SiC(CH3)), 33.2 (C4), 37.2 (C2), 67.9 (C5), 68.3 (C1). Found: m/z
246.2025. M+ requires 246.2015.
Experimental
All reactions were carried out under N2.Tetrahydrofuran (THF) was dis-
tilled after refluxing over Na–benzophenone before use. CH2Cl2 was
distilled over CaH2 before use. Silica gel 60F254 (Merck) was used
for preparative thin-layer chromatography. NMR spectra were recorded
on JEOL JNM-GSX270 or JNM-LA500 instruments. Internal refer-
ences for 1H NMR spectra were Me4Si (TMS; 0.0 ppm) for CDCl3 and
CD3OD (3.31 ppm). Chemical shifts for 13C NMR spectra were refer-
encedtoCDCl3 (77.0 ppm)andCD3OD(49.49 ppm). MSwererecorded
on a JEOL JMS-SX102A instrument under electron ionization (EI) con-
ditions (70 eV). Optical rotations were recorded on a JASCO DIP-370
polarimeter. IR spectra were recorded on a Horiba FT-IR720. Elemental
analyses were carried out on a Perkin–Elmer 2400II analyzer.
(2S,4R)-2,4-Dimethyl-5-hydroxypentyl Acetate 7[8]
(2R,4S)-1-(tert-Butyldimethylsilyloxyl)-5-iodo-
2,4-dimethylpentane 10
To a suspension of diol 6[20] (266 mg, 2.01 mmol) and PPL on Celite
(1.02 g, 506 g mol−1) in Et2O (25 mL) was added vinyl acetate (0.8 mL,
8.68 mmol) at 25◦C. After stirring the mixture for 18 h, the Celite was
filtered off, and the filtrate was evaporated. The resulting residue was
purified by column chromatography (SiO2; EtOAc/hexane, 1 : 2) to give
7 (218 mg, 62%, 99% e.e.) as a colourless oil, RF (EtOAc/hexane, 1 : 2)
0.20, [α]2D2 +10.3 (c 2.18, CHCl3) [lit.[8b] +10.4 (c 1.2, CHCl3)]. δH
(500 MHz, CDCl3) 0.95 (3 H, d, J 4.0, 4-CH3), 0.97 (3 H, d, J 4.0,
2-CH3), 0.99–1.03 (1 H, m, H3), 1.41–1.48 (1 H, m, H3), 1.69–1.79
(1 H, m, H3), 1.86–1.95 (1 H, m, H2), 2.06 (3 H, s, OAc), 3.42 (1 H, dd,
J 6.4, 10.7, H5), 3.51 (1 H, dd, J 5.5, 10.7, H5), 3.86 (1 H, dd, J 6.7,
10.7, H1), 3.96 (1 H, dd, J 5.5, 10.7, H1).
To a mixture of alcohol 9 (241 mg, 0.98 mmol) in benzene (9.0 mL)
were added imidazole (165 mg, 2.42 mmol), PPh3 (644 mg, 2.46 mmol),
and I2 (505 mg, 1.99 mmol) at 25◦C. The mixture was stirred at 25◦C
for 30 min. The mixture was quenched with saturated Na2S2O3 and
the aqueous layer was extracted with Et2O. The organic layer was
washed with H2O and brine, dried over MgSO4, filtered, and evapo-
rated. The resulting residue was purified by column chromatography
(SiO2; EtOAc/hexane, 1 : 95) to give 10 (312 mg, 90%) as a colourless
oil, RF (EtOAc/hexane, 1 : 5) 0.87, [α]2D2 +3.50 (c 2.09, CHCl3). vmax
(film)/cm−1 2954, 2927, 2888, 2857, 1461, 1388, 1361, 1253, 1191,

Stereoselective Synthesis of a Side Chain of Scyphostatin
443
1095, 1072. δH (500 MHz, CDCl3) 0.04 (6 H, s, SiCH3), 0.89 (3 H, d,
J 6.7, 4-CH3), 0.90 (9 H, s, SiC(CH3)3), 0.99 (3 H, d, J 6.7, 2-CH3),
1.38–1.45 (2 H, m, H3), 1.51–1.59 (1 H, m, H4), 1.60–1.68 (1 H, m, H2),
3.12 (1 H, dd, J 6.4, 9.8, H5), 3.26 (1 H, dd, J 4.0, 9.8, H5), 3.36 (1 H,
dd, J 6.1, 9.8, H1), 3.44 (1 H, dd, J 5.5, 9.8, H1). δC (125 MHz, CDCl3)
−5.4 (2 C, SiCH3), 17.2 (2-CH3), 18.0 (4-CH3), 18.3 (SiC(CH3)3),
21.5 (C3), 26.0 (3 C, SiC(CH3)3), 31.9 (C4), 33.2 (C2), 40.2 (C5), 68.2
(C1). Found: C 43.7, H 8.3, m/z 299.0331. C13H29IOSi requires C 43.8,
H 8.2%, M+ − But 299.0328.
−5.4 (2 C, SiCH3), 11.9, 14.3 [17.4 (8R), 17.5 (8S)], 18.3, 20.1,
20.4, 26.0 (3 C, SiC(CH3)3), 29.6 [30.1 (8S), 30.2 (8R)], [33.1 (8S),
33.2 (8R)], [35.1 (8R), 35.2 (8S)], [41.1 (8S), 41.2 (8R)], [42.0 (8S),
42.2 (8R)], 59.9, 68.5, [130.0 (8S), 130.1 (8R)], [147.9 (8S), 148.0
(8R)], [168.4 (8S), 168.5 (8R)]. Found: C 68.7, H 11.5, m/z 384.3074.
C22H44O3Si requires C 68.7, H 11.5%, M+ 384.3060.
δH for E-11 (500 MHz, CDCl3) [0.02 (s, 8S-SiCH3), 0.03 (s, 8R-
SiCH3)], 0.82 (3 H, dd, J 7.0, 11.0, H10), [0.85 (d, J 4.3, 8S-4-CH3),
0.86 (d, J 4.6, 8R-4-CH3)], 0.89 (9 H, s, SiC(CH3)3), [0.90 (d, J 6.7,
8S-2-CH3), 0.91 (d, J 6.4, 8R-2-CH3)], [0.98 (d, J 6.7, 8S-8-CH3),
0.99 (d, J 6.7, 8R-8-CH3)], 1.29 (3 H, t, J 7.1, CO2CH2CH3), 1.30–
1.44 (4 H, m, H3,H9), 1.65–1.79 (2 H, m, H2,H4), [1.97 (dd, J 9.4,
13.8, 8R-H5), 2.03 (dd, J 8.8, 12.5, 8S-H5)], [2.32 (dd, J 5.5, 12.5,
8S-H5), 2.37 (dd, J 5.8, 13.8, 8R-H5)], 2.37–2.43 (1 H, m, H8), 3.31
(1 H, dd, J 7.0, 9.3, H1), 3.45 (1 H, dd, J 5.3, 9.4, H1), [4.17 (q, J
7.1, 8S-CO2CH2CH3), 4.18 (q, J 7.1, 8R-CO2CH2CH3)], [6.53 (d, J
11.0, 8R-H7), 6.55 (d, J 10.7, 8S-H7)]. δC (125 MHz, CDCl3) −5.4
(2 C, SiCH3), [11.8 (8S), 11.9 (8R)], 14.3, 17.3, 17.5 [18.3 (8R), 19.8
(8S)], [20.2 (8S), 20.3 (8R)], 25.9 (3 C, SiC(CH3)3), [29.6 (8R), 29.7
(8S)], [30.1 (8S), 30.4 (8R)], [33.2 (8R), 33.3 (8S)], [33.7 (8S), 33.8
(8R)], [34.7 (8R), 34.8 (8S)], [41.4 (8R), 41.6 (8S)], 60.3 [68.3 (8S),
68.4 (8R)], [130.1 (8R), 130.2 (8S)], [148.7 (8R), 148.8 (8S)], 168.5
(CO2CH2CH3). Found: m/z 327.2342. M+ − But requires 327.2324.
Ethyl 7-(tert-Butyldimethylsilyloxy)-2-(diethoxyphosphoryl)-
4,6-dimethylheptanoate 4
To a mixture of NaH (65% in mineral oil, 49.6 mg, 1.24 mmol,
washed with hexane) in dimethyl sulfoxide (DMSO; 1.0 mL) was added
(EtO)2P(O)CH2CO2Et (259 mg, 1.16 mmol) in DMSO (0.5 mL) at
25◦C. The mixture was stirred at 25◦C for 30 min, and to the solu-
tion was added the iodide 10 (413 mg, 1.16 mmol) in DMSO (1.0 mL)
at 25◦C.After stirring for 29 h, the mixture was quenched with saturated
NH4Cl, and the aqueous layer was extracted with CH2Cl2. The com-
bined organic layer was washed with H2O and brine, dried over MgSO4,
filtered, and evaporated. The resulting residue was purified by column
chromatography (SiO2; EtOAc/hexane, 1 : 1) to give 4 as a mixture of
diastereomers (ratio of major to minor approximately 6 : 4, colourless
oil, 371 mg, 71%, 86% based on consumed 10), RF (EtOAc) 0.65. δH
(500 MHz, CDCl3) 0.03 (6 H, s, SiCH3), 0.85 (3 H, d, J 6.7, 4-CH3),
0.88 (3 H, d, J 6.1, 6-CH3), 0.89 (9 H, s, SiC(CH3)3), 0.87–1.02 (3 H,
m), 1.28 (3 H, t, J 7.2, CO2CH2CH3), 1.32 (3 H, t, J 7.2, POCH2CH3),
1.33 (3 H, t, J 7.2, POCH2CH3), 1.39–1.52 (minor, 1 H, m), [1.53–1.61
(minor, m, 1 H), 2.10–2.19 (major, m, 1 H)], [1.63–1.71 (major, 1 H, m),
1.77–1.91 (minor, 1 H, m)], [3.01 (minor, ddd, J 5.1, 8.8, 24.1, H2), 3.08
(major, ddd, J 2.4, 12.2, 22.8, H2)], [3.27(minor, dd, J 6.7, 9.4, H7), 3.33
(major, dd, J 6.7, 9.4, H7)], [3.41 (major, dd, J 5.4, 9.4, H7), 3.49 (minor,
dd, J 4.7, 9.4, H7)], 4.09–4.25 (6 H, m, OCH2CH3). δC (125 MHz,
CDCl3) −5.4 (2 C, SiCH3), [14.0 (minor, OCH2CH3), 14.1 (major,
OCH2CH3)], [16.2 (minor, d, J 3.1, 2 POCH2CH3), 16.3 (major, d, J
3.1, 2 POCH2CH3)], 16.9 (6-CH3), 17.8 (4-CH3), 18.3 (SiC(CH3)3),
[19.5 (major, C5), 20.4 (minor, C5)], 25.9 (3 C, SiC(CH3)3), [28.7
(major, d, J 14.5, C3), 29.8 (minor, d, J 13.5, C3)], [33.1 (major, d, J
4.1, C4), 34.2 (minor, d, J 5.2, C4)], [40.3 (minor, C6), 41.3 (major,
C6)], [43.6 (major, d, J 130.4, C2), 43.9 (minor, d, J 130.4, C2)], [61.2
(major, CO2CH2CH3), 61.3 (minor, CO2CH2CH3)], [62.4 (minor, d, J
5.2, POCH2CH3), 62.5 (major, d, J 6.2, POCH2CH3)], [62.6 (minor, d,
J 6.2, POCH2CH3), 62.7 (major, d, J 6.2, POCH2CH3)], [68.0 (minor,
C7), 68.4 (major, C7)], [169.1 (major, d, J 5.2, CO2CH2CH3), 169.7
(minor, d, J 5.2, CO2CH2CH3)]. δP (202 MHz, CDCl3) 24.0. Found: C
55.7, H 10.2, m/z 395.2019. C21H45O6PSi requires C 55.7, H 10.0%,
(3R)-4-(tert-Butyldimethylsilyloxy)-3-methylbutan-1-ol 15
DIBAL (1.0 M solution in toluene, 75 mL, 75 mmol) was added to a
solution of 13 (10.6 g, 49.8 mmol) in CH2Cl2 (125 mL) at −78◦C. After
stirring the mixture at −78◦C for 1 h, saturated NH4Cl was added to the
reaction mixture at −78◦C. The reaction mixture was warmed to 25◦C
and stirred for 30 min.The mixture was extracted with Et2O.The organic
layer was washed with H2O and brine, dried over Na2SO4, and filtered.
Evaporation of the solution afforded the crude aldehyde 14 as colourless
oil. The crude product was used for the next reaction without further
purification, RF (EtOAc/hexane, 1 : 10) 0.37. δH (500 MHz, CDCl3)
0.03 (6 H, s, SiCH3), 0.88 (9 H, s, SiC(CH3)3), 0.94 (3 H, d, J 6.7, 3-
CH3), 2.16–2.31 (2 H, m, H2), 2.46–2.54 (1 H, m, H3), 3.36 (1 H, dd, J
7.2, 9.3, H4), 3.56 (1 H, dd, J 4.9, 9.3, H4), 9.77 (1 H, t, J 2.1, CHO). δC
(125 MHz, CDCl3) −5.5 (2 SiCH3), 16.7 (3-CH3), 18.2 (SiC(CH3)3),
25.9 (3 C, SiC(CH3)3), 31.4 (C2), 48.2 (C3), 67.7 (C4), 202.6 (CHO).
To a solution of the crude aldehyde 14 in MeOH (125 mL) was
added NaBH4 (1.90 g, 50.1 mmol) at 0◦C. The reaction mixture was
stirred at 25◦C for 24 h and quenched with satuarted NH4Cl. The
aqueous layer was extracted with Et2O and the combined organic
layer was washed with H2O and brine, dried over Na2SO4, filtered,
and evaporated. The crude product was purified by column chromato-
graphy (SiO2; EtOAc/hexane, 1 : 10) and alcohol 15 was obtained as
a colourless oil (9.8 g, 89%), RF (EtOAc/hexane, 1 : 10) 0.27, [α]2D2 +6.9
(c 9.84, CHCl3) {(3S)-15, lit.[14b] [α]D27 −6.96 (c 4.80, CHCl3)}. vmax
(film)/cm−1 3347, 2956, 2857, 1463, 1388, 1361, 1255, 1093, 1052,
1006. δH (500 MHz, CDCl3) 0.07 (6 H, s, SiCH3), 0.90 (3 H, d, J 5.2,
3-CH3), 0.91 (9 H, s, SiC(CH3)3), 1.51–1.64 (2 H, m, H2), 1.72–1.83
(1 H, m, H3), 3.43 (1 H, dd, J 7.3, 10.2, H4), 3.53 (1 H, dd, J 4.6, 10.2,
H4), 3.59–3.66 (1 H, m, H1), 3.67–3.75 (1 H, m, H1). δC (125 MHz,
CDCl3) −5.5 (2 C, SiCH3), 17.3 (3-CH3), 18.3 (SiC(CH3)3), 25.8
(3 C, SiC(CH3)3), 33.9 (C2), 38.0 (C3), 61.1 (C1), 68.7 (C4). Found:
m/z 161.0998. M+ − But 161.0997.
M
+ − But 395.2019.
(2R,4S)-1-(tert-Butyldimethylsilyloxy)-6-ethoxycarbonyl-
2,4,8-trimethyldec-6-ene 11
To a mixture of NaH (60% in mineral oil, 78.0 mg, 1.85 mmol, washed
with hexane) in THF (10.0 mL) was added phosphonate 4 (800 mg,
1.77 mmol) in THF (2.0 mL) at 0◦C. The mixture was stirred at 0◦C
for 30 min, and to the solution was added 2-methylbutanal (19.8 mg,
2.13 mmol) in THF (0.5 mL) at 0◦C. After stirring at 0–25◦C for 12 h,
the mixture was quenched with saturated NH4Cl, and the aqueous layer
was extracted with Et2O. The combined organic layer was washed with
H2O and brine, dried over MgSO4, filtered, and evaporated. The result-
ing residue was purified by preparative TLC (silica gel; EtOAc/hexane,
1 : 1) to give E-11 and Z-11 as a mixture of diastereomers (colourless
oil, 442 mg, 66%; ratio of E to Z, 27 : 73), RF (EtOAc/hexane, 1 : 5)
0.71. δH for Z-11 (500 MHz, CDCl3) 0.03 (6 H, s, SiCH3), 0.83 (3 H,
t, J 7.2, H10), [0.83 (d, J 6.7, 8R-4-CH3), 0.84 (d, J 7.6, 8S-4-CH3)],
0.88 (3 H, d, J 6.7, 2-CH3), 0.89 (9 H, s, SiC(CH3)3), [0.96 (d, J 6.7, 8S-
8-CH3), 0.99 (d, J 6.4, 8R-8-CH3)], 1.29 (3 H, t, J 7.0, CO2CH2CH3),
1.23–1.40 (4 H, m, H3, H9), 1.58–1.67 (1 H, m, H4), 1.67–1.81 (2 H,
m, H2,H5), 2.43 (1 H, dd, J 4.3, 13.4, H5), 2.85–2.95 (1 H, m, H8), 3.30
(1 H, dd, J 4.3, 13.4, H1), 3.44 (1 H, dd, J 5.5, 9.8, H1), 4.18 (2 H, q,
J 7.0, CO2CH2CH3), 5.51 (1 H, d, J 10.0, H7). δC (125 MHz, CDCl3)
(2R)-1-(tert-Butyldimethylsilyloxy)-4-(4-methoxybenzyloxy)-
2-methylbutane 16
A mixture of 15 (671.8 mg, 3.08 mmol) in CH2Cl2 (30 mL) was added to
a solution of PMBC(NH)CCl3 (2.17 g, 7.69 mmol) and PPTS (387.0 mg,
1.54 mmol) in CH2Cl2 (10 mL) at 0◦C. The reaction mixture was stirred
at 25◦C for 1 day and quenched with saturated NH4Cl. The aqueous
layer was extracted with CH2Cl2 and the combined organic layer was
washed with H2O and brine, dried over Na2SO4, filtered, and evap-
orated. The resulting residue was purified by column chromatography
(SiO2; EtOAc/hexane, 1 : 20) to give 16 as a colourless oil (1.04 g, 99%),
RF (CH2Cl2) 0.77, [α]D22 + 0.39 (c 10.4, CHCl3). vmax (film)/cm−1

444
R. Takagi et al.
2954, 2929, 2856, 1513, 1245, 1100, 1020. δH (500 MHz, CDCl3) 0.03
(6 H, s, SiCH3), 0.89 (9 H, s, SiC(CH3)3), 0.90 (3 H, d, J 6.1, 2-
CH3), 1.34–1.44 (1 H, m, H2), 1.70–1.80 (2 H, m, H4), 3.39 (1 H, dd,
J 5.6, 10.1, H1), 3.46 (1 H, dd, J 5.5, 10.1, H1), 3.49 (1 H, dd, J 2.2,
7.0, H4), 3.50 (1 H, dd, J 2.1, 7.0, H4), 3.81 (3 H, s, OCH3), 4.44 (2
H, s, CH2Ar), 6.88 (2 H, d, J 8.4, C6H4OCH3), 7.26 (2 H, d, J 8.4,
C6H4OCH3). δC (125 MHz, CDCl3) −5.4 (2 C, SiCH3), 16.8 (2-CH3),
18.3 (SiC(CH3)3), 25.9 (3 C, SiC(CH3)3), 33.0 (C2), 33.2 (C3), 55.2
(OCH3), 68.2 (CH2Ar), 68.4 (C1), 72.5 (C4), 113.7 (2 C, Ar), 129.2
(2 C, Ar), 130.8 (ipso-Ar), 159.1 (ipso-Ar). Found: m/z 338.2277. M+
requires 338.2279.
(4R)-6-(4-Methoxybenzyloxy)-4-methylhex-2-yne 20
To a solution of 19 (1.50 g, 3.95 mmol) in THF (7.9 mL) was added
n-butyllithium (1.57 M solution in THF, 6.2 mL, 9.9 mmol) at 0◦C.
The reaction mixture was stirred at 25◦C for 30 min and MeI (1.3 mL,
20 mmol) was added to the solution at 0◦C. After stirring the mixture at
25◦C for 12 h, saturated NH4Cl was added and the aqueous layer was
washed with H2O and brine, dried over Na2SO4, filtered, and evapo-
rated.The crude product was purified by column chromatography (SiO2;
EtOAc/hexane, 1 : 30) to give 20 as a colourless oil (819.9 mg, 89%),
RF (EtOAc/hexane, 1 : 10) 0.33, [α]2D2 −65.4 (c 42.0, CHCl3). vmax
(film)/cm−1 2964, 2933, 2917, 2857, 2836, 1612, 1513, 1105, 1025. δH
(500 MHz, CDCl3) 1.14 (3 H, d, J 7.0, 4-CH3), 1.59–1.75 (2 H, m, H5),
1.77 (3 H, s, H1), 2.52–2.63 (1 H, m, H4), 3.55–3.60 (2 H, m, H6), 3.80
(3 H, s, OCH3), 4.44 (2 H, s, CH2Ar), 6.87 (2 H, d, J 8.5, Ar), 7.27
(2 H, d, J 8.5, Ar). δC (125 MHz, CDCl3) 3.47 (C1), 21.5 (4-CH3), 22.9
(C5), 37.2 (C4), 55.3 (OCH3), 68.1 (CH2Ar), 72.6 (C6), 75.8 (C3), 83.2
(C2), 113.7 (2 C, Ar), 129.2 (2 C, Ar), 130.8 (ipso-Ar), 159.1 (ipso-Ar).
Found: C 77.4, H 8.8, m/z 232.1463. C15H20O2 requires C 77.6, H 8.7%,
M+ 232.1473.
(2R)-4-(4-Methoxylbenzyloxy)-2-methylbutan-1-ol 17
TBAF (1.0 M solution inTHF, 3.6 mL, 3.6 mmol) was added to a solution
of 16 (801.0 mg, 2.37 mmol) inTHF (4.0 mL) at 0◦C.After being stirred
for 6 h, the reaction mixture was quenched with saturated NH4Cl and
the aqueous layer was extracted with Et2O. The combined organic layer
was washed with H2O and brine, dried over Na2SO4, filtered, and evap-
orated. The resulting residue was purified by column chromatography
(SiO2; EtOAc/hexane, 1 : 10) to give 17 as a colourless oil (526.8 mg,
99%), RF (EtOAc/hexane, 1 : 10) 0.12, [α]2D2 + 9.66 (c 5.70, CHCl3)
{(2S)-17: lit.[23] [α]D25 −7.9 (c 2.34, CHCl3)}. vmax (film)/cm−1 3421,
2954, 2911, 2869, 2838, 1610, 1511, 1247, 1089, 1033. δH (500 MHz,
CDCl3) 0.90 (3 H, d, J 6.7, 2-CH3), 1.52–1.61 (1 H, m, H3), 1.62–1.71
(1H, m, H3), 1.75–1.85(1H, m, H2), 2.62–2.68(1H, m, OH), 3.38–3.35
(1H, m, H1), 3.46–3.52(2H, m, H1, H4), 3.54–3.59(1H, m, H4), 3.80(3
H, s, OCH3), 4.45 (2 H, s, CH2Ar), 6.88 (2 H, d, J 8.5, CH2C6H4OCH3),
7.25 (2 H, d, J 8.5, CH2C6H4OCH3). δC (125 MHz, CDCl3) 17.2
(2-CH3), 34.1 (C2), 34.2 (C3), 55.2 (OCH3), 68.1 (CH2Ar), 68.4 (C1),
72.8 (C4), 113.8 (2 C, Ar), 129.4 (2 C, Ar), 130.1 (ipso-Ar), 159.3
(ipso-Ar). Found: m/z 224.1412. M+ requires 224.1408.
(2E,4R)-2-Dimethylphenylsilyl-6-(4-methoxybenzyloxy)-
4-methylhex-2-ene 21
To a suspension of Li (580.6 mg, 83.7 mmol) inTHF (60 mL) was added
PhMe2SiCl (5.0 mL, 30 mmol) at −10◦C. The reaction mixture was
stirred at −10◦C for 2 days. The generated red solution of PhMe2SiLi
(33.2 mL, 6.59 mmol)wasaddedtoCuCN(743.4 mg, 8.30 mmol)at0◦C
and the mixture was stirred at 25◦C for 30 min. To the reaction mixture
was added a solution of 20 (963.3 mg, 4.15 mmol) in THF (3.0 mL)
at −40◦C. After stirring the mixture at −40◦C for 2 days, saturated
NH4Cl was added to the reaction mixture, and the reaction mixture was
then warmed to 25◦C, and filtered through Celite.The aqueous layer was
extracted with Et2O and the combined organic layer was washed with
H2O and brine, dried over Na2SO4, filtered, and evaporated. Purification
by column chromatography (SiO2; EtOAc/hexane, 1 : 40) gave 21 as
a colourless oil (1.53 g, 99%), RF (EtOAc/hexane, 1 : 10) 0.33, [α]D22
−33.9 (c 23.3, CHCl3). vmax (film)/cm−1 2956, 2925, 2854, 1614, 1513,
1247, 1108. δH (500 MHz, CDCl3) 0.31 (6 H, s, SiCH3), 0.95 (3 H, d,
J 6.7, 4-CH3), 1.44–1.54 (1 H, m, H5), 1.63–1.73 (1 H, m, H5), 1.64
(3 H, d, J 1.6, H1), 2.72–2.81 (1 H, m, H4), 3.36 (1 H, dt, J 7.3, 9.2,
H6), 3.42 (1 H, ddd, J 5.2, 7.2, 9.2, H6), 3.79 (3 H, s, OCH3), 4.38 (2 H,
s, CH2Ar), 5.54 (1 H, dq, J 1.6, 9.1, H3), 6.86 (2 H, d, J 8.5, Ar), 7.23
(2 H, d, J 8.5, Ar), 7.30–7.35 (3 H, m, Ph), 7.45–7.49 (2 H, m, Ph). δC
(125 MHz, CDCl3) −3.4 (2 C, SiCH3), 14.8 (C1), 20.7 (4-CH3), 29.3
(C5), 37.0 (C4), 55.1 (OCH3), 68.4 (CH2Ar), 72.6 (C6), 113.7 (2 C,
Ar), 127.6 (2 C, Ph), 128.7 (C3), 129.2 (2 C, Ar), 130.6 (ipso-Ar), 132.7
(C2), 133.9 (2 C, Ph), 138.8 (ipso-Ph), 147.1 (ipso-Ph), 159.1 (ipso-Ar).
Found: C 74.7, H 8.9, m/z 368.2172. C23H32O2Si requires C 75.0, H
8.8%, M+ 368.2187.
(3R)-1,3-Dibromo-4-(4-methoxybenzyloxy)-3-methylpent-1-ene 19
To a solution of (COCl)2 (1.0 mL, 11.6 mmol) in CH2Cl2 (30 mL) was
slowly added DMSO (0.83 mL, 11.6 mmol) at −78◦C. After stirring
the mixture for 30 min, 17 (1.31 g, 5.82 mmol) in CH2Cl2 (28 mL) was
added to the reaction mixture.The reaction mixture was stirred at −78◦C
for 45 min and Et3N (4.9 mL, 34.9 mmol) was added.The resulting mix-
ture was stirred at −78◦C for 1 h, warmed to 25◦C, and quenched with
saturated NH4Cl. The aqueous layer was extracted with CH2Cl2 and
the combined organic layer was washed with H2O and brine, dried
over Na2SO4, and filtered. After evaporation, crude product 18 was
obtained as a colourless oil. The crude product 18 was used for the next
reaction without further purification, RF (EtOAc/hexane, 1 : 4) 0.35. δH
(500 MHz, CDCl3) 1.10 (3 H, d, J 7.0, 2-CH3), 1.64–1.72 (1 H, m, H3),
1.99–2.07 (1 H, m, H3), 2.49–2.56 (1 H, m, H2), 3.45–3.55 (2 H, m,
H4), 3.80 (3 H, s, OCH3), 4.41 (2 H, s, CH2Ar), 6.87 (2 H, d, J 8.7, Ar),
7.23 (2 H, d, J 8.7, Ar), 9.63 (1 H, d, J 1.8, CHO). Found: m/z (FAB)
223.1333. M+ requires 223.1334.
To a solution of CBr4 (3.86 g, 11.6 mmol) in CH2Cl2 (18 mL) was
added PPh3 (6.11 g, 23.3 mmol) in CH2Cl2 (28 mL) at 0◦C, and the
solution was stirred at 25◦C. After 20 min, a solution of the crude prod-
uct 18 in CH2Cl2 (28 mL) was added to the reaction mixture at 0◦C.
The reaction mixture was stirred at 25◦C for 12 h and quenched with
saturtaed NH4Cl. The aqueous layer was extracted with CH2Cl2 and the
organic layer was washed with H2O and brine, dried over Na2SO4, fil-
tered, and evaporated. Purification by column chromatography (SiO2;
EtOAc/hexane, 1 : 20) gave 19 as a colourless oil (2.2 g, 100%), RF
(EtOAc/hexane, 1 : 10) 0.23, [α]2D2 −24.4 (c 8.03, CHCl3) {lit.[24] [α]2D6
−18.8 (c 1.17, CHCl3)}. vmax (film)/cm−1 2958, 2929, 2857, 2834,
1612, 1511, 1245, 1110, 1050. δH (500 MHz, CDCl3) 1.02 (3 H, d, J
6.7, 3-CH3), 1.54–1.64 (1 H, m, H4), 1.65–1.73 (1 H, m, H4), 2.61–2.72
(1 H, m, H3), 3.38–3.48 (2 H, m, H5), 3.81 (3 H, s, OCH3), 4.41 (1 H, d,
J 11.5, CH2Ar), 4.44 (1 H, d, J 11.5, CH2Ar), 6.19 (1 H, d, J 9.4, H2),
6.88 (2 H, d, J 8.7, Ar), 7.27 (2 H, d, J 8.7, Ar). δC (125 MHz, CDCl3)
19.3 (3-CH3), 35.6 (C4), 36.0 (C3), 55.3 (OCH3), 67.8 (CH2Ar), 72.8
(C5), 87.7 (C1), 113.8 (2 C, Ar), 129.3 (2 C, Ar), 130.5 (ipso-Ar), 143.8
(C2), 159.2 (ipso-Ar). Found: m/z 375.9677. M+ requires 375.9674.
(3R,4E)-5-Dimethylphenylsilyl-3-methylhex-4-en-1-ol 22
To a mixture of 21 (687.7 mg, 1.87 mmol) in CH2Cl2 (19 mL) and
H2O (1.9 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(900 mg, 3.96 mmol) at 0◦C. The mixture was stirred at 25◦C for 2 h
and quenched with saturated Na2CO3. The aqueous layer was extracted
with CH2Cl2. The combined organic layer was washed with H2O and
brine, dried over Na2SO4, filtered, and evaporated.The resulting residue
was purified by column chromatography (SiO2; EtOAc/hexane, 1 : 10)
to give 22 as a colourless oil (366.4 mg, 80%), RF (CH2Cl2) 0.42,
[α]D22 −34.8 (c 5.37, CHCl3). vmax (film)/cm−1 3390, 2956, 2925, 2869,
1427, 1247, 1108, 1051. δH (500 MHz, CDCl3) 0.32 (6 H, s, SiCH3),
0.98 (3 H, d, J 6.7, 3-CH3), 1.46–1.55 (1 H, m, H2), 1.58–1.66 (1 H, m,
H2), 1.68 (3 H, d, J 1.8, H6), 2.70–2.82 (1 H, m, H3), 3.54–3.67 (2 H,
m, H1), 5.60 (1 H, dq, J 1.8, 9.4, H4), 7.32–7.35 (3 H, m, Ph), 7.45–7.50
(2 H, m, Ph). δC (125 MHz, CDCl3) −3.4 (2 C, SiCH3), 14.9 (C6), 20.8
(3-CH3), 29.4 (C2), 40.1 (C3), 61.6 (C1), 127.7 (2 C, Ph), 128.8 (C4),
133.1 (C5), 133.9 (2 C, Ph), 138.6 (ipso-Ph), 147.1 (ipso-Ph). Found:
m/z 248.1596. M+ requires 248.1601.

Stereoselective Synthesis of a Side Chain of Scyphostatin
445
(3R,4E)-3-Methyl-5-dimethylphenylsilylhex-4-en-1-yl
2ꢀ,2ꢀ-Dimethylpropionate 23
(7-CH3), 21.3(3-CH3), 26.0(3C, SiC(CH3)3), 27.2(3C, COC(CH3)3),
28.1 (C7), 29.2 (C3), 33.1 (C9), 36.3 (C2), 38.7 (COC(CH3)3), 41.4
(C8), 47.6 (C6), 63.0 (C1), 68.4 (C10), 131.6 (C4), 133.5 (C5), 178.6
(CO2). Found: C 70.2, H 11.9, m/z 426.3529. C25H50O3Si requires C
70.4, H 11.8%, M+ 426.3536.
To a mixture of 22 (766.3 mg, 3.09 mmol) and pyridine (1.25 mL,
15.4 mmol) in CH2Cl2 (15 mL) was added pivaloyl chloride (0.57 mL,
4.63 mmol) at 0◦C. The mixture was stirred at 25◦C for 12 h, quenched
with saturated NH4Cl, and evaporated. The aqueous layer was extracted
with CH2Cl2. The combined organic layer was washed with H2O and
brine, dried over Na2SO4, filtered, and evaporated.The resulting residue
was purified by column chromatography (SiO2; EtOAc/hexane, 1 : 40)
to give 23 as a colourless oil (926.5 mg, 90%), RF (CH2Cl2) 0.71, [α]D22
−33.9 (c 23.2, CHCl3). vmax (film)/cm−1 2958, 2925, 1727, 1155. δH
(500 MHz, CDCl3) 0.33 (6 H, s, SiCH3), 1.00 (3 H, d, J 6.7, 3-CH3),
1.20 (9 H, s, COC(CH3)3), 1.51–1.59 (1 H, m, H2), 1.64–1.72 (1 H, m,
H2), 1.66 (3 H, d, J 1.8, H6), 2.70–2.82 (1 H, m, H3), 3.97 (1 H, ddd, J
6.4, 6.9, 11.0, H1), 4.08 (1 H, dt, J 5.5, 11.0, H1), 5.56 (1 H, dq, J 1.8,
9.4, H4), 7.31–7.40 (3 H, m, Ph), 7.46–7.53 (2 H, m, Ph). δC (125 MHz,
CDCl3) −3.4 (SiCH3), 1.0 (SiCH3), 14.8 (C6), 20.6 (3-CH3), 27.2 (3
C, COC(CH3)3), 29.2 (COC(CH3)3), 35.8 (C2), 38.7 (C3), 62.8 (C1),
127.7 (2 C, Ph), 128.8 (C5), 133.4 (C4), 133.9 (2 C, Ph), 138.6 (ipso-
Ph), 146.4 (ipso-Ph), 178.6 (CO2). Found: C 72.2, H 9.7, m/z 332.2183.
C20H32O2Si requires C 72.2, H 9.9%, M+ 332.2172.
For 12ꢀ, δH (500 MHz, CDCl3) 1.00 (6 H, d, J 6.7, 3-CH3, 8-CH3),
1.19 (18 H, s, COC(CH3)3), 1.50–1.59 (2 H, m, H2, H9), 1.64–1.72 (2
H, m, H2, H9), 1.76 (6 H, s, 5-CH3, 6-CH3), 2.57–2.68 (2 H, m, H3,
H8), 3.92–3.99 (2 H, m, H1, H10), 4.03–4.10 (2 H, m, H1, H10), 5.23
(2 H, d, J 9.4, H4, H7). Found: m/z 394.3083. M+ requires 394.3083.
(3R,4E,7S,9R)-10-(tert-Butyldimethylsilyloxy)-
3,7,9-trimethyldec-4-en-1-ol 25
To a suspension of LiAlH4 (35.1 mg, 0.91 mmol) in THF (4.5 mL) was
added 24 (191.7 mg, 0.45 mmol) in THF (1.0 mL) at 0◦C. The reac-
tion mixture was stirred at 25◦C for 6 h and quenched with H2O. The
formed precipitate was filtered off. The filtrate was washed with H2O
and brine, dried over Na2SO4, filtered, and evaporated. The resulting
residue was purified by column chromatography (SiO2; EtOAc/hexane,
1 : 10) to give 25 as a colourless oil (149.7 mg, 97%), RF (CH2Cl2) 0.23,
[α]D22 −19.3 (c 7.24, CHCl3). vmax (film)/cm−1 3365, 2954, 2927, 2857,
1471, 1461, 1251, 1093. δH (500 MHz, CDCl3) 0.04 (6 H, s, SiCH3),
0.79 (3 H, d, J 6.4, 7-CH3), 0.82–0.87 (1 H, m, H8), 0.88 (3 H, d, J 6.7,
9-CH3), 0.89 (9 H, s, SiC(CH3)3), 0.95 (3 H, d, J 6.7, 3-CH3), 1.23–
1.31 (1 H, m, H8), 1.40–1.50 (2 H, m, H2, OH), 1.56–1.74 (4 H, m, H2,
H6, H7, H9), 1.58 (3 H, d, J 1.2, 5-CH3), 2.00 (1 H, dd, J 3.8, 11.6, H6),
2.47–2.57 (1 H, m, H3), 3.31 (1 H, dd, J 6.7, 9.6, H10), 3.45 (1 H, dd,
J 5.2, 9.6, H10), 3.55–3.67 (2 H, m, H1), 4.90 (1 H, dd, J 1.2, 9.1, H4).
δC (125 MHz, CDCl3) −5.4 (2 C, SiCH3), 16.1 (5-CH3), 17.7 (9-CH3),
18.3 (SiC(CH3)3), 20.0 (7-CH3), 21.5 (3-CH3), 26.0 (3 C, SiC(CH3)3),
28.1 (C7), 29.4 (C3), 33.1 (C9), 40.5 (C2), 41.3 (C8), 47.7 (C6), 61.7
(C1), 68.3 (C10), 132.1 (C4), 133.3 (C5). Found: m/z 342.2958. M+
requires 342.2954.
(3R,4E)-5-Iodo-3-methylhex-4-en-1-yl 2ꢀ,2ꢀ-Dimethylpropionate 12
To a mixture of 23 (403.2 mg, 1.21 mmol) in THF (0.6 mL) and MeCN
(2.4 mL) was added NIS (686.0 mg, 3.05 mmol) at 25◦C. The mixture
was stirred at 25◦C for 2 days and quenched with saturated Na2S2O3.
The aqueous layer was extracted with Et2O. The combined organic layer
was washed with H2O and brine, dried over Na2SO4, filtered, and evap-
orated. The resulting residue was purified by column chromatography
(SiO2; EtOAc/hexane, 1 : 40) to give 12 as a colourless oil (378.1 mg,
96%), RF (EtOAc/hexane, 1 : 10 (twice)) 0.71, [α]2D2 −69.4 (c 18.7,
CHCl3). vmax (film)/cm−1 2360, 2331, 1635, 1165. δH (500 MHz,
CDCl3) 1.00 (3 H, d, J 6.7, 3-CH3), 1.20 (9 H, s, C(CH3)3), 1.50–
1.58 (1 H, m, H2), 1.61–1.70 (1 H, m, H2), 2.37 (3 H, d, J 1.2, H6),
2.51–2.60 (1 H, m, H3), 3.97 (1 H, ddd, J 5.8, 6.2, 11.1, H1), 4.09 (1
H, dt, J 5.7, 11.1, H1), 5.94 (1 H, dq, J 1.2, 10.1, H4). δC (125 MHz,
CDCl3) 20.4 (3-CH3), 27.2 (3 C, C(CH3)3), 27.6 (C(CH3)3), 32.5 (C6),
35.5 (C2), 38.7 (C3), 62.4 (C1), 93.4 (C5), 145.9 (C4), 178.4 (CO2).
Found: C 44.5, H 6.5, m/z 324.0586. C12H21IO2 requires C 44.5, H
6.5%, M+ 324.0573.
(3R,4E,7S,9R)-10-(tert-Butyldimethylsilyloxy)-
3,5,7,9-tetramethyldec-4-en-1-yl Methanesulfonate 26
To a solution of 25 (300.4 mg, 0.88 mmol) in THF (5.0 mL) were added
Et3N (0.37 mL, 2.63 mmol) and MsCl (0.1 mL, 1.32 mmol) in THF
(0.4 mL) at 0◦C. The reaction mixture was stirred at 25◦C for 3 h and
quenched with saturated NH4Cl. The aqueous layer was extracted with
Et2O and the combine organic layer was washed with H2O and brine,
dried over Na2SO4, and filtered. After concentration, purification by
column chromatography (SiO2; EtOAc/hexane, 1 : 30) gave 26 as a
colourless oil (360.4 mg, 98%), RF (CH2Cl2) 0.65. vmax (film)/cm−1
2956, 2927, 2856, 1643, 1471, 1461, 1359, 1294, 1176, 1091. δH
(500 MHz, CDCl3) 0.03 (6 H, s, SiCH3), 0.79 (3 H, d, J 6.4, 7-CH3),
0.82–0.93 (1 H, m, H8), 0.88 (3 H, d, J 6.7, 9-CH3), 0.89 (9 H, s,
SiC(CH3)3), 0.97 (3 H, d, J 6.7, 3-CH3), 1.23–1.31 (1 H, m, H8), 1.55–
1.74 (4 H, m, H2, H6, H7, H9), 1.57 (3 H, s, 5-CH3), 1.75–1.84 (1
H, m, H2), 2.03 (1 H, dd, J 4.3, 12.2, H6), 2.49–2.60 (1 H, m, H3),
2.97 (3 H, s, CH3SO2), 3.33 (1 H, dd, J 6.7, 9.3, H10), 3.45 (1 H,
dd, J 5.2, 9.3, H10), 4.10–4.17 (1 H, m, H1), 4.19–4.25 (1 H, m, H1),
4.83 (1 H, d, J 9.4, H4). δC (125 MHz, CDCl3) −5.4 (2 C, SiCH3), 16.1
(5-CH3), 17.6 (9-CH3), 18.3 (SiC(CH3)3), 19.8 (7-CH3), 21.3 (3-CH3),
25.9 (3 C, SiC(CH3)3), 28.1 (C7), 28.8 (C3), 33.1 (C9), 36.6 (C2), 37.3
(CH3SO2), 41.4 (C8), 47.6 (C6), 68.3 (C1), 68.9 (C10), 130.5 (C4),
134.6 (C5). Found: m/z 363.2038. M+ − But requires 363.2025.
(3R,4E,7S,9R)-10-(tert-Butyldimethylsilyloxy)-3,7,9-trimethyldec-
4-en-1-yl 2ꢀ,2ꢀ-Dimethylpropionate 24
To ZnCl2 (339.1 mg, 2.49 mmol), which was flame-dried under vacuum,
was added 10 (886.6 mg, 2.49 mmol) in Et2O (5.5 mL). The solution
was cooled to −78◦C and ButLi (1.47 M solution in pentane, 4.98 mL,
7.46 mmol) was added. After being stirred at −78◦C for 5 min, the
reaction mixture was warmed to 0◦C. After 1.5 h, Pd(PPh3)4 (8.81 mg,
5.67 × 10−2 mmol) was added to the reaction mixture at 0◦C. To the
reaction mixture was slowly added 12 (366.7 mg, 1.13 mmol) in THF
(5.5 mL) at 0◦C. The mixture was stirred at 0◦C for 2.5 h and quenched
with saturated NH4Cl. The aqueous layer was extracted with Et2O and
the combined organic layer was washed with H2O and brine, dried over
Na2SO4, filtered, and evaporated. The crude product was purified by
column chromatography (SiO2; EtOAc/hexane, 1 : 30) to give a mixture
of 24 and 12ꢀ (24: colourless oil, 411.9 mg, 85%; 12ꢀ: colourless oil,
32.7 mg, 7%).
For 24, RF (EtOAc/hexane, 1 : 10)0.54, [α]2D2 −22.9(c 7.20, CHCl3).
vmax (film)/cm−1 2956, 2927, 2857, 1731, 1481, 1471, 1165, 1100. δH
(500 MHz, CDCl3) 0.04 (6 H, s, SiCH3), 0.79 (3 H, d, J 6.4, 7-CH3),
0.82–0.92 (1 H, m, H8), 0.88 (3 H, d, J 6.4, 9-CH3), 0.89 (9 H, s,
SiC(CH3)3), 0.96 (3 H, d, J 7.0, 3-CH3), 1.19 (9 H, s, C(CH3)3), 1.22–
1.34 (1 H, m, H8), 1.43–1.52 (1 H, m, H2), 1.55 (3 H, s, 5-CH3),
1.57–1.74 (4 H, m, H2, H6, H7, H9), 2.01 (1 H, dd, J 4.0, 12.8, H6),
2.45–2.56 (1 H, m, H3), 3.32 (1 H, dd, J 6.7, 9.8, H10), 3.45 (1 H,
dd, J 5.5, 9.8, H10), 3.96 (1 H, dt, J 9.4, 10.8, H3), 4.07 (1 H, dt,
J 7.6, 10.8, H1), 4.86 (1 H, d, J 9.4, H4). δC (125 MHz, CDCl3) − 5.4
(2 C, SiCH3), 16.1 (5-CH3), 17.7 (9-CH3), 18.3 (SiC(CH3)3), 19.9
(3R,4E,7S,9R)-10-(tert-Butyldimethylsilyloxy)-
3,5,7,9-tetramethyldec-4-ene 27
To a suspension of LiAlH4 (45.5 mg, 1.21 mmol) in THF (3.0 mL) was
added 26 (249.7 mg, 0.59 mmol) in THF (2.0 mL) at 0◦C. The mixture
was stirred at 25◦C for 6 h and quenched. The formed precipitate was
filtered off and the filtrate was washed with H2O and brine, dried over
Na2SO4, filtered, and evaporated. The resulting residue was purified
by column chromatography (SiO2; EtOAc/hexane, 1 : 30) to give 27
as a colourless oil (191.4 mg, 99%), RF (EtOAc/hexane, 1 : 10) 0.77,
[α]D22 −7.14 (c 3.78, CHCl3). vmax (film)/cm−1 2958, 2927, 2856, 2360,

446
R. Takagi et al.
2331, 1635, 1463, 1259, 1049. δH (500 MHz, CDCl3) 0.03 (6 H, s,
SiCH3), 0.80 (3 H, d, J 6.1, 7-CH3), 0.83 (3 H, t, J 7.3, H1), 0.88 (3
H, d, J 7.0, 9-CH3), 0.91 (9 H, s, SiC(CH3)3), 0.94 (3 H, d, J 7.0,
3-CH3), 0.86–0.92 (1 H, m, H2), 1.15–1.24 (1 H, m, H8), 1.25–1.36
(2 H, m, H2), 1.56 (3 H, d, J 1.2, 5-CH3), 1.61–1.75 (3 H, m, H6, H7,
H9), 1.94–2.05 (1 H, m, H6), 2.19–2.29 (1 H, m, H3), 3.31 (1 H, dd, J
7.0, 9.6, H10), 3.46 (1 H, dd, J 4.9, 9.6, H10), 4.85 (1 H, d, J 9.4, H4).
δC (125 MHz, CDCl3) −5.4 (2 C, SiCH3), 12.0 (C1), 16.2 (5-CH3),
17.8 (9-CH3), 18.4 (SiC(CH3)3), 20.1 (7-CH3), 21.1 (3-CH3), 26.0 (3
C, SiC(CH3)3), 28.2 (C7), 30.5 (C3), 33.2 (C9), 34.1 (C2), 41.2 (C8),
47.9 (C6), 68.3 (C10), 132.4 (C5), 132.9 (C4). Found: C 73.6, H 12.9,
m/z 326.3004. C20H42O2Si requires C 73.5, H 12.4%, M+ 326.3005.
CHCl3) {lit.[4h] [α]D25 −2.35 (c 0.34, CHCl3)}. vmax (film)/cm−1 2958,
2923, 2871, 2358, 2343, 1714, 1617, 1455, 1369, 1270, 1250, 1120,
1005. δH (500 MHz, CD3OD) 0.83 (3 H, d, J 6.4, 10-CH3), 0.86 (3 H, t,
J 7.5, H16), 0.91 (3 H, d, J 6.6, 14-CH3), 0.97–1.07 (1 H, m, H9), 1.01
(3 H, d, J 6.6, 8-CH3), 1.14–1.24 (1 H, m, H15), 1.28 (3 H, t, J 7.1,
OCH2CH3), 1.30–1.35 (1 H, m, H15), 1.35–1.40 (1 H, m, H9), 1.54 (3
H, d, J 1.2, 12-CH3), 1.56–1.63 (1 H, m, H10), 1.80 (1 H, dd, J 7.2,
13.0, H11), 1.90 (1 H, dd, J 7.2, 13.0, H11), 2.20–2.31 (1 H, m, H14),
2.32–2.42 (1 H, m, H8), 4.18 (2 H, q, J 7.1, OCH2CH3), 4.84 (1 H,
dq, J 1.2, 9.6, H13), 5.76 (1 H, dd, J 8.7, 15.1, H7), 5.87 (1 H, d, J
15.3, H2), 6.17 (1 H, dd, J 10.7, 15.1, H6), 6.30 (1 H, dd, J 11.2, 14.7,
H4), 6.60 (1 H, ddd, J 0.5, 10.7, 14.7, H5), 7.30 (1 H, ddd, J 0.5, 11.2,
15.3, H3). δC (125 MHz, CD3OD) 13.0 (C16), 15.0 (OCH2CH3), 16.8
(C18), 20.3 (C19), 22.0 (C17), 22.3 (C20), 29.9 (C10), 32.1 (C15), 35.8
(C14), 36.7 (C8), 45.6 (C9), 50.0 (C11), 61.8 (OCH2CH3), 121.2 (C2),
129.6 (C4), 130.3 (C6), 133.9 (C12), 134.6 (C13), 143.3 (C5), 146.9
(C3), 147.7 (C7), 169.4 (CO2). Found: C 79.2, H 11.2, m/z 332.2707.
C22H36O2 requires C 79.5, H 10.9%, M+ 332.2715.
(2R,4S,6E,8R)-2,4,6,8-Tetramethyldec-6-en-1-ol 28
To a solution of 27 (123.3 mg, 0.38 mmol) in THF (3.8 mL) was added
TBAF (1.0 M solution in THF, 0.76 mL, 0.76 mmol) at 25◦C. The reac-
tion mixture was stirred at 25◦C for 6 h and quenched with saturated
NH4Cl. The aqueous layer was extracted with Et2O and the combined
organic layer was washed with H2O and brine, dried over Na2SO4, fil-
tered, and evaporated. The resulting residue was purified by column
chromatography (SiO2; EtOAc/hexane, 1 : 20) to give 28 as a colourless
oil (79.4 mg, 99%), RF (CH2Cl2) 0.32, [α]2D2 −17.0 (c 1.20, CHCl3)
{lit.[4h] [α]2D5 −14.4 (c 1.10, CHCl3)}. vmax (film)/cm−1 3629, 2958,
2915, 2871, 2360, 2331, 1457, 1376, 1039. δH (500 MHz, CDCl3) 0.82
(3 H, d, J 6.1, 4-CH3), 0.83 (3 H, t, J 7.3, H10), 0.89 (3 H, d, J 10.4,
2-CH3), 0.92–0.97 (1 H, m, H3), 0.93 (3 H, d, J 6.7, 8-CH3), 1.14–1.24
(1 H, m, H3), 1.27–1.36 (2 H, m, H9), 1.37–1.50 (1 H, m, OH), 1.56
(3 H, d, J 1.2, H5), 1.62–1.70 (2 H, m, H2, H5), 1.71–1.79 (1 H, m, H4),
1.99 (1 H, dd, J 9.1, 16.5 Hz, H5), 2.19–2.22 (1 H, m, H8), 3.36 (1 H, dd,
J 6.9, 10.8 Hz, H1), 3.53 (1 H, dd, J 5.0, 10.8, H1), 4.86 (1 H, dd, J 9.1,
H7). δC (125 MHz, CDCl3) 11.6 (C10), 15.8 (6-CH3), 17.1 (2-CH3),
19.8 (4-CH3), 20.6 (8-CH3), 27.8 (C4), 30.1 (C8), 32.8 (C2), 33.7 (C9),
40.5 (C3), 47.3 (C5), 67.9 (C1), 131.8 (C6), 132.7 (C7). Found: m/z
212.2141. M+ requires 212.2140.
For (2Z,4E,6E)-30, RF (EtOAc/hexane, 1 : 10) 0.42, [α]2D2 − 0.42
(c 0.21, CHCl3). δH (500 MHz, CDCl3) 0.80 (3 H, d, J 6.4, 10-CH3),
0.84 (3 H, t, J 7.6, H16), 0.90 (3 H, d, J 6.4, 14-CH3), 0.99–1.05 (1 H,
m, H9), 1.00 (3 H, d, J 6.7, 8-CH3), 1.07–1.12 (1 H, m, H9), 1.16–1.23
(2 H, m, H9, H15), 1.30 (3 H, t, J 7.3, OCH2CH3), 1.52 (3 H, d, J 0.9,
12-CH3), 1.57–1.59 (1 H, m, H10), 1.73–1.79 (1 H, m, H11), 1.86–1.91
(1 H, m, H11), 2.20–2.28 (1 H, m, H11), 2.31–2.38 (1 H, m, H8), 4.19
(2 H, q, J 7.3, OCH2CH3), 4.84 (1 H, d, J 9.1, H13), 5.60 (1 H, d, J
11.4, H2), 5.71 (1 H, dd, J 8.8, 14.9, H7), 6.19 (1 H, dd, J 10.7, 14.9,
H6), 6.45 (1 H, dd, J 10.7, 15.1, H5), 6.58 (1 H, t, J 11.4, H3), 7.42 (1
H, dd, J 11.4, 15.1, H4). Found: m/z 332.2724. M+ requires 332.2715.
For (2E,4Z,6E)-30, RF (EtOAc/hexane, 1 : 10) 0.42, [α]2D2 + 21.5 (c
0.15, CHCl3). δH (500 MHz, CDCl3) 0.82 (3 H, d, J 6.4, 10-CH3), 0.83
(3 H, t, J 6.4, H16), 0.90 (3 H, d, J 6.7, 14-CH3), 0.95–1.00 (1 H, m,
H9), 1.00–1.07 (1 H, m, H15), 1.01 (3 H, d, J 6.7, 8-CH3), 1.15–1.37
(2 H, m, H9, H15), 1.30 (3 H, t, J 7.2, OCH2CH3), 1.52 (3 H, d, J 1.2,
12-CH3), 1.56–1.58 (1 H, m, H10), 1.77 (1 H, dd, J 7.3, 13.4, H11),
1.89 (1 H, dd, J 7.0, 13.4, H11), 2.19–2.28 (1 H, m, H14), 2.34–2.42 (1
H, m, H8), 4.22 (2 H, q, J 7.2, OCH2CH3), 4.84 (1 H, d, J 9.1, H13),
5.70 (1 H, dd, J 8.3, 14.9, H7), 5.85 (1 H, d, J 15.0, H2), 5.99 (1 H, t,
J 11.4, H4), 6.28 (1 H, t, J 14.4, H5), 6.56 (1 H, dd, J 11.4, 14.9, H6),
7.74 (1 H, dd, J 11.4, 15.0, H3). Found: m/z 332.2711. M+ requires
332.2715.
Ethyl (2E,4E,6E,8R,10S,12E,14R)-8,10,12,14-Tetramethylhexadeca-
2,4,6,12-tetraenoate 30
DMSO (0.21 mL, 3.0 mmol) in CH2Cl2 (4.0 mL) was slowly added to
a solution of (COCl)2 (0.20 mL, 2.25 mmol) in CH2Cl2 (0.5 mL) at
−78◦C. After stirring the mixture for 30 min, 28 (158.9 mg, 0.75 mmol)
in CH2Cl2 (4.0 mL) was added at −78◦C. To the solution was added
Et3N (1.56 mL, 11.2 mmol) at −78◦C. After being stirred at −78◦C for
1 h, the reaction mixture was warmed to 25◦C and stirred for 30 min.
The reaction mixture was quenched with saturated NH4Cl and the aque-
ous layer was extracted with CH2Cl2. The combined organic layer was
washed with H2O and brine, dried over Na2SO4, and filtered.After evap-
oration, crude product 29 was obtained. The crude product was used for
the next reaction without further purification, RF (EtOAc/hexane, 1 : 10)
0.50. δH (500 MHz, CDCl3) 0.76 (3 H, t, J 7.5, H10), 0.77 (3 H, d, J 6.7,
4-CH3), 0.83 (3 H, d, J 6.7, 8-CH3), 0.98–1.06 (1 H, m, H3), 1.01 (3 H,
d, J 7.0, 2-CH3), 1.08–1.17 (1 H, m, H3), 1.48 (3 H, d, J 0.9, 6-CH3),
1.54–1.62 (1 H, m, H4), 1.21–1.30 (2 H, m, H9), 1.63–1.72 (1 H, m,
H5), 1.89 (1 H, dd, J 6.4, 13.1, H5), 2.11–2.22 (1 H, m, H2), 2.34–2.44
(1 H, m, H8), 4.80 (1 H, d, J 9.1, H7), 9.48 (1 H, d, J 2.7, CHO).
To an LDA solution [diisopropylamine (0.19 mL, 1.35 mmol), BunLi
(1.57 M in THF, 0.55 mL, 0.86 mmol), THF (2.0 mL), 0◦C, 30 min]
was added phosphonate 5 (413.3 mg, 1.50 mmol) in THF (3.0 mL) at
−78◦C. After the mixture was stirred for 30 min, the crude aldehyde
29 in THF (3.0 mL) was added at −78◦C. The solution was stirred at
−78◦C for 2 h and quenched with H2O.The aqueous layer was extracted
with Et2O and the combined organic layer was washed with H2O
and brine, dried over Na2SO4, filtered, and evaporated. The resulting
residue was purified by column chromatography (SiO2; EtOAc/hexane,
1 : 30) to give a mixture of (2E,4E,6E)-, (2Z,4E,6E)-, (2E,4Z,6E)-,
and (2E,4E,6Z)-30 (212.7 mg, 85%). The four geometric isomers
were separated by HPLC (Wako Sil-II; hexane/PriOH, 4000 : 1). For
(2E,4E,6E)-30, RF (EtOAc/hexane, 1 : 10) 0.42, [α]2D2 −1.57 (c 0.19,
For (2E,4E,6Z)-30, RF (EtOAc/hexane, 1 : 10) 0.42, [α]22 +59.8 (c
0.24, CHCl3). δH (500 MHz, CDCl3) 0.79 (3 H, d, J 6.7, 10-DCH3), 0.84
(3 H, t, J 7.4, H16), 0.89 (3 H, d, J 6.7, 14-CH3), 0.97 (3 H, d, J 6.7,
8-CH3), 0.99–1.03 (1 H, m, H9), 1.03–1.08 (1 H, m, H15), 1.14–1.36
(2 H, m, H9, H15), 1.30 (3 H, t, J 7.1, OCH2CH3), 1.46–1.51 (1 H, m,
H10), 1.51 (3 H, d, J 1.2, 12-CH3), 1.78 (1 H, dd, J 7.2, 13.0, H11),
1.87 (1 H, dd, J 7.2, 13.0, H11), 2.18–2.28 (1 H, m, H14), 2.73–2.83
(1 H, m, H8), 4.21 (2 H, q, J 7.1, OCH2CH3), 4.84 (1 H, d, J 8.8, H13),
5.37 (1 H, t, J 11.0, H7), 5.86 (1 H, d, J 15.5, H2), 6.05 (1 H, t, J 11.0,
H6), 6.29 (1 H, dd, J 11.3, 14.5, H4), 6.84 (1 H, dd, J 11.0, 14.5, H5),
7.34 (1 H, dd, J 11.3, 15.5, H3). Found: m/z 332.2706. M+ requires
332.2715.
(2E,4E,6E,8R,10S,12E,14R)-8,10,12,14-Tetramethylhexadeca-
2,4,6,12-tetraenoic acid 2
To a solution of (2E,4E,6E)-30 (25.8 mg, 8.0 × 10−2 mmol) in MeOH
(8.0 mL) was added 5.0 M LiOH (0.54 mL, 3.20 mmol) at 25◦C, and
the reaction mixture was stirred at 25◦C. After 2 days, MeOH was
removed under vacuum. The residue was extracted with EtOAc and
the combined organic layer was washed with brine, dried over Na2SO4,
filtered, and evaporated. Purification by column chromatography (SiO2;
CHCl3/MeOH, 15 : 1) gave (2E,4E,6E)-2 as a colourless oil (23.4 mg,
100%), RF (EtOAc/hexane, 2 : 1) 0.58, [α]2D2 −3.53 (c 0.41, CHCl3).
vmax (film)/cm−1 3446, 2958, 2915, 2869, 2360, 2329, 1683, 1614,
1265, 1100. δH (500 MHz, CDCl3) 0.80 (3 H, d, J 6.4, 10-CH3), 0.84
(3 H, t, J 7.5, H16), 0.90 (3 H, d, J 6.7, 14-CH3), 0.97–1.06 (1 H, m,
H9), 1.00 (3 H, d, J 6.7, 8-CH3), 1.13–1.24 (1 H, m, H15), 1.24–1.38 (2
H, m, H9, H15), 1.53 (3 H, s, 12-CH3), 1.53–1.59 (1 H, m, H10), 1.76

Stereoselective Synthesis of a Side Chain of Scyphostatin
447
(1 H, dd, J 7.5, 13.4, H11), 1.89 (1 H, dd, J 6.9, 13.4, H11), 2.18–2.29
(1 H, m, H14), 2.30–2.42 (1 H, m, H8), 4.84 (1 H, d, J 9.4, H13), 5.76
(1 H, dd, J 8.5, 14.9, H7), 5.84 (1 H, d, J 14.5, H2), 6.12 (1 H, dd,
J 10.7, 14.9, H6), 6.24 (1 H, dd, J 11.4, 14.3, H4), 6.56 (1 H, dd, J
10.7, 14.3, H5), 7.39 (1 H, dd, J 11.4, 14.5, H3), 11.2–12.5 (1 H, br
s, CO2H). δC (125 MHz, CDCl3) 12.0 (C16), 16.2 (C18), 19.5 (C19),
21.0 (C17), 21.3 (C20), 28.3 (C10), 30.5 (C15), 34.1 (C14), 35.0 (C8),
43.9 (C9), 48.3 (C11), 119.1 (C2), 127.6 (C4), 128.2 (C6), 132.0 (C12),
133.1 (C13), 142.5 (C5), 147.1 (C3), 147.2 (C7), 172.9 (CO2). Found:
C 79.0, H 10.6, m/z 304.2397. C20H32O2 requires C 78.9, H 10.6%,
M+ 304.2402.
(h) T. R. Hoye, M. A. Tennakoon, Org. Lett. 2000, 2, 1481.
doi:10.1021/OL0058386
[5] M. Inoue, W. Yokota, M. G. Murugeshm, T. Izuhara, T. Katoh,
45th Symposium on the Chemistry of Natural Products, Oct.
6–8, 2003, pp. 49–54, Kyoto.
[6] S. Saito, N. Tanaka, K. Fujimoto, H. Kogen, Org. Lett. 2000,
2, 505. doi:10.1021/OL991351P
[7] Preliminary presentation of our initial route: H. Nishitani,
S. Takenami, R. Takagi, K. Ohkata, Chemical Society of Japan
Annual Meeting, Mar. 28–31, 2000, 3PB027, Chiba.
[8] (a) G. M. R. Tombo, H.-P. Schär, X. F. Busquets, O. Ghisalba,
Tetrahedron Lett. 1986, 27, 5707. doi:10.1016/S0040-4039(00)
85306-X
(b) J. C. Anderson, S. V. Ley, S. P. Marsden, Tetrahedron Lett.
1994, 35, 2087. doi:10.1016/S0040-4039(00)73057-7
[9] The enantioselectivity in the PPL-catalyzed asymmetric acety-
lation was determined by converting the alcohol 7 into its
benzoate, followed by analysis with a DAICEL CHIRALCEL-
OD column (hexane/AcOEt, 400 : 1). (The racemate of 18 was
used as a control.)
[10] The geometric isomers were separated with preparative TLC.
The geometries of the isomers were determined by dif-NOE.
When the H13ꢀ vinyl proton of the Z-isomer was irradiated,
the intensity of the H11ꢀ methylene proton signal was enhanced
by 9.1%.
[11] The diasteromer mixture of Z-11 was converted into a dias-
teromeric mixture of the ethyl ester 31 via six steps (34%:
hydride reduction of the ester, mesylation of the alcohol, hydride
reduction of the mesylate, cleavage of the TBS ether, oxidation,
and HWE using 5).
Acknowledgments
NMR, MS, optical rotation, and elemental analyses mea-
surements were made using instruments at the Natu-
ral Science Centre for Basic Research and Development
(N-BARD), Hiroshima University. We thank Dr Yoshikazu
Hiraga for measurements of NMR (JEOL JMN-LA500) at
the Hiroshima Prefectural Institute of Science and Technol-
ogy. We thank Dr Satoshi Kojima for reading the manuscript
and making several helpful suggestions. Financial support of
this work through Grants-in-Aid for Scientific Research (nos
11740355 and 14740349) provided by the Japan Society for
the Promotion of Science are heartily acknowledged.
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