Total synthesis of (+)-dienomycin C

Article abstract of DOI:10.1016/j.tet.2010.08.048

Total synthesis of (+)-dienomycin C was achieved via Sharpless asymmetric epoxidation, Pd-catalyzed hydrogenolysis with formic salt, and Pd(II)-catalyzed cyclization of urethane.

Full text of DOI:10.1016/j.tet.2010.08.048

Tetrahedron 66 (2010) 8458e8463
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of (þ)-dienomycin C
Hajime Yokoyama, Yuko Hayashi, Yumi Nagasawa, Hiromi Ejiri, Masahiro Miyazawa, Yoshiro Hirai
*
Graduate School of Science and Engineering, University of Toyama, Gofuku 3190, Toyama 930-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 April 2010
Received in revised form 17 August 2010
Accepted 17 August 2010
Total synthesis of (þ)-dienomycin C was achieved via Sharpless asymmetric epoxidation, Pd-catalyzed
hydrogenolysis with formic salt, and Pd(II)-catalyzed cyclization of urethane.
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 18 September 2010
Keywords:
Alkaloid
Synthesis
Dienomycin C
Pd(II)-catalyzed cyclization of urethane
1. Introduction
cyclization to asymmetric synthesis of (þ)-dienomycin C. The key
synthetic problem for (þ)-dienomycin C is the construction of three
The piperidine alkaloids (ex (1), (2)), many of which have been
isolated from the plant kingdom, have great potential as a source of
new drugs. Dienomycin C 1 was isolated from the culture filtrate of
the Streptomyces strain MC67-C1 by Umezawa in 1970.1 This com-
pound (Fig. 1) has a characteristic antibacterial activity against
some strains of Mycobacterium tuberculosis. Racemic dienomycin C
was synthesized by Troin’s group in 1996.2 In 1999, Comins’s group
reported the first total synthesis of (þ)-dienomycin C3 and in the
same year, Troin’s group independently achieved a total synthesis
of (þ)-dienomycin C.4
consecutive chiral centers on the piperidine ring. We planned to
achieve this by using the combination of Sharpless asymmetric
epoxidation,6 Pd-catalyzed hydrogenolysis with formic salt7 and Pd
(II)-catalyzed cyclization of the urethane.5
Our starting material was 1,3-propanediol 3 (Scheme 1). Its
hydroxy group was protected by TBS group in 81% yield. The
protected alcohol was oxidized by Swern oxidation to afford the
aldehyde and followed by Z-selective WittigeHorner reaction to
give the ester in 86% yield (two steps). The ester was treated with
DIBAL in THF to give allyl alcohol 4 in 51% yield. Sharpless asym-
metric epoxidation6 of the allyl alcohol 4 with (
D
)-(ꢀ)-DET,
OH
OH
1) TBSCl, NaH, THF, 81%.
HO
OH
2) (COCl)2, DMSO, Et3N, CH2Cl2.
HO
OH
TBSO
3) (PhO)2P(O)CHMeCO2Et,
NaH, THF, -78oC, 2 steps 86%.
4) DIBAL, THF, -78oC, 51%.
4
OH
3
N
H
Ph
N
H
OH
DMJ(2)
(+)-dienomycin C (1)
1) (COCl)2, DMSO,
Et3N, CH2Cl2.
O
(D)-(-)-DET, Ti(OiPr)4,
tBuOOH, CH2Cl2, 90%,
78%ee.
TBSO
Fig. 1. The piperidine alkaloids.
2) (EtO)2P(O)CH2CO2Et, NaH,
THF, -78oC, 2 steps 92%.
5
2. Results and discussion
OH
OH
O
For many years, we have been studying the Pd(II)-catalyzed
cyclization of urethane and its application to the total synthesis of
natural products.5 Here, we report the application of this
TBSO
n
TBSO
Pd2(dba)3CHCl3, P Bu3, Et3N,
HCOOH, dioxane, 90%.
7
6
CO2Et
Scheme 1. Preparation of the alcohol 7.
CO2Et
* Corresponding author. E-mail address: hirai@sci.u-toyama.ac.jp (Y. Hirai).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.048

H. Yokoyama et al. / Tetrahedron 66 (2010) 8458e8463
8459
tBuOOH, and Ti(OiPr)4 in CH2Cl2 provided the epoxide 5 in 90%
yield and 78%ee.8 Oxidation of the epoxide 5 by means of Swern
oxidation followed by WittigeHorner reaction gave the a,b-un-
saturated ester 6 in 92% yield. This ester 6 was treated with
Pd2(dba)3CHCl3, nBu3P, HCO2H, and Et3N in dioxane to give the
alcohol 7 as a single isomer in 90% yield.7
disadvantageous, because of non-bonding interaction between the
carbamate moiety and -allyl-oxy palladium complex. anti-Attack
of nitrogen nucleophile to complex IA occurs from the opposite
side of the complex IA to give the -Pd complex II. Consequently,
p
s
syn-elimination of PdCl(OH) afforded the cyclized product 10.
Further mechanism’s studies were in progress.11
After protection of the alcohol 7 with MOMCl, reduction of the
ester group with DIBAL followed by protection of the resulting allyl
alcohol with DHP and deprotection of TBS group via TBAF treat-
ment provided the alcohol 8 in 79% yield (Scheme 2). Mesylation of
the hydroxyl moiety followed by continuous addition of NaN3 gave
the azide in 75% yield. Reduction of the azide moiety with LiAlH4
and protection of the resulting amine with (Boc)2O provided the
Boc-protected amine in 96% yield. Deprotection of the THP group
gave the allyl alcohol 9 in 98% yield. Next the allyl alcohol 9 was
treated with PdCl2(MeCN)2 in THF at rt to give the cyclized product
10 as a single isomer in 82% yield. Ozonolysis, followed by Wittig
reaction with (EtO)2P(O)CH2CH]CHPh provided the diene 11 in
78% yield(two steps).
OMOM
H
Cl
9
10
O
Pd
N
II
Boc
H
H
Pd
O
O
Pd
NH
Me
Boc
MOMO
NH
Me
MOMO
>
Boc
IB
IA
Fig. 2. The plausible reaction mechanism of the Pd(II)-catalyzed cyclization.
HO
MOMO
1) MOMCl, iPr2EtN, CH2Cl2, 89%.
2) DIBAL, THF, -78oC, 99%.
3) DHP, p-TsOH, CH2Cl2, 98%.
3. Conclusion
8
OTHP
TBSO
CO2Et
HO
7
4)TBAF, THF, 92%.
OMOM
OMOM
In conclusion, we have accomplished a total synthesis of natural
(þ)-dienomycin C. This reconfirms the reported stereochemistry
(2R,3R,4S) of (þ)-dienomycin C.
1) MsCl, Et3N, CH2Cl2.
PdCl2(MeCN)2,
THF, rt,82%.
2) NaN3, NH4Cl, DMF, 2 steps 75%.
3) LiAlH4, THF.
N
NH
4) (Boc)2O, Et3N, CH2Cl2, 2 steps 96%.
Boc
9
Boc
10
OMOM
5) p-TsOH, MeOH, 98%.
OH
4. Experimental
4.1. General
concd HCl,
MeOH, 58%.
1) O3, then Me2S, CH2Cl2-MeOH.
(+)-dienomycin C ((+)-1)
2) (EtO)2P(O)CH2CH=CHPh,
nBuLi, THF, -78oC, 2 steps 78%.
N
Ph
1H NMR spectra were measured with JEOL Model ECX-300/
TRH(300 MHz), JEOL Model JNM-ECP600(600 MHz) spectropho-
tometer. Chemical shifts were relative to tetramethylsilane or
chloroform (7.26 ppm) as an internal standard. Splitting patterns
are designated as s (singlet), d (doublet), t (triplet), q (quartet),
quint (quintet), m (multiplet) and br (broadened). Coupling
constants were given in hertz. 13C NMR spectra were measured
with JEOL Model ECX-300/TRH(75 MHz), JEOL Model JNM-
ECP600(150 MHz) spectrophotometer. Chemical shifts were rel-
ative to tetramethylsilane or chloroform (77.0 ppm) as an internal
standard. Infrared spectra (IR) were recorded on JASCO Model
FT/IR-7300 or FT/IR-6100 spectrophotometer. List of infrared
absorptions were diagnostic. High-resolution mass spectra were
measured with JEOL Model JMS-700 mass spectrometer. Optical
Boc
11
Scheme 2. Last stage of synthesis of (þ)-dienomycin C (þ)-1.
Finally, deprotection with concd HCl gave (þ)-dienomycin C
(þ)-1 in 58% yield. All spectra data were in agreement with liter-
ature values.4 Based on these mechanisms, we could determine the
absolute configuration of (þ)-dienomycin C (þ)-1 as (2R,3R,4S).
Moreover we synthesized (ꢀ)-(2S,3S,4R)-dienomycin C (ꢀ)-1 by
using similar strategy (Scheme 3)9 and reconfirmed the reported
stereochemistry (2R,3R,4S) of (þ)-dienomycin C.
HO
OH
TBSO
4
3
OH
rotations ([
a]D) were determined with JASCO Model P-1020
O
(L)-(+)-DET, Ti(OiPr)4,
tBuOOH, CH2Cl2, 83%,
70%ee.
polarimeter.
TBSO
12
4.2. 1-(tert-Butyldimethylsilyloxy)-propan-3-ol
OH
OMOM
OMOM
To a solution of 1,3-propanediol (5.00 g, 65.7 mmol) in THF
(66 mL) was added NaH (3.01 g, 69.0 mmol, 55% in dispersion oil) at
0
PdCl2(MeCN)2,
THF, rt, 75%.
(-)-dienomycin C ((-)-1)
ꢁC under an argon atmosphere and the reaction mixture was
NH
stirred for 1 h. The reaction mixture was cooled at 0 ꢁC, then TBSCl
(10.4 g, 69.0 mmol) added at same temperature. The resulting
mixture was stirred at room temperature for 1 h. The reaction
mixture was quenched with ice and the resulting mixture was
extracted with ethyl acetate (20 mLꢂ3). The combined organic
layers were washed with water (20 mLꢂ3) and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (eluent; Hex/AcOEt¼19:1) to
afford 1-(tert-butyldimethylsilyloxy)-propan-3-ol (10.1 g, 81%) as
N
Boc
13
Boc
14
OH
Scheme 3. Synthesis of (ꢀ)-dienomycin C (ꢀ)-1.
The plausible reaction mechanism of the Pd(II)-catalyzed
cyclization10 is shown in Fig. 2. If the stereochemical outcome of
this reaction could be explained in terms of six-membered tran-
sition state, the palladium complex IA and IB seem to be in equi-
librium. The stereoselective formation of 10 could be explained by
assuming the transition state IA. The transition state IB would be
colorless oil. 1H NMR (300 MHz, CDCl3)
(t, J¼5.5 Hz, 2H),1.78 (tt, J¼5.5, 5.5 Hz, 2H), 0.90 (s, 9H), 0.08 (s, 6H);
d: 3.84 (t, J¼5.5 Hz, 2H), 3.80

8460
H. Yokoyama et al. / Tetrahedron 66 (2010) 8458e8463
13C NMR (75 MHz, CDCl3)
d
: 62.9, 62.5, 34.1, 25.8, 18.2, ꢀ5.5; IR
(2.94 g, 14.3 mmol) and a solution of 5-(tert-butyldimethylsily-
loxy)-2-methyl-2-penten-1-ol 4 (2.99 g, 13.0 mmol) in CH2Cl2
(10 mL). The resultant mixture was stirred for 15 min and to
a solution of 5.33 M solution of tBuOOH in toluene (5.35 mL,
28.5 mmol) was added dropwise at same temperature. The re-
action flask was then placed into a ꢀ20 ꢁC freezer and allowed to
remain at that temperature for 5 days. To the reaction mixture was
added 10% aqueous tartaric acid at ꢀ20 ꢁC with stirring for 30 min
at 0 ꢁC. The reaction mixture was filtered through a pad of Celite.
The aqueous layers were extracted with CH2Cl2 (10 mLꢂ3). The
combined organic layers were washed with saturated aqueous
Na2S2O3, concentrated in vacuo. To a solution of the crude epoxy
alcohol in diethyl ether (15 mL) was added 1 N aqueous NaOH
(15 mL) and the resulting mixture was stirred for 30 min at 0 ꢁC.
The aqueous layer was extracted with diethyl ether (5 mLꢂ3). The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (eluent; Hex/AcOEt¼97:3) to
afford (2R,3S)-5-(tert-butyldimethylsilyloxy)-2,3-epoxy-2-meth-
ylpenten-1-ol (2.88 g, 90%) as colorless oil. 1H NMR (300 MHz,
(neat): 3600e3050, 2930, 2858, 1472, 1256, 1098; HRMS m/z (EI)
t
calcd for C5H13O2Si (Mþꢀ Bu) 133.0685, found 133.0685.
4.3. Ethyl 5-(tert-Butyldimethylsilyloxy)-2-methyl-2-
pentenoate
To a stirred ꢀ78 ꢁC solution of dimethylsulfoxide (3.18 mL,
47.3 mmol) in CH2Cl2 (70 mL) under N2 atmosphere was added
oxalyl chloride (2.07 mL, 23.7 mmol). The resultant mixture was
stirred for 15 min and to a solution of 1-(tert-butyldimethylsilyl-
oxy)-propan-3-ol (3.00 g, 15.8 mmol) in CH2Cl2 (10 mL) was added
dropwise. After stirring for 20 min at ꢀ78 ꢁC, triethylamine
(9.92 mL, 71.1 mmol) was added at ꢀ78 ꢁC, and the resulting
mixture was allowed to warm into room temperature. After 30 min,
the reaction mixture was quenched with 10% aqueous HCl and the
resulting mixture was extracted with CH2Cl2 (20 mLꢂ3). The
combined organic layers were washed with saturated aqueous
NaHCO3 and brine, dried over MgSO4. Concentration afforded the
crude aldehyde, which was used in the next step without further
purification. To a suspension of NaH (0.825 g, 18.9 mmol, 55% in
dispersion oil) in THF (85 mL) was added ethyl 2-diphenylphos-
phonopropionate (6.85 g, 20.5 mmol) at 0 ꢁC under N2 atmosphere
and the mixture was stirred at the same temperature for 30 min. A
solution of the crude aldehyde in THF (10 mL) was added to the
Wittig mixture at ꢀ78 ꢁC. After stirring for 15 min at ꢀ78 ꢁC, the
reaction mixture was stirred at 0 ꢁC for 1 h. The reaction mixture
was quenched with saturated aqueous NH4Cl and the resulting
mixture was extracted with hexane (20 mLꢂ3). The combined or-
ganic layers were washed with brine, dried over MgSO4, and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (eluent; Hex/AcOEt¼99:1) to afford ethyl 5-(tert-
butyldimethylsilyloxy)-2-methyl-2-pentenoate (3.70 g, two steps
CDCl3)
d
: 3.87 (ddd, J¼3.8, 4.5, 10.3 Hz, 1H), 3.76 (dt, J¼2.8, 11.0 Hz,
1H), 3.68 (d, J¼11.7 Hz, 1H), 3.53 (d, J¼11.7 Hz, 1H), 2.81 (dd, J¼4.1,
9.6 Hz, 1H), 2.05 (dq, J¼3.4, 14.4 Hz, 1H), 1.79e1.66 (m, 1H), 1.44 (s,
3H), 0.92 (s, 9H), 0.11 (s, 6H); 13C NMR (75 MHz, CDCl3)
d: 64.5,
62.4, 60.6, 60.6, 31.2, 26.0, 20.4, 18.5, ꢀ5.5or ꢀ5.6; IR (neat):
20
3600e3050, 2955, 2929, 2858, 1472, 1257, 1095; [
a
]
ꢀ13.2ꢁ (c
D
0.93, CHCl3); HRMS m/z (EI) calcd for C8H15O2Si (Mþꢀ BuꢀH2O)
t
171.0841, found 171.0832.
4.6. Ethyl (4R,5S)-7-(tert-butyldimethylsilyloxy)-4,5-epoxy-4-
methyl-2-heptenoate (6)
86%) as colorless oil. 1H NMR (300 MHz, CDCl3)
d: 6.01 (tq, J¼1.4,
To a stirred ꢀ78 ꢁC solution of dimethylsulfoxide (2.22 mL,
33.0 mmol) in CH2Cl2 (45 mL) under N2 atmosphere was added
oxalyl chloride (1.44 mL, 16.5 mmol). The resultant mixture was
stirred for 20 min and a solution of (2R,3S)-5-(tert-butyldime-
thylsilyloxy)-2,3-epoxy-2-methylpenten-1-ol 5 (2.70 g, 11.0 mmol)
in CH2Cl2 (10 mL) was added dropwise. After stirring for 20 min at
ꢀ78 ꢁC, triethylamine (6.88 mL, 49.3 mmol) was added at ꢀ78 ꢁC,
and the resulting mixture was allowed to warm into room
temperature. After 15 min, the reaction mixture was quenched with
10% aqueous HCl and the resulting mixture was extracted
with CH2Cl2 (10 mLꢂ3). The combined organic layers were washed
with saturated aqueous NaHCO3 and brine, dried over MgSO4.
Concentration afforded the crude aldehyde, which was used in the
next step without further purification. To a suspension of NaH
(0.669 g, 15.3 mmol, 55% in dispersion oil) in THF (100 mL) was
added ethyl diethylphosphonoacetate (3.27 mL, 16.5 mmol) at 0 ꢁC
under an argon atmosphere and the mixture was stirred at the
same temperature for 30 min. A solution of the crude aldehyde in
THF (10 mL) was added to the Wittig mixture at ꢀ78 ꢁC. After
stirring for 20 min at ꢀ78 ꢁC, the reaction mixture was stirred at
7.2 Hz, 1H), 4.20 (q, J¼7.2 Hz, 2H), 3.68 (t, J¼6.5 Hz, 2H), 2.68 (dtq,
J¼1.4, 6.5, 7.2 Hz, 2H), 1.91 (dt, J¼1.4, 1.4 Hz, 3H), 1.30 (t, J¼6.9 Hz,
3H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3)
d: 168.0,
139.3, 128.4, 62.5, 60.0, 33.2, 25.9, 20.7, 18.3, 14.2, ꢀ5.4; IR (neat):
2929, 2858, 1717, 1463, 1255, 1213, 1102, 837, 776; HRMS m/z (EI)
t
calcd for C10H19O3Si (Mþꢀ Bu) 215.1103, found 215.1116.
4.4. 5-(tert-Butyldimethylsilyloxy)-2-methyl-2-penten-1-ol (4)
To a solution of ethyl 5-(tert-butyldimethylsilyloxy)-2-methyl-2-
pentenoate (2.18 g, 8.00 mmol) in THF (45 mL) was added diiso-
butylaluminum hydride (0.95 M in n-hexane solution) (23.9 mL,
22.7 mmol) at ꢀ78 ꢁC under N2 atmosphere. The mixture was stirred
for 1 h at the same temperature. The reaction mixture was quenched
with 10% aqueous HCl and the resulting mixture was extracted with
diethyl ether (10 mLꢂ3). The combined organic layers were washed
with saturated aqueous NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (eluent; Hex/AcOEt¼97:3) to afford 5-(tert-butyl-
dimethylsilyloxy)-2-methyl-2-penten-1-ol (0.939 g, 51%) as color-
0
ꢁC for 1 h. The reaction mixture was quenched with saturated
less oil. 1H NMR (300 MHz, CDCl3)
J¼5.8 Hz, 2H), 3.62 (t, J¼5.8 Hz, 2H), 2.34e2.27 (m, 3H), 1.82 (s, 3H),
0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3)
: 137.9, 124.6,
d
: 5.30 (t, J¼7.9 Hz, 1H), 4.05 (d,
aqueous NH4Cl and the resulting mixture was extracted with
hexane (20 mLꢂ3). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (eluent; Hex/
AcOEt¼49:1) to afford ethyl (4R,5S)-7-(tert-butyldimethylsilyloxy)-
4,5-epoxy-4-methyl-2-heptenoate (3.18 g, two steps 92%) as col-
d
62.5, 61.5, 31.1, 25.9, 22.2, 18.5, ꢀ5.5; IR (neat): 3600e3050, 2929,
2858,1472,1255,1104; HRMS m/z (EI) calcd for C8H17O2Si (Mþꢀ Bu)
t
173.0998, found 173.0982.
orless oil. 1H NMR (300 MHz, CDCl3)
d
: 6.88 (d, J¼15.8 Hz, 1H), 6.00
4.5. (2R,3S)-5-(tert-Butyldimethylsilyloxy)-2,3-epoxy-2-
methylpenten-1-ol (5)
(d, J¼15.5 Hz, 1H), 4.21 (q, J¼7.2 Hz, 2H), 3.74 (t, J¼6.2 Hz, 2H), 3.14
(t, J¼6.2 Hz, 1H), 1.71 (dt, J¼6.2, 6.2 Hz, 2H), 1.48 (s, 3H), 1.30 (t,
J¼7.2 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3)
d:
To a stirred ꢀ20 ꢁC solution of Ti(OiPr)4 (4.06 g, 14.3 mmol) and
165.9, 145.6, 123.5, 64.5, 60.5, 60.2, 59.6, 31.6, 25.9, 21.4, 18.3, 14.2,
MS4A (6.49 g) in CH2Cl2 (30 mL) were added
D
-(ꢀ)-diethyl tartrate
ꢀ5.4; IR (neat): 2930, 2858, 1723, 1472,1366,1303, 1257, 1175, 1097;

H. Yokoyama et al. / Tetrahedron 66 (2010) 8458e8463
8461
20
[
a]
ꢀ26.4ꢁ (c 0.95, CHCl3); HRMS m/z (EI) calcd for C12H21O4Si
reaction mixture was quenched with 10% aqueous HCl and the
resulting mixture was extracted with ethyl acetate (10 mLꢂ3). The
combined organic layers were washed with saturated aqueous
NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (eluent;
Hex/AcOEt¼17:3) to afford (4R,5S)-7-(tert-butyldimethylsilyloxy)-5-
methoxymethyloxy-4-methyl-2-hepten-1-ol (2.20 g, 99%) as yellow
D
(Mþꢀ Bu) 257.1209, found 257.1200.
t
4.7. Ethyl (4R,5S)-7-(tert-butyldimethylsilyloxy)-5-hydroxy-4-
methyl-2-heptenoate (7)
To a mixture of Pd2(dba)3CHCl3 (0.247 g, 0.239 mmol) in di-
oxane (40 ml) was added n-Bu3P (59.3
solution was added formic acid (1.80 mL, 47.7 mmol) and Et3N
(2.49 mL, 18.0 mmol) in dioxane (10 mL) at room temperature, and
the mixture was stirred for 5 min. A solution of ethyl (4R,5S)-7-
m
L, 0.239 mmol). To the
oil. 1H NMR (300 MHz, CDCl3)
d
: 5.68e5.66 (m, 2H), 4.66 (d, J¼1.0 Hz,
2H), 4.12 (d, J¼3.1 Hz, 2H), 3.72e3.62 (m, 3H), 3.39 (s, 3H), 2.52e2.46
(m,1H),1.67e1.62 (m, 2H),1.06 (d, J¼6.9 Hz, 3H), 0.89 (s, 9H), 0.04 (s,
6H); 13C NMR (75 MHz, CDCl3)
d: 134.5, 129.5, 96.4, 78.6, 63.7, 59.8,
(tert-butyldimethylsilyloxy)-4,5-epoxy-4-methyl-2-heptenoate
6
55.7, 39.8, 34.4, 25.9, 18.2, 15.2, ꢀ5.4; IR (neat): 3600e3050, 2930,
(3.00 g, 9.54 mmol) in dioxane (10 mL) was added to the solution,
and the mixture was stirred for 3 h. The reaction mixture was di-
luted with diethyl ether and filtered through a silica gel pad and
followed by Florisil sequentially with diethyl ether. The filtrate was
concentrated in vacuo. The residue was purified by silica gel
column chromatography (eluent; Hex/AcOEt¼19:1) to afford
ethyl (4R,5S)-7-(tert-butyldimethylsilyloxy)-5-hydroxy-4-methyl-
2-heptenoate (2.72 g, 90%) as colorless oil. 1H NMR (300 MHz,
1255, 1097, 1039; [a]
20 1.2ꢁ (c 0.94, CHCl3); HRMS m/z (EI) calcd for
D
C15H31O3Si (MþꢀOMe) 287.2042, found 287.2048.
4.10. (4R,5S)-7-(tert-Butyldimethylsilyloxy)-5-
methoxymethyloxy-4-methyl-1-tetrahydropyranyloxy-2-
heptene
To
a
solution of (4R,5S)-7-(tert-butyldimethylsilyloxy)-5-
CDCl3)
d
: 6.95 (dd, J¼8.3, 15.8 Hz, 1H), 5.89 (dd, J¼1.0, 15.8 Hz, 1H),
methoxymethoxy-4-methyl-2-hepten-1-ol (2.05 g, 6.44 mmol) in
CH2Cl2 (65 mL) were added p-toluene sulfonic acid monohydrate
(56.3 mg, 0.33 mmol) and 3,4-dihydro-2H-pyran (0.70 mL,
7.66 mmol) at 0 ꢁC under an argon atmosphere, and the mixture
was stirred at room temperature for 1 h. The reaction mixture was
quenched with saturated aqueous NaHCO3 and the resulting mix-
ture was extracted with CH2Cl2 (5 mLꢂ3). The combined organic
layers were washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (eluent; Hex/AcOEt¼19:1) to afford (4R,5S)-
7-(tert-butyldimethylsilyloxy)-5-methoxymethyloxy-4-methyl-1-
tetrahydropyrayloxy-2-heptene (2.54 g, 98%) as yellow oil. 1H NMR
4.20 (q, J¼7.2 Hz, 2H), 3.95e3.80 (m, 3H), 2.50e2.39 (m, 1H),
1.76e1.70 (m, 2H), 1.30 (t, J¼7.2 Hz, 3H), 1.11 (d, J¼6.9 Hz, 3H), 0.92
(s, 9H), 0.10 (s, 6H); 13C NMR (75 MHz, CDCl3)
d: 166.5, 150.7, 121.6,
75.0, 62.8, 60.1, 42.6, 35.3, 25.8, 18.0, 15.2, 14.2, ꢀ5.7; IR (neat):
3600e3050, 2957, 2930, 2884, 2858, 1721, 1472, 1369, 1257, 1093;
20
[
a
]
12.2ꢁ (c 0.96, CHCl3); HRMS m/z (EI) calcd for C14H27O3Si
D
(MþꢀOEt) 271.1729, found 271.1720.
4.8. Ethyl (4R,5S)-7-(tert-butyldimethylsilyloxy)-5-
methoxymethyloxy-4-methyl-2-heptenoate
To a solution of ethyl (4R,5S)-7-(tert-butyldimethylsilyloxy)-5-
hydroxy-4-methyl-2-heptenoate 7 (2.51 g, 7.93 mmol), and eth-
yldiisopropylamine (2.08 mL, 11.9 mmol) in CH2Cl2 (40 mL) was
added chloromethyl methyl ether (0.78 mL, 10.3 mmol) at 0 ꢁC
under an argon atmosphere and the mixture was stirred at room
temperature. After stirring for 6 h at 0 ꢁC, ethyldiisopropylamine
(1.38 mL, 7.92 mmol) and chloromethyl methyl ether (0.60 mL,
7.90 mmol) were added to the reaction mixture and stirred for
16.5 h at the room temperature. The reaction mixture was
quenched with H2O, and the resulting mixture was extracted with
CH2Cl2 (10 mLꢂ3). The combined organic layers were washed
with 10% aqueous HCl, saturated aqueous NaHCO3 and brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (eluent; Hex/
AcOEt¼49:1) to afford ethyl (4R,5S)-7-(tert-butyldimethylsilyl-
oxy)-5-methoxymethoxy-4-methyl-2-heptenoate (2.55 g, 89%) as
(300 MHz, CDCl3) d: 5.66e5.60 (m, 2H), 4.66 (s, 2H), 4.63e4.61 (m,
1H), 4.23e4.18 (m, 1H), 3.98e3.83 (m, 2H), 3.72e3.63 (m, 3H),
3.54e3.46 (m, 1H), 3.38 (s, 3H), 2.54e2.47 (m, 1H), 1.85e1.52 (m,
8H), 1.05 (dd, J¼1.0, 6.9 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); IR (neat):
20
2931, 1471, 1097, 1039; [
a
]
2.6ꢁ (c 0.97, CHCl3); HRMS m/z (EI)
D
calcd for C15H27O5 (MþꢀTBS) 287.1858, found 287.1860.
4.11. (4R,5S)-7-Hydroxy-5-methoxymethyloxy-4-methyl-1-
tetrahydropyranyloxy-2-heptene (8)
To a solution of (4R,5S)-7-(tert-butyldimethylsilyloxy)-5-meth-
oxymethyloxy-4-methyl-1-tetrahydropyranyloxy-2-heptene (2.49 g,
6.18 mmol) in THF (12 mL) was added TBAF (1.0 M THF solution)
(7.42 mL, 7.42 mmol) at 0 ꢁC under an argon atmosphere. The
resulting mixture was allowed to warm into room temperature for
17.5 h. The reaction mixture was quenched with saturated aqueous
NH4Cl and the resulting mixture was extracted with ethyl acetate
(5 mLꢂ3). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (eluent; Hex/
AcOEt¼17:3) to afford (4R,5S)-7-hydroxy-5-methoxymethyloxy-4-
methyl-1-tetrahydropyranyloxy-2-heptene (1.64 g, 92%) as yellow
yellow oil. 1H NMR (300 MHz, CDCl3)
d
: 6.95 (dd, J¼7.6, 15.8 Hz,
1H), 5.84 (d, J¼15.8 Hz, 1H), 4.66 (q, J¼6.9 Hz, 2H), 4.19 (q,
J¼7.2 Hz, 2H), 3.75e3.65 (m, 3H), 3.38 (s, 3H), 2.68e2.62 (m, 1H),
1.68e1.60 (m, 2H), 1.29 (t, J¼7.6 Hz, 3H), 1.11 (d, J¼6.9 Hz, 3H), 0.88
(s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3)
d: 166.5, 150.6,
121.5, 96.5, 77.9, 60.2, 59.5, 55.7, 40.2, 34.6, 25.9, 18.2, 14.5, 14.2,
20
ꢀ5.4; IR (neat): 2930, 2857, 1722, 1256, 1098, 1038; [
a
]
9.2ꢁ (c
oil. 1H NMR (300 MHz, CDCl3)
d: 5.65e5.63 (m, 2H), 4.72e4.61 (m,
3H), 4.23e4.18 (m, 1H), 3.98e3.93 (m, 1H), 3.92e3.82 (m, 1H),
3.80e3.66 (m, 3H), 3.54e3.47 (m, 1H), 3.42 (s, 3H), 2.53e2.46 (m,
D
1.19, CHCl3); HRMS m/z (EI) calcd for C14H27O5Si (Mþꢀ Bu)
t
303.1628, found 303.1613.
1H), 1.85e1.50 (m, 8H), 1.04 (dd, J¼1.4, 6.9 Hz, 3H); IR (neat):
20
4.9. (4R,5S)-7-(tert-Butyldimethylsilyloxy)-5-
methoxymethyloxy-4-methyl-2-hepten-1-ol
3600e3050, 2945, 1454, 1036; [
a
]
ꢀ74.6ꢁ (c 1.06, CHCl3); HRMS
D
m/z (EI) calcd for C13H23O3 (MþꢀMOM) 227.1647, found 227.1629.
To a solution of ethyl (4R,5S)-7-(tert-butyldimethylsilyloxy)-5-
methoxymethoxy-4-methyl-2-heptenoate (2.50 g, 6.93 mmol) in
THF (40 mL) was added diisobutylaluminum hydride (1.02 M n-
hexane solution) (23.8 mL, 24.3 mmol) at ꢀ78 ꢁC under N2 atmo-
sphere. The mixture was stirred for 1 h at the same temperature. The
4.12. (4R,5S)-7-Azido-5-methoxymethyloxy-4-methyl-1-
tetrahydropyranyloxy-2-heptene
To a solution of (4R,5S)-7-hydroxy-5-methoxymethyloxy-4-
methyl-1-tetrahydropyranyloxy-2-heptene 8 (1.50 g, 5.20 mmol)

8462
H. Yokoyama et al. / Tetrahedron 66 (2010) 8458e8463
in CH2Cl2 (26 mL) were added triethylamine (0.75 mL, 5.41 mmol)
and methanesulfonyl chloride (0.45 mL, 5.81 mmol) at 0 ꢁC under
an argon atmosphere. The mixture was stirred for 1 h at the same
temperature. The reaction mixture was quenched with water and
the resulting mixture was extracted with CH2Cl2 (10 mLꢂ3). The
combined organic layers were washed with saturated aqueous
NaHCO3 and brine, dried over MgSO4. Concentration afforded
the crude product, which was used in the next step without
further purification. To a solution of the crude (4R,5S)-7-meth-
anesulfonyloxy-5-methoxymethyloxy-4-methyl-1-tetrahydropyra-
nyloxy-2-heptene in DMF (26 mL) were added NaN3 (1.01 g,
15.5 mmol) and NH4Cl (0.83 g, 15.5 mmol) at room temperature
under an argon atmosphere and the mixture was stirred over night
at 55 ꢁC. The reaction mixture was quenched with water and the
resulting mixture was extracted with diethyl ether (10 mLꢂ3). The
combined organic layers were washed with water (10 mLꢂ3) and
brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (eluent; Hex/
AcOEt¼19:1) to afford (4R,5S)-7-azido-5-methoxymethyloxy-4-
methyl-1-tetrahydropyranyloxy-2-heptene (1.23 g, two steps 75%)
argon atmosphere. The resulting mixture was allowed to warm into
room temperature. After stirring for 4 h, the reaction mixture was
quenched with saturated aqueous NaHCO3 and the resulting mix-
ture was extracted with ethyl acetate (5 mLꢂ3). The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (eluent; Hex/AcOEt¼4:1) to afford (4R,5S)-N-(tert-
butoxycarbonyl)-1-hydroxy-5-methoxymethyloxy-4-methyl-2-hep-
tenylamide (0.78 g, 98%) as colorless oil. 1H NMR (300 MHz, CDCl3)
d
: 5.68e5.63 (m, 2H), 4.86 (br s, 1H), 4.69e4.62 (m, J¼6.9, 8.9 Hz,
2H), 4.11e4.10 (m, 2H), 3.52 (dt, J¼4.1, 8.3 Hz, 1H), 3.39 (s, 3H),
3.25e3.16 (m, 2H), 2.51e2.45 (m, 1H), 1.89 (br s, 1H), 1.71e1.54 (m,
2H), 1.44 (s, 9H), 1.04 (d, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d:
156.0, 133.9, 129.9, 96.5, 79.6, 79.1, 63.6, 55.9, 39.8, 37.5, 31.1, 28.4,
20
14.8; IR (neat): 3600e3050, 2932, 1696, 1037; [
a
]
ꢀ16.1ꢁ (c 1.02,
D
CHCl3); HRMS m/z (EI) calcd for C11H19NO4 (MþꢀOtBuꢀH) 229.1314,
found 229.1322.
4.15. (2R,3R,4S)-N-(tert-Butoxycarbonyl)-4-
methoxymethyloxy-3-methyl-2-vinyl-piperidine (10)
as yellow oil. 1H NMR (300 MHz, CDCl3)
d: 5.65e5.62 (m, 2H),
4.69e4.61 (m, 3H), 4.24e4.19 (m,1H), 3.99e3.84 (m, 2H), 3.61e3.41
(m, 3H), 3.39 (s, 3H), 3.37e3.32 (m, 1H), 2.55e2.49 (m, 1H),
1.88e1.53 (m, 8H), 1.05 (dd, J¼0.7, 6.9 Hz, 3H); 13C NMR (75 MHz,
To a solution of (4R,5S)-N-(tert-butoxycarbonyl)-1-hydroxy-5-
methoxymethyloxy-4-methyl-2-heptenylamide
9
(702 mg,
2.31 mmol) in THF (23 ml) was added bis(acetonitrile)palladium
(II) dichloride (59.9 mg, 0.231 mmol) at 0 ꢁC under an argon at-
mosphere, and the mixture was stirred for 4.5 h at room tem-
perature. The reaction mixture was filtered through a pad of silica
gel and followed by a pad of Florisil sequentially with diethyl
ether. Concentration afforded the crude product was purified by
silica gel column chromatography (eluent; Hex/AcOEt¼9:1) to
afford (2R,3R,4S)-N-(tert-butoxycarbonyl)-4-methoxymethyloxy-
3-methyl-2-vinyl-piperidine (544 mg, 82%) as colorless oil. 1H
CDCl3) d: 134.8, 127.3, 97.8, 96.4, 78.6, 67.7 or 67.6, 62.2, 55.8, 48.3,
39.7 or 39.6, 30.6, 30.2, 25.4,19.5,14.5 or 14.3; IR (neat): 2942, 2096,
1455, 1263, 1037; [
a
]
D
20 ꢀ34.6ꢁ (c 0.97, CHCl3); HRMS m/z (EI) calcd
for C13H22NO3 (MþꢀOMOMꢀN2) 240.1600, found 240.1584.
4.13. (4R,5S)-N-(tert-Butoxycarbonyl)-5-methoxymethyloxy
-4-methyl-1-tetrahydropyranyloxy-2-heptenylamide
To
a
solution of (4R,5S)-7-azido-5-methoxymethyloxy-4-
NMR (300 MHz, CDCl3)
d
: 5.77 (ddd, J¼3.8, 10.7, 17.2 Hz, 1H), 5.20
methyl-1-tetrahydropyranyloxy-2-heptene (1.13 g, 3.61 mmol) in
THF (36 mL) was added LiAlH4 (0.27 g, 7.11 mmol) at 0 ꢁC under an
argon atmosphere for 1 h. The reaction mixture was quenched with
saturated aqueous Na2SO4 and was filtered through a pad of Celite.
Concentration afforded the crude product, which was used in the
next step without further purification. To a solution of the crude
(4R,5S)-5-methoxymethoxy-4-methyl-1-tetrahydropyranyloxy-2-
heptenylamine in CH2Cl2 (7 mL) were added di-tert-butyl dicar-
bonate (1.24 mL, 5.40 mmol) and triethylamine (0.76 mL,
5.45 mmol) at room temperature under an argon atmosphere, and
the mixture was stirred over night at the same temperature. The
reaction mixture was diluted with ethyl acetate and quenched with
10% aqueous HCl. The aqueous phase was extracted with ethyl
acetate (5 mLꢂ3). The combined organic layers were washed with
saturated aqueous NaHCO3 and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography (eluent; Hex/AcOEt¼19:1) to afford
(4R,5S)-N-(tert-butoxycarbonyl)-5-methoxymethyloxy-4-methyl-
1-tetrahydropyranyloxy-2-heptenylamide (1.35 g, two steps 96%)
(ddd, J¼1.0, 2.4, 10.7 Hz, 1H), 5.07 (ddd, J¼1.0, 2.1, 17.2 Hz, 1H),
4.65 (s, 2H), 4.08 (dd, J¼4.8, 13.8 Hz, 1H), 3.83 (dt, J¼4.8, 11.4 Hz,
1H), 3.36 (s, 3H), 2.91 (dt, J¼3.8, 13.4 Hz, 1H), 2.20 (t, J¼6.5 Hz,
1H), 1.79e1.58 (m, 3H), 1.46 (s, 9H), 1.04 (d, J¼6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d: 155.8, 136.4, 115.7, 94.6, 79.6, 72.4, 58.8,
20
55.3, 38.5, 36.1, 28.3, 26.0, 11.5; IR (neat): þ2929, 1696, 1042; [
a]
D
ꢀ17.4ꢁ (c 1.07, CHCl3); MS (EI), m/z 285 (M ); HRMS m/z (EI) calcd
for C15H27NO4 285.1940, found 285.1916.
4.16. (2R,3R,4S)-N-(tert-Butoxycarbonyl)-4-
methoxymethyloxy-3-methyl-2-(4-phenyl-1,3-butadienyl)-
piperidine (11)
A gas of O3 was bubbled into a solution of (2R,3R,4S)-N-(tert-
butoxycarbonyl)-4-methoxymethyloxy-3-methyl-2-vinyl-piperi-
dine 10 (202 mg, 0.708 mmol) in CH2Cl2/MeOH (5 mL, 1:4) at
ꢀ78 ꢁC until the solution was turned to blue. Then an argon gas
bubbled through the solution until its color was clear. Dimethyl
sulfide (0.16 mL, 2.19 mmol) was added to the reaction mixture.
The resulting mixture was allowed to warm into room tempera-
ture. After stirring for 15 min, the reaction mixture was quenched
with water, and the resulting mixture was extracted with hexane
(5 mLꢂ3). The combined organic layers were washed with brine,
dried over MgSO4. Concentration afforded the crude aldehyde,
which was used in the next step without further purification. To
as colorless oil. 1H NMR (300 MHz, CDCl3)
d: 5.63e5.61 (m, 2H),
4.82 (br s, 0.75H), 4.69e4.61 (m, 3H), 4.23e4.17 (m, 1H), 3.98e3.83
(m, 2H), 3.54e3.49 (m, 2H), 3.39 (s, 3H), 3.28e3.15 (m, 2H),
2.51e2.05 (m, 1H), 1.88e1.52 (m, 8H), 1.44 (s, 9H), 1.03 (dd, J¼1.0,
6.9 Hz, 3H); IR (neat): 3353, 2938, 1715, 1038; [
a
]
20 ꢀ39.7ꢁ (c 1.05,
D
CHCl3); MS (EI), m/z 387 (Mþ).
a
suspension of diethyl (E)-cinnamylphosphonate (198 mg,
4.14. (4R,5S)-N-(tert-Butoxycarbonyl)-1-hydroxy-5-
methoxymethyloxy-4-methyl-2-heptenylamide (9)
0.779 mmol) in THF (3 mL) was added n-BuLi (0.55 mL,
0.913 mmol) at ꢀ78 ꢁC under an argon atmosphere and the
mixture was stirred at the same temperature for 40 min. A so-
lution of the crude aldehyde in THF (4 mL) was added to the
Wittig mixture at ꢀ78 ꢁC. After stirring for 10 min at ꢀ78 ꢁC, the
reaction mixture was stirred over night at room temperature. The
reaction mixture was quenched with saturated aqueous NH4Cl
To a solution of (4R,5S)-N-(tert-butoxycarbonyl)-5-methoxy-
methyloxy-4-methyl-1-tetrahydropyranyloxy-2-heptenylamide
(1.02 g, 2.63 mmol) in methanol (26 mL) was added p-toluene
sulfonic acid monohydrate (22.7 mg, 0.13 mmol) at 0 ꢁC under an

H. Yokoyama et al. / Tetrahedron 66 (2010) 8458e8463
8463
and the resulting mixture was extracted with diethyl ether
4.19. (4S,5R)-N-(tert-Butoxycarbonyl)-1-hydroxy-5-
(5mlꢂ3). The combinedorganiclayers werewashed withbrine, dried
over MgSO4, and concentrated in vacuo. The residue was purified by
silicagelcolumnchromatography(eluent;Hex/AcOEt¼19:1) to afford
(2R,3R,4S)-N-(tert-butoxycarbonyl)-4-methoxymethyloxy-3-
methyl-2-(4-phenyl-1,3-butadi-
methoxymethyloxy-4-methyl-2-heptenylamide (13)
According to the same producere,9 the enantiomer 13 was
prepared in 78% yield; [
20 17.1ꢁ (c 1.06, CHCl3).
a
]
D
enyl)-piperidine (212 mg, two steps 78%) as colorless oil. 1H NMR
4.20. (2S,3S,4R)-N-(tert-Butoxycarbonyl)-4-
(300 MHz, CDCl3)
d
: 7.40e7.20 (m, 5H), 6.78 (dd, J¼10.3,15.5 Hz,1H),
methoxymethyloxy-3-methyl-2-vinyl-piperidine (14)
6.51 (d, J¼15.8 Hz, 1H), 6.21 (ddd, J¼1.7, 10.3, 15.5 Hz, 1H), 5.77 (dd,
J¼4.5, 15.5 Hz, 1H), 4.67e4.65 (m, 2H), 4.16e4.09 (m, 1H), 3.86 (dt,
J¼4.8,11.4 Hz,1H), 3.37 (s, 3H), 2.94 (dt, J¼3.8,13.1 Hz,1H), 2.26e2.18
(m, 1H), 1.76e1.64 (m, 3H), 1.48 (s, 9H), 1.05 (d, J¼6.9 Hz, 3H); IR
(neat): 2931, 1693, 1456, 1365, 1259, 1151, 1106; HRMS m/z (EI) calcd
for C23H33NO4 (Mþ) 387.2410, found 387.2395.
According to the same producere,9 the enantiomer 14 was
prepared in 75% yield; [a]
20 18.7ꢁ (c 0.98, CHCl3).
D
4.21. Dienomycin C ((L)-1) and dienomycin C ((L)-1)
hydrochloride salt
According to the same producere,9 (ꢀ)-dienomycin C was pre-
20 ꢀ44.4ꢁ (c 0.97, methanol, as hydrochloride
4.17. Dienomycin C ((D)-1) and dienomycin C ((D)-1)
hydrochloride salt
pared in 43% yield; [
a
]
D
salt).
A solution of (2R,3R,4S)-N-(tert-butoxycarbonyl)-4-methoxy-
Acknowledgements
methyloxy-3-methyl-2-(4-phenyl-1,3-butadienyl)-piperidine
11
(82.3 mg, 0.212 mmol) in methanol (2 mL) was added a catalytic
amount of concd HCl at room temperature under an argon atmo-
sphere and the mixture was stirred at 40 ꢁC for 26 h. Concentration
afforded the crude product was purified by silica gel column
chromatography (eluent; Hex/AcOEt¼9:1/AcOEt/MeOH¼9:1) to
afford dienomycin C ((þ)-1) (33.1 mg) as the hydrochloride salt,
white solid. The solid was recrystallized (mp 208e211 ꢁC). The
dienomycin C as the hydrochloride salt were diluted with benzene
and 1 N aqueous NaOH added. The aqueous layer was extracted
with benzene. The combined organic layers were concentrated in
vacuo to afford dienomycin C ((þ)-1) (30.3 mg, 58%) as white solid.
The analytical sample of dienomycin C ((þ)-1) was recrystallized
This work was supported by Grant-in Aid for Scientific Research
on Priority Areas (18032032 and 20590101) from The Ministry of
Education, Culture, Sports, Science and Technology (MEXT).
Supplementary data
Experimental procedures, products characterization and copies
of NMR spectra. Supplementary data associated with this article
can be found in online version at doi:10.1016/j.tet.2010.08.048.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
(16.3 mg). 1H NMR (300 MHz, CDCl3)
d: 7.40e7.19 (m, 5H), 6.76 (dd,
References and notes
J¼10.3,15.8 Hz,1H), 6.52 (d, J¼15.8 Hz,1H), 6.36 (dd, J¼10.7,15.1 Hz,
1H), 5.72 (dd, J¼8.6, 15.1 Hz, 1H), 3.94 (q, J¼2.8 Hz, 1H), 3.26 (dd,
J¼8.9, 9.6 Hz, 1H), 3.12 (dq, J¼4.1, 11.7 Hz, 1H), 2.88 (dt, J¼3.4,
11.0 Hz, 1H), 1.85e1.75 (m, 2H), 1.60e1.54 (m, 1H), 0.93 (d, J¼6.9 Hz,
1. (a) Umezawa, S.; Tsuchiya, T.; Tatsuta, K.; Horiuchi, Y.; Usui, T.; Umezawa, H.;
Hamada, M.; Yagi, A. J. Antibiot. 1970, 23, 20; (b) Umezawa, S.; Tatsuta, K.;
Horiuchi, Y.; Tsuchiya, T.; Umezawa, H. J. Antibiot. 1970, 23, 28.
2. Ripoche, I.; Bennis, K.; Canet, J.-L.; Gelas, J.; Troin, Y. Tetrahedron Lett. 1996, 37,
3991.
3H); 13C NMR (75 MHz, CDCl3)
d: 137.2, 135.7, 132.5, 132.1, 128.6,
3. Comins, D. L.; Green, G. M. Tetrahedron Lett. 1999, 40, 217.
4. Ripoche, I.; Canet, J.-L.; Gelas, J.; Troin, Y. Eur. J. Org. Chem. 1999, 1517 The ab-
solute configuration of natural dienomycin C 1 was given and was discussed.
5. (a) Hirai, Y.; Terada, T.; Amemiya, Y.; Momose, T. Tetrahedron Lett. 1992, 33,
7893; (b) Yokoyama, H.; Hirai, Y. Heterocycles 2008, 75, 2133.
6. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
7. Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J. J. Am. Chem. Soc. 1989,
111, 6280.
128.5, 127.5, 126.3, 69.0, 59.2, 40.3, 40.0, 33.4, 15.0; IR (neat):
3600e3050, 2930, 1448; MS (EI), m/z 243 (Mþ); HRMS m/z (EI)
20
calcd for C16H21NO (Mþ) 243.1623, found 243.1627; [
a
]
45.4ꢁ (c
45.1ꢁ (c
D
25
0.88, methanol, as hydrochloride salt) (lit.1þ65ꢁ);8
[a]
D
0.81, methanol, as free base).
8. The enantiomeric ratio of the epoxide 5 was determined by 1H NMR analysis of
O-Methylmandelate ester derivatives of 5. The absolute stereochemistry of the
epoxide 5 was determined by the modified Mosher’s method of the alcohol 7.
9. The all experimental procedures of the synthesis of (ꢀ)-1 was involved in the
Supplementary data.
4.18. (2S,3R)-5-(tert-Butyldimethylsilyloxy)-2,3-epoxy-2-
methylpenten-1-ol (12)9
10. The reaction mechanism was shown in Ref. 5b.
According to the Sharpless asymmetric epoxidation by using
11. Recently, 1,3-chirality transfer of Pd(II)-catalyzed cyclization of ethers was re-
ported, see: Uenishi, J.; Ohmi, M.; Ueda, A. Tetrahedron: Asymmetry 2005, 16,
1299.
L
-(þ)-diethyl tartrate, (þ)-12 was prepared from 4 in 83% yield.
[
a]
D
20 14.6ꢁ (c 1.11, CHCl3).