Total Synthesis of (-)-Graminin A Based on Asymmetric Cyclization Carbonylation of Propargyl Acetate

Article abstract of DOI:10.1021/acs.joc.9b02886

The first total synthesis of (-)-graminin A is described. Key features of our synthetic approach involve a palladium-catalyzed asymmetric cyclization carbonylation of prochiral propargylic acetate, conversion of the orthoester product into methyl 4-oxo-3-furancarboxylate, and copper complex-mediated aldol condensation of (+)-gregatin B bearing a diene moiety. A new synthesis of (+)-gregatin B and the first synthesis of (-)-graminin A were achieved.

Full text of DOI:10.1021/acs.joc.9b02886

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Article
TOTAL SYNTHESIS OF (-)-GRAMININ A BASED ON ASYMMETRIC
CYCLIZATION CARBONYLATION OF PROPARGYL ACETATE
Yoichi Ito, Taichi Kusakabe, Yogesh Daulat Dhage, Keisuke
Takahashi, Ken Sakata, Hiroaki Sasai, and Keisuke Kato
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02886 • Publication Date (Web): 02 Dec 2019
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Total Synthesis of (-)-Graminin A Based on Asymmetric Cyclization
Carbonylation of Propargyl Acetate
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Yoichi Ito,† Taichi Kusakabe,† Yogesh Daulat Dhage,† Keisuke Takahashi,† Ken Sakata,† Hiroaki
Sasai,‡ Keisuke Kato*†
† Faculty of Pharmaceutical Sciences, Toho University2-2-1 Miyama, Funabashi, Chiba 274-8510 (Japan)
‡ The Institute of Scientific and Industrial Research (ISIR) Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047
(Japan)
Supporting Information Placeholder
MeO2C
O
Chiral ligand
Pd(NO3)2
CO2Me
Me
O
Aldol
condensation
CO2Me
R
Me
R
5
3 steps
O
Me
AcOEt
Me
O
O
p-Benzoquinone
CO, MeOH
O
O
Me
Butanal
O
OMe
Me
Me
R =
R =
(-)-graminin A
Me
Me
(+)-gregatin B
ABSTRACT: The first total synthesis of (-)-graminin A is described. Key features of our synthetic approach involve a palladium-
catalyzed asymmetric cyclization carbonylation of prochiral propargylic acetate, conversion of the orthoester product into the methyl
4-oxo-3-furancarboxylate, and copper complex mediated aldol condensation of (+)-gregatin B bearing a diene moiety. A new
synthesis of (+)-gregatin B and the first synthesis of (-)-graminin A were achieved.
INTRODUCTION
Although the 2D structure was proposed as described above, the
absolute configuration was not determined, and high resolution
NMR data were not reported. Gregatins B-E having the 5R
configuration exhibit dextro optical rotation. Interestingly,
when the alkyl substituent on C2 (R1) was changed to the alkene
moiety (gregatin A), the sign of the optical rotation was
reversed.
Methyl 4-oxo-3-furancarboxylates are important structural
motifs, because they exist in a variety of natural products with
unique biological activities.1 Gregatins and aspertetronins were
isolated from Cephalosporium gregatum and Aspergillus
rugulosus, respectively.2 The core structure of these compounds
has been revised twice, with Burghart-Stoll and Brückner
assigning the true structure based on total synthesis and NMR
spectroscopic comparison to related compounds.3 Graminin A
was isolated as the main component from the culture filtrate of
Cephalosporium gramineum (Figure 1).4
Scheme 1. Our previous work and this work
Previous work5a
MeO2C
Pd(tfa)2 (5 mol %)
p-benzoquinone
(1.5 equiv)
O
CO2Me
Me
AcO
Me
R1
R2
AcO
Me
O
Me
O
O
O
O
(+)-gregatin B
(+)-gregatin C
(+)-gregatin D
Me
OH
DMSO / MeOH, CO
Me
OMe
Me
O
Me
1
2
3-Furanone-4-carboxylates synthesis.5b,5c
O
O
Me
Me
Me
OH
O
CO2Me
CO2Me
R1
R
R2
CO2Me
5R
Me
(+)-gregatin B
Me
R = H :
Me
O
Me
OH
Me
O
Me
O
Coupling reaction
(+)-gregatin E
R = OH :
Me
Key furanone 3
Me
O
(+)-gregatin E
(-)-gregatin A
Me
Me
This work
Me
MeO2C
-aspertetronin A
(ent
)
Asymmetric
Same as
above
Me
Key furanone 3
CO2Me
O
Me
Cyclization-
Carbonylation
O
O
O
Me
5
2
OMe
Me
Me
O
5
4
Me
Me
O
(From ethyl acetate)
O
(-)-graminin A
CO2Me
CO2Me
R
Me
Me
O
Me
O
Same as above
Aldol reaction
Me
Me
Figure 1. Gregatins A-E and Graminin A
(-)-graminin A
(+)-gregatin B
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On the basis of the sign of the optical rotation and structural
similarities, we assumed that the absolute configuration of C5
in (-)-graminin A to be R.
4
Pd(tfa)2/L3
Pd(tfa)2/L4
Pd(tfa)2/L5
Pd(tfa)2/L6
Pd(tfa)2/L7
Pd(tfa)2/L8
0 °C, 18 h
34
(1.6/1)
-42/-28
-52/-55
-17/-31
55/54
5
0 °C ~ rt, 69 h 27
(1.8/1)
Previously, we reported the total synthesis of gregatins B and
E based on palladium-catalyzed cyclization carbonylation of
optically active propargyl acetate 1 (Scheme 1, previous
work).5a The orthoester 2 was converted into the key furanone
3 by using our previously reported procedure.5b The previous
synthesis had two disadvantages: 1) Seven steps were required
to prepare the optically active propargyl acetate 1. 2)
Conversion of the acetoxymethyl group into an alkyne moiety
was necessary. To improve the efficiency of the synthesis, we
investigated a second generation route (Scheme 1, this work).
Key features of this work involve a palladium-catalyzed
asymmetric cyclization carbonylation of prochiral propargylic
acetate 4 and Cu complex-mediated aldol reaction of (+)-
gregatin B bearing a diene moiety.
6
0 °C, 48 h
0 °C, 25 h
-20 °C, 41 h
0 °C, 23 h
18
(1.6/1)
7
27
(1.6/1)
10
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60
8
66
(1.2/1)
22/-24
-46/-40
-25/-17
9
49
(1.7/1)
10
PdCl2
0 °C ~ rt, 100
h
58
(1.5/1)
(CH3CN)2/L4
Pd(BF4)2
11
12
0 °C, 46 h
56 (2/1)
-53/-51
-62/-59
(CH3CN)4/L4
Pd(NO3)2/L4 -10 °C, 84 h
62
(1.9/1)
RESULTS AND DISCUSSION
The prochiral propargylic acetate 4 was obtained from ethyl
acetate via a three-step sequence. Thus, addition of TMS-
acetylide followed by desilylation, and subsequent acetylation
afforded 4 in 74% yield (three steps). Initially, we screened
several kinds of mono- to tri-dentate ligands for the asymmetric
cyclization carbonylation of prochiral propargylic acetate 4
(Table 1, entries 1-5).6
Among them, sulfoxide-oxazoline (sox) ligand7 L4 gave
moderate enantioselectivity (Table 1, entry 5). In the case of L5
bearing an achiral oxazoline moiety, lower enantioselectivity
resulted (Table 1, entry 6). The use of L6 bearing chiral
oxazoline and achiral phosphine moieties gave almost the same
result as that using L4 (Table 1, entries 5 and 7). These results
suggested that the stereochemistry of the oxazoline plays an
important role in chiral induction. Diastereomer L7 and
isopropyl oxazoline L8 reduced the enantioselectivity (Table 1,
entries 8 and 9). Next, we investigated the palladium counterion
Table 1. Asymmetric cyclization carbonylation of 4: ligand
screening and investigation of palladium counterion
-
MeO2C
(Table 1, entries 10-12). The use of NO3 as a counterion
Ligand (7.5 mol %)
Me
Pd(tfa)2 (5 mol %)
resulted in improved yield and enantioselectivity (Table 1, entry
12).Finally, we investigated three kinds of sox ligands L9-L11
bearing additional substituents at the C5 position of the
oxazoline ring (Table 2, entries 1-4). Among them, 5,5-
dimethyloxazoline L10 improved the enantioselectivity,
affording 72% ee of 5 in 65% yield (Table 2, entry 3). The
absolute configuration and ee value were determined after
conversion to the known key furanone 3.
O
O
O
Me
p-benzoquinone (1.5 equiv)
MeOH,Temp
O
OMe
Me
Me
CO (balloon)
4
5
N
N
P
P
O
O
PR2
PR2
t-Bu
t-Bu
N
Pd
N
Br
Ph
Ph
R = 3,5-Xylyl
C1
L1
L2
Table 2. Ligand tuning
O
O
Ph
Ph
R1
OMe
PPh2
N
N
R2
O
S
S
MeO2C
Ph
p-Tol
p-Tol
O
O
Ligand (7.5 mol %)
Pd(NO3)2 (5 mol %)
N
Me
L4
L5
(S, SS)-
(SS)-
L3
S
O
p-Tol
Me
O
O
p-benzoquinone (1.5 equiv)
O
O
O
O
O
MeOH, CO (balloon)
OMe
i-Pr
Ph
: R = Ph, R2 = H
1
Me
Me
4
L9
N
N
N
: R = Me, R2 = Me
5
1
L10
L11
: R = i-Bu, R2 = i-Bu
1
S
S
PPh2
L6
p-Tol
p-Tol
L8
O
O
(R)-
(R, SS)-
L7
(S, SS)-
Yield
ee (%)a
Entry
Ligand Conditions
Entry Catalyst
Conditions
rt, 30h
Yield
[%] (dr)
ee (%)
(%)
64
52
65
60
1
2
3
4
L9
-10 °C, 84 h
-10 °C, 48 h
-20 °C, 94 h
-20 °C, 72 h
65
70
72
72
1
C1
60
0/0
L10
L10
L11
(1.5/1)
2
3
Pd(tfa)2/L1
Pd(tfa)2/L2
rt, 18h
63 (1/1)
-43/26
0 °C ~ rt, 46 h 10
(1.5/1)
-43/-47
aAbsolute configuration and ee value were determined after
conversion to the furanone 3.
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A model for the observed stereochemical outcome of the
5
6
7
8
cyclization carbonylation is proposed as shown in Scheme 2.
Based on the results using L4 and L6 (Table 1, entries 5 and 7),
the major coordination site of the substrate is assumed to be next
to the oxazoline. The alkyne-coordinated complex B should be
slightly favored over complex A, because the alkyne moiety has
a linear or straight geometry, leading to the major enantiomer.
Table 3. Investigation of aldol reaction using model
substrate 7
9
10
11
12
13
14
15
16
17
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20
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2+
2SbF6
O
-
CO2Me
OH
O
O
Scheme 2. Working model of the asymmetric cyclization
carbonylation of 4
O
N
N
O
Cu
O
Me
H
Me
Me
CO2Me
Me
8
C2
(3 equiv.)
2+
OMe
O
MeO
Reagent
Solvent
rt, time
+
X-
O
CO2Me
+
X-
-
2SbF6
O
O
7
O
Me
N
N
Me
N
S
N
S
Cu
C3
Pd
Pd
9
steric hindrance
O
O
O
H
O
O
H
H
CO2Me
H
H
X
CO2Me
H
X
C
CH2CH2CH3
CHO
O
nPr
H3C
O
O
O
O
O
O
CH2CH3
10
11
CO2Me
or
H
or
H
O
O
H3C
H3C
Entry
1a
Reagent / Solvent
Time
(h)
Yield of
8 (%)
Yield of
9 (%)
A
B
MeO2
C
MeO2
Me
C
Piperidine / AcOH 23
(1:5) in CH2Cl2
-
5
minor
major
O
O
S
R
Me
OMe
2b
Piperidine / AcOH 0.2
(1:5) in DMSO
-
15
-
OMe
O
O
Me
Me
3c
tBuOK (1.5 eq.)
0.5
2.0
72
96
74
48
-
in THF
4d
K2CO3 (1.0 eq) in
DMSO
-
With the optimal conditions in hand, we investigated the
concise synthesis of (+)-gregatin B (Scheme 3). Asymmetric
cyclization carbonylation of 4 using the conditions of entry 3 in
Table 2 gave the orthoester 5 in 65% yield. The orthoester was
converted into the key furanone 3 according to our previously
reported procedure.5a,b Thus, acid treatment of orthoester 5
followed by Knoevenagel-type condensation gave the key
furanone 3 in 74% yield (two steps, 72% ee). The optical purity
of 3 was enriched by recrystallization from CH2Cl2 / hexane
(65% yield, 96% ee). Regioselective palladium-catalyzed
hydrostannylation8 of 3 followed by reaction with iodine
afforded iodide (R)-6 in 71% yield. Finally, (+)-gregatin B was
obtained using the Suzuki-Miyaura coupling reaction in 80%
yield.5a
5
C2 (5 mol %) in
-
53
67
83
DMF
6e
C2 (5 mol %) in
-
DMF
7e
C3 (5 mol %) in
DMF
a Recovery 94%. b 10 was obtained in 78% yield. c -20°C, 11 was
obtained in 19% yield. d11 was obtained in 70% yield. e f40 °C.
Prior to the synthesis of graminin A, we investigated the
vinylogous aldol reaction9 of model substrate 7 with butanal
(Table 3). Acidic conditions gave enone 9 (Table 3, entries 1
and 2), while basic conditions predominantly gave aldol adduct
8 (Table 3, entry 3). However, in both cases, 8 and 9 were
obtained in low yields due to recovery of 7 (Table 3, entry 1) or
over reactions (Table 3, entries 2-4). Over reaction products 10
and 11 should be produced by conjugate addition of butanal and
7 to the aldol condensation product 9, respectively. Recently,
[Cu(II)(box)]X2 was reported as a useful catalyst for activation
of -ketoesters.10 Inspired by these studies, box complex C2
and bipyridine complex C3 were tested in this reaction. The
reaction of 7 with butanal in the presence of C2 (5 mol %) in
DMF afforded desired enone 9 in 53% yield (Table 3, entry 5).
A higher reaction temperature increased the yield of 9, and
bipyridine complex C3 gave a satisfactory yield (Table 3,
entries 6 and 7). Mechanistically, the -ketoester moiety was
activated by the copper complex, which makes the methyl
group more acidic. Thus, the vinylogous aldol reaction
Scheme 3. Concise total synthesis of (+)-gregatin B
MeO2C
O
1) HCl aq
rt, 5 h
CO2Me
Me
Me
Table 2, entry 3
O
Me
O
O
2) NaHCO3
rt, 14 h, 74%
(2 steps)
O
Me
O
OMe
Me
Me
3
(96% ee)
3) Recrystallization (65%)
4
5
(72% ee)
: 65%
Me Me
O
1) Pd(dba)2 (5 mol %)
Me
B
t-Bu3P (25 mol %)
n-Bu3SnH (1.5 equiv)
0 oC, 2 h
O
O
O
Et
Me
CO2Me
CO2Me
(1.5 equiv)
I
Et
Pd(PPh3)4 (10 mol %)
TBAF (1.55 equiv)
2) I2 (1.1equiv)
0 oC, 1 h
Me
Me
(+)-gregatin B
[]D19 +207.8 (c 0.56, CHCl3
lit.2b: []D +207 (c 0.84, CHCl3
O
O
Me
Me
10 oC,
6 :
: 80%
71%
13 h
)
)
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4
5
proceeded smoothly without base. We selected C3 as suitable
catalyst for the synthesis of (-)-graminin A.
4”
5”
2H, sext 1.59
3H, t 0.99 or 1.00
-
-
a400 MHz, CDCl3. b250 MHz, CDCl3.
6
7
8
9
104.85
196.95
163.82
51.08
O
128.48
O
127.31
1'
Me
25.92
O
2''
3'
2'
5'
4'
6'
148.11 21.50
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Synthesis of (-)-graminin A
Me
5
4''
5''
Me
Me Me
O
Me
O
13.44
1''
3''
O
131.67
138.79
Me
Me
185.01
90.35
O
O
B
35.31
120.02
13.70
H
O
CO2Me
Me
CO2Me
nPr
Et
22.45
(3.0 equiv)
(1.5 equiv)
I
I
Complex mixture
6
((±)- : 12%)
Pd(PPh3)4 (10 mol %)
TBAF (1.5 equiv)
Me
Me
(±)-
O
C3
O
(10 mol %)
DMF, 40°C, 17 h
Synthetic (-)-graminin A
13C NMR (100 MHz, C6D6)
104.62
6
(±)-
12 :
75%
THF 10 o
C
O
CO2Me
O
Et
C3
(10 mol %)
CO2Me
Me
196.66
163.74
Me
(-)-graminin A
Et
O
Me
O
O
: 51%
Me
(+)-gregatin B
O
25.87 128.46 127.38
50.99
(4.5 equiv)
40 oC, 87 hr
O
Me
O
[]D21 -144.8 (c 0.54, CHCl3
lit.4: []D20 -145 (c 0.98, CHCl3
)
H
)
DMF
5'
4'
3'
2'
1'
6'
143.21
2''
Me
5
3''
(-)-Graminin A has two kinds of diene moieties. We
investigated two routes for the construction of the second diene
moiety (Scheme 4). In the first route, the vinylogous aldol
condensation of iodo vinyl furanone (±)-6 with butanal
proceeded smoothly, affording (±)-12 in 75% yield.
Unfortunately, the conjugated diene moiety was unstable under
basic conditions and the Suzuki-Miyaura coupling reaction of
(±)-12 gave a complex mixture, with only a small amount (12%)
of (±)-6 recovered by retro-aldol reaction. In the second route,
we investigated the vinylogous aldol reaction of (+)-gregatin B
with butanal using C3 as a catalyst, and desired (-)-graminin A
was obtained in 51% yield. As shown in Table 4 and Fig. 2, the
1H NMR and 13C NMR data for (-)-graminin A were almost
identical to those for (-)-gregatin A3b except for signals
corresponding to C3”-H to C5”-H and C3” to C5”.
Me
O
Me
13.42
1''
184.69
18.65
131.46
138.66
121.23
22.50
90.15
Synthetic (-)-gregatin A3b
13C NMR (126 MHz, C6D6)
Figure 2. 13C NMR of graminin A and gregatin A
CONCLUSIONS
A new total synthesis of (+)-gregatin B and the first total
synthesis of (-)-graminin A have been achieved. The optically
active furanone skeleton was effectively constructed based on
PdII-catalyzed asymmetric cyclization carbonylation of
prochiral propargyl acetate 4, followed by ring conversion. The
(E,E)-diene moiety was successfully prepared by the Suzuki-
Miyaura coupling reaction. The vinylogous aldol condensation
of (+)-gregatin B with butanal was achieved by using a cationic
copper catalyst. This methodology would be applicable for the
synthesis of related natural products such as graminin C,10
aspertetronin A, gregatine A and penicilliol A.11
Table 4. 1H NMR spectra of (-)-graminin A and (-)-gregatin
A
O
O
CO2Me
CO2Me
6' 5'
Me
3'
1'
5'
3'
1'
6'
2''
5
2'' 4''
Me
5
5''
Me
2'
4'
Me
O
4' 2'
Me
O
Me
3''
1''
3''
1''
(-)-gregatin A
(-)-graminin A
EXPERIMENTAL SECTION
Position Proton
Synthetic (-)-
Natural gregatin
A (ppm)b
General Information. All melting points were determined on
a microscopic melting point apparatus and are uncorrected. 1H
NMR and 13C NMR spectra were recorded at 400 MHz (1H
NMR) and 100 MHz (13C NMR) using CDCl3 or C6D6 as the
solvent and TMS as the internal standard. In the case of DMSO-
d6, solvent peak was used as a reference (2.49 ppm for 1H, and
39.5 ppm for 13C). Coupling constants (J) are reported in Hertz
(Hz), and spin multiplicities are represented by the following
symbols: s (singlet), br-s (broad singlet), d (doublet), br-d
(broad doublet), t (triplet), q (quartet), sext (sextet) and m
(multiplet). High-resolution mass spectra were obtained using
high-resolution EI (double focusing) or FAB (double focusing)
or ESI-TOF mass spectrometers. Infrared spectra (IR) were
recorded on a FT-IR spectrophotometer and are reported as
wavelength numbers (cm−1). Determination of enantiomeric
excesses was performed by chiral HPLC analysis of
noncrystallized samples. Column conditions are reported in the
graminin A (ppm)a
6’
3H, t
0.99 or 1.00
2.06-2.13
5.81
0.96
5’
2H, m
1H, dt
1H, dd
1H, dd
1H, d
3H, s
2.06
4’
5.7-6.0 (m)
3’
5.98
2’
6.27
6.24
1’
5.57
5.54
C5-Me
OMe
1”
1.55
1.53
3H, s
3.84
3.83
1H, dt
1H, dt
2H, q
7.32
7.32 (br-d)
7.18 (dq)
2.05 (3H, dd)
2”
7.19
3”
2.35
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experimental section below. All reagents were purchased from
remaining catalyst was washed in MeOH (1 mL) twice and
stirred for 94 h at the same temperature. The mixture was
diluted with CH2Cl2 (50 mL) and washed with 2 M NaOH (50
mL). The aqueous layer was extracted with CH2Cl2 (25 mL ×
2) and the combined organic layers were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by
column chromatography on silica gel. The fraction eluted with
hexane/EtOAc (20/1) afforded the orthoester 5 (73.3 mg, 65%)
as a colorless oil. (mixture of diastereomers, ratio = 2:1)
Absolute configuration and ee value were determined after
conversion to the furanone 3.
commercial sources and used without purification. All
evaporations were performed under reduced pressure. Column
chromatography was performed using silica gel (particle size
100-210 mm (regular), 40-50 mm (flash)).
3-Methylpenta-1,4-diyn-3-yl acetate (4). To a solution of
trimethylsilylacetylene (4.13 g, 0.042 mol) in THF (50 mL) was
added dropwise n-BuLi (15.5 mL, ca. 2.65 M in THF, 0.041
mol) at -40 °C under Ar. After the solution was stirred at -40 °C
for 0.5 h, EtOAc (1.76 g, 0.020 mol) was added to the stirred
solution via syringe at −40 °C. After stirring at the same
temperature for 12 h, the mixture was diluted with saturated
NH4Cl (70 mL) and extracted with EtOAc (40 mL x 2). The
combined organic layers were dried over MgSO4 and
concentrated in vacuo. To a solution of the crude product in
MeOH (30 mL) was added K2CO3 (2.76 g, 0.020 mol) at 0 °C,
and the mixture was stirred at room temperature for 1.5 h. The
mixture was diluted with brine (50 mL) and extracted with
CH2Cl2 (50 mL x 3). The combined organic layers were dried
over MgSO4 and concentrated in vacuo to give the
corresponding alcohol, which was dissolved in pyridine (6.33
g, 0.080 mol) and Ac2O (6.13 g, 0.060 mol). To this solution
was added 4-dimethylaminopyridine (24.4 mg, 0.20 mmol) at
room temperature. After stirring at the same temperature for 27
h, the mixture was diluted with H2O (80 mL) and extracted with
EtOAc (80 mL x 2). The organic layer was washed with 2 M
HCl (80 mL) and saturated NaHCO3 (80 mL), dried over
MgSO4 and concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel (hexane/EtOAc
= 10/1) to afford acetate 4 (2.02 g, 74% yield, 3 steps) as a
colorless oil. 1H NMR (CDCl3) δ 0.91 (3H, s), 2.10 (3H, s), 2.65
(2H, s); 13C{1H} NMR (CDCl3) δ 14.1, 30.4, 63.1, 72.9, 80.0,
168.3; IR (KBr): 3293, 3252, 3006, 1752, 1238 cm-1; HRMS
(EI) m/z: [M+] calcd for C8H8O2 136.0524; found 136.0522.
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Methyl
(5R)-5-ethynyl-2,5-dimethyl-4-oxo-4,5-
dihydrofuran-3-carboxylate (3). To a solution of 5 (79.6 mg,
0.352 mmol) in MeOH (3 mL) was added 2 M HCl (3 mL) at 0
°C. After stirring at room temperature for 1.0 h, the reaction
mixture was diluted with CH2Cl2 (20 mL) and washed with
brine (10 mL). The aqueous layer was extracted with CH2Cl2 (2
x 10 mL), and the combined organic layers were dried over
MgSO4, and concentrated in vacuo. To a solution of the crude
product in MeOH (4 mL) was added NaHCO3 (296 mg, 3.52
mmol), and the mixture was stirred at room temperature for 14
h. The mixture was diluted with CH2Cl2 (20 mL) and washed
with brine (10 mL). The aqueous layer was extracted with
CH2Cl2 (2 x 10 mL), and the combined organic layers were
dried over MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(hexane/EtOAc = 20/1) to afford furanone 3 (50.8 mg, 74%
yield, 72% ee, 2 steps) as a white solid. Mp. 88-90°C; 1H NMR
(CDCl3)  1.71 (3H, s), 2.65 (3H, s), 2.66 (1H, s), 3.85 (3H, s);
13C{1H} NMR (CDCl3)  17.9, 23.9, 51.8, 76.1, 77.5, 82.8,
106.2, 162.8, 193.7, 196.1; IR (KBr): 3250, 2979, 2945, 2884,
2123, 1712, 1590 cm-1; HRMS (EI) m/z: [M+] calcd for
C10H10O4 194.0579; found 194.0577; HPLC: Chiralcel OD-H,
hexane/IPA = 15/1, flow rate = 0.5 mL / min., tR = 23.2 min.
(R), 26.5 min. (S). The optical purity of 3 (229.0 mg, 72%ee)
was enriched by recrystallization from CH2Cl2 / hexane (148.0
Methyl
(E)-2-(5-ethynyl-2-methoxy-2,5-dimethyl-1,3-
dioxolan-4-ylidene)acetate (5) (Table 1). The reaction was
performed according to the typical procedure for asymmetric
cyclization carbonylation of 4. The orthoester 5 was obtained as
mg, 65% yield, 96% ee). []20 +85.9 (c 0.60, CHCl3).
D
Methyl
(E)-(5R)-5-(2-iodovinyl)-2,5-dimethyl-4-oxo-4,5-
1
a mixture of diastereomers. H NMR (CDCl3) diastereomer
dihydrofuran-3-carboxylate (6). Pd(dba)2 (6.0 mg, 0.01 mmol)
and tBu3P (25.7 µL, 1.0 M in toluene, 0.026 mmol) were added
successively to CH2Cl2 (3 mL) and the resulting mixture was
stirred at room temperature for 10 min under Ar. A solution of
(R)-3 (100 mg, 0.51 mmol) in CH2Cl2 (3 mL) was added, and
the reaction mixture was cooled to 0 °C. A solution of Bu3SnH
(224.9 mg, 0.77 mmol) in CH2Cl2 (4 mL) was added dropwise
at 0 °C via syringe over 15 min. The reaction mixture was
stirred at 0 °C for 2 h. The reaction mixture was concentrated
and the residue was purified by column chromatography on
10% w/w anhydrous K2CO3-silica12 (hexane/EtOAc = 70/1 to
A :  1.68 (3H, s), 1.96 (3H, s), 2.66 (1H, s), 3.36 (3H, s), 3.71
(3H, s), 5.45 (1H, s); diastereomer B :  1.73 (3H, s), 2.03 (3H,
s), 2.65 (1H, s), 3.30 (3H, s), 3.71 (3H, s), 5.44 (1H, s); 13C{1H}
NMR (CDCl3) diastereomer A :  24.7, 27.0, 50.1, 51.1, 73.3,
78.7, 80.8, 90.4, 124.1, 166.0, 168.8; diastereomer B :  24.0,
25.5, 49.4, 51.1, 73.2, 77.6, 81.4, 90.5, 124.3, 166.0, 168.2; IR
(KBr): 2346, 2122, 1724, 1660, 1097 cm-1; HRMS (EI) m/z:
[M+] calcd for C11H14O5 226.0841; found 226.0845; HPLC:
Chiralcel OD-H, hexane/EtOH = 200/1, flow rate = 1.0 mL /
min., diastereomer A: tR = 8.6 min. (S), 48.0 min. (R);
diastereomer B: tR = 9.2 min. (S), 18.6 min. (R).
Typical procedure for asymmetric cyclization carbonylation
of 4 (Table 2, Entry 3). To a 30-mL two-necked round-bottom
flask containing a magnetic stirring bar, the substrate 4 (68.2
mg, 0.5 mmol), p-benzoquinone (81.8 mg, 0.75 mmol) and
MeOH (7 mL) was fitted with a rubber septum and a three-way
stopcock connected to a balloon filled with carbon monoxide.
The apparatus was purged with carbon monoxide by pump-
filling via the three-way stopcock. A MeOH (1 mL) solution of
Pd(NO3)2 (5.8 mg, 0.025 mmol) and L10 (0.0375 mmol) was
added to the stirred solution via syringe at −20 °C. The
5/1) to afford the vinylstannane (204.7 mg, 82% yield) as a
1
colorless oil. []20 +88.3 (c 0.65, CHCl3); H NMR (CDCl3)
D
 0.80-0.98 (15H, m), 1.24-1.52 (12H, m), 1.52 (3H, s), 2.66
(3H,s), 3.83 (3H, s), 5.90 (1H, d, 2JSn-H = 59.6 Hz, J = 19.0 Hz),
3
6.35 (1H, d, JSn-H = 61.0 Hz, J = 19.0 Hz); 13C{1H} NMR
(CDCl3)  9.5, 13.7, 17.9, 22.2, 27.2, 28.9, 51.6, 93.2, 106.6,
131.1, 141.4, 163.5, 195.6, 197.7; IR (KBr): 2949, 2902, 2864,
2841, 1711, 1590, 1202 cm-1; HRMS (ESI+) m/z: [M+H]+ calcd
for C22H39O4Sn 487.1870; found: 487.1871.
To a mixture of the vinylstannane (285.2 mg, 0.588 mmol) in
THF (2 mL) was added a THF (2 mL) solution of I2 (164 mg,
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0.647 mmol) at 0 °C. After stirring at 0 °C for 1 h, the reaction
1585, 1443, 1393, 1200, 1111, 1056 cm-1; HRMS (EI) m/z:
mixture was diluted with EtOAc (20 mL) and washed with 10%
Na2S2O3 (20 mL). The aqueous layer was extracted with EtOAc
(2 x 20 mL), and the combined organic layers were dried over
MgSO4 and concentrated in vacuo. The crude product was
purified by flash chromatography on 10% w/w anhydrous
K2CO3-silica12 (hexane/EtOAc = 4/1 to 3/1) to afford (+)-6 (176
mg, 93% yield) as a white solid. Mp 136-138°C; [α]19D +107.0
(c 0.70, CHCl3); 1H NMR (CDCl3)  1.53 (3H, s), 2.65 (3H, s),
3.84 (3H, s), 6.56 (1H, d, J = 14.8 Hz), 6.66 (1H, d, J = 14.8
Hz); 13C{1H} NMR (CDCl3)  17.9, 22.1, 51.7, 79.7, 92.6,
106.9, 140.3, 162.9, 195.7, 196.0; IR (KBr): 1709, 1577, 1226,
1201, 1135, 954 cm-1; HRMS (EI) m/z: [M+] calcd for
C10H11O4I 321.9702; found 321.9704.
Synthesis of (+)-gregatin B. To a solution of (+)-6 (64.4 mg,
0.2 mmol), boronate3a (56.2 mg, 0.309 mmol) and Pd(PPh3)4
(23.1 mg, 0.02 mmol) in THF (deoxygenated, 4 mL) was added
dropwise TBAF (310 L, 1.0 M in THF, 0.31 mmol) at 0 °C.
After stirring at 10 °C for 13 h under Ar, the mixture was diluted
with EtOAc (20 mL) and washed with sat. NH4Cl (20 mL). The
aqueous layer was extracted with EtOAc (2 x 10 mL), and the
combined organic layers were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (hexane/EtOAc = 4.5/1) to afford
gregatin B (39.8 mg, 80% yield) as a pale yellow solid. The
spectroscopic data was in agreement with that reported in the
literature.3b []19D +207.8 (c 0.56, CHCl3).
Aldol reaction using model substrate 7 (Table 3). For entries
1 and 2 : To a solution of furanone 7 (100 mg, 0.45 mmol) and
butylaldehyde (97 mg, 1.35 mmol) in solvent (5.0 mL) was
added piperidine / AcOH = 1:5 (0.5 mL) at room temperature.
After the solution was stirred for 0.2 ~ 23 h, the mixture was
diluted with CH2Cl2 (40 mL) and washed with H2O (2 x 40 mL).
The aqueous layer was extracted with CH2Cl2 (40 mL), and the
combined organic layers were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (hexane/EtOAc = 15/1 to
10/1) to afford 9 and 10.
[M+] calcd for C20H30O5 350.2093; found 350.2092.
For entries 3 and 4: To a solution of furanone 7 (45 mg, 0.20
mmol) and butylaldehyde (43.3 mg, 0.60 mmol) in solvent (1.5
mL) was added tBuOK (33.7 mg, 0.30 mmol) or K2CO3 (27.6
mg, 0.20 mmol) at -20 °C or room temperature under Ar. After
the solution was stirred for 0.5 ~ 2.0 h, the mixture was diluted
with sat. NH4Cl aq. (15 mL) and EtOAc (15 mL). The aqueous
layer was extracted with EtOAc (15 mL), and the combined
organic layers were dried over MgSO4 and concentrated in
vacuo. The crude product was purified by column
chromatography on silica gel (hexane/EtOAc = 4/1 to 2/1) to
afford 8 and 11.
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Methyl
2-(2-hydroxypentyl)-4-oxo-1-oxaspiro[4.5]dec-2-
ene-3-carboxylate (8). Colorless oil; 48% yield, 28.2 mg (0.095
mmol); 1H NMR (CDCl3) δ 0.96 (3H, t, J = 7.2 Hz), 1.37-1.87
(14H, m), 2.65 (1H, br-s), 3.13-3.23 (2H, m), 3.84 (3H, s), 4.10
(1H, br-s); 13C{1H} NMR (CDCl3) δ 14.0, 18.7, 21.4, 21.4, 24.3,
31.6, 31.7, 38.7, 40.0, 51.9, 69.9, 92.5, 108.2, 164.6, 196.1,
200.1; IR (KBr): 3459, 2935, 2864, 1704, 1579, 1440, 1391,
1202, 1113, 1057 cm-1; HRMS (EI) m/z: [M+] calcd for
C16H24O5 296.1624; found 296.1623.
Dimethyl
2,2'-(2-propylpropane-1,3-diyl)bis(4-oxo-1-
oxaspiro[4.5]dec-2-ene-3-carboxylate) (11). Yellow oil; 70%
yield, 35.0 mg (0.07 mmol); 1H NMR (CDCl3) δ 0.90 (3H, t, J
= 7.2 Hz), 1.38-1.81 (24H, m), 2.57-2.60 (1H, m), 3.08 (2H, dd,
J = 14.0, 6.4 Hz), 3.18 (2H, dd, J = 14.0, 7.2 Hz), 3.82 (6H, s);
13C{1H} NMR (CDCl3) δ 14.7, 19.4, 21.5, 24.3, 31.7, 34.9, 36.0,
51.6, 92.3, 107.9, 163.4, 196.7, 200.3; IR (KBr): 2934, 2860,
1705, 1583, 1439, 1390, 1198, 1111, 1056 cm-1; HRMS (FAB)
m/z: [M+H]+ calcd for C28H39O8 503.2645; found 503.2644.
For entries 5 – 7 : The reaction was performed according to the
synthesis of (±)-12 using furanone 7 (45 mg, 0.20 mmol),
butylaldehyde (43.3 mg, 0.60 mmol) and DMF (1.5 mL)
afforded 9 in 83% yield, 41.7 mg (0.15 mmol), (Entry 7).
Methyl 5-((E)-2-iodovinyl)-5-methyl-4-oxo-2-((E)-pent-1-en-
1-yl)-4,5-dihydrofuran-3-carboxylate ((±)-12). To a solution of
(±)-6 (25.0 mg, 0.078 mmol) and C3 (5.8 mg, 0.0078 mmol) in
DMF (1.0 mL) was added butylaldehyde (16.8 mg, 0.23 mmol)
at room temperature. After the solution was stirred at 40 °C for
17 h, the mixture was diluted with EtOAc (20 mL) and washed
with H2O (20 mL). The aqueous layer was extracted with
EtOAc (2 x 10 mL), and the combined organic layers were dried
over MgSO4 and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel
(hexane/EtOAc = 25/1 to 20/1) to afford (±)-12 (21.8 mg, 75%
yield) as a yellow solid. Mp 68-72°C; 1H NMR (CDCl3) δ 1.00
(3H, t, J = 7.4 Hz), 1.55 (3H, s), 1.56-1.62 (2H, m), 2.36 (2H,
q, J = 6.8 Hz), 3.85 (3H, s), 6.58 (2H, m), 7.19 (1H, dt, J = 16.0,
6.8 Hz), 7.30 (1H, dd, J = 16.0, 0.8 Hz); 13C{1H} NMR (CDCl3)
δ 13.8, 21.3, 22.2, 35.6, 51.7, 79.3, 91.7, 103.8, 119.1, 140.9,
150.3, 163.1, 185.4, 196.4; IR (KBr): 2955, 2874, 1704, 1642,
1554, 1446, 1398, 1200, 1059 cm-1; HRMS (EI) m/z: [M+] calcd
for C14H17IO4 376.0172; found 376.0173.
Methyl (E)-4-oxo-2-(pent-1-en-1-yl)-1-oxaspiro[4.5]dec-2-
ene-3-carboxylate (9). White solid; Mp 83-85°C; 15% yield,
1
19.0 mg (0.068 mmol); H NMR (CDCl3) δ 1.00 (3H, t, J = 7.2
Hz), 1.35-1.82 (12H, m), 2.34 (2H, dq, J = 7.2, 1.6 Hz), 3.84
(3H, s), 7.14 (1H, dt, J = 15.8, 7.2 Hz), 7.32 (1H, dt, J = 15.8,
1.6 Hz); 13C{1H} NMR (CDCl3) δ 13.9, 21.5, 21.7 (2C), 24.4,
31.9 (2C), 35.5, 51.7, 91.2, 104.4, 119.6, 149.0, 163.9, 185.4,
200.8; IR (KBr): 2935, 2874, 1737, 1700, 1642, 1552, 1433,
1404, 1199, 1062, 981, 940, 822 cm-1; HRMS (EI) m/z: [M+]
calcd for C16H22O4 278.1518; found 278.1517.
Methyl 2-(3-formyloctan-4-yl)-4-oxo-1-oxaspiro[4.5]dec-2-
ene-3-carboxylate (10). Inseparable mixture of diastereomers
(ratio = 7:3); colorless oil; 78% yield, 121.0 mg (0.346 mmol);
1H NMR (CDCl3) δ 0.86-0.92 (3H, m), 0.95 (3H, t, J = 7.4 Hz),
1.25-1.83 (17H, m), 2.47 (1H, br-s), 3.05 (0.6H, dd, J = 6.4, 5.2
Hz), 3.10 (1.4H, d, J = 7.4 Hz), 3.83 (3H, s), 9.71 (0.7H, d, J =
2.4 Hz), 9.74 (0.3H, d, J = 2.0 Hz); 13C{1H} NMR (CDCl3)
major diastereomer: δ 12.5, 14.1, 18.2, 20.1, 21.4 (2C), 24.2,
31.6 (2C), 33.0, 33.3, 36.3, 51.7, 56.2, 92.2, 107.7, 163.4, 197.2,
200.4, 204.5; mimor diastereomer: δ 12.5, 14.0, 18.3, 20.3, 21.4
(2C), 24.2, 31.8 (2C), 32.6, 33.6, 31.6, 51.7, 56.0, 92.3, 107.7,
163.4, 197.2, 200.3, 204.4; IR (KBr): 2939, 2867, 2712, 1711,
Suzuki-Miyaura coupling reaction of (±)-12. To a solution of
(±)-12 (20.0 mg, 0.054 mmol), boronate3a (29.5 mg, 0.080
mmol) and Pd(PPh3)4 (6.3 mg, 5.4 mol) in THF (deoxygenated,
2.5 mL) was added dropwise TBAF (80 L, 1.0 M in THF,
0.080 mmol) at 0 °C. After stirring at 0 °C for 22 h under Ar,
the mixture was diluted with EtOAc (20 mL) and washed with
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sat. NH4Cl (20 mL). The aqueous layer was extracted with
EtOAc (2 x 10 mL), and the combined organic layers were dried
over MgSO4 and concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel (hexane/acetone
= 15/1 to 5/1) to afford (±)-6 (2.0 mg, 15% yield) along with a
complex mixture.
cm-1; HRMS (FAB) m/z: [M+H]+ calcd for C21H19BrNO2
396.0599; found 396.0598.
2
3
4
5
6
7
Ph
O
Ph
N
Br
Synthesis of (-)-graminin A. To a solution of (+)-gregatin B
(37.5 mg, 0.15 mmol) and C3 (5.6 mg, 0.0075 mmol) in DMF
(1.5 mL) was added butylaldehyde (16.2 mg, 0.23 mmol) at
room temperature. After the solution was stirred at 40 °C for 17
h, C3 (5.6 mg, 0.0075 mmol), butylaldehyde (16.2 mg, 0.23
mmol) and DMF (0.5 mL) were again added, and additional
butylaldehyde (16.2 mg, 0.23 mmol) was added 46 h later. After
stirring at 40 °C for 24 h, the reaction mixture was purified by
flash chromatography on silica gel (hexane/AcOEt = 97/3 to
72/28) to afford graminin A (23.1 mg, 51% yield) as a colorless
oil.TLC: hexane/EtOAc = 6/1 (Rf = 0.23); [α]21D -144.8 (c 0.54,
CHCl3); 1H NMR (CDCl3) δ 0.99 (3H, t, J = 7.6 Hz), 1.00 (3H,
t, J = 7.6 Hz), 1.55 (3H, s), 1.59 (2H, sext, J = 7.6 Hz), 2.06-
2.13 (2H, m), 2.35 (2H, dq, J = 7.2, 1.2 Hz), 3.84 (3H, s), 5.57
(1H, d, J = 15.6 Hz), 5.81 (1H, dt, J = 15.2, 6.8 Hz), 5.98 (1H,
dd, J = 15.2, 10.4 Hz), 6.27 (1H, dd, J = 15.6, 10.4 Hz), 7.19
(1H, dt , J = 15.6, 6.8 Hz), 7.32 (1H, dt, J = 15.6, 1.2 Hz);
13C{1H} NMR (CDCl3) δ 13.3, 13.8, 21.4, 22.5, 25.7, 35.5, 51.6,
90.5, 103.8, 119.4, 126.2, 127.8, 131.6, 139.3, 149.6, 163.5,
185.4, 198.4; 1H NMR (C6D6) δ 0.68 (3H, t, J = 7.2 Hz), 0.82
(3H, t, J = 7.2 Hz), 1.12-1.22 (2H, m), 1.41 (3H, s), 1.79-1.89
(4H, m), 3.56 (3H, s), 5.51 (1H, dt, J = 15.2, 6.4 Hz), 5.57 (1H,
d, J = 15.2 Hz), 5.83 (1H, dd, J = 15.2, 10.8 Hz), 6.42 (1H, dd,
J = 15.2, 10.8 Hz), 6.96 (1H, dt, J = 16.0, 6.8 Hz), 7.59-7.63
(1H, dt, J = 16.0, 1.6 Hz); 13C{1H} NMR (C6D6) δ 13.4, 13.7,
21.5, 22.5, 25.9, 35.3, 51.1, 90.4, 104.9, 120.0, 127.3, 128.5,
131.7, 138.8, 148.1, 163.8, 185.0, 197.0; IR (KBr): 1711, 1642,
1554, 1397, 1202, 1052, 989 cm-1; HRMS (FAB) m/z: [M+H]+
calcd for C18H25O4 305.1753; found 305.1726.
15a
8
9
Synthesis of (4R,5S)-2-(2-bromophenyl)-4,5-diphenyl-4,5-
dihydrooxazole (15a). 14a (1.52 g, 3.84 mmol) dissolved in
toluene (150 mL) was refluxed in a Dean–Stark apparatus with
(NH4)6Mo7O24·4H2O (474 mg, 0.384 mmol) for 48 h. The
reaction mixture was cooled to room temperature and quenched
with sat.NaHCO3 (150 mL) and extracted with EtOAc (100 mL)
twice. The combined organic phase was dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified by column chromatography (hexane/EtOAc = 5/1) to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
give 15a (0.90 g, 62%) as a white solid. Mp 97-99°C; [α]27
D
144.3 (c 0.51, CHCl3); 1H NMR (CDCl3) δ 5.78 (1H, d, J = 10.2
Hz), 6.05 (1H, d, J = 10.2 Hz), 7.00-7.10 (10H, m), 7.34 (1H,
dt, J = 8.0, 1.6 Hz), 7.42 (1H, dt, J = 7.6, 1.2 Hz), 7.73 (1H, dd,
J = 8.0, 1.2 Hz), 7.95 (1H, dd, J = 7.6, 1.6 Hz); 13C{1H} NMR
(CDCl3) δ 74.8, 85.8, 122.2, 126.7 (2C), 127.1, 127.4, 127.6,
127.8 (2C), 127.8 (2C), 128.0 (2C), 129.5, 131.9, 132.1, 134.3,
136.3, 137.5, 164.4; IR (KBr): 1654, 1463, 1325, 1087, 1023,
952, 733, 699 cm-1; HRMS (FAB) m/z: [M+H]+ calcd for
C21H17BrNO 378.0494; found 378.0492.
Ph
O
Ph
N
S
p-Tol
O
L9
Synthesis
of
(4R,5S)-4,5-diphenyl-2-(2-((R)-p-
tolylsulfinyl)phenyl)-4,5-dihydrooxazole (L9). To a solution of
15a (1.00 g, 2.64 mmol) in Et2O (20 mL) was slowly added n-
BuLi (2.6 M in hexane, 1.22 mL, 3.17 mmol) at –78 °C under
Ar atmosphere. After stirring at –78 °C for 0.5 h, a solution of
(1S,2R,5S)-(+)-menthyl (R)- p-toluenesulfinate (0.93 g, 3.17
mmol) in Et2O (10 mL) was added dropwise, stirred at –78 °C
for 0.5 h, then room temperature for 4 h. To the mixture was
added sat. NH4Cl (40 mL) and extracted with EtOAc (30 mL)
twice. The combined organic phase was dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified by column chromatography (hexane/EtOAc = 3/1) to
give L9 (0.82 g, 72%) as white solid. Mp 80-83°C; [α]25D 225.6
(c 0.45, CHCl3); 1H NMR (CDCl3)  2.30 (3H, s), 5.77 (1H, d,
J = 10.4 Hz), 5.92 (1H, d, J = 10.4 Hz), 6.56-6.58 (2H, m), 6.88-
7.05 (10H, m), 7.49-7.52 (2H, m), 7.62 (1H, dt, J = 7.2, 1.2 Hz),
7.84 (1H, dt, J = 8.0, 1.2 Hz), 8.19 (1H, dd, J = 7.2, 1.2 Hz),
8.52 (1H, d, J = 8.0, 1.2 Hz); 13C{1H} NMR (CDCl3)  21.4,
75.0, 85.1, 124.8, 125.5, 126.3 (2C), 126.9 (2C), 127.0, 127.4
(2C), 127.5, 127.7 (2C), 127.9 (2C), 129.6 (2C), 130.1, 130.4,
132.3, 136.1, 136.9, 140.9, 143.5, 146.8, 162.0 IR (KBr): 3031,
1646, 1452, 1327, 1087, 1027, 962, 811, 732, 696 cm-1; HRMS
(EI) m/z: [M+] calcd for C28H23NO2S 437.1449; found 437.1450.
Preparation of ligand L9. 14
HO
Ph
Ph
O
N
H
14a
Br
Synthesis
of
2-bromo-N-((1R,2S)-2-hydroxy-1,2-
diphenylethyl)benzamide (14a). To a solution of (1S, 2R)-(+)-
2-amino-1,2-diphenylethanol (13a) (1.20 g, 5.62 mmol) and
Et3N (1.13 g, 11.20 mmol) in CH2Cl2 (dehydrated, 20 mL) was
slowly added a CH2Cl2 (10 mL) solution of 2-bromobenzoyl
chloride (1.23 g, 5.62 mmol) at 0ºC under Ar. After stirring for
12 h at room temperature, the reaction mixture was quenched
with water (140 mL) and extracted with CH2Cl2/MeOH = 8/1
(70 mL) three times. The combined organic phase was dried
over MgSO4, filtered, and concentrated in vacuo. The solid was
washed with hexane/Et2O = 1/5 to give 14a (2.22 g, 100%) as a
1
white solid. Mp 215-218°C; [α]26 -12.4 (c 0.47, DMSO); H
D
NMR (DMSO-d6) δ 4.77 (1H, dd, J = 8.4, 5.2 Hz), 5.15 (1H, t,
J = 9.0 Hz), 5.44 (1H, d, J = 5.6 Hz), 6.79 (1H, dd, J = 7.4, 1.8
Hz), 7.22-7.36 (8H, m), 7.40-7.45 (4H, m), 7.56 (1H, dd, J =
7.6, 1.2 Hz), 8.81 (1H, d, J = 9.2 Hz); 13C{1H} NMR (DMSO-
d6) δ 58.5, 75.1, 118.8, 126.7, 127.1, 127.2 (2C), 127.3, 127.6
(2C), 127.7 (2C), 128.3 (2C), 128.4, 130.7, 132.6, 139.1, 140.9,
143.4, 165.7; IR (KBr): 3303, 1645, 1535, 1323, 1027, 750, 700
Preparation of ligand L10. 14
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Me
Me
HO
(1S,2R,5S)-(+)-menthyl (R)- p-toluenesulfinate (1.10 g, 3.82
O
mmol) in Et2O (10 mL) was added dropwise, stirred at –78 °C
for 0.5 h, then room temperature for 4 h. To the mixture was
added sat. NH4Cl (40 mL) and extracted with EtOAc (30 mL)
twice. The combined organic phase was dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel (hexane / acetone
= 7/1 to 6.5/1) afforded L10 (0.83 g, 67%) as a white solid.
N
H
Ph
Br 14b
Synthesis
of
(R)-2-Bromo-N-(2-hydroxy-2-methyl-1-
phenylpropyl)benzamide (14b). To a solution of (R)-1-amino-
2-methyl-1-phenylpropan-2-ol (13b)
13a
(603 mg, 3.65 mmol)
and Et3N (1.10 g, 10.87 mmol) in CH2Cl2 (dehydrated, 12 mL)
was slowly added a CH2Cl2 (3 mL) solution of 2-bromobenzoyl
chloride (794 mg, 3.62 mmol) at 0ºC under Ar. After stirring
for 12 h at room temperature, the reaction mixture was
quenched with water (30 mL) and extracted with CH2Cl2 (30
mL) three times. The combined organic phase was dried over
MgSO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel (hexane /
EtOAc = 92/8 to 34/66) afforded 14b (1.22 g, 96%) as a white
solid. TLC: hexane/EtOAc = 2/1 (Rf = 0.16); Mp 118-120°C;
9
TLC: hexane/EtOAc = 3/1 (Rf = 0.20); Mp 96-97°C; [α]26
100.2 (c 0.48, CHCl3); H NMR (CDCl3) δ 0.86 (3H, s), 1.62
D
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(3H,s), 2.34 (3H, s), 5.08 (1H, s), 6.87-6.90 (2H, m), 7.08-7.10
(2H, m), 7.19-7.26 (3H, m), 7.2-7.55 (2H, m), 7.57 (1H, dt, J =
7.6, 1.2 Hz), 7.77 (1H, dt, J = 7.6, 1.2 Hz), 8.01 (1H, dd, J =
7.6, 1.2 Hz), 8.44 (1H, dd, J = 8.0, 1.2 Hz); 13C{1H} NMR
(CDCl3) δ 21.3, 23.8, 28.7, 79.0, 87.8, 125.4, 125.8, 126.9 (2C),
127.2 (2C), 127.4, 128.0 (2C), 129.5 (2C), 129.7, 130.3, 132.0,
138.1, 140.7, 143.7, 146.3, 160.8; IR (KBr): 3526, 3464, 2981,
2869, 1641, 1456, 1335, 1083, 1017, 746 cm-1; HRMS (EI) m/z:
[M+] calcd for C24H23NO2S 389.1449; found 389.1449.
[α]26 23.2 (c 0.53, CHCl3); H NMR (CDCl3) δ 1.09 (3H, s),
1.43 (3H, s), 1.92 (1H, br-s), 5.02 (1H, d, J = 8.8 Hz), 7.15 (1H,
1
D
d, J = 8.0 Hz), 7.23-7.40 (7H, m), 7.46 (1H, dt, J = 7.6, 1.6 Hz),
7.57 (1H, dd, J = 8.0, 0.8 Hz); 13C{1H} NMR (CDCl3) δ 27.9,
27.9, 62.0, 72.8, 119.2, 127.5, 127.7, 128.2 (2C), 128.3 (2C),
129.7, 131.2, 133.4, 137.7, 138.9, 167.0; IR (KBr): 3414, 3352,
1633, 1529, 1463, 1368, 1200, 1154, 742 cm-1; HRMS (FAB)
m/z: [M+H]+ calcd for C17H19BrNO2 348.0599; found 348.0599.
Preparation of ligand L11.14
iBu
iBu
Ph
OH
NHBoc
16
Synthesis of tert-butyl (R)-(2-hydroxy-2-isobutyl-4-methyl-1-
Me
Me
phenylpentyl)carbamate (16). 16 was prepared according to
O
Ph
N
the reported procedure.13b To a solution of
(R)-tert-
butoxycarbonylaminophenylacetic acid methyl ester13a (1.0 g,
4.25 mmol) in THF (dehydrated, 20 mL) was added
LaCl3·2LiCl (0.6 M in THF, 21.0 mL, 12.6 mmol) at room
temperature under Ar. After stirring for 2 h at room temperature,
the reaction mixture was added iBuMgBr (1.0 M in THF, 12.8
mL, 12.8 mmol ) at 0°C, then stirred for 18 h at 0°C ~ rt. To the
mixture was added sat. NH4Cl (100 mL) and extracted with
EtOAc (100 mL) twice. The organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography on
silica gel (hexane / EtOAc = 96/4 to 68/32) afforded 16 (1.24 g,
83%) as a white solid. TLC: hexane/EtOAc = 5/1 (Rf = 0.30);
Mp 112-114°C; [α]25D 1.3 (c 0.51, CHCl3); 1H NMR (CDCl3) δ
0.83 (3H, d, J = 6.8 Hz), 0.86 (3H, d, J = 6.4 Hz), 0.88-0.93
(1H, m), 0.99 (6H, d, J = 6.4 Hz), 1.24-1.78 (15H, m), 4.58 (1H,
d, J = 9.2 Hz), 5.58 (1H, d, J = 8.4 Hz), 7.24-7.34 (5H, m);
13C{1H} NMR (CDCl3) δ 23.8, 24.1, 24.3, 24.9, 25.0 (2C), 28.4
(3C), 44.0, 46.0, 60.6, 77.7, 79.3, 127.3, 128.2 (2C), 128.4 (2C),
140.0, 155.3; IR (KBr): 3449, 3411, 2953, 2870, 1670, 1522,
1362, 1254, 1169, 875 cm-1; HRMS (FAB) m/z: [M+H]+ calcd
for C21H36NO3 350.2695; found 350.2695.
Br
15b
Synthesis of (R)-2-(2-bromophenyl)-5,5-dimethyl-4-phenyl-
4,5-dihydrooxazole (15b). 14b (1.20 g, 3.45 mmol) dissolved
in xylene (150 mL) was refluxed in a Dean–Stark apparatus
with tetraisopropyl orthotitanate (98 mg, 0.345 mmol) for 17h.
The reaction mixture was cooled to room temperature and
quenched with sat.NaHCO3 (150 mL) and extracted with
EtOAc (100 mL) twice. The combined organic phase was dried
over MgSO4, filtered, and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(hexane / EtOAc = 98/2 to 82/18) afforded 15b (1.07 g, 94%)
as a white solid. TLC: hexane/EtOAc = 10/1 (Rf = 0.19); Mp
84-85°C; [α]26D -10.5 (c 0.53, CHCl3); 1H NMR (CDCl3) δ 0.98
(3H, s), 1.70 (3H, s), 5.09 (1H, s), 7.27-7.40(7H, m), 7.67 (1H,
dd, J = 8.0, 1.2 Hz), 7.77 (1H, dd, J = 7.6, 1.6 Hz); 13C{1H}
NMR (CDCl3) δ 23.8, 29.1, 78.7, 88.2, 121.9, 127.1, 127.3 (2C),
127.5, 128.3 (2C), 130.4, 131.4, 131.6, 133.9, 138.6, 163.4; IR
(KBr): 2974, 2874, 1665, 1465, 1334, 1246, 1086, 1032, 751
cm-1; HRMS (FAB) m/z: [M+H]+ calcd for C17H17BrNO
330.0494; found 330.0493.
Me
Me
iBu
HO
O
iBu
O
Ph
N
N
H
Ph
S
O
p-Tol
Br
14c
L10
Synthesis
of
(R)-2-bromo-N-(2-hydroxy-2-isobutyl-4-
Synthesis
of
(R)-5,5-dimethyl-4-phenyl-2-(2-((R)-p-
methyl-1-phenylpentyl)benzamide (14c). To a solution of 16
(1.19 g, 3.41 mmol) in CH2Cl2 (6 mL) was added TFA (6 mL)
at 0ºC, and the mixture was stirred for 1 h at room temperature.
The reaction mixture was concentrated in vacuo, the residue
was diluted with CH2Cl2 (40 mL) and washed with 2M NaOH
tolylsulfinyl)phenyl)-4,5-dihydrooxazole (L10). To a solution
of 15b (1.05 g, 3.18 mmol) in Et2O (15 mL) was slowly added
n-BuLi (2.6 M in hexane, 1.47 mL, 3.82 mmol) at –78 °C under
Ar atmosphere. After stirring at –78 °C for 0.5 h, a solution of
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(60 mL). The aqueous phase was extracted with CH2Cl2 (40 mL)
Synthesis
of
(R)-5,5-diisobutyl-4-phenyl-2-(2-((R)-p-
twice and the combined organiclayers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude aminoalcohol
13c was used without further purification. To a solution of 13c
and Et3N (1.03 g, 10.22 mmol) in CH2Cl2 (dehydrated, 12 mL)
was slowly added a CH2Cl2 (3 mL) solution of 2-bromobenzoyl
chloride (748 mg, 3.41 mmol) at 0ºC under Ar. After stirring
for 12 h at room temperature, the reaction mixture was
quenched with water (30 mL) and extracted with CH2Cl2 (30
mL) three times. The combined organic phase was dried over
MgSO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (hexane/EtOAc = 94/6 to
51/49) to give 14c (1.47 g, 100%, 2 steps) as white solid. TLC:
tolylsulfinyl)phenyl)-4,5-dihydrooxazole (L11). To a solution
of 15c (1.00 g, 2.41 mmol) in Et2O (15 mL) was slowly added
n-BuLi (2.6 M in hexane, 1.12 mL, 2.90 mmol) at –78 °C under
Ar atmosphere. After stirring at –78 °C for 0.5 h, a solution of
(1S,2R,5S)-(+)-menthyl (R)- p-toluenesulfinate (0.85 g, 2.90
mmol) in Et2O (10 mL) was added dropwise, stirred at –78 °C
for 0.5 h, then room temperature for 3 h. To the mixture was
added sat. NH4Cl (40 mL) and extracted with EtOAc (30 mL)
twice. The combined organic phase was dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (hexane/EtOAc = 95/5 to
60/40) to give L11 (0.49 g, 43%) as pale yellow solid. TLC:
hexane/EtOAc = 4/1 (Rf = 0.21); Mp 102-105°C; [α]26D 86.7 (c
0.54, CHCl3); 1H NMR (CDCl3) δ 0.68 (3H, d, J = 6.8 Hz), 0.75
(3H, d, J = 6.8 Hz), 0.90-1.05 (8H, m), 1.60-1.71 (2H, m), 1.88-
2.03 (2H, m), 2.33 (3H, s), 5.29 (1H, s), 6.78-6.80 (2H, m), 7.06
(2H, d, J = 8.0 Hz), 7.16 (2H, t, J = 8.0 Hz), 7.21-7.25 (1H, m),
7.50-7.53 (2H, m), 7.57 (1H, dt, J = 7.6, 1.2 Hz), 7.78 (1H, dt,
J = 7.6, 1.2 Hz), 7.96 (1H, dd, J = 7.8, 1.0 Hz), 8.47 (1H, dd, J
= 8.0, 1.2 Hz); 13C{1H} NMR (CDCl3) δ 21.3, 23.6, 24.0, 24.1,
24.4, 24.8, 24.9, 44.1, 46.8, 77.9, 91.8, 124.9, 125.6, 125.8,
127.0 (2C), 127.2, 127.8 (2C), 127.9 (2C), 129.5 (2C), 130.3,
131.9, 138.1, 140.6, 143.8, 146.4, 160.6; IR (KBr): 2953, 1645,
1460, 1336, 1084, 1031 cm-1; HRMS (EI) m/z: [M+] calcd for
C30H35NO2S 473.2389; found 473.2389.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
hexane/EtOAc = 3/1 (Rf = 0.30); Mp 98-99°C; [α]25 -2.6 (c
D
0.54, CHCl3); 1H NMR (CDCl3) δ 0.81 (3H, d, J = 6.8 Hz), 0.87
(3H, d, J = 6.4 Hz), 0.92-0.98 (1H, m), 1.02 (3H, d, J = 6.8 Hz),
1.03 (3H, d, J = 6.4 Hz), 1.43-1.48 (2H, m), 1.64-1.89 (4H, m),
5.07 (1H, d, J = 8.8 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.23-7.42
(7H, m), 7.46 (1H, dd, J = 7.6, 2.0 Hz), 7.57 (1H, dd, J = 7.8,
1.0 Hz); 13C{1H} NMR (CDCl3) δ 23.7, 24.1, 24.2, 24.2, 25.0,
25.0, 44.2, 46.2, 60.0, 77.7, 119.2, 127.5, 127.6, 128.3 (2C),
128.7 (2C), 129.8, 131.2, 133.4, 137.8, 139.1, 166.4; IR (KBr):
3403, 3300, 2952, 1631, 1537, 1462, 1153, 1032, 745, 701 cm-
1; HRMS (FAB) m/z: [M+H]+ calcd for C23H31BrNO2 432.1538;
found 432.1538.
iBu
iBu
O
Ph
N
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
15c
Br
Synthesis of (R)-2-(2-bromophenyl)-5,5-diisobutyl-4-phenyl-
4,5-dihydrooxazole (15c). 14c (1.40 g, 3.24 mmol) dissolved in
xylene (150 mL) was refluxed in a Dean–Stark apparatus with
tetraisopropyl orthotitanate (92 mg, 0.324 mmol). After stirring
for 27 h at reflux temperature, tetraisopropyl orthotitanate (92
mg, 0.324 mmol) was again added, and additional
tetraisopropyl orthotitanate (276 mg, 0.972 mmol) was added
24 h later. After stirring at same temperature for 17 h, the
reaction mixture was cooled to room temperature and quenched
with sat.NaHCO3 (150 mL) and extracted with EtOAc (100 mL)
twice. The combined organic phase was dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (hexane/EtOAc = 98/2 to
82/18) to give 15c (1.09 g, 81%) as yellow oil. TLC:
Copy of 1H and 13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: kkk@phar.toho-u.ac.jp
ORCD
Keisuke Kato: 0000-0003-4408-4181
hexane/EtOAc=10/1 (Rf = 0.45); [α]25 27.2 (c 0.55, CHCl3);
D
Notes
1H NMR (CDCl3) δ 0.71 (3H, d, J = 6.8 Hz), 0.76 (3H, d, J =
6.4 Hz), 1.01-1.20 (8H, m), 1.69-1.78 (2H, m), 1.94-2.09 (2H,
m), 5.03 (1H, s), 7.25-7.39 (7H, m), 7.68 (1H, d, J = 7.8, 1.0
Hz), 7.77 (1H, d, J = 7.6, 2.0 Hz); 13C{1H} NMR (CDCl3) δ
23.7, 24.2, 24.3, 24.7, 25.1, 25.1, 44.3, 47.0, 77.5, 92.6, 122.0,
127.2, 127.4, 128.1 (2C), 128.2 (2C), 130.5, 131.4, 131.6, 134.1,
138.7, 163.4; IR (KBr): 2954, 1658, 1465, 1331, 1097, 740, 693
cm-1; HRMS (FAB) m/z: [M+H]+ calcd for C23H29BrNO
414.1433; found 414.1433.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by JSPS KAKENHI Grant Number
24790026.
REFERENCES
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from the Plant Endophytic Fungus Penicillium sp. sh18. J. Nat.
iBu
iBu
O
Ph
N
S
p-Tol
O
L11
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