Total syntheses of phomallenic acids B and C utilizing palladium-catalyzed coupling of propargylic tosylates with terminal alkynes

Article abstract of DOI:10.1055/s-2008-1032116

Total syntheses of (±)-phomallenic acids B and C, potent FAS II inhibitors, have been achieved by a palladium-catalyzed coupling of propargylic tosylates and terminal alkynes. Attempts to find an enantiospecific coupling using optically active propargylic

Full text of DOI:10.1055/s-2008-1032116

PAPER
1099
Total Syntheses of Phomallenic Acids B and C Utilizing Palladium-Catalyzed
Coupling of Propargylic Tosylates with Terminal Alkynes
Total
Syntheses of
P
ho
a
mallenic
A
s
cids
B
and
a
C
hiro Yoshida,* Mohammad Al-Amin, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6337294; E-mail: yoshida@ph.tokushima-u.ac.jp
Received 17 December 2007; revised 10 January 2008
H
Abstract: Total syntheses of ( )-phomallenic acids B and C, potent
OH
FAS II inhibitors, have been achieved by a palladium-catalyzed
coupling of propargylic tosylates and terminal alkynes. Attempts to
find an enantiospecific coupling using optically active propargylic
compounds resulted in racemization of the products.
( )n
O
H
phomallenic acid B (1) n = 1
phomallenic acid C (2) n = 2
Key words: alkynes, allene, coupling, palladium, phomallenic acid
Pd-catalyzed coupling
Phomallenic acids B and C (1 and 2) (Scheme 1), isolated
by Merck scientists from the fermentation broth of Phoma
sp. (MF7018, CBS118751),1 are new inhibitors of FabF,
an essential enzyme in the bacterial type II fatty acid syn-
thesis pathway (FAS II), and exhibit a spectrum of anti-
bacterial activity against clinically important pathogens,
including methicillin-resistant Staphylococcus aureus.2
Potential medicinal applications and their unique diyne-
allene structure make these compounds attractive targets
for chemical synthesis. Very recently, Wu et al. complet-
ed the first total synthesis of phomallenic acid C in enan-
tiomerically pure form, but no synthesis of phomallenic
acid B has been reported.3 Herein, the total syntheses of
( )-phomallenic acids B and C utilizing palladium-cata-
lyzed coupling of propargylic compounds and terminal
alkynes as the key step, as well as efforts toward an enan-
tiospecific synthesis, are described.
X
H
OMe
+
( )n
O
3 n = 1
4 n = 2
5
O
OMe
TMS
TMS
+
( )n
HO
O
6 n = 1
7 n = 2
8
Scheme 1
cat. Pd(0)
cat. Cu(I)
X
R2
Pd
R4
R3
R1
+
R2
*
Our strategy for phomallenic acids B and C is outlined in
the retrosynthetic analysis shown in Scheme 1. We antic-
ipated that the core diyne-allene unit could be constructed
by the palladium-catalyzed coupling of 3 and 4 with the
diyne 5. The propargylic compounds 3 and 4 would be
prepared from the suberic and azelaic acid monomethyl
esters (6 and 7) and bis(trimethylsilyl)acetylene (8). It is
known that optically active propargylic oxiranes and car-
bonates react with terminal alkynes in the presence of pal-
ladium to furnish the chiral alkynylallenes via anti-SN2¢
attack of palladium (Scheme 2).4 In this process, tri- and
tetrasubstituted alkynylallenes have been prepared in op-
tically pure form, but there are no examples of the asym-
metric synthesis of 1,3-disubstituted alkynylallenes.5
Since we were interested in the enantiospecificity in the
coupling of the propargylic compound 3 with the diyne 5,
we applied this coupling to the asymmetric synthesis of
phomallenic acid B (1).
R4
amine
R3
1
R2
R1
Cu
R4
R3
*
R1
Scheme 2
The syntheses of ( )-phomallenic acids B and C were ini-
tially examined (Scheme 3). The suberic and azelaic acid
monomethyl esters (6 and 7) were reacted with oxalyl
chloride to afford the corresponding acid chlorides, which
were subsequently reacted with bis(trimethylsilyl)acety-
lene (8) in the presence of AlCl3 leading to the alkynyl ke-
tones 96 and 10 in 68% and 67% yield, respectively, for
the two steps. Luche reduction of the carbonyl moiety in
9 and 10 furnished the propargylic alcohols 11 and 12 in
92% and 99% yield, respectively. Cleavage of the tri-
methylsilyl function, followed by tosylation of the hydrox-
SYNTHESIS 2008, No. 7, pp 1099–1105
x
x
.
x
x
.2
0
0
8
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1032116; Art ID: F23107SS
© Georg Thieme Verlag Stuttgart · New York

1100
M. Yoshida et al.
PAPER
yl group in the resulting 13 and 14 afforded the and methyl chloroformate in 65% and 76% yield, respec-
propargylic tosylates 3a and 4a. We next examined the tively.
palladium-catalyzed coupling as the key reaction. When
the reactions of 3a and 4a with the diyne 5 were carried
out in the presence of 10 mol% Pd(PPh3)4, 10 mol% CuI,
and diisopropylamine in benzene at room temperature, the
desired coupling products 15 and 16 were produced in
80% and 67% yield, respectively. Finally, hydrolysis of
the methyl ester in 15 and 16 with LiOH completed the to-
With the optically active propargylic compounds 3a–c in
hand, we then examined the enantiospecific coupling with
the diyne 5. When the reaction of (–)-3a and 5 was carried
out using 10 mol% Pd(PPh3)4, 10 mol% CuI, and diisopro-
pylamine in benzene at room temperature, the coupled
diynylallene 15 was produced (entry 1 in Table 1). The
observed enantiomeric excess was determined on a chiral
column by HPLC analysis, but it was clear that the result-
tal synthesis of ( )-phomallenic acids B and C (1 and 2).
The spectral properties (1H and 13C NMR) of the synthe-
ing product had completely racemized. Reactions in the
sized compounds 1 and 2 were identical with those of the
natural products.
presence of Pd2(dba)3·CHCl3 with dppe4a (entry 2) or
ZnCl2 as additives8 (entry 3) also gave the racemic prod-
The asymmetric synthesis of (–)-phomallenic acid B (1) uct 15, and attempts using the propargylic acetate 3b and
was next examined. The optically active propargylic com- carbonate 3c in the presence of LiCl9 were likewise unsuc-
pounds 3 were prepared by enzymatic kinetic resolution cessful (entries 4 and 5).
of the propargylic alcohol ( )-13 (Scheme 4). After
screening various lipases, we found that enzymatic ester-
ification using Candida antarctica lipase (CAL) was the
most successful. When ( )-13 was treated with vinyl ace-
A plausible mechanism for the observed racemization is
shown in Scheme 5. One possibility is that racemization
of the allenylpalladium intermediate had occurred. It has
been reported that optically active allenylpalladium is ra-
tate in the presence of CAL in Et2O for 50 minutes, the op-
cemized on formation of the dinuclear complex.10 We an-
tically active propargylic acetate (–)-3b was obtained in
ticipated an equilibrium between the allenylpalladium
(R)-18 and (S)-18 via formation of the dinuclear complex-
es 19–21. Another possible explanation is the racemiza-
tion of the resulting allenes. It is known that optically
active allenes are racemized in the presence of palladi-
um(II)/LiBr, in which the racemization proceeded via the
32% yield with 90% ee along with (+)-13 in 44% yield
with 66% ee. The absolute configurations of the resulting
products were determined using the improved Mosher
method developed by Kusumi et al.7 After hydrolysis of
the acetyl function in (–)-3b with K2CO3 in MeOH, the re-
sulting alcohol (–)-13 was treated with (R)- or (S)-MTPA
in the presence of DCC and DMAP to yield the MTPA es-
ters (R,S)-(+)-17 and (S,S)-(–)-17, respectively. On the ba-
sis of the Dd values [Dd = d(S)-ester–d(R)-ester], the absolute
configuration of (–)-13 was determined to be S. Optically
active propargylic tosylate (–)-3a and carbonate (–)-3c
were prepared by the reaction of (–)-13 with tosyl chloride
anti-bromopalladation process.11 A similar isomerization
of the allene (R)-22 to (S)-22 via the intermediates 23–25,
triggered by the resulting palladium(II) species and CuI,
might occur in our coupling reaction conditions. The com-
plete racemization observed in the coupling indicates that
the resulting 1,3-disubstituted alkynylallenes might be too
1) (COCl)2
DMF, benzene, 5 °C
O
O
NaBH4, CeCl3
OMe
OMe
( )n
HO
( )n
TMS
TMS
MeOH, –50 °C to r.t.
2)
8
O
TMS
O
AlCl3, CH2Cl2, 0 °C
9 n = 1 2 steps 68%
10 n = 2 2 steps 67%
6 n = 1
7 n = 2
OTs
OH
( )n
OH
( )n
K2CO3, MeOH
r.t.
TsCl, DMAP
OMe
OMe
OMe
( )n
pyridine, r.t.
O
O
TMS
O
3a n = 1 68%
4a n = 2 57%
13 n = 1 96%
14 n = 2 92%
11 n = 1 92%
12 n = 2 99%
H
5
H
OH
10 mol% Pd(PPh3)4
10 mol% CuI
LiOH
MeOH, 0 °C
OMe
( )n
( )n
O
H
O
i-Pr2NH, benzene, r.t.
H
15 n = 1 80%
16 n = 2 67%
phomallenic acid B (1) n = 1 85%
phomallenic acid C (2) n = 2 72%
Scheme 3
Synthesis 2008, No. 7, 1099–1105 © Thieme Stuttgart · New York

PAPER
Total Syntheses of Phomallenic Acids B and C
1101
OH
CAL, vinyl acetate
OMe
Et2O, r.t., 50 min
O
( )-13
OAc
H
OH
OMe
OMe
+
H
O
O
(–)-3b
32%, 90% ee
(+)-13
44%, 66% ee
(R)- or (S)-MTPA
DCC, DMAP
OH
H
K2CO3, MeOH
r.t., 98%
OMe
O
(–)-3b
CH2Cl2, r.t.
(–)-13
∆δ = δS–δR
OMTPA
+0.045
H
(Ph)
(S,S)
(R,S)
(OMe)
Ph
OMe
MeO
O
H
O
MeO2C
( )4
–0.107
CF3
(R,S)-(+)-17 98%
(S,S)-(–)-17 96%
–0.019
H
O
+0.033
X
H
TsCl or ClCO2Me
DMAP, pyridine
OMe
(–)-13
r.t.
O
(–)-3a X = OTs 65%
(–)-3c X = OCO2Me 87%
Scheme 4
reactive toward the palladium complexes compared to the ic,3 which underscores the instability of the allenic moi-
tri- and tetrasubstituted allenes.12
eties, and thus the biological activities could be due to the
racemic form.
In conclusion, we have completed the total syntheses of
( )-phomallenic acids B and C (1 and 2) utilizing palladi-
um-catalyzed coupling of propargylic tosylates with a
diyne to furnish the core diyne-allene unit. Our attempts
to realize the asymmetric synthesis utilizing enantiospe-
cific coupling of optically active propargylic compounds
were unsuccessful. However, it has been recently reported
that the isolated natural compounds are also nearly racem-
All nonaqueous reactions were carried out under a positive atmo-
sphere of argon in dried glassware unless otherwise indicated. Ma-
terials were obtained from commercial suppliers and used without
further purification except when otherwise noted. Solvents were
dried and distilled according to standard protocols. Hepta-1,3-diyne
(5) was prepared by following the literature procedure.13
Table 1 Conditions for the Enantiospecific Coupling
H
cat. Pd(0)
X
10 mol% CuI, i-Pr2NH
OMe
OMe
+
solvent, r.t.
H
O
O
H
15
5
3a–c
Entry
X
Palladium catalyst
10 mol% Pd(PPh3)4
Additive
–
Solvent
benzene
dioxane
Yield (%)
ee (%)
1
2
OTs (3a)
OTs (3a)
80
53
0
0
5 mol% Pd2(dba)3·CHCl3,
20 mol% dppe
–
3
4
5
OTs (3a)
10 mol% Pd(PPh3)4
10 mol% Pd(PPh3)4
10 mol% Pd(PPh3)4
ZnCl2
LiCl
THF
63
0
–
0
OAc (3b)
benzene
THF
N.R.
45
OCO2Me (3c)
LiCl
Synthesis 2008, No. 7, 1099–1105 © Thieme Stuttgart · New York

1102
M. Yoshida et al.
PAPER
L
I
+
Pd
H
L
L
PdLn
H
I
L
Pd
H
Pd
R
H
P+dLn
Pd
R
Pd
R
R
R
L
H
Pd
I
H
H
H
H
H
L
(R)-18
19
20
21
(S)-18
R'
R
+
Pd
+
Pd
H
Pd(II)
I–
H
+
Pd
H
R
H
R
R
R'
R
R
·
H
R'
H
Pd(II)
I–
H
R'
H
I
I
I
H
H
(R)-22
23
24
25
(S)-22
Scheme 5
10-Trimethylsilyl-8-oxodec-9-ynoic Acid Methyl Ester (9)
1H NMR (400 MHz, CDCl3): d = 4.35 (1 H, m), 3.67 (3 H, s), 2.31
(2 H, t, J = 8.0 Hz), 1.80–1.76 (1 H, m), 1.72–1.62 (4 H, m), 1.48–
1.42 (2 H, m), 1.37–1.33 (4 H, m), 0.17 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 174.4, 107.1, 89.3, 62.6, 60.5,
51.6, 37.7, 34.2, 29.1, 25.0, 24.9, 0.0.
HRMS (ESI): m/z calcd for C14H26NaO3Si (M+ + Na): 293.1549;
found: 293.1548.
To a stirred solution of suberic acid monomethyl ester (6; 5.0 g, 26.6
mmol) in benzene (40 mL) cooled to 5 °C were added oxalyl dichlo-
ride (2.78 mL, 31.9 mmol) and DMF (0.21 mL, 2.66 mmol). A vig-
orous evolution of CO2 was observed immediately. After stirring
the mixture for 1 h at r.t., it was filtered through a pad of Celite, fol-
lowed by solvent removal under reduced pressure to give a colorless
oil. Distillation under reduced pressure (bp 98–101 °C/4.5 mmHg)
gave the acid chloride as a colorless oil. To a stirred solution of this
acid chloride and bis(trimethylsilyl)acetylene (8; 3.29 mL, 14.5
mmol) in CH2Cl2 was added AlCl3 (2.90 g, 21.78 mmol) portion-
wise over 0.5 h at 0 °C. After stirring the mixture for 3 h at the same
temperature, it was filtered through a pad of Celite. The filtrate was
shaken with cold aq 10% HCl and the organic layer was extracted
with CH2Cl2 (3 × 100 mL). The combined extracts were washed
with brine (50 mL) and dried (MgSO4). Concentration under re-
duced pressure gave the residue, which was chromatographed on
silica gel with hexane–EtOAc (90:10) as eluent to give the alkynyl
ketone 9 (4.27 g, 2 steps 68%) as a yellow oil.
8-Hydroxydec-9-ynoic Acid Methyl Ester (13)
To a stirred solution of propargyl alcohol 11 (1.00 g, 3.70 mmol) in
MeOH (30 mL) was added K2CO3 (1.02 g, 7.38 mmol) at r.t., and
the stirring was continued for 1.5 h at the same temperature. The
mixture was diluted with H2O (60 mL) and extracted with EtOAc
(3 × 60 mL). The combined extracts were washed with brine (60
mL) and dried (MgSO4). Concentration under reduced pressure
gave a colorless oil, which was chromatographed on silica gel with
hexane–EtOAc (70:30) as eluent to give the desilylated propargylic
alcohol 13 (701 mg, 96%) as a colorless oil.
IR (neat): 3440, 3292, 2938, 2859, 2106, 1735 cm–1.
IR (neat): 2949, 2860, 2150, 1740, 1677, 1436 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.37 (1 H, m), 3.67 (3 H, s), 2.46
(1 H, d, J = 2.0 Hz) 2.31 (2 H, t, J = 7.6 Hz), 1.86–1.82 (1 H, m),
1.74–1.60 (4 H, m), 1.48–1.45 (2 H, m), 1.36–1.33 (4 H, m).
13C NMR (100 MHz, CDCl3): d = 174.3, 85.0, 72.6, 61.9, 51.4, 37.4,
33.9, 28.8, 28.7, 24.7, 24.6.
HRMS (ESI): m/z calcd for C11H18NaO3 (M+ + Na): 221.1154;
found: 221.1153.
1H NMR (400 MHz, CDCl3): d = 3.67 (3 H, s), 2.55 (2 H, t, J = 7.2
Hz), 2.30 (2 H, t, J = 7.6 Hz), 1.68–1.57 (4 H, m), 1.37–1.31 (4 H,
m), 0.24 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 188.6, 174.9, 102.8, 98.4, 52.2,
45.9, 34.7, 29.5, 29.3, 25.4, 24.4, 0.0.
HRMS (ESI): m/z calcd for C14H24NaO3Si (M+ + Na): 291.1392;
found: 291.1397.
8-(Toluene-4-sulfonyloxy)dec-9-ynoic Acid Methyl Ester (3a)
To a stirred solution of desilylated propargylic alcohol 13 (500 mg,
2.52 mmol) and DMAP(30.8 mg, 0.252 mmol) in pyridine (18 mL)
was added TsCl (3.36 g, 17.64 mmol) at r.t., and the stirring was
continued for 15 h at the same temperature. The mixture was diluted
with H2O (30 mL) and extracted with EtOAc (3 × 50 mL). The com-
bined extracts were washed with aq sat. NH4Cl and dried (MgSO4).
After removal of the solvent under reduced pressure, the residue
was chromatographed on silica gel with hexane–EtOAc (75:25) as
eluent to give the propargylic tosylate 3a (604 mg, 68%) as a color-
less oil.
8-Hydroxy-10-trimethylsilyldec-9-ynoic Acid Methyl Ester (11)
To a stirred solution of alkynyl ketone 9 (1.50 g, 5.59 mmol) in
MeOH (40 mL) was added CeCl3 (1.52 g, 6.15 mmol) at r.t. After
stirring the mixture for 10 min at the same temperature, it was
cooled to –50 °C and then NaBH4 (317 mg, 8.39 mmol) was added.
The mixture was stirred for an additional 10 min at the same tem-
perature, then diluted with H2O (80 mL), and extracted with
CH2Cl2. The combined organic extracts were washed with brine (80
mL) and dried (MgSO4). Concentration under reduced pressure
gave a colorless oil, which was chromatographed on silica gel with
hexane–EtOAc (75:25) as eluent to give the propargylic alcohol 11
(1.40 g, 92%) as a colorless oil.
IR (neat): 3277, 2936, 2861, 2107, 1735, 1597, 1490 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.82 (2 H, d, J = 8.4 Hz), 7.34 (2
H, d, J = 8.4 Hz), 5.07–5.03 (1 H, m), 3.67 (3 H, s), 2.45 (3 H, s),
IR (neat): 3450, 2939, 2859, 2170, 1740, 1437 cm–1.
Synthesis 2008, No. 7, 1099–1105 © Thieme Stuttgart · New York

PAPER
Total Syntheses of Phomallenic Acids B and C
1103
2.41 (1 H, d, J = 2.0 Hz), 2.29 (2 H, t, J = 7.2 Hz), 1.86–1.76 (2 H,
HRMS (ESI): m/z calcd for C15H26NaO3Si (M+ + Na): 305.1549;
m), 1.61–1.57 (2 H, m), 1.44–1.39 (2 H, m), 1.30–1.26 (4 H, m).
found: 305.1551.
13C NMR (100 MHz, CDCl3): d = 174.0, 144.8, 133.8, 129.6, 128.0,
9-Hydroxy-11-trimethylsilylundec-10-ynoic Acid Methyl Ester
(12)
By following the same procedure described for 11, propargylic al-
cohol 12 was prepared from alkynyl ketone 10: yield: 99%; color-
less oil.
IR (neat): 3437, 2934, 2857, 2170, 1741, 1437 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.35 (1 H, q, J = 5.6 Hz), 3.67 (3
H, s), 2.30 (2 H, t, J = 7.6 Hz), 1.78–1.74 (1 H, m), 1.73–1.60 (4 H,
m), 1.58–1.45 (4 H, m), 1.46–1.32 (4 H, m), 0.18 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 174.5, 107.1, 89.3, 62.9, 51.9,
37.7, 34.2, 31.7, 29.2, 29.1, 25.1, 22.7, 0.0.
78.9, 76.1, 70.9, 51.4, 35.5, 33.9, 28.7, 28.4, 24.7, 24.2, 21.6.
HRMS (ESI): m/z calcd for C18H24NaO5S (M+ + Na): 375.1242;
found: 375.1234.
( )-Phomallenic Acid B Methyl Ester (15)
To a stirred solution of hepta-1,3-diyne (5; 62.7 mg, 0.681 mmol) in
i-Pr2NH (2 mL) was added Pd(PPh3)4 (26.2 mg, 0.023 mmol) and
CuI (8.60 mg, 0.045 mmol) at r.t. A solution of the propargylic to-
sylate 3a (80.0 mg, 0.227 mmol) in benzene (2 mL) was then added
dropwise to the stirred solution for 30 min at the same temperature.
After stirring for 15 min, the resulting mixture was filtered through
a pad of Celite followed by removal of the solvent under reduced
pressure. The residue was chromatographed on silica gel with hex-
ane–EtOAc–Et3N (95:4:1) as eluent to give the phomallenic acid B
methyl ester (15) (49.4 mg, 80%) as a yellowish oil.
HRMS (ESI): m/z calcd for C15H28NaO3Si (M+ + Na): 307.1705;
found: 307.1714.
9-Hydroxyundec-10-ynoic Acid Methyl Ester (14)
By following the same procedure described for 13, desilylated pro-
pargylic alcohol 14 was prepared from propargylic alcohol 12:
yield: 92%; colorless oil.
IR (neat): 2932, 2857, 2219, 1937, 1738 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.44 (1 H, q, J = 6.8 Hz), 5.39–
5.34 (1 H, m), 3.67 (3 H, s), 2.32–2.26 (4 H, m), 2.07–2.01 (2H, m),
1.66–1.52 (4 H, m), 1.44–1.40 (2 H, m), 1.34–1.30 (4 H, m), 0.99 (3
H, t, J = 7.9 Hz).
13C NMR (100 MHz, CDCl3): d = 214.2, 174.2, 93.7, 83.6, 75.2,
74.5, 68.4, 65.3, 51.4, 34.0, 29.6, 29.0, 28.9, 28.5, 27.9, 24.8, 21.7,
13.4.
IR (neat): 3436, 3292, 2933, 2857, 2117, 1736, 1437 cm–1.
1H NMR (400 MHz, CDCl3): = 4.39–4.34 (1 H, m), 3.67 (3 H, s),
2.46 (1 H, d, J = 2.4 Hz), 2.30 (2 H, t, J = 7.2 Hz), 1.79–1.76 (1 H,
m), 1.74–1.62 (4 H, m), 1.60–1.53 (2 H, m), 1.47–1.42 (2 H, m),
1.36–1.32 (4 H, m).
13C NMR (100 MHz, CDCl3): = 174.3, 85.0, 72.7, 62.1, 60.4, 51.4,
37.5, 33.9, 29.0, 28.9, 24.8, 24.7.
HRMS (ESI): m/z calcd for C18H24NaO2 (M+ + Na): 295.1674;
found 295.1675.
HRMS (ESI): m/z calcd for C12H20NaO3 (M+ + Na): 235.1310;
found: 235.1315.
( )–Phomallenic Acid B (1)
To a stirred solution of phomallenic acid B methyl ester (15; 10.0
mg, 0.037 mmol) in MeOH–H2O (3:1, 1.0 mL) was added LiOH
(15.5 mg, 0.37 mmol) at 0 °C, and the stirring was continued for 5
h at r.t. The mixture was quenched with aq sat. NH4Cl and extracted
with Et2O (3 × 10 mL). The combined extracts were washed with
brine (5 mL) and dried (MgSO4). After removal of the solvent under
reduced pressure, the residue was chromatographed on silica gel
with hexane–Et2O (50:50) as eluent to give ( )-phomallenic acid B
(1) (8.0 mg, 85%) as a yellowish oil.
9-(Toluene-4-sulfonyloxy)undec-10-ynoic Acid Methyl Ester
(4a)
By following the same procedure described for 3a, propargylic to-
sylate 4a was prepared from propargylic alcohol 14: yield: 57%;
colorless oil.
IR (neat): 3278, 2933, 2858, 2117, 1735, 1597, 1490, 1436 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.82 (2 H, d, J = 8.0 Hz), 7.33 (2
H, d, J = 8.0 Hz), 5.07–5.03 (1 H, m), 3.67 (3 H, s), 2.45 (3 H, s),
2.4 (1 H, d, J = 2.0 Hz), 2.29 (2 H, t, J = 7.6 Hz), 1.82–1.78 (2 H,
m), 1.62–1.57 (2 H, m), 1.42–1.39 (2 H, m), 1.30–1.26 (6 H, m).
13C NMR (100 MHz, CDCl3): d = 174.2, 144.8, 133.9, 129.0, 128.0,
79.0, 76.1, 76.0, 71.0, 51.4, 35.5, 33.9, 28.9, 28.5, 24.8, 24.4, 21.6.
IR (neat): 3600–3350 (br), 2924, 2855, 2215, 1945, 1710, 1462
cm–1.
1H NMR (400 MHz, CD3CN): d = 8.80 (1 H, br s), 5.53 (1 H, q,
J = 6.8 Hz), 5.47–5.40 (1 H, m), 2.30 (2 H, br t, J = 4.0 Hz), 2.23 (2
H, t, J = 7.2 Hz), 2.03 (2 H, dq, J = 6.8, 4.0 Hz), 1.55–1.46 (4 H, m),
1.44–1.26 (6 H, m), 0.95 (3 H, t, J = 7.6 Hz).
HRMS (ESI): m/z calcd for C19H26NaO5S (M+ + Na): 389.1399;
found: 389.1387.
13C NMR (100 MHz, CD3CN): d = 215.0, 175.1, 94.5, 85.1, 75.7,
75.1, 69.5, 65.7, 33.9, 29.4, 29.2, 29.0, 28.5, 25.4, 22.2, 21.5, 13.5.
HRMS (ESI): m/z calcd for C17H22NaO2 (M+ + Na): 281.1517;
( )-Phomallenic Acid C Methyl Ester (16)
By following the same procedure described for 15, phomallenic
acid C methyl ester (16) was prepared from propargylic tosylates
4a: yield: 67%; yellowish oil.
IR (neat): 2931, 2856, 2230, 1945, 1739, 1435 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.44 (1 H, q, J = 6.8 Hz), 5.39–
5.35 (1 H, m), 3.67 (3 H, s), 2.33–2.27 (4 H, m), 2.07–2.01 (2 H, m),
1.64–1.52 (6 H, m), 1.44–1.40 (2 H, m), 1.31–1.26 (4 H, m), 0.99 (3
H, t, J = 7.6 Hz).
13C NMR (100 MHz, CDCl3): d = 214.3, 174.2, 93.8, 83.7, 75.2,
68.5, 65.9, 65.4, 53.4, 51.5, 34.0, 28.6, 28.0, 24.9, 21.7, 21.5, 15.3,
14.1, 13.5.
found: 281.1522.
11-Trimethylsilyl-9-oxoundec-10-ynoic Acid Methyl Ester (10)
By following the same procedure described for 9, alkynyl ketone 10
was prepared from azelaic acid monomethyl ester 7; yield for 2
steps: 67%; yellowish oil.
IR (neat): 2935, 2857, 2150, 1740, 1676, 1436 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.67 (3 H, s), 2.54 (2 H, t, J = 7.2
Hz), 2.30 (2 H, t, J = 7.6 Hz), 1.67–1.58 (4 H, m), 1.31–1.25 (6 H,
m), 0.24 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 188.6, 174.9, 102.8, 98.3, 52.2,
45.9, 34.8, 29.7, 29.5, 25.6, 24.6, 23.1, 0.0.
HRMS (ESI): m/z calcd for C19H26NaO2 (M+ + Na): 309.1831;
found: 309.1837.
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1104
M. Yoshida et al.
PAPER
( )-Phomallenic Acid C (2)
(5 mL) and dried (MgSO4). After concentration under reduced pres-
sure, the residue was chromatographed on silica gel with hexane–
EtOAc (70:30) as eluent to give the (R)-MTPA ester (R,S)-(+)-17;
yield: 24.6 mg (98%); colorless oil; [a]D25 +9.36 (c 1.90, CHCl3).
By following the same procedure described for 1, ( )-phomallenic
acid C (2) was prepared from phomallenic acid C methyl ester (16):
yield: 72%; yellowish oil.
IR (neat): 3600–3350 (br), 2930, 2858, 2219, 1948, 1708, 1457
cm–1.
1H NMR (400 MHz, CD3CN): d = 9.0–8.6 (1 H, br s), 5.53 (1 H, q,
J = 6.4 Hz), 5.47–5.41 (1 H, m), 2.30 (2 H, t, J = 8.0 Hz), 2.23 (2 H,
t, J = 7.6 Hz), 2.10–2.01 (2 H, m), 1.55–1.48 (4 H, m), 1.45–1.26 (8
H, m), 0.95 (3 H, t, J = 6.0 Hz).
13C NMR (100 MHz, CD3CN): d = 215.0, 175.1, 94.7, 85.2, 75.4,
75.0, 69.3, 65.6, 34.1, 29.7, 29.6, 29.46, 29.2, 28.7, 25.5, 22.5, 21.6,
13.7.
IR (neat): 3291, 2947, 2858, 2130, 1834, 1749, 1498, 1452 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.54–7.52 (2 H, m), 7.42–7.34 (3
H, m), 5.50 (1 H, dt, J = 2.0, 6.8 Hz), 3.67 (3 H, s), 3.55 (3 H, s),
2.49 (1 H, d, J = 2.0 Hz), 2.30 (2 H, t, J = 7.6 Hz), 1.89–1.80 (2 H,
m), 1.63–1.57 (2 H, m), 1.49–1.42 (2 H, m), 1.34–1.24 (4 H, m).
HRMS (ESI): m/z calcd for C21H25F3NaO5 (M+ + Na): 437.1552;
found: 437.1558.
(S)-MTPA Ester [(S,S)-(–)-17]
By following the same procedure described for (R,S)-(+)-17, (S)-
MTPA ester (S,S)-(–)-17 was prepared from (–)-propargylic alcohol
(–)-13 with (S)-MTPA: yield 96%; colorless oil; [a]D25 –52.21 (c
1.10, CHCl3).
HRMS (ESI): m/z calcd for C18H24NaO2 (M+ + Na): 295.1674;
found: 295.1677.
Optical Resolution of Propargyl Alcohol ( )-13
To a stirred solution of propargylic alcohol ( )-13 (536 mg, 2.70
mmol) and enzyme lipase CAL (1.07 g, 5.41 mmol) in Et2O (10
mL) was added vinyl acetate (0.25 mL, 2.70 mmol) at r.t. After stir-
ring for 50 min, the resulting solution was filtered through a pad of
Celite, followed by removal of the solvent under reduced pressure.
The residue was chromatographed on silica gel with hexane–EtOAc
(75:25) as eluent to give the propargylic acetate (–)-3b (208 mg,
32%) and the propargyl alcohol (+)-13 (236 mg, 44%) as colorless
oils.
IR (neat): 3304, 2929, 2853, 2129, 1832, 1752, 1497, 1453 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.56–7.53 (2 H, m), 7.43–7.34 (3
H, m), 5.53 (1 H, dt, J = 2.0, 6.4 Hz), 3.67 (3 H, s), 3.60 (3 H, s),
2.54 (1 H, d, J = 2.0 Hz), 2.28 (2 H, t, J = 7.6 Hz), 1.82–1.76 (2 H,
m), 1.63–1.56 (4 H, m), 1.34–1.24 (4 H, m).
HRMS (ESI): m/z calcd for C21H25F3NaO5 (M+ + Na): 437.1552;
found: 437.1552.
8-(Toluene-4-sulfonyloxy)dec-9-ynoic Acid Methyl Ester
[(–)-3a]
By following the same procedure described for 3a, optically active
propargyl tosylate (–)-3a was prepared from propargylic alcohol
(–)-13: yield 65%; colorless oil; [a]D25 –36.23 (c 1.00, CHCl3) as a
colorless oil. Other spectral data coincide with those of racemic 3a.
(–)-8-Acetoxydec-9-ynoic Acid Methyl Ester (–)-3b
Yield: 32%; ee: 90%; [a]D25 –49.67 (c 0.92, CHCl3). Enantiomeric
excess was determined by preparing the MTPA ester 17.
IR (neat): 3287, 2936, 2860, 2129, 1740, 1436 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.36–5.32 (1 H, m), 3.67 (3 H, s),
2.45 (1 H, d, J = 2.0 Hz), 2.30 (2 H, t, J = 7.2 Hz), 2.10 (3 H, s),
1.80–1.72 (2 H, m), 1.67–1.54 (2 H, m), 1.47–1.42 (2 H, m), 1.38–
1.32 (4 H, m).
13C NMR (100 MHz, CDCl3): d = 174.2, 169.9, 81.2, 73.4, 63.7,
51.4, 34.4, 33.9, 29.0, 28.7, 24.8, 24.7, 20.9.
HRMS (ESI): m/z calcd for C13H20NaO4 (M+ + Na): 263.1259;
found: 263.1266.
(–)-8-Methoxycarbonyloxydec-9-ynoic Acid Methyl Ester
[(–)-3c]
To a stirred solution of (–)-propargylic alcohol (–)-13 (40 mg, 0.202
mmol) and a catalytic amount of DMAP in pyridine (2 mL) was
added methyl chlorocarbonate (93.5 mL, 1.21 mmol) at 0 °C, and the
temperature of the mixture was gradually allowed to attain r.t. After
stirring for 22 h at the same temperature, the mixture was diluted
with H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The com-
bined extracts were washed with aq sat. NH4Cl (10 mL) and brine
(10 mL), and dried (MgSO4). After removal of the solvent, the res-
idue was chromatographed on silica gel with hexane–EtOAc
(75:25) as eluent to give the (–)-propargylic carbonate (–)-3c (45.2
mg, 87%) as a colorless oil; [a]D25 –32.69 (c 0.90, CHCl3).
(+)-8-Hydroxydec-9-ynoic Acid Methyl Ester [(+)-13]
Yield: 44%; ee: 66%; [a]D25 +2.77 (c 0.97, CHCl3). Other spectral
data coincides with those of racemic 13. Enantiomeric excess was
determined by preparing the MTPA ester 17.
IR (neat): 3303, 2938, 2859, 2123, 1749, 1442 cm–1.
(–)-8-Hydroxydec-9-ynoic Acid Methyl Ester [(–)-13]
To a stirred solution of (–)-propargylic acetate (–)-3b (160 mg,
0.666 mmol) in MeOH (10 mL) was added K2CO3 (276 mg, 2.0
mmol) at r.t., and the stirring was continued at the same temperature
for 1 h. The mixture was diluted with H2O (20 mL) and extracted
with EtOAc (3 × 20 mL). The combined extracts were washed with
brine (20 mL) and dried (MgSO4). After concentration under re-
duced pressure, the resulting residue was chromatographed on silica
gel with hexane–EtOAc (70:30) as eluent to give the (–)-propargyl-
ic alcohol (–)-13 (129 mg, 98%) as a colorless oil; [a]D25 –4.57 (c
1.10, CHCl3). Other spectral data coincide with those of racemic 13.
1H NMR (400 MHz, CDCl3): d = 5.21–5.17 (1 H, m), 3.81 (3 H, s),
3.67 (3 H, s), 2.50 (1 H, d, J = 2.4 Hz), 2.30 (2 H, t, J = 7.6 Hz),
1.85–1.78 (2 H, m), 1.64–1.59 (2 H, m), 1.49–1.46 (2 H, m), 1.35–
1.32 (4 H, m).
13C NMR (100 MHz, CDCl3) d = 174.1, 154.9, 80.2, 75.6, 68.5,
53.6, 35.2, 34.4, 33.9, 28.9, 25.8, 24.7, 23.5.
HRMS (ESI): m/z calcd for C13H20NaO5 (M+ + Na): 279.1208;
found: 279.1213.
Coupling of Optically Active Propargyl Compound 3 with
Diyne 5; Reaction of 3a in the Presence of ZnCl2 (Table 1, Entry
3)
To a stirred solution of ZnCl2 (26.7 mg, 0.196 mmol) in THF (1 mL)
was added Pd(PPh3)4 (7.50 mg, 7.0 mmol), CuI (2.50 mg, 0.013
mmol), and hepta-1,3-diyne (5; 18.0 mg, 0.195 mmol) in i-Pr2NH
(1 mL) at r.t., and the stirring was continued for 5 min at the same
temperature. Then a solution of (–)-propargylic tosylate (–)-3a
(R)-MTPA Ester [(R,S)-(+)-17]
To a stirred solution of (–)-propargyl alcohol (–)-13 (12.0 mg, 0.061
mmol) in CH2Cl2 (2 mL) was added (R)-MTPA (21.3 mg, 0.091
mmol), DCC (25.0 mg, 0.121 mmol), and a catalytic amount of
DMAP at r.t. After stirring for 1.5 h at the same temperature, the
mixture was added to aq sat. NH4Cl (5 mL) and extracted with
EtOAc (3 × 10 mL). The combined extracts were washed with brine
Synthesis 2008, No. 7, 1099–1105 © Thieme Stuttgart · New York

PAPER
Total Syntheses of Phomallenic Acids B and C
1105
(23.0 mg, 0.065 mmol) in THF (1 mL) was added dropwise to the
stirred solution over 30 min at the same temperature. After stirring
for 15 min, the resulting solution was filtered through a pad of
Celite. Concentration of the solvent under reduced pressure gave a
residue, which was chromatographed on silica gel with hexane–
EtOAc–Et3N (95:4:1) as eluent to give the phomallenic acid B
methyl ester (15) (11.2 mg, 63%, 0% ee) as a yellowish oil. Enantio-
meric excess was determined on chiral column by HPLC analysis
(CHIRALCEL OB-H column, 5% i-PrOH–hexane, 1.0 mL/min,
l = 254 nm, 25 °C, tR = 10.8 min and 12.2 min).
(2) Young, K.; Jayasuriya, H.; Ondeyka, J. G.; Herath, K.;
Zhang, C.; Kodali, S.; Galgoci, A.; Painter, R.; Brown-
Driver, V.; Yamamoto, R.; Silver, L. L.; Zheng, Y.; Ventura,
J. I.; Sigmund, J.; Ha, S.; Basilio, A.; Vicente, F.; Tormo, J.
R.; Pelaez, F.; Youngman, P.; Cully, D.; Barrett, J. F.;
Schmatz, D.; Singh, S. B.; Wang, J. Antimicrob. Agents
Chemother. 2006, 50, 519.
(3) Very recently Wu and co-workers reported the first total
synthesis of phomallenic acid C: Jian, Y.-J.; Tang, C.-J.;
Wu, Y. J. Org. Chem. 2007, 72, 4851.
(4) (a) Yoshida, M.; Hayashi, M.; Shishido, K. Org. Lett. 2007,
9, 1643. (b) Dixneuf, P. H.; Guyot, T.; Ness, M. D.; Roberts,
S. M. Chem. Commun. 1997, 2083.
Coupling of Optically Active Propargyl Compound 3 with
Diyne 5; Reaction of 3c in the Presence of LiCl (Table 1, Entry
5)
(5) The enantiospecific synthesis of 1,3-disubstituted allenes by
palladium-catalyzed coupling of optically active propargylic
compounds with organoboron compounds has been
reported: (a) Yoshida, M.; Okada, T.; Shishido, K.
Tetrahedron 2007, 63, 6996. (b) Molander, G. A.;
Sommers, E. M.; Baker, S. R. J. Org. Chem. 2006, 71, 1563.
(c) Yoshida, M.; Gotou, T.; Ihara, M. Tetrahedron Lett.
2004, 45, 5573.
(6) Tueting, D. R.; Echavarren, A. M.; Stille, J. K. Tetrahedron
1989, 45, 979.
(7) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
To a stirred solution of Pd(PPh3)4 (8.0 mg, 0.007 mmol), CuI (3.0
mg, 0.0156 mmol), LiCl (6.7 mg, 0.156 mmol), and i-Pr2NH (0.22
mL, 1.56 mmol) in THF (1 mL) was added aq solution of the prop-
argyl carbonate (–)-3c (20.0 mg, 0.078 mmol) and hepta-1,3-dyine
(5; 28.8 mg, 0.312 mmol) in THF (1.5 mL) at r.t. After stirring for
30 min at the same temperature, the mixture was filtered through a
pad of Celite followed by removal of the solvent under reduced
pressure. The residue was chromatographed on silica gel with hex-
ane–EtOAc–Et3N (95:4:1) as eluent to give the phomallenic acid B
methyl ester (15) (10.1 mg, 45%, 0% ee) as a yellowish oil.
(8) Condon-Gueugnot, S.; Linstrumelle, G. Tetrahedron 2000,
56, 1851.
Acknowledgment
(9) Mandai, T.; Nakata, T.; Murayama, H.; Yamaoki, H.;
Ogawa, M.; Kawada, M.; Tsuji, J. Tetrahedron Lett. 1990,
31, 7179.
(10) Ogoshi, S.; Nishida, T.; Shinagawa, T.; Kurosawa, H. J. Am.
Chem. Soc. 2001, 123, 7164.
(11) Horváth, A.; Bäckvall, J. E. Chem. Commun. 2004, 964.
(12) Molander et al. reported the racemization of chiral
alkenylallenes in the palladium-catalyzed coupling of
propargylic phosphates with alkenyl trifluoroborates; see
ref. 5b.
This study was supported in part by a Grant-in-Aid for the Encou-
ragement of Young Scientists (B) from the Japan Society for the
Promotion of Science (JSPS), Takeda Science Foundation, Uehara
Memorial Foundation, and Astellas Foundation for Research on
Medicinal Resources.
References
(1) Ondeyka, J. G.; Zink, D. L.; Young, K.; Painter, R.; Kodali,
S.; Galgoci, A.; Collado, J.; Tormo, J. R.; Basilio, A.;
Vicente, F.; Wang, J.; Singh, S. B. J. Nat. Prod. 2006, 69,
377.
(13) Seigel, K.; Brückner, R. Chem. Eur. J. 1998, 4, 1116.
Synthesis 2008, No. 7, 1099–1105 © Thieme Stuttgart · New York