Succinylation of Tertiary Alcohols under High Pressure

Article abstract of DOI:10.1055/s-2001-14564

The efficient succinylation of the sterically hindered tertiary alcohols 1 was performed by reaction with succinic acid monomethyl and monoallyl ester (4a and 4b), respectively, in CH2Cl2 in the presence of dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine under high pressure to give the methyl and allyl succinates 5a and 5b, respectively, in high yields. The succinates 5a,b were efficiently converted into the hemisuccinate 3a by treatment with lithium propyl mercaptide or by palladium(0)-catalyzed deallylation.

Full text of DOI:10.1055/s-2001-14564

PAPER
1027
Succinylation of Tertiary Alcohols under High Pressure
Succinylation
o
a
Tertiary A
k
lcohols
U
nd
e
e
r
High Pre
s
ssure hi Shimizu,* Katsuya Hiramoto, Tadashi Nakata*
RIKEN (The Institute of Physical and Chemical Research), Wako, Saitama 351–0198, Japan
Fax +81(48)4624666; E-mail: tshimizu@postman.riken.go.jp; nakata@postman.riken.go.jp
Received 22 January 2001; revised 21 March 2001
thesis of the hemisuccinates 3a of the sterically hindered
tertiary alcohols 1 were further investigated. We now re-
port an efficient synthesis of the methyl and allyl succi-
nates 5a,b of the hindered tertiary alcohols 1 with succinic
Abstract: The efficient succinylation of the sterically hindered ter-
tiary alcohols 1 was performed by reaction with succinic acid
monomethyl and monoallyl ester (4a and 4b), respectively, in
CH2Cl2 in the presence of dicyclohexylcarbodiimide and 4-(dime-
thylamino)pyridine under high pressure to give the methyl and allyl acid monomethyl and monoallyl esters 4a,b in CH2Cl2 in
succinates 5a and 5b, respectively, in high yields. The succinates
5a,b were efficiently converted into the hemisuccinate 3a by treat-
ment with lithium propyl mercaptide or by palladium(0)-catalyzed
no)pyridine (DMAP) under high pressure (1.5 GPa) and
deallylation.
the presence of dicyclohexylcarbodiimide (DCC) or 1,3-
diisopropylcarbodiimide (DIC) and 4-(dimethylami-
the conversion of the succinates 5a,b into the hemisucci-
Key words: succinates, hemisuccinates, acylation, tertiary alco-
nates 3a (X = CH2CH2) (Scheme 2).
hols, high pressure
O
R1
R3
CO2R
DCC, DMAP
HO2C
OR
+
1
R2
O
Introduction and Background
CH2Cl2
O
4a: R = Me
b: R =allyl
1.5 GPa
5a: R = Me
b: R = allyl
Dicarboxylic acid monoester groups are unique substitu-
ents found in several biologically active natural products
such as reveromycins,1 (–)-A26771B,2 malolactomycin A
and B,3 etc. In addition, the dicarboxylic acid monoesters
attract much attention as the prodrugs of steroids,4 anthra-
cyclins,5,6 and taxol7–9 because of their water-soluble
property. Several methods for preparation of dicarboxylic
acid monoesters with cyclic anhydrides, acid chlorides
and carboxylate anions have been reported.4–9 However,
few methods are known for the acylation of sterically hin-
dered alcohols.10,11 We have already reported the one-step
and efficient synthesis of dicarboxylic acid monoesters
3a–c of sterically hindered alcohols 1 including tertiary
alcohols with cyclic anhydrides 2a–c in pyridine in the
presence of DMAP under high pressure (Scheme 1).12
Pd(Ph3P)4, Ph3P
pyrrolidine
(R = allyl)
n-PrSLi, HMPA
(R = Me)
3a
Scheme 2
Succinylation of Tertiary Alcohol
To develop more efficient methods for the succinylation,
several intermediates in the synthetic studies of reveromy-
cin A13,14 were chosen as the substrates having a sterically
hindered tertiary hydroxyl group. We first examined the
introduction of the hemisuccinate or succinate to the alco-
hol 715 derived from the known lactone 613 (Scheme 3).
These results are shown in Table 1 (entries 1–4). The ini-
tial attempt using our reported procedure under high pres-
sure (succinic anhydride 2a in pyridine in the presence of
DMAP at 1.5 GPa)12 resulted in the recovery of 7 (entry
1). 3-Methoxycarbonylpropionyl chloride (14) and the
mixed anhydride 15 (Figure 1) also did not give the de-
sired succinate 8 even under high pressure (entries 2 and
3). After several attempts, we found that the succinylation
of 7 with succinic acid monomethyl ester (4a) in the pres-
ence of DCC and DMAP in CH2Cl2 at 1.5 GPa proceeded
to give the methyl succinate 8 in 19% yield, with a 70%
recovery of 7 (entry 4). This result means that the method
using the succinic acid monomethyl ester (4a) and DCC
under high pressure is more efficient than our previous
procedure12 for the succinylation of hindered alcohols.
This new method was then applied to the alcohol 1016 hav-
ing an alkyne group in place of the CH2OBOM group. The
O
O
X
R1
R1
R3
DMAP, pyridine
1.5 GPa
+
R2
OH
R2
O
X
OH
O
R3
O
O
2a: X = -CH2CH2-
3a: X = -CH2CH2-
1
b: X = -CH2CH2CH2-
c: X = -CH2OCH2-
b: X = -CH2CH2CH2-
c: X = -CH2OCH2-
Scheme 1
However, in the synthetic studies of reveromycin A hav-
ing a tertiary alcohol hemisuccinate, we have encountered
difficulty in the acylation of the tertiary alcohol even us-
ing our developed method with cyclic anhydride under
high pressure. Thus, more efficient methods for the syn-
Synthesis 2001, No. 7, 01 06 2001. Article Identifier:
1437-210X,E;2001,0,07,1027,1034,ftx,en;F01101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1028
T. Shimizu et al.
PAPER
OR
O
CO2R
n-Bu
1. LAH, THF
HO2C
O
O
2. BOMCl, i-Pr2NEt
O
O
CH2Cl2
4a: R = Me
4b: R = allyl
n-Bu
2a
OBOM
O
O
Me
Cl
Cl
O
O
Me
Cl
CO2Me
O
CO2Me
Me
7: R =H
8: R = CO(CH2)2CO2Me
O
Me
Cl
O
O
6
14
15
OR
Figure 1 Acylating reagents
O
1. DIBAH, Et2O
2. CBr4, Ph3P
n-Bu
OMTM
O
n-Bu
OMe
2,6-lutidine, CH2Cl2
N
Me
chloride (14) and the mixed anhydride 15 did not react at
all with the tertiary hydroxyl group of 10 even under high
pressure and 10 was quantitatively recovered in every
case (entries 7, 8 and 9).
3. n-BuLi, THF
4. MeLi, NaHCO3
acetone, H2O
O
O
Me
O
Me
Me
Me
9
10: R =H
11: R = CO(CH2)2CO2Me
12: R = CO(CH2)2CO2allyl
13: R = CO(CH2)2CO2H
We next extended the acylation method using the succinic
acid monoester under high pressure to a variety of tertiary
alcohols such as linalool (16), -terpineol (20) and the
6,6-spiroacetal derivatives, 24,13 2613 and 2817 (Figure 2,
Table 2). The reactions of the acyclic alcohols 16 and 20
with succinic acid monomethyl ester (4a) smoothly pro-
ceeded to afford the methyl succinates 17 and 21 in 92%
and 92% yields, respectively (entries 1 and 3). The succin-
ic acid monoallyl ester (4b) also reacted with 16 and 20 to
give the corresponding allyl succinates 18 and 22 in 97%
and 95% yields, respectively (entries 2 and 4). In compar-
ison with the new method, 16 and 20 were converted into
the hemisuccinates in 66% and 79% yields along with the
recovered 16 and 20 by our previous procedure with suc-
cinic anhydride (2a) under high pressure.12 The reaction
Scheme 3
yield of the methyl succinate 11 increased to 77% yield,
which should be due to the reduced steric hindrance of the
alkyne group (entry 10). The succinic acid monoallyl ester
(4b) also afforded the allyl succinate 12 under the same
conditions in 75% yield (entry 11). The use of DIC in
place of DCC under high pressure was also effective for
producing 11 in a similar yield (entry 12), while the same
reaction did not proceed at atmospheric pressure (entry 6).
Succinic anhydride (2a), 3-methoxycarbonylpropionyl
Table 1 Succinylation of Tertiary Alcohols 7 and 10
Entry
Alcohol
Reagent
(equiv)
Additive
(equiv)
Solvent
Conditions
Succinatea Yield (%)
1
2
7
7
2a (5)
14 (2)
15 (5)
4a (5)
14 (2)
4a (2)
2a (5)
14 (2)
15 (2)
4a (3)
4b (3)
4a (3)
DMAP (0.1)
pyridine
pyridine
pyridine
CH2Cl2
pyridine
CH2Cl2
pyridine
pyridine
pyridine
CH2Cl2
CH2Cl2
CH2Cl2
1.5 GPa, r.t., 1 d
1.5 GPa, r.t., 1 d
1.5 GPa, r.t., 1 d
1.5 GPa, r.t., 3 d
r.t., 1 dd
8*
8
0b
0b
DMAP (0.1)
3
7
DMAP (0.1)
8
0b
4
7
DCC (5), DMAP (0.1)
DMAP (0.1)
8
19c
0b
5
10
10
10
10
10
10
10
10
11
6
DIC (2), DMAP (0.1)
DMAP (0.1)
r.t., 1 dd
11
11*
11
11
11
12
11
0b
7
1.5 GPa, r.t., 1 d
1.5 GPa, r.t., 1 d
1.5 GPa, r.t., 1 d
1.5 GPa, r.t., 2 d
1.5 GPa, r.t., 2 d
1.5 GPa, r.t., 2 d
0b
8
DMAP (0.1)
0b
9
DMAP (0.1)
0b
10
11
12
DCC (3), DMAP (0.1)
DCC (3), DMAP (0.1)
DIC (3), DMAP (0.1)
77e
75
71f
a 8* and 11* denote the corresponding hemisuccinates, respectively.
b The alcohol 7 was recovered in >90%.
c The alcohol 7 was recovered in 70%.
d The reaction was carried out at atmospheric pressure.
e The alcohol 10 was recovered in 10%.
f The alcohol 10 was recovered in 18%.
Synthesis 2001, No. 7, 1027–1034 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Succinylation of Tertiary Alcohols Under High Pressure
1029
Table 2 Succinylation of Tertiary Alcohols 16, 20, 24, 26 and 28 under High Pressure and Deprotection of the Succinates 17, 18, 21 and 22
Entry
Alcohol
Reagent
(equiv)
Additive
(equiv)
Solvent
Succinatea
Yield (%) Depro-
tectionb
Hemisuc- Yield (%)
cinate
1
2
3
4
5
6
7
8
16
16
20
20
24
24
26
28
4a (3)
4b (3)
4a (3)
4b (3)
2a (5)
4b (3)
4b (3)
4b (3)
DCC (3), DMAP (0.1)
DCC (3), DMAP (0.1)
DCC (3), DMAP (0.1)
DCC (3), DMAP (0.1)
DMAP (0.1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
pyridine
CH2Cl2
CH2Cl2
CH2Cl2
17
18
21
22
25*
25
27
29
92
97
92
95
0
A
B
A
B
19
19
23
23
(98)
(96)
(96)
(96)
DCC (3), DMAP (0.1)
DCC (3), DMAP (0.1)
DCC (3), DMAP (0.1)
85
76
74
a The reaction was carried out at 1.5 GPa at r.t. for 1 d. 25* denotes the corresponding hemisuccinate.
b A: PrSLi, HMPA, B: Pd(Ph3P)4, Ph3P, pyrrolidine.
Me
Me
Me OR
Me
OR
Me
Me
16: R = H
20: R = H
17: R = CO(CH2)2CO2Me
18: R = CO(CH2)2CO2allyl
19: R = CO(CH2)2CO2H
21: R = CO(CH2)2CO2Me
22: R = CO(CH2)2CO2ally
23: R = CO(CH2)2CO2H
OR
OR
H
OR
n-Bu
n-Bu
n-Bu
H
H
H
O
OMPM
O
OMPM
O
OMPM
O
O
O
H
H
TBDPSO
Me
TBDPSO
Me
TBDPSO
Me
26: R =H
27: R = CO(CH2)2CO2allyl
28: R =H
29: R = CO(CH2)2CO2allyl
24: R =H
25: R = CO(CH2)2CO2allyl
Me
Me
Me
OMPM
OMPM
OMPM
O
O
O
O
TBDPSOH2C
H
H
H
O
O
CH2OTBDPS
H
RO
n-Bu
n-Bu
n-Bu
OR
RO
H
CH2OTBDPS
Figure 2 Structures of compounds 16–29
of 24, having an axial hydroxyl group, with 2a resulted in
the recovery of 24 (entry 5). As expected, however, the
Conversion of Succinates into the Hemisuccinates
new method with succinic acid monoallyl ester (4b), DCC The hemisuccinates are essential groups for the biological
and DMAP under high pressure efficiently produced the activity and solubility of reveromycins and other pro-
desired succinate 25 in 85% yield (entry 6). The diastere- drugs. The conversions of the tertiary alcohol succinates
omers 26 and 28, having an equatorial hydroxyl group, into the hemisuccinates were then examined using the me-
also reacted with 4b, DCC and DMAP under high pres- thyl succinate 3018 and allyl succinate 3118 as the model
sure to give the corresponding succinates 27 and 29 in compounds (Figure 3). Treatment of the methyl succinate
76% and 74% yields, respectively, together with uniden- 30 with potassium trimethylsilanolate19 gave a mixture of
tified polar compounds (entries 7 and 8).
the acid 32 and 2-methly-1-phenylpropan-2-ol formed by
the non-selective hydrolysis. Lithium propyl mercaptide20
smoothly reacted with 30 to give the acid 32 by the selec-
Synthesis 2001, No. 7, 1027–1034 ISSN 0039-7881 © Thieme Stuttgart · New York

1030
T. Shimizu et al.
PAPER
pressure apparatus using a direct piston-cylinder equipment is capa-
ble of holding a 150 mL reaction volume at 1.5 GPa. The optical ro-
tations were measured using a Jasco DIP-370 digital polarimeter. IR
spectra were measured with a JASCO VALOR-III FT-IR spectrom-
tive O-alkyl cleavage of the methyl ester in 95% yield
(Method A). The method using lithium propyl mercaptide
could not be applied to the methyl sorbate (33), which cor-
responds to the side chain of reveromycin A, because the
competitive Michael addition reactions occurred. On the
other hand, the allyl ester 31 was efficiently converted
into the acid 32 by the palladium(0)-catalyzed hydro-
1
eter. H and 13C NMR spectra were recorded on a JEOL JNM-
EX270 (270 MHz and 67.5 MHz), JNM-GSX (500 MHz and 125
MHz), and JNM-ECP (500 MHz and 125 MHz). Chemical shifts
are reported in ppm relative to TMS (0 ppm) for the 1H NMR and to
the center of CDCl3 (77.0 ppm) for the 13C NMR as internal stan-
dards. Mass specta were recorded on Jeol JMA-HX110 and Shi-
madzu Kratos Maldi III mass spectrometers. Flash column
chromatography was performed using silica gel 60N (spherical,
neutral, 40–100 m) (Kanto Chemical Co. Inc.). HPLC was per-
formed using Sensyu Pak PEGASIL Silica 120–5 (300 250 mm)
(Sensyu Scientific Co., Ltd.).
21
genolysis of the allyl ester using Pd(Ph3P)4 or
Pd2(dba)3CHCl322 (Method B). The present methods using
lithium propyl mercaptide for the methyl succinates and
Pd(Ph3P)4 for the allyl succinates were applied to a variety
of succinates, 11, 12, 17, 18, 21 and 22 (Table 2, entries
1–4) to afford the corresponding hemisuccinates in almost
quantitative yields. The allyl succinates, 3414 and 3614,
having an unsaturated allyl ester were also effectively
converted into the hemisuccinates, 35 and 37, by the pal-
ladium(0)-catalyzed deallylation, respectively (Figure 3).
Succinylation of Tertiary Alcohols; Succinic Acid (1R)-1-Butyl-
1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]pent-4-ynyl Ester
Methyl Ester (11); Typical Procedure
In a 1 mL teflon vessel were placed 1016 (84.1 mg, 0.35 mmol), suc-
cinic acid monomethyl ester (4a; 138.7 mg, 1.05 mmol), DCC
(216.6 mg, 1.05 mmol) and DMAP (4 mg, 0.04 mmol). The vessel
was filled with CH2Cl2 and compressed to 1.5 GPa at r.t. for 2 d in
a high pressure instrument. The resulting mixture was diluted with
EtOAc (50 mL) and washed with 1 N HCl (1 mL), 2 N aq Na2CO3
(2 1 mL) and brine (2 5 mL). The organic layer was dried
(MgSO4), filtered and concentrated in vacuo. The residue was puri-
fied by column chromatography with hexane–EtOAc (2:1) to give
11 (91.7 mg, 77%) as a colorless oil and 10 (8.4 mg, 10%) (Table 1,
entry 10).
Me
Me
O
CO2Me
Me
Bn
O
CO2R
30: R = Me
31: R = allyl
32: R = H
33
O
O
O
H
CO2R
n-Bu
11
H
Rf 0.35 (hexane–EtOAc, 5:1); [ ]D –3.0 (c = 1.5, CHCl3).
O
OH
1H NMR (270 MHz, CDCl3): = 0.90 (t, J = 6.9 Hz, 3 H), 1.23–1.40
(m, 4 H), 1.32 (s, 3 H), 1.42 (s, 3 H), 1.84 (m, 2 H), 1.94 (dd, J = 2.6,
2.6 Hz, 1 H), 2.11 (m, 1 H), 2.22–2.40 (m, 3 H), 2.59 (m, 4 H), 3.69
(s, 3 H), 3.88 (dd, J = 8.7, 6.9 Hz, 1 H), 3.96 (dd, J = 8.7, 7.1 Hz, 1
H), 4.57 (dd, J = 7.1, 6.9 Hz, 1 H).
RO2C
Me
Me
34: R = allyl
35: R = H
13C NMR (67.5 MHz, CDCl3): = 13.4, 14.0, 23.1, 24.6, 25.4, 26.1,
28.9, 29.9, 32.6, 33.9, 51.8, 65.2, 68.1, 78.2, 84.1, 85.4, 109.0,
170.9, 172.3.
IR (neat): = 3289, 2958, 2936, 1736 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C19H30O6Na 377.1940, found
O
O
CO2R
H
n-Bu
Me
O
OH
RO2C
Me
O
377.1940.
H
Me
Succinylation of 10 with DIC
Following the typical procedure for the succinylation of 10, the al-
cohol 10 (48.0 mg, 0.2 mmol) was succinylated with DIC in place
of DCC to give 11 (48.3 mg, 71%) as a colorless oil and 10 (8.6 mg,
18%) (Table 1, entry 12).
36: R = allyl
37: R = H
Figure 3 Structures of compounds 30–37
Succinic Acid (1R)-5-Benzyloxy-1-butyl-1-[(4S)-2,2-dimethyl-
1,3-dioxolan-4-yl]pentyl Ester Methyl Ester (8)
Following the typical procedure for the succinylation of 10, the al-
cohol 715 (36.7 mg, 0.1 mmol) was succinylated to give 8 (8.9 mg,
19%) as a colorless oil and 7 (25.7 mg, 70%) (Table 1, entry 4).
Conclusion
In conclusion, we have found an efficient method for the
preparation of the methyl and allyl succinates of a variety
of sterically hindered tertiary alcohols by reaction with
succinic acid monoester in CH2Cl2 in the presence of DCC
and DMAP under high pressure. The methyl and allyl suc-
cinates were quantitatively converted into the hemisucci-
nates by treatment with lithium propyl mercaptide and by
palladium(0)-catalyzed deallylation, respectively.
8
Rf 0.60 (hexane–EtOAc, 1:1); [ ]D –1.5 (c = 1.0, CHCl3).
1H NMR (270 MHz, CDCl3): = 0.88 (t, J = 6.9 Hz, 3 H), 1.21–1.40
(m, 6 H), 1.32 (s, 3 H), 1.42 (s, 3 H), 1.68 (m, 2 H), 1.88 (m, 2 H),
2.58 (s, 4 H), 3.56 (t, J = 6.5 Hz, 2 H), 3.68 (s, 3 H), 3.90 (dd, J = 8.5,
6.9 Hz, 1 H), 3.95 (dd, J = 8.5, 6.9 Hz, 1 H), 4.55 (dd, J = 6.9, 6.9
Hz, 1 H), 4.60 (s, 2 H), 4.75 (s, 2 H), 7.25–7.40 (m, 5 H).
The apparatus for chemical reaction under high pressure has been
developed at RIKEN instrumentation center. The RIKEN high-
Synthesis 2001, No. 7, 1027–1034 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Succinylation of Tertiary Alcohols Under High Pressure
IR (neat): = 2973, 2931, 1737, 1648 cm–1.
1031
13C NMR (67.5 MHz, CDCl3): = 14.0, 23.3, 24.0, 24.8, 25.6, 26.1,
29.0, 30.0, 31.6, 33.1, 51.8, 65.3, 68.2, 69.3, 78.7, 86.4, 94.6, 109.1,
127.7, 127.8, 128.4, 137.9, 171.2, 172.7.
HRMS (FAB, M + Na+): m/z calcd for C17H26O4Na 317.1729, found
317.1727.
IR (neat): = 2955, 2935, 2874, 1736, 1456, 1380, 1370 cm–1.
Succinic Acid Methyl Ester 1-Methyl-1-(4-methylcyclohex-3-
enyl)ethyl Ester (21)
Following the typical procedure for the succinylation of 10, the al-
cohol 20 (46.3 mg, 0.3 mmol) was succinylated to give 21 (74.0 mg,
92%) as a colorless oil (Table 2, entry 3); Rf 0.75 (hexane–EtOAc,
2:1).
1H NMR (500 MHz, CDCl3): = 1.42 (s, 3 H), 1.44 (s, 3 H), 1.64
(br s, 3 H), 1.75–1.87 (m, 2H), 1.90–2.18 (m, 5 H), 2.52–2.60 (m, 4
H), 3.69 (s, 3 H), 5.36 (br s, 1 H).
13C NMR (125 MHz, CDCl3): = 23.1, 23.3, 23.3, 23.8, 26.3, 29.1,
30.3, 37.3, 42.7, 51.7, 85.4, 120.2, 133.9, 171.3, 172.9.
HRMS (FAB, M + Na+): m/z calcd for C26H40O7Na 487.2672, found
487.2674.
Succinic Acid Allyl Ester (1R)-1-Butyl-1-[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl] Ester (12)
Following the typical procedure for the succinylation of 10, the al-
cohol 1016 (48.0 mg, 0.2 mmol) was succinylated with the succinic
acid monomallyl ester (4b) in place of 4a to give 12 (57.1 mg, 75%)
as a colorless oil (Table 1, entry 11); Rf 0.40 (hexane–/EtOAc, 5:1);
[ ]D –1.3 (c = 1.5, CHCl3).
1H NMR (500 MHz, CDCl3): = 0.90 (t, J = 6.9 Hz, 3 H), 1.25–1.40
(m, 4 H), 1.32 (s, 3 H), 1.43 (s, 3 H), 1.84 (m, 2 H), 1.94 (dd, J = 2.8,
2.8 Hz, 1 H), 2.10 (ddd, J = 13.8, 10.5, 5.5 Hz, 1 H), 2.27 (ddd,
J = 13.8, 10.5, 5.5 Hz, 1 H), 2.27–2.40 (m, 2 H), 2.61 (m, 4 H), 3.89
(dd, J = 8.3, 6.9 Hz, 1 H), 3.97 (dd, J = 8.3, 6.9 Hz, 1 H), 4.57 (dd,
J = 6.9, 6.9 Hz, 1 H), 4.60 (ddd, J = 5.3, 1.4, 1.4 Hz, 1 H), 5.24 (ddt,
J = 10.6, 1.4, 1.4 Hz, 1 H), 5.32 (ddt, J = 17.0, 1.4, 1.4 Hz, 1 H), 5.92
(ddt, J = 17.2, 10.6, 5.5 Hz, 1 H).
IR (neat): = 2931, 1732, 1438 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C15H24O4Na 291.1572, found
291.1573.
Succinic Acid Allyl Ester 1-Methyl-1-(4-methylcyclohex-3-
enyl)ethyl Ester (22)
Following the typical procedure for the succinylation of 10, the al-
cohol 20 (46.3 mg, 0.3 mmol) was succinylated with the succinic
acid monoallyl ester (4b) in place of 4a to give 22 (83.9 mg, 95%)
as a colorless oil (Table 2, entry 4); Rf 0.80 (hexane–EtOAc, 2:1).
1H NMR (500 MHz, CDCl3): = 1.41 (s, 3 H), 1.44 (s, 3 H), 1.64
(br s, 3 H), 1.75–1.87 (m, 2 H), 1.90–2.07 (m, 5 H), 2.54–2.64 (m,
4 H), 4.59 (d, J = 5.5 Hz, 1 H), 5.23 (ddt, J = 10.5, 1.4, 1.4 Hz, 1 H),
5.32 (ddt, J = 17.4, 1.4, 1.4 Hz, 1 H), 5.36 (br s, 1 H), 5.91 (ddt,
J = 17.4, 10.5, 5.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): = 23.1, 23.3, 23.3, 23.8, 25.1, 29.3,
30.3, 37.3, 42.7, 65.3, 85.4, 118.3, 120.3, 132.1, 133.9, 171.3,
172.1.
IR (neat): = 2975, 2930, 1732, 1680, 1650 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C17H26O4Na 317.1729, found
13C NMR (125 MHz, CDCl3): = 13.4, 13.9, 23.2, 24.7, 25.4, 26.1,
29.1, 29.1, 29.9, 34.0, 65.3, 65.4, 68.2, 78.3, 84.2, 85.6, 109.2,
118.3, 132.0, 171.2, 171.8.
IR (neat): = 3292, 2934, 1736, 1648 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C21H32O6Na 403.2097, found
403.2098.
Succinic Acid 1,5-Dimethyl-1-vinylhex-4-enyl Ester Methyl
Ester (17)
Following the typical procedure for the succinylation of 10, the al-
cohol 16 (46.3 mg, 0.3 mmol) was succinylated to give 17 (73.8 mg,
92%) as a colorless oil (Table 2, entry 1); Rf 0.70 (hexane–EtOAc,
2:1).
1H NMR (500 MHz, CDCl3): = 1.54 (s, 3 H), 1.59 (br s, 3 H), 1.67
(br s, 3 H), 1.75 (ddd, J = 13.7, 10.1, 6.9 Hz, 1 H), 1.84 (ddd,
J = 13.7, 9.2, 7.3 Hz, 1 H), 1.97 (m, 2 H), 2.60 (br s, 4 H), 3.69 (s, 3
H), 5.08 (tq, J = 7.4, 0.9 Hz, 1 H), 5.12 (dd, J = 11.0, 0.9 Hz, 1 H),
5.15 (dd, J = 17.4, 0.9 Hz, 1 H), 5.96 (dd, J = 17.4, 11.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): = 17.5, 22.3, 23.5, 25.6, 29.0, 30.1,
39.8, 51.7, 83.4, 113.2, 123.7, 131.8, 141.6, 170.9, 172.8.
317.1726.
Succinic Acid Allyl Ester (2S,3R,6S,8R,9S)-3-Butyl-2-(tert-
butyldiphenylsilanyloxymethyl)-8-[2-(4-methoxybenzyloxy)-
ethyl]-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl ester (25)
Following the typical procedure for the succinylation of 10, the al-
cohol 2413 (243.2 mg, 0.36 mmol) was succinylated with the succin-
ic acid monoallyl ester (4b) in place of 4a to give 25 (249.6 mg,
85%) as a colorless oil (Table 2, entry 6); Rf 0.50 (hexane–EtOAc,
3:1); [ ]D –6.3 (c = 1.5, CHCl3).
IR (neat): = 2975, 2929, 1739, 1646 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C15H24O4Na 291.1572, found
291.1572.
1H NMR (500 MHz, CDCl3): = 0.77 (t, J = 6.9 Hz, 3 H), 0.79 (d,
J = 6.4 Hz, 3 H), 1.05 (s, 9 H), 1.05–2.00 (m, 16 H), 2.27 (m, 1 H),
2.57 (m, 4 H), 3.37 (ddd, J = 9.2, 9.2, 5.5 Hz, 1 H), 3.56 (ddd,
J = 9.2, 9.2, 5.5 Hz, 1 H), 3.67 (ddd, J = 7.8, 7.3, 2.7 Hz, 1 H), 3.73
(dd, J = 11.0, 4.6 Hz, 1 H), 3.79 (s, 3 H), 3.81 (dd, J = 11.0, 6.9 Hz,
1 H), 4.22 (dd, J = 6.9, 4.6 Hz, 1 H), 4.28 (d, J = 11.5 Hz, 1 H), 4.30
(d, J = 11.5 Hz, 1 H), 4.58 (ddd, J = 6.0, 1.4, 1.4 Hz, 2 H), 5.23 ((ddt,
J = 10.5, 1.4, 1.4 Hz, 1 H), 5.31 (ddt, J = 17.0, 1.4, 1.4 Hz, 1 H), 5.90
(ddt, J = 17.0, 10.5, 6.0 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 2 H), 7.21 (d,
J = 8.7 Hz, 2 H), 7.3–7.8 (m, 10 H).
13C NMR (125 MHz, CDCl3): = 13.8, 17.8, 19.1, 22.9, 24.5, 25.2,
26.8, 27.5, 29.2, 30.1, 32.8, 32.8, 33.2, 34.2, 34.6, 55.2, 63.7, 65.3,
67.1, 72.5, 73.6, 77.6, 83.5, 95.9, 113.7, 118.3, 127.7, 129.1, 129.7,
130.9, 132.1, 133.3, 133.6, 135.6, 135.7, 159.0, 171.1, 171.9.
Succinic Acid 1,5-Dimethyl-1-vinylhex-4-enyl Ester Prop-1-
ynyl Ester (18)
Following the typical procedure for the succinylation of 10, the al-
cohol 16 (46.3 mg, 0.3 mmol) was succinylated with the succinic
acid monoallyl ester (4b) in place of 4a to give 18 (85.7 mg, 97%)
as a colorless oil (Table 2, entry 2); Rf 0.75 (hexane–EtOAc, 2:1).
1H NMR (500 MHz, CDCl3): = 1.54 (s, 3 H), 1.59 (br s, 3 H), 1.67
(br s, 3 H), 1.75 (ddd, J = 13.7, 10.1, 6.9 Hz, 1 H), 1.84 (ddd,
J = 13.7, 9.2, 7.3 Hz, 1 H), 1.97 (m, 2 H), 2.61 (m, 4 H), 4.59 (br d,
J = 5.5 Hz, 2 H), 5.08 (br t, J = 7.0 Hz, 1 H), 5.12 (d, J = 11.0 Hz, 1
H), 5.15 (d, J = 17.4 Hz, 1 H), 5.23 (br d, J = 10.5 Hz, 1 H), 5.31 (br
dd, J = 17.4, 1.4 Hz, 1 H), 5.90 (ddt, J = 17.4, 10.5, 5.5 Hz, 1 H),
5.96 (dd, J = 17.4, 11.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): = 17.5, 22.3, 23.5, 25.6, 29.1, 30.0,
39.8, 65.3, 83.4, 113.2, 118.3, 123.7, 131.8, 132.0, 141.6, 170.9,
172.0.
IR (neat): = 2956, 2860, 1736, 1650, 1614, 1589, 1514 cm–1.
HRMS (FAB, M + Na+) m/z calcd for C48H66O9Na 837.4374, found
837.4378.
Synthesis 2001, No. 7, 1027–1034 ISSN 0039-7881 © Thieme Stuttgart · New York

1032
T. Shimizu et al.
PAPER
Succinic Acid Allyl Ester (2S,3R,6R,8R,9S)-3-Butyl-2-(tert-
butyldiphenylsilanyloxymethyl)-8-[2-(4-methoxybenzyloxy)-
ethyl]-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl Ester (27)
Following the typical procedure for the succinylation of 10, the al-
cohol 2613 (182.8 mg, 0.27 mmol) was succinylated with the succin-
ic acid monoallyl ester (4b) in place of 4a to give 27 (167.8 mg,
76%) as a colorless oil (Table 2, entry 7); Rf 0.53 (hexane–EtOAc,
3:1); [ ]D +0.4 (c = 1.5, CHCl3).
1H NMR (500 MHz, CDCl3): = 0.84 (t, J = 6.9 Hz, 3 H), 0.84 (d,
J = 6.4 Hz, 3 H), 1.06 (s, 9 H), 1.10–2.08 (m, 16 H), 2.20 (m, 1 H),
2.27–2.54 (m, 4 H), 3.27 (ddd, J = 9.6, 9.6, 1.8 Hz, 1 H), 3.69 (m, 1
H), 3.73 (dd, J = 11.0, 7.3 Hz, 1 H), 3.79 (m, 1 H), 3.79 (s, 3 H), 3.87
(dd, J = 11.0, 3.2 Hz, 1 H), 4.43 (d, J = 11.5 Hz, 1 H), 4.48 (d,
J = 11.5 Hz, 1 H), 4.50 (ddd, J = 5.0, 1.4, 1.4 Hz, 2 H), 4.79 (dd,
J = 7.3, 3.2 Hz, 1 H), 5.19 (ddt, J = 10.5, 1.4, 1.4 Hz, 1 H), 5.26 (ddt,
J = 17.0, 1.4, 1.4 Hz, 1 H), 5.85 (ddt, J = 17.0, 10.5, 5.0 Hz, 1 H),
6.87 (d, J = 8.7 Hz, 2 H), 7.27 (d, J = 8.7 Hz, 2 H), 7.3–7.8 (m, 10 H).
and Ph3P (1.3 mg, 5.0 mol) in CH2Cl2 (10 mL) at 0°C under N2.
After stirring for 1 h, the resulting mixture was diluted with EtOAc
(50 mL) and extracted with 2 N aq Na2CO3 (6 1 mL). The com-
bined extracts were acidified with 1 N HCl (pH 1–3) and extracted
with EtOAc (6 10 mL). The combined extracts were washed with
brine and dried (MgSO4). After removal of the solvent, the residue
was purified by column chromatography with hexane–EtOAc, (2:1)
to give 32 (23.8 mg, 95%) as a colorless solid; Rf 0.65 (hexane–
EtOAc–AcOH, 50:50:1); mp 77–79°C.
1H NMR (500 MHz, CD3OD): = 1.46 (s, 6 H), 2.56 (m, 4 H), 3.11
(s, 2 H), 7.20–7.40 (m, 5 H).
13C NMR (125 MHz, CD3OD): = 26.0, 29.0, 30.1, 46.2, 82.9,
126.5, 128.0, 130.5, 137.1, 171.5, 178.4.
IR (ATR): = 1708, 1230, 1168, 1111 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C14H18O4Na 273.1103, found
273.1109.
13C NMR (125 MHz, CDCl3): = 14.0, 17.4, 19.4, 23.1, 25.6, 26.8,
26.9, 27.3, 29.1, 29.4, 30.1, 30.4, 34.0, 34.9, 35.3, 55.2, 62.9, 65.2,
66.8, 72.6, 73.6, 75.2, 83.1, 96.7, 113.7, 118.3, 127.4, 127.5, 129.4,
129.4, 131.1, 132.1, 134.1, 135.8, 160.0, 170.7, 171.9.
IR (neat): = 2955, 2859, 1737, 1650, 1614, 1514 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C48H66O9Na 837.4374, found
Succinic Acid (1R)-Mono-{1-butyl-1-[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]pent-4-ynyl} Ester (13)
Following the typical procedure for the preparation of 32, the
hemisuccinate 13 was formed from 11 (17.7 mg, 0.05 mmol) and 12
(15.2 mg, 0.04 mmol) as a colorless oil in 94% and 97% yields, re-
spectively; Rf 0.50 (hexane–EtOAc–AcOH, 50:50:1); [ ]D +4.7
(c = 0.2, CHCl3).
837.4388.
1H NMR (270 MHz, CDCl3): = 0.90 (t, J = 6.9 Hz, 3 H), 1.25–1.38
(m, 4 H), 1.33 (s, 3 H), 1.43 (s, 3 H), 1.82–1.88 (m, 2 H), 1.95 (dd,
J = 2.8, 2.8 Hz, 1 H), 2.10 (ddd, J = 13.7, 10.1, 6.0 Hz, 1 H), 2.27
(ddd, J = 13.7, 10.5, 5.5 Hz, 1 H), 2.30–2.42 (m, 2 H), 2.59 (m, 4 H),
3.89 (dd, J = 8.7, 6.9 Hz, 1 H), 3.97 (dd, J = 8.7, 7.3 Hz, 1 H), 4.57
(dd, J = 7.3, 6.9 Hz, 1 H).
13C NMR (67.5 MHz, CDCl3): = 13.4, 13.9, 23.2, 24.6, 25.4, 26.1,
29.0, 30.0, 32.6, 34.0, 65.3, 68.2, 78.3, 84.3, 85.4, 109.2, 171.4,
175.2.
Succinic Acid Allyl Ester (2R,3S,6S,8R,9S)-3-Butyl-2-(tert-
butyldiphenyl-silanyloxymethyl)-8-[2-(4-methoxybenzyloxy)-
ethyl]-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl Ester (29)
Following the typical procedure for the succinylation of 10, the al-
cohol 2817 (28.4 mg, 0.04 mmol) was succinylated with the succinic
acid monoallyl ester (4b) in place of 4a to give 29 (25.4 mg, 74%)
as a colorless oil (Table 2, entry 8); Rf 0.50 (hexane–EtOAc, 3:1);
[ ]D +14.2 (c = 1.5, CHCl3).
1H NMR (500 MHz, CDCl3): = 0.80 (d, J = 6.4 Hz, 3 H), 0.81 (t,
J = 6.9 Hz, 3 H), 1.03 (s, 9 H), 1.05–2.15 (m, 17 H), 2.41–2.60 (m,
4 H), 3.65 (dd, J = 10.5, 8.7 Hz, 1 H), 3.69 (ddd, J = 9.6, 9.6, 6.0 Hz,
1 H), 3.73 (ddd, J = 10.1, 10.1, 2.3 Hz, 1 H), 3.77 (s, 3 H), 3.79 (dd,
J = 10.5, 0.5 Hz, 1 H), 3.92 (ddd, J = 9.6, 9.6, 5.0 Hz, 1 H), 4.49 (s,
2 H), 4.50 (dd, J = 8.7, 0.5 Hz, 1 H), 4.54 (ddd, J = 6.0, 1.4, 1.4 Hz,
2 H), 5.20 (ddt, J = 10.5, 1.4, 1.4 Hz, 1 H), 5.27 (ddt, J = 17.0, 1.4,
1.4 Hz, 1 H), 5.85 (ddt, J = 17.0, 10.5, 6.0 Hz, 1 H), 6.84 (d, J = 8.7
Hz, 2 H), 7.29 (d, J = 8.7 Hz, 2 H), 7.30–7.80 (m, 10 H).
13C NMR (125 MHz, CDCl3): = 14.0, 17.5, 19.1, 23.1, 25.5, 26.7,
26.9, 28.1, 29.2, 30.1, 30.2, 33.3, 34.1, 35.0, 35.1, 55.2, 62.5, 65.3,
68.0, 72.2, 72.7, 73.6, 83.0, 95.1, 113.6, 118.3, 127.6, 127.6, 129.4,
129.4, 129.5, 129.6, 131.1, 132.0, 133.6, 135.6, 135.7, 159.0, 170.6,
171.8.
IR (neat): = 2931, 2859, 1737, 1650, 1615, 1588, 1513 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C48H66O9Na 837.4374, found
IR (neat): = 3309, 2958, 2929, 2857, 1733, 1717, 1457, 1371 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C18H28O6Na 363.1784, found
363.1783.
Succinic Acid Mono-(1,5-dimethyl-1-vinylhex-4-enyl) Ester
(19)
Following the typical procedure for the preparation of 32, the
hemisuccinate 19 was formed from 16 (26.8 mg, 0.1 mmol) and 17
(29.4 mg, 0.1 mmol) as a colorless oil in 98% and 96% yields, re-
spectively (Table 2, entries 1, 2); Rf 0.30 (hexane–EtOAc–AcOH,
50:25:1).
1H NMR (500 MHz, CDCl3): = 1.54 (s, 3 H), 1.59 (br s, 3 H), 1.67
(br s, 3 H), 1.76 (ddd, J = 13.7, 10.1, 6.9 Hz, 1 H), 1.84 (ddd,
J = 13.7, 8.7, 7.8 Hz, 1 H), 1.97 (m, 2 H), 2.61 (m, 4 H), 5.08 (tq,
J = 6.9, 1.4 Hz, 1 H), 5.12 (d, J = 11.0 Hz, 1 H), 5.15 (d, J = 17.9 Hz,
1 H), 5.96 (dd, J = 17.9, 11.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): = 17.5, 22.3, 23.5, 25.6, 28.9, 29.8,
39.8, 83.6, 113.2, 123.7, 131.8, 141.5, 170.9, 173.8.
IR (neat): = 2977, 2935, 1733, 1717, 1647, 1413, 1374 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C14H22O4Na 277.1416, found
277.1415.
837.4374.
Conversion of Succinates into the Hemisuccinates; Succinic
Acid Mono-(1,1-dimethyl-2-phenylethyl) Ester (32); Typical
Procedure
Method A: A 0.55 M solution of PrSLi in HMPA20 (273 L, 0.15
mmol) was added to 30 (26.4 mg, 0.1 mmol) at r.t. under N2. After
stirring for 1 h, ice and Et2O (15 mL) were added to the mixture. The
aqueous layer was acidified with 1 N HCl and extracted with EtOAc
(4 10 mL). The combined extracts were washed with brine and
dried (MgSO4). After removal of the solvent, the residue was puri-
fied by column chromatography with hexane–EtOAc, (2:1) to give
32 (23.8 mg, 95%) as a colorless solid.
Succinic Acid Mono-[1-methyl-1-(4-methylcyclohex-3-
enyl)ethyl] Ester (23)
Following the typical procedure for the preparation of 32, the
hemisuccinate 23 was formed from 21 (26.8 mg, 0.1 mmol) and 22
(29.4 mg, 0.1 mmol) as a colorless oil in 96% and 96% yields, re-
spectively (Table 2, entries 3,4); Rf 0.30 (hexane–EtOAc–AcOH,
50:25:1).
Method B: Pyrrolidine (50 L, 0.6 mmol) was added to a stirred
mixture of 31 (29.0 mg, 0.1 mmol), Pd(Ph3P)4 (2.9 mg, 2.5 mol)
Synthesis 2001, No. 7, 1027–1034 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Succinylation of Tertiary Alcohols Under High Pressure
1033
1H NMR (500 MHz, CDCl3): = 1.41 (s, 3 H), 1.44 (s, 3 H), 1.64
(br s, 3 H), 1.75–2.08 (m, 7 H), 2.52–2.64 (m, 4 H), 5.36 (br s, 1 H).
13C NMR (125 MHz, CDCl3): = 23.1, 23.3, 23.3, 23.8, 26.3, 29.1,
30.1, 37.3, 42.6, 85.8, 120.2, 133.9, 171.3, 178.2.
IR (neat): = 2965, 2935, 1732, 1717, 1370 cm–1.
(2) (a) Michael, K. H.; Demarco, P. V.; Nagarajan, R. J. J.
Antibiot. 1977, 30, 571. (b) Arai, K.; Rawlinga, B. J.;
Yoshizawa, Y.; Vederas, J. C. J. Am. Chem. Soc. 1989, 111,
3391.
(3) Koshino, H.; Kobinata, K.; Uzawa, J.; Uramoto, M.; Isono,
K.; Osada, H. Tetrahedron 1993, 49, 8827.
(4) (a) Yamamoto, R.; Fujisawa, S.; Kawamura, M. Yakugaku
Zasshi 1971, 91, 855. (b) Chem. Abstr. 1971, 75, 118453.
(5) Israel, M.; Potti, P. G.; Seshadri, R. J. Med. Chem. 1985, 28,
1223.
(6) Tsuchiya, T.; Takagi, Y.; Umezawa, S.; Takeuchi, T.;
Komuro, K.; Nosaka, C.; Umezawa, H.; Fukatsu, S.; Yoneta,
T. J. Antibiot. 1988, 41, 988.
(7) Magri, N. F.; Kingston, D. G. I. J. Nat. Prod. 1988, 51, 298.
(8) Deutsch, H. M.; Glinski, J. A.; Hernandez, M.; Haugwitz, R.
D.; Narayanan, V. L.; Suffness, M.; Zalkow, L. H. J. Med.
Chem. 1989, 32, 788.
(9) Nicolaou, K. C.; Riemer, C.; Kerr, M. A.; Rideout, D.;
Wrasidlo, W. Nature 1993, 364, 464.
(10) (a) Kita, Y.; Maeda, H.; Omori, K.; Okuno, T.; Tamura, Y.
Synlett 1993, 273. (b) Kita, Y.; Maeda, H.; Takahashi, F.;
Fukui, S. J. Chem. Soc., Chem. Commun. 1993, 410.
(11) Saitoh, K.; Siina, I.; Mukaiyama, T. Chem. Lett. 1998, 679.
(12) Shimizu, T.; Kobayashi, R.; Ohmori, H.; Nakata, T. Synlett
1995, 650.
HRMS (FAB, M + Na+): m/z calcd for C14H22O4Na 277.1416, found
277.1415.
Succinic Acid (2S,3R,6S,8R,9S)-Mono-{3-butyl-2-[(1E,3E)-4-
carboxy-3-methylbuta-1,3-dienyl]-8-(2-hydroxyethyl)-9-
methyl-1,7-dioxaspiro[5.5]undec-3-yl} Ester (35)
Following the typical procedure for the preparation of 32, the
hemisuccinate 35 was formed from 34 (5.8 mg, 0.01 mmol) as a col-
orless oil in 88% yield; Rf 0.45 (CH2Cl2–MeOH, 85:15).
1H NMR (500 MHz, CD3OD): = 0.89 (d, J = 6.0 Hz, 3 H), 0.90 (t,
J = 6.9 Hz, 3 H), 1.10–2.20 (m, 17 H), 2.33 (d, J = 0.9 Hz, 3 H),
2.50–2.80 (m, 4 H), 3.51 (m, 1 H), 3.70–3.80 (m, 2 H), 4.68 (d,
J = 7.8, 1 H), 5.91 (br s, 1 H), 6.43 (dd, J = 15.6, 7.8 Hz, 1 H), 6.47
(d, J = 15.6, 1 H).
IR (neat): = 3500, 2958, 2935, 2855, 1733, 1717, 1610, 1514 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C26H40O9Na 519.2570, found
519.2567.
Succinic Acid (2S,3R,6S,8R,9S)-Mono-{3-butyl-2-[(1E,3E)-4-
carboxy-3-methylbuta-1,3-dienyl]-8-(4-hydroxy-3-methylbut-
2-enyl)-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl} Ester (37)
(13) Shimizu, T.; Kobayashi, R.; Osako, K.; Nakata, T.
Tetrahedron Lett. 1996, 37, 6755.
(14) Shimizu, T.; Masuda, T.; Hiramoto, K.; Nakata, T. Org. Lett.
2000, 2, 2153.
Following the typical procedure for the preparation of 32, the
hemisuccinate 37 was formed from 36 (6.2 mg, 0.01 mmol) as a col-
orless oil in 87% yield; Rf 0.45 (CH2Cl2–MeOH, 85:15).
1H NMR (500 MHz, CD3OD): = 0.83 (d, J = 6.0 Hz, 3 H), 0.89 (t,
J = 6.9 Hz, 3 H), 1.20–1.90 (m, 16 H), 1.71 (s, 3 H), 2.05 (m, 1 H),
2.31 (d, J = 1.4 Hz, 3 H), 2.58–2.70 (m, 4 H), 3.48 (dt, J = 9.6, 4.1
Hz, 1 H), 3.97 (s, 2 H), 4.66 (d, J = 8.7, 1 H), 5.57 (br t, J = 6.4 1 H),
5.92 (br s, 1 H), 6.46 (d, J = 15.6 Hz, 1 H), 6.51 (dd, J = 15.6, 8.7 1
H).
13C NMR (125 MHz, CD3OD): = 14.1, 14.2, 14.5, 18.1, 23.8, 25.1,
25.5, 28.8, 29.9, 31.1, 32.2, 32.8, 34.4, 35.2, 36.8, 69.0, 76.2, 79.7,
84.2, 97.1, 121.6, 121.9, 134.3, 137.3, 139.1, 152.6, 170.2, 173.4,
175.9.
(15) The alcohol 7 was prepared from the known lactone 613 in
two steps:(1)LAH, THF, 0°C (90%);(2)BOMCl, i-Pr2NEt,
CH2Cl2, 0°C to r.t. (79%). 1H NMR (270 MHz, CDCl3):
= 0.92 (t, J = 6.7 Hz, 3 H), 1.20–1.80 (m, 10 H), 1.37 (s, 3
H), 1.42 (s, 3 H), 2.03 (s, 1 H), 3.54 (dt, J = 9.6, 6.3 Hz, 1 H),
3.60 (dt, J = 9.6, 6.3 Hz, 1 H), 3.87 (dd, J = 8.2, 7.8 Hz, 1 H),
3.93 (dd, J = 7.8, 6.1 Hz, 1 H), 4.03 (dd, J = 8.2, 6.1 Hz, 1 H),
4.60 (s, 2 H), 4.75 (s, 2 H), 7.25–7.40 (m, 5 H). 13C NMR
(67.5 MHz, CDCl3): = 14.2, 23.3, 23.5, 25.6, 25.8, 26.5,
31.0, 36.6, 64.6, 68.3, 69.3, 72.7, 79.8, 94.5, 108.7, 127.6,
127.7, 128.3, 128.4, 137.8.
(16) The alcohol 10 was prepared from the known amide 913 in
four steps:(1)DIBAH, Et2O, 0°C (90%);(2)CBr4, Ph3P, 2,6-
lutidine, CH2Cl2, 0°C (80%);(3)BuLi, THF, –78°C to r.t.
(68%);(4)MeI, NaHCO3, acetone, H2O, 60°C (83%). 1H
NMR (270 MHz, CDCl3): = 0.92 (t, J = 6.7, 3 H), 1.22–
1.36 (m, 4 H), 1.36 (s, 3 H), 1.42 (s, 3 H), 1.48–1.70 (m, 4
H), 1.97 (dd, J = 2.8, 2.8, 1 H), 2.22 (dddd, J = 16.6, 9.5, 7.2,
2.8, 1 H), 2.34 (dddd, J = 16.6, 9.2, 6.4, 2.8, 1 H), 3.87 (dd,
J = 7.9, 7.9, 1 H), 3.97 (dd, J = 7.9, 6.4, 1 H), 4.06 (dd,
J = 7.9, 6.4, 1 H). 13C NMR (67.5 MHz, CDCl3): = 12.7,
14.2, 23.3, 25.5, 25.9, 26.4, 33.1, 36.2, 62.5, 64.6, 72.9, 79.4,
84.3, 108.9.
(17) The alcohol 28 was prepared from the enantiomer of the
amide 912 using the same procedure for the preparation of
2413: 1H NMR (500 MHz, CDCl3): = 0.77 (d, J = 6.4 Hz, 3
H), 0.92 (t, J = 6.9 Hz, 3 H), 1.05 (s, 9 H), 1.20–1.80 (m, 16
H), 2.00 (m, 1 H), 3.36 (ddd, J = 10.1, 101, 2.3 Hz, 1 H), 3.62
(ddd, J = 9.2, 8.7, 6.9 Hz, 1 H), 3.69 (dd, J = 9.6, 6.9 Hz, 1
H), 3.73 (ddd, J = 9.2, 9.2, 5.0 Hz, 1 H), 3.77 (s, 3 H), 3.77
(dd, J = 6.9, 6.0 Hz, 1 H), 3.85 (dd, J = 9.6, 6.9 Hz, 1 H), 4.47
(d, J = 11.5 Hz, 1 H), 4.52 (d, J = 11.5 Hz, 1 H), 6.86 (d,
J = 8.7 Hz, 2 H), 7.28 (d, J = 8.7 Hz, 2 H), 7.30–7.80 (m, 10
H). 13C NMR (125 MHz, CDCl3): = 14.2, 17.6, 19.1, 23.4,
24.7, 26.8, 28.0, 29.5, 30.6, 33.4, 33.7, 35.0, 35.1, 55.2, 63.6,
67.3, 71.2, 72.2, 72.8, 74.4, 95.0, 113.8, 127.8, 127.8, 129.3,
129.8, 129.9, 130.8, 132.7, 132.8, 135.6, 135.7, 159.1.
IR (neat): = 3500, 2957, 2935, 2853, 1733, 1715, 1610, 1510 cm–1.
HRMS (FAB, M + Na+): m/z calcd for C29H44O9Na 559.2883, found
559.2875.
Acknowledgement
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and Cul-
ture, Japan, and by the Special Project Funding for Basic Science
(Multibioprobes) from RIKEN. We thank Messrs. A. Matsumoto
and T. Watanabe for operation of the high-pressure equipment, and
Ms. K. Harata for the mass spectral measurements.
References
(1) (a) Takahashi, H.; Osada, H.; Koshino, H.; Kudo, T.;
Amano, S.; Shimizu, S.; Yoshihama, M.; Isono, K. J.
Antibiot. 1992, 45, 1409. (b) Takahashi, H.; Osada, H.;
Koshino, H.; Sasaki, M.; Onose, R.; Nakakoshi, M.;
Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1414.
(c) Koshino, H.; Takahashi, H.; Osada, H.; Isono, K. J.
Antibiot. 1992, 45, 1420.
Synthesis 2001, No. 7, 1027–1034 ISSN 0039-7881 © Thieme Stuttgart · New York

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T. Shimizu et al.
PAPER
= 1.44 (s, 6 H), 2.58 (m, 4 H), 3.05 (s, 2 H), 4.59 (ddd,
J = 5.6, 1.4, 1.4, 2 H), 5.23 (ddt, J = 10.6, 1.4, 1.4, 1 H), 5.32
(ddt, J = 17.2, 1.4, 1.4, 1 H), 5.91 (ddt, J = 17.2, 10.6, 5.6, 1
H), 7.15–7.35 (m, 5 H).
(18) The reaction of 2-methyl-1-phenylpropan-2-ol with the
succinic acid monomethyl ester (4a, 2 equiv), DCC (2.4
equiv) and DMAP (0.1 equiv) in CH2Cl2 at r.t. smoothly
proceeded to give the methyl succinate 30 after 4.5 h in 98%
yield even under atmospheric pressure: 1H NMR (270 MHz,
CDCl3): = 1.45 (s, 6 H), 2.56 (m, 4 H), 3.06 (s, 2 H), 3.68
(s, 3 H), 7.15–7.35 (m, 5 H). The allyl succinate 31 was also
prepared using the succinic acid monoallyl ester (4b) in the
same manner in 96% yield: 1H NMR (270 MHz, CDCl3):
(19) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25,
5831.
(20) Bartlett, P. A.; Johnson, W. S. Tetrahedron Lett. 1970, 4459.
(21) Deziel, R. Tetrahedron Lett. 1987, 28, 4371.
(22) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis 1986, 623.
Synthesis 2001, No. 7, 1027–1034 ISSN 0039-7881 © Thieme Stuttgart · New York