Manganese(III)-assisted specific intramolecular addition

Article abstract of DOI:10.1055/s-0030-1259977

Oligomethylene-tethered -alkenyl 3-oxobutanoates and 3-oxobutanamides underwent manganese(III)-mediated oxidative intramolecular addition to produce dihydrofuran-fused macrolides and macrocyclic amides from 8 to 26 members. A similar reaction of the oligooxamethylene-tethered -alkenyl 3-oxobutanoates also gave dihydrofuran-fused crown ether type macrolides which had a phase-transfer ability with sodium and potassium picrates. The manganese(III)-assisted specific intramolecular addition could be explained by the -complexation of the -alkenyl part with the manganese(III) enolate. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259977

PAPER
1365
Manganese(III)-Assisted Specific Intramolecular Addition
M
n(III)-Assiste
d
S
o
pecific Intra
s
m
olecula
r
u
Addition ke Ito, Shunsuke Jogo, Noriko Fukuda, Ryo Okumura, Hiroshi Nishino*
Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, Kurokami 2-39-1, Kumamoto 860-8555,
Japan
Fax +81(96)3423374; E-mail: nishino@sci.kumamoto-u.ac.jp
Received 1 February 2011; revised 3 March 2011
using manganese(III) chemistry, and prompted us to in-
Abstract: Oligomethylene-tethered w-alkenyl 3-oxobutanoates
vestigate the scope and limitations of the cyclization. In
and 3-oxobutanamides underwent manganese(III)-mediated oxida-
this paper, the full results of the earlier work,8 structure
determination, and plausible mechanism for the unique in-
tive intramolecular addition to produce dihydrofuran-fused mac-
rolides and macrocyclic amides from 8 to 26 members. A similar
reaction of the oligooxamethylene-tethered w-alkenyl 3-oxobu- tramolecular addition are described.
tanoates also gave dihydrofuran-fused crown ether type macrolides
which had a phase-transfer ability with sodium and potassium pi-
Ph
Ph
O
O
crates. The manganese(III)-assisted specific intramolecular addi-
tion could be explained by the p-complexation of the w-alkenyl part
with the manganese(III) enolate.
(CH2)x
(CH2)y
+
Ph
O
O
O
O
Ph
x = 2–28
y = 2–26
Key words: intramolecular addition, macrocyclization, oxidation,
radical, crown ether
AcOH
argon
Mn(OAc)3
100 °C
The intramolecular addition reaction is an important tool
for the construction of cyclic compounds.1 Normally, al-
though it is difficult to prepare small rings, such as cyclo-
propane and cyclobutane, because of ring strain, the
synthesis of a five- and six-membered rings is somewhat
easier since the bond angle and eclipsing strain are can-
celled.2 It is also difficult to make more than nine-mem-
bered ring compounds due to enthalpic and entropic
influences.3 However, ring-closing metathesis (RCM) al-
leviated this problem and it became easy to prepare mac-
rocyclic compounds.4 However, it needs a special and
expensive Grubbs catalyst. Recently, we5,6 and others7 de-
veloped an efficient oxidative radical cyclization using a
manganese(III) enolate complex as a carbon radical pro-
moter. When either oligomethylene bis(3-oxobutanoate)s
(y = 2–26) or N,N¢-oligomethylene bis(3-oxobutanam-
ide)s were used as the enolate source in the reaction with
electron-rich terminal alkadienes (x = 2–28), intermolec-
ular addition took place and the corresponding
macrodiolides6 or macrocyclic diamides8 from 11 to 62
members having two fused dihydrofuran rings were pro-
duced in moderate to good yields (Scheme 1). This mac-
rocyclization is specific to manganese(III) chemistry, and
we expected that the reaction might be applied to the in-
tramolecular addition of oligomethylene-tethered w-alke-
nyl 3-oxobutanoates. In fact, we initially examined the
reaction of 8,8-diphenyl-5-oxaoct-7-enyl 3-oxobutanoate
with manganese(III) acetate, and we confirmed that the
unique intramolecular addition certainly proceeded and a
10-membered cyclization product was obtained.9 This re-
sult constitutes a unique aspect of intramolecular addition
(CH2)x
Ph
Ph
Ph
Ph
O
O
(22–86%)
(CH2)y
O
O
O
O
Scheme 1
Oligomethylene-tethered w-alkenyl 3-oxobutanoates 1n
(n = 2–10, 20) were synthesized by the reaction of
diketene with the corresponding w-alkenyl-oxaoligometh-
ylen-1-ols, which were prepared by the Williamson ether
synthesis of 1,1-diaryl-3-bromoprop-1-enes with the cor-
responding 1,w-diols.
With the butanoates 1n in hand, we initially explored the
reaction using 8,8-diphenyl-5-oxaoct-7-enyl 3-oxobu-
tanoate (14) under stoichiometric conditions (Scheme 2
and Table 1, entry 3). Fortunately, the desired intramolec-
ular addition of the 3-oxobutanoate 14 (n = 4) took place
and a macrolide 24 was produced, however, 15% of 14 was
recovered unchanged. In order to determine the optimized
reaction conditions, we then scrutinized the reaction under
Ph
Ph
O
O
(CH2)n
1n: n = 2–10, 20
O
O
Ph
Ph
O
O
Mn(OAc)3
(CH2)n
O
AcOH
argon
reflux
SYNTHESIS 2011, No. 9, pp 1365–1374
x
x
.
x
x
.2
0
1
1
O
2n
Advanced online publication: 30.03.2011
DOI: 10.1055/s-0030-1259977; Art ID: F16411SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

1366
Y. Ito et al.
PAPER
various conditions (entries 4–6). As a result, when the re- obutanoates might occur3a,b under the current conditions
action was carried out at reflux under an argon atmo- since a 62-membered macrodiolide could also be synthe-
sphere, it yielded the macrolide 24 with the best yield sized using a similar manganese(III)-based cyclization.6a
(entry 6). Similar reactions of either, the shorter methyl-
Ph
Ph
ene-tethered 3-oxobutanoates 12 (n = 2) and 13 (n = 3) or
the longer 3-oxobutanoates 15–110 (n = 5–10) also yielded
the desired cyclic products in acceptable yields (entries 1,
2, and 7–12).
Ph
Ph
Mn(OAc)3
O
O
O
AcOH, reflux
argon
O
O
O
Table 1 Reaction of Oligomethylene-Tethered w-Alkenyl 3-Oxo-
butanoates 1n with Manganese(III) Acetatea
10
Ph Ph
Entry n
Ratio 1n/ Temp
Mn(III) (°C)
Time Product Yieldb Ring
(min)
Mn(OAc)3
(%)
55
82
35d
47
75
94
76
74
52
51
56
51
62
sizec
O
EtOH, reflux
argon
O
O
1
2
2
3
4
4
4
4
5
6
7
8
9
1:5
1:5
1:2
1:4
1:10
1:5
1:8
1:6
1:5
1:5
1:7
1:5
1:5
reflux
reflux
100
15
22
23
24
24
24
24
25
26
27
28
29
210
220
8
64%
10
9
Scheme 3
3
120
120
60
10
10
10
10
11
12
13
14
15
16
26
4
100
The structure of the 10-membered macrolide 24 seemed to
be rigid and immobilized because of the dihydrofuran-
fused medium-sized ring system. In fact, it was observed
that the methylene protons H7 and H9 appeared at d = ca.
3.9 (1 H) and 3.4 (1 H) and d = ca. 3.1 (1 H) and 2.9 (1 H),
respectively, in the 1H NMR spectrum, one of which was
shielded by one of the phenyl groups (Figure 1). On the
other hand, the methine proton of H10 (d = 4.34) attached
to the ring junction was deshielded by the other phenyl
group. In addition, the methylene protons H4 adjacent to
the ester oxygen appeared at d = ca. 4.8 and 3.8, one of
which was deshielded by the diamagnetic anisotropic ef-
fect of the ester carbonyl group. This tendency was signif-
icant until the 12-membered macrolide 26. In order to
determine the exact structure of the cyclic compounds, X-
ray crystallographic analysis was performed using the
macrolides 22, 23, 24, and 26, and the structures of these
macrolides were confirmed (Figure 1, Figure 2 and Sup-
porting Information).
5
100
6
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
15
7
25
8
20
9
20
10
11
15
25
12
13
10
20
25
15
a Reaction conditions: 1n (0.2 mmol), Mn(OAc)3·2H2O, AcOH (100
mL), argon atmosphere.
b Isolated yield based on use of 1n.
c Size of ring fused to the dihydrofuran ring.
d 15% of butanoate 14 was recovered.
In order to define the limitations of the cyclization, the re-
action of the shortest 3-oxobutanoate 10 (n = 0) was con-
ducted under similar conditions (Scheme 3).10 However,
the reaction in acetic acid did not afford the expected
bicyclic compounds, but the reaction in ethanol caused
tandem cyclization to produce an oxabicyclo[3.1.0]hex-
anone.5b Since the yield of the medium-sized macrolides
27–210 (n = 7–10) was moderate (entries 9–12), the long-
est 3-oxobutanoate 120 was prepared by the reaction of
icosane-1,20-diol with 3-bromo-1,1-diphenylprop-1-ene
followed by condensation with diketene, and the reaction
using 120 was carried out. As a result, the corresponding
26-membered macrolide 220 was produced in a better
yield than that of the medium-sized macrolides 27–210 (en-
try 13). This suggested that the intramolecular addition of
those much longer than the icosamethylene-tethered 3-ox-
Figure 1 ORTEP drawing of macrolide 24 and the proton assign-
ment
Synthesis 2011, No. 9, 1365–1374 © Thieme Stuttgart · New York

PAPER
Mn(III)-Assisted Specific Intramolecular Addition
1367
Table 2 Reaction of N-(w-Alkenyl)-3-oxobutanamides 3n with
Manganese(III) Acetatea
Entry n
Ar
Ratio 3n/ Time Product Yieldb Ring
Mn(III) (min)
(%) sizec
1
2
3
4
5
6
7
8
2
3
4
5
6
8
8
8
Ph
1:3
1:5
1:4
1:4
1:4
1:4
1:4
1:4
1:5
1:6
5
60
10
20
20
10
10
10
20
15
42
25
67
58
54
56
47
25
8
9
Ph
43
Ph
44
10
11
12
14
14
14
16
26
Ph
45
Ph
46
Ph
48
4-ClC6H4
4-MeC6H4
Ph
48-Cl
48-Me 40
9
10
20
410
39
34
Figure 2 ORTEP drawing of macrolide 22
10
Ph
420
The result of the cyclization reaction encouraged us to un-
dertake an investigation of a similar reaction using N-(w-
alkenyl)-3-oxobutanamides 3n since many biologically
active macrocyclic lactams from 14 to 20 members were
isolated from natural sources.11 We then undertook the
preparation of the 3-oxobutanamides 3n (n = 2–6, 8, 10,
20). The w-alkenyl-oxaoligomethylen-1-ols were con-
verted under Mitsunobu conditions12 into the correspond-
ing phthalimides followed by hydrolysis according to the
Gabriel amine synthesis followed by condensation of
diketene to finally produce 3n.
a Reaction conditions: 3n (0.2 mmol), Mn(OAc)3·2H2O, boiling
AcOH (100 mL), argon atmosphere.
b Isolated yield based on use of 3n.
c Ring size fused to the dihydrofuran ring.
With the 3-oxobutanamides 3n in hand, we examined the
reaction of 3n with manganese(III) acetate under the same
reaction conditions described above (Scheme 4 and
Table 2). Fortunately, the expected intramolecular addi-
tion proceeded and similar macrocyclic amides 4n from 8
to 26 members were obtained in the yields shown in
Table 2, although the yields were lower than those ob-
tained for the macrolides 2n. Since a single crystal of the
macrocyclic amide 45 (Ar = Ph, n = 5) was successfully
grown from chloroform–hexane, the X-ray crystallo-
graphic analysis was obtained, and the dihydrofuran-
fused 11-membered ring structure was confirmed
(Figure 3).
Figure 3 ORTEP drawing of macrolide 45
We were pleased to confirm that the specific intramolec-
ular addition succeeded using the oligomethylene-teth-
ered w-alkenyl 3-oxobutanoates 1n and 3-oxobutanamides
3n, so that we next applied the reaction to the oligooxa-
methylene-tethered w-alkenyl 3-oxobutanoates 5n (n = 1–
4) in order to synthesize crown ether type macrolides. The
3-oxobutanoates 5n (n = 1–4) were prepared in a manner
similar to the synthesis of 1n except for using polyethylene
glycols. The reactions of the 3-oxobutanoates 5n with
manganese(III) acetate were carried out under the same
reaction conditions to furnish the desired crown ether type
macrolides 6n (n = 1–4) (Scheme 5 and Table 3). The ten-
dency of the reaction was similar to that of the 3-oxobu-
tanoates 1n and the 3-oxobutanamides 3n, however, better
yields of the crown ether type macrolides 6n was achieved
in comparison to that of the macrolides 2n and the macro-
Ar
Ar
O
(CH2)n
3n: n = 2–6, 8, 10, 20
NH
O
O
Ar
Ar
O
Mn(OAc)3
(CH2)n
O
AcOH
argon
reflux
NH
O
4n
Scheme 4
Synthesis 2011, No. 9, 1365–1374 © Thieme Stuttgart · New York

1368
Y. Ito et al.
PAPER
cyclic amides 4n. X-ray analysis of a single crystal of the
17-membered macrolide 63 grown in ethanol deserves
comments. The crystal of 63 incorporated one water mol-
ecule in the internal cavity of the macrocycle (Figure 4).
The distance between the hydrogen atoms of the water
and the ether oxygen atoms of 63 was 1.975 (H33–O6) and
2.032 Å (H32–O4), respectively. This suggested the com-
plexation of 63 as a host along with water as a guest, and
led us to assume that, in general, the crown ether type
macrolides 6n might have some inclusion abilities like
those described for the crown ethers. We next examined
the extraction experiment of 6n with alkali ion picrate
salts. As a result, we found that sodium picrate was ex-
tracted with deuterochloroform containing either the mac-
rolide 63 or the macrolide 64, structurally quite similar to
the 15-crown-5 and 18-crown-6, respectively.13
Ph
Figure 4 ORTEP drawing of macrolide 63
Ph
O
O
O
n
5n: n = 1–4
Ph
O
O
Ph
Ph
O
O
III
Ph
Ph
O
O
Ph
Mn
III
Mn
Mn(OAc)3
O
O
(CH2)n
O
(CH2)n
O
O
III
Mn
AcOH
argon
reflux
n
O
O
O
O
O
III
6n
Mn
A
III
Mn
O
III
Scheme 5
Mn
macrocyclization
(SET)
Table 3 Reaction of Oligooxamethylene-Tethered w-Alkenyl
3-Oxobutanoates 5n with Manganese(III) Acetatea
Mn(OAc)3
dihydrofuranation
(oxidative cyclization)
1n
Entry
n
Ratio 5n/ Time
Product Yieldb
(%)
Ring
sizec
2n
Mn(III)
(min)
Scheme 6
1
2
3
4
1
2
3
4
1:3
5
61
62
63
64
90
57
80
54
11
14
17
20
1:3
5
proceeded rather than polymerization even under more
concentrated and diluted reaction conditions.14
1:5
15
15
In summary, although it is difficult to synthesize medium-
sized cyclic compounds,3a,b the manganese(III)-based ox-
idative macrocyclization followed by dihydrofuranation
was effective for the synthesis of macrolides from 9 to 12
members. It was also possible to prepare the macrolides of
more than 20 members without polymerization. It is a
unique characteristic of the manganese(III)-promoted ox-
idative radical cyclizations.
1:5
a Reaction conditions: 5n (0.2 mmol), Mn(OAc)3·2H2O, boiling
AcOH (100 mL), argon atmosphere.
b Isolated yield based on use of 5n.
c Ring size fused to the dihydrofuran ring.
The intramolecular addition may be explained to proceed
via p-complexation of the electron-rich w-alkenyl part
with manganese(III) enolate such as the ring closure met-
athesis using Grubbs catalyst (A in Scheme 6).6a,9b Al-
though, in the case of the manganese(III) oxidation, the
interaction of the alkene (electron donor) with the manga-
All melting points are uncorrected. All of 1H NMR and 13C NMR
spectra were recorded at 300 MHz for 1H and 75 Hz for 13C, respec-
tively, with TMS as the internal standard. The EIMS spectra were
recorded at the ionizing voltage of 70 eV. HRMS were measured at
nese(III) enolate (electron acceptor) would be weak, the the Institute for Materials Chemistry and Engineering, Kyushu Uni-
versity, Fukuoka, Japan. The elemental analyses were performed at
complexation must be essential for the cyclization to ap-
the Analytical Center of Kumamoto University, Kumamoto, Japan.
proximate the reaction site of the alkene part to the man-
Mn(OAc)3·2H2O was prepared according to the method described
in the literature.5
ganese(III) enolate since the cyclization predominantly
Synthesis 2011, No. 9, 1365–1374 © Thieme Stuttgart · New York

PAPER
Mn(III)-Assisted Specific Intramolecular Addition
IR (CHCl3): 1740, 1715 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): d = 7.35–7.15 (m, 10 H), 6.20 (t,
J = 6.6 Hz, 1 H), 4.15 (t, J = 6.6 Hz, 2 H), 4.01 (d, J = 6.6 Hz, 2 H),
3.41 (s, 2 H), 3.38 (m, 2 H), 2.24 (s, 3 H), 1.72 (m, 2 H), 1.64 (m, 2
H).
13C NMR (75 MHz, CDCl3): d = 200.4, 167.0, 144.4, 141.8, 139.1,
130.0, 128.02, 128.00, 127.43, 127.38, 127.35, 125.5, 69.5, 68.4,
65.1, 49.9, 30.0, 26.1, 26.0.
1369
The crystallographic data has been deposited with the CCDC for
compounds 22 (CCDC 794694), 24 (CCDC 794696), 45 (CCDC
794699), and 63 (CCDC 794698). These data can be obtained free
of charge at www.ccdc.cam.ac.uk/conts/retreiving.html or from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB12 1EZ, UK; fax: +44(1223)336033; e-mail:
deposit@ccdc.ccdc.cam.ac.uk.
8,8-Diphenyl-5-oxaoct-7-en-1-ol; Typical Procedure
Propiophenone (33.2 mL, 250 mmol) in anhyd Et2O (60 mL) was
dropwise added to PhMgBr [prepared by the reaction of PhBr (31.4
mL, 300 mmol) with Mg (7.29 g, 300 mmol) in anhyd Et2O (180
mL)]. After the addition, the mixture was cooled to r.t. and hydro-
lyzed with crushed ice, and then 2 M HCl was added in order to dis-
solve any unchanged Mg. The aqueous soln was extracted with
CHCl3 and 1,1-diphenylpropan-1-ol (52.6 g, 248 mmol; 99%) was
obtained. The propanol (52.6 g, 248 mmol) was heated under reflux
in AcOH (120 mL) for 3 h to give 1,1-diphenylprop-1-ene (42.9 g,
221 mmol; 89%). The propene (1.94 g, 10 mmol) was dissolved in
CCl4 (10 mL), and NBS (1.78 g, 10 mmol), and then a catalytic
amount of (BzO)2 was added. The mixture was heated under reflux
for 12 h and, then after cooling, the precipitated succinimide was fil-
tered off, quantitatively giving 3-bromo-1,1-diphenylprop-1-ene.
HRMS (FAB, CHCl3/NBA): m/z [M – H] calcd for C23H25O4:
365.1753; found: 365.1752.
Other w-alkenyl 3-oxobutanoates 1n (n = 2, 3, 5–10, 20) and 5n
(n = 1–4) were prepared in a similar manner.
15,15-Diphenyl-3,6,9,12-tetraoxapentadec-14-enyl 3-Oxobu-
tanoate (53)
Pale-yellowish oil; yield: 73%; Rf = 0.42 (Et2O).
IR (CHCl3): 1744, 1717 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): d = 7.33–7.14 (m, 10 H), 6.23 (t,
J = 6.6 Hz, 1 H), 4.23 (m, 2 H), 4.08 (d, J = 6.6 Hz, 2 H), 3.71–3.56
(m, 14 H), 3.46 (s, 2 H), 2.25 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 200.3, 166.9, 144.4, 141.6, 139.0,
129.6, 128.2, 128.0, 127.40, 127.36, 127.33, 125.4, 70.5, 70.4, 69.4,
68.7, 64.2, 49.8, 30.0.
Butane-1,4-diol (1.35 g, 15.0 mmol) was allowed to react with 60%
NaH (1.20 g, 30 mmol) in anhyd THF (20 mL) at 60 °C for 10 min
under argon, and then the 3-bromo-1,1-diphenylprop-1-ene (1.37 g,
5.0 mmol) in anhyd THF (10 mL) was slowly added. After the ad-
dition, the mixture was heated under reflux for 3 h, and the reaction
was quenched with ice. The aqueous mixture was extracted with
CHCl3 and purified by chromatographic separation (silica gel,
CHCl3) to give 8,8-diphenyl-5-oxaoct-7-en-1-ol as a pale-yellowish
oil (0.88 g, 3.12 mmol, 62%); Rf = 0.44 (Et2O–hexane, 4:1).
HRMS (FAB, CHCl3/NBA): m/z [M – H] calcd for C27H33O7:
469.2226; found 469.2241.
N-(10,10-Diphenyl-7-oxadec-9-enyl)-3-oxobutanamide (36)
10,10-Diphenyl-7-oxadec-9-en-1-ol (1.31 g, 4.2 mmol) prepared by
a similar manner to that mentioned above, Ph3P (1.44 g, 5.5 mmol),
and phthalimide (0.81 g, 5.5 mmol) were stirred in anhyd THF (15
mL) at 0 °C under argon, and then DEAD (2.5 mL, 5.5 mmol) was
added. The mixture was continued to stir at 0 °C for 12 h, then
quenched with H2O. The aqueous soln was extracted with CHCl3 to
give the corresponding phthalimide (1.80 g, 97%). Ethylenediamine
(1.2 mL) was dropwise added to a mixture of the phthalimide (0.80
g, 1.8 mmol) and MeOH (10 mL) for 30 min at r.t., and then extract-
ed with CHCl3 to give 10,10-diphenyl-7-oxadec-9-en-1-amine
(0.49 g, 88%). The amine (0.85 g, 2.7 mmol) was treated with
diketene (0.32 mL, 4.1 mmol) in anhyd THF (10 mL) to afford 36
(0.73 g, 68%).
IR (CHCl3): 3600–3100 cm–1 (OH).
1H NMR (300 MHz, CDCl3): d = 7.38–7.14 (m, 10 H), 6.21 (t,
J = 6.6 Hz, 1 H), 4.04 (d, J = 6.6 Hz, 2 H), 3.61 (t, J = 5.7 Hz, 2 H),
3.41 (t, J = 5.6 Hz, 2 H), 2.92 (br s, 1 H), 1.67–1.60 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 144.7, 141.7, 139.1, 129.7, 128.14,
128.11, 127.55, 127.48, 125.2, 70.3, 68.5, 62.5, 30.0, 26.7.
HRMS (FAB, CHCl3/NBA): m/z [M – H] calcd for C19H21O2:
281.1542; found: 281.1544.
15,15-Diphenyl-3,6,9,12-tetraoxapentadec-14-en-1-ol
Pale-yellowish oil; yield: 85%; Rf = 0.42 (Et2O–hexane 4:1).
IR (CHCl3): 3600–3000 cm–1 (OH).
1H NMR (300 MHz, CDCl3): d = 7.39–7.14 (m, 10 H), 6.23 (t,
J = 6.6 Hz, 1 H), 4.08 (d, J = 6.6 Hz, 2 H), 3.70–3.55 (m, 16 H),
2.89 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 144.5, 141.7, 139.1, 129.7, 128.3,
128.2, 128.10, 128.07, 127.53, 127.45, 127.42, 125.4, 72.5, 70.5,
70.3, 70.2, 69.4, 68.8, 61.7.
IR (CHCl3): 3444, 3358 (NH), 1713 (C=O), 1663 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.40–7.16 (m, 10 H), 6.95 (br s, 1
H), 6.22 (t, J = 6.6 Hz, 1 H), 4.02 (d, J = 6.6 Hz, 2 H), 3.40–3.36 (m,
4 H), 3.25 (m, 2 H), 2.25 (s, 3 H), 1.75–1.35 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 204.9, 165.3, 144.4, 141.9, 139.3,
129.8, 128.1, 127.6, 127.5, 125.8, 70.3, 68.5, 64.2, 49.5, 39.5, 31.1,
29.7, 26.7, 25.9.
Other N-(w-alkenyl)-3-oxobutanamides 3n (n = 2–5, 8, 10, 20) were
synthesized in a similar manner.
HRMS (FAB, CHCl3/NBA): m/z [M – H] calcd for C23H29O5:
385.2015; found: 385.2013.
Reaction of 1n, 3n, and 5n with Mn(OAc)3; General Procedure
To a soln of the 3-oxobutanoates 1n, 5n, or 3-oxobutanamides 3n
(0.2 mmol) in glacial AcOH (100 mL), Mn(OAc)3·2H2O was added,
and the mixture was sufficiently degassed under reduced pressure
for 30 min using an ultrasonicator for exchange with an argon atmo-
sphere. The mixture was then heated at reflux temperature under an
argon atmosphere for the period mentioned in Tables 1– 3 until the
brown color of Mn(III) disappeared. The color typically turned a
transparent yellow. The solvent was removed in vacuo, and the res-
idue was triturated with H2O (20 mL). The aqueous soln was then
extracted with CHCl3 (3 × 20 mL). The combined extracts were
washed with sat. aq NaHCO3 (30 mL) and H2O, and then concen-
trated to dryness. The crude products 2n, 4n, and 6n were separated
8,8-Diphenyl-5-oxaoct-7-enyl 3-Oxobutanoate (14); Typical
Procedure
8,8-Diphenyl-5-oxaoct-7-en-1-ol (0.85 g, 3.0 mmol) was stirred in
anhyd THF (10 mL) containing imidazole (0.82 g, 12.0 mmol) at r.t.
and diketene (0.23 mL, 3.0 mmol) was slowly added at 0 °C. After
the addition, the mixture was stirred at r.t. for 4 h and the reaction
was quenched with H2O at 0 °C. The aqueous soln was extracted
with CHCl3 and the crude product was separated by column chro-
matography (silica gel, CHCl3), affording 14 as a pale-yellowish oil
(0.78 g, 2.13 mmol, 72%); Rf = 0.25 (CHCl3).
Synthesis 2011, No. 9, 1365–1374 © Thieme Stuttgart · New York

1370
Y. Ito et al.
PAPER
by TLC (silica gel, CHCl3, CHCl3–MeOH, or Et2O–hexane). The
analytical samples were further purified by recrystallization from an
appropriate solvent. The molar ratio and product yields are summa-
rized in Tables 1–3. The specific details are given below.
IR (CHCl3): 1691 (C=O), 1660 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.52–7.25 (m, 10 H), 4.74 (td,
J = 10.8, 2.4 Hz, 1 H), 4.26 (dd, J = 11.7, 4.2 Hz, 1 H), 3.93 (t,
J = 8.7 Hz, 1 H), 3.70 (dt, J = 10.8, 3.3 Hz, 1 H), 3.25 (t, J = 11.7
Hz, 1 H), 3.15–3.12 (m, 1 H), 2.94 (dd, J = 11.7, 4.2 Hz, 1 H), 2.29
(s, 3 H), 1.86–1.22 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 166.9, 166.2, 144.3, 139.8, 128.3,
128.1, 128.0, 127.9, 127.2, 126.19, 126.17, 108.1, 93.6, 73.4, 66.0,
63.2, 44.5, 30.3, 26.1, 20.5, 14.2.
11-Methyl-9,9-diphenyl-3,6,10-trioxabicyclo[6.3.0]undec-1(11)-
en-2-one (22)
Colorless cubes (cyclohexane); mp 183.1–183.5 °C; Rf = 0.20
(CHCl3).
IR (CHCl3): 1703 (C=O), 1647 cm–1 (C=C).
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C24H27O4:
378.1909; found: 379.1909.
1H NMR (300 MHz, CDCl3): d = 7.51–7.25 (m, 10 H), 4.43 (dd,
J = 10.7, 5.7 Hz, 1 H), 4.34 (dd, J = 7.5, 3.5 Hz, 1 H), 4.30 (t, J =
4.2 Hz, 1 H), 3.78 (dt, J = 12.8, 3.9 Hz, 1 H), 3.66 (dd, J = 7.4, 3.5
Hz, 1 H), 3.37 (dd, J = 12.0, 5.7 Hz, 1 H), 3.06 (t, J = 12.0 Hz, 1 H),
2.31 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 169.3, 168.4, 143.9, 139.6, 128.4,
128.18, 128.15, 127.6, 126.0, 126.0, 105.4, 93.4, 72.5, 70.3, 68.8,
50.0, 14.5.
Anal. Calcd for C24H26O4: C, 76.17; H, 6.92. Found: C, 76.15; H,
7.00.
15-Methyl-13,13-diphenyl-3,10,14-trioxabicyclo[10.3.0]penta-
dec-1(15)-en-2-one (26)
Colorless cubes (hexane); mp 171.3–171.6 °C; Rf = 0.12 (CHCl3).
IR (CHCl3): 1690 (C=O), 1649 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.54–7.53 (m, 2 H), 7.51–7.22 (m,
8 H), 4.68 (ddd, J = 10.5, 6.0, 4.0 Hz, 1 H), 4.12 (dd, J = 9.0, 5.1 Hz,
1 H), 3.86 (ddd, J = 10.7, 6.3, 4.0 Hz, 1 H), 3.32 (td, J = 6.6, 3.0 Hz,
1 H), 3.20 (ddd, J = 9.4, 6.3, 3.0 Hz, 1 H), 3.01 (dd, J = 8.8, 5.1 Hz,
1 H), 2.95 (t, J = 9.0 Hz, 1 H), 2.26 (s, 3 H), 1.72–1.48 (m, 8 H).
Anal. Calcd for C21H20O4·0.2H2O: C, 74.19; H, 6.05. Found: C,
74.35; H, 6.00.
12-Methyl-10,10-diphenyl-3,7,11-trioxabicyclo[7.3.0]dodec-
1(12)-en-2-one (23)
Colorless cubes (cyclohexane); mp 138.2–138.5 °C; Rf = 0.34
13C NMR (75 MHz, CDCl3): d = 166.4, 165.4, 144.5, 140.4, 128.1,
127.85, 127.82, 127.1, 126.3, 126.2, 108.2, 93.6, 72.6, 71.3, 62.9,
48.4, 25.78, 25.76, 25.4, 23.6, 14.3.
(CHCl3–MeOH, 99:1).
IR (CHCl3): 1709 (C=O), 1651 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.54–7.20 (m, 10 H), 4.92 (ddd,
J = 7.2, 8.1, 3.3 Hz, 1 H), 4.44 (ddq, J = 10.8, 6.0, 1.2 Hz, 1 H), 3.84
(ddd, J = 11.3, 9.5, 7.2 Hz, 1 H), 3.69 (ddd, J = 9.8, 4.8, 2.4 Hz, 1
H), 3.59 (td, J = 9.8, 1.2 Hz, 1 H), 3.16 (dd, J = 11.9, 6.0 Hz, 1 H),
3.06 (t, J = 10.8 Hz, 1 H), 2.27 (s, 3 H), 1.73–1.60 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 167.2, 165.4, 144.4, 140.1, 128.3,
128.04, 128.02, 127.3, 126.2, 107.5, 93.1, 71.4, 66.8, 61.2, 47.3,
27.6, 13.8.
HRMS (FAB, CHCl3/NBA): m/z [M + H] calcd for C25H29O4:
393.2066; found: 393.2066.
16-Methyl-14,14-diphenyl-3,11,15-trioxabicyclo[11.3.0]hexa-
dec-1(16)-en-2-one (27)
Colorless cubes (hexane); mp 142.0–142.2 °C; Rf = 0.64 (EtOAc–
hexane, 1:4).
IR (CHCl3): 1690 (C=O), 1639 cm–1 (C=C).
HRMS (FAB, CHCl3/NBA): m/z [M + H] calcd for C22H23O4:
351.1596; found: 351.1588.
1H NMR (300 MHz, CDCl3): d = 7.58–7.54 (m, 2 H), 7.47–7.18 (m,
8 H), 4.25 (ddd, J = 5.8, 11.4, 5.7 Hz, 1 H), 4.07 (dd, J = 11.3, 4.5
Hz, 1 H), 4.01 (dd, J = 9.0, 1.8 Hz, 1 H), 3.26–3.18 (m, 2 H), 3.05–
2.98 (m, 2 H), 2.32 (s, 3 H), 1.75–1.25 (m, 10 H).
Anal. Calcd for C22H22O4: C, 75.41; H, 6.33. Found: C, 75.13; H,
6.39.
13C NMR (75 MHz, CDCl3): d = 166.9, 166.2, 145.0, 140.6, 128.1,
127.7, 127.5, 127.1, 126.6, 126.2, 105.7, 94.6, 70.4, 69.9, 64.4,
50.7, 27.2, 26.8, 26.6, 25.3, 25.0, 14.4.
13-Methyl-11,11-diphenyl-3,8,12-trioxabicyclo[8.3.0]tridec-
1(13)-en-2-one (24)
Colorless cubes (hexane); mp 154.5–155.0 °C; Rf = 0.11 (CHCl3).
IR (CHCl3): 1697 (C=O), 1654 cm–1 (C=C).
Anal. Calcd for C26H30O4: C, 76.82; H, 7.44. Found: C, 76.54; H,
7.62.
1H NMR (300 MHz, CDCl3): d = 7.52–7.49 (m, 2 H), 7.33–7.24 (m,
8 H), 4.83 (ddd, J = 10.9, 5.3, 2.9 Hz, 1 H), 4.34 (ddq, J = 11.7, 5.0,
0.8 Hz, 1 H), 3.88 (ddd, J = 11.8, 8.4, 2.9 Hz, 1 H), 3.79 (dt,
J = 10.9, 1.7 Hz, 1 H), 3.40 (ddd, J = 8.4, 4.7, 2.4 Hz, 1 H), 3.12 (t,
J = 11.7 Hz, 1 H), 2.90 (dd, J = 11.7, 5.0 Hz, 1 H), 2.28 (d, J = 0.8
Hz, 3 H), 2.02 (m, 1 H), 1.78 (m, 1 H), 1.60 (m, 1 H), 1.50 (m, 1 H).
17-Methyl-15,15-diphenyl-3,12,16-trioxabicyclo[12.3.0]hepta-
dec-1(17)-en-2-one (28)
Colorless cubes (hexane); mp 102.8–103.3 °C; Rf = 0.28 (CHCl3).
IR (CHCl3): 1696 (C=O), 1648 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.60–7.57 (m, 2 H), 7.35–7.19 (m,
8 H), 4.24–4.11 (m, 2 H), 4.02 (d, J = 6.9 Hz, 1 H), 3.26 (dd, J = 9.0,
2.7 Hz, 1 H), 3.06 (t, J = 9.6 Hz, 1 H), 2.99(dd, J = 9.0, 6.9 Hz, 1
H), 2.78–2.73 (m, 1 H), 2.32 (s, 3 H), 1.73–1.26 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 166.9, 165.6, 145.0, 140.4, 128.0,
127.6, 127.2, 126.92, 126.90, 126.4, 104.2, 94.50, 68.5, 68.1, 62.9,
51.29, 27.5, 26.3, 25.9, 25.4, 23.2, 22.2, 14.4.
13C NMR (75 MHz, CDCl3): d = 166.3, 166.0, 144.3, 139.7, 128.2,
128.0, 127.9, 127.2, 126.20, 126.15, 108.0, 93.0, 71.8, 67.3, 65.0,
44.4, 28.0, 24.3, 14.0.
HRMS (FAB, CHCl3/NBA): m/z [M + H] calcd for C23H25O4:
365.1753; found: 365.1753.
Anal. Calcd for C23H24O4: C, 75.80; H, 6.64. Found: C, 75.60; H,
6.80.
HRMS (FAB, CHCl3/NBA): m/z [M + H] calcd for C27H33O4:
421.2379; found: 421.2373.
14-Methyl-12,12-diphenyl-3,9,13-trioxabicyclo[9.3.0]tetradec-
1(14)-en-2-one (25)
Colorless microcrystals (EtOH); mp 167–168 °C; Rf = 0.35
(CHCl3).
Anal. Calcd for C27H32O4: C, 77.11; H, 7.67. Found: C, 77.00; H,
7.65.
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Mn(III)-Assisted Specific Intramolecular Addition
1371
18-Methyl-16,16-diphenyl-3,13,17-trioxabicyclo[13.3.0]octa-
dec-1(18)-en-2-one (29)
Colorless microcrystals (EtOH); mp 91.5–93.0 °C; Rf = 0.76
(CHCl3).
12-Methyl-10,10-diphenyl-7,11-dioxa-3-azabicyc-
lo[7.3.0]dodec-1(12)-en-2-one (43)
Colorless amorphous; Rf = 0.22 (CHCl3–MeOH, 98:2).
IR (CHCl3): 3500–3100 (CONH), 1660 (C=O), 1639 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.55–7.10 (m, 10 H, Harom), 5.81
(br d, J = 9.0 Hz, 1 H), 4.18 (m, 1 H), 3.94 (m, 1 H), 3.64 (dd,
J = 12.0, 3.0 Hz, 1 H), 3.26 (m, 3 H), 2.89 (br t, J = 12.0 Hz, 1 H),
2.31 (s, 3 H), 1.74–1.65 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 170.3, 163.4, 144.5, 140.5, 129.7,
128.4, 128.0, 127.8, 126.5, 126.2, 108.9, 92.4, 75.8, 72.6, 53.8,
41.6, 29.4, 13.8.
IR (CHCl3): 1701 (C=O), 1647 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.81–7.78(m, 2 H), 7.60–7.18 (m,
8 H), 4.13–4.09 (m, 2 H), 3.98 (d, J = 7.5 Hz, 1 H), 3.32 (dd, J = 9.3,
1.8 Hz, 1 H), 2.99 (dd, J = 9.3, 7.8 Hz, 1 H), 2.82 (ddd, J = 10.2, 6.6,
3.0 Hz, 1 H), 2.65 (ddd, J = 10.2, 7.8, 3.0 Hz, 1 H), 2.32 (s, 3 H),
1.72–1.64 (m, 14 H).
13C NMR (75 MHz, CDCl3): d = 167.4, 165.8, 145.1, 140.4, 132.3,
130.0, 128.2, 127.6, 127.1, 126.94, 126.89, 126.3, 103.8, 94.8, 69.0,
68.0, 63.3, 51.6, 28.4, 28.3, 26.5, 25.9, 25.0, 23.8, 22.7, 14.3.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C22H24O3N:
350.1756; found: 350.1786.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C28H35O4:
435.2535; found: 435.2539.
13-Methyl-11,11-diphenyl-8,12-dioxa-3-azabicyc-
lo[8.3.0]tridec-1(13)-en-2-one (44)
19-Methyl-17,17-diphenyl-3,14,18-trioxabicyclo[14.3.0]nona-
dec-1(19)-en-2-one (210)
Colorless microcrystals (CHCl3–hexane); mp 167–168 °C;
Rf = 0.19 (CHCl3).
Colorless amorphous; Rf = 0.75 (CHCl3).
IR (CHCl3): 1684 (C=O), 1647 cm–1 (C=C).
IR (CHCl3): 3500–3200 (CONH), 1670 (C=O), 1626 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.54–7.12 (m, 11 H), 4.08 (d,
J = 10.2 Hz, 1 H), 3.82–3.71 (m, 2 H), 3.57 (dd, J = 10.2, 1.8 Hz, 1
H), 3.11 (m, 1 H), 2.85 (t, J = 10.2 Hz, 1 H), 2.79–2.77 (m, 1 H),
2.41 (s, 3 H), 1.88–1.50 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 167.5, 164.4, 144.4, 140.7, 128.4,
128.01, 127.98, 127.8, 126.6, 126.2, 109.3, 92.1, 74.8, 73.2, 51.9,
39.8, 28.0, 27.4, 14.0.
1H NMR (300 MHz, CDCl3): d = 7.61–7.59 (m, 2 H), 7.50–7.16 (m,
8 H), 4.19 (ddd, J = 4.7, 9.5, 5.1 Hz, 1 H), 4.13 (ddd, J = 10.1, 9.5,
5.1 Hz, 1 H,), 4.00 (d, J = 7.5 Hz, 1 H), 3.32 (dd, J = 9.2, 1.5 Hz, 1
H), 3.06 (t, J = 7.5 Hz, 1 H), 2.77 (ddd, J = 4.8, 9.6, 4.8 Hz, 1 H),
2.68 (ddd, J = 4.8, 9.6, 4.8 Hz, 1 H), 2.33 (s, 3 H), 1.63–1.30 (m, 16
H).
13C NMR (75 MHz, CDCl3): d = 167.5, 165.8, 145.2, 140.4, 128.2,
128.0, 127.6, 127.1, 127.0, 126.9, 126.4, 103.4, 94.6, 68.7, 68.6,
62.9, 51.5, 28.5, 28.1, 27.2, 27.0, 26.5, 25.8, 25.1, 24.8, 14.5.
Anal. Calcd for C23H25NO3: C, 76.01; H, 6.93; N, 3.85. Found: C,
75.97; H, 6.98; N, 3.84.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C29H37O4:
449.2692; found: 449.2692.
14-Methyl-12,12-diphenyl-9,13-dioxa-3-azabicyclo[9.3.0]tet-
radec-1(14)-en-2-one (45)
Colorless microcrystals (CHCl3–hexane); mp 188–189 °C;
Rf = 0.13 (CHCl3).
IR (CHCl3): 3500–3200 (CONH), 1666 (C=O), 1620 cm–1 (C=C).
29-Methyl-27,27-diphenyl-3,24,28-trioxabicyclo[24.3.0]nona-
cos-1(29)-en-2-one (220)
Colorless amorphous; Rf = 0.79 (CHCl3).
IR (CHCl3): 1690 (C=O), 1647 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.63–7.60 (m, 2 H), 7.38–7.19 (m,
8 H), 4.21–4.11 (m, 1 H) 4.05–4.00 (m, 2 H), 3.45 (dd, J = 9.2, 2.4
Hz, 1 H), 3.01 (t, J = 8.7 Hz, 1 H), 2.87–2.81 (m, 1 H), 2.69–2.62
(m, 1 H), 2.33 (s, 3 H), 1.74–1.03 (m, 36 H).
13C NMR (75 MHz, CDCl3): d = 167.7, 165.8, 145.2, 140.5, 128.4,
128.1, 127.7, 127.2, 127.14, 127.0, 126.5, 125.7, 103.5, 94.7, 70.6,
69.2, 63.6, 51.5, 29.7, 29.23, 29.19, 29.1, 29.0, 28.73, 28.68, 28.5,
28.4, 28.2, 28.1, 27.7, 27.6, 26.2, 25.8, 14.5.
1H NMR (300 MHz, CDCl3): d = 7.71 (br d, J = 8.4 Hz, 1 H), 7.54–
7.51 (m, 2 H), 7.40–7.17 (m, 8 H), 3.97 (d, J = 10.2 Hz, 1 H), 3.87
(ddd, J = 17.3, 8.8, 4.4 Hz, 1 H), 3.54–3.48 (m, 2 H), 3.34 (t, J = 9.9
Hz, 1 H), 2.89 (t, J = 10.2 Hz, 1 H), 2.79 (br t, J = 11.7 Hz, 1 H),
2.42 (s, 3 H), 1.73–1.67, 1.53–1.43 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 165.9, 164.6, 144.4, 140.7, 128.3,
128.02, 127.96, 127.7, 126.5, 126.1, 109.4, 92.3, 75.0, 69.8, 51.0,
39.7, 28.9, 25.5, 22.2, 14.3.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C24H28O3N:
378.2069; found: 378.2064.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C39H57O4:
589.4257; found: 589.4272.
15-Methyl-13,13-diphenyl-10,14-dioxa-3-azabicyc-
lo[10.3.0]pentadec-1(15)-en-2-one (46)
11-Methyl-9,9-diphenyl-6,10-dioxa-3-azabicyclo[6.3.0]undec-
1(11)-en-2-one (42)
Colorless microcrystals (CHCl3–hexane); mp 193–194 °C;
Rf = 0.52 (CHCl3–MeOH, 98:2).
Colorless microcrystals (CHCl3–hexane); mp 136–138 °C;
Rf = 0.22 (CHCl3–MeOH, 96:4).
IR (KBr): 3709–3163 (CONH), 1651 (C=O), 1601 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.52–7.50 (m, 2 H), 7.49–7.19 (m,
8 H), 6.25 (br s, 1 H), 4.39 (dd, J = 10.7, 6.0 Hz, 1 H), 3.65–3.50 (m,
3 H), 3.38 (dd, J = 11.9, 6.0 Hz, 1 H), 3.29–3.22 (m, 1 H), 3.06 (t,
J = 11.7 Hz, 1 H), 2.26 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.6, 163.5, 144.7, 140.3, 128.3,
128.1, 127.9, 127.5, 126.2, 125.9, 106.2, 92.2, 71.3, 70.4, 51.8,
42.3, 14.5.
IR (CHCl3): 3500–3150 (CONH), 1663 (C=O), 1616 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.53–7.25 (m, 10 H), 7.16 (br s, 1
H), 3.90 (d, J = 9.9 Hz, 1 H), 3.69–3.60 (m, 1 H), 3.48–3.43 (m, 1
H), 3.19 (dd, J = 9.3, 1.8 Hz, 1 H), 3.13 (dd, J = 8.8, 2.1 Hz, 1 H),
3.10 (m, 1 H), 3.00 (t, J = 8.8 Hz, 1 H), 2.38 (s, 3 H), 1.75–1.25 (m,
8 H).
13C NMR (75 MHz, CDCl3): d = 166.6, 164.6, 144.5, 140.7, 128.2,
128.0, 127.9, 127.54, 126.50, 126.1, 109.9, 92.5, 75.2, 71.8, 50.3,
38.3, 25.7, 24.74, 24.66, 23.5, 14.6.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C25H30O3N:
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C21H22O3N:
392.2226; found: 392.2211.
336.1600; found: 336.1598.
Synthesis 2011, No. 9, 1365–1374 © Thieme Stuttgart · New York

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PAPER
17-Methyl-15,15-diphenyl-12,16-dioxa-3-azabicyc-
lo[12.3.0]heptadec-1(17)-en-2-one (48)
Colorless microcrystals (CHCl3–hexane); mp 208–209 °C;
Rf = 0.39 (CHCl3).
29-Methyl-27,27-diphenyl-24,28-dioxa-3-azabicyc-
lo[24.3.0]nonacos-1(29)-en-2-one (420)
Colorless amorphous; Rf = 0.49 (CHCl3–MeOH, 98:2).
IR (CHCl3): 3500–3100 (CONH), 1661 (C=O), 1613 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.51–7.49 (m, 2 H), 7.36–7.21 (m,
9 H), 3.84 (dd, J = 9.3, 2.9 Hz, 1 H), 3.32–3.04 (m, 6 H), 2.35 (s, 3
H), 1.64–1.29 (m, 36 H).
13C NMR (75 MHz, CDCl3): d = 166.4, 164.9, 144.6, 140.8, 128.2,
128.1, 128.0, 127.9, 127.5, 126.5, 126.1, 109.6, 93.0, 74.5, 71.9,
50.3, 39.4, 29.9, 29.8, 29.7, 29.5, 29.4, 29.22, 29.17, 29.0, 28.7,
28.4, 28.2, 27.8, 27.7, 27.3, 27.2, 27.1, 27.0, 26.2, 14.7.
IR (KBr): 3600–3100 (CONH), 1663 (C=O), 1626 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.52–7.49 (m, 2 H), 7.36–7.22 (m,
8 H), 6.89 (br t, J = 6.0 Hz, 1 H), 3.82 (dd, J = 9.2, 3.7 Hz, 1 H),
3.50–3.40 (m, 1 H), 3.32–3.24 (m, 2 H), 3.20 (m, 1 H), 3.18 (t,
J = 9.0 Hz, 1 H), 2.95 (dd, J = 9.0, 3.7 Hz, 1 H), 2.34 (s, 3 H), 1.69–
1.38 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 166.4, 164.7, 144.6, 140.6, 128.2,
127.9, 127.8, 127.4, 126.5, 126.0, 110.0, 93.3, 74.2, 71.1, 50.0,
36.9, 26.9, 26.3, 24.6, 23.2, 22.0, 21.7, 14.7.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C39H58O3N:
588.4417; found: 588.4407.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C27H34O3N:
420.2539; found: 420.2534.
14-Methyl-12,12-diphenyl-3,6,9,13-tetraoxabicyclo[9.3.0]tet-
radec-1(14)-en-2-one (61)
15,15-Bis(4-chlorophenyl)-17-methyl-12,16-dioxa-3-azabicyc-
lo[12.3.0]heptadec-1(17)-en-2-one (48-Cl)
Colorless microcrystals (EtOH); mp 168.4–169.0 °C; Rf = 0.24
(Et2O–hexane 1:1).
Colorless amorphous; Rf = 0.43 (CHCl3).
IR (CHCl3): 3500–3150 (CONH), 1661 (C=O), 1614 cm–1 (C=C).
IR (CHCl3): 1695 (C=O), 1663 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.54–7.51 (m, 2 H), 7.36–7.22 (m,
8 H), 4.99–4.91 (m, 1 H), 4.29 (dd, J = 11.7, 4.2 Hz, 1 H), 3.98 (dt,
J = 9.2, 0.9 Hz, 1 H), 3.81–3.58 (m, 5 H), 3.25 (t, J = 11.7 Hz, 1 H),
3.18 (m, 1 H), 2.96 (dd, J = 11.6, 4.2 Hz, 1 H), 2.28 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.9, 165.8, 144.1, 139.8, 128.2,
128.0, 127.3, 126.2, 126.1, 107.9, 93.5, 73.6, 71.5, 69.6, 69.4, 62.7,
45.0, 14.2.
1H NMR (300 MHz, CDCl3): d = 7.42–7.21 (m, 8 H), 6.83 (br t,
J = 5.0 Hz, 1 H), 3.73 (dd, J = 9.8, 2.7 Hz, 1 H), 3.46–3.40 (m, 1 H),
3.33–3.24 (m, 2 H), 3.19 (m, 1 H), 3.16 (t, J = 9.0 Hz, 1 H), 2.91
(dd, J = 9.0, 3.6 Hz, 1 H), 2.30 (s, 3 H), 1.53–1.26 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 166.1, 164.3, 142.7, 138.7, 134.0,
133.6, 128.5, 128.3, 127.9, 127.4, 110.1, 92.4, 73.6, 71.1, 49.9,
37.1, 26.8, 26.2, 24.6, 23.2, 22.0, 21.7, 14.7.
Anal. Calcd for C23H24O5: C, 72.61; H, 6.36. Found: C, 72.50; H,
6.42.
HRMS (FAB, acetone/NBA): m/z [M
+ H] calcd for
C27H3235Cl2O3N: 488.1759; found: 488.1740.
17-Methyl-15,15-diphenyl-3,6,9,12,16-pentaoxabicyc-
lo[12.3.0]heptadec-1(17)-en-2-one (62)
Colorless microcrystals (EtOH); mp 125.0–125.5 °C; Rf = 0.22
(CHCl3).
15,15-Bis(4-methylphenyl)-17-methyl-12,16-dioxa-3-azabicyc-
lo[12.3.0]heptadec-1(17)-en-2-one (48-Me)
Colorless amorphous; Rf = 0.38 (CHCl3).
IR (CHCl3): 3500–3200 (CONH), 1659 (C=O), 1611 cm–1 (C=C).
IR (CHCl3): 1699 (C=O), 1645 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.38–7.18 (m, 8 H), 6.82 (br t,
J = 5.0 Hz, 1 H), 3.76 (dd, J = 9.9, 2.4 Hz, 1 H), 3.48–3.40 (m, 1 H),
3.33–3.25 (m, 2 H), 3.24–3.14 (m, 1 H), 3.17 (t, J = 9.9 Hz, 1 H),
2.91 (dd, J = 8.9, 3.6 Hz, 1 H), 2.35 (s, 3 H), 2.31 (s, 3 H), 2.30 (s,
3 H), 1.61–1.23 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 166.5, 164.8, 141.9, 137.8, 137.4,
136.9, 128.8, 128.6, 126.3, 125.9, 110.0, 93.3, 74.4, 71.1, 49.9,
36.9, 26.9, 26.3, 24.6, 23.1, 21.9, 21.7, 21.04, 21.00, 14.8.
1H NMR (300 MHz, CDCl3): d = 7.67–7.63 (m, 2 H), 7.38–7.18 (m,
8 H), 4.59 (ddd, J = 12.0, 7.2, 2.1 Hz, 1 H), 4.13 (ddd, J = 8.4, 3.0,
1.5 Hz, 1 H), 4.03 (dd, J = 9.0, 3.0 Hz, 1 H), 3.93 (ddd, J = 12.0, 5.4,
2.1 Hz, 1 H), 3.76–3.48 (m, 7 H), 3.43 (ddd, J = 10.3, 5.7, 2.4 Hz, 1
H), 3.32 (ddd, J = 12.8, 6.8, 2.4 Hz, 1 H), 2.87 (t, J = 9.0 Hz, 1 H),
2.68 (ddd, J = 12.8, 5.7, 2.1 Hz, 1 H), 2.35 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 168.2, 165.6, 145.1, 140.6, 128.2,
128.05, 128.00, 127.6, 127.1, 127.0, 126.7, 126.3, 103.1, 95.0, 70.4,
69.6, 69.5, 69.3, 68.8, 68.7, 62.2, 51.9, 14.2.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C29H38O3N:
448.2852; found: 488.2838.
Anal. Calcd for C25H28O6: C, 70.74; H, 6.65. Found: C, 70.48; H,
6.63.
19-Methyl-17,17-diphenyl-14,18-dioxa-3-azabicyc-
lo[14.3.0]nonadec-1(19)-en-2-one (410)
Colorless amorphous; Rf = 0.24 (CHCl3).
20-Methyl-18,18-diphenyl-3,6,9,12,15,19-hexaoxabicyc-
lo[15.3.0]icos-1(20)-en-2-one (63)
Colorless cubes (EtOH); mp 114.1–114.5 °C; Rf = 0.17 (CHCl3).
IR (CHCl3): 1697 (C=O), 1645 cm–1 (C=C).
IR (CHCl3): 3400–3200 (CONH), 1661 (C=O), 1614 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.54–7.51 (m, 2 H), 7.36–7.22 (m,
8 H), 6.79 (br s, 1 H), 3.83–3.80 (dd, J = 6.0, 4.4 Hz, 1 H), 3.34–
3.26 (m, 2 H), 3.20 (dd, J = 9.5, 8.1 Hz, 1 H), 3.14 (m, 2 H), 3.01
(dd, J = 9.5, 4.4 Hz, 1 H), 2.34 (s, 3 H), 1.55–1.37 (m, 16 H).
13C NMR (75 MHz, CDCl3): d = 166.1, 164.6, 144.8, 140.6, 128.2,
127.83, 127.78, 127.4, 126.7, 126.1, 108.6, 93.3, 73.1, 70.7, 50.9,
38.0, 28.4, 28.3, 25.8, 25.7, 25.4, 25.3, 25.1, 24.3, 14.6.
1H NMR (300 MHz, CDCl3): d = 7.63–7.60 (m, 2 H), 7.38–7.15 (m,
8 H), 4.40 (dt, J = 12.2, 4.7 Hz, 1 H), 4.16–4.07 (m, 2 H), 3.73–3.56
(m, 11 H), 3.38 (t, J = 4.5 Hz, 2 H), 3.09 (t, J = 9.6, 8.4 Hz, 1 H),
2.82 (dt, J = 12.0, 4.5 Hz, 1 H), 2.65 (dt, J = 12.0, 4.5 Hz, 1 H), 2.34
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 168.4, 165.4, 145.0, 140.6, 128.0,
127.6, 127.2, 127.0, 126.9, 126.4, 103.0, 94.7, 70.7, 70.63, 70.57,
70.54, 70.2, 69.9, 69.5, 69.3, 62.7, 51.4, 14.5.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C29H38O3N:
448.2852; found: 448.2858.
HRMS (FAB, CHCl3/NBA): m/z [M + H] calcd for C27H33O7:
469.2226; found: 469.2252.
Synthesis 2011, No. 9, 1365–1374 © Thieme Stuttgart · New York

PAPER
Mn(III)-Assisted Specific Intramolecular Addition
1373
Anal. Calcd for C27H32O7·0.25H2O: C, 68.56; H, 6.92. Found: C,
68.71; H, 6.87.
(4) (a) Fürstner, A.; Langemann, K. Synthesis 1997, 792.
(b) Maier, M. E. Angew. Chem. Int. Ed. 2000, 39, 2073.
(c) Prunet, J. Angew. Chem. Int. Ed. 2003, 42, 2826.
(d) Yet, L. Chem. Rev. 2003, 103, 4283. (e) Samojłowicz,
C.; Bieniek, M.; Grela, K. Chem. Rev. 2009, 109, 3708.
(f) Monfette, S.; Fogg, D. E. Chem. Rev. 2009, 109, 3783.
(g) Alcaide, B.; Almendros, P.; Luna, A. Chem. Rev. 2009,
109, 3817.
23-Methyl-21,21-diphenyl-3,6,9,12,15,18,22-heptaoxabicyc-
lo[18.3.0]tricos-1(23)-en-2-one (64)
Colorless amorphous; Rf = 0.10 (CHCl3).
IR (CHCl3): 1693 (C=O), 1645 cm–1 (C=C).
1H NMR (300 MHz, CDCl3): d = 7.62–7.59 (m, 2 H), 7.37–7.16 (m,
8 H,), 4.33–4.19 (m, 2 H), 4.07 (d, J = 7.8 Hz, 1 H), 3.80–3.50 (15
H), 3.40–3.27 (m, 2 H), 3.13 (t, J = 8.7 Hz, 1 H), 2.99 (ddd,
J = 10.5, 6.8, 3.3 Hz, 1 H), 2.72 (td, J = 10.5, 4.2 Hz, 1 H), 2.33 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 168.4, 165.4, 144.9, 140.5, 128.1,
127.7, 127.21, 127.18, 127.0, 126.5, 103.1, 94.8, 71.0, 70.9, 70.8,
70.72, 70.66, 70.62, 70.3, 70.2, 69.40, 69.37, 63.3, 51.1, 14.5.
(5) (a) Tsubusaki, T.; Nishino, H. Tetrahedron 2009, 65, 9448.
(b) Asahi, K.; Nishino, H. Synthesis 2009, 409. (c) Cong,
Z.-Q.; Miki, T.; Urakawa, O.; Nishino, H. J. Org. Chem.
2009, 74, 3978. (d) Cong, Z.-Q.; Nishino, H. Synthesis
2008, 2686. (e) Asahi, K.; Nishino, H. Tetrahedron 2008,
64, 1620. (f) Asahi, K.; Nishino, H. Tetrahedron Lett. 2006,
47, 7259. (g) Chowdhury, F. A.; Nishino, H. J. Heterocycl.
Chem. 2005, 42, 1337. (h) Fujino, R.; Nishino, H. Synthesis
2005, 731. (i) Nguyen, V.-H.; Nishino, H. Tetrahedron Lett.
2004, 45, 3373. (j) Kumabe, R.; Nishino, H. Heterocycl.
Commun. 2004, 10, 135. (k) Kajikawa, S.; Nishino, H.;
Kurosawa, K. Heterocycles 2001, 54, 171. (l) Nguyen, V.-
H.; Nishino, H.; Kajikawa, S.; Kurosawa, K. Tetrahedron
1998, 54, 11445. (m) Ouyang, J.; Nishino, H.; Kurosawa, K.
J. Heterocycl. Chem. 1997, 34, 81. (n) Nishino, H.;
Nguyen, V.-H.; Yoshinaga, S.; Kurosawa, K. J. Org. Chem.
1996, 61, 8264. (o) Nishino, H.; Ishida, K.; Hashimoto, H.;
Kurosawa, K. Synthesis 1996, 888. (p) Nishino, H.;
Hashimoto, H.; Korp, J. D.; Kurosawa, K. Bull. Chem. Soc.
Jpn. 1995, 68, 1999.
HRMS (FAB, acetone/NBA): m/z [M + H] calcd for C29H37O8:
513.2488; found: 513.2476.
Extraction Experiment
Alkali ion picrate salts (0.04 mmol) was dissolved in distilled H2O
(1 mL) in a 5-mL sample vial, and a crown ether type macrolide 6n
(n = 1–4) (0.04 mmol) in CDCl3 (1 mL) was added. The mixture
was vigorously stirred at r.t. for 3 d. Li+, Na+, K+, Lb+, and Cs+ ions
were examined as the alkali ion picrate salts. After 3 d, the organic
layer was picked up by a Pasteur pipette and measured by 1H NMR
1
spectroscopy. The H NMR spectrum of the combination of mac-
rolide 63 and Na+ picrate showed a small but a sharp peak at d =
9.00. The 1H NMR spectrum of the combination of the macrolide 64
and K+ picrate also revealed a peak at d = 8.95. The Li+, Lb+, and
Cs+ ion picrates were not extracted by the macrolides 6n (n = 1–4).
(6) (a) Ito, Y.; Yoshinaga, T.; Nishino, H. Tetrahedron 2010, 66,
2683. (b) Yoshinaga, T.; Nishino, H.; Kurosawa, K.
Tetrahedron Lett. 1998, 39, 9197. (c) Ouyang, J.; Nishino,
H.; Kurosawa, K. J. Heterocycl. Chem. 1995, 32, 1783.
(7) (a) Melikyan, G. G. Org. React. 1997, 49, 427; and
references cited therein. (b) More recent review: Demir, A.
S.; Emrullahoglu, M. Curr. Org. Synth. 2007, 4, 321; and
references cited therein.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of the spectra of all the products 2n, 4n, 6n, the ORTEP
drawing of 22, 23, 24, 26, 45, 63, and CIFs of 22, 24, 45, and 63.
(8) Chowdhury, F. A.; Nishino, H.; Kurosawa, K. Heterocycl.
Commun. 1999, 5, 111.
(9) (a) Jogo, S.; Nishino, H.; Yasutake, M.; Shinmyozu, T.
Tetrahedron Lett. 2002, 43, 9031. (b) Ito, Y.; Nishino, H.
Heterocycl. Commun. 2009, 15, 467.
Acknowledgment
This research was supported by Grants-in-Aid for Scientific Re-
search (C), No. 19550046 and No. 22550041, from the Japan Society
for the Promotion of Science. We gratefully acknowledge Professor
Teruo Shinmyouzu, Institute for Materials Chemistry and Enginee-
ring, Kyushu University, Japan, and Dr. Mikio Yasutake, Graduate
School of Science and Engineering, Saitama University, Japan, for
the measurement of the high resolution FAB mass spectrum and X-
ray crystal structure analysis.
(10) (a) Oumar-Mahamat, H.; Moustrou, C.; Surzur, J. M.;
Bertrand, M. P. Tetrahedron Lett. 1989, 30, 331.
(b) Oumar-Mahamat, H.; Moustrou, C.; Surzur, J. M.;
Bertrand, M. P. J. Org. Chem. 1989, 54, 5684. (c) Swain,
N. A.; Brown, R. C. D.; Bruton, G. Chem. Commun. 2002,
2042. (d) Skerry, P. S.; Swain, N. A.; Harrowven, D. C.;
Smyth, D.; Bruton, G.; Brown, R. C. D. Chem. Commun.
2004, 1772. (e) Swain, N. A.; Brown, R. C. D.; Bruton, G.
J. Org. Chem. 2004, 69, 122.
(11) (a) Smith, A. B. III; Wood, J. L.; Wong, W.; Gould, A. E.;
Rizzo, C. J.; Barbosa, J.; Komiyama, K.; Omura, S. J. Am.
Chem. Soc. 1996, 118, 8308. (b) Xu, Z.; Johannes, C. W.;
Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena, G. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 10302.
(c) Creighton, C. J.; Reitz, A. B. Org. Lett. 2001, 3, 893.
(d) Chow, C. P.; Shea, K. J.; Sparks, S. M. Org. Lett. 2002,
4, 2637. (e) Liu, L.; Chen, Q.; Wu, Y.-D.; Li, C. J. Org.
Chem. 2005, 70, 1539. (f) Llàcer, E.; Urpí, F.; Vilarrasa, J.
Org. Lett. 2009, 11, 3198.
(12) Clive, D. L. J.; Huang, X. Chem. Commun. 2003, 2062.
(13) (a) Pederson, C. J. J. Am. Chem. Soc. 1967, 89, 7017.
(b) Frensdorff, H. K. J. Am. Chem. Soc. 1971, 93, 600.
(c) Poonia, N. S. J. Am. Chem. Soc. 1974, 96, 1012.
(d) Lehn, J. M.; Sauvage, J.-P. J. Am. Chem. Soc. 1975, 97,
6700. (e) Sung, N. K.; Cho, D. W.; Choi, J. H.; Choi, K. W.;
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References and Notes
(1) (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127. (b) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105,
1735. (c) Inoue, M. Chem. Rev. 2005, 105, 4379.
(2) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
734. (b) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476.
(c) Sammes, P. G.; Weller, D. J. Synthesis 1995, 1205.
(3) (a) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14,
95. (b) Casadei, M. A.; Galli, C.; Mandolini, L. J. Am. Chem.
Soc. 1984, 106, 1051. (c) Porter, N. A.; Chang, V. H.-T.
J. Am. Chem. Soc. 1987, 109, 4976. (d) Roxburgh, G. J.
Tetrahedron 1993, 49, 10749. (e) Yet, L. Tetrahedron 1999,
55, 9349. (f) Yet, L. Chem. Rev. 2000, 100, 2963.
Synthesis 2011, No. 9, 1365–1374 © Thieme Stuttgart · New York

1374
Y. Ito et al.
PAPER
(14) When the reaction of 14 (0.2 mmol) with Mn(OAc)3 (1.0
mmol) was carried out for 10 min under concentrated
conditions using AcOH (25 mL), the macrolide 24 was
isolated in 85% yield (cf. Table 1, entry 6). While the
reaction of 17 (0.2 mmol) with Mn(OAc)3 (1.2 mmol) was
conducted for 15 min under dilute conditions using AcOH
(400 mL), the macrolide 27 was obtained in 50% yield (cf.
Table 1, entry 9).
Synthesis 2011, No. 9, 1365–1374 © Thieme Stuttgart · New York