Synthetic Study on Acremoxanthone A: Construction of Bicyclo [32.2]nonane CD Skeleton and Fusion of AB Rings

Article abstract of DOI:10.1055/s-0036-1588600

Toward the total synthesis of acremoxanthone A, a model study has revealed a convergent approach to construct the ABCDE ring system. The key steps include: (1) an effective construction of the bicyclo[3.2.2]nonane skeleton, (2) protocol for generating the bridgehead anion and trapping, and (3) 1,3-dipolar cycloaddition of a nitrile oxide to the internal alkene.

Full text of DOI:10.1055/s-0036-1588600

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2016, 27, A–G
A
letter
Synlett
Y. Hirano et al.
Letter
Synthetic Study on Acremoxanthone A: Construction of Bicyclo
3.2.2]nonane CD Skeleton and Fusion of AB Rings
[
Yoichi Hirano
OH
Kensei Tokudome
Hiroshi Takikawa
Keisuke Suzuki*
G
1
,2-addition of
bridgehead anion
O
E
CO2Me
E
F
B
O
O
D
O
–
B
C
Department of Chemistry, Tokyo Institute of Technology,
+
OH
H
H
H
D
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan
+
N
ksuzuki@chem.titech.ac.jp
C
O–
A
O
C
OAc
N
A
O
nitrile oxide
OMe
OH
OMe
cycloaddition
OH
acremoxanthone A
Received: 01.08.2016
Accepted after revision: 30.08.2016
Published online: 21.09.2016
OH
HO
MeO2C
O
G
O
E
CO2Me
DOI: 10.1055/s-0036-1588600; Art ID: st-2016-u0499-l
OH
F
O
O
Abstract Toward the total synthesis of acremoxanthone A, a model
study has revealed a convergent approach to construct the ABCDE ring
system. The key steps include: (1) an effective construction of the bicy-
clo[3.2.2]nonane skeleton, (2) protocol for generating the bridgehead
anion and trapping, and (3) 1,3-dipolar cycloaddition of a nitrile oxide
to the internal alkene.
B
OH
H
D
OH
O
C
OAc
OH
A
O
O
OH
OH
OH
acremoxanthone A
xanthoquinodin A1
Key words natural products, anthraquinone, xanthone, bridgehead,
bicyclic compounds, halogen–lithium exchange, cycloaddition
OH
CO2Me
O
G
Acremoxanthones,1 xanthoquinodins,2 and beticolins,3
constitute an emerging class of natural products derived
O
F
HO
Cl
O
O
E
4
from the type-II polyketide biosynthesis, sharing a charac-
HO
O
teristic composite structure of anthraquinone and xan-
thone (Figure 1). Particularly, the dual connectivity
O
OH
5
C
B
O
through two C–C bonds (red) conforms a unique bicy-
clo[3.2.2]nonane skeleton (yellow), a rare scaffold in natural
products. Due to the challenges posed by the molecular
complexity and potential biological activities, these natural
products have been ranked as an interesting class of targets
HO
HO
A
O
beticolin-0
Figure 1 Naturally occurring anthraquinone–xanthone composites
6
for chemical synthesis.
In our continued interest in the synthesis of complex
polyketide-derived molecular architectures, we became
interested in the synthesis of acremoxanthone A, and paid
initial attention to the construction of the polycyclic struc-
ture, including the unique bridged bicyclic structure.
and further disconnection of bond B suggested a bridge-
head anion III and an acceptor synthon IV. As the precursor
to anion III, we envisioned using iodide 2 by an iodine–
metal exchange reaction.
Herein, we describe the results of these projects, achiev-
ing construction of the model ABCDE rings of acremoxan-
thone A.
7
As an initial feasibility study, we addressed the con-
struction of the ABCDE ring system by setting pentacycle 1
as the model target (Scheme 1). The retrosynthetic analysis
started by replacing the 1,3-diketone moiety in 1 by an
The keys of this study include:
(1) synthesis of iodide 2,
(2) bridgehead metalation,
8
isoxazoline, suggesting precursor I. The interface of the
B/CD rings could be disconnected by assuming an intramo-
lecular 1,3-dipolar cycloaddition of nitrile oxide (bonds A),
(3) synthesis of the A-ring building block, and
(4) union of AB and CDE ring systems.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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Synlett
Y. Hirano et al.
Letter
troxide (NMO, acetone, H O, rt) and the acetonide
2
formation (2-methoxypropene, PPTS, rt) gave ketone 7 in
77% yield (two steps). Dehydrogenation of 7 under Mukai-
yama conditions (LDA; PhS(Cl)=Nt-Bu, –78 °C) afforded
E
O
D
O
A
D
13
C
B
B
C
enone 8 in 97% yield.
O
O
OH
N
bonds A
OH
OR
HO
1
I
1) K2CO3
DMF
S
+
O
O
Br
2) NaOH (aq)
Br
Br
bond B
O
O
–
32%
2 steps)
I
5
6
4
+
(
+
N
III
O–
2
C
N
OH
1) OsO , NMO
LDA
4
OR
OR
O
O
O
O
O
Br
O
Br
2)
OMe
THF, 0 °C
then
PhS(Cl)=N Bu
II
IV
t
Scheme 1 Synthetic approach for construction of the ABCDE rings
PPTS
77%
2 steps)
–78 °C
97%
7
8
(
Scheme 3 Preparation of enone 8
(1) Synthesis of Iodide 2
We first focused our attention to the synthesis of 2
based on the retrosynthetic analysis shown in Scheme 2.
The two main challenges were: 1) introduction of an iodide
at the bridgehead position, and 2) construction of the bicy-
clo[3.2.2]nonane framework. Sulfonate V was envisioned as
With enone 8 in hand, cyclization into the bicyclic
structure was examined (Table 1). We first applied radical
6a
conditions (n-Bu SnH, AIBN, benzene, reflux), which un-
3
fortunately gave none of the desired ketone 9. Instead, ke-
tone 11 was produced in 23% yield, resulting from the 6-
exo-trig cyclization (Table 1, entry 1). At this juncture, we
turned our attention to the palladium-catalyzed conjugate
addition,14 which gave positive results. Upon treatment of 8
the precursor to 2, assuming a S 1-type displacement of
N
9
sulfonate V by an iodide. In spite of the difficulties often
met with the bridgehead substitutions, we had an opti-
mistic view by the precedents on the bicyclo[3.2.2]nonane
system (vide infra). For installation of two C=C bonds in
the bicyclo[3.2.2]nonane skeleton in V, oxygen functional-
ities were placed at the respective positions as in VI, and
disconnection (red) suggested bromoenone 3 as the precur-
sor, which could be derived from cyclohexenone 4, assum-
ing dihydroxylation of the olefin and the α,β-unsaturation.
10
11
with Pd(OAc)2 (0.2 equiv) in the presence of Ph P (0.8
3
equiv) and Et N (12 equiv) in DMA (110 °C, 3 h), the desired
3
ketone 9 was obtained in 59% yield (Table 1, entry 2). A
small amount of ketone 10 was also formed (17% yield)
from the 6-exo-trig cyclization via the Heck reaction. Use of
tris(o-tolyl)phosphine or tributylphosphine as the ligand
failed to improve the yield of 9 (Table 1, entries 3 and 4).
Pleasingly, the yield of 9 was improved to 68% yield by using
15
i-Pr NEt instead of Et N (Table 1, entry 5).
2
3
Recrystallization of 9 (Et O–hexane) and 10 (CH Cl –
I
RO2SO
HO
HO
2
2
2
SN1
hexane) gave nice single crystals, and X-ray diffraction
O
16
2
V
VI
analyses established their respective structures (Figure 2).
Having constructed the bicyclo[3.2.2]nonane skeleton as
in 9, further conversion into the bridgehead alcohol 18 was
examined (Scheme 4). Treatment of ketone 9 with KHMDS
HO
OH
O
Br
O
Br
(
THF, 0 °C, 30 min) followed by PhNTf (–78 °C to 0 °C, 3 h)
2
1,4-addition
gave enol triflate 13 in 90% yield. Reduction of the triflate
moiety in 13 by transfer hydrogenation (HCO H, i-Pr NEt,
3
4
2
2
cat. Pd(OAc) , Ph P, DMF, 30 °C, 1 h) gave olefin 14 in high
2
3
Scheme 2 Retrosynthetic analysis of iodide 2
yield, which was converted into cyclic sulfate 17 by expo-
sure to acid followed by treatment with NaH and 1,1′-sulfo-
nyldiimidazole (16).17 Elimination of 17 using TBAI (1.5
equiv) and DBU (3.0 equiv) (toluene, reflux, 3 h) and acidifi-
cation gave alcohol 18 in 78% yield.
Scheme 3 shows the preparation of enone 8, starting
12
with the α-alkylation of known β-diketone 5 with bro-
mide 6 (K CO , DMF, 0 °C), and the base-induced elimina-
2
3
tion of thioglycolic acid (NaOH aq, Et O, rt) gave cyclohexe-
2
none 4 in 32% yield. Dihydroxylation of 4 using osmium te-
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Y. Hirano et al.
Letter
Table 1 Palladium-Catalyzed Conjugate Addition
conditions
O
O
O
+
Br
O
O
O
O
O
O
8
9 (7-endo)
10 (6-exo)
Entry
Reagents
n-Bu SnH, AIBN
Solvent
Temp (°C)
Time (h)
Yield (%) of 9 Yield (%) of 10
1a
2
benzene
DMAc
DMAc
DMAc
DMAc
reflux
110
110
110
110
3
3
–
–
3
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
, PPh
, P(o-tolyl)
, P(n-Bu) , Et
, PPh , i-Pr
3
, Et
3
N
59
50
–
17
50
–
3
3
, Et
3
N
2
4b
N
15
3
3
3
5
3
2
NEt
68
17
a
Ketone 11 was obtained in 23% yield.
Resorcinol 12 was obtained in 68% yield.
DMA = N,N-dimethylacetamide.
b
c
OH
O
OH
Br
O
O
11
12
For converting alcohol 18 into iodide 2, we tried to pre-
We noted relevant precedent in the solvolytic study on
the bridgehead sulfonates (Scheme 5, below).11 Triflate A is
relatively unreactive, reflecting the difficulty of the bicy-
clo[2.2.2] system in accommodating the planarity required
for generating bridgehead carbenium ion. By contrast, the
pare triflate 19 as a potential intermediate, which turned
out to be highly unstable (Scheme 5). Upon treatment of al-
cohol 18 with Tf O (pyridine, CH Cl , –78 °C to 0 °C, 2 h),
2
2
2
formation of triflate 19 was suggested by TLC monitoring,
although a small amount of alcohol 18 remained. After
4
18
bicyclo[3.2.2] triflate B reacts much faster (3.5 × 10 times).
quenching, the crude material was primarily composed of
1
triflate 19 ( H NMR), while the purification on SiO chroma-
2
HCO2H
i-Pr2NEt
tography gave an almost 1:1 mixture of 18 and 19. The im-
plication was that triflate 19 underwent facile S 1-type hy-
drolysis even by the weak acidity of silica gel, suggesting
tolerance of the bicyclo[3.2.2] system for the S 1 ionization.
KHMDS
Pd(OAc)2
PPh3
THF, 0 °C
N
O
O
then PhNTf2
78 → 0 °C
DMF, 30 °C
–
O
O
N
O
OTf
13
9
0%
87%
9
H2SO4
THF, rt
NaH, 16
O
HO
THF, 0 °C
O
HO
14
15
TBAI, DBU
toluene
reflux
O
O
S
O
then H2SO4
rt
N
N
HO
N
N
O
S
O
O
7
8%
17
18
16
(
3 steps)
Figure 2 X-ray crystal structures of 9 and 10
Scheme 4 Preparation of alcohol 18
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Y. Hirano et al.
Letter
Tf2O
pyridine
Li
I
CH2Cl2
–78 → 0 °C
+
+
(1)
HO
TfO
I
Li
42% (18: 42%)
18
19
2
A
MsCl
Et3N
MgI2
Li
H
(2)
CH2Cl2
CS2, rt
0
°C
MsO
I
95%
93%
20
2
I
+
Li–I
TfO
TfO
MsO
k / s–1
25 °C in EtOH, ref. 11c)
(3)
(
A
B
C
Li
H
2
.1 x 10–3
6.7 x 101
4.8 x 10–5
Scheme 5 Synthesis of iodide 2 via S 1-type iodination
N
A
21
Scheme 6 Iodine–lithium exchange between bridgehead iodide 2 and
t-BuLi
We found an interesting hint in the [3.2.2] mesylate C,
which is much less reactive than triflate B or even A. By
analogy, mesylate 20 should have higher hydrolytic stabili-
ty, but our idea was that it could be activated by a Lewis
tained, suggesting the E2 reaction of lithio species A with
alkyl iodides (s-BuI and n-BuI) was faster than that of the
less basic alkyllithiums.
9a
acid for the S 1-type ionization. Mesylate 20 was pre-
N
pared in 95% yield from alcohol 18 (MsCl, Et N) as a stable
3
compound that reacted with MgI (5.0 equiv, CS , rt, 7 h),
2
2
cleanly giving iodide 2 in 93% yield.
Table 2 Generation of Bridgehead Anion and Trapping
(
2) Bridgehead Lithiation
The stage was now set to study generation of a bridge-
R–Li
3 equiv)
(
PhCHO
head anion from iodide 2. Scheme 6 illustrates the ex-
change reaction with t-BuLi, which manifests two potential
issues. The first was the unknown preference of the iodine–
lithium exchange, as the lithio species A corresponds also to
+
HO
THF
78 °C
–78 → 0 °C
I
H
–
2
22
21
19
a tertiary anion. The following reaction of t-BuLi with t-
BuI (Scheme 6, eq. 2) serves to shift the equilibrium to the
Entry
RLi
t-BuLi
22 (%)
21 (%)
a
20
preferred direction. The second issue is that alkyllithium
A, being basic enough, may sacrifice itself in a similar man-
ner (Scheme 6, eq. 3) to give hydrocarbon 21. For minimiz-
ing the latter competing path, the inverse addition would
be an effective protocol, that is, to add the iodide 2 into t-
1
2
73
40
49
–
s-BuLi
n-BuLi
43
28
3
a
A slight loss of the yield of 21 was inevitable due to its volatility.
21
BuLi.
With these precautions in mind, we examined the halo-
gen–lithium exchange of bridgehead iodide 2 (Table 2). The
extent of the exchange was assessed by trapping with benz-
(3) Design and Synthesis of A-Ring Building Block
Scheme 7 shows the design and synthesis of the A-ring
unit building block useful for connecting with the CD rings,
that is, hydroxylamine derivative 23 as an equivalent of
synthon IV. The oxime formation relied on a modified
22
aldehyde. Pleasingly, when iodide 2 was added into t-BuLi
(
(
3.0 equiv, THF, –78 °C, 10 min) followed by benzaldehyde
3.3 equiv, –78 °C to 0 °C, 1 h), alcohol 22 was obtained in
23
Fukuyama protocol via isomerization of a nitroso inter-
mediate.24 The known bromobenzene 24 was treated with
25
73% yield (Table 2, entry 1). This result proved the viability
of the C–C bond formation at the bridgehead position.
For convenience, the possibility of using s-BuLi or n-
BuLi was examined (Table 2, entries 2 and 3). It turned out
that although iodide 2 was consumed, the yield of adduct
NBS in the presence of catalytic AIBN (CCl , reflux, 2 h), giv-
4
ing benzyl bromide 25, which was allowed to react with
alkoxyamide 2626 and K CO (DMF, rt, 3 h), giving bromide
2
3
27 in 60% yield. Bromide 27 was treated with n-BuLi (THF,
–90 °C, 10 min), and trapping with DMF (–90 °C, 1 h) gave
aldehyde 23 in 86% yield.
22 was not satisfactory. Considerable amount of 21 was ob-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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Y. Hirano et al.
Letter
O
O
+
H
A
N
OH
N
OAllyl
OR
MeO Ts
IV
23
H
N
OAllyl
Br
Br
Ts
26
NBS, AIBN
CCl4, reflux
K2CO3
DMF, rt
Br
OMe
Br
OMe
25
6
0% (2 steps)
24
O
H
n-BuLi
N
OAllyl
THF, –90 °C
then DMF
N
OAllyl
MeO Ts
MeO Ts
86%
27
23
Scheme 7 Preparation of aldehyde 23
(
4) Union of AB and CDE Ring Systems
With aldehyde 23 in hand, connection of the A ring and
the CDE rings was examined (Scheme 8). Addition of iodide
into t-BuLi (3 equiv, THF, –78 °C, inverse addition, vide su-
2
pra) followed by the reaction with aldehyde 23 (–78 °C to
Scheme 9 Construction of ABCDE ring system
7
0
°C, 2 h) smoothly gave alcohol 282 in 80% yield.
In conclusion, a viable synthetic approach has been de-
veloped to the ABCDE ring system of acremoxanthone A.
Further work directed toward completion of the total syn-
thesis in our laboratory is in progress.
t-BuLi
THF
78 °C
0 min
I
–
1
HO
2
Acknowledgment
–
78 → 0 °C
O
2 h
H
N
OAllyl
This work was supported by Grant-in-Aid for Scientific Research (S)
(No. 16H06351) and Grant-in-Aid for Young Scientists (B) (No.
MeO Ts
26750363) from Japan Society for the Promotion of Science (JSPS).
80%
28
N
OAllyl
We are grateful to Ms. Sachiyo Kubo for X-ray analyses. We also thank
Dr. Masahiko Isaka (BIOTEC, NSTDA, Thailand) for his encouraging
discussion.
MeO Ts
23
Scheme 8 Nucleophilic addition of bridgehead anion to aldehyde 23
Supporting Information
Scheme 9 shows the construction of the ABCDE ring
system. Oxidation of alcohol 28 (IBX, THF, DMSO, 50 °C)
gave ketone 29 in 78% yield. Deallylation of 29 (Pd(PPh ) ,
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588600.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
3
4
dimedone, THF, 60 °C) followed by the elimination of p-tol-
uenesulfinate (NaOH aq, 0 °C) gave two isomeric oxime
products. One was (E)-30 (32%), and its Z counterpart was
isolated in the form of hemiacetal (Z)-30′ (55%, Scheme 9, A).
Pleasingly, both components served to generate the corre-
sponding nitrile oxide under oxidative conditions
References and Notes
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(
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29
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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Letter
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7
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(
(
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(
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(20) Neumann, H.; Seebach, D. Tetrahedron Lett. 1976, 45, 7347.
(21) Zimmerman, H. E.; Lapin, Y. A.; Nesterov, E. E.; Sereda, G. A.
J. Org. Chem. 2000, 65, 7740.
7) (a) Yamashita, Y.; Hirano, Y.; Takada, A.; Takikawa, H.; Suzuki, K.
Angew. Chem. Int. Ed. 2013, 52, 6658. (b) Takahashi, N.;
Kanayama, T.; Okuyama, K.; Kataoka, H.; Fukaya, H.; Suzuki, K.;
Matsumoto, T. Chem. Asian J. 2011, 6, 1752.
(22) Due to the volatility of the protonated compound 21, the D O
2
8) (a) Stork, G.; Danishefsky, S.; Ohashi, M. J. Am. Chem. Soc. 1967,
quenching is not reliable.
(23) Kitahara, K.; Toma, T.; Shimokawa, J.; Fukuyama, T. Org. Lett.
2008, 10, 2259.
(24) In the original report (ref. 22), a TBS group was employed for O-
protecting hydroxylamine. However, our preliminary studies
suggested that the O-TBS group was labile under conditions
using organolithium reagents, and we used an O-allyl group
instead.
8
(
9, 5459. (b) Kashima, C. Heterocycles 1979, 12, 1343.
c) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D.
Synthesis 1987, 857.
9) (a) Martínez, A. G.; Vilar, E. T.; López, J. C.; Alonso, J. M.; Hanack,
M.; Subramanian, L. R. Synthesis 1991, 353. (b) Ioannou, S.;
Nicolaides, A. V. Tetrahedron Lett. 2009, 50, 6938.
(
10) For a review, see: Kraus, G. A.; Hon, Y.-S.; Thomas, P. J.; Laramay,
S.; Liras, S.; Hanson, J. Chem. Rev. 1989, 89, 1591.
11) (a) Bingham, R. C.; Schleyer, P. v. R. J. Am. Chem. Soc. 1971, 93,
(25) Gore, M. P.; Gould, S. J.; Weller, D. D. J. Org. Chem. 1992, 57,
2774.
(
3
189. (b) Gleicher, G. J.; Schleyer, P. v. R. J. Am. Chem. Soc. 1967,
(26) (a) Cooley, J. H.; Misra, B. N.; Throckmorton, J. R.; Bills, W. D.
J. Med. Chem. 1968, 11, 196. (b) Koyama, J.; Sugita, T.; Suzuta,
Y.; Irie, H. Chem. Pharm. Bull. 1983, 31, 2601.
89, 582. (c) Takeuchi, K.; Akiyama, F.; Ikai, K.; Shibata, T.; Kato,
M. Tetrahedron Lett. 1988, 29, 873.
(
12) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Zanirato, V. Tet-
(27) Experimental Procedure for the Nucleophilic Addition of
Bridgehead Anion
rahedron Lett. 1984, 25, 4291.
(
(
13) Mukaiyama, T.; Matsuo, J.; Kitagawa, H. Chem. Lett. 2000, 1250.
14) (a) Kelly, S. A.; Foricher, Y.; Mann, J.; Bentley, J. M. Org. Biomol.
Chem. 2003, 1, 2865. (b) Foricher, Y.; Mann, J. Tetrahedron Lett.
A flask was charged with t-BuLi (1.69 M in n-pentane, 479 μL,
810 μmol), to which a solution of iodide 2 (79.4 mg, 270 μmol,
azeotropically dried with toluene) in THF (3.0 mL) was added at
–78 °C. After stirring for 10 min at this temperature, a solution
of aldehyde 23 (347 mg, 891 μmol, azeotropically dried with
toluene) in THF (6.0 mL) was added. The reaction was allowed
to warm gradually to 0 °C over 1.5 h. After stirring for 30 min at
this temperature, the reaction was stopped by adding sat. aq
2000, 41, 2007. For reviews, see: (c) Dounay, A. B.; Overman, L.
E. Chem. Rev. 2003, 103, 2945. (d) Beletskaya, I. P.; Cheprakov, A.
V. Chem. Rev. 2000, 100, 3009.
(15) Experimental Procedure for the Palladium-Catalyzed Conju-
gate Addition
A mixture of enone 8 (4.82 g, 14.3 mmol), Pd(OAc)2 (641 mg,
NH Cl, and the mixture was extracted with EtOAc (3×). The
4
2
.86 mmol), Ph P (3.00 g, 11.4 mmol), and i-Pr NEt (29.9 mL,
combined organic extracts were washed with brine, dried
(Na SO ), and concentrated in vacuo. The residue was purified
3
2
171 mmol) in DMA (240 mL) was degassed by sonication under
2
4
reduced pressure. After stirring for 3 h at 110 °C, the reaction
by flash column chromatography (silica gel, hexane–toluene–
was stopped by adding sat. aq NH Cl, and the mixture was
acetone = 7:1:1) to afford alcohol 28 (121 mg, 80%) as colorless
4
extracted with Et O (4×). The combined organic extracts were
oil.
2
1
washed with brine, dried (Na SO ), and concentrated in vacuo.
R = 0.29 (hexane–EtOAc = 2:1). H NMR (600 MHz, CDCl ): δ =
2
4
f
3
The residue was purified by flash column chromatography
silica gel, hexane–EtOAc = 9:1 to 8:1) to afford ketone 9 (2.51 g,
8%) and ketone 10 (608 mg, 17%) both as white solids.
R = 0.43 (hexane–acetone = 4:1). mp 98–99 °C (Et O–hexane,
2.33 (s, 3 H), 2.34 (br s, 1 H), 2.47 (s, 3 H), 2.55 (br d, 1 H, J = 17.1
Hz), 3.08 (br d, 1 H, J = 17.1 Hz), 3.75 (dd, 1 H, J = 6.6, 6.3 Hz),
3.78 (s, 3 H), 3.93 (br, 1 H), 4.13 (br, 1 H), 4.20 (br, 1 H), 4.62 (br,
1 H), 4.91–5.16 (m, 3 H), 5.40–5.53 (m, 1 H), 5.73 (d, 1 H, J = 8.0
Hz), 6.38 (dd, 1 H, J = 8.0, 6.3 Hz), 6.42 (d, 1 H, J = 8.1 Hz), 6.54
(
6
f
2
1
colorless plate). H NMR (600 MHz, CDCl ): δ = 1.42 (s, 3 H), 1.52
3
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

G
Synlett
Y. Hirano et al.
Letter
(
dd, 1 H, J = 8.1, 6.6 Hz), 6.65 (s, 1 H), 6.90 (d, 1 H, J = 7.2 Hz),
the mixture was extracted with EtOAc (3×). The combined
organic extracts were washed with brine, dried (Na SO ), and
6
7
2
1
1
1
5
5
.93–7.04 (m, 2 H), 7.04–7.14 (m, 2 H), 7.40 (d, 2 H, J = 8.1 Hz),
2
4
13
.87 (d, 2 H, J = 8.1 Hz). C NMR (150 MHz, CDCl ): δ = 21.7,
concentrated in vacuo. The residue was purified by PTLC
(hexane–EtOAc = 1:1) to afford isoxazoline 31 (6.6 mg, 80%) as a
white solid.
3
2.0, 34.6, 43.7, 46.2, 46.9, 55.9, 73.3, 78.5, 111.3, 117.9, 119.6,
20.7, 125.2, 126.2, 127.1, 129.6, 129.7, 130.1, 130.6 (2 C),
32.4, 132.5, 133.70, 133.72, 136.7, 139.0, 139.5, 142.9, 144.9,
58.5. IR (neat): 3542, 2937, 1355, 1303, 1167, 913, 730, 539,
1
R = 0.43 (hexane–EtOAc = 1:1). H NMR (600 MHz, CDCl ): δ =
f
3
2.46 (s, 3 H), 3.06 (d, 1 H, J = 18.0 Hz), 3.74 (dd, 1 H, J = 6.6, 1.2
Hz), 3.78 (d, 1 H, J = 18.0 Hz), 3.98 (s, 3 H), 4.21 (d, 1 H, J = 10.5
Hz), 5.20 (dd, 1 H, J = 10.5, 1.2 Hz), 5.63 (d, 1 H, J = 9.0 Hz), 6.58
(dd, 1 H, J = 9.0, 6.6 Hz), 7.04 (s, 1 H), 7.10–7.15 (m, 2 H), 7.17 (d,
–1
+
05 cm . ESI-HRMS: m/z calcd for C33H36NO S [M + H] :
5
58.2309; found: 558.2302.
(
28) Das, B.; Holla, H.; Mahender, G.; Banerjee, J.; Reddy, M. R. Tetra-
hedron Lett. 2004, 45, 7347.
13
1 H, J = 7.6 Hz), 7.18–7.23 (m, 1 H), 7.61 (s, 1 H). C NMR (150
(
29) Experimental Procedure for 1,3-Dipolar Cycloaddition
To a solution of hemiacetal (Z)-30′ (8.2 mg, 23 μmol) in MeCN
MHz, CDCl ): δ = 22.0, 35.7, 45.6, 50.1, 56.3, 56.8, 82.0, 116.5,
3
117.4, 121.1, 126.4, 126.5, 127.5, 128.9, 131.98, 132.00, 135.3,
135.7, 136.5, 142.0, 150.2, 156.9, 197.4. IR (neat): 2924, 2852,
(
(
0.5 mL) were added NaHCO3 (2.5 mg, 30 μmol) and PhI(OAc)2
9.6 mg, 30 μmol) at 0 °C. After stirring for 16 h at room tem-
–1
1687, 1602, 1311, 1066, 900, 753, 733 cm . ESI-HRMS: m/z
+
perature, the reaction was stopped by adding sat. aq NH Cl, and
calcd for C23H20NO [M + H] : 358.1443; found: 358.1442.
4
3
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G