Lewis-acid-mediated ring-exchange reaction of dihydrobenzofurans and its application to the formal total synthesis of (-)-quinocarcinamide

Article abstract of DOI:10.1016/j.tetlet.2012.09.030

An unusual Lewis-acid-mediated ring-exchange reaction of dihydrobenzofurans is described. The fused tricyclic ring system is the key structural element for this reaction as it restricts C-N bond rotation and/or destabilizes the benzofuran ring. We achieved the formal total synthesis of (-)-quinocarcinamide using a combination of this reaction and the Au(I)-catalyzed 6-endo-dig hydroamination of an alkyne.

Full text of DOI:10.1016/j.tetlet.2012.09.030

Tetrahedron Letters 53 (2012) 6273–6276
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Lewis-acid-mediated ring-exchange reaction of dihydrobenzofurans
and its application to the formal total synthesis of (ꢀ)-quinocarcinamide
⇑
⇑
Hiroaki Chiba, Yuki Sakai, Shinya Oishi, Nobutaka Fujii , Hiroaki Ohno
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2012
Revised 5 September 2012
Accepted 7 September 2012
Available online 14 September 2012
An unusual Lewis-acid-mediated ring-exchange reaction of dihydrobenzofurans is described. The fused
tricyclic ring system is the key structural element for this reaction as it restricts C–N bond rotation
and/or destabilizes the benzofuran ring. We achieved the formal total synthesis of (ꢀ)-quinocarcinamide
using a combination of this reaction and the Au(I)-catalyzed 6-endo-dig hydroamination of an alkyne
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
(ꢀ)-Quinocarcinamide
Lewis acid
Ring-exchange
Dihydrobenzofuran
Introduction
appropriate nucleophilic functionality in the substrate. We em-
barked on an investigation to clarify the structural requirements
Quinocarcin is a pentacyclic tetrahydroisoquinoline alkaloid,
isolated by Takahashi and Tomita1 in 1983. Its intricate polycyclic
architecture and potent broad-spectrum antitumor activity2,3 have
attracted both synthetic and biological chemists, culminating in
several efficient syntheses, reported by Fukuyama,4 Garner, Tera-
shima, Myers, Zhu, and Stoltz.5 We recently reported the enantio-
selective total synthesis of (ꢀ)-quinocarcin using Au(I)-catalyzed
intramolecular hydroamination of alkynes (Scheme 1).6 In this syn-
thesis, we had to overcome the challenging problem of cleaving the
dihydrobenzofuran ring7,8 in 6, which was a key structural element
for the 6-endo-dig over 5-exo-dig hydroamination. Based on the LiI-
mediated ring-opening halogenation of benzofurans in the pres-
ence of SiCl4 and BF3ꢁAcOH reported by Zewge et al.,7 we attempted
a ring-exchange strategy using neighboring group participation of
the carbonyl oxygen of lactam 6 to afford an oxazolidinium inter-
mediate 7. Exposure of lactam 6 to BF3ꢁEt2O and SiCl4 in 1,2-dichlo-
which would accelerate the ring-opening reaction. Its synthetic
application to the formal total synthesis of (ꢀ)-quinocarcinamide
is also described.
2,5-cis-
pyrrolidine
formation
9 steps
(22%)
OTBDPS
Br
.
HO
O
O
NHTs
(95%)
dr = 96:4
AcO
1
2 (dr = 55:45)
AcO
7 steps
(54%)
MeO2C
Sonogashira
coupling
OTBDPS
CO2Me
N
N
then TFA
(90%)
Ts
Me
2,5-cis-3
2,5-cis-4
MeO2C
CO2Me
Lewis-acid-
mediated
H
CO2Me
H
N
N
Me
Au(I)-catalyzed
hydroamination
ring-opening
SiCl4, BF3·Et2O
then CsCl
Me
N
roethane (1,2-DCE) afforded
a suspension, which possibly
(6-endo-digselective)
NH2
contained the expected oxazolidinium intermediate 7. Addition
of H2O to the resulting suspension led to recovery of the starting
material 6, but work-up with CsCl afforded the desired chlorinated
phenol 8 in 92% yield.
Based on these results, we thought that easier ring-opening of
dihydrobenzofuran would be achieved by introduction of an
H
1,2-DCE, 20 °C
then MeCN, 60 °C
(92%)
then reduction and
amide formation
(85%)
O
O
O
5
6
CO2Me
CO2Me
Me
N
CO2H
H
H
H
H
H
N
H
Me
Me
N
N
N
N
O
7
H
H
H
O
OH
O
OMe
O
Cl
SiCl3
⇑
Cl
8
Corresponding authors. Tel.: +81 75 753 4551; fax: +81 75 753 4570 (N.F.); tel.:
(
)-Quinocarcin
+81 75 753 4571; fax: +81 75 753 4570 (H.O.).
E-mail addresses: nfujii@pharm.kyoto-u.ac.jp (N. Fujii), hohno@pharm.kyoto-u.
ac.jp (H. Ohno).
Scheme 1. Total synthesis of (ꢀ)-quinocarcin.6
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.030

6274
H. Chiba et al. / Tetrahedron Letters 53 (2012) 6273–6276
Table 1
Results and discussion
Investigation of dihydrobenzofuran ring-exchange reactions
We tested our theory using the reaction of N-Boc-dihydroiso-
quinoline 9 (Scheme 2). Treatment of 9 with SiCl4 and BF3ꢁEt2O
in 1,2-DCE afforded oxazolidinone 10 in 84% yield. In this case,
the reaction proceeded at room temperature and work-up with
CsCl (to suppress the reverse reaction) was not necessary. When
the reaction was performed in the absence of BF3ꢁEt2O, the starting
material 9 was only recovered. This is in good accordance with the
literature.7 This ring-exchange reaction is interesting and unusual
because the normally stable dihydrobenzofuran ring can be selec-
tively converted into oxazolidinone by simultaneous C–O bond
cleavage of the dihydrobenzofuran and C–O bond formation of
the oxazolidinone ring. We thought that the possible requirements
for the ring-exchange reaction would be: (1) restricted C–N bond
rotation to give the appropriate arrangement of the carbonyl
oxygen at the back of the furan C–O bond as shown in A, and (2)
slightly distorted tricyclic ring systems in 6 and 9 to destabilize
the benzofuran ring. Restriction of the C–N bond in 9 can be
achieved by the tricyclic ring system and/or an aminomethyl sub-
stituent at the C-3 position of dihydroisoquinoline.
To clarify the structural requirements for the ring-exchange
reaction, we investigated the reaction using N-Boc-3-amin-
odihydrobenzofurans 11a–c (Table 1, entries 1–3). These
substrates contain the minimum necessary functionalities for the
reaction. Treatment of dihydrobenzofurans 11a–c with BF3ꢁEt2O
and SiCl4 in 1,2-DCE did not provide the oxazolidinones 12. In-
stead, amines 13a/b and 11a, formed by removal of the Boc group,
were obtained in modest yields. Similarly, methyl carbamate 11d
did not produce oxazolidinone 12b, but underwent elimination
of methyl benzylcarbamate (entry 4). These observations show
that (1) restricted C–N bond rotation and/or (2) a distorted tricyclic
ring system are important for a successful ring-exchange reaction.
We then investigated partial restriction of the C–N bond rota-
tion by introduction of a substituent at the 4-position of the benzo-
furan ring. Treatment of 4-iododihydrobenzofurans 11e/f6 with
BF3ꢁEt2O and SiCl4 only gave the corresponding amines 13e/f, with-
out promoting the ring-exchange reaction (entries 5 and 6). In
sharp contrast, tricyclic dihydroisoquinoline 11g (entry 7), which
was prepared by Sonogashira coupling of aryl iodide 11e with
phenylacetylene, followed by Au(I)-catalyzed 6-endo-dig hydroam-
ination of an alkyne, afforded the corresponding ring-exchange
product 12g in 95% yield upon exposure to identical reaction con-
ditions. When the tricyclic tetrahydroisoquinoline-type substrate
11h was used, the corresponding ring-exchange product 12h was
obtained in 45% yield along with 18% yield of the amine 13h. These
SiCl4
R
R
R
BF3·Et2O
NBoc
N
NH
O
1,2-DCE
20 °C
OH
O
11
O
O
13
12
Entry
1
Dihydrobenzofuran
Phenola (%)
Aminea (%)
H
N
NH2
NHBoc
O
O
O
OH
O
O
13a (38%)
11a
12a (0%)
Bn
N
NHBn
NBnBoc
O
2
OH
O
O
11b
13b (48%)
12b (0%)
Boc
N
NHBoc
NBoc2
O
O
O
3
OH
O
O
11a (63%)
11c
12c (0%)
Bn
N
Bn
N
NHBn
4b
CO2Me
O
OH
O
O
13b (0%)
11d
12b (0%)
4
I
I
I
H
N
NH2
NHBoc
O
O
5
6
OH
O
O
O
O
11e
13e (67%)
12e (0%)
4
I
I
I
Bn
N
NBnBoc
NHBn
OH
O
O
13f (43%)
11f
12f (0%)
Ph
Ph
Ph
N
NH
NBoc
O
O
7
OH
12g (95%)
Ph
O
O
O
13g (0%)
11g
Ph
Ph
Ph
N
NH
NBoc
8
OH
12h (45%)
Ph
O
O
O
13h (18%)
11h
Ph
Lewis-Acid -Mediated
Ring-Exchange
N
NH
3
NCO2Me
O
O
N
CO2Me
N
CO2Me
SiCl4, BF3·Et2O
9
Me
Me
OH
O
N
O
NBoc
O
O
O
1,2-DCE, 20 °C
84%
13g (0%)
12g (42%)
11i
OH
O
O
9
10
N
NH
NBoc
10
11c
SiCl4
BF3·Et2O
OH
O
O
R =
N
Me
CO2Me
13j (0%)
11j
12j (0%)
Br
Br
Br
R
O
R
N
NH
NBoc
O
N
O
N
Cl
O
OH
O
O
O
O
O
O
Cl3Si
13k (0%)
12k (75%)
11k
Cl4Si
A
B
a
b
c
Isolated yields. No starting materials were recovered in all cases.
Methyl benzylcarbamate was formed in 59% yield.
SiBr4 was used in place of SiCl4.
Scheme 2. Lewis-acid-mediated ring-exchange reaction of N-Boc-dihydroisoquin-
oline 9.

H. Chiba et al. / Tetrahedron Letters 53 (2012) 6273–6276
6275
Sonogashira
Coupling
a
Au(I)-Cat .
Experimental
N
CO2Me
I
Hydroamination
Me
(6-endo-dig selective)
Lewis-acid-mediated ring-exchange reaction
b
NHBoc
NHBoc
(92%)
O
(96%)
O
General procedure: synthesis of methyl (R)-2-{[(10-hydroxy-3-
oxo-3,10b-dihydro-1H-oxazolo[4,3-a]isoquinolin-5-yl)methyl]
(methyl)amino}acetate (10) (Scheme 2)
11e
(R)-
14
Lewis-Acid-Mediated
Ring-Exchange
N
CO2Me
N
CO2Me
SiCl4 (0.03 mL, 0.27 mmol) and BF3ꢁEt2O (0.004 mL, 0.03 mmol)
were added to a stirred solution of 9 (20.4 mg, 0.05 mmol) in 1,2-
DCE (2 mL) under argon at room temperature. After stirring for 4 h,
Et3N (0.3 mL) and EtOH (2 mL) were added. An insoluble residue
was filtered off and the filtrate was concentrated under reduced
pressure. The residue was purified by column chromatography
over silica gel with n-hexane–EtOAc (1:1) to give 10 as a white so-
lid (14.5 mg, 84% yield): Rf = 0.24 (n-hexane–EtOAc 1:1); mp 165–
Me
Me
Scheme 2
NBoc
N
O
(84%)
O
OH
O
10
9
CO2H
Me
H
H
Williams11
c,d
N
CO2Et
N
Me
O
N
N
(63%)
H
166 °C; ½a 2D5
ꢂ
ꢀ164.7 (c 0.98, EtOH); IR (neat, cmꢀ1): 3265 (OH),
OMe
O
OMe
O
OH
1731 (C@O); 1H NMR (500 MHz, CD3OD) d 2.45 (s, 3H), 3.34 (d,
J = 14.3 Hz, 1H), 3.41 (d, J = 16.6 Hz, 1H), 3.46 (d, J = 16.6 Hz, 1H),
3.67 (s, 3H), 4.34 (d, J = 14.3 Hz, 1H), 4.56 (dd, J = 10.9, 9.2 Hz,
1H), 5.04 (dd, J = 9.2, 8.0 Hz, 1H), 5.26 (dd, J = 10.9, 8.0 Hz, 1H),
6.03 (s, 1H), 6.63 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 7.4 Hz, 1H), 7.07
(dd, J = 7.4, 7.4 Hz, 1H); 13C NMR (125 MHz, CD3OD) d 42.1, 51.9,
56.2, 57.3, 58.2, 71.1, 115.8, 116.0, 118.1, 119.1, 130.2, 133.3,
134.8, 154.4, 156.9, 173.0. Anal. Calcd. for C16H18N2O5: C, 60.28;
H, 5.85; N, 8.72. Found C, 60.37; H, 5.70; N, 8.80.
15
(
)-Quinocarcinamide
Scheme 3. Application to the formal total synthesis of (ꢀ)-quinocarcinamide.
Reagents and conditions: (a) methyl 2-[methyl(propargyl)amino]acetate, Pd(OAc)2,
n-Bu4NOAc, DMF, 80 °C; (b) IPr–AuCl, AgNTf2, 1,2-DCE, 45 °C; (c) Me2SO4, Cs2CO3,
acetone, 0 °C; (d) K2CO3, EtOH, 20 °C. IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-
2-ylidene.
results showed that the appropriate fused ring structure, which
would restrict the arrangement of the carbonyl oxygen and desta-
bilize the benzofuran ring, is vital for this unusual ring-exchange
reaction. Tricyclic dihydroisoquinoline substrate 11i, N-methoxy-
carbonyl analogue of 11g, was also converted into the same phenol
12g albeit in lower yield (entry 9). Unfortunately, treatment of
substrate 11j, with no substituent at the C-3 position of dihydro-
isoquinoline, led to a complex mixture of unidentified products
(entry 10). On the other hand, when using substrate 11k, we ob-
tained the resulting phenol 12k in 75% yield bearing a C-3 bromo
substituent, which is useful for further elaborations. It is notewor-
thy that in this case SiBr4 was used in place of SiCl4 because the
reaction of the bromide 11k under the standard conditions caused
halogen-exchange to form a considerable amount of the corre-
sponding chloride (ca. 50% yield, judged by 1H NMR and GC–MS,
entry 11).
Next, we applied this ring-exchange reaction to the formal total
synthesis of quinocarcinamide. Quinocarcinamide is formed by a
Cannizzaro-type self-redox disproportionation of quinocarcin,
which serves as its own reductant.9 As previously described,6 the
optically active precursor 9 was prepared by Sonogashira coupling
of the protected 4-iodo-2,3-dihydrobenzofuran-3-amine (R)-11e
with a propargylamine derivative, followed by Au(I)-catalyzed
6-endo-dig selective hydroamination of the corresponding alkyne
14 (Scheme 3). A Lewis-acid-mediated ring-exchange reaction of
9, shown in Scheme 2, subsequent methylation of the resulting
phenol 10, and transesterification10 gave the optically active ethyl
ester 15, whose spectral properties were identical to those re-
ported for ( )-15 by Flanagan and Williams in their total synthesis
of ( )-quinocarcinamide.11 This unusual Lewis-acid-mediated ring-
exchange reaction of dihydrobenzofuran therefore provides easy
access to the asymmetric synthesis of (ꢀ)-quinocarcinamide.
Formal synthesis of (ꢀ)-quinocarcinamide
Synthesis of ethyl (R)-2-{[(10-methoxy-3-oxo-3,10b-dihydro-
1H-oxazolo[4,3-a]isoquinolin-5-yl)methyl](methyl)amino}
acetate (15) (Scheme 3)
Cs2CO3 (1.03 g, 3.16 mmol) was added to a stirred solution of 10
(0.33 g, 1.05 mmol) in acetone (50 mL) under argon at room temper-
ature. After stirring the mixture for 30 min, Me2SO4 (0.1 mL,
1.07 mmol) was added at ꢀ10 °C, and the resulting mixture was stir-
red for 4 h at 0 °C. H2O (50 mL) and EtOAc (50 mL) were added and
the mixture was allowed to warm to room temperature. The organic
phase was separated and washed with brine, dried over MgSO4, and
concentrated under reduced pressure. Purification by column chro-
matography over silica gel with n-hexane–EtOAc (2:1) gave the cor-
responding methyl ether as a yellow oil (0.34 g, 97%).
K2CO3 (40.5 mg, 0.29 mmol) was added to a stirred solution of
this methyl ether (19.5 mg, 0.06 mmol) in EtOH (2 mL) under ar-
gon at room temperature. After stirring the mixture for 9 h, satu-
rated aqueous NH4Cl (2 mL) was added. The resulting mixture
was extracted with EtOAc. The extract was washed with H2O and
brine, dried over MgSO4, and concentrated under reduced pressure
followed by purification by column chromatography over silica gel
with n-hexane–EtOAc (2:1) to give 15 as a yellow oil (12.9 mg,
63%): Rf = 0.47 (n-hexane–EtOAc 1:1); ½a D25
ꢀ199.8 (c 0.87, CHCl3);
ꢂ
IR (neat, cmꢀ1): 1761 (C@O); 1H NMR (500 MHz, CDCl3) d 1.27 (t,
J = 7.2 Hz, 3H), 2.51 (s, 3H), 3.42 (d, J = 16.6 Hz, 1H), 3.52 (d,
J = 16.6 Hz, 1H), 3.58 (d, J = 14.9 Hz, 1H), 3.81 (s, 3H), 4.17 (q,
J = 7.2 Hz, 2H), 4.30 (d, J = 14.9 Hz, 1H), 4.50 (dd, J = 10.9, 9.2 Hz,
1H), 4.98 (dd, J = 9.2, 8.0 Hz, 1H), 5.27 (dd, J = 10.9, 8.0 Hz, 1H),
6.02 (s, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 7.22
(dd, J = 8.6, 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 14.3, 41.6,
54.7, 55.4, 56.1, 57.6, 60.3, 69.4, 109.7, 112.7, 118.2, 119.1, 129.3,
132.4, 135.3, 154.6, 155.0, 171.2; HRMS (FAB) Calcd for
Conclusions
In summary, we investigated the Lewis-acid-mediated ring-ex-
change reaction of dihydrobenzofurans. A tricyclic ring system for
the restriction of the C–N bond rotation and/or destabilization of
the benzofuran ring is the key structural element for the success of
this ring-exchange reaction. A combination of this reaction with
the Au(I)-catalyzed 6-endo-dig hydroamination of an alkyne was
used to achieve the formal total synthesis of (ꢀ)-quinocarcinamide.
C
18H23N2O5 (MH+): 347.1607; found: 347.1609.
Acknowledgments
This work was supported by a Grant-in-Aid for the Encourage-
ment of Young Scientists (A) (H.O.) and Platform for Drug Design,

6276
H. Chiba et al. / Tetrahedron Letters 53 (2012) 6273–6276
H.; Hirata, T.; Kasai, M.; Fujimoto, K.; Ashizawa, T.; Morimoto, M.; Sato, A. J.
Med. Chem. 1991, 34, 1959; (d) Kahsai, A. W.; Zhu, S. T.; Wardrop, D. J.; Lane, W.
S.; Fenteany, G. Chem. Biol. 2006, 13, 973.
Discovery, and Development from the MEXT, Japan. H.C. is grateful
for Research Fellowships from the Japan Society for the Promotion
of Science (JSPS) for Young Scientists.
4. For total synthesis of ( )-quinocarcin, see Fukuyama, T.; Nunes, J. J. J. Am. Chem.
Soc. 1988, 110, 5196.
5. (a) Garner, P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc. 1992, 114, 2767; (b) Garner,
P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc. 1993, 115, 10742; (c) Katoh, T.; Kirihara,
M.; Nagata, Y.; Kobayashi, Y.; Arai, K.; Minami, J.; Terashima, S. Tetrahedron
1994, 50, 6239; (d) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 16796; (e)
Wu, Y.-C.; Liron, M.; Zhu, J. J. Am. Chem. Soc. 2008, 130, 7148; (f) Allan, K. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 17270.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.
030.
6. Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. Angew. Chem. Int. Ed. 2012, 51, 9169.
7. Zewge, D.; King, A.; Weissman, S.; Tschaen, D. Tetrahedron Lett. 2004, 45, 3729.
References and notes
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was prepared for model experiment in quinocarcin synthesis.
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