Concise synthesis of arnottin I and (-)-arnottin II

Article abstract of DOI:10.1021/jo061905j

Application of the Buchwald protocol to the coupling of o-bromobenzoates and 1-tetralones directly affords benzodihydronaphthopyrones with a fused tetracyclic system. Aromatization of the 7,8-dimethoxy-2,3-methylenedioxy derivative yielded arnottin I, whe

Full text of DOI:10.1021/jo061905j

Concise Synthesis of Arnottin I and (-)-Arnottin II
†
,†
‡
‡
Fujiko Konno, Tsutomu Ishikawa,* Masatoshi Kawahata, and Kentaro Yamaguchi
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33 Yayoi, Inage, Chiba 263-8522,
Japan, and Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri UniVersity,
1
314-1 Shido, Sanuki, Kagawa 769-2193, Japan
benti@p.chiba-u.ac.jp
ReceiVed September 15, 2006
Application of the Buchwald protocol to the coupling of o-bromobenzoates and 1-tetralones directly
affords benzodihydronaphthopyrones with a fused tetracyclic system. Aromatization of the 7,8-dimethoxy-
2,3-methylenedioxy derivative yielded arnottin I, whereas oxidation with dioxirane afforded dihydroarnottin
II composed of a spiro phthalide-tetralone system. Sharpless asymmetric dihydroxylation using AD-
mix yielded optically active dihydroarnottin II with good enantioselectivity. The absolute stereochemistry
of the stereogenic center in the (+)-spiro product was determined to be R by X-ray crystallographic
analysis of the dibromo derivative. (+)-Dihydroarnottin II was subjected to successive bromination and
dehydrobromination to prepare (-)-arnottin II. The R-configuration of natural (-)-arnottin II, previously
assigned by application of the exciton chirality method to the Cotton effects observed in the CD spectrum,
was confirmed by asymmetric synthesis.
4
Introduction
alkaloid, chelerythrine. Thus, the former was found to have
the same 6H-benzo[d]naphtho[1,2-b]pyran-6-one skeleton as
gilvocarcin antibiotics, and the latter is a spiro derivative of
Arnottin I (1) and (-)-arnottin II (2) are non-alkaloidal minor
components isolated from the bark of Xanthoxylum arnottianum
Maxim. (Rutaceae). Their structures have been determined to
5
3,4-dehydro-1-tetralone with a phthalide skeleton. The absolute
1
stereochemistry of the spiro carbon in 2 was assigned as R using
be 7,8-dimethoxy-2,3-methylenedioxy-6H-benzo[d]naphtho[1,2-
the exciton chirality method to analyze the Cotton effects in
2
b]pyran-6-one and 3,4-dehydro-6,7-methylenedioxy-1-tetralone-
6
the CD spectrum. Herein, we report the concise synthesis of
3
2
-spiro-3′-(6,7-dimethoxyphthalide), respectively, by indepen-
arnottin I (1) and (-)-arnottin II (2) from dihydroarnottin I (3).
Dihydroarnottin I was directly prepared by palladium (Pd)-
catalyzed coupling of o-bromobenzoate 4 and 6,7-methylene-
dent synthetic approaches using a common 2-benzofuranyl-1-
tetralone, which was linearly derived from a chalcone. The
benzofuranyltetralone was also used as the synthetic intermediate
for the preparation of a fully aromatized benzo[c]phenanthridine
7
dioxy-1-tetralone (5) using the Buchwald protocol, by arom-
atization with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),
†
Chiba University.
Tokushima Bunri University.
‡
(5) Nakano, H.; Matsuda, Y.; Ito, K.; Ohkubo, S.; Morimoto, M.; Tomita,
F. J. Antibiot. 1981, 34, 266-270. Matsumoto, T.; Hosoya, T.; Suzuki, K.
J. Am. Chem. Soc. 1992, 114, 3568-3570.
(
1) Ishii, H.; Ishikawa, T.; Haginiwa, J. Yakugaku Zasshi 1977, 97, 890-
00.
2) Ishii, H.; Ishikawa, T.; Murota, M.; Aoki, Y.; Harayama, T. J. Chem.
Soc., Perkin Trans. I 1993, 1019-1022.
3) Ishikawa, T.; Murota, M.; Watanabe, T.; Harayama, T.; Ishii, H.
Tetrahedron Lett. 1995, 36, 4269-4272.
4) Ishii, H.; Ishikawa, T.; Takeda, S.; Ueki, S.; Suzuki, M.; Harayama,
9
(
(6) Harada, N.; Nakanishi, K. Acc. Chem. Res. 1972, 5, 257-263. Harada,
N.; Chen, S. L.; Nakanishi, K. J. Am. Chem. Soc. 1975, 97, 5345-5352.
Imajo, S.; Nakamura, A.; Shingu, K.; Kato, A.; Nakagawa, N. J. Chem.
Soc., Chem. Commun. 1979, 868-869. Imajo, S.; Kato, A.; Shingu, K.;
Kuretani, H. Tetrahedron Lett. 1981, 22, 2179-2182.
(
(
T. Chem. Pharm. Bull. 1990, 38, 1775-1777. Ishii, H.; Ishikawa, T.;
(7) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360-1370. Åhman, J.; Wolfe, J. P.; Troutman, M. V.;
Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918-1919.
Takeda, S.; Suzuki, M.; Harayama, T. Chem. Pharm. Bull. 1992, 40, 2002-
2
006.
10.1021/jo061905j CCC: $33.50 © 2006 American Chemical Society
9
818
J. Org. Chem. 2006, 71, 9818-9823
Published on Web 12/01/2006

Concise Synthesis of Arnottin I and (-)-Arnottin II
was used by the latter.10 We expected that the direct formation
of benzodihydronaphthopyrones, a basic skeleton of 3, would
result from the easy cyclization of the coupling product, 2-aryl-
SCHEME 1. Retrosynthesis of Arnottin I (1) and
(-)-Arnottin II (2)
1-tetralone, due to the presence of an ester function at the ortho
position of the 2-aryl group. Therefore, we applied Buchwald’s
7
protocol to the reaction of o-bromobenzoates and 1-tetralones
(e.g., 4 and 5, respectively). First, we examined the reactions
of simpler bromobenzenes 6 and 1-tetralone itself (7) in the
presence of a Pd-catalyst, ligand, and base in toluene (PhMe)
at 80 °C as preliminary model coupling experiments (Table 1).
Treatment of 2-bromotoluene (6, X ) 2-Me) with 7 under
the Buchwald conditions (Pd(OAc)2, with 2-dicyclohexylphos-
phino-2′-(N,N-dimethylamino)biphenyl and sodium tert-butoxide
t
[
BuONa]) afforded 2-(2-methylphenyl)-1-tetralone (8, X )
1
2
2
-Me) as the coupling product in satisfactory yield (entry 1
in Table 1); however, a complex mixture was formed for 3,4-
methylenedioxybromobenzene (6, X ) 3,4-OCH2O) (entry 2
in Table 1). Replacement of the ligand and base led to the
formation of 2-aryl-1-tetralone 8 (X ) 3,4-OCH2O)13 but in
low yield (entry 3 in Table 1). On the other hand, we found
that a combination of Pd2(dba)3, xantphos, and potassium
phosphate (K3PO4) gave the best result when methyl 2-bro-
mobenzoate (6, X ) 2-CO2Me) was used as an aryl unit, and,
as expected, a benzodihydronaphthopyrone system 98b was
directly formed (entries 7 and 8 in Table 1).
and by Sharpless asymmetric dihydroxylation (AD) using AD-
mix followed by dehydrogenation. In addition, we determined
the absolute stereochemistry of the spiro carbon in 2 by X-ray
crystallographic analysis.
Careful examination of the other products in these reaction
mixtures suggested the presence of 1-naphthol derived from
Results and Discussion
1
-tetralone (7). Therefore, we investigated the effect of sodium
Our retrosynthetic strategy for arnottin I (1) and (-)-arnottin
II (2) through 7,8-dimethoxy-2,3-methylenedioxy-6H-benzo[d]-
disulfite (Na2S2O5) as an antioxidant, and we found that it
remarkably improved product formation (entry 9 in Table 1).
In this last reaction, tert-butyl ester was used in place of the
methyl ester. We subsequently discovered that the ester unit
also affects the coupling reaction (Table 2).
Next, we examined the formation of dihydroarnottin I (3) by
Pd-coupling reaction of alkyl o-bromobenzoates (4) and 6,7-
methylenedioxy-1-tetralone (5) (Table 2). Employing the condi-
tions (Pd2(dba)3, xantphos, K3PO4, and Na2S2O5) noted in entry
1
1,12-naphtho[1,2-b]pyran-6-one (dihydroarnottin I) (3) as a
common key intermediate is shown in Scheme 1. Previously,
benzodihydronaphthopyrone skeletons have been prepared as
synthetic intermediates for benzo[c]phenanthridine bases from
either 2-(o-hydroxycarbonylphenyl)-4-phenylbutyric acid deriva-
8
9
tives or 2-aryl-1-tetralone. We designed the direct formation
of dihydroarnottin I (3) using the Pd-catalyzed coupling of an
alkyl 6-bromo-2,3-dimethoxybenzoate (4) and 6,7-methylene-
dioxy-1-tetralone (5). Dihydroarnottin I (3) itself was also
prepared from opianic acid and acetophenone, in seven steps
by Bailey and Worthing8 50 years ago; however, a straight-
forward synthesis has not yet been reported.
9
of Table 1, treatment of 4 and 5 afforded the desired product
3; however, the yield was low (entry 1 in Table 2). A prolonged
reaction time led to a slight increase in the yield (entry 2 in
Table 2), and promising results were obtained by changing the
base from K3PO4 to cesium carbonate (Cs2CO3) (entry 3 in
Table 2). We found that the alkyl function of the ester, the
solvent, and the reaction temperature played important roles in
the coupling reaction (entries 4-7 in Table 2). Overall, the best
conditions for the formation of dihydroarnottin I (3) by Pd-
coupling reaction were a combination of Pd2(dba)3, xantphos,
Cs2CO3, and Na2S2O5 in PhMe using tert-butyl 6-bromo-2,3-
dimethoxybenzoate as an aryl unit (entry 3 in Table 2).
a
Preparation of Benzodihydronaphthopyrone Systems.
Several approaches to arylation at the R-position of carbonyl
7
,10,11
compounds have been reported.
Of these, Pd-catalyzed
coupling reactions7 seem to be the most promising routes.
,10
The 2-arylation of 1-tetralones using the Pd-catalyzed coupling
7
reaction has also been achieved by Buchwald’s and Nolan’s
1
0
groups. A combination of palladium acetate (Pd(OAc)2) or
tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) and a biphe-
nyl-type phosphine ligand including 2,2′-bis(diphenylphos-
Synthesis of Arnottin I (1) and (-)Arnottin II (2). Arnottin
I (1) was easily prepared by simple aromatization of dihydroar-
7
phino)-1,1′-binaphthyl (BINAP) was used by the former group,
14
nottin I (3) with DDQ (see Scheme 5). On the other hand,
whereas an N-heterocyclic carbene-palladium complex catalyst
oxidative ring contraction of the six-membered enol lactone unit
in dihydroarnottin I (3) to the five-membered γ-lactone unit
(
8) (a) Bailey, A. S.; Worthing, C. R. J. Chem. Soc. 1956, 4535-4543.
(
b) Chatterjea, J. N.; Bhakta, S. C.; Chattopadhyay, A. K. J. Indian Chem.
Soc. 1974, L1, 757-762.
(12) Marion, N.; Ecarnot, E. C.; Navarro, O.; Amoroso, D.; Bell, A.;
Nolan, S. P. J. Org. Chem. 2006, 71, 3816-3821.
(
(
9) Duval, O.; Gomes, M. Tetrahedron Lett. 1988, 29, 3243-3246.
10) Viciu, M. S.; Germaneau, F.; Nolan, S. P. Org. Lett. 2002, 4, 4053-
(13) Onda, M.; Harigaya, Y.; Horie, J. Heterocycles 1977, 8, 89-95.
(14) Preparation of arnottin I (1) has also been reported (a) by
Pd-catalyzed method using 1-naphthyl 2-halobenzoate, see: Harayama, T.;
Yasuda, H. Heterocycles 1997, 46, 61-64. Harayama, T.; Yasuda, H.;
Akiyama, T.; Takeuchi, Y.; Abe, H. Chem. Pharm. Bull. 2000, 48, 861-
864. (b) By Ni-catalyzed method, see: Madan, S.; Cheng, C.-H. J. Org.
Chem. 2006, 71, 8312-8315.
4
056.
(
11) Paradisi, C. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: New York, 1991;
Vol. 4, Chapter 2.1. Kessar, S. V. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: New
York, 1991; Vol. 4, Chapter 2.3.
J. Org. Chem, Vol. 71, No. 26, 2006 9819

Konno et al.
TABLE 1. Preliminary Pd-Coupling Reactions of Bromobenzenes 6 and 1-Tetralone (7)
entry
X in 6
2-Me
Pd
liganda
base (equiv)
time (h)
results
t
t
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
A
A
B
A
B
C
C
C
C
BuONa (1.3)
BuONa (1.3)
K3PO4 (2.3)
20
15
15
20
20
20
20
15
15
8 (X ) 2-Me): 76%
CMb
8 (X ) 3,4-OCH2O): 15%
3,4-OCH2O
3,4-OCH2O
2-CO2Me
2-CO2Me
2-CO2Me
2-CO2Me
2-CO2Me
t
b
BuONa (1.3)
CM
K3PO4 (2.3)
K3PO4 (2.3)
K3PO4 (2.3)
K3PO4 (2.3)
K3PO4 (2.3)
NRc
9: 10%
9: 44%
9: 46%
9: 81%
d
8
e
t
9
2-CO2 Bu
a
The following ligands were used: A, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl; B, 2-dicyclohexylphosphino-2′-methylbiphenyl; or C,
b
9
,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos). Complex mixture. c No reaction. d Reaction was carried out at 100 °C using 1.6 mol % of
Pd catalyst and 3.6 mol % of ligand. Na2S2O5 (10 mol %) was added as an antioxidant.
e
TABLE 2. Pd-Coupling Reactions of Alkyl o-Bromobenzoates 4
and 6,7-Methylenedioxy-1-tetralone (5)
SCHEME 2. Reported Oxidative Ring Contraction of
Bicyclic Enol Lactone 10
entry
4
solvent
base
time (h)
3 (%)
a
t
1
R ) Bu
PhMe
PhMe
PhMe
PhMe
PhMe
o-xylene
o-xylene
K3PO4
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
Cs2CO3
24
48
48
27
48
20
20
18
37
73
21
30
22
21
a
t
2
R ) Bu
a
t
3
R ) Bu
a
4
R ) Me
R ) Me
SCHEME 3. Oxidation of Dihydroarnottin I (3) to
a
a
5
Dihydroarnottin II (12) with Dioxirane and Possible
b
t
6
R ) Bu
Reaction Pathways
b
t
7
R ) Bu
a
Reaction was carried out at 100-105 °C. b Reaction was carried out
at 125-130 °C.
was required for the preparation of (-)-arnottin II (2). Such
ring contractions can be mediated by either N-bromosuccinim-
1
5
16
ide or bromine under basic conditions, and the application
16c
of oxidative ring contraction to bicyclic enol lactone 10 using
an aqueous bromine-sodium hydrogen carbonate system yielded
cyclic R-spiro(γ-lactonyl)ketone 11 through formal bond migra-
tion, wherein inversion of the stereogenic center may have
occurred (Scheme 2).
These brominative oxidations, however, cannot be simply
applied to the asymmetric synthesis of (-)-arnottin II (2)
because their use under asymmetric conditions has not been
described. Epoxidation (or dihydroxylation) of a bicyclic enol
ether, applied under asymmetric conditions, could also yield a
spiro lactonylketone after oxidation, followed by spontaneous
ring contraction. Epoxidation is illustrated in Scheme 3, wherein
two potential pathways exist because of the possible generation
of stable benzylic cations at the 4b and 10a positions in pathways
a
Reagents and conditions: (a) 1,1,1-trifluoroacetone, OXONE, NaHCO3,
EDTA-Na2‚2H2O in acetonitrile-CHCl3.
(
15) Rosenthal, D.; Grabowich, P.; Sabo, E. F.; Fried, J. J. Am. Chem.
Soc. 1963, 85, 3971-3979.
16) (a) Mandal, A. K.; Jawalkar, D. G. Tetrahedron Lett. 1986, 27, 99-
00. (b) Bevinakatti, H. S.; Newadkar, R. V.; Borude, D. P.; Mandal, A.
a and b, respectively. Pathway a, in which the stereogenic center
is retained, is predicted to be more likely based on the electronics
of the system and is supported by the high level of asymmetric
induction observed during the subsequent AD reaction (see
(
1
K. J. Org. Chem. 1988, 53, 3843-3845. (c) Mandal, A. K.; Jawalkar, D.
G. J. Org. Chem. 1989, 54, 2364-2369.
9820 J. Org. Chem., Vol. 71, No. 26, 2006

Concise Synthesis of Arnottin I and (-)-Arnottin II
SCHEME 4. Reported AD of 2-Phenyl-1-tetralone
tert-Butyldimethylsilyl Ether (13)
below). As expected, treatment of 3 with dioxirane using a slight
modification of the previous report,17 1,1,1-trifluoroacetone in
place of acetone, resulted in the formation of dihydroarnottin
II (12) as the sole isolable product in 47% yield.
Unfortunately, asymmetric epoxidations using chiral dioxirane
17a
systems, such as OXONE-trifluoroacetylcamphor and OX-
ONE-pyranose derivative,18 or camphorylsulfonyloxaziridine,
failed. Therefore, we focused on the Sharpless AD method.
Sharpless2 has reported the catalytic AD of tetrasubstituted
olefins, including the enol ether of 2-alkyl (or 2-aryl)-1-
tetralones, in which the best ligand partners of dihydroquinine
19
0
(DHQ) (or dihydroquinidine [DHQD]) are phthalazine (PHAL)
and pyrimidine (PYR) and in which high enantioselectivity is
observed. In the case of 2-phenyl-1-tetralone tert-butyldimeth-
ylsilyl ether (13),2 2-hydroxy-2-phenyl-1-tetralone (14) was
obtained in 94-98% yield with 93-97% ee; thus, the combina-
tion of (DHQ)2-PYR afforded the (S)-hydroxylated product S-14
0b
2
0b
in 97% ee (Scheme 4). According to their mnemonic device,
it is reasonable that a dihydroxylation product with a (4bS,-
0bR)-configuration is formed by the application of AD using
a diastereomeric (DHQD)2-ligand system to benzodihydronaph-
thopyrones, thereby generating an (R)-spiro product, as shown
in Figure 1.
FIGURE 1. Expected asymmetric induction in the AD of benzodi-
hydronaphthopyrones using a (DHQD) -ligand system.
2
1
SCHEME 5. Syntheses of Arnottin I (1) and (-)-Arnottin
II (2) from Dihydroarnottin I (3)a
We examined AD of dihydroarnottin I (3) under the reported
standard conditions2 (AD-mix in 50% tert-BuOH-H2O), but
we observed almost no reaction. We achieved a significant
improvement in yield by increasing the amounts of osmium and
ligand to 11 and 55 mol %, respectively, and by the addition of
dichloromethane (CH2Cl2) as a cosolvent (Scheme 5). The
combination of AD-mix-â and (DHQD)2-PHAL afforded (+)-
dihydroarnottin II (+)-12 in 83% yield and 88% ee, whereas
ent-(-)-dihydroarnottin II (-)-12 was obtained in 85% yield
and 88% ee when AD-mix-R and (DHQ)2-PHAL were used.
Introduction of a double bond into (+)-dihydroarnottin II (+)-
0b
a Reagents and conditions: (a) DDQ, benzene, 90 °C, 12 h (94% yield).
1
2 by application of the reported procedure (bromination-
(b) AD-mix-â, (DHQD)2-PHAL, MeSO2NH2, K2OsO2(OH)4, 50% tert-
BuOH-H2O, CH2Cl2, 0 °C, 95 h (83% yield). (c) AD-mix-R, (DHQ)2-
PHAL, MeSO2NH2, K2OsO2(OH)4, 50% tert-BuOH-H2O, CH2Cl2, 0 °C,
7 h (95% yield). (d) Br2, CHCl3, room temperature, 30 h (86% yield). (e)
i) NBS, AIBN, benzene, 85 °C, 24 h and 65 °C, 20 h; (ii) DBU, benzene,
3
dehydrobromination) gave (-)-arnottin II (2), which was
identical to the natural product except for the specific rotation.
6
(
The synthetic (-)-arnottin II, obtained in 98% ee after recrys-
tallization, showed an [R]25D -217 (c 0.026, MeOH) ([R]
25
D
reflux, 1 h (47% yield).
-
3
-
241 [c 0.105, CHCl3]), whereas an [R]589 -280 (c 9 × 10 ,
3
MeOH) had been reported for the natural compound. Chiral
HPLC analysis of the stored natural arnottin II indicated that it
was enantiomerically pure (see Supporting Information). Thus,
it was concluded that the large discrepancy (∆ 63) in the [R]D
data between synthetic and natural (-)-arnottin II could be due
to the limited use of the natural sample for optical rotation
dispersion in the previous experiment.
Among several attempts at derivatizing (+)-12 to determine
the absolute stereochemistry of the stereogenic center, we
succeeded in preparing a single crystal of (-)-dibromodihy-
droarnottin II ((-)-15) by treatment with bromine. The stereo-
genic center of the dibrominated product (-)-15 was unam-
biguously established to be of R-configuration by X-ray
(17) (a) Curci, R.; D’Accolti, L.; Fiorentio, M.; Rosa, A. Tetrahedron
Lett. 1995, 36, 5831-5834. (b) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org.
Chem. 1995, 60, 3887-3889. (c) Yang, D.; Jiao, G.-S.; Yip, Y.-C.; Wong,
M.-K. J. Org. Chem. 1999, 64, 1635-1639.
(18) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224-11235.
2
1
crystallographic analysis. These facts indicated not only that
asymmetric induction is reasonable, even with tetrasubstituted
enol ethers incorporated into a ring system, but also that the
configuration for a natural (-)-arnottin II (2) was correctly
(
(
19) Davis, F. A.; Sheppard, A. C. J. Org. Chem. 1990, 55, 3715-3717.
20) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Am. Chem. Soc. 1992, 57, 2768-2771. (b) Morikawa,
K.; Park, J.; Andersson, P. G.; Hashiyama, T.; Sharpless, K. B. J. Am. Chem.
Soc. 1993, 115, 8463-8464. (c) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. ReV. 1994, 94, 2483-2547.
6
assigned by applying the exciton chirality rule to the CD
spectrum.
J. Org. Chem, Vol. 71, No. 26, 2006 9821

Konno et al.
In conclusion, we developed a concise and straightforward
synthesis of arnottin I (1) and (-)-arnottin II (2) by applying
Buchwald’s protocol for the Pd-coupling arylation of ketones
and the Sharpless AD method for the introduction of oxygen.
We previously reported the chemical conversion of arnottin II
to homochelidonine, a partially hydrogenated benzo[c]phenan-
thridine alkaloid.22 The current results present another formal
asymmetric synthesis of homochelidonine.
of AD-mix-â (1.4 g), K
2
OsO
2
(OH)
4 2
(7 mg, 10 mol %), (DHQD) -
PHAL (78 mg, 50 mol %), H
2
O (5 mL), and tert-BuOH (5 mL)
was stirred at room temperature for 15 min. To the mixture was
added a mixture of methanesulfonamide (29 mg, 0.3 mmol) and 3
2 2
(71 mg, 0.2 mmol) in CH Cl (10 mL), and the resultant mixture
was stirred at 0 °C for 95 h. After addition of sodium sulfite (2 g),
the mixture was stirred at room temperature for 1 h and extracted
with CH
N HCl (7 mL) and extracted with AcOEt (5 mL × 2). The combined
organic solutions were washed with brine (5 mL), dried (Na SO ),
2 2
Cl (10 mL). The aqueous solution was acidified with 2
2
4
Experimental Section
and evaporated. Purification of the residue by column chromatog-
raphy (AcOEt/hexane ) 1:3) followed by recrystallization from
AcOEt-hexane gave (+)-dihydroarnottin II ((+)-12) (62 mg, 83%)
as colorless needles, mp 145-147 °C. IR (ATR): νmax 1753, 1685
7
,8-Dimethoxy-2,3-methylenedioxy-6H-benzo[d]-3,4-dihy-
dronaphtho[1,2-b]pyran-6-one (Dihydroarnottin I) (3): Entry
3
1
in Table 2. A mixture of methyl o-bromobenzoate (4) (317 mg,
mmol), 6,7-methylenedioxy-1-tetralone (5) (285 mg, 1.5 mmol),
-1 1
cm . H NMR (400 MHz, CDCl
3
): δ (ppm) 2.46 (ddd, J ) 13.6,
6
.2, 5.4 Hz, 1H), 2.64 (ddd, J ) 13.6, 8.2, 5.8 Hz, 1H), 3.20 (ddd,
Pd
8% Cs
in PhMe (2 mL) was stirred at 105 °C for 48 h. The mixture was
2
(dba)
3
(37 mg, 0.04 mmol), xantphos (51 mg, 0.088 mmol),
J ) 17.4, 8.2, 5.4 Hz, 1H), 3.30 (ddd, J ) 17.4, 6.2, 5.4 Hz, 1H),
9
2
CO
3
(749 mg, 2.3 mmol), and Na (19 mg, 0.1 mmol)
2 2 5
S O
3
8
.89 (s, 3H), 4.12 (s, 3H), 6.06 (s, 2H), 6.76 (s, 1H), 6.89 (d, J )
13
.2 Hz, 1H), 7.14 (d, J ) 8.2 Hz, 1H), 7.41 (s, 1H). C NMR
diluted with CHCl
washed with CHCl
3
(20 mL), filtered through a Celite pad, and
(15 mL). The combined organic solutions were
(
1
3
100 MHz, CDCl ): δ (ppm) 26.0, 33.9, 56.8, 62.4, 85.0, 102.0,
07.2, 108.0, 116.7, 118.2, 119.0, 125.6, 140.4, 141.0, 147.6, 148.7,
53.2, 153.3, 166.8, 188.6. Anal. Calcd for C20 : C, 65.22;
3
washed with water (10 mL) and brine (5 mL), dried (Na
evaporated. The residue was washed with AcOEt (5 mL) to afford
(228 mg, 64%) as a yellow solid. The aqueous layer was acidified
with 2 N HCl (2 mL) and extracted with CHCl
(5 mL × 2). The
organic solution was dried (Na SO ) and evaporated. The residue
33 mg) was refluxed in benzene (1 mL) with p-TsOH‚H O (2 mg,
.01 mmol) for 1 h using Dean-Stark apparatus. Additional 3 (32
2 4
SO ), and
1
16 7
H O
H, 4.38. Found: C, 65.15; H, 4.41; HRFABMS m/z: 369.0984
3
+
22
(
calcd for C20
H
17
O
7
(M + H): 369.0974). [R]
); 88% ee by chiral HPLC (CHIRALPAK IA, 0.46 cm ×
Cl /EtOH ) 15:5:4; flow rate ) 0.5 mL/
(major) ) 14.4 min, t
D
+61 (c 0.05,
3
CHCl
2
3
2
4
5 cm); n-hexane/CH
2
2
(
0
2
min; detection wavelength ) 254 nm; t
R
R
(
minor) ) 21.8 min.
R)-(-)-5-Bromo-6,7-methylenedioxy-1-tetralone-2-spiro-3′-
4-bromo-6,7-dimethoxyphthalide) ((-)-15). A mixture of (+)-
mg [total 260 mg, 73%]) was given by filtration of separated solid.
Recrystallization from CH Cl gave yellow prisms, mp 250-251
C. IR (ATR): νmax 1730 cm . H NMR (400 MHz, CDCl
ppm) 2.82 (dif. t, J ) 7.3 Hz, 2H), 2.92 (dif. t, J ) 7.3 Hz, 2H),
(
2
2
-
(
1 1
°
(
3
): δ
dihydroarnottin II (+)-12 (76 mg, 0.206 mmol) and a solution of
.37 M solution of Br in CHCl (1.5 mL, 2.06 mmol) was stirred
at room temperature for 30 h, washed with 5% Na aq (2 mL
3) and brine (2 mL), dried (Na SO ), and evaporated. Purification
of the residue (99 mg) by column chromatography (hexane/AcOEt
4:1-1:1) followed by recrystallization (AcOEt) gave (-)-15 (93
1
2
3
3
8
.95 (s, 3H), 3.99 (s, 3H), 5.98 (s, 2H), 6.71 (s, 1H), 7.28 (d, J )
2 2 3
S O
13
.8 Hz, 1H), 7.34 (s, 1H), 7.36 (d, J ) 8.8 Hz, 1H). C NMR
): δ (ppm) 21.7, 27.6, 56.7, 61.5, 101.2, 103.5,
07.1, 108.3, 115.3, 117.7, 120.1, 122.8, 130.8, 132.2, 146.7, 146.8,
48.0, 151.8, 152.3, 158.4. Anal. Calcd for C20 : C, 68.18;
×
2
4
(100 MHz, CDCl
3
1
1
)
16 6
H O
mg, 86%) as colorless prisms, mp 281-282 °C. IR (ATR): νmax
H, 4.58. Found: C, 68.13; H, 4.50.
-1 1
1757, 1676 cm . H NMR (400 MHz, CDCl
3
): δ (ppm) 2.27-
Arnottin I (7,8-Dimethoxy-2,3-methylenedioxy-6H-benzo[d]-
naphtho[1,2-b]pyran-6-one) (1). A suspension of 3 (106 mg, 0.3
mmol) and DDQ (136 mg, 0.6 mmol) in benzene (5 mL) was
2
.31 (m, 1H), 3.22-3.36 (m, 3H), 3.94 (s, 3H), 4.10 (s, 3H), 6.15
(
d, J ) 1.2 Hz, 1H), 6.16 (d, J ) 1.2 Hz, 1H), 7.33 (s, 1H), 7.50
13
(s, 1H). C NMR (100 MHz, CDCl
3
): δ (ppm) 25.2, 31.3, 57.0,
2.4, 84.7, 102.2, 102.3, 106.6, 109.8, 120.2, 122.9, 126.9, 139.8,
40.0, 147.0, 148.1, 151.6, 154.1, 165.3, 186.2. Anal. Calcd for
refluxed for 2 h. After addition of CHCl
was successively washed with H
O (5 mL), 1 N NaOH (3 mL ×
), H SO ), and
O (3 mL × 5), and brine (3 mL), dried (Na
evaporated. Recrystallization of the residue from CHCl afforded
3
(70 mL), the mixture
6
1
2
5
2
2
4
24
C
-
20
H14Br
O
2 7
: C, 45.66; H, 2.61. Found: C, 45.40; H, 2.68. [R]
121 (c 0.08, CHCl ).
Arnottin II (2). A mixture of dihydroarnottin II (+)-12 (68 mg,
.185 mmol), NBS (33 mg, 0.185 mmol), and AIBN (3 mg, 0.0185
D
3
2
3
1
(99 mg, 94%) as colorless prisms, mp 299-300 °C (lit. mp 293-
-
1 1
2
97 °C). IR (ATR):
): δ (ppm) 3.99 (s, 3H), 4.03 (s, 3H), 6.10 (s, 2H), 7.14 (s,
H), 7.44 (d, J ) 8.8 Hz, 1H), 7.53 (d, J ) 8.8 Hz, 1H), 7.83 (d,
νmax 1736 cm . H NMR (600 MHz,
0
CDCl
3
mmol) in dry benzene (5 mL) was heated under argon. After being
stirred at 85 °C for 24 h and then at 65 °C for 20 h, DBU (78 mg,
1
13
J ) 8.8 Hz, 1H), 7.85 (s, 1H), 7.88 (d, J ) 8.8 Hz, 1H). C NMR
125 MHz, CDCl ): δ (ppm) 56.6, 61.6, 99.1, 101.5, 104.0, 112.1,
15.5, 117.75, 117.83, 119.7, 120.3, 123.2, 129.8, 131.2, 146.1,
48.6, 148.9, 151.9, 153.1, 157.7. Anal. Calcd for C20 : C,
8.57; H, 4.03. Found: C, 68.30; H, 4.02. HREIMS m/z: 350.0799
0
.499 mmol) was added to the filtrate. The resultant mixture was
refluxed for 1 h under argon, diluted with AcOEt (10 mL), washed
with 2 N HCl (2 mL), 10% NaHSO (2 mL), sat. NaHCO (1 mL),
and brine (2 mL), dried (Na SO ), and evaporated. Purification of
(
3
1
1
6
3
3
14 6
H O
2
4
the residue by column chromatography (benzene/AcOEt ) 100:2)
afforded arnottin II (2) (32 mg, 47%). Recrystallization from
+
(
calcd for C20
R)-(+)-6,7-Methylenedioxy-1-tetralone-2-spiro-3′-(6,7-
dimethoxyphthalide) (Dihydroarnottin II) ((+)-12). A mixture
14 6
H O (M ): 350.0790).
(
3
CH Cl2-Et O afforded pale yellow needles, mp 222-224 °C (lit.
2 2
-1
1
mp 225-226 °C). IR (ATR): νmax 1776, 1687 cm . H NMR (400
MHz, CDCl ): δ (ppm) 3.86 (s, 3H), 4.17 (s, 3H), 6.09 (d, J )
0.0 Hz, 1H), 6.10 (s, 2H), 6.69 (d, J ) 10.0 Hz, 1H), 6.78 (s,
H), 6.78 (d, J ) 8.0 Hz, 1H), 7.05 (d, J ) 8.0 Hz, 1H), 7.34 (s,
H). 13C NMR (100 MHz, CDCl
): δ (ppm) 56.9, 62.7, 84.3, 102.4,
07.6, 107.9, 115.5, 117.2, 119.1, 123.0, 128.3, 130.2, 134.4, 139.1,
3
(
21) X-ray data were collected on a Bruker SMART 1000 CCD detector.
The crystal structure was solved by direct methods SHELXS-97 (Sheldrick,
997) and refined by full-matrix least-squares SHELXL-97 (Sheldrik, 1997).
1
1
1
1
1
3
All non-hydrogen atoms were refined anisotropically. All hydrogen atoms
were included at their calculated positions. Crystal data for (-)-15: C20H14-
-
1
Br2O7; M ) 526.13 g mol , orthorhombic, P212121, colorless prisma
148.4, 149.0, 153.4, 153.9, 167.5, 191.0. Anal. Calcd for
2
5
measuring 0.40 × 0.30 × 0.05 mm, T ) 150 K, a ) 7.3016(10) Å, b )
C
H
O
: C, 65.57; H, 3.85. Found: C, 65.31; H, 3.80. [R]
20
14
7
D
3
8
.4264(12) Å, c ) 30.356(4) Å, V ) 1867.7(5) Å , Z ) 4, Dcalcd ) 1.871
3
-3
-
217 (c 0.026, MeOH) (lit. [R]589 -280 [c 9 × 10 , MeOH]),
-
3
-1
2
Mg m , µ ) 4.383 mm , Tmax ) 0.8106, Tmin ) 0.2731, GOF on F )
25
[R]
D
3
-240 (c 0.105, CHCl ); 98% ee by chiral HPLC (CHIRAL-
1
0
.056, R1 ) 0.0551, wR2 ) 0.1428 [I > 2σ(I)], R1 ) 0.0693, and wR2 )
.1547 (all data), absolute structure parameter ) 0.000(17). CCDC-611350.
PAK IA, 0.46 cm × 25 cm); n-hexane/CH
flow rate ) 0.5 mL/min; detection wavelength ) 254 nm; t
) 13.5 min, t (minor) ) 19.8 min.
2
Cl
2
/EtOH ) 15:5:4;
(22) Yoshida, M.; Watanabe, T.; Ishikawa, T. Tetrahedron Lett. 2002,
R
(major)
4
3, 6751-6753.
R
9822 J. Org. Chem., Vol. 71, No. 26, 2006

Concise Synthesis of Arnottin I and (-)-Arnottin II
Note Added after ASAP Publication. The incorrect X-ray
data for (-)-15 was cited in ref 21 in the version published
ASAP December 7, 2006; the corrected version was published
ASAP December 12, 2006.
data of 8 (X ) 2-Me; X ) 3,4-OCH O) and 9, synthesis of (()-
2
and (-)-12, NMR charts of 1, 2, 3, (+)- and (-)-12, and (-)-15,
chiral HPLC charts of synthetic and natural 2 and (+)- and (-)-
12, ORTEP drawing of (-)-15, and X-ray data of (-)-15 in CIF
format. This material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Preparation of starting
bromobenzoates, general experimental procedure in Table 1, spectral
JO061905J
J. Org. Chem, Vol. 71, No. 26, 2006 9823