Design and synthesis of lamellarin D analogues targeting topoisomerase I

Article abstract of DOI:10.1021/jo901589e

(Chemical Equation Presented) A general synthetic route to rationally designed lamellarinDanalogues, 1-dearyllamellarinD(1) and 1-substituted 1-dearyllamellarin D (2), has been developed. The key pentacyclic intermediate 22 was prepared by palladium-catalyzed direct arylation of 12, which in turn was synthesized via C-2-selective lithiation of 15 followed by palladium-catalyzed cross-coupling as the key reactions. Compound 22 was converted to a wide range of C-1-substituted analogues 2 via regioselective electrophilic substitution and palladium-catalyzed cross-coupling reactions.

Full text of DOI:10.1021/jo901589e

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Design and Synthesis of Lamellarin D Analogues Targeting
Topoisomerase I
Takeshi Ohta,† Tsutomu Fukuda,† Fumito Ishibashi,† and Masatomo Iwao*,‡
†Graduate School of Science and Technology, and ‡Department of Applied Chemistry, Faculty of
Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
iwao@nagasaki-u.ac.jp
Received July 22, 2009
A general synthetic route to rationally designed lamellarin D analogues, 1-dearyllamellarin D (1) and
1-substituted 1-dearyllamellarin D (2), has been developed. The key pentacyclic intermediate 22 was
prepared by palladium-catalyzed direct arylation of 12, which in turn was synthesized via C-2-
selective lithiation of 15 followed by palladium-catalyzed cross-coupling as the key reactions.
Compound 22 was converted to a wide range of C-1-substituted analogues 2 via regioselective
electrophilic substitution and palladium-catalyzed cross-coupling reactions.
Introduction
cell lines and their corresponding parental cell lines.3 In
addition, they demonstrated that lamellarin I reverses
Lamellarins are a family of marine alkaloids possessing a
common 14-phenyl-6H-[1]benzopyrano[40,30:4,5]pyrrolo-
[2,1-a]isoquinoline ring system.1 Since the first isolation of
lamellarins A-D by Faulkner et al. in 1985, more than 30
lamellarins (A-Z and R-χ, including their acetate and
sulfate derivatives) have been isolated from mollusks, asci-
dians, and sponges.2 These differ in the number and position
of the OH and OMe groups on the common scaffold.
Lamellarins have attracted considerable attention owing to
their antitumor activity. In 1996, Quesada et al. reported that
the triacetates of lamellarins D, K, and N exhibit potent
cytotoxicity against both multidrug-resistant (MDR) cancer
(2) (a) Andersen, R. J.; Faulkner, D. J.; Cun-heng, H.; Van Duyne, G. D.;
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J. Nat. Prod. 1999, 62, 419–424. (i) Reddy, M. V. R.; Rao, M. R.; Rhodes, D.;
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(1) For reviews, see: (a) Cironi, P.; Albericio, F.; Alvarez, M. Progress in
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(3) Quesada, A. R.; Gravalos, M. D. G.; Puentes, J. L. F. Br. J. Cancer
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1997, 36, 155–156. (b) Peschko, C.; Winklhofer, C.; Steglich, W. Chem.
Eur. J. 2000, 6, 1147–1152.
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2260. (b) Banwell, M. G.; Flynn, B. L.; Hockless, D. C. R.; Longmore, R. W.;
Rae, A. D. Aust. J. Chem. 1999, 52, 755–765.
Heterocyclic Chemistry 2004, 16, 1–26. (b) Bailly, C. Curr. Med. Chem.
Anticancer Agents 2004, 4, 363–378. (c) Handy, S. T.; Zhang, Y. Org. Prep.
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Anti-Cancer Agents Med. Chem. 2008, 8, 746–760. (f ) Kluza, J.; Marchetti, P.;
Bailly, C. In Modern Alkaloids: Structure, Isolation, Synthesis and Biology;
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DOI: 10.1021/jo901589e
r
Published on Web 09/30/2009
J. Org. Chem. 2009, 74, 8143–8153 8143
2009 American Chemical Society

Ohta et al.
JOCArticle
FIGURE 1. Structure-activity relationships of lamellarin D in
regard to cytotoxicity.
MDR by direct inhibition of P-glycoprotein-mediated drug
efflux at noncytotoxic doses. Following these significant
discoveries, synthetic endeavors for lamellarin alkaloids
have been initiated by several research groups.4-9 In 1997,
we achieved the first total synthesis of lamellarins D and H
by means of N-ylide-mediated cyclization.6a Using this
method, we prepared a range of differentially substituted
non-natural lamellarin D analogues and evaluated their
cytotoxicity against a HeLa cell line.10a Structure-activity
relationship study indicated that the hydroxyl groups at C-8
and C-20 positions (lamellarin numbering2a) of lamellarin D
are essential for its potent cytotoxicity, whereas the hydroxyl
group at C-14 is less important (Figure 1).10a
Recently, Bailly et al. reported that lamellarin D is a potent
inhibitor of topoisomerase I.11 This enzyme relaxes supercoils
generated during DNA replication and transcription via rever-
sible single-strand cleavage and religation. Topoisomerase I
inhibitors stabilize the topoisomerase I-DNA cleavage complex
and inhibit the religation step.12 This action by the inhibitors
causes single-strand DNA breakages that are transformed into
FIGURE 2. Lamellarin D-DNA-topoisomerase I ternary com-
plex model.14
double-strand breakages lethal for growing cells. Bailly has
proposed11 a theoretical model of a lamellarin D-DNA-topo-
isomerase I ternary complex based on the topotecan-DNA-
topoisomerase I crystallographic data.13 According to this
model, lamellarin D intercalates at the site of DNA cleavage
and is stabilized with both the +1(C-G) and -1(A-T) base
pairs forming stacking interactions. Hydrogen bonds between
lamellarin D and the specific amino acid residues of topoisomerase
I further stabilize the ternary complex. The hydroxyl groups at
C-8 and C-20 and the carbonyl oxygen are at a hydrogen bond
distance from Asn722, Glu356, and Arg364, respectively. On
the other hand, the aryl group at C-1 is directed toward the
major groove cavity and does not have any direct interaction
with the protein (Figure 2).14
This model clearly indicates that the planar pentacyclic
lamellarin core that has the hydroxyl groups at C-8 and C-20
is essential for this activity, while the aryl group at C-1 is trivial.
Therefore, it is reasonable to assume that simplified 1-dearyl-
lamellarin D (1), and more interestingly 1-substituted 1-dearyl-
lamellarin D (2) that has a variety of functional groups X at
C-1, may hold potent topoisomerase I inhibitory activity. To
investigate this idea, we have developed a general synthetic route
to this type of novel and promising lamellarin D analogues.
(6) (a) Ishibashi, F.; Miyazaki, Y.; Iwao, M. Tetrahedron 1997, 53, 5951–
5962. (b) Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi, F.
Tetrahedron Lett. 2003, 44, 4443–4446. (c) Fujikawa, N.; Ohta, T.; Yamaguchi,
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Kutyashev, I. B.; Barkov, A. Y.; Shklyaev, Y. V. Tetrahedron Lett. 2008, 49,
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Results and Discussion
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Marchal, A.; Olsen, C. A.; Francesch, A.; Cuevas, C.; Albericio, F.; Alvarez,
Attempted Synthesis of 1-Dearyllamellarin D (1) via Oxi-
dative Cyclizations. In 2003,6b we devised a short and flexible
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Manzanares, I.; Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392–7399. (b)
Marco, E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi, F.;
Bailly, C.; Gago, F. J. Med. Chem. 2005, 48, 3796–3807.
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Waring, M., Ed.; RSC Publishing: Cambridge, U.K., 2006; Chapter 3; pp 44-68.
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A. B. Jr.; Stewart, L. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 15387–15392. (b)
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MOE program (Chemical Computing Group Inc.).
8144 J. Org. Chem. Vol. 74, No. 21, 2009

Ohta et al.
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route to 3,4-diarylpyrrole marine alkaloids using Hinsberg-
type pyrrole synthesis and palladium-catalyzed Suzuki-
Miyaura coupling as the key reactions. This synthetic strat-
egy has been applied successfully to the total synthesis of
lamellarins D, L, N6c and R 20-sulfate.6d In these syntheses,
the key pentacyclic framework of lamellarins was con-
structed by oxidative cyclizations, such as phenyliodine(III)
bis(trifluoroacetate) (PIFA)-mediated cyclization15 and
palladium(II)-mediated decarboxylative ring closure.16 We
first attempted to apply this approach for the synthesis of
1-dearyllamellarin D (1).
SCHEME 1. Synthesis of 8 and 9 for Oxidative Cyclizations
Synthesis of substrates 8 and 9 for the oxidative cyclizations
is shown in Scheme 1. Suzuki-Miyaura coupling of the known
3,4-dihydroxypyrrole bistriflate 36c with 1.2 equiv of arylboro-
nic acid 46c in the presence of 2 mol % of Pd(PPh3)4 afforded
monocoupling product 5 in 75% yield. This compound was
treated with hydrochloric acid in methanol to remove the
MOM protecting group. The crude product was treated with
a catalytic amount of p-toluenesulfonic acid in refluxing
dichloromethane to afford lactone 6 in 97% yield. The tri-
fluoromethanesulfonyloxy group on the pyrrole ring was
cleanly hydrogenolyzed with H2 over 5% Pd-C to yield 7.
Alkaline hydrolysis of 7 followed by acid-catalyzed relactoni-
zation afforded acid 8. Decarboxylation of 8 by heating in hot
quinoline over copper(I) oxide afforded 9 in excellent yield.
The stage was now set for the implementation of the
oxidative cyclizations. First, we tested PIFA-mediated cycli-
zation developed by Kita.15 Surprisingly, treatment of 9 with
PIFA-BF3 OEt2 in dichloromethane at -40 °C did not
3
produce the expected pentacyclic compound but afforded
the abnormally cyclized 10 in 49% yield (Scheme 2). The
structure of 10 was confirmed by analyses of its NOESY,
HMQC, and HMBC spectra. This type of decarbonylative
cyclization at the 2 position of similar pyrrole derivatives has
recently been reported by Banwell.17 The results, however,
are quite puzzling because the substrates possessing an aryl
group at C-4 of the pyrrole ring undergo normal cyclization
SCHEME 2. Unusual Cyclization of 9 with PIFA-BF3 OEt2
3
(15) (a) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.;
Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684–3691.
(b) Takada, T.; Arisawa, M.; Gyoten, M.; Hamada, R.; Tohma, H.; Kita, Y.
J. Org. Chem. 1998, 63, 7698–7706. (c) Tohma, H.; Morioka, H.; Takizawa,
S.; Arisawa, M.; Kita, Y. Tetrahedron 2001, 57, 345–352. (d) Hamamoto, H.;
Anilkumar, G.; Tohma, H.; Kita, Y. Chem. Eur. J. 2002, 8, 5377–5383.
(16) (a) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.
2002, 124, 11250–11251. (b) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am.
Chem. Soc. 2005, 127, 10323–10333. (c) Wang, C.; Piel, I.; Glorius, F. J. Am.
Chem. Soc. 2009, 131, 4194–4195.
(17) Axford, L. C.; Holden, K. E.; Hasse, K.; Banwell, M. G.; Steglich,
W.; Wagler, J.; Wills, A. C. Aust. J. Chem. 2008, 61, 80–93.
(18) Bromination of 9 with 1.0 equiv of NBS in DMF afforded mono-
bromide I in 93% yield, whereas bromination with 2.0 equiv of NBS yielded
dibromide II in 97% yield. These results suggest relative reactivity of the
pyrrole ring and the pendant aromatic ring against elecrophilic reagents.
to provide the lamellarin skeleton in excellent yields.6b-d
This discrepancy may be rationalized by following mechan-
istic considerations. It is well-known that PIFA-mediated
aromatic substitutions proceed via initial single-electron
transfer (SET) from electron-rich aromatic rings followed
by an attack of nucleophiles to the cation radical interme-
diate.15a Therefore, in substrate 9, the cation radical should
be generated at the most electron-rich pyrrole ring.18,19 This
intermediate will be intercepted by the pendant aromatic ring
at C-2, presumably owing to the easy extrusion of car-
bon monoxide via radical-mediated fragmentation.20 In the
(19) For PIFA-mediated cyclization, coupling, and functionalization of
pyrroles, see: (a) Moreno, I.; Tellitu, I.; Domınguez, E.; SanMartın, R. Eur.
´ ´
J. Org. Chem. 2002, 2126–2135. (b) Dohi, T.; Morimoto, K.; Maruyama, A.;
Kita, Y. Org. Lett. 2006, 8, 2007–2010. (c) Dohi, T.; Morimoto, K.;
Takenaga, N.; Goto, A.; Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y.
J. Org. Chem. 2007, 72, 109–116.
(20) Smith, M. B.; March, J. March’s Advanced Organic Chemistry:
Reaction, Mechanism, and Structure, 5th ed.; Wiley: New York, 2001; p 1354.
J. Org. Chem. Vol. 74, No. 21, 2009 8145

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SCHEME 3. Palladium(II)-Mediated Decarboxylative Ring
Closure of 8
SCHEME 4. Retrosynthetic Analysis of 11
substrate that has an aryl ring at C-4, however, the interac-
tion between the π-electron system of the pyrrole and PIFA
may be prohibited by the sterically demanding aryl ring.21
Thus, the SET occurs at the pendant aromatic ring prefer-
entially, and the resulting cation radical cyclizes to the most
nucleophilic C-5 of the pyrrole ring to produce the lamellarin
skeleton.
Next, palladium(II)-mediated decarboxylative ring clo-
sure of 8 was tested (Scheme 3). In this reaction, the desired
compound 1122 was obtained in 21% yield by heating a
mixture of 8 and 1.1 equiv of Pd(OAc)2 in acetonitrile. The
yield, however, is much lower than that obtained in similar
cyclizations performed in natural product synthesis.6b,c The
low yield may be accounted for by the sensitivity of the
pyrrole moiety of 11 under oxidative conditions.
SCHEME 5. Synthesis of the Pyrrole-lactone 13
Synthesis of 1-Dearyllamellarin D (1) via Palladium(0)-
Catalyzed Direct Arylation. Owing to failure to produce a
sufficient amount of 11 by application of the previously
established procedures, we decided to develop a new syn-
thetic route. Transition-metal-catalyzed direct arylation has
been recognized as a useful way to produce a variety of biaryl
derivatives.23 In this reaction, aryl halides or pseudohalides
and simple arenes are employed as the cross-coupling part-
ners. An intramolecular version of this reaction has been
frequently employed in the syntheses of carbo- and hetero-
cyclic compounds, including biologically significant natural
products.23 In the field of lamellarin syntheses, Albericio and
acetic acid at reflux temperature to afford N-benzenesulfo-
nyl-3-bromopyrrole (16) in 70% yield.26,27 Directed lithia-
tion of 16 with LDA in THF at -78 °C followed by a reac-
tion with methyl chloroformate produced 2-methoxycar-
bonylated pyrrole 17 regioselectively in 83% yield.28
Suzuki-Miyaura coupling of 17 with the boronic acid 46c
afforded 18 in 81% yield. Deprotection of MOM (HCl/
MeOH) and the benzenesulfonyl group (TBAF)27 produced
the desired lactone 13 in excellent yield.
Bromo-alcohol 14 was prepared using a modified Jordis
procedure29a (Scheme 6). Wittig reaction of O-isopropyliso-
vanillin (19) with the ylide generated from (methoxy-
methyl)triphenylphosphonium chloride and potassium
tert-butoxide afforded the enol ether 20 in 93% yield as an
E/Z mixture. Acid-catalyzed hydrolysis of 20 followed by
reduction of the resulting aldehyde with sodium borohydride
produced 21 in 88% yield. Bromination of 21 with NBS in
DMF afforded 14 in 83% yield.
ꢀ
Alvarez, for example, have utilized palladium-catalyzed intra-
molecular direct arylation in their modular syntheses of lamel-
larin D.8c,d As shown retrosynthetically in Scheme 4, we
anticipated that compound 11 could be obtained in good yield
by direct arylation of 12 because unfavorable oxidative condi-
tions are precluded. The precursor 12, in turn, can be easily
prepared by convergent assembly of the pyrrole-lactone 13 and
the bromo-alcohol 14 by means of a Mitsunobu reaction.24
Synthesis of the pyrrole-lactone 13 was achieved using a
combination of directed lithiation and palladium-catalyzed
cross-coupling reactions25 (Scheme 5). N-Benzenesulfonyl-
pyrrole (15) was brominated with 1.0 equiv of bromine in
(21) The SET from aromatic ring to PIFA is sensitive to the steric
hindrance of the aromatic substrate, see: Dohi, T.; Ito, M.; Morimoto, K.;
Iwata, M.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 1301–1304.
(22) Synthesis of 11 using Banwell’s intramolecular [3 þ 2]cycloaddition
strategy5a was described in a patent; see: Bailly, C.; Francesch Solloso, A;
Mateo Urbano, M. C.; Jimenez Guerrero, J. A.; Pastor Del Catillo; A.;
Cuevas Marchante, C. WO Patent 2004014917, 2004; Chem. Abstr. 2004,
140, 199492.
Mitsunobu reaction of the lactone 13 with alcohol 14 using
diisopropyl azodicarboxylate (DIAD) and triphenylpho-
sphine afforded 12 in 77% yield (Scheme 7). Intramolecular
direct arylation of 12 in the presence of 5 mol % of Pd(PPh3)4
(23) For excellent reviews, see: (a) Campeau, L.-C.; Fagnou, K. Chem.
Commun. 2006, 1253–1264. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
Rev. 2007, 107, 174–238. (c) Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036–
1045. (d) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173–1193.
(24) Kreipl, A. T.; Reid, C.; Steglich, W. Org. Lett. 2002, 4, 3287–3288.
(25) (a) James, C. A.; Snieckus, V. J. Org. Chem. 2009, 74, 4080–4093. (b)
James, C. A.; Coelho, A. L.; Gevaert, M.; Forgione, P.; Snieckus, V. J. Org.
Chem. 2009, 74, 4094–4103.
(26) Zonta, C.; Fabris, F.; De Lucchi, O. Org. Lett. 2005, 7, 1003–1006.
(27) Fukuda, T.; Sudo, E.; Shimokawa, K.; Iwao, M. Tetrahedron 2008,
64, 328–338.
(28) For directed lithiation of a similar pyrrole, see: Robertson, J.;
Kuhnert, N.; Zhao, Y. Heterocycles 2000, 53, 2415–2420.
€
(29) (a) Treu, M.; Jordis, U. Molecules 2002, 7, 374–381. (b) Schroter, S.;
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SCHEME 6. Synthesis of the Bromo-alcohol 14
TABLE 1. Electrophilic Substitution Reaction of 22
entry
electrophilic reagent
E
23
yield (%)
1
2
3
4
5
NBS
NCS
Br
Cl
F
23a
23b
23c
23d
23e
92
96
53
97
99
SELECTFLUORa
SCHEME 7. Synthesis of 1-Dearyllamellarin D (1)
Me2N+dCH2 I-
POCl3, DMF
CH2NMe2
CHO
3
a1-Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoro-
borate).
TABLE 2. Palladium-Catalyzed Suzuki-Miyaura Coupling of 23a
and K2CO3 in dimethyl acetamide (DMA) at 125 °C af-
forded 11 in 89% yield. Dehydrogenation of 11 using active
manganese dioxide under mild conditions (CH2Cl2, reflux,
2 days) produced 22 in good yield. Attempted dehydrogena-
tion using conventional DDQ6d (CH2Cl2, reflux, 18 h)
resulted in decomposition of the starting material. Finally,
selective deprotection of the isopropyl groups with 6.0 equiv
of BCl36c afforded 1-dearyllamellarin D (1) in 66% yield.
Synthesis of 1-Substituted 1-Dearyllamellarin D (2) via
Regioselective C-1 Functionalization of 22. An efficient synth-
esis of 1 being established, we focused on the synthesis of a
variety of 1-substituted 1-dearyllamellarin D (2) via regiose-
lective functionalization of intermediate 22. At first, we
tested electrophilic substituion reactions of 22.30 As shown
in Table 1, a range of electrophilic reagents reacted smoothly
with 22 to afford 1-substituted products 23a-e in good yield.
Integrity of the 1-substituted structures of these products
was unambiguously confirmed by analyses of their HMQC
and HMBC spectra.
To obtain a wider range of lamellarin D analogues, we
next examined Suzuki-Miyaura coupling of the bromide
23a (Table 2). The reaction of 23a with the boronic acid 24a6c
under the standard conditions (10 mol % of Pd(PPh3)4, aq
Na2CO3, DME, reflux, 24 h) recovered the starting material
23a in 95% yield (entry 1). Failure of the reaction may be
accounted for by severe steric hindrance at the C-1 position
of 23a. Recently, Qiu et al. reported that the CsF-Ag2O
aAqueous Na2CO3 (6.6 equiv). bCsF (2.0 equiv) and Ag2O (1.2 equiv).
cTrimethylboroxine was used.
system is an excellent promoter in the Suzuki-Miyaura
coupling of a highly congested tetrabromoperylene deriva-
tive.31 Thus, we tested this promoter in the cross-coupling of
23a. As shown in entry 2 of the table, dramatic improvement
was observed and the desired 25a was isolated in 69% yield.
Compound 25a thus obtained was shown by spectroscopic
comparisons to be identical with an authentic sample pre-
pared previously in our laboratories.6c Because the conver-
sion of 25a to lamellarin D (1) has already been reported,6c a
new and diverted total synthesis32 of lamellarin D has been
thus achieved. Reactions of 23a with other boronic acids
24b-d afforded the corresponding 1-arylated compounds
25b-d in good yields under similar conditions (entries 3-5).
Cross-coupling with trimethylboroxine (24e)33 gave the
1-methylated compound 25e (entry 6).
(31) Qiu, W.; Chen, S.; Sun, X.; Liu, Y.; Zhu, D. Org. Lett. 2006, 8, 867–
870.
(30) DFT calculation of 22 indicated high atomic charge and extended
HOMO at the C-1 position. The calculation suggested that electrophilic
substitution reaction could occur at C-1 selectively. See Supporting Informa-
tion.
(32) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329–8351.
(33) (a) Gray, M.; Andrews, I. P.; Hook, D. F.; Kitteringham, J.; Voyle,
M. Tetrahedron Lett. 2000, 41, 6237–6240. (b) Ngo, H. L.; Lin, W. J. Org.
Chem. 2005, 70, 1177–1187.
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Ohta et al.
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TABLE 3. Deprotection of Isopropyl Groups
75%). Recrystallization from dichloromethane-hexane gave
colorless powder. Mp 165-166 °C; IR (KBr) 1730, 1518, 1414,
1216, 1132, 1025, 989 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.37
(d, J = 6.0 Hz, 6H), 1.38 (d, J = 6.0 Hz, 6H), 3.02 (t, J = 7.0 Hz,
2H), 3.34 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 3.91 (s,
3H), 4.52 (sep, J = 6.0 Hz, 1H), 4.57 (sep, J = 6.0 Hz, 1H),
6.71-6.74 (m, 2H), 6.76-6.80 (m, 2H), 6.83 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 22.0, 22.2, 37.6, 48.7, 51.7, 51.8, 55.8, 56.1,
56.6, 71.4, 71.8, 96.0, 105.4, 112.2, 112.3, 115.3, 116.9, 117.1, 118.1
(q, J = 321 Hz), 118.5, 121.6, 124.2, 130.2, 136.2, 145.3, 147.3,
148.0, 149.3, 149.4, 159.3, 161.2. Anal. Calcd for
C33H40F3NO13S: C, 53.01; H, 5.39; N, 1.87. Found: C, 52.94;
H, 5.32; N, 1.71.
Methyl 3,4-Dihydro-7-isopropoxy-3-[2-(3-isopropoxy-4-metho-
xyphenyl)ethyl]-8-methoxy-4-oxo-1-(trifluoromethanesulfonyloxy)-
[1]benzopyrano[3,4-b]pyrrole-2-carboxylate (6). To a solution of
5 (4.29 g, 5.74 mmol) in methanol (420 mL) was added concd
HCl (42.0 mL) at room temperature. After being refluxed for 1
h, the mixture was cooled to room temperature, quenched with
water, and evaporated under reduced pressure. The product was
extracted with dichloromethane, and the extract was washed
with water and brine, dried over Na2SO4, and evaporated. The
residue was dissolved in dichloromethane (330 mL), and
p-toluenesulfonic acid monohydrate (273 mg, 1.44 mmol) was
added. The mixture was refluxed for 2 h, cooled to room
temperature, and evaporated. The residue was purified by
column chromatography over silica gel 60N (hexane-ethyl
acetate = 3:1) to give 6 as white solid (3.75 g, 97%). Recrys-
tallization from dichloromethane-hexane gave colorless pow-
der. Mp 121-122 °C; IR (KBr) 1737, 1517, 1425, 1258, 1228,
1159, 1139 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.34 (d, J = 6.2
Hz, 6H), 1.44 (d, J = 6.1 Hz, 6H), 3.03 (t, J = 7.3 Hz, 2H), 3.81
(s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.49 (sep, J = 6.2 Hz, 1H), 4.61
(sep, J = 6.2 Hz, 1H), 5.14 (t, J = 7.3 Hz, 2H), 6.66 (dd, J = 1.8
and 8.2 Hz, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.76 (d, J = 8.2 Hz,
1H), 6.92 (s, 1H), 7.36 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
21.8, 22.1, 37.5, 48.8, 52.4, 56.1, 56.2, 71.4, 71.7, 103.2, 105.2,
106.1, 112.1, 115.6, 116.7, 118.5 (q, J = 321 Hz), 120.1, 121.6,
123.2, 129.4, 129.5, 146.0, 147.4, 147.6, 148.9, 149.3, 153.9,
158.9. Anal. Calcd for C30H32F3NO11S: C, 53.65; H, 4.80; N,
2.09. Found: C, 53.35; H, 4.82; N, 1.88.
Methyl 3,4-Dihydro-7-isopropoxy-3-[2-(3-isopropoxy-4-meth-
oxyphenyl)ethyl]-8-methoxy-4-oxo-[1]benzopyrano[3,4-b]pyrrole-
2-carboxylate (7). A mixture of 6 (3.75 g, 5.58 mmol), 5% Pd-C
(2.81 g), i-Pr2NEt (1.17 mL, 6.72 mmol), ethanol (100 mL), and
THF (100 mL) was vigorously stirred under hydrogen atmo-
sphere at room temperature for 20 h. The mixture was filtered
through a pad of Celite, and the filtrate was evaporated. The
residue was purified by column chromatography over silica gel
60N (hexane-ethylacetate=3:1) togive 7 ascolorlesssolid (2.84
g, 97%). Recrystallization from dichloromethane-hexane gave
colorless needles. Mp 137.5-138 °C; IR (KBr) 1736, 1707, 1512,
1442, 1267, 1233, 1181, 1141 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.35 (d, J = 6.0 Hz, 6H), 1.43 (d, J = 6.2 Hz, 6H), 3.02 (t, J =
7.6 Hz, 2H), 3.82 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 4.51 (sep, J =
6.0 Hz, 1H), 4.58 (sep, J = 6.0 Hz, 1H), 5.13 (t, J = 7.6 Hz, 2H),
6.78 (s, 2H), 6.84 (s, 1H), 6.92 (s, 1H), 7.11 (s, 1H), 7.21 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 21.9, 22.1, 37.8, 48.4, 52.0, 56.1,
56.5, 71.4, 71.7, 103.7, 104.7, 108.0, 109.3, 112.0, 116.8, 119.2,
121.6, 128.8, 130.4, 130.9, 145.9, 147.3, 147.6, 148.2, 149.1, 155.0,
160.7. Anal. Calcd for C29H33NO8: C, 66.53; H, 6.35; N, 2.68.
Found: C, 66.30; H, 6.42; N, 2.55.
a-78 °C, 0.5 h f rt, 3 h. b-78 °C, 1 h f rt, 3 h. c-78 °C, 1 h f rt, 5 h.
Finally, selective deprotection of the isopropyl groups of
23 and 25 was performed (Table 3). Treatment of 23a-e,
25b, 25d, and 25e with 6.0 equiv of boron trichloride6c in
dichloromethane at -78 °C and then at room temperature
produced a variety of 1-substituted 1-dearyllamellarin D
analogues 2a-h. The yields of the products were dependent
on the substituent at C-1.
Conclusion
We have developed an efficient route for the synthesis of 1-
dearyllamellarin D (1) using directed lithiation, Suzuki-
Miyaura coupling, and palladium-catalyzed direct aryla-
tion as the key reactions. Several electrophilic substitution
reactions of the key intermediate 22 proceeded at C-1
selectively under mild conditions. The 1-brominated com-
pound 23a thus prepared underwent Suzuki-Miyaura cou-
pling with arylboronic acids and trimethylboroxine using
Ag2O-CsF as a promoter. We believe the procedures de-
scribed herein are highly useful for the synthesis of lamallarin
analogues that have a variety of substituents at the C-1 position
of the pentacyclic lamellarin framework. Biological evaluations
of the analogues 1 and 2a-h prepared in this study are in
progress. The results will be reported in due course.
Experimental Section
Dimethyl N-[2-(3-Isopropoxy-4-methoxyphenyl)ethyl]-3-(4-
isopropoxy-5-methoxy-2-methoxymethoxyphenyl)-4-(trifluorome-
thanesulfonyloxy)pyrrole-2,5-dicarboxylate (5). Under an argon
atmosphere, a two-necked, round-bottomed flask was charged
with bistriflate 36c (2.02 g, 3.00 mmol), boronic acid 46c (0.972 g,
3.60 mmol), Pd(PPh3)4 (69 mg, 0.06 mmol) and Na2CO3 (2.10 g,
14.8 mmol). The flask was evacuated and refilled with argon. To
this mixture were added THF (60 mL) and degassed water (6 mL)
sequentially. The mixture was refluxed for 2.5 h, cooled to room
temperature, and evaporated. The product was extracted with
dichloromethane, and the extract was washed with water and
brine, dried over Na2SO4, and evaporated. The residue was
purified by column chromatography over silica gel 60N
(toluene-ethyl acetate=10:1) to give 5 as colorless solid (1.69 g,
3,4-Dihydro-7-isopropoxy-3-[2-(3-isopropoxy-4-methoxyphe-
nyl)ethyl]-8- methoxy-4-oxo-[1]benzopyrano[3,4-b]pyrrole-2-car-
boxylic Acid (8). Under an argon atmosphere, a suspension of 7
(2.60 g, 4.97 mmol) in a degassed mixture of 40% aqueous KOH
(200 mL) and ethanol (200 mL) was refluxed for 3 h. The
solution was cooled to room temperature and concentrated
8148 J. Org. Chem. Vol. 74, No. 21, 2009

Ohta et al.
JOCArticle
under reduced pressure. The pH of the solution was adjusted to 2
with concd HCl, and the product was extracted with dichlor-
omethane. The extract was washed with water and brine, dried
over Na2SO4, and evaporated under reduced pressure.
The residue was dissolved in dichloromethane (400 mL) and
p-toluenesulfonic acid monohydrate (0.237 g, 1.25 mmol) was
added. The mixture was refluxed for 1 h and cooled to room
temperature. The mixture was washed with water, dried over
Na2SO4, and evaporated. The residue was purified by column
chromatography over silica gel 60N (dichloromethane-
methanol = 20:1) to give 8 as pale yellow solid (2.38 g, 94%).
Recrystallization from dichloromethane-hexane gave pale yel-
low powder. Mp 197.5-198 °C; IR (KBr) 1737, 1681, 1513,
8,9-Dihydro-3,11-diisopropoxy-2,12-dimethoxy-6H-[1]benzopyra-
no[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (11).22 Under an ar-
gon atmosphere, a mixture of 9 (100 mg, 0.196 mmol) and
Pd(OAc)2 (48.0 mg, 0.214 mmol) in acetonitrile (58 mL) was
refluxed for 16 h. The mixture was cooled to room temperature
and evaporated. The residue was dissolved in dichloromethane
and filtered through a pad of Celite to remove palladium black.
The filtrate was evaporated, and the residue was purified by
column chromatography over silica gel 60N (hexane-ethyl
acetate = 1:1-1:3) to give 11 as colorless solid (19.0 mg,
21%). Recrystallization from dichloromethane-hexane gave
colorless needles. Mp 180-180.5 °C; IR (KBr) 1697, 1509,
1426, 1274, 1239, 1142, 1003 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.42 (d, J = 5.8 Hz, 12H), 3.08 (t, J = 6.8 Hz, 2H), 3.95 (s, 3H),
3.96 (s, 3H), 4.56 (sep, J = 5.8 Hz, 1H), 4.60 (sep, J = 5.8 Hz,
1H), 4.70 (t, J = 6.8 Hz, 2H), 6.78 (s, 1H), 6.81 (s, 1H), 6.93 (s,
1H), 7.18 (s, 1H), 7.19 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
21.9, 22.1, 28.3, 42.3, 56.3, 56.5, 71.6, 71.6, 95.3, 103.8, 104.8,
108.3, 110.2, 115.0, 115.1, 120.1, 125.7, 131.2, 140.2, 146.0,
147.3, 147.7, 148.3, 149.7, 155.5. Anal. Calcd for C27H29NO6:
C, 69.96; H, 6.31; N, 3.02. Found: C, 69.87; H, 6.32; N, 2.84.
N-Benzenesulfonyl-3-bromopyrrole (16). A solution of bro-
mine (52.6 g, 329 mmol) in acetic acid (200 mL) was added
dropwise to a solution of 1526 (68.2 g, 329 mmol) in acetic acid
(600 mL) at room temperature, and the mixture was refluxed for
1 h. The mixture was cooled to room temperature and evapo-
rated. To the residue was added saturated aqueous NaHCO3,
and the mixture was extracted with dichloromethane. The
extract was washed with brine, dried over Na2SO4, and evapo-
rated. The residue was purified by column chromatography over
silica gel 60N (hexane-toluene = 2:1) to give 3-bromopyrrole
16 as colorless solid (65.6 g, 70%). Recrystallization from
methanol gave colorless granules. Mp 66.5-67 °C; IR (KBr)
1
1263, 1233, 1178, 1143 cm-1; H NMR (400 MHz, CDCl3) δ
1.35 (d, J = 6.1 Hz, 6H), 1.43 (d, J = 6.1 Hz, 6H), 3.06 (t, J =
7.7 Hz, 2H), 3.81 (s, 3H), 3.96 (s, 3H), 4.53 (sep, J = 6.1 Hz, 1H),
4.60 (sep, J = 6.1 Hz, 1H), 5.17 (t, J = 7.7 Hz, 2H), 6.80 (s, 2H),
6.88 (s, 1H), 6.93 (s, 1H), 7.15 (s, 1H), 7.40 (s, 1H), 9.00 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 21.9, 22.1, 37.8, 48.6, 56.1,
56.5, 71.5, 71.8, 103.6, 104.7, 109.1, 109.8, 112.1, 116.9, 120.2,
121.7, 128.8, 129.8, 130.3, 145.9, 147.3, 147.7, 148.3, 149.2,
155.0, 164.6. Anal. Calcd for C28H31NO8: C, 66.00; H, 6.13;
N, 2.75. Found: C, 65.70; H, 6.16; N, 2.69.
7-Isopropoxy-3-[2-(3-isopropoxy-4-methoxyphenyl)ethyl]-8-meth-
oxy-[1]benzopyrano[3,4-b]pyrrol-4(3H)-one (9). Under an argon
atmosphere, a mixture of 8 (1.20 g, 2.36 mmol) and copper(I) oxide
(337 mg, 2.36 mmol) in quinoline (60 mL) was heated at 220 °C for
15 min. After cooling to room temperature, the mixture was filtered
through a pad of Celite to remove copper(I) oxide. The filtrate was
diluted with dichloromethane and washed successively with 6 M
aqueous HCl and brine, dried over Na2SO4, and evaporated. The
residue was purified by column chromatography over silica gel 60N
(hexane-ethyl acetate = 3:1) to give 9 as colorless solid (1.06 g,
97%). Recrystallization from dichloromethane-hexane gave color-
less prisms. Mp 161-162 °C; IR (KBr) 1694, 1519, 1269, 1237, 1135
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.28 (d, J = 6.0 Hz, 6H), 1.42
(d, J = 6.0 Hz, 6H), 3.05 (t, J = 6.9 Hz, 2H), 3.81 (s, 3H), 3.93 (s,
3H), 4.41 (sep, J = 6.0 Hz, 1H), 4.59 (sep, J = 6.0 Hz, 1H), 4.60 (t,
J = 6.9 Hz, 2H), 6.41 (d, J = 2.8 Hz, 1H), 6.61-6.66 (m, 2H), 6.76
(d, J = 8.0 Hz, 1H), 6.82 (d, J = 2.8 Hz, 1H), 6.95 (s, 1H), 7.10 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 21.9, 22.1, 37.7, 50.9, 56.0,
56.6, 71.4, 71.6, 100.5, 103.8, 104.8, 110.4, 112.1, 114.9, 116.8, 121.4,
130.5, 131.2, 132.8, 146.1, 147.3, 147.4, 147.7, 149.2, 155.4. Anal.
Calcd for C27H31NO6: C, 69.66; H, 6.71; N, 3.01. Found: C, 69.40;
H, 6.78; N, 2.91.
1369, 1173, 1057, 728, 620, 588 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 6.29 (dd, J = 1.6 and 3.3 Hz, 1H), 7.09 (dd, J = 2.4
and 3.3 Hz, 1H), 7.18 (dd, J = 1.6 and 2.4 Hz, 1H), 7.51-7.56
(m, 2H), 7.61-7.67 (m, 1H), 7.85-7.89 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 102.2, 116.4, 119.7, 121.3, 127.0, 129.6, 134.3,
138.4. Anal. Calcd for C10H8BrNO2S: C, 41.97; H, 2.82; N, 4.89.
Found: C, 41.67; H, 2.52; N, 4.82.
Methyl N-Benzenesulfonyl-3-bromopyrrole-2-carboxylate (17).
Under an argon atmosphere, a hexane solution of n-butyllithium
(1.53 M, 29.3 mL, 44.8 mmol) was added dropwise to a solution
of diisopropylamine (8.40 mL, 59.9 mmol) in THF (150 mL) at
-78 °C. After being stirred for 15 min, the mixture was allowed to
warm to 0 °C and immediately recooled to -78 °C. A solution of
16 (8.58 g, 30.0 mmol) in THF (90 mL) was added dropwise to the
mixture at -78 °C. After being stirred for 1 h, a solution of methyl
chloroformate (5.22 mL, 67.5 mmol) in THF (60 mL) was added
dropwise, and the mixture was stirred for 30 min at -78 °C. The
reaction mixture was allowed to warm to room temperature,
quenched with saturated aqueous NH4Cl, and evaporated. The
products were extracted with diethyl ether, and the extract was
washedwithwater andbrine, driedoverNa2SO4, andevaporated.
The residue was purified by column chromatography over silica
gel 60N (hexane-toluene = 1:2) to give 17 as colorless solid (8.54
g, 83%). Recrystallization from diethyl ether-hexane gave color-
less prisms. Mp 77-77.5 °C; IR (KBr) 1720, 1452, 1360, 1257,
1174, 1144, 600 cm-1; 1H NMR(400MHz, CDCl3) δ 3.80(s, 3H),
6.40 (d, J = 3.4 Hz, 1H), 7.53-7.58 (m, 3H), 7.62-7.68 (m, 1H),
7.93-7.97 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 52.1, 109.7,
115.3, 123.3, 126.8, 127.9, 129.0, 134.1, 138.7, 159.3. Anal. Calcd
for C12H10BrNO4S: C, 41.88; H, 2.93; N, 4.07. Found: C, 41.76;
H, 2.80; N, 4.00.
1-(2-Hydroxy-4-isopropoxy-5-methoxyphenyl)-8-isopropoxy-
9-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline (10). Under an
argon atmosphere, a solution of PIFA (52.0 mg, 0.121 mmol)
and BF3 OEt2 (30.0 μL, 0.243 mmol) in dichloromethane (0.24
3
mL) was added dropwise to a solution of 9 (50.0 mg, 0.107
mmol) in dichloromethane (6 mL) at -40 °C. After being stirred
for 1.5 h, the mixture was quenched with saturated NH4Cl and
allowed to warm to room temperature. The product was ex-
tracted with dichloromethane, and the extract was washed with
water and brine, dried over Na2SO4, and evaporated. The
residue was purified by column chromatography over silica gel
60N (hexane-ethyl acetate = 3:1) to give 10 as unstable gray
foam (23.0 mg, 49%). IR (KBr) 3454, 1508, 1244, 1208, 1165,
1
1110, 1008 cm-1; H NMR (500 MHz, benzene-d6) δ 1.14 (d,
J = 6.0 Hz, 6H), 1.22 (d, J = 6.0 Hz, 6H), 2.49 (br s, 2H), 3.33 (s,
3H), 3.38 (s, 3H), 3.41 (t, J = 6.5 Hz, 2H), 4.29 (sep, J = 6.0 Hz,
1H), 4.36 (sep, J = 6.0 Hz, 1H), 5.55 (br s, 1H), 6.32 (d, J = 2.7
Hz, 1H), 6.41 (d, J = 2.7 Hz, 1H), 6.64 (s, 1H), 6.86 (s, 1H), 7.01
(s, 1H), 7.20 (s, 1H); 13C NMR (125 MHz, benzene-d6) δ 22.1,
22.4, 29.3, 44.7, 55.0, 56.5, 71.3, 71.8, 104.8, 108.1, 111.0, 114.2,
115.5, 116.3, 117.6, 120.9, 123.4, 123.8, 126.8, 145.4, 146.2,
148.7, 148.8, 150.8; HREIMS m/z calcd for C26H31NO5 (M+)
437.2202, found 437.2202.
Methyl N-Benzenesulfonyl-3-(4-isopropoxy-5-methoxy-2-meth-
oxymethoxyphenyl)pyrrole-2-carboxylate (18). Under an argon
atmosphere, a degassed solution of Na2CO3 (11.6 g, 0.109 mol) in
water (32.0 mL) was added to a solution of 17 (5.66 g, 16.4 mmol),
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Ohta et al.
JOCArticle
46c (6.70 g, 24.8 mmol) and Pd(PPh3)4 (1.15 g, 0.995 mmol) in
DME (300 mL) at room temperature, and the mixture was
refluxed for 24 h. The mixture was cooled to room temperature
and evaporated. The products were extracted with dichloro-
methane, and the extract was washed with water and brine, dried
over Na2SO4, and evaporated. The residue was purified by
column chromatography over silica gel 60N (toluene-ethyl
acetate=10:1) to give 18 as yellow solid (6.59 g, 81%). Recrys-
tallization from dichloromethane-hexane gave colorless prisms.
Mp 131.5-132.5 °C; IR (KBr) 1736, 1512, 1374, 1232, 1179, 1113,
959, 608 cm-1;1H NMR (400 MHz, CDCl3) δ1.37 (d, J =6.1Hz,
6H), 3.19 (s, 3H), 3.62 (s, 3H), 3.79 (s, 3H), 4.52 (sep, J = 6.1 Hz,
1H), 4.86 (s, 2H), 6.40 (d, J = 3.2 Hz, 1H), 6.75 (s, 1H), 6.77 (s,
1H), 7.52-7.58 (m, 3H), 7.61-7.67 (m, 1H), 8.00-8.04 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 22.1, 51.9, 55.9, 56.6, 71.6,
96.6, 105.9, 114.1, 114.3, 116.6, 122.6, 125.4, 127.8, 128.9, 131.1,
133.8, 139.3, 145.5, 147.8, 148.6, 161.3. Anal. Calcd for
C24H27NO8S: C, 58.88; H, 5.56; N, 2.86. Found: C, 58.97; H,
5.66; N, 2.75.
7-Isopropoxy-8-methoxy[1]benzopyrano[3,4-b]pyrrol-4(3H)-
one (13). To a solution of 18 (6.28 g, 12.8 mmol) in methanol (400
mL) was added concd HCl (40 mL). The mixture was refluxed
for 2 h, cooled to room temperature, and evaporated. The
products were extracted with dichloromethane, and the extract
was washed with water and brine, dried over Na2SO4, and
evaporated. Under an argon atmosphere, the residue was dis-
solved in THF (350 mL), and a THF solution of TBAF (1.0 M,
19.5 mL, 19.5 mmol) was added dropwise to the mixture at room
temperature. After being refluxed for 2 h, the mixture was
cooled to room temperature, quenched with water, and evapo-
rated. The products were extracted with dichloromethane, and
the extract was washed with water and brine, dried over Na2SO4,
and evaporated. The residue was purified by column chroma-
tography over silica gel 60N (hexane-ethyl acetate = 2:1) to
give 13 as white solid (3.45 g, 98%). Recrystallization from
dichloromethane-hexane gave colorless powder. Mp
190.5-191 °C; IR (KBr) 3220, 1699, 1444, 1255, 1217, 1107,
1066 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.43 (d, J = 6.2 Hz,
6H), 3.96 (s, 3H), 4.59 (sep, J = 6.2 Hz, 1H), 6.66 (t, J = 2.3 Hz,
1H), 7.00 (s, 1H), 7.19 (s, 1H), 7.44 (t, J = 2.7 Hz, 1H), 11.24 (br
s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.9, 56.5, 71.7, 102.5,
104.0, 105.1, 110.5, 116.2, 129.6, 130.8, 145.9, 147.7, 147.8,
156.7. Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13.
Found: C, 65.91; H, 5.54; N, 5.00.
2-(3-Isopropoxy-4-methoxyphenyl)ethanol (21).29b Under an
argon atmosphere, 2 M aqueous HCl (13 mL) was added to a
solution of 20 (19.6 g, 88.2 mmol) in THF (400 mL) at room
temperature. After being refluxed for 2 h, the mixture was
cooled to room temperature and evaporated. The product was
extracted with diethyl ether, washed with water, saturated
aqueous NaHCO3, and brine, dried over Na2SO4, and evapo-
rated. The residue was dissolved in ethanol (350 mL), and
NaBH4 (6.67 g, 0.176 mol) was added portionwise to the
solution at 0 °C. The mixture was stirred for 30 min at 0 °C
and then for 16 h at room temperature. The mixture was
quenched with water and evaporated. The product was ex-
tracted with dichloromethane, and the extract was washed with
water and brine, dried over Na2SO4, and evaporated. The
residue was purified by column chromatography over silica gel
60N (hexane-ethyl acetate = 3:1) to give 21 as colorless oil
(16.3 g, 88%). Bp 99-103 °C (0.2 mmHg, bulb-to-bulb); IR
(neat) 3407, 1511, 1261, 1233, 1137, 1111, 1030 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.35 (d, J = 6.0 Hz, 6H), 1.82 (br s, 1H),
2.77 (t, J = 6.6 Hz, 2H), 3.80 (t, J = 6.6 Hz, 2H), 3.82 (s, 3H),
4.51 (sep, J = 6.0 Hz, 1H), 6.76 (dd, J = 1.9 and 7.9 Hz, 1H),
6.78 (d, J = 1.9 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 22.1, 38.7, 56.1, 63.7, 71.5, 112.3, 117.1,
121.5, 131.0, 147.3, 149.2; HREIMS m/z calcd for C12H18O3
(M+) 210.1256, found 210.1252.
2-(2-Bromo-5-isopropoxy-4-methoxyphenyl)ethanol (14).29
A
solution of NBS (14.0 g, 78.7 mmol) in DMF (30 mL) was added
dropwise to a solution of 21 (16.3 g, 77.5 mmol) in DMF (80 mL)
at 0 °C. The mixture was stirred for 20 h at 0 °C and diluted with
water. The product was extracted with dichloromethane, and
the extract was washed with water and brine, dried over Na2SO4,
and evaporated. The residue was purified by column chroma-
tography over silica gel 60N (hexane-ethyl acetate = 3:1) to
give 14 as pink solid (18.5 g, 83%). Recrystallization from
dichloromethane-hexane gave colorless needles. Mp
67.5-68.5 °C; IR (KBr) 3336, 3258, 1514, 1263, 1215, 1170,
1029, 850 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.34 (d, J = 6.2
Hz, 6H), 2.92 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.83 (t, J = 6.7
Hz, 2H), 4.49 (sep, J = 6.2 Hz, 1H), 6.82 (s, 1H), 7.02 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 22.0, 38.9, 56.2, 62.3, 71.9,
114.9, 116.4, 118.6, 129.7, 146.6, 149.8. Anal. Calcd for C12-
H17BrO3: C, 49.84; H, 5.93. Found: C, 49.79; H, 6.15.
3-[2-(2-Bromo-5-isopropoxy-4-methoxyphenyl)ethyl]-7-isopro-
poxy-8-methoxy[1]benzopyrano[3,4-b]pyrrol-4(3H)-one (12). Un-
der an argonatmosphere, triphenylphosphine (8.23 g, 31.4 mmol)
and DIAD (6.2 mL, 31.5 mmol) were added in sequence to a
mixed solution of 13 (4.29 g, 15.7 mmol) and 14 (9.07 g, 31.4
mmol) in THF (500 mL). After being refluxed for 16 h, the
mixture was cooled to room temperature, diluted with water, and
evaporated. The product was extracted with dichloromethane,
and the extract was washed with water and brine, dried over
Na2SO4, and evaporated. The residue was purified by column
chromatography over silica gel 60N (hexane-ethyl acetate=3:1)
to give a mixture of 12 and diisopropyl hydrazinedicarboxylate.
The latter hydrazine derivative was easily removed by bulb-to-
bulb distillation (130 °C, 0.1 mmHg) to leave 12 as white solid
(6.61 g, 77%). Recrystallization from dichloromethane-hexane
gave colorless powder. Mp 139-140 °C; IR (KBr) 1718, 1501,
1262, 1233, 1208, 1111, 1037 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.18 (d, J = 5.9 Hz, 6H), 1.43 (d, J = 5.9 Hz, 6H), 3.20 (t, J =
6.9 Hz, 2H), 3.82 (s, 3H), 3.93 (s, 3H), 4.27 (sep, J = 5.9 Hz, 1H),
4.58 (sep, J = 5.9 Hz, 1H), 4.64 (t, J = 6.9 Hz, 2H), 6.40 (d, J =
2.6 Hz, 1H), 6.51 (s, 1H), 6.84 (d, J = 2.6 Hz, 1H), 6.95 (s, 1H),
7.00 (s, 1H), 7.09 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8,
21.9, 37.8, 48.8, 56.2, 56.6, 71.6, 71.7, 100.6, 103.8, 104.8, 110.4,
114.4, 115.0, 116.0, 117.9, 129.1, 131.3, 132.9, 146.1, 146.8, 147.4,
147.7, 149.8, 155.4. Anal. Calcd for C27H30BrNO6: C, 59.56; H,
5.55; N, 2.57. Found: C, 59.29; H, 5.55; N, 2.43.
3-Isopropoxy-4,β-dimethoxystyrene (20). Under an argon
atmosphere, potassium tert-butoxide (17.5 g, 156 mmol) was
added portionwise to a suspension of (methoxymethyl)-
triphenylphosphonium chloride (44.6 g, 130 mmol) in THF
(260 mL) at 0 °C. After 15 min, a solution of 19 (20.2 g, 104
mmol) in THF (70 mL) was added dropwise, and the solution
was stirred for 2 h at 0 °C and then for 4 h at room temperature.
The mixture was quenched with water and evaporated. The
residue was extracted with dichloromethane, and the extract was
washed with water and brine, dried over Na2SO4, and evapo-
rated. The residue was purified by column chromatography over
silica gel 60N (hexane-ethyl acetate = 3:1) and then by dis-
tillation (93-94 °C, 0.07 mmHg) to give 21.6 g (93%) of 20 [(E)-
isomer:(Z)-isomer = ca. 1:1] as colorless oil. IR (neat): 1645,
1510, 1462, 1263, 1212, 1138, 1031 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.35 (d, J = 6.2 Hz, 6H), 1.36 (d, J = 6.2 Hz, 6H), 3.65
(s, 3H), 3.73 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 4.46-4.57 (m,
2H), 5.14 (d, J = 7.0 Hz, 1H), 5.75 (d, J = 12.8 Hz, 1H), 6.03 (d,
J = 7.0 Hz, 1H), 6.76-6.81 (m, 4H), 6.91 (d, J = 12.8 Hz, 1H),
7.08 (dd, J = 2.0 and 8.4 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 22.2, 22.2, 56.0, 56.1, 56.4, 60.5,
71.4, 71.6, 104.8, 105.5, 111.8, 112.5, 113.5, 116.5, 118.3, 121.4,
129.0, 129.3, 146.5, 146.8, 147.4, 147.7, 148.7, 149.0; HREIMS
m/z calcd for C13H18O3 (M+) 222.1256, found 222.1243.
8150 J. Org. Chem. Vol. 74, No. 21, 2009

Ohta et al.
8,9-Dihydro-3,11-diisopropoxy-2,12-dimethoxy-6H-[1]benzo-
JOCArticle
(s, 1H), 8.66 (s, 1H), 9.06 (d, J = 7.3 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ21.9, 22.0, 56.0, 56.2, 71.1, 71.4, 82.2, 102.9, 105.2,
105.2, 108.1, 108.8, 110.0, 113.0, 118.1, 122.6, 124.9, 127.9, 132.1,
146.3, 146.5, 148.4, 148.8, 150.0, 154.4. Anal. Calcd for
C27H26BrNO6: C, 60.01; H, 4.85; N, 2.59. Found: C, 59.93; H,
4.83; N, 2.46.
pyrano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (11).22 Under an
argon atmosphere, a mixture of 13 (6.60 g, 12.1 mmol), K2CO3
(3.69 g, 26.7 mmol) and Pd(PPh3)4 (701 mg, 0.607 mmol) in N,N-
dimethylacetamide (85 mL) was heated at 125 °C for 20 h. After
cooling to room temperature, the mixture was diluted with water
and extracted with dichloromethane. The extract was washed
with water and brine, dried over Na2SO4, and evaporated. The
residue was purified by column chromatography over silica gel
60N (dichloromethane-ethyl acetate = 20:1) to give 11 as
colorless solid (5.01 g, 89%). The spectroscopic data of this
product are identical with those described above.
14-Chloro-3,11-diisopropoxy-2,12-dimethoxy-6H-[1]benzopyra-
no[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (23b). A solution of
NCS (8.8 mg, 65.9 μmol) in DMF (1.0 mL) was added dropwise
to a solution of 22 (30.0 mg, 65.0 μmol) in DMF (3.0 mL) at 0 °C.
The mixture was stirred for 1 h at 0 °C and for 12 h at room
temperature. The solution was diluted with water, and the product
was extracted with dichloromethane. The extract was washed with
water and brine, dried over Na2SO4, and evaporated. The residue
was purified by column chromatography over silica gel 60N
(dichloromethane-ethyl acetate = 20:1) to give 23b as colorless
solid (30.8 mg, 96%). Recrystallization from dichlorometha-
ne-hexane gave colorless powder. Mp 225.5-226.5 °C; IR
3,11-Diisopropoxy-2,12-dimethoxy-6H-[1]benzopyrano[40,30:4,5]-
pyrrolo[2,1-a]isoquinolin-6-one (22). A mixture of 11 (1.26 g, 2.72
mmol) and activated MnO2 (<5 μm, 12.6 g, 145 mmol) in
dichloromethane (200 mL) was refluxed for 48 h. After cooling to
room temperature, the mixture was passed through a pad of Celite
and evaporated. The residue was purified by column chromatog-
raphy over silica gel 60N (dichloromethane-ethyl acetate=20:1) to
give 22 as pale yellow solid (1.00 g, 80%). Recrystallization from
dichloromethane-hexane gave colorless needles. Mp 180-181 °C;
IR (KBr) 1698, 1489, 1440, 1276, 1220, 1148, 1108 cm-1; 1H NMR
(500 MHz, CDCl3) δ 1.44 (d, J = 6.2 Hz, 6H), 1.48 (d, J = 6.2 Hz,
6H), 3.99 (s, 3H), 4.06 (s, 3H), 4.59 (sep, J = 6.2 Hz, 1H), 4.72 (sep,
J = 6.2 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.94 (s, 1H), 7.05 (s, 1H),
1
(KBr) 1712, 1512, 1461, 1436, 1272, 1220, 1110, 1042 cm-1; H
NMR (500 MHz, CDCl3) δ 1.46 (d, J = 6.2 Hz, 6H), 1.49 (d, J =
6.2 Hz, 6H), 3.92 (s, 3H), 3.95 (s, 3H), 4.59 (sep, J = 6.2 Hz, 1H),
4.70 (sep, J = 6.2 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.83 (s, 1H),
6.96 (s, 1H), 7.88 (s, 1H), 8.33 (s, 1H), 8.95 (d, J = 7.3 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 21.9, 22.0, 55.9, 56.2, 71.1, 71.4, 98.0,
102.9, 105.0, 105.4, 106.8, 108.5, 110.0, 112.8, 117.8, 122.4, 124.6,
126.5, 131.4, 146.4, 146.6, 148.4, 148.7, 150.2, 154.4. Anal. Calcd
for C27H26ClNO6: C, 65.39; H, 5.28; N, 2.82. Found: C, 65.20; H,
5.27; N, 2.69.
7.07 (s, 1H), 7.26 (s, 1H), 7.48 (s, 1H), 9.00 (d, J = 7.3 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 21.9, 21.9, 56.2, 56.5, 71.3, 71.5, 91.2,
103.5, 104.5, 105.2, 109.0, 109.6, 110.4, 112.0, 118.2, 123.2, 124.0,
132.1, 138.4, 146.6, 147.2, 148.5, 149.2, 151.0, 155.3. Anal. Calcd
for C27H27NO6: C, 70.27; H, 5.90; N, 3.03. Found: C, 70.07; H, 5.93;
N, 2.89.
14-Fluoro-3,11-diisopropoxy-2,12-dimethoxy-6H-[1]benzopy-
rano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (23c). SELECT-
FLUOR (23.4 mg, 66.1 μmol) was added to a solution of 22
(30.0 mg, 65.0 μmol) in acetnitrile (1.0 mL) containing H2O (100
μL) at 0 °C. After being stirred for 15 h at 0 °C, the mixture was
quenched with water. The product was extracted with dichlor-
omethane, and the extract was washed with water and brine,
dried over Na2SO4, and evaporated. The residue was purified by
column chromatography over silica gel 60N (dichloro-
methane-ethyl acetate=20:1) to give 23c as gray solid (16.6
mg, 53%). Recrystallization from dichloromethane-hexane
gave colorless needles. Mp 208.5-209.5 °C; IR (KBr) 1703,
1505, 1476, 1280, 1227, 1109, 1046 cm-1; 1H NMR (500 MHz,
CDCl3) δ 1.45 (d, J = 6.1 Hz, 6H), 1.48 (d, J = 6.1 Hz, 6H), 3.95
(s, 3H), 3.98 (s, 3H), 4.59 (sep, J = 6.1 Hz, 1H), 4.70 (sep, J = 6.1
Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 6.88 (s, 1H), 7.01 (s, 1H), 7.36
(s, 1H), 7.64 (s, 1H), 8.84 (d, J = 7.2 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 21.9, 22.0, 55.9, 56.3, 71.3, 71.5, 102.6 (d,
J = 4.3 Hz), 103.2, 104.9 (d, J = 8.5 Hz), 106.0 (d, J = 3.1
Hz), 107.2, 110.3, 112.3, 116.6 (d, J = 10.4 Hz), 116.8 (d, J = 3.7
Hz), 122.1, 123.3 (d, J = 19.5 Hz), 123.5, 138.2 (d, J=244 Hz),
146.1, 147.1, 148.4, 148.8, 150.9, 154.7. Anal. Calcd for
C27H26FNO6: C, 67.63; H, 5.47; N, 2.92. Found: C, 67.48; H,
5.48; N, 2.78.
3,11-Dihydroxy-2,12-dimethoxy-6H-[1]benzopyrano[40,30:4,5]-
pyrrolo[2,1-a]isoquinolin-6-one(1). Under an argonatmosphere, a
heptane solution of BCl3 (1.0 M, 390 μL, 0.390 mmol) was added
dropwise to a solution of 22 (30.0 mg, 65.0 μmol) in dichlor-
omethane(6.5 mL) at -78°C. After beingstirred for 30min atthe
same temperature, the reaction mixture was allowed to warm to
room temperature and stirred for 3 h. The mixture was quenched
with saturated NaHCO3, and the product was extracted with
ethyl acetate. The extract was washed with water and brine, dried
over Na2SO4, and evaporated. The residue was purified by
column chromatography over silica gel 60N (dichloro-
methane-ethyl acetate = 20:1) to give 1 as gray powder (16.1
mg, 66%). Mp 234-246 °C (dec) (sealed capillary); IR (KBr)
3441, 1689, 1457, 1284, 1217, 1146 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 3.95 (s, 3H), 4.03 (s, 3H), 6.89 (s, 1H), 7.15 (d, J =
7.3 Hz, 1H), 7.20 (s, 1H), 7.53 (s, 1H), 7.62 (s, 1H), 7.77 (s, 1H),
8.83 (d, J = 7.3 Hz, 1H), 9.82 (s, 1H), 9.94 (s, 1H); 13C NMR (100
MHz, DMSO-d6) δ 55.8, 55.9, 92.2, 103.5, 104.9, 105.6, 107.5,
108.1, 111.2, 112.0, 117.1, 121.9, 123.8, 131.9, 138.2, 145.3, 146.0,
148.1, 148.8, 149.5, 154.1; HREIMS m/z calcd for C21H15NO6
(M+) 377.0899, found 377.0892.
14-Bromo-3,11-diisopropoxy-2,12-dimethoxy-6H-[1]benzopyra-
no[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (23a). A solution of
NBS (234 mg, 1.31 mmol) in DMF (6.0 mL) was added dropwise
toa solution of 22 (601 mg, 1.30 mmol) in DMF (20.0 mL) at 0 °C.
The mixture was stirred for 1 h at 0 °C and for 14 h at room
temperature. The solution was diluted with water, and the product
was extracted with dichloromethane. The extract was washed with
water and brine, dried over Na2SO4, and evaporated. The residue
was purified by column chromatography over silica gel 60N
(dichloromethane-ethyl acetate = 20:1) togive 23a as pale yellow
solid (647 mg, 92%). Recrystallization from dichloromethane-
hexane gave colorless powder. Mp 212-213 °C; IR (KBr) 1706,
14-(N,N-Dimethylaminomethyl)-3,11-diisopropoxy-2,12-dime-
thoxy-6H-[1]benzopyrano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one
(23d). A mixture of 22 (200 mg, 0.433 mmol) and N,N-dimethyl-
methyleneammonium iodide (241 mg, 1.30 mmol) in dichloro-
methane (7.0 mL) was refluxed for 24 h. After cooling, saturated
NaHCO3 was added, and the product was extracted with dichlor-
omethane. The extract was washed with water and brine, dried
over Na2SO4, and evaporated. The residue was purified by
column chromatography over silica gel 60N (dichloro-
methane-ethyl acetate=20:1) to give 23d as white solid (218
mg, 97%). Recrystallizationfromdichloromethane-hexane gave
yellow powder. Mp 214.5-215.5 °C; IR (KBr) 1698, 1428, 1264,
1229, 1180, 1113, 1057 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.45
(d, J = 6.2 Hz, 6H), 1.48 (d, J = 6.2 Hz, 6H), 2.49 (s, 6H), 4.00 (s,
3H), 4.05 (s, 3H), 4.10 (br s, 2H), 4.61 (sep, J = 6.2 Hz, 1H), 4.74
(sep, J = 6.2 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.96 (s, 1H), 7.09
1
1515, 1433, 1271, 1215, 1110, 1042 cm-1; H NMR (500 MHz,
CDCl3) δ 1.46 (d, J = 6.2 Hz, 6H), 1.49 (d, J = 6.2 Hz, 6H), 3.93
(s, 3H), 3.99 (s, 3H), 4.60 (sep, J = 6.2 Hz, 1H), 4.72 (sep, J =6.2
Hz, 1H), 6.86 (s, 1H), 6.86 (d, J = 7.3 Hz, 1H), 6.98 (s, 1H), 8.18
J. Org. Chem. Vol. 74, No. 21, 2009 8151

Ohta et al.
JOCArticle
(s, 1H), 7.91 (s, 1H), 8.39 (s, 1H), 9.23 (d, J=7.3 Hz, 1H); 13
C
colorless powder. Mp 208-209 °C; IR (KBr) 1705, 1431, 1261,
1225, 1029 cm-1;1H NMR (400 MHz, CDCl3) δ1.40 (d, J=6.0 Hz,
6H), 1.44(d, J= 6.0 Hz, 6H), 3.44 (s, 3H), 3.45 (s, 3H), 3.89 (s, 3H),
4.00 (s, 3H), 4.56 (sep, J = 6.0 Hz, 1H), 4.70 (sep, J = 6.0 Hz, 1H),
6.74 (s, 1H), 6.95 (s, 1H), 7.01 (d, J = 7.4 Hz, 1H), 7.10 (s, 1H),
7.13-7.18 (m, 2H), 7.16 (s, 1H), 7.21-7.25 (m, 1H), 9.21 (d, J =
7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8, 21.8, 21.9, 21.9,
55.2, 55.5, 56.2, 56.3, 71.2, 71.4, 103.4, 105.5, 105.6, 107.8, 109.9,
110.4, 110.9, 111.9, 112.3, 114.5, 119.0, 123.2, 124.2, 124.7, 128.3,
129.4, 134.4, 146.5, 146.6, 147.9, 148.5, 149.0, 149.9, 150.2, 155.6;
HREIMS m/z calcd for C35H35NO8 (M+) 597.2363, found
597.2372.
3,11-Diisopropoxy-2,12-dimethoxy-14-(4-methoxymethoxyphe-
nyl)-6H-[1]benzopyrano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one
(25c). According to the general procedure, 23a (30.0 mg, 55.5
μmol) and 24c (15.2 mg, 83.5 μmol) were reacted. After chro-
matographic purification over silica gel 60N (dichloro-
methane-ethyl acetate = 20:1), 25c was obtained as pale yellow
solid (26.1 mg, 79%). Recrystallization from dichloromethane-
hexane gave colorless powder. Mp 200-201 °C; IR (KBr) 1703,
1430, 1264, 1179, 1039, 992 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.40 (d, J = 6.1 Hz, 6H), 1.43 (d, J = 6.1 Hz, 6H), 3.43 (s, 3H),
3.45 (s, 3H), 3.50 (s, 3H), 4.57 (sep, J = 6.1 Hz, 1H), 4.69 (sep,
J = 6.1 Hz, 1H), 5.28 (s, 2H), 6.69 (s, 1H), 6.96 (s, 1H), 7.01
(d, J=7.3 Hz, 1H), 7.09 (s, 1H), 7.12 (s, 1H), 7.28-7.33 (m, 2H),
7.53-7.58 (m, 2H), 9.21 (d, J=7.3 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 21.8, 21.9, 55.1, 55.4, 55.9, 71.3, 71.5, 94.3,
103.6, 105.5, 105.7, 107.9, 110.0, 110.6, 110.7, 112.3, 117.4,
119.1, 123.2, 124.7, 129.4, 129.5, 133.1, 134.5, 146.6, 146.6,
147.9, 148.5, 150.2, 155.6, 157.1; HREIMS m/z calcd for
C35H35NO8 (M+) 597.2363, found 597.2352.
NMR (125 MHz, CDCl3) δ 21.9, 22.0, 44.9, 54.3, 56.2, 56.5, 71.2,
71.4, 103.5, 107.3, 107.7, 108.2, 110.1, 110.4, 112.7, 119.1, 123.0,
125.2, 130.4, 136.5, 146.4, 146.7, 147.9, 148.5, 150.6, 155.2. Anal.
Calcd for C30H34N2O6: C, 69.48; H, 6.61; N, 5.40. Found: C,
69.18; H, 6.71; N, 5.32.
14-Formyl-3,11-diisopropoxy-2,12-dimethoxy-6H-[1]benzopyra-
no[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (23e). Phosphorus oxy-
chloride (21.0 μL, 229 μmol) was added dropwise to DMF
(1.00 mL, 12.9 mmol) at 0 °C. After being stirred for 1 h at 0 °C,
22 (31.8 mg, 68.9 μmol) was added, and the mixture was stirred for
15 min at 0 °C. The reaction mixture was heated at 60 °C, and
stirring was continued for 24 h. After cooling, the mixture was
quenched with saturated NaHCO3, and the product was extracted
with dichloromethane. The extract was washed with water and
brine, dried over Na2SO4, and evaporated. The residue was
purified by column chromatography over silica gel 60N
(dichlorometh-
ane-ethyl acetate = 20:1) to give 23e as pale yellow solid
(33.5 mg, 99%). Recrystallization from dichloromethane-hexane
gave colorless powder. Mp 228-228.5 °C (sealed capillary); IR
(KBr) 1718, 1657, 1517, 1271, 1227, 1180, 1109 cm-1; 1H NMR
(500 MHz, CDCl3) δ 1.48 (d, J = 6.2 Hz, 6H), 1.52 (d, J = 6.2 Hz,
6H), 3.98 (s, 3H), 4.01 (s, 3H), 4.64 (sep, J= 6.2 Hz, 1H), 4.78 (sep,
J=6.2 Hz, 1H), 6.87 (s, 1H), 7.06 (s, 1H), 7.13 (d, J = 7.1 Hz, 1H),
8.19 (s, 1H), 8.54 (s, 1H), 9.25 (d, J = 7.1 Hz, 1H), 10.70 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 21.9, 21.9, 56.2, 56.3, 71.3, 71.5,
102.5, 108.4, 108.5, 109.1, 109.2, 110.5, 112.5, 115.1, 118.0, 122.6,
127.2, 133.9, 139.6, 146.8, 147.4, 149.5, 150.6, 151.0, 154.7, 183.5;
HREIMS m/z calcd for C28H27NO7 (M+) 489.1788, found
489.1792.
Suzuki-Miyaura Coupling of Bromide 23a with Arylboronic
Acid 24. General Procedure. Under an argon atmosphere, a
mixture of 23a (31.0 mg, 57.4 μmol), 24 (90.5 μmol), CsF (17.0
mg, 0.112 mmol), Ag2O (16.0 mg, 69.0 μmol), and Pd(PPh3)4 (7.0
mg, 6.1 μmol) in DME (2 mL) was heated at 80 °C for 24 h. After
cooling, the mixture was diluted with water, and the product was
extracted with dichloromethane. The extract was washed with
water and brine, dried over Na2SO4, and evaporated. The residue
was purified by column chromatography to give 25.
3,11-Diisopropoxy-2,12-dimethoxy-14-phenyl-6H-[1]benzopy-
rano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (25d). According to
the general procedure, 23a (30.0 mg, 55.5 μmol) and 24d (10.2
mg, 83.7 μmol) were reacted. After chromatographic purifica-
tion oversilica gel 60N (dichloromethane-ethyl acetate = 20:1),
25d was obtained as pale yellow solid (24.2 mg, 81%). Recrys-
tallization from dichloromethane-hexane gave colorless pow-
der. Mp 229.5-230.5 °C; IR (KBr) 1705, 1430, 1264, 1227, 1178,
1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.40 (d, J = 6.0 Hz,
6H), 1.43 (d, J = 6.0 Hz, 6H), 3.35 (s, 3H), 3.37 (s, 3H), 4.57 (sep,
J = 6.0 Hz, 1H), 4.69 (sep, J = 6.0 Hz, 1H), 6.61 (s, 1H), 6.96 (s,
1H), 7.02 (d, J=7.4 Hz, 1H), 7.05 (s, 1H), 7.09 (s, 1H), 7.51-7.59
(m, 1H), 7.62-7.67 (m, 4H), 9.23 (d, J = 7.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 21.8, 21.9, 55.0, 55.3, 71.2, 71.5, 103.5,
105.4, 105.6, 108.0, 109.9, 110.4, 111.2, 112.4, 119.0, 123.2, 124.7,
128.4, 129.3, 129.5, 132.0, 134.2, 136.3, 146.5, 146.6, 147.8, 148.4,
150.2, 155.6; HREIMS m/z calcd for C33H31NO6 (M+)
537.2151, found 537.2137.
3,11-Diisopropoxy-2,12-dimethoxy-14-methyl-6H-[1]benzopyra-
no[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (25e). According to the
general procedure, 23a (30.0 mg, 55.5 μmol) and trimethylboroxine
(24e) (12.0 μL, 85.8 μmol) were reacted. The product was purified
by column chromatography over silica gel 60N (dichloro-
methane-ethyl acetate = 20:1) and subsequently by semiprepara-
tive HPLC (COSMOSIL, 5C18-MS-II) (CH3CN) to give 25e as
pale yellow solid (21.6 mg, 82%). Recrystallization from dichloro-
methane-hexane gave pale yellow powder. 174.5-187 °C (dec)
(sealed capillary); IR (KBr) 1688, 1468, 1430, 1277, 1227, 1053
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.45 (d, J=6.1 Hz, 6H), 1.48
(d, J = 6.1 Hz, 6H), 3.06 (s, 3H), 3.99 (s, 3H), 4.05 (s, 3H), 4.62
(sep, J = 6.1 Hz, 1H), 4.74 (sep, J = 6.1 Hz, 1H), 6.93 (d, J = 7.4
Hz, 1H), 7.01 (s, 1H), 7.13 (s, 1H), 7.68 (s, 1H), 7.96 (s, 1H), 9.20 (d,
J = 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.8, 21.9, 22.0,
56.2, 56.8, 71.3, 71.5, 103.9, 105.6, 106.3, 107.0, 107.9, 110.9, 111.0,
112.1, 119.8, 123.3, 125.1, 129.2, 134.7, 146.8, 146.8, 148.0, 148.3,
150.4, 155.4; HREIMS m/z calcd for C28H29NO6 (M+) 475.1995,
found 475.2001.
3,11-Diisopropoxy-14-(4-isopropoxy-3-methoxyphenyl)-2,12-
dimethoxy-6H-[1]benzopyrano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-
6-one (25a).6c According to the general procedure, 23a (31.0 mg,
57.4 μmol) and 24a (19.0 mg, 90.5 μmol) were reacted. After
successive purifications by column chromatography over silica
gel 60N using different solvent systems (dichloromethane-ethyl
acetate = 20:1 and hexane-ethyl acetate = 2:1), 25a was
obtained as pale yellow solid (24.8 mg, 69%). Recrystallization
from dichloromethane-hexane gave colorless powder. Mp
1
190.5-191.5 °C; H NMR (400 MHz, CDCl3) δ 1.41 (d, J=
6.1 Hz, 6H), 1.44 (d, J = 6.1 Hz, 12H), 3.44 (s, 3H), 3.45 (s, 3H),
3.84 (s, 3H), 4.57 (sep, J=6.1 Hz, 1H), 4.64 (sep, J = 6.1 Hz,
1H), 4.70 (sep, J = 6.1 Hz, 1H), 6.75 (s, 1H), 6.97 (s, 1H), 7.02 (d,
J = 7.4 Hz, 1H), 7.10 (s, 1H), 7.13 (s, 1H), 7.16-7.19 (m, 3H),
9.22 (d, J = 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8,
21.8, 21.9, 21.9, 21.9, 21.9, 55.1, 55.4, 56.1, 71.2, 71.4, 71.8,
103.4, 105.4, 105.6, 107.7, 109.9, 110.4, 110.9, 112.2, 115.0,
116.9, 118.9, 123.1, 123.8, 124.6, 128.7, 129.3, 134.3, 146.4,
146.5, 147.0, 147.7, 148.3, 150.0, 151.3, 155.4. These spectro-
scopic data are identical with those previously reported.6c
14-(3,4-Dimethoxyphenyl)-3,11-diisopropoxy-2,12-dimethoxy-
6H-[1]benzopyrano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (25b).22
According to the general procedure, 23a (130 mg, 0.241 mmol) and
24b (66.0 mg, 0.363 mmol) were reacted. After successive purifica-
tions by column chromatography over silica gel 60N using different
solvent systems (dichloromethane-ethyl acetate = 40:1 and tolue-
ne-ethyl acetate = 5:1), 25b was obtained as pale yellow solid (125
mg, 87%). Recrystallization from dichloromethane-hexane gave
8152 J. Org. Chem. Vol. 74, No. 21, 2009

Ohta et al.
JOCArticle
Deprotection of Isopropyl Groups of 23 and 25. General
Procedure. Under an argon atmosphere, a heptane solution of
BCl3 (1.0 M, 390 μL, 0.390 mmol) was added dropwise to a
solution of 23 or 25 (64.8 μmol) in dichloromethane (6.5 mL) at
-78 °C. After being stirred under the conditions shown in
Table 3, the mixture was quenched with saturated aqueous
NaHCO3, and the product was extracted with ethyl acetate.
The extract was washed with brine, dried over Na2SO4, and
evaporated. The residue was triturated with dichloromethane
and filtered to give 2.
14-Bromo-3,11-dihydroxy-2,12-dimethoxy-6H-[1]benzopyrano-
[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (2a). According to the
general procedure, 23a (35.0 mg, 64.8 μmol) was reacted to give
2a as pale gray powder (26.1 mg, 88%). Mp > 300 °C (sealed
capillary); IR (KBr) 3439, 1697, 1433, 1281, 1212, 1161, 1045
cm-1;1H NMR (400MHz, DMSO-d6) δ3.80(s,3H), 3.89 (s,3H),
6.73 (s, 1H), 6.99 (d, J = 7.3 Hz, 1H), 7.07 (s, 1H), 7.99 (s, 1H),
8.49 (s, 1H), 8.79 (d, J=7.3 Hz, 1H), 9.92 (br s, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 55.2, 55.5, 80.9, 103.5, 104.5, 104.7,
106.9, 107.1, 111.4, 112.8, 116.4, 121.4, 124.8, 127.1, 131.5, 144.4,
146.0, 148.2, 148.3, 148.5, 153.2; HREIMS m/z calcd for C21H14-
BrNO6 (M+) 455.0004, found 454.9993.
14-Chloro-3,11-dihydroxy-2,12-dimethoxy-6H-[1]benzopyrano-
[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (2b). According to the
general procedure, 23b (48.3 mg, 97.4 μmol) was reacted to give
2b as pale gray powder (20.9 mg, 52%). Mp > 300 °C (sealed
capillary); IR (KBr) 3446, 1701, 1437, 1281, 1215, 1159, 1047
cm-1; 1H NMR (400 MHz, DMSO-d6) δ3.86 (s, 3H), 3.94 (s, 3H),
6.83 (s, 1H), 7.12 (d, J=7.4Hz, 1H), 7.17 (s, 1H), 7.87 (s, 1H), 8.36
(s, 1H), 8.86 (d, J =7.4 Hz, 1H), 9.97 (br s, 1H), 10.07 (br s, 1H);
13C NMR (100 MHz, DMSO-d6) δ 55.1, 55.5, 96.3, 103.5, 104.2,
104.8, 105.6, 106.6, 111.3, 112.7, 116.1, 121.2, 124.6, 125.7, 130.8,
144.6, 145.9, 148.2, 148.5, 148.5, 153.2; HREIMS m/z calcd for
C21H14ClNO6 (M+) 411.0510, found 411.0503.
14-Fluoro-3,11-dihydroxy-2,12-dimethoxy-6H-[1]benzopyrano-
[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (2c). According to the
general procedure, 23c (60.0 mg, 125 μmol) was reacted to give
2c as pale gray powder (18.1 mg, 37%). Mp > 300 °C (sealed
capillary); IR (KBr) 3455, 3222, 1695, 1478, 1432, 1286, 1209,
1160, 1053 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H),
3.92 (s, 3H), 6.80 (s, 1H), 7.01 (d, J = 7.3 Hz, 1H), 7.13 (s, 1H),
7.21 (s, 1H), 7.50 (s, 1H), 8.63 (d, J = 7.3 Hz, 1H), 9.92 (br s, 2H);
13C NMR (100 MHz, DMSO-d6) δ 55.3, 55.7, 101.4 (d, J = 4.8
Hz), 103.6, 104.2 (d, J = 8.9 Hz), 105.3 (d, J = 2.9 Hz), 105.5 (d,
J = 3.1 Hz), 111.4, 112.3, 115.0 (d, J = 4.3 Hz), 115.9 (d, J = 9.5
Hz), 120.9, 122.8 (d, J=19.7 Hz), 123.4, 136.7 (d, J =242 Hz),
145.2, 145.6, 148.2, 148.6, 149.2, 153.5 (d, J=2.7 Hz); HREIMS
m/z calcd for C21H14FNO6 (M+) 395.0805, found 395.0808.
14-(N,N-Dimethylaminomethyl)-3,11-dihydroxy-2,12-dimeth-
oxy-6H-[1]benzopyrano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one
(2d). According to the general procedure, 23d (26.3 mg, 50.7
μmol) was reacted to give 2d as pale gray powder (11.6 mg,
53%). Mp 215-230 °C (dec) (sealed capillary); IR (KBr) 3459,
1673, 1428, 1284, 1238, 1166, 1059 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 2.43 (s, 6H), 3.93 (s, 3H), 4.00 (s, 3H), 4.08 (s, 2H),
6.89 (s, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.21 (s, 1H), 7.89 (s, 1H),
8.34 (s, 1H), 9.07 (d, J=7.3 Hz, 1H), 9.94 (br s, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 44.3, 53.4, 55.6, 55.9, 103.8, 106.8,
107.0, 107.2, 107.5, 108.4, 111.4, 112.6, 117.5, 121.8, 124.9,
130.0, 136.0, 144.6, 146.2, 147.7, 148.2, 148.8, 154.1; HREIMS
m/z calcd for C24H22N2O6 (M+) 434.1478, found 434.1500.
14-Formyl-3,11-dihydroxy-2,12-dimethoxy-6H-[1]benzopyrano-
[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (2e). According to the
general procedure, 23e (41.5 mg, 84.8 μmol) was reacted to give
2e as pale yellow powder (20.0 mg, 58%). Mp 185-195 °C (dec)
(sealed capillary); IR (KBr) 3417, 1698, 1518, 1419, 1390, 1281,
1157 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 3.94 (s, 3H), 4.04 (s,
3H), 6.92 (s, 1H), 7.33 (s, 1H), 7.51 (d, J = 7.3 Hz, 1H), 8.51 (s,
1H), 8.62 (s, 1H), 9.25 (d, J = 7.3 Hz, 1H), 10.23 (br s, 2H), 10.79
(s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 55.6, 55.8, 103.4, 107.1,
108.4, 109.5, 109.7, 111.1, 111.7, 114.9, 116.6, 121.7, 127.2, 133.0,
139.2, 144.9, 147.0, 149.3, 149.5, 150.5, 153.9, 183.7; HREIMS m/z
calcd for C22H15NO7 (M+) 405.0849, found 405.0861.
14-(3,4-Dimethoxyphenyl)-3,11-dihydroxy-2,12-dimethoxy-6H-
[1]benzopyrano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (2f).7e,22
According to the general procedure, 25b (57.4 mg, 96.0 μmol)
was reacted to give 2f as pale gray powder (41.2 mg, 84%). Mp
280-295 °C (dec) (sealed capillary); IR (KBr) 3383, 1698, 1433,
1278, 1142, 1026 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 3.36 (s,
3H), 3.37 (s, 3H), 3.77 (s, 3H), 3.87 (s, 3H), 6.68 (s, 1H), 6.88 (s,
1H), 7.09 (s, 1H), 7.16 (dd, J = 1.9 and 8.1 Hz, 1H), 7.20 (s, 1H),
7.22 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.29 (d, J = 8.1
Hz, 1H), 9.02 (d, J = 7.4 Hz, 1H), 9.84 (br s, 1H), 9.93 (br s, 1H);
13C NMR (100 MHz, DMSO-d6) δ 54.4, 55.0, 55.8, 55.9, 103.7,
105.2, 105.6, 106.4, 108.2, 110.4, 111.4, 112.3, 113.0, 114.6, 117.4,
121.9, 123.6, 124.6, 127.2, 128.8, 133.9, 144.5, 146.2, 147.8, 148.3,
148.5, 148.9, 149.8, 154.2; HREIMS m/z calcd for C29H23NO8
(Mþ) 513.1424, found 513.1408.
3,11-Dihydroxy-2,12-dimethoxy-14-phenyl-6H-[1]benzopyrano-
[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (2g). According to the
general procedure, 25d (24.2 mg, 45.0 μmol) was reacted to give
2g as pale gray powder (19.8 mg, 97%). Mp 263-280 °C (dec)
(sealed capillary); IR (KBr) 3446, 1675, 1425, 1279, 1241, 1200,
1167, 1041 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 3.27 (s, 3H),
3.29 (s, 3H), 6.51 (s, 1H), 6.86 (s, 1H), 6.94 (s, 1H), 7.18 (s, 1H),
7.19 (d, J = 7.3 Hz, 1H), 7.59-7.72 (m, 5H), 8.98 (d, J = 7.3 Hz,
1H), 9.87 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 54.4, 54.9,
103.8, 105.1, 105.3, 106.7, 108.1, 110.4, 111.6, 112.4, 117.3, 122.0,
124.7, 128.5, 128.6, 129.5, 131.5, 133.7, 135.4, 144.6, 146.3, 147.8,
148.3, 148.6, 154.3; HREIMS m/z calcd for C27H19NO6 (Mþ)
453.1212, found 453.1216.
3,11-Dihydroxy-2,12-dimethoxy-14-methyl-6H-[1]benzopyrano-
[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (2h). According to the
general procedure, 25e (58.5 mg, 123 μmol) was reacted to give
2h as pale gray powder (31.0 mg, 64%). Mp 280-295 °C (dec)
(sealed capillary); IR (KBr) 3384, 1688, 1427, 1280, 1206, 1153,
1052 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 2.76 (s, 3H), 3.88 (s,
3H), 3.94 (s, 3H), 6.80 (s, 1H), 6.96 (d, J = 7.2 Hz, 1H), 7.12 (s,
1H), 7.45 (s, 1H), 7.72 (s, 1H), 8.81 (d, J = 7.2 Hz, 1H), 9.84 (br s,
2H); 13C NMR (100 MHz, DMSO-d6) δ 13.0, 55.3, 55.8, 103.8,
104.7, 105.5, 106.1, 106.2, 108.9, 111.6, 111.8, 118.0, 121.6, 124.4,
128.3, 133.9, 144.7, 145.9, 147.4, 147.7, 148.5, 153.8; HREIMS m/z
calcd for C22H17NO6 (Mþ) 391.1056, found 391.1058.
Acknowledgment. We thank Japan Society for the Pro-
motion of Science (JSPS) and Japan Science and Technology
Agency (JST) for financial support.
Supporting Information Available: General experimental
methods, experimental data for I and II, DFT-calculated atomic
charge distribution and HOMO of 22, Cartesian coordinates of
1
the DFT-optimized geometry of 22, H NMR and 13C NMR
spectra of all compounds synthesized in this work, and NOESY
spectrum of 10 and HMQC, HMBC spectra of 10, 22, and
23a-e. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 21, 2009 8153