Total synthesis of asperlicin C, circumdatin F, demethylbenzomalvin A, demethoxycircumdatin H, sclerotigenin, and other fused quinazolinones

Article abstract of DOI:10.1039/b910545j

Using scandium triflate and microwaves, the direct double dehydrocyclization of anthranilate-containing tripeptides was achieved, affording the total syntheses of (i) quinazolino[3,2-a]benzodiazepinediones (1a-f), (ii) diazepino[2,1-b]quinazolinediones (2a-e), and (iii) pyrazino[2,1-b]quinazolinediones (3a-e) with good overall isolated yields (23-43%, 37-47% and 31-56%, respectively). Among the quinazolino[3,2-a] benzodiazepinediones synthesized, 1a (sclerotigenin), 1b (circumdatin F), and 1f (asperlicin C) are natural products.

Full text of DOI:10.1039/b910545j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Total synthesis of asperlicin C, circumdatin F, demethylbenzomalvin A,
demethoxycircumdatin H, sclerotigenin, and other fused quinazolinones†
Ming-Chung Tseng,‡a Huei-Yun Yang‡b and Yen-Ho Chu*b
Received 29th May 2009, Accepted 29th September 2009
First published as an Advance Article on the web 5th November 2009
DOI: 10.1039/b910545j
Using scandium triflate and microwaves, the direct double dehydrocyclization of anthranilate-
containing tripeptides was achieved, affording the total syntheses of (i) quinazolino[3,2-a]-
benzodiazepinediones (1a–f), (ii) diazepino[2,1-b]quinazolinediones (2a–e), and (iii)
pyrazino[2,1-b]quinazolinediones (3a–e) with good overall isolated yields (23–43%, 37–47% and
31–56%, respectively). Among the quinazolino[3,2-a]benzodiazepinediones synthesized, 1a
(sclerotigenin), 1b (circumdatin F), and 1f (asperlicin C) are natural products.
genin (1a, R = H), circumdatin F (1b, R = CH3), and asperlicin
C (1f, R = CH2indole) are natural products.
Introduction
Many natural products are heterocyclic compounds, and a good
number of them are quinazolinone alkaloids.1 Due in part to its
wide range of useful pharmacological properties, the structure
of quinazolinone has been extensively utilized as a valuable
scaffold for drug discovery in medicinal chemistry. Some synthetic
quinazolinones, such as Raltitrexed, Ispinesib and Tempostatin,
have been on the market or are currently in clinical trials for
cancer treatment. In recent years, more natural products with
the quinazolinone core structure have been isolated and purified.1
These alkaloids in general fall into two families: with the quina-
zolinone fused to a benzodiazepinedione, as in asperlicin C, or to
a diketopiperazine, as in fumiquinazoline F. Among them, natural
products consisting of two anthranilic acids (Abz) and an amino
acid condensed together forming the quinazolino[3,2-a][1,4]-
benzodiazepine core unit have been isolated from various microor-
ganisms. These include asperlicins A–E from Aspergillus alliaceus,2
benzomalvins A–C from Penicillium sp,3 circumdatins A–H from
Aspergillus ochraceus,4 and sclerotigenin from Penicillium scleroti-
genum and Penicillium commune;5 a number of them are biologi-
cally active (e.g., circumdatin H is an inhibitor of the mammalian
mitochondrial respiratory chain, with an IC50 value of 1.5 mM4a).
We recently reported the use of metal triflates to facilitate total
syntheses of the conformationally constrained quinazolino[3,2-
a][1,4]-benzodiazepines and pyrazino[2,1-b]quinazolinones.6 On
the basis of our previous findings, in this full paper, we
extend our synthetic protocol to the structurally diverse
members: (i) quinazolino[3,2-a]benzodiazepinediones (1a–f), (ii)
diazepino[2,1-b]quinazolinediones (2a–e), and (iii) pyrazino[2,1-
b]quinazolinediones (3a–e). Among 1a–f synthesized, scleroti-
In the literature, there have been three synthetic strate-
gies primarily developed for the preparation of quinazoli-
nobenzodiazepines (1). The Snider, Thomas, and Eguchi
groups separately reported the employment of a powerful
Staudinger/intramolecular aza-Wittig tandem reaction, known
as the Eguchi protocol,7 for the total synthesis of sclerotigenin
(1a), circumdatin F (1b), asperlicin C (1f) and benzomalvin
A.7 Though it provided a direct route to heterocyclic natural
products, this protocol nevertheless suffered from the limited
solubility of the benzodiazepine in conventional solvents and the
formation of the bis-adduct upon acylation reaction. With a 2.5%
overall yield, Witt and Bergman afforded a six-step total synthesis
of circumdatin F (1b) by adopting the Ganesan procedure
aInstitute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan,
ROC
bDepartment of Chemistry and Biochemistry, National Chung Cheng Uni-
versity, Chia-Yi, Taiwan, ROC. E-mail: cheyhc@ccu.edu.tw; Fax: +886-5-
2721040; Tel: +886-5-2428148
† Electronic supplementary information (ESI) available: Complete 1H and
13C NMR spectra of all compounds 1a–f, 2a–e, and 3a–e. See DOI:
10.1039/b910545j
‡ Both authors contributed equally to this work.
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Table 1 Screening of Lewis acid catalysts for dehydrative cyclization of
Gly-Abz-Abz-OMe (6a) to sclerotigenin (1a)
(triphenylphosphine, iodine and a tertiary amine) in which the
formation of an iminobenzoxazine intermediate was the key step.8
In addition, Bock’s group completed the first total syntheses
of asperlicins C and E, featuring a regioselective annulation of
benzodiazepinedione with anthranilic acid.9 From the synthesis
point of view, both the Eguchi and the Ganesan protocols
are two important methods exploited for the construction of
quinazolinone rings. Most recently, Liu and co-workers achieved
syntheses of racemic quinazolinobenzodiazepines (1) using a one-
pot do◦mino procedure that owes its success to microwave heating
at 230 C.10 All of these aforementioned experimental procedures,
however, either required a number of synthetic steps or proceeded
with long reaction times and low to moderate yields; hence,
alternative reagents and efficient reaction conditions to facilitate
the direct transformation to the quinazolinones are to be of great
value.
Entry
Lewis acid
Reaction time/min
Isolated yield (%)
1
2
3
4
5
6
7
8
9
Al(OTf)3
Cu(OTf)2
La(OTf)3
Mg(OTf)2
Sc(OTf)3
Sm(OTf)3
Sn(OTf)2
Yb(OTf)3
Zn(OTf)2
60
23
—
25
20
61
39
50
39
7
N.R.a
20
50
10
20
10
10
15
a No reaction.
Results and discussion
by catalytic hydrogenation (96% yield) to afford the desired Gly-
Abz-Abz-OMe 6a (56% isolated yield in four steps). With the aid
of metal triflates, we then employed microwaves11 to deliberately
facilitate the concomitant double dehydrocyclization reaction as
the last step in the total synthesis. Therefore, compound 6a was
treated with all nine metal triflates in DMF by microwaves with
the temperature controlled at 140 ◦C, to see if the dehydrative
cyclization would successfully achieve 1a.
Table 1 summarises the screening results and, among metal
triflates tested, Sc(OTf)3 showed the best activity with the shortest
reaction time (10 min) and the highest isolated yield (61%,
entry 5). Table 1 shows that the catalytic activities of the
triflates greatly depend on the associated cation. The Lewis acids
Al(OTf)3, La(OTf)3, Mg(OTf)2, Sm(OTf)3, Sn(OTf)2, Yb(OTf)3
and Zn(OTf)2 were moderately effective (longer reaction time or
lower yield), but Cu(OTf)2 was totally inactive. No sclerotigenin
1a was formed in the absence of Lewis acid. The solvent effect was
investigated (Table 2), and DMF was found to be the best choice
We envisioned that our strategy of using metal triflates to access
quinazolinones should be useful to construct compounds such
as 1–3 so that the molecular diversity of quinazolinone-based
molecules may be explored. For the work presented in this paper,
we first began our experiments by synthesizing quinazolino[3,2-
a]benzodiazepinediones (1a–f) and optimizing their preparation.
Our route to natural and unnatural 1a–f is shown in Scheme 1.
Since the natural product sclerotigenin (1a) gave the lowest
isolated yield among the quinazolino[3,2-a]benzodiazepinediones
(1) synthesized in our recent preliminary communication,6a in this
full paper, we decided to choose 1a as our synthetic target on
which to optimize the reaction conditions, including screening
for the optimization of metal triflates and solvents. At first, we
selected nine metal triflates available in our laboratory, and carried
out the screening to identify the most effective Lewis acids that
efficiently facilitate the formation of the ring structure 1a from
its open-chain tripeptide precursor (6a). This precursor, Gly-Abz-
Abz-OMe 6a, was readily prepared in a straightforward manner:
a direct coupling of anthranilic acid 4 with isatoic anhydride in
heated water to generate Abz-Abz 5 with a high isolated yield
(87%), which was subsequently converted to its methyl ester (80%
yield) in hot acidic methanol, followed by condensing with Cbz-
Gly in the presence of EDC (84% yield), and finally deprotection
Table 2 Optimization of solvents used for dehydrative cyclization of Gly-
Abz-Abz-OMe (6a) to sclerotigenin (1a)
Reaction
time/min
Isolated
yield (%)
Entry
Solvent
b.p./◦C
1
2
3
4
5
6
7
8
9
o-Xylene
Anisole
143
154
155
155
162
162
189
232
—
N.R.a
N.R.a
10
—
—
61
—
—
—
58
21
—
DMF
DMFb
N.R.a
N.R.a
N.R.a
5
Diglyme
Diglymec
DMSO
HMPA
[bdmim][NTf2]
5
N.R.a
a No reaction was observed after 10 min reaction time. b Instead of
Sc(OTf)3, triflic acid (1 equiv.) was used as a Brønsted protic acid. c Ionic
liquid [bdmim][NTf2] (10%, v/v) was added to attempt to promote the
microwaved reaction.
Scheme
diazepinediones (1a–f).
1
Synthesis of 7-substituted quinazolino[3,2-a]benzo-
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Table 3 Optimization in stoichiometry of the Sc(OTf)3 catalyst used for
dehydrative cyclization of Gly-Abz-Abz-OMe (6a) to sclerotigenin (1a)
Entry
Sc(OTf)3/equiv.
Reaction time/min
Isolated yield (%)
1
2
3
1
0.5
0.2
10
15
60
61
54
44
Fig. 1 1H NMR (400 MHz) spectra of the highlighted (a) methyl protons
of synthetic circumdatin F (1b) prepared from L-Ala (top) and D,L-Ala
(bottom), and (b) aryl proton of the target compound 1c prepared from
L-Leu (top) and D,L-Leu (bottom) in CDCl3 after the addition of 0.132
and 0.59 equiv., respectively, of the chiral shift reagent (+)-Eu(hfc)3.
(entry 3). We also found that the dehydrocyclization reaction
did not need to be performed in anhydrous solvent; that is, the
straight use of on-the-shelf DMF as the reaction medium sufficed.
Moreover, the amount of Sc(OTf)3 used in the reaction was tested
(Table 3), and 1 mol equiv. proved to be the most practical
stoichiometry in terms of reaction time and isolated yield (entry
1). This direct formation of 1a from 6a is attractive simply because
the construction of two rings could be concomitantly prepared in
one reaction step.
The successful preparation of 1a using metal triflates allowed
us to pursue further the total syntheses of more complex target
compounds with greater diversity (1b–f, Table 4). The results in
Table 4 show that compounds 1b–f, including the natural products
circumdatin F (1b) and asperlicin C (1f), were readily synthesized
with good yields in 10–15 min by Sc(OTf)3 and microwaves
from their linear tripeptides 6b–f. In the case of 1e, which has
a constrained proline ring, a low isolated yield was obtained (44%,
entry 4). Under the experimental conditions, circumdatin F (1b)
gave the highest isolated yield (78%, entry 1). The overall yields
for 1a–f in this five-step total synthesis were 23–43%.
sity: diazepino[2,1-b]quinazolinediones (2a–e) and pyrazino[2,1-
b]quinazolinediones (3a–e). Adopting a similar approach, starting
compounds b-alanine (7) and glycine methyl ester (10) were
incorporated in a straightforward manner to construct the desired
2a–e and 3a–e, respectively (Schemes 2 and 3). To our delight,
the key Sc(OTf)3-catalyzed dehydrocyclization reactions of 9a–
e and 12a–e tripeptides proceeded smoothly and required very
short reaction times (1–3 min) to afford the target products 2a–
e and 3a–e with good to high isolated yields (67–86% and 49–
86%, respectively) (Tables 5 and 6). In our hands, compounds 2c
Whether or not any racemization had taken place at the amino
acid was examined through 1H NMR spectroscopy in the presence
of europium(III) tris[3-(heptafluoropropyl hydroxymethylene)-(+)-
camphorate], (+)-Eu(hfc)3, as a chiral shift reagent.12 The results
in Fig. 1 clearly show that, as representative examples, synthetic 1b
(circumdatin F) and 1c are stereochemically pure and essentially
free of racemization. This nicely suggests that, under our ex-
perimental conditions, the Sc(OTf)3-promoted dehydrocyclization
reaction appeared to preserve chirality during the total synthesis
of optically active quinazolinobenzodiazapines (1).13
We extended our protocol further by broadening its scope in
synthesis to prepare new compounds with greater molecular diver-
Scheme 2 Synthesis of 1-substituted diazepino[2,1-b] quinazolinediones
(2a–e)
Table 4 Quinazolino[3,2-a]benzodiazepinediones (1b–f) prepared from Sc(OTf)3-promoted dehydrocyclization of linear tripeptides, X-Abz-Abz-OMe
(6b–f), in DMF at 140 ◦C by microwavesa
Entry
X
R
Product
Reaction time/min
Isolated yield (%)
1
2
3
4
5
L-Ala
L-Leu
L-Phe
L-Pro
L-Trp
H
CH3
CH2Ph
(CH2)3
CH2indole
1b (circumdatin F)
1c
1d (demethylbenzomalvin A)
1e (demethoxycircumdatin H)
1f (asperlicin C)
15
10
15
10
15
78
46
61
44
68
a Reaction conditions: tripeptide, 30 mg; Sc(OTf)3, 1 equiv.; DMF, 0.3 mL. Individual microwave-assisted reactions were carried out in a reaction vessel
and temperature-controlled at 140 ◦C using a commercial CEM Discover instrument (CEM Corporation, Matthews, NC, USA). 30 W microwave power
was applied throughout the reaction period.
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Table 5 Diazepino[2,1-b]quinazolinediones (2a–e) prepared from
Sc(OTf)3-promoted dehydrocyclization of linear tripeptides, X-Abz-b-
Ala-OMe (9a–e), in DMF at 140 ◦C with microwavesa
Table 6 Pyrazino[2,1-b]quinazolinediones (3a–e) prepared from
Sc(OTf)3-promoted dehydrocyclization of linear tripeptides, X-Abz-Gly-
OMe (12a–e), in DMF at 140 ◦C with microwavesa
Reaction
time/min
Isolated
yield (%)
Reaction
time/min
Isolated
yield (%)
Entry
X
R
Product
Entry
X
R
Product
1
2
3
4
5
Gly
H
CH3
CH2Ph
(CH2)3
CH2indole
2a
2b
2c
2d
2e
1
1
3
1
3
67
80
86
70
71
1
2
3
4
5
Gly
H
CH3
CH2Ph
(CH2)3
CH2indole
3a
3b
3c
3d
3e
1
1.5
2
2
2
86
84
73
49
76
L-Ala
L-Phe
L-Pro
L-Trp
L-Ala
L-Phe
L-Pro
L-Trp
a Reaction conditions: tripeptide, 30 mg; Sc(OTF)3, 1 equiv.; DMF,
0.3 mL. Individual microwave-assisted reactions were carried out in a
reaction vessel and temperature-controlled at 140 ◦C using a commercial
CEM Discover instrument (CEM Corporation, Matthews, NC, USA).
30 W microwave power was applied throughout the reaction period.
a Reaction conditions: tripeptide, 30 mg: Sc(OTf)3, 1 equiv.; DMF,
0.3 mL. Individual microwave-assisted reactions were carried out in a
reaction vessel and temperature-controlled at 140 ◦C using a commercial
CEM Discover instrument (CEM Corporation, Matthews, NC, USA).
30 W microwave power was applied throughout the reaction period.
Scheme 3 Synthesis of 1-substituted pyrazino[2,1-b] quinazolinediones
(3a–e)
(entry 3, Table 5) and 3a (entry 1, Table 6) gave the highest yield
(86%). The overall yields for the syntheses of 2a–e and 3a–e were
37–47% and 31–56% in a total of five and four reaction steps,
Fig. 3 1H NMR (400 MHz) spectra of the highlighted aryl proton of the
target compound 3b prepared from L-Ala (top) and D,L-Ala (bottom)
in CDCl3 after the addition of 2.80 equiv. of the chiral shift reagent
(+)-Eu(hfc)3.
1
respectively. Chiral resolution experiments by H NMR in the
presence of (+)-Eu(hfc)3 in CDCl3 unambiguously showed that,
using 2b and 3b as illustrative examples, new quinazolinones 2 and
3 synthesized in this work are enantiopure and free of noticeable
racemization (Fig. 2 and 3).13 This unambiguously demonstrates
that, under our experimental conditions, the chirality is preserved
(including during the Sc(OTf)3-promoted dehydrocyclization
reaction) throughout the synthesis of quinazolindiones 2a–e and
3a–e. The successful application of our synthetic protocol to access
various fused quinazolinones 1–3 demonstrates the utility of this
new method. Both the synthetic scheme and the chiral 1H NMR
Fig. 2 1H NMR (400 MHz) spectra of the highlighted aryl and methyl protons of the target compound 2b prepared from L-Ala (top) and D,L-Ala
(bottom) in CDCl3 after the addition of 1.26 equiv. of the chiral shift reagent (+)-Eu(hfc)3.
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procedure depicted in this work should be effective means of
preparing and characterizing constrained, quinazolinone-based
peptidomimetics.
dried (Na2SO4), concentrated under reduced pressure to afford
a solid residue and further purified by flash chromatography
(ethyl acetate–hexane = 1 : 5–1 : 8) to give the desired product
Cbz-X-Abz-Abz-OMe (X= L-amino acid) (78–86% yield) as white
solids.
This Cbz-protected tripeptide was then deprotected by catalytic
hydrogenation. To a solution of tripeptide (100 mg) in methanol
(30 mL) was added a catalytic amount of 20% Pd(OH)2/C and
a balloon of hydrogen. This deprotection reaction by hydrogena-
tion was allowed to proceed until the protected tripeptide was
completely consumed (0.5 h). The reaction mixture was filtered
and concentrated under reduced pressure to give the product 6a–f
as a colorless solid (91–97% yield).
To a microwave reaction vessel was added 6a–f (30 mg), Sc(OTf)3
(1 equiv.) and DMF (0.3 mL). The vessel was placed inside a
CEM Discover single-mode microwave synthesizer equipped with
a magnetic stirrer, where it was exposed to microwaves at 140 ◦C
(30 W) for 10–15 min. After reaction the DMF was removed under
reduced pressure and the mixture was poured into water (5 mL).
The solution was extracted with dichloromethane (3 ¥ 5 mL).
The combined organic layers were dried (Na2SO4) and evaporated
to afford a brown residue, and finally purified by flash column
chromatography (ethyl acetate–hexane = 1 : 1–1 : 5) to obtain the
desired quinazolino[3,2-a][1,4]benzodiazepine products 1a–f (44–
78% yield) as white solids.
Conclusions
In conclusion, the total syntheses of sclerotigenin (1a), circum-
datin F (1b) and asperlicin C (1f) natural products, and their
analogous compounds (1c–e) were achieved in five steps with 23–
43% overall isolated yields starting from anthranilic acid. Using
the synthetic approaches developed in this report, structurally
similar diazepino[2,1-b]quinazolinones (2a–e) and pyrazino[2,1-
b]quinazolinones (3a–e) were readily synthesized with good
overall isolated yields of 37–47% and 31–56%, respectively. In
continuously exploring the search for natural and synthetic
quinazolinone compounds that produce useful pharmacological
activities and other tailored properties, the compounds with a
quinazolinone ring fused with a- and b-amino acids prepared in
this work shall provide a convenient entry to new quinazolinone
entities.
Experimental section
Gerneral
Flash chromatography was performed on silica gel (230–400
mesh). TLC was carried out on aluminium-backed silica plates
precoated with silica (0.2 mm), which were developed using
standard visualizing agents, such as UV fluorescence and iodine.
Unless otherwise indicated, all reactions were carried out without
the aid of dry nitrogen or argon. NMR spectra were recorded on a
Bruker AVANCE DPX 400 at 400 MHz (1H) and 100.6 MHz (13C),
both in CDCl3 unless otherwise stated. Chemical shifts are quoted
in parts per million (ppm). Melting points were determined on
a Fargo MP-2D apparatus (Taiwan, ROC) and are uncorrected.
Solvents and reagents were obtained from commercial sources and
were used without further purification.
6,7-Dihydroquinazolino[3,2-a][1,4]benzodiazepine-5,13-dione
(sclerotigenin)
White solid, mp 308–310 ◦C; dH (400 MHz; DMSO-d6) 4.00 (1H,
dd, J = 15.4, 6.6 Hz, NCH2), 4.18 (1H, dd, J = 15.4, 5.1 Hz,
NCH2), 7.58-7.65 (4H, m, ArH), 7.71 (1H, d, J = 8.0 Hz, ArH),
7.79 (1H, d, J = 7.4 Hz, ArH), 7.89 (1H, t, J = 7.6 Hz, ArH),
8.18 (1H, d, J = 7.7 Hz, ArH), 8.89 (1H, t, J = 5.3 Hz, NH);
dC (100 MHz; DMSO-d6) 46.4, 121.2, 127.1, 127.3, 127.8, 128.7,
129.0, 129.6, 130.8, 130.9, 133.6, 135.4, 146.3, 155.0, 161.2, 167.2;
FAB-HRMS m/z [M + H]+ calcd for C16H12O2N3 278.0930, found
278.0927.
General procedure for the total synthesis of quinazolino[3,2-
a][1,4]benzodiazepines (1a–f). A suspension of isatoic anhydride
(2.5 g, 15.3 mmol) and anthranilic acid 4 (2.3 g, 16.8 mmol) in
water (50 mL) was refluxed for 2 h and then cooled. The solid
product was filtered, washed with water, and dried to obtain Abz-
Abz 5 (3.4 g, 87% yield) as a pale yellow powder with excellent
purity.
(7S)-6,7-Dihydro-7-methylquinazolino[3,2-a][1,4]-benzodiazepine-
5,13-dione (circumdatin F)
To a solution of sulfuric acid (2 mL) in methanol (50 mL) was
added Abz-Abz 5 (2 g, 7.8 mmol). The reaction mixture was heated
at reflux for 5 d and then cooled. The solution was concentrated
under reduced pressure to give a brown oil and poured into water
(20 mL). The pH was adjusted to 8 with 10% NaOH in an ice
bath and then extracted with CH2Cl2 (3 ¥ 20 mL). The combined
organic layers were dried (Na2SO4) and evaporated to afford
a brown residue, and purified by flash chromatography (ethyl
acetate–hexane = 1 : 7) to give the desired methyl ester (1.67 g,
80% yield) as a light yellow solid.
For tripeptide preparation, EDC (1.1 equiv.) was added to
a solution of the aforementioned methyl ester (1.1 equiv.) and
N-Cbz-protected L-amino acid (100 mg) in CH2Cl2 (2 mL). The
reaction mixture was stirred at ambient temperature for 2–6 h.
The mixture was washed with 10% citric acid (3 ¥ 5 mL) and
◦
White solid, mp 261–263 C; dH (400 MHz; CDCl3) 1.74 (3H, t,
J = 6.8 Hz, CH3), 4.43 (1H, quin, J = 6.4 Hz, NCH), 6.40 (1H,
d, J = 5.6 Hz, NH), 7.56-7.66 (4H, m, ArH), 7.75-7.82 (2H, m,
ArH), 8.00 (1H, dd, J = 7.2, 1.2 Hz, ArH), 8.34 (1H, d, J = 7.9 Hz,
ArH); dC (100 MHz; CDCl3) 15.4, 50.2, 121.5, 127.4, 127.5, 127.8,
128.5, 129.4, 130.0, 130.8, 131.4, 133.7, 134.9, 146.2, 155.2, 161.8,
168.4; FAB-HRMS m/z [M + H]+ calcd for C17H14O2N3 292.1086,
found 292.1090.
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(7S)-7-Benzyl-6,7-dihydroquinazolino[3,2-a][1,4]-benzodiazepine-
(7S)-6,7-Dihydro-7-isobutylquinazolino[3,2-a][1,4]-
5,13-dione
benzodiazepine-5,13-dione
White solid, mp 227–229 ◦C; dH (400 MHz; CDCl3) 0.90 (3H,
d, J = 6.5 Hz, CH3), 1.00 (3H, d, J = 6.5 Hz, CH3), 1.86-2.04
(2H, m, CH2), 2.14-2.21 (1H, m, CH), 4.20 (1H, q, J = 2.4 Hz,
NCH), 6.66 (1H, d, J = 6.5 Hz, NH), 7.49-7.81 (6H, m, ArH),
7.96 (1H, d, J = 7.4 Hz, ArH), 8.29 (1H, d, J = 7.8 Hz, ArH); dC
(100 MHz; CDCl3) 22.2, 233, 24.6, 38.3, 52.6, 121.7, 127.6, 127.8,
128.0, 128.6, 129.2, 130.0, 131.0, 131.5, 133.7, 135.0, 146.4, 154.9,
161.9, 168.1; FAB-HRMS m/z [M + H]+ calcd for C20H20O2N3
334.1556, found 334.1613.
White solid, mp 140–142 ◦C; dH (400 MHz; CDCl3) 3.30 (1H,
dd, J = 14.4, 8.4 Hz, PhCH2), 3.69 (1H, dd, J = 14.8, 5.6 Hz,
PhCH2), 4.40 (1H, q, J = 6.0 Hz, NCH), 7.20-7.34 (5H, m,
ArH), 7.39-7.47 (2H, m, ArH), 7.57-7.66 (4H, m, ArH), 7.87
(1H, d, J = 7.6 Hz, ArH), 8.04 (1H, d, J = 6.0 Hz, NH),
8.10 (1H, d, J = 7.6 Hz, ArH); dC (100 MHz; CDCl3) 36. 1,
55.3, 120.8, 127.1, 127.3, 127.6, 127.8, 128.4, 128.5, 128.8, 129.7,
130.1, 130.4, 131.1, 133.2, 134.6, 137.1, 153.7, 161.2, 168.7; FAB-
HRMS m/z [M + H]+ calcd for C23H18O2N3 368.1399, found
368.1390.
General procedure for the total synthesis of
diazepino[2,1-b]quinazolinediones (2a–e)
(7S)-6,7-Dihydro-7-hexahydropyrrolo[1¢,2¢:1,2]
quinazolino[3,2-a][1,4]-benzodiazepine-5,13-dione
To a round-bottom flask containing methanol (50 mL) and
b-alanine 7 (1 g, 11.2 mmol) at 0 ◦C was added slowly thionyl
chloride (2.5 equiv.). The progress of the reaction was monitored
by TLC. After the completion of the reaction (1 h), the mixture
solution was evaporated (to remove methanol and excess thionyl
chloride) and then lyophilized to afford the product methyl
b-alaninate HCl (91% yield).
White solid, mp 228–230 ◦C; dH (400 MHz; CDCl3) 2.06-2.19
(2H, m, CH2), 2.29-2.45 (1H, m, CH2), 3.16-3.21 (1H, m, CH2),
3.58-3.65 (1H, m, CH2), 3.77-3.82 (1H, m, CH2), 4.55 (1H,
d, J = 7.6 Hz, NCH), 7.50-7.61 (5H, m, ArH, NH), 7.70-
7.81 (2H, m, ArH), 8.0 (1H, d, J = 7.7 Hz, ArH), 8.0 (1H,
dd, J = 8.0, 0.92 Hz, ArH); dC (100 MHz; CDCl3) 23.6,
26.9, 46.4, 58.8, 121.5, 127.4, 127.5, 127.5, 128.3, 128.6, 129.9,
130.7, 132.3, 133.2, 134.7, 146.0, 153.6, 161.6, 164.4; FAB-
HRMS m/z [M + H]+ calcd for C20H18O2N3 318.1368, found
318.1243.
A suspension of isatoic anhydride (2.5 g, 15.3 mmol), methyl
b-alaninate HCl (2.3 g, 16.8 mmol), and triethylamine (3.13 mL)
in ethyl acetate (50 mL) was refluxed for 2 h and then cooled.
The solid precipitate was filtered off and the organic layer was
extracted with aqueous KOH. The resulting organic solution was
then evaporated to obtain the crude product, and purified by flash
chromatography (dichloromethane–methanol = 150 : 1) to afford
the desired product 8 (82% yield).
For tripeptide preparation, EDC (1.2 equiv.) was added to
a solution of 8 (1.1 equiv.) and N-Cbz-protected L-amino acid
(100 mg) in CH2Cl2 (2 mL). The reaction mixture was stirred at
ambient temperature for 0.5–1 h. The mixture was washed with
10% citric acid (3 ¥ 5 mL), dried (Na2SO4), and concentrated
under reduced pressure to afford a solid residue, which was further
purified by flash chromatography (ethyl acetate–hexane = 1 : 1) to
give Cbz-X-Abz-b-Ala-OMe (X= L-amino acid) (78–86% yield).
This Cbz-protected tripeptide was then deprotected by catalytic
hydrogenation. To a solution of tripeptide (100 mg) in methanol
(30 mL) was added a catalytic amount of 20% Pd(OH)2/C and a
balloon of hydrogen. This deprotection reaction by hydrogenation
was allowed to proceed until the protected tripeptide was com-
pletely consumed (15–30 min). The reaction mixture was filtered
and concentrated under reduced pressure to give the product 9a–e
as a colorless solid (90–96% yield).
(7S)-6,7-Dihydro-7-((indol-2-yl)methyl)quinazolino[3,2-a][1,4]-
benzodiazepine-5,13-dione (asperlicin C)
White solid, mp 313–314 ◦C; dH (400 MHz; DMSO-d6) 3.36-3.44
(1H, m, indolyl-CH2), 3.66 (1H, dd, J = 14.8, 4.8 Hz, indolyl-CH2),
4.39-4.41 (1H, m, NCH), 6.92 (1H, t, J = 7.6 Hz, ArH), 7.02 (1H,
t, J = 7.6 Hz, ArH), 7.32-7.34 (2H, m, ArH), 7.52-7.70 (6H, m,
ArH), 7.85 (4H, d, J = 8.0 Hz, ArH), 7.91 (1H, d, J = 7.2 Hz,
ArH), 8.20 (1H, d, J = 8.0 Hz, ArH), 8.92 (1H, d, J = 6.4 Hz,
ArH), 10.87 (1H, bs, NH); dC (100 MHz; DMSO-d6) 25.6, 57.1,
110.0, 111.6, 118.5, 119.2, 121.1, 122.2, 124.7, 127.1, 127.3, 127.7,
127.8, 128.7, 129.0, 130.9, 131.4, 132.6, 135.1, 136.2, 147.2, 155.9,
161.3, 167.6; FAB-HRMS m/z [M + H]+ calcd for C25H19O2N4
407.1508, found 407.1502.
To a microwave reaction vessel was added 9a–e (30 mg),
Sc(OTf)3 (1 equiv.) and DMF (0.3 mL). The vessel was placed
inside a CEM Discover single-mode microwave synthesizer
equipped with a magnetic stirrer, where it was exposed to
microwaves at 140 ◦C (30 W) for 1–3 min. After reaction
the DMF was removed under reduced pressure to afford a
brown residue, and finally purified by flash column chromatog-
raphy (dichloromethane–methanol = 40 : 1) to obtain the desired
424 | Org. Biomol. Chem., 2010, 8, 419–427
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diazepino[2,1-b]quinazolinediones 2a–e (67–86% yield) as white
solids.
3.01 (1H, m, NCH2CH2CHH), 3.39-3.46 (1H, m, NCHH), 3.53-
3.61 (1H, m, NCHH ), 4.19(1H, td, J = 12.8, 2.2 Hz, CNCHH),
4.92 (1H, d, J = 6.4 Hz, CNCHH ), 5.45 (1H, t, J = 6.4 Hz,
CONCH), 7.55 (1H, t, J = 7.4 Hz, ArH), 7.67 (1H, d, J = 8.
1 Hz, ArH), 7.83 (1H, td, J = 7.4, 1.5 Hz, ArH), 8.14 (1H, d,
J = 8.0 Hz, ArH); dC (100 MHz; DMSO-d6) 22.2, 29.0, 35.4, 35.9,
48.2, 56.5, 120.7, 126.6, 127.4, 127.6, 134.7, 146.7, 154.8, 160.6,
167.0; FAB-HRMS m/z [M + H]+ calcd for C15H15O2N3 269.1164,
found 269.1243.
2H-[1,4]Diazepino[2,1-b]quinazoline-3,7-(1H,4H,5H)-dione
White solid, mp 250–253 ◦C; dH (400 MHz; DMSO-d6) 2.66 (2H,
t, J = 6 Hz, COCH2), 4.41 (2H, d, CONHCH2 ), 4.49 (2H, t, J =
6 Hz, NCH2 ), 7.54 (1H, t, J = 7.4 Hz, ArH), 7.65 (1H, d, J =
8.2 Hz, ArH), 7.83 (1H, t, J = 7.6, Hz, ArH), 8.13 (2H, m, ArH
and CONH); dC (100 MHz, DMSO-d6) 35.1, 36.7, 45.8, 120.6,
126.6, 127.3, 127.3, 134.7, 147.1, 155.0, 160.5, 170.1; FAB-HRMS
m/z [M + H]+ calcd for C12H11O2N3 229.0851, found 229.0930.
(1S)-1-(1H-Indol-3-ylmethyl)-2H-[1,4]diazepino[2,1-
b]quinazoline-3,7-(1H,4H,5H)-dione
(1S)-1-Methyl-2H-[1,4]diazepino[2,1-b]quinazoline-3,7-
(1H,4H,5H)-dione
White solid, mp 306–309 ◦C; dH (400 MHz; DMSO-d6) 2.53-2.57
(1H, m, COCHH), 2.81 (1H, d, J = 18.2, COCHH), 3.27-3.33
(1H, m, indolyl-CHH), 3.62 (1H, dd, J = 14.8, 5.2 Hz, indolyl-
CHH), 4.23 (1H, t, J = 12.4 Hz, NCHH), 4.89 (1H, dd, J = 14.8,
4.2 Hz, NCHH), 5.31-5.34 (1H, m, CONHCH), 7.01 (1H, t, J =
7.4 Hz, ArH), 7.08 (1H, t, J = 7.2 Hz, ArH), 7.36 (1H, d, J =
8.0 Hz, Nind-CH), 7.44 (1H, s, Nind-H ), 7.53-7.59 (2H, m, ArH),
7.75 (1H, d, J = 7.7 Hz, ArH), 7.85 (1H, t, J = 7.7 Hz, ArH), 8.16
(1H, d, J = 8.0 Hz, ArH), 10.90 (1H, s, CONH); dC (DMSO-d6;
100 MHz) 26.4, 34.9, 35.7, 52.5, 110.1, 111.6, 118.6, 118.9, 120.6,
121.2, 124.9, 126.6, 127.3, 127.5, 127.6, 134.7, 136.4, 146.8, 156.4,
160.7, 169.9; FAB-HRMS m/z [M + H]+ calcd for C21H18O2N4
358.1430, found 358.1508.
White solid, mp 289–291; dH (400 MHz; DMSO-d6) 1.5 (3H, d,
J = 6.4 Hz, CH3), 2.81 (1H, d, J = 18.3 Hz, COCHH ), 4.20 (1H,
t, J = 12.6 Hz, NCHH ), 4.90 (1H, dd, J = 14.8, 3.52 Hz, NCHH),
5.21-5.22 (1H, m, CONHCH), 7.54 (1H, t, J = 7.6 Hz, ArH), 7.67
(1H, d, J = 8.1 Hz, ArH), 7.83 (1H, t, J = 7.6 Hz, ArH), 7.89
(1H, s, CONH), 8.14 (1H, d, J =7.8 Hz, ArH); dC (100 MHz;
DMSO-d6) 16.9, 35.0, 35.6, 47.9, 120.6, 126.6, 127.2, 127.6, 134.7,
146.8, 156.9, 160.7, 169.9; FAB-HRMS m/z [M + H]+ calcd for
C13H13O2N3 243.1008, found 243.1086.
General procedure for the total synthesis of
pyrazino[2,1-b]quinazolinediones (3a–e)
(1S)-1-(Phenylmethyl)-2H-[1,4]diazepino[2,1-b]quinazoline-3,7-
(1H,4H,5H)-dione
A suspension of isatoic anhydride (1 g, 6.1 mmol), methyl glycinate
HCl 10 (767 mg, 6.1 mmol), and triethylamine (3.13 mL) in ethyl
acetate (50 mL) was refluxed for 2 h and then cooled. The solid
precipitate was filtered off and the organic layer was extracted with
aqueous KOH. The resulting organic solution was then evaporated
to afford the desired product 11 (79% yield).
White solid, mp 207–209 ◦C; dH (400 MHz; CDCl3) 2.75-3.00 (2H,
m, Phe-CHH and COCHH), 3.20 (1H, dd, J = 14.8, 9.1 Hz, Phe-
CHH), 3.75 (1H, dd, J = 14.8, 4.8 Hz, COCHH), 4.01 (1H, td,
J = 14.3, 3.4 Hz, NCHH), 5.09-5.13 (1H, m, CONHCH), 5.27
(1H, dt, J = 15.2, 4.2 Hz, NCHH), 7.28-7.40 (5H, m, ArH), 7.53
(1H, td, J = 8, 1.2 Hz, ArH), 7.74-7.82 (2H, m, ArH), 8.30 (1H,
d, J = 8.0 Hz, ArH); dC (100 MHz; CDCl3) 35.0, 35.5, 37.6, 54.2,
120.7, 127.0, 127.5, 127.5, 127.7, 129.1, 129.1, 129.2, 129.3, 134.5,
135.9, 146.6, 153.4, 161.1, 170.1; FAB-HRMS m/z [M + H]+ calcd
for C19H17O2N3 319.1321, found 319.1355.
For tripeptide preparation, EDC (1.2 equiv.) was added to a
solution of 11 (1.1 equiv.) and N-Cbz-protected L-amino acid
(100 mg) in CH2Cl2 (2 mL). The reaction mixture was stirred
at ambient temperature for 0.5–1 h. The mixture was washed
with 10% citric acid (3 ¥ 5 mL) and dried (Na2SO4), concentrated
under reduced pressure to afford a solid residue, which was further
purified by flash chromatography (ethyl acetate–hexane = 1 : 1) to
give Cbz-X-Abz-Gly-OMe (X= L-amino acid) (80–89% yield).
This Cbz-protected tripeptide was then deprotected by catalytic
hydrogenation. To a solution of tripeptide (100 mg) in methanol
(30 mL) was added a catalytic amount of 20% Pd(OH)2/C and a
balloon of hydrogen. This deprotection reaction by hydrogenation
was allowed to proceed until the protected tripeptide was com-
pletely consumed (15–30 min). The reaction mixture was filtered
and concentrated under reduced pressure to give the product 12a–e
as the colorless solid (88–96% yield).
(1S)-Hexahydropyrrolo[1¢,2¢:1,2][1,4]diazepino[2,1-b]quinazoline-
3,7-(1H,4H,5H)-dione
White solid, mp 250–253 ◦C; dH (400 MHz; DMSO-d6) d 1.79-1.97
(2H, m, NCH2CH2), 2.15-2.23 (1H, m, NCH2CH2CHH), 2.52-
2.60 (1H, m, COCHH), 2.82 (1H, d, J = 18.3 Hz, COCHH), 2.92-
To a microwave reaction vessel was added 12a–e (30 mg),
Sc(OTf)3 (1 equiv.) and DMF (0.3 mL). The vessel was placed
inside a CEM Discover single-mode microwave synthesizer
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equipped with a magnetic stirrer, where it was exposed to
microwaves at 140 ◦C (30 W) for 1–2 min. After reaction
the DMF was removed under reduced pressure to afford a
brown residue, and finally purified by flash column chromatog-
raphy (dichloromethane–methanol = 40 : 1) to obtain the desired
pyrazino[2,1-b]quinazolinediones 3a–e (49–86% yield) as white
solids.
2.19 (1H, m, CONCH2CHH), 2.43-2.62 (2H, m, CONCHCH2),
2.63-2.66 (1H, m, CONCHCHH), 3.36 (2H, overlap with H2O,
CONCH2CH2), 3.68 (1H, t, J = 11 Hz, NCH), 4.45 (1H, dd, J =
20.0, 2.4 Hz, COCHH), 4.89 (1H, dd, J = 17.2, 2.5 Hz, COCHH),
7.58 (1H, td, J = 8.4, 1.8 Hz, ArH), 7.72 (1H, dd, J = 8.1, 2.0 Hz,
ArH), 7.85-7.89 (1H, m, ArH), 8.16 (1H, d, J = 7.8 Hz, ArH); dC
(100 MHz; CDCl3) 20.8, 37.2, 39.1, 44.8, 45.9, 88.6, 120.3, 126.5,
127.6, 135.0, 146.9, 152.2, 159.9, 163.4; FAB-HRMS m/z [M +
H]+ calcd for C14H13O2N3 255.1008, found 255.0930.
2H-Pyrazino[2,1-b]quinazoline-3,6-(1H,4H)-dione
(1S)-1-(1H-Indol-3-ylmethyl)-2H-pyrazino[2,1-b]quinazoline-3,6-
(1H,4H)-dione
White solid, mp 274–276 ◦C; dH (400 MHz; DMSO-d6) 4.43 (2H,
d, J = 2.4 Hz, NCH2), 4.53 (2H, s, COCH2 ), 4.76 (2H, s, CH2),
7.53 (1H, t, J = 7.6 Hz, ArH), 7.64 (1H, d, J = 8.1 Hz, ArH), 7.84
(1H, td, J = 7.6, 1.2 Hz, ArH), 8.14 (1H, d, J = 7.9 Hz, ArH),
8.6 (1H, s, CONH); dC (100 MHz; DMSO-d6) 44.8, 44.9, 119.9,
126.4, 126.9, 127.0, 134.9, 147.3, 150.3, 160.0, 166.2; FAB-HRMS
m/z [M + H]+ calcd for C11H10O2N3 215.0695, found 215.077.
◦
White solid, mp 256–258 C; [a]2D0 = -33.5◦ (c 1.0, DMSO); dH
(400 MHz; DMSO-d6) 2.84 (1H, d, J = 18.0 Hz, COCHH), 3.25
(1H, dd, J = 14.5, 4.4 Hz, indolyl-CHH), 3.42 (1H, dd, J = 14.4,
5.2 Hz, indolyl-CHH), 4.19 (1H, d, J = 18.0 Hz, COCHH), 4.80
(1H, q, J = 4.2 Hz, CONHCH), 6.59 (1H, t, J = 7.6 Hz, ArH),
6.94-6.98 (2H, m, ArH), 7.02 (1H, d, J = 2.3 Hz, Nind-CH), 7.31
(1H, d, J = 8.3 Hz, ArH), 7.53 (1H, t, J = 7.9 Hz, ArH), 7.75
(1H, d, J = 8.0 Hz, ArH), 7.88 (1H, t, J = 7.8 Hz, ArH), 8.03
(1H, d, J = 7.9 Hz, ArH), 8.66 (1H, d, J = 3.4 Hz, Nind-H), 11.00
(1H, s, CONH); dC (100 MHz; DMSO-d6) 30.9, 32.5, 44.3, 56.5,
79.4, 107.7, 111.6, 117.7, 118.6, 119.7, 121.3, 125.3, 126.2, 126.9,
127.0, 127.2, 134.9, 136.1, 147.3, 151.9, 159.7, 164.9; FAB-HRMS
m/z [M + H]+ calcd for C20H17O2N4 345.1352, found 345.1358.
(1S)-1-Methyl-2H-pyrazino[2,1-b]quinazoline-3,6-(1H,4H)-dione
◦
White solid, mp 239–240 C; [a]2D0 = -44.2◦ (c 1.0, DMSO); dH
(400 MHz; CDCl3) 1.74 (3H, d, J = 6.9 Hz, CH3), 4.70 (1H, q,
J = 6.8 Hz, CONHCH ), 4.76 (2H, s, CH2 ), 6.78 (1H, s, NH),
7.52 (1H, t, J = 7.5 Hz, ArH), 7.68 (1H, d, J = 8.0 Hz, ArH),
7.78 (1H, td, J = 7.2, 1.5 Hz, ArH), 8.29 (1H, dd, J = 8.0, 1.4 Hz,
ArH); dC (100 MHz; CDCl3) 20.6, 44.9, 51.7, 120.3, 127.1, 127.6,
127.6, 135.0, 147.3, 151.3, 160.9, 166.5; FAB-HRMS m/z [M +
H]+ calcd for C12H12O2N3 230.0930, found 230.0930.
Acknowledgements
We thank Ms. Ping-Yu Lin of Academia Sinica (Taiwan, ROC)
for her excellence in mass analyses. This work was supported by a
multi-year Grant-in-Aid from ANT Technology (Taipei, Taiwan)
and in part by the National Science Council (Taiwan, ROC).
(1S)-1-(Phenylmethyl)-2H-pyrazino[2,1-b]quinazoline-3,6-
(1H,4H)-dione
Notes and references
1 For reviews, see: (a) J. P. Michael, Nat. Prod. Rep., 2008, 25, 166–187;
(b) J. P. Michael, Nat. Prod. Rep., 2007, 24, 223–246; (c) S. B. Mhaske
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D. Cusack, T. P. O’Sullivan and P. J. Guiry, Tetrahedron, 2005, 61,
10153–10202; (e) J. P. Michael, Nat. Prod. Rep., 2004, 21, 650–668;
(f) J. P. Michael, Nat. Prod. Rep., 2003, 20, 476–493; (g) J. P. Michael,
Nat. Prod. Rep., 2002, 19, 742–760; (h) J. P. Michael, Nat. Prod. Rep.,
2001, 18, 543–559; (i) J. P. Michael, Nat. Prod. Rep., 2000, 17, 603–620.
2 (a) M. A. Goetz, R. L. Monaghan, R. S. L. Chang, J. Ondeyka, T. B.
Chen and V. J. Lotti, J. Antibiot., 1988, 41, 875–877; (b) J. M. Liesch,
O. D. Hensens, D. L. Zink and M. A. Goetz, J. Antibiot., 1988, 41,
878–881; (c) J. M. Liesch, O. D. Hensens, J. P. Springer, R. S. L. Chang
and V. J. Lotti, J. Antibiot., 1985, 38, 1638–1641.
◦
White solid, mp 230–231 C; [a]2D0 = -105.9◦ (c 1.0, DMSO); dH
(400 MHz; CDCl3) 3.25-3.49 (3H, m, Phe-CH2 and NCHH), 4.62
(1H, d, J = 18.8 Hz, NCHH), 4.91-4.94 (1H, m, CONCH), 7.05-
7.10 (2H, m, ArH), 7.23-7.29 (3H, m, ArH), 7.53 (1H, t, J =
7.5 Hz, ArH), 7.73 (1H, d, J = 8.0 Hz, ArH), 7.82 (1H, td, J =
8.2, 2.1 Hz, ArH), 8.27 (1H, d, J = 7.9, Hz, ArH); dC (100 MHz;
CDCl3) 42.9, 44.5, 57.5, 120.1, 127.1, 127.4, 127.5, 128.2, 129.3,
130.0, 134.7, 135.1, 147.3, 150.1, 160.6, 166.5; FAB-HRMS m/z
[M + H]+ calcd for C18H16O2N3 306.1243, found 306.1243.
3 H. H. Sun, C. J. Barrow, D. M. Sedlock, A. M. Gillum and R. Cooper,
J. Antibiot., 1994, 47, 515–522.
(1S)-Hexahydropyrrolo[1¢,2¢:1,2]pyrazino[2,1-b]quinazoline-3,6-
(1H,4H)-dione
4 (a) M. P. Lo´pez-Gresa, M. C. Gonzalez, J. Primo, P. Moya, V. Romero
and E. Estornell, J. Antibiot., 2005, 58, 416–419; (b) J.-R. Dai, B. K.
Carte, P. J. Sidebottom, A. L. Yew, S.-W. Ng, Y. Huang and M. S.
Butler, J. Nat. Prod., 2001, 64, 125–126; (c) L. Rahbæk, J. Breinholt,
J. C. Frisvad and C. Christophersen, J. Org. Chem., 1999, 64, 1689–
1692; (d) L. Rahbæk and J. Breinholt, J. Nat. Prod., 1999, 62, 904–905.
5 (a) T. O. Larsen, K. Frydenvang and J. C. Frisvad, Biochem. Syst. Ecol.,
2000, 28, 881–886; (b) B. K. Joshi, J. B. Gloer, D. T. Wicklow and P. F.
Dowd, J. Nat. Prod., 1999, 62, 650–652.
◦
White solid, mp 220–222 C; [a]2D0 = -36.8◦ (c 1.0, DMSO); dH
(400 MHz; DMSO-d6) 1.89-2.01 (1H, m, CONCH2CHH), 2.11-
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6 (a) M.-C. Tseng, C.-Y. Lai, Y.-W. Chu and Y.-H. Chu, Chem. Commun.,
2009, 445–447; (b) M.-C. Tseng and Y.-H. Chu, Tetrahedron, 2008, 64,
9515–9520.
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(b) F. He, B. M. Foxman and B. B. Snider, J. Am. Chem. Soc., 1998, 120,
6417–6418; (c) A. Grieder and A. W. Thomas, Synthesis, 2003, 1707–
1711; (d) T. Sugimori, T. Okawa, S. Eguchi, A. Kakehi, E. Yashima and
Y. Okamoto, Tetrahedron, 1998, 54, 7997–8008. For a recent review of
the Eguchi protocol used for natural product synthesis, see: S. Eguchi,
ARKIVOC, 2005, (ii), 98–119.
8 A. Witt and J. Bergman, J. Org. Chem., 2001, 66, 2784–
2788.
9 M. G. Bock, R. M. DiPardo, S. M. Pitzenberger, C. F. Homnick,
S. M. Springer and R. M. Freidinger, J. Org. Chem., 1987, 52, 1646–
1647.
11 For the two most recent reviews of microwave heating for synthetic
organic reactions, see: (a) S. Caddick and R. Fitzmaurice, Tetrahedron,
2009, 65, 3325–3355; (b) C. O. Kappe, Chem. Soc. Rev., 2008, 37, 1127–
1139.
12 R. R. Fraser, in Asymmetric Synthesis, ed. J. D. Morrison, Academic
Press, New York, 1983, vol. 1, pp. 173–196.
13 In our hands, rapid cyclization of 6a–f, 9a–e and 12a–e by microwaves
resulted in minimal racemization, if any. Prolonged reaction times by
conventional heating resulted in enantiomeric erosion. These similar
experimental observations have been reported for other synthetic
reactions: (a) B. Severino, F. Fiorino, A. Esposito, F. Frecentese, F.
De Angelis, E. Perissutti, G. Caliendo and V. Santagada, Tetrahedron,
2009, 65, 206–211; (b) M. Hosseini, N. Stiasni, V. Barbieri and C. O.
Kappe, J. Org. Chem., 2007, 72, 1417–1424; (c) J.-F. Liu, P. Ye, B.
Zhang, G. Bi, K. Sargent, L. Yu, D. Yohannes and C. M. Baldino,
J. Org. Chem., 2005, 70, 6339–6345; (d) J. J.-Y. Yang, Y.-H. Chu and
S.-T. Chen, in Optimization of Solid-Phase Combinatorial Synthesis, ed.
B. Yan and A. W. Czarnik, Marcel Dekker, New York, 2002, p. 305.
10 J.-F. Liu, M. Kaselj, Y. Isome, J. Chapnick, B. Zhang, G. Bi, D.
Yohannes, L. Yu and C. M. Baldino, J. Org. Chem., 2005, 70, 10488–
10493.
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