Three-component one-pot total syntheses of glyantrypine, fumiquinazoline F, and fiscalin B promoted by microwave irradiation

Article abstract of DOI:10.1021/jo0508043

A microwave-promoted three-component one-pot reaction has been developed to provide access to the core pyrazino[2,1-b]quinazoline-3,6-dione (1) scaffold, which is common to several families of alkaloids with significant biological activities. By adapting this synthetic strategy through the use of selected Boc-amino acids and amino acid esters, we have accomplished highly efficient and concise total syntheses of glyantrypine (2), fumiquinazoline F (3), and fiscalin B (5), achieving overall yields of 55, 39, and 20%, respectively.

Full text of DOI:10.1021/jo0508043

Three-Component One-Pot Total Syntheses of Glyantrypine,
Fumiquinazoline F, and Fiscalin B Promoted by Microwave
Irradiation†
Ji-Feng Liu,* Ping Ye, Bailin Zhang, Grace Bi, Katie Sargent, Libing Yu,
Daniel Yohannes, and Carmen M. Baldino
ArQule, Inc., Division of Chemical Technologies, 19 Presidential Way, Woburn, Massachusetts 01801
jliu@arqule.com
Received April 20, 2005
A microwave-promoted three-component one-pot reaction has been developed to provide access to
the core pyrazino[2,1-b]quinazoline-3,6-dione (1) scaffold, which is common to several families of
alkaloids with significant biological activities. By adapting this synthetic strategy through the use
of selected Boc-amino acids and amino acid esters, we have accomplished highly efficient and concise
total syntheses of glyantrypine (2), fumiquinazoline F (3), and fiscalin B (5), achieving overall yields
of 55, 39, and 20%, respectively.
Introduction
Fungal quinazolinone metabolites which incorporate
the core pyrazino[2,1-b]quinazoline-3,6-dione (1) scaffold
represent several families of alkaloids (Figure 1).1 Rep-
resentative natural products containing scaffold 1 include
glyantripine (2),2 fumiquinazolines F (3) and G (4),3
fiscalin B (5),4 alantripinione (6),5 ardeemin (7),6 and
N-acetylardeemin (8), many of which have exhibited
significant biological activities.2-4,6a,b Because of the
unique structural features and pharmaceutical relevance
† This paper is dedicated with respect and affection to the memory
of Professor Satoru Masamune who passed away on November 9, 2003.
(1) For recent reviews on quinazoline alkaloids, see: (a) Michael,
J. P. Nat. Prod. Rep. 2004, 21, 650. (b) Johne, S. In Supplements to
the 2nd Edition of Rodd’s Chemistry of Carbon Compounds; Ansell,
M. F., Ed.; Elsevier: Amsterdam, 1995; Vol. IV I/J, pp 223-240.
(2) Penn, J.; Mantle, P. G.; Bilton, J. N.; Sheppard, R. N. J. Chem.
Soc., Perkin Trans. 1 1992, 1495.
(3) (a) Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto, T.;
Kawai, K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi, H.; Shingu,
T. Tetrahedron Lett. 1992, 33, 1621. (b) Takahashi, C.; Matsushita,
T.; Doi, M.; Minoura, K.; Shingu, T.; Kumeda, Y.; Numata, A. J. Chem.
Soc., Perkin Trans. 1 1995, 2345.
(4) (a) Wong, S.-M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.; Gillum,
A. M.; Cooper, R. J. Antibiot. 1993, 46, 545. (b) Fujimoto, H.; Negishi,
E.; Yamaguchi, K.; Nishi, N.; Yamazaki, M. Chem. Pharm. Bull. 1996,
44, 1843.
(5) Larsen, T. O.; Frydenvang, K.; Frisvad, J. C.; Christophersen,
C. J. Nat. Prod. 1998, 61, 1154.
FIGURE 1. Pyrazino[2,1-b]quinazoline-3,6-dione (1) and
representative natural products.
of these alkaloids,6 several research groups have devoted
much effort to their total syntheses.6e-11
10.1021/jo0508043 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/01/2005
J. Org. Chem. 2005, 70, 6339-6345
6339

Liu et al.
SCHEME 1. Available Approaches for the
Synthesis of Pyrazino[2,1-b]quinazoline-3,6-diones
SCHEME 2. One-Pot Synthesis of
2,3-Disubstituted Quinazolin-4-ones
G (4), and fiscalin B (5) in only four to five synthetic steps.
This method has also been extended to the synthesis of
more complex fumiquinazolines.7c,11,12 The reaction mech-
anism was later verified by Snider,13 confirming that the
intermediacy of an iminobenzoxazine 1514 formed from
the dehydrative cyclization of intermediate 14. Hart and
Magomedov have also shown that the rearrangement of
the iminobenzoxazine 15 to the quinazolinones can be
carried out with Li(AlMe3SPh).11
Very recently, we developed an efficient microwave-
assisted three-component one-pot methodology for the
synthesis of various 2,3-disubstituted quinazolin-4-ones
18 from readily available anthranilic acids 13 (Scheme
2).15 This novel approach allows access to a broader
chemistry scope relative to existing methods, accom-
modating an expanded array of carboxylic acids (R1CO2H)
and amines (R2NH2). Although our microwave method
readily provided substituted quinazolin-4-one cores such
as 18 via a one-pot process, we were intrigued by the
possibility of extending this methodology toward a one-
pot total synthesis of the fungal quinazolin-4-one natural
products.16 This synthetic approach of quinazoline dehy-
dration followed by diketopiperazine-like cyclization
represents, in principle, the most efficient and straight-
forward route to fumiquinazoline alkaloids. Yet, it has
not been successfully utilized to date in the total syn-
thesis of natural products containing core 1. In this
paper, we report the application of this approach to the
three-component one-pot17 total syntheses of glyantrypine
(2), fumiquinazoline F (3), and fiscalin B (5).
Thus far, two major synthetic strategies have been
reported to access the core ring system 1, which have
subsequently led to the total synthesis of several natural
products (Scheme 1). Snider,7 Avendan˜o,8 and So¨llhuber8
took advantage of an aza-Wittig approach9 (Approach 1)
to construct 1 by reacting diketopiperazines 11 (derived
from amino acids 9 and 10 via a multistep reaction
sequence) with o-azidobenzoyl chloride (12), a protocol
that was successfully employed in the total syntheses of
glyantrypine (2),8 fumiquinazoline F (3),8a fumiquinazo-
line G (4),7a,b,8a and fiscalin B (5).8a Alternatively, Gane-
san10 reported a remarkably straightforward approach
(Approach 2) highlighted by the dehydration of interme-
diate 14 using Ph3P/I2 as a dehydrating agent, affording
glyantrypine (2), fumiquinazoline F (3), fumiquinazoline
Results and Discussion
Synthesis Plan. Our retrosynthetic strategy (Scheme
3) envisions a highly efficient three-component one-pot
reaction sequence that allows for the in situ construction
of key intermediates and the necessity of only a single
(6) Some examples include: (a) Karwowski, J. P.; Jackson, M.;
Rasmussen, R. R.; Humphrey, P. E.; Poddig, J. B.; Kohl, W. L.; Scherr,
M. H.; Kadam, S.; McAlpine, J. B. J. Antibiot. 1993, 46, 374.
(b) Hochlowski, J. E.; Mullally, M. M.; Spanton, S. G.; Whittern, D.
N.; Hill, P.; McAlpine, J. B. Isolation and structure. J. Antibiot. 1993,
46, 380. (c) Wiese, M.; Pajeva, I. K. Curr. Med. Chem. 2001, 8, 685.
(d) Me´ndez-Vidal, C.; Rodr´ıguez de Quesada, A. Cancer Lett. 1998, 132,
45. (e) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.;
Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121,
11953.
(12) (a) Kende, A. S.; Fan, J.; Chen, Z. Org. Lett. 2003, 5, 3205.
(b) Chen, Z.; Fan, J.; Kende, A. S. J. Org. Chem. 2004, 69, 79.
(13) He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397.
(14) Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973.
(15) Liu, J.-F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.;
McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241.
(16) For a recent review of microwave-assisted organic synthesis,
see: Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6251. For recent
applications of microwave technology in complex natural product
synthesis, see: (a) Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N.
J. Am. Chem. Soc. 2004, 126, 706. (b) Baran, P. S.; O’Malley, D. P.;
Zografos, A. L. Angew. Chem., Int. Ed. 2004, 43, 2674.
(7) (a) He, F.; Snider, B. B. Synlett 1997, 483. (b) Snider, B. B.;
Busuyek, M. V. Tetrahedron 2001, 57, 3301. (c) Snider, B. B.; Zeng,
H. J. Org. Chem. 2003, 68, 545.
(17) For multicomponent reactions, see: (a) Multicomponent Reac-
tions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, Germany,
2005. (b) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(c) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.-Eur. J.
2000, 6, 3321. (d) Weber, L. Curr. Med. Chem. 2002, 9, 2085.
(e) Do¨mling, A. Curr. Opin. Chem. Biol. 2002, 6, 306. (f) Hulme, C.;
Gore, V. Curr. Med. Chem. 2003, 10, 51. (g) Orru, R. V. A.; De Greef,
M. Synthesis 2003, 1471. (h) Balme, G.; Bossharth, E.; Monteiro, N.
Eur. J. Org. Chem. 2003, 4101. (i) Jacobi von Wangelin, A.; Neumann,
H.; Go¨rdes, D.; Klaus, S.; Stru¨bing, D.; Beller, M. Chem. Eur. J. 2003,
9, 4286. (j) Murakami, M. Angew. Chem., Int. Ed. 2003, 42, 718.
(k) Zhu, J. Eur. J. Org. Chem. 2003, 1133.
(8) (a) Herna´ndez, F.; Lumetzberger, A.; Avendan˜o, C.; So¨llhuber,
M. Synlett 2001, 1387. (b) Cledera, P.; Avendan˜o, C.; Mene´ndez, J. C.
J. Org. Chem. 2000, 65, 1743.
(9) Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45,
6375.
(10) (a) Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432.
(b) Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 1022. (c) Wang, H.;
Ganesan, A. J. Comb. Chem. 2000, 2, 186.
(11) (a) Hart, D. J.; Magomedov, N. A. Tetrahedron Lett. 1999, 40,
5429. (b) Hart, D. J.; Magomedov, N. A. J. Am. Chem. Soc. 2001, 123,
5892.
6340 J. Org. Chem., Vol. 70, No. 16, 2005

Glyantrypine, Fumiquinazoline, and Fiscalin Syntheses
TABLE 1. In Situ N-Deprotection under Microwave
Irradiation
SCHEME 3. Retrosynthetic Strategy for the Total
Synthesis of Fumiquinazoline Alkaloids
temp
(°C)
time
(min)
entry
18a/18ba
1
2
3
4
180
200
210
220
3
3
3
4
100/0
80/20
10/90
0/100
a Determined by LC-MS (ELSD) of the crude reaction mixture.
Compounds 18a (60% yield) and 18b (50% yield) were isolated on
preparative HPLC and characterized.
reagent (P(OPh)3) to complete the total synthesis. The
pyrazino[2,1-b]quinazoline-3,6-dione (1) could be obtained
by a diketopiperazine-like cyclization after an N-depro-
tection of quinazolinone 20, and the quinazolinone 20
could be formed in situ through the reaction of interme-
diate 19 with the amino acid ester 10 under the micro-
wave conditions. N-protected benzoxazin-4-one (19) could
be generated in situ from the reaction of anthranilic acid
(13a) with a protected R-amino acid 9. Although we have
successfully applied this approach to a variety of model
systems, the natural products presented a number of
additional challenges. One critical hurdle was the iden-
tification of an appropriate protecting group for R-amino
acid 9. The ideal protecting group needed to be compat-
ible with the microwave reaction conditions for the
formation of 19 and 20 (typically 150-220 °C, pyridine/
P(OPh)3)15 but labile enough to be deprotected in situ
prior to the diketopiperazine-like cyclization.
SCHEME 4. Optimization of the One-Pot
Microwave-Promoted Synthesis of
Pyrazino[2,1-b]quinazoline-3,6-dione (1)a
Determination of Protecting Groups. To establish
the forward synthetic route, we started our investigation
by examining the formation of quinazolin-4-ones employ-
ing amino acids with standard protecting groups such
as Boc, Cbz, Bn, and Fmoc. Boc-amino acids were
identified as the optimal performers under the reaction
conditions.18 More importantly, when a Boc was used as
the protecting group, we observed the desired quinazo-
linone ring formation to give 18a, followed by the in situ
deprotection of the N-Boc group to form 18b (Table 1).
Although 18a was formed at a lower temperature
(180 °C), the reaction conditions were optimized to yield
18b as the only product once the reaction temperature
was increased to 220 °C. These results pointed to the
possibility of further simplifying the sequence by con-
ducting a series of transformations to form the pyrazino-
[2,1-b]quinazoline-3,6-dione (1) in one-pot, provided that
the selection of an appropriate amino ester 10 compatible
with the reaction conditions is made.
Synthesis of the Pyrazino[2,1-b]quinazoline-3,
6-dione Core. With these encouraging results in hand,
we began the construction of the simplified target pyrazi-
no[2,1-b]quinazoline-3,6-dione (1) skeletons through the
one-pot process (Scheme 4). Glycinemethylester hydro-
chloride (10a) was chosen as the simplest reactant that
could be used to develop the diketopiperazine-like cy-
clization. With the addition of 10a to the initially
a Conditions (i) for 1a, 1c, and 1d, mixture of the corresponding
13 (1.0 equiv), 9a (1.0 equiv), and P(OPh)3 (1.2 equiv) in pyridine,
microwave heating, 150 °C, 10 min; for 1b, mixture of correspond-
ing 13a (1.0 equiv), 9b (1.0 equiv), and P(OPh)3 (1.2 equiv) in
pyridine, 55 °C, conventional heating, 16 h; (ii) addition of the
corresponding 10 (1.0 equiv), microwave heating, 220 °C, 1.5 min.
generated benzoxazin-4-one (19a), the formation of the
intermediate 20a was observed at 150-200 °C under
microwave irradiation. Gratifyingly, further irradiation
of the reaction mixture at higher temperatures (200-
220 °C) affected the ring closure, which yielded 1a (50%
unoptimized), thus achieving the one-pot synthesis of the
target core scaffold. Isolation of intermediate 20a (de-
tailed in the Experimental Section) provided us with
direct evidence for our distinct synthetic route to access
scaffolds incorporating core 1.
Once the reaction sequence had been established, it
was desirable to optimize the conditions to apply the
method to the total synthesis of the natural products
(Scheme 4). It is important to note that for the formation
of the Boc-protected benzoxazin-4-one (19) two different
sets of heating conditions were developed to maximize
(18) The reaction utilizing Boc-amino acids provided reaction mix-
tures with fewer side products.
J. Org. Chem, Vol. 70, No. 16, 2005 6341

Liu et al.
SCHEME 5. One-Pot Total Synthesis of
Glyantrypine (2), Fumiquinazoline F (3), and
Fiscalin B (5)a
determined by chiral SFC/MS. Fortunately, enantiomeri-
cally pure 2 could be generated either via semiprepara-
tive chiral SFC or simply by recrystallization from
methanol. The unnatural enantiomer of 2 was also
synthesized by employing L-tryptophan methylester hy-
drochloride and purified via preparative chiral SFC.
To further investigate the impact of microwave heating
on the stereogenic center at C4, we examined various sets
of conditions for the ring closure by modifying the
temperature and time of microwave irradiation. The
results clearly identified that effective diketopiperazine-
like cyclization occurred only at temperatures ranging
from >210 to <230 °C, but the degree of epimerization
and ratio of the side products increased as a function of
prolonged reaction time and increasing temperature. For
example, the reaction did not proceed to completion when
heated at 210 °C for 3 min. A prolonged reaction time
for 2 resulted in enantiomeric erosion (40% ee at 6 min).
On the other hand, when the reaction was carried out at
higher microwave temperatures (230 °C), unidentified
side products emerged after 1.5 min of heating, presum-
ably as a result of decomposition. Moreover, the ee of 2
was decreased to 52% when the reaction was carried out
for 3 min at 220 °C. Thus, the optimal conditions for the
ring closure were determined to be microwave irradiation
at 220 °C for 1.5 min, and these optimized conditions
were used in the syntheses of the target molecules.
A one-pot total synthesis of fumiquinazoline F (3) in
39% yield was also achieved using the thermal-micro-
wave heating protocol (Scheme 5). The ee for 3 was
determined to be 72% (by analytical chiral SFC/MS),
which was improved to >99% ee through recrystallization
from methanol, as described for 2. It was observed that
both the C1 and C4 stereogenic centers were epimerized
partially under the reaction conditions.22 An investigation
of the impact of the reaction conditions on epimerization
resulted in outcomes similar to those identified in the
case of 2 (the ee for 3 decreased to 50% when the reaction
was carried out for 3 min at 220 °C), where epimerization
increased with prolonged reaction time and elevated
temperatures. The combined remaining fractions after
the isolation of 3 were concentrated and separated by
preparative HPLC to yield fumiquinazoline G (4) as a
minor byproduct in 3% yield.23 Fiscalin B (5) was also
obtained following the thermal-microwave heating pro-
tocol (Scheme 5) but only in 20% yield with 50% ee, which
could be attributed to steric hindrance created by the
isopropyl group.24 Despite evidence of epimerization, the
successful application of this methodology to access
sterically hindered fiscalin B in a one-pot reaction
demonstrates the utility of this new method.25
a Conditions for 2: 13a (1.0 equiv), 9a (1.0 equiv), and P(OPh)3
(1.2 equiv), pyridine, microwave heating, 150 °C, 10 min; then 10d
(1.0 equiv), microwave heating, 220 °C, 1.5 min. Conditions for 3
or 5: 13a (1.0 equiv), 9b (1.0 equiv) or 9c (1.0 equiv), and P(OPh)3
(1.2 equiv), pyridine, conventional heating, 55 °C, 16 h; then 10d
(1.0 equiv), microwave heating, 220 °C, 1.5 min.
the yields and accommodate the required functionality.
For example, N-Boc-glycine (9a) was converted to 19a
using microwave heating at 150 °C for 10 min, whereas
conventional heating of N-Boc-L-alanine (9b) at 55 °C for
16 h proved to be the best set of conditions to generate
19b.19 In either case, addition of the amino acid esters
10a, 10b, and 10c to the in situ generated Boc-protected
benzoxazin-4-one (19) followed by microwave heating at
220 °C for 1.5 min afforded the corresponding final
products 1a, 1b, 1c, and 1d with yields of 62, 56, 64, and
79%, respectively. Therefore, these two complementary
methods (microwave-microwave or thermal-microwave
heating) provided maximum flexibility for applying our
one-pot process to various natural products. Moreover,
1b, a key intermediate in the total synthesis of alantry-
pinone (6) as reported by Kende,12 could be readily
synthesized in this fashion on a 5-g scale in 57% yield,
reinforcing the practical advantages of this approach.
Total Synthesis of Glyantrypine, Fumiquinazo-
line F, and Fiscalin B. Finally, we report the applica-
tion of this synthetic strategy to the one-pot total
syntheses of the alkaloids glyantrypine (2), fumiquinazo-
line F (3), and fiscalin B (5) (Scheme 5). Microwave
irradiation of anthranilic acid (13a) with N-Boc-glycine
(9a) followed by the addition of D-tryptophan methylester
hydrochloride (10d) provided glyantrypine (2) in 55%
yield.20,21 Because of epimerization at C4 under these
reaction conditions, 2 was obtained with 70% ee as
(19) In all cases where we have used conventional heating to
generate intermediates corresponding to 19, microwave heating could
generate the same products, albeit in lower yields.
(20) As a comparison, a control reaction was carried out in a sealed
tube under conventional heating in an oil bath at 210 °C (the minimal
temperature required for the reaction to proceed) for 15 min. The
product 2 was formed, but the crude reaction mixture was more
complex with multiple side products and fully racemized products
(LC/MS, ELSD ) 60%, ee ) 0%) as compared with the microwave
conditions which provided the product in higher yield with minimal
side reactions and with much less enantiomeric erosion (LC/MS, ELSD
) 75%, ee ) 70%). Additionally, the conventional heating conditions
(sealed tube) are not practical for parallel synthesis of analogue
libraries of the natural products, which is an effort that we are
pursuing.
(22) This was evidenced by the fact that the ee of 3 was decreased
with higher reaction temperature and longer reaction time. Both
samples of 3, with 72% ee and 50% ee, have identical 1H NMR and
13C NMR relative to enantiomerically pure 3.
(23) 1H NMR is identical with fumiquinazoline G in ref 9b. The
chiral SFC/MS analysis confirmed that it is a racemate of 4.
(24) The ee of 5 was determined by chiral SFC/MS. Enantiomerically
pure (>99% ee) 5 could be obtained via preparative chiral SFC
separation. The sample has [R]D ) -613 (c 0.064, CHCl3) {lit.10b [R]30
D
) -609 (c 0.59, CHCl3)}. See the Experimental Section for details.
(25) Steric hindrance is an important factor in unsuccessful quinazoli-
none ring formation in Fiscalin B total synthesis. See the discussion
in: Buenadicha, F. L.; Avendan˜o, C.; So¨llhuber, M. Tetrahedron:
Asymmetry 2001, 12, 3019. See ref 10b.
(21) The synthesis of
3 was also achieved with the use of
D-tryptophan methylester, resulting in an identical yield and optical
purity under the same microwave conditions as those used for
D-tryptophan methylester hydrochloride (10d).
6342 J. Org. Chem., Vol. 70, No. 16, 2005

Glyantrypine, Fumiquinazoline, and Fiscalin Syntheses
the mixture to room temperature, we added glycine methyl-
ester hydrochloride (10a) (25 mg, 200 µmol), and the resulting
mixture was heated in the microwave at 150 °C for 3 min. The
reaction mixture was then concentrated in vacuo, and the
residue was purified by preparative HPLC (ProntoSIL
120-10-C18 column (50 × 20 mm) with a flow rate of 44 mL/
min utilizing an acetonitrile/water mobile phase) to afford 20a
as a white solid (38 mg, 55%): 1H NMR (400 MHz, CDCl3)
δ 8.26 (dd, 1H, J ) 8.2, 1.2 Hz), 7.78 (ddd, 1H, J ) 8.2, 7.6,
1.2 Hz), 7.70 (d, 1H, J ) 7.6 Hz), 7.50 (ddd, 1H, J ) 8.2, 7.6,
1.2 Hz), 5.93 (bs, 1H), 4.86 (s, 2H), 4.35 (t, 2H, J ) 4.8 Hz),
3.80 (s, 3H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.1,
161.9, 155.8, 151.6, 146.7, 135.0, 127.5, 127.4, 127.3, 120.5,
80.5, 53.2, 44.0, 43.2, 28.6; HRMS calcd for (C17H21N3O5 + Na)
370.1381, found 370.1371; MS m/z 348.12 (M + H).
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
(1a). To a conical-bottomed Smith Process vial were added
anthranilic acid (13a) (28 mg, 200 µmol), N-Boc-glycine (9a)
(35 mg, 200 µmol), and triphenyl phosphite (63 µL, 220 µmol)
along with 1 mL of anhydrous pyridine. The sealed vial was
irradiated in the microwave for 10 min at 150 °C. After cooling
the mixture to room temperature, we added glycine methyl-
ester hydrochloride (10a) (25 mg, 200 µmol), and the resulting
mixture was heated in the microwave at 220 °C for 1.5 min.
The reaction mixture was then concentrated in vacuo, and the
residue was purified by silica gel flash chromatography
(dichloromethane/ethyl acetate/MeOH ) 50:48:2) to afford 1a
as a white solid (24 mg, 56%): mp 285-287 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.59 (bs, 1H), 8.12 (dd, 1H, J ) 8.0,
1.6 Hz), 7.83 (ddd, 1H, J ) 7.2, 6.0, 0.8 Hz), 7.63 (d, 1H, J )
8.0 Hz), 7.52 (dd, 1H, J ) 8.0, 8.0 Hz), 4.51 (s, 1H), 4.42 (d,
1H, J ) 2.0 Hz); 13C NMR (100 MHz, DMSO-d6) δ 166.7,
160.5, 150.8, 147.8, 135.4, 127.5, 127.4, 126.9, 45.43, 45.37;
HRMS calcd for (C11H9N3O2 + H) 216.0768, found 216.0769;
MS m/z 216.12 (M + H).
(1S)-1-Methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazo-
line-3,6-dione (1b). To a conical-bottomed Smith Process vial
were added anthranilic acid (13a) (28 mg, 200 µmol), N-Boc-
L-alanine (9b) (38 mg, 200 µmol), and triphenyl phosphite
(63 µL, 220 µmol) along with 1 mL of anhydrous pyridine. The
vial was then heated at 55 °C for 16 h. After cooling the
mixture to room temperature, we added glycine methylester
hydrochloride (10a) (25 mg, 200 µmol), and the resulting
mixture was heated in the microwave at 220 °C for 1.5 min.
The reaction mixture was then concentrated in vacuo, and the
residue was purified by silica gel flash chromatography
(dichloromethane/ethyl acetate/MeOH ) 50:48:2) to afford 1b
as a white solid (28.5 mg, 62%): mp 238-240 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.67 (bs, 1H), 8.13 (dd, 1H, J ) 8.0,
1.2 Hz), 7.81 (ddd, 1H, J ) 8.0, 7.2, 1.6 Hz), 7.63 (dd, 1H, J )
7.6, 0.8 Hz), 7.51 (ddd, 1H, J ) 8.0, 7.2, 1.6 Hz), 4.63 (d, 1H,
J ) 17.6 Hz), 4.60 (dq, 1H, J ) 7.0, 1.6 Hz), 4.48 (d, 1H, J )
17.6 Hz), 1.52 (dd, 3H, J ) 7.0, 1.0 Hz); 13C NMR (100 MHz,
DMSO-d6) δ 166.7, 160.7, 153.3, 147.4, 135.4, 127.8, 127.4,
126.8, 120.0, 50.9, 45.0, 19.9; HRMS calcd for (C12H11N3O2 +
H) 230.0924, found 230.0925; MS m/z 230.27 (M + H).
Gram-Scale Synthesis of 1b. To a 40 mL glass vial were
added anthranilic acid (13a) (1.37 g, 10 mmol), N-Boc-L-alanine
(9b) (1.89 g, 10 mmol), triphenyl phosphite (2.62 mL, 12 mmol),
and pyridine (15 mL). Four copies of this reaction were
prepared, and the reaction mixtures were heated at 55 °C for
16 h. After cooling the mixtures to room temperature, we
transferred the four reactions to four vessels for the Reactor
HPR 100-mL rotor for the microwave labstation, and then
glycine methylester hydrochloride (10a) (1.25 g, 10 mmol) was
added to each vessel. These four reactions were then set on
the rotor in parallel and heated in the microwave labstation
at 210 °C for 7 min with an 18-min temperature ramp. The
reaction mixtures were combined and then concentrated in
vacuo, and the residue was purified by silica gel flash
Summary
We have developed a novel and highly efficient three-
component one-pot reaction sequence promoted by mi-
crowave irradiation for the synthesis of 4-quinazoline-
3,6-diones (1) and have also demonstrated the utility
and versatility of this strategy through the total synthe-
ses of several natural products from readily available
starting materials. Notwithstanding the partial epimer-
ization under the reaction conditions, the approach
provides an efficient and practical entry into a broad
range of natural products. In addition, the methodology
features a significantly wide chemistry scope, enabling
the construction of natural product-templated and diver-
sity-oriented screening libraries, which will be described
in due course.
Experimental Section
[3-(2-Methoxyethyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
methyl]carbamic Acid tert-Butyl Ester (18a). To a conical-
bottomed Smith Process vial were added anthranilic acid (13a)
(28 mg, 200 µmol), N-Boc-glycine (9a) (35 mg, 200 µmol), and
triphenyl phosphite (63 µL, 220 µmol) along with 1 mL of
anhydrous pyridine. The sealed vial was irradiated in the
microwave for 10 min at 150 °C. After cooling the mixture to
room temperature, we added 2-methoxyethylamine (17.5 µL,
200 µmol), and the resulting mixture was heated in the
microwave at 180 °C for 3 min. The reaction mixture was then
concentrated in vacuo, and the residue was purified by
preparative HPLC26 (ProntoSIL 120-10-C18 column (50 ×
20 mm) with a flow rate of 44 mL/min utilizing an acetonitrile/
water mobile phase) to afford 18a as a white foam (40 mg,
60%): 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, 1H, J ) 8.0,
1.2 Hz), 7.74 (td, 1H, J ) 8.0, 1.2 Hz), 7.67 (d, 1H, J )
8.0 Hz), 7.47 (td, 1H, J ) 8.0, 1.2 Hz), 6.07 (bs, 1H), 4.57 (d,
2H, J ) 4.4 Hz), 4.24 (t, 2H, J ) 5.2 Hz), 3.68 (t, 2H, J )
5.2 Hz), 3.28 (s, 3H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 162.2, 156.0, 153.1, 146.8, 134.6, 127.2, 127.1, 127.0, 120.8,
80.0, 70.1, 59.3, 43.6, 43.1, 28.7; HRMS calcd for (C17H23N3O4
+ Na) 356.1589, found 356.1578; MS m/z 334.29 (M + H).
2-Aminomethyl-3-(2-methoxyethyl)-3H-quinazolin-4-
one (18b). To a conical-bottomed Smith Process vial were
added anthranilic acid (13a) (28 mg, 200 µmol), N-Boc-glycine
(9a) (35 mg, 200 µmol), and triphenyl phosphite (63 µL,
220 µmol) along with 1 mL of anhydrous pyridine. The sealed
vial was irradiated in the microwave for 10 min at 150 °C.
After cooling the mixture to room temperature, we added
2-methoxyethylamine (17.5 µL, 200 µmol), and the resulting
mixture was heated in the microwave at 220 °C for 4 min. The
reaction mixture was then concentrated in vacuo, and the
residue was purified by preparative HPLC (ProntoSIL
120-10-C18 column (50 × 20 mm) with a flow rate of 44 mL/
min utilizing an acetonitrile/water mobile phase and 0.1%
trifluoroacetic acid as a modifier) to afford 18b as a white solid
TFA salt (35 mg, 50%): 1H NMR (400 MHz, CD3OD) δ 8.20
(dd, 1H, J ) 8.4, 1.2 Hz), 7.81 (td, 1H, J ) 8.4, 1.2 Hz), 7.72
(d, 1H, J ) 8.4 Hz), 7.51 (td, 1H, J ) 8.4, 1.2 Hz), 4.30 (t, 2H,
J ) 5.2 Hz), 4.09 (s, 2H), 3.70 (t, 2H, J ) 5.2 Hz), 3.30 (s, 3H);
HRMS calcd for (C12H15N3O2 + H) 234.1244, found 234.1238;
MS m/z 234.24 (M + H).
[2-(tert-Butoxycarbonylaminomethyl)-4-oxo-4H-
quinazolin-3-yl]acetic Acid Methyl Ester (20a). To a
conical-bottomed Smith Process vial were added anthranilic
acid (13a) (28 mg, 200 µmol), N-Boc-glycine (9a) (35 mg,
200 µmol), and triphenyl phosphite (63 µL, 220 µmol) along
with 1 mL of anhydrous pyridine. The sealed vial was
irradiated in the microwave for 10 min at 150 °C. After cooling
chromatography (dichloromethane/ethyl acetate/MeOH
)
(26) Goetzinger, W.; Zhang, X.; Bi, G.; Towle, M.; Cherrak, D.;
Kyranos, J. N. Int. J. Mass. Spectrom. 2004, 238, 153.
50:48:2) to afford 1b as a white solid (5.2 g, 57%), with
J. Org. Chem, Vol. 70, No. 16, 2005 6343

Liu et al.
analytical data consistent with that reported in the previous
experiments.
set at 30 °C, and the outlet pressure was at 100 bar. Fraction
collection was triggered on the basis of UV214nm trace. After
chiral purification, the ee of 2 was determined to be 100% using
the analytical conditions described above. Alternatively, enantio-
merically pure 2 (100% ee) could also be obtained after
recrystallization from MeOH as light yellow crystals: mp 155-
157 °C; [R]D ) -535 (c 0.028, CHCl3) {lit.10b mp 159-161 °C
(4S)-4-Methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazo-
line-3,6-dione (1c). To a conical-bottomed Smith Process vial
were added anthranilic acid (13a) (28 mg, 200 µmol), N-Boc-
glycine (9a) (35 mg, 200 µmol), and triphenyl phosphite
(63 µL, 220 µmol) along with 1 mL of anhydrous pyridine. The
sealed vial was irradiated in the microwave for 10 min at
150 °C. After cooling the mixture to room temperature, we
added D-alanine methylester hydrochloride (10b) (28 mg,
200 µmol), and the resulting mixture was heated in the
microwave at 220 °C for 1.5 min. The reaction mixture was
then concentrated in vacuo, and the residue was purified by
silica gel flash chromatography (dichloromethane/ethyl acetate/
MeOH ) 50:48:2) to afford 1c as a white solid (29.4 mg, 64%):
mp 217-219 °C; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H,
J ) 8.0 Hz), 7.78 (ddd, 1H, J ) 8.0, 7.2, 0.8 Hz), 7.64 (d, 1H,
J ) 8.4 Hz), 7.52 (dd, 1H, J ) 7.6, 3.4 Hz), 6.90 (bs, 1H, N-H),
5.46 (q, 1H, J ) 7.2 Hz), 4.69 (d, 1H, J ) 16.8 Hz), 4.51 (dd,
1H, J ) 16.4, 4.8 Hz), 1.66 (d, 3H, J ) 6.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 170.2, 160.4, 147.8, 147.2, 135.1, 127.6,
127.21, 127.18, 120.6, 52.0, 45.3, 17.2; HRMS calcd for
(C12H11N3O2 + H) 230.0924, found 230.0927; MS m/z 230.10
(M + H).
(4S)-4-(2-Methylpropyl)-9-chloro-2H-pyrazino[2,1-b]-
quinazoline-3,6-(1H,4H)dione (1d). To a conical-bottomed
Smith Process vial were added 4-chloroanthranilic acid (13b)
(35 mg, 200 µmol), N-Boc-glycine (9a) (35 mg, 200 µmol), and
triphenyl phosphite (63 µL, 220 µmol) along with 1 mL of
anhydrous pyridine. The sealed vial was irradiated in the
microwave for 10 min at 150 °C. After cooling the mixture to
room temperature, we added D-valine methylester hydrochlo-
ride (10c) (34 mg, 200 µmol), and the resulting mixture was
heated in the microwave at 220 °C for 1.5 min. The reaction
mixture was then concentrated in vacuo, and the residue was
purified by silica gel flash chromatography (dichloromethane/
ethyl acetate/MeOH ) 50:48:2) to afford 1d as a white solid
(46 mg, 79%): mp 219-221 °C; 1H NMR (400 MHz, CDCl3)
δ 8.21 (d, 1H, J ) 8.8 Hz), 7.63 (d, 1H, J ) 2.0 Hz), 7.45 (dd,
1H, J ) 8.6, 1.8 Hz), 6.73 (bd, 1H, J ) 4.4 Hz), 5.24 (dd, 1H,
J ) 8.0, 1.2 Hz), 4.70 (d, 1H, J ) 17.2 Hz), 4.43 (dd, 1H, J )
17.6, 5.2 Hz), 2.33-2.45 (m, 1H), 1.15 (d, 3H, J ) 7.2 Hz), 1.08
(d, 3H, J ) 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 168.3, 160.4,
149.8, 148.2, 141.3, 128.9, 128.2, 126.8, 119.0, 61.0, 45.7, 32.0,
20.1, 19.0; HRMS calcd for (C14H14N3O2C1 + Na) 314.0667,
found 314.0668; MS m/z 292.04 (M + H).
(foam); [R]30 ) -522 (c 0.24, CHCl3)}; 1H NMR (400 MHz,
D
DMSO-d6) δ 10.93 (bs, 1H), 8.31 (d, 1H, J ) 4.4 Hz), 8.18 (d,
1H, J ) 7.2 Hz), 7.82 (td, 1H, J ) 7.7, 1.6 Hz), 7.54 (t, 2H,
J ) 8.4 Hz), 7.30 (dd, 1H, J ) 8.0, 0.8 Hz), 7.24 (d, 1H, J )
7.6 Hz), 6.99 (t, 1H, J ) 7.4 Hz), 7.85 (d, 1H, J ) 2.8 Hz), 6.76
(t, 1H, J ) 7.4 Hz), 5.26 (t, 1H, J ) 5.0 Hz), 3.79 (dd, 1H, J )
17.2, 4.4 Hz), 3.41 (d, 2H, J ) 5.0 Hz), 3.05 (d, 1H, J ) 16.8
Hz); 13C NMR (100 MHz, DMSO-d6) δ 168.5, 160.7, 149.8,
147.5, 136.5, 135.6, 127.7, 127.6, 127.2, 127.0, 124.9, 122.1,
120.4, 119.4, 118.3, 112.1, 108.3, 57.2, 44.2, 27.1; HRMS calcd
for (C20H16N4O2 + Na) 367.1165, found 367.1172; MS m/z
345.25 (M + H).
(1S,4R)-4-(1H-Indol-3-ylmethyl)-1-methyl-2H-pyrazino-
[2,1-b]quinazoline-3,6(1H,4H)-dione (fumiquinazoline F)
(3). To a conical-bottomed Smith Process vial were added
anthranilic acid (13a) (28 mg, 200 µmol), N-Boc-L-alanine (9b)
(38 mg, 200 µmol), and triphenyl phosphite (63 µL, 220 µmol)
along with 1 mL of anhydrous pyridine. The vial was heated
in a heating block at 55 °C for 16 h. After cooling the mixture
to room temperature, we added D-tryptophan methylester
hydrochloride (10d) (51 mg, 200 µmol), and the resulting
mixture was irradiated in the microwave at 220 °C for 1.5 min.
Using this procedure, we ran two copies of the reaction on the
Personal Chemistry Creator and Smith stations and the
combined reaction mixture was concentrated in vacuo, and the
residue was purified by silica gel flash chromatography
(dichloromethane/ethyl acetate/MeOH ) 50:48:2) to give a
desired product 3 as a white solid (56 mg, 39%). The combined
remaining fractions were concentrated and separated by
preparative HPLC employing a ProntoSIL 120-10-C18 column
(50 × 20 mm). The flow rate was at 44 mL/min utilizing an
acetonitrile/water mobile phase. After dry-down on the freeze-
dryer, 4 mg (3%) of 4 was obtained as pale yellow foam.
The ee of 3 was determined to be 72% using the method
and conditions described above for 2. Light yellow cubical
crystals were obtained after recrystallization from MeOH, and
the ee was determined to be 100% using the same conditions
as above. 3: mp 134-136 °C; [R]D ) -479 (c 0.038, CHCl3)
{lit.10b mp 137 °C (foam); [R]30 ) -516 (c 0.74, CHCl3)};
D
1H NMR (400 MHz, CDCl3) δ 8.30 (dd, 1H, J ) 8.0, 1.2 Hz),
8.14 (bs, 1H), 7.78 (td, 1H, J ) 7.2, 1.2 Hz), 7.59 (d, 1H, J )
7.6 Hz), 7.53 (t, 1H, J ) 6.8 Hz), 7.38 (d, 1H, J ) 7.6 Hz), 7.29
(d, 1H, J ) 8.0 Hz), 7.11 (t, 1H, J ) 7.6 Hz), 6.90 (t, 1H, J )
7.6 Hz), 6.70 (d, 1H, J ) 2.0 Hz), 6.27 (bs, 1H, NH), 5.68 (t,
1H, J ) 4.0 Hz), 3.70 (dd, 1H, J ) 15.2, 3.6 Hz), 3.64 (dd, J )
15.3, 5.2 Hz), 3.07 (q, 1H, J ) 6.4 Hz), 1.36 (d, 3H, J )
6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 169.5, 160.8, 151.9,
147.2, 136.2, 134.9, 127.5, 127.3, 127.1, 123.7, 122.8, 120.4,
120.3, 118.7, 111.4, 109.6, 57.8, 49.4, 27.3, 19.4; HRMS calcd
for (C21H18N4O2 + Na) 381.1322, found 381.1323; MS m/z
359.34 (M + H).
Fumiquinazoline G (4). The ee of 4 was determined to be
0% using the method and conditions as described above for 2.
1H NMR [lit.10b] δ 8.39 (dd, 1H, J ) 8.0, 1.2), 8.05 (bs, 1H),
7.79 (td, 1H, J ) 7.6, 1.6), 7.57 (d, 1H, J ) 8.4), 7.54 (td, 1H,
J ) 8.0, 1.2), 7.29 (dd, 1H, J ) 14.4, 8.0), 7.10 (td, 1H, J )
7.2, 0.8), 6.87 (td, 1H, J ) 7.2, 0.8), 6.73 (d, 1H, J ) 2.4), 6.26
(bs, 1H), 5.57 (dd, 1H, J ) 5.6, 3.2), 4.46 (qd, 1H, J ) 7.2, 2.8),
3.81 (dd. 1H, J ) 14.8, 4.8), 3.73 (dd, J ) 14.8, 3.2), 0.54
(d, 3H, J ) 6.8); MS m/z 359.35 (M + H).
(R)-4-(1H-indol-3-ylmethyl)-2H-pyrazino[2,1-b]quinazo-
line-3,6(1H,4H)-dione (glyantrypine) (2). To a conical-
bottomed Smith Process vial were added anthranilic acid (13a)
(28 mg, 200 µmol), N-Boc-glycine (9a) (35 mg, 200 µmol), and
triphenyl phosphite (63 µL, 220 µmol) along with 1 mL of
anhydrous pyridine. The sealed vial was irradiated in the
microwave for 10 min at 150 °C. After cooling the mixture to
room temperature, we added D-tryptophan methylester hy-
drochloride (10d) (51 mg, 200 µmol), and the resulting mixture
was heated in the microwave at 220 °C for 1.5 min. Using this
procedure, we ran two copies of the reaction on the Personal
Chemistry Creator and Smith stations and the combined
reaction mixture was concentrated in vacuo, and the residue
was purified by silica gel flash chromatography (dichloro-
methane/ethyl acetate/MeOH ) 50:48:2) to afford 2 as a white
crystal (76 mg, 55%). The ee of this sample was determined
to be 70% on an analytical SFC/MS system equipped with a
ChiralCel OD-H column (4.6 × 250 mm) with a flow rate of
3 mL/min and 25% MeOH in CO2 as the mobile phase (30 °C,
130 bar outlet pressure). When the analytical HPLC was
coupled with APCI sourced mass spectrometric detection, a
makeup flow (0.3 mL/min) of 0.1% formic acid in MeOH was
used. The chiral purification was carried out on a SFC
MiniGram system equipped with a ChiralCel OJ-H Column
(20 × 250 mm) with a flow rate of 60 mL/min and a mobile
phase composed of 20% MeOH in CO2. The column oven was
(1S,4R)-4-(1H-Indol-3-ylmethyl)-1-isopropyl-2H-pyrazi-
no[2,1-b]quinazoline-3,6(1H,4H)-dione (fiscalin B) (5). To
a conical-bottomed Smith Process vial were added anthranilic
acid (13a) (28 mg, 200 µmol), Boc-L-valine (9c) (44 mg,
200 µmol), and triphenyl phosphite (63 µL, 220 µmol) along
6344 J. Org. Chem., Vol. 70, No. 16, 2005

Glyantrypine, Fumiquinazoline, and Fiscalin Syntheses
with 1 mL of anhydrous pyridine. The vial was heated in a
heating block at 55 °C for 16 h. After cooling the mixture to
room temperature, we added D-tryptophan methylester hy-
drochloride (10d) (51 mg, 200 µmol), and the resulting mixture
was irradiated in the microwave at 220 °C for 1.5 min. Using
this procedure, we ran two copies of reactions on the Personal
Chemistry Creator and Smith stations and the combined
reaction mixture was concentrated in vacuo, and the residue
was purified by silica gel flash chromatography (dichloro-
methane/ethyl acetate/MeOH ) 50:48:2) to give the desired
product 5 as a pale yellow solid (31 mg, 20%). The ee of 5 was
determined to be 50% using the method and conditions
described above for 2. After chiral purification (carried out on
the semi-prep SFC system as described above for 2), the ee of
5 (now a white solid) was determined to be 100% (using the
same method and conditions as for 2): mp 167-169 °C;
J ) 7.6 Hz), 6.93 (t, 1H, J ) 7.2 Hz), 6.60 (d, 1H, J ) 2.8 Hz),
5.76 (bs, 1H), 5.67 (dd, 1H, J ) 5.6, 2.8 Hz), 3.74 (dd, 1H, J )
15.0, 3.2 Hz), 3.63 (dd, 1H, J ) 15.0, 5.2 Hz), 2.70 (d, 1H, J )
2.1 Hz), 2.63 (m, 1H), 0.64 (d, 3H, J ) 7.2 Hz), 0.63 (d, 3H,
J ) 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 169.6, 161.1, 150.5,
147.3, 136.2, 134.9, 127.4, 127.4, 127.3, 127.1, 123.8, 122.8,
120.4, 120.3, 119.0, 111.3, 109.6, 58.3, 57.0, 29.7, 27.6, 19.0,
15.0; HRMS calcd for (C23H22N4O2 + Na) 409.1635, found
409.1644; MS m/z 387.22 (M + H).
Acknowledgment. The authors thank Ms. Martina
DeSomma, Ms. Jun Zhao, and Mr. Ted Manley for
technical support.
1
Supporting Information Available: Copies of HNMR
[R]D ) -613 (c 0.064, CHCl3) {lit.10b mp 176.5-178.5 °C; [R]30
and 13CNMR spectra for compounds 1a-d, 2, 3, 5, 18a, 18b,
and 20a. This material is available free of charge via the
Internet at http://pubs.acs.org.
D
1
) -609 (c 0.59, CHCl3)}; H NMR (400 MHz, CDCl3) δ 8.37
(dd, 1H, J ) 8.0, 1.2 Hz), 8.07 (bs, 1H), 7.77 (ddd, 1H, J ) 8.4,
6.8, 1.6 Hz), 7.55 (d, 1H, J ) 7.6 Hz), 7.53 (t, 1H, J ) 7.2 Hz),
7.44 (d, 1H, J ) 8.0 Hz), 7.28 (d, 1H, J ) 7.6 Hz), 7.12 (t, 1H,
JO0508043
J. Org. Chem, Vol. 70, No. 16, 2005 6345