Microwave-assisted concise total syntheses of quinazolinobenzodiazepine alkaloids

Article abstract of DOI:10.1021/jo051876x

One-pot total syntheses of the quinazolinobenzodiazepine alkaloids sclerotigenin (1), (±)-circumdatin F (2), and (±)-asperlicin C (3) via novel microwave-assisted domino reactions were achieved in 55%, 32%, and 20% yields, respectively, from commercially

Full text of DOI:10.1021/jo051876x

Microwave-Assisted Concise Total Syntheses of
Quinazolinobenzodiazepine Alkaloids
Ji-Feng Liu,* Mira Kaselj, Yuko Isome, Jennifer Chapnick, Bailin Zhang, Grace Bi,
Daniel Yohannes, Libing Yu, and Carmen M. Baldino
ArQule, Inc., Division of Chemical Technologies, 19 Presidential Way, Woburn, Massachusetts 01801
jliu@arqule.com
Received September 7, 2005
One-pot total syntheses of the quinazolinobenzodiazepine alkaloids sclerotigenin (1), (()-circumdatin
F (2), and (()-asperlicin C (3) via novel microwave-assisted domino reactions were achieved in
55%, 32%, and 20% yields, respectively, from commercially available starting materials. A two-
step total synthesis of (()-benzomalvin A (4) was accomplished with an overall yield of 16%.
Additionally, analogues of circumdatin E were synthesized via the three-component one-pot
sequential reactions promoted by microwave irradiation. Finally, a two-step formal total synthesis
of (()-asperlicin E (5) was also realized by using this microwave-assisted protocol.
Introduction
A wide variety of quinazolinobenzodiazepine alkaloid
natural products have been reported in recent years
(Figure 1).1 Circumdatins A-G were obtained from a
terrestrial isolate of the fungus Aspergillus ochraceus and
are suggested to be suitable chemotaxonomic markers for
this species.2 Sclerotigenin (1), an antiinsectant, was
isolated from organic extracts of sclerotia of Penicillium
sclerotigenum (NRRL 3461).3 Asperlicin C (3) and asper-
licin E (5), of the asperlicin family of CCK antagonists,
were isolated from the fermentation broths produced by
Aspergillus alliaceus.4 Benzomalvin A (4) was isolated
(1) For recent reviews on quinazoline alkaloids, see: (a) Michael,
J. P. Nat. Prod. Rep. 2004, 21, 650-668. (b) Johne, S. Rodd’s Chemistry
of Carbon Compounds, Supplements to the 2nd ed.; Ansell, M. F., Ed.;
Elsevier: Amsterdam, The Netherlands, 1995; Vol. IV I/J, pp 223-
240.
(2) (a) Dai, J.-R.; Carte, B. K.; Sidebottom, P. J.; Yew, A. L.; Ng,
S.-W.; Huang, Y.; Butler, M. S. J. Nat. Prod. 2001, 64, 125-126. (b)
Rahbæk, L.; Breinholt, J.; Frisvad, J. C.; Christophersen, C. J. Org.
Chem. 1999, 64, 1689-1692. (c) Rahbæk, L.; Breinholt, J. J. Nat. Prod.
1999, 62, 904-905.
(3) Joshi, B. K.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Nat.
Prod. 1999, 62, 650-652.
(4) Goetz, M. A.; Monaghan, R. L.; Chang, R. S. L.; Ondeyka, J.;
Chen, T. B.; Lotti, V. J. J. Antibiot. 1988, 41, 875-877.
FIGURE 1. Structures of various quinazolinobenzodiazepine
alkaloids.
from a fungus culture of Penicillium sp and showed
inhibitory activity against substance P at neurokinin
NK1 receptor in the guinea pig, rat, and human.5
There have been three general methodologies reported
for the total syntheses of these natural products. Snider,
(5) Sun, H. H.; Barrow, C. J.; Sedlock, D. M.; Gillum, A. M.; Cooper,
R. J. Antibiot. 1994, 47, 515-522.
10.1021/jo051876x CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/03/2005
10488
J. Org. Chem. 2005, 70, 10488-10493

Total Syntheses of Quinazolinobenzodiazepine Alkaloids
a novel domino process15 for the synthesis of quinazoli-
nobenzodiazepine alkaloids including sclerotigenin (1),
(()-circumdatin F (2), and (()-asperlicin C (3). The new
method sets a new standard for the synthesis of these
quinazolinobenzodiazepine alkaloids as it uses only one
reagent and one protecting group for the entire synthesis
from readily available anthranilic acids and Boc-amino
acids with only one step. With this new concise method,
we have realized a two-step total synthesis of (()-
benzomalvin A (4). Finally, we also detail herein a concise
synthesis of two differentially substituted analogues of
circumdatin E (6) via one-pot reactions.16
SCHEME 1. One-Pot Syntheses of
2,3-Disubstituted Quinazolin-4-ones and
Pyrazino[2,1-b]quinazoline-3,6-diones
Results and Discussion
Attempts for Three-Component One-Pot Sequen-
tial Synthesis of 1. Initially, we envisioned that our
three-component one-pot, sequential, synthetic strategy12
for the synthesis of the pyrazino[2,1-b]quinazoline-3,6-
dione core could be useful for the synthesis of quinazoli-
nobenzodiazepines. However, instead of creating two
fused six-membered rings, we sought a six-membered
ring fused to a seven-membered ring via similar one-pot
MAOS (microwave-assisted organic synthesis).17 There-
fore, we chose sclerotigenin (1), the simplest alkaloid of
this type, as a synthetic target on which to test our
design. The total synthesis of 1 was achieved via a three-
component one-pot reaction with 60% yield (Scheme 2)
by coupling anthranilic acid (7a) with N-Boc-glycine (9a)
in the presence of triphenyl phosphite (P(OPh)3) in
pyridine under microwave irradiation at 150 °C for 10
min, followed by the addition of methyl anthranilate
(12a) and microwave irradiation at 250 °C for 15 min.18
It is noteworthy that although a homo-coupling-dehydra-
tion pathway to form byproducts such as 13 and 14 was
possible, in practice, we observed that the formation of
desired 1 was dominant, while the presence of byproducts
was in fact negligible.19 This may be attributed to the
coupling reaction of anthranilic acid 7a with N-Boc amino
acid 9a being faster than the homo-coupling reaction of
anthranilic acid 7a under the reaction conditions.
Thomas, and Eguchi respectively reported the synthesis
of sclerotigenin,6a,7 circumdatin F,6a asperlicin C,6b and
benzomalvin A8 via an aza-Wittig protocol. Bergman
reported the synthesis of both circumdatin C and F with
a Ganesan-Mazurkiewicz cyclization to form an imi-
nobenzoxazine intermediate as a key step.9 In addi-
tion, Bock completed the first total syntheses of asper-
licin C and asperlicin E featuring a regioselective annu-
lation of benzodiazepinedione with anthranilic acid for
both syntheses.10 All of these methodologies required
multiple synthetic steps that proceed in low to moderate
yields.
We recently reported an efficient microwave-assisted
one-pot methodology for the synthesis of various 2,3-
disubstituted quinazolin-4-ones 8 from commercially
available starting materials.11 On the basis of this
approach, we achieved a one-pot total synthesis of
pyrazino[2,1-b]quinazoline-3,6-dione cores and corre-
sponding natural products represented by 10 (Scheme
1).12,13
To further extend the application of our new methodol-
ogy, we investigated the total syntheses of quinazoli-
nobenzodiazepine alkaloids, another important class in
the quinazolinone alkaloid family.14 Herein, we describe
Plan of the Modified Synthetic Route. The impor-
tant observation of the dominance of Path B in Scheme
2 drove us to redesign the synthetic route and further
simplify what was operationally a sequential process by
(6) (a) Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57, 3301-
3307. (b) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998,
120, 6417-6418.
(7) Grieder, A.; Thomas, A. W. Synthesis 2003, 1707-1711.
(8) Sugimori, T.; Okawa, T.; Eguchi, S.; Kakehi, A.; Yashima, E.;
Okamoto, Y. Tetrahedron 1998, 54, 7997-8008.
(9) Witt, A.; Bergman, J. J. Org. Chem. 2001, 66, 2784-2788.
(10) Bock, M. G.; DiPardo, R. M.; Pitzenberger, S. M.; Homnick, C.
F.; Springer, S. M.; Freidinger, R. M. J. Org. Chem. 1987, 52, 1646-
4647.
(11) Liu, J.-F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.;
McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241-1244.
(12) Liu, J.-F.; Ye, P.; Zhang, B.-L.; Bi, G.; Sargent, K.; Yu, L.;
Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70, 6339-6345.
(13) For recent applications of microwave technology in natural
product synthesis, see: (a) Baxendale, I. R.; Ley, S. V.; Piutti, C. Angew.
Chem., Int. Ed. 2002, 41, 2194-2197. (b) Kang, Y.; Mei, Y.; Du, Y.;
Jin, Z. Org. Lett. 2003, 5, 4481-4484. (c) Grainger, R. S.; Patel, A.
Chem. Commun. 2003, 1072-1073 (d) Raheem, I. T.; Goodman, S. N.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706-707. (e) Baran, P.
S.; O’Malley, D. P.; Zografos, A. L. Angew. Chem., Int. Ed. 2004, 43,
2674-2677. (f) Hughes, R. A.; Thompson, S. P.; Alcaraz, L.; Moody, C.
J. Chem. Commun. 2004, 946-948. (g) Wolkenberg, S. E.; Wisnoski,
D. D.; Leister, W. H.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett.
2004, 6, 1453-1456. (h) Le´pine, R.; Zhu, J. Org. Lett. 2005, 7, 2981-
2984.
(14) Our one-pot microwave methodology has been applied success-
fully in the total syntheses of pyrrolo[2,1-b]quinazoline alkaloids and
their derivatives; see: Liu, J.-F.; Ye, P.; Sprague, K.; Sargent, K.;
Yohannes, D.; Baldino, C. M.; Wilson, C. J.; Ng, S.-C. Org. Lett. 2005,
7, 3363-3366.
(15) According to Tietze, a “Domino reaction is a process involving
two or more bond forming transformations which takes place under
the same reaction conditions without adding additional reagents and
catalysts, and in which the subsequent reactions result as a conse-
quence of the functionality formed in the previous step.” See: (a) Tietze,
L. F. Chem. Rev. 1996, 96, 115-136. (b) Tietze, L. F.; Haunert, F. In
Stimulating Concepts in Chemistry; Shibasaki, M., Stoddart, J. F.,
Vo¨gtle, F., Eds.; Wiley-VCH: Weinheim, Germany, 2000.
(16) For multicomponent reactions, see: (a) Multicomponent Reca-
tions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, Germany,
2005.
(17) For a recent review of microwave-assisted organic synthesis
(MAOS), see: (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250-
6285. (b) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahe-
dron 2001, 57, 9225-9283. (c) Perreux, L.; Loupy, A. Tetrahedron 2001,
57, 9199-9223.
(18) It was found that both triphenyl phosphite and pyridine are
essential for dehydration-cyclization.
(19) The reactions were monitored by LC-MS.
J. Org. Chem, Vol. 70, No. 25, 2005 10489

Liu et al.
SCHEME 2. Initial Attempts for the One-Pot
Sequential Synthesis of 1a
SCHEME 3. One-Step Total Syntheses of 1, (()-(2),
and (()-(3) and Synthesis of (()-(15)a
a Reagents and conditions: for 1, 2, 3, and 15, mixture of 7a
(2.0 equiv), the corresponding 9a-d (1.0 equiv), and P(OPh)3 (1.2
equiv) in pyridine, microwave heating, 230 °C, 20 min.
higher temperature and longer reaction time) required
to drive the reaction to completion.12 The success of the
synthesis of 1 via the domino process encouraged us to
pursue the syntheses of (()-(2), (()-(3), and (()-15 (a
precursor of 4) employing the same strategy.22 As ex-
pected, under the same reaction conditions used for the
synthesis of 1, reaction of anthranilic acid (7a, 2.0 equiv)
with the corresponding racemic N-Boc amino acids 9b,
9c, and 9d (1.0 equiv) provided (()-(2), (()-(3), and
(()-15 in yields of 32%, 20%, and 23%, respectively.23
Synthesis of (()-Asperlicin E (5) and (()-Ben-
zomalvin A. Given that asperlicin C (3) has been
described as a precursor of asperlicin E (5) in Bock’s total
synthesis,10 we have, with the achievement of the one-
step synthesis of (()-asperlicin C (3), completed the
formal total synthesis of (()-asperlicin E (5) in only two
steps from commercially available starting materials
(Scheme 4). Furthermore, methylation of (()-15 with MeI
in the presence of LiHMDS allowed us to complete the
total synthesis of (()-benzomalvin A (4) in two steps with
an overall yield of 16%.24,25
The conformational dynamic behavior of benzomalvin
A (4) has been extensively investigated by Sun26 and
Eguchi.8 Benzomalvin A (4), despite being separable from
the other conformer (benzomalvin D) on the HPLC, can
isomerize and approach a 4:1 (A:D) ratio at room tem-
perature in hours (Figure 3). The N-Me amide in 4 was
claimed to be responsible for this equilibrium behavior.8,25
However, we observed that (()-15, the precursor of 4
having amide N-H, also exists as two conformers. These
two conformers could not remain conformationally pure
even after separation by HPLC due to the lower rota-
tional energy barrier of amide N-H compared to amide
N-Me. The 3:1 conformer ratio as determined by 1H
NMR immediately after HPLC separation came to equi-
librium (in CDCl3) as a 1.5:1 mixture at room tempera-
a Reagents and conditions: 7a (1.0 equiv), 9a (1.0 equiv), and
P(OPh)3 (1.2 equiv), pyridine, microwave heating, 150 °C, 10 min;
then 12a (1.0 equiv), microwave heating, 250 °C, 15 min.
FIGURE 2. Retrosynthetic strategy for the “symmetric”
quinazolinobenzodiazepine alkaloids via domino reactions.
carrying out a series of transformations via a domino
process to make the “symmetric” quinazolinobenzodiaz-
epine alkaloids (R3 on both phenyl rings).20 The modified
retrosynthetic strategy is depicted in Figure 2. We
postulated that due to the differential reactivities of the
coupling partners, the reaction sequence would be I, II,
and III to yield the desired products, rather than II, I,
then III to form the byproducts, for example.21 This new
design allows access to the natural products 1, 2, 3, and
other “symmetric” quinazolinobenzodiazepines in a one-
step operation.
One-Step Total Syntheses of 1, (()-(2), and
(()-(3) and Synthesis of (()-(15). Toward this end, we
employed the following modified reaction process aimed
at achieving an operationally simplified synthesis (Scheme
3). Reaction of anthranilic acid (7a, 2.0 equiv) with N-Boc-
glycine 9a (1.0 equiv) in the presence of P(OPh)3 in
pyridine under microwave irradiation at 230 °C for 20
min yielded the desired product 1 in a yield of 55%. When
compared to the six-membered ring, the seven-membered
ring benzodiazepine analogue is much more challenging
to close owing to the stronger reaction conditions (i.e.,
(22) Since we encountered enantiomeric erosion in the synthesis of
quinazolinone alkaloids with the pyrazino[2,1-b]quinazoline-3,6-dione
core (ref 12), we elected to perform the syntheses of the racemates of
the quinazolinobenzodiazepine alkaloids in the work described herein.
(23) Although the yields are relatively low, they are still comparable
or better than that of reported multistep syntheses (refs 6-10). The
low yields may be attributed to the inefficient formation of the fused
seven-membered rings, which resulted in the decomposion of the
intermediates and generation of side products.
(20) “Symmetric” quinazolinobenzodiazepine alkaloids here refer to
alkaloids originating from two identical 2-aminobenzoic acids, while
“nonsymmetric” quinazolinobenzodiazepine alkaloids here refer to
alkaloids originating from the two different 2-aminobenzoic acids.
(21) The domino process requires 2 equiv of anthranilic acids 7 and
1 equiv of N-Boc amino acids 9 in the reaction mixture.
(24) The first total synthesis of 4 was accomplished in six steps from
9d, see ref 8.
(25) The O-methylation product was also isolated in 12% yield in
an alkylation step, see the Experimental Section.
(26) Sun, H. H.; Barrow, C. J.; Cooper, R. J. Nat. Prod. 1995, 58,
1575-1580.
10490 J. Org. Chem., Vol. 70, No. 25, 2005

Total Syntheses of Quinazolinobenzodiazepine Alkaloids
SCHEME 4. Formal Total Syntheisis of (()-(5) and
Total Synthesis of (()-(4)a
irradiation at 150 °C for 10 min, followed by the addition
of methyl anthranilate (12a) and further microwave
irradiation at 230 °C for 15 min, afforded 16 and 17,
analogues of circumdatin E (6), in yields of 34% and 29%,
respectively.23
Summary
Microwave-assisted one-pot total syntheses of the
quinazolinobenzodiazepine alkaloids sclerotigenin (1),
(()-circumdatin F (2), and (()-asperlicin C (3) have been
achieved via novel domino reactions. Efficient two-step
total synthesis of (()-benzomalvin A (4) and formal total
synthesis of (()-asperlicin E (5) have been completed.
Analogues of circumdatin E possessing differentially
substituted aryl rings have also been prepared via the
three-component one-pot sequential reactions promoted
by microwave irradiation. The one-pot synthetic ap-
proaches developed herein to access both “symmetric” and
“nonsymmetric” quinazolinobenzodiazepine alkaloids em-
ploy commercially available inputs and only one reagent,
one protecting group, and one solvent. These combined
advantages offer great opportunities to rapidly synthesize
quinazolinone natural product-templated libraries for
phenotypic screening as well as other screening para-
digms. Further application of this methodology to the
total syntheses of other scaffolds as well as to the
construction of natural product-templated screening
libraries will be reported in due course.
a Reagents and conditions: (i) 15 (1.0 equiv), LiHMDS (2.5
equiv), THF, -78 °C, 15 min, and 0 °C, then MeI (1.5 equiv), rt,
30 min.
Experimental Section
Sclerotigenin (1): (a) Three-Component One-Pot Pro-
cedure (Scheme 2). To a conical-bottomed Smith Process vial
were added anthranilic acid (7a) (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 on a Biotage Smith
Synthesizer for 10 min at 150 °C. After the mixture was cooled
to room temperature, methyl anthranilate (12a) (30 mg, 200
µmol) was added and the resulting mixture was heated in the
microwave at 250 °C for 15 min. The reaction mixture was
then concentrated in vacuo, and the residue was purified by
preparative HPLC (ProntoSIL 120-10-C18 column (50 × 20
mm2) with a flow rate at 44 mL/min utilizing an acetonitrile/
water mobile phase) to afford 1 as a light yellow solid (33 mg,
60%); mp 270-273 °C (lit.6a mp 277-280 °C; lit.3 mp 235-
FIGURE 3. Conformational isomers of 4 and 15.
SCHEME 5. Three-Component One-Pot Syntheses
of Analogues of Circumdatin E (6)a
1
238 °C); H NMR (400 MHz) δ 8.32 (d, J ) 8.4 Hz, 1H), 7.97
a Reagents and conditions: mixture of corresponding 7 (1.0
equiv), 9e (1.0 equiv), and P(OPh)3 (1.2 equiv), pyridine, microwave
heating, 150 °C, 10 min; then 12a (1.0 equiv), microwave heating,
230 °C, 15 min.
(d, J ) 8.4 Hz, 1H), 7.81 (t, J ) 8.6 Hz, 1H), 7.69 (d, J ) 8.0
Hz, 1H), 7.67-7.61 (m, 2H), 7.60-7.47 (m, 2H), 7.23 (br s, NH),
4.27 (dd, J ) 15.2, 6.4 Hz, 1H); 13C NMR (100 MHz) δ 168.0,
161.4, 153.5, 146.2, 135.1, 133.4, 131.5, 130.4, 129.7, 129.1,
128.1, 127.9, 127.6, 127.3, 121.5 47.1; MS m/z 278.20 (M +
H); HRMS calcd for (C16H11N3O2 + Na) 300.0743, found
300.0743.
(b) One-Step Procedure (Scheme 3). To a conical-
bottomed Smith Process vial were added anthranilic acid (7a)
(56 mg, 400 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 on a Biotage Smith Synthesizer for 20 min at 230
°C. The reaction mixture was then concentrated in vacuo, and
the residue was purified by preparative HPLC (ProntoSIL 120-
10-C18 column (50 × 20 mm2) with a flow rate at 44 mL/min
utilizing an acetonitrile/water mobile phase) to afford 1 as a
light yellow solid (30.5 mg, 55%) with identical spectral data
as the above procedure.
ture within several hours. Synthesis of (()-benzomalvin
A (4) from this conformer mixture of (()-15 provided the
same ratio as the two conformers of 4 that was reported
previously.8
Three-Component One-Pot Sequential Synthesis
of Circumdatin E Analogues. While the domino ap-
proach is applicable to the syntheses of the “symmetric”
quinazolinobenzodiazepine alkaloids, the three-compo-
nent one-pot sequential synthesis strategy was used for
the synthesis of the “nonsymmetric” quinazolinobenzo-
diazepine alkaloids (different substituents on the two
phenyl rings).20 As shown in Scheme 5, the reaction of
anthranilic acids 7b and 7c with N-Boc-proline (9e) in
the presence of P(OPh)3 in pyridine under microwave
Circumdatin F (2). To a conical-bottomed Smith Process
vial were added anthranilic acid (7a) (56 mg, 400 µmol), N-Boc-
J. Org. Chem, Vol. 70, No. 25, 2005 10491

Liu et al.
alanine (9b) (38 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 on a Biotage Smith
Synthesizer for 20 min at 230 °C. The reaction mixture was
then concentrated in vacuo, and the residue was purified by
preparative HPLC (ProntoSIL 120-10-C18 column (50 × 20
mm2) with a flow rate at 44 mL/min utilizing an acetonitrile/
water mobile phase) to afford (()-2 as light yellow crystals
mixture was stirred at -78 °C for 15 min and then stirred at
0 °C for another 15 min. The mixture was cooled to -78 °C,
and MeI (20 µL, 300 µmol) was then added. After being stirred
at room temperature for 2 h, the reaction mixture was
quenched with two drops of saturated aqueous NH4Cl, and
then concentrated in vacuo. The residue was purified by
preparative TLC (hexane/ethyl acetate ) 1/1) to afford 4 as a
light yellow solid (53 mg, 70%); mp 97-100 °C (lit.8 mp 98-
1
(19 mg, 32%); mp 245-247 °C (lit.6a mp 249.2-250.1 °C); H
1
101 °C); H NMR (400 MHz) δ 8.32 (dd, J ) 7.8, 1.0 Hz, 1H),
NMR (400 MHz) δ 8.33 (d, J ) 8.0 Hz, 1H), 7.98 (d, J ) 7.6
Hz, 1H), 7.82 (t, J ) 8.0 Hz, 1H), 7.50 (d, J ) 8.0 Hz, 1H),
7.68-7.52 (m, 4H), 6.32 (br s, NH), 4.42 (dq, J ) 6.6, 6.6 Hz,
1H), 1.73 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz) δ 167.5,
161.6, 154.9, 146.1, 134.9, 133.5, 131.4, 130.5, 129.9, 129.0,
128.4, 128.7, 127.6, 127.5, 121.5, 49.8, 15.5; MS m/z 292.14
(M + H); HRMS calcd for (C17H13N3O2 + Na) 314.0900, found
314.0901.
7.94 (dd, J ) 7.4, 1.2 Hz, 1H), 7.84-7.81 (m, 2H), 7.65-7.50
(m, 4H), 7.30-7.16 (m, 5H), 4.88 (dd, J ) 8.0, 7.0 Hz, 1H),
3.80 (dd, J ) 14.6, 8.0 Hz, 1H), 3.42 (dd, J ) 14.6, 7.0 Hz,
1H), 3.10 (s, 3H); 13C NMR (100 MHz) δ 167.3, 161.2, 151.8,
145.9, 136.6, 134.8, 132.9, 131.4, 130.9, 129.9, 129.0, 128.9,
128.8, 128.7, 127.7, 127.5, 126.9, 121.7, 58.2, 33.1, 27.9; MS
m/z 382.22 (M + H); HRMS calcd for (C24H19N3O2 + Na)
404.1369, found 404.1366.
Asperlicin C (3). To a conical-bottomed Smith Process vial
were added anthranilic acid (7a) (56 mg, 400 µmol), 2-tert-
butoxycarbonylamino-3-(1H-indol-3-yl)propionic acid (9c) (61
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 on a Biotage Smith Synthesizer
for 20 min at 230 °C. The reaction mixture was then concen-
trated in vacuo, and the residue was purified by preparative
HPLC (ProntoSIL 120-10-C18 column (50 × 20 mm2) with a
flow rate at 44 mL/min utilizing an acetonitrile/water mobile
phase) to afford (()-3 as a light yellow solid after being dried
with a freeze dryer (16.5 mg, 20%); 1H NMR of major con-
former (400 MHz, DMSO-d6) δ 10.84 (br s, 1H), 8.87 (d,
J ) 6.4 Hz, 1H), 8.20 (d, J ) 8.4 Hz, 1H), 7.90 (t, J ) 8.0 Hz,
1H), 7.84 (d, J ) 8.0 Hz, 1H), 7.68-7.45 (m, 6H), 7.35-7.25
(m, 2H), 7.01 (t, J ) 8 Hz, 1H), 6.89 (t, J ) 8 Hz, 1H), 4.37
(m, 1H), 3.61 (dd, J ) 15.2, 5.2 Hz, 1H), 3.40-3.30 (m, 1H);
The O-methylation product was also isolated as a light
1
yellow solid (9 mg, 12%); H NMR (400 MHz) δ 8.23 (dd, J )
7.8, 0.8 Hz, 1H), 8.12 (dd, J ) 8.0, 1.6 Hz, 1H), 7.78-7.68 (m,
4H), 7.51-7.44 (m, 3H), 7.35 (dd, J ) 8.0, 1.0 Hz, 1H), 7.20-
7.10 (m, 2H), 6.94 (dd, J ) 8.0, 1.6 Hz, 1H), 6.80 (dd, J ) 10.0,
8.0 Hz, 1H), 3.39 (s, 3H), 2.85 (dd, J ) 14.0, 8.4 Hz, 1H), 2.60
(dd, J ) 14.0, 10.0 Hz, 1H); 13C NMR (100 MHz) δ 168.3, 160.8,
151.3, 147.3, 140.7, 134.8, 134.6, 132.5, 131.9, 128.7, 128.6,
127.54, 127.51, 127.3, 127.2, 126.2, 121.4, 57.3, 36.2, 34.5; MS
m/z 382.20 (M + H); HRMS calcd for (C24H19N3O2 + Na)
404.1369, found 404.1369.
13C NMR of major conformer (100 MHz, DMSO-d6)
δ
161.94, 161.23, 156.27, 146.17, 136.2, 135.45, 133.18, 131.30,
130.09, 129.0, 127.8, 127.5, 127.27, 127.11, 124.72, 121.19,
121.10, 118.56, 111.62, 109.93. 54.75, 24.55; MS m/z 407.20
(M + H); HRMS calcd for (C25H18N4O2 + Na) 429.1322, found
429.1328.
Analogue of Circumdatin E, 16. To a conical-bottomed
Smith Process vial were added 2-amino-4-fluorobenzoic acid
(7b) (31 mg, 200 µmol), N-Boc-proline (9e) (43 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 on Biotage Smith Synthesizer for 10 min at 150
°C. After the mixture cooled to room temperature, methyl
anthranilate (12a) (30 mg, 200 µmol) was added and the
resulting mixture was heated in the microwave at 230 °C for
15 min. The reaction mixture was concentrated in a Savant,
and the residue was separated by preparative HPLC (Pron-
toSIL 120-10-C18 column (50 × 20 mm2) with a flow rate at
44 mL/min utilizing an acetonitrile/water mobile phase and
0.1% trifluoroacetic acid as a modifier) to afford 16 as a light
6,7-Dihydro-7-benzylquinazolino[3,2-a][1,4]-benzodi-
azepine-5,13-dione ((()-15). To a conical-bottomed Smith
Process vial were added anthranilic acid (7a) (56 mg, 400
µmol), 2-tert-butoxycarbonylamino-3-phenylpropionic acid (9d)
(53 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 on a Biotage Smith Synthesizer
for 20 min at 230 °C. Using this procedure, two copies of the
reaction were run, the combined reaction mixture was then
concentrated in vacuo, and the residue was purified by
preparative HPLC (ProntoSIL 120-10-C18 column (50 × 20
mm2) with a flow rate at 44 mL/min utilizing an acetonitrile/
water mobile phase and 0.1% trifluoroacetic acid as a modifier)
to afford a conformer mixture (3:1 soon after the HPLC
separation; 1.5:1 when NMR was recorded) of (()-15 as a light
yellow solid TFA salt (44 mg, 23%); 1H NMR (400 MHz) δ 8.32
(d, J ) 8.0 Hz, 0.6H), 8.27 (d, J ) 7.2 Hz, 0.4H), 8.23 (d, J )
8.0 Hz, 0.4H), 7.90 (d, J ) 7.6 Hz, 0.6H), 7.84-7.71 (m, 1.8H),
7.66-7.43 (m, 4.2H), 7.30-7.10 (m, 4.4H), 6.99 (d, J ) 7.8 Hz,
0.6H), 6.76 (t, J ) 9.2 Hz, 0.4H), 6.42 (d, J ) 6.0 Hz, NH),
4.48 (q, J ) 8.0 Hz, 0.6H), 3.76 (dd, J ) 14.8, 6.0 Hz, 0.6H),
3.28 (dd, J ) 14.8, 8.0 Hz, 0.6H), 3.03 (dd, J ) 14.0, 8.0 Hz,
0.4H), 2.80 (dd, J ) 14.0, 9.2 Hz, 0.4H); 13C NMR (100 MHz)
δ 169.7, 167.5, 161.5, 161.2, 154.1, 150.9, 147.2, 146.1, 136.2,
135.2, 134.9, 134.7, 134.5, 133.2, 132.7, 132.1, 131.4, 130.3,
130.0, 129.6, 129.4, 129.0, 128.8, 128.6, 127.8, 127.7, 127.6,
127.5, 127.4, 127.3, 127.2, 127.0, 125.8, 121.7, 121.5, 120.6,
56.6, 55.2, 35.5, 34.1; MS m/z 368.16 (M + H); HRMS calcd
for (C23H17N3O2 + Na) 390.1213, found 390.1212.
1
yellow solid TFA salt (30.5 mg, 34%); H NMR (400 MHz) δ
2.24-2.32 (m, 2H), 2.48 (s, 3H), 3.16 (t, J ) 7.8 Hz, 2H), 4.20
(t, J ) 7.2 Hz, 2H), 7.53 (br s, 2H), 8.06 (s, 1H); 13C NMR (100
MHz) δ 19.8, 21.4, 32.6, 46.7, 120.4, 126.0, 126.8, 135.8, 136.5,
147.3, 158.8, 161.2; MS m/z 336.18 (M + H); HRMS calcd for
(C19H14FN3O2 + H) 336.1143, found 336.1143.
Analogue of Circumdatin E, 17. To a conical-bottomed
Smith Process vial were added 2-amino-5-methylbenzoic acid
(7c) (30 mg, 200 µmol), N-Boc-proline (9e) (43 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 on a Biotage Smith Synthesizer for 10 min at 150
°C. After the mixture cooled to room temperature, methyl
anthranilate (12a) (30 mg, 200 µmol) was added and the
resulting mixture was heated in the microwave at 230 °C for
15 min. The reaction mixture was concentrated in a Savant,
and the residue was separated by preparative HPLC (Pron-
toSIL 120-10-C18 column (50 × 20 mm2) with a flow rate at
44 mL/min utilizing an acetonitrile/water mobile phase and
Benzomalvin A (4). To a solution of 15 (96 mg, 200 µmol,
TFA salt) in THF (2 mL) at -78 °C under N2 atmosphere was
added LiHMDS (1 M solution in THF, 0.5 mL). The reaction
10492 J. Org. Chem., Vol. 70, No. 25, 2005

Total Syntheses of Quinazolinobenzodiazepine Alkaloids
0.1% trifluoroacetic acid as a modifier) to afford 17 as a light
yellow solid TFA salt (26 mg, 29%); 1H NMR (400 MHz,
DMSO-d6) δ 2.19-2.26 (m, 1H), 2.54-2.64 (m, 1H), 3.04-3.20
(m, 2H), 5.03 (dd, J ) 10, 2.6 Hz, 1H), 7.51 (td, J ) 7.6, 1.1
Hz, 1H), 7.64 (d, J ) 8.0 Hz, 1H), 7.82 (td, J ) 8.0, 1.2 Hz,
1H), 8.11 (dd, J ) 8.2, 1.4 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6) δ 24.2, 31.3, 59.8, 120.7, 126.5, 127.0, 127.5, 135.2, 149.7,
160.3, 160.6, 172.1; MS m/z 332.18 (M + H); HRMS calcd for
(C20H17N3O2 + H) 332.1394, found 332.1395.
Acknowledgment. The authors thank Dr. Jeffrey
Link and Mr. Ted Manley for technical microwave
support.
1
Supporting Information Available: Copies of H NMR
and 13C NMR spectra for compounds 1-4 and 15-17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO051876X
J. Org. Chem, Vol. 70, No. 25, 2005 10493