Fluorous synthesis of substituted sclerotigenin library

Article abstract of DOI:10.1021/cc9001636

A fluorous linker-assisted synthetic protocol has been developed for preparation of sclerotigenin-type benzodiazepine-quinazolinone library containing 144 analogues. Amide coupling of fluorous trimethoxybenzyl (TMB)-protected amino esters with anthranilic

Full text of DOI:10.1021/cc9001636

J. Comb. Chem. 2010, 12, 125–128
125
Fluorous Synthesis of Substituted Sclerotigenin Library
Yimin Lu,† Tadamichi Nagashima,† Bruhaspathy Miriyala,† Joanne Conde,† and
Wei Zhang*,†,‡
Fluorous Technologies, Inc., 970 William Pitt Way, Pittsburgh, PennsylVania 15238, and Department of
Chemistry, UniVersity of Massachusetts Boston, 100 Morrissey BouleVard, Boston, Massachusetts 02125
ReceiVed October 20, 2009
A fluorous linker-assisted synthetic protocol has been developed for preparation of sclerotigenin-type
benzodiazepine-quinazolinone library containing 144 analogues. Amide coupling of fluorous trimethoxybenzyl
(TMB)-protected amino esters with anthranilic acids followed by base-promoted cyclizations afforded
4-benzodiazepine-2,5-diones. Further derivatization of benzodiazepinediones by reacting with azidobenzoyl
chlorides, cyclization, and fluorous linker cleavage afforded the desired compound library. The reaction
intermediates were purified by fluorous solid-phase extraction (F-SPE) and final products were further purified
by prep-HPLC.
Introduction
acids 2, and nine 2-azidobenzoyl chlorides 5. All the reaction
intermediates were purified by F-SPE. The final products
were treated with F-SPE, then followed by prep-HPLC to
ensure >90% purity for biological screening.
Natural alkaloid sclerotigenin was isolated from the
sclerotia of Penicillium sclerotigenum.1 It is the simplest
compound in the family of benzodiazepine-quinazolinones.
Sclerotigenin and other members in the family, such as
circumdatins A-G isolated from the terrestrial fungus As-
pergillus ochraceus,2a benzomalvins A-C isolated from the
fungus Penicillium sp,2b and asperlicin derived from the
fungus Aspergillus alliaceus,2c possess a wide range of
biological activities (Scheme 1).3 Sclerotigenin is an attrac-
tive library scaffold for production of substituted analogues
for biological screening.
1,4-Benzodiazepine-2,5-dione is a privileged ring system
which can be found in numerous biological active com-
pounds.4 In the current project, 1,4-benzodiazepine-2,5-dione
is a key intermediate for the synthesis of benzodiazepine-
quinazolinone alkaloids. In our continuous effort of develop-
ing fluorous linker-facilitated synthesis of drug-like and
natural product analogues,5,6 we have introduced different
methods for the preparation of benzodiazepine-2,5-diones.7
Report here is the synthesis of benzodiazepinedione scaffold
using fluorous trimethoxybenzyl (TMB)-type linker to fa-
cilitate intermediate purification by fluorous solid-phase
extraction (F-SPE).8,9 A general synthetic route for library
synthesis is highlighted in Scheme 2. The synthesis started
with the coupling of fluorous TMB-protected amino esters
1 with anthranilic acids 2 to afford amides 3. Base-promoted
cyclizations of 3 yielded 4-benzodiazepine-2,5-diones 4.
N-Acylation of benzodiazepinediones with azidobenzoyl
chlorides 5 gave compounds 6. The reductions of the azido
group and subsequent cyclization afforded compounds 7.
Final products 8 were obtained by cleavage of the fluorous
linker. A library containing 144 compounds were prepared
from four F-TMB-protected amino esters 1, four anthranilic
Results and Discussion
A number of conventional solution-phase and solid-phase
synthetic protocols for benzodiazepines have been reported
in the literature.10 We modified the solid-phase method
developed by the Ellman group and used F-TMB-type linker
for fluorous synthesis.11 F-TMB-type linker was readily
prepared by the reaction of 4-hydroxy-2,6-dimethoxybenz-
aldehyde with 3-(perfluorooctyl)propyl iodide. F-TMB was
attached to four different amino esters by reductive amination
to produce compounds 1{1-4} (Scheme 3).
Four F-TMB-attached amino esters 1{1-4} in N-meth-
ylpyrrolidine (NMP) were reacted with four anthranilic acids
2{1-4} in the presence of 1-ethyl-3-(3′-dimethylaminopro-
pyl)carbodiimide (EDCI) to form sixteen amide coupling
products 3{R1,R2} (Scheme 4). The 1,4-benzodiazepine-2,5-
Scheme 1. Sclerotigenin-Type Benzodiazepine-
Quinazolinone Natural Products
* To whom correspondence should be addressed. wei2.zhang@umb.edu.
† Fluorous Technologies, Inc.
‡ University of Massachusetts Boston.
10.1021/cc9001636  2010 American Chemical Society
Published on Web 12/15/2009

126 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Lu et al.
Scheme 2. Proposed Synthetic Route for Sclerotigenin-Type Benzodiazepine-Quinazolinones
Table 1. Yields and Purities of Sixteen 1,4-Benzodiazepine-
Scheme 3. Synthesis of F-TMB and Attached Amino Esters
1{1-4}
2,5-diones 4{1-4,1-4}
entry
4{R1,R2}
yield
1
2
3
4
5
6
7
8
4{1,1}
4{1,2}
4{1,3}
4{1,4}
4{2,1}
4{2,2}
4{2,3}
4{2,4}
4{3,1}
4{3,2}
4{3,3}
4{3,4}
4{4,1}
4{4,2}
4{4,3}
4{4,4}
57%
69%
69%
44%
54%
59%
56%
60%
64%
42%
45%
55%
73%
88%
87%
86%
9
10
11
12
13
14
15
16
Scheme 4. Synthesis of 1,4-Benzodiazepine-2,5-dione
4{1-4,1-4}
Scheme 5. Synthesis of Substituted Sclerotigenin
8{1-4,1-4,1-9}
dione ring formation was accomplished by base-promoted
cyclization of 3 in heated tetrahydrofuran (THF). Sixteen
1,4-benzodiazepine-2,5-dione analogues 4{1-4,1-4} with
substitution variations at R1 and R2 were prepared with >90%
purity. The yields of the cyclization products after recrys-
tallization are listed in Table 1.
The next step of the library synthesis was the reactions of
16 1,4-benzodiazepine-2,5-dione analogues 4{1-4,1-4} with
9 different azidobenzoyl chlorides 5{1-9} to generate 144
N-acylated products 6{1-4,1-4,1-9} (Scheme 5). Compounds
4 in THF were treated with BuLi at -78 °C, warmed up to
room temperature, and then mixed with azidobenzoyl chlorides
5. MeOH was added to quench the reactions to give N-acylated
products 6. The resulting crude mixture was concentrated and
used for the next step without further purification. In the
cyclization step to form the core of sclerotigenin, compounds
6 in CH2Cl2 were treated with triphenylphosphine (TPP) at room
temperature for 3 h. The reaction mixtures were purified by
automatic F-SPE on the RapidTrace system.9b In this step, we
found reactions with R1 ) Me did not afford products 6{1-4}.
The last step of fluorous linker cleavage was accomplished by
the treatment of compounds 7 with 90:5:5 TFA/DMS/H2O at
room temperature for 3 days. The concentrated reaction mixtures
were purified by automatic F-SPE on the RapidTrace system
followed by prep-HPLC. Yields and purities of the final
products are listed in Table 2. After F-SPE the purity of the
final products were in the range of 50-70%. After prep-HPLC
separation only compounds have >90% purities were collected
and submitted for biological test.

Fluorous Synthesis of Substituted Sclerotigenin Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 127
Table 2. Yields [%] (Purity UV220 [%]) of Final Products
8{1-4,1-4,1-9}
RapidTrace SPE system was purchased from Caliper Life
Sciences. One drum vials were used for all the reactions.
Preparative HPLC were performed on a Waters Delta Prep
system. LC-MS spectra were obtained on an Agilent 1100
system. Genevac EZ-2 vacuum centrifuge was used for
solvent evaporation. Products purities were determined by
LC-MS with a C18 column.
(a) Products 8{1,1-4,1-9}
8{1,R2,R3}
2{1}
2{2}
2{3}
2{4}
5{1}
5{2}
5{3}
5{4}
5{5}
5{6}
5{7}
5{8}
5{9}
15 (92)
21 (92)
16 (93)
16 (92)
14 (92)
23 (91)
21 (92)
19 (93)
11 (9)
15 (90)
17 (92)
14 (93)
16 (92)
12 (93)
9 (92)
9 (91)
9 (93)
8 (92)
15 (90)
18 (92)
14 (92)
12 (91)
19 (92)
17 (93)
12 (93)
15 (93)
General Procedures for the Synthesis of F-TMB-
Attached Amino Esters 1{1-4}. To a solution of amino
ester hydrochloride (42 mmol), 2,6-dimethoxy-4-[3-(per-
fluorooctyl)propyloxy]benzaldehyde (40 mmol), N,N-diiso-
propylethylamine (40 mmol), and acetic acid (1 mL) in
CH2Cl2 (300 mL) was added 4 Å molecular sieves (3 g) at
25 °C. NaBH(OAc)3 (60 mmol) was added after 4 h, and
the reaction was quenched with water after an additional 3 h.
The CH2Cl2 layer was washed with aq. NH4Cl and brine.
After most of the solvent was removed using a rotary
evaporator, the residue was passed through a pad of silica
gel (50 mL). The product was eluted with hexanes-EtOAc
(1:1, 300 mL). The concentrated product was further
triturated with hexanes-Et2O to give the desired compound
11 (90)
14 (92)
18 (92)
15 (92)
(b) Products 8{2,1-4,1-9}
8{2,R2,R3}
2{1}
2{2}
2{3}
2{4}
5{1}
5{2}
5{3}
5{4}
5{5}
5{6}
5{7}
5{8}
5{9}
11 (95)
38 (98)
13 (97)
12 (95)
10 (98)
9 (98)
10 (98)
11 (98)
10 (95)
1
1. Analytical data for 1{1}: H NMR (270 MHz, CDCl3) δ
(c) Products 8{3,1-4,1-9}
6.08 (s, 2H), 4.02 (t, 2H, J ) 5.8 Hz), 3.78 (s, 6H), 3.59 (s,
3H), 3.26 (t, 1H, J ) 7.1 Hz), 2.45-2.00 (m, 5H), 1.82-1.35
(m, 3 H), 0.88 (d, 3H, J ) 6.5 Hz), 0.81 (d, 3H, J ) 6.4
Hz). 13C NMR (67.5 MHz, CDCl3) δ 176.4, 159.3, 108.9,
90.7, 66.3, 59.0, 55.5, 51.3, 42.8, 39.9, 28.2, 27.9, 27.5, 24.8,
22.6, 22.0, 20.5. LC-MS (ESI+) m/z 772 [M+1]+.
General Procedures for Amide Coupling to Synthesize
3{1-4,1-4}. To a solution of 1 (5.6 mmol) in N-methylpyr-
rolidine (30 mL), anthranilic acid (11 mmol) and EDCI-HCl
(11 mmol) were added as solids at 23 °C. The same amounts
of the acid and EDCI-HCl were added after 2 and 4 h. One
day after the final addition, the reaction mixture was diluted
with DMSO (400 mL) and loaded onto an F-SPE cartridge
(50 g). The non-fluorous components were eluted with
MeCN-H2O (1:1, 300 mL, and 4:1, 200 mL) and most of
the solvent was drained. The amide coupling product was
eluted with MeCN (400 mL). The MeCN fraction was
concentrated to give desired compounds, and product purities
was checked by LC-MS analysis. The crude products were
used for next step reactions without further purification.
8{ 3,R2,R3}
2{1}
2{2}
2{3}
2{4}
5{1}
5{2}
5{3}
5{4}
5{5}
5{6}
5{7}
5{8}
5{9}
11 (91)
18 (95)
15 (90)
13 (92)
23 (94)
20 (93)
18 (92)
11 (91)
16 (91)
27 (95)
17 (93)
24 (96)
23 (95)
22 (95)
29 (93)
18 (93)
17 (96)
14 (90)
22 (95)
5 (97)
23 (95)
18 (94)
24 (96)
21 (97)
19 (90)
13 (90)
15 (92)
19 (91)
18 (91)
22 (91)
15 (90)
15 (92)
(d) Products 8{4,1-4,1-9}
8{ 4,R2,R3}
2{1}
2{2}
2{3}
2{4}
5{1}
5{2}
5{3}
5{4}
5{5}
5{6}
5{7}
5{8}
5{9}
16 (91)
10 (94)
11 (94)
11 (91)
18 (91)
21 (93)
11 (92)
5 (93)
14 (94)
9 (92)
14 (91)
10 (93)
12 (93)
11 (92)
16 (91)
18 (93)
11 (93)
11 (92)
16 (90)
10 (93)
15 (96)
10 (93)
16 (90)
14 (94)
14 (95)
15 (91)
19 (92)
14 (92)
8 (90)
14 (95)
9 (90)
11 (92)
Conclusions
General Procedures for Base-Promoted Cyclization
to Synthesize 4-Benzodiazepine-2,5-diones 4{1-,1-4}. A
solution of 3 (5 mmol) in THF was treated with a solution
of lithium acetanilide (0.33 M in THF, 30 mL). The mixture
was refluxed for 1 h. After cooling, AcOH (0.6 mL) was
added, and the solvent was removed in a rotary evaporator.
MeOH (30 mL) was added to the residue, and it was heated
until the solvent started to boil. The mixture was left at 25
°C for 1 d, and product 4 was obtained as white solid after
With the assistance of fluorous TMB linker and F-SPE
for intermediate purification and final product pre-purifica-
tion, a library containing 144 sclerotigenin analogues was
synthesized. Among them, 103 final products were obtained
with greater than 90% purity. Ninety-two compounds have
been submitted to NIH repository and are currently being
evaluated in several high-throughput screening programs.
Results on their biological activities can be found in
PubChem (http://pubchem.ncbi.nlm.nih.gov).
1
filtration. Analytical data for 4{1,2}: H NMR (270 MHz,
CDCl3) δ 9.55 (s, 1H), 7.99 (d, J ) 8.5 Hz, 1H), 7.16 (dd,
J ) 7.1, 1.9 Hz 1,), 6.90 (d, J ) 1.8 Hz, 1H), 6.09 (s, 2H),
5.23 (d, J ) 13.8 Hz, 1H), 4.56 (d, J ) 13.8 Hz, 1H),
4.15-3.85 (m, 3H), 3.75 (s, 6H), 2.45-2.00 (m, 4H),
1.60-1.45 (m, 1H), 1.35-1.15 (m, 2H), 0.80 (d, J ) 6.4
Hz, 3H), 0.73 (d, J ) 6.6 Hz, 3H). 13C NMR (67.5 Hz,
CDCl3) δ 173.5, 165.1, 160.6, 160.1, 137.7, 136.2, 133.3,
Experimental Section
General Information. All fluorous reagents and silica gel
(40-60 µm particle size) used in this project are available
from Fluorous Technologies, Inc.12 Other reagents and
solvents were obtained from commercial sources. The

128 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Lu et al.
125.5, 124.6, 119.4, 104.1, 90.6, 66.3, 59.5, 55.5, 42.0, 38.3,
27.9 (t, J ) 22 Hz), 25.2, 22.3, 22.1, 20.5. LC-MS (ESI +)
m/z 893 [M+1]+.
References and Notes
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General Procedures for N-Acylation to Synthesize
6{1-4}. Benzodiazopinone 4 (0.9 mmol) in THF (10 mL)
was cooled to -78 °C and BuLi (1.6M, 1.1 mL, 1.8 mmol)
was added dropwise. The reaction mixture was warmed to
25 °C and distributed to a row of 9 vials containing
azobenzoylchlorides 5{1-9} (0.4 mmol) in DCM (0.4 mL).
The vials were shaken at 25 °C for 3 h before MeOH (0.5
mL) was added to each vial. The reaction mixtures were left
to stand overnight and concentrated. LC-MS analysis indi-
cated that most reactions where R1 ) Me did not afford
products 6{1-4}. The crude products were used for next
step without further purification.
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General Procedures for Reduction and Cyclization to
Synthesize 7{1-4}. The crude intermediates 6{1-4} in
DCM (1 mL) were added TPP (0.4 mmol) in DCM (1 mL),
and the reaction mixtures were shaken at 25 °C for 3 h before
being concentrated. The residues were dissolved in DMF (0.7
mL) and purified by RapidTrace FSPE (2 g). The elution
sequence was as follows: loading (1 mL), rinsing with DMF/
H2O (9:1) (1 mL), eluting with DMF/H2O (9:1) 6 mL, air-
dry (6 mL), eluting with MeOH (6 mL, collected) and
MeOH/THF/TFA (12 mL). The MeOH fraction was con-
centrated to give crude products, and their purities were
checked by LC-MS analysis. The crude products 7{1-4}
were used for the next step without further purification.
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General Procedures for Fluorous Linker Cleavage
and Final Product Purification. The crude intermediates
7{1-4} were dissolved in TFA/DMS/H2O (90:5:5) (1 mL),
and the mixture was shaken for 3 days, evaporated over 2
days, and concentrated. The residue was dissolved in DMF
(0.7 mL) and purified by RapidTrace FSPE (2 g). The elution
sequence was as follows: loading (1 mL, collected), rinsing
with DMF/H2O (9:1) (1 mL, collected), eluting with DMF/
H2O (9:1) (4 mL, collected), and MeOH/THF/TFA (12 mL).
The collected fraction (DMF/H2O) was concentrated and
analyzed by LC-MS. Preparative HPLC afforded the pure
products 8 in 5-20% yield for 3 steps. Analytical data for
8{1,2,1}: 1H NMR (275 Hz, CDCl3) δ 0.90 (d, J ) 6.5 Hz,
3H), 1.00 (d, J ) 6.5 Hz, 3H), 1.80-2.05 (m, 2H),
2.05-2.25 (m, 1H), 4.10-4.35 (m, 1H), 6.66 (d, J ) 6.2
Hz, 1H), 7.45-7.59 (m, 2H), 7.67 (d, J ) 1.9 Hz, 1H),
7.70-7.85 (m, 2H), 7.91 (d, J ) 8.4 Hz, 1H), 8.31 (dd, J )
1.4, 8.0 Hz, 1H); 13C NMR (67.5 Hz, CDCl3) δ 22.0, 23.1,
24.3, 38.0, 52.4, 121.3, 127.5, 127.8, 127.9, 128.7, 128.9,
129.5, 131.0, 134.3, 135.2, 137.4, 146.0, 154.1, 161.5, 167.1;
LC-MS (ESI+) 368 [M+1]+.
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53–68.
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Supporting Information Available. LC-MS spectra of
purified final products and 1H NMR spectra of representative
final products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) Web address: www.fluorous.com.
Acknowledgment. This work was supported by the National
Institutes of General Medical Sciences P41GM081269.
CC9001636