Fluorous synthesis of sclerotigenin-type benzodiazepine-quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2006.11.127

A new synthetic protocol for sclerotigenin-type benzodiazepine-quinazolinone library scaffold is introduced. A fluorous benzyl protecting group is used for the synthesis of 4-benzodiazepine-2,5-dione intermediate and also as a phase tag for fluorous solid

Full text of DOI:10.1016/j.tetlet.2006.11.127

Tetrahedron Letters 48 (2007) 563–565
Fluorous synthesis of sclerotigenin-type
benzodiazepine–quinazolinones
Wei Zhang,a,* John P. Williams,b Yimin Lu,a Tadamichi Nagashimaa and Qainli Chua
aFluorous Technologies, Inc., University of Pittsburgh Applied Research Center, 970 William Pitt Way, Pittsburgh, PA 15238, USA
bNeurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA
Received 24 October 2006; revised 17 November 2006; accepted 21 November 2006
Available online 12 December 2006
Abstract—A new synthetic protocol for sclerotigenin-type benzodiazepine–quinazolinone library scaffold is introduced. A fluorous
benzyl protecting group is used for the synthesis of 4-benzodiazepine-2,5-dione intermediate and also as a phase tag for fluorous
solid-phase extraction (F-SPE).
Ó 2006 Elsevier Ltd. All rights reserved.
Sclerotigenin was isolated from the sclerotia of Peni-
cillium sclerotigenum and has shown a promising anti-
insectan activity.1 It is the simplest member of the
benzodiazepine–quinazolinone natural alkaloid family.
Other members in this family such as circumdatins A–
G isolated from terrestrial fungus Aspergillus ochraceus2
and benzomalvins A–C isolated from fungus Penicillium
sp. also possess interesting biological activities.3
fold using fluorous benzyl as a protecting group and also
as a phase tag for fluorous solid-phase extraction
(F-SPE).7 Further derivatization of benzodiazepinediones
leads to the formation of sclerotigenin ring skeleton.
Taking the advantage that the numbers of conventional
solution-phase and solid-phase synthetic methods for
benzodiazepine have been reported in the literature,8
O
N
HO
O
O
O
N
H
O
H
N
N
N
i-Bu
N
N
H
N
N
O
O
N
HO
O
N
N
N
N
O
Ph
H
Me
H
H
H
Me
sclerotigenin
circumdatin C
benzomalvin A
(-) asperlicin
Privileged 1,4-benzodiazepine-2,5-dione ring systems are
the key intermediates for the synthesis of benzodiaze-
pine–quinazolinone alkaloids.4 As part of our continu-
ous effort on the development of fluorous synthetic
protocols, we have employed a series of fluorous pro-
tecting groups for library synthesis.5,6 Reported here is
a new approach to synthesize benzodiazepinedione scaf-
we adopted Ellman’s solid-phase method for fluorous
synthesis (Scheme 1).9 Fluorous benzaldehyde
1
prepared by the reaction of 2,6-dimethoxy-4-hydroxy-
benzaldehyde with 3-(perfluorooctyl)propanol was used
as the starting material. Compound 2 was produced
by reductive amination of 1 with an amino ester.
Compound 2 reacted with an anthranilic acid in the
presence of 1-ethyl-3,3-(dimethylaminopropyl)carbo-
diimide (EDCI) and N-methylpyrrolidine (NMP). The
1,4-benzodiazepine-2,5-dione ring formation was
accomplished by base-promoted cyclization of 3. Com-
pounds 2–4 generated in this reaction sequence were
purified by simple workup or F-SPE with FluoroFlashÒ
Keywords: Sclerotigenin; Benzodiazepine–quinazolinone; 1,4-Benzodi-
azepine-2,5-dione; Fluorous synthesis; Solid-phase extraction.
*
Corresponding author. Tel.: +1 412 826 3062; fax: +1 412 826
3053; e-mail: w.zhang@fluorous.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.127

564
W. Zhang et al. / Tetrahedron Letters 48 (2007) 563–565
O
1
R
OMe
NH2
Me
2
R
O
NH2 . HCl
H
N
OMe
NH2
O
PhN
O
CO2H
F-Bn
OLi
OMe
O
NaBH(OAc)3
R2
R1
HN
CHO
OMe
R2
R1
F-Bn
OMe
N
THF
reflux, 1 h
F-SPE
EDCI, NMP
F-SPE
DIPEA, AcOH
DCM, 25 oC
N
C8F17
O
R1
F-Bn
O
1
4a-i
2, 64-95%
3a-i
43-69% (2 steps)
OMe
a
b
c
d
e
f
g
h
i
R1
R2
i
-Bu
H
i
-Bu i-Bu Me Me Me Bn Bn Bn
F-Bn =
4-Cl 5-Cl
H
5-Cl 4-Me
H
4-Cl 4-Me
C8F17
O
OMe
Scheme 1. Fluorous synthesis of benzodiazepinediones 4.
NO2
O2N
90:5:5
TFA-H2O-DMS
O
H
N
CO2Cl
Zn, AcOH
O
O
N
N
O
R2
R1
F-Bn
O
N
μw
N
N
sonication
R2
HPLC
t-BuN=P(NMe2)3
F-SPE
N
120 oC,10 min
F-SPE
R1
F-Bn
R2
R1
R2
R1
O
N
N
N
F-Bn
H
O
O
O
4a-i
5a-i, 72-90%
6a-i, 21-73%
7a-i, 63-100%
Scheme 2. Parallel synthesis of nine benzodiazepine–quinazolinones 7.
Table 1. Yields for the analogs of compounds 5–7
a
b
c
d
e
f
g
h
i
R1
i-Bu
H
82
44
83
i-Bu
4-Cl
80
50
86
i-Bu
5-Cl
90
67
91
Me
H
75
21
91
Me
5-Cl
94
51
63
Me
4-Me
90
62
71
Bn
H
75
70
100
Bn
4-Cl
72
65
89
Bn
4-Me
81
73
97
R2
5a–i (%)
6a–i (%)
7a–i (%)
cartridges.10 In F-SPE, the first wash with 80:20 MeOH–
H2O eluted the non-fluorous components. The desired
fluorous compound was eluted with 100% MeOH. A
total of nine analogs of compound 4 with substitution
variations (R1 and R2) were prepared.11
6 were removed by treating with 90:5:5 TFA–H2O–di-
methylsulfide (DMS) under microwave radiation, fol-
lowed by F-SPE on RapidTraceÒ workstation to give
the final product 7 with the sclerotigenin ring skeleton.13
In summary, we have developed a new approach for the
synthesis of fluorous 1,4-benzodiazepine-2,5-diones. The
key intermediates can be readily converted to sclerotige-
nin ring skeleton. The new method which produces the
library scaffold with substitution variation coupled with
the simple F-SPE separation provides an alternative
for solution-phase parallel synthesis of benzodiazepine–
quinazolinone analogs.
With nine different benzodiazepinediones 4 in hand, we
then conducted parallel synthesis to construct the quin-
azolinone ring skeleton (Scheme 2).1c Compound 4
was acylated with 2-nitrobenzoyl chloride in the pres-
ence of t-BuN@P(NMe2)3 as a base to give compound
5 (Table 1). If substituted 2-nitrobenzoyl chloride was
employed for acylation, the third diversity point (R3)
could be introduced. Compounds 5 were purified by
automated RapidTraceÒ F-SPE.12 The nitro group of
5 was reduced with zinc dust in acetic acid under sonica-
tion conditions. Resulted amino group simultaneously
underwent cyclization to form the quinazolinone ring
of 6. The parallel sonication reactions of 5 gave the
reduction/cyclization products 6 in a broad range of
yield (21–73%). Since some reactions had low yields,
F-SPE was not sufficient for purification. Reverse-phase
chromatography was applied to purify compounds 6.
The capability to purify fluorous compounds by non-flu-
orous technique is a useful option. It could be a difficult
task in solid-phase synthesis to separate resin-bound
impurities. At the last step, F-benzyl tags of compounds
Acknowledgments
This work was supported by the National Insti-
tutes of General Medical Sciences SBIR grant
(2R44GM067326-02A1).
References and notes
1. (a) Penhoat, M.; Bohn, P.; Dupas, G.; Papamicael, C.;
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NMR (270 MHz, CDCl3) d 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, 3H), 0.88
(d, 3H, J = 6.5 Hz), 0.81 (d, 3H, J = 6.4 Hz). 13C NMR
(67.5 MHz, CDCl3) d 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 (APCI+) m/z 772 [M+1]+. To a solution of 2
(R1 = i-Bu, 4.3 g, 5.6 mmol) in N-methylpyrrolidine
(30 mL), 4-chloroanthranilic acid (1.9 g, 11 mmol) and
EDCI–HCl (2.1 g, 11 mmol) were added as solids at 23 °C.
The same amounts of the acid and EDCI–HCl were added
after 2 h and 4 h. One day after the final addition, the
reaction mixture was diluted with DMSO (300 mL), and
was loaded onto an F-SPE cartridge (50 g), and the flask
was rinsed with DMSO (100 mL), and was loaded to the
silica gel. The non-fluorous components were eluted with
MeCN–H2O (1:1, 300 mL, and 4:1, 200 mL), and then
most of the solvent was drained from the cartridge. The
amide coupling product was eluted with MeCN (0.4 L).
The MeCN solution was concentrated in a rotary evap-
orator, and the residue 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 evapo-
rator. MeOH (30 mL) was added to the residue, and it was
heated until the solvent started to boil. The mixture was
left at 23 °C for 1 d, and product 4b (R1 = i-Bu, R2 = 4-
Cl) was collected as a solid by filtration (3.5 g, 69% yield
based on the amount of 2). 1H NMR (270 MHz, CDCl3) d
9.55 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.16 (dd, J = 7.1,
1.9 Hz 1H), 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) d 173.5, 165.1,
160.6, 160.1, 137.7, 136.2, 133.3, 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 (APCI+) m/z 893 [M+1]+.
2. Rahbaek, L.; Breinholt, J. J. Nat. Prod. 1999, 62, 904–
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2003, 103, 893–930.
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Chen, C. H.-T.; Curran, D. P.; Geib, S. Eur. J. Org. Chem.
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6. Selected reviews on fluorous synthesis: (a) Curran, D. P.
Aldrichim. Acta 2006, 39, 3–9; (b) Curran, D. P. In
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37, 1174–1196; see also Ref. 12.
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Tetrahedron 2006, 62, 11837–11865; (b) Curran, D. P. In
Handbook of Fluorous Chemistry; Gladysz, J. A., Curran,
D. P., Horvath, I. T., Eds.; Wiley-VCH: Weinheim, 2004;
pp 101–127; (c) Curran, D. P. Synlett 2001, 1488–1496; see
also (d) Zhang, W.; Lu, Y.; Nagashima, T. J. Comb.
Chem. 2005, 7, 893–897.
8. For a recent review on solid-phase synthesis of benzo-
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Shankaraiah, N.; Reddy, D. R. Mini-Rev. Med. Chem.
2006, 6, 53–68.
12. Zhang, W.; Lu, Y. J. Comb. Chem. 2006, 8, 890–896.
13. A general procedure for the synthesis of compounds 5–7. To
a solution of 4 in CH2Cl2 was added t-butylimino-
tris(dimethylamino)phosphorane (10 equiv) and 2-nitro-
benzoic acid (2 equiv). The reaction mixture was stirred
for 10 min and then concentrated in a rotary evaporator.
The residue was dissolved in DMF (1 mL) and purified on
RapidTraceÒ SPE workstation with 2 g cartridges to
afford 5 in 72–90% yield. A solution of 5 in acetic acid
(1 mL) was added Zn dust (20 equiv) and sonicated at
room temperature for 2 h. The Zn was filtered and the
filtrate was diluted with EtOAc and washed with NaHCO3
and brine. The EtOAc solution was dried and concen-
trated in a rotary evaporator. The residue was dissolved in
MeCN and purified by C18 HPLC to afford 6 in 21–73%
yields. A solution of 6 in TFA–H2O–DMS (90:5:5) was
stirred for 3 days before being concentrated in a rotary
evaporator. The residue was dissolved in DMF (1 mL) and
purified by RapidTraceÒ SPE workstation to afford 7 in
63–100% yields. Analytical date for compound 7b (R1 =
i-Bu, R2 = 4-Cl): 1H NMR (275 Hz, CDCl3) d 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) d 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; LCMS (APCI+) 368 [M+1]+.
9. Boojamra, C. G.; Burow, K. M.; Thompson, L. A.;
Ellman, J. A. J. Org. Chem. 1997, 62, 1240–1256.
10. FluoroFlashÒ SPE cartridges are available from Fluorous
Technologies, Inc. (www.fluorous.com).
11. A general procedure for the synthesis of compounds 2 and 4.
To a solution of leucine methyl ester hydrochloride (7.6 g,
42 mmol), 2,6-dimethoxy-4-[3-(perfluorooctyl)propyloxy]-
benzaldehyde 1 (26 g, 40 mmol), and N,N-diisopropylethyl-
˚
amine (7 mL, 0.04 mol) in CH2Cl2 (0.3 L) was added 4 A
molecular sieves (3 g) at 23 °C. NaBH(OAc)3 (13 g,
60 mmol) was added after 4 h, then water was added after
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 2 (R1 = i-Bu, 3.9 g, 95% yield). 1H