Synthesis of circumdatin F and sclerotigenin. Use of the 2-nitrobenzyl group for protection of a diketopiperazine amide; synthesis of ent-fumiquinazoline G

Article abstract of DOI:10.1016/S0040-4020(01)00208-3

The Eguchi aza Wittig protocol has been used for the synthesis of sclerotigenin and circumdatin F by selective acylation of the more acidic anilide nitrogen of a benzodiazepinedione without the need for protecting groups. The use of the 2-nitrobenzyl grou

Full text of DOI:10.1016/S0040-4020(01)00208-3

TETRAHEDRON
Pergamon
Tetrahedron 57 02001) 3301±3307
Synthesis of circumdatin F and sclerotigenin. Use of the
2-nitrobenzyl group for protection of a diketopiperazine
amide; synthesis of ent-fumiquinazoline G
Barry B. Sniderp and Marina V. Busuyek
Department of Chemistry MS 015, Brandeis University, Waltham, MA 02454-9110, USA
Received 6 December 2000; accepted 10 January 2001
AbstractÐThe Eguchi aza Wittig protocol has been used for the synthesis of sclerotigenin and circumdatin F by selective acylation of the
more acidic anilide nitrogen of a benzodiazepinedione without the need for protecting groups. The use of the 2-nitrobenzyl group as a
photochemically labile protecting group for the amide nitrogen of a diketopiperazine permits the use of the aza Wittig procedure for the
synthesis of fumiquinazoline G. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
cyclization4 of the resulting imide 2a withBu 3P in benzene
at 608C afforded 66% of asperlicin C 03a). This sequence
provides a short and ef®cient route to the fused quinazoli-
none ring system without the need for protection of the less
acidic amide nitrogen. Since this work was completed,
Rahbñk reported the isolation of the related quinazolinone
circumdatin F 03b) as a minor component from the
fungus Aspergillus ochraceus.5 Gloer reported the isolation
of the antiinsectan sclerotigenin 03c) from Penicillium
sclerotigenum.6 The selective acylation-aza Wittig
sequence should provide an equally ef®cient route to these
compounds.
A wide variety of quinazolinone natural products have been
isolated in recent years. These fall into two general families
withthe quinazolinone fused to a benzodiazepinedione as in
asperlicin C 03a)1 0see Scheme 1) or to a diketopiperazine as
in fumiquinazolines G 04a), and F 04b)2 and ®scalin B 04c)3
0see Scheme 2). Different applications of the Eguchi aza
Wittig protocol4 provide ef®cient entry to bothclasses of
natural products. We recently reported an improved synthe-
sis of asperlicin C 03a).1 Selective acylation of the more
acidic anilide nitrogen of 1a withazidobenzoyl chloride,
DMAP, and Et3N in CH2Cl2, followed by aza Wittig
Application of the Eguchi protocol to the synthesis of
the fumiquinazolines and ®scalins 04a±c) requires the
preparation of N-protected diketopiperazine 5, since it is
not possible to selectively acylate one of the two nitrogens
of a diketopiperazine. We have previously reported a
solution to this problem using the 2,4-dimethoxybenzyl
protecting group.7 We report here an improved solution
using the photolabile 2-nitrobenzyl protecting group.
O
N3
2-N3C6H4COCl
Et3N, DMAP
NH
N
O
O
HN
HN
O
O
R
R
Bu3P
C6H6
60 °C
2a, R = CH2Indole
2b, R = Me
2c, R = H
1a, R = CH2Indole
1b, R = Me
1c, R = H
O
N
2. Synthesis of circumdatin F and sclerotigenin
3a, R = CH2Indole (asperlicin C) (66%)
3b, R = Me (circumdatin F) (69%)
3c, R = H (sclerotigenin) (43% + 9% 6)
Benzodiazepinedione 1b8 was insoluble in CH2Cl2, but
could be selectively acylated with2-azidobenzoyl
chloride4,9 and Et3N and DMAP in THF to afford crude
2b, which was treated with Bu3P in benzene at 608C to
give 69% of 0S)-02)-circumdatin F 03b) with 1H NMR spec-
tral data identical to those reported 0see Scheme 1).5
Although the optical rotation of natural circumdatin F was
not determined due to the small amount isolated, the
absolute stereochemistry is probably the same as 3b since
O
HN
N
R
Scheme 1.
Keywords: aza Wittig reaction; alkaloids; photochemistry; protecting
groups.
Corresponding author. Tel: 1781-736-2550; fax: 1781-736-2516;
e-mail: snider@brandeis.edu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020001)00208-3

3302
B. B. Snider, M. V. Busuyek / Tetrahedron 57 .2001) 3301±3307
R
R
N
O
O
PG
O
NH
N
N
HN
O
N
N
H
H
4a, R = β-methyl (fumiquinaozline G)
4b, R = α-methyl (fumiquinazoline F)
4c, R = α-isopropyl (fiscalin B)
5
Scheme 2.
the closely related alkaloid circumdatin C is derived from
l-alanine.5
ably different due to the slow ¯ipping of the ring and the
very anisotropic environment due to the adjacent carbonyl
group.12 Similar shift differences have been observed in 7 0d
5.4 and 4.2)11 and 8 0d 6.66 and 4.34).13
Acylation of the parent benzodiazepinedione 01c) was more
challenging due to its insolubility in CH2Cl2, THF, and other
common organic solvents. Eventually we found that
acylation could be accomplished in modest yield in 2:1
As expected, there is also a barrier to ¯ipping the seven-
membered ring of the substituted analogues 3a and 3b,
although this had not been noted previously due to the
small amount of the minor conformer present at equi-
CH2Cl2/DMSO. Treatment of crude imide 2c withBu P in
3
benzene at 608C provided 43% of sclerotigenin 03c) with
spectral data identical to those of the natural product.6,10
librium. The H NMR spectrum indicates that circumdatin
1
F 03b) exists as a 99:1 mixture of conformers in CDCl3. Th e
aliphatic protons of the major conformer absorb at d 4.37
and 1.71, while those of the minor conformer absorb at d
4.69 and 1.13. The 1H NMR spectrum indicates that
asperlicin C 03a) exists as a 27:1 mixture of conformers in
DMSO-d6.1b The aliphatic protons of the major conformer
absorb at d 4.40, 3.63 and 3.39, while those of the minor
conformer absorb at d 4.67, 2.80 and 2.49.
A second quinazolinone was isolated from this reaction in
9% yield. Initially, we thought that it might be 7 resulting
from acylation of the other amide, which is less hindered in
the parent 1c than in the substituted analogues 1a and 1b.
However, the 1H NMR spectral absorptions for the methyl-
ene protons in DMSO-d6 did not matchthose of authentic
7
0see Scheme 3).11 Full NMR and MS characterization indi-
cated that the minor product was the bis adduct 6. The yield
of this product could be improved by acylation with 2 equiv.
of 2-azidobenzoyl chloride, which gave 38% of 6 and 26%
of sclerotigenin 03c). The formation of the bis quinazolinone
appears to be restricted to the unhindered parent 1c, since
none of the analogous product could be obtained from 1b
with2 equiv. of 2-azidobenzoyl chloride.
3. Synthesis of ent-fumiquinazoline G
A series of cytotoxic quinazolinones including fumiquina-
zolines G and F 04a and 4b) were isolated by Numata from a
strain of fungus Aspergillus fumigatus separated from the
gastrointestinal tract of the ®sh Pseudolabrus japonicus.2
Fiscalin B 04c), which inhibits binding of substance P to
human U-373 MG intact cells, was isolated by a Sterling
Winthrop group from the fungus Neosartorya ®scheri.3 We
recently reported a synthesis of fumiquinazoline G 04a),
which was carried out in the more available enantiomeric
The methylene protons of 3c absorb at d 4.24 and 4.31 in the
1H NMR spectrum indicating that they are non-equivalent
on the NMR time scale because of a signi®cant barrier to
¯ipping the seven-membered ring.6 The chemical shifts of
the methylene protons of 6 at d 5.98 and 4.57 are remark-
2 eq 2-N3C6H4COCl
O
Et3N, DMAP
N
N
NH
O
Bu3P, C6H6, 60 °C
N
HN
N
O
H
H
1c
O
(δ 5.98, 4.57)
6 (38% + 26% 3c)
NH
N
N
N
N
N
N
O
N
8
H
H
H
H
O
(δ 5.4, 4.2)
7
O
(δ 6.66, 4.34)
Scheme 3.

B. B. Snider, M. V. Busuyek / Tetrahedron 57 .2001) 3301±3307
3303
O
not ideal. Furthermore, the preparation of the diketo-
piperazine by condensation of the pyruvamide is limited
to the preparation of alanine-derived diketopiperazines.
We therefore needed a more general route to protected
diketopiperazines that could be deprotected after the genera-
tion of the quinazolinone. We decided to investigate the
2-nitrobenzyl protecting group since it can be easily cleaved
photochemically.15
Me
O
DMB
O
toluene, ∆
cat TFA (89%)
O
DMB
O
N
HN
R
HN
10
HN
H2, Pd (100%)
9
R
LDA, THF -78 °C
2-N3C6H4COCl (85%)
Me
N
Me
The shortest route to 2-nitrobenzyl diketopiperazine 15 is
the cyclization of amino ester 16, which could be prepared
by coupling of the secondary amino ester 17 withteh
protected amino acid 18 0see Scheme 5). Alternatively, 15
could be prepared by cyclization of amino ester 19, which
could be prepared by coupling primary amino ester 20
withprotected amino acid 21. This sequence requires
additional steps for the protection of the amino group of
17 and hydrolysis of the methyl ester to prepare 21.
R1
O
N
O
R1
O
Bu3P, C6H6, 60 °C
(65-85%)
N
N
N
O
N3
O
R
R
13, R1 = DMB
14, R1 = H
11, R1 = DMB
12, R1 = H
CAN (67%)
MeCN/H2O
Scheme 4.
Reductive amination16 of 2-nitrobenzaldehyde with alanine
methyl ester 022) and NaBH3CN in MeOH afforded 65% of
the required amino ester 17 0see Scheme 6). Unfortunately,
attempted coupling of 17 withTroc- or Boc-tryptopahn
using DCC and DMAP, DCC and Et0I-Pr)2N, HATU and
Et0I-Pr)2N, or HATU and HOBT was unsuccessful. We
series using l-amino acids 0see Scheme 4).1b,7 Heating
pyruvamide 9 in toluene at re¯ux containing a catalytic
amount of TFA afforded the enamide, which was hydro-
genated selectively from the less hindered b-face to give
89% of 10. Formation of the amide anion with LDA in
THF and acylation with2-azidobenzoyl chloride afforded
85% of 11, which was converted to quinazolinone 13 in
65±85% yield withBu 3P in benzene at 608C. Unfortunately,
we were unable to cleanly remove the 2,4-dimethoxybenzyl
0DMB) protecting group from 13 witheither TFA or ceric
ammonium nitrate 0CAN) in aqueous MeCN.1b,7 AvendanÄo
17
were also unable to acylate 17 withteh acyl ¯uoride
prepared from Boc-tryptophan. Steric hindrance from the
2-nitrobenzyl group retards acylation of the hindered
secondary amine of protected amino ester 17 as has been
observed recently by AvendanÄo for related DMB protected
amino acids.14b
Â
and Menendez have since reported similar problems
cleaving the DMB group in related compounds with either
CAN or TFA/anisole.14 Fortunately, oxidative deprotection
of acyclic imide 11 withCAN in aqueous MeCN afforded
67% of unprotected imide 12, which could be cyclized with
Bu3P in benzene at 608C to give 65±85% of quinazolinone
14.
The protected amino acid 21 was therefore prepared by
coupling 17 with10 equiv. of allyl clhoroformate in
pyridine/THF to give 87% of 23 and hydrolysis of the
methyl ester to give 96% of 21. A large excess of allyl
chloroformate was needed to obtain good yields of 23.
Condensation of the acid of 21 with tryptophan methyl
ester 020a) using DCC proceeded uneventfully to give
65% of dipeptide 24a. Deprotection of the Aloc group
Although this sequence was successful, the harsh conditions
required for deprotection of the DMB group, which can only
be carried out on the imide and not the quinazolinone, are
withPd0PPh ) gave the free dipeptide amino methyl
3 4
ester. Unfortunately, diketopiperazine formation withthe
Me
NO2
Me
NO2
Me
NO2
17
O
N
MeO2C
H2N
N
MeO2C
RHN
N
HN
15
H
O
O
CO2H
16
Indole
Indole
18
Indole
Me
NO2
Me
NO2
21
O
N
HO2C
N
H
HN
CO2R
Aloc
H2N
CO2R
Indole
Indole
20a, R = Me
20b, R = Ph
19a, R = Me
19b, R = Ph
Scheme 5.

3304
B. B. Snider, M. V. Busuyek / Tetrahedron 57 .2001) 3301±3307
Me
NO2
Me
NO2
MeO2C
NH2
CHO
R2O2C
N
R1
22
NaBH3CN, MeOH
17, R1 = H, R2 = Me (65%)
23, R1 = Aloc, R2 = Me (87%)
21, R1 = Aloc, R2 = H (96%)
allylOCOCl, pyr
NaOH, MeOH
H2N
CO2R
Me
NO2
1) Pd(PPh3)4
AcOH, CH2Cl2
1 h, 40 °C
Me
NO2
O
O
Indole
N
N
20a, R = Me
20b, R = Ph
Aloc
HN
HN
CO2R
O
2)
cat AcOH
CH2Cl2
DCC
CH2Cl2
Indole
15 (81% from 24b)
Indole
24a, R = Me (65%) 8 h, rt
24b, R = Ph (82%)
1) NaH, THF -5 to 25 °C
2-N3C6H4COCl
Me
Me
NO2
(75%)
N
N
NH
N
N
hν
MeOH
15 h
N
2) Bu3P, C6H6
O
O
60 °C (78%)
O
O
Indole
Indole
ent-7a
25
(ent-fumiquinazoline G, 87%)
Scheme 6.
hindered secondary amine could not be effected on heating
in CH2Cl2 or CHCl3 containing a catalytic amount of AcOH.
2-azidobenzoyl chloride followed by an aza Wittig reaction
is general, providing very short and ef®cient syntheses of
circumdatin F 03b) and sclerotigenin 03c). We have
developed a general procedure for the synthesis of N-02-
nitrobenzyl)diketopiperazines, which can be deprotected
cleanly on irradiation in MeOH through Pyrex at 254 nm.
The utility of this sequence has been demonstrated in a short
synthesis of ent-fumiquinazoline G 0ent-7a).
We therefore decided to use an activated phenyl ester to
facilitate formation of the diketopiperazine since we had
used this strategy effectively to form the benzodiazepine-
dione of asperlicin.1,18 Treatment of Troc-tryptophan phenyl
ester1 withZn in AcOH afforded amino ester 20b,18 which
was condensed with 21 using DCC in CH2Cl2 to give 82% of
dipeptide 24b. Deprotection of the Aloc group with
Pd0PPh3)4 in AcOH/CH2Cl2 afforded the more reactive
dipeptide secondary amine phenyl ester, which cyclized
on stirring in CH2Cl2 at 258C containing a trace of AcOH
for 8 hto afford 81% of the desired monoprotected diketo-
piperazine 15 and 13% of the easily separated epimerized
diastereomer witha b-CH2indole side chain.
4. Experimental
4.1. General
NMR spectral data are reported in CDCl3 unless otherwise
indicated. Chemical shifts are reported in d and coupling
constants in Hz.
The quinazolinone was introduced by acylation of 15 with
NaH and 2-azidobenzoyl chloride4,9 in THF at 25±258C to
give 75% of the imide, which was treated with Bu3P in
benzene at 60±708C to afford 78% of protected ent-fumi-
quinazoline G 025). We were delighted to ®nd that photo-
lysis of a dilute MeOH solution of 25 at 254 nm through
Pyrex provided 87% of ent-fumiquinazoline G 0ent-7a).
Neither the quinazolinone nor the indole interferes with
the photochemical deprotection. Procedures using
NaHSO3 in aqueous MeOH to trap the nitrosobenzaldehyde
produced in the photolysis were less successful.15d
4.1.1. ,7S)-6,7-Dihydro-7-methylquinazolino[3,2-a][1,4]-
benzodiazepine-5,13-dione ,circumdatin F, 3b). Et3N
0350 mL, 2.5 mmol, 1.25 equiv.) was added to a solution
of 1b8 0380 mg, 2 mmol) in dry THF 040 mL). The resulting
mixture was stirred for 15 min and treated withDMAP
0170 mg, 1.4 mmol, 0.7 equiv.). Freshly prepared 2-azido-
benzoyl chloride4,9 0from 408 mg, 2.5 mmol, 1.25 equiv. of
2-azidobenzoic acid)9 in dry THF 02 mL) was added drop-
wise to the solution and the resulting mixture was stirred for
2 hat 20 8C. The solvent was removed under reduced
pressure. The residue was dissolved in CH2Cl2 030 mL),
which was washed with water 03£30 mL) and dried
In conclusion, we have shown that selective acylation of the
more acidic anilide nitrogen of benzodiazepinediones 1 with

B. B. Snider, M. V. Busuyek / Tetrahedron 57 .2001) 3301±3307
3305
0Na2SO4). Concentration gave 650 mg of crude 2b as a
yellowishfoamy solid.
1, Jˆ1.8, 6.3, 7.9 Hz), 7.58±7.48 0m, 2), 6.38 0d, 1,
1
Jˆ14.6 Hz), 4.44 0d, 1, Jˆ14.6 Hz); H NMR 0DMSO-d6)
8.17 0dd, 1, Jˆ1.2, 7.3 Hz), 8.15 0dd, 1, Jˆ1.2, 7.3 Hz), 8.06
0dd, 1, Jˆ1.2, 7.3 Hz), 7.89±7.83 0m, 2), 7.79±7.71 0m, 3),
7.70 0dd, 1, Jˆ1.8, 6.5 Hz), 7.66 0dd, 1, Jˆ1.8, 6.5 Hz), 7.57
0ddd, 1, Jˆ1.2, 7.3, 7.3 Hz), 7.56 0ddd, 1, Jˆ1.2, 7.3,
7.3 Hz), 5.98 0d, 1, Jˆ14.0 Hz), 4.57 0d, 1, Jˆ14.0 Hz);
13C NMR 161.1, 160.2, 151.4, 150.8, 147.5, 146.3, 135.0,
134.8, 134.4, 131.6, 131.4, 130.5, 129.1, 128.4, 128.1,
128.0, 127.8, 127.5, 127.34, 127.33, 121.7, 120.3, 46.3;
HRMS 0DEI) calculated for C23H14N4O2 0M1) 378.1117,
found 378.1118.
Crude 2b 0650 mg) was dissolved in dry benzene 010 mL)
and 0n-Bu)3P 0485 mL, 1.9 mmol) was added to the solution
in one portion. The resulting mixture was stirred at rt under
N2 for 2 min and at 608C for 1 h. The reaction mixture was
cooled and concentrated. The residue was diluted with
CH2Cl2 050 mL), which was washed with 0.5 M HCl
03£50 mL) and brine 050 mL), dried 0Na2SO4) and concen-
trated. Flash chromatography on silica gel 05:1 CH2Cl2/
EtOAc) gave 403 mg 069% from 1b) of 3b as a white
1
solid: mp 249.2±250.18C; H NMR 8.22 0d, 1, Jˆ7.9 Hz),
7.97 0d, 1, Jˆ7.3 Hz), 7.72 0t, 1, Jˆ7.9 Hz), 7.68±7.50 0m,
4), 7.46 0t, 1, Jˆ7.9 Hz), 7.28 0br, NH), 4.37 0dq, 1, Jˆ6.7,
6.7 Hz), 1.71 0d, 3, Jˆ6.7 Hz); 1H NMR 0CD3OD) 8.26 0dd,
1, Jˆ1.2, 7.9 Hz), 7.89±7.85 0m, 3), 7.78 0d, 1, Jˆ7.9 Hz),
7.71±7.56 0m, 3), 4.43 0q, 1, Jˆ6.7 Hz), 1.67 0d, 3,
Jˆ6.7 Hz); 13C NMR 168.0, 161.5, 154.9, 146.0, 134.7,
133.5, 131.2, 130.6, 129.8, 128.8, 128.3, 127.6, 127.4,
127.2, 121.3, 49.9, 15.2; [a]Dˆ176.08 0c 0.230, EtOH).
The 1H NMR spectral data in CD3OD are identical to
those of the natural product.5
A similar reaction with0115 mg, 0.7 mmol, 2 equiv.) of
2-azidobenzoyl chloride,4,9 098 mL, 0.7 mmol, 2 equiv.) of
Et3N and 60 mg 00.34 mmol) of 1c gave 49 mg 038%) of 6
and 25 mg 026%) of 3c.
4.1.3. N-,2-Nitrobenzyl)-l-alanine methyl ester ,17).
NaOH 0200 mg, 5 mmol) was added to a solution of
l-alanine methyl ester hydrochloride 0698 mg, 5 mmol) in
anhydrous MeOH 015 mL) and resulting mixture was stirred
for 5 min. 2-Nitrobenzaldehyde 0831 mg, 5.5 mmol) and
anhydrous Na2SO4 0500 mg) were added to this solution
and the mixture was stirred at rt for 8 h under N2. Th e
4.1.2. 6,7-Dihydroquinazolino[3,2-a][1,4]benzodiazepine-
5,13-dione ,sclerotigenin, 3c). A solution of 1c8 056 mg,
0.3 mmol) in dry DMSO 04 mL) was diluted withdry
CH2Cl2 04 mL). Et3N 056 mL, 0.375 mmol, 1.25 equiv.)
was added to the solution and the reaction mixture was
stirred for 15 min, and treated withDMAP 028 mg,
0.21 mmol, 0.7 equiv.). Freshly prepared 2-azidobenzoyl
chloride4,9 01.25 equiv.) in dry CH2Cl2 04 mL) was added
dropwise to the solution and the resulting mixture was stir-
mixture was cooled to 08C and treated withNaCNBH
3
0315 mg, 5 mmol). The resulting mixture was stirred for
20 min at 258C. Methanol was removed under reduced
pressure and the residue was taken up in CH2Cl2 050 mL).
The resulting solution was washed with aqueous NaHCO3
02£50 mL), H2O 050 mL) and brine 050 mL), dried
0Na2SO4) and concentrated to give a thick brown oil.
Flashchromatography on silica gel 025:1 CH 2Cl2/EtOAc)
gave 770 mg 065%) of oily 17: 1H NMR 7.93 0d, 1,
Jˆ7.9 Hz), 7.63 0d, 1, Jˆ7.3 Hz), 7.58 0dd, 1, Jˆ7.3,
7.3 Hz), 7.41 0dd, 1, Jˆ7.9, 7.3 Hz), 4.10 0d, 1,
Jˆ14.7 Hz), 3.98 0d, 1, Jˆ14.7 Hz), 3.71 0s, 3), 3.38 0q,
1, Jˆ7.3 Hz), 1.32 0d, 3, Jˆ7.3 Hz); 13C NMR 175.8,
149.1, 135.2, 133.1, 131.0, 128.0, 124.7, 56.4, 51.8, 48.9,
19.1; IR 0neat) 1735, 1527, 1347; [a]Dˆ2319.68 0c 0.310,
EtOH).
red for 2 hat 20 8C, diluted withCH Cl2 030 mL), washed
2
withwater 04 £40 mL), dried 0Na2SO4), and concentrated to
give 75 mg of crude 2c as a yellowishfoamy solid.
Crude 2c was dissolved in dry benzene 04 mL) and 0n-Bu)3P
060 mL, 0.24 mmol) was added to the solution in one
portion. The resulting mixture was stirred under N2 at rt
for 2 min and at 608C for 2 h. The reaction mixture was
concentrated and the residue was dissolved in CH2Cl2
030 mL). The resulting solution was washed with 0.5 M
HCl 03£20 mL) and brine 020 mL), dried 0Na2SO4) and
concentrated giving 120 mg of crude 3c as a thick brown
oil. The crude mixture was triturated several times with
hexane to remove most of the 0n-Bu)3PO. The hexane
insoluble residue was puri®ed on silica gel 01:1 CH2Cl2/
EtOAc) giving 11 mg 09%) of 6 followed by 38 mg 043%)
of 3c as a white solid.
4.1.4. N-,2-Nitrobenzyl)-N-Aloc-l-alanine methyl ester
,23). Allyl chloroformate 02.23 mL, 21 mmol) was added
dropwise to a solution of 17 0500 mg, 2.1 mmol) in pyridine
01.68 mL, 21 mmol) and dry THF 05 mL) at 08C. The result-
ing mixture was stirred for 2 h. Ether 0100 mL) was added to
the reaction mixture and the organic phase was washed with
H2O 02£100 mL) and brine 0100 mL), dried 0Na2SO4) and
concentrated. Flash chromatography on silica gel 0CH2Cl2)
1
gave 588 mg 087%) of 23 as a colorless oil: H NMR 01:1
Data for 3c: mp 277±2808C, lit. 6 mp 235±2388C; 1H NMR
8.32 0d, 1, Jˆ7.9 Hz), 7.97 0d, 1, Jˆ7.3 Hz), 7.81 0t, 1,
Jˆ7.3 Hz), 7.70 0d, 1, Jˆ7.9 Hz), 7.65±7.64 0m, 2), 7.58±
7.53 0m, 2), 7.11 0br s, NH), 4.31 0dd, 1, Jˆ6.1, 15.3 Hz),
4.24 0dd, 1, Jˆ6.7, 15.3 Hz); 13C NMR 168.2, 161.3, 153.6,
146.2, 135.1, 133.7, 131.4, 130.4, 129.8, 129.1, 128.1,
mixture of rotamers) 8.10±8.01 0m, 1), 7.71±7.59 0m, 2),
7.48±7.39 0m, 1), 5.91 0tdd, 0.5£1, Jˆ5.5, 10.4, 17.1 Hz),
5.84±5.71 0m, 0.5£1), 5.32 0br d, 1, Jˆ17.1 Hz), 5.23 0dd, 1,
Jˆ1.2, 10.4 Hz), 5.14±5.04 0m, 2), 4.81±4.54 0m, 2), 4.47±
4.36 0m, 1), 3.73 0s, 0.5£3), 3.71 0s, 0.5£3), 1.42 0d, 3,
Jˆ7.3 Hz); 13C NMR 171.9, 156.2, 134.5, 133.5, 132.2,
129.1, 128.6, 127.9, 125.0, 0117.9, 117.7), 066.8, 66.5),
055.9, 55.7), 52.4, 047.9, 47.0), 015.7, 15.0); [a]Dˆ
2424.28 0c 0.240, EtOH).
1
127.8, 127.6, 127.3, 121.5, 47.1. The H and 13C NMR
spectral data are identical to those of the natural product.6
1
Data for 6: mp 310.7±311.98C; H NMR 8.34 0br d, 1,
Jˆ7.9 Hz), 8.29 0br d, 1, Jˆ7.9 Hz), 8.15 0br d, 1,
4.1.5. N-,2-Nitrobenzyl)-N-Aloc-l-alanine ,21). A solu-
tion of 23 01.70 g, 5.3 mmol) in MeOH 010 mL) and 1 M
Jˆ7.9 Hz), 7.84±7.76 0m, 4), 7.76±7.67 0m, 2), 7.64 0ddd,

3306
B. B. Snider, M. V. Busuyek / Tetrahedron 57 .2001) 3301±3307
aqueous NaOH 05 mL) was stirred for 2 hat 25 8C. The
MeOH was evaporated, and the residue was diluted with
water 050 mL) and washed with CH2Cl2 02£50 mL). The
pH of the aqueous phase was adjusted to 1±2 with 1 M
HCl and the solution was extracted with CH2Cl2
03£50 mL). The combined organic layers were dried
0Na2SO4) and evaporated to give 1.57 g 096%) of 21 as a
and evaporated. Flash chromatography on silica gel
0EtOAc) gave 50 mg 013%) of the diastereomer, followed
by 320 mg 081%) of 15 as a white solid: mp 221.7±223.38C;
1H NMR 8.17 0br s, NH), 8.04 0dd, 1, Jˆ1.2, 7.9 Hz), 7.65
0br d, 1, Jˆ7.9 Hz), 7.52±7.43 0m, 2), 7.41 0d, 1, Jˆ7.9 Hz),
7.26 0t, 1, Jˆ7.9 Hz), 7.21 0d, 1, Jˆ7.9 Hz), 7.20 0d, 1,
Jˆ7.9 Hz), 7.14 0d, 1, Jˆ2.4 Hz), 5.89 0br s, NH), 5.30 0d,
1, Jˆ17.1 Hz), 4.58 0d, 1, Jˆ17.1 Hz), 4.43 0ddd, 1, Jˆ3.6,
3.6, 8.5 Hz), 3.87 0q, 1, Jˆ7.3 Hz), 3.48 0dd, 1, Jˆ3.6,
14.6 Hz), 3.29 0dd, 1, Jˆ8.5, 14.6 Hz), 1.17 0d, 3,
Jˆ7.3 Hz); 1H NMR 0CD3OD) 7.98 0dd, 1, Jˆ1.2,
7.9 Hz), 7.59 0d, 1, Jˆ7.9 Hz), 7.45±7.36 0m, 3), 7.14 0t,
1, Jˆ7.9 Hz), 7.12 0s, 1), 7.06 0t, 1, Jˆ7.9 Hz), 6.93 0d, 1,
Jˆ7.9 Hz), 4.88 0d, 1, Jˆ17.1 Hz), 4.56 0d, 1, Jˆ17.1 Hz),
4.46 0br t, 1, Jˆ4.3 Hz), 3.75 0q, 1, Jˆ6.7 Hz), 3.55 0dd, 1,
Jˆ4.3, 15.0 Hz), 3.18 0dd, 1, Jˆ4.3, 15.0 Hz), 0.37 0d, 3,
Jˆ6.7 Hz); 13C NMR 0CD3OD) 170.1, 168.9, 149.8, 138.0,
134.8, 132.6, 130.0, 129.5, 129.2, 126.1, 126.0, 122.9,
120.5, 120.3, 112.6, 109.6, 58.02, 57.97, 47.3, 31.1, 18.6,
[a]Dˆ2837.38 0c 0.108, EtOH); HRMS 0DEI) calculated
for C21H20N4O4 0M1) 392.1485, found 392.1504. A 13C
NMR spectrum could not be obtained in CDCl3 because
of low solubility.
1
yellow oil: H NMR 01:1 mixture of rotamers) 11.2±11.1
0br, 1, OH), 8.07 0br t, 1, Jˆ8 Hz), 7.71±7.60 0m, 2), 7.50±
7.40 0m, 1), 5.98±5.88 0m, 0.5£1), 5.81±5.73 0m, 0.5£1),
5.33 0br d, 0.5£1, Jˆ17 Hz), 5.24 0br d, 0.5£1, Jˆ10 Hz),
5.15±5.08 0m, 0.5£2), 5.12 0br d, 1, Jˆ18 Hz), 4.80±4.41
0m, 4), 1.45 0d, 3, Jˆ7.3 Hz); 13C NMR 0176.9, 176.8),
156.3, 0147.7, 147.5), 0134.0, 133.7), 133.5, 131.9, 0128.9,
128.5), 127.8, 124.9, 0118.0, 117.6), 066.9, 66.6), 55.6,
047.8, 47.1), 015.3, 14.6); HRMS 0DEI) calculated for
C14H17N2O6 0MH1) 309.1087, found 309.1074.
4.1.6. Dipeptide 24b. A suspension of Troc-tryptophan
phenyl ester1 0910 mg, 2 mmol) and Zn dust 02.6 g,
40 mmol, 20 equiv.) in acetic acid 05 mL) was stirred for
30 min at rt. The solution was ®ltered through Celite and the
®ltrate was concentrated. The residue was dissolved in
EtOAc 030 mL) and the resulting solution was washed
1
Data for the diastereomer: H NMR 8.31 0br s, NH), 8.05
withwater 030 mL) and saturated NaHCO 03£30 mL),
3
dried 0Na2SO4) and concentrated giving l-tryptophan
phenyl ester 20b that was dissolved in dry CH2Cl2 03 mL)
and used for the next step.
0dd, 1, Jˆ1.2, 7.9 Hz), 7.69 0d, 1, Jˆ7.9 Hz), 7.58±7.44 0m,
2), 7.41 0d, 1, Jˆ7.9 Hz), 7.26, 0t, 1, Jˆ7.9 Hz), 7.18 0d, 1,
Jˆ7.9 Hz), 7.17 0d, 1, Jˆ7.9 Hz), 7.14 0br s, 1), 5.91 0br s,
NH), 5.40 0d, 1, Jˆ16.5 Hz), 4.57 0d, 1, Jˆ16.5 Hz), 4.41
0dd, 1, Jˆ3.7, 9.8 Hz), 3.77 0q, 1, Jˆ6.9 Hz), 3.75 0dd, 1,
Jˆ3.7, 14.7 Hz), 3.13 0dd, 1, Jˆ9.8, 14.7 Hz), 1.46 0d, 3,
A solution of 21 0515 mg, 1.7 mmol) and 1,3-dicyclohexyl-
carbodiimide 0362 mg, 1.75 mmol, 1.05 equiv.) in dry
CH2Cl2 05 mL) was stirred for 5 min at rt. The freshly
prepared solution of 20b was added and the resulting
mixture was stirred for 25 min at rt. The insoluble by-
product 0DCU) was ®ltered off and the ®ltrate was
concentrated giving crude 24b. Flash chromatography on
silica gel 020:1 CH2Cl2/EtOAc) gave 24b 0800 mg, 82%)
1
Jˆ6.9 Hz); HMR 0CD3OD) 7.96 0dd, 1, Jˆ1.2, 7.9 Hz),
7.61 0d, 1, Jˆ7.9 Hz), 7.41 0d, 1, Jˆ7.9 Hz), 7.35 0t, 1,
Jˆ7.9 Hz), 7.17 0t, 1, Jˆ7.9 Hz), 7.11 0t, 1, Jˆ7.9 Hz),
7.10 0s, 1), 7.00 0t, 1, Jˆ7.9 Hz), 6.38 0d, 1, Jˆ7.9 Hz),
4.95 0d, 1, Jˆ17.1 Hz), 4.54 0br dd, 1, Jˆ4.0, 4.3 Hz),
4.51 0d, 1, Jˆ17.1 Hz), 3.57 0dd, 1, Jˆ4.3, 14.7 Hz), 3.29
0q, 1, Jˆ7.0 Hz), 3.22 0dd, 1, Jˆ4.0, 14.7 Hz), 1.34 0d, 3,
Jˆ7.0 Hz); [a]Dˆ2548.78 0c 0.170, EtOH).
1
as a yellowishfoamy solid: mp 75.3±76.7 8C; H NMR
0broadened due to mixture of rotamers) 8.32 0br s, NH),
8.01 0d, 1, Jˆ7.9 Hz), 7.61 0d, 1, Jˆ7.9 Hz), 7.50±7.41
0m, 1), 7.40±7.30 0m, 5), 7.24±7.17 0m, 2), 7.16±7.09 0m,
2), 6.94 0d, 2, Jˆ7.3 Hz), 5.77±5.58 0m, 1), 5.20±5.00 0m,
3), 4.92±4.66 0m, 2), 4.61 0br d, 1, Jˆ18 Hz), 4.45 0dd, 1,
Jˆ5.5, 13.4 Hz), 4.40±4.26 0m, 1), 3.47 0dd, 1, Jˆ5.5,
14.7 Hz), 3.41 0dd, 1, Jˆ6.7, 14.7 Hz), 1.27 0d, 3,
Jˆ7.3 Hz); [a]Dˆ2611.528 0c 0.165, EtOH); HRMS
0DEI) calculated for C31H30N4O7 0M1) 570.2115, found
570.2126.
4.1.8. Acylation of 15. NaH 024.5 mg of 60% mineral oil
dispersion, 0.61 mmol, 1.2 equiv.) was added in one portion
to a solution of 15 0200 mg, 0.51 mmol) in dry THF 05 mL)
at 258C, and the resulting mixture was stirred for 15 min. A
solution of freshly prepared 2-azidobenzoyl chloride4,9 in
dry THF 01 mL) was added dropwise, and the reaction
mixture warmed to rt and stirred for 2 h. The solvent was
concentrated and the residue was dissolved in CH2Cl2
030 mL). The resulting solution was washed with water
02£30 mL) and brine 030 mL), dried 0Na2SO4) and concen-
trated. Flash chromatography on silica gel 020:1 EtOAc/
4.1.7. Diketopiperazine 15. A solution of 24b 0570 mg,
1 mmol) in AcOH 03 mL) and CH2Cl2 05 mL) was treated
withPd0PPh ) 0116 mg, 0.1 mmol) at rt, and the reaction
1
CH2Cl2) gave 205 mg 075%) of pure imide: H NMR 8.13
3 4
mixture was stirred for 1 hin a 40 8C water bathand concen-
trated. The residue was dissolved in EtOAc 030 mL), and the
resulting solution was washed with saturated NaHCO3
03£30 mL), dried 0Na2SO4) and evaporated to give crude
amino phenyl ester.
0br s, NH), 7.98 0d, 1, Jˆ7.9 Hz), 7.63 0d, 1, Jˆ7.9 Hz),
7.56±7.41 0m, 4), 7.39±7.32 0m, 2), 7.30±7.16 0m, 3),
7.11 0d, 1, Jˆ7.9 Hz), 7.02 0d, 1, Jˆ7.9 Hz), 5.37 0dd, 1,
Jˆ3.5, 5.2 Hz), 5.36 0d, 1, Jˆ15.9 Hz), 4.25 0d, 1,
Jˆ15.9 Hz), 3.94 0q, 1, Jˆ7.0 Hz), 3.78 0dd, 1, Jˆ3.5,
15.3 Hz), 3.66 0dd, 1, Jˆ5.2, 15.3 Hz), 0.35 0d, 3,
Jˆ7.0 Hz); 13C NMR 170.0, 168.2, 166.5, 148.7, 135.84,
135.80, 133.7, 131.7, 130.9, 129.4, 128.8, 128.7, 128.2,
127.7, 125.4, 125.2, 124.4, 122.7, 120.3, 119.3, 118.0,
111.2, 109.3, 59.1, 56.4, 43.8, 28.7, 16.5; [a]Dˆ317.08 0c
0.225, EtOH).
A solution of the crude amino phenyl ester in CH2Cl2
010 mL) was treated withAcOH 02 drops) dissolved in
CH2Cl2 02 mL), and the resulting mixture was stirred for
8 hat rt. The reaction mixture was washed withNaHCO
010 mL), water 010 mL) and brine 010 mL), dried 0Na2SO4),
3

B. B. Snider, M. V. Busuyek / Tetrahedron 57 .2001) 3301±3307
3307
selective acylation is not an issue see: Sugimori, T.; Okawa,
T.; Eguchi, S.; Kakehi, A.; Yashima, E.; Okamoto, Y.
Tetrahedron 1998, 54, 7997±8008. Depew, K. M.; Marsden,
S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953±
11963.
4.1.9. N-,Nitrobenzyl)fumiquinazoline G ,25). A solution
of the above imide 0150 mg, 0.28 mmol) in dry benzene
010 mL) was treated with0 nBu)3P 070 mL, 0.28 mmol).
The resulting mixture was stirred under N2 for 2 min at
rt and 1.5 hat 75 8C and concentrated. Flashcrhomato-
graphy of the residue on silica gel 015:1 CH2Cl2/EtOAc)
gave 108 mg 078%) of 25 as a foamy solid: mp 128±
5. 0a) Rahbñk, L.; Breinholt, J.; Frisvad, J. C.; Christophersen,
C. J. Org. Chem. 1999, 64, 1689±1692. 0b) Rahbñk, L.;
Breinholt, J. J. Nat. Prod. 1999, 62, 904±905.
1
1298C; H NMR 8.39 0br d, 1, Jˆ7.8 Hz), 8.08 0br s, NH),
7.99 0d, 1, Jˆ7.8 Hz), 7.79 0t, 1, Jˆ7.8 Hz), 7.58±7.52 0m,
2), 7.49±7.38 0m, 3), 7.30 0d, 1, Jˆ7.8 Hz), 7.24 0d, 1,
Jˆ7.8 Hz), 7.15 0t, 1, Jˆ7.8 Hz), 6.98 0t, 1, Jˆ7.8 Hz),
6.81 0d, 1, Jˆ2.4 Hz), 5.72 0dd, 1, Jˆ4.3, 5.5 Hz), 5.46 0d,
1, Jˆ16.5 Hz), 4.41 0d, 1, Jˆ16.5 Hz), 4.37 0q, 1,
Jˆ6.7 Hz), 3.85 0dd, 1, Jˆ5.5, 14.7 Hz), 3.80 0dd, 1,
Jˆ4.3, 14.7 Hz), 0.63 0d, 3, Jˆ6.7 Hz); 13C NMR 166.2,
160.7, 151.6, 147.2, 135.8, 134.9, 133.8, 131.0, 129.0,
128.6, 127.8, 127.1, 126.9, 126.7, 125.2, 123.4, 122.6,
120.1, 118.8, 111.2, 109.8, 64.2, 64.1, 57.3, 56.4, 43.9,
27.3, 20.3; [a]Dˆ2295.78 0c 0.175, EtOH); HRMS 0DEI)
calculated for C28H23N5O4 0M1) 493.1750, found 493.1732.
6. Joshi, B. K.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Nat.
Prod. 1999, 62, 650±652.
7. 0a) He, F.; Snider, B. B. Synlett 1997, 483±484. 0b) Wang, H.;
Ganesan, A. J. Org. Chem. 1998, 63, 2432±2433 For another
fumiquinazoline G synthesis see: . 0c) Wang, H.; Ganesan, A.
J. Org. Chem. 2000, 65, 1022±1030.
8. 0a) Kim, D. H. J. Heterocycl. Chem. 1975, 12, 1323±1324.
0b) Akssira, M.; Boumzebra, M.; Kasmi, H.; Dahdouh, A.;
Roumestant, M. L.; Viallefont, Ph. Tetrahedron 1994, 50,
9051±9060. 0c) Mohiuddin, G.; Reddy, P. S. N.; Ahmed, K.;
Ratnam, C. V. Indian J. Chem. 1985, 905±907.
9. Ardakani, M. A.; Smalley, R. K.; Smith, R. H. J. Chem. Soc.,
Perkin Trans. 1 1983, 2501±2506.
4.1.10. ent-Fumiquinazoline G ,ent-7a). A solution of 25
025 mg, 0.05 mmol) in anhydrous MeOH 025 mL) in a
Pyrex ¯ask was purged withN for 5 min. The reaction
10. For an alternative synthesis see: Harrison, D. R.; Kennewell,
P. D.; Taylor, J. B. J. Heterocycl. Chem. 1977, 14, 1191±
1196.
2
mixture was irradiated in a cylindrical photoreactor with
seventeen, 12 in. long 254 nm lamps 0G8T5 SYLVANIA)
under N2 for 14 hand concentrated. Flashchromatography
of the residue on silica gel deactivated with 5% H2O 01:1
CH2Cl2/EtOAc) gave 16 mg 087%) of ent-7a as a white
11. Bock, M. G.; DiPardo, R. M.; Cochran, D. W.; Homnick,
C. H.; Freidinger, R. M. Heterocycles 1985, 23, 273±276.
12. Sun, H. H.; Barrow, C. J.; Cooper, R. J. Nat. Prod. 1995, 58,
1575±1580.
1
solid: the H and 13C NMR spectral data are identical to
13. Mohiuddin, G.; Reddy, P. S.; Ahmed, K.; Ratnam, C. V.
J. Chem. Res., Synop. 1987, 7, 224±225.
Â
14. 0a) Buenadicha, F. L.; Bartolome, M. T.; Aguirre, M. J.;
those previously reported;2,7 [a]Dˆ1477.88 0c 0.072,
CHCl3) 0lit. 2 for enantiomer [a]Dˆ2462.8 0c 0.61,
CHCl3)).
È
AvendanÄo, C.; Sollhuber, M. Tetrahedron: Asymmetry 1998,
9, 483±501. 0b) Caballero, E.; AvendanÄo, C.; Menendez, J. C.
Â
Heterocycles 2000, 53, 1765±1782.
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6375±6386. For other applications of this reaction where