Total syntheses of the benzodiazepine alkaloids circumdatin F and circumdatin C

Article abstract of DOI:10.1021/jo001696h

Total syntheses of circumdatin F and circumdatin C, which both possess a 3H-quinazolin-4-one as well as a 1,4-benzodiazepin-5-one moiety, are described. A tripeptide derivative was synthesized as a key intermediate and dehydrated to a benzoxazine by react

Full text of DOI:10.1021/jo001696h

2784
J . Org. Chem. 2001, 66, 2784-2788
Tota l Syn th eses of th e Ben zod ia zep in e Alk a loid s Cir cu m d a tin F
a n d Cir cu m d a tin C
Anette Witt and J an Bergman*
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute and
So¨derto¨rn University College, Novum Research Park, SE-141 57 Huddinge, Sweden
jabe@cnt.ki.se
Received December 4, 2000
Total syntheses of circumdatin F and circumdatin C, which both possess a 3H-quinazolin-4-one as
well as a 1,4-benzodiazepin-5-one moiety, are described. A tripeptide derivative was synthesized
as a key intermediate and dehydrated to a benzoxazine by reaction with triphenylphosphine, iodine,
and a tertiary amine. The natural products were attained via rearrangements to an amidine
intermediate, deprotection with 45% HBr in acetic acid, and cyclization on silica gel.
In tr od u ction
In 1999, several new fused benzodiazepine alkaloids
were isolated from a terrestrial isolate of the fungus
Aspergillus ochraceus.1 Circumdatin F (1) and C (2) are
prototypical members, while others such as circumdatin
D (3) and E (4) feature an additional tetrahydropyrrole
ring (Figure 1). The related alkaloid, asperlicin (5),
produced by Aspergillus alliaceus, is a potent cholecys-
tokinin antagonist,2 and benzomalvin A (6), isolated from
a fungus culture of Penicillium sp, showed inhibitory
activity against substance P at the guinea pig, rat, and
human neurokinin NK1 receptors, respectively.3 Scle-
rotigenin (7) was recently isolated from organic extracts
of sclerotia of Penicillium sclerotigenum (NRRL 3461),4
a potential antiinsectan benzodiazepine alkaloid. The
total syntheses of asperlicin (5)5 and benzomalvin A (6)6
have been reported, and a synthesis of sclerotigenin (7)7
was reported already 20 years ago, i.e., before its iden-
tification as a natural product. Now we wish to report
the total syntheses of circumdatin F (1) and C (2).
F igu r e 1.
Resu lts a n d Discu ssion
Retrosynthetically, compounds 1 and 2 could formally
be biosynthesized from two appropriately substituted
anthranilic acid units and L-alanine. Dehydration of a
peptide precursor X (Figure 2) represents a route to the
quinazoline ring of these natural products.8 However, the
* To whom correspondence should be addressed. Tel.: +46-8-608
92 04. Fax: +46-8-608 15 01.
(1) (a) Rahbæk, L.; Breinholt, J .; Frisvad, J . C.; Christophersen, C.
J . Org. Chem. 1999, 64, 1689-1692. (b) Rahbæk, L.; Breinholt, J . J .
Nat. Prod. 1999, 62, 904-905.
(2) (a) Goetz, M. A.; Lopez, M.; Monaghan, R. L.; Chang, R. S. L.;
Lotti, V. J .; Chen, T. B. J . Antibiot. 1985, 38, 1633-1637. (b) Liesch,
J . M.; Hensens, O. D.; Springer, J . P.; Chang, R. S. L.; Lotti, V. J . J .
Antibiot. 1985, 38, 1638-1641. (c) Sun, H. H.; Byard, S. J .; Copper, R.
J . Antibiot. 1994, 47, 599-601.
F igu r e 2.
(3) Sun, H. H.; Barrow, C. J .; Sedlock, D. M.; Gillum, A. M.; Copper,
R. J . Antibiot. 1994, 47, 515-522.
aza-Wittig disconnection6 might be useful, but the pre-
cursor Y will require additional manipulation of protect-
ing groups.
(4) J oshi, B. K.; Gloer, J . B.; Wicklow, D. T.; Dowd, P. F. J . Nat.
Prod. 1999, 62, 650-652.
(5) He, F.; Foxman, B. M.; Snider, B. B. J . Am. Chem. Soc. 1998,
120, 6417-6418.
(6) Sugimori, T.; Okawa, T.; Eguchi, S.; Kakehi, A.; Yashima, E.;
Okamoto, Y. Tetrahedron 1998, 54, 7997-8008 and references therein.
(7) Harrison, D. R.; Kennewell, P. D.; Taylor, J . B. J . Heterocycl.
Chem. 1977, 14, 1191-1196.
(8) For recent reviews on quinazoline alkoloids, see: (a) Michael, J .
P. Nat. Prod. Rep. 2000, 17, 603-620. (b) J ohne, S. In Supplements to
the Second Edition of Rodd’s Chemistry of Carbon Compounds; Ansell,
M. F., Ed.; Elsevier: Amsterdam, 1995; Vol.IV I/J , pp 223-240.
10.1021/jo001696h CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/22/2001

Circumdatin F and Circumdatin C
J . Org. Chem., Vol. 66, No. 8, 2001 2785
Sch em e 1
Sch em e 3a
Sch em e 2a
a
Reagents and conditions: (a) methyl anthranilate or 15,
toluene, rt, 48 h; (b) Cbz-L-Ala, DCC, CH2Cl2, rt; (c) LiOH, MeOH/
THF/H2O (3:1:1), rt, 3 h; (d) methyl anthranilate or 15, PCl3,
toluene, reflux, 3h.
a
Reagents and conditions: (a) Ac2O, EtOH, 40-50 °C, 3 h;
nilate 15 in an overall yield of 65% from 2-amino-5-
hydroxybenzoic acid. N-Acetylation and O-benzylation of
4-amino-2-hydroxybenzoic acid methyl ester are known
according to this methodology.13
(b) BnBr, K2CO3, acetone, reflux, 3.5 h; (c) HCl(g) in MeOH, reflux,
8 h.
Wangand Ganesan havereported9 a routetofumiquinazo-
line G (11), wherein the protected tripeptide 8 was used
as a key intermediate (Scheme 1) in the cyclization step.
These workers proposed the cyclization product to be a
quinazolin-4-one 9, but He and Snider showed10 it rather
to be the 4-imino-4H-3,1-benzoxazine 10. We considered
this synthetic strategy to be useful for syntheses of cir-
cumdatin F (1) and C (2), but rather than to create two
six-membered rings, we wanted to induce cyclization in-
volving one six-membered and one seven-membered ring.
Circumdatin C (2) can be considered as derived from
5-hydroxyanthranilic acid, and several suitably protected
5-hydroxy derivatives of, e.g., methyl anthranilate are
known.11,12 The benzylated derivative 1511 was prepared
from the known 2-amino-5-hydroxybenzoic acid methyl
ester 12,12 obtained by esterification of commercially
available 2-amino-5-hydroxybenzoic acid in 95% yield
followed by N-acetylation with acetic anhydride in etha-
nol to the N-acetyl derivative 13 (Scheme 2). Compound
13 was O-benzylated with benzyl bromide and K2CO3 in
acetone to compound 14, which was treated with HCl in
methanol at reflux to give methyl 5-(benzyloxy)anthra-
N-Sulfinylanthraniloyl chloride (16),14a previously de-
scribed as a sulfinamide anhydride,14b was prepared from
anthranilic acid and thionyl chloride and treated with
methyl anthranilate or compound 15 to yield 2-(2-amino-
benzoylamino)-benzoic acid methyl ester (17a )15 or 2-(2-
amino-benzoylamino)-5-benzyloxybenzoic acid methyl es-
ter (17b), respectively. Condensation of 17a ,b with
N-Cbz-L-alanine16 and DCC afforded the tripeptide de-
rivatives 21a ,b ()X, Figure 2) in 58% and 63% yield,
respectively (Scheme 3).
In a second synthetic approach the tripeptide deriva-
tives 21a ,b were made via condensation of N-Cbz-L-
alanine16 with methyl anthranilate under standard cou-
pling conditions with DCC and N-hydroxybenzotriazole,
which resulted in 57% yield of the corresponding amide
18 (Scheme 3). Hydrolysis of the ester functionality using
LiOH yielded the acid 1917 in 82% yield. Construction of
analogues of the acid 19 were executed according to this
protocol.18
(13) MacKenzie, A. R.; Moody, C. J .; Rees, C. W. Tetrahedron 1986,
42, 3259-3268.
(14) (a) Gar´ın, J .; Merino, P.; Orduna, J .; Tejero, T.; Uriel, S.
Tetrahedron Lett. 1991, 32, 3263-3264. (b) Kametani, T.; Higa, T.;
Van Loc, C.; Ihara, M.; Koizumi, M.; Fukumoto, K. J . Am. Chem. Soc.
1976, 98, 6186-6188.
(15) Kamat, V. P.; Kirtany, J . K. Org. Prep. Proced. Int. 1994, 26,
494-497.
(16) Bergmann, M.; Zervas, L. Chem. Ber. 1932, 65, 1192-1201.
(17) Chiba, T.; Endo, A.; Sugawara, S. Akita Kogyo Koto Senmon
Gakko Kenkyu Kiyo 1999, 37-39.
(9) (a) Wang, H.; Ganesan, A. J . Org. Chem. 1998, 63, 2423-2433.
(b) Wang, H.; Ganesan, A. J . Org. Chem. 2000, 65, 1022-1030.
(10) He, F.; Snider, B. B. J . Org. Chem. 1999, 64, 1397-1399.
(11) Venuti, M. C.; Stephenson, R. A.; Alvares, R.; Bruno, J . J .;
Strosberg, A. M. J . Med. Chem. 1988, 31, 2136-2145.
(12) Rodionow, W. M.; Fedorowa, A. M. Bull. Soc. Chim. Fr. 1939,
478-486.

2786 J . Org. Chem., Vol. 66, No. 8, 2001
Witt and Bergman
Sch em e 4
Sch em e 5a
When peptide coupling reagents such as DCC19 or
1-methyl-2-chloropyridinium iodide20 were used on com-
pound 19 the sole product was an intramolecular cycliza-
tion to the benzoxazinone derivative 2017 (Scheme 4) and
no coupling products 21a ,b were detected. The acid 19
was treated with PCl3 and then heated with methyl
anthranilate or compound 15 in toluene to give the
tripeptide derivatives 21a ,b in 41% and 43% yield, as
racemates.
Cyclization of the tripeptide derivatives 21a ,b with
PPh3 and I2 in the presence of EtN(i-Pr)2 in CH2Cl2 at
room temperature gave the 4-imino-4H-3,1-benzoxazines
22a ,b in 57% and 36% isolated yields, respectively, after
separation on silica gel. A further less pure quantity of
the component 22a was isolated in 20% yield. According
1
to H NMR, this material contained starting material
a
Reagents and conditions: (a) PPh3, I2, EtN(i-Pr)2, CH2Cl2, rt,
6 h; (b) 20% piperidine in EtOAc, rt, 5 h; (c) 45% HBr in HOAc,
60 °C, 1h; (d) SiO2, triethylamine or EtN(i-Pr)2, EtOAc, rt.
(15%) but could nevertheless be used directly in the
synthesis of circumdatin F (1) without purification until
the last step. Similarly compound 22b and starting
material (95:5) was isolated in 38% yield and could be
converted to circumdatin C (2) in the same fashion as
compound 22a .
When compounds 22a ,b were treated with 20% pip-
eridine in EtOAc at room temperature, the amidine
carboxamides 23a ,b were isolated in 67% and 77% yield,
respectively, and used immediately in the deprotection
by heating at 50 °C with 45% HBr in HOAc. During the
deprotection of 23b both the benzyl- and the Cbz-group
were removed, as expected by the use of strong acid.21 It
is presumed that the HBr salts of deprotected 23a ,b
cyclize to 3H-quinazolin-4-one, which quickly eliminate
methanol thus yielding circumdatin F (1) and C (2) in
25% and 30% yield, respectively, from the amidine
carboxamides 23a ,b (Scheme 5).
recorded on a FT-IR instrument. Mass spectra were recorded
using a GC/MS system operating in the electron impact (EI)
mode at 70 eV. Only fragments larger than 20% of the base
peak are given. The element compositions were determined
by H. Kolbe Mikroanalytisches Laboratorium, Mu¨lheim an der
Ruhr, Germany. HRMS analyses were performed by Sveriges
Lantbruksuniversitet (SLU), Uppsala, Sweden. Melting points
were measured using the capillary method and are uncor-
rected. All reagents were of commercial quality and were used
as received. All solvents were purified by distillation or were
HPLC grade. Reactions were monitored by thin-layer chro-
matography, on aluminum plates coated with silica gel with
fluorescent indicator. Separations by flash chromatography
were preformed on silica gel. Optical rotation values were
determined in a polarimeter equipped with a 1 mL cell
measuring 10 cm using the emission wavelength of a sodium
lamp; concentrations are given in g/100 mL.
2-(2-Am in o-ben zoyla m in o)-ben zoic Acid Meth yl Ester
(17a ). Methyl anthranilate (1.16 g, 7.7 mmol) dissolved in
toluene (20 mL) was added dropwise to a solution of compound
1614a (2.02 g, 10 mmol) in toluene (20 mL) at room tempera-
ture. The mixture was stirred at ambient temperature for 48
h, poured into cold water (50 mL), and extracted with CHCl3
(50 mL × 2). The organic phases were washed with saturated
NaHCO3 (50 mL) and brine (50 mL) and dried (Na2SO4). The
solution was concentrated under reduced pressure to afford
an oily residue, which was purified by flash chromatography
(20% diethyl ether in hexane as eluent) to give compound 17a
The spectra of the synthetic 1 and 2 were identical with
the published spectroscopic data.1 Due to low solubility
in MeOH-d4 we did ran spectra in CDCl3 and DMSO-d6,
respectively. The specific optical rotation of the synthetic
circumdatin C ([R]20D -91° (c 0.17, MeOH)) differed from
the reported value for natural circumdatin C ([R]22D -75°
(c 0.16, MeOH)).1a Synthetic circumdatin F gave the
optical rotation, [R]20 -55° (c 0.94, CHCl3), no value for
D
the natural circumdatin F has been published.
In conclusion, the total synthesis of circumdatin F (1)
has been achieved in 5 steps and 5.5% overall yield from
17a , and circumdatin C (2) was attained in 10 steps and
0.9% overall yield from 2-amino-5-hydroxybenzoic acid.
(0.95 g, 46%) as a light yellow solid: mp 116-117 °C (lit.15
,
mp 128 °C); IR (KBr) 3474, 3364, 1684, 1660, 1519, 1450, 1262,
765, 743 cm-1; δH (300 MHz, CDCl3) 3.96 (s, 3H), 5.52 (br s,
2H), 6.74 (dd, J ) 8.3, 1.0, 1H), 6.79 (ddd, J ) 8.0, 7.0, 1.1,
1H), 7.11 (ddd, J ) 8.1, 7.1, 1.1, 1H), 7.28 (ddd, J ) 8.3, 7.0,
1.4, 1H), 7.59 (ddd, J ) 8.6, 7.1, 1.6, 1H), 7.75 (dd, J ) 8.0,
1.4, 1H), 8.08 (dd, J ) 8.1, 1.6, 1H), 8.83 (dd, J ) 8.6, 1.0,
1H), 11.83 (s, 1H); δC (75 MHz, CDCl3) 52.6 (q), 115.5 (s), 116.0
(s), 117.3 (d), 117.8 (d), 120.7 (d), 122.6 (d), 127.9 (d), 131.2
(d), 133.1 (d), 134.8 (d), 142.1 (s), 149.8 (s), 168.3 (s), 169.1 (s).
2-(2-Am in o-ben zoyla m in o)-5-ben zyloxyben zoic Acid
Meth yl Ester (17b). Compound 17b was prepared similarly
to compound 17a using compound 15, but compound 17b was
purified by recrystallization from 35% ethyl acetate in hex-
ane: yield, 27%; mp 149-150 °C; IR (KBr) 3475, 3360, 1686,
1660, 1523, 1227, 1008, 836, 753, 692 cm-1; δH (300 MHz,
DMSO-d6) 3.86 (s, 3H), 5.15 (s, 2H), 6.52 (s, 2H), 6.63 (ddd, J
) 7.9, 7.1, 0.9, 1H), 6.78 (d, J ) 8.3, 1H), 7.23 (ddd, J ) 8.3,
Exp er im en ta l Section
Gen er a l Asp ects. NMR spectra were recorded at 300 MHz
for 1H and 75 or 125 MHz for 13C; δ values are given in ppm,
coupling constants are reported in hertz. Infrared spectra were
(18) Mohapatra, D. K.; Datta, A. Bioorg. Med. Chem. Lett. 1997, 7,
2527-2530.
(19) Bodanszky, M.; Bodanszky, A. The practice of peptide synthesis;
Springer-Verlag: Berlin, 1994.
(20) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163-
1166.
(21) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley and Sons: New York, 1991.

Circumdatin F and Circumdatin C
J . Org. Chem., Vol. 66, No. 8, 2001 2787
7.0, 1.2, 1H), 7.26-7.52 (m, 6H), 7.54 (d, J ) 3.0, 1H), 7.59 (d,
J ) 8.0, 1H), 8.33 (d, J ) 9.1, 1H), 11.02 (s, 1H); δC (75 MHz,
DMSO-d6) 52.6 (q), 69.6 (t), 114.1 (s), 115.1 (d), 115.5 (d), 116.9
(d), 118.8 (s), 121.0 (d), 123.0 (d), 127.4 (d), 127.7 (d), 127.9
(d), 128.4 (d), 132.5 (d), 133.8 (s), 136.7 (s), 150.3 (s), 153.5 (s),
167.1 (s), 167.6 (s).
[R]20 -16° (c 0.93, CHCl3); mp 126-127 °C; IR (KBr) 3308,
D
1719, 1684, 1540, 1251, 1080, 736 cm-1; δH (300 MHz, CDCl3)
1.33 (d, J ) 6.9, 3H), 3.76 (s, 3H), 4.47 (q, J ) 6.9, 1H), 5.10
(s, 2H), 5.61 (d, J ) 6.8, 1H), 7.00 (d, J ) 7.9, 1H), 7.17 (ddd,
J ) 8.1, 7.0, 1.1, 1H), 7.27-7.56 (m, 8H), 7.64 (ddd, J ) 7.7,
6.9, 1.4, 1H), 7.98 (dd, J ) 7.9, 1.4, 1H), 8.28 (d, J ) 7.6, 1H);
δC (75 MHz, CDCl3) 19.7 (q), 49.0 (d), 52.1 (q), 67.1 (t), 119.2
(s), 121.6 (s), 122.8 (d), 123.8 (d), 126.6 (d), 127.0 (d), 128.3
(d), 128.4 (d), 128.7 (d), 128.9 (d), 131.3 (d), 133.2 (d), 134.1
(d), 136.5 (s), 141.9 (s), 146.2 (s), 147.1 (s), 155.6 (s), 159.8 (s),
166.8 (s); GC/MS (EI) m/z (rel intensity) 457 (M+, 1%), 279
(100). Anal. Calcd for C26H23N3O5: C, 68.26; H, 5.07; N, 9.19.
Found: C, 68.20; H, 4.96; N, 9.11.
2-[2-(N-Ben zyloxyca r b on yl-L-a la n yl)-ben zoyla m in o]-
ben zoic Acid Meth yl Ester (21a ). Meth od A. DCC (180 mg,
0.87 mmol) dissolved in CH2Cl2 (3 mL) was added to a solution
of compound 17a (195 mg, 0.72 mmol) and N-Cbz-L-Ala16 (193
mg, 0.86 mmol) in CH2Cl2 (6 mL) at 0 °C, and the mixture
was stirred at ambient temperature overnight. After filtration
through Celite, the organic phase was washed with 2 M HCl
(10 mL), saturated NaHCO3 (10 mL), and water (10 mL). The
organic phase was dried (Na2SO4) and concentrated under
reduced pressure to afford a solid residue, which was purified
by flash chromatography (30% ethyl acetate in hexane as
eluent) to give compound 21a (200 mg, 58%) as a white solid:
N-{2-[1-N-(Ben zyloxycar bon yl)-am in oeth yl]-4H-3,1-ben -
zoxa zin -4-ylid en e}-5-ben zyloxy-ben zoic Acid Meth yl Es-
ter (22b). Compound 22b was prepared similarly to compound
22a using compound 21b: yield, 36% as a white solid; [R]20
D
-21° (c 1.1, CHCl3); mp 154-155 °C; IR (KBr) 3284, 1731,
1682, 1543, 1497, 1268, 1231, 1069, 1014, 748 cm-1; δH (300
MHz, DMSO-d6) 1.26 (d, J ) 6.9, 3H), 3.69 (s, 3H), 4.20-4.32
(m, 1H), 5.00 (s, 2H), 5.10 (s, 2H), 7.02-7.59 (m, 15H), 7.69-
7.83 (m, 2H), 8.14 (d, J ) 7.5, 1H); δC (75 MHz, DMSO-d6)
17.5 (q), 48.8 (d), 51.9 (q), 65.4 (t), 69.6 (t), 115.2 (d), 118.7 (s),
119.9 (d), 123.1 (s), 124.2 (d), 126.1 (d), 126.2 (d), 127.6 (d),
127.7 (d), 127.8 (d), 127.9 (d), 128.3 (d), 128.4 (d), 128.6 (d),
134.2 (d), 136.8 (s), 136.9 (s), 139.0 (s), 141.6 (s), 145.6 (s), 154.2
(s), 155.6 (s), 160.5 (s), 165.9 (s). Anal. Calcd for C33H29N3O6:
C, 70.33; H, 5.19; N, 7.45. Found: C, 70.26; H, 5.09; N, 7.36.
Am id in e Ca r boxa m id e (23a ). Piperidine (distilled from
CaH2, 1.5 mL) was added to a solution of compound 22a (275
mg, 0.60 mmol) in EtOAc (6 mL). The reaction mixture was
stirred at room temperature for 5 h and concentrated under
reduced pressure to an yellow oil. The residue was purified
by flash chromatography (30% ethyl acetate in hexane) to give
compound 23a (220 mg, 67%) as a light yellow oil: δH (300
MHz, CDCl3) 1.35 (d, J ) 6.8, 3H), 1.35-1.63 (m, 6H), 2.96-
3.30 (m, 4H), 3.73 (s, 3H), 4.74-4.89 (m, 1H), 4.99 and 5.13
(AB q, J ) 12.2, 2H), 6.62-6.78 (m, 2H), 7.03 (dd, J ) 7.5,
7.4, 1H), 7.10 (dd, J ) 8.0, 7.1, 1H), 7.24-7.39 (m, 6H), 7.57
(dd, J ) 8.4, 7.1, 1H), 7.95 (d, J ) 7.4, 1H), 8.02 (d, J ) 7.8,
1H), 8.65 (d, J ) 8.4, 1H), 11.96 (s, 1H); δC (75 MHz, CDCl3)
21.6 (q), 24.3 (t), 25.9 (t), 48.0 (d), 49.3 (t), 52.4 (q), 66.7 (t),
117.6 (s), 121.7 (d), 121.9 (d), 122.9 (d), 123.5 (d), 125.5 (s),
128.1 (d), 128.2 (d), 128.6 (d), 130.8 (d), 131.2 (d), 132.0 (d),
134.0 (d), 136.8 (s), 140.8 (s), 149.4 (s), 156.1 (s), 161.5 (s), 166.6
(s), 168.0 (s). The product thus obtained was used without
further purification.
[R]20 -21° (c 1.05, CHCl3); mp 147-148 °C; IR (KBr) 3298,
D
2928, 1697, 1651, 1583, 1540, 1445, 1268, 1066, 754 cm-1; δH
(300 MHz, CDCl3) 1.55 (d, J ) 7.1, 3H), 3.97 (s, 3H), 4.41-
4.54 (m, 1H), 5.14 and 5.17 (AB q, J ) 12.3, 2H), 5.60 (d, J )
6.4, 1H), 7.15 (ddd, J ) 8.3, 7.2, 1.0, 1H), 7.20-7.45 (m, 6H),
7.47-7.60 (m, 2H), 7.89 (d, J ) 7.1, 1H), 8.10 (dd, J ) 8.0,
1.6, 1H), 8.69 (d, J ) 8.3, 1H), 8.78 (d, J ) 8.4, 1H), 11.78 (s,
1H), 12.09 (s, 1H); δC (75 MHz, CDCl3) 19.3 (q), 52.1 (d), 52.8
(q), 67.2 (t), 115.8 (s), 120.8 (s), 120.8 (d), 121.7 (d), 123.4 (d),
123.7 (d), 127.3 (d), 128.1 (d), 128.2 (d), 128.7 (d), 131.2 (d),
133.3 (d), 134.9 (d), 136.5 (s), 140.2 (s), 141.3 (s), 155.9 (s),
167.8 (s), 169.1 (s), 171.3 (s). Anal. Calcd for C26H25N3O6: C,
65.68; H, 5.30; N, 8.84. Found: C, 65.79; H, 5.28; N, 8.81.
Meth od B. PCl3 (105 mg, 0.76 mmol) was added to a
mixture of 19 (113 mg, 0.33 mmol) and methyl anthranilate
(67 mg, 0.44 mmol) in toluene (3 mL, distilled over Na) under
N2. The mixture was heated at reflux for 3 h and then
concentrated under reduced pressure to afford a solid residue,
which was purified as in method A to give compound 21a (60
mg, 41%).
2-[2-(N-Ben zyloxyca r b on yl-L-a la n yl)-b en zoyla m in o]-
5-ben zyloxy-ben zoic Acid Meth yl Ester (21b). Meth od A.
Compound 21b was prepared similarly to compound 21a using
compound 17b, but compound 21b was purified by recrystal-
lization from ethyl acetate/chloroform (4:1) in 52% yield. The
evaporated mother liquor was purified by flash chromatogra-
phy (40% ethyl acetate in hexane as eluent) to give additional
21b (230 mg, 11%): total yield, 63% as a white solid; [R]20
D
-8.6° (c 1.0, CHCl3); mp 192-193 °C; IR (KBr) 3318, 1697,
1538, 1285, 1229, 1067, 1016, 751, 698 cm-1; δΗ (300 MHz,
DMSO-d6) 1.31 (d, J ) 7.3, 3H), 3.83 (s, 3H), 4.00-4.13 (m,
1H), 4.89 and 5.00 (AB q, J ) 12.5, 2H), 5.12 (s, 2H), 7.19 (dd,
J ) 9.0, 3.0, 1H), 7.24-7.48 (m, 11H), 7.53 (d, J ) 3.0, 1H),
7.58 (ddd, J ) 8.4, 7.2, 1.4, 1H), 7.88 (d, J ) 7.1, 1H), 7.95 (d,
J ) 6.5, 1H), 8.08 (d, J ) 9.0, 1H), 8.43 (d, J ) 8.3, 1H), 11.01
(s, 1H), 11.31 (s, 1H);_δC (125 MHz, DMSO-d6) 17.8 (q), 52.3
(d), 53.2 (q), 66.3 (t), 70.2 (t), 116.3 (d), 120.9 (d), 121.4 (d),
121.9 (s), 122.6 (s), 123.9 (d), 125.2 (d), 128.2 (d), 128.3 (d),
128.3 (d), 128.4 (d), 128.5 (d), 128.8 (d), 129.0 (d), 132.7 (s),
133.0 (d), 137.2 (s), 137.3 (s), 139.0 (s), 155.1 (s), 156.5 (s), 167.1
(s), 167.6 (s), 172.2 (s). Anal. Calcd for C33H31N3O7: C, 68.15;
H, 5.37; N, 7.22. Found: C, 68.22; H, 5.32; N, 7.18.
Am id in e Ca r boxa m id e (23b). Compound 23b was pre-
pared similarly to compound 23a using compound 22b: yield,
77% as a colorless oil; δH (300 MHz, CDCl3) 1.36 (d, J ) 6.8,
3H), 1.42-1.58 (m, 6H), 3.00-3.27 (m, 4H), 3.72 (s, 3H), 4.76-
4.88 (m, 1H), 4.95-5.20 (m, 4H), 6.63-6.76 (m, 2H), 7.02 (dd,
J ) 8.1, 7.0, 1H), 7.21 (dd, J ) 9.2, 3.0, 1H), 7.24-7.53 (m,
11H), 7.55 (d, J ) 3.0 1H), 8.06 (dd, J ) 7.9, 1.4, 1H), 8.51 (d,
J ) 9.2, 1H), 11.79 (s, 1H); δC (75 MHz, CDCl3) 21.5 (q), 24.3
(t), 25.9 (t), 48.0 (d), 49.2 (t), 52.5 (q), 66.7 (t), 70.6 (t), 116.0
(d), 119.1 (s), 121.0 (d), 121.7 (d), 121.9 (d), 125.2 (s), 125.4
(d), 127.7 (d), 128.1 (d), 128.2 (d), 128.2 (d), 128.5 (d), 128.8
(d), 131.2 (d), 131.9 (d), 134.3 (s), 136.8 (s), 136.8 (s) 149.4 (s),
154.1 (s), 156.1 (s), 161.5 (s), 166.2 (s), 167.5 (s). The product
thus obtained was used without further purification.
Cir cu m d a tin F (1). Compound 23a (190 mg, 0.35 mmol)
was dissolved in 45% HBr in HOAc (5 mL) and heated to 60
°C. Upon cessation of gas evolution (less than 1 h), diethyl
ether (5 + 5 mL) was added to precipitate the hydrobromide
of compound 23a . The mixture was left in an ice bath for a
couple of hours. The resulting orange precipitate was collected
and dried. Triethylamine (0.06 mL, 0.43 mmol) was added to
a solution of the HBr salt of deprotected 23a (135 mg, 0.28
mmol) dissolved in EtOAc (3 mL), and within 15 min, silica
gel (600 mg, silica gel 60, 230-400 mesh ASTM, Merck) was
added. The mixture was stirred at room temperature over-
night. After filtration through Celite, the solvent was concen-
trated under reduced pressure. The residue was purified by
flash chromatography (60% ethyl acetate in hexane) to give
Meth od B. Compound 21b was prepared similarly to
compound 21a using compound 17b, but compound 21b was
purified by flash chromatography (40% ethyl acetate in hexane
as eluent): yield, 43%.
N-{2-[1-N-(Ben zyloxycar bon yl)-am in oeth yl]-4H-3,1-ben -
zoxa zin -4-ylid en e}-ben zoic Acid Meth yl Ester (22a ). Ph3P
(1.57 g, 6.0 mmol), I2 (1.52 g, 6.0 mmol), and N, N-diisopro-
pylethylamine (2.0 mL, 11.6 mmol) were added to a solution
of compound 21a (570 mg, 1.2 mmol) in CH2Cl2 (25 mL). The
reaction mixture was stirred at room temperature for 6 h and
quenched with aqueous Na2CO3 (25 mL). The organic phase
was separated, dried (Na2SO4), and concentrated under re-
duced pressure. The dark residue was purified by flash
chromatography (30% ethyl acetate in hexane with 2% Et3N)
to give compound 22a (310 mg, 57%) as a light yellow solid:

2788 J . Org. Chem., Vol. 66, No. 8, 2001
Witt and Bergman
compound 1 (25 mg, 25%) as a white solid: [R]20 -55° (c 0.
1673, 1656, 1605, 1387, 1290, 1252, 1214, 778 cm-1; δΗ (300
MHz, DMSO-d6) 1.52 (d, J ) 6.7, 3H), 4.30-4.40 (m, 1H), 7.01
(dd, J ) 8.8, 2.9, 1H), 7.11 (d, J ) 2.9, 1H), 7.41 (d, J ) 8.8,
1H), 7.58 (ddd, J ) 8.0, 7.0, 1.1, 1H), 7.73 (d, J ) 8.0, 1H),
7.88 (ddd, J ) 8.4, 6.9, 1.5, 1H), 8.17 (dd, J ) 8.0, 1.1, 1H),
8.69 (d, J ) 5.9, 1H), 10.18 (s, 1H); δC (75 MHz, DMSO-d6)
14.9 (q), 49.5 (d), 114.1 (d), 117.8 (d), 120.9 (s), 124.4 (s), 126.7
(d), 127.3 (d), 127.3 (d), 130.0 (d), 132.4 (s), 134.9 (d), 145.9
(s), 156.8 (s), 157.2 (s), 161.1 (s), 166.6 (s). Anal. Calcd for
D
94, CHCl3); IR (KBr) 3278, 3180, 2962, 1685, 1654, 1615, 1449,
1363, 1261, 1096, 1018, 780 cm-1; δH (300 MHz, CDCl3)
1.73 (d, J ) 6.6, 3H), 4.32-4.48 (m, 1H), 7.22 (br d, J ) 5.3,
1H), 7.81-7.56 (m, 6H), 7.96 (d, J ) 7.2, 1H), 8.26 (d, J ) 7.9,
1H); δC (75 MHz, CDCl3) 15.5 (q), 50.1 (d), 121.6 (s), 127.6 (d),
127.7 (d), 127.9 (d), 128.5 (d), 129.1 (d), 130.1 (d), 130.8 (s),
131.5 (d), 133.7 (s), 135.0 (d), 146.3 (s), 155.2 (s), 161.8 (s),
168.2 (s); GC/MS (EI) m/z (rel intensity) 292 (M++ 1, 18%),
291 (M+, 100), 249 (66), 248 (64), 247 (37), 220 (24), 146 (32),
124 (21); HRMS (EI) m/z calcd for C17H13N3O2 291.1008, found
291.0989.
C
17H13N3O3: C, 66.44; H, 4.26; N, 13.67. Found: C, 66.34; H,
4.21; N, 13.61.
Cir cu m d a tin C (2). Circumdatin C was prepared similarly
to circumdatin F (1) using compound 23b and N,N-diisopro-
pylethylamine as a base. Compound 2 was isolated by chro-
matography on silica gel column (75% ethyl acetate in hexane)
Su p p or tin g In for m a tion Ava ila ble: Experimental data,
1H and 13C NMR spectral data for 12, 13, 14, 15, 18, 19, and
20. This material is available free of charge via the Internet
at http://pubs.acs.org.
as a beige solid: yield, 30%; [R]20D -91° (c 0. 17, MeOH) (lit.1a
,
[R]20 -75° (c 0.16, MeOH)); IR (KBr) 3336, 3183, 3072, 2940,
J O001696H
D