An efficient, PIFA mediated approach to benzo-, naphtho-, and heterocycle-fused pyrrolo[2,1-c][1,4]diazepines. An advantageous access to the antitumor antibiotic DC-81

Article abstract of DOI:10.1021/jo047872u

(Chemical Equation Presented) The synthesis of a series of optically pure benzo-, naphtho-, and heterocycle-fused pyrrolo[2,1-c][1,4]-diazepin-5,11-dione derivatives starting from L-proline methyl ester is presented. The synthetic plan includes an aroylat

Full text of DOI:10.1021/jo047872u

An Efficient, PIFA Mediated Approach to Benzo-, Naphtho-, and
Heterocycle-Fused Pyrrolo[2,1-c][1,4]diazepines. An Advantageous
Access to the Antitumor Antibiotic DC-81
Arkaitz Correa, Imanol Tellitu,* Esther Dom´ınguez,* Isabel Moreno, and Raul SanMartin
Departamento de Quı´mica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa, Universidad del Pa´ıs
Vasco-Euskal Herriko Unibertsitatea (UPV/EHU), P.O. Box 644-48080, Bilbao, Spain
qoptecoi@lg.ehu.es
Received December 1, 2004
The synthesis of a series of optically pure benzo-, naphtho-, and heterocycle-fused pyrrolo[2,1-c]-
[1,4]-diazepin-5,11-dione derivatives starting from L-proline methyl ester is presented. The synthetic
plan includes an aroylation step at the proline nitrogen followed by transformation of the ester
residue into a N-methoxyamide group. The subsequent key cyclization step embraces the PIFA
mediated formation of a N-acylnitrenium intermediate and its succeeding intramolecular trapping
by the aromatic ring. The presented general approach solves the need of starting from not very
accessible amino (or a related functionality) aromatic starting materials, and its effectiveness is
demonstrated in the synthesis of the antitumor antibiotic DC-81.
Introduction
The development of new approaches for the efficient
construction of a number of heterocycles continues to be
essential for accessing natural products and their struc-
tural analogues. Among them, the pyrrolo[2,1-c][1,4]-
benzodiazepine (PBD) scaffold has gained over the years
an ongoing interest for synthetic and clinical studies,
mainly as potential antitumor and gene targeted drugs.1
It is accepted that this class of antitumor antibiotics
produced by Streptomyces species,2 members of which
include DC-81 (1), tomaymycin (2), and anthramycin (3)
(see Figure 1), exerts its biological activity by selective
covalent binding between the iminesor equivalents
functionality and the N-2 of guanine in the minor groove
of DNA.3 The resulting DNA adduct leads to a number
FIGURE 1. Representative examples of pyrrolo[2,1-c][1,4]-
benzodiazepines.
of biological effects including inhibition of DNA replica-
tion.4 Such interaction is only effective with an (S)
configuration at carbon C(11a) of the PBD,5 which
explains the wide use of L-proline (or its derivatives) in
the preparation of this type of products.
* Address correspondence to this author. Phone: (34) 94 601 5438.
Fax: (34) 94 601 2748.
(1) Thurston, D. E. In Molecular Aspects of Anticancer Drug-DNA
Interactions; Neidle, S., Waring, M. J., Eds.; The Macmillan Press
Ltd.: London, UK, 1993; Vol. 1, pp 54-88.
In contrast to the numerous synthetic studies that the
(2) (a) Tendler, M. D.; Korman, S. Nature 1963, 199, 501. (b) Hurley,
L. H. J. Antibiot. 1977, 30, 349-370.
specialized bibliography encompasses,6 which reflects the
(3) (a) Hurley, L. H.; Petrusek, R. L. Nature 1979, 282, 529-531.
(b) Cheatham, S.; Kook, A.; Hurley, L. H.; Barkley, M. D.; Remers, W.
J. Med. Chem. 1988, 31, 583-590. (c) Wang, J. J.; Hill, G. C.; Hurley,
L. H. J. Med. Chem. 1992, 35, 2995-3002. (d) Mountzouris, J. A.;
Wang, J. J.; Thurston, D. E.; Hurley, L. H. J. Med. Chem. 1994, 37,
3132-3140.
(4) Hurley, L. H.; Needham-VanDevanter, D. R. Acc. Chem. Res.
1986, 19, 230-237.
(5) Hurley, L. H.; Reck, T.; Thurston, D. E.; Langley, D. R.; Holden,
K. G.; Hertzberg, R. P.; Hoover, J. R.; Gallagher, G., Jr.; Faucette, L.
F.; Mong, S.-M.; Johnson, R. K. Chem. Res. Toxicol. 1988, 1, 258-268.
10.1021/jo047872u CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/17/2005
2256
J. Org. Chem. 2005, 70, 2256-2264

Advantageous Access to the Antitumor Antibiotic DC-81
FIGURE 3. The aromatic amidation approach applied to the
synthesis of 1,4-diazepines and PBD’s.
heteroarene-fused pyrrolodiazepines of type VI would be
of great interest. As we have found lately, this projected
idea would be facilitated if the C(9a)-N(10) bond were
completed in an advanced step of the synthesis (bond in
bold in Figure 3), in such a way that the required
nonfunctionalized aromatic and heteroaromatic precur-
sors, bearing different substituents, could be more easily
available. A successful preliminary study was recently
carried out on structures of type V using glycine or
alanine as starting materials.11 In this case, the key
cyclization step was accomplished assisted by the ac-
tion of the hypervalent iodine12 reagent PIFA [phen-
yliodine(III) bis(trifluoroacetate)] on N-methoxyamide
substrates. At that stage, nonetheless, attempts to extend
this method to the corresponding PBD derivatives start-
ing from proline proved to be an elusive goal, which
reflects the unavoidable protection of nitrogen N(4) in
order to elude, as observed in its absence, benzylic
oxidation with concomitant degradation.
Trying to circumvent this drawback we considered that
placing a carbonyl group at the C(5) position (in VI)
would not only operate as the compelled protection of the
nitrogen atom against the I(III) oxidative reagent, but it
also would be an important structural component present
in several members of the family of the naturally occur-
ring PBD derivatives, as shown in Figure 1. Therefore,
herein we would like to report a novel access to the
construction of the PBD skeleton, and heterocyclic ana-
logues, through a PIFA mediated aromatic amidation
process.
FIGURE 2. Different approaches to the construction of PBD
derivatives.
extensive interest in PBD derivatives, most of them fit
only into the four approaches schematically represented
in Figure 2. Nevertheless, they all lack wide generality
and some others are tedious. For example, one of the
broadly used methods involves the intramolecular aza-
Wittig reaction of azidocarbonyl compounds7 or the
reductive cyclization of acyclic nitroaldehydes8 of type I.
Analogously, the PBD skeleton also has been achieved
by deprotective cyclization of amino dithioacetals of type
II using mercuric chloride in aqueous acetonitrile,9a or,
more recently, bismuth triflate9b and iron trichloride.9c
Apart from the fact of using highly toxic chemicals, which
hinders the scale-up of the process, both approaches
require a considerable effort to prepare the corresponding
starting materials, particularly if they contain other
substituents on the aromatic ring. Otherwise, similar
synthons of type III can be transformed into the tricycle
under milder conditions after generation of the aldehyde
moiety.9d Alternatively, isatoic anhydrides of type IV
have been used as a quick entrance to these target
molecules.9e Finally, the advantages of the solid-phase
synthesis have also found application in the field of
synthesis of PBD derivatives.10
In view of these precedents we were aware that a short
approach amenable to the preparation of arene- and
Synthesis of Pyrrolobenzodiazepines. The pro-
jected synthesis started with the successful benzoylation
of L-proline as shown in Scheme 1.13 Experimental
conditions for the transformation of the resulting amido
acid 5a into methoxyamide 6a by its reaction with
methoxylamine were optimized using the cocktail EDC‚
HCl, HOBt, and triethylamine as base.14 It is accepted15
that N-alkoxyamides, such as 6, react with I(III) reagents
(6) (a) For a comprehensive review of different synthetic approaches
to the PBD skeleton, see: Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh,
G.; Reddy, G. S. K. Curr. Med. Chem. Anti-Cancer Agents 2002, 2, 215-
254. (b) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433-465.
(c) See also: Hu, W.-P.; Wang, J.-J.; Lin, F.-L.; Lin, Y.-C.; Lin, S.-R.;
Hsu, M.-H. J. Org. Chem. 2001, 66, 2881-2883 and the abundant
references therein.
(7) (a) O’Neil, I. A.; Thompson, S.; Murray, C. L.; Kalindjian, S. B.
Tetrahedron Lett. 1998, 39, 7787-7790. (b) Molina, P.; D´ıaz, I.;
Ta´rraga, A. Tetrahedron 1995, 51, 5617-5630. (c) Eguchi, S.; Ya-
mashita, K.; Matsushita, Y.; Kakehi, A. J. Org. Chem. 1995, 60, 4006-
4012.
(8) Kamal, A.; Praveen Reddy, B. S.; Narayan Reddy, B. S. Tetra-
hedron Lett. 1996, 37, 2281-2284.
(9) (a) Thurston, D. E.; Murty, V. S.; Langley, D. R.; Jones, G. B.
Synthesis 1990, 81-84. For a recent application of this approach in
the synthesis of tetrahydroisoquinolino-fused benzodiazepines, see:
Kothakonda, K. K.; Bose, D. S. Bioorg. Med. Chem. Lett. 2004, 14,
4371-4373. (b) Kamal, A.; Reddy, P. S. M. M.; Reddy, D. R. Tetrahe-
dron Lett. 2003, 44, 2857-2860. (c) Kamal, A.; Laxman, E.; Reddy, P.
S. M. M. Synlett 2000, 1476-1478. (d) Chen, Z.; Gregson, S. J.; Howard,
P. W.; Thurston, D. E. Bioorg. Med. Chem. Lett. 2004, 14, 1547-1549.
(e) See, for example: Wang, T.; Lui, A. S.; Cloudsdale, I. S. Org. Lett.
1999, 1, 1835-1837. Kamal, A.; Reddy, B. S. N.; Reddy, G. S. K. Synlett
1999, 1251-1252.
(10) (a) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.;
Reddy, Y. N. Tetrahedron Lett. 2004, 45, 7667-7669. (b) Kamal, A.;
Reddy, K. L.; Devaiah, V.; Shankaraiah, N. Synlett. 2004, 1841-1843.
(c) Kamal, A.; Reddy, S. K.; Reddy, K. L.; Raghavan, S. Tetrahedron
Lett. 2002, 43, 2103-2106. (d) Barry, J. M.; Howard, P. W.; Thurston,
D. E. Tetrahedron Lett. 2000, 41, 6171-6174.
(11) (a) Herrero, M. T.; Tellitu, I.; Dom´ınguez, E.; Moreno, I.;
SanMartin, R. Tetrahedron Lett. 2002, 43, 8273-8275. (b) Correa, A.;
Herrero, M. T.; Tellitu, I.; Dom´ınguez, E.; Moreno, I.; SanMartin, R.
Tetrahedron 2003, 59, 7103-7110.
(12) For general reviews on polyvalent iodine compounds, see: (a)
Varvoglis, A. Chem. Soc. Rev. 1981, 10, 377-407. (b) Moriarty, R. M.;
Vaid, R. K. Synthesis 1990, 431-447. (c) Varvoglis, A. In The Organic
Chemistry of Polycoordinated Iodine; VCH: New York, 1992. (d) Stang,
P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123-1178. (e) Varvoglis,
A. In Hypervalent Iodine in Organic Synthesis; Academic Press: San
Diego, CA, 1997. (f) Kitamura, T.; Fujiwara, Y. Org. Prep. Proced. Int.
1997, 29, 409-458. (g) Varvoglis A. Tetrahedron 1997, 53, 1179-1255.
(h) Wirth, T.; Hirt, U. H. Synthesis 1999, 1271-1287. (i) Ochiai, M.
Chem. Hypervalent Compd. 1999, 359-387. (j) Koser, G. F. Aldrichim.
Acta 2001, 34, 89-102. (k) Zhdankin, V. V.; Stang, P. J. Chem. Rev.
2002, 102, 2523-2584. (l) Wirth, T. Top. Curr. Chem. 2003, 224,
1-264.
(13) Boto, A.; Herna´ndez, R.; Sua´rez, E. J. Org. Chem. 2000, 65,
4930-4937.
(14) Sukekatsu, N. Chem Lett. 1997, 1-2.
J. Org. Chem, Vol. 70, No. 6, 2005 2257

Correa et al.
SCHEME 1. First Attempt at the Synthesis of
Pyrrolobenzodiazepinesa
SCHEME 2. Synthesis of Pyrrolobenzodiazepines
11b-da
a Reagents and conditions: (i) L-Pro, Et3N, CH2Cl2, rt (76%);
(ii) NH2OMe‚HCl, EDC‚HCl, Et3N, HOBt, CH2Cl2, 0 °C f rt (78%);
(iii) PIFA, CF3CH2OH, rt (24%).
to give, after release of PhI, positively charged N-acyl-
nitrenium species of type VII. Finally, such intermedi-
ates, which are stabilized by the electron donating alkoxy
group, are trapped intramolecularly by an aromatic
group. Unfortunately, the treatment of amide 6a with
PIFA under a variety of experimental conditions proved
to be unproductive, and a complex mixture of products
was obtained in all cases. Among them, N,N-dialkoxy-
amide 7 was the only isolated (24% yield) and identified
compound when the reaction was carried out in trifluo-
roethanol. This result not only reflects a partial solvent
participation in the course of the reaction, but it is also
evidence of the generation of the proposed acylnitrenium
intermediate. The low nucleophilic character of the
phenyl group, diminished by the presence of the adjacent
carbonyl group, can be responsible for this negative
observation.
a Reagents and conditions: (i) L-Pro methyl ester, EDC‚HCl,
HOBt, Et3N, CH2Cl2, 0 °C f rt (100% for 9b; 88% for 9c; 95% for
9d); (ii) LiOH, THF/H2O, rt (76% for 5b; 86% for 5c; 98% for 5d);
(iii) NH2OMe‚HCl, EDC‚HCl, Et3N, HOBt, CH2Cl2, 0 °C f rt (94%
for 6b; 94% for 6c; 77% for 6d); (iv) PIFA (see Table 1); (v)
Mo(CO)6, MeCN/H2O, reflux (73% for 11b; 76% for 11c; 85% for
11d).
TABLE 1. PIFA-Mediated Transformation of Amides
6b-d into PBD’s 10b-d
solvent
T (°C)
additive
% 10b
% 10c
% 10d
1
2
3
4
5
TFEA
0
-20
rt
none
BF3‚OEt2
TFA
none
none
0
0
20
70
64
0
0
54
57
46
0
0
70
60
53
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
0
This explanation was confirmed by the encouraging
results obtained when the I(III)-based cyclization condi-
tions were tested on methoxyamides 6b-d where the
methoxy groups, and the naphthalene unit, played a
determinant role in the success of the reaction. In this
case (see Scheme 2) these precursors were prepared by
reaction of carboxylic acids 8b-d and L-proline methyl
ester, followed by hydrolysis of the amidoesters 9b-d
with LiOH, and final treatment of the resulting carboxy-
lic acids 5b-d, as expressed above, with methoxylamine
in satisfactory global yields (71%, 71%, and 72%, respec-
tively). Nevertheless, the decisive cyclization step had to
be optimized (see Table 1) with respect to the solvent,
temperature of the reaction, and the presence of addi-
tives. Chemistry with hypervalent iodine reagents often
requires low nucleophilic polar solvents, such as dichlo-
romethane or trifluoroethanol (TFEA), and, in some
cases, the aid of additives, such as boron trifluoride or
trifluoroacetic acid, to enhance their activity.16 In our
hands, a combination of such parameters did not afford
unique standard conditions for all cases. Thus, while
cyclization of methoxyamides 6b,c was best carried out
in CH2Cl2 as solvent in the absence of any additive and
working at room temperature, optimal conditions to
afford pyrrolodiazepine 10d included, additionally, the
use of 3 equiv of TFA. In all cases, the represented
structures were obtained as the unique regioisomers.
Finally, the appended N-methoxy groups were easily
removed17 with molybdenum hexacarbonyl in refluxing
aqueous acetonitrile to afford the target pyrrolodiaze-
pines 11b-d in suitable global yields.18
Synthesis of Heterocycle-Fused Pyrrolodiaze-
pines. The above-described synthetic pathway to the
synthesis of PBD derivatives includes a limited number
of steps and satisfactory global yields, which make it very
competitive in comparison to the existing ones. Neverthe-
less, it would be of higher interest if it also could be
extended to the preparation of heterocyclic analogues. In
this context, the corresponding thieno- and pyrrolo-fused
derivatives were selected as models for our research, not
only because of the enhanced physiological activity that
subtle structural modifications can exert with respect to
(15) (a) Kikugawa, Y.; Kawase, M. Chem. Lett. 1990, 581-582. (b)
Romero, A. G.; Darlington, W. H.; Jacobsen, E. J.; Mickelson, J. W.
Tetrahedron Lett. 1996, 37, 2361-2364. (c) Romero, A. G.; Darlington,
W. H.; McMillan, M. W. J. Org. Chem. 1997, 62, 6582-6587. (d) Chang,
C.-Y.; Yang, T.-K. Tetrahedron: Asymmetry 2003, 14, 2081-2085.
(16) (a) Romero has employed TFA as an additive in a PIFA-
mediated oxidative cyclization of a N-methoxyamide to obtain the
tetrahydroquinoline skeleton with excellent results. However, the role
of TFA remains unknown. See ref 15c. (b) It has been proposed that
the coordination of Lewis acids with the trifluoroacetoxy ligands
activates the iodine(III) reagent. See: Takada, T.; Arisawa, M.; Gyoten,
M.; Hamada, R.; Tohma, H.; Kita, Y. J. Org. Chem. 1998, 63, 7698-
7706.
(17) (a) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351-3354. (b) The Li/DTBB-induced
reduction alternative did not produce the expected results. See, for
example: Yus, M.; Radivoy, G.; Alonso, F. Synthesis 2001, 6, 914-
918. (c) These substrates turned out to be unreactive toward hydro-
genation using Pearlman’s catalyst. See, for example: Chang, C.-Y.;
Yang, T.-K. Tetrahedron: Asymmetry 2003, 14, 2081-2085.
(18) For an alternative synthesis of 11d, see: Mamatha, M.; Reddy,
M. S. Synth. Commun. 2003, 33, 237-241.
2258 J. Org. Chem., Vol. 70, No. 6, 2005

Advantageous Access to the Antitumor Antibiotic DC-81
SCHEME 3. Synthesis of Heterocycle-Fused
Pyrrolodiazepines 11e,fa
SCHEME 4. Synthesis of DC-81 (1)a
a Reagents and conditions: (i) L-Pro methyl ester, EDC‚HCl,
HOBt, Et3N, CH2Cl2, 0 °C f rt (97% for 9e; 100% for 9f); (ii) LiOH,
THF/H2O, rt (89% for 5e; 98% for 5f); (iii) NH2OMe‚HCl, EDC‚HCl,
Et3N, HOBt, CH2Cl2, 0 °C f rt (75% for 6e; 98% for 6f); (iv) PIFA,
CH2Cl2, rt (53% for 10e assisted by TFA; 60% for 10f); (v) Mo(CO)6,
MeCN/H2O, reflux (69% for 11e; 87% for 11f).
a Reagents and conditions: (i) NaClO2, NaH2PO4, H2O2, MeCN/
H2O, 10 °C (100%); (ii) L-Pro methyl ester, EDC‚HCl, HOBt, Et3N,
CH2Cl2, 0 °C f rt (100%); (iii) LiOH, THF/H2O, rt (96%); (iv)
NH2OMe‚HCl, EDC‚HCl, Et3N, HOBt, CH2Cl2, 0 °C f rt (91%);
(v) PIFA, CH2Cl2, rt (67%); (vi) Mo(CO)6, MeCN/H2O, reflux (82%);
(vii) NaBH4, TFA, glyme, reflux (70%); (viii) NMO, TPAP, MeCN,
rt (60%); (ix) EtOH, 10% Pd/C, 1,4-cyclohexadiene, rt (90%).
the more deeply studied PBD’s, but also because no
synthesis of a dipyrrolodiazepine has been previously
reported in the literature to the best of our knowledge.19
Both pyrrolodiazepines 11e,f were prepared in the
same way as commented on before (see Scheme 3).20 The
syntheses started, respectively, from 3-thiophenecarboxy-
lic acid (8e) and 1-methyl-2-pyrrolecarboxylic acid (8f)
by amidation with L-proline methyl ester followed by
hydrolysis of the resultant amidoesters 9e,f with LiOH,
and final treatment of the so-obtained carboxylic acids
5e,f with methoxylamine in satisfactory (65% and 96%,
respectively) global yields.
Once again, the iodine(III)-mediated cyclization step
was checked for the presence of additives with CH2Cl2
as solvent and at room temperature. In this case, TFA
proved to be essential in the preparation of pyrrolodi-
azepine 10e (from 15% to 53%), but lethal when applied
to the synthesis of 10f (from 60% to traces). On the other
hand, no oxidation of sulfur or nitrogen was detected in
any of the attempted experiments. Finally, the optical
integrity of newly synthesized pyrrolodiazepines 11b-f
was verified by chiral HPLC.21 These analyses showed
that the final compounds had an identical optical purity
as the commercially available starting L-proline methyl
ester.
(from 8 to 14 steps) is partly due to several factors: the
availability of the starting materials; the presence of an
unstable imine function in the tricyclic framework; and
the required protection of the phenolic hydroxy group.
The key feature of our synthesis is based on the
formation of the tricycle 11g, a common synthetic inter-
mediate in many approaches to PBD 1, by a PIFA
mediated aromatic amidation reaction as described above.
Thus, as shown in Scheme 4, carboxylic acid 8g, easily
obtained by applying a known23 protocol for the oxidation
of commercially available 4-benzyloxy-3-methoxybenzal-
dehyde (12), was transformed into the amidoester 9g by
acylation with L-proline methyl ester. Subsequent basic
hydrolysis and treatment of the resulting carboxylic acid
5g with methoxylamine produced amide 6g. Finally, the
action of PIFA under optimized conditions (in the absence
of additives) yielded PBD 10g which, on treatment with
Mo(CO)6, rendered the known PBD intermediate 11g in
48% overall yield (6 steps). The synthetic sequence was
completed by selective reduction with NaBH4 at the C-11
position, followed by dehydrogenation of the resulting
tricycle 12 across the 9,10-position using tetrapropylam-
moniun perruthenate (TPAP). Final debenzylation of the
resultant diazepine 13 rendered the desired antibiotic
DC-81 (1).
Synthesis of the Antibiotic DC-81 (1). To demon-
strate the suitability of the proposed access to the PBD
skeleton we attempted the synthesis of the antitumor
antibiotic DC-81 (1). Synthetic approaches to DC-81 have
been documented, and the length of those syntheses22
(19) (a) There is considerable interest in developing low molecular
weight molecules with sequence selectivity DNA interactive properties
as tools for molecular biology and as possible therapeutic agents to
inactivate particular genes. Lown, J. W.; Kumar, R. Mini Rev. Med.
Chem. 2003, 3, 323-339. (b) It is sensible to maintain its tetrahydro-
genated nature because when the PBD includes a fully unsaturated
pyrrole ring the imine double bond remains unreactive toward nu-
cleophiles showing, hence, little interest from a biological point of view.
See ref 6b.
(20) For an alternative synthesis of 11e, see: Jolivert-Fouchet, S.;
Fabis, F.; Rault, S. Tetrahedron Lett. 1998, 39, 5369-5372.
(21) Enantiomer separation was carried out by chiral HPLC using
Chiralcel OJ, and mixtures of Hex/iPrOH as eluent.
In conclusion, the powerful potential of the hypervalent
iodine reagent PIFA in organic synthesis, which includes
(22) For previously reported representative syntheses of DC-81 (1)
or synthetic intermediates, see: (a) Bose, D. S.; Jones, G. B.; Thurston,
D. E. Tetrahedron 1992, 48, 751-758. (b) Kamal, A.; Praveen Reddy,
B. S.; Narayan Reddy, B. S. Tetrahedron Lett. 1996, 37, 6803-6806.
(c) Prabhu, K. R.; Sivanand, P. S.; Chandrsekaran, S. Synlett 1998,
47-48. (d) Kamal, A.; Howard, P. H.; Narayan Reddy, B. S.; Praveen
Reddy, B. S.; Thurston, D. E. Tetrahedron 1997, 53, 3223-3230. (e)
See also refs 6c, 7, 8, and 9a.
(23) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567-569.
J. Org. Chem, Vol. 70, No. 6, 2005 2259

Correa et al.
ester hydrochloride in 97% yield as a yellowish solid after
purification by column chromatography (EtOAc) followed by
crystallization from hexanes. Mp 66-68 °C (hexanes); 1H NMR
(CDCl3) δ 1.84-2.24 (m, 4H), 3.38-3.55 (m, 2H), 3.68 (s, 3H),
its ability to generate N-acylnitrenium ions from ad-
equately substituted amides, has been employed satis-
factorily in the preparation of a series of optically pure
pyrrolobenzodiazepines and heterocycle-fused pyrrolodi-
azepines from L-proline. Following this new approach, an
alternative synthesis of the antibiotic DC-81 (1) has been
pleasingly accomplished rendering the desired hetero-
cycle in 18% (9 steps) overall yield.
4.45-4.58 (m, 1H), 7.22-7.34 (m, 2H), 7.69-7.70 (m, 1H); 13
C
NMR (CDCl3) δ 24.8, 28.4, 48.8, 51.5, 59.0, 124.9, 127.3, 127.7,
136.2, 163.3, 172.1; IR (KBr) 1736, 1619 cm-1; MS (EI) m/z
(%) 239 (M+, 7), 180 (41), 111 (100), 83 (16); HRMS calcd
for C11H13NO3S 239.0616, found 239.0614; [R]20D -65.0 (c 0.1,
CH2Cl2).
Methyl (2S)-N-(1-Methyl-2-pyrrolylcarbonyl)pyrroli-
din-2-carboxylate (9f).26 According to the general procedure
amidoester 9f was obtained from carboxylic acid 8f and (S)-
proline methyl ester hydrochloride in 100% yield as a chro-
matographically pure yellowish oil after purification by column
chromatography (EtOAc). 1H NMR (CDCl3) δ 1.80-2.23 (m,
4H), 3.65 (s, 3H), 3.50-3.75 (m, 2H), 3.76 (s, 3H), 4.51-4.53
(m, 1H), 5.99-6.02 (m, 1H), 6.52-6.62 (m, 2H); 13C NMR
(CDCl3) δ 25.0, 28.5, 36.0, 49.3, 51.5, 59.0, 106.3, 113.6, 124.7,
126.7, 161.3, 172.5; IR (film) 1743, 1613 cm-1; MS (EI) m/z
(%) 236 (M+, 6), 177 (15), 108 (100), 80 (10), 53 (18); HRMS
Experimental Section
Typical Procedure for the Synthesis of Methyl Car-
boxylates 9b-g. Synthesis of Methyl (2S)-N-(3,4-Di-
methoxybenzoyl)pyrrolidin-2-carboxylate (9b).24 A solu-
tion of EDC‚HCl (3.15 g, 16.5 mmol) and HOBt (2.07 g, 15.5
mmol) in CH2Cl2 (29 mL) was added to a suspension of
carboxylic acid 8b (2.00 g, 11.0 mmol), (S)-proline methyl ester
hydrochloride (2.18 g, 13.2 mmol), and Et3N (2.30 mL, 16.5
mmol) in the same solvent (27 mL). The mixture was cooled
(0 °C) and Et3N (1.83 mL, 13.2 mmol) was added dropwise.
After the mixture was stirred for 2 h, the temperature was
raised to room temperature and stirring was continued until
the conversion was complete. Then, the solution was washed
with water and extracted with CH2Cl2 (3 × 15 mL). The
organic layer was separated and dried over sodium sulfate,
and the solvent was evaporated at reduced pressure. The
resulting residue was column chromatographed (EtOAc)
followed by crystallization from hexanes to afford amidoester
9b as a white solid (100%). Mp 67-69 °C (hexanes); 1H NMR
(CDCl3) δ 1.90-2.00 (m, 3H), 2.25-2.27 (m, 1H), 3.62-3.68
(m, 2H), 3.74 (s, 3H), 3.87 (s, 6H), 4.59-4.61 (m, 1H), 6.81-
6.93 (m, 1H), 7.15-7.18 (m, 2H); 13C NMR (CDCl3) δ 25.0, 28.8,
49.7, 51.7, 55.4, 58,9, 109.6, 110.6, 120.1, 127.8, 148.1, 150.2,
168.6, 172.4; IR (KBr) 1740, 1633 cm-1; MS (EI) m/z (%) 293
(M+, 13), 234 (12), 165 (100); HRMS calcd for C15H19NO5
calcd for C12H16N2O3 236.1161, found 236.1160; [R]20 -35.8
D
(c 0.1, CH2Cl2).
Methyl (2S)-N-(4-Benzyloxy-3-methoxybenzoyl)pyrro-
lidin-2-carboxylate (9g). According to the general procedure
amidoester 9g was obtained from carboxylic acid 8g and (S)-
proline methyl ester hydrochloride in 100% yield as a chro-
matographically pure colorless oil after purification by column
chromatography (EtOAc). 1H NMR (CDCl3) δ 1.85-2.27 (m,
4H), 3.58-3.66 (m, 2H), 3.74 (s, 3H), 3.87 (s, 3H), 4.59-4.61
(m, 1H), 5.17 (s, 2H), 6.82-7.42 (m, 8H); 13C NMR (CDCl3) δ
25.2, 29.0, 49.9, 51.9, 55.7, 59.1, 70.4, 111.3, 112.2, 120.2, 126.9,
127.7, 128.3, 128.4, 136.3, 148.9, 149.5, 168.8, 172.6; IR (film)
1743, 1626 cm-1; MS (EI) m/z (%) 369 (M+, 14), 241 (20), 91
(100); HRMS calcd for C21H23NO5 369.1576, found 369.1578;
[R]20 -40.6 (c 0.1, CH2Cl2).
D
Synthesis of (2S)-N-benzoylproline (5a).27 Benzoyl chlo-
ride (1.45 mL, 12.5 mmol) was added dropwise to a cold (0 °C)
solution of (S)-proline (1.15 g, 10 mmol) and triethylamine (5
mL) in dry CH2Cl2 (15 mL). The solution was allowed to reach
room temperature and stirring was continued overnight. Then,
the reaction mixture was acidified with 2 M HCl and extracted
with EtOAc. The organic layer was separated, dried over Na2-
SO4, and concentrated under vacuum. The residue was purified
by crystallization from hexanes to afford benzoylproline (5a)
in 76% yield. Mp 153-155 °C (hexanes) (lit.27 mp 156-157
°C).
293.1263, found 293.1266; [R]20 -62.4 (c 0.1, CH2Cl2).
D
Methyl (2S)-N-(3-Methoxybenzoyl)pyrrolidin-2-car-
boxylate (9c).25 According to the general procedure ami-
doester 9c was obtained from carboxylic acid 8c and (S)-proline
methyl ester hydrochloride in 88% yield as a colorless oil after
purification by column chromatography (EtOAc). 1H NMR
(CDCl3) δ 1.85-2.06 (m, 3H), 2.27-2.36 (m, 1H), 3.49-3.69
(m, 2H), 3.77 (s, 3H), 3.82 (s, 3H), 4.63-4.68 (m, 1H), 6.89-
6.98 (m, 1H), 7.09-7.11 (m, 2H), 7.14-7.33 (m, 1H); 13C NMR
(CDCl3) δ 25.0, 31.1, 49.2, 52.0, 55.1, 58.9, 112.2, 116.0, 119.1,
129.1, 137.1, 159.1, 169.0, 172.5; IR (film) 1743, 1625 cm-1
;
Typical Procedure for the Synthesis of Amino Acids
5b-g. Synthesis of (2S)-N-(3,4-Dimethoxybenzoyl)pro-
line (5b).28 LiOH‚H2O (2.77 g, 65.9 mmol) was added to a
solution of amidoester 9b (3.22 g, 11.0 mmol) in THF/H2O (110
mL, 4/1). The mixture was stirred at room temperature until
conversion was complete. Then, the solution was treated with
HCl (5% aq) and extracted with Et2O (3 × 5 mL). The organic
extracts were dried over sodium sulfate and the solvent was
evaporated under reduced pressure to afford amino acid 5b
as a white solid, which was crystallized from hexanes (76%).
Mp 151-153 °C (hexanes) (lit.28 dec 154-156 °C); 1H NMR
(CDCl3) δ 1.87-2.01 (m, 2H), 2.22-2.30 (m, 2H), 3.61-3.64
(m, 2H), 3.88 (s, 6H), 4.66-4.69 (m, 1H), 6.81-684 (m, 1H),
7.14-7.24 (m, 2H), 9.80 (br s, 1H); 13C NMR (CDCl3) δ 24.8,
28.5, 50.0, 55.3, 55.4, 59.1, 109.7, 110.5, 120.3, 127.9, 148.0,
150.3, 169.6, 174.3; IR (KBr) 3500, 1731, 1602 cm-1; MS (EI)
m/z (%) 279 (M+, 6), 235 (22), 165 (100); HRMS calcd for
MS (EI) m/z (%) 263 (M+, 3), 204 (20), 135 (100), 107 (19), 92
(15), 77 (21); HRMS calcd for C14H17NO4 263.1158, found
263.1155; [R]20 -60.8 (c 1.0, CH2Cl2).
D
Methyl (2S)-N-(2-Naphthoyl)pyrrolidin-2-carboxylate
(9d).25 According to the general procedure amidoester 9d was
obtained from carboxylic acid 8d and (S)-proline methyl ester
hydrochloride in 95% yield as a white solid after purification
by column chromatography (EtOAc) followed by crystallization
from hexanes. Mp 112-114 °C (hexanes) (lit.25 mp 112-115
°C); 1H NMR (CDCl3) δ 1.80-2.35 (m, 4H), 3.46-3.73 (m, 2H),
3.77 (s, 3H), 4.67-4.72 (m, 1H), 7.47-7.50 (m, 2H), 7.61-7.65
(m, 1H), 7.80-7.85 (m, 3H), 8.04 (s, 1H); 13C NMR (CDCl3) δ
25.2, 29.2, 49.8, 52.1, 59.0, 124.2, 126.4, 126.9, 127.0, 127.1,
127.6, 127.9, 128.2, 128.3, 132.3, 133.2, 133.7, 169.5, 172.6;
IR (KBr) 1743, 1625 cm-1; MS (EI) m/z (%) 283 (M+, 6), 224
(16), 155 (100), 127 (49); HRMS calcd for C17H17NO3 283.1208,
found 283.1205; [R]20 -70.4 (c 0.1, CH2Cl2).
D
C14H17NO5 279.1107, found 279.1111; [R]20 -185.2 (c 0.1,
D
Methyl (2S)-N-(3-Thiophenecarbonyl)pyrrolidin-2-car-
boxylate (9e). According to the general procedure amidoester
9e was obtained from carboxylic acid 8e and (S)-proline methyl
CH2Cl2).
(26) Hegedus, L.; Ma´the´, T.; Keglevich, G. Appl. Catal. A 2003, 245,
179-183.
(24) Knefeli, F.; Mayer, K. K.; Poettinger, T.; Stoeber, G.; Wiegrebe,
W. Arch. Pharm. 1983, 316, 773-781.
(25) Tsuji, M.; Kuwano, E.; Saito, T.; Eto, M. Biosci. Biotechnol.
Biochem. 1992, 56, 778-782.
(27) Yamada, K.; Takeda, M.; Iwakuma, T. J. Chem. Soc., Perkin
Trans. 1 1983, 265-270.
(28) Smith, F. T.; DeRuiter, J.; Carter, D. A. J. Heterocycl. Chem.
1989, 26, 1815-1817.
2260 J. Org. Chem., Vol. 70, No. 6, 2005

Advantageous Access to the Antitumor Antibiotic DC-81
(2S)-N-(3-Methox:ybenzoyl)proline (5c). According to
the general procedure amino acid 5c was obtained from
amidoester 9c as a white solid after purification by column
chromatography (EtOAc) followed by crystallization from
hexanes (86%). Mp 92-94 °C (hexanes);1H NMR (CDCl3) δ
1.82-2.10 (m, 2H), 2.22-2.30 (m, 2H), 3.54-3.60 (m, 2H), 3.82
(s, 3H), 4.71 (t, J ) 6.3 Hz, 1H), 6.92-7.12 (m, 3H), 7.28-7.34
(m, 1H), 8.01 (br s, 1H); 13C NMR (CDCl3) δ 25.0, 28.8, 50.1,
55.2, 59.3, 112.3, 116.4, 119.2, 129.3, 136.6, 159.3, 170.3, 174.9;
IR (KBr) 3420, 1731, 1600 cm-1; MS (EI) m/z (%) 250 (M + 1,
7), 205 (39), 204 (32), 136 (13), 135 (100), 107 (27), 92 (22), 77
(29), 64 (14); HRMS calcd for C13H15NO4 249.1001, found
and Et3N (1.60 mL, 11.3 mmol) in the same solvent (27 mL).
The mixture was cooled (0 °C) and Et3N (1.3 mL, 9.0 mmol)
was added dropwise. After the mixture was stirred for 2 h,
the temperature was raised to room temperature and stirring
was continued until the conversion was complete. Then, the
solution was washed with water and extracted with CH2Cl2
(3 × 15 mL). The organic layer was separated and dried over
sodium sulfate, and the solvent was evaporated at reduced
pressure. The resulting residue was column chromatographed
(EtOAc) and crystallized from hexanes to afford N-methoxy-
amide 6b as a white solid (94%). Mp 144-146 °C (hexanes);
1H NMR (42 °C, CDCl3) δ 1.81-2.50 (m, 4H), 3.58-3.63 (m,
2H), 3.77 (s, 3H), 4.18 (s, 3H), 4.19 (s, 3H), 4.53-4.61 (m, 1H),
6.85-688 (m, 1H), 7.09-7.12 (m, 2H), 9.72 (br s, 1H); 13C NMR
(CDCl3) δ 25.1, 27.7, 50.4, 55.5, 57.4, 63.5, 109.8, 110.4, 120.3,
127.5, 148.1, 150.3, 169.1, 169.8; IR (KBr) 3192, 1681, 1607
cm-1; MS (EI) m/z (%) 308 (M+, 3), 262 (12), 234 (10), 166 (10),
165 (100); HRMS calcd for C15H20N2O5 308.1372, found
249.1002; [R]20 -43.8 (c 0.1, CH2Cl2).
D
(2S)-N-(2-Naphthoyl)proline (5d).29 According to the
general procedure amino acid 5d was obtained from ami-
doester 9d as a white solid after purification by column
chromatography (EtOAc) followed by crystallization from
hexanes (98%). Mp 146-148 °C (hexanes) (lit.29 mp 170 °C);
1H NMR (CDCl3) δ 1.80-2.35 (m, 4H), 3.53-3.80 (m, 2H),
4.76-4.81 (m, 1H), 7.47-7.87 (m, 6H), 8.07 (s, 1H), 10.16 (br
s, 1H); 13C NMR (CDCl3) δ 25.1, 28.8, 50.3, 59.6, 124.1, 126.6,
127.3, 127.7, 128.1, 128.5, 132.3, 132.6, 133.9, 170.8, 174.9;
IR (KBr) 3420, 1731, 1596 cm-1; MS (EI) m/z (%) 269 (M+, 1),
225 (22), 224 (12), 156 (14), 155 (100), 127 (86), 83 (10), 77
(17), 70 (15), 57 (20); HRMS calcd for C16H15NO3 269.1052,
308.1381; [R]20 -141.8 (c 0.1, CH2Cl2).
D
(2S)-N-(3-Methoxybenzoyl)-2-(N′-methoxycarbamoyl)-
pyrrolidine (6c). According to the general procedure N-
methoxyamide 6c was obtained from amino acid 5c in 94%
yield as a yellowish oil after purification by column chroma-
tography (EtOAc). 1H NMR (42 °C, CDCl3) δ 1.75-2.06 (m,
3H), 2.36-2.46 (m, 1H), 3.49-3.54 (m, 2H), 3.75 (s, 3H), 3.80
(s, 3H), 4.59-4.61 (m, 1H), 6.94-7.05 (m, 3H), 7.29-7.32 (m,
1H), 9.77 (br s, 1H); 13C NMR (CDCl3) δ 24.9, 28.0, 50.0, 54.9,
57.4, 63.5, 112.1, 115.8, 118.9, 129.0, 137.0, 159.0, 169.0, 170.0;
IR (film) 3186, 1684, 1617 cm-1; MS (EI) m/z (%) 278 (M+, 1),
232 (18), 204 (22), 135 (100), 107 (16), 77 (12); HRMS calcd
for C14H18N2O4 278.1267, found 278.1267; [R]20D -139.7 (c 0.1,
CH2Cl2).
found 269.1048; [R]20 -183.0 (c 0.1, CH2Cl2).
D
(2S)-N-(3-Thiophenecarbonyl)proline (5e).30 According
to the general procedure amino acid 5e was obtained from
amidoester 9e as a white solid after purification by column
chromatography (EtOAc) followed by crystallization from
hexanes (89%). Mp 116-118 °C (hexanes) (lit.30 mp 140 °C);
1H NMR (CDCl3) δ 1.85-2.19 (m, 4H), 3.67-3.71 (m, 2H),
4.58-4.63 (m, 1H), 7.15-7.34 (m, 2H), 7.71-7.73 (s, 1H), 11.40
(br s, 1H); 13C NMR (CDCl3) δ 25.1, 28.5, 49.7, 59.8, 126.7,
127.5, 128.9, 135.8, 165.1, 174.7; IR (KBr) 3330, 1731, 1584
cm-1; MS (EI) m/z (%) 225 (M+, 1), 181 (25), 180 (16), 111 (100),
83 (9); HRMS calcd for C10H11NO3S 225.0460, found 225.0460;
(2S)-2-(N′-Methoxycarbamoyl)-N-(2-naphthoyl)pyrro-
lidine (6d). According to the general procedure N-methoxy-
amide 6d was obtained from amino acid 5d in 77% yield as
a white solid after purification by column chromatography
(EtOAc) followed by crystallization from hexanes. Mp
[R]20 -201.2 (c 0.1, CH2Cl2).
D
1
131-133 °C (hexanes); H NMR (42 °C, CDCl3) δ 1.83-2.20
(2S)-N-(1-Methyl-2-pyrrolylcarbonyl)proline (5f). Ac-
cording to the general procedure amino acid 5f was obtained
from amidoester 9f as a yellow oil after purification by column
chromatography (EtOAc) (98%). 1H NMR (CDCl3) δ 1.89-2.26
(m, 4H), 3.54-3.83 (m, 2H), 3.77 (s 3H), 4.67 (t, J ) 6.7 Hz,
1H), 6.08-6.09 (m, 1H), 6.61-6.96 (m, 2H), 10.37 (br s, 1H);
13C NMR (CDCl3) δ 25.1, 28.3, 36.5, 49.9, 59.7, 106.8, 114.7,
124.4, 127.6, 162.5, 175.0; IR (film) 3448, 1731, 1590 cm-1; MS
(EI) m/z (%) 222 (M+, 1), 178 (18), 109 (12), 108 (100), 80 (10),
53 (15); HRMS calcd for C11H14N2O3 222.1004, found 222.1003;
(m, 3H), 2.47-2.53 (m, 1H), 3.60-3.62 (m, 2H), 3.79 (s, 3H),
4.69-4.71 (m, 1H), 7.49-7.60 (m, 3H), 7.85-8.00 (m, 4H), 9.85
(br s, 1H); 13C NMR (CDCl3) δ 25.4, 27.4, 50.5, 57.5, 63.9, 124.0,
126.6, 127.2, 127.3, 127.6, 128.1, 128.4, 132.2, 132.9, 133.8,
169.1, 170.8; IR (KBr) 3189, 1735, 1608 cm-1; MS (EI) m/z (%)
298 (M+, 1), 224 (11), 155 (100), 127 (55), 77 (10); HRMS calcd
for C17H18N2O3 298.1317, found 298.1320; [R]20D -152.0 (c 0.1,
CH2Cl2).
(2S)-2-(N′-Methoxycarbamoyl)-N-(3-thiophenecarbon-
yl)pyrrolidine (6e). According to the general procedure
N-methoxyamide 6e was obtained from amino acid 5e in 75%
yield as a white solid after purification by column chromatog-
raphy (EtOAc) followed by crystallization from hexanes. Mp
[R]20 -216.8 (c 0.1, CH2Cl2).
D
(2S)-N-(4-Benzyloxy-3-methoxy)benzoylproline (5g).
According to the general procedure amino acid 5g was obtained
from amidoester 9g as a white solid after purification by
column chromatography (EtOAc) followed by crystallization
from hexanes (96%). Mp 134-136 °C (hexanes); 1H NMR
(CDCl3) δ 1.84-2.06 (m, 3H), 2.20-2.25 (m, 1H), 3.60-3.65
(m, 2H), 3.89 (s, 3H), 4.69 (t, J ) 6.7, 1H), 5.17 (s, 2H), 6.83-
6.87 (m, 1H), 7.08-7.43 (m, 7H), 8.93 (br s, 1H); 13C NMR
(CDCl3) δ 25.2, 28.6, 50.3, 55.9, 59.6, 70.6, 111.4, 112.4, 120.4,
127.1, 127.8, 128.4, 136.3, 149.0, 149.8, 170.1, 174.8; IR (KBr)
3200, 1731, 1596 cm-1; MS (EI) m/z (%) 355 (M+, 3), 311 (6),
91 (100); HRMS calcd for C20H21NO5 355.1420, found 355.1423;
1
115-116 °C (hexanes); H NMR (42 °C, CDCl3) δ 1.85-2.33
(m, 4H), 3.66-3.70 (m, 2H), 3.69 (s, 3H), 4.53-4.55 (m, 1H),
7.27-7.30 (m, 2H), 7.66-7.68 (m, 1H), 10.06 (br s, 1H); 13C
NMR (CDCl3) δ 25.3, 27.6, 49.8, 57.9, 63.7, 125.4, 127.4, 128.3,
136.2, 165.0, 169.1; IR (KBr) 3189, 1672, 1602 cm-1; MS (EI)
m/z (%) 254 (M+, 1), 208 (22), 180 (31), 111 (100), 83 (8); HRMS
calcd for C11H14N2O3S 254.0725, found 254.0723; [R]20D -169.4
(c 0.1, CH2Cl2).
(2S)-2-(N′-Methoxycarbamoyl)-N-(2-N-methylpyrrolyl-
carbonyl)pyrrolidine (6f). According to the general proce-
dure N-methoxyamide 6f was obtained from amino acid 5f in
98% yield as a white solid after purification by column
chromatography (EtOAc) followed by crystallization from
hexanes. Mp 149-151 °C (hexanes); 1H NMR (CDCl3) δ 1.87-
2.44 (m, 4H), 3.65-3.80 (m, 2H), 3.69 (s, 3H), 3.79 (s, 3H),
4.51-4.53 (m, 1H), 6.03-6.04 (m, 1H), 6.52-6.67 (m, 2H),
10.25 (br s, 1H); 13C NMR (CDCl3) δ 25.4, 27.2, 36.5, 50.1, 57.6,
63.8, 106.9, 114.5, 127.4, 124.8, 162.9, 169.4 (CO); IR (KBr)
3201, 1678, 1602 cm-1; MS (EI) m/z (%) 251 (M+, 2), 177 (17),
108 (100), 53 (10); HRMS calcd for C12H17N3O3 251.1270, found
[R]20 -151.0 (c 0.1, CH2Cl2).
D
Typical Procedure for the Synthesis of N-Methoxy-
amides 6a-g. Synthesis of (2S)-N-(3,4-Dimethoxyben-
zoyl)-2-(N′-methoxycarbamoyl)pyrrolidine (6b). A solu-
tion of EDC‚HCl (2.15 g, 11.3 mmol) and HOBt (1.42 g, 10.5
mmol) in CH2Cl2 (28 mL) was added to a suspension of amino
acid 5b (2.10 g, 7.5 mmol), NH2OMe‚HCl (0.75 g, 9.0 mmol),
(29) Yoshikawa, K.; Achiwa, K. Chem. Pharm. Bull. 1995, 43, 2048-
2053.
(30) Ladure´e, D.; Lancelot, J.-C.; Robba, M.; Chenu, E.; Mathe´, G.
J. Med. Chem. 1989, 32, 456-461.
251.1269; [R]20 -161.8 (c 0.1, CH2Cl2).
D
J. Org. Chem, Vol. 70, No. 6, 2005 2261

Correa et al.
(2S)-N-(4-Benzyloxy-3-methoxybenzoyl)-2-(N′-meth-
oxycarbamoyl)pyrrolidine (6g). According to the general
procedure N-methoxyamide 6g was obtained from amino acid
5g in 91% yield as a white solid after purification by column
chromatography (EtOAc) followed by crystallization from
(s, 3H), 3.53-3.86 (m, 2H), 3.98-4.01 (m, 1H), 7.51-7.55 (m,
2H), 7.82-7.83 (m, 3H), 8.24-8.28 (m, 1H); 13C NMR (CDCl3)
δ 23.6, 25.8, 46.4, 56.9, 61.0, 124.3, 126.1, 127.0, 127.9, 128.2,
128.7, 131.3, 135.4, 164.5, 165.0; IR (KBr) 1696, 1631 cm-1
;
MS (EI) m/z (%) 296 (M+, 25), 268 (25), 200 (12), 199 (87), 196
(59), 156 (22), 141 (55), 140 (86), 128 (100), 113 (21); HRMS
calcd for C17H16N2O3 296.1161, found 296.1161; [R]20D +427.2
(c 0.1, CH2Cl2); ee 97% (Chiralcel OJ, Hex/iPrOH 90:10, 1.0
mL/min, tR ) 42.66 min).
1
hexanes. Mp 56-58 °C (hexanes); H NMR (CDCl3) δ 1.81-
2.08 (m, 3H), 2.49-2.51 (m, 1H), 3.55-3.58 (m, 2H), 3.75 (s,
3H), 3.89 (s, 3H), 4.57-4.58 (m, 1H), 5.17 (s, 2H), 6.84-7.10
(m, 3H), 7.29-7.39 (m, 5H), 9.98 (br s, 1H); 13C NMR (CDCl3)
δ 25.2, 27.5, 50.4, 57.4, 62.2, 63.6, 70.4, 111.0, 112.2, 120.2,
126.9, 127.7, 128.0, 128.3, 136.1, 148.8, 149.6, 169.1, 170.0;
IR (KBr) 3460, 1678, 1608 cm-1; MS (EI) m/z (%) 384 (M+, 1),
241 (30), 122 (12), 91 (100); HRMS calcd for C21H24N2O5
(10aS)-9-Methoxy-1,2,3,9,10,10a-hexahydro-5H-pyrrolo-
[2,1-c]thieno[3,2-f][1,4]diazepin-5,10-dione (10e). Pyr-
rothienodiazepine 10e was obtained in 53% yield from N-
methoxyamide 6e following the typical procedure described
before but adding TFA (3 equiv) to the solution of the amide.
Purification was carried out by column chromatography
(EtOAc) to afford pyrrolothienodiazepine 10e as a yellowish
oil. 1H NMR (CDCl3) δ 1.98-2.11 (m, 3H), 2.78-2.79 (m, 1H),
3.61-3.65 (m, 2H), 3.90 (s, 3H), 4.05-4.19 (m, 1H), 7.00 (d, J
) 5.5 Hz, 1H), 7.28 (d, J ) 5.5 Hz, 1H); 13C NMR (CDCl3) δ
23.6, 26.6, 46.8, 57.8, 63.3, 118.9, 127.1, 124.1, 144.3, 161.9,
164.5; IR (film) 1702, 1631 cm-1; MS (EI) m/z (%) 252 (M+,
25), 225 (11), 224 (88), 155 (100), 152 (43), 140 (24), 127 (45),
125 (29), 124 (10), 99 (15), 97 (99), 96 (28), 83 (20), 80 (39), 70
(23), 52 (13); HRMS calcd for C11H12N2O3S 252.0569, found
384.1685, found 384.1682; [R]20 -105.8 (c 0.1, CH2Cl2).
D
(2S)-N-Benzoyl-2-(N′-methoxycarbamoyl)pyrrolidine
(6a). According to the general procedure N-methoxyamide 6a
was obtained from amino acid 5a in 78% yield as a yellow oil
after purification by column chromatography (EtOAc). 1H
NMR (CDCl3) δ 1.77-2.04 (m, 3H), 2.34-2.51 (m, 1H), 3.34-
3.54 (m, 2H), 3.71 (s, 3H), 4.53-4.55 (m, 1H), 7.36-7.47 (m,
5H), 10.27 (br s, 1H); 13C NMR (CDCl3) δ 25.1, 28.0, 50.2, 57.5,
63.6, 126.9, 128.0, 130.1, 135.5, 169.1, 170.4; IR (KBr) 3192,
1690, 1620 cm-1; MS (EI) m/z (%) 248 (M+, 1), 202 (20), 174
(32), 148 (13), 105 (100), 77 (29); HRMS calcd for C13H16N2O3
248.1161, found 248.1163; [R]20 -76.5 (c 1.0, CH2Cl2).
252.0562; [R]20 +325.6 (c 0.1, CH2Cl2).
D
D
Typical Procedure for the Synthesis of Pyrrolodiaze-
pines 10b-g. Synthesis of (11aS)-7,8,10-Trimethoxy-
1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]-
benzodiazepin-5,11-dione (10b). A solution of PIFA (1.05
g, 2.43 mmol) in 49 mL of CH2Cl2 was added at room
temperature to a solution of amide 6b (0.50 g, 1.62 mmol) in
32 mL of the same solvent, and the new solution was stirred
until total consumption of the starting material (TLC, EtOAc).
Then, the mixture was washed with Na2CO3 (10% aq) and
extracted with CH2Cl2 (3 × 5 mL). The organic layer was
separated, dried over Na2SO4, and filtered, and the solvent
was evaporated at reduced pressure. The resulting residue was
purified by column chromatography (EtOAc) followed by
crystallization from hexanes to afford pyrrolobenzodiazepine
10b as a white solid (70%). Mp 189-191 °C (hexanes). 1H NMR
(CDCl3) δ 1.88-2.11 (m, 3H), 2.75-2.78 (m, 1H), 3.51-3.62
(m, 1H), 3.69 (s, 3H), 3.74-3.78 (m, 1H), 3.90 (s, 3H), 3.91 (s,
3H), 3.94-3.95 (m, 1H), 6.99 (s, 1H), 7.35 (s, 1H); 13C NMR
(CDCl3) δ 23.6, 26.4, 46.9, 56.0, 56.1, 56.8, 62.3, 102.2, 111.0,
119.9, 130.7, 147.0, 152,1, 164.6, 165.9; IR (KBr) 1695, 1631
cm-1; MS (EI) m/z (%) 306 (M+, 43), 278 (12), 247 (19), 209
(69), 206 (55), 179 (53), 165 (26), 164 (23), 151 (100), 150 (28),
136 (22), 70 (16); HRMS calcd for C15H18N2O5 306.1216, found
(10aS)-9-Methoxy-6-methyl-1,2,3,9,10,10a-hexahydro-
5H-dipyrrolo[2,3-f:2,1-c][1,4]diazepin-5,10-dione (10f). Ac-
cording to the general procedure dipyrrolodiazepine 10f was
obtained from N-methoxyamide 6f in 60% yield as a yellowish
solid after purification by column chromatography (EtOAc)
followed by crystallization from hexanes. Mp 144-146 °C
1
(hexanes); H NMR (CDCl3) δ 1.97-2.07 (m, 3H), 2.77-2.91
(m, 1H), 3.55-3.58 (m, 2H), 3.75 (s, 3H), 3.88 (s, 3H), 4.03-
4.05 (m, 1H), 6.08 (d, J ) 2.8 Hz, 1H), 6.70 (d, J ) 2.8 Hz,
1H); 13C NMR (CDCl3) δ 23.5, 26.5, 36.3, 46.1, 57.7, 61.8, 98.3,
116.1, 127.2, 127.9, 159.6, 162.9; IR (KBr) 1684, 1625 cm-1
;
MS (EI) m/z (%) 249 (M+, 44), 190 (67), 152 (13), 150 (10), 149
(100), 122 (77), 93 (94), 66 (39), 52 (14); HRMS calcd for
C12H15N3O3 249.1113, found 249.1113; [R]20 +222.6 (c 0.1,
D
CH2Cl2).
(11aS)-8-Benzyloxy-7,10-dimethoxy-1,2,3,10,11,11a-
hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-di-
one (10g). According to the general procedure pyrrolobenzo-
diazepine 10g was obtained from N-methoxyamide 6g in 67%
yield as a white solid after purification by column chromatog-
raphy (EtOAc) followed by crystallization from hexanes. Mp
121-123 °C (hexanes); 1H NMR (CDCl3) δ 2.02-2.11 (m, 3H),
2.75-2.76 (m, 1H), 3.54 (s, 3H), 3.54-3.75 (m, 2H), 3.76-3.93
(m, 1H), 3.94 (s, 3H), 5.16-5.29 (m, 2H), 7.00 (s, 1H), 7.36 (s,
1H), 7.29-7.43 (m, 5H); 13C NMR (CDCl3) δ 23.2, 26.0, 46.5,
55.6, 56.3, 61.6, 70.3, 104.0, 111.0, 126.9, 127.7, 128.1, 119.7,
130.0, 135.3, 147.0, 150.5, 164.1, 165.4; IR (KBr) 1696, 1631
cm-1; MS (EI) m/z (%) 382 (M+, 9), 91 (100), 65 (12); HRMS
calcd for C21H22N2O5 382.1529, found 382.1530; [R]20D +191.6
(c 0.1, CH2Cl2).
Typical Procedure for the Synthesis of Pyrrolodiaze-
pines 11b-g. Synthesis of (11aS)-7,8-Dimethoxy-1,2,3,-
10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-
5,11-dione (11b). A solution of Mo(CO)6 (430.3 mg, 1.63 mmol)
and pyrrolobenzodiazepine 10b (500.0 mg, 1.63 mmol) in
CH3CN/H2O (26 mL, 15/1) was refluxed under nitrogen for 4-5
h. The reaction mixture turned brown after some minutes at
reflux, indicating that the reaction had taken place. Then, the
crude reaction was washed with water (15 mL) and extracted
with CH2Cl2 (3 × 15 mL). The organic layer was separated,
dried over Na2SO4, and filtered, and the solvent was evapo-
rated at reduced pressure. The resulting residue was purified
by column chromatography (EtOAc) followed by crystallization
from hexanes to afford pyrrolobenzodiazepine 11b as a white
solid (73%). Mp 189-191 °C (hexanes); 1H NMR (CDCl3) δ
1.87-2.02 (m, 3H), 2.66-2.73 (m, 1H), 3.53-3.64 (m, 1H),
3.72-3.78 (m, 1H), 3.88 (s, 3H), 3.91 (s, 3H), 4.04-4.06 (m,
306.1215; [R]20 +184.2 (c 0.1, CH2Cl2).
D
(11aS)-7,10-Dimethoxy-1,2,3,10,11,11a-hexahydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione (10c). Accord-
ing to the general procedure pyrrolobenzodiazepine 10c was
obtained from N-methoxyamide 6c in 57% yield as a yellowish
1
oil after purification by column chromatography (EtOAc). H
NMR (CDCl3) δ 1.98-2.10 (m, 3H), 2.73-2.75 (m, 1H), 3.47-
3.49 (m, 2H), 3.64 (s, 3H), 3.81 (s, 3H), 3.87-3.93 (m, 1H),
7.03-7.08 (m, 1H), 7.33-7.43 (m, 2H); 13C NMR (CDCl3) δ
23.5, 26.4, 47.0, 55.6, 56.8, 62.1, 112.5, 119.9, 121.3, 128.7,
129.7, 157.4, 164.6, 165.8; IR (film) 1696, 1630 cm-1; MS (EI)
m/z (%) 276 (M+, 32), 248 (27), 217 (32), 179 (41), 176 (39),
149 (30), 135 (20), 121 (100), 106 (12), 77 (10), 65 (11); HRMS
calcd for C15H16N2O4 276.1110, found 276.1111; [R]20D +256.2
(c 0.1, CH2Cl2).
(13aS)-12-Methoxy-1,2,3,12,13,13a-hexahydro-5H-naph-
tho[2,1-f]pyrrolo[2,1-c][1,4]diazepin-5,13-dione (10d).
Naphthopyrrolodiazepine 10d was obtained in 70% yield from
N-methoxyamide 6d following the typical procedure described
before but adding TFA (3 equiv) to the solution of the amide.
Purification was carried out by column chromatography
(EtOAc) followed by crystallization from hexanes to afford
diazepine 10d as a white solid. Mp 201-203 °C (hexanes); 1H
NMR (CDCl3) δ 1.96-2.21 (m, 3H), 2.69-2.73 (m, 1H), 3.48
2262 J. Org. Chem., Vol. 70, No. 6, 2005

Advantageous Access to the Antitumor Antibiotic DC-81
1H), 6.50 (s, 1H), 7.43 (s, 1H), 8.74 (br s, 1H); 13C NMR (CDCl3)
CH2Cl2); ee 99% (Chiralcel OJ, Hex/iPrOH 90:10, 1.0 mL/min,
tR ) 44.18 min).
δ 23.4, 26.0, 47.2, 56.0, 56.1, 56.8, 103.8, 111.9, 119.1, 129.8,
146.2, 152.1, 165.3, 171.1; IR (KBr) 3225, 1689, 1607 cm-1
;
(11aS)-8-Benzyloxy-7-methoxy-1,2,3,10,11,11a-hexahy-
dro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione (11
g).6c According to the general procedure pyrrolobenzodiazepine
11g was obtained from pyrrolobenzodiazepine 10g in 82% yield
as a white solid after purification by column chromatography
(EtOAc) followed by crystallization from hexanes. Mp 187-
189 °C (hexanes) (lit.6c mp 190-193 °C); HRMS calcd for
MS (EI) m/z (%) 276 (M+, 42), 247 (16), 220 (15), 207 (25), 192
(15), 179 (54), 164 (37), 136 (28), 70 (100), 68 (13); HRMS calcd
for C14H16N2O4 276.1110, found 276.1108; [R]20D +365.6 (c 0.1,
CH2Cl2); ee 98% (Chiralcel OJ, Hex/iPrOH 90:10, 1.0 mL/min,
tR ) 73.41 min).
(11aS)-7-Methoxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo-
[2,1-c][1,4]benzodiazepin-5,11-dione (11c).31 According to
the general procedure pyrrolobenzodiazepine 11c was obtained
from pyrrolobenzodiazepine 10c in 76% yield as a white solid
after purification by column chromatography (EtOAc) followed
by crystallization from hexanes. Mp 198-200 °C (hexanes);
1H NMR (CDCl3) δ 1.99-2.08 (m, 3H), 2.71-2.73 (m, 1H),
3.57-3.59 (m, 2H), 3.81 (s, 3H), 3.88-4.05 (m, 1H), 6.95-6.99
(m, 2H), 7.41-7.43 (m, 1H), 9.07 (br s, 1H); 13C NMR (CDCl3)
δ 23.4, 26.1, 47.2, 55.6, 56.6, 113.1, 120.2, 122.7, 128.0, 128.9,
156.5, 165.2, 171.2; IR (KBr) 3225, 1690, 1608 cm-1; MS (EI)
m/z (%) 246 (M+, 38), 217 (20), 190 (21), 162 (18), 149 (35),
121 (18), 106 (40), 70 (100); HRMS calcd for C13H14N2O3
246.1004, found 246.0997; [R]20D +374.4 (c 0.1, CH2Cl2); ee 98%
(Chiralcel OJ, Hex/iPrOH 90:10, 1.0 mL/min, tR ) 30.50 min).
C20H20N2O4 352.1423, found 352.1423; [R]20 +185.0 (c 0.1,
D
CH2Cl2).
(2S)-N-Benzoyl-2-[N′-methoxy-N′-(3,3,3-trifluoroethoxy)-
carbamoyl]pyrrolidine (7). A solution of PIFA (537 mg, 1.25
mmol) in 13 mL of CF3CH2OH was added at room temperature
to a solution of amide 6a (220 mg, 0.83 mmol) in 9 mL of the
same solvent, and the new solution was stirred until total
consumption of the starting material (TLC, EtOAc). Then, the
mixture was washed with Na2CO3 (10% aq), extracted with
CH2Cl2 (3 × 15 mL), washed with brine, dried over sodium
sulfate, and filtered, and the solvent was evaporated at
reduced pressure. The resulting residue was purified by
column chromatography (EtOAc,) to afford pyrrolidine 7 as a
colorless oil (24%). 1H NMR (CDCl3) δ 1.83-2.02 (m, 3H),
2.26-2.34 (m, 1H), 3.49-3.69 (m, 2H), 3.90 (s, 3H), 4.44 (q, J
) 8.3 Hz, 2H), 4.90-4.96 (m, 1H), 7.32-7.55 (m, 5H); 13C NMR
(CDCl3) δ 25.3, 28.8, 46.7, 49.9, 61.5, 70.0 (q, J ) 34.1 Hz),
126.5, 128.1, 130.2, 122.7 (q, J ) 280.8 Hz), 135.6, 169.4, 177.2;
IR (KBr) 1744, 1630 cm-1; MS (EI) m/z (%) 301 (M - 45, 4),
174 (44), 105 (100), 77 (23).
(13aS)-1,2,3,12,13,13a-Hexahydro-5H-naphtho[2,1-f]pyr-
rolo[2,1-c][1,4]diazepin-5,13-dione (11d).18 According to the
general procedure naphthopyrrolodiazepine 11d was obtained
from naphthopyrrolodiazepine 10d in 85% yield as a white
solid after purification by column chromatography (EtOAc)
followed by crystallization from hexanes. Mp 203-205 °C
(hexanes) (lit.18 mp 216 °C); 1H NMR (CDCl3) δ 2.05-2.08 (m,
3H), 2.75-2.77 (m, 1H), 3.57-3.68 (m, 1H), 3.84-3.91 (m, 1H),
4.16-4.18 (m, 1H), 7.61-8.09 (m, 6H), 8.53 (br s, 1H); 13C NMR
(CDCl3) δ 23.4, 25.9, 47.2, 56.8, 122.5, 124.6, 125.4, 125.8,
126.0, 127.1, 127.9, 128.4, 131.4, 135.2, 165.5, 170.8; IR (KBr)
3237, 1690, 1626 cm-1; MS (EI) m/z (%) 266 (M+, 32), 237 (11),
210 (11), 169 (33), 141 (21), 140 (20), 114 (23), 83 (10), 70 (100);
Oxidation of Aldehyde 12. Synthesis of 4-Benzyloxy-
3-methoxybenzoic Acid (8g).33 To a stirred solution of
aldehyde 12 (5.00 g, 20.66 mmol), NaH2PO4 (744 mg, 6.20
mmol), and H2O2 (35%, 2.30 mL, 21.69 mmol) in 120 mL of
MeCN/H2O (5/1, v/v), was added a solution of NaClO2 (3,27 g,
28.92 mmol) in 30 mL of H2O dropwise keeping the temper-
ature at 10 °C with water cooling. The mixture was stirred at
room temperature for 90 min, then Na2S2O3 (0.42 g, 3.20 mmol)
was added and the mixture was stirred for a further 5 min to
decompose the excess of H2O2. The mixture was diluted with
aq NaCl and extracted with EtOAc (3 × 30 mL). The organic
extracts were separated, washed with aq NaCl (×2), and
extracted with aq NaHCO3 (×3). The alkaline extracts were
separated, acidified (conc HCl), and extracted with EtOAc (×2).
The organic extracts were dried over Na2SO4 and evaporated
to give 8g in 100% yield as a white solid after crystallization
from hexanes. Mp 170-172 °C (hexanes) (lit.33 mp 171-172
°C); HRMS calcd for C15H14O4 258.0892, found 258.0892.
(11aS)-8-Benzyloxy-7-methoxy-1,2,3,10,11,11a-hexa-
hydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one (13).9e
NaBH4 (880 mg, 22.7 mmol) was added to a solution of
diazepine 11g (800 mg, 2.27 mmol) in glyme (6 mL) at room
temperature followed by a dropwise addition of TFA (0.52 mL,
6.82 mmol) in 6 mL of the same solvent over a period of 15
min, and the mixture was refluxed overnight. Then, the
reaction mixture was cooled and carefully quenched with brine.
The organic layer was separated, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The resulting
residue was purified by column chromatography (EtOAc)
followed by crystallization from hexanes to afford pyrroloben-
zodiazepine 13 in 70% yield as a white solid. Mp 167-169 °C
HRMS calcd for C16H14N2O2 266.1055, found 266.1054; [R]20
+535.0 (c 0.1, CH2Cl2).
D
(10aS)-1,2,3,9,10,10a-Hexahydro-5H-pyrrolo[2,1-c]-
thieno[3,2-f][1,4]diazepin-5,10-dione (11e).32 According to
the general procedure pyrrolothienodiazepine 11e was ob-
tained from pyrrolothienodiazepine 10e in 69% yield as a white
solid after purification by column chromatography (EtOAc)
followed by crystallization from hexanes. Mp 263-265 °C
(hexanes) (lit.32 mp 266-271 °C); 1H NMR (CDCl3) δ 1.97-
2.12 (m, 3H), 2.73-2.75 (m, 1H), 3.61-3.67 (m, 2H), 4.19 (d,
J ) 7.1 Hz, 1H), 6.87 (d, J ) 5.5 Hz, 1H), 7.29 (d, J ) 5.5 Hz,
1H), 9.50 (br s, 1H); 13C NMR (DMSO-d6) 23.4, 25.9, 46.6, 57.4,
117.8, 124.2, 126.8, 143.8, 161.8, 169.5; IR (KBr) 3193, 1695,
1687 cm-1; MS (EI) m/z (%) 222 (M+, 35), 194 (21), 193 (35),
166 (30), 126 (11), 125 (66), 97 (26), 70 (100), 52 (24); HRMS
calcd for C10H10N2O2S 222.0463, found 222.0465; [R]20D +568.3
(c 1.0, EtOH); ee 98% (Chiralcel OJ, Hex/iPrOH 92:8, 0.9
mL/min, tR ) 42.20 min).
(10aS)-6-Methyl-1,2,3,9,10,10a-hexahydro-5H-dipyrrolo-
[2,3-f:2,1-c][1,4]diazepin-5,10-dione (11f). According to the
general procedure dipyrrolodiazepine 11f was obtained from
dipyrrolodiazepine 10f in 87% yield as a white solid after
purification by column chromatography (EtOAc) followed by
crystallization from hexanes. Mp 203-205 °C (hexanes); 1H
NMR (CDCl3) δ 1.94-2.10 (m, 3H), 2.44-2.71 (m, 1H), 3.54-
3.57 (m, 2H), 3.85 (s, 3H), 4.04-4.07 (m, 1H), 5.81 (d, J ) 2.7
Hz, 1H), 6.61 (d, J ) 2.7 Hz, 1H), 9.20 (br s, 1H); 13C NMR
(CDCl3) δ 23.6, 26.2, 36.4, 46.3, 57.8, 99.1, 116.6, 127.3, 127.8,
160.4, 169.3; IR (KBr) 3150, 1685, 1676 cm-1; MS (EI) m/z (%)
219 (M+, 100), 190 (48), 163 (56), 149 (13), 122 (25), 94 (32),
85 (22), 83 (33), 79 (33), 70 (49), 66 (14), 52 (15); HRMS calcd
for C11H13N3O2 219.1008, found 219.1008; [R]20D +233.8 (c 0.1,
1
(hexanes); H NMR (CDCl3) δ 1.52-1.81 (m, 3H), 2.10-2.15
(m, 1H), 3.02-3.11 (m, 1H), 3.37-3.42 (m, 1H), 3.51-3.73 (m,
3H), 3.77 (s, 3H), 4.56 (br s, 1H), 4.93 (s, 2H), 6.05 (s, 1H),
7.25-7.30 (m, 5H), 7.57 (s, 1H); 13C NMR (CDCl3) δ 22.6, 30.6,
48.2, 52.5, 56.1, 57.6, 70.2, 102.4, 110.0, 115.1, 127.0, 127.8,
128.5, 136.3, 141.4, 141.6, 151.5, 166.2; IR (KBr) 3315, 1625
cm-1; MS (EI) m/z (%) 338 (M+, 49), 219 (16), 91 (100), 70 (29);
[R]20 +115.6 (c 0.1, CH2Cl2).
D
(11aS)-8-Benzyloxy-7-methoxy-1,2,3-trihydro-5H-pyr-
rolo[2,1-c][1,4]benzodiazepin-5-one (14).6c NMO (142 mg,
(31) Li, X.; Ma, C.; He, X.; Yu, J.; Han, D.; Zhang, C.; Atack, J. R.;
Cook, J. M. Med. Chem. Res. 2003, 11, 504-537.
(32) Walter, A.; Flynn, T. J. Heterocycl. Chem. 1992, 29, 1477-1480.
(33) Baggaley, K. H.; Fears, R.; Hindley, R. M.; Morgan, B.; Murrel,
E.; Thorne, D. E. J. Med. Chem. 1977, 20, 1388-1393.
J. Org. Chem, Vol. 70, No. 6, 2005 2263

Correa et al.
1.18 mmol) and TPAP (21 mg, 0.06 mmol) were added to a
solution of the compound 13 (200 mg, 0.59 mmol) in MeCN
(35 mL) in the presence of 250 mg of 4 Å powdered molecular
sieves After stirring at room temperature for 1.5 h the solvent
was removed under vacuum. The reaction mixture was then
taken up in EtOAc and filtered through a pad of silica eluting
with the same solvent. The filtrate was evaporated and the
residue purified by flash chromatography (EtOAc) followed by
crystallization from Et2O to afford diazepine 14 as a white solid
(60%). Mp 63-65 °C (Et2O) (lit.6c mp 58-61 °C); [R]20D +435.3
(c 0.2, CH2Cl2).
resulting residue was purified by flash chromatography (EtOAc/
acetone, 1:1) to render DC-81 (1) as a colorless solid (90%).
Mp 130-132 °C (lit.6c mp 135-138 °C); [R]20 +171.5 (c 0.1,
D
CH2Cl2) (lit.34 [R]22 +135 (c 0.2, CHCl3)).
D
Acknowledgment. Financial support from the Uni-
versity of the Basque Country (9/UPV 41.310-13656/
2001) and the Spanish Ministry of Science and Tech-
nology (MCYT BQU 2001-0313) is gratefully acknow-
ledged. A.C. thanks the Basque Government for a
predoctoral scholarship.
(11aS)-8-Hydroxy-7-methoxy-1,2,3-trihydro-5H-pyrrolo-
[2,1-c][1,4]benzodiazepin-5-one (1).6c DC-81. To a solution
of diazepine 14 (100 mg, 0.30 mmol) in absolute EtOH (3 mL)
was added 10% Pd/C (10 mg) under argon atmosphere. Then,
1,4-cyclohexadiene (0.3 mL, 3 mmol) was added to the solution
dropwise. The resulting solution was stirred at room temper-
ature for 2.5 h until TLC (EtOAc) indicated that the reaction
was complete. The reaction mixture was filtered through a pad
of Celite, the solvent was removed under vaccuum, and the
Supporting Information Available: 1H NMR and 13C
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO047872U
(34) Japanese Patent: JP 58,180,487 [83,180,487] (Cl. CO7D487/
04); Kyowa Hakko Kogyo Co. Ltd., Jpn Kokai Tokkyo Koho, Appl. 21
Oct. 1983, 82/63, 630, 16 Apr 1982 (Chem. Abstr. 1984, 100, 173150K).
2264 J. Org. Chem., Vol. 70, No. 6, 2005