Enantiospecific synthesis of 5-phenylpyrrolo[2,1-c][1,4]benzodiazepines

Article abstract of DOI:10.1016/j.tetlet.2008.09.168

Enantiomerically pure 5-phenylpyrrolo[2,1-c][1,4]benzodiazepines were synthesized starting from 2-aminobenzophenones and 2-amino-4-methoxyxanthone, using l-proline as a chiral building block.

Full text of DOI:10.1016/j.tetlet.2008.09.168

Tetrahedron Letters 49 (2008) 7174–7177
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantiospecific synthesis of 5-phenylpyrrolo[2,1-c][1,4]benzodiazepines
*
Loreto Legerén, Eduardo Gómez, Domingo Domínguez
Departamento de Química Orgánica, Facultad de Química, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2008
Revised 26 September 2008
Accepted 30 September 2008
Available online 2 October 2008
Enantiomerically pure 5-phenylpyrrolo[2,1-c][1,4]benzodiazepines were synthesized starting from
2-aminobenzophenones and 2-amino-4-methoxyxanthone, using
L-proline as a chiral building block.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to Professor Luis Castedo on the
occasion of his 70th birthday
Keywords:
Pyrrolobenzodiazepine
Xanthene
Proline
Benzodiazepinone
Cyclodehydration
The 5-aryl-1,4-benzodiazepin-2-ones constitute an important
class of privileged templates as they are able to provide ligands
for diverse receptors such as the cholecystokinin receptor (CCK)
and several central nervous system (CNS) receptors.1 Besides the
well-known clinically effective psychoactive drugs such as diaze-
pam,2 more than 10,000 benzodiazepines have been found to have
pharmacological properties ranging from inhibition of the prolifer-
ation of tumor cells,3 to antiviral4 and analgesic5 activities, to the
blocking of sodium channel in the treatment of neuropathic pain.6
Pyrrolo[2,1-c][1,4]benzodiazepin-11-ones exhibit different bio-
logical properties.7 They are useful for treatment of anxiety in
warm-blooded animals,8 and as a new class of anti-ischemic
agents.9 Their N10–C11 imino derivatives (PBDs), which can be ob-
tained from them chemically,10 are gene-specific antitumor agents
capable of binding to specific DNA sequences, forming aminal
bonds by nucleophilic attack of the NH2 of a guanine at their elec-
trophilic C11 position.11
In view of the biological relevance of the above molecular fam-
ilies, we became interested in the synthesis of hybrids combining
the 5-aryl- and pyrrolo-benzodiazepinone frameworks, such as un-
known compounds 5-phenylpyrrolo[2,1-c][1,4]benzodiazepin-11-
one (1a) and the chromeno-fused derivative 2, a rigid analogue
in which the phenyl ring is conformationally frozen by the ether
bridge (Fig. 1). A search of the literature showed only two previous
reports of this structural motif, both concerning 3,11-diones in
H
N
H
N
O
H
O
H
N
H
N
H
O
O
1a
2
Figure 1. 5-Phenylpyrrolo[2,1-c][1,4]benzodiazepin-11-ones.
which the pyrrolidinone ring was constructed by intramolecular
N-acylation of a 5-phenyl-1,4-benzodiazepin-2-one with a propan-
oate substituent at position 3.12 Furthermore, only two other
groups of tricyclic 5-aryl-3,4-fused [1,4]benzodiazepines have
been described in the literature, the imidazo[5,1-c]13 and imidazo-
[2,1-c]14 derivatives.
For the synthesis of 1a, we started from 2-aminobenzophenone
3a. This was condensed with L-Boc-Pro in the presence of isobutyl
chloroformate15 to provide amide 4a, which was subsequently
deprotected with TFA to afford 5a, both steps proceeding in quan-
titative yield (Scheme 1). Reduction of the benzophenone carbonyl
group with NaBH4 in EtOH at rt gave a 99% yield of benzhydrol 6a
as a 10:3 mixture of stereoisomers, as evidenced by 1H NMR.
All attempts to construct the N4–C5 bond of the required diaz-
epinone ring by acidic cyclodehydration failed. Treatment of the
diastereomeric mixture 6a in acetic acid at rt for 48 h had no effect;
heating this solution under reflux for 2 h led to extensive
decomposition of the starting amide; and heating at 60 °C for
* Corresponding author. Fax: +34 981595012.
E-mail address: domingo.dominguez@usc.es (D. Domínguez).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.168

L. Legerén et al. / Tetrahedron Letters 49 (2008) 7174–7177
7175
R4
N
H
H
O
O
H
H
N
H
N
N
R
NH2
O
N
H
1
O
OH
DCB
O
R1
R1
R1
NaBH4
5
R1
L
-Boc-Pro, IBCF
7
N
2
R2
EtOH, r.t.
R2
180 ºC, 3.5 h
R2
H
Et3N, THF, 0 ºC
R2
R3
R3
R3
R3
3
1a-c, R4= H
7a, R4= Me
a, R1= R2= R3= H
NaH
4a-c, R= Boc
5a-c, R= H
TFA
CH2Cl2, r.t.
6a-c
b, R1= Cl, R2= F, R3= H
MeI, DMF
1
2
3
1a
)
c
(for
, R = R = H, R = OMe
H
N
H
11a
1
5
N
H
H
3
N
L
-Pro, DCC
DMAP, CH2Cl2
O
H
N
N
(-)-8 (31%)
LAH/THF/reflux
(for 1a)
H
+
H
N
H
H
11
1
5
N
H
3
10
9
(-)- (38%)
Scheme 1. Synthesis of cis and trans pyrrolo[2,1-c][1,4]benzodiazepines (ꢁ)-8 and (ꢁ)-9.
Table 1
24 h afforded (2-acetamidophenyl)(phenyl)methyl acetate as the
main product, indicating cleavage of the amide bond of 6a and
subsequent N,O-diacetylation of the resulting (2-aminophe-
nyl)(phenyl)methanol in the acetic acid medium. The use of p-
TsOH in toluene, whether in catalytic quantities or in large excess,
likewise produced no reaction at rt and decomposition at temper-
atures over 60 °C. Stirring for 24 h at rt in methanol saturated with
HCl gave a 58% yield of the methyl ether resulting from an inter-
molecular displacement of the hydroxyl of 6a by the solvent; while
treatment with HCl–saturated diethyl ether in dichloromethane for
48 h at rt caused decomposition. Finally, heating at 100 °C in PPA
for 1 h also led to decomposition of the starting material. Attempts
to carry out the cyclodehydration using Lewis acid catalysts such
as TiCl4 or BF3ꢀOEt2 led to very complex reaction mixtures.
Thermal cyclodehydration conditions tried for amide 6a
Entry Conditions
Solvent
Time
Temperature
Result
1
2
3
Dean–Stark
4 Å MS
4 Å MS
Toluene 24 h
Toluene 24 h
Dioxane 3 h
Reflux
Reflux
130 °C (sealed
tube)
125 °C
6a
6a
6a
4
5
Bmim
—
7 h
6a
SiO2
(preabsorbed)
5 min 170 °C
Decomposition
6
DCB
3.5 h
180 °C (sealed
tube)
1a (1:1, 86%)
N-methylated derivative 7a (obtained in 63% yield by treatment
of 1a with sodium hydride and methyl iodide in DMF), but LAH
reduction of 1a to the corresponding benzodiazepines allowed
chromatographic separation of less polar and more polar isomers
in 38% and 31% isolated yields, respectively.18 Unambiguous iden-
tification of the relative stereochemistry of the minor isomer was
possible on the basis of a 5% NOE on the intensity of the multiplet
at 2.98–3.06 ppm (H11a) upon irradiation of the singlet at 4.86 ppm
(H5), which clearly showed the cis arrangement of these protons
(Scheme 1, 8). By contrast, in the major isomer irradiation, of the
singlet at 5.19 ppm (H5) enhanced the multiplets at 2.92–
3.00 ppm (H11 ) and 2.82–2.87 ppm (H3 ) by 2.3% and 2.2%,
The reluctance of the system to undergo acidic cyclodehydra-
tion was attributed to 6a existing mainly as its trans amide bond
rotamer, in which the large distance between N4 and C5 (4.10 Å
according to MM2 calculations) favors alternative reactions of an
activated hydroxyl. We inferred that cyclodehydration under neu-
tral conditions would require sufficient thermal energy to bring
about rotation to the cis rotamer for the cyclization (Table 1). Nev-
ertheless, prolonged heating of 6a in refluxing toluene achieved no
change, regardless of whether water was removed using a Dean–
Stark trap (entry 1) or 4 Å molecular sieves (entry 2). Heating in
dioxane in a sealed tube at 130 °C (entry 3) or in the ionic liquid
Bmim16 at 125 °C (entry 4) was also ineffective, and pre-adsorption
on silica followed by heating in an oven at 170 °C led to extensive
decomposition (entry 5). Finally, however, heating in dichloroben-
zene at 180 °C in a sealed tube for 3.5 h (entry 6) led to an excellent
86% yield of the cyclodehydrated product 1a, a yellow solid con-
sisting of a 1:1 mixture of the cis and trans stereoisomers.17 Chro-
matography failed to separate both this mixture and its
a
a
respectively, confirming the location of H5 on the
H11a (Scheme 1, 9).
a-face trans to
The optical activity of (ꢁ)-8 and (ꢁ)-9 suggested preservation of
the stereochemistry of C11a (provided by the starting -proline).
Their enantiomeric purity initially seemed to have been confirmed
when derivatization of (ꢁ)-8 with -proline afforded what ap-
peared to be a diastereomerically pure amide, 10. Furthermore,
L
L

7176
L. Legerén et al. / Tetrahedron Letters 49 (2008) 7174–7177
H
H
R
O
O
N
H
N
R
H
N
O
O
NH
NH
MeO
7
H
AcOH
r.t.
NaBH4
L
-Boc-Pro, IBCF
10a
O
OH
O
N
H
MeO
EtOH, reflux
MeO
Et3N, THF, 0 ºC MeO
14a
O
O
O
1
11, R=H
HNO 3
80 ºC
4
12, R=NO2
13, R=NH2
14, R=Boc
15, R=H
16
2
(+)-
TFA
CH2Cl2
NH4HCO2
Pd/C, EtOH
Scheme 2. Synthesis of (14aR,10aS)-pyrrolo[1,2-a]xanthene[1,9-e,f][1,4]diazepin-10-one (2).
when this reaction was carried out on the unseparated mixture of
(ꢁ)-8 and (ꢁ)-9, H5 singlets at 4.90 and 5.15 ppm in the 1H NMR
spectrum of the product appeared to show the presence of only
two stereoisomers, amide 10 and the analogous derivative of
(ꢁ)-9. However, since the spectrum of the derivatization product
of rac-8 (obtained starting from 3 and rac-Pro) did not clearly show
amide 10 and the corresponding diastereoisomer, and since deriv-
atization of rac-9 afforded an analogous result, we sought and ob-
tained additional evidence of enantiomeric purity. Successive
additions of the chiral shift reagent Eu(hfc)3 did not cause chemical
shift changes in the 1H NMR spectrum of (ꢁ)-8, but complexation
of the carbonyl of 1a by Eu(hfc)3 shifted its H5 signals at 4.69 and
5.02 ppm with no splitting, indicating an enantiomeric excess
of more than 95%. By contrast, addition of 30% of Eu(hfc)3 to
rac-1a19 clearly split its H5 signals.
derivative 2 by NOE experiments in which irradiation of the singlet
at 4.69 ppm (H14a) caused a 1.9% enhancement of the intensity of
the doublet at 3.74 ppm (H10a). This difference in stereoselectivity
compared with the reactions of the open analogues 6a and 6c can
be attributed to the more rigid nature of 16, which leads to the
reactions at the two diastereotopic faces of the intermediate xan-
thylium cation having very different transition states.
In conclusion, we have synthesized enantiopure cis and trans
stereoisomers of 5-phenylpyrrolo[2,1-c][1,4]benzodiazepine, (ꢁ)-
8, and (ꢁ)-9, in five steps and 69% overall yield from 2-aminoben-
zophenone, the key step being a non-stereoselective cyclodehydra-
tion; and have also stereoselectively prepared the pentacyclic
cis-pyrrolo[2,1-c][1,4]benzodiazepinone (+)-2 in six steps from
the starting xanthone, in a global yield of 38%.
We thus accomplished a five-step synthesis of enantiomerically
pure 5-phenylpyrrolo[2,1-c][1,4]benzodiazepine 1a from 2-amino-
benzophenone in 69% yield. Unfortunately, this protocol seems to
be of limited scope, since attempts to cyclize the substituted benz-
hydrol 6b,20 whether thermally (DCB, 180 °C) or with Lewis acid
catalysis (BF3ꢀOEt2, DCE, reflux), led to complex mixtures, probably
due to the electron-withdrawing halogen substituents making the
intermediate carbocation unstable. In the case of the methoxy-
substituted benzhydrol 6c,21 heating at 180 °C in DCB led to
decomposition, and reaction in acetic acid at rt afforded only in a
very modest 18% yield of the cyclodehydration product.
We also synthesized the chromeno-fused pentacyclic derivative
2, a rigid analogue of 1a in which the conformation of the phenyl
substituent is fixed by the ether bridge. We started from 4-meth-
oxy-9H-xanthen-9-one (11), which is easily prepared in two steps
from commercially available guayacol and o-chlorobenzoic acid.22
Treatment of 11 with hot concentrated nitric acid afforded the
nitro derivative 12,23 which was catalytically reduced by hydrogen
transfer to give aminoxanthone 13 in 67% overall yield from xan-
Acknowledgments
Support of this work by the Spanish Ministry of Education and
Science in collaboration with the European Regional Development
Fund (through Project CTQ2005-02338), and by the Xunta de Gali-
cia (through Projects PGIDITO6PXIC209067PN and 2007/XA084,
and a pre-doctoral grant to L.L.) is gratefully acknowledged.
References and notes
1. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti,
V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield,
J. J. Med. Chem. 1988, 31, 2235–2246; (b) Horton, D. A.; Bourne, G. T.; Smythe,
M. L. Chem. Rev. 2003, 103, 893–930; (c) Ferrini, S.; Ponticelli, F.; Taddei, M. J.
Org. Chem. 2006, 71, 9217–9220.
2. Sternbach, L. H. Angew. Chem., Int. Ed. Engl. 1971, 10, 34–43.
3. Dourlat, J.; Liu, W.-Q.; Gresh, N.; Garbay, C. Bioorg. Med. Chem. Lett. 2007, 17,
2527–2530.
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2007034127; Chem. Abstr. 2007, 146, 351219.
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Pharm. Chem. J. 2005, 39, 641–643.
thone 11. Acylation of 13 with N-Boc-L-proline, previously acti-
6. Hoyt, S. B.; London, C.; Gorin, D.; Wyvratt, M. J.; Fisher, M. H.; Abbadie, C.; Felix,
J. P.; Garcia, M. L.; Li, X.; Lyons, K. A.; McGowan, E.; MacIntyre, D. E.; Martin, W.
J.; Priest, B. T.; Ritter, A.; Smith, M. M.; Warren, V. A.; Williams, B. S.;
Kaczorowski, G. J.; Parsons, W. H. Bioorg. Med. Chem. Lett. 2007, 17, 4630–4634.
7. Kamal, A.; Ramana, A. V.; Reddy, K. S.; Ramana, K. V.; Hari Babu, A.; Prasad, B. R.
Tetrahedron Lett. 2004, 45, 8187–8190.
8. Wright, W. B., Jr. U.S. Patent 3,947,408, 1976; Chem. Abstr. 1976, 85, 46771.
9. Mishra, J. K.; Garg, P.; Dohare, P.; Kumar, A.; Siddiqi, M. I.; Ray, M.; Panda, G.
Bioorg. Med. Chem. Lett. 2007, 17, 1326–1331.
10. (a) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433–465; (b) 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.
11. Puvvada, M. S.; Forrow, S. A.; Hartley, J. A.; Stephenson, P.; Gibson, I.; Jenkins, T.
C.; Thurston, D. E. Biochemistry 1997, 36, 2478–2484.
12. (a) Walser, A.; Silverman, G.; Fryer, R. I. J. Org. Chem. 1973, 38, . 3502–3507; (b)
Mulzer, J.; Schöder, F.; Lobbia, A.; Buschmann, J.; Luger, P. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1737–1739.
13. Jaunin, R.; Wolf, A. Helv. Chim. Acta 1973, 56, 2569–2583.
14. Rizzeto, E.; Castellano, S.; Florio, C.; Vadori, M.; Stefancich, G. Pharmazie 2006,
61, 505–510.
vated with isobutyl chloroformate, provided a quantitative yield
of amide 14, which was then deprotected to 15 in 82% yield by
treatment with trifluoroacetic acid (Scheme 2). Reduction of 15
with sodium borohydride in refluxing ethanol gave amidoxanthy-
drol 16, apparently as a mixture of two epimeric alcohols with
two rotamers each, the 1H NMR spectrum showing four singlets
for benzylic protons between 5.75 and 5.97 ppm. Finally, reaction
of this mixture with AcOH at rt smoothly afforded diazepinone
(+)-2 in 70% overall yield from 15.24 That this cyclodehydration
and that of the open analogue 6c took place under much milder
conditions than those of 6a and 6b suggest that this reaction
may proceed through an SN1 type mechanism, with loss of water
from C5 and the formation of a carbocation intermediate that in
the cases of 16 and 6c would be stabilized by the electron-donating
substituents.
A distinctive feature of the cyclization of 16 was that it pro-
duced just a single stereoisomer, which was identified as the cis
15. Lehman, T.; Gmeiner, P. Heterocycles 1999, 51, 1398–1400.
16. Welton, T. Chem. Rev. 1999, 99, 2071–2084.

L. Legerén et al. / Tetrahedron Letters 49 (2008) 7174–7177
7177
17. (5R,11aS)- and (5S,11aS)-5-phenyl-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c]-
[1,4]benzodiazepin-11-ones (1a): solution of amidoalcohol 6a (370 mg,
1.3 mmol) in dichlorobenzene (12 mL) was deoxygenated with a stream of
argon and stirred at 180 °C for 3.5 h in
sealed tube.. The solvent was
1.49–1.57 (m, 1H, H1b), 1.70–1.87 (m, 2H, H2 , H2b), 1.90–1.98 (m, 1H, H1 ),
a
a
A
2.82–2.87 (m, 1H, H3 ), 2.92–3.00 (m, 2H, H11 , H11b), 3.17 (dd, J = 12.9, 2.7 Hz,
a
a
1H, H3b), 3.19–3.25 (m, 1H, H11a), 5.19 (s, 1H, H5), 6.70 (dd, J = 7.8, 0.8 Hz, 1H,
ArH), 6.77 (td, J = 7.4, 1.2 Hz, 1H, ArH), 7.0 (dd, J = 7.5, 1.2 Hz, 1H, ArH), 7.10 (td,
J = 7.6, 1.5 Hz, 1H, ArH), 7.20–7.23 (m, 1H, ArH), 7.27–7.30 (m, 2H, ArH), 7.43–
7.45 (m, 2H, ArH). 13C NMR/DEPT, (CDCl3, 100 MHz), d (ppm): 22.52 (C2), 29.04
(C1), 51.40 (C3), 51.93 (C11), 57.01 (C11a), 69.18 (C5), 118.87 (CH), 119.86 (CH),
126.65 (CH), 127.71 (CH); 127.77 (2 ꢂ CH), 129.22 (2 ꢂ CH), 129.36 (C), 132.09
(CH), 140.78 (C), 148.41 (C). MS (ESI), m/z (%): 265 ([M+H]+, 100). HRMS (ESI,
[M+H]+) calcd for C18H21N2: 265.1699, found: 265.1707.
a
evaporated under reduced pressure and the residue was purified by flash
chromatography on silica gel (95:5 CH2Cl2/MeOH), affording a mixture of the
cis and trans diastereoisomers 1a (1:1 ratio, 311 mg, 86%) as a yellow solid, mp
105–107 °C. IR (CHCl3) 3216 and 3204 (N–H st), 1674 (CO), 1487 (N–H d). 1H
NMR (CDCl3, 400 MHz), d (ppm): 1.77–1.87 and 1.94–2.02 (m, 7H), 2.34–2.44
(m, 2H), 2.58–2.66 (m, 1H), 2,82 (t, J = 6.8 Hz, 1H) and 2.93 (td, J = 8.4, 2.3 Hz,
1H), 3.64 (dd, J = 8.7, 2.8 Hz, 1H, H11a) and 3.77 (d, J = 7.0 Hz, 1H, H11a), 4.69 (s,
1H, H5) and 5.02 (s, 1H, H5), 6.58 (d, J = 7.5 Hz, 1H, ArH) and 6.84 (d, J = 7.33 Hz,
1H, ArH), 7.00–7.50 (m, 16H, ArH), 7.60 (br s, 1H, NH) and 7.95 (br s, 1H, NH).
13C NMR/DEPT (CDCl3, 75 MHz), d (ppm): 23.19 and 24.04 (2 ꢂ CH2), 24.73 and
25.51 (2 ꢂ CH2), 52.17 and 55.71 (2 ꢂ CH2), 60.84 and 60.86 (2 ꢂ CH), 66.57
and 75.57 (2 ꢂ CH), 121.04 and 122.30 (2 ꢂ CH), 124.38 and 125.45 (2 ꢂ CH),
127.17 and 127.50 (2 ꢂ CH), 127.68 and 127.76 (2 ꢂ CH), 128.17 and 128.42
(4 ꢂ CH), 128.50 and 128.71 (4 ꢂ CH), 129.27 and 131.28 (2 ꢂ CH), 133.63 (C),
134.96 (C), 135.29 (C), 137.53 (C), 140.21(C), 145.28 (C), 171.94 (CO), 174.49
(CO). MS (CI), m/z (%): 279 ([M+H]+,100), 278 (M+, 36), 251 (20), 182 (35). MS
(EI), m/z (%): 278 (M+, 11), 180 (100). HRMS (EI) calcd for C18H18N2O: 278.1419,
found: 278.1411.
19. Obtained from
D,L-proline and 2-aminobenzophenone as a 1:1 mixture of cis
and trans ( )-1a.
20. Prepared in three steps and 78% yield from commercially available 2-amino-5-
chloro-20-fluorobenzophenone.
21. Prepared in three steps and 79% yield from 2-amino-40-methoxy-
benzophenone, which was synthesized in 33% overall yield from aniline by
conversion to the pivaloylamide, ortho-lithiation and trapping with p-
methoxybenzaldehyde, oxidation with MnO2 and hydrolysis.
22. Galt, R. H. B.; Horbury, J.; Matusiack, Z. S.; Pearce, R. J.; Shaw, J. S. J. Med. Chem.
1989, 32, 2357–2362.
23. Kudav, N. A.; Kulkarni, A. B. Indian J. Chem., Sect. B. 1976, 14, 484–485.
24. (+)-(14aR,10aS)-6-methoxy-9,10a,11,12,13,14a-hexahydro-10H-pyrrolo[1,2-a]xan-
thene[1,9-e,f][1,4]diazepin-10-one (2): NaBH4 (70 mg, 1.85 mmol) was added
portion-wise to a stirred solution of amidoxanthone 15 (200 mg, 0.59 mmol) in
EtOH (30 mL), and the resulting mixture was heated under reflux for 7 h. After
cooling to 0 °C, HCl (10%) was added until gas release ceased, and the solvent
was then removed under reduced pressure. The residue was partitioned
between CH2Cl2 and brine, and the organic layer was washed with water, dried
with anhydrous Na2SO4, filtered, and concentrated, affording 16 as a mixture of
stereoisomers. This crude was dissolved in AcOH (10 mL) and stirred at rt for
72 h. After evaporation of the solvent, water was added (10 mL), followed by a
few drops of 5 N NaOH to make a slightly basic solution that was extracted
with CH2Cl2. The organic extract was washed with brine, dried with Na2SO4,
filtered, and concentrated. Flash chromatography (SiO2, 91:9 CH2Cl2/MeOH)
18. Reduction of the diastereomeric mixture of lactams 1a: LiAlH4 (88 mg,
2.32 mmol) was added portion-wise to
a stirred solution of 1a (75 mg,
0.27 mmol) in THF (16 mL), and the resulting mixture was heated under
reflux for 6 h. After cooling to 0 °C, the solution was neutralized with HCl (1 M),
diluted with ice water, and extracted with dichloromethane (3 ꢂ 10 mL). The
organic extract was washed with brine, dried with Na2SO4, filtered, and
concentrated. Purification by flash chromatography on silica gel (95:5 CH2Cl2/
MeOH) gave a mixture of the two diastereoisomers of 8 (1:0.8 ratio, 58 mg,
81%), and chromatography of this mixture on silica gel (2:8 hexanes/EtOAc)
provided (ꢁ)-8 (27 mg, 38%) and (ꢁ)-9 (22 mg, 31%) as amorphous solids:
(ꢁ)-(5R,11aS)-5-phenyl-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzo-
diazepine (8): ½a D20
ꢃ
ꢁ7.2 (c 1, CH2Cl2). IR (KBr): 3429 (N–H st), 1631 (N–H d),
1080 (C–N st) cmꢁ1
.
1H NMR (CDCl3, 300 MHz), d (ppm): 1.46–1.54 (m, 1H,
gave 2 (127 mg, 70%) as an amorphous solid: ½a D20
ꢃ
+48.4 (c 1, CH2Cl2); IR (KBr)
H1 ), 1.67–1.78 (m, 2H, H2 , H2b), 1.93–2.10 (m, 1H, H1b), 2.34 (q, J = 8.4 Hz, 1H,
3433 and 3277 (N–H st), 1673 (CO), 1501 (N–H d) cmꢁ1 1H NMR (CDCl3,
.
a
a
H3b), 2.77–2.81 (m, 1H, H3 ), 2.90–2.95 (m, 1H, H11 ), 2.98–3.06 (m, 1H, H11a),
500 MHz), d (ppm): 1.73–1.79 (m, 2H, H11 , H12b), 2.03–2.05 (m, 1H, H12b),
a
a
a
3.32 (dd, J = 11.9, 2.9 Hz, 1H, H11b), 4.86 (s, 1H, H5), 6.72–6.76 (m, 3H, ArH),
7.00–7.07 (m, 1H, ArH), 7.25–7.28 (m, 1H, ArH), 7.32–7.35 (m, 2H, ArH), 7.42–
7.43 (m, 2H, ArH). 13C NMR/DEPT (CDCl3, 75 MHz), d (ppm): 21.96 (C2), 28.77
(C1), 52.33 (C11), 53.23 (C3), 65.45 (C11a), 70.61 (C5), 120.07 (CH), 120.87 (CH),
126.87 (CH), 127.46 (CH), 128.04 (2 ꢂ CH), 129.29 (2 ꢂ CH), 130.77 (CH),
132.78 (C), 142.83 (C), 148.65 (C). MS (CI), m/z (%): 265 ([M+H]+, 100), 206 (2),
187 (2). MS (ESI), m/z (%): 265 ([M+H]+,100). HRMS (ESI, [M+H]+) calcd for
C18H21N2: 265.1699, found: 265.1707.
2.40–2.43 (m, 1H, H11 ), 2.62 (q, J = 8.5 Hz, 1H, H13b), 3.15–3.18 (m, 1H, H13 ),
a
a
3.74 (dd, J = 7.4, 2.1 Hz, 1H, H10a), 3.94 (s, 3H, OCH3), 4.69 (s, 1H, H14a), 6.74 (d,
J = 8.5 Hz, 1H, ArH), 6.89 (d, J = 8.6 Hz, 1H, ArH) 7.09–7.13 (m, 1H, ArH), 7.27–
7.33 (m, 3H, ArH), 8.28 (s, 1H, NHCO). 13C NMR/DEPT (CDCl3, 125 MHz), d
(ppm): 23.37 (C12), 23.54 (C11), 51.23 (C13), 54.93 (C14a), 56.59 (OCH3), 60.84
(C10a), 111.67 (CH), 111.69 (C), 115.32 (CH), 117.60 (CH), 117.70 (C), 119.55 (C),
123.01(CH), 129.20 (CH), 130.34 (CH), 141.61 (C), 146.01 (C), 151.82 (C),
171.92 (CO). MS (EI), m/z (%): 322 (M+, 6), 225 (72), 210 (100). HRMS (EI) calcd
for C19H18N2O3: 322.1317, found: 322.1304.
(ꢁ)-(5S,11aS)-5-phenyl-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzo-
diazepine (9): ½a D20
ꢃ
ꢁ78.5 (c 1, CH2Cl2). 1H NMR, (CDCl3, 400 MHz), d (ppm):