Chemoenzymatic synthesis of pyrrolo[2,1-b]quinazolinones: Lipase-catalyzed resolution of vasicinone

Article abstract of DOI:10.1021/jo0011484

A facile synthesis of bronchodilatory pyrrolo[2,1-b]quinazoline alkaloids by azidoreductive cyclization strategy employing TMSCl-NaI and bakers' yeast is described. Both the chemical and enzymatic methods are mild and take place at room temperature in good yields. Further, synthesis and resolution of vasicinone has been carried out by employing different lipases. It has been observed that lipase PS provides acetate of (S)-vasicinone in 98% ee.

Full text of DOI:10.1021/jo0011484

J . Org. Chem. 2001, 66, 997-1001
997
Ch em oen zym a tic Syn th esis of P yr r olo[2,1-b]qu in a zolin on es:
Lip a se-Ca ta lyzed Resolu tion of Va sicin on e†
Ahmed Kamal,* K. Venkata Ramana, and Maddamsetty V. Rao
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
ahmedkamal@iict.ap.nic.in
Received J uly 28, 2000
A facile synthesis of bronchodilatory pyrrolo[2,1-b]quinazoline alkaloids by azidoreductive cyclization
strategy employing TMSCl-NaI and bakers’ yeast is described. Both the chemical and enzymatic
methods are mild and take place at room temperature in good yields. Further, synthesis and
resolution of vasicinone has been carried out by employing different lipases. It has been observed
that lipase PS provides acetate of (S)-vasicinone in 98% ee.
In tr od u ction
activity particularly bronchodilatory activity. A series of
analogues of vasicinone have recently been synthesized
and evaluated for their bronchodilatory activity.3 Deoxy-
vasicinone, though obtained in nature, may be considered
as a precursor for the synthesis of vasicinone, and the
former has been prepared by various methods such as
carbonylation catalyzed by palladium,4 coupling O-methyl
butyrolactim with anthranilic acid,5 cycloaddition of
anthranilic acid iminoketene to a methyl butyrolactam
(via sulfinamide anhydride),6 and intramolecular aza-
Wittig reaction using PPh3 and PBu3.7 (() Vasicinone has
also been synthesized from deoxyvasicinones by bromi-
nation with NBS followed by acetoxylation with NaOAc-
AcOH treatment and lead tetraacetate free radical
oxidation.5 (3S)-(-)-Vasicinone has been claimed to have
better bronchodilation activity than the racemic form and
has been recently synthesized by asymmetric hydroxy-
lation using Davis reagent.7a
Vasicinone (1) is a pyrrolo[2,1-b]quinazoline alkaloid
isolated from the aerial parts of Adhatoda vasica (fam-
ily: Acanthaceae; Sanskrit-Vasaka), an evergreen sub-
herbaceous bush used extensively in indigenous medicine
for cold, cough, bronchitis, and asthma.1 The related
pyrrolo[2,1-b]quinazoline alkaloids namely, vasicine (2),
vasicinolone (3), and 3-deoxyvasicinone (4) have also been
reported to be isolated from these types of plants.2 Most
of these quinazoline alkaloids (examples 5 and 6) are
known to possess a broad spectrum of pharmacological
We have been interested in structural modification for
synthetic analogues of vasicinone and exploration of
convenient and efficient synthetic methods by the azido
reductive processes employing TMSCl-NaI and bakers’
yeast. Furthermore, resolution of vasicinone employing
different lipases has also been investigated.
Resu lts a n d Discu ssion
Azid o Red u ctive Cycliza tion Em p loyin g TMSCl-
Na I. The intramolecular aza-Wittig reaction has been
used extensively for the synthesis of five- to seven-
(3) (a) Fitzgerald, J . S.; J ohns, S. R.; Lamberton, J . A.; Redclife, A.
H. Aust. J . Chem. 1966, 19, 151. (b) Stephen, T.; Stephen, H. J . Chem.
Soc. 1956, 4694. (c) Hermecz, I.; Vasvari-Debreczy, L.; Horvath, A.;
Balogh, M.; Kokosi, J .; DeVos, C.; Rodriguez, L. J . Med. Chem. 1987,
30, 1543. (d) Dunn, A. D.; Kinnear, K. I.; Norrie, R.; Ringan, N.; Martin,
D. J . Heterocycl. Chem. 1987, 24, 175. (e) Sharma, S. C.; Zutshi, U.;
Gupta, O. P.; Dhar, K. L.; Atal, C. K. Indian J . Chem. 1996, 35B, 345.
(f) Malhotra, S.; Koul, S. K.; Sharma, R. L.; Anand, K. K.; Gupta, O.
P.; Dhar, K. L. Indian J . Chem. 1988, 27B, 937.
* To whom correspondence should be addressed. Fax: 91-40-
7173757.
(4) Mori, M.; Kobayashi, H.; Kimura, M.; Ban, Y. Heterocycles 1985,
23, 2803.
† IICT Commun. No. 4592.
(1) Amin, A. H.; Mehta, D. R. Nature 1959, 183, 1317.
(2) (a) J oshi, B. S.; Newton, M. G.; Lee, D. W.; Barber, A. D.;
Pelletier, S. W. Tetrahedron: Asymmetry 1996, 7, 25. (b) Atal, C. K. In
Chemistry and Pharmacology of Vasicine; Raj Bandu Industrial Co.:
Delhi, 1980. (c) Ghosal, S.; Chauhan, P. S. R. B.; Mehta, R. Phytochem-
istry 1975, 14, 830. (d) Chatterjee, A.; Ganguly, M. Phytochemistry
1968, 7, 307.
(5) (a) Onaka, T. Tetrahedron lett. 1971, 4387. (b) Morris, R. C.;
Hanford, W. E.; Roger, A. J . Am. Chem. Soc. 1935, 57, 951.
(6) Kametani, T.; Loc, C. V.; Higa, T.; Koizumi, M.; Ihara, M.;
Fukumoto, K. J . Am. Chem. Soc. 1977, 99, 2306.
(7) (a) Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y. J . Org.
Chem. 1996, 61, 7316. (b) Takeuchi, H.; Hagiwara, S.; Eguchi, S.
Tetrahedron 1989, 45, 6375.
10.1021/jo0011484 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/13/2001

998 J . Org. Chem., Vol. 66, No. 3, 2001
Kamal et al.
membered nitrogen heterocycles including vasicinone.7
Cyclizations with triphenylphosphine usually takes place
in about 5 h under reflux conditions in xylene. Tribu-
tylphosphine, a rather expensive reagent, takes about 2
h for the cyclization under reflux conditions in toluene.
We have recently reported8 the reduction of azides to
amines employing TMSCl-NaI. This has prompted us
to envisage an azidoreductive cyclization process to
obtain the pyrrolo[2,1-b]quinazolinone system employing
TMSCl-NaI under mild conditions in quantitative yield.
This has been further generalized for the cyclization of
similar azidobenzoyl lactams7 to obtain the corresponding
pyrido- and azepino-quinazolinones (4-6). The appropri-
ate precursors 2-azidobenzoyl lactams have been pre-
pared by coupling 2-azidobenzoic acids with respective
lactams. Reductive cyclization with TMSCl-NaI provided
the corresponding [2,1-b]quinazolinones in quantitative
yields, and these reactions have been monitored by TLC.
It is interesting to note that this process employing in
situ generated TMSI is spontaneous (10-15 min), and
the reaction takes place at room temperature.
Sch em e 1a
En zym e-Catalyzed Redu ctive Cyclization by Bak-
er s’ Yea st. There has been a growing interest in bioca-
talysis and transformations mediated by bakers’ yeast.9
Reduction of carbonyl compounds has become a valuable
strategy in organic synthesis, although the reduction or
oxidation of other functionalities has not been investi-
gated in detail. During our efforts to unravel newer
applications of bakers’ yeast,10,11 we have recently ob-
served the reduction12 of aryl azides to arylamines
employing bakers’ yeast under extremely mild conditions.
In continuation of this endeavor, the reductive cyclization
of 2-azidobenzoyl lactams to pyrrolo[2,1-b]quinazolones
has been accomplished by the application of bakers’ yeast.
Similarly, this yeast-mediated cyclization has been ex-
tended to obtain pyrido[2,1-b]quinazolinone and azepino-
[2,1-b]quinazolinone ring systems in good yields. These
reactions have been monitored by TLC. However, enzy-
matic cyclization of 4-chloro-2-azidobenzoyl lactams pro-
duced corresponding quinazolones in low yields (2%).
Interestingly, cyclization with presonicated bakers’ yeast13
produced the cyclized product in improved yields (20%).
It is presumed that the ultrasonic effect on yeast cells is
associated with an enhancement of the diffusion process
of the substrates on removal of the outer membrane.
However, the increase in enzyme activity and membrane-
associated factors can also play a role in this process. It
is conceived that the cyclization of 2-azidobenzoyl lactams
to [2,1-b]quinazolinones take place via the reduction of
azido functionality to the amino group, although this
intermediate (11) could not be isolated (Scheme1). A
control incubation using a boiled yeast preparation
afforded >95% recovery of the starting material 8. The
products have been characterized by mass spectrometry
a
Reaction conditions: (i) SOCl2, benzene, lactam 6 or 7; (ii)
TMSCl-NaI, MeCN; (iii) bakers’ yeast.
and other spectroscopic data, and the reactions are
monitored by TLC. The enzymatic route described here
suggests an alternative strategy for the preparation of
this class of heterocyclic compounds by reductive cycliza-
tion approach under mild conditions without the use of
heat or acid.
Syn th esis a n d Lip a se-Med ia ted Resolu tion of
Va sicin on e. Most of the synthetic methods reported for
vasicinone and deoxyvasicinone have been targeted for
their dl racemic mixture except for the recent asymmetric
oxidation of deoxyvasicinone with the Davis oxidation
reagent. However, no efforts have been made in the
literature to resolve the racemic vasicinone, although the
pharmacological activity has been shown to differ for the
individual isomers of vasicinone. Therefore, we investi-
gated the resolution of optically active vasicinone by
employing various lipases. The lipase-catalyzed transes-
terification of an enantiomeric mixture of hydroxy com-
pound in organic solvents is well established for obtaining
enantiomerically pure compound.14 For this purpose
vasicinone has been obtained from deoxyvasicinone by
its NBS bromination to obtain 3-bromovasicinone as
described in the literature in about 57% yield. Treatment
with KOAc in the presence of 18-crown-6 gave the desired
acetylvasicinone in quantitative yields (Scheme 2), al-
though the reported procedures5 for acetyl vasicinone are
low yielding. Acetyl vasicinone thus obtained has been
(8) Kamal, A.; Rao, N. V.; Laxman, E. Tetrahedron Lett. 1997, 38,
6945.
(9) (a) Servi, S. Synthesis 1990, 1. (b) Czuk, R.; Glanzer, B. I. Chem.
Rev. 1991, 91, 491.
(10) Kamal, A.; Rao, M. V.; Meshram, H. M. J . Chem. Soc., Perkin
Trans. 1 1991, 2056.
(11) Kamal, A.; Reddy, B. S. P. Bioorg. Med. Chem. Lett. 1991, 1,
159.
(12) (a) Kamal, A.; Damayanthi, Y.; Laxminarayana, B.; Reddy, B.
S. N. Indian Patent Appl., No. 108/DEL/98, Oct 1996. (b) Kamal, A.;
Damayanthi, Y.; Reddy, B. S. N.; Laxminarayana, B.; Reddy, B. S. P.
Chem. Commun. 1997, 1015.
(13) (a) Bujons, J .; Guajardo, R.; Kyler, K. S. J . Am. Chem. Soc.
1988, 110, 604. (b) Kamal, A.; Rao, M. V.; Rao, A. B. J . Chem. Soc.,
Perkin Trans. 1 1990, 2755.
(14) (a) Carreah, G.; Ottolina, G.; Riva, S. Trends Biotechnol. 1995,
13, 63. (b) Schmid, R. D.; Verger, R. Angew. Chem. Int. Ed. 1998, 37,
1609. (c) Theil, F. Chem. Rev. 1995, 95, 2203.

Synthesis of Pyrrolo[2,1-b]quinazolinones
J . Org. Chem., Vol. 66, No. 3, 2001 999
Sch em e 2
Ta ble 1. Tr a n sester fica tion of Va sicin on e w ith Va r iou s
Lip a ses in Diisop r op yl Eth er for 48 h
resolution of vasicinone and its acetate, thus providing
a convenient and practical route of preparation for both
(S) and (R) isomers of vasicinone.
lipases
13b
no.
name
amount (mg) conversion (%)a R:S
Exp er im en ta l Section
1
2
3
4
5
PS ‘Amano’
250
100
150
500
270
50
51
53
52
15
96:4
62:38
66:34
54:46
49:51
Gen er a l. Unless specified all solvents and reagents were
reagent grade and used without purification. Benzene was
dried and distilled over sodium while THF was dried and
distilled from sodium benzophenone ketyl under nitrogen.
Reactions involving moisture sensitive reagents were per-
formed under an inert atmosphere of nitrogen in glassware
that had been oven dried. Melting points have been recorded
on an Electrothermal melting point apparatus and are uncor-
rected. Infrared spectra were recorded on KBr pellet and are
reported in wavenumbers (cm-1). 1H NMR on a 200 MHz
instrument was recorded as solutions in CDCl3, and chemical
shifts are reported in parts per million (ppm, δ). Coupling
constants are reported in hertz (Hz). Spectral patterns are
designated as s, single; br, broad; m, multiplet; and comp,
complex multiplet. Low resolution mass spectra were recorded
on a VG 7070H Micromass mass spectrometer at 200 °C, 70
eV, with a trap current of 200 µA and 4 kV acceleration
voltage. HRMS were recorded on a VG Autospec N mass
spectrometer at 200 °C, 70 eV, with a trap current of 200 µA
and 7 kV acceleration voltage. Analytical TLC of all reactions
was performed on Merck prepared plates (silica gel 60 F-254
on glass). Column chromatography was performed using Acme
silica gel (60-120 mesh, unless otherwise mentioned). Per-
centage yields are given for compounds. HPLC analysis was
performed on an instrument that consisted of a Shimadzu LC-
6A system controller, SPD-6A fixed wavelength UV monitor
as detector, FCV-100B fraction collector, and chromatopac
C-R4A data processor as a recording integrator.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-(2-Azi-
d oben zoyl) La cta m s (8-10). 2-Azidobenzoic acid (0.01 mol)
was suspended in dry benzene (15 mL) under nitrogen, and
SOCl2 (0.05 mol) was added. To this was added a catalytic
amount of DMF and stirred at room temperature for 5 h. The
solvent was removed under vacuum to obtain an oily residue
of the acid chloride. This was taken up in dry THF (20 mL)
and added dropwise under nitrogen to the corresponding
lactam (0.01 mol) and Et3N (0.02 mol) also taken up in dry
THF (20 mL). The mixture was stirred for 2 h, and the solvent
was removed under reduced pressure to obtain a viscous
residue. The residue was taken up into EtOAc (50 mL) and
washed with water (2 × 25 mL). The organic layer was
separated and dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The residue thus obtained was
purified by silica gel column chromatography (60-120 mesh,
1:4 EtOAc-hexane) to obtain the N-(2-azidobenzoyl) lactams
8-10 in 75-83% yields.
Candida rugosa
porcine pancrease
liver acetone powder
wheat germ
Ta ble 2. Resolu tion of (+) Va sicin on e by Lip a se P S
‘Am a n o’ Em p loyin g Differ en t Solven ts
13b
no.
solvents
time (h) conversion (%)a
R:S
1
2
3
4
5
6
7
8
9
toluene
THF
diisopropyl ether
1,2-dimethoxyethane
1,4-dioxane
tert-butylmethyl ether
dibutyl ether
acetonitrile
46
48
48
48
48
48
48
24
20
48
45
51
35
28
25
38
53
51
98:2
100:-
96:4
100:-
93:7
100:-
95:5
78:22
48:52
amyl alcohol
a
b
Based on HPLC. Enantiomeric ratio based on chiral HPLC
analysis.16
enzymatically hydrolyzed employing lipase PS “Amano”
to its (R)-alcohol and (S)-acetate in 98% ee. Alternately,
acetylvasicinone has been chemically hydrolyzed to ra-
cemic vasicinone which has been resolved by transes-
terification with different lipases as shown in the Table
1. It has been observed that lipase PS gives the best
results from the conversion as well as enantiomeric
excess point of view. On the basis of these findings, a
variety of solvents have been investigated for the resolu-
tion of vasicinone by transesterification using vinyl
acetate to understand their role in this process, and the
results are described in Table 2. It is observed that THF
followed by toluene and diisopropyl ether provide good
selectivity with good conversions, and interestingly (R)-
acetate is obtained in >99% ee employing lipase PS in
THF.
Con clu sion
In conclusion, we have reported the synthesis of
deoxyvasicinone from anthranilic acid and 2-pyrrolidi-
none with TMSCl-NaI as well as bakers’ yeast utilizing
the intramolecular azido reductive process. This method
has been extended toward the preparation of racemic
vasicinone. Further, we investigated the lipase-catalyzed
N-(2-Azid oben zoyl)p yr r olid in -2-on e (8a ): mp 81-83 °C;
IR (KBr) 2150, 1750, 1680 cm-1; 1H NMR (200 MHz, CDCl3) δ
2.2 (q, 2H, J ) 6.8, 8.0 Hz), 2.6 (t, 2H, J ) 8 Hz), 4.0 (t, 2H,
J ) 7.6 Hz), 7.2 (m, 3H), 7.5 (t, 1H); MS (EI) m/z 230 (M+).

1000 J . Org. Chem., Vol. 66, No. 3, 2001
Kamal et al.
1
N-(2-Azid o-5-m eth ylben zoyl)p yr r olid in -2-on e (8b): H
NMR (200 MHz, CDCl3) δ 2.1 (q, 2H, J ) 7.5, 6.8 Hz), 2.4 (s,
3H), 2.6 (t, 2H, J ) 6.3 Hz), 4.0 (t, 2H, J ) 8.0 Hz), 7.0 (s, 1H),
7.1-7.3 (m, 2H).
N-(2-Azid o-4-ch lor oben zoyl)p yr r olid in -2-on e (8c): mp
137-139 °C; 1H NMR (200 MHz, CDCl3) δ 2.2 (q, 2H, J ) 7.6,
6.8 Hz), 2.6 (t, 2H, J ) 8 Hz), 4.0 (t, 2H, J ) 7.6 Hz), 7.1-7.3
(m, 3H); MS (EI) m/z 264 (M+).
CDCl3) δ 2.0 (m, 4H), 3.0 (t, 2H, J ) 6.4 Hz), 4.0 (t, 2H, J )
6.0 Hz), 7.4 (t, 1H, J ) 7.4 Hz), 7.6 (d, 1H, J ) 8.0 Hz), 7.7 (t,
1H, J ) 7.4 Hz), 8.2 (d, 1H, J ) 8.0 Hz); MS (EI) m/z 200 (M+).
HRMS calcd for C12H12N2O 200.94963, found 200.094511.
2-Meth yl-6,7,8,9-tetr a h yd r op yr id o[2,1-b]qu in a zolin -11-
on e (5b): 1H NMR (200 MHz, CDCl3) δ 2.0 (m, 4H), 2.5 (s,
3H), 3.0 (t, 2H, J ) 5.0 Hz), 4.1 (t, 2H, J ) 5.0 Hz), 7.5 (s, 2H),
8.0 (s, 1H); MS (EI) m/z 214 (M+).
N-(2-Azid oben zoyl)-δ-va ler ola cta m (9a ): mp 92-94 °C;
IR (KBr) 2130, 1706, 1664 cm-1; 1H NMR (200 MHz, CDCl3) δ
1.9 (m, 4H), 2.5 (t, 2H, J ) 6.4 Hz), 3.9 (t, 2H, J ) 6.0 Hz) 7.2
(m, 2H), 7.5 (t, 1H).
N-(2-Azid o-5-m eth ylben zoyl)-δ-va ler ola cta m (9b): mp
128-130 °C; 1H NMR (200 MHz, CDCl3) δ 2.0 (m, 4H), 2.4 (s,
3H), 2.6 (t, 2H, J ) 6.5 Hz), 3.9 (t, 2H, J ) 6.0 Hz), 7.0 (s, 1H),
7.1-7.3 (m, 2H); MS (EI) m/z 230 (M+ - 28); HRMS m/z (M+
- 28) calcd for C13H14N2O 230.105528, found 230.105300.
N-(2-Azid o-4-ch lor oben zoyl)-δ-va ler ola cta m (9c): mp
114-118 °C; 1H NMR (200 MHz, CDCl3) δ 2.0 (m, 4H), 2.5 (t,
2H, J ) 6.4 Hz), 3.85 (t, 2H, J ) 6.0), 7.1-7.4 (m, 3H); MS
(EI) m/z 250 (M - 28).
3-Ch lor o-6,7,8,9-tetr a h yd r op yr id o[2,1-b]qu in a zolin -11-
on e (5c): mp 132-133 °C; H NMR (200 MHz, CDCl3) δ 2.0
(m, 4H), 3.0 (t, 4H, J ) 8.0 Hz), 4.0 (t, 2H, J ) 7.4 Hz), 7.4
(dd, 1H, J ) 6.6 Hz), 7.6 (d, 1H, J ) 1.6 Hz), 8.2 (d, 1H, J )
6.5 Hz); MS (EI) m/z 234 (M+); HRMS calcd for C12H11ClN2O
234.0056418, found 234.055991.
7,8,9,10-H exa h yd r oa zep in o[2,1-b ]q u in a zolin -12(6H )-
on e (6a ): mp 97-99 °C; 1H NMR (200 MHz, CDCl3) δ 1.8 (s,
6H), 3.0 (d, 2H), 4.4 (d, 2H), 7.4 (t, 1H, J ) 7.4 Hz), 7.6 (d, 1H,
J ) 8.0 Hz), 7.7 (t, 1H, J ) 7.4 Hz), 8.2 (d, 1H, J ) 8.0 Hz);
MS (EI) m/z 214 (M+).
1
2-Meth yl-7,8,9,10-h exa h yd r oa zep in o[2,1-b]qu in a zolin -
12(6H)-on e (6b): mp 68-70 °C; 1H NMR (200 MHz, CDCl3) δ
1.8 (s, 6H), 2.4 (s, 3H), 3.0 (d, 2H, J ) 6.0 Hz), 4.3 (d, 2H, J )
5 Hz), 7.4 (s, 2H), 8.0 (s, 1H); MS (EI) m/z 228 (M+).
3-Ch lor o-7,8,9,10-h exa h yd r oa zep in o[2,1-b]qu in a zolin -
12(6H)-on e (6c): mp 101-104 °C; 1H NMR (200 MHz, CDCl3)
δ 1.9 (s, 6H), 3.0 (d, 2H), 4.4 (d, 2H), 7.4 (d, 1H), 7.6 (d, 1H, J
) 1.6 Hz), 8.1 (d, 1H, J ) 6.5 Hz); MS (EI) m/z 248 (M+); HRMS
calcd for C13H13ClN2O 248.071641, found 248.071641.
Syn th esis of Va sicin on e. 3-Br om o-3-d eoxyva sicin on e
(12). To a solution of 4a (1.8 g, 0.01mol) in dry CCl4 (50 mL)
were added NBS (1.7 g, 0.01mol) and benzoyl peroxide (24 mg,
0.01 mmol). The reaction mixture was refluxed for 5 h and
filtered after cooling to room temperature. The filtrate was
evaporated under reduced pressure, and the residue was
purified by column chromatography on silica gel (60-120
mesh, 7:3 EtOAc-hexane) to obtain 12 (1.2 g, 52%): mp 141-
N-(2-Azid oben zoyl)-∈-ca p r ola cta m (10a ): mp 70-72 °C;
IR (KBr) 2127, 1707, 1671 cm-1; 1H NMR (200 MHz, CDCl3) δ
1.9 (s, 6H), 2.6 (d, 2H), 4.0 (d, 2H), 7.1-7.5 (m, 4H); MS (EI)
m/z 230 (M+ - 28).
N-(2-Azid o-5-m eth ylben zoyl)-∈-ca p r ola cta m (10b): mp
1
98-100 °C; H NMR (400 MHz, CDCl3) δ 1.9 (m, 6H), 2.3 (s,
3H), 2.7 (d, 2H), 4.0 (d, 2H), 7.0 (d, 1H, J ) 11 Hz), 7.1 (s,
1H), 7.2 (d, 1H, J ) 2.5 Hz).
N-(2-Azid o-4-ch lor oben zoyl)-∈-ca p r ola cta m (10c): mp
1
104-106 °C; H NMR (200 MHz, CDCl3) δ 1.9 (s, 6H), 2.7 (d,
2H), 4.0 (d, 2H), 7.0-7.3 (m, 3H); MS (EI) m/z 264 (M+ - 28).
Gen er a l P r oced u r e for th e Syn th esis of [2,1-b] F u sed
Qu in a zolon es. Meth od A. To a solution of 8-10 (1 mmol)
in MeCN (15 mL) were added NaI (5 mmol) and TMSCl (2
mmol) and stirred for 15 min at room temperature. The
reaction mixture was diluted with CH2Cl2 (20 mL) and washed
with saturated aqueous Na2S2O3 solution (2 × 10 mL) followed
by brine (1 × 15 mL). The organic phase was separated and
dried over anhydrous Na2SO4. Evaporation under reduced
pressure afforded a solid which was purified over a short silica
column (60-120 mesh, 1:1 EtOAc-hexane) to obtain the
corresponding cyclized products 4-6 in quantitative yields.
Meth od B (En zym a tic). To a suspension of bakers’ yeast
(2 g) in water (15 mL) incubated for 30 min at 37.5 °C on a
rotary shaker was added a solution of precursor 8-10 (0.1
mmol) taken up in 30% water in EtOH (1 mL). This was
incubated for 24 h, and an additional amount of 2 g of bakers’
yeast was added. The reaction was further continued for 24 h
and extracted with EtOAc (3 × 20 mL) upon complete
conversion (monitored on TLC, 1:1 EtOAc-hexane). The
organic phase was washed with dilute aqueous Na2CO3 (4 ×
15 mL) followed by brine (2 × 15 mL). The organic layer was
separated, dried over anhydrous Na2SO4, and evaporated
under reduced pressure to obtain a residue which was purified
by flash column chromatography on silica gel (EtOAc-hexane,
1:1) to obtain the pure cyclized products 4-6 in 25-50% yields.
2,3-Dih yd r op yr r olo[2,1-b]qu in a zolin -9-on e (4a ): mp
104-106 °C; 1H NMR (200 MHz, CDCl3) δ 2.3 (q, 2H, J ) 7.5
and 8.0 Hz), 3.2 (t, 2H, J ) 8.0 Hz), 4.2 (t, 2H, J ) 7.5 Hz), 7.5
(t, 1H, J ) 7.4 Hz), 7.6-7.8 (m, 2H), 8.3 (d, 1H, J ) 8.0 Hz);
MS (EI) m/z 186 (M+); HRMS calcd for C11H10N2O 186.079313,
found 186.078920.
1
142 °C; IR (KBr) 1684, 776 cm-1; H NMR (200 MHz, CDCl3)
δ 2.5-2.9 (m, 2H), 4.1-4.3 (m, 1H), 4.3-4.5 (m, 1H), 5.2 (dd,
1H, J ) 4.6, 1.8 Hz), 7.4-7.6 (m, 2H), 7.6-7.8 (m, 1H), 8.3 (d,
1H, J ) 8 Hz); MS (EI) m/z 264 (M+ - 1); HRMS calcd for
11H9N2O 263.989824, found 263.990046.
(()-Acetylva sicin on e (13). To a solution of 12 (2.6 g, 0.01
C
mol) in MeCN (20 mL) were added KOAc (3.92 g, 0.04 mol)
and 18-crown-6 (0.2 g, 0.001 mol) and stirred at room tem-
perature for 1 h. The reaction mixture was diluted with CH2-
Cl2 (40 mL) and filtered through Celite. The filtrate was
concentrated, and the residue was purified through a short
column (silica gel 60-120 mesh, 1:1 EtOAc-hexane) to afford
2.2 g (90%) of (()-13: mp 137-139 °C; IR (KBr) 1732, 1681,
1
1465 cm-1; H NMR (200 MHz, CDCl3) δ 2.2 (s, H), 2.2-2.4
(m, 1H), 2.7-2.9 (m, 1H), 4.1-4.4 (m, 2H), 6.0 (t, 1H, J ) 7.6,
5.4 Hz), 7.4-7.6 (m, 1H), 7.7 (d, 2H, J ) 3 Hz), 8.3 (d, 1H, J
) 8 Hz); MS (EI) m/z 244 (M+ - 1).
(()-Va sicin on e (1). To a solution of (()-13 (2.4 g, 0.1 mol)
in EtOAc was added a solution of NaOH in 50% aqueous
MeOH and stirred vigorously for 15 min. The reaction mixture
was diluted with EtOAc and washed with water. The combined
EtOAc layers were dried over anhydrous Na2SO4 and concen-
trated under reduced pressure to obtain 2 g (97%) of (()-1:
mp 203-204 °C; 1H NMR (200 MHz, CDCl3) δ 2.3-2.5 (m, 1H),
2.6-2.8 (m, 1H), 4.0-4.2 (m, 1H), 4.3-4.5 (m, 1H), 5.1-5.3
(m, 2H), 7.5-7.6 (m, 1H), 7.7-7.8 (m, 2H), 8.4 (d, 1H, J ) 8.1
Hz); MS (EI) m/z 202 (M+).
3-Met h yl-2,3-d ih yd r op yr r olo[2,1-b]q u in a zolin -9-on e
(4b): mp 99-101 °C; 1H NMR (200 MHz, CDCl3) δ 2.3 (q, 2H,
J ) 7.3, 7.8 Hz), 2.5 (s, 3H), 3.2 (t, 2H, J ) 7.8 Hz), 4.2 (t, 2H,
J ) 7.5 Hz), 7.5 (s, 2H), 8.0 (s, 1H); MS (EI) m/z 200 (M+).
6-Ch lor o-2,3-d ih yd r op yr r olo[2,1-b]q u in a zolin -9-on e
(4c): mp 186-188 °C; 1H NMR (200 MHz, CDCl3) δ 2.3 (q,
2H, J ) 7.3, 7.8 Hz), 3.2 (t, 2H, J ) 7.8 Hz), 4.2 (t, 2H, J ) 7.5
Hz), 7.4 (d, 1H, J ) 6.5 Hz), 7.6 (d, 1H, J ) 2 Hz), 8.1 (d, 1H,
J ) 6.5 Hz); MS (EI) m/z 220 (M+). HRMS calcd for C11H9-
ClN2O 220.040341, found 220.040296.
En zym a tic Hyd r olysis of (()-Acetylva sicin on e. To a
solution of acetylvasicinone (200 mg, 1 mmol) in MeCN (18
mL) and phosphate buffer pH 7 (20 mL) was added 80 mg of
lipase PS and stirred on a rotary shaker for 7 h at room
temperature. The reaction mixture was extracted with EtOAc
(3 × 20 mL). The organic layer was separated and dried over
anhydrous Na2SO4. Filtration and evaporation under reduced
pressure gave a crude solid, which was purified by column
chromatography (silica gel, 60-120 mesh, 1:1 EtOAc-hexane)
to afford (R)-1 and (S)-13. Further, (S)-13 was hydrolyzed to
(S)-1 as mentioned in the above procedure at 0 °C. The
enantiomeric purity of these products were determined by
6,7,8,9-T e t r a h y d r o p y r id o [2,1-b ]q u in a zo lin -11-o n e
(5a ): mp 96-98 °C; IR (KBr) 1657 cm-1; 1H NMR (200 MHz,

Synthesis of Pyrrolo[2,1-b]quinazolinones
J . Org. Chem., Vol. 66, No. 3, 2001 1001
chiral HPLC.16 (R)-1: 80 mg, mp 200-201 °C; [R]22 ) +105
En zym a tic Tr a n sester ifica tion of Va sicin on e. A mix-
ture of (()-1 (200 mg, 1 mmol), vinyl acetate (2 mL), and
triethylamine (2 mL) in an organic solvent (as mentioned in
Table 2) was stirred for 10 min in the presence of 4 Å molecular
sieves (1 g) to which was added lipase (e.g., PS “Amano” 250
mg) as shown in the Table 1. The reaction mixture was stirred
at 50 °C and was monitored by HPLC. After about 50%
conversion, the reaction mixture was filtered to remove the
enzyme and the molecular sieves. The filtrate was evaporated
under reduced pressure, and the crude mixture was purified
by column chromatography (silica gel, 60-120 mesh, 1:1
EtOAc-hexane) to obtain (+)-13 and (-)-1. The products thus
obtained were analyzed by HPLC.16 The results are sum-
marized in Tables 1 and 2. (R)-13: 1H NMR (200 MHz, CDCl3)
δ 2.2 (s, 3H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 4.1-4.4 (m,
2H), 6.0 (t, 1H, J ) 5.8 Hz),7.4-7.6 (m, 1H), 7.7 (m, 2H), 8.3
(d, 1H, J ) 7.9 Hz); MS (EI) m/z 244.
D
(c 1, CHCl3), lit.17a [R]22 ) +148 (c 1.35 mg mL-1, EtOH); IR
D
3131, 1664 cm-1 1H NMR (200 MHz, CDCl3) δ 2.2-2.4 (m,
;
1H), 2.6-2.8 (m, 1H), 3.9-4.1 (m, 1H), 4.3-4.5 (m, 1H), 4.8
(s, 1H), 5.2 (t, 1H, J ) 7.4 Hz), 7.4-7.6, (m, 1H), 7.7-7.8, (m,
2H), 8.3 (d, 1H, J ) 7.4 Hz); MS (EI) m/z 202 (M+); HRMS
calcd for C11H10N2O 202.074228, found 202.074030. (S)-13: 1H
NMR (200 MHz, CDCl3) δ 2.2 (s, 3H), 2.2-2.4 (m, 1H), 2.6-
2.9 (m, 1H), 4.1-4.4 (m, 2H), 6.0 (t, 1H, J ) 5.8 Hz), 7.4-7.6,
(m, 1H), 7.7-7.8, (s, 2H), 8.3 (d, 1H, J ) 7.9 Hz); MS (EI) m/z
244 (M+); HRMS calcd for C13H12N2O3 244.084792, found
244.085651. (S)-1: mp 200-201 °C; [R]22D ) -87 (c 0.5, CHCl3),
lit.17b [R]22D ) -90 (c 0.5, CHCl3); IR 3132, 1644 cm-1; 1H NMR
(200 MHz, CDCl3) δ 2.2-2.4 (m 1H), 2.6-2.8 (m, 1H), 4.0-4.1
(m, 1H), 4.3-4.5 (m, 1H), 4.7 (s, 1H), 5.2 (t, 1H, J ) 7.2 Hz),
7.4-7.6, (m, 1H), 7.7-7.8, (m, 2H), 8.3 (d, 1H, J ) 7.4 Hz);
MS (EI) m/z 202 (M+); HRMS calcd for C11H10N2O 202.0474228,
found 202.074528.
Ack n ow led gm en t. One of the authors (K.V.R.) is
thankful to CSIR, New Delhi, for the award of Senior
Research Fellowship.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H NMR,
IR, EIMS, HRMS spectra, and HPLC chromatograms of
selected compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) J aen, J . C.; Gregor, V. E.; Lee, C.; Davis, R.; Emmerling, M.
Bioorg. Med. Chem. Lett. 1996, 6, 737.
(16) Determined by chiral HPLC (Chiracel OD column, Diacel)
employing hexane-2-propanol (85:15) as mobile phase, 0.7 mL/min
flow, and monitored at 254 nm wavelength.
(17) (a) Rajlakshmi, P.; Aditya, N. C. J . Ind. Chem. Soc. 1988, 65,
814. (b) Mehta, D. R.; Naravane, J . S.; Desai, R. M. J . Org. Chem.
1963, 28, 445.
J O0011484