Total synthesis of a pyrroloindoloquinazoline alkaloid

Article abstract of DOI:10.1021/ol401709t

A highly concise stereoselective synthesis of a newly identified alkaloid with a pyrroloindoloquinazoline skeleton has been achieved. To this end, a chiral auxiliary mediated asymmetric acetate aldol reaction on tryptanthrin was explored and the resulting

Full text of DOI:10.1021/ol401709t

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Total Synthesis of a
Pyrroloindoloquinazoline Alkaloid
Digvijay Gahtory, Mangilal Chouhan, Ratnesh Sharma, and Vipin A. Nair*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research, Sector 67, Mohali, Punjab 160062, India
vn74nr@yahoo.com
Received June 17, 2013
ABSTRACT
A highly concise stereoselective synthesis of a newly identified alkaloid with a pyrroloindoloquinazoline skeleton has been achieved. To this end,
a chiral auxiliary mediated asymmetric acetate aldol reaction on tryptanthrin was explored and the resulting adduct was converted to the product
by a novel one-pot reductive cyclization/transamidation using NiCl2 6H2O/NaBH4 in methanol.
3
Nature is replete with plants and fungi containing indole
alkaloids, one of the largest classes of alkaloids encom-
passing over thousands of compounds.1 Many of these
compounds possess significant physiological activity, and
some of them are used in medicine. Among the various
plant sources, Isatis indigotica (Cruciferae family), a bien-
nial herbaceous plant widely distributed in China, has been
extensively focused upon lately due to the diverse struc-
tures of chemical constituents isolated and their significant
biological profiles.2 Phytochemical studies of this plant
resulted in the isolation of indigotin, indirubin, epigotrin,
2-hydroxy-3-butenyl thiocyanate, 3-(20-hydroxyphenyl)-
4(3H)-quinazolinone, purin, isaindigotidione, isatisine,
organic acids, and many amino acids.3ꢀ7 Shi et al. has
recently reported the isolation of 17 new alkaloids and 14
known analogues from the aqueous extract of the roots
of Isatis indigotica.8 Some of these compounds have
shown promising antiviral activity against influenza virus
A/Hanfang/359/95(H3N2) and an inhibitory effect over
Coxsackie virus B3 replication. One among the newly
identified natural products was a racemic mixture of
alkaloid 4 with a pyrrolo[2,3-b]indolo[5,5a,6-b,a]quinazo-
line skeleton (Figure 1). This structure represents a fusion
between the widely distributed hexahydropyrroloindole
(HPI) alkaloidsand the relatively scarceindoloquinazoline
alkaloids. Both these scaffolds have been independently
known to possess a wide array of biological properties.9
On similar lines, the pyrroloindoloquinazoline skeleton is
also expected to show interesting biological properties.
Isolation of more natural products containing such an
intriguing skeleton is anticipated in the near future and
hence arises the need to develop a highly efficient strategy
for its stereoselective synthesis.
A decade prior to the isolation of this compound from
Isatisindigotica, Bremner etal. had observedthe formation
of pyrroloindoloquinazoline skeleton, while investigating
the photoinduced cyclization of N-(2-(1-indolylmethyl)-
phenyl)chloroacetamide to yield indole fused medium
sized heterocyclic scaffolds.10 However this strategy
(1) Seigler, D. S. Plant Secondary Metabolism, 1st ed.; Springer: 1999;
p 628.
(2) Liu, J. F.; Jiang, Z. Y.; Wang, R. R.; Zheng, Y. T.; Chen, J. J.;
Zhang, X. M.; Ma, Y. B. Org. Lett. 2007, 9, 4127.
(3) Huang, Q. S.; Yoshihira, K.; Natori, S. Planta Med. 1981, 42, 308.
(4) Wu, X. Y.; Liu, Y. H.; Sheng, W. Y.; Sun, J.; Qin, G. W. Planta
Med. 1997, 63, 55.
(5) Peng, S. P.; Gu, Z. L. Chin. Wild Plant Resources 2005, 24, 4.
(6) Shi, X.; Ni, Y.; Liu, Y. H. Chin. Hosp. Pharm. J. 2006, 26, 1397.
(7) Wu, X. Y.; Qin, G. W. Tetrahedron 1997, 53, 13323.
(8) (a) Chen, M.; Gan, L.; Lin, S.; Wang, X.; Li, L.; Li, Y.; Zhu, C.;
Wang, Y.; Jiang, B.; Jiang, J.; Yang, Y.; Shi, J. J. Nat. Prod. 2012, 75,
(9) (a) Sanchis, P. R.; Savina, S. A.; Albericio, F.; Alvarez, M.
Chem.;Eur. J. 2011, 17, 1388. (b) Shoji, N.; Umeyama, A.; Saito, N.;
Arihara, S. J. Nat. Prod. 1989, 52, 1160.
(10) Bremner, J. B.; Russell, H. F.; Skelton, B. W.; White, A. H.
Heterocycles 2000, 53, 277.
1167. (b) Optical rotation of (þ)-4: natural compound [R]20 þ194.2
D
(c 0.2, MeOH); synthetic compound [R]20D þ192.1 (c 0.2, MeOH).
r
10.1021/ol401709t
XXXX American Chemical Society

Scheme 1. Retrosynthetic Strategy for Pyrroloindoloquinazoline
Figure 1. A few natural products with indole fused heterocyclic
ring skeleton.
for the synthesisof tryptanthrin, thisprocedurewas chosen
on the basis of operational simplicity, environmental im-
plications, and easily available starting materials, while the
othermethods employed corrosivereagentssuchasthionyl
chloride or phosphorus oxychloride.14 The key step in our
synthesis is an aldol reaction between tryptanthrin and
the acetylated auxiliary, N-acetyl-(S)-4-isopropyl-1-[(R)-
1-phenylethyl]imidazolidin-2-one 8. The distinct advan-
tage of high selectivity in acetate aldol reactions with no
endocyclic cleavage made this auxiliary a preferred option.
The lithium enolate of 8 was generated using LiHMDS in
anhydrous THF at ꢀ78 °C and subsequently reacted with
tryptanthrin to obtain the aldol adduct 9. A highly appre-
ciable syn acetate aldol selectivity of 98:2 was observed as
afforded low yields, no stereoselectivity, and other fused
heterocycles in significant amounts, and to date no other
reports are available. Based on our interests in the asym-
metric synthesis11 of β-hydroxy carbonyl functionality
containing natural products, we found compound (þ)-4,
(2aS,2a1S)-2a-hydroxy-2,2a-dihydro-1H-6b,11b-diazabe-
nzo[b]cyclopenta[lm]fluorene-1,7-(2a1H)-dione, as a suit-
able target to further explore our current research on chiral
auxiliary mediatedaldol reactions.12 Our efforts resultedin
a highly concise stereoselective synthesis of this molecule.
This method encompasses a chiral auxiliary mediated
diastereoselective acetate aldol reaction on tryptanthrin,
followed by a novel one-pot reductive cyclization proce-
1
dure using the NiCl2 6H2O/NaBH4 system in methanol
ascertained from the H NMR spectra of the crude pro-
3
which proceeds through a transamidation mechanism. The
retrosynthetic analysis of compound (þ)-4 is illustrated in
Scheme 1. Taking further strides from the asymmetric
acetate aldol reactions of the imidazolidin-2-one chiral
auxiliary that we had recently reported,11b,12a the reaction
on tryptanthrin was conceptualized to suit our design. We
envisioned that a dicarbonyl compound or its synthetic
equivalent could serve as a suitable starting material to
generate the first asymmetric center by an aldol reaction.
The aldol substrate could be further modified by func-
tional group transformations and then cyclized to yield the
desired product.
Synthesis of (þ)-4 was achieved using two overlapping
yet distinct strategies as illustrated in Scheme 2. Tryptan-
thrin 7 was synthesized by reacting commercially available
isatoic anhydride 6 and isatin 5 in the presence of
triethylamine.13 Though several methods are available
duct. The stereoselectivity witnessed can be explained on
the basis of transition state models depicted in Scheme 3.
The front side of the lithium enolate E-1 is shielded by the
bulky isopropyl group of the auxiliary which disfavors the
approach of the electrophile. In contrast, the rear side is
less hindered and hence more accessible. Tryptanthrin has
a highly planar geometry owing to the sp2 imine linkage
between the rings B and C. As a virtue of this planar
geometry, the electrophile can adopt two spatial arrange-
ments as depicted by the transition states TS-A and TS-B.
In both transition states, lithium coordinates with the
oxygen atom of the electrophilic carbonyl group. In TS-A,
due to the close proximity of the phenyl group of the
auxiliary to the rings C and D of the electrophile, the
transition state is sterically hindered and this disfavors the
formation of the aldol with the (R) configuration. In TS-B,
lesser crowding between the A ring and the phenyl group
minimizes repulsions favoring the formation of the aldol
with the (S) configuration.
(11) (a) Kumar, V.; Kumar, K.; Pal, A.; Khatik, G. L.; Nair, V. A.
Tetrahedron 2013, 69, 1747. (b) Khatik, G. L.; Khurana, R.; Kumar, V.;
Nair, V. A. Synthesis 2011, 3123. (c) Kumar, V.; Khatik, G. L.; Nair,
V. A. Synlett 2011, 2997. (d) Kumar, V.; Raghavaiah, P.; Mobin, S. M.;
Nair, V. A. Org. Biomol. Chem. 2010, 8, 4960.
(12) (a) Khatik, G. L.; Kumar, V.; Nair, V. A. Org. Lett. 2012, 14,
2442. (b) Chouhan, M.; Sharma, R.; Nair, V. A. Org. Lett. 2012, 14,
5672.
The cyclization of 9 to the desired final product (þ)-4
was achieved by two different methods. Reduction of the
imine 9 using NaBH4 in acetic acid afforded 10 stereo-
selectively. The chemoselective reduction of the imine bond
in tryptanthrin using this reagent had been reported.15
(13) Sharma, V. M.; Prasanna, P.; Seshu, K. V. A.; Renuka, B.; Rao,
C. V. L; Kumar, G. S.; Narasimhulu, C. P.; Babu, P. A.; Puranik, R. C.;
Subramanyam, D.; Venkateswarlu, A.; Rajagopal, S.; Kumar, K. B. S.;
Rao, C. S.; Mamidi, N. V. S. R.; Deevi, D. S.; Ajaykumar, R.;
Rajagopalan, R. Bioorg. Med. Chem. Lett. 2002, 12, 2303.
(14) (a) Jao, C. W.; Lin, W. C.; Wu, Y. T.; Wu, P. L. J. Nat. Prod.
2008, 71, 1275. (b) Jahng, K. C.; Kim, S. I.; Kim, D. H.; Seo, C. S.; Son,
J. K.; Lee, S. H.; Lee, E. S.; Jahng, Y. Chem. Pharm. Bull. 2008, 56, 607.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Synthesis of a Pyrrolo[2,3-b]indolo[5,5a,6-b,a]quinazoline
Scheme 3. Plausible Mechanism for Stereoselectivity in Acetate Aldol Reaction on Tryptanthrin
It was then cyclized by an electrophilic activation mech-
anism16 using lithium perchlorate and triethylamine in
acetonitrile to obtain the target molecule. However, in
order to further simplify the process and improve the yield
we envisaged a different approach. Using a combination of
system is known for effecting the reduction of imines and
isoxazolines,17 there are no reports available on the reduc-
tive transamidation of imines. Quite interestingly, follow-
ing the stereoselective reduction, the transition metal
also promoted the cyclization/transamidation in a one-pot
process. Noteworthy is the fact that reductive cyclization
took place stereoselectively in the substrate controlled
asymmetric induction.
NiCl2 6H2O/NaBH4 in methanol provided a novel one-
3
pot alternative to the reduction and subsequent cycliza-
tion of the aldol intermediate. Although this catalytic
A plausible mechanism for the reductive cyclization is
demonstrated in Scheme 4. It is expected that nickel forms
(15) Bergman, J.; Tilstam, U.; Tornroos, K. W. J. Chem. Soc., Perkin
Trans. 1 1987, 519.
(16) Kumar, V.; Nair, V. A. Tetrahedron Lett. 2010, 51, 966.
(17) Singh, A.; Roth, G. P. Tetrahedron Lett. 2012, 53, 4889.
Org. Lett., Vol. XX, No. XX, XXXX
C

results in the attack at the carbonyl carbon and a solvent
assisted auxiliary cleavage in a single step. The polar protic
medium stabilizes the partial charges of the transition
state, favoring the forward reaction kinetics. The spectral
data of the final compound (þ)-4 were found to be in
good agreement with those of the natural product.8a The
absolute configuration was confirmed by comparing the
optical rotation data with the reported values.8b A simi-
lar procedure using the N-acetyl-(R)-4-isopropyl-1-[(S)-1-
phenylethyl]imidazolidin-2-one auxiliary for aldol reac-
tion with tryptanthrin can be adopted for the synthesis
of (ꢀ)-4.
Scheme 4. Plausible Mechanism for Reductive Cyclization
In conclusion, the total synthesis of a recently isolated
pyrrolo[2,3-b]indolo[5,5a,6-b,a]quinazoline alkaloid was
successfully achieved. The highly concise synthetic strat-
egy involves (i) a chiral auxiliary mediated asymmetric
acetate aldol reaction on tryptanthrin and (ii) a reductive
a chelate complex18 with the π-electron cloud of the
aromatic ring which suitably stacks the nickelꢀborohy-
dride complex below the plane of the ring. This facilitates
the interaction between the hydroxyl oxygen and the
oxophilic boron, and consequently a hydride transfer
occurs from the nickelꢀboron complex to the electrophilic
iminecarbon ina stereoselective fashion. Generation ofthe
nitrogen nucleophile, stabilized by the Lewis acidic boron,
cyclization/transamidation using NiCl2 6H2O/NaBH4 in
3
methanol. We anticipate that the present work opens the
door to the systematic synthesis of pyrroloindoloquinazo-
line alkaloids in an efficient manner.
Acknowledgment. Research funding from the Depart-
ment of Science and Technology, Government of India
and NIPER is gratefully acknowledged.
(18) (a) Sergeev, A. G.; Hartwig, J. F. Science 2011, 332, 439. (b)
Tobisu, M.; Yamakawa, K.; Shimasaki, T.; Chatani, N. Chem. Com-
mun. 2011, 47, 2946. (c) Kelley, P.; Lin, S.; Edouard, G.; Day, M. W.;
Agapie, T. J. Am. Chem. Soc. 2012, 134, 5480. (d) Sergeev, A. G.; Webb,
J. D.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 20226. (e) Cornella, J.;
Supporting Information Available. Experimental pro-
cedures, 1H NMR, 13C NMR, and HRMS (ESI) data of
the compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
ꢀ
Gomez-Bengoa, E.; Martin, R. J. Am. Chem. Soc. 2013, 135, 1997. (f)
Chouhan, M.; Kumar, K.; Sharma, R.; Grover, V.; Nair, V. A. Tetra-
hedron Lett. 2013, DOI: http://dx.doi.org/10.1016/j.tetlet.2013.06.072.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX