Aryne insertion reactions leading to bioactive fused quinazolinones: Diastereoselective total synthesis of cruciferane

Article abstract of DOI:10.1021/ol4018062

Insertion reactions of an in situ generated arynes to a variety of suitably substituted 1,3-quinazolin-4-ones have been demonstrated for a new efficient one-step approach to a diverse range of fused quinazolinone architectures. The present protocol has been effectively utilized to accomplish the concise total synthesis of recently isolated bioactive natural products tryptanthrin, phaitanthrins A-C, and cruciferane.

Full text of DOI:10.1021/ol4018062

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Aryne Insertion Reactions Leading
to Bioactive Fused Quinazolinones:
Diastereoselective Total Synthesis
of Cruciferane
Sagar D. Vaidya and Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory (CSIR),
Pune 411 008, India
np.argade@ncl.res.in
Received June 26, 2013
ABSTRACT
Insertion reactions of an in situ generated arynes to a variety of suitably substituted 1,3-quinazolin-4-ones have been demonstrated for a new
efficient one-step approach to a diverse range of fused quinazolinone architectures. The present protocol has been effectively utilized to
accomplish the concise total synthesis of recently isolated bioactive natural products tryptanthrin, phaitanthrins AÀC, and cruciferane.
Quinazolinones are an important class of compounds
and a building block for a large number of structurally
diverse alkaloids with a wide range of biological activities.1,2
More specifically, the fused quinazolinones such as asperli-
cins, benzomalvins, circumdatins, phaitanthrins, and their
synthetic congeners have been imperative targets due to
their structural architectures and promising bioactivities
(Figure 1).3 Several well-designed synthetic routes involving
intramolecular cyclization strategies have been known for
these significant targets.3,4 After Kobayashi’s discovery
of a very mild way of generating highly reactive aryne
intermediates,5a chemistry of arynes has become a subject
of contemporary interest.5 Since then, plenty of meticulous
new applications of aryne reactions have been continuously
reported by synthetic chemists.6 On the basis of our con-
tinuing interest in the synthesis of quinazolinone alkaloids7
and their retrosynthetic disconnections, we reasoned that
the selective insertion of aryne between the 3-position
nitrogen atom and suitable 2-position substituent of 1,3-
quinazolin-4-ones would constitute an appropriate one-step
new synthetic approach to the desired fused quinazolinone
(1) (a) Demeununck, M.; Baussanne, I. Curr. Med. Chem. 2013, 20,
794. (b) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009,
48, 348. (c) Roy, A. D.; Subramanian, A.; Roy, R. J. Org. Chem. 2006,
71, 382. (d) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787 and
references cited therein.
(2) (a) Amin, A. H.; Mehta, D. R.; Samarth, S. S. Prog. Drug. Res.
1970, 14, 218. (b) Johne, S. Prog. Drug. Res. 1982, 26, 259. (c) Johne, S.
Prog. Chem. Org. Nat. Prod. 1984, 46, 159. (d) Sinha, S.; Srivastava, M.
Prog. Drug. Res. 1994, 43, 143. (e) Xie, H.; Zhang, Y.; Zhang, S.; Chen,
X.; Wang, W. Angew. Chem., Int. Ed. 2011, 50, 11773. (f) Li, L.; Ge, J.;
Wu, H.; Xu, Q.-H.; Yao, S. Q. J. Am. Chem. Soc. 2012, 134, 12157 and
references cited therein.
(3) (a) Haynes, S. W.; Gao, X.; Tang, Y.; Walsh, C. T. J. Am. Chem.
Soc. 2012, 134, 17444. (b) Zhichkin, P.; Kesicki, E.; Treiberg, J.;
Bourdon, L.; Ronsheim, M.; Ooi, H. C.; White, S.; Judkins, A.; Fairfax,
D. Org. Lett. 2007, 9, 1415. (c) Hart, D. J.; Magomedov, N. A. J. Am.
Chem. Soc. 2001, 123, 5892. (d) He, F.; Foxman, B. M.; Snider, B. B.
J. Am. Chem. Soc. 1998, 120, 6417.
(5) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
12, 1211. (b) Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C. Org.
Biomol. Chem. 2013, 11, 191. (c) Bhojgude, S. S.; Biju, A. T. Angew.
Chem., Int. Ed. 2012, 51, 1520. (d) Gampe, C. M.; Carreira, E. M. Angew.
Chem., Int. Ed. 2012, 51, 3766. (e) Tadross, P. M.; Stoltz, B. M. Chem.
Rev. 2012, 112, 3550. (f) Chen, Y.; Larock, R. C. In Modern Arylation
Methods; Ackerman, J., Ed.; Wiley/VCH: New York, 2009; pp 401À473.
~
ꢀ
ꢀ
(g) Pena, D.; Perez, D.; Guitian, E. Angew. Chem., Int. Ed. 2006, 45, 3579
and references cited therein.
^
(4) (a) Larraufie, M.-H.; Courillon, C.; Ollivier, C.; Lacote, E.;
(6) (a) Hendrick, C. E.; McDonald, S. L.; Wang, Q. Org. Lett. 2013,
15, 3444. (b) Yun, S. Y.; Wang, K.-P.; Lee, N.-K.; Mamidipalli, P.; Lee,
D. J. Am. Chem. Soc. 2013, 135, 4668. (c) Goetz, A. E.; Garg, N. K.
Nature Chem. 2013, 5, 54. (d) Hoye, T. R.; Baire, B.; Niu, D.;Willoughby,
P. H.; Woods, B. P. Nature 2012, 490, 208.
Malacria, M.; Fensterbank, L. J. Am. Chem. Soc. 2010, 132, 4381. (b)
Giri, R.; Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 686. (c) Xiao,
Z.; Yang, M. G.; Li, P.; Carter, P. H. Org. Lett. 2009, 11, 1421. (d)
Toumi, M.; Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 5027.
(e) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008, 130,
416. (f) Snider, B. B.; Wu, X. Org. Lett. 2007, 9, 4913.
(7) Kshirsagar, U. A.; Argade, N. P. Org. Lett. 2010, 12, 3716.
r
10.1021/ol4018062
XXXX American Chemical Society

systems. We herein report our detailed studies on aryne-
insertion reactions of quinazolinones and their applications
in the synthesis of several natural and unnatural quinazoli-
none systems (Schemes 1À5 and Table 1).
Scheme 2. Preliminary Studies on Aryne Insertion Reactions of
2-Halomethylquinazolinones
nucleophilicity with electrophilicity of 2-position carbon
unit in an intermediate B for intramolecular cyclization
would be feasible to make the reaction furnish desired aryne
insertion product D.
The bioactive tryptanthrin (6a) has been isolated from
numerous natural sources, and several synthesis of 6a have
been known.8a,b The fused quinazoline alkaloids tryptan-
thrin, phaitanthrins AÀE and (()-cruciferane, have been
recently isolated from Phaius mishmensis and Isatis tinctoria
(Isatis indigotica Fortune) and are potential antiviral and
anticancer agents.8cÀe We surmise that the tryptanthrin
could be a biogenetic precursor of (()-cruciferane. Exotic
(()-cruciferane is the first natural product with pyrroloin-
doloquinazoline skeleton and also encompasses an angular
oxygen function alike antitumor antibiotics mitomycins.9
On the basis of their structural features, we selected these as
synthetic targets and instigated our studies on aryne inser-
tion reactions of 1,3-quinazolin-4-ones. Initial aryne inser-
tion reaction of 2-chloromethylquinazolinone 1a with an in
situ generated aryne intermediate exclusively furnished the
corresponding N-arylated quinazolinone 2 in 91% yield
(Scheme 2). The above experiment clearly indicated that the
lone pair of electrons on 3-position nitrogen atom of
quinazolinone is sufficiently nucleophilic to attack arynes
under the present reaction conditions. However, reaction of
2-bromomethylquinazolinone 1b with aryne was not possi-
ble, as the starting material 1b underwent a self-coupling
reaction to form the linear pentacyclic dimer 310 in 88%
yield via conjugative intermolecular-intramolecular nucleo-
philic substitution pathway.
Rewardingly, the insertion reaction of an in situ gener-
ated aryne from precursor 5a to quinazolinone 4a in aceto-
nitrile at 25 °C was very clean and furnished the desired
natural product tryptanthrin (6a) in 94% yield via
N-arylation followed by a concomitant intramolecular
cyclization route (Table 1, entry 1). As anticipated, the inter-
mediate carbanion attacked on the proximal carbethoxy
moiety to generate a new carbonÀcarbon bond prior to
prototropic shift and exclusively delivered product 6a. As
described in Table 1, several requisite starting quinazoli-
nones 4aÀh bearing suitable carbonyl units were prepared
to study the generality of present approach.11 Similarly,
insertion reaction of symmetrical aryne from precursor 5b
Figure 1. Bioactive fused quinazolinone and dihydroquinazoli-
none alkaloids.1d,8
Scheme 1. Synthetic Proposal for Aryne Insertion Reactions of
1,3-Quinazolin-4-ones
As depicted in Scheme 1, our synthetic proposal for aryne
insertion reactions of 1,3-quinazolin-4-ones was mainly
based on the following fundamental concepts, namely:
(i) the lone pair of electrons on the 3-position nitrogen
atom in quinazolinone A would be sufficiently nucleophilic
to regioselectively attack an in situ generated reactive arynes
to afford a zwitterionic intermediate B; (ii) the intermediate
B upon intramolecular prototropic shift would provide
the undesired N-arylated product C via a strained four-
membered transition state (path a); (iii) however, the
intermediate B upon intramolecular cyclization with a
displacement of suitable leaving group from 2-position of
quinazolinone would lead to the desired aryl insertion
product D via five/six/seven-membered transition states
(path b); and (iv) tailoring the compatibility of carbanion
(8) (a) Tucker, A. M.; Grundt, P. ARKIVOC 2012, No. i, 546. (b)
€
Bergman, J.; Lindstrom, J.-O.; Tilstam, U. Tetrahedron 1985, 41, 2879.
(c) Jao, C.-W.; Lin, W.-C.; Wu, Y.-T.; Wu, P.-L. J. Nat. Prod. 2008, 71,
1275. (d) 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) Fukuyama, T.; Yang, L. J. Am. Chem. Soc. 1987, 109, 7881.
(10) Gompper, R.; Breitschaft, W. Angew. Chem. 1983, 95, 727.
€
1167. (e) Danz, H.; Stoyanova, S.; Wippich, P.; Brattstrom, A.;
Hamburger, M. Planta Med. 2001, 67, 411.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Aryne Insertion Reactions of Quinazolinonesa,b
Scheme 3. Proposed Mechanism for Aryl Insertion and
C-Arylation
regioselective and exclusively formed the desired product 6c
in 87% yield (Table 1, entry 3). The lone pair of electrons
on nitrogen atom in compound 4a selectively attacked
an electron deficient meta-position of aryne12a to form the
product 6c. Reaction of quinazolinone 4a with yet another
unsymmetrical aryne from precursor 5d was also highly
regioselective and exclusively delivered the desired product
6d in 73% yield (Table 1, entry 4). The lone pair of electrons
on nitrogen atom in compound 4a selectively attacked
a relatively electron deficient β-position carbon atom of R-
naphthalyne to form the product 6d. This observation is in
accordance with literature precedence.12b
Reaction of quinazolinone 4b with the Weinreb amide
unit at the 2-position and symmetrical aryne from pre-
cursor 5a also gave the desired product 6a in 84% yield
(Table 1, entry 5). Reaction of quinazolinone 4c bearing an
acyl unit at 2-position and symmetrical aryne from pre-
cursor 5a yielded the desired cycloadduct 6e in 89% yield
(Table 1, entry 6). Reaction of quinazolinone 4d bearing a
formyl unit at 2-position with symmetrical aryne from
precursor 5a underwent excessive decomposition and
failed to provide the desired product 6f (Table 1, entry 7).
Reaction of quinazolinone 4e with an acid-chloride unit at
2-position and symmetrical aryne from precursor 5a also
afforded the desired product 6a but only in 63% yield
(Table 1, entry 8). The decline in yield could be due to
relatively less stability of an acid chloride under the present
reaction conditions.
Reaction of quinazolinone 4f bearing the R,β-unsatu-
rated unit at 2-position with symmetrical aryne from
precursor 5a (1.20/2.40 mmol) exclusively furnished the
double aryne inclusion product 6g in 35/77% yield
(Table 1, entry 9). As depicted in Scheme 3, product 6g
was formed via N-arylation followed by a Michael addi-
tion to form the intermediate 7, which on an in situ
prototropic shift formed the more stable doubly conju-
gated carbanionic intermediate 8. Intermediate 8 bearing
net negative charge being relatively more reactive than the
starting material 4f itself undergoes second arylation pro-
cess at a faster rate and forms product 6g with a generation
of new quaternary center. Reaction of quinazolinone 4g
with an active methylene unit (ÀCH2CO2Me) at the
2-position and symmetrical aryne from precursor 5a
(1.20/2.40 mmol) underwent stepwise double C-arylation
a Reaction conditions: quinazolinone (1.00 mmol), aryl triflate
(1.20 mmol), CsF (2.40 mmol), NaHCO3 (1.20 mmol), CH3CN (10 mL),
25 °C, 6 h. b Reaction conditions: quinazolinone (1.00 mmol), aryl triflate
(2.40 mmol), CsF (4.80 mmol), NaHCO3 (2.40 mmol), CH3CN (15 mL),
25 °C, 6 h. c The corresponding simple N-arylated product 6j was also
formed in 41% yield (Supporting Information).
to quinazolinone 4a provided the desired product 6b in 83%
yield (Table 1, entry 2). Reaction of quinazolinone 4a
with unsymmetrical aryne from precursor 5c was highly
(11) (a) Kraus, G. A.; Guo, H. J. Org. Chem. 2009, 74, 5337.
(b) Zhou, H. B.; Liu, G. S.; Yao, Z. J. J. Org. Chem. 2007, 72, 6270.
(c) Bergman, J.; Brynolf, A. Tetrahedron 1990, 46, 1295.
(12) (a) Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.;
Stoltz, B. M. Org. Lett. 2010, 12, 1224. (b) Heaney, H. Chem. Rev. 1962,
62, 81.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Synthesis of Phaitanthrin A, Phaitanthrin B, and
Cruciferane
Figure 2. Proposed TS for reductive intramolecular cyclization.
transition state 12 from Figure 2, initially the boron atom
forms a complex with an adjacent oxygen atom and
delivers a hydride from the same phase to imine moiety
to generate nitrogen anion in the opposite phase, which
undergoes concomitant intramolecular cyclization to form
a γ-lactam unit. We feel that the present selective intramo-
lecular cyclization follows a concerted pathway, and it is a
both enthalpically (formation of amide bond) and entro-
pically (formation of five-membered ring) favored process.
The demethylation of quinazolinone 6c using BBr3/BCl3
was not very efficient and product 13 was obtained only in
15% yield. Finally, LiCl-induced demethylation of quina-
zolinone 6c in refluxing DMF afforded the desired natural
product phaitanthrin C (13) in 82% yield (Scheme 5). The
analytical and spectral data obtained for natural products
tryptanthrin, phaitanthrins AÀC and cruciferane were in
complete agreement with the reported data.8c,d
In summary, we have demonstrated a new simple and
efficient one-step aryne-based synthetic protocol for a
diverse range of fused quinazolinones. It has also been
successfully utilized to accomplish a concise total synthesis
of five recently isolated different bioactive quinazolinone
based natural products. More specifically, the first total
synthesis of (()-cruciferane has been accomplished in three
steps with 66% overall yield via two natural products as the
intermediates. In the synthesis of cruciferane, selective re-
duction of an imine moiety in the quinazolinone unit in the
presence of an aliphatic ester moiety is noteworthy from
a basic chemistry point of view. The present transition metal
free convergent approach to fused quinazolinones is general
in nature and will be useful to design several focused
minilibraries of natural and unnatural quinazolinone sys-
tems for SAR studies.
Scheme 5. Synthesis of Phaitanthrin C
process and exclusively provided a new quaternary carbon
bearing product6hin 39/88% yield (Table 1, entry 10). The
monoarylated intermediate product exhibits higher enol
character than the starting material 4g and hence enhances
the formation of diarylated product 6h. Present observa-
tion is in accordance with a recent literature report by
Mhaske and co-workers.13 Finally, reaction of quinazoli-
none 4h with symmetrical aryne from precursor 5a af-
forded the desiredseven memberedproduct 6i in 56% yield
(Table 1, entry 11). The corresponding simple N-arylated
product was also formed in 41% yield and it could be
attributed to a slower rate of generation of seven mem-
bered ring systems utilizing the relatively less reactive
aromatic ester unit.
In the next part of our study, the fused quinazolinone
systems were used for the synthesis of recently isolated
bioactive natural products (Scheme 4). K2CO3-induced
chemoselective aldol condensation of acetone with natural
product tryptanthrin (6a) gave the phaitanthrin A (9)
in 79% yield.8c Several attempts to perform the Refor-
matsky reaction on tryptanthrin (6a) were unsuccessful.
However, chemoselective condensation of tryptanthrin
(6a) with methyl acetate using LDA as the base at
À78 °C was successful and provided the desired natural
product phaitanthrin B (10) in 86% yield. The sodium
borohydride induced hydroxyl directed14 highly chemo-
and diastereoselective reductive intramolecular cyclization
of phaitanthrin B (10) furnished yet another natural prod-
uct (()-cruciferane (11) in 82% yield. As indicated in the
Acknowledgment. S.D.V. thanks CSIR, New Delhi,
for the award of research fellowship. N.P.A. thanks the
Department of Science and Technology, New Delhi, for
financial support.
Supporting Information Available. Experimental pro-
cedures, tabulated analytical and spectral data of com-
pounds 2, 3, 4b, 4f, 6aÀe, 6gÀj, 9À11, and 13. 1H NMR,
13C NMR, and DEPT spectra of compounds 3, 4f, 6aÀe,
gÀj, 9À11, and 13. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) Dhokale, R. A.; Thakare, P. R.; Mhaske, S. B. Org. Lett. 2012,
14, 3994.
€
(14) Bergman, J.; Tilstam, U.; Tornroos, K.-W. J. Chem. Soc., Perkin
Trans. 1 1987, 519.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX