Stereoselective construction of deoxy-cruciferane alkaloids by NHC-catalyzed intramolecular annulation of homoenolate with quinazolinone

Article abstract of DOI:10.1039/c9ob01243e

Chiral N-heterocyclic carbene (NHC)-catalyzed intramolecular [3 + 2] annulation of enals with an unactivated imine moiety of quinazolinone via formal homoenolate cycloaddition has been demonstrated. It is an excellent approach for stereoselective syntheses of deoxy-cruciferane alkaloids comprising a biologically important pyrroloindoline scaffold. Notably, this is the first report on the NHC-catalyzed asymmetric intramolecular homoenolate annulation with cyclic N-acyl amidine.

Full text of DOI:10.1039/c9ob01243e

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DOI: 10.1039/C9OB01243E
COMMUNICATION
Stereoselective Construction of Deoxy-Cruciferane Alkaloids by
NHC-Catalyzed Intramolecular Annulation of Homoenolate with
Quinazolinone
Received 00th January 20xx,
Accepted 00th January 20xx
Milind M. Ahireab, Mahesh D. Pola, Dattatry S. Kavalea, Rajesh G. Gonnade,bc and Santosh B.
DOI: 10.1039/x0xx00000x
Mhaske*ab
Previous Work: Intermolecular
Chiral N-heterocyclic carbene (NHC)-catalyzed intramolecular [3 +
2] annulation of enals with unactivated imine moiety of
quinazolinone via formal homoenolate cycloaddition has been
demonstrated. It is an excellent approach for stereoselective
syntheses of deoxy-cruciferane alkaloids comprising biologically
important pyrroloindoline scaffold. Notably, this is the first report
on the NHC-catalyzed asymmetric intramolecular homoenolate
annulation with cyclic N-acyl amidine.
O
O
O
O
O
O
S
S
N
N
H
'NHC'
'NHC'
(1)
(2)
MeO
MeO
R
Ar
R
Ar
p-Tol
O
O
O
p-Tol
O
N
HN
N
H
HN
N
Lewis acid
EtO2C
O
Ar
Ar
CO2Et
O
Ph
N
'NHC'
Ph
H
Brønsted acid
(3)
(4)
R
R1
R1
R
trans or cis
O
Over the past decade, astonishing developments in the area of
N-heterocyclic carbene (NHC)-catalyzed transformations
revealed its important synthetic utilities in organic chemistry.1
NHCs are being employed as organocatalysts and ligands for p-
block elements and transition-metal catalysts.1,2 Furthermore,
organocatalysis by N-heterocyclic carbene provides a platform
for the synthesis of pharmaceutically important compounds
and natural products.3 NHCs have the ability to alter the
polarity of aldehyde or enal functionality to access numerous
valuable synthetic processes via NHC-linked intermediates,
such as Breslow intermediates, enolates, acylazoliums,
homoenolates, and α,β-unsaturated acylazoliums, etc.
Particularly, NHC-catalyzed reactions of homoenolate anion
intermediates and its intervention with different electrophilic
partners such as imines, ketones, and aldehydes through
cycloaddition reaction provide access to an array of novel
carbo- and heterocyclic compounds via carbon−carbon or
carbon−heteroatom bond formation.1,2
NHC-catalyzed annulation of enals with imines via
homoenolate equivalent is a unique strategy for the synthesis
of substituted γ-lactams. Bode group reported NHC-catalyzed
addition of enals to N-4-methoxybenzenesulfonyl imines as
well as saccharin-derived ketimines (Scheme 1, eq 1).4a,b In
2010, Scheidt and co-worker developed highly diastereo- and
enantioselective [3+2] cycloaddition reaction of α,β-
unsaturated aldehydes with hydrazones using co-operative
NBoc
O
BocN
Ar
H
O
'NHC'
O
N
Me
N
Ar
Me
This Work: Intramolecular (first Example)
O
H
O
'NHC'
(5)
N
N
N
N
H
O
O
Scheme 1 NHC-Catalyzed Annulation of Enal with Various Imines and This Work.
catalysis of NHC and Lewis acid (Scheme 1, eq 2).4c Rovis and
co-workers reported NHC and Brønsted acid co-operative
catalysis for enantioselective synthesis of trans-γ-lactams
(Scheme 1, eq 3).4d Furthermore, Chi group demonstrated the
enantioselective construction of spirocyclic oxindole-γ-lactams
via NHC-catalyzed annulation of isatin N-Boc ketimines and
unsaturated aldehydes (Scheme 1, eq 4).4e Overall, our survey
revealed that the NHC-catalyzed intermolecular annulation of
enals with imines is well documented in the literature (Scheme
1, eq 1-4).4 Interestingly, until now NHC-catalyzed
intramolecular
annulation
of
homoenolate
with
alkenes/aldehydes/ketones is known,5 however such
intramolecular cycloaddition is not reported with imine,
probably because of a difficulty in the preparation of
substrates containing imine and aldehyde functionality in the
same molecule. NHC−homoenolate pathway for the synthesis
of heterocycles is always a challenging but much desired
synthetic transformation. We envisioned that intramolecular
homoenolate cycloaddition with imine (IHCI) would be a good
strategy to access the privileged γ-lactam containing scaffolds
such as pyrroloindolines.
a. Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411008,
India. Email: sb.mhaske@ncl.res.in
b. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
c. Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory,
Pune 411008, India.
†
Electronic
supplementary
information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x. CCDC 1904732.
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O
Me
N
bromoaniline (7a) and methyl acrylate (6a) usViniegw ArrteicpleoOrntleinde
S
S
palladium-catalyzed Heck coupling reactiDoOn.I: 10.1039/C9OB01243E
N
OH
NHMe
N
benzylic
oxidation
NHC-catalyzed
[3 + 2] cycoaddition
Me
O
HO
N
N
HO
N
O
H
HO
O
H
O
H
O
O
O
S
Me
N
N
N
S
N
N
N
N
N
NHMe
H
H
H
N
N
N
H
N
Me
N
O
N
H
H
O
O
O
O
HO
O
O
Psychotrimine
()-Cruciferane
()-Cruciferane
Chaetomin
1a
2a
3a
Fig. 1 Natural Products Containing Pyrroloindoline Skeleton.
NH2
Br
O
N
O
OMe
O
NH2
5a
OMe
Heck coupling
Pyrroloindolines are an important class of compounds and
a common structural motif for a large number of natural
products and pharmacologically important compounds.6 This
family of natural products is an attractive synthetic target for
the scientific community due to excellent bioactivities, such as
6a
4a
7a
Scheme 2 Retrosynthetic Analysis of Cruciferane.
Our investigation for the NHC-catalyzed intramolecular
antifungal, antibacterial, antiviral, and analgesic (Figure 1).7 annulation reaction began with the synthesis of the key
The alkaloid (±)-cruciferane containing pyrroloindoline scaffold component quinazolinone-aldehyde 3a (Scheme 3). The
fused with quinazolinone was isolated in the racemic form methyl cinnamate derivative 5a was synthesized using the
from the herbaceous plant Isatis indigotica (Cruciferae Heck coupling reaction of o-bromoaniline (7a) and methyl
family).8 The dried roots and leaves of this plant are commonly acrylate (6a) in high yield.11 The treatment of anthranilic acid
used in traditional Chinese medicine for the treatment of (8a) with triethyl orthoformate in the presence of a catalytic
influenza, cold, fever, and infections. The alkaloid (±)- amount of PTSA provided unstable benzoxazinone 4a,12 which
cruciferane featuring a novel pyrroloindoloquinazolinone core was reacted further without purification with amine 5a in the
and possessing potential hepatoprotective activity particularly presence of EDCI in toluene to deliver quinazolinone-ester 9a
caught our attention. The formation of the racemic
A) Synthesis of 5a-h
pyrroloindoloquinazoline skeleton in low yield was observed
O
Br
Pd(PPh3)2Cl2
R1
R1
by Bremner et al., much before the isolation of (±)-cruciferane,
during photoinduced cyclization of N-(2-(1-indolylmethyl)-
phenyl)chloroacetamide.9 Until now, five total syntheses of
cruciferane are reported in the literature.10 Most of the
synthetic routes to cruciferane involve the use of tryptanthrin
as the key intermediate.
O
Et3N, 100 oC, 24 h
OMe
NH2
NH2
OMe
7a-h
6a
5a-h (81-90%)
B) Synthesis of 3a-h
O
R1
O
N
OMe
CO2H
5a-h
CH(OEt)3
N
N
O
R2
R2
EDCI.HCl (1.5 equiv)
toluene, reflux, 11-12 h
PTSA (5 mol%)
reflux, 3 h
NH2
O
R2
The challenging structural architecture and potential
biological activity of (±)-cruciferane prompted us to investigate
the application of our envisioned IHCI strategy for the
stereoselective construction of the pyrroloindoloquinazolinone
scaffold of cruciferane. The development of such novel
synthetic methodologies and their successful application in the
synthesis of bioactive scaffolds and natural products starting
from simple precursors is always an interesting task for
synthetic organic chemists. In this context, we report herein,
an intramolecular NHC-catalyzed [3 + 2] annulation of enal
with the internal imine of quinazolinone (Scheme 1, eq 5),
which stereoselectively furnish the core structure of the
cruciferane natural product.
8a-h
4a-h
9a-h (55-85%)
O
OH
R1
R1
MnO2
DIBAL-H
-50 oC, THF, 5-6 h
N
N
N
N
DCM, rt, 12 h
O
O
R2
R2
10a-h
3a-h (43-71%)
Scheme 3 Synthesis of quinazolinone-aldehydes 3a-h.
in very good yield. Notably, the yield was very poor in the
absence of EDCI. The quinazolinone-ester 9a was reduced to
alcohol 10a using DIBAL-H in THF at -50 °C. The alcohol 10a
could not be isolated or purified; hence, the crude product was
subjected to the oxidative condition using activated MnO2 to
furnish the desired aldehyde 3a in good yield. The other
quinazolinone-aldehydes 3b-h were synthesized in moderate
to good yields following the same route as used for 3a
(Scheme 3). The quinazolinone-aldehydes 3a-h have
strategically positioned two reacting centres, α,β-unsaturated
aldehyde and imine of quinazolinone, embedded in a single
molecule as desired for our envisioned intramolecular
cycloaddition process.
Scheme 2 illustrates our retrosynthetic analysis, wherein,
we envisioned a convergent construction of cruciferane
alkaloid
1a
through
benzylic
oxidation
of
pyrroloindoloquinazolinone 2a. The chirality in compound 2a
was imagined via N-heterocyclic carbene-catalyzed
asymmetric intramolecular [3 + 2] cycloaddition of NHC-linked
homoenolate intermediate of unsaturated aldehyde and
internal imine present in the quinazolinone 3a. The
construction of quinazolinone 3a was planned from
benzoxazinone 4a and the amine 5a. The benzoxazinone 4a
could be easily accessed from anthranilic acid. The amine 5a
could be accessible from the commercially available o-
With the key intermediate 3a in hand, we initiated
optimization of the desired intramolecular cycloaddition
protocol. Table 1 shows selected representative reaction
2 | J. Name., 2012, 00, 1-3
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conditions that were used for the optimization. Our effort temperatures, we observed improvement in the yield, and we
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o
DOI: 10.1039/C9OB01243E
towards the [3 + 2] annulation reaction began by treating the
could achieve the best yield 42% and 78:22 er at 65 C (Table
1, entry 7). Recrystallization of this compound did not show
any improvement in the er. The reaction in benzene furnished
the product with little lower yield and er (Table 1, entry 8). The
NHC-precatalysts C showed a drastic reduction in the yield
though it has a similar backbone as the precatalyst B, except
the absence of the bulkier mesitylene aromatic ring (Table 1,
entry 9). The precatalyst D however furnished the product 2a
in 13% yield and comparable er (Table 1, entry 10). Screening
of various bases did not show improvement in the yield (Table
1, entry 11 to 16). Further optimization of the reaction
condition using different additives such as Lewis4c and
Brønsted acid4d did not improve the reaction yield or er to
much extent.
Table 1 Optimization of Reaction Conditionsa
O
H
O
N
'NHC'
N
N
H
N
O
O
2a
3a
N
BF4
BF4
O
C6F5
Mes
N
N
Mes
Cl
N
N
N
N
N
N
Mes
BF4
N
N
N
OBn
O
O
D
A
B
C
entry NHC base
solvent
temp yield er
(oC)
65
rt
(%)b
<2
6
Deoxy-cruciferane 2a was prepared in sufficient quantities
using the optimized reaction condition (Table 1, entry 7) and
its benzylic oxidation to achieve the total synthesis of (–)-
cruciferane was attempted. However, when the compound 2a
was subjected to several oxidative conditions (see SI) using
organic and inorganic oxidizing reagents, it always ended up in
either decomposition or recovery of the starting material. The
development of novel selective oxidizing reagent or reaction
conditions would be necessary for this transformation.
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
16
A
B
B
B
B
B
B
B
C
D
B
B
B
B
B
B
K2CO3
toluene
DCE
DCM
DMSO
DMF
toluene
ND
70:30
ND
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K3PO4
DBU
rt
<2
rt/65 NR
rt/65 NR
ND
ND
rt
NR
42
35
<2
13
NR
NR
NR
NR
12
ND
toluene 65
benzene 65
78:22
75:25
ND
71:29
ND
ND
ND
ND
78:22
toluene
toluene
toluene
toluene
toluene
toluene
65
65
65
65
rt
BF4
Mes
N
O
N
N
H
O
15 mol%
O
R1
R1
N
N
N
K2CO3 (30 mol%)
N
H
toluene, 65 o
3-12 h
C
rt
65
O
R2
O
R2
PhCO2Na toluene
PhCO2Na ACN, MS rt/60 trace ND
2a-h
3a-h
aReaction conditions: 3a (1.0 equiv, 0.18 mmol), pre-NHC catalyst
B (15 mol %), K2CO3 (30 mol%), solvent (2 mL), 4 h, under argon
atmosphere. bIsolated yields. rt = room temperature, NR = no
reaction, ND = not determined, MS = 4 Å molecular sieves
H
H
H
H
O
O
O
O
F
Cl
Me
N
N
N
N
N
N
H
N
H
N
H
H
O
O
O
O
2a, 42%, 4 h,
2d, 40%, 4 h,
2b, 35%, 3 h,
2c, 37%, 4 h,
er = 78:22
er = 76:24
er = 73:27
er = 71:29
aldehyde 3a in the presence of achiral triazolium-derived pre-
NHC catalyst A and various bases in different solvents at
H
H
H
H
O
O
O
O
MeO
Me
N
N
N
N
varying
temperatures.
The
expected
product
N
N
H
N
H
N
H
H
pyrroloindoloquinazolinone 2a was observed only when 3a
was treated with 15 mol% of pre-NHC catalyst A and 30 mol%
of K2CO3 in toluene at 65 C (Table 1, entry 1). Encouraged by
O
O
O
O
Me
I
NO2
2e, 39%, 3 h,
er = 77:23
2f, 32%, 6 h,
er = 77:23
2g, 62%, 4 h,
er = 81:19
2h, 22%, 12 h,
er = 85:15
o
this result, we began the screening of chiral NHC-catalysts in
combination with various solvents. Interestingly, the expected
cyclized product 2a was obtained in 6% yield in the presence of
chiral triazolium-derived pre-NHC catalyst B and 30 mol% of
K2CO3 in 1,2-dichloroethane (DCE) at room temperature (Table
1, entry 2). The yield did not improve even after heating the
reaction mixture at higher temperatures. Herein, we observed
only a single diastereoisomer formation as confirmed by the
crude 1H-NMR spectral analysis. The racemic version of the
aReaction conditions: 3a-h (1.0 equiv, 0.18 mmol), pre-NHC catalyst
B (15 mol %), K2CO3 (30 mol%), toluene (2 mL), 3-12 h, under argon
atmosphere. bIsolated yields. er = enantiomeric ratio.
Scheme 4 Synthesis of Various Deoxy-Cruciferanesa,b
We planned to synthesize various deoxy-cruciferane
analogues using the optimized cycloaddition condition to
demonstrate the scope and generality of the protocol by
varying different substituents. Gratifyingly,
a range of
substituents were tolerated on both the aromatic rings of the
molecule and the desired annulated products deoxy-
cruciferanes 2a-h were obtained in good to moderate yields
and optimal er (Scheme 4). The yield and er observed for the
unsubstituted aldehyde 3a to obtain 2a (42%, 78:22 er) was
maintained in the methyl, methoxy, and halo-substituted
pre-NHC catalyst
B was prepared to determine the
enantiomeric ratio (er) of the product by direct comparison
using chiral HPLC. Interestingly, the product 2a was obtained in
70:30 er (Table 1, entry 2). Further variations in solvents did
not show much improvement in the yield (Table 1, entries 3-6).
However, when the reaction in toluene was heated at various
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J. Name., 2013, 00, 1-3 | 3
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aldehydes 3b-f to deliver the products 2b-f, though with Conclusions
slightly less yield and er. Interestingly, the reaction worked In summary,
View Article Online
straightforward acceDssOI:t1o0.10p3y9r/rCo9lOoBin0d12o4l3oE-
a
very smoothly with iodo substituted quinazolinone-aldehyde quinazolinone scaffold has been developed using NHC catalysis
3g and delivered the expected product 2g in good yield (62%) and applied in the synthesis of deoxy-cruciferane alkaloids.
and er (81:19). Additionally, the developed protocol worked Novel NHC-catalyzed intramolecular stereoselective [3 + 2]
well on the substrate 3h having electron-withdrawing nitro cycloaddition of enal with quinazolinone was utilized as the
substituent although in diminished yield but with a slight key-step. The developed protocol provides
a
single
improvement in the enantiomeric ratio. The absolute diastereomer of cyclized products with a good enantiomeric
configuration of deoxy-cruciferane 2a was unambiguously ratio. The scope of the protocol was demonstrated by
assigned on the basis of X-ray crystallographic analysis (Figure synthesizing
varyingly
substituted
deoxy-cruciferane
2, see SI) and extrapolated to the deoxy-cruciferane analogues analogues. Currently, we are working on the improvement and
2b-h.
application of the NHC-catalyzed intramolecular annulation
strategy developed herein to access other bioactive molecules
and natural products.
Conflicts of interest
There are no conflicts to declare.
Acknowledgments
M.M.A. thanks CSIR-New Delhi for the research fellowship.
S.B.M. gratefully acknowledges generous financial support
from DST-SERB, New Delhi.
Fig. 2 X-ray crystallographic structure of 2a
A plausible mechanism of the developed IHCI protocol is
depicted in figure 3. The homoenolate intermediate [I] is
formed by the reaction of an in situ generated NHC catalyst
with the aldehyde 3. The homoenolate anion attacks the imine
moiety of the quinazolinone scaffold. Probably, the hydrogen
bonding between the imine nitrogen and enol facilitates this
reaction. Further cyclization proceeds via intermediates [II]
and [III] to construct the second pentacyclic ring, thus
furnishing the desired deoxy-cruciferanes 2 and regenerating
the NHC catalyst for the next catalytic cycle. The intermediate
[I] displaying the hydrogen bonding interaction reasonably
explains the observed enantio- and diastereoselctivity.
Additionally, the formation of the cis-5-5 ring system is
favourable, which justifies the complete diastereoselection.
Further studies on the mechanism are essential.
Notes and references
1
For selected recent reviews on NHC catalysis, see: (a) D.
Enders, O. Niemeier and A. Henseler, Chem. Rev. 2007, 107,
5606−5655. (b) J. Douglas, G. Churchill and A. D. Smith,
Synthesis 2012, 44, 2295−2309. (c) S. De Sarkar, A. Biswas, R.
C. Samanta and A. Studer, Chem. Eur. J. 2013, 19,
4664−4678. (d) M. Fevre, J. Pinaud, Y. Gnanou, J. Vignolle
and D. Taton, Chem. Soc. Rev. 2013, 42, 2142−2172. (e) S. J.
Ryan, L. Candish and D. W. Lupton, Chem. Soc. Rev. 2013, 42,
4906−4917. (f) M. N. Hopkinson, C. Richter, M. Schedler and
F. Glorius, Nature 2014, 510, 485−496. (g) D. M. Flanigan, F.
Romanov-Michailidis, N. A. White and T. Rovis, Chem. Rev.
2015, 115, 9307−9387. (h) R. S. Menon, A. T. Biju and V. Nair,
Chem. Soc. Rev. 2015, 44, 5040−5052. (i) R. S. Menon, A. T.
Biju and V. Nair, Beilstein J. Org. Chem. 2016, 12, 444−461. (j)
C. Zhang, J. F. Hooper and D. W. Lupton, ACS Catal. 2017, 7,
2583−2596. (k) M. Zhao, Y.-T. Zhang, J. Chen and L. Zhou,
Asian J. Org. Chem. 2018, 7, 54−69. (l) X.-Y. Chen, Q. Liu, P.
Chauhan and D. Enders, Angew. Chem., Int. Ed. 2018, 57,
3862-3873. (m) K. J. R. Murauski, A. A. Jaworski, and K. A.
Scheidt, Chem. Soc. Rev. 2018, 47, 1773-1782. (n) X. Bugaut,
and F. Glorius, Chem. Soc. Rev. 2012, 41, 3511-3522.
O
H
O
N
R2
H
R2
N
N
N
N
N
Mes
N
R1
O
NHC*
R1
N
O
2
3
2
For selected reviews, (a) S. Díez-Gonzalez, N. Marion and S.
P. Nolan, Chem. Rev. 2009, 109, 3612-3676. (b) E. Peris,
Chem. Rev. 2018, 19, 9988-10031. (c) M. Iglesias and L. A.
Oro, Chem. Soc. Rev. 2018, 47, 2772-2808.
base
Mes
N
H
N
N
NHC*
N
N
O
Mes
R2
H
O
N
3
4
J. Izquierdo, G. E. Hutson, D. T. Cohen and K. A. Scheidt,
Angew. Chem., Int. Ed. 2012, 51, 11686−11698.
N
H
BF4
R2
[III]
R1
N
N
O
Selected examples (a) M. He and J. W. Bode, Org. Lett. 2005,
7, 3131−3134. (b) M. Rommel, T. Fukuzumi and J. W. Bode, J.
Am. Chem. Soc. 2008, 130, 17266−17267. (c) D. E. A. Raup, B.
Cardinal-David, D. Holte and K. A. Scheidt, Nat. Chem. 2010,
2, 766-771. (d) X. D. Zhao, D. A. DiRocco and T. Rovis, J. Am.
Chem. Soc. 2011, 133, 12466-12469. (e) H. Lv, B. Tiwari, J.
Mo, C. Xing and Y. R. Chi, Org. Lett. 2012, 14, 5412-5415.
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O
R1
[I]
Homoenolate
O
H
NHC*
NH
H
R2
N
R1
[II]
O
5
Fig. 3 A plausible mechanism of the IHCI protocol
4 | J. Name., 2012, 00, 1-3
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