Sequential five-component synthesis of spiropyrrolidinochromanones

Article abstract of DOI:10.1021/jo900992w

(Chemical Equation Presented) Herein we report a novel, diastereoselective, one-pot, two-step, sequential synthesis of highly functionalized natural product-like spiropyrrolidinochromanones. The process consists of an Ugi four-component condensation of 3-

Full text of DOI:10.1021/jo900992w

pubs.acs.org/joc
Hence, the synthesis of spiranes incorporating two privileged
Sequential Five-Component Synthesis of
Spiropyrrolidinochromanones
heterocycles could be a valuable strategy to discover new
bioactive compounds in the context of chemical genomics.
Benzopyrans and pyrrolidinones have been recognized as
two prominent types of privileged structures, which have
shown to interact with a variety of biological receptors. The
benzopyrane ring system is central to important classes of
bioactive natural products as coumarins, chromones, and
flavonoids. Some of them contain spiro-fused structures,
such as cytotoxic rotenoid amorphispironone,5 antimalarial
robustadials,6 and antileishmanial euglobals7 from Eucaly-
ptus, and the biflavonoids daphnodorins and genkwanol,
isolated from Daphne species.8 Synthetic spirobenzopyranes,
such as sorbinil9 and SNK-860,10 have been shown to be
potent aldose reductase inhibitors and, hence, potentially
useful to prevent long-term diabetic complications. On the
other hand, the spiropyrrolidine motif is common to most
oxindole alkaloids, many of which show singular biological
activities. Antitumor agents vinblastine and vincristine11 and
cell cycle regulating spirotryprostatins are representative
examples.12 Other spiropyrrolidines with relevant biological
activities include nicotinic receptor blockers,13 matrix metallo-
protease inhibitors,14 and frog and millipede poisons.15
Moreover, spiropyrrolidinochromanones have been al-
ready recognized as biologically relevant synthetic targets.
However, their synthesis is limited to the 1,3-dipolar cy-
cloaddition reaction of azomethine ylides with 3-methylene-
chroman-4-ones,16 a strategy that allows a limited variety of
Stefano Marcaccini,*,† Ana G. Neo,‡ and
Carlos F. Marcos*,‡
†
ꢀ
Dipartimento di Chimica Organica “Ugo Schiff”, Universita
di Firenze, 50019 Sesto Fiorentino FI, Italy, and ‡Laboratorio
´
´
ꢁ
ꢁ
de Quımica Organica y Bioorganica, LOBO, Departamento
de Quımica Organica e Inorganica, Facultad de Veterinaria,
ꢁ
ꢁ
ꢁ
Universidad de Extremadura, 10071 Caceres, Spain
stefano.marcaccini@unifi.it; cfernan@unex.es
Received May 12, 2009
Herein we report a novel, diastereoselective, one-pot,
two-step, sequential synthesis of highly functionalized
natural product-like spiropyrrolidinochromanones. The
process consists of an Ugi four-component condensation
of 3-formylchromones with amines, isocyanides, and
glyoxylic acids followed by a nucleophilic conjugate
addition and intramolecular cyclization. The experimen-
tal simplicity and tolerance to a wide variety of substitu-
ents makes this method suitable for combinatorial
synthesis.
(5) Li, L. P.; Wang, H. K.; Chang, J. J.; Mcphail, A. T.; Mcphail, D. R.;
Terada, H.; Konoshima, T.; Kokumai, M.; Kozuka, M.; Estes, J. R.; Lee,
K. H. J. Nat. Prod. 1993, 56, 690–698.
(6) (a) Xu, R.; Snyder, J. K.; Nakanishi, K. J. Am. Chem. Soc. 1984, 106,
734–736. (b) Cheng, Q.; Snyder, J. K. J. Org. Chem. 1988, 53, 4562–4567.
(7) (a) Bharate, S. B.; Bhutani, K. K.; Khan, S. I.; Tekwani, B. L.; Jacob,
M. R.; Khan, I. A.; Singh, I. P. Bioorg. Med. Chem. 2006, 14, 1750–1760.
(b) Singh, I. P.; Bharate, S. B. Nat. Prod. Rep. 2006, 23, 558–591.
(8) (a) Baba, K.; Taniguchi, M.; Kozawa, M. Phytochemistry 1992, 31,
975–980. (b) Baba, K.; Taniguchi, M.; Kozawa, M. Phytochemistry 1993, 33,
913–916. (c) Taniguchi, M.; Fujiwara, A.; Baba, K.; Wang, N. H. Phyto-
chemistry 1998, 49, 863–867.
(9) Sarges, R.; Bordner, J.; Dominy, B. W.; Peterson, M. J.; Whipple,
E. B. J. Med. Chem. 1985, 28, 1716–1720.
(10) Unno, R.; Yamaguchi, T.; Usui, T.; Kakigami, T.; Fukushima, M.;
Mizuno, K.; Baba, Y.; Kurono, M. Chem. Pharm. Bull. 1994, 42, 1474–1478.
(11) Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.; Kakei, H.;
Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 4904–4916.
(12) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651–
12666.
Spiroheterocyclic structures are common scaffolds of many
bioactive natural products, including oxindole alkaloids,1
shellfish toxins,2 and bioactive marine macrolides.3 All these
molecules incorporate at least two spiro-fused biologically
privileged heterocyclic rings4 disposed in a rigid geometry
defined by the spiro motif. This three-dimensional arrange-
ment is crucial in the interaction with biological receptors.
(13) Badio, B.; Shi, D.; Shin, Y.; Hutchinson, K. D.; Padgett, W. L.; Daly,
J. W. Biochem. Pharmacol. 1996, 52, 933–939.
(14) Freeman-Cook, K. D.; Reiter, L. A.; Noe, M. C.; Antipas, A. S.;
Danley, D. E.; Datta, K.; Downs, J. T.; Eisenbeis, S.; Eskra, J. D.; Garmene,
D. J.; Greer, E. M.; Griffiths, R. J.; Guzman, R.; Hardink, J. R.; Janat, F.;
Jones, C. S.; Martinelli, G. J.; Mitchell, P. G.; Laird, E. R.; Liras, J. L.;
Lopresti-Morrow, L. L.; Pandit, J.; Reilly, U. D.; Robertson, D.; Vaughn-
Bowser, M. L.; Wolf-Gouviea, L. A.; Yocum, S. A. Bioorg. Med. Chem. Lett.
2007, 17, 6529–6534.
(1) (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–2219.
(b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748–8758.
(2) O’Connor, P. D.; Brimble, M. A. Nat. Prod. Rep. 2007, 24, 869–885.
(3) (a) Yeung, K. S.; Paterson, I. Chem. Rev. 2005, 105, 4237–4313.
(b) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041–2114.
(4) The term privileged structure was first coined by Evans et al. in 1988
and was defined as “a single molecular framework able to provide ligands for
diverse receptors”. (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.
(15) Daly, J. W.; Garraffo, H. M.; Jain, P.; Spande, T. F.; Snelling, R. R.;
Jaramillo, C.; Rand, A. S. J. Chem. Ecol. 2000, 26, 73–85.
(16) (a) Grigg, R.; Liu, A.; Shaw, D.; Suganthan, S.; Washington, M. L.;
Woodall, D. E.; Yoganathan, G. Tetrahedron Lett. 2000, 41, 7129–7133.
(b) Subramaniyan, G.; Raghunathan, R. Tetrahedron 2001, 57, 2909–2913.
(c) Subramaniyan, G.; Raghunathan, R.; Castro, A. M. M. Synthesis 2002,
2440–2444. (d) Manian, R. D. R. S.; Jayashankaran, J.; Kumar, S. S.;
Raghunathan, R. Tetrahedron Lett. 2006, 47, 829–832. (e) Panja, S. K.;
Karmakar, P.; Chakraborty, J.; Ghosh, T.; Bandyopadhyay, C. Tetrahedron
Lett. 2008, 49, 4397–4401.
6888 J. Org. Chem. 2009, 74, 6888–6890
Published on Web 07/27/2009
DOI: 10.1021/jo900992w
r
2009 American Chemical Society

Marcaccini et al.
JOCNote
SCHEME 1. General Synthesis of Spiropyrrolidinochroma-
nones
FIGURE 1. pm3-minimized model of (S)-5a being approached by
benzylamine.
Our approach relies on the high reactivity of electron-
deficient position 2 of chromones.22 The addition of nucleo-
philes to this position generates a negative charge on carbon 3,
which can be trapped with electrophiles. We intend to use an
Ugi condensation to prepare chromones containing an elec-
trophilic moiety able to trap the anionic intermediate gene-
rated by the addition of nucleophiles to chromone position 2.
In this way, it will be possible to obtain spiranic structures,
in which each of the four components of the Ugi reaction and
the nucleophile will provide an element of diversity. Theore-
tically, having a choice of just five different compounds of
each of the five components, it would be possible to obtain
more than 3000 different products.
To test our hypothesis, we performed the reaction between
6-methyl-3-formylchromone (1, R1=CH3), aniline (2, R2=
C6H5), cyclohexyl isocyanide (3, R3=c-C6H11), and phenyl-
glyoxilic acid (4, R4 = H) by simply combining the four
components in methanol solution. Stirring the mixture at
room temperature readily gave the expected Ugi four-com-
ponent adduct 5a, which was not isolated. Evaporation of
the solvent and subsequent addition of diethyl ether and
benzylamine (6, R5=CH2Ph) led to the formation of spiro-
pyrrolidinonechromanone 7a (Scheme 1). As anticipated,
conjugate addition of the amine to chromone carbon 2
generates an enolate anion which intramolecularly attacks
the carbonyl on the glyoxylamide side chain, resulting in the
formation of a new spiranic pyrrolidinone ring.
possible products. A more general synthesis of spiropyrroli-
dinobenzopyranes allowing a wide range of substituents
would be a valuable strategy for the discovery of new
biologically active compounds.
Multicomponent reactions (MCRs), and particularly
those involving isocyanides (IMCRs), are highly convergent
processes that have proven useful for the efficient prepara-
tion of complex molecules from simple starting materials.17
One of the major interests of our laboratory is the combina-
tion of IMCRs with postcondensation transformations for
the preparation of natural product-like heterocycles.18
Furthermore, IMCRs have been used by us19 and others20
for the preparation of spiroheterocycles.
Here, we propose a versatile synthesis of spiropyrroli-
dinonechromanones based on an Ugi four-component con-
densation.21 The advantage of this method is that a high
degree of diversity can be attained by reacting, in a combi-
natorial way, five components in a one-pot, two-step,
sequential process.
€
€
(17) Reviews: (a) Ugi, I.; Domling, A.; Horl, W. Endeavour 1994, 18, 115–
122. (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169–3210. (c)
€
The reaction occurs with remarkably high diastereoselec-
tivity: Three new stereogenic centers are formed in the
cyclization process, and according to NMR data, only one
diastereomer is obtained.
Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80. (d) Zhu, J. P. Eur. J.
Org. Chem. 2003, 1133–1144. (d) Ulaczyk-Lesanko, A.; Hall, D. G. Curr.
Opin. Chem. Biol. 2005, 9, 266–276. (e) Isambert, N.; Lavilla, R. Chem.;Eur.
J. 2008, 14, 8444–8454. (f) Ganem, B. Acc. Chem. Res. 2009, 42, 463–472.
(18) (a) Neo, A. G.; Carrillo, R. M.; Barriga, S.; Moman, E.; Marcaccini,
S.; Marcos, C. F. Synlett 2007, 327–329. (b) Neo, A. G.; Marcos, C. F.;
Marcaccini, S.; Pepino, R. Tetrahedron Lett. 2005, 46, 7977–7979. (c)
Marcos, C. F.; Marcaccini, S.; Pepino, R.; Polo, C.; Torroba, T. Synthesis
2003, 691–694. (d) Marcaccini, S.; Pepino, R.; Marcos, C. F.; Polo, C.;
Torroba, T. J. Heterocycl. Chem. 2000, 37, 1501–1503. (e) Bossio, R.;
Marcos, C. F.; Marcaccini, S.; Pepino, R. Synthesis 1997, 1389–1390. (f)
Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Heterocycles 1997, 45,
1589–1592. (g) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R.
Tetrahedron Lett. 1997, 38, 2519–2520.
(19) (a) Bossio, R.; Marcaccini, S.; Paoli, P.; Papaleo, S.; Pepino, R.;
Polo, C. Liebigs Ann. Chem. 1991, 843–849. (b) Bossio, R.; Marcaccini, S.;
Pepino, R. Liebigs Ann. Chem. 1993, 1229–1231. (c) Bossio, R.; Marcaccini,
S.; Papaleo, S.; Pepino, R. J. Heterocycl. Chem. 1994, 31, 397–399.
(20) (a) Nair, V.; Menon, R. S.; Deepthi, A.; Devi, B. R.; Biju, A. T.
Tetrahedron Lett. 2005, 46, 1337–1339. (b) Nair, V.; Dhanya, R.; Viji, S.
Tetrahedron 2005, 61, 5843–5848. (c) Habashita, H.; Kokubo, M.; Hamano,
S.; Hamanaka, N.; Toda, M.; Shibayama, S.; Tada, H.; Sagawa, K.;
Fukushima, D.; Maeda, K.; Mitsuya, H. J. Med. Chem. 2006, 49, 4140–
4152. (d) Shaabani, A.; Rezayan, A. H.; Ghasemi, S.; Sarvary, A. Tetra-
hedron Lett. 2009, 50, 1456–1458.
Semiempirical calculations on adduct 5a reveal that parti-
cularly stable conformations exhibit a parallel arrangement
of their chromone and glyoxylamide aromatic rings. This
geometry minimizes unfavorable steric interactions and
possibly favors π-stacking stabilization. On the other hand,
in such conformations only one side of the chromone ring is
available to the nucleophilic attack of benzylamine
(Figure 1). We hypothesize that the carbonyl of the side
chain amide group can form a hydrogen bond with the
nucleophilic amine, “guiding” its approach to chromone
carbon 2. Furthermore, the amide carbonyl can act as a
general basic catalyst, enhancing the nucleophilic character
of the amine and facilitating a successive transfer of the
amine proton to the forming 40 hydroxyl group.
(21) (a) Ugi, I.; Meyr, R. Angew. Chem. 1958, 70, 702–703. (b) Ugi, I.;
€
Meyr, R.; Fetzer, U.; Steinbruckner, C Angew. Chem. 1959, 71, 386.
(22) Sabitha, G. Aldrichim. Acta 1996, 29, 15–25.
J. Org. Chem. Vol. 74, No. 17, 2009 6889

Marcaccini et al.
JOCNote
TABLE 1. Synthesis of Spiropyrrolidinonechromanones 7a-j
diastereomeric spiranes. Accordingly, both 7c and 7d were
obtained as practically equimolar mixtures of two diastereo-
mers as judged by its NMR spectra. We have also performed
separate reactions with (R)-R-methylbenzylamine and with
racemic (()-R-methylbenzylamine (results not shown), ob-
taining an identical mixture of diastereomers as when using
the S enantiomer (Table 1, entry d).
In summary, we have developed a practical method that
allows obtaining, in a one-pot two-step sequential reaction,
highly functionalized spiropyrrolidinonechromanones
with a wide variety of substituents. Furthermore, we have
shown that this reaction sequence can take place with high
diastereoselectivity. The experimental simplicity of this
method and the possibility to isolate the final products by
filtration with a reasonable grade of purity makes it suitable
for the combinatorial synthesis of libraries of potentially
bioactive spiranes.
yielda,b
(%)
R1
R2
R3
R4
R5
a
b
c
d
e
f
g
h
i
CH3 C6H5
CH3 C6H5
CH3 C6H5
CH3 4-Cl-Ph
CH3 4-Cl-Ph
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
H
PhCH2
3-Cl-PhCH2
rac-C5H9OCH2
(S)-PhCH(CH3)
72
68
70
56
H
H
H
H
c
3,4-(OCH2O)PhCH2 57
H
H
H
H
H
3-Cl-Ph
3-Cl-Ph
PhCH2
4-CH3-Ph (CH3)3C
C6H5
OCH3 PhCH2
OCH3 4-Cl-PhCH2
H
H
63
58
3,4-(OCH2O)PhCH2 45
3-Cl-PhCH2
PhCH2
74
68
j
2,6-(CH3)2- H
Ph
aExperimental procedure and representative data are
b
found in the Experimental Section. Yields correspond to
pure isolated products; procedures have not been optimized.
cC5H9OCH2: 2-tetrahydrofurfurylmethyl.
The structure shown in Figure 1 is the only stable con-
formation on which the amide carbonyl can assist the attack
of benzylamine on the less hindered face of (S)-5a. Nucleo-
philic addition of benzylamine on the C-2 less hindered Re
face of (S)-5a should produce sp3-hybridized C-2 with S
configuration. In a concerted mechanism, the Re face of the
resulting transitional anion on C-3 must attack the neighbor-
ing glyoxylamide carbonyl, resulting in the formation of
two stereocenters of respective configurations 3R and 20S.
According to this model, π-π interaction of the benzylamine
and chromone rings will further stabilize the transition state.
Analogously, attack of benzylamine on enantiomeric Ugi
adduct (R)-5a would obviously give the opposite spiranic
enantiomer.
The structure and relative stereochemistry of compound 7a
was unequivocally determined by monocrystal X-ray diffrac-
tion analysis (see the Supporting Information). Hence, 7a was
assigned the structure (2S,20S,3R,40S)-2-(benzylamino)-N-cy-
clohexyl-40-hydroxy-6-methyl-4,50-dioxo-10,40-diphenylspiro-
[chromane-3,30-pyrrolidine]-20-carboxamide (Figure 1). This
structure is in accordance with the proposed mechanism.
In order to study the scope of the method, we applied
the same procedure to different combinations of chromo-
nes (1), aromatic or aliphatic amines (2), aromatic or alipha-
tic isocyanides (3), glyoxilic acids (4), and primary amine
nucleophiles (6). In all cases, we obtained the expected
spiropyrrolidinochromanones 7a-j in moderate yields
(Table 1). Hence, the reaction was shown to be tolerant
to a wide range of substituents on the different compo-
nents. The products have been characterized by the usual
spectroscopic techniques, and their IR, 1H NMR, 13C NMR,
MS, and HRMS spectroscopic data are in agreement
with the proposed structure. Table 1 summarizes the
results of the tandem Ugi-nucleophilic addition-cycliza-
tion process.
Experimental Section
General Procedure for the Synthesis of Spiropyrrolidinochro-
manones. 3-Formylchromone or 6-methyl-2-formylchromone
(1) (2 mmol) was dissolved in MeOH (4 mL). The aniline (2)
(2 mmol), isocyanide (3) (2 mmol), and phenylglyoxilic acid (4)
(2 mmol) were successively added, and the resulting mixture was
stirred for 24-48 h at rt, readily leading to the formation of the
expected Ugi four-component adduct (5), which was not iso-
lated. Evaporation of the solvent, resuspension in Et2O (5 mL),
and addition of amine 6 (4 mmol) led to the immediate forma-
tion of a precipitate. The reaction mixture was stirred at rt
overnight, and the solid was filtered and washed with i-Pr2O,
yielding spiropyrrolidinochromanone (7) practically pure. For
analytical purposes the product was further purified by recrys-
tallization from EtOH.
Representative Data. 2-(Benzylamino)-N-cyclohexyl-40-hy-
droxy-6-methyl-4,50-dioxo-10,40-diphenylspiro[chromane-3,30-
pyrrolidine]-20-carboxamide (7a): obtained as a white solid
(72%); mp 172-172.5 °C; IR (cm-1) 3440, 2933, 1682, 1636,
1493, 1284, 698; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, 1H,
J=7.3 Hz), 8.14 (s, 1H), 7.57 (d, 2H, J=7.8 Hz), 7.50 (t, 2H, J=
7.7 Hz), 7.36 (t, 1H, J=7.3 Hz), 7.21-7.07 (m, 6H), 7.04 (d, 1H,
J=8.4 Hz), 6.90 (m, 4H), 6.43 (d, 1H, J=8.4 Hz), 5.70 (d, 1H, J=
12.0 Hz), 5.16 (s, 1H), 3.87-3.74 (m, 3H), 3.54-3.47 (m, 1H), 2.07
(s, 3H), 1.61-0.71 (m, 10H) ; 13C NMR (100 MHz, DMSO-d6) δ
190.4 (C), 171.4 (C), 168.9 (C), 153.9 (C), 139.0 (C), 136.9 (CH),
135.4 (C), 129.0 (C), 128.8 (CH), 128.2 (CH), 127.7 (CH), 127.7
(CH), 127.2 (CH), 126.9 (CH), 126.6 (CH), 126.0 (CH), 125.6
(CH), 125.0 (CH), 120.3 (C), 118.0 (CH), 88.8 (CH), 81.6 (C), 64.1
(CH), 61.3 (C), 49.4 (CH2), 48.4 (CH), 31.3 (CH2), 30.9 (CH2),
24.9 (CH2), 24.0 (CH2), 23.7 (CH2), 19.8 (CH3); MS (FAB) m/z
630 (Mþ þ 1, 56), 478 (6), 405 (100); HRMS (FAB) calcd for
C39H40N3O5 630.2968, found 630.2969.
Acknowledgment. We acknowledge financial support
from the Instituto de Salud Carlos III (PI081234) and Junta
de Extremadura and FEDER (PRI07A032 and PRI08-
A039).
Importantly, when nonchiral amines were used as nucleo-
philes, the product was always obtained as a single diastereo-
mer (Table 1, entries a, b, e-j). We presume compounds 7b,
e-j all have the same stereochemistry as 7a, as they must be
formed by a similar reaction mechanism. In the case of using
chiral amines (Table 1, entries c and d), its addition to both
Ugi adduct enantiomers must result in the formation of two
Supporting Information Available: Characterization data of
the products, copies of 1H and 13C NMR spectra, X-ray crystal-
lographic data of 7a, and the CIF file for structure 7a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
6890 J. Org. Chem. Vol. 74, No. 17, 2009