A rapid, one-pot, microwave-influenced synthesis of spiro-2,5- diketopiperazines via a cascade Ugi/6-exo-trig aza-Michael reaction

Article abstract of DOI:10.1021/jo102305q

A rapid, cascade reaction process has been developed to access biologically validated spiro-2,5-diketopiperazines. The facile and environmentally benign method capitalizes on commercially available starting reagents for a sequential Ugi/6-exo-trig aza-Mic

Full text of DOI:10.1021/jo102305q

NOTE
pubs.acs.org/joc
A Rapid, One-Pot, Microwave-Influenced Synthesis of Spiro-2,5-
diketopiperazines via a Cascade Ugi/6-Exo-Trig Aza-Michael Reaction
Soumava Santra and Peter R. Andreana*
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
S Supporting Information
b
ABSTRACT: A rapid, cascade reaction process has been developed
to access biologically validated spiro-2,5-diketopiperazines. The facile
and environmentally benign method capitalizes on commercially
available starting reagents for a sequential Ugi/6-exo-trig aza-Michael
reaction, water as a solvent, and microwave irradiation without any
extraneous additives.
he vast majority of prescription drugs are small molecule
natural products, derivatives thereof, or synthetically de-
T
signed constructs aimed at a biological target possessing some
specific function.1 The involvement of heteroatoms for hetero-
cyclic small molecule scaffolds has long been known to be a
crucial component in the drug discovery process. Despite the
tremendous advancements in the areas of synthetic and combi-
natorial chemistries, suitably functionalized heterocyclic “privi-
leged” scaffolds are not easily or readily accessible. Consequently,
the exponentially increased cost of lead generation and optimiza-
tion has led to the introduction of far fewer drugs over the past
decade.2 Thus, a platform that allows rapid entry into new drug
leads and expedites optimization is a necessary component to
overcome these limitations. Concerted efforts among the scien-
tific community to design and develop new reactions and
strategies that rapidly access heterocyclic scaffolds are being
pursued.3
Figure 1. Biologically relevant spiro-DKPs.
small molecules used in proteomics-based approaches for new
therapeutics.10
There are few literature reports describing the synthesis of
spiro-DKPs. These include a ring-closing metathesis strategy,11a
a post-Ugi cyclization,11b a Diels-Alder type reaction,11c an
intramolecular aminolysis process,11d,11e as well as others.11f-11i
Many of the reported methods are lengthy and employ harsh
conditions including highly toxic reagents. Recently, however, we
reported a facile, one-pot microwave influenced synthesis of
DKPs via a multicomponent reaction cascade.12 As an extension
of this strategy and a means to overcome shortcomings with
current methodology, we report on the synthesis of spiro-DKPs
via a cascade Ugi four component coupling (U-4CC)/6-exo-trig
aza-Michael reaction under microwave irradiation using water as
the solvent.
As part of an ongoing research program aimed at developing a
rapid drug discovery platform that includes the concepts of green
chemistry, we became interested in spiro-2,5-diketopiperazines
(spiro-DKPs) because of their known biological effects. Reports
note similarities in effects to β-turn mimetics, and they have also
been shown to be specific glycogen phosphorylase inhibitors
(A)4 as an emerging therapeutic approach to treat type 2
diabetes.5 Moreover, they also possess antiproliferative effects
(B), anti-inflammatory activity (B), and neuroprotective effects
(C).6 Recently, spiro-DKP D exhibited high potency against
drug-resistant human tumor cell lines, as measured by IC50.7
Isolated spiro-DKP E from cosmopolitan fungus Aspergillus
versicolor B-17 has also been shown to possess remarkable
cytotoxicity against murine cancer cell line tsFT210
(Figure 1).8 Aplaviroc (F), which was developed by GlaxoS-
mithKline, has potent anti-HIV activity as well as inhibitory
effects against highly multidrug-resistant variants of HIV-1
through binding to the CCR5 coreceptor, which is crucial for
entry of HIV type-1 into host cells.9 Furthermore, spiro-DKPs
are valuable synthetic precursors that can lead to R,R-disubsti-
tuted constrained amino acids, which have become important
We initially elected to use p-methoxybenzylamine (PMB-
NH2; 1a), cyclopentanone (2a), fumaric acid monoethyl ester
(3a), and n-butyl isocyanide (4a) in the U-4CC reaction
(Scheme 1). Purified acyclic product 5a was then subjected to
microwave irradiation utilizing various temperatures, pressures,
Received: November 19, 2010
Published: February 25, 2011
r
2011 American Chemical Society
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and times to find optimal conditions for the cyclization product
6a (Table 1).
pot protocol for efficiency and minimization of chromatography. A
two stage strategy was employed to ensure that the U-4CC reaction
was not out competed by the Passarini three-component coupling
(P-3CC) reaction. We further extended our studies to examine the
substrate scope of this novel one-pot strategy.
When the microwave was equilibrated to 300 W, 200 °C, and
18.5 bar for 1 h, spiro-DKP 6a was obtained in 85% yield
(Table 1). It must be noted that the aza-Michael reaction, for
the acyclic Ugi product 5a derived from a cyclic ketone,13 took a
substantially longer reaction time to complete as compared to the
acyclic Ugi product derived from an aldehyde.12 A likely explana-
tion could be due to the ring strain of the resulting spiro-DKP.
Extending the microwave irradiation time-course past 60 min
only led to decomposition of starting material. We also noted
that when purified 6a alone was subjected to microwave irradia-
tion for greater than a 60 min time frame, under the exact
conditions as noted in Table 1, degradation was observed.
With conditions for the 6-exo-trig aza-Michael pathway in hand,14
we re-examined the reaction for a potential one-pot protocol.
Utilizing a two-stage microwave irradiation strategy: (i) stage 1, 1
M LiCl or H2O, 300 W, 70 °C, 10 bar, 1 h, then (ii) stage 2, 300 W,
200 °C, 18.5 bar, 1 h; we attempted to obtain spiro-DKPs in a one-
In general, the process is compatible with a range of cyclic
ketones, amines, and isocyanides (Table 2). Although fumaric
acid monoethyl ester (3a) has been utilized exclusively, other
Michael acceptors can also be employed.15 Despite scarce
literature reports on the use of cyclobutanone (2e) in the
U-4CC,16 2e worked well with no unwanted side reactions or
products. During the progress of this work, Pirrung and co-
workers also reported that cyclobutanone (2e) reacted in the
U-4CC and P-3CC reactions. They attributed the low LUMO
energy and suitable hydrophobicity of cyclobutanone (2e) for
the success of the coupling reaction and utilized this key
component for the construction of dipeptides having identical
physical properties to that of aspartame.17 Furthermore, it must
be noted that the cyclobutane ring, embedded in the spiro-DKP
product 6e, did not undergo ring opening under high tempera-
ture and pressure, contrary to literature reports.18
In order to understand the reactivity difference of acyclic Ugi
product 5 derived from cyclic ketones over aldehydes in this
cascade process, we replaced 1a with p-hydroxybenzyl amine
(PHB-NH2; 1e) while other coupling components were kept the
same as noted in entry 2 (Table 1). Since n-butyl isocyanide (4a)
is a less bulky isocyanide, formation of spiro-DKP 6f was initially
expected.12 However, we were able to isolate biologically relevant
2-azaspiro[4.5]deca-6,9-diene-3,8-dione (7a, 85%) via a 5-exo-
trig Michael pathway (Scheme 2). Replacement of 4a with bulky
tert-butyl isocyanide (4c) using the same reaction protocol
afforded 7b in 80% yield (Scheme 2).12 Important to note is
that 7a and 7b were obtained in a shorter time period (40 min vs
60 min) as compared to 6a-e.
Scheme 1. Two-Step Protocol for the Synthesis of Spiro-
DKP 6a
Table 1. Optimization of the Microwave Irradiationa Con-
ditions for the 6-Exo-Trig Aza-Michael Cyclization
time
power
(W)
T
pressure
(bar)
yield of 6a
(%)c
entry solventb (min)
(°C)
A proposed mechanism for the formation of spiro-DKPs is
shown in Scheme 3. We argue that the acyclic Ugi product 5 can
adopt either a trans-amide (500) or cis-amide (5000) conformation
in equilibrium favoring 500 at room temperature.19 Due to
the ring size of the spiro-DKPs, the acyclic Ugi product in the
cis-amide conformation (5000) can only undergo a 6-exo-trig aza-
Michael reaction giving 6.20 Moreover, the cis-amide conforma-
tion brings the N lone pair (HOMO) and π* of the Michael
1
2
3
4
5
6
H2O
H2O
H2O
H2O
H2O
H2O
20
30
30
40
50
60
300
300
300
300
300
300
200
200
200
200
200
200
18
50
60
65
70
80
85
18
18.5
18.5
18.5
18.5
a CEM Discover Microwave. b 2.5 mL. c Isolated.
Table 2. Substrate Scope of the Microwave-Influenceda One-Pot Synthesis of Spiro-DKPs
entry
R1
R2
R3
R4
compd/% yieldb
1
2
3
4
5
cyclopentyl (2a)
cyclohexyl (2b)
4-thio-pyran (2c)
4-pyran (2d)
ethoxycarbonyl (3a)
ethoxycarbonyl (3a)
ethoxycarbonyl (3a)
ethoxycarbonyl (3a)
ethoxycarbonyl (3a)
4-methoxybenzyl (1a)
4-methoxybenzyl (1a)
3,4-dimethoxybenzyl (1b)
3,4-methylenedioxybenzyl (1c)
benzyl (1d)
n-butyl (4a)
n-butyl (4a)
benzyl (4b)
benzyl (4b)
benzyl (4b)
6a/85
6b/80
6c/82
6d/83
6e/98
cyclobutane (2e)
a CEM Discover Microwave. b Isolated.
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Scheme 2. Use of p-Hydroxybenzylamine Provides
2-Azaspiro[4.5]deca-6,9-diene-3,8-diones (7a and 7b)
contiguous bonds, a tertiary spiro-carbon center, and one new
stereogenic center. Further structural, functional, and substituent
diversity can be achieved from these compounds through
chemical manipulation. Future experiments will be aimed at
evaluating antifungal, antileukemic, and anti-HIV properties of
the spiro-DKPs via SAR studies. In addition, efforts are underway
to extend the methodology to access other spiro compounds that
will contribute to a small molecule focused library.
’ EXPERIMENTAL SECTION
General Procedure 1 for Spiro-DKPs (Commencing from
the Acyclic Ugi Product). To a 10 mL vial equipped with a magnetic
stirring bar was added 0.12 mmol (50 mg) of purified acyclic Ugi product
(e.g., 5a) and the mixture taken up in a mixture of 1.5 mL of 1 M LiCl and
1 mL of MeOH or 2.5 mL of distilled H2O with a pH of 7.0. The vial was
capped according to the manufacturer's suggestion and placed in the
microwave cavity. The reaction ran for 1 h at 200 °C, 18.5 bar, and
300 W. After the vial was cooled to room temperature, ethyl acetate was
added, and the mixture was shaken vigorously. The organic layer was
separated, and the aqueous layer was extracted with ethyl acetate (2 ꢀ 2
mL). The organic layers were combined, dried over Na2SO4, and then
filtered. The filtrate was dried under vacuum and purified by silica gel column
chromatography using a 1:2 mixture of ethyl acetate and hexane as the eluent.
General Procedure 2 for the One-Pot Synthesis of Spiro-
DKPs (Commencing from Four Starting Materials). To a 10
mL vial equipped with magnetic stirring bar, 4-methoxybenzylamine
(1a, 15 mg, 0.11 mmol), cyclopentanone (2a, 9.3 mg, 0.11 mmol),
furmaric acid monoethyl ester (3a, 16 mg, 0.11 mmol), and n-butyl
isocyanide (4a, 9.3 μL, 0.11 mmol) were added to a mixture of 1.5 mL of 1
M LiCl and 1 mL of MeOH or 2.5 mL of distilled H2O with a pH of 7.0. The
vial was capped according to the manufacturer's suggestion and placed in the
single-mode microwave cavity. The microwave was run at two separate
stages: (1) 1 h at 70 °C, 10 bar, and 300 W; (2) 1 h, 200 °C, 18.5 bar, and
300 W. After the vial was cooled to room temperature, ethyl acetate was
added, and the reaction mixture was shaken vigorously. The organic layer
was separated, and the aqueous layer was extracted again with ethyl acetate
(2 ꢀ 2 mL). The organic layers were combined and washed with NaHCO3
(2 ꢀ 3 mL), 1 N HCl (2 ꢀ 3 mL), and finally with brine (2 ꢀ 3 mL). The
organic layer was separated. All aqueous layers were combined and extracted
with additional ethyl acetate (3 mL). The organic layers were then
combined, dried over Na2SO4, and filtered. The filtrate was dried under
vacuum and purified using silica gel column chromatography employing a
1:2 mixture of ethyl acetate and hexanes as the eluent.
Scheme 3. Proposed Mechanism for the Formation of Spiro-
DKPs
acceptor (LUMO) in the same plane for optimum orbital overlap
and therefore favors the B€urgi-D€unitz angle of attack.21 Thus, in
the first step, with microwave irradiation 500 isomerizes to 500 due
to a low energy barrier,19 ultimately forming the zwitterionic boat
intermediate 8.22 Intermediate 8 is believed to be stabilized by
hydrogen bonding which assists in absorbing microwave
energy.23 Protonation-deprotonation provides the final product
6. When an electron-donating group (Z = OMe) is present on
the aryl-R3 component, a 5-exo-trig Michael reaction can likely
take place to form the unstable intermediate 9, which in turn can
rapidly reverse to form the cis-amide 500. This is most likely due to
the highly reversible oxocarbenium ion in 9, which is not stable
yet does not undergo Me-O bond cleavage under our reaction
conditions.12,24 When, Z = H, stable 2-azaspiro[4.5]deca-6,9-
diene-3,8-dione zwitterionic intermediate (10) forms and de-
protonation-protonation provides the final product 7 regardless
of substituents on R4. This is surprising since less bulky iso-
cyanides (e.g., 4a) were shown to provide DKPs via a 6-exo-trig
aza-Michael pathway.12 A likely explanation could be that the
5-exo-trig Michael pathway occurs at a faster rate due to a
favorable trans-amide conformation. This further validates our
hypothesis that the spiro-DKP formation occurs via a cis-amide
conformation.
Ethyl 2-(5,8-Dibenzyl-6,9-dioxo-5,8-diazaspiro[3.5]nonan-
7-yl)acetate (6e). 1H NMR (500 MHz, CDCl3): δ 7.21-7.37 (m, 8
H, Ph), 7.16-7.21 (m, 2 H, Ph), 5.17 (d, 1 H, J = 15.3 Hz, -CH2Ph), 5.10
(d, 1H, J= 15.9 Hz, -CH2Ph), 4.70 (d, 1 H, J= 15.9 Hz, -CH2Ph), 4.38 (t
from dd overlap, 1 H, J = 5.5 Hz, Hc), 4.29 (d, 1 H, J = 15.3 Hz, -CH2Ph),
4.10 (q, 2 H, J = 7.3 Hz, -OCH2CH3), 2.85 (dd, 1 H, J = 16.2, 5.5 Hz, Hd),
2.80-2.84 (m, 1 H, cyclobutane), 2.78 (dd, 1 H, J = 16.2, 5.5 Hz, Hd),
2.46-2.69 (m, 3 H, cyclobutane), 2.07-2.19 (m, 1 H, cyclobutane), 1.78-
1.89 (m, 1 H, cyclobutane), 1.23 (t, 3 H, J = 7.3 Hz, -OCH2CH3). 13
C
NMR (100 MHz, CDCl3): δ 169.7, 169.6, 166.5, 137.8, 136.1, 128.9, 128.7,
127.9, 127.2, 126.4, 63.1, 61.2, 56.2, 53.4, 48.0, 46.4, 37.1, 34.4, 31.2, 14.5,
14.1. HRMS (EIMS): calcd for C25H28N2O4 420.2049, found 420.2051.
’ ASSOCIATED CONTENT
In summary, we have developed a rapid and efficient process
for the synthesis of biologically relevant spiro-2,5-diketopiper-
azines from readily available starting materials. The reaction
proceeds via a cascade U-4CC/6-exo-trig aza-Michael reaction in
water under the influence of microwaves and generates four
S
Supporting Information. Experimental details and char-
b
acterization of new compounds 5a and 6a-e including 1H, 13C,
and gDQFCOSY spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
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NOTE
’ AUTHOR INFORMATION
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Corresponding Author
*E-mail: pra@chem.wayne.edu.
’ ACKNOWLEDGMENT
We thank Wayne State University for start-up funds. S.S.
thanks WSU for a 2009 Summer Dissertation Fellowship.
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