Diastereoselective synthesis of diketopiperazine bis-α,β- epoxides

Article abstract of DOI:10.1021/jo102096d

Functionalized diketopiperazines (dioxopiperazines) are an important class of molecules in medicinal chemistry and material science. Herein we report a diastereoselective synthesis of diketopiperazine bis-α,β-epoxides via the oxidation of exocyclic olefin

Full text of DOI:10.1021/jo102096d

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rigidity, hydrogen bond donor and acceptor groups, and resis-
Diastereoselective Synthesis of Diketopiperazine
Bis-r,β-epoxides
tance to proteolysis in vivo.11-13 The structural complexity and
the promising biological activities associated with such diketo-
piperazines continue to inspire synthetic chemists.
Shin Ando, Amy L. Grote, and Kazunori Koide*
While 2,5-diketopiperazine has been the subject of syn-
thetic studies dating back to the 1900s by Emil Fischer
et al.,14 it has been studied more intensively in recent years.
Typically, chiral amino acid derivatives are dimerized and
cyclized, allowing for substitution at the C3 and C6 posi-
tions.13,15 As a means to introduce desired substituents at the
3 and 6 positions of the 2,5-diketopiperazines, a majority of
synthetic studies have been devoted to the elimination-
nucleophilic attack of compounds A in the presence of nucle-
ophiles, often under acidic conditions, to form B (Scheme 1a).16
This approach was employed in the synthetic studies of dike-
topiperazine natural products,17-21 including the landmark
total synthesis by Kishi and co-workers.22
Department of Chemistry, University of Pittsburgh,
219 Parkman Avenue, Pittsburgh, Pennsylvania 15260,
United States
koide@pitt.edu
Received October 27, 2010
We became interested in alternative approaches toward
functionalizing 2,5-diketopiperazines (Scheme 1b). Mono-
epoxide variants of C have been previously reported as a
means to further elaborate the DKP framework.23-25 Our
group set out to establish a method for accessing bis-ep-
oxides C, which we thought would serve as a precursor to
more complex DKPs. Specifically, we wished to exploit the
dual reactivity of bis-epoxides C under acidic and basic con-
ditions to control the regioselectivity of the subsequent ring-
opening. We envisioned that under acidic conditions, com-
pounds D could be formed from C via acyliminium ion
intermediates similarly to Scheme 1a. Under basic condi-
tions, compounds E could be formed by nucleophilic attack
at the less-hindered carbons of compounds C. In order to test
this hypothesis, it was necessary to synthesize compounds
C. Herein, we report a diastereoselective method to prepare
a variety of bis-epoxides C using a two-step bromohydra-
tion-etherification pathway. As we will describe in a sepa-
rate report in due course, these bis-epoxides are pivotal
intermediates for complex 2,5-diketopiperazines.
Functionalized diketopiperazines (dioxopiperazines) are
an important class of molecules in medicinal chemistry
and material science. Herein we report a diastereoselec-
tive synthesis of diketopiperazine bis-R,β-epoxides via the
oxidation of exocyclic olefins. Although six diastereo-
mers may be formed by this approach, only one or two of
them were observed.
2,5-Diketopiperazines (also known as piperazine-2,5-diones
and 2,5-dioxopiperazines) are cyclic dipeptides and part of
many biologically active natural products that include poly-
thiodiketopiperazines MPC1001s,1,2 emestrin,3 and bionectin4
among others.5 The 2,5-diketopiperazine has been an im-
portant scaffold in material science6-8 and medicinal chem-
istry9,10 and is often utilized for biological properties associated
with its mimicry of peptidic pharmacophores, conformational
The attempted condensation of piperazine-2,5-dione 1 with
benzaldehyde under various conditions did not yield the corre-
sponding aldol product 5a, which is consistent with the literature
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DOI: 10.1021/jo102096d
r
Published on Web 01/20/2011
J. Org. Chem. 2011, 76, 1155–1158 1155
2011 American Chemical Society

Ando et al.
JOCNote
SCHEME 1. (a) Approach Employed by Others To Access
Substituted Diketopiperazines; (b) Our Proposed Approach
SCHEME 2. Preparation of Compounds 6a-ha
(Scheme 2).26 However, the N-acetylated derivative 2 could
be coupled with benzaldehyde under basic conditions (Et3N
in DMF, 120 °C) to form alkene 5a in 72% yield.26 Other
aromatic aldehydes also reacted smoothly to form 5b-h in
52-96% yields (Table 1). The acetyl group drove the other-
wise thermodynamically unfavorable aldol reaction to com-
pletion by the aldol addition-acetyl migration-elimination
cascade (2 to 5 via 3 and 4) to form exclusively cis products as
shown in Scheme 2.26 One plausible explanation for the cis
selectivity is an E1cb pathway through the transition state
8β. An alternative transition state, 8r, is presumably dis-
favored due to the steric repulsion between the ion pair and
the aromatic ring. This mechanism would mitigate an un-
desired stereospecific E2 pathway, accounting for high yields
in some cases. As has been observed with similar diketopi-
perazines, the alkene intermediates 5a-h were readily crys-
tallized and exhibited extraordinarily poor solubility in a
variety of protic and aprotic solvents.27-29 This is presum-
ably due to the combination of intermolecular hydrogen bond-
ing and π-π stacking capabilities, which promote tight
crystal packing.29,30 Due to the poor solubility, the products
from this reaction were crystallized and used in the following
step without 13C NMR analysis.
aConditions: (i) Ac2O (neat), reflux, 5 h, 90%; (ii) ArCHO (2.5 equiv),
Et3N (3.0 equiv), DMF, 120 °C, 7-17 h; see Table 1 for isolated yields;
(iii) MeI (4.0 equiv), NaH (for 5a-f) or K2CO3 (for 5g and 5h)
(3.0 equiv), DMF, 25 °C, 12 h; see Table 1 for isolated yields.
TABLE 1. Isolated Yields for the Formation of Compounds 5 and 6
product
yield (%)
product
yield (%)
5a
5b
5c
5d
5e
5f
72
52
68
56
88
96
54
68
6a
6b
6c
6d
6e
6f
60
61
89
78
45
46
60
50
5g
5h
6g
6h
side products from this reaction were the result of O-methy-
lation to form highly conjugated imidates, as represented by
7h. These O-methylated byproducts were significantly more
hydrophobic than their N-methylated counterparts and could
be readily separated by silica gel chromatography.
With the N-methylated intermediates in hand, our studies
continued with an examination of epoxidation conditions for
the phenyl-substituted compound 6a. The use of both nu-
cleophilic and electrophilic reagents such as m-CPBA,25
DMDO,24 H2O2/NaOH, and TBHP/VO(acac)2 either showed
no reaction or resulted in monoepoxidation. The desired bis-
epoxidation could be accomplished by means of a two-step
sequence involving bromohydration with NBS and H2O,
followed by epoxide ring closing of the crude bromohydrin
under basic conditions (Table 2).23 Of the six potential
We have been interested in the MPC1001 class of natural
products, all of which are N-alkylated in the diketopiperazine
rings.1,2 Thus, we proceeded to methylate the secondary amides
5a-h with MeI and NaH or K2CO3 to form the tertiary
amides 6a-h in 45-89% yields (Table 1).31 The most notable
(27) Ajo, D.; Casarin, M.; Bertoncello, R.; Busetti, V.; Ottenheijm,
H. C. J.; Plate, R. Tetrahedron 1985, 41, 5543–5552.
ꢀ
(28) Ongania, K. H.; Granozzi, G.; Busetti, V.; Casarin, M.; Ajo, D.
Tetrahedron 1985, 41, 2015–2018.
(29) Williams, L. J.; Jagadish, B.; Lyon, S. R.; Kloster, R. A.; Carducci,
M. D.; Mash, E. A. Tetrahedron 1999, 55, 14281–14300.
(30) Palacin, S.; Chin, D. N.; Simanek, E. E.; MacDonald, J. C.;
Whitesides, G. M.; McBride, M. T.; Palmore, G. T. R. J. Am. Chem. Soc.
1997, 119, 11807–11816.
(31) Kubo, A.; Saito, N.; Yamoto, H.; Yamauchi, R.; Hiruma, K.; Inoue,
S. Chem. Pharm. Bull. 1988, 36, 2607–2614.
1156 J. Org. Chem. Vol. 76, No. 4, 2011

Ando et al.
JOCNote
SCHEME 3. Control Experiments To Examine the Reversibil-
ity of the Two-Step Sequence: (a) Possible Bromide-Promoted
Conversion of S,S,S,R-9a to S,S,S,S-9a; (b) Possible Base-Cat-
alyzed Epimerization between syn-F and anti-F
FIGURE 1. Structures of six possible bis-epoxides.
compounds showed one peak for the methine hydrogen
atoms, indicating C2 symmetry (S,S,S,S-9b-h or S,R,R,
S-9b-h, Figure 1). All of these compounds also exhibited
strong NOE signals between the N-methyl groups and
methine protons, indicating the cis relationship between
them. The only structures that could be consistent with these
data were S,S,S,S-9b-h.
The relative stereochemistry of S,S,S,R-9b-h was deter-
mined in a slightly different manner. These compounds showed
a significant difference on the chemical shift of the two
N-methyl groups (Δδ = ∼0.7 ppm in all of the cases; Table
S1, Supporting Information), indicating that the two N-methyl
groups in each compound were in different proximity to the
aromatic rings. This excluded S,R,S,R-9 and S,S,R,R-9.
NOE experiments would not distinguish between S,S,S,R-
9 and S,S,R,S-9. However, the 1H NMR analysis of a deriv-
ative (cf. compound D in Scheme 1b) of compound S,S,S,R-
9a revealed that the relative stereochemistry at the two
benzylic positions after epoxide opening was opposite.32 All
together, the structures that are most consistent with these
spectroscopic data are S,S,S,R-9b-h. To further support the
structures, we compared the 1H NMR spectra of these com-
pounds with that of S,S,S,R-9a (confirmed by X-ray crystal-
lographic analysis) as shown in Table S1 (Supporting Infor-
mation).
The observed diastereoselectivity clearly demonstrates
that there is some steric or electronic bias directing the stereo-
chemical outcome. Although we cannot rule out the possi-
bility that some of the six possible diastereomers (see Scheme
S2 in the Supporting Information) decomposed in a stereo-
specific manner, it is surprising that only one or two diaster-
eomers were isolated. When the aromatic moieties were phenyl
groups, the asymmetric compound S,S,S,R-9a was the major
product (60% yield). The minor and symmetric product, S,S,
S,S-9a might be more thermodynamically favored because
neither of the phenyl groups is proximal to the N-methyl
group. Therefore, with the phenyl group, the reaction might
be kinetically controlled.
TABLE 2. Observed Diastereoselectivity in the Bis-epoxidation of 6
yielda (%)
product
solvent (step i)
temp (°C) (step ii)
SSSS
SSSR
9a
9b
9c
9d
9e
9fb
9g
9h
MeCN
25
25
reflux
reflux
25
25
25
25
34
62
56
51
54
6
60
1,4-dioxane
1,4-dioxane
MeCN
MeCN
MeCN
<1
<1
<1
24
55
<10
37
MeCN
MeCN
75
42
aIsolated yield. bIsolated as a mixture of S,S,S,S- and S,S,S,R-9.
diastereomeric epoxides(Figure1), onlytwowere observedfor
the phenyl-substituted analogue. The X-ray crystallographic
analysis of these two compounds (Figures S54 and S55 in the
Supporting Information) showed that they were the C2-sym-
metric compound S,S,S,S-9a (and its enantiomer) and the
asymmetric compound S,S,S,R-9a (and its enantiomer). The
two-step epoxidation strategy was applied to the substrates
shown in Table 2. For most substrates, the major product
was the C2-symmetric diastereomer S,S,S,S-9 (and its
enantiomer) rather than the asymmetric diastereomer S,S,S,
R-9 (and their enantiomers). Scheme S1 in the Supporting
Information shows the compounds that did not provide the
desired bis-epoxides.
With a π-donor (Br or O) at the ortho or para position
(compounds 6b, 6c, 6d, 6e, and 6g), the symmetric com-
pounds S,S,S,S-9 were the major products (Table 2). This
suggested that the two-step process might be reversible with
these π-donors at the ortho or para position, which would
The relative stereochemistry of S,S,S,S-9b-h was de-
termined by 1H NMR spectroscopic analysis. All of these
(32) Ando, S.; Koide, K. Submitted for publication.
J. Org. Chem. Vol. 76, No. 4, 2011 1157

Ando et al.
JOCNote
SCHEME 4. Possible Pathways Leading to S,S,S,S-9 and S,S,
S,R-9
other methods for the preparation of piperazine-2,5-diones
have been reported, our route is notable for its ability to
produce a varietyof aromatic analogues and promises accessi-
bility to more complex R- and β-substituted substrates. Our
progress toward achieving the goal depicted in Scheme 1b
will be reported in due course.
Experimental Section
Preparation of Compounds S,S,S,S-9a and S,S,S,R-9a (Racemic).
NBS (78 mg, 0.44 mmol) was added to a suspension of com-
pound 6a (64 mg, 0.20 mmol) in H2O/MeCN (2.2 mL of 1:10
mixture) while on an ice bath with stirring. The resulting
mixture was then allowed to warm to 25 °C and stirred for 18 h
at the same temperature. EtOAc (4.0 mL) was added to the reaction
mixture, and the resulting solution was dried over Na2SO4, filtered,
and concentrated under reduced pressure. The mixture of diaster-
eomers was used for the next step. The crude residue was dissolved
inEtOAc(2.0mL), andEt3N (0.20 mL, 1.4 mmol) was added to the
resulting mixture at 25 °C under a nitrogen atmosphere. After being
stirred for 23 h at 25 °C, the reaction mixture was filtered to remove
the insoluble salts. The filtrate was concentrated under reduced
pressure, and the crude residue was purified by flash chromatogra-
phy (10-40% EtOAc in hexanes) on silica gel (12 mL) to afford
compound S,S,S,S-9a (racemic mixture, 25 mg, 36%) as a white
solid and compound S,S,S,R-9a (racemic mixture, 42 mg, 60%)
as a colorless crystalline. To prepare samples for X-ray crystal-
lography, compound S,S,S,S-9a (racemic) was recrystallized from
EtOAc, and compound S,S,S,R-9a (racemic) was recrystallized
from hexanes-EtOAc. Data for compound S,S,S,S-9a (racemic):
mp =140-142 °C; Rf = 0.29 (30% EtOAc in hexanes); IR (KBr
pellet) νmax = 3063, 2935, 1694 (CdO), 1455, 1429, 1378, 1271,
1167, 1072, 762, 726 cm-1; 1H NMR (300 MHz, CDCl3, 293 K,
Figure S23, Supporting Information) δ = 7.49-7.38 (m, 10H),
4.02 (s, 2H), 2.89 (s, 6H); 13C NMR (75 MHz, CDCl3, 293 K,
Figure S24, Supporting Information) δ = 160.7, 130.4, 129.1,
128.4, 126.8, 71.4, 63.0, 26.3; HRMS (EIþ) calcd for
C20H18N2O4 [M]þ 350.1267, found 350.1264. Data for compound
S,S,S,R-9a (racemic): mp =179-181 °C; Rf = 0.20 (30% EtOAc
in hexanes); IR (KBr pellet) νmax = 3055, 2925, 2854, 1693 (CdO),
1453, 1427, 1373, 1272, 1160, 933, 877, 742 cm-1; 1H NMR (300
MHz, CDCl3, 293 K, Figure S25, Supporting Information) δ =
7.57-7.52 (m, 2H), 7.43-7.38 (m, 3H), 7.21 (dd, J = 7.2, 7.2 Hz,
1H), 7.07 (dd, J = 7.5, 7.5 Hz, 2H), 7.02 (dd, J = 7.2, 7.2 Hz, 2H),
4.38 (s, 1H), 4.33 (s, 1H), 3.10 (s, 3H), 2.39 (s, 3H); 13C NMR (100
MHz, CDCl3, 293 K, Figure S26, Supporting Information) δ =
164.3, 160.6, 131.1, 130.5, 129.4, 129.1, 128.8, 128.5, 127.5, 127.0,
71.8, 7.05, 62.8, 62.6, 29.7, 26.5; HRMS (EIþ) calcd for
C20H18N2O4 [M]þ 350.1267, found 350.1265.
enable isomerization from the asymmetric S,S,S,R-9 to sym-
metric S,S,S,S-9. The reversibility appeared to stem from
the enhanced reactivity of the benzylic epoxides toward
Et3NHþBr- (Scheme 3a, S,S,S,R-9a to S,S,R,S-10a and S,S,
R,S-10a to S,S,R,R-10a). To test this hypothesis, asymmetric
compound S,S,S,R-9a was treated with Et3NHþBr- and
Et3N in refluxing MeCN. Under these conditions, no reac-
tion appeared to take place, invalidating our hypothesis, at
least when Ar = Ph.
Another mechanistic possibility was that Et3N-catalyzed
epimerizations of carbinol carbon stereocenters were involved
in the stereocontrol (Scheme 3b). Thus, we treated 12a with
Ag2O in the absence of base. In this reaction, bromide ions
should be sequestered from the reaction mixture as insoluble
AgBr, excluding the transformations shown in Scheme 3a.
Under these conditions, S,S,S,S-9a and S,S,S,R-9a were
formed in a 1:2 ratio.33 Because the Ag2O- and Et3N-pro-
moted reactions provided the two epoxides in similar ratios,
the origin of diastereoselectivity using Et3N is unlikely to
involve the aforementioned epimerizations.
The preference for a syn relationship between the two
hydroxy groups is a well-documented phenomenon in the
synthesis of similar diketopiperazines.18,34,35 Therefore, our
working hypothesis is that syn diols are the reactive inter-
mediates after the bromohydration step. Because SN2 reac-
tions are stereospecific, the origin of stereoselectivity would
be the formation of bromohydrins 12 (Scheme 4). More
specifically, it would be during the second bromohydration
that the syn- or antirelationship between the two bromide
groups would be established (11 to 12). Further studies are
needed to thoroughly understand the origin of the diaster-
eoselectivity in this step.
Acknowledgment. This work was supported by the US
National Institutes of Health (R01 CA120792). We thank
Dr. Damodaran Krishnan, Dr. Steve Geib, Dr. John Williams,
and Dr. Bhaskar Godugu for assistance with NMR, X-ray, and
mass spectroscopic analyses, respectively. A.L.G. is a recipient
of the Arts and Sciences Fellowship and the Mary E. Warga
Predoctoral Fellowship from the University of Pittsburgh.
In this study, we achieved the synthesis of diketopiperazine
bis-R,β-epoxides 9 in four steps from inexpensive glycine anhy-
dride 1. The bromohydration-cyclization sequence favored
the formation of the C2-symmetric diastereomer. Although
Supporting Information Available: Experimental proce-
dures and spectroscopic data for all new compounds and
additional figures, schemes, and X-ray crystal structures. This
material is available free of charge via the Internet at http://
pubs.acs.org.(33) See the Supporting Information for the de-
tails of this experiment.
(33) See the Supporting Information for the details of this experiment.
(34) Iwasa, E.; Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.;
Yoshida, M.; Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4078–4079.
€
(35) Ohler, E.; Tataruch, F.; Schmidt, U. Chem. Ber. 1973, 106, 396–398.
1158 J. Org. Chem. Vol. 76, No. 4, 2011