Enantioselective organocatalytic synthesis of 2-oxopiperazines from aldehydes: Identification of the elusive epoxy lactone intermediate

Article abstract of DOI:10.1021/acs.orglett.6b02699

An organocatalytic linchpin catalysis approach was envisaged to convert simple aldehydes into enantioenriched 2-oxopiperazines. A four-step reaction sequence (chlorination, oxidation, substitution, and cyclization) was developed and led to different substitution patterns in high yields and selectivities. The reaction mechanism was studied, and the previously elusive epoxy lactone intermediate was identified by HRMS.

Full text of DOI:10.1021/acs.orglett.6b02699

Letter
pubs.acs.org/OrgLett
Enantioselective Organocatalytic Synthesis of 2‑Oxopiperazines from
Aldehydes: Identification of the Elusive Epoxy Lactone Intermediate
Nikolaos Kaplaneris, Constantinos Spyropoulos, Maroula G. Kokotou, and Christoforos G. Kokotos*,*
*Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis,
Athens 15771, Greece
S
* Supporting Information
ABSTRACT: An organocatalytic linchpin catalysis approach was
envisaged to convert simple aldehydes into enantioenriched 2-
oxopiperazines. A four-step reaction sequence (chlorination,
oxidation, substitution, and cyclization) was developed and led to
different substitution patterns in high yields and selectivities. The
reaction mechanism was studied, and the previously elusive
epoxy lactone intermediate was identified by HRMS.
he 2-oxopiperazine moiety constitutes a common
structural motif in a number of pharmaceuticals and
allylic alkylation approach for the synthesis of chiral 2-
oxopiperazines.8
T
medicinally interesting natural products (Figure 1).1 It
Having been actively involved in the field of organocatalysis,9
and in particular in the field of organocatalytic oxidation,10 and
being inspired by MacMillan’s enantioselective linchpin SOMO
catalysis,11,12 we introduce herein the use of enamine-promoted
linchpin catalysis for the enantioselective synthesis of 2-
oxopiperazines13 along with mechanistic investigations regard-
ing the reaction outcome. A mild organocatalytic α-chlorination
of heptanal (1a) was coupled with a selective oxidation, leading
to chiral α-chloro acids in a single-flask operation. Nucleophilic
substitution by N,N′-dibenzylethylenediamine (3a) can give
rise to a substituted amino acid derivative that could be cyclized
upon reaction conditions affording chiral 2-oxopiperazine 4a
(Table 1). This would summarize a four-step reaction sequence
in just one operation, without requiring any intermediate
purifications, that affords stereodefined molecules of increased
molecular complexity beginning from trivial and cheap starting
Figure 1. Natural products and pharmaceuticals bearing or derived
from the 2-oxopiperzine core.
materials. From the available chlorination protocols,11,14
a
modified procedure utilizing MacMillan’s third-generation
catalyst 2 in conjunction with chloroquinone as the chlorinating
agent14a led to a highly enantioselective and fast protocol that
can be coupled with Pinnick oxidation to afford α-
chloroheptanoic acid almost quantitatively. This chlorination
protocol provides high levels of asymmetric induction and
avoids postreaction epimerization. Treatment of this acid with
diamine 3a in a pressure vessel at 100 °C for 2 h led to a
moderate yield of 2-oxopiperazine 4a with 93% ee (entry 1).
Increasing the amount of the diamine had a positive effect on
the reaction yield (entry 2). Increasing or decreasing the
reaction temperature did not improve the reaction outcome
(entries 3 and 4 vs entry 2). It has to be noted that decreasing
the reaction temperature led to a slight erosion of the
represents the structural core of several biologically active
molecules, such as Leu-enkephalin analogues,2a cholecystokinin
receptor antagonists,2b RGD mimetics,2c the neurokinin-2
receptor ligand,2d and promising candidates for the treatment
of rheumatoid arthritis,3a depression,3b sexual dysfunction,3c
and arterial thrombosis.3d Representative examples include the
HIV protease inhibitor indivanir4a and the antischistosomiasis
and soil-transmitted helminthiasis drug praziquantel4b (Figure
1).
For such an often-occurring moiety, one would expect a
plethora of synthetic approaches. Unfortunately, until very
recently, only approaches based on chiral pool techniques were
available in the arsenal of a synthetic chemist.5 This daunting
challenge was recently addressed with complementary methods
based on chiral-auxiliary-promoted dynamic resolutions6 and
multistep metal-catalyzed processes.7 In 2015, Stoltz and co-
workers reported an elegant palladium-catalyzed asymmetric
Received: September 8, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b02699
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Table 1. Design Plan and Optimization of the Reaction
Conditions Leading to Chiral 2-Oxopiperazines
Scheme 1. Enantioselective Synthesis of 2-Oxopiperazines:
Aldehyde Substrate Scope
a
yield
ee
c
b
entry
conditions
(%)
(%)
1
2
3
4
5
BnNHCH2CH2NHBn (3 equiv), 100 °C, 2 h
BnNHCH2CH2NHBn (5 equiv), 100 °C, 2 h
BnNHCH2CH2NHBn (5 equiv), 80 °C, 2 h
BnNHCH2CH2NHBn (5 equiv), 120 °C, 2 h
47
57
54
56
75
93
93
85
92
93
BnNHCH2CH2NHBn (5 equiv), 100 °C, MW,
2 h
a
Catalyst 2 in THF, chloroquinone (1.1 equiv), heptanal (1 equiv) for
15 min at rt. t-BuOH, H2O, 2-methyl-2-butene, NaH2PO4.H2O, and
b
NaClO2 for 90 min at rt. Then MeCN and diamine. Isolated yields.
c
Determined by chiral HPLC analysis.
We then diverted our efforts to an exploration of the diamine
substrate scope (Scheme 2). The substitution pattern on the
enantiointegrity of the product, which is due to competing
mechanistic pathways, as will be discussed in detail later.
Extending the reaction time led to a slight increase in the yield,
but prolonging the reaction time (8 or 18 h) allows
postepimerization to occur, leading to higher yields but
significantly lower ee’s. Microwave irradiation constitutes a
solution to this problem, since performing the reaction in a
microwave reactor (entry 5) afforded the optimum reaction
conditions, leading to the isolation of 2-oxopiperazine 4a in
75% yield with 93% ee.
Scheme 2. Enantioselective Synthesis of 2-Oxopiperazines:
Diamine Substrate Scope
We next explored the scope of the aldehyde component. As
highlighted in Scheme 1, a variety of functional groups can be
readily tolerated on the aldehyde part. Linear aliphatic
aldehydes led to high yields and enantioselectivities (4a−c),
while branched aliphatic aldehydes, which are thought to be
more sterically demanding, can also be employed, leading to
similar high yields and selectivities (4d−f). A plethora of
functional groups, such as aryl moieties, triple bonds, and
protected alcohols and amines, can be employed without loss of
reaction efficiency or enantiocontrol (4g−k). An additional
chiral center at the β position of the carbonyl group could be
problematic, since additional concerns regarding enamine
formation, the geometry of the enamine formed, and whether
there is substrate or catalyst control in the protocol would
emerge. In these cases, the reaction time for chlorination step
had to be increased (from 30 min to 1 h). When an aliphatic
side chain was employed, the reaction yield remained high, but
unfortunately a slight deterioration of the stereocontrol was
observed (4l). On the other hand, when (S)- or (R)-3-
phenylbutyraldehyde was employed, excellent enantiocontrol
was observed, albeit in moderate yields (4m, 4n). Thus, in the
latter cases, the resident stereogenicity does not govern the
generation of the stereocenter and the catalyst clearly plays a
dominant role in the reaction outcome, demonstrating catalyst-
directed induction rather than substrate-enforcing control.
aromatic moiety does not affect the reaction outcome (5a−f).
Similarly as before, treatment of the chiral α-chloro acid with
either (1S,2S)- or (1R,2R)-diphenylethylenediamine led to the
incorporation of three chiral centers on the 2-oxopiperazine
skeleton with high stereocontrol in excellent yields (5g, 5h).
One limitation of the current protocol is that decreased
enantioselectivities are observed when diamines that do not
possess an aromatic moiety are utilized (5i, 5j).
In order to determine the absolute configuration of the
product, commercially available Boc-Phe-OH (6) was con-
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DOI: 10.1021/acs.orglett.6b02699
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verted to (S)-2-oxopiperazine 4g (Scheme 3). Initially, amide
bond formation followed by Boc deprotection led to an amino
Scheme 3. Determination of the Absolute Configuration of
the Product
alcohol, which was used in a Mitsunobu reaction to ensure
cyclization followed by benzylation. This linear sequence of
reactions led to (S)-4g, for which [α]D = −22.6 (c = 0.5,
CH2Cl2). It is known that imidazolidinone catalyst 2 provides
(S)-2-chloroheptanoic acid.11,12 Since 2-oxopiperazine 4g,
obtained from (S)-2-chloroheptanoic acid, has the same
absolute stereochemistry [(S)], the direct SN2 reaction pathway
is not operative, and thus, a different mechanistic pathway is
followed that leads to retention of the stereochemistry. Usually
retention of stereochemistry occurs when a neighboring effect
is in place. In this case, the carboxylic group, which is in close
proximity, displaces the chloride, leading to a highly labile and
transient epoxy lactone intermediate, which in turn is attacked
by the diamine to afford the desired amino acid with retention
of stereochemistry, relieving it from its strain.
To probe this reaction mechanism, we decided to study the
displacement and the cyclization reaction by ESI (positive
ionization mode) high-resolution mass spectrometry (HRMS).
Epoxy lactone intermediates have been postulated as active
species when retention of stereochemistry occurs next to a
carboxylic group,15 but because of their labile nature, they have
never been detected or isolated. In fact, only doubly substituted
epoxy lactones, whose stability is favored because of the
electronic nature of their substituents, leading to longer
lifetimes, have been identified by IR spectroscopy.16 In contrast,
monosubstituted epoxy lactones are considered to be highly
reactive and have never been identified. We initiated our study
by employing 2-chloroheptanoic acid in MeCN and 5 equiv of
diamine 3a. When the reaction mixture was heated at 100 °C,
the epoxy lactone intermediate was identified (Figure 2).17 The
reaction was performed in MeCN utilizing conventional
heating equipped with a condenser. After 20 or 80 min, a
peak corresponding to epoxy lactone was clearly detected in the
reaction mixture (Figure 2), while at the end of the reaction,
product 4a was observed. It has to be highlighted that after 80
min, the product of the substitution reaction of the chloride by
the diamine was also observed. In addition, the product derived
from the amidation reaction (which still bears the chloride)
could not be observed. Thus, without any doubt, the
substitution reaction occurs first, followed by the cyclization
step. Going back to the HRMS study, after 20, 40, 60, and 80
min, the epoxy lactone intermediate, although a rather short-
lived species, was detected in the reaction mixture when the
reaction was carried out at 100 °C.17 Throughout the study of
the reaction by HRMS, special care had to be taken (reaction
Figure 2. Direct detection of the epoxy lactone intermediate. Shown
are HRMS spectra of the reaction of 2-chloroheptanoic acid in MeCN
with 5 equiv of diamine 3a at 100 °C for reaction times of (A) 20 min
and (B) 80 min.
carried out next to the HRMS instrument, fast dilution with hot
MeCN, immediate HRMS run in a total time of few seconds)
in order to observe the epoxy lactone.18 Delaying the whole
process by a few seconds led to reaction or consumption of the
epoxy lactone toward product formation, having as a direct
consequence the failure to observe the intermediate. Thus, very
fast and thorough experimentation was required for the
identification of such a labile species. When the reaction was
performed at room temperature, the epoxy lactone inter-
mediate was not observed. Similarly, just heating of 2-
chloroheptanoic acid led to no detection of the epoxy lactone.
The two competing reaction mechanisms, the direct SN2
reaction and the epoxy lactone mechanism, which lead to
opposite enantiomers, have distinct reaction conditions that are
operative. At 100 °C, the epoxy lactone mechanism dominates,
leading to the product with retention of stereochemistry in high
degree. Decreasing the reaction temperature has the conse-
quence that the direct SN2 pathway starts to compete with the
epoxy lactone pathway, leading to lower enantiomeric excess of
the product. At high temperature, the epoxy lactone mechanism
outperforms the inversion pathway, while at room temperature,
the two pathways have similar activation energy and the
enantiomeric excess observed is low. In addition, performing
the reaction at rather elevated temperatures (above 100 °C)
leads to slight erosion of the enantioinduction.
In conclusion, an organocatalytic enamine-based protocol for
the asymmetric generation of 2-oxopiperazines from aldehydes
is described. Four efficient and consecutive transformations,
without the need for intermediate purification, occur to provide
a linchpin process. A broad substrate scope is described with
respect to the aldehyde and the diamine skeleton, leading to
polyfunctionalized motifs often present in numerous pharma-
ceuticals, enzyme inhibitors, and β-turn structures. Finally, the
process provides the final product with retention of the
stereochemistry due a neighbor carboxylate group. The elusive
and short-lived epoxy lactone intermediate, which has been
C
DOI: 10.1021/acs.orglett.6b02699
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(6) (a) Jang, J. I.; Kang, S. Y.; Kang, K. H.; Park, Y. S. Tetrahedron
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suggested in the literature to account for this retention but has
never been characterized and identified, was detected using
HRMS. This study constitutes the first successful example of
observing this epoxy lactone intermediate, verifying the
hypothesis that has been proposed in the past. This cultivates
the notion that HRMS analysis is a powerful technique for the
identification and observation of hypothesized species.
(8) Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne,
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02699.
Experimental procedures, full optimization data, charac-
terization data, NMR spectra, HPLC traces, and HRMS
experiments and conditions (PDF)
(11) Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2009, 48, 5121.
AUTHOR INFORMATION
(12) Kokotos, C. G. Enantioselective α-Functionalization of
Aldehydes via Organocatalytic Linchpin Catalysis. Postdoctoral report,
Princeton University, Princeton, NJ, 2009.
(13) For an organocatalytic multistep procedure for the synthesis of
piperazin-2-ones, see: Meninno, S.; Vidal-Albalat, A.; Lattanzi, A. Org.
Lett. 2015, 17, 4348.
(14) (a) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2004, 126, 4108. (b) Halland, N.; Braunton, A.; Bachmann,
S.; Marigo, M.; Jorgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790.
(c) Marigo, M.; Bachmann, S.; Halland, N.; Braunton, A.; Jorgensen,
K. A. Angew. Chem., Int. Ed. 2004, 43, 5507.
■
Corresponding Author
*E-mail: ckokotos@chem.uoa.gr
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
(15) The epoxy lactone intermediate was first postulated in:
Cowdrey, W. A.; Hughes, E. D.; Ingold, C. K. J. Chem. Soc. 1937, 0,
1208.
(16) (a) Adam, W.; Liu, J.-C.; Rodriguez, O. J. Org. Chem. 1973, 38,
2269. (b) Crandall, J. K.; Sojka, S. A.; Komin, J. B. J. Org. Chem. 1974,
39, 2172. (c) Coe, P. L.; Sellars, A.; Tatlow, J. C.; Whittaker, G.;
Fielding, H. C. J. Chem. Soc., Chem. Commun. 1982, 362. (d) Sander,
W. W. J. Org. Chem. 1989, 54, 4265. (e) Wierlacher, S.; Sander, W.;
Liu, M. T. H. J. Org. Chem. 1992, 57, 1051. (f) Showalter, B. M.;
Toscano, J. P. J. Phys. Org. Chem. 2004, 17, 743.
(17) For further comments and reaction setup for the HRMS
mechanistic experiments, see the Supporting Information.
(18) The epoxy lactone intermediate is quite short-lived. After a few
seconds, it reacts and is no longer visible by HRMS. Attempts to
identify the epoxy lactone by NMR spectroscopy were not successful,
probably because of the low concentration of the intermediate coupled
with its short lifetime.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the Operational Program
“Education and Lifelong Learning” for financial support
through the NSRF Program “ENIΣXYΣH METAΔIΔAKTO-
PΩN EPEYNHTΩN” (PE 2431) cofinanced by ESF and the
Greek State.
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