Enantioselective synthesis of α-secondary and α-tertiary piperazin-2- Ones and piperazines by catalytic asymmetric allylic alkylation

Article abstract of DOI:10.1002/anie.201408609

The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2- ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.

Full text of DOI:10.1002/anie.201408609

Angewandte
Chemie
DOI: 10.1002/anie.201408609
Asymmetric Catalysis
Enantioselective Synthesis of a-Secondary and a-Tertiary Piperazin-2-
ones and Piperazines by Catalytic Asymmetric Allylic Alkylation**
Katerina M. Korch, Christian Eidamshaus, Douglas C. Behenna, Sangkil Nam, David Horne,
and Brian M. Stoltz*
Abstract: The asymmetric palladium-catalyzed decarboxyla-
tive allylic alkylation of differentially N-protected piperazin-2-
ones allows the synthesis of a variety of highly enantioenriched
tertiary piperazine-2-ones. Deprotection and reduction affords
the corresponding tertiary piperazines, which can be employed
for the synthesis of medicinally important analogues. The
introduction of these chiral tertiary piperazines resulted in
imatinib analogues which exhibited comparable antiprolifer-
ative activity to that of their corresponding imatinib counter-
parts.
P
iperazine is a common structural motif in pharmaceuticals
and is considered to be a privileged scaffold in medicinal
chemistry.[1] Piperazine itself has been used as an anthelmintic
and notable piperazine-containing, small-molecule pharma-
ceuticals include imatinib (1; a kinase-inhibiting anticancer
agent),[2] ciprofloxacin (2; a potent fluoroquinolone anti-
biotic),[3] piribedil (3; an antiparkinsonian agent),[4] and
indinavir (4; an HIV protease inhibitor, Figure 1a).[5]
Common methods for the selective asymmetric preparation
of substituted piperazines[6] include enantioselective hydro-
genation,[7] enzyme-mediated chiral resolution,[8] a-lithiation
mediated by (À)-sparteine and other chiral diamines,[9]
palladium-catalyzed cyclizations,[10] or synthesis from amino
acids or other members of the chiral pool.[11] One of the most
Figure 1. a) Representative piperazine and piperazin-2-one containing
pharmaceuticals. b) Representative bioactive natural products possess-
ing piperazin-2-one core structures.
[*] K. M. Korch, Dr. C. Eidamshaus, Dr. D. C. Behenna,
Prof. Dr. B. M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, Division of Chemistry and Chemical Engi-
neering, California Institute of Technology
1200 E. California Blvd, MC 101-20, Pasadena, CA 91125 (USA)
E-mail: stoltz@caltech.edu
straightforward methods for the synthesis of chiral pipera-
zines is the reduction of the corresponding chiral keto- or
diketopiperazine. However, methods for the asymmetric
preparation of these piperazine precursors are currently
limited.
Dr. S. Nam, Prof. Dr. D. Horne
Molecular Medicine, Beckman Research Institute
City of Hope Comprehensive Cancer Center
1500 East Duarte Road, Duarte, CA 91010 (USA)
Piperazin-2-ones possess an additional functionality (i.e.,
the carbonyl) which allows the synthesis of more highly
substituted piperazine-2-ones, and, upon reduction, yield
substituted piperazine derivatives. Although piperazin-2-
ones are employed infrequently in medicinal chemistry, they
can be found in some pharmaceutical agents including the
p53/MDM2 inhibitor (À)-nutlin-3 (5; Figure 1a),[12] and in
several naturally occurring bioactive compounds including
the marcfortines,[13] pseudotheonamides,[14] and malbranchea-
mides (Figure 1b).[15] Piperazin-2-ones also play a crucial role
as conformationally constrained peptidomimetics. These
piperazin-2-ones mimic inverse g-turns in peptides, which
play crucial roles in the secondary structures of proteins.[16]
Chiral piperazin-2-ones[17] can be prepared from amino acids
or other members of the chiral pool[18] or by chiral-auxiliary-
[**] We wish to thank the NIH-NIGMS (R01GM080269) for financial
support. This material is based upon work supported by the
National Science Foundation Graduate Research Fellowship under
Grant No. DGE-1144469 (fellowship to K.M.K.). We also wish to
thank the Deutsche Forschungsgemeinschaft (DFG postdoctoral
fellowship to C.E.), Amgen, Abbott, Boehringer Ingelheim, and
Caltech for financial support. Corey Reeves is acknowledged for
providing allyl cyanoformate and for insightful discussions. Douglas
Duquette is acknowledged for providing allyl 1H-imidazole-1-
carboxylate reagents and for insightful discussions. Scott Virgil is
acknowledged for assistance with instrumentation and insightful
discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408609.
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mediated alkylations[19] or dynamic resolutions.[20] However,
most of the available methods are not capable of generating
chiral a-tertiary piperazin-2-ones (6; Figure 2) and there are
no previous examples for preparation of this motif by catalytic
enantioselective methods. Thus, there is an unaddressed
absence of catalytic asymmetric synthesis strategies to these
valuable compounds.
Table 1: Catalytic enantioselective piperazin-2-one decarboxylative allylic
alkylation. Scope of protecting-group tolerance and scope of
a-substituents.[a]
Figure 2. a-Tertiary piperazin-2-one and a-tertiary piperazine.
Our research group has had a longstanding interest in the
construction of a-tetrasubstituted carbonyl compounds
including quaternary centers using transition-metal catalysis
and has developed reaction conditions for the asymmetric
allylic alkylation of lactams to furnish a-quaternary lactam
products.[21] Morpholin-3-ones were also identified as viable
substrates under the same reaction conditions, thus generat-
ing an a-tertiary stereocenter.[22] We sought to extend this
catalyst system to enantioselectively generate a-tertiary
piperazin-2-ones (6), which, upon subsequent reduction,
would generate chiral tertiary piperazines (7). a-Tertiary
piperazine species are not well precedented in the literature
presumably because of the difficulties associated with their
preparation, and no general methods exist for their asym-
metric synthesis, let alone catalytic asymmetric synthesis. A
direct, catalytic asymmetric synthesis of tertiary piperazin-2-
ones and their subsequent reduction to the piperazines would
provide access to an invaluable scaffold, thus enabling the
exploration of unprecedented chemical space (Figure 3).
[a] Conditions: piperazin-2-one 8 (1.0 equiv), [Pd2(pmdba)3] (5 mol%),
(S)-(CF3)3-tBuPHOX (12.5 mol%) in toluene (0.014m) at 408C for 12–
48 h. All reported yields are those for the isolated products. The ee values
were determined by SFC using a chiral stationary phase. Bz=benzoyl,
PMB=para-methoxybenzyl.
allylic alkylation,[21e] we began our studies with the 1,4-
bis(benzoyl)ated piperazin-2-one 8a (Table 1). When utiliz-
ing
tris(4,4’-methoxydibenzylideneacetone)dipalladium(0)
([Pd2(pmdba)3]) at a 5 mol% loading and the (S)-(CF3)3-
tBuPHOX ligand at 12.5 mol% loading in a 0.014m solution
of toluene, the bis(N-benzoyl)ated a-allylated product 9a was
formed in high yield but with a modest ee value. It was
reasoned that the sp2-hybridized nature of the N4 position
was detrimental to the enantioselectivity of the reaction
because of its ability to stabilize the enolate intermediate.[23]
Taking into consideration the need for an alkyl-protecting
group at the N4 position, we next examined the 4-benzylpi-
perazin-2-one 8b (R1 = Bz, R2 = Bn, R3 = Me, R4 = H). Under
our standard reaction conditions, the N-benzyl-protected a-
allylated compound 9b was obtained in good yield and
ee value. Additional N4-protecting groups were investigated
for the chemoselective deprotection of N4. The para-
methoxybenzyl-protecting group, which can be removed by
acidic or oxidative conditions, would allow orthogonal
deprotection. The 4-methoxybenzylpiperazin-2-one 9c was
also obtained with a good ee value but with slightly lower
yield than that of 9b. Given the slightly higher yield, the 4-
Figure 3. Entry into largely unexploited chemical space.
Medicinal chemistry has long utilized linearly substituted,
nonchiral piperazines and has also, although less frequently,
utilized chiral a-secondary piperazines, as in indinavir (4).[22]
Access to enantiopure a-tertiary piperazines would provide
a unique opportunity to explore these three-dimensionally
elaborated piperazines in drug discovery.
Given that secondary and tertiary nitrogen atoms may
exhibit undesired reactivity in palladium-catalyzed reactions,
it is necessary to protect both nitrogen atoms of the
ketopiperazine ring. Taking into consideration our prior
results, in which N-benzoyl-protected lactams reacted with
high enantioselectivities in the decarboxylative asymmetric
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Table 2: Scope of allyl substituents for a-secondary piperazin-2-ones.[a]
benzyl-protecting group was selected for further optimiza-
tion.
In efforts to increase the eevalue of the allylic alkylated
products, additional protecting groups at N1 were examined.
Considering that benzoylated compounds provided the best
results in the lactam case,[21e] we examined additional acyl-
protecting groups (Table 1). The para-fluoro and para-
methoxy benzoyl compounds 9d and 9e, respectively, were
obtained with nearly identical ee values and just slightly lower
yields, thus demonstrating that substantial electronic changes
of the N1 substituent do not have a strong influence on the
reaction efficiency or selectivity. However, the reaction is
somewhat sensitive toward ortho substitution at the N1-
benzoyl group as 9 f was obtained in a significantly lower
enantiomeric excess compared to that of 9d and 9e. Addi-
tionally, the 1-carboxybenzyl ketopiperazine 9g was also
prepared in high yield, albeit with moderate ee value. Given
these data, the unsubstituted benzoyl group was selected as
the optimal choice for an N1-protecting group, and the benzyl
group was selected as the optimal N4 group.
With protecting groups for both nitrogen atoms inves-
tigated, the scope of the reaction with regard to the a-
substituent was examined. Piperazin-2-ones bearing alkyl
(9h, 9i) and benzyl (9j) groups were prepared, as was the
benzyl ether 9k, which provides an additional handle for
further functionalization (Table 1). Additionally, the bicyclic
product 9n, which is reminiscent of the marcfortine core, was
obtained in good yield in the reaction. The effect of expanding
ring size was also examined. The 1,4-diazepan-2-one 9o was
formed with only moderate enantiomeric excess, a result that
suggests that the reaction is sensitive to ring size, contrary to
the lactam examples.[21e]
[a] Conditions: piperazin-2-one 8 (1.0 equiv), [Pd2(pmdba)3] (5 mol%),
(S)-(CF3)3-tBuPHOX (12.5 mol%) in toluene (0.014m) at 408C for 12–
48 h. All reported yields are those for the isolated products. The ee values
were determined by SFC using a chiral stationary phase.
allyl substrates were tested. Numerous allyl groups are
compatible, including the methallyl 11b, chloroallyl 11c,
and phenylallyl 11d which were all obtained in fair to
excellent yield and high enantioselectivity.
The ketopiperazine products can be converted into the
related piperazines in two steps, hydrolysis of the benzoyl
group to thepiperazine-2-one 12 and subsequent reduction of
the amide to the piperazine 13 (Scheme 1a). The deprotected
Common piperazine pharmacophores include N-aryl-
piperazines and N-methylpiperazines,[24] and we sought to
determine if 4-aryl ketopiperazines and 4-methyl ketopiper-
azines were also competent substrates in this chemistry. The
low ee values observed for 9a suggests that an sp2-hybridized
N4 would prove detrimental to the enantioselectivity of the
reaction. Despite this, the 4-phenyl compound 9p, with its
partial sp2 character of the aniline nitrogen atom, could be
obtained in good yield and with excellent enantiomeric excess
(Table 1). The 4-methylketopiperazine 9q could also be
prepared in good yield but with slightly diminished ee value.
Contrary to results with the piperdinone substrates, we
were delighted to find that even the unsubstituted a-
secondary ketopiperazine 11a could be obtained in excellent
yield and enantioselectivity (Table 2). Previous attempts to
generate trisubstituted stereocenters by our asymmetric
allylic alkylation of lactam and ketone substrates were
unsuccessful. Such experiments have generally resulted in
mixtures of mono-, di-, and unallylated products, and the
desired trisubstituted product was formed in poor yield and
with only moderate ee value. We were delighted to find that in
the case at hand, the unsubstituted a-secondary ketopiper-
azine 11a could be obtained with no detectable amounts of di-
or unallylated byproducts. It is likely that the low acidity of
the a-hydrogen atom of the monosubstituted piperazin-2-one
substrate and product is key to obtaining a high yield of the
monoallylated product. Given this exciting result, additional
Scheme 1. a) Protecting-group removal and reduction to yield the
piperazine 13. b) Protecting-group removal and alkylation to yield the
piperazin-2-one 15. c) Cross-metathesis with ethyl acrylate. d) Oxida-
tive cleavage of PMB-protecting group. DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, NHC=N-heterocyclic carbene, H–G=
Hoveyda–Grubbs catalyst, TFA=trifluoromethanesulfonyl, THF=tetra-
hydrofuran.
N1 can be further alkylated to form, for instance, the diallyl
piperazin-2-one 15 (Scheme 1b). Cross-metathesis can also
be performed (Scheme 1c). Additionally, the 4-methoxyben-
zyl group can be selectively cleaved under oxidative con-
ditions to form the piperazine-2-one 17 (Scheme 1d).
Finally, we have demonstrated that these tertiary piper-
azines can successfully be incorporated into known piper-
azine-containing pharmaceuticals, thus leading to novel
analogues with comparable bioactivities in preliminary test-
ing. Substitution on the piperazine ring has been shown to
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modulate bioactivity and, in some cases, result in more
specific and stronger enzyme binding.[25] We considered
imatinib (1), an antiproliferative agent developed for the
treatment of several cancers, notably including Philadelphia
chromosome-positive chronic myelogenous leukemia
(CML),[2] to be an ideal candidate for proof of concept.
Imatinib targets the Abl tyrosine kinase domain of the Bcr-
Abl fusion protein, and it is known that genetic point
mutations can render imatinib ineffective because it is no
longer able to bind to the enzyme.[26] The piperazine moiety of
the molecule forms two key hydrogen bonds to two amino
acid residues, and thus plays a crucial role in binding.[27]
Given that the piperazine is so crucial to the binding of
imatinib, we wanted to explore whether highly substituted
and congested piperazine analogues would disrupt these
interactions. The enantiomerically pure, benzylated analogue
18 (Scheme 2) was assessed for its antiproliferative activity
In summary, we have developed the first catalytic
enantioselective synthesis of a-tertiary piperazin-2-ones.
These important molecules can be easily converted into
novel a-tertiary piperazines. This method utilizes palladium
catalysts derived from [Pd2(pmdba)3] and electron-deficient
PHOX ligands to deliver a-tertiary piperazin-2-ones in good
to excellent yields and enantioselectivities. This method also
allows the synthesis of a-secondary piperazin-2-ones in
modest to excellent yields and good to excellent enantiose-
lectivities. In addition to being tolerant of a variety of N-
substitutions, this reaction is also tolerant of substitution at
the stereocenter including fused bicycles such as those found
in piperazine-2-one-containing natural products. We have
further demonstrated that these chiral piperazin-2-ones can
be reduced to the corresponding chiral piperazines, and these
chiral a-tertiary piperazines can successfully be incorporated
into known piperazine-containing pharmaceuticals. Specifi-
cally, these piperazines can be incorporated into the imatinib
framework without major perturbation of the drugꢀs anti-
proliferative activity against the human K562 CML cell line,
thus indicating the enormous potential that these novel three-
dimensionally elaborated chiral piperazines have in drug
discovery.
Received: August 27, 2014
Published online: && &&, &&&&
Scheme 2. Synthesis of imatinib analogues from the precursor 19.
DMF=N,N-dimethylformamide.
Keywords: allylic compounds · asymmetric catalysis ·
enantioselectivity · heterocycles · palladium
.
against the human K562 CML cell line. The N-substituted
analogue 18 was found to have significantly less antiprolifer-
ative activity than imatinib (1; Table 3), thus signifying that
too much bulk around N4 might perturb key interactions. We
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4
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
K. M. Korch, C. Eidamshaus,
D. C. Behenna, S. Nam, D. Horne,
B. M. Stoltz*
&&&& — &&&&
Enantioselective Synthesis of a-
Secondary and a-Tertiary Piperazin-2-
ones and Piperazines by Catalytic
Asymmetric Allylic Alkylation
The ’pipe’line: The title reaction allows
the synthesis of highly enantioenriched
tertiary piperazine-2-ones. Deprotection
and reduction affords the corresponding
tertiary piperazines, which can be
employed for the synthesis of medicinally
important analogues including imatinib
analogues. Bz=benzoyl, PHOX=phos-
phinooxazoline, pmdba=bis(p-methoxy-
benzylidene)acetone.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!