Enantioselective synthesis of: Gem -disubstituted N -Boc diazaheterocycles via decarboxylative asymmetric allylic alkylation

Article abstract of DOI:10.1039/c8sc03967d

An enantioselective synthesis of diverse N4-Boc-protected α,α-disubstituted piperazin-2-ones using the palladium-catalyzed decarboxylative allylic alkylation reaction has been achieved. Using a chiral Pd-catalyst derived from an electron deficient PHOX ligand, chiral piperazinones are synthesized in high yields and enantioselectivity. The chiral piperazinone products can be deprotected and reduced to valuable gem-disubstituted piperazines. This reaction is further extended to enable the enantioselective synthesis of α,α-disubstituted tetrahydropyrimidin-2-ones, which are hydrolyzed into corresponding chiral β^2,2-amino acids.

Full text of DOI:10.1039/c8sc03967d

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Enantioselective synthesis of gem-disubstituted N-
Boc diazaheterocycles via decarboxylative
asymmetric allylic alkylation†
Cite this: Chem. Sci., 2019, 10, 788
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have been paid for by the Royal Society
of Chemistry
*
Alexander W. Sun, ‡ Stephan N. Hess‡ and Brian M. Stoltz
An enantioselective synthesis of diverse N4-Boc-protected a,a-disubstituted piperazin-2-ones using the
palladium-catalyzed decarboxylative allylic alkylation reaction has been achieved. Using a chiral Pd-
catalyst derived from an electron deficient PHOX ligand, chiral piperazinones are synthesized in high
yields and enantioselectivity. The chiral piperazinone products can be deprotected and reduced to
valuable gem-disubstituted piperazines. This reaction is further extended to enable the enantioselective
synthesis of a,a-disubstituted tetrahydropyrimidin-2-ones, which are hydrolyzed into corresponding
chiral b2,2-amino acids.
Received 6th September 2018
Accepted 29th October 2018
DOI: 10.1039/c8sc03967d
rsc.li/chemical-science
specicity for a target, as receptor–ligand binding is oen
dened by three dimensional contacts.5b Furthermore,
Introduction
depending on the chemical composition of the chiral center,
other properties such as metabolism, aqueous solubility, and
cell-penetration may be optimized.5a The prevalence of pipera-
zine in bioactive molecules makes it an excellent scaffold upon
which to introduce chirality and increase molecular complexity.
Chiral gem-disubstitution on any of four carbon atoms in the
piperazine ring could dramatically alter physicochemical
properties (Fig. 2). Despite this potential, there are no gem-
disubstituted piperazines among the current 98 FDA approved
piperazine-containing non-natural product derived drugs.6 In
Nitrogen containing heterocycles are ubiquitous components of
biologically active small molecules.1 For instance, piperazine,
a representative diazaheterocycle, is the third most prevalent
heterocycle in small molecule pharmaceuticals1 and can be
found in bioactive molecules such as the antiviral natural
product herquline A,2 the blockbuster psychiatric drug aripi-
prazole,3 and the HIV integrase inhibitor dolutegravir4 (as the
oxidized counterpart, piperazin-2-one) (Fig. 1).
In the eld of medicinal chemistry and fragment-based drug
discovery, an emerging paradigm to enhance drug-like proper-
ties of small molecules involves reducing molecular atness by
incorporating chiral centers.5 This method of increasing
molecular complexity can enhance binding affinity and
contrast,
a signicant number contain mono-substituted
piperazines, which can be prepared through a variety of strat-
egies,7 including cyclization of chiral precursors,7b–d enantiose-
lective hydrogenation of pyrazines,7e,f palladium-catalyzed
cyclizations,7g–i or asymmetric lithiation.7j,k
The dearth of piperazine gem-disubstitution in the pharma-
copoeia highlights the signicant challenge of installing fully
substituted chiral centers into diazaheterocycles.8 The state of
the art is perhaps best exemplied by the Bode laboratory's
extensive development of tin (SnAP) and silicon (SLAP) coupling
reagents to generate spiro-substituted piperazines (Scheme
1a).9 However, this method is not yet enantioselective and
involves potentially toxic tin reagents. Other non-
enantioselective methods to synthesize gem-disubstituted
piperazines include [4 + 2] cycloadditions of 1,2 diamines with
Fig. 1 Representative piperazine and piperazine-2-one pharmaceu-
ticals and natural products.
Warren and Katherine Schlinger Laboratory for Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125, USA. E-mail: stoltz@caltech.edu
† Electronic supplementary information (ESI) available: Experimental procedures,
1H NMR, 13C NMR, and IR spectra. See DOI: 10.1039/c8sc03967d
‡ These authors contributed equally.
Fig. 2 Advantages of chiral gem-disubstituted piperazines.
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Scheme 2 Comparison of routes to piperazin-2-one decarboxylative
alkylation substrates.
piperazines. In an effort to expand upon our group's long-
standing interest in transition-metal catalyzed allylic alkylation,
we sought to identify an alternative protecting group that could
overcome the aforementioned limitations by enabling both
facile substrate synthesis and protecting group cleavage. Aer
extensive explorations directed toward this goal, we were
pleased to discover that replacing the N4-benzyl protecting
group with a simple Boc (tert-butoxycarbonyl) protecting group
addressed the issue of difficult substrate synthesis. Presumably,
the electron-withdrawing Boc group attenuates the nucleophi-
licity of N4, enabling divergent access to a wider array of
Scheme 1 Existing approaches for gem-disubstituted piperazines and
substrates
3 via enolate functionalization of dicarbonyl
piperazinones.
compound 2, which could be synthesized in only two steps from
Boc-piperazinone 1 (Scheme 2b, see the ESI† for full synthetic
details).
propargyl alcohols developed by Rawal (Scheme 1b),7g and the
ring expansion of oxetane spirocycles by Carreira (Scheme 1c).10
To our knowledge, the only method enabling the highly
enantioselective synthesis of gem-disubstituted piperazines was
published by our group in 2015.11 We leveraged the palladium-
catalyzed decarboxylative asymmetric allylic alkylation reaction
to synthesize chiral a,a-disubstituted N4-benzylated piperazin-2-
ones (Scheme 1d). These piperazin-2-ones could then be reduced
into desirable chiral gem-disubstituted piperazines. However, we
encountered two issues during the course of our attempts to
utilize this method to synthesize disubstituted piperazines for
medicinal chemistry purposes: rst, the optimal nucleophilic
benzyl-protected N4 signicantly complicated substrate synthesis
via nucleophilic side reactions, leading to low yields of products.
As a result, we failed to synthesize many desired substrates via
standard enolate functionalization of the dicarbonyl precursor.
Instead, we resorted to a low-yielding 5-step convergent sequence
beginning from an amino acid (Scheme 2a). As a result, our
substrate scope displayed limited functional group diversity.
Second, in the course of working with a N4-PMB-protected
piperazin-2-one, we failed to remove the recalcitrant PMB
group using a variety of common cleavage conditions that were
orthogonal to the sensitive allyl functionality.
With a streamlined approach toward a wide range of decar-
boxylative alkylation substrates, we began optimizing the reac-
tion conditions: with model substrate 3m, conditions based on
our previous report11 using 10 mol% (S)-(CF3)3-t-BuPHOX ligand
and 4 mol% Pd2(pmdba)3 in 0.014 M toluene gave the product
3m in only 76% ee (Table 1, entry 1). Other commonly used
allylic alkylation ligands such as (S)-t-BuPHOX (L2) and (S,S)-
ANDEN-Ph Trost (L3) were tested, both giving suboptimal
enantioselectivities (entries 2 and 3). We then examined the
effect of solvent on the enantioselectivity (entries 4–6), ultimately
nding that 2 : 1 hexanes–toluene provided high yield and ee.
Employing these satisfactory reaction conditions, we then
explored the substrate scope of the decarboxylative alkylation of
various N4-Boc protected piperazinones (Table 2). We rst
tested the a-monosubstituted piperazinone 3a, nding that
typical conditions in a 0.033 M solution of toluene afforded the
product 4a in high yield and enantioselectivity. Another mon-
osubstituted piperazinone 4b with a N1-anisoyl protecting
group, was also obtained in high yield and ee. Furthermore,
replacement of the N4-Boc protecting group with Cbz (3c), and
2-chloro substitution of the allyl group (3d) similarly provided
good results.
Next, we examined a,a-disubstituted substrates, nding that
for the simple cases of methyl substitution (3e, 3f), performing
the reaction at 0.033 M concentration in toluene gave high
yields and ee, with no improvement with the use of 2 : 1
hexanes–toluene at 0.014 M concentration. The exception was
Results and discussion
The substrate-dependent drawbacks of our approach leave
room for an improved method to synthesize chiral disubstituted
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scope explorationa
Entry
Ligand
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
L2
L2
L3
L1
L1
L1
Tol
Tol
Tol
THF
MTBE
2 : 1 Hex/Tol
75
70
83
—
—
93
76
1
52
13
80
93
a
b
Screens performed on a 0.04 mmol scale. All reported yields are for
c
isolated products. The ee values were determined by chiral SFC
analysis. Bz ¼ benzoyl, Boc ¼ tert-butoxycarbonyl, pmdba ¼ bis(4-
methoxybenzylidene)acetone.
a
Conditions: piperazin-2-one 3 (1.0 equiv.), Pd2(dba)3 (4 mol%), (S)-
(CF3)3-tBuPHOX (10 mol%), in 2 : 1 hexanes/toluene (0.014 M) at
N4-benzoyl protected substrate 3g, which in our previous work
gave 52% ee in toluene;11 under our optimized conditions in
2 : 1 hexanes–toluene, the substrate gave an improved albeit
modest ee of 70%. Larger substituents such as a-benzylated
compound 3h or benzyloxymethyl ether 3i required the use of
2 : 1 hexanes–toluene to achieve high enantioselectivity. This
unique mixed-solvent requirement was observed in all substit-
uents other than methyl. A wide range of functional groups was
tolerated: notably, the nitrile, ketone, and methylcarbamate
substrates, which could not be accessed in our previously
described efforts, gave high ee and yields (3j–m).
b
40 ꢀC for 12–24 h. Pd2(pmdba)3 (4 mol%) instead of Pd2(dba)3.
c
Toluene (0.033 M) instead of 2 : 1 hexanes/toluene. All reported
yields are for isolated products. The ee values were determined by
chiral
dibenzylideneacetone.
SFC
analysis.
An
¼
4-methoxybenzoyl,
dba
¼
accessible (Scheme 3C). Additionally, tetrahydropyrimidinones
may be reductively transformed into hexahydropyrimidines,
which are found in bioactive molecules such as the antibiotic
hexetidine and the macrocyclic natural product verbamethine.14
With the N-Boc piperazin-2-one substrates providing excel-
lent results, we wondered whether an isomeric substrate class,
the N-Boc tetrahydropyrimidin-2-ones (5), would perform
similarly as well (Scheme 3C). The resulting a,a-disubstituted
tetrahydropyrimidin-2-one products (6) are especially inter-
esting as they may be hydrolyzed to afford valuable b2,2-amino
acids (7), which are used in peptidomimetic therapeutics and in
the design of unnatural peptides and proteins with unique
secondary and tertiary structures.12 In fact, there is strong
precedent for an allylic alkylation approach toward b2,2-amino
acids. In 2018 the Shibasaki group described the decarbox-
ylative allylic alkylation of an N,O heterocycle to set the
quaternary stereocenter, followed by N–O bond heterolysis to
generate b2,2-amino acids (Scheme 3A).13a Later in 2018, Cossy
and co-workers described a similar approach involving inter-
molecular allylic alkylation (Scheme 3B).13b Notably, the
substrate scope for these two examples is limited to mostly a-
benzylic and a-aryl compounds. If decarboxylative alkylation
could be achieved with the versatile tetrahydropyrimidin-2-one
scaffold, a broader range of chiral b2,2-amino acids might be
Scheme 3 Synthetic approaches toward b2,2-amino acids using the
allylic alkylation reaction.
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Beginning our investigations with methyl substrate 5a (Table
Chemical Science
3), we were pleased to nd that our optimized conditions in 2 : 1
hexanes–toluene furnished the desired decarboxylative alkyl-
ation product 6a in high yield and ee. The reaction proved
amenable to a variety of a-substituents, including ethyl (6b),
methyl ester (6c), 2-chloroallyl (6d), and benzyl (6e). Further-
more, the reaction is scalable, with the benzyl substrate 5e
giving good results in a 1 gram reaction. In contrast, the nitrile
and benzyloxymethyl ether products 6f and 6g were isolated
with reduced enantioselectivities. Pleasingly, the uorine and
propargyl substrates 5h and 5i performed well, and may serve as
a precursor to a novel uorinated b2,2-amino acid, or for bio-
rthogonal click reactions, respectively.
Having demonstrated excellent results for the decarbox-
ylative alkylation of piperazin-2-ones and tetrahydropyrimidin-
2-ones, we began exploring their synthetic utility. In contrast
to the relative difficulty of removing the N4-benzyl type pro-
tecting groups in our previous work, both Boc groups of 4m
were easily removed by treatment with excess TFA to give ami-
nopiperazinone 8 (Scheme 4a). With LiOH, the benzoyl group
could be orthogonally removed to provide the free amide 9
(Scheme 4b). The amide 9 could then be reduced with LiAlH4 to
the corresponding chiral aminopiperazine 10. To further illus-
trate the synthetic versatility realized by Boc-deprotection of N4,
we hydrogenated the allyl olen of methyl piperazinone 4e
before cleaving the Boc group to obtain 11. We then applied
Gaunt's15 method of C–H carbonylation on the aliphatic amine
Scheme 4 Product derivatization: (a) Boc cleavage to the free amine.
(b) Benzoyl cleavage and reduction to the piperazine. (c) Boc cleavage,
of 11 to forge the fused b-lactam 12, which bears resemblance to allyl hydrogenation, and C–H carbonylation of the free amine. (d, e)
f
hydrolysis and subsequent protection of the b2,2-amino acid. KOH,
the core of various b-lactam antibiotics and b-lactamase
1 : 1 MeOH/H2O, rt; then, HCl, MeOH, rt. BQ ¼ benzoquinone. Piv ¼
pivalate.
Table 3 Pd-Catalyzed decarboxylative alkylation of tetrahydropyr-
imidin-2-ones. Scope of a-substituentsa
inhibitors (Scheme 4c). Lastly, we transformed four tetrahy-
dropyrimidinone substrates, 6c–e and 6h, into their corre-
sponding acyclic forms (Scheme 4d, e). Using a two-step
protocol involving TFA-mediated Boc cleavage followed by
saponication with LiOH, we successfully obtained the crude
b
2,2-amino acid (Scheme 4d); to facilitate silica gel chromato-
graphic isolation, we chose to mask the free amine and
carboxylic acid with Boc and benzyl groups, respectively,
resulting in protected b2,2-amino acid 13. We note that in this
four step sequence, we only performed one chromatographic
separation to isolate the protected b-amino acid. In contrast,
novel unprotected b2,2-amino acids 14–16 bearing pendant
carboxylic acid, chloroallyl, and uorine atom functional
groups could be obtained directly by purication with reverse
phase preparatory HPLC following the two-step deprotection
sequence (Scheme 4e).
Conclusions
In summary, we have developed a decarboxylative asymmetric
allylic alkylation reaction to synthesize unprecedented chiral
a,a-disubstituted piperazin-2-ones and tetrahydropyrimidin-2-
ones. This work represents a signicant improvement upon
existing technology, featuring ease of substrate synthesis, facile
a
Conditions: tetrahydropyrimidin-2-one 5 (1.0 equiv.), Pd2(pmdba)3
(4 mol%), (S)-(CF3)3-tBuPHOX (10 mol%), in 2 : 1 hexanes/toluene
(0.014 M) at 40 ꢀC for 12–24 h. All reported yields are for isolated
b
products. Reaction performed with 1 gram of substrate 5e. The ee
values were determined by chiral SFC analysis.
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N4-Boc deprotection, and broader substrate scope. The result-
ing piperazinones can be transformed into valuable chiral gem-
disubstituted piperazines that are anticipated to provide ster-
eodened access to new chemical space in drug discovery.
Similarly, the tetrahydropyrimidinone scaffold could be hydro-
Chem. Commun., 2013, 4, 515–519; (e) S. Monteleone,
J. E. Fuchs and K. R. Liedl, Front. Pharmacol., 2017, 8, 552.
6 Using the drugbank.ca database, we curated a structure
search of piperazine-containing small molecule drugs. Out
of 98 drugs, none were gem-disubstituted on the piperazine
ring.
lyzed to provide access to corresponding protected and free b2,2
-
amino acids. We anticipate this decarboxylative allylic alkyl-
ation protocol will nd utility in the eld of medicinal chemistry
as well as in natural products synthesis.
7 For a review, see: (a) K. E. Gettys, Z. Ye and M. Dai, Synthesis,
2017, 49, 2589–2604; (b) R. Holl, D. Schepmann and
¨
B. Wunsch, Med. Chem. Commun., 2012, 3, 673–679; (c)
G. Sudhakar, S. Bayya, K. J. Reddy, B. Sridhar, K. Sharma
and S. R. Bathula, Eur. J. Org. Chem., 2014, 1253–1265; (d)
S. Chamakuri, P. Jain, S. K. Reddy Guduru, J. W. Arney,
K. R. MacKenzie, C. Santini and D. W. Young, J. Org.
Chem., 2018, 83, 6541–6555; (e) R. Kuwano and Y. Ito,
J. Org. Chem., 1999, 64, 1232–1237; (f) W.-X. Huang,
L.-J. Liu, B. Wu, G.-S. Feng, B. Wang and Y.-G. Zhou, Org.
Lett., 2016, 18, 3082–3085; (g) T. D. Montgomery and
V. H. Rawal, Org. Lett., 2016, 18, 740–743; (h) J. S. Nakhla
and J. P. Wolfe, Org. Lett., 2007, 9, 3279–3282; (i)
B. M. Cochran and F. E. Michael, Org. Lett., 2008, 10, 329–
332; (j) B. P. McDermott, A. D. Campbell and A. Ertan,
Synlett, 2008, 875–879; (k) J. D. Firth, P. O'Brien and
L. Ferris, J. Am. Chem. Soc., 2016, 138, 651–659.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
The NIH-NIGMS (R01GM080269) and Caltech are thanked for
support of our research program. Additionally, A. W. S. thanks
the NIH-NIGMS for a predoctoral fellowship (Ruth L. Kirsch-
stein Institutional National Research Service Award
F30GM120836) and a UCLA-Caltech Medical Scientist Training
Program Fellowship (T32GM008042). S. N. H. thanks the Bayer
Foundation for an Otto Bayer Scholarship. Dr David Vander-
Velde is thanked for assistance with structural assignments via
NMR analysis. Dr Scott Virgil, Dr Marchello Cavitt, Dr Brendan
O'Boyle, Dr Justin Hilf, Dr Corey Reeves, and Kevin Yang are
thanked for helpful discussions.
8 (a) J. Meyers, M. Carter, N. Y. Mok and N. Brown, Future Med.
Chem., 2016, 8, 1753–1767; (b) C. M. Marson, in Advances in
Heterocyclic Chemistry, ed. E. F. V. Scriven and C. A.
Ramsden, Academic Press, 2017, pp. 13–33; (c) C.-V. T. Vo
and J. W. Bode, J. Org. Chem., 2014, 79, 2809–2815.
9 (a) W.-Y. Siau and J. W. Bode, J. Am. Chem. Soc., 2014, 136,
17726–17729; (b) K. Geoghegan and J. W. Bode, Org. Lett.,
2015, 17, 1934–1937; (c) S.-Y. Hsieh and J. W. Bode, Org.
Lett., 2016, 18, 2098–2101.
Notes and references
1 E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem.,
2014, 57, 10257–10274.
¨
10 S. A. Ruider, S. Muller and E. M. Carreira, Angew. Chem., Int.
2 (a) S. Omura, A. Hirano, Y. Iwai and R. Masuma, J. Antibiot.,
1979, 32, 786–790; (b) T. Chiba, Y. Asami, T. Suga,
Y. Watanabe, T. Nagai, F. Momose, K. Nonaka,
Ed., 2013, 52, 11908–11911.
11 K. M. Korch, C. Eidamshaus, D. C. Behenna, S. Nam,
D. Horne and B. M. Stoltz, Angew. Chem., Int. Ed., 2015, 54,
179–183.
¯
M. Iwatsuki, H. Yamada, S. Omura and K. Shiomi, Biosci.,
Biotechnol., Biochem., 2017, 81, 59–62; (c) X. Yu, F. Liu,
Y. Zou, M.-C. Tang, L. Hang, K. N. Houk and Y. Tang,
J. Am. Chem. Soc., 2016, 138, 13529–13532.
3 M. A. Grady, T. L. Gasperoni and P. Kirkpatrick, Nat. Rev.
Drug Discovery, 2003, 2, 427–428.
4 (a) H. Wang, M. D. Kowalski, A. S. Lakdawala, F. G. Vogt and
L. Wu, Org. Lett., 2015, 17, 564–567; (b) R. E. Ziegler,
B. K. Desai, J.-A. Jee, B. F. Gupton, T. D. Roper and
T. F. Jamison, Angew. Chem., Int. Ed., 2018, 57, 7181–7185.
5 (a) K. Hirata, M. Kotoku, N. Seki, T. Maeba, K. Maeda,
S. Hirashima, T. Sakai, S. Obika, A. Hori, Y. Hase, et al.,
ACS Med. Chem. Lett., 2016, 7, 23–27; (b) A. W. Hung,
A. Ramek, Y. Wang, T. Kaya, J. A. Wilson, P. A. Clemons
and D. W. Young, Proc. Natl. Acad. Sci. U. S. A., 2011, 108,
6799–6804; (c) F. Lovering, J. Bikker and C. Humblet,
J. Med. Chem., 2009, 52, 6752–6756; (d) F. Lovering, Med.
´
12 (a) B. Weiner, W. Szymanski, D. B. Janssen, A. J. Minnaard
and B. L. Feringa, Chem. Soc. Rev., 2010, 39, 1656–1691; (b)
D. L. Steer, R. A. Lew, P. Perlmutter, A. I. Smith and
M.-I. Aguilar, Curr. Med. Chem., 2002, 9, 811–822; (c)
D. Seebach, A. K. Beck and D. J. Bierbaum, Chem.
Biodiversity, 2004, 1, 1111–1239.
13 (a) J.-S. Yu, H. Noda and M. Shibasaki, Angew. Chem., Int. Ed.,
2018, 57, 818–822; (b) M. Nascimento de Oliveira,
S. Arseniyadis and J. Cossy, Chem.–Eur. J., 2018, 24, 4810–
4814.
14 (a) A. Guggisberg, K. Drandarov and M. Hesse, Helv. Chim.
Acta, 2000, 83, 3035–3042; (b) K. Drandarov, A. Guggisberg
and M. Hesse, Helv. Chim. Acta, 2002, 85, 979–989.
15 J. R. Cabrera-Pardo, A. Trowbridge, M. Nappi, K. Ozaki and
M. J. Gaunt, Angew. Chem., Int. Ed., 2017, 56, 11958–11962.
792 | Chem. Sci., 2019, 10, 788–792
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