Access to Unprotected β-Fluoroalkyl β-Amino Acids and Their α-Hydroxy Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b00622

Unprotected β-(het)aryl-β-fluoroalkyl β-amino acids and their α-hydroxy derivatives can be readily obtained using a decarboxylative Mannich-type reaction without protection/deprotection steps. This protocol utilizes lithium hexamethyldisilazide and (het)arylfluoroalkyl ketones to generate NH-ketimine intermediates. The mild reaction conditions allow the preparation of original fluorinated β-amino acids as useful building blocks in a practical and scalable manner.

Full text of DOI:10.1021/acs.orglett.9b00622

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Access to Unprotected β‑Fluoroalkyl β‑Amino Acids and Their
α‑Hydroxy Derivatives
Volodymyr Sukach,*,‡,† Serhii Melnykov,#,⊥ Sylvain Bertho,† Iryna Diachenko,† Pascal Retailleau,§
Mykhailo Vovk,# and Isabelle Gillaizeau*,†
‡
́
Le Studium Loire Valley Institute for Advanced Studies, 1, rue Dupanloup, Orleans 45000, France
†
́
́
́
Institute of Organic and Analytical Chemistry, ICOA UMR 7311 CNRS, Universite d’Orleans, rue de Chartres, Orleans 45100,
France
#Institute of Organic Chemistry of NAS of Ukraine, 5, Murmanska Str., Kyiv 02660, Ukraine
⊥Enamine LTD, 78 Chervonotkats’ka Str., Kyiv 02094, Ukraine
§
́
́
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Universite Paris-Sud, Universite Paris-Saclay, Avenue de la
Terrasse, Gif-sur-Yvette 91198, France
S
* Supporting Information
ABSTRACT: Unprotected β-(het)aryl-β-fluoroalkyl β-amino
acids and their α-hydroxy derivatives can be readily obtained
using a decarboxylative Mannich-type reaction without
protection/deprotection steps. This protocol utilizes lithium
hexamethyldisilazide and (het)arylfluoroalkyl ketones to
generate NH-ketimine intermediates. The mild reaction
conditions allow the preparation of original fluorinated β-
amino acids as useful building blocks in a practical and
scalable manner.
he β-amino acids are the most prominent nonproteino-
which inhibit MMP,10 and more recently, into oligo-β-
peptides, which are able to form significantly more stable
helices due to the effects of CF3 groups.11 β-Substituted
derivatives of β-fluoroalkyl-β-amino acids are scarce.12 The
synthesis of racemic 3-amino-4,4,4-trifluoro-3-phenylbutanoic
acid was first described in 1991 by Kukhar’s group via a hetero
Diels−Alder cycloaddition using ketene (Scheme 1a).13
However, harsh reaction conditions or substrate scope
limitations call for the development of new routes.
T
genic amino acids1 and are found as a structural motif in
many natural products2 or biologically active molecules such as
β-lactam antibiotics (Figure 1).3 They are key synthetic
In 2013, Grellepois14 published the first diastereo- and
enantioselective synthesis of β-alkyl(aryl)-β-trifluoromethyl-β-
amino acid derivatives based on a CuI-catalyzed Reformatsky
reaction (Scheme 1b). Enantiopure N-tert-butanesulfinyl
trifluoromethyl ketimines generated in situ from stable
precursors were thus advantageously used. Similar reports,
using lithium enolate, gave rise to promising MGAT2
inhibitors15 or modulators of mGluR4.16 Recently, Ohshima
and co-workers investigated a catalytic Mannich-type reaction
with various (di)ketones and dialkyl malonates using
trifluoromethyl NH-ketimines as electrophiles (Scheme
1c).17 However, it required a strong metal-based Lewis acid
catalyst and isolation of NH-ketimines that are not readily
accessible, weakening its synthetic potential. Furthermore, this
group also reported a catalytic enantioselective decarboxylative
Mannich-type reaction of N-unprotected ketimines from
Figure 1. β-Amino acids in bioactive compounds.
precursors for important marketed pharmaceutical products
(i.e., sitagliptin, paclitaxel).4 Fluorinated analogues of amino
acids have received considerable attention in recent years due
to their potential in preparing bioactive molecules with
remarkable properties.5−7β-Amino acids bearing a fluoroalkyl
group at β-position are of particular interest as unique
intermediates in the design of bioactive peptide mimetics or
enzyme inhibitors. 3-Amino-4,4,4-trifluorobutanoic acid8 has
been incorporated into partially modified retropeptides
exhibiting a β-turn-like conformation9 into peptidomimetics,
Received: February 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00622
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Preparation of β-Substituted β-Trifluoromethyl-
β-Amino Acids
Scheme 2. Prelminary Synthesis of β-Amino Acid 4a from
Ketone 1a Using LiHMDS
reaction mixture by 19F NMR monitoring. In these conditions,
3-amino-4,4,4-trifluoro-3-phenylbutanoic acid 4a was formed
in quantitative NMR yield and precipitated from acetonitrile.
After a simple workup, 4a was isolated as hydrochloride salt in
87% yield.
We also demonstrated that 3-amino-4,4,4-trifluoro-3-phenyl-
butanoic acid 4a could be obtained in higher overall yield
directly from 2a (route B). In this case, the cleavage of the N-
TMS bond is likely to quickly occur in the presence of malonic
acid leading to the in situ formation of the reactive NH-
ketimine 3a. It is worth noting that a one-pot procedure can
also be advantageously used (route C). In this case, the
equimolar amount of TMSOLi, resulting from the trans-
formation of ketone to ketimine, was quenched with TMSCl
before MA addition to prevent the formation of TMSOH. Its
dimerization with concomitant water release may result in
hydrolysis of 3a.24 Gratifyingly, the one-pot protocol directly
led to the unprotected amino acid 4a, which precipitates from
the reaction mixture. However, in this case, the yield of pure
isolated product 4a dropped to 46% due to the still poorly
controlled partial hydrolysis of in situ formed 3a to ketone 1a
(see the Supporting Information). Since the best yield of
unprotected β-amino acid 4a was observed using method B,
various conditions were then screened from N-TMS ketimine
2a (see the Supporting Information). A series of common
solvents were next examined, revealing that briefly heating the
reaction mixture in acetonitrile (2 h at 80 °C) in the presence
of 2 equiv of MA was best suited to the reaction.
With the optimized conditions in hand, the scope of this
two-step reaction was examined with respect to the ketone
derivatives 1a−y (Scheme 3). The reaction proceeded
smoothly with a wide functional group tolerance. Initially,
the effect of the substituents on the aromatic ring of
arylfluoroalkyl ketone (1a−u) was investigated. Both elec-
tron-donating (i.e., alkoxy, alkyl, or dialkylamino groups) and
withdrawing groups (i.e., halogen, trifluoroalkyl, or nitro
groups) with different substitution patterns were tolerated,
thus giving the corresponding quaternary β-(het)aryl-β-
fluoroalkyl-β-amino acids in good yields (4a−u). In addition,
heteroaryl substituted ketones 1v−w were also suitable for this
reaction, providing the original β-hetaryl β-trifluoromethyl β-
amino acids 4v−w. Introduction of the CClF2 and C2F5 groups
led to the hitherto unknown β-fluoroalkyl β-amino acids 4x−y.
Additionally, the alternative one-pot procedure (method C)
was applied to ketones 1b,j affording the attempted products
4b,j in lower yields. A variety of original unprotected β-
isatins, providing N-unprotected 3-tetrasubstituted 3-amino-
oxindole derivatives.18
The literature survey clearly pointed out the lack of simple
and flexible protocols for accessing β-(het)aryl-β-fluoroalkyl-β-
amino acids, which may limit their broader synthetic
application. Despite the above-mentioned existing methods,
only the simplest β-amino acid possessing a β-phenyl
substituent has been characterized so far.13 This is in striking
contrast to β-substituted analogues, which are readily available
in one step by the Rodionov reaction,19 a three-component
decarboxylative reaction of aldehydes, malonic acid (MA), and
ammonium acetate. However, this approach suffers from
limitations, providing a major challenge to develop sustainable
alternatives.20 In the context of our studies on trifluoromethyl
NH-ketimines,21 we present herein the first decarboxylative
addition of malonic acids to generate in situ fluoroalkyl NH-
ketimines as an attractive and direct access to unprotected β-
fluoroalkyl-β-amino acids that has heretofore remained unex-
plored. Our approach complements the mechanistically similar
Rodionov reaction, postulated to proceed via formation of the
NH-aldimines,19a by introducing a new class of substrates
challenging fluoroalkyl ketones.
Initially, we attempted to synthesize the starting NH-
ketimine 3a, used as a model substrate, from the corresponding
trifluoromethyl ketone 1a via the N-TMS derivative 2a to
avoid the use of highly toxic trifluoroacetonitrile or of
triphenylphosphine imine, which is not readily available
(Scheme 2, route A).22 Compound 2a was isolated in almost
quantitative yield according to the known procedure using
lithium hexamethyldilazide (LiHMDS).23 Removal of the TMS
group was achieved upon acidic treatment affording 3a in 56%
isolated yield after distillation. Then, we first studied the
reaction of 3a with MA. To our delight, the addition of MA (3
equiv) in anhydrous acetonitrile proceeded smoothly to full
completion in 24 h at room temperature. The concurrent
decarboxylation of the initially formed MA adduct (not shown
in Scheme 2, but see the mechanism discussion below)
occurred much faster since it could not be detected in the
B
DOI: 10.1021/acs.orglett.9b00622
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Organic Letters
Letter
Scheme 3. Scope of Ketones 1a−y in the Synthesis of β-
Scheme 4. Synthesis of β-Fluoroalkyl β-Amino Esters 6a−d
a b
,
a
Fluoroalkyl β-Amino Acids 4a−y
and α-Hydroxy-β-Amino Acids 7a−h
a
Isolated yields were calculated from the corresponding starting
ketones 1. For compounds 7, the structures and yields refer to isolated
major diastereomers with >98:2 dr.
desired products 7a−h as single diastereomers (>98:2 dr),
albeit in lower yields, directly upon simple workup of the
reaction mixture and crystallization. 19F NMR analysis revealed
that in the reaction of 2a with 5d a mixture of diastereomeric
products (83:17 dr) was initially formed in 80% NMR yield
(see the Supporting Information). The (2R*,3S*) relative
configurations of the chiral centers in products 7a−h were
unambiguously proved by the XRD study of 7b. Consequently,
the obtained compounds 7 are the first racemic β-fluoroalkyl
analogues of Paclitaxel’s side chain amino acid, (2R,3S)-α-
hydroxy β-phenylalanine.7c,26
a
Reaction conditions: Method B was used with isolation of crude N-
TMS ketimines 2a−y unless otherwise specified; syntheses were
performed on a 1.5 mmol scale in 1 mL of CH3CN. Isolated yields
were calculated on the basis of the corresponding starting ketones
1a−y. The reaction was performed on a 10 mM scale. One-pot
procedure C was used with addition of TMSCl (1 equiv, 0−5 °C, 2 h
at rt) before addition of MA (see the Supporting Information for
experimental details).
b
c
d
fluoroalkyl β-amino acids were thus readily furnished in
synthetically useful yields without any chromatographic
purification steps and in a convenient and easy way for scale-
up (preparation of 4a was achieved in 75% yield under optimal
conditions on a 10 mM scale). There are also a great many
uses for β-fluoroalkyl β-amino acids, which can be transformed
to a variety of useful compounds.
In agreement with the previously reported literature
results,27 a proposed mechanism for the decarboxylative
addition of MA and tartronic acid to NH-ketimine 3a is
outlined in Scheme 5. First, it should be noted that the rate of
Subsequently, we explored the use of substituted MA in this
decarboxylative Mannich-type reaction with ketimines 2
(Scheme 4). To our delight, a range of malonic acid half
esters 5a−d were suitable for the reaction leading to β-amino
esters 6a−d (Y = H) in moderate to good yield, which
demonstrated the remarkable scope of this method. Installation
of a chiral auxiliary derived from optically pure (−)-menthol in
the starting compound 5c led to β-amino esters 6c with 65:35
dr. Compound 6d featuring an ethoxycarbonyldifluoromethyl
group was obtained in moderate yield from the corresponding
ethyl 2,2-difluoro-3-oxo-3-phenylpropanoate 1z. Noticeably, α-
hydroxy-β-amino acids are important naturally occurring
compounds primarily known as components of the taxane
family of anticancer drugs.25 Their corresponding β-aryl-β-
fluoroalkyl derivatives remain elusive and represent an
attractive synthetic target owing to the presence of the
fluorinated functional group. We attempted to further confirm
the broad generality and effectiveness of the developed method
by involving commercially available hydroxymalonic (tar-
tronic) acid 5d (Scheme 4, Y = OH) as substrate. 5d (3
equiv) reacted smoothly with the corresponding crude N-TMS
ketimines 2 under the reaction conditions and afforded the
Scheme 5. Proposed Mechanistic Pathways for the
Decarboxylative Addition of Malonic or Tartronic Acid to
3a
4a formation is not sensitive to the presence of organic acid or
base catalysts (TFA, TfOH, pyridine, Et3N, etc., including
chiral organocatalysts). We assume that in this case a mutual
substrate catalysis is observed since 3a itself is a weak organic
base while MA is mildly acidic (pKa1 = 2.83). Therefore, both
substrates are capable of activating each other’s corresponding
electrophilic (CN bond) or nucleophilic (CH2 group)
centers, thus causing externally added catalyst inefficiency. The
reactive C-nucleophilic species generated from malonic
C
DOI: 10.1021/acs.orglett.9b00622
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Organic Letters
Letter
(tartronic) acid is assumed to be enolate monoanion
(approximate pKaCH = 13−14 for MA).28 In the first step, its
reversible addition to protonated ketimine 3a gives rise to
intermediate I. Then, irreversible decarboxylation of I leads to
4a (Y = H). In the case of tartronic acid addition (Y = OH),
preferential formation of the major diastereomer 7a is
determined, according to the classic Curtin−Hammett
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00622.
■
S
Experimental procedures, NMR data, and crystal
structure of the products (PDF)
‡
principle, by the relatively large difference in ΔGII and
‡
ΔGIII energies of the transition states derived from the
Accession Codes
respective most populated conformers II and III, which are
CCDC 1864064 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
stabilized by the intramolecular electrostatic interaction and
+
hydrogen bonding between syn-clinal NH3 and COO−/
COOH groups. These mechanistic assumptions imply that
intermediates II and III should undergo rapid reversible
interconversion by proton transfer and slower irreversible
−
decarboxylation (presumably via the leaving CO2 group and
the formation of a noncyclic anionic transition state)29 into
diastereomeric products.
AUTHOR INFORMATION
Corresponding Authors
■
To demonstrate the utility of this reaction and gain access to
molecular diversity, we performed a short-step synthesis of the
novel relevant 4-amino-4-(trifluoromethyl)-3,4-dihydroquino-
lin-2(1H)-one derivative 10 as an attractive scaffold for
medicinal chemistry (Scheme 6).30 The key cyclization step
*E-mail: isabelle.gillaizeau@univ-orleans.fr.
*E-mail: vsukach@gmail.com.
ORCID
Volodymyr Sukach: 0000-0002-2891-343X
Pascal Retailleau: 0000-0003-3995-519X
Mykhailo Vovk: 0000-0001-7739-670X
Isabelle Gillaizeau: 0000-0002-7726-3592
Notes
Scheme 6. Application of β-Amino Acid 4a to the Synthesis
of Original Heterocyclic Systems
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Smart Loire Valley
Fellowships Programme (V.S.) funded from the European
Union’s Horizon 2020 research and innovation programme
under the Marie Skłodowska-Curie grant agreement No.
665790. S.B. thanks the Region Centre Val de Loire. The
authors thank Cyril Colas (ICOA) for fruitful discussions
(HRMS).
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