Enantioselective Aza-Reformatsky Reaction with Ketimines

Article abstract of DOI:10.1021/acs.orglett.9b03669

Here, an enantioselective aza-Reformatsky reaction using acyclic ketimine substrates is presented. Using α-phosphorated ketimines as electrophilic substrates and a simple BINOL-derived ligand, phosphorated analogues of aspartic acid holding chiral tetrasubstituted carbons are efficiently obtained with excellent enantioselectivity through an asymmetric organocatalytic Reformatsky-type reaction. The phosphorated analogues of aspartic acid have been used for the synthesis of phosphorus-containing enantiopure tetrasubstituted β-lactams.

Full text of DOI:10.1021/acs.orglett.9b03669

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Aza-Reformatsky Reaction with Ketimines
Aitor Maestro, Edorta Martinez de Marigorta, Francisco Palacios,* and Javier Vicario*
́
Departamento de Química Organica I, Facultad de Farmacia, University of the Basque Country, UPV/EHU Paseo de la Universidad
7, 01006 Vitoria-Gasteiz, Spain
S
* Supporting Information
ABSTRACT: Here, an enantioselective aza-Reformatsky
reaction using acyclic ketimine substrates is presented.
Using α-phosphorated ketimines as electrophilic substrates
and a simple BINOL-derived ligand, phosphorated analogues
of aspartic acid holding chiral tetrasubstituted carbons are
efficiently obtained with excellent enantioselectivity through
an asymmetric organocatalytic Reformatsky-type reaction.
The phosphorated analogues of aspartic acid have been used for the synthesis of phosphorus-containing enantiopure
tetrasubstituted β-lactams.
Although not strictly catalytic, more recently Ando et al.
eformatsky reaction is a valuable synthetic process that is
1
Rwidely used for the effective formation of C−C bonds. have reported the synthesis of α,α-difluoro-β-lactams by an
imino-Reformatsky protocol promoted by 75% of amino-
alcohol ligands.6 Pedro and Vila et al. have performed
successful imino-Reformatsky processes with cyclic imines
using 20% of prolinol-derived ligand.7 Remarkably, their
catalytic system is equally effective when cyclic ketimines are
used as substrates, which allows the synthesis of quaternary
cyclic β-aminoesters with excellent ees (Scheme 1).
This transformation consists of a nucleophilic addition, in
general to aldehyde or ketone substrates, of a zinc enolate,
which is generated in situ through a metal insertion into
activated carbon halides.2 The discovery that organozinc
species can be used as a metal source3 offered more convenient
homogeneous conditions for this reaction, and since then,
many efforts have been made in developing catalytic systems
for the enantioselective Reformatsky reaction using ketones
and aldehydes.4 Imines are, however, suitable substrates for
this reaction, providing access to β-amino acid derivatives in a
simple synthetic protocol. The first catalytic enantioselective
imino-Reformatsky reaction was reported by Cozzi in 2006
using in situ preformed aldimines and 20−30% of N-
methylephedrine as a chiral ligand (Scheme 1).5
Due to the poor electrophilic character of ketimine carbons
and the additional steric hindrance on the substrate, the
formation of tetrasubstituted carbons from ketimines is always
a challenging task. In addition, the enantiotopic faces of
ketimines are not as easily discriminated as those of aldimines
when asymmetric synthesis is sought.8 These obstacles are
vitally important when acyclic substrates are used. In this
context, we reported recently the organocatalyzed nucleophilic
addition of cyanide or nitromethane to phosphorated
ketimines9 and the diastereoselective addition of organo-
metallic reagents to TADDOL-derived α-iminophosphonates10
for the asymmetric preparation of tetrasubstituted α-amino-
phosphonate derivatives.
Scheme 1. Precedents in Enantioselective Aza-Reformatsky
Reaction
In this case, we were intrigued about the possibility of
accessing phosphorated analogues of aspartic acid holding
tetrasubstituted carbons, using α-ketiminophosphonates as
electrophile substrates in an asymmetric aza-Reformatsky
reaction (Scheme 1). As far as we know, there are no
examples of such a reaction using acyclic ketimines as
substrates.
Moreover, it is well-known that α-aminophosphonates are
an important class of compounds that can behave as stable
analogues of the transition state of peptide cleavage. Due to
this fact, they often inhibit enzymes implicated in proteolysis
processes, and for this reason, α-aminophosphonic acid
Received: October 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
derivatives and their phosphapeptides show an assorted
biological activity.11 The biological activity of drugs in
general12 and α-aminophosphonic acids in particular13 is
known to be strongly dependent on its absolute configuration,
and for this reason, the development of new methods for the
preparation of enantioenriched α-aminophosphonate deriva-
tives is an important task in organic and medicinal chemistry.
Based on the zinc intermediates proposed by Noyori14 and
inspired by the mechanisms for other enantioselective
Reformatsky processes proposed by Cozzi5 and Feringa,15
initially we chose several diols and β-aminoalcohols as chiral
inductors in the aza-Reformatsky reaction of α-ketimino-
phosphonates (Figure 1). Our required imine electrophile
substrates can be easily obtained by a formal oxidation of the
parent tertiary α-aminophosphonates as reported.9
entry 1). Then, in order to minimize the ratio of β-hydride
transfer that leads to the formation of the reduced product,
dimethylzinc was used as metal source, but only quaternary α-
aminophosphonate 3 (R = Me) was observed, which
presumably results from the nucleophilic addition of
dimethylzinc to the imine electrophile.
It is known that diakylzinc species under an oxygen
atmosphere are able to form the very reactive alkylperoxides
(RZnOOR),16 which are excellent radical initiators. In fact,
some enantioselective Reformatsky reactions have been
reported, making use of organozinc reagents in the presence
of air or oxygen.5,15,17 Consequently, the reaction was
performed in dichloromethane under a dry air atmosphere
using diethylzinc as the metal source, but although the reaction
proceeded equally fast, again only reduced α-aminophospho-
nate 4 was observed (Table 1, entry 3). Switching to
dimethylzinc as the metal source, the formation of aza-
Reformatsky product 2 was observed together with 10% of 1,2-
addition product 3 (Table 1, entry 4). Due to the unfeasibility
of the β-hydride transfer reaction, no formation of reduced
compound 4 was noticed in this case. Although the same ratio
2:3 was obtained when the reaction was performed in low
polar or strong polar solvents such as toluene or N,N-
dimethylformamide, respectively (Table 1, entries 5 and 6), the
amount of 2 could be increased using tetrahydrofurane or
acetonitrile as solvents (Table 1, entries 7 and 8).
Next, we tested enantiopure (R)-BINOL (II) as a chiral
ligand, under the optimal reaction conditions, but only modest
enantioselectivity was obtained (Table 1, entry 9). To our
delight, when anthracenyl-substituted BINOL ligand III was
used in the same conditions, very high enantioselectivity was
observed (Table 1, entry 10). Surprisingly, the use of (S)-
VAPOL (IV) resulted in decreased enantiomeric excess
compared to simple (R)-BINOL (II) (Table 1, entry 11).
Finally, we even tested β-aminoalcohol derivative V that
showed very good enantioselection (Table 1, entry 12).
With the optimal reaction conditions in our hands, we then
extended the scope of the enantioselective aza-Reformatsky
reaction to differently substituted α-ketiminophosphonates 1
(Figure 2). Excellent enantiomeric excesses were obtained in
all cases. The reaction tolerates the presence of para- and meta-
alkyl substituents at the aromatic ring (Figure 2, 2b−c) as well
as strong electron-donating groups at the para position of the
aromatic imine (Figure 1, 2d). Several halogen-substituted
aromatic ketimines were also successfully used in the reaction,
including para-substituted aromatic rings containing fluorine,
chlorine, or bromine (Figure 2, 2e−g), meta-substituted
aromatic rings holding fluorine and chlorine (Figure 2, 2h−
i), as well as ortho-fluorophenyl-substituted ketimines (Figure
2, 2j). Moreover, dichloro- and difluoro-phenyl-substituted
imines showed excellent enantioselectivities (Figure 2, 2k−m),
and even perfluorophenyl-substituted substrates were tested
with success using the same catalytic system (Figure 2, 2n).
Furthermore, an excellent result was observed for imine 1o
holding an aromatic ring that is substituted with a chlorine and
a strong electron-donating methoxy group. Besides, good
reactivity and excellent enantioselectivity are also obtained
using aromatic imines substituted with electron-withdrawing
groups such as p-nitro or p-trifluoromethyl substituents (Figure
2, 2p−q). The reaction can be also extended to the use of
imines holding biphenyl or heteroaromatic substituents
(Figure 2, 2r−s). Finally, in order to further deprotect
selectively the ester group, benzyl iodoacetate was used as a
Figure 1. Ligands tested in this study.
For the optimization of the reaction conditions, first we
studied the reaction of dimethyl α-iminophosphonate 1 with
ethyl iodoacetate in the presence of an organozinc reagent and
20 mol % of racemic BINOL I. Depending on the organozinc
reagent used in the reaction, besides the desired product 2,
compounds 3 and 4 were observed in the reaction mixture,
resulting from a direct nucleophilic addition of organozinc
reagent or the reduction of an imine bond, respectively (Table
1).
First, when diethylzinc was used as the metal source in
dichloromethane, the reaction proceeded fast, but only
reduced α-aminophosphonate 4 was observed (Table 1,
Table 1. Optimization of the Reaction Conditions
c
d
entry
solvent
R
cat. conversion/%
2:3:4
ee/%
a
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et
Me
Et
I
I
I
I
I
I
I
I
II
III
IV
V
100
100
100
100
100
100
100
100
100
100
100
100
0:0:100
0:100:0
0:0:100
90:10:0
90:10:0
90:10:0
95:5:0
-
-
-
-
-
-
-
-
64
99
38
97
a
b
b
Me
Me
Me
Me
Me
Me
Me
Me
Me
b
toluene
b
DMF
THF
b
b
b
b
b
b
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
97:3:0
97:3:0
97:3:0
97:3:0
10
11
12
97:3:0
a
b
c
Under N2 atmosphere. Under dry air atmosphere. Determined by
d
1H NMR. Determined by chiral HPLC.
B
DOI: 10.1021/acs.orglett.9b03669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Thus, 1.00 g of ketimine 1a reacted with benzyl iodoacetate
in the presence of 20 mol % of BINOL ligand III to yield the
aza-Reformatsky product 2t in 84% yield and 87% ee. With the
aim of determining the absolute configuration of the
stereogenic carbon of the major enantiomer in our substrates,
using enantioenriched compound 2t, a substantial amount of
the enantiopure β-lactam 7 was prepared. A crystal of the
major enantiomer of 7 was isolated and submitted to X-ray
diffraction analysis, revealing an S absolute configuration of the
quaternary stereocenter (Figure 3).
Figure 2. Scope of the reaction.
reagent in the aza-Reformatsky reaction with our α-
iminophosphonate substrates, again with an excellent result
(Figure 2, 2t).
Figure 3. X-ray structure of lactam 7 showing its absolute
configuration (gray: C, white: H, red: O, blue: N, purple: P).
Next, with the purpose of illustrating the applications of our
enantioenriched substrates, some synthetic transformations of
α-aminophosphonate derivatives 2 were accomplished. A
selective deprotection of the phosphonate group can be easily
performed in a few hours using dimethylphosphonate
derivative 2a in the presence of trimethylsilyl bromide18 to
afford α-aminophosphonic acid derivative 5 in very good yield.
For the selective deprotection of the ester group, we chose
benzylic ester 2t as the substrate. A vigorous stirring of
compound 2t under hydrogen atmosphere in the presence of a
catalytic amount of palladium yielded the expected phosphory-
lated β-amino acid derivative 6 in excellent yield. Finally,
activation of the carboxylic group in 6 with N,N-dicyclohex-
ylcarbodiimide (DCC) in the presence of dimethylaminopyr-
idine (DMAP) led to the formation of phosphorated β-lactam
derivative 7 bearing a tetrasubstituted stereocenter (Scheme
2).
In summary, although successful enantioselective Reformat-
sky reactions have been described during the last years using
acyclic aldehydes, aldimines, or ketones, we report here the
first example of an enantioselective aza-Reformatsky reaction
using acyclic ketimines as electrophile substrates. Phospho-
rated analogues of aspartic acid holding tetrasubstituted
carbons are efficiently obtained with excellent enantioselectiv-
ity, using α-ketiminophosphonates, with a simply function-
alized BINOL ligand as the chiral inductor. In addition, besides
that phosphorus-containing enantiopure tetrasubstituted β-
lactams have not been reported so far, we describe here the
first asymmetric synthesis of phosphorylated β-lactams using a
catalytic approach.
ASSOCIATED CONTENT
* Supporting Information
■
In order to authenticate the synthetic potential of our
asymmetric methodology, a multigram-scale reaction was
performed for the synthesis of α-aminophosphonate 2t.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03669.
Scheme 2. Synthetic Applications of the Phosphorated
Analogues of Aspartic Acid 2
Thermal ellipsoid plot for 7 and full experimental details,
1
characterization, and copies of H, 13C, and 31P NMR
spectra for compounds 1, 2, 5, 6, and 7 and 19F NMR
for compounds 1e,h,j,l,m,n,q and 2e,h,j,l,m,n,q (PDF)
Accession Codes
CCDC 1957474 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.
C
DOI: 10.1021/acs.orglett.9b03669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Carbon Centers with High Enantioselectivity. Angew. Chem., Int. Ed.
2011, 50, 5998.
AUTHOR INFORMATION
■
Corresponding Authors
(9) (a) Vicario, J.; Ezpeleta, J. M.; Palacios, F. Asymmetric
Cyanation of α-Ketiminophosphonates Catalyzed by Cinchona
Alkaloids. Enantioselective Synthesis of Tetrasubstituted α-Amino-
phosphonic Acid Derivatives From Trisubstituted α-Aminophospho-
nates. Adv. Synth. Catal. 2012, 354, 2641. (b) Vicario, J.; Ortiz, P.;
Ezpeleta, J. M.; Palacios, F. Asymmetric Synthesis of Functionalized
Tetrasubstituted α-Aminophosphonates through Enantioselective
Aza-Henry Reaction of Phosphorylated Ketimines. J. Org. Chem.
2015, 80, 156.
*E-mail: francisco.palacios@ehu.eus.
*E-mail: javier.vicario@ehu.eus.
ORCID
Francisco Palacios: 0000-0001-6365-0324
Javier Vicario: 0000-0002-8976-0991
Author Contributions
(10) Vicario, J.; Ortiz, P.; Palacios, F. Synthesis of Tetrasubstituted
α-Aminophosphonic Acid Derivatives from Trisubstituted α-Amino-
phosphonates. Eur. J. Org. Chem. 2013, 2013, 7095.
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
(11) (a) Hiratake, J.; Oda, J. Aminophosphonic and Aminoboronic
Acids as Key Elements of a Transition State Analogue Inhibitor of
Enzymes. Biosci., Biotechnol., Biochem. 1997, 61, 211. (b) Kafarski, P.;
Lejczak, B. Aminophosphonic Acids of Potential Medical Importance.
Curr. Med. Chem.: Anti-Cancer Agents 2001, 1, 301. (c) Berlicki, L.;
Kafarski, P. Computer-Aided Analysis and Design of Phosphonic and
Phosphinic Enzyme Inhibitors as Potential Drugs and Agrochemicals.
Curr. Org. Chem. 2005, 9, 1829. (d) Van der Jeught, K.; Stevens, C. V.
Direct Phosphonylation of Aromatic Azaheterocycles. Chem. Rev.
2009, 109, 2672.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
Financial support by Ministerio de Ciencia, Innovacion y
Universidades (RTI2018-101818-B-I00, MCIU/AEI/FEDER,
UE), and Gobierno Vasco (GV, IT 992-16) is gratefully
acknowledged. The authors are thankful for the technical and
human support provided by SGIker (UPV/EHU/ERDF, EU).
(12) (a) Nguyen, L. A.; He, H.; Pham-Huy, C. Chiral Drugs: An
Overview. Int. J. Biomedical Sci. 2006, 2, 85. (b) Kasprzyk-Hordern, B.
Pharmacologically active compounds in the environment and their
chirality. Chem. Soc. Rev. 2010, 39, 4466.
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