Enantioselective Synthesis of α-Amino Phosphonates via Pd-Catalyzed Asymmetric Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.5b03664

A highly enantioselective palladium-catalyzed hydrogenation of a series of linear and cyclic α-iminophosphonates has been achieved, providing efficient access to optically active α-aminophosphonates with up to 99% ee. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b03664

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of α‑Amino Phosphonates via Pd-
Catalyzed Asymmetric Hydrogenation
Zhong Yan,† Bo Wu,† Xiang Gao,† Mu-Wang Chen,† and Yong-Gui Zhou*,†,‡
†State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A highly enantioselective palladium-catalyzed hydro-
genation of a series of linear and cyclic α-iminophosphonates has been
achieved, providing efficient access to optically active α-amino-
phosphonates with up to 99% ee.
α-Aminophosphonic acids are valuable and prevalent sub-
structures with important biological and pharmacological
properties.1 Owing to their structural analogy to α-amino
acids, optically active α-aminophosphonic acids have found
widespread applications as potentially active substrates,
including enzyme inhibitors,2 antibacterial agents,3 and
herbicides.4 Notably, the biological properties of α-amino-
phosphonic acids are closely linked with the absolute
configuration of the stereogenic α-carbon to phosphorus. For
example, (S,R)-alafosfalin serves as a better antibacterial reagent
against both Gram-positive and Gram-negative microorganisms
than the other three diastereoisomers,5 and (R)-1-amino-3,4-
dichlorobenzylphosphonic acid exhibits more potent inhibition
on phenylalanine ammonia-lyase than the S enantiomer (Figure
1).6 Therefore, developing an efficient and convenient method
to optically active α-aminophosphonic acids is of great
significance and highly desirable.
hydrogenation of α,β-dehydroaminophosphonates by using a
rhodium catalytic system with up to 76% ee.9 Then a plethora
of research focused on the Rh-, Ru-, or Ir-catalyzed hydro-
genation of the corresponding olefinic precursors that had been
described and provided both α- and β-aminophosphonic acid
derivatives with good to excellent enantioselectivities (eq 1,
Scheme 1).10 Notably, in 1994, Burk’s group documented
enantioselective synthesis of α-aminophosphonate through Rh-
DuPhos-catalyzed hydrogenation of hydrazone substrate, but
only one example was reported.11 Subsequently, Goulioukina’s
group developed a straightforward strategy for the preparation
of optically active α-aminophosphonates via the Rh- or Pd-
Scheme 1. Synthesis of Chiral Aminophosphonates via
Asymmetric Hydrogenation
Figure 1. Selected biologically active molecules containing chiral α-
aminophosphonic acid motif.
In the past decades, organic chemists have developed several
catalytic asymmetric protocols for the synthesis of optically
active α-aminophosphonic acids and their derivatives.7 Most
enantioselective methods rely on the construction of stereo-
selective C−C, C−N, C−P, and C−H bond formation. Among
these protocols, transition-metal-catalyzed asymmetric hydro-
genation is particularly attractive and convenient from an atom
efficiency point of view.8 However, the asymmetric hydro-
genation strategy has only received limited attention to date. In
Received: December 25, 2015
1985, Schollkopf’s group reported the first asymmetric
̈
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03664
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Organic Letters
Letter
catalyzed asymmetric hydrogenation of α-iminophosphonates
with moderate to high ee values (eq 2, Scheme 1).12 Despite
continuing progress in the asymmetric hydrogenation of linear
α-iminophosphonates, these reports rarely involve cyclic imine
substrates.
of TFE was crucial for the reactivity. To further improve the
reaction efficiency, an enhanced survey of the mixed solvent
was conducted, and TFE/CH2Cl2 (1/4) was the optimal
reaction medium with 85% ee (Table 1, entries 5−8). We
further turned our attention toward chiral ligands (Table 1,
entries 8−12). Of various commercially available diphosphine
ligands investigated, electron-withdrawing (R)-DifluorPhos
(L5) proved to be the most favorable ligand resulted in 97%
ee, albeit with low reactivity (Table 1, entry 12). Fortunately,
when we adjusted the ratio of TFE/CH2Cl2 to 2/1, the
enantioselectivity could be maintained and the reactivity
increased obviously at the same time (Table 1, entry 14).
With the optimized reaction conditions in hand, we then
investigated the substrate scope of the reaction. The results
were summarized in Scheme 2. Pleasingly, a series of aryl-
During the past few years, our group has been involved in the
development of Pd-catalyzed homogeneous asymmetric hydro-
genation of various unsaturated compounds and a series of
functional imine substrates with good to excellent enantiose-
lectivities.8f,13 Considering the ready availability and easy
preparation of N-tosyl α-ketiminophosphonates,14 we envi-
sioned that optically active α-aminophosphonates could be
easily synthesized through Pd-catalyzed asymmetric hydro-
genation of these compounds. The challenging aspects of this
process include the control of enantioselectivity and the
improvement of reactivity. Herein, we report a Pd-catalyzed
asymmetric hydrogenation of both linear and cyclic α-imino-
phosphonates with good to excellent enantioselectivities (eq 3,
Scheme 1).
a
Scheme 2. Substrate Scope: Linear α-Iminophosphonates 1
Initially, (E)-diethyl(phenyl(tosylimino)methyl)phosphonate
1a was chosen as the model substrate. We tested the
hydrogenation of 1a with Pd(OCOCF3)2/(S)-SynPhos as
catalyst in the presence of 4 Å MS as additive in TFE (600
psi hydrogen gas, 40 °C and 24 h). Gratifyingly, the reaction
proceeded smoothly, and moderate 75% ee was obtained
(Table 1, entry 1). A variety of solvents were tested under the
same conditions. As shown in Table 1, good enantioselectivity
but poor reactivity could be obtained in CH2Cl2, and the
reaction proceeded with no reactivity in toluene and THF
(Table 1, entries 2−4). The results suggested that the presence
a
Table 1. Evaluation of Reaction Parameters
a
Conditions: 1 (0.10 mmol), Pd(OCOCF3)2 (2.0 mol %), (R)-
DifluorPhos (2.4 mol %), 4 Å MS (50 mg), TFE/CH2Cl2 (2/1) (1.5
mL), H2 (600 psi), 40 °C, 24 h.
b
c
entry
solvent
ligand
yield (%)
ee (%)
1
TFE
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L5
L5
92
10
NR
NR
93
95
98
97
88
75
97
81
89
93
75 (R)
90 (R)
NA
substituted α-ketiminophosphonates were successfully con-
verted to the corresponding α-aminophosphonates with good
to excellent ee values (85−97% ee). It was noteworthy that the
substrates (1a−d) bearing different phosphonate substituents
all afforded excellent enantioselectivities. In contrast to ethyl
substituent, the length of the alkyl chain had little influence on
enantioselectivity, and the high steric hindrance of isopropyl
rarely affected the enantiocontrol. Additionally, substrates with
different halogen groups on the phenyl ring also proceeded
smoothly, giving the desired adducts (2e−g) in high ee values
and yields. However, the ee value decreased dramatically to
85%, when a strong electron-withdrawing nitro group was
introduced (2h). In particular, when a methyl group was
introduced at the 4-position of the phenyl ring (2i), the
transformation displayed both high reactivity and enantiose-
lectivity. The absolute configuration of the product 2a (which
can be increased to 99% ee by a simple recrystallization with
dichloromethane and n-hexane) was unambiguously deter-
mined to be S by X-ray crystallographic analysis (Figure 2).
Furthermore, in order to demonstrate the versatility of our
method, a series of cyclic six- and five-membered ring α-
iminophosphonates were also synthesized by the combination
of slightly modified literature procedures (Scheme 3).15 Readily
available salicylaldehyde and N-tert-butylbenzenesulfonamide
2
CH2Cl2
3
toluene
4
THF
NA
5
TFE/CH2Cl2 (4:1)
TFE/CH2Cl2 (2:1)
TFE/CH2Cl2 (1:2)
TFE/CH2Cl2 (1:4)
TFE/CH2Cl2 (1:4)
TFE/CH2Cl2 (1:4)
TFE/CH2Cl2 (1:4)
TFE/CH2Cl2 (1:4)
TFE/CH2Cl2 (1:2)
TFE/CH2Cl2 (2:1)
78 (R)
80 (R)
84 (R)
85 (R)
91 (S)
93 (S)
87 (S)
97 (S)
97 (S)
96 (S)
6
7
8
9
10
11
12
13
14
a
Conditions: 1a (0.10 mmol), Pd(OCOCF3)2 (2.0 mol %), L (2.4
mol %), 4 Å MS (50 mg), solvent (1.5 mL), H2 (600 psi), 40 °C, 24 h.
Isolated yields. Determined by chiral HPLC. NR: no reaction. NA:
no analysis.
b
c
B
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Organic Letters
Letter
a
Scheme 4. Substrate Scope: Cyclic α-Iminophosphonates 3
Figure 2. X-ray crystal structure of compound (S)-2a.
Scheme 3. Synthesis of Cyclic α-Iminophosphonates 3
a
Conditions: 3 (0.10 mmol), Pd(OCOCF3)2 (2.0 mol %), (R)-
DifluorPhos (2.4 mol %), 4 Å MS (50 mg), TFE/CH2Cl2 (2/1) (1.5
mL), H2 (600 psi), 40 °C, 24 h.
Scheme 5. Desulfonylation of (S)-2a
In summary, we have successfully realized the asymmetric
hydrogenation of a series of linear and cyclic α-iminophosph-
onates with a palladium catalyst, providing an efficient access to
optically active α-aminophosphonates with up to 99% ee.
Further efforts to achieve the asymmetric hydrogenation of
other functionalized α-iminophosphonates are ongoing in our
laboratory.
were used as the starting materials and converted to the
sulfonylimine intermediates 6, followed by nucleophilic
addition of phosphites to afford α-aminophosphonates 7 and
oxidation dehydrogenation. Notably, for the selective dehydro-
genation process of α-aminophosphonates 7, only freshly
prepared manganese dioxide gave high yield and selectivity.
Pleasingly, the asymmetric hydrogenation strategy also fit
well for those cyclic α-iminophosphonates 3, and they were
successfully converted to the corresponding α-aminophospho-
nates with excellent ee values (91−99% ee). As shown in
Scheme 4, it was noteworthy that the substrates bearing an
isopropyl phosphonate substituent afforded higher enantio-
meric excess than the diethyl phosphonate substituent.
Considering the steric effect of aryl substituents, the substrates
(3d−f) were synthesized and the slightly higher enantiose-
lectivity was obtained when a methoxy group was introduced
on the 7-position of the phenyl ring. Notably, when a methyl
group was introduced at the same position (3c), the highest
99% ee was obtained. Meanwhile, the five-membered ring α-
iminophosphonates were also transformed completely, and
excellent ee values were obtained. When the 5-position of the
phenyl ring was introduced a methyl group, excellent reactivity
could be obtained.
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.5b03664.
Experimental procedures, characterization data, and
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ygzhou@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The 4-methylbenzenesulfonyl group could be removed from
(S)-2a by treatment with methanesulfonic acid in trifluoroacetic
acid/thioanisole to provide optically active α-amino phospho-
nate (S)-8 (Scheme 5) without racemization.16
■
We are grateful for the financial support from the National
Natural Science Foundation of China (21532006 and
21372220).
C
DOI: 10.1021/acs.orglett.5b03664
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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DOI: 10.1021/acs.orglett.5b03664
Org. Lett. XXXX, XXX, XXX−XXX