Asymmetric Synthesis of α-Amino Phosphonic Acids using Stable Imino Phosphonate as a Universal Precursor

Article abstract of DOI:10.1002/chem.201903572

A practical method for synthesizing chiral α-amino phosphonic acid derivatives was developed. Readily available and stable N-o-nitrophenylsulfenyl (Nps) imino phosphonate was utilized as a substrate for a highly enantioselective Friedel–Crafts-type additi

Full text of DOI:10.1002/chem.201903572

A Journal of
Accepted Article
Title: Asymmetric Synthesis of α-Amino Phosphonic Acids Using
Stable Imino Phosphonate as a Universal Precursor
Authors: Tsubasa Inokuma, Takuya Sakakibara, Takatoshi Someno,
Kana Masui, Akira Shigenaga, Akira Otaka, and Ken-ichi
Yamada
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10.1002/chem.201903572
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Asymmetric Synthesis of α-Amino Phosphonic Acids Using
Stable Imino Phosphonate as a Universal Precursor
Tsubasa Inokuma,* Takuya Sakakibara, Takatoshi Someno, Kana Masui, Akira Shigenaga, Akira
Otaka, and Ken-ichi Yamada*[a]
Abstract:
A
practical method for synthesizing chiral α-amino
requires laborious manipulations. To prepare N-alkoxycarbonyl
and N-acyl imines, unstable imines were generated from
unstable precursors, α-halo amino acids, by an elimination
reaction with a resin-supported base and used immediately
before they hydrolyzed. Although the N-PMP imine is more
stable, it also hydrolyzes on silica gel. The precursor of the imine
is formylphosphonate hydrate, which is synthesized from diethyl
diazomethylphosphonate by oxidation using dimethyldioxirane.[6]
Furthermore, removal of the PMP protection after constructing
the amino phosphonate unit has not been reported and is likely
difficult due to the harsh conditions required for the deprotection.
These issues hamper the synthesis of α-amino phosphonic acid
derivatives by these established methods on a preparative scale,
and the development of a novel imine substrate that overcomes
these obstacles is in high demand.
phosphonic acid derivatives was developed. Readily available and
stable N-o-nitrophenylsulfenyl (Nps) imino phosphonate was utilized
as a substrate for a highly enantioselective Friedel–Crafts-type
addition of indole or pyrrole nucleophiles catalyzed by chiral
phosphoric acid. The resulting adduct was easily converted to N-9-
fluorenylmethyloxycarbonyl (Fmoc) amino phosphonic acid, which is
useful for synthesizing peptides containing an amino phosphonic
acid.
Introduction
α-Amino phosphonate derivatives often serve as protease
inhibitory agents acting as amino acid mimics or transition state
(TS) analogues of protease substrates (Figure 1).[1] For example,
α-indolyl and pyrrolyl amino phosphonates 1[2a] and 2[2b] possess
antibacterial and anticancer activity, respectively. Peptides 3[2c]
and 4[2d] containing a phosphonamide linkage exhibit inhibitory
activity against angiotensin-converting enzyme and HIV
protease, respectively. Therefore, this type of new compounds is
a promising novel drug candidate. Numerous methods exist for
synthesizing this structural motif in an asymmetric manner,
including asymmetric hydrogenation of α-imino phosphonate[3] or
enantioselective addition of phosphite to imine.[4] In these
protocols, the preparation of imines having different substituents
is necessary for the synthesis of amino phosphonate variants
bearing different side chains. On the other hand, the addition of
nucleophiles to α-imino phosphonate produces diverse
derivatives from the same imine as a universal precursor by
changing only the nucleophiles.[5] Kobayashi reported an
NH
NH
OEt
R
Cl
Ph
∗
OH
OH
P
OEt
H2N
OEt
Ph
N
P
OEt
P
N
O
H
H
O
NO2
O
α-aminophosphonic acid
1
2
antibacterial
anticancer
H
Ph
O
Ph
OH
O
O
N
H
N
H
N
H
N
O
N
BnO
P
N
H
Ph
N
HO
P
O
H
MeO
O
H
O
Me
O
Ph
3
4
ACE inhitor
HIV protease inhibitor
Figure 1. Examples of the biologically active α-amino phosphonate derivatives.
enantioselective
catalytic
Mannich
reaction
of
N-
trichloroethoxycarbonyl (Troc) imino phosphonate and silyl enol
ether, allylsilane, or enamide nucleophiles.[5a-c] Recently,
Vicario’s group applied a similar N-acyl imino phosphonate to
the asymmetric installation of indole.[5d] Zhao reported
enantioselective alkynylation of N-4-methoxyphenyl (PMP) imino
phosphonate.[5e] The preparation of these imines, however,
The o-nitrophenylsulfenyl (Nps) group[7] has attracted
attention as a protective group of the nitrogen atom of imine for
the synthesis of α-amino acid derivatives. Hiemstra and we
independently reported an asymmetric Friedel–Crafts-type
addition of indole to N-Nps imino ester[8] or amide.[9] We also
reported that the N-Nps imino amide could be prepared by
MnO2-mediated oxidation of readily available N-Nps-glycine
amide. The imine was so stable that it was easily purified by
silica gel column chromatography and could be stored on the
bench for more than 6 months. Furthermore, the Nps group
could be removed under mild conditions in high chemical
yield.[10] We envisioned that N-Nps imino phosphonate would be
a suitable substrate for the efficient synthesis of α-amino
phosphonic acids. Here we report the preparation of N-Nps
[a]
Dr. T. Inokuma, T. Sakakibara, K. Masui, Dr. A. Shigenaga, Prof. Dr.
A. Otaka, Prof. Dr. K. Yamada
Institute of Biomedical Sciences and Graduate School of
Pharmaceutical Sciences, Tokushima University; Tokushima 770-
8505, Japan
E-mail: tinokuma@tokushima-u.ac.jp (T.I.)
yamak@tokushima-u.ac.jp (K.Y.)
imino phosphonate as
a novel substrate for asymmetric
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Screening of the alkyl groups of 5 and catalyst.[a]
Mannich-type reactions and its application to the practical
synthesis of α-amino phosphonic acids.
Results and Discussion
We first established a synthetic route for N-Nps imino
phosphates 5a–c, bearing different alkyl substituents at
phosphonate ester moieties (Scheme 1). The three-component
reaction using dialkyl phosphite 6a–c, tritylamine, and
formaldehyde smoothly produced 7a–c in good yield.[11] Then,
the trityl groups of 7a–c were exchanged with an Nps group by
removing the trityl group under acidic conditions followed by
treatment with NpsCl. Thus-obtained 8a–c were oxidized by
[12]
MnO2
to give the desired imino phosphonates 5a–c. As
expected, 5a–c, as well as the corresponding imino amide, were
sufficiently stable to be purified by silica gel column
chromatography.[9,13]
entry
R
10
11
yield (%)[b]
ee (%)[c]
63
OR
OR
OR
OR
P
TrtNH2, HCHO
H
GP
P
N
1
Me (5a)
i-Pr (5b)
Bn (5c)
Bn (5c)
Bn (5c)
Bn (5c)
Bn (5c)
Bn (5c)
Bn (5c)
10a
10a
10a
10b
10c
10d
10e
10f
11aa
11ba
11ca
11ca
11ca
11ca
11ca
11ca
11ca
65
55
73
67
92
93
86
75
85
H
O
a: 84% b: quant. c: 89%
O
6a-c
2
87
PG = Trt (7a-c)
PG = Nps (8a-c)
1) HCl
2) i-Pr2NEt
NpsCl
a: 44% b: 75%
c: 94% (in 2 steps)
a: R = Me
b: R = i-Pr
c: R = Bn
3
86
4
82
5
1
OR
MnO2
NO2
S
Nps
OR
N
P
6
58
Nps =
a: 58%
b: 47%
c: 73%
O
5a-c
7[d]
8
66
73
Scheme 1. Synthesis of N-Nps imino phosphates 5a–c.
9
10g
59
[a] The reaction was carried out using 5 (0.10 mmol), 9a (0.12 mmol), and
phosphoric acid 10 (5 µmol) in the indicated solvent for 4 h. [b] Isolated yield.
[c] Determined by chiral HPLC analysis. [d] The reaction time was 2 h.
After successfully preparing substrates 5a–c, we examined
the conditions for asymmetric addition. We used indole as a
nucleophile to synthesize α-indolyl amino phosphonate, which is
often found in biologically important α-amino phosphonate
derivatives (Table 1).[2] First, imino phosphonates 5a–c were
subjected to an asymmetric Friedel–Crafts-type reaction with
indole 9a using BINOL-derived chiral phosphoric acid[14] as the
asymmetric catalyst.[15,16] In the presence of BINOL-derived
phosphoric acid catalyst 10a in toluene,[9] 5a gave adduct 11aa
in good yield with moderate selectivity (63% ee, entry 1). The
use of more bulky substrates 5b or 5c improved the
stereoselectivity (entries 2 and 3). On the basis of both the high
selectivity and the ease of removing the benzyl groups, we
selected 5c as the substrate for further study. We next tested
other BINOL-derived phosphoric acids 10b–g; however, only
moderate to good enantioselectivity was provided (entries 4–9),
and 10a induced the best stereoselectivity (entry 3). Solvent
screening was also performed and toluene was the optimal
reaction media (see SI). The absolute configuration of 11 was
determined by converting 11ba to a known compound (see
SI).[5d]
Having established the optimal conditions, we next examined
the scope of nucleophiles (Table 2). Indoles 9b–e, which
possess an electron-withdrawing or an electron-donating group
at the 5-position, gave desired adducts 11cb–ce in high
enantioselectivities (entries 1–4). We examined the effect of the
substituent position and found that methyl-substitution at the 5-,
6-, or 7-position was tolerated, but the reaction involving 2- or 4-
substituted indoles 9f and 9g resulted in decreased selectivity
(entries 5–9). The use of 6-benzyloxyindole 9k successfully
produced adduct 11ck, which could be regarded as
a
conformationally-fixed analogue of phosphotyrosine (entry 10).
The reaction was also applicable to the synthesis of α-pyrrole
substituted derivatives, which have structures similar to
anticancer compound 2 (entries 11). Although the yields of the
reactions using substituted pyrroles 9m or 9n were very low, the
enantioselectivities were still satisfactory (entries 12 and 13).
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TSmajor
Table 2. Scope of nucleophiles.[a]
Ar
N
O
O
O
H
P
O
H
Ar
OBn
H
2.20 Å
N S
P
O
BnO
1.06 Å C8H6N
H
H
O–P 1.60 Å
O=P 1.70 Å
1.05 Å
C=N
entry
1
9
time (h)
11
yield (%)[b]
ee (%)[c]
85
TSminor
9b
9c
9d
9e
9f
24
24
24
3
11cb
11cc
11cd
11ce
11cf
11cg
11ch
11ci
11cj
11ck
11cl
11cm
11cn
67
58
70
87
95
52
73
75
72
79
83
23
8
2
86
Ar
O
O
O
P
H
3
85
N
SPh
N
O
Ar
H
4
87
2.20 Å
H
O
Bn ))((
P
5
6
40
O OBn
1.06 Å C8H6N
1.06 Å C=N
H
H
O–P 1.61 Å
O=P 1.64 Å
6
9g
9h
9i
4
59
7
4
86
Figure 2. ChemDraw presentation and Chem3D perspective view of transition
state structures TSmajor and TSminor to give (R)- and (S)-product, respectively, at
the B3LYP/6-31G** level of theory.
8
4
77
9
9j
6
78
10
11
12
13
9k
9l
4
85
3
75
9m
9n
24
24
83
76
[a] The reaction was carried out using 5c (0.10 mmol), 9 (0.12 mmol) and
catalyst 10a (5 µmol). [b] Isolated yield. [c] Determined by chiral HPLC
analysis.
Scheme 2. Effect of indole NH proton.
The TS geometries were calculated at the B3LYP/6-31G**
level of theory for a simplified substrate and catalyst, providing
geometries TSmajor and TSminor that give (R)- and (S)-products,
respectively (Figure 2). The C=N bond as well as indole N–H is
likely activated by the hydrogen-bond network involving a
phosphoric acid catalyst. When N-methyl substituted indole 9o
was used, the reaction was sluggish and the resulting
stereoselectivity was poor (Scheme 2), suggesting that the
hydrogen bond, C8H6NH···O=P (1.65 and 1.66Å, respectively) is
important for stabilizing the TSs.[17] Analysis of the TSminor
geometry revealed that the steric repulsion between one of the
bulky substituents of the catalyst and the dibenzyl phosphonate
We then converted adduct 11ca into an Fmoc-amino
phosphonate (Scheme 3). The Nps group of 11ca was removed
using 2-PySH[10] and an Fmoc group was installed without
racemization. Removal of one of the Bn groups of 12 was
accomplished without any racemization using NaI in acetone[18]
to successfully yield Fmoc amino phosphonate monobenzyl
ester 13, which is useful for the synthesis of the various amino
phosphonic acid derivatives and the peptides containing
phosphonamide linkage.
moiety of the substrate are key factors that destabilize TSminor
,
consistent with the experimental results that substrates bearing
the more bulky phosphonate had better enantioselectivity (Table
1, entries 1–3). The ΔΔG‡ between TSmajor and TSminor was 0.98
kcal/mol at the wB97x-D/6-311+G**//B3LYP/6-31G** level of
theory, corresponding to 67% ee at 27 °C; this is in good
agreement with the experimental results (Table 1, entry 8).
Scheme 3. Conversion of 11ca into Fmoc amino phosphonate 13.
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Conclusions
We developed a novel method for the enantioselective
synthesis of α-amino phosphonic acid derivatives using readily
available and stable N-Nps imino phosphonate substrate 5c as a
universal precursor. We also successfully converted adduct
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Acknowledgements
This research was supported in part by JSPS KAKENHI
Grant No. JP18K14869 and JP18K06579, a research program
for the development of an intelligent Tokushima artificial
exosome (iTEX) and the Research Clusters program (No.
1802001) from Tokushima University, and Shionogi & Co., Ltd.
Award in Synthetic Organic Chemistry, Japan from Shionogi &
Co., Ltd.
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Keywords: amino phosphonic acid • asymmetric catalysis •
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organocatalysis
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Entry for the Table of Contents
FULL PAPER
Tsubasa Inokuma,* Takuya Sakakibara,
Takatoshi Someno, Kana Masui, Akira
Shigenaga, Akira Otaka, Ken-ichi
Yamada*
Page No. – Page No.
Asymmetric Synthesis of α-Amino
Phosphonic Acids Using Stable Imino
Phosphonate as a Universal
Precursor
Stable imino phosphonate: Enantioselective Friedel–Crafts–type reaction of imino
phosphonate and indoles or pyrroles is achieved. The readily available and stable
N-2-Nitrophenylsulfenyl (Nps) imino phosphonate can be used as a universal
substrate. The protective groups of the adducts (Nps and Bn) could be readily
removed to generate the biologically important α-amino phosphonic acid
derivatives.
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