Catalytic asymmetric hydrophosphonylation of ketimines

Article abstract of DOI:10.1021/ja4059316

Catalytic asymmetric hydrophosphonylation of aromatic and aliphatic N-thiophosphinoyl ketimines with dialkyl phosphite was efficiently promoted by as little as 0.5 mol% of catalyst loading at ambient temperature. The catalyst can be recovered for repeated

Full text of DOI:10.1021/ja4059316

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Hydrophosphonylation of Ketimines
Liang Yin,† Youmei Bao,† Naoya Kumagai,*,† and Masakatsu Shibasaki*,†,‡
†Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
‡JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
transfer conditions. An initial attempt was made with ketimine
1a and diethyl phosphite 2a (Table 1). With 10 mol% of the
soft Lewis acid/hard Brønsted base cooperative catalyst
consisting of [Cu(CH3CN)4]PF6/Li(OC6H4-p-OMe), chiral
phosphine ligands were screened (entries 1−5).15 (R,R)-Ph−
BPE outperformed the bisphosphine ligands with axial chirality
or ferrocene-embedded bisphosphine ligands, and the desired
product 3a was obtained in 96% yield with 97% enantiomeric
excess (ee) (entry 5). Given its operational simplicity and
the relatively high acidity of phosphite 2a, amine bases instead
of Li(OC6H4-p-OMe) were examined in combination with
[Cu(CH3CN)4]PF6/(R,R)-Ph−BPE (entries 6−8). Although a
coordinative amine base such as DBU led to a significant
decrease in enantioselectivity (entry 6), substoichiometric
amounts of trialkylamines functioned as effective Brønsted
bases to produce 3a with high enantioselectivity (entries 7,8).
Et3N was selected as the optimal base because it is an
inexpensive stock reagent in chemical laboratories, and the
amount of [Cu(CH3CN)4]PF6/(R,R)-Ph−BPE could be
reduced to as little as 0.5 mol% to complete the reaction
(entry 9).16 The thiophosphinoyl group was indispensable
in this soft Lewis acid/hard Brønsted base cooperative catalytic
system. In contrast to the smooth progress of the reaction of 1a
(Table 1), the reaction of N-phosphinoyl ketimine 1a′, an
oxygen analogue of 1a, barely proceeded under otherwise
identical reaction conditions even after 96 h (Scheme 1),
ABSTRACT: Catalytic asymmetric hydrophosphonyla-
tion of aromatic and aliphatic N-thiophosphinoyl
ketimines with dialkyl phosphite was efficiently promoted
by as little as 0.5 mol% of catalyst loading at ambient
temperature. The catalyst can be recovered for repeated
use, and facile removal of the thiophosphinoyl group
allowed for ready access to the phosphonic acid
analogue of enantioenriched α,α-disubstituted α-amino
acids.
hosphonic acid is regarded as an isosteric functional group
P
for carboxylic acids, and α-amino phosphonic acids are
frequently used as surrogates for proteinogenic α-amino acids
in medicinal chemistry.1 The most prominent feature of
phosphonic acid is its tetrahedral configuration, which mimics
the intermediary tetrahedral structure of the reactions of
carboxylic acid derivatives.2 Because of the increasing demand
for phosphonic acid analogues of α-amino acids, a wide variety
of synthetic methodologies have been devised.3 However,
even with the significant advance in the arsenal of modern
synthetic chemistry, only a few enantioselective synthetic
methods are available for their α-tetrasubstituted variants. Use
of the chiral pool and chiral auxiliaries paved the way to this
class of elusive synthetic targets,4 and the first catalytic
enantioselective approach was reported by Ito et al. using
catalytic asymmetric allylation of α-acetamido-β-keto phos-
phonates, albeit with limited generality and moderate
enantioselectivity.5,6 Nakamura and Shibata et al. demon-
strated another approach using catalytic asymmetric hydro-
phosphonylation of N-mesitylenesulfonyl ketimines (Pudovik
reaction) to produce tetrasubstituted α-aryl α-amino
phosphonic acids with high enantioselectivity.7−10 However,
the reaction using aliphatic ketimines delivered the corre-
sponding products with unsatisfactory enantioselectivity.
Herein, we report a general protocol to access α-tetra-
substituted α-amino phosphonic acids bearing aromatic or
aliphatic substituents with 0.5−2 mol% of catalyst loading.
The catalyst can be recovered and used repeatedly without
any loss of catalytic activity.
Scheme 1. Reaction with N-Phosphinoyl Ketimine 1a′
suggesting that the soft−soft interaction of the PS group and
Cu(I) played a pivotal role in promoting the reaction.17
The substrate generality of the present catalytic asymmetric
hydrophosphonylation protocol is summarized in Table 2.
The reactivity of thiophosphinoyl ketimine 2 was partly
dependent on the electronic nature of the adjacent aromatic
group. The reactions using ketimines bearing electron-
withdrawing CF3 or halogen substituents reached completion
The catalytic asymmetric construction of a tetrasubstituted
stereogenic center has been a sustained topic for decades.11 In
our continuing program in this field, we identified that
N-thiophosphinoyl ketimines 112 serve as suitable soft Lewis
basic electrophiles to produce α-tetrasubstituted amines in soft
Lewis acid/hard Brønsted base cooperative catalysis.13,14 Use of
secondary phosphite 2 as the nucleophile permits direct access
to tetrasubstituted α-amino phosphonates under proton
Received: June 13, 2013
Published: July 2, 2013
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 1. Catalytic Asymmetric Hydrophosphonylation of N-Thiophosphinoyl Ketimines
b
c
entry
ligand
(R)-BINAP
x
base
y
time (h)
yield (%)
ee (%)
d
e
1
2
3
4
5
6
7
8
10
10
10
10
10
5
LiOAr
LiOAr
10
10
10
10
10
50
50
50
25
24
24
24
24
24
24
24
24
72
63
85
70
31
96
94
97
98
90
−75
−82
d
e
(R)-DIFLUORPHOS
(R)-DTBM-SEGPHOS
(R,Rp)-TANIAPHOS
(R,R)-Ph-BPE
d
LiOAi
53
66
97
67
97
97
d
LiOAr
LiOAr
DBU
d
(R,R)-Ph-BPE
(R,R)-Ph-BPE
5
Cy2NMe
Et3N
(R,R)-Ph-BPE
5
f
9
(R.R)-Ph-BPE
0.5
Et3N
96
a
b
c
d
e
1a: 0.1 mmol. 2a: 0.2 mmol, 0.5 M in 1a. Determined by 1H NMR analysis. Determined by HPLC analysis. Ar = C6H4-p-OMe. S enantiomer
f
was the major product. 1a: 0.2 mmol. 2a: 0.4 mmol, 0.5 M in 1a. Isolated yield.
enantioselectivity was observed in the reaction using a
ketimine having an ethyl substituent (entry 18).
Scheme 2. Practical Aspect
The present catalysis is robust and could be applied under
solvent-free conditions without temperature control
(Scheme 2a). Whereas the reaction was run for five days
because of the low solubility of ketimine 2a, the operational
simplicity and volume production are noteworthy. Further-
more, the Cu(I)/(R,R)-Ph−BPE complex was sufficiently
stable to be recovered and reused.18 The reaction mixture
for hydrophosphonylation of 2a on a 1 g scale was directly
followed by silica gel chromatography to separate the
product 3a and Cu(I)/(R,R)-Ph−BPE complex, which was
used for the second run without any loss in catalytic activity
and enantioselectivity (Scheme 2b). The thiophosphinoyl
group of the product 2a was readily removed by treatment
with HClO4 aq./EtOH at 80 °C to give α-amino
phosphonate 4 in 82% yield (Scheme 3).
Scheme 3. Removal of Thiophosphinoyl Group
with a 0.5 mol% catalyst loading irrespective of their o-, m-,
and p-positions (entries 2−7). Ketimines with electron-
donating substituents exhibited lower electrophilicity and a
higher catalyst loading (1−2 mol%) was required, whereas
enantioselectivity was generally high (entries 8−11). Of
particular note is that the present catalysis is applicable to
aliphatic ketimines having sp3 carbons adjacent to the CN
group, which showed moderate enantioselectivity in the
previously developed protocol (entries 12−15).7 As for the
other dialkyl phosphites, dimethyl and dibenzyl phosphite
were compatible (entries 16, 17). A slight decrease in
In summary, we have developed a robust and general
protocol to produce enantioenriched tetrasubstituted α-amino
phosphonic acid derivetives. Ambient temperature, volumetric
productivity, and reusability of the catalyst are advantageous for
practical application.
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Journal of the American Chemical Society
Communication
a
Table 2. Substrate Generality
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization of new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
nkumagai@bikaken.or.jp; mshibasa@bikaken.or.jp
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JST, ACT-C, and
KAKENHI (No. 25713002). L.Y. thanks the JSPS for the
Postdoctoral Fellowship for Foreign Researchers.
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afford the product 3a in comparable yield and ee under heterogeneous
conditions. Details will be reported as a full paper in due course.
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stoichiometric amount (1.1 equiv) of Li(OC6H4-p-OMe), 1a′
exhibited a higher reaction rate than 1a (1a: 0 °C, 30 min, 35%
yield and 60% recovery of 1a; 1a′: 0 °C, 30 min, 94% yield). See
Supporting Information for details.
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