Carbene-catalyzed enal γ-carbon addition to α-ketophosphonates for enantioselective access to bioactive 2-pyranylphosphonates

Article abstract of DOI:10.1039/c8cc03017k

A carbene-catalyzed enantioselective [4+2] cycloaddition reaction between α,β-unsaturated aldehydes and α-ketophosphonates is developed. The reaction affords chiral 2-pyranylphosphonates with excellent enantioselectivities. The optically enriched phosphonate products bear multiple functional groups, including unsaturated lactone and phosphonate moieties that often lead to unique bio-activities. Preliminary studies show that the products from our reactions exhibit anti-bacterial (X. oryzae pv. oryzae) and anti-viral (Tobacco Mosaic Virus) activities for potential use in plant protection.

Full text of DOI:10.1039/c8cc03017k

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Carbene-catalyzed enal γ-carbon addition to α-ketophosphonates
for enantioselective access to bioactive 2-pyranylphosphonates
Jun Sun,a Fangcheng He,a Zhongyao Wang,a Dingwu Pan,a Pengcheng Zheng,a Chengli Mou,c
Zhichao Jin*a and Yonggui Robin Chi*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A carbene-catalyzed enantioselective [4+2] cycloaddition reaction heterocyclic carbene (abbreviated as NHC or carbene) organic
between α,β-unsaturated aldehydes and α-ketophosphonates is catalysts.5
developed. The reaction affords chiral 2-pyranylphosphonates
with excellent enantioselectivities. The optically enriched
a) bioactive compounds contaning phosphonates:
phosphonate products bear multiple functional groups, including
OH
unsaturated lactone and phosphonate moieties that often lead to
unique bio-activities. Preliminary studies show that the prodcuts
from our reactions exhibit anti-bacterial (X. oryzae pv. oryzae) and
anti-viral (Tobacco Mosaic Virus) activities for potential use in
plant protections.
CH3
N
N
H3C
H2N
N
H3C
H
N
N
S
O
N
NH4
HN
OPh
OC2H5
HN
P
O
O
O
Ph
O
HO
P
OPh
OC2H5
P
O
O
Ph
NHBoc
renin inhibitors
(humanmedicine)
HO
anti-virus
(humanmedicine)
HO
anti-bacteria
Phosphonate-containing molecules
exhibit ubiquitous
(agriculturechemical)
biological activities with proven applications in medicines and
agriculture chemicals.1 For example, chiral phosphonate
compounds could be used as renin inhibitors,1a,b anti-viral,1f
and anti-bacterial reagents1g,i (Figure 1a). Over the years,
several types of methods have been developed for the
incorporation of phosphonate moieties in enantioselective
manners to realize various chiral functional molecules (Figure
1b). One of the most straightforward methods is based on the
Pudovik-type reaction.2 A stereoselective Carbon-Phosphine
(C-P) bond is directly formed under the catalysis of chiral bases
or transition metal catalysts (Figure 1b-1). Another important
approach is to use functionalized phosphonates (such as
acylphosphonates) as electrophiles in asymmetric catalytic
reactions (Figure 1b-2).3,4 For example, Scheidt and co-workers
b) synthesis of chiral phosphonates:
(1) phosphonatesas nucleophiles PudovikReaction:

chiral bases or
transmetal/ Ligand*
OH
R'
O
*
O
P
O
H
O
+
R
P
R'
R'
O
R
H
O
O
R'
(2) functionalizedphosphonatesas electrophiles:
O
R'
O
R'
O
O
R'
O
P
O
P
O
R
O
R
R'
R'
R
P
R'
O
O
O
c) This work:
N
N
O
O
N
O
R2
O
O
P
(NHC cat.)
[O]
O
H
OR2
OR2
O
R1
R2
+
P
R
O
R1
R
1
2
reported the asymmetric addition of the
β
-carbons of
3
up to 88% yield
95:5to 99:1e.r.
NHC / [O]
base
O
cinamylaldehydes to ketophosphonates via a formal [3+2]
process to afford 5-membered lactone products with 78-91%
ee under the catalysis of rationally designed chiral N-
N
N
O
N
lactone
formation
R
-
NHC
N
N
2
R1
O
N
P
R2O
OR2
R
II
I
O
Figure 1. Asymmetric Catalytic Methodologies for Chiral
Phosphonate Synthesis.
We are interested in developing new activation and reaction
modes enabled by NHC catalysts for quick access to functional
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molecules. One element that caught our attention is 2-pyranylphosphonate products afforded in good yields and e.r.
phosphine as it is widely present in functional molecules values (3q to 3s). Phosphonates derived from different
ranging from catalysts / ligands to medicines. We have alcohols also worked well in this catalytic process, affording
recently reported an efficient access to P-stereogenic the corresponding chiral phosphonates in moderate yields
phosphinates via NHC-catalyzed desymmetrization of with excellent enantioselectivies (3t to 3u). It should be noted
bisphenols.6 Here we report a highly enantioselective synthesis that no or trace products could be isolated when switching the
of 2-pyranylphosphonates bearing a phosphonate moiety aryl groups on either of the substrates
1 or 2 to alkyl groups
directly connected to a chiral carbon centre under oxidative
NHC catalysis (Figure 1c). The reaction of enal with an NHC
(3v to 3x).
catalyst in the presence of an oxidant generates a vinyl enolate Table 1. Condition optimization.a
intermediate (
carbon of
intermediate II that subsequently undergoes
formation process to furnish the final product ( ). In our earlier
reaction between enal -carbon and trifluromethylketone
I
) with a nucleophilic carbon.7 Addition of the
to -ketophosphonate substrate ( ) affords
lactone
γ-
I
α
2
a
3
γ
under oxidative NHC catalysis, the use of a Lewis acid co-
catalyst is necessary in order to achieve high
enantioselectivities.7b In our present studies, the use of NHC
catalyst alone is sufficient for high enantioselectivities. This is
likely due to the unique stereo-electronic properties of the α-
ketophosphonate substrates. The chiral phosphonate-
containing compounds obtained through our method showed
anti-bacterial (X. oryzae pv. oryzae) and anti-viral (Tobacco
Mosaic Virus) activities in our preliminary studies searching for
new scaffolds of plant-protecting chemicals.
Entry
Cat.
A
B
Base
Solvent
THF
Yield [%]b
0
e.r.c
--
1
2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Et3N
The asymmetric [4+2] cycloaddition reaction between the
THF
< 5
10
--
α,β-unsaturated aldehyde 1a and α-ketophosphonate 2a was
3
C
THF
90:10
--
selected as the model reaction for condition optimization
(Table 1). To our delight, the aminoindanol-derived NHC
catalyst C8 could give the desired product in low but promising
isolated yield with good enantioselectivity (Table 1, entry 3).
Other NHC catalysts we tested were not effective for this
transformation (eg., entries 1, 2 and 4). Both of the product
yield and enantioselectivity could be dramatically increased
when switching the basic additives to the ones with weaker
basicities (entries 5 to 8). The 2-pyranylphosphonate product
3a could be afforded in 63% yield with 97:3 e.r. valule when
4
D
C
THF
< 5
26
5
THF
89:11
97:3
97:3
97:3
95:5
--
6
C
THF
42
7
C
DMAP
NaOAc
NaOAc
NaOAc
THF
31
8
C
THF
63
9
C
toluene
CH3CN
23
10
C
<10
carrying out the reaction using NHC catalyst
C with NaOAc as
aReaction conditions: 1a (0.12 mmol). 2a (0.1 mmol), NHC
the base in THF (entry 8). Investigations on the solvent effect
did not result in further improvements of the reaction
outcome (entries 9 to 10).
(0.02 mmol), base (0.12 mmol), (0.12mmol), THF (2 mL), 30
4
oC, 48 h. Yields were isolated yields after purification by SiO2
column chromatography. cE.r. values were determined via
HPLC using a chiral stationary phase.
b
With an optimized reaction condition at hand (as stated in
Table 1, entry 8), we then tested the substrate scope for this
[4+2] reaction using substrates
substitution patterns (Table 2). Both electron-donating and
electron-withdrawing groups were well tolerated on the
benzene rings of the -unsaturated aldehydes . All the
1 and 2 with different
The optically enriched phosphonate products were
evaluated for their plant disease-relevant anti-bacteria and
anti-virus activities.9 Bacterial blight disease (abbreviated as BB)
is a widespread rice infection disease that can lead to big
economic loss.10 This disease is caused by X. oryzae pv.
oryzae.11 We tested the in-vitro anti-bacterial activity of our
chiral products (3) against X. oryzae through turbidimeter test
with bismerthiazol and DMSO used as the positive and
negative controls respectively (Table 3).12 Several of our
optically enriched 2-pyranylphosphonate products were found
to show promising activities. For example, products 3f and 3u
exhibited similar inhibitory rate against X. oryzae pv. oryzae
β
-
α
,
β
1
chiral lactone products could be afforded in moderate to good
yields with excellent enantioselectivities (3b to 3m). Notably,
installing steric hindered substituents on the 2-position of the
β
-benzene groups would lead to drops on the product yields
(
3f to 3g). The substituted β-benzene groups on substrates
1
could also be replaced with a napthynyl group (3n) or a hetero
aromatic group (3o to 3p) without deteriorating the product
yields and e.r. values. Substituents with various electronic
properties could also be installed on the phenyl group
attached to the ketone motif of the phosphonate 2a, with the
2 | J. Name., 2012, 00, 1-3
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when compared to the commercially available bactericide
Tobacco mosaic virus (abbreviated as TMV) is a damaging
bismerthiazol at the concentrations of both 100 μg/mL and plant virus that is difficult to be controlled.13 We carried out
200 μg/mL.
anti-viral studies of our phosphonates (3) against TMV (Table
4).14 Comparing with the commercially available anti-viral drug
of ningnanmycin,15 products 3i
, 3o and 3u showed similar
Table 2. Substrate scope.a
curative effects, and products 3p and 3r showed comparable
protective effects.
Table 3. Anti-bacterial activity of our products (
3
).
X. oryzae pv. oryzae inhibition rate (%)a
Compound
100 μg/mL
10.8 ± 3.0
200 μg/mL
45.8 ± 1.5
3b
54.2 ± 2.0
44.4 ± 4.2
47.1 ± 4.7
0
60.8 ± 1.2
59.9 ± 4.4
72.7 ± 5.8
3f
3u
bismerthiazolb
DMSOc
0
b
aAll data were average data of three replicates. Commercial
c
bactericide, used as the positive control. DMSO was used as
the negative control.
Table 4. In vivo inhibitory effects of our products (3) against
TMV.a
Curative effect (%)
44.8 ± 2.9
Protective effect (%)
24.3 ± 3.5
Compound
3i
3o
43.1 ± 4.4
24.1 ± 2.9
3p
30.4 ± 3.4
44.8 ± 2.7
3r
27.6 ± 5.6
44.4 ± 7.9
3u
50.4 ± 3.2
23.6 ± 1.8
ningnanmycinb
45.5 ± 2.3
44.6 ± 1.3
aAll data were average data of three replicates at the
concentrations of 500 μg/mL. bCommercially available anti-
viral drug, used as positive control.
Conclusions
In summary, we have developed an NHC-catalyzed
enantioselective formal [4 + 2] reaction of α,β-unsaturated
aldehydes and -ketophosphonates. A variety of chiral 2-
α
pyranylphosphonates were afforded as the final products with
excellent enantioselectivities. Several of the optically enriched
phosphonate compounds generated from our reactions
exhibited anti-bacterial and anti-viral activities in our
preliminary studies searching for new plant-protection agents.
Further studies for quick access to phosphine-containing chiral
molecules and their applications are in progress.
aReactions were carried out under condition as in Table 1,
entry 8. Yields were isolated yields after purification by SiO2
column chromatography. E.r. values were determined via HPLC
using a chiral stationary phase.
Conflicts of interest
There are no conflicts to declare.
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We acknowledge financial support by the National Natural
Science Foundation of China (No. 21772029, 21472028),
National Key Technologies R&D Program (No. 2014BAD23B01),
“Thousand Talent Plan”, The 10 Talent Plan (Shicengci) of
Guizhou Province, Guizhou Province Returned Oversea
Student Science and Technology Activity Program, Guizhou
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N
N
O
O
R2
O
N
O
O
P
(NHC cat.)
[O]
H
OR2
OR2
O
O
R1
R2
+
P
R
O
R1
R
up to 88% yield, 95:5 to 99:1 e.r.
anti-bacterial (X. oryzae pv. oryzae) & anti-viral (Tobacco Mosaic Virus)
A carbene-catalyzed [4+2] reaction of enals and α-ketophosphonates is developed to
afford chiral 2-pyranylphosphonates with potential use in plant protections.