Enantioselective synthesis of tertiary α-hydroxy phosphonates catalyzed by carbohydrate/cinchona alkaloid thiourea organocatalysts

Article abstract of DOI:10.1002/anie.201204287

A pinch of sugar: The new bifunctional carbohydrate/cinchonine-based thiourea 1 has been designed for the asymmetric addition reaction of α-ketophosphonates and trimethylsilyl cyanide, the product of which can be hydrolyzed to afford tertiary α-hydroxy phosphonates with excellent enantioselectivities. Copyright

Full text of DOI:10.1002/anie.201204287

Angewandte
Chemie
DOI: 10.1002/anie.201204287
Organocatalysis
Enantioselective Synthesis of Tertiary a-Hydroxy Phosphonates
Catalyzed by Carbohydrate/Cinchona Alkaloid Thiourea
Organocatalysts**
Shasha Kong, Weidong Fan, Guiping Wu, and Zhiwei Miao*
In memory of Ruyu Chen
the combination of carbohydrates and tertiary amine thiour-
eas have been reported in recent years.[12] However, there is
no precedent for the combination of both cinchona alkaloid
and carbohydrate moieties in a single chiral organic molecule
for asymmetric reactions. The objective of this work is to
explore the viability of integrating cinchona alkaloid and
carbohydrate fragments into a unique thiourea derivative for
enantioselective addition of trimethylsilyl cyanide (TMSCN)
to acylphosphonates to produce tertiary a-hydroxy phospho-
nates.
À
Functionalization of Ca H bonds in phosphonic acid com-
pounds have attracted extensive attention because of their
use in pharmaceutical applications[1] and excellent inhibitory
bioactivities towards several important groups of enzymes,
including rennin,[2] HIV protease,[1b] and various classes of
protein tyrosine kinases and phosphatases.[1c] It has been
established that the biological activity of phosphonic acids is
largely determined by the absolute configuration of the
stereogenic a-carbon atom.[3] The development of method-
ologies for their preparation,[4] particularly in enantiomeri-
cally enriched forms has received deserved attention.
Although some asymmetric methods for preparing a-hydroxy
phosphonates have been described, including both enzy-
matic[5] and chemical methods,[6] these methods are primarily
concentrated on the synthesis of secondary a-hydroxy phos-
phonates. To the best of our knowledge, there are only a few
examples of organocatalyst-promoted aldol reactions with
acyl phosphonates to produce tertiary a-hydroxy phospho-
nates.[7]
The catalytic asymmetric cyanation of carbonyl com-
pounds is a well-studied reaction in asymmetric catalysis.[13]
We initially investigated the use of catalysts 1–6 (Figure 1) for
For the past decade, hydrogen-bond catalysis has received
a great deal of attention because of their high asymmetry-
inducing ability and ready availability.[8] Chiral thiourea-
based organic molecules have proven to be extraordinarily
useful as catalysts for the enantioselective activation of imine
and carbonyl derivatives toward nucleophilic addition.[9]
Bifunctional cinchona alkaloid derivatives possessing hydro-
gen-bonding moieties, such as thiourea, have been widely
used in a diverse range of asymmetric organic reactions in
recent years.[10] In the meantime, a large number of carbohy-
drates have been used as ligands for numerous enantioselec-
tive reactions.[11] Additionally, organocatalysts derived from
[*] S. S. Kong, W. D. Fan, G. P. Wu, Prof. Dr. Z. W. Miao
State Key Laboratory and Institute of Elemento-Organic Chemistry,
Nankai University
Weijin Road 94, Tianjin 300071 (P.R. China)
E-mail: miaozhiwei@nankai.edu.cn
Prof. Dr. Z. W. Miao
Figure 1. Catalyst structures.
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical
Biology (Ministry of Education), Tsinghua University
Qinghuayuan, Beijing 100084 (P.R. China)
the catalytic asymmetric addition reaction of TMSCN (8) to
diethyl benzoyl phosphonate (7a) as a model reaction.
Catalyst screening was performed in toluene in the presence
of 10 mol% of the catalyst at À788C for 24 hours. Cinchona
alkaloid derivatives (1 and 2) and bifunctional thioureas (3–6)
bearing different chiral diamine skeletons were chosen as the
[**] We thank the National Natural Science Foundation of China
(21072102), the Committee of Science and Technology of Tianjin
(11JCYBJC04200), and the State Key Laboratory of Elemento-
Organic Chemistry in Nankai University for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204287.
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catalyst candidates (Table 1).[14] The reaction of the phospho-
nate 7a with 8 in the presence of the catalyst 1 in toluene as
solvent at À788C afforded the desired addition product 9a
with 29% ee and in 89% yield (Table 1, entry 1). The
(entry 10), therefore 6b was selected as the best catalyst for
additional optimization.
To optimize the reaction conditions further, the solvent
effects were investigated with 6b, and the best result was
obtained in toluene. When the reaction was performed in
CH2Cl2 or THF, a lower ee value was obtained (Table 1,
entries 11 and 12). A similar result was obtained when the
reaction was performed in methyl tert-butyl ether (MTBE;
entry 13). Further screening indicated that the reaction
conducted in a mixture of MTBE/PhCH3 (v/v, 1:1) or
MTBE/PhCH3 (v/v, 2:1) offered a better reaction yield with
a moderate enantioselectivity (entries 14 and 15). Adjusting
the catalyst loading demonstrated only a small influence on
the outcome of the enantioselectivity of the reaction. The use
of 5 mol% of 6b led to a slight decrease on enantioselectivity
and yield (entry 16). Increasing the amount of the catalyst
from 10 to 15 mol% did not affect the yield, but resulted in
a higher ee value (entry 17). Acid hydrolysis of the trimethyl-
silyl oxycyanophosphonate 9a can deliver the a-hydroxy-a-
cyanophosphonate 10a in quantitative yield without any
purification (entry 18).
To further improve the reactivity and enantioselectivity,
the effect of additives was investigated. Alcohol additives
were reported to improve the reactivity and enantioselectivity
on cyanosilylation of carbonyl groups.[15] In our investigation,
the beneficial effects of CF3CH2OH, CH3OH, iPrOH, and
tBuOH were observed (Table 2, entries 1–4). After screening
different kinds of aromatic phenolic compounds (entries 5–
10), it was found that p-nitrophenol gave superior results in
terms of reactivity and enantioselectivity (entry 7). When
using 3 mL toluene as the solvent and a prolonged reaction
time of 36 hours, the optimal result was gained (entry 11).
Thus, the optimal reaction conditions for this transformation
were determined to be 0.5 mmol acylphosphonate, 1.2 equiv-
alents of TMSCN, 10 mol% of 6b combined with 10 mol% of
p-nitrophenol in 3 mL toluene at À788C for 36 hours.
Based on the above optimization efforts, the substrate
scope of this reaction was investigated. As shown in Table 3,
Table 1: Screening of the catalysts.[a]
Entry
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1
2
3a
3b
4
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
CH2Cl2
THF
89
85
81
89
85
87
81
80
90
88
88
84
85
94
90
89
90
90
29
À17
À14
À57
À47
À43
45
5a
5b
6a
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
À69
9
81
10[d]
11
12
13
14
15
16[g]
17[h]
18
72
49
68
71
79
77
70
MTBE
[e]
[f]
MTBE/PhCH3
MTBE/PhCH3
PhCH3
PhCH3
PhCH3
83
81[i]
[a] Unless otherwise specified, all reactions were carried out using diethyl
benzoylphosphonate (7a; 0.5 mmol, 1 equiv) and TMSCN (8; 0.6 mmol,
1.2 equiv) in 2 mL solvent with 10 mol% of the catalyst at À788C for
24 h. [b] Yield of the isolated product 9a after column chromatography.
[c] Determined by HPLC (Chiralcel AS-H) analysis of 9a. [d] The reaction
was performed at À408C for 10 h. [e] v/v=1:1. [f] v/v=2:1. [g] 5 mol%
of catalyst 6b was used. [h] 15 mol% of catalyst 6b was used.
[i] Determined by HPLC (Chiralcel AD-H) analysis of 10a. THF=tetra-
hydrofuran. MTBE = methyl tertbutyl ether.
replacement of 1 with cinchonine 2 as the catalyst resulted
asymmetric induction in the opposite sense with up to 17% ee
and in a similar yield (entry 2). The catalyst 3a could also
catalyze this reaction to provide the desired a-hydroxy
phosphonate 9a in 81% yield, but the enantioselectivity was
rather poor (entry 3). Moreover, the N,N-dimethyl-protected
thiourea catalyst 3b was employed and effectively provided
the silylcyanation product in 89% and 57% ee (entry 4). This
result suggested that a tertiary amine thiourea structure is
essential to effect this reaction. Next, we explored the 3,5-
Table 2: Screening of the additive.[a]
Entry
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
CF3CH2OH
CH3OH
iPrOH
tBuOH
2,4-di-tert-butylphenol
2,4-dichlorophenol
4-nitrophenol
3,5-dinitrophenol
1,4-dihydroxybenzene
4-nitrobenzoic acid
4-nitrophenol
97
95
97
98
94
95
94
98
95
95
90
81
82
84
85
79
77
85
82
83
81
91
bis(trifluoromethyl)phenylthiourea
4 and cinchona-based
thioureas 5a and 5b as catalysts, and found that the desired
products were obtained in yields of 81–87% with moderate
ee values of 43–47% (entries 5–7). Consequently, the carbo-
hydrate/cinchona alkaloid thiourea derivatives 6a and 6b
were tested, and a better result (90% yield, 81% ee) was
obtained with 6b (entries 8 and 9). This result indicated that
compared with 5a and 5b, the carbohydrate/cinchona alka-
loid thioureas 6a and 6b had an advantage in the catalytic
asymmetric reaction as a result of the chiral auxiliary. When
the reaction was carried out at À408C using 6b as the catalyst,
a lower enantiomeric excess value of 72% was obtained
9
10
11[d]
[a] Reactions were carried out on a 0.5 mmol scale with 1.2 equiv of
TMSCN in 2 mL of toluene. [b] Yield of isolated 9a after column
chromatography. [c] Determined by HPLC (Chiralcel AD-H) analysis of
10a. [d] The reaction time is 36 h in 3 mL of toluene.
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Table 3: Scope of the reaction.[a]
tivity with an opposite sense of asymmetric induction and up
to 94% ee (entry 20).
To determine the absolute configuration of the main
isomer of TMSCN addition to the a-ketophosphonates 7,
a single-crystal X-ray diffraction study of 10b was per-
formed.[17] The molecular structure of 10b shows that the
absolute configuration of the a-hydroxy phosphonate product
is S.
A possible mechanism for the reaction is shown in
Scheme 1. In complex A a-ketophosphonate coordinates to
the thiourea moiety of bifunctional catalyst 6b through
Entry Product R1
R2 t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
10b
10c
10d
10e
10 f
10g
10h
10a
10i
C6H5
Me
Me
Me
Me
Me
Me
Me
Et
48
48
36
48
36
36
48
36
36
36
36
36
36
36
36
36
36
36
36
36
85
82
89
89
88
80
89
90
85
85
90
87
85
83
85
86
80
82
85
85
99
86
94
93
93
89
92
91
84
83
87
86
86
85
58
56
27
58
93
À94
p-ClC6H4
p-CH3C6H4
p-BrC6H4
p-FC6H4
p-CH3OC6H4
m-CH3C6H4
C6H5
p-ClC6H4
p-CH3C6H4
p-BrC6H4
p-FC6H4
9
Et
Et
Et
Et
Et
Et
Et
Me
Et
10
11
12
13
14
15
16
17
18
19
20
10j
10k
10l
10m
10n
10o
10p
10q
10r
p-CH3OC6H4
m-CH3C6H4
o-CH3OC6H4
o-CH3OC6H4
C2H5
C2H5
Me
=
10s
trans-PhCH CH Et
C6H5 Et
10t[d]
[a] Reaction conditions: a-ketophosphonates 7 (0.5 mmol), TMSCN (8;
0.6 mmol), in 3 mL of toluene at À788C in the presence of 10 mol% of
the catalyst 6b and 10 mol% p-nitrophenol as additive for 36 h. [b] Yield
of isolated product after silica gel chromatography of 9. [c] Determined
by HPLC analysis of 10 using a chiral stationary phase. [d] 10 mol% of
catalyst 6c was employed.
Scheme 1. Plausible reaction mechanism.
a broad range of a-ketophosphonates were subjected to the
addition reaction, and converted into the corresponding
tertiary a-hydroxy phosphonates in high yields with moderate
to good enantioselectivities. A variety of a-ketophosphonates
(7) bearing aromatic rings with electron-donating and elec-
tron-withdrawing groups at either the para or meta position
underwent the reaction to afford high enantioselectivities
ranging from 83 to 99% ee (Table 3, entries 1–14). The
enantioselectivity was dependent upon the size of the R2
group. When the bulk of R2 group was increased from
methyl to ethyl, a lower enantioselectivity resulted (entries 8–
14). Remarkably, when ortho-methoxybenzoyl phosphonate
was employed in this reaction with the same catalyst loading,
the reaction proceeded in high yield and with low enantio-
selectivity (entries 15 and 16). When aliphatic a-ketophosph-
onates were employed as substrates, the reaction gave the
corresponding products with poor enantiomeric excesses and
moderate yields (entries 17 and 18). a-Hydroxy phosphonates
having unsaturated side chains are very useful, as the side
chain can be elaborated to introduce other functional
groups.[16] Thus, we briefly studied the addition reaction of
diethyl cinnamoyl phosphonate. The reaction proceeded
smoothly at À788C, and the desired product was obtained
in 85% yield and 93% ee (entry 19). Although for this
specific substrate Michael addition is possible, no such
product was observed in the crude reaction mixture. Notably,
the chiral catalyst 6c exhibited a similar level of stereoselec-
a hydrogen-bonding interaction. The role of the p-nitro-
phenol additive is presumably to generate HCN as the active
nucleophile in the addition reaction. The nucleophilic attack
of cyanide (CNÀ) from the Si face of the a-ketophosphonate
leads to the formation of the S-configured enantiomer as the
major product. The attack of cyanide to the Re face of the a-
ketophosphonate is restricted by the cinchona alkaloid
scaffold of the catalyst, and the carbohydrate moiety serves
as the chiral auxiliary. The mechanism indicates that the
thiourea and carbohydrate moieties as well as cinchona
alkaloid scaffold of the bifunctional catalyst play a significant
role in controlling the enantioselectivity of the addition
reaction.
To further investigate the mechanism, the formation of 9a
was monitored by 31P NMR spectroscopy as shown in
Figure 2. The starting 7a in toluene showed signal in the
31P NMR spectrum at d = À1.27 ppm. After catalyst 6b
(0.0356 g, 10 mol%) was added to the solution of 7a, the
peak shifted from d = À1.27 to À1.12 ppm as complex A is
formed; a new single peak at d = 7.26 ppm also appeared. The
new single peak was assigned as the decomposition product,
diethyl phosphite, of 7a. When TMSCN and p-nitrophenol
were added to the mixture, the expected nucleophilic addition
product was produced (single peak at d = 12.00 ppm) in
30 minutes. In the meantime, there are two intermediates that
appeared during the synthesis of 9a. The signals at dp = À2.14
and dp = 12.95 ppm may belong to intermediates B and C,
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Figure 2. Time-elapsed 31P NMR spectra for the synthesis of 9a.
respectively. As time progressed, the 31P NMR signals of the
starting material disappeared gradually and the signals of 9a
(single peak at d = 12.00 ppm) increased. The reaction was
almost complete after 36 hours according to the 31P NMR
spectra (Figure 2).
In conclusion, we have developed a novel carbohydrate/
cinchonine-based thiourea as an organocatalyst for the
catalytic asymmetric addition reaction of a-ketophospho-
nates and TMSCN with good to excellent enantiomeric excess
and high yields. The initial product, the TMS ether cyano-
phosphonate, can readily be transformed into cyanohydrin
phosphonate by mild acidic hydrolysis. A plausible reaction
mechanism has been proposed to explain the origin of the
asymmetric induction. Additional applications of these cata-
lysts to other asymmetric reactions are currently underway in
our laboratory.
Received: June 2, 2012
Published online: && &&, &&&&
Keywords: asymmetric synthesis · carbohydrate ·
.
organocatalysis · tertiary a-hydroxy phosphonates · thiourea
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4
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Organocatalysis
S. S. Kong, W. D. Fan, G. P. Wu,
Z. W. Miao*
&&&& — &&&&
Enantioselective Synthesis of Tertiary a-
Hydroxy Phosphonates Catalyzed by
Carbohydrate/Cinchona Alkaloid
Thiourea Organocatalysts
A pinch of sugar: The new bifunctional
carbohydrate/cinchonine-based thiourea
1 has been designed for the asymmetric
addition reaction of a-ketophosphonates
and trimethylsilyl cyanide, the product of
which can be hydrolyzed to afford tertiary
a-hydroxy phosphonates with excellent
enantioselectivities.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!