Catalytic enantioselective protonation of α-oxygenated ester enolates prepared through phospha-brook rearrangement

Article abstract of DOI:10.1002/anie.201007568

(Chemical Equation Presented) Phosphonates go chiral: The organocatalytic enantioselective reaction of α-ketoesters with phosphites using cinchona alkaloids and Na₂CO₃ has afforded α-phosphonyloxy esters with high enantioselectivities (see scheme). This process allows the formation of both enantiomers of the product. A catalyst loading of as low as 2 mol% does not result in a significant decrease of the enantioselectivity.

Full text of DOI:10.1002/anie.201007568

DOI: 10.1002/anie.201007568
Asymmetric Synthesis
Catalytic Enantioselective Protonation of a-Oxygenated Ester
Enolates Prepared through Phospha-Brook Rearrangement**
Masashi Hayashi and Shuichi Nakamura*
The enantioselective protonation of prochiral enolates has
been studied extensively as one of the simplest and most
straightforward methods of accessing a wide range of
optically active a-substituted carbonyl compounds. The
most challenging step of this process is the development of
a catalytic enantioselective protonation of enolates, for which
the substrate scope is relatively limited.[1] While the reaction
affords a convenient synthetic method for the preparation of
chiral a-oxygenated esters, there are no reports on the
catalytic enantioselective protonation of enolates derived
from a-oxygenated esters. In particular, the development of
an enantioselective synthesis of optically active phosphoric
monoesters constructed with chiral secondary alcohols is
highly desirable because of the biological activity of such
compounds, which are present in DNA, fostriecin,[2] cytosta-
tine,[3] and enigmazole,[4] and for their synthetic importance.[5]
Herein, we report a novel synthesis of optically active
phosphoric esters through the catalytic enantioselective
protonation of a-phosphonyloxy enolates, which were
prepared from the nucleophilic addition of phosphites to
a-ketoesters and a subsequent phospha-Brook rearrange-
ment (Scheme 1).[6]
and co-workers reported their pioneering work on the
enantioselective addition of phosphites to a-ketoesters using
15 mol% of a chiral thiourea catalysts to give a-hydroxy
phosphonates as hydrophosphonylation products with up to
91% ee.[7a] Feng and co-workers also reported the enantiose-
lective hydrophosphonylation of trifluoromethyl ketones
using 10 mol% of chiral aluminum catalysts.[7d] Ooi and co-
workers demonstrated the highly enantioselective addition of
a phosphite to ynones using 5 mol% of tetraaminophospho-
nium phosphite as a chiral catalyst.[7c] Despite the impressive
progress achieved in the enantioselective reaction of ketones
with phosphites, all of these reactions gave chiral a-hydroxy
phosphonates. Recently, we have reported the first enantio-
selective reaction of phosphites with various ketimines
catalyzed by cinchona alkaloids and Na2CO3 to give chiral
a-amino phosphonates as hydrophosphonylation products
with high enantioselectivity.[9] We herein report the synthesis
of optically active a-phosphonyloxy esters by the reaction of
a-ketoesters with phosphites under reaction conditions sim-
ilar to those used in our first report (Scheme 2).
Only a few examples of enantioselective reactions of
ketones with phosphites have been reported.[7,8] In 2009, Feng
Scheme 2. Reaction of ketimines or ketones with phosphites in the
presence of cinchona alkaloids and Na2CO3.
The enantioselective reaction of ethyl phenylglyoxylate
1a with diphenyl phosphite (3.0 equiv) was carried out in the
presence of 10 mol% of cinchona alkaloids and stoichiomet-
ric amounts of Na2CO3 (1.5 equiv) at room temperature
(Table 1). The reaction of 1a with diphenyl phosphite using
quinine and Na2CO3 resulted in product 2aa, which was
obtained through nucleophilic addition of the phosphite to 1a
and subsequent phospha-Brook rearrangement. The reaction
without Na2CO3 proceeded slowly to give 2aa in low yield
together with addition product 3aa with a 46% yield (Table 1,
entries 1 and 2). Optimization studies of the reaction of 1a
with various cinchona alkaloids have shown that quinine and
quinidine are efficient organocatalysts in the reaction of 1a
with diphenyl phosphite (Table 1, entries 3–6, see also the
Supporting Information). The reaction with diphenyl phos-
Scheme 1. Enantioselective protonation of a-phosphonyloxy enolates
prepared through a phospha-Brook rearrangement.
[*] M. Hayashi, Prof. S. Nakamura
Department of Frontier Materials, Graduate School of Engineering,
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Fax: (+81)52-735-5245
E-mail: snakamur@nitech.ac.jp
Homepage: http://www.ach.nitech.ac.jp/~organic/shibata/shiba-
ta.html
[**] This work was supported by the Tatematsu Foundation. We are
grateful to Zeon Co. for a gift of cyclopentyl methyl ether.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007568.
phite (1.3 equiv) and
a catalytic amount of Na2CO3
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Table 1: Enantioselective reaction of ethyl phenylglyoxylate 1a with diaryl
phosphites using various cinchona alkaloids and Na2CO3.
Table 2: Enantioselective reaction with various ketones 1a–k using
quinine or quinidine.
Entry
Catalyst (mol%)
Ar
Yield of 2 [%]
ee [%][a]
1[b]
2
3
4
quinine (10)
quinine (10)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
17[c]
99
91
98
88
97
93
94
79
98
94
97
98
58 (S)
46 (S)
63 (R)
22 (R)
19 (S)
39 (S)
64 (R)
70 (R)
74 (R)
92 (R)
92 (R)
91 (S)
90 (R)
Entry 1: R
Cat. T [8C]
t [h] Yield [%] ee [%][a]
quinidine (10)
cinchonine (10)
cinchonidine (10)
Ac-quinidine (10)
quinidine (10)
quinidine (10)
quinidine (10)
quinidine (10)
quinidine (2)
quinine (10)
1
1a: Ph
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
À40
72
48
96
48
60
24
24
18
48
48
92
84
73
99
83
99
94
98
99
97
91
98
90
79
99
90
99
92
99
99
99
92
91 (S)
89 (S)
84 (S)
90 (S)
83 (S)
89 (S)
88 (S)
88 (S)
85 (S)
79 (S)
87 (S)
92 (R)
91 (R)
87 (R)
90 (R)
87 (R)
91 (R)
90 (R)
90 (R)
88 (R)
85 (R)
90 (R)
2
1b: p-MeC6H4
1c: o-MeC6H4
1d: m-MeC6H4
1e: p-MeOC6H4
1 f: p-FC6H4
À30
5
3[b]
4
À30 to 0
À30
6
7[d]
5
6
À30
8[d,e]
9[d,e]
10[d,e,f]
11[d,e,f]
12[d,e,f]
13[d,e,f,g]
À30
o-MeOC6H4
o-MeOC6H4
o-MeOC6H4
o-MeOC6H4
o-MeOC6H4
7
8
9
1g: p-ClC6H4
1h: p-BrC6H4
1i: 2-naphthyl
1j: PhCH2CH2
1k: cyclohexyl
1a: Ph
1b: p-MeC6H4
1c: o-MeC6H4
1d: m-MeC6H4
1e: p-MeOC6H4
1 f: p-FC6H4
1g: p-ClC6H4
1h: p-BrC6H4
1i: 2-naphthyl
1j: PhCH2CH2
1k: cyclohexyl
À30
À30
À30
10
11[b]
12
13
14[b]
15
16
17
18
19
20
21
22[b]
À30 to 0
quinidine (10)
À30 to 23 48
[a] The absolute configuration of 2 is given in parentheses. [b] Reaction
carried out without using Na2CO3. [c] 3aa (46%) was obtained.
[d] Phosphite (1.3 equiv) and Na2CO3 (0.2 equiv) was used. [e] Cyclo-
pentyl methyl ether was used as a solvent. [f] The reaction was carried
out at À408C. [g] Water (10.0 equiv) was added.
À40
96
48
96
48
60
18
24
18
48
48
72
À30
À30 to 0
À30
À30
À30
À30
À30
À30
(0.2 equiv) also led to good results (Table 1, entry 7). The
reaction in cyclopentyl methyl ether (CPME) afforded 2aa
with a higher enantioselectivity than in toluene (Table 1
entry 8). It should be noted that an electron-rich phosphite
such as bis(o-methoxyphenyl) phosphite enhanced the enan-
tioselectivity of the product (Table 1, entry 9). The reaction at
lower temperature (À408C) resulted in even more rigorous
enantiofacial control (Table 1, entry 10). Importantly,
decreasing the catalyst loading to 2 mol%, which represents
the lowest catalyst loading employed in the asymmetric
hydrophosphonylation of ketones, had little effect on enan-
tioselectivity and yield (Table 1, entry 11). The reaction with
quinine gave (S)-2ba with an opposite configuration com-
pared with that obtained in the reaction with quinidine
(Table 1, entry 12). Most enantioselective protonations are
generally sensitive to moisture and water: however, the
reaction observed in the presence of water also afforded the
product 2ba with high enantioselectivity (Table 1, entry 13).
With these optimized conditions, the reaction of a series of
ketones and bis(o-methoxyphenyl) phosphite using quinine
or quinidine was examined (Table 2). The reaction of
a-ketoesters bearing electron-donating groups such as
methyl or methoxy groups with quinine gave the correspond-
ing products 2bb–be in high yields (73–99%) and high
enantioselectivities (83–90% ee), although a-ketoesters with
sterically demanding groups such as an o-methyl gave product
2bc in lower yield compared with the reaction of 1a (Table 2,
entries 2–5). The reaction of electron-deficient a-ketoesters
bearing fluoro, chloro, or bromo groups in the para position of
the benzene ring gave products 2bf–bh with 88–89% ee
(Table 2, entries 6–8). The a-ketoester with a 2-naphthyl
group also gave the product 2bi with 99% yield and 85% ee
À30 to 0
À30 to 0
[a] The absolute configuration of 2a is given in parentheses. [b] Na2CO3
(1.0 equiv) was used.
(Table 2, entry 9). On the other hand, the reaction with
quinidine instead of quinine gave the opposite enantiomer of
products 2ba–bk with high enantioselectivity (Table 2,
entries 12–22).
In order to clarify the reaction pathway of the enantio-
selective reaction, we tried some reactions using racemic
a-hydroxy phosphonate rac-3aa (Scheme 3). The reaction of
rac-3aa with bis(o-methoxyphenyl) phosphite in the presence
of quinidine and Na2CO3 afforded the phospha-Brook
rearrangement product 2aa in high yield and with high
enantioselectivity. In this reaction, product 2ba or 3ba from
the cross-hydrophosphonylation with bis(o-methoxyphenyl)
Scheme 3. Control experiments for the phospha-Brook rearrangement
from rac-3aa.
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phosphite could not be observed, therefore, retro-hydro-
phosphonylation of rac-3aa could be ruled out. The enantio-
selectivity of the reaction of a-ketoesters with phosphite
results from the enantioselective protonation of prochiral
enolates in the kinetic process. On the other hand, the
reaction of rac-3aa with only quinidine also promptly
proceeded to give 2aa with high enantioselectivity. This
result implies that Na2CO3 activates only the addition of
phosphites to 1a.
The catalytic cycle for the addition of phosphite, the
phospha-Brook rearrangement, and the enantioselective
protonation is shown in Scheme 4. The most acidic compound
in the reaction is diphenyl phosphite. Therefore, Na2CO3
reacts with diphenyl phosphite to give the sodium salt of
phosphite, which reacts with 1a to give the addition product
Figure 1. Suggested transition state for the protonation of a-phospho-
nyloxy enolate using quinidine and diphenyl phosphite.
quinidine. Through this transition state,
the
protonated
quinuclidine
ring
approaches the Si face of the enolate.
We also examined the synthesis of an
optically active phosphoric acid mono-
ester from an a-phosphonyloxy ester. The
o-methoxyphenyl group in 2bk was
removed through reductive cleavage with
PtO2 and hydrogen in EtOH to give the
optically active phosphoric acid mono-
ester 4 with 98% yield without loss of
enantioselectivity (Scheme 5).[5a] The
enantiopurity was determined by HPLC
analysis after conversion into the methyl
ester derivative 5.
In conclusion, a novel system for
enantioselective protonation reactions
through a phospha-Brook rearrangement
has been developed. This approach is the
first example of catalytic enantioselective
protonation of a-oxygenated ester eno-
lates. More significantly, it gives direct
access to both enantiomers of the optically
Scheme 4. Catalytic cycle for the addition of phosphites, the phospha-Brook rearrangement,
and the enantioselective protonation.
3aa. The nitrogen atom of the cinchona alkaloids would
activate the nucleophilicity of the hydroxy group in 3aa to
give a-phosphonyloxy enolates by phospha-Brook rearrange-
ment. On the other hand, protection of the hydroxy group in
quinidine did not give a good result (Table 1, entry 6). This
result implies that the hydrogen bonding between the hydroxy
groups of the cinchona alkaloids and a-phosphonyloxy
enolates plays a key role in exerting enantioselectivity.
Then, the generated a-phosphonyloxy enolates was proton-
ated by the protonated cinchona alkaloids to give product 2aa
with high enantioselectivity together with the regeneration of
cinchona alkaloids. Therefore, cinchona alkaloids also act as
proton transfer reagents.
From the above consideration, Figure 1 shows a proposed
transition state for the enantioselective protonation using
quinidine.[10] The diphenylphosphonyl group in a-phospho-
nyloxy enolates is placed at the opposite position, thus
avoiding the steric repulsion with the quinuclidine ring in
Scheme 5. Synthesis of the optically active phosphoric acid monoester
4. TMS=trimethylsilyl.
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Communications
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active phosphoric esters having secondary alcohols with
satisfactory yields and enantioselectivity using commercially
available cinchona alkaloids. Furthermore, although most
enolates used for enantioselective protonations are prepared
from silyl enol ether or silyl ketene acetal, this is the first
report of an enantioselective protonation of ester enolates
prepared through the phospha-Brook rearrangement. This
method is an attractive alternative for the catalytic in situ
formation of enolates. Further studies to investigate the
potential of these catalytic systems in other processes are
under way.
Experimental Section
General procedure: Ethyl phenylglyoxylate 1a (0.1 mmol) was added
to a solution of quinidine (0.1 mmol), Na2CO3 (0.02 mmol), and bis(o-
methoxyphenyl) phosphite (0.13 mmol) in CPME (2.0 mL) at À408C,
and the solution was stirred for 72 h. After warming to room
temperature, water was added to the reaction mixture and the
aqueous layer was extracted with CH2Cl2 (5 mL ꢀ 3). The combined
organic extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure to give the crude product, which was purified
by column chromatography on silica gel to give (R)-phosphate.
(S)-Phosphate was obtained by using quinine instead of quinidine.
Received: December 2, 2010
Published online: January 31, 2011
Keywords: enantioselectivity · enolates · organocatalysis ·
.
phospha-Brook rearrangement · protonation
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