Diphenylprolinol silyl ether as a catalyst in an asymmetric, catalytic and direct α-benzoyloxylation of aldehydes

Article abstract of DOI:10.1039/b902287b

Diphenylprolinol silyl ether was found to promote asymmetric, catalytic and direct α-benzoyloxylation of aldehydes with benzoyl peroxide to afford oxidized products in good yields with excellent enantioselectivity. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b902287b

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Diphenylprolinol silyl ether as a catalyst in an asymmetric,
catalytic and direct a-benzoyloxylation of aldehydesw
Hiroaki Gotoha and Yujiro Hayashi*ab
Received (in Cambridge, UK) 3rd February 2009, Accepted 18th March 2009
First published as an Advance Article on the web 14th April 2009
DOI: 10.1039/b902287b
Diphenylprolinol silyl ether was found to promote asymmetric,
catalytic and direct a-benzoyloxylation of aldehydes with
benzoyl peroxide to afford oxidized products in good yields with
excellent enantioselectivity.
Optically active a-acyloxy- or a-hydroxy-aldehydes are
important intermediates in organic synthesis. a-Oxygenation
Fig. 1 The organocatalysts examined in this study.
of aldehydes is one of the direct and straightforward methods
for their synthesis, and there are several enantioselective and
catalytic methods. For instance, the nitroso aldol reaction of
aldehyde and nitrosobenzene catalyzed by proline, which has
been developed independently by three groups including our
group, is one of the powerful methods for the formation of
a-aminoxy aldehydes, which are easily transformed into
a-hydroxy aldehydes.1,2 Our group not only developed this
reaction, but also applied it as a key reaction in the synthesis of
complex natural products, such as fumagillol,3 ovalicin,3
panepophenanthrin4 and cytotrienin A.5 The aldehyde was
also converted to a-hydroxyaldehydes using TEMPO as an
a-benzoyloxylation of aldehydes, which will be described in
this communication.13
We chose the reaction of propanal and benzoyl peroxide as
a model reaction, and the catalysts were investigated first
(Fig. 1). As the generated 2-benzoyloxypropanal is easily
racemized, isolation and characterization were performed
after conversion to the corresponding 2-benzoyloxypropanol
by treatment of the reaction mixture with NaBH4. The results
are summarized in Table 1. Proline scarcely promoted the
reaction, with very low enantioselectivity (entry 1) while
diphenylprolinol trimethylsilyl ether 1 gave good enantio-
selectivity with low yield (38%, entry 2). The organocatalyst
1
oxidant with MacMillan’s catalyst,6 while O2 is employed as
an oxidant in the organocatalyst-mediated reaction.7 In spite
of these successful a-oxidations of aldehydes, there has been
no direct, catalytic, a-acyloxylation of aldehydes so far. We
have been interested in benzoyl peroxide as an oxidant. This
reagent is widely employed as a radical initiator in organic
synthesis, while there is one report in which it is used as a
stoichiometric oxidant with a chiral metallo-enamine to afford
an a-benzoyloxylated carbonyl compound.8
1
reacts with benzoyl peroxide slowly, affording the
N-benzoyloxy derivative as a side product, which was partially
Table 1 Effect of catalyst and solvent in a-benzoyloxylation of
propanala
On the other hand, reactions using organocatalysts have
been developing rapidly, and many types of organocatalysts
with superior features have been devised.9 Diphenylprolinol
silyl ether,10 which has been developed independently by our
group11 and Jørgensen’s group,12 is an effective organo-
catalyst, which has been employed in several asymmetric
reactions. We have found highly enantioselective reactions
catalyzed by diphenylprolinol silyl ether via an enamine
mechanism such as the Michael reaction of aldehydes with
nitroalkenes,11a tandem Michael/Henry reaction,11d Michael
reaction11g and Mannich reaction11i of acetaldehyde. In the
search for a-oxygenation of aldehydes using diphenylprolinol silyl
ether as a catalyst, we have found the highly enantioselective
Entry
Catalyst
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13d
14e
Proline
DMF
DMF
DMF
DMF
DMF
NMP
CH3CN
MeOH
CH2Cl2
Et2O
11
38
45
27
42
24
15
27
0
37
44
59
68
78
9
83
87
81
79
87
86
78
—
90
90
88
92
92
1
2
3
4
2
2
2
2
2
2
2
2
2
1,4-Dioxane
THF
THF
THF
a
Unless otherwise shown, the reaction was performed by employing
propanal (0.81 mmol), benzoyl peroxide (0.27 mmol) and organo-
catalyst (0.027 mmol) in solvent (0.54 mL) at room temperature for
20 h. The reaction mixture was treated with NaBH4 at 0 1C, and
a Department of Industrial Chemistry, Faculty of Engineering,
Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo,
162-8601, Japan. E-mail: hayashi@ci.kagu.tus.ac.jp;
b
the product was isolated as an alcohol. Isolated yield of alcohol.
c
Fax: +81-(0)3-5261-4631; Tel: +81-(0)3-5228-8318
b Research Institute for Science and Technology, Tokyo University of
Science, Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan
w Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b902287b
d
Determined by HPLC analysis on a chiral phase. Organocatalyst 2
e
was employed (20 mol%, 0.054 mmol) in THF (2.7 mL). Organo-
catalyst 2 (10 mol%) was added at the start and also after 4 h.
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Chem. Commun., 2009, 3083–3085 | 3083

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suppressed when bulkier tert-butyldimethyl silyl ether 2 was
employed, in which better yield and enantioselectivity were
realized (entry 3). Trifluoromethyl substituted diarylprolinol
silyl ethers 3 and 4 are not effective in the present reaction
(entries 4 and 5). Next, screening of the solvent was investi-
gated. As shown in Table 1, among the solvents examined such
as NMP, CH3CN, THF, Et2O, 1,4-dioxane, MeOH and
CH2Cl2, THF was found to be the best choice (entry 12).
When the reaction proceeds, an equimolar amount of benzoic
acid would be generated, which might affect the reaction.
Therefore, additives were investigated. Neither bases such as
2,6-lutidine, Et3N, K2CO3, NaHCO3 nor acids such as
CF3CO2H, TsOHꢁH2O and 2,4-dinitrophenylsulfonic acid
are effective, decreasing the yield. By further screening the
reaction conditions, yield and enantioselectivity were
increased to 68% and 92% ee, when 20 mol% of diphenyl-
Table 2 Catalytic, asymmetric a-benzoyloxylation of aldehydes
Yieldb
(%)
eec
(%)
Entry Aldehyde
Conditiona Product
1
2
3
4
A
A
B
B
B
78
54
72
58
77
92
90
94
91
92
5
prolinol tert-butyldimethyl silyl ether
2 was employed
a
(entry 13). With successive addition of catalyst 2 after a 4 h
interval, good yield (78%) was obtained with the excellent
enantioselectivity (92% ee, entry 14).z
Condition A: The reaction was performed by employing aldehyde
(0.81 mmol) and benzoyl peroxide (0.27 mmol) in THF (2.7 mL) at
room temperature for 20 h. Catalyst 2 (0.027 mmol) was added at the
start and also after 4 h. Condition B: The reaction was performed by
employing aldehyde (0.27 mmol) and benzoyl peroxide (0.40 mmol) in
THF (2.7 mL) at room temperature for 20 h. Catalyst 2 (0.027 mmol)
The reaction conditions were optimized using propanal as a
model aldehyde, in which propanal as three equivalents with
respect to benzoyl peroxide (condition A) was employed. This
condition (condition A) would be suitable when the aldehyde
is inexpensive. Next, we investigated the reaction conditions
using 1.5 mol ratio of benzoyl peroxide to aldehyde,
appropriate for the case of an expensive aldehyde, in which
3-phenylpropanal was selected as a model aldehyde. When
benzoyl peroxide was employed as 1.5 equivalents to aldehyde
in the presence of 20 mol% of catalyst 2 (condition B), the
desired product was obtained in good yield with excellent
enantioselectivity (Table 2, entry 3). Under both conditions A
and B, the generality of the reaction was investigated, and the
results are summarized in Table 2. Not only propanal, but also
linear chain aldehydes such as n-butanal react with benzoyl
peroxide, affording a-benzoyloxyaldehyde in moderate yield
with excellent enantioselectivity (entry 2). Aldehydes contain-
ing aromatic or silyl ether moieties were successfully employed
in this reaction (entries 3 and 4). Alkenes do not interfere with
the reaction, affording the a-benzoyloxylated aldehyde in
good yield with excellent enantioselectivity (entry 5).
b
was added at the start and also after 4 h. Isolated yield of alcohol.
c
Determined by HPLC analysis on a chiral phase.
The absolute configuration of 2-benzoyloxypropanol was
determined to be S by comparison with the data in the
literature.14 The reaction is thought to proceed via a transition
state in which benzoyl peroxide approaches the face opposite
the bulky diphenyl(tert-butyldimethylsiloxy)methyl group.
In summary, we have found a highly enantioselective
a-benzoyloxylation of aldehydes with benzoyl peroxide
catalyzed by diphenylprolinol silyl ether. Because the oxidant
is inexpensive, and excellent enantioselectivity has been
obtained, the present method would be one of the more useful
enantioselective a-oxidation methods of aldehydes.
Notes and references
z Typical procedure of asymmetric a-benzoyloxylation of propanal
(Table 1, entry 14, condition A).
Optically active a-benzoyloxyaldehydes are important
synthetic intermediates, because several additional trans-
formations are possible. The following example is a successful
transformation of this key intermediate to a more functiona-
lized synthetic intermediate in the same pot without isolation
of the intermediate with tendency of racemization. A Wittig
reagent was added to the reaction mixture of 3-phenyl-
propanal, benzoyl peroxide and catalyst 2, affording
g-benzoyloxy a,b-unsaturated ester 5 in good yield without
compromising the enantioselectivity (eqn (3)). It should be
noted that it is a synthetic advantage to perform several trans-
formations in a single pot without isolation of the racemizable
a-benzoyloxyaldehydes.
To a solution of benzoyl peroxide (88.0 mg, 0.27 mmol, contains
25% water) and propanal (58.0 mL, 0.81 mmol) in THF (2.7 mL) was
added catalyst 2 (9.9 mg, 0.027 mmol, 10 mol%) at the room
temperature. After stirring the reaction mixture at room temperature
for 4 h, further catalyst 2 (9.9 mg, 0.027 mmol, 10 mol%), was added.
After stirring the reaction mixture at room temperature for an
additional 16 h, MeOH (2.7 mL) and an excess amount of NaBH4
was added at 0 1C to the reaction mixture, which was stirred for 5 min.
The resulting mixture was quenched with saturated aqueous NaHCO3.
The organic materials were extracted with AcOEt and dried over
anhydrous Na2SO4, then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(AcOEt–hexane = 1 : 20–1 : 3) to afford (S)-1-hydroxypropan-2-yl
benzoate (39.3 mg, 78%).
Enantiomeric excess was determined by HPLC using a Chiralpak
AS-H column (10 : 1 hexane–i-PrOH; flow rate 1.0 mL minꢂ1, major
enantiomer; tR = 4.5 min, minor enantiomer; tR = 5.3 min.)
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Chem. Commun., 2009, 3083–3085 | 3085