A highly active 4-siloxyproline catalyst for asymmetric synthesis

Article abstract of DOI:10.1002/adsc.200404166

trans-4-tert-Butyldimethylsiloxy-L-proline displays a greater catalytic activity than the parent proline without compromising the enantioselectivity, which widens the substrate scope in the α-aminoxylation of carbonyl compounds, as well as O-nitrosoaldol/

Full text of DOI:10.1002/adsc.200404166

COMMUNICATIONS
A Highly Active 4-Siloxyproline Catalyst for Asymmetric
Synthesis
Yujiro Hayashi,a,* Junichiro Yamaguchi,a Kazuhiko Hibino,a Tatsunobu Sumiya,a
Tatsuya Urushima,a Mitsuru Shoji,a Daisuke Hashizume,b Hiroyuki Koshinob
a
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
Fax: (þ81)-3-5261-4631, e-mail: hayashi@ci.kagu.tus.ac.jp
b
RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Received: June 9, 2004; Accepted: September 13, 2004
Abstract: trans-4-tert-Butyldimethylsiloxy-l-proline
displays a greater catalytic activity than the parent
proline without compromising the enantioselectivity,
which widens the substrate scope in the a-aminoxy-
lation of carbonyl compounds, as well as O-nitroso-
aldol/Michael, and Mannich reactions.
to find a more soluble catalyst, which led us to try
trans-4-tert-butyldimethylsiloxy-l-proline (1), easily
prepared from commercially available trans-4-hy-
droxy-l-proline in large quantities[14] (Figure 1). The
proline catalyst 1 not only provides reproducible results,
but also accelerates the reaction dramatically with a re-
duced amount of the catalyst, promoting reactions that
cannot be catalyzed by proline itself. As the catalyst 1
possesses a higher reactivity than the parent proline,
its superiority to proline will be discussed in this paper.
First of all, the reactivity of the catalyst 1 was investi-
gated in the a-aminoxylation of cyclohexanone in the
Keywords: asymmetric synthesis; Mannich reaction;
organic catalysis; oxidation; proline
Organic catalyst-mediated asymmetric reactions[1] rep- presence of 30 mol % of the catalyst [Eq. (1)]. The in-
resent a rapidly developing field of research and numer- crease in the solubility of 1 in organic solvents greatly wi-
ous impressive results have appeared recently following dens the choice of possible reaction medium (Table 1).
the discovery of the proline-catalyzed aldol reaction, For instance, the reaction scarcely proceeded in
which is the intermolecular variant of the Hajos–Par- CH2Cl2 and THF in the presence of proline owing to its
[2]
À
À
rish Eder–Sauer Wiechert reaction,
reported by poor solubility, while these solvents can be employed
List, Lerner and Barbas in 2000.[3] Among several organ- in the reaction with 1, affording the product in moderate
ic catalysts developed for asymmetric reactions, proline yield (entries 1 and 2), although DMF is the solvent of
has occupied a central role. It has been successfully em- choice in this reaction. Moreover, use of 1 can reduce
ployed not only in the aldol,[3,4] but also in Mannich,[5] the reaction time dramatically: while it takes 60 minutes
Michael,[6] a-amination,[7] and a-aminoxylation[8] reac- for the disappearance of nitrosobenzene catalyzed by
tions. Several modifications of proline catalyst such as 30 mol % of proline, the reaction was completed within
the substitution of the carboxylic acid moiety of proline one minute in the presence of 1 (entry 6). The catalyst
with an amide or tetrazole function have been per- loading can be reduced in the case of 1: when the amount
formed to improve the enantioselectivity and reactivity. of catalyst was reduced to 10 mol %, 15 minutes was
Substituted proline amides have been employed in the enough in the case of 1, while slow addition of nitroso-
aldol reaction to improve the enantioselectivity,[9] while benzene over5.5 h is necessary in the case ofproline (en-
5-pyrrolidin-2-yltetrazole was found to be a more reac- try 7). Even in the presence of 5 mol % of catalyst 1, re-
tive organic catalyst than proline in aldol,[10] a-aminoxy- producible results have been obtained, while the reac-
lation[11] and O-nitroso-aldol/Michael[12] reactions as re- tion scarcely proceeded with the same amount of proline
ported by Yamamoto et al. and in the Mannich reaction as catalyst (entry 8). As for the enantioselectivity, excel-
by Ley et al.[13]
lent selectivity can be achieved with both proline and 1.
During our study of proline-catalyzed a-aminoxyla-
tions of aldehydes,[8 g] the reproducibility of the reaction
was poor, especially at low catalyst loading, owing to the
poor solubility of proline in the organicsolvent. After in-
tensive investigations, reproducible results were ob-
tained using ultrasound irradiation of a DMF suspen-
sion of proline.[8g] This solubility problem prompted us Figure 1.
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DOI: 10.1002/adsc.200404166
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Yujiro Hayashi et al.
Table 1. The solvent effect in a-aminoxylation of cyclohexanone catalyzed by proline and the highly active proline 1.[a]
COMMUNICATIONS
Entry
Solvent
Catalyst [mol %]
Proline
1
Time [min]
Yield [%][b]
ee [%][c]
Time [min]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
THF
30
30
30
30
30
30
10
5
60
60
60
60
60
<5
11
26
34
31
37
77
<5
nd[d]
>99
>99
>99
>99
>99
>99
nd[d]
2
15
15
15
1
67
58
65
50
68
78
76
73
>99
>99
>99
>99
>99
>99
>99
>99
CH2Cl2
CH3CN
CH3NO2
DMSO
DMF
60
1
DMF
DMF
330[e]
330[e]
15[f]
90[g]
[a]
Unless otherwise shown, reactions were conducted with a catalytic amount of catalyst, 1.0 equiv. nitrosobenzene, and 2.0
equivs. cyclohexanone at room temperature, and nitrosobenzene was added in one portion.
Yield of isolated product.
[b]
[c]
[d]
[e]
[f]
À
Determined by chiral HPLC with a Chiralpak AD H column.
Not determined.
Slow addition of nitrosobenzene over 5.5 h.
Slow addition of nitrosobenzene over 15 minutes.
Slow addition of nitrosobenzene over 90 minutes.
[g]
3,3-dimethyl-2-cyclohexen-1-one was treated with 1,
the O-nitroso-aldol/Michael adduct was isolated in
ð1Þ
76% yield with>99% ee [Eq. (3)]. The regiochemistry
was determined by an X-ray crystallographic analysis[15]
of amino diol 5, synthesized by reduction of the carbonyl
À
The results of other ketones and aldehydes in the pres- group and reductive cleavage of the N O bond, as
ence of 10 mol % of proline and 1 are summarized in Ta- shown in Scheme 1, and the absolute stereochemistry
ble 2 [Eq. (2)]. In the reactions of 4,4-dimethylcyclohex- was determined by the modified Mosher method[16]
anone and tetrahydrothiopyran-4-one, in which slow ad- with the MTPA ester 6. Proline can promote the reac-
dition (24 h) of nitrosobenzene is essential, the reaction tion, but the yield of the product is synthetically unsatis-
time was reduced dramatically to 2 h (entries 2 and 3). factory (Table 3, entry 1). The same high reactivity of 1
Catalyst 1 is effective when proline does not yield any was observed in the reaction of cyclohexen-1,4-dione
product: no desired product was obtained from cyclo- monoethylene ketal, in which a moderate yield was ob-
heptanone and diethyl ketone in the presence of pro- tained in the presence of 1, in contrast to the low yield
line,[8e, g] while 1 promoted the reactions effectively, pro- under catalysis by proline (entry 2).
ducing the desired products in moderate yield with ex-
cellent enantioselectivity (entries 4 and 5). The higher
reactivity of 1 was found not only in the a-aminoxylation
of ketones but also in that of aldehydes: the reaction of
phenylacetaldehyde with nitrosobenzene was complet-
ð3Þ
ed within 2 h using 10 mol % of 1, while the product
was isolated in less than 5% yield in the presence of pro-
line, although the reaction time was much longer (24 h) Catalyst 1 is effective not only in the a-aminoxylation of
(entry 6). Two hours are enough for the reaction of 3- carbonyl compounds, but also in the Mannich reaction.
phenylpropanal catalyzed by 1, which is in marked con- Although proline is an effective catalyst in the three-
trast to 24 h for the same reaction catalyzed by proline
(entry 7).
ð2Þ
During the investigation of a-aminoxylations, we en-
countered the O-nitroso-aldol/Michael reaction, which
Scheme 1. Determination of absolute and relative stereo-
was recently reported by Yamamoto et al.[12]: when chemistry of 2.
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4-Siloxyproline Catalyst for Asymmetric Synthesis
COMMUNICATIONS
Table 2. The comparison between proline and highly active proline 1 in a-aminoxylation.
Entry
Substrate
Product
Proline
1
Time [h]
Yield [%][a]
77
Ee [%][b]
Time [h]
Yield [%][a]
76
Ee [%][b]
1[c]
5.5[d]
24[d]
>99
0.25[d]
>99
2[c]
84
>99
2[d]
74
>99
3[c]
24[d]
24[d]
69
>99
2[d]
68
45
>99
>99
4[c]
5[e]
6[g]
<5
nd[f]
2[d]
1[d]
24[d]
24
<5
<5
67
nd[f]
nd[f]
98
50
50
76
>99
99
2
7[g]
24
2
98
[a]
Yield of isolated product.
Determined by chiral HPLC analysis.
Reactions were conducted with 10 mol % catalyst, 1.0 equiv. nitrosobenzene, and 2.0 equivs. ketone in DMF at 08C with
[b]
[c]
slow addition of nitrosobenzene.
Addition time of nitrosobenzene.
Reactions were conducted with 10 mol % catalyst, 1.0 equiv. nitrosobenzene, and 10.0 equivs. ketone in DMF at 08C with
[d]
[e]
slow addition of nitrosobenzene.
Not determined.
Reactions were conducted with 10 mol % catalyst, 1.0 equiv. nitrosobenzene, and 3.0 equivs. aldehyde in CH3CN at 08C, and
[f]
[g]
nitrosobenzene was added in one portion.
Table 3. The comparison between proline and highly active proline 1 in the O-nitroso-aldol/Michael reaction.[a]
Entry
1
Enone
Product
Proline
1
Time [h]
Yield [%][b]
27
ee [%][c]
Time [h]
Yield [%][b]
76
Ee [%][c]
3
6
>99
0.5
6
>99
2
25
>99
56
>99
[a]
Reactions were conducted with 30 mol % catalyst, 2.5 equivs. nitrosobenzene, and 1.0 equiv. ketone in DMSO at room tem-
perature.
Yield of isolated product.
Determined by chiral HPLC with a Chiralpak AD-H column.
[b]
[c]
component Mannich reaction of aldehydes, p-anisidine ficient aldehydes, while electron-rich aldehydes are
and ketones [Eq. (4)],[5a, b] there is a limitation: the reac- poor substrates.[17] In the presence of 5 mol % of the cat-
tion can be successfully applied to reactive, electron-de- alyst, proline scarcely promotes the reaction of alde-
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Yujiro Hayashi et al.
COMMUNICATIONS
Table 4. The comparison between proline and highly active proline 1 in Mannich reaction.[a]
Entry
RCHO
Proline
1
Time [h]
Yield [%]
ee [%][b]
Time [h]
Yield [%]
ee [%][b]
1
2
3
4
benzaldehyde
2-naphthaldehyde
p-anisaldehyde
20
24
20
20
<5
<5
<5
<5
nd[c]
nd[c]
nd[c]
nd[c]
20
24
20
20
63
62
55
48
96[d]
93[e]
90[d]
98[d]
3,4-dimethoxybenzaldehyde
[a]
Reactions were conducted with 5 mol % of catalyst in DMF at À208C.
[b]
[c]
[d]
Isolated yield.
Not determined.
Determined by chiral HPLC analysis of the anti-1,3-aminosilyl ether derived from the Mannich adduct by the following pro-
cedure: (1) reduction with NaBH4, (2) silylation with TBSOTf and 2,6-lutidine, (3) separation of the anti- from the syn-iso-
mer.
[e]
Determined by chiral HPLC analysis.
DMF solution (0.5 mL) of nitrosobenzene (64.2 mg,
0.6 mmol) over 15 minutes at room temperature. The reaction
was quenched with pH 7 phosphate buffer solution, the organic
materials were extracted with ethyl acetate three times and the
combined organic materials were washed with brine three
times, dried over anhydrous Na2SO4, and concentrated under
vacuum after filtration. Purification by silica gel column chro-
matography (ethyl acetate:hexane, 1:20–1:5) gave a-anili-
noxycyclohexanone; yield: 93.4 mg (0.455 mmol, 76%). The
enantiomeric excess was determined by HPLC with a Chiral-
hydes such as benzaldehyde, 2-naphthaldehyde, p-anis-
aldehyde, and 3,4-dimethoxybenzaldehyde, which can
be catalyzed by 1, producing the Mannich adducts in
moderate yields with excellent enantioselectivity (Ta-
ble 4).
À
pak AD H column (40:1 hexane:2-propanol), 1.0 mL/min;
major enantiomer tr¼34.3 min, minor enantiomer tr¼
28.1 min. The absolute stereochemistry was determined after
conversion to (R)-2-hydroxycyclohexanone.[8e, g]
ð4Þ
In summary, we have demonstrated that subtle modifi-
cation of proline increases the activity and that 4-tert-bu-
tyldimethylsiloxyproline (1) displays a greater catalytic
activity without compromising on enantioselectivity,
thus widening the substrate scope in a-aminoxylation
of carbonyl compounds as well as the O-nitroso aldol/
Michael, and Mannich reactions. There are several note-
worthy features in this reaction: (1) excellent enantiose-
lectivity can be achieved with 1, (2) 1 can catalyze reac-
tions that proline does not promote, (3) the loading of
the catalyst can be reduced with reproducible results,
(4) most organic solvents can be employed as a reaction
medium owing to its increased solubility in organic sol-
vents, and (5) 1 can be easily prepared in large quantities
from trans-4-hydroxyproline, both enantiomers of
which are commercially available. As proline is a widely
used organic catalyst, 1 with the above mentioned supe-
rior features will be an indispensable new catalyst in
asymmetric synthesis.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
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4-Siloxyproline Catalyst for Asymmetric Synthesis
COMMUNICATIONS
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b¼6.4429(2), c¼14.8750(4) ꢁ, b¼100.9474(9)8, V¼
1324.00(8) ꢁ3, Z¼4, R(F)¼0.0441 (2874 reflections
with I>2s(I)), wR(F2)¼0.0840 (all data, 3293 reflec-
tions), and S¼1.027. A CIF file for the structure of 5
was deposited to the Cambridge Crystallographic Data
Centre with the deposition number, CCDC 238002. Cop-
ies of the data can be obtained free of charge via http://
www.ccdc.cam.ac.uk or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK, fax: (þ44)-1223-336033, or deposit@ccdc-
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Adv. Synth. Catal. 2004, 346, 1435–1439
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