Spiro-Pyrrolidine-Catalyzed Asymmetric Conjugate Addition of Hydroxylamine to Enals and 2,4-Dienals

Article abstract of DOI:10.1002/adsc.201501025

A spiro-pyrrolidine-catalyzed tandem aza-1,4-addition/hemi-acetalization reaction was developed with excellent enantioselectivity (12 examples of ≥99% ee), and several substrates proceeded with higher ee (up to 10% increase) compared with the literature data. Particularly, an interesting and unusual aza-1,6-/oxa-1,4-addition for some substrates was also observed.

Full text of DOI:10.1002/adsc.201501025

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DOI: 10.1002/adsc.201501025
Spiro-Pyrrolidine-Catalyzed Asymmetric Conjugate Addition of
Hydroxylamine to Enals and 2,4-Dienals
Qing-Yun Dou,a Yong-Qiang Tu,a,* Ye Zhang,a Jin-Miao Tian,a Fu-Min Zhang,a
and Shao-Hua Wanga,b,*
a
State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou, and Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, Peopleꢀs
Republic of China
Fax: (+86)-931-891-2582; e-mail: tuyq@lzu.edu.cn
School of Pharmacy, Lanzhou University, Lanzhou, Peopleꢀs Republic of China
b
Fax: (+86)-931-891-2973; e-mail: wangshh@lzu.edu.cn
Received: November 6, 2015; Revised: December 30, 2015; Published online: February 17, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501025.
Abstract:
A
spiro-pyrrolidine-catalyzed tandem
sized (Figure 1).[4–6] As such a new type of catalyst
possesses two special structural features together, i.e.,
a chiral pyrrolidine framework and a spiro-skeleton. it
is likely that this compound might be used as a com-
plement to current secondary amine organocatalysts
through its unique asymmetric induction property,
which has been supported by an organocatalytic
asymmetric 1,4-conjugate addition.[6] These promising
results encouraged us to further explore the catalytic
properties of 1.
aza-1,4-addition/hemi-acetalization reaction was de-
veloped with excellent enantioselectivity (12 exam-
ples of ꢀ99% ee), and several substrates proceeded
with higher ee (up to 10% increase) compared with
the literature data. Particularly, an interesting and
unusual aza-1,6-/oxa-1,4-addition for some sub-
strates was also observed.
Keywords: asymmetric catalysis; aza-1,4-addition;
aza-1,6-addition; spiro-pyrrolidines
A chiral isoxazolidine skeleton, as the key structur-
al moiety, broadly exists in a variety of bioactive mol-
ecules (Figure 2).[7] Undoubtedly, the efficient con-
struction of this five-membered ring is certainly a key
step for the syntheses of these molecules. Of all the
Asymmetric catalysis, as one of the most useful meth- synthetic strategies developed, the organocatalytic
ods for controlling the enantioselectivity of a chemical asymmetric aza-conjugate addition represents one of
transformation, is always an attractive topic in the the most efficient ways.[8,9] Since the first aminocata-
field of synthetic chemistry. In spite of the achieve- lytic intermolecular aza-1,4-addition via iminium ion
ments in this field, it is also true that there is no cata- activation was achieved in 2006,[9a] numerous analo-
lyst that is universal even for one particular type of gous conjugate additions have been developed. In
reaction. Therefore, developing new catalysts, which spite of the impressive contributions that have been
can be a beneficial complement for the current cata- made in the field of aza-1,4-addition, exploration of
lysts, is always highly desirable. In the case of secon- more efficient asymmetric catalytic systems to en-
dary amine catalysis, pyrrolidine-based catalysts 2 and hance the stereoselectivity is still an important task.
3 developed by Jørgensen, Hayashi and MacMillan Based on our previous research results, it is clear that
have shown broad utilities for the asymmetric func- the secondary amine catalyst 1 showed some special
tionalization of carbonyl compounds via the corre-
sponding iminium or enamine activiation mode,
which has been recognized as an important part of
asymmetric organocatalysis.[1,2] However, it is also
hard to see a significant improvement of the stereose-
lectivities of their analogues by limited changes on
the known skeleton.[2c,d,3] Recently, based on our pre-
vious research results of the semipinacol rearrange-
ment reaction, spiro-pyrrolidine 1 has been synthe- amino catalysts.
Figure 1. Structure of the spiro-pyrrolidine 1 and other
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Spiro-Pyrrolidine-Catalyzed Asymmetric Conjugate Addition
Figure 2. Selected bioactive molecules containing the isoxazolidine skeleton.
stereocontrol properties via its unique skeleton,[6] gioselectivity depends largely on the substituents at
which prompted us to further investigate its efficiency the d-position of 2,4-dienals.
in the asymmetric construction of the isoxazolidine
Initially, in order to prove the catalytic efficiency of
skeleton. In this communication, we report a tandem the spiro-pyrrolidine, (R,R)-1 was first tested in the
reaction between N-hydroxycarbamates and enals asymmetric addition of N-Cbz-protected hydroxyl-
with broad substrate scope and high enantioselectivity amine 4a to cinnamaldehyde 5a. Among different sol-
(Scheme 1). It is also important to notice that a new vents investigated, toluene afforded the best result to
tandem reaction consisting of an iminium-type aza- give the desired product 6a in 95% yield with 86% ee
1,6-addition and an oxa-1,4-addition of 2,4-dienals at room temperature (Table 1, entries 1–4). Lowering
was also developed under the same conditions. To the the reaction temperature to 08C could increase the
best of our knowledge, the aminocatalytic asymmetric enantioselectivity but led to longer reaction times
1,6-addition to 2,4-dienals remains a challenging (Table 1, entry 5). Therefore, an extensive screening
task.[10] Further investigations suggested that the re- of the acid additive was performed to promote the re-
action rate, which revealed that benzoic acid was the
best choice (Table 1, entry 8) and other substituted
benzoic acids had little influence on the ee values
(Table 1, entries 9–11). The best level of yield (93%)
and enantioselectivity (99% ee) was achieved when
the reaction was conducted at À108C with the addi-
tion of 50 mL of H2O, which also acted as a handle for
increasing the reaction rate (Table 1, entry 13). In ad-
dition, the enantiomer (6a’) could be obtained with
À99% ee when (S,S)-1 was used under the optimized
conditions (Table 1, entry 14). When the reaction was
performed with a catalyst loading of 10 mol%, prod-
uct 6a was obtained with 99% ee and 87% yield after
80 h (Table 1, entry 15).
Under the optimized reaction conditions (Table 1,
entry 13), the substrate scope of such a reaction was
explored for the conjugate addition of N-hydroxycar-
bamates 4 to a variety of b-substituted enals 5 using
catalyst (R,R)-1. As listed in Table 2, a variety of b-
substituted enals provided the corresponding 5-hy-
droxyisoxazolidines 6 as a single diastereoisomer with
high yields and enantioselectivities. Among the sub-
strates tested, excellent results were achieved for 5
bearing different substitutions at the phenyl group re-
gardless of their electronic properties, giving the ad-
Scheme 1. Strategies for the construction of isoxazolidine
skeleton.
ducts 6b–j with up to 99% ee (Table 2, entries 1–8).
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Qing-Yun Dou et al.
Table 1. Optimization studies for the conjugate addition of
4a and 5a.[a]
Table 2. Substrate scope of the 1,4-addition reaction.[a]
Entry
Additive
Temp.
[oC]
Time
[h]
Yield
[%][b]
ee
[%][c]
1[d]
2[e]
3[f]
4
5
6
7
8
9
10
11
12
13[g]
14[g,h]
15[i]
–
–
–
–
–
PTS
phenol
BA
4-OMeBA
3-NO2BA
2-FBA
BA
BA
BA
BA
25
25
25
25
0
0
0
0
0
0
0
À10
À10
À10
À10
24
24
24
24
60
48
36
18
18
18
18
80
48
48
80
72
<5
<5
95
93
–
87
94
88
82
93
87
93
90
88
85
–
–
86
97
–
95
97
97
96
97
99
99
-99
99
Entry
4
5 (R1)
Time [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
4b Ph
48
48
48
48
60
95 (6b)
91 (6c)
95 (6d)
90 (6e)
93 (6f)
67 (6g)
93 (6h)
87 (6i)
88 (6j)
94 (6k)
85 (6l)
72 (6m)
91 (6n)
92 (6o)
82 (6p)
91 (6q)
>99
>99
>99
99
99
97
4b 4-ClC6H4
4b 4-BrC6H4
4b 4-NO2C6H4
4b 4-OMeC6H4
4b 4-(NMe2)C6H4 48
4a 4-ClC6H4
4a 4-NO2C6H4
4a 2-OMeC6H4
4b 1-naphthyl
4a 2-furyl
4b Bn
4a Me
4a n-Pr
4a cyclohexyl
4a CO2Et
48
48
60
48
60
48
24
36
48
24
99
>99
>99
>99
96
99
91
98
99
96
9
10
11
12
13
14
15
16
[a]
Reactions performed on
a 0.125 mmol scale using
1.2 equiv. of 5a, 20 mol% (R,R)-1, 50 mol% additive in
toluene (1.0 mL). BA =benzoic acid.
Isolated yield.
Determined by HPLC analysis.
In CHCl3 (1.0 mL).
In THF (1.0 mL).
In MeOH (1.0 mL).
H2O (50 mL) was added.
Catalyst (S,S)-1 instead of catalyst (R,R)-1.
10 mol% (R,R)-1 was added
[b]
[c]
[d]
[e]
[f]
[a]
Reactions performed on
a 0.125 mmol scale using
1.2 equiv. of 5, 20 mol% (R,R)-1, 50 mol% benzoic acid,
50 mL H2O in toluene (1.0 mL) at À108C.
Isolated yield.
[b]
[c]
[g]
[h]
[i]
Determined by HPLC analysis.
linear 2,4-dienals. To our delight, when 2,4-hexadienal
7a and N-protected hydroxylamine (4a and 4b) were
The enals containing 1-naphthyl as well as 2-furyl mixed in the presence of catalyst (R,R)-1, a cascade
groups also performed well to provide 6k and 6l with reaction with an aza-1,6-addition as the initial step
99% ee and 96% ee, respectively (Table 2, entries 10 proceeded smoothly to generate 8a and 8b, respec-
and 11). Additionally, changing the substituent R1 tively, with complete regioselectivity (Table 3, en-
from an aromatic group to an aliphatic one, benzyl or tries 1 and 2). In contrast, under the catalysis of chiral
ethoxycarbonyl, also led to the formation of the de- pyrrolidine (R)-2, the reaction of 7a and 4a only af-
sired products 6m–q with high stereoselectivity forded product 9a, which involved an aza-1,4-addition
(Table 2, entries 12–16). The absolute configuration of as the initial step (Table 3, entry 3). These results indi-
6 was determined by comparison with the literature cated the potential catalytic differences between the
data and X-ray analysis of racemic 6j as an exam- two types of catalysts, which might bring some com-
ple.[9e,11] Remarkably, several reactions of enals, espe- plementary effects in their future applications.
cially 4-chlorocinamaldehyde (Table 2, entry 2), pro-
As only few methods for organocatalytic enantiose-
ceeded with the same or higher ee (up to 10% in- lective vinylogous 1,6-additions to linear 2,4-dienals
crease) with spiro-pyrrolidine 1 compared to the di- have been developed, and there is no report about
arylprolinol silyl ether 2 (Table 2, entries 1–4, 14 and the reaction with N-protected hydroxylamine, some
16).[9e]
other d-substituted 2,4-dienals were subjected to this
Encouraged by above results and the remote ste- tandem reaction. With respect to the bulkier d-ethyl-
reocontrol property of 1,[6] we then applied catalyst and d-n-pentyl-substituted 2,4-dienals (7b and 7c), the
(R,R)-1 to the reaction between hydroxylamines and reaction afforded a mixture of aza-1,6- and aza-1,4-
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Spiro-Pyrrolidine-Catalyzed Asymmetric Conjugate Addition
Table 3. Conjugate addition of 2,4-dienals.[a]
Entry Substrates
Products
1,4-Addition
1,6-Addition
1
7a: R2 =Me, R3 =R4 =R5 =H
7a: R2 =Me, R3 =R4 =R5 =H
7a: R2 =Me, R3 =R4 =R5 =H
7b: R2 =Et, R3 =R4 =R5 =H
7c: R2 =n-pentyl, R3 =R4 =R5 =H
7d: R2 =cyclohexyl, R3 =R4 =R5 =H
7e: R2 =Ph, R3 =R4 =R5 =H
7f: R2 =Ph, R3 =Me, R2 =R4 =H
7g: R2 =Ph, R4 =Me, R2 =R3 =H
8a: 77% yield,[b] dr=2:1,[c] 87/94% ee[d]
–
–
2[g]
3[h]
4
8b: 75% yield, dr=2:1,[c] 86/93% ee[d]
–
9a: 78% yield, dr=7:1,[c] 79% ee[f]
9c: 26% yield, dr>10:1,[e] 91% ee[f]
9d: 32% yield, dr>10:1,[e] 90% ee[f]
9e: 71% yield, dr>20:1,[e] 91% ee[f]
9f: 85% yield, dr>20:1,[e] 91% ee[f]
–
8c: 50% yield, dr=2:1,[c] 87/94% ee[d]
5
6
7
8
8d: 42% yield, dr=2:1,[c] 91/97% ee[d]
–
–
–
–
9
–
[a]
Reactions performed on a 0.125 mmol scale over 48 h using 1.2 equiv. of 7, 20 mol% (R,R)-1, 50 mol% benzoic acid,
50 mL H2O in toluene (1.0 mL) at À108C.
Determined by 1H NMR analysis.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
Determined by HPLC analysis, details see the Supporting Information.
Determined by 1H NMR analysis.
The ee of the major diastereomer of 9 and determined by HPLC analysis.
4b instead of 4a.
Catalyst (R)-2 instead of catalyst (R,R)-1.
[g]
[h]
addition/cyclization products with low regioselectivity Experimental Section
(Table 3, entries 4 and 5). Furthermore, much bulkier
d-cyclohexyl- and d-phenyl-substituted 2,4-dienals (7d Preparation of Isoxazolidines 6
and 7e) gave only aza-1,4-addition/cyclization prod-
To a solution of catalyst (R,R)-1 (20 mol%, 0.025 mmol),
ucts (Table 3, entries 6 and 7). As for the formation of
products 8 and 9 in different ratios with the use of dif-
ferent substituent R2, it might be attributed to the
subtle variation of the conjugation system of the reac-
tion intermediate. Therefore, the bulkier R2 was, the
higher was the ratio in favor of product 9. We also
tested the reactions of b,d- and a,d-disubstituted sub-
strates (7f and 7g),[12] unfortunately, neither aza-1,6-
addition nor aza-1,4-addition product was obtained.
(Table 3, entries 8 and 9).
In conclusion, spiro-pyrrolidine 1 was found to be
a particularly efficient and unique amino catalyst for
the tandem aza-1,4-addition/hemi-acetalization reac-
tion between enals and N-hydroxycarbamates with
excellent enantioselectivities and a broad substrate
scope. As a potential complement for current secon-
dary amine catalysts, it could further improve the
enantioselectivity of previous excellent results up to
99% ee. Also, a new cascade aza-1,6-/oxa-1,4-conju-
gate addition was observed when these catalytic sys-
tems were evolved into some linear 2,4-dienals. Fur-
ther studies on spiro-pyrrolidine 1 are currently un-
derway.
benzoic acid (50 mol%, 0.0625 mmol) and enal 5 (1.2 equiv.,
0.15 mmol) in toluene (1.0 mL) at À108C were added hy-
droxycarbamate
4
(1.0 equiv., 0.125 mmol) and H2O
(50 mL). The resulting mixture was stirred for 24–72 h and
then the product was purified by flash column chromatogra-
phy to afford 6.
Acknowledgements
This work was supported by NSFC (No. 21202073, 21290180,
21272097, 21372104 and 21472077), the “111” Program of
MOE, the Project of MOST (2012ZX 09201101-003) and the
fundamental research funds for the central universities (lzujb-
ky-2014-k20 and lzujbky-2015-k12).
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