Gold catalyzed enantioselective intermolecular [3+2] dipolar cycloaddition of N-allenyl amides with nitrones

Article abstract of DOI:10.1039/c3cc41769g

A gold catalyzed enantioselective [3+2] dipolar cycloaddition of N-allenyl amides with nitrones was developed to give chiral 4-alkylidenyl isoxazolidine derivatives in high yields and excellent enantioselectivities by using BINOL derived chiral phosphoram

Full text of DOI:10.1039/c3cc41769g

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Gold catalyzed enantioselective intermolecular
[3+2] dipolar cycloaddition of N-allenyl amides
with nitrones†
Guo-Hua Li,ab Wen Zhou,a Xiao-Xiao Li,a Qing-Wei Bi,b Zhen Wang,a
Zhi-Gang Zhao,*b Wen-Xiang Hu*c and Zili Chen*a
Cite this: Chem. Commun., 2013,
49, 4770
Received 8th March 2013,
Accepted 29th March 2013
DOI: 10.1039/c3cc41769g
www.rsc.org/chemcomm
A
gold catalyzed enantioselective [3+2] dipolar cycloaddition of
N-allenyl amides with nitrones was developed to give chiral 4-alkylidenyl
isoxazolidine derivatives in high yields and excellent enantioselectivities
by using BINOL derived chiral phosphoramidate Au(I) catalysts.
Scheme 1 A 1,3-dipolar cycloaddition–reduction sequence to give chiral amino
alcohols via isoxazolidine.
Stereoselective 1,3-dipolar cycloadditions of nitrones with C–C unsatu-
rated bonds have long been the topic of many studies.1 In particular,
the asymmetric nitrone–alkene cycloadditions have received a great
deal of attention. Various chiral metal complexes2 as well as organic
catalysts3 were devised for this transformation. Moreover, enantio-
selective 1,3-dipolar nitrone–alkyne cycloadditions using chiral Cu(II)
catalyst or organocatalysts were documented.4 However, the asym-
metric nitrone–allene dipolar cycloaddition reaction is not reported
yet.5 This may be due to the challenge posed by the substrate
requirement in the previous methods.2–4
Recent advances in gold chemistry provided new opportunities
for allene’s asymmetric transformation.6 The initial examples of
enantioselective gold catalyzed allene cycloadditions are exclusively
intramolecular reactions.7,8 In the process of this research, two
intermolecular asymmetric reactions, including [2+2]9a and [4+2]9b
cycloaddition of allenes with alkenes or dienes, were also achieved.9
Nevertheless, all these reports focused on the preparation of
the carbocycle products. We herein disclosed the first example of
gold catalyzed enantioselective intermolecular [3+2] dipolar cyclo-
addition of N-allenyl amides10 with nitrones11 by using BINOL
derived chiral phosphoramidate Au(I) catalysts12 to give chiral
4-alkylidenyl isoxazolidine derivatives in high yields and
excellent enantioselectivities (Scheme 1). Further modification
of isoxazolidines 3a and 3f through a coupling reaction and
RANEYs-Ni reduction provided chiral 1,3-amine alcohol derivatives
in high yields.
The reaction of tosyl N-allenyl amide 1a with diphenyl nitrone
2a was chosen for our initial investigation. After a series of
experiments, Ph3PAuCl/AgNTf2 shows to be the best catalyst
combination in DCE to give the desired dipolar cycloadduct 3a
in almost quantitative yield (Scheme 2).13
Based on the optimized result of this racemic reaction, we started
to identify an effective chiral ligand for this new [3+2] dipolar
cycloaddition. At first, the chiral diphosphine ligand L1 was tested,
but it gave no desired product (Table 1, entry 1). Spiro ligands L2 and
L3 were then evaluated. The (R)-1,10-spirobiindane-7,70-diol derived
(R)-SIPHOS L2 provided 3a in a moderate yield with 33% ee (Table 1,
entry 2), while (R)-SIPHOS-PE L3, with a (R,R)-bis(1-phenylethyl) amine
moiety in the ligand, gave a reversed enantioselectivity (ꢀ31% ee,
Table 1, entry 3). This meant that the chiral bis(1-phenylethyl)amine
unit played an important role in L3’s asymmetric transition state. A
similar phenomenon, though not so evident, could be observed in
experiments using BINOL derived phosphoramidate ligands L4, L5
and L6. L5 and L6 gave the same major enantiomer as L4 did, while
(R,R)- or (S,S)-bis(1-phenylethyl)amine units enhanced or decreased
3a’s enantioselectivity (Table 1, entries 4–6). These results indicated
that the (R)-BINOL unit played a major role in the asymmetric
induction process, which could be reinforced or weakened by the
chiral amine moiety. We envisioned that further modification of the
a Department of Chemistry, Renmin University of China, Beijing 100872, China.
E-mail: zilichen@ruc.edu.cn
b College of Chemistry & Environment Protection Engineering, Southwest University
for Nationalities, Chengdu 610041, China. E-mail: zzg63129@yahoo.com.cn
c Department of Chemistry, Capital Normal University, Beijing 100048, China.
E-mail: huwx66@163.com
† Electronic supplementary information (ESI) available: Experimental proce-
dures, the plausible mechanism and data for all new compounds. CCDC
907212. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3cc41769g
Scheme 2 Racemic [3+2] dipolar cycloaddition.
c
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Table 1 Optimization studies of the enantioselective [3+2] dipolar cycloaddition
of 1a and 2aa
Table
2
The representative 1,3-dipolar cycloaddition reactions for various
N-allenylic sulfonamides and nitronesa
Entry
L*
Sol/temp. [1C]
t [h]
Yield [%]
eeb [%]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/rt
DCE/ꢀ20
DCM/ꢀ20
DCM/ꢀ20
DCM/ꢀ20
20
5.5
2.5
3
2
5
4
5
5
3
2
20
1
20
4.5
4.5
10
10
NR
59
76
84
79
73
84
57
66
83
85
NR
90
NR
99
99
74
99
33
ꢀ31
24
40
9
87
27
50
20
67
9
L9
10
11
12
13
14
15c
16c
17c,d
18c,e
L10
L11
L12
L13
L14
L13
L13
L13
L13
92
94
98
98
98
a
Unless noted, all reactions were carried out at a 0.1 mmol scale in
a
Unless noted, all reactions were carried out at a 0.1 mmol scale in
3 mL solvent with the addition of 5 mol% catalyst at ꢀ20 1C, NR = no
b
3 mL DCM with the addition of 2 mol% L13AuCl, 5 mol% AgNTf2 and
reaction. The ee value was determined using HPLC on a Chiralpak
b
c
c
d
100 mg 4 Å MS at ꢀ20 1C. 0.5 equiv. of AgNTf2 was utilized. 1 mmol
AD-H column (see ESI). 100 mg 4 Å MS was added. 2 mol% catalyst
d
e
scale reaction was performed. L9 was utilized as the chiral ligand.
was used. 2 mol% L13AuCl and 5 mol% AgNTf2 were added.
substitution patterns were tested by using N-allenyl p-fluoro-
benzyl sulfonamides (1a) or N-allenyl benzyl sulfonamides (1b) as the
reaction partners. As shown in Table 2, both electron donating and
mild electron withdrawing substituted nitrones gave the desired
isoxazolidines in good to excellent yield with a high level of enantio-
selectivities (for the Ar2 group: 3a–3h, 3i–3m, for the Ar1 group: 3o and
3p, Table 2).16 However, pyridinyl nitrone exhibited a poor reactivity,
possibly due to the coordination of the chiral auric cation with pyridine
(3n, Table 2). Low yields were also obtained in the reactions of p-esteryl
with o-methyl substituted phenyl nitrones, where high levels of asym-
metric induction were still maintained (3q–3r, Table 2). In the reactions
of cyclic N-allenyl sulfonamides with various nitrones, L9 was found to
be the optimal chiral ligand. The corresponding cycloadducts were
thus synthesized in good yields and excellent enantioselectivities (3t–3v,
Table 2). In addition, a 1 mmol scale reaction of 1a with 2a was
performed, giving 3a in 90% yield with 97% ee.
Next, the reaction of oxazolidin-2-one derived N-allenyl oxazo-lidin-
2-one 1e was investigated, in which ligand L12 could provide the
best enantioselective induction. Although cycloaddition of 1e with
diphenyl nitrone 2a gave isoxazolidine 3w with a low ee value (3w,
Scheme 3), the presence of a substituent on the phenyl group greatly
enhanced the enantioselectivity of the product. p-Methyl or m-chloro
substituted nitrones provided the corresponding cycloadducts 3x and
3y in excellent enantioselectivities (3x–y, Scheme 3). The poor perfor-
mance of 3z might be due to the small size of the fluoro group.
BINOL unit by placing bulky groups at the 3,30-position of BINOL
would improve its asymmetric induction level.14 To our delight,
3,30-diphenyl substituted (R,R,R)-L7 provided a much higher enantio-
selectivity, in contrast to the poor performance of its (R,S,S)-isomer L8
(Table 1, entries 7 and 8). Although 2-naphthalenyl and 4-biphenyl
ligands (R,R,R)-L9 and (R,R,R)-L11 did not further improve the
enantioselectivity, 9-phenanthrenyl substituted (R,R,R)-L13 provided
the desired cycloadduct (S)-3a in 90% yield with 92% ee (Table 1,
entries 9, 11, and 13). Nevertheless, the cycloaddition did not proceed
in the presence of (R,S,S)-L12 and (R,S,S)-L14, possibly because of the
strong opposing effects of the two chiral units (Table 1, entries 12 and
14). Temperature and solvent were subsequently optimized. The best
result was obtained in DCM at ꢀ20 1C with the addition of 100 mg
4 Å MS to give 3a in 99% yield and 98% ee (Table 1, entries 15 and 16).
Decreasing the catalyst loading to 2 mol% led to a reduced reaction
yield (Table 1, entry 17). We considered that gold–nitrone coordina-
tion might impair the activity of the gold catalyst. A slightly excessive
amount of AgNTf2 (5 mol%) was then added under the conditions of
2 mol% of L13AuCl, and it was found that the desired product 3a can
be obtained in almost quantitative yield and high enantioselectivity
after 10 h of reaction (Table 1, entry 18).‡15
With the optimized reaction conditions in hand, we then
examined the substrate scope. At first, nitrones with different
Scheme 3 Enantioselective [3+2] dipolar cycloadditions of oxazolidin-2-one
derived N-allenyl amide 1d with nitrones.
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Scheme 4 Further modification of 3a and 3f through a coupling reaction and
RANEYs-Ni reduction
1,3-Amino alcohol motifs are important structural elements in
a diverse range of natural products and pharmaceuticals, which
can be prepared from isoxazolidines through a ring opening
reaction.17 With our established enantioselective intermolecular
[3+2] cycloaddition of N-allenyl amides with nitrones, the N–O
bond fission reaction of cycloadducts 3 via reduction was then
investigated. After a brief screening of several reductants, it was
found that isoxazolidine 3a could be reduced by RANEYs nickel
efficiently in ethanol at 0 1C, furnishing the desired amino alcohol
4a in 99% yield and 98% enantioselectivity (Scheme 4, eqn (1)).18
Coupling of 3f with phenyl boronic acid, followed by RANEYs
nickel reduction, provided biphenyl functionalized amino alcohol
product 6 (Scheme 4, eqn (2)). High enantioselectivity was still
maintained after two steps of reactions.
ˇ
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In summary, we have demonstrated a novel and practical
protocol of gold-catalyzed enantioselective intermolecular [3+2]
dipolar cycloaddition of N-allenyl amides with nitrones to give
chiral isoxazolidines by using modified BINOL derived chiral
phosphoramidate Au(I) catalysts, in which an excessive amount
(5 mol%) of silver salts were added to reduce the undesired
gold–nitrone coordination and to enhance the catalytic activity
of the auric cation. Further derivation of compounds 3a and 3f
could provide two chiral 1,3-amino alcohols 4a and 6 in high
enantioselectivities. This is the first report, to the best of our
knowledge, on enantioselective allene–nitrone cycloaddition to
give chiral 4-alkylidenyl isoxazolidine derivatives in excellent
yields and high enantioselectivities.
´
´
´
E. Dıez, I. Alonso, R. Fernandez, J. Lassaletta, F. Lopez and
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´
F. D. Toste, J. Am. Chem. Soc., 2011, 133, 5500 and references
‡ General procedure for the enantioselective gold catalyzed [3+2]
cycloaddition reaction of N-allenyl amides with nitrones: a solution of
L13AuCl (2 mol%)/AgNTf2 (5 mol%) in dry CH2Cl2 (3 mL) with 100 mg
activated 4 Å MS was stirred at rt for three minutes. Then, N-allenyl
amide 1a (32 mg, 0.1 mmol) and diphenyl nitrone 2a (39 mg, 0.2 mmol)
were added to the solution at ꢀ20 1C. The mixture was stirred at ꢀ20 1C
until complete consumption of the starting material 1a (TLC monitoring).
The concentration of the reaction mixture in vacuo followed by purification
through flash chromatography (hexane–EtOAc = 10/1) afforded 3a (51 mg,
99% yield) as a white solid.
therein.
´
14 Reference for ligand modification: A. Z. Gonzalez, D. Benitez,
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1 Recent reviews: (a) V. Nair and T. D. Suja, Tetrahedron, 2007, 63, 12247; 16 The absolute configuration of (s)-3f was determined by X-ray dif-
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crystallographic data for compound 3f. See the ESI† for details.
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would lead to partially racemic products.
c
4772 Chem. Commun., 2013, 49, 4770--4772
This journal is The Royal Society of Chemistry 2013