Formation of isoxazolidines by enantioselective copper-catalyzed annulation of 2-nitrosopyridine with allylstannanes

Article abstract of DOI:10.1002/anie.201105515

Click! Formal [3+2] cycloadditions of 2-nitrosopyridine with various allylstannanes give 4-stannyl-substituted isoxazolidines. The use of [Cu(MeCN)₄]PF₆, in combination with a Walphos ligand, leads to excellent enantioselectivies and high yields. With cis-2- alkenylstannanes as nucleophiles, 3-alkyl-4-stannyl-substituted isoxazolidines are formed with excellent diastereo- and enantioselectivities. Copyright

Full text of DOI:10.1002/anie.201105515

DOI: 10.1002/anie.201105515
Asymmetric Catalysis
Formation of Isoxazolidines by Enantioselective Copper-Catalyzed
Annulation of 2-Nitrosopyridine with Allylstannanes**
Indranil Chatterjee, Roland Frçhlich, and Armido Studer*
Allenylsilanes[1] and allylsilanes[2] have been successfully used
by Danheiser et al. and Knçlker et al. as nucleophiles in
reactions with activated alkenes using Lewis acids in formal
[3+2] cycloadditions for the formation of substituted cyclo-
=
pentanes. Analogous transformations with heteroolefins C X
(X = O, NR) have also been accomplished to provide the
corresponding five-membered heterocycles.[3] These annula-
À
tions occur through initial C C bond formation at the g-C
tigations we decided to study other p systems in the reaction
with 2-nitrosopyridine. Initial experiments were conducted
with allyltrimethylsilane. Various Lewis acids were tested;
however, the addition reaction did not occur under the
applied conditions. The starting materials were recovered
unchanged.
atom of the unsaturated silane with the p acceptor, followed
by cationic 1,2-silyl migration and subsequent cyclization
[Eq. (1)]. Similar annulations with more-reactive allylstan-
We therefore switched to the more nucleophilic allylstan-
nanes.[8] Pleasingly, reaction of allyltributyltin with 2-nitro-
sopyridine in CH2Cl2 using [Cu(MeCN)4]PF6 as the catalyst
(10 mol%) and (S)-Binap[9a] as the ligand (10 mol%) for 16 h
at À208C provided 1a in 31% yield with encouraging
selectivity (66% ee; Scheme 1, Table 1, entry 1). Interestingly,
the possible allylation product (allyl transfer to the nitroso
compound) was not identified. The reaction was clean but
stopped at low conversion.
Both the yield and the selectivity were increased when the
ligands Segphos,[9b] Solphos,[9c] and Difluorphos[9d] were used
(Table 1, entries 2–4). The Walphos-CH3 ligand[9e] delivered
the highest yield (77%; Table 1, entry 5). The selectivity was
nanes are very rare. To our knowledge, only with a,b-
unsaturated acyl iron complexes as acceptors have such
formal [3+2] cycloadditions been observed [Eq. (2)].[4]
Herein we describe unprecedented highly stereoselective
annulations of allylstannanes with 2-nitrosopyridine for the
preparation of 4-stannyl-substituted isoxazolidines
[Eq. (3)].
1
Nitrosopyridines have been used successfully by Yama-
moto[5] and us[6] as dienophiles in stereoselective Cu-catalyzed
nitroso-Diels–Alder reactions. More recently, we showed that
cycloadditions of 2-nitrosopyridine with various ketenes can
be catalyzed by CuI salts to give 1,2-oxazetidin-3-ones with
high enantioselectivities.[7] Based on these successful inves-
[*] I. Chatterjee, Dr. R. Frçhlich, Prof. Dr. A. Studer
Organisch-Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: studer@uni-muenster.de
[**] We thank the Deutsche Forschungsgemeinschaft (DFG) for funding
and Solvias AG for donation of ligands.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105515.
Scheme 1. Model reaction and ligands tested.
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Table 1: Optimization studies.
phenyl-substituted tin derivative gave the lowest yield,
whereas the trimethyl-substituted systems provided the high-
est yield. Along this line, allyldialkylphenyltin derivatives
provided intermediate yields (1d and 1e; Table 1, entries 16
and 17). Switching from methyl to butyl substituents did not
influence reactivity to a large extent (compare Table 1, entries
6 and 14, and 16 and 17).
Under optimized conditions we reacted various isomeri-
cally pure 2-alkenyltributylstannanes with 2-nitrosopyridine
using catalyst loadings of 10 and 5 mol% (Table 2). Z-2-
Entry
Ligand
Cat.
[mol%]
Prod.
Yield
[%][a]
ee
[%][b]
1
(S)-Binap
10
10
10
10
10
10
5
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1e
31
35
43
52
77
77
73
58
–
66[c]
77
2
(R)-Segphos
3
(R)-Solphos
61
4
5
6
7
8
9
10
11[e]
12
13
14
15
16
17
(S)-Difluorphos
(R,P)-Walphos-CH3
(R,P)-Walphos-CF3
(R,P)-Walphos-CF3
(R,P)-Walphos-CF3
(R,P)-Walphos-CF3
–
(R,P)-Walphos-CF3
(R,P)-Walphos-CF3
(R,P)-Walphos-CF3
(R,P)-Walphos-CF3
(R,P)-Walphos-CF3
(R,P)-Walphos-CF3
(R,P)-Walphos-CF3
86[c]
74
96
96
96
2
10[d]
–
–
–
–
Table 2: Variation of the allyltin compound.
–
10
10
5
10
5
<5
47
45
76
71
63
62
96 (99)[f]
96 (99)[f]
98
98
97
96
10
10
Entry R1
R2
Prod. Yield
[%][a,b]
d.r.
ee
[%][c]
[a] Yield of isolated product (reactions conducted at 0.14 mmol scale).
[b] Determined by HPLC on a chiral stationary phase (see the Supporting
Information). [c] R enantiomer formed. [d] With ligand in the absence of
[Cu(MeCN)4]PF6. [e] In THF as a solvent. [f] After crystallization.
1
2
3
4
5
6
7
8
Me
Et
n-Pr
n-Hex
CH2CH2CH(CH3)2
iPr
tBu
CH2OCH2Ph
OMe
H
H
H
Me
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2 f
2g
2h
2i
>99 (97) >99:1 >99
83 (81) >99:1
80 (78) >99:1
99
98
84 (82) >99:1 >99
81 (80) >99:1 >99
81 (80) >99:1 >99
71 (63) >99:1 >99
further increased to 96% ee without affecting the yield by
switching to the CF3 congener (Table 1, entry 6). Reducing
the catalyst loading to 5 and 2 mol% led to slightly lower
yields while the excellent selectivity was maintained (Table 1,
entries 7 and 8, respectively). The ligand alone did not
catalyze the process (Table 1, entry 9) and a background
reaction did not occur (Table 1, entry 10). In THF only a trace
amount (< 5%) of the product was formed (Table 1,
entry 11). With triphenylallyltin, isoxazolidine 1b was
formed in significantly lower yield but also excellent selec-
tivity (Table 1, entries 12 and 13). Enantiomerically pure
material was isolated after a single crystallization. Based on
the X-ray structure of 1b the absolute configuration (S en-
antiomer) was unambiguously determined (Figure 1).[10]
Absolute configuration of other products was assigned in
analogy. The highest selectivity (98% ee) was achieved with
allyltrimethyltin (Table 1, entries 14 and 15).
93 (93) >99:1
94 (93) >99:1
98
9
96
10
11
12
13
14
Me 2j
Et 2k
Ph 2l
72 (72)
2:1
98[d]
64
45 (44) >99:1
29 (26) >99:1
45
Me 2m
63 (61)
–
96
CH2CH2CH(CH3)2 Me 2n
46 (44) >99:1 >99
[a] Yield of isolated product (reactions conducted at 0.14 mmol scale).
[b] Yield with 10 mol% cat. loading and (in brackets) with 5 mol% cat.
loading. [c] Determined by HPLC on a chiral stationary phase (see the
Supporting Information). [d] Minor isomer 2a was formed with
>99% ee.
Butenyltributyltin was the most reactive substrate in these
studies and the formal [3+2] cycloaddition delivered adduct
2a in a quantitative yield with perfect selectivity (Table 2,
entry 1). At 5 mol% catalyst loading the yield was still very
high (97%). For this stannane we conducted the reaction
using 0.5 mol% of the catalyst (run on a 1 mmol scale) and
obtained 2a as a single isomer in 96% yield. The cis relative
configuration and the regiochemistry were unambiguously
assigned by 1H NMR spectroscopy (see the Supporting
Information). Increasing the size of the R1 substituent in the
cis-2-alkenyltributylstannanes led to slightly lower but still
very good yields, perfect diastereoselectivties, and excellent
enantioselectivities (Table 2, entries 2–8). Also stannylated
enol ethers proved to be good substrates, as shown by the
preparation of 2i (Table 2, entry 9).
It is evident from these results that the size of the “non-
allylic” substituents at Sn strongly influences reactivity: the
To investigate the stereospecificity of the annulation we
tested E-2-butenyltributyltin and found that reaction was
sluggish compared to the transformation with the cis isomer.
Surprisingly, reaction was not stereospecific and 2j was
isolated along with the minor isomer 2a (ratio 2:1). Enantio-
Figure 1. X-ray crystal structure of 1b.
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selectivity was high for both isomers (Table 2, entry 10) and
the absolute stereochemistry adjacent to the N atom was
opposite in 2a and 2j. This was experimentally proven by
transforming these diastereoisomeric compounds into enan-
tiomeric allyl-1-methylamine derivatives (see the Supporting
Information). As expected, the absolute stereochemistry next
to the Sn atom did not alter upon switching from the cis-
allylstannane to its trans derivative. Likely isomerization
occurred during reaction.[11]
À
Scheme 3. Reductive N O bond cleavage.
The larger ethyl- and phenyl-substituted trans isomers
reacted with excellent stereospecificity (d.r. > 99:1) but
moderate enantioselectivity and lower yields (Table 2,
entries 11 and 12).[12] Importantly, our method allowed
formation of quaternary C centers with excellent selectivity
(Table 2, entries 13 and 14). For the unsymmetrically sub-
stituted stannane leading to 2n, both the diastereoselectivity
and the enantioselectivity were excellent (Table 2, entry 14).
We propose the following model to explain the stereo-
chemical outcome of the highly selective reaction with cis-
allylstannanes (Scheme 2). Based on the rigid ground-state
In conclusion we have reported first examples of highly
enantioselective formal [3+2] cycloadditions of allyltin deriv-
atives with 2-nitrosopyridine to give substituted isoxazoli-
dines. Our process represents a new approach to isoxazoli-
dines which are important heterocycles. The products
obtained are interesting compounds for further synthetic
transformations. The reactions occur under mild conditions
and the starting materials are readily prepared.
Received: August 4, 2011
Published online: October 5, 2011
Keywords: asymmetric synthesis · copper · cycloadditions ·
.
heterocycles · rearrangements
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should occur to the Re face of the nitroso compound. Since
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A
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À
which undergoes C C bond rotation to give D which
eventually cyclizes to provide the observed products.
À
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corresponding N-protected amino alcohols 3a and 3b were
isolated in 75% and 76% yield, respectively (Scheme 3).
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Communications
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[12] It seems that the pyridyl group might stabilize the intermediately
formed cationic stannacyclopropane (see structure in
C
[10] CCDC 837081 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[11] There was no indication of isomerization of the thermodynami-
cally more stable E-2-butenyltributyltin to its Z isomer in the
absence of 2-nitrosopyridine under the reaction conditions (1H
NMR analysis). However, since the cis isomer is very reactive,
only little isomerization would explain the reaction outcome.
Scheme 2). In the reaction of the trans-allyltributylstannanes
this interaction forces the substituent R to be placed next to the
shielding phenyl group. This is likely the reason why a drop in
selectivity was observed with trans-allyltributylstannanes with R
substituents larger than methyl.
[13] Y. Yamamoto, H. Yatagai, Y. Naruta, K. Maruyama, J. Am.
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