(2S,5R)-2-Methylaminomethyl-1-methyl-5-phenylpyrrolidine, a chiral diamine ligand for copper(ii)-catalysed Henry reactions with superb enantiocontrol

Article abstract of DOI:10.1039/c4cc02429j

A cis-2-aminomethyl-5-phenylpyrrolidine, which is easily available from methyl Boc-l-pyroglutamate, was found to be a highly efficient chiral ligand for Cu(ii)-catalysed Henry reactions. Excellent yields (>90%) and superb levels of enantiocontrol (98.5-99.6% ee) were reached with aromatic, heteroaromatic, vinylic, and aliphatic aldehydes (36 examples). This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02429j

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(2S,5R)-2-Methylaminomethyl-1-methyl-5-
phenylpyrrolidine, a chiral diamine ligand for
copper(II)-catalysed Henry reactions with superb
enantiocontrol†
Cite this: Chem. Commun., 2014,
50, 6623
Received 2nd April 2014,
Accepted 1st May 2014
Dagmar Scharnagel,‡ Felix Prause,‡ Johannes Kaldun,‡ Robert G. Haase and
DOI: 10.1039/c4cc02429j
Matthias Breuning*
www.rsc.org/chemcomm
A cis-2-aminomethyl-5-phenylpyrrolidine, which is easily available
from methyl Boc-L-pyroglutamate, was found to be a highly efficient
chiral ligand for Cu(II)-catalysed Henry reactions. Excellent yields
(490%) and superb levels of enantiocontrol (98.5–99.6% ee)
were reached with aromatic, heteroaromatic, vinylic, and aliphatic
aldehydes (36 examples).
Fig. 1 cis-2-Aminomethyl-5-arylpyrrolidines 1 and 3 and a square-pyramidal
metal complex of 1, 2.
The Henry (or nitroaldol) reaction is a powerful tool for C–C bond
formation, because it permits rapid access to valuable synthetic
intermediates such as 1,2-amino alcohols and a-hydroxy acids.1
Tremendous advances have been made over the last two decades
in the development of enantioselective versions of this reaction.2
Among the many highly efficient systems based on heterobimetal,3
transition metal,4–6 organo7 and enzyme8 catalysis, chirally modified
copper complexes have received particular attention due to the
wide structural variability of the ligands (diamines, amino
alcohols, amino imines, amino pyridines, imino pyridines, Schiff
bases, box-type ligands, salen-type ligands, and others),5,6 the
ease of preparation and the, in part, high levels of stereocontrol
reached. Several of these catalysts permit 99% ee in the addition
of nitromethane to some of the aldehydes tested,5 but none is
capable of providing 99% ee for the majority of substrates.
Herein we present the first copper catalyst that fulfils this
demand, giving, for the addition of nitromethane to a broad
range of aldehydes, the corresponding ß-nitro alcohols in high
yield and excellent 99% ee.
As illustrated by complex 2, such a shielding might be of
particular importance in asymmetric transition metal catalysts
preferring Jahn–Teller distorted octahedral geometries, because
it selectively blocks one apical position and thereby reduces the
number of possible transition states. The equatorial coordina-
tion sites L1 and L2 are still differentiated by the intrinsic
steric and electronic properties of the C1-symmetric diamine 1,
which might offer another advantage over C2-symmetric ligands.
Copper(II)-catalysed Henry reactions, which are supposed to
proceed via such a pentacoordinate intermediate,10 might provide
an ideal test system to probe the potential of the diamines 1.11 After
investigating some derivatives, we quickly identified the simple
compound 3 as the ligand of choice for these reactions.12
Diamine 3 is easily accessible from commercially available
methyl Boc-L-pyroglutamate (4, Scheme 1). Treatment of 4 with
phenylmagnesium chloride and re-cyclisation of the resulting,
ring-opened ketone delivered the diastereomerically pure pyrrolidine
5 after crystallization.13 Exhaustive reduction followed by OH/NHMe
exchange afforded the target molecule 3 in overall seven simple
steps and 40% yield.
eq
eq
In the course of our studies on bicyclic diamines9 we became
interested in 2-aminomethylpyrrolidines of general type 1 (Fig. 1),
which carry an additional cis-aryl group in 5-position, as compared
to proline derived diamines. Chelation of a metal with 1 will lead
to a rigid bicyclic system, in which the aryl substituent is forced
into an endo-position directly on top of the active metal site.
The enantioselective Henry reactions between the aromatic
aldehydes 6a–u and nitromethane (11 equivalents) were performed
on a 1 mmol scale in THF at À25 1C (Table 1, entries 1–21).
¨
Organic Chemistry Laboratory, University of Bayreuth, Universitatsstraße 30,
95447 Bayreuth, Germany. E-mail: matthias.breuning@uni-bayreuth.de
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, HPLC- and NMR spectra. See DOI: 10.1039/c4cc02429j
‡ These authors contributed equally to this work.
Scheme 1 Synthesis of diamine 3 from pyroglutamate 4.
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The copper(II) complex [3ÁCuBr2], prepared prior to use by stirring
Aliphatic aldehydes 12 provided significantly lower enantio-
CuBr2 with a slight excess of pyrrolidine 3 in THF, was used as the selectivities and yields under these conditions. Nonanal (12b),
chiral catalyst and NEt3 (1.5 mol%) as the base. Under these for example, delivered the Henry product 13b in unsatisfying
conditions12 and in the presence of just 2 mol% [3ÁCuBr2], 53% yield and 94.5% ee after 40 h. In order to compensate the
the Henry products 7a–u were formed within 18 to 67 h in excellent lower reactivity, we raised the amount of catalyst to 8 mol%
92–99% yield. Outstanding 99% ee, in several cases even more than and the temperature to À20 1C, which afforded 13b in good
99.5% ee, were obtained with electronically more or less neutral 86% yield, but low 92.1% ee. Finally, a significant increase in the
(6a–g), electron-deficient (6h–o) and electron-rich (6p–u) aromatic level of chirality transfer was observed by changing the copper
aldehydes, carrying substituents in ortho-, meta-, or para-position.
salt from CuBr2 to CuCl2.14 Under these modified conditions,
Hetarylic aldehydes 8a–f were also treated with nitromethane both, linear (12a–c) and a-branched (12d–g) aliphatic aldehydes
under these conditions (Table 1, entries 22–27). And again, the provided the Henry products 13a–g in excellent 98.5–99.5% ee
Henry products 9a–f were obtained in excellent yields (90–99%) and 495% yield (Table 2).
and superb 499.0% ee, irrespective of the heterocycle (furyl,
The stereochemical outcome of the Henry reactions can be
thiophenyl, or NBoc-pyrryl) and the substitution pattern.
explained via the transition state 14 (Fig. 2). As mentioned earlier,
The a,b-unsaturated aldehydes 10a and 10b solely afforded the aryl group of the chiral ligand 3 blocks the upper apical
the 1,2-addition products 11a and 11b. The latter one is the position at the Cu(II) ion, thus leaving three open coordination
only compound tested within this context that delivered less sites, two equatorial ones and one apical one. Based on the known
than 99.0% ee, namely 98.7%.
model,10 the nitronate should bind apically for maximum activa-
In all cases, the re-face of the aldehyde was attacked by the tion, since its negative charge is less stabilised in this position by
nitronate; the, in part, opposite absolute stereo descriptors in the copper ion. Of the two higher Lewis-acidic equatorial sites, the
the products are a formal consequence of the CIP-notation.
aldehyde should coordinate to the one next to the pyrrolidine
moiety for two reasons: (i) this allows the sterically more demand-
ing counter ion X to occupy the less congested position next to the
aminomethyl group9b and (ii) with the weaker electron donating
secondary amine opposite, the electrophilicity of the carbonyl
group is increased thus facilitating a nucleophilic attack. Further-
more, the aldehyde must be oriented inwards in order to avoid
severe steric repulsions with the chiral backbone. The C–C
bond formation will presumably proceed via a six-membered,
Table 1 Aromatic, heteroaromatic and vinylic aldehyde scopea
Time
(h)
Yieldb
(%)
eec (%)
(config.)
Entry
Compounds
R
1
2
3
4
5
6
7
8
6a, 7a
6b, 7b
6c, 7c
6d, 7d
6e, 7e
6f, 7f
6g, 7g
6h, 7h
6i, 7i
6j, 7j
6k, 7k
6l, 7l
6m, 7m
6n, 7n
6o, 7o
6p, 7p
6q, 7q
6r, 7r
Ph
2-Me-Ph
3-Me-Ph
4-Me-Ph
24
18
20
22
38
65
42
20
22
21
18
19
42
20
21
42
48
67
48
39
40
40
112
72
86
21
160
120
90
92
99
99
93
99
99
99
97
95
94
99
96
95
99
94
97
99
99
98
99
93
91
96
99
95
99
90
90
97
99.3 (S)
99.2 (S)
99.5 (S)
99.4 (S)
99.6 (S)
99.4 (S)
99.0 (S)
99.0 (S)
99.4 (S)
99.4 (S)
99.6 (S)
99.5 (S)
99.5 (S)
99.6 (S)
99.6 (S)
99.5 (S)
99.3 (S)
99.2 (S)
99.3 (S)
99.6 (S)
99.1 (S)
99.6 (R)
99.5 (R)d
99.4 (S)
99.2 (R)
99.5 (R)
99.4 (S)
99.3 (S)
98.7 (S)d
Table 2 Aliphatic aldehyde scopea
4-Ph-Ph
1-Naphthyl
2-Naphthyl
2-O2N-Ph
3-O2N-Ph
4-O2N-Ph
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
4-F-Ph
4-NC-Ph
2-MeO-Ph
3-MeO-Ph
4-MeO-Ph
2,4-(MeO)2-Ph
2,5-(MeO)2-Ph
3,4-(MeO)2-Ph
2-Furyl
5-Me-2-furyl
3-Furyl
2-Thiophenyl
NBoc-2-pyrryl
NBoc-3-indolyl
(E)-PhCHQCH
(E)-1-Penten-1-yl
Time
(h)
Yieldb
(%)
eec
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Entry
Compounds
R
(%) (config.)
1
2
3
4
5
6
7
12a, 13a
12b, 13b
12c, 13c
12d, 13d
12e, 13e
12f, 13f
12g, 13g
nBu
nOct
PhCH2CH2
iPr
cPent
cHex
tBu
40
60
40
44
44
44
44
95
97
95
96
99
99
99
98.5 (S)
98.6 (S)
99.5 (S)
99.1 (S)
98.9 (S)
99.4 (S)
98.6 (S)
6s, 7s
6t, 7t
a
Performed on a 1 mmol scale in THF (600 mL) and MeNO2 (600 mL E
b
c
11 eq.). Isolated yield. Determined by HPLC analysis on a chiral
phase; absolute configurations were established by comparison with
literature data.
6u, 7u
8a, 9a
8b, 9b
8c, 9c
8d, 9d
8e, 9e
8f, 9f
10a, 11a
10b, 11b
a
Performed on a 1 mmol scale in THF (600 mL) and MeNO2 (600 mL E
b
c
11 eq.). Isolated yield. Determined by HPLC analysis on a chiral
phase; absolute configurations were established by comparison with
literature data. Absolute configuration was assigned based on a re-face
d
Fig. 2 Proposed transition state 14.
attack on the aldehyde.
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Financial support of the German research foundation (DFG)
is gratefully acknowledged.
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14 A similar effect on the ee was not observed with aromatic aldehydes.
15 A boat-type transition state cannot fully be excluded, but seems less
likely.
16 Initial studies on Henry reactions with other nitroalkanes revealed
acceptable to good diastereoselectivities and excellent enantio-
selectivities in the major syn-diastereomer. The reaction of benzalde-
hyde (6a) with nitropropane, for example, afforded the corresponding
ß-nitro alcohol in 99% yield with a syn/anti ratio of 79: 21 and 98% ee
in the major diastereomer.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 6623--6625 | 6625