Densely substituted l -proline esters as catalysts for asymmetric michael additions of ketones to nitroalkenes

Article abstract of DOI:10.1021/acs.joc.5b00495

Homochiral methyl 4-aminopyrrolidine-2-carboxylates are readily obtained by means of asymmetric (3 + 2) cycloadditions between azomethine ylides and nitroalkenes, followed by catalytic hydrogenation of the intermediate 4-nitro cycloadducts. These 4-aminopyrrolidine-2-carboxylate esters belong to the l-series of natural amino acids and catalyze asymmetric Michael additions of ketones to nitroalkenes. However, the enantioselectivity observed with these novel unnatural organocatalysts is opposite to that obtained with l-proline. Since both 4-nitro and 4-amino l-proline esters are efficient organocatalysts of aldol reactions, these results permit to modulate asymmetric quimioselective aldol and conjugate addition reactions.

Full text of DOI:10.1021/acs.joc.5b00495

Article
pubs.acs.org/joc
Densely Substituted L‑Proline Esters as Catalysts for Asymmetric
Michael Additions of Ketones to Nitroalkenes
Andrea Ruiz-Olalla,† María de Gracia Retamosa,†,‡ and Fernando P. Cossío*,†,‡
†Departamento de Química Organ
Centro de Innovacion en Química Avanzada (ORFEO−CINQA), P° Manuel Lardizabal 3, 20018 San Sebastian
Spain
‡Donostia International Physics Center (DIPC), P° Manuel Lardizabal 4, 20018 San Sebastian
́
ica I/Kimika Organiko I Saila, Universidad del País Vasco/Euskal Herriko Unibertsitatea, and
/Donostia, Gipuzkoa,
́
́
́
/Donostia, Gipuzkoa, Spain
S
* Supporting Information
ABSTRACT: Homochiral methyl 4-aminopyrrolidine-2-carboxylates are
readily obtained by means of asymmetric (3 + 2) cycloadditions between
azomethine ylides and nitroalkenes, followed by catalytic hydrogenation of
the intermediate 4-nitro cycloadducts. These 4-aminopyrrolidine-2-
carboxylate esters belong to the L-series of natural amino acids and catalyze
asymmetric Michael additions of ketones to nitroalkenes. However, the
enantioselectivity observed with these novel unnatural organocatalysts is
opposite to that obtained with L-proline. Since both 4-nitro and 4-amino L-
proline esters are efficient organocatalysts of aldol reactions, these results
permit to modulate asymmetric quimioselective aldol and conjugate
addition reactions.
Chart 1. Enantiopure Ligands Based on
Ferrocenylphosphino Pyrrolidines
INTRODUCTION
■
Catalytic conjugate addition reactions constitute a very
powerful method for the generation of C−C bonds in a
stereocontrolled manner.1 Among many different catalysts to
perform this reaction, L-proline (L-Pro) derivatives have been
described as suitable organocatalysts2 that promote the
reactions between ketones and nitroalkenes3 (Scheme 1).
Scheme 1. Michael Addition of Ketones to Nitroalkenes
Catalyzed by L-Pro Derivatives
ligands have been applied to (3 + 2) cycloadditions between
azomethine ylides and C60.6 We have found that reaction
between β-nitrostyrenes 2 and imines catalyzed by Cu(I) salts
and NH−D−EhuPhos leads to the formation of exo-cyclo-
adducts, whereas the same reaction leads to the formation of
the corresponding endo-cycloadducts in the presence of NMe−
L−EhuPhos. We also found that the exo-L-cycloadducts thus
formed catalyze aldol reactions yielding the opposite
enantiomers with respect to those found when L-Pro and its
derivatives are used as organocatalysts.5 In contrast, when endo-
L-cycloadducts were used, the sense of chiral induction in aldol
reactions was similar to that found with L-Pro. These results
showed the subtle effects of distal substituents with respect to
the active site of the organocatalysts.
Different authors4 have described L-Pro-based organocatalysts
incorporating functional groups at the α-position such as
carboxylate, alcohol, amide, phosphino, tetrazole, etc. It is
remarkable that in all these cases the (2S,1′R)-Michael adducts
were reported as the major isomers.3,4
In this paper, we report our results on the ability of densely
substituted proline esters as organocatalysts in conjugate
additions. We shall show that the primary (3 + 2) 4-nitro
cycloadducts are not well suited to catalyze these reactions,
whereas their corresponding amino derivatives are efficient
Recently, we have described5 two novel enantiopure ligands
(Chart 1) based on ferrocenylphosphino proline esters that are
able to catalyze the (3 + 2) cycloaddition between nitroalkenes
and azomethine ylides derived from imines. Recently, these
Received: March 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00495
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
organocatalysts for the conjugate Michael reaction between
cyclic ketones and β-nitrostyrenes. Therefore, a simple
modification of one functional group in these densely
substituted pyrrolidine derivatives results in the emergence of
novel catalytic properties.
our attempts to catalyze the conjugate addition between
cyclohexanone 1a and (E)-β-nitrostyrene 2a with exo- and
endo-L-6aa in the absence of any additive or in the presence of
30 mol % of benzoic acid met with no success (vide infra). We
reasoned that a combination of steric and electrostatic adverse
effects (repulsion between the nitro groups of the Michael
acceptor and the organocatalysts) should be the responsible for
this lack of reactivity. Since the ability of primary amines to
catalyze conjugate additions is known,7 we decided to
transform (3 + 2) 4-nitro cycloadducts 6 into the
corresponding 4-amino analogues 7 (Scheme 2). Catalytic
hydrogenation of the nitro group in a flow reactor at 65 °C
resulted in the formation of the corresponding 4-amino proline
methyl esters with good to excellent yields.
RESULTS AND DISCUSSION
■
We prepared 4-nitroproline methyl esters endo- and exo-L-6aa−
ba following the procedure described in our previous work5
(Scheme 2). Cycloadducts exo-L-6aa−ac were obtained in high
Scheme 2. Enantioselective Synthesis of Unnatural L-Proline
a,b
Methyl Esters 6aa−ac and 7aa−ac
We tested the ability of compounds exo-L-7aa and endo-L-7aa
to catalyze the aldol reaction between cyclohexanone 1a and
2,3,4,5,6-pentafluorobenzaldehyde 8 (Table 1). We observed a
Table 1. Aldol Reaction between Cyclohexanone 1a and
Aldehyde 8 Catalyzed by Unnatural L-Proline Esters exo-L-
6aa, endo-L-6aa, exo-L-7aa, and endo-L-7aa
yield
c
ee
(%)
a
b
d
entry
catalyst
mol %
additive
anti:syn
(%)
1
exo-L-6aa
endo-L-6aa
exo-L-7aa
endo-L-7aa
exo-L-7aa
endo-L-7aa
exo-L-7aa
endo-L-7aa
exo-L-7aa
exo-L-7aa
exo-L-7aa
30
30
30
30
30
30
30
30
10
5
TFA
95:05
96:04
95:05
95:05
92:08
77:23
85:15
81:19
91:09
90:10
92:08
73
83
75
60
61
65
63
62
67
68
65
89
2
TFA
−81
66
3
none
4
none
−10
45
5
PhCO2H
PhCO2H
TFA
6
−12
80
7
8
TFA
−70
82
9
TFA
10
TFA
82
e
11
5
TFA
88
a
Reactions were monitorized by TLC and stirred for 1 to 16 h at room
temperature until consumption of the starting material (Conversion >
a
Numbers in parentheses correspond to yields of isolated pure (3 + 2)
b
99%). The anti:syn ratios were measured by 19F-NMR of crude
b
cycloadducts. Ra−Ni: Raney nickel.
c
reaction mixtures. Yields refer to isolated pure aldol adducts.
d
Enantiomeric excesses measured by HPLC correspond to the
yields and enantiomeric excesses in the presence of NH-D-
EhuPhos and a suitable Cu(I) salt. It is remarkable that our
enantiopure ligand belonging to the D-series promotes the
formation of L-pyrrolidines via (3 + 2) cycloadditions at −20
°C between azomethine ylides derived from imines 5a,b and
nitroalkenes 2a−c (Scheme 2). Cycloadducts exo-L-6ab−ac
were obtained with excellent ee’s ranging from 94% to >99%
(see the Experimental Section). Similarly, (3 + 2) cycloadducts
endo-L-6aa−ba were obtained in good yields and ee’s at
temperatures ranging from −60 to −80 °C via catalytic ligand
NMe-L-EhuPhos (Scheme 2). Compound endo-L-6ba showed
the lowest chemical yield and ee, with an L:D enantiomeric ratio
of ca. 88.5:11.5; thus, it was purified by semipreparative HPLC
resolution in a chiral column (see the Experimental Section).
The ee’s of cycloadducts 6aa and 6ac were ≥99% after
recrystallization in ethyl acetate/hexane mixture, with the only
exception of compound endo-L-6ab, for which an ee value of
95% was measured by HPLC.
major anti-diastereomer 9 calculated as ee = 100([2R,1′S] −
e
[2S,1′R])/([2R,1′S] + [2S,1′R]). Reaction carried out at 0 °C for
48 h.
behavior similar to that reported for 4-nitro precursors exo-L-
6aa and endo-L-6aa (Table 1, entries 1 and 2). Thus, our
experiments indicate that exo-L-7aa promotes the preferential
formation of anti aldol adduct (2R,1′S)-9, whereas endo-L-7aa
catalyzes the aldol reaction between 1a and 8 to yield the
enantiomeric aldol adduct (2S,1′R)-9 as the major product,
although with a lower ee (Table 1, entries 7 and 8). A similar
enantiodivergent outcome was observed for the nitro analogues
exo-L-6aa and endo-L-6aa.5,8 Our results also indicate that TFA
is a convenient additive for this reaction, whereas the presence
of benzoic acid and the absence of any acidic additive result in
significantly lower ee’s (Table 1, entries 3−6). It is also
interesting to note that exo-L-7aa catalyzes this model aldol
reaction even with a relatively low catalytic load of 5 mol %
(Table 1, entries 10 and 11).
In sharp contrast with the satisfactory results provided by 4-
nitroproline methyl esters in organocatalytic aldol reactions,5
B
DOI: 10.1021/acs.joc.5b00495
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The Journal of Organic Chemistry
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Once we verified that novel organocatalysts endo- and exo-L-
7aa behave similarly to their 4-nitro analogues, we tested both
novel compounds in the model conjugate addition between
cyclohexanone 1a and (E)-β-nitrostyrene 2a to yield compound
3aa. The results obtained are gathered in Table 2. As we have
previously mentioned, (3 + 2) cycloadducts endo-L-6aa and exo-
L-6aa did not yield detectable amounts of adducts 3aa after up
to 7 days of reaction at room temperature. In the presence of
30 mol % of TFA, exo-L-6aa promoted a conversion of only
35% as detected by H NMR after 1 day of reaction. Even in
1
this case, a very low diastereoselectivity was measured (Table 2,
entries 1−3). In contrast, both 4-amino analogues endo-L-7aa
and exo-L-7aa were found to be able to catalyze these Michael
additions, yielding the corresponding syn-cycloadducts 3aa after
16−48 h of reaction in the absence of any additive (Table 2,
entries 5 and 6). When exo-L-7aa was used as catalyst, the
(2R,1′S)-3aa adduct was obtained as the major enantiomer,
which is the opposite stereoisomer obtained by using natural L-
Pro derivatives. In contrast, endo-L-7aa promoted the
preferential formation of (2S,1′R)-3aa, although with a
significantly lower ee.
Table 2. Conjugate Addition Reaction between
Cyclohexanone 1a and (E)-β-Nitrostyrene 2a Catalyzed by
Unnatural L-Proline Esters exo-L-7aa and endo-L-7aa
Addition of compounds with acidic groups resulted in faster
and more selective reactions. Thus, p-nitrophenol promoted a
relatively fast reaction (Table 2, entry 7), whereas p-
toluensulfonic acid (Table 2, entry 8) was inefficient in this
respect. Carboxylic acids proved to be more convenient
additives for this reaction. Trifluoroacetic acid (TFA, Table 2,
entry 14) was the most efficient additive for endo-L-7aa in terms
of stereocontrol, although the conversion in this case was found
to be less satisfactory. In the case of exo-L-7aa, TFA, benzoic
acid, salicylic acid and, especially, 4-nitrobenzoic acid (Table 2,
entries 11, 15, 17, and 18, respectively) proved to be
convenient additives in terms of conversion, chemical yields,
diastereoselectivity, and enantioselectivity. Lower catalytic loads
and temperatures did not improve significantly the outcome
obtained with a catalytic load of 30 mol % and at room
temperature, respectively (Table 2, entries 12, 13, 19, and 20).
It is noteworthy that, in all the cases studied, the behavior was
found to be consistently enantiodivergent for exo-L-7aa and
endo-L-7aa, and the enantiocontrol was lower in the latter case
(Table 2, entries 14, 16, and 21).
conv.
a
time
yield
c
ee
b
d
entry catalyst
additive
none
(%)
(h) syn:anti
(%)
(%)
e
1
exo-L-
6aa
<0.5
<0.5
35
72
168
24
24
48
16
64
168
40
96
20
36
96
24
36
24
16
16
36
60
16
n. d.
n. d. n. d.
n. d. n. d.
n. d. 60
2
exo-L-
6aa
benzoic acid
TFA
n. d.
3
exo-L-
6aa
67:33
n. d.
4
endo-L- TFA
6aa
20
n. d. n. d.
5
exo-L-
7aa
none
>99
>99
>99
21
93:07
94:04
98:02
n. d.
65
72
61
77
6
endo-L- none
7aa
−44
78
7
exo-L-
7aa
p-
nitrophenol
TsOH·H2O
8
exo-L-
7aa
n. d. 66
9
exo-L-
7aa
AcOH
>99
>99
>99
>99
44
90:10
88:12
93:07
87:13
n. d.
60
63
75
85
84
86
91
91
Once reaction conditions of room temperature, 30 mol %
catalytic load, and 4-nitrobenzoic acid as additive were selected,
the scope of the reaction in the presence of exo-L-7aa was
assessed. The results are collected in Table 3 (see also Scheme
3).
10
11
12
13
14
15
16
17
18
19
20
21
exo-L-
butyric acid
TFA
7aa
exo-L-
7aa
f
exo-L-
7aa
TFA
According to our results, cyclopentanone 1b reacts easily
with 2a, but in the presence of exo-L-7aa, no diastereocontrol is
observed (Table 3, entries 2 and 3). Cycloheptanone 1c is
more selective, and the syn:anti diastereomeric ratio and the ee
are closer to the values obtained for cyclohexanone 1a (Table 3,
entries 1, 4, and 5). In this latter case, TFA is a more
convenient acidic additive. When the reaction was carried out
in the presence of acetone 1d, a lower enantiocontrol was
observed, although the chemical yield was acceptable (Table 3,
entry 6). Nitroalkenes 2b−l incorporating different aryl and
heteroaryl substituents are suitable Michael acceptors for this
reaction, and the (2R-1′S)-3aa-am adducts are always the major
isomers with ee’s in the range 74−92% (Table 3, entries 7−16).
Electron-withdrawing substituents such as nitro (2g), trifluor-
omethyl (2e), and halogen (2h,j) lead to more electrophilic
Michael acceptors but do not decrease significantly the ee’s
(Table 3, entries 8, 11, 12, and 13). Finally, 2-furyl (2l) and 2-
naphthyl (2m) groups in the starting nitroalkenes result in low
yields in the corresponding adducts 3al and 3am, respectively
(Table 3, entries 15 and 16). Nitroalkenes 2b and 2c did not
yield satisfactory results since the former led to complex
reaction mixtures (maybe because of the instability of this
compound) and the latter was inert under these reaction
conditions.
g
exo-L-
7aa
TFA
n. d. n. d.
endo-L- TFA
7aa
>99
>99
>99
>99
>99
>99
>99
>99
95:05
99:01
90:10
94:06
93:07
95:05
86:14
89:11
65
65
58
70
81
70
83
79
−78
88
exo-L-
7aa
benzoic acid
endo-L- benzoic acid
7aa
−64
90
exo-L-
7aa
salicylic acid
h
exo-L-
7aa
PNBA
92
f
exo-L-
7aa
PNBA
PNBA
87
g
exo-L-
7aa
89
endo-L- PNBA
7aa
−42
a
Conversions were measured by 1H NMR on crude reaction mixtures.
The syn:anti ratios were measured by H NMR on crude reaction
b
1
c
d
mixtures. Yields of isolated pure Michael adducts 3aa. Enantiomeric
excesses of major syn-diastereomer 3aa were measured by HPLC
computed as ee = 100([2R,1′S] − [2S,1′R])/([2R,1′S] + [2S,1′R]).
e
f
n. d.: Not determined. Reaction performed with 20 mol % catalyst
g
h
load. Reaction performed at 0 °C. PNBA: 4-nitrobenzoic acid.
C
DOI: 10.1021/acs.joc.5b00495
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The Journal of Organic Chemistry
Article
Table 3. Chemical Yields, Diastereoselectivities, and Enantiomeric Excesses Observed in Conjugate Addition Reactions
between Ketones 1a−d and Nitroalkenes 2a−m To Yield Adducts (2R,1′S)-3aa−7da Catalyzed by Unnatural L-Proline Ester
a,b
exo-L-7aa
c
d
e
entry
R1, R2
R3
1
2
(2R,1′S)-3
syn:anti
yield (%)
ee (%)
1
2
-(CH2)4-
-(CH2)3-
-(CH2)3-
-(CH2)5-
-(CH2)5-
CH3, H
Ph
Ph
Ph
Ph
Ph
Ph
1a
1b
1b
1c
1c
1d
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
2d
2e
2f
3aa
3ba
3ba
3ca
3ca
3da
3ad
3ae
3af
93:07
47:53
50:50
78:22
93:07
-
81
88
75
20
84
79
58
90
75
89
93
72
90
83
59
92
64
72
71
80
−41
87
88
88
86
88
88
92
74
84
82
f
3
4
f
5
g
6
7
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
4-CH3−C6H4
4-CF3−C6H4
4-CH3O−C6H4
4-NO2−C6H4
3−Br-C6H4
3-CH3O−C6H4
2−F-C6H4
2-CH3O−C6H4
2-furyl
93:07
73:27
89:11
78:22
95:05
99:01
84:16
97:03
90:10
77:23
8
9
10
11
12
13
14
15
2g
2h
2i
3ag
3ah
3ai
2j
3aj
2k
2l
3ak
3al
16
2-naphthyl
2m
3am
23
a
b
1
See Scheme 3 for the definition of reactants, products, and reaction conditions. Reactions were monitorized by TLC or H NMR and stirred at
c
d
1
room temperature until conversion >99%. The syn:anti ratios were measured by H NMR or HPLC on crude reaction mixtures. Yields refer to
e
isolated pure Michael adducts 3. Enantiomeric excesses were measured by HPLC and were computed ee = 100([2R,1′S] − [2S,1′R])/([2R,1′S] +
[2S,1′R]). TFA was used as additive instead of 4-nitrobenzoic acid. Reaction carried out with 16 equiv of acetone 1d in the presence of exo-D-7aa as
catalyst to provide (R)-3da.
f
g
Scheme 3. Conjugate Addition between Ketones 1a−d and
Nitroalkenes 2a−m To Yield Adducts (2R,1′S)-3aa−da
Scheme 4. A Plausible Mechanism for the Michael Addition
between Ketones 1 and Nitroalkenes 2 in the Presence of
Unnatural 4-Amino-L-Proline Catalysts 7
a
Catalyzed by Unnatural L-Proline Ester exo-L-7aa
a
i: exo-L-7aa (30 mol %), 4-nitrobenzoic acid (30 mol %), rt, 16 h.
With this experimental information, we attempted to
understand the origins of the observed behavior of catalysts 7
and, in particular, the enantiodivergent outcome obtained with
the endo and exo series of 4-amino-L-proline methyl esters 7aa.
The accepted mechanism9 for enamine organocatalysis
possessing a primary amino group10 in this kind of reactions
consists of the formation of intermediate imines INT1 (Scheme
4), which isomerize to the corresponding enamines INT2.
These latter intermediates react with Michael acceptors 2 to
form iminium−nitronate intermediates INT3 via transition
structures TScc. This step determines the stereochemical
outcome of the reaction and can be hampered with an out-
of-cycle intramolecular Henry−Mannich addition reaction11 to
generate the (2 + 2) cyclobutane intermediate INT3′, which
have been detected when aldehydes were used as Michael
nucleophiles. Hydrolysis of intermediates INT3 leads to the
release of Michael adducts 3 with concomitant regeneration of
protonated diamine 7H+, which is the active species. This
protonated state and the promotion of the imine−enamine
stages is closely related to the nature of the acidic species
present in the reaction mixture, but it is not essential. Actually,
the catalytic reaction is feasible in the absence of acids (see
Table 2, entries 5 and 6), although considerable acceleration is
achieved with relatively strong acids such as TFA or PNBA.
The alternative mechanism involving formation of enamine
intermediates via the amino group of the pyrrolidine ring and
D
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The Journal of Organic Chemistry
Article
protonation of the primary amino group is less likely (see the
Supporting Information). Thus, from the reported pKa values
for protonated pyrrolidine and benzylamine in acetonitrile12
(19.58 and 16.76, respectively) or water13 (11.27 and 9.3,
respectively), we can estimate the 7H+:7′H+ ratio (Scheme 4)
as ca. 99:01. This result is consistent with the lower
organocatalytic activity of (3 + 2) cycloadducts lacking the
exocyclic primary amino group. Actually, when a mixture of
exo-L-7aa (1 equiv), cyclohexanone 1a (8 equiv), and 4-
nitrobenzoic acid (1 equiv) was stirred at room temperature for
available (Figure 2), although in the case of exo-INT2 there is a
narrower disposition of the nucleophilic enamine moiety, as
shown by the Ω values gathered in Figure 2B. It is also
interesting to remark that, along both the Monte Carlo and
MD simulations, the enamine moiety occupies equatorial
positions with respect to the pyrrolidinium rings (Figure 2A),
whereas the methoxycarbonyl group is isoclinal with respect to
this ring.
The configuration of the transition structures (TSs)
associated with the formation of the C−C bonds show
appreciable differences with respect to reactive enamine
intermediates INT2. As it is shown in Figure 3, LUMO
activation of the Michael acceptor and its interaction with the
nucleophilic enamine moiety result in axial and isoclinal
dispositions of the enamine with respect to the pyrrolidinium
ring, since the equatorial disposition cannot achieve the
required critical C−C bond distance of ca. 2.1 Å. In these
TSs, the nucleophilic attack angle θ is in the range 106−109°,
1
5 min, H NMR analysis of the reaction mixture showed the
formation of the imine INT1 via reaction of the ketone with the
primary amino group, with no detectable CC−H bonding
pattern associated with the enamine moiety, as proved by the
corresponding COSY experiment. In contrast, a similar
experiment using the nitro analogue exo-L-6aa (1 equiv) and
cyclohexanone as solvent without any additive at 70 °C
permitted the detection of the enamine formed between the
NH group of this organocatalyst and cyclohexanone (see the
Supporting Information). From these studies, we concluded
that protonated 7H+ species is the most likely intermediate
along the catalytic cycle.
which is close to the expected Burgi−Dunitz angle15 for saddle
̈
points associated with nucleophilic additions to sp2-hybridized
carbon atoms.
In the reaction catalyzed by exo-L-7aa, two transition
structures leading to syn-3aa were found. Our calculations
indicate that saddle point (R,1′S)-TSccX leading to (2R,1′S)-
3aa lies 2.3 kcal/mol below the alternative TS leading to
(2S,1′R)-3aa (Figure 3). In both saddle points, the dihedral
angle ω is of ca. 170°, thus ensuring an antiperiplanar
orientation between the phenyl group of β-nitrostyrene 2a
and the enamine moiety. In addition, the presence of two
hydrogen bonds between the pyrrolidinium cation and the
nitro and methoxycarbonyl groups of 2a and the organo-
catalyst, respectively, contribute to the stabilization and loss of
conformational freedom of these transition structures. The
preference for (R,1′S)-TSccX with respect to (S,1′R)-TSccX
stems from the presence in the latter saddle point of a
considerable steric congestion between the cyclohexyl group
and one phenyl group of exo-L-7aa, which is forced to adopt an
isoclinal (instead of equatorial) disposition (Figure 3).
In the case of transition structures associated with endo-L-7aa,
the chief features of saddle points (R,1′S)-TSccN and (S,1′R)-
TSccN are quite similar to those found for the exo series (see
Figure 3), although now the nucleophilic enamine moieties are
Within this mechanism, the efficiency of the catalysts 7 is
associated with the HOMO activation promoted by the
enamine moiety as well as by the LUMO activation of the
Michael acceptor 2 induced by the hydrogen bond formed
between the nitro group and the protonated amino group of
the pyrrolidine ring (Figure 1). According to this scheme, the
isoclinal with respect to the pyrrolidine rings. Thus, the Burgi−
̈
Dunitz angles are similar and the hydrogen bond arrays are also
present. The main difference is that in (R,1′S)-TSccN there is a
ω dihedral angle of ca. 120°, which leads to a steric clash
between the cyclohexyl moiety and the phenyl group of 2a,
thus resulting in the preferential formation of Michael adduct
(2S,1′R)-3aa. The relatively lower ee reported experimentally
for endo-L-7aa (Table 2, entries 14, 16 and 21) should be
related with the larger flexibility of the enamine moiety
associated with this latter organocatalysts, as shown in the MD
simulations (see the distribution of Ω dihedral angles in Figure
2B). As a consequence, the Boltzmann average for different
conformations of the transition structures should result in an
energetic preference for endo-L-7aa, which is somewhat lower
than the 2.3 kcal/mol obtained for the “frozen” DFT
conformations shown in Figure 3.
Figure 1. Activation of the substrates and origins of the enantiocontrol
in the conjugate addition between ketones 1 and nitroalkenes 2 in the
presence of exo and endo organocatalytic 4-amino-L-proline esters 7.
origins of the stereocontrol should stem from the configuration
of the chiral centers of the pyrrolidine ring and, in particular,
from the endo/exo disposition of the primary amino group of
the 4-amino-L-proline methyl esters 7aa.
Molecular mechanics studies involving Monte Carlo
conformational searches and molecular dynamics simulations
(MM and MD, respectively, see the Experimental Section for
details) of intermediates endo-INT2 and exo-INT2 show mainly
twist conformations for the pyrrolidine ring14 (see Figure S5 of
the Supporting Information). These simulations also show a
considerable conformational flexibility of the enamine moiety.
Both distal and proximal dispositions with respect to the
protonated amine and carboxymethyl groups are energetically
We also calculated the alternative transition structures
(R,1′S)-TSccX′ and (S,1′R)-TSCCN′ associated with C−C
bond formation through enamines connected directly to the
pyrrolidine ring via 7′H+ species (vide supra). In both cases,
these saddle points were calculated to lie ca. 6 kcal/mol above
E
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Figure 2. (A) Fully optimized (OPLS-2005 force field) structures of endo-INT2 (left) and exo-INT2 (right). The ball-and-stick structures
correspond to the minimum energy conformations after Monte Carlo conformational searches, and the stick representations correspond to the 10
structures of lower energy (ca. 4 kcal/mol). Ω and φ dihedral angles are defined as Ω = C8−C7−N6−C4 and φ = C7−N6−C4−C5. Descriptors ax,
eq, and iso denote axial, equatorial, and isoclinal positions, respectively. (B) Molecular dynamics simulations (OPLS-2005 force field, 1000 ps, see the
Experimental Section) showing the distribution of Ω and φ dihedral angles of endo-INT2 (left) and exo-INT2 (right) along the production time.
the previously discussed congeners, thus confirming the
catalytic cycle based on 7H+ as the most likely one (see the
Supporting Information).
Finally, we tested the effect of a quaternary center at C4 by
studying the behavior of exo-L-7ac (Scheme 2, Table 4, entry
5). The presence of an equatorial methyl group in the
corresponding transition structures resulted in a lower reactivity
of this more substituted organocatalysts, since 7 days were
required for a conversion of 85%. However, the effect of this
additional substituent on stereocontrol of the reaction was
quite low.
In summary, our DFT model shows that most of the
activation energy and the stereoselection observed with these
novel organocatalysts are related to the transition from
equatorial enamine moieties of intermediates INT2 to axial
or at least isoclinal nucleophiles interacting with LUMO-
activated nitroalkenes in the corresponding TScc saddle points,
with a quite rigid polycyclic array of hydrogen bonds, most of
the remaining substituents of the organocatalyst occupying
equatorial (or al least isoclinal) positions. Almost any
disruption of this delicate balance can result in lower catalytic
activities and/or lower stereocontrol.
To complete our study, we explored the possibility of
carrying out chemoselective aldol/conjugate additions using
these organocatalysts. To this end, we prepared double
electrophile 14 from of 4-vinylbenzaldehyde according to the
procedure reported by Maiti et al.16 (Scheme 6). As expected,
reaction between 14 and 1a resulted in the formation of anti-
aldol 15 as the main stereoisomer, with no detectable formation
of the Michael cycloadduct after 48 h of reaction at 0 °C.
Conjugate addition between 15 and 1a resulted in the
formation of adduct anti-16 as the major isomer, in which
the expected stereochemistry was observed in the two new
chiral centers (vide supra). However, the other isomer was
To check the stereochemical model emerged from the DFT
and MM/MD calculations, we prepared compound 10 by N-
acylation of exo-L-7aa (Scheme 5). All our attempts to catalyze
the 1a + 2a → 3aa reaction with amide 10 met with no success,
a result compatible with our hypothesis that the primary amine
moiety in exo-L-7aa is essential for catalysis. Similarly, we
prepared N-methyl derivative 12 by reaction of exo-L-6aa with
formaldehyde followed by hydrogenation of 11 with Raney
nickel. Also in this case, compound 12 was unable to catalyze
the 1a + 2a → 3aa reaction, probably because of the disruption
of the hydrogen bonding array required for the LUMO
activation of Michael electrophile 2a.
Our DFT model also predicted that the substitution pattern
at the C3 position of exo-L-7aa should be relevant in the
preferential formation of Michael adduct (2R,1′S)-3aa, whereas
this effect should be irrelevant or lower in magnitude in
reactions catalyzed by endo-L-7aa. To test the effect of bulky
substituents at either C3 or C5, we prepared tert-butyl
derivatives exo- and endo-L-7ab,ba (Scheme 2). The results
are gathered in Table 4. These experimental results show that
the presence of a tert-butyl group at C3 in exo-L-7ab results in a
slightly higher ee with no apparent effect on the catalytic
activity (Table 4, entry 1). In contrast, the presence of the tert-
butyl group at C5 in exo-L-7ba erodes completely the catalytic
activity of this compound (Table 4, entry 2). This substitution
scheme is less important in the endo series, as expected from the
lower dependence of the substituents on the corresponding
transition structures (Table 4, entries 3 and 4).
F
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a
Table 4. Conjugate Addition Reaction 1a + 2a → 3aa
Catalyzed by exo- and endo-L-7ab,ba, and exo-L-7ac
time
(h)
conv.
b
yield
d
ee
(%)
c
e
entry
catalyst
(%)
syn:anti
(%)
1
2
3
4
5
exo-L-7ab
exo-L-7ba
endo-L-7ab
endo-L-7ba
exo-L-7ac
16
48
>99
<1
93:07
77
94
f
n. d.
n. d.
61
n. d.
−16
−11
73
16
>99
87
52:48
44:56
89:11
g
144
168
45
85
69
a
Reaction conditions: Catalyst (30 mol %), 4-nitrobenzoic acid (30
mol %), room temperature (see the Experimental Section of further
b
c
1
details). Determined by H NMR on crude reaction mixtures. The
syn:anti ratios were measured by 1H NMR or HPLC on crude reaction
d
mixtures. Yields refer to isolated pure Michael adducts 3.
e
Enantiomeric excesses were measured by HPLC and were computed
f
ee = 100([2R,1′S] − [2S,1′R])/([2R,1′S] + [2S,1′R]). n. d.: not
determined. The optical purity of the catalyst was 97.5%.
g
Scheme 6. Synthesis of Compounds 15 and 16 by Sequential
Aldol and Conjugate Additions Catalyzed by L-Pro, exo-L-6aa
a
and exo-L-7aa
Figure 3. Fully optimized and relative Gibbs energies at 298 K (M06-
2X/6-31+G**//B3LYP/6-31G*+TCGE level of theory, see the
Experimental Section) of transition structures TSccX and TSccN
corresponding to the C−C bond forming step (Scheme 4, Figure 1)
associated with the Michael reaction between cyclohexanone 1a and
(E)-β-nitrostyrene 2a in the presence of organocatalysts exo-L-7aa and
endo-L-7aa, respectively. Distances and angles are given in angtroms
(Å) and deg (°), respectively. Dihedral angles ω are defined as ω =
Ca−Cb−Cc−Cd.
Scheme 5. Preparation of Compounds 10, 11, and 12 from
a
exo-L-6aa
a
TEMPO, (2,2,6,6,-tetramethylpiperidin-1-yl)oxyl; PNBA, 4-nitro-
benzoic acid.
found to be syn-16, in which the original anti stereochemistry of
aldol 15 had been modified. This structure was established by
X-ray diffraction analysis17 (see the Supporting Information).
Experiments with a mixture of anti-16, 1a, exo-L-7aa and 4-
nitrobenzoic acid resulted in the partial isomerization to syn-16
1
of 30% as determined by H NMR on the crude reaction
a
mixture after 24 h of reaction at room temperature. This latter
result demonstrates that the syn-16 isomer stems from the in
situ isomerization of the ketone moiety of the aldol adduct.
Numbers in parentheses correspond to yields of isolated pure
products.
G
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products showed positive definite Hessians. Transition structures
(TSs) showed one and only one imaginary frequency associated with
nuclear motion along the chemical transformation under study. Free
energies at 298 K were calculated by including the corresponding
thermal corrections to Gibbs free energies (TCGE). Molecular
mechanics (MM) and molecular dynamics (MD) calculations of
intermediates exo-INT2 and endo-INT2 were carried out using the
OPLS-2005 force field26 as implemented in MacroModel package.27
MD simulations were performed with SHAKE28 to constrain the C−H
bonds. The temperature was set up to 298 K. The system was
equilibrated for 500 ps with time steps of 1 fs. The production run was
started from this point and lasted additional 1000 ps with time steps of
1 fs. In all cases, we observed that during the production period the
energy and temperature of the whole system were equilibrated. During
the production run, the coordinates of 1000 structures were saved.
General Remarks. Unless otherwise stated, reagents and
substrates were purchased from commercial suppliers. Cyclohexanone
1a was freshly distilled on thermally activated 4 Å molecular sieves
before use. Catalysts NMe-L-EhuPhos and NH-D-EhuPhos were
prepared following our previously described procedure.5 Imines 5a,b
and nitroalkenes 2a−m are known compounds and were synthesized
following reported procedures.29 Compounds exo-L-6aa, endo-L-6aa,
and exo-L-6ba have been described in previous works from our
group.5,8 Adducts 9 and 3aa−am are known compounds (see the
Supporting Information for additional details). Compound 14 was
prepared according to a previously reported procedure.16 TLC was
performed on silica gel 60 F254, using aluminum plates and visualized
with UV lamps or potassium permanganate stain. Flash chromatog-
raphy was carried out on columns of silica gel 60 (230−400 mesh).
Hydrogenation reactions were performed with a flow reactor equipped
with a Raney-Nickel cartridge. Hydrogen gas was generated electro-
chemically. Optical rotations were measured using a polarimeter with a
thermally jacketed 5 cm cell at approximately 20 °C, and
concentrations (c) are given in g/100 mL. FT-IR spectra were
recorded with a spectrophotometer equipped with a single-reflection
ATR module; wavenumbers are given in cm−1. HRMS analyses were
carried out using the electron impact (EI) mode at 70 eV or by Q-
TOF using electrospray ionization (ESI) mode. 1H NMR spectra were
Natural L-Pro was also able to react with 14 to yield the anti
aldol adduct ent-15, as expected from previous work reported
by our group5 and from the stereochemical outcomes reported
for many L-Pro-based aldol reactions.18 However, when ent-15
reacted with 1a in the presence of exo-L-7aa, a 63:37 mixture of
diastereomers of ent−anti-16 and ent−syn-16 was observed.
This unexpected result indicates that the stereochemistry of the
final Michael cycloadducts is determined by the chiral centers
of the aldol moiety and not by those of the organocatalyst. This
conclusion was confirmed by repeating the reaction between
anti-15 and 1a in the presence of racemic proline. Under these
conditions, anti-16 and syn-16 were obtained with a
diastereomeric ratio of 87:13, i.e., exactly the same stereo-
control observed in the presence of exo-L-7aa. Therefore, this
final part of our study leads to the conclusion that when using
these organocatalysts it is possible to control aldol and Michael
addition reactions, but the stereocontrol of the conjugate
addition is completely determined by the configuration of the
previously formed aldol adduct.
CONCLUSIONS
■
From the experimental and computational results reported in
this work the following conclusions can be drawn: (i) 3-
Aminopyrrolidin carboxylate methyl esters are efficient
enamine organocatalysts for the conjugate addition on
nitroalkenes in the presence of carboxylic acids. (ii) exo-L-
Cycloadducts lead to the stereochemistry that it would be
expected from D-proline. (iii) Endo analogues produce the same
sense of induction observed when L-proline is used as
organocatalyst. However, endo amino cycloadducts are less
stereoselective than their exo congeners. (iv) Substitution of
either the exocyclic or pyrrolidine amino group destroys the
catalytic activity. (v) The presence of bulky substituents at the
C3 position of the exo organocatalyst can improve the chiral
induction in these conjugate additions. (vi) All these results are
compatible with computational models that suggest a larger
conformational freedom in enamine intermediates involved in
the catalytic cycle of endo cycloadducts as well as quite rigid
transition structures associated with the C−C bond forming
step, in which there is a hydrogen bond array involving
pyrrolidinium cations. (vii) It is possible to control the aldol
and Michael additions in double electrophiles. Both exo-L-
aminopyrrolidin carboxylate methyl esters and natural L-proline
can promote the enantiodivergent formation of aldol adducts.
However, the stereochemical outcome of the subsequent
conjugate addition is completely dictated by the configuration
of the aldol moiety.
recorded at 400 or 500 MHz for 1H NMR and 75 or 100 MHz for 13
C
NMR, using CDCl3 as the solvent and TMS as an internal standard
(0.00 ppm). The data are reported as s = singlet, d = doublet, t =
triplet, m = multiplet or unresolved, br s = broad signal, coupling
constant(s) in Hz, integration. 13C NMR spectra were recorded with
1H- decoupling at 100 MHz and referenced to CDCl3 at 77.00 ppm.
General Procedure for the Synthesis of endo-Cycloadducts
6. A solution of NMe-L-EhuPhos (0.015 mmol) and Cu-
(CH3CN)4PF6 (5.2 mg, 0.014 mmol) in 1.0 mL of dry THF was
stirred at −60 °C for 15 min. Then, a solution of imine 5 (0.45 mmol)
in 1.0 mL of solvent, triethylamine (3.2 μL, 0.023 mmol), and the
corresponding nitroalkenes 2 (0.50 mmol) in 1.0 mL of solvent were
successively added. The reaction was monitored by TLC, and once the
starting material was consumed, the mixture was filtered through a
Celite pad and the filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (ethyl
acetate/hexanes 1:2) to yield the corresponding endo-cycloadduct 6.
The enantiomeric excess was determined by comparison of the HPLC
chromatogram recorded for the racemic mixture with that
corresponding to the enantiomerically enriched cycloadduct.
All these results indicate that both the organocatalytic
efficiency and stereoselectivity of the (3 + 2) cycloadducts
reported in this work are the result of a delicate balance among
different phenomena. Therefore, unexpected effects can be
found in other reactions involving enamine catalysis.
Methyl (2S,3R,4S,5S)-(3-tert-Butyl)-4-nitro-5-phenylpyrrolidine-2-
carboxylate (endo-L-6ab). The expected product was obtained from
imine 5a and nitroalkene 2b. Yield: 116 mg, 84%, orange solid; mp =
113 °C; [α]25D = +14.4 (c 0.50, CHCl3), ee, 95%. FTIR (neat, cm−1):
1728, 1545, 1197, 1198, 733, 694. Carbon atoms in densely substituted
pyrrolidine rings are numbered as in pyrrolidine, the nitrogen atom
numbered 1, and proceeding toward the carboxyl ester group.30 1H
NMR (400 MHz, CDCl3) δ 7.32 (m, 5H, ArH), 5.12 (m, 1H, C4H),
4.45 (dd, J = 11.6, 6.1 Hz, 1H, C5H), 3.85 (s, 3H, CO2Me), 3.27 (t, J =
10.8 Hz, 1H, C2H), 2.97 (d, J = 5.3 Hz, 1H, C3H), 1.05 (s, 9H,
(CH3)3); 13C NMR (101 MHz, CDCl3) δ 172.6, 134.3, 128.4, 128.2,
126.0, 93.2, 67.9, 61.9, 61.1, 52.5, 32.4, 27.4; HRMS (ESI) for
EXPERIMENTAL SECTION
■
Computational Methods. All the computational studies were
carried out by means of either Gaussian 0919 or Maestro20 suites of
programs. Density Functional Theory21 (DFT) calculations were
performed using the B3LYP22 and M06-2X23 functionals. This latter
highly parametrized method is well suited for the treatment of
nonbonding interactions and dispersion forces, which can be relevant
in densely substituted interaction systems.24 The 6-31G* and 6-
31+G** basis sets were used. All the stationary points were
characterized by harmonic analysis.25 Reactants, intermediates and
H
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C16H22N2O4: calculated [M + H]+, 307.1658. Found [M + H]+,
307.1673. HPLC (Chiralcel IB, hexane/iPrOH = 90:10, flow rate 0.5
mL/min, λ = 210 nm), tR (minor) = 29.05 min, tR (major) = 30.53
min; ee = 95%.
and concentrated under reduced pressure. The crude mixture was
filtered through a plug of silica eluting with ethyl acetate affording the
pure product.
Methyl (2S,3S,4R,5S)-1-Methyl-4-nitro-3,5-diphenylpyrrolidine-2-
carboxylate (11). Yield: 406 mg, 78%, dark yellow solid; mp = 63−64
Methyl (2S,3R,4S,5S)-(5-tert-Butyl)-4-nitro-3-phenylpyrrolidine-2-
carboxylate (endo-L-6ba). The expected product was obtained from
imine 5b and nitroalkene 2a. Yield: 94 mg, 68%; ee, 77% (91% yield
was obtained as an 82:18 diastereomeric ratio exo:endo), orange syrup;
[α]25D = −113.6 (c 1.08, CHCl3); ee, 99% after semipreparative HPLC
purification (Chiralcel IA, hexane/iPrOH = 99:1, flow rate 3 mL/min,
λ = 210 nm). FTIR (neat, cm−1): 1740, 1543, 908, 729, 698; 1H NMR
(400 MHz, CDCl3) δ 7.39 (t, J = 7.4 Hz, 2H, ArH), 7.33 (d, J = 7.1
Hz, 1H, ArH), 7.22 (d, J = 7.4 Hz, 2H, ArH), 4.98 (d, J = 4.2 Hz, 1H,
C4H), 4.04 (d, J = 5.7 Hz, 1H, C2H), 3.97 (d, J = 5.7 Hz, 1H, C3H),
3.82 (s, 3H, CO2Me), 3.23 (s, 1H, C5H), 3.11 (s, 1H, NH), 1.08 (s,
9H, (CH3)3); 13C NMR (101 MHz, CDCl3) δ 171.8, 139.5, 129.0,
127.7, 127.1, 92.6, 74.8, 67.4, 56.7, 52.3, 32.5, 26.7; HRMS (ESI) for
C16H22N2O4: calculated [M + H]+, 307.1658. Found [M + H]+,
307.1673. HPLC (Chiralcel IA, hexane/iPrOH = 99:1, flow rate 1 mL/
min, λ = 210 nm), tR (major) = 21.57 min; ee = >99%.
General Procedure for the Synthesis of exo-Cycloadducts 6.
A solution of NH-D-EhuPhos (0.015 mmol) and Cu(CH3CN)4PF6
(5.2 mg, 0.014 mmol) in 1.0 mL of dry THF was stirred at −20 °C for
15 min. Then, a solution of imine 5 (0.45 mmol) in 1.0 mL of solvent,
triethylamine (3.2 μL, 0.023 mmol), and the corresponding nitro-
alkenes 2 (0.50 mmol) in 1.0 mL of solvent were successively added.
The course of the reaction was monitored by TLC, and once the
starting material was consumed, the mixture was filtered through a
Celite pad and the filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (ethyl
acetate.hexanes 1:2) to yield the corresponding exo-cycloadduct 6. The
enantiomeric excess was determined by comparison of the HPLC
chromatogram recorded for the racemic mixture with that
corresponding to the enantiomerically enriched cycloadduct.
°C; [α]25 = +31.9 (c 0.75, CHCl3). FTIR (neat, cm−1): 3061, 3030,
D
1
2951, 1739, 1702, 1551, 1448, 1365, 1203, 1175, 751, 696; H NMR
(400 MHz, CDCl3) δ 7.51 (d, J = 7.3 Hz, 2H, ArH), 7.45−7.21 (m,
8H, ArH), 5.00 (m, 1H, C4H), 4.24 (dd, J = 9.3, 5.9 Hz, 1H, C3H),
3.97 (d, J = 8.0 Hz, 1H, C5H), 3.92 (d, J = 9.3 Hz, 1H, C2H), 3.27 (s,
3H, CO2Me), 2.33 (s, 3H, NCH3); 13C NMR (400 MHz, CDCl3) δ
169.7, 137.8, 137.2, 129.1, 129.0, 128.6, 128.4, 128.0, 127.6, 97.1, 75.1,
71.8, 51.4, 51.1, 39.3. HRMS (ESI) for C19H20N2O4: calculated [M +
H]+, 341.1501. Found [M + H]+, 341.1501.
General Procedure for the Synthesis of Amino Derivatives 7
and 12. A solution of the corresponding 4-nitro cycloadducts 6 (1
mmol) in 100 mL of methanol was pumped at 1 mL/min through the
H-Cube Hydrogenation Reactor using a Raney/Nickel CatCart as
catalyst. The pressure of the system was set to 20 bar and the
temperature to 65 °C. After all the reaction mixture had passed
through the reactor, the solvent was reduced to dryness. The crude
mixture was filtered through a plug of silica eluting with ethyl acetate
affording the pure product.
Methyl (2S,3S,4S,5S)-4-Amino-3,5-diphenylpyrrolidine-2-carbox-
ylate (endo-L-7aa). The expected product was obtained from endo-L-
6aa. Yield: 207 mg, 70%, yellow syrup; [α]25 = +24.2 (c 0.60,
D
1
CHCl3). FTIR (neat, cm−1): 3382, 1727, 1219, 700; H NMR (500
MHz, CDCl3) δ 7.51 (d, J = 7.3 Hz, 2H, ArH), 7.44−7.31 (m, 8H,
ArH), 4.63 (d, J = 6.1 Hz, 1H, C5H), 4.12 (d, J = 7.8 Hz, 1H, C2H),
3.74 (s, 3H, CO2Me), 3.64 (t, J = 6.2 Hz, 1H, C3H), 3.24 (t, J = 6.2
Hz, 1H, C4H), 1.70 (bs, 2H, NH2); 13C NMR (126 MHz, CDCl3) δ
174.3, 140.2, 139.8, 128.6, 128.2, 127.6, 127.5, 127.2, 126.9, 65.4, 64.9,
62.9, 57.0, 52.0. HRMS (ESI) for C18H20N2O2: calculated [M + H]+,
297.1603. Found [M + H]+, 297.1610.
Methyl (2S,3S,4S,5S)-4-Amino-3-(tert-butyl)-5-phenylpyrrolidine-
2-carboxylate (endo-L-7ab). The expected product was obtained
from endo-L-6ab. Yield: 226 mg, 82%, orange syrup; [α]25D = +37.4 (c
0.34, CHCl3) (ee 95%). FTIR (neat, cm−1): 2952, 1735, 1199, 1170,
755, 701; 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 5H, ArH), 4.19 (d, J
= 3.5 Hz, 1H, C5H), 3.78 (s, 3H, CO2Me), 3.73 (d, J = 6.2 Hz, 1H,
C2H), 3.30 (d, J = 3.3 Hz 1H, C4H), 2.05 (d, J = 5.6 Hz, 1H, C3H),
1.02 (s, 9H, (CH3)3); 13C NMR (101 MHz, CDCl3) δ 175.1, 138.5,
128.2, 127.0 (two signals ArC), 67.2, 62.5, 60.4, 57.5, 52.1, 32.3, 27.8.
HRMS (ESI) for C16H24N2O2: calculated [M + H]+, 277.1916. Found
[M + H]+, 277.1926.
Methyl (2S,3S,4R,5S)-(3-tert-Butyl)-4-nitro-5-phenylpyrrolidine-2-
carboxylate (exo-L-6ab). The expected product was obtained from
imine 5a and nitroalkene 2b. Yield: 99 mg, 72% (83% yield was
obtained as an 87:13 diastereomeric ratio exo:endo), white syrup;
[α]25 = +11.4 (c 1.28, CHCl3), ee 98%. FTIR (neat, cm−1): 1735,
D
1549, 1200, 1174, 730, 699; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J
= 7.0 Hz, 2H, ArH), 7.41−7.32 (m, 3H, ArH), 5.07 (t, J = 8.2 Hz, 1H,
C4H), 4.67 (d, J = 7.9 Hz, 1H, C5H), 4.23 (d, J = 7.9 Hz, 1H, C2H),
3.77 (s, 3H, CO2Me), 3.11 (t, J = 8.2 Hz, 1H, C3H), 2.42 (bs, 1H,
NH), 0.98 (s, 9H, (CH3)3); 13C NMR (101 MHz, CDCl3) δ 173.8,
138.8, 128.9, 128.6, 126.7, 92.7, 68.1, 61.7, 59.6, 52.0, 32.8, 27.8.
HRMS (ESI) for C16H22N2O4: calculated [M + H]+, 307.1658. Found
[M + H]+, 307.1676; HPLC (Chiralcel IB, hexane/iPrOH = 80:20,
flow rate 1 mL/min, λ = 210 nm), tR (major) = 18.76 min, tR (minor)
= 44.74 min; ee = 98%.
Methyl (2S,3S,4S,5S)-4-Amino-5-(tert-butyl)-3-phenylpyrrolidine-
2-carboxylate (endo-L-7ba). The expected product was obtained
from endo-L-6ba. Yield: 240 mg, 87%, yellow syrup; [α]25D = +51.3 (c
0.87, CHCl3). FTIR (neat, cm−1): 3342, 2951, 1735, 1217, 757, 701;
1H NMR (500 MHz, CDCl3) δ 7.38−7.16 (m, 5H, ArH), 3.90 (d, J =
Methyl (2S,3S,4R,5S)-4-Methyl-4-nitro-3,5-diphenylpyrrolidine-2-
carboxylate (exo-L-6ac). The expected product was obtained from
imine 5a and nitroalkene 2c. Yield: 101 mg, 66%, white solid; mp =
4.9 Hz, 1H, C2H), 3.73 (s, 3H, CO2Me), 3.46 (s, 1H, NH), 3.44−3.40
(m, 1H, C4H), 3.20−3.19 (m, 1H, C3H), 2.90 (d, J = 4.4 Hz, 1H,
C5H), 2.26 (bs, 2H, NH2), 1.11 (s, 9H, (CH3)3)); 13C NMR (126
MHz, CDCl3) δ 175.1, 142.1, 128.6, 127.3, 126.8, 70.4, 65.0, 62.2,
60.3, 52.3, 32.6, 28.3. HRMS (ESI) for C16H24N2O2: calculated [M +
H]+, 277.1916. Found [M + H]+, 277.1923.
114−115 °C; [α]25 = +84.2 (c 1.00, CHCl3), ee 94%. FTIR (neat,
D
cm−1): 3339, 1742, 1536, 1381; 1H NMR (400 MHz, CDCl3) δ 7.61−
7.18 (m, 10H, ArH), 5.04 (s, 1H, C5H), 4.67 (d, J = 8.2 Hz, 1H, C3H),
4.47 (d, J = 8.2 Hz, 1H, C2H), 3.44 (s, 3H, CO2Me), 2.84 (bs, 1H,
NH), 0.88 (s, 3H. CH3); 13C NMR (400 MHz, CDCl3) δ 171.3, 136.7,
136.5, 129.7, 128.5 (two signals), 128.3, 127.8, 127.8, 98.3, 69.8, 63.0,
56.0, 51.8, 20.8. HRMS (ESI) for C19H20N2O4: calculated [M + H]+,
341.1501. Found [M + H]+, 341.1503; HPLC (Chiralcel IA,
hexane/iPrOH = 85:15, flow rate 1 mL/min, λ = 254 nm), tR
(minor) = 10.9 min, tR (major) = 13.4 min; ee = 94%.
Methyl (2S,3R,4R,5S)-4-Amino-3,5-diphenylpyrrolidine-2-carbox-
ylate (exo-L-7aa). The expected product was obtained from exo-L-6aa.
Yield: 266 mg, 90%, white solid; mp = 75−77 °C; [α]25D = +100.1 (c
1
0.50, CHCl3). FTIR (neat, cm−1): 1731, 1173, 1107, 696; H NMR
(500 MHz, CDCl3) δ 7.70−7.64 (m, 2H, ArH), 7.42 (dd, J = 10.3, 4.7
Hz, 2H, ArH), 7.38−7.30 (m, 3H, ArH), 7.28−7.24 (m, 3H, ArH),
4.29 (d, J = 9.8 Hz, 1H, C5H), 3.93 (d, J = 8.9 Hz, 1H, C2H), 3.66 (dd,
J = 10.3, 9.0 Hz, 1H, C3H), 3.49 (t, J = 10.1 Hz, 1H, C4H), 3.24 (s,
3H, CO2Me), 1.65 (bs, 2H, NH2); 13C NMR (126 MHz, CDCl3) δ
174.3, 140.8, 137.5, 128.7, 128.4, 128.2, 127.9, 127.3, 127.3, 70.3, 63.8,
62.9, 57.1, 51.3. HRMS (ESI) for C18H20N2O2: calculated [M + H]+,
297.1603. Found [M + H]+, 297.1604.
General Procedure for the Methylation of exo-L-6aa.31
Pyrrolidine exo-L-6aa (500 mg, 1,53 mmol) was dissolved in 10 mL
of 88% aqueous formic acid. Ten milliliters of 35% aqueous
formaldehyde was added and the reaction mixture was heated at 100
°C for 2 h. After cooling to room temperature, the acidic solution was
basified with saturated K2CO3 solution from which a precipitated
appeared. Then, this solution was diluted with H2O and extracted with
CH2Cl2. The combined organic layers were dried over Na2SO4, filtered
Methyl (2S,3R,4R,5S)-4-Amino-3-(tert-butyl)-5-phenylpyrrolidine-
2-carboxylate (exo-L-7ab). The expected product was obtained from
I
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The Journal of Organic Chemistry
Article
exo-L-6ab. Yield: 248 mg, 90%, white syrup; [α]25 = +62.7 (c 1.85,
room temperature and filtered through a plug of Celite and diluted
with ethyl acetate. After removal of all the solvent, the residue was
purified by silica gel chromatography (hexane/EtOAc 80:20) to afford
14.
D
1
CHCl3). FTIR (neat, cm−1): 2948, 1729, 1196, 1175, 701; H NMR
(400 MHz, CDCl3) δ 7.58 (d, J = 7.3 Hz, 2H, ArH), 7.37 (t, J = 7.3
Hz, 2H, ArH), 7.31 (d, J = 7.1 Hz, 1H, ArH), 4.05 (d, J = 7.9 Hz, 1H,
C5H), 3.76 (s, 3H, CO2Me), 3.71 (d, J = 8.1 Hz, 1H, C2H), 3.43 (t, J =
8.4 Hz, 1H, C4H), 2.10 (t, J = 8.3 Hz, 1H, C3H), 1.49, (bs, 2H, NH2),
1.05 (s, 9H, (CH3)3); 13C NMR (101 MHz, CDCl3) δ 175.6, 142.0,
128.5, 127.6, 127.4, 71.5, 61.4, 61.1, 60.5, 51.6, 32.2, 28.6. HRMS
(ESI) for C16H24N2O2: calculated [M + H]+, 277.1916. Found [M +
H]+, 277.1921.
(E)-4-(2-Nitrovinyl)benzaldehyde (14). Yield: 898 mg, 65%, yellow
solid; mp = 113−114 °C. FTIR (neat, cm−1): 3112, 2837, 1639, 1538,
1
966, 810, 730; H NMR (500 MHz, CDCl3) δ 10.07 (s, 1H, CHO),
8.03 (d, J = 13.7 Hz, 1H, CHNO2), 7.97 (d, J = 8.1 Hz, 2H, ArH), 7.72
(d, J = 8 Hz, 2H, ArH), 7.64 (d, J = 13.7 Hz, 1H, CHAr); 13C NMR
(126 MHz, CDCl3) δ 191.2, 139.1, 138.5, 137.4, 135.7, 130.5, 129.7,
77.4, 77.2, 76.9. HRMS (ESI) for C9H8NO3: calculated [M + H]+,
178.0504. Found [M + H]+, 178.0504.
General Procedure for the Synthesis of Aldol Adduct 9
under Different Conditions. The corresponding aldehyde 8 (0.25
mmol) was dissolved in neat ketone 1a (1.5 mL, 15.3 mmol, 61.2
equiv), the resulting mixtures in one case was cooled to 0 °C, and the
organocatalyst (0.0125−0.075 mmol, 0.05−0.3 equiv) was added,
followed by additive acid (75.0 μmol, 0.3 equiv). The resulting
mixtures were stirred at room temperature or at 0 °C, then warmed to
room temperature, diluted with ethyl acetate, washed with 0.1 M (pH
7) phosphate buffer solution, dried onto sodium sulfate, filtered and
concentrated under reduced pressure. The afforded crude product was
purified by flash chromatography over silica gel using ethyl acetate/
hexane system as eluent.
Methyl (2S,3R,4R,5S)-4-Amino-5-(tert-butyl)-3-phenylpyrrolidine-
2-carboxylate (exo-L-7ba). The expected product was obtained from
exo-L-6ba. Yield: 218 mg, 79%, yellow oil; [α]25 = +81.7 (c 0.52,
D
1
CHCl3). FTIR (neat, cm−1): 2950, 1734, 1204, 700; H NMR (400
MHz, CDCl3) δ 7.31 (d, J = 6.7 Hz, 2H), 7.25 (d, J = 7.2 Hz, 3H),
4.20 (d, J = 9.4 Hz, 1H), 3.43 (t, J = 7.8 Hz, 1H), 3.30 (t, J = 8.5 Hz,
1H), 3.23 (s, 3H, CO2Me), 2.72 (d, J = 8.1 Hz, 1H), 1.14 (s, 9H); 13
C
NMR (101 MHz, CDCl3) δ 173.5, 139.6, 128.3, 128.3, 127.0, 74.7,
63.1, 59.2, 58.9, 51.2, 33.1, 27.3. HRMS (ESI) for C16H24N2O2:
calculated [M + H]+, 277.1916. Found [M + H]+, 277.1923.
Methyl (2S,3S,4R,5S)-4-Amino-4-methyl-3,5-diphenylpyrrolidine-
2-carboxylate (exo-L-7ac). The expected product was obtained from
exo-L-6ac. Yield: 260 mg, 84%, white solid; mp = 102−103 °C; [α]25
D
= +61.7 (c 0.40, CHCl3). FTIR (neat, cm−1): 3347, 1735, 1205, 728,
1
702; H NMR (400 MHz, CHCl3) δ 7.53 (d, J = 7.3 Hz, 2H, ArH),
(R)-2-[(S)-Hydroxy(4-((E)-2-nitrovinyl)phenyl)methyl]cyclohexan-
1-one (15). Yield: 48 mg, 70%, yellow solid; mp = 137−138 °C;
7.37 (d, J = 7.5 Hz, 2H, ArH), 7.29 (m, 6H, ArH), 4.41 (d, J = 10.2
Hz, 1H, C2H), 4.11 (s, 1H, C5H), 3.51 (d, J = 10.3 Hz, 1H, C3H), 3.45
(s, 3H, CO2Me), 1.51, (bs, 2H, NH2), 0.62 (s, 3H, CH3); 13C NMR
(101 MHz, CDCl3) δ 173.8, 138.6, 137.3, 129.7, 128.0, 127.8, 127.4,
127.2, 126.9, 72.9, 62.3, 61.7, 61.3, 51.4, 22.3. HRMS (ESI) for
C19H22N2O2: calculated [M + H]+, 311.1760. Found [M + H]+,
311.1770.
[α]25 = −12.8 (c 0.60, CHCl3); ee 86%. FTIR (neat, cm−1): 3498,
D
2944, 2858, 1678, 1337, 827; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J
= 13.7 Hz, 1H, CHNO2), 7.58 (d, J = 13.6 Hz, 1H, CHAr), 7.54 (d, J
= 8.4 Hz, 2H, ArH), 7.42 (d, J = 7.9 Hz, 2H, ArH), 4.83 (dd, J = 8.6,
3.1 Hz, 1H, CHOH), 4.02 (d, J = 2.8 Hz, 1H, OH), 2.60 (m, 1H,
COCHCOH), 2.49 (m, 1H, −CH2−), 2.36 (m, 1H, −CH2−), 2.15−
2.07 (m, 1H, −CH2−), 1.82 (d, J = 13.1 Hz, 1H, −CH2−), 1.68 (m,
1H, −CH2−), 1.62−1.56 (m, 2H, −CH2−), 1.36 (m, 1H, −CH2−);
13C NMR (101 MHz, CDCl3) δ 215.0, 145.5, 138.6, 137.0, 129.1,
Methyl (2S,3R,4R,5S)-4-Amino-1-methyl-3,5-diphenylpyrrolidine-
2-carboxylate (12). The expected product was obtained from 11.
Yield: 242 mg, 78%, bright yellow solid; mp = 108−110 °C; [α]25
=
D
+93.5 (c 0.51, CHCl3). FTIR (neat, cm−1): 3389, 3027, 2950, 2796,
129.0, 128.0, 74.3, 57.2, 42.6, 30.7, 27.6, 24.7. HRMS (ESI) for
C15H17NO4Na: calculated [M + Na]+, 298.1055. Found [M + Na]+,
298.1056. HPLC (Chiralcel AD-H, hexane/iPrOH = 80:20, flow rate 1
mL/min, λ = 210 nm), tR (major) = 26.43 min, tR (minor) = 29.17
min; ee = 86%.
1
1741, 1453, 1435, 1197, 1177, 1056, 746, 696; H NMR (400 MHz,
CDCl3) δ 7.57 (d, J = 7.5 Hz, 2H, ArH), 7.40 (t, J = 7.5 Hz, 2H, ArH),
7.37−7.19 (m, 6H, ArH), 3.72 (d, J = 10.4 Hz, 1H, C5H), 3.52 (t, J =
8.4 Hz, 1H, C3H), 3.40−3.32 (m, 1H, C4H), 3.21 (s, 3H, CO2Me),
3.18 (d, J = 8.3 Hz, 1H, C2H), 2.25 (s, 3H, NCH3), 1.35 (bs, 2H,
NH2); 13C NMR (101 MHz, CDCl3) δ 171.9, 140.3, 139.5, 128.7,
128.6, 128.3, 127.9, 127.9, 127.1, 78.9, 72.1, 66.0, 55.4, 51.1, 39.9.
HRMS (ESI) for C19H22N2O2: calculated [M + H]+, 311.1760. Found
[M + H]+, 311.1773.
General Procedure for the Synthesis of Amide Derivative
10. Amine exo-L-7aa (0.67 mmol, 200 mg) and K2CO3 (0.80 mmol,
111 mg) were dissolved in 2.5 mL of DCM. Benzoyl chloride (0.67
mmol, 78 μL) was added to the reaction mixture and it was let stir
until consumption of the starting material, followed by TLC. Then, the
reaction mixture was washed with H2O three times, brine and dried
onto Na2SO4, and the solvent was evaporated under reduced pressure
to afford 10.
(S)-2-[(R)-Hydroxy(4-((E)-2-nitrovinyl)phenyl)methyl]cyclohexan-
1-one (ent-15). Yield: 51 mg, 75%, yellow solid; [α]25D = 8.0 (c 0.90,
1
CHCl3), ee, −64%. H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 13.6
Hz, 1H, CHNO2), 7.58 (d, J = 13.6 Hz, 1H, CHAr), 7.54 (d, J = 7.9
Hz, 2H, ArH), 7.42 (d, J = 7.9 Hz, 2H, ArH), 4.83 (dd, J = 8.1, 2.9 Hz,
1H, CHOH), 4.02 (d, J = 3.0 Hz, 1H, OH), 2.61 (m, 1H,
COCHCOH), 2.49 (m, 1H, −CH2−), 2.36 (td, J = 13.4, 6.2 Hz, 1H,
−CH2−), 2.11 (m, 1H, −CH2−), 1.82 (d, J = 12.7 Hz, 1H, −CH2−),
1.74−1.49 (m, 3H, −CH2−), 1.37 (m, 1H, −CH2−). HPLC
(Chiralcel AD-H, hexane/iPrOH = 80:20, flow rate 1 mL/min, λ =
210 nm), tR (minor) = 26.51 min, tR (major) = 28.82 min; ee = −64%.
General Procedure for the Synthesis of Michael Adducts 3
under Different Conditions. A reaction mixture of amine catalyst 7
(0.03 mmol), additive acid (0.03 mmol), ketone 1 (0.8 mmol) and
nitroalkene 2 (0.1 mmol) was allowed to stir at room temperature.
The progress of the reaction was monitored by TLC (1:3 of EtOAc/
Hex). After consumption of the nitroalkene, ketone was evaporated
under reduced pressure. The afforded crude product was purified by
flash chromatography over silica gel using ethyl acetate/hexane system
as eluent.
Methyl (2S,3R,4R,5S)-4-Benzamido-3,5-diphenylpyrrolidine-2-
carboxylate (10). Yield: 115 mg, 43%, white solid; mp = 258−260
°C; [α]25 = −54.9 (c 0.49, DMF). FTIR (neat, cm−1): 1734, 1654,
D
1
1383, 1174, 1153, 726. H NMR (500 MHz, DMSO-d6) δ 7.50 (s,
2H), 7.43−7.06 (m, 13H), 4.67 (d, J = 8.5 Hz, 1H), 3.81 (dd, J = 11.8,
8.5 Hz, 1H), 3.70 (dd, J = 11.7, 9.0 Hz, 1H), 3.26 (s, 1H, signal under
water peak), 3.04 (s, 3H), 1.48 (bs, 1H); 13C NMR (126 MHz,
DMSO-d6, 70 °C) δ 171.1, 169.4, 141.2, 136.1, 134.9, 128.9, 128.2,
127.8, 127.4, 127.3, 126.9, 126.8, 126.2, 126.1, 70.1, 64.9, 61.7, 52.3,
50.6. HRMS (ESI) for C25H24N2O3: calculated [M + H]+, 401.1865.
Found [M + H]+, 401.1869.
Synthesis of Adducts 16. Adduct 16 was synthesized according
to the procedure above-described using alkene 15 and amine exo-L-7aa
as catalyst. The reaction was let stir at 0 °C until consumption of the
starting material.
General Procedure for the Synthesis of 14. To a flask was
added AgNO2 (23.4 mmol, 3.6 g), TEMPO (3.12 mmol, 487 mg), and
oven-dried molecular sieves 4 Å (2.34 g). Then, the olefin 1332 (7.8
mmol, 1.012 g) previously dissolved in 32 mL of 1,2-dichloroethane
was added. The reaction mixture was placed in a preheated oil bath at
70 °C and stirred vigorously for 12 h. Then, the mixture was cooled to
(R)-2-[(S)-1-(4-((S)-Hydroxy((R)-2-oxocyclohexyl)methyl)phenyl)-
2-nitroethyl]cyclohexan-1-one (anti-16). Yield: 20 mg, 53%, white
solid; mp = 82−83 °C; [α]25 = 6.8 (c 0.31, CHCl3). FTIR (neat,
D
cm−1): 3517, 2925, 2856, 1700, 1550; 1H NMR (500 MHz CDCl3) δ
7.27 (d, J = 8.9 Hz, 2H, ArH), 7.15 (d, J = 7.6 Hz, 2H, ArH), 4.94 (dd,
J = 12.8, 4.4 Hz, 1H, CHNO2), 4.75 (d, J = 8.9 Hz, 1H, CHOH), 4.63
J
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The Journal of Organic Chemistry
Article
(dd, J = 12.6, 9.8 Hz, 1H, CHNO2), 4.02 (s, 1H, OH), 3.76 (q, J = 5.3
Hz, 1H, CHAr), 2.66 (d, J = 3.2 Hz, 1H, CH), 2.57 (t, J = 13.7 Hz,
1H, CH), 2.47 (d, J = 9.6 Hz, 2H, −CH2−), 2.36 (d, J = 11.8 Hz, 2H,
−CH2−), 2.07 (m, 2H, −CH2−), 1.87−1.45 (m, 8H, −CH2−), 1.24
(m, 2H, −CH2−); 13C NMR (101 MHz, CDCl3) δ 215.6, 211.9,
140.5, 137.4, 128.2, 127.6, 78.8, 74.5, 57.2, 52.6, 43.6, 42.8, 42.7, 33.2,
30.8, 28.5, 27.8, 25.0, 24.7. HRMS (ESI) for C21H27NO5Na: calculated
[M + Na]+, 396.1787. Found [M + Na]+, 396.1793.
the UPV/EHU (UFI COSYC) and the DIPC for generous
allocation of computational resources.
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2-nitroethyl]cyclohexan-1-one (syn-16). Yield: 4 mg, 11%, pale
yellow solid; mp = 110−112 °C [α]25 = 7.9 (c 0.31 CHCl3). FTIR
D
1
(neat, cm−1): 3498, 2935, 2860, 1700, 1549; H NMR (500 MHz,
CDCl3) δ 7.28 (d, J = 8.4 Hz, 2H, ArH), 7.16 (d, J = 7.9 Hz, 2H,
ArH), 5.37 (s, 1H, CHOH), 4.97 (dd, J = 12.5, 4.5 Hz, 1H, CHNO2),
4.65 (dd, J = 12.7, 9.9 Hz, 1H, CHNO2), 3.78 (m, 1H, CHAr), 3.07
(bs, 1H, OH), 2.69 (m, 1H, CH), 2.58 (d, J = 8.5 Hz, 1H, CH), 2.48
(m, 2H, −CH2−), 2.40 (m, 2H, −CH2−), 2.11 (m, 2H, −CH2−),
1.89−1.54 ((m, 8H, −CH2−), 1.26 (m, 2H, −CH2−); 13C NMR (101
MHz, CDCl3) δ 214.9, 211.9, 141.0, 136.4, 128.0, 126.4, 78.8, 70.4,
56.9, 52.6, 43.6, 42.7, 42.7, 33.2, 28.5, 28.0, 26.0, 25.0, 24.8. HRMS
(ESI) for C21H27NO5Na: calculated [M + Na]+, 396.1787. Found [M
+ Na]+, 396.1789.
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(S)-2-[(R)-1-(4-((R)-Hydroxy((S)-2-oxocyclohexyl)methyl)phenyl)-
2-nitroethyl]cyclohexan-1-one (ent−anti-16). Yield: 14 mg, 37%,
́
́
1
white solid; [α]25 = −4.7 (c 0.41, CHCl3). H NMR (400 MHz,
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D
CDCl3) δ 7.27 (d, J = 8.9 Hz, 2H, ArH), 7.15 (d, J = 7.5 Hz, 2H,
ArH), 4.94 (d, J = 12.7 Hz, 1H, CHNO2), 4.75 (d, J = 8.7 Hz, 1H,
CHOH), 4.63 (t, J = 11.4 Hz, 1H, CHNO2), 4.02 (s, 1H, OH), 3.75
(d, J = 11.1 Hz, 1H, CHAr), 2.65 (s, 1H, CH), 2.56 (s, 1H, CH),
2.52−2.32 (m, 4H, −CH2−), 2.07 (m, 2H, −CH2−), 1.84−1.48 (m,
8H, −CH2−), 1.23 (m, 2H, −CH2−).
(S)-2-[(R)-1-(4-((R)-Hydroxy((R)-2-oxocyclohexyl)methyl)phenyl)-
2-nitroethyl]cyclohexan-1-one (ent−syn-16). Yield: 7 mg, 19%, pale
1
yellow solid; [α]25 = −5.4 (c 0.34, CHCl3). H NMR (400 MHz,
D
CDCl3) δ 7.25 (d, J = 8.4 Hz, 2H, ArH), 7.13 (d, J = 7.9 Hz, 2H,
ArH), 5.35 (s, 1H, CHOH), 4.94 (dd, J = 12.3, 4.9 Hz, 1H, CHNO2),
4.62 (t, J = 11.2 Hz, 1H, CHNO2), 3.76 (m, 1H, CHAr), 3.04 (bs, 1H,
OH), 2.66 (td, J = 11.2, 5.0 Hz, 1H, CH), 2.56 (t, J = 9.2 Hz, 1H,
CH), 2.50−2.33 (m, 4H, −CH2−), 2.07 (s, 2H, −CH2−), 1.89−1.49
(m, 8H, −CH2−), 1.23 (m, 2H, −CH2−).
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́
ASSOCIATED CONTENT
́
■
S
* Supporting Information
́
́
Copies of 1H NMR and 13C NMR spectra for all novel
compounds described in this work. HPLC chromatograms of
aldol and Michael adducts reported in Tables 1−4. Energies,
harmonic analyses and Cartesian coordinates of transition
structures shown in Figure 3 and of those associated with the
formation of enamines through the NH-pyrrolidine moiety of
exo-L-7aa. Crystallographic data (CIF) for compound syn-16.
Complete ref 18. The Supporting Information is available free
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AUTHOR INFORMATION
■
(14) For related conformational studies on pyrrolidinium cations see:
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Corresponding Author
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
161.
This work was supported by the Spanish MINECO (Grant
CTQ2013-45415-P) and by the Gobierno Vasco/Eusko
Jaurlaritza (Grant IT-324-07). A.R.-O. thanks the MINECO
for her Ph.D. fellowship. M.G.R. thanks the DIPC for a
postdoctoral contract. The authors thank the SGI/IZO-SGIker,
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(17) The relative configuration of syn-16 was assigned by X-ray
diffraction crystallography (CCDC 1045088). See Supporting
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