Synthesis of prolines by enantioselective 1,3-dipolar cycloaddition of azomethine ylides and alkenes catalyzed by chiral phosphoramidite-silver(I) complexes

Article abstract of DOI:10.1002/ejoc.200900774

The endo-diastereo- and enantioselective 1,3-dipolar cyclo-addition of azomethine ylides and electrophilic alkenes is ef-ficiently catalysed by chiral phosphoramidite-silver(I) Per-chlorate complexes. The reaction allows the presence of dif-ferent types o

Full text of DOI:10.1002/ejoc.200900774

FULL PAPER
DOI: 10.1002/ejoc.200900774
Synthesis of Prolines by Enantioselective 1,3-Dipolar Cycloaddition of
Azomethine Ylides and Alkenes Catalyzed by Chiral Phosphoramidite-Silver(I)
Complexes
Carmen Nájera,*[a] María de Gracia Retamosa,[a] María Martín-Rodríguez,[a]
José M. Sansano,*[a] Abel de Cózar,[b] and Fernando P. Cossío[b][‡]
Dedicated to Professor Peter Stanetty on the occasion of his 65th birthday
Keywords: Asymmetric catalysis / Cycloaddition / Azomethine ylides / Silver / Phosphorus
The endo-diastereo- and enantioselective 1,3-dipolar cyclo- Computational studies support a two-step mechanism pre-
addition of azomethine ylides and electrophilic alkenes is ef-
ficiently catalysed by chiral phosphoramidite–silver(I) per-
chlorate complexes. The reaction allows the presence of dif-
dicting exactly the experimental results and the origin of
both the diastereo- and enantioselections, as well as a rea-
sonable explanation concerning the different reaction rates
ferent types of substituents in the 1,3-dipole and can be ap- observed for some substrates.
plied to the synthesis of enantiomerically enriched, highly
substituted prolines. This methodology was applied to the to-
tal synthesis of the inhibitors of the hepatitis C virus (HCV).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
plex in substoichiometric amounts.[10] Later on, many other
contributions regarding the employment of the chiral com-
plexes formed by silver(I),[10,11] copper(I),[12] zinc(II),[13]
nickel(II)[14] and calcium(II)[15] were reported. Recently, or-
ganocatalyzed processes[16] have been employed but with
notable structural restrictions; for instance, highly activated
iminomalonates are needed as 1,3-dipole precursors in ad-
dition to α,β-unsaturated aldehydes or ketones as di-
polarophiles.
Silver and copper complexes are the most employed cata-
lysts generating excellent enantioselections in the resulting
proline derivatives. Whilst a chiral copper(I)-catalyzed pro-
cess occurs with high exo-diastereoselection, the silver(I)-
catalyzed reaction yields the corresponding endo adducts.
In general, chiral bidentate ligands such as bisphosphanes,
aminophosphanes, sulfur-containing phosphanes, bisoxaz-
olines and diimines are used as chiral ligands. A common
problem in these reactions is their sensitivity to the presence
of very bulky substituents in the 1,3-dipole and in the di-
polarophile as well.
In a previous communication[11c] we reported the first
enantioselective 1,3-DC of azomethine ylides and alkenes
by using monodentate ligands such as chiral phosphor-
amidites together with AgClO4. The main advantages of
this type of catalyst are its availability, the easy modulation
of the two stereogenic elements of the chiral ligand and the
use of α-branched imino esters. All these aspects are com-
bined to obtain high enantioselectivities of the resulting
Introduction
The catalytic enantioselective 1,3-dipolar cycloaddition
(1,3-DC),[1] involving azomethine ylides and electrophilic
alkenes, constitutes a straightforward transformation[2] in
the generation of up to four stereogenic centres in only one
step. The highly diastereo- and enantioselective nature of
the reaction allows enantiomerically substituted proline de-
rivatives to be obtained;[3] these compounds are important
structures in scientific areas such as biology (peptide de-
sign),[3,4] medicine (antiviral,[5] neuroexcitatory[6] and insec-
ticide agents[7]) and organic chemistry (organocatalysts).[8]
Grigg et al. pioneered the catalytic enantioselective 1,3-
DC by employing large amounts of chiral cobalt com-
plexes.[9] In 2002, the enantioselective synthesis of enantio-
merically pure prolines through the 1,3-DC of azomethine
ylides and electron-deficient alkenes was successfully
achieved by employing a chiral bisphosphane–silver(I) com-
[a] Departmento de Química Orgánica (Facultad de Ciencias) and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Ctra. Alicante-San Vicente s/n, 03080 Alicante, Spain
Fax: +34-96-590-3549
E-mail: cnajera@ua.es
jmsansano@ua.es
[b] Department of Organic Chemistry I, University of the País Va-
sco-Euskal Herriko Unibertsitatea,
P. K. 1072, 20018 San Sebastián-Donostia, Spain
[‡] For correspondence on computational studies,
E-mail: fpcossio@ehu.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900774.
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Eur. J. Org. Chem. 2009, 5622–5634

Synthesis of Prolines by Enantioselective 1,3-Dipolar Cycloaddition
pyrrolidines. In this work, we describe the full account of Michael-type additions and carbonyl addition reactions,[19b]
this reaction and a DFT-based study focused on the eluci- they were not previously used as ligands in the 1,3-DC of
dation of the origin of the diastereo- and enantioselectivity azomethine ylides and dipolarophiles.
observed in the process.[17]
Initially, the optimization of the reaction was carried out
at room temperature employing tert-butyl acrylate and
methyl or isopropyl N-benzylideneiminoglycinates 4aa or
4ab, respectively. Employing 5 mol-% of catalyst, formed by
in situ addition of a 1:1 mixture of phosphoramidite and
the silver salt (Scheme 1, Table 1) was employed in the pres-
ence of an organic base (5 mol-%). The catalysts formed by
AgClO4 (5 mol-%) and ligands (Sa)-1 or 2 (5 mol-%) and
triethylamine as base (5 mol-%) gave a lower er value of
cycloadduct 5aa than with the catalyst system consisting of
a 1:1 mixture of AgClO4 (5 mol-%) and (Sa,R,R)-3 (5 mol-
%; Table 1, Entries 1–3). When a 2:1 mixture of AgClO4/
(Sa,R,R)-3 (5 mol-%) was used instead, the er value was
also lower than the result described for the 1:1 mixture
(Table 1, Entry 4). Other silver salts like acetate, triflate,
fluoride or tetrafluoroborate did not improve the enantio-
meric ratio generated by AgClO4 (Table 1, Entries 5–8).
Results and Discussion
Although chiral phosphoramidites 1, 2 and 3[18] (Fig-
ure 1) have been extensively used in asymmetric hydrogena-
tions[19] and many other transformations such as allylations,
Figure 1. Phosphoramidites 1–3.
Scheme 1.
Table 1. Optimization of the 1,3-DC of imino esters 4 (1 equiv.) and tert-butyl acrylate (1 equiv.) in toluene catalyzed by the chiral ligand
(5 mol-%) and the AgI salt (5 mol-%) with the use of a base (5 mol-%).
Entry
R
Imino ester
AgX
Ligand
Base
T [°C]
t [h]
Cycloadduct
Conv. [%]
er[a]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
4aa
4aa
4aa
4aa
4aa
4aa
4aa
4aa
4aa
4aa
4aa
4aa
4aa
4aa
4ab
4ab
4ab
4ab
4ab
4ab
4ab
4ab
AgClO4
AgClO4
AgClO4
AgClO4
AgOAc
AgOTf
AgF
(Sa)-1
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
20
20
20
20
20
20
20
20
0
–20
–20
–20
–20
–20
0
–20
–20
–20
–20
–20
–20
–20
8
8
8
8
8
8
8
8
16
16
17
16
17
17
16
16
16
17
16
16
16
16
5aa
5aa
98
98
98
95
98
98
90
95
96
98
97
97
96
Ͼ98
Ͼ98
Ͼ98
97
94
97
76:24
69:31
85:15
74:26
80:20
84:16
76:24
60:40
87:17
90:10
79:21
89:11
94:6
(Sa,R)-2
(Sa,R,R)-3
(Sa,R,R)-3
(Sa,R,R)-3
(Sa,R,R)-3
(Sa,R,R)-3
(Sa,R,R)-3
(Sa,R,R)-3
(Sa,R,R)-3
(Sa)-1
(Sa,R,R)-3
(Sa,R,R)-3
(Ra,S,S)-3
(Sa,R,R)-3
(Sa,R,R)-3
(Sa,R,R)-3
(Sa)-1
5aa
[b]
5aa
5aa
5aa
5aa
AgBF4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
5aa
9
5aa
10
11
12
13
14
15
16
17
18
19
20
21
22
Et3N
Et3N
5aa
5aa
DIPEA[c]
DABCO[d]
DABCO
Et3N
5aa
5aa
ent-5aa
5ab
6:94
93:7
Et3N
DABCO
Et3N
Et3N
Et3N
Et3N
Et3N
5ab
Ͼ99:1
Ͼ99:1
53:47
Ͻ1:99
28:72
28:72
98:2
5ab
5ab
(Ra,S,S)-3
(Sa,R,R)-3
(Sa,S,S)-3
(Sa,R,R)-3
ent-5ab
ent-5ab
ent-5ab
5ab
95
95
76
[e]
AgClO4
[a] Determined by chiral HPLC analysis (Daicel, Chiralpak AS) of the crude product. More than 98:2 endo/exo ratio by 1H NMR
spectroscopy. [b] Reaction performed with ligand 3 (2 equiv.) and silver perchlorate (1 equiv.). [c] DIPEA = diisopropylethylamine.
[d] DABCO = 1,4-diazabicyclo[2.2.2]octane. [e] 3 mol-% of the catalyst was employed.
Eur. J. Org. Chem. 2009, 5622–5634
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C. Nájera, J. M. Sansano et al.
FULL PAPER
To further improve the enantioselectivity of the process, dipole precursor 4aa and triethylamine and a 1:1 mixture
the temperature, the base and the nature of the ester group of (Sa,R,R)-3/AgClO4 complex were put together, the ESI
were studied. When the reaction of 4aa was run at 0 or experiment revealed a very abundant species with m/z =
–20 °C with Et3N the enantioselection was improved 824, which is due to the formation of chiral silver complex–
(Table 1, compare Entries 3, 9 and 10). Other bases such as dipole adduct I (Figure 2) and a tiny peak at m/z = 1000 as
DIPEA or DABCO (5 mol-%) were also used at –20 °C, a result of the combination of two molecules of dipole to
resulting in even better enantioselections (96:4er) with the chiral silver complex. Intermediate complex I can also
DABCO (Table 1, compare Entries 10, 12 and 13). Under explain the high diastereo- and enantioselection offered by
these conditions, monophos ligand (Sa)-1 was also em- the matched combination of the stereochemical elements of
ployed but with lower chiral induction than for the reaction ligand (Sa,R,R)-3.
with ligand 3 (Table 1, compare Entries 10 and 11). In con-
trast, the substitution of the methyl group by an isopropyl
group at the imino ester (Table 1, Entries 15–22) was very
satisfactory in terms of enantioselection (Ͼ99:1) and con-
versions of product 5ab when the reaction was performed
at –20 °C independently of the base used (Table 1, compare
Entries 10 with 16 and 13 with 17). The best reaction condi-
tions were employed in the reaction of imino ester 4ab with
the chiral complex generated from ligand (Sa)-1, but disap-
pointing results were again achieved (Table 1, compare En-
Figure 2. Suggested structure of intermediate complex I.
tries 17 and 18). It was also noticeable that tert-butyl imino
ester 4ac (R = tBu) was not appropriate as a substrate for
this particular transformation, because the yields, conver-
sions and enantioselectivities were extremely low.
Analogous 31P NMR (CDCl3, 10 mol-% aq. poly-
phosphoric acid as internal reference) spectroscopic experi-
When enantiomeric ligand (Ra,S,S)-3 was employed, ments also revealed interesting aspects. Only a wide band
both imino esters (4aa and 4ab) afforded at –20 °C the cor- centred at δ = 126.9 ppm was observed when a 1:1 mixture
responding enantiomer of 5aa and 5ab (Table 1, Entries 14 of (Sa,R,R)-3/AgClO4 was formed in solution, which corre-
and 19). By contrast, complexes formed by phosphoramid- sponded to its polymeric character detected by X-ray dif-
ites (Ra,R,R)-3 or (Sa,S,S)-3 and AgClO4 demonstrated to fraction analysis. However, two separated bands were ob-
be mismatched combinations, because the reaction of 4ab served at δ = 124.9 and 132.0 ppm in the case of a 2:1 mix-
and tert-butyl acrylate afforded, in each case, compound ture as a consequence of partial disaggregation. The al-
ent-5ab with a 28:72er (Table 1, Entries 20 and 21). A lower most-complete disaggregation of the polymeric sheets of the
catalyst loading (3 mol-%) in the reaction at –20 °C gave a 1:1 complex was achieved with the addition of 1 equivalent
lower yield but similar enantioselectivity of 5ab (Table 1, of the 1,3-dipole generated from 4aa and triethylamine. The
Entry 22).
result was the transformation of the original 31P NMR
Other solvents such as THF, dichloromethane, diethyl band into two perfectly defined doublets at δ = 125.1
ether, acetonitrile and methanol gave both lower conver- (JP,109 = 76 Hz) and 133.61 ppm (JP,107 = 73 Hz), which
Ag
Ag
sions and er values. In all of the examples shown in the seems to correspond to the phosphorus atom of complex I.
tables, the endo adduct[20] was obtained as the major stereo-
Because perchlorates are classified as low-order explos-
isomer with a dr value higher than 98:2 (1H NMR). All of ives, the thermal stability of the 1:1 mixture of (Sa,R,R)-3/
the er data were determined by chiral HPLC analysis, and AgClO4 was studied. The thermogravimetric (TG) and
the absolute configuration was assigned by comparison of differential thermal analysis (DTA) of this complex (Fig-
the optical rotations between the newly generated products ure 3) revealed that the loss of water occurred from 50 to
and the reported data for the same compounds.[11]
150 °C without any variation in the heat of the system. The
The new 1:1 and 2:1 complexes of AgClO4 and phos- exothermic decomposition of the complex started at 200 °C
phoramidite (Sa,R,R)-3 were characterised by X-ray crystal- approximately, continuing till 600 °C with a noticeable heat
lographic diffraction of the monocrystals.[11c] Whilst the 1:1 liberation.
(Sa,R,R)-3/AgClO4 complex formed cross-linked sheets, the
Then, the general scope of the enantioselective 1,3-DC
2:1 mixture afforded well-defined crystals. The formation of of azomethine ylides, generated from imino esters, with
these polymeric assemblies are typical of silver(I) com- electrophilic alkenes, catalyzed by a 5 mol-% of a 1:1 com-
plexes, independent of the mono- or bidentate character of plex of (Sa,R,R)-3/AgClO4 in toluene and in the presence
the corresponding ligand.[21] These complexes are soluble in of a base was studied. Firstly, glycine-derived imino esters
toluene and could not be recovered from the reaction mix- 4 were allowed to react with tert-butyl acrylate under the
ture as in the case of the complex formed by binap and previously described conditions by using triethylamine or
AgClO4.[11b,11d]
DABCO (5 mol-%) at several temperatures (Scheme 2,
The MS (ESI) experiments of the 1:1 and 2:1 (Sa,R,R)- Table 2). The presence of an isopropyl ester in molecule
3/AgClO4 complexes revealed [M+1]+ peaks at m/z = 646 4ab, rather than the methyl ester, was very important be-
and 1187, respectively. When an equimolar amount of 1,3- cause the reaction performed at –20 °C, independently of
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Synthesis of Prolines by Enantioselective 1,3-Dipolar Cycloaddition
Figure 3. TG and DTA plots of the (Sa,R,R)-3/AgClO4 complex.
the used base, afforded endo-cycloadduct 5ab in good yield and cyclopent-2-enone were very suitable dipolarophiles by
(81%) with Ͼ99:1er (Table 2, Entries 1–4). ortho-Substi- employing triethylamine as base at –20 °C. The yields were
tuted aryl imines 4ba and 4ca gave satisfactory results by in the 72–81% range and the enantioselections were very
employing DABCO as base at –20 °C. The er value of both important, especially in the examples run with chalcone
cycloadducts 5ba and 5ca was very high after purification (Ͼ99:1er; Table 3, Entries 3–8).
(Ͼ99:1; Table 2, Entries 5–8). In these last examples, the
α-Substituted imino esters derived from alanine, phenyl-
presence of an isopropyl group was not so advantageous as alanine and leucine reacted with tert-butyl acrylate to give
before.
endo-cycloadducts 16–19 in good purified yields and very
high enantioselectivities (Table 3, Entries 9–15). The best
results were always achieved by using Et3N as base at
–20 °C rather than by employing DABCO (Table 3, En-
tries 9–15). N-Methylmaleimide (NMM) furnished good
yields of cycloadducts 20 and 21 and high enantiomeric ra-
tios under the analogous reaction conditions; phenylalanine
derivative 7aa was the less reactive system (Table 3, En-
tries 16–19). Chalcone and (E)-pent-3-enone also reacted
with alanine dipole precursors 6aa and 6ga to give good
yields of proline derivatives 22aa and 23ga, with 90:10 and
84:16er, respectively (Table 3, Entries 20 and 21). In all of
these examples the presence of isopropyl or tert-buyl esters
produced lower enantioselectivities and very long reaction
times. Many of these cycloadducts are known compounds
and comparison of their physical and spectroscopic data
with the reported data confirm the absolute configuration
represented on each structure.
Scheme 2.
For para-substituted aryl imimes, the best results were
achieved by using Et3N as base at –20 °C and isopropyl
rather than methyl esters of N-arylideneimino glycinates 4.
The increment in the enantiomeric ratio was very small for
endo-cycloadducts 5da, 5db and 5fa, 5fb (Table 2, Entries 9–
13 and 18–21, respectively), but was significant for endo-5eb
(99:1er; Table 2, Entries 14–17). 2-Naphthyl derivative 4ga
furnished better yields and enantioselectivities for the
methyl esters than the analogous isopropyl esters (not
It has been demonstrated that enantiomerically pure pro-
shown in Table 2) by using Et3N as base at –20 °C. The line derivative 19ha is the key precursor to a series of antivi-
corresponding endo-product 5ga was obtained in 84% yield ral agents inhibitors of the hepatitis C virus (HCV) poly-
and 96:4er after flash chromatography (Table 2, Entries 22– merase[15a,16b,22] such as prolinamide 26.[5a,23] Intermediate
24).
prolinamide 25 was synthesized in 88% yield (estimated by
Different dipolarophiles were allowed to react with 1H NMR) from enantiomerically pure 19ha by simple
several imino esters (Scheme 3, Table 3). Glycine-derived amidation with 4-(trifluoromethyl)benzoyl chloride in re-
imino esters reacted in very good yields with maleimides at fluxing dichloromethane over 19 h. The crude product was
higher temperatures (r.t. or 0 °C) to afford excellent submitted, in a second step, to hydrolysis of the tert-butyl
enantioselectivities of the corresponding cycloadducts 9aa ester with trifluoroacetic acid followed by methyl ester hy-
and 10aa (Table 3, Entries 1 and 2). Fumarates, chalcone drolysis by using an aqueous solution of KOH in meth-
Eur. J. Org. Chem. 2009, 5622–5634
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C. Nájera, J. M. Sansano et al.
Table 2. 1,3-DC of glycine derived imino esters 4 and tert-butyl acrylate catalyzed by (Sa,R,R)-3/AgClO4 complex (5 mol-%).
FULL PAPER
[b]
Entry
Ar
R
4
Base
T [°C]
Cycloadduct
Yield [%][a]
erendo
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Me
Me
iPr
iPr
Me
Me
Me
Me
Me
Me
Me
iPr
iPr
Me
Me
iPr
iPr
Me
Me
iPr
iPr
Me
Me
Me
4aa
4aa
4ab
4ab
4ba
4ba
4ca
4ca
4da
4da
4da
4db
4db
4ea
4ea
4eb
4eb
4fa
4fa
4fb
4fb
4ga
4ga
4ga
Et3N
DABCO
Et3N
–20
–20
–20
–20
0
–20
0
–20
–20
0
–20
–20
–20
0
–20
–20
–20
0
–20
–20
0
–20
0
–20
5aa
5aa
5ab
5ab
5ba
5ba
5ca
5ca
5da
5da
5da
5db
5db
5ea
5ea
5eb
5eb
5fa
5fa
5fb
5fb
5ga
5ga
5ga
80
80
83
81
78
83
79
80
78
77
77
80
78
77
79
80
76
77
76
77
77
84
78
76
90:10 (90:10)
94:6 (94:6)
Ͼ99:1 (Ͼ91:1)
Ͼ99:1 (Ͼ91:1)
95:5 (95:5)
99:1 (Ͼ99:1)
94:6 (95:5)
98:2 (Ͼ99:1)
90:10 (90:10)
90:10 (91:9)
91:9 (92:8)
95:5 (96:4)
94:6 (95:5)
94:6 (94:6)
95:5 (96:4)
99:1 (99:1)
94:6 (95:5)
92:8 (93:7)
94:6 (95:5)
95:5 (97:3)
92:8 (94:6)
95:5 (96:4)
90:10 (90:10)
92:8 (94:6)
DABCO
DABCO
DABCO
DABCO
DABCO
Et3N
DABCO
DABCO
Et3N
DABCO
DABCO
DABCO
Et3N
DABCO
DABCO
DABCO
Et3N
2-MeC6H4
2-MeC6H4
2-ClC6H4
2-ClC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-naphthyl
2-naphthyl
2-naphthyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
DABCO
Et3N
DABCO
DABCO
[a] Yield obtained after flash chromatography of the endo product. [b] Determined by chiral HPLC analysis (Daicel, Chiralpak AS) of
the crude product. More than 98:2 endo/exo ratio by 1H NMR spectroscopy. The er values of purified product 5 are given in parentheses.
Scheme 3.
anol for 16 h. Resulting dicarboxylic acid 26 was finally ob-
tained in 81% yield from compound 25 (50% overall yield
from imino ester 8ha; Scheme 4). The purity of the antiviral
agent was Ͼ98% and only 0.7 ppm of silver were present in
this sample according to inductively coupled plasma mass
spectrometry (ICP-MS) analysis. On the basis of this instru-
mental technique, purified samples of compound 19ha only
contained around 4 ppm of silver.
With the aim to better understand the origin of the ob-
served stereocontrol, we carried out different calculations
Scheme 4.
(see below for technical details) on the interaction modes
between tert-butyl acrylate and complex II formed by 1,3-
dipole precursor 4aa and (Sa)-monophos (1). Because we
Calculations located and characterized the four possible
determined that nonlinear effects are not observed in these transition structures and their main organic features are
reactions, only monomeric species were considered along gathered in Figure 4. The less energetic saddle points are
the different reaction paths. Our results indicate that the those that exhibit the tert-butoxycarboxyl group in an endo
formal [3+2] cycloaddition is actually a stepwise process,[24] relationship with respect to the phenyl group of 4aa. Both
in which the first step consists of a Michael addition of II TS1-SRR and TS1-RSS lack the highly stabilizing bonding
on tert-butyl acrylate. This step determines the stereochemi- interaction between the tert-butoxycarbonyl moiety and the
cal outcome of the whole reaction. Possible cycloadducts 27 metallic centre. As a consequence, these transition struc-
and corresponding transition structures TS1 that lead to tures are ca. 10 kcal/mol less stable than their endo ana-
them are depicted in Scheme 5.
logues.
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Eur. J. Org. Chem. 2009, 5622–5634

Synthesis of Prolines by Enantioselective 1,3-Dipolar Cycloaddition
Table 3. 1,3-DC of glycine methyl imino esters 4 and α-substituted methyl imino esters 6–8 with assorted dipolarophiles, catalyzed by
(Sa,R,R)-3/AgClO4 complex (5 mol-%).
[a] Yield obtained after flash chromatography of the endo product. [b] Determined by chiral HPLC analysis (see the Experimental Section)
1
of the crude product. More than 98:2 endo/exo ratio by H NMR spectroscopy. [c] The er values of the purified endo cycloadduct are
given in parentheses. [d] The reaction required 6 h. [e] A 70:30 endo/exo mixture was obtained in the crude product. [f] The reaction
required 48 h.
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C. Nájera, J. M. Sansano et al.
FULL PAPER
Scheme 5.
Figure 4. Chief geometric features saddle relative energies [kcal/mol] of the four transition structures associated with the first step in the
reaction between tert-butyl acrylate and complex II formed by (Sa)-monophos (1) and imine 4aa. Bond lengths [Å] and angles are given
[°]. These fully optimized structures were computed at the B3LYP/LanL2DZ&6-31G* level. The energies were computed at the B3LYP/
LanL2DZ &6-31G*+∆ZPVE level of theory.
The two possible endo-TS1 saddle points were much thyl groups is ca. 57–58°. In the case of TS1-SSR, this leads
closer in energy (Figure 4). However, TS1-SSR was calcu- to the blockage of the Re-Si face of the dipole. Because
lated to be 1.31 kcal/mol lower in energy than TS1-RRS. It there is a stronger steric congestion between one naphthyl
is observed that the dihedral angle formed by the two naph- group and the tert-butyl group of the dipolarophile in TS1-
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Synthesis of Prolines by Enantioselective 1,3-Dipolar Cycloaddition
Figure 5. Reaction coordinate associated with the reaction between tert-butyl acrylate and complex II. Bond lengths [Å] and angles [°]
are given. The relative energies were computed at the B3LYP/LanL2DZ&6-31G*+∆ZPVE level of theory.
RRS (Figure 4), this results in the preferential formation of ferent reactivity, presumably, originated from better hyper-
endo-(2S,4S,5R)-27, which is in good agreement with the conjugation of the enolate in the presence of the thienyl
experimental results.
substituent as a result of the existence of a more planar
The reaction coordinate associated with the 1,3-DC be- conformation of complexes III than in complex IV. This
tween tert-butyl acrylate and complex II to form cycload- hypothes is supported by NOESY experiments performed
duct endo-(2S,4S,5R)-27 is gathered in Figure 5. Reaction on complexes III and IV, whose results are depicted in Fig-
between the dipolarophile and complex II results in the for- ure 6 (bottom). The phenyl ring has to rotate in intermedi-
mation of complex 28. The computed reaction barrier to ate complex IV, such as it was observed for complex II, to
form zwiterionic intermediate 29-SSR via TS1-SSR is ca. ensure the interaction of the aromatic π-electronic current
13 kcal/mol. In this first step, complex II and tert-butyl ac- with the silver cation.[25]
rylate behave as a silver enolate and a Michael acceptor,
respectively. Intermediate 29-SSR cyclises to endo-
(2S,4S,5R)-27 via an intramolecular Mannich-like reaction
through TS2-SSR with a reaction barrier of ca. 3 kcal/mol.
Therefore, the Michael addition reaction determines the
stereoselectivity of the stepwise 1,3-DC and it is also the
limiting step.
It is interesting to note that endo-(2S,4S,5R)-27 is ca.
5 kcal/mol less stable than 28 because of the strain induced
by the coordination pattern around the metallic centre after
the complete cyclisation. This ensures the catalyst recovery
and the delivery of endo-NH-cycloadduct 5aa.
The simulation of the geometry of intermediate complex
II also revealed that a torsion dihedral angle (ca. 23°) exists
between the imaginary dipole-containing plane and the
plane defined by the imine aromatic ring (Figure 6, top; see
also Figure 4). This detail, a priori insignificant, can seri-
ously affect the reaction rate. It was experimentally ob-
served that the optimised enantioselective reaction of imino
ester 8ha (methyl 2-thienyliminoleucinate) and tert-butyl ac-
rylate was completed in 48 h, but the analogous reaction
attempted with imino ester 8aa (methyl phenyliminoleucin-
ate) did not proceed at all after 48 h. In fact, 2-thienylimin-
oglycinate could not be used as starting material because
it reacted with itself (forming the presumed imidazolidine
according to H NMR) rather than add to the dipolaro-
phile, unlike methyl phenyliminoglycinate (4aa) did. This dif- tom).
Figure 6. Geometrical features of complex II (angle given in °; top);
nOe effects observed in intermediate complexes III and IV (bot-
1
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C. Nájera, J. M. Sansano et al.
FULL PAPER
General Procedure for the 1,3-Dipolar Cycloaddition of Imino Esters
and Dipolarophiles: A solution of the imino ester (1 mmol) and di-
polarophile (1 mmol) in toluene (5 mL) was added to a suspension
containing the phosphoramidite (0.05 mmol) and AgClO4
(0.05 mmol, 10 mg) in toluene (5 mL). To the resulting suspension
was added triethylamine (0.05 mmol, 7 µL), and the mixture was
stirred at the temperature indicated in the text in the absence of the
light for 16–48 h. The precipitate was filtered, and the organic
phase was directly evaporated. The residue was purified by
recrystallisation or by flash chromatography to yield the pure endo-
cycloadducts (see Tables 2 and 3 for details).
Conclusions
The novel equimolar monodentate phosphoramidite
(Sa,R,R)-3-silver perchlorate complex is a very efficient chi-
ral catalyst for a wide range of 1,3-dipolar cycloaddition
reactions between azomethine ylides and dipolarophiles.
This type of monodentate complex opens new perspectives
in this and other reactions, as it can promote cycloadditions
involving sterically hindered components; finetuning of the
complex can be achieved by modifying the temperature,
base and ester substituent. A direct application of this
methodology is the direct synthesis of dicarboxylic acid 26,
a very effective agent inhibitor of the HCV polymerase. It
was isolated in 50% overall yield (four steps) with 93:7er.
The overall cyclisation process occurred through a noncon-
certed reaction; a Michael-type addition was the determi-
nant step of the stereochemical outcome of the cyclisation
reaction.
4-tert-Butyl 2-Methyl (2S,4S,5R)-5-Phenyl-2,4-pyrrolidinedicarbox-
ylate (5aa):[11j] Yield: 254 mg (80%).
4-tert-Butyl 2-Isopropyl (2S,4S,5R)-5-Phenyl-2,4-pyrrolidinedicar-
boxylate (5ab): Sticky oil (276 mg, 83%); [α]2D0 = +20.1 (c = 0.9,
CHCl3, 99%ee by HPLC); Rf = 0.46 (n-hexane/ethyl acetate, 3:2).
1
IR (KBr): ν = 1727, 1705, 2977 cm–1. H NMR: δ = 1.03 [s, 9 H,
˜
CO2C(CH3)3], 1.30 [d, J = 6.3 Hz, 3 H, CO2CH(CH3)2], 2.26 (m,
1 H, CH2), 2.44 (m, 1 H, CH2), 2.69 (br. s, 1 H, NH), 3.26 (m, 1
H, CHCO2tBu), 3.89 (dd, J = 8.4, 8.4 Hz, 1 H, CHCO2iPr), 4.48
(d, J = 7.9 Hz, 1 H, CHPh), 5.15 [sept, J = 6.3 Hz, 1 H,
CO2CH(CH3)2], 7.21–7.38 (m, 5 H, ArH) ppm. 13C NMR: δ = 21.8
[CO2CH(CH3)2], 27.4 [CO2C(CH3)3], 34.3 (CH2), 50.3
(CHCO2tBu), 60.2 (CHCO2iPr), 65.6 [CO2CH(CH3)2], 68.6 (Ph-
CH), 80.5 [CO2C(CH3)3], 127.2, 127.3, 128.1 (ArCH), 139.5 (ArC),
171.8, 172.8 (CO2iPr, CO2tBu) ppm. MS (EI): m/z (%) = 333 (0.78)
[M+], 246 (47), 205 (12), 191 (13), 190 (100), 172 (13), 163 (11), 145
(12), 144 (31), 117 (22). HRMS: calcd. for C19H27NO4 333.1940;
found 333.1929. HPLC (Chiralpak AS; 1 mL/min; n-hexane/
iPrOH, 99:1; λ = 220 nm): tR = 15.3 (major), 58.5 (minor) min.
Experimental Section
General: All reactions were carried out in the absence of light. An-
hydrous solvents were freshly distilled under an argon atmosphere.
Aldehydes were also distilled prior to use for the elaboration of
the imino esters. Melting points were determined with a Reichert
Thermovar hot plate apparatus and are uncorrected. Only the
structurally most important peaks of the IR spectra (recorded with
a Nicolet 510 P-FT) are listed. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were obtained with a Bruker AC-300 by using
CDCl3 as the solvent and TMS as the internal standard, unless
otherwise stated. Optical rotations were measured with a Perkin–
Elmer 341 polarimeter. HPLC analyses were performed with a JA-
SCO 2000-series equipped with a chiral column (detailed for each
compound in the main text) by using mixtures of n-hexane/isopro-
pyl alcohol as the mobile phase at 25 °C. Thermal analysis studies
were done with a TG-DTA Mettler Toledo TGA/SDTA851e/SF/
1100. Low-resolution electron impact (EI) mass spectra were ob-
tained at 70 eV with a Shimadzu QP-5000, and high-resolution
mass spectra were obtained with a Finnigan VG Platform or a Fin-
nigan MAT 95S. Microanalyses were performed with a Perkin–El-
mer 2400 and a Carlo–Erba EA1108 instrument. Analytical TLC
was performed on Schleicher & Schuell F1400/LS silica gel plates
and the spots were visualized under UV light (λ = 254 nm). Merck
silica gel 60 (0.040–0.063 mm) was used for flash chromatography.
4-tert-Butyl 2-Methyl (2S,4S,5R)-5-(2-Methylphenyl)-2,4-pyrrolid-
inedicarboxylate (5ba):[11j] Yield: 276 mg (83%).
4-tert-Butyl 2-Methyl (2S,4S,5R)-5-(2-Chlorophenyl)-2,4-pyrrolid-
inedicarboxylate (5ca):[11j] Yield: 283 mg (80%).
4-tert-Butyl 2-Methyl (2S,4S,5R)-5-(4-Methylphenyl)-2,4-pyrrolid-
inedicarboxylate (5da):[11j] Yield: 260 mg (78%).
4-tert-Butyl 2-Isopropyl (2S,4S,5R)-5-(4-Methylphenyl)-2,4-pyrrol-
idinedicarboxylate (5 db): Sticky oil (278 mg, 80%); [α]2D0 = +44.1 (c
= 1, CHCl3, 99%ee by HPLC); Rf = 0.43 (n-hexane/ethyl acetate,
3:2). IR (liq.): ν = 1727, 3018 cm–1. 1H NMR: δ = 1.07 [s, 9 H,
˜
CO2C(CH3)3], 1.30 [d, J = 6.2 Hz, 3 H, CO2CH(CH3)2], 2.32 (s, 3
H, PhCH3), 2.50 (m, 1 H, CH2), 2.44 (m, 1 H, CH2), 3.31 (dd, J
= 13.9, 7.7 Hz, 1 H, CHCO2tBu), 4.07 (dd, J = 8.4, 8.2 Hz, 1 H,
CHCO2iPr), 4.59 (d, J = 7.8 Hz, 1 H, CHPh), 5.15 [m, 1 H,
CO2CH(CH3)2], 7.13 (d, J = 8.0 Hz, 2 H, ArH), 7.23 (d, J = 8.1 Hz,
2 H, ArH) ppm. 13C NMR: δ = 21.0 (ArCH3), 21.7 [CO2CH(CH3)
2], 27.5 [CO2C(CH3)3], 33.6 (CH2), 51.0 (CHCO2tBu), 59.7
(CHCO2iPr), 65.2 [CO2CH(CH3)2], 69.6 (ArCH), 81.2
[CO2C(CH3)3], 127.0, 129.1 (ArCH), 137.5, 137.6 (ArC), 171.4,
171.6 (CO2iPr, CO2tBu) ppm. MS (EI): m/z (%) = 347 (1.35)
[M]+, 290 (16), 274 (12), 260 (46), 219 (25), 205 (14), 204 (100), 186
(25), 177 (12), 160 (13), 159 (21), 158 (42), 143 (17), 131 (46), 57
(12), 56 (14). HRMS: calcd. for C20H29NO4 347.2097; found
347.2102. HPLC (Chiralpak AS; 1 mL/min; n-hexane/iPrOH, 95:5;
λ = 220 nm): tR = 6.8 (major), 18.6 (minor) min.
Computational Methods: All the calculations were obtained with
the GAUSSIAN03 suite of programs.[26] Electron correlation was
partially taken into account by using the hybrid functional
B3LYP[27] and the standard 6-31G* basis set[28] for hydrogen, car-
bon, oxygen, phosphorus and nitrogen, and the Hay–Wadt small
core effective potential (ECP)[29] including double-ξ valence basis
set[30] for silver atoms (LanL2DZ keyword). Zero-point vibrational
energy (ZPVE) corrections were computed at the B3LYP/
LanL2DZ&6-31G* level and were not scaled. All stationary points
were characterized by harmonic analysis. Reactants intermediates
and cycloadducts have positive definite Hessian matrices. Transi-
tion structures show only one negative eigenvalue in their diago-
nalysed force constant matrices, and their associated eigenvectors
were confirmed to correspond to the motion along the reaction
coordinate under consideration (for more details see the Support-
ing Information).
4-tert-Butyl 2-Methyl (2S,4S,5R)-5-(4-Methoxyphenyl)-2,4-pyrrolid-
inedicarboxylate (5ea):[11j] Yield: 275 mg (79%).
4-tert-Butyl 2-Isopropyl (2S,4S,5R)-5-(4-Methoxyphenyl)-2,4-pyr-
rolidinedicarboxylate (5eb): Sticky oil (290 mg, 80%); [α]2D0 = +26.6
(c = 0.9, CHCl3, 98%ee by HPLC); Rf = 0.37 (n-hexane/ethyl ace-
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Synthesis of Prolines by Enantioselective 1,3-Dipolar Cycloaddition
1
tate, 3:2). IR (liq.): ν = 1730, 1727, 2978 cm–1. H NMR: δ = 1.07
(100), 143 (29), 119 (22), 118 (19), 117 (96), 116 (14), 115 (28),
˜
[s, 9 H, CO2C(CH3)3], 1.30 [d, J = 6.3 Hz, 6 H, CO2CH(CH3)2], 106 (11), 104 (10), 91 (12), 90 (10). HRMS: calcd. for C20H27NO6
2.25 (m, 1 H, CH2), 2.41 (m, 1 H, CH2), 3.24 (dd, J = 14.7, 7.7 Hz, 377.1838; found 377.1843. HPLC (Chiralpak OD-H; 1 mL/min; n-
1 H, CHCO2tBu), 3.79 (s, 3 H, OCH3), 3.86 (m, 1 H, CHCO2iPr),
hexane/iPrOH, 80:20; λ = 220 nm): tR = 6.6 (major), 13.5
4.43 (d, J = 7.9 Hz, 1 H, CHAr), 5.14 [sept, J = 6.3 Hz, 1 H, (minor) min.
CO2CH(CH3)2], 6.85 (d, J = 8.8 Hz, 2 H, ArH), 7.28 (d, J = 8.7 Hz,
3,4-Diisobutyl 2-Methyl (2S,3S,4S,5R)-5-Phenyl-2,3,4-pyrrolidine-
2 H, ArH) ppm. 13C NMR: δ = 21.8 [CO2CH(CH3)2], 27.5
[CO2C(CH3)3], 34.2 (CH2), 50.4 (CHCO2tBu), 55.3 (OCH3),
60.1 (CHCO2iPr), 65.0 [CO2CH(CH3)2], 68.7 (PhCH), 80.5
[CO2C(CH3)3], 113.5, 128.3 (ArCH), 131.8, 158.8 (ArC), 171.9,
172.9 (CO2iPr, CO2tBu) ppm. MS (EI): m/z (%) = 363 (2.9) [M]+,
306 (41), 290 (23), 276 (43), 235 (61), 221 (10), 220 (70), 202 (32),
193 (14), 176 (27), 175 (39), 174 (30), 159 (19), 148 (18), 147 (100),
135 (11), 132 (16), 57 (14), 56 (41), 55 (18). HRMS: calcd. for
C20H29NO5 363.2046; found 363.2029. HPLC (Chiralpak AS;
1 mL/min; n-hexane/iPrOH, 95:5; λ = 220 nm): tR = 9.5 (major),
24.9 (minor) min.
tricarboxylate (12aa): Sticky oil (320 mg, 79%); [α]2D0 = 47.1 (c =
0.5, CHCl3, 82%ee by HPLC); Rf = 0.56 (n-hexane/ethyl acetate,
1
1:5). IR (liq.): ν = 1737 1730, 2958 cm–1. H NMR: δ = 0.66 [d, J
˜
= 6.7 Hz, 3 H, CH(CH3)2], 0.68 [d, J = 6.6 Hz, 3 H, CH(CH3)2],
0.95 [d, J = 6.7 Hz, 6 H, CH(CH3)2], 1.51 [d, J = 6.7 Hz, 1 H,
CH(CH3)2], 1.63 (br. s, 1 H, NH), 1.97 [d, J = 6.7 Hz, 1 H,
CH(CH3)2], 3.25 [dd, J = 10.5, 6.6 Hz, 1 H, CH2CH(CH3)2], 3.50
[dd, J = 10.6, 6.6 Hz, 1 H, CH2CH(CH3)2], 3.63 (m, 2 H,
2ϫCHCO2iBu), 3.83 (s,
3 H, CO2CH3), 3.96 [m, 2 H,
CH2CH(CH3)2], 4.19 (d, J = 7.3 Hz, 1 H, CHCO2Me), 4.66 (d, J
= 7.5 Hz, 1 H, CHPh), 7.25–7.32 (m, 5 H, ArH) ppm. 13C NMR:
4-tert-Butyl 2-Methyl (2S,4S,5R)-5-(4-Chlorophenyl)-2,4-pyrrolid- δ = 18.8, 18.9, 19.0 [CH(CH3)2], 27.2, 27.7 [CH(CH3)2], 51.3
inedicarboxylate (5fa):[11j] Yield: 269 mg (76%).
(CHCO2iBu), 52.5 (CO2CH3), 54.0 (CHCO2iBu), 63.4
[CHCO2Me], 65.5 (PhCH), 71.1, 71.5 (2ϫCH2), 126.9, 127.8,
128.3, 138.1 (ArC), 171.4, 172.1, 172.2 (CO2Me, 2ϫCO2iBu) ppm.
MS (EI): m/z (%) = 405 (11) [M]+, 346 (11), 345 (22), 332 (20), 304
(20), 272 (36), 245 (11), 244 (54), 219 (11), 202 (38), 188 (38), 178
(11), 177 (90), 170 (26), 164 (46), 155 (12),149 (14), 146 (54), 145
(46), 144 (82), 143 (24), 119 (12), 118 (19), 117 (100), 116 (13), 115
(21), 106 (11), 105 (11), 90 (11), 57 (46), 56 (21), 55 (12). HRMS:
calcd. for C22H31NO6 405.2151; found 405.2151. HPLC (Chiralpak
OD-H; 1 mL/min; n-hexane/iPrOH, 80:20; λ = 220 nm): tR = 8.5
(major), 16.7 (minor) min.
4-tert-Butyl 2-Isopropyl (2S,4S,5R)-5-(4-Chlorophenyl)-2,4-pyrrolid-
inedicarboxylate (5fb): Colourless prisms (283 mg, 77%); m.p. 88–
90 °C (CH2Cl2/hexane); [α]2D0 = +23.6 (c = 0.8, CHCl3, 94%ee by
HPLC); R = 0.46 (n-hexane/ethyl acetate, 3:2). IR (liq.): ν = 1737,
˜
f
1709, 2978 cm–1. 1H NMR: δ = 1.06 [s, 9 H, CO2C(CH3)3], 1.29 [d,
J = 6.3 Hz, 3 H, CO2CH(CH3)2], 1.30 [d, J = 6.3 Hz, 3 H,
CO2CH(CH3)2], 2.26 (m, 1 H, CH2), 2.44 (m, 1 H, CH2), 3.26 (dd,
J = 14.7, 7.8 Hz, 1 H, CHCO2tBu), 3.89 (dd, J = 8.4, 8.4 Hz, 1 H,
CHCO2iPr), 4.43 (d, J = 7.8 Hz, 1 H, CHPh), 5.15 [sept, J =
6.2 Hz, 1 H, CO2CH(CH3)2], 7.25–7.31 (m, 4 H, ArH) ppm. 13C
NMR: δ = 21.8 [CO2CH(CH3)2], 27.5 [CO2C(CH3)3], 33.9 (CH2),
50.1 (CHCO2tBu), 60.0 (CHCO2iPr), 64.8 [CO2CH(CH3)2], 68.8
(ArCH), 80.8 [CO2C(CH3)3], 128.2, 128.6, 133.1, 138.3 (ArC),
171.5, 172.9 (CO2iPr, CO2tBu) ppm. MS (EI): m/z (%) = 367 (0.66)
[M]+, 282 (14), 280 (40), 239 (10), 226 (33), 225 (13), 224 (100), 206
(15), 197 (12), 180 (12), 179 (13), 178 (18), 151 (19), 57 (11).
HRMS: calcd. for C19H26ClNO4 367.1550; found 367.1547. HPLC
(Chiralpak AS; 1 mL/min; n-hexane/iPrOH, 95:5; λ = 220 nm), tR
= 6.7 (major), 16.5 (minor) min.
2-Methyl (2S,3R,4S,5R)-4-Benzoyl-3,5-diphenyl-2-pyrrolidinecar-
boxylate (13aa): Colourless needles (262 mg, 80%); m.p. 152 °C
(hexane/ethyl acetate). [α]2D0 = –20 (c = 1, CH2Cl2, 99%ee by
1
HPLC). IR (KBr): ν = 1673, 1741, 3435 cm–1. H NMR: δ = 2.65
˜
(s, 1 H, NH), 3.74 (s, 3 H, CO2Me), 4.21–4.09 (m, 2 H, CHCOPh
and CHCO2Me), 4.52 (t, J = 7.5 Hz, 1 H, CHPh), 5.00 (d, J =
8.6 Hz, 1 H, CHAr), 7.13–7.04 (m, 5 H, ArH), 7.26–7.21 (m, 3 H,
ArH), 7.41–7.31 (m, 5 H, ArH), 7.54–7.51 (m, 2 H, ArH) ppm. 13
C
NMR: δ = 52.30 (CH3CO2), 52.65 (CHPh), 60.56 (CHCOPh),
66.62 (CHCO2Me), 67.63 (PhCHNH), 127.11, 1.27.34, 127.72,
128.01, 128.10, 128.18, 128.76, 132.75, 137.35, 138.90, 140.68
(ArC), 173.30 and 198.61 (2ϫCO) ppm. MS (EI): m/z (%) = 326
(12) [M]+. HRMS (EI): calcd. for C23H21NO [M – C2H3O2]+
327.1623; found 327.1622. HPLC (Chiralpak OD-H; 1 mL/min; n-
hexane/iPrOH, 90:10; λ = 220 nm): tR = 18.4 (major), 33.2
(minor) min.
4-tert-Butyl 2-Methyl (2S,4S,5R)-5-(2-naphthyl)-2,4-pyrrolidine-
dicarboxylate (5ga):[11j] Yield: 299 mg (78%).
Methyl (1S,3R,3aS,6aR)-5-Methyl-3-phenyl-4,6-dioxooctahydropyr-
rolo[3,4-c]pyrrole-1-carboxylate (9aa):[11b] Yield: 230 mg (80%).
Methyl (1S,3R3aS,6aR)-5-Ethyl-3-phenyl-4,6-dioxooctahydropyr-
rolo[3,4-c]pyrrole-1-carboxylate (10aa):[11b] Yield: 236 mg (78%).
2-Methyl (2S,3R,4S,5R)-4-Benzoyl-5-(2-methylphenyl)-3-phenyl-2-
pyrrolidinecarboxylate (14ba): Colourless prisms (141, 70%); m.p.
128 °C; [α]2D0 = –9 (c = 1.15, CH2Cl2, 99%ee by HPLC). IR (KBr):
3,4-Diisopropyl 2-Methyl (2S,3S,4S,5R)-5-Phenyl-2,3,4-pyrrolidine-
tricarboxylate (11aa): Sticky oil (305 mg, 81%); [α]2D0 = 32.1 (c =
0.5, CHCl3, 82%ee by HPLC); Rf = 0.37 (n-hexane/ethyl acetate,
ν = 1672, 1746, 3373 cm–1. 1H NMR: δ = 2.14 (s, 3 H, CH3Ph),
˜
1
3:2). IR (liq.): ν = 1741, 1731, 2982 cm–1. H NMR: δ = 0.65 [d, J
˜
3.77 (s, 3 H, CO2CH3), 4.12–410 (m, 2 H, CHCOPh and
CHCO2Me), 4.52–4.43 (m, 1 H, CHPh), 5.11 (d, J = 8.3 Hz, 1 H,
CHAr), 6.75 (d, J = 7.7 Hz, 1 H), 6.92 (t, J = 6.4 Hz, 1 H, ArH),
7.17–7.05 (m, 3 H, ArH), 7.41–7.24 (m, 9 H, ArH) ppm. 13C NMR:
δ = 19.9 (CH3Ph), 52.7 (CH3CO2), 54.4 (CHPh), 59.7 (CHCO2Me),
63.3 (CHCOPh), 68.5 (CHAr), 126.5, 126.6, 127.5, 127.7, 127.9,
127.9, 128.3, 129.3, 130.3, 132.8, 135.2, 136.2, 138.1, 142.1 (ArC),
173.22 (CO2Me), 200.93 (COPh) ppm. MS (EI): m/z (%) = 340 (15)
[M]+. HRMS (EI): calcd. for C24H22NO [M – C2H3O2]+ 341.1780;
found 340.1685. HPLC (Chiralpak OD-H; 1 mL/min; n-hexane/
iPrOH, 90:10; λ = 220 nm): tR = 19.7 (major), 24.8 (minor) min.
= 6.2 Hz, 3 H, CH(CH3)2], 0.94 [d, J = 6.2 Hz, 3 H, CH(CH3)2],
1.27 [d, J = 6.2 Hz, 3 H, CH(CH3)2], 1.28 [d, J = 6.2 Hz, 3 H,
CH(CH3)2], 2.86 (br. s, 1 H, NH), 3.55 (m, 2 H, 2ϫCHCO2iPr),
3.83 (s, 3 H, CO2CH3), 4.14 (d, J = 7.3 Hz, 1 H, CHCO2Me), 4.56
[sept, J = 6.2 Hz, 1 H, CH(CH3)2], 4.65 (d, J = 7.3 Hz, 1 H, CHPh),
5.08 [sept, J = 6.2 Hz, 1 H, CH(CH3)2], 7.22–7.34 (m, 5 H, ArH)
ppm. 13C NMR: δ = 20.8, 21.4, 21.6 [CH(CH3)2], 51.4, 52.4
(CHCO2iPr), 53.8 (CO2CH3), 63.4 [CHCO2Me], 65.2 (PhCH),
68.2, 68.8 [CH(CH3)2], 127.0, 127.7, 128.2, 138.4 (ArC), 170.5,
171.5, 171.6 (CO2Me, CO2iPr) ppm. MS (EI): m/z (%) = 377 (14)
[M]+, 318 (33), 317 (23), 316 (23), 290 (20), 276 (17), 274 (12), 258
(38), 248 (15), 230 (43), 228 (17), 216 (10), 205 (25), 202 (50), 188
(47), 187 (23), 177 (67), 170 (34), 149 (12), 146 (29), 145 (46), 144
2-Methyl (2S,3R,4S,5R)-4-Benzoyl-5-(4-methylphenyl)-3-phenyl-2-
pyrrolidinecarboxylate (14da): Colourless prisms (256 mg, 75%);
Eur. J. Org. Chem. 2009, 5622–5634
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5631

C. Nájera, J. M. Sansano et al.
FULL PAPER
m.p. 154 °C; [α]2D0 = –25 (c = 1.06, CH2Cl2, 90%ee by HPLC). IR
Methyl
(2S,3R,4S,5R)-4-Benzoyl-2-methyl-3,5-diphenyl-2-pyrrol-
(KBr): ν = 1675, 1741, 3374 cm–1. 1H NMR: δ = 2.17 (s, 3 H,
idinecarboxylate (22aa):[12b,31] Yield: 324 mg (81%).
˜
CH3Ph), 3.73 (s, 3 H, CO2Me), 4.18–4.07 (m, 2 H, CHCOPh and
CHCO2Me), 4.50 (t, J = 7.8 Hz, 1 H, CHPh), 4.97 (d, J = 8.6 Hz,
1 H, CHAr), 6.9 (d, J = 8.0 Hz, 2 H, ArH), 6.99 (d, J = 8.1 Hz, 2
H, ArH), 7.39–7.42 (m, 9 H, ArH), 7.55 (d, J = 6.4 Hz, 2 H, ArH)
ppm. 13C NMR: δ = 20.9 (CH3Ph), 52.2 (CO2CH3), 52.6 (CHPh),
60.6 (CHCO2Me), 66.4 (CHCOPh), 67.6 (CHAr), 127.2, 128.0,
128.7, 128.7, 132.7, 136.0, 137.2, 137.4, 140.7 (ArC), 173.4
(CO2Me), 198.6 (COPh) ppm. MS (EI): m/z (%) = 340 (45) [M]+.
HRMS (EI): calcd. for C24H22NO [M – C2H3O2]+ 341.1780; found
340.1705. HPLC (Chiralpak OD-H; 1 mL/min; n-hexane/iPrOH,
90:10; λ = 220 nm): tR = 19.7 (major), 24.8 (minor) min.
Methyl (2S,3R,4S,5R)-4-Acetyl-2,3-dimethyl-5-(2-naphthyl)-2-pyr-
rolidinecarboxylate (23ga): Pale-yellow oil (189 mg, 71%); [α]2D0
=
20 (c = 1.02, CH Cl , 65%ee by HPLC). IR (NaCl): ν = 1689,
˜
2
2
1722, 2958, 3312 cm–1. 1H NMR: δ = 1.19 (d, J = 6.2 Hz, 3 H,
CH3CH), 1.38 (s, 3 H, CH3CN), 1.61 (s, 3 H, CH3CO), 2.99–3.04
(m, 1 H, CHCH3), 3.29 (t, J = 10.3 Hz, 1 H, CHCO), 3.82 (s, 3 H,
OCH3), 4.90 (d, J = 9.5 Hz, 1 H, CHN), 7.37–7.34 (m, 2 H, ArH),
7.48–7.43 (m, 3 H, ArH) ppm. 13C NMR: δ = 19.77 (CH3CH),
24.99 (CH3CCO), 30.60 (CHCH3), 42.58 (CHCO), 52.17 (CH3O),
62.23 (CHCO), 64.47 (CHN), 125.05, 125.88, 126.38, 127.31 127.60
128.18, 132.72, 137.67 (ArC), 175.57 (CO2), 206.59 (COCH3) ppm.
MS (EI): m/z = 266 [M]+. HRMS (EI): calcd. for C18H20NO [M –
Methyl (1S,3R,3aS,6aR)-Octahydro-3-(naphthalen-2-yl)-4-oxocyclo-
penta[c]pyrrole-1-carboxylate (15ga):[12b] Yield: 222 mg (72%).
+
C2H3O2] 266.1555; found 266.1552. HPLC (Chiralpak OD-H;
1 mL/min; n-hexane/iPrOH, 90:10; λ = 220 nm): tR = 10.5 (major),
12.2 (minor) min.
4-tert-Butyl 2-Methyl (2S,4S,5R)-2-Methyl-5-phenyl-2,4-pyrrolid-
inedicarboxylate (16aa):[11j] Yield: 238 mg (78%).
Synthesis of Antiviral Compound (2S,4S,5R)-26: To a solution of
(2S,4S,5R)-8ha (1.2 mmol, 441 mg) dissolved in dichloromethane
(25 mL) was slowly added triethylamine (1.2 mmol, 166 µL) and 4-
(trifluoromethyl)benzoyl chloride (1.2 mmol, 182 µL) at 0 °C. The
resulting mixture was heated at reflux overnight, and the solvent
was removed in vacuo (15 Torr). Crude compound (2S,4S,5R)-25
was allowed to react with trifluoroacetic acid/dichloromethane
mixture (9.6 mL:18 mL). The resulting mixture was stirred at room
temperature overnight, and the solvent was evaporated in vacuo.
The residue was dissolved in a solution of KOH (1  in MeOH/
H2O, 4:1; 50 mL). This reaction was heated at reflux for 16 h.
Methanol was evaporated and aqueous HCl (0.5 , 20 mL) and
ethyl acetate were added (2ϫ20 mL). The combined organic phase
was dried (MgSO4) and evaporated to yield the crude (2S,4S,5R)-
26, which was recrystallised from acetone/chloroform.
4-tert-Butyl 2-Methyl (2S,4S,5R)-2-Benzyl-5-phenyl-2,4-pyrrolidine-
dicarboxylate (17aa):[11j] Yield: 293 mg (77%).
4-tert-Butyl 2-Methyl (2S,4S,5R)-2-Methyl-5-(2-thienyl)-2,4-pyrrol-
idinedicarboxylate (18ha): Sticky oil (257 mg, 79%); [α]2D0 = +46.3
(c = 1, CHCl3, 92%ee by HPLC); Rf = 0.30 (n-hexane/ethyl acetate,
1
3:2). IR (liq.): ν = 1728, 1725, 2977 cm–1. H NMR: δ = 1.15 [s, 9
˜
H, CO2C(CH3)3], 1.46 (s, 1 H, CCH3), 2.07 (dd, J = 13.7, 7.7 Hz,
1 H, CH2), 2.70 (dd, J = 13.7, 7.7 Hz, 1 H, CH2), 3.35 (dd, J =
15.2, 7.7 Hz, 1 H, CHCO2tBu), 3.79 (s, 3 H, CO2CH3), 4.81 (d, J
= 7.5 Hz, 1 H, CHAr), 6.91–6.95 (m, 2 H, ArH), 7.17 (dd, J = 4.9,
0.9 Hz, 1 H, ArH) ppm. 13C NMR: δ = 27.6 (CCH3), 27.8 (CCH3),
39.4 (CH2), 50.6 (CHCO2tBu), 52.5 [CO2C(CH3)3], 60.3 (ArCH),
80.8 [CO2C(CH3)3], 124.1, 124.8, 126.5, 143.5 (ArC), 171.0, 176.3
(CO2Me, CO2tBu) ppm. MS (EI): m/z (%) = 325 (3.4) [M]+, 268
(22), 267 (10), 266 (65), 252 (26), 211 (12), 210 (100), 197 (56), 166
(15), 165 (15), 164 (18), 137 (67), 96 (11), 57 (18), 53 (10). HRMS:
calcd. for C16H23NO4S 325.1348; found 325.1347. HPLC (Chi-
(2S,4S,5R)-2-Isobutyl-5-(2-thienyl)-1-[4-(trifluoromethyl)benzoyl]-
2,4-pyrrolidinedicarboxylic Acid [(2S,4S,5R)-(+)-26]:[5a] Yield:
395 mg (71% from 19ha).
ralpak OD-H; 1 mL/min; n-hexane/iPrOH, 99:1; λ = 220 nm): tR
=
Supporting Information (see also the footnote on the first page of
this article): The main geometrical features of the stationary points
found along the reaction coordinate depicted in Figure 5; total elec-
tronic energies, zero-point correction of energies, thermal correc-
tions to Gibbs free energies and number of imaginary frequencies
of all stationary points discussed in this article; Cartesian coordi-
nates of all the stationary points discussed.
13.4 (major), 14.8 (minor) min.
4-tert-Butyl 2-Methyl (2S,4S,5R)-2-Isobutyl-5-(2-thienyl)-2,4-pyr-
rolidinedicarboxylate (19ha): Viscous oil (257 mg, 70%); [α]2D0
=
+38.6 (c = 1, CHCl3, 84%ee by HPLC); Rf = 0.49 (n-hexane/ethyl
acetate, 3:2). IR (liq.): ν = 1735, 1728, 2952 cm–1. 1H NMR: δ =
˜
0.82 [d, J = 6.1 Hz, 3 H, CH(CH3)2], 0.93 [d, J = 6.4 Hz, 3 H,
CH(CH3)2], 1.14 [s, 9 H, CO2C(CH3)3], 1.58 [m, 1 H, CH2CH-
(CH3)2], 1.75 [m, 2 H, CH2CH(CH3)2], 2.06 (dd, J = 13.6, 7.6 Hz,
1 H, CCH2), 2.61 (dd, J = 13.7, 8.0 Hz, 1 H, CCH2), 3.05 (br. s, 1
H, NH), 3.29 (dd, J = 15.4, 7.8, 7.6 Hz, 1 H, CHCO2tBu), 3.77 (s,
3 H, CO2CH3), 4.76 (d, J = 7.5 Hz, 1 H, CHAr), 6.90–6.94 (m, 2
H, ArH), 7.16 (dd, J = 4.8, 1.4 Hz, 1 H, ArH) ppm. 13C NMR: δ
= 22.7 [CH(CH3)2], 24.3 [CH(CH3)2], 25.0 [CH(CH3)2], 27.6
[CO2C(CH3)3], 39.9 (CH2CHCO2tBu), 49.0 [CH2CH(CH3)2], 50.3
(CHCO2tBu), 52.2 (CO2CH3), 60.3 (ArCH), 68.1 (CCO2Me), 80.7
[CO2C(CH3)3], 124.1, 124.9, 126.4, 143.9 (ArC), 171.1, 176.4
(CO2Me, CO2tBu) ppm. MS (EI): m/z (%) = 367 (0.9) [M]+, 310
(14), 309 (13), 308 (65), 254 (18), 253 (16), 252 (100), 208 (11), 196
(41), 179 (14), 57 (12). HRMS: calcd. for C19H29NO4S 367.1817;
found 367.1821. HPLC (Chiralpak AD; 1 mL/min; n-hexane/
iPrOH, 99:1; λ = 220 nm): tR = 11.1 (major), 13.7 (minor) min.
Acknowledgments
This work was supported by the DGES of the Spanish Ministerio
de Educación y Ciencia (MEC) (Consolider INGENIO 2010
CSD2007-00006, CTQ2007-62771/BQU and CTQ2004-00808/
BQU) and by the University of Alicante. M. G. R. and M. M.-R.
thank the University of Alicante and MEC, respectively, for a pre-
doctoral fellowship. The authors also thank the SGI/IZO-SGIker
UPV/EHU for generous allocation of computational resources.
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Yield:
5632
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5622–5634

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Received: July 13, 2009
Published Online: September 28, 2009
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