N,2,3,4-Tetrasubstituted Pyrrolidines through Tandem Lithium Amide Conjugate Addition/Radical Cyclization/Oxygenation Reactions

Article abstract of DOI:10.1002/ejoc.201600621

Enantioselective syntheses of densely functionalized pyrrolidines deriving their chirality from (R)-1-(phenyl)ethylamine are reported. Allylic amines and β-substituted-α,β-unsaturated esters are used as the building blocks in this one-pot reaction. Single

Full text of DOI:10.1002/ejoc.201600621

DOI: 10.1002/ejoc.201600621
Full Paper
Tandem Reactions
N,2,3,4-Tetrasubstituted Pyrrolidines through Tandem Lithium
Amide Conjugate Addition/Radical Cyclization/Oxygenation
Reactions
František Kafka,[a] Radek Pohl,[a] Ivana Císařová,[b] Richard Mackman,[c] Gina Bahador,[c] and
Ullrich Jahn*[a]
Abstract: Enantioselective syntheses of densely functionalized pare, store and handle, was applied as SET oxidant and persist-
pyrrolidines deriving their chirality from (R)-1-(phenyl)ethyl- ent free radical TEMPO served as the oxygenating agent intro-
amine are reported. Allylic amines and ꢀ-substituted-α,ꢀ-unsat- ducing a protected hydroxy function, which proved to be bene-
urated esters are used as the building blocks in this one-pot ficial for further derivatization. Exclusive 2,3-trans and up to 6:1
reaction. Single electron transfer (SET) oxidation served to 3,4-cis/trans diastereoselectivities were achieved in the targeted
merge the reactivities of anionic enolate and radical intermedi- tetrasubstituted pyrrolidines.
ates. Ferrocenium hexafluorophosphate, which is easy to pre-
Introduction
Polysubstituted pyrrolidines are ubiquitous in Nature.[1] Se-
lected examples are the neuroexcitatory compounds kainic and
allokainic acids,[2] the DNA polymerase inhibitor plakoridine
A,[3] the anti-inflammatory compounds codonopsine[4] and (+)-
erysotrine,[5] and the antitussic and anthelminthic compound
neostenine, which comes from the Stemona family of alkaloids
(Figure 1).[6] Moreover, this ring system has many applications in
medicinal chemistry,[7] and also in the preparation of unnatural
amino acids, which have been used in the synthesis of pepti-
domimetic foldamers, for example.[8]
This means that efficient enantio- and diastereoselective ap-
proaches to polysubstituted pyrrolidines are required. Among
the many potential approaches, tandem reactions are an at-
Figure 1. Pyrrolidine-ring-containing natural products.
tractive way to assemble polyfunctionalized derivatives in a
time- and resource-efficient manner.[9] Tandem processes, in
tive generation of multiple types of reactive intermediates, such
as carbanions, radicals, or carbocations, at will,[11] thus overcom-
ing potential reactivity pitfalls.[12] Such polar–radical or radical–
polar crossover reactions have found a number of applications
in natural product synthesis.[13]
Oxidative SET reactions can be mediated by iron(III),[14] man-
ganese(III),[14,15] copper(II),[10c] or cerium(IV) ammonium nitrate
(CAN).[14] Organic molecules, such as 2-iodoxybenzoic acid (IBX)
have also been used as SET oxidants.[16] The use of photoredox
catalysis for carrying out SET-induced transformations has
gained growing interest.[17] Among the FeIII-based SET oxidants,
ferrocenium hexafluorophosphate holds a privileged role[18] be-
cause of its easy preparation and handling, and the possibility
of tuning its redox properties by the choice of substituents.[19]
SET oxidation-mediated tandem anionic conjugate addition/5-
exo radical cyclization reactions were recently used in the syn-
thesis of polysubstituted tetrahydrofurans[20] and densely func-
which the oxidation level of intermediates can be switched, are
particularly appealing, because their reactivity patterns can be
modified without the need to isolate reaction intermediates.
Single-electron transfer (SET) is the key to the interconversion
of radical and polar intermediates by overall oxidative, reduc-
tive, or redox-neutral pathways.[10] It also enables the consecu-
[a] Institute of Organic Chemistry and Biochemistry, Czech Academy of
Sciences,
Flemingovo namesti 2, 16610 Prague 6, Czech Republic
E-mail: jahn@uochb.cas.cz
http://www.uochb.cz/web/structure/616.html
[b] Department of Inorganic Chemistry, Faculty of Science, Charles University
in Prague,
Albertov 6, 12843 Prague 2, Czech Republic
[c] Gilead Sciences, Inc.,
333 Lakeside Drive, Foster City, CA 94404, USA
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600621.
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tionalized cyclopentanes.[21] Ferrocenium ion induced oxidative
In contrast, intermolecular additions of N-centered radicals F
5-exo radical cyclizations of enolates coupled with oxygenation to unactivated alkenes do not typically proceed well.[29] Re-
by the persistent free radical TEMPO [(2,2,6,6-tetramethylpiper- cently, additions of amidyl radicals to activated styrene-type
idin-1-yl)oxyl] have also been used in the synthesis of natural olefins have been reported, but these reactions are limited to
products, such as the oxidative-stress marker 15-F2t-isopro- this substrate class.[30] Similarly, anionic 5-exo cyclizations of
stane,[22] or the (–)-enantiomer of the antimetastatic fusarisetin enolate C to D are slow and limited to highly electron-deficient
A.[23]
Based on an early racemic lithium amide conjugate addition/
alkenes (R3 = EWG, electron-withdrawing group). Anionic cycli-
zations using zinc enolates,[31] or zinc-ene[32] reactions have
been reported, but the possible substitution patterns are very
limited. Moreover, the functionality of cyclized organometallic
intermediate D cannot easily be increased; protonated pyrrol-
idines E are normally obtained. Therefore, SET seems to be a
very attractive prospect for joining the easier steps from the
purely radical and anionic approaches to create a tandem proc-
ess. Upon SET oxidation, enolate C forms an α-carbonyl radical
G, which cyclizes in a favored 5-exo mode to give radical H.
Coupling of radical H with with a radical X· or its surrogate gives
the final pyrrolidine carboxylate I, with additional functionality
at the exocyclic position.
SET oxidation/radical cyclization sequence,[24] we hypothesized
that enantiomerically enriched pyrrolidines could be synthe-
sized through tandem organometallic–radical reactions initi-
ated by aza-Michael additions of enantiomerically pure lithium
amides A– to (E)-ꢀ-substituted α,ꢀ-unsaturated esters B to give
ꢀ-amino ester enolates C (Scheme 1). This is based on pioneer-
ing work by Davies,[25] who showed that homochiral lithium N-
(1-phenyl)ethylamides A– undergo highly diastereoselective
aza-Michael additions to α,ꢀ-unsaturated esters B. So far, how-
ever, amides A– have merely played the role of a chiral ammo-
nia surrogate, i.e., the N-substituents were removed later in the
reaction sequence. Only recently have more “carbon-economic”
In this paper, we report a modular asymmetric tandem ani-
examples been found, in which the alkyl[26] or aryl[27] substitu- onic/radical approach to N,2,3,4-tetrasubstituted pyrrolidines
ents of the lithium amides remain as functional groups in the using homochiral allylic lithium amides and α,ꢀ-unsaturated
target molecules. A unique carbon-economic combination of esters. The chirality of (R)-1-(phenyl)ethylamine induces the
amide conjugate additions with [3+2] cycloadditions to give configuration of three contiguous stereocenters in the pyrrol-
cyclic α,ꢀ,γ-triamino-acid derivatives was developed very re- idine ring in this one-pot reaction. Coupling with the persistent
cently.[28]
radical TEMPO terminates the sequence, introducing a useful
masked hydroxy group that can subsequently be released.
Results
Aza-Michael Additions
A series of N-allylic ꢀ-amino esters 3a–3f was synthesized from
α,ꢀ-unsaturated ester acceptors 1 and allylic lithium amides 2a–
and 2b–, in analogy with Davies' procedure (Table 1).[33] The
conjugate additions of 2a– to tert-butyl esters 1a and 1b pro-
ceeded in good yields and with good diastereoselectivities
(Table 1, entries 1–3). The yields were better in THF than in 1,2-
Table 1. Conjugate addition of allylic lithium amides to unsaturated esters.[a]
Entry[a]
1
R1
R2
2
R3
Time 3, yield [%] dr
[min]
1[b]
2[b]
3
4
5
1a
1b
1b
1c
1d
1d
Me
Ph
Ph
Me
Ph
Ph
tBu 2a
tBu 2a
tBu 2b
Me 2a
Me 2a
Me 2b
H
H
Me
H
H
60
90
70
60
60
60
3a, 96
3b, 56[c]
3c, 95
3d, 95
3e, 92
3f, 39
>99:1
>99:1
>15:1
>99:1
>99:1
3.7:1
6
Me
[a] General conditions: BuLi (1.1–1.3 mmol) was added to 2 (1.1–1.3 mmol)
in THF at –78 °C, and after 15 min 1 (1 mmol) was added. [b] Carried out in
DME at –78 °C. [c] Better yields were obtained using THF in the tandem
sequence, vide infra.
Scheme 1. Tandem anionic/radical vs. purely organometallic or radical strate-
gies for the synthesis of tetrasubstituted pyrrolidines.
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dimethoxyethane (DME) (Table 1, entry 2 vs. 3–5). Methyl esters ble reaction rate. Collum and coworkers have recently described
1c and 1d gave high yields and diastereoselectivities only with a positive effect of catalytic lithium chloride (1–2 mol-%) on the
amide 2a– (Table 1, entries 4 and 5). Both the yield and the rate of lithium amide conjugate additions.[34] Therefore, se-
diastereoselectivity of the addition dropped when prenylamine- lected conjugate additions to α,ꢀ-unsaturated esters 1 were
derived 2b– was used (Table 1, entry 6). Ethyl (E)-4-(benzyl- carried out in the presence of lithium chloride (1–8 mol-%;
oxy)but-2-enoate and ethyl (E)-4-{[(tert-butyl)dimethylsilyl]- Table 2, entries 2, 3, 5, and 6). Indeed, when catalytic lithium
oxy}but-2-enoate gave rather complex reaction mixtures with chloride was used and the addition temperature was raised to
little or none of the desired products (i.e., 3) isolated (not
shown). The likely explanation is a competitive γ-deprotonation
by the lithium amides (i.e., 2), giving rise to side products (vide
infra).
–40 °C, an increase in the yield of 18–33 % was found (Table 2,
entry 3 vs. 1, and entry 5 vs. 4). The diastereoselectivity was not
significantly influenced by using the catalyst for the reaction of
1e with 2a–, but it decreased slightly in the reaction with 2b–
(Table 2, entry 5). A significant yield increase was also observed
Ethyl sorbate 1e proved to be a difficult acceptor, prone to
Michael-type polymerization that negatively affected the yield for the addition of 2b– to methyl cinnamate 1d (Table 2, en-
(Table 2, entry 1); a good diastereoselectivity was nevertheless try 6, compare Table 1, entry 6); the diastereoselectivity, how-
retained. Therefore, the low yield was attributed to an unfavora- ever, remained low at 4.4:1.
Table 2. Lithium amide conjugate additions catalyzed by lithium chloride.[a]
Entry
1
R1
R2
2
Temp. [°C]
LiCl [mol%]
t [min]
3, yield [%]
dr
1
2
3
4
5
6
1e
1e
1e
1e
1e
1d
MeCH=CH
MeCH=CH
MeCH=CH
MeCH=CH
MeCH=CH
Ph
Et
Et
Et
Et
Et
Me
2a
2a
2a
2b
2b
2b
–78
–40
–40
–78
–40
–78
–
8
1
–
2
1
120
30
25
30
150
120
3g, 39
3g, 65
3g, 72
3h, 49
3h, 67
3f, 66
10:1
19:1
9:1
10:1
7.4:1
4.4:1
[a] General conditions as in Table 1, addition of LiCl as 0.1
M solution after formation of the lithium amide.
Table 3. Tandem conjugate addition/radical cyclization/oxygenation reactions.[a]
Entry
1
R1
R2
2
R3
Solvent
6 + 7, yield [%]
6/7
Other products, yield [%]
1
2
3
4
1a
1a
1b
1b
1a
1b
1c
1d
1e
1e
1f
Me
Me
Ph
Ph
Me
Ph
Me
Ph
tBu
tBu
tBu
tBu
tBu
tBu
Me
Me
Et
2a
2a
2a
2a
2b
2b
2a
2a
2a
2a
2a
H
H
H
H
Me
Me
H
H
H
THF
DME
THF
DME
THF
THF
THF
THF
THF
THF
THF
a, 64
a, 54
b, 76
b, 40
c, 72
d, 78
e, 59
f, 49
3.5:1
4:1
6:1
6:1
2:1
1:1
3:1
6:1
3a, 16
3a, 21
3b, 7
3b, 8
–
3c, 7
–
–
5[b]
6
7
8
9
MeCH=CH
MeCH=CH
CH2OBn
g, 42
g, 48
h, 42
2.5:1
2.5:1
3:1
–
10[c]
11
Et
Et
H
H
3g, 8
3i, 21
[a] General conditions: BuLi (1.1 mmol) was added to 2 (1.1 mmol) in THF at –78 °C, and after 30 min 1 (1 mmol) was added. After the formation of 3– was
complete, 5 (0.2 mmol) was added, followed by a mixture of 4 (1 mmol) and 5 (0.8 mmol) in portions. Further 4 was added, until the reaction mixture
remained green-blue. [b] Experiment was run in duplicate with an identical outcome. [c] With catalytic LiCl (1 mol-%).
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Tandem Aza-Michael Addition/Radical Cyclization/
Oxygenation Reactions
The ester enolates formed after the aza-Michael addition were
subjected to the SET oxidation/radical cyclization/oxygenation
sequence in situ. A range of N,2,3,4-tetrasubstituted pyrroli-
dines 6 and 7 was synthesized by this tandem approach in
moderate to good yields using ester acceptors 1a–1f, lithium
amides 2a– and 2b–, ferrocenium hexafluorophosphate 4 as the
SET oxidant, and persistent radical TEMPO 5 as the oxygenation
reagent (Table 3). Better yields of pyrrolidines 6 and 7 were
obtained using THF as the solvent than with DME (Table 3,
entries 1 and 3 vs. 2 and 4). Therefore, THF was chosen for all
subsequent reactions. Methyl esters gave yields somewhat
lower than those obtained with tert-butyl esters, but still ac-
ceptable, with lithium amide 2a– (Table 3, entries 7 and 8).
When ethyl sorbate (1e) and 4-(benzyloxy)crotonate (1f) were
used as the Michael acceptors with lithium amide 2a–, the
yields were moderate (Table 3, entries 9–11); these yields im-
proved somewhat with LiCl catalysis (Table 3, entry 10). The
main side products were the easily separable noncyclized ꢀ-
amino esters (i.e., 3), which were isolated in 7–21 % yield
(Table 3, entries 1–4, 6, and 10–11). The lithium amide derived
from prenylamine 2b reacted less selectively in the polar conju-
gate addition with 1d, 1f or ethyl (E)-4-{[(tert-butyl)dimethyl-
silyl]oxy}but-2-enoate; this translated into low yields of pyrrol-
idines 6 and 7, and the formation of inseparable side products
(not shown). Another factor contributing to the observed low
yields was γ-deprotonation, which competed with the aza-
Michael addition, resulting in the formation of γ-oxygenated
esters, such as 8, which formed in yields up to 30 %.
Scheme 2. Tandem conjugate addition of crotylamide 2c–/radical cyclization.
ium amide 2a– gave the addition product (i.e., 10) in moderate
yield, but with excellent diastereoselectivity in the addition, and
good diastereoselectivity in the protonation step (Scheme 3).
For this example, the addition of LiCl did not increase the effi-
ciency of the conjugate-addition step. The tandem aza-Michael
addition/radical cyclization reaction gave the desired 3,3-disub-
stituted pyrrolidine (i.e., 11) in a low 18–26 % yield, albeit with
the best observed diastereoselectivity for the cyclization. Some
aza-Michael adduct 10 was also isolated. Alkoxyamine 12 and
dimer 13 were obtained as side products in 25–29 % and 8–
18 % yields, respectively. Their formation can be attributed to
significant γ-deprotonation of 9 by 2a– competing with the aza-
Michael addition, thus the yield of cyclization product 11 is
reasonable based on the observed extent of the conjugate ad-
dition. Carrying out the Michael addition step at –40 °C and the
oxidative cyclization at –20 °C led to a decrease in the yield of
11 to 18 %, and a decrease in the 3,4-diastereoselectivity to 5:1.
Also, compounds 12 (22 %) and 10 (6 %) were isolated, but the
formation of dimer 13 was not observed.
The absolute stereochemistry depends on the diastereose-
lectivity of the initial Michael addition, which was in most cases
excellent. The absolute configuration of pyrrolidine 6c was as-
signed earlier by X-ray crystallographic analysis, and the relative
configurations of all other derivatives were assigned by the sim-
ilarity of their NMR spectroscopic data.[35] The tandem se-
quence gave pyrrolidines 6 and 7 with an exclusive 2,3-trans
diastereoselectivity. With lithium amide 2a–, the 3,4-cis/trans se-
lectivity (i.e., the 6/7 ratio) ranged from 2.5 to 6:1, whereas with
lithium amide 2b–, the 6/7 ratio remained low (Table 3, en-
tries 5 and 6).
The use of lithium amide 2c– bearing 1,2-disubstituted
alkene units resulted in the formation of pyrrolidines with an
exocyclic stereogenic center adjacent to C-4 (Scheme 2). Four
inseparable diastereomers of 6iA, 6iB, 7iC, and 7iD (from 1a)
or 6jA, 6jB, 7jC, and 7jD (from 1b) were formed in 63 and 88 %
yields, respectively. The rather complex NMR spectra prohibited
the assignment of the particular diastereomers at this stage.
However, their configurations were assigned after reductive de-
protection to the corresponding lactones and alcohols (vide
infra).
Scheme 3. The tandem aza-Michael addition/radical reaction with ethyl
tiglate (9).
Oxidative Cyclizations of ꢀ-Substituted-ꢀ-Amino Esters 3
Isolated ꢀ-substituted ꢀ-amino esters 3 can be deprotonated
with LDA (lithium diisopropylamide) in THF or DME at –78 °C,
Ethyl tiglate (9), an example of an α,ꢀ-disubstituted unsatu- and subjected to oxidative cyclization conditions to give
rated ester, was also studied. The aza-Michael addition with lith- N,2,3,4-tetrasubstituted pyrrolidines 6 and 7 in 60–89 % yield
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(Table 4). This broadly reflects the yields of the tandem proc-
esses (Table 4, entries 1–4). The outcome of the cyclization reac-
tion of 3 was affected neither by the choice of solvent (Table 4,
entry 2) nor by whether tert-butyl (entries 1 and 2), methyl
(entries 3 and 4), or ethyl (entries 5 and 6) esters were used.
The diastereoselectivity of the cyclization followed the pre-
ferred 3,4-cis orientation[24] for R3 = H (Table 4, entries 1, 3,
4, and 5), with the 6/7 ratio ranging from 2:1 to 5.5:1. Both
diastereomers had a 2,3-trans configuration exclusively, and
were formed in enantiomerically pure form. For derivatives with
R3 = CH3 (Table 4, entries 2 and 6), almost equal amounts of 6
and 7 were formed. Sometimes small amounts of starting mate-
rial 3 were recovered (10–14 %; Table 4, entries 4 and 5). Inter-
estingly, the cyclizations of substrates 3g and 3h also pro-
ceeded smoothly in 61–70 % yields (Table 4, entries 5 and 6).
Table 4. Oxidative radical cyclization reactions of chiral ꢀ-amino esters 3a–
3h.[a]
Scheme 4. Preparation of silyl ketene acetals 14 from enolates 3a–. TMS =
trimethylsilyl.
Reductive Cleavage of the Alkoxyamine Units in
Compounds 6 and 7
Reductive cleavage of the N–O bond in tetrasubstituted pyrrol-
idines 6 and 7 gave bicyclic lactones 16 from the 3,4-cis isomers
and trans-(1-hydroxyalkyl)pyrrolidines 17 from the trans-conge-
ners, respectively (Table 5). Complete lactonization occurred
starting from 3,4-cis isomers 6, i.e., no free alcohol cis-17 was
isolated. The reaction products were separable by column chro-
matography, thus diastereomeric mixtures of 6 and 7 can be
resolved into individual and enantiomerically pure 16 and 17.
The combined yields of lactones 16, formed from major pyrrol-
idine diastereomers 6, and pyrrolidinols 17a–17d, formed from
the corresponding trans-isomers 7a–7d, were with 71–94 %
good to excellent (Table 5, entries 1–3, and 6). Diastereomeri-
6 + 7,
yield [%]
Other prod-
ucts, yield [%]
Entry
3
R1
R2 R3 Solvent
6/7
1
2
3
4
5
6
3a Me
3c Ph
3d Me
3e Ph
tBu
H
THF
a, 75
d, 73
e, 60
f, 89
g, 61
k, 70
3.6:1
1:1
3:1
–
–
–
tBu Me DME
Me
Me
H
H
H
THF
THF
THF
5.5:1 3e, 10
3g MeCH=CH Et
3h MeCH=CH Et Me THF
2:1
1:1
3g, 14
–
[a] Standard conditions: 3 (1 mmol), LDA (1.25 mmol) at –78 °C, then 5
(0.2 mmol), followed by a homogenized mixture of 4 (1.0 mmol) and the
remaining 5 (0.8 mmol). When the addition was complete, further 4 (0.3 to
0.5 mmol) was added in small portions.
Table 5. Reductive alkoxyamine cleavage of pyrrolidines 6/7.[a]
Elucidation of the Geometry of Enolates 3–
The conjugate addition of lithium amides 2a–, 2b–, and 2c– to
α,ꢀ-unsaturated esters 1 should result in the formation of the
(Z)-enolates.[24,25a,33b] Indeed, conjugate addition of lithium am-
ide 2a– to ester 1a and subsequent enolate trapping by chloro-
trimethylsilane in THF gave silyl ketene acetal 14 with a (Z)
configuration in 73 % yield (Scheme 4). No (E)-silyl ketene acetal
was detected. In addition, N-silylated amine 15 (6 %) and recov-
ered amine 2a (36 %) were detected. The products were not
purified, so the overall yield exceeded 100 %. Repeating the
experiment in DME provided (Z)-14, 15, and 2a in more than
quantitative yield in a 7:1.5:1 ratio. Enolate (E)-3a– was gener-
ated by protonation of (Z)-3a– and subsequent deprotonation
with LDA. Quenching by chlorotrimethylsilane gave silyl ketene
acetal (E)-14 in a 120 % crude yield. No (Z)-14 or 15, which
could potentially be formed by retro-Michael addition, were ob-
served.
16, yield
[%]
17, yield
[%]
Yield of 6
+ 7[b] [%]
Entry 6 + 7 6/7
Time [h]
1
2
3
4
5
6
7
8
a
b
b
c
c
d
f
3.6:1
6:1
4.7:1
1:0
3
3
4
3
4
3
2.5
2.5
16a, 67
16b, 68
16b, 59
16c, 65
–
16d, 57
16b, 54
16g, 51
17a, 18
17b, 11
17b, 12
–
17c, 82
17d, 37
17f, 12
17g, 18
11
–
25
–
–
–
0:1
1:1.3
4.7:1
2.3:1
–
–
g
[a] General conditions: A mixture of 6 and 7 was heated with zinc powder
(50 equiv.) in a AcOH/H2O/THF mixture (3:1:1) until the reaction was com-
plete. [b] Recovered starting material had the same 6/7 ratio.
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cally pure starting materials 6c and 7c gave single products, 16j and 17j) were formed in 73 % overall yield as a separable
thus epimerization did not occur under the reaction conditions mixture.
(Table 5, entries 4 and 5). Some of the reactions were carried
out on multigram scale (Table 5, entries 6 and 7). For methyl
esters 6f/7f and ethyl esters 6g/7g, the combined yields of
16b/17f and 16g/17g ranged from 66 to 69 %, probably be-
cause of a small amount of ester hydrolysis under the acidic
reaction conditions (Table 5, entries 7 and 8).
This allowed full assignment of the NMR resonances, and
also determination of the absolute stereochemistry of (3S)-16j
and [4(1S)]-17j by X-ray crystallographic analysis (Figure 3). This
was crucial for determining the absolute configuration at the
exocyclic stereocenter in 17j, since it could not be assigned
using NOE techniques. The crystal structure of (3S)-16j revealed
Lactones 16 are, in contrast to alcohols 17 or starting materi- an (S)-configuration at C-3, and a trans orientation of 6-H and
als 6 and 7, mostly crystalline compounds. The structure of 6a-H. In [4(1S)]-17j, the configuration at the 1-(hydroxyethyl)
compound 16b, formed from the major component 6b or 6f group was determined to be (S). Moreover, the trans orientation
was confirmed by X-ray crystallography (Figure 2), thus provid- of the phenyl group at C-2 and the carboxylate at C-3, and the
ing further evidence for the absolute configuration.
trans orientation of 3-H and 4-H were confirmed.
Figure 3. Crystal structures of lactone (3S)-16j (left) and hydroxyethyl pyrroli-
dine [4(1S)]-17j (right) with atom-numbering schemes. The displacement el-
lipsoids are drawn at the 30 % probability level.
Transformations of Pyrrolidines 7 and 17
Figure 2. Crystal structure of 16b with atom-numbering scheme. The dis-
placement ellipsoids are drawn at the 30 % probability level.
To illustrate possible synthetic applications, a simple carboxyl-
ate interconversion was carried out. Methyl ester 18 was syn-
thesized in 89 % yield by acid-catalyzed transesterification of
Reductive cleavage of the TMP (2,2,6,6-tetramethylpiperidin-
yl) unit in the four inseparable diastereomers of pyrrolidines 6j
and 7j also allowed them to be separated and their configura-
tions to be assigned (Scheme 5). The deprotected products (i.e.,
Scheme 5. Reductive cleavage of the alkoxyamine unit in pyrrolidines 6j/7j.
Scheme 6. Synthetic modifications of pyrrolidines 7b and 17d.
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17d. Furthermore, compound 17d was subjected to mesyl- tecting group was exchanged by hydrodebenzylation of 7b in
ation/elimination using MsCl/DMAP (4-dimethylaminopyridine)/ the presence of Boc2O (Boc = tert-butoxycarbonyl) to give 21
Et3N (Scheme 6). The desired kinetic product, alkene 19, was in 47 % yield.
isolated in 60 % yield, along with a small amount of isomeric
product 20 containing a C-4-exocyclic double bond. The N-pro-
Activities Against the Hepatitis C Virus
Table 6. Antiviral activity of compounds 11–19 against different HCV geno-
types.
All the newly synthesized heterocyclic compounds were tested
against different genotypes of the hepatitis C (HCV) virus in 1A,
1B, and 2A replicon assays. Compounds 11 and 17d, as well as
both diastereomers of 17j and 19, were active in the replicon
1B assay in low micromolar concentrations (Table 6). However,
no significant activity was observed for the replicon 2A HCV
strain. Compound 11 was the only compound to show activity,
at the low micromolar level, in the replicon 1A assay. The cyto-
toxicities of the tested compounds were measured using Huh-
7 cells, and were found to be at or above the threshold value
of 44.4 μ , except for compounds 11 and [4(1R)]-17j in the
M
replicon 1A antiviral assay.
Replicon 1B[a]
Replicon 1A
Replicon 1A
CC50 [μM]
Discussion
Compound
EC50 [μM]
EC50 [μM]
The tandem reactions show some remarkable features. The
asymmetric aza-Michael addition, pioneered by Davies,[25a,33]
typically applies N-benzyl-N-(1-phenylethyl)amines, which thus
serve as a chiral ammonia surrogate. In this paper, the reactivity
of N-allylic amines 2 was explored to allow their application in
one-pot C–N, C–C, and C–O bond-formation steps, thus adding
11
17d
[4(1R)]-17j
[4(1R/1S)]-17j
19
3.5
1.5
2.6
2.0
2.9
2.8
16.5
44.4
29.2
44.4
44.4
30.1
13.6
38.7
21.0
[a] CC50 values for the Replicon 1B were at the threshold value of 44.4 μM.
Scheme 7. Rationalization of the lithium amide conjugate addition results.
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much value to the applications of lithium amides in organic from radicals 30 by hydrogen abstraction from THF. For esters
chemistry.
Lithium amides 2– typically exist as dimers in ethereal solu-
1f or 9, γ-oxygenated esters 8 or 12 are formed by SET oxid-
ation of the competitively formed dienolate 27 (cf. Table 3, and
Schemes 3 and 7).
tions (Scheme 7),[36] but they have to deaggregate to mono-
mers 23– via open dimers 22– to undergo reasonably fast con-
jugate addition, as shown by Collum et al. in a recent study.[34]
Catalytic amounts of lithium chloride promote deaggregation
of 2– and faster conjugate addition to unsaturated esters 1, as
demonstrated here for methyl ester 1d and sorbate 1e, which
undergo the conjugate addition significantly less efficiently in
the absence of LiCl (cf. Table 2 vs. Table 1). This can be attrib-
uted to the much faster conjugate addition of monomeric 23–
to 1 via cyclic transition state 25 than that of dimers 2– or 22–
via sterically much more encumbered transition state 24. In this
way, the addition of LiCl partially limits competing anionic po-
lymerization of 1. However, γ-deprotonation to give dienolates
27, which is detrimental to the yields of the subsequent radical
cyclization step, cannot be prevented by the addition of LiCl
(cf. Scheme 3). It must be also noted that esters 1 have to be
substituted in the ꢀ position (R1 ≠ H), since acrylates polymerize
faster than they undergo aza-Michael addition under identical
conditions, irrespective of whether or not LiCl is present.[37]
The aza-Michael addition step via cyclic transition state 25
leads to the formation of (Z)-enolate 3–, as shown by the forma-
tion of silyl ketene acetal (Z)-14 (cf. Scheme 5), which may exist
as a chelate as shown, or in an open form. The resulting amino
ester enolates (i.e., 3–) typically aggregate to form homodimers
28 or mixed aggregates with lithium amides (not shown). The
high diastereoselectivity is based on the large difference in the
steric demand of the 1-phenylethyl auxiliary in the transition
states 25 vs. 26, which effectively dictates the facial selectiv-
ity.[38]
Protonation of the resulting enolates (i.e., 3–) to give ꢀ-sub-
stituted ꢀ-amino esters 3 was used to determine the diastereo-
selectivity of the addition step and to synthesize substrates for
oxidative radical cyclizations (cf. Table 4).
Chelated (Z)-enolates (Z)-3– are easily oxidized by ferro-
cenium hexafluorophosphate 4 to give chelated α-carbonyl
radicals 29 (Scheme 8). According to very recent results, this
Scheme 8. Diastereoselectivity of the radical cyclization leading to pyrrol-
idines 6 and 7.
The diastereoselectivity of the radical cyclization can, in prin-
single-electron oxidation process can also be carried out cata- ciple, be explained by considering chelated and nonchelated
lytically in 4.[35] The resulting radicals can either remain che- radicals 29 and 30, respectively. Indeed, convincing evidence
lated or transform into open radicals 30. Alternatively, ꢀ-amino was previously provided that chelated radicals 29 cyclize, be-
esters 3 give (E)-enolates (E)-3– on deprotonation with LDA (cf. cause the tandem reactions starting from 1 and 2 gave the
Scheme 5). These enolates are also efficiently oxidized, but opposite diastereoselectivity to that obtained in the oxidative
should only form nonchelated radicals 30, since radicals with cyclizations starting from 3; this was attributed to the steric
an ester group in the α position have been shown to have a demand of the nitrogen-protecting group and the chelated (Z)-
significant rotational barrier, which should preserve the config- or nonchelated (E)-enolate geometry of enolates 3–.[24] How-
uration of the precursor under the very mild reaction condi- ever, with a 1-phenylethyl group at nitrogen, the acyclic radicals
tions.[39] Irrespective of the pathway by which they were gener- were found to cyclize with exclusive 2,3-trans and very similar
ated, radicals 29 and/or 30 undergo efficient 5-exo cyclization 3,4-cis diastereoselectivity, irrespective of whether the (Z)-enol-
to give diastereomeric radicals 32 and 33. The radical cycliza- ate resulting from conjugate addition or the (E)-enolate result-
tion must be very fast, since the formation of acyclic coupling ing from deprotonation of ꢀ-amino esters 3 by LDA was used
products 31, which is also fast,[40] does not compete under the (cf. Tables 3 and 4, and Scheme 4). This implies that chelated
reaction conditions. The introduction of the oxygen functional- radical 29, formed after SET oxidation, is probably destabilized
ity proceeds by a final coupling step with persistent radical by the bulk of the N-protecting group, and easily collapses to
TEMPO 5. Small amounts of ꢀ-amino esters 3 were recovered form open radical 30 to minimize strain. Therefore, the subse-
from some reactions. These products were probably formed quent cyclization proceeds via the same open Beckwith–Houk
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of amine 2a–2c (1.1 mmol) in dry THF (10 mL) at –78 °C. The reac-
tion mixture turned bright orange during the addition. After 30 min,
a solution of ester 1 (1.0 mmol) in dry THF (0.5–0.6 mL) was added
dropwise. The reaction was run until TLC indicated the complete
conversion of 1 (usually 30 min). TEMPO 5 (0.031 g, 0.2 mmol) was
added, followed by thoroughly mixed 4 (0.331 g, 1.0 mmol) and 5
(0.125 g, 0.8 mmol) in small portions. After the complete consump-
tion of 4, further portions of 4 (0.100–0.165 g, 0.3–0.5 mmol) were
added until the mixture stayed blue and inhomogeneous. The reac-
tion mixture was stirred at –78 °C for 40–60 min, then it was
quenched with saturated NH4Cl solution (4 drops). The mixture was
warmed to room temp., diluted with diethyl ether, and filtered
through a pad of silica gel. Evaporation of the filtrate gave an or-
ange inhomogeneous residue, which was adsorbed at silica gel, and
purified by flash chromatography.
transition state for both starting enolate geometries
(Scheme 8).[41]
For derivatives with R3 = R4 = H, chair-31, in which the sub-
stituent in the 2-position and the ester group are in an anti
arrangement, is more populated; this leads predominantly to
cyclic radical 32, which couples with excess TEMPO 5 to give
2,3-trans-3,4-cis pyrrolidines 6. The minor diastereomers must
result from a cyclization via boat transition state boat-30, since
the same relative 1,2,3-orientation is found in 2,3-trans-3,4-
trans-pyrrolidines 7. In derivatives bearing methyl substituents
at the N-allyl unit, the cyclization transition states chair-30 and
boat-30 have apparently similar energies, thus giving almost
equal amounts of 6 and 7 after 5-exo radical cyclization and
coupling with 5.
N,2,3,4-Tetrasubstituted Pyrrolidine-3-carboxylates 6 and
Through Oxidative Radical 5-exo Cyclizations of ꢀ-Amino Ester
Enolates (General Procedure): n-Butyllithium (1.6 in hexanes;
7
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Conclusions
0.78 mL, 1.25 mmol) was added dropwise to a stirred solution of
dry diisopropylamine (0.18 mL, 1.25 mmol) in anhydrous DME or
THF (10 mL; see Table 4) at –78 °C. After 20–30 min, a solution of
ꢀ-amino ester 3a–3h (1.0 mmol) in dry solvent (0.6 mL) was added
dropwise. After 30 min, 5 (0.031 g, 0.2 mmol) was added as a solid.
Subsequently a thoroughly homogenized mixture of 5 (0.125 g,
0.8 mmol) and 4 (0.331 g, 1.0 mmol) was added in small portions
with vigorous stirring at –78 °C. Since discoloration of 4 still oc-
curred, further 4 (0.10–0.15 g) was added in small portions, until a
dark blue-green color persisted in the reaction mixture for 60 min.
The reaction mixture was then quenched with saturated NH4Cl solu-
tion (4 drops). The mixture was diluted with diethyl ether, and fil-
tered through a pad of silica gel. The filtrate was evaporated, and
the crude heterogeneous mixture was adsorbed at silica gel, and
purified by flash chromatography.
Enantioselective tandem aza-Michael addition/radical cycliza-
tion sequences using allylic lithium amides and α,ꢀ-unsaturated
esters gave N,2,3,4-tetrasubstituted pyrrolidines 6 and 7 in up
to 78 % yield with up to 6:1 3,4-cis/3,4-trans diastereoselectivity.
Single-electron transfer (SET) oxidation allowed facile lithium
amide conjugate additions and 5-exo radical cyclizations to be
combined. Ferrocenium hexafluorophosphate was used as a
mild, nontoxic SET oxidant that is easy to prepare, easy to han-
dle, and can be stored under ambient conditions. The tandem
sequence leads to the formation of C–N, C–C, and C–O bonds,
including three contiguous stereogenic centers, in a simple
one-pot procedure. Exclusive 2,3-trans diastereoselectivity was
observed in all the cyclization reactions. Pyrrolidines bearing an
additional exocyclic stereogenic center can be synthesized us-
ing lithium (E)-but-2-en-1-ylamide 2c–. Oxidative radical cycliza-
tions of ꢀ-amino esters 3 are an alternative to the tandem con-
jugate addition/radical cyclization sequences, especially for
such cases where an aza-Michael addition may not be the
method of choice for their preparation.
The reactivity of the pyrrolidines was briefly investigated. Re-
ductive cleavage of the N–O bond of the alkoxyamine unit was
successfully carried out; this helped to separate diastereomeric
mixtures of pyrrolidines into enantiomerically pure lactones 16
and trans-hydroxyalkyl pyrrolidines 17. The nitrogen-protecting
group was removed, and the ester and alcohol groups could be
selectively manipulated. Some of the derivatives showed prom-
ising activities against the HCV virus.
General Procedure for the Reductive N–O Bond Cleavage of
N,2,3,4-Tetrasubstituted Pyrrolidines 6 and 7: A diastereomeric
mixture of 6 and 7 was dissolved in acetic acid (typically 6 mL/
mmol of substrate), and water (2 mL/mmol of substrate) was added.
THF was added dropwise to the resulting turbid solution until it
became clear. Zinc dust (10 μm; 50 mmol/mmol of substrate) was
added portionwise with vigorous stirring, and then the resulting
mixture was heated at 85–95 °C until TLC indicated that the starting
material had been consumed. The reaction mixture was cooled to
room temperature, diluted with CH2Cl2 to three times its volume,
and filtered. The filtrate was neutralized with saturated K2CO3 solu-
tion to a pH of ca. 10. The layers were separated, and the organic
phase was washed twice with water, dried with MgSO4, and evapo-
rated. The crude product was purified by flash chromatography to
give lactones 16, followed by trans-4-hydroxyalkyl-pyrrolidines 17.
This tandem anionic/radical approach is currently being ex-
panded to allow the synthesis of pentasubstituted pyrrolidines,
and spiro- and bicyclic compounds containing pyrrolidine units.
We are also working on synthetic approaches to alkaloids and
their analogs containing these structural units; the antiviral ac-
tivities of these target compounds will be investigated.
Acknowledgments
Generous financial support from the Institute of Organic Chem-
istry and Biochemistry, Czech Academy of Sciences (RVO:
613889633), the Grant Agency of the Czech Republic (13-
40188S), the COST action CM1201, “Biomimetic Radical Chemis-
try”, and the Gilead Sciences & IOCB Research Center is grate-
fully acknowledged. I. C. thanks the Ministry of Education,
Youth, and Sports of the Czech Republic (MSM0021620857) for
financial support. The authors thank Mgr. Denisa Hidasová for
carrying out the aza-Michael reaction of 9 in the presence of
Experimental Section
N,2,3,4-Tetrasubstituted Pyrrolidine-3-carboxylates 6 and
Through Tandem Aza-Michael Additions/Oxidative Radical 5-
exo Cyclizations (General Procedure): n-Butyllithium (1.6 in hex-
anes; 0.69 mL, 1.1 mmol) was added dropwise to a stirred solution LiCl.
7
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[21] a) P. R. Jagtap, L. Ford, E. Deister, R. Pohl, I. Císařová, J. Hodek, J. Weber,
R. Mackman, G. Bahador, U. Jahn, Chem. Eur. J. 2014, 20, 10298–10304;
b) M. Holan, R. Pohl, I. Císařová, B. Klepetářová, P. G. Jones, U. Jahn, Chem.
Eur. J. 2015, 21, 9877–9888; c) U. Jahn, Chem. Commun. 2001, 1600–
1601.
Keywords: Tandem reactions · Nitrogen heterocycles ·
Michael addition · Radical reactions · Cyclization · Enolates
[22] a) U. Jahn, E. Dinca, Chem. Eur. J. 2009, 15, 58–62; b) U. Jahn, E. Dinca,
J. Org. Chem. 2010, 75, 4480–4491; c) U. Jahn, J.-M. Galano, T. Durand,
Angew. Chem. Int. Ed. 2008, 47, 5894–5955; Angew. Chem. 2008, 120,
5978–6041; d) E. Jahn, T. Durand, J.-M. Galano, U. Jahn, Chem. Listy 2014,
108, 301–319.
[1] a) D. O'Hagan, Nat. Prod. Rep. 2000, 17, 435–446; b) D. O'Hagan, Nat.
Prod. Rep. 1997, 14, 637–651.
[2] A. F. Parsons, Tetrahedron 1996, 52, 4149–4174.
[3] S. Takeuchi, M. Ishibashi, J. Kobayashi, J. Org. Chem. 1994, 59, 3712–3713.
[4] C. L. J. Wang, J. C. Calabrese, J. Org. Chem. 1991, 56, 4341–4343.
[5] Y. Tsuda, S. Hosoi, N. Katagiri, C. Kaneko, T. Sano, Chem. Pharm. Bull.
1993, 41, 2087–2095.
[23] J. Xu, E. J. E. Caro-Diaz, M. H. Lacoske, C.-I. Hung, C. Jamora, E. A. Theodor-
akis, Chem. Sci. 2012, 3, 3378–3386.
[24] U. Jahn, M. Müller, S. Aussieker, J. Am. Chem. Soc. 2000, 122, 5212–5213.
[25] a) S. G. Davies, O. Ichihara, I. A. S. Walters, J. Chem. Soc. Perkin Trans. 1
1994, 1141–1147; Reviews: b) S. G. Davies, A. D. Smith, P. D. Price, Tetra-
hedron: Asymmetry 2005, 16, 2833–2891; c) S. G. Davies, A. M. Fletcher,
P. M. Roberts, J. E. Thomson, Tetrahedron: Asymmetry 2012, 23, 1111–
1153.
[26] a) S. G. Davies, J. A. Lee, P. M. Roberts, J. P. Stonehouse, J. E. Thomson, J.
Org. Chem. 2012, 77, 7028–7045; b) S. G. Davies, A. M. Fletcher, P. M.
Roberts, A. D. Smith, Tetrahedron 2009, 65, 10192–10213; c) E. A. Brock,
S. G. Davies, J. A. Lee, P. M. Roberts, J. E. Thomson, Org. Lett. 2011, 13,
1594–1597.
[27] S. A. Bentley, S. G. Davies, J. A. Lee, P. M. Roberts, J. E. Thomson, Org.
Lett. 2011, 13, 2544–2547.
[28] V. Kapras, R. Pohl, I. Císařová, U. Jahn, Org. Lett. 2014, 16, 1088–1091.
[29] S. Z. Zard, Chem. Soc. Rev. 2008, 37, 1603–1618.
[30] W. Kong, N. Fuentes, A. García-Domínguez, E. Merino, C. Nevado, Angew.
Chem. Int. Ed. 2015, 54, 2487–2491; Angew. Chem. 2015, 127, 2517–2521.
[31] P. Karoyan, G. Chassaing, Tetrahedron Lett. 1997, 38, 85–88.
[32] G. Q. Wei, J. M. Chalker, T. Cohen, J. Org. Chem. 2011, 76, 7912–7917.
[33] a) S. G. Davies, D. R. Fenwick, J. Chem. Soc. Chem. Commun. 1995, 1109–
1110; b) S. G. Davies, E. M. Foster, C. R. McIntosh, P. M. Roberts, T. E.
Rosser, A. D. Smith, J. E. Thomson, Tetrahedron: Asymmetry 2011, 22,
1035–1050.
[34] Y. Ma, A. C. Hoepker, L. Gupta, M. F. Faggin, D. B. Collum, J. Am. Chem.
Soc. 2010, 132, 15610–15623.
[35] F. Kafka, M. Holan, D. Hidasová, R. Pohl, I. Císařová, B. Klepetářová, U.
Jahn, Angew. Chem. Int. Ed. 2014, 53, 9944–9948; Angew. Chem. 2014,
126, 10102–10106.
[36] a) T. D. W. Claridge, S. G. Davies, D. Kruchinin, B. Odell, P. M. Roberts, A. J.
Russell, J. E. Thomson, S. M. Toms, Tetrahedron: Asymmetry 2013, 24, 947–
952; for general reviews, see: b) H. J. Reich, Chem. Rev. 2013, 113, 7130–
7178; c) R. E. Mulvey, S. D. Robertson, Angew. Chem. Int. Ed. 2013, 52,
11470–11487; Angew. Chem. 2013, 125, 11682–11700.
[37] U. Jahn, F. Kafka, R. Pohl, P. G. Jones, Tetrahedron 2009, 65, 10917–10929.
[38] J. F. Costello, S. G. Davies, O. Ichihara, Tetrahedron: Asymmetry 1994, 5,
1999–2008.
[39] W. Lung-min, H. Fischer, Helv. Chim. Acta 1983, 66, 138–147.
[40] a) J. Sobek, R. Martschke, H. Fischer, J. Am. Chem. Soc. 2001, 123, 2849–
2857; b) W. G. Skene, J. C. Scaiano, N. A. Listigovers, P. M. Kazmaier, M. K.
Georges, Macromolecules 2000, 33, 5065–5072; c) U. Jahn, J. Org. Chem.
1998, 63, 7130–7131; d) E. Dinca, P. Hartmann, J. Smrček, I. Dix, P. G.
Jones, U. Jahn, Eur. J. Org. Chem. 2012, 4461–4482.
[6] K. J. Frankowski, J. E. Golden, Y. Zeng, Y. Lei, J. Aubé, J. Am. Chem. Soc.
2008, 130, 6018–6024.
[7] a) A. Trapero, A. Llebaria, J. Med. Chem. 2012, 55, 10345–10346; b) P.
Angelov, Y. K. S. Chau, P. J. Fryer, M. G. Moloney, A. L. Thompson, P. C.
Trippier, Org. Biomol. Chem. 2012, 10, 3472–3485; c) U. Iserloh, Y. Wu,
J. N. Cumming, J. Pan, L. Y. Wang, A. W. Stamford, M. E. Kennedy, R.
Kuvelkar, X. Chen, E. M. Parker, C. Strickland, J. Voigt, Bioorg. Med. Chem.
Lett. 2008, 18, 414–417; d) A. Blum, J. Böttcher, A. Heine, G. Klebe, W. E.
Diederich, J. Med. Chem. 2008, 51, 2078–2087; e) G. T. Wang, Y. Chen, S.
Wang, R. Gentles, T. Sowin, W. Kati, S. Muchmore, V. Giranda, K. Stewart,
H. Sham, D. Kempf, W. G. Laver, J. Med. Chem. 2001, 44, 1192–1201.
[8] a) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173–180; b) D. J. Hill, M. J.
Mio, R. B. Prince, T. S. Hughes, J. S. Moore, Chem. Rev. 2001, 101, 3893–
4012.
[9] a) K. C. Majumdar, G. V. Karunakar, B. Sinha, Synthesis 2012, 44, 2475–
2505; b) B. B. Touré, D. G. Hall, Chem. Rev. 2009, 109, 4439–4486; c) H.
Pellissier, Chem. Rev. 2013, 113, 442–524; d) H. Huang, P. Xie, in: Stereose-
lective Multiple Bond-Forming Transformations in Organic Synthesis (Eds.:
J. Rodriguez, D. Bonne), Wiley, Hoboken, 2015, p. 9–44.
[10] a) U. Jahn, Top. Curr. Chem. 2012, 320, 121–189; b) U. Jahn, Top. Curr.
Chem. 2012, 320, 191–322; c) U. Jahn, Top. Curr. Chem. 2012, 320, 323–
451.
[11] J. A. Murphy, Pure Appl. Chem. 2000, 72, 1327–1334.
[12] a) L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic
Synthesis, Wiley-VCH, 2006, p. 219–279; b) J. A. Murphy, in: Encyclopedia
of Radicals in Chemistry, Biology and Materials, vol. 2 (Eds.: C. Chatgilialo-
glu, A. Studer), Wiley, Hoboken, 2012, p. 817–847.
[13] M. Albert, L. Fensterbank, E. Lacôte, M. Malacria, Top. Curr. Chem. 2006,
264, 1–62.
[14] J. W. Burton, in: Encyclopedia of Radicals in Chemistry, Biology and Materi-
als, vol. 2 (Eds.: C. Chatgilialoglu, A. Studer), Wiley, Hoboken, 2012, p.
901–941.
[15] A. S. Demir, M. Emrullahoglu, Curr. Org. Synth. 2007, 4, 323–351.
[16] a) K. C. Nicolaou, P. S. Baran, Y. L. Zhong, S. Barluenga, K. W. Hunt, R.
Kranich, J. A. Vega, J. Am. Chem. Soc. 2002, 124, 2233–2244; b) B. Janza,
A. Studer, J. Org. Chem. 2005, 70, 6991–6994; c) P. Patil, A. Nimonkar,
K. G. Akamanchi, J. Org. Chem. 2014, 79, 2331–2336.
[17] a) E. Jahn, U. Jahn, Angew. Chem. Int. Ed. 2014, 53, 13326–13328; Angew.
Chem. 2014, 126, 13542–13544; b) N. Hoffmann, ChemSusChem 2012, 5,
352–371; c) C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013,
113, 5322–5363.
[18] Š. Toma, R. Šebesta, Synthesis 2015, 47, 1683–1695.
[19] D. A. Khobragade, S. G. Mahamulkar, L. Pospíšil, I. Císařová, L. Rulíšek, U.
Jahn, Chem. Eur. J. 2012, 18, 12267–12277.
[41] a) A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985, 41, 3925–3941; b)
D. C. Spellmeyer, K. N. Houk, J. Org. Chem. 1987, 52, 959–974.
[20] a) U. Jahn, D. Rudakov, Synlett 2004, 1207–1210; b) U. Jahn, D. Rudakov,
Org. Lett. 2006, 8, 4481–4484; c) U. Jahn, D. Rudakov, P. G. Jones, Tetrahe-
dron 2012, 68, 1521–1539.
Received: May 14, 2016
Published Online: ■
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Tandem Reactions
F. Kafka, R. Pohl, I. Císařová,
R. Mackman, G. Bahador,
U. Jahn* ............................................. 1–11
N,2,3,4-Tetrasubstituted
Pyrrolid-
ines through Tandem Lithium Am-
ide Conjugate Addition/Radical Cy-
clization/Oxygenation Reactions
Readily available chiral allylic amines to 6:1 3,4-cis/trans configuration in a
and α,ꢀ-unsaturated esters are used to tandem polar lithium amide conjugate
synthesize densely substituted pyrrol- addition/radical cyclization/oxygena-
idines with exclusive 2,3-trans and up tion sequence.
DOI: 10.1002/ejoc.201600621
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