Синтез фторованих похідних піролізидину, індолізидину та хінолізидину
This review provides literature data dealing with the synthesis of fluorinated pyrrolizidines, indolizidines, and quinolizidines. Synthesis of trifluoromethylated derivatives requires to use of commercially available building blocks bearing pre-installed trifluoromethyl group or synthetic trifluorom...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2022
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Ukrainica Bioorganica Acta| _version_ | 1871193541568364544 |
|---|---|
| author | Klipkov, Anton A. Gerus, Igor I. Sorochinsky, Alexander E. |
| author_facet | Klipkov, Anton A. Gerus, Igor I. Sorochinsky, Alexander E. |
| author_institution_txt_mv | [
{
"author": "Anton A. Klipkov",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Igor I. Gerus",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Alexander E. Sorochinsky",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
}
] |
| author_sort | Klipkov, Anton A. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:52Z |
| description | This review provides literature data dealing with the synthesis of fluorinated pyrrolizidines, indolizidines, and quinolizidines. Synthesis of trifluoromethylated derivatives requires to use of commercially available building blocks bearing pre-installed trifluoromethyl group or synthetic trifluoromethylated templates incorporating a chiral auxiliary as starting materials. On the other hand, nucleophilic or radical difluoromethylation followed by cyclization reactions using different types of stable and readily available difluoromethylating agents was established as an efficient approach for the synthesis of difluoromethylenated pyrrolizidines, indolizidines, and quinolizidines. Furthermore, a new possibility to synthesize monofluorinated quinolizidines opens the reaction of α-trifluoromethyl alkenes and dihydroisoquinoline acetic acids using visible light photocatalysis. Generality and limitations of these methods are discussed. |
| doi_str_mv | 10.15407/bioorganica2022.01.022 |
| first_indexed | 2025-07-17T12:19:23Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
UDC 547.321/.74/.94
DOI: https://doi.org/10.15407/bioorganica2022.01.022
22
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
REVIEW
Synthesis of fluorinated pyrrolizidine, indolizidine and quinolizidine
derivatives
Anton A. Klipkov1,2, Igor I. Gerus1*, Alexander E. Sorochinsky1
1 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
2 National University of “Kyiv-Mohyla Academy”, 2 Skovoroda St., Kyiv, 04070, Ukraine
Abstract: This review provides literature data dealing with the synthesis of fluorinated pyrrolizidines, indolizidines, and quinolizidines.
Synthesis of trifluoromethylated derivatives requires to use of commercially available building blocks bearing pre-installed trifluoromethyl
group or synthetic trifluoromethylated templates incorporating a chiral auxiliary as starting materials. On the other hand, nucleophilic or
radical difluoromethylation followed by cyclization reactions using different types of stable and readily available difluoromethylating
agents was established as an efficient approach for the synthesis of difluoromethylenated pyrrolizidines, indolizidines, and quinolizidines.
Furthermore, a new possibility to synthesize monofluorinated quinolizidines opens the reaction of α-trifluoromethyl alkenes and
dihydroisoquinoline acetic acids using visible light photocatalysis. Generality and limitations of these methods are discussed.
Keywords: fluorine; pyrrolizidine; indolizidine; quinolizidine alkaloids; synthetic strategies.
Introduction
Pyrrolizidine, indolizidine, and quinolizidine alkaloids
constitute a significant group of naturally occurring
alkaloids commonly found in plants, microorganisms,
insects, or animals that can be identifiable by two fused
aliphatic rings with nitrogen atoms located at a bridgehead
position (Figure 1) [1]. This group of 1-azabicycloalkanes
has attracted much attention as synthetic targets because of
their structural diversity and wide range of bioactivities
including, but not limited to, anti-bacterial, antiviral, anti-
tumor, or anti-inflammatory properties [2]. Furthermore,
polyhydroxylated pyrrolizidine, indolizidine, and quino-
lizidine alkaloids are interesting compounds as potential
glycosidases inhibitors [3]. The high toxicity of pyrro-
lizidine, indolizidine, and quinolizidine alkaloids allows
their application in agriculture as natural insecticides [4].
Pyrrolisidine alkaloid heliotridane, indolizidine alkaloid
monomorine, and quinolizidine alkaloid epilupinine are
Received:
Revised:
Accepted:
Published online:
25.03.2022
08.04.2022
20.04.2022
30.06.2022
Corresponding author. Tel.: +380-50-722-5815;
e-mail: igerus@hotmail.com (I. I. Gerus)
ORCID: 0000-0001-5086-9466
N
CH3H
Heliotridane
N
N
1-azabicyclo[3.3.0]octane
Pyrrolizidine
Indolizidine
1-azabicyclo[4.3.0]nonane
N
H
CH3
Bu
Monomorine
N
1-azabicyclo[4.4.0]decane
N
H
OH
EpilupinineQuinolizidine
Figure 1. The bicyclic structures and examples for pyrrolizidine,
indolizidine, and quinolizidine alkaloids.
some of the simplest examples of this group of alkaloids
(Figure 1).
© Klipkov A. A. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
mailto:igerus@hotmail.com
https://orcid.org/0000-0001-6167-076X
A. A. Klipkov, I. I. Gerus, A. E. Sorochinsky
23
The introduction of a fluorine atom or fluorine-
containing group into the alkaloid related saturated
N-heterocycles could simultaneously alter metabolic
stability, lipophilicity, and bioavailability as well as restrict
conformations as compared to parent molecules [5].
Fluorine substitution generally reduces the basicity of the
cyclic amines so that they can exist in the neutral form at
the biological pH. Combination of these physicochemical
properties is brought about by fundamental physical
characteristics of fluorine atom (high electronegativity,
relatively small size, low polarizability, high strength of the
C−F bond) which induce maximum alteration in
electrostatic charge distribution, but with minimal changes
in molecular size and shape. Due to the high polarity, the
C–F bond has been used as isosteric and isopolar
replacement for the hydroxy groups in biologically relevant
compounds while the difluoromethylene group is
considered as isosteric and isopolar replacement for
carbonyl and ether groups [6]. At the same time,
trifluoromethyl group is commonly used as isosteric
replacement for ethyl or isopropyl group in addition to its
high electronegativity (inductive sigma constant of +0.42)
and lipophilicity (Hansch parameter of +0.88) [7], which
enhance the metabolic stability and increase the
lipophilicity and membrane permeability of bioactive
molecule compared with the nonfluorinated parent
compound. Currently, there are several traditional and
modern methods for the construction of fluoro-
functionalized pyrrolizidine, indolizidine, and quinolizidine
derivatives including 1,3-dipolar cycloaddition of
azomethine ylides to electrophilic olefins, intramolecular
reductive amination, intramolecular radical cyclization,
construction of appropriate aliphatic ring starting from
pyrroles and selective defluorination of trifluoromethyl
compounds. However, analysis of the relevant literature
indicated that the synthesis of fluorinated pyrrolizidine,
indolizidine, and quinolizidine derivatives has never been
reviewed. Only difluoromethylenated pyrrolizidines and
indolizidines have received attention as sub-subject within
recent review dedicated to the synthetic application of
α,α-difluoro-α-phenylsulfanyl-α-trimethylsilylmethane as a
useful reagent for constructing difluoromethylenated
compounds [8]. Therefore, the aim of the present review is
to provide consideration of synthetic methods used to
prepare fluorinated pyrrolizidine, indolizidine, and
quinolizidine derivatives including their polycyclic and
unsaturated analogues with a particular emphasis on regio-
and stereoselective synthesis. The collected literature may
offer solutions for developing of methodology to access
fluorinated alkaloids of biological interest.
1. Trifluoromethylated pyrrolizidines, indolizidines
and quinolizidines
The known methods for direct trifluoromethylation of
organic compounds [9] were not used for the transfer of the
trifluoromethyl group from a reagent into the desired
position of pyrrolisidines, indolysidines, and quinolizidines.
Therefore, trifluoromethylated 1-azabicycloalkanes have
been synthesized starting from available trifluoromethyl-
containing compounds using established chemical reactions.
For example, the 1,3-dipolar cycloaddition of azomethine
ylides to electrophilic olefins has been described as an
efficient and simple methodology for the synthesis of
trifluoromethylated pyrrolizidines. When trifluorothio-
acetamide 1 was alkylated with a slight excess of methyl
triflate, the corresponding trifluoromethyl thioamidium salt
2 was formed (Scheme 1) [10].
Scheme 1. Diastereoselective 1,3-dipolar cycloadditions of azomethine ylide derived from trifluorothioacetamide 1 to electrophilic olefins.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
24
TfOH, THF
N
H CO2Me
9
CF3
NaBH4
THF, 0 oC N
H CO2Me
CF3
H
10 79%
H3B
1. H3O+
2. OH- N
H CO2Me
CF3H
11 55%
N
H R
CF3MeS
3a, 4a
m-CPBA
CH2Cl2
N
H R
OHF3C
12 R = CO2Me 84%
13 R = CN 44%
3a
3a, 4a
Scheme 2. Reduction and hydrolysis of the thioaminals 3a and 4a.
Table 1. 1,3-Dipolar cycloaddition with β-trifluoromethyl acrylamide 14 and azomethine ylides 17 generated from L-proline
and aldehydes.
N
H
CO2H
H R
O
+ F3C N
O
O
+
N
H
R
CF3
minor
N
CF3H
R
N
O
O
major
+
N
O
O
14
15 16
DMSO
80 oC
N
H R
anti-17
N
R H
syn-17
Entry R Combined isolated yields (%) Ratio 15:16
1 C6H5 66 4.4:1
2 4-Me-C6H4 78 4.7:1
3 4-MeO-C6H4 82 4.7:1
4 3-MeO-C6H4 62 3.9:1
5 2-MeO-C6H4 81 5.9:1
6 4-F-C6H4 68 3.5:1
7 4-Cl-C6H4 54 2.9:1
8 1-naphthyl 72 5.8:1
9 2-naphthyl 76 4.8:1
10 (Me)2CHCH2 66 1.6:1
Deprotonation of thioamidium salt 2 by non-nucleophilic
base such DBU at low temperature generated
trifluoromethyl azomethine ylide 8 which underwent
cycloaddition to electron-deficient olefins allowing one-pot
access to thioaminals 3-5 with high diastereoselectivity. The
analogous cycloaddition to N-methyl- and N-phenyl-
maleimides as dipolarophiles led to tricyclic derivatives 6
and 7 respectively with a lower diastereomeric ratio. The
structure and the stereochemistry of the cycloadducts 3-7
were assigned based on their 1H, 13C and 19F NMR spectra
as well as X-ray analysis. The stereochemical outcome
could be rationalized by endo dipolarophile addition to a
more stable anti-form of trifluoromethyl azomethine ylide
8.
The resulting thioaminals 3-5 were useful intermediates
for further transformation into trifluoromethylated
pyrrolizidine derivatives. Treatment of thioaminal 3a with
A. A. Klipkov, I. I. Gerus, A. E. Sorochinsky
25
triflic acid and subsequent reaction of intermediate iminium
salt 9 with NaBH4 gave rise to aminoborane 10 which was
purified either by chromatography or by distillation
(Scheme 2). The stereochemical outcome was explained by
hydride attack on iminium salt 9 from a less sterically
hindered face of the bicyclic system. Deprotection of
aminoborane 10 with acid followed by basic work-up
afforded free base 11 in 55% yield. Hydrolysis of
thioaminals 3a and 4a with m-chloro-perbenzoic acid
afforded hemiaminals 12 and 13 as thermodynamically
preferred diastereomers. These hemiaminals 12 and 13 were
stable at room temperature due to the electron-withdrawing
effect of the trifluoromethyl group. X-Ray crystal structure
analysis confirms the stereochemistry of 12 and shows the
existence of intramolecular hydrogen bonds between the
hydroxyl and ester groups.
Trifluoromethylated pyrrolizidines were also prepared by
using the intermolecular 1,3-dipolar cycloaddition of non-
fluorinated azomethine ylides 17 decarboxylatively
generated from L-proline and aromatic or aliphatic
aldehydes with β-trifluoromethyl acrylamide 14 (Table 1)
[11]. The 1,3-dipolar cycloaddition was performed in
DMSO at 80 °C, affording a mixture of trifluoromethylated
pyrrolizidines 15 and 16 with moderate regioselectivity (up
to 6/1) and excellent diastereoselectivity of each
regioisomer (>20/1) in 54-82% combined isolated yields.
According to DFT calculations, anti-form of azomethine
ylides 17 was more stable than syn-form. Regio- as well as
diastereoselectivities of the 1,3-dipolar cycloaddition with
anti-form of azomethine ylide 17 were determined by steric
effects and electrostatic interactions in the transition states.
The structures of 15 and 16 were assigned based on 1H-,
19F-, 13C NMR, COSY, and NOESY analyses.
A one-pot three-component reaction of azomethine ylide
generated in situ from proline and ninhydrin 19 with
(E)-3,3,3-trifluoro-1-nitropropene 18 occurred in benzene at
35 °C to give a mixture of two regioisomers 22a and 22b in
ratio 84:16 with trans-configuration of the CF3 and NO2
groups (Scheme 3) [12]. A similar reaction of (E)-3,3,3-
trifluoro-1-nitropropene 18 with azomethine ylide derived
from indenoquinoxalinone 20 and proline in isopropanol at
45 °C gave a mixture of spirocycloadducts 23a and 23b
with higher regioselectivity (96:4). In the case of
indenoquinoxalinone 21 as carbonyl component exclusively
endo-isomer of spiropyrrolizidine 24 was obtained. The
major spirocycloadducts 22-24 were formed as a result of
endo addition (with respect to NO2) of azomethine ylide to
the most electrophilic β-C atom of the dipolarophile in high
yields (86-94%). The structure of cycloadducts 22-24 was
established by NMR spectroscopy and X-ray diffraction
analysis.
Scheme 3. Reaction of (E)-3,3,3-trifluoro-1-nitropropene 18 with azomethine ylides derived from ninhydrin 19 indenoquinoxalinones
20, 21 and proline.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
26
N OF3C
O O
+
H
N
(R,R)-26 (22 mol%)
Zn(NTf2)2 (20%)
N OF3C
O O
NH
O
N
OO
N
Ph Ph
(R,R)-26
4A MS, CH2Cl2, -60 oC
OHF3C
O
NH
H2 (10 atm)
5% Rh-Al2O3
EtOH, rt
NO
O
P O
3
N
CF3
O
H
N
CF3HNEt3, MeCN
reflux LiAlH4, Et2O
reflux N
CF3H
H
NO2
O
O2N NO2
Picric acid
Et2O, rt
25
27
97%, 98% ee
29
dr 10:1
syn-32
54%
33
35%
OHF3C
O
NH
28
80%
1) 1N NaOH
THF, rt
2) 1N HCl. rt
syn-31
dr 5:1
30% total
yield from 28
30
Scheme 4. Synthesis of trifluorinated heliotridane picrate 33.
The catalytic asymmetric Friedel-Crafts alkylation of
unprotected pyrrole with β-trifluoromethylated acrylate 25
followed by the reduction of the heteroaromatic molecule
provided the stereoselective route to trifluoromethylated
pyrrolizidine derivative 32 (Scheme 4) [13]. The interest in
the synthesis of 32 was driven by the pharmacological
properties of parent pyrrolizidine alkaloid heliotridane [2b].
The Friedel-Crafts alkylation works most efficiently under
catalysis formed by Zn(NTf2)2 and bisoxazoline (R,R)-26 in
CH2Cl2 at the low reaction temperature to afford pyrrole
derivative 27 with an excellent level of enantioselectivity
and in nearly quantitative yield. Friedel-Crafts adduct 27
after transformation into β-trifluoromethylated carboxylic
acid 28 and rhodium-catalyzed hydrogenation of pyrrole
moiety gave rise to 2-pyrrolidine carboxylic acid 29.
Phosphine oxide 30 was shown to be effective reagent for
the lactamization of 2-pyrrolidine carboxylic acid 29 into
trifluoromethylated hexahydropyrrolizin-3-one 31 with
moderate diastereoselectivity. In particular, phosphine
oxide 30 was superior to other commonly used dehydrating
agents. The major isomer syn-31 was separated by column
chromatography and its structure was proved by 2D 1H
NMR (1H-1H COSY) and 19F NMR spectra. Lithium
aluminium hydride deoxygenation of syn-31 provided
access to trifluorinated heliotridane analogue syn-32, which
was finally isolated as a picrate 33.
The stereoselective synthetic approaches to
trifluoromethylated indolizidine derivatives were based on
intramolecular reductive amination reactions. For example,
the first synthesis of non-racemic trifluoro analogue 40 of
the well-known alkaloid monomorine [1a] has been
achieved starting from chiral bicyclic lactam 35 which
could be easily prepared by cyclocondensation of the
(S)-phenylglycinol with 6,6,6-trifluoro-5-oxohexanoic 34 in
the presence of p-toluenesulfonic acid (Scheme 5) [14]. The
reaction of the bicyclic lactam 35 with N-(5-chloro-2-
pyridinyl)triflimide promoted by potassium
bis(trimethylsilyl)amide gave triflate 36 in excellent yield.
The coupling of triflate 36 with 1-heptyne-3-ol using
PdCl2(PPh3)2 and CuI as catalysts afforded enamine 37 in
65% yield. The endo facial hydrogenation of enamine 37
over PtO2 in toluene afforded the oxazoline-protected
piperidine 38 which underwent Dess-Martin periodinane
oxidation to carbonyl precursor 39 in 91% yield and >98%
enantiomeric purity according to chiral HPLC. One-pot
reductive removal of the chiral auxiliary and the following
reductive amination of the deprotected piperidine
intermediate afforded trifluorinated analogue of
monomorine 40 with the appropriate arrangement of chiral
centers adjacent to the nitrogen atom in 62% yield after
purification.
Indolizidines bearing a trifluoromethyl group have also
been obtained from enantiopure aminoketal 41 as starting
material (Scheme 6) [15]. Intramolecular Mannich reaction
of aminoketal 41 with ethyl (E)-oxobutenoate under acidic
conditions afforded cyclization product 42 in good
diastereoselectivity (de 85%). The disubstituted piperidine
42 was isolated in 68% yield and high enantiopurity.
Reduction of 42 using an excess of diisobutylaluminum
hydride at low temperature led to allylic alcohol 43 in 90%
yield. Allylic alcohol 43 was subsequently converted into
aldehyde 44 by MnO2 mediated oxidation. Catalytic
hydrogenation of 44 at room temperature in ethanol then
produced in situ the corresponding iminium intermediate
which was further reduced to give trifluoromethylated
indolizidine 45. At the same time reaction of aldehyde 44
with methyl magnesium bromide at -78 °C in tetra-
hydrofuran led to a mixture of epimers 46 in 71% yield
A. A. Klipkov, I. I. Gerus, A. E. Sorochinsky
27
Scheme 5. Stereoselective synthesis of trifluorinated monomorine 40.
that was oxidized with MnO2 to corresponding enone 47.
Palladium hydroxide catalyzed hydrogenation of 47
afforded, highly stereoselectively according to GC/MS and
1H NMR analysis of crude reaction mixture,
trifluoromethylated indolizidine 48. Applying the same
reaction sequence with butyl magnesium chloride trifluoro
derivative of natural alkaloid monomorine 51 was obtained
via intermediates 49 and 50 also in a highly stereoselective
manner.
Synthesis of indolizidine derivatives bearing a
trifluoromethyl group at the bridgehead carbon adjacent to
nitrogen was achieved by intramolecular cyclization of
trifluoromethyl dihydropyridinones containing an orto-
iodobenzoyl and haloalkyl side-chains under free-radical
conditions. For this purpose, 6,6,6-trifluoro-5-oxohexanoic
52 was first converted into a mixture of corresponding acyl
azide 53 and azido lactone 54 in ratio 1:1 (Scheme 7) [16].
Then the thermally unstable acyl azide 53 without isolation
underwent Staudinger/aza-Wittig reaction with PPh3 or
PBu3 to give cyclic acyl imine 55. The reactive cyclic acyl
imine 55 was isolated only as adduct 56 with methanol in
low 9% yield. When the reaction was conducted in benzene
without any nucleophile cyclic acyl imine 55 isomerized to
the enamide form 57.
N-Iodobenzoylation and N-haloalkylation of enamide 57
deprotonated with sodium hydride in THF gave
o-iodobenzoyl derivative 58a and haloalkyl products 58b-e
which were an efficient intermediate for the synthesis of
trifluoromethylated indolizidinone and quinolizidine
derivatives (Table 2). The radical cyclization of products 58
promoted with tributyltin hydride (SnBu3H) and a catalytic
amount of azobisisobutyronitrile (AIBN) gave
corresponding indolizidinone derivatives 59 in high yields.
It is worthy note that both (E)- and (Z)-3-bromoallyl
derivatives 58c isolated as pure isomers afforded the
cyclization product 59c in the same yield. The radical
cyclization also proved effective in the synthesis of
quinolizidinone 59e although with lower yield than that of
other cyclized products.
Finally, selective reduction of cyclic products 59a,b,d by
BH3/THF complex at room temperature afforded
corresponding trifluoromethylated indolizidine derivatives
60 and 61 in 86-93% yields (Scheme 8).
An analogous strategy employing enantiomerically pure
3-substituted 6,6,6-trifluoro-5-oxohexanoic acids 62
promoted the asymmetric synthesis of indolizidine
derivatives 65 and 66 bearing a trifluoromethyl group at the
bridgehead carbon (Scheme 9) [17]. The reaction of chiral
ketoacids 62 with ammonium carbonate under refluxing in
toluene followed by addition of catalytic amount of
p-toluenesulfonic acid gave dihydropyridinones 63 in
74-80% yields.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
28
Scheme 6. Stereoselective synthesis of trifluoromethylated indolizidine derivatives 45, 48 and 51.
F3C OH
O O
F3C N3
O O
1. SOCl2
2. TMSiN3
52
53 PR3 N
O
F3C
N
O
F3C
H
N
O
H
H3CO
F3C
55
56
9%
57
34-49%
benzene
CH3OH
R = Ph. Bu
O
O
F3C
N3
+
54
Scheme 7. Staudinger/aza-Wittig reaction of acyl azide 53.
Scheme 8. Reduction of cyclic imide 59a and amides 59b,d.
A. A. Klipkov, I. I. Gerus, A. E. Sorochinsky
29
Table 2. Synthesis and radical cyclization of acyl and alkyl derivatives of enamide 57.
Entry Halides Benzoylation/alkylation
products 58
Yield,
%
Radical cyclization
products 59
Yield,
%
1
I
Cl
O
F3C
N
O OI
58a
71 N
O O
CF3
59a
97
2
I
Br
F3C
N
OI
58b
60 N
O
CF3
59b
92
3
Br Br
Br
F3C
N
O
58c
77 N
O
CF3
59c
64 from E
65 from Z
4
I I
I
F3C
N
O
58d
60
N
O
CF3
59d
84
5
I
I
F3C
N
O
I
58e
76
N
O
CF3
59e
50
An iodopropyl group was attached by deprotonation of
enamide 63 with NaH in anhydrous DMF followed by the
addition of an excess amount of 1,3-diiodopropane at room
temperature. The stereoselective radical cyclization of the
iodopropylpyridinones 64 achieved by the reaction with
triethylborane and oxygen in the presence of
tris(trimethylsilyl)silane at room temperature gave syn/anti
mixtures of Indolizidines 65 and 66. The anti relative
configuration of minor isomer 66c was established by X-ray
analysis. Consequently, all major products had the syn
relative configurations.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
30
Scheme 9. Stereoselective synthesis of indolizidine derivatives 65 and 66.
Scheme 10. Preparation of difluoromethylenated pyrrolizidine and indolizidine derivatives 69 and 70.
A. A. Klipkov, I. I. Gerus, A. E. Sorochinsky
31
2. Difluoromethylenated pyrrolizidines, indolizi-
dines and quinolizidines
The difluoromethylene group is a valuable structural unit
and the development of general and practical methodologies
for the introduction of difluoromethylene group in organic
molecules has been the subject of considerable synthetic
efforts. One existing strategy for the synthesis of
difluoromethylenated pyrrolizidines and indolizidines was
elaborated based on nucleophilic difluoro(phenyl-
sulfanyl)methylation of cyclic imides with N-unsaturated
substituents followed by radical cyclization. The addition of
PhSCF2SiMe3 [18] to N-allylic and N-homoallylic phtha-
limide and succinimide derivatives 67 under the initiation of
a catalytic amount of a fluoride salt afforded the
corresponding adducts 68 in moderate to good yields
(Scheme 10) [19]. The further reductive desulfanylation of
the α-difluoro(phenylthio)methylated alcohols 68 with
Bu3SnH and substoichiometric amounts of 2,2′-azobis-
isobutyronitrile (AIBN) in toluene under refluxing
temperature afforded radical intermediates that underwent
intramolecular radical cyclization to give difluoro-
methylenated pyrrolizidine 69 and indolizidine 70
derivatives with trans stereoselectivity. The relative
stereochemistry of the major trans-isomers 69a and 70a
obtained in pure form was established based on the X-ray
crystallographic data.
Reduction of the resulting adducts 69b (trans/cis 77:23)
and 70a (trans/cis 88:12) by treatment with
triethylsilane/boron trifluoride–diethyl ether complex gave
the corresponding difluoromethylenated pyrrolizidinone 71
and indolizidinone 75 with high stereoselectivity, as
confirmed by the NOE experiments (Scheme 11).
Additionally, nucleophilic displacement of the hydroxyl
group, using allyltrimethylsilane in the presence of a Lewis
acid led to corresponding products 72 and 76 in good
yields. Both compounds 72 and 76 were also obtained as
single diastereomers. Reduction of 72 and 76 using lithium
aluminum hydride in THF at reflux temperature provided
the corresponding difluoromethylenated pyrrolizidine 73
and indolizidine 77. The conversion of pyrrolizidinones 72
into diastereomerically pure alkyl-substituted difluoro-
methylenated pyrrolizidines 74 was accomplished by
treatment with n-butyllithium/cerium chloride or
isopropylmagnesium chloride in THF and subsequent
reduction with NaBH3CN. The relative stereochemistries of
compounds 73, 74, and 77 were established by NOE
experiments. The stereochemical outcome of the described
reactions can be explained by the preferential attack of
nucleophiles from the less sterically hindered face of the
iminium intermediate.
N
O
H
F F CH3
N
O
H
FF
Bn
N
O
HO
FF
Bn
Et3SiH
BF3 Et2O
trans/cis = 77:23
69b
N
O
HO
F F CH3
Et3SiH
BF3 Et2O
trans/cis = 88:12
70a 75
98%, single
diastereomer
N
O
FF
Bn
N
FF
Bn
73
84%
SiMe3
LAH, THF
SiMe3
N
O
F F CH3
LAH, THF
N
F F CH3
77
60%
71
77%, single
diastereomer
72
67%, single
diastereomer
76
53%, single
diastereomer
BF3 . Et2O
N
FF
Bn
74
R = n-Bu 80%
R = i-Pr 65%
1. n-BuLi/CeCl3
or i-PrMgCl
2. NaBH3CN
H R
BF3 . Et2O
Scheme 11. Preparation of difluoromethylenated pyrrolizidines 73, 74, and indolizidine 77.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
32
Scheme 12. Fluoride-catalyzed reaction of PhSCF2SiMe3 with chiral imides 78.
N
RO
RO
O
n
cis-80a 37%
cis-80b 12%
cis-80c 39%
cis-80d 15%
HO CF2SPh
N
RO
HO FRO
O
Me
F
n
Bu3SnH, AIBN
+
N
RO
HO FRO
O
Me
F
n
80c 80d
N
HO
H FHO
R
Me
F
82
R = Et, n-Bu, i-Pr
N
HO
H FHO
Me
F
81
80a,b
N
HO
R
FHO F
Me
83
R = Et, n-Bu
toluene, reflux
syn-79a-d trans-80a 15%
trans-80b 34%
trans-80c 13%
trans-80d 43%
H
Scheme 13. Fluoride-catalyzed reaction of PhSCF2SiMe3 with chiral imides 78.
The same nucleophilic addition/radical cyclization
strategy was also applied for asymmetric syntheses of
difluoromethylenated dihydroxypyrrolizidines and
dihydroxyindolizidines [20]. The fluoride-catalyzed
nucleophilic difluoro(phenylsulfanyl)methylation of chiral
N-alkenyl-3,4-dihydroxylated succinimides 78 readily
available from L-tartaric acid gave separable by column
chromatography mixtures of syn- and anti-isomers of
adducts 79 with moderate to good diastereoselectivities
(Scheme 12). The observed stereochemical outcomes for
the fluoride-catalyzed addition can be explained by
approaches of the nucleophile to the carbonyl group of the
imide from the direction that minimizes the steric repulsion
with the adjacent OR group leading to the syn-isomer as the
major product.
Reductive cleavage of the syn-isomers 79 with
Bu3SnH/AIBN afforded corresponding difluoromethyl
radicals that underwent intramolecular radical cyclization to
the alkenyl moiety providing difluoromethylenated
compounds 80 as mixtures of cis- and trans-isomers, which
could be easily separated by preparative thin-layer
chromatography (Scheme 13).
The relative stereochemistries of cis-80 and trans-80
were established by X-ray crystallography. Furthermore, the
cis- and trans-isomers of compounds 80 were transformed
to difluoromethylenated dihydroxypyrrolizidines 81 and 82
as well as dihydroxyindolizidines 83 by reductive cleavage
of the hydroxyl group and organometallic addition to
carbonyl group followed by hydrogenolysis.
A. A. Klipkov, I. I. Gerus, A. E. Sorochinsky
33
Recently it has been demonstrated that PhSCF2SiMe3
could undergo fluoride-catalyzed nucleophilic addition to
chiral polyoxygenated cyclic nitrones with high
diastereoselectivity [21]. The reaction of PhSCF2SiMe3 with
chiral nitrones 84 employing 1 mol % of tetra-
butylammonium fluoride in THF followed by reductive
cleavage of the N-O bond by treatment with Zn powder, a
catalytic amount of In metal, and a saturated aqueous
NH4Cl solution yielded pyrrolidines 85 as a single isomer in
60-73% yields (Scheme 14). The relative stereochemistry of
85 was confirmed by NOE experiments. The observed
stereochemical outcome could be rationalized in a way that
the nucleophile derived from PhSCF2SiMe3 preferably
approached the nitrones 84 from the opposite face to the
C3-OBn group to avoid steric repulsion.
The introduction of alkenyl side chains onto the nitrogen
atom of pyrrolidines 85 followed by treatment with
Bu3SnH/AIBN in refluxing toluene afforded the
corresponding difluorinated polyhydroxypyrrolizidines 86
and polyhydroxyindolizidines 87 as mixtures of cis- and
trans-isomers which could be only partially separated by
column chromatography. It should be noted that radical
cyclization led to the preferentially formation of the trans-
isomers of pyrrolizidines 86 as well as cis-isomers of
indolizidines 87. Subsequent hydrogenolysis of the benzyl
protecting provided access to chiral difluoromethylenated
polyhydroxypyrrolizidine and polyhydroxyindolizidine
derivatives.
Oxidative phenylsulfanyldifluoromethylation of
α-Csp3-H of tetrahydroisoquinoline derivatives was
achieved with TMSCF2SPh employing TEMPO+BF4
− as an
oxidant. This process proceeded via oxidation of
tetrahydroisoquinoline ring to corresponding iminium ions
which readily reacted with TMSCF2SPh to provide
precursors for preparing difluoromethylenated
quinolizidines. The choice of reaction parameters including
oxidants, fluoride sources, solvents, and additives was
found to be critical to the success of the reaction. Under the
optimized conditions N-allyl or N-homoallyl tetrahydro-
isoquinolines 88 and TMSCF2SPh were treated with
TEMPO+BF4
−, CsF as a fluoride source, and AcOH as an
additive in CH3CN at room temperature to give moderate to
good yields of adducts 89 (Scheme 15) [22]. E-Isomers of
N-homoallyl substituted tetrahydroisoquinolines 88 under
the reaction conditions underwent isomerization to yield
adducts 89 as an inseparable mixture of E and Z isomers.
The reductive desulfanylation of N-allyl substituted adducts
89 with Bu3SnH in the presence of AIBN in refluxing
toluene followed by intramolecular cyclization of resulting
difluoromethyl radical gave rise to difluoromethylenated
indolizidines 90 with moderate to high trans
stereoselectivity. On the other hand N-homoallyl substituted
adducts 89 afforded difluoromethylenated quinolizidines 91
with only moderate cis stereoselectivity.
N+
BnO OBn
R1
O-
84
R1 = H, CH2OBn
1. PhSCF2SiMe3
TBAF (1 mol%)
THF, -10 oC
2. 2% HCl or TBAF
3. Zn, 20 mol% In
sat. NH4Cl, MeOH
N
H
BnO OBn
R1
85
60-73%
CF2SPh
1. N-alkenylation
2. radical cyclization
N
R2
BnO
R1
H F
BnO
F
or
N
BnO H
BnO
86
87
F F
R2
N
CH3
BnO H F
BnO
F
86a (88%)
trans:cis 89:11
N
BnO H F
BnO
F
N
CH3
BnO H F
BnO
F
N
BnO H F
BnO
F
Ph
86b (75%)
trans:cis 82:18
BnO
86c (87%)
trans:cis 70:30
BnO
Ph
86a (87%)
trans:cis 64:36
N
BnO H
BnO
F F
CH3
87a (78%)
cis:trans 66:34
N
BnO H
BnO
F F
CH3
87b (69%)
cis:trans 59:41
N
BnO H
BnO
F F
87c (74%)
cis:trans 60:40
N
BnO H
BnO
F F
87d (70%)
cis:trans 60:40
CH3
F
Scheme 14. Preparation of difluoromethylenated pyrrolizidines 86 and indolizidines 87.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
34
Scheme 15. Oxidative phenylsulfanyldifluoromethylation of tetrahydroisoquinolines 88. Synthesis of difluorinated indolizidines 90 and
quinolizidines 91.
A series of difluoromethylenated pyrrolizidine and
indolizidine derivatives have been efficiently synthesized
via a copper-catalyzed radical annulation of amine-
containing olefins. In this case, ethyl bromodifluoroacetate
was employed as CF2 source. When the reaction involved
aliphatic primary amine-containing olefins 92 with CuI as a
catalyst, PMDETA (pentamethyldiethylenetriamine) as both
multidentate ligand and base in dimethyl sulfoxide the
difluoromethylenated pyrrolizidine and indolizidine
derivatives 93a,b,d,e were obtained in good yields (Scheme
16) [23]. However, difluoromethylenated pyrrolizidine
derivative 93c without geminal substitution was obtained
with a much lower yield. The benzylamine bearing allyl
group at orto-position was also found to be effective in this
transformation rendering a good yield of difluoro-
methylenated tetrahydroisoquinoline derivative 93f. The
reaction conditions were optimized to avoid the generation
of bromodifluoroacetamides as byproducts.
The reactions using o-allylaniline derivatives 94 with
electron-donating and electron-withdrawing groups as
substrates proceeded smoothly with acetonitrile as a solvent
instead of dimethyl sulfoxide to give the difluorinated
benzopyrrolizidine derivatives 95a-i in good to excellent
yields (Scheme 17). Aniline containing orto-homoallyl unit
afforded difluoroalkylated benzoindolizine derivative 95j in
high efficiency.
A. A. Klipkov, I. I. Gerus, A. E. Sorochinsky
35
Scheme 16. Oxidative phenylsulfanyldifluoromethylation of
tetrahydroisoquinolines 88. Synthesis of difluorinated
indolizidines 90 and quinolizidines 91.
Scheme 17. Construction of difluorinated pyrrolizidine and
indolizidine derivatives 95 from ethyl bromodifluoroacetate and
anilines 94 through a copper-catalyzed radical cascade annulation.
In the presence of radical scavengers such as TEMPO,
the reaction of o-allylaniline was inhibited, and a TEMPO-
CF2CO2Et adduct was formed in 14% yield as estimated by
19F NMR spectroscopy analysis. This result suggested that
the reaction involved a free radical process. The authors
proposed a plausible mechanism shown in Scheme 18. The
catalytic cycle was initiated by the generation of
electrophilic fluoroalkyl radical A and Cu(II) species from
the single-electron transfer reaction of the BrCF2CO2Et with
CuBr. Then, the addition of fluoroalkyl radical A to alkene
gave a more stable alkyl radical B, which is subsequently
oxidized into a cation intermediate C by Cu(II) species. The
cationic intermediate C was nucleophilically attacked by
the intramolecular nitrogen of the amine to afford
difluorinated pyrrolidine intermediate D (path a). The
authors also proposed an alternative pathway when trapping
of alkyl radical B by Cu(II) led to Cu(III) complex E. Then
reductive elimination of E afforded intermediate D and
regenerated Cu(I) species (path b). Finally, the desired
product was obtained through intramolecular ester-amide
exchange.
Scheme 18. Proposed mechanism of the copper-catalyzed radical
annulation [23].
Catalytic asymmetric radical aminodifluoromethylation
of alkenes employing fluoroalkylsulfonyl chlorides as
radical precursors provided an efficient route towards
difluoromethylenated pyrrolizidine with high
enantioselectivity. This method involved the use of
N-alkenyl ureas 96 as substrate with methyl
fluorosulfonyldifluoroacetate as stable and mild difluoro-
methylating reagent in conjunction with CuBr/chiral
phosphoric acid (S)-97 as a dual-catalytic system and
Ag2CO3 as a base in ethyl isobutyrate (Scheme 19) [24].
The screening of chiral phosphoric acids and Cu salts
revealed that the dual catalyst composed of CuBr and (S)-97
was the most efficient in terms of enantioselectivity. On the
other hand, silver carbonate was found to be particularly
effective in avoiding hydroamination side reaction caused
by in situ generated HCl. Under optimal reaction conditions
N-alkenyl ureas 96 bearing electron-withdrawing or
electron-donating groups at different positions on the
aromatic ring reacted smoothly to afford difluoroacetyl-
containing products 98 in excellent yields with 95-97% ee.
The absolute configuration of 98 was determined based on
X-ray crystallographic analysis. Treatment of difluoroacetyl
amine 98 (R=3-OMe) with BH3•SMe2 provided
difluoromethyleneted pyrrolidine 99 in 43% yield with no
loss in the enantioselectivity.
Oxidation of Cu(I) species by MeO2CCF2SO2Cl through
a single-electron transfer to afford an electrophilic
fluoroalkyl radical and chiral monophosphate or
bisphosphate Cu(II) B or B’, along with the generation of a
stoichiometric amount of sulfur dioxide and chloride anion
was described in the proposed mechanism (Scheme 20).
Stoichiometric amount of Ag2CO3 acted as a chloride
scavenger via the formation of insoluble AgCl. The addition
reaction of fluoroalkyl radical to alkene occurred to
generate the alkyl radical C, which could be trapped by
Cu(II) phosphate B or B’ to form a Cu(II) species D, in
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
36
Scheme 19. Catalytic asymmetric radical aminodifluoromethylation of N-alkenyl ureas 96.
Scheme 20. Proposed mechanism.
which alkyl radical intermediate could be trapped by Cu(II)
phosphate to generate a Cu(III) species E. The chiral
phosphate could control the facial selectivity of reaction via
both hydrogen-bonding interactions with the N-H bond
adjacent to the aryl group and ion-pairing interactions in a
concerted transition state. Then, reductive elimination of the
resulting Cu(III) species E could deliver the final product
98 along with the regeneration of the copper Cu(I) and the
phosphoric acid.
3. Monofluorinated quinolizidine derivatives
Recently, a novel enantioselective synthetic approach to
monofluorinated quinolizidines 102 was described by
employing visible light-induced decarboxylative/defluori-
native cross-coupling of dihydroisoquinoline acetic acids
100 and α-(trifluoromethyl)styrenes 101 with iridium
photocatalysts (Scheme 21) [25].
In this reaction, α-amino acids were employed as
precursors of α-amino radicals through a decarboxylative
process. Optimal yields of monofluorinated quinolizidines
102 could be obtained with Ir(dmppy)2(dtbbpy)PF6 103
photocatalyst. The reaction exhibited a broad range of
substrate scope with respect to both dihydroisoquinoline
acids derivatives 100 and α-(trifluoromethyl)styrenes 101,
excellent functional group tolerance, and high diastereo-
and regioselectivity. Configuration of isolated major
diastereomer 103d was confirmed by the NOESY spectra.
Relatively the mechanism, initial single-electron transfer
from α-amino acid 100 to excited Ir(III)* generated
α-amino radical A and Ir(II) species (Scheme 22).
Subsequently, the addition of α-amino radical A to
α-trifluoromethylstyrene 101 provided α-CF3 alkyl radical
B, which could undergo single-electron reduction with Ir(II)
species to afford carbanion C along with the regeneration of
the Ir(III) catalyst. Finally, β-fluoride elimination took place
to provide difluoroalkene D. The intramolecular annulation
process of compounds D occurred via single-electron
transfer with Ir(III)* to give radical cation E. Deprotonation
of E generated α-aminoalkyl radical F. Two possible paths
were proposed by the authors for the formation of
quinolizidine 102a from radical F. In path (a), radical
addition to C=C double bond generated radical G, followed
by single-electron reduction with Ir(II) led to carbanion H
and β-fluoride elimination giving final product 102a.
Alternatively, in the path (b) C=C double bond could be
reduced by Ir(II) followed by the elimination of fluoride to
form fluoroalkenyl biradical I. The formation of
quinolizidine 102a occurred via intramolecular coupling of
biradical intermediate I.
A. A. Klipkov, I. I. Gerus, A. E. Sorochinsky
37
Scheme 21. Visible light-induced reaction of dihydroisoquinoline acetic acids 100 with α-(trifluoromethyl)styrenes 101.
Conclusions
The collected literature covers most of the available
synthetic procedures for fluorinated pyrrolizidine,
indolizidine, and quinolizidine derivatives. The classical
synthetic methods including cycloaddition reactions,
reduction of the heteroaromatic molecules, condensations of
carbonyl compounds, and radical cyclization processes have
been successfully applied to the construction of
trifluoromethylated and difluoromethylenated 1-azabicyclic
skeleton. They often involved the use of chiral substrates
bearing pre-installed trifluoromethyl group. New copper-
catalyzed radical cascade annulation of amine-containing
olefins and ethyl bromodifluoroacetate was reported as
efficient access to difluoromethylenated pyrrolizidine and
indolizidine derivatives. Recently, catalytic asymmetric
radical aminodifluoromethylation of alkenes employing
methyl fluorosulfonyldifluoroacetate as radical precursor
provided an efficient route towards difluoromethylenated
pyrrolizidine with high enantioselectivity. Finally, the
modern reaction of α-trifluoromethyl alkenes and
dihydroisoquinoline acetic acids using visible light
photocatalysis was described as an effective strategy to
provide the availability of monofluorinated quinolizidines.
Although several strategies for diastereo- and
enantioselective synthesis of fluorinated pyrrolizidines,
indolizidines, and quinolizidines were described in the
literature these saturated 1-azabicyclic compounds are still
valuable and challenging targets for synthetic chemists.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
38
Notes
Acknowledgments and finances. The work was funded
by the National Academy of Sciences of Ukraine (Grant
No. 2.1.10.19-22).
The authors declare no conflict of interest.
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A. A. Klipkov, I. I. Gerus, A. E. Sorochinsky
39
Синтез фторованих похідних піролізидину, індолізидину та хінолізидину
A. A. Кліпков1,2, І. І. Герус1*, О. Є. Сорочинський1
1 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, вул. Мурманська, 1, Київ, 02094, Україна
2 Національний університет «Києво-Могилянська академія», вул. Сковороди, 2, Київ, 04070, Україна
Резюме: У огляді наведено літературні дані, що стосуються синтезу фторованих піролізидинів, індолізидинів та хінолізидинів. Для синтезу
трифторметильованих похідних в якості вихідних речовин застосувуються комерційно доступні будівельні блоки, що містять трифторметильну
групу, або синтетичні трифторметильовані базові молекули, що включають хіральний ауксилар. З іншого боку, нуклеофільне або радикальне
дифторметилювання з подальшими реакціями циклізації на основі стабільних і легкодоступних дифторметилюючих агентів було визнано
ефективним підходом для синтезу дифторметиленовмісних піролізидинів, індолізидинів та хінолізидинів. Крім того, реакція фотокаталізу
α-трифторметилалкенів і дигідроізохінолін оцтових кислот відкриває нові можливості для синтезу монофторованих хінолізидинів.
Обговорюється доступність та обмеження цих методів.
Ключові слова: фтор; піролізидин; індолізидин; хінолізидинові алкалоїди; стратегія синтезу.
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| id | oai:ojs2.bioorganica.com.ua:article-11 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:21Z |
| publishDate | 2022 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/d1/1a36e775de77e2344e7bd8f87b6abed1.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-112026-07-19T14:56:52Z Synthesis of fluorinated pyrrolizidine, indolizidine and quinolizidine derivatives Синтез фторованих похідних піролізидину, індолізидину та хінолізидину Klipkov, Anton A. Gerus, Igor I. Sorochinsky, Alexander E. fluorine pyrrolizidine indolizidine quinolizidine alkaloids synthetic strategies фтор піролізидин індолізидин хінолізидинові алкалоїди стратегія синтезу This review provides literature data dealing with the synthesis of fluorinated pyrrolizidines, indolizidines, and quinolizidines. Synthesis of trifluoromethylated derivatives requires to use of commercially available building blocks bearing pre-installed trifluoromethyl group or synthetic trifluoromethylated templates incorporating a chiral auxiliary as starting materials. On the other hand, nucleophilic or radical difluoromethylation followed by cyclization reactions using different types of stable and readily available difluoromethylating agents was established as an efficient approach for the synthesis of difluoromethylenated pyrrolizidines, indolizidines, and quinolizidines. Furthermore, a new possibility to synthesize monofluorinated quinolizidines opens the reaction of α-trifluoromethyl alkenes and dihydroisoquinoline acetic acids using visible light photocatalysis. Generality and limitations of these methods are discussed. У огляді наведено літературні дані, що стосуються синтезу фторованих піролізидинів, індолізидинів та хінолізидинів. Для синтезу трифторметильованих похідних в якості вихідних речовин застосувуються комерційно доступні будівельні блоки, що містять трифторметильну групу, або синтетичні трифторметильовані базові молекули, що включають хіральний ауксилар. З іншого боку, нуклеофільне або радикальне дифторметилювання з подальшими реакціями циклізації на основі стабільних і легкодоступних дифторметилюючих агентів було визнано ефективним підходом для синтезу дифторметиленовмісних піролізидинів, індолізидинів та хінолізидинів. Крім того, реакція фото каталізу α-трифторметилалкенів і дигідроізохінолін оцтових кислот відкриває нові можливості для синтезу монофторованих хінолізидинів. Обговорюється доступність та обмеження цих методів. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2022-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/11 10.15407/bioorganica2022.01.022 Ukrainica Bioorganica Acta; Vol. 17 No. 1 (2022): Ukrainica Bioorganica Acta; 22-39 Ukrainica Bioorganica Acta; Том 17 № 1 (2022): Ukrainica Bioorganica Acta; 22-39 1814-9766 1814-9758 10.15407/bioorganica2022.01 en https://bioorganica.com.ua/index.php/journal/article/view/11/14 Copyright (c) 2022 Anton A. Klipkov, Igor I. Gerus, Alexander E. Sorochinsky https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | фтор піролізидин індолізидин хінолізидинові алкалоїди стратегія синтезу Klipkov, Anton A. Gerus, Igor I. Sorochinsky, Alexander E. Синтез фторованих похідних піролізидину, індолізидину та хінолізидину |
| title | Синтез фторованих похідних піролізидину, індолізидину та хінолізидину |
| title_alt | Synthesis of fluorinated pyrrolizidine, indolizidine and quinolizidine derivatives |
| title_full | Синтез фторованих похідних піролізидину, індолізидину та хінолізидину |
| title_fullStr | Синтез фторованих похідних піролізидину, індолізидину та хінолізидину |
| title_full_unstemmed | Синтез фторованих похідних піролізидину, індолізидину та хінолізидину |
| title_short | Синтез фторованих похідних піролізидину, індолізидину та хінолізидину |
| title_sort | синтез фторованих похідних піролізидину, індолізидину та хінолізидину |
| topic | фтор піролізидин індолізидин хінолізидинові алкалоїди стратегія синтезу |
| topic_facet | fluorine pyrrolizidine indolizidine quinolizidine alkaloids synthetic strategies фтор піролізидин індолізидин хінолізидинові алкалоїди стратегія синтезу |
| url | https://bioorganica.com.ua/index.php/journal/article/view/11 |
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