Подофілотоксин та арилтетралінові лігнани: методи синтезу кілець A, B, C, D
Podophyllotoxin, its derivatives and structural analogues are an extensive group of aryl-tetralin-lignans of interest in pharmacology due to their promising anticancer and antitumor activity. The synthesis methods that have been proposed to date seek to resolve synthetic, stereochemical, pharmacodyn...
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| Дата: | 2024 |
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| ISSN: | 2518-1548 |
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Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874364483022880768 |
|---|---|
| author | Flores-Hernández, Francisco Zárate-López, Tania Isabel Alcaráz-Cano, Marco Antonio Escalante, Jaime Rivera-Ramírez, José Domingo |
| author_facet | Flores-Hernández, Francisco Zárate-López, Tania Isabel Alcaráz-Cano, Marco Antonio Escalante, Jaime Rivera-Ramírez, José Domingo |
| author_institution_txt_mv | [
{
"author": "Francisco Flores-Hernández",
"institution": "Laboratorio de Química Farmacéutica, Departamento de Farmacobiología, Centro Universitario de Ciencias Exactas e Ingenierías Universidad de Guadalajara",
"orcid": ""
},
{
"author": "Tania Isabel Zárate-López",
"institution": "Laboratorio de Química Farmacéutica, Departamento de Farmacobiología, Centro Universitario de Ciencias Exactas e Ingenierías Universidad de Guadalajara",
"orcid": ""
},
{
"author": "Marco Antonio Alcaráz-Cano",
"institution": "Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos",
"orcid": "0000-0003-1754-0751"
},
{
"author": "Jaime Escalante",
"institution": "Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos",
"orcid": ""
},
{
"author": "José Domingo Rivera-Ramírez",
"institution": "Laboratorio de Química Farmacéutica, Departamento de Farmacobiología, Centro Universitario de Ciencias Exactas e Ingenierías Universidad de Guadalajara",
"orcid": ""
}
] |
| author_orcid_str_mv | 0000-0003-1754-0751 |
| author_sort | Flores-Hernández, Francisco |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 25 |
| container_issue | 2 |
| container_start_page | 3 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 22 |
| datestamp_date | 2026-08-23T16:14:17Z |
| description | Podophyllotoxin, its derivatives and structural analogues are an extensive group of aryl-tetralin-lignans of interest in pharmacology due to their promising anticancer and antitumor activity. The synthesis methods that have been proposed to date seek to resolve synthetic, stereochemical, pharmacodynamic and environmental aspects. In this review we have updated and brought together different classifications of lignan and podophyllotoxin synthesis. Transformation methods focus on the strategies used to form or functionalize rings A, B, C and D, as well as the configuration of the system of four stereogenic centers that fuse rings C and D. |
| doi_str_mv | 10.24959/ophcj.24.308942 |
| first_indexed | 2025-07-23T04:43:30Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 3
Review Article
http://ophcj.nuph.edu.ua
UDC [547.7+547.6]:54.057
F. Flóres-Hernández1, T. I. Zárate-López1, M. A. Alcaráz-Cano2,
J. Escalante2, J. D. Rivera-Ramírez1
1 Laboratorio de Química Farmacéutica, Departamento de Farmacobiología, Centro Universitario de Ciencias
Exactas e Ingenierías Universidad de Guadalajara, 1421 Blvd. Gral. Marcelino García Barragán, Olímpica,
44430 Guadalajara, México
2 Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos,
1001 Avenida Universidad, 62209 Cuernavaca, México
Podophyllotoxin and Aryltetralin Lignans:
Methods for the Synthesis of Rings A, B, C, D
Abstract
Podophyllotoxin, its derivatives and structural analogs are an extensive group of aryl-tetralin-lignans of interest in pharma-
cology due to their promising anticancer and antitumor activity. The synthesis methods proposed to date are aimed at solv-
ing synthetic, stereochemical, pharmacodynamic and environmental aspects. In this review, we have updated and brought
together different classifications of lignan and podophyllotoxin synthesis. Transformation methods focus on the strategies
used to form or functionalize rings A, B, C and D, as well as the configuration of the system of four stereogenic centers that
fuse rings C and D.
Keywords: lignans; podophyllotoxin; aryltetralin-lignans; etoposide; teniposide
Ф. Флорес-Ернандес1, Т. І. Сарате-Лопес1, М. А. Алькарас-Кано2, Х. Ескаланте2, Х. Д. Рівера-Рамірес1
1 Лабораторія фармацевтичної хімії, Департамент фармакобіології,
Університетський центр точних наук та техніки, Університет Гвадалахари,
бульвар Марселіно Гарсія Барраган, 1421, Олімпіка, м. Гвадалахара, 44430, Халіско, Мексика
2 Центр хімічних досліджень, Автономний університет штату Морелос,
Університетський проспект, 1001, Куернавака, 62209, Морелос, Мексика
Подофілотоксин та арилтетралінові лігнани: методи синтезу кілець A, B, C, D
Анотація
Подофілотоксин, його похідні та структурні аналоги є великою групою арилтетралінових лігнанів, що становлять ін-
терес для фармакології, зокрема завдяки їхній багатонадійній протипухлинній дії. Методи синтезу, запропоновані
сьогодні, спрямовані на вирішення синтетичних, стереохімічних, фармакодинамічних та екологічних аспектів. У цьо-
му огляді ми оновили й об’єднали різні класифікації синтезу подофілотоксину та споріднених сполук. Обговорені
методи зосереджені на стратегіях формування або функціоналізації кілець A, B, C і D, а також на конфігурації чотирьох
стереогенних центрів, які поєднують кільця C і D.
Ключові слова: лігнани; подофілотоксин; арилтетралінові лігнани; етопозид; теніпозид
Citation: Flóres-Hernández, F.; Zárate-López, T. I.; Alcaráz-Cano, M. A.; Escalante, J.; Rivera-Ramírez, J. D. Podophyllotoxin and aryltetralin
lignans: Methods for the synthesis of rings A, B, C, D. Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2), 3 – 25.
https://doi.org/10.24959/ophcj.24.308942
Received: 23 July 2024; Revised: 5 September 2024; Accepted: 7 September 2024
Copyright© 2024, F. Flóres-Hernández, T. I. Zárate-López, M. A. Alcaráz-Cano, J. Escalante, J. D. Rivera-Ramírez. This is an open access
article under the CC BY license (http://creativecommons.org/licenses/by/4.0).
Funding: The authors thank the Consejo Nacional de Humanidades Ciencia y Tecnología (CONAHCYT) for the funding granted to carry out
this research through the Ciencia Frontera project No. 610262 called “The chemo-enzymatic synthesis of podophyllotoxin-type lignans
using green chemistry bases and their evaluation as probable antitumor compounds.”
Conflict of interest: The authors have no conflict of interest to declare.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 4
Журнал органічної та фармацевтичної хімії 2024, 22 (2)
■ The Structure, Chemical
and Pharmacological Properties
of Podophyllotoxin
Podophyllotoxin (1) is the most prominent and
abundant metabolite of the lignan family. It has
been isolated from the roots, seeds, fruits and re-
sins of plant species of the Berberidaceae family,
mainly from the genus Podophyllum and Bursera.
The first isolation dates to 1880 when Poewys-
sotzky obtained it from podophyllin resin [1, 2].
The description of a podophyllotoxin molecu-
le uses structural, steric, and reactive criteria,
which serve to determine aspects of transforma-
tion and design of the biological activity when de-
rivatives and analogs are prepared. Structurally,
podophyllotoxin is an aryltetralin lignan. Lignans
are a family of secondary metabolites of the shi-
kimic acid pathway and can be divided into four
groups: lignans, neolignans, oxyneolignans, and
lignanoids (trimers and analogs) [3]. Cyclolignans
form the σ backbone when two phenylpropanoid
units (C6C3) are linked through their respective
positions 8, also called β positions (this is a non-
IUPAC nomenclature system based on their bio-
genesis; 2 and 3, Scheme 1, A). In nature, phenyl-
propanoid units are found in the form of propenyl-
phenols 4 and cinnamyl alcohols 5 (Scheme 1, B),
which, via the enzymatic oxidation, form lignans
of type 6 and 7 (Scheme 1, C). The prefix arylte-
tralin comes from the fact that podophyllotoxin
contains a tetralin unit substituted with an aryl
group (8). In the complete molecule of podophyl-
lotoxin, it is possible to distinguish its five rings,
which nomenclature was proposed by Moss [1]:
the first four are fused, dioxolane (A), tetralin
(B and C) and β-lactone (D); for its part, ring E
(3,4,5-trimethoxyphenyl) is linked to tetralin.
From the stereochemical point of view, four con-
tiguous stereogenic centers can be distinguished
in positions 7 (R), 8 (S), 7’ (R), and 8’ (S), which
are denoted as 4, 3, 1, and 2, in accordance with
the rules of systematic numbering for 1. In this
review, each position will be denoted referring
to this last classification. Finally, it is possible
to distinguish that the lactone ring (D) is fused
to ring C in a relative trans-configuration.
From the pharmacological point of view, po-
dophyllotoxin has been used for hundreds of years
in traditional Chinese, Japanese, and Indian Ayur-
vedic medicine due to its antiviral and antitumor
properties [2]. It has been used as an antidote
against poisoning, as purgative, anthelmintic, and
as a poison to treat venereal warts, and it has
anti-HIV properties. By 1942, Kaplan reported the
best treatment for that time of condylomata acu-
minata caused by the human papillomavirus [3].
By 1946, it was found that it could inhibit cell
division and destroy rapidly proliferating cells
due to its antimitotic and cytotoxic properties.
Other reported activities include transcriptase
inhibition, cardiovascular effects, immunomo-
dulation, antileishmanial activity, high density
lipoprotein activity, antifungal, antipsoriasis,
antimalarial, antiasthmatic and anti-HIV activi-
ty [2].
The mechanism of action of podophyllotoxin
is in microtubules. By binding to the colchicine
Me
MeO
O
O
O
O
O
O
OH
MeO
OMe
OMe
O
1
7
8
1
2
34
E
B DA C
1
2
3
4
5
6 7(α)
8(β)
9(γ)
1'
2'
3'
4'
5'
6'
7'(α')
8'(β')
9'(γ')
8(β)
8'(β')
A
2 3
B
R2MeO
HO
R1
4: R1 = H
a) R2 = CH2OH
b) R2 = CO2H
c) R2 = Me
R2MeO
HO
R1
5: R1 = OMe
O
O
H
H
OH
OMe
HO
MeO
6
5
6
Scheme 1. The structure of podophyllotoxin (1), structural definitions of lignans (2, 3, and 8), and examples of lignans
in nature (4, 5, 6, and 7)
ISSN 2308-8303 (Print) / 2518-1548 (Online) 5
Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
site of the beta-tubulin subunit, it prevents it
from binding to guanosine triphosphate (GTP).
Thus, by interrupting the formation and stabi-
lization of the microtubules that make up the
cytoskeleton of eukaryotic cells, it interrupts
the formation of the mitotic spindle and causes
destabilization of the microtubule structure in
the G2/M phase (Figure 1) [3, 4].
In addition, podophyllotoxin is highly effec-
tive in the treatment of skin diseases, such as
genital warts caused by the human papillomavi-
rus (HPV), molluscum contagiosum and precan-
cerous lesions, as well as it is highly potential
as an anticancer agent due to its ability to stop
cell division. Its antitumor activity has been pro-
ven in the treatment of Wilms tumors, genital tu-
mors, non-Hodgkin lymphomas and lung cancer.
However, its use for cancer treatment is limited
since it is toxic and can cause serious gastroin-
testinal side effects, such as irritation, ulceration,
pain, inflammation, and burns. For this reason,
podophyllotoxin has been used as a precursor to
obtain semisynthetic derivatives that are clini-
cally applied as cytostatics in the treatment of
various types of cancer [5].
Etoposide (9), teniposide (10) and etopofos (11)
(Figure 2) are synthetic derivatives of podo-
phyllotoxin with efficacy, enhanced selectivity,
and low toxicity. They are used in chemotherapy
against testicular cancer, lung cancer, and lym-
phoma, leukemia, Kaposi’s sarcoma. However, they
have such limitations as the development of drug
resistance and myelosuppression.
These compounds have a structural base of
aryltetralin lignans similar to podophyllotoxin.
However, the differences are that the configura-
tion of position 4 is opposite (S) and the substi-
tuent of that position is a protected glycosyl group.
Additionally, etopofos contains a phosphate group
in position 4’ of ring E [6]. These structural varia-
tions generate a mechanism that is now based on
the irreveersible inhibition of topoisomerase II,
by forming a ternary DNA-topoisomerase-drug
complex, which causes the accumulation of DNA-
drug complexes. This prevents cell replication
and transcription, causing double strand breaks
in DNA and leading to apoptosis. Etoposide also
shows other biological activities, such as cyto-
toxic, insecticidal, antifungal, antiviral, anti-
inflammatory, neurotoxic, immunosuppressive,
Figure 1. The representation of the position and constitution of microtubules in the eukaryotic cell and of the colchicine site
in the β subunit of tubulin
O
O
O
MeO
OR2
OMe
O
O Etoposide (9)
OO
OR1
HO
HO
R1 = Me
S
Teniposide (10)
R1 = Me
Etopofos (11)
R2 = H
R2 = P
OH
O
OH
R2 = H
R1 =
Figure 2. Chemical structures of etoposide (9), teniposide (10) and etopofos (11)
ISSN 2308-8303 (Print) / 2518-1548 (Online) 6
Журнал органічної та фармацевтичної хімії 2024, 22 (2)
antirheumatic, antispasmogenic and hypolipide-
mic action [5].
These findings demonstrated the therapeutic
potential of aryl-tetralin lignans and led to the
development of a new class of antineoplastics
known as podophyllotoxin analogs and deriva-
tives. These compounds are used in combination
with other chemotherapeutic agents to improve
efficacy and reduce side effects of cancer treat-
ments. In some cases, podophyllotoxin deriva-
tives have been shown to be effective in treating
cancers that are resistant to other chemothera-
peutic treatments (Figure 3) [7].
Thus, an extensive multidisciplinary research
network has been generated, so the demand for
podophyllotoxin and its derivatives continues to
increase. The proof of this is the growing number
of works and research areas in this field. For the
first half of 2023, for example, considering the
search engines Google academics and Concordia
University Library, the number of publications
referring to podophyllotoxin until 2022 (a range
of approximately 80 years) was around 4000 pub-
lications, approximately 50 publications per year.
However, only in the period of 2022 to 2023
(18 months) approximately 700 publications were
recorded with podophyllotoxin as a central topic,
something like 39 monthly publications, at least
one daily! By April 2024, around 500 articles
had already been published on this topic, three
per day.
■ The Synthesis of Aryltetralin Lignans
Type Podophyllotoxin
The history of podophyllotoxin synthe-
sis methods
In this bibliographic review, we will present
a general overview of the efforts to obtain podo-
phyllotoxin or one of its derivatives. This review
of the most used synthesis methods is carried
out, considering three aspects: (a) starting ma-
terials, (b) strategies to form rings A, B, C or D
and (c) strategies for controlling the configura-
tion of positions 1, 2, 3 and 4. Our aim is to gen-
erate a document that allows us to identify the
existing methodologies for constructing strate-
gic intermediate positions or structures, as well
as the reaction conditions, catalysts, reagents,
reaction media and efficient, rapid transforma-
tion sequences and economics that made them
possible.
The race for the synthesis of podophyllotoxin
and its derivatives began in the 1950s after a long
accumulation of scientific evidence about its bio-
logical activity. The first methods for obtaining
it used two strategies: the intramolecular Diels-
Alder reaction (vide infra) and the epimerization
of picropodophyllotoxin by racemization of posi-
tion 2 via the formation of enolates. Through this
latter methodology, diasteromeric mixtures of
45/55 of podophyllotoxin (1) and picropodophyl-
lotoxin (13) were reported, which could be sepa-
rated via crystallization with a yield of 38 % of
podophyllotoxin (Scheme 2). Years later, San Fe-
liciano also used this strategy in the synthesis
of podophyllotoxin [8, 9].
The second stage of these studies around the
family of molecules began in the 1970s [10] with
the first efforts to obtain the glycosylated ana-
logs – etoposide [5], teniposide and etopophos [3].
Although the synthesis of these compounds is not
related either the neolignan structure or the re-
solution of its stereogenic centers, or, on the other
hand, their mechanism of action was not related
to the synthesis of tubulin, but with topoisome-
rase, their notable therapeutic activity gave cer-
tainty to the pharmacological potential of their
chemical structure and encouraged the search for
new lignans.
O
O
Ar1
OMe
O
O
O
Ar1
O
O
OH
O
O
Ar1
O
O
OH
O
O
Ar1
OH
O
OH OH
O
O
Ar1
O
O
O
O
Ar1
O
O
O
Ar1
O
O
O
O
O
O
Ar1
O
O
12 (e )pipodophillotoxin
16 (y )atein
13 (p )icropodphillotoxin
17 (p )odophillic aldehyde
14 (p )odophillic acid
18 ( )(+)-burseran
15 (d )eoxipodophillotoxin
19 ( )�-apopicropodophillotoxin
Figure 3. The podophyllotoxin analogs most studied from a pharmacological point of view
ISSN 2308-8303 (Print) / 2518-1548 (Online) 7
Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
The synthesis of rings A and B
The third stage was the search for total syn-
thesis methods of podophyllotoxin and its ana-
logs (Scheme 3). In 1991, Ward provided a va-
luable compilation of all the synthesis methods
available up to that time and defined a general
classification of four methods according to the type
of transformation used, which was useful for later
classifications. Thus, the methods of (a) oxoester,
(b) hydroxyester, (c) Diels-Alder, and (d) conjuga-
te addition, could be distinguished. These methods
share two characteristics, each one focuses on the
specific formation of ring C and, they all started
from some derivative of 1,3-benzodioxol (methy-
lenedioxyphenyl or piperonyl group). These start-
ing materials have predominated in the search
1
O
O
Ar1
O
O
OH
13
O
O
Ar1
O
O
O
O
O
Ar1
O
O
OHO
Na
Scheme 2. Epimerization of picropodophyllotoxin (13), through the protection of the hydroxyl group with a pyranyl group, and sodium
enolate formation to obtain podophyllotoxin (1)
O
O
O
O
OH
O
O
O
O
O
Ar1
O
O
O
OTIPS
O
O
Ar1
O
O
OH
Ar1
O
O CO2Me
Me
Ar1
O
CO2Et
Me
MeO
O
O
OH
O
O
O
O OHO
Ar3
O
O
O
O
Cl
O
O
O
OH
Br
O
O O
Ar1
O
O
O
MgBr
H
26
24
28
27
29
O
O OH
21
O
O
CO2H
O
Ar1
O
O
OMe
O
O
O
H
O
Br
22
MeO
HO
OH
31
O
O
30
OH
O
NH2
O
O
H
O
20
O
O
SR
SR
O
O
O
O
Ph
O
O
Ar1
CO2Me
CO2Me
O
O
Ar2 CO2Et
CO2Et
O
O CN
OTBS
O
O OMe
OMe
O
O
O
O
OH
O
O
O
O
O
I
Br
O
O
O
CO2Me
MeO2C
Ar
O
O
O
O
Br
O
O
N
O
Br
Me
Ph
Me
H
O
O
O
O
Ar1
CO2Et
O
20
O
O
Ar1
CO2Et
CO2H
O
O
O
O
Ar1
CO2Me
CO2Et
O
O
O
Ar1
O
O
O
O
Ar1 O
I, 48, 50, 7c, 52
II, 57
III, 22, 23
IV, 46
V, 61
VI, 64a
VII, 18, 24
VIII, 39
IX, 48
X, 32, 33
XI, 25b
XII, 25a
XIII, 44a,
35b
XIV, 67
XV, 68
XVI, 60
XVII, 28, 66
XVIII, 26
XIX, 35a,
35b, 67
XX
XXI, 69,
71
XXII, 27
XXIII
XXIV, 63
XXV, 62
XXVI
XXVII, 10
R2
R1 R3
Ar
1
: R1 = R2 = R3 = OMe
Ar
2
: R1 = R3 = OMe; R2 = OH
Ar
3
: R1 = H; R2 = OH; R3 = OMe
Ar
4
: R1 = R3 = OMe; R2 = OCH2Ph
Ar
5
: R1 = H; R2 = OCH2O = R3
Ar
6
: R1 = H; R2 = R3 = OMe
23
25
O
O
O
O
Ar1
OH
MeO2C
Note: in Roman numeral the synthetic route; in Arabic numeral the bibliographic reference
Scheme 3. The main starting materials in the synthesis of aryltetralin lignan analogs of podophyllotoxin.
Compounds with rings A and B fused are usually chosen.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 8
Журнал органічної та фармацевтичної хімії 2024, 22 (2)
for transformations and functionalization, and
are the most useful since rings A and B are al-
ready fused. From this group of compounds, pi-
peronal (20, also known as heliotropin), homopi-
peronyl alcohol (21), bromopiperonal (22), asym-
metric aryl ketones derived from piperonal (23
and 24), vanillin derivatives (25), piperonyl chlo-
ride (26), safrole (27), sesamol (28), 3,4-methy-
lenedioxydihydrocinnamic acid (29), phenyl ala-
nine (30), and coniferyl alcohol (31) are the most
prominent prototypes, in which it is possible to
carry out transformations of positions 5 or 6 of
ring C (see Scheme 1). Due to their relative abun-
dance in nature, few reports have focused on their
synthesis during the search for aryltetralin lig-
nans. The reports by Urlacher [11] and Sattely
[12] are notable since it was possible to synthe-
size ring A, to subsequently obtain deoxypodo-
phyllotoxin (15) and podophyllotoxin (1) from co-
niferyl alcohol or phenylalanine, and a cascade
of modified metabolic reactions.
Other precursors similar to this group of com-
pounds are vanillinic acid and vanillin, which
despite lacking ring A, have been used to syn-
thesize structural analogs of podophyllotoxin.
There are useful methods for forming the
1,3-dioxol ring on phenyl rings: for example, the
reaction between 1,2-diphenols (catechols) and
methylene bromide [13], methylene chloride [14],
or methyl enolates [15]. The reaction of ortho-
quinones and imines catalyzed by palladium to
obtain substituted 1,3-dioxol rings [16] or ob-
taining of piperonal using black pepper pipero-
nal synthase has also been reported [17]. The reac-
tivity relationships of the positions attached to
the aromatic ring between safrole, isosafrole, pi-
peronal and sesamol have been studied; starting
from catechol, it is possible to find safrole and
isosafrole as intermediates until reaching pipe-
ronal, from which, in turn, protocols have been
described to obtain sesamol [18 – 21].
Regarding alternatives to functionalize the
1,3-benzodioxol system in the search for arylte-
tralin lignans, we can generalize two cases:
1. One can take advantage and transform
a substituent into the 1,3-benzodioxol system,
which carbon will be the position 4 of the aryl-
teralin lignan. A side substituent has generally
been a benzylic position in the form of carbonyl
or primary and secondary alcohol that will become
positions 2 and 3. Piperonal (20) and bromopipe-
ral (22) (Scheme 2, transformations I to XVI) are
the most used reagents for this purpose. In these
compounds the carbonyl group is transformed
into the secondary alcohol of position 4, also ac-
companied by reactions that introduce the car-
bons of positions 2 and 3 whether they include
ring D or not. Other useful substrates to fol-
low this transformation route are those used in
transformations VII, XIX, XX, XXI, XXII, XXIII,
XXV and XXVII. When it comes to asymmetric
syntheses or resolution, this transformation route
has served to assemble molecule with the neces-
sary configuration in positions 3 and 4.
2. A less studied route starts from 1,3-ben-
zodioxols with a substituent that in subsequent
transformations would be position 1 of the tetralin-
lignan. This is probably because it would involve
choosing or preparing a diarylmethanyl system,
which means more synthetic steps to reach the
corresponding aryltetralin lignan. The formation
of these types of bonds is usually designed to occur
in the intermediate or final stages of the most of
synthetic routes (see Scheme 4). In the litera-
ture it is possible to find examples of transfor-
mations XVIII and XXI.
The methods of constructing ring C
As mentioned before, most of the variants for
the synthesis of aryltetralin lignans focus on the
construction of ring C. This way makes it pos-
sible to configure the four stereogenic centers of
the lignans. From the pharmacological point of
view, variations in positions 1 and 4 have shown
good results. In general, the closure of ring C is
the final step of a variety of transformations, in
which we can distinguish the following three cases:
A. dihydroxyester and oxoester strategies – the
ring closure through the formation of a diaryl-
methanyl bond between position 1 of the tetra-
lin system and position 6 of the 1,3-benzodioxol
ring (Scheme 4, A);
B. the ring closure through Diels-Alder cyc-
loadditions (Scheme 4, B);
C. the conjugated addition – the ring closure
through a cascade of Michael-type reactions
and the nucleophilic substitution by α anions
(Scheme 4, C).
The next three sections focus on the most use-
ful examples of these strategies.
Strategy A. Dihydroxyester and oxoester
strategies
One of the first contributions was the work
of Curran [22] where the key intermediate was
a 1,3-dicarbonyl system (32). Here, the α carbon
will become that of position 2 of the tetralin lig-
nan, which is also in position β (or position 1 of
the tetralin lignan, which is also a benzylic car-
bon) has attached to ring E in some of its variants
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
(see Scheme 3). Thus, with the formation of the
bond between position 6 and 1 through two dif-
ferent strategies, ring C (33 and 34) is formed
(Scheme 5).
A strategy similar to that of Curran regard-
ing the closure of ring C has been used indepen-
dently by Daugan [26], Koga [27], and Uda [28]
for the construction of deoxypodophyllotoxin epi-
mers (15). The key step of these three transfor-
mations is the formation of the two enantiomers
of intermediate 35 obtained by resolution and enan-
tioselective synthesis. Thus, with the transforma-
tion of each enantiomer, the corresponding epi-
mer 36 was obtained, and after resolution the
epimers of 15 were generated, where the final
step of synthesis was the formation of ring C
since rings A, B and D were previously incorpo-
rated (Scheme 6).
Vandewalle proposed the same ring C clo-
sure method using protected diols in the form
of 1,3-dioxane [29] as a preliminary method and
silylene ether (37) [30] integrated into positions
2 and 4 of tetralin. In turn, this substrate con-
tains a carbonyl group in position 2. Through the
aldol addition to an aryl aldehyde, position 1 and
ring E are incorporated. The result is position 2
activated for the nucleophilic substitution (38)
by the aryl carbon of position 6 that will close
ring C (Scheme 7).
As can be seen, 1,3-dicarbonyl-α,β-unsatura-
ted systems that have ring E attached to posi-
tion β (position 1 of aryltetralin lignan) is a key
substrate to carry out this type of the cycle clo-
sure. Curran noted this advantage by proposing
the Michael addition between the piperonal-
derived Michael donor and the Michael accep-
tor 39 where the intermediate α anion carried out
the intramolecular nucleophilic substitution re-
sulted in the formation of ring C of compound 40
(Scheme 8) [31].
A similar strategy was proposed by Zhang [32,
33], in which a piperonal bromine derivative (41)
O
O
Ar
O
O
Ar
A
O
O
O
O
OR
X
Ar
OR
Ar
R
O
O
R
B
C
O
O
Ar
R
R O
O
Ar
R
R
O
O
O
O
Ar1
O
O
O
Ar1 O
Scheme 4. The ring C closure strategies in the synthesis of aryltetralin lignans: (A) formation of the bond between positions 6 and 1;
(B) the Diels-Alder cycloaddition; (C) the Michael reaction cascade – nucleophilic substitution by enolates
O
O
CO2Et
CO2Et
Ar
1. 1.3-1.5 equiv (CF3COO)3Ta
ClCH2CH2Cl, 84 oC, 30 min
2. Me2SO4, K2CO3, acetone, 12 h
O
O
CO2Et
CO2Et
Ar1
1.5 equiv NaIO4, EtOH, RT, 2 h
ClCH2CH2Cl, TFA O
O
CO2Et
CO2Et
Ar2
32
33, 55 %
34, 100 %
Scheme 5. The ring C closure proposed by Curran
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Журнал органічної та фармацевтичної хімії 2024, 22 (2)
protected with a chiral pseudoephedrine auxiliary
carried out the Michael-type reaction with an ac-
ceptor containing ring E (Scheme 9). A sequen-
tial process of the Michael addition and nucleo-
philic substitution were used to incorporate an
allyl group in the α-position to obtain intermedi-
ate 42. Its oxidation generated the correspond-
ing dialdehyde used further for the cyclization
of ring C via the aldol addition to obtain inter-
mediate 43. The formation of ring D was carried
out via the lactonization to obtain podophyllo-
toxone with the subsequent reduction generated
the podophyllotoxin enanitomer ((+)-1).
The extensive oxoester pathway constructs
ring C in the form of a γ-oxoester intermediate 44
(Scheme 10). This strategy was originated by
O
O
Ar5
O
Ar5
O
CH2OR
O
O
CH2OR
1. LDA
2. Ar5CHO
3. H2/Pd-C
2. IO4
3. CrO3
1. BuLi
2. Ar5CH2CHO
1. Separation
2. Cl2CCO
3. Zn/HOAc
4. Bu3SnH
LDA
TFA
O
O
Ar5
O
Ar5
O
CH2OR
1. LDA
2. Ar5CH2Br
Ar5 CO2Me
CO2H
H2 Ar5 CO2Me
CO2H
1. Resolution
2. Ca(BH4)2
Koga
Dougan
Ar1 H
O
O
O (+)-15
O
O
Ar5
Resolution
(-)-35, 64 %
(+)-35, 57 %
36a
rac-35
1. LiAlH4
O
OHO
Ar1
Koga
O
O
CH2OR
1. LiAlH4
2. H2, Pd/C
3. IO4
4. CrO3
LDA
Ar1 H
O
TFA
O
O (-)-15
36a
O
OHO
Ar1
Uda
SP
MeO
O
MeO pTol
O
S
pTol
O
Ar5
Scheme 6. The ring C closure for the synthesis of deoxypodophyllotoxin epimers (15)
O
CO2TMS
Si
O
O
O LDA
O
CO2H
Si
O
O
O
Ar1
HO
1. Me3SiCl, Et3N
2. MsCl, Et3N
O
CO2H
Si
O
O
O
Ar1
37 38, 34 %
Ar1 H
O
56 %
Scheme 7. The ring C closure via the nucleophilic substitution in position 2
O
O
O
O
O
1. 1.2 equiv Ph3P CH
+
3Br−, K2CO3,
18-crown-6, THF, 36 h
O
O
Br
OCH3
Br
1.05 equiv BuLi,
THF -100 oC to RT to 1 h
Ar1
CO2Et
CO2Et
OMe
CO2Et
CO2Et
Ar1
H 39 (1.05 equiv)
40
Br
O
O
OMe
CO2Et
CO2Et
Ar1
Br
77 %, diasteromeric mixture
2. 3 equiv Br2, MeOH, RT, 36 h
Scheme 8. The ring C closure using the Michael addition and aldol reaction sequence
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
Gensler (Route A) [34] with the construction of
ring C through the aldol condensation between
diaryl ketone 45 and diethyl succinate to gene-
rate 46, upon which the ring closure was carried
out via the Friedel-Crafts type acetylation. Rogers
designed γ-aryllactone 48, which enolate carried
out the addition-elimination on piperonyl chlo-
ride 47 and generated intermediate 49, which, af-
ter the rearrangement and decarboxylation (50),
gave the oxoester intermediate (Route B) [35].
For their part, Wattanasin [36] and Doyle [37]
(Route C) proposed the formation of trisubstituted
cyclopropyl intermediate 52 from α,β-unsaturated
piperonyl ketones 51 for constructing the corre-
sponding oxoesters 44. Curran (Route D) also pro-
posed the formation of type 44 oxoesters in two
independent methodologies. The first is based on
his own previous contributions from the 1,3-di-
carbonyl system (32) [38], and the second from a
methoxybromide (53) derived from piperonal to
generate 55, a structural analog of 33 [29].
Strategy B. Addition via the Diels-Alder
reaction
Another route for the construction of ring C
is through the Diels-Alder reaction remained in
force for almost 50 years. One of its advantages is
that it allows almost all alternative configurations
of the tetraline system to be addressed. From the
synthetic point of view, the diene occurs in a va-
riant of the system that already contains the
methylenedioxyphenyl nucleus (rings A and B),
either as a resonance hybrid or as a formal structure
O
O
N
O
Ph
Br
OtBu
O
Ar1
O
O OtBu
O
42, 65 %
Ar1
O
O
O OtBu
OAr1
O O
O
O OtBu
OAr1
OH OH
O
O OtBu
OAr1
O OH
O
O
O
OAr1
O
nBuLi, THF, -78 oC, 0.5 h
TMEDA, 1.5 h
OsO4, NMNO
tBuOH/THF/H2O
94 %
L-proline, CH2Cl2
then NaBH4, MeOH
81 %
O
O
O
OAr1
OH
(+)-1, 98 %
L-selectride HCl/H2O, MeCN
41
43, 80 %90 %
allyl bromide, RT, 2 h
then AcOH/H2O in THF
then NaIO3/SiO2
CH2Cl2, RT
MnO2
MeCNthen DCC in CH2Cl2THF, -78 oC
Scheme 9. The synthesis of podophyllotoxin and its enantiomer proposed by Zhang
O
O
O
Ar
O
O
O
CO2Et
Ar
O
O
CO2Et
CO2Et
Ar2
O
O
CO2Et
CO2Et
Ar2
O
O
CO2Et
CO2Et
Ar2
OMe
O
O
Li
Br
OMe
CO2Et
Ar2
CO2Et
+
1. Tl(O2CCF3)3
2. NaHSO3
3. Me2SO4
1. NBS/H2O
2. OH−/MeOH
O
O
O
CO2Et
Kende
Ar1
Et2O BF3
or
SnCl4, MeNO2
1. H2, Pd/C
2. AcCl
3. SnCl4
O
O
Ar1
O
CO2Et
CO2Me
SnCl4, CHCl3
RT, 12 h
1. TFA, NaHCO3
2. CeO3/Py
3. OH−/MeOH
50, 91 %
O
O
Ar
CO2Et
CO2EtEtO2C
CO2Et
KOtBu
Ar1EtO2C
O
O
Cl
O
+
Ar1
OEtO2C
MeO2C
O
CO2MeKO2C
Mn(OAc)3 2H2O
AcOH, 70 oC
KH, THF
Route B
44
O
O
O
Ar1
Route C
45 46
Route A
47 48 49, 80 % 51
32 55, 55 %
5354, 88 %
Route D
66-100 %
53-95 %
60 %
50 %
*
RT, 24 h
O
O
O
Ar1
O
EtO2C
CO2Me
O
Me2S CO2Et
*
52, >90 %
Scheme 10. The oxoester pathway in constructing ring C of aryl tetralin lignans
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Журнал органічної та фармацевтичної хімії 2024, 22 (2)
that is in equilibrium with a precursor. Thus, the
most notable contributions offer alternatives
for the design of dienophiles that allow the con-
struction or almost complete incorporation of
rings D and E.
For the purposes of studying the Diels-Alder
pathway, we can divide the contributions into
intermolecular reactions (Scheme 11) and in-
tramolecular reactions (Scheme 12). Many in-
termolecular methods use dimethyl fumarate or
its analogs as dienophiles, in which precursors
of aryltetralin lignans are obtained where rings
A, B, C, and E are already included, and ring D
will be formed later. Thus, one of the first contri-
butions was proposed by Rodrigo [39] through
the formation of an isobenzofuran ring substi-
tuted in position 1 with ring E (56). This system
functioned as a diene and reacted with dimethyl
acetylenedicarboxylate (DMAD, 57) generating
an adduct already containing the aryltetralin-
lignan system (58). This adduct was also formed
by Berkowitz by a similar synthesis route [40].
O
O Br
1. BuLi
2. Bu3P CuI O
O
CHO O
O
OH
CH2OH
Ar1
CO2Me
Diene Dienophile
O
O
Ar1
OH
h�
OMe
OMe
O
O
O
O
Ar
Glinksi et Durst
(1983)
O
O
O
Ar
Jones et Thomson
(1987 et 1994)
CO2Me
CO2Me
O
O
AcOH O
O
Ar1
OMe
OH
Rodrigo
(1980)
Ar1
OMe
O
OMe
OO
MeO O
O
Ar
CO2Me
CO2Me
O
O
O
SO2
Ar
O
O
CH2SiMe3
OH
Ar
O
O
Ar
OO O
O
O
O
OAr
O
Ogasawara
(1985)
O
O
Ar1
OH
O
O
Ar1
OH
O
O
CO2Me
Ar
CO2Me
HO
Charlton
(1995)
MeO
O
OMe
O
MeO
O
OMe
O
MeO
O
OMe
O
O
O
OH
Ar1
O
O
tBu
O
O
O
O
Ar1
OH
O
O
tBu
O
Choy (1990)O
O
OAc
Ar1
56
57
58
59 60
61
62 63 64, 58 %
65
66
67, 64 %
69
68 70, 62 %
O
O
O
OTBS
71
O
O
OTBS ArH2N
O
OMe
O
Ar = C6F4(4-CF3)
O
O
CO2Me
OTBS
NHAr
OMaimone
(2014, 2019)
72
73
O
O Br
OMe
OMe
Berkowitz
(1996)
*
3. ArCH2Br
4. H3O+
Ar1
Scheme 11. Examples of an intermolecular Diels-Alder reaction in the synthesis of aryltetralin lignans
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
Another method was proposed by Durst [41]
forming a diene via irradiation promoting the
tautomeric equilibrium between a piperonal de-
rivative and the corresponding enol (59). The latter
when reacting with dimethyl fumarate generates
the adduct with ring C formed (60). This pro-
duct and its analogs and precursors were also
obtained by Thomson [42, 43] in his strategy from
a diene in the form of isochromenone (61) which
also reacts with dimethyl fumarate.
Charlton [44] for his part, used benzocyclobu-
tanol (62) to form an enol-type diene (63) reacted
with dimethyl fumarate to generate a product
similar to the Durst’s substituted with a hydroxyl
group in position 1 (64).
The last two intermolecular Diels-Alder stra-
tegies employ α,β-unsaturated cyclopentacarbo-
nyls as dienophiles. This alternative has the ad-
vantage that the products obtained are tetralin
lignans, analogs of podophyllotoxin with the five
integrated rings. Ogasawara [45] used maleic an-
hydride (66), which, when reacted with dimethy-
lenecyclohexa-1,3-diene (65), generated the deoxy-
podophyotoxin analog 67. In this methodology, it
is notable how the diene can be obtained from two
different substrates. Choy [46] used a dienophile
integrated with a chiral auxiliary (R)-(4-oxocyc-
lopent-2-en-1-yl)methyl pivalate (69), meanwhile
the diene (similar to 59) was generated in a stra-
tegy similar to that of Charlton frombenzocyclo-
butanol (68). In this case, the product obtained was
a mixture of picropodophyllotoxin epimers (70).
Finally, the Maimone’s [47, 48] strategy used
benzocyclobutanol 71 and the fumarate deriva-
tive 72 to obtain product 73 similar to 60.
Although the intermolecular Diels-Alder re-
actions for constructing podophyllotoxin and its
analogs are the most versatile and widespread,
first the corresponding intramolecular variants
were developed. A generic example is represented
by the synthesis of lignan lactones 75 via the
Diels-Alder reaction in which both the diene
(E-propyl styrene system) and the dienophile
(an α,β-unsaturated ester that in the β position is
linked to the corresponding E ring) are present in
the same substrate (74) [49 – 53]. It highlights the
synthesis of the substrates through the classical
Fischer esterification [54] and various ways of ac-
tivating the corresponding Diels-Alder addition,
such as microwave irradiation [55]. This stra-
tegy has been used to synthesize tetralin lig-
nans, such as taiwanin (76) and justicidin (77)
(Scheme 12) [56].
Thus, proposals for the synthesis of podophyl-
lotoxin through an intramolecular Diels-Alder re-
action have been presented regularly. Durst and
Speltz reported two strategies. From carbama-
tes (78) [57, 58] and carbonates (79) [59] they ge-
nerated dienes similar to those prepared by Choy
and Charlton (80 and 81) and cyclized to generate
ring C (82 and 83, Scheme 13).
Czarnocki [60] also provided his version of
a periciclic reaction to form ring C using proli-
nol as a chiral auxiliary. Intermediate 84 under-
went an electrocyclic reaction that generated com-
pound 85 (Scheme 14).
Strategy C. Conjugate addition
Another widely used and standardized metho-
dology in constructing ring C is activating posi-
tion 4 as a nucleophile. This strategy can be car-
ried out through α-carbon reactions, Knoevenagel-
type reactions, or activations via the Corey-Seebach
or other umpolung reactions, which have been
the most efficient and selective in this group of
transformations.
Starting from piperonal (20), the general
strategy is that described in all the proposals of
Scheme 15 [61]. The carbonyl of piperonal (po-
sition 4) is activated as a nucleophile (86), which
acts as a Michael donor with α,β-unsaturated
furan-2-one (87) which can be substituted with
a chiral auxiliary in the γ position (R3). Once the
O
O
OH
Klemm
(1963 – 1966) O
O
O
O
Ar1
O
O
O
Ar1 O
O
O
O
O
O
O
taiwanin
7574
O
O
O
O
O
justicidin
O
76 77
Scheme 12. The example of the intramolecular Diels-Alder reaction in the synthesis of aryl-tetralin lignans
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Журнал органічної та фармацевтичної хімії 2024, 22 (2)
1,4-addition is made, the corresponding enolate
acts as a nucleophile for the aldol addition with
an aryl aldehyde or a benzyl halide that already
contains the corresponding E ring. Thus, the ge-
neric product of this transformation is a system
of two phenylpropanoid units (88, similar to 3)
bonded by their carbons 8 and 8’ (positions 3 and
2 of the tetralin lignan, respectively). This sys-
tem has the dithiane group in position 4, while
in position 1 it may have a hydroxyl group (R4),
depending on whether there is the aldol addi-
tion or the nucleophilic substitution.
The subsequent transformation consists of the
release of the dithian group to generate a methy-
lene (89, Route A), a methine-hydroxyl group
(90, Route B) or a keto group (91, Route C) in po-
sition 4. The ring closure is carried out via the
nucleophilic substitution from position 6 to 1 to
generate the analogs of deoxypodophyllotoxin (92),
podophyllotoxin (93), and podophyllotoxone (94).
O
O
Ar1
O
N
O
O
O
O
Ar1
O
N
O
O
H
MeOH/TFA O
O
Ar1
O
N
O
O
[1,5]-H shift
84 85
Scheme 14. The intramolecular Diels-Alder cycloaddition using prolinol derivatives as a chiral auxiliary
O
O SR2
SR1
O
O
O
O
SR2R1S
O
O
Ar
R4
R3
ArCHO or
ArCH2Br
O
O
O
O
Ar
R4
O
O
O
O
Ar
R4 O
O
OH
O
O
Ar
R4
O
O
O
O
OAr
O
O
O
O
OAr
O
O
O
OAr
OH
A B C
D
E F G
86
87
88
89 90 91
92 93 94
R3
Scheme 15. The general scheme of the conjugate addition method for the synthesis of aryl-tetralin lignans
O
O
OAc
Ar1 O
O
O
O
Ar1
H
N
CO2Me
1.LiOH, H2O
2. heating
O
O
O NH
CO2Me
Ar1
MeO2C NCO
Ph3SnOAc O
O
NHO
CO2Me
Ar1
O O
O
O
O
O
Ar1
O
CO2Me
O
O
OO
CO2Me
Ar1
O
O
O
O O
CO2Me
Ar1
O
78, 47 %
79
80
81
82
83
Scheme 13. Intramolecular Diels-Alder reactions using benzocyclobutanes as diene precursors
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
The first two examples of this methodology
were the works by Ziegler [62] and González
[60, 63] (Scheme 16) where through dithiolanes
(86a) the hydroxyl-lignans 88a and 88b were ob-
tained, their ring C closure was reported to ob-
tain the corresponding epimers: epipodophyllo-
toxin (12), picropodophyllotoxin (13), podophyll-
otoxanes (94a – c). In the 1970s, Ziegler provided
evidence to conclude that only 1,3-dithyan nu-
cleophiles could carry out the corresponding Mi-
chael addition; however, years later Iwasaki and
Ward improved the use of 1,3-diketones or α-cyano-
esters (see Schemes 22, 23 and 24). For his part,
Ward [64] used this same methodology from thio-
phenylacetals (86b) when constructing epimeric de-
rivatives of podophyllotoxin 95, from ketone 91a.
Later Ward also showed the option of em-
ploying a single thioether substituent (86d,e) to
obtain analogs of desoxypodophyllotoxin (92a)
and epipodophyllotoxin (93a) (Scheme 17).
In the early 1990s, Kutney [65] made two out-
standing contributions to the synthesis of inter-
mediates similar to 88 lacking ring A. The first
was the use of benzyl halides as a source of ring
E (Scheme 18; 88f and 88g); intermediates 89a,
89b and rac-90d and rac-90e were obtained from
them. The second contribution consisted of the
latter being reacted with a peroxidase with cata-
lytic promiscuity from Catharanthus roseus plant,
which had already made similar ring closures.
Thus, the closure of ring C could be achieved in
intermediate 89a to generate 92b and (S)-90e
to generate 93b.
A similar method to that of Scheme 16 was
developed by Bhat [66], in which instead of a thio-
acetal, phenylsulfoxide 86h was used as a nu-
cleophile to subsequently follow the Pelter-Ward
route (Scheme 19). It is noteworthy that it was
possible to synthesize podophyllotoxin (1) in just
a few steps of synthesis.
One of the strategies to control the diaster-
oselectivity of type 88 compounds was to incor-
porate a menthyl group (in its two configura-
tions) as a chiral auxiliary in furanone 87 (87b)
(Scheme 20) and react it with the correspond-
ing anions of thioketals (86i) [67 – 70] and dithio-
lanes (86j) [71].
The idea of including chiral auxiliaries in ty-
pe 87 furanones was originally proposed by Koga
and his collaborators [25, 72]. In the similar syn-
thesis to those previously explained, dithiane 96
(ring E activated as dithiane) was used to carry
out the Michael type addition on lactone 87c
and obtain the activated intermediate 97, a phe-
nylpropanoid system with rings D and E joined
through positions 1 and 2 (Scheme 21). In this
case, rings A and B are integrated as piperonyl
bromide through a nucleophilic substitution to
O
O
O
Ar
O
O
+ O
O
O
Ar
O
O
+ 12 + 13
O
O
O
Ar
O
R2R1
HO
O
O
O
Ar1 OHO
O
O
O
O
Ar1 OHO
OH
O
O
O
Ar1 O
OBzO
OO
O
R2
R1
Ziegler and González,
86a: R1 = S(CH2)3S = R2
Pelter, 86b: R1 = R2 = SPh
Ziegler: Ar1CH2Cl
González: CHOAr6
Pelter and Ward: CHOAr1
87a
Ziegler, 88a: R1 = S(CH2)3S = R2; Ar1;
93 % (52/48 eritro:treo)
González, 88b: R1 = S(CH2)3S = R2; Ar6;
66 % (isomers mixture)
Pelter, 88c: R1 = R2 = SPh; Ar1;
97 % (eritro/treo mixture)
Pelter
NIS
Ziegler, 94a; Ar1; 90 %
González, 94b; Ar6
Ziegler and González, only treo
94c
91a, 85 % 90a, 55 % 95
Scheme 16. First examples of the conjugate addition as a synthesis method of aryltetralin lignans
Ar1CHO O
O
O
O
Ar1
HO
SR
1. Ni Raney
2. TFA
O
O
O
OAr1
HClO4
O
Ar1
OH
O
O
O
O
SR
Ar1 O
O
O
86d: R = Ph
86e: R = tBu
O
O SR
O
O
+
1. Hg2+
2. H2O88d,e
50 %
92a, 60 %
93a, 60 %
87a
Scheme 17. The synthesis of deoxypodophyllotoxin (85) and epipodophyllotoxin (86) from thioethers derived from piperonal
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R2O
R1O
SPh
SPh
O
O
+
Ar4CH2Br
R2O
PhS SPh
O
O
Ar4
1. I2, MeOH
2. HCl/THF
R1O
R2O
O
O
Ar4
O
R1O
R2O
O
O
Ar4
OH
H2, Pd/C
1. BCl3
2. CaCO3
R1O
R2O
O
O
Ar2
OH
R1O
R2O
O
O
Ar2
R1O
R2O
O
OAr2
R1 = H; R2 = Me
R1O
R2O
(S) O
O
Ar2
OH
R1O
R2O
O
O
Ar2
Catharanthus roseus
pH 6.4, H2O2
R1 = H; R2 = iPr
OH
Catharanthus roseus
pH 6.4, H2O2
86f: R1 = H; R2 = Me
86g: R1 = H; R2 = iPr
87a 88f: R1 = H; R2 = Me
88g: R1 = H; R2 = iPr
89a: R1 = H; R2 = Me
89b: R1 = H; R2 = iPr
92b: R1 = H; R2 = Me
91b: R1 = H; R2 = Me
91c: R1 = H; R2 = iPr
90b: R1 = H; R2 = Me
90c: R1 = H; R2 = iPr
rac-90d: R1 = H; R2 = Me
rac-90e: R1 = H; R2 = iPr
(S)-90d: R1 = H; R2 = Me
(S)-90e: R1 = H; R2 = iPr
93b: R1 = H; R2 = Me
R1O
only;
only;
Scheme 18. The closure of C ring using the enzymatic catalysis with peroxidase from Catharantus roseus
O
O
S
Ar1
O
O
O
O
PhO
O
O
O
H 4 steps
S
PhO
HO
1, 25 %
86h
60 %
1. TFA, 0 oC, 3 h
2. HgO, BF3 OEt2, 28 h
1. nBuLi, THF
-78 oC, 1 h
2. 79a, 1 h
3. Ar1CHO, THF, 2 h
*
Scheme 19. The synthesis of podophyllotoxin using phenylsulfoxides
O
O R2
R1
O
O
+
Omenth
Ar1CHO O
O
O
O
R1 R2
Ar1HO
Omenth
1 NiCl2, NaBH4
2. NaBH4, NaOH O
O
O
OArHO
TFA
Pelter, 86i: R1 = R2 = SPh
O
O
O
O
ArHO
O
O
O
O O
Si
CO2Me
Ar
HO
(-)-12, 81 %
Pelter
Vandewalle
Vandewalle, 78j: R1 = S(CH2)3S = R2
87b
(-)-15
KOH, NaBH4O
O
O
O
R1 R2
Omenth
O
O
O
O
R1 R2
Ar1HO
O
O
O
O
R1 R2
84 %
1. LDA
2. Ti(NEt2)3Cl
3. Ar1CHO
HgCl2
CaCO3
83 %
81 % 86 %
~60 %
Scheme 20. The conjugate addition using chiral menthyl auxiliaries in furanones
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
obtain 98. The removal of the ester, benzyl and
dithiane groups generated lignan 99, which sub-
sequent oxidation generated (+)-burseran (100),
a direct precursor of an epimer of deoxypodo-
phyllotoxin.
As mentioned above, Ziegler studied the ac-
tivation of position 4 as a nucleophile by placing
it in the α-position of thioacetals and carbonyl
systems; however, the latter did not generate
good results in the synthesis of podophyllotoxin-
type lignans at the time (Scheme 22).
This technique was later improved by Iwasa-
ki [73] and Ward [74] by implementing TBS-type
protecting groups in position 4 (86k) and thus
obtaining 88h-type compounds (Scheme 23, A).
The second stage of this methodology was proposed
by Enders [75, 76] and his collaborators by incorpo-
rating secondary amines as chiral auxiliaries (86l),
preserving the nitrile group (Scheme 23, B).
The Michael-type addition of the corresponding
nucleophile proceeded with diasteromeric excess-
es of up to 98 %. The subsequent removal of the
auxiliary and the aldol condensation with differ-
ent aldehydes reached 88 % yield and up to 96 %
enantiomeric excess for compound 91d.
The use of menthol as a chiral auxiliary has
also been implemented in this methodology.
Storer [77] reacted α-anion 86m with ketone 87b
to obtain 88i, which could be oxidized to ketone
91e and reduced to alcohol 90f (Scheme 24).
Recently, Hazra [78] provided a new metho-
dology for the formation of type 88 (88j) interme-
diates through aldol-type reactions with bromo-
piperonal (22) and in situ formation of D ring
(Scheme 25). This compound was cyclized to
form intermediate 90g from which it was possible
Ar1
S S
+
OBn
O
O Ar1
S
S
OBn
O
O
87c96 97
O
O
Br
Ar1
SS
OBn
O
O
98, 96 %
O
O
Ar1
OH
OH
OH
99, 98 %
O
O
Ar1
O
O
100, 85 %
O
O
THF Ni-Ra
LiAlH4, THF
tBuOH, NaIO4
Scheme 21. The first inclusion of chiral auxiliaries in the conjugated addition for the synthesis of lignans
O
O
R2
R1
O
O
Ar
O H
O
O
R2R1
O
O
Ar86
87
88
a) No reaction R1 = R2 = CO2Me
b) No reaction R1 = CN; R2 = OCH(OEt)CH3
c) No reaction R1 = CN; R2 = N(CH2CH2)2
d) No reaction R1 = H; R2 = SOPh
e) No reaction R1 = R2 = SEt
f) Reaction proceeds R1 = R2 = S(CH2)3S
Scheme 22. Proposals for activation of position 4 in the α-carbon form of carbonyls and thioacetals
O
O
OTBS
CN
O
O
Ar1
O H
O
O
OTBSNC
O
OAr1HO
86k 88h, 84 %
O
O
N
CN
O
OPh
O
O
N
NC
O
O
O
OPh
O
O
O
OAr1HO
91d, 54-88 %
O
Ar = a) Ar1; b) piperonyl;
c) p-anisyl; d) veratryl
86l 94-98 %
56-58 % de
THF or Et2O, LDA
-78 oC, 87a
60-98 % de, >96 % ee
1. tBuLi, THF, -78 oC, ArCH2Br or
ZnCl2, Ar1CHO, NH4Cl, H2O
2. AgNO3, H2O, THF, TA
87a
A
B
Scheme 23. The activation of position 4 through α anions of nitriles
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Журнал органічної та фармацевтичної хімії 2024, 22 (2)
to differentially obtain podophyllotoxin (1) and
two of its epimers (–)-13 and (+)-13.
The synthesis of podophyllotoxin and analogs
reported by Fuchs [79] could also be included in
the conjugate additions. The reaction of pipe-
ronal with bromomethylfuranone (87d) yields
rac-trans-101, which after the Michael type ad-
dition generates rac-trans-90a (hydroxyyatein)
from which racemic yatein 16 could be formed
(Scheme 26). It highlights the integration of a
biocatalytic protocol using the enzyme 2-ODD-PH
to carry out the formation of cycle C and the ste-
reoselective obtaining of hydroxyyatein (+)-90a.
Renata [80] also used the enzyme 2-ODD-PH
in the cyclization of yatein (16), it was prepared via
cross-heterocoupling of enolates of compounds 102
O
O
OTBDMS
NC O
O
Ar1
O H
O
O
OTBDMS
NC
O
OAr1HO
86m 88i
Omenth Omenth
TBAF O
O
O
OAr1HO
OmenthO
O
O
O
OAr1
HO
OH
NaBH4
91e
90f
87c
Scheme 24. The use of menthol as a chiral auxiliary in the conjugate addition of alpha anions to nitrile
O
O
H
O
Br
MeO
H
O
O
+
O
O
OH
Br
O
O
1. L-proline (cat.)
DMF, 4 oC, 24 h
then NaBH4, MeOH, 0 oC, 2 h
2. pTSA, toluene, 65 oC, 8 h
O
O
OTBS
Br
O
O
TBSOTf
THF, 0 oC, 12 h
O
O
OTBS
Br
O
O
1. LiHMDS, Ar1CHO
THF, -78 oC, 6 h
2. MsCl, Et3N 0 oC to RT, 4 h
then DBU, rt, 12h
22
88j, 84 %
Pd, DMF, DIPEAO
O
OTBS
O
OAr1
O
O
OTBS
O
O
+
1, 54 % (-)-13, 52 % (+)-13, 88 %
1. Pd/C, HCO2Na, H2O
1-pentanol, 40 oC, 12 h
2. TBAF, AcOH-THF 0 oC, 2 h
1. Pd/C, HCO2Na, H2O
1-pentanol, 40 oC, 12 h
2. TBAF, THF RT, 2 h
1. Pd/C, H2 (1 atm)
MeOH, RT, 12 h
2. TBAF, THF, 0 oC, 2 h
94 %
90g, 84 % Ar1
80 oC, 12 h
Scheme 25. The alternative in the synthesis of lignans by the conjugate addition
O
OBr
O
O
H
O
+
O
O
OH
O
O
H
rac-trans-101
Zn0, NH4Cl
toluene/DME, RT
20 87d
O
O
OH
O
O
H
rac-trans-90a
O
B
O
Ar1
Ar1
H
[(RhIcod)Cl]2, Et3N,
1,4-dioxane/H2O,
70 oC, 3 h
rac-16, 95 %
H2, Pd/C,
HClO4
2-ODD-PH
FeII, Na ascorbate
TRIS (pH = 7.4), 18 oC
O
O
OH
O
O
H
(+)-90a Ar1H
+12, 38 %
>99 % ee
Scheme 26. Obtaining hydroxyyatein and epipodophyllotoxin via an alternate conjugated addition from piperonal
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
and 103 from which dehydroxypodophyllotoxin
(15) was subsequently obtained (Scheme 27).
A strategy that shares the same reasoning
as the conjugate additions described so far is the
Bach’s [81] strategy, in which the formation of
ring C is the critical step in the podophyllotoxin
synthesis. Starting from (3,4,5-trimethoxy)-benzal-
dehyde and vinylfuranone 104, rings D and E
were incorporated via the aldol addition to sub-
sequently incorporate the piperonyl group via
the Friedel-Crafts alkylation to obtain interme-
diate 105. With the formation of the correspond-
ing ring C a 4-exovinylpodophyllotoxin (106)
could be generated, its reduction generated po-
dophyllotoxin (1) (Scheme 28).
The synthesis of ring D
The synthesis of ring D in aryl-tetralin lig-
nans of the podophyllotoxin type and their struc-
tural analogs is a poorly differentiated topic in dis-
cussions of the total synthesis of these compounds.
The main methods consider that the most criti-
cal transformations are those that allow the
synthesis of ring C with the proper configura-
tion of its four tetrahedral carbons and that the
synthesis of ring D is usually easier to carry out,
either as an intermediate or final step. Although
in most methods the formation of ring D is rela-
tively simple, it is worth pointing out some pe-
culiarities in this regard.
Incorporation of preformed rings
The simplest method to obtain ring D is its
incorporation through a precursor that already
contains it (Scheme 29). The works of Koga,
Daugan and Uda mentioned in Scheme 5 and
the general strategy of the conjugate addition in
Scheme 12 are examples of this methodology.
Another way to reach this ring is through the
Diels-Alder type intramolecular cycloadditions pro-
posed by Klemm, described in Scheme 12. In this
strategy, the ester group, which will later be the
O
O
O
O
O
O
Ar1
αKG, 2-ODD-PH
O2, Fe2+
O
O
O
O
15, 95 %
Ar1
Y*
O
OAr1
OtBu
O
O
Y*
O
N
O
O
iPr
Y* =
Ar1
OtBu
O
LDA, CuII
LiBH4, DBU, ∆
1, 58 %
1. CrO3, 3,5-DMP
2. L-Selectride
16, 51 %
102
103
+
Scheme 27. The synthesis of yatein, deoxypodophyllotoxin and podophyllotoxin implementing the enzymatic cyclization
and cross-heterocoupling
O
O
O
O
OH
H
O
Ar1 +
O
O
HO
Ar1
O
OAr1
O
O
OH
O
OAr1
O
O
OTf
O
OAr1
O
1, 75 %
1. OsO4, NMO
NaIO4, CH2Cl2
2. LiAlH(OtBu)3
Et2O
O
Pd(OAc)2, PPh3 Tf2O, NEt3
89 %
LDA, THF
AuCl3, CH3NO2
20 oC, 1 h
104, 94 % 105, 98 %
106, 58 %
-78 oC, 30 min
CH2Cl2MeCN
Scheme 28. The podophyllotoxin synthesis through a 4-exovinyl-podophyllotoxin formed via the Friedel-Crafts acylation
O
O
R
O
O
Ar
O
O
O
OAr
Koga, Daugan
and Uda
conjugated
addition
Scheme 29. The incorporation of ring D through precursors that already have formed it
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Журнал органічної та фармацевтичної хімії 2024, 22 (2)
lactone, is already formed, and the cycloaddition
will complete the formation of rings C and D
(Scheme 30).
Lactonization
When the incorporation of the complete D ring
is not possible, a strategy that is convenient due
to its simplicity and variety of conditions is the
formation of the lactone-type bond from precur-
sors that have a hydroxymethyl group or its syn-
thetic equivalent in position 3 and an acid deriv-
ative in position 2. Thus, we can find examples
where the synthesis of ring D is the last step to
synthesize podophyllotoxin (Scheme 31) or to ob-
tain its analogs or precursors of it (Scheme 32).
Thus, we can find the contributions of Rodrigo,
[82, 83] Trujillo,[60, 62] Curran, [23] Koga, [25]
Wattanasin, [84] Takano, [44] Wong, [85] Durst,
[40, 56, 57] Vandewalle, [70] Thomson, [42]
Charlton, [43] Meyers, [86] and Zhang [30, 31, 79].
It is possible to find variants where ring D is
formed before incorporating other rings as in
the case of Hazra [25].
Sherburn [87] reported an interesting case of
the formation of ring D, and the incorporation of
ring E. Starting from vinyl piperonal 27 and cro-
tonyl-oxazolidinone 107, the aldol reaction pro-
duct 108 was obtained, its chiral auxiliary re-
lease generated 109. The formation of ring C was
through the metathesis to generate tetralin 110.
The key to forming rings D and E was the incorpo-
ration of a thiocarbonate group (111). Thus, the
epimeric protein derivative of podophyllotoxin 112
R1
R2
O
O
Ar
Ac2O
O
OAr
R2
R1
+ O
OAr
R1
R2
H2, Lindlar catalyst H2, Pd/C
R1
R2
O
O
Ar
O
OAr
R1
R2
a) R1 = R2 = H
b) R1 = R2 = -OCH2O- , Ar1
c) R1 = R2 = -OCH2O- , Ar4
d) R1 = R2 = CH3O, Ar4
e) R1 = R2 = CH3O, Ar = Ph
f) R1 = R2 = R5 = H, Ar4
Ac2O
Scheme 30. The ring D formation by the intramolecular Diels-Alder addition
O
O OMe
OAr1
OH
O
O
O
O
OAr1
OH
Ra-Ni
Rodrigo
(1989)
O
O
Cl
Ar4
O
NaO
O
O OMe
OAr4
O
DMF
Trujillo
O
O OMe
OAr4
OH
ZnCl2
Thomson
OH
TBAF, ZnCl2
Vandewalle
O
Si
tButBu
O
O CO2H
Ar1
NHO
O
LiOH
H+, HNO2
Durst
O
O
Ar1
OH
O
O
Ar1
O
O
OH
3. DCC
Wong
1. OH−
2. H+OMe
O
OH
Durst
(1982)
O
O
Ar1
O
OH
O
O
O
O
O
O
Ar4
HO
Rodrigo
(1981)
O
O OtBu
OAr1
O OH
O
O
O
OAr1
O
L-selectride
THF, -78 oC
HCl/H2O, MeCN
then DCC in CH2Cl2
Zhang
+
Scheme 31. The ring D synthesis via esterification to form lactones to obtain podophyllotoxin
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
could be transformed into a podophyllotoxone (113),
podophyllotoxin ester 114 and in podophyllotox-
in epimer 115 (Scheme 33).
Within the variety of options around ring D,
it is possible to find that analogs have been
proposed with a change in the position of the
lactone function (referred to in this context as
retrolactone: 117 and 118, Scheme 34A) [58,
59], a greater number of atoms forming the ring
(Scheme 34B), [88] of saturated heterocycles
(Scheme 34C), [66, 89] or in different positions
(Scheme 34D) [90].
■ Conclusion
Taking podophyllotoxin as a natural prototy-
pe (1), the synthesis of aryltetralin lignans con-
tinues to be a topic of interest due to their poten-
tial as therapeutic agents. During the last seven
decades, the variety and quantity of works refer-
ring to the synthesis of these compounds have
been so enriched that methodological classifica-
tions have been organized and have made it easier
to understand the state of progress of this area
of knowledge. The present bibliographic review
O
O CO2H
Ar1
X
CH2O, NaOH
O
O
Ar1
X
O
O
O
O CO2H
Ar1
CO2H (CF3CO)2O O
O
Ar1
O
O
O
NaBH4
O
O CO2H
Ar1
OH
OH H
Charlton
Curran (X = OH)
Wattanasin (1982) (X = (C)=O)
O
O
Ar1
OH
O
O
Ar1
O
O
OH
1. NaIO4
2. CrO3
Koga
Charlton and
Ogasawara
O
O OH
OH
Br
OH
O
pTSA, toluene
65 oC, 8 h
Hazra
O
O
O
Br
OH
O
15
Scheme 32. The ring D synthesis via esterification to form lactones and analogs and precursors of podophyllotoxin
O
O
O
OAr1
OTBS
MeOH, H2SO4
25 C, 2 h
O
O
H
O
Y*
O
N
O
O
Bn
Y* =
+
O
O
TBSO
Y*
O
O
O
OTBS
OH
O
O
OTBS
OHO
O
OTBS
O
SO
Ar1
O
O OMe
OAr1
O OH
O
O
O
OAr1
OH
27 107 108, 78 % 109, 94 %
110, 91 %
1. Bu2BOTf, NEt3, CH2Cl2, -78 oC to 0 oC, 1 h
2. H2O2, Et2O, 25 oC, 14 h
3. TBSOTf, 2,6-lutidine, CH2Cl2, 25 oC, 0.5 h
NaBH4 (15 equiv)
THF/H2O, 25 oC, 12 h
Grubbs catalyst,
CH2Cl2, 25 oC, 2 h
pyridine, CH2Cl2
25 oC, 2.5 h
111 , 89 %
Cl
S
O
Ar1(Me3Si)3SiH, AIBN
PhH, 80 oC, 8 h
nBu4NF, AcOH, THF, 25 oC, 8 h
112, 38 %
PCC, CH2Cl2, 25 oC, 5 h
1. DBU, THF, 25 oC, 6 h
2. LiEt3BH, THF, -78 C, 1 h
SiO2, MeOH, 56 C, 2 hO
O
O
OAr1
O
113, 96 % 114, 96 %
115, 81 %
3. ZnCl2, sieves, THF,
2.5 h
o
o
o
Scheme 33. The ring E incorporation and the ring D formation in the synthesis of podophyllotoxin and podophyllotoxone epimers
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Журнал органічної та фармацевтичної хімії 2024, 22 (2)
has proposed a new classification focused on how
to synthesize and functionalize the five rings
of podophyllotoxin and its structural analogs,
which will give the opportunity for synthetic
and pharmaceutical chemistry groups to have a
guide for optimizing already existing compound
synthesis, as well as proposals from other repre-
sentatives of this family.
■ References
1. Seegers, C.; Setroikromo, R.; Quax, W. Towards Metabolic Engineering of Podophyllotoxin Production. In Natural Products and Cancer
Drug Discovery, Farid, A. B., Ed. IntechOpen: Rijeka, 2017. https://doi.org/10.5772/67615.
2. Cheng, W.-H.; Shang, H.; Niu, C.; Zhang, Z.-H.; Zhang, L.-M.; Chen, H.; Zou, Z.-M. Synthesis and Evaluation of New Podophyllotoxin De-
rivatives with in Vitro Anticancer Activity. Molecules 2015, 20, 12266 – 12279. https://doi.org/10.3390/molecules200712266.
3. Gordaliza, M.; Garcıá, P. A.; Miguel del Corral, J. M.; Castro, M. A.; Gómez-Zurita, M. A. Podophyllotoxin: distribution, sources, applica-
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O
O CO2H
Ar1
CO2H
O
O
Ar1
O
O
O O
O
Ar1
O
O
Ac2O Na-Hg
Rai
O
O
Ar1
OH
OH
O
O
Ar1
O
MeOH, HCl
Gensler (1976)
Enders (2002)
O
O
O
Ar1
SR
O
HClO4
Ward
MeO
MeO
O
Ar5
SR
OMe
O
1. Hg2+
2. H2O
MeO
MeO
O
Ar5
OH
OMe
O
88d: R = Ph
88e: R = tBu
116a: R = Ph
116b: R = tBu
117, 62 %
O
O
O
Ar6
PhS
O
TFA
González
88c
SPh
HO
O
O
O
Ar6
O
118, 62 %
O
O
Ar1
O
O
Ar1
O
O
Mn(OAc)3 2H2O
AcOH, AcOK
A
B
C
D
*
Scheme 34. Structural variants in ring D
ISSN 2308-8303 (Print) / 2518-1548 (Online) 23
Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
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https://doi.org/10.1021/jm00215a004.
90. Suresh Babu, M.; Madhavu Lokanatha Rai, K. Synthesis of Podophyllotoxin and its Derivatives via NiCl2/NaBH4 Reduction of Isoxazoline
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Information about the authors:
Francisco Flóres-Hernández is bachelor’s degree applicant in Chemistry, Pharmacy, and Biology, University of Guadalajara (México).
Tania Isabel Zárate-López earned a bachelor’s degree in chemistry, Pharmacy, and Biology at the University Colima (2020).
As a PhD student in Biotechnological Processes at the University of Guadalajara (México), she developed chemoenzymatic and friendly
environmental synthetic methods for the preparation of aryl-tetralin lignans reported in the thesis “Development of a Method for
Synthesis of Podophylotoxin and Related Aryl-tetralin Lignans, Implementing Chemo-enzymatic and Green Chemistry Strategies”.
https://orcid.org/0000-0002-1766-3682.
Marco Antonio Alcaráz-Cano earned a bachelor’s degree (2021) in Molecular Design and Nano-Chemistry at the Chemical Research
Center (CIQ) of the Institute for Research in Basic and Applied Sciences (IICBA) at the Autonomous University of the State of Morelos
(UAEM), with a thesis «Review of Synthesis Methods for Podophyllotoxin Reported from 2000 – 2021» under the supervision of
Dr. Jaime Escalante. He is currently a master’s degree applicant in the Laboratory of Nanochemistry and Nanocarbon under the
supervision of Dr. María Luisa García Betancourt at the Chemical Research Center (CIQ) – UAEM. https://orcid.org/0000-0003-1754-0751.
Jaime Escalante studied chemistry at the UNAM in Mexico City (1985), received a M.Sc. (1991) and Ph.D. (1995) from CINVESTAV-IPN,
Mexico City, with a thesis on Asymmetric Synthesis of β-amino acids (supervisor E. Juaristi). Following a post-doctoral stay at the
University of Illinois at Chicago, USA (with D. Crich). Later, he returned to Mexico, where he is now a Professor of Chemistry at the
Chemical Research Center of Autonomous Morelos State University. He has also served as a Visiting Professor at ETH-Zurich.
https://orcid.org/0000-0001-5485-0244.
José Domingo Rivera-Ramírez (corresponding author) received a PhD in 2015 with a dissertation on the mechanism of selectivity
of lipases mediated by the polarity of solvents. From 2014 to 2018, started to work on Signa-Apotex Inc. in the R&D department.
In 2018, he moved to the University of Guadalajara (México) as assistant professor. In 2020, he founded the Laboratorio de Química
Farmacéutica. His current research lines are focused on the synthesis of lignans and capsaicinoids employing green methodologies
and in the elucidation of promiscuous enzymatic mechanisms. https://orcid.org/0000-0003-3188-7321;
e-mail for correspondence: domingo.rivera@academicos.udg.mx.
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| id | oai:ojs.journals.uran.ua:article-308942 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-24T01:01:07Z |
| publishDate | 2024 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/67/769a41697db3649a70b7d88d0d597b67.pdf |
| spelling | oai:ojs.journals.uran.ua:article-3089422026-08-23T16:14:17Z Podophyllotoxin and Aryltetralin Lignans: Methods for the Synthesis of Rings A, B, C, D Подофілотоксин та арилтетралінові лігнани: методи синтезу кілець A, B, C, D Flores-Hernández, Francisco Zárate-López, Tania Isabel Alcaráz-Cano, Marco Antonio Escalante, Jaime Rivera-Ramírez, José Domingo lignans podophyllotoxin aryltetralin-lignans etoposide teniposide лігнани подофілотоксин арилтетралінові лігнани етопозид теніпозид Podophyllotoxin, its derivatives and structural analogues are an extensive group of aryl-tetralin-lignans of interest in pharmacology due to their promising anticancer and antitumor activity. The synthesis methods that have been proposed to date seek to resolve synthetic, stereochemical, pharmacodynamic and environmental aspects. In this review we have updated and brought together different classifications of lignan and podophyllotoxin synthesis. Transformation methods focus on the strategies used to form or functionalize rings A, B, C and D, as well as the configuration of the system of four stereogenic centers that fuse rings C and D. Подофілотоксин, його похідні та структурні аналоги є великою групою арилтетралінових лігнанів, що становлять інтерес для фармакології, зокрема завдяки їхній багатонадійній протипухлинній дії. Методи синтезу, запропоновані сьогодні, спрямовані на вирішення синтетичних, стереохімічних, фармакодинамічних та екологічних аспектів. У цьому огляді ми оновили й об’єднали різні класифікації синтезу подофілотоксину та споріднених сполук. Обговорені методи зосереджені на стратегіях формування або функціоналізації кілець A, B, C і D, а також на конфігурації чотирьох стереогенних центрів, які поєднують кільця C і D. National University of Pharmacy 2024-11-08 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/308942 10.24959/ophcj.24.308942 Journal of Organic and Pharmaceutical Chemistry; Vol. 22 No. 2 (2024); 3-25 Журнал органической и фармацевтической химии; Том 22 № 2 (2024); 3-25 Журнал органічної та фармацевтичної хімії; Том 22 № 2 (2024); 3-25 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/308942/304825 Copyright (c) 2024 Francisco Flores-Hernández, Tania Isabel Zárate-López, Marco Antonio Alcaráz-Cano, Jaime Escalante, José Domingo Rivera-Ramírez http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | лігнани подофілотоксин арилтетралінові лігнани етопозид теніпозид Flores-Hernández, Francisco Zárate-López, Tania Isabel Alcaráz-Cano, Marco Antonio Escalante, Jaime Rivera-Ramírez, José Domingo Подофілотоксин та арилтетралінові лігнани: методи синтезу кілець A, B, C, D |
| title | Подофілотоксин та арилтетралінові лігнани: методи синтезу кілець A, B, C, D |
| title_alt | Podophyllotoxin and Aryltetralin Lignans: Methods for the Synthesis of Rings A, B, C, D |
| title_full | Подофілотоксин та арилтетралінові лігнани: методи синтезу кілець A, B, C, D |
| title_fullStr | Подофілотоксин та арилтетралінові лігнани: методи синтезу кілець A, B, C, D |
| title_full_unstemmed | Подофілотоксин та арилтетралінові лігнани: методи синтезу кілець A, B, C, D |
| title_short | Подофілотоксин та арилтетралінові лігнани: методи синтезу кілець A, B, C, D |
| title_sort | подофілотоксин та арилтетралінові лігнани: методи синтезу кілець a, b, c, d |
| topic | лігнани подофілотоксин арилтетралінові лігнани етопозид теніпозид |
| topic_facet | lignans podophyllotoxin aryltetralin-lignans etoposide teniposide лігнани подофілотоксин арилтетралінові лігнани етопозид теніпозид |
| url | https://ophcj.nuph.edu.ua/article/view/308942 |
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