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2 General Terms and Concepts in Synthetic Organic Chemistry28
The mechanism of the process is shown here [22]:
In steroidal chemistry, the backbone rearrangement is another example of the
cascade reaction. Under the catalysis of the acidic clay mineral, montmorillonite
K-10, cholest-5-enes undergoes a series of Wagner–Meerwein rearrangement to give
a mixture of an equal amount of 20R- and 20S-5β,14β-dimethyl-18,19-dinor-8α,
9β,10α-cholest-13(17)-enes [23].
R
R
H H
H
R
=
H; Me
Montmorillonite K-10
cyclohexane
R
R
H
H H
13
17
20
1
5
10
13
17
20
1
5
10
98%
20R : 20S = 1:1
R
=
H; Me
N
Ph
Bz
2
Heat
O
O
O
N
O
Ph
Bz
(+/–)-3
Thermo cascade reactions
Ph
BzHN
–
Ph
BzHN
H
Heat
BzHN
Ph
O
O
O
HN
Ph
Bz
D-A
O
O
O
HO
2
C
H
+
H
+
+
H
H
R
R
H
H
H
+
H
H
R
R
H
H
R
R
H
H
H
H
R
R
H
H
H
R
R
H
H
Epimerization
at C-20
20R : 20S = 1:1
20R
– H
+
H
+
H
+
+
+
2.31 Flow Chemistry 29
2.30 Multicomponent Reaction
A multicomponent reaction (MCR) is a chemical reaction in which three or
more compounds react to form a single product. By definition, an MCR is one in
which more than two reactants are combined in a sequential manner to produce
a highly selective product that retains most of the atoms of the starting materials.
Multicomponent reactions have been known for over 170 years. The first recorded
MCR was the synthesis of α-aminocyanide by Strecker in 1850, from which α-amino
acids could be derived [24].
Numerous MCRs have been developed, with isocyanide-based variants being the
most extensively documented. Other notable types are free-radical-mediated, organo-
boron compound-based, and metal-catalyzed MCRs, among others [25]. Some typical
examples include Biginelli reaction [26], Bucherer–Bergs reaction [27], and Ugi reac-
tion [28]. The Ugi reaction is a four-component reaction involving a ketone or alde-
hyde, an amine, an isocyanide, and a carboxylic acid to form a bis-amide.
The mechanism of Ugi reaction is depicted as follows:
2.31 Flow Chemistry
Flow chemistry, also known as continuous flow processing, is a method in which
chemical reactions are conducted within a continuously moving stream of fluid, as
opposed to traditional batch production. In this system, reactants are pumped through
a reactor—typically a network of interconnected tubes or channels—where they mix
and interact. When reactive substances come into contact under controlled conditions,
a chemical reaction is initiated and sustained as the mixture flows through the system.
Flow chemistry has been used in petrochemical and bulk chemical production
for more than 100 years. The original Haber–Bosch process was continuous in
1913. But it is only in the past 10 years that continuous processes have garnered
R
1
OH
O
+
C
O
+
+
N
C
C
N
O
O
H
NH
2
R
2
R
3
R
4
R
5
N
C
H
2
O
R
2
R
4
R
3
R
1
R
5
+
−
C
O
C
O
N
H
H
C
N
H
O
H
O
O
H
C
N
O
–
O
C
N
C
N
–
O
O
C
N
H
C
N
O
O
C
N
H
N
C
C
N
O
O
H
R
3
R
4
NH
2
R
2
R
2
R
3
R
4
R
2
R
3
R
4
R
1
R
1
R
2
R
3
R
4
H
+
R
5
R
2
R
3
R
4
R
5
R
1
R
5
R
3
R
4
R
2
R
1
R
3
R
4
R
5
R
2
R
1
+
−
+
2 General Terms and Concepts in Synthetic Organic Chemistry30
significant interest in the pharmaceutical and fine chemical industries. The pro-
duction of advanced intermediates for fine chemicals and APIs relies primarily on
traditional batch processing. Simple batch reactors were used because the synthesis
of these intermediates often involves multiple reactions, and simple stirred tank
reactors offer great versatility and flexibility.
However, batch reactors also have some significant limitations. One driving force
behind the adoption of continuous manufacturing as a technological innovation is
the ability to perform reactions that are more difficult to perform in batch mode.
Some of these new reactions could only be performed in flows [29, 30]. Controlled
oxidation of primary alcohols to aldehydes using Jones reagent is not possible in
traditional stirred reactors. In a continuous flow reactor, Wiles et al. were able to
selectively oxidize a series of primary alcohols to aldehydes or carboxylic acids
depending on the flow rate employed [31].
2.32 Atom Economy
Atom economy (atom efficiency/percentage) is the conversion efficiency of a
chemical process in terms of all atoms involved and the desired products produced.
The simplest definition was introduced by Barry Trost in the 1990s [32] and is equal
to the ratio between the mass of desired product and the total mass of all products,
expressed as a percentage. Atom economy stands as a cornerstone principle within
green chemistry [33], serving as one of the most prevalent metrics for evaluating
the sustainability and environmental efficiency of chemical processes or syntheses.
A high atom economy indicates that the majority of reactant atoms are effec-
tively used in forming the desired product, with minimal production of undesired
by-products or side products. This efficiency lowers not only waste generation but
also the economic and environmental burdens associated with waste management.
Atom economy is calculated as follows:
Atomeconomy =
molecular weight of desired product
_______________________________
molecular weight of all products
× 100%
An atom economy of 100% represents the ideal scenario, where all reactant atoms
are incorporated into the desired product.
A Diels–Alder reaction serves as an excellent example of a highly atom-efficient pro-
cess. For instance, the atom economy of the following Diels–Alder reaction is 100% [34].
OH
0.01 M in DCM
0.150 g silica-supported Jones’ reagent
in borosilicate glass flow reactor
(0.3 cm (i.d.) · 3.0 cm (length))
O
flow rate: 0.650 mL/min
flow rate: 0.050 mL/min
100% 0%
0% 100%
CO
2
H
O
+
O
O
O
Neat grinding
100%
O
O
O
O
H
H
2.33 Green Chemistry 31
In contrast, the Mitsunobu reaction is not a good atom economic reaction
because it produces a lot of wastes including triphenylphosphine oxide and dialkyl
hydrazine-1,2-dicarboxylate. In the following example, the atom economy is only
36% based on 87% yield [35].
Atom economy = 335.3 ÷ (335.3 + 278.3 + 204.2)× 87% × 100% = 35.7%
2.33 Green Chemistry
Green chemistry, similar to sustainable chemistry or circular chemistry, is an
area of chemistry and chemical engineering focused on the design of products and
processes that minimize or eliminate the use and generation of hazardous substances.
In 2000, Paul Anastas and John C. Warner published a set of principles to guide
the practice of green chemistry [36]. Since then, more than a dozen textbooks
and reference books have been published in the field [37]. There are also journals
that publish research and review articles in the field of green chemistry [38]. The
12 principles propose a series of ways to reduce the environmental and health
impacts of chemical production and identify research priorities for the development
of green chemistry technologies.
The 12 principles of green chemistry are [36]:
1. Prevention: Preventing waste is better than treating or cleaning up waste after
it is generated.
2. Atom Economy: Synthetic methods should try to maximize the incorporation
of all materials used in the process into the final product.
3. Less Hazardous Chemical Syntheses: Synthetic methods should avoid using
or generating substances toxic to humans and/or the environment.
4. Designing Safer Chemicals: Chemical products should be designed to achieve
their desired function while being as nontoxic as possible.
5. Safer Solvents and Auxiliaries: Auxiliary substances should be avoided
wherever possible, and as nonhazardous as possible when they must be used.
6. Design for Energy Efficiency: Energy requirements should be minimized,
and processes should be conducted at ambient temperature and pressure
whenever possible.
OH
O
+
O
OH F
F
+
+
O
N
N O
O
O
DIAD, MW: 202.2
MW: 167.1
MW: 186.2
MW: 262.3
THF
0 °C - rt, 2 h
O
O
O F
F
Desired product
MW: 335.3
+
+
O
N
H
H
N O
O
O
MW: 204.2
MW: 278.3
87%
Wastes
O
2
N
Ph
3
P
O
2
N
Ph
3
P
=
O
2 General Terms and Concepts in Synthetic Organic Chemistry32
7. Use of Renewable Feedstocks: Whenever it is practical to do so, renewable
feedstocks or raw materials are preferable to nonrenewable ones.
8. Reduce Derivatives: Unnecessary generation of derivatives—such as the use
of protecting groups—should be minimized or avoided if possible.
9. Catalysis: Catalytic reagents that can be used in small quantities to repeat a
reaction are superior to stoichiometric reagents (ones that are consumed in a
reaction).
10. Design for Degradation: Chemical products should be designed so that they
do not pollute the environment; when their function is complete, they should
break down into nonharmful products.
11. Real-time Analysis for Pollution Prevention: Analytical methodologies
need to be further developed to allow real-time, in-process monitoring and con-
trol before hazardous substances form.
12. Inherently Safer Chemistry for Accident Prevention: Whenever pos-
sible, the substances in a process, and the forms of those substances, should be
chosen to minimize risks such as explosions, fires, and accidental releases.
In 2024, Kai Rossen, Krishna Ganesh, and Kai Oliver Donsbach suggested that
greenhouse gas emissions generated throughout the entire drug production pro-
cess should be incorporated into the framework of green chemistry [39].
2.34 Partial Synthesis, Total Synthesis, and Formal
Synthesis
Partial synthesis, also known as semi-synthesis, involves starting with a nat-
urally occurring compound or a simpler molecule and then modifying it through
chemical reactions to obtain the desired product. This approach is often used when
the target compound is complex and difficult to create from scratch. By using partial
synthesis, chemists can take advantage of existing chemical structures and modify
them to achieve the desired compound.
For example, artesunate is a more hydrophilic artemisinin derivative developed
by Amivas [40]. It was granted Food Drug Administration (FDA) approval for the
initial treatment of severe malaria. The active dihydroartemisinin is the metabolite
of artesunate. Artesunate was semi-synthesized from natural product artemisinin,
which could be isolated from Artemisia annua. Researchers from Jiangsu Swithin
Biological Medicine Engineering Research Center reported a process-scale (6.4 kg)
synthesis of artesunate [41].
O
O
O
H
H
O
O
Artemisinin
KBH
4
dioxane
0 °C
O
O
OH
H
H
O
O
Dihydroartemisinin
O
O
O
94%
one-pot
O
O
O
H
H
O
O
OH
O
O
Artesunate
DMAP, 35 °C
2.34 Partial Synthesis, Total Synthesis, and Formal Synthesis 33
Total synthesis, on the other hand, involves creating the target compound from
simple starting materials. This approach requires a deep understanding of the
reactions employed and often involves multiple steps to build the desired mole-
cule from the ground up. Total synthesis is a powerful tool for chemists to demon-
strate their abilities to create complex molecules that may not be readily available
in large quantities from natural resources. The term “total synthesis” is often used
to describe the total synthesis of structurally and stereochemically complex natural
products.
A contrasting example of total synthesis is the total synthesis of artemisinin devel-
oped by Zhu and Cook at Indiana University as shown here [42].
Partial synthesis and total synthesis can be understood like this. A partial synthesis
is similar to convert an office building into a library, while a total synthesis is to build a
new library from bricks, wood, steel bars, cement, and other materials on the ground.
A formal synthesis is the synthesis of a complex intermediate en route to the
natural product or pharmaceutical compound. This means that you can intersect
someone else’s route and say that the molecule can be made from there or that the
molecule is known through isolation studies to degrade or be transformed into the
desired product via some pathway. The key here is that you don’t make the actual
product and thus you’re relying on someone else’s report for the final steps.
For example, atropurpuran is a non-alkaloidal diterpene natural product isolated
from the roots of Aconitum hemsleyanum [43]. Suzuki et al. reported the formal syn-
thesis of atropurpuran [44]. They completed the synthesis of the key intermediate
(Xu’s intermediate) and claimed the formal synthesis of atropurpuran, since Xu’s
intermediate was further converted to the target compound atropurpuran by Xu’s
group [45].
O
2.
Br
O
61%
72%
O
TIPSO OMe
O
TIPSO
OMe
PdCl
2
H
2
O
2
61%
O
TIPSO
OMe
O
1. (NH
4
)
2
MoO
4
H
2
O
2
, t-BuOH
2. p-TSA, DCM
42%
O
O
O
H
H
O
O
Artemisinin
O
O
P N
Ph
Ph
L*=
in situ
1
O
2
generated
1. Me
2
Zn, L*
Cu(OTf)
2
toluene
1. TsNHNH
2
MeOH
2. BuLi
3. DMF
Et
2
AICI
DCM
98%
O
Me
O
OH
Atropurpuran
O
Me
O
OH
OMe
OMe
OMe
O
ref. 5
21 steps
Xu’s intermediate
ref. 6
3 steps
2 General Terms and Concepts in Synthetic Organic Chemistry34
2.35 Linear Synthesis and Convergent Synthesis
When a multistep synthesis is conducted, two strategies need to be considered: a
linear synthesis or a convergent synthesis. A linear synthesis is one in which all
the reagents and building blocks are added in a sequential fashion. In a convergent
synthesis, two or more separate pathways may be followed with the pieces joined at
a later time to form the final product.
The difference in efficiency between linear synthesis and convergent synthesis
can be demonstrated through the following example. Consider a target compound
composed of eight structural units, commonly referred to as building blocks
(A-B-C-D-E-F-G-H). In a linear synthesis approach, the process would proceed as
follows.
There are seven synthetic steps. If the yield for each step is 80%, the overall yield
will be 80% × 80% × 80% × 80% × 80% × 80% × 80% = 21%.
However, if you perform the synthesis in a convergent pathway, there will be
only as less as three steps. If the yield for each step is 80%, the overall yield will be
80% × 80% × 80% = 51%.
You can regard a multistep linear synthesis as completing a marathon (26 miles)
run. While a convergent synthesis of the same molecule is four runs to complete the
total 26 miles. For an amateur runner who has basic running training and usually
only runs about 3 miles each time, completing a marathon within 4 hours is not an
easy work. He or she may need more than half-year of systematic training to achieve
this goal. However, if we divide these 26 miles into four sections, each section being
about 6.5 miles, it will be a much easier job for an amateur runner to complete a
total distance of 26 miles in four runs and each run to be finished within an hour.
Ineleganolide (1) is a diterpenoid natural product isolated from the Formosan soft
coral Sinularia inelegans by Duh and coworkers in 1999 [46]. In 2022, Wood and
Tuccinardi reported the first total synthesis of ineleganolide [47]. That synthesis can
A
B
C
D
E
F
G
H
A
+
B A B
80%
C
80%
A
B
C
D
80%
A
B
C
D
E
80%
A
B
C
D
E
F
80%
A
B
C
D
E
F
G
80%
A
B
C
D
E
F
G
H
80%
A
+
B
A B
80%
C + D
C D
80%
E + F
E F
80%
G + H
G H
80%
A
B
C
D
80%
E
F
G
H
80%
80%
A
B
C
D
E
F
G
H
2.35 Linear Synthesis and Convergent Synthesis 35
be considered a linear synthesis. They started from cyclopentenone 2 and furan 3,
and the final product was synthesized in 23 steps with 0.3% overall yield.
Shortly thereafter, Gross et al. reported a convergent synthesis of ineleganolide
(1) [48]. The synthesis was started from compound 8 and 10 to prepare the two key
building blocks 9 and 11. The ester 12 was prepared by coupling of 9 and 11 by ester-
ification. After further six steps were performed, the target compound (+)-ineleg-
anolide (1) was synthesized in 16 steps, counted from the longest route from 8, and
the overall yield was 1.5%, five times higher than the linear synthesis [47].
O
OTIPS
O
TBSO
+
3
2
overall yield 74%
8 steps
O
OTIPS
TBSO
4
O
O
H
H
TBSO
OH
5
3 steps
overall yield 77%
O
OAc
6
O
OTIPS
TBSO
4
O
O
H
H
Compound 6
21%
O
OTIPS
TBSO
7
O
O
H
H
OAc
OH
H
14 steps
overall yield
1.9%
H
H
O
(+)-Ineleganolide (1)
O
O
H
H
H
O
O
H
H
H
OTES
TBSO
CHO
8
8 steps
overall yield 16%
OH
9
O
O
O
O
HO
2
C
O
87%
11
O
12
O
O
O
(+)-Ineleganolide (1)
O
O
H
H
H
O
O
H
H
H
O
10
3 steps
Compound 9
overall yield 11%
6 steps
2 General Terms and Concepts in Synthetic Organic Chemistry36
2.36 Divergent Synthesis
Divergent synthesis is a strategy designed to create a diverse library of chemical
compounds by initially reacting a core molecule with a set of reactants. The first
generation of compounds is then subjected to further reactions, producing the
second generation of compounds. This process rapidly expands, leading to a large
number of new compounds. For example, a starting molecule (A) generates com-
pounds A1, A2, and A3 in the first generation. Subsequently, A1 generates A1-1,
A1-2, and A1-3 in the second generation, and so on. In the context of medicinal
chemistry, divergent synthesis typically involves the creation of a central scaffold,
from which a series of new compounds are systematically derived.
One example is selected from our previous work. In a medicinal chemistry project,
chemists from Alectos Therapeutics performed a divergent synthesis of a series of
cyclohexane derivatives [49]. Those compounds were screened for OGA inhibition.
The scaffold 3 was synthesized from starting materials, furan (1) and methyl acry-
late (2) [50, 51], in 13 steps. From scaffold 3, dozens of compounds with structure
diversified were further prepared.
2.37 Click Chemistry
Click chemistry refers to a category of straightforward, atom-efficient reactions
widely employed to connect two selected molecular entities. Rather than denot-
ing a single specific reaction, click chemistry represents an approach to creating
products inspired by natural processes, where substances are formed by linking
small, modular units. In numerous applications, click reactions are used to attach a
biomolecule to a reporter molecule.
O
+
13 Steps
1
2
HO
HO
OH
N
O
N
Aminocarbooxazoline
HO
HO
OH
N
S
N
Aminocarbothiazoline
HO
HO
OH
N
O
R
Carbooxazoline
HO
HO
OH
N
O
N
Carbooxazoline
HO
HO
OH
N
O
N
Cis-Oxazine
HO
HO
OH
N
O
N
Trans-Oxazine
F
HO
OH
N
O
N
6.6-Diflourooxazoline
F
BnO
BnO
OBn
OH
3
R
1
R
2
R
1
R
2
R
1
R
2
NH
2
CO
2
Me
R
2
R
1
R
2
R
1
R
1
R
2
2.38 Parallel Synthesis 37
These reactions typically take place in a single vessel, are unaffected by the
presence of water, and produce few, harmless by-products. They are characterized
as “spring-loaded,” meaning they possess a strong thermodynamic driving force
that propels the reaction rapidly and irreversibly toward a high yield of a single
product. Additionally, click reactions often exhibit high specificity, sometimes dem-
onstrating both regio- and stereo-specificity.
The term “click chemistry” was first introduced in 1998 by Jan Dueser [52], the
wife of K. Barry Sharpless, and was later comprehensively described by Sharpless,
Kolb, and Finn in 2001 [53]. In 2022, the Nobel Prize in Chemistry was awarded
jointly to Carolyn R. Bertozzi, Morten P. Meldal, and K. Barry Sharpless for their
contributions to the development of click chemistry and bioorthogonal chemistry.
A classic example of click chemistry is the copper-catalyzed reaction between
an azide and an alkyne, which forms a 1,2,3-triazole through a process known as
Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) [54]. The first synthesis of a
triazole, achieved by reacting diethyl acetylenedicarboxylate with phenyl azide, was
reported by Arthur Michael in 1893 [55]. This family of 1,3-dipolar cycloaddition
reactions gained prominence in the mid-twentieth century, largely due to the exten-
sive studies on their reaction kinetics and conditions by Rolf Huisgen, after whom
the reactions were later named [56].
The copper(I)-catalyzed version of the Huisgen 1,3-dipolar cycloaddition was
discovered simultaneously and independently by two research groups: one led
by Valery V. Fokin and K. Barry Sharpless at the Scripps Research Institute in
California [57], and the other by Morten Meldal at the Carlsberg Laboratory
in Denmark [58]. Unlike the non-catalyzed reaction originally described by
Huisgen, which produces a mixture of 1,4- and 1,5-isomers, proceeds slowly,
and requires elevated temperatures (around 100 °C) [59], the copper-catalyzed
variant selectively yields only the 1,4-isomer.
2.38 Parallel Synthesis
Parallel synthesis significantly reduces time and enhances compound dif-
ferentiation by conducting multiple synthetic experiments concurrently. This
approach is widely employed to expedite the discovery of novel compounds and to
identify optimal process conditions. In medicinal chemistry, parallel synthesis plays
a crucial role in the discovery and development of potential drug candidates. For in-
stance, it facilitates the creation of libraries containing diverse chemical structures,
which can then be screened for potential biological activity.
Parallel synthesis is applied across various stages, including lead generation, lead
optimization, and the screening of optimal reaction conditions. In process scale-up
and development, parallel synthesis accelerates process optimization by offering
deeper insights into the impact of key reaction variables. These variables include
solvent systems, optimal temperatures and concentrations, appropriate reagents,
reaction times, and the selection of catalysts. By enabling the simultaneous explo-
ration of these factors, parallel synthesis streamlines the optimization process and
enhances efficiency in chemical development.