Specific Examples and Related Innovation of Industrialized Application of Green Pharmaceuticals
Ongoing Pursuit of Practical Biotin Process
Biotin 1 ([Fig. 2]), a water-soluble B series vitamin, was first isolated from egg yolk in 1936.[6] It distributes widely in microorganisms, plants, and animals, and plays crucial
roles as a coenzyme in the metabolism of fatty acids, sugars, and α-amino acids.[7]
Fig. 2 Structure of biotin (1).
The chemical synthesis of biotin was accomplishedwith the first total synthesis of
racemic biotin and subsequent optical resolution by Harris et al fromMerck in 1943.[8] Subsequently, Goldberg and Sternbach at Hoffmann-La Roche applied for patents on
the first commercially applicable biotin synthesis in 1946.[9] As shown in [Scheme 1], the cyclic anhydride 3 was synthesized from commercially available fumaric acid (2), and could be converted into the racemic sulfonium salt 4 after several functional group transformations. Subsequent optical resolution of
4 by the use of camphorsulfonic acid and two additional operations smoothly delivered
biotin. Since these pioneering works, the synthesis of biotin has long challenged
industrial and academic chemists, and continued to stimulate interest in developing
an optimum synthetic approach toward this legendary molecule.[7] In 1970, Gerecke and coworkers at Hoffmann-La Roche significantly improved the original
Goldberg–Sternbach approach,[10] which featured a ring opening of the cyclic anhydride 3 to a racemic mixture of hemiester 5 by alcoholysis, and the following resolution was realized via the crystalline ephedrine
salt of the diastereomeric hemiester. Subsequent reduction/cyclization sequence delivered
chiral lactone 6, which could then be built up in several steps into biotin viaa thiation/Grignard/homologation
sequence. It is worth noting that this procedure was operated on a commercial scale
by Roche until the 1990s, and lactone 6 has been the most commonly utilized chiral intermediate in the processes delivering
biotin.[7]
Scheme 1 The Roche's original and improved process.
In 2001, Chen, one of the authors of this article, developed an improved resolution
route for the synthesis of chiral Roche's lactone 6 at Fudan University ([Scheme 2]).[11] Central in the synthesis was the replacementof the ephedrine with chloramphenicol
base 8 as the resolving agent, providing the desired enantioenriched half-ester 9 in 37% yield, which was comparable to the yield obtained via Roche's approach.
Scheme 2 The improved resolution approach by Chen.
An impressive development of efficient asymmetric strategies—that is, the direct conversion
of cyclic meso-anhydride 3 to optically active lactone 6—was realized by Matsuki et al in 1993.[12] Employing (R)-BINAL-H (11), the asymmetric reduction of 3 delivered 6 in 76% yield and 90% ee. Subsequently, this transformation was further extended by Chen et al to a method
utilizing thiocarboxylic anhydride 10, which was readily synthesized from anhydride 3 via thiation ([Scheme 3]).[13] Reaction of 10 in the presence of (R)-BINAL-H (11) smoothly afforded thiolactone 12 in a higher efficiency with 83% yield and 98.5% ee. Enantioenriched 12 could then be built up in several steps into biotin. Moreover, the plausible mechanism
of this enantioselective transformation was proposed by Chen, as illustrated in [Scheme 3], and the Si-face of the carbonyl group should be selectively reduced by means of a favorable
n–π* interaction between the oxygen nonbonding orbital and the lowest unoccupied molecular
orbital (LUMO) of the thioanhydride moiety.
Scheme 3 Chen's asymmetric reduction approach and the plausible mechanism.
In 1999, Shimizu et al reported the enantioselective reduction of meso-N-benzyl imide 13 into the corresponding chiral hydroxylactam 14 with borane in the presence of an oxazaborolidine catalyst derived from L-threonine. Despite a 98% ee, the yield of 14 was moderate (65%).[14] Indeed, this asymmetric CBS (Corey-Bakshi-Shibata)-type reduction has been studied
extensively by Chen and coworkers ([Scheme 4]).[15] With in situ generated borane from cheap, safe, and convenient lithium hydride/sodium
hydride and boron trifluoride etherate, they prepared three types of oxazaborolidine
catalysts, chloramphenicol base derivative 15, polymer-supported sulfonamide 16, and polymer-supported amino alcohol 17. Treatment of imide 13 with these chiral oxazaborolidines provided hydroxylactam 14 in excellent outcome of yields and enantioselectivities (82–91% yield, ≥98% ee). The latter underwent further reduction and acid treatment, leading to lactone 6 in 92% yield, which could readily be converted into biotin through thiation and the
subsequent introduction of a C5 side chain using modified di-Grignard approach, with
1,4-dibromobutane and carbon dioxide as the reactants.[15d] Thus, this route would be greatly beneficial to the scalable synthesis of biotin.
Scheme 4 Chen's oxazaborolidine-catalyzed asymmetric reduction process.
The enantioselective alcoholysis of meso-cyclic anhydrides is a powerful strategy to conveniently access optically active
hemiesters as valuable building blocks for many natural products and biologically
active substances.[16] In particular, Deng,[17] Song,[18] Bolm,[19] Connon,[20] Chen,[21] and their coworkers have made numerous impressive progresses in the opening of anhydrides
by chiral Lewis bases, as demonstrated by cinchona alkaloids and their derivatives.
Toward ongoing pursuit of asymmetric synthesis of biotin, Chen and coworkers developed
a novel organocatalytic anhydride desymmetrization strategy ([Scheme 5]).[21]
[22] In this pivotal transformation, two contiguous stereogenic centers were readily
established through a rapid chloramphenicol base and cinchona alkaloid catalyzed enantioselective
alcoholysis of meso-cyclic anhydride 3 to afford hemiesters 18, with excellent yields and enantiomeric excesses (up to 99% yield, 98.5% ee). Conversion of hemiesters 18 to biotin was readily achieved viaa well-known process. Given such highefficiency
of the desymmetrization, Chen developed an asymmetric alcoholysis strategy that has
great potential for use in the mass production of biotin.
Scheme 5 Chen's asymmetric alcoholysis process.
After unremitting efforts and continuous innovation, Chen successfully solved several
critical bottleneck reaction problems and key transformations, and developed four
new cutting-edge and eco-friendly technologies and processes for the biotin synthesis,
including chemical resolution, asymmetric reduction, and asymmetric alcoholysis processes.
Indeed, Chen's synthetic methods represent a major breakthrough in the industrial
production of biotin.[23] Notably, triggered by the endeavors of asymmetric synthesis of biotin, Chen has
conducted a deep and extensive research on chloramphenicol base chemistry for decades,
achieving a series of significant progresses involving chiral catalysts, chiral auxiliaries,
synthetic methodologies, and total synthesis.[24]
[25]
Revolutionary Artificial Synthesis of Artemisinin
Each year, hundreds of millions of people are infected with malaria around the world.
In 2010 alone, the number of infected people was as high as 200 million, and the number
of deaths was as high as 655,000. According to the World Health Organization (WHO),
approximately 40% of world's population is threatened by malaria. Every year, an estimated
350 to 500 million people are infected with malaria, and 3,000 children die every
day because of it.[26]
Artemisinin is a natural ingredient used in the effective treatment of malaria. After
a team of Chinese scientists successfully extracted it from plants in the 1970s, the
development of related drugs was performed. In 2005, artemisinin-based combination
therapy was recommended by the WHO as the best way to treat malaria.[27] It is of great medical, economic, and social significance to solve the problem of
raw materials for artemisinin production. However, artemisinin antimalarials are in
short supply. The international market for artemisinin is approximately 180 tons.
Even so, there are still many people who need it for the treatment.
Artemisinin is a kind of terpenoid compound, originally extracted from the plant Artemisia annua ([Fig. 3]). The main domestic production method is still extraction from A. annua, but the plant occupies cultivated land anddepends on the environment. The production
of artemisinin is mainly performed by repeatedly extracting A. annua L. with an organic solvent and purifying and separating it. Among the steps, the leaching
step has problems of low selectivity and serious solvent loss, and the purification
and separation processes ([Fig. 4]) have long processing times and high energy consumption, resulting in limited processing
capacity and limited production capacity. Furthermore, the extraction process is cumbersome.
Fig. 3 Plant Artemisia annua.
Fig. 4 Artemisinin extraction process.
At present, the production of artemisinin still relies mostly on plant extraction.
Seventy percent of artemisinin raw materials come from China. In 2006, scientists
from Amyris Inc. and the University of California, Berkeley, United States, developed
a biological process using engineered yeast for the production of large quantities
of artemisinic acid 20 (AA;[Scheme 6]),[28] thus, the two remaining challenges are how to convert AA into dihydroartemisinic
acid (DHAA) and DHAA into artemisinin.
Scheme 6 Biosynthesis of artemisinic acid (AA) by Amyris-UC Berkeley from sugar.
The transformation of artemisinic acid into artemisinin antimalarials is also far
from simple. Artemisinin is a sesquiterpene lactone compound containing a peroxy group.
The rare peroxygen is fixed and connected with two quaternary carbon atoms, forming
a bridge. The full synthesis of this peculiar structure is extremely challenging.[29]
In 2011, Wu and colleagues reported the synthesis of artemisinin in the absence of
light from artemisinic acid.[30] The process was performed at room temperature to obtain artemisinin ina total yield
of 41% in 2013, using an improved synthetic technology ([Scheme 7]).[31]
Scheme 7 Wu's approach to the synthesis of artemisinin.
The research team led by Zhang, at the School of Chemistry and Chemical Engineering,
Shanghai Jiao Tong University (SJTU), finally developed a conventional and practical
asymmetric hydrogenation synthesis method for (R)-DHAA 21 ([Scheme 8]), a key intermediate for artemisinin.[32]
Scheme 8 Zhang's conventional and practical asymmetric hydrogenation synthesis of (R)-DHAA 21.
In 2005, Zhang led a team that converted artemisinic acid into (R)-DHAA 21, and then used a specific catalyst they developed to allow efficient production of
DHAA through a conventional reaction device without a photochemical reaction, which
is often less effective. Finally, artemisinin was obtained in high yield by oxidative
rearrangement. In 2012, they developed a chemical synthesis method that does not require
the use of light to further increase the synthesis efficiency of artemisinin. This
was a major advance made by Chinese scientists in the field of high-efficiency synthesis
of artemisinin, which will make large-scale production of artemisinin a reality ([Scheme 9]).[33]
Scheme 9 Zhang's key reaction in the revolutionary artificial synthesis of artemisinin.
From 2012 to 2016, Zhang and coworkers worked diligently to industrialize this technology.
They achieved a smooth 30- to 500-L (multikilogram) scale-up or pilot synthesis, making
a low-cost artemisinin supply a reality. For the first time, the high-efficiency synthesis
of the antimalarial drug artemisinin was made possible, and artemisinin is expected
to achieve large-scale industrial production by Shanghai Fosun Pharmaceutical (Group).
Scalable Total Synthesis of Antitumor Marine Nature Product Trabectedin (ET-743)
The first marketed modern marine drug for the treatment of soft tissue sarcoma was
trabectedin 31 (ET-743).[34] Its analogues are undergoing phase III clinical studies for the treatment of small-cell
lung cancers. Current production requires the use of another rare natural product,
tunicate, which can only generate 1.0 g of ET-743 from 1.0 ton of tunicate via semisynthesis,
requiring 21 steps of reaction with only 1% total yield.[35] The market price of the drug substance is >$10,000/g. Over the past 20 years, four
routes have been developed for the total synthesis of ET-743 from readily available
raw materials,[36]
[37]
[38]
[39] but the total number of steps for each route isall above 40, contributing to their
low overall yield and preventing scale-up for industrial production.
In 2019, Maand coworkers at Shanghai Institute of Organic Chemistry (SIOC) developed
a novel, highly efficient, and practical total synthesis method of ET-743 from Cbz-protected
(S)-tyrosine.[40] This new synthetic method delivers a 1.6% overall yield in 26 total steps, with
a light-mediated remote C–H bond activation to assemble a benzo[1,3]dioxole-containing
intermediate 27 ([Scheme 10]). This new method is one-third shorter than the original synthetic route and can
be conveniently scaled up. The process and related technologies have been licensed
and transferred to a Chinese pharmaceutical company and will make a positive contribution
to cancer therapy.
Scheme 10 Scalable total synthesis of antitumor marine nature product trabectedin (ET-743).
Cu(I)/Oxalic Diamide Catalyzed Coupling Reaction and Its Application in Pharmaceutical
Processes
Ma and coworkers at SIOC first developed the amino acid-promoted Ullmann coupling
reaction,[41] a reaction that has been applied thousands of times in the synthesis and development
of functional molecules ([Scheme 11]).[42] The application includes a ton-scale production for the antihypertensive drug perindopril
41 ([Scheme 12]),[43] intermediates by DSM and tons of production for Xiidra (Lifitegrast) 44 ([Scheme 13]),[44] a treatment of signs and symptoms of dry-eye disease by Shire, and two other drug
candidates 48,[45] at phaseII clinical trials for the prevention of heart attack, and 53,[46] at phaseII clinical trials for the treatment of anxiety ([Scheme 14]).
Scheme 11 Ma's amino acid-promoted Ullmann coupling reaction.
Scheme 12 Ton-scale production of intermediates for perindopril.
Scheme 13 Tons-scale production of Xiidra (Lifitegrast) under Ma's conditions.
Scheme 14 Synthesized drug candidates via the amino acid-promoted Ullmann coupling.
Aryl sulfone has been one of the top fivemost frequently used scaffolds in drug structures
based on statistics of approximately 7,000 Food and Drug Administration (FDA)-approved
drugs and experimental drugs. The classical method for preparing aryl sulfones is
the direct sulfonylation of arenes, and in the late stage of manipulation it gives
unsatisfactory regioselectivity and poor functional group tolerance. Ma's amide ligand
55, HMNPC, derived from 4-hydroxy-L-proline and 2-methylnaphthalen-1-amine, is an excellent
and highly practical ligand for CuI-catalyzed direct coupling of (hetero)aryl halides
with sulfinic acid salts under mild conditions.[47] The reaction proceeds at room temperature with only 0.5 mol% CuI and the ligand,
representing the first example for Cu-catalyzed arylation with a low catalytic loading
underroom temperature conditions ([Scheme 15]).
Scheme 15 CuI-catalyzed direct coupling of (hetero)aryl halides with sulfinic acid salts.
For the first time in 2015, Ma and coworkers discovered a much more effective oxalyl
diamine ligand which achieved a copper-catalyzed coupling reaction of an inexpensive
aryl chloro compound under mild conditions,[48] coupling aryl bromide and iodide with very low catalyst loading ([Scheme 16]). Under these milder and more practical conditions, thisuseful method is expected
to be applied to a large-scale production, and more than 10 different APIs and bulk
drugs or key intermediates have been prepared or are under preparation by a jointventure
in China using this technology (CE PHARM).
Scheme 16 Highly effective oxalyl diamine ligand/copper-catalyzed coupling reaction of aryl
chloro compounds.
It is undeniable that, over the past three decades, palladium-catalyzed C–C cross-coupling
reactions, e.g., Suzuki coupling, Negishi coupling, the Heck reaction, and Pd-catalyzed
C–N, C–O, and C–S formations, have changed synthetic organic chemistry dramatically.
However, from the perspective of economic and sustainable development, under the same
circumstances, if a cheaper copper catalyst is capable of carrying outa similar transformation
yielding comparable experimental results while avoiding harsh experimental conditions,
process chemists will prefer to use the copper-catalyzed reactions. The competition
between copper and palladium over the past two decades can be traced to a new systematic
study of Cu/oxalic diamide ligands (from 2013 to 2018;[Fig. 5]), and copper-catalyzed coupling reactions will find broader applications at academic
laboratories and in the pharmaceutical industry.
Fig. 5 Cu versus Pd, a 20-year competition in catalyzing C–X coupling.
Chiral Bicycle Imidazole Nucleophilic Catalyst (R-DPI) for Biologically Active Protide Prodrugs
In 2017, DiRocco and coworkers at Merck, United States, published their latest research
on stereoselective phosphorylation[49] for the high-efficiency synthesis of the phase III clinical new nucleoside prodrug
63, MK-3682 ([Scheme 17]). Their work is based on the original work of Zhang on chiral bicyclic imidazole
framework catalysts,[50]
[51] in which he designed and synthesized a multifunctional catalyst with a chiral bicyclic
imidazole skeleton, which achieved asymmetric synthesis of nucleoside with high stereoselectivity
and high yield. Compared with the existing small-molecule catalysts, the chiral bicyclic
imidazole catalyst skeleton introducedby Zhang's team can be constructed in high yield
viaa one-step reaction of inexpensive imidazole and acrolein, which can be easily
prepared on a large industrial scale ([Scheme 18]).[52]
Scheme 17 Chiral imidazole catalyst (R-DPI) for protide prodrug MK-3682.
Scheme 18 Synthesis of chiral bicyclic imidazole catalyst R-DPI and related R-PDPI derivative.
Chiral Catalysts for Asymmetric Synthesis of Silodosin, (S)-Duloxetine, and Bulk Drugs
In China, research on asymmetric synthesis of chiral molecules has seen significant
improvement in the past decade, with the achievement of excellent research results[53]
[54]
[55]; however, their application in the pharmaceutical industry still needs development.
First, the main limitation of catalytic chiral technology is the turnover number of
the catalyst. Generally speaking, catalysts with a turnover number of more than 10,000
in the laboratory are valued for further industrialization. Second, a secondary limitation
on catalytic chiral technology in industry is its strict reaction conditions, which
cannot be too harsh and must be suitable for industrial use. Third, the requirements
for the scale-up or production using this technology must be safe and environmentally
friendly. Fourth, the cost of the catalyst cannot be too high. Finally, the pharmaceutical
company's own R&D unit and process optimization capabilities should be able to adopt
and utilize the new technology, which has also been a key issue.[56]
In asymmetric catalysis studies, chiral phosphorus ligands have been widely used,
and many highly efficient chiral phosphorus ligands have been reported. However, since
a chiral ligand or chiral catalyst is usually only effective for one reaction or one
type of substrate, there are still many chiral compounds that lack effective enantioselective
synthesis methods. Therefore, the development of new and effective chiral ligands
and catalysts is still one of the central tasks of asymmetric catalysis research.
In his research, Zhou of Nankai University found that the chiral spirobiindane structure
is an ideal chiral skeleton. It has strong structural rigidity and a stable configuration.
The series of chiral ligands ([Scheme 19]) derived from the skeleton have been widely used in metal catalysis and organic
small-molecule catalysis.[57]
Scheme 19 The series of chiral ligands derived from chiral spirobiindane structure.
By using the novel Ir-SIPHOX catalyst ([Scheme 20]), process chemists at Zhejiang Jiuzhou Pharmaceutical accomplished the first asymmetric
synthesis of silodosin with high efficiency (S/C = 6,000) and high enantioselectivity
(97% ee) viaa new approach in which the key transformation is the asymmetric hydrogenation
of an unsaturated carboxylic acid intermediate.[58]
Scheme 20 Asymmetric hydrogenation of unsaturated carboxylic acid intermediate.
Using the electron-donating and rigid P-stereogenic bisphospholane ligand DuanPhos,
Zhang at Chiral Quest developed a concise process for the preparation of (S)-duloxetine 89, and asymmetric hydrogenation generated chiral alcohol 88 with excellent results (S/C = 10,000, >99% ee), reducing the total cost by 74% and wastewater by 84% compared with its original
route ([Scheme 21]).[59] Founded in 2008 and utilizing Zhang's chiral catalysts, Chiral Quest has developed
more than 20 new process routes in scale-up, generating hundreds of tons of pharmaceutical
intermediates for (S)-duloxetine (for treatment of major depressive disorder), Ramipril (for hypertension),
Sitagliptin (for diabetes), and commodity chiral 3-amino-1-butanol (50 tons/year).
Scheme 21 The preparation of (S)-duloxetine via asymmetric hydrogenation.
Eco-Friendly Process for Praziquantel
Praziquantel 99 is an antiparasitic drug developed in 1980 by Bayer and Merck KGaA. Since its introduction,
praziquantel has become a special drug against various worms such as schistosomes
due to its high efficiency, low toxicity, wide antiparasitic spectrum, and convenient
oral administration. It is also widely used in the treatment of parasitic diseases
inanimals. The synthetic route of praziquantel reported by the original company is
shown in [Scheme 22].[60]
Scheme 22 The original synthetic route of praziquantel by Bayer and Merck KGaA.
The route used isoquinoline 90 as a starting material, reacting it with benzoyl chloride and potassium cyanide to
obtain compound 92, and then compound 93 by high-pressure (150 atm) hydrogenation reduction. Compound 96 is produced in two steps, and then concentrated phosphoric acid is used to convert
it to 97, before it is finally reacted with benzoyl chloride to obtain the target compound.
For decades, praziquantel bulk drug manufacturers have adopted this approach.
However, Zhang realized that there are many shortcomings in this process route, such
as the use of a large amount of highly toxic potassium cyanide, as well as high-temperature
and -pressure (150atm) conditions. In addition, the use of concentrated phosphoric
acid inevitably leads to eutrophic water pollution. According to statistics, for every
500 tons of praziquantel produced, 310 tons of potassium cyanide are used, and phosphoric
acid waste liquid reaches up to 2,430 tons ([Fig. 6]). This obviously cannot meet the current environmental protection policy requirements
and does not conform to green chemistry principles. In response to these problems,
Zhang and his team invented the production process of praziquantel via a well-designed
and novel synthetic route, as shown in [Scheme 23].[61]
Fig. 6 The footprint when 500 tons of praziquantel is produced.
Scheme 23 Novel production process for praziquantel.
The new route successfully avoids the extensive use of highly toxic potassium cyanide
and phosphoric acid, and cleverly bypasses high-temperature and -pressure conditions.
The new process not only drastically reduces the generation of large amounts of waste,
but also reduces production costs to half of that of the original process. The new
route has achieved a production scale of 100 tons.
Effective Preparation of Active Pharmaceutical Ingredients and Key Intermediates
In recent years, the use of enzymes and biocatalytic reactions to carry out pharmaceutical
processes in industry has become a very important direction for greening scaled-up
reactions. The chiral intermediate (3R)-3-aminoazepane is a key motif in the bacterial conjunctivitis antibiotic besifloxacin
and in the antitumor clinical drug nazartinib, an estimated glomerular filtration
rate (EGFR) antagonist. According to retrosynthetic analysis, the intermediate (3R)-3-aminoazepane 106 is the key raw material for the synthesis of both drugs. Although there are three
known synthetic methods ([Scheme 24]),[62] they face some shortcomings and flaws. Method A uses nonnatural amino acids as raw
materials, requires low-temperature operation, and lactamization results in serious
racemization. On the other hand, the final amide reduction on scale is very challenging
and difficult, and safe production and reduced environmental pollution are not guaranteed.
The starting material used in method B is expensive and sodium azide is used, and
a large amount of isomer impurities (racemic) are generated, which are neither safe
nor economical. The starting material of method C is expensive, which involves the
reduction and protection of carboxylic acid and deprotection, and thus is not a good
method in view of green chemistry principles.
Scheme 24 Three known synthetic methods for (3R)-3-aminoazepane.
Process chemists at HEC found that the above synthetic methods are not ideal, and
a better method of preparing 106 is by enzyme or biocatalytic transformation. Although at least six synthetic routes
are known,[63] there are several disadvantages, among which are the high price of starting materials,
the use of precious metal catalysts, unconventional chemical operation, and low overall
yields ([Scheme 25]).
Scheme 25 The known catalytic transformation for 116.
After careful consideration, HEC chemists finally developed a new route that uses
commercially available piperidin-2-one 117 as a starting material to access the target molecule effectively in seven steps ([Scheme 26]). (3R)-3-Aminoazepane 106 is prepared with 46.2% overall yield, 99.92% purity, and 99.2% ee.[64] The practical enzymatic reaction catalyzed by transaminase is a key transformation.
This new route avoids the use of expensive metal catalysts or chromatography. It is
worth mentioning that the careful choice and optimization of the Dieckmann condensation
reaction is a clever use of the telescoping process that avoids unnecessary separation
and purification, while, at the same time, turning waste into treasure since a mixture
of 121 and 122 gave only 123.
Scheme 26 The HEC practical enzymatic process for (3R)-3-aminoazepane.
P-Chiral Phosphorus Ligands and Enantioselective Synthesis of the Alkaloid (-)-Corynoline
As the field of asymmetric catalysis rapidly progresses, the search for new, efficient,
and practical asymmetric catalytic transformations to facilitate the green synthesis
of chiral natural products and drugs will continue to be a major ongoing effort in
organic chemistry. Chiral phosphorus ligands have played a significant role in recent
advances in transition-metal-catalyzed asymmetric transformations. However, there
are numerous challenging issues of reactivity and selectivity in catalysis. The development
of new and efficient chiral phosphorus ligands with new structural motifs remains
highly desirable. P-Chiral phosphorus ligands have been overlooked and are under development
as most P-chiral phosphorus ligands are either difficult to prepare or operationally
inconvenient. The development of efficient, practical, and operationally convenient
P-chiral phosphorus ligands with new structural motifs remains an important subject
of research.
Tang and his team of SIOC developed a series of efficient and practical P-chiral bis-
and mono-phosphorus ligands ([Scheme 27]).[65] Their unique structural and physical properties include P-chirality, conformational
clarity, high tunability of electronic and steric properties, and operational simplicity
as air-stable solids, making them exceptional ligands for several asymmetric catalytic
reactions. With their powerful P-chiral phosphorus ligands, in 2018, a concise, five-step
synthesis of acetyl cholinesterase inhibitor (−)-corynoline 139 from known indanone was achieved ([Scheme 28]),[66] in which the key step is an enantioselective palladium-catalyzed α-arylation on
the sterically hindered substrates. Next, radical dibromination at two benzylic positions
gave dibromide, and treatment with methylamine then provided tertiary amine 137 in 37% yield over two steps. A subsequent marvelous Büchner–Curtius–Schlotterbeck
reaction successfully converted the sterically hindered indanone into (−)-corynolon
138 in 56% yield.
Scheme 27 Variety of P-chiral phosphorus ligands.
Scheme 28 The five-step route of enantioselective synthesis of (−)-corynoline.
Obviously, the construction of all-carbon quaternary centers is challenging due to
the large steric effect, but it is also appealing. In particular, asymmetric catalytic
methods applicable to the synthesis of chiral natural products and pharmaceutical
molecules containing all-carbon quaternary centers remain in high demand. Although
there has been a great deal of synthetic effort, efficient asymmetric syntheses, particularly
those based on asymmetric catalytic methods, are still lacking. In this case, the
chiral all-carbon quaternary center was constructed with the assistance of the bulky
P-chiral ligand BI-DIME, which was efficient for various cross-coupling reactions
of sterically hindered substrates ([Scheme 29]). The method is practical and highly efficient, featuring excellent enantioselectivities
and good functional group compatibility with up to 98% yield and 99% ee values. This reaction is expected to be extensively applicable in drug discovery
and process chemistry.[67]
Scheme 29 Pd(OAc)2/BI-DIME catalyzed asymmetric α-arylation of sterically hindered substrates.
Practical Asymmetric Synthesis of Chiral Cyclohexyl Spirobiindanes and Its Applications
Transition-metal-catalyzed asymmetric reactions are a hot issue and at the frontier
of current organic chemistry research. Many of these chiral spiro ligands and related
catalysts have not only shown high catalytic activity and high enantioselectivity
for various asymmetric reactions, but they have also made enantiocontrol of many catalytic
asymmetric reactions, which are difficult in obtaining high enantioselectivities,
easier and more feasible. Spiroketal-based diphosphine (SKP) ligands, developed by
Ding's group at SOIC, turned out to be the most appropriate and versatile ligands
([Scheme 30]).[68]
Scheme 30 Synthesis of chiral, aromatic spiroketals.
The chiral spiro skeleton has become a “privileged structure,” and chiral spiro ligands
and catalysts have been used in the syntheses of different types of chiral compounds
including chiral natural products and chiral drugs.[69] For the synthesis of carbohydrates, which are polyhydroxylated compounds bearing
multiple stereogenic centers, catalyst-directed stereoselective carbonyl addition
in the absence of protecting groups has only been achieved using enzymes. In 2016,
direct anomeric propargylation of unprotected aldoses with excellent levels of catalyst-directed
diastereoselectivity was achieved ([Scheme 31]).[70] The key features of anomeric propargylation is the chirality of the catalyst derived
from the SKP skeleton, not the internal stereogenic centers of substrates, which predominantly
controls the stereochemistry of the propargylation step.
Scheme 31 Synthesis of sialic acids derivatives via (SKP-Cu)-catalyzed stereodivergent propargylation.
Nickel Catalyst for Practical Asymmetric Hydrogenation of N-Sulfonyl Imines
Chiral amine compounds are important synthesis intermediates and have a wide range
of applications in the synthesis of pharmaceuticals and fine chemicals. Asymmetric
catalytic hydrogenation through imines is the most direct and efficient method of
obtaining chiral amine compounds.[71] In the past two decades, significant progress has been made in the asymmetric catalytic
hydrogenation of imines. Various highly active, highly stereoselective chiral ligands
and catalysts have been designed and synthesized,[72] various new asymmetric catalytic methods and strategies have been developed and
successfully applied, and important hydrogenation reactions of various special imine
substrates have been important breakthroughs in pharmaceutical production. However,
the asymmetric catalytic hydrogenation of N-sulfonyl imine still has low reactivity, a narrow substrate range, and harsh reaction
conditions. Catalysts for these reactions are precious metals such as Rh, Ru, Ir,
and Pd (compared with very cheap Ni), on the other hand, chiral ligands are also expensive;
therefore, the development of a more economical, highly efficient, highly selective,
and environmentally friendly asymmetric hydrogenation process or scale-up by the use
of Ni is the future direction of asymmetric catalytic hydrogenation of imines.
Although hydrogenation reactions using chiral sulfenamides and N-tert-butanesulfinyl imines has been reported occasionally for more than a decade,[73] these reactions all use quantitative chiral sulfenamides as the starting material,
such as (R) or (S)-tert-butanesulfinamide, which are clearly not atom-economical. Furthermore, the catalyst
is essentially a precious metal, such as Ru. The high loading of the catalyst indicates
that it cannot comply with green-chemistry principles for sustainable development.
In 2001, it was reported that, in trifluoroethanol, fluorinated amino acids were prepared
by Pd-catalyzed asymmetric hydrogenation of fluorinated iminoesters under the combined
action of palladium and (R)-BINAP.[74] In 2006, the palladium- and TangPhos-catalyzed hydrogenation of N-tosylimines also made progress,[75] but it is not ideal for broad applications and for scale-up in terms of the high
loading of Pd, cost of the chiral ligands, and the limit of general applicability,
attributed to the low turnover number.
Chiral sulfonamides are common pharmacophores and are considered to be useful isosteres
of carboxylic acids and carboxamides in drug discovery. In 2018, Zhou and coworkers
developed a stepwise reductive amination of aryl ketones and the corresponding tosylamines
via nickel-catalyzed asymmetric transfer hydrogenation ([Scheme 32]).[76] Formic acid was used as a safe and economical surrogate of high-pressure hydrogen
gas. As a result, a drug candidate 158 for the treatment of type II diabetes was effectively prepared.
Scheme 32 Reductive amination of aryl ketones.
In 2019, a breakthrough in the first asymmetric catalytic hydrogenation of N-sulfonyl imines catalyzed by an inexpensive metal, Ni (only 0.5 mol% loading), with
chiral ligand (R,R)-QuinoxP* was reported in Angewandte Chemie International Edition ([Scheme 33]). This paper was highlighted as a very important paper (VIP) and appeared as the
cover story.[77] The pioneering work performed by Zhang's group involved a practical and robust transformation
that has many advantages, including excellent enantioselectivities, high conversion
rates, and amazingly high turnover numbers (S/C = 10,500 so far when using Ni), all
while using minimal (0.5 mol%) and the cheapest nickel for asymmetric hydrogenation
of prochiral N-sulfonyl imines. We believe that this novel method will have wider application in
the near future for pharmaceutical process development.
Scheme 33 Ni/(R,R)-QuinoxP*-catalyzed asymmetric catalytic hydrogenation of N-sulfonyl imines.
This excellent catalytic system is also suitable for three types of cyclic N-sulfonyl imine substrates, including five- or six-membered cyclic benzosultams which
are important bioactive molecules or drug candidates ([Scheme 34]).
Scheme 34 Ni/(R,R)-QuinoxP*-catalyzed asymmetric catalytic hydrogenation of cyclic N-sulfonyl imine.
It is worth noting that the
t
Bu-sulfonyl groups could be easily removed by using AlCl3 to yield the corresponding chiral amines in excellent conversion without loss of
ee ([Scheme 35]); nevertheless, we still hope a better deprotection method will be discovered in
the future to make the entire process more eco-friendly.
Scheme 35 Removal of chiral auxiliary t-Bu-sulfonyl group.
Revolutionary Process of HMG-CoA Reductase Inhibitors' Side Chain
Statins, as HMG-CoA reductase inhibitors, are a class of very important drugs that
regulate cholesterol biosynthesis, and which have led to reduced risk of atherosclerosis
and cardiovascular disease.[78] The pursuit of more potent statins uninterruptedly continued at the level of these
natural and synthetic analogues, and, as a result of structural refinements, the third
generation of synthetic statins—the so-called superstatins—represented by atorvastatin
[[Fig. 7], (168)], rosuvastatin (169), fluvastatin (170), and pitavastatin (171)—was developed and launched on the market as more efficient hypolipidemic drugs.[79] In particular, atorvastatin (168) was the first pharmaceutical product to reach annual sales of 10 billion dollars,
and used to be the top-selling drug in the world.[80] Structurally, these synthetic superstatins commonly possess a pivotal syn-1,3-diol moiety with two stereogenic centers, which attaches to a heterocyclic core
and poses an ongoing challenge for economical and eco-friendly synthesis toward statin
targets.[81]
Fig. 7 Representative superstatins.
Obviously, central to the asymmetric synthesis of superstatins is the construction
of the crucial chiral side chain. Continuous endeavors over more than 40 years have
resulted in the development of numerous strategies for stereoselective generation
of two stereocenters in the side chains of these statins.[81] The industrial approaches have mostly centered on the manipulation of the chiral
side chain 175 by well-established diastereoselective Narasaka–Prasad reduction of chiral β-hydroxy-3-ketoester
7 starting from readily available L-isoascorbic acid (172) or (S)-epichlorohydrin (173;[Scheme 36]). However, the major drawback of these large-scale syntheses liesin utilizing toxic
cyanide as C1-synthon for lateral chain elongation.[81]
[82]
Scheme 36 Outline of the industrial process of superstatins.
Chen and coworkers designed a recyclable dimerization of (R,R)-salen catalyst [FDU-06–12 catalyst (177)] to solve the problem of constructing a C-3 stereocenter in the process of chemical
kinetic resolution (176→178) and also discovered the key technology of intramolecular diastereoselective oxidative
bromocyclization (179→180) for C-5 stereocenter assembly ([Scheme 37]); in particular, this process could avoid the use of cyanide and greatly simplify
the synthesis of the side chain and reduce costs. Then, Chen and coworkers achieved
the efficient syntheses of atorvastatin (168), rosuvastatin (169), and pitavastatin (171).[83]
Scheme 37 Chen's resolution approach.
In 2014, Chen's group accomplished an efficient asymmetric synthesis of atorvastatin
(168) through a novel approach that involved an organocatalytic enantioselective cyclic
anhydride desymmetrization to establish C-3 stereogenicity and a cyanide-free assembly
of the C7 amino-type side chain via a C5 + C2 strategy as the key transformations.[84] Employing their developed bifunctional sulfonamide catalyst (182) ([Scheme 38]), the enantioselective alcoholysis of 181 proceeded smoothly to deliver 183 in 93% yield and 90% ee. Subsequently, the cyanide-free installation of the C7 cyano-type side chain 184 occurred efficiently through a diethyl pyrocarbonate (DEPC)-promoted condensation
of chiral hemiester 183 (C5 synthon) with methyl cyanoacetate (C2 synthon). The key C7 cyano-type side chain
184 was elaborated in several steps to amine 185, which could then be converted into atorvastatin (168) through a well-established sequence including a classical Paal–Knorr pyrrole approach.
Scheme 38 Chen's asymmetric alcoholysis approach.
Furthermore, Chen's group successfully developed a more streamlined approach to produce
chiral syn-1,3-diol derivatives via asymmetric reduction strategies.[85]
[86a] Employing the NaBH4–L-tartaric acid system ([Scheme 39]), the prochiral ketone of readily available β-ketoester 186 can be reduced smoothly, to deliver the crucial enantioenriched homoallylic alcohols
187. This key transformation gives excellent control of the C-3 stereocenter (up to 86%
yield, >99% ee) and places other necessary functional groups in the right position. The subsequent
quantitative esterification with (Boc)2O led to ester 188, which was used in a diastereoselective oxidative bromocyclization protocol, affording
syn-1,3-diol derivatives 189 in high yield (up to 94%), which have been proved powerfully useful as intermediates
in the total syntheses of superstatins. In addition, Chen and coworkers recently developed
a novel enzymatic strategy for producing the pivotal chiral homoallylic alcohols 187.[87] As shown in [Scheme 39], the biocatalytic approach involved the use of β-ketoester 186, which underwent bioreduction mediated by a ketoreductase (KRED) to afford the precursor
of bromocyclization, homoallylic alcohols 187in up to 88% yield with 99.9% ee. An isopropanol dehydrogenase served as a cofactor recycling enzyme in this process.
The aforementioned efficient chemical/enzymatic reduction–bromocyclization strategy
would be greatly beneficial to the scalable synthesis of superstatins.
Scheme 39 Chen's chemical and enzymatic reduction–bromocyclization approach.
Most recently, in the continuous consideration of the synthesis of the syn-1,3-diol moiety, Chen's group developed a one-pot diastereo-controlled synthesis
of chiral syn-1,3-diol derivatives via CO2 fixation/bromocyclization using in situ-generated
t
BuOBr in excellent yield and with both relative and absolute stereocontrol.[86] As illustrated in [Scheme 40], chiral homoallylic alcohol 190 was subjected to
t
BuOCl and NaBr under a continuously bubbling CO2 system to generate the crucial bromocarbonate product 180 in 76% yield with > 99% ee and >19:1 dr. Subsequently, a well-known three-step sequence afforded the general intermediate
kaneka alcohol 191, which could then be readily transformed to superstatins, such as atorvastatin (168), rosuvastatin (169), and pitavastatin (171). Notably, this methodology is the first example of using CO2 as an oxygen source to construct chiral syn-1,3-diol moieties, as well as the most ideal synthesis of the essential structures,
with excellent environmental protection potential and huge commercial value. This
procedure was patented and successfully applied in the asymmetric synthesis of statins
on a pilot plant scale in a pharmaceutical company.
Scheme 40 Chen's bromocarboxylation approach using CO2 as an oxygen source.
