Asymmetric Synthesis of US-FDA Approved Drugs over Five Years (2016–2020): A Recapitulation of Chirality

Chirality is a major theme in the design, discovery, and development of new drugs. Historically, pharmaceuticals have been synthesized as racemic mixtures. However, the enantiomeric forms of drug molecules have distinct biological properties. One enantiomer may be responsible for the desired therapeutic effect (eutomer), whereas the other may be inactive, interfere with the therapeutic form, or exhibit toxicity (distomer). Classical chemical synthesis usually leads to a racemic mixture unless stereospecific synthesis is employed. To meet the requirements of single-enantiomeric drugs, asymmetric synthesis has evolved at the forefront of drug discovery. Asymmetric synthesis involves the conversion of an achiral starting material into a chiral product. This review emphasizes the methods used for synthesizing FDA-approved chiral drugs during 2016–2020, with a special focus on asymmetric synthesis by means of chiral induction, resolution, or chiral pool.


Background
Chirality is an all-encompassing phenomenon [1]. The earliest scientific evidence for chirality was found by Biot in 1815 while discovering the optical rotation of camphor [2]. In 1848, Louis Pasteur discovered that two tartaric acid molecules with the same properties differed in the sign of their optical rotation [3]. In general, this fundamental discovery was the basis for the development of stereochemistry and, particularly, the phenomenon of "chirality". In nature, both macroscopic as well as microscopic objects can be chiral [4]. A molecule is described as chiral when it can exist in two forms, enantiomers, which have the same chemical structure but are non-superimposable mirror images of each other [5]. The human body is naturally composed of chiral amino acids, sugars, enzymes or receptors, and nucleic acids. Enzymes that are chiral only bind to the enantiomer that has the exact groups that fit into their binding site. Hence, each enantiomer, with respect to its configuration, has a specific action in the body and is selectively metabolized [6]. For instance, thalidomide was initially sold as a racemic drug for the treatment of women with morning sickness; however, it also had a teratogen effect and was subsequently withdrawn from the market. The R-enantiomer showed a positive therapeutic effect, whereas the S-enantiomer resulted in the development of birth defects [7] (Figure 1).

Chirality in FDA Drugs
Our understanding of the concept of chirality has played an essential role in the application of chiral bioactive compounds in pharmaceuticals, agrochemicals, flavors, and fragrances [8][9][10]. Chiral drugs offer several benefits, including that (1) chiral drugs can have higher potency compared to their non-chiral counterparts due to better pharmacokinetic and pharmacodynamic properties; (2) by isolating a specific enantiomer, chiral drugs can reduce unwanted side effects; (3) chiral drugs can enhance drug delivery by targeting specific enzymes or receptors; and (4) using a single enantiomer can reduce the cost of production and lead to lower drug prices for patients. In recent years, the trend in chiral drug discovery has shifted toward the development of single enantiomer drugs. This trend is driven by several factors: increased understanding of the importance of chirality in drug action and toxicity; advancements in analytical techniques that enable the separation and characterization of enantiomers; the need for more effective and safer drugs, as well as the potential for improved patent protection and market exclusivity; and increased regulatory focus on the safety and efficacy of chiral drugs. Overall, the trend in chiral drug discovery is toward the development of single enantiomer drugs, which offer the potential for improved safety, efficacy, and cost-effectiveness.

Chirality in FDA Drugs
Our understanding of the concept of chirality has played an essential role in the application of chiral bioactive compounds in pharmaceuticals, agrochemicals, flavors, and fragrances [8][9][10]. Chiral drugs offer several benefits, including that (1) chiral drugs can have higher potency compared to their non-chiral counterparts due to better pharmacokinetic and pharmacodynamic properties; (2) by isolating a specific enantiomer, chiral drugs can reduce unwanted side effects; (3) chiral drugs can enhance drug delivery by targeting specific enzymes or receptors; and (4) using a single enantiomer can reduce the cost of production and lead to lower drug prices for patients. In recent years, the trend in chiral drug discovery has shifted toward the development of single enantiomer drugs. This trend is driven by several factors: increased understanding of the importance of chirality in drug action and toxicity; advancements in analytical techniques that enable the separation and characterization of enantiomers; the need for more effective and safer drugs, as well as the potential for improved patent protection and market exclusivity; and increased regulatory focus on the safety and efficacy of chiral drugs. Overall, the trend in chiral drug discovery is toward the development of single enantiomer drugs, which offer the potential for improved safety, efficacy, and cost-effectiveness.
Since the FDA's 1992 policy [11], the synthesis of single enantiomers has gained more attention than that of racemic drugs. About 56% of the pharmaceuticals available in the market and used in therapy are chiral, and amongst those drugs, 88% are administered as racemates [12]. As of 2001, racemic drugs can no longer be registered. As drugs can have structural homology across similar biological targets [13], it is widely believed that knowledge of new chemical entities and approaches to their construction will enhance our ability to discover new drugs more efficiently. In order to reduce the toxicity and side effects associated with the inactive enantiomer, the synthesis of enantiomerically pure compounds is essential. In this context, chirality has become an important challenge in the Since the FDA's 1992 policy [11], the synthesis of single enantiomers has gained more attention than that of racemic drugs. About 56% of the pharmaceuticals available in the market and used in therapy are chiral, and amongst those drugs, 88% are administered as racemates [12]. As of 2001, racemic drugs can no longer be registered. As drugs can have structural homology across similar biological targets [13], it is widely believed that knowledge of new chemical entities and approaches to their construction will enhance our ability to discover new drugs more efficiently. In order to reduce the toxicity and side effects associated with the inactive enantiomer, the synthesis of enantiomerically pure compounds is essential. In this context, chirality has become an important challenge in the synthesis of drugs [14]. This review presents the synthetic routes for 89 new molecular entities approved by the FDA within the period of 2016-2020. The synthetic sequences described in this review have all been previously reported in patents or articles and represent the process scale or discovery routes of potential chiral drugs. In recent years, the number of chiral drugs approved has been growing in number. For instance, 20 out of the 35 pharmaceuticals approved by the FDA in 2020 are chiral [15]. A chiral drug can be synthesized from commercially available substrates (with stereocenters) or a chiral pool (naturally occurring substrates). Other ways to develop a chiral drug candidate are by employing a chiral auxiliary, using a chiral reagent, or by resolving the racemic precursor. The purpose of this review article is to analyze the recent chiral drugs and highlight the importance of asymmetric synthesis in biologically active compounds, and pharmaceuticals in particular.

Acalabrutinib (2017)
Acalabrutinib, developed by Acerta Pharma, is used for the treatment of mantle cell lymphoma (MCL) [19]. Starting from the 4-bromo benzoic acid (A 3 ), four steps are carried out to obtain the intermediate, A 4 . Commercially available chiral proline derivative, A 5 , undergoes amidation with A 4 via acid chloride to yield acalabrutinib in 86% yield (Scheme 2) [20,21]. Chirality can be induced at any stage, either as a fragment or from an achiral substrate. Due to the large size of the dataset, only the step where chirality is being introduced is discussed here. Starting from drugs with one chiral center, a year-wise classification is presented.

Pemafibrate (2017)
Pemafibrate, developed by Kowa Pharmaceuticals, is used for the treatment of hyperlipidemia [22]. Chiral fragment A 9 is synthesized from enantiopure (S)-2-hydroxybutyrolactone (A 7 ) via a ring-opening reaction in the presence of trimethylsilyl iodide. The hydrogenative reduction of A 8 and triflate addition using 2,6-lutidine produces A 9 . A 9 undergoes inversion of the configuration using potassium carbonate and acetonitrile, resulting in the formation of pemafibrate in 75% yield (Scheme 3) [23].

Letermovir (2017)
AiCuris developed letermovir for the treatment of cytomegalovirus infections [24]. A stereogenic center is installed in letermovir during the urea cyclization step. Urea (A 11 ) undergoes cyclization in a biphasic mixture of aqueous K 3 PO 4 and toluene in the presence of a cinchona-alkaloid-based phase-transfer catalyst and results in the formation of quinazolinone racemate (A 12 ) (Scheme 4) [25]. Pemafibrate, developed by Kowa Pharmaceuticals, is used for the treatment of hyperlipidemia [22]. Chiral fragment A9 is synthesized from enantiopure (S)-2-hydroxybutyrolactone (A7) via a ring-opening reaction in the presence of trimethylsilyl iodide. The hydrogenative reduction of A8 and triflate addition using 2,6-lutidine produces A9. A9 undergoes inversion of the configuration using potassium carbonate and acetonitrile, resulting in the formation of pemafibrate in 75% yield (Scheme 3) [23].

Letermovir (2017)
AiCuris developed letermovir for the treatment of cytomegalovirus infections [24]. A stereogenic center is installed in letermovir during the urea cyclization step. Urea (A11) undergoes cyclization in a biphasic mixture of aqueous K3PO4 and toluene in the presence of a cinchona-alkaloid-based phase-transfer catalyst and results in the formation of quinazolinone racemate (A12) (Scheme 4) [25]. Aerie Pharmaceuticals developed netarsudil for the treatment of ocular hypertension [26]. The Evans oxazolidinone (A15) acts as a chiral auxiliary and is later removed in the presence of hydrogen peroxide. Diester A14 undergoes regioselective hydrolysis, followed by acid chloride formation and amidation to give the ester derivative, A16. Treatment of  AiCuris developed letermovir for the treatment of cytomegalovirus infections [24]. A stereogenic center is installed in letermovir during the urea cyclization step. Urea (A11) undergoes cyclization in a biphasic mixture of aqueous K3PO4 and toluene in the presence of a cinchona-alkaloid-based phase-transfer catalyst and results in the formation of quinazolinone racemate (A12) (Scheme 4) [25]. Aerie Pharmaceuticals developed netarsudil for the treatment of ocular hypertension [26]. The Evans oxazolidinone (A15) acts as a chiral auxiliary and is later removed in the presence of hydrogen peroxide. Diester A14 undergoes regioselective hydrolysis, followed by acid chloride formation and amidation to give the ester derivative, A16. Treatment of Scheme 4. Synthesis of Letermovir.

Netarsudil (2017)
Aerie Pharmaceuticals developed netarsudil for the treatment of ocular hypertension [26]. The Evans oxazolidinone (A 15 ) acts as a chiral auxiliary and is later removed in the presence of hydrogen peroxide. Diester A 14 undergoes regioselective hydrolysis, followed by acid chloride formation and amidation to give the ester derivative, A 16 . Treatment of Evans oxazolidinone compounds with LiHMDS and Boc-protected benzotriazolylmethylamine produces A 17 , through which essential stereochemistry for netarsudil is installed (Scheme 5) [27].

Duvelisib Monohydrate (2018)
Duvelisib monohydrate, initially developed by Intellikine and later licensed to Verastem Oncology [44], is used in the treatment of both chronic lymphocytic leukemia and small lymphocytic lymphoma [45,46]. The kilogram-scale synthesis of duvelisib disclosed by Intellikine is discussed in Scheme 12 [47]. Weinreb amide A 44 treated with n-hexyl lithium is combined with benzamide A 43 to form the chiral isoquinoline A 45 in four steps. In the last step, salt resolution is performed with D-tartaric acid in methanol, and then with ammonium hydroxide to enhance the enantiopurity of A 45 . Encorafenib, in combination with binimetinib, is used for the treatment of metastatic melanoma [42]. Currently, encorafenib is marketed by Pfizer. Chirality is introduced as follows: (S)-(−)-1,2-diaminopropane dihydrochloride (A39) is treated with benzyl chloroformate and methyl chloroformate in the presence of a base, resulting in the carbamate derivative, A40. Upon hydrogenation, the chiral subunit, A41, is obtained (Scheme 11) [43]. Duvelisib monohydrate, initially developed by Intellikine and later licensed to Verastem Oncology [44], is used in the treatment of both chronic lymphocytic leukemia and small lymphocytic lymphoma [45,46]. The kilogram-scale synthesis of duvelisib disclosed by Intellikine is discussed in Scheme 12 [47]. Weinreb amide A44 treated with nhexyl lithium is combined with benzamide A43 to form the chiral isoquinoline A45 in four steps. In the last step, salt resolution is performed with D-tartaric acid in methanol, and then with ammonium hydroxide to enhance the enantiopurity of A45. Elagolix sodium, used for treating women with endometriosis, was developed by Abbvie and Neurocrine Biosciences [48]. Similar to duvelisib monohydrate, chirality is induced during the alkylation of uracil with mesylate derivative; the latter compound is synthesized by the reaction of (−)-N-Boc-D-α-phenylglycinol with methanesulfonyl chloride (Scheme 13) [49]. Elagolix sodium, used for treating women with endometriosis, was developed by Abbvie and Neurocrine Biosciences [48]. Similar to duvelisib monohydrate, chirality is induced during the alkylation of uracil with mesylate derivative; the latter compound is synthesized by the reaction of (−)-N-Boc-D-α-phenylglycinol with methanesulfonyl chloride (Scheme 13) [49].
3.1.14. Tegoprazan (2018) Tegoprazan, initially discovered by Pfizer and further developed by RaQualia Pharmaceuticals and CJ Healthcare, is used for the treatment of gastroesophageal reflux disease (GERD) [50]. The scalable synthesis of tegoprazan is given in Scheme 14 [51]. The introduction of an enantiopure chromanol side chain A 53 on the benzimidazole ring is the key step of the synthesis that occurs in the presence of tri-n-butylphosphine with 1,1 -(azodicarbonyl)dipiperidine (ADDP). Then, 3,5-difluorophenol (A 50 ) undergoes condensation with methyl propiolate to afford enol ethers (A 51 ) in both the E and Z forms (1:1 mixture). Hydrogenation, followed by intramolecular Friedel-Crafts acylation and asymmetric reduction with ozaborolidine catalyst (A 52 ), produces chromanol (A 53 ). Finally, recrystallization of the latter compound yields the enantiopure chiral subunit, A 53 .
3.1.14. Tegoprazan (2018) Tegoprazan, initially discovered by Pfizer and further developed by RaQualia Phar maceuticals and CJ Healthcare, is used for the treatment of gastroesophageal reflux dis ease (GERD) [50]. The scalable synthesis of tegoprazan is given in Scheme 14 [51]. The introduction of an enantiopure chromanol side chain A53 on the benzimidazole ring is the key step of the synthesis that occurs in the presence of tri-n-butylphosphine with 1,1′ (azodicarbonyl)dipiperidine (ADDP). Then, 3,5-difluorophenol (A50) undergoes conden sation with methyl propiolate to afford enol ethers (A51) in both the E and Z forms (1:1 Scheme 13. Synthesis of Elagolix sodium.  Novartis Pharmaceuticals developed alpelisib [52,53]. It is used for the treatment of metastatic breast cancer. The chiral center is introduced by L-proline amide A 56  Solriamfetol, developed by SK Biopharmaceuticals [57], is used for the treatment of Ehlers-Danlos syndromes (EDS) associated with obstructive sleep apnea (OSA) and narcolepsy [58]. The kilogram-scale synthesis of solriamfetol is shown in Scheme 16 [59]. Solriamfetol is synthesized in 89% yield in a single step from D-phenylalaninol (A 58 ) and sodium cyanate in the presence of acid.

Alpelisib (2019)
Novartis Pharmaceuticals developed alpelisib [52,53]. It is used for the treatment o metastatic breast cancer. The chiral center is introduced by L-proline amide A56 on the im idazole ring of A55 in the presence of triethylamine during the final step of synthesis (Scheme 15) [54][55][56]. Solriamfetol, developed by SK Biopharmaceuticals [57], is used for the treatment o Ehlers-Danlos syndromes (EDS) associated with obstructive sleep apnea (OSA) and nar colepsy [58]. The kilogram-scale synthesis of solriamfetol is shown in Scheme 16 [59]. Sol riamfetol is synthesized in 89% yield in a single step from D-phenylalaninol (A58) and so dium cyanate in the presence of acid. Solriamfetol, developed by SK Biopharmaceuticals [57], is used for the treatment o Ehlers-Danlos syndromes (EDS) associated with obstructive sleep apnea (OSA) and nar colepsy [58]. The kilogram-scale synthesis of solriamfetol is shown in Scheme 16 [59]. Sol riamfetol is synthesized in 89% yield in a single step from D-phenylalaninol (A58) and so dium cyanate in the presence of acid.

Pretomanid (2019)
Pretomanid, an antimycobacterial agent, is used to treat tuberculosis (TB). It is the first TB drug to be developed by TB Alliance [60]. Epoxide (A 61 ) plays its role as a chiral substrate by coupling with prochiral nitroimidazole (A 60 ) in the presence of DIPEA, affording A 62 (Scheme 17) [61]. Pretomanid, an antimycobacterial agent, is used to treat tuberculosis (TB). first TB drug to be developed by TB Alliance [60]. Epoxide (A61) plays its role as substrate by coupling with prochiral nitroimidazole (A60) in the presence of DIP fording A62 (Scheme 17) [61]. BeiGene, Inc. developed zanubrutinib for the treatment of mantle cell lym [62]. In contrast to the chiral pool approach discussed above, Zanubrutinib is the fi that is produced by chiral resolution. Zanubrutinib is obtained in its pure enant form via resolution methodology by treating it with L-dibenzoyltartaric acid (L (Scheme 18) [63].  [62]. In contrast to the chiral pool approach discussed above, Zanubrutinib is the first drug that is produced by chiral resolution. Zanubrutinib is obtained in its pure enantiomeric form via resolution methodology by treating it with L-dibenzoyltartaric acid (LDBTA) (Scheme 18) [63].

Zanubrutinib (2019)
BeiGene, Inc. developed zanubrutinib for the treatment of mantle cell lymphoma [62]. In contrast to the chiral pool approach discussed above, Zanubrutinib is the first drug that is produced by chiral resolution. Zanubrutinib is obtained in its pure enantiomeric form via resolution methodology by treating it with L-dibenzoyltartaric acid (LDBTA) (Scheme 18) [63]. Darolutamide is used in the treatment of non-metastatic castrate-resistant prostate cancer [64]. It was developed by Orion Corporation and Bayer Healthcare [65]. The key step in the asymmetric synthesis of darolutamide is the insertion of chiral isopropylamine fragment, A67, into the biaryl scaffold in A66, followed by acid-mediated deprotection of the Boc group to generate an intermediate A68 (Scheme 19) [66]. Darolutamide is used in the treatment of non-metastatic castrate-resistant prostate cancer [64]. It was developed by Orion Corporation and Bayer Healthcare [65]. The key step in the asymmetric synthesis of darolutamide is the insertion of chiral isopropylamine fragment, A 67 , into the biaryl scaffold in A 66

Berotralstat (2020)
Berotralstat is used to treat the prophylaxis of hereditary angioedema (HAE) attacks [71]. Following the same procedure as avapritinib, berotralstat is synthesized in its pure enantiomeric form by means of supercritical fluid chromatography in the final step (Scheme 22) [72]. Berotralstat is used to treat the prophylaxis of hereditary angioedema (HAE) attack [71]. Following the same procedure as avapritinib, berotralstat is synthesized in its pur enantiomeric form by means of supercritical fluid chromatography in the final step (Scheme 22) [72].

Osilodrostat (2020)
Osilodrostat, used for treating Cushing's disease, is a 11β-hydroxylase inhibitor [75]. Chiral osilodrostat is generated in a manner similar to that of berotralstat. Chiral HPLC separation of the intermediate A 80 directly results in drug formation (Scheme 24) [76].

Oliceridine (2020)
Oliceridine, a central nervous system (CNS) drug, is used to treat moderate-to-severe acute pain [77]. In the total synthesis of oliceridine, the chiral intermediate A 83 is obtained by the decarboxylic reaction of A 82 , followed by SFC chiral separation (Scheme 25) [78]. Oliceridine, a central nervous system (CNS) drug, is used to treat moderate-to-severe acute pain [77]. In the total synthesis of oliceridine, the chiral intermediate A83 is obtained by the decarboxylic reaction of A82, followed by SFC chiral separation (Scheme 25) [78].

Remimazolam (2020)
Acacia Pharma developed remimazolam, an ultrashort-acting benzodiazepine [79] Treatment of A85 with the chiral substrate, A86 in chloroform generated the substituted product, which upon base-promoted F-moc deprotection and acetic acid promoted con densation resulted in the formation of cyclized intermediate A87 in three steps (Scheme 26 [80].

Remimazolam (2020)
Acacia Pharma developed remimazolam, an ultrashort-acting benzodiazepine [79]. Treatment of A 85 with the chiral substrate, A 86 in chloroform generated the substituted product, which upon base-promoted F-moc deprotection and acetic acid promoted condensation resulted in the formation of cyclized intermediate A 87 in three steps (Scheme 26) [80].

Remimazolam (2020)
Acacia Pharma developed remimazolam, an ultrashort-acting benzodiazepine [79] Treatment of A85 with the chiral substrate, A86 in chloroform generated the substituted product, which upon base-promoted F-moc deprotection and acetic acid promoted con densation resulted in the formation of cyclized intermediate A87 in three steps (Scheme 26 [80]. Scheme 26. Synthesis of Remimazolam.

Ozanimod (2020)
Ozanimod is used to treat relapsing multiple sclerosis [81]. The chiral sulfinamid fragment, A90, acts as a chiral auxiliary group by inserting a chiral center on the inden derivative, A89. Ozanimod is synthesized in successive steps from intermediate A9

Ozanimod (2020)
Ozanimod is used to treat relapsing multiple sclerosis [81]. The chiral sulfinamide fragment, A 90 , acts as a chiral auxiliary group by inserting a chiral center on the indene derivative, A 89

Deutetrabenazine (2017)
Deutetrabenazine has been approved for the treatment of chorea (abnormal involuntary movements) associated with Huntington's disease [94]. The synthesis of deutetrabenazine is described in Scheme 32 [95]. The reaction of dihydroisoquinoline fragment B19 and quaternary ammonium salt B20 in the presence of a base resulted in the formation of the desired product. Unfortunately, deutetrabenazine is obtained as a racemic mixture (cis-diastereomer) in 67% yield.

Deutetrabenazine (2017)
Deutetrabenazine has been approved for the treatment of chorea (abnormal involuntary movements) associated with Huntington's disease [94]. The synthesis of deutetrabenazine is described in Scheme 32 [95]. The reaction of dihydroisoquinoline fragment B 19 and quaternary ammonium salt B 20 in the presence of a base resulted in the formation  (2017) Deutetrabenazine has been approved for the treatment of chorea (abnormal involun tary movements) associated with Huntington's disease [94]. The synthesis of deutetra benazine is described in Scheme 32 [95]. The reaction of dihydroisoquinoline fragment B1 and quaternary ammonium salt B20 in the presence of a base resulted in the formation o the desired product. Unfortunately, deutetrabenazine is obtained as a racemic mixture (cis-diastereomer) in 67% yield. Scheme 32. Synthesis of Deutetrabenazine.

Vaborbactam (2017)
Rempex Pharmaceuticals discovered vaborbactam, and it was then developed by The Medicines company. Vaborbactam, in combination with meropenem, is used to treat com plicated urinary tract infections [96]. The key step in its synthesis is obtaining a pure en antiomeric form by enantioselective lipase resolution of the racemic substrate, B22. Subse quently, the chiral centers are inserted via Matteson homologation (Scheme 33) [97]. Rempex Pharmaceuticals discovered vaborbactam, and it was then developed by The Medicines company. Vaborbactam, in combination with meropenem, is used to treat complicated urinary tract infections [96]. The key step in its synthesis is obtaining a pure enantiomeric form by enantioselective lipase resolution of the racemic substrate, B 22 . Subsequently, the chiral centers are inserted via Matteson homologation (Scheme 33) [97].

Telotristat Ethyl (2017)
Lexicon Pharmaceuticals developed telotristat ethyl, which has two chiral carbons, for the treatment of carcinoid syndrome diarrhea [98]. One of the chiral carbons is implanted from commercially available N-Boc-tyrosine methyl ester B33 and the other, shown in B32, from asymmetric transfer hydrogenation using an Iridium catalyst and ligand B31 (Scheme 34) [99,100].

Telotristat Ethyl (2017)
Lexicon Pharmaceuticals developed telotristat ethyl, which has two chiral carbons, for the treatment of carcinoid syndrome diarrhea [98]. One of the chiral carbons is implanted from commercially available N-Boc-tyrosine methyl ester B 33 (2017) Lexicon Pharmaceuticals developed telotristat ethyl, which has two chiral carbons, for the treatment of carcinoid syndrome diarrhea [98]. One of the chiral carbons is implanted from commercially available N-Boc-tyrosine methyl ester B33 and the other, shown in B32, from asymmetric transfer hydrogenation using an Iridium catalyst and ligand B31 (Scheme 34) [99,100].

Larotrectinib (2018)
Array BioPharma and LOxo Oncology discovered larotrectinib, which was further developed in collaboration with Bayer AG. It is used to treat solid tumors with neurotrophic receptor tyrosine kinase gene fusions [101]. Ellman's auxiliary (B 36 ) is responsible for the chirality in larotrectinib. The second stereogenic center is derived from a commercially available pyrrolidinol fragment (Scheme 35) [102]. Array BioPharma and LOxo Oncology discovered larotrectinib, which was furthe developed in collaboration with Bayer AG. It is used to treat solid tumors with neu rotrophic receptor tyrosine kinase gene fusions [101]. Ellman's auxiliary (B36) is responsi ble for the chirality in larotrectinib. The second stereogenic center is derived from a com mercially available pyrrolidinol fragment (Scheme 35) [102].

Glasdegib (2018)
Glasdegib was developed by Pfizer and is used for the treatment of acute myeloid leukemia [103]. Glasdegib is a good example of chiral resolution in drug synthesis. The key chiral substrate, B46, (anti-form) is obtained by dynamic kinetic resolution of the racemic mixture, B44, with transaminase enzyme ATA-306 in the presence of borate buffer (Scheme 36) [104].

Evocalcet (2018)
The Mitsubishi Tanabe Pharma corporation discovered evocalcet and Kyowa Kirin further developed the drug for secondary hyperparathyroidism (SHPT) treatment [111]. The diastereomeric mixture, B 58 , obtained from N-Boc pyrrolidinol (B 56 ), is treated with triphosgene and tert-butanol to obtain both syn (B 59 ) and anti (B 60 ) diastereomers. These two compounds are separated by chromatography. For this drug, the chromatography approach is predominantly used over the chiral pool approach, as evocalcet, with two chiral centers, is synthesized from the syn-pyrrolidine derivative, B 59 (Scheme 39) [111]. The diastereomeric mixture, B58, obtained from N-Boc pyrrolidinol (B56), is treated with triphosgene and tert-butanol to obtain both syn (B59) and anti (B60) diastereomers. These two compounds are separated by chromatography. For this drug, the chromatography approach is predominantly used over the chiral pool approach, as evocalcet, with two chiral centers, is synthesized from the syn-pyrrolidine derivative, B59 (Scheme 39) [111].

Baloxavir Marboxil (2018)
Baloxavir marboxil was first approved by Pharmaceuticals and Medical Devices Agency (PMDA) and was further developed by Shionogi Inc. for the treatment of influenza A and B infections [112]. Baloxavir marboxil is constructed from different subunits, including chiral piperazine (B64), benzothiepine (B65), and alkyl chloride side chains. Resolution is carried out via the reaction of piperazine fragment B62 with chiral acid B63. Subsequent recrystallization results in B64 (Scheme 40) [113]. Eisai Co., Ltd. (Bunkyo City, Tokyo) discovered fosravuconazole L-lysine ethanolate [114], a prodrug of ravuconazole and broad-spectrum antifungal agent. The process-scale synthesis of fosravuconazole is outlined in Scheme 41 [115]. The chiral pool synthesis of fosravuconazole L-lysine ethanolate starts with a single chiral center in lactate (B 68 ) and another is induced from intermediate B 69 by Corey-Chaykovsky epoxidation and sequential ring opening in a single step. Ravuconazole is converted into fosravuconazole in three successive steps (Scheme 41) [116]. Lumateperone is an antipsychotic drug used to treat schizophrenia [117]. In the ninestep synthesis of lumateperone, stereocenters are generated during the reduction of tricyclic indole intermediate B73 with triethylsilyl hydride, followed by treatment with (R)mandelic acid in methanol. Thus, the formed (S)-mandelic acid diastereomeric salt under- Lumateperone is an antipsychotic drug used to treat schizophrenia [117]. In the ninestep synthesis of lumateperone, stereocenters are generated during the reduction of tricyclic indole intermediate B 73 with triethylsilyl hydride, followed by treatment with (R)-mandelic acid in methanol. Thus, the formed (S)-mandelic acid diastereomeric salt undergoes freebasing with aqueous NaOH to afford chirally pure cis-indoline B 74  Lumateperone is an antipsychotic drug used to treat schizophrenia [117]. In t step synthesis of lumateperone, stereocenters are generated during the reduction clic indole intermediate B73 with triethylsilyl hydride, followed by treatment w mandelic acid in methanol. Thus, the formed (S)-mandelic acid diastereomeric sal goes free-basing with aqueous NaOH to afford chirally pure cis-indoline B74 (Sch [118].

Tenapanor (2019)
Tenapanor was developed by Ardelyx Inc. to treat irritable bowel syndrome with constipation [119]. Scheme 43 describes the synthesis of tenapanor. The tetrahydroisoquinoline intermediate, B 76 , generated during the synthesis reacts with linker B 77 , followed by chiral resolution (SFC separation), resulting in the formation of chiral fragment B 78 [120]. Lemborexant, developed by Eisai Co., Ltd. is used for the treatment of insomnia [121]. Starting with 2-(3-fluorophenyl) acetonitrile (B80), chirality is induced from epoxide B81 by step-by-step substitution, hydrolysis, ring-opening, and ring-closure reactions. Thus, the generated intermediate B82 undergoes reduction with NaBH4, followed by lipase-induced transesterification, eventually leading to the synthesis of lemborexant in five steps (Scheme 44) [122].

Cefiderocol (2019)
Shionogi et al. developed cefiderocol, a cephalosporin antibacterial drug. It is used for the treatment of complicated urinary tract infections (cUTI) [123]. Linear synthesis o cefiderocol is shown in Scheme 45 [124]. Chirality is induced by azetidinone ring B88 which was previously synthesized from the phthalimide derivative, B84.

Cefiderocol (2019)
Shionogi et al. developed cefiderocol, a cephalosporin antibacterial drug. It is used for the treatment of complicated urinary tract infections (cUTI) [123]. Linear synthesis of cefiderocol is shown in Scheme 45 [124]. Chirality is induced by azetidinone ring B 88 , which was previously synthesized from the phthalimide derivative, B 84 .

Upadacitinib (2019)
Upadacitinib is used to treat rheumatoid arthritis [125]. Chiral pyrrolidine frag B94, which is essential for the synthesis of upadacitinib, is obtained by asymmetric hy genation of B93 in the presence of a ruthenium catalyst. The latter compound B93 wa tained by the condensation of Cbz-protected glycine ethyl ester B91 and ethyl acryla in the presence of sodium tertiary butoxide (Scheme 46) [126].

Upadacitinib (2019)
Upadacitinib is used to treat rheumatoid arthritis [125]. Chiral pyrrolidine fragment B 94 , which is essential for the synthesis of upadacitinib, is obtained by asymmetric hydrogenation of B 93 in the presence of a ruthenium catalyst. The latter compound B 93 was obtained by the condensation of Cbz-protected glycine ethyl ester B 91

Upadacitinib (2019)
Upadacitinib is used to treat rheumatoid arthritis [125]. Chiral pyrrolidine fragme B94, which is essential for the synthesis of upadacitinib, is obtained by asymmetric hyd genation of B93 in the presence of a ruthenium catalyst. The latter compound B93 was o tained by the condensation of Cbz-protected glycine ethyl ester B91 and ethyl acrylate in the presence of sodium tertiary butoxide (Scheme 46) [126].

Tenofovir Alafenamide Fumarate (2016)
Tenofovir alafenamide fumarate was discovered and developed by Gilead for the treatment of chronic hepatitis B viral infections [127]. The reaction of adenine (C 1 ) with (R)propylene carbonate (C 2 ) affords intermediate C 3 , with a single chiral center. In successive steps, the monophosphonate ester, C 5 , is treated with thionyl chloride, and the L-alanine derivative, C 6 , affords racemic intermediate C 7 , with two chiral centers. Simulated moving bed chromatography is employed to resolve the racemic mixture and obtain diastereomers. Tenofovir alafenamide fumarate is synthesized from diastereomer C 8 and fumaric acid (Scheme 47) [128].

Bictegravir (2018)
A combination of bictegravir, emtricitabine, and tenofovir alafenamidecan be used to treat HIV-1 infections [129]. The process-scale synthesis of bictegravir was reported and developed by Gilead (Scheme 48) [130,131]. The late-stage installation of chiral substrate C 13 to the pyridone derivative results in bictegravir in three steps. Synamino pentanol (C 13 ) is previously obtained from commercially available cyclopentanoic acid (C 10 ) in six steps. Acid C 10 is converted to amide C 11 , which then undergoes oxidation to form the chiral alcohol subunit, C 13 . treatment of chronic hepatitis B viral infections [127]. The reaction of adenine (C1) with (R)-propylene carbonate (C2) affords intermediate C3, with a single chiral center. In successive steps, the monophosphonate ester, C5, is treated with thionyl chloride, and the Lalanine derivative, C6, affords racemic intermediate C7, with two chiral centers. Simulated moving bed chromatography is employed to resolve the racemic mixture and obtain diastereomers. Tenofovir alafenamide fumarate is synthesized from diastereomer C8 and fumaric acid (Scheme 47) [128].

Bictegravir (2018)
A combination of bictegravir, emtricitabine, and tenofovir alafenamidecan be used to treat HIV-1 infections [129]. The process-scale synthesis of bictegravir was reported and developed by Gilead (Scheme 48) [130,131]. The late-stage installation of chiral substrate C13 to the pyridone derivative results in bictegravir in three steps. Synamino pentanol (C13) is previously obtained from commercially available cyclopentanoic acid (C10) in six steps. Acid C10 is converted to amide C11, which then undergoes oxidation to form the chiral alcohol subunit, C13.

Fam-Trastuzumab Deruxtecan-Nxki (2019)
Daiichi Sankyo and AstraZeneca developed fam-trastuzumab deruxtecan-nxki, an antibody-drug conjugate. The structure is composed of the GGFG linker C 23 , polycyclic chiral fragment C 27 , and anti-HER2 monoclonal antibody (mAb). Various stages of inducing chirality in a single drug are shown in Scheme 50 and described below [135]:

1.
The linker C 23 with one chiral center is obtained by a chiral pool approach (i.e., amino acid derivative C 22 imparts its stereocenter to the drug); 2.
The polycyclic chiral fragment C 27 is prepared by [4 + 2] cycloaddition, followed by chiral resolution adopting supercritical fluid chromatography of the racemic intermediate, C 26 .

Pralsetinib (2020)
Pralsetinib, developed by Blueprint Medicines, is used in the treatment of metastatic non-small cell lung cancer [136]. The key step during its synthesis is the benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP)-stimulated amide coupling between the ester intermediate C 29 and the chiral amine fragment C 30 , to result in a mixture of diastereomers. The last step involves the isolation of pralsetinib by superfluid chromatography (Scheme 51) [137].
ing chirality in a single drug are shown in Scheme 50 and described below [135]: 1. The linker C23 with one chiral center is obtained by a chiral pool approach (i.e., amino acid derivative C22 imparts its stereocenter to the drug); 2. The polycyclic chiral fragment C27 is prepared by [4 + 2] cycloaddition, followed by chiral resolution adopting supercritical fluid chromatography of the racemic intermediate, C26. Scheme 50. Synthesis of Fam-trastuzumabderuxtecan-nxki.

Pralsetinib (2020)
Pralsetinib, developed by Blueprint Medicines, is used in the treatment of metastatic non-small cell lung cancer [136]. The key step during its synthesis is the benzotriazole-1yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP)-stimulated amide coupling between the ester intermediate C29 and the chiral amine fragment C30, to result in a mixture of diastereomers. The last step involves the isolation of pralsetinib by superfluid chromatography (Scheme 51) [137].

Rimegepant (2020)
Biohaven developed rimegepant for the treatment of migraines [138]. The asymmetric synthesis of rimegepant is carried out by the following step-by-step process (Scheme 52) [

Rimegepant (2020)
Biohaven developed rimegepant for the treatment of migraines [138]. The asymmetric synthesis of rimegepant is carried out by the following step-by-step process (Scheme 52) [139]:
The last chiral center in C 36 is obtained by lithium-mediated reduction.

Midostaurin (2017)
Midostaurin is used for the treatment of FLT3 mutation-positive Acute Myeloid Leukemia (AML) [142]. Its chiral pool synthesis begins with staurosporine (D 5 ), a molecule produced by fermentation. Acylation of chiral substrate D 5 with benzoic anhydride (D 6 ) results in the formation of midostaurin in a single step (Scheme 54) [143].
Recrystallization with isopropanol provides pure chiral tricyclic fragment D 20 from the corresponding enone derivative, D 19 . Paratek Pharmaceuticals discovered sarecycline; however, the drug was solely developed by Allergan. It belongs to the tetracycline class of antibiotics and is used for the treatment of inflammatory lesions of acne vulgaris [152]. A semi-synthetic tetracycline antibiotic, sancycline (D22), upon iodination with N-iodosuccinimide and further purifica- Paratek Pharmaceuticals discovered sarecycline; however, the drug was solely developed by Allergan. It belongs to the tetracycline class of antibiotics and is used for the treatment of inflammatory lesions of acne vulgaris [152]. A semi-synthetic tetracycline antibiotic, sancycline (D 22 ), upon iodination with N-iodosuccinimide and further purification provided the iodosancycline salt, D 23 , is required for the synthesis of sarecycline hydrochloride (Scheme 58) [153][154][155].

Sarecycline Hydrochloride (2018)
Paratek Pharmaceuticals discovered sarecycline; however, the drug was solely developed by Allergan. It belongs to the tetracycline class of antibiotics and is used for the treatment of inflammatory lesions of acne vulgaris [152]. A semi-synthetic tetracycline antibiotic, sancycline (D22), upon iodination with N-iodosuccinimide and further purification provided the iodosancycline salt, D23, is required for the synthesis of sarecycline hydrochloride (Scheme 58) [153][154][155]. Vibegron was discovered by Merck and developed by Kyorin Pharmaceutical Co., Ltd. (Tokyo, Japan) and Kissei Pharmaceutical Co., Ltd. (Matsumoto, Japan). It is used for the treatment of overactive bladder [158]. The key step in the synthesis of vibegron is to facilitate both the epimerization and reduction of racemic mixtures D 30 and D 31 . Ketoreductase and the cofactor NADPNa are used to form the (R)-isomer D 32 (Scheme 60) [159]. Scheme 59. Synthesis of Omadacycline.

Vibegron (2018)
Vibegron was discovered by Merck and developed by Kyorin Pharmaceutica Ltd. (Tokyo, Japan) and Kissei Pharmaceutical Co., Ltd. (Matsumoto, Japan). It is us the treatment of overactive bladder [158]. The key step in the synthesis of vibegron facilitate both the epimerization and reduction of racemic mixtures D30 and D31. K ductase and the cofactor NADPNa are used to form the (R)-isomer D32 (Scheme 60) Scheme 60. Synthesis of Vibegron.

Ubrogepant (2019)
Ubrogepant was developed by Allergan, Inc. It is used to treat migraines in a [160]. Resolution by means of SFC separation, focused on racemic spiro intermedia resulted in the formation of mono-configurational fragment D35, as depicted in Sche [161]. Ubrogepant was developed by Allergan, Inc. It is used to treat migraines in adults [160]. Resolution by means of SFC separation, focused on racemic spiro intermediate D 34 resulted in the formation of mono-configurational fragment D 35 , as depicted in Scheme 61 [161]. Cedazuridine, in combination with decitabine, is used for the treatment of myelodys plastic syndrome [162]. Chiral chromatographic separation of racemic intermediate D3 affords the chiral cedazuridine, D39, in a three-step synthesis (Scheme 62) [163]. Cedazuridine, in combination with decitabine, is used for the treatment of myelodysplastic syndrome [162]. Chiral chromatographic separation of racemic intermediate D 38 affords the chiral cedazuridine, D 39 , in a three-step synthesis (Scheme 62) [163]. Cedazuridine, in combination with decitabine, is used for the treatment of myelodysplastic syndrome [162]. Chiral chromatographic separation of racemic intermediate D38 affords the chiral cedazuridine, D39, in a three-step synthesis (Scheme 62) [163]. Scheme 62. Synthesis of Cedazuridine.

Vibegron (2020)
Vibegron is used to treat overactive bladder with symptoms, such as urge urinary incontinence and urinary frequency [158]. Large-scale synthesis of the drugs is outlined in Scheme 63. Chiral amine, D40, generated from hexynoic acid, undergoes acid-amine coupling with another chiral acid, D41, followed by chiral SFC separation, to give the drug in pure form (Scheme 63) [164].

Vibegron (2020)
Vibegron is used to treat overactive bladder with symptoms, such as urge urinary incontinence and urinary frequency [158]. Large-scale synthesis of the drugs is outlined in Scheme 63. Chiral amine, D 40 , generated from hexynoic acid, undergoes acid-amine coupling with another chiral acid, D 41 , followed by chiral SFC separation, to give the drug in pure form (Scheme 63) [164].

Narlaprevir (2016)
Narlaprevir was developed by Schering-Plough Corporation and the Texas Liver Institute and succeeded by R-Pharm Pharmaceuticals. It is an anti-infective drug used for the treatment of hepatitis C virus (HCV) genotype 1 infections [165]. The kilogram-scale synthesis of narlaprevir is presented in Scheme 64 [166,167]. Chirality is induced during the conversion of the acid intermediate E1 to the urea derivative, E2, in the presence of leucine. Another three chiral centers from the bicyclic amine, E3, are introduced by peptide coupling conditions. Narlaprevir was developed by Schering-Plough Corporation and the Texas Liver Institute and succeeded by R-Pharm Pharmaceuticals. It is an anti-infective drug used for the treatment of hepatitis C virus (HCV) genotype 1 infections [165]. The kilogram-scale synthesis of narlaprevir is presented in Scheme 64 [166,167]. Chirality is induced during the conversion of the acid intermediate E 1 to the urea derivative, E 2 , in the presence of leucine. Another three chiral centers from the bicyclic amine, E 3 , are introduced by peptide coupling conditions. Narlaprevir was developed by Schering-Plough Corporation and the Texas Liver Institute and succeeded by R-Pharm Pharmaceuticals. It is an anti-infective drug used for the treatment of hepatitis C virus (HCV) genotype 1 infections [165]. The kilogram-scale synthesis of narlaprevir is presented in Scheme 64 [166,167]. Chirality is induced during the conversion of the acid intermediate E1 to the urea derivative, E2, in the presence of leucine. Another three chiral centers from the bicyclic amine, E3, are introduced by peptide coupling conditions. Scheme 64. Synthesis of Narlaprevir. Scheme 64. Synthesis of Narlaprevir.

Elbasvir (2016)
Merck developed the combination of elbasvir and grazoprevir for the treatment of chronic HCV infections [168]. Elbasvir, which contains five chiral carbons, is shown in Scheme 65. The key step in the synthesis of elbasvir is the asymmetric reduction of imine derivative E 6 in the presence of a ruthenium catalyst, E 7 [169]. Merck developed the combination of elbasvir and grazoprevir for the treatment of chronic HCV infections [168]. Elbasvir, which contains five chiral carbons, is shown in Scheme 65. The key step in the synthesis of elbasvir is the asymmetric reduction of imine derivative E6 in the presence of a ruthenium catalyst, E7 [169]. Latanoprostene bunod was discovered by the NicOx-Pfizer collaboration and developed by Bausch and Lomb. It is used to reduce intraocular pressure in patients with open-angle glaucoma or ocular hypertension [170]. In this chiral pool approach, latanoprost acid (E 10 ) is treated with 4-bromobutyl nitrate in the presence of K 2 CO 3 and KI (Scheme 66) [171,172]. Scheme 65. Synthesis of Elbasvir.

Latanoprostene Bunod (2017)
Latanoprostene bunod was discovered by the NicOx-Pfizer collaboration and developed by Bausch and Lomb. It is used to reduce intraocular pressure in patients with openangle glaucoma or ocular hypertension [170]. In this chiral pool approach, latanoprost acid (E10) is treated with 4-bromobutyl nitrate in the presence of K2CO3 and KI (Scheme 66) [171,172].

Drugs with More Than Five Chiral Centers
For drugs with more than five chiral centers, only the step in which chirality is induced is described in the scheme.
3.6.1. Velpatasvir (2016) Velpatasvir, an antiviral drug developed by Gilead Sciences, is used, in combination with sofosbuvir, for the oral treatment of chronic HCV genotypes (1-6) [175]. The combination of chiral subunits in velpatasvir is shown in Scheme 68 [176]. Of all the chiral centers present in the drug, only the initial chiral induction by means of crystallization is

Drugs with More Than Five Chiral Centers
For drugs with more than five chiral centers, only the step in which chirality is induced is described in the scheme. Velpatasvir, an antiviral drug developed by Gilead Sciences, is used, in combination with sofosbuvir, for the oral treatment of chronic HCV genotypes (1)(2)(3)(4)(5)(6) [175]. The combination of chiral subunits in velpatasvir is shown in Scheme 68 [176]. Of all the chiral centers present in the drug, only the initial chiral induction by means of crystallization is highlighted. Commercially available glutamate (F 1 ) undergoes intramolecular condensation to form dihydropyrrole (F 2 ). The reduction of ester functionalities, followed by alkylation and crystallization, results in the cis form, Obeticholic acid, in combination with ursodeoxycholic acid, is used in the treatment of primary biliary cholangitis [177]. This drug was discovered at the Universita de Perugia and developed by Intercept Pharmaceuticals. In this chiral pool strategy, hydrogenation of the olefin intermediate F6, followed by heating to reflux, resulted in the epimerized fragment α-ethyl ketone F7 (Scheme 69) [178,179].  Obeticholic acid, in combination with ursodeoxycholic acid, is used in the treatment of primary biliary cholangitis [177]. This drug was discovered at the Universita de Perugia and developed by Intercept Pharmaceuticals. In this chiral pool strategy, hydrogenation of the olefin intermediate F 6 , followed by heating to reflux, resulted in the epimerized fragment α-ethyl ketone F 7 (Scheme 69) [178,179].

Grazoprevir Hydrate (2016)
Merck discovered grazoprevir hydrate, a drug that, in combination with elbasvir, has been used to treat HCV infections. Similar to danoprevir, the key chiral subunit, F 12 , is formed by enzymatic resolution of the racemic cyclopropyl intermediate, F 11 . Commercially available boronate (F 9 ) is converted to the cyclopropane derivative, F 10 , under Simmons-Smith conditions. Finally, the enantiomer is produced by resolution with a novozyme, followed by crystallization [180]. The remaining subunits are successively inserted in a step-by-step sequence (Scheme 70).

Obeticholic Acid (2016)
Obeticholic acid, in combination with ursodeoxycholic acid, is used in the treatmen of primary biliary cholangitis [177]. This drug was discovered at the Universita de Perugia and developed by Intercept Pharmaceuticals. In this chiral pool strategy, hydrogenation of the olefin intermediate F6, followed by heating to reflux, resulted in the epimerized fragment α-ethyl ketone F7 (Scheme 69) [178,179]. Merck discovered grazoprevir hydrate, a drug that, in combination with elbasvir, ha been used to treat HCV infections. Similar to danoprevir, the key chiral subunit, F12, i formed by enzymatic resolution of the racemic cyclopropyl intermediate, F11. Commer cially available boronate (F9) is converted to the cyclopropane derivative, F10, under Sim mons-Smith conditions. Finally, the enantiomer is produced by resolution with a novo zyme, followed by crystallization [180]. The remaining subunits are successively inserted in a step-by-step sequence (Scheme 70). Ertugliflozin, discovered by Pfizer and co-developed by Pfizer and Merck, is used for the treatment of type II diabetes mellitus [181]. The synthesis of ertuglifozin commences from a chiral pool of glucose derivative F14 (Scheme 71) [182]. Oxidation, amidation, and treatment under Parikh-Doering conditions (SO3. Py) affords the chiral intermediate, Ertugliflozin, discovered by Pfizer and co-developed by Pfizer and Merck, is used for the treatment of type II diabetes mellitus [181]. The synthesis of ertuglifozin commences from a chiral pool of glucose derivative F 14 (Scheme 71) [182]. Oxidation, amidation, and treatment under Parikh-Doering conditions (SO 3 . Py) affords the chiral intermediate, F 15 . Oxalate salt (F 18 ) formation occurs via a series of reactions, viz., pivalate group removal and protection of the hindered OH group.
Ertugliflozin, discovered by Pfizer and co-developed by Pfizer and Merck, is used for the treatment of type II diabetes mellitus [181]. The synthesis of ertuglifozin commences from a chiral pool of glucose derivative F14 (Scheme 71) [182]. Oxidation, amidation, and treatment under Parikh-Doering conditions (SO3. Py) affords the chiral intermediate, Voxilaprevir, in combination with sofosbuvir and velpatasvir, is used to treat chronic HCV genotypes [183]. Gilead described the synthesis of voxilaprevir in nine steps from the pyrrolidinol derivative, F23. The enone formed by the reaction of pyrrolidinone (F20) with Grignard reagent, followed by hydrogenation, results in the addition of an ethyl group on the pyrrolidine ring (F21). Reduction, subjection to citric acid, and Boc protection introduce three stereocenters to the alcohol derivative, F23. Chiral centers are inserted in Scheme 71. Synthesis of Ertugliflozin-L-pyroglutamic acid.
3.6.5. Voxilaprevir (2017) Voxilaprevir, in combination with sofosbuvir and velpatasvir, is used to treat chronic HCV genotypes [183]. Gilead described the synthesis of voxilaprevir in nine steps from the pyrrolidinol derivative, F 23 . The enone formed by the reaction of pyrrolidinone (F 20 ) with Grignard reagent, followed by hydrogenation, results in the addition of an ethyl group on the pyrrolidine ring (F 21 ). Reduction, subjection to citric acid, and Boc protection introduce three stereocenters to the alcohol derivative, F 23 . Chiral centers are inserted in such a way that three are from the pyrrolidinol fragment (F 20 ); three are from the cyclopropyl fragment, and two are from the cyclopropyl amine fragment (Scheme 72) [184]. 3.6.6. Pibrentasvir (2017) Pibrentasvir, in combination with glecaprevir, was discovered and developed by Abbvie and Enanta Pharmaceuticals and is used for the treatment of chronic HCV genotypes (1-6) [185]. Pibrentasvir is formed via the union of different chiral subunits at vari- Pibrentasvir, in combination with glecaprevir, was discovered and developed by Abbvie and Enanta Pharmaceuticals and is used for the treatment of chronic HCV genotypes (1)(2)(3)(4)(5)(6) [185]. Pibrentasvir is formed via the union of different chiral subunits at various stages of synthesis. The very first stereogenic formation is initiated by the chiral diol fragment, F 26 , which was synthesized by asymmetric bis reduction in the presence of (R)-(+)-α,αdiphenyl-2-pyrrolidinemethanol by the Corey-Bakshi-Shibata (CBS) reduction mechanism (Scheme 73) [186]. 3.6.7. Glecaprevir (2017) Glecaprevir was first discovered and developed by Abbvie and Enanta Pharmaceuticals. Glecaprevir, in combination with pibrentasvir, has been used to treat chronic HCV infections. Glecaprevir is an assembly of chiral fragments. Of these, one notable step is the resolution of the cyclopropane intermediate, F28, utilizing esterase as a resolving agent (Scheme 74) [187]. Glecaprevir was first discovered and developed by Abbvie and Enanta Pharmaceuticals. Glecaprevir, in combination with pibrentasvir, has been used to treat chronic HCV infections. Glecaprevir is an assembly of chiral fragments. Of these, one notable step is the resolution of the cyclopropane intermediate, F 28  Plitidepsin, a natural marine product, is a potent antiproliferative drug [189]. The combination of different subunits comprises the synthesis of plitidepsin in seven steps. The chiral fragment necessary for the synthesis of the drug is generated starting from the conversion of N-Boc isoleucine F 36 to keto ester F 37 , followed by the sequential reduction, silylation, and deprotection of the ester to give plitidepsin carboxylic acid F 38 in good yield (Scheme 76) [190].
3.6.7. Glecaprevir (2017) Glecaprevir was first discovered and developed by Abbvie and Enanta Pha ticals. Glecaprevir, in combination with pibrentasvir, has been used to treat chron infections. Glecaprevir is an assembly of chiral fragments. Of these, one notable st resolution of the cyclopropane intermediate, F28, utilizing esterase as a resolvin (Scheme 74) [187]. Plitidepsin, a natural marine product, is a potent antiproliferative drug [189]. The combination of different subunits comprises the synthesis of plitidepsin in seven steps. The chiral fragment necessary for the synthesis of the drug is generated starting from the conversion of N-Boc isoleucine F36 to keto ester F37, followed by the sequential reduction, Plitidepsin, a natural marine product, is a potent antiproliferative drug [189]. The combination of different subunits comprises the synthesis of plitidepsin in seven steps. The chiral fragment necessary for the synthesis of the drug is generated starting from the conversion of N-Boc isoleucine F36 to keto ester F37, followed by the sequential reduction, silylation, and deprotection of the ester to give plitidepsin carboxylic acid F38 in good yield (Scheme 76) [190]. The Medicines Development for Global Health (MDGH) developed moxidectin. It is used for the treatment of onchocerciasis, also known as river blindness [191]. Moxidectin belongs to the milbemycin class comprised of 16-membered macrocyclic lactones. The The Medicines Development for Global Health (MDGH) developed moxidectin. It is used for the treatment of onchocerciasis, also known as river blindness [191]. Moxidectin belongs to the milbemycin class comprised of 16-membered macrocyclic lactones. The chiral pool substrate nemadectin (F 40 ), obtained by fermentation of Streptomyces cyanogriseus ssp. noncyanogenus, is converted to the ketone intermediate, F 41 , which then undergoes oxime formation and selective saponification of the ester-protecting group to afford moxidectin F 42 . It is worth mentioning that the oxime F 42 retains (E)-configuration throughout the last two steps. (Scheme 77) [192]. Ionis Pharmaceuticals, Inc. discovered plazomicin, which was then further developed by Achaogen. It is used for the treatment of complicated urinary tract infections [193]. Unlike the chiral pool syntheses, commercially available and natural sisomicin commences the synthesis of plazomicin. Ionis Pharmaceuticals, Inc. discovered plazomicin, which was then further developed by Achaogen. It is used for the treatment of complicated urinary tract infections [193]. Unlike the chiral pool syntheses, commercially available and natural sisomicin commences the synthesis of plazomicin. The key intermediate F 44 was synthesized by converting sisomicin to protected amine F 43 in three step sequences and incorporation of Boc-(S)-HABA to amine (Scheme 78) [194][195][196][197][198][199].  [200]. Cycloaddition of cycloheptatriene (F 46 ) and maleic anhydride (F 47 ) delivers mixtures F 48 and F 49 , which then undergo recrystallization with methyl tert-butyl ether (MTBE) to isolate the endo isomer, F 49 (Scheme 79) [201]. SIGA Technologies and the United States Department of Health Services Bio Advances Research and Development Authority developed tecovirimat [200]. Cyc tion of cycloheptatriene (F46) and maleic anhydride (F47) delivers mixtures F48 which then undergo recrystallization with methyl tert-butyl ether (MTBE) to iso endo isomer, F49 (Scheme 79) [201]. Nabriva Therapeutics developed lefamulin for the treatment of community-acquired bacterial pneumonia [202]. The total synthesis of lefamulin is performed in five steps, beginning with pleuromulin F 51 . The key subunit involved in the synthesis, F 52 , is obtained by the reaction with cyclohexanethiol in the presence of sodium hydroxide and benzyl(tributyl)ammonium chloride (BTBAC) in methyl tert-butyl ether (MTBE) (Scheme 80) [203]. Nabriva Therapeutics developed lefamulin for the treatment of community-acquired bacterial pneumonia [202]. The total synthesis of lefamulin is performed in five steps, beginning with pleuromulin F51. The key subunit involved in the synthesis, F52, is obtained by the reaction with cyclohexanethiol in the presence of sodium hydroxide and benzyl(tributyl)ammonium chloride (BTBAC) in methyl tert-butyl ether (MTBE) (Scheme 80) [203]. 3.6.14. Afamelanotide (2019) Afamelanotide was developed by Clinuvel Pharmaceuticals. It is used to treat erythropoietic protoporphyria [204]. Afamelanotide, with the amino acid sequence Ac-Ser-Tyl-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, is synthesized in 31 steps from the commercially available resin, F54 (Scheme 81) [205,206]. 3.6.14. Afamelanotide (2019) Afamelanotide was developed by Clinuvel Pharmaceuticals. It is used to treat erythropoietic protoporphyria [204]. Afamelanotide, with the amino acid sequence Ac-Ser-Tyl-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH 2 , is synthesized in 31 steps from the commercially available resin, F 54 (Scheme 81) [205,206] 3.6.14. Afamelanotide (2019) Afamelanotide was developed by Clinuvel Pharmaceuticals. It is used to treat erythropoietic protoporphyria [204]. Afamelanotide, with the amino acid sequence Ac-Ser-Tyl-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, is synthesized in 31 steps from the commercially available resin, F54 (Scheme 81) [205,206]. Sage Therapeutics developed brexanolone, which is used in the treatment of postpartum depression [207]. Pregnenolone (F56) initiates the linear synthesis of brexanolone (F57) in a sequential hydrogenation reduction and Mitsunobu reaction with diethylazodicarboxylate (DEAD) and triphenylphosphine (Scheme 82) [208]. Sage Therapeutics developed brexanolone, which is used in the treatment of postpartum depression [207]. Pregnenolone (F 56 ) initiates the linear synthesis of brexanolone (F 57 ) in a sequential hydrogenation reduction and Mitsunobu reaction with diethylazodicarboxylate (DEAD) and triphenylphosphine (Scheme 82) [208]. Bremelanotide is used in the treatment of hypoactive sexual desire disorde premenopausal women [209]. Similar to afamelanotide, the synthesis begins with R Amide-AM-resin (F58) and continues with the successful linkage of chiral amino acid rivatives, removal of N-Fmoc protecting group, and condensation with Fmoc-Trp(B OH (Scheme 83) [210]. Bremelanotide is used in the treatment of hypoactive sexual desire disorder in premenopausal women [209]. Similar to afamelanotide, the synthesis begins with Rink-Amide-AM-resin (F 58 ) and continues with the successful linkage of chiral amino acid derivatives, removal of N-Fmoc protecting group, and condensation with Fmoc-Trp(Boc)-OH (Scheme 83) [210].

Lurbinectedin (2020)
Lurbinectedin is used in the treatment of metastatic small-cell lung cancer in patients who have undergone platinum-based chemotherapy [211]. The total synthesis of lurbinectedin is carried out in 27 steps starting from the chiral pool L-tyrosine, F 61 (Scheme 84) [212].

Conclusions
The concept of chirality has gained considerable attention owing to its importance in the field of medicinal chemistry. The importance of chirality is evidenced by the fact tha most of the new drugs introduced annually into the market are single enantiomers. In general, drugs have structural homology across similar biological targets, and it is widely

Conclusions
The concept of chirality has gained considerable attention owing to its importance in the field of medicinal chemistry. The importance of chirality is evidenced by the fact that most of the new drugs introduced annually into the market are single enantiomers. In general, drugs have structural homology across similar biological targets, and it is widely believed that knowledge of new chemical entities and approaches to their construction will enhance our ability to discover new drugs more efficiently. Incorporating chirality into drug discovery is a promising approach to better engage biological targets with enhanced drug properties. Chirality has the efficacy to remedy the challenges of drug optimization by exploiting the three-dimensional nature of biology. Moreover, chiral small molecules are upsurging as an attractive clinical advantage in drug discovery. Our quest to find the way by which chirality is induced led us to summarize the asymmetric synthesis of 89 FDA drugs approved from 2016 to 2020. The majority of the drugs were employed for the treatment of infectious diseases (28 drugs), oncology (20 drugs), metabolic and gastrointestinal disorders (14 drugs), central nervous system disorders (12 drugs), and others (15 drugs). With 89 new drugs approved by the FDA in hand, we extracted a subgroup of small molecules featuring one or more chiral centers, and analyzed their synthetic profile. The recent major progress in new asymmetric synthetic methodologies and enantiomeric separation techniques encourage the effort of chiral drug development. With regard to the methods routinely utilized to check the enantiomeric purity at the different stages of the discovery process, the term "chiral SFC" proved to emerge in the list of the synthesized drugs. Furthermore, we found out that all the drugs have been approved as single enantiomers with a well-defined absolute stereochemistry.
It has since become clear that the individual enantiomers can have vastly different effects on the body, leading to a shift toward the development of single enantiomers as drugs. This trend is driven by advances in analytical techniques that allow for the separation and characterization of individual enantiomers, as well as a growing understanding of the pharmacology of chiral compounds. Additionally, the increasing focus on personalized medicine and the development of targeted therapies has led to a greater appreciation of the importance of chirality in drug discovery and development. Chiral drugs are now a major area of research and development in the pharmaceutical industry, with many companies investing heavily in the discovery and development of new chiral drugs. In terms of the costs of drug substances, the asymmetric synthesis of chiral drugs is still expensive. So, technological advances in asymmetric synthesis and chiral resolution/separation are continuously required.