catalysts

Review Epoxide Syntheses and Ring-Opening Reactions in Drug Development

Fotini Moschona, Ioanna Savvopoulou, Maria Tsitopoulou, Despoina Tataraki and Gerasimos Rassias * Department of Chemistry, University of Patras, 26504 Patra, Greece; [email protected] (F.M.); [email protected] (I.S.); [email protected] (M.T.); [email protected] (D.T.) * Correspondence: [email protected]; Tel.: +30-2610997912



Received: 23 August 2020; Accepted: 23 September 2020; Published: 27 September 2020


Abstract: This review concentrates on success stories from the synthesis of approved medicines and drug candidates using epoxide chemistry in the development of robust and efficient syntheses at large scale. The focus is on those parts of each synthesis related to the substrate-controlled/diastereoselective and catalytic asymmetric synthesis of epoxide intermediates and their subsequent ring-opening reactions with various nucleophiles. These are described in the form of case studies of high profile pharmaceuticals spanning a diverse range of indications and molecular scaffolds such as heterocycles, terpenes, steroids, peptidomimetics, alkaloids and main stream small molecules. Representative examples include, but are not limited to the antihypertensive diltiazem, the antidepressant reboxetine, the HIV protease inhibitors atazanavir and indinavir, efinaconazole and related triazole antifungals, tasimelteon for sleep disorders, the anticancer agent carfilzomib, the anticoagulant rivaroxaban the antibiotic linezolid and the antiviral oseltamivir. Emphasis is given on aspects of catalytic asymmetric epoxidation employing metals with chiral ligands particularly with the Sharpless and Jacobsen–Katsuki methods as well as organocatalysts such as the chiral ketones of Shi and Yang, Pages’s chiral iminium salts and typical chiral phase transfer agents.

Keywords: epoxides; drug development; catalytic asymmetric epoxidation; organocatalysis; process development and manufacturing routes; Sharpless and Jacobsen–Katsuki asymmetric epoxidation; chiral ketones/dioxiranes; iminium/oxaziridinium salts; epoxide ring opening

1. Introduction Epoxides are versatile electrophiles that support the stereospecific formation of ring-opened products with a wide array of nucleophiles. The implications of this reactivity in the context of drug design and desired biologic action as well as manifestation of adverse effects has been reviewed previously [1–4] although these are best exemplified by the plethora of natural products and the 14 approved drugs containing the epoxide functionality [5,6]. In the context of organic synthesis, the ring strain-induced electrophilicity of epoxides renders them excellent reactive intermediates for constructing in stereoselective/specific manner key bonds in larger and more complex molecules. From an academic perspective, general aspects of epoxide synthesis and ring-opening reactions spanning various levels of organic chemistry research have been reviewed extensively [7–9]. What is lesser known is how pivotal has been the successful management of epoxide chemistry on scale leading to robust, cost-effective and safe manufacturing processes. Emphasis is also given in the way certain intermediates are handled due to safety, reactivity, inappropriate state (oils, low melting point solids) or physical properties (hygroscopicity, poor filtration characteristics) or even time constraints. For example, in several cases a “telescoped” process is implemented which is a process term to describe a reaction that despite work up, washes, filtration of unwanted materials (inorganics, charcoal),

Catalysts 2020, 10, 1117; doi:10.3390/catal10101117 www.mdpi.com/journal/catalysts Catalysts 2020, 10, x FOR PEER REVIEW 2 of 69

Catalysts 2020, 10, x FOR PEER REVIEW 2 of 69 term to describe a reaction that despite work up, washes, filtration of unwanted materials (inorganics,term to describe charcoal), a reaction etc., avoids that any despite isolation work and up,a solution washes, of thefiltration intermediate of unwanted is carried materials forward Catalysts 2020, 10, 1117 2 of 65 in(inorganics, the next step, charcoal), not necessarily etc., avoids in any the isolationsame reactor. and a Thesolution more of common the intermediate term “one-pot” is carried implies forward no processing/workin the next step, notup andnecessarily the reagents in the for same the nextreactor. step The are addedmore common sequentially term in “one-pot” the same vessel.implies The no etc.,focusprocessing/work avoids of this any review isolationup and is thethe and reagentsimplementation a solution for the of next theof st intermediateepoxideep are addedchemistry is sequentially carried from forward a inprocess the insame thedevelopment vessel. next step, The notperspectivefocus necessarily of this and review in is the presented sameis the reactor. implementation through The morededicated common of epoxidediscussions term chemistry “one-pot” to high impliesfrom profile a no processapproved processing development drugs/work and up andclinicalperspective the candidates. reagents and foris presented the next step through are added dedicated sequentially discussions in thesame to high vessel. profile The focusapproved of this drugs review and is theclinical implementation candidates. of epoxide chemistry from a process development perspective and is presented through1.1. LY459477—Development dedicated discussions of a to Selective high profile Route approved via a Desymmetrization drugs and clinical Process candidates. of a Meso-Epoxide

1.1. LY459477—DevelopmentLY459477 (1) is a potent of a(EC Selective50 1 nm) Route orthosteric via a Desymmetrization agonist for rodent Process and of a humanMeso-Epoxide mGlu2 and 1.1. LY459477—Development of a Selective Route via a Desymmetrization Process of a Meso-Epoxide mGlu3LY459477 receptors. (1 )Development is a potent (EC of an50 1appropriate nm) orthosteric large-scale agonist synthesis for rodent of LY459477 and human was mGlu2required and to supportmGlu3LY459477 receptors. clinical (1 )trials isDevelopment a potent for schizophrenia, (EC 50of 1an nm) appropriate orthosteric generalized la agonistrge-scale anxiety for synthesis rodentdisorder and of and LY459477 human bipolar mGlu2 was disorders required and mGlu3 [10]. to receptors.Moreover,support clinical Developmentthe supply trials forroute of schizophrenia, an for appropriate LY459477 generalized large-scaleserved as synthesisan anxiety excellent disorder of LY459477platform and wasfor bipolar the required development disorders to support [10]. of clinicalsubsequentMoreover, trials the structurally for supply schizophrenia, route related for mGlu2/3 generalizedLY459477 agonists served anxiety as as drug disorderan excellent candidates and bipolarplatform for neuropsychiatric disorders for the development [10]. Moreover,disorders of the[11].subsequent supply routestructurally for LY459477 related servedmGlu2/3 as agonists an excellent as drug platform candidates for the for development neuropsychiatric of subsequent disorders structurally[11]. The chemotype related mGlu2 of LY459477/3 agonists was asbased drug on candidates a cyclopentene for neuropsychiatric scaffold first introduced disorders [by11 ].Hodgson and Thescientists chemotypechemotype at GlaxoSmithKline ofof LY459477 LY459477 was was (then based based Glaxo on on a cyclopentene aWe cyclopllcome)entene [12] sca scaffoldff whereold first firstthe introduced keyintroduced intermediate, by Hodgson by Hodgson chiral and scientistsalcoholand scientists 2,at was GlaxoSmithKline obtainedat GlaxoSmithKline from (thendesymmetrization Glaxo(then Wellcome)Glaxo ofWe thellcome) [12 meso] where [12]epoxide the where key 3 (Scheme intermediate,the key 1).intermediate, chiral alcohol chiral2, wasalcohol obtained 2, was from obtained desymmetrization from desymmetrization of the meso of epoxide the meso3 (Schemeepoxide 13). (Scheme 1).

Scheme 1. Retrosynthesis of LY459477 into the key alcohol and epoxide intermediates. Scheme 1. Retrosynthesis of LY459477 into the key alcohol and epoxide intermediates. Scheme 1. Retrosynthesis of LY459477 into the key alcohol and epoxide intermediates. A team of process chemists from Eli Lilly developed the original synthesis further in order to A team of process chemists from Eli Lilly developed the original synthesis further in order to deliver deliverA teamcyclopentene of process precursor chemists 5 onfrom a multikilogram Eli Lilly developed scale (Scheme the original 2). The synthesis synthesis further comprises in order of six to cyclopentene precursor 5 on a multikilogram scale (Scheme2). The synthesis comprises of six discreet discreetdeliver cyclopentene steps but proceeds precursor through 5 on aseveral multikilogram telescoped scale stages (Scheme with 2).only The two synthesis isolable comprises intermediates; of six steps but proceeds through several telescoped stages with only two isolable intermediates; monoacid 4 monoaciddiscreet steps 4 and but proceedscyclopentene through 5. Peracid-mediated several telescoped epoxidation stages with ofonly 5 twodelivers isolable the intermediates;oxygen atom and cyclopentene 5. Peracid-mediated epoxidation of 5 delivers the oxygen atom preferentially on the preferentiallymonoacid 4 and on the cyclopentene same face of 5 the. Peracid-mediated cyclopentene as theepoxidation NHBoc subs of tituent5 delivers as result the ofoxygen a hydrogen atom same face of the cyclopentene as the NHBoc substituent as result of a hydrogen bonding interaction bondingpreferentially interaction on the betweensame face the of oxidantthe cyclopentene and the latteras the functionality. NHBoc substituent A variety as result of conditions of a hydrogen were between the oxidant and the latter functionality. A variety of conditions were examined for optimum examinedbonding interaction for optimum between diastereoselectivity the oxidant and thein latterthe epoxidationfunctionality. of A variety5 towards of conditions the desirable were diastereoselectivity in the epoxidation of 5 towards the desirable diastereomer 6a, concluding to diastereomerexamined for 6a optimum, concluding diastereoselectivity to magnesium monoperoxyphthalate in the epoxidation in ofa biphasic 5 towards water/ethyl the desirable acetate magnesium monoperoxyphthalate in a biphasic water/ethyl acetate mixture with n-Bu4NHSO4 as a mixturediastereomer with 6an-Bu, concluding4NHSO4 as to a magnesiumphase transfer monoperoxyphthalate catalyst (Scheme 3). in This a biphasic method water/ethyl was successfully acetate phase transfer catalyst (Scheme3). This method was successfully scaled up to 11 kg and the final scaledmixture up with to 11 n-Bu kg 4andNHSO the4 asfinal a phaseproduct transfer was recrystallized catalyst (Scheme from 3).EtOAc/heptane This method givingwas successfully 6a at 75% product was recrystallized from EtOAc/heptane giving 6a at 75% yield with 3% of the diastereomer 6b. yieldscaled with up to3% 11 of kg the and diastereomer the final product 6b. was recrystallized from EtOAc/heptane giving 6a at 75% yield with 3% of the diastereomer 6b.

Scheme 2. Synthesis of meso-epoxide precursor 55..

The desymmetrizationScheme of epoxide 2. Synthesis6a into of chiral meso-epoxide allylic alcoholprecursor2 5.demanded a wide screen of chiral lithiated mono- and diamines as well as amino alcohols, temperatures, additives, reaction times and stoichiometry in order to achieve maximum yield and enantioselectivity. Best results were obtained with diamine 7 (Scheme4) a ffording the desired chiral allylic alcohol in 72% yield and >99% ee, followed closely by the corresponding diamine with an ethylene linker between the nitrogen atoms (71% yield and 89% ee) whereas the analog with the butylene spacer proved non selective. Interestingly, under the same conditions diastereomeric epoxide 6b essentially does not rearrange. Catalysts 2020, 10, 1117 3 of 65

The rearrangement of epoxides to allylic alcohols has been demonstrated to proceed via abstraction of either the syn-β H or the anti-β H, with cyclopentane skeletons favoring the former mode. This was Catalystsalso shown 2020, to10, bex FOR the PEER case REVIEW for 6a through deuterium labeling studies. 3 of 69

Catalysts 2020, 10, x FOR SchemePEER REVIEW 3. Substrate-controlledSubstrate-controlled diastereoselective epoxidation of 55.. 4 of 69

The desymmetrization of epoxide 6a into chiral allylic alcohol 2 demanded a wide screen of chiral lithiated mono- and diamines as well as amino alcohols, temperatures, additives, reaction times and stoichiometry in order to achieve maximum yield and enantioselectivity. Best results were obtained with diamine 7 (Scheme 4) affording the desired chiral allylic alcohol in 72% yield and >99% ee, followed closely by the corresponding diamine with an ethylene linker between the nitrogen atoms (71% yield and 89% ee) whereas the analog with the butylene spacer proved non selective. Interestingly, under the same conditions diastereomeric epoxide 6b essentially does not rearrange. The rearrangement of epoxides to allylic alcohols has been demonstrated to proceed via abstraction of either the syn-β H or the anti-β H, with cyclopentane skeletons favoring the former mode. This was also shown to be the case for 6a through deuterium labeling studies. A transition state consistent with above findings was proposed and involves the complexation of the lithiated diamine with both the (deprotonated under the reaction conditions) Boc group and the epoxide. In the latter case the lithium cation serves as a Lewis acid activating the epoxide towards ring opening with concomitant abstraction of the adjacent enantiotopic epoxide-syn-β H. This epoxide activation would be absent in the analogous complex of the lithiated diamine and the Boc group of diastereoisomer 6b (being in opposite sides) thus consistent with the inertness of the latter. The proposed transition state also exemplifies the importance of the distance between the two lithiated amino groups as this must match the distance between the epoxide and Boc oxygen atoms so that a stable complex is formed. This in turn supports the alignment of one of the basic nitrogen atoms with one of the two enantiotopic syn-β H atoms, abstraction of which leads to high enantioselectivities.

Scheme 4. Desymmetrization of meso epoxide 6a with chiral bases. Scheme 4. Desymmetrization of meso epoxide 6a with chiral bases. A transition state consistent with above findings was proposed and involves the complexation of theThe lithiated cost-effectiveness diamine with and both of thethis (deprotonated competitive synthesis under the stems reaction from conditions) the inexpensive Boc group starting and thematerials epoxide. including In the chiral latter diamine case the 7 lithiumwhich can cation be easily serves prepared as a Lewis from acid (R)- activatingα-methyl benzylamine the epoxide towardsand is recovered ring opening up to with 80% concomitant from the pilot-plant abstraction operations. of the adjacent Overall, enantiotopic an important epoxide- chiralsyn- βandH. Thispharmaceutically epoxide activation privileged would bescaffold absent inis the accessed analogous in complex multikilogram of the lithiated quantities diamine through and the Bocthe groupdesymmetrization of diastereoisomer of a meso6b (beingepoxide. in opposite sides) thus consistent with the inertness of the latter. The proposed transition state also exemplifies the importance of the distance between the two lithiated amino groups as this must match the distance between the epoxide and Boc oxygen atoms so that a stable complex is formed. This in turn supports the alignment of one of the basic nitrogen atoms with one of the two enantiotopic syn-β H atoms, abstraction of which leads to high enantioselectivities.

Catalysts 2020, 10, 1117 4 of 65

The cost-effectiveness and of this competitive synthesis stems from the inexpensive starting materials including chiral diamine 7 which can be easily prepared from (R)-α-methyl benzylamine and is recovered up to 80% from the pilot-plant operations. Overall, an important chiral and pharmaceutically Catalystsprivileged 2020, sca10, xff FORold PEER is accessed REVIEW in multikilogram quantities through the desymmetrization5 ofof 69 a meso epoxide.

1.2. Tasimelteon Tasimelteon—Comparison —Comparison ofof Large-ScaleLarge-Scale CatalyticCatalytic AsymmetricAsymmetric EpoxidationEpoxidation Processes Processes Towards Towards a a Chiral Chiral Dihydrobenzofuran Epoxide Agonism atat the the melatonin melatonin receptors receptors 1 and 1 and 2 has 2 produced has produced drug molecules drug molecules that have that been have approved been approvedfor the treatment for the of treatment insomnia of and insomnia circadian and rhythms circadian sleep–wake rhythms disorders sleep–wake (ramelteon, disorders tasimelteon) (ramelteon, as tasimelteon)well as for depression as well as (agomelatine)for depression [ 13(agomelati]. Duringne) the [13]. development During the of deve tasimelteon,lopment of10 tasimelteon,(Scheme5) by10 (SchemeBristol-Myers 5) by Squibb,Bristol-Myers provision Squibb, of large provision quantities of large of 11 quantities, required of the 11 development, required the of development a supply route. of aOne supply of the route. first synthesesOne of the examined first syntheses by process examined chemists by process at BMS involvedchemists chiralat BMS epoxide involved12 aschiral the epoxidekey intermediate 12 as the askey this intermediate could be transformed as this could to be acid transformed11 by reaction to acid with 11 triethyl by reaction phosphonoacetate with triethyl phosphonoacetatefollowed by ester hydrolysis followed by [14 ester]. hydrolysis [14].

Scheme 5. Retrosynthetic analysis of tasimelteon into key epoxide intermediate 12. Scheme 5. Retrosynthetic analysis of tasimelteon into key epoxide intermediate 12. Initially the Jacobsen–Katsuki asymmetric epoxidation (AE) [15–17] was attempted and its Initially the Jacobsen–Katsuki asymmetric epoxidation (AE) [15–17] was attempted and its optimization involved extensive screening of catalysts, solvents, oxidants, additives, reaction optimization involved extensive screening of catalysts, solvents, oxidants, additives, reaction temperature and time. It quickly became evident that the reaction needed to be carried out at temperature and time. It quickly became evident that the reaction needed to be carried out at very very low temperature in order to achieve significant enantioselectivity which never actually exceeded low temperature in order to achieve significant enantioselectivity which never actually exceeded 76% ee. mCPBA (meta-chloroperoxybenzoic acid) provided higher enantioselectivities than MMPP 76% ee. mCPBA (meta-chloroperoxybenzoic acid) provided higher enantioselectivities than MMPP (magnesium monoperoxyphthalate) or bleach and addition of NMO (N-methylmorpholine N-oxide) (magnesium monoperoxyphthalate) or bleach and addition of NMO (N-methylmorpholine N-oxide) was also beneficial. DCM proved the best solvent both in terms of conversion and enantioselectivities, was also beneficial. DCM proved the best solvent both in terms of conversion and yet this also proved the Achilles heel of the process since it caused significant safety and operational enantioselectivities, yet this also proved the Achilles heel of the process since it caused significant issues. Specifically, the moderate solubility of mCPBA in DCM exacerbated by the low reaction safety and operational issues. Specifically, the moderate solubility of mCPBA in DCM exacerbated temperature at 75 to 65 C, caused precipitation of the reagent leading to inconsistent reaction by the low reaction− temperature− ◦ at −75 to −65 °C, caused precipitation of the reagent leading to mixtures. More frequently than not, large exotherms and abrupt gas evolution were observed upon inconsistent reaction mixtures. More frequently than not, large exotherms and abrupt gas evolution addition of the mCPBA solution in the reaction mixture which caused serious safety concerns. Adjusting were observed upon addition of the mCPBA solution in the reaction mixture which caused serious for concentration, time and order of reagent addition did not solve these issues. Solvents in which safety concerns. Adjusting for concentration, time and order of reagent addition did not solve these mCPBA dissolves better, like EtOAc or ethanol were attempted as DCM replacements, but the reaction issues. Solvents in which mCPBA dissolves better, like EtOAc or ethanol were attempted as DCM did not proceed. Finally, by keeping DCM as the reaction and using the minimum amount of ethanol replacements, but the reaction did not proceed. Finally, by keeping DCM as the reaction and using to dissolve and transfer the mCPBA into the reaction mixture solved these issues and provided a fast the minimum amount of ethanol to dissolve and transfer the mCPBA into the reaction mixture reaction reaching 95% conversion within the three hours employed for addition of the mCPBA at solved these issues and provided a fast reaction reaching 95% conversion within the three hours 70 C. The optimized process involving catalyst M1 (Scheme6) was successfully scaled up to 1 kg employed− ◦ for addition of the mCPBA at −70 °C. The optimized process involving catalyst M1 scale and delivered chiral epoxide 12 in 80% yield and 74% ee. This was deemed acceptable at this (Scheme 6) was successfully scaled up to 1 kg scale and delivered chiral epoxide 12 in 80% yield and point since a resolution step, using dehydroabietylamine (leelamine), was to be implemented later in 74% ee. This was deemed acceptable at this point since a resolution step, using dehydroabietylamine the synthesis at the amine intermediate which upgraded the optical purity to 99% ee. (leelamine), was to be implemented later in the synthesis at the amine intermediate which upgraded Despite the temporary success in supplying the initially required quantities of drug substance, the optical purity to 99% ee. the necessity for a resolution step, the varying levels of manganese salts in the isolated intermediates and the apparently unavoidable formation of benzofuran impurity 14 (>3%), undermined the potential of this route in developing into a manufacturing process. Overoxidized impurity 14 in particular, presumably formed by mCPBA or catalyst-induced hydroxylation at the benzylic position followed by dehydration [18,19], posed significant quality issues as it transformed through the synthesis to

Catalysts 2020, 10, 1117 5 of 65 species that were difficult to purge, such as the acid 15, due to the high similarity with the desired intermediatesCatalysts 2020, 10, andx FOR ultimately PEER REVIEW with the final product. 6 of 69

Scheme 6. Catalytic asymmetric epoxidation of 13 and conversion to cyclopropane intermediate 11. Scheme 6. Catalytic asymmetric epoxidation of 13 and conversion to cyclopropane intermediate 11. This prompted the investigation of an alternative route to epoxide 12. Towards this end, Sharpless Despite the temporary success in supplying the initially required quantities of drug substance, Asymmetric Dihydroxylation on alkene 13 followed by transformation of the chiral diol 16 (Scheme7) to the necessity for a resolution step, the varying levels of manganese salts in the isolated intermediates the epoxide was considered next [20]. Encouraging results were obtained from preliminary experiments and the apparently unavoidable formation of benzofuran impurity 14 (>3%), undermined the as diol 16 was isolated with high ee as a crystalline and easy to handle solid. Significant work was potential of this route in developing into a manufacturing process. Overoxidized impurity 14 in dedicated before selecting potassium ferricyanide as the osmium reoxidant over the less expensive particular, presumably formed by mCPBA or catalyst-induced hydroxylation at the benzylic NMO. Potassium ferricyanide requires larger solvent quantities to be suspended adequately, produces position followed by dehydration [18,19], posed significant quality issues as it transformed through a significant solid waste that must be removed during isolation and constitutes an additional burden in the synthesis to species that were difficult to purge, such as the acid 15, due to the high similarity terms of toxic materials in the process. Nevertheless, it provided consistently high enantioselectivities with the desired intermediates and ultimately with the final product. (98–99% ee) thus eliminating the necessity for a resolution step and robust reactions whereas the This prompted the investigation of an alternative route to epoxide 12. Towards this end, process with NMO proved sensitive to the rate of addition of alkene 13. The next issue that had to be Sharpless Asymmetric Dihydroxylation on alkene 13 followed by transformation of the chiral diol 16 dealt with was the poor solubility of 13 in tert-butanol/water mixtures which was eventually solved by (Scheme 7) to the epoxide was considered next [20]. Encouraging results were obtained from replacing tert-butanol with isopropanol. Interestingly the reaction failed to proceed with commercially preliminary experiments as diol 16 was isolated with high ee as a crystalline and easy to handle available AD-Mix-α, and potassium persulfate was used and required the in situ preparation of the solid. Significant work was dedicated before selecting potassium ferricyanide as the osmium catalyst. The final problem intrinsically linked to the Asymmetric Dihydroxylation reaction was the reoxidant over the less expensive NMO. Potassium ferricyanide requires larger solvent quantities to reduction of the toxic osmium species to pharmaceutically acceptable levels which for the isolated diol be suspended adequately, produces a significant solid waste that must be removed during isolation intermediate was set at <10 ppm. Following a screening of resins, filter aids and reagents as well as the and constitutes an additional burden in terms of toxic materials in the process. Nevertheless, it development of an appropriate analytical method, the use of a sodium sulfite wash in the work up provided consistently high enantioselectivities (98–99% ee) thus eliminating the necessity for a reduced the osmium levels to less than 6 ppm as determined by inductively coupled plasma atomic resolution step and robust reactions whereas the process with NMO proved sensitive to the rate of emission spectroscopy (ICP-ES). addition of alkene 13. The next issue that had to be dealt with was the poor solubility of 13 in The optimized process (Scheme7) was gradually scaled up to 1, 8 and 15 kg scale furnishing tert-butanol/water mixtures which was eventually solved by replacing tert-butanol with diol 16 in 90% yield, HPLC purity of 98% and >99% ee and as a crystalline solid, provided the water isopropanol. Interestingly the reaction failed to proceed with commercially available AD-Mix-α, and content of the organic solution after work up was <1% w/w. potassium persulfate was used and required the in situ preparation of the catalyst. The final problem Finally, diol 16 was transformed to the desired epoxide 12 through the Kolb -Sharpless method [21], intrinsically linked to the Asymmetric Dihydroxylation reaction was the reduction of the toxic by treatment with trimethyl orthoacetate and trimethylsilyl chloride followed by base. In this process, osmium species to pharmaceutically acceptable levels which for the isolated diol intermediate was the initially formed orthester 17 is converted in situ to chloroacetate intermediate 18 with inversion of set at <10 ppm. Following a screening of resins, filter aids and reagents as well as the development of configuration and after hydrolysis of the ester and ring closure, also with inversion of configuration, an appropriate analytical method, the use of a sodium sulfite wash in the work up reduced the osmium levels to less than 6 ppm as determined by inductively coupled plasma atomic emission spectroscopy (ICP-ES).

Catalysts 2020, 10, 1117 6 of 65

provides the desired chiral epoxide 12. When the traditional conditions of K2CO3/MeOH were used for the latter part of the process, significant amounts of impurity 19 were observed (up to 10%) presumably via opening of the epoxide by methoxide anion. The epoxide stability issue surfaced required investigation of appropriate solvents, bases, reaction temperature and times temperatures as well as work up procedures in order to inhibit the formation of impurity 19. The optimum conditions found involved confirming by HPLC the completion of chloroacetate formation, followed by charging Catalysts 2020, 10, x FORt PEER REVIEW 7 of 69 a solution of KO Bu in THF at 0–5 ◦C and maintaining at the same temperature until conversion to the epoxide was complete ( 1 h) (Scheme7). No deterioration of the epoxide quality is observed under The optimized process~ (Scheme 7) was gradually scaled up to 1, 8 and 15 kg scale furnishing these conditions even after prolonged reaction times. The optimized process was successfully scaled diol 16 in 90% yield, HPLC purity of 98% and >99% ee and as a crystalline solid, provided the water up to 8 kg batches delivering the epoxide 90–95% yield and >98% ee. content of the organic solution after work up was <1% w/w.

Scheme 7. Synthesis of chiral epoxide 12 via Sharpless asymmetric dihydroxylation of 13. Scheme 7. Synthesis of chiral epoxide 12 via Sharpless asymmetric dihydroxylation of 13. Finally, diol 16 was transformed to the desired epoxide 12 through the Kolb -Sharpless method [21], by treatmentFinally, diol with 16 trimethyl was transformed orthoacetate to the and desired trimethylsilyl epoxide chloride 12 through followed the Kolb by base. -Sharpless In this method process, the[21], initially by treatment formed with orthester trimethyl17 is convertedorthoacetate in situand totrimethylsilyl chloroacetate chloride intermediate followed18 with by base. inversion In this of configurationprocess, the initially and after formed hydrolysis orthester of the 17 esteris converted and ring in closure, situ to also chloroacetate with inversion intermediate of configuration, 18 with providesinversion theof configuration desired chiral and epoxide after12 hydrolysis. When the of traditional the ester and conditions ring closure, of K2CO also3/ MeOHwith inversion were used of forconfiguration, the latter partprovides of the process,the desired significant chiral amountsepoxide of12 impurity. When 19thewere traditional observed conditions (up to 10%) of presumablyK2CO3/MeOH via were opening used offor the the epoxide latter part by of methoxide the process, anion. significant The epoxide amounts stability of impurity issue surfaced19 were requiredobserved investigation (up to 10%) ofpresumably appropriate via solvents, opening bases, of the reaction epoxide temperature by methoxide and times anion. temperatures The epoxide as wellstability as work issue up surfaced procedures required in order investigation to inhibit the of formationappropriate of solvents, impurity 19bases,. The reaction optimum temperature conditions foundand times involved temperatures confirming as well by HPLC as work the completionup procedur ofes chloroacetate in order to inhibit formation, the formation followed byof impurity charging t a19 solution. The optimum of KO Bu conditions in THF at found 0–5 ◦C involved and maintaining confirming at the by same HPLC temperature the completion untilconversion of chloroacetate to the t epoxideformation, was followed complete by( ~charging1 h) (Scheme a solution7). No of deterioration KO Bu in THF of theat 0–5 epoxide °C and quality maintaining is observed at the under same thesetemperature conditions until even conversion after prolonged to the epoxide reaction was times. complete The optimized (~1 h) (Scheme process 7). wasNo deterioration successfully scaledof the upepoxide to 8 kg quality batches is delivering observed theunder epoxide these 90–95% conditions yield andeven> 98%after ee. prolonged reaction times. The optimizedOverall, process the eff wasorts successfully to develop a scaled large-scale up to route 8 kg to batches tasimelteon delivering culminated the epoxide in interrogating 90–95% yield the performanceand >98% ee. and viability of two of the most popular asymmetric transformations, namely the Jacobsen–KatsukiOverall, the efforts Asymmetric to develop Epoxidation a large-scale androute the to tasimelteon Sharpless culminated Asymmetric in Dihydroxylation.interrogating the Bothperformance processes and required viability careful of two navigation of the most through popular safety asymmetric and product transformations, quality issues arisingnamely from the reagents,Jacobsen–Katsuki catalysts Asymmetric and associated Epoxidation process impurities and the Sharpless as well as Asymmetric technical diffi Dihydroxylation.culties in several Both unit operations.processes required Despite careful the shorter navigation route othroughffered by safety the Asymmetric and product epoxidation quality issues process, arising the lowerfrom enantioselectivityreagents, catalysts achieved and associated renders process imperative impurities the implementation as well as technical of a resolution difficulties step andin several in addition, unit suoperations.ffers from Despite a persistent the shorter impurity. route The offered Asymmetric by the Dihydroxylation Asymmetric epoxidation route although process, more the process lower enantioselectivity achieved renders imperative the implementation of a resolution step and in addition, suffers from a persistent impurity. The Asymmetric Dihydroxylation route although more process intensive, provides excellent enantioselectivity, superior purity profile and higher overall yield of the final drug substance (43% vs 22%).

1.3. Efinaconazole, Ravuconazole, Isavuconazole, Albaconazole —Synthesis via Two Successive Chiral Epoxide Intermediates and Ring Opening Reactions The introduction of fluconazole in 1988 was a major breakthrough in the treatment of fungal infections harming humans, animals and plants [22,23]. Fungal infections vary in severity from mild

Catalysts 2020, 10, 1117 7 of 65 intensive, provides excellent enantioselectivity, superior purity profile and higher overall yield of the final drug substance (43% vs 22%).

1.3. Efinaconazole, Ravuconazole, Isavuconazole, Albaconazole—Synthesis via Two Successive Chiral Epoxide Intermediates and Ring Opening Reactions The introduction of fluconazole in 1988 was a major breakthrough in the treatment of fungal Catalystsinfections 2020 harming, 10, x FOR humans,PEER REVIEW animals and plants [22,23]. Fungal infections vary in severity from8 mildof 69 to fatal particularly when the people infected receive chemotherapy, immunosuppressant treatment or toare fatal immunocompromised particularly when the such people as HIV infected patients. receive Azole chemotherapy, antifungals work immu bynosuppressant inhibiting primarily treatment the orcytochrome are immunocompromised P450-dependent lanosterolsuch as HIV 14α -demethylasepatients. Azole (Erg11p, antifungals CYP51) work involved by inhibiting in the biosynthesis primarily theof ergosterolcytochrome which P450-dependent is essential forlanosterol fungi membrane 14α-demethylase integrity. (Erg11p, Over the CYP51) years, involved issues related in the to biosynthesisbioavailability, of toxicity,ergosterol resistance, which is limited essential spectrum for fungi activity membrane and cost integrity. has prompted Over the intense years, research issues relatedin antifungal to bioavailability, research including toxicity, analogs resistance, of the limited triazole spectrum class. This activity effort and has producedcost has prompted approved intensedrugs suchresearch as efinaconazole in antifungal [24 ],research isavuconazole including (in itsanalogs prodrug of formthe triazole isavuconazonium class. This sulfate)effort has [25] producedand clinical approved candidates drugs like ravuconazolesuch as efinaconazole [26] and albaconazole [24], isavuconazole [27] (Scheme (in8). its In theprodrug triazole form and isavuconazoniumimidazole classes sulfate) of antifungals [25] and optimum clinical biologiccandidates activity like ravuconazole requires the R,R [26]stereochemistry and albaconazole at both[27] (Schemethe benzylic 8). In and the adjacent triazole stereocenter. and imidazole In thisclasses context, of antifungals epoxide 24 optimum presents biologic a key intermediate activity requires for the thesynthesis R,R stereochemistry of these molecules, at both but the also benzylic an attractive and adjace diversificationnt stereocenter. point for In thethis preparation context, epoxide of related 24 presentsanalogs. a The keyR,S intermediatestereochemistry for the of synthesis24 ensures of thatthes regardlesse molecules, of but the nucleophilealso an attractive used, diversification the subsequent pointring openingfor the preparation of the epoxide of related which analogs. proceeds The with R,S inversion stereochemistry of configuration, of 24 ensures will deliverthat regardless the correct of thestereochemistry nucleophile used, hence the active subsequent analogs. ring opening of the epoxide which proceeds with inversion of configuration, will deliver the correct stereochemistry hence active analogs.

Scheme 8. Approved triazole antifungals and their common synthetic precursor epoxide 24.

ThereScheme have 8. been Approved several triazole approaches antifungals in accessing and their key common epoxide synthetic24 over theprecursor years byepoxide various 24. academic groups and pharma companies. Almost invariably the key feature of these efforts concentrated in establishingThere have the Sbeenstereochemistry several approaches at the stereocenter in accessing bearing key theepoxide methyl 24 group over sothe that years it is by inverted various to academic groups and pharma companies. Almost invariably the key feature of these efforts the correct R configuration in the subsequent reaction with the choice nucleophile, namely CN− for concentratedravu/isavuconazole, in establishing methylene the piperidineS stereochemistry for efinaconazole at the stereocenter and 7-chloroquinazolin-4(3H)-one bearing the methyl group forso thatalbaconazole. it is inverted A summary to the ofcorrect these R routes configuration outlined in in Scheme the subsequent9 below. One reaction of the earlywith attemptsthe choice to - nucleophile,install the S stereochemistrynamely CN for in 24ravu/isavuconazole,, involved the use of methylene the Sharpless piperidine asymmetric for epoxidationefinaconazole reaction and 7-chloroquinazolin-4(3H)-oneon allylic alcohol 25 to provide for epoxy albaconazole. alcohol 26A insummary 95% yield of andthese 76% routes ee [28outlined]. Mesylation in Scheme of the 9 below.primary One alcohol of the followed early attempts by triazole to install displacement the S stereochemistry furnished the keyin 24 epoxide, involved24. the A variationuse of the of Sharplessthis approach asymmetric was reported epoxidation in a recent reaction synthesis on allylic of efinaconazolealcohol 25 to provide where the epoxy triazole alcohol analog 26 in rather 95% yieldthan hydroxy-substitutedand 76% ee [28]. Mesylation alkene 25 was of subjectedthe primary to the alcohol Sharpless followed asymmetric by triazole dihydroxylation displacement [29]. furnished the key epoxide 24. A variation of this approach was reported in a recent synthesis of efinaconazole where the triazole analog rather than hydroxy-substituted alkene 25 was subjected to the Sharpless asymmetric dihydroxylation [29]. Despite the ability to upgrade the optical purity downstream the synthesis, the issue with these routes is the preparation of the cis double bond in the alkene substrate. In the case of 25 extensive manipulation was required to isomerize the predominant trans isomer (formed by Wittig reaction on the corresponding acetoxy-acetophenone) which negated further development work.

Catalysts 2020, 10, 1117 8 of 65

Despite the ability to upgrade the optical purity downstream the synthesis, the issue with these routes is the preparation of the cis double bond in the alkene substrate. In the case of 25 extensive manipulation was required to isomerize the predominant trans isomer (formed by Wittig reaction on theCatalysts corresponding 2020, 10, x FOR acetoxy-acetophenone) PEER REVIEW which negated further development work. 9 of 69

Scheme 9. Summary of approaches towards an asymmetric synthesis of 2424..

Earlier thanthan that, that, chemists chemists at Sankyoat Sankyo (legacy (legac companyy company of Daichi of Daichi Sankyo) Sankyo) after proving after proving the viability the of a synthesis with racemic lactic acid derivatives, switched to the chiral pool and used D-( )-lactic viability of a synthesis with racemic lactic acid derivatives, switched to the chiral pool and− used acidD-(−)-lactic [30–33 ].acid This [30–33]. was convertedThis was converted to the THP-protected to the THP-protected morpholine morpholine amide and amide reacted and with reacted the 2,4-difluorophenylwith the 2,4-difluorophenyl Grignard Grignard reagent producing reagent producing ketone 27 ketone. Corey–Chaykovsky 27. Corey–Chaykovsky epoxidation epoxidation reaction withreaction trimethyl with sulfoxoniumtrimethyl sulfoxonium ylide yielded yl THP-protectedide yielded THP-protected epoxy alcohol 28 epoxyin 4:1 diastereomericalcohol 28 in ratio 4:1 favoringdiastereomeric the desired ratio R,Rfavoringstereochemistry. the desired The R, R same stereochemistry. result was obtained The same from result the mCPBA was obtained epoxidation from ofthe terminal mCPBAalkene epoxidation29 (produced of terminal via aalkene Wittig 29 reaction (produced from via27 ),a thusWittig no reaction advantage from was 27 gained), thus byno addingadvantage the was extra gained step in by the adding synthesis. the extra Ring openingstep in the of thesynthesis. epoxide Ring by triazole opening to of form the 30epoxidefollowed by bytriazole THP deprotectionto form 30 followed and mesylation by THP a ffdeprotectionords hydroxy and mesylate mesylation31 which affords upon hydroxy base treatment mesylate ring 31 closeswhich toupon the base second treatment epoxide ring of the closes synthesis to the andseco keynd epoxide intermediate of the24 synthesis. These andand subsequentkey intermediate steps rectify24. These the opticaland subsequent purity. The steps steps rectify of triazole the installationoptical purity. and mesylationThe steps couldof triazole be reversed installation providing and mesylation could be reversed providing actually a cleaner profile overall, as the 1,2,4-triazole was shown to react chemoselectively with 32 by ring opening the epoxide. Interestingly, the corresponding triflate reacts with inversed chemoselectivity, giving the SN2 triflate substitution product when treated with the triazole. This aspect was investigated in the context of inversing the configuration of that center if the L-(+)-lactic acid was initially employed. Both enantiomers of lactic acid occur naturally, but the S enantiomer is much more abundant, and its utilization would reduce the cost of the triazole antifungals.

Catalysts 2020, 10, 1117 9 of 65 actually a cleaner profile overall, as the 1,2,4-triazole was shown to react chemoselectively with 32 by ring opening the epoxide. Interestingly, the corresponding triflate reacts with inversed chemoselectivity, giving the SN2 triflate substitution product when treated with the triazole. This aspect was investigated in the context of inversing the configuration of that center if the L-(+)-lactic acid was initially employed. Both enantiomers of lactic acid occur naturally, but the S enantiomer is much more abundant, and its utilizationCatalysts 2020 would, 10, x FOR reduce PEER REVIEW the cost of the triazole antifungals. 10 of 69 In analogy to 27, its enantiomer, 33, would give the opposite and undesired stereochemistry at theIn stereogenic analogy to epoxide27, its enantiomer, carbon in the33, Corey–Chaykovskywould give the opposite epoxidation and undesired reaction. stereochemistry For this reason, at ketonethe stereogenic33 was converted epoxide carbon to allylic in alcoholthe Corey–Chay34 and subjectedkovsky toepoxidation vanadium reaction. catalyzed For epoxidation this reason, to provideketone 33 epoxy was alcoholconverted35 [to34 allylic]. The alcohol same transformation 34 and subjected has to also vanadium been reported catalyzed with epoxidation the use of the to Sharplessprovide epoxy asymmetric alcohol epoxidation35 [34]. The reactionsame transformation which gives has35 with also 86%been ee reported [35,36]. with Inversion the use of of the theS stereochemistrySharpless asymmetric at the hydroxyl-bearingepoxidation reaction carbon which has gives been reported35 with 86% via both ee [35,36]. Mitsunobu Inversion conditions of the on S thestereochemistry alcohol and displacementat the hydroxyl-bearing its triflate bycarbon nitrite has or been hydroxide reported anions. via both Some Mitsunobu degree of conditions retention on of configurationthe alcohol and is alsodisplacement observed duringits triflate these by extended nitrite or manipulations hydroxide anions. rendering Some the degree routes of from retention the less of costlyconfiguration L-(+)-Lactic is also acid observed less effi cientduring overall. these Itexte isnded worth manipulations noting that reducing rendering the costthe routes contribution from the of D-(less costly)-Lactic L-(+)-Lactic acid, particularly acid less in efficient the case overall. of efinaconazole It is worth (a noting full course that reducing of efinaconazole, the cost 10%,contribution therapy − forof D-( one-nail−)-Lactic costs acid, $2,307) particularly [37] has promptedin the case intensive of efinaconazole investigations (a full for course alternative of efinaconazole, preparations of10%,27 andtherapy related for derivatives. one-nail costs These $2,307) include [37] utilization has prom of Evans’pted intensive auxiliary [38investigations], asymmetric for hydroxylation alternative ofpreparations 2,4-difluoro of propiophenone 27 and related [39 ],derivatives. enzymatic resolution These include [40], asymmetric utilization cyanohydrin of Evans’ auxiliary formation [38], [41], asymmetric Henryhydroxylation reaction [of42 ]2,4-difluoro and the oxidative propiophenone ring opening [39], of βenzymatic-methyl-2,4-difluorostyrene resolution [40], oxideasymmetric [43]. The cyanohydrin latter is a particularly formation resourceful[41], asymmetric and rarely Henry encountered reaction transformation[42] and the oxidative that deserves ring aopening special of mention. β-methyl-2,4-difluorostyrene oxide [43]. The latter is a particularly resourceful and rarely encounteredIn a styrene transformation oxide substrate that deserves (Scheme a 10special), activation mention. of the epoxide oxygen atom with TMS (trimethylsilyl)In a styrene or oxide TBDMS substrate triflate (Scheme (tert-butyldimethylsilyl 10), activation of trifluoromethanesulfonate) the epoxide oxygen atom causes with TMS ring opening(trimethylsilyl) with concomitant or TBDMS generationtriflate (tert-butyldimethylsilyl of the benzylic cation (probablytrifluoromethanesulfonate) an equilibrium) thanks causes to ring the resonanceopening with stabilization concomitant provided generation by the of aryl the substituent.benzylic cation In the (probably absence an or equilibrium) more potent nucleophiles,thanks to the dimethylresonance sulfoxide stabilization may engageprovided the by cation the aryl and substitu form a sulfoxoniument. In the absence intermediate or more akin potent to that nucleophiles, encountered indimethyl Swern-type sulfoxide oxidations may engage of alcohols. the cation Introduction and form of triethylamine a sulfoxonium at thisintermediate advanced akin stage to of that the reactionencountered eliminates in Swern-type triethylammonium oxidations triflate of alcohols. and dimethyl Introduction sulfide toof generatetriethylamine the ketone. at this The advanced starting cisstage/trans of geometrythe reaction of theeliminates epoxide triethylammonium substituents is inconsequential triflate and dimethyl as this information sulfide to isgenerate lost in the product.ketone. The More starting important, cis/trans the stereochemistry geometry of atthe the ep carbonoxide preserving substituents the originalis inconsequential bond to the epoxideas this oxygeninformation is retained is lost inin thethe alcoholproduct. product. More important, The generality the stereochemistry of this reaction hasat the been carbon demonstrated preserving with the severaloriginal stilbene bond to andthe epoxide styrene oxides.oxygen is retained in the alcohol product. The generality of this reaction has been demonstrated with several stilbene and styrene oxides.

Scheme 10. Innovative oxidative ring opening of epoxidesepoxides with electron donating substituents.

The ringring opening opening of epoxideof epoxide24 with 24 variouswith various nucleophiles nucleophiles has also beenhas also investigated been investigated extensively. Almostextensively. invariably, Almost alkali invariably, and alkaline alkali earth and metal alkali saltsne earth are reported metal salts as the are optimum reported additives as the optimum to aid the nucleophile in the ring opening of 24 [44–47]. In a recent iteration (t-BuO) Mg was found to facilitate additives to aid the nucleophile in the ring opening of 24 [44–47]. In a recent2 iteration (t-BuO)2Mg thewas reaction found to of facilitate24 with athe secondary reaction amineof 24 with used a directly secondary in its amine hydrochloride used directly form in [48 its]. Thehydrochloride first event isform the [48]. neutralization The first event of the is salt the to neutralizatio form the amine-freen of the salt base, to tform-BuOH the and amine-freet-BuOMgCl base, which t-BuOH in turnand actst-BuOMgCl as Lewis which acid toin activateturn acts the as Lewis epoxide. acid This to activate was demonstrated the epoxide. on This 700 was g scale demonstrated in the synthesis on 700 of g efinaconazolescale in the synthesis which wasof efinaconazole isolated in 96% which yield. was isolated in 96% yield. From all interconnected routes discussed above (Scheme 9) and variations thereof, process chemists at Bristol-Myers Squibb selected to develop further the process from 27, that leads to the key epoxide 24 via intermediates 28, 32, 34 as the manufacturing route of choice for ravuconazole [49]. This process that proceeds through the synthesis and ring opening of two epoxide intermediates has its roots in Sankyo’s original approach towards triazole antifungals and ever since has been regarded as the standard method to prepare these and related scaffolds [50–54].

1.4. AZD-4818—Development of a Multikilogram Synthesis of a Chiral Epoxide Precursor to A CCR1 Antagonist

Catalysts 2020, 10, 1117 10 of 65

From all interconnected routes discussed above (Scheme9) and variations thereof, process chemists at Bristol-Myers Squibb selected to develop further the process from 27, that leads to the key epoxide 24 via intermediates 28, 32, 34 as the manufacturing route of choice for ravuconazole [49]. This process that proceeds through the synthesis and ring opening of two epoxide intermediates has its roots in Sankyo’s original approach towards triazole antifungals and ever since has been regarded as the standard method to prepare these and related scaffolds [50–54].

Catalysts1.4. AZD-4818—Development 2020, 10, x FOR PEER REVIEW of a Multikilogram Synthesis of a Chiral Epoxide Precursor to A CCR1 Antagonist11 of 69

The CCR1 (chemokine(chemokine receptorreceptor 1) 1) is is a a G G protein-coupled protein-coupled receptor receptor expressed expressed on on a wide a wide range range of cell of celltypes types including including monocytes, monocytes, NK cells, NK basophils, cells, basophils, eosinophils, eosinophils, mast cells, osteoclastsmast cells, and osteoclasts predominantly and predominantlyin neutrophils, dendriticin neutrophils, cells and dendritic T lymphocytes. cells Basedand T on lymphocytes. animal models, Based pharmacological on animal blockademodels, pharmacologicalof CCR1 has been blockade proposed of to CCR1 combat has inflammatory been proposed and to autoimmune combat inflammatory diseases such and as autoimmune rheumatoid diseasesarthritis, multiplesuch as sclerosisrheumatoid and morearthritis, recently multiple cancer sclerosis thus CCR1 and antagonists more recently have attractedcancer thus significant CCR1 antagonistsinterest [55– have57]. attracted significant interest [55–57]. Astra Zeneca’s compound AZD-4818 (Scheme 11)11) is a CCR1 antagonist and a clinical candidate for the treatment of immune and inflammationinflammation disordersdisorders [[56,58].56,58].

Scheme 11. Early medicinal chemistry route to AZD-4818. Scheme 11. Early medicinal chemistry route to AZD-4818. Initial modifications of the original medicinal chemistry route to CCR1 (Scheme 11), identified Initial modifications of the original medicinal chemistry route to CCR1 (Scheme 11), identified the formation of the intermediate 40 from 4-(acetylamino)-3-hydroxyphenyl acetate (39) and the formation of the intermediate 40 from 4-(acetylamino)-3-hydroxyphenyl acetate (39) and ((2S)-2-methyloxiranyl)-methyl 3-nitrobenzenesulfonate (38) as the critical step of the synthesis [59]. ((2S)-2-methyloxiranyl)-methyl 3-nitrobenzenesulfonate (38) as the critical step of the synthesis [59]. Epoxy nosylate 38 turned out to be a highly energetic material that decomposed in an autocatalytic Epoxy nosylate 38 turned out to be a highly energetic material that decomposed in an autocatalytic manner even at low temperatures. In addition, during the first 43 and 120 kg campaigns, robustness manner even at low temperatures. In addition, during the first 43 and 120 kg campaigns, robustness issues in the asymmetric Sharpless epoxidation of 2-methyl-2-propen-1-ol (36) became a concern which issues in the asymmetric Sharpless epoxidation of 2-methyl-2-propen-1-ol (36) became a concern prompted the investigation of alternative routes towards 40. which prompted the investigation of alternative routes towards 40. AstraZeneca process chemists considered connecting the aromatic moiety to an appropriate AstraZeneca process chemists considered connecting the aromatic moiety to an appropriate glycerol fragment that would bear a latent epoxide functionality to be revealed later in the synthesis. glycerol fragment that would bear a latent epoxide functionality to be revealed later in the synthesis. An acetonide-protected diol serves well this purpose [60] thus a chiral glycerol intermediate 42R was An acetonide-protected diol serves well this purpose [60] thus a chiral glycerol intermediate 42R prepared initially in the racemic form 42rac followed by enzymatic resolution of its succinate derivative was prepared initially in the racemic form 42rac followed by enzymatic resolution of its succinate (Scheme 12). Extensive optimization of this sequence enabled isolation of 42R in 22% overall yield derivative (Scheme 12). Extensive optimization of this sequence enabled isolation of 42R in 22% at >98% ee. Its subsequent nucleophilic aromatic substitution with 3-fluoro-4-nitrophenol was also overall yield at >98% ee. Its subsequent nucleophilic aromatic substitution with carefully optimized and demonstrated successfully in multikilogram batches (156 kg in two batches). 3-fluoro-4-nitrophenol was also carefully optimized and demonstrated successfully in multikilogram batches (156 kg in two batches). Intermediate 43 however could not be isolated as a solid hence its solution was used directly in the next reaction.

Catalysts 2020, 10, 1117 11 of 65

Intermediate 43 however could not be isolated as a solid hence its solution was used directly in the nextCatalysts reaction. 2020, 10, x FOR PEER REVIEW 12 of 69

Scheme 12. Process route to key intermediate 43; carried forward asas a solution thereof.

At this point two options were considered with respect to the sequencesequence of the followingfollowing steps involving thethe reductionreduction ofof thethe nitronitro groupgroup andand acetonideacetonide hydrolysishydrolysis/epoxide/epoxide formationformation (Scheme(Scheme 13 13).). In Route A the solution of intermediate 43 was carried forward in a telescoped process to hydrogenate the nitro group followed by N-acetylation. Inclusion of acetic anhydride at the onset of the hydrogenation to trap the toxic aminophenol intermediate as it forms negatively affected the performance of the hydrogenation reaction and led to mixtures of N-, O- and diacetylated products. Attempts to isolate anilide 44 thus produced were not successful although TsOH (p-Toluenesulfonic acid) catalyzed deprotection to the diol 45 allowed for isolation of a crystalline intermediate. Three batches totaling 107 kg of the diol intermediate 45 were produced in this way. The subsequent formation of bromide 46 proceeded smoothly although this intermediate too proved unstable to store or handle for long times; best case scenario without degradation was 24 h at 5 C. Inevitably this was carried over − ◦ as a solution into the deacetylation of the hydroxyl group followed by the ring closure to form epoxide 40. An additional problem appeared in the consistent crystallization and purification of the epoxide due to the nature of the reaction medium built over the telescoped process. This aspect combined with the limited stability of bromide 46 led the Astra Zeneca process team to examine Route B (Scheme 13), namely the reverse sequence of events where epoxide generation from 43 precedes the reduction of the nitro group. The TsOH deprotection step to 47 and subsequent conversion to the acetoxy bromide 48 followed by formation of epoxide 49 were accomplished using the same conditions as in Route A for the anilide intermediates. In this sequence both bromide 48 and nitrophenol epoxide 49 were much more stable than their anilide counterparts 46 and 44 from Route A. Nitrophenol epoxide 49 could actually be isolated in good yield and quality. Initial attempts to hydrogenate the nitro group produced significant amounts of reductive ring opening of the epoxide hence a wide range of catalysts and conditions were screened for the selective hydrogenation to the aniline. This was achieved with a Pt/C catalyst in THF (4 bar H2) which was telescoped with the acetylation of both the aniline and phenol groups by addition of acetic anhydride. Despite the better behaving intermediates of Route B, a number of impurities (Scheme 14) found in the key epoxide intermediate 40 isolated from this process casted serious doubts over its potential as a manufacturing route. One set of impurities (50–52) was shown to form by water attack on the terminal epoxide under

Scheme 13. Scaled-up routes to intermediate 40 from 43; route A was finally selected.

Catalysts 2020, 10, x FOR PEER REVIEW 12 of 69

Catalysts 2020, 10, 1117 12 of 65 the processing conditions generating initially impurity 50. The generated primary alcohol participated in a transesterification process producing deacetylated phenol impurity 51 which in turn is acetylated again by aceticScheme anhydride 12. Process giving route rise to key to impurityintermediate52 .43 These; carried impurities forward as were a solution ultimately thereof. managed by control of the water content and processing conditions. This was not however the case with a second set of impuritiesAt this point (53, 54 two). These options arise were from considered the aniline reactingwith respect with theto the epoxide sequence moiety of ofthe its following nitro precursor steps involvingthus generating the reduction dimer 53 ofwhich the nitro in turn group gets and reduced acetonide to 54 hydrolysis/epoxideand associated acetylated formation derivatives. (Scheme 13).

Scheme 13. Scaled-up routes to intermediate 40 from 43; route A was finally selected. Scheme 13. Scaled-up routes to intermediate 40 from 43; route A was finally selected. These side reactions became more pronounced in conditions simulating large-scale processing and the dimeric impurities could not be purged in the already challenging crystallization of intermediate 40. This issue rendered Route B inappropriate for future deliveries and exemplified Route A as the process of choice which was subsequently optimized further. The final coupling of 40 and 41 (Scheme 11) had been optimized in earlier campaigns and posed no issues in subsequent large-scale deliveries. The successful preparation of AZD-4818, at the required specifications depends heavily on the purity of the key epoxide intermediate 40 that the new process achieved in supplying at an appropriate quality. The synthetic efforts towards Astra Zeneca’s CCR1 antagonist, highlights the quality of skills, expertise and perseverance of process chemists in managing sensitive, non-crystalline intermediates and multiple telescoped stages on scale. Catalysts 2020, 10, x FOR PEER REVIEW 13 of 69

In Route A the solution of intermediate 43 was carried forward in a telescoped process to hydrogenate the nitro group followed by N-acetylation. Inclusion of acetic anhydride at the onset of the hydrogenation to trap the toxic aminophenol intermediate as it forms negatively affected the performance of the hydrogenation reaction and led to mixtures of N-, O- and diacetylated products. Attempts to isolate anilide 44 thus produced were not successful although TsOH (p-Toluenesulfonic acid) catalyzed deprotection to the diol 45 allowed for isolation of a crystalline intermediate. Three batches totaling 107 kg of the diol intermediate 45 were produced in this way. The subsequent formation of bromide 46 proceeded smoothly although this intermediate too proved unstable to store or handle for long times; best case scenario without degradation was 24 h at −5 °C. Inevitably this was carried over as a solution into the deacetylation of the hydroxyl group followed by the ring closure to form epoxide 40. An additional problem appeared in the consistent crystallization and purification of the epoxide due to the nature of the reaction medium built over the telescoped process. This aspect combined with the limited stability of bromide 46 led the Astra Zeneca process team to examine Route B (Scheme 13), namely the reverse sequence of events where epoxide generation from 43 precedes the reduction of the nitro group. The TsOH deprotection step to 47 and subsequent conversion to the acetoxy bromide 48 followed by formation of epoxide 49 were accomplished using the same conditions as in Route A for the anilide intermediates. In this sequence both bromide 48 and nitrophenol epoxide 49 were much more stable than their anilide counterparts 46 and 44 from Route A. Nitrophenol epoxide 49 could actually be isolated in good yield and quality. Initial attempts to hydrogenate the nitro group produced significant amounts of reductive ring opening of the epoxide hence a wide range of catalysts and conditions were screened for the selective hydrogenation to the aniline. This was achieved with a Pt/C catalyst in THF (4 bar H2) which was telescoped with the acetylation of both the aniline and phenol groups by addition of acetic anhydride. Despite the better behaving intermediates of Route B, a number of impurities (Scheme 14) found in the key epoxide intermediate 40 isolated from this process casted serious doubts over its potential as a manufacturing route. One set of impurities (50–52) was shown to form by water attack on the terminal epoxide under the processing conditions generating initially impurity 50. The generated primary alcohol participated in a transesterification process producing deacetylated phenol impurity 51 which in turn is acetylated again by acetic anhydride giving rise to impurity 52. These impurities were ultimately managed by control of the water content and processing conditions. This was not however the case with a second set of impurities (53, 54). These arise from the aniline reacting with the epoxide moiety of its nitro precursor thus generating dimer 53 which in Catalysts 2020, 10, 1117 13 of 65 turn gets reduced to 54 and associated acetylated derivatives.

Catalysts 2020, 10, x FOR PEER REVIEW 14 of 69

These side reactions became more pronounced in conditions simulating large-scale processing and the dimeric impurities could not be purged in the already challenging crystallization of intermediate 40. This issue rendered Route B inappropriate for future deliveries and exemplified Route A as the process of choice which was subsequently optimized further. The final coupling of 40 and 41 (Scheme 11) had been optimized in earlier campaigns and posed no issues in subsequent large-scale deliveries. The successful preparation of AZD-4818, at the required specifications depends heavily on the purity of the key epoxide intermediate 40 that the new process achieved in supplying at an appropriate quality. The synthetic efforts towards Astra Zeneca’s CCR1 antagonist, highlights the quality of skills, expertise and perseverance of process chemists in managing sensitive, non-crystalline intermediates and multiple telescoped stages on scale.

1.5. BMS-960—DevelopmentScheme 14. Impurities inand Route Scale B; up53 ofand a Chiral54 were Epoxide difficult Route to purge through hence an Route Enzymatic A was Reduction selected. Scheme 14. Impurities in Route B; 53 and 54 were difficult to purge hence Route A was selected. 1.5. BMS-960—DevelopmentSphingosine 1-phosphate and Scale(S1P) upregulates of a Chiral throug Epoxideh five Route high-affinity through an Enzymatic G protein-coupled Reduction S1P receptors multiple physiological and pathophysiological processes including cell proliferation and survival,Sphingosine cell migration, 1-phosphate inflammatory (S1P) regulates mediator throughsynthesis five and high-a tissueffi remodelingnity G protein-coupled [61–63]. The S1P1 S1P receptors receptor multiplein particular physiological has received and pathophysiological intensive investigation processes for including the modulation cell proliferation of various and survival,autoimmune cell migration,and inflammatory inflammatory diseases mediator with the synthesis products and of this tissue effort remodeling being two [61 approved–63]. The drugs S1P1 receptorfor multiple in particular sclerosis: has fingolimod received intensiveand ozanimod investigation [64–66]. for Research the modulation on S1P1 of agonists various autoimmunecontinues to andunfold inflammatory both in terms diseases of novel with molecules the products and ofadditi thisonal effort indications. being two approvedIn this context drugs Bristol-Myers for multiple sclerosis:Squibb developed fingolimod BMS-960 and ozanimod (Scheme [64 15,–66 a]. potent Research agonist on S1P1 of the agonists S1P1 continuesreceptor. toFor unfold the ongoing both in termsbiologic of and novel toxicological molecules andinvestigations, additional indications.a reasonable In supply this context route was Bristol-Myers required that Squibb would developed address BMS-960the issues (Scheme of the 15original, a potent medicinal agonist ofchemistry the S1P1 sy receptor.nthesis. ForThese the ongoingincluded biologic the low and yielding toxicological (36%) investigations,alkylation of amine a reasonable 56 with supply bromoketone route was 55 requiredand the inefficient that would separa addresstion the of issuesdiastereomers of the original of 58 medicinal chemistry synthesis. These included the low yielding (36%) alkylation of amine 56 with generated from NaBH4 reduction of 57. bromoketoneBristol-Myers55 and Squibb the ine chemistsfficient separation examined of the diastereomers potential of ofan58 alternativegenerated route from that NaBH could4 reduction deliver ofenantiopure57. 58 via optically pure epoxide 59 [67].

Scheme 15. Alternative syntheses of key intermediate 58, precursor ofof BMS-960BMS-960..

Initial efforts focused on the preparation of racemic 59 with a view to subject it to chiral separation. The Corey–Chaykovsky reaction from the p-cyanobenzaldehyde and trimethyl sulfonium iodide [68] met with low yields. In contrast, NaBH4 reduction of the commercially

Catalysts 2020, 10, 1117 14 of 65

Bristol-Myers Squibb chemists examined the potential of an alternative route that could deliver enantiopure 58 via optically pure epoxide 59 [67]. Initial efforts focused on the preparation of racemic 59 with a view to subject it to chiral separation. The Corey–Chaykovsky reaction from the p-cyanobenzaldehyde and trimethyl sulfonium iodide [68] Catalysts 2020, 10, x FOR PEER REVIEW 15 of 69 met with low yields. In contrast, NaBH4 reduction of the commercially available bromoketone 55 gaveavailable initially bromoketone racemic bromohydrin55 gave initially60 racemicwhich was bromohydrin transformed 60 which to racemic was transformed59 in high yield to racemic when subjected59 in high to yield mild when base. Thesubjected chiral to separation mild base. of racemicThe chiral59 howeverseparation proved of racemic unviable 59 however hence a two-step proved asymmetricunviable hence synthesis a two-step was asymmetric considered synthesis next. After was careful considered consideration next. After of careful asymmetric consideration reduction of methods,asymmetric B-chlorodiisopinocampheylborane reduction methods, B-chlorodiisopinocampheylborane (DIP-chloride) was initially (DIP-chloride) tested and provided was initially good yieldstested (85%)and provided and enantiomeric good yields excess (85%) (90% and ee) enanti of chiralomeric bromohydrin excess (90%60 ee). Despiteof chiral these bromohydrin encouraging 60. results,Despite upgradethese encouraging of the optical results, purity upgrade through of chiral the optical separation purity was through still required chiral henceseparation an enzymatic was still reductionrequired hence was pursued. an enzymatic reduction was pursued. Towards thisthis end,end, aa largelarge arrayarray ofof bothboth NADH-NADH- andand NADPH-dependentNADPH-dependent ketoreductases was screened for the reduction of 55 and several enzymes were identifiedidentified that could produce either enantiomer of bromohydrin 60 inin >>99%99% yield and enantiomeric excesses of >99%.>99%. In thethe end, end, based based on on its activity,its activity, selectivity selectivit andy substrate-to-enzyme and substrate-to-enzym ratio,e ketoreductase ratio, ketoreductase enzyme KREDNADH-110enzyme KREDNADH-110 (Codexis) (Codexis) was selected was for selected the synthesis for the of synthesis the (S)-enantiomer of the (S)-enantiomer of 60. Though of both 60. NADHThough andboth NADPH NADH cofactors and mustNADPH be regenerated cofactors formust cost reduction,be regenerated KREDNADH-110 for cost alsoreduction, has the additionalKREDNADH-110 advantage also of has requiring the additional the lower advantage cost NADH of requiring cofactor. the lower cost NADH cofactor. The conversionconversion ofof ( S(S)-)-6060to to the the epoxide epoxide was was optimized optimized with with sodium sodiumtert -butoxidetert-butoxide giving giving the bestthe resultsbest results (>93% (>93% and 100% and ee)100% and ee) eventually and eventually this was th boltedis was on bolted the enzymatic on the enzymatic reduction thusreduction developing thus adeveloping telescoped processa telescoped (Scheme process 16). The (Scheme next step 16). in thisThe synthesisnext step was in thethis epoxide synthesis ring-opening was the epoxide reaction ofring-opening the chiral ( Sreaction)-60 with of amino-esterthe chiral (S56)-60to with give amino-ester the desired key56 to intermediate give the desired58. This key reactionintermediate took place58. This in areaction regiospecific took mannerplace in ata 50regiospecific◦C with a catalytic manner amountat 50 °C of with DMAP a catalytic (4-dimethylaminopyridine) amount of DMAP in(4-dimethylaminopyridi 77% yield. ne) in 77% yield.

Scheme 16. Scale up of enzymatic reduction to halohydrin and epoxide formation en route to 58.. As will be further discussed below, halohydrins (and equivalent species) provide a powerful As will be further discussed below, halohydrins (and equivalent species) provide a powerful route to epoxide synthesis. In this case a chiral halohydrin produced via an enzymatic reduction of an route to epoxide synthesis. In this case a chiral halohydrin produced via an enzymatic reduction of appropriate bromoketone at 100 g scale gave access to the key epoxide and its ring opened product. an appropriate bromoketone at 100 g scale gave access to the key epoxide and its ring opened This approach was pivotal for the development of a cost effect and efficient route towards BM-960. product. This approach was pivotal for the development of a cost effect and efficient route towards BM-960.

1.6. Atazanavir (BMS-232632)—Process Research and Development towards an Efficient Synthesis of an HIV Protease Inhibitor Atazanavir (BMS-232632) (Scheme 17) is a potent HIV-1 protease inhibitor and an FDA approved drug for HIV/AIDS both as monotherapy and in combination with other anti-HIV agents [69–72]. Atazanavir (BMS-232632) is an aza-peptidomimetic transition state inhibitor for the HIV-1 protease that was discovered by Novartis [73], but after a preliminary investigation it was licensed to Bristol Myers Squibb who developed it fully to the point of FDA approval.

Catalysts 2020, 10, 1117 15 of 65

1.6. Atazanavir (BMS-232632)—Process Research and Development towards an Efficient Synthesis of an HIV ProteaseCatalysts 2020 Inhibitor, 10, x FOR PEER REVIEW 16 of 69 Atazanavir (BMS-232632) (Scheme 17) is a potent HIV-1 protease inhibitor and an FDA approved drugIn for order HIV to/AIDS do so, both a reliable as monotherapy cost-effective and and in robust combination process with had otherto be anti-HIVdeveloped agents by the [ 69Bristol–72]. AtazanavirMyers Squibb (BMS-232632) process department. is an aza-peptidomimetic The original medicinal transition chemistry state inhibitor route for was the HIV-1unsuitable protease for thatlarge-scale was discovered deliveries by due Novartis to a number [73], but of issues after a including preliminary hazardous investigation reagents it was and licensed solvents, to several Bristol protection/deprotection steps, expensive amide coupling reagents and elaborate chromatographic Myers Squibb who developed it fully to the point of FDA approval. purifications.

Scheme 17. Retrosynthetic analysis of atazanavir leading to key epoxide intermediate 62. Scheme 17. Retrosynthetic analysis of atazanavir leading to key epoxide intermediate 62. In order to do so, a reliable cost-effective and robust process had to be developed by the Bristol Myers In order to develop a viable manufacturing route to atazanavir it was imperative that both Squibb process department. The original medicinal chemistry route was unsuitable for large-scale deliveries N,N’-bis-Boc-protected hydrazino–amino alcohol 61 and the chiral epoxide 62 intermediates were due to a number of issues including hazardous reagents and solvents, several protection/deprotection accessed in a scalable and robust manner. steps, expensive amide coupling reagents and elaborate chromatographic purifications. The synthesis of optically pure epoxide 62 in particular was of great concern as its quality In order to develop a viable manufacturing route to atazanavir it was imperative that both influences heavily the performance of the downstream chemistry and isolation/purification of N,N’-bis-Boc-protected hydrazino–amino alcohol 61 and the chiral epoxide 62 intermediates were subsequent intermediates. In the original route 62 was made in 80% ee by mCPBA epoxidation of the accessed in a scalable and robust manner. corresponding allylic Boc-protected amine. The main reason for the enantiomeric leakage was the The synthesis of optically pure epoxide 62 in particular was of great concern as its quality influences aldehyde precursor Boc-Phe-H which racemized to a significant extend even when the Wittig heavily the performance of the downstream chemistry and isolation/purification of subsequent reaction was performed at −78 °C. Additionally, the need for chromatographic purification for both intermediates. In the original route 62 was made in 80% ee by mCPBA epoxidation of the corresponding the aldehyde and epoxide intermediates combined with the low yield of the two-step sequence, allylic Boc-protected amine. The main reason for the enantiomeric leakage was the aldehyde precursor forced the development of a new, more robust and suitable for scale-up synthesis of 62. Boc-Phe-H which racemized to a significant extend even when the Wittig reaction was performed at The Bristol Myers Squibb process group responded to this challenge [74] by exploiting the 78 ◦C. Additionally, the need for chromatographic purification for both the aldehyde and epoxide −readily synthesized and also commercially available vicinal diol 63 (Scheme 18). Based on the work intermediates combined with the low yield of the two-step sequence, forced the development of a new, of Moyano and Pericàs [75], they developed further the three step process to access the key epoxide. more robust and suitable for scale-up synthesis of 62. The Bristol Myers Squibb process group responded to this challenge [74] by exploiting the readily synthesized and also commercially available vicinal diol 63 (Scheme 18). Based on the work of Moyano and Pericàs [75], they developed further the three step process to access the key epoxide. Initial selective silylation of the primary alcohol followed by mesylation of the secondary alcohol proceeded cleanly although the silyloxy mesylate 64 was not a crystalline intermediate. Using this oil directly in the silyl deprotection step provided the crystalline and easy to purify hydroxy mesylate 64. For this step they introduced the inexpensive and easier to handle ammonium fluoride in place of TBAF (tetra-n-butylammonium fluoride) and isolated the mesylate intermediate 65 in 80% yield and excellent quality. After extensive screening of bases and reaction conditions, KOtBu in THF/IPA turned out to be the most successful combination for the ring closure of hydroxy mesylate 65 to epoxide 62. The latter was isolated directly in 90% yield and in 100% ee without need for chromatography. The regiospecific ring opening of the epoxide with protected hydrazine 66 was accomplished in refluxing isopropanol and provided key intermediate 61 in >85% yield. Finally, deprotection of the Boc groups telescoped into an EDCI-promoted (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide) coupling with N-methoxycarbonyl-L-tert-leucine at both the amino and hydrazino termini, gave atazanavir-free base which was ultimately converted to its bisulfate salt. Scheme 18. Process route to atazanavir via asymmetric synthesis of epoxide 62.

Initial selective silylation of the primary alcohol followed by mesylation of the secondary alcohol proceeded cleanly although the silyloxy mesylate 64 was not a crystalline intermediate. Using this oil directly in the silyl deprotection step provided the crystalline and easy to purify

Catalysts 2020, 10, x FOR PEER REVIEW 16 of 69

In order to do so, a reliable cost-effective and robust process had to be developed by the Bristol Myers Squibb process department. The original medicinal chemistry route was unsuitable for large-scale deliveries due to a number of issues including hazardous reagents and solvents, several protection/deprotection steps, expensive amide coupling reagents and elaborate chromatographic purifications.

Scheme 17. Retrosynthetic analysis of atazanavir leading to key epoxide intermediate 62.

In order to develop a viable manufacturing route to atazanavir it was imperative that both N,N’-bis-Boc-protected hydrazino–amino alcohol 61 and the chiral epoxide 62 intermediates were accessed in a scalable and robust manner. The synthesis of optically pure epoxide 62 in particular was of great concern as its quality influences heavily the performance of the downstream chemistry and isolation/purification of subsequent intermediates. In the original route 62 was made in 80% ee by mCPBA epoxidation of the corresponding allylic Boc-protected amine. The main reason for the enantiomeric leakage was the aldehyde precursor Boc-Phe-H which racemized to a significant extend even when the Wittig reaction was performed at −78 °C. Additionally, the need for chromatographic purification for both the aldehyde and epoxide intermediates combined with the low yield of the two-step sequence, forced the development of a new, more robust and suitable for scale-up synthesis of 62. The Bristol Myers Squibb process group responded to this challenge [74] by exploiting the Catalystsreadily2020 synthesized, 10, 1117 and also commercially available vicinal diol 63 (Scheme 18). Based on the16 work of 65 of Moyano and Pericàs [75], they developed further the three step process to access the key epoxide.

Scheme 18. Process route to atazanavir via asymmetric synthesis of epoxide 62. Scheme 18. Process route to atazanavir via asymmetric synthesis of epoxide 62. This process (Scheme 18) was scaled-up successfully and delivered 3.5 kg of atazanavir bisulfate Initial selective silylation of the primary alcohol followed by mesylation of the secondary thus demonstrating reproducibility and robustness in this epoxide-enabling manufacturing route to an alcohol proceeded cleanly although the silyloxy mesylate 64 was not a crystalline intermediate. approved drug. Using this oil directly in the silyl deprotection step provided the crystalline and easy to purify

1.7. WAY-255719—Ring Opening of a Chiral Epoxide with Grignard Reagents

The 5-HT2c receptor is one of the 14 serotonin receptors and is located in several regions of the brain. Activation of this G protein-coupled receptor by serotonin inhibits dopamine and norepinephrine release in certain areas of the brain therefore 5-HT2c receptor agonism has demonstrated benefits in the treatment of obesity (lorcaserin), substance use disorders (SUD) and impulse control disorders while antagonism augments treatment of anxiety, depression and schizophrenia [76]. In this context Wyeth (legacy company of Pfizer) discovered WAY-255719 [77] a potent 5-HT2C full agonist with greater than 100-fold selectivity over the related 5-HT2A and 5-HT2B receptors. WAY-255719 demonstrated anti-psychotic activity in several animal models thus was selected among several other analog compounds to advance into development as a drug candidate. The medicinal chemistry route to WAY-255719 (Scheme 19) had a number of issues including a low yielding (<45%) Suzuki reaction to biaryl 67, extremely low temperature for phenol demethylation, a thermally intensive and protracted Claisen rearrangement, racemic epoxide formation, hazardous azide chemistry and a special hydrogenation to ensure chemoselectivity over the aromatic chlorides. In addition to the nine steps, the racemic amine product had to be converted to its Cbz derivative in order achieve chiral resolution and finally be subjected to hydrogenolysis to afford enantiopure WAY-255719. Initial improvements, including chiral separation on the amine without Cbz derivatization (on 100 g scale took one week to complete using a 25 cm 3 cm column) succeeded in delivering × up to 100 g of the desired product, but clearly a much better synthesis was needed for larger scale deliveries and commercial manufacturing. An asymmetric route that would negate the need for chiral chromatography therefore became a critical objective for the viability of the project. One of the ideas that prioritized high for the asymmetric synthesis of the chiral 2-substituted dihydrobenzofuran domain involved the introduction of an appropriately functionalized enantiopure three-carbon fragment directly at the position ortho to the methoxy group of 67. Reaction of the corresponding aryl Grignard with glycidol surrogates presented an attractive option to access 70 directly because many of the latter are commercially available in enantiopure form and there is literature precedence for their reaction with organometallic reagents, at least on small scales. Catalysts 2020, 10, x FOR PEER REVIEW 18 of 69

Catalysts 2020, 10, 1117 17 of 65 Catalysts 2020, 10, x FOR PEER REVIEW 18 of 69

Scheme 19. Initial improvements made on the medicinal chemistry route to WAY-255719.

One of the ideas that prioritized high for the asymmetric synthesis of the chiral 2-substituted dihydrobenzofuran domain involved the introduction of an appropriately functionalized enantiopure three-carbon fragment directly at the position ortho to the methoxy group of 67. Reaction of the corresponding aryl Grignard with glycidol surrogates presented an attractive option to access 70 directly because many of the latter are commercially available in enantiopure form and there is literature precedence for their reaction with organometallic reagents, at least on small scales. Having first developed a much higher yielding Suzuki–cross coupling reaction for generating 67 and resolved HBr-induced demethylation issues in the subsequent bromination to 72 (Scheme 20) attention was turned into the formation of the Grignard reagent 73 and reaction with glycerol tosylate 74SchemeScheme [78]. 19. 19. InitialInitial improvements improvements made made on on the the medicinal medicinal chemistry chemistry route route to WAY-255719. Generation of the Grignard reagent 73 from the aryl bromide under standard conditions with Having first developed a much higher yielding Suzuki–cross coupling reaction for generating 67 and magnesiumOne of themetal ideas was that accompanied prioritized highby magnesium for the asymmetric oxidatively synthesis inserting of the into chiral the 2-substitutedaryl-chloride resolved HBr-induced demethylation issues in the subsequent bromination to 72 (Scheme 20) attention bonds.dihydrobenzofuran Chemoselective domain formation involved of the desiredthe introd organometallicuction of reagentan appropriately 73 was accomplished functionalized by a was turned into the formation of the Grignard reagent 73 and reaction with glycerol tosylate 74 [78]. Grignardenantiopure exchange three-carbon reaction fragment with isopropyl directly magnesium at the position bromide. ortho to the methoxy group of 67. Reaction of the corresponding aryl Grignard with glycidol surrogates presented an attractive option to access 70 directly because many of the latter are commercially available in enantiopure form and there is literature precedence for their reaction with organometallic reagents, at least on small scales. Having first developed a much higher yielding Suzuki–cross coupling reaction for generating 67 and resolved HBr-induced demethylation issues in the subsequent bromination to 72 (Scheme 20) attention was turned into the formation of the Grignard reagent 73 and reaction with glycerol tosylate 74 [78]. Generation of the Grignard reagent 73 from the aryl bromide under standard conditions with magnesium metal was accompanied by magnesium oxidatively inserting into the aryl-chloride bonds. Chemoselective formation of the desired organometallic reagent 73 was accomplished by a Grignard exchange reaction with isopropyl magnesium bromide.

Scheme 20. Development of a telescoped process for multi-kilogram delivery of WY-255719.

Generation of the Grignard reagent 73 from the aryl bromide under standard conditions with magnesium metal was accompanied by magnesium oxidatively inserting into the aryl-chloride bonds. Chemoselective formation of the desired organometallic reagent 73 was accomplished by a Grignard exchange reaction with isopropyl magnesium bromide. In the absence of Lewis acid catalysts, reactions between epoxides and organometallic reagents are known to proceed slowly and with formation of side products. In this case copper(I) salts provided optimum results with little difference among CuCN, Li2CuCl4 and CuI at 5–10 mol%. Without the copper catalyst the reaction did not proceed at all. Initially CuCN was selected due to its stability,

Catalysts 2020, 10, x FOR PEER REVIEW 19 of 69

Scheme 20. Development of a telescoped process for multi-kilogram delivery of WY-255719.

In the absence of Lewis acid catalysts, reactions between epoxides and organometallic reagents are known to proceed slowly and with formation of side products. In this case copper(I) salts providedCatalysts 2020 optimum, 10, 1117 results with little difference among CuCN, Li2CuCl4 and CuI at 5–10 mol%.18 of 65 Without the copper catalyst the reaction did not proceed at all. Initially CuCN was selected due to its stability, nonhygroscopic nature and availability in small particle size although it was later replaced withnonhygroscopic CuI to avoid nature issues andassociated availability with cyanide in small toxicity. particle Another size although critical itprocess was later parameter replaced was with the reactionCuI to avoid temperature issues associatedleading to witheither cyanide incomplete toxicity. reactions Another below critical −25 °C process or significant parameter formation was the of reaction temperature leading to either incomplete reactions below 25 C or significant formation of impurities above −20 °C. Within the −25 to −20 °C window, the reaction− ◦is complete after 4–5 h giving impurities above 20 C. Within the 25 to 20 C window, the reaction is complete after 4–5 h giving an oil consisting predominantly− ◦ the −hydroxy− tosylate◦ 75 with an approximately 10% (HPLC) of the terminalan oil consisting epoxide predominantly76. This was not the an hydroxy issue because tosylate subsequent75 with an treatment approximately of the crude 10% (HPLC) product of with the NaOH-inducedterminal epoxide ring76. Thisclosure was of not 75 an to issue epoxide because 76 quantitatively. subsequent treatment Theoretically, of the crudethe enantiomer product with of epoxideNaOH-induced 76 can ringform closure by direct of 75 displacementto epoxide 76 quantitatively.of the tosylate Theoretically,in 74 without the epoxide enantiomer opening. of epoxide This however76 can form does by not direct happen displacement in practice of and the tosylateindeed 76 in 74formswithout via epoxide epoxide opening opening. of This74 to however 75 and subsequentdoes not happen closure in on practice the other and side indeed by 76chlorideforms displacement. via epoxide opening This was of 74confirmedto 75 and as subsequentthe Wyeth teamclosure established on the other that side no byloss chloride of enantiomeric displacement. purity This occurred, was confirmed whereas as direct the Wyeth tosylate team displacement established wouldthat no lead loss ofto enantiomericthe terminal purityepoxide occurred, of opposite whereas stereo direct configuration tosylate displacement and 76 with would reduced lead ee. to The the processterminal was epoxide further of streamlined opposite stereo by eliminatin configurationg the and separate76 with step reduced for the ee.conversion The process of 75 was to 76 further since thisstreamlined transformation by eliminating could be the accomplished separate step quantita for thetively conversion during of alkaline75 to 76 washessince this in transformationthe work up of thecould Grignard be accomplished reaction with quantitatively 74. Thus, after during solvent alkaline swapping washes to in DMF the work the resulting up of the solution Grignard of reaction 76 was withtelescoped74. Thus, in the after second solvent epoxide swapping ring-opening to DMF the reaction resulting with solution potassium of 76 wasphthalimide telescoped to in give the intermediatesecond epoxide 77 in ring-opening 53% yield with reaction respect with to 74 potassium, 98.7% purity phthalimide by HPLC to and give 99% intermediate ee. Activation77 in of 53% the alcoholyield with as respectits mesylate to 74, 98.7% ester purity followed by HPLC by andtreatment 99% ee. with Activation BBr3 ofgave the alcoholdirectly asthe its mesylatecyclized dihydrobenzofuranester followed by treatment intermediate with BBr 783. gaveApparently, directly theonce cyclized the phenol dihydrobenzofuran is demethylated, intermediate it cyclizes78. Apparently,spontaneously once via the the phenol intramolecular is demethylated, SN2 reaction it cyclizes on the spontaneouslymesylate; the uncyclized via the intramolecular phenol/mesylate SN2 intermediatereaction on the was mesylate; never thedetected uncyclized in phenolthis pr/mesylateocess. Deprotection intermediate wasand neverhydrochloride detected in thissalt formation/crystallizationprocess. Deprotection and of hydrochloride the right polymorph salt formation gives WAY-255719/crystallization with of the purity right >99.5% polymorph and 98.6% gives WAY-255719ee. with purity >99.5% and 98.6% ee. After a a tremendous tremendous amount amount of ofwork work (including (including with with model model substrates) substrates) the Wyeth the Wyeth process process team managedteam managed to develop to develop a robust a robust manufacturing manufacturing rout routee for forWAY-255719 WAY-255719 without without the the pitfalls pitfalls of of the original synthesissynthesis The The new new route route proceeds proceeds through through a telescoped a telescoped process process encompassing encompassing four chemical four chemicaltransformations, transformations, namely two namely consecutive two epoxideconsecut ring-openingive epoxide /ring-closingring-opening/ring-closing reaction sequences reaction and sequenceshas delivered and 10 has kg delivered batches of 10 the kg API batc athes specification. of the API at specification.

1.8. Linezolid Linezolid and and Rivaroxaban Rivaroxaban—Exploiting —Exploiting GlycerolGlycerol SurrogatesSurrogates inin ChiralChiral OxazolidinoneOxazolidinone SynthesesSyntheses Linezolid and rivaroxaban (Scheme 21)21) share strikingstriking structural similarity therefore common synthetic strategies have been describeddescribed forfor theirtheir syntheses.syntheses. The The chiral chiral oxazolidine moiety is accessed conveniently conveniently from from the the chiral chiral pool, pool, perhap perhapss almost almost invariantly invariantly with with the use the of use glycerol of glycerol (79), (epichlorohydrin79), epichlorohydrin (80) and (80) conveniently and conveniently functional functionalizedized glycerol glycerol derivatives derivatives (81, 82 (81 Scheme21)., 82 Scheme 21).

Scheme 21. Structures of rivaroxaban, linezolid and glycerol equivalents from the chiral pool. Scheme 21. Structures of rivaroxaban, linezolid and glycerol equivalents from the chiral pool. In contrast to the high similarity of their chemical structure and syntheses, the biologic and pharmaceutical profiles of linezolid and rivaroxaban could not be more different. Linezolid (trade name Zyvox) discovered and developed by Pharmacia UpJohn (legacy company of Pfizer) is a protein synthesis inhibitor and member of the oxazolidinone class of antibiotics [79]. It shows excellent activity against major Gram-positive bacteria and is very effective in the treatment of infections of the Catalysts 2020, 10, x FOR PEER REVIEW 20 of 69

In contrast to the high similarity of their chemical structure and syntheses, the biologic and pharmaceutical profiles of linezolid and rivaroxaban could not be more different. Linezolid (trade name Zyvox) discovered and developed by Pharmacia UpJohn (legacy company of Pfizer) is a protein synthesis inhibitor and member of the oxazolidinone class of antibiotics [79]. It shows excellentCatalysts 2020 activity, 10, 1117 against major Gram-positive bacteria and is very effective in the treatment19 of of 65 infections of the respiratory tract and skin disorders. The rare, if any, cases of cross resistance with otherrespiratory antibiotics tract andis attributed skin disorders. to its Theunique rare, mechanism if any, cases of of action. cross resistance In contrast with to other common antibiotics protein is synthesisattributed inhibitors to its unique which mechanism halt protein of action. synthesis In contrast at the to elongation common proteinphase, synthesislinezolid inhibitorsinhibits protein which synthesishalt protein at synthesisthe initiation at the phase. elongation It does phase,so by binding linezolid at inhibits the 23S protein component synthesis of the at 50S the ribosome initiation subunitphase. It which does so is by responsible binding at thefor 23Sthe componentpeptidyl transferase of the 50S ribosomeactivity thus subunit preventing which is formation responsible of for a functionalthe peptidyl 70S transferase initiation activity complex thus [80]. preventing Because formation of its action of a functional on ribozymes, 70S initiation linezolid complex has been [80]. designatedBecause of itsas actiona riboswitch on ribozymes, [81,82]. linezolidDespite the has hi beengh degree designated of structural as a riboswitch resemblance, [81,82]. rivaroxaban Despite the possesseshigh degree no ofantibiotic structural activity resemblance, whatsoever rivaroxaban and does possessesnot bind to no RNA antibiotic molecules. activity Rivaroxaban whatsoever (trade and namedoes notXarelto) bind towas RNA discovered molecules. and Rivaroxaban developed (trade by Bayer name and Xarelto) Ortho-McNeil was discovered Pharmaceutical, and developed Inc. (legacyby Bayer company and Ortho-McNeil of Johnson and Pharmaceutical, Johnson). It was Inc. approved (legacy companyin Germany, of Johnson Canadaand andJohnson by the). FDA It was in 2008approved for the in Germany,treatment, Canada prevention and by and the reduction FDA in 2008 in forthe therisk treatment, of recurrent prevention deep vein and reductionthrombosis, in stroke,the risk systemic of recurrent and deep pulmonary vein thrombosis, embolism. stroke, More systemicrecently andit also pulmonary obtained embolism.approval for More reducing recently the it riskalso obtainedof major approvalcardiovascular for reducing events, the such risk as of death, major cardiovascularmyocardial infarction events, suchand asstroke. death, Rivaroxaban myocardial inhibitsinfarction both and free stroke. and Rivaroxabanprothrombinase inhibits complex both boun free andd Factor prothrombinase Xa and prevents complex thrombin bound formation, Factor Xa butand not prevents its action thrombin [83]. formation,It has a rapid but not onset its action of action [83]. and It has was a rapid the onsetfirst approved of action and oral was Factor the firstXa inhibitor.approved oral Factor Xa inhibitor. As a consequenceconsequence ofof the the structural structural similarity similarity between between linezolid linezolid and and rivaroxaban rivaroxaban there there is great is great deal dealof overlap of overlap in the in respective the respective reported reported syntheses. synthe In fact,ses. In most fact, of most the known of the synthesesknown syntheses for one molecule for one moleculehave been have tested been in thetested preparation in the preparation of the other of withthe other modifications with modifications on the terminal on the aniline terminal and aniline amide andas appropriate. amide as appropriate. The original The Bayer original synthesis Bayer of rivaroxabansynthesis of isrivaroxaban described in is Scheme described 22[ 84in]. Scheme 22 [84]. O O O N O ON NH OH O O 82 O N NH2 N 83 84 O

CDI

O O O O O O MeNH2 (aq) O ON N ON N NH2 N

86 85 O

X=Clor X Cl p-NO2Ph-O S O 87

O O O ON N H N Cl S Rivaroxaban O Scheme 22. Original Bayer synthesis of rivaroxaban. Bayer and others have since patented several other syntheses [85–87] yet over the years it was the first route that attracted numerous suitors who put much effort in developing it further into a viable large-scale process. In this context, all modifications reported concern reaction conditions, solvents and reagents in each of the steps without changing any of the intermediates/transformations of the Bayer route [88–90]. The reported syntheses for rivaroxaban and linezolid have been reviewed Catalysts 2020, 10, x FOR PEER REVIEW 21 of 69

Bayer and others have since patented several other syntheses [85–87] yet over the years it was the first route that attracted numerous suitors who put much effort in developing it further into a Catalystsviable large-scale2020, 10, 1117 process. In this context, all modifications reported concern reaction conditions,20 of 65 solvents and reagents in each of the steps without changing any of the intermediates/transformations of the Bayer route [88–90]. The reported syntheses for rivaroxaban extensivelyand linezolid [91 have] and been repetition reviewed of this extensively is beyond the[91] scope and ofrepetition the present of this work. is Thebeyond following the scope cases of were the selectedpresent simplywork. The because following they exemplify cases were the syntheticselected simply creativity because and versatility they exemplify that may the be expressedsynthetic throughcreativity the and chemistry versatility of that the epoxidemay be expressed functionality. through the chemistry of the epoxide functionality. For example in the synthesis of Yuan et al. [[9922]] (Scheme 2323),), the penultimate intermediate 85 of the Bayer synthesis is targeted via a completelycompletely difffferenterent strategy where the oxazolidinone ring is constructed first first (92) followed by installment of the phthalimido group (93) and attachment of the oxazolidinone 9393on on the the morpholinone-substituted morpholinone-substituted aromatic aromatic ring 91ringvia 91 a Goldbergvia a Goldberg coupling coupling reaction. Thereaction. same The reaction same was reaction used towas install used the to morpholinoneinstall the morpholinone88 on the aromatic 88 on the ring. aromatic This and ring. other This eff andorts attemptother efforts to address attempt the to synthesis address ofthe the synthesis morpholinone of the morpholinone aryl moiety as thisaryl is moiety a significant as this cost is a contributorsignificant forcost rivaroxaban. contributor for rivaroxaban.

SchemeScheme 23. The23. The Yuan Yuan et al. et synthesis al. synthesis of the of rivaroxabanthe rivaroxaban N-Phth-intermediate N-Phth-intermediate via a via Goldberg a Goldberg reaction. reaction. Similar to the reaction of epichlorohydrin with sodium cyanate, the Lewis acid or base catalyzed cycloadditionSimilar to of the epoxides reaction with of isocyanates epichlorohydrin gives N-substituted with sodium rather cyanate, than the the N–HLewis oxazolidinones acid or base (Schemecatalyzed 24 cycloaddition upper portion). of This epoxides transformation with isocya hasnates been usedgives by N-substitute Bayer as thed last rather step inthan a convergent the N–H synthesisoxazolidinones of rivaroxaban (Scheme where24 upper the 4-morpholinone-benzeneportion). This transformation isocyanate has been (94) isused reacted by Bayer with anas epoxidethe last (step95) bearingin a convergent the domain synthesis of the targetof rivaroxaba moleculen where with the the thiophene 4-morpholinone-benzene carboxamide already isocyanate formed (94 [86) is]. Inreacted a variation with ofan thisepoxide strategy (95 (Scheme) bearing 24 thelower domain portion), of thethe epoxidetarget molecule/isocyanate with cycloaddition the thiophene was usedcarboxamide in the beginning already thusformed building [86]. In the a rivaroxaban variation of skeleton this strategy in a linear (Scheme fashion 24 [93lower]. portion), the epoxide/isocyanateOne of the earlier cycloaddition Bayer attempts was used involved in the the beginning use of the thus anion building of Cbz-(4-morpholino)-aniline the rivaroxaban skeleton toin a ring linear open fashion glycerol [93]. butyrate (98). The resulting secondary alkoxide bites back on the carbamate and displaces benzyl alcohol (Scheme 25)[94]. In this way the hydroxymethyl oxazolidinone 103a is generated in a single step and with the butyrate is lost in the work up, two steps are eliminated from the synthesis. In an improvement of this, the cryogenic BuLi deprotonation of the carbamate was replaced LitBuO at room temperature and 103a was isolated in 80% [95]. Further improvement that saves the subsequent mesylation step of alcohol 103a was reported recently where glycerol butyrate/ t Li BuO is replaced with epibromohydrin (99)/Cs2CO3 [96].

Catalysts 2020, 10, x FOR PEER REVIEW 22 of 69

Catalysts 2020, 10, 1117 21 of 65 Catalysts 2020, 10, x FOR PEER REVIEW 22 of 69

Scheme 24. Direct synthesis of chiral oxazolidinones via epoxide/isocyanate cycloadditions.

One of the earlier Bayer attempts involved the use of the anion of Cbz-(4-morpholino)-aniline to ring open glycerol butyrate (98). The resulting secondary alkoxide bites back on the carbamate and displaces benzyl alcohol (Scheme 25) [94]. In this way the hydroxymethyl oxazolidinone 103a is generated in a single step and with the butyrate is lost in the work up, two steps are eliminated from the synthesis. In an improvement of this, the cryogenic BuLi deprotonation of the carbamate was replaced LitBuO at room temperature and 103a was isolated in 80% [95]. Further improvement that saves theScheme subsequent 24. DirectDirect mesylation synthesis synthesis step of of chiral chiral of alcohol oxazolidinones 103a was via reported epoxide/isocyanate epoxide recently/isocyanate where cycloadditions. glycerol butyrate/ LitBuO is replaced with epibromohydrin (99)/Cs2CO3 [96]. One of the earlier Bayer attempts involved the use of the anion of Cbz-(4-morpholino)-aniline to ring open glycerol butyrate (98). The resulting secondary alkoxide bites back on the carbamate and displaces benzyl alcohol (Scheme 25) [94]. In this way the hydroxymethyl oxazolidinone 103a is generated in a single step and with the butyrate is lost in the work up, two steps are eliminated from the synthesis. In an improvement of this, the cryogenic BuLi deprotonation of the carbamate was replaced LitBuO at room temperature and 103a was isolated in 80% [95]. Further improvement that saves the subsequent mesylation step of alcohol 103a was reported recently where glycerol butyrate/ LitBuO is replaced with epibromohydrin (99)/Cs2CO3 [96].

Scheme 25. SynthesisSynthesis of oxazolidinone intermediates via condensation of carbamates with epoxides.

Pharmacia Upjohn also tried this approach in the early days of linezolid development where several carbamates of the linezolid aniline were screened in the-in-the reaction with epoxide 100 with the view of of accessing accessing the the drug drug substance substance direct directlyly [97] [97 In] In this this case case however however the the deprotonation deprotonation of theof the acetamide acetamide side side chain chain competed competed resulting resulting in an in intramolecular an intramolecular ring ringopening opening of the of epoxide the epoxide and formationand formation of 101 of.101 This. This issue issue was was bypassed bypassed with with the the use use of of electrophile electrophile 102102 whichwhich also also loses loses the acetate groupgroup afterafter displacementdisplacement and and the the secondary secondary alcohol alcohol cyclizes cyclizes onto onto the the carbamate carbamate to produceto produce the oxazolidine thus linezolid. the oxazolidineScheme 25. Synthesisthus linezolid. of oxazolidinone intermediates via condensation of carbamates with epoxides. Arguably, either enantiomer [[98]98] of any glycerol derivative available in bulk has been tested at somePharmacia point in the Upjohn synthesis also oftried the this chiral approach oxazolidinoneoxazolid ininone the earlydomains days in in of these linezolid two important development medicines. medicines. where severalDespite carbamatesthe entirely ofdifferent di fftheerent linezolid pharmacology aniline were and mode screened of action, in the-in-the the significantsignificant reaction structural with epoxide similarity 100 withbetween the viewlinezolid linezolid of accessing and and rivaroxaban rivaroxaban the drug hassubstance has benefited benefited direct the thely development [97] development In this case of ofviable however viable large-scale large-scalethe deprotonation processes processes for of theeachfor eachacetamide since since in most side in most chaincases cases thecompeted respective the respective resulting synthetic synthetic in an approaches intramolecular approaches have haveringbeen opening beenequally equally ofapplicable the applicableepoxide to bothand to formationmolecules.both molecules. of 101. This issue was bypassed with the use of electrophile 102 which also loses the acetate group after displacement and the secondary alcohol cyclizes onto the carbamate to produce 1.9. ACT-209905—Ring Opening of an Epoxide with Ammonia Surrogates the oxazolidine thus linezolid. Arguably,ACT-209905 either is an enantiomer immunomodulating [98] of any S1P1glycerol agonist derivative under available development in bulk by has Actelion been tested for the at sometreatment point of in autoimmune the synthesis disorders. of the chiral The oxazolid scope andinone potential domains of S1P1 in these agonism two important was discussed medicines. earlier Despiteunder BMS-960. the entirely One different of the key pharmacology features in ACT-209905 and mode (Schemeof action, 26 the) is significant the chiral alcohol structural present similarity in the betweenpendant aliphaticlinezolid chainand rivaroxaban attached to has the phenol.benefited The the approach development was toof formviable the large-scale amide last processes from amine for each since in most cases the respective synthetic approaches have been equally applicable to both molecules.

Catalysts 2020, 10, x FOR PEER REVIEW 23 of 69

1.9. ACT-209905—Ring Opening of an Epoxide with Ammonia Surrogates ACT-209905 is an immunomodulating S1P1 agonist under development by Actelion for the treatment of autoimmune disorders. The scope and potential of S1P1 agonism was discussed earlier under BMS-960. One of the key features in ACT-209905 (Scheme 26) is the chiral alcohol present in the pendant aliphatic chain attached to the phenol. The approach was to form the amide last from amine 104 resulting from ammonia-induced opening of epoxide 105 which in turn should be accessed using phenol 106 and the inexpensive glycidol as the chiral building block. This approach was adopted by the medicinal chemistry team who used the Mitsunobu reaction to condense phenol 106 with glycidol into ether 105 and then excess ammonia in methanol to generate 104. CatalystsOverall,2020, 10 ,this 1117 constituted a 12-step synthesis that served the project team well for up to 22half of 65a kilo drug substance deliveries. For larger scale demands this route presented several issues particularly around the cost-effective synthesis of phenol 106, the workup difficulties and 104 resulting from ammonia-induced opening of epoxide 105 which in turn should be accessed using chromatographic purification of the Mitsunobu reaction as well as amine dimers generated by the phenol 106 and the inexpensive glycidol as the chiral building block. reaction of amine 104 with epoxide 105.

Scheme 26. Retrosynthesis of th thee S1P1 agonist ACT-209905.

ThisThe Actelion approach process was adopted team byhad the to medicinal respond with chemistry a reasonable team who supply used theroute Mitsunobu amid tight reaction project to condensedeadlines phenolwhich106 precludedwith glycidol extensive into etherdevelopment105 and then and excess raw materials ammonia inwith methanol long lead-times to generate [99].104. HavingOverall, resolved this constitutedthe synthesis a 12-stepof the challenging synthesis that phenol served 106 the focus project was team turned well on for an up alternative to half a kilo to drugMitsunobu substance reaction deliveries. for securing For larger the epoxy scale demandsintermediate this 105 route. presented several issues particularly aroundEconomics the cost-e andffective literature synthesis precedence of phenol and106, thesuggested workup alkylation difficulties of and the chromatographic phenol with purification(R)-epichlorohydrin of the Mitsunobu may provide reaction a asviable well asoption. amine Cognizant dimers generated of the by fact the that reaction reaction of amine of 104the withphenoxide epoxide anion105. at the carbon bearing the chlorine atom in epichlorohydrin would produce the undesiredThe Actelion enantiomer process of 105, team careful had to reaction respond conditions with a reasonable were employed supply route to safeguard amid tight that project only deadlinesepoxide ring which opening precluded ensues. extensive development and raw materials with long lead-times [99]. Having resolvedIn neat the (10 synthesis equivalents) of the challengingepichlorohydrin phenol and106 Mefocus4NCl was as phase turned transfer on an alternative catalyst, in to the Mitsunobu absence reactionof base, forit took securing two days the epoxy for the intermediate phenol to be105 fu. lly consumed at 25 °C. From the onset, a product mixtureEconomics of epoxide and literature105 and precedencechlorohydrin and 107 suggested is observed alkylation whose of thecomposition phenol with shifted (R)-epichlorohydrin from 30:70 to may60:40 provide (105:107 a) viableas the option.reaction Cognizant progressed. of theIncreasing fact that the reaction temperature of the phenoxide from 25 to anion 30 and at the 40 carbon°C the bearingreaction thecompleted chlorine in atom 1.5 indays epichlorohydrin and 15 h, respectively would produce although the undesireda slight erosion enantiomer of ee was of 105 observed, careful reactionfrom 96 conditionsto 94%. Addition were employed of methanol to safeguard and aqueou thats only NaOH epoxide led to ring full opening conversion ensues. of the halohydrin 107 toIn epoxide neat (10 105 equivalents) (Scheme 27). epichlorohydrin These conditions and Mewere4NCl succe asssfully phase transfer scaled up catalyst, and delivered in the absence 17 kg of base,epoxide it took 105 two. days for the phenol to be fully consumed at 25 ◦C. From the onset, a product mixture of epoxide 105 and chlorohydrin 107 is observed whose composition shifted from 30:70 to 60:40 (105:107) as the reaction progressed. Increasing the temperature from 25 to 30 and 40 ◦C the reaction completed in 1.5 days and 15 h, respectively although a slight erosion of ee was observed from 96 to 94%. Addition of methanol and aqueous NaOH led to full conversion of the halohydrin 107 to epoxide 105 (Scheme 27). These conditions were successfully scaled up and delivered 17 kg of epoxide 105. The use of glycerol derivatives bearing a latent amine group such as 81 in place of epichlorohydrin may potentially eliminate the need for reaction of the epoxide with ammonia, but time constraints did not allow this option to be explored or source this or equivalent reagent. The reaction of the epoxide with ammonia typically produced up to 20% of the bis-alkylated amine impurity which could be removed only by chromatography. An enormous excess of ammonia was required to suppress the second alkylation and drive the reaction to amine 104. Catalysts 2020, 10, 1117 23 of 65 Catalysts 2020, 10, x FOR PEER REVIEW 24 of 69

Scheme 27. The ACT-209905 process including rectification of an undesired epoxide ring-opening. Scheme 27. The ACT-209905 process including rectification of an undesired epoxide ring-opening. Clearly a protected ammonia equivalent was required. The potassium salt of phthalimide reacted The use of glycerol derivatives bearing a latent amine group such as 81 in place of very slowly with 105 in DMF even at elevated temperatures. Sodium azide gave a fast and complete epichlorohydrin may potentially eliminate the need for reaction of the epoxide with ammonia, but reaction however its subsequent Pd-catalyzed hydrogenation was incompatible with oxadiazole ring. time constraints did not allow this option to be explored or source this or equivalent reagent. The No reaction occurred with hexamethyldisilazane (HMDS), but its lithium salt (LiHMDS) proved reaction of the epoxide with ammonia typically produced up to 20% of the bis-alkylated amine an excellent nucleophile in the opening of the epoxide ring and gave none of the dimeric impurity. impurity which could be removed only by chromatography. An enormous excess of ammonia was After solvent swapping to TBME and aqueous wok up the amine was isolated in 55% yield required to suppress the second alkylation and drive the reaction to amine 104. Further purification of amine 104 was not required and was treated directly with a mixture of Clearly a protected ammonia equivalent was required. The potassium salt of phthalimide glycolic acid, EDCI and HOBt in THF followed by crystallization from EtOAc afforded ACT-209905 in reacted very slowly with 105 in DMF even at elevated temperatures. Sodium azide gave a fast and 49% yield with 98.6% purity and er 98.4:1. (Scheme 27) This chemistry was scaled up and delivered the complete reaction however its subsequent Pd-catalyzed hydrogenation was incompatible with desired active pharmaceutical ingredient at 12 kg scale. oxadiazole ring. No reaction occurred with hexamethyldisilazane (HMDS), but its lithium salt Undeterred by project constraints the Actelion process team delivered a scalable and efficient route (LiHMDS) proved an excellent nucleophile in the opening of the epoxide ring and gave none of the to ACT-209905 that apparently encompasses the first example of a large-scale epoxide ring opening dimeric impurity. After solvent swapping to TBME and aqueous wok up the amine was isolated in with LiHMDS as ammonia surrogate. 55% yield 1.10.Further SL65.0102–10—Refocusing purification of amine Attention 104 was from not the required Active Pharmaceutical and was treated Ingredient directly to with the Chiral a mixture Epoxide of Startingglycolic Materialacid, EDCI and HOBt in THF followed by crystallization from EtOAc afforded ACT-209905 in 49% yield with 98.6% purity and er 98.4:1. (Scheme 27) This chemistry was scaled up and The 5-HT4 receptor is widely expressed in the periphery and development of 5-HT4R agonists has delivered the desired active pharmaceutical ingredient at 12 kg scale. led to approved drugs for gastrointestinal disorders. The 5-HT4 receptor is also highly expressed in the Undeterred by project constraints the Actelion process team delivered a scalable and efficient CNS in areas which are involved in cognitive functions (learning, memory) and their stimulation leads route to ACT-209905 that apparently encompasses the first example of a large-scale epoxide ring to production of acetylcholine and regulation of the neurotrophic soluble amyloid-protein precursor opening with LiHMDS as ammonia surrogate. alpha (sAPP) [100–103]. Consequently, 5HT4 receptor agonists have attracted attention for their

Catalysts 2020, 10, x FOR PEER REVIEW 25 of 69

1.10. SL65.0102–10—Refocusing Attention from the Active Pharmaceutical Ingredient to the Chiral Epoxide Starting Material The 5-HT4 receptor is widely expressed in the periphery and development of 5-HT4R agonists has led to approved drugs for gastrointestinal disorders. The 5-HT4 receptor is also highly expressed Catalystsin the 2020CNS, 10 in, 1117 areas which are involved in cognitive functions (learning, memory) and24 their of 65 stimulation leads to production of acetylcholine and regulation of the neurotrophic soluble amyloid-protein precursor alpha (sAPP) [100–103]. Consequently, 5HT4 receptor agonists have therapeutic potential in the treatment of Alzheimer’s Disease and cognitive impairment [104,105]. attracted attention for their therapeutic potential in the treatment of Alzheimer’s Disease and SL65.0102–10 is a selective 5-HT4 partial agonist that was discovered and developed by Sanofi as cognitive impairment [104,105]. SL65.0102–10 is a selective 5-HT4 partial agonist that was promising agent for the treatment of cognitive impairment. discovered and developed by Sanofi as promising agent for the treatment of cognitive impairment. The Sanofi process team developed the original medicinal chemistry route by optimizing and The Sanofi process team developed the original medicinal chemistry route by optimizing and streamlining the first three steps involving epoxide 82 ring opening, mesylation of the resulting alcohol streamlining the first three steps involving epoxide 82 ring opening, mesylation of the resulting 108 and intramolecular displacement of the mesylate 109 by the N-benzyl end of the piperazine alcohol 108 and intramolecular displacement of the mesylate 109 by the N-benzyl end of the (Scheme 28). This process was successfully scaled up to 60 kg batches affording intermediate 110 piperazine (Scheme 28). This process was successfully scaled up to 60 kg batches affording directly in 74% yield. intermediate 110 directly in 74% yield.

Scheme 28. InitialInitial improvements improvements to to the medicinal chemistry route towards SL65.0102–10SL65.0102–10..

The medicinalmedicinal chemistry chemistry 2-step 2-step deprotection deprotection of 110 ofby 110 hydrogenolysis by hydrogenolysis of the benzyl of ammoniumthe benzyl ammoniummoiety followed moiety by hydrazinefollowed treatmentby hydrazine was replacedtreatment by was a single replaced step doubleby a deprotectionsingle step double in 20% deprotectionaqueous HCl. in Despite 20% aqueous the slow HCl. rate andDespite technical the slow difficulties rate and in removing technical the difficulties generated in benzyl removing chloride the generatedand benzyl benzyl alcohol chloride this step and performed benzyl alcohol well on this scale step and performed deliveredthe well key on amino scale methyland delivered piperazine the 111key inamino 48.5% methyl yield inpiperazine 35 kg batches. 111 in The48.5% final yield step in coupling35 kg batches. of 111 Thewith final acid step112 couplingwas also of optimized 111 with acidand provided112 was also SL65.0102–10 optimized inand 76.7% provided yield andSL65.0102–10 excellent qualityin 76.7% even yield at and 20 kg excellent batches quality [106]. even at 20 kgNevertheless, batches [106]. the lack of a reliable supplier of 82 at the quantities jeopardized the agreed projectNevertheless, deliveries hence the lack the of Sanofi a reliable process supplier chemists of 82 wereat the forcedquantities to develop jeopardized a quickly the agreed a large-scale project deliveriessynthesis forhence this the starting Sanofi material. process chemists The available were conventionalforced to develop reactors a quickly however a large-scale were inappropriate synthesis forto hostthis starting safely thematerial. epichlorohydrin The available involved conventional in the reactors standard however synthesis were of inappropriate82.(S)-(+)-solketal to host safely[(S)-(+ )-1,2-isopropylideneglycerol]the epichlorohydrin involved113 andin (Rthe)-(-)-3-chloro-1,2-propanediol standard synthesis of 11482. were(S)-(+)-solketal identified [(asS)-(+)-1,2-isopropylideneglycerol] suitable (S)-epichlorohydrin surrogates 113 and which(R)-(-)-3-chloro-1,2-propanediol are cheap and available in114 bulk. were Respectively,identified as suitabletwo alternative (S)-epichlorohydrin syntheses of 82 surrogateswere investigated which are and cheap evaluated and available at pilot plant in bulk. scale Respectively, (Scheme 29). two alternativeThe (S syntheses)-(+)-solketal of 82 (10 were) route investigated to 82 through and intermediatesevaluated at pilot115, plant 116 and scale117a (Schemecomprises 29). 6 steps and was scaled up to 50 kg batches in the pilot plant thus enabling imminent deliveries of SL65.0102–10. In parallel optimization of the (R)-(-)-3-chloro-1,2-propanediol route through the orthoformate derivative of 115 [21,107] demonstrated significant benefits over the (S)-(+)-solketal route both in terms of number of steps and required isolations of intermediates. The (R)-(-)-3-chloro-1,2-propanediol became the method of choice and generated over 180 kg of 82 in excellent quality (98% purity and >99% ee) for subsequent campaigns towards SL65.0102–10. Catalysts 2020, 10, 1117 25 of 65 Catalysts 2020, 10, x FOR PEER REVIEW 26 of 69

Scheme 29. Process development towards chiral epoxide 81 enabling a convergent API route. Scheme 29. Process development towards chiral epoxide 81 enabling a convergent API route. Overall, project deadlines combined with difficulties in sourcing convenient raw materials drove The (S)-(+)-solketal (10) route to 82 through intermediates 115, 116 and 117a comprises 6 steps the project team focus both on the API and the chiral epoxide starting material and succeeded and was scaled up to 50 kg batches in the pilot plant thus enabling imminent deliveries of at both fronts. The Sanofi process team developed a second-generation route to SL65.0102–10 by SL65.0102–10. In parallel optimization of the (R)-(-)-3-chloro-1,2-propanediol route through the improving the 12 steps/8 isolations in the first route to 10 steps/5 isolations capable of performing at orthoformate derivative of 115 [21,107] demonstrated significant benefits over the (S)-(+)-solketal multikilogram scale. route both in terms of number of steps and required isolations of intermediates. The (1.11.R)-(-)-3-chloro-1,2-propanediol Carfilzomib—A Natural Epoxide became Product theTurned method into of a choice Drug and and the generated Challenge ofover Its 180 kg of 82 in Diastereoselectiveexcellent quality Epoxidation(98% purity and >99% ee) for subsequent campaigns towards SL65.0102–10. Overall, project deadlines combined with difficulties in sourcing convenient raw materials Carfilzomib (trade name Kyprolis) is a highly selective irreversible inhibitor of the drove the project team focus both on the API and the chiral epoxide starting material and succeeded chymotrypsin-like activity of both the constitutive (β5c subunit) and the immuno-isoform (β5i or at both fronts. The Sanofi process team developed a second-generation route to SL65.0102–10 by LMP7 subunit) of the 20S proteasome [108,109]. It was approved by the FDA for multiple myeloma in improving the 12 steps/8 isolations in the first route to 10 steps/5 isolations capable of performing at 2012 and by the European Medicines Agency in 2015. Carfilzomib is a great example of an anticancer multikilogram scale. drug that was developed through a series of systematic modifications of a natural product, in this case epoxomicin. Epoxomicin was discovered by Bristol Myers Squibb Research Institute (Tokyo) in 1.11. Carfilzomib —A Natural Epoxide Product Turned into a Drug and the Challenge of its Diastereoselective 1992 and demonstrated significant antitumor activity, but its development was abandoned because Epoxidation its mode of action was unclear and being a peptide did not have the appropriate pharmacokinetic profile.Carfilzomib Prof. CM Crews(trade (Yalename University) Kyprolis) and is Prof.a highly R Deshaies selective (California irreversible Institute inhibitor of Technology) of the chymotrypsin-likeamong others, founded activity Proteolix of both (later the acquired constitutive by Onyx (β5c Pharmaceuticals; subunit) and the legacy immuno-isoform company of Amgen)(β5i or LMP7and decided subunit) to of develop the 20S epoxomicinproteasome derivatives[108,109]. It withwas approved desirable by drug-like the FDA properties, for multiple particularly myeloma inimproved 2012 and potency by the and European solubility. Medicines This effort Agency born carfilzomib in 2015. Carfilzomib whose mechanism is a great of actionexample was of also an anticancerelucidated [drug110]. that was developed through a series of systematic modifications of a natural product,Carfilzomib in this case (Scheme epoxomicin. 30) is aEpoxomicin tetrapeptide was comprising discovered two by leucines,Bristol Myers phenylalanine Squibb Research and a Institutehomo-phenylalanine (Tokyo) in 1992 with and a thedemonstrated terminal morpholino significant antitumor cap benefiting activity, the but PK its profile. development Critical was for abandonedbiologic activity because however its mode is the of action chiral keto-epoxidewas unclear and warhead being whicha peptide was did maintained not have the throughout appropriate the pharmacokineticSAR work and constitutes profile. Prof. the principle CM Crews synthetic (Yale University) challenge. Theand synthesisProf. R Deshaies of the methyl (California or benzyl Institute ester of theTechnology) tripeptide among core hPheLeu-Phe others, foun118dedis Proteolix achieved (later using acquired standard by solution Onyx Pharmaceuticals; phase peptide coupling legacy companyconditions of and Amgen) only minor and improvementsdecided to develop have been epox madeomicin over derivatives the years [111with–116 desirable]. drug-like properties,In the originalparticularly synthesis improved of carfilzomib potency [ 117and] the so keto-epoxidelubility. This waseffort prepared born carfilzomib by lithium/halogen whose mechanismexchange between of actiont-BuLi was also (tert -Butyllithium)elucidated [110]. and 2-bomopropene and addition of the resulting vinyl anionCarfilzomib on the Weinreb (Scheme amide 30)120 isat a tetrapeptide78 ◦C thus a ffcomprisingording vinyl two ketone leucines,121 (Scheme phenylalanine 31). Hydrogen and a homo-phenylalanine with a the terminal− morpholino cap benefiting the PK profile. Critical for biologic activity however is the chiral keto-epoxide warhead which was maintained throughout the SAR work and constitutes the principle synthetic challenge. The synthesis of the methyl or benzyl

Catalysts 2020, 10, x FOR PEER REVIEW 27 of 69 ester of the tripeptide core hPheLeu-Phe 118 is achieved using standard solution phase peptide coupling conditions and only minor improvements have been made over the years [111–116]. Catalysts 2020, 10, 1117 26 of 65 Catalysts 2020, 10, x FOR PEER REVIEW 27 of 69

119a peroxideester of the oxidation tripeptide of the core latter hPheLeu-Phe produces the 118 Boc-protected is achieved amino using keto-epoxide standard solutionin aphase 63:37 mixturepeptide ofcoupling diastereomers conditions the and desired only isomer minor ofimprovements which is obtained have bybeen column madechromatography. over the years [111–116].

Scheme 30. Retrosynthesis of carfilzomib into epoxyketone 119 and final coupling step.

In the original synthesis of carfilzomib [117] the keto-epoxide was prepared by lithium/halogen exchange between t-BuLi (tert-Butyllithium) and 2-bomopropene and addition of the resulting vinyl anion on the Weinreb amide 120 at −78 °C thus affording vinyl ketone 121 (Scheme 31). Hydrogen peroxide oxidationScheme 30. of Retrosynthesis the latter produces of carfilzomibcarfilzomib the Boc-protected into epoxyketone amino 119 and keto-epoxide finalfinal couplingcoupling 119a step.step. in a 63:37 mixture of diastereomers the desired isomer of which is obtained by column chromatography. In the original synthesis of carfilzomib [117] the keto-epoxide was prepared by lithium/halogen exchange between t-BuLi (tert-Butyllithium) and 2-bomopropene and addition of the resulting vinyl anion on the Weinreb amide 120 at −78 °C thus affording vinyl ketone 121 (Scheme 31). Hydrogen peroxide oxidation of the latter produces the Boc-protected amino keto-epoxide 119a in a 63:37 mixture of diastereomers the desired isomer of which is obtained by column chromatography.

Scheme 31. Original and improved syntheses of the key chiral epoxyketone 119. Scheme 31. Original and improved syntheses of the key chiral epoxyketone 119. Obviously,the cryogenic temperatures, the pyrophoric t-BuLi and the chromatographic purification renderObviously, this synthesis the unsuitablecryogenic fortemperatures, manufacturing. the Thepyrophoric issue with t-tBuLi-BuLi wasand successfullythe chromatographic addressed purificationlater by Onyx render Pharmaceuticals, this synthesis as theyunsuit replacedable for it withmanufacturing. the isopropenylmagnesium The issue with bromide t-BuLi thuswas successfully addressed later by Onyx Pharmaceuticals, as they replaced it with the enabling the formation of vinyl ketone 121 to proceed in THF at 0–5 ◦C[111]. isopropenylmagnesiumIn the sameScheme work, 31. marginal bromide Original and improvementthus improved enabling syntheses (drthe 2:1)formation wasof the achieved key of vinylchiral in ketoneepoxyketone the epoxidation 121 to 119. proceed of 121 in withTHF atcalcium 0–5 °C hypochlorite [111]. in aqueous NMP at 15 C or with bleach in aqueous pyridine at 5 C. − ◦ − ◦ InAsObviously, the carfilzomib same work,the had cryogenic marginal grown as temperatures,improvement an Amgen asset (drthe and 2:1) pyrophoric established was achieved t- marketedBuLi in theand product,epoxidation the chromatographic Amgen of 121 process with calciumchemistspurification hypochlorite made render further thisin improvements aqueous synthesis NMP unsuit to at the −15 processable °C orfor with upstream manufacturing. bleach and in downstreamaqueous The pyridineissue of thewith at pyridine − 5t- °C.BuLi /bleach was epoxidationsuccessfullyAs carfilzomib reactionaddressed andhad resolvedgrownlater byas issues anOnyx relatedAmgen Pharmaceuticals, to asset a) the and epimerization established as they of marketed121 replaceddue to product, the it interaction with Amgen the of processtheisopropenylmagnesium enone chemists/residual made inorganics bromidefurther/silica improvementsthus during enabling its purification, theto formationthe process b) quality,of upstreamvinyl yieldketone and and 121 robustnessdownstream to proceed issues inof THF the of pyridine/bleachtheat 0–5 oxidation °C [111]. step epoxidation due to pH-dependent reaction and decomposition resolved issues of bleach,related c)to impuritya) the epimerization built-up derived of 121 by due the In the same work, marginal improvement (dr 2:1) was achieved in the epoxidation of 121 with solvent stabilizer [118]. calciumOther hypochlorite parties interested in aqueous in improving NMP at −15 the °C synthesis or with bleach and optical in aqueous purity pyridine of the keyat −5 carfilzomib °C. intermediateAs carfilzomib119, interrogated had grown the influenceas an Amgen of the 121 assetN-protecting and established group(s) marketed in the Ca(OCl) product,2 epoxidation Amgen process chemists made further improvements to the process upstream and downstream of the pyridine/bleach epoxidation reaction and resolved issues related to a) the epimerization of 121 due

CatalystsCatalysts 20202020,, 1010,, xx FORFOR PEERPEER REVIEWREVIEW 2828 ofof 6969 toto thethe interactioninteraction ofof thethe enone/residualenone/residual inorganics/silicainorganics/silica duringduring itsits purification,purification, b)b) quality,quality, yieldyield andand robustnessrobustness issuesissues ofof thethe oxidationoxidation stepstep duedue toto pHpH-dependent-dependent decompositiondecomposition ofof bleach,bleach, c)c) impurityimpurity built-upbuilt-up derivedderived byby thethe sosolventlvent stabilizerstabilizer [118].[118]. CatalystsOtherOther2020 ,partiesparties10, 1117 interestedinterested inin improvingimproving thethe synthesissynthesis andand opticaloptical puritypurity ofof thethe keykey carfilzomibcarfilzomib27 of 65 intermediateintermediate 119119,, interrogatedinterrogated thethe influenceinfluence ofof thethe 121121 N-protectingN-protecting group(s)group(s) inin thethe Ca(OCl)Ca(OCl)22 epoxidationepoxidation reactionreaction [119].[119]. Apparently,Apparently, thethe naturenature andand numbernumber ofof protectingprotecting groupsgroups hashas aa greatgreat reaction [119]. Apparently, the nature and number of protecting groups has a great impact on the yield impactimpact onon thethe yieldyield andand diastereoselectivitydiastereoselectivity ofof ththee epoxidationepoxidation sincesince thisthis improvedimproved fromfrom 40%40% andand drdr 2:1and2:1 withwith diastereoselectivity thethe mono-Bocmono-Boc derivative ofderivative the epoxidation 119a119a toto since64%64% and thisand improveddrdr 10:110:1 withwith from thethe 40% bis-Bocbis-Boc and dr analoganalog 2:1 with 119b119b the.. The mono-BocThe latterlatter 119a 119b wasderivativewas marginallymarginallyto betterbetter 64% and thanthan dr the 10:1the bis-Cbz withbis-Cbz the and bis-Bocand mixedmixed analog Boc/CbzBoc/Cbz. Theanaloganalog latter structuresstructures was marginally 119c119c betterandand 119d,119d, than 119c 119d respectivelytherespectively bis-Cbz and (Scheme(Scheme mixed 32).32). Boc /Cbz analog structures and , respectively (Scheme 32).

SchemeScheme 32.32. EffectEffectEffect ofof nitrogennitrogen atomatom protection protection on on the the diastereoselectivity diastereoselectivity of of the the enone enone epoxidation epoxidation Another approach was to enhance the substrate control in the epoxidation reaction by using the AnotherAnother approachapproach waswas toto enhanceenhance thethe substratesubstrate cocontrolntrol inin thethe epoxidationepoxidation reactionreaction byby usingusing thethe allylic alcohol(s) 122 as the substrate (Scheme 33). The Cbz substrate generated the syn and anti alcohols allylicallylic alcohol(s)alcohol(s) 122122 asas thethe substratesubstrate (Scheme(Scheme 33).33). TheThe CbzCbz substratesubstrate generatedgenerated thethe synsyn andand antianti 122 in dr 9:1 which were in turn epoxidized using vanadium catalysis. The syn and anti epoxides alcoholsalcohols 122122 inin drdr 9:19:1 whichwhich werewere inin turnturn epoxidizedepoxidized usingusing vanadiumvanadium catalysis.catalysis. TheThe synsyn andand antianti 123 were obtained in the same ratio which was also maintained in the subsequent oxidation of the epoxidesepoxides 123123 werewere obtainedobtained inin thethe samesame ratioratio whichwhich waswas alsoalso maintainedmaintained inin thethe subsequentsubsequent hydroxyl groups back to the ketone state. Interestingly the Boc-protected ketone 121 gave a 4:1 mixture oxidationoxidation ofof thethe hydroxylhydroxyl groupsgroups backback toto thethe ketoketonene state.state. InterestinglyInterestingly thethe Boc-protectedBoc-protected ketoneketone 121121 of the syn and anti alcohols 122, but this did not transcend to the syn and anti epoxides 123. These were gavegave aa 4:14:1 mixturemixture ofof thethe synsyn andand antianti alcoholsalcohols 122,122, butbut thisthis diddid notnot transcendtranscend toto thethe synsyn andand antianti obtained in a 1:1 ratio suggesting a mismatched conformation of the major Boc diastereoisomer 122syn epoxidesepoxides 123123.. TheseThese werewere obtainedobtained inin aa 1:11:1 ratioratio suggestsuggestinging aa mismatchedmismatched conformationconformation ofof thethe majormajor exemplifying once more the influence exerted by the protecting group in the stereochemical course of BocBoc diastereoisomerdiastereoisomer 122122synsyn exemplifyingexemplifying onceonce moremore thethe influenceinfluence exertedexerted byby thethe protectingprotecting groupgroup inin the epoxidation [111,115,116]. thethe stereochemicalstereochemical coursecourse ofof thethe epoxidationepoxidation [111,115,116].[111,115,116].

Scheme 33. Effect of nitrogen atom protection on the diastereoselectivity of the allylic-OH epoxidation. SchemeScheme 33.33. EffectEffect ofof nitrogennitrogen atomatom protectionprotection onon thethe diastereoselectivitydiastereoselectivity ofof thethe allylic-OHallylic-OH epoxidation. epoxidation.In another attempt, the Sharpless asymmetric hydroxylation was applied on 121 although the diastereoselectivity of this was not reported. In this case the synthesis of carfilzomib required additional InIn anotheranother attempt,attempt, thethe SharplessSharpless asymasymmetricmetric hydroxylationhydroxylation waswas appliedapplied onon 121121 althoughalthough thethe steps associated with transforming the diol to the epoxide through protection as the diacetate prior diastereoselectivitydiastereoselectivity ofof thisthis waswas notnot reported.reported. InIn thisthis casecase thethe synthesissynthesis ofof carfilzomibcarfilzomib requiredrequired to Boc removal and coupling with the tripeptide, deprotection of the diol, activation of the primary additionaladditional stepssteps associatedassociated withwith transformingtransforming thethe dioldiol toto thethe epoxideepoxide throughthrough protectionprotection asas thethe alcohol as mesylate followed by ring closure to the epoxide. The additional process intensity and length render this approach unattractive for further development. Other efforts involved the oxidation of the epoxyketone moiety at the dipeptide or tripeptide stages post deprotection and coupling of 121 to the adjacent amino acids in carfilzomib or even Catalysts 2020, 10, x FOR PEER REVIEW 29 of 69 diacetate prior to Boc removal and coupling with the tripeptide, deprotection of the diol, activation of the primary alcohol as mesylate followed by ring closure to the epoxide. The additional process intensity and length render this approach unattractive for further development. CatalystsOther2020 ,efforts10, 1117 involved the oxidation of the epoxyketone moiety at the dipeptide or tripeptide28 of 65 stages post deprotection and coupling of 121 to the adjacent amino acids in carfilzomib or even at des-oxyat des-oxy carfilzomib carfilzomib itself. itself. The The diastereoselectiviti diastereoselectivitieses (where (where reported) reported) were were no no better better than than those obtained with 121 [[120–123].120–123]. This and other a approachespproaches are discussed in more detail in an excellent patent review by D.L. Hughes [[124].124]. The cause of carfilzomibcarfilzomib had attracted the application of alternativealternative catalytic epoxidation methods. In In one one of of them, them, epoxidation epoxidation of 121 of 121 hashas been been reported reported to occur to occur with with93% de 93% and de 85% and yield 85% yieldwith the with lanthanum(III) the lanthanum(III) BINOL BINOL complex, complex, in to inluene toluene at atambient ambient temperature temperature with with TBHP TBHP ( (terttert-Butyl-Butyl hydroperoxide) in the presence of triphenyl phosphinephosphine [125] [125] (the real additive being the triphenyl phosphine oxideoxide generatedgenerated in in situ situ by by the the oxidant) oxidant) [126 [126].]. This This reaction reaction was was demonstrated demonstrated at 100 at g 100 scale g scalenevertheless nevertheless it requires it requires a catalyst-loading a catalyst-loading of at leastof at 20least mol% 20 mol% for best for results. best results. In contrastcontrast to to this this requirement, requirement, a chiral a chiral manganese manganese complex complex (M2, Scheme (M2, 34 Scheme) developed 34) specificallydeveloped specifically for the epoxidation of enones with H2O2, sufficed at 0.2 mol% to epoxidize (S)-ketone 121 for the epoxidation of enones with H2O2, sufficed at 0.2 mol% to epoxidize (S)-ketone 121 in 96% yield, inbut 96% at dr yield, 1:7 favoring but at dr the 1:7 undesired favoring diastereoisomer the undesired diastereoisomer of 119a-syn (S at of the 119a- ketone,synR (Sat at the the epoxide) ketone, [ 127R at]. the epoxide) [127].

Et H N N N H N O N N BocHN Et Et Mn N N Mn N N O Et N N OTf 119a-syn OTf OTf OTf dr 95 : 5 M2 M3

DBU 20 mol% o Amgen Process TBME, 20 C 50% overall

1. morpholine CDI, TBME M3 0.04 mol% O N 2. Mg, Br BocHN BocHN MeCN, AcOH BocHN THF/ H O -20 oC O 2-MeTHF O 2 2, O

Boc-D-leucine-OH ent-121 119a-anti dr 91 : 9 Scheme 34. Catalytic asymmetric (substrate-controlled) epoxidation followed by epimerization. Scheme 34. Catalytic asymmetric (substrate-controlled) epoxidation followed by epimerization. The Amgen process chemists took notice of this and decided to investigate if the diastereoselectivity The Amgen process chemists took notice of this and decided to investigate if the of this excellent performing catalytic epoxidation could be reversed. A thorough optimization led to a diastereoselectivity of this excellent performing catalytic epoxidation could be reversed. A thorough more efficient Mn ligand/active catalyst M3 nevertheless the diastereoselectivity of this process remained optimization led to a more efficient Mn ligand/active catalyst M3 nevertheless the overwhelmingly substrate-controlled producing the undesired diastereoisomer of 119a-anti in 91:9 diastereoselectivity of this process remained overwhelmingly substrate-controlled producing the ratio. This was ingeniously exploited by employing the enantiomer of enone 121 (i.e., the R enantiomer) undesired diastereoisomer of 119a-anti in 91:9 ratio. This was ingeniously exploited by employing to generate the correct epoxide stereochemistry (S) followed by epimerization of the α-carbon into the the enantiomer of enone 121 (i.e., the R enantiomer) to generate the correct epoxide stereochemistry S stereochemistry for which DBU (1,8-Diazabicyclo[5.4.0] undec-7-ene) emerged as the optimum base (S) followed by epimerization of the α-carbon into the S stereochemistry for which DBU (79% yield, dr 95:5). (1,8-Diazabicyclo[5.4.0] undec-7-ene) emerged as the optimum base (79% yield, dr 95:5). The higher crystallinity of the R,S diastereoisomer allowed also for the development of a The higher crystallinity of the R,S diastereoisomer allowed also for the development of a crystallization process which obviated the need for chromatography. The Amgen process group crystallization process which obviated the need for chromatography. The Amgen process group transformed entirely the synthesis of 119a by developing a continuous process for the Grignard transformed entirely the synthesis of 119a by developing a continuous process for the Grignard addition of 2-propenyl to the Boc-D-leucine morpholine amide instead of the Weinreb amide 120 addition of 2-propenyl to the Boc-D-leucine morpholine amide instead of the Weinreb amide 120 and telescoping this into the catalytic epoxidation reaction. This remarkably innovative process and telescoping this into the catalytic epoxidation reaction. This remarkably innovative process was was demonstrated at 2 kg scale and delivered enantiopure 119a-syn in 50% yield in a much greener, safer and efficient manner [128]. The development of carfilzomib has been established as a point of reference in anticancer drug research and has inspired the development of several other related and unrelated natural products for various indications most notably cancers. After years of research and development by various Catalysts 2020, 10, x FOR PEER REVIEW 30 of 69 demonstrated at 2 kg scale and delivered enantiopure 119a-syn in 50% yield in a much greener, safer and efficient manner [128].

CatalystsThe2020 development, 10, 1117 of carfilzomib has been established as a point of reference in anticancer29 drug of 65 research and has inspired the development of several other related and unrelated natural products for various indications most notably cancers. After years of research and development by various groups, AmgenAmgen process process chemists chemists achieved achieved a highly a highly diastereoselective diastereoselective and viable and inviable large-scale in large-scale catalytic catalyticepoxidation epoxidation process for process the terminal for the terminal vinyl ketone vinyl moiety. ketone moiety.

1.12. Diltiazem—A Diltiazem—A Rare Example of Chiral Epoxide In Industrialdustrial Synthesis via Asymmetric Organocatalysis Followed by Ring Opening with Retention of Configuration Followed by Ring Opening with Retention of Configuration Diltiazem (Cardizem) is a calcium channel blocker and is FDA approved for atrial arrhythmia, Diltiazem (Cardizem) is a calcium channel blocker and is FDA approved for atrial arrhythmia, hypertension, paroxysmal supraventricular tachycardia and chronic stable angina. Diltiazem is a chiral hypertension, paroxysmal supraventricular tachycardia and chronic stable angina. Diltiazem is a 1,5-benzothiazepine with the threo (2S,3S)-isomer demonstrating superior vasodilating properties. chiral 1,5-benzothiazepine with the threo (2S,3S)-isomer demonstrating superior vasodilating The end game in the various syntheses of diltiazem almost invariably involves the attachment of the properties. The end game in the various syntheses of diltiazem almost invariably involves the dimethylamino-ethyl side chain on the amide nitrogen of intermediate 124 (Scheme 35) followed by attachment of the dimethylamino-ethyl side chain on the amide nitrogen of intermediate 124 O-acetylation. Lactam 124 is obtained by cyclisation of an appropriate carboxyl derivative 125 such as (Scheme 35) followed by O-acetylation. Lactam 124 is obtained by cyclisation of an appropriate an ester or amide. carboxyl derivative 125 such as an ester or amide.

Scheme 35. RetrosynthesisRetrosynthesis of diltiazem to chiral precursor 125.125.

Initially, development of manufacturing routes to diltiazem were based on both chemical [129] Initially, development of manufacturing routes to diltiazem were based on both chemical [129] and enzymatic [130] resolutions of appropriate intermediates. The route based on resolution of and enzymatic [130] resolutions of appropriate intermediates. The route based on resolution of S S 126 (2S,3S)-3-(4-methoxyphenyl) glycidic glycidic acid acid methyl methyl ester, ester, ( 126 Schemescheme 36)36) in particular, provided significantsignificant cost benefitsbenefits [[131].131]. In In the the context context of of asymmetric asymmetric synthesis, synthesis, setting setting up up the correct stereochemistry ofof thethe thio-thio- andand acetoxy-acetoxy- substituents substituents precipitates precipitates a a major major challenge challenge in in the the synthesis synthesis of trans 126 ofdiltiazem. diltiazem. Standard Standard ring ring opening opening of the of the -epoxidetrans-epoxideby 126 nucleophilic by nucleophilic attack ofattack 2-amino-(or of 2-amino-(or 2-nitro) 2-nitro)thiophenol thiophenol with inversion with inversion of configuration of configuration at the benzylic at the carbonbenzylic would carbon generate would thegenerate undesired the erythro 127 undesiredisomer erythro .isomer One strategy 127. One to overcomestrategy to this overcome issue was this demonstrated issue was demonstrated by Jacobsen who by Jacobsen used the cis 128 whocorresponding used the corresponding-epoxide thuscis-epoxide starting with128 thus inverted starting stereochemistry with inverted at the stereochemistry benzylic carbon at [ 132the]. Indeed, ring opening of the cis-epoxide 128 (R = iPr) with 2-nitrothiophenol provided intermediate benzylic carbon [132]. Indeed, ring opening of the cis-epoxide 128 (R = iPr) with 2-nitrothiophenol 129 i provided(X = O, intermediate R = Pr, Scheme 129 (X 36 = ).O, Reduction R = iPr, Scheme of the 36). nitro Reduction group followed of the nitro by the group standard followed end by game the standardsteps yielded end diltiazem.game steps The yielded synthesis diltiazem. of cis-epoxide The synthesis128 was of realized cis-epoxide in 96% 128 ee was (10:1 realizedcis/trans inratio) 96% byee (10:1applying cis/trans the Jacobsen–Katsuki ratio) by applying epoxidation the Jacobsen–Katsuki protocol with aepoxidation chiral salen complexprotocol onwith the correspondinga chiral salen cis complex-cinnamate on the ester. corresponding The availability cis-cinnamate of the latter ester. alkene The constitutesavailability theof the Achilles’ latter alkene heel of constitutes this route as the it trans Achilles’is obtained heel by of photoisomerization this route as it is obtained of the by photoisomerizationisomer. of the trans isomer. An alternative strategy had been developed a decade earlier by chemists at Tanabe Seiyaku (legacy company company of of Mitsubishi Mitsubishi Tanabe Tanabe Pharma), Pharma), the the inventors inventors of ofdiltiazem, diltiazem, who who recognized recognized that that the easy-to-accessthe easy-to-access transtrans epoxideepoxide 126126 couldcould be beexploited exploited in ina aring-opening ring-opening reaction reaction with with retention retention of configurationconfiguration at the benzylic carbon [[133].133]. This transformation is largely facilitated by the p-methoxy phenyl substituent supporting the opening of the ring by virtue of its electron donating capacity (Scheme 37) and ability to stabilize the resulting benzylic cation (other less electron donating substituents do not work as well, if at all). This reaction is further assisted by Lewis acid activation of the epoxide, presumably in a form involving prior complexation with the nucleophile, thus allowing the reaction to proceed in a pseudo-intramolecular fashion. A similar case culminating the reduction of a chiral epoxide with retention of configuration has been described by Merck chemists in the synthesis of the PDE IV inhibitor CDP840 [134]. Catalysts 2020, 10, x FOR PEER REVIEW 31 of 69

Catalysts 2020, 10, 1117 30 of 65 Catalysts 2020, 10, x FOR PEER REVIEW 31 of 69

Scheme 36. Ring opening of epoxides 126 and 128 with retention and inversion of configuration.

This transformation is largely facilitated by the p-methoxy phenyl substituent supporting the opening of the ring by virtue of its electron donating capacity (Scheme 37) and ability to stabilize the resulting benzylic cation (other less electron donating substituents do not work as well, if at all). This reaction is further assisted by Lewis acid activation of the epoxide, presumably in a form involving prior complexation with the nucleophile, thus allowing the reaction to proceed in a pseudo-intramolecular fashion. A similar case culminating the reduction of a chiral epoxide with retention of configuration has been described by Merck chemists in the synthesis of the PDE IV Scheme 36. Ring opening of epoxides 126 and 128 with retention and inversion of configuration. inhibitorScheme CDP840 36. Ring[134]. opening of epoxides 126 and 128 with retention and inversion of configuration.

This transformation is largely facilitated by the p-methoxy phenyl substituent supporting the opening of the ring by virtue of its electron donating capacity (Scheme 37) and ability to stabilize the resulting benzylic cation (other less electron donating substituents do not work as well, if at all). This reaction is further assisted by Lewis acid activation of the epoxide, presumably in a form involving prior complexation with the nucleophile, thus allowing the reaction to proceed in a pseudo-intramolecular fashion. A similar case culminating the reduction of a chiral epoxide with Scheme 37. Mechanism of epoxide ring opening with retention of configuration.configuration. retention of configuration has been described by Merck chemists in the synthesis of the PDE IV inhibitorThe TanabeTanabeCDP840 chemistschemists [134]. later later expanded expanded their their original original work work and and screened screened a wide a wide array array of catalysts of catalysts and solventsand solvents for this for transformation this transformation [135]. [135]. Best results Best results (90% yield (90%129c yield, 92:8 129cthreo, 92:8/erythro threo/erythroratio) were ratio) obtained were 4 withobtained iron (III)with salts, iron particularly (III) salts, withparticularly the chloride with and the the chlo sulfate,ride atand 10 −themol% sulfate, catalyst-loading at 10–4 mol% in refluxingcatalyst-loading xylene in (Scheme refluxing 38, xylene upper). (Scheme 38, upper). Chemists at Roche, in their effort to develop diltiazem analogs such as naltiazem, accomplished this thermally (Scheme 38, lower) in the presence of 2-aminothiophenol alone which is acidic enough to support protonation of the epoxide and self-ring opening to the stabilized benzylic cation thus inviting the attackScheme by 37. the Mechanism thiolate anion of epoxide [136]. ring This opening process with was retention demonstrated of configuration. on kg scale affording intermediate 129* in 98% yield. In this case, the prerequisite chiral epoxide was synthesized via employingThe Tanabe a chiral chemists auxiliary later in aexpanded diastereoselective their original Darzens work reaction and screened between a p-anisaldehydewide array of catalysts and the chloroacetateand solvents for ester this of transformation (1R,2S)-2-phenylcyclohexanol [135]. Best results130* (90%. This yield reaction 129c, 92:8 produces threo/erythro a 62:38 ratio) mixture were of theobtained two diastereomeric with iron (III) epoxides salts, 131*particularlyfrom which with the the desired chloride diastereoisomer and the sulfate, is isolated at 10 by–4 simplemol% crystallizationcatalyst-loading in in 54% refluxing yield (400 xylene g scale). (Scheme 38, upper). In terms of preparation of the appropriate chiral epoxy cinnamate ester 129a, the Tanabe chemists addressed an occupational health issue in their original enzymatic resolution process [131]. Because the epoxy ester intermediate was shown to be a severe irritant, the enzymatic resolution was modified to produce optically pure and safe to handle epoxy amide 129c either directly using ammonia or by converting resolved methyl ester 129a to the primary amide. The epoxy amide 129c performed well in the ring opening and the subsequent acid-catalyzed lactamization, eventually allowing for successful preparation of diltiazem in multigram scale.

Catalysts 2020, 10, 1117 31 of 65 Catalysts 2020, 10, x FOR PEER REVIEW 32 of 69

Scheme 38. Alternative synthesis of diltiazem intermediate 129 via asymmetric Darzen reaction. Scheme 38. Alternative synthesis of diltiazem intermediate 129 via asymmetric Darzen reaction. In order to improve further on the efficiency of the synthesis of the chiral epoxide the Tanabe Chemists at Roche, in their effort to develop diltiazem analogs such as naltiazem, accomplished chemists investigated alternative routes that would preclude the >50% yield loss associated with this thermally (Scheme 38, lower) in the presence of 2-aminothiophenol alone which is acidic enough resolution methods (either chemical or enzymatic). Thus, a catalytic asymmetric epoxidation of to support protonation of the epoxide and self-ring opening to the stabilized benzylic cation thus p-methoxy cinnamate esters (132) became the next objective of the Tanabe investigation. Given the inviting the attack by the thiolate anion [136]. This process was demonstrated on kg scale affording electron deficient nature of the alkene potion in the cinnamic substrate, a powerful electrophilic oxidant intermediate 129* in 98% yield. In this case, the prerequisite chiral epoxide was synthesized via must be used in order for the epoxidation to take place. For this reason, chiral dioxiranes generated in employing a chiral auxiliary in a diastereoselective Darzens reaction between p-anisaldehyde and situ from appropriate chiral ketones were considered for this task [137,138]. the chloroacetate ester of (1R,2S)-2-phenylcyclohexanol 130*. This reaction produces a 62:38 mixture Yang’s chiral ketone 133 (Scheme 39) emerged as the optimum organocatalyst for this of the two diastereomeric epoxides 131* from which the desired diastereoisomer is isolated by transformation in terms of ease of preparation, catalyst-loading and stability [139]. The process simple crystallization in 54% yield (400 g scale). was gradually scaled up to 100 g with 5 mol% of the ketone catalyst in the presence of OxoneTM as In terms of preparation of the appropriate chiral epoxy cinnamate ester 129a, the Tanabe the terminal oxidant and delivered the crude chiral epoxy cinnamate in 89% yield and 78% ee [139]. chemists addressed an occupational health issue in their original enzymatic resolution process [131]. A special recrystallization process was developed for isolating the product without contamination from Because the epoxy ester intermediate was shown to be a severe irritant, the enzymatic resolution was the catalyst which not only upgraded the quality of the intermediate to 99% ee (64% yield), but also modified to produce optically pure and safe to handle epoxy amide 129c either directly using allowed for the recovery of the catalyst. In a subsequent effort, the crystallization process was coupled ammonia or by converting resolved methyl ester 129a to the primary amide. The epoxy amide 129c to a lipase-catalyzed transesterification step that also allowed for recycling of the unwanted epoxide performed well in the ring opening and the subsequent acid-catalyzed lactamization, eventually enantiomer [140]. allowing for successful preparation of diltiazem in multigram scale. The asymmetric epoxidation of α,β-unsaturated ketones may be accomplished by the Julia Colona In order to improve further on the efficiency of the synthesis of the chiral epoxide the Tanabe protocol with nucleophilic oxidants such as hydrogen peroxide. In this, the substrate associates with chemists investigated alternative routes that would preclude the >50% yield loss associated with polyleucine catalyst via hydrogen bonding and becomes activated towards a conjugate addition by the resolution methods (either chemical or enzymatic). Thus, a catalytic asymmetric epoxidation of oxidant within the chiral environment of the catalyst. This approach was demonstrated in the synthesis p-methoxy cinnamate esters (132) became the next objective of the Tanabe investigation. Given the of diltiazem via the catalytic asymmetric epoxidation of ketone 134 (Scheme 39) followed by a Bayer electron deficient nature of the alkene potion in the cinnamic substrate, a powerful electrophilic Villiger reaction on epoxide 135 to generate the t-butyl cinnamate ester 136 [141]. Using the conditions oxidant must be used in order for the epoxidation to take place. For this reason, chiral dioxiranes developed by Roche and the established endgame reactions, a second alternative synthesis of diltiazem generated in situ from appropriate chiral ketones were considered for this task [137,138]. based on an organocatalyst was achieved. It is worth noting that this synthesis was performed three Yang’s chiral ketone 133 (Scheme 39) emerged as the optimum organocatalyst for this consecutive times at 4 g scale with reuse of the immobilized polyleucine catalyst each time, without transformation in terms of ease of preparation, catalyst-loading and stability [139]. The process was deterioration of the yield or ee. gradually scaled up to 100 g with 5 mol% of the ketone catalyst in the presence of Oxone™ as the terminal oxidant and delivered the crude chiral epoxy cinnamate in 89% yield and 78% ee [139]. A special recrystallization process was developed for isolating the product without contamination from the catalyst which not only upgraded the quality of the intermediate to 99% ee (64% yield), but also allowed for the recovery of the catalyst. In a subsequent effort, the crystallization process was

Catalysts 2020, 10, x FOR PEER REVIEW 33 of 69 coupled to a lipase-catalyzed transesterification step that also allowed for recycling of the unwanted epoxide enantiomer [140]. The asymmetric epoxidation of α,β-unsaturated ketones may be accomplished by the Julia Colona protocol with nucleophilic oxidants such as hydrogen peroxide. In this, the substrate associates with polyleucine catalyst via hydrogen bonding and becomes activated towards a conjugate addition by the oxidant within the chiral environment of the catalyst. This approach was demonstratedCatalysts 2020, 10, 1117in the synthesis of diltiazem via the catalytic asymmetric epoxidation of ketone32 of134 65 (Scheme 39) followed by a Bayer Villiger reaction on epoxide 135 to generate the t-butyl cinnamate ester 136 [141]. Using the conditions developed by Roche and the established endgame reactions, a secondOverall, alternative the process synthesis development of diltiazem efforts based towards on diltiazeman organocatalyst encompass was two rareachieved. aspects It of is epoxide worth notingchemistry that performed this synthesis on scale, was namely performed the asymmetric three consecutive synthesis times of an epoxideat 4 g scale using with an organocatalyst reuse of the immobilizedand its subsequent polyleucine ring opening catalyst with each retention time, without of configuration. deterioration of the yield or ee.

Scheme 39. SynthesisSynthesis of of chiral chiral epoxy epoxy cinnamate cinnamate inte intermediatesrmediates using asymmetric organocatalysis. 1.13. Reboxetine—Epoxide Intermediates Transcending from a Racemic to an Asymmetric Synthesis Overall, the process development efforts towards diltiazem encompass two rare aspects of epoxideCNS chemistry disorders performed are largely associatedon scale, namely with deregulation the asymmetric of neurotransmitter synthesis of an and epoxide neurohormone using an organocatalystsignaling. Prominent and its subsequent members ofring the op formerening with category retention include of configuration. the biogenic amines serotonin, norepinephrine (noradrenaline) and dopamine. Depression encompasses several disorders with 1.13.various Reboxetine—Epoxide symptoms, ailments Intermediates and disabilities Transcending that mayfrom a a ffRacemicect our to emotions, an Asymmetric thoughts, Synthesis actions and physical condition of the entire human body. Intervention at the serotoninergic and noradrenergic CNS disorders are largely associated with deregulation of neurotransmitter and neurohormone signaling has produced the state of the art of antidepressants (SSRIs, NRIs and SNRIs) [142,143] signaling. Prominent members of the former category include the biogenic amines serotonin, primarily through inhibition of the reuptake of the respective neurotransmitters in the synaptic cleft. norepinephrine (noradrenaline) and dopamine. Depression encompasses several disorders with Reboxetine is a highly potent and selective norepinephrine reuptake inhibitor that is approved in many various symptoms, ailments and disabilities that may affect our emotions, thoughts, actions and countries, but not the FDA, for the acute treatment of depressive illness/major depression. Its efficacy physical condition of the entire human body. Intervention at the serotoninergic and noradrenergic for these indications has been a matter of controversy instead clearer benefit is observed in cases with signaling has produced the state of the art of antidepressants (SSRIs, NRIs and SNRIs) [142,143] symptoms of anhedonia and somatic pain. Furthermore, reboxetine appears to be widely endorsed primarily through inhibition of the reuptake of the respective neurotransmitters in the synaptic cleft. (off label) for SSRI-resistant panic disorder and attention deficit hyperactivity disorder (ADHD). Reboxetine is a highly potent and selective norepinephrine reuptake inhibitor that is approved in Reboxetine was discovered by Farmitalia which was acquired by Pharmacia in 1993 and succeeded in many countries, but not the FDA, for the acute treatment of depressive illness/major depression. Its obtaining regulatory approvals. Pharmacia merged with Upjohn in 1995 forming Pharmacia-Upjohn efficacy for these indications has been a matter of controversy instead clearer benefit is observed in which in turn was acquired by Pfizer in 2003. cases with symptoms of anhedonia and somatic pain. Furthermore, reboxetine appears to be widely Reboxetine has two stereogenic centers and consequently there are four diastereoisomers, two sets endorsed (off label) for SSRI-resistant panic disorder and attention deficit hyperactivity disorder of enantiomers, associated with its structure. The registered NRI antidepressant, reboxetine mesylate (ADHD). Reboxetine was discovered by Farmitalia which was acquired by Pharmacia in 1993 and (trade name Edronax, Scheme 40), comprises actually one set enantiomers the (S,S and the R,R), namely the set of syn diastereomers and is therefore marketed in a diastereomerically pure yet racemic form. For this reason, the initial synthesis of reboxetine were racemic. More recent studies have shown that the (S,S)-enantiomer (esreboxetine, Scheme 40) is more active than its enantiomer in certain biologic assays [144] and (S,S)-reboxetine succinate is under development at Pfizer for the treatment of fibromyalgia. A number of reboxetine syntheses have been described over the years and these have been recently reviewed [145]. The discussion that follows focuses on the relevant epoxide-involving routes particularly those of large scale/manufacturing potential. Catalysts 2020, 10, x FOR PEER REVIEW 34 of 69 succeeded in obtaining regulatory approvals. Pharmacia merged with Upjohn in 1995 forming Pharmacia-Upjohn which in turn was acquired by Pfizer in 2003. Reboxetine has two stereogenic centers and consequently there are four diastereoisomers, two sets of enantiomers, associated with its structure. The registered NRI antidepressant, reboxetine mesylate (trade name Edronax, Scheme 40), comprises actually one set enantiomers the (S, S and the CatalystsR, R), namely2020, 10, the 1117 set of syn diastereomers and is therefore marketed in a diastereomerically pure33 of yet 65 racemic form.

Scheme 40. Stereochemistry of reboxetine (approved drug) and esreboxetine (clinical(clinical candidate).candidate).

TheFor this first reason, synthesis the for initial reboxetine synthesis mesylate of reboxe (thetine racemic were approved racemic. drug)More wasrecent reported studies byhave its inventorsshown that Farmitalia-Carlo the (S,S)-enantiomer Erba. By (esreboxetine, the time the drugScheme became 40) is a Pfizermore active asset it than had grownits enantiomer in demand in andcertain a more biologic efficient assays route [144] was and needed, (S,S)-reboxetine but there was succinate limited freedomis under fordevelopment changes due at the Pfizer restrictions for the thattreatment apply of to fibromyalgia. registered processes A number with of regulatoryreboxetine bodies.syntheses Pfizer have process been described chemists over made the several years modificationsand these have (Scheme been recently 41) to the reviewed Farmitalia [145]. route The and discussion developed that a process follows which focuses involves on the 12 chemicalrelevant transformationsepoxide-involving yet routes only threeparticularly isolations those improving of large thescale/manufacturing yield of the drug substancepotential. from 11 to about Catalysts 2020, 10, x FOR PEER REVIEW 35 of 69 25% [The146 ].first synthesis for reboxetine mesylate (the racemic approved drug) was reported by its inventors Farmitalia-Carlo Erba. By the time the drug became a Pfizer asset it had grown in demand and a more efficient route was needed, but there was limited freedom for changes due the restrictions that apply to registered processes with regulatory bodies. Pfizer process chemists made several modifications (Scheme 41) to the Farmitalia route and developed a process which involves 12 chemical transformations yet only three isolations improving the yield of the drug substance from 11 to about 25% [146]. In particular, due to work up difficulties, long processing times and size of waste, the reagent for the epoxidation of cinnamyl alcohol 137 was switched from monoperoxyphthalic acid (prepared from H2O2 and phthalic anhydride) to peracetic acid (Scheme 41). The epoxide 138 was telescoped into the ring-opening reaction with 2-ethoxyphenol which was now run in water in the presence of a phase transfer catalyst instead of dioxane. Diol 139 was isolated after the telescoped epoxidation and ring-opening process in 65% yield at > 0.3 ton scale. The protecting group for the primary alcohol in the next step was changed from p-nitrobenzoyl to TMS in order to limit the extensive migration of the acyl group (>20%) to the secondary alcohol which would ultimately lead to the wrong API diastereomer. The regioselectivity of the TMS protection towards exclusive formation of 140 was carefully controlled before addition of mesyl chloride to generate mesylate 141. Acid treatment removes the silyl group revealing hydroxy mesylate 142 followed by base-induced epoxide formation. Ring opening of epoxide 143 with ammonia required large excess of the latter to suppress further reaction of the generated amine 144 with a second molecule of epoxide. The dimeric amine generated in this way was difficult to purge down downstream if formed at >8% at this stage. After careful optimization of these steps the telescoped process from diol 139 spanning 5 steps was run at 275 kg batches and delivered key intermediate amine 144 as its mesylate salt in 63% yield and excellent quality.

Scheme 41. Pfizer’s manufacturing route for reboxetine. Scheme 41. Pfizer’s manufacturing route for reboxetine.

The construction of the morpholine ring was realized via a telescoped three step sequence involving amidation of 144 with chloroacetyl chloride, cyclisation of 145 and reduction of the resulting morpholinone. Features of this process such as the dimethyl carbonate solvent in the amidation step and the final Vitride reduction were maintained in order to avoid major deviations from the registered process. Modifications in the reduction step nevertheless led to significant minimization of certain impurities and improved the work up. These were implemented in 125 kg batch processes delivering reboxetine mesylate at specification in 62% yield over the three steps. The progression of esreboxetine succinate to clinical candidate status precipitated the need for kilogram scale deliveries of enantiopure reboxetine. Initially this was achieved by resolution of reboxetine mesylate itself involving conversion to the free base, resolution with (S)-mandelic acid, conversion to the free base and succinate salt formation [147]. Despite delivering 100 kg this process was deemed highly inefficient as 3 kg of reboxetine mesylate were required to produce 1 kg of esreboxetine succinate. In addition, using an established drug substance as a starting material carried several supply and regulatory issues. For these reasons, resolution at the stage of amino alcohol 144 was considered next. A wide range of resolving agents and solvent systems were screened with (R)-camphanic acid providing the most robust, scalable and efficient resolution. Unfortunately, it is the (S)-camphanic acid that is cheaper and more widely available which conversely induces crystallization of the undesired enantiomer of reboxetine as its (S)-camphanate salt. A process was thus developed that removed the unwanted diastereomeric salt by filtration and the synthesis progressed with the desired enantiomer retained in the liquors as free base in 88% ee; this was upgraded to 99% ee to upon its isolation as the benzoate salt. This process was scaled up to 150 kg batches and delivered

Catalysts 2020, 10, 1117 34 of 65

In particular, due to work up difficulties, long processing times and size of waste, the reagent for the epoxidation of cinnamyl alcohol 137 was switched from monoperoxyphthalic acid (prepared from H2O2 and phthalic anhydride) to peracetic acid (Scheme 41). The epoxide 138 was telescoped into the ring-opening reaction with 2-ethoxyphenol which was now run in water in the presence of a phase transfer catalyst instead of dioxane. Diol 139 was isolated after the telescoped epoxidation and ring-opening process in 65% yield at > 0.3 ton scale. The protecting group for the primary alcohol in the next step was changed from p-nitrobenzoyl to TMS in order to limit the extensive migration of the acyl group (>20%) to the secondary alcohol which would ultimately lead to the wrong API diastereomer. The regioselectivity of the TMS protection towards exclusive formation of 140 was carefully controlled before addition of mesyl chloride to generate mesylate 141. Acid treatment removes the silyl group revealing hydroxy mesylate 142 followed by base-induced epoxide formation. Ring opening of epoxide 143 with ammonia required large excess of the latter to suppress further reaction of the generated amine 144 with a second molecule of epoxide. The dimeric amine generated in this way was difficult to purge down downstream if formed at >8% at this stage. After careful optimization of these steps the telescoped process from diol 139 spanning 5 steps was run at 275 kg batches and delivered key intermediate amine 144 as its mesylate salt in 63% yield and excellent quality. The construction of the morpholine ring was realized via a telescoped three step sequence involving amidation of 144 with chloroacetyl chloride, cyclisation of 145 and reduction of the resulting morpholinone. Features of this process such as the dimethyl carbonate solvent in the amidation step and the final Vitride reduction were maintained in order to avoid major deviations from the registered process. Modifications in the reduction step nevertheless led to significant minimization of certain impurities and improved the work up. These were implemented in 125 kg batch processes delivering reboxetine mesylate at specification in 62% yield over the three steps. The progression of esreboxetine succinate to clinical candidate status precipitated the need for kilogram scale deliveries of enantiopure reboxetine. Initially this was achieved by resolution of reboxetine mesylate itself involving conversion to the free base, resolution with (S)-mandelic acid, conversion to the free base and succinate salt formation [147]. Despite delivering 100 kg this process was deemed highly inefficient as 3 kg of reboxetine mesylate were required to produce 1 kg of esreboxetine succinate. In addition, using an established drug substance as a starting material carried several supply and regulatory issues. For these reasons, resolution at the stage of amino alcohol 144 was considered next. A wide range of resolving agents and solvent systems were screened with (R)-camphanic acid providing the most robust, scalable and efficient resolution. Unfortunately, it is the (S)-camphanic acid that is cheaper and more widely available which conversely induces crystallization of the undesired enantiomer of reboxetine as its (S)-camphanate salt. A process was thus developed that removed the unwanted diastereomeric salt by filtration and the synthesis progressed with the desired enantiomer retained in the liquors as free base in 88% ee; this was upgraded to 99% ee to upon its isolation as the benzoate salt. This process was scaled up to 150 kg batches and delivered close to perfect yields for a resolution step (47% on average) rendering the overall route to esreboxetine three times more efficient and cost-effective than the process implementing the resolution at the reboxetine mesylate stage [147]. Following this logic, a resolution further upstream in the synthesis could increase the efficiency of the synthesis and such an attempt has been described by Reddy et al. the resolution of epoxide 146 catalyzed by Jacobsen cobalt salen complex M4 (Scheme 42)[148]. Resolved epoxide 147, following ring opening with ammonia, was converted to the morpholine derivative 148 via the standard 3-step procedure and protected with Boc. In this approach whatever advantage was gained by conducting the resolution early, is lost in the manipulation of the Bn and Boc protecting groups and necessity to invert the stereochemistry of the benzylic alcohol 148 and then again of the benzylic bromide 149 with 2-ethoxyphenol. Catalysts 2020, 10, x FOR PEER REVIEW 36 of 69 close to perfect yields for a resolution step (47% on average) rendering the overall route to

Catalystsesreboxetine2020, 10 ,three 1117 times more efficient and cost-effective than the process implementing35 ofthe 65 resolution at the reboxetine mesylate stage [147].

Scheme 42. Reddy’s kinetic resolution of an early epox epoxideide intermediate using Jacobsen’s catalyst M4M4..

ItFollowing must be notedthis logic, that alla resolution reported syntheses further upstream that involve in the the synthesis formation could of the increase O-aryl bondthe efficiency from the benzylicof the synthesis alcohol and do sosuch with an the attempt use Mitsunobu has been desc or equivalentribed by Reddy reactions et al. or the chromium resolution tricarbonyl of epoxide arene 146 complexescatalyzed by depending Jacobsen oncobalt the stereochemistrysalen complex M4 at the (Scheme benzylic 42) alcohol. [148]. Such methods may be acceptable for theResolved preparation epoxide of analog 147, following structures ring in smallopening scale with but ammonia, are render was the converted synthesis uncompetitive to the morpholine and practicallyderivative invalid148 via inthe a largestandard scale 3-step/manufacturing procedure set and up protec due toted waste with and Boc. toxicity In this issues approach of the whatever reagents involvedadvantage (Cr, was azodicarboxylates) gained by conducting [149– 155the ].resolution early, is lost in the manipulation of the Bn and Boc protectingFrom a process groups chemist’s and necessity perspective, to invert the bestthe approachstereochemistry for constructing of the benzylic the aryl-benzylic alcohol 148 ether and fragmentthen again in of reboxetine the benzylic is tobromide install 149 this with by using 2-ethoxyphenol. the phenol in a nucleophilic substitution reaction at theIt benzylicmust be noted center that preferably all reported early syntheses on. It is thereforethat involve not the a coincidenceformation of that the bothO-aryl racemic bond from and asymmetricthe benzylicsyntheses alcohol do of so reboxetine with the byuse the Mitsunobu process team or equivalent of Pfizer employ reactions this or very chromium strategy. tricarbonyl The Pfizer teamarene consideredcomplexes thatdepending an asymmetric on the stereochemistry synthesis that couldat the o benzylicffset the 50%alcohol. yield Such reduction methods associated may be withacceptable their nearly for the perfect preparation resolution of processesanalog structur would bees everin small more scale efficient but and are cost render saving. the Withsynthesis more freedomuncompetitive to operate and practically now in the invalid context in of a esreboxetine large scale/manufacturing development, theset up racemic due to route waste was and modified toxicity intoissues an of asymmetric the reagents one involved simply (Cr, by replacing azodicarboxylates) the racemic [149–155]. epoxidation of cinnamyl alcohol in the first step byFrom a Sharpless a process asymmetric chemist’s perspect epoxidationive, ofthe the best very approach same allylic for constructing alcohol in 92% the ee aryl-benzylic (Scheme 43)[ ether156]. Withoutfragment isolation, in reboxetine chiral is epoxide to install150 thiswas by subjected using the to phenol the ring-opening in a nucleophilic reaction substitution by the phenol reaction as in the at previousthe benzylic process center and preferably recrystallization early on. ofthe It diolis therefore151 allowed not a the coincidence upgrade of that optical both purity racemic to > 98%.and Inasymmetric this first iteration,syntheses only of reboxetine minor modifications by the process were team made of to Pfizer the rest employ of the this stages very (Scheme strategy. 41 The) in orderPfizer toteam accommodate considered the that diff erencesan asymmetric in solubility synthesis and behavior that could of the offset enantiopure the 50% intermediates yield reduction from thoseassociated of the with racemic their ones. nearly Still, perfect it was possibleresolution to improveprocesses the would asymmetric be ever process more furtherefficient in and the nextcost iteration [147]. In particular, the 20 C TMS protection of the primary alcohol in 151 suffered from saving. With more freedom to operate− ◦ now in the context of esreboxetine development, the racemic moderateroute was yields modified and incomplete into an asymmetric regiocontrol one (either simply by direct by silylationreplacing ofthe the racemic secondary epoxidation alcohol or viaof TMScinnamyl migration) alcohol and in lackedthe first robustness step by a in Sharpless larger scale asymmetric processing. epoxidation of the very same allylic alcoholAn in innovative 92% ee protection(Scheme 43) step [156]. was introducedWithout isolation, using an chiral enzyme-catalyzed epoxide 150acetylation was subjected to form to 152the whichring-opening occurred reaction consistently by the withphenol almost as in completethe previous regiocontrol process and even recrystallization at 20 ◦C. This was of the telescoped diol 151 intoallowed the mesylationthe upgrade step of optical and mesylate purity to153 >98%.was In subjected this firstdirectly iteration, in only the base-inducedminor modifications acetate were ester hydrolysismade to the and rest ring-closure of the stages to epoxide(Scheme154 41). in This orde sequencer to accommodate saved one step the /differencesoperation from in solubility the synthesis and sincebehavior the correspondingof the enantiopure TMS intermediateintermediates141 fromrequired those acidicof the deprotection racemic ones. prior Still, to epoxideit was possible formation. to Anotherimprove stepthe wasasymmetric eliminated process from thefurther synthesis in the by next ring iteration opening [147]. of epoxide In particular,154 to intermediate the −20 °C155 TMSby usingprotection 2-aminoethyl of the primary hydrogen alcohol sulfate in 151 instead suffered of ammonia. from moderate This reagent yields bearsand incomplete the ethylene regiocontrol portion of the(either morpholine by direct already silylation preinstalled of the secondary at the nitrogen alcohol atom or via and TMS more migration) important, and at lacked the correct robustness oxidation in state,larger obviatingscale processing. the need for a reduction step. The ring opening of epoxide 154 had to be optimized against formation dimeric impurities (amine 155 reacting with a second epoxide molecule) by careful control of reagent stoichiometry, reaction temperature, order and duration of additions. Morpholine ring closure under basic conditions was telescoped into the succinate salt generation thus providing esreboxetine succinate in 81% yield at specification. Catalysts 2020, 10, 1117 36 of 65 Catalysts 2020, 10, x FOR PEER REVIEW 37 of 69

Scheme 43. Pfizer’s final process for the asymmetric synthesis of esreboxetine. Scheme 43. Pfizer’s final process for the asymmetric synthesis of esreboxetine. The new asymmetric process for reboxetine succinate afforded a 58% improvement in overall An innovative protection step was introduced using an enzyme-catalyzed acetylation to form yield,152 reducedwhich occurred processing consistently times, significant with almost cost savings complete and regiocontrol waste reduction even by at 90% 20 hence°C. This it received was a Greentelescoped Chemistry into the Award mesylation [157]. step and mesylate 153 was subjected directly in the base-induced acetateAlthough ester ahydrolysis number of and syntheses ring-closure have beento epoxide reported 154 for. This racemic sequence and enantiopuresaved one step/operation reboxetine and derivatives,from the synthesis including since several the ofco questionablerresponding TMS merit intermediate [130], there are141 two required efforts acidic that alsodeprotection employ the prior early installationto epoxide of formation. the phenol Another and proceed step was through eliminated epoxide from intermediates the synthesis and by deservering opening to be of mentioned. epoxide 154Aparicio to intermediate et al. reported 155 by an using asymmetric 2-aminoethyl synthesis hydrogen of reboxetine sulfate basedinstead on of a ammonia. chiral auxiliary This reagent approach to facilitatebears the aethylene diastereoselective portion of Darzensthe morpholine/Corey alreadChaykovskyy preinstalled reaction at (Schemethe nitrogen 44) using atom chiraland more amido − sulfoniumimportant, salt at156 the [correct158]. The oxidation corresponding state, obviating ylide wasthe need reacted for witha reduction benzaldehyde step. The and ring generated opening of the twoepoxide diastereomeric 154 had to epoxides be optimized (only theagainst desired formation one is shown,dimeric157 impurities) in dr 73:27. (amine These 155 werereacting inseparable, with a sosecond they were epoxide progressed molecule) into theby careful epoxide control ring-opening of reagent reaction stoichiometry, with 2-ethoxyphenol reaction temperature, which, as expected order occurredand duration at the benzylicof additions. position Morpho withline inversion ring closure of configuration. under basic Thisconditions time the was diastereomeric telescoped into hydroxy the amidessuccinate were salt separable generation by chromatographythus providing esreboxetine and the desired succinate one in158 81%was yield isolated at specification. as a crystalline solid. OptimizationThe new of asymmetric the amide reductionprocess for step reboxetine followed succinate by the three-step afforded a process 58% improvement (via the morpholinone) in overall foryield, morpholine reduced formation processing and times, hydrogenolysis significant ofco thest savings chiral auxiliary and waste provided reduction enantiopure by 90% reboxetine.hence it received a Green Chemistry Award [157]. Although a number of syntheses have been reported for racemic and enantiopure reboxetine and derivatives, including several of questionable merit [130], there are two efforts that also employ

Catalysts 2020, 10, x FOR PEER REVIEW 38 of 69

Catalyststhe early2020 installation, 10, 1117 of the phenol and proceed through epoxide intermediates and deserve37 to of be 65 mentioned.

Scheme 44. Aparicio’s approach to esreboxetine using a diastereoselective Darzens reaction. Scheme 44. Aparicio’s approach to esreboxetine using a diastereoselective Darzens reaction. Another innovative and efficient approach has been reported by Yu and Ko who applied the Sharpless’Aparicio asymmetric et al. reported dihydroxylation an asymmetric reaction synthesis on protected of reboxetine cinnamyl based alcohol on137 a chiralgenerating auxiliary the cisapproach-diol 160 to(Scheme facilitate 45 a). diastereoselective Formation of the cyclicDarzens/Corey sulfate 161−Chaykovskyfollowed by TBAFreaction treatment (Scheme reveals 44) using the terminalchiral amido alkoxide sulfonium which salt ring 156 opens [158]. intramolecularly The corresponding the cyclic ylide sulfate was reacted with inversion with benzaldehyde of configuration and atgenerated the adjacent the two carbon diastereomeric forming epoxy epoxid sulfatees (only162. Azidethe desired addition one atis thisshown, point 157 ring) in opens dr 73:27. the newlyThese formedwere inseparable, epoxide generating so they intermediate were progressed163 in whichinto thethe benzylicepoxide alcohol ring-opening is in an activatedreaction formwith ready2-ethoxyphenol for displacement. which, as The expected latter isoccurred realized at by the the benzylic addition position of 2-ethoxyphenol with inversion which of configuration. affords key intermediateThis time the164 diastereomericwhose conversion hydroxy to esreboxetine amides we isre straightseparable forward. by chromatography Optimization ofand these the steps desired led tooneCatalysts an 158 impressive 2020 was, 10 isolated, x FOR one-pot PEER as a telescopedREVIEWcrystalline processsolid. Optimizati from 161 onto 164of thein 84%amide yield. reduction step followed by39 of the 69 three-step process (via the morpholinone) for morpholine formation and hydrogenolysis of the chiral auxiliary provided enantiopure reboxetine. Another innovative and efficient approach has been reported by Yu and Ko who applied the Sharpless’ asymmetric dihydroxylation reaction on protected cinnamyl alcohol 137 generating the cis-diol 160 (Scheme 45). Formation of the cyclic sulfate 161 followed by TBAF treatment reveals the terminal alkoxide which ring opens intramolecularly the cyclic sulfate with inversion of configuration at the adjacent carbon forming epoxy sulfate 162. Azide addition at this point ring opens the newly formed epoxide generating intermediate 163 in which the benzylic alcohol is in an activated form ready for displacement. The latter is realized by the addition of 2-ethoxyphenol which affords key intermediate 164 whose conversion to esreboxetine is straight forward. Optimization of these steps led to an impressive one-pot telescoped process from 161 to 164 in 84% yield.

Scheme 45. Yu and Ko’s approach to esreboxetine usingusing Sharpless’Sharpless’ asymmetricasymmetric dihydroxylation.dihydroxylation.

Both of the syntheses described above required chromatographic purifications nevertheless, they were conducted in gram scale and represent inspiring epoxide-mediated synthesis of reboxetine who are novel and aligned with the Pfizer strategy therefore rank highest among academic routes.

1.14. FK-788—Replacement of an Asymmetric Synthesis by a Resolution Process with Recycling of the Undesired Enantiomer; the Meinwald Rearrangement on Scale

Prostaglandin I2 (PGI2 p), commonly known as prostacyclin, is a lipid product of arachidonic acid metabolism and is generated in greatest abundance by vascular tissues primarily by COX1 [159,160]. It is arguably the most potent endogenous vasodilator and exerts its signaling through the IP receptor, a GPCR. Although primarily recognized for protection against vascular remodeling and platelet formation, PGI2 has been found to regulate both the innate and adaptive immune systems and this has been aimed mainly at anti-inflammatory or immunosuppressive applications [161]. More recently, prostacyclin was directly linked with obesity treatment [162] and inhibition of lung tumor progression [163]. Prostaglandin I2 (PGI2) has been approved as a medicine under the name of epoprostenol, but its short half-life (42 s) has prompted intense research for more appropriate alternatives which has produced the synthetic analogs iloprost and treprostinil [164]. Improved selectivity among prostaglandin receptors and desirable pharmacokinetic profile continue to be at the heart of research for novel IP agonists. FK-788 (Scheme 46) is a prostacyclin structurally unrelated IP agonist with significant potency, selectivity, solubility and bioavailability that was discovered by Fujisawa (legacy company of Astellas Pharma) [165]. In the medicinal chemistry route (Scheme 46), the chiral center was introduced at intermediate 165 by an asymmetric dihydroxylation at the unsaturated ester 166. Besides the toxicity of osmium and cyanide reagents involved in this step, persistent impurities formed both in the downstream chemistry and in the reactions leading to 166 from 167, forced Astellas chemists to develop an alternative route to FK-788 that could be used for large-scale deliveries.

Catalysts 2020, 10, 1117 38 of 65

Both of the syntheses described above required chromatographic purifications nevertheless, they were conducted in gram scale and represent inspiring epoxide-mediated synthesis of reboxetine who are novel and aligned with the Pfizer strategy therefore rank highest among academic routes.

1.14. FK-788—Replacement of an Asymmetric Synthesis by a Resolution Process with Recycling of the Undesired Enantiomer; the Meinwald Rearrangement on Scale

Prostaglandin I2 (PGI2 p), commonly known as prostacyclin, is a lipid product of arachidonic acid metabolism and is generated in greatest abundance by vascular tissues primarily by COX1 [159,160]. It is arguably the most potent endogenous vasodilator and exerts its signaling through the IP receptor, a GPCR. Although primarily recognized for protection against vascular remodeling and platelet formation, PGI2 has been found to regulate both the innate and adaptive immune systems and this has been aimed mainly at anti-inflammatory or immunosuppressive applications [161]. More recently, prostacyclin was directly linked with obesity treatment [162] and inhibition of lung tumor progression [163]. Prostaglandin I2 (PGI2) has been approved as a medicine under the name of epoprostenol, but its short half-life (42 s) has prompted intense research for more appropriate alternatives which has produced the synthetic analogs iloprost and treprostinil [164]. Improved selectivity among prostaglandin receptors and desirable pharmacokinetic profile continue to be at the heart of research for novel IP agonists. FK-788 (Scheme 46) is a prostacyclin structurally unrelated IP agonist with significant potency, selectivity, solubility and bioavailability that was discovered by Fujisawa (legacy company of Astellas Pharma) [165]. In the medicinal chemistry route (Scheme 46), the chiral center was introduced at intermediate 165 by an asymmetric dihydroxylation at the unsaturated ester 166. Besides the toxicity of osmium and cyanide reagents involved in this step, persistent impurities formed both in the downstream chemistry and in the reactions leading to 166 from 167, forced Astellas chemists to develop anCatalysts alternative 2020, 10, routex FOR toPEER FK-788 REVIEW that could be used for large-scale deliveries. 40 of 69

Scheme 46. Retrosynthetic analysis of FK-788. Scheme 46. Retrosynthetic analysis of FK-788. Initial attempts aimed at alternative asymmetric syntheses, for example using the Jacobsen–Katsuki Initial attempts aimed at alternative asymmetric syntheses, for example using the asymmetric epoxidation on appropriate substrates, had limited success. In the end it was envisaged Jacobsen–Katsuki asymmetric epoxidation on appropriate substrates, had limited success. In the end that the racemic key intermediate, diol 174, could be accessed relatively easily and that a diastereomeric it was envisaged that the racemic key intermediate, diol 174, could be accessed relatively easily and resolution of this would enable the provision of FK-788 in enantiomerically pure form [166]. Astellas’ that a diastereomeric resolution of this would enable the provision of FK-788 in enantiomerically process team initially developed and scaled up a process capable of converting 1-tetralone 168 to pure form [166]. Astellas’ process team initially developed and scaled up a process capable of 2-tetralone 169. converting 1-tetralone 168 to 2-tetralone 169. Accordingly, 168 was protected, reduced and dehydrated to furnish intermediate 153 (Scheme 47). Accordingly, 168 was protected, reduced and dehydrated to furnish intermediate 153 (Scheme Epoxidation of this to 170 followed by TsOH-catalyzed Meinwald rearrangement gave 2-tetralone 47). Epoxidation of this to 170 followed by TsOH-catalyzed Meinwald rearrangement gave 171. It must be noted that the latter transformation was attempted by hydroxide-ring opening of the 2-tetralone 171. It must be noted that the latter transformation was attempted by hydroxide-ring epoxide 170 to diol 171 followed by dehydration of the benzylic alcohol towards the enol tautomer of opening of the epoxide 170 to diol 171 followed by dehydration of the benzylic alcohol towards the 172 (Scheme 47). The yield of 171 by this sequence however did not exceed 48% even after stringent enol tautomer of 172 (Scheme 47). The yield of 171 by this sequence however did not exceed 48% optimization. In contrast screening of several acids for the Meinwald rearrangement produced several even after stringent optimization. In contrast screening of several acids for the Meinwald good yielding hits with TsOH being the best (73%). Interestingly, the Corey Chaykovsky epoxidation rearrangement produced several good yielding hits with TsOH being the− best (73%). Interestingly, of 171 with trimethyl sulfonium iodide did not work, but did so, with the sulfoxonium analog which the Corey−Chaykovsky epoxidation of 171 with trimethyl sulfonium iodide did not work, but did so, provided epoxide 173 in 74% yield. Acid-catalyzed ring opening of epoxide 173 in aqueous THF with the sulfoxonium analog which provided epoxide 173 in 74% yield. Acid-catalyzed ring opening furnished racemic diol 174. This ring opening was also attempted under alkaline conditions which of epoxide 173 in aqueous THF furnished racemic diol 174. This ring opening was also attempted under alkaline conditions which needed to be harsh and gave 174 in reduced yield (58%). Again, among several acids TsOH proved the best in catalyzing the ring opening of 173 to 174. Several chiral acids were screened for the derivatization of 174 into diastereomeric esters yet only (-)-camphanate esters 175 proved crystalline. Double recrystallization of diastereomeric esters 175 from ethanol provided enantiopure camphanate ester 176 in 34% yield and in >99% ee. Hydrolysis of the chiral auxiliary (and recycling thereof) generated the key intermediate, chiral diol 176 which was converted to FK-788 using established conditions (Scheme 47). It is worth noting that the Astellas team managed to develop an impressive telescoped process for converting 168 to 174, spanning 7 chemical steps which was run at 25 kg scale producing 11 kg (25%) of 174 as the only isolable intermediate in the entire sequence. The resolution and subsequent steps towards FK-788 were performed successfully at 10–15 kg scale.

Catalysts 2020, 10, 1117 39 of 65 needed to be harsh and gave 174 in reduced yield (58%). Again, among several acids TsOH proved the best in catalyzing the ring opening of 173 to 174. Several chiral acids were screened for the derivatization of 174 into diastereomeric esters yet only (-)-camphanate esters 175 proved crystalline. Double recrystallization of diastereomeric esters 175 from ethanol provided enantiopure camphanate ester 176 in 34% yield and in >99% ee. Hydrolysis of the chiral auxiliary (and recycling thereof) generated the key intermediate, chiral diol 176 which was converted to FK-788 using established conditions (Scheme 47). It is worth noting that the Astellas team managed to develop an impressive telescoped process for converting 168 to 174, spanning 7 chemical steps which was run at 25 kg scale producing 11 kg (25%) of 174 as the only isolable intermediate in the entire sequence. The resolution andCatalysts subsequent 2020, 10, x FOR steps PEER towards REVIEW FK-788 were performed successfully at 10–15 kg scale. 41 of 69

Scheme 47. Astellas’ process route to FK-788 via resolution of diol 174. Scheme 47. Astellas’ process route to FK-788 via resolution of diol 174. Obviously, the maximum achievable yield for standard resolution processes cannot exceed 50% unlessObviously, the undesired the maximum isomer could achievable be somehow yield for transformed standard resolution in the desire processes one. cannot The Astellas exceed team 50% decidedunless the to undesired explore this isomer scenario could by be isolating somehow the transformed remaining 175 in thepresent desire in one. the liquorsThe Astellas of 176 teamand recovereddecided to 52%explore of this this that scenario was foundby isolating to be enrichedthe remaining in the 175 unwanted present diastereomerin the liquors inof dr176 31:69. and Hydrolysisrecovered 52% of this of gavethis 178that inwas er 31:69found (Scheme to be enriched 48, only majorin the isomer unwanted is shown). diastereomer Two strategies in dr 31:69. were investigatedHydrolysis of in this recycling gave 178 the inS -enantiomerer 31:69 (Scheme of the 48, diol only into major the desiredisomer Ris. shown). Two strategies were investigatedThe first in (Scheme recycling 48 theupper) S-enantiomer involved periodate of the diol cleavage into the ofdesired the diol R. back into the 2-tetralone 155 which was subjected to the same Corey Chaykovsky epoxidation and acid catalyzed ring opening O OH O − of 173 to furnish the same racemic diol 174Meas3SOI in the mainstream synthesis.MsOH(cat) The overall yield forOH this three-stepNaIO4 sequence was 49%, namely 25%t-BuOK from the recovered esters, whichDME (aq) meant that applying the TBAHS THF OBn 49% same resolution with camphanicOBn acid (34%) would give an additional 8.5% of the desired R-diol 177. over 3 steps OBn AlternativelyPhMe/H2O (Scheme 48 lower)171 mesylation of the primary alcohol173 in 178 followed by based-induced174rac

OH OH

178 R:S = 31:69 OBn

MsCl NMM OH O OH THF OMs KOtBu MsOH(cat) OH DME DME (aq) 66% OBn OBn OBn over 3 steps 179 180 177 R:S = 67:33

Scheme 48. Recycling of unwanted diol enantiomer 178 into scalemic diol 177.

Catalysts 2020, 10, x FOR PEER REVIEW 41 of 69

Scheme 47. Astellas’ process route to FK-788 via resolution of diol 174. Catalysts 2020, 10, 1117 40 of 65 Obviously, the maximum achievable yield for standard resolution processes cannot exceed 50% unless the undesired isomer could be somehow transformed in the desire one. The Astellas team decidedring closure to explore of 179 to this epoxide scenario180 and by acid-catalyzedisolating the remaining ring opening 175 gave present diol 177in theenriched liquors in of the 176 desired and Rrecovered-enantiomer 52% (er of 2:1)this in that 66% was yield found (33% to from be theenriched recovered in the esters). unwanted Resolution diastereomer of the scalemic in dr 31:69. diol Hydrolysismixture via of the this camphanate gave 178 inesters er 31:69 furnished (Scheme the 48, enantiopureonly major is diolomer177 is shown).in 11.2% Two from strategies the recycling were processinvestigated thus in 44%recycling overall. the S-enantiomer of the diol into the desired R.

O OH O Me3SOI MsOH(cat) OH

NaIO4 t-BuOK DME (aq) TBAHS THF OBn 49% OBn over 3 steps OBn PhMe/H2O 171 173 174rac

OH OH

178 R:S = 31:69 OBn

MsCl NMM OH O OH THF OMs KOtBu MsOH(cat) OH DME DME (aq) 66% OBn OBn OBn over 3 steps 179 180 177 R:S = 67:33 Scheme 48. Recycling of unwanted diol enantiomer 178 into scalemic diol 177. Scheme 48. Recycling of unwanted diol enantiomer 178 into scalemic diol 177. It is worth noticing that the acid-catalyzed ring opening of 180 to 177 (Scheme 48 lower) proceeds with water attack on tertiary carbon on which more positive charge is built when the epoxide oxygen is protonated and the tertiary C–O bond is weekend thus facilitating the ring opening with inversion of configuration at that stereogenic center. This stereochemical/ mechanistic information is lost in the reaction with the racemic counterpart (172 to 174 in Schemes 47 and 48 upper) since the racemic epoxide gives racemic diol irrespective of which epoxide end is attacked.

1.15. A Lead Candidate for Asthma—Improved Synthesis via a Decarboxylative Rearrangement of an α-Carboxyl Epoxide Asthma is a lifelong respiratory disease which is characterized by a huge variety of symptoms, especially concerning the lungs. As there is no treatment for asthma, it is a great challenge for the pharmaceutical companies to find APIs capable of lifelong management of the disease. One of Novartis’ recent entries in this area was the lead compound 181, a triaryl thiazole [167]. The original medicinal chemistry route followed the retrosynthetic analysis shown in Scheme 49 where the imidazole ring was introduced last by SNAr on thiazole intermediate 182 which in turn was constructed after α-bromination of the ketone 183 and condensation with N-acetyl thiourea. Ketone 183 was synthesized from nitroethane condensation on aldehyde 184 followed by reduction of the nitro group. In addition to chromatographic purifications and low yields, these steps were hampered by serious process safety concerns that ultimately rendered this reaction sequence unsuitable for large-scale preparations of 181. The process group at Novartis decided to develop a synthesis that would involve the same starting materials (registered and raw) and the same end game transformations. This shifted the focus on an alternative synthesis of 183 from 184 that would not succumb to safety and purification issues. Reaction of aldehyde 184 with sodium thiomethoxide generated substituted aldehyde 185 which was subjected to a Darzens condensation with α-chloro methyl propionate to generate initially epoxide 186 (Scheme 50). Hydrolysis of the ester followed by heating in acidic conditions drove the decarboxylative rearrangement to ketone 187 presumably via transition state 188. Oxidation of the thiomethyl substituent to the corresponding sulfone was achieved by tungstate catalysis as reported Catalysts 2020, 10, x FOR PEER REVIEW 42 of 69

The first (Scheme 48 upper) involved periodate cleavage of the diol back into the 2-tetralone 155 which was subjected to the same Corey−Chaykovsky epoxidation and acid catalyzed ring opening of 173 to furnish the same racemic diol 174 as in the mainstream synthesis. The overall yield for this three-step sequence was 49%, namely 25% from the recovered esters, which meant that applying the same resolution with camphanic acid (34%) would give an additional 8.5% of the desired R-diol 177. Alternatively (Scheme 48 lower) mesylation of the primary alcohol in 178 followed by based-induced ring closure of 179 to epoxide 180 and acid-catalyzed ring opening gave diol 177 enriched in the desired R-enantiomer (er 2:1) in 66% yield (33% from the recovered esters). Resolution of the scalemic diol mixture via the camphanate esters furnished the enantiopure diol 177 in 11.2% from the recycling process thus in 44% overall. It is worth noticing that the acid-catalyzed ring opening of 180 to 177 (Scheme 48 lower) proceeds with water attack on tertiary carbon on which more positive charge is built when the epoxide oxygen is protonated and the tertiary C–O bond is weekend thus facilitating the ring opening with inversion of configuration at that stereogenic center. This stereochemical/ mechanistic information is lost in the reaction with the racemic counterpart (172 to 174 in Schemes 47 and 48 upper) since the racemic epoxide gives racemic diol irrespective of which epoxide end is attacked.

1.15. A Lead Candidate for Asthma—Improved Synthesis via a Decarboxylative Rearrangement of an α-carboxyl Epoxide Asthma is a lifelong respiratory disease which is characterized by a huge variety of symptoms, especially concerning the lungs. As there is no treatment for asthma, it is a great challenge for the pharmaceutical companies to find APIs capable of lifelong management of the disease. One of Novartis’ recent entries in this area was the lead compound 181, a triaryl thiazole [167]. The original medicinal chemistry route followed the retrosynthetic analysis shown in Scheme 49 where the imidazole ring was introduced last by SNAr on thiazole intermediate 182 which in turn Catalystswas constructed2020, 10, 1117 after α-bromination of the ketone 183 and condensation with N-acetyl thiourea.41 of 65 Ketone 183 was synthesized from nitroethane condensation on aldehyde 184 followed by reduction of the nitro group. In addition to chromatographic purifications and low yields, these steps were 184 183 hamperedby Noyori [by168 serious]. Impressively, process thesafety conversion concerns of that ultimatelyto was rendered developed this as telescopedreaction sequence process 183 unsuitableencompassing for large-scale five chemical preparations steps performed of 181. on 100 g scale delivering 73% of 99.5% pure.

Catalysts 2020, 10, x FOR PEER REVIEW 43 of 69

telescopedScheme process 49. RetrosynthesisRetrosynthesis encompassing of clinical five chemical candidate steps 181 intoperformed pivotal ketoneon 100 183 g scale and itsdelivering precursor 73%184. of 183 99.5% pure. The process group at Novartis decided to develop a synthesis that would involve the same starting materials (registered and raw) and the same end game transformations. This shifted the focus on an alternative synthesis of 183 from 184 that would not succumb to safety and purification issues. Reaction of aldehyde 184 with sodium thiomethoxide generated substituted aldehyde 185 which was subjected to a Darzens condensation with α-chloro methyl propionate to generate initially epoxide 186 (Scheme 50). Hydrolysis of the ester followed by heating in acidic conditions drove the decarboxylative rearrangement to ketone 187 presumably via transition state 188. Oxidation of the thiomethyl substituent to the corresponding sulfone was achieved by tungstate catalysis as reported by Noyori [168]. Impressively, the conversion of 184 to 183 was developed as

Scheme 50. Large-scale synthesis of clinical candidate 181 via a decarboxylative Darzens reaction. Scheme 50. Large-scale synthesis of clinical candidate 181 via a decarboxylative Darzens reaction. It is worth pointing out that this two-step construction of the sulfone was much more efficient and It is worth pointing out that this two-step construction of the sulfone was much more efficient cost-effective than introducing it in one step by means of SNAr on 185 with sodium methanesulfinate. Furthermore,and cost-effective the Noyori than oxidationintroducing could it bein performedone step onby aldehydemeans of185 S,N butAr foron reasons185 with yet sodium unclear themethanesulfinate. corresponding Furthermore, 3-fluoro-4-methylsulfone the Noyori benzaldehydeoxidation could failed be performed to give the on Darzens aldehyde reaction. 185, but for reasonsDevelopment yet unclear and the ofcorresponding the α-chlorination 3-fluoro-4-m of ketoneethylsulfone183 proved benzaldehyde a much better failed choice to give than the its brominationDarzens reaction. due to significant side product formation with the latter. Formation of chloroketone 189 wasDevelopment telescoped and in the of thiazolethe α-chlorination forming step of (Scheme ketone 18350) whereproved some a much degree better of N-deacetylation choice than its provedbromination unavoidable due to significant hence the treatmentside product with format aceticion anhydride with the latter. after the Formation installation of chloroketone of the imidazole 189 substituentwas telescoped in the in last the step. thiazole forming step (Scheme 50) where some degree of N-deacetylation provedOverall, unavoidable an innovative hence the solution treatment to with the safety,acetic anhydride efficiency after and the purity installation issues in of accessingthe imidazole key intermediatesubstituent in183 the waslast step. developed by a decarboxylative rearrangement of an epoxide generated by a DarzensOverall, reaction. an innovative This further solution demonstrates to the thesafety, versatility efficiency and richand chemistrypurity issues of epoxides in accessing in robust, key large-scaleintermediate synthesis 183 was of developed pharmaceuticals. by a decarboxylative rearrangement of an epoxide generated by a Darzens reaction. This further demonstrates the versatility and rich chemistry of epoxides in robust, large-scale synthesis of pharmaceuticals.

1.16. Δ-9-Tetrahydrocannabinol—From 3-carene to 2-carene Oxide and Δ-9-THC in Large Scale (-)-trans-Δ-9-tetrahydrocannabinol (Δ-9-THC) is the primary psychoactive compound among the 113 cannabinoids found in the female marijuana plant and is a partial agonist of the CB1 receptor. In its medicinal form is known as dronabinol and is FDA approved under the trade names of Marinol (gelatin capsules) and Syndros (oral solution) for the treatment of HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting. Its 1:1 mixture with cannabidiol, known as nabiximols (trade name Sativex), is approved in Europe for treating spasticity associated with multiple sclerosis [169]. United States federal law currently registers dronabinol as a Schedule III controlled substance, but all other cannabinoids remain Schedule I under the Single Convention on Narcotic Drugs., except synthetics like nabilone. Current research is focusing on expanding the medicinal applications of (-)-trans-Δ-9-THC and synthetic analogs to treating body weight

Catalysts 2020, 10, 1117 42 of 65

1.16. ∆-9-Tetrahydrocannabinol—From 3-Carene to 2-Carene Oxide and ∆-9-THC in Large Scale (-)-trans-∆-9-tetrahydrocannabinol (∆-9-THC) is the primary psychoactive compound among the 113 cannabinoids found in the female marijuana plant and is a partial agonist of the CB1 receptor. In its medicinal form is known as dronabinol and is FDA approved under the trade names of Marinol (gelatin capsules) and Syndros (oral solution) for the treatment of HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting. Its 1:1 mixture with cannabidiol, known as nabiximols (trade name Sativex), is approved in Europe for treating spasticity associated with multiple sclerosis [169]. United States federal law currently registers dronabinol as a Schedule III controlled substance, but all other cannabinoids remain Schedule I under the Single Convention on Narcotic CatalystsDrugs., 2020 except, 10, x syntheticsFOR PEER REVIEW like nabilone. Current research is focusing on expanding the medicinal44 of 69 applications of (-)-trans-∆-9-THC and synthetic analogs to treating body weight disorders, neuropathic disorders, neuropathic and cancer associated pain, but negating potential psychotropic and and cancer associated pain, but negating potential psychotropic and tolerance effects [170–172]. tolerance effects [170–172]. Current and projected requirements for (-)-trans-∆-9-THC warrant a robust scalable process for its Current and projected requirements for (-)-trans-Δ-9-THC warrant a robust scalable process for production which is primarily based on the Friedel–Crafts alkylation/cyclisation between olivetol and its production which is primarily based on the Friedel–Crafts alkylation/cyclisation between olivetol p-menth-2-ene-1,8-diol which in turn is accessed from 2-carene oxide (Scheme 51)[173–175]. and p-menth-2-ene-1,8-diol which in turn is accessed from 2-carene oxide (Scheme 51) [173–175].

Scheme 51. Synthesis of ∆-9-THC from p-menth-2-ene-1,8-diol and its retrosynthesis to 2-carene. Scheme 51. Synthesis of Δ-9-THC from p-menth-2-ene-1,8-diol and its retrosynthesis to 2-carene. As this process evolved over the years there have been two lingering issues that undermined its efficacyAs this and process cost-eff ectiveness.evolved over The the first years is associated there have with been the two starting lingering material issues 2-carene that undermined (Scheme 51its) whichefficacy is and relatively cost-effectiveness. expensive. The The first second is associat issueed is with related the withstarting the material isolation 2-carene and purification (Scheme 51) of whichp-menth-2-ene-1,8-diol is relatively expensive. from the otherThe second terpenoid issue products is related of the with process the often isolation requiring and chromatography purification of p-andmenth-2-ene-1,8-diol/or extensive extractions from and the evaporation other terpenoi of its solutionsd products to dryness. of the process often requiring chromatographyProcess chemists and/or from extensive Cedarburg extractions Pharmaceuticals and evaporation (legacy company of its solutions of Albany to dryness. Molecular Research, Inc., AMRI)Process focused chemists on solvingfrom Cedarburg these issues Pharmaceuticals by assessing other (legacy starting company materials andof Albany ways to Molecular crystallize Research,p-menth-2-ene-1,8-diol Inc., AMRI) focused directly on as solving it was produced these issues [176 by]. Inassessing contrast other to 2-carene, starting 3-carene materials is and relatively ways tocheap crystallize and available p-menth-2-ene-1,8-diol in bulk. 3-Carene directly is equilibrated as it was to produced 2-carene when[176]. heatedIn contrast with baseto 2-carene, at high 3-carenetemperature is relatively resulting cheap in approximately and available a 60 in/40 bulk. mixture 3-Carene of the 3is/ 2-careneequilibrated isomers to 2-carene (Scheme when52). This heated was withconducted base at at high 85 kg temperature scale and theresulting mixture in ofapproximately isomers after a separation 60/40 mixture from of the the aqueous 3/2-carene phase isomers was (Schemedistilled thus52). This providing was conducted quick access at 85 to kg technical scale and grade the mixture 2-carene. of Followingisomers af ater screening separation of from reagents the aqueousfor the epoxidation phase was ofdistilled the 3/ 2-carenethus providing isomers, quick peracetic access acid to technical emerged grade as the 2-carene. optimum Following oxidant for a screeningthis transformation. of reagents Thefor the epoxidation epoxidation reaction of the was3/2-carene carried isomers, out in 60 peracetic kg scale acid and emerged after work as the up, optimumthe solution oxidant of the for carene this oxides transformation. was subjected The directlyepoxidation to acid-catalyzed reaction was ring carried opening. out in Under 60 kg mildly scale and after work up, the solution of the carene oxides was subjected directly to acid-catalyzed ring opening. Under mildly acidic conditions only 2-carene oxide ring opens via participation of the cyclopropane ring which also ring opens itself to support the built up of positive charge at the adjacent carbon of the protonated epoxide (Scheme 52). This neighboring group assistance by the cyclopropane moiety cannot take place with the remotely positioned epoxide in 3-carene oxide which survives intact under these conditions. Screening of antisolvents at this stage of the process identified heptane as the optimum choice enabling crystallization of p-menth-2-ene-1,8-diol directly from the reaction mixture while retaining the more soluble 3/2-carene oxides.

Catalysts 2020, 10, 1117 43 of 65 acidic conditions only 2-carene oxide ring opens via participation of the cyclopropane ring which also ring opens itself to support the built up of positive charge at the adjacent carbon of the protonated epoxide (Scheme 52). This neighboring group assistance by the cyclopropane moiety cannot take place with the remotely positioned epoxide in 3-carene oxide which survives intact under these conditions. Screening of antisolvents at this stage of the process identified heptane as the optimum choice enabling crystallization of p-menth-2-ene-1,8-diol directly from the reaction mixture while retaining the more Catalystssoluble 2020 3/2-carene, 10, x FOR oxides. PEER REVIEW 45 of 69

Scheme 52. Process route to p-menth-2-ene-1,8-diol from 2-carene via epoxidation/rearrangement. Scheme 52. Process route to p-menth-2-ene-1,8-diol from 2-carene via epoxidation/rearrangement. In this way a much-improved process for the large-scale synthesis of p-menth-2-ene-1,8-diol, a key In this way a much-improved process for the large-scale synthesis of p-menth-2-ene-1,8-diol, a intermediate in the synthesis of ∆-9-THC, was accomplished based on manipulation of inexpensive key intermediate in the synthesis of Δ-9-THC, was accomplished based on manipulation of feedstock and a selective epoxide rearrangement. inexpensive feedstock and a selective epoxide rearrangement. 1.17. Oseltamivir—Development of Three Manufacturing Routes via the Same Key Epoxide Intermediate 1.17. Oseltamivir —Development of Three Manufacturing Routes via the Same Key Epoxide Intermediate Oseltamivir phosphate (trade name Tamiflu) is an antiviral drug indicated for the treatment of influenzaOseltamivir A and phosphate influenza B.(trade It was name discovered Tamiflu) at is Gileadan antiviral Sciences, drug but indicated was licensed for the totreatment Roche for of influenzaclinical development, A and influenza approval B. It and was marketing. discovered GlaxoSmithKline’s at Gilead Sciences, zanamivir but was (Relenza)licensed to (discovered Roche for clinicalby the Australian development, company approval Biota) and was marketing. the first neuraminidaseGlaxoSmithKline’s inhibitor zanamivir to be FDA(Relenza) approved (discovered (1999), byfollowed the Australian by oseltamivir company later Biota) in the was same the year. first Oseltamivir neuraminidase however inhibitor was theto be first FDA orally approved active product (1999), (zanamivirfollowed by is oseltamivir inhaled) hence later itin became the same more year. popular. Oseltamivir Over however the years, was in additionthe first toorally the Rocheactive processes,product (zanamivir there have is been inhaled) dozens hence of oseltamivir it became syntheses more popular. published Over by the prominent years, in academic addition research to the Rochegroups processes, [177] that there have expandedhave been thedozens synthetic of osel creativitytamivir syntheses in organic published chemistry by and prominent continue academic to inspire researchthe next generationgroups [177] of that chemists. have expanded Nevertheless, the synt a comparisonhetic creativity of all in major organic syntheses chemistry published and continue up to to2008 inspire demonstrated the next that generation the Roche of routes chemists. are superior Nevertheless, with respect a comparison to length, complexityof all major and syntheses across a publishednumber of up green to chemistry2008 demonstrated and efficiency that parametersthe Roche [routes178]; the are most superior efficient with academic respect routeto length, up to complexitythat point was and the across latest froma number the Fang of green group chemis [179]. try and efficiency parameters [178]; the most efficientA number academic of route other up routes to that have point been was published the latest from since the then Fang [180 group–187] [179]. yet the Roche shikimic acid-basedA number manufacturing of other routes process have remains been thepublishe most viabled since and then proficient [180–187] to date.yet the Roche shikimic acid-based manufacturing process remains the most viable and proficient to date. Consequently, the following discussion concentrates on the Roche manufacturing route to the key epoxide intermediate 190 (Scheme 53) and the subsequent ring-opening step by amine nucleophiles.

Catalysts 2020, 10, 1117 44 of 65

Consequently, the following discussion concentrates on the Roche manufacturing route to the key epoxideCatalysts 2020 intermediate, 10, x FOR PEER190 REVIEW(Scheme 53) and the subsequent ring-opening step by amine nucleophiles.46 of 69

Scheme 53. Retrosynthesis of oseltamivir into quinic and shikimic acid. Scheme 53. Retrosynthesis of oseltamivir into quinic and shikimic acid. Both quinic and shikimic acid provide an appropriately functionalized carbocyclic framework and Both quinic and shikimic acid provide an appropriately functionalized carbocyclic framework were used to deliver oseltamivir on 100 kg scale. Quinic acid however requires an additional series of and were used to deliver oseltamivir on 100 kg scale. Quinic acid however requires an additional dehydration steps to generate the double bond which is already present in the shikimic acid. Despite series of dehydration steps to generate the double bond which is already present in the shikimic intense optimization efforts, the dehydration-associated steps have not been particularly straight acid. Despite intense optimization efforts, the dehydration-associated steps have not been forward or high yielding hence shikimic acid emerged as the ideal starting material [188]. Gilead’s particularly straight forward or high yielding hence shikimic acid emerged as the ideal starting original preference for the quinic acid route [189] was based on the limited supply of shikimic acid at material [188]. Gilead’s original preference for the quinic acid route [189] was based on the limited that time. During Roche’s development efforts shikimic acid became available in multi-hundred-ton supply of shikimic acid at that time. During Roche’s development efforts shikimic acid became quantities by extraction of star anis and by a fermentation process using a genetically engineered E. coli available in multi-hundred-ton quantities by extraction of star anis and by a fermentation process strain [190]. using a genetically engineered E. coli strain [190]. Shikimic acid esterification, acetonide protection and mesylation were telescoped to provide mesylate 191 in 82% yield after recrystallization (Scheme 54). Acid catalyzed transketalization with excess 3-pentanone gave new mesylate 192 almost quantitatively. The regioselective reductive ring opening of the ketal required extensive optimization since the original Gilead conditions involving BH Me S and TMSOTf (trimethylsilyl trifluoromethanesulfonate) were not attractive 3· 2 for manufacturing (safety, cost and availability). A thorough screening was undertaken to identify suitable Lewis acids to facilitate the ring opening of the acetal to the corresponding oxenium cation and compatible reducing agents to reduce the latter to the desired hydroxy ether 193. The combination of TES (triethyl silane) and TiCl4 proved a viable option as it worked well provided the reaction temperature was kept between 32 to 36 C (no reaction at lower temperatures and significant − − ◦ deprotection to the diol at higher temperatures). After work up of this stage the solution of 193 was treated directly with base which induced the ring closure of the hydroxy mesylate to the desired epoxide 190 in 80% for the latter two steps and 64% overall from shikimic acid. The direct ketal formation of shikimic acid ethyl ester with 2-pentanone would save one step from the synthesis (the transketalization of the acetonide intermediate) and naturally this was also investigated. In contrast to the hydroxy- and mesyl-acetonide intermediates which are crystalline and allow for upgrade of their purity by recrystallization, the pentylideneketal analog derivatives are oils and had to be progressed impure downstream with significant yield penalty in downstream purification. Nevertheless, an improvement of the direct pentylideneketal process was reported by Roche that enables pure 194 to be generated and progressed without isolation in the formation of 192 [191]. Interestingly the strategy to pursue the installation of the 2-pentyl ether in 190 via the reductive ring opening of the pentylideneketal ketal 192 was enforced by the failure of the corresponding epoxy alcohol 195 to undergo alkylation with 2-pentyl iodide. All attempts led to aromatized products presumably via base-induced epoxide isomerization/ring opening to the corresponding allylic alcohol followed by dehydration. This undesired aromatization process was frequently encountered in subsequent reactions of 190 with various amines/nitrogenous nucleophiles and posed a significant issue in the progression ofthe synthesis via the ring opening of the epoxide. Scheme 54. Process development of an efficient route to key epoxide intermediate 190.

Shikimic acid esterification, acetonide protection and mesylation were telescoped to provide mesylate 191 in 82% yield after recrystallization (Scheme 54). Acid catalyzed transketalization with excess 3-pentanone gave new mesylate 192 almost quantitatively. The regioselective reductive ring opening of the ketal required extensive optimization since the original Gilead conditions involving BH3·Me2S and TMSOTf (trimethylsilyl trifluoromethanesulfonate) were not attractive for

Catalysts 2020, 10, x FOR PEER REVIEW 46 of 69

Scheme 53. Retrosynthesis of oseltamivir into quinic and shikimic acid.

Both quinic and shikimic acid provide an appropriately functionalized carbocyclic framework and were used to deliver oseltamivir on 100 kg scale. Quinic acid however requires an additional series of dehydration steps to generate the double bond which is already present in the shikimic acid. Despite intense optimization efforts, the dehydration-associated steps have not been particularly straight forward or high yielding hence shikimic acid emerged as the ideal starting material [188]. Gilead’s original preference for the quinic acid route [189] was based on the limited supply of shikimic acid at that time. During Roche’s development efforts shikimic acid became Catalystsavailable2020 in, 10 multi-hundred-ton, 1117 quantities by extraction of star anis and by a fermentation process45 of 65 using a genetically engineered E. coli strain [190].

Scheme 54. Process development of an efficient route to key epoxide intermediate 190. Scheme 54. Process development of an efficient route to key epoxide intermediate 190. In the original Gilead synthesis this was achieved with sodium azide producing a 9:1 mixture of the correspondingShikimic acid azidoesterification, alcohols acetonide195a/b although protecti thison selectivityand mesylation is inconsequential were telescoped as both to isomers,provide mesylateupon treatment 191 inwith 82% trimethylyield after phosphine, recrystallization convert (Scheme to the same 54). aziridine Acid catalyzed197 (Scheme transketalization 55). Aziridine with ring excessopening 3-pentanone again with azidegave attack,new mesylate followed 192 by almost acetylation, quantitatively. azide reduction The re withgioselective Raney Ni reductive and addition ring openingof phosphoric of the acid, ketal gave required oseltamivir. extensive This optimization part of the process since deliveredthe original successfully Gilead conditions multiple kilogramsinvolving BHof the3·Me drug2S and substance, TMSOTf but the(trimethylsilyl azide chemistry trifluoromet raised concernshanesulfonate) for long term were manufacturing. not attractive Pressed for by competition from GlaxoSmithKline who at that time were slightly ahead with the development of zanamivir, a decision was made to render the azide route fit for manufacturing and registration rather than initiate the development of an azide-free route as this could take much longer and would be probably best to investigate it later. Working together with process safety and azide chemistry experts the Roche team quickly determined operating windows that ensured safety and precluded decomposition of the azide intermediates and consequently yield losses. This, combined with other improvements in this latter part of the synthesis, precipitated the manufacturing route to oseltamivir (Scheme 55)[192]. In particular, the ring opening of the epoxide 190 to 196a/b required excess azide to drive the reaction to completion and avoid aromatization of the substrate; for safety reasons this was conducted at less than 70 ◦C. The hazardous trimethyl phosphine was replaced with the less reactive yet safer triphenyl analog which assisted by MsOH facilitated the Staudinger reduction of the azide and subsequent formation of aziridine 197; for safety reasons this was conducted at less than 50 ◦C. Aziridine formation was coupled with aziridine ring opening by azide to generate 198 followed by acetylation of the amine. For safety reasons these steps were conducted at less than 50, 35 and 25 ◦C, respectively. Thus, acetamido azide 199 was isolated directly after a three-stage telescoped process in DMSO in 70% yield from 196a/b (Scheme 55). The reduction of azide by hydrogenation and hydride Catalysts 2020, 10, 1117 46 of 65 methods was found to generate several impurities related to double bond reduction and isomerization. Raney Ni was replaced with tributyl phosphine for an extremely selective Staudinger reduction/reaction which was coupled to the final salt forming step with phosphoric acid. This provided oseltamivir in 55%Catalysts yield 2020 from, 10, x epoxideFOR PEER190 REVIEWwhich translates to 35% overall yield from shikimic acid. 48 of 69

CO2Et

O N3 OH Et Et CO2Et CO2Et 196a 9 NaN ,NH Cl Ph P, MsOH 3 4 : 3 EtOH, H O Et N, DMSO O 2 1 196b 3 O O 86% 50 oC, 1h NH Et Et Et Et CO2Et 190 197

O OH N Et Et 3 55% from 190 NaN3,DMSO o 35% from shikimic acid H2SO4,35 C, 4h

CO2Et CO2Et CO2Et . 1. EtOH, H2O H3PO4 o Bu3P, 5-20 C Ac2O AcOH(cat) O N3 70% O N3 O NH2 2. H PO 3 4 NHAc NH2 NHAc o Et Et Et Et Et Et EtOH, 50 C 90% oseltamivir 199 198 Scheme 55. Roche’s manufacturing route to oseltamivir. Scheme 55. Roche’s manufacturing route to oseltamivir. Roche followed this with two azide-free processes (Scheme 56). In the first one, a wide screen of appropriateIn particular, amines the/latent ring ammonia opening of nucleophiles the epoxide and 190 Lewis to 196a/b acids required were screened excess in azide order to to drive identify the conditionsreaction to thatcompletion led to e ffiandcient avoid epoxide aromatization ring opening of the with substrate; minimum for aromatization safety reasons of 190this [193was]. Fromconducted this, allylamineat less than in 70 the °C. presence The hazardous of magnesium trimethy bromidel phosphine etherate was replaced was demonstrated with the less to providereactive theyet safer amino triphenyl alcohol 200analogin 97%which yield assisted (dr 9:1) by withMsOH only facilitated traces aromatization the Staudinger products reduction being of the formed. azide Pd-catalyzedand subsequent de-allylation, formation followedof aziridine by 197 protection; for safety of the reasons amine this as its was benzaldehyde conducted at imine less allowedthan 50 °C. for cleanAziridine formation formation of mesylate was coupled201. Further with aziridine treatment ring with opening allylamine by azide causes to generate a transimination 198 followed reaction by toacetylation occur, freeing of the upamine. the For amino safety group reasons next these to the steps mesylate. were conducted The thus at produced less than amino50, 35 and mesylate, 25 °C, cyclizesrespectively. to the Thus, corresponding acetamido aziridine azide 199 which was isisolated further directly attacked, after and a ringthree-stage opened telescoped by allylamine process with inversionin DMSO ofin configuration. 70% yield from Careful 196a/b adjustment (Scheme of55). the The apparent reduction pH allowsof azide for by selective hydrogenation acetylation and of thehydride primary methods amino was group found while to thegenerate secondary several is deactivatedimpurities related in its protonated to double form bond to reduction give the trans and vicinalisomerization. diamine Raney intermediate Ni was replaced202. Despite with thetributyl complexity phosphine of this for domino an extremely process selective involving Staudinger several equilibria,reduction/reaction ring closing which and was opening coupled events, to the202 finalis the salt only forming intermediate step with isolated phosphoric in relatively acid. goodThis yield.provided Pd-catalyzed oseltamivir de-allylation in 55% yield followed from epoxide by phosphate 190 which saltformation translates atofforded 35% overall oseltamivir yield in from 35% yieldshikimic from acid.190 (23% from shikimic acid). BasedRoche primarilyfollowed this on the with discovery two azide-free of the e processesfficient Mg(II) (Scheme promoted 56). In ring the openingfirst one, of a wide190 by screen amines, of aappropriate second generation amines/latent route was ammonia developed nucleophiles [194]. In this,and allylamineLewis acids was were replaced screened with in torder-butylamine to identify and conditions that led to efficient epoxide ring opening with minimum aromatization of 190 [193]. From the magnesium bromide etherate with the cheaper magnesium chloride. Interestingly the performance ofthis, the allylamine ring opening in the was presence highly dependent of magnesium on the bromide order of additionetherate withwas demonstrated pre-mixing the to amine provide and the amino alcohol 200 in 97% yield (dr 9:1) with only traces aromatization products being formed. catalyst leading to superior yield of 203 whereas premixing the epoxide with magnesium chloride led Pd-catalyzed de-allylation, followed by protection of the amine as its benzaldehyde imine allowed for clean formation of mesylate 201. Further treatment with allylamine causes a transimination reaction to occur, freeing up the amino group next to the mesylate. The thus produced amino mesylate, cyclizes to the corresponding aziridine which is further attacked, and ring opened by allylamine with inversion of configuration. Careful adjustment of the apparent pH allows for selective acetylation of the primary amino group while the secondary is deactivated in its protonated form to give the trans vicinal diamine intermediate 202. Despite the complexity of this domino

Catalysts 2020, 10, 1117 47 of 65 to significant amounts of the corresponding chlorohydrin. The bulky group on nitrogen allowed for Catalysts 2020, 10, x FOR PEER REVIEW 49 of 69 clean activation of the alcohol as the mesylate which eventually cyclized to aziridine 204. Ring opening of the latter with bis-allyl-amine followed by acetylation gave after HCl treatment the hydrochloride process involving several equilibria, ring closing and opening events, 202 is the only intermediate salt 205. Pd-catalyzed de-allylation followed by phosphate salt formation afforded oseltamivir in 58% isolated in relatively good yield. Pd-catalyzed de-allylation followed by phosphate salt formation yield from 190 (37% from shikimic acid) which compares favorably with the azide route. afforded oseltamivir in 35% yield from 190 (23% from shikimic acid).

Scheme 56. Roche’sRoche’s second second generation manufacturing routes to oseltamivir (azide-free).

Overall, under tremendous pressure for an expedited registration, a remarkable joined effort by Based primarily on the discovery of the efficient Mg(II) promoted ring opening of 190 by process groups at Gilead, Roche and external contractors led to the development of a safe azide-based amines, a second generation route was developed [194]. In this, allylamine was replaced with manufacturing process for the complex molecule of oseltamivir. Innovative navigation through epoxide t-butylamine and the magnesium bromide etherate with the cheaper magnesium chloride. and aziridine chemistry led to an azide-free, second generation route that also delivers the drug Interestingly the performance of the ring opening was highly dependent on the order of addition substance at specification and with improved efficiency. with pre-mixing the amine and the catalyst leading to superior yield of 203 whereas premixing the epoxide1.18. Indinavir—A with magnesium Member ofchloride Approved led HIV to Proteasesignific Inhibitorsant amounts Synthesized of the bycorresponding Chiral Epoxide chlorohydrin. Intermediates The bulky group on nitrogen allowed for clean activation of the alcohol as the mesylate which eventuallyHighly cyclized active antiretroviralto aziridine 204 therapy. Ring (HAART) opening of is thethe currentlatter with standard bis-allyl-amine in HIV treatment followed and by acetylationinvolves combination gave after HCl of drugstreatment targeting the hydrochloride different stages salt of205 viral. Pd-catalyzed infection suchde-allylation as entry, followed reverse bytranscription, phosphate integrationsalt formation and afford maturationed oseltamivir/release [195in 58%]. HAART yield from has revolutionized190 (37% from HIVshikimic treatment acid) whichand increased compares considerably favorably with the the life azide expectancy route. to the point that is now considered a manageable chronicOverall, disease. under Key tremendous contribution pressure to the combination for an expedited treatment registration, is provided a remarkable in the form joined of a effort protease by processinhibitor groups which is at represented Gilead, Roche in 10 of and the approximatelyexternal contractors 30 approved led drugsto the for development HIV [196–198 ].of Merck’sa safe azide-basedindinavir (trade manufacturing name Crixivan, process Scheme for 57the) wascomplex the third molecule HIV protease of oseltamivir. inhibitor Innovative to be FDA-approved, navigation throughone year epoxide after Roche’s and saquinaviraziridine chemistry and Abbott’s led (nowto an AbbVie)azide-free, ritonavir; second these generation were followed route that in quick also delivers the drug substance at specification and with improved efficiency.

1.18. Indinavir—A Member of Approved HIV Protease Inhibitors Synthesized by Chiral Epoxide Intermediates

Catalysts 2020, 10, x FOR PEER REVIEW 50 of 69

Highly active antiretroviral therapy (HAART) is the current standard in HIV treatment and involves combination of drugs targeting different stages of viral infection such as entry, reverse transcription, integration and maturation/release [195]. HAART has revolutionized HIV treatment and increased considerably the life expectancy to the point that is now considered a manageable chronic disease. Key contribution to the combination treatment is provided in the form of a protease inhibitor which is represented in 10 of the approximately 30 approved drugs for HIV [196–198]. Merck’s indinavir (trade name Crixivan, Scheme 57) was the third HIV protease inhibitor to be FDA-approved, one year after Roche’s saquinavir and Abbott’s (now AbbVie) ritonavir; these were followed in quick succession by nelfinavir (Eli Lilly/Agouron), amprenavir (GlaxoSmithKline/Vertex) and lopinavir (also by Abbott). Protease inhibitors aim to halt maturation and release of viral particles by inhibiting certain cleaving events performed by the protease on the viral polyprotein, a process that releases mature, essential viral proteins (p7, 9, 17, 24) and active viral enzymes (protease, reverse-transcriptase and Catalystsintegrase2020 among, 10, 1117 others). 48 of 65 HIV protease inhibitors have been designed primarily as transition state inhibitors equipped with a non-hydrolysable peptidomimetic isostere. Arguably, the 1,2-aminoalcohol motif has succession by nelfinavir (Eli Lilly/Agouron), amprenavir (GlaxoSmithKline/Vertex) and lopinavir emerged the most successful consequently epoxide intermediates (Scheme 57) have been recruited (also by Abbott). extensively in the synthesis of this essential domain in HIV protease inhibitors [199].

Scheme 57. HIV protease inhibitors and their retrosynthesis into key epoxide intermediates. Scheme 57. HIV protease inhibitors and their retrosynthesis into key epoxide intermediates. Protease inhibitors aim to halt maturation and release of viral particles by inhibiting certain cleavingIndinavir events is performed synthesized by via the epoxide protease 206 on (Scheme the viral 57) polyprotein, the stereochemistry a processthat of which, releases including mature, essentialthat at the viral amide proteins α-carbon, (p7, are 9, 17, induced 24) and by active the aminoindanol viral enzymes portion (protease, which reverse-transcriptase therefore acts as a chiral and integraseauxiliary amongin their others). generation [200]. Cis-aminoindanol (1S,2R)-AI and its enantiomer are key componentsHIV protease in several inhibitors drug havemolecules, been designed chiral auxi primarilyliaries and as transitioncatalysts and state are inhibitors conveniently equipped accessed with aby non-hydrolysable indene [201]. One peptidomimetic of the earlier large-scale isostere. Arguably, synthesis theof (1 1,2-aminoalcoholS,2R)-AI by Sepracor motif (Scheme has emerged 58, left) the mostinvolved successful the catalytic consequently asymmetric epoxide epoxidation intermediates of indene (Scheme using 57) have(R,R been)-M5 recruitedto give (1 extensivelyS,2S)-indene in theoxide synthesis 207. Ring of opening this essential by ammonia domain infollowed HIV protease by benzamide inhibitors formation [199]. and exposure to strong acid Indinavir is synthesized via epoxide 206 (Scheme 57) the stereochemistry of which, including that at the amide α-carbon, are induced by the aminoindanol portion which therefore acts as a chiral auxiliary in their generation [200]. Cis-aminoindanol (1S,2R)-AI and its enantiomer are key components in several drug molecules, chiral auxiliaries and catalysts and are conveniently accessed by indene [201]. One of the earlier large-scale synthesis of (1S,2R)-AI by Sepracor (Scheme 58, left) involved the catalytic asymmetric epoxidation of indene using (R,R)-M5 to give (1S,2S)-indene oxide 207. Ring opening by ammonia followed by benzamide formation and exposure to strong acid generates oxazoline 206 which is hydrolyzed to (1S,2R)-AI. Both the ring opening, and the cyclisation step occur with inversion of configuration. Merck developed an alternative synthesis (Scheme 58, right) that uses (1R,2R)-indene oxide 209 and proceeds with retention of configuration through oxazoline 210 generated by a Ritter reaction (Scheme 58, right). This transformation probably proceeds through the benzylic cation 211 (formed by protonation of the epoxide or the associated diol) followed by attack of the most competent nucleophile present in the reaction, namely acetonitrile. This can take place at either diastereotopic side of the planar benzylic cation, Catalysts 2020, 10, 1117 49 of 65 but only the cis adduct may cyclize to a bicyclic oxazoline with a cis ring junction. The instability of the nitrilium intermediate 212 renders its formation reversible and given the inability of the trans adduct to cyclize, all reaction is channeled through the cyclisation of the cis adduct. It is worth mentioning that in the Merck epoxidation process, P3NO, 4-(phenylpropyl)pyridine N-oxide (Scheme 58) was found to be a superior external ligand to those employed regularly and at 4 mol%, it supported a robust reaction with reducedCatalysts 2020 catalyst-loading, 10, x FOR PEER (0.7 REVIEW mol% (R,R)-M3, Scheme 58) capable of delivering (1R,2R)-indene oxide51 of209 69 in 90% yield and 88% ee at multikilogram scale. After hydrolysis of oxazoline 210 and recrystallization ofgenerates(1S,2R)-AI oxazolineas its tartrate 206 salt,which the is optical hydrolyzed purity is to upgraded (1S,2R)-AI to >. 99%.Both the ring opening, and the cyclisation step occur with inversion of configuration.

Scheme 58. Syntheses of (1S,2R)-aminoindanol via Jacobsen–Katsuki asymmetric epoxidation. Scheme 58. Syntheses of (1S,2R)-aminoindanol via Jacobsen–Katsuki asymmetric epoxidation. 1.19. Metal-Catalyzed Asymmetric Epoxidations in Drug Development—Further Examples of the Sharpless and Jacobsen–KatsukiMerck developed Methodologies an alternative synthesis (Scheme 58, right) that uses (1R,2R)-indene oxide 209 and proceeds with retention of configuration through oxazoline 210 generated by a Ritter reaction (SchemeThe 58, Sharpless right). This asymmetric transformation epoxidation probably of proceeds allylic alcohols through and the thebenzylic Jacobsen–Katsuki cation 211 (formed salen cis complexes-catalyzedby protonation of the epoxidation epoxide or of the cyclic associated and alkenes diol) followed have dominated by attack the of field the of most metal competent catalyzed asymmetricnucleophile epoxidationspresent in the employed reaction, atnamely various acetonitri developmentle. This stages can take of pharmaceuticals. place at either diastereotopic Examples of theseside of are the highlighted planar benzy below.lic cation, but only the cis adduct may cyclize to a bicyclic oxazoline with a cis ringOno junction. Pharmaceutical The instability developed of the andnitrilium performed intermediate a Sharpless 212 renders asymmetric its formation epoxidation reversible of allylic and alcoholgiven the213 inabilityon 678 of g scalethe trans to access adduct the to key cyclize, chiral all epoxide reaction214 is channeleden route to through the highly the selectivecyclisation EP2 of receptor agonist 215 (Scheme 59)[202]. the cis adduct. It is worth mentioning that in the Merck epoxidation process, P3NO, 4-(phenylpropyl)pyridineEisai used the Sharpless N-oxide method (Scheme to develop 58) was an innovativefound to be approach a superior for external the chiral ligand tertiary-alkyl to those nitrileemployed motif regularly present and in at the 4 mol%, calcium it supported channel a blockers robust reaction enopamil, with norenopamil reduced catalyst-loading and verapamil (0.7 (Schememol% (R ,59R)-M3,)[203 Scheme]. Accordingly, 58) capable asymmetric of delivering epoxidation (1R,2R)-indene of 216 oxideto 217 209followed in 90% yield by protection and 88% ee of theat multikilogram alcohol provided scale. the Afte epoxider hydrolysis substrate of218 oxazolinefor the rearrangement210 and recrystallization to aldehyde of219 (1.S This,2R)-AI involved as its thetartrate MAD-catalyzed salt, the optical migration purity ofis theupgraded isopropyl to >99%. group onto the benzylic carbon atom with concomitant epoxide ring opening and formation of the aldehyde. 1.19. Metal-Catalyzed Asymmetric Epoxidations in Drug Development—Further Examples of the Sharpless and Jacobsen–Katsuki Methodologies The Sharpless asymmetric epoxidation of allylic alcohols and the Jacobsen–Katsuki salen complexes-catalyzed epoxidation of cyclic and cis alkenes have dominated the field of metal catalyzed asymmetric epoxidations employed at various development stages of pharmaceuticals. Examples of these are highlighted below. Ono Pharmaceutical developed and performed a Sharpless asymmetric epoxidation of allylic alcohol 213 on 678 g scale to access the key chiral epoxide 214 en route to the highly selective EP2 receptor agonist 215 (Scheme 59) [202].

Catalysts 2020, 10, 1117 50 of 65 Catalysts 2020, 10, x FOR PEER REVIEW 52 of 69

Scheme 59. Application of Sharpless’ asymmetric epoxid epoxidationation to the synthesis of drug candidates.

GlaxoSmithKline’sEisai used the Sharpless effort method for a to scalable develop synthesis an innovative of GSK966587, approach for an the antimicrobial chiral tertiary-alkyl clinical candidatenitrile motif [204 present], pivoted in the on calcium the asymmetric channel blockers epoxidation enopamil, of allylic norenopamil alcohol 220 andusing verapamil the Sharpless (Scheme method59) [203]. which Accordingly, delivered asymmetric epoxide 221 epoxidationin 81% yield andof 216 90% to ee 217 in 10followed g scale (Schemeby protection 60). Under of the the alcohol basic ring-openingprovided the conditionsepoxide substrate of 221 with 218 amine for the222 ,rearrangement the undesired intramolecularto aldehyde 219. SNAr This reaction involved between the theMAD-catalyzed primary alcohol migration and the of adjacent the isopropyl aryl fluoride group in on theto product the benzylic was observed carbon atom thus anwith alternative concomitant way wasepoxide sought ring to opening install the and amine formation portion. of the The aldehyde. ring opening of 221 with HCl gave initially chlorohydrin 223 whichGlaxoSmithKline’s cyclized thermally effort under for a neutral scalable conditions synthesis to 224of GSK966587,with concomitant an antimicrobial O-demethylation. clinical candidateActivation [204], ofpivoted the primary on the alcoholasymmetric triggered epoxidation cyclisation of allylic to epoxide alcohol225 220which using was the ultimatelySharpless openedmethod bywhich amine delivered222 to furnish epoxide GSK966587. 221 in 81% yield and 90% ee in 10 g scale (Scheme 60). Under the GlaxoSmithKline process group optimized the Jacobsen–Katsuki method for epoxidizing 226 to basic ring-opening conditions of 221 with amine 222, the undesired intramolecular SNAr reaction 227betweenen route the toprimary the potassium alcohol channeland the openeradjacent BRL aryl 55834 fluoride (Scheme in the 61, product left) [205 ].was The observed reaction thus initially an requiredalternative at way least was 8 mol% sought of the to Jacobseninstall the salen amine complex portion./catalyst The ring(R,R opening)-M5 in orderof 221 to with complete HCl gave and produceinitially 227chlorohydrinwith high enantioselectivity.223 which cyclized Lower thermally catalyst loadings under ledneutral to erosion conditions of ee and to incomplete224 with reactionconcomitant even O-demethylation. after 50 h. This was attributed to catalyst decomposition with active degradants potentially promoting racemic product formation. Examination of several additives known to benefit catalyst stability identified 4-Ph-pyridine N-oxide and isoquinoline N-oxide with the latter allowing the catalyst-loading to be lowered to 0.1 mol% and, in contrast to the former, could be removed by in the aqueous washes. This enabled the synthesis of BRL 55834 in multikilogram scale.

Catalysts 2020, 10, 1117 51 of 65 Catalysts 2020, 10, x FOR PEER REVIEW 53 of 69

Catalysts 2020, 10, x FORScheme PEER 60.REVIEW SynthesisSynthesis of GSK966587 via two chiral epoxide intermediates. 54 of 69

Activation of the primary alcohol triggered cyclisation to epoxide 225 which was ultimately opened by amine 222 to furnish GSK966587. GlaxoSmithKline process group optimized the Jacobsen–Katsuki method for epoxidizing 226 to 227 en route to the potassium channel opener BRL 55834 (Scheme 61, left) [205]. The reaction initially required at least 8 mol% of the Jacobsen salen complex/catalyst (R,R)-M5 in order to complete and produce 227 with high enantioselectivity. Lower catalyst loadings led to erosion of ee and incomplete reaction even after 50 h. This was attributed to catalyst decomposition with active degradants potentially promoting racemic product formation. Examination of several additives known to benefit catalyst stability identified 4-Ph-pyridine N-oxide and isoquinoline N-oxide with the latter allowing the catalyst-loading to be lowered to 0.1 mol% and, in contrast to the former, could be removed by in the aqueous washes. This enabled the synthesis of BRL 55834 in multikilogram scale.

Scheme 61. Application of Jacobsen’s asymmetric epoxidation to the synthesis of drug candidates. Scheme 61. Application of Jacobsen’s asymmetric epoxidation to the synthesis of drug candidates. Several years later, Pfizer reported the same approach to prepare 229 from 228 en route to a similarSeveral potassium years channellater, Pfizer opener, reported230 (Scheme the same 61, right)approach [206]. to In prepare this case 229 4-phenyl from 228 pyridine en route N-oxide to a similar potassium channel opener, 230 (Scheme 61, right) [206]. In this case 4-phenyl pyridine N-oxide proved the optimum external ligand for the epoxidation process which was demonstrated successfully at a scale of 225 g. Under the oxidative conditions the diaryl sulfide in 228 is also transformed to the sulfone.

1.20. Organocatalytic Asymmetric Epoxidation in Drug Development—Chiral Ketones, Iminium Salts and Phase Transfer Catalysts The advent of organocatalysis has provided additional options in both normal and asymmetric epoxidation where a variety of organocatalytic systems have been developed including ketone/dioxirane, iminium/oxaziridinium salt, polyleucine/H2O2 and phase transfer catalysts/inorganic oxidants [137,138,207,208]. Two such systems were discussed in the diltiazem synthesis with Yang’s chiral ketone/dioxirane selected as the system of choice for the large-scale process. Among academic efforts Shi’s fructose-derived chiral ketone (commonly known as epoxone) has been established as the broadest scope organocatalytic system imparting high enantioselectivities in the epoxidation of various alkene substrates [137,138]. This prompted DSM process chemists to challenge its application in the large-scale synthesis of a key intermediate associated with a scaffold exhibiting significant antiviral activity (231, Scheme 62) [209].

Catalysts 2020, 10, 1117 52 of 65 proved the optimum external ligand for the epoxidation process which was demonstrated successfully at a scale of 225 g. Under the oxidative conditions the diaryl sulfide in 228 is also transformed to the sulfone.

1.20. Organocatalytic Asymmetric Epoxidation in Drug Development—Chiral Ketones, Iminium Salts and Phase Transfer Catalysts The advent of organocatalysis has provided additional options in both normal and asymmetric epoxidation where a variety of organocatalytic systems have been developed including ketone/dioxirane, iminium/oxaziridinium salt, polyleucine/H2O2 and phase transfer catalysts/inorganic oxidants [137,138,207,208]. Two such systems were discussed in the diltiazem synthesis with Yang’s chiral ketone/dioxirane selected as the system of choice for the large-scale process. Among academic efforts Shi’s fructose-derived chiral ketone (commonly known as epoxone) has been established as the broadest scope organocatalytic system imparting high enantioselectivities in the epoxidation of various alkene substrates [137,138]. This prompted DSM process chemists to challenge its application in the large-scale synthesis of a key intermediate associated with a scaffold exhibiting significant antiviral Catalystsactivity 2020 (231, 10, Scheme, x FOR PEER 62)[ REVIEW209]. 55 of 69

Scheme 62. Scheme 62. DevelopmentDevelopment of of a a large-scale large-scale organocatalytic asymmetric epoxidation/lactonization. epoxidation/lactonization. It was envisaged that 231 could be accessed from amino lactone 232 which in turn can be It was envisaged that 231 could be accessed from amino lactone 232 which in turn can be derived from hydroxy lactone 233. The latter was shown to form spontaneously upon epoxidation of derived from hydroxy lactone 233. The latter was shown to form spontaneously upon epoxidation of unsaturated acid 234 under basic conditions. Having earlier optimized the synthesis of the chiral ketone unsaturated acid 234 under basic conditions. Having earlier optimized the synthesis of the chiral catalyst, DSM chemists looked into the tandem epoxidation/lactonization process. Oxirane formation ketone catalyst, DSM chemists looked into the tandem epoxidation/lactonization process. Oxirane from this ketone-catalyst requires a pH range of 10–11, at which the decomposition of catalyst, primarily formation from this ketone-catalyst requires a pH range of 10–11, at which the decomposition of via a Baeyer-Villiger reaction, becomes competitive hence the high catalyst loadings. The reaction also catalyst, primarily via a Baeyer-Villiger reaction, becomes competitive hence the high catalyst needs to be run under dilute conditions due to the low solubility of Oxone. After careful optimization loadings. The reaction also needs to be run under dilute conditions due to the low solubility of of the reaction conditions and mode of reagent addition this process delivered more than 100 kg of 233 Oxone. After careful optimization of the reaction conditions and mode of reagent addition this over several batches nevertheless issues related to process robustness and reproducibility persisted. process delivered more than 100 kg of 233 over several batches nevertheless issues related to process Substrate-controlled epoxidations may be subject to match/mismatched interactions with chiral robustness and reproducibility persisted. catalysts/promoters therefore more efficient processes can be designed when a matched case is identified. Substrate-controlled epoxidations may be subject to match/mismatched interactions with chiral Epoxone has also been used to install the epoxide functionality in cryptophycin 51, a synthetic analog catalysts/promoters therefore more efficient processes can be designed when a matched case is of the natural product cryptophycin 1 (Scheme 63). Cryptophycin 51 was advanced to Phase I/II clinical identified. Epoxone has also been used to install the epoxide functionality in cryptophycin 51, a studies by Eli Lilly but was terminated due to adverse effects; research on this scaffold continues with synthetic analog of the natural product cryptophycin 1 (Scheme 63). Cryptophycin 51 was advanced analog structures [210,211]. In the effort to support early supplies of the drug substance a battery of to Phase I/II clinical studies by Eli Lilly but was terminated due to adverse effects; research on this epoxidation protocols was tested with the ultimate intermediate 236 and epoxone emerged as the most scaffold continues with analog structures [210,211]. In the effort to support early supplies of the drug diastereoselective agent giving a β/α ratio of 3.5:1 (mCPBA, Jacobsen methods 1.9:1) [212]. Eli Lilly substance a battery of epoxidation protocols was tested with the ultimate intermediate 236 and epoxone emerged as the most diastereoselective agent giving a β/α ratio of 3.5:1 (mCPBA, Jacobsen methods 1.9:1) [212]. Eli Lilly chemists considered investigating a better matched case in the substrate-controlled epoxidations of earlier non-macrocyclic intermediates such as 237, 238 and 239 (Scheme 63). The former gave the most diastereoselective epoxidation, but low conversions made purification difficult and this option was abandoned. Optimization of 240 epoxidation increased the diastereoselectivity from 5:1 to 6.5:1 with >95% conversion and this was achieved with less epoxone (2 instead of 4 equivalents typically used in this work). Although not a true catalytic process, it enabled an improved synthesis for this complex drug candidate.

Catalysts 2020, 10, 1117 53 of 65 chemists considered investigating a better matched case in the substrate-controlled epoxidations of earlier non-macrocyclic intermediates such as 237, 238 and 239 (Scheme 63). The former gave the most diastereoselective epoxidation, but low conversions made purification difficult and this option was abandoned. Optimization of 240 epoxidation increased the diastereoselectivity from 5:1 to 6.5:1 with >95% conversion and this was achieved with less epoxone (2 instead of 4 equivalents typically used in this work). Although not a true catalytic process, it enabled an improved synthesis for this complex drugCatalysts candidate. 2020, 10, x FOR PEER REVIEW 56 of 69

Scheme 63. Application of Shi’s chiral ketone (epoxone)(epoxone) to the synthesis of cryptophycin 51.

A similar requirement for enhanced substrate control has been reported by Novartis in the A similar requirement for enhanced substrate control has been reported by Novartis in the synthesis of epothilone and analogs thereof where epoxone provided the highest diastereoselectivity synthesis of epothilone and analogs thereof where epoxone provided the highest diastereoselectivity in the epoxidation of the macrocyclic alkene (8–10:1) in the final step [213]. in the epoxidation of the macrocyclic alkene (8–10:1) in the final step [213]. Another interesting case of matched substrate-controlled epoxidation was reported by Rusinov Another interesting case of matched substrate-controlled epoxidation was reported by Rusinov and Chertorizhskii in the synthesis of the contraceptive mifepristone who used a chiral phase transfer and Chertorizhskii in the synthesis of the contraceptive mifepristone who used a chiral phase Q1 240 catalysttransfer catalyst ( , Scheme (Q1, Scheme 64) to enhance64) to enhance the desired the desired diastereoselectivity diastereoselectivity in the in epoxidationthe epoxidation of of 240to 14:1 from 3.5:1 typically seen in the absence of the chiral species [214]. The diastereoselectivity to 14:1 from 3.5:1 typically seen in the absence of the chiral species [214]. The diastereoselectivity was was heavily dependent on the protecting group of the alcohol (7.75:1 with TMS in place of TBDMS). heavily dependent on the protecting group of the alcohol (7.75:1 with TMS in place of TBDMS). The 241 Thestereochemistry stereochemistry of epoxide of epoxide 241 is criticalis critical in ininstalling installing the the aryl aryl group group with with the the correct correct stereochemistry stereochemistry as this is dictated by the prerequisite antiperiplanar geometry in the SN2’ ring opening of the allylic as this is dictated by the prerequisite antiperiplanar geometry in the SN2’ ring opening of the allylic 242 epoxide. TheThe resulting resulting alcohol alcohol is242 dehydrated is dehydrated removing removing thus the initialthus stereochemicalthe initial stereochemical information ofinformation the epoxide of intermediate, the epoxide butintermediate, the stereochemistry but the st atereochemistry the carbon atom at the bearing carbon aryl atom group bearing constitutes aryl chiralgroup memoryconstitutes of thischiral process. memory of this process. In contrast, in the synthesis of the osteoporosis drug candidate 243 (Scheme 65) of Aventis (legacy company of Sanofi), process chemists found that this could form with the desired stereochemistry following isomerization of 244 and several unsaturated intermediates including those with the opposite stereochemistry, generated in previous steps. The initial focus from enhancing the substrate controlled epoxidation of 245 to 246 was shifted in the equilibration/isomerization process post the SN2’ Grignard addition (247) and culminated the development of a robust and more efficient process that avoided the losses associated with the rejection of the α-epoxide isomer. Consequently, the epoxidation

Catalysts 2020, 10, x FOR PEER REVIEW 57 of 69

Catalysts 2020, 10, 1117 54 of 65 process mediated by hexachloroacetone and hydrogen peroxide (β/α 1.8:1) was retained (β/α 2.1:1 withCatalysts hexafluoroacetone) 2020, 10, x FOR PEER [REVIEW215]. 57 of 69

Scheme 64. Application of chiral phase transfer catalyst-mediated asymmetric epoxidation.

In contrast, in the synthesis of the osteoporosis drug candidate 243 (Scheme 65) of Aventis (legacy company of Sanofi), process chemists found that this could form with the desired stereochemistry following isomerization of 244 and several unsaturated intermediates including those with the opposite stereochemistry, generated in previous steps. The initial focus from enhancing the substrate controlled epoxidation of 245 to 246 was shifted in the equilibration/isomerization process post the SN2’ Grignard addition (247) and culminated the development of a robust and more efficient process that avoided the losses associated with the rejection of the α-epoxide isomer. Consequently, the epoxidation process mediated by Scheme 64. Application of chiral phase transfer catalyst-mediated asymmetric epoxidation. hexachloroacetoneScheme 64. Applicationand hydrogen of chiral phaseperoxide transfer (β catalyst-mediated/α 1.8:1) was asymmetric retained epoxidation.(β/α 2.1:1 with hexafluoroacetone) [215]. In contrast, in the synthesis of the osteoporosis drug candidate 243 (Scheme 65) of Aventis (legacy company of Sanofi), process chemists found that this could form with the desired stereochemistry following isomerization of 244 and several unsaturated intermediates including those with the opposite stereochemistry, generated in previous steps. The initial focus from enhancing the substrate controlled epoxidation of 245 to 246 was shifted in the equilibration/isomerization process post the SN2’ Grignard addition (247) and culminated the development of a robust and more efficient process that avoided the losses associated with the rejection of the α-epoxide isomer. Consequently, the epoxidation process mediated by hexachloroacetone and hydrogen peroxide (β/α 1.8:1) was retained (β/α 2.1:1 with hexafluoroacetone) [215].

Scheme 65. Application of the catalytic ketone/dioxirane epoxidation system in drug development. The iminium/oxaziridinium salt system is analogous to the ketone/dioxirane system and possesses significant reactivity as an electrophilic oxygen transfer agent by virtue of the positively charged nitrogen atom bonded to the oxygen in the oxaziridinium intermediate. The Page group was among the pioneers in developing this system in organocatalytic asymmetric epoxidations [216–219].

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Scheme 65. Application of the catalytic ketone/dioxirane epoxidation system in drug development.

The iminium/oxaziridinium salt system is analogous to the ketone/dioxirane system and possesses significant reactivity as an electrophilic oxygen transfer agent by virtue of the positively chargedCatalysts 2020 nitrogen, 10, 1117 atom bonded to the oxygen in the oxaziridinium intermediate. The Page group55 of 65 was among the pioneers in developing this system in organocatalytic asymmetric epoxidations [216–219]. In the synthesis of GlaxoSmithKline’s former drug candidate for hypertension ( )-cromakalim In the synthesis of GlaxoSmithKline’s former drug candidate for hypertension (−−)-cromakalim (or levcromakalim, the active enantiomer of cromakalim) the asymmetric catalytic epoxidation of 248 (or levcromakalim, the active enantiomer of cromakalim) the asymmetric catalytic epoxidation of to 249 was achieved with Iminium salt 250 (Scheme 66)[220]. 248 to 249 was achieved with Iminium salt 250 (Scheme 66) [220].

Scheme 66. Application of chiral iminium salt-catalyzed epoxidation system in drug synthesis. Scheme 66. Application of chiral iminium salt-catalyzed epoxidation system in drug synthesis. Standard iminium salt-catalyzed epoxidations require aqueous solutions of the inorganic triple salt Oxone,Standard the iminium stoichiometric salt-catalyzed oxidant, epoxidations thus limiting require the temperature aqueous solutions range at whichof the theinorganic epoxidation triple saltreaction Oxone, may the be stoichiometric performed. In oxidant, this work, thus the limi organic-solventting the temperature soluble TPPP range (tetraphenylphosphonium at which the epoxidation reactionperoxymonosulfate; may be theperformed. latter anion In is thethis active work, component the inorganic-solvent Oxone) was usedsoluble allowing TPPP the (tetraphenylphosphonium peroxymonosulfate; the latter anion is the active component in Oxone) reaction to be conducted in pure organic solvent (CHCl3) at lower temperatures. This afforded higher wasenantioselectivities used allowing in the comparison reaction with to thebe typicalconducted conditions in pure involving organic aqueous solvent acetonitrile. (CHCl3) at With lower the temperatures.modified protocol This the afforded desired higher epoxide enantioselectivi249 was obtainedties inin 62% comparison yield and with 97% eethe and typical its ring conditions opening involvingwith pyrrolidin-2-one aqueous acetonitrile. gave levcromakalim With the modified in 52% yield.protocol the desired epoxide 249 was obtained in 62% yield and 97% ee and its ring opening with pyrrolidin-2-one gave levcromakalim in 52% yield. 2. Conclusions 2. Conclusions This work may be viewed as a tribute to process development chemists who respond to the challengeThis work to transform may be seemingly viewed as impossible a tribute to or process problematic development syntheses chemists into robust, who reproducible respond to andthe challengesafe manufacturing to transform routes. seemingly Arguably, impossible this could or notproblematic be demonstrated syntheses better into than robust, by casesreproducible of successful and safemanagement manufacturing of epoxide routes. synthesis Arguably, and ring-opening this could not reactions be demonstrated at the highest better level whichthan by has cases enabled of successfulthe manufacturing management of drugs of epoxide and clinical synthesis candidates and ring-opening at specification reactions to support at the pivotalhighest clinical level which trials hasand enabled the availability the manufacturing of medicines of to drugs society. and From clinical an educational candidates perspective, at specification the chemistry to support discussed pivotal clinicalprovides trials an insight and the on availability the synthetic of optionsmedicines generated to society. by epoxides From an and educational how these perspective, are affected the by chemistrythe ability discussed to control provides reactant andan insight product on regio- the synthetic and stereochemistry options generated as well by as epoxides side reactions and how and theseimpurity are affected formation. by the The ability established to control syntheses reactant described and product in this regio- review and may stereochemistry potentially constitute as well as a sidepoint reactions of reference and and impurity inspiration formation. for academic The esta andblished industrial syntheses research described in this and in relatedthis review fields. may potentially constitute a point of reference and inspiration for academic and industrial research in this andAuthor related Contributions: fields. F.M., I.S., M.T., D.T., G.R. selected the case studies, drew the relevant reaction/structure schemes and provided descriptions of the key chemical transormations. In addition, F.M. managed all references. AuthorG.R. added Contributions: process development F.M., I.S., M.T., details D.T., in eachG.R. caseselected and the also case wrote studies, the introduction drew the relevant and conclusion reaction/structure sections. schemesAll authors and have provided read and descriptions agreed to the of published the key versionchemical of thetransormations. manuscript. In addition, F.M. managed all references.Funding: This G.R. research added process received development no external funding.details in each case and also wrote the introduction and conclusion sections. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest: The authors declare no conflict of interests.

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