Olefin Metathesis in Drug Discovery and Development Examples from

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The Metathesis Reaction in Drug Discovery and Development – A Review of Recent Patent Literature David L Hughes, Philip Wheeler, and Doina Ene Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00319 • Publication Date (Web): 13 Nov 2017 Downloaded from http://pubs.acs.org on November 13, 2017

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Organic Process Research & Development

The Metathesis Reaction in Drug Discovery and Development – A Review of Recent Patent Literature David Hughes,*a Philip Wheeler,*b Doina Eneb a

Cidara Therapeutics, 6310 Nancy Ridge Dr., STE 101, San Diego, CA 92121, USA

b

Materia, Inc. 60 N San Gabriel Blvd. Pasadena, CA 91107, USA

e-mail of corresponding author: [email protected]

1 ACS Paragon Plus Environment


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TABLE OF CONTENTS GRAPHIC


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ABSTRACT The olefin metathesis reaction is finding increasing use in drug discovery and process chemistry, with a number of applications now implemented at commercial manufacturing scale. Catalyst improvements over the past decade have allowed use of the metathesis reaction with highly functionalized substrates, allowing chemists to access increasingly diverse chemical space, including most notably macrocycles, constrained small ring spirocycles, and fused-ring systems. For scientists employed in the pharmaceutical industry, the patent literature is the primary avenue for communication of synthetic routes to drug candidates. While most examples of the metathesis reaction in the patent literature offer only sketchy experimental details and provide little context on reaction development, the wide scope of substrates within the pharmaceutical patent literature provides a true indication of reaction scope and functional group compatibility. The current article reviews applications of the metathesis reactions in drug discovery and development in the pharmaceutical industry disclosed in the patent literature from January 2016 to August 2017. KEYWORDS Metathesis, ring closing metathesis, Grubbs, ruthenium, patent literature, drug discovery, drug development



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1. Introduction The expanding use of the metathesis reaction in the pharmaceutical industry has largely paralleled the advances in catalyst design and development that have accommodated increasingly complex and functionalized substrates.1 A number of reviews of the metathesis reaction in the pharmaceutical industry have been published over the past five years. In a discussion addendum in Organic Syntheses in 2012, O’Leary, Pedersen, and Grubbs reviewed the first two publicly disclosed efforts to implement the metathesis reaction at scale in the pharmaceutical industry - the pioneering work at BoehringerIngelheim on the ring-closing macrocyclization toward the synthesis of HCV drug candidate ciluprevir using Hoveyda-Grubbs I catalyst 1 and later nitro-Grela catalyst 2 (Chart 1), and the construction of a seven-membered azapane ring in GSK’s cathepsin K inhibitor SB-462795 using Hoveyda-Grubbs II catalyst 3.2 The development of the RCM for ciluprevir and other HCV drug candidates was further reviewed by the Boehringer-Ingelheim team in 20143 and well as Farina and Horvath in a 2015 review chapter.4 In 2015 Kong published a review on the synthesis of macrocyclic clinical candidates that included a section on ring-closing metathesis (RCM) and presented a nice comparison of macrocyclization approaches.5 In 2016 Fogg and co-workers reviewed pharmaceutical and fine chemical applications of the metathesis reaction, including a discussion of simeprevir, the first approved drug that includes a metathesis reaction in its manufacturing route, promoted by M2 catalyst 4.6 The current article, a follow up to a previous review on the metathesis reaction that covered the patent literature up to year 2015,7 is focused on pharmaceutical applications published in the patent literature during the years 2016 and 2017. Section 2 offers a snapshot of applications in drug discovery while Section 3 covers five examples of routes to recently approved drugs that include metathesis reactions.


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The structures of the ruthenium metathesis catalysts used for the examples discussed in this review are presented in Chart 1. While molybdenum and tungsten metathesis catalysts are used in petrochemical, polymer, and other industrial applications,8 examples in the pharmaceutical industry are rare and are not included in this review. Chart 1. Homogeneous Ru Catalysts Discussed in this Review

2. The Metathesis Reaction in Drug Discovery 5 ACS Paragon Plus Environment


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The metathesis reaction has enabled creation of new chemical space for Medicinal Chemists, especially the ring-closing metathesis reaction to generate macrocycles and medium-sized rings that have historically been difficult to construct. A search of the patent literature from 2016 through mid-2017 uncovered more than 200 patents and patent applications that disclose a metathesis reaction as a key step in the synthesis of a molecule of pharmaceutical interest. A significant portion of the disclosures in this period describe new macrocyclic inhibitors of HCV NS3/4A protease. This class of compound remains a common target for ring-closing metathesis approaches, but to minimize overlap with previous reviews and with the content in Section 3, we have decided to focus on macrocyclic compounds intended for non-HCV indications in Section 2.1. Although a common definition of macrocycle starts at twelve-membered rings,9 we have chosen to group examples of eight- to eleven-membered rings with the macrocyclic compounds to prevent some examples from being split into multiple sections. These examples can also be found in Section 2.1. In the formation of large rings by any method, an entropic barrier to intramolecular reactivity is commonly encountered.10 For rings in the 8- to 11-membered range, ring strain often adds an additional enthalpic barrier to ring closure.11 Therefore, the rate of intermolecular reaction can approach or even surpass the rate of intramolecular reaction. To mitigate this issue, macrocyclizations are often run at low concentration to slow down unwanted intermolecular reactions and favor the desired intramolecular cyclization. For ring-closing metathesis reactions in particular, the relative rates (both forward and backward) of catalyst initiation, cyclization, cross-metathesis oligomerization and catalyst decomposition must be balanced carefully to provide optimal conditions.12 Where possible, we will point out reaction concentrations, but the reader should bear in mind, the conditions reported in patent applications are rarely optimal.


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To form rings in the five to seven-membered range, there are often multiple bond disconnections that might be considered, including strategies that would not involve olefin metathesis. However, the tolerance of RCM to steric and conformational constraints such as those presented by caged and spirocyclic systems provides ample opportunity for its use in accessing smaller rings. Furthermore, the need for high dilution conditions to close five to seven-membered rings by ring-closing metathesis tends to be the exception, not the rule.13 Several examples of this type are described in Section 2.2. 2.1 Eight-Membered and Larger Rings Synta Pharmaceuticals have disclosed a series of tricyclic triazoles, with either 6- or 8-membered central rings, as inhibitors of heat shock protein (HSP) 90 for the treatment of cancer.14 Construction of the 8membered ring system was accomplished via RCM, as outlined in Scheme 1. The synthesis began with Friedel-Crafts reaction of 1-allyl-3,5-dimethoxybenzene (8) with allyl thioisocyanate to afford thioamide 9 in 46% yield after silica gel chromatography. Reaction with oxamic hydrazide mediated by mercuric chloride with microwave heating afforded triazole 10 in 80% yield after silica gel chromatography. The RCM of 10 was carried out on a 200 mg scale using Grubbs II catalyst 6 (10 mol %) in refluxing dichloromethane at 0.03M to furnish the cyclooctene 11 in 66% yield. Hydrogenation followed by deprotection of the methoxy groups yielding the dihydroxy compound 12. Scheme 1. Route to HSP 90 Inhibitors via RCM to Construct the 8-Membered Central Ring



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A series of cyclic sulfonamides were evaluated by Janssen for the treatment of hepatitis B.15 The RCM reaction was used to construct 8-, 11-, and 12-membered cyclic sulfonamides (compounds 13, 14, and 15). The synthesis of the 8-membered analogue is outlined in Scheme 2. The sequence starts with reaction of sulfonyl chloride 16 with chiral amine 17 using NaHCO3 in MeCN to afford sulfonamide 18. Palladium-catalyzed cross coupling with potassium allyltrifluoroborate (19) using microwave heating afforded intermediate 20 in which the double bond isomerized to the internal position. Amidation was carried out with 3,4-difluoroaniline mediated by LiHMDS to furnish amide 21. The metathesis precursor 22 was then prepared by Mitsunobu reaction of 21 with 3-butene-1-ol in THF. The subsequent RCM reaction was conducted in 1,2-dichloroethane (DCE) at 80 oC and 0.003M concentration using Grubbs II catalyst 6 (10 mol %) to generate the 8-membered sulfonamide 13 in 80% yield. 8 ACS Paragon Plus Environment

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Scheme 2. HBV Inhibitor Intermediate 8 via an RCM Route

The 11- and 12-membered compounds were prepared in a similar fashion. The 11-membered product 14 was formed as an undisclosed E/Z mixture while only the E-isomer was generated for the 12membered product 15. The RCM was also carried out with the methyl ester prior to amidation in several examples.



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Figure 1. Eleven- and Twelve-Membered Cyclic Sulfonamides Prepared by RCM

Glycomimetics has disclosed a series of triglyceride mimetics as E-selectrin antagonists for the potential treatment of inflammatory diseases and cancer.16 In these modified triglycerides, one sugar has been replaced with a cyclohexane ring system and the galactose sugar has been modified with a 9- or 10membered ring generated via an RCM reaction (Scheme 3). The RCM is carried out using Grubbs II catalyst 6 (10 mol %) on the highly oxygenated diene 23 at 0.005M in dichloromethane at room temperature to afford the 9- and 10-membered ring systems 24 in 81-86% yield. Scheme 3. Triglyceride Mimetics Prepared Via RCM


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In a patent disclosure published in December 2016, coworkers at the University of Tokyo, Tohoku University, and Shionogi disclosed a series of fused pyrazoles with inhibitory activity against autotaxin.17 Autotaxin is an enzyme involved in the biosynthesis of lysophosphatidic acid (LPA), a lipid mediator implicated in a number of physiological and pathological conditions.18 One of the compounds in the series contains a 14-membered macrocycle 27 that was formed via ring-closing metathesis catalyzed by Grubbs II catalyst 6 (3.3 mol%) in 45% yield (Scheme 4). The product 26 was formed as a 2:1 mixture of olefin isomers, but the olefin was hydrogenated to give the saturated hydrocarbon linker 27 in the subsequent step. Scheme 4. RCM and Hydrogenation to Form a 14-membered Macrocyclic Fused Pyrazole

Bristol-Myers Squibb disclosed a series of macrocyclic pyridine-, pyridone-, and imidazole-containing compounds that inhibit coagulation factor XIA and may be useful medicaments for thromboembolic disorders.19 A general retrosynthetic approach to these compounds features a ring-closing metathesis of



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a diene substrate accessed by acylation of an aniline with a terminal olefin-containing activated carboxylic acid (Scheme 5). Scheme 5. General Retrosynthetic Approach to Macrocyclic Factor XIA Inhibitors

In a representative example, the 12-membered ring macrocycle 35 was formed by RCM of 34 catalyzed by Grubbs II catalyst 6 (20 mol%) in the presence of p-toluenesulfonic acid (TsOH, 1.1 equiv) in refluxing CH2Cl2 at 0.012M in 71% yield (Scheme 6). The E-isomer was isolated cleanly, but no mention of the ratio in the crude mixture was made. The TsOH was added to the preform the pyridinium in this case, but was also used to mask other RCM substrates containing basic heterocycles. Scheme 6. Synthesis of 12-Membered Macrocyclic Core of Factor XIA Inhibitors


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t-Bu

O Cl

H

O S

NH2

(1.0 equiv) t-Bu

O S

Cl

N

CuSO4 (2.1 equiv) CH2Cl2, 23 °C

N 28

O

29

N 30

84% over 3 steps

NH2

B O

O2N

NH2

Zn (10 equiv) NH4Cl (10 equiv)

BocHN

Pd(dppf)Cl2 (10 mol%) K3PO4 (2.0 equiv) DMSO/H2O, 90 °C yield not reported

Cl

BocHN

2. HCl (10 equiv) MeOH, 23 °C 3. Boc2O (1.0 equiv), Et3N, CH2Cl2, 23 °C

N

76%

O 2N

1. InCl3 (1.5 equiv) allyl-MgBr (1.5 equiv) THF, 23 °C

MeOH, 23 °C 98%

N

H2N

NH2

BocHN N 32

31 Me O

O Cl

H2N

OMe

pyridine CH2Cl2 -78 °C 88%

H N

O OH

OMe

H N

HN

OMe

Me O

BocHN

T3P, pyridine EtOAc, -10 to 23 °C

N

97%

33

O

BocHN N 34

Me O TsOH hydrate (1.1 equiv) Grubbs II (20 mol%) CH2Cl2 (0.012M) 40 °C 71%

H N

HN

OMe O

BocHN N 35

In another patent application published in March of 2017, additional macrocyclic inhibitors of factor XIA were disclosed by Bristol-Myers Squibb.20 These compounds appear to be related to the compounds previously described, with a pyrazole replacing one of the aromatic rings in the macrocycle. The approach to these compounds is very similar to the strategy described for the previous series, featuring a ring-closing metathesis to form the common 12-membered macrocyclic ring. In a representative sequence (Scheme 7), chloropyridine 36 was subjected to Pd-catalyzed direct arylation 13 ACS Paragon Plus Environment


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conditions with nitropyrazole 37 to afford cross-coupling product 38 in 67% yield.21 The arylation was followed by reduction of the nitro group to form aminopyrazole 39. The aminopyrazole was acylated with (R)-2-methylbut-3-enoic acid and treated with Grubbs II catalyst 6 (40 mol%) at 120 °C in DCE in a sealed microwave vessel to close the 12-membered macrocyclic core. Under these conditions, ethylene produced from the productive metathesis reaction would be unable to vent. The removal of ethylene can drive metathesis reactions forward,22 and concentration of ethylene in the reaction mixture can contribute to catalyst decomposition.23 Furthermore, the reaction was concentrated without a quench of the catalyst, which may lead to oligomerization and/or olefin isomerization.24 Despite the non-ideal conditions, the E-olefin 41 was isolated by chromatography in 38% yield. The ratio to the Z-olefin in the crude mixture was not mentioned. Scheme 7. Preparation of 12-Membered Pyrazole-containing Macrocycle


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Coworkers at Amgen disclosed routes to several macrocyclic sulfonyl amides with inhibitory activity against MCL-1,25 a target indicated in the potential treatment of myeloid leukemia.26 This compound series contains several challenging features, including a cyclobutane fused with the 16-membered ring and spiro-fused benzoxazepane. Each of the routes described in the patent includes a metathesis reaction to form a carbon-carbon bond contained in the macrocycle; however, in some cases this bond is formed in a cross metathesis reaction and not an RCM macrocyclization (Figure 2).

Figure 2. Metathesis Bond Disconnections in Macrocyclic MCL-1 Inhibitors

The inventors took advantage of aldehyde 42 as a common intermediate to several olefin metathesis precursors. For instance, homoallyl alcohol 43 was accessed stereoselectively using a boron-mediated asymmetric allylation,27 whereas allylic alcohol 44 was obtained by asymmetric vinylation (Scheme 8).28 Scheme 8. Stereoselective Installation of Olefin Handles onto a Common Intermediate



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Homoallylic alcohol 43 was used as a precursor to a series of macrocycles containing a saturated hydrocarbon chain. In an exemplary route to 49 (Scheme 9), 43 was saponified to give the carboxylate 45, which was reacted under peptide coupling conditions with sulfonamide 46 to give diene 47. This diene was then treated with Hoveyda-Grubbs catalyst 3 in toluene at 106 oC to provide the macrocyclic olefin 48 as a 1:1 mixture of E:Z isomers in 68% yield, followed by hydrogenation to furnish the final product 49. Scheme 9. Elaboration of Homoallyl Alcohol 43 to Macrocycle 49


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For the preparation of macrocycles retaining an E-alkene in the ring, two routes converge on intermediate 50, which was obtained from 44 upon saponification (Scheme 10). In one route, the allylic alcohol 50 was reacted with alkene-bearing sulfonamide 51 in a cross metathesis using Hoveyda-Grubbs II catalyst 3 to form the acyclic primary sulfonamide 52 in 81% yield, which was then subjected to macrolactamization conditions to furnish 53. In the other route, the sequence was reversed. First, the alkene-bearing sulfonamide 54 was reacted with the activated carboxylate of 50, followed by ringclosing metathesis. Scheme 10. Alternate Routes to 16-Membered Macrocyclic MCL-1 Inhibitors Containing EAlkenes. 17 ACS Paragon Plus Environment


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OH Cl O N O 50

O S NH2 O

51

O

EDC•HCl, DMAP CH2Cl2 , 0 °C 76%

81%

O N

OH

O S NH2 O

Cl

O S NH2

54

HG-II (10 mol%) DCE, 23 °C

OH

OH

Cl O N

OH

O

N H

SO2

O 55

52 EDC•HCl, DMAP CH2Cl2 (0.0016M), 23 °C 2.6%

HG-II (10 mol%) DCE (0.002M), 60 °C 77% OH

OH Cl

Cl

O

O N

N H

N

SO2

SO2

O

O 53

N H 56

MeI (5 equiv) KHMDS (3.4 equiv) MeTHF/THF, -44 °C 96% OMe Cl O N

N H

SO2

O 57

ACS Paragon Plus Environment

18

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Though the substrates are not identical and none of the conditions reported in the patent have likely not been optimized, it appears from these entries that the ring-closing metathesis of 55 is much more efficient than the macrolactamization of 52 (77% versus 2.6% reported yield), even at similar concentrations (0.002M versus 0.0016M). The ratios of E:Z isomers are not reported; however the Eisomer is listed as the major isomer in both cases. The ring-closing metathesis of diene 55 is reported on gram-scale and is followed by alkylation with methyl iodide to give >100g of methyl ether 57 in multiple combined batches.29 GlaxoSmithKline and Astex have disclosed a series of cyclic sulfonamides with potential application as regulators of NRF2, a transcription factor that may have therapeutic value in treating chronic obstructive pulmonary disease.30 Of the many compounds described, three are macrocycles formed by ring-closing metathesis. In one example, diene substrate 60 was prepared via Mitsunobu reaction of cyclic sulfonamide 58 with benzylic alcohol 59 (Scheme 11). The diene 60 was then treated with Grubbs 1st generation catalyst 5 and stirred at reflux in dichloromethane (0.002M) for 27h, at which point Grubbs 2nd generation catalyst 6 was added. Though it is not specified in the description, one might conclude that Grubbs I catalyst 5 was ineffective at this transformation and the addition of 6 was necessary to achieve conversion. After 69 h, the reaction mixture was concentrated without any quench of the catalyst. Under these conditions, significant oligomerization in the presence of active 2nd generation catalyst might be expected upon concentration.31 Nonetheless, the desired product 61 was isolated in 35% yield after chromatographic purification. The macrocyclic olefin was then hydrogenated, and the ester moiety saponified, to give carboxylic acid 62. Scheme 11. Synthetic Sequence Affording an 18-Membered Macrocyclic Ring by RCM



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In a granted patent published in 2016, coworkers at Chugai disclose a series of spiroimidazolone derivatives as orally bioavailable small molecule mimics of parathyroid hormone (PTH).32 Peptide mimics of PTH such as teriparatide are used to treat osteoporosis,33 but must be administered by injection.34 Among the compounds disclosed, several macrocyclic structures are described with rings ranging from 24 to 29 members, each prepared by RCM of the corresponding acyclic diene (Scheme 12). Scheme 12. General Synthetic Approach to Spiroimidazolone RCM Precursors


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O

O

HN F3C

N

O

HN

O O S

N

O

F3C

N n

N

O

Me

N

O O S

O

Me N

Me

Me

n

O HN F3C

N

NH

Cl +

O

NHMe n

O O S

+ O

Me OMe

Routes to several macrocyclic derivatives converge at spirocyclic piperidine 63 bearing a distal homoallylic aryl ether (Scheme 13). In a representative route, 63 was treated with sulfonyl chloride 64 to form the sulfonamide. The carboxylate was unmasked to afford 65 and then reacted under peptide coupling conditions with methylpent-4-enylamine to give the requisite diene 66. The 26-membered macrocycle was closed using Grubbs II catalyst 6 (20 mol%) at very low concentration (0.001M), furnishing the desired product 67 in 94% yield, presumably as a mixture of olefin isomers. The RCM was followed by hydrogenation to give the saturated hydrocarbon chain product 68, therefore the E:Z selectivity was inconsequential. Scheme 13. Macrocyclic Spiroimidazolone Prepared by RCM



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O

O HN

HN F3C

ClO2S

NH

N

1. Et3N (2.6 equiv) CH2Cl2, 0 °C

+ O

O

F3C

N

2. aq. NaOH MeOH, 23 °C 82% over 2 steps

Me OMe

O

O O S

O

Me OH

64

63

N

65 O HN

F3C

N

N

O O S

NHMe

Grubbs II (20 mol%) O

HATU, i-Pr2NEt DMF, 23 °C 84%

O

Me N

DCE (0.001M), 40 °C 94%

Me

66

O

O

HN F3C

N

N

O

HN

O O S

F3C

N

H2, Pd/C O

MeOH/EtOAc, 23 °C 94%

Me N

N

O

O

Me N

Me

O O S

Me

68

67

2.1 Five- to Seven-Membered Rings Roche has used an RCM to prepare 7-membered imino-oxo-thiadiazine 72 as an intermediate for the preparation of BACE inhibitors for the potential treatment and prevention of Alzheimer’s disease (Scheme 14).35 The RCM of diene 70 was conducted in refluxing dichloromethane at low concentration (0.015M) using Grubbs II catalyst 6 (5 mol %) to afford 71 in 83% yield. Prior to addition of the catalyst, the substrate solution was degassed by sonication and argon purge for 10 minutes to drive out


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any dissolved oxygen.36 The double bond was then reduced and the Cbz group removed by hydrogenation to furnish 72 in 92% yield, which was further elaborated into BACE inhibitors. Scheme 14. RCM to Prepare 7-Membered Imino-oxo-thiadiazine Intermediate

Merck has disclosed 6,7-bicylic sulfonamides as HIV protease inhibitors.37 An RCM is used to close the 6,7-bicylic ring structure, as outlined in Scheme 15. Diketopiperazine 73 was reduced to the piperazine 74 with LiAlH4, then the vinyl sulfone was installed using 2-chloroethylsulfonyl chloride under basic conditions. The metathesis of diene 75 was carried out with the Grubbs II catalyst 6 (20 mol %) in refluxing dichloromethane at 0.9M concentration. This example serves to illustrate that when closing smaller ring sizes, high dilution conditions are only necessary when ring strain or other conformational challenges disfavor cyclization (Section 1). It seems in this case no such barrier exists to the



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intramolecular cyclization, despite the apparent challenge presented by the bicyclic system. The double bond was reduced and the benzyl groups removed by hydrogenation to generate the key intermediate 77. Scheme 15. RCM Approach to 6,7-Bicyclic HIV Protease Inhibitors

In another patent application from Merck, the synthesis of a series of compounds with inhibitory activity against CYP450 is disclosed.38 These compounds may be useful for improving the pharmacokinetic profile of drugs by increasing half-life through an intentional drug-drug interaction.39 These compounds share the general structural components illustrated in Scheme 16: namely, a saturated N-heterocyclic fragment joined with an arylimidazole via an amide bond. Both 6- and 7-membered N-heterocycles are described, and in some instances, the ring is fused to another N-heterocycle. Scheme 16. General Retrosynthetic Strategy to Prepare CYP450 Inhibitors


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The sequence to access azapane derivative 86 begins with a ring-closing metathesis reaction of the simple protected amine diene 78 (Scheme 17). The RCM was catalyzed by 2nd generation Grubbs catalyst 6 at less than 1 mol% loading and carried out at relatively high concentration (0.24M), but only provided 50% yield of the desired 7-membered ring 79. Subsequent epoxidation, azide addition and Staudinger reduction gave the amino alcohol 82. The azide addition is not particularly regioselective, and the regioisomers were separated and carried through the same acylation, alkylation, and reduction sequence to give two constitutional isomers of the fused piperidine 86. These are each used in the amide coupling to prepare compounds for testing against CYP450. Scheme 17. RCM and Subsequent Steps to Prepare CYP450 Inhibitor Fragment



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In the synthesis of a polycyclic HIV integrase inhibitor, coworkers at Gilead describe a ring-closing metathesis to form a fused piperidine within a complex substrate (Scheme 18).40 Each of the two terminal olefin partners was installed as an allyl group. To control the stereochemistry of the homoallylic amine, an auxiliary-controlled addition of allyl Grignard to sulfinimine 88 was employed. The RCM of 92 was catalyzed by Grubbs I catalyst 5 (13 mol% added in three portions) and carried out in refluxing dichloromethane at low concentration (0.01M). No yields or stereoselectivities were reported. Scheme 18. Synthesis of a Fused Polycyclic HIV Inhibitor via RCM


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O t-Bu NHTeoc

O S

NH2 O

87

N

MeCN 23 to 50 °C

O

O

OMe

NaHCO3, MeOH/H2O 23 °C

NH S t-Bu 90

HCl

DBU

CH2Cl2 23 °C

MeOH 50 °C

F Cl

ClH3N Br OMe

HN

NaH, DMF 0 to 23 °C

O O

O O

O

H N

89 OMe

MeO NH2

NH

S t-Bu

O O

O

NHTeoc O

THF -78 to -35 °C

S t-Bu 88

TBAF

MgBr

NHTeoc

Ti(OEt)4 THF, 23 °C

O

O

O

NaOH 0 °C

OMe

F HATU, i-Pr2NEt CH2Cl2, 23 °C

91 O

O

H N

N H

N

O O

O

F Cl F

Grubbs I (13 mol%) CH2Cl2 (0.01M), 47 °C

OMe

F N H

N

O O

92

O

H N

Cl F

OMe 93

In a patent application from Eli Lilly and Co. published in August 2017, a series of compounds is disclosed with inhibitory activity against AICARFT, a key enzyme in the folic acid metabolism cycle and potential target for the treatment of cancers.41 The compounds share a core characterized by anisoquinolone and thiophene linked by a sulfonamide (Figure 3).



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Figure 3. General Structure of AICARFT Inhibitor Series

As part of the structure-activity relationship study, a variety of heterocycles was appended at the 5position of the thiophene. Two of these substituents are 5-pyridones accessed by isomerization and ringclosing metathesis of an allylic amide (Scheme 19). For simplicity, the sequence leading to gem-3dimethyl compound 96 is shown, but the chemistry is also used to access the rac-3-ethyl-3-methyl analog. Scheme 19. Synthesis of Pyridone 96 using Isomerization/Ring-closing Metathesis

At first glance, it may not be immediately apparent why the 6-membered ring 96 would be the major product of this reaction, since the ring-closure of the terminal olefins would lead to the 7-membered lactam 98 (Scheme 20). This may indeed occur, though it would be reversible under the reaction conditions.42 The decomposition of ruthenium-based metathesis catalysts to species capable of promoting olefin isomerization has been studied in detail,43 and the isomerization of the allylic amide 95 to the enamide 97 would be thermodynamically driven.44 This enamide then undergoes ring-closing metathesis to give the observed product 96 in 70% yield. Scheme 20. Isomerization and Ring-closing Metathesis 28 ACS Paragon Plus Environment

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Researchers at Merck disclosed a series of compounds with inhibitory activity against GPCR40, a potential target for the treatment of Type II diabetes.45 These compounds share a common tricyclic core: a cyclopentane fused to a pyridine and cyclopropyl ring. The cyclopropane is accessed via cyclopropanation of the corresponding cyclopentene, which itself is closed via ring-closing metathesis. To set up the RCM, 2-aminopyridine 99 was subjected to two consecutive Stille couplings to install each of the olefin handles (Scheme 21). The resultant diene 101 was treated with Grubbs II catalyst 6 to close the ring, followed by a rhodium-catalyzed cyclopropanation to give the desired tricyclic core 103. No yields are reported for any of the reactions in the sequence. Scheme 21. Construction of Tricyclic Core Using Ring-closing Metathesis and Cyclopropanation



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3. Metathesis Approaches to Approved Drugs During 2016 and 2017, patents and patent applications were published disclosing routes involving metathesis reactions to several recently approved drugs. Since the sponsors have not disclosed manufacturing routes to these drugs, we do not speculate on which of these routes - if any - are used for commercial manufacture. 3.1 Voxilaprevir Discovered and developed by Gilead Sciences, voxilaprevir is an HCV protease NS3/4A inhibitor that is part of the 3-drug combination tablet marketed under the tradename Vosevi. On Jul 18, 2017, the FDA approved Vosevi (sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg) for the re-treatment of chronic HCV infection.46 Vosevi also received marketing approval from the European Commission on Jul 28, 2017.47


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Figure 4. Structures of HCV NS3A/4 Inhibitors Volilaprevir and Glaceprevir Two routes to the voxilaprevir macrocylic core have been disclosed in Gilead patents and patent applications. The first approach employs a ring-closing metathesis (RCM) reaction to form the macrocycle while the second uses a cross-metathesis to construct the framework for a subsequent ringclosing macrolactamization. Both routes are claimed and compounds 112a-c, 113a-c, and 124 - 128 are claimed.48,49 The examples are described on small scale with few details.

In Gilead’s first patent disclosure that included the synthesis of voxilaprevir, now issued as U.S. Patent 9,296,782, RCM of analogue 104, incorporating a Me group instead of Et group appended to the pyrrolidine, was carried out in 1,2-dichloroethane at 95 oC using Zhan 1B catalyst 7 (15 mol %) (Scheme 22).48a The reaction generated an 85:15 mixture of the desired macrocycle 105 and byproduct 106 arising from HF elimination. The combined yield of the two compounds, which were inseparable by flash chromatography, was 45%. Many other analogues were prepared via this method but no yields nor byproduct information were provided.

Scheme 22. RCM of Voxilaprevir Analogue



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In the subsequent RCM described with the voxilaprevir metathesis precursor 112a (Et group appended to the pyrrolidine), the terminal alkene fragments for the metathesis were altered.48 The fragment incorporating the difluoro group was lengthened to four carbons such that the reaction center was one carbon further removed from the electronegative difluoro center and the terminal olefin fragment attached to the cyclopropyl group was shortened to a three-carbon chain. Under similar conditions used in the previous example (236 mg scale in 1,2-dichloroethane at 100 oC using Zhan 1B catalyst 7 (10 mol %)) macrocycle 113a was isolated in 92% yield after purification by silica gel chromatography. The HF-elimination byproduct was not mentioned in this example. In U.S. Patent 9,440,991 granted to Gilead, RCM of the t-butyl ester (112a), methyl ester (112b), and free acid (112c) are reported, although experimental procedures are provided for only the methyl and tbutyl esters.49a The terminal alkene configuration noted in the paragraph above was used, given that this arrangement provided improved yields and purity. The metathesis precursors 112a-112c were prepared from key fragments 107, 108, and 111 (Scheme 23). Fragments 107 and 108 were coupled via SNAr chemistry using Cs2CO3 in dimethylacetamide at 100-110 oC. After aq. work up, the product 109 was crystallized from 2-PrOH. The Boc group was 32 ACS Paragon Plus Environment

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removed using p-TsOH-H2O in 2-MeTHF. At the end of the reaction, MTBE was added to crystallize 110 as its p-TsOH salt. Coupling of 110 with the cyclopropyl fragment 111 was carried out with EDC/NMM in DMF. Work up with toluene afforded the product 112b as a solution in toluene which was used directly in the subsequent RCM step. For the RCM reaction, the main changes from the original Medicinal Chemistry route included replacing 1,2-dichloroethane (class 1 solvent)50 with toluene and use of slow addition. For the t-butyl substrate 112a (1.0 g scale), the Zhan 1B catalyst 7 (2.5 mol %) was dissolved in toluene and warmed to 110 oC, then a solution of the t-butyl ester 112a was added to the hot catalyst solution over 30 min. The final concentration was approx. 0.05 M. With slow addition of the substrate, the concentration of the substrate remains low throughout the process, minimizing oligomerization byproducts.51 No yield nor purity was provided for macrocycle product 113a. In the example using the methyl ester 112b (4.7 g scale), the order of addition was reversed. The metathesis precursor 112b was dissolved in toluene and heated to reflux, then a solution of the Zhan 1B catalyst 7 (3.3 mol %) in toluene was added to the hot substrate solution over a 2 h period. The final concentration was approx. 0.1 M. This order of addition is common for RCM reactions and helps reduce degradation of the catalyst over the course of the reaction. Since no yield nor purity of either macrocycle product 113a or 113b was provided, the advantage of one order of addition versus the other remains unclear. Scheme 23. RCM Route to the Voxilaprevir Macrocycle



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Two routes were established for the preparation of difluoro fragment 107 via the common intermediate 117 (Scheme 24).48,49 Reaction of ethyl 3,3,3-trifluoropyruvate with allyl alcohol mediated by


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pyridine/SOCl2 in CH2Cl2 afforded ether 115 as a crude liquid that was used directly in the next step. Reductive dehalogenation52 of 115 using zinc powder (2.0 equiv), TMS-Cl (1.0 equiv) and CuI (1.3 mol %) in DMF furnished diene 116, which was isolated as a crude liquid. Claisen rearrangement was carried out in toluene at 80 oC followed by ester hydrolysis with LiOH in aq. THF to produce ketoacid 117 as a crude material. Reaction of 117 with 4-methoxy-o-phenylenediamine (118) in EtOH produced regioisomers 119 and 120 in a ratio of 4:1 that were isolated without purification. Conversion to chloride 107 was accomplished with POCl3 in DMF with the desired regioisomer isolated by crystallization from hexanes. No yields were provided for any of the steps. Scheme 24. Route to Difluoro Intermediate 107

An alternate route to 107 from intermediate 117 was devised to address the lack of regiocontrol in the initial route (Scheme 25).49 Difluoro intermediate 117 was condensed with aniline (neat) at 150 oC to form ketoamide 121, which was isolated as a crude material. Conversion to the corresponding imino35 ACS Paragon Plus Environment


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ether intermediate was carried out with PCl5 in CH2Cl2 followed by reaction with KCN in CH3CN to afford imino-nitrile 122 which was used directly in the next step without purification. Reaction with 4methoxy-o-phenylenediamine (118) in HOAc/toluene afforded quinoxaline 123, which was purified by crystallization from 2-PrOH/water. Diazotization and conversion to chloride 117 was accoplished using t-BuNO2 and BCl3 in CH2Cl2 followed by crystallization from 2-PrOH/water. No yields were provided.

Scheme 25. Alternate Route to Difluoro Intermediate 107 from 117 O OEt F

F O 117

PhNH2 (Neat) 150 oC

F F Tol, HOAc H2 N H2 N

N OMe

118

1) PCl5 NHPh CH2Cl2 2) KCN F O CH3CN 121

O

O

NH2

N 123

F

1) BCl3, CH2Cl2 t-BuNO2 OMe 2) Crystallize from 2-PrOH

NPh F

F

CN

122 F F N Cl

N

OMe

107

Cross Metathesis Route to Voxilaprevir Macrocycle An alternate route to the voxilaprevir macrocycle employed a cross metathesis to set up a subsequent macrolactamization (Scheme 26).49 In the previous examples, the two major fragments were connected first by amide bond formation followed by RCM. In the alternate route, the fragments are initially joined via a cross metathesis reaction followed by a macrolactamization. For the cross metathesis, the terminal olefin precursor comprised a 4-carbon chain for the cyclopropyl fragment and a 3-carbon chain for the difluoro fragment. This was the arrangement that gave the 36 ACS Paragon Plus Environment

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poorest results (low yield and HF-elimination product) in the initial RCM approach shown in Scheme 22. The cross metathesis was carried out with 1.0 equiv of difluoro fragment 125 (180 mg scale), 1.9 equiv of cyclopropyl fragment 124, Zhan 1B catalyst 7 (7.3 mol %) and toluene (15 vol) at 95 oC. The olefin product 126 was purified by silica gel chromatography. No information was provided on the outcome of the reaction such as yield, homodimerization, or the HF-elimination byproduct. Hydrogenation of the double bond with Pt/C and acidic deprotection of the Boc group on the pyrrolidine afforded the macrolactamization precursor 127. Macrolactamation was carried out on 20 mg of substrate 127 using high dilution conditions (100 vol DMF) and large reagent excess (10 equiv) to afford intermediate 128 in 59% assay yield. The small scale example for the macrolactamization route makes comparison with RCM difficult. Slow substrate addition, which allows for higher concentrations in the RCM approach, can likewise be applied to macrolactamization reactions, as shown with the published synthesis of NS3/4A inhibitor grazoprevir.53

Scheme 26. Cross Metathesis and Macrolactamization Route to the Voxilaprevir Core



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3.2 Glecaprevir On Aug 3, 2017 the FDA approved Mavyret (a fixed dose combination of glecaprevir (100 mg) and pibrentasvir (40 mg)) to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6.54 Glecaprevir, an HCV protease NS3/4A inhibitor discovered by Enanta and developed by Abbvie, has a structure very similar to voxilaprevir, including an 18-membered macrocycle incorporating a difluoro group in the 5-atom backbone of the macrocycle (Figure 4). The metathesis precursor 133 was prepared from fragments 129, 130, and 132 as outlined in Scheme 27.55 Fragments 129 and 130 were coupled via SNAr chemistry using Na-t-OBu followed by formation of methyl ester product 131 with trimethylsilyldiazaomethane. After deprotection of the Boc group of 131 with HCl, amide bond formation with fragment 132 mediated by HATU afforded metathesis precursor 133.


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Since the trans double bond resulting from the RCM becomes a part of the final glecaprevir structure, the RCM must be carried out as shown in Scheme 27, with the metathesis precursor 133 incorporating the 3-carbon fragment containing the difluoro group and the 4-atom fragment containing the allylic ether. This was the configuration of terminal olefins that gave the poorer results in the voxilaprevir case, leading to HF-elimination and a 45% overall yield (Scheme 22). In the current example, reported on a gram scale, the reaction in refluxing toluene was sluggish, requiring 37 h using Zhan 1B catalyst 7 (added incrementally, 13% total), furnishing 134 in 59% after purification by silica gel chromatography. No information was provided on reaction concentration or the ratio of E/Z isomers.55 Scheme 27. Ring-Closing Metathesis Route to Construct the Glecaprevir Macrocycle



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The 4-step preparation of the 3-carbon difluoro fragment 129 (Scheme 28)55 is more straightforward than the 4-carbon difluoro fragment 107 used for voxilaprevir (Schemes 24 and 25) due to the availability of difluoro starting material 135 and the absence of regiochemistry issues with use of the unsubstituted o-phenylenediamine. Indium-mediated reaction of difluorobromide 135 with ethyl glyoxolate in DMF/water afforded the alcohol 136, which was then oxidized to the ketoester 137 using TPAP/NMO in CH2Cl2. Reaction with o-phenylenediamine in EtOH afforded quinoxaline 138, which was then converted to chloride 129 with POCl3. 40 ACS Paragon Plus Environment

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Scheme 28. Route to Glecaprevir Difluoro Fragment 129

3.3 Rolapitant Rolapitant is an NK-1 inhibitor that was approved in the US in Sep 2015 (tradename Varubi) and the EU in Apr 2017 (tradename Varuby) to prevent delayed phase chemotherapy-induced nausea and vomiting (emesis).56

The Pharmacodia web site describes 4 routes to rolapitant, two of which include ring-closing metathesis reactions to form the 6-membered spiro lactam moeity.57 It should be noted that both non-metathesis routes suffer from poor stereoselectivity in the step forming the tetrasubstituted pyrrolidinone stereocenter present in the API (Figure 5).58 The introduction of new bond disconnections enabled by metathesis allowed for this stereocenter to be accessed from a chiral pool starting material, pyroglutamic acid,59 or via a chiral auxiliary.60



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Figure 5. Alternative Bond Disconnection Strategies to Access Rolapitant

The metathesis route patented by Opko Health incorporates the 3,5-bis-(trifluoromethyl)phenyl ether group early in the synthesis and conducts the RCM as the penultimate step (Scheme 29)59 while the approach developed by Qilu Pharmaceutical company employs the RCM at an earlier intermediate and installs the 3,5-bis-(trifluoromethyl)phenyl ether group at the end of the synthesis (Scheme 30).60 3.3.1 Rolapitant (Opko Health Approach) The final steps to rolapitant as outlined in a 2016 patent and 2016 patent application from Opko Health are outlined in Scheme 29.59 Scheme 29. Late-Stage RCM Route to Rolapitant


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This sequence starts with deprotection of acetal 140 using Et3N in aq. EtOH, followed by condensation of the resulting aldehyde with amine 139. The imine product was reduced with NaBH(OAc)3 to afford RCM-precursor 141, which was crystallized from 2-PrOH/water as its tosylate salt in overall 88% yield. Formation of the 6-membered ring was carried out in toluene at 60-80 °C at a substrate concentration of 0.07M using Hoveyda-Grubbs II catalyst 3 (1 mol %). Although 141 was used as its p-TsOH salt, additional acid was shown to have a beneficial effect on the reaction. Without additional p-TsOH, 7 mol % catalyst was required for complete reaction. When 1.5 equiv p-TsOH was used, the catalyst level could be reduced to just 1%. Lower or higher levels of acid gave inferior results. The beneficial effect of acid on metathesis reactions involving amines has been well documented,61 but the positive impact of acid beyond 1.0 equiv required to fully protonate the amine is unclear. Protonation of the amide (pKa = 0) may also be occurring to minimize coordination of this center with the ruthenium catalyst. 43 ACS Paragon Plus Environment


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After complete reaction, a reductive work up with aq. Na2S2O5 was employed to facilitate Ru removal. The inventors proposed this work up cleaved the bond between the carbene and ruthenium to generate Ru salts that were either water soluble or insoluble solids. In one example, the phase transfer catalyst Bu4NCl was added to the work up to increase interfacial contact and accelerate Ru reduction. Finally, crystallization as the HCl salt from toluene/heptanes afforded spiro product 142 in 85% isolated yield for the RCM step. While the patent specification notes that the HCl salt of 142 can be hydrogenated directly, the only example of this step describes a salt break followed by hydrogenatation using Pd/C in toluene. The inventors note that toluene is an unusual solvent for the hydrogenation since these in polar solvents such as alcohols are generally preferable. Crystallization by addition of conc. HCl provided rolapitant HCl monohydrate salt in an isolated yield of 95%.59 3.3.2 Rolapitant (Qilu Pharmaceutical Approach) In an alternate approach to rolapitant, disclosed by Qilu Pharmaceutical Company,60 the RCM is carried out at an earlier stage, then the 3,5-bis(trifluoromethyl)phenyl fragment is appended as a final step via SN2 displacement (Scheme 30). The RCM of diene 145a is described on a 300 g scale using HoveydaGrubbs II catalyst 3 (10 mol %), providing an 83% yield of spiro product 146a after purification by silica gel chromatography. A number of other N- and O-substituted metathesis precursors were studied (Table 1), all affording yields in the 81-85% range. No improvement in yield was observed by protecting the basic nitrogen (compounds 145f and 145g) although catalyst loadings were high (10 mol%) in all examples. After reduction of the double bond and deprotection of the silyl group, alcohol 147 was deprotonated with NaH in DMA and reacted with bromide 148 to afford rolapitant in 93% yield after purification by


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silica gel chromatography. No information was provided on whether any epimerization at the benzylic position occurred during the SN2 displacement. Scheme 30. Early Stage RCM Route to Rolapitant

Table 1. RCM of N- and O-Substituted Metathesis Precursors



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R1

R2

Yield (%)

145a

OTBDPS

H

83

145b

Ac

H

85

145c

PhCH2

H

85

145d

4-ClC6H4C(O)

H

81

145e

t-BuC(O)

H

84

145f

OTBDPS

CF3C(O)

85

145g

OTBDPS

PhCH2

85

Compound

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Number

3.4 Eribulin Eribulin mesylate, marketed by Eisai under the trade name Halaven, was approved in the US in 2010 and in Europe in 2011 for the treatment of metastatic breast cancer.62 Starting from available raw materials, the initial commercial route required 62 steps with a longest linear sequence of 30 steps, making eribulin the most complex marketed drug manufactured by total synthesis.63 The macrocycle was constructed via an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction between C13-C14 (Scheme 31).64 This complex cyclization requires 4 metals (Cr, 10 %; Ni, 10%; Zr, 1.1 equiv; and Mn, 4 equiv) and is carried out at a concentration of 0.015M in THF, affording the macrocycle in 97% crude yield.65 Scheme 31. Original C13-C14 Macrocyclization Approach to Eribulin


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Figure 6. Disconnections for Eribulin Macrocyclization

A 2016 patent application from Eisai discloses a number of alternate approaches to the macrocyclization, two of which involve ring-closing metathesis reactions.66 The RCM disconnections (C3-C4 and C15-C16) are presented in Figure 6 along with the original NHK disconnection.64



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The C15-C16 RCM, outlined in Scheme 32, was carried out with metathesis precursor 151 at 70 oC in toluene using Hoveyda-Grubbs II catalyst 3 (12 mol %) to afford 152 in 33% yield on a 30 mg scale.

Scheme 32. C15-C16 Macrocyclization of Eribulin Precursor MeO

3

30a 30

32

O

TBSO 35

TBSO

27

O

6

1

O O H TBDPSO

8

H O H 10

O

MeO OTBDPS 13

TESO

24

O 17

16

32

O H TBDPSO

O

O

TBSO 35

O

6

1

30

TBSO 15

20

Tol, 70 oC HGII

3

30a

27

10

O

O

OTBDPS 13

15

O

24 20

O 151

8

H O H

17

OTES 16

152

For the C3-C4 cyclization, the precursor 153 already includes the polycyclic C8-C14 moiety (Scheme 33). The macrocyclization reaction was carried out on a 12 mg scale in toluene with HGII catalyst (20%) to afford macrocycle 154 in 67% yield after isolation via silica gel chromatography. Scheme 33. C3-C4 Macrocyclization of an Eribulin Precursor


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MeO

MeO

3 30a

TESO

32 35

30

O

4

30a

TESO

1

HO TESO

TESO

6

O H

10 8 27

O

O

24

15

O

O

O

Tol, 70 oC HGII

32

35

30

O

3

1

4

HO TESO

TESO

6

O H

10 8 27

1 mM H 3h

O

O

24

13

15

O

16

17

O

O

H

13

16 17

20

20

153

154

3.5 Prostaglandins – Bimatoprost, Tavoprost, Latanoprost, and Unoprostone IRIX Pharmaceuticals has developed alternate routes to several prostaglandin drugs based on RCM methodology.67,68 For the closely related drugs bimatoprost, tavoprost, and latanoprost, an RCM was used to generate 10-membered macrolactones.67Since the macrolactones are created with a cis-double bond, the lactone was then hydrolyzed to reveal the side chain incorporating the cis-double bond. Four examples of the RCM reaction using Grubbs I catalyst 5 carried out in refluxing dichloromethane are presented in Table 2. Using 4-10 mol % catalyst, yields of the substrates containing only an oxygen heteroatom ranged from 83-85%, but the thiophene-containing product was only produced in 35% yield.

Table 2. RCM to Form 10-Membered Macrolactonesa Drug Name

RCM precursor

Catalyst

Yield

Product

Loading (mole %)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

bimatoprost

4

85%

tavoprost

10

83%

latanoprost

6

85%

prostaglandin

7

35%

Page 50 of 67

analogue

a

Conditions: 0.02-0.03M in dichloromethane, 18 h at 40 oC, Grubbs I catalyst

Conversion of the lactones to final products involved nucleophilic ring opening of the lactone followed by deprotection, as exemplified in Scheme 34 for bimatoprost. Scheme 34. Macrolactam Amidation and Deprotection of Bimatoprost


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Synthesis of Unoprostone A route to unoprostone comprising two metathesis reactions is presented in Scheme 35.68 Cyclopentane 155 was esterified with 5-hexenoic acid using DIC/DMAP, then the resulting ester 156 was subjected to RCM with Grubbs I catalyst 5 (0.2 mol%) in toluene (0.025M) at 75 °C to afford macrolactone 157 in 65% yield on a 49 g scale. The TBS group was removed using NH4HF2 in MeOH, then the lactone opened with NaOH to afford free acid 158. Alkylation with 2-iodopropane afforded ester 159. Cross metathesis was carried out with 2 equiv vinyl heptyl ketone using Grubbs I catalyst 2 (0.3 mol %) in toluene at 75 °C to afford diene 160 in 35% yield. Selective reductive of the enone double bond afforded unoprostone.

Scheme 35. Route to Unoprostone Using Two Metathesis Reactions



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 52 of 67

A second route to unoprostone also uses two metathesis reactions, as outlined in Scheme 36.68 In step 1, cross metathesis of 161 using Grubbs 1 catalyst 5 afforded dimer 162 in 89% yield. Diastereoselective conjugate addition of the cuprate of 163 provided the bis-addition product 164. Diastereoselective reduction with the R-CBS catalyst followed by esterification furnished symmetrical triene 166. Double


Page 53 of 67

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


RCM of the triene afforded the single macrolactone 167 in 70% yield. Deprotection and opening of the lactone with 2-PrOH afforded unoprostone. Scheme 36. Alternate Route to Unoprostone OTBS

O

O

O Grubbs I tol, 75 oC 89%

O

I

O

t-BuLi, CuCN, -70 oC

EtO

O OEt

OEt

163

162

161 TBSO

EtO

TBSO

EtO O

O

HO

R-CBS

O

5-hexenoic acid

BH3-THF

DIC, DMAP, THF OH

O

O

O OEt

OEt

OTBS

OTBS 165

164 TBSO

EtO O

O

Grubbs I

O

O tol, 75 oC 70%

O O OEt

OTBS 166

O O

1)TBAF, THF 2) IBX, tol, DMSO

O OEt 167

OTBS

3) 2-PrOH, H2SO4 75 oC

CO2i-Pr

HO

HO

O

unoprostone isopropyl ester



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 54 of 67

Summary Olefin metathesis is firmly established as a powerful carbon-carbon bond forming reaction used in drug discovery and development alike. Though its first foothold in pharmaceutical synthesis was its application toward macrocyclic peptides, ring-closing metathesis is used routinely to form rings of virtually any size, and in the presence of both steric challenges and polar functional groups. These advances are due in part to the increasing availability of more tolerant catalysts, but also due to a better understanding of the practical aspects of carrying out metathesis chemistry that include the removal of ethylene and the use of additives to tame coordinating groups and prevent olefin isomerization. Work to understand and characterize the mechanistic pathways leading to catalyst deactivation continues, which may lead to more optimal catalysts and conditions for recalcitrant substrates.69 Macrocyclization remains a strength of olefin metathesis. As macrocyclic compounds continue to draw attention as potential modulators of historically challenging targets,70 ring-closing metathesis will likely remain a common method to access them. For forming rings in the five- to seven- membered range, ring-closing metathesis is a convenient and predictable method, effective even for complex substrates such as bicyclic and spirocyclic systems. As demonstrated by the rolapitant example (Section 3.3), ring-closing metathesis may also provide more efficient and/or selective routes to compounds previously made by other methods.


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Despite its prevalence in specialty chemical and agrochemical applications, cross metathesis is still relatively rare in pharmaceutical chemistry.71 More than 90% of the examples in the patent literature from 2016 and 2017 were ring-closing metathesis reactions, suggesting that there may be untapped potential for cross metathesis approaches. Prior to this writing, metathesis had already proven itself in the pilot plant, and it appears that at least some of that success has translated to use at commercial scale. The information highlighted in this review about approved drugs is no doubt only part of each story, but we hope it may serve to illuminate some of the key factors that a process chemist should be aware of as he or she considers olefin metathesis as a potential tool. These include ethylene removal, the use of acids and other additives to suppress unwanted reactivity, and slow addition techniques to maximize throughput in RCM macrocyclizations. Table 3 provides a summary of the substrates and conditions for the ring closing metathesis reactions covered in this review. Table 3. Summary of Metathesis Examples in this Review

Company

Substrate

Rin g Size 8

Synta Pharmaceutical s

Catalyst (Loading ) Grubbs II (10%)

Conc

Yiel d

0.03M

66%



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 56 of 67

Janssen

8

Grubbs II (10%)

0.03M

80%

Janssen

11

Grubbs II (6.6 mol%)

0.01M

--

Janssen

12

Grubbs II (10 mol%)

0.003M

59%

Glycomimetics

9, 10

Grubbs II (10%)

0.005M

8186%

14

Grubbs II (3.3%)

0.05M

45%

n

O

O

O OMe

O

HO OBn

O O OBn

O

OBn BnO 23 University of Tokyo, Tohoku University, Shionogi


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Bristol-Myers Squibb

12

Grubbs II (20%)

0.012M

71%

Bristol-Myers Squibb

12

Grubbs II (40%)

0.04M

38%

Amgen

16

HoveydaGrubbs II (20%)

0.0014 M

68%

Amgen

16


0.002M

68%

GSK, Astex

18

Grubbs I (10%) + Grubbs II (15%)

0.002M

35%



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 58 of 67

Chugai

26

Grubbs II (20%)

0.001M

94%

Roche

7

Grubbs II (5%)

0.015M

83%

Merck

7

Grubbs II (20%)

0.9M

--

Merck

7

Grubbs II (0.8%)

0.24M

50%

Gilead

6

Grubbs I (13%)

0.01M

--

Lilly

6

Grubbs II (5%)

0.24M

70%


Page 59 of 67

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Merck

5

Grubbs II (3%)

0.2M

--

Gilead

18

Zhan 1B (15%)

0.005M

45%

Gilead

18

Zhan 1B (2.53.3%)

0.05 – 0.1M

--

Enanta

18

Zhan 1B (13%)

--

59%



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Opko-Health

Page 60 of 67

6


0.07M

85%

6


0.2M

83%

Eisai

32


2.7 mM

33%

Eisai

24


1 mM

67%

IRIX

10

Grubbs I (4%)

0.020.03M

85%

Qilu Pharmaceutical

O HN HN Ph

OTBDPS 145a


Page 61 of 67

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


IRIX

10

Grubbs I (10%)

0.020.03M

83%

IRIX

10

Grubbs I (6%)

0.020.03M

85%

IRIX

10

Grubbs I (7%)

0.020.03M

35%

IRIX

10

Grubbs I (0.2%)

0.025M

65%

IRIX

10

Grubbs I (0.5%)

0.014M

70%

References

1

This trend is consistent with Prof. Hoveyda’s assertion ten years ago that the full potential of olefin metathesis will only be realized by the development of additional catalysts with broader scope and practicality: Hoveyda, A.; Zhugralin, A. R. Nature, 2007, 450, 243-251. 61 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

2

Page 62 of 67

O'Leary, D. J.; Pederson, R.; Grubbs, R. H. Org. Synth. 2012, 89, 170-182.

3

Fandrick, K. R., Savoie, J., Yee, N., Song, J. J.; Senanayake, C. H. Challenges and Opportunities for Scaling the Ring-Closing Metathesis Reaction in the Pharmaceutical Industry, in Olefin Metathesis: Theory and Practice (ed. Grela, K.), John Wiley & Sons, Inc., Hoboken, NJ, USA, (2014), chapter 12. 4

Farina, V.; Horváth, A. Ring-Closing Metathesis in the Large-Scale Synthesis of Pharmaceuticals, in Handbook of Metathesis, 2nd ed. (eds. Grubbs, R. H.; Wenzel, A. G.; O'Leary, D. J.; Khosravi, E.), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, (2015), pp. 633-658. 5

Kong, J. Synthetic Approaches Used in the Scale Up of Macrocyclic Clinical Candidates, in Practical Medicinal Chemistry with Macrocycles: Design, Synthesis, and Case Studies. (eds. Marsault, E.; Peterson, M. L.), John Wiley, Hoboken, (2017) pp. 377-410. 6

Higman, C. S.; Lummiss, J. A. M.; Fogg, D. E. Angew. Chem., Int. Ed. 2016, 55, 3552-3565.

7

Hughes, D. L. Org. Process Res. Dev. 2016, 20, 1008-1015.

8

Mol, J. C.; J. Mol. Cat. A Chem. 2004, 213, 39.

9

Parker, S. P. McGraw-Hill Dictionary of Scientific and Technical Terms, 6th edition; McGraw-Hill Education: U.S.A., 2003.

10

Marti-Centelles, V.; Pandey, M. D.; Burguete, M. I.; Luis, S. V. Chem. Rev. 2015, 115, 8736.

11

Galli, C. Mandolini, L. Chem. Eur. J. 2000, 3117.

12

Fürstner, A.; Top. Catal. 1997, 4, 285.

13

Kuhn, K. M.; Champagne, T. M.; Hong, S. H.; Wei, W.-H.; Nickel, A.; Lee, C. W.; Virgil, S. C.; Grubbs, R. H.; Pederson. R. L. Org. Lett. 2010, 12, 984.

14

Burlison, J. A.; Ying, W. Tricyclic Triazole Compounds that Modulate HSP90 Activity. U.S. Patent Application 2016/0009724, Jan 14, 2016. 15

Vendeville, S. M. H.; Last, S. J.; Demin, S. D.; Grosse, S. C.; Hache, Y. P.; Hu, L.; Pieters, S. M. A.; Rombouts, G.; Vandyck, K.; Verschuren, W. G.; Raboisson, P. J.-M. B. Cyclized Sulfamoylarylamide Derivatives and the Use Thereof as Medicaments for the Treatment of Hepatitis B. U.S. Patent Application 2017/0002025 A1, Jan 5, 2017. 16

Magnani, J. L.; Peterson, J. M.; Zierke, M.; Smiesko, M.; Ernst, B. E-Selectin Antagonists Modified by Macrocycle Formation to the Galactose. U.S. Patent Application 2016/0333043 A1, Nov 17, 2016. 17

Nagano, T.; Okabe, T.; Kojima, H.; Kawaguchi, M.; Nureki, O.; Ishitani, R.; Nishimasu, H.; Aoki, J.; Fujikoshi, C.; Katou, M.; Odan, M.; Tanaka, N.; Tateno, Y.; Yamane, J.. Fused pyrazole derivative having autotaxin inhibitory activity. U.S. Patent Application 2016/0376278 A1, Dec. 29, 2016. 18

Aikawa, S.; Hashimoto, T.; Kano, K.; Aoki, J. The Journal of Biochemistry 2015, 157, 81.


Page 63 of 67

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


19

Pinto, D. J. P.; Corte, J. R.; Gilligan, P. J.; Fang, T.; Smith II, L. M.; Wang, Y.; Yang, W.; Ewing, W. R. Novel Macrocycles as Factor XIA inhibitors. U.S. Patent Application 2016/0068544 A1, Mar. 10, 2016.

20

Dilger, A. K.; Corte, J. R.; De Lucca, I.; Fang, T.; Yang, W.; Wang, Y.; Pabbisetty, K. B.; Ewing, W. R.; Zhu, Y.; Wexler, R. R.; Pinto, D. J. P.; Orwat, M. J.; Smith II, L. M. Macrocyclic Factor XIA Inhibitors Condensed with Heterocycles. U.S. Patent Application 2017/0057961 A1, Mar. 2, 2017.

21

Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009, 131, 3042.

22

Pietraszuk, C.; Marciniec, B.; Fischer, H. Organometallics, 2000, 19, 913.

23

Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2007, 129, 7961. 24

Several groups have noted a catalyst quench is crucial in preserving a macrocyclic product before solvent is removed. For example, see: Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.; Gallou, F.; Wang, X.-J.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M.; Donsbach, K.; Nicola, T.; Brenner, M.; Winter, E.; Kreye, P.; Samstag, W. Journal of Organic Chemistry 2006, 71, 7133.

25

Brown, S. P.; Li, Y.; Lizarzaburu, M. E.; Lucas, B. S.; Paras, N. A.; Taygerly, J.; Vimolratana, M.; Wang, X.; Yu, M.; Zancanella, M.; Zhu, L.; Gonzalez Buenrostro, A.; Li, Z. Compounds that inhibit MCL-1 protein. U.S. Patent Application 2017/0088560 A1, Mar. 30, 2017. 26

Bose, P.; Grant, S. Leukemia Research Reports, 2013, 2, 12.

27

Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A. J. Am. Chem. Soc., 2005, 127, 8044.

28

Brubaker, J. D.; Myers, A. G. Org. Lett. 2007, 9, 3523.

29

Compound 57 was disclosed as a Phase I candidate in April 2017. See: (a) Brown, S. Interdiction at a protein-protein interface: Structure-based design of the Mcl-1 inhibitor AMG 176. 253rd National Meeting of the American Chemical Society, San Francisco, CA, Apr 2–26, 2017, American Chemical Society, Washington, D.C., 2017, MEDI 354. (b) Caenepeel, S. R.; Belmontes, B.; Sun, J.; Coxon, A.; Moody, G.; Hughes, P. E. Preclinical evaluation of AMG 176, a novel, potent and selective Mcl-1 inhibitor with robust anti-tumor activity in Mcl-1 dependent cancer models. Proceedings of the American Association for Cancer Research Annual Meeting 2017; Washington, DC, Apr 1-5, 2017. doi:10.1158/1538-7445.AM2017-2027 30

Boehm, J. C.; Davies, T. G.; Woolford, A. J.; Griffiths-Jones, C. M.; Willems, H. M. G.; Norton, D.; Saxity, G.; Heightman, T. D.; Li, T.; Kerns, J. K.; Davis, R. S. U.S Patent Application 2016/0318917 A1, Nov. 3, 2016. 31

Several groups have noted a catalyst quench is crucial in preserving a macrocyclic product before solvent is removed. For example, see: Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.; Gallou, F.; Wang, X.-J.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu,



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 64 of 67

J.; Smith-Keenan, L. L.; Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M.; Donsbach, K.; Nicola, T.; Brenner, M.; Winter, E.; Kreye, P.; Samstag, W. Journal of Organic Chemistry 2006, 71, 7133. 32

Esaki, T.; Nishimura, Y.; Isshiki, Y.; Okamoto, N.; Furuta, Y.; Mizutani, A.; Ohta, M.; Lai, W. W.; Kotake, T. Spiroimidazolone Derivative. U.S. Patent 9,487,517 B2, Nov. 8, 2016. 33

https://www.forteo.com/ (Accessed Sep. 27, 2017).

34

https://medlineplus.gov/druginfo/meds/a603018.html (Accessed Sep. 27, 2017).

35

Guba, W.; Haap, W.; Kuglstatter, A.; Peters, J.-U.; Sander, U. O.; Schnider, C.; Wermuth, R.; Woltering, T. 5-Aryl-1-imino-1-oxo-[1,2,4]thiadiazines. U.S. Patent Application 2016/0318952 A1, Nov 3, 2016. 36

Minimizing the level of oxygen and/or peroxides in a Ru-catalyzed metathesis reaction mixture typically improves catalyst lifetime and turnover number. >100,000 turnovers have been reported in cross metathesis reactions, but removal of oxygen and peroxides is critical. See: Patel, J.; Mujcinovic, S.; Jackson, W. R.; Robinson, A. J.; Serelis, A. K.; Such, C. Green Chem. 2006, 8, 450.

37

Williams, P. D.; McCauley, J. A.; Bungard, C. J.; Bennett, D. J.; Waddell, S. T.; Morriello, G. J.; Chang, L.; Dwyer, M. P.; Holloway, M. K.; Crespo, A.; Chu, X.-J.; Wiscount, C.; Loughran, H. M.; Manikowski, J. J.; Schulz, J.; Keertikar, K. M.; Hu, B.; Zhong, B.; Ji, T. Piperazine Derivatives as HIV Protease Inhibitors. U.S. Patent Application 2017/0073354 A1, Mar 16, 2017. 38

Coburn, C. A.; Maletic, M.; Luo, Y.; Qi, Z.; Li, C.; Yu, T.; Soll, R. Imidazole Derivatives and Methods of Use Thereof for Improving the Pharmacokinetics of a Drug. U.S. Patent Application 2016/0108048 A1, Apr. 21, 2016.

39

Larson, K. B.; Wang, K.; Delille, C.; Otofokun, I.; Acosta, E. P. Clin. Pharmacokinet. 2014, 53, 865.

40

Cai, Z. R.; Jin, H.; Lazerwith, S. E.; Pyun, H.-J. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use. U.S. Patent Application 2016/0289246A1, Oct. 6, 2016. 41

Brooks, H. B.; Dally, R. D.; Durham, T. B.; Fales, K. R.; Frimpong, K.; McCowan, J. R.; Njoroge, F. G.; Shepherd, T. A.; Si, C.; Thrasher, K. J.; Toth, J. L.; Wu, Z. 1-oxo-1,2-dihydroisoquinolin-7-yl-(5substituted-thiophen-2-yl)-sulfonamide compounds, formulations containing those compounds, and their use as AICARFT inhibitors in the treatment of cancers. U.S. Patent Application 2017/0233378 A1, Aug. 17, 2017. 42

Monfette, S.; Fogg. D. E.; Chem. Rev. 2009, 109, 3783.

43

The specific identity of the complex responsible for isomerization is still under debate. Initially, a homogeneous ruthenium hydride was suspected (a-c). More recently, Fogg and coworkers have found evidence that nanoparticle Ru is involved (d). (a) Lehman Jr., S. E.; Schwendeman, J. E.; O’Donnell, P. M.; Wagener, K. B. Inorg. Chim. Acta 2003, 345, 190. (b) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160.(c) Higman, C. S; Plais, L.; Fogg, D. E. ChemCatChem, 2013, 5, 3548. (d) Higman, C. S.; Lanterna, A. E..; Marin, M. L.; Scaiano, J. C.; Fogg, D. E. ChemCatChem, 2016, 8, 2446. 64 ACS Paragon Plus Environment

Page 65 of 67

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

44


Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2002, 41, 4732.

45

Bitfu, T.; Biju, P.; Colletti, S. L.; Cui, M.; Hagmann, W. K.; Hu, B.; Josien, H.; Kar, N. F.; Nair, A.; Nargund, R.; Sperbeck, D. M.; Zhu, C. U.S. Patent Application 2016/0207887 A1, Jul. 21, 2016. 46

FDA approval of Vosevi: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm567467.htm (Accessed Sep. 27, 2017) 47

EU approval of Vosevi:

http://www.gilead.com/news/press-releases/2017/7/european-commission-grants-marketingauthorization-for-gileads-vosevi-sofosbuvirvelpatasvirvoxilaprevir-for-the-treatment-of-all-genotypesof-chronic-hepatitis-c (Accessed Sep. 27, 2017) 48

(a) Bjornson, K.; Canales, E.; Cottell, J. J.; Karki, K. K.; Katana, A. A.; Kato, D.; Kobayashi, T.; Link, J. O.; Martinez, R.; Phillips, B. W.; Pyun, H.-J.; Sangi, M.; Schrier, A. J.; Siegel, D.; Taylor, J. G.; Tran, C. V.; Martin, T. A. T.; Vivian, R. W.; Yang, Z.-Y.; Zablocki, J.; Zipfel, S. Inhibitors of Hepatitis C Virus. U.S. Patent 9,296,782 B2, Mar 29, 2016. (b) Bjornson, K.; Canales, E.; Cottell, J. J.; Karki, K. K.; Katana, A. A.; Kato, D.; Kobayashi, T.; Link, J. O.; Martinez, R.; Phillips, B. W.; Pyun, H.-J.; Sangi, M.; Schrier, A. J.; Siegel, D.; Taylor, J. G.; Tran, C. V.; Martin, T. A. T.; Vivian, R. W.; Yang, Z.-Y.; Zablocki, J.; Zipfel, S. Inhibitors of Hepatitis C Virus. U.S. Patent 9,655,944, May 23, 2017. 49

(a) Cagulada, A.; Chan, J.; Chan, L.; Colby, D. A.; Karki, K. K.; Kato, D.; Keaton, K. A.; Kondapally, S.; Levins, C.; Littke, A.; Martinez, R.; Pcion, D.; Reynolds, T.; Ross, B.; Sangi, M.; Schrier, A. J.; Seng, P.; Siegel, D.; Shapiro, N.; Tang, D.; Taylor, J. G.; Tripp, J.; Waltman, A. W.; Yu, L. Synthesis of an Antiviral Compound. U.S. Patent 9,440,991 B2, Sep 13, 2016. (b) Cagulada, A.; Chan, J.; Chan, L.; Colby, D. A.; Karki, K. K.; Kato, D.; Keaton, K. A.; Kondapally, S.; Levins, C.; Littke, A.; Martinez, R.; Pcion, D.; Reynolds, T.; Ross, B.; Sangi, M.; Schrier, A. J.; Seng, P.; Siegel, D.; Shapiro, N.; Tang, D.; Taylor, J. G.; Tripp, J.; Waltman, A. W.; Yu, L. Synthesis of an Antiviral Compound. U.S. Patent Application 2017/0210756 A1, Jul 27, 2017. (c) Bringley, D.; Chan, J.; Fung, P.; Keaton, K.; Lapina, O.; Morrison, H.; Pcion, D. Crystalline forms of an antiviral compound. U.S. Patent 9,562,058, Feb 17, 2017. 50

ICH Q3C — Tables and List Guidance for Industry, June 2017, Revision 3. Class 1 solvents are those that should be avoided. https://www.fda.gov/downloads/drugs/guidances/ucm073395.pdf. (Accessed Sep. 27, 2017) 51

Slow addition or simulated high dilution conditions have been employed to maximize reactor throughput in other examples: (a) Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.; Senanayake, C. Org. Process Res. Dev. 2009, 13, 250. (b) Ormerod, D. J.; Depre, D. P. M.; Horvath, A. (Janssen Pharmaceuticals, Inc., USA) Processes and intermediates for preparing a macrocyclic protease inhibitor of HCV. U.S. Patent Application 2017/0152253 A1, Jun. 1, 2017. (c) Kong, J.; Chen, C-y.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey, J.; Li, H.; Zacuto, M. J. J. Org. Chem. 2012, 77, 3820.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 66 of 67

52

Pollex, A. Product Class 4: Haloalkenes in Houben-Weyl Methods of Molecular Transformations, Science of Synthesis, Vol 32, (Mulzer, J., ed), Thieme, Stuttgart, Germany, 2008, Chapter 4.1.1.2.2, pp. 439-441. 53

Kuethe, J.; Zhong, Y.-L.; Yasuda, N.; Beutner, G.; Linn, K.; Kim, M.; Marcune, B.; Dreher, S. D.; Humphrey, G.; Pei, T. Org. Lett. 2013, 15, 4174. 54

Mavyret FDA approval: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm570038.htm (Accessed Sep 27, 2017). 55

Or, Y. S.; Ma, J.; Wang, G.; Long, J.; Wang, B. Macrocyclic Proline Derived HCV Serine Protease Inhibitors. U.S. Patent Application 2014/0194350 A1. (b) Or, Y. S.; Ma, J.; Wang, G.; Long, J.; Wang, B. Macrocyclic Proline Derived HCV Serine Protease Inhibitors. U.S. Patent Application 2017/0088583 A1, Mar 30, 2017. (c) Or, Y. S.; Ma, J.; Wang, G.; Long, J.; Wang, B. Macrocyclic Proline Derived HCV Serine Protease Inhibitors. U.S. Patent 8,648,037 B2, Feb 11, 2014. (d) Or, Y. S.; Ma, J.; Wang, G.; Long, J.; Wang, B. Macrocyclic Proline Derived HCV Serine Protease Inhibitors. U.S. Patent Application 2014/0194350 A1, Jul 10, 2014. (e) Or, Y. S.; Ma, J.; Wang, G.; Long, J.; Wang, B. Macrocyclic Proline Derived HCV Serine Protease Inhibitors. U.S. Patent Application 2016/0145298 A1, May 26, 2016. 56

FDA approval of Varubi: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm460838.htm (Accessed Sep. 27, 2017). 57

https://www.pharmacodia.com/web/drug/1_538.html (accessed Aug 29, 2017).

58

(a) Paliwal, S.; Reichard, G.; Wang, C.; Xiao, D.; Tsui, H.-C.; Shih, N.-Y.; Arredondo, J. D.; Wrobleski, M. L.; Palani, A.) US Patent 7,049,320 B2, May 23, 2006. (b) Mergelsberg, I.; Scherer, D. H.; Huttentoch, M. E.; Tsui, H.-C.; Paliwal, S.; Shih, N.-Y. (Opko Health, USA) US Patent 8,552,191 B2, Oct. 8, 2013. 59

(a) Wu, G.; Werne, G.; Fu, X.; Orr, R. K.; Chen, F. X.; Cui, J.; Sprague, V. M.; Zhang, F.; Xie, J.; Zeng, L.; Castellanos, L. P.; Chen, Y.; Poirier, M.; Mergelsberg, I. Process and Intermediates for the Synthesis of 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]8-phenyl-1,7-diazaspiro[4.5]decan-2-one Compounds. U.S. Patent 9,249,144 B2, Feb 2, 2016. (b) Wu, G.; Werne, G.; Fu, X.; Orr, R. K.; Chen, F. X.; Cui, J.; Sprague, V. M.; Zhang, F.; Xie, J.; Zeng, L.; Castellanos, L. P.; Chen, Y.; Poirier, M.; Mergelsberg, I. Process and Intermediates for the Synthesis of 8-[{1-(3,5-Bis(trifluoromethyl)phenyl)-ethoxy}-methyl]8-phenyl-1,7-diaza-spiro[4.5]decan-2-one Compounds. U.S. Patent Application 2016/0145256 A1, May 26, 2016.

60

Tian, Z.; Qi, X.; Hu, X.; Wendong, S.; Gao, Y.; Li, D.; Jiang, Z.; Long, S.; Wu, Z.; Fan, C. Methods of Preparing an NK-1 Receptor Antagonist and Intermediates. Chinese Patent Application CN105017251, Nov 11, 2015.


Page 67 of 67

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


61

(a) William, A.D; Lee, A. C.-H. CHIMIA 2015, 69, 142-145. (b) Woodward, C. P.; Spiccia, N.; Jackson, W. R.; Robinson, A. J. Chem. Commun. 2010, 47, 779-781. (c) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871. (d) Compain, P. Adv. Synth. Catal. 2007, 349, 1829-1847. (e) Dieters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199-2238. 62

http://www.eisai.com/news/news201125.html (accessed Aug 23, 2017).

63

(a) Extance, A. Chemistry World, Jun 29, 2015. https://www.chemistryworld.com/feature/organicodysseys/8670.article (accessed Aug 23, 2017). (b) Halford, B. Chem. Eng. News, 2011, 89 (43), 16. 64

(a) Yu, M. J.; Zheng, W.; Seletsky, B. M. Nat. Prod. Rep. 2013, 30, 1158-1164. (b) Bauer, A. Story of Eribulin Mesylate: Development of the Longest Drug Synthesis, in Synthesis of Heterocycles in Contemporary Medicinal Chemistry. (Ed. Casar, Z.) Springer, Switzerland, 2016, pp. 209-270; this article also discusses the metathesis routes.

65

Fukuyama, T.; Chiba, H.; Takigawa, T.; Komatsu, Y.; Kayano, A.; Tagami, K. Org. Process Res. Dev. 2016, 20, 100-104. 66

Fang, F. G.; Kim, D.-S.; Choi, H.-W.; Chase, C. E.; Lee, J. Macrocyclization Reactions and Intermediates Useful in the Synthesis of Analogs of Halichondrin B. U.S. Patent Application 2016/0264594 A1, Sep 15, 2016. 67

Yiannikouros, G. P.; Kalaritis, P.; Gamage, C. P.; Abernathy, S. B. Synthesis of Prostanoids. U.S. Patent 8,476,471 B2, Jul 2, 2013.

68

Yiannikouros, G. P.; Kalaritis, P.; Gamage, C. P.; Arefyev, D. V. Novel Synthesis Routes for Prostaglandins and Prostaglandin Intermediates Using Metathesis. U.S. Patent Application 2016/0237056 A1, Aug 18, 2016.

69

(a) McClennan, W. L.; Ruth, S. A.; Lummiss, J. A. M.; Fogg, D. E. J. Am. Chem. Soc. 2016, 138, 14668. (b) Santos, A. G.; Bailey, G. A.; dos Santos, E. N.; Fogg, D. E. ACS Catalysis, 2017, 7, 3181. (c) Engel, G.; Smit, W.; Foscato, M.; Occhipinti, G.; Törnroos, K. W.; Jensen, V. R. J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b07694 (d) Bailey, G. A.; Lummiss, J. A. M.; Foscato, M.; Occhipinti, G.; McDonald, R.; Jensen, V. R.; Fogg, D. E. J. Am. Chem. Soc. 2017,

70

Heinis, C. Nat. Chem. Bio. 2014, 10, 696.

71

Cross metathesis has been identified recently as “underutilized” in medicinal chemistry, particularly as a tool for generating multiple analogues for SAR studies: Brown, D. G.; Bostrom, J. J. Med. Chem. 2016, 59, 4443.


Olefin Metathesis in Drug Discovery and Development Examples from

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