Ring-Closing Metathesis in Pharmaceutical Development

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Ring-Closing Metathesis in Pharmaceutical Development: Fundamentals, Applications and Future Directions Miao Yu, Sha Lou, and Francisco Gonzalez-Bobes Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 22 Jun 2018 Downloaded from http://pubs.acs.org on June 22, 2018

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Organic Process Research & Development

Ring-Closing Metathesis in Pharmaceutical Development: Fundamentals, Applications and Future Directions Miao Yu*, Sha Lou*, and Francisco Gonzalez Bobes* Chemical & Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey, 08903-0191, United States

ACS Paragon Plus Environment


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Table of Contents Graphic:

Catalyst Ring-Closing Metathesis

Laboratory Reaction

Process Development


API Manufacturing

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Organic Process Research & Development Page 3

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Abstract: Ring-Closing Metathesis (RCM) has become indispensable in organic synthesis for both academic investigations and industrial applications. This review provides an overview of RCM reactions, focusing on the practical aspects that researchers in an industrial environment may find of interest. Key elements of reaction design and lessons learned from these applications are discussed to help those considering implementing RCM reactions on scale, particularly in manufacturing active pharmaceutical ingredients (APIs). Advances in developing more effective catalysts and new methodologies, such as enantioselective RCM and stereoselective macrocyclic RCM are also briefly discussed.

Key Words: Ring-Closing Metathesis, Industrial Application, Process Development, Reaction Scale-up, Pharmaceutical Manufacturing



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Table of Contents 1. 2.

Introduction ............................................................................................................................. 5 Commonly-Used Olefin Metathesis Catalysts ........................................................................ 7 2.1 Ruthenium-based olefin metathesis catalysts ....................................................................... 7 2.2 Molybdenum-based olefin metathesis catalysts.................................................................. 10 3. Practical Considerations in Application of Ring-Closing Metathesis Reactions in Pharmaceutical Development ....................................................................................................... 11 3.1 Defining the cyclization strategy ........................................................................................ 11 3.2 Desired RCM versus other reaction pathways .................................................................... 14 3.3 Impact of substrate conformation ....................................................................................... 15 3.4 Selecting the right catalyst .................................................................................................. 17 3.5. Reaction parameters: concentration and temperature ........................................................ 20 3.6. Ethylene removal to prevent catalyst decomposition and reduce undesired reaction pathways ................................................................................................................................... 23 3.7 Input quality control ............................................................................................................ 28 3.8 Solvent effects ..................................................................................................................... 31 3.9 Deactivation and removal of Ru-related by-products ......................................................... 33 4. Recent Advances in Ring-Closing Metathesis Reactions ......................................................... 39 4.1 Other Ruthenium-based catalysts with enhanced reactivity ............................................... 39 4.2 Enantioselective ring-closing metathesis (ERCM) ............................................................. 43 4.3 Stereoselective formation of alkenes in macrocyclic rings................................................. 48 5. Conclusion ................................................................................................................................ 53


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1.

Introduction Olefin metathesis reactions have broadly impacted organic synthesis over the past few

decades. In particular, alkene ring-closing metathesis (RCM) reactions are widely used in synthesis1, 2. Carbocyclic and heterocyclic compounds of many ring sizes are accessible by this powerful reaction. While five- and six-membered rings can be prepared conveniently, the synthesis of medium and macrocyclic alkene rings by RCM can be more challenging in terms of selectivity for the desired cyclization versus oligomers or undesired alkene isomers. Though RCM has been widely used in academic laboratories and drug discovery for the syntheses of numerous biologically active and structurally complex molecules, examples of its application in the pharmaceutical industry on production scales are still rare. Summarized in Figure 1 are representative applications of RCM reactions for production of active pharmaceutical ingredients (APIs) that have been commercialized or advanced in clinical studies. Among these examples, RCM reactions were mainly used to address the challenge to prepare macrocyclic peptides, common structural motifs in HCV NS3/4A serine protease inhibitors. Pioneering work to scale up RCM reaction was reported by Boehringer-Ingelheim in 2005, for preparation of the 15-membered macrocyclic alkene in Ciluprevir (or BILN-2061).3 Additional examples have been reported by teams at Janssen4, AbbVie5, Merck6 and Roche7, to construct other complex macrocyclic rings. In other cases, functionalities, such as the azapane in Relacatib8 and the spirocyclic amine in Rolapitant9, were accessed efficiently with RCM followed by hydrogenation of the alkene products.

Figure 1. Representative Examples of APIs Prepared by RCM Reactions



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Me

MeO

MeO NH

S

N

S

N

N

N O

O H N O

Me

O

O O

N

H N

N

Me NH O S O

N

N

H N

O

O

O

H N

CO2H

N

iPr

O

O NH O S O

N

N

O O

HN

O

Simeprevir (2)4

Ciluprevir (1)3 O

N

Paritaprevir (3)5

F

Me

MeO

S

N

O N O H N

O O

Et

N

O

N O

O

HN

O

O tBu

O

O S

NH O

H N

O

N O

O

H N

HN

S

O O

O

N Me

H N

CF3 O

O O

N

NH O S Me O

Vaniprevir (4)6 OMe

N

O H N N O

O

O

N

H N

IDX316 (6)59

Danoprevir (5)7

O O

NH O S Me O

HN

O

H N

O

CF3 O N S O N Me

O

8

O

MK-6325 (7)

NH

O

Relacatib (8)

NH O Me

CF3

Rolapitant (9)9

39

Considering the increasing interest on the therapeutic potential of macrocyclic compounds as pharmaceutical candidates10, the application of RCM reactions in process chemistry settings may increase in the future. Herein, we aim to provide an overview of RCM reactions, focusing on the practical aspects that researchers in an industrial environment may find of interest. The goal is not just to provide a review of applications in pharmaceutical development but highlight key elements of reaction design and lessons learned from these scale-up studies, which may help those considering applying RCM reactions on scale. The review includes a brief introduction of fundamental aspects of RCM reactions that may


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influence development of an RCM reaction and practical aspects of reaction development mostly from examples of RCM applications in manufacturing of APIs. Recent literature examples of new catalysts and methodologies in the field, such as enantioselective RCM and stereoselective macrocyclic RCM are also briefly discussed. A comprehensive review of the RCM field is outside the scope of this manuscript. Many specialized monographs and reviews existed for those interested. 11, 12

2.

Commonly-Used Olefin Metathesis Catalysts

2.1 Ruthenium-based olefin metathesis catalysts Catalyst development has been an area of major focus in the field of olefin metathesis. Through a fundamental understanding of reaction mechanism and using organometallic design principles, a series of remarkable catalysts have been developed and enable reactions that were either not feasible before or delivered unprecedented efficiency and selectivity. In this section, ruthenium- and molybdenum-based olefin metathesis catalysts commonly used in metathesis reactions (Figure 2) are briefly discussed, including highlights of their discovery, mechanism of action, and comparisons of their reactivity and stability. The first well-defined and metathesis-active ruthenium-based catalyst13 was discovered by the Grubbs group in 1992 by reacting 3,3-diphenylcyclopropene with RuCl2(PPh3)4; however, the complex showed low reactivity and was only effective in the ROMP (Ring-Opening Metathesis Polymerization) of norbornene.13a Substitution of PPh3 with PCy3 increased the metathesis activity of the complex and led to the discovery of Ru-0, which was effective in catalytic RCM.13b-c The composition of two anionic and two neutral ligands of Ru-0 still represents the structural design of most current Ru-based olefin metathesis catalysts; however, the lengthy synthesis of the cyclopropane and the low initiation rate of the resultant diphenylvinyl carbene have limited the synthetic utility of the complex. To address these issues, benzylidene complex Ru-1 was prepared in 1996, which is widely referred as “1st generation Grubbs catalyst”.13d Extensive mechanistic investigations have revealed that the 1st generation catalysts engage in catalysis via a dissociative pathway through a 14-electron complex. Phosphine dissociation is the rate determining step as the 14-electron complex is prone to re-coordinate with free phosphine



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even in the presence of excess amount of electron-rich olefins.14 While Ru-1 has demonstrated good reactivity in many olefin metathesis reactions, there are still several cases in which it is ineffective, such as reactions involving electron-poor or substituted olefins.15 Figure 2. Commonly-used olefin metathesis catalysts

The use of N-heterocyclic carbene (NHC) ligands16 led to major advances in the field of Ru-catalyzed metathesis reactions. Replacing one phosphine ligand with an NHC ligand was hypothesized to favor the dissociation of the trans phosphine from ruthenium, due to stronger σ donor ability of NHCs relative to phosphine ligands17, to generate the active 14-electron catalyst. The new complex, Ru-2, commonly referred to as the “2nd generation Grubbs” catalyst, demonstrated enhanced catalytic activity in the RCM of diethyl diallylmalonate at a rate of 100– 1000 times greater than the rate observed with Ru-1. 18 Remarkably, Ru-2 is capable of catalyzing metathesis reactions involving substituted olefins and electron-poor olefins, where Ru-1 is ineffective.15, 18, 19 Though the improved activity of Ru-2 was initially attributed to the enhanced phosphine dissociation rate, kinetic data indicated a slower rate of phosphine dissociation than that of Ru-120. Catalysts containing an NHC ligand, however, demonstrated a higher preference for coordination of olefin substrate instead of re-coordination of phosphine, which is likely due to the increased donor effect of NHC that stabilizes metal-to-olefin backbonding to a much greater extent for π-acidic olefinic substrates than σ-donating phosphine ligands. As shown in Scheme 1, the active 14 electron phosphine-free-complex I21 is generated via a dissociative mechanism and the forward reaction (coordination of the olefin) is significantly faster than re-binding of phosphine (k2>k-1). Scheme 1. Mechanistic investigations for olefin metathesis reactions with Ru-2.


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Catalyst stability in solution is a major factor that limits turnover numbers, particularly in reactions involving more challenging substrates, resulting in many cases in the need for high catalyst loadings and/or continuous addition of the fresh catalyst to the reaction. This can be a major issue for applications on large scales. The 1st generation catalysts, such as Ru-1, decompose through either unimolecular or bimolecular pathways, and undergo rapid decomposition in solution when exposed to oxygen, in spite of their excellent stability in the solid state.22 The 2nd generation catalysts, such as Ru-2, display better thermal stability than the 1st generation catalyst Ru-1, both in the solid state and in solution.18-20, 22 The enhanced thermal stability of the 2nd generation catalysts is attributed to the reduced rates of phosphine dissociation.19 In addition, NHC ligands offer steric and electronic stabilization of the coordinately unsaturated 14-electron intermediate (such as I), which improves catalyst longevity.23 Further improvement of catalyst stability was achieved by the Hoveyda group in 1999.24 Treatment of 2-isopropoxystyrene with Ru-1 generates a new complex, Ru-3, which exhibits exceptionally high stability towards air and moisture, and allows catalyst recycling because of its stability towards silica gel column chromatography. Studies in a model reaction indicated that Ru-3 initiates RCM 30 times slower but propagates four times faster in the catalytic cycle than Ru-1. The improved propagation rate supports the intermediacy of an olefin complex and is consistent with the known rate-retarding effects of phosphine re-coordination.14a The relatively slow initiation rate associated with Ru-3 can be explained by the less facile dissociation of the chelating styrenyl ether ligand while Ru-1 initiates by the more facile dissociation of PCy3 to form the 14-electron complex (Scheme 2). Scheme 2. Mechanism of olefin metathesis reactions with Ru-3.



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Combining the improved stability from the chelated styrenyl ether ligand of Ru-3 and the enhanced catalytic reactivity from the NHC ligand of Ru-2, the Hoveyda group reported catalyst Ru-4 in 2000.25 The so-called “Hoveyda” or “Hoveyda-Grubbs” catalyst not only demonstrates excellent reactivity but also is extremely robust to air and moisture. Additionally, Ru-4 was shown to be recyclable, an important economical consideration for most commercial processes. Comparing with the aforementioned catalysts, Ru-4 displays broad substrate scope and reactivity26, including electron-poor olefin substrates, such as acrylonitriles,27 fluorinated alkenes,28 sulfones29 and vinyl chlorides.30

2.2 Molybdenum-based olefin metathesis catalysts In addition to the ruthenium-based catalysts, high oxidation state molybdenum- and tungsten-based alkylidenes are also efficient catalysts, which may provide complementary modes of reactivity as well as functional group tolerance. Among the catalysts developed since the discovery of a tantalum-based alkylidene complex in 1970s,31 the four-coordinate 14 electron alkylidene complex Mo-1 (Figure 2), known as “Schrock’s catalyst”, was identified to afford high reactivity and functional group tolerance in olefin metathesis reactions.32 Mo-1 has been applied in many RCM reactions for the synthesis of biologically relevant molecules, where the same transformations were significantly less efficient with Ru catalysts. Such an advantage has been demonstrated in the formation of macrocyclic rings in Fluvirucin B1 (Sch 38516)33 and cylindrocyclophanes34, as well as the medium rings in FR-90048235 and Balanol36. Comparing with the aforementioned ruthenium-based catalysts, Mo-1 is more sensitive to air and moisture.


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Thus, these complexes has been seldom considered for achieving RCM processes for large-scale plant operations, in which catalyst stability and ease of handling become key factors.

3. Practical Considerations in Application of Ring-Closing Metathesis Reactions in Pharmaceutical Development 3.1 Defining the cyclization strategy Cost considerations of a commercial API manufacturing process often drive the improvement of the process efficiency under constrained timelines for pharmaceutical development. Though process efficiency is dictated by many parameters, it is often significantly affected by the selected route, and the process cannot be extensively optimized until the synthetic route is defined. 37 Consequently, as the cyclic molecule progresses through pharmaceutical development to the stage of on-scale production, the first goal of process development is the identification of the most efficient cyclization strategy if required. Vaniprevir (4) is a macrocyclic HCV NS3 protease inhibitor developed by Merck. An RCMbased approach to the 20-membered macrocyclic intermediate was identified as a scalable route, as all the key components could be assembled together in a convergent manner with minimal linear steps.6 As shown in Scheme 3, three possible RCM options were evaluated for macrocyclization with precursors that contain styryl-homoallyl, allyl-allyl and homoallyl-vinyl dienes. According to a prior attempt by the same group, employing styryl-homoallyl diene 10 in RCM required a high catalyst loading (>10 mol%) to obtain a satisfactory yield, which could not be further improved by screening of catalysts and reaction conditions.38 The RCM with allyl-allyl diene precursor 13 towards intermediate 12 was further investigated as 13 is more straightforward to access than the homoallyl-vinyl substrate 15. Retrosynthetically, the dieneester 13 could be derived from the sequential couplings of allyl isoindoline HCl salt 16, prolinol ester 17 and ene-acid 18. Using this strategy, the synthesis of Vaniprevir can be achieved with the longest linear sequence of only nine steps. Scheme 3. Three possible options for macrocyclic RCM route to Vaniprevir (4).




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In the synthesis Vaniprevir, besides the RCM route, alternative strategies to construct the 20-membered macrocycle were also investigated, including palladium-catalyzed cross coupling reactions and macrolactamization.38 As a large number of Pd-catalyzed cross-coupling reactions and the corresponding catalysts were available to explore the approach, several substrates were generated to evaluate Heck, Suzuki39 and Sonogashira40 reactions towards macrocyclic intermediates 19 or 20. For the Heck reaction of 21, the optimal conditions only led to formation of 47% product, which was achieved under high dilution conditions (8 mg/mL or 0.013 mM) and competing oligomerization, debromination and 19-membered ring formation were encountered. Suzuki cyclization of 9-BBN adduct 22 provided only a trace amount of product due to the low reactivity and side reactions. The Sonogashira reaction of 23 also only afforded the macrocyclic product 20 in 34% yield due to generation of a substantial amount of dimer even under high dilution conditions (5 mg/mL or 0.008 mM). In contrast, subjecting 25 to an HATU- or EDC/HOPO-mediated macrolactamization condition led to the formation of 24 in up to 75% yield, which served as another robust and cost-effective approach to Vaniprevir, instead of using the RCM reaction to build the macrocycle. Eventually, the macrolactamization approach was selected as the commercial manufacturing route to Vaniprevir41, mainly due to


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its ease of operation on-scale as the RCM reaction requires slow addition of both the substrate and the catalyst solutions simultaneously to refluxing toluene6. Scheme 4. Alternative macrocyclization strategies to Vaniprevir (4). O

N

O O O

Heck or Suzuki

OMe

O

N

O

O

HN O

O S

Vaniprevir (4)

NH O

N

H N

O O

O tBu

O

O

O tBu

O

OMe

O

Br

Et

O

N

O

N

Sonogashira N

H N

22

O

N O

O

O tBu

21

O

H N

OMe

O

19 O

O

N

H N

tBu

O

Br

or

O

O

O

O

N R2 B

O

Br

N

H N

O

N

OMe

N

H N

O

OMe O

O O

tBu

20

tBu

23 O

N

O

N

Macrolactamization

O

OMe

O

O NH

O H N

O O

N OMe O tBu

24

H N

O O

O OH tBu

25

Another example of defining a cyclization strategy was illustrated in the synthesis of Rolapitant (9), a selective NK1 receptor antagonist that has been approved for the treatment of chemotherapy-induced nausea and vomiting.9 The core structure is a diazaspirocyclic ring that contains two quaternary stereogenic centers (Scheme 5). The initial approach to build the spirocycle involved nitro-reduction followed by lactamization of the piperidine intermediate 26 to prepare the pyrrolidinone ring.42 Compound 26 was synthesized from 27 by alkylation with a Michael acceptor; 27 was prepared by nitration/reduction of 28, which can be obtained in 5 steps from N-Cbz-(L)-Phg-OH. An efficient synthesis of 9 was completed in 10 total steps; however, installation of the second quaternary center of 27 resulted in poor control of the stereochemistry, which required separation of diastereomers by crystallization. Therefore, alternative strategies to build the spirocycle with high diastereoselectivity were evaluated and RCM was deemed effective for this purpose.9 Chiral intermediates 30 and 31 were accessed from commercially available materials in 6 and 5 steps, respectively, thus the stereoselectivity of two quaternary centers was controlled independently. Coupling of the two fragments by




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reductive amination generated diene 29, which was subjected to RCM condition followed by hydrogenation to deliver 9 in two steps. Though a total of 14 steps were required, the new strategy was considered advantageous due to the improved stereocontrol and the more convergent synthesis (9 steps for the longest linear sequence). Scheme 5. Synthetic strategies to Rolapitant (9).

3.2 Desired RCM versus other reaction pathways As in any other cyclization method, the synthetic efficiency of an RCM reaction is limited by the competition between desired intramolecular RCM and intermolecular dimerization or oligomerization reactions. As depicted in Scheme 6, once the catalyst initiates the metathesis process on the diene substrate, it not only can undergo ring closure to give the desired RCM product, but also can react with another molecule of substrate through cross-metathesis (CM) to generate a dimer. The dimeric compound, which contains two terminal olefins, can then either undergo RCM to form cyclic dimer, or further react with other diene molecules to form an oligomer. Because of the nature of olefin metathesis, all these steps can be reversible depending on the substrate structures, reaction conditions and the catalyst being employed.43 Accordingly, synthesis of 5 or 6-membered rings by RCM is typically straightforward, with superior selectivity versus undesired reaction pathways. In RCM reactions producing medium or macrocyclic rings, it is relatively difficult to predict which reaction conditions would deliver the optimal result. Thereby efficient formation of desired ring closure cannot always be guaranteed.


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It should be noted that the desired RCM product sometimes can be generated from undesired acyclic dimers, which requires the catalyst to react with the internal olefinic site.44 RCM product, dimer and oligomer distributions could vary significantly, depending on the thermodynamic preference, the competence of the catalyst and the rate of competing catalyst decomposition pathways under the experimental conditions (i.e. temperature, concentration, etc). Scheme 6. Possible reaction pathways in RCM reactions.

3.3 Impact of substrate conformation Since RCM reactions can be reversible depending on experimental conditions and catalyst choice, thermodynamic factors are particularly relevant for selective formation of desired product. Among all factors, ring strain of product is one of the major contributors that determines the ease of RCM. It increases significantly in medium rings, due to the staggering and transannular interaction between atoms forced into proximity from opposite sides of the ring.45 Though ring strain diminishes in macrocyclic rings, it still remains higher than in 5- or 6membered rings. Studies from Grubbs and Bach’s laboratories revealed ring size has significant influence on the selectivity of RCM reactions versus formation of acyclic dimers, by simply altering the number of methylenes on the diene chain.46 Structural restriction towards rotation is another factor for effective RCM, which may reduce the entropic penalty incurred upon ring closure. RCM tends to work better in the presence of conformational constraints that favor ring formation, such as appropriate




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substitutions on the diene chain (Thorpe–Ingold effect47). These conformational constraints may include the presence of another ring, a gem-dimethyl group, or functionalities introducing rigid frameworks on the substrate chain.48 Therefore, diethyl diallylmalonates are broadlystudied RCM substrates to evaluate the reactivity of different metathesis catalysts. Other examples of designing suitable RCM substrates to bring two reacting olefinic sites in closer proximity for cyclization include installing of a removable pentafluorobenzyl group that is proposed to favor intramolecular π-stacking interaction49, as well as removing a structurally rigid functionality to alleviate unfavorable conformational bias50. Other than modification of substrate structure to facilitate ring closure, addition of a Lewis acid to RCM reactions of estercontaining substrates can restrain conformational mobility to increase probability of intramolecular reaction. RCM reactions of such substrates to form medium or macrocyclic rings is typically challenging as Z-conformation of esters is preferred due to the hyperconjugation and dipole effect. In order to achieve proximity for intramolecular cyclization, isomerization of the Z-conformer to the E-conformer is required; thereby such substrates likely oligomerize under metathesis conditions. Ti(OiPr)4 51 and the more sterically hindered aluminum tris(2,6diphenylphenoxide)52 were effective to suppress oligomerization and promote desired RCM to form these challenging medium and macrocyclic rings. In the initial discovery route to Ciluprevir and its analogues, conformations of an acyclic tripeptide intermediate 32 is partially determined by the ratio of the proline cis/trans isomerism, thereby the ratio of rotamers of the tertiary amide bond appeared crucial to the RCM reaction (Table 1).53 Without any substitution at the α-carbon on the olefinic side chain, the proline cis/trans isomer ratio was approximately 1:1 and the outcome of the RCM reaction of 32a was poor (entry 1). In contrast, after an N-BOC group was incorporated at the α-carbon of the side chain, the cis/trans isomer ratio changed to 9:1 and the overall conversion of diene 32b was significantly improved (entry 2). Because the tertiary amide rotational barrier is >13 kcal/mol, the inter-conversion of these isomers could not be achieved at the temperatures typically used for RCM. Unlike the 15-membered ring of a macrocyclic peptide 33b, which was efficiently produced in 80% yield with high Z-selectivity, formation of the energetically more strained 14– or 13–membered ring system failed to afford the Z-isomer of the macrocyclic


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product, but provided the E isomer 33c in 45% yield (entry 3).53 The ring size of the macrocyclic product is an important factor that oftentimes significantly impacts RCM yield and the resulting olefin geometry. Such conformation-controlled effects on the outcome of the RCM reaction were also observed in the synthesis of salicylihalamide and epothilones.54 Table 1. Conformation of RCM precursors and Ring Size of RCM products influence RCM performance.

entry

Substrate

Substrate

Proline

Conv/Yield

Z:E selectivity

/product

structure

cis/trans

1

32a/33a

R1=H; n=2; R2=R3=H

1:1

Ring-Closing Metathesis in Pharmaceutical Development

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