Recent Advances in Asymmetric Hydrogenation of Tetrasubstituted

Perspective pubs.acs.org/JACS

Recent Advances in Asymmetric Hydrogenation of Tetrasubstituted Olefins Stefan Kraft, Kristen Ryan, and Robert B. Kargbo* Drug Discovery Services, Medicinal Chemistry, Albany Molecular Research Inc., 26 Corporate Circle, Albany, New York 12201-5098, United States ABSTRACT: The asymmetric hydrogenation of tetrasubstituted olefins provides direct access to very useful biological molecules and intermediates. The development of the technology has been slow, due in part to the synthetic challenges involved in developing chiral catalysts for a successful asymmetric induction. We briefly recount the breakthroughs in functionalized and unfunctionalized tetrasubstituted olefins, from the reports of Zhou and Buchwald for functionalized and unfunctionalized substrates, respectively, to the advent of chiral phosphoramidite ligands. The main emphasis of this Perspective lies in bringing into focus the complexity and challenges of inducing an asymmetric reduction for these substrates, which includes a brief discussion of the mechanism, the latest developed chiral catalysts, and the enormous scientific opportunities that still exist in developing “go to” catalyst systems for the various substrate types.

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INTRODUCTION The growing complexity of drug discovery is driven in part by the overall need to deliver candidates with greater potency, safety, selectivity, activity, and so forth.1 Such complexity has brought to focus the need for development of the once obscure and inaccessible 1,2-contiguous stereocenter via direct asymmetric hydrogenation. The compound scope for this motif comprises essentially privileged scaffolds, which are capable of productive interactions within the binding pockets on protein surfaces, leading to a wide range of hydrophobic contacts and electrostatic bonding.2 A dichotomy exists between the need for stereoselective construction of these compounds in a simple and regiochemical fashion and the requirement for the utilization of readily available reagents. This balance has continued to be extremely challenging. However, asymmetric hydrogenation of tetrasubstituted olefins (AHTOs) provides direct access to these very important classes of compounds,3 possessing rotatable bonds in either linear or hub scaffold configurations (Figure 1).4 The benchmark of a successful asymmetric hydrogenation dates back to 2001 with the award of the Nobel Prize in Chemistry to Noyori and Knowles utilizing Rh(I)- and Ru(II)diphosphine chiral catalyst systems.5 In this regard, while methods for asymmetric hydrogenation of di- and trisubstituted olefins have experienced a rapid and successful development, asymmetric hydrogenation of tetrasubstituted olefins has grown at a very dismal rate.6 In this Perspective, we aim to bring into focus significant pivotal developments of asymmetric hydrogenation protocols for tetrasubstituted olefins, the number of © 2017 American Chemical Society

Figure 1. Representative structures of biologically relevant compounds.

which has accelerated in the past few years. Consequently, we will also highlight the difficulties in hydrogenating these substrates, the crucial development of chiral metal−ligand complexes capable of enhancing both activity and selectivity, and the enormous opportunities that still exist in the development of the once hypothetical stereoselective hydrogenation of functionalized and unfunctionalized tetrasubstituted olefins. An example of a notable breakthrough in AHTOs comes from Burk and co-workers. In 1995, they reported the pivotal asymmetric hydrogenation of cyclic and acyclic tetrasubstituted enamides with product enantiomeric excesses (ee’s) exceeding 98% using a chiral diphosphine-rhodium catalyst (vide inf ra).7 On the other hand, a 1999 report by Buchwald disclosed the first significant use of zirconocene catalysis for the asymmetric hydrogenation of the formidable Received: July 11, 2017 Published: August 11, 2017 11630

DOI: 10.1021/jacs.7b07188 J. Am. Chem. Soc. 2017, 139, 11630−11641

Perspective

Journal of the American Chemical Society unfunctionalized tetrasubstituted olefin, a substrate lacking coordinating groups, providing enantioselectivities of up to 93% (vide inf ra).8

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UNFUNCTIONALIZED TETRASUBSTITUTED OLEFINS One of the most difficult substrate types for asymmetric hydrogenation is the unfunctionalized tetrasubstituted olefin. They are generally the least reactive class of alkenes and devoid of nearby heteroatoms for coordination to metal centers, an interaction which is necessary for asymmetric reductions to proceed with high efficiency and enantioselectivity.9 Invariably, coordination of the metal is dictated by the less sterically encumbered carbon atom which is generally not the prochiral carbon in olefins that bear one such center (for example, trisubstituted or 1,1-disubstituted alkenes).10 There are limited reports for asymmetric hydrogenation involving unfunctionalized tetrasubstituted olefins. This may be partly due to the difficulties associated with an asymmetric induction and fewer biologically relevant compounds containing their hydrogenated products (Figure 1). The catalyst/ligand combinations described in this Perspective for use with unfunctionalized olefins are summarized in Figure 2.

Figure 3. Examples of AHTOs utilizing precatalyst cat. 1.

hydrocarbon solvents, and at pressures of either 80 or 1000− 2000 psig H2. As shown in Figure 3 for the synthesis of indane 1 (80 and 1700 psig), the reactivity and enantioselectivity in the preparation of product depended markedly on H2 pressure. For compound 2, the butyl substitution was sufficient to provide good yield and enantioselectivity at 80 psig. On the other hand, erosion of enantioselectivity occurred at 80 psig when the benzylic position was substituted with groups such as ethyl 3 (5% ee) or phenyl 4 (29% ee). An increase in hydrogen pressure was required to produce appreciable enantioselectivities for these substrates. The mechanism of the hydrogenation was thought to be complex and heavily substrate dependent. The proposed mechanism proceeds via initial coordination of the cationic zirconocene hydride to the olefin π-system. Any unfavorable steric interactions between the aromatic ring of the indene and the tetrahydroindenyl core of the ligand disfavors the asymmetric reduction due to crowding in the reaction transition state. This effect can be partially overcome at higher hydrogen pressures, as can be seen in the comparison of products 3 at 80 and 1700 psig (Figure 3). As the transformation mechanism continues, complete insertion of the zirconium hydride into the carbon−carbon double bond is followed by hydrogenolysis, leading to product formation and regeneration of the chiral zirconium hydride catalyst. An important feature of the zirconium catalyst is the high electrophilicity, which helps to overcome the reactivity of the sterically hindered olefins. However, the very low predictability of the sense of enantioselectivity, high catalyst loadings, and stability of the highly electrophilic catalyst may have prevented the widespread application of the protocol over the years. The shortcomings of the new catalyst systems for AHTOs persisted until in 2007, when Pfaltz and co-workers (Figure 4)11 made use of iridium complexes with chiral bidentate N,Pligands to address some of the issues that surrounded the use of the highly reactive zirconocene catalyst. The iridium catalysts were based on chiral phosphanyl oxazoline ligands, which showed high activity in the asymmetric hydrogenation of unfunctionalized tetrasubstituted alkenes at remarkably low catalyst loadings. The group prepared a library of 17 ligands, and the optimum ligand structure (L1, Figure 2) provided the greatest ee values at lower hydrogen pressures as shown for the products in Figure 4. Unlike the observation from the Buchwald group, substitution at the benzylic position (to provide compound 9) did not lead to the erosion of the

Figure 2. Summary of (pre)catalyst/ligand combinations encountered for unfunctionalized olefins, and conversion units in this Perspective.

In 1999, the Buchwald group reported the first viable catalytic, homogeneous hydrogenation of unfunctionalized tetrasubstituted alkenes.8 Unlike functionalized olefins, unfunctionalized tetrasubstituted olefins are particularly challenging for asymmetric reduction, largely due to steric encumbrance. To circumvent these problems, Buchwald and coworkers utilized cationic zirconocene complexes, which are effective at binding to olefins due to their high electrophilicity, to hydrogenate a series of indene substrates to provide indanes 1−4 (Figure 3). The active catalyst was generated from the combination of chiral zirconocene (EBTHI)ZrMe2 and the non-coordinating acid [PhMe2NH]+[B(C6F5)4]−. Exposure to a hydrogen atmosphere generated the chiral cationic zirconocene hydrides that can reduce tetrasubstituted olefins with very high enantioselectivities (Figure 3). The reactions were run at 0.25 M olefin concentrations, at room temperature in aromatic 11631


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Journal of the American Chemical Society

properties (Figure 5).14 They also carried out the asymmetric hydrogenation of a number of other challenging tetrasubstituted unfunctionalized olefins in good to excellent enantiopurity (16, 85−95% ee) using rhodium-BIBOP catalyst (Figure 2, L5). Key to their successful synthetic approach was use of “disruptive innovation” (change in synthetic efficiency using new chemistry, displacing any prior synthetic route).15 As described, Zhang’s group abandoned the conventional strategy of the sequential functionalization of a commercial isoquinoline and pursued a riskier isoquinoline construction strategy. The “disruptive innovation” resulted in the discovery of new reactions and novel processes. As a result, the team developed the first rhodium-catalyzed AHTOs for unfunctionalized olefins, as well as deriving a remarkable kinetic resolution of β-alkyl phenylethylamine derivatives via palladium-catalyzed triflimide-directed C−H olefination. An important feature of the modified C2-symmetric ligand, anthryl-MeO-BIBOP (Figure 2, L5) is its deep and well-defined chiral pocket, which afforded the optimal yield and ee values for the indenyl AHTOs. The catalyst system also exhibits tolerance to polar functional groups such as an alcohol, an ester, and a sulfonamide (Figure 5, 16). Despite the low boiling point of some of the substrates, they were obtained in respectable (up to 81%) yields for volatile substrates such as 2,3-dimethyl-1Hindene.

Figure 4. Selected examples of iridium-oxazoline asymmetric hydrogenation.

iridium-ligand activity and enantioselectivity. Unfortunately, low conversion was seen for phenyl-substituted indene compounds leading to 10 and 11. The more difficult parafluorophenyl-substituted alkene required ligand L2 for 89% ee (compound 13) at 5 bar hydrogen pressure. Interestingly, the tricyclic ring system (compound 14), which is found in a variety of natural products,12 smoothly reacted with the iridium catalysts (90% yield and >99% ee). The quest for modular, stable, and reactive chiral iridium catalysts continued until 2013, when Bussaca reported a variety of structurally diverse Boehringer−Ingelheim phosphinoimidazoline (BIPI) ligands, which were utilized as cationic iridium (COD)BArF complexes of BIPI.13 One key feature of these imidazoline-based catalysts was that they were stable enough to be purified by chromatography. In addition, the naphthyl periposition (C-8) was identified as a critical stereocontrol element. After systematic ligand optimization studies, the naphthyl core was found to be superior over the phenyl core, possibly due to conformational restriction of the phosphine substituents (Figure 2, L4). One downside was that the preparation of the 1,8-disubstituted naphthalene core was very challenging. While the higher halogens such as Cl or Br suffered reduction by the phosphine-borane anion, only the 8-fluoro-BIPI ligand was prepared and successfully applied in the asymmetric hydrogenation of the difficult tetrasubstituted olefin substrates. The iridium-ligand combination afforded remarkable ee’s (up to 96%, Figure 5 compound 15) in the hydrogenation of the indene substrates. The Zhang research group recently disclosed another notable asymmetric hydrogenation. The team reported the first gramscale total synthesis of an unusual isoquinoline alkaloid delavatine A, which displayed some promising anticancer

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MECHANISTIC ASPECTS AND SELECTIVITY Mechanistic work on asymmetric hydrogenations of tetrasubstituted olefins is conspicuously absent in the literature. It is commonly assumed that such reactions are subject to the same stereoelectronic parameters and therefore proceed by pathways analogous to those that were identified for trisubstituted alkenes. We will briefly review the mechanistic aspects and selectivity for rhodium- and iridium-catalyzed asymmetric hydrogenation and highlight some of the similarities and differences in the nature and sequences of elementary steps during catalytic hydrogenations. Among the three most prominent metals (Rh, Ru, and Ir), rhodium catalysis16 has been mechanistically investigated most extensively due to the outstanding performances of early catalysts in the asymmetric synthesis of amino acid derivatives.17 In broad terms, this transformation is most effective in conjunction with alkenes that bear additional coordinating groups; substrates therefore occupy two coordination sites on the metal during hydrogenation. Intimately tied to the rhodium platforms were historically bidentate C2-symmetrical chiral phosphines such as 2,3-O-isopropylidene-2,3-dihydroxy-1,4bis(diphenylphosphino)butane (DIOP) with backbone chirality 18 or ethane-1,2-diylbis[(2-methoxyphenyl)phenylphosphane] (DIPAMP), a P-chiral ligand,5l and seminal mechanistic studies were undertaken using dehydroamino acids as substrates (Figure 6).19 Rh-based catalytic cycles commonly operate on the basis of an “unsaturated” mechanism,19a,20 in which a Lewis acidic and hydride-free solvato complex A, such as [(P-P)RhI(S)2]+ (S = solvent, P-P = chiral diphosphine), engages a prochiral alkene such as methyl(Z)-α-acetamidocinnamate (MAC) to form square planar adduct RhI-complexes (P-P)RhI(MAC)]+ (Figure 6, B1 and B2). Critically, in a directed hydrogenation model,20 the substrate is bonded in a bidentate fashion in which the Lewis basic carbonyl-oxygen of the acetamide connects to the metal center in addition to the olefin moiety. The substrate association is a dynamic process at ambient temperatures, and

Figure 5. Examples of application of iridium-BIPI and rhodium-BIOP catalysts. 11632


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A useful stereocomplementarity model for rhodiumcatalyzed asymmetric hydrogenations (Figure 7, (P-P) = S,S-

Figure 7. Front view of key intermediates B1, B2, C1, and C2. Reproduced with permission from ref 25a. Copyright 2002 American Chemical Society.

DIPAMP) should consider the bias due to steric interactions in the square-planar configurations of B1 and B2 (thermodynamic recognition) as well as the bias from steric clashes in an octahedral ligand environment of C1 and C2 (formed in the rate-determining step). Simplified analyses can be undertaken with the quadrant models.5l,19a,24 Based on ligand sectors with differential steric repulsion toward alkene faces, the popular C2or pseudo-C2-symmetrical ligand scaffolds express themselves in alternating quadrant patterns (large (I)/small (II)/large (III)/ small(IV)),23a,25 in which the smallest substituent on the alkene will face the most crowded quadrant. In trisubstituted olefins, the hydrogen substituent plays this critical role handily. However, tetrasubstituted alkenes that are generally considered more crowded and less suitable for metal coordination to begin with incur an additional setback in this model, as they lack an H-substituent and therefore fare less well in stereodifferentiations. Overall, steric interactions increase sharply in the course of the H2 oxidative addition to B1 and B2 (by approximately 35−40 kcal/mol) and subtle distinctions for major and minor pathways (in the order of a few kcal/mol) can be challenging to elucidate.26 Nevertheless, plausible arguments based on molecular mechanics have been put forth and revealed that oxidative H2 addition causes a reorientation from a transdisposition to a cis-disposition of the ligand chelate and substrate plane in C1 and C2.27 As a consequence, the migration of the carbonyl-oxygen to an apical position on the Rh induces a pivoting action of the coordinated alkene moiety from a “perpendicular” orientation of the CC axis in B1 and B2 (relative to the P−Rh−P plane) to a parallel alignment in C1 and C2 (Figure 7).27,28 The relevance of individual contacts between alkene substituents and ligand periphery varies with the alkene orientation (“perpendicular” vs “parallel”) and with the re/si face coordination, which inadvertently leads to oscillations in diastereomeric complementarities. One has to take into account all the changes that the re and si faces experience in B1 and B2 (Figure 7) during their respective transformation to C1 and C2when matching fits turn into mismatches and vice versa (“anti-lock-key”).19b,29 A closer look at this model reveals that it is the steric interactions in one sector that govern the stereodifferentiation between the minor manifold in Figure 6 (building steric repulsion in sector III (Figure 7) between

Figure 6. Halpern−Brown mechanism for asymmetric hydrogenation of MAC. Reproduced with permission from ref 19a. Copyright 1982 The American Association for the Advancement of Science.

for (P-P) = S,S-DIPAMP, an 11/1 ratio in coordinating the alkene re-face (B2) over the si-face (B1) was detected.19a However, in the next step, the thermodynamic ratio is “overruled” by a kinetic bias. In the rate-determining21 oxidative addition of H2, an octahedral dihydride complex (P-P)RhIIIH2(MAC)]+ (Figure 6, C1 and C2) are produced with an approximately 580-fold higher reactivity of the minor component B1 over that of the major constituent B2 with (PP) = S,S-DIPAMP (Curtin−Hammett principle).22 The cycle is finalized by facile migratory insertion of the alkene into a Rh− H bond (D1, the corresponding minor intermediate D2 from C2 is not shown in Figure 6) followed by reductive C−H elimination to regenerate A. In contrast, the recently popular electron-rich phosphinesrhodium complexes follow a dihydride pathway, in which H2oxidative addition to form octahedral [(P-P)RhIIIH2(solvent}2]+ precedes substrate coordination. Ultimately, however, this route still proceeds through the octahedral intermediates (P-P)RhIIIH2(substrate)]+ analogous to C1 and C2.23 11633


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was crucial for the enantioselective formation of compound 13 in Figure 4.

ligand and substrate carboxylate during the alkene pivot in B2 → C2) versus the major manifold (relieving a steric clash in sector 1 between ligand and carboxylate during the reaction B1 → C1).20 Nevertheless, the intramolecular sequence of events dictates that a given substrate has to bind to the square planar form (B1 and B2) and additionally allow for oxidative addition of H2 (without alkene dissociation) with concomitant substrate realignment. On the other hand, a tetrasubstituted olefin substrate may fail on both levels (extremely poor binding and/or exceptionally low reactivity) in the oxidative addition, migratory insertion, or reductive addition step.30a Consequently, a given prochiral substrate with minimized steric repulsion in the octahedral coordination environment of the rhodium dihydride (C1 in Figure 7) would still have to be able to at least weakly coordinate to Rh (in a potentially mismatched fashion) in its square planar precursor state. Asymmetric hydrogenations of non-coordinating alkenes frequently involve iridium catalysts with bidentate mixed donor ligands (N,P or C,P)30b and operate on an IrIII/IrV catalytic cycle.31 Product formation is determined by positioning the olefin trans to the phosphine and aligning the CC bond in a collinear fashion with the H−IrIII−(H2) axis (Figure 8). Subsequent migratory insertion is accompanied by H2 oxidative addition of the dihydrogen ligand.32

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FUNCTIONALIZED TETRASUBSTITUTED OLEFINS The asymmetric hydrogenation of functionalized, tetrasubstituted olefins is more developed compared to that of the AHTOs for unfunctionalized tetrasubstituted olefins. This is due in part to the demand for efficient and convenient access to chiral compounds such as α-amino acids, β,β-disubstituted αamino acids, chiral carboxylic acids, 1,2-chiral cyclic α-amino acids, and so forth.35 These compounds are structural motifs of significant interest to the pharmaceutical, perfumery, biochemical, and agrochemical industries.36 The asymmetric synthesis of these compounds represents a considerable synthetic challenge due to the difficulties of controlling the formation of vicinal stereogenic centers, appropriate directing and protecting groups, and the ability to employ a chiral catalyst that synergistically balances the steric and electronic factors of the substrates synchronously.37 In addition, the congested steric environments of the substrates render them unreactive to the ligand−metal complex, regardless of how reactive the chiral catalyst might be. Furthermore, strong binding affinity of a chelating/directing group may deactivate the catalyst and render the process noncatalytic.38 Despite all of these obstacles, Burk and coworkers achieved arguably the first truly successful AHTOs on β,β-disubstituted α-enamides in 1995.7 The team carried out an asymmetric hydrogenation method study on both cyclic and acyclic enamide precursors (see Figure 10) with a catalyst tolerance for both E- or Z-substitution. Optimal conditions for the reaction employed a cationic Me-BPE-Rh catalyst in methanol and at 60 psi H2 pressure (see Figure 9, L7). The flexibility of the Me-BPE-Rh catalyst allowed a greater range of β-substituents on the α-enamides, which afforded higher enantioselectivities compared to the Me-DuPHOS-Rh catalyst (Figure 9, L6). It is worth noting the structural sensitivity of the catalyst. While high levels of selectivity were achieved for the preparation of isopropyl substrate product 17 (Figure 10), the switch to catalysts with minor ligand modification (n-PrDuPHOS and i-Pr-DuPHOS-Rh) afforded dismal selectivities at 45% and 14% ee, respectively. Furthermore, the ester functionality was not a requirement for high enantioselectivity, as the free acid of the isopropyl substrate gave 94% ee using L7Rh catalyst. Sensitive functionalities were well tolerated in the reaction conditions, such as the keto group in 19 which was unaffected. In the case of the β-vinylic amino acid 18, 99% de) of the (2S,3S)-diastereomers. The chiral catalyst systems used in AHTOs are very substrate specific, and a slight change in substrate can have a dramatic effect on catalyst performance. In 2010, Benhaim and coworkers disclosed the first report of AHTOs on trifluoromethyl substrates in the preparation of β-trifluoromethyl α-amino acids.43 Optimal ligand screening was carried out, and two of the top-performing catalysts, (R)-Ph-BPE-Rh and (R)-TCFPRh (Figure 9, L10 and L11, respectively), were then examined with a series of substrates (Figure 13).

Figure 9. Summary of ligands encountered for functionalized olefin reductions in this Perspective.

Figure 10. Examples of application of rhodium complexes of DuPHOS (L6) and BPE (L7).

Figure 13. Examples of application of rhodium-BPE and -TCFP catalyst. Figure 11. Examples of application of ruthenium-Tunaphos catalysis.

The substituent effect on the substrate was investigated with various R groups such as alkyl or aryl (Figure 13). At 70 psi of hydrogen, for a simple ethyl group, rhodium-L11 performed the best for compound 35 compared to use with rhodium-L10. An increase in the steric effect by introducing a benzyl group (36) eroded the reactivity for rhodium-L10; however, rhodiumL11 gave outstanding conversion and enantioselectivity. When an aryl group was directly attached to the double bond (37 and 38), the AHTOs required higher hydrogen pressure (250 psi),

hand, slight erosion of selectivity was seen for the six- and seven-membered substrates leading to 26 and 27, respectively. Furthermore, the chiral trans diastereomeric products can be prepared by epimerization in which the products are heated in a basic alcoholic solution. The group demonstrated such utility by preparing methyl trans-(1R,2R)-2-tert-butoxycarbonylaminocyclopentane carboxylate in high yield. It should be mentioned, 11635


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hydrogenation of enamide over nitrile reduction. However, due to undesired nitrile hydrolysis during the asymmetric hydrogenation, the team settled for the AHTOs of primary amide 46 during the process synthesis of 47. Also in 2012, a switch from a keto-substrate to an ester functionality was reported by Zhou in the palladium-catalyzed asymmetric hydrogenation of tetrasubstituted cyclic β-(arylsulfonamido)acrylates (Figure 16).45 It is likely that the

and rhodium-L10 performed better compared to rhodium-L11 (Figure 13). It is worth noting that rhodium-L11 catalyst required a methylene spacer for both reactivity and selectivity, possibly relieving the steric congestion in the substrate. Early in 2012, May at Eli Lilly and Company reported an interesting AHTOs involving α,β-unsaturated ketones, catalyzed by rhodium-Josiphos, and promoted by zinc(II)-triflate (Figure 14).44a AHTOs adjacent to a ketone functionality are

Figure 16. Examples of application of palladium-DuanPhos catalyst.

Figure 14. Examples of application of rhodium-Josiphos catalyst.

hydrogenation is controlled via Bronsted acid-catalyzed tautomerization of enesulfonamides to an N-sulfonylimine intermediate, which is followed by a dynamic kinetic resolution during the hydrogenation sequence. Screening of potential ligands showed that (1R,1′R,2S,2′S)DuanPhos, developed by Zhang,46 performed the best (Figure 16). It is interesting to note that compound 51 was used in the expeditious route to the key intermediate of a bioactive drug molecule for the treatment of Alzheimer’s disease.47 In 2013, Zhou and co-workers introduced chiral spiroiridium complexes that were highly effective for the asymmetric hydrogenation of α,β-unsaturated carboxylic acids under mild reaction conditions.48 Optimal ligand structure constituted a benzyl group on the oxazoline ring and bulky 3,5-di-tertbutylphenyl groups on the phosphorus atom for both reactivity and enantioselectivity (Figure 9, L16). Consequently, the substituents on the phenyl ring of the substrates had relatively weak influence on both the reactivity and enantioselectivity (54, Figure 17) and afforded yields of 96−98% and

prone to epimerization of the product, and furthermore require an additional degree of chemoselectivity in avoiding carbonyl reduction. The team carried out a high-throughput screening and identified an effective rhodium-L12 complex (Figure 9, L12). The method allowed a reasonably broad scope, however, when the ketone substituents were changed from phenyl to alkyl such as methyl, higher catalyst loading was required. In addition, increased steric bulk on the olefin substrate led to an increase in selectivity (Figure 14, 42 and 43 compared to 44 and 45, respectively). Furthermore, a key feature of this protocol was the use of catalytic zinc triflate, which significantly improved substrate/catalyst ratio (S/C) and suppressed epimerization at the carbonyl α-position of the hydrogenated products. On the other hand, the use of triflic acid led to epimerization of the product, while trifluoroacetic acid, methanesulfonic acid, and nitric acid failed to promote the reaction. The rate acceleration of the zinc triflate was rationalized as facilitating the formation of an electron-rich ketal, resulting in a better directing group and also increased rate of substrate−ligand complex formation (Figure 14, 41). However, electron-poor substrates are common alkene substrates for AHTOs catalyzed by rhodium catalyst systems. A noteworthy example of a complex and electron-rich tetrasubstituted alkene was that used in an asymmetric hydrogenation carried out by a Merck team during an efficient four- or six-step synthesis of cannabinoid-1 receptor inverse agonist taranabant (47, Figure 15).44b The team carried out a comprehensive high-throughput screen of solvents, ligands, and additives and found nearly complete selectivity for asymmetric

Figure 17. Examples of application of iridium-SIPHOX catalyst.

enantioselectivities of 90−96% ee for both electron-withdrawing and electron-donating groups. Of interest is the potential of compound 55 as a building block for the chiral bioactive molecule Aliskiren (Figure 1). The protocol was amenable to other functional groups such as α-aryloxy-β,βdimethyl acrylic acids (Figure 17, 56), which afford a direct route to chiral α-aryloxy isopentyl carboxylic acids that are the

Figure 15. Example of application of rhodium-Josiphos catalyst. 11636


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excellent enantioselectivities in most cases, regardless of the size of substitution on the olefin. However, the method was limited to E-substrates and also suffered from low catalytic turnover numbers. In 2015, the group reported a rhodium-JosiPhoscatalyzed asymmetric hydrogenation of o-alkoxy tetrasubstituted enamides.53 The AHTOs furnished chiral β-amino alcohol analogues, such as 65 in Figure 19, in high yields and excellent enantioselectivities. Interestingly, the rhodium-DuanPhos catalyst was ineffective for the synthesis of β-amino alcohol 65 (only 5% conversion). The AHTOs to generate β,β-diaryl-α-amines, where the βaryl substituents are nonidentical, represents a considerable synthetic challenge due to the difficulty in controlling the E/Z geometry during their preparation (Figure 20). Furthermore,

key structural component in numerous bioactive molecules and organocatalysts.49 However, for cyclic systems, the orientation of the double bond was critical for the asymmetric hydrogenation. For example, the tetrasubstituted endocyclic olefin 57 did not undergo the hydrogenation using standard hydrogenated conditions. Nonetheless, the Zhou team has built on the successes of the chiral spiro-iridium complexes. In a recent report, the team disclosed the asymmetric hydrogenation of tetrasubstituted cyclic enones to chiral cycloalkanols with three contiguous stereocenters (Figure 18).50 The team envisioned

Figure 18. Examples of application of iridium-SpiroPAP catalyst.

the asymmetric hydrogenation of the CC bond of cycloalkenones 58 could install the β-alkyl-substituted tertiary stereocenter, followed by asymmetric hydrogenation of the CO bond via dynamic kinetic resolution, resulting in three contiguous stereocenters. After screening various chiral spiroiridium catalysts, Ir-Spiro-PAP was found to perform the best. The protocol was amenable to form both the cyclopentanols, such as 60 and 61, in high yields (90−95%) and with excellent enantioselectivities (92 to >99%) and >99% cis,trans-selectivity. In addition, cyclohexanols such as 62 and 63 were afforded in high yields (90 to 98%) and with excellent enantioselectivities (96 to >99% ee) and excellent diastereoselectivities (cis,cisisomer: >99%). In 2014, Zhang reported an AHTOs that provided a concise route to chiral α-hydroxyl-β-amino acid derivatives such as 64 (Figure 19), accompanied by excellent enantioselectivities.51 These compounds are valuable chiral building blocks in synthetic chemistry and in many biologically active compounds.52 The team carefully screened a series of chiral ligands and found a rhodium-DuanPhos catalyst that was efficient for a wide range of β-aryl-α-acetoxy β-enamido esters with electronrich or -poor aryl groups. The protocol afforded high yields and

Figure 20. Examples of application of rhodium-Josiphos catalyst.

controlling the facial selectivity during hydrogenation in forming two vicinal stereogenic centers possesses an incredible challenge. To address these issues, two teams from Merck prepared tetrasubstituted olefins in high yields without the loss of E/Z geometry during their preparation as well as during the asymmetric induction.54 They identified catalyst systems that afforded high levels of enantioselectivities (Figure 20). To illustrate the steric congestion of this system, the group carried out molecular modeling of N-Boc β,β-diarylalanine methyl esters such as 71 or 72, which showed that the phenyl groups were twisted out of conjugation and effectively shield both faces of the double bond. Asymmetric hydrogenation of these highly congested olefins gave poor reactivity with both ruthenium and iridium catalysts. However, rhodium-ligand catalysts (Figure 9, L17 and L18) exhibited good reactivity and selectivity on multigram scale at catalyst loadings as low as 1.0 mol%. The group tested over 150 ligands and settled for the readily available Josiphos family of ligands. A variety of N-acyl and N-methoxycarbonyl β,β-diarylamino acids were hydrogenated with high asymmetric induction. Interestingly, pyridine (69), substituted phenyl rings (71 and 72), and azaindoles (70 and 73) were tolerated during the asymmetric hydrogenation. Noteworthy, are the high enantioselectivities achieved for substrates 71 and 72 with the increase in bulk around the

Figure 19. Examples of application of rhodium-Josiphos and rhodiumDuanPhos catalysts. 11637


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Journal of the American Chemical Society olefin. These required revised conditions of ligand L18, possibly relieving steric congestion with the substrate. Given the unquestionable challenges of the AHTOs, in 2016 Christensen and co-workers at Merck Research Laboratories used the power of high-throughput experimentation (HTE) to rapidly identify conditions for asymmetric hydrogenation in the presence of the labile cyclopropyl substituents (Figure 21).55

Figure 23. Examples of application of rhodium-phosphoramidite catalyst.

olefins and all-alkyl alkenes and with tetrasubstituted polyenes. However, the sense of π-facial selectivity can be influenced by remote donor substituents. The synthetic utility of the protocol was highlighted with the rapid synthesis of two natural products, (−)-enterodiol and (−)-lasiol.

Figure 21. Examples of application of ruthenium-JosiPhos catalyst.

The team found that the olefin geometry defined the relative stereochemistry at the α- and β-positions. They also evaluated 24 chiral phosphine ligands in two solvents (2-methyltetrahydrofuran and methanol), resulting in 96 experimental permutations. It was found that rhodium catalysts led to low conversion, possibly due to decomposition via cyclopropyl ring opening. On the other hand, ruthenium catalyst afforded the product in high conversion and selectivity. The team settled on the use of the cationic ruthenium-Josiphos complex (Figure 9, L13) and synthesized the α-methyl-β-cyclopropylcinnamate analogues on multigram scales, at 200 g and eventually in kilogram quantities, all with excellent enantioselectivities (Figure 21, 75−77). Chiral cycloalkylamines and their derivatives are important motifs in many bioactive molecules and drugs, and are valuable intermediates in organic synthesis. In early 2017, Zhang disclosed an efficient rhodium-catalyzed AHTOs involving cyclic enamides, which afforded cyclic chiral amides with high yields and excellent enantioselectivities.3a The team screened a number of chiral rhodium-ligand complexes and found rhodium-Binapine (Figure 9, L19) to be the most effective catalyst for the six- and seven-membered rings (Figure 22, 78−

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CONCLUSIONS AND OPEN CHALLENGES The aspects of asymmetric hydrogenation of tetrasubstituted olefins (AHTOs) delineated in this Perspective have highlighted how ad hoc changes to substrates, reaction conditions, or catalyst systems may be utilized as a means of rendering a successful asymmetric induction on tetrasubstituted olefin substrates. Although these protocols outlined herein were mostly effective strategies, they lack the predictability or generality that would allow for the development of a universal metal−ligand complex suitable for a general AHTOs application. From this Perspective, it is evident that there is a chiral catalyst to substrate specificity, and consequently no chiral catalyst has addressed all the different substrates presented. However, important hurdles have been surmounted within this research period, including achieving high levels of enantioselectivity and extending the scope of substrates from the limited unfunctionalized precursors to a variety of functionalized olefin substrates. There are loose trends emerging, the first of which suggests that rhodium-based catalysts are often superior to those of ruthenium-, iridium-, or palladium-centered chiral systems, although the data are thus far still preliminary. In addition, phosphine-based ligands such as Josiphos are frequently selected as the ligand system of choice. The development of AHTOs is moving through the second phase of evolution in which more successes are being reported. This needs to continue for AHTOs development to further advance, and in particular for the identification of readily available and reliable “go to” chiral catalyst systems. This is analogous to the early maturity of the olefin metathesis reaction, Suzuki and Buchwald coupling protocols, and so forth, for which reliable commercially available catalyst systems now exist for a wide range of substrates. The challenge for AHTOs to get to this well-developed phase is awash with significant scientific opportunities. The Wallace and Christensen examples (Figures 15 and 21, respectively) highlight the power of leveraging HTE57 to assess substrates tailored to chiral metal complexes.50 These examples not only attest to the complexity of asymmetric hydrogenation of tetrasubstituted olefin precursors, but also provide a guide to rapidly identify conditions for an AHTOs. Given the complexity, it is clear that more HTE should be carried out for a variety of tetrasubstituted substrate types. However, it may

Figure 22. Examples of application of rhodium-Binapine and -tBuJosiPhos catalysts.

80). However, for cyclopentene enamides, the Rh-Binapine was ineffective, whereas Rh-tBu-Josiphos was found to catalyze the reaction most effectively in 95% yield, albeit with a decreased 77% ee. An intriguing mode of olefin activation was recently disclosed by Takacs and co-workers at the University of Nebraska− Lincoln.56 The group reported a remarkably facile boranepromoted, oxime-directed, and Rh-catalyzed AHTOs in high yields and with high selectivities (Figure 23). The mild protocol required short reaction times and only a slight excess above stoichiometric H2. The method works well for aryl-substituted 11638


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dictates the coordination of the chiral catalyst rather than the prochiral carbon, and consequently, AHTOs on E/Z olefin mixtures often yield very low enantioselectivity. In this regard, a chiral catalyst system that would directly select the prochiral carbon, regardless of the E/Z ratio is highly desirable, especially for use with unfunctionalized tetrasubstituted substrates. A departure from established, “off the shelf” C2- and pseudo-C2symmetrical catalyst may provide solutions to that conundrum.62 We hope this report serves not only to adequately introduce readers to this emerging field but also to inspire future research efforts toward the development of readily available chiral catalyst systems for more exemplary AHTOs.

be counterproductive for researchers in early drug discovery programs to be involved in such HTE processes, since rigorous and rapid interrogation of chemical space is generally required at that stage of most drug discovery campaigns. On the other hand, those process chemistry teams equipped with rapid parallel synthesis equipment should be able to harness the potentially enormous scientific discoveries through HTE investigations on fixed templates. It may also instigate collaborative work between academia and industry to complement scientific endeavors. The challenging funding situation within academic research frequently deprioritizes diversion of resources toward efforts toward solving difficult problems such as AHTOs, when easier research work that could produce rapid research papers is often more readily available. Consequently, direct funding to address AHTOs would go a long way to unravel the scientific “gold mine” that still exists for AHTOs. The mechanism of asymmetric hydrogenation of tetrasubstituted alkene substrates is often discussed with the assumption that the less challenging trisubstituted mechanistic data directly applies. It is worth noting that despite the huge benefit in knowledge gained from the study of reaction mechanisms, there is still little understanding of even the welldeveloped catalytic processes. A recent example involves the well-developed Pd(0)/(II) precatalyst, which underperformed when compared to a Pd(I) precatalyst.58 This came as a surprise to the scientific community. The reaction mechanism of the AHTOs is still a largely untouched area in metal catalysis. Additionally, although rapid ligand modification has been very fundamental in the pivotal reports of AHTOs, in situ ligand modification is sometimes observed, often unexpected, and consequently overlooked. A report by the Buchwald group describing an in situ ligand modification during the course of a difficult catalytic transformation59 should be a reminder that research efforts may have just scratched the surface of scientific breakthroughs in catalysis. To date, there has been no report of a successful AHTOs using nonmetallic reaction conditions. The major metals thus far utilized (rhodium, iridium, and ruthenium) are classified as “critical metals” due to their scarcity, high cost, and supply risk.60 As a result, replacement of these metals with environmentally friendly and earth-abundant metals in AHTOs is highly desirable.61 In addition, substituents for these metals with nonmetallic protocols will invariably reduce the environmental impact of the use of these metals. Another opportunity for advancement lies in the absence of reports to date for an AHTOs involving olefin substitution patterns bearing synthetic handles that would be available for further synthetic manipulations. Groups such as halides, silanes, boranes, triflates, and so forth would likely possess unwanted synthetic complications. On the other hand, successful AHTOs products bearing these functional handles may provide avenues for rapid scaffold diversification and reduction of reaction steps. For example, the report by Burk7 to carry out AHTOs on polyene substrate did not entirely eliminate over-reduction byproduct formation. Asymmetric hydrogenation of unfunctionalized tetrasubstituted olefins is still in its infancy compared to the work already performed on functionalized substrates. In addition to very few available chiral catalysts for successful asymmetric hydrogenation, the need for pure geometrical substrate isomers still exists. For example, the (E)-tetrasubstituted olefin substrates often give the opposite alkane enantiomers compared to the analogous (Z)-tetrasubstituted alkene precursors. This is due to the notion that the sterically less hindered carbon atom often

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Robert B. Kargbo: 0000-0002-5539-6343 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to Dr. R. Jason Herr, Dr. Kevin F. McGee, Dr. Zhicai Yang, and Dr. Hélène Decornez for illuminating discussions and/or proofreading the manuscript, to Rachel Pelly for pie charts, and Prof. Gregory R. Cook for inspiring the table of contents artwork.

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REFERENCES

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