Recent Advances in Asymmetric Hydrogenation of Tetrasubstituted

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Recent Advances in Asymmetric Hydrogenation of Tetrasubstituted Olefins Stefan Kraft, Kristen Ryan, and Robert B Kargbo J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07188 • Publication Date (Web): 11 Aug 2017 Downloaded from http://pubs.acs.org on August 11, 2017

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Journal of the American Chemical Society

Recent Advances in Asymmetric Hydrogenation of Tetrasubstituted Olefins Stefan Kraft, Kristen Ryan and Robert B. Kargbo* Drug Discovery Services, Medicinal Chemistry, AMRI, 26 Corporate Circle, Albany, NY 12201-5098 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.

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, while requiring 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 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 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

Figure 1. Representative structures of biologically relevant compounds.

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 AHTO comes from Burk and co-workers. In 1995, they reported the pivotal asymmetric hydrogenation of cyclic and acyclic tetrasubstituted enamides with product ee’s exceeding 98% using a chiral diphosphine-rhodium cata-

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lyst (vide infra).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 unfunctionalized tetrasubstituted olefin, a substrate lacking coordinating groups, providing enantioselectivities of up to 93% (vide infra).8 UNFUNCTIONALIZED OLEFINS

TETRASUBSTITUTED

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. 1 psi = 6.8947 x 10-2 bar = 6.8046 x 10-2 atm

Catalyst/ ligands

Cl Zr

O

R12P

Cl

N R2 Ir: 2007

Zr: 1999

L1: R1= Cy; R2= CH2tBu L2: R1= Cy; R2= Bn L3: R1= Ph; R2= iPr

cat. 1: (R,R)- or (S,S)-(EBTHI)ZrMe2 [PhMe2NH]+[BC6F5)4]O

Cy N

F

Cy

PCy2 N Ir: 2013

L4: BIPI

Cy

R

R

O HH O P P MeO t-Bu t-Bu R = 9-nathyl

OMe

Rh: 2017

L5: Anthryl-MeO-BIBOP

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, homogenous 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 co-workers 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).

H

Me

Me H 1 a 86% ee (95:5) 93% ee (>99:1)b H

Et

Me 3 H 5% ee (9:1)a 52% ee (95:5)b

Page 2 of 14 H

Me

Bu 2 H 92% ee (99:1)a H

Ph

Me 4 H 29% ee (>99:1)a 78% ee (>99:1)c

[H2 pressure (psig): 80a, 1,700b and 2,000c, cis:trans in parenthesis]

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

The active catalyst was generated from the combination of chiral zirconocene (EBTHI)ZrMe2 and the noncoordinating 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 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 psig 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 ᴫ-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 carboncarbon 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, very low predictability of the sense of enantioselectivity, high catalyst loadings and the 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 AHTO persisted until in 2007, when Pfaltz and coworkers (Figure 4)11 made use of iridium complexes with


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chiral bidentate N,P-ligands 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 iridium-ligand activity and enantioselectivity. Unfortunately, low conversion was seen for phenyl-substituted indene compounds leading to 10 and 11. The more difficult para-fluorophenyl-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).

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

The quest for modular, stable, and reactive chiral iridium-catalysts continued until in 2013, when Bussaca reported a variety of structurally diverse 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 peri-position (C-8) was identified as a critical stereo-control 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.

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

The Zhang research group recently disclosed another notable asymmetric hydrogenation. The team reported the first gram-scale total synthesis of an unusual isoquinoline alkaloid delavatine A, which displayed some promising anticancer 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 took 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 AHTO 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 AHTO. 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. 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 analogous pathways that were identified for tri-substituted 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. Amongst the three most prominent metals (Rh, Ru, and Ir), rhodium catalysis16 has been mechanistically investigated most extensively due to the outstanding



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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 C2symmetrical chiral phosphines such as 2,3-Oisopropylidene-2,3-dihydroxy-1,4bis(diphenylphosphino)butane (DIOP) with backbone or ethane-1,2-diylbis[(2chirality18 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 [(PP)RhI(S)2]+ (S = solvent, P-P = chiral diphosphine) engages a prochiral alkene such as methyl-(Z)-αacetamidocinnamate (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 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 con stituent B2 with (P-P) = 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 recent popular electron-rich phosphinesrhodium complexes follow a dihydride pathway, in which H2-oxidative addition to form octahedral [(PP)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

Figure 6. Halpern-Brown mechanism for asymmetric hydrogenation of MAC. Reproduced from reference 19a with permission from The American Association for the Advancement of Science.

A useful stereo-complementarity model for rhodiumcatalyzed asymmetric hydrogenations (Figure 7, (P-P) = S,S-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 C2- or 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-


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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/mole) can be challenging to elucidate.26 Nevertheless, plausible arguments based on molecular mechanics have been put forth and has revealed that oxidative H2addition causes a reorientation from a trans-disposition 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

dral 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 a 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 co-linear fashion with the HIrIII-(H2) axis (Figure 8). Subsequent migratory insertion is accompanied with H2-oxidative addition of the dihydrogen ligand.32 O t-Bu

H Me

Me or Ph

H

Ph

H

t-Bu

H2

Tol

Me N Ir

P H

Me

(o-Tol)2P

Tol

P, N ligand = (S)-tBu-PHOX

H

Me

Me Ph

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

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 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 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 (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 or migratory insertion or reductive addition step.30a Consequently, a given prochiral substrate with minimized steric repulsion in the octahe-

HH

N

Me

(R) 81% ee

Me

(S) 63% ee

Me

(R) 99% ee

A

Me

Me

Me Ph

Me

Ph

Me Me

Me

Ar

Me

B

Me L2,Fig. 2

Ar

C Me Ar = (4-F-C6H4) (Compound 13, Fig. 4)

Figure 8. Quadrant representations (3-D and 2-D) for the interaction of iridium-complexes with prochiral alkenes. Reproduced from reference 30e with permission from Royal Society of Chemistry.

According to a highly predictive quadrant model by Andersson and coworkers for Ir-oxazoline-phosphine complexes1,30b,33 the preferential alkene coordination within an octahedral dihydride-dihydrogen complex [(N,P)IrIIIH2(H2)(alkene)]+ is dictated by the positioning of the smallest alkene substituent facing the most hindered sector of the catalyst [black in Figure 8, using examples of Ir-(t-Bu-PHOX) catalysts with a large protruding t-Bu group],30b,34 while the respective substituents on the prochiral carbon have only a secondary impact in the assembly of the diastereomeric adduct (selection through the grey sector). However, the latter selectivity element was crucial for the enantioselective formation of compound 13 in Figure 4. FUNCTIONALIZED TETRASUBSTITUTED OLEFINS



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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 (nPr-DuPHOS and i-Pr-DuPHOS-Rh) afforded dismal selectivities at 45% and 14% ee, respectively. Furthermore, the

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

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

The asymmetric hydrogenation of functionalized, tetrasubstituted olefins is more developed compared to the AHTO 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 α-amino 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 co-workers achieved arguably the first truly successful AHTO 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 (Figure 10) with a catalyst tolerance for both Eor Z-substitution. Optimal conditions for the reaction employed a cationic Me-BPE-Rh catalyst in methanol and at 60 psi H2 pressure (Figure 9, L7). The flexibility of the Me-BPE-Rh catalyst allowed a greater range of β-

ester functionality was not a requirement for high enantioselectivity, as the free acid of the isopropyl substrate gave 94% ee using L7-Rh 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 AHTO are very substrate specific and a slight change in substrate can have a dramatic effect on catalyst performance. In 2010, Benhaim and co-workers disclosed the first report of AHTO on trifluoromethyl substrates in the preparation of βtrifluoromethyl α-amino acids.43 Optimal ligand screening was carried out, and two of the top-performing catalysts, (R)-Ph-BPE-Rh and (R)-TCFP-Rh (Figure 9, L10 and L11, respectively), were then examined with a series of substrates (Figure 13).

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

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



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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 AHTO catalyzed by rhodium catalyst systems. A noteworthy example of a complex and electron rich tetrasubstituted alkene was an asymmetric hydrogenation carried out by a Merck team during an efficient four or six steps 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 hydrogenation of enamide over nitrile reduction. However, due to undesired nitrile hydrolysis during the asymmetric hydrogenation, the team settled for the AHTO of primary amide 46 during the process synthesis of 47.

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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-tert-butylphenyl 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 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 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

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

Also in 2012, a switch from a keto-substrate to an ester functionality was reported by Zhou in the palladiumcatalyzed asymmetric hydrogenation of tetrasubstituted cyclic β–(arylsulfonamido)acrylates (Figure 16).45 It is likely that the hydrogenation is controlled via Bronsted acidcatalyzed tautomerization of enesulfonamides to an Nsulfonylimine intermediate, which is followed by a dynamic kinetic resolution during the hydrogenation sequence.

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

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

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 the asymmetric hydrogenation of the C=C bond of cycloalkenones 58 could install the β-alkylsubstituted tertiary stereocenter, followed by asymmetric hydrogenation of the C=O bond via dynamic kinetic resolution, resulting in three contiguous stereocenters. After screening various chiral spiro-iridium catalysts, Ir-SpiroPAP was found to perform the best. The protocol was amenable to form both the cyclopentanols such as 60 and 61 in high yields (90 to 95%) with excellent enantioselectivities (92 to >99%) and >99% cis,trans-selectivity. In addition, cyclohexanols such as 62 and 63 were afforded

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


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Journal of the American Chemical Society 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).

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

in high yields (90 to 98%) and with excellent enantioselectivities (96 to >99% ee) and excellent diastereoselectivities (cis,cis-isomer: >99%). In 2014, Zhang reported an AHTO 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-αacetoxy β-enamido esters with electron-rich or poor aryl groups. The protocol afforded high yields and 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 rhodiumJosiPhos catalyzed asymmetric hydrogenation of o-alkoxy tetrasubstituted enamides.53 The AHTO furnished chiral β-amino alcohol analogues such as 65 in Figure 19, afforded high yields and excellent enantioselectivities. Interestingly, the rhodium-DuanPhos catalyst was ineffective for the synthesis of β-amino alcohol 65 (only 5% conversion).

To illustrate the steric congestion of this system, the group carried out molecular modeling of N-Boc β,βdiarylalanine 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 highlycongested 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

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

enantioselectivities achieved for substrates 71 and 72 with the increase in bulk around the olefin. These required revised conditions of ligand L18, possibly relieving steric congestion with the substrate. Figure 19. Examples of application of rhodium-Josiphos and rhodium-DuanPhos catalysts.

The AHTO 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, controlling the facial selectivity during hydrogenation in forming two vicinal stereogenic centers possesses an incredible challenge. To address these issues,

Given the unquestionable challenges of the AHTO, 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 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



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methanol), resulting in 96-experimental permutations. It was found that rhodium catalysts led to low conversion,

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

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-βcyclopropylcinnamate analogs on multigram scales, at 200 g and eventually in kilogram quantities, all with excellent enantioselectivities (Figure 21, 75 to 77). Chiral cycloalkylamines and their derivatives are important motifs in many bioactive molecules, drugs, and are valuable intermediates in organic synthesis. In early 2017, Zhang disclosed an efficient rhodium-catalyzed AHTO involving cyclic enamides, which afforded cyclic chiral amides with high yields and with 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 sixand seven-membered rings (Figure 22, 78–80). 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.

Figure 22. Examples of application of rhodium-Binapine and -tBu-JosiPhos catalysts.

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 borane promoted, oxime directed, and Rh-catalyzed AHTO in high yields and with high selectivities (Figure 23). The mild protocol required short reaction times and with only a slight excess above stoichiometric H2. The

Figure 23. Examples of phosphoramidite catalyst.

application

of

rhodium-

method works well for aryl-substituted olefins, all-alkyl alkenes and with tetrasubstituted polyenes. However, the sense of ᴫ-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. 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 AHTO 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 the achievement of 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 AHTO is moving through the second phase of evolution in which more successes are being reported. This needs to continue for AHTO 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 AHTO 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 high-


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throughput experimentation (HTE)57 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 AHTO. Given the complexity, it is clear that more high-throughput experimentation should be carried out for a variety of tetrasubstituted substrate types. However, it may 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 AHTO, when easier research work that could produce rapid research papers is often more readily available. Consequently, direct funding to address AHTO would go a long way to unravel the scientific ‘gold mine’ that still exists for AHTO. The mechanism of asymmetric hydrogenation of tetrasubstituted alkene substrates is often discussed with the assumption that the less challenging tri-substituted 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 well-developed 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 AHTO is still a largely untouched area in metal catalysis. Additionally, although rapid ligand modification has been very fundamental in the pivotal reports of AHTO, 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 AHTO using non-metallic reaction conditions. The major metals thus far utilized (rhodium, iridium, and ruthenium) are classified as “critical metals” due to their scarcity, most expensive and supply risk.60 As a result, replacement of these metals with environmentally friendly and earth abundant metals in AHTO is highly desirable.61 In addition, substituents for these metals with non-metallic 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 AHTO 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 AHTO 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 AHTO 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 dictates the coordination of the chiral catalyst rather than the prochiral carbon, and consequently, AHTO 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-C2-symmetrical 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 towards the development of readily available chiral catalyst systems for more exemplary AHTO.

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT 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 abstract artwork.

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Recent Advances in Asymmetric Hydrogenation of Tetrasubstituted

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