Iridium-Catalyzed Selective Isomerization of Primary Allylic Alcohols

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Iridium-Catalyzed Selective Isomerization of Primary Allylic Alcohols Houhua Li and Clément Mazet* Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva, Switzerland

CONSPECTUS: This Account presents the development of the iridium-catalyzed isomerization of primary allylic alcohols in our laboratory over the past 8 years. Our initial interest was driven by the long-standing challenge associated with the development of a general catalyst even for the nonasymmetric version of this seemingly simple chemical transformation. The added value of the aldehyde products and the possibility to rapidly generate molecular complexity from readily accessible allylic alcohols upon a redox-economical isomerization reaction were additional sources of motivation. Certainly influenced by the success story of the related isomerization of allylic amines, most catalysts developed for the selective isomerization of allylic alcohols were focused on rhodium as a transition metal of choice. Our approach has been based on the commonly accepted precept that hydrogenation and isomerization are often competing processes, with the latter being usually suppressed in favor of the former. The cationic iridium complexes [(Cy3P)(pyridine)Ir(cod)]X developed by Crabtree (X = PF6) and Pfaltz (X = BArF) are usually considered as the most versatile catalysts for the hydrogenation of allylic alcohols. Using molecular hydrogen to generate controlled amounts of the active form of these complexes but performing the reaction in the absence of molecular hydrogen enabled deviation from the typical hydrogenation manifold and favored exclusively the isomerization of allylic alcohols into aldehydes. Isotopic labeling and crossover experiments revealed the intermolecular nature of the process. Systematic variation of the ligand on the iridium center allowed us to identify the structural features beneficial for catalytic activity. Subsequently, three generations of chiral catalysts have been investigated and enabled us to reach excellent levels of enantioselectivity for a wide range of 3,3-disubstituted aryl/alkyl and alkyl/alkyl primary allylic alcohols leading to β-chiral aldehydes. The combination of the isomerization reaction with enamine catalysis in a sequential process gave access to α,β-chiral aldehydes in high diastereomeric ratio and excellent enantioselectivity. Catalyst-controlled diastereoselective isomerization of stereochemically complex steroid scaffolds has been achieved, giving access indifferently to derivatives with the natural and unnatural C20 configuration, a long-standing challenge in the field. Structural diversification at close proximity of the reactive site and within the polycyclic domain served to further demonstrate the generality and the potential of the method. Models based on quadrant diagrams enabled rationalization of the high levels of enantio- and diastereocontrol obtained in the isomerization of allylic alcohols.

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INTRODUCTION

drawn to increasingly more demanding isomerization reactions.6

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A central focus of our research activities is to develop selective isomerizations from readily available and simple substrates to access a variety of synthetically useful and more complex building blocks and versatile functions. In the early stages of our research program, we were attracted by the seemingly simple, yet underdeveloped, isomerization of primary allylic alcohols into aldehydes.1 Despite important seminal contributions, it was clear that this transformation had not realized its full potential, in particular if one compares it to the success of the related isomerization of allylic amines.2 This Account summarizes nearly 8 years of investigations into this area starting from the identification of a general catalytic system (which was lacking at the time),3 followed by the development of several generations of chiral catalysts for the enantio- and diastereoselective versions of this reaction.4 As our understanding of this transformation matured,5 our attention was © XXXX American Chemical Society

IRIDIUM-CATALYZED ISOMERIZATION OF ALLYLIC ALCOHOLS

Initial Goals, Strategy, and Literature Precedents

Our initial approach was based on the notion that isomerizations are very common side reactions observed during transition metal-catalyzed hydrogenations of olefins.7 Typically, researchers active in this area successfully suppress these undesired processes by either adjusting the reaction conditions (i.e., increase in hydrogen pressure) or fine-tuning the catalyst structure. We hypothesized that under certain reaction conditions, selected hydrogenation catalysts might be diverted Received: March 23, 2016

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DOI: 10.1021/acs.accounts.6b00144 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

alkenes.17,18 The two precatalysts (5.0 mol %) were activated using the protocol described by Baudry and Ephritikhine and engaged in the isomerization of our model substrate 2a, a demanding trisubstituted allylic alcohol (Figure 2A). Gratify-

from their initial task and turned into isomerization catalysts instead (Figure 1). Crabtree’s catalyst 1a was introduced in the

Figure 1. Conceptual approach: promoting isomerization by diverting hydrogenation catalysts from their initial task. Crabtree (1a) and Pfaltz (1b) iridium catalysts. Active form of the catalyst upon exposure to molecular hydrogen.

Figure 2. (A) Model reaction. (B) Unreactive iridium complexes toward the isomerization of primary allylic alcohols using the molecular hydrogen activation protocol.

late 1970s initially for the hydrogenation of unfunctionalized olefins, surpassing at the time the most potent rhodium and ruthenium catalysts.8 Independent studies by Stork and Khane and Crabtree and Davis later established its effectiveness in the directed hydrogenation of allylic and homoallylic alcohols.9,10 The mild reaction conditions, the compatibility of the catalyst with heavily substituted allylic alcohols and the highly predictable outcome in diastereoselective hydrogenations favored rapid dissemination of the method within the synthetic community.11 It is now often perceived as the last resort solution for substrates that are particularly resistant to directed hydrogenation.12 Moreover, as a plethora of chiral analogs of this catalyst had been reported in recent years for asymmetric hydrogenations,13 the development of an enantioselective version of the isomerization of allylic alcohols seemed a realistic goal.14 If successful, such an approach would certainly complement existing methods giving access to α- and or βchiral aldehydes.15 We therefore elected 1a as the ideal starting point of our investigations. In support of our initial hypothesis, there were scattered reports in the literature describing the isomerization of allylic alcohols using related iridium complexes.16 In 1978, Baudry and Ephritikhine described the isomerization of a handful of allylic alcohols having a mono- or disubstituted olefinic moiety using [(MePh2P)2Ir(cod)]PF6.16a Allylic alcohols with higher substitution patterns were not compatible with the method. The authors observed that 1a led to irreproducible results. Importantly, it was also noted that the precatalyst had to be activated by molecular hydrogen and the solution subsequently degassed to avoid competing hydrogenation. This original experimental protocol would later serve as a basis for our own investigations (vide supra).3−6 In 2005, in an attempt to reduce a trisubstituted exocyclic allylic alcohol, Fehr and Farris observed that 1a favored an unexpected isomerization/lactolization sequence involving a neighboring hydroxy group rather than the initially planned hydrogenation.16e This result further suggested the potential of 1a to be used for exclusive isomerization of allylic alcohols.

ingly, both systems led to productive isomerization into aldehyde 3a without any traces of the corresponding hydrogenation product. After 4 h, whereas 1b delivered 3a quantitatively, the aldehyde was isolated in 74% yield with 1a. At a reduced loading of 1.0 mol %, 3a was still obtained quantitatively with 1b but no catalytic activity was detected with 1a. These results were consistent with the marked reactivity difference between 1a and 1b in hydrogenation reactions.18 Subsequently, all cationic iridium complexes were systematically prepared with the bulky and lipophilic BArF anion.3−6 At first sight, these results were in support of our initial hypothesis, and it may have been tempting to draw definitive conclusions on the ability to systematically transform efficient hydrogenation catalysts into equally efficient isomerization catalysts. Nevertheless, upon evaluation of structurally related cationic iridium complexes for the isomerization of 2a, it was noted that most variations were detrimental to catalytic activity (Figure 2B).3,5a This was particularly unexpected because many of the complexes surveyed had proven effective in the hydrogenation of several classes of olefins, including allylic alcohols. These observations clearly indicate that not all hydrogenation catalysts can be readily turned into isomerization catalysts of allylic alcohols by activation with molecular hydrogen. The generality of the reaction was delineated using 1b.3 Representative products obtained with this method are reported in Figure 3. Aside from the usually low catalyst loading and expedient reaction time, of particular note is the mildness of the reaction conditions, which contrasted with the elevated temperatures often required for previously reported systems. Primary allylic alcohols with a variety of olefinic substitution patterns consistently underwent quantitative isomerization. Even a substrate with a tetrasubstituted double bond 2p could be isomerized when the loading and temperature were both increased and the reaction time extended (10 mol % 1b, 65 °C, 22 h). In an attempt to improve reactivity, several analogs of catalyst 1b were synthesized using electronically distinct psubstituted pyridyl ligands (Z = −CF3, −CO2Et, −Cl, −Me, −OMe, −NMe2).5a It was found that complexes with the more

Isomerization of Allylic Alcohols with Crabtree Catalyst

Our investigations commenced with a comparative study between the original version of Crabtree’s catalyst 1a and the more robust and more active variant 1b introduced by Pfaltz and co-workers for the hydrogenation of unfunctionalized B


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Figure 5. Structural requirements for the design of catalytic active iridium catalyst and leading candidates for the enantioselective isomerization of primary allylic alcohols.

The highly modular chiral phosphino-alkyloxazoline scaffold introduced by Helmchen and co-workers for Pd-catalyzed allylic substitution reactions was selected as a first viable option and was tuned according to the design elements identified with the achiral catalyst 1b and enabled rapid identification of a lead structure 4a. 4a,20 Using a similar activation protocol, unprecedented levels of enantioselectivity were obtained for (E)-configured substrates combining a large alkyl substituent and an aryl group. Substrates with smaller alkyl substituents were less reactive, gave lower enantioselectivity, and were accompanied by competing (E)/(Z) isomerization of the starting material. The reaction being stereospecific, (Z)configured allylic alcohols delivered the chiral aldehyde of opposite absolute configuration in low enantioselectivities and in much reduced yields. The economically more attractive isomeric structure 5, originally introduced by Burgess and coworkers, was evaluated next for the isomerization of primary allylic alcohols.4b,21 Although similar performances were obtained for aryl/alkyl substrates with large alkyl substituents, catalyst 5a outperformed 4a in the isomerization of the more challenging 3,3-dialkyl primary allylic alcohols (Figure 6). The third generation of chiral (dialkyl)phosphinoalkyloxazoline ligands 6a was designed on the basis of linear free energy relationships between the ee values and the size of the substituents of the substrate.4c To improve selectivity without impairing reactivity, the homologation of the alkyl bridge linking the donor units was expected to increase the steric bulk in proximity to the reactive sites while maintaining enough flexibility in the structure to accommodate substrate binding. The improved enantioselectivities obtained for substrates with small alkyl groups lent credence to our initial hypothesis although the yields remained moderate in most cases. Figure 6 provides a comparative overview of the performances of all three generations of catalysts developed for the asymmetric isomerization for the most representative primary allylic alcohols. Notably, with the third generation of catalyst 6a, geraniol was isomerized into citronellal in 49% yield and 82% ee, a value which coincidentally matches the enantiopurity of the natural product (Figure 6). Noticeably, (Z)-configured and tetrasubstituted

Figure 3. Representative scope for the iridium-catalyzed isomerization of primary allylic alcohols with 1b.

electron-donating pyridyl ligands were twice as reactive as the parent catalyst (Z = −H) in the isomerization of 2c (Figure 4).

Figure 4. Effect of electronic tuning of the pyridyl ligand on the catalytic activity of Crabtree catalyst analogs.

Interestingly, excellent correlations of the 13C chemical shift of the olefinic carbon of the cyclooctadienyl moiety trans to the nitrogen atom were obtained with the pKa and with the Mayr− Patz nucleophilicity parameter of the pyridyl ligands.19 Finally, SARs were established by simply correlating cyclooctadiene 13C chemical shifts with half-life values obtained by monitoring the catalytic isomerization of 2c. Enantioselective Isomerization of Allylic Alcohols

The structural limitations identified upon evaluation of several analogs of 1a and 1b imposed clear restrictions on the design of chiral ligands and catalysts for the development of the enantioselective isomerization of primary allylic alcohols. Indeed, from a rapid evaluation of several chiral iridium hydrogenation catalysts, it clearly appeared that the combination of an sp2 N-donor with a formal trialkylphosphine donor was necessary to maintain a level of reactivity similar to the one displayed by 1b (Figure 5). C


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Figure 6. Comparative performances of the best chiral catalysts of first, second and third generation; n.d. indicates not determined.

Figure 7. (A) Productive isomerization manifold and competing E/Z isomerization manifold. (B) Combined electronic and steric quadrant diagrams. (C) Curtin−Hammett principle enabled by rapid equilibrium between diastereomeric iridium dihydride intermediates.

BArF with the hydrides located trans to the N atom are generated. When a chiral (P,N) ligand is employed, two isomeric species can be generated and coordinate the allylic alcohol in a two-point-binding mode.9,10 The productive isomerization pathway starts with migratory insertion at C3 leading to a secondary alkyl hydride intermediate. Decoordination of the alcohol followed by β-H elimination generates an enol-dihydride intermediate, which rapidly tautomerizes and liberates the aldehyde. Migratory insertion at C3 is proposed to be both rate- and enantiodeterming, while competing migratory insertion at C2 might be responsible for the concurrent (E)/ (Z) isomerization observed for the less reactive substrates (i.e.,

primary allylic alcohols remained problematic candidates. Secondary allylic alcohols were also unreactive. Mechanistic Investigations

Preliminary mechanistic studies have been carried out using a chiral cationic iridium complex of first generation 4b, which displayed similar performances to 4a.4a Isotopic labeling studies and crossover experiments were in support of an unprecedented intermolecular dihydride mechanism, which is disclosed in Figure 7A. It is now well-established that upon activation by molecular hydrogen of [(P,N)Ir(cod)]BAr F precatalysts, iridium dihydrides of general formula [(P,N)Ir(H)2(solv)2]D


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Accounts of Chemical Research Z-configured or with small alkyl substituents). In the absence of molecular hydrogen pressure, the typical reductive elimination in the hydrogenation pathway is not observed. Of note, the iridium-catalyzed isomerization of primary allylic alcohols operates via a mechanism distinct from the iridium-catalyzed dehydrogenation of alcohols.22 We suspect that triggering the reaction by molecular hydrogen activation and the nature of the donor atoms on the supporting ligand play a key role in selecting isomerization over dehydrogenation. Despite its apparent simplicity, a reasonable model that accounts for the high levels of enantioselectivity observed for 3,3-disubstituted (E)-configured primary allylic alcohols was proposed using a quadrant diagram (Figure 7B).23 The combination of electronic and steric discriminations generated by the C1-symmetric chiral (P,N) ligand only leave the southeastern quadrant open to accommodate either the aryl substituent of aryl/alkyl substrates or the larger alkyl substituent of alkyl/alkyl substrates. Moreover, because they lead to products of opposite absolute configuration, the existence of a rapid exchange between the two isomeric cisdihydrides detected by NMR spectroscopy was proposed. This hypothesis was further supported by the results of the labeling experiments, which revealed that both hydrides are exclusively transferred at C3 during isomerization (Figure 7C).

potential of this method with representative variations of both the nucleophilic and the electrophilic components. The products were obtained in moderate yields but with systematically high levels of diastereo- and enantiocontrol. Catalyst-Controlled Diastereoselective Isomerization of Allylic Alcohols

The development of diastereoselective methods where a chiral catalyst must control the absolute configuration of a given stereocenter independently of a stereochemically complex environment is a contemporary problem in selective catalysis.24,25 To assess the potential of the iridium-catalyzed isomerization of primary allylic alcohols in such a context, we first explored diastereoselective isomerizations of chiral racemic allylic alcohols, rac-2q, with achiral catalyst 1b and with sterically more demanding analogs 1c−e (Figure 9).5b

Sequential Isomerization of Allylic Alcohols

The reduced reactivity of allylic alcohols with a tetrasubstituted CC bond and the rapid uncatalyzed tautomerization for 2substituted substrates did not afford enantioenriched α-chiral aldehydes using the iridium catalyzed isomerization. To circumvent these limitations, a resolution reaction was developed in collaboration with the Alexakis group to access enantioenriched β-chiral and α,β-chiral aldehydes in a single operation.4d This approach relied on the sequential combination of cationic iridium catalyst 5a and proline 7 or prolinederived amino-catalysts such as 8 or 9. Figure 8 illustrates the

Figure 9. Effect of catalyst tuning on diastereoselective isomerization of racemic primary allylic alcohols.

We found that diastereoselectivity can be quantified using steric descriptors (Charton, Sterimol) either for the substrate substituents or for the catalyst substituents.26,27 We also observed that the site selectivity for [Ir−H] insertion can be reversed leading to the formation of homoallylic alcohols preferentially over aldehydes when sterically demanding iridium catalysts are employed. The inherent stereochemical complexity of steroidal derivatives appeared as particularly well-suited to extend this study to enantiopure substrates.6 Moreover, we envisioned this would provide an exciting opportunity to address a longstanding challenge in the field: the stereoselective installation of C20, the first exocyclic stereocenter of the side chain directly adjacent to the polycyclic framework.28 Due to the influence of olefin geometry on the selective outcome of the Ir-catalyzed isomerization of allylic alcohols, we based our strategy on the selectivity principle used for prochiral olefinic substrates in stereospecific enantioselective transformations (Figure 10A).24 At the outset of our investigations, we devised a route that gave access to geometrically pure (E) and (Z) allylic alcohols while offering sufficient modularity to ensure structural diversification at close proximity of the prochiral olefinic moiety. From the pivotal β-keto ester 10,29 (E)-enol-tosylate 11a and (Z)-enoltriflate 12a were synthesized based on protocols reported by Tanabe and Frantz on simpler precursors.30,31 These key intermediates were subsequently engaged in stereoretentive Negishi cross-couplings followed by a deprotection/reduction operation to furnish the targeted allylic alcohols in geometrically pure form (Figure 10B).32 The modularity and efficiency

Figure 8. Representative scope for the one-pot isomerization/αfunctionalization sequence. E


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When the catalyst of opposite absolute configuration, (R)-5a was used, improved stereocontrol was achieved for (E)configured allylic alcohols, and the aldehydes were all isolated in moderate to good yield as single diastereoisomers (dr > 50:1). Although isomerization of (Z)-13a−j required increased catalyst loading, the unnatural C20-(S) epimer was obtained essentially as a single isomer in all cases (dr > 50:1), thus highlighting the ability of the chiral catalyst to override the innate bias imposed by the steroid scaffold. The existence of a locked conformation around C17−C20 for both olefin geometries was proposed to account for the high levels of diastereocontrol observed in the match and mismatch situations. Less satisfactory results were obtained for alkyl-containing primary allylic alcohols (Figure 11B). Starting indifferently from (E)-13k and (Z)-13k, the natural C20-(R) isomer was formed preferentially and in low yield. Isomerization of (E)-l gave C20-(S)-14l (67% yield, >50:1), while isomerization of (Z)-l furnished homoallylic alcohol (E)-15 exclusively. Comparison of these results with the excellent levels of diastereocontrol obtained for aryl-containing substrates clearly indicates that site selectivity of [Ir−H] insertion strongly depends on the size and nature of the substituent at C20. The limits of the method were explored further by subjecting elaborated derivatives to catalysis (Figure 11C). Hence, (E) and (Z)-configured steroidal allylic alcohols bearing a disiloxaneprotected glycosyl moiety at C3 16, the corresponding polyhydroxylated derivatives 17, and the related C3-azido substrates 18 were all isomerized to the corresponding C20-(R) and C20-(S) isomers respectively with consistently high levels of catalyst diastereocontrol (dr > 50:1). More remarkably, a substrate with a Δ5,7-unstaturation, (E)-19, was isomerized to the C20-(R) aldehyde in 71% yield and >50:1 dr, thus offering potential entry into the vitamin D series.

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CONCLUSION AND PERSPECTIVES Over the past several years, we have demonstrated that iridium hydrogenation catalysts supported by P,N ligands can be effectively turned into isomerization catalysts to convert allylic alcohols into valuable aldehydes in an overall redox economical process. After having identified a general catalyst 1b for the nonasymmetric variant of the reaction, three successive generations of chiral catalysts have been developed imparting high levels of enantioselectivity for a variety of 3,3-disubstituted primary allylic alcohols. The sequential combination of the iridium-catalyzed isomerization of allylic alcohols with enamine catalysis gave access to α,β-chiral aldehydes in excellent diastereo- and enantioselectivity. Exquisite catalyst-controlled diastereoselective isomerizations have been performed using stereochemically complex steroidal scaffolds and allowed us to tackle the long-standing “C20 challenge”. Our conceptual approach has been followed by others, and it is interesting to note that ruthenium-based hydrogenation catalysts, which operate via distinct mechanistic pathways, have also been turned successfully into isomerization catalysts by fine-tuning the experimental protocol.33,34 Nonetheless, there are still many challenges that lie ahead in this field. The identification of a general and selective system able to catalyze the isomerization of both primary and secondary allylic alcohols, as well as any type of alkenyl alcohols independently of the olefinic substitution pattern is still required. We recently made a first step in this direction using well-defined palladium− hydride complexes, a catalytic system that operates under

Figure 10. (A) Selectivity model for stereospecific transformations applied to steroidal allylic alcohols. (B) Straightforward access to steroidal allylic alcohols. (C) Scope of steroidal allylic alcohols. Yields over 2 steps (Negishi cross-coupling/reduction−deprotection).

of the approach enabled us to rapidly generate a collection of 24 substrates (Figure 10C). Figure 11A displays the results for the isomerization of aryl and heteroaryl-containing derivatives. The innate bias imposed by the substrate was systematically evaluated with the achiral catalyst 1b and both olefin geometries. In all cases, aldehydes with the natural C20 configuration were obtained predominantly. With (E)-configured allylic alcohols, high levels of diastereoselectivity were measured (20:1−50:1; match situation), while with the (Z) isomers much reduced diastereomeric ratios were obtained (1.4:1−2.7:1; mismatch situation). With chiral catalyst (S)-5a, only low yields of product were obtained. F


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Figure 11. Stereospecific isomerization of steroidal allylic alcohols. All ratios are given as C20-(R)/C20-(S). (A) Scope of aryl and heteroaryl substrates. In parentheses are given the innate diastereoselectivity as measured with achiral catalyst 1b. (B) Diastereoselective isomerization of alkylcontaining steroidal primary allylic alcohols. (C) Structural diversification.

relatively mild conditions and tolerates potentially reactive functional groups.35,36 Interestingly, following this direction, the use of ex situ or in situ generated transition metal hydrides has become a recurrent strategy in our laboratory.37 We now look forward to addressing the many challenges remaining in the area and to explore the unexpected discoveries that will certainly arise during this exciting journey.

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Clément Mazet was born in Nancy, France, in 1975. After receiving his undergraduate training with the late John A. Osborn (University of Strasbourg, France), he performed his graduate studies under the supervision of Lutz H. Gade in the same University (Ph.D. in 2002). He completed his education with postdoctoral stays in the laboratories of Andreas Pfaltz (University of Basel, Switzerland, 2003−2005) and Eric N. Jacobsen (Harvard University, Boston, MA, USA, 2006− 2007). In November 2007, he joined the University of Geneva (Switzerland) where his independent research program focuses on mechanistic and synthetic chemistry with emphasis on all aspects of selective catalysis. In recognition of his work, he received the Zasshikai Lectureship Award from the University of Tokyo (2012) and the Werner Prize from the Swiss Chemical Society (2013).

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

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Houhua Li was born in Jiangxi, China, in 1985. He studied carbohydrate chemistry under the supervision of Prof. Xinshan Ye during his B.Sc. and M.Sc. in Peking University (China). In 2009, he moved to the National Institute of Biological Sciences (NIBS) and worked with Prof. Xiaoguang Lei on Lycopodium alkaloid synthesis. He joined the University of Geneva (Switzerland) in 2011 to start his graduate studies in the laboratory of Clément Mazet to work on the iridium-catalyzed selective isomerization of allylic alcohols.

ACKNOWLEDGMENTS

The former and current group members who have contributed to this exciting journey are all warmly thanked for their sincere and continuous dedication. Generous financial support by the University of Geneva and the Swiss National Sciences Foundation is also acknowledged. G


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