Review pubs.acs.org/Organometallics
Rhodium Asymmetric Hydrogenation Observed during its Exponential Growth Phase John M. Brown* Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K.
ABSTRACT: The field of asymmetric hydrogenation grew rapidly after the early 1970s. What had begun as a demonstration of enantioselectivity in catalysis by purely chemical means became an important tool both for academic research and for industry. Right from the beginning, a question was posed as to how relatively simple catalysts were able to generate such unprecedented levels of stereoselectivity. This article provides an account of Oxford-based contributions to the field of rhodium complex catalyzed asymmetric hydrogenation from 1978 onward, when the initial realization of this practical catalytic method for synthesis of single enantiomers had already been achieved. NMR-based experiments that help to elucidate the structures of reactive intermediates in catalysis are strongly emphasized here and linked to the present understanding of the mechanism of a reaction that has sustained interest over the intervening years.
■
INTRODUCTION As academic research gradually returned to a more normal state after World War II, organic synthesis fluorished. Many new reactions were discovered or developed, and the art of synthesis led to success in approaches to molecules of ever-increasing complexity. In this era the contribution of catalysis beyond the application of simple acids and bases was quite low, and the level of involvement did not develop rapidly. To give a context, the seminal paper of Diels and Alder on their [4 + 2] cycloaddition was published in 1928;1 it was not until 1960 that the acceleration of this reaction by catalytic amounts of simple Lewis acids was discovered.2 At that stage chemists engaged in total synthesis did not give any priority to involving catalytic steps in their plan. Asymmetric synthesis was being developed by just a few pioneers, and when single enantiomers were needed in total synthesis, this was effected through incorporation of a resolution step or involvement of molecules from the chiral pool. In Woodward’s famous synthesis of reserpine the last step is a classical resolution using camphorsulfonic acid.3 In the titanic Woodward/Eschenmoser collaboration leading to the synthesis of cobyric acid and hence Vitamin B12, the various stereogenic centers of the natural product provide examples of both resolution and the utilization of precursors from the chiral pool.4 It was the dramatic developments that largely arose in and directly after the 1970s that made catalytic asymmetric synthesis a standard component of the synthetic chemist’s toolkit, with hydrogenation playing a leading role in establishing this state of affairs. Sporadic early contributions had demonstrated the feasibility of homogeneous hydrogenation catalyzed by various transition© XXXX American Chemical Society
metal complexes, starting with the very early contributions of Calvin and of Iskube.5 The reaction was not developed enough for general synthetic use, and so it remained for Wilkinson and co-workers to provide the discovery that provided the crucial bridge to applications in organic chemistry.6,7 The synthesis and applications of [RhCl(PPh3)3] showed that this readily prepared rhodium complex was active for hydrogenation of a range of alkenes under near-ambient conditions. The first paper, in which Wilkinson’s catalyst and its activity in homogeneous hydrogenation of alkenes and alkynes was announced, provided very interesting precedents for later work.6a The high activity in such hydrogenations was mentioned briefly, but the main focus lay in the characterization of metal hydrides arising from the catalyst through observation of their characteristic high-field 1H NMR signals. This suggested a catalytic pathway that involved dissociation of a phosphine from the ClRhP3H2 adduct, to be replaced by the alkene substrate. Their phosphine-dissociated intermediate was central to the reaction mechanism later verified by Halpern’s detailed kinetic study of cyclohexene hydrogenation.8 The importance of an alkene reduction method that tolerated most other functional groups was immediately recognized by Birch and Walker and led to a series of papers that firmly established the scope of this new synthetic reaction (Scheme 1a).9 Other early authors reinforced this contribution.10 It also proved to be a valuable resource for the site-specific introduction of deuterium or tritium by Rh complex catalyzed addition.11 Received: July 30, 2014
A
dx.doi.org/10.1021/om500780c | Organometallics XXXX, XXX, XXX−XXX
Organometallics
Review
the Monsanto synthesis of L-Dopa. One especially fortunate aspect was the consistent success afforded by dehydroamino acids or esters and close relatives in hydrogenation, so that one of the most synthetically useful reactions gave the most selective results. Scientific breakthroughs rarely proceed in isolation or occur purely through the efforts of one group. Before the publication of Knowles’ optimized results, a communication had appeared from Kagan and Dang. By the standards of the time this paper demonstrated excellent results in the Rh complex catalyzed hydrogenation of dehydroamino acids, with up to 82% ee observed in a rapid and efficient reaction (Scheme 2), but it
Scheme 1. (a) Early Application of Wilkinson’s Catalyst (Ref 10b) and (b) Demonstration of Heterogeneous Asymmetric Hydrogenation (Ref 14b)
Scheme 2. Original Examples of Homogeneous Asymmetric Hydrogenation with Good ee Values
Few chemists were engaged with homogeneous asymmetric catalysis at that point, with the most extensive contributions coming from Pracejus’ group.12 The application of transitionmetal complexes to asymmetric catalysis was very limited in this regard, with the only success coming from the copper complex catalyzed cyclopropanation of styrene with ethyl diazoacetate by Nozaki and Noyori, which gave optically active cis and trans products, albeit in low ee.13 Heterogeneous asymmetric catalysis had been reported, notably for asymmetric hydrogenation or transfer hydrogenation, and included a wellreferenced early paper from Akabori’s group (Scheme 1b).14 Furthermore, this procedure had been demonstrated to be effective for functional reactants of interest to organic chemists, notably α-substituted acrylic acids and dehydroamino acids or their precursors. In these pioneering experiments the products were formed in low ee, however. Together with the obvious synthetic potential of the phosphine-based Wilkinson catalyst, the early work arising from heterogeneous catalysis must have encouraged the first successful efforts toward homogeneous asymmetric catalysis through alkene reduction. Progress toward that goal also required a source of enantiomerically pure phosphines. Within less than 4 years after the publication of Wilkinson’s first paper, the proof of principle stage for homogeneous asymmetric hydrogenation had been reached. In a survey of various mixed aryl-/alkylphosphine analogues of PPh3 in Rh complex catalyzed alkene hydrogenation, Horner had noted the possibility and then later carried out a hydrogenation reaction that gave a product with detectable optical activity.15 Knowles’ work confirmed this in practice, however; his paper rapidly followed Horner’s first work with firm evidence of success. In this work Wilkinson’s catalyst was modified by employing the incompletely resolved ligand PhP(Me)Pri in place of PPh3, and with this complex atropic acid was hydrogenated rapidly in 15% ee.16 One parallel development had proved crucial; Mislow had been concerned with the stereochemistry of phosphorus componds and had recently developed a stereospecific synthesis of phosphine oxides, as well as a method for their reduction without racemization.17 This work provided the basis for the Monsanto group to gradually improve their procedures by ligand variation and to focus on the more practical problem of dehydroamino acid reduction, such that the next milestone publication reported ee values of up to 90% using (R)-oAnP(Me)Cx (CAMP) as the ligand for the reduction of (Z)-Nacetyldehydrophenylalanine.18 After suitable modifications that arose from further development, this provided the platform for
provided a step change for entirely different reasons. Their ligand DIOP was derived from natural tartaric acid by simple elaboration of the carboxyl groups (CO2H → CH2PPh2) and protection of the hydroxyl groups as a cyclic acetonide. The ensuing difunctional ligand formed a chelate complex at rhodium, and its enantiomeric purity was ensured on account of the chiral pool source.19 Kagan’s work inspired the development of many families of diphosphine chelates with (R,R)-Dipamp, based on extension of the original Monsanto work on P-resolved monophosphines and using copper-promoted anionic C−C coupling of P−CH3 groups, among the first of these.20 Bosnich and co-workers prepared Chiraphos and Prophos, diphosphines based on simple alkane backbones that were highly successful in asymmetric hydrogenation.21 In essence, the catalytic asymmetric synthesis of aromatic amino acids had become a solved problem, one ready for commercial as well as academic development. For the more general application of asymmetric hydrogenation, a far wider range of phosphine ligands would be required, and ligand design became an important preoccupation of the asymmetric catalysis community. A huge range of chelating diphosphine ligands were synthesized in the following three decades, and key examples are shown in Scheme 3.22
■
DISCUSSION Early Work. In late 1974 the author moved from the University of Warwick to Oxford, and this afforded the opportunity to develop new directions of research. Given his background in physical organic chemistry applied to organometallic problems, the emerging area of homogeneous catalysis was very appealing. The Dyson Perrins Laboratory had a state of the art Bruker WH90 instrument at that time. This FT NMR machine with iron-frame magnet was equipped with a 10 mm probe that allowed experiments to be carried out in robust 8 mm insert tubes with external 2H solvent lock, a feature that encouraged direct transfer of in situ reacting systems prepared on a a vacuum line. So could reactive intermediates in catalysis be characterized directly by NMR? Not every contemporary worker in the field would have agreed, given a view at the time that true intermediates would be highly transient entities by their nature. The specific challege was to contribute to the B
dx.doi.org/10.1021/om500780c | Organometallics XXXX, XXX, XXX−XXX
Organometallics
Review
were observed, in comparable concentration at ambient temperature. Kagan had shown that simple α-substituted enamides lacking the α-carboxy group gave high ee values in asymmetric hydrogenation and suggested that the substrate coordinated in a chelating fashion through the alkene and amide carbonyl group.25 At around this point the first paper from Halpern’s group on cationic Rh complexes relevant to hydrogenation appeared.26 In their careful physicochemical study it was shown that the bisPPh3 complex reacted with H2 to form a dihydride in a manner comparable to that for [RhCl(PPh3)3], while the chelating Diphos complex showed no affinity for hydrogen (Diphos = 1,2-bis(diphenylphosphino)ethane). It was suggested that the mechanism of hydrogenation with chelating cationic rhodium complexes involved alkene coordination prior to H2 addition (Scheme 4).
Scheme 3. Representative Early Chelate Ligands for Asymmetric Catalysis (Top) and Representative Ligands for Rh Asymmetric Hydrogenation Developed after 1990 (Bottom)
Scheme 4. Contrasting Pathways for Addition of H2 to Cationic Bis-Phosphine Complexes and Cationic Chelates
rapidly emerging field of asymmetric hydrogenation. One early memory of the author stems from a group meeting at Warwick where Kagan’s work with DIOP had been discussed, and a Dreiding model of a metal chelate derived from the ligand was then assembled. This seemed very floppy,23 and thus hard to reconcile with the high enantioselectivity shown in catalysis. By late 1977 Dr. Penny Chaloner, David Parker, and Barry Murrer had joined the research group, and they were closely involved in developing the asymmetric hydrogenation project, providing the backbone for all such publications from that period. Our initial strategy was simple and involved trying to simulate the conditions of asymmetric hydrogenation in NMRdirected experiments and identify the species present. Key chelating ligands were acquired, largely as gifts or through inhouse synthesis, since the chemical suppliers did not provide a portfolio of asymmetric ligands at that stage. The approach that was adopted required well-characterized precursor complexes, encouraging the synthesis of bench-stable cationic chelate diphosphine rhodium(I) diene complexes, the diene component being norbornadiene or cycloocta-1,5-diene.24 These complexes were distinctive yellow-orange crystalline solids, and on hydrogenation in MeOH solution a discernible color change to a lighter brown-yellow occurred after the diene component was reduced. When the reaction was carried out in the presence of excess dehydroamino acid or ester substrate, a different color change was observed, to deeper orange or red depending on the ligand. Early NMR experiments with these precursor complexes failed to find the characteristic high-field 1 H metal hydride signals under H2 like those that had been seen with Wilkinson’s catalyst, and attention was focused on the intriguing 31P spectra that were seen in the absence and presence of substrate. Hydrogenation of the Rh complex alone in MeOH caused a loss of the original Rh-coupled doublet and replacement by a new Rh-coupled doublet at lower field with larger JRhP coupling. When the experiment was carried out with DIOP as ligand and (Z)-1b or (Z)-1c was present in excess as substrate, a single eight-line spectrum was observed, as expected for a single species with nonsymmetrical coordination. Thus, a single species with two distinct phosphorus nuclei would generate an AB quartet in its 31P spectra, further strongly spin coupled to 103Rh. This spectrum did not alter substantially on cooling to −60 °C. For the same process with (E)-1d, which was known to be an inferior substrate for asymmetric hydrogenation, two distinct overlapping eight-line species
The appearance of this paper from Halpern’s group accelerated the submission of our first paper on the NMR spectra of enamide complexes,27a and soon after the 31P spectra of a series of Rh enamide complexes prepared from (Z)-1a and chelating diphosphines was reported by Baird and coworkers.27b The enamide mode of coordination was fully endorsed by Halpern’s crystal structure of the enamide complex from (Z)-1b and Diphos, so that information from different sources provided a convergent view of substrate binding in asymmetric hydrogenation (Scheme 5).28 As far as the substrate-free experiments on H2 affinity of solvate complexes were concerned, not all monophosphine complexes behave like the PPh3 case shown in Scheme 4. Cationic Rh complexes of the electron-rich phosphines favored in Knowles’ early work have lower affinity for H2; with (oAnP(Me)Ph)2Rh+ only the solvate species was detected under an H2 atmosphere.29 By way of contrast, 7-ring chelating alkyldiphosphines may readily form Rh dihydrides, again in contrast to the Diphos case.30 More evidence for the solution structures of dehydroamino acid and ester complexes was obtained from their singly 13C labeled analogues, including the carbonyl carbons of ester and amide and the less substituted alkene carbon (e.g. 13Cbenzaldehyde). The relevant 13C spectra showed a shielded alkene Cβ and a deshielded amide carbonyl carbon relative to the substrate, with the ester CO not being strongly affected. This demonstrated rhodium binding to the alkene and the amide carbonyl group across a range of complexes of (Z)-1c or its ester (Z)-1e. For the acid (E)-1d the 13C chemical shift changes the favored association of rhodium with the acid/ester C
dx.doi.org/10.1021/om500780c | Organometallics XXXX, XXX, XXX−XXX
Organometallics
Review
A full paper summarizing the Oxford NMR work on enamide complexes to that date appeared in early 1980.33 Figure 1 shows a sequence of 31P spectra of Chiraphos complexes, starting with the NBD complex A, which is converted into the solvent complex B under hydrogen. Further reaction with (Z)1b gives rise to the enamide complex C. In the original work the second diastereomer of this complex could not be observed, but the
