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Asymmetric isomerization of allylic alcohols
Tetrahedron Letters 56 (2015) 6159–6169
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Digest Paper
Asymmetric isomerization of allylic alcohols Dominique Cahard a,b,⇑, Sylvain Gaillard c,d, Jean-Luc Renaud c,d,⇑ a
Normandie Université, INSA de Rouen, Laboratoire C.O.B.R.A., 76821 Mont-Saint-Aignan Cedex, France CNRS, UMR 6014, 76821 Mont-Saint-Aignan Cedex, France Normandie University, University of Caen Normandie, Laboratoire de Chimie Moléculaire et Thioorganique, 14050 Caen, France d CNRS, UMR 6507, 14050 Caen, France b c
a r t i c l e
i n f o
Article history: Received 20 July 2015 Revised 7 September 2015 Accepted 23 September 2015 Available online 25 September 2015 Keywords: Isomerization Catalysis Chirality Allylic alcohols Atom economy
a b s t r a c t In this digest, we report the recent advances in asymmetric isomerization of allylic alcohols. We present the different aspects of this asymmetric transformation that include the diastereo-, and enantioselective isomerizations and the kinetic resolution. In addition, we described also our contribution involving fluorinated enantiopure allylic alcohol with achiral catalyst by the enantiospecific approach. Finally, the description of tandem reactions involving such an asymmetric isomerization of allylic alcohols is presented as a perspective. Ó 2015 Elsevier Ltd. All rights reserved.
Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diastereoselective isomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enantioselective isomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ruthenium catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rhodium catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iridium catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Palladium catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kinetic resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enantiospecific isomerization: a case study of trifluoromethylated allylic alcohols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tandem asymmetric reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction The development of new chemical reactions with a low environmental impact is a major concern for the chemists. Efficiency of a process can be defined in terms of complexity, selectivity, and atom economy. Catalysis meets all these criteria and is a key ⇑ Corresponding authors. Tel.: +33 (0)235522466 (D.C.); tel.: +33 (0)231452842; fax: +33 (0)231452877 (J.-L.R.). E-mail addresses: [email protected] (D. Cahard), jean-luc.renaud@ ensicaen.fr (J.-L. Renaud). http://dx.doi.org/10.1016/j.tetlet.2015.09.098 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
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technology for green chemistry.1 The isomerization of allylic alcohols into the corresponding saturated carbonyl compounds is a catalytic process that is 100% atoms efficient.2 In this method, a transition metal assists the migration of the carbon–carbon double bond into an enolate or enol, which tautomerizes to the carbonyl compound. It is a conceptually attractive approach, which compares favorably with the more conventional sequential two-step oxidation and reduction reactions or vice versa. Many transition metals have been employed in the isomerization of allylic alcohols, but ruthenium, rhodium, and iridium complexes dominate the field of the asymmetric versions.2
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Scheme 1. Three possible mechanisms for the isomerization of allylic alcohols.
While the related asymmetric isomerization of allylic amines has already found application in industry, the asymmetric isomerization of allylic alcohols is still a challenge in organic chemistry even if great progresses have been made in the last decade. In this digest, every aspects of asymmetric isomerization of allylic alcohols will be presented, including our own efforts devoted to the synthesis of chiral fluorinated compounds, as well as tandem asymmetric reactions. Diastereoselective isomerization In the course of synthesizing ‘Superambrox’, Fehr and Farris did not observed any hydrogenation of the highly substituted C@C double bond in the presence of Crabtree or Chaudret catalyst, but Scheme 2. Diastereoselective synthesis of ‘Superambrox.
Scheme 3. Synthesis of furan derivatives and proposed mechanism.
Essentially three different mechanisms have been proposed for this reaction, which strongly depend upon the nature of the catalyst, the reaction conditions and involve either a metal hydride addition–elimination mechanism (Scheme 1a), a p-allyl metal hydride mechanism (Scheme 1b), or a mechanism involving a metal alkoxide (Scheme 1c).1 The mechanism (a) occurs usually in acidic medium, (b) in neutral conditions with low valent metal complexes, whereas mechanism (c) occurs in basic medium.
Figure 1. Chiral ruthenium complexes used in enantioselective isomerization of allylic alcohols.
D. Cahard et al. / Tetrahedron Letters 56 (2015) 6159–6169 Table 1 Asymmetric isomerization of nerol or geraniol
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Enantioselective isomerization Ruthenium catalysts
a
Substrate
Complex (mol %)
Yield (%)
ee (%)
Refs.
Nerol Geraniol Nerol Geraniol Geraniol Nerol Geraniol Geraniol Nerol Geraniol Geraniol Nerol Geraniol Nerol Geraniol Nerol Geraniol Geraniol Nerol
[Ru-1] (0.625) [Ru-2] (5) [Ru-2] (5) [Ru-3] (5) [Ru-4] (5) [Ru-4] (5) [Ru-5] (5) [Ru-6] (0.5) [Ru-6] (0.5) [Rh(binap)][ClO4] (5) [Rh-1] (5) [Rh-1] (5) [Rh-2] (5) [Rh-2] (5) [Rh-3] (5) [Rh-3] (5) [Ir-2] (5) [Ir-3] (5) [Ir-3] (5)
26 73 18 71 97 35 32 58 68 70 88 90 75 85 62–85 70–96 20 49 26
12.4 19 n.d.a 8 17 n.d.a 13 >99 >99 37 60 51 44 32 9–22 16–31 53 82 31
5 6 6 6 6 6 6 7 7 10 12 12 12 12 12 12 17 19 19
n.d.: not determined.
Scheme 4. [Ru-6]-catalyzed enantioselective isomerization of primary allylic alcohols.
a hydroxyl-oriented diastereoselective isomerization of the allylic alcohol (Scheme 2).3 The trans-fused tetrahydrofuran fragment was isolated in 46–76% yield (depending on the catalyst) and with a perfect control of the relative stereochemistry and of the two contiguous centers. The same group reported later a general route to transtetrahydrofurans, even from tetrasubstituted alkenes that are reluctant substrates in isomerization (Scheme 3).4 Diols with a secondary or tertiary alcohol led mainly, or exclusively, to the trans-tetrahydrofurans in good yields within minutes. This methodology was applied to the synthesis of menthalactone (Scheme 3). To gain further information on the reaction pathway, a ruthenium-catalyzed isomerization of a deuterated allylic alcohol and a crossover experiment were performed. After coordination of the ruthenium catalyst with the two hydroxyl groups, a stereoselective addition of a ruthenium hydride to the alkene could generate a ruthenium intermediate (Scheme 3). A subsequent b-elimination and a tautomerization/lactol formation provide the trans-lactol (Scheme 3).
The first attempt to isomerize stereoselectively nerol and/or geraniol into citronellal was reported by Süss-Fink and co-workers in 1989.5 Toward this goal, the authors modified the trinuclear ruthenium cluster system (Ru3(CO)12) with (S)-proline ([Ru-1], Fig. 1). The corresponding chiral methoxymethylpyrrolidine carbamoyl cluster catalyzed the isomerization of nerol with an enantiomeric excess of 12.4% (Table 1). Salzer and co-workers prepared several chiral ruthenium complexes and evaluated them in the isomerization of nerol and geraniol.6 The citronellal was obtained in low to high yields, but in very low enantiomeric excesses ([Ru-2], [Ru-3], [Ru-4] and [Ru-5], Fig. 1, Table 1). Ohkuma and co-workers reported an efficient enantioselective isomerization of primary allylic alcohols into the corresponding aldehydes catalyzed by the well-defined [RuCl2(Tol-Binap)(dbapen)] system ([Ru-6], Fig. 1) in ethanol at room temperature (Scheme 4).7 In the same reaction conditions, some Noyori’s complexes such as [RuCl2(Tol-binap)(DMF)n], [RuCl(Tol-binap)(p-cym)][Cl], [(C2H5)2NH2][RuCl(Tol-binap)(l-Cl)3], or a combination of [Ru(cod)Cl2]n and Tol-binap, provided the aldehydes in lower yields whereas some others, such as ([RuCl2(Tol-binap)(dpen)] and [Ru(O2CCH3)2(Tol-binap)], did not catalyze this reaction. Compared to previous catalytic systems, [Ru-6] was efficient even at low catalyst loading for a broad range of alkyl/aryl or alkyl/alkyl 3,3-disubstituted allylic alcohols. Worth to note is the isomerization of geraniol and nerol (see Table 1). Both isomers were isomerized in good yields (58–68%) and with a perfect stereoselectivity (ee >99%) in the presence of only 0.5 mol % of ruthenium complex. This catalytic system is to date the most efficient system for the synthesis of this important industrial material. The absolute configuration depends on the geometry of the starting alkene. The best solvent was ethanol, other alcohols afforded also the aldehydes but in slower rates and aprotic solvent gave very low activities. Hydrogen-bond network was suggested to explain these observations, but no further clues were provided to shed light on the role of the solvent in this process. Interestingly, unlike the work of Sowa (vide infra),8 no subsequent reduction of the final aldehyde by a ruthenium hydride species was reported. Based on these results and on deuterium labeling experiments, the following mechanism was proposed (Scheme 5). The basic conditions imply the formation of a ruthenium–alkoxide intermediate. Then, the 1,3-intramolecular hydrogen shift took place and was followed by a protonation of the g3-oxoallyl intermediate by an incoming allylic alcohol with concomitant regeneration of the ruthenium complex. Because of the bulkiness of the NBu2 moiety, the dbapen ligand is hemilabile and can liberate a vacant site, and finally allow the coordination of the olefin. The enantioselective isomerization of secondary allylic alcohols is rare in the literature and the first example appeared in 2005 by the group of Ikariya.9 The half-sandwich [Cp⁄Ru(P–N)] complex ([Ru-7], Fig. 1), in which the P–N ligand derived from (L)-proline, was able to catalyze the isomerization of secondary allylic alcohols and to furnish the corresponding ketones in good yields with enantiomeric excesses ranging from 62% to 74% (Scheme 6). As also noticed with primary allylic alcohols, alcohols with (E)- and (Z)geometry led to ketones with opposite absolute configurations as a result of a kinetic dynamic resolution. At first glance, the mechanism of this isomerization could involve the oxidation of the alcohol followed by a Michael type addition, as suggested by isotope labeling.10 However, a more
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Scheme 5. Proposed mechanism for the [Ru-6]-catalyzed enantioselective isomerization.
Scheme 6. [Ru-7]-catalyzed enantioselective isomerization of secondary allylic alcohols.
careful analysis revealed further valuable information. With sterically demanding allylic alcohols, the b-hydride abstraction is reversible (in the absence of any other hydrogen acceptor),10 and racemization of chiral non-racemic secondary alcohols occurs. Moreover, a H-D scrambling was suggested to explain the deuterium distribution at the a- and b-carbons. The proposed mechanism is shown in Scheme 7.
Scheme 7. Proposed mechanism for the [Ru-7]-catalyzed enantioselective isomerization.
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Scheme 8. [Rh(binap)]-catalyzed isomerization of allylic derivatives.
Rhodium catalysts The rhodium–binap complex represents the most efficient combination for the enantioselective isomerization of allylic amines to enamines, the key step for the industrial production of ( )-menthol and related terpenes.11 However, the corresponding reaction with allylic alcohols did not reach such a degree of refinement (Scheme 8). Chapuis et al. evaluated various chiral diphosphines rhodium complexes in the enantioselective isomerization of geraniol and nerol into citronellal (Fig. 2).12 The best result was obtained with a binap ligand and the aldehyde was produced in good yields with enantiomeric excesses up to 61% from the (E)-isomer and 51% from the (Z)-isomer ([Rh-1], [Rh-2], [Rh-3], Fig. 2 and Table 1). As part of their program devoted to the design and the use of phosphaferrocene ligands in stereoselective reactions,13 Fu and co-workers established that a combination of a cationic Rh+ precursor and a planar–chiral phosphaferrocene could catalyze the enantioselective isomerization of primary allylic alcohols in moderate to high yields (55–91%) and enantioselectivities (64–86%) at 70 °C in THF (Scheme 9).14 In these conditions, the selectivity was dependent on the counteranion (BF4 was the best one) and on the solvent, but not on temperature. Two important features of this complex have to be highlighted: (i) first, the process was not limited to alkenes bearing aromatic substituents. As example, 3-cyclohexyl-but-2-en-1-ol furnished the corresponding aldehyde in 75% yield with 72% ee. (ii) Second, the reactivity of this catalytic system differs from all other systems. With this combination, (Z)allylic alcohols led to unprecedented higher selectivities than the (E)-isomer. This Rh+/L⁄1-catalyzed isomerization process was used
Figure 2. Diphosphines evaluated by Chapuis et al.
Scheme 9. Asymmetric isomerization using the first generation of rhodium– phosphaferrocene complex.
for the synthesis of the enantioenriched 4-(p-methoxyphenyl)-5methyl hexanoic acid, a key intermediate in the synthesis of 7-hydroxycalamenene and 7-hydroxycalamenenal (Scheme 9).14 A slight modification of the ligand structure can modify the reactivity.15 Indeed, the replacement of the phenyl substituent by a tolyl enhanced the selectivities, yields and scope. Surprisingly, selectivities were higher at higher temperature (100 °C vs 70 °C) and depended on the steric demand of the alkyl substituents, but not of the aromatic moiety linked to the alkene (Scheme 10).15 Finally, the (E)-allylic alcohols furnished the aldehydes in higher yields and enantiomeric excesses (86–98% yields and 75–92% ee from the (E)-isomer, 60–90% yields and 57–90% ee from the (Z)isomer) with this new complex [Rh(cod)L⁄2][BF4], unlike with [Rh (cod)L⁄1][BF4]. Mechanistic studies established that the isomerization proceeds via an intramolecular 1,3-hydrogen migration and that the catalyst differentiates between the enantiotopic C1 hydrogens.
Scheme 10. Asymmetric isomerization using the second generation of rhodium– phosphaferrocene complex.
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Iridium catalysts Mantilli and Mazet demonstrated in 2009 that Crabtree’s catalyst was able to promote the isomerization of primary allylic alcohols into aldehydes using low catalyst loading, at room temperature after an initial activation of the cyclooctadiene ligand.16 Worth to note, hydrogen was taken out of the reaction medium to prevent competitive hydrogenation reaction. Variation of the steric and electronic properties of the ligand and the nature of the counter anion, as well, changed dramatically both the catalytic activity and the stability of the iridium complex (Scheme 11).16 With the right combination (namely, the association of an electron rich and bulky phosphine and a N-donor ligand, a [BArF4] anion), even reluctant substrates such as primary allylic alcohols with tetrasubstituted alkene isomerized! Based on these findings, the group of Mazet designed three generations of catalysts ([Ir-1], [Ir-2] and [Ir-3], Fig. 3). The first generation was based on dialkylphosphanylmethyl oxazoline iridium complexes ([Ir-1], Fig. 3).17 Both substituents on the phosphorous atom and on the oxazoline have an impact on the rate and the selectivity. Thus, an increase in the steric demand on the phosphorous atom led to higher enantioselectivities, when aryl substituted oxazoline enhanced the rate. Then, depending on the structure of allylic alcohols, modest to high, and even perfect, control of the enantioselectivity was achieved. Unlike the (E)-isomers, the (Z)-primary allylic alcohols did not furnish good yields and selectivities (Fig. 3, Table 2).17 To overcome the high cost of these ligands, mainly derived from non-natural (L)-tert-leucine, Mantilli and Mazet reported a second generation of iridium complexes featuring a different connectivity
Scheme 11. Complexes evaluated by Mazet et al.
Figure 3. Chiral ruthenium complexes used in enantioselective isomerization of allylic alcohols.
Table 2 Asymmetric isomerization of primary allylic alcohols
[Ir-1] [Ir-2] [Ir-3] [Ir-4]
Conv. (%)
ee (%)
Refs.
75 73 65 88
97 96 >99 >99
17 18 19 20
and a higher diversity. This series was synthesized from (D)- or (L)serine and dialkylphosphines ([Ir-2], Fig. 3).18 Similar reactivities and selectivities were achieved for most substrates but, more importantly, an enhancement was observed for the more challenging 3,3-dialkyl primary allylic alcohols (Table 2).18 Based on further investigation on the enantiodiscrimination mechanism, Mazet’s group developed a third generation of iridium catalysts for the enantioselective isomerization of previously unsuccessful allylic alcohols (such as alcohols with small alkyl substituents on the alkenes).19 The catalyst design was based on Charton analysis, a relationship/correlation between enantiomeric ratios and steric parameters on the catalyst, the idea to bring closer the phosphine alkyl substituent and the oxazoline moiety, and also to maintain enough flexibility in the ligand backbone to allow the isomerization of sterically demanding or non-demanding allylic alcohols ([Ir-3], Fig. 3). With this third generation, perfect enantioselectivities were reached with sterically hindered allylic alcohols, but more importantly, high levels of enantioselectivity were achieved with alcohols having small alkyl group (Table 2), albeit in low to moderate yields.19 While these results validated the working hypothesis, secondary allylic alcohols, tetrasubstituted or 2,3-disubstituted allylic alcohols, and homoallylic alcohols remained unreactive. (Z)-Isomers were still challenging substrates with this new generation. To highlight this lower reactivity, nerol furnished citronellal in 26% yield with 31% enantiomeric excess, when geraniol isomerized into citronellal in 49% yield with 82% enantiomeric excess (Table 1). To overcome these limitations, Andersson reported the use of another P–N ligand family, known to be highly active in the asymmetric olefin hydrogenation ([Ir-4], Fig. 3).20 After a rapid screening of various P–N ligands in a model reaction, the ligand shown in Figure 3 emerged as the most active and selective. As already reported by Mazet,16–19 the steric accessibility of the catalyst was the most important feature in the ligand structure. But the most striking difference between the Mazet and Andersson ligands was the nature of the phosphine. While bulky electron rich phosphines were required in Mazet’s catalyst, aryl (phenyl or tolyl) substituents were tolerated on the phosphorous atom in Andersson’s complex.20 A variety of (E)-trisubstituted allylic alcohols were evaluated and provided the corresponding aldehydes in modest to high yields and almost perfect enantioselectivity (Table 2). 3,3-Dialkyl allylic alcohols isomerized into aldehydes in high enantiomeric excesses, albeit in very low yields. The (Z)-isomers of some 3-alkyl-3-aryl allylic alcohols isomerized as well in high enantioselectivities, regardless the steric hindrance of the substituents, but yields were moderate. However, this catalytic system was not yet general as the reactivity was impeded by the size of the substituents. Thus, nerol did not react (unlike with Mazet’s catalyst), while (Z)-3cyclohexyl-but-2-en-1-ol led to the aldehyde in 50% yield with 98% ee.
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Palladium catalysts Even if the advances in metal-catalyzed isomerization have led to extremely active and selective catalysts, and found application in industry, further developments and improvements are required. All the above-mentioned catalytic systems are substrate-specific, depend on the steric parameters (higher the substitution, lower the reactivity) and are active with the one or the other of the isomers. Moreover, they are not general for the isomerization of primary and secondary allylic alcohols. In 2014, the group of Mazet reported a palladium-catalyzed isomerization of highly substituted allylic alcohols.21 The catalytic system tolerated various functional groups such as halides, hydroxyl, and nitro groups and N-methylpyrrole. It is also insensitive to the nature and substitution of the alkene. The isomerization of a primary or secondary alcohol with a tetrasubstituted alkene provided the carbonyl compound in good yields as a mixture of diastereomers. Both experimental studies and DFT calculations supported a chain-walking mechanism, namely an iterative insertion, migration/b-elimination sequence. Preliminary enantioselective isomerization reactions were carried out in the presence of (R,R)-i-Pr-Duphos, a ligand sharing electronic and steric properties with the dicyclophosphinoethane ligand (dcpe). 3-Cyclohexyl-3-phenylprop-2(E)-enol delivered 3-cyclohexyl-3-phenyl propenal in 65% yield with 73% ee. The aldehyde was isolated in 50% yield and 48% ee from the (Z)-isomer (Scheme 12).21
Scheme 13. Rhodium-catalyzed kinetic resolution of allylic alcohols.
Scheme 14. Rhodium-catalyzed kinetic resolution of 4-hydroxy-2-cyclopentanone.
Scheme 12. Palladium-catalyzed asymmetric isomerization.
reaction rate was obtained with 2-cyclohexen-1-ol (32% yield and 99% ee after 24 h) and 2-cyclopent-1-ol did not react at all. More importantly, while 4-hydroxy-2-cyclopentanone, a key intermediate in prostaglandin synthesis, was recovered in 91% ee at 72% conversion after 14 days at 0 °C in coordinating solvent in the presence of [Rh((R)-binap)(MeOH)][ClO4] (Noyori’s reaction),25 this secondary alcohol did not react under the new conditions and only cyclopent-4-ene-1,3-dione was observed as the side product (Scheme 14).24 Further experiments demonstrated that this unsaturated dione coordinated to the rhodium center and inhibited the catalyst activity in dichloromethane.
Kinetic resolution
Enantiospecific isomerization: a case study of trifluoromethylated allylic alcohols
Kinetic resolution was also applied in isomerization of chiral racemic allylic alcohols. A chiral catalyst can isomerize preferentially one enantiomer providing the corresponding ketones or aldehydes in addition to an enantioenriched solution of the other enantiomer. Up to now, few works have been reported in the literature.22–25 The pioneering work by Ohkubo et al. with [RhCl( )-Diop] allowed the generation of (S)-3-buten-2-ol in very low ee (1.7%) at 31% conversion.22 In 2010, Crochet and co-workers demonstrated that chiral arene–ruthenium complexes were able to promote the kinetic resolution of allylic alcohols, albeit again in low ee’s (up to 17% at 55% conversion).23 The group of Zhang made recently the first breakthrough, in the presence of rhodium complexes.24 Based on an initial report by Noyori and co-workers,25 Zhang and co-workers modified the reaction conditions, the counter anion in the complex and showed that [Rh(cod)Cl]2/(R)-binap/ AgO2CCF3 in non-coordinating solvent was an effective combination for the kinetic resolution of racemic alcohols (Scheme 13). Selectivity factors up to 24 and ee up to 99.4% were obtained from rac-aryl-2-propenol derivatives. Selectivity factors and enantioselectivities were lower with alkyl-2-propenol derivatives. A lower
In addition to the aforementioned studies on enantioselective isomerization of primary and secondary allylic alcohols, we conducted a study on enantiospecific isomerization of secondary allylic alcohols.26 In an enantiospecific reaction, both the stereochemistry of the reactant and the mechanism determine the stereochemistry of the product. This approach required the preparation of optically enriched secondary allylic alcohols as well as analytical methods to measure ee values and absolute configurations of reactants and products. We conducted a series of experiments in order to ascertain an enantiospecific mechanism in the case of c-CF3 secondary allylic alcohols. This reaction was developed with the intention of synthesizing enantiopure b-CF3 ketones otherwise difficult to access. The fact was that all our attempts to isomerize c-CF3 secondary allylic alcohols by means of chiral ruthenium complexes led to racemic or poorly enantioenriched ketones (Scheme 15, top). While, starting from an enantioenriched c-CF3 allylic alcohol with 99% ee, the isomerization by means of achiral RuCl2(PPh3)3 gave the corresponding b-CF3 ketone with 99% ee as well, and thus with 100% enantiospecificity (Scheme 15, bottom).26 To illustrate this methodology, we synthesized a CF3-analog of citronellol as shown in Scheme 16.26
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Scheme 15. Isomerization of fluorinated allylic alcohols.
Scheme 16. Synthesis of (S)-CF3-citronellol.
This methodology was also applied recently by Liu and coworkers.27 In the presence of a supported Noyori’s catalyst and [RuCl2(PPh3)3], the tandem reduction–isomerization of b-CF3-a,bunsaturated ketones into the corresponding chiral saturated ketones was carried out in water. High yields, enantiomeric excesses and enantiospecificities were reached in these conditions. The heterogeneous catalyst was recovered and reused eight times without any detrimental effects. A detailed mechanistic study with the c-CF3 secondary allylic alcohols was conducted to determine the exact operative pathway. A first series of observations indicated that the strong electronwithdrawing effect of the CF3 group very significantly enhanced the rate of the migration insertion step relative to non-fluorinated substrates while maintaining excellent reactivity even at relatively low temperature for trisubstituted olefinic substrates. Secondly, a specific fluorine effect was observed in a comparison with the reactivity of non-fluorinated allylic alcohols. Indeed, the rate-limiting
step permuted from insertion for non-fluorinated allylic alcohols to b-elimination for fluorinated allylic alcohols. In the proposed mechanism (Fig. 4), cesium carbonate facilitates the formation of a 16-electron ruthenium alkoxide complex that is further coordinated on the C@C double bond to account for the reactivity observed. Subsequent b-hydride elimination produces the enone– hydride ruthenium complex, in which the enone remains coordinated until the 1,3-migratory insertion of the hydride takes place from a single face of the trigonal carbon center. The stereochemical information of the starting optically enriched c-CF3 allylic alcohol is entirely transferred to the chiral isomerization product. The resulting ruthenium enolate is then protonated by an incoming allylic alcohol and tautomerizes into the final saturated ketone concomitantly with the release of the catalyst. In the case of non-fluorinated allylic alcohols, the second step is the rate-limiting step and reactions are equilibrated with decoordination of the ruthenium hydride complex from the enone allowing for enantioselective but not enantiospecific process. Additionally, we demonstrated that an intramolecular syn-specific 1,3-hydride shift takes place within the coordination sphere of the ruthenium center. Tandem asymmetric reactions Allylic alcohols can be considered as latent enolates (or enols) and can be used to perform tandem and sequential reactions by trapping the enolate intermediates in order to create new C–C or C–het bonds instead of the protonation and tautomerization into the corresponding carbonyl compounds.28 Several reviews and recent articles report non-asymmetric tandem reactions involving allylic alcohols as starting material.28,29 The group of Grée reported a diastereoselective tandem isomerization–Mannich reaction from allylic alcohols with N-tert-butyl sulfinimines as electrophiles and [NiHCl(dppe)]/MgBr2 [dppe = 1,2-bis(diphenylphosphinoethane)]
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Figure 4. Mechanisms for fluorinated and non-fluorinated substrates.
Scheme 17. Diastereo- and enantioselective tandem isomerization/Mannich reaction.
Scheme 18. Enantioselective tandem isomerization/halogenation or isomerization/amination reaction.
as catalytic system.29 This approach allowed the synthesis of b-amino ketones and b-amino alcohols as key intermediates in the synthesis of ent-Nikkomycins and ent-Funebrine (Scheme 17). In the case where the isomerization is followed by a further addition of a reagent and/or catalyst, the reaction is sequential. Alexakis, Mazet and Quintard have designed a sequential
asymmetric isomerization followed by an a-alkylation using a chiral organometallic catalyst based on iridium in the first step and a chiral organocatalyst derivative of (L)-proline in the second step (Scheme 18).30 The enantioselective isomerization allowed to control the stereogenic center at the b position of the carbonyl function. The aldehyde thus obtained reacted with a chiral amine
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Scheme 19. Ruthenium-catalyzed enantioselective synthesis of citronellol.
providing an enamine, which, by alkylation, allowed the creation of a second stereogenic center in the a position to the carbonyl function in a diastereoselective manner. The corresponding chiral aldehydes are obtained in moderate to good yields with excellent diastereomeric ratios (up to 1:49) and excellent enantiomeric excesses (up to 99%) for the major diastereomer. The scope of this methodology has been extended to other types of electrophiles such as N-fluorobenzenesulfonimide (NFSI), N-chlorosuccinimide (NCS), or diethyl azodicarboxylate (DEAD). The corresponding products were obtained in moderate yields, high diastereoselectivities, and excellent enantioselectivities after reduction of the aldehyde function into alcohol to avoid epimerization of the stereogenic centers featuring the heteroatom. Apart from tandem reactions taking advantage of the enolate intermediate and generating an a-functionalized carbonyl compound, this carbonyl function can also be transformed into alcohol through transfer hydrogenation. Such tandem reaction enables after an isomerization step of allyl alcohols to reduce the aldehydes or ketones formed in the same reaction conditions. An alcoholic solvent like isopropanol solubilizes the reactants and also acts as a hydride source for reduction of the carbonyl function.31 The result of the one-pot operation is equivalent to a reduction of a C@C double bond without resorting to the use of dihydrogen gas or techniques requiring high pressures. This methodology has been applied by Sowa and co-workers to the enantioselective synthesis of (R)- and (S)-citronellol in 78% and 70% yields with 98% and 93% enantiomeric excesses, respectively.8 However, the amount of precatalyst used is rather high, 10 mol % of [RuCl2(cod)]n [cod: 1,5cyclooctadiene] and 20 mol % (S)-Tol-binap, but may be decreased to 3 mol % when using [RuCl2{(S)-Tol-binap}(p-cymene)], which is easier to handle and that produces a higher yield despite a slight loss of enantioselectivity (Scheme 19). It is important to note in this example that the synthetic route allows the selective reduction of the allylic C@C double bond, which would not have been possible via conventional reduction or hydrogenation.8 The asymmetric isomerization followed by a subsequent reduction of the aldehyde can be also catalyzed by a {Ru(cod)Cl2}n/i-Pr-Duphos system in a basic solution of iso-propanol at 83–100 °C to give the chiral alcohols in 19–98% yields with 72–98% enantiomeric excess.
Despite these interesting results, the substrate scope appeared rather limited. As noticed previously with other ruthenium complexes or with other noble metals (vide supra), in the presence of a combination of ruthenium and Tol-binap ligand, the final absolute configuration depends on the geometry of the starting alkene. This is in sharp contrast with the Duphos ligand, which provided (R)-citronellol from both geraniol and nerol. This unique feature of the Duphos ligand was previously described in hydrogenation of functionalized alkenes.32 Sowa conducted also a deuterium labeling experiment and demonstrated that (i) 1,3-intramolecular hydrogen shift is one of the catalytic step; (ii) the enol intermediate is hydrolyzed by i-PrOH; and (iii) the last step is a transfer hydride process. The same group extended the tandem isomerization/asymmetric transfer-hydrogenation reaction to secondary allylic alcohols with the aid of a ruthenium catalyst, which was generated in situ in isopropyl alcohol from [RuCl(l-Cl)(p-cymene)]2 and the chiral ligand (1S,2S)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine, (S,S)-TsDPEN (Scheme 20, top). Chiral secondary alcohols were obtained in up to 97% yield with up to 93% ee value.33 This was an improvement of the early attempt by Williams and co-workers who reported a modest 7% ee under similar reaction conditions in 1,4-butanediol in the presence of KOH at 110 °C.34 The results by Sowa and co-workers were comparable in terms of ee values with those obtained by Adolfsson who reported a couple of months before the same one-pot procedure for the direct conversion of allylic alcohols into chiral non-racemic saturated alcohols. Adolfsson performed the reaction under milder conditions, a 10-fold lower amount of catalyst, and a chiral a-amino acid hydroxyamide ligand in a mixture ethanol/THF (Scheme 20, bottom).35 Conclusion and perspectives In conclusion, many efforts have been devoted to the development of asymmetric isomerization of primary and secondary allylic alcohols. To date, the most represented catalysts are based on noble metals, and more specifically on ruthenium, rhodium and iridium complexes. High enantioselectivities were reached with various allylic alcohols. However, despite these successes, the catalysts are still often substrate dependent. A research avenue to the future will be the development of new tandem enantioselective transformations and the development of chiral earth-abundant complexes, due to economic constraint. Acknowledgments This work is promoted by the interregional CRUNCh network, supported by the ‘Ministère de la Recherche et des Nouvelles Technologies’, CNRS (Centre National de la Recherche Scientifique) and the LABEX SynOrg (ANR-11-LABX-0029). Johnson-Matthey is acknowledged for a generous loan of catalysts and helpful discussions.
Scheme 20. Enantioselective tandem isomerization/hydride transfer reaction.
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References and notes 1. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, 1998. p 30. 2. (a) Uma, R.; Crévisy, C.; Grée, R. Chem. Rev. 2003, 103, 27–51; (b) van der Drift, R. C.; Bouwman, E.; Drent, E. J. Organomet. Chem. 2002, 650, 1–24; (c) Mantilli, L.; Mazet, C. Chem. Lett. 2011, 40, 341–344; (d) Lorenzo-Luis, P.; Romerosa, A.; Serrano-Ruiz, M. ACS Catal. 2012, 2, 1079–1086; (e) Ahlsten, N.; Bartoszewicz, A.; Martin-Matute, B. Dalton Trans. 2012, 41, 1660–1670; (f) Cadierno, V.; Crochet, P.; Gimeno, J. Synlett 2008, 1105–1124. 3. Fehr, C.; Farris, I. Angew. Chem., Int. Ed. 2006, 45, 6904–6907. 4. Fehr, C.; Magpantay, I.; Saudan, L.; Sommer, H. Eur. J. Org. Chem. 2010, 6153– 6156. 5. Süss-Fink, G.; Jenke, T.; Heitz, H.; Angela Pellinghelli, M.; Tiripicchio, A. J. Organomet. Chem. 1989, 379, 311–323. 6. Doppiu, A.; Salzer, A. Eur. J. Inorg. Chem. 2004, 2244–2252. 7. Arai, N.; Sato, K.; Azuma, K.; Ohkuma, T. Angew. Chem., Int. Ed. 2013, 52, 7500– 7504. 8. Wu, R.; Beauchamps, M. G.; Laquidara, J. M.; Sowa, J. R. Angew. Chem., Int. Ed. 2012, 51, 2106–2110. 9. Ito, M.; Kitahara, S.; Ikariya, T. J. Am. Chem. Soc. 2005, 127, 6172–6173. 10. Ito, M.; Osaku, A.; Kitahara, S.; Hirakawa, M.; Ikariya, T. Tetrahedron Lett. 2003, 44, 7521–7523. 11. (a) Tani, K.; Yamagata, T.; Otsuka, S.; Akutagawa, S.; Kumobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R. J. Chem. Soc., Chem. Commun. 1982, 600–601; (b) Tani, K.; Yamagata, T.; S Akutagawa, S.; Kumobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S. J. Am. Chem. Soc. 1984, 106, 5208–5217. 12. Chapuis, C.; Barthe, M.; de Saint Laumer, J.-Y. Helv. Chim. Acta 2001, 84, 230– 242. 13. Fu, G. C. Acc. Chem. Res. 2006, 39, 853–860. 14. Tanaka, K.; Qiao, S.; Tobisu, M.; Lo, M. M. C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 9870–9871. 15. Tanaka, K.; Fu, G. C. J. Org. Chem. 2001, 66, 8177–8186. 16. Mantilli, L.; Mazet, C. Tetrahedron Lett. 2009, 50, 4141–4144. 17. Mantilli, L.; Gérard, D.; Torche, S.; Besnard, C.; Mazet, C. Angew. Chem., Int. Ed. 2009, 48, 5143–5147.
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18. Mantilli, L.; Mazet, C. Chem. Commun. 2010, 445–447. 19. Mantilli, L.; Gérard, D.; Torche, S.; Besnard, C.; Mazet, C. Chem. Eur. J. 2010, 16, 12736–12745. 20. Li, J.-Q.; Peters, B.; Andersson, P. G. Chem. Eur. J. 2011, 17, 11143–11145. 21. Larionov, E.; Lin, L.; Guénée, L.; Mazet, C. J. Am. Chem. Soc. 2014, 136, 16882– 16894. 22. Ohkubo, K.; Ohgushi, T.; Kusaga, T.; Yoshinaga, K. Inorg. Nucl. Chem. Lett. 1977, 13, 631–636. 23. Fernández-Zúmel, M. A.; Lastra-Barreira, B.; Scheele, M.; Díez, J.; Crochet, P.; Gimeno, J. Dalton Trans. 2010, 39, 7780–7785. 24. Ren, K.; Zhang, L.; Hu, B.; Zhao, M.; Tu, Y.; Xie, X.; Zhang, T. Y.; Zhang, Z. ChemCatChem 2013, 5, 1317–1320. 25. Kitamura, M.; Manabe, K.; Noyori, R. Tetrahedron Lett. 1987, 28, 4719–4720. 26. (a) Bizet, V.; Pannecoucke, X.; Renaud, J.-L.; Cahard, D. Angew. Chem., Int. Ed. 2012, 51, 6467–6470; (b) Bizet, V.; Pannecoucke, X.; Renaud, J.-L.; Cahard, D. J. Fluorine Chem. 2013, 152, 56–61; (c) Bizet, V.; Pannecoucke, X.; Renaud, J.-L.; Cahard, D. Adv. Synth. Catal. 2013, 355, 1394–1402; (d) Cahard, D.; Bizet, V.; Dai, X.; Gaillard, S.; Renaud, J.-L. J. Fluorine Chem. 2013, 155, 78–82. 27. Xia, X.; Wu, M.; Jin, R.; Cheng, T.; Liu, G. Green Chem. 2015, 17, 3916–3922. 28. (a) Li, H.; Achard, M.; Bruneau, C.; Sortais, J.-B.; Darcel, C. RSC Adv. 2014, 4, 25892–25897; (b) Gómez, A. B.; Erbing, E.; Batuecas, M.; Vázquez-Romero, A.; Martín-Matute, B. Chem. Eur. J. 2014, 20, 10703–10709; (c) Ahlsten, N.; Bermejo Gómez, A.; Martín-Matute, B. Angew. Chem., Int. Ed. 2013, 52, 6273– 6276. 29. Cao, H. T.; Roisnel, T.; Valleix, A.; Grée, R. Eur. J. Org. Chem. 2011, 3430–3436. 30. Quintard, A.; Alexakis, A.; Mazet, C. Angew. Chem., Int. Ed. 2011, 50, 2354–2358. 31. (a) Cadierno, V.; Crochet, P.; Francos, J.; Garcia-Garrido, S. E.; Gimeno, J.; Nebra, N. Green Chem. 2009, 11, 1992–2000; (b) Diaz-Alvarez, A. E.; Crochet, P.; Cadierno, V. Catal. Commun. 2011, 13, 91–96. 32. (a) Burk, M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996, 118, 5142–5143; (b) Jerphagnon, T.; Renaud, J.-L.; Demonchaux, P.; Ferreira, A.; Bruneau, C. Tetrahedron: Asymmetry 2003, 14, 1973–1977. 33. Shoola, C. O.; Del Mastro, T.; Wu, R.; Sowa, J. R., Jr. Eur. J. Org. Chem. 2015, 1670– 1673. 34. Maytum, H. C.; Francos, J.; Whatrup, D. J.; Williams, J. M. J. Chem. Asian J. 2010, 5, 538–542. 35. Slagbrand, T.; Lundberg, H.; Adolfsson, H. Chem. Eur. J. 2014, 20, 16102–16106.
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Digest Paper
Asymmetric isomerization of allylic alcohols Dominique Cahard a,b,⇑, Sylvain Gaillard c,d, Jean-Luc Renaud c,d,⇑ a
Normandie Université, INSA de Rouen, Laboratoire C.O.B.R.A., 76821 Mont-Saint-Aignan Cedex, France CNRS, UMR 6014, 76821 Mont-Saint-Aignan Cedex, France Normandie University, University of Caen Normandie, Laboratoire de Chimie Moléculaire et Thioorganique, 14050 Caen, France d CNRS, UMR 6507, 14050 Caen, France b c
a r t i c l e
i n f o
Article history: Received 20 July 2015 Revised 7 September 2015 Accepted 23 September 2015 Available online 25 September 2015 Keywords: Isomerization Catalysis Chirality Allylic alcohols Atom economy
a b s t r a c t In this digest, we report the recent advances in asymmetric isomerization of allylic alcohols. We present the different aspects of this asymmetric transformation that include the diastereo-, and enantioselective isomerizations and the kinetic resolution. In addition, we described also our contribution involving fluorinated enantiopure allylic alcohol with achiral catalyst by the enantiospecific approach. Finally, the description of tandem reactions involving such an asymmetric isomerization of allylic alcohols is presented as a perspective. Ó 2015 Elsevier Ltd. All rights reserved.
Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diastereoselective isomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enantioselective isomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ruthenium catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rhodium catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iridium catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Palladium catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kinetic resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enantiospecific isomerization: a case study of trifluoromethylated allylic alcohols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tandem asymmetric reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction The development of new chemical reactions with a low environmental impact is a major concern for the chemists. Efficiency of a process can be defined in terms of complexity, selectivity, and atom economy. Catalysis meets all these criteria and is a key ⇑ Corresponding authors. Tel.: +33 (0)235522466 (D.C.); tel.: +33 (0)231452842; fax: +33 (0)231452877 (J.-L.R.). E-mail addresses: [email protected] (D. Cahard), jean-luc.renaud@ ensicaen.fr (J.-L. Renaud). http://dx.doi.org/10.1016/j.tetlet.2015.09.098 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
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technology for green chemistry.1 The isomerization of allylic alcohols into the corresponding saturated carbonyl compounds is a catalytic process that is 100% atoms efficient.2 In this method, a transition metal assists the migration of the carbon–carbon double bond into an enolate or enol, which tautomerizes to the carbonyl compound. It is a conceptually attractive approach, which compares favorably with the more conventional sequential two-step oxidation and reduction reactions or vice versa. Many transition metals have been employed in the isomerization of allylic alcohols, but ruthenium, rhodium, and iridium complexes dominate the field of the asymmetric versions.2
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Scheme 1. Three possible mechanisms for the isomerization of allylic alcohols.
While the related asymmetric isomerization of allylic amines has already found application in industry, the asymmetric isomerization of allylic alcohols is still a challenge in organic chemistry even if great progresses have been made in the last decade. In this digest, every aspects of asymmetric isomerization of allylic alcohols will be presented, including our own efforts devoted to the synthesis of chiral fluorinated compounds, as well as tandem asymmetric reactions. Diastereoselective isomerization In the course of synthesizing ‘Superambrox’, Fehr and Farris did not observed any hydrogenation of the highly substituted C@C double bond in the presence of Crabtree or Chaudret catalyst, but Scheme 2. Diastereoselective synthesis of ‘Superambrox.
Scheme 3. Synthesis of furan derivatives and proposed mechanism.
Essentially three different mechanisms have been proposed for this reaction, which strongly depend upon the nature of the catalyst, the reaction conditions and involve either a metal hydride addition–elimination mechanism (Scheme 1a), a p-allyl metal hydride mechanism (Scheme 1b), or a mechanism involving a metal alkoxide (Scheme 1c).1 The mechanism (a) occurs usually in acidic medium, (b) in neutral conditions with low valent metal complexes, whereas mechanism (c) occurs in basic medium.
Figure 1. Chiral ruthenium complexes used in enantioselective isomerization of allylic alcohols.
D. Cahard et al. / Tetrahedron Letters 56 (2015) 6159–6169 Table 1 Asymmetric isomerization of nerol or geraniol
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Enantioselective isomerization Ruthenium catalysts
a
Substrate
Complex (mol %)
Yield (%)
ee (%)
Refs.
Nerol Geraniol Nerol Geraniol Geraniol Nerol Geraniol Geraniol Nerol Geraniol Geraniol Nerol Geraniol Nerol Geraniol Nerol Geraniol Geraniol Nerol
[Ru-1] (0.625) [Ru-2] (5) [Ru-2] (5) [Ru-3] (5) [Ru-4] (5) [Ru-4] (5) [Ru-5] (5) [Ru-6] (0.5) [Ru-6] (0.5) [Rh(binap)][ClO4] (5) [Rh-1] (5) [Rh-1] (5) [Rh-2] (5) [Rh-2] (5) [Rh-3] (5) [Rh-3] (5) [Ir-2] (5) [Ir-3] (5) [Ir-3] (5)
26 73 18 71 97 35 32 58 68 70 88 90 75 85 62–85 70–96 20 49 26
12.4 19 n.d.a 8 17 n.d.a 13 >99 >99 37 60 51 44 32 9–22 16–31 53 82 31
5 6 6 6 6 6 6 7 7 10 12 12 12 12 12 12 17 19 19
n.d.: not determined.
Scheme 4. [Ru-6]-catalyzed enantioselective isomerization of primary allylic alcohols.
a hydroxyl-oriented diastereoselective isomerization of the allylic alcohol (Scheme 2).3 The trans-fused tetrahydrofuran fragment was isolated in 46–76% yield (depending on the catalyst) and with a perfect control of the relative stereochemistry and of the two contiguous centers. The same group reported later a general route to transtetrahydrofurans, even from tetrasubstituted alkenes that are reluctant substrates in isomerization (Scheme 3).4 Diols with a secondary or tertiary alcohol led mainly, or exclusively, to the trans-tetrahydrofurans in good yields within minutes. This methodology was applied to the synthesis of menthalactone (Scheme 3). To gain further information on the reaction pathway, a ruthenium-catalyzed isomerization of a deuterated allylic alcohol and a crossover experiment were performed. After coordination of the ruthenium catalyst with the two hydroxyl groups, a stereoselective addition of a ruthenium hydride to the alkene could generate a ruthenium intermediate (Scheme 3). A subsequent b-elimination and a tautomerization/lactol formation provide the trans-lactol (Scheme 3).
The first attempt to isomerize stereoselectively nerol and/or geraniol into citronellal was reported by Süss-Fink and co-workers in 1989.5 Toward this goal, the authors modified the trinuclear ruthenium cluster system (Ru3(CO)12) with (S)-proline ([Ru-1], Fig. 1). The corresponding chiral methoxymethylpyrrolidine carbamoyl cluster catalyzed the isomerization of nerol with an enantiomeric excess of 12.4% (Table 1). Salzer and co-workers prepared several chiral ruthenium complexes and evaluated them in the isomerization of nerol and geraniol.6 The citronellal was obtained in low to high yields, but in very low enantiomeric excesses ([Ru-2], [Ru-3], [Ru-4] and [Ru-5], Fig. 1, Table 1). Ohkuma and co-workers reported an efficient enantioselective isomerization of primary allylic alcohols into the corresponding aldehydes catalyzed by the well-defined [RuCl2(Tol-Binap)(dbapen)] system ([Ru-6], Fig. 1) in ethanol at room temperature (Scheme 4).7 In the same reaction conditions, some Noyori’s complexes such as [RuCl2(Tol-binap)(DMF)n], [RuCl(Tol-binap)(p-cym)][Cl], [(C2H5)2NH2][RuCl(Tol-binap)(l-Cl)3], or a combination of [Ru(cod)Cl2]n and Tol-binap, provided the aldehydes in lower yields whereas some others, such as ([RuCl2(Tol-binap)(dpen)] and [Ru(O2CCH3)2(Tol-binap)], did not catalyze this reaction. Compared to previous catalytic systems, [Ru-6] was efficient even at low catalyst loading for a broad range of alkyl/aryl or alkyl/alkyl 3,3-disubstituted allylic alcohols. Worth to note is the isomerization of geraniol and nerol (see Table 1). Both isomers were isomerized in good yields (58–68%) and with a perfect stereoselectivity (ee >99%) in the presence of only 0.5 mol % of ruthenium complex. This catalytic system is to date the most efficient system for the synthesis of this important industrial material. The absolute configuration depends on the geometry of the starting alkene. The best solvent was ethanol, other alcohols afforded also the aldehydes but in slower rates and aprotic solvent gave very low activities. Hydrogen-bond network was suggested to explain these observations, but no further clues were provided to shed light on the role of the solvent in this process. Interestingly, unlike the work of Sowa (vide infra),8 no subsequent reduction of the final aldehyde by a ruthenium hydride species was reported. Based on these results and on deuterium labeling experiments, the following mechanism was proposed (Scheme 5). The basic conditions imply the formation of a ruthenium–alkoxide intermediate. Then, the 1,3-intramolecular hydrogen shift took place and was followed by a protonation of the g3-oxoallyl intermediate by an incoming allylic alcohol with concomitant regeneration of the ruthenium complex. Because of the bulkiness of the NBu2 moiety, the dbapen ligand is hemilabile and can liberate a vacant site, and finally allow the coordination of the olefin. The enantioselective isomerization of secondary allylic alcohols is rare in the literature and the first example appeared in 2005 by the group of Ikariya.9 The half-sandwich [Cp⁄Ru(P–N)] complex ([Ru-7], Fig. 1), in which the P–N ligand derived from (L)-proline, was able to catalyze the isomerization of secondary allylic alcohols and to furnish the corresponding ketones in good yields with enantiomeric excesses ranging from 62% to 74% (Scheme 6). As also noticed with primary allylic alcohols, alcohols with (E)- and (Z)geometry led to ketones with opposite absolute configurations as a result of a kinetic dynamic resolution. At first glance, the mechanism of this isomerization could involve the oxidation of the alcohol followed by a Michael type addition, as suggested by isotope labeling.10 However, a more
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Scheme 5. Proposed mechanism for the [Ru-6]-catalyzed enantioselective isomerization.
Scheme 6. [Ru-7]-catalyzed enantioselective isomerization of secondary allylic alcohols.
careful analysis revealed further valuable information. With sterically demanding allylic alcohols, the b-hydride abstraction is reversible (in the absence of any other hydrogen acceptor),10 and racemization of chiral non-racemic secondary alcohols occurs. Moreover, a H-D scrambling was suggested to explain the deuterium distribution at the a- and b-carbons. The proposed mechanism is shown in Scheme 7.
Scheme 7. Proposed mechanism for the [Ru-7]-catalyzed enantioselective isomerization.
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Scheme 8. [Rh(binap)]-catalyzed isomerization of allylic derivatives.
Rhodium catalysts The rhodium–binap complex represents the most efficient combination for the enantioselective isomerization of allylic amines to enamines, the key step for the industrial production of ( )-menthol and related terpenes.11 However, the corresponding reaction with allylic alcohols did not reach such a degree of refinement (Scheme 8). Chapuis et al. evaluated various chiral diphosphines rhodium complexes in the enantioselective isomerization of geraniol and nerol into citronellal (Fig. 2).12 The best result was obtained with a binap ligand and the aldehyde was produced in good yields with enantiomeric excesses up to 61% from the (E)-isomer and 51% from the (Z)-isomer ([Rh-1], [Rh-2], [Rh-3], Fig. 2 and Table 1). As part of their program devoted to the design and the use of phosphaferrocene ligands in stereoselective reactions,13 Fu and co-workers established that a combination of a cationic Rh+ precursor and a planar–chiral phosphaferrocene could catalyze the enantioselective isomerization of primary allylic alcohols in moderate to high yields (55–91%) and enantioselectivities (64–86%) at 70 °C in THF (Scheme 9).14 In these conditions, the selectivity was dependent on the counteranion (BF4 was the best one) and on the solvent, but not on temperature. Two important features of this complex have to be highlighted: (i) first, the process was not limited to alkenes bearing aromatic substituents. As example, 3-cyclohexyl-but-2-en-1-ol furnished the corresponding aldehyde in 75% yield with 72% ee. (ii) Second, the reactivity of this catalytic system differs from all other systems. With this combination, (Z)allylic alcohols led to unprecedented higher selectivities than the (E)-isomer. This Rh+/L⁄1-catalyzed isomerization process was used
Figure 2. Diphosphines evaluated by Chapuis et al.
Scheme 9. Asymmetric isomerization using the first generation of rhodium– phosphaferrocene complex.
for the synthesis of the enantioenriched 4-(p-methoxyphenyl)-5methyl hexanoic acid, a key intermediate in the synthesis of 7-hydroxycalamenene and 7-hydroxycalamenenal (Scheme 9).14 A slight modification of the ligand structure can modify the reactivity.15 Indeed, the replacement of the phenyl substituent by a tolyl enhanced the selectivities, yields and scope. Surprisingly, selectivities were higher at higher temperature (100 °C vs 70 °C) and depended on the steric demand of the alkyl substituents, but not of the aromatic moiety linked to the alkene (Scheme 10).15 Finally, the (E)-allylic alcohols furnished the aldehydes in higher yields and enantiomeric excesses (86–98% yields and 75–92% ee from the (E)-isomer, 60–90% yields and 57–90% ee from the (Z)isomer) with this new complex [Rh(cod)L⁄2][BF4], unlike with [Rh (cod)L⁄1][BF4]. Mechanistic studies established that the isomerization proceeds via an intramolecular 1,3-hydrogen migration and that the catalyst differentiates between the enantiotopic C1 hydrogens.
Scheme 10. Asymmetric isomerization using the second generation of rhodium– phosphaferrocene complex.
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Iridium catalysts Mantilli and Mazet demonstrated in 2009 that Crabtree’s catalyst was able to promote the isomerization of primary allylic alcohols into aldehydes using low catalyst loading, at room temperature after an initial activation of the cyclooctadiene ligand.16 Worth to note, hydrogen was taken out of the reaction medium to prevent competitive hydrogenation reaction. Variation of the steric and electronic properties of the ligand and the nature of the counter anion, as well, changed dramatically both the catalytic activity and the stability of the iridium complex (Scheme 11).16 With the right combination (namely, the association of an electron rich and bulky phosphine and a N-donor ligand, a [BArF4] anion), even reluctant substrates such as primary allylic alcohols with tetrasubstituted alkene isomerized! Based on these findings, the group of Mazet designed three generations of catalysts ([Ir-1], [Ir-2] and [Ir-3], Fig. 3). The first generation was based on dialkylphosphanylmethyl oxazoline iridium complexes ([Ir-1], Fig. 3).17 Both substituents on the phosphorous atom and on the oxazoline have an impact on the rate and the selectivity. Thus, an increase in the steric demand on the phosphorous atom led to higher enantioselectivities, when aryl substituted oxazoline enhanced the rate. Then, depending on the structure of allylic alcohols, modest to high, and even perfect, control of the enantioselectivity was achieved. Unlike the (E)-isomers, the (Z)-primary allylic alcohols did not furnish good yields and selectivities (Fig. 3, Table 2).17 To overcome the high cost of these ligands, mainly derived from non-natural (L)-tert-leucine, Mantilli and Mazet reported a second generation of iridium complexes featuring a different connectivity
Scheme 11. Complexes evaluated by Mazet et al.
Figure 3. Chiral ruthenium complexes used in enantioselective isomerization of allylic alcohols.
Table 2 Asymmetric isomerization of primary allylic alcohols
[Ir-1] [Ir-2] [Ir-3] [Ir-4]
Conv. (%)
ee (%)
Refs.
75 73 65 88
97 96 >99 >99
17 18 19 20
and a higher diversity. This series was synthesized from (D)- or (L)serine and dialkylphosphines ([Ir-2], Fig. 3).18 Similar reactivities and selectivities were achieved for most substrates but, more importantly, an enhancement was observed for the more challenging 3,3-dialkyl primary allylic alcohols (Table 2).18 Based on further investigation on the enantiodiscrimination mechanism, Mazet’s group developed a third generation of iridium catalysts for the enantioselective isomerization of previously unsuccessful allylic alcohols (such as alcohols with small alkyl substituents on the alkenes).19 The catalyst design was based on Charton analysis, a relationship/correlation between enantiomeric ratios and steric parameters on the catalyst, the idea to bring closer the phosphine alkyl substituent and the oxazoline moiety, and also to maintain enough flexibility in the ligand backbone to allow the isomerization of sterically demanding or non-demanding allylic alcohols ([Ir-3], Fig. 3). With this third generation, perfect enantioselectivities were reached with sterically hindered allylic alcohols, but more importantly, high levels of enantioselectivity were achieved with alcohols having small alkyl group (Table 2), albeit in low to moderate yields.19 While these results validated the working hypothesis, secondary allylic alcohols, tetrasubstituted or 2,3-disubstituted allylic alcohols, and homoallylic alcohols remained unreactive. (Z)-Isomers were still challenging substrates with this new generation. To highlight this lower reactivity, nerol furnished citronellal in 26% yield with 31% enantiomeric excess, when geraniol isomerized into citronellal in 49% yield with 82% enantiomeric excess (Table 1). To overcome these limitations, Andersson reported the use of another P–N ligand family, known to be highly active in the asymmetric olefin hydrogenation ([Ir-4], Fig. 3).20 After a rapid screening of various P–N ligands in a model reaction, the ligand shown in Figure 3 emerged as the most active and selective. As already reported by Mazet,16–19 the steric accessibility of the catalyst was the most important feature in the ligand structure. But the most striking difference between the Mazet and Andersson ligands was the nature of the phosphine. While bulky electron rich phosphines were required in Mazet’s catalyst, aryl (phenyl or tolyl) substituents were tolerated on the phosphorous atom in Andersson’s complex.20 A variety of (E)-trisubstituted allylic alcohols were evaluated and provided the corresponding aldehydes in modest to high yields and almost perfect enantioselectivity (Table 2). 3,3-Dialkyl allylic alcohols isomerized into aldehydes in high enantiomeric excesses, albeit in very low yields. The (Z)-isomers of some 3-alkyl-3-aryl allylic alcohols isomerized as well in high enantioselectivities, regardless the steric hindrance of the substituents, but yields were moderate. However, this catalytic system was not yet general as the reactivity was impeded by the size of the substituents. Thus, nerol did not react (unlike with Mazet’s catalyst), while (Z)-3cyclohexyl-but-2-en-1-ol led to the aldehyde in 50% yield with 98% ee.
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Palladium catalysts Even if the advances in metal-catalyzed isomerization have led to extremely active and selective catalysts, and found application in industry, further developments and improvements are required. All the above-mentioned catalytic systems are substrate-specific, depend on the steric parameters (higher the substitution, lower the reactivity) and are active with the one or the other of the isomers. Moreover, they are not general for the isomerization of primary and secondary allylic alcohols. In 2014, the group of Mazet reported a palladium-catalyzed isomerization of highly substituted allylic alcohols.21 The catalytic system tolerated various functional groups such as halides, hydroxyl, and nitro groups and N-methylpyrrole. It is also insensitive to the nature and substitution of the alkene. The isomerization of a primary or secondary alcohol with a tetrasubstituted alkene provided the carbonyl compound in good yields as a mixture of diastereomers. Both experimental studies and DFT calculations supported a chain-walking mechanism, namely an iterative insertion, migration/b-elimination sequence. Preliminary enantioselective isomerization reactions were carried out in the presence of (R,R)-i-Pr-Duphos, a ligand sharing electronic and steric properties with the dicyclophosphinoethane ligand (dcpe). 3-Cyclohexyl-3-phenylprop-2(E)-enol delivered 3-cyclohexyl-3-phenyl propenal in 65% yield with 73% ee. The aldehyde was isolated in 50% yield and 48% ee from the (Z)-isomer (Scheme 12).21
Scheme 13. Rhodium-catalyzed kinetic resolution of allylic alcohols.
Scheme 14. Rhodium-catalyzed kinetic resolution of 4-hydroxy-2-cyclopentanone.
Scheme 12. Palladium-catalyzed asymmetric isomerization.
reaction rate was obtained with 2-cyclohexen-1-ol (32% yield and 99% ee after 24 h) and 2-cyclopent-1-ol did not react at all. More importantly, while 4-hydroxy-2-cyclopentanone, a key intermediate in prostaglandin synthesis, was recovered in 91% ee at 72% conversion after 14 days at 0 °C in coordinating solvent in the presence of [Rh((R)-binap)(MeOH)][ClO4] (Noyori’s reaction),25 this secondary alcohol did not react under the new conditions and only cyclopent-4-ene-1,3-dione was observed as the side product (Scheme 14).24 Further experiments demonstrated that this unsaturated dione coordinated to the rhodium center and inhibited the catalyst activity in dichloromethane.
Kinetic resolution
Enantiospecific isomerization: a case study of trifluoromethylated allylic alcohols
Kinetic resolution was also applied in isomerization of chiral racemic allylic alcohols. A chiral catalyst can isomerize preferentially one enantiomer providing the corresponding ketones or aldehydes in addition to an enantioenriched solution of the other enantiomer. Up to now, few works have been reported in the literature.22–25 The pioneering work by Ohkubo et al. with [RhCl( )-Diop] allowed the generation of (S)-3-buten-2-ol in very low ee (1.7%) at 31% conversion.22 In 2010, Crochet and co-workers demonstrated that chiral arene–ruthenium complexes were able to promote the kinetic resolution of allylic alcohols, albeit again in low ee’s (up to 17% at 55% conversion).23 The group of Zhang made recently the first breakthrough, in the presence of rhodium complexes.24 Based on an initial report by Noyori and co-workers,25 Zhang and co-workers modified the reaction conditions, the counter anion in the complex and showed that [Rh(cod)Cl]2/(R)-binap/ AgO2CCF3 in non-coordinating solvent was an effective combination for the kinetic resolution of racemic alcohols (Scheme 13). Selectivity factors up to 24 and ee up to 99.4% were obtained from rac-aryl-2-propenol derivatives. Selectivity factors and enantioselectivities were lower with alkyl-2-propenol derivatives. A lower
In addition to the aforementioned studies on enantioselective isomerization of primary and secondary allylic alcohols, we conducted a study on enantiospecific isomerization of secondary allylic alcohols.26 In an enantiospecific reaction, both the stereochemistry of the reactant and the mechanism determine the stereochemistry of the product. This approach required the preparation of optically enriched secondary allylic alcohols as well as analytical methods to measure ee values and absolute configurations of reactants and products. We conducted a series of experiments in order to ascertain an enantiospecific mechanism in the case of c-CF3 secondary allylic alcohols. This reaction was developed with the intention of synthesizing enantiopure b-CF3 ketones otherwise difficult to access. The fact was that all our attempts to isomerize c-CF3 secondary allylic alcohols by means of chiral ruthenium complexes led to racemic or poorly enantioenriched ketones (Scheme 15, top). While, starting from an enantioenriched c-CF3 allylic alcohol with 99% ee, the isomerization by means of achiral RuCl2(PPh3)3 gave the corresponding b-CF3 ketone with 99% ee as well, and thus with 100% enantiospecificity (Scheme 15, bottom).26 To illustrate this methodology, we synthesized a CF3-analog of citronellol as shown in Scheme 16.26
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Scheme 15. Isomerization of fluorinated allylic alcohols.
Scheme 16. Synthesis of (S)-CF3-citronellol.
This methodology was also applied recently by Liu and coworkers.27 In the presence of a supported Noyori’s catalyst and [RuCl2(PPh3)3], the tandem reduction–isomerization of b-CF3-a,bunsaturated ketones into the corresponding chiral saturated ketones was carried out in water. High yields, enantiomeric excesses and enantiospecificities were reached in these conditions. The heterogeneous catalyst was recovered and reused eight times without any detrimental effects. A detailed mechanistic study with the c-CF3 secondary allylic alcohols was conducted to determine the exact operative pathway. A first series of observations indicated that the strong electronwithdrawing effect of the CF3 group very significantly enhanced the rate of the migration insertion step relative to non-fluorinated substrates while maintaining excellent reactivity even at relatively low temperature for trisubstituted olefinic substrates. Secondly, a specific fluorine effect was observed in a comparison with the reactivity of non-fluorinated allylic alcohols. Indeed, the rate-limiting
step permuted from insertion for non-fluorinated allylic alcohols to b-elimination for fluorinated allylic alcohols. In the proposed mechanism (Fig. 4), cesium carbonate facilitates the formation of a 16-electron ruthenium alkoxide complex that is further coordinated on the C@C double bond to account for the reactivity observed. Subsequent b-hydride elimination produces the enone– hydride ruthenium complex, in which the enone remains coordinated until the 1,3-migratory insertion of the hydride takes place from a single face of the trigonal carbon center. The stereochemical information of the starting optically enriched c-CF3 allylic alcohol is entirely transferred to the chiral isomerization product. The resulting ruthenium enolate is then protonated by an incoming allylic alcohol and tautomerizes into the final saturated ketone concomitantly with the release of the catalyst. In the case of non-fluorinated allylic alcohols, the second step is the rate-limiting step and reactions are equilibrated with decoordination of the ruthenium hydride complex from the enone allowing for enantioselective but not enantiospecific process. Additionally, we demonstrated that an intramolecular syn-specific 1,3-hydride shift takes place within the coordination sphere of the ruthenium center. Tandem asymmetric reactions Allylic alcohols can be considered as latent enolates (or enols) and can be used to perform tandem and sequential reactions by trapping the enolate intermediates in order to create new C–C or C–het bonds instead of the protonation and tautomerization into the corresponding carbonyl compounds.28 Several reviews and recent articles report non-asymmetric tandem reactions involving allylic alcohols as starting material.28,29 The group of Grée reported a diastereoselective tandem isomerization–Mannich reaction from allylic alcohols with N-tert-butyl sulfinimines as electrophiles and [NiHCl(dppe)]/MgBr2 [dppe = 1,2-bis(diphenylphosphinoethane)]
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Figure 4. Mechanisms for fluorinated and non-fluorinated substrates.
Scheme 17. Diastereo- and enantioselective tandem isomerization/Mannich reaction.
Scheme 18. Enantioselective tandem isomerization/halogenation or isomerization/amination reaction.
as catalytic system.29 This approach allowed the synthesis of b-amino ketones and b-amino alcohols as key intermediates in the synthesis of ent-Nikkomycins and ent-Funebrine (Scheme 17). In the case where the isomerization is followed by a further addition of a reagent and/or catalyst, the reaction is sequential. Alexakis, Mazet and Quintard have designed a sequential
asymmetric isomerization followed by an a-alkylation using a chiral organometallic catalyst based on iridium in the first step and a chiral organocatalyst derivative of (L)-proline in the second step (Scheme 18).30 The enantioselective isomerization allowed to control the stereogenic center at the b position of the carbonyl function. The aldehyde thus obtained reacted with a chiral amine
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Scheme 19. Ruthenium-catalyzed enantioselective synthesis of citronellol.
providing an enamine, which, by alkylation, allowed the creation of a second stereogenic center in the a position to the carbonyl function in a diastereoselective manner. The corresponding chiral aldehydes are obtained in moderate to good yields with excellent diastereomeric ratios (up to 1:49) and excellent enantiomeric excesses (up to 99%) for the major diastereomer. The scope of this methodology has been extended to other types of electrophiles such as N-fluorobenzenesulfonimide (NFSI), N-chlorosuccinimide (NCS), or diethyl azodicarboxylate (DEAD). The corresponding products were obtained in moderate yields, high diastereoselectivities, and excellent enantioselectivities after reduction of the aldehyde function into alcohol to avoid epimerization of the stereogenic centers featuring the heteroatom. Apart from tandem reactions taking advantage of the enolate intermediate and generating an a-functionalized carbonyl compound, this carbonyl function can also be transformed into alcohol through transfer hydrogenation. Such tandem reaction enables after an isomerization step of allyl alcohols to reduce the aldehydes or ketones formed in the same reaction conditions. An alcoholic solvent like isopropanol solubilizes the reactants and also acts as a hydride source for reduction of the carbonyl function.31 The result of the one-pot operation is equivalent to a reduction of a C@C double bond without resorting to the use of dihydrogen gas or techniques requiring high pressures. This methodology has been applied by Sowa and co-workers to the enantioselective synthesis of (R)- and (S)-citronellol in 78% and 70% yields with 98% and 93% enantiomeric excesses, respectively.8 However, the amount of precatalyst used is rather high, 10 mol % of [RuCl2(cod)]n [cod: 1,5cyclooctadiene] and 20 mol % (S)-Tol-binap, but may be decreased to 3 mol % when using [RuCl2{(S)-Tol-binap}(p-cymene)], which is easier to handle and that produces a higher yield despite a slight loss of enantioselectivity (Scheme 19). It is important to note in this example that the synthetic route allows the selective reduction of the allylic C@C double bond, which would not have been possible via conventional reduction or hydrogenation.8 The asymmetric isomerization followed by a subsequent reduction of the aldehyde can be also catalyzed by a {Ru(cod)Cl2}n/i-Pr-Duphos system in a basic solution of iso-propanol at 83–100 °C to give the chiral alcohols in 19–98% yields with 72–98% enantiomeric excess.
Despite these interesting results, the substrate scope appeared rather limited. As noticed previously with other ruthenium complexes or with other noble metals (vide supra), in the presence of a combination of ruthenium and Tol-binap ligand, the final absolute configuration depends on the geometry of the starting alkene. This is in sharp contrast with the Duphos ligand, which provided (R)-citronellol from both geraniol and nerol. This unique feature of the Duphos ligand was previously described in hydrogenation of functionalized alkenes.32 Sowa conducted also a deuterium labeling experiment and demonstrated that (i) 1,3-intramolecular hydrogen shift is one of the catalytic step; (ii) the enol intermediate is hydrolyzed by i-PrOH; and (iii) the last step is a transfer hydride process. The same group extended the tandem isomerization/asymmetric transfer-hydrogenation reaction to secondary allylic alcohols with the aid of a ruthenium catalyst, which was generated in situ in isopropyl alcohol from [RuCl(l-Cl)(p-cymene)]2 and the chiral ligand (1S,2S)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine, (S,S)-TsDPEN (Scheme 20, top). Chiral secondary alcohols were obtained in up to 97% yield with up to 93% ee value.33 This was an improvement of the early attempt by Williams and co-workers who reported a modest 7% ee under similar reaction conditions in 1,4-butanediol in the presence of KOH at 110 °C.34 The results by Sowa and co-workers were comparable in terms of ee values with those obtained by Adolfsson who reported a couple of months before the same one-pot procedure for the direct conversion of allylic alcohols into chiral non-racemic saturated alcohols. Adolfsson performed the reaction under milder conditions, a 10-fold lower amount of catalyst, and a chiral a-amino acid hydroxyamide ligand in a mixture ethanol/THF (Scheme 20, bottom).35 Conclusion and perspectives In conclusion, many efforts have been devoted to the development of asymmetric isomerization of primary and secondary allylic alcohols. To date, the most represented catalysts are based on noble metals, and more specifically on ruthenium, rhodium and iridium complexes. High enantioselectivities were reached with various allylic alcohols. However, despite these successes, the catalysts are still often substrate dependent. A research avenue to the future will be the development of new tandem enantioselective transformations and the development of chiral earth-abundant complexes, due to economic constraint. Acknowledgments This work is promoted by the interregional CRUNCh network, supported by the ‘Ministère de la Recherche et des Nouvelles Technologies’, CNRS (Centre National de la Recherche Scientifique) and the LABEX SynOrg (ANR-11-LABX-0029). Johnson-Matthey is acknowledged for a generous loan of catalysts and helpful discussions.
Scheme 20. Enantioselective tandem isomerization/hydride transfer reaction.
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