Broad Scope Synthesis of Ester Precursors of Nonfunctionalized Chiral Alcohols Based on the Asymmetric Hydrogenation of α,β-Dialkyl-, α,β-Diaryl-, and α-Alkyl-β-aryl-vinyl Esters

1 A broad scope synthesis of ester precursors of non-functionalized chiral alcohols based on the asymmetric hydrogenation of ,-dialkyl-, ,-diaryland -alkyl--aryl-vinyl esters Félix León,¶ Pedro J. González-Liste,§ Sergio E. García-Garrido,§ Inmaculada Arribas,¶ Miguel Rubio,¶,† Victorio Cadierno§,* and Antonio Pizzano¶,* ¶Instituto de Investigaciones Químicas (IIQ) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), CSIC and Universidad de Sevilla, Américo Vespucio 49, 41092 Sevilla, Spain. §Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Química Organometálica “Enrique Moles”, Universidad de Oviedo, 33006 Oviedo, Spain. Corresponding Author *E-mail: [email protected] (A. P.). *E-mail: [email protected] (V. C.). Present Addresses † Repsol Technology Center, 28935 Móstoles, Madrid, Spain. 2 GRAPHICAL ABSTRACT 3 Abstract The catalytic asymmetric hydrogenation of trisubstituted enol esters using Rh catalysts bearing chiral phosphine-phosphite ligands (P-OP) has been studied. Substrates covered comprise ,- dialkyl, -alkyl--aryl and ,-diarylvinyl esters, the corresponding hydrogenation products being suitable precursors to prepare synthetically relevant chiral non-functionalized alcohols. A comparison of reactivity indicates that it decreases in the order: ,-dialkyl > -alkyl--aryl > ,-diaryl. Based on the highly modular structure of P-OP ligands employed, catalyst screening identified highly enantioselective catalysts for ,-dialkyl (95-99 % ee) and nearly all of - alkyl--aryl substrates (92-98 % ee), with the exception of -cyclohexyl--phenylvinyl acetate which exhibited a low enantioselectivity (47 % ee). Finally, ,-diarylvinyl substrates showed somewhat lower enantioselectivities (79-92 % ee). In addition, some of the catalysts provided a high enantioselectivity in the hydrogenation of E/Z mixtures (ca. Z/E = 75:25) of ,- dialkylvinyl substrates, while a dramatic decrease on enantioselectivity was observed in the case of -methyl--anisylvinyl acetate (Z/E = 58:42). Complementary deuteration reactions are in accord with a highly enantioselective hydrogenation for both olefin isomers in the case of ,- dialkylvinyl esters. In contrast, deuteration shows a complex behavior for -methyl-- anisylvinyl acetate derived from the participation of the E isomer in the reaction. 4 Introduction Catalytic asymmetric hydrogenation constitutes one of the most efficient tools for the preparation of chiral building blocks with high enantioselectivity.1,2 As well, due to the inherent advantages that usually characterize this kind of processes (e.g. high catalyst efficiency, perfect atom economy, simple work-up), they have extensively been used in industrial applications.3 Among diverse classes of compounds prepared using asymmetric hydrogenation reactions, a particularly remarkable one corresponds to non-functionalized chiral alcohols of general structure A (R1, R2 = alkyl, aryl; Figure 1). Figure 1. Hydrogenation routes to alcohols A A very convenient and direct route to alcohols A is provided by the asymmetric hydrogenation of ketones B (path a). The feasibility of this option is, however, strongly dependent on the nature of R1 and R2 substituents. Thus, the hydrogenation of aryl-alkyl ketones constitutes one of the highest achievements in asymmetric catalysis due to the exceptional levels of catalyst activity and enantioselectivity reached.4 As well, very efficient catalysts have been described for the hydrogenation of tert-alkyl-alkyl ketones.5 Nonetheless, the hydrogenation of dialkyl ketones 5 characterized by less bulky alkyl substituents has a considerable difficulty and high enantioselectivities have only been achieved in a limited number of cases.4i,6,7 Likewise, benzylalkyl ketones constitutes another class of problematic substrates and no satisfactory hydrogenation catalysts have so far been reported.8,9 However, chiral alkanols and homobenzylic alcohols are very versatile building blocks for synthesis,10 therefore the development of efficient methods to obtain them in a high enantiomeric purity has a considerable interest. Towards this aim, the asymmetric hydrogenation of enol esters C constitutes an appealing alternative, as esters D can trivially be converted into alcohols A through deacylation (path b).11 Although the hydrogenation of B and C are mechanistically different reactions, the preparation of A with high enantioselectivity by either path a or b ultimately depends on an effective discrimination of prochiral substrate faces by the corresponding hydrogenation catalyst. In this regard, the hydrogenation of enol esters is characterized by substrate chelation, which enables a powerful recognition of the olefinic substrate.12 In contrast, the differentiation of enantiotopic faces of ketones bearing not very dissimilar R1 and CH2R2 substituents is an extremely difficult task, as evidenced by the background mentioned above. In this context, a meaningful case is provided by the hydrogenation of -alkylvinyl esters (C, R1 = alkyl, R2 = H), which has enabled a broad scope and highly efficient route for the synthesis of chiral 2-alkanols.13 A highly valuable expansion of path b route corresponds to the hydrogenation of trisubstituted substrates C (R1, R2 = alkyl, aryl), as it may provide access to a vast range of chiral esters considering the countless possible combinations of R1 and R2. Nevertheless, the inclusion of a substituent in position of the vinyl fragment introduces fundamental reactivity aspects to study. Firstly, in comparison with widely studied disubstituted substrates,14 increase in olefin substitution should be accompanied by a reduced catalyst activity,15 further to the relatively low 6 reactivity of enol esters.16 Secondly, the enantioselectivity of the hydrogenation may critically be dependent on the olefin configuration,17 which can limit severely the usefulness of this approach as enol esters are often obtained as E/Z mixtures and their separation is usually cumbersome. On the other hand, nearly all enol esters examined in asymmetric hydrogenation possess an - electron-withdrawing substituent (carboxylate, phosphonate, trifluoromethyl, cyano or aryl), which is an important element in the course of the reaction.18 As a result of this background, there is very little information in the literature about the enantioselective hydrogenation of trisubstituted substrates bearing an alkyl substituent in  position.19,20 Precedents are limited to a study on the hydrogenation of -alkyl--methylvinyl esters, as mixtures of the corresponding E and Z isomers, described by Goossen and coworkers. Thus, these authors have reported enantioselectivities up to 98 % ee in the case of the -methyl-substituted substrates, as well as a decrease down to 82 and 78 % ee for esters bearing -nPr and -nBu substituents, respectively.19 Finally, we would like to remark also here that no precedents of the asymmetric hydrogenation of ,-diarylvinyl esters have been described so far in the literature. In a preliminary contribution we studied the synthesis and hydrogenation of -alkyl--arylsubstituted substrates C2 (Figure 2),21 using Rh catalysts based on chiral phosphine-phosphite ligands (P-OP).22 Herein we present a broader study on the hydrogenation of trisubstituted enol esters covering in addition those of types C1 and C3. Moreover, the reduction of mixtures of E/Z-isomers, providing information about the influence of substrate configuration on the reaction, has also been studied in detail. 7 Figure 2. General structures of enol esters C1-C3 Results and Discussion Synthesis of substrates. In order to examine the scope of the asymmetric hydrogenation of trisubstituted enol esters of types C1-C3, a wide range of substrates covering the three types of structures has been prepared (Figure 3). Thus, regarding those of type C1, compounds 1a and 1b have been prepared by a gold catalyzed addition of benzoic acid to 2-butyne (Scheme 1a), following the procedure described by Kim and Chary.23,24 Also based on the work of these authors, 1c and 1d were synthesized by a gold catalyzed tandem addition-isomerization reaction (Scheme 1b). Worth to note, 1a and 1b were obtained as the pure Z isomers, while 1c and 1d as mixtures with a Z/E ratio of 74:26 and 72:28, respectively. 8 Figure 3. Range of enol esters 1 covered in the present study Regarding substrates of type C2, we have previously prepared -methyl--aryl vinyl acetates 1e-1i, with generally good yields and selectivity (Z:E ≥ 95:5) upon the acylation of methyl benzyl ketones.21,25 Moreover, a range of 1-alkyl-2-arylvinyl substrates (1k-1q, 1t-1z) where stereoselectively prepared as the Z isomers by a Suzuki coupling over (Z)--iodoalkenyl acetates.21,26 In order to complete the set of compounds C2, new substrate 1j bearing a 1-ethyl substituent has been prepared in good yield (62 %) by the former method. Likewise, compounds 1r and 1s, possessing 2-phenylethyl and 3-phenylpropyl substituents, have been prepared by the 9 Suzuki coupling route in good yields from the corresponding iodo-alkenes 2 (75 and 79 %, respectively; Scheme 2). Scheme 1. Synthesis of enol esters 1a-1d To widen the range of substrates, several examples of type C3 have also been prepared. Initially, diphenyl substrate 1aa was prepared in moderate yield by the reaction of Scheme 1a. Moreover, several examples characterized by a -Ph and diverse aryl or heteroaryl fragments in  position have been synthesized by the Suzuki coupling route (1ab-1ae; Scheme 2). Finally, with the intention to explore the introduction of an alkyl substituent in position of the C=C bond, a Negishi type coupling was studied using (Z)--benzyl--iodovinyl acetate.27 This reaction provided the (Z)-enol ester 1af, albeit in a rather low yield (Scheme 3). 16 chiral ligands,33 finally pointing to catalyst from 4h as the more efficient one which could reduce 1n under mild conditions (4 bar H2, 40 ºC, DCE, S/C = 100-250, 24 h) with 98 % ee (entries 10, 11, Table 2). A relevant feature of 1n is a markedly lower reactivity than that of 1a towards hydrogenation (entries 1-5, 8 and 9). In contrast, the attainment of a good enantioselectivity is not as demanding and relatively good enantioselectivities, with values between 92 and 98 % ee, were obtained with catalysts 4e, 4h and 4i (entries 5, 8 and 9, respectively). As well, a positive effect on conversion was observed when DCE was used as solvent (entry 10). Since the incorporation of the P-stereogenic phophine fragment is the most demanding aspect of the preparation of the P-OP ligand 3h, we explored the behavior of catalysts based on ligands 3f and 3g, characterized by a non-stereogenic trialkylphosphine fragment and by a less elaborated synthesis, as a possible practical improvement. However, corresponding catalyst precursors 4f and 4g provided lower conversion values than 4h, pointing again to the achievement of a suitable catalyst activity as a challenging aspect of the present catalytic system. Notwithstanding that, 4f and 4g showed relatively good enantioselectivities, 92 and 94 % ee, respectively (entries 6, 7). Table 2. Hydrogenation of 1n performed with catalyst precursors 4a Entry Cat. Prec. Solvent Conv (%) % ee (conf) 1 4a DCM 13 n.d. 2 4b DCM <5 n.d. 3 4c DCM <5 n.d. 4 4d DCM <5 n.d. 17 5 4e DCM 62 96 (S) 6 4f DCM 59 92 (R) 7 4g DCM 34 94 (S) 8 4h DCM 79 98 (S) 9 4i DCM 38 94 (R) 10 4h DCE 100 98 (S) 11b 4h DCE 98 98 (S) aReactions at 40 ºC, [Rh] = 1 × 10-3 M, S/C = 100, 4 bar H2 initial pressure and 24 h reaction time, unless otherwise stated. Conversion determined by 1H NMR and enantiomeric excess by chiral HPLC. See experimental section for determination of configuration. b[Rh] = 1 × 10-3 M, S/C = 250. Regarding substrate scope, 4h provided high enantioselectivities with a wide range of substrates (Table 3). Thus, compounds 1i (entry 5), 1k-1p (entries 7-12) and 1t-1z (entries 1925) were hydrogenated with enantioselectivities between 93 and 98 % ee using our standard or similar reaction conditions (see footnotes of Table 3 for details). Worth to note, 4h provided a somewhat lower enantioselectivity in the case of 1e (91 % ee, not shown), outperformed by 4e (97 % ee, entry 1). Upon this result, 4e was used with satisfactory results in the case of substrates 1f-1h (entries 2-4). Regarding newly added substrates, 1j was satisfactorily hydrogenated with 4h (94 % ee, entry 6), while 1r and 1s showed a lower reactivity under standard conditions leading to uncompleted reactions (entries 15, 17). A similar decrease was observed in the hydrogenation of 4-phenyl-1buten-2-yl benzoate13d and it is probably related to the formation of low reactive Rh-6-arene species.11a,16b In contrast, full conversion and good enantioselectivities were observed under 20 bar H2 for 1r (93 % ee, entry 16) and 1s (88 % ee, entry 18). 18 Finally, a limitation of the present reaction was found with the -cyclohexyl-substituted substrate 1q. This compound exhibited a markedly low reactivity and only a good conversion was obtained with 4i under 20 bar H2 (90 %), while both 4h and 4i provided a rather low enantioselectivity (40-47 % ee, entries 13, 14). Table 3. Hydrogenation of -alkyl--arylvinyl estersa Entry Subs. (Ak, Ar) Cat. Prec. H2 (bar) % conv. % ee (conf.) 1 1e (Me, 4-MeO-C6H4) 4e 4 100 97 (S) 2 1f (Me, 4-Me-C6H4) 4e 10 100 91 (S) 3 1g (Me, 4-F-C6H4) 4e 4 100 98 (S) 4 1h (Me, 2-MeO-C6H4) 4e 4 100 99 (S) 5 1i [Me, 3,4-(MeO)2-C6H3] 4h 4 100 93 (S) 6 1j (Et, Ph) 4h 4 100 94 (S) 7 1k (nPr, Ph) 4h 4 100 94 (S) 8 1l (nBu, Ph) 4h 4 100 98 (S) 9 1m (nPen, Ph) 4h 4 100 98 (S) 10 1n (nHex, Ph) 4h 4 100 98 (S) 11 1o [(CH2)2iPr, Ph] 4h 4 100 98 (S) 12b 1p (cC3H5, Ph) 4h 4 100 92 (n.d.) 13c 1q (Cy, Ph) 4h 20 50 47 (n.d.) 14c 1q (Cy, Ph) 4i 20 90 40 (n.d.) 15 1r [(CH2)2Ph, Ph] 4h 4 89 96 (S) 19 16 1r [(CH2)2Ph, Ph] 4h 20 100 93 (S) 17 1s [(CH2)3Ph, Ph] 4h 4 84 87 (S) 18 1s [(CH2)3Ph, Ph] 4h 20 100 88 (S) 19 1t (nHex, 4-F-C6H4) 4h 4 100 96 (S) 20d 1u (nHex, 4-MeO-C6H4) 4h 4 100 93 (S) 21 1v (nHex, 4-Me-C6H4) 4h 20 100 93 (S) 22 1w (nHex, 4-Cl-C6H4) 4h 4 100 95 (S) 23 1x (nHex, 4-Ph-C6H4) 4h 4 100 96 (S) 24 1y [nHex, 3,4-(MeO)2-C6H3] 4h 20 100 95 (S) 25 1z [nHex, 3,5-(MeO)2-C6H3] 4h 4 100 96 (S) aHydrogenations performed at 40 ºC in DCE, [Rh] = 1 × 10-3 M, S/C = 100, at initial pressure (bar H2) indicated, and 24 h reaction time unless otherwise stated. Conversion determined by 1H NMR and enantiomeric excess by chiral HPLC. See experimental section for determination of configuration. bReaction performed at 30 ºC. c48 h reaction time. d[Rh] = 2 × 10-3 M, S/C = 100. Enabled by the rather versatile synthetic procedures for substrates 1, an appealing application of the present system is the hydrogenation of 1af, which switches the position of the olefin substituent containing the aryl fragment and should then provide the corresponding homobenzylic ester 5af with opposite configuration (with regard to that observed in the hydrogenation of 1j-1o with 4h; entries 6-11 in Table 3). Gratifyingly, hydrogenation of 1af with 4h under our standard reaction conditions provided (R)-5af with excellent conversion and enantioselectivity (Scheme 5). Scheme 5. Hydrogenation of 1af 20 Hydrogenation of ,-diarylvinyl esters. To complete this exploratory analysis we next examined the hydrogenation of 1aa as an example of structure of type C3. Reactions performed in DCM under our standard conditions (4 bar H2, 40 ºC and S/C = 100) with several catalyst precursors (entries 1-6, Table 4), afforded rather low conversion values, being only moderate in the case of 4h (entry 5). However, full conversion and good enantioselectivity was observed when DCE was used as solvent (92 % ee, entry 7). Despite the similitude between DCM and DCE, it is noteworthy that a significant increase on conversion with the latter is both observed with representative substrates 1n and 1aa, further providing satisfactory results for the series of substrates C2 and C3. In this context it is pertinent to mention that an enhancement on enantioselectivity was observed by the group of Ding in the hydrogenation of related enol esters when using DCE instead of DCM,13b while a significantly better performance in DCE over DCM in the hydrogenation of an acyl hydrazone with a Rh-diphosphine catalyst has been reported by Haddad and coworkers.34 We have not found an explanation to the solvent effect observed herein, but it should be noted that despite DCE and DCM are rather similar solvents, characterized by a poorly coordinating character, the former has some ability to act as a chelating ligand.35 As intermediates containing coordinated solvent are proposed in the hydrogenation catalytic cycle, it is not unreasonable to expect a different influence of these solvents in the catalytic process. In addition, some ,-diarylvinyl substrates of type C3 were examined to complete the results obtained with 1aa. By comparison with these results, it appears that substitution of aryl ring of position  is detrimental for conversion (substrates 1ab-1ad; entries 8, 11, 14; Table 4). This is both observed with electron-donor and electron-withdrawing substituents and may be then 21 attributed to steric effects. Overall, substrates of type C3 seem less reactive than those of type C2. However full conversion reactions were obtained at higher substrate concentration or under 20 bar of H2. Thus, enantioselectivities up to 91 % ee (1ab, entry 10), 82 % ee (1ac, entry 12) and 88 % ee (1ad, entry 16) were observed.36 In addition, the thienyl-substituted enol ester 1ae also provided full conversion and a relatively good enantioselectivity (79 % ee, entry 18). Table 4. Hydrogenation of diaryl-substituted substrates C3 performed with catalyst precursors 4a Entry Subs. (Ar) Cat. Prec. Solvent Conv (%) % ee (conf) 1 1aa (Ph) 4a DCM 6 n.d. 2 1aa (Ph) 4b DCM <5 n.d. 3 1aa (Ph) 4c DCM 7 n.d. 4 1aa (Ph) 4d DCM 8 n.d. 5 1aa (Ph) 4h DCM 51 93 (R) 6 1aa (Ph) 4i DCM 43 91 (S) 7 1aa (Ph) 4h DCE 100 92 (R) 8 1ab (4-CF3-C6H4) 4h DCE 67 87 (R) 9b 1ab (4-CF3-C6H4) 4h DCE 100 90 (R) 10c 1ab (4-CF3-C6H4) 4h DCE 100 91 (R) 11 1ac (4-MeO-C6H4) 4h DCE 37 86 (R) 12b 1ac (4-MeO-C6H4) 4h DCE 100 82 (R) 13c 1ac (4-MeO-C6H4) 4h DCE 100 77 (R) 14 1ad (4-PhO-C6H4) 4h DCE 35 69 (R) 22 15b 1ad (4-PhO-C6H4) 4h DCE 100 71 (R) 16c 1ad (4-PhO-C6H4) 4h DCE 100 88 (R) 17 1ae (3-thienyl) 4h DCE 44 71 (R) 18c 1ae (3-thienyl) 4h DCE 100 79 (R) aReactions at 40 ºC, [Rh] = 1 × 10-3 M, S/C = 100, 4 bar H2 initial pressure and 24 h reaction time, unless otherwise stated. Conversion determined by 1H NMR and enantiomeric excess by chiral HPLC. See experimental section for determination of configuration. b[Rh] = 4 × 10-3 M, S/C = 100. cReactions performed under 20 bar H2 Mechanistic considerations. The catalyst screening performed with representative substrates 1a, 1n and 1aa indicates that product configuration is determined by the configuration of the biaryl fragment of the phosphite. Thus, for catalysts with a configuration S of this fragment, S enantiomers are observed for products proceeding from dialkylvinyl substrates (1a-1d, Scheme 6). Likewise, S enantiomers are selectively formed from -alkyl--aryl vinyl esters (1e-1z) using 4h or 4e. On the other hand, R products are obtained in the case of the hydrogenation of diaryl vinyl substrates (1aa-1ae) catalyzed by 4h. Therefore, the sense of hydrogen addition is coincident for the three types of products (the changes in product configuration are due to the change of priority order of substituents of the stereogenic carbon). It should be finally added that this stereochemical relation between phosphite configuration and the sense of hydrogen addition is analogous to that observed in the hydrogenation of structurally related olefins (enamides and -acyloxyphosphonates) and discussed in detail elsewhere.22a,b 23 Scheme 6. Comparison of product configuration observed in the hydrogenation of 1 The high enantioselectivity obtained in the hydrogenation of mixtures of olefin isomers of 1c and 1d with 4a is remarkable. This can be attributed to an efficient transfer of chirality of catalyst to both isomers of the substrate or, alternatively, to the existence of an E-Z olefin isomerization process prior to the hydrogenation.37 Following well established cis addition of hydrogen to the olefin bond,38 the deuteration of E and Z isomers will produce different diastereomers (Scheme 7), which could eventually be distinguished by NMR. As a requisite for this analysis, diastereotopic protons at position  should generate separate signals. This was observed for 5c (as well as for 5e, see below) while 5d exhibited overlapped signals. Thus, the deuteration of 1c with 4a showed a 72:28 ratio of diastereomers by 1H NMR, labelled at positions  and , namely M-5c-d2 and m-5c-d2 (major and minor, respectively).39 This ratio is rather close to that of isomers of the starting material (74:26) and is in accord with the absence of a significant isomerization between the isomers of the starting material. Moreover, analysis by ESI-MS did not show appreciable amounts of trideuterated products, typically formed in olefin isomerization reactions by a reversible olefin insertion step.37a In this context, it is also pertinent to recall that the variation on enantioselectivity upon deuteration has been taken as an indication 24 of competing mechanistic pathways in asymmetric olefin hydrogenation reactions catalyzed by Rh complexes.40 This seems not to occur in the present case, as a value of 96 % ee was observed in the deuteration of 1c, slightly lower to that obtained in the standard hydrogenation (99 % ee; entry 13 in Table 1). Overall, the results obtained are in good accord with an independent hydrogenation of each isomer of 1c by 4a both producing (R)-5c with high enantioselectivity. Scheme 7. Stereoisomers of dideuterated 5-d2 resulting from cis deuteration of Z and E isomers of enol esters 1 In our preliminary communication we observed only moderate enantioselectivities in the hydrogenation of a mixture of isomers of 1e in a Z:E = 58:42 ratio,41 in sharp contrast with results obtained in the hydrogenation of 1c and 1d. This committed us to investigate in more detail the hydrogenation of 1e. To this aim mixtures with Z:E = 95:5 and 58:42 ratios were tested with several catalyst precursors (Table 5). Remarkably, the hydrogenation of the Z:E = 58:42 mixture provided significantly lower enantioselectivities with all catalysts tested (ǀ% eeǀ = 1547 % ee) than those performed with the Z:E = 95:5 mixture, indicating that the hydrogenation of E-1e is appreciably less enantioselective with catalysts 4 than that of Z-1e. The difference is particularly dramatic in the case of 4h, for which values of 44 and 91 % ee, respectively, were 25 observed (entry 4). As well, slower reactions with the 58:42 mixture were observed. Thus, with the exception of the reaction prepared with 4h, no complete conversions were observed in the rest of the hydrogenations (entries 1-3, 5). Moreover, an analysis of the remaining unreacted substrate in these reactions showed an enrichment in isomer E, indicating a slower reaction of the latter compared with the Z isomer. Accordingly, the decrease in enantioselectivity observed in reactions performed with 4d and 4e is attenuated by uncompleted reactions. Table 5. Hydrogenation of 1e (Z:E = 58:42) performed with catalyst precursors 4a Entry Cat. Prec. Conv (%) Z:E (%)b % ee (conf)c % ee (conf)d 1 4a 94 0:100 58 (R) 78 (R) 2 4d 75 0:100 80 (S) 95 (S) 3 4e 76 12:88 81 (S) 97 (S) 4 4h 100 - 44 (S) 91 (S) 5 4i 89 23:77 55 (R) 74 (R) aReactions at 40 ºC in DCE, [Rh] = 1 × 10-3 M, S/C = 100, 4 bar H2 initial pressure and 24 h reation time. Conversion determined by 1H NMR and enantiomeric excess by chiral HPLC. Configuration was determined by comparison of the optical rotation sign with literature data. bZ/E ratio of remaining substrate. c% ee of 5e obtained in the hydrogenation of Z/E-1e. d% ee of 5e obtained in the hydrogenation of the Z:E = 95:5 ratio mixture. In addition, we have studied the deuteration of the isomer mixtures of 1e differing in the E/Z ratio with 4h, as this precursor provides the only catalyst able to complete the reaction in both cases. In contrast to the experiment with 1c, the deuteration of the Z:E = 58:42 mixture not only showed the expected M-5e-d2 and m-5e-d2, but as well a third isotopomer 5e’-d2 labelled at positions  and ’ (Scheme 8, see SI for NMR spectra), with a 59:28:13 respective ratio. Worth to note, an analysis by MS-ESI did not show an appreciable presence of trior monodeuterated 32 (0.024 g, 0.05 mmol), AgPF6 (0.013 g, 0.05 mmol) and toluene (3.0 mL) were introduced into a Teflon-capped sealed tube, and the reaction mixture stirred at 60 (1a-b) or 110 °C (1aa) for 15 h. After that time, the solvent was removed in vacuo and the crude reaction mixture purified by column chromatography over silica gel using diethyl ether / hexane (1:10) as eluent, yielding the corresponding enol esters as pure Z isomers. (Z)-But-2-en-2-yl benzoate (1a):19,24 colorless oil. Yield: 0.118 g (67%). (Z)-Hex-3-en-3-yl benzoate (1b):24,46 pale yellow oil. Yield: 0.131 g (64%). (Z)-1,2-Diphenylvinyl heptanoate (1aa):24 white solid. Yield: 0.163 g (53%). General procedure for the synthesis of enol esters 1c-d: under an argon atmosphere, the corresponding terminal alkyne (1.2 mmol) and benzoic acid (0.122 g, 1 mmol), [AuCl(PPh3)] (0.024 g, 0.05 mmol), AgOTf (0.016 g, 0.05 mmol) and toluene (5.0 mL) were stirred at room temperature for 15 h. After that time, the solvent was removed in vacuo and the crude reaction mixture purified by column chromatography over silica gel using diethyl ether / hexane (1:10) as eluent. The corresponding enol esters 1c-d were obtained as a mixture of stereoisomers in 6284% yield. Configuration of corresponding isomers was assigned by 2D-NOESY experiments. Oct-2-en-2-yl benzoate (1c):47 pale yellow oil. Yield: 0.195 g (84%, Z/E = 74:26). Z-1c: 1H NMR (CDCl3, 300 MHz): δ = 8.10 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 5.11 (t, J(H,H) = 6.8 Hz, 1H), 2.00 (s, 3H), 1.97 (m, 2H), 1.31 (m, 6H), 0.86 (t, J(H,H) = 6.9 Hz, 3H) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 164.5, 145.0, 133.3, 130.0 (3C), 128.5 (2C), 117.5, 31.5, 28.9, 25.5, 22.5, 19.7, 14.0 ppm. E-1c: 1H NMR (CDCl3, 300 MHz): δ = 8.10 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 5.26 (t, J(H,H) = 7.7 Hz, 1H), 2.09 (q, J(H,H) = 7.8 Hz, 2H), 1.97 (s, 3H), 1.31 (m, 6H), 33 0.89 (t, J(H,H) = 7.4 Hz, 3H) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 165.4, 145.5, 133.2, 130.3, 129.9 (2C), 128.4 (2C), 118.0, 31.7, 29.3, 26.7, 22.6, 15.4, 14.1 ppm. 1-Cyclohexylprop-1-en-2-yl benzoate (1d): pale yellow oil. Yield: 0.151 g (62%, Z/E = 72:28). Z-1d: 1H NMR (CDCl3, 300 MHz): δ = 8.10 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 4.97 (d, J(H,H) = 9.2 Hz, 1H), 2.20 (m, 1H), 1.98 (d, J(H,H) = 0.5 Hz, 3H), 1.68 (m, 5H), 1.20 (m, 5H) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 164.7, 143.6, 133.2, 130.0 (3C), 128.5 (2C), 123.1, 35.0, 32.9 (2C), 26.0, 25.8 (2C), 19.7 ppm. E-1d: 1H NMR (CDCl3, 300 MHz): δ = 8.10 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 5.12 (d, J(H,H) = 9.7 Hz, 1H), 2.20 (m, 1H), 2.0 (d, J(H,H) = 0.8 Hz, 3H), 1.68 (m, 5H), 1.20 (m, 5H) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 165.3, 143.6, 133.1, 130.6, 129.9 (2C), 128.4 (2C), 123.5, 36.2, 33.3 (2C), 26.0 (2C), 25.9, 15.5 ppm. HRMS (ESI) m/z: [M+H]+ Calcd for C16H21O2 245.1542; Found 245.1538. Synthesis of enol ester 1j: over a suspension of NaH (0.35 g, 60% in mineral oil, 8.8 mmol), washed with pentane (3 x 10 mL) in dry 1,2-dimethoxyethane (10 mL), was added dropwise a solution of 1-phenylbutan-2-one (0.78 g, 5.2 mmol) in 1,2-dimethoxyethane (10 mL). The resulting mixture was stirred for 1 h, giving a bright yellow suspension, which was allowed to stand for 1 h. The supernatant was added slowly over distilled acetic anhydride (1.0 mL, 10 mmol) cooled at 0 ºC. After all the supernatant enolate solution was transferred, the residual sodium hydride was washed with additional 1,2-dimethoxyethane (5 mL), the mixture allowed to stand for 30 min and the resulting supernatant added to the acetic anhydride solution. The mixture obtained was stirred at room temperature for 0.5 h and poured into a mixture of nhexane (25 mL), water (25 mL) and NaHCO3 (2.5 g, 30 mmol). Phases obtained were separated and the aqueous one was extracted with n-hexane (30 mL). The combined n-hexane fractions 34 were dried over anhydrous MgSO4 overnight, filtered and solvent evaporated. The resulting oil was purified by column chromatography over silica gel using n-hexane / AcOEt (90:10) as eluent, yielding 1j as the pure Z isomer in 62 % yield. (Z)-1-Phenylbut-1-en-2-yl acetate (1j): pale orange oil. Yield: 0.600 g (62%). 1H NMR (CDCl3, 400 MHz):  = 7.38 (d, J(H,H) = 7.7 Hz, 2H), 7.31 (t, J(H,H) = 7.9 Hz, 2H), 7.21 (t, J(H,H) = 7.5 Hz, 1H), 5.99 (s, 1H), 2.42 (q, J(H,H) = 7.6 Hz, 2H), 2.19 (s, 3H), 1.17 (t, J(H,H) = 7.7 Hz, 3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz):  = 168.7, 151.4, 134.6, 128.4, 128.3 (2C), 127.0 (2C), 114.9, 27.5, 21.2, 11.4 ppm. IR (film): ν = 1757 (s, C=O), 1679 (m, C=C) cm-1. HRMS (ESI) m/z: [M+Na]+ Calcd for C12H14O2Na 213.0886; Found 213.0882. General procedure for the synthesis of enol esters 1r-s and 1ab-1ae: under an argon atmosphere, the corresponding (Z)-β-iodoenol acetate 2 (1.0 mmol), [Pd(PPh3)4] (0.058 g, 0.05 mmol) and toluene (3.0 mL) were introduced into a Teflon-capped sealed tube, and the mixture was stirred at room temperature for 10 min. Then, 0.5 mL of a 4.0 M NaOH aqueous solution (2.0 mmol of NaOH) and the corresponding boronic acid (1.5 mmol) were added to the sealed tube and the reaction mixture stirred at 80 ºC for 12 h. After that time, the solvent was removed in vacuo and the crude reaction mixture purified by column chromatography over silica gel using diethyl ether / hexane (1:100) as eluent. The corresponding enol esters 1r-s and 1aa-1ad were obtained as pure Z isomers in 42-80% yield. (Z)-1,4-Diphenylbut-1-en-2-yl acetate (1r): orange oil. Yield: 0.200 g (75%). 1H NMR (CDCl3, 400 MHz): δ = 7.46 (m, 2H), 7.41 (m, 4H), 7.32 (m, 4H), 6.07 (s, 1H), 2.99 (t, J(H,H) = 7.7 Hz, 2H), 2.83 (t, J(H,H) = 7.7 Hz, 2H), 2.22 (s, 3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ = 168.5, 149.0, 140.9, 134.3, 128.4 (4C), 128.3 (2C), 128.2 (2C), 127.1, 126.1, 116.4, 36.1, 35 33.3, 20.9 ppm. IR (film): ν = 1757 (s, C=O), 1602 (m, C=C) cm-1. HRMS (ESI) m/z: [M+Na]+ Calcd for C18H18O2Na 289.1204; Found 289.1199. (Z)-1,5-Diphenylpent-1-en-2-yl acetate (1s): orange oil. Yield: 0.221 g (79%). 1H NMR (CDCl3, 400 MHz): δ = 7.47 (m, 2H), 7.40 (m, 4H), 7.30 (m, 4H), 6.08 (s, 1H), 2.80 (t, J(H,H) = 10.2 Hz, 2H), 2.54 (t, J(H,H) = 10.2 Hz, 2H), 2.26 (s, 3H), 1.99 (m, 2H) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ = 168.5, 149.4, 141.8, 134.4, 128.5 (2C), 128.4 (4C), 128.2 (2C), 127.1, 125.9, 116.2, 35.2, 33.9, 28.5, 21.1 ppm. IR (film): ν = 1755 (s, C=O), 1602 (m, C=C) cm-1. HRMS (ESI) m/z: [M+Na]+ Calcd for C19H20O2Na 303.1361; Found 303.1356. (Z)-1-Phenyl-2-(4-(trifluoromethyl)phenyl)vinyl acetate (1ab): yellow solid. Mp: 46-49 ºC. Yield: 0.129 g (42%). 1H NMR (CDCl3, 400 MHz): δ = 7.62 (brs, 4H), 7.56 (m, 2H), 7.41 (m, 3H), 6.73 (s, 1H), 2.32 (s, 3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ = 168.4, 148.5, 138.1, 135.2, 129.4 (q, J(C,F) = 32.4 Hz), 129.3, 128.9 (4C), 125.6 (q, 2C, J(C,F) = 3.6 Hz), 125.1 (2C), 124.2 (q, J(C,F) = 270.3 Hz), 115.6, 21.2 ppm. 19F{1H} NMR (CDCl3, 376 MHz): δ = -62.6 ppm. IR (KBr): ν = 1753 (s, C=O), 1615 (m, C=C) cm-1. HRMS (ESI) m/z: [M+Na]+ Calcd for C17H13F3O2Na 329.0765; Found 329.0761. (Z)-2-(4-Methoxyphenyl)-1-phenylvinyl acetate (1ac):48 yellow solid. Yield: 0.201 g (75%). (Z)-2-(4-Phenoxyphenyl)-1-phenylvinyl acetate (1ad): yellow solid. Mp: 122-124 ºC. Yield: 0.238 g (72%). 1H NMR (CDCl3, 300 MHz): δ = 7.51 (m, 4H), 7.35 (m, 5H), 7.14 (m, 1H), 7.05 (m, 2H), 6.99 (m, 2H), 6.68 (s, 1H), 2.33 (s, 3H) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 168.7, 157.0, 156.8, 146.0, 135.7, 130.3 (2C), 130.0 (2C), 129.4, 128.8 (2C), 128.7, 124.7 (2C), 123.8, 119.4 (2C), 118.7 (2C), 116.2, 21.3 ppm. IR (KBr): ν = 1761 (s, C=O), 1607 (m, C=C) cm-1. HRMS (ESI) m/z: [M+Na]+ Calcd for C22H18O3Na: 353.1154; Found 353.1149. 36 (Z)-1-Phenyl-2-(thiophen-3-yl)vinyl acetate (1ae): yellow solid. Mp: 103-105 ºC. Yield: 0.195 g (80%). 1H NMR (CDCl3, 300 MHz): δ = 7.55 (m, 2H), 7.37 (m, 6H), 6.80 (s, 1H), 2.38 (s, 3H) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 168.6, 145.7, 135.3, 135.2, 128.7 (2C), 128.6, 127.8, 125.7, 124.6 (2C), 124.4, 111.3, 21.2 ppm. IR (KBr): ν = 1755 (s, C=O), 1595 (m, C=C) cm-1. HRMS (ESI) m/z: [M+Na]+ Calcd for C14H12O2SNa 267.0456; Found 267.0449. Synthesis of (Z)-1-phenyldec-2-en-2-yl acetate (1af): under an argon atmosphere, [Pd(PPh3)4] (0.04 g, 0.034 mmol) and THF (5.0 mL) were introduced into a Teflon-capped sealed tube, followed by TMEDA (0.280 mL; 1.9 mmol) and (Z)-1-iodo-3-phenylprop-1-en-2-yl acetate (0.5 g, 1.7 mmol). n-Heptylzinc bromide (0.5 M in THF; 3.8 mL, 1.9 mmol) was then added dropwise to the sealed tube and the reaction mixture stirred at room temperature for 12 h. After that time, the reaction was quenched with saturated NH4Cl solution and the product extracted with dichloromethane, dried over MgSO4 and the solvent removed in vacuo. The crude reaction mixture was then purified by column chromatography over silica gel using diethyl ether / hexane (1:50) as eluent, yielding (Z)-1af in 10% yield. (Z)-1-Phenyldec-2-en-2-yl acetate (1af): yellow oil. Yield: 0.047 g (10%). 1H NMR (CDCl3, 300 MHz): δ = 7.31 (m, 2H), 7.23 (m, 3H), 5.03 (t, J(H,H) = 7.3 Hz, 1H), 3.51 (s, 2H), 2.09 (s, 3H), 1.93 (q, J(H,H) = 7.1 Hz, 2H), 1.31 (m, 10H), 0.88 (t, J(H,H) = 6.5 Hz, 3H) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 169.0, 147.4, 137.6, 129.2 (2C), 128.5 (2C), 126.7, 118.6, 40.0, 31.9, 29.3, 29.2, 29.1, 25.6, 22.8, 20.8, 14.2 ppm. IR (film): ν = 1760 (s, C=O), 1605 (m, C=C) cm-1. HRMS (ESI) m/z: [M+Na]+ Calcd for C18H26O2Na: 297.1830; Found 297.1825. 37 General procedure for asymmetric hydrogenation: in a glovebox, a solution of 4 (0.5 µmol) and substrate 1 (0.05 mmol) in 1,2-dichloroethane (0.5 mL) was placed in a HEL CAT-18 or in a HEL 16 mL reactor. The reactor was purged with hydrogen and finally pressurized at 4 bar. Deuteration reactions were prepared in the 16 mL reactor, deoxygenating it with argon and vacuum cycles and finally pressurizing it under 4 bar D2. The reaction was heated at 40 ºC and magnetically stirred for 24 h. Then, the reactor was depressurized and the resulting solution slowly evaporated under vacuum. The remaining residue was analyzed by 1H NMR to determine conversion and subsequently dissolved in a i-PrOH / n-hexane (1:10) mixture and passed through a short pad of silica gel to remove catalyst decomposition products. The solution obtained was carefully evaporated and the residue obtained was analyzed by chiral chromatography to determine enantiomeric excess as described below. Racemic mixtures were obtained by hydrogenation of 1 with commercially available [Rh(COD)(DiPFc)]BF4 [DiPFc = 1,1’- bis(diisopropylphosphino)ferrocene] with the exception of 5p. In the hydrogenation of 1p a complex mixture was observed and (rac)-5p was alternatively prepared by acylation of 1cyclopropyl-2-phenylethan-1-ol.21 sec-Butyl benzoate (5a): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 7.6 min (R), t2 = 8.2 min (S). Hexan-3-yl benzoate (5b): Chiralcel AD-H, 99:1 n-hexane:i-PrOH, flow 0.5 mL/min, t1 = 9.2 min (R), t2 = 9.4 min (S). Octan-2-yl benzoate (5c): Chiralcel AD-H, n-hexane, flow 1.0 mL/min, t1 = 20.0 min (R), t2 = 21.8 min (S). 1-Cyclohexylpropan-2-yl benzoate (5d): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 5.2 min (R), t2 = 6.3 min (S). 38 1-(4-Methoxyphenyl)propan-2-yl acetate (5e): Chiralcel AD-H, 99:1 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 10.4 min (R), t2 = 11.0 min (S). 1-(4-Methylphenyl)propan-2-yl acetate (5f): Chiralcel AD-H, 99:1 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 12.4 min (R), t2 = 15.6 min (S). 1-(4-Fluorophenyl)propan-2-yl acetate (5g): Chiralcel AD-H, n-hexane, flow 1.0 mL/min, t1 = 22.0 min (R), t2 = 24.7 min (S). 1-(2-Methoxyphenyl)propan-2-yl acetate (5h): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 29.2 min (S), t2 = 32.8 min (R). 1-(3,4-Dimethoxyphenyl)propan-2-yl acetate (5i): Chiralcel AD-H, 98:2 n-hexane:iPrOH, flow 1.0 mL/min, t1 = 22.9 min (R), t2 = 24.9 min (S). 1-Phenylbutan-2-yl acetate (5j): Chiralcel AD-H, n-hexane, flow 1.0 mL/min, t1 = 23.3 min (S), t2 = 25.8 min (R). 1-Phenylpentan-2-yl acetate (5k): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 14.8 min (S), t2 = 16.9 min (R). 1-Phenylhexan-2-yl acetate (5l): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 16.8 min (R), t2 = 18.1 min (S). 1-Phenylheptan-2-yl acetate (5m): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 18.2 min (R), t2 = 22.8 min (S). 1-Phenyloctan-2-yl acetate (5n): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 9.7 min (R), t2 = 10.8 min (S). 5-Methyl-1-phenylhexan-2-yl acetate (5o): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 12.8 min (R), t2 = 15.3 min (S). 39 1-Cyclopropyl-2-phenylethyl acetate (5p): Chiralcel OB-H, 99:1 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 17.5 min (S), t2 = 18.8 min (R). 1-Cyclohexyl-2-phenylethyl acetate (5q): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 7.3 min (R), t2 = 8.1 min (S). 1,4-Diphenylbutan-2-yl acetate (5r): Chiralcel AD-H, 99.5:0.5 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 10.6 min (R), t2 = 11.7 min (S). 1,5-Diphenylpentan-2-yl acetate (5s): Chiralcel AD-H, 99.5:0.5 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 8.6 min (S), t2 = 12.0 min (R). 1-(4-Fluorophenyl)octan-2-yl acetate (5t): Chiralcel AD-H, 98:2 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 13.9 min (S), t2 = 15.0 min (R). 1-(4-Methoxyphenyl)octan-2-yl acetate (5u): Chiralcel OB-H, 99:1 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 9.9 min (R), t2 = 11.5 min (S). 1-(4-Methylphenyl)octan-2-yl acetate (5v): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 14.4 min (R), t2 = 18.2 min (S). 1-(4-Chlorophenyl)octan-2-yl acetate (5w): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 15.5 min (R), t2 = 20.7 min (S). 1-([1,1'-Biphenyl]-4-yl)octan-2-yl acetate (5x): Chiralcel AD-H, 98:2 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 12.5 min (S), t2 = 14.0 min (R). 1-(3,4-Dimethoxyphenyl)octan-2-yl acetate (5y): Chiralcel OB-H, 95:5 n-hexane:i-PrOH, flow 0.7 mL/min, t1 = 20.0 min (R), t2 = 22.9 min (S). 1-(3,5-Dimethoxyphenyl)octan-2-yl acetate (5z): Chiralcel AD-H, 98:2 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 12.9 min (S), t2 = 13.5 min (R). 40 1,2-Diphenylethyl heptanoate (5aa): Chiralcel OB-H, n-hexane, flow 1.0 mL/min, t1 = 7.7 min (R), t2 = 8.3 min (S). 1-Phenyl-2-(4-(trifluoromethyl)phenyl)ethyl acetate (5ab): Chiralcel AD-H, 99:1 nhexane:i-PrOH, flow 1.0 mL/min, t1 = 7.2 min (S), t2 = 8.9 min (R). 2-(4-Methoxyphenyl)-1-phenylethyl acetate (5ac): Chiralcel AD-H, 99:1 n-hexane:iPrOH, flow 1.0 mL/min, t1 = 14.0 min (R), t2 = 21.5 min (S). 2-(4-Phenoxyphenyl)-1-phenylethyl acetate (5ad): Chiralcel AD-H, 97:3 n-hexane:iPrOH, flow 0.6 mL/min, t1 = 13.3 min (S), t2 = 14.2 min (R). 1-Phenyl-2-(thiophen-3-yl)ethyl acetate (5ae): Chiralcel OB-H, 97:3 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 10.0 min (R), t2 = 12.3 min (S). 1-Phenyldecan-2-yl acetate (5af): Chiralcel AD-H, 99:1 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 6.6 min (R), t2 = 7.5 min (S). Determination of configuration of products 5: for products 5a,49 5c,11d 5d,11d 5e,50 5g51 and 5h52 configuration was assigned by comparison of the sign of optical rotation with that described in the literature. For compounds 5b, 5f, 5i and 5j configuration was assigned by analogy with the previous data. For ester 5n configuration was determined by deacylation and comparison of the sign of optical rotation of the resulting alcohol with that described in the literature.53 For compounds 5k-5m, 5o and 5r-5z configuration was assigned assuming an analogous stereochemical course of the hydrogenation with that of 5n. In addition, configuration of 5ac was assigned upon comparison of the sign of optical rotation with that described in the literature,54 while configuration of products 5aa, 5ab, 5ad and 5ae were assigned by analogy with the latter 41 data. Finally, for 5af, configuration was assigned assuming an analogous stereochemical course of the hydrogenation with that of 5b and 5c. Characterization of compounds 5: full characterization of products 5e-i, 5k-q and 5t-z has been reported in our preliminary communication.21 (S)-sec-Butyl benzoate (5a):49 obtained according to the general procedure (S/C = 100) as a pale yellow oil using 4d and DCM, instead of DCE, as solvent (8.4 mg, 94 % yield, 99 % ee). Alternatively, obtained using 0.5 mmol 1a and 0.5 µmol 4d in DCE (0.5 mL) under 20 bar H2 at 40 ºC for 24 h (83.0 mg, 93 % yield, 95 % ee). (R)-Hexan-3-yl benzoate (5b):19 obtained according to the general procedure (S/C = 100) as a pale yellow oil using 4a (9.8 mg, 95 % yield, 99 % ee). [α]D20 = -2.1° (c 1.1, CHCl3, 99 % ee). (R)-Octan-2-yl benzoate (5c):11d obtained according to the general procedure (S/C = 100) as a pale yellow oil using 4a (11.7 mg, 94 % yield, 99 % ee). (R)-2,3-Dideutero-octan-2-yl benzoate (5c-d2): obtained according to the general procedure (S/C = 100) as a pale yellow oil using 4a under 4 bar D2 (11.1 mg, 93 % yield, 96 % ee). 1H NMR (CDCl3, 400 MHz):  = 8.04 (d, J(H,H) = 8.1 Hz, 2H), 7.55 (t, J(H,H) = 7.3 Hz, 1H), 7.44 (t, J(H,H) = 7.7 Hz, 2H), 1.71 (m, 0.7 H, CDH major diastereomer), 1.58 (m, 0.3 H, CDH minor diastereomer), 1.32 (m, 11H), 0.87 (t, J(H,H) = 6.5 Hz, 3H) ppm. 2H NMR (CHCl3, 61 MHz):  = 5.14 (brs), 1.71 (brs, CDH minor diastereomer), 1.59 (brs, CDH major diastereomer) ppm. 13C{1H} NMR (CDCl3, 100 MHz):  = 166.3, 132.8, 131.1 (2C), 129.6 (2C), 128.4, 70.1 (t, J(C,D) = 19 Hz), 35.7 (t, J(C,D) = 19 Hz), 31.9, 29.3, 25.6, 22.7, 20.1, 14.2 ppm. 48 3H), 1.62 (s, 9H), 1.59 (d, J(H,P) = 13.6 Hz, 9H), 1.38 (s, 9H), 1.26 (d, J(H,P) = 13.1 Hz, 9H) ppm. 31P{1H} NMR (CD2Cl2, 162 MHz):  = 121.3 (dd, J(P,Rh) = 250 Hz, J(P,P) = 48 Hz), 23.9 (dd, J(P,Rh) = 134 Hz, J(P,P) = 48 Hz) ppm. 13C{1H} NMR (CD2Cl2, 100 MHz):  = 145.5 (d, J(C,P) = 8 Hz), 144.9 (d, J(C,P) = 14 Hz), 137.5 (d, J(C,P) = 2 Hz), 137.4 (d, J(C,P) = 4 Hz), 136.7 (d, J(C,P) = 1 Hz), 136.0 (d, J(C,P) = 2 Hz), 134.5 (d, J(C,P) = 2 Hz), 134.4 (d, J(C,P) = 2 Hz), 129.5 (d, J(C,P) = 2 Hz), 129.5 (d, J(C,P) = 2 Hz), 128.9, 128.8, 114.2 (dd, J(C,P) = 11 Hz, J(C-Rh) = 5Hz), 101.8 (dd, J(C,P) = 14 Hz, J(C,Rh) = 5Hz), 99.3 (dd, J(C,P) = 10 Hz, J(C,Rh) = 4 Hz), 84.0 (dd, J(C,P) = 13 Hz, J(C,Rh) = 7 Hz), 65.2, 39.7 (d, J(C,P) = 14 Hz), 38.9 (d, J(C,P) = 11 Hz), 35.2, 35.0, 32.8, 32.2, 31.8, 31.6 (d, J(C,P) = 5 Hz), 30.1, 30.1, 29.9 (d, J(C,P) = 4 Hz), 27.8, 20.5, 20.3, 20.2 (dd, J(P,P) = 20 Hz, J(P,P) = 7 Hz), 16.6, 16.3 ppm. Elem Anal Calcd (%) for C42H66BF4O3P2Rh: C 57.94, H 7.64; Found: C 57.51, H 7.44. Supporting Information. Selected NMR spectra and chromatograms. This material is available free of charge via the Internet at http://pubs.acs.org/. Acknowledgements We gratefully thank Ministerio de Economia, Industria y Competitividad of Spain (Grants CTQ2013-42501-P, CTQ2013-40591-P, CTQ2016-75193-P, CTQ2016-75986-P and CTQ201681797-REDC; AEI/FEDER, UE) and the Regional Government of Asturias (Project GRUPIN14006) for financial support. References 49 1. For reviews covering the hydrogenation of different types of substrates, see: (a) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40-73. (b) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357–1366. (c) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev. 2011, 111, 1713–1760. (d) Zhu, Y.; Burgess, K. Acc. Chem. Res. 2012, 45, 1623–1636. (e) Wang, D. S.; Chen, Q. A.; Lu, S. M.; Zhou, Y. G. Chem. Rev. 2012, 112, 2557–2590. (f) Verendel, J. 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