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IntroductIon

Transition metal-mediated asymmetric hydrogenation is a well established and efficient methodology for the catalytic reduction of many prochiral substrates that contain C=C, C=O and C=N bonds (1). Significant breakthroughs in the field have led to the development of a wide variety of chiral Ru-, Rh- and Ir-coordination compounds capable of mediating this transformation with very high enantioselectivities (1). These catalysts comprise a metal matched with a ligand sphere to encode reaction enantioselectivity. Although ligands containing diverse binding groups have been used to create an asymmetric (or disymmetric) environment around the metal centre, phosphorus containing derivatives have undoubtedly played an outstanding role in the field of asymmetric hydrogenation as most of the ligands incorporate phosphorus functionalities (1m). Recently we described a new library of P-OP l igands (phosphine-phosphinites and phosphine-phosphites) derived from enantiopure epoxides and their catalytic activity in Rh-mediated asymmetric hydrogenation (2a, c). Our P-OP ligands incorporate an understudied structural motif: two consecutive stereogenic centres between the two phosphorus functionalities. Herein we describe in full detail the efficiency of our “lead” phosphine-phosphite ligand in Rh-catalysed asymmetric hydrogenation of diversely functionalised alkenes (33 examples).

results and dIscussIon

ligand synthesisOur synthetic strategy is based on the use of enantiomerically pure epoxy ethers as starting materials, from which our lead

P-OP ligand 3 was available in two well precedented transformations: ring-opening of epoxy ether 1 with a n u c l e o p h i l i c p h o s p h o r u s d e r i v a t i v e ( p o t a s s i u m diphenylphosphide) (3) followed by O-phosphorylation of the intermediate phosphino-alcohol with a trivalent phosphorus electrophile (chlorophosphite derived from (S)-bINOL, Scheme 1) (4). The ring opening of epoxy ether 1 proceeded smoothly at -30ºC to room temperature and took place in a regioselective and stereospecific manner, as reported by brunner and Togni for related compounds (3). The intermediate phosphino-alcohol was rather prone to oxidation and subsequent protection as its corresponding borane adduct 2 allowed for more convenient handling and storage, giving 2 in 80 percent overall yield. The free phosphino-alcohol was obtained by decomplexation of the borane complex 2 using dAbCO at 60ºC in toluene (5). The phosphino-alcohol was then derivatized with the chlorophosphite derived from (S)-bINOL in the presence of triethylamine as the auxiliary base, in a 66 percent overall yield.

catalytic studiesCatalytic studies were carried out under typical “screening” conditions (2a, c). The pre-catalytic chiral rhodium complex (1 mol%) was generated in situ from [Rh(nbd)2]bF4 and a 10 mol% excess of P-OP ligand 3 to ensure that no metal precursor remained uncomplexed. Hydrogenations were carried out in solution (0.2 M of substrate in dCM, THF or MeOH) and at 20 bar of H2 pressure, unless otherwise stated. Conversions were determined after 12 hours for the sake of convenience and were, in almost all studied cases, complete after this reaction time. In situ generated [Rh(nbd)(3)]bF4 exhibited high enantioselectivity for the asymmetric hydrogenation of a structurally diverse array of substrates. Table 1 shows the results obtained with [Rh(nbd)(3)]bF4 as the pre-catalys t in the asymmetr ic hydrogenat ion of 2 - a m i n o a c r y l a t e s 4 . I n g e n e r a l , u n s u b s t i t u t e d

AbSTRACT an enantiomerically pure P-OP ligand (phosphine-phosphite)-

straightforwardly available from Sharpless epoxy ethers by epoxide ring-opening with a P-nucleophile followed by O-phosphorylation with a P-electrophile- shows an excellent performance in the Rh-catalysed asymmetric hydrogenation of a wide variety of functionalised alkenes (33 examples).

KEYWORdS: asymmetric hydrogenation, modular ligands, P-OP ligands, phosphine-phosphites.

P-OP-mediated asymmetric hydrogenation of functionalised alkenesHÉCTOR FERNÁNdEZ-PÉREZ1, PAbLO ETAYO1, JOSÉ L. NÚÑEZ-RICO1, ANTON VIdAL-FERRAN1,2**Corresponding author1. Institute of Chemical Research of Catalonia (ICIQ), Avinguda Països Catalans 16, Tarragona, 43007, Spain2. Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08010-barcelona, Spain

Anton Vidal-Ferran

Scheme 1. Synthesis of our "lead" P-OP ligand 3.

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Furthermore, no noticeable effects on enantioselectivity were observed with the catalytic system derived from ligand 3 upon changing the solvent or H2 pressure (2c).High enantioselectivities were also observed for a-aryl substituted enamides 6 (see Table 2, Entries 1-5), whereas

[Rh(nbd)(3)]bF4 failed to mediate the asymmetr ic hydrogenat ion of the analogous tert-butyl substituted enamide (Entry 6 in Table 2). Itaconate derivatives 8 are another class of compounds that afford interesting enantiopure derivatives upon asymmetric hydrogenation. High enantioselectivities were also obtained for several itaconate derivatives (Entries 1-4, Table 3), for the related Roche’s esters

(Entries 5-6, Table 3) and for the enol ester phosphonate 10 (Scheme 2). Lastly, a very high Z-selectivity was observed in the hydrogenation of 12 (E:Z ratio 1:2.8): catalytic precursor containing ligand 3 reduced only the Z-isomer (56% ee, Scheme 2).Computational studies have revealed the main influence of the different molecular fragments (7) on the stereochemical outcome of the reaction (2b, c). The presence of the bINOL-derived phosphite group has a dual effect on the behaviour of c1 ligand 3. On one hand, the electronic properties of phosphite hinder binding of the substrate in two out of the four possible reaction manifolds, while on the other its steric effects allow discrimination between the two remaining manifolds. The direction of stereodiscrimination is predominantly controlled by the binaphthyl group and the high achieved selectivity is the result of a combined action between the chiral bINOL-phosphite moiety and ligand backbone chirality.

experimental partThe general procedure for the Rh-catalysed asymmetric hydrogenations is the following: a solution of the required amount of [Rh(nbd)2]bF4 (1 mol%), the P-OP ligand 3 (1.1 mol%) and the alkene (1 mmol) in the corresponding dry and deoxygenated solvent (5.0 mL) was loaded into an autoclave under N2 atmosphere. The autoclave was purged three times with H2 (at a pressure not higher than the selected one) and finally, the autoclave was pressurized with H2 to the desired pressure. The reaction mixture was stirred at the desired temperature for the stated reaction time. The autoclave was subsequently depressurized, the reaction mixture passed through a short pad of SiO2 and further eluted with EtOAc. The resulting solution was evaporated in vacuo and the c o n v e r s i o n w a s d e t e r m i n e d b y 1 H - N M R a n d e n a n t i o s e l e c t i v i t i e s w e r e d e t e r m i n e d b y c h i r a l chromatography. The absolute configurations were assigned on the comparison with published data, except for hydrogenated compounds indicated in Entry 4 in Table 1 and Entry 4 in Table 3. In these cases absolute configuration was tentatively assigned to be (R) and (S) respectively by analogy based on the stereochemical outcome for analogous substrates.

2-aminoacrylates (Entries 1 and 2 in Table 1), b-alkyl- (Entries 3-6) or b-aryl-substituted a-aminoacrylates (regardless of the electronical or positional nature of the substituents on the aromatic ring, Entries 7-21) were hydrogenated with high enantioselectivity with the catalytic system derived from ligand 3 (up to 99 percent ee). The hydrogenation of hydroxycarbonyl (Entries 1, 7, and 20) or methoxycarbonyl substituted substrates (Entries 2-6, 8-19, and 21) took place with high enantioselectivities. Two remarkable features of our catalyst should be pointed out at this point: Firstly, the tolerance to a broad variety of carbamate-type amino protecting groups, given the excellent enantioselectivities observed in such cases (boc, Cbz and Fmoc: 9 examples; Entries 4-6, 11-13, and 19-21), and, secondly, the good performance for b-alkyl-substituted dehydroamino acids (4 examples, Entries 3-6), as certain ligands afford high enantioselectivity for substrates with aromatic substituents but not for the corresponding alkyl-analogues (6). Interestingly, the catalytic system derived from ligand 3 showed a very high Z-selectivity: analogous substrates to the ones in Entries 12, 13 and 19 but with an E-configuration could not be fully reduced by [Rh(nbd)(3)]bF4, even at increased H2 pressure (2c). Although results indicated in Table 1 involve using 1 mol % of catalyst, a reduction of substrate/catalyst ratio down to 2500/1 for Z-Mac (4 with R1=Ph, R2=Me and G=Ac) still gave quantitative yields and up to 99% ee (2c).

We describe in full detail the efficiency of our "lead

ligand" phosphine-phosphite in Rh-catalysed asymmetric hydrogenation of diversely functionalised

alkenes (33 examples)

Table 1. Asymmetric hydrogenation of (Z)-2-aminoacrylates.

Table 2. Asymmetric hydrogenation of a-substituted enamides.

Table 3. Asymmetric hydrogenation of itaconates and analogous derivatives. Scheme 2. Hydrogenation of other substrates.

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catalysis, 1, pp. 183 (1999); (c) T. Ohkuma, R. N o y o r i , c o m p r e h e n s i v e a s y m m e t r i c catalysis, 1, pp. 199 (1999); (d) H.-U. blaser, F . Sp indler , comprehens ive asymmetr ic Catalysis, 1, p. 247 (1999); (e) W.S. Knowles, angew. chem. Int. Ed., 41, p. 1998 (2002); (f) R. Noyori, angew. chem. Int. Ed., 41, p. 2008 (2002); (g) W. Tang, X. Zhang, chem. Rev., 103 , p. 3029 (2003) ; (h) I .d. Gr idnev, T . Imamoto, acc. chem. Res., 37, p. 633 (2004);

(i) X. Cui, K. burgess, chem. Rev., 105, p. 3272 (2005); (j) W.S. Knowles, R. Noyori, acc. chem. Res., 40, p. 1238 (2007); (k) A.J. Minnaard, b.L. Feringa et al., acc. chem. Res., 40, p. 1267 (2007); (l) W. Zhang, Y. Chi et al., acc. chem. Res., 40, p. 1278 (2007); (m) Phosphorus L igands in asymmetr ic catalys is , A. börner Ed.; Wi ley-VCH, Weinheim, Vol. 1-3 (2008).

2. (a) H. Fernandez-Perez, M.A. Pericas et al. , adv. Synth. catal., 350, p. 1984 (2008); (b) S.M.A. donald, A. Vidal-Ferran et al., can. J. chem., 87, p. 1273 (2009); (c) H. Fernandez-Perez, S.M.A. donald et al . , chem. Eur. J. (2010), dOI: 10.1002/chem.200902915.

3. (a) H. brunner, A. Sicheneder, angew. chem., 100, p. 730 (1988); (b) F. Gorla, A. Togni et al., Organometallics, 13, p. 1607 (1994).

4. N. Sakai, S. Mano et al., J. am. chem. Soc., 115, p. 7033 (1993) as a seminal piece of work.

5. (a) H. brisset, Y. Gourdel et al., Tetrahedron Lett., 34, p. 4523 (1993).

6. (a) G. Zhu, P. Cao et al., J. am. chem. Soc., 119, p. 1799 (1997); (b) G. Zhu, X. Zhang, J. Org. chem., 63, p. 3133 (1998) and references cited therein.

7. See the following references as other examples of covalent modular approaches to asymmetric catalysis: (a) C. Jimeno, A. Vidal-Ferran et al., Org. Lett., 8, p. 3895 (2006); (b) d. Popa, C. Puigjaner et al., adv. Synth. catal., 349, p. 2265 (2007); (c) d. Popa, R. Marcos et al., adv. Synth. catal., 351, p. 1539 (2009). &

conclusIons

Enantiopure phosphine-phosphite 3, easily derived from Sharpless epoxy ethers, has proven to be a highly efficient ligand in the Rh-catalysed hydrogenation of a diverse array of substrates (33 examples). 2 -Aminoacry la tes 4 , a - subs t i tu ted enamides 6, itaconates and related compounds 8, and enol ester phosphonate 10 were hydrogenated with high enantioselectivity, regardless of the electronic or posit ional nature of the subst i tuents. Furthermore, the catalytic system derived from P-OP ligand 3 is able to tolerate a broad range of carbamate-type amino protecting groups (boc, Cbz, Fmoc). The remarkably good performance and modular nature of the catalyst makes it attractive for future applications. Work is in progress to discover new catalysts for asymmetric hydrogenation in still challenging fields (C=N and unfunctionalised C=C bonds).

acknowledgements

We thank MIcINN (Grant CTQ2008-00950/bQU), dURSI (Grant 2009GR623), Consolider Ingenio 2010 (Grant CSd2006-0003), and ICIQ Foundation for financial support. H. F. gratefully acknowledges the “Programa Torres Quevedo” for financial support and P.E. thanks the “Educational department of Navarra’s Government” for a postdoctoral contract.

references and notes

1. (a) J.M. brown, comprehensive asymmetric catalysis, 1, pp. 122 (1999); (b) R.L. Halterman, comprehensive asymmetric

The high achieved selectivity is the result of a

combined action between the chiral BINOL-

phosphite moiety and ligand backbone chirality