Acerca del autor

Pher Andersson became Docent at Uppsala University in 1994 and Professor in 1997. Among his many awards are the Bjurzons award (1992) the Oscar award (1995), the Junior Individual Grant for outstanding young researchers (1997), and the Astra Zeneca Award in Organic Chemistry (2004).

Ian Munslow currently holds a post doc position at the group of Professor Andersson.

De la contraportada

Reductions are the counterpart of oxidations and are widely used in synthetic organic chemistry. They vary widely in their specifics, ranging from hydrogenations to hydride transfer or simply electron transfers, and their vast number makes a comprehensive review virtually impossible. This monograph thus covers recent developments, focusing on general and synthetically useful reductions in frequent use by chemists.
The high quality contributions treat the reduction of carbonyles, alkenes, imines and alkynes, as well as reductive aminations and cross and heck couplings, before finishing off with sections on kinetic resolutions and hydrogenolysis.
With its comprehensive overview of modern reduction methods, this book allows readers to find reliable solutions quickly and easily, making it an indispensable lab companion for every organic, catalytic and natural products chemist, as well as chemists in industry.

Fragmento. © Reproducción autorizada. Todos los derechos reservados.

Modern Reduction Methods

John Wiley & Sons

Chapter One

Jean-Pierre Genet

1.1 Introduction

While a variety of methods is now available for the stereoselective reduction of olefins, catalytic hydrogenation continues to be the most useful technique for addition of hydrogen to various functional groups. Catalytic hydrogenations can be carried out under homogeneous or heterogeneous conditions, both employing a similar range of metals. Heterogeneous catalysts have had a strong impact on the concept of catalysis. They have provided powerful tools to the chemical industry and organic chemistry, allowing the chemo-, regio- and stereo-selective reduction of a wide range of functional groups and generally easy catalyst separation. Homogeneous catalysts have found applications in a number of special selectivity problems or where enantioselectivity is the most important. Today, highly selective catalysts have revolutionized asymmetric synthesis. For two decades, homogeneous asymmetric hydrogenation has been dominated by rhodium(I)-based catalysts of prochiral enamides. Knowles and Horner initiated the development of homogeneous asymmetric hydrogenation in the late 1960s using modified Wilkinson's catalysts. An important improvement was introduced when Kagan and Dang demonstrated that the biphosphine DIOP, having the chirality located within the carbon skeleton, was superior to a monophosphine in Rh-catalyzed asymmetric hydrogenation of dehydroamino acids. Knowles made a significant discovery of a [ITLITL.sub.2]-symmetric chelating [P.sup.*]-stereogenic biphosphine DIPAMP that was employed with rhodium(I) for the industrial production of L-DOPA.

In the 1990s, the next breakthrough was Noyori's demonstration that the well-designed chiral complex containing Ru(II)-BINAP catalyzes asymmetric hydrogenation of prochiral olefins and keto groups to produce enantiomerically enriched compounds with excellent enantioselectivity. Not surprisingly, such versatile Rh- and Ru-based systems have had significant industrial impact and have been widely investigated in modern organometallic laboratories. For these beautiful achievements W. S. Knowles and R. Noyori were awarded the 2001 Nobel Prize in chemistry. Today, asymmetric hydrogenation is a core technology; thousands of very efficient chiral ligands with diverse structures have been developed. Combinatorial approaches combined with high-throughput screening techniques have facilitated the discovery of new catalysts and increased the cost-effectiveness of a given process. The catalysts used in asymmetric hydrogenation are not limited to those with Rh or Ru metals. Catalysts derived from other transition metals such as Ir, Pd, Ti, Pt are also effective. Asymmetric hydrogenation of functionalized olefins with Rh, Ru and Ir will be the predominant topics of this chapter.

1.2 Asymmetric Hydrogenation of Dehydroamino Acids

1.2.1 Rh-Catalyzed Reactions

Since the invention of the well-designed Rh-complexes containing chiral biphosphines for the asymmetric hydrogenation of dehydroamino acids and the synthesis of L-DOPA, this reaction has become the model reaction to evaluate the efficiency of new chiral ligands. Indeed, a wide range of chiral phosphorus ligands with great structural diversity have been found to be effective for the synthesis of (R)- or (S)-enantiomers (Scheme 1.1).

1.2.1.1 Hydrogenation with Chiral Bisphosphine Ligands

For the Rh-catalyzed hydrogenation of 2-(acetamido)acrylic acid derivatives and (Z)-2-(acetamido) cinnamic acids and esters, cationic Rh catalysts and low hydrogen pressure are generally used. Examples are shown in Scheme 1.2. The reaction of (Z)-[alpha]-(acetamido)cinnamic acid in the presence of preformed [Rh-(S)-BINAP[(MeOH).sup.2]]Cl[O.sub.4] produces (S)-N-acetylphenylalanine with nearly 100% ee. The Rh-tetra-Me-BITIOP and Rh-CyP-PHOS catalysts developed by Sannicolo and Chan respectively were also found efficient in this reaction. Pye and Rossen have developed a ligand based on a paracyclophane backbone, [2,2]-Phanephos, which has shown high enantioselectivity, up to 99% ee, in rhodium-catalyzed hydrogenation.

Twenty years after the discovery of DIPAMP by Knowles, several new generations of [P.sup.*]-chiral bisphosphines have been developed. Mathey and coworkers have designed BIPNOR, a bisphosphane with two chiral non-racemizable bridgehead phosphorus centers. BIPNOR has shown good enantioselectivities up to 98% ee in the hydrogenation of [alpha]-(acetamido) cinnamic acids. A rigid [P.sup.*]-chiral bisphospholane ligand Tangphos has been reported by Zhang. This readily accessible ligand is very efficient for asymmetric hydrogenation of (acylamino)acrylic acid. A new class of bisphosphine bearing one or two benzophospholanes has been designed by Saito (1,2-bis-(2-isopropyl-2,3-dihydro-1H-phosphindo-1-1-yl) benzene (i-Pr-BeePHOS)). i-Pr-Beephos has been found to provide high enantioselectivity in the Rh-catalyzed asymmetric hydrogenation of [alpha]-dehydroamino acids. Leitner has developed a series of mixed phosphoramidite-phosphine (Quinaphos), phosphinite-phosphine and Ito the TRAP ligands that have obtained excellent efficiency in Rh-asymmetric hydrogenation of dehydroalanine derivatives. Since the discovery in 1994 of Josiphos, a ferrocene-based ligand devised by Togni and Spindler, this class of bisphosphines including Taniaphos, Mandyphos families, phosphinoferrocenyl phosphines and (iminophosphoranyl) ferrocenes have also shown excellent enantioselectivities in Rh-catalyzed reactions. As shown in Scheme 1.2, the biphosphines are highly efficient in the asymmetric hydrogenation of (Z)-dehydroamino acid derivatives with very high enantioselectivity. However, there are many reactions of interest where catalysts bearing these phosphines perform poorly in terms of enantioselectivity and efficiency. In particular, the hydrogenation of the (E)-isomeric substrates gives poor enantioselectivities and proceeds at a much lower rate. Interestingly, a new class of [ITLITL.sub.2]-symmetric bisphospholane ligands has been prepared by Burk et al. and used in rhodium-catalyzed asymmetric hydrogenation. The Rh-Duphos catalyst provides high enantioselectivities for both (E)- and (Z)-dehydroamino acid derivatives [22] as shown in Scheme 1.3. In these hydrogenations, no separation of (E)- and (Z)-isomeric substrates is necessary. The hydrogenation of [alpha],-dienamides with Rh-Duphos proceeds chemoselectively, only one alkene function being reduced to give chiral [gamma],[gamma]-unsaturated amino acids with both high regioselectivity (>98%) and ee (99%).

A short and efficient synthesis of optically pure (R)- and (S)-3-(hetero) alanines has been developed from isomerically pure (Z)-[alpha]-amino-[alpha],-dehydro-t-butyl esters using Rh-MeDuphos (Equation 1.1).

[FORMULA NOT REPRODUCIBLE IN ASCII] (1.1)

Hydrogenation of ,-disubstituted-dehydroamino acids remains a relatively difficult problem. Duphos ligands and analogues provide excellent enantioselectivity up to 99% ee for a wide range of substrates. The modular nature of these ligands, which allows simple adjustment of their steric and electronic properties, can be achieved through the ability to modify both the phospholane core and the R-substituents. Since their useful application in Rh-asymmetric hydrogenation of olefins, many structural modifications of the phospholane core have been reported. The conformationally rigid and bulky bisphosphane Penphos has been designed by Zang. A series of modified Duphos and DPE ligands containing hydroxyl ether and ketal groups at C3 and C4 of the phospholane have been reported. The ligands (4) with four hydroxyl groups enabled hydrogenation to be carried out in aqueous solution while maintaining the high efficacy of Duphos and DPE ligands. The fully functionalized enantiopure bisphospholane Rophos is highly effective for the hydrogenation of unsaturated phosphonate (Equation 1.2).

[FORMULA NOT REPRODUCIBLE IN ASCII] (1.2)

The synthesis of a new class of chiral bisphosphetane ligands related structurally to the Duphos and DPE ligands (Scheme 1.4) such as 1,2-bis(phosphetano) benzenes CnrPHOS, 1,2-bis(phosphetano) ethanes BPE and 1,1-bis(phosphetano) ferrocene has been reported by Marinetti and Genet. Later in 2000, Burk et al. reported a similar synthesis of these interesting 1,1-bis(phosphetano)ferrocene ligands named FerroTANE. Interestingly, (S,S)-i-Pr-CnrPHOS provides moderate ee of (R)-methyl-N-acetylphenylalanine at 5bar (500kPa) of hydrogen (74%). However, at 100bar of [H.sub.2] higher optical yields are observed (up to 90% ee). This nonconventional stereochemical issue can be related to the electron-rich nature of the phosphetane ligands.

Imamoto and coworkers have developed a series of electron-rich [P.sup.*]-chiral bisphosphanes such as Bis[P.sup.*], Miniphos and 1,1-di-t-butyl-2,2-dibenzophos-phenetyl. The Miniphos ligand leads to highly strained [ITLITL.sub.2]-symmetric chelates when bound to a metal center. These ligands having both a conformational rigidity and an ideal chiral environment have shown significant enantioselectivities up to 99% ee in the hydrogenation of [alpha]-dehydroamino acids as shown in Scheme 1.5.

1.2.1.2 Mechanism of the Asymmetric Hydrogenation with Rhodium Catalysts

The practical importance of asymmetric hydrogenation has stimulated a great interest in the mechanistic aspects of this reaction. Over the last 30 years, the mechanism of the rhodium-catalyzed asymmetric hydrogenation has been actively investigated. Success in this field is evident from theoretical and experimental studies. The acylamino substituent plays a crucial role in the enantioselection. The amide carbonyl group provides an additional binding site for the catalyst, placing the substrate precisely within the coordination sphere of rhodium (Scheme 1.6) giving rise to two diastereomeric catalyst-substrate complexes competing for [H.sub.2] addition. Previously, it has been well accepted that the "unsaturated-alkene" mechanism (Halpern-Brown), pathway (a), Scheme 1.6, via (7) was operating with a wide range of phosphines, the Rh-(S)-BINAP giving (R) configured [alpha]-amino acids.

Gridnev and Imamoto, through experimental and computational studies, have established that the Rh-catalyzed asymmetric hydrogenation with electron-rich [P.sup.*]-stereogenic ligands such as Miniphos proceeds with a different mechanism. A "dihydride" mechanism (pathway (b), Scheme 1.6) via (8) is proposed. However, it is suggested that the differences in these mechanisms are not significant in the stereoselection since they join at a single pathway (c), forming the common intermediate (9) before stereoselection occurs. They also suggested a new approach for the prediction of the sense of enantioselectivity.

1.2.1.3 Rh-Catalyzed Hydrogenation with Monophosphorus Ligands

The high degree of enantioselectivity resulting from chiral biphosphanes in the Rh-catalyzed asymmetric hydrogenation of [alpha]-dehydroamino acids can be explained as a result of decreased rotational freedom in the postulated metallacycle of the catalytic pathway. However, isolated cases have been reported in which this long-standing theory is not as general as usually assumed. More recently, it has been recognized that chiral phosphite (10), phosphoramidites such as Monophos, monodentate phospholane (11) and phosphinane (12), are excellent ligands in this hydrogenation reaction as shown in Scheme 1.7. Zhou introduced a novel monodentate phosphorus ligand containing 1,1-spirobiindane backbone which was found to be particularly effective in the hydrogenation of methyl-2-acetamidocinnamate at 1 bar ([10.sup.5] Pa) pressure of [H.sup.2], with up to 97.8% ee at 0C [37]. Interestingly, enantioselectivities up to 99% were achieved in the rhodium-catalyzed asymmetric hydrogenation of the N-formyl dehydroamino ester using Monophos ligand where a mixture of E and Z isomers was reduced with excellent ee values using 2mol% of catalyst. Ding has recently reported an efficient system of heterogenization of Ferringa's catalyst by a self-supported strategy that can be recycled several times for the enantioselective hydrogenation of dehydroalanine derivatives.

1.2.2

Ruthenium- and Iridium-Catalyzed Reactions

1.2.2.1 Ruthenium

The development of chiral ruthenium-BINAP complexes has considerably enhanced the scope of enantioselective hydrogenation of olefins and keto groups. The axially 1,1'-binaphthyl moiety generally displays very high chiral recognition properties. The optically active bis-(triarylphosphines), BIPHEMP and MeO-BIPHEMP, containing the axially chiral biphenyl core have been developed by Roche. In this context, several structural variations of the BINAP and MeO-BIPHEMP have been designed by many research groups and applied extensively to the reduction of olefins and keto groups.

Unlike the Rh-based hydrogenation of [alpha]-(arylamino) acrylates, the corresponding Ru-chemistry has not been studied extensively. The first two examples were described 20 years ago by Ikariya-Saburi using Ru-(S)-BINAP and by James and coworkers with Ru-(S,S)-Chiraphos. These complexes catalyze the hydrogenation of (Z)-[alpha]-(acylamino) cinnamates giving (S)-phenylalanine derivatives with 92% [40] and 97% ee respectively. More recently several chiral Ru-(bisphosphine) catalysts have been used in this reaction as shown in Table 1.1. The [Ru-(R,R)-DIPAMP([Br.sub.2])] and [Ru-(R,R)-DIPAMP[(2-methylallyl).sub.2]] complexes also catalyze the asymmetric hydrogenation of N-acetyldehydroalanine giving (R)-N-acetylalanine with 35-38% ee The non-[ITLITL.sub.2] symmetric biaryl (bisphosphino)-MeO-NAPhe-PHOS and TriMe-NAPhePHOS (R = [R.sup.1] = H) ligands designed by Genet and Marinetti have been used in Ru-catalyzed asymmetric hydrogenation of dehydroamino acids giving 70% ee. These results are comparable to those obtained with MeO-BIPHEP (68%).

The bis-steroidal atropisomeric phosphine (13) has been developed from equilenine and gives up to 87% ee in the hydrogenation of (Z)-[alpha]-acetamidocinnamic acid. A new atropisomeric ligand containing a bis-benzodioxane core Synphos was reported independently by Genet and Vidal and by Chan. A Ru-(S)-Synphos complex catalyzes a symmetric hydrogenation of (Z)-(acylamino) cinnamate giving (S)-protected phenylalanine in 86% ee. Chan and coworkers have developed a P-PHOS ligand containing a dipyridyl unit that is highly efficient for the asymmetric hydrogenation of (Z)-2-acetamidocinnamate obtaining 88% ee at 1bar ([10.sup.5] Pa) of [H.sup.2] [47]. Lemaire and coworkers have reported a Ru-(5,5)-perfluoroalkylated BINAP which is a useful catalyst in the asymmetric hydrogenation of methyl-2-acetamidoacrylate in supercritical carbon dioxide with full conversion and high enantioselectivity (74% ee).

The Ru-complexes of the atropisomeric family exhibit slight differences in enantioselectivity toward the same substrate. This may be attributed to the electronic and stereoelectronic properties of these ligands. The optical purities are significantly reduced in comparison with those of the Rh-catalyzed reaction. More interestingly, the Rh and Ru hydrogenation catalysts consisting of the same chiral biphosphines exhibit an opposite sense of asymmetric hydrogenation of dehydroamino acids.

(Continues...)

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