Fangyuan Wang

Long-Sheng Zheng

Qi-Wei Lang

Congcong Yin

Ting Wu

Phannarath Phansava

Gen-Qiang Chen

Virginie Ratovelomanana-Vidal
email: virginie.vidal@chimieparistech.psl.eu

Xumu Zhang
email: zhangxm@sustech.edu.cn

Rh(III)-Catalyzed diastereoselective transfer hydrogenation: an efficient entry to key intermediates of HIV protease inhibitors †

A highly efficient diastereoselective transfer hydrogenation of a-aminoalkyl a ' -chloromethyl ketones catalyzed by a tethered rhodium complex was developed and successfully utilized in the synthesis of the key intermediates of HIV protease inhibitors. With the current Rh(III) catalyst system, a series of chiral 3-amino-1-chloro-2hydroxy-4-phenylbutanes were produced in excellent yields and diastereoselectivities (up to 99% yield, up to 99 : 1 dr). Both diastereomers of the desired products could be efficiently accessed by using the two enantiomers of the Rh(III) catalyst.

HIV infections are one of the world's greatest public health challenges, especially in the poor areas. 1 In 2018, over 37.9 million individuals worldwide were suffering from this disease, of which only 23.3 million had access to antiretroviral therapy, 1.7 million were newly infected and 0.77 million died. [START_REF] Sidib´e | World AIDS Day Report[END_REF] HIV-1 protease inhibitors (HIV PIs) are considered to be one of the most promising chemotherapeutic agents against HIV infections. 3 To date, the approved HIV PIs by the US Food and Drug Administration (FDA) such as Atazanavir, Saquinavir, Ritonavir and Darunavir have been recommended by the World Health Organization as essential drugs for a basic health system. 4 Consequently, the development of highly effi cient synthetic methods to access these HIV PIs is very important to reduce the cost and increase their usage in poverty-stricken areas. As can be seen from Fig. 1, the HIV PIs have in common a chiral hydroxyethylamine moiety. To the best of our knowledge, the nucleophilic ring opening of the amino epoxides was the key step to construct this moiety and the amino epoxide intermediates (100s of tons annually) can be prepared after base treatment of 3-amino-1-chloro-2-hydroxy-4phenylbutanes 2 or 3 which in turn can be obtained by diastereoselective reduction of N-protected chloroketones 1.

During the last few decades, considerable efforts have been devoted to the diastereoselective reduction of chloroketones 1. 5 NaBH 4 or LiAlH 4 reduction 6 and Meerwein-Ponndorf-Verley (MPV) reduction 7 of the corresponding ketones could only produce the diastereomer 2 and low temperature (0 to -78 1C) was needed to control the diastereoselectivity (Scheme 1a). Biocatalytic methods for the reduction of N-protected chloroketones 1 have also been reported. 8 However, these methods usually suffer from long reaction time, and the reaction outcome is highly substrate dependent. Besides, the preparation of the enzyme also requires elaborate and intricate methods, which limits their applicability and reproducibility (Scheme 1b). An asymmetric transfer hydrogenation of a-aminoalkyl a ' -chloromethyl ketones 1 was reported 9 in 2004 using chiral Rh(III)/TsDPEN (N-( p-toluenesulfonyl)-1,2-diphenylethylenediamine) complex in a HCOOH/NEt 3 mixture delivering optically active alcohols with up to 90 : 10 dr and up to 1000 TON. A Rh(III)catalyzed asymmetric hydrogenation of 1 was described 10 with 92 : 8 dr, but with only 11% conversion (Scheme 1c). The combination of enzyme catalysis and asymmetric hydrogenation was also disclosed in 2003, albeit with low efficiency. 11 Scheme 1 Previous work and this work.

Scheme 2 Evaluation of catalysts for the asymmetric transfer hydrogenation. a Unless otherwise specified, the reactions were conducted with 1a (0.2 mmol), catalyst (100 mL, 0.002 M in MeOH), HCOOH/Et3N azeotropic mixture (40 mL) and MeOH (1.9 mL) at 25 1C, 12 h. The conversions were determined by 1 H NMR analysis and the dr values were determined by LCMS analysis.

Although significant progress has been achieved, the highly efficient and diastereoselective reduction of a-aminoalkyl a ' -chloromethyl ketones 1 is still highly demanded.

Asymmetric transfer hydrogenation (ATH) has emerged as a new branch of enantioselective synthesis. 12 A variety of Ru, Rh, Ir catalysts in combination with the TsDPEN ligand was reported by Noyori, 13 Wills, 14 Xiao 15 and other groups. 16 These catalysts showed excellent catalytic performances in the ATH of ketones, 17 imines, 18 especially a-chloro ketones. 19 In particular, the tethered catalysts 20 developed by Wills and Ikariya, show greater activity and are more stable than the original non tethered catalysts. Herein, we report a transfer hydrogenation strategy for the synthesis of chiral 3-amino-1-chloro-2-hydroxy-4-phenylbutane 2 with high effi ciency (TON up to 4900) and high diastereoselectivity (up to 99 : 1 dr) (Scheme 1d).

We initially examined the transfer hydrogenation of 1a using the commercially available TsDPEN-derived Ru, Rh and Ir complexes (0.1 mol%) in an azeotropic mixture of formic acid and triethylamine at 25 1C, and the results are depicted in Scheme 2. Catalysts cat.1, cat.2, cat.3 and cat.4 exhibited moderate activity and diastereoselectivity for this transformation. The use of (S,S)cat.5 afforded 2a with 89% conversion and 8 : 92 dr. Pleasingly, the catalytic activity of tethered catalyst cat.6 21 outperformed that of the catalysts previously evaluated, both in conversion and diastereoselectivity. Reduction of 1a with (R,R)-cat.6 in azeotropic mixture of formic acid and triethylamine (S/C = 1000) in 0.1 M MeOH at 25 1C afforded 2a with 99 : 1 dr value in complete conversion. The other diastereomer 3a was obtained quantitatively using the enantiomer of the complex, (S,S)-cat.6, with 99 : 1 dr, demonstrating that the diastereoselectivity of the reduction was mainly controlled by the chirality of the ligand rather than the chirality of the adjacent stereogenic center.

Encouraged by these promising results, we further examined the effect of the solvents and the ratio of formic acid and triethylamine on the reaction (Table 1). The solvents played an important role in this catalytic transformation. When toluene, THF, dioxane and i PrOH were used as solvent, 499% conversions were achieved after 3 h with 97 : 3 to 99 : 1 dr values (entries 2-4 and 6). The same conversions (499%) were obtained in only 2 h in MeOH and 1 h in DCM with 99 : 1 dr value (entries 5 and 7). We next explored the influence of the catalyst loading. Using 0.02 mol% cat.6, 97% conversion was observed in DCM after 24 h with 99 : 1 dr, while only 55% conversion was achieved in MeOH for the same reaction time (entries 8 and 9). Additionally, the influence of the formic acid/ triethylamine ratio was studied. Thus, the use of 3 : 2 and 1 : 1 mixtures as hydrogen donor source led to 96 : 4 dr and 98 : 2 dr respectively in full conversions in 4 h (entries 10 and 11).

With the optimal reaction condition in hand (entry 9), we evaluated the effect of N-protecting groups, and the results are summarized in Scheme 3. Chloromethyl ketones with various N-protecting groups could be reduced with (S,S)-cat.6 and (R,R)cat.6, delivering the desired chiral alcohols 2 and 3. The yield and diastereoselectivity of the products were influenced by the configuration of catalyst cat.6 as well as by the N-protecting group. The reduction of 1b and 1e with (S,S)-cat.6 gave the products with higher dr values than (R,R)-cat.6. The reaction of 1a bearing a benzoyl protecting group gave the product with the highest dr value.

The substrate scope of this transformation was also evaluated, and the results are shown in Scheme 4. For substrates with electrondonating (Me and MeO) or electron-withdrawing groups (F, Cl, Br and CF 3 ) on the para position of the phenyl group, the reaction proceeded smoothly to provide the corresponding products in high yield and diastereoselectivity (2f-2g and 2h-2k). The reaction also tolerated substrates with meta-or ortho-substitution on the phenyl group (2l and 2m), and excellent yields and dr values were obtained. Slightly lower diastereoselectivity was achieved for substrates with naphthyl group or disubstituted phenyl group (2n-2o and 2p-2q). Heterocyclic substituted compounds containing 2-thienyl or 2-furyl substituents were also tested furnishing 2r and 2s with excellent yield and dr value. When the aryl substituent was replaced by isopropyl or cyclohexyl groups, the corresponding products 2t and 2u were formed with 96 : 4 and 99 : 1 dr respectively. The other diastereomer 3 could be prepared in similar or higher diastereoselectivity (3h, 3p, 3n, 3r and 3u) by using (S,S)-cat.6.

To demonstrate the synthetic utility of this asymmetric transfer hydrogenation, four gram-scale transformations were conducted (Scheme 5). Under the standard reaction conditions, 1a was converted to 2a in 97% yield and 99 : 1 dr while 3a was obtained in 93% yield and 99 : 1 dr using catalyst (S,S)-cat.6. Moreover, 2b and 3b were also obtained with 499 : 1 dr after recrystallization under the standard reaction conditions.

In conclusion, we have developed an efficient Rh(III)-catalyzed diastereoselective transfer hydrogenation of a-aminoalkyl a ' -chloromethyl ketones. As far as asymmetric transfer hydrogenation is concerned, this practical, operationally simple diastereoselective and functional-group-tolerant method allows to effi ciently access both diastereomers of the corresponding alcohols at low catalyst loading, in high yield and diastereoselectivity (up to 99% yield, up to 99 : 1 dr, up to 4900 TON). Direct access to a variety of chloro hydroxylamines was achieved using the disclosed method providing an effi cient and concise route to 1-chloro-2hydroxy-4-phenylbutanes, which are key intermediates of HIV protease inhibitors.

X. Zhang is indebted to Shenzhen Nobel Prize Scientists Laboratory Project (C17213101), Southern University of Science and Technology (start-up fund), Shenzhen Science and Technology

Fig. 1

 1 Fig. 1 Selected privileged peptidomimetic HIV-1 inhibitors and their versatile synthetic intermediates.

a

  Reaction condition: 0.2 mmol of 1a in 2.0 mL of solvent, catalyst (100 mL, 0.002 M in MeOH), HCOOH/Et3N azeotropic mixture (40 mL), 25 1C.b The molar ratio of substrate and catalyst. c Determined by 1 H NMR analysis.d Determined by LCMS analysis.e The catalyst (0.002 M in DCM).

Scheme 4

 4 Scheme 4 Substrate scope of the Rh(III) catalyzed transfer hydrogenation. a

Table 1

 1 Optimization of reaction conditions for the Rh-catalyzed transfer hydrogenation of 1a

a Entry HCOOH/NEt3 S/C b Solvent Time (h) Conv. c (%) dr d

Innovation Committee (No. KQTD20150717103157174 and JSGG20170821140353405), National Natural Science Foundation of China (No. 21432007 and 21672094) and SZDRC Discipline Construction Program for financial support.

Conflicts of interest

The authors declare no competing financial interests.

Notes and references


Catherine Aubertin

Claire Weill

Bruno Dorin

Thierry Caquet

Allison Loconto

Bruno Losch

Xavier Poux

Losch

Sustainable land-Use transitions : moving beyond the 30x30 target and the land sparing/land sharing debates (Policy Brief)

come   L'archive ouverte pluridisciplinaire

KEY MESSAGE 1

We must push thinking beyond the false binary of preservation vs. production

The 30x30 target revives historical policies that supported the preservation of nature. The first policies promoted nature preservation through 'enclosed areas' that prohibited human activities and, according to a colonial logic, excluded local populations. However, in 1992, the CBD recognised the notion of sustainable use and enhancement of biodiversity -that is, the protection and even enrichment of biodiversity human societies can bring to natural environments. This approach has been supported in the Millennium Ecosystem Assessment with the conceptualisation of ecosystem services. Thus, while land use changes related to agriculture are recognised as the primary factor in biodiversity loss (IPBES, 2019), some forms of agriculture are also seen as a central option for restoring degraded ecosystems and ecological functions (Vidal et al., 2020). In this sense, nature-based solutions are a 'conservation' approach that has gained recent public attention.

The 30x30 target thus revives the lively international debate around land sparing and land sharing options (Loconto et al., 2020), as sustainable land use must contribute to increasing biodiversity and food security while addressing climate change and other sustainability goals.

The productivity gains of intensive agriculture have led to an increased production of food, especially for animals, and of agrofuels and bio-based materials. However, it has not slowed down the conversion of natural ecosystems (e.g., deforestation). The growing demand for animal proteins related to rising living standards has been the main driver of both agricultural expansion and industrial intensification (IPBES, 2019). Livestock uses crop feed and herbage over 80% of agricultural land, with huge variations between extensive and intensive systems. Bending the growth curve of unsustainable animal products consumption and production is therefore a key issue in the debate over biodiversity conservation.

Land Sparing and Land Sharing

Land sparing -saving land by separating production and preserved areas. A first answer to the food security challenge -feeding a world of 10 billion people by 2050 (Borlaug, 2002) -comes from the Green Revolution. The approach is to intensify agriculture to make it more productive without consuming more land. Specialized monocultures with standardized rotations (e.g., maize and soy), the intensive use of synthetic inputs, irrigation and biotechnology are seen as the most efficient way to meet the increased demand for cheap food. This approach promotes the preservation of protected areas outside of agricultural production zones.

Land sharing -spreading out and combining agricultural production and biodiversity conservation in the same areas.

A second answer lies in the search for an environmental and social alternative to industrial agriculture. It is built on an 'ecology of reconciliation' between biodiversity and agriculture, i.e., on the interactions of humans and 'other living beings' within complex agricultural systems. It uses more labour and demands a diversification of agricultural production zones without necessarily extending them. Land sharing also promotes changes on the demand side such as improved diets and reduced food losses and waste.

In both approaches, smaller portions of land can still be preserved under indigenous or community management.

KEY MESSAGE 2

Different regions of the world do not face the same sustainable land use challenges

In order to design the basis for partnerships and international alliances, it is necessary to distinguish between the expectations and priorities in terms of land sparing/land sharing, according to the characteristics of the main world regions. Thus, while agricultural yields in the richest countries seem to have reached their limits under industrial agriculture -soil degradation, reduced landscape biodiversity and climate change mark this limit -progress in yield are still possible in poor and middle-income countries, where the starting point of existing farming systems varies greatly.

Every agricultural situation is unique. Land fertility, topography, soil type and quality, and climate determine productivity thresholds. Yet labour availability and productivity, land status, access to markets, world views, the type and importance of needs (for food, income and jobs) related to demographic and economic realities also contribute to the feasibility of different options. At the local level, the issue is to conciliate biodiversity gains and agricultural benefits. At the international level, it is to reconcile the protection of the planet, the fairness of trade (for agricultural and forestry raw materials) and the access to resources. In particular, the export of biomass from agriculturalbased countries where their local economy is minimally diversified to the richest countries must be questioned in terms of equity, social justice, environmental integrity and the protection of human, plant and animal health (Chotte and Orr, 2021). Indeed, while a certain number of ecoregions cover relatively intact natural environments that could be suitable for conservation, other areas may be more suitable for increased economic activity (urban green belts). It is then a question of thinking in terms of functional biodiversity. Creating large stable habitats and sufficiently strong 'meshworks' to protect specific areas and facilitate exchanges and ecological continuity is an important approach. These 'meshworks' preserve ecological functions (e.g., pollination, soil fertility) and management methods (i.e., derived from the socio-cultural context) that support production processes. In many cases, production systems integrated

Biodiversity conservation in Europe: the land-sharing perspective

In Europe, a large share of biodiversity associated with agriculture is a legacy from extensive farming systems over centuries. The stock of all kind of species (flora, fauna and micro-organisms) in semi-natural open landscapes results from the historical evolution of extensive agropastoral mixed systems. Agricultural development since the mid 20 th century, based on intensification in synthetic inputs, increased production up until the end of the 1990s. However, it brought with it negative impacts on biodiversity on a large scale. Thus, following an intensification pathway for future production is a risky option for biodiversity conservation. First, because a plateau in yields seems to have been reached, increased use of inputs will no longer lead to higher yields. It is only an increasingly expensive way to maintain them. Second, the spatial expansion of intensive farming systems would further threaten the existing "High Nature Value" systems that currently contain high levels of biodiversity within the agricultural production zones. Aligned with the EU Green Deal, a promising pathway stands in reducing the dependency on synthetic inputs by maximizing the ecological services of mixed production systems, notably in terms of nitrogen fixation, resilience to pests and water shortage. Research from organic farming shows that these systems can be rather productive, 3-4 times more than industrial systems. Modern agroecological systems might be less productive than the current intensive ones, but they are much more resource-efficient and more resilient, both climatically, ecologically and socio-economically. The main change would be the shift from intensive livestock systems fed on imported soya to more extensive livestock systems able to value European-grown legumes. Overall grain-fed livestock production would need to drop, but this leads to positive outcomes for consumers' health (Aubert et al., 2019).

into complex landscapes are highly productive while being rich in biodiversity (UN, 2010). The objective of land sparing -producing a lot on a scarce area -can thus be reached through highly efficient low input farming systems, spontaneously associated with land sharing. In that case, labour with adequate skills and equipment including low tech and high tech innovations replaces the use of expensive inputs and heavy machinery.

Africa: Adapted agricultural models to tackle unique structural challenges

Diversity is a high value asset. The continent is vast, straddling several climatic zones; it is unevenly inhabited with both sparsely populated and historically densely populated areas. But a major demographic transition is underway: the population is predicted to double by 2050 to reach around 2.5 billion people. This growth will take place in cities, but the rural population will continue to grow for a long time, unlike in other regions of the world. A major distinction must be made between North Africa and South Africa on the one hand (i.e., largely urbanised with slow population growth and diversified economies) and the rest of sub-Saharan Africa on the other (i.e., where, despite pronounced differences, agriculture is the first sector of workforce occupation and rural population is the majority). This 'middle Africa' corresponds to 70% of the continent's surface area and 77% of its population. Available data estimate that the area suitable for agriculture is between 247 and 456 million ha (when including forests) for an additional 250 million rural people by 2050. This prospect of rural densification could have serious consequences for fragile ecosystems subject to the impacts of climate change. In many countries, agricultural growth based on land extension is impossible and farm sizes are shrinking rapidly due to generational repartitioning among a growing population. Tensions on resources are thus increasing. Migration, which has already begun, will accelerate towards the less populated areas with agricultural potential, with strong pressure on forests (Losch, 2016). The identification of sustainable agricultural and food models that provide decent jobs is the major challenge to be solved by African societies.

KEY MESSAGE 3

The notion of 'freed land' is a fallacy

Climate policies shed new light on the land sparing /land sharing debate. Claims have been made that free land could be used for large-scale bioenergy production. However, total substitution of fossil fuels by biomass production is impossible due to its high impact on land consumption (Pörtner et al., 2021). Likewise, proposals to compensate for greenhouse gas emissions through massive tree planting or REDD+ mechanisms are prohibited by the physical limits of the planet.

The idea that there is 'free land' out in the world somewhere that can be used to establish new protected areas is a colonial vision. Even forest classification systems have reinforced this fallacy (Cheyns et al., 2020). It ignores the sovereignty of States and the rights of indigenous and local populations. IPCC, IPBES, IUCN and FAO emphasize the importance of indigenous people, who occupy 28% of land and manage 80% of terrestrial biodiversity. Rather than creating sanctuaries of their territories through preservation or imposing afforestation, it is paramount that they maintain secure rights over their land and autonomy in decisions over its use. The Global Indigenous Agenda for the governance of indigenous lands, territories, waters, coastal seas and natural resources launched at the World Conservation Congress in 2021 is part of the solution to both the climate crisis and the erosion of biodiversity.

In this context, intensifying the restoration of degraded land while learning from local and indigenous knowledge is of outmost importance.

KEY MESSAGE 4

Sustainable land use transitions should be assessed according to multiple sustainability criteria

The scientific literature on land sparing/land sharing shows contrasting performances according to the criteria used to assess the profitability of farms, the effectiveness of conservation activities, and the benefits of biodiversity. However, most of these assessments based on modelling are not satisfactory.

First, models tend to favour surface area and agricultural production because data are more easily accessible than for agricultural and nonagricultural biodiversity, water flows, carbon stocks, etc.. The labelling of products and their ecological footprints (calculated in terms of space consumed, biomass production and GHG emissions) barely take into account biodiversity (limited to the identification of a few key species), land degradation and the effects of synthetic inputs. Moreover, include yields of only a few industrial crops (wheat, rice, maize, soya, sugarcane, etc.), for which data exist. This means that leguminous crops, fruit and vegetables and the possibility of crop combinations with several cycles per year are not counted. Consequently, intensive monoculture appears to be better for the environment than land sharing (Blamford et al., 2021). Although several recent syntheses provide quantitative elements on land sharing (Aubert et al., 2019;DeClerck et al., 2021), developing and informing approaches based on "field" data and local cultivation practices are still needed in order to have a complete picture of land sharing production systems and biodiversity effects.

Second, global modelling does not take into account the diversity of farming systems. Agroecology, in particular, cannot be reduced to a set of specifications. It is a project that implies major socio-economic changes, including a different vision of the relationship between agriculture and biodiversity. This project brings into play all the synergies between humans and other living beings within ecosystems. It also considers the social, institutional, political and technical interactions over the long, or even very long, term.

In the end, the type of agri-food systems that will be promoted in the coming decade will determine what can be achieved from an environmental viewpoint (i.e., climate, water, biodiversity, human and ecosystem health) and from a nutrition and health perspective. This vision will directly influence the overall economic, demographic and Agroecology, a game changer for India?

During the 1960s, as in Europe, India embarked firmly on an industrialisation of its agriculture, later called the Green Revolution (GR). It encouraged specialisation in monocultures -wheat, rice, sugarcane -with massive upstream subsidies for "modern" inputs (i.e., credit, laboratory seeds, irrigation, fossil fuel for pumping water, chemical fertilisers, etc.) and downstream price supports to producers and consumers. Today the Indian GR basins achieve annual food calorie yields far exceeding those of Western Europe. But in 50 years, the active Indian agricultural population has continued to grow and farm sizes have shrunk (1 ha on average in 2015). Indian farmers have therefore not been able to increase their production and income by enlarging and mechanising their farms as in Europe. The overall results of the GR raise concern on several counts: farmer income -increasing cost of inputs, yields and economies of scale capped or decreasing; nutrition -chronic under-nutrition and malnutrition despite massive imports of pulses and vegetable oils, far too expensive fruit and vegetables, over-abundant production of carbohydrates, etc.; national budget -several tens of billions of euros per year in subsidies; and the environment -its effects on soil, water, air, biodiversity is a real ecological suicide. In India, where land is particularly scarce and expensive, technical and institutional innovations are nevertheless flourishing. They aim to exploit the astonishing local productive capacities of nature and mankind. As in Andhra Pradesh (53 million inhabitants and 10 million farmers in 2020) where, in less than six years, nearly a million micro-farmers have adopted a complex form of agroecology called "Natural Farming" (Dorin, 2021). Supply is no longer the first pillar of food security which is mostly a question of access to food for low-income populations. • Everywhere today, consumption patterns are essentially driven by the food industry and international trade. Food systems can be improved using the potential of local dynamics and innovations. Instead of adopting expensive techniques associated with land sparing, agroecological techniques reduce costs and increase resilience and opportunities for producers. Public regulations and support systems, like payments for ecosystem services, will be needed to facilitate the transition towards sustainable landuse.

• Develop multifaceted risk-assessment thinking, where the compared impacts of land sparing/ land sharing scenarios on soil functioning and functional biodiversity, on locked-in markets and on-farm economies, are assessed against risks of ecosystem resilience loss. • In any debate on where and how we use land, what biomasses we produce and for whom, the local socio-economic dynamics and societal dimensions are critical. The concerns of people must be fully part of the sustainability discussion.

  Projections should not be made to meet assumed consumption needs. Rather, land use scenarios should be compatible with planetary boundaries. In this regard, it is essential to look at how diets can be rebalanced (e.g., among legumes, dairy, and meat as protein sources) and how supply chains can be diversified in order to distribute benefits more fairly.• Stop thinking only in terms of supply and demand.

	social transformations of all countries around the
	world. Agroecological systems have a fundamental
	comparative advantage to contribute to more
	inclusive and job-intensive agri-food systems,
	particularly in countries where employment
	alternatives are limited.
	To support sustainable land use transitions and to
	identify agricultural models benefiting biodiversity
	and other sustainable development objectives, we
	make the following recommendations:
	• Assess exhaustively the environmental impacts
	of food systems, in local agricultural areas and
	beyond (e.g., water, local and remote pollution,
	carbon and nitrogen cycles, GHG emissions).
	When possible, these assessments should
	reference energy equivalents, production cycles,
	diversity and abundance of species or even food
	quality, impact on diets and health, number and
	types of jobs created, modes of governance and
	reduction of inequalities. Multiple criteria can
	better capture the true impacts of production.
	• Develop different sustainability trajectories
	informed by research and inclusive stakeholder
	dialogues.

REFERENCES:

-Aubert P-M, Schwoob, M-H, Poux, X. (2019)


Ricardo Molina Betancourt

Pierre-Georges Echeverria

Tahar Ayad

Phannarath Phansavath
email: phannarath.phansavath@chimieparistech.psl.eu

Virginie Ratovelomanana-Vidal
email: virginie.vidal@chimieparistech.psl.eu

Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution

come

Introduction

Enantiomerically pure alcohols and amines are structural motifs of central importance for the manufacture of chemical products such as organic materials, agrochemicals, flavors, fragrances, and pharmaceuticals. Therefore, it is not surprising that the development of truly efficient methods to prepare such structures remains a paramount goal of practical significance in both academia and industry. Among the plethora of transformations available in the organic chemistry toolbox, homogeneous late-transitionmetal-catalyzed asymmetric hydrogenation (AH) [START_REF]The Handbook of Homogeneous Hydrogenation[END_REF] and asymmetric transfer hydrogenation (ATH) 1n,2 are undoubtedly regarded as two of the most efficient, environmentally benign and straightforward approaches to build up diastereomerically and enantiomerically pure alcohols and amines in high yields and selectivities from their prochiral carbonyl and imine starting materials. In the meantime, dynamic kinetic resolution (DKR), 3 an effective alternative to traditional kinetic resolution, has emerged as increasingly fruitful, with many applications in asymmetric synthesis and catalysis over the past decades. In a DKR process, the kinetic resolution step is initiated with an in situ racemization. As a result, the substrate can be fully converted into a single product with a 100% theoretical yield. Consequently, under DKR conditions the AH or ATH of a homochiral substrate bearing a labile stereocenter allows the synthesis of a single, enantiomerically pure diastereomer. To succeed in obtaining an efficient DKR, the rate of racemization (k rac ) of the ketone or imine must be faster than the rate of the asymmetric reduction (k1 and k2) and one enantiomer must AH or ATH via DKR Ru, Rh, Ir, Mn, Pd, Cu complexes

OH O R 1 R 3 O O Bn N O O OH R 1 R 2 R 1 * CO2Et X R 2 R R n OH OH R X HO R OH N N
react faster than the other one (k 1 > k 2 or k 2 > k 1 ). Moreover, the asymmetric transformation has to be irreversible, i.e. the product formed during the reaction must be stable to avoid any racemization (Figure 1). In this regard, the first examples of homogeneous catalytic AH of β-keto esters with a configurationally labile a-stereocenter using dynamic stereomutation were independently reported in 1989 by the groups of Noyori 4 and Genêt. [START_REF] Jugé | EP 0489071A1[END_REF] More precisely, these authors demonstrated that Ru(II) complexes bearing either BINAP or CHIRAPHOS ligands were highly efficient catalysts for the stereoselective hydrogenation of 2-(acylamino)-3-oxobutanote giving the Virginie Vidal was born in Paris. She received her Ph.D. from Paris-Sud University under the supervision of Prof. H. P. Husson and Dr. J. Royer (Gif, France). She then pursued post-doctoral appointments with Prof. S. Hanessian (Montreal University, Canada, 1989-1990)

Biographical Sketches

Conditions for an efficient dynamic kinetic resolution: This (update) 3q review covers the period from January 2016 to May 2020 and intends to summarize the latest developments in the rapidly expanding area of late-transition-metal-catalyzed AH and ATH of substituted ketones and imines under cooperative DKR that simultaneously create two or more stereogenic centers in a single synthetic step. Excellent overviews of the topics cited in sections of this current short review have been recently published. 1v,w,2z-ac,3r The structures of the ligands and complexes reported in this review are depicted in Figure 2 and Figure 3.

Asymmetric Hydrogenation via Dynamic Kinetic Resolution

a-Substituted Ketones

In 2016, Zhou and co-workers succeeded in developing a new strategy to access chiral 2,3-cis-dimethyldihydrobenzofurans through a scalable Ru-catalyzed AH of racemic 3-(aryloxy)butan-2-ones employing a dynamic kinetic resolution (DKR) as the enantioselective step (Scheme 1). 8 The hydrogenation was performed using 0.02 mol% of chiral spiro ruthenium catalyst (Sa,R,R)-CAT1 under 50 atm of hydro-gen in i-PrOH in the presence of t-BuOK at room temperature for 2.5 h to provide the targeted chiral alcohols in 99% yield with a high diastereoselectivity (anti/syn 95:5) and up to 97% ee. This protocol allowed the development of the first total synthesis of (+)-PI-220 and (+)-3-epi-furaquinocin C.

Chiral amino alcohols are important structural features that are present in numerous biologically active natural products, drugs, and pharmaceuticals. In 2017, Zhang, Dong, and co-workers demonstrated that the combination of an iridium complex with the chiral f-Amphox-t-Bu ligand (L1) in the presence of Cs2CO3 could be efficiently used for the synthesis of chiral N,N-disubstituted a-amino β-unfunctionalized alcohols (Scheme 2). 9 Indeed, under the cooperative dynamic kinetic AH, a broad range of racemic aamino β-unfunctionalized ketones were smoothly converted into the corresponding amino alcohols in almost quantitative yields and high levels of stereoselectivity. Worthy of note is that this reaction can be performed under low catalyst loading (up to S/C 5000) with high TON (up to 100000 and more importantly, proved to be applicable for the preparation of a key intermediate of the preclinical antitumor agent (S,S)-R116010.

) 1 R 2 R R 3 + Y Y R 2 R 1 k Y Y R R 2 krac R 1 M* -H Y R 3 Y = O, NH 1 R 3 Figure 1 R 3 R 3 R 3 Y M* -H R 2 R 2 k2 R + 1 R 1 R 2
In 2018, Zhang, Dong, and co-workers investigated the stereoselective hydrogenation of Ir-mediated AH of racemic benzo-fused cyclic ketones via a DKR process using a new family of chiral ferrocene-based amino phosphine alcohol (f-Amphol) ligands. 10 The f-Amphol ligand L2 with a 3,5-ditert-butylphenyl group was identified as the optimal ligand, giving the targeted chiral benzo-fused cyclic alcohols in 75-96% yields and consistently excellent 99% ee. However, and as depicted in Scheme 3, the diastereomeric ratios of the reaction proved to be highly dependent on the size of the benzo-fused ring. The synthetic utility of the methodology was demonstrated by preparing a key intermediate of an anticonvulsant drug eslicarbazepine acetate (BIA 2-093, not shown).

Kozlowski and co-workers designed, in 2018, a new series of highly modular and tunable heterophosphole dimeric ligands that proved to be effective chiral inducers in the first copper-catalyzed AH of racemic 2-substituted 1tetralones and related heteroaryl ketones through DKR that furnished the corresponding optically enriched 2-substituted 1-tetralols (Scheme 4). 11 Optimization of the reaction parameters revealed that the catalytic system composed of CuCl2, electron-rich P(3,5-xylyl)3 as ancillary phosphine, and the electron-poor azaphosphole N-BABIPhos L3 was CuCl2/L3 H2 (400-700 psi)

t-BuOK (0.25 equiv) t-AmylOH, 20 °C, 24 h (S/C = 20) R 2 R 1 = Me, Ph, allyl, Bn R 2 = CH2, OH or O O OH R 1 R 1 R 2
84-99% yield cis/trans 3:1 to >99:1 0-48% ee or In 2019, Ohkuma and co-workers described the preparation of cis-2-substituted cycloalkan-1-ols from racemic 2alkylidenecycloalkan-1-ols via an isomerization/AH sequence through a DKR (Scheme 5). The use of [RuCl2{(S)-xylyl-Segphos}{(R)-DMAPEN}] complex (S P ,R N )-CAT2 in the presence of a mixture of t-BuOH/Et3N and KOH under 4-20 atm of hydrogen afforded the corresponding cis-alcohols in 82-97% yields with cis/trans selectivities up to 99:1 dr and up to 98% ee. The reaction proceeded through isomerization of the allylic alcohol into the racemic a-substituted ketone which was reduced by AH through DKR. 12 In 2020, de Ruiter and co-workers reported the AH/DKR of a-substituted ketones catalyzed by a new chiral iridium carbene-oxazoline complex CAT3 based on an imidazo [1,5a]pyridine backbone (Scheme 6). 13 The hydrogenation of asubstituted cyclohexanones, acetophenones, and tetralones and β-keto sulfonamides under 6 atm of hydrogen in the presence of t-BuOK proceeded with up to >99:1 dr and up to 79% ee via DKR of the in situ formed enolate.

OH O S R 3 O R 4 CAT3 t-
Zhou, Yu, and co-workers reported the first efficient Pdcatalyzed AH of 2-arylcycloalkanones through DKR under acidic conditions. 14 The reaction was performed with Pd(OCOCF3)2 with (R)-Segphos [(R)-L4] as a ligand in the presence of TsOH•H2O providing a facile access to chiral trans-2-arylcycloalkan-1-ols in 28-94% yield, up to 98% ee, and trans selectivities for cyclohexanones up to >20:1 dr, whereas cyclopentanones and cycloheptanones gave lower yields (Scheme 7). The role of the Brønsted acid was essential in accelerating the racemization of the 2-arylcycloalkanones via the enol intermediate.

) n R = Ph, 2-MeOC6H4, 2-MeOC6H4, 28-94% yield 2-MeC6H4, 2-F3CC6H4, 3-MeC6H4, 3:1 to >20:1 4-MeC6H4, 4-MeOC6H4, 4-FC6H4, 9-98% ee 4-F3CC6H4, 4-ClC6H4, 2,4-Me2C6H3, Bn, 1-naphthyl, 2-naphthyl, 4-F-1-naphthyl 4-MeO-1-naphthyl, 4-Me-1-naphthyl n = 0-2 Scheme 7

a-Substituted β-Keto Esters and Amides

A new class of chiral ferrocenyl P,N,N-ligands was designed by Hu and Hou in 2016 for the AH of numerous aalkyl-substituted acyclic β-aryl-β-keto esters containing diversely substituted aryl groups via DKR. 15 Various ketone substrates were reacted in the presence of 0.005 mol% of [Ir(COD)Cl] and 0.011 mol% of the ligand (S ,R ,R )-L5 un-

2 c p c
der 20 atm of H2 in the presence of 5 mol% of t-BuOK to de-

Scheme 11

15.3-97.4% ee 88.7 to >98.0% de liver enantioenriched anti-β-hydroxy esters in 90-96% yield with up to 95:5 dr and 63-99% ee (Scheme 8). The effectiveness of this new ligand stems from the introduction of a second stereogenic center which increases the structural rigidity and steric hindrance.

Zhang and co-workers described the synthesis of syn-aamido-β-hydroxy esters through AH/DKR of the corresponding a-amido-β-keto esters using the preformed complex [RuCl(p-cymene)(S)-SunPhos]Cl obtained from [Ru-Cl 2 (p-cymene)] 2 and (S)-SunPhos [(S)-L6] (Scheme 9). 16 This study revealed the importance of the steric and electronic effects of the substituents on the aryl moiety and that the stereoselectivities were also deeply influenced by the nature of the amino protecting group. The hydrogenation proceeded in 66-96% yields with high reactivity (TON up to 940), 58:42 to >99:1 dr, and 51 to >99% ee.

ing Ru-catalyzed AH of β-keto-η-lactams through DKR (Scheme 11). 18 Using [Ru(OAc) 2 {(S)-TolBINAP}] complex [with (S)-TolBINAP = (S)-L7)] and HCl/LiCl as additives to enhance the reactivity, under 5.8-6.1 atm of H2, a wide range of substrates were reduced with up to >98% de and up to 97.4% ee.

In 2017, Zhou, Xie, and co-workers explored the same transformation using (R)-Ir-SpiroSAP complex (R)-CAT7 19 (Scheme 12). Under optimized conditions, racemic βketo-lactams were reduced using 0.1 mol% of the Ir catalyst with KOH as a base under 10-50 atm of H2 in methanol to furnish chiral β-hydroxy-lactams in 87-99% yield, 97:3 to >99:1 dr and 83-99.9% ee. Reaction conditions are tolerant Zhou, Xie, and co-workers displayed a highly enantioselective preparation of chiral cyclopentanols allowing control of three contiguous stereocenters (Scheme 10). 17 The reaction was performed using (R)-Ir-SpiroPAP complex (R)-CAT5 (0.1 mol%) and t-BuOK under 10 atm of H2 in EtOH giving enantioselectivities ranging from 92 to >99.9% ee and 95:5 to >99:1 dr. The key feature of this reaction is a one-pot, two-step sequential reduction of the C=C bond followed by AH of the C=O bond of the resulting β-keto esters upon DKR. The utility of this methodology was shown by the synthesis of all stereoisomers of the antiulcer drug rosaprostol.

β-Hydroxy-η-lactam is a common skeleton found in numerous bioactive compounds. As such, in 2016 Maguire and co-workers developed a highly stereoselective synthesis us- to different ring sizes as well as different ketone substituents (alkyl or aryl). Furthermore, the synthetic utility of this method was successfully demonstrated by the preparation of optically pure (S)-N-methyl-1-[(R)-pyrrolidin-3yl]ethan-1-amine, a key intermediate en route to the antibiotic premafloxacine.

Continuing a long-established interest in transitionmetal-catalyzed asymmetric reductions, 3f,20 our group prepared several key fragments of the cytotoxic macrolide mirabalin through a flexible strategy based on either Ru-catalyzed AH or Rh-promoted ATH (Scheme 13). 21 The syn-isomer of the C1-C36 subunit and two isomers of the C44-C65 side chain of mirabalin were thus prepared by using an AH/DKR approach with either the ruthenium complex [Ru-Br2{(S)-Synphos}] {i.e. [RuBr2(S)-L9] bearing the in-house developed L9 ligand} 22 or catalyst CAT8 23 which afforded good levels of diastereo-and enantioselectivities. On the other hand, the anti-isomer of the C1-C36 fragment was obtained by performing an ATH reaction with the rhodium complex (R,R)-CAT9. 24 Cheung and co-workers reported a synthesis of the monobactam antibiotic LYS228 based on an AH/DKR of a racemic a-amino-β-keto ester to introduce the anti-β-amino alcohol moiety (Scheme 14). The hydrogenation was carried out with Noyori's catalyst [RuCl2((S)-BINAP)] [with BINAP = (S)-L8] under 21 atm and delivered the anti-a-amino-β-hydroxy ester with 97% de and 99% ee. 25 In 2019, Brückner and Baumann developed a novel route to atropisomerically pure biindolyldiphosphane ligands that did not rely on the resolution of a racemic mixture (Scheme 15). 26 The new ligands (R,R,M)-L10 and (R,R,P)-L10 were remarkably efficient in the Ru(II)-cata-lyzed AH of ethyl 1-oxo-,2,3,4-tetrahydronaphthalene-2carboxylate, affording the corresponding reduced compound with perfect trans selectivity and excellent enantioinduction, outperforming BINAP (L8) in this case in terms of enantioselectivity.

Considering the importance of exploring alternative synthetic methods using non-precious metal complexes for long-term sustainability and because a-substituted β-hydroxy amides are useful building blocks to access bioactive molecules and chiral drugs, Ding and co-workers succeeded in developing, in 2020, the first application of Mn catalysts in the AH of racemic a-substituted β-keto amides through DKR (Scheme 16). 27 A screening of the reaction parameters demonstrated that the reaction proceeded smoothly in MeOH at room temperature for 16 h in the presence of t-BuOK under 10 atm of hydrogen by using 1 mol% of the complex (R,R)-CAT10 incorporating a lutidine-based chiral P,N,N-ligand. The reaction tolerated a broad scope of substrates and the anti-a-alkyl-or -a-aryl-substituted β-hydroxy amides were produced in 91-99% yield and TON up to 10000, with up to >99% dr and up to >99% ee. The origin of high stereoselectivities has been detailed by DFT calculation study. The synthetic utility of the method was showcased in the enantioselective formal synthesis of the opioid drug tapentadol. The hydrogenation was efficiently scaled on 10 mmol in the presence of 0.01 mol% of (R,R)-CAT10 and t-BuOK under 50 atm of hydrogen at 70 °C for 48 h in MeOH to provide the key intermediate to access the chiral drug tapentadol in 99% yield with 97:3 dr and 90% ee.

a-Substituted Esters

In 2019, Bergens and co-workers outlined the first highly active and enantioselective hydrogenation of a-substituted acyclic esters through a DKR process by using an in situ prepared ruthenium complex obtained from [Ru(1-3:5,6η 6 -C 8 H 11 )(η 6 -anthracene)]BF 4 and (R,R)-L11 under 4 atm of hydrogen in the presence of NaOEt or i-PrONa as a base (Scheme 17). 28 In this case, the ATH/DKR reaction led to βchiral primary alcohols, with only one stereocenter present in the reduced compound. Under the optimized conditions, the reaction proceeded with up to 100% conversion, up to 95% ee, and 1000 turnovers to afford the corresponding alcohols.

In 2019, Xie and co-workers reported the first Ir-catalyzed enantioselective hydrogenation of racemic a-(arylamino) δ-and η-lactones through DKR pattern to provide a novel route to chiral 2-(arylamino)alkane-1,4-and -1,5-diols, respectively (Scheme 18). 29 A wide range of a-(arylamino)-η-butyrolactones and a-(arylamino)-δ-valerolactones were hydrogenated under mild conditions in the presence of 0.2 mol% of site-specifically modified chiral spiro iridium complex (R)-CAT6 in n-PrOH at 25-30 °C in the presence of t-BuOK to deliver the corresponding chiral 2-(arylamino)butane-1,4-diols in up to 97% yields with 88-98% ee as well as 2-(arylamino)pentane-1,5-diols in 85-96% yields with 90-97% ee. This AH reaction could be performed on a gram scale using a lower catalyst loading: hydrogenation of racemic a-(arylamino)-η-butyrolactone was conducted in the presence of 0.05 mol% of (R)-CAT6 (S/C = 2000) producing the useful building block (S)-2-(arylamino)butane-1,4diol in 90% yield with 97% ee allowing access to chiral 3-(arylamino)-1-aza/oxocycloalkane derivatives present in numerous pharmaceuticals.

Imine Derivatives

In 2018, Lefort and co-workers developed an efficient catalytic asymmetric reductive amination under DKR conditions for the preparation of a key intermediate in the total synthesis of tofacitinib, a drug used for the treatment of rheumatoid arthritis. 30 A high-throughput screening showed that the best catalytic system for this transformation was the combination of an iridium complex with (S)-BiPheP [(S)-L12] as a ligand (Scheme 19). The use of acidic conditions for the imine formation and the racemization was found to be essential for the success of this protocol. Zhang, Zhang, and co-workers described the AH of aldimines through DKR catalyzed by the rhodium complex (R)-CAT11 of P-stereogenic diphosphine ligand trichickenfootphos (Scheme 20). 31 When subjected to the optimized reaction conditions using 2 mol% of the Rh complex in i-PrOH/TFE at room temperature for 24 h, a series of enantioenriched arylglycines were prepared in 15-83% yield and up to 87% ee. The proposed mechanism involved a racemization of the substrate via an unstable intermediate in acidic medium. One of the enantiomers is reduced at a faster rate to deliver the main product in the preferred configuration. In 1950, Doering and Young 32 reported the pioneer example of a catalytic ATH highlighting an asymmetric version of the Meerwein-Ponndorf-Verley (MPV) reduction of ketone derivatives catalyzed with rac-aluminum alkoxides using (S)-butan-2-ol as the hydrogen source to produce chiral alcohols with enantioselectivities ranging from 5.9 to 22%. In 1995, Noyori, Ikariya, and co-workers 33 designed novel Ru(II)-arene catalysts combined with N-sulfonylated 1,2-diamines or amino alcohols as chiral ligands which were successfully used in the ATH of ketones and imines and represented a major breakthrough in the field. After this discovery, intense efforts have been devoted to the development of novel efficient catalysts in both academia and industry. Consequently, ATH is now recognized as one of the most effective and practical methods to access enantiomerically pure compounds because of its practicality, broad substrate scope, and high stereoselectivities. Of particular interest is the application of ATH through DKR conditions that offers a challenging route for the enantioselective preparation of enantioenriched alcohols and amines and whose pioneer examples were reported by the groups of Knochel 6 and Noyori and Ikariya. 7 In this section, we will focus our attention on the ATH of carbonyl compounds and imines.

a-Substituted Ketones

Because the mGluR5 receptor has attracted interest for a few therapeutic indications, in 2016 González-Bobes and co-workers reported the enantioselective preparation of a pharmaceutical candidate mGluR5 modulator via the ATH of an a-amino ketone derivative (Scheme 21). 34 The key reactions to access the chiral core of the targeted molecule involved an aza-benzoin condensation and a transfer hydrogenation through a DKR process. The ATH was performed at room temperature in THF using 1.5 mol% of (S,S)-Ts-DENEB [(S,S)-CAT12] with HCO2H/DABCO (3:5) as the hydrogen donor for 24 h to provide the corresponding anti-β-amino alcohol intermediate in 80% yield with >200:1 dr and 98.5% ee. Considering the relatively low catalyst turnovers of the ketoreductases (80% yield, 41 h, 30 °C), this transition-metal-catalyzed process compared favorably with the biocatalytic method. In 2016, Fang and co-workers achieved a practical access to a series of cis-benzoannulated compounds using ATH, via DKR. 35 This novel, mild and general synthetic route allowed access to a novel structural class of significance in medicinal chemistry, including daldinins A, B, and C natural products (10.1%, 7.6%, 6.8% overall yields, respectively). Transfer hydrogenation of the racemic lactone derivative was conducted at 25 °C for 6 In 2017, Fang and co-workers reported the Ru-catalyzed synthesis of cis-2,3-dihydrobenzofuran-3-ols by aqueous transfer hydrogenation via DKR by using complex (R,R)-CAT13, HCO2Na as a hydrogen source, and CTAB as a phasetransfer catalyst in a CH 2 Cl 2 /H 2 O (1:1) mixture at room temperature (Scheme 23). 36 A variety of 2-alkylbenzofuran-3(2H)-ones were thus converted under mild conditions into cis-2-alkyl-2,3-dihydrobenzofuran-3-ols with 97:3 to >99:1 dr and 80 to >99% ee.

In 2016, McErlean and co-workers accomplished the first total synthesis of the natural marine product (+)-panacene in 17% overall yield (Scheme 24). 37 The racemic 3-oxo-2,3-dihydrobenzofuran-2-acetate was subjected to ATH/DKR using (S,S)-CAT13 in DMF in the presence of HCO2H as the hydrogen source and i-Pr2NEt as a base to furnish the desired enantioenriched tricyclic lactone in 78% yield with 73% ee, which could be upgraded to 96% after recrystallization. This spontaneous lactonization enabled efficient generation of the tricyclic core of (+)-panacene.

An efficient synthetic route for the construction of biologically relevant cis-2-(azaheteroaryl)cycloalkan-1-ols based on the DKR of racemic 2-substituted cycloalkan-1ones via ATH was reported by Bhanage and Vyas in 2016. 39 The reaction, performed in dichloromethane at 27 °C, was best catalyzed by a Ru-(R,R)-TsDPEN tethered complex (R,R)-CAT14 as a catalyst in combination with a HCO2H/Et3N (5:2) mixture as the hydrogen source to afford β-(azaheteroaryl)cycloalkanols containing two adjacent stereocenters. The reaction tolerated a broad substrate scope and gave 59-96% yield, up to 99:1 dr, and 25-99.9% ee depending on the substitution pattern on the azaheteroaryl groups as well as the cycloalkanone ring size (Scheme 26). Interestingly, the usefulness of the method was demonstrated through the efficient asymmetric synthesis of an antileishmanial agent and the preparation of a chiral ionic liquid (not shown). In 2018, Bhanage and Vyas reported the efficient Ruprolinamide-catalyzed ATH of 2-(azaheteroaryl)-and 2-(phenylsulfonyl)cycloalkan-1-ones through a DKR process (Scheme 27). 40 The reaction was performed in aqueous medium as a surfactant by using [Ru(p-cymene)Cl2]2 and a prolinamide ligand L13 with bulky ortho-isopropyl substituents in the presence of HCO2Na as a hydrogen source, de-In 2018, Fang and co-workers succeeded in developing a DKR of racemic benzofuran-3(2H)-one derivatives through Ru-promoted ATH (Scheme 25). 38 The optimized conditions established for this reaction employed 0.5 mol% of [RuCl(pcymene)((R,R)-TsDPEN)] [(R,R)-CAT13] as catalyst in MeOH at 65 °C in combination with HCO2Na as the hydrogen source and CTAB as phase-transfer catalyst. Accordingly, and even if the scope of this transformation is rather limited, a number of benzofuran-3(2H)-ones were efficiently reduced to give the corresponding cis-2,3-dihydrobenzofuranols in 31-90% yield with up to >99:1 dr and 85-99% ee. Zhang, Guo, and co-workers devised a synthetic approach that allows an efficient access to valuable chiral carbocyclic nucleosides through Ru-catalyzed ATH relying upon the kinetic conversion of stereolabile 2-(purin-9yl)cyclopentones (Scheme 28). 41 Under the best operating conditions, which used N-(pentafluorophenylsulfonyl)-(R,R)-DPEN and [RuCl2(p-cymene)]2 as the catalytic system [affording complex (R,R)-CAT15] and a 1:1 azeotropic HCO2H/Et3N mixture as the hydrogen donor in dioxane at room temperature, a wide variety of enantioenriched cis-2-(purin-9-yl)cyclopentanols were isolated in 78-97% yield, >20:1 cis/trans dr, and 70-99% ee.

O O CO2H n R R CO2H n O or R 1 O CO2H R 2 R 1 O R 2 O O CO2H R 2 R 1 R 1
Zhang, Guo, and co-workers extended their work to the ATH/DKR of 2-(purin-3-yl)cyclopentanones catalyzed by (R,R)-CAT15 to access a wide range of N 3 -purine nucleosides in 75-96% yield, >20:1 dr and 94-99.9% ee (Scheme 29). 42 Moreover, the catalytic system was suitable for 2-(pyrimidinyl)cyclopentanones, cyclohexanones and cycloheptanones as well. contiguous stereocenters in a single step from racemic 1-or 2-tetralone derivatives through a DKR-ATH/lactonization sequence (Scheme 30). They used oxo-tethered Ru(II) complex (R,R)-CAT12 with HCO2H/Et3N (5:2) as the hydrogen source to perform the asymmetric tandem lactone synthesis which proceeded in 65-95% yield with up to >99:1 dr for the cis products and excellent enantioselectivities (93 to >99% ee). 43 Notably, this approach features an ATH/DKR transformation catalyzed by oxo-tethered Ru(II) complex (R,R)-CAT12 and the subsequent syn-selective lactonization. These efficient methods were successfully used in the enantioselective synthesis of chiral fused lactones including natural wine lactone (not shown).

In a similar fashion, in 2020 Lv and co-workers developed the Ru-catalyzed ATH/DKR of benzo-fused η-keto carboxylic acids that led to spontaneous lactonization (Scheme 31). 44 A series of chiral tricyclic η-lactones were thus prepared in 70-92% yield, >20:1 dr, and 96-99% ee, by using the tethered Ru(II) complex (S,S)-CAT14 with the Touge, Kayaki, and co-workers developed a straightforward and versatile methodology for the asymmetric synthesis of chiral fused η-and δ-lactones containing multiple HCO2H/Et3N (5:2) azeotrope as both the hydrogen donor and the solvent.

Efforts by Mohar and co-workers established DKR/ATH as an efficient process to access valuable trans-β-amido alcohols. They introduced a new enantiomerically pure ansa-RuCl[syn-ULTAM-(CH2)3Ph] (R,S)-CAT17 complex to successfully deliver the targeted products in 94 to >99% ee and 77:23 to >99:1 dr, using HCO2H/Et3N (3:2) mixture at 60 °C in chlorobenzene (Scheme 32). 45 In addition, a reversal of diastereoselectivity trans to cis) was observed by changing the protecting group on the nitrogen atom from acetyl to phthalimide. More interestingly, they showed by DFT calculations that the trans-diastereoselectivity was favored due to the existence of two attractive stabilizations: classical CH/π electrostatic interaction and atypical O=S=O•••H-NAc H-bond.

In 2018, Cheng, Liu, and co-workers described a tandem procedure involving a substitution reaction and subsequent DKR/ATH for the synthesis of enantiopure cis-β-hydroxy sulfones starting from racemic 2-bromoindan-1-ones. 46 Bromide substitution with sodium arylsulfinate led to racemic 2-(arylsulfonyl)indan-1-ones that underwent in situ ATH via DKR using Noyori-type catalyst [RuCl(mesitylene)((S,S)-TsDPEN)] [(S,S)-CAT18] and HCO2Na as a hydrogen source in a mixture of H2O/i-PrOH (1:3) at 60 °C (Scheme 33). Under the best operating conditions, several 2-bromoindan-1-ones or 2-bromo-1-tetralones bearing different groups on the aryl ring were converted into the corresponding β-hydroxy sulfones in 89-97% yield, 92-99% ee, and 91:9-99:1 dr.

(hydroxymethyl)chroman-4-ols under DKR process (Scheme 34). 47 The optimal reaction conditions used 0.5 mol% of TsDPEN-based tethered Rh(III) complex (R,R)-CAT9 as the catalyst and a HCO2H/Et3N (5:2) mixture as the hydrogen source in CH2Cl2 at 30 °C. This ATH/DKR reaction delivered the corresponding 3-(hydroxymethyl)chroman-4ols in 72-92% yield with up to 98:2 dr (cis/trans) and up to >99% ee, irrespective of the nature and position of the substituents on the aryl group.

In 2017, Metz and Quin studied the Ru-catalyzed ATH/DKR of racemic isoflavanones using complex (R,R)-CAT12 and HCO2H/Et3N (3:1) to access enantioenriched isoflavanols with cis diastereoselectivities and enantioselectivities >99% ee. Oxidation of the resulting isoflavanols enabled an efficient synthesis of the cardioprotective isoflavanone (R)-dihydrodaidzein (Scheme 35) and a formal synthesis of the bioactive isoflavan (R)-equol (not shown). 48 In 2019, our group achieved, under mild reaction conditions, the Rh(III)-mediated enantioselective transfer hydrogenation of diversely substituted 3-formyl-4H-chromen-4one derivatives, providing a range of enantioenriched cis-3-Following their report on the therapeutic potential of anti-angiogenic homoisoflavanone derivatives in retinal and choroidal neovascularization models, Seo, Corson, and co-workers described an enantioselective synthesis of cremastranone and its homoisoflavanone derivatives through Ru-catalyzed ATH/DKR of 5,6,7-substituted homoisoflavanones (Scheme 36). 49 The reaction was performed with [RuCl(p-cymene)((R,R)-TsDPEN)] [(R,R)-CAT13] in acetonitrile in the presence of HCO2H as the hydrogen source and DBU as a base. The reaction yielded the corresponding 3benzylchroman-4-ols in 87-96% yield, >20:1 dr, and 93-98% ee.

Chiral 2-substituted quinuclidin-3-ols represent key synthetic intermediates of numerous biologically active compounds. In 2020, Zhang, Wang, and co-workers reported the Ru-catalyzed ATH through DKR for the enantioselective synthesis of cis-2-[(het)arylmethyl]quinuclidin-3-ols (Scheme 37). 50 After an extensive screening of the reaction parameters, the reaction proceeded in the presence of 1 through Ru-catalyzed ATH of a-trifluoroacetyl-substituted benzofused five-to seven-membered cyclic ketones coupled with either one or two consecutive DKR processes. 51 As outlined in Scheme 38, when the reaction was carried out in chlorobenzene at 40 °C using the ansa-Ru(II) complex (S,S)-CAT4 ligated with the enantiopure piperidino-SO 2 DPEN(CH 2 ) 4 (η 6 -Ph) ligand and HCO 2 H/Et 3 N (5:2) azeotropic mixture as the hydrogen source, under DKR, diverse carbinols with two adjacent stereocenters were isolated in 51-92% yield, >99% de, and up to >99.9% ee. Interestingly, when the reaction was performed with the same catalytic system at 60 °C and with a higher catalyst loading with HCO2H/Et3N (3:2), an unprecedented double DKR process occurred, providing various a-CF3-substituted 1,3-diols that bear three contiguous stereocenters with similar results in terms of reactivity and selectivity. mol% of (R,R)-CAT15 with HCO NH as the hydrogen source 2 4 in i-PrOH/CH2Cl2 at 50 °C for 72 h providing the corresponding cis-2-[(het)arylmethyl]quinuclidin-3-ols in 92-99% yield with diastereoselectivities up to >99:1 dr and 95 to >99% ee. The position of the substitution on the aryl ring or the electronic properties of the quinuclidin-3-ones did not have a significant influence on the reactivity and stereoselectivity of the ATH transformation. Compounds having electron-withdrawing substituents displayed relatively lower enantioselectivities compared to those bearing electron-donating groups at the aryl ring. This operationally simple protocol offered an alternative route to cis-2-[(het)arylmethyl]quinuclidin-3-ols and enlarged the scope for the ATH of bicyclic ketones. Moreover, the practicality of this method was confirmed by the gram-scale experiment leading to perfect enantioinduction using a simple recrystallization.

In 2016, Mohar and co-workers published a divergent and efficient stereoselective approach for the preparation of varied carbinols that possess either two of three contiguous stereogenic centers depending on the operating conditions

a-Substituted β-Keto Esters, Amides, and Sulfonamides

In 2018, our group reported an unprecedented Rh-catalyzed ATH of a-benzamido-β-keto esters via DKR to produce the corresponding syn-a-benzamido-β-hydroxy esters, which had not previously been directly attained through ATH (Scheme 39). 52 The reaction proceeded using 0.5 mol% of tethered Rh(III) complex (R,R)-CAT9 in the presence of HCO2H/Et3N (5:2) azeotropic mixture as the hydrogen donor in CH2Cl2 at 0 °C. Compounds bearing substituted aryl groups (R) on the ketone functional group delivered the corresponding reduced syn-products in 63-98% yield irrespective of the electron-donating or electron-withdrawing character of the substituents. Thus, a series of a-benzamido-β-keto esters were efficiently converted under mild conditions into the corresponding syn-a-benzamido-β-hydroxy esters with up to >99:1 dr (syn/anti) and >99% ee for a broad range of substrates with tolerance for a diverse set of functional groups. Furthermore, this method can be scaled to gram-scale. Of note, preliminary ATH experiments were conducted in CH2Cl2 at 30 °C employing tethered and untethered Ru-complexes with HCO2H/Et3N (5:2) as the hydrogen source, producing the corresponding anti-1,2-ami- no alcohols as the major isomers albeit with low enantioselectivities. To our knowledge, this reversal of diastereoselectivity from anti to syn provided by switching from Ru complexes to the use of a Rh catalyst had not previously been observed for the ATH of N-monoprotected a-amino-βketo esters.

In 2017, Wang and co-workers described the ATH/DKR of β-aryl-a-dibenzylamino-β-keto esters using (R,R)-CAT12 to access syn-β-aryl-a-dibenzylamino-β-hydroxy esters in up to 98% yield with >20:1 (syn/anti) dr and 94-99% ee (Scheme 40). 53 This reaction was used in a gram-scale synthesis of droxidopa. In 2019, Zhang, Wang, and co-workers developed an efficient and scalable synthesis of eliglustat, a specific and potent inhibitor of glucosylceramide synthase, via a Ru-catalyzed ATH/DKR approach (Scheme 41). 54 The required two contiguous stereocenters were installed by ATH in the presence of the [RuCl(p-cymene)((R,R)-TfDPEN)] complex [(R,R)-CAT16], generated from (R,R)-TfDPEN and [Ru(p-cymene)Cl ] , and the HCO H/Et N (5:2) azeotrope as the hy-mopsinic acid, (+)-nephrosteranic acid, and (+)-roccellaric acid (not shown) (Scheme 42). 55 Under the optimized reaction conditions, the ATH was realized using (R,R)-or (S,S)-[RuCl(p-cymene)(TsDPEN)] complexes [(R,R)-or (S,S)-CAT13] with HCO2H/Et3N (5:2) in DMF at room temperature for 18 h in yields up to 82% with up to 9:1 dr and up to 97% ee. drogen source. Slow addition of HCO2H was crucial to ensure high conversion and selectivity. The desired syn-product was obtained on a 100-g scale in 90% yield and an excellent >99% ee. Paraconic acid natural products exhibit antimicrobial, antibiotic, and anti-HIV-1 biological properties and represent an important class of compound in medicinal chemistry. In 2019, Appayee and co-workers accomplished the first ATH/DKR of 3-acylsuccinimides and developed a stereodivergent method to successfully access the synthesis of several bioactive paraconic acid derivatives such as (-)methylenolactocin, (+)-nephrosterinic acid, and (+)-protolichestirinic acid, as well as (-)-phaseolinic acid, (-)-nephro-Smith and co-workers reported the development of an effective enantioselective process scale synthesis of the HIV-1 inhibitor BNM-III-170 using an ATH/DKR approach to set the two stereocenters of the molecule. 56 They used [RuCl(p-cymene)((S,S)-TsDPEN)]

[(S,S)-CAT13] and HCO2H/Et3N (5:2) as the catalytic system and managed to produce the desired product in 92% yield and >98% ee Chen, Wu, and co-workers devised an efficient method for the stereoselective synthesis of florfenicol, an antibiotic with broad spectrum of activity which is a 3′-fluorinated derivative of thiamphenicol. 57 The key step of the synthesis relied on ATH via DKR of an a-Boc-amino-β-keto ester using in situ generated Ru catalyst bearing a chloramphenicolbased ligand L14 in the presence of the polysorbate-type nonionic surfactant Tween 20 and HCO2Na as the hydrogen source (Scheme 44). The reaction proceeded smoothly at 25 °C in water to provide the anti-(2S,3S)-a-Boc-amino-β-hydroxy ester in 85% yield, 96:4 dr, and 78% ee; the latter could be improved to 85% ee after one recrystallization from ethyl acetate. The chloramphenicol-based ligand L14 was recovered in 94% yield after addition of 20% citric acid followed by neutralization with saturated NaHCO3 and back extraction with dichloromethane.

In 2019, Touge and co-workers reported a robust and efficient synthesis of ceramide D-erythro-CER[NDS], a drug used for the treatment of skin disease, employing ATH combined with DKR process as a pivotal step (Scheme 45). 58 The reaction was performed on 80.0 kg scale of methyl 2-acetamido-3-oxooctadecanoate using 0.1 mol% of the oxo-tethered Ru(II) complex (R,R)-CAT12 as a catalyst under 9.5 atm N2 at 85 °C in the presence of 2 equiv of HCO2H and 0.3 equiv of Et3N affording 77.4 kg of the corresponding anti-aacetamido-β-hydroxy ester with an excellent yield (96.2%) and 85:15 dr. This optimal process was carried out using vertical 100-L pipes-in-series reactor and a residence time of 6 h. After 3 chemical steps, 58.0 kg of the targeted ceramide were obtained in optically pure form (>99.5:0.5 dr, >99% ee). A sustainable enantioselective route to access syn-β-hydroxy-a-methoxy esters was developed in 2019 by our group. The key step relied on using tethered Rh(III) complex (R,R)-CAT19 to perform ATH through DKR of racemic βketo-a-methoxy esters (Scheme 46). 59 The reaction was carried out in an open flask in 2-MeTHF with an azeotropic mixture of HCO2H/Et3N (5:2) at 30 °C or in water with HCO2Na (5.0 equiv) and CTBA (0.2 equiv) as surfactant at 40 °C. These optimized reaction conditions were applied to the preparation of a wide variety of β-hydroxy-a-methoxy ester derivatives adorned with either electron-donating or electron-withdrawing groups on the aromatic ring in up to 98% yield, syn diastereoselectivity up to >99:1 dr, and up to >99% ee. In 2019, Somfai and Yu reported ATH combined with DKR of η,δ-unsaturated a-amido-β-keto esters, and explored the ability of Ru complexes to perform preferentially a chemoselective 1,2-reduction of the carbonyl function (Scheme 47). 60 The ATH/DKR protocol catalyzed with [Ru-Cl2(mesitylene)]2 combined with (S,S)-DPAE [(S,S)-L15] was performed in dioxane at room temperature using HCO2H/Et3N (1.5:3) as the hydrogen source to access the 48). 61 Under these reaction conditions, the reaction led to the syn-products in 48-75% yield, diastereoselectivities up to >95:5 (syn/anti) dr, and 26-98% ee. This method allowed the scope of the ATH/DKR leading to relevant η-alkyl-β-hydroxy-N-Me-amino acids to be expanded. This strategy was used to access a convergent synthesis of the unusual a-amino-β-hydroxy acid MeBmt. mation and the pH values of the solution showed a crucial role on the reaction rate. Consequently, the ATH was carried out under mild conditions at 25 °C with 10% of Ru catalyst in the presence of HCO2Na/HCO2H buffer (pH 6.0) and Tween 20 for 12 h. This method showed good functional group tolerance toward a range of aryl-and alkyl-substituted a-Boc-amino-β-keto esters, although hetaryl-substituted compounds led to lower diastereoselectivities; 79-92% yield, up to 96% de, and up to 87% ee were achieved. This method was applied to the stereoselective synthesis of a key intermediate for the preparation of the antiobiotic vancomycin.

Our group reported a mild catalytic ATH of a range of aamino-β-aryl-β-keto ester hydrochlorides catalyzed by a Rh(III) complex (R,R)-CAT9 (Scheme 50). 63 The reduction was carried out using HCO2H/Et3N (5:2) as the hydrogen donor source to provide the corresponding anti-a-amino-βaryl-β-hydroxy esters in good yields, up to 97:3 dr, and up to >99% ee. An interesting reversal of the diastereoselection was observed for a-amino-β-hetaryl-β-keto ester hydrochlorides, which under the standard reaction conditions gave the unexpected syn products. This transformation served as an atom-economical and stereoselective method to access anti-and syn-a-amino-β-hydroxy ester derivatives found in natural products and bioactive molecules with a high level of enantioinduction (up to >99% ee).

In 2016, Chen and co-workers described the Ru-catalyzed synthesis of anti-a-Boc-amino-β-hydroxy esters using transfer hydrogenation of racemic a-Boc-amino-β-keto esters via DKR process employing a series of readily available and cost-effective Ru-chloramphenicol L14 complexes as catalysts (Scheme 49). 62 The results demonstrated that the stereochemical outcome of the transformation was affected by the nature of the chiral ligands. Several phasetransfer catalysts (PTC) were investigated for this transfor- In 2018, Lv, Zhang, and co-workers described an efficient ATH/DKR of a-aryl-β-keto sulfonamides by using 2 mol% of the Ru(II) complex (S,S)-CAT14 with HCO2H/Et3N (5:2) as the hydrogen donor in DMF at 60 °C to produce the corresponding a-aryl-β-hydroxy sulfonamides in high yields (90-97%) with up to 20:1 dr and up to 99% ee (Scheme 51). 64 The electronic properties and the position of the substituent groups on the aryl ring had no significant influence on the ATH. When the aryl group was replaced by a polycyclic aromatic or a hetaryl group, such as 2-naphthyl or 2-thienyl, the β-keto sulfonamides were still hydrogenated efficiently. Switching from the piperidino group (X = CH2, n = 1) of the sulfonamide to a pyrrolidino (X = CH2, n = 0), morpholino (X = O, n = 1), or dimethylamino group did not affect the stereochemical course of the transformation. Additionally, this practical operationally simple method accommodated a broad substrate scope and the reduction proceeded smoothly on a gram scale as well at 60 °C in the presence of 0.5 mol% of the Ru complex delivering the asubstituted β-hydroxy sulfonamide core in 95% yield with the same diastereo-and enantioinduction (up to 20:1 dr, 99% ee).

a,β-Disubstituted Cyclic Ketones

Ashley, Sherer, and co-workers disclosed in 2017, an efficient Ru-catalyzed ATH under DKR of substituted chroman-4-ones possessing β-stereolabile centers (Scheme 52). 65 Under strongly basic conditions, a wide range of valuable chroman-4-ols were produced in 71-96% yield with up to >99% ee and up to >50:1 dr using 2 mol% of either (S,S)-CAT12 or [RuCl(mesitylene)((S,S)-TsDPEN)] [(S,S)-CAT18] in combination with HCO2H as a hydrogen source and either Et3N or DBU as a base at 40 °C in acetonitrile. From a mechanistic point of view, this cooperative DKR/ATH transforma-tion occurs via racemization of the stereocenter distal to the activating ketone group through a β-elimination process to deliver the corresponding achiral enone, which could then be converted back into either enantiomer of the starting β-substituted chromanone by conjugate addition.

In 2018, Mohar and co-workers described the synthesis of indanol derivatives using the tethered Ru(II) complex (S,S)-CAT4 via a DKR/ATH process (Scheme 53). 66 This reaction was conducted at 60 °C with a low catalyst loading (S/C = 1000) in the presence of HCO2H/Et3N (3:2) mixture as a hydrogen donor to furnish 2,3-disubstituted indan-1-ols in 42-97% yield, >99:1 dr, and up to 99.9% ee.

β-Substituted Ketones

An enantioselective synthesis of syn-1,3-amino alcohols was reported in 2018 by our group based on Ru-catalyzed ATH of ring-substituted β-amino ketones via DKR. 67 The key feature of this approach relied on epimerization of the βstereocenter by an intermolecular elimination (retro-Mannich)/addition sequence. This transformation was carried out using [RuCl(S,S)-TsDPEN(benzene)] [(S,S)-CAT20] in dichloromethane in the presence of HCO2H/Et3N (5:2) as the hydrogen source at 30 °C (Scheme 54). With these reaction conditions, various syn-1,3-amino alcohols were obtained in 60-85% yield, up to 71:29 dr, and 81-99% ee.

Wang, Liu, and co-workers developed a DKR/ATH methodology for the asymmetric reduction of racemic η-aryl-ηketo malononitriles leading to convenient 2-aryl-3,4-dihydro-2H-pyran-5-carbonitrile intermediates in a one-pot operation (Scheme 55). 68 Under optimized conditions employing [RuCl(mesitylene)(S,S)-TsDPEN] [(S,S)-CAT18] in combination with HCO2Na in i-PrOH/H2O (3:1) at 60 °C, several 2-aryl-3,4-dihydro-2H-pyran-5-carbonitriles were synthesized in 71-99% yield with 90-99% ee and 80:20 to 98:2 dr. A striking feature of this reaction was a complex reaction sequence involving retro-Michael addition, followed by an ATH upon DKR and a subsequent spontaneous diastereoselective cyclization reaction.

catalyst and substrate control and the non-adjacent benzylic center of the ketone substrate to be more acidic than that of the alcohol product. DFT computations allowed prediction of the relative acidities of the intermediates involved in the transformation. These results enabled the development of a sustainable and scalable route toward η-secretase modulator BMS-932481.

Imine Derivatives

Mohar and co-workers showed that the chiral ansa-Ru(II) complex (S,S)-CAT4 was an effective catalyst for the ATH of a-(sulfonylimino) and a-(sulfonylamino) aryl ketones under DKR conditions (Scheme 57). 70 Notably, this protocol was performed at 60 °C in a HCO H/Et N (3:2) bi-

2 3
In 2018, Strotman and co-workers developed efficient asymmetric routes to η-secretase modulator BMS-932481, as a potential candidate for the treatment of Alzheimer's disease (Scheme 56). 69 . The first strategy involved a challenging enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to install the benzylic stereocenter through a combination of high throughput experimentation and process optimization. The second route showed a unique vinylogous dynamic kinetic resolution (VDKR) ketone reduction, with a racemizable stereocenter conjugated with a pyrimidine ring. The ATH was carried out in the presence of 0.5 mol% of [RuCl(mesitylene)((S,S)-TsDPEN)] [(S,S)-CAT18] which was selected for further development, in HCO2H/Et3N (2:1) as the hydrogen source in DMA at 40 °C for 5 h providing the expected (5S,7S)-cis-alcohol in high yield with excellent diastereo-and enantioselectivities. Moreover, the ATH was scaled-up to 400 g with 146:1 dr and 99.4% ee observed for the reduction. After work-up and isolation, the (5S,7S)-cis-alcohol was obtained in 84% yield with >200:1 dr and 99.7% ee. This transformation required nary mixture under a low catalyst loading of S/C = 10000, giving optically active 4-hydroxy-1,2,3,4-tetrahydro-1,2benzothiazine S,S-dioxides with two contiguous stereogenic centers in 97-100% isolated yield with up to >99.9% ee and consistently high levels of cis diastereofacial selectivity.

In 2018, Lee and co-workers reported a convenient and highly stereoselective ATH to access cyclic sulfamidates, cis-4-aryl-5-alkyl-1,2,3-oxathiazolidine S,S-dioxides (Scheme 58). 71 Attempts to increase the stereoselectivity of ATH reactions of 5-alkyl-substituted cyclic sulfamidates showed that stronger bases than Et3N, such as DBU, facilitated rapid racemization of the configurationally labile cyclic imine substrates and led to better stereoselectivities. Consequently, the Rh-catalyzed ATH/DKR was conducted in combination with HCO2H/DBU (1:1) as the hydrogen source employing (S,S)-or (R,R)-[RhClCp*(TsDPEN)] [(S,S)-or (R,R)-CAT21] in acetonitrile within 1 h at room temperature in 90-99% yield, cis diastereoselectivities of >25:1 dr, and 53-99.9% ee. The reduced products are potentially valuable intermediates for the preparation of chiral 1,2-functionalized amines and 1,2-amino alcohols.

Wang and co-workers described the Ru-catalyzed reductive amination of 2-formyl-2′-hydroxybiphenyls with arylamines to access chiral 2-(arylamino)-2′-hydroxybiphenyls under mild conditions and with a wide substrate scope (Scheme 59). 72 The enantiomerically enriched 2-(arylamino)-2′-hydroxybiphenyls were obtained in 60-94% yield by using (S,S)-CAT15 and HCO2H/Et3N (5:2) as the hydrogen donor at room temperature, with 91-99% ee through a DKR process.

Conclusion

Undoubtedly, transition-metal-catalyzed asymmetric reduction reactions (AH and ATH) are still widely used and considered as cornerstone reactions in the toolbox of medicinal and process chemists endowed with a powerful retrosynthetic disconnection strategy. 73 Furthermore, by introducing chirality and resolution processes (such as DKR), it allows the control of several stereocenters starting from racemic substrates. As highlighted in this review, the development of more stereodiscriminant ligands and catalysts as well as the use of continuous chemistry partake to the construction of complex reaction sequences with high stereoselectivities granting rapid access to biological active molecules.

  Key words asymmetric hydrogenation, asymmetric transfer hydrogenation, dynamic kinetic resolution, chiral alcohols, chiral amines, enan-

  , Prof. P. Potier and Dr. R. H. Dodd (Gif, Phannarath Phansavath was born in Vientiane (Laos). She received her Ph.D. from Pierre and Marie Curie University in 1997 under the supervision of Prof. M. Malacria and Dr C. Aubert. After postdoctoral studies in the Tahar Ayad was born in Saint-Etienne (France). He received his Ph.D. degree (2003) from the University of Toulouse under the supervision of Dr. Y. Génisson and Dr. M. Baltas working on total synthesis of imino sugars that exhibit antituberculosis activity. After his Ph.D., he was engaged in a Pierre-Georges Echeverria was born in 1987 in France. He graduated from the engineering school ENSIACET (Toulouse, France) in 2011. He moved to ENSCP Chimie ParisTech to continue his education under the supervision of Dr. Phannarath Ricardo Molina Betancourt was born in 1995 in Guatemala. He graduated from the National Graduate School of Chemistry of Montpellier (ENSCM; Montpellier, France) in 2019. He 1991). She was appointed as a CNRS Associate Researcher with Prof. J. P. Genêt at Ecole Nationale Supérieure de Chimie de Paris. She is currently CNRS Research Director at Chimie Paris-Tech (Paris, France). Her research interests focus on transition-metal catalysis for atomand step-economical reactions group of Prof. C. Bolm at the Institut für Organische Chemie, RWTH Aachen (Germany), she was appointed assistant professor in 1999 in the group of Prof. J.-P. Genêt at Ecole Nationale Supérieure de Chimie de Paris post-doctoral position with Professor Robert S. Coleman at Ohio State University working on total synthesis of oximidin I and II. After a brief period spent in Toulouse University working as an associate professor in R. Chauvin's group in 2005, he joined the group led by Professor J. P. Genêt and Dr. V. Vidal at Phansavath and Dr. Virginie Vidal, earning his Ph.D. in 2014. During this time, his research focused on the total synthesis of mirabalin and the development of different methodologies to control amino alcohol moieties by asymmetric reduction. In moved to ENSCP Chimie Paris-Tech to continue his education as a Ph.D. student under the supervision of Dr. Phannarath Phansavath and Dr. Virginie Vidal focusing on the develop-and the design of atropisomeric ligands (Synphos and Difluorphos) for asymmetric catalysis. The synthesis of biorelevant targets is also a focus in her group. She was Chair of the Division of Organic Chemistry of the French Chemical Society (2009-2012). (ChimieParisTech). Her current research interests include total synthesis of biologically relevant natural products and transitionmetal-catalyzed asymmetric reactions. the Ecole Nationale Supérieure de Paris, Chimie ParisTech. His present research fields include ligands synthesis, transitionmetal-catalyzed asymmetric reactions and, the synthesis of biologically relevant active compounds. 2015 he joined the group of Prof. Alois Fürstner at the Max-Planck-Institut für Kohlenforschung as a postdoctoral fellow working on iron catalysis. He is R&D scientist at Minakem since 2016

  Figure 2

  Scheme 1

  Figure 3

R

  Scheme 10

  Scheme 14

  Scheme 19

  Scheme 16

  Scheme 21

  Scheme 23

  Scheme 26

  Scheme 27

  Scheme 28

  Scheme 31

  Scheme 33 89-97% yield 92-99% R = H, 5-Br, 5-Cl, 6-MeO / 91:9 to 99:1 Ar = Ph, 4-MeC6H4, 4-( -Bu)C6H4, 2,4,6-Me3C6H2, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-F3CC6H4, 2-FC6H4, 2-naphthyl n

  Scheme 38

  Scheme 40

2 (

 2 Scheme 41

  Scheme 45

  Scheme 46

  Scheme 50

  Scheme 51

  Scheme 54

  Scheme 58

  Scheme 59

Acknowledgment

We gratefully acknowledge financial support from our industrial partners.

Funding Information

We thank the CNRS (Centre National de la Recherche Scientifique) and the MENESR (Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche) for financial support. R.M.B. is grateful to the MENESR for a grant (2019-2022).