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Letter

Integrated Heterogeneous Metal/Enzymatic Multiple Relay Catalysis for Eco-friendly and Asymmetric Synthesis Carlos Palo-Nieto, Samson Afewerki, Mattias Anderson, Cheuk-Wai Tai, Per Berglund, and Armando Cordova ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01031 • Publication Date (Web): 16 May 2016 Downloaded from http://pubs.acs.org on May 18, 2016

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ACS Catalysis

Integrated Heterogeneous Metal/Enzymatic Multiple Relay Catalysis for EcoFriendly and Asymmetric Synthesis Carlos Palo-Nieto,1 Samson Afewerki,1 Mattias Anderson,3 Cheuk-Wai Tai,2 Per Berglund3 & Armando Córdova*1,2

1. Mid Sweden University, Department of Natural Sciences, Holmgatan 10, 85170, Sundsvall (Sweden) 2. Berzelii Centre EXSELENT on Porous Materials, Department of Materials and Environmental Chemistry, Stockholm University, 10691 Stockholm (Sweden) 3. KTH Royal Institute of Technology, Division of Industrial Biotechnology, School of Biotechnology, Alba Nova University Center, SE-106 91 Stockholm, Sweden

Correspondence and requests for materials should be addressed to A.C. (email: [email protected]).

Abstract. Organic synthesis is in general performed using stepwise transformations where isolation and purification of key intermediates is often required prior to further reactions. Herein we disclose the concept of integrated heterogeneous metal/enzymatic multiple relay catalysis for eco-friendly and asymmetric synthesis of valuable molecules (e.g. amines and amides) in one-pot using a combination of heterogeneous metal and enzyme catalysts. Here reagents, catalysts and different conditions can be introduced along the one-pot procedure involving multi-step catalytic tandem operations. Several novel

co-catalytic

relay

sequences

(reductive

amination/amidation,

aerobic

oxidation/reductive amination/amidation, reductive amination/kinetic resolution and reductive amination/dynamic kinetic resolution) were developed. They were next applied to the direct synthesis of various biologically and optically active amines or amides in one-pot from simple aldehydes, ketones or alcohols, respectively. Keywords: Heterogeneous metal, enzyme, reductive amination, relay catalysis, heterogeneous catalysis, tandem reactions, kinetic resolution, dynamic kinetic resolution

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One-pot operations such as multi-component, domino, cascade and tandem reactions are of immense significance in Nature and chemical research.1 In fact, the biochemistry of the cell is based on multi-enzymatic relay catalysis (or sequential catalysis) of ingeniously linked transformations in “one-pot”. In chemical synthesis, these transformations, which include important “green chemistry parameters” (e.g. reduction of steps, waste and solvents, etc.) are becoming a new tool for the synthetic chemist.2 However, when catalyzing these cascade or tandem sequences using different types of catalysts (i.e. metal catalyst, organocatalyst or enzyme catalyst) compatibility and inactivation problems can occur. Thus, there is a significant need for the development of new concepts that unify different types of catalysts. Here, homogeneous relay catalysis, which combines the use of organometallic and organocatalysts, was recently disclosed.3,4 A one-pot relay catalytic tandem operation describes a process where substrate 1 (S1) is converted to intermediate 1 (I1) by catalyst system 1 followed by conversion of I1 to the final product (P) by reacting it with another substrate using another catalyst system 2. Here additional substrates and catalyst can be introduced during the reaction pathway. While homogeneous relay catalysis has begun to be exploited as means for accomplishing transformations, which are not possible using the 2


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catalysts individually in one-pot, the reports of multi-catalyst systems for relay catalysis involving heterogeneous catalysts are very few.5-7 The inclusion of heterogeneous catalysis is highly desirable since it would allow for different reactivity not possible using homogeneous organometallic catalysts (e.g reductions and oxidations) and allow for facile removal and recycling of the transition metals.8 It can also be implemented in flow-chemistry processes.9 Recently, a multiple relay catalysis strategy for eco-friendly asymmetric synthesis, which employs a combination of heterogeneous metal and amine catalysts was disclosed.7 In this approach, the heterogeneous metal catalyst takes part in several steps of the catalytic relay sequence and can operate in cooperation with the amine catalyst.7 However, a heterogeneous metal/enzyme multiple relay catalysis strategy applied to asymmetric synthesis has so far not been reported. In this approach, the heterogeneous metal catalysts would also as described vide supra take part in several consecutive reaction steps (Fig. 1), which could be asymmetric and open up for a plethora of enzyme catalyzed10 reactions (e.g. kinetic resolution (kr, Fig. 1b) or dynamic kinetic resolution (dkr, Fig. 1c).11-13

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Figure 1. (a) One-pot combined heterogeneous metal/enzyme relay catalysis strategy. (b) One-pot catalytic kr relay sequence. (c) One-pot catalytic dkr relay sequence. M = Heterogeneous metal. E = Enzyme catalyst. S = substrate, I = Intermediate. P = product.

The proposed heterogeneous metal/enzyme multiple relay catalysis strategy contributes to the significant need for expansion of eco-friendly and asymmetric synthesis from simple feedstock chemicals. It also has the possibility of providing new transformations and allow for synthesis of small molecules from starting materials, which are not accepted as substrates by the enzymatic catalyst.14-16 Here methodology for the assembly of biologically and optically active amines or amides is of immense importance. Thus, we decided to investigate the assembly of these valuable compounds by a heterogeneous metal/enzyme relay catalysis strategy (Figure 1, Scheme. 1). For example, the integration of heterogeneous metal catalysis with heterogeneous enzymatic catalysis could create a novel co-catalytic one-pot reductive amination/direct amidation relay sequence to give amides 3 from aldehydes 1 and HCO2NH4 via amines 2 using acids 4 as acyl donors for the enzyme (Scheme 1). Here a lipase-catalyzed amidation would make the reaction irreversible. Moreover, the catalytic relay sequence may also be further expanded to include an initial catalytic aerobic oxidation reaction of an alcohol 5. In this context, the direct conversion of alcohols to amines 2 and amides 3 is a very difficult task in organic chemistry.17

Scheme 1. One-pot reductive amination/direct amidation relay sequence.

However, key for its success would be the discovery of a highly chemoselective heterogeneous metal-catalyzed reductive amination transformation,18,19 which employs 4


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ammonium formate as both the amine and hydrogen source (Leuckart reaction). Here we present a novel integrated heterogeneous metal/enzymatic multiple relay catalysis strategy for the sustainable and enantioselective tandem synthesis of valuable and biologically active amines and/or amides starting from an aldehyde, ketone or an alcohol, respectively. Combined heterogeneous metal/enzyme relay catalysis strategy. We began to investigate a heterogeneous metal-catalyzed reductive amination transformation. Here the Leuckart reaction is a classical process for the reductive amination of aldehydes or ketones by formamide, ammonium formate, or formic acid with formamide.20 However, it suffers from several drawbacks such as requirement of high temperatures (150-240 °C), which leads to high consumption of energy and increased production costs, the formation of N-formyl derivatives, low chemoselectivity in the synthesis of primary amines and long reaction times. Thus, most of the current reductive amination procedures for the synthesis of primary amines are performed in two steps (e.g. separate imine-type formation and reduction reactions). However, these two-step procedures take as much time as the traditional Leuckart reaction. Therefore, it is evident that there is a compelling need for fast and inexpensive methods for this classical reaction preferably under eco-friendly conditions. Transition metal catalysts such as Rh, Ru and Ir have been used for the synthesis of primary amines under the Leuckart-type conditions.21 However, the use of Pd/C as the catalyst leads to reduction of the carbonyl substrate to the corresponding methylene derivative.22,23 Thus, there are serious chemoselectivity issues to take into consideration when performing a possible Pd-nanoparticle-catalyzed mild direct synthesis of primary amines starting from aldehydes/ketones using ammonium formate as amino donor and hydrogen source (Scheme 2) For example, aldehydes 1 can be reduced either to the desired amines 2, dialkyl amine 2’, alcohols 5 or alkanes 6. Furthermore, the aldehyde substrates can oligomerize and polymerize.

Scheme 2. Chemo-selectivity issues for a Pd-catalyzed reaction between HCO2NH4 and carbonyl compounds. 5


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Despite these drawbacks, palladium is arguably one of the most powerful and versatile transition-metal catalysts, which can be used for a variety of organic transformations and immobilized on various heterogeneous supports.24 This could also lead to efficient recycling with consequent economic and environmental advantages. Heterogeneous palladium catalysts can also be efficiently combined with simple chiral amine cocatalysts without loss of their reactivity.25 Hence, there might be a chance of discovering a highly chemoselective reductive amination using ammonium formate and a heterogeneous palladium catalyst. Next, this novel transformation could be integrated with a heterogeneous/enzyme multiple relay catalysis strategy as described vide supra (Figure 1, Scheme 1). The initial screening studies were performed using vanillin 1a, which can be produced from the renewable resource lignin, as the model substrate, solid HCO2NH4 as the amine donor and reducing agent in the presence of different palladium catalysts (Table 1). Table 1. Condition screening.

6


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Time (h)

Conv(%)[a]

1

HCO2NH4 Temp (°C) (Equiv) Pd(0)-AmP-MCF 3 22

12

90

Ratio (2a:6a:5a)[a] 38:62:0

2

-

3

80

24

99

88:12:0

4

Pd(0)-AmP-MCF

3

80

2.5

>99

94:6:0

5

Pd(0)-AmP-MCF

3

60

7

>99

86:14:0

6

Pd(PPh3)4

3

80

24

95

81:15:4

8

Pd(0)-AmP-CPG

3

80

2.5

>95

79:14:7

9

Pd(OH)2/C

3

80

20

>99

55:45:0

10

Pd/C

3

80

20

>99

34:60:6

11

Pd(OAC)2

3

80

20

>99

39:38:23

12[b]

Pd(0)-AmP-MCF

3

80

12

>99

42:5:53

13[d]

Pd(0)-AmP-MCF

3

80

24

>99

46:54:0

Entry

Catalyst

[a] Determined by 1H-NMR analysis of the crude reaction mixture. [b] The reaction was run with Ms 4Å. [c] 6.6 mol% cat. [d] 1 mol% cat. For example, aldehyde 1a was converted to the desired amine 2a in poor chemoselectivity together with significant amounts of 6a in the presence of palladium(0)-aminopropyl-mesocellular foam (Pd0-AmP-MCF,24a,b 5 mol%) in toluene at room temperature (entry 1). Increasing the temperature significantly accelerated the reaction as well as switched the chemoselectivity towards amine 2a formation (entries 3-5). This was also the case when employing palladium(0)-aminopropyl-controlled pore glass (Pd0-AmP-CPG)25b as the catalyst (entry 7). The use of other commercially available heterogeneous and homogeneous Pd catalysts resulted in low chemoselectivity (entries 9-11). Moreover, the same relay sequence using homogeneous Pd(PPh3)4 as catalyst or performing the reaction in the absence of a palladium source did not deliver amine 2a (only starting material was detected, entries 2 and 6). With these results in 7


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hand, we decided to probe the scope of the catalytic amination of a range of aldehydes using Pd0-Amp-MCF or Pd0-Amp-CPG (6.6 mol%) as the heterogeneous catalysts and HCO2NH4 (3 equiv) at 80 oC in toluene (Table 2). Table 2. Aldehyde 1 substrate scope.

Entry

Pd(0) cat.

R

Time (h)

Prod.

Yield (%)[a]

1

Pd(0)-AmP-MCF

2.5

2a

87

2

Pd(0)-AmP-CPG

2.5

2a

78

3

Pd(0)-AmP-MCF

3

2b

85

4

Pd(0)-AmP-MCF

3

2c

92[b]

5

Pd(0)-AmP-MCF

n-Pent

4

2d

91[b]

6

Pd(0)-AmP-CPG[c]

n-Pent

3.5

2d

87[b]

7

Pd(0)-AmP-MCF

n-Octyl

4

2e

78

8

Pd(0)-AmP-MCF

4

2f

85

9

Pd(0)-AmP-CPG[c]

2f

76

10

Pd(0)-AmP-MCF

3

2g

90

11

Pd(0)-AmP-MCF

3

2h

71[b]

12

Pd(0)-AmP-MCF

3

2i

72

13

Pd(0)-AmP-MCF

3

2j

93[b]

14

Pd(0)-AmP-MCF

3.5

2k

63

15

Pd(0)-AmP-MCF

3

2l

55[d]

Et

CO2Et

[a] Isolated yield of pure 2. [b] 1H-NMR yield using mesitylene as internal standard. [c] 6.6 mol% cat. [d] 1 (0.4 mmol). 8


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The reactions were highly chemoselective and a variety of aldehydes were converted to the corresponding amines 2a-2k and glycine derivative 2l. (55-93 % yield, Table 2). Notably, the transformation was chemospecific towards amine 2-formation when aliphatic aldehydes were used as substrates. The total synthesis of natural products is a highly desirable aim. Here, nonivamide 3a and capsaicin 3b are pungent amides that have been a part of the human diet of the Americas since minimum 7500 BC (chili pepper, Fig. 2).26,27 They activate the TRPV1 receptor and a wide variety of physiological and biological activities induced by them have recently been reported.26-28 According to Eq. 1 they should be possible to assemble via a heterogeneous metal/enzyme

reductive

amination/amidation

or

aerobic

oxidation/reductive

amination/amidation sequence.

Figure 2. Examples of biologically active Capsaicinoids.

Thus, we embarked on development of a one-pot co-catalytic reaction between aldehyde 1a, HCO2NH4 and nonanoic acid 4a using commercially available Candida antarctica lipase B (Novozyme-435, CALB) immobilized on a macroporous resin as the cocatalyst (Scheme 1, See SI). CALB was chosen as the catalyst for its ability to amidate 2a.6 The one-pot co-catalytic relay sequence gave nonivamide 3a in high yield (74%) using a Pd(0)-nanoparticle and enzyme catalyst system. However, no amide 3a was formed if either the enzyme or the Pd catalyst was absent. Thus, the enzyme and the Pdcatalyst operated synergistically during the in situ amidation step. The scope of the cocatalytic one-pot cascade transformation sequence and the total synthesis of capsaicin 3b and “phenylcapsaicin”28 3c were next investigated (Table 3). Table 3. Reductive amination/amidation catalytic relay.

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Prod. 3a

Yield[a] 74

2[b]

3a

74

3[c]

3b

73

4

3c

78

5

3d

62

Entry 1

R

R1

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6

n-Prop

3e

76

7 8

n-Pent n-Pent

3f 3g

40[d] 70

3h

71

9

[a] Isolated yield of pure product 6. [b] Pd0-AmP-CPG (6.6 mol%) as catalyst. [c] Starting acid 4b (Z:E = 85:15). [d] 100% conv. to 2d and 3f (50:50 ratio). The co-catalytic one-pot total syntheses were highly chemoselective and gave the corresponding valuable 3b and 3c after one-step purification in 73 and 78% overall yield, respectively. Moreover, the synergistically heterogeneous Pd and lipase-catalyzed in situ amidation step tolerated aromatic, heterocyclic and aliphatic substituents with respect to the aldehyde component as well as functional acids to give 3a-3d mostly in good to high overall yields (two in situ steps). Here, a clear substrate specificity of CALB with respect towards both the in situ generated amine substrate and the acid substrates was observed. For example, acid 4a was a better donor for the intermediate vanillyl amine 2a as compared to n-hexyl amine 2d (entries 1 and 7). The long-chain alkyne functionalized fatty acid 4b turned out to be a very good donor for the enzyme. Moreover, we observed that the excess ammonia also could serve as a nucleophile for 10


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the enzyme-catalyzed amidation of the acyl donors. Performing the co-catalytic one-pot reductive amination/amidation cascade reaction at a 0.5g scale of 1a provided 3a in good yield (51%, 0.5g). We also designed a co-catalytic aerobic oxidation/reductive amination/amidation sequence starting from an alcohol substrate 5a (Scheme 3). Notably, alcohol 5a was converted to nonivamide 3a in one-pot (49% yield) using a multi-catalyst system.

Scheme 3. Catalytic aerobic oxidation/reductive amination/amidation relay sequence.

Combined heterogeneous metal/enzyme asymmetric relay catalysis. We first had to develop a heterogeneously Pd(0)-nanoparticle catalyzed reductive amination of ketones 1 with HCO2NH4 to give chiral primary amines. The extensive condition screening revealed that the Pd0-Amp-MCF-catalyzed reductive amination of acetophenone 1m gave the corresponding alcohol 5m as the major product in toluene (See SI). To our delight, the chemoselectivity switched to 2m when the transformation was performed in MeOH with a decreased and optimized catalyst loading (Table 4). Thus, the scope of the catalytic reductive amination of ketones 1 was investigated using this condition (Table 4).

Table 4. Ketone 1 substrate scope.

Entry

Ketone

Amine

1

Ratio 2:5[a]

Time (h)

Conv. (%)[a]

88:12

1.5

>99

11


Yield of 3 [b] (%) 74

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2

94:6

3

94

77

3

93:7

4.5

95

78

4

95:5

3.5

96

82

5

89:11

1.5

>99

79

6

97:3

1.5

>99

84

7

99:1

2.5

85

68

8

99:1

3

93

75

[a] Determined by 1HNMR analysis of the crude reaction mixture. [b] Isolated yield of pure racemic 3.

The catalytic transformation exhibited high chemoselectivity and the corresponding racemic amides 3 were isolated in high yields after in situ amidation of amines 2. We could now begin to test the heterogeneous metal/enzyme asymmetric relay catalysis strategy. The heterogeneous metal/enzyme co-catalyzed reductive amination/kr relay sequence was first investigated (Fig. 1b and Scheme 4).

Scheme 4. Heterogeneous metal/enzyme co-catalyzed reductive amination/kr relay sequence.

12


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Here ester 7 was employed as the acyl donor since it has been previously been shown to improve the rate of the irreversible acylation of amines by hydrogen bond-activation in the active site of CALB.29 The use of Pd-nanoparticles in combination with CALB as co-catalysts for the dkr of secondary amines has recently been reported.12 Thus, if the metal catalyst could take active part in the racemization of the intermediate amine 2 during the lipase-catalyzed amidation step a dkr would occur and the yield would be > 50%. If not, the yield would be lower (kr). The catalytic relay sequence was performed in one-pot converting ketones 1m and 1n to the corresponding amides (R)-3m and (R)3n in 36% and 25% overall isolated yield with 97 and 92% ee, respectively. While >76% of the ketone 1m was converted to 2m, it was next converted in around 50% to amide (R)-3m by the co-catalytic amidation. Thus, the final transformation of the catalytic relay sequence had performed according to a kinetic resolution step. Formic acid is an inhibitor of CALB, however, the Pd0-Amp-MCF-catalyzed the conversion of the excess formic acid to H2, CO2 and H2O as described vide supra so that catalytic amidation could occur. We next turned our focus on developing a heterogeneous metal/enzyme co-catalyzed reductive amination/dkr relay sequence (Fig. 1c and Scheme 5).

It is known from the literature that the addition of H2 gas can promote the

racemization of amines 2 during a dynamic kinetic resolution step.12b,c We therefore increased the Pd catalyst loading as well as added H2 after the catalytic reductive amination to 2 had been completed (Scheme 5). The co-catalytic reaction sequences assembled the corresponding amides (R)-3 in good overall yields with high ee’s from ketones 1.

Scheme 5. Heterogeneous metal/enzyme co-catalyzed reductive amination/dkr relay sequence. (a) Isolated overall yield from 1. (b) Na2CO3 instead of Mol Sieve (4Å).

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We also investigated a heterogeneous metal/enzyme co-catalyzed reductive amination/kinetic resolution relay sequence using a combination of Pd0-Amp-MCF and transaminase (ATA, EC 2.6.1.18)30 as catalysts (Scheme 6). ATA enzymes were chosen since they have been shown to be very important catalysts for industrial production of biologically active amines.30b,c The one-pot catalytic relay sequence was successful and the corresponding amines (S)-2 or (R)-2 were assembled from ketones 1 and ammonium formate with high ees, respectively. The (R)-enantiomer of amine 2m was obtained with an enantiomeric excess of 87% using ATA113 or 85% using Cv-ATA, respectively. No conversion of the (R)-enantiomer was detected in these reactions, but the (S)-enantiomer was not fully converted thus resulting in lower ee values as compared to the excellent ones (>99%) obtained using ATA117.

Scheme 6. Heterogeneous metal/enzyme co-catalyzed reductive amination/kinetic resolution relay sequence. (a) Yield based on reacted ketone based on chiral-phase HPLC analysis.

Recycling. The recycling and life-time of heterogeneous catalysts are significant issues for practical applications. Thus, we investigated the possibility of recycling both the Pd0-Amp-MCF and Pd0-Amp-CPG after the reductive amination reactions of 1d and 14


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ketone 1m, respectively (see SI). Both catalysts displayed excellent recyclability and chemoselectivity and no leaching was observed. To determine the Pd species in our catalytic reductive amination system a hot filtration tests was performed. Thus, the Pd0AmP-MCF catalyst was filtered off after 20% conversion to 2a and the solid free filtrate was allowed to stir for 3 h under identical reaction conditions. Analysis of the catalyst free reaction by NMR analysis determined that no further conversion of the substrate had occurred. Based on our experiments and the literature, the Pd catalyst is proposed to accelerate: (1) The transfer hydrogenation of the in situ generated imine intermediates, which are derived by condensation between 1 and HCO2NH4, to form 2. Here the presence of iminium intermediates prior to formation of 2 was confirmed by HRMS analysis of the reactions. (2) The decomposition of formate/formic acid to H2, H2O and CO2. These catalytic processes allowed for the significant lower temperature and faster rates than normally required for the Leuckart reactions. Notably, the latter process is essential for the synergistically catalyzed one-pot transformation, since remaining HCO2NH4 after the in situ formation of the amine 2 intermediate inhibited the catalytic activity of CALB. In summary, we have designed a novel concept for eco-friendly and asymmetric synthesis based on highly chemo- and enantioselective heterogeneous metal/enzyme relay catalysis. Here catalytic relay sequences were designed for the chemo- and enantioselective synthesis of amines and amides in one-pot using heterogeneous multicatalyst systems. We began our investigation by the development of a mild and efficient Pd-catalyzed direct synthesis of primary amines from aldehydes or ketones using HCO2NH4 as amine source and reducing agent. The catalytic reaction was highly chemoselective towards amine-formation and represents a heterogeneous, recyclable and environmentally benign protocol for the simple one-step synthesis of a wide variety of primary amines and glycine esters in high to excellent yields. Integration with enzyme catalysis allowed for direct one-pot amide formation and one-step total syntheses of biologically active capsaicinoids starting from an aldehyde or alcohol substrate. The heterogeneous metal/enzyme catalysis strategy was also applied to the direct on-pot asymmetric synthesis of amines and amides (up to >99% ee) when using ketones as substrates. In all of the investigated catalytic relay sequences, the 15


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heterogeneous metal and enzyme operated in synergy during the in situ amidations and the corresponding amides were mostly isolated in good to high overall yields. Future application of heterogeneous metal-catalyzed reductive aminations, mechanistic and medicinal studies as well as development of co-catalytic multi-component reactions are ongoing and will be disclosed in due course. Experimental methods Catalytic reductive amination of aldehydes. A microwave-vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 0.6 mmol, 3.0 equiv.) and Pd0-nanocatalyst (Pd0-AmPMFC, 13.4 mg, 0.01 mmol, 8 wt%, 5 mol%) or (Pd0-AmP-CPG, 569Å, 74.0 mg, 2 wt%, 6.6 mol%) in toluene (1 mL) was stirred at 80 oC under N2 atmosphere for the time shown in Table 2. Next, the crude reaction mixture was filtrated through Celite using CHCl3 (10 mL) as eluent, concentrated and the crude amide 3 was purified by silica gel flash column chromatography. Reductive amination/amidation catalytic relay. A microwave-vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 0.6 mmol, 3.0 equiv.) and Pd0-nanocatalyst (Pd0AmP-MFC, 13.4 mg, 0.01 mmol, 8 wt%, 5 mol%) or (Pd0-AmP-CPG, 569Å, 74.0 mg, 2 wt%, 6.6 mol%) in toluene (1 mL) was stirred at 80 oC under N2 atmosphere for the time shown in Table 2. Next, molecular sieves 4Å, acid 5 (0.2 mmol, 1.0 equiv.) and Novozyme-435 immobilized on a macroporous anionic resin (120 mg/mmol) were added. After 36 h of stirring at at 80 oC, the crude reaction mixture was filtrated through Celite using CHCl3 (10 mL) as eluent, concentrated and the crude amide 3 was purified by silica gel flash column chromatography. Aerobic oxidation/reductive amination/amidation catalytic realy: To a microwave-vial containing a solution of alcohol 5a (0.2 mmol, 1.0 equiv.) and Pd0-AmP-CPG (10.1 mg, 0.002 mmol, 1 mol %) in dry toluene(0.25 mL) was connected a O2 balloon. After stirring the reaction mixture for 16h at 80 oC, HCO2NH4 (37.8 mg, 0.6 mmol, 3.0 equiv.), Pd0-AmP-MFC (10.8 mg, 0.008 mmol, 8 wt%, 4 mol%) and toluene (0.75 mL) were added under N2 conditions and the reaction mixture was stirred at 80 oC for 2.5 h. Next, molecular sieves 4Å, acid 4a (0.2 mmol, 1.0 equiv.) and lipase (120 mg/mmol) were added to the reaction mixture, which was stirred at 80 oC for 40h. The crude reaction mixture was filtrated through Celite using CHCl3 (10 mL) as eluent and next concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography. Catalytic reductive amination of ketones. A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd0-nanocatalyst (Pd0-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wt%, 1 mol%) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70 oC 16


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for the time shown in table 4. Next, the solvent was evaporated and a solution of DIPEA (0.052 mL, 0.3 mmol, 1.5 equiv.) in dry dichloromethane (2.0 mL) followed by the addition of methoxy acetylchloride (0.4 mL, 0.51 mmol/mL, 1 equiv.) were added to the vial, which was flushed with Ar. After stirring overnight at room temperature, reaction mixture was filtered through Celite with CH2Cl2 (2.5 mL) and the solvent was removed under reduced pressure. The racemic α-methoxy-acetamides 3 were next isolated by silica gel flash column chromatography. Reductive amination/kr catalytic relay. A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd0-nanocatalyst (Pd0-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wt%, 1 mol%) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70 oC for the time shown in table 4. Next, the solvent was evaporated and Pd0- Pd0-AmP-MFC (5.4 mg, 0.008 mmol, 8 wt%, 2 mol%), Novozyme-435 (50 mg/mmol) and Mol. sieves (4 Å, 100 mg) were added to the vial with amine product. The vial was evacuated three times and refilled with H2. Dry toluene (0.6 mL) was added to the vial and the mixture was heated 70 oC followed by addition of ethyl methoxyacetate (47 µL, 0.4 mmol) and stirred for 6h. Next, the crude reaction mixture was filtrated through Celite using CHCl3 (10 mL) as eluent and evaporated. The crude material was purified by silica gel flash column chromatography.

Reductive amination/dkr catalytic relay. A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd0-nanocatalyst (Pd0-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wt%, 1 mol%) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70 oC for the time shown in table 4. Next, the solvent was evaporated and Pd0-Nanocatalyst (Pd0AmP-MFC, 10.72 mg, 0.008 mmol, 8 wt%, 4 mol%), Novozyme-435 (50 mg/mmol) and additive (mol. siev. 4 Å (100 mg) or dry Na2CO3 (20 mg)] were added to the vial with amine product. The vial was evacuated three times and refilled with H2. Dry toluene (0.6 mL) was added to the vial, and a balloon containing H2 was connected to the vial. The mixture was heated 70 oC followed by addition of ethyl methoxyacetate (47 µL, 0.4 mmol) and stirred for the time shown in the Scheme 5. Next, the crude reaction mixture was filtrated through Celite using CHCl3 (10 mL) as eluent and evaporated. The crude material was purified by silica gel flash column chromatography.

Reductive amination/kr catalytic relay. A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd0-nanocatalyst (Pd0-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wt%, 1 mol%) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70 oC for the time shown in table 4. Next, the vial was put on ice and methanol (0.367 mL) was added, followed by 6 mL of an aqueous buffer solution (50 mM HEPES, pH 8.2) containing amine 17


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transaminase (ATA) and 2-5 equivalents sodium pyruvate (1 equiv. = 0.2 mmol, 22 mg). The tubes were put in darkness and room temperature for 24 hours with gentle mixing on an orbital shaker. Enantiomeric excess (ee) was determined by HPLC analysis (triplicate samples).

Supporting Information Available: Full experimental procedures, data and spectra. This material is available free of charge via the Internet at http://pubs.acs.org. Acknowledgements. Dedicated to Prof. Karl Hult on the occasion of his 70th birthday. We gratefully acknowledge financial support from the European Union and Mid Sweden University. The Knut and Alice Wallenberg Foundation is acknowledged for an equipment grant for the electron microscopy facilities at Stockholm University. KTH Royal Institute of Technology is acknowledged for the award of a PhD student excellence position to M. A.

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Scheme1 52x17mm (300 x 300 DPI)


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scheme2 39x10mm (300 x 300 DPI)


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scheme5 68x20mm (300 x 300 DPI)


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Table1 165x165mm (300 x 300 DPI)


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Table2 166x199mm (300 x 300 DPI)


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Table3 212x288mm (300 x 300 DPI)


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Table4 240x324mm (300 x 300 DPI)


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Figure1 188x204mm (300 x 300 DPI)


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TOC 194x210mm (300 x 300 DPI)


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