Multicatalysis protocol enables direct and versatile enantioselective reductive transformations of secondary amides

The catalytic asymmetric geminal bis-nucleophilic addition to nonreactive functional groups is a type of highly desirable yet challenging transformation in organic chemistry. Here, we report the first catalytic asymmetric reductive/deoxygenative alkynylation of secondary amides. The method is based on a multicatalysis strategy that merges iridium/copper relay catalysis with organocatalysis. A further combination with the palladium-catalyzed alkyne hydrogenation allows the one-pot enantioselective reductive alkylation of secondary amides. This versatile protocol allows the efficient synthesis of four types of α-branched chiral amines, which are prevalent structural motifs of active pharmaceutical ingredients. The protocol also features excellent enantioselectivity, chemoselectivity, and functional group tolerance to be compatible with more reactive functional groups such as ketone and aldehyde. The synthetic utility of the method was further demonstrated by the late-stage functionalization of two drug derivatives and the concise, first catalytic asymmetric approach to the κ-opioid antagonist aticaprant.


INTRODUCTION
Despite the substantial advance made over the past decades on the catalytic asymmetric reactions, the catalytic enantioselective reductive functionalization of nonreactive functional groups at a high oxidation state such as amides and nitriles remains highly challenging (Fig. 1A). The challenge originates not only from the low reactivity of those functional groups but also from the need to undertake a geminal bis-addition of two different nucleophiles onto the same carbon in a highly enantioselective manner [>90% enantiomeric excess (ee)] and in one pot. For the functionalization of nitriles, Hoveyda and colleagues reported in 2019 an elegant catalytic enantioselective reductive allylation methodology to yield chiral ,-disubstituted homoallylic primary amines (cf. Fig. 1A) (1).

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namely, nitrogen heterocycles, which are also active pharmaceutical ingredients (APIs) (Fig. 1D). The importance of the latter is highlighted by the fact that in U.S. Food and Drug Administrationapproved drugs, 59% of unique small-molecule drugs contain a nitrogen heterocycle (56).
On the basis of abovementioned considerations, we decided to explore a catalytic, enantioselective reductive alkynylation of secondary amides. However, such transformations present several challenges: (i) After the planned Ir-catalyzed hydrosilation of a secondary amide, the presumed imine intermediate is much less reactive than the iminium

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ion (i in Fig. 1B) generated from a tertiary amide; (ii) the compatibility of all the reagents used in a one-pot environment to realize the fully catalytic and highly chemo-and enantioselective reaction; and (iii) high versatility and functional group tolerance are needed to cover both aromatic (benzamidetype) and aliphatic amides and diverse functionalized terminal alkynes.

Development of an enantioselective reductive alkynylation of secondary amides
To tackle the abovementioned multiple challenges, a multicatalysis (57)(58)(59)(60) approach was envisioned. The multicatalysis is an emerging strategy for developing unprecedented and challenging transformations that could not be achieved by a single catalytic system. Here, we disclose the results of this investigation, which include the first direct asymmetric transformation of secondary amides into -chiral secondary propargylamines or chiral -branched secondary amines. The methodology relies on the catalysis in trio or in quartet, namely, by merging Ir/Cu relay catalysis with Cu/N-protected l-proline cooperative catalysis, or further with sequential Pd-catalyzed hydrogenation of the chiral propargylamines (Fig. 1C). In view of the frequent occurrence of N-naphthylmethyl and Nbenzyl secondary amine motifs in medicinal agents (cf. Fig. 1D), we opted for the reductive alkynylation of N-(naphthalen-1-ylmethyl)benzamide (1a) with phenylacetylene (2a) as the model reaction. Jacobsen's chiral thiourea C1 and chiral phosphoric acid C2 were first evaluated as organocatalysts (42,57) in our multicatalysis strategy (Table 1). Disappointedly, the desired propargylamine 3a was not observed, only the imine intermediate was obtained in 84 and 76% yield, respectively ( Table 1, entries 1 and 2). Encouragingly, when N-Ac-l-proline (A1) was used both as a chiral catalyst and as an imine activator, the desired deoxygenative alkynylation reaction occurred to give the -chiral propargylamine 3a in 47% yield with 63% ee (Table 1, entry 3).
Notably, when P(1-naphthyl) 3 was introduced as an additive, an excellent ee of 91% and a good yield of 52% were obtained ( Table 1, entry 4). A survey of the effect of other N-protected l-proline derivatives A2 to A6 showed that all were effective affording 3a in good to excellent ee's (76 to 93%). However, eight other P additives (cf. P2 to P4 and table S3 in the Supplementary Materials) turned out to be less effective for the reaction. Further examining the effect of copper catalyst showed that many copper salts such as CuOTf, (CuOTf) 2 ⋅toluene, Cu(OTf) 2 , and Cu(MeCN) 4 PF 6 were equally effective for the reaction, affording propargylamine 3a in excellent ee's (92 to 93%) and good yields (70 to 78%). Unexpectedly, CuBr, which is the catalyst of choice for the deoxygenative alkynylation of tert amides (38), was totally ineffective for the current reaction. The striking difference between CuBr and CuOTf in the asymmetric induction may be explained by the acidity of corresponding acid (HBr versus TfOH) generated from an alkyne and CuBr/CuOTf. TfOH (pK a = −15) is a much stronger acid than HBr (pK a = −9) and forms a strong H-bond with the carbonyl of N-Boc-l-proline (A4). This hydrogen bonding enhances the imine N⋅⋅⋅H hydrogen bonding in the intermediate vii, thus enhancing the asymmetric induction (Fig. 8A). Assessment of other reaction parameters including the amounts of reagents and additive, catalyst loadings as well as reaction temperature and time allowed defining the optimal reaction conditions ( Table 1, entry 14). Several N-protected proline derivatives (entries 4 and 7 to 9) and copper salts (entries 13 to 16) are promising and efficient in catalyzing the enantioselective reaction. These results showed that the reaction is robust. Because (CuOTf) 2 ⋅ toluene is cheaper than the other copper salts and a stable solid, it was used for the subsequent investigations.

Scope of the reaction and chemoselectivity
With the optimal reaction conditions in hands, we turned our attention to examine the reaction scope of this catalytic enantioselective reductive alkynylation reaction. The scope with respect to the amide was first examined. As shown in Fig. 2, the reaction proceeded with simple aryl amides such as p-tolyl (1a-2) and m-tolyl (1a-3) and was compatible with benzamides bearing either strong electron-donating (1a-4 to 1a-6) (the structures of all amides used are listed in table S1) or electron-withdrawing groups (1a-7 and 1a-8) at the para-or metaposition of the phenyl ring providing the corresponding pro pargylamines 3b to 3h in good to excellent yields (68 to 95%) and with high enantioselectivities (90 to 95% ee). Heteroaromatic amides were also viable substrates providing the corresponding -chiral propargylamines (3i and 3j) in 68 and 64% yields and with high enantioselectivity (93% ee). The reaction of 2-methylbenzamide also proceeded smoothly to give the desired propargylamine (3k) in excellent enantioselectivity (80% yield, 95% ee). In view of the importance of trifluoromethyl, fluoro, and heteroaromatic groups in biological and medicinal chemistry as well as in the agrochemical field, the smooth enantioselective synthesis of amines 3g to 3j is of value. The enantioselective reductive alkynylation reaction showed remarkable chemoselectivity and functional group tolerance. For example, the amide substrates containing an ester moiety (1a-13 and 1a-14) or a keto group (1a-15) took place chemo selectively at the less electrophilic amide group, leaving the more reactive ester and ketone groups intact. The CuOTf, Cu(OTf) 2 , and Cu(MeCN) 4 PF 6 catalyzed syntheses of 3a, 3b, 3d, and 3g showed that they are also effective catalysts for the alkynylation.
The catalytic reductive alkynylation of aliphatic amides in high enantioselectivity presents a formidable challenge because of the absence of a rigid aromatic ring that appears to be a valuable control element for the enantioselective addition. Moreover, for -hydrogencontaining amides, the situation may be further complicated by the possible isomerization of the imine intermediates to unreactive enamines. The reported enantioselective reductive alkynylation of tertiary amides is only compatible with benzamide derivatives (43).
To our delight, the current catalytic enantioselective reaction tolerated both ,-unsaturated amide 1a-12 and aliphatic amides. For 1a-12, alkenyl propargylamine 3l was obtained in 74% yield with 96% ee (Fig. 2). For aliphatic amides, not only hindered pivalamide 1a-16 and adamantane-1-carboxamide 1a-17 but also less hindered -hydrogencontaining secondary amides 1a-18 to 1a-22 reacted to afford the desired secondary propargylamines 3p to 3v in good yields (62 to 76%) and excellent enantioselectivities (89 to 99% ee)  Fig. 2). To the best of our knowledge, the synthesis of 3r to 3v represents the first examples of catalytic asymmetric synthesis of hydrogencontaining secondary propargylamines in high enantioselectivity. Note that for the syntheses of 3i and 3r to 3t, the reaction time of the Ir-catalyzed hydrosilylation was shortened to 0.5 hours to avoid over reduction.

Scope of alkynes and functional group tolerance of the reaction
The alkyne coupling partner also tolerated variation. The reactions were compatible with phenylacetylene derivatives bearing substituents at the para- (2b, 2e, and 2i), meta-(2c, 2f), and ortho-position (2d and 2g) of the benzene ring and 2-ethynylthiophene (2h) (Fig. 3) (the structures of all alkynes used are listed in table S2). Notably, phenylacetylene derivatives that contain on the benzene ring a chloro (2j), trifluoromethyl (2k), ester (2l), or even an aldehyde (2m) group all reacted successfully to give the desired products 3ae to 3ah in good yields and excellent enantioselectivities. Last, alkylacetylenes (2n and 2o) were proven to be viable substrates.

Extension to N-benzylamides
Besides N-(naphthalen-1-ylmethyl)amides, N-benzylamides were also suitable substrates for the catalytic enantioselective reductive alkynylation reaction to afford the corresponding chiral propargylamines (3ak to 3as) in 63 to 88% yields and 90 to 92% ee (Fig. 4). The absolute configuration of the propargylamines was determined as R by comparing the specific optical rotation data of amine 3aq with that reported in (51). afforded 2.359 g of 3a (68% yield) without losing enantio selec tivity (93% ee) (Fig. 5A). The absolute configuration of propargyl amine 3a, a representative of the series of N-(naphthalen-1-ylmethyl)propargylamines, was determined as R by comparing the specific optical rotation data of its hydrogenation product (S)-4 ( Fig. 5B) with that reported for its enantiomer (see the Supplementary Materials). To showcase the versatility of propargylamines in organic synthesis, derivatization of 3a was performed. Thus, 3a was partially hydrogenated with Lindlar's catalyst to allylic amine (S)-5 in 84% yield and 93% ee (Fig. 5C). By using functionalized alkyne 2t, the resulting propargylamine 3av was synthesized in excellent ee (96%) (Fig. 5D), which was further converted, in one pot, into 2-substituted piperidine (S)-6 in 94% ee, demonstrating the value of current method for the asymmetric synthesis of chiral, cyclic tertiary amines in high enantiomeric excess. Note that motifs such as -substituted tertiary amine (S)-6 are inaccessible by the method previously developed for tertiary benzamides (43), and the present synthesis is among the most efficient methods for its asymmetric synthesis in high enantiopurity (52).

Synthetic applications of the reaction
To further demonstrate the synthetic utility of the method, the late-stage deoxygenative alkynylations of amide derivatives (1a-23 and 1a-24) of two drugs SR11237 and adapalene were undertaken. Under the standard conditions, the catalytic asymmetric alkynylation reactions proceeded without incident to yield the desired propargylamines 3at and 3au in 78 and 73% yield and in 90 and 94% ee, respectively (Fig. 6). Next, we addressed the catalytic asymmetric synthesis of aticaprant (S)-8 (formerly known as LY-2456302 and CERC-501), a high-affinity and selective -opioid receptor antagonist (61,62). Under standard conditions, the catalytic asymmetric reductive alkynylation of functionalized amide 1a-25 with 3,3-diethoxyprop-1-yne (2u) produced the desired propargylamine 3aw in 63% yield and in 88% ee. Pd/C-catalyzed catalytic hydrogenation, hydrogenolysis, and reductive alkylation under acidic conditions proceeded in tandem to afford 2-arylpyrrolidine (S)-7 in 84% yield. Because racemic 7 has previously been converted into aticaprant (S)-8 by a two-step protocol followed by resolution (61,62), this work constitutes the first formal catalytic asymmetric total synthesis of aticaprant (S)-8.

Catalytic enantioselective reductive alkylation of secondary amides
Considering that the catalytic asymmetric alkylation of amides remains unknown, we investigated the catalytic alkynylation, followed by complete reduction in one pot. Thus, after the catalytic alkynylation under standard conditions, the resulting reaction mixture was subjected to Pd/C-catalyzed hydrogenation under H 2 (1 atm). In this manner, -substituted chiral amines 9a to 9f were obtained in good yields and excellent enantioselectivity (Fig. 7). Notably, more reactive functional groups such as ester, ketone, and aldehyde on the amide or alkyne coupling partner were tolerated.

Plausible mechanism of the reaction
Plausible mechanisms for the multicatalysis-based asymmetric reductive alkynylation/alkylation of secondary amides are outlined in To confirm the dual roles of N-Boc-l-proline (A4), we carried out the reductive alkynylation reactions of secondary amide 1a-1 with N-Boc-l-proline methyl ester or l-proline instead of N-Boc-l-proline (A4) (Fig. 8B-1). In the first case, the expected propargylamine 3a was obtained in only 18% yield in racemic form along with imine ii-a in 63% yield (Fig. 8B-1). In the second case, only imine ii-a was obtained in 86% yield (Fig. 8B-2a). To increase the solubility of proline, in the alkynation step, a 20% (v/v) of dimethyl sulfoxide was added as a cosolvent. However, only imine was formed in 69% yield (Fig. 8B-2b). These control experiments showed that neither Boc-l-proline methyl ester nor l-proline (being a zwitterion in the reaction medium) can promote the alkynylation or provide any asymmetric induction even when the alkynylation occurs as a side reaction, likely because none of them can activate imine ii through H-bonding. An additional evidence for the H-bond asymmetric catalysis was provided by the catalytic reductive alkynylation of o-methoxybenzamide 1a-26, a substrate bearing an additional H-bond acceptor (OMe) at the ortho-position of the phenyl group (Fig. 8B-3). This amide reacted with moderate stereoselectivity (65% ee) reflecting the competing H-bonding effect of the appropriately positioned OMe (Fig. 8B-3).

DISCUSSION
By designing a multicatalysis system, we have achieved the direct asymmetric reductive alkynylation and reductive alkylation of secondary amides to yield chiral -branched secondary propargylamines and -branched secondary amines, respectively. The method is characterized by mild reaction conditions, wide scope for both amides and alkynes, good yields, and high enantioselectivities. Another notable feature of our method is the exceptional chemoselectivity and functional group tolerance to allow the reactions to take place preferentially at the less reactive amide group over the more reactive ester, ketone, and aldehyde moieties. The observed unusual chemoselectivity can be understood from two aspects. First, the multicatalysis protocol avoids the direct nucleophilic addition to amides, instead, it involves an Ir-catalyzed O-silylation of the amide carbonyl (partial reduction) as the first step of the reaction sequence. Second, due to the delocalization of the nitrogen lone pair of an amide, the oxygen of the amide C═O is more electron rich as compared with those of aldehyde, ketone, and ester and thus is more reactive vis-à-vis electrophilic silyl species (34). Consequently, the amide carbonyl can be chemoselectively hydrosilylated, leading to the chemoselective asymmetric alkynylation reaction. The products can be elaborated in one step into two other types of -branched amines: chiral primary amines and chiral tertiary aza-heterocycles. This method is expected to find applications in the total synthesis of alkaloids and N-containing medicinal agents, and the multicatalysis strategy will be useful for the catalytic asymmetric transformations of other carboxylic acid derivatives.

General procedure B (catalytic asymmetric reductive alkylation of secondary amides)
In a glove box, to a stirring solution of a secondary amide (0.25 mmol, 1.0 equiv) and [IrCl(COE) 2 ] 2 (0.75 mol, 0.3 mol %) in anhydrous CH 2 Cl 2 (1.25 ml, 0.25 M) was added EtSiH 2 (0.5 mmol, 2.0 equiv, 65 l) at room temperature under an Ar atmosphere. After being stirred for 1.5 hours, the resulting mixture was transferred out of the glove box and added to a mixture of N-Boc-l-proline (0.075 mmol, 30 mol %), (CuOTf) 2 ·toluene (0.0125 mmol, 5 mol %), and P(1-naphthyl) 3 (0.025 mmol, 10 mol %) and stirred for 30 min at 0 °C. To the resultant mixture, an alkyne (1.0 mmol, 4 equiv) was added, and the reaction mixture was stirred at 0 °C for 2 days. Then, CH 2 Cl 2 was removed, and Pd/C (10 weight %) and MeOH (2 ml) were added. The mixture was stirred under a H 2 atmosphere at room temperature until the propargylamine intermediate was completely consumed. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel to give the desired enantioenriched chiral -branched amine 7.