& Catalysis

Expedient Synthesis of Chiral a-Amino Acids through Nickel-Catalyzed Reductive Cross-Coupling

Xi Lu,[a, b, c] Jun Yi,[a] Zhen-Qi Zhang,[a] Jian-Jun Dai,[a] Jing-Hui Liu,[a] Bin Xiao,*[a] Yao Fu,[a] andLei Liu*[a, b, c]

Abstract: A novel method for the synthesis of non-naturall- and d-amino acids by a Ni-catalyzed reductive cross-coupling reaction is described. This strategy enables theracemization-free cross-coupling of serine/homoserine-derived iodides with aryl/acyl/alkyl halides. It providesconvenient access to varieties of enantiopure and func-tionalized amino acids, which are important buildingblocks in bioactive compounds and pharmaceuticals.

As important building blocks for bioactive molecules, chirala-amino acids are extensively used in many fields, such asdrug discovery and protein engineering.[1, 2] In these areas, anoften-encountered problem is that the needed amino acid (es-pecially when it is structurally unprecedented) is not readily ac-cessible, so that chemical synthesis has to be carried out to ac-quire it in enantiopure form.[3] Although many methods havebeen developed for this purpose with different strategies ofasymmetric synthesis[4–10] or chiral resolution,[11] most of themrequire multiple steps and therefore, are labor intensive andtime consuming. It remains an important challenge to developmore step-economic approaches for expedient synthesis ofchiral a-amino acids.

A conceptually unique strategy for amino acid synthesis isside-chain modification of existing amino acids. Jacksonet al.[12–14] previously reported Negishi coupling of amino acidderived organozinc. However, prior preparation and handlingof sensitive organozinc reagents brings complications to themethod and limits the scope. An alternative approach is direct-ing group-controlled C�H bond modification of amino acids.The groups of Corey[15] and Daugulis[16] reported b- and g-aryl-ation of N-phthaloyl-a-amino amides. More recently, C�H alkyl-

ation of the N-protected a-amino amides has also beenachieved.[17] Further studies in this area are needed to improvethe flexibility of the directing groups.[18]

Here we report a new strategy for synthesis of chiral a-amino acids from readily available serine/homoserine-derivediodides. This method enables simple and gram-scale prepara-tion of diverse enantiopure l- or d-amino acids. Key to themethod is the development of a very mild procedure of Ni-cat-alyzed reductive cross-coupling,[19–23] which presents the firstapplication of this emerging reaction methodology to aminoacid synthesis. Notably, aryl and acyl halides exhibit differentenantioselectivity results as compared with alkyl halides in theNi-catalyzed reaction with amino acid iodides due to the in-volvement of an unexpected side reaction. Thus our work alsoprovides new insights into the mechanism and scope of Ni-cat-alyzed reductive cross-coupling reactions.

Our study began with the synthesis of a non-natural aminoacid (3 a, Table 1). In our initial trials[20] the desired amino acidwas produced, but only in very low yields. Bipyridine ligandswere screened to improve the reaction, but the best yield was31 % (entry 1). Considerable homocoupling of 1 a and decom-position of 2 a occurred, which were attributed to the high re-action temperature (80 8C) and thermosensitivity of 2 a. Afterthe reaction temperature was lowered to 25 8C, elimination of2 a was significantly suppressed and the yield was 57 %(entry 2). Further tests revealed that the optimal ligand wasL1 a (entries 2–12). Solvent effects were studied and the bestsolvent was NMP (entries 13–15). Under the optimal condi-tions, the NMR yield of 3 a was 78 % (isolated yield = 74 %,entry 15). Finally, when 4-methoxy-bromobenzene was used inthe reaction, a moderate yield was also obtained (entry 16). Im-portantly, the present Ni-catalyzed reaction is not sensitive toair or moisture. Through HPLC analysis we confirmed that theoptical purity of product 3 a was >99 % (see the SupportingInformation).

The substrate scope of the new amino acid synthesis wasexamined. As shown in Table 2, moderate to good yields (34–86 %) were obtained for various substituted amino acids. Im-portantly, many commonly used amino acid protecting groups(namely, Boc (3 a), Cbz (3 g), Alloc (3 h) for the amino group,and tBu (3 a), Me (3 b), Bn (3 g), Allyl (3 h) for the carboxylgroup) can be tolerated in the reaction. These products are di-rectly amenable to many applications such as solid-phase syn-thesis of peptides.

Many halogen-containing amino acids can be readily pro-duced. Due to the mild conditions, aryl chlorides (3 e, 3 f) and

[a] X. Lu, J. Yi, Z.-Q. Zhang, J.-J. Dai, J.-H. Liu, Prof. B. Xiao, Prof. Y. Fu,Prof. L. LiuDepartment of ChemistryUniversity of Science and Technology of China, Hefei 230026 (China)E-mail : binxiao@ustc.edu.cn

lliu@mail.tsinghua.edu.cn

[b] X. Lu, Prof. L. LiuState Key Laboratory for Oxo Synthesis and Selective OxidationLanzhou Institute of Chemical Physics, Chinese Academy of SciencesLanzhou 730000 (China)

[c] X. Lu, Prof. L. LiuDepartment of Chemistry, Tsinghua University, Beijing 100084 (China)

Supporting information for this article is available on the WWW underhttp ://dx.doi.org/10.1002/chem.201405296.

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bromides (3 g) can be tolerated. For a di-iodide substrate, wecan obtain the amino acid carrying an aryl iodide group (3 h).These halogen groups provide opportunities for further trans-formations at the C�X bonds through other cross-coupling re-actions. Moreover, the new method provides convenientaccess to various fluoro-substituted amino acids. For example,trifluoromethyl phenylalanine (3 b), fluorotyrosine (3 c), andfluorotryptophan (3 d) can be made in good yields. Thesefluoro-substituted amino acids are useful tools to study thestructures and interactions of proteins and peptides by19F NMR.[24]

Some acidic protons (3 c and 3 i) do not need protectionduring the reaction. An unprotected benzaldehyde can also betolerated (3 j). Other active groups, including ester (3 k), keto(3 l), and nitrile (3 m), are compatible with the reaction. Hetero-aromatic side chain amino acids (e.g. pyridine 3 n and pyrimi-dine 3 o) can be made. HPLC tests on four randomly selectedamino acids (3 c, 3 f, 3 g, 3 m) again showed that the reactionwas racemization free. X-ray crystal analysis of 3 f’ confirmedthat the cross-coupling proceeded with retention of the abso-lute configuration at the a-carbon (Scheme 1).

To explore the scalability of the new amino acid synthesis inpreparative organic synthesis, we made a d-serine-derivediodide (2 f) from commercially available materials, which wasthen treated with an aryl iodide (1 p) on a gram scale(Scheme 2). The target d-a-amino acid was thus synthesized intwo mild steps from readily available substrates in 49 % overallyield.

The scope of the new amino acid synthesis can be extendedto acyl chlorides (Table 3). Benzoyl chloride was converted to5 a without racemization according to HPLC analysis. Addition-ally, acyl chlorides carrying an aryl chloride (5 b) and bromide

Table 2. Substrate scope for coupling with aryl iodides and bromides.[a]

[a] = Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Mn powder(1.5 mmol), NiCl2 (0.05 mmol), L1 a (0.05 mmol), in 2 mL NMP at 25 8C for20 h. Isolated yields. PG = protecting group. Boc = t-butoxycarbonyl.Cbz = benzyloxycarbonyl. Bz = benzoyl. Bn = benzyl. Alloc = allyloxycar-bonyl. Ts = tosyl. TBS = t-butyldimethylsilyl.

Scheme 1. X-ray of 3 f’. The thermal ellipsoids are displayed at 30 %probability.

Table 1. Optimization of coupling of l-serine-derived iodide with arylhalide.[a]

Entry Ligand Solvent T [oC] Yield [%][a]

1 L1 a DMPU 80 312 L1 a DMPU 25 573 L1 b DMPU 25 524 L1 c DMPU 25 325 L1 d DMPU 25 Trace6 L2 a DMPU 25 477 L2 b DMPU 25 438 L2 c DMPU 25 Trace9 L2 d DMPU 25 4910 L3 DMPU 25 911 L4 DMPU 25 Trace12 L5 DMPU 25 Trace13 L1 a DMAc 25 6714 L1 a DMF 25 5515 L1 a NMP 25 78 (74)[b]

16[c] L1 a NMP 25 38 (33)[b]

[a] Reaction conditions: 1 a (0.5 mmol), 2 a (0.6 mmol), Mn powder(1.5 mmol), NiCl2 (10 mol %), ligand (10 mol %), in 2 mL solvent for 20 h.1H NMR yields versus internal standard. [b] Isolated yields in parentheses.[c] 1-Bromo-4-methoxy-benzene was used instead of 1 a. DMPU = 1,3-di-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. DMAc = N,N-dimethylacet-amide. DMF = N,N-dimethylformamide. NMP = 1-methyl-2-pyrrolidinone.

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(5 c) group afforded the products successfully. Heterocycles,such as thiophene (5 d), furan (5 e), and pyrrole (5 f), posed noproblems in the synthesis. The coupling proceeded equallywell with aliphatic acyl chlorides to produce interesting non-natural amino acids (5 g–i).

Surprisingly, in the Ni-catalyzed reaction of 2 b with alkyliodide 6 b, the product (7 b) exhibited nontrivial racemization(ee = 81 % for L1 a, Scheme 3). Change of the ligand to Pz2Pyimproved the yield, but reduced the ee value to 7 %. After anal-ysis we identified the byproduct 2 b’, which was presumablyproduced via Ni activation of the C�I bond and subsequent b-elimination. Treatment of 6 b with pure 2 b’ under the Ni catal-ysis [Eq. (2)] produced the target amino acid as a racemate. Wetherefore concluded that the reaction between 6 b and 2 b’caused the racemization in the coupling with alkyl iodides. In-terestingly, when an aryl iodide 1 a was treated with 2 b’[Eq. (3)] , no arylated amino acid was formed. Collectively, ourexperiments show that Ni can catalyze the reaction betweenan alkyl iodide (but not an aryl iodide) and 2 b’. Notably, the eevalue with ligand L1 a was much higher than that with Pz2Py,indicating the possibility of tuning the ligands to avoidracemization.

Furthermore, we tested the use of homoserine-derived io-dides to synthesize amino acids. Under slightly modified reac-

tion conditions, Ni-catalyzed reductive cross-coupling of homo-serine-derived iodides with aryl/acyl/alkyl halides can be readilyachieved (9 a–h, Table 4). HPLC analysis suggested that thisprocess is racemization free (9 a, 9 g). Various synthetically rele-vant functional groups, such as ether (9 a) and ester (9 b, 9 c,9 h), were compatible with the reaction. Heterocycles, such aspyridine (9 d), quinoline (9 e), furan (9 f), and thiophene (9 g),can also be tolerated in the reaction.

The new amino acid synthesis can be used in the prepara-tion of even more complex non-natural amino acids. With es-

Scheme 2. Gram-scale reaction for the synthesis of a d-a-amino acid.

Table 3. Substrate scope for coupling with acyl chlorides.[a]

[a] Conditions: 4 (0.75 mmol), 2 c (0.5 mmol), Zn powder (1.5 mmol), NiCl2

(0.05 mmol), L1 a (0.05 mmol), in 2 mL NMP at 0 8C for 20 h. Isolatedyields. [b] Mn powder was used instead of Zn powder.

Scheme 3. Coupling of l-serine-derived iodides and alkyl halides.

Table 4. Substrate scope for the coupling of homoserine-derived iodides.

[a] Conditions for aryl halides: Aryl-X (0.5 mmol), 6 a (0.6 mmol), Mn(1.5 mmol), NiCl2 (0.05 mmol), L1 a (0.05 mmol), in 2 mL NMP at 60 8C for20 h. [b] Conditions for acyl chlorides: Acyl-Cl (0.75 mmol), 6 a (0.5 mmol),Zn (1.5 mmol), NiCl2 (0.05 mmol), L1 a (0.05 mmol), in 2 mL NMP at 0 8Cfor 20 h. [c] Conditions for alkyl halides: Alkyl-X (1.0 mmol), 6 a(0.5 mmol), Mn (1.5 mmol), NiCl2 (0.05 mmol), L1 a (0.05 mmol), in 2 mLNMP at 25 8C for 20 h. [d] Isolated yields.

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tradiol derivative 10, we obtained amino acid 11 in 45 % yield[Eq. (4)] . We also used levofloxacin carboxylic acid (12) to pre-pare an amino acid 13 in 42 % yield [Eq. (5)] .

Finally, peptides can also be functionalized by the Ni-cata-lyzed reductive cross-coupling reaction. For example, weachieved a new expedient synthesis of 16, a key intermediatefor the total synthesis of Indolactam V[25] (Figure 1). The start-ing material was Boc-l-Val-d-Ser-OMe, which was made fromBoc-l-Val and d-Ser-OMe. Through two more steps (i.e. , iodo-nation and reductive cross-coupling) dipeptide 16 was madein 39 % overall yield.

In conclusion, we report a new step-economic and practicalmethod for the synthesis of chiral a-amino acids through a Ni-catalyzed reductive cross-coupling reaction. This method en-ables robust cross-coupling between l- or d-serine/homoser-ine-derived iodides with diverse aryl/acyl/alkyl halides with re-tention of the absolute configuration at the a-chiral center. Itprovides a convenient access to a large variety of functional-ized amino acids that are often needed in the synthesis of nat-ural products as well as studies on drug development. Weexpect that the new amino acid synthesis will find many appli-cations by bench chemists as well as chemical biologists. Ournext challenge is to develop ligands to avoid the elimination-

addition side reaction in the cross-coupling of serine-derivediodides with alkyl iodides.

Acknowledgements

This study was supported by the “863” Program of the Ministryof Science and Technology (2012AA02A700), the National BasicResearch Program of China (973 program, No. 2013CB932800),NSFC (Nos. 21472181, 91313301, 21221062), and SRFDP(20133402120034).

Keywords: amino acids · catalysis · C�C bond formation ·nickel · reductive cross-coupling

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Figure 1. Functionalization of a peptide for total synthesis of Indolactam V.

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COMMUNICATION

& Catalysis

X. Lu, J. Yi, Z.-Q. Zhang, J.-J. Dai, J.-H. Liu,B. Xiao,* Y. Fu, L. Liu*

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Expedient Synthesis of Chiral a-AminoAcids through Nickel-CatalyzedReductive Cross-Coupling

Non-natural : A novel method was de-veloped for the synthesis of non-naturalamino acids by nickel-catalyzed reduc-tive cross-coupling between aryl/acyl/alkyl halides and serine/homoserine-de-rived iodides. This method providesa convenient access to a large variety offunctionalized non-natural amino acidsin enantiopure manners (see scheme,PG = protecting group).

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