Syntheses and Transformations of Î±-Amino Acids via Palladium

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Syntheses and Transformations of α‑Amino Acids via PalladiumCatalyzed Auxiliary-Directed sp3 C−H Functionalization Gang He,† Bo Wang,‡ William A. Nack,‡ and Gong Chen*,†,‡ †

State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China ‡ Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States CONSPECTUS: α-Amino acids (αAA) are one of the most useful chiral building blocks for synthesis. There are numerous general strategies that have commonly been used for αAA synthesis, many of which employ de novo synthesis focused on enantioselective bond construction around the Cα center and others that consider conversion of existing αAA precursors carrying suitable functional groups on side chains (e.g., serine and aspartic acid). Despite significant advances in synthetic methodology, the efficient synthesis of enantiopure αAAs carrying complex side chains, as seen in numerous peptide natural products, remains challenging. Complementary to these “conventional” strategies, a strategy based on the selective functionalization of side chain C−H bonds, particularly sp3 hybridized C−H bonds, of various readily available αAA precursors may provide a more straightforward and broadly applicable means for the synthesis and transformation of αAAs. However, many hurdles related to the low reactivity of C(sp3)−H bonds and the difficulty of controlling selectivity must be overcome to realize the potential of C−H functionalization chemistry in this synthetic application. Over the past few years, we have carried out a systematic investigation of palladium-catalyzed bidentate auxiliary-directed C−H functionalization reactions for αAA substrates. Our strategies utilize two different types of amide-linked auxiliary groups, attached at the N or C terminus of αAA substrates, to exert complementary regio- and stereocontrol on C−H functionalization reactions through palladacycle intermediates. A variety of αAA precursors can undergo multiple modes of C(sp3)−H functionalization, including arylation, alkenylation, alkynylation, alkylation, alkoxylation, and intramolecular aminations, at the β, γ, and even δ positions to form new αAA products with diverse structures. In addition to transforming αAAs at previously unreachable positions, these palladium-catalyzed C−H functionalization strategies enable new retrosynthetic logic for the synthesis of many basic αAAs from a common alanine precursor. This approach reduces the synthetic difficulty for many αAAs by bypassing the requirement for stereocontrol at Cα and relies on straightforward and convergent single-bond coupling transformations at the β-methyl position of alanine to access a wide range of β-monosubstituted αAAs. Moreover, these β-monosubstituted αAAs can undergo further C−H functionalization at the β-methylene position to generate various β-branched αAAs in a stereoselective and programmable fashion. These new strategies offer readily applicable methods for synthesis of challenging αAAs and may facilitate the efficient total synthesis of complex peptide natural products. separated αAAs to generate more complex tertiary cyclic structures.4 There are numerous general strategies that have been commonly used for αAA synthesis, many of which employ de novo synthesis focused on enantioselective bond construction around the Cα center and others that consider conversion of existing αAA precursors carrying suitable functional groups (FG) on side chains (e.g., serine and aspartic acid) (Scheme 1B).5 Although a range of powerful de novo synthesis methods, such as enantioselective hydrogenation of enamides and αalkylation of glycine synthons, have been developed for αAA synthesis, these methods often have limited scope and are not well-suited for the synthesis of αAAs with more complex side

1. INTRODUCTION α-Amino acids (αAA) are one of the most important and versatile building blocks for both biological and chemical synthesis. 1 Whereas nature only uses a small set of proteinogenic αAAs to construct the primary sequence of proteins, a vast pool of nonproteinogenic AA units are employed, especially by microorganisms, for the synthesis of peptide-based secondary metabolites.2 Many of these nonproteinogenic αAAs units are biosynthetically derived from common proteinogenic αAAs through various enzymecatalyzed C−H functionalization transformations such as oxygenation, halogenation, and alkylation (Scheme 1A).3 In addition to diversifying the primary and secondary structures of peptides at the building block level, nature also uses enzymatic C−H functionalization to cross-link the side chains of spatially © XXXX American Chemical Society

Received: January 14, 2016

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DOI: 10.1021/acs.accounts.6b00022 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

Scheme 1. Pd-Catalyzed Auxiliary-Directed C−H Functionalization for Syntheses and Transformations of α-Amino Acids

functionalization of more complex substrates such as αAAs remains very difficult. Directing group (DG) controlled metalcatalyzed C(sp3)−H functionalization reactions may address both reactivity and selectivity issues associated with complex substrates. Most notably, the laboratories of Sanford,9 Yu,10 and Daugulis11 reported that N-based DGs can facilitate Pd(OAc)2catalyzed regioselective C(sp3)−H oxygenation, halogenation, and arylation reactions around 2005, opening new avenues for Pd-catalyzed C−H functionalization chemistry.12 Over the past decade, this chemistry has been greatly advanced, providing increasingly practical and powerful tools for organic synthesis. Because earlier studies were focused on discovering new Pdcatalyzed C(sp3)−H functionalization reactions, synthetic applications of this chemistry were barely explored when we started our own research program in 2008. Inspired by the pioneering work of Sames, Du Bois, Corey, and others, we began to explore whether Pd-catalyzed DG-controlled C(sp3)− H functionalization could offer truly useful methods for αAA synthesis.13 The structure of αAAs prompted us to focus on C− H functionalization reactions mediated by NH2 and CO2Hlinked DGs. Building upon a report from Daugulis11 on Pdcatalyzed bidentate auxiliary-controlled C(sp3)−H arylation reactions,14 we have since carried out a systematic investigation

chains. Additionally, synthesis strategies based on FG conversion of certain αAAs often suffer from relatively poor redox and step economy. Overall, the efficient synthesis of αAAs carrying complex side chains and multiple stereogenic centers remains a significant challenge. Complementary to these “conventional” strategies, a strategy based on the selective functionalization of side chain C−H bonds, particularly sp3 hybridized C−H bonds, of various readily available αAA precursors may provide a more straightforward and broadly applicable means for the synthesis and transformation of αAAs.6,7 However, many hurdles related to the low reactivity of C(sp3)−H bonds must be overcome to realize the potential of C−H functionalization chemistry in this synthetic application. Among the known methods for C(sp3)−H functionalization, transition-metal-catalyzed reactions have the most potential to enable a diversity of bond formation reactions as well as exhibit delicate selectivity controls. Over the past few decades, the research groups of Bergman, Hartwig, Davies, and many others have convincingly shown that the selective and efficient functionalization of unactivated C(sp3)−H bonds of simple aliphatic substrates can be achieved under the catalysis of late transition metal complexes via a variety of mechanisms.8 However, achieving catalyst-controlled selective C(sp3)−H B


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Accounts of Chemical Research of Pd-catalyzed C−H functionalization reactions for αAA substrates (Scheme 1C). Along with other research groups,15−18 we have developed new strategies for the synthesis and transformation of αAAs based on Pd-catalyzed directed functionalization of the side chain C−H bonds of αAA precursors. In this Account, we summarize our efforts in this area and provide commentary on the features and synthetic utility of these Pd-catalyzed C−H functionalization reactions of αAA substrates. The contents are organized into three sections: Pd-catalyzed C(sp3)−H arylation for the total synthesis of C− C cross-linked peptide natural products, Pd-catalyzed C−H functionalization of αAAs directed by N-linked auxiliaries, and Pd-catalyzed C−H functionalization of αAAs directed by Clinked auxiliaries.

Scheme 2. Total Synthesis of Celogentin C via Directed βC(sp3)−H Arylation of Leu

2. Pd-CATALYZED C(SP3)−H ARYLATION FOR TOTAL SYNTHESIS OF COMPLEX PEPTIDE NATURAL PRODUCTS Our motivation for exploring C−H functionalization chemistry stems from our interest in synthetic and biological studies of cyclic peptide natural products with unusual cross-linkages. In addition to commonly encountered disulfide, ester, or amide linkages, nature also uses various enzyme-catalyzed C−H functionalization reactions to form carbon−carbon and carbon−heteroatom cross-linkages to generate complex cyclic structures. Many of these natural products possess useful biological activities, but their unusual cross-linked structures pose significant synthetic challenges. Celogentin C exhibits potent anticancer activity and possesses a unique bicyclic structure containing a notable C(sp3)−C(sp2) linkage between the Cβ of a leucine (Leu) and the C6 of a tryptophan (Trp) residue (Scheme 2A). Inspired by the proposed biosynthesis of the celogentins, we speculated that metal-catalyzed DGcontrolled β-C−H arylation of a Leu substrate with a suitable Trp partner could give key pseudo dipeptide intermediate Leu∼Trp 2. An earlier report by Daugulis provided precedent for this transformation. In 2005, Daugulis reported that simple alkyl carboxylic acids equipped with an amide-linked 8aminoquinoline (AQ) auxiliary react with aryl iodides at the β-methylene position to give β-arylated products in good yield and excellent selectivity under Pd(OAc)2 catalysis (Scheme 2B).12 Similarly, alkyl amines equipped with the 2-picolinic acid (PA) auxiliary undergo C(sp3)−H arylation at the γ position. These reactions likely proceed through a Pd(II)/(IV) catalytic cycle via 5-membered palladacycle intermediates. Importantly, Corey had demonstrated that AQ-coupled NPhth-protected αAA substrates are susceptible to β-C−H arylation using the Daugulis protocol.13c To our delight, we found that Pd-catalyzed β-C−H arylation of Leu-(AQ) 3 with Trp-based aryl iodide 4 proceeded in excellent yield and diastereoselectivity under optimized conditions (Scheme 2C). However, removal of the amide-linked AQ group of β-arylated product 6 was particularly challenging, likely due to significant steric hindrance. This problem was addressed by replacing the N-Phth group with a much smaller N3 group. Boc activation of the resulting α azido amide, followed by amide cleavage with LiO2H, gave the α-azido acid 8 in good yield and with complete stereoretention at Cα. This streamlined synthesis of Leu-Trp 8 allowed us to complete the total synthesis of celogentin C 1 entirely from commercially available αAA units.19,20 Encouraged by our success with celogentin C, we later featured a directed C(sp3)−H arylation reaction in our total synthesis of hibispeptin A 9, a cyclic peptide natural product

with a C(sp3)−C(sp2) cross-linkage between an isoleucine (Ile) and a 4-hydroxy phenacylamine (Hpa) residue (Scheme 3A). Synthesis of the Ile∼Hpa dipeptide via Pd-catalyzed C(sp3)−H arylation presented a challenge due to the diminished reactivity of sterically hindered aryl iodides (see 14). After a systematic evaluation of different auxiliary groups, we found that Ile 12 equipped with a 1-(2-pyridyl)ethylamine (PE) auxiliary efficiently underwent the desired γ-methyl C−H arylation with hindered aryl iodides. To facilitate removal of the amidelinked auxiliary, we introduced the PR auxiliary bearing a TIPSprotected OH group. Pd-catalyzed γ-methyl C−H arylation of C


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Accounts of Chemical Research Scheme 3. Total Synthesis of Hibispeptin A via Directed γC(sp3)−H Arylation of Ile

Scheme 4. Picolinamide-Directed γ-C(sp3)−H Arylation and Alkenylation

palladation, oxidative addition (OA) of aryl iodides, and reductive elimination (RE). The carboxylate group of αAA substrates might provide conformational assistance to promote the γ-C−H palladation step as analogous substrates without any α or β substitutes gave considerably lower yields. Deuterium exchange experiments indicated that C(sp3)−H bonds at both γ and δ positions of PA-coupled αAA substrates can undergo reversible palladation; however, transformations proceeding through 5-membered palladacycle intermediates are more favorable than those proceeding through 6-membered palladacycles, and γ selectivity is typically observed. The steric features of the palladacycle intermediates also strongly influence the reactivity and selectivity of the C−H functionalization processes. For instance, γ-methyl C−H arylation of PA-coupled valine (Val) with PhI proceeds through an α,β-trans-palladacycle intermediate, forming dolaphenvaline (Dpv) 21 with high diastereoselectivity. Although methylene C−H arylation is easily achieved with the AQ directing group, PA-directed methylene C−H arylation is considerably more challenging than methyl C−H arylation except for certain substrates with uniquely constrained structures (see 22). The reactivity of C(sp3)−H bonds in these PA-directed arylation reactions follows the general order of γ 1° > γ 2° > δ 1° ≫ δ 2°, and 3 °C−H bonds are completely unreactive. In addition to PAdirected γ-C(sp3)−H arylation with aryl iodides, γ-C−H alkenylation with vinyl halides also proceeds in moderate yield (see 23). To facilitate removal of the amide-linked auxiliary, we introduced a more easily removable PAr auxiliary with an OTBS methylene group at the ortho position of PA (see 24). The synthetic utility of this PAr-directed γ-C(sp3)−H arylation was demonstrated by a formal synthesis of

PR-coupled Ile 10 with fully protected aryl iodide 14 gave 16 in satisfying yield and selectivity (Scheme 3B). The PR auxiliary of 16 was cleanly removed as an oxazolidinone group in three steps to give tri-Boc protected pseudo dipeptide 18. Access to 18 enabled the first total synthesis of hibispeptin A.21

3. Pd-CATALYZED C−H FUNCTIONALIZATION OF α-AMINO ACIDS DIRECTED BY AN N-LINKED PICOLINAMIDE GROUP In parallel to our exploration of Pd-catalyzed C(sp3)−H arylation for target-oriented synthesis of complex αAAs found in natural products using C-linked directing groups, we investigated transformations of αAA substrates using Pdcatalyzed γ-C−H arylation directed by the N-linked picolinamide auxiliary. The PA auxiliary’s ability to target more distal side chain C−H bonds of αAAs complements the proximal targeting ability of C-linked auxiliaries, broadening the synthetic utility of Pd-catalyzed directed C−H functionalization reactions of αAAs. Although relatively harsh conditions were required for the PA-directed Pd-catalyzed C(sp3)−H arylation of simple alkyl amine substrates in the original Daugulis report (Scheme 2B), we were delighted to find that a range of PA-coupled αAA substrates underwent γ-C(sp3)−H arylation with various aryl iodides in good to excellent yields under milder conditions (Scheme 4).22 These arylation reactions likely proceed through a Pd(II)/Pd(IV) catalytic cycle via a sequence of C−H D


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Accounts of Chemical Research (+)-obafluorin from readily accessible starting materials threonine (Thr) and 4-nitrophenyl iodide. In addition to γ-C(sp3)−H arylation and alkenylation reactions, we later discovered that γ-methyl groups of PAcoupled αAA substrates can readily undergo C−H alkylation with primary alkyl halides with the addition of dibenzylphosphate additive (Scheme 5).23 For instance, (PA)-Thr reacted

Scheme 6. Picolinamide-Directed Intramolecular Dehydrogenative C−H Amination

Scheme 5. Picolinamide-Directed C−H Alkylation with Primary Alkyl Halides

with α-haloacetate to give carboxymethylated product 28 in good yield. As exemplified by 30, these C−H alkylation reactions can be used with easily accessible isotope-enriched reagents, offering a convenient method for the preparation of isotope-labeled αAA products. δ-C(sp2)−H alkylation of aromatic αAA substrates such as phenylalanine (Phe) also worked well (see 31). However, the scope is limited to only primary alkyl halides with relatively high electrophilicity; secondary and tertiary alkyl halides are unreactive. These reactions likely proceed via concerted OA of Pd(II) palladacycle with alkyl halide followed by RE of the Pd(IV) intermediate (see 27). The use of the phosphate additive is critical to achieve high conversion of αAA starting materials; however, its functional role is still currently unclear. The PA auxiliary’s unique ability to facilitate Pd-catalyzed C(sp3)−H functionalization via hypervalent palladium intermediates prompted us to explore other transformations of C(sp3)−H bonds, such as forming C−O, C−N, or C−halogen bonds under oxidative conditions. Inspired by Sanford’s seminal work on Pd-catalyzed PhI(OAc)2-mediated C−H oxygenation reactions,24 we next explored whether the PA auxiliary could facilitate a similar C(sp3)−H oxygenation of αAAs using a suitable oxidant. To our surprise, we observed that PA-coupled αAA substrates bearing a γ-methyl group (e.g., (PA)-Val) readily undergo intramolecular dehydrogenative C− H amination (IDCA) reactions to form 4-membered azetidines along with γ-C−H acetoxylated side products under Pd catalysis with PhI(OAc)2 oxidant (Scheme 6A).25 It should be noted that the selectivity of these γ sp3 IDCA reactions is strongly dependent on the substrate. For instance, in contrast to (PA)-Val, PA-coupled L-α-aminobutanoic acid (Abu) lacking the β-Me group largely formed γ-C−H acetoxylated product (see 36). The underpinnings of this substrate-dependent

reactivity remain unclear at the moment; we suspect that torsional strain may influence the RE pathways of Pd(IV) intermediates (see 32). As shown in Scheme 6B, certain PAcoupled αAA substrates bearing a δ-methyl group such as (PA)Leu underwent sp3 IDCA at the more remote δ position to give 5-membered pyrrolidine products. PA-coupled aromatic αAA substrates such as (PA)-Phe also underwent δ sp2 IDCA to give indoline products in good yield. Published concurrently with our study, Daugulis reported similar Pd-catalyzed PA-directed δ IDCA reactions forming 5-membered pyrrolidines and indolines.26,27 Later, we reported an improved protocol for indoline synthesis via δ sp2 IDCA reactions using reduced loading of catalyst (0.5 mol %).28 The weakened tertiary amide linkage of the C−N cyclized products was easily cleaved under weakly basic conditions to give the corresponding free N−H heterocycles in good yield. During our investigation of Pd-catalyzed PA-directed IDCA reactions, we observed that the concentration of OAc ligand influences the reaction outcome. This observation led us to investigate whether other nucleophilic reagents such as alcohols or amines might undergo ligand exchange with OAc ligands of Pd(IV) palladacycle intermediates (see 32 and 43) and subsequently afford C−H alkoxylated or aminated products via a similar RE pathway. To our delight, changing the reaction E


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alkylation of αAAs with alkyl halides (Scheme 8A). Gratifyingly, the C−H alkylation of various AQ-coupled β-monosubstituted

solvent from toluene to a mixture of alcohol and xylene cleanly diverted the γ IDCA reaction pathway of PA-coupled αAAs to intermolecular γ-C−H alkoxylation, forming various ether derivatives of αAAs with high efficiency and selectivity (Scheme 7).29 For instance, instead of forming azetidine 33 via γ IDCA

Scheme 8. Aminoquinoline-Directed β-C(sp3)−H Alkylation of αAAs with Primary Alkyl Halides

Scheme 7. Picolinamide-Directed C−H Alkoxylation with Alcohols

in toluene (Scheme 6A), reaction of (PA)-Val cleanly gave dimethoxylated product 44 when conducted in a mixture of MeOH and xylene. The reaction of (PA)-Abu with Roche ester provided 46 with a complex ether-linked side chain. Even sterically hindered t-BuOH is effective as seen in its reaction with (PA)-Abu to give t-Bu ether product 45. Aromatic αAAs such as (PA)-Phe underwent C(sp2)−H alkoxylation at the δ ortho position (see 47). In contrast, the analogous intermolecular C−H amination reactions of PA-coupled αAAs with various amines have not been achieved.

4. Pd-CATALYZED C−H FUNCTIONALIZATIONS OF α-AMINO ACIDS DIRECTED BY C-LINKED AUXILIARY GROUPS Our success with N-linked PA-directed side chain C−H functionalization of αAAs at the distal γ and δ positions prompted us to reinvestigate C-linked AQ-directed C−H functionalization of αAAs at the proximal β position. Branching at the β position of constituent αAAs provides unique control of the structure of peptide backbones via its effect on χ angles.30 In addition to the three proteinogenic β-branched αAAs (Val, Ile, and Thr), nature frequently applies enzyme-catalyzed β-C− H functionalization, such as C−H methylation and hydroxylation, to proteinogenic αAAs, generating a variety of nonproteinogenic β-branched αAAs for the biosynthesis of complex peptide natural products. Compared with β-monosubstituted αAAs (e.g., Phe), β-disubstituted (β-branched) αAAs are much more difficult to synthesize due to their additional stereogenic center at Cβ. Encouraged by results from Corey,13c Daugulis,15b and ourselves, we envisioned that Pdcatalyzed AQ-directed β-methylene C−H functionalization of αAA precursors might provide straightforward and generally applicable solutions for the stereoselective synthesis of βbranched αAAs. Informed by our success with PA-directed C(sp3)−H alkylation reactions (Scheme 5) and earlier studies on AQdirected methyl C(sp3)−H alkylation by Daugulis,15 we investigated Pd-catalyzed AQ-directed β-methylene C−H

αAAs with MeI and α-haloacetate worked very well with the addition of dibenzylphosphate.31 For instance, the reaction of Phe-(AQ) 72 with methyl iodoacetate gave β-carboxymethylated βCMe-Phe 49 in excellent yield and diastereoselectivity. The diastereoselectivity of the C−H alkylation reaction is controlled by the α,β-trans configuration of the 5-membered palladalactam intermediate (see 48). To access βPh-Glu 52, a diastereomer of 49, glutamic acid (Glu) 56 was subjected to Pd-catalyzed AQ-directed β-C−H arylation with PhI. Similarly, diastereomers βMe-Glu 51 and βCMe-Abu 54 were prepared from β-C−H alkylation of Glu-(AQ) 56 and Abu-(AQ) 57, F


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Accounts of Chemical Research respectively. Many other βMe and βCMe αAAs can be stereoselectively synthesized from αAA precursors using the same strategy. MeI and α-haloacetate are the two best alkylating reagents for AQ-directed β-methylene C−H alkylation, just as in the PA-directed alkylation system. Other primary halides give lower yields, and secondary and tertiary halides are unreactive. As shown in Scheme 8B, Pd-catalyzed AQ-directed β-methyl C−H alkylation of alanine (Ala) 55 gave less satisfying results under the standard conditions. For instance, carboxymethylation of Ala-(AQ) 55 with methyl iodoacetate gave Glu-(AQ) 56 in moderate yield due to the formation of overalkylated side products. Similarly, methylation of Ala-(AQ) 55 with MeI does not provide monoalkylated Abu-(AQ) 57, but instead forms dimethylated Val-(AQ) 58 in excellent yield. We later returned to these β-methyl C−H alkylation reactions of Ala-(AQ) 55 and developed a more efficient reaction that proceeds at room temperature (see Scheme 12). Published concurrently with our study, Shi reported a similar Pd-catalyzed phosphate-promoted AQ-directed C−H alkylation of αAAs with alkyl halides.17a During our investigation of Pd-catalyzed AQ-directed βmethylene C−H alkylation of αAAs, we discovered a new set of transformations of βMe-αAAs (Scheme 9A). Similar to intramolecular dehydrogenative C−H amination (IDCA) reactions of substrates bearing the PA group, AQ-coupled βMe-αAAs undergo IDCA at the γ-methyl group through 6membered palladacycle intermediates to form 2-pyrrolidinone

products with PhI(OAc)2 oxidant.32 For instance, γ IDCA of Ile-(AQ) 13 gave product 64 and γ IDCA of Val-(AQ) 58 gave product 62, both in excellent yield and diastereoselectivity. In addition to the AQ directing group, the structurally simpler pyridylmethyl amine (PM) auxiliary also facilitated γ-IDCA reactions under the same reaction conditions (see 65).33 IDCA reactions at the γ-methylene position are generally much less efficient except if at the benzylic positions of certain substrates. For instance, Ile-(AQ) 13 was first arylated at γ-methyl position to give 66, which then underwent stereoselective IDCA at the γ-benzylic position to give pyrrolidinone 67 in good yield. Subjecting AQ-coupled αAA substrates Ala-(AQ) 55, Abu(AQ) 57, and Phe-(AQ) 72 to the same conditions predominantly formed β-C−H acetoxylated products.34 To allow for removal of the AQ auxiliary from the cyclized pyrrolidinone products, we developed the 5-methoxy-8-aminoquinoline (MQ) auxiliary (Scheme 9C). The MQ auxiliary can be cleanly removed with cerium ammonium nitrate (CAN) at room temperature. Although Pd-catalyzed AQ-directed β-methylene C−H functionalization offers simple and efficient strategies for the stereoselective synthesis of β-branched αAAs, the applicability of these strategies depends on the availability and cost of the corresponding β-monosubstituted αAA precursors. To circumvent this dependence, we wondered whether Ala-(AQ) 55 could be used as a universal precursor to access all kinds of βmonosubstituted αAAs via Pd-catalyzed monoselective functionalization of its β-C−H bond. Achieving monoselective Pdcatalyzed C−H functionalization of Ala-(AQ) 55 is challenging due to the AQ auxiliary’s ability to functionalize β-methylene C−H bonds. An earlier study by Corey showed that C−H arylation of Ala-(AQ) 55 with aryl iodides under the original Daugulis conditions formed exclusively homodiarylated products.13c Previously, we observed that methylation of Ala-(AQ) 55 with MeI predominantly formed Val-(AQ) 58 (Scheme 8B). In 2012, Daugulis nicely demonstrated that phthaloyl alanine bearing a 2-thio-methylaniline auxiliary can undergo β-methyl C−H arylation with aryl iodides to give various aromatic αAA products in excellent monoselectivity.15b However, this auxiliary’s ability to facilitate methylene C−H functionalization was rather limited. It is important to note that the above reactions and most other known Pd-catalyzed C(sp3)−H functionalization reactions proceed at relatively high reaction temperatures (>100 °C). We suspected that running the C−H arylation of Ala(AQ) 55 at a lower reaction temperature might suppress kinetically less favored methylene C−H arylation. After systematic evaluation of various reaction parameters, we were pleased to find that Pd-catalyzed C−H arylation of Ala-(AQ) 55 with aryl iodides could proceed with excellent efficiency and monoselectivity at room temperature with the addition of trifluoroacetate (TFA) additive (Scheme 10A).35 A wide range of natural and unnatural β-monoaryl αAAs such as phenylalanine (Phe) 72, tyrosine (Tyr) 73, and tryptophan (Trp) 74 were easily prepared from readily accessible aryl iodides and Ala-(AQ). As shown in Schemes 8A and 10B, these AQcoupled β-monoaryl αAAs were subjected to further βmethylene C−H functionalizations to form complex βbranched αAAs in a diastereoselective and programmable manner. The use of an N-Phth protecting group for αAA substrates is critical to all of the above-mentioned Pd-catalyzed AQ-directed C−H functionalization reactions discussed. It should be noted that the amide coupling of Phth-Ala-OH with

Scheme 9. Aminoquinoline-Directed IDCA Reactions of αAAs

G


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Accounts of Chemical Research Scheme 10. Monoselective β-C−H Arylation of Ala-(AQ) at Room Temperature

Scheme 11. β-C−H Alkenylation and Alkynylation of Ala(AQ) at Room Temperature

tion of Ala-(AQ) 55 with alkenyl iodides, providing a wide range of β-alkenyl αAAs.36 Reaction of Ala-(AQ) 55 with electron-deficient alkenyl iodides of varied substitution patterns proceeded in good yield, excellent monoselectivity, and with complete stereoretention (see 83−85). Alkynylation of Ala(AQ) 55 with TIPS-protected acetylene bromide 89 gave βalkynyl αAA 88. As shown in Scheme 12, the TFA-promoted room temperature reaction conditions were also applicable to the Scheme 12. β-C−H Alkylation of Ala-(AQ) at Room Temperature

8-aminoquinoline is particularly prone to racemization under various conditions. Enantiopure Ala-(AQ) 55 can be obtained via amide coupling of carbamate-protected alanine followed by exchange of N-protecting groups (Scheme 10C). The AQ auxiliary of β-monoaryl αAA products can be removed via a two-step sequence to give phthaloyl αAAs in >98% ee (Scheme 10D). As shown in Scheme 11, similar room temperature reaction conditions were used to effect Pd-catalyzed β-C−H alkenyla-

Pd-catalyzed C−H alkylation of Ala-(AQ) 55 with primary alkyl halides, providing β-alkyl αAA products.37 In contrast to dialkylated product Val-(AQ) 58 obtained under our phosphate-promoted reaction conditions at 110 °C (Scheme 8B), reaction of Ala-(AQ) 55 with MeI at room temperature provided monoalkylated Abu-(AQ) 57 in excellent yield. Similarly, alkylation of Ala-(AQ) 55 with methyl iodoacetate H


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Accounts of Chemical Research furnished Glu-(AQ) 56. Compared with AQ-directed βmethylene C−H alkylation reactions at higher reaction temperatures, this room temperature β-methyl C−H alkylation of Ala-(AQ) tolerates a broader scope of alkyl halides, including many primary alkyl iodides bearing moderately electronwithdrawing groups such as α-iodomethyl ketones and iodoacetonitrile (see 90−93).

challenges, better mechanistic understanding and development of new catalysts, ligands, auxiliary groups, and reagents will be critical. In addition, we hope that the lessons learned from these investigations promote the development of other metal- or nonmetal-catalyzed C−H functionalization reactions of αAAs and lead to development of an expanded toolbox of C−H functionalization reactions for the synthesis and transformation of αAAs.

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5. SUMMARY AND OUTLOOK As the applications of αAAs at the frontiers of molecular science continue to evolve, chemists must address developing demand for more efficient synthetic methods as well as new αAAs with novel structures and functions. Complementary to the established methods of de novo synthesis of αAAs or limited transformations of side chain functional groups, we sought to develop a more straightforward and versatile means to access new αAAs via the selective functionalization of side chain sp3 C−H bonds of existing αAA precursors. For several years, we have systematically investigated the applications of Pd-catalyzed auxiliary-directed C−H functionalization for αAAs synthesis. Our strategies encompass two types of amide-linked auxiliary groups attached on either the N or C terminus of αAA substrates. These auxiliary types exhibit complementary regioand stereoselectivity in side chain C−H functionalization reactions proceeding through palladacycle intermediates. Nlinked PA-directed C−H functionalization reactions can transform αAA substrates at the distal γ and δ positions to generate more complex αAA products. In contrast, C-linked AQ-directed C−H functionalization reactions are uniquely suited to transform αAA substrates at the proximal β position. With the ability to selectively functionalize previously unreachable side chain sp3 C−H bonds, readily available αAA precursors can now be used for broader applications in organic synthesis. Many previously underutilized αAAs such as Val, Thr, and Abu may now be viewed as valuable chiral “C−H” synthons that can be readily functionalized at methyl and methylene positions to give αAA products difficult to access by other means. In addition to transforming existing αAAs to generate complex structures, AQ-directed sp3 C−H functionalization reactions enable new retrosynthetic logic for the synthesis of many basic αAAs from a common alanine precursor. In contrast to conventional de novo synthesis bond construction focused around the Cα center, the β-methyl position of Ala-(AQ) can be directly manipulated to access a wide range of βmonosubstituted αAAs. Moreover, these AQ-coupled βmonosubstituted αAAs can undergo further C−H functionalization at the β-methylene position to generate various challenging β-branched αAAs in a stereoselective and programmable fashion. Although Pd-catalyzed amide-linked auxiliary-directed C(sp3)−H functionalization reactions have enabled unprecedented approaches to synthesize and transform αAAs, these strategies require significant development to offer truly practical and broadly applicable methods for αAA chemistry. Achieving reactivity from more challenging coupling partners such as sterically hindered aryl iodides, electronically unbiased vinyl iodides and less reactive alkyl halides, improved regio- and stereocontrol, an expansion of reaction modes to incorporate other heteroatomic groups, reduced loading of Pd catalyst, avoidance of the use of expensive materials such as stoichiometric silver additives, and easier removal of amidelinked auxiliaries all must be addressed. To confront these

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Corresponding Author

*E-mail: [email protected] or [email protected]. Notes

The authors declare no competing financial interest. Biographies Gang He received his B.S. degree from Nankai University in China and his Ph.D. degree in organic chemistry from SIOC in China under the guidance of Professor Dawei Ma. He then conducted his postdoctoral research with Professor Gong Chen at the Pennsylvania State University. In 2014, he joined the faculty at Nankai University. Bo Wang received his B.S. degree from Shenyang Pharmaceutical University in China and his Ph.D. degree in medicinal chemistry from the same university under the guidance of Professor Mao-Sheng Cheng. He is currently conducting his postdoctoral research with Professor Gong Chen at the Pennsylvania State University. William A. Nack obtained his B.S. degree from the State University of New York at Geneseo in 2011. He is currently pursuing his Ph.D. studies with Professor Gong Chen at the Pennsylvania State University. Gong Chen received his B.S. degree from Nanjing University in China and his Ph.D. degree in bioorganic chemistry from Columbia University under the guidance of Professor Dalibor Sames. He then became a postdoctoral research fellow at Memorial Sloan-Kettering Cancer Center with Professor Samuel Danishefsky. He joined the faculty at the Pennsylvania State University in 2008 and recently took a faculty position at Nankai University in China.

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ACKNOWLEDGMENTS We are indebted to all present and former group members for their contributions to the work described herein. We thank the Pennsylvania State University and the National Science Foundation (CAREER CHE-1055795) for financial support of this work.

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REFERENCES

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