Recent Progress in the Asymmetric Syntheses of α‐Heterofunctionalized (Masked) α‐ and β‐Amino Acid Derivatives

The asymmetric synthesis of α-heterofunctionalized αand -amino acid derivatives has been a heavily investigated topic over the last years, benefiting from the development of novel catalysis concepts as well as from the introduction of suited new precursor entities. Within this short review, we wish

to give an illustrative overview of the most successfully applied concepts to access these targets, like asymmetric α-heterofunctionalizations or asymmetric C-C-bond forming reactions of already heterofunctionalized precursors.
that contain other, non-halogen, heteroatom groups (e.g. OR, SR, NR 2 , ...) in the α-position. Given the increasing number of recent publications dealing with the development of novel synthesis and catalysis concepts to access α-heterofunctionalized αand -AA derivatives stereoselectively, it is the intention of this short review to provide an illustrative (but not encyclopedic) overview about some of the most significant (recent) achievements in the field (primarily covering developments from the last 10-15 years but also highlighting selected pioneering older studies). It should be noted, that the majority of the reports covered herein focused primarily on the development of stereoselective methods for the synthesis of masked/ protected AA-derivatives, while full deprotection to the free amino acids or incorporation into peptides was in a lot of cases either not attempted or, if tried, sometimes also not possible (i.e. for the case of α-F-α-AA). Scheme 1. Most commonly described strategies to access α-heterofunctionalized αand -amino acid derivatives.
The first part of this review will focus on α-heterofunctionalized α-AA (Scheme 1A). Here the most commonly reported strategies rely on the use of masked (protected) α-AA derivatives that undergo stereoselective α-heterofunctionalization reactions with suited electrophilic heteroatom transfer reagents. The second part will cover methods for the asymmetric synthesis of α-heterofunctionalized -AA (Scheme 1B). Here several fundamentally different strategies have emerged. On the one hand, suitable masked -AA derivatives can undergo asymmetric electrophilic or nucleophilic α-heterofunctionalization reactions. In addition, the use of α-heterofunctionalized pronucleophiles in asymmetric C-C-bond forming reactions (i.e. Mannich type approaches), or asymmetric hydrogenation reactions of appropriately substituted alkenes represent complementary powerful methods to access masked α-heterofunctionalized -AA derivatives as well.

α-Amino Acid Derivatives
The asymmetric synthesis of chiral α-heterofunctionalized -AA derivatives has been thoroughly investigated over the last years. Hereby the choice of appropriately masked or protected α-AA analogs is of crucial importance, as a direct functionalization of the free α-AA is usually not possible. In addition, it should be emphasized that in most of the cases reported so far, the main focus was on the development of methods to facilitate the stereoselective introduction of the heteroatom in the masked surrogate, while further manipulations to the free α-AA have rarely been described.

α-F-α-AA Derivatives
The synthesis of fluorine-containing amino acids is one of the most prominent tasks in amino acid/peptide chemistry nowadays. [6] While the introduction of fluorine or a fluorine-containing group in the amino acid side chain is well established, [8] the stereoselective syntheses of α-F-α-AA derivatives are rather challenging targets transformations. [9][10][11][12] First, only a handful of asymmetric approaches for the α-introduction of fluorine in masked α-AA derivatives have been developed so far (vide infra). [11] In addition, the H-N-C-F structural motive easily undergoes HF-elimination, especially when the N-lone pair is not delocalized in e.g. a (sulfon)-amide bond. [9] As a consequence, and despite the successful development of methods for the α-fluorination of N-protected α-AA derivatives, [11,12] further manipulations and N-deprotection to the free α-F-α-AA are very difficult or almost impossible. Nevertheless, interesting stereoselective approaches towards masked α-F-α-AA have been reported (Scheme 2), [11] and the development of novel strategies to ac-

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One classical approach to carry out asymmetric α-fluorination reactions of prochiral nucleophiles relies on the use of Nfluorinated Cinchona derivatives F as chiral electrophilic F-transfer reagents. [10,11] Cahard and co-worker, [11a,11b] as well as Togni's group [11c] have shown that this methodology also allows accessing the masked enantioenriched α-F-α-AA derivatives 2, 4, and 6 as outlined in Scheme 2. Unfortunately, however, as already stated above, further manipulations were found to be rather difficult and the synthesis of free α-F-α-AA or peptides thereof still represents one of the major challenges in the field of amino acid chemistry.
Recently, the (asymmetric) di-or trifluoromethylthiolation of (prochiral) nucleophiles became an important and heavily investigated topic. [16] Owing to the value of the incorporation of these F-containing groups in potentially biologically relevant molecules, [16] it comes as no surprise that the development of methods for the asymmetric synthesis of α-di-/trifluoromethylthiolated-α-AA has attracted the attention of the synthesis community lately (Scheme 4). [17] Shen and co-workers succeeded in carrying out the asymmetric α-difluoromethylthiolation of azlactones 12 with excellent enantioselectivities by using the chiral CF 2 HS-reagent 15 (Scheme 4A). [17a] On the other hand, the analogous α-CF 3 S-derivatives 18 could be accessed with very high selectivities under asymmetric phase-transfer catalysis conditions by using the established Cinchona alkaloid ammonium salt C4, as reported by the groups of Della Sala and Aleman recently (Scheme 4B). [17b] Scheme 4. Recently reported methods for the asymmetric syntheses of α-CF 2 HS-and α-CF 3 S-α-AA derivatives.

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α-NR 2 -α-AA Derivatives
The direct asymmetric α-amination of α-AA derivatives has so far received very little attention only, but in general, such an approach provides an interesting entry towards quaternary stereogenic centers containing two (orthogonal) nitrogenbased functional groups. In 2012, the groups of Guo and Zhou showed that the addition of α-nitroesters 5 to diazocarboxylate 19 can be rendered enantioselective by using the Cinchonaderived organocatalyst C5 under cryogenic conditions (Scheme 5). [18] To the best of our knowledge, this report represents the only highly enantioselective example to access masked or protected α-AA derivatives with an additional α-Nfunctional group. However, no comprehensive studies concerning further manipulations of these interesting compounds were reported so far.

-Amino Acid Derivatives
Owing to the higher structural diversity of -amino acids compared to α-amino acids a much broader variety of complementary asymmetric syntheses protocols to access α-heterofunctionalized -AA derivatives have been developed so far. These methods differ fundamentally, by either carrying out the heterofunctionalization in the stereodefining step or by using already heterofunctionalized starting materials e.g. asymmetric C-C bond forming reactions.

α-Halogen--AA Derivatives via Asymmetric Electrophilic α-Halogenations
A variety of different approaches for electrophilic asymmetric α-halogenation reactions using differently decorated -AA derivatives or precursors have been reported so far, and in the following chapter some of the most versatile concepts shall be discussed.
Asymmetric electrophilic α-halogenation reactions of -keto esters are very commonly investigated target transformations. [19] The hereby accessed α-halogenated 1,3-dicarbonyl compounds can be utilized for a variety of further manipulations, among them also conversions to the corresponding αhalogenated -AA derivatives (Scheme 6). As an impressive early example in the field (2002), Sodeoka's group has shown that the α-fluorinated -keto esters 23 can be accessed with high selectivities under asymmetric Pd-catalysis using NFSI as the electrophilic F-transfer reagent (Scheme 6A). [19a] Compounds 6 were then successfully converted into the α-F--AA derivatives 24 via reduction to the alcohol, followed by a stereospecific Mitsunobu-type inversion. Hereby, the formation of ei-ther the syn or the anti diastereomer could be perfectly controlled by variation of the reduction conditions. [19a] In 2011, Shibatomi and co-workers developed a practical one-pot dihalogenation protocol to access the α-Cl-α-F--AA derivatives 26 from simple -keto esters 21 (Scheme 6B). [19b] Hereby the starting material 21 was first α-chlorinated, followed by an asymmetric Cu-catalyzed α-fluorination with NFSI, giving the highly functionalized -keto ester 25 (which could be transferred into 26 by established means). Scheme 6. Asymmetric syntheses of α-halogenated -AA starting from -keto esters.
Isoxazolinones 27 can be considered as versatile masked -AA derivatives as well and the asymmetric α-fluorination of those compounds has been reported by the groups of Ma and Wang (Scheme 7). [20] First, Ma and co-workers reported the chiral thiourea C7-catalyzed addition of 27 to nitroalkenes 28 followed by α-fluorination (Scheme 7A). [20a] Two years later, Wang et al. developed a direct Cinchona dimer C8-catalyzed α-fluorination of α-substituted isoxazolinones 27 (Scheme 7B). [20b] Both protocols allowed for high enantioselectivities for a broader substrate scope, but unfortunately, to the best of our knowledge, no further manipulations towards e.g. free -amino acids were reported so far. Cyanoacetates 30 can be considered as oxidized -AA derivatives as well, and these commonly employed nucleophiles have been subjected to several α-fluorination attempts with different catalysis strategies in the past (Scheme 8).
[21] While Shibata's group utilized the simple Cinchona derivative C9 in combination with Selectfluor, [21a] Kim et al. reported methods for the α-fluorination of 30 with NFSI either using the chiral ammonium salt catalyst C10, [21b] or the Pd complex C11. [21c] Unfortunately, and to the best of our knowledge, in neither of these cases any reductions of the cyano group towards the corresponding -AA were described. Besides the enantioselective electrophilic approaches relying on asymmetric catalysis modes discussed so far, also diastereoselective α-halogenations of chiral (auxiliary containing) -AA precursors emerged as promising strategies to access α-halogenated--AA with high stereoselectivities (Scheme 9). [22][23][24][25] For example, around 20 years ago Tomasini and co-workers showed that the LiHMDS-mediated α-halogenation of cyclic (compounds 32) and acyclic (compounds 35) chiral -AA derivatives allows for the synthesis of α-Cl, α-Br, and α-I-derivatives 33 and 36 with high diastereoselectivities under operationally simple conditions (Scheme 9A, 9B). [22] These compounds then served as valuable building blocks for further transformations, like e.g. the synthesis of chiral aziridines from acyclic derivatives 34. [22a] Abell and co-workers investigated the α-fluorination of chiral auxiliary-based carboxylic acid derivatives like compounds 37, which were α-fluorinated with high diastereoselectivities using NFSI. The resulting products 38 could then be converted into the corresponding α-alkylated α-F--AA 39 straightforwardly by established means (Scheme 9C). [23] Alternatively, Seebach [24] and Abell [25] also showed that the -substituted chiral -amino esters 40 can be α-fluorinated with high diastereoselectivities with NFSI and using LDA as the base (Scheme 4D). Accordingly, all these reports shown in Scheme 9 clearly demonstrate the potential and simplicity of diastereoselective approaches for cases where the required chiral precursors are as easily available as shown in these examples.
Alternatively, aza-Michael-initiated approaches of simple vinylogous acceptor molecules 42 also allowed for highly stereoselective syntheses of α-halogenated -amino acid derivatives as outlined in Scheme 10. [26,27] Here, two fundamentally different approaches to control the absolute configuration were developed. First, Duggan and co-workers showed that the use of the chiral Li-base 43 in combination with NFSI allows for the highly stereoselective synthesis of 44, which could then be converted into the free α-F--AA 45 directly (Scheme 10A). [26] More, recently, Liu, Feng, and co-workers developed a chiral Fe-catalyzed protocol for the aza-Michael addition of TMSN 3 with direct bromination of the α-position, giving the versatile products 46 with excellent diastereo-and enantioselectivities (Scheme 10B). [27] Scheme 10. Asymmetric aza-Michael-initiated syntheses of α-halogenated--AA.

α-Halogen--AA Derivatives via Asymmetric Nucleophilic α-Halogenations
Besides the introduction of the halogen via an electrophilic α-halogenation approach, also the addition of nucleophilic halide-sources to appropriately substituted starting materials has been successfully utilized to access enantioenriched α-halogen--AA derivatives (Scheme 11). [28][29][30][31][32] In this context, the majority of the reported methods rely on stereospecific addition reactions of the halide nucleophile to chiral, enantioenriched starting materials. Aziridines or (in situ formed) aziridinium species are amongst the most versatile substrates for such approaches and in general, this concept is very well-established, with first reports dating back to the 1980s when Shanzer's [28] and later on Seebach's [24] groups showed that the chiral amines 47 and 48 can both be converted into the α-F--AA derivatives 49 by using DAST. This reagent fulfills two functions, first, it activates the alcohol for in situ aziridinium formation and in addition it serves as a nucleophilic F-source for the ring-opening again (Scheme 11A). The intermediate ring formation via this neighboring group effect of the amine group also provides a rationale for the observed stereochemistry in these reactions (retention of configuration starting from 48 and inversion from 47). Besides in situ aziridinium formation, also preformed chiral aziridinium species like compound 50 can be directly utilized for such ring-opening reactions (Scheme 11B). [30] This approach allowed De Kimpe's group to access a variety of differently α-halogenated esters 51 with perfect stereocontrol and in high yields.
Scheme 11. Stereospecific regioselective ring-opening reactions with nucleophilic halide sources. halide species has also been explored to large extent, highlighting the value of chiral aziridines for further manipulations (Scheme 11C). [31] Conceptually similarly, chiral sulfamidates 54 show analogous reactivities and can undergo ring-opening towards products 55 upon treatment with TBAF as a nucleophilic F-source as well (Scheme 11D). [32]
ing the α-halo amides 61 for Cu-catalyzed Mannich reactions, which yielded the amides 62 with very high levels of enantioand diastereoselectivities (Scheme 12B). [35] Very recently, the same group also succeeded in engaging simple α-fluoro nitriles 63 for Mannich reactions, giving the nitriles 64 which could then be converted into the free α-F--AA 65 (Scheme 12C). [36] Besides the above mentioned metal-catalyzed strategies, also asymmetric organocatalytic Mannich-type approaches have been used very successfully to access a variety of different α-halogenated--AA (Scheme 13). [37][38][39][40] In 2010, Jiang, Tan, and co-workers succeeded in controlling the asymmetric addition of the α-F--ketoamide 66 to aldimines 57 in the presence of the chiral bicyclic guanidine catalyst C12 (Scheme 13A). [37] Alternatively, Kim's group shortly after made use of the bifunctional cyclohexanediamine-based thiourea catalyst C13, which allowed them to achieve high levels of selectivities for the reaction between the α-F--keto esters 68 and aldimines 57 (Scheme 13B). [38] In 2015, Zhao et al. investigated the Mannich addition of α-Br-thioester 70 to aldimines 57 and found the Cinchona alkaloid-based urea catalyst C14 being best suited for this approach (Scheme 13C). [39] Expanding the applicability of thioesters, Wennemers' group developed a highly selective protocol for the use of α-F-thiomalonates 72 for Mannich reactions in the presence of low quantities of the squaramide catalyst C15 (Scheme 13D). [40] Scheme 13. Organocatalytic Mannich-type approaches for the synthesis of αhalogenated--AA.
An alternative strategy to construct the α-F--AA skeleton via an asymmetric C-C bond formation relies on the direct use of α-F-carboxylic acids in -lactam-forming reactions, as demonstrated by Birman's group recently (Scheme 14). [41] Starting from simple starting materials 57 and 74, they developed an elegant protocol for the synthesis of the α-F--lactam 75 by means of an isothiourea C16-catalyzed lactamization. Thislactam then undergoes nucleophilic ring-opening reactions with various O-nucleophiles, resulting in a synthetically useful alternative as compared to the Mannich protocols shown in Scheme 13. Scheme 14. Asymmetric synthesis of α-F--lactams.
A conceptually different approach to access α-F--AA derivatives by means of an asymmetric C-C-bond forming reaction was recently reported by Stoltz and co-workers (Scheme 15). [42] By carrying out a Pd-catalyzed asymmetric decarboxylative αallylation of allyl ester 77, the cyclic masked α-F--AA 78 was obtained with high enantioselectivity. This compound could then be converted into the free α-allyl-α-F--AA 79 subsequently, giving access to a -amino acid substitution pattern that is otherwise difficult to access with classical Mannich type approaches.

α-ORand α-SR--AA Derivatives via Asymmetric Electrophilic or Nucleophilic Heterofunctionalizations
The asymmetric synthesis of α-chalcogenated -amino acids can be achieved by a variety of different strategies,  as outlined in the following chapters.
With respect to the introduction of various SR-groups the electrophilic α-chalcogenation of suited -AA precursors is a very powerful approach for this task. [43][44][45] In 2006, Davies and co-workers introduced a highly selective aza-Michael initiated protocol for the synthesis of the α-sulfanylated -AA 82 (Scheme 16A). [43] Hereby they made use of the addition of the chiral Li-amide 43 to Michael acceptor 42 to form the chiral enolate 80 in situ, which can then be trapped with a suited electrophilic S-transfer reagent giving product 81. The chiral auxiliary can then be removed in a further step to access the amino acid 82 with high enantiopurity. A versatile strategy to access 2,2 -AA ( -AA with no additional substituents in theposition) was recently introduced by Brière's group, who reported the use of isoxazolidin-5-ones 83 as easily available masked 2,2 -AA precursors that undergo enantioselective α-sulfanylation reactions (Scheme 16B). [44] Key to success for achieving high levels of enantioselectivities was the use of the commercially available Maruoka phase-transfer catalyst C17 and the hereby accessed products 84 could easily be converted into the free amino acids 85 upon reductive N-O-cleavage. Building on this seminal contribution, the groups of Della Sala and Aleman [45a] and Cahard and Waser [45b] simultaneously reported the α-trifluoromethylthiolation of 83 under rather similar phase-transfer catalytic conditions (Scheme 16C and Scheme 16D). Again the heterocyclic products 86 could be converted in the free α-SCF 3 --AA 87 or also incorporated in the α-AA--AA dipeptide 89 directly, [45b] highlighting the general potential of this isoxazolidin-5-one heterocyclic platform.
Scheme 16. Approaches for the asymmetric synthesis of α-SR--AA via electrophilic strategies.
Besides electrophilic α-sulfanylation approaches the addition of nucleophilic S-reagents to appropriately substituted -AA precursors has been successfully carried out to achieve the synthesis of enantioenriched α-SR--AA derivatives. [46][47][48] As an early example, Avenoza, Peregrina, and co-workers showed that thiols or thiolates can be added in a stereospecific manner to the chiral sulfamidates 90. The resulting Weinreb amide-containing products 91 could then be converted into the free α-SR-2,2 -AA 92 by established methods (Scheme 17).
A conceptually different nucleophilic thiolation approach was developed by Xiao's group in 2009. Relying on chiral thiourea C19 organocatalysis, they succeeded in carrying out the highly enantioselective thia-Michael addition of thiols 93 to the -nitro acrylates 94 with as little as 0.3 mol-% of the catalyst (Scheme 18). [47] The resulting products 95 could then be reduced and deprotected giving the α-sulfanylated -AA 96 in an efficient manner. Scheme 18. Asymmetric thia-Michael strategy to access α-SR-2,2 -AA.
An efficient strategy for the synthesis of α-hydroxylated carbonyl derivatives is the nucleophilic ring-opening of glycidic esters 97. By using amine nucleophiles, direct access to αhydroxy--AA derivatives is possible. [49,50] Most commonly, this approach has been carried out in a diastereoselective manner, by using enantioenriched epoxides 97. [49] In addition, Kureshy et al. recently also showed that racemic epoxides 97 can be resolved very efficiently by the addition of simple aniline derivatives 98 in the presence of the chiral Cr-catalyst C20 (Scheme 19). [50] Scheme 19. Kinetic resolution of epoxides 97 to access α-OH--AA derivatives.
In 2008, Córdova and co-workers reported the enamine-catalyzed Mannich addition of aldehydes 100 to various imines 57 (Scheme 20A). [51] The resulting α-oxygenated--amino aldehydes 101 could then be oxidized to the amino acids 102 straightforwardly. Very recently, Takemoto's group developed a very selective and highly divergent method for the addition of glyoxylate cyanohydrin 103 to imines 57 (Scheme 20B). [52] Depending on the modifications of the catalyst C22, either the syn-or the anti-diastereomer of products 104 could be accessed with excellent levels of enantio-and diastereoselectivities, resulting in a powerful catalysis concept for the divergent synthesis of highly functionalized small molecules.
Over the years, Shibasaki's group contributed like maybe no other to the development of robust and highly selective metalcatalyzed Mannich type approaches using diversely functionalized enolate precursors (see also Scheme 12 for the already discussed synthesis of α-halogenated--AA via Mannich reactions). [35,36,54] With respect to the synthesis of α-OH--AA derivatives, they succeeded in controlling the addition of the free-OH-containing amide 105 to various imines 57 by using a chiral indium catalyst system (Scheme 21A). [54a] The resulting pyrroleamides 106 could then be transferred into the esters 107 straightforwardly. More recently, they also expanded their chiral Cu-catalyzed Mannich protocol (compare with Scheme 12B) towards amides 108 (Scheme 21B), [54b] giving the masked α-oxygenated -AA derivatives 109 with very high levels of enantioselectivity and almost perfect control of diastereoselectivity.
ester 113 using a chiral La-catalyst (Scheme 22B). [56] Again, the nitro group could be reduced then and incorporation of the product in the dipeptide Bestatin (117) was successfully demonstrated. Recently, Shibasaki's group reported a broadly applicable method for the addition of a variety of different nitroalkanes 111 to α-keto esters 112 giving the α-hydroxy--nitroesters 118 with excellent levels of enantio-and diastereoselectivities (Scheme 22C). [57] Again, reduction of the nitro group was successfully demonstrated.
Scheme 22. Asymmetric Henry-type reactions for the syntheses of α-OH--AA derivatives.
Next to the classical Henry-type addition reactions of nitroalkanes to α-oxo-esters shown in Scheme 22, also the enantioselective addition of hydrazone derivatives like compound 119 to α-keto esters 112 was reported for the successful enantioselective synthesis of α-OH--AA derivatives (Scheme 23). By utilizing the chiral H-bonding catalysts C23 or C24, the groups of Fernandez and Lassaletta succeeded in carrying out the addition of 119 to 112 with excellent enantioselectivities and subsequent transformations then gave access to the corresponding α-OH--AA derivatives 115 in an elegant manner. [58] Scheme 23. Asymmetric addition of hydrazone derivatives 119 to α-keto esters 112.
An alternative, conceptually remarkable, approach to access the α-oxygenated--AA skeleton in an asymmetric fashion was developed by Johnson and co-workers in 2004. [59] Starting from acylsilanes 121 and cyanoformates 122, they succeeded in accessing the silyl ethers 123 via an Al(salen) complex C25-catalyzed cyanation -1,2-Brook rearrangement -C-acylation sequence as outlined in Scheme 24. Hereby, the catalyst first forms a nucleophilic CN-species with 122, which gives 125 upon addition to starting material 121. This intermediate then undergoes a 1,2-Brook rearrangement towards the silyloxy nitrile anion 126, which finally performs the asymmetric Cacylation giving product 123. A final reduction of the nitrile group was also successfully reported, thus resulting in an efficient and, compared to the other approaches described before, complementary synthesis strategy for the asymmetric formation of α-oxygenated--AA 124 from simple starting materials.

α-OR--AA Derivatives via Reductive Approaches
Besides the asymmetric C-X or C-C bond forming reactions discussed so far, asymmetric reductive approaches of already appropriately constituted sp 2 -hybridized -AA precursors represent another powerful way to access chiral α-oxygenated--AA derivatives (Scheme 25). [60,61] Around 10 years ago, Zhang's group introduced a highly selective protocol for the asymmetric hydrosilylation of the α-O-acylated -aminoesters 127 by using the chiral Lewis base catalyst C26 (Scheme 25A). [60a] A few years later, Zhang, Lv and their co-workers then showed that the same substrates can also be hydrogenated with excellent enantio-and diastereoselectivities employing asymmetric Rh-catalysis (ligand L10; Scheme 25B). [60b] An alternative reductive approach which directly yielded the free-OH-containing -amino ester 99 was reported by Johnson's group in 2013 (Scheme 25C). [61] Hereby, they started from the racemic α-diazoesters 129, which were first converted in the α-oxoesters 130, followed by a Ru complex C27-catalyzed transfer hydrogenation. Scheme 25. Reductive approaches for the synthesis of α-oxygenated--AA derivatives.

α-ORand α-SR--AA Derivatives by Miscellaneous Approaches
The asymmetric aminohydroxylation of α, -unsaturated esters provides a direct entry to α-hydroxy--AA derivatives, as demonstrated by McLeod and co-workers in 2008 for esters 131 already (Scheme 26). [62] Noteworthy, in that specific study the major target was on the utilization of products 134 to access various 3-and 4-amino sugars, rather than on -amino acid chemistry. Nevertheless, this example clearly underscores the potential of asymmetric aminohydroxylation reactions for α-OH--AA syntheses. Another interesting methodology for the construction of -AA derivatives was recently reported by Shao, He, and coworkers (Scheme 27). [63] Starting from the α-SR-acrylate 135 and the isocyanide 136, they carried out an asymmetric Ag-catalyzed (3+2) cyclization reaction, which, after reductive workup, gave the α-SR--proline derivatives 137 with excellent enantio-and good diastereoselectivities. In addition to using α-keto esters as acceptors as outlined above (see Scheme 22 and Scheme 23), enolizable derivatives like compounds 138 can also be utilized to access α-OH--AA derivatives via asymmetric α-amination approaches, as reported by Jørgensen's group in 2002 already. [64] By controlling the αamination of 138 with diazocarboxylate 19 by using the chiral Cu-catalyst C28, they achieved high levels of enantioselectivities for the formation of products 139 (Scheme 28). The ketofunctionality could then be reduced with high diastereoselectivity, providing a direct route to the α-OH--AA derivative 140. Scheme 28. Asymmetric amination of α-keto esters 138.

α-NR 2 -and α-PR 2 --AA Derivatives via Asymmetric Electrophilic α-Heterofunctionalizations
The synthesis and chemistry of α, -diamino acids have attracted much attention in the past and comprehensive reviews covering this important compound class have been reported. [7] Given these detailed previous overviews, we will only try to give some general outline of the most commonly applied methods to synthesize these compounds in the following chapters, with a special focus on those (more recent) reports that have not been discussed in the existing reviews. [7] The asymmetric synthesis of α, -diamino acids via asymmetric α-amination reactions of suited -AA-based building blocks has received relatively little attention so far, [7,[65][66][67] with interesting organocatalytic approaches by the groups of Greck [65] and Brière [66] standing out (Scheme 29). In 2011, Greck′s research group reported a stereoselective one pot Mannich-reaction/ α-amination protocol to assemble the parent α, -diamino carbonyl skeleton (Scheme 29A). [65] Carrying out the Mannich reaction of acetaldehyde (141) with imine 57 under enamine catalysis (using catalyst C29) first, followed by direct α-amination with reagent 19 gave product 142 with excellent stereoselectivity. Carefully optimized downstream chemistry then gave access to the syn-configured α, -diamino acid 143. [65] Very recently, Brière and co-workers developed an asymmetric α-amination reaction of α-substituted isoxazolidin-5-ones 83 with diazocarboxylate 19 (Scheme 29B). [66] The reaction proceeded smoothly by using the Maruoka catalyst C17 and reductive N-O cleavage of the primary reaction product 144 then yielded the 2,2 -amino acid derivative 145 with satisfying enantioselectivity. Scheme 29. Asymmetric α-amination methods of -AA precursors.
Besides these asymmetric electrophilic α-amination reactions of suited -AA precursors, also the asymmetric α-phosphorylation of cyanoacetates 30 with diarylphosphine chlorides 146 was successfully carried out en route to α-P--AA derivatives, as reported by Jørgensen and co-workers (Scheme 30). [68] By using the dimeric Cinchona alkaloid catalyst C30, they introduced a protocol for the direct formation of products 147, which could then be transferred into the protected α-phosphorylated--AA 148 directly by means of established functional group interconversion reactions.
Eur. J. Org. Chem. 2021, 202-219 www.eurjoc.org © 2020 The Authors. Published by Wiley-VCH GmbH 213 acidic hydrolysis, the obtained anti-configured -amino-α-azido products were then converted straightforwardly to the corresponding diamino acids 151 by reduction of the azido group under Pd-catalysis. On the other hand, syn-diamino esters 153 were synthesized successfully by He's and Zhang′s research groups very recently (Scheme 31B). [71] By the reaction of Nphosphinoylimines 57 with glycine aldimines 152 under bifunctional Cu-urea catalysis the desired syn-products 153 were obtained with very high levels of diastereo-and enantioselectivity, thus providing a powerful alternative to Shibasaki's anti-selective protocol.
With respect to the utilization of ketimines, Xie and co-workers developed a highly diastereo-and enantioselective synthetic route to access Mannich products 156 by reacting imine 154 with glycine Schiff base 155 using Cu(OAc) 2 in combination with ligand L15 (Scheme 32A). [72] This methodology gave access to the highly functionalized α, -diamino acid derivatives 156 with excellent selectivities, and further protecting group hydrolysis was demonstrated as well. Very recently, the groups of Yang and Deng [73] and Wu [74] independently reported the addition of glycine Schiff bases 155 to isatin-derived ketimine derivatives 157 under Cu(I)-catalysis (Scheme 31B). Noteworthy, the diastereoselectivity of this transformation could be efficiently controlled by nature of the employed ligand (and conditions), thus resulting in a highly divergent catalysis concept to access these densely functionalized target molecules. Scheme 32. Cu-catalyzed asymmetric Mannich reactions with ketimines.
Azlactones 12 are amongst the most frequently employed masked α-amino acid starting materials for asymmetric syntheses (see Scheme 3 and Scheme 4 for already discussed examples). Accordingly, it comes as no surprise that they have also been heavily utilized for asymmetric Mannich-type approaches to access chiral α, -diamino acid derivatives (Scheme 33). [7,[75][76][77] A powerful asymmetric procedure was published in 2011 by Toste′s group, who applied the L18(AuOBz) 2 complex to control the asymmetric reaction between azlactones 12 and aldimines 57.
[75b] Shortly after, Hui and co-workers utilized the chiral nucleophilic ring-opening reactions, were reported as well, illustrating the power of these methods to access a multitude of chiral α, -diamino acid derivatives from simple starting materials with high levels of stereocontrol.
In 2016, Terada and co-workers investigated the asymmetric addition of azlactones 12 and thiazolones 161 to the acetaldehyde-based enamide 160 under chiral phosphoric acid catalysis (enamide 160 tautomerizes to the corresponding imine under acidic conditions). [77] Interestingly, while the classical azlactones 12 performed with very low selectivities only, their sulfurcontaining analogs 161 could be employed with very high enantio-and diastereoselectivities when using the chiral phosphoric acid catalyst C33, giving access to the masked α,diamino acids 162 with excellent selectivities (Scheme 34). [77] Scheme 34. Asymmetric phosphoric acid-catalyzed addition of thiazolones 161 to enamides 160.
Besides the use of azlactones 12 as masked α-amino acid starting materials for α, -diamino acid syntheses, the glycine Schiff bases 155 have been used very extensively for asymmetric Mannich reactions, i.e. in combination with asymmetric ionpairing catalysis. [78,79] Most of the seminal reports in this field have been summarized in previous reviews on α, -diamino acids [7] and will therefore not be covered herein anymore. However, one more recent report that really underscores the potential of this non-covalent organocatalytic activation strategy was reported by Maruoka's group in 2015 (Scheme 35). [79] By starting from the stable aminals 163, they developed a highly efficient protocol to generate the corresponding N-Boc aldimines in situ under basic conditions, thus avoiding the preformation of these usually sensitive imines. The in situ formed imines then reacted with Schiff bases 155 with very high diastereo-and enantioselectivities in the presence of the chiral ammonium salt ion-pairing catalyst C34, giving the α, -diamino ester 164 upon hydrolysis of the imine group then.
An interesting direct Mannich approach towards orthogonally N-protected α, -diamino esters was developed by Baudoux, Rouden, and co-workers in 2017 (Scheme 36). [80] By using the α-amido malonic acid half ester 165 in a decarboxylative Mannich reaction with aldimine 57, they were able to directly access the diamino ester 166 in a racemic manner first. [80a] In addition, the newly designed Cinchona alkaloid-based thioamide catalyst C35 gave some promising levels of enantioselectivity for both diastereomers, demonstrating the general potential of this interesting concept. Scheme 36. Decarboxylative organocatalytic Mannich approach for the syntheses of α, -diamino esters 166.
A very inspiring biomimetic concept demonstrating the direct use of free amine-containing α-aminoesters 167 for Mannich reactions was recently reported by the groups of Yuan and Zhao (Scheme 37). [81] Scheme 37. Direct Mannich addition of free amine-containing esters 167.
By utilizing the chiral pyridiniumcarbaldehyde C36 as a catalyst, they succeeded in developing a protocol for the direct highly stereoselective addition of 167 to 57 with very low catalyst loadings. The chiral catalyst hereby forms a Schiff base with 167 under the reaction conditions, mimicking the behavior of Nature's transamination and amino acid decarboxylation cofactor pyridoxal phosphate. [81] This chiral enolate species then adds to the imine 57 with excellent face-differentiation, followed by hydrolysis of the catalyst 36 again.
A versatile strategy for the synthesis of α, -diamino esters utilizing α-diazoesters 170 as starting materials were introduced by Hu's group around 10 years ago (Scheme 38). [82,83] By using a catalyst system consisting of Rh 2 (OAc) 2 and a chiral phosphoric acid (C37 or C38) together with tartaric acid as a co-catalyst, the products 172 could be accessed directly from diazoester 170, carbamate 171, and imines 57. Hereby the Rhcarbenoid species 173 is formed first, which is trapped by the addition of 171 resulting in the ylide-type intermediate 174.
The latter then undergoes the chiral phosphoric acid controlled Mannich reaction with 57. Noteworthy, the diastereoselectivity of the reaction can be controlled very efficiently by nature of the catalyst. While C37 favors the syn-product, C38 allows for the opposite anti-diastereoselectivity (Scheme 38). [82,83] Besides Mannich approaches of appropriately decorated αamino acid derivatives as outlined so far, asymmetric aza-Henry type reactions utilizing different nitroalkanes have been successfully applied to access the α, -diamino acid scaffold as well. [7,[86][87][88] Retrosynthetically, it can be differentiated between two complementary strategies. First, α-nitroesters like compound 5 can be added to aldimines 57 in the presence of a chiral (organo)-catalyst, as reported by the groups of Huang and Dong [88a] and He, Liu, and co-workers (Scheme 39A). [88b] In both cases, chiral ion-pairing catalysts were successfully employed, either the bis-thiourea-containing guanidinium salt C39, or the Cinchona alkaloid-based quaternary ammonium salt C40. On the other hand, a simple nitroalkane, i.e. nitromethane (110), can be added to an α-imino ester like compound 176 to access the target α, -diamino ester skeleton as well (Scheme 39B). [87] As demonstrated by Lin and Duan re-Scheme 39. Asymmetric aza-Henry type reactions to access the α, -diamino acid motive. cently, this reaction can be controlled efficiently by using the bifunctional ammonium salt C41 as a catalyst, giving products 177 with excellent enantioselectivities.

α-NR 2 --AA Derivatives Starting from Alkenes
As outlined in Scheme 25 for the synthesis of α-oxygenated--AA derivatives, the stereoselective reduction of appropriately substituted α, -unsaturated carbonyl compounds is a powerful strategy to access chiral -AA surrogates. In analogy to those already illustrated approaches, also the stereoselective reduction of α, -diamino-α, -unsaturated carboxylic acid derivatives can be successfully carried out to access enantioenriched α,diamino acids. [89,90] For example, compounds 178 can be converted into the orthogonally N-protected esters 179 with very high enantioselectivities and good diastereoselectivities by employing a C42-catalyzed hydrosilylation, as developed by Zhang's group in 2013 (Scheme 40). [90] Scheme 40. Asymmetric hydrosilyation of α, -unsaturated esters 178.
Besides carrying out asymmetric reductions of α, -diamino alkenes as shown in Scheme 40, another synthetically usefully alkene-based strategy towards α, -diamino acids are aza-Michael-initiated approaches (Scheme 41 and Scheme 42). [91][92][93][94] Several complementary, either catalyst-or chiral auxiliarycontrolled asymmetric protocols have been reported to achieve this transformation. One of the most commonly employed strategies is to carry out the addition of suited N-nucleophiles to chiral Ni complexes 180, as demonstrated by numerous research groups over the last years (Scheme 41A). [92] These reactions usually proceed with high diastereoselectivities and the resulting products 181 can easily be hydrolyzed to the free amino acids 182 then, thus resulting in a rather broadly applicable and general synthesis strategy. Very recently, Navo, Peregrina, and co-workers then reported another very useful auxiliary approach by adding secondary amines to the novel chiral acceptor molecules 183, which resulted in the formation of single diastereomers of products 184, which again could easily be hydrolyzed to obtain the targets 182 with more or less perfect enantiopurity (Scheme 41B). [93] In addition to these very powerful and often used auxiliary methods, also catalytic asymmetric approaches have been reported. In 2016, Takemoto et al. introduced a highly selective chiral phosphoric acid C33-catalyzed (3+2)-cyclization reaction between the vinylogous azlactones 185 and hydroxylamides 186 (Scheme 42). [94] The hereby obtained products 187 can then easily undergo nucleophilic ring-opening, giving again access to the parent α, -diamino acid scaffold, as exemplified for compounds 188 again.

Synopsis
As outlined in this short review, a broad variety of different asymmetric synthesis and catalysis concepts to access potentially biologically active α-heterofunctionalized αand -amino acid derivatives have been introduced over the last decades. While the most commonly employed approaches for α-amino acid derivatives obviously rely on electrophilic α-heterofunctionalization reactions of suited (masked) α-amino acids, a much broader diversity of conceptually different strategies to access -amino acids are available. Here not only asymmetric electrophilic α-heterofunctionalizations, but also asymmetric C-C-bond forming reactions, i.e. Mannich type reactions have been used very successfully. In addition, it should be emphasized that not only asymmetric catalysis approaches, but sometimes also chiral auxiliary-controlled methods have been employed with excellent selectivities, thus providing a complementary approach, i.e. where catalytic methods are still limited.
All these methods have their obvious benefits but often also limitations and it is clear that with respect to potential larger scale syntheses the single methods have to be evaluated with respect to their potential and limitations, e.g. with respect to costs and atom efficiency, to mention two relevant points of consideration only. Thus, by looking at the sometimes high loadings of complicated and/or expensive catalysts or the costs and the difficulties in removing and recovering the chiral auxiliaries that are necessary it is clear that, despite all the progress that was made in this field, further developments are required to really make the methods interesting for industry-related approaches as well. In addition, it becomes obvious that some classes of α-heterofunctionalized amino acids have still been reported only sparingly. This can either be attributed to the sensitive nature of the compounds themselves, as is the case for α-fluorinated α-amino acids, or because of a lack of reliable asymmetric procedures (e.g. to the best of our knowledge there are no really generally applicable methods for asymmetric α-phosphorylations and also the development of asymmetric α-hydroxylations of suited -amino acid precursors is still in its infancy, to mention two examples only).
Accordingly, we are convinced that this field will remain a heavily investigated one, which is also sparking the development of new catalysis concepts and the introduction of new suited precursor scaffolds.