Towards α,α -disubstituted amino acids containing vicinal stereocenters via stereoselective transition-metal catalyzed allylation

Designer amino acids find use across many scientific disciplines. The preparation of amino acids bearing acyclic vicinal stereocenters remains a challenge in synthesis. Herein, we highlight transition-metal catalyzed allylations for the stereoselective synthesis of disubstituted α -amino acid precursors bearing vicinal stereocenters. Allylation of azlactones, α -imino esters, and aldimine esters with dienes and allylic leaving groups are among the most common strategies. These developments provide context for our work featuring the asymmetric addition of α -nitroesters to alkynes.


Introduction
Amino acids comprise the backbones of proteins and are fundamental building blocks of living organisms.6][7] Additionally, amino acids have been used as intermediates in total synthesis 8,9 and as chiral catalysts. 10,113][14] These amino acids can impart unique conformations for folded peptides. 15

Figure 1.
[14] Acyclic vicinal stereocenters are important yet challenging motifs to access.Nonetheless, chemists have accessed these scaffolds using strategies such as allylations, conjugate additions, sigmatropic rearrangements, and ring openings. 16For allylations, transition-metal catalysis generally offers excellent diastereocontrol, with high enantio-and regioselectivity. 16This approach uses allylic carbonates and acetates as surrogates to generate transition-metal-π-allyl complexes that can be intercepted by a nucleophile.A challenge of allylation involves the control of regioselectivity, determined by which side of the π-allyl complex is attacked by the nucleophile. 17- 20The "branched" isomer is defined by the attack of the nucleophile on the side with R 2 , resulting in a product where R 2 and the nucleophile are bonded to the same carbon atom (Figure 2).Contrarily, the "linear" isomer is a result of a nucleophilic attack on the π-allyl complex from the opposing side of R 2 .Herein, we discuss advancements in the use of transition-metal catalyzed allylation for the synthesis of acyclic DAA motifs bearing vicinal stereocenters.This review is organized by the amino acid derived coupling partners: azlactones, α-imino esters, and aldimine esters (Figure 3).These developments provide context for our work on the addition of α-nitroesters to alkynes to access DAA precursors.

Allylation of Azlactones
Azlactones are the earliest coupling partners used for the synthesis of DAA precursors using a transition-metal catalyzed allylation strategy.These acidic pronucleophiles readily tautomerize and react at the C4 carbon atom (Figure 4).The first example was reported by Trost which detailed an asymmetric Mo-catalyzed allylation of azlactones using ligand L1. 17 This transformation was highly diastereoselective, and the strategic choice of base contributed to a regioselective preference for the branched product 1.This is followed by in situ hydrolysis to give protected amino ester 2. This one-pot protocol led to improved yields and diastereoselectivity compared to earlier multi-step procedures.The substrate scope explored numerous azlactones and aryl-substituted allylic carbonates.A selection of aryl substituents for R 2 were reported with good results (2a, 2b).High branched selectivity was observed for methyl or benzyl R 1 substituents (2a, 2b, 2c).Substrates containing longer alkyl chains, however, suffered from lower regioselectivity (2d, 2e).Altogether, high enantio-and diastereoselectivities were observed.Computational mechanistic studies provided a model for understanding diastereoselectivity. Molecular Mechanics (MM2) calculations suggested that TS1 is approximately 2-10 kcal mol -1 lower in energy than TS2 leading to the observed products.Subsequently, Hartwig reported an Ir-catalyzed allylation of azlactones where high diastereo-and enantioselectivities were achieved using O,O,P,N-BINOL ligand L2 for the synthesis of DAA precursors 3 (Figure 5). 18The transformation gave high regioselectivities for meta-and para-substituted phenyl R 2 groups (3a-3d).However, electron-donating substituents were less reactive (3b), and ortho-substituted aryl groups resulted in lower diastereo-and enantioselectivities (3e).This work expands upon the scope of Trost's Mo-catalyzed method by introducing heteroaromatic substituents and dienyl carbonates (3f and 3g).Notably, aliphatic allylic carbonates resulted in low diastereoselectivity.As with Trost's method, Hartwig's Ir-catalyzed process favors the branched regioisomer.Furthermore, this method is applicable to azlactones derived from natural amino acids (3h-3j).
Further studies offer insight into the mechanism.Experiments replacing [Ag] with phosphoric acid 4 resulted in the same diastereoselectivity.Meanwhile, experiments without phosphate or phosphoric acid co-catalyst 4 resulted in diminished dr, suggesting that the phosphate anion, instead of the silver cation, is responsible for the high diastereoselectivity.These studies also confirm the counterion-assisted allylation via metalacyclic Ir complex 5. Zhang was the first to develop Pd-catalyzed allylation of azlactones.Similar to Hartwig, 18 Zhang's method uses O,O,P,N-BINOL ligand L3 to give protected amino acids 6 bearing tethered allylic alcohols (Figure 6). 19The enantioselectivity decreases as the sterical hindrance of the R 1 substituent increases (6a and 6b).Ortho-and para-substituted aryl ethers at R 2 were well tolerated giving excellent enantioselectivities (6c-6e).Additionally, heteroaromatic substituents showed great reactivity but modest enantioselectivity (6f).The branched regioselectivity is dependent upon hydrogen-bonding between the incoming azlactone nucleophile and the hydroxyl group of the Pd-π-allyl complex (intermediate 7).Removal of the hydroxyl coordinating group via allylic acetate 8 leads to a reversal of regioselectivity, as seen in 9. Therefore, the strategic choice of a Pd-π-allyl precursor (cyclic carbonates or acetates) allows for complementary control of regioselectivity.Other transition-metal π-allyl precursors include 1,3-dienes.Meek and co-workers reported a Rh-catalyzed hydrofunctionalization of 1,3-dienes with azlactones for the preparation of DAA precursors. 21Afterwards, Wang and Dong developed an asymmetric Pd-catalyzed allylation of azlactones with 1,3-dienes using the phosphinooxazoline ligand L4 (Figure 7). 20A Pd-H is generated by oxidative addition to HBF 4 •Et 2 O, and the 1,3diene undergoes migratory insertion to generate cationic Pd-π-allyl complex 14 .Intermediate 14 is then trapped by an azlactone pronucleophile to give DAA precursor 10.Wang and Dong note that steric hindrance from the tert-butyl group in the ligand likely contributed to the selectivity.The substrate scope tolerates a broad array of both aromatic and aliphatic substituents.Compared to substrates with methyl R 1 substituents (10a), substrates bearing more sterically hindered groups at R 1 maintained high enantioselectivities (>93% ee) and diastereoselectivities (>10:1 dr), albeit with lower yields (10b).This strategy tolerates olefin side chains giving access to handles for further functionalization (10c) (vide infra).Both electron-rich (10d) and electron-poor (10e) para-aryl R 3 substituents showed high reactivity and diastereoselectivity; however, the diastereoselectivity is reduced when aryl R 1 substituents are introduced (10f).For the scope of 1,3-dienes, both electron-donating (10g) and withdrawing (10h) para-substituted phenyl groups gave higher diastereoselectivities compared to ortho-(10i) and meta-substituents (10j).Alkyl R 2 substituents (10k) were tolerated with high enantioselectivity but suffered from lower diastereoselectivity. Heteroaromatic furanyl (10l) and electron-withdrawing methyl ester substrates (10m) were reported to maintain good selectivity and yield.Although broad, the scope was limited to terminal 1,3-dienes.
Synthetic applications of these allylated azlactones were demonstrated.Reductive ring opening of 10a gave the β-amino alcohol 11 with complete retention of stereochemistry.Hydrolysis of allyl-substituted allylation product 10c with K 2 CO 3 gave the protected amino ester 12.A ring closing metathesis of 12 with Grubbs-II gave cyclopentene 13.These cyclic intermediates can be used for the synthesis of biologically relevant compounds such as metabotropic receptor antagonists. 22

Synergistic Dual Catalysis
The simultaneous activation of two coupling partners with two independent catalysts is known as synergistic catalysis. 23This strategy has become a useful tool for the synthesis of complex molecular architectures, 24 and it has been especially useful in transition-metal catalyzed allylations.When each co-catalyst is chiral, synergistic catalysis can provide divergent control over the relative stereochemistry of two generated vicinal stereocenters.By the simple exchange of a catalyst with its enantiomer, one can access the opposite diastereomer.Herein, we highlight recent advancements in the use of synergistic transition-metal catalysis for the allylation of α-imino esters to access DAA motifs.

Allylation of α-imino esters
The earliest synergistic approach for the synthesis of DAA precursors was reported by Han. 25 Here, a chiral Ir catalyst was used along with a phase transfer ammonium co-catalyst to solubilize the in situ generated 2-azaallyl anion 16 (Figure 8).The use of an ammonium co-catalyst was necessary for high yield and enantioselectivity.The solvated anion 16 then attacks the Ir-π-allyl complex 17 to generate the amino ester 15.This method tolerates a range of aromatic substitutions.High enantio-and diastereoselectivity is achieved with orthosubstituted phenyl groups at the R 2 position (15a, 15b).In addition, para-(15c, 15f) and meta-substituted (15d) phenyl and naphthalene (15e) substituents are tolerated at the R 1 position.Ortho-subsituted aryl nitroesters (not shown) are not tolerated likely due to steric hindrance.
There are many notable advantages offered by Han's report.Contrary to the use of azlactones, dual catalysis provides single-step direct access to the acyclic amino ester motif.Additionally, a wide selection of aryl R 1 substituents, which were inaccessible by azlactone methods, are available using synergistic catalysis (vide supra).This expansion of scope allows for the preparation of biologically interesting compounds. 26For instance, acylation of 15f followed by cyclization with iodine provides the quaternary proline analogue 18.These highly substituted proline derivatives are crucial for nucleating secondary structures in peptides. 26In addition, deprotection of 15f can be facilitated by TFA to provide the corresponding DAA 19.

Allylation of aldimine esters
Zhang 27 and Wang 28 independently reported the first synergistic methods using two transition-metal cocatalysts (Cu and Ir) to prepare α-AAs bearing vicinal stereocenters.By altering the ligand stereochemistry of either complex, all four stereoisomers could be accessed (Figure 9).A Cu catalyst bearing the chiral PHOX ligand L6 activates the aldimine ester to form cyclic ylide 20.Meanwhile, an Ir catalyst containing the chiral O,O,P,N ligand L3 coordinates to the allylic carbonate, generating the π-allyl complex 21.Lastly, transition-metal complexes 20 and 21 are coupled to generate a new C-C bond forming amino ester 22.Therefore, the Cu catalyst controls the α-carbon stereochemistry, and the Ir catalyst controls the β-carbon's stereochemistry.

Figure 9. Synergistic dual catalysis allows controlled access to all four stereoisomers (top). Mechanism shows that each metal catalyst controls stereochemistry of one of the vicinal stereocenters (bottom).
The substrate scope of Zhang's study was quite broad. 27All stereoisomers of model substrate 23a were accessed in similar yields and selectivities by judicious combinations of the Cu and Ir catalysts (Figure 10).Electron-donating and electron withdrawing ortho-, meta-, and para-substituted phenyl rings at the R 2 position resulted in excellent enantioselectivities and good diastereoselectivities (23b, 23c, 23d, 23e).Heteroaromatic substituents such as indolyl 23f suffered from lower diastereoselectivity.When the aromatic substituent was replaced with a methyl group in R 2 , the enantioselectivity and diastereoselectivity remained high, but the yield dropped.A variety of aldimine esters were also well tolerated, particularly those with OMe as X.The allylation of α-AAs (23g) and dipeptides (23h) were also demonstrated.Stereo-divergent access to two stereoisomers of Gly-L-Leu derivative (23h) was achieved with high diastereoselectivity, while also retaining the configuration of the pre-existing stereocenter.Similarly, Wang reported an Ir and Cu dual catalyzed allylation of aldimine esters (Figure 11). 28The results show improved scope with para-, meta-, and ortho-substituted phenyl allylic carbonates.Notably, para-fluoro substitutions gave higher diastereoselectivity but meta-halogenated rings gave lower selectivities compared to Zhang's work (24b).Observed diastereoselectivity was >20:1 for all reported allylic substrates, including aromatic, furyl, thienyl, and methyl (24a) for R 2 .The only exceptions were 2-thiazolyl and para-Cl-C 6 H 4 , which gave 7:1 dr and 14:1 dr, respectively.In all cases, the enantioselectivity was at or above 98% ee.A variety of aldimine esters also provided excellent results, including alkyl, benzyl and aryl R 1 substituents (24c-24e).Additionally, all four stereoisomers of product 24e were accessed with comparable yields and selectivities by altering the stereochemistry of the Ir and Cu co-catalysts.

AUTHOR(S)
Wang demonstrated applications of this method.For instance, plant growth regulator (2S,3S)-2-amino-3cyclopropylbutanoic acid 26 was synthesized.Imino ester 24f was first constructed using this highly selective synergistic coupling and was then converted to compound 25 via cyclopropanation in 99% yield.Lastly, cyclopropane 25 was hydrogenated to the carboxylic acid 26 in 99% yield and 10:1 dr with full retention of stereochemistry.These three steps offer highly efficient and selective access to 26 compared to previously reported 6-8 step syntheses. 29,30Next, Zi reported a variation of Zhang's and Wang's works using a Pd and Cu dual catalyst system and 1,3dienes (Figure 12). 31In contrast to prior reports, however, a Pd-π-allyl complex bearing a chiral Josiphos ligand L9 is formed by the insertion of a 1,3-diene into a Pd-H bond.The use of transition-metal hydrides has been effective for coupling of unsaturated motifs such as allenes, alkynes, and 1,3-dienes with various nucleophiles. 32- 44This Pd-π-allyl complex then engages with the Cu-activated aldimine ester to generate the coupled product 27.
The scope of this transformation builds upon the previously reported methods.Firstly, all four stereoisomers of 27a were accessed in >99% ee; however, the diastereoselectivities varied for each case, which could be a result of matched-mismatched pairs.Halogen-substituted phenyl dienes (27b), lactams (27d), lactones, and cyclic imine-derived aldimine esters (27e) resulted in high reactivities and selectivities.Moreover, bulkier esters such as 27f gave increased reactivities.Electron-withdrawing and electron-donating phenyl R 4 substituents provided good yields as well as excellent diastereo-and enantioselectivities.A few other aromatic and heteroaromatic substituents (2-naphthyl, 2-furyl, and 2-thiophenyl) were also reported to give good yields and high selectivities.The scope was limited by alkyl substituted dienes which gave decreased yields 27c.Additionally, the reaction performs will with the use of ketimine substrates (27g).In contrast to previous reports, this method allows for the addition of 1,4-disubstituted dienes enabling an expanded scope towards other alkylsubstituted β-stereocenters (27h, 27i); however, accessing DAAs bearing aryl R 2 substituents with this method remains a challenge.

Alkynes as Atom Economical Metal-Allyl Precursors
6][47][48][49][50] Similar atom economical 52 isomerizations have been used in conjunction with nucleophiles to generate C-Heteroatom and C-C bonds with high enantioselectivities. [33][34][35][36][37][38][39][40][41][42][43] Using this method, the branched regioisomer is preferred making this a complementary approach to previous reports by Ooi. 44,51This autotandem catalytic process begins with a migratory insertion of alkyne 28 into Rh-H 29 to generate intermediate 30.This is followed by β-hydride elimination to generate allene 31 (Figure 13).The allene 31 then undergoes migratory insertion into Rh-H 29 to generate Rh-π-allyl complex 32.As before, π-allyl complex 32 can be intercepted by a nucleophile to generate product 33.We envisioned employing this strategy for the asymmetric synthesis of DAA precursors. 44An examination of α-nitrocarbonyl derivatives indicated α-nitroesters as the best coupling partners.These substrates provided high yields and diastereoselectivities as well as high enantioselectivities with the use of MeO-BIPHEP L11 as a chiral ligand (Figure 14).The substrate scope was sensitive to both the sterics and electronics of each coupling partner.In nearly all cases, high diastereo-and regioselectivities (>20:1 dr and rr) were observed.For αnitroesters derived from the canonical amino acids, sterically hindered side chains such as valine derivative 34a gave no reactivity.Electron poor groups such as para-fluorophenylalanine derivative 34b, and tyrosine derivative 34c gave moderate yields but high enantioselectivities.Interestingly, methionine derivative 34d gave excellent enantioselectivity but showed a reduced diastereoselectivity of 6:1 dr.Heteroaromatic R 1 substituents such as the indole in tryptophan derivative 34e performed well under the standard conditions.As with valine derivative 34a, phenyl substitution at R 1 resulted in no reaction (34g).The reaction was more tolerant of steric hindrance for substitutions at R 3 (34f).For the scope of alkynes, electron-withdrawing 34h and electrondonating 34i para-substituted phenyl alkynes gave moderate to good yields (56% to 88%) and excellent enantioselectivities (90% ee to 94% ee).Meta-substituted electron-rich 34k and electron-poor 34j phenyl alkynes also resulted in good reactivity and selectivity (58% to 79% yield, 92% to 96% ee).Sterically hindered ortho-chloro-substituted phenyl alkyne 34l as well as 2-naphthyl alkyne 34m gave high enantioselectivities but only moderate yields.Unfortunately, alkyl substituents resulted in no reactivity.Nonetheless, product 34n was efficiently reduced to the protected amino ester 35 with indium powder.and co-workers, showing the substrate scope of nitroesters (34a-34g) and alkynes (34h-34m), and applications of the coupled product 34n.
We undertook mechanistic studies.Deuterated phenyl alkyne 36 was coupled with nitroester 37 to give product 38 (Figure 15).The presence of hydrogen atoms at the δ-position indicates a reversible β-hydride elimination step.A Rh-H complex was observed by 1 H NMR. Lastly, a proper balance between the rates of isomerization and allylation were found to be critical for the transformation's efficiency.When alkyne 28n was replaced with allene 31n, yields were significantly diminished with higher equivalencies of allene 31n.At substoichiometric amounts of allene, however, higher yields could be restored.4][55][56] Moreover, allene 31n polymerizes under the reaction conditions in the absence of nucleophile 37 indicating a decomposition pathway and supporting the need to control the relative rates of both the isomerization and allylation cycles to maintain high reaction efficiency.

Conclusions
The works in this review offer insights into reaction scope, and versatility for the asymmetric preparation of DAA precursors consecutive stereocenters.We recently added to this reaction toolbox by demonstrating the isomerization of alkynes with Rh-H tandem catalysis.This report provides an acyclic and atom-economical method to prepare these amino acid precursors, opening the door for further exploration to expand the scope and advance applications.Such future efforts could target other biologically relevant motifs such as β-amino acids.

Figure 3 .
Figure 3. Methods of preparing DAA precursors organized by coupling partner.

Figure 12 .
Figure 12.Zi 31 and co-workers' Pd and Cu dual-catalyzed coupling of aldimine esters and dienes.

Figure 15 .
Figure 15.Mechanistic studies support the proposed catalytic cycle.
Dr. Patrick D. Parker was born and raised in Nashville, Tennessee.He obtained his Bachelor of Science degree in chemistry and mathematics from Lipscomb University.Patrick received his PhD in chemistry at North Carolina State University with Joshua Pierce and is currently completing his postdoctoral studies with Vy Dong at UC Irvine.He will soon be starting his professional career as a process chemist at Gilead Sciences, Inc. Prof. Vy M. Dong was born in Big Spring, Texas and grew up in Anaheim, California.She graduated from UC Irvine, where she majored in chemistry and completed an honor's project with Larry Overman.Vy obtained her PhD from Caltech with David MacMillan and completed postdoctoral studies with Robert Bergman and Ken Raymond at UC Berkeley.She began her independent career at the University of Toronto and returned to UC Irvine as a full professor in 2012.The Dong research team is interested in developing new catalysts, methods, and reagents for organic synthesis.This paper is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)