Synergistic Cu/Pd‐Catalyzed Asymmetric Allenylic Alkylation of Azomethine Ylides for the Construction of α‐Allene‐Substituted Nonproteinogenic α‐Amino Acids

Abstract

An unprecedented asymmetrica llenylic alkylation of readily available imine esters, whichw as enabled by as ynergistic Cu/Pd catalysis, has been developed. This dual catalytic system possesses good substrate compatibility,d elivering ad iversea rray of nonproteinogenic a-allenylic a-mono-or a,a-disubstituted a-aminoa cids (a-AAs) with high yields and generally excellent enantioselectivities.F urthermore, the scalability and practicability of the current synthetic protocol were proven by performing gram-scale reactions and by the first catalytic asymmetric synthesis of naturallyo ccurring (S)-g-allenic a-amino acid, respectively.Opticallya ctive nonproteinogenic a-monosubstituted or a,adisubstituted a-amino acids (a-AAs) are privileged constituents of numerousb iologically active natural compounds and pharmaceutical ingredients. [1] For example, these versatile structure motifs have been frequently found in unique enzyme inhibitors [2] and pharmacologically importantn onnatural peptides and proteinsw ith enhanced functionalities. [3] Alternatively, allene-containing compounds have also attracted considerable attention due to their important chemical and biologicalp roperties in synthetic transformations [4] and drug molecules [5] as well as naturalp roducts. [4c, 5a, 6] In view of these unique features of both nonproteinogenic a-AAs and allene units,d eveloping an efficient approach to access nonproteinogenic a-A As bearing an allenic moiety in ah ighly enantioselectivem anner is of great significancea nd also very desirable.With operationally simplicity and synthetically utility,t he palladium-catalyzed enantioselective allenylic alkylation of racemic 2,3-allenol derivatives involving chiral vinyl-p-allylpalladium intermediate [7] has emerged as one of the commonly used tools to synthesize enantiomerically enriched allenes or allenylic substitution products. Among these elegant methodologies using chiral palladium h 3 -butadienyl species as electrophiles, most of the reported examples focusedo nt he construction of allenes with axial chirality, [8] and the established protocols capable of achieving allene derivatives containingc entral chirality [8g, 9] are stillraretod ate (Scheme 1a). Furthermore, the enantiocontrol of nucleophiles has not been touched yet in all of the known cases,p robably due to the synthetic challenges in the palladium-catalyzed asymmetric allylation reaction, that is, the long distance between the catalytic site of the chiral palladium complexa nd the reaction site in nucleophile reagents. [10] Recently,w eand others have developedanew seto fd ual catalytic systemsf or efficient asymmetrica llylic alkylation reactions [10b, 11,12] of readily available iminee sters, in which ac hiral Cu I complex anda chiral [13] or chiral Pd 0 complex [14] has been combined and successfully used as the synergisticc atalysts, leading to various a-quaternary nonproteinogenic a-AAs [15] Scheme1.Catalytic asymmetric allenylic alkylation of non-prochiral nucleophiles withc hiral Pd complex (previous wor...

Catalytic Asymmetric Reactions with N-Metallated Azomethine Ylides

“…In 2019, with [Cu I /( S , S p )- L6c + Pd 0 / t BuXPhos] as dual catalysts, we developed an efficient catalytic asymmetric allenylic alkylation of azomethine ylides that allowed the rapid construction of a series of synthetically useful α-allenylic α-amino acids 76 with high stereoselectivities (Scheme a) . Additionally, this protocol provided the first catalytic asymmetric synthesis of naturally occurring ( S )-2-aminohexa-4,5-dienoic acid 77 (Scheme b).…”

Palladium-Catalyzed Stereoselective Construction of 1,3-Stereocenters Displaying Axial and Central Chirality via Asymmetric Alkylations

“…Moreover, transition metal-catalyzed 1,4-addition of enynes serves as a powerful strategy for the concise and efficient synthesis of multi-substituted chiral allenes [ 26 , 27 , 28 , 29 , 30 ]. It is worth noting that although great progress has been achieved for the enantioselective construction of allenyl axial chirality [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ], only two reports documented the asymmetric concurrent creation of 1,3-stereocenters bearing allenyl axial chirality and central chirality, contributed by the Trost group [ 11 ] and the Ma/Zhang group [ 39 ], respectively. Both studies exploited the strategy of Pd-catalyzed asymmetric allenylic alkylation employing racemic allenyl acetate electrophile through dynamic kinetic transformation.…”

A Pd-catalyzed highly selective three-component protocol for trisubstituted allenes

“…Such A-1-type allenyl malonates have been demonstrated as highly versatile building blocks for natural allene product synthesis 12 and are traditionally prepared via the transition metal catalyzed reactions of 2,3-allenol derivatives with malonates. 13,14 Although the precursors for 2,4-disubstituted 2,3-allenol derivatives, 2,3-allenols, are conveniently available via allenation of the propargyl alcohol (ATA) with aldehydes 15,16 ( Scheme 1d ), the current method is highly efficient and diverse due to the readily availability of the three starting materials and irreplaceable due to the inaccessibility of D-type allenols via the ATA reaction.…”