Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

Abstract

SummaryPd-catalyzed enantioselective alkylation in conjunction with further synthetic elaboration enables the formal total syntheses of a number of “classic” natural product target molecules. This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods will impact both academic and industrial settings, where the synthesis of stereogenic quaternary carbons is a continuing challenge.

Synthetic Approaches to Tricyclic Aminoketones in the Total Synthesis of Aspidosperma and Kopsia Alkaloids

“…Among the aforementioned precursors, tricyclic lactams, including five‐ and six‐membered lactams, are the most common advanced intermediates for the synthesis of tricyclic aminoketones 1 . A total of 18 synthetic strategies were achieved to synthesize 1 via the construction of tricyclic lactams [10–23] . These tricyclic lactams are almost converted into 1 via a three‐step reaction sequence involving ketalization, reduction, and deketalization as first reported by Stork and Dolfini.…”

“…In 2014, Stoltz and co‐workers reported an enantioselective palladium‐catalyzed decarboxylative allylation as a key step in their synthesis of (−)‐aspidospermine ((−)‐ 8 ) (Scheme 10). [18] 1,3‐Cyclohexanedione 68 was used as the starting material and was transformed to β ‐ketoester 69 by a three‐step reaction sequence involving etherification, acylation and alkylation. Subsequently, the authors found that the combination of 69 with [Pd(dmdba) 2 ] and ( S )‐ t ‐Bu‐PHOX rendered the enantioselective palladium‐catalyzed decarboxylative allylation to construct the α ‐quaternary carbon stereocenter in 82 % yield and 86 % ee .…”

“…Therefore, this review will summarize the synthetic approaches to the tricyclic aminoketones 1 since 1963, including highlight the construction of the C‐/D‐/E‐ring with the all‐carbon quaternary stereogenic center, and subsequent give a brief introduction to complete the synthesis of aspidosperma and kopsia alkaloids. In addition, this review will discuss the formation of tricyclic aminoketones 1 based on their precursors, including tricyclic lactams, [10–23] tricyclic vinylogous amides, [24–28] tricyclic enones, [29–31] tricyclic ethers, [32] tricyclic ketals, [33] tricyclic esters, [34] and non‐tricyclic precursors [35–38] …”

Enantioselective palladium-catalyzed allylic alkylation reactions in the synthesis of Aspidosperma and structurally related monoterpene indole alkaloids

“…In one such instance, β-amidoester 31 was exposed to a solution of Pd 2 (pmdba) 3 (5 mol %) and ( S )-(CF 3 ) 3 - t -BuPHOX ( L1 , 12.5 mol %) in toluene to furnish α-quaternary lactam 32 in 97% yield and with 99% ee (Scheme 2). Lactam 32 can be further elaborated to chiral building blocks 33–35 40 that previously required lengthy synthetic sequences to achieve high levels of enantiopurity. Consequently, the swift preparation of heterocycles 33–35 completed enantioselective formal syntheses of (–)-quebrachamine ( 2 ), 41 (–)-vincadifformine ( 4 ), 42 and (+)-rhazinilam ( 18 ), 43 respectively.…”

Construction of tertiary chiral centers by Pd-catalyzed asymmetric allylic alkylation of prochiral enolate equivalents

“…Since our initial efforts in this area, leading to the formation of α-quaternary ketones 2 from racemic β-ketoesters 1 in good yields and enantioselectivities using ( S )-4-( tert -butyl)-2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole [( S )- t -BuPHOX] 4 as a chiral ligand, 5 we have expanded the scope 6 and demonstrated the use of these methods in a number of applications. 7 We recently developed the asymmetric allylic alkylation, giving α-quaternary lactams 4 from racemic β-amidoesters 3 using ( S )-2-(2-(bis(4-(trifluoromethyl)phenyl)phosphino)-5-(trifluoromethyl)phenyl)-4-( tert -butyl)-4,5-dihydrooxazole [( S )-(CF 3 ) 3 - t -BuPHOX] 8 as a chiral ligand. 9 In the context of preparing trisubstituted tertiary stereocenters (i.e., Scheme 2, 3a ), this methodology encountered problems; (1) allylic alkylation of β-amidoester 3a gave a mixture of mono-, di-allylated and unallylated lactams, and (2) the ee value of 4a produced was low (Scheme 2a).…”