Three-Component Reactions with (S)-Methyl Pyroglutamate: An Efficient Way to Diversely Substituted Asymmetric Amidocyclohexenes

Abstract

Chiral N-dienyl lactams are crucial building blocks for the synthesis of complex organic compounds. However, their generation is rather challenging. This paper reports the novel one-pot reaction of (S)-methyl pyroglutamate as the amide component with different aldehydes and dienophiles (AAD reaction) to give novel chiral 1-amido-2-cyclohexenes. The corresponding N-dienyl lactams generated in situ undergo subsequent Diels-Alder reactions in good yield and diastereoselectivity. The scope and limitations of the three-component protocol were investigated. X-ray and NMR spectroscopic analysis of the products as well as DFT calculations of the intermediates were also performed to explain the observed stereoselectivity and structural features.

Expanding the Chemical Space in Practice: Diversity-Oriented Synthesis

“…Concerning the degree of stereochemical diversity, neither reactions in Scheme 4 induced any stereodivergence (dd stero = 1). Interestingly, Beller and co-workers [41,42] have recently demonstrated that this [4+2] cycloaddition reaction can be adapted to selectively produce optically pure cycloadducts by introducing a chiral auxiliary as building block (2). The corresponding d.e.…”

“…Schreiber and co-workers took advantage of the dominant stereo-induction from the -hydroxy-aldehyde group in the Petasis reaction [61,62] to develop an efficient highly diasterodivergent 3CR [63]. By reacting the "masked" -hydroxy-aldehydes (2S)- (43) or (2R)-(43) with L-phenylalanine methyl ester (41) and (E)-2-cyclopropylvinylboronic acid (42) in ethanol, the vicinal amino-alcohols (44) and the corresponding diastereomers (45) can selectively be obtained in good yield with excellent stereoselectivity (Scheme 12). This stereodivergent MCR (dd stereo = 2) enriches the vicinal amino-alcohol scaffold with a new diastereomer in nonracemic form.…”

Stereocontrolled Domino Reactions

“…In 2007, Beller and co-workers reported the diastereoselective three-component reaction of ( S )-methyl pyroglutamate 486 with aldehydes and dienophiles, such as N -methyl maleimide or maleic anhydride, which led to a range of chiral substituted 1-amido-2-cyclohexenes 487 . As shown in Scheme , these bicyclic products were formed in moderate to good yields and as single diastereomers.…”

Synthesis of sp3-rich heterocyclic frameworks by a divergent synthesis strategy

“…The reactive nitrogen was first modulated to introduce an additional functional handle that was linked up with the adjacent carbonyl group. An aldehydeamide-dienophile (AAD) multicomponent reaction 14,15 pro- vided complex, sp 3 -enriched [5,7,6]-and [5,6,6]-tricyclic fragments (6a, 6b, 7) (Scheme 1). This introduced an amide and an alkene for further vector exploration.…”