Petasis Reaction - Applications in Enantioselective Synthesis

Applications in Enantioselective Synthesis

With chiral amine nucleophile
Generally speaking, when chiral amine is used in Petasis coupling, the stereochemical outcome of Petasis reaction is strongly correlated to the chirality of the amine, and high to excellent diastereoselectivity is observed even without the usage of bulky chiral inducing groups. Chiral benzyl amines, 2-substituted pyrrolidines, and 5-substituted 2-morpholinones have been shown to induce good to excellent diastereomeric excess under different Petasis reaction conditions.

With chiral N-acyliminium ions
Chiral N-acyliminium ion “starting materials” are generally prepared by in-situ dehydration of cyclic hemiaminal. They also carry a chiral hydroxyl group that is in proximity with the iminium carbon; boronic acids react with such chiral hydroxyl groups to form a chiral and electron-rich boronate species, followed by side-selective and intramolecular boronate vinyl/aryl transfer into the iminium carbon. Hence, the reaction is highly diastereoselective, with cis- boronate aryl/vinyl transfer being the predominant pathway. Hydroxypyrrolidines and Hydroxy-γ- and δ-lactams have been shown to react very diastereoselectively, with good to excellent yield. However, such procedures are limited to the usage of vinyl- or electron-rich aryl- boronic acids only.

Batey and coworkers take advantage of the high diastereoselectivity of this reaction to prepare (±)-6-deoxycastanospermine in 7 steps, with an impressive overall yield of 32% (from the vinyl boronic ester). The key acyclic precursor to deoxycastanospermine (A) is formed first by condensing vinyl boronic ester 1 with Cbz-protected hydroxy-pyrrolidine 2 with a PBM coupling, followed by dihydroxylation and TBS protetction. A then undergo intramolecular cyclization via a one-pot imine formation and reduction sequel, followed by TBS deprotection, to afford (±)-6-deoxycastanospermine.

With thiourea catalyst
Takemoto and coworkers of Kyoto University recently reported an enantioselective Petasis-type reaction to transform quinolines into respective chiral 1,2-dihydroquinolines (product) using alkenyl boronic acids and chiral thiourea catalyst. Good yields (59-78%) and excellent enantioselectivities (82-96%) are reported.

Takemoto and coworkers observed that addition of chloroformates are required as electrophilic activating agents, and the reaction does not proceed without them. Also, a 1,2-amino alcohol functionality is required on the catalyst for the reaction to proceed stereoselectively. They rationalize these findings by suggesting that the chloroformate reagent reacted with the quinoline nitrogen to make an N-acyated quinolinium intermediate B, which is further activated by electrophilic chiral thiourea. They also suggest that the 1,2-amino alcohol functionality of the catalyst is chelating to the alkenyl boronic acids and that such chelation directed the stereochemical outcome.

With chiral biphenols
Schaus and Lou of Boston University reported the following reaction, in which chiral α-amino acids with various functionalities are conveniently furnished by mixing alkenyl diethyl boronates, secondary amines, glyoxylates and chiral biphenol catalyst in toluene in one-pot:

This reaction tolerates a wide range of functionalities, both on the sides of alkenyl boronates and the secondary amine: the electron-richness of the substrates does not affect the yield and enantioselectivity, and sterically demanding substrates (dialkylsubstituted alkenyl boronates and amines with α-stereocenter) only compromise enantioselectivity slightly. Reaction rates do vary on a case-by-case basis.
Interestingly, under the reported condition, boronic acids substrates failed to give any enantioselectivity. Also, 3Å molecular sieve is used in the reaction system. While the authors did not provide the reason for such usage in the paper, it was speculated that 3Å molecular sieves act as water scavenger and prevent the decomposition of alkenyl diethyl boronates into their respective boronic acids. The catalyst could be recycled from the reaction and reused without compromising yield or enantioselectivity.
More recently, Yuan with coworkers from Chengdu Institute of Organic Chemistry, Chinese Academy of Science combined both approaches (chiral thiourea catalyst and chiral biphenol) in a single catalyst, reporting for the first time the catalytic system that is capable of performing enantioselective Petasis reaction between salicylaldehydes, cyclic secondary amines and aryl- or alkenylboronic acids:

In one application the Petasis reaction is used for quick access to a multifunctional scaffold for divergent synthesis. The reactants are the lactol derived from L-phenyl-lactic acid and acetone, l-phenylalanine methyl ester and a boronic acid. The reaction takes place in ethanol at room temperature to give the product, an anti-1,2-amino alcohol with a diastereomeric excess of 99%.

Notice that the authors cannot assess syn-1,2-amino alcohol with this method due to intrinsic mechanistic selectivity, and the authors argue that such intrinsic selectivity hampers their ability to access the full matrix of stereoisomeric products for the usage of small molecule screening. In a recent report, Schaus and co-workers reported that syn amino alcohol can be obtained with the following reaction condition, using a chiral dibromo-biphenol catalyst their group developed:

Although the syn vs. anti diastereomeric ratio ranges from mediocre to good (1.5:1 to 7.5:1), the substrate scope for such reactions remain rather limited, and the diastereoselectivity is found to be dependent on the stereogenic center on the amine starting material.