Angelw: Breit group, University of Freiburg, Germany, realizes the asymmetric intramolecular hydrogenation of propadiene catalyzed by rhodium

Nitrogen-containing heterocycles are the parent nuclear skeletons of many bioactive natural products and functional molecules For example, pyrrolidine and piperidine containing α - chiral centers are important structural segments (scheme 1) of natural products (peripentadenine and peripentones), drugs (tacrolimus) and chiral ligands (sparteine) At present, the asymmetric synthesis methods of α - chiral N-heterocyclic compounds mainly include allylic substitution, allylic oxidation and nucleophilic substitution / addition Recently, transition metal catalyzed intramolecular hydroamination / cyclization of alkenes or alkynes has attracted much attention due to its more atomic economy (scheme 2) Yamamoto group uses sulfonamide as nucleophilic reagent to carry out PD catalyzed intramolecular addition with alkynes and propadienes; recently, toste, widenhoefer and Liu Xinyuan have realized the asymmetric addition of amides and amines with intramolecular propadienes by using chiral Au (I) complex and chiral br ø nstedt acid However, all of the above methods have substrate limitation In recent years, a series of rhodium catalyzed chemical, regioselective and enantioselective coupling reactions between propanediene and alkyne and various nucleophile precursors have been reported by Bernhard Breit group, University of Freiburg, Germany, and an alternative method of allyl substitution has been established Recently, the research group has developed a rhodium catalyzed intramolecular asymmetric hydroamination method for the synthesis of N-heterocyclic products (scheme 2), which was recently published on angel Chem Int ed (DOI: 10.1002 / anie 201904833) (picture source: angelw Chem Int ed.) first, the author used toluenesulfonamide (1a) in the presence of [{Rh (COD) Cl} 2] / dppf (L1) to try the reaction (Table 1), and obtained allylated pyrrolidine 2a in 58% yield It was also found that the chiral bidentate ligands showed potential enantioselectivity Therefore, the author screened a series of Jos Phos ligands, and found that L3 with higher steric hindrance and L4 without electron produced lower yield and enantioselectivity, while L5 with more electron can produce higher yield and enantioselectivity In addition, the yield and enantioselectivity were further improved by optimizing additives, solvents and concentrations (image source: angelw Chem Int ed.) later, the author examined the substrate range of the reaction (scheme 3) First of all, the scope of 5-membered ring was studied: except for tosyl substituted amines, nosyl and MBS substituted amines can react well in yield and enantioselectivity, and the substituents on alkyl chain or propadiene can also produce high yield and enantioselectivity to obtain the expected products Two enantiomers, 2G and 2H, can be obtained with high yield and enantioselectivity Next, the suitability of polysubstituted propanedienes was studied As the reactant, they are easy to isomerize into corresponding dienes It was found that the reaction can obtain 3,3-disubstituted pyrrolidine 2I and 1,1-disubstituted pyrrolidine 2J with high yield and enantioselectivity Furthermore, we have achieved a closed-loop with phenylsubstituted propadiene and intramolecular alkyne, and obtained isoindoline 2L with high enantioselectivity In addition to piperidine 2B, tetrahydroisoquinoline 2M and tetrahydroquinoline 2n, as well as high value carbamate 2p and ethyl carbamate 2q, and 1,4-benzoxazine 2O with good yield and slightly low enantioselectivity were also obtained The intramolecular allylation developed by the author can be used to synthesize different natural products and key intermediates (scheme 4), such as pyrrolidine 1a and piperidine 1b, which can directly obtain ent-2a and 2b of gram scale respectively In order to prove the practicability of allylated 5-membered and 6-membered N-heterocycles, various transformations (scheme 5) of ent-2a and 2b have been carried out Firstly, the action of Toluenesulfonyl group as the activation protecting group of amines was proved by cracking and introducing BOC under reduction condition; secondly, the olefin part can be functionalized by metathesis and subsequent hydrogenation and deprotection to obtain (+ - coniine hydrochloride In addition, they can also be applied to the synthesis of (- - pipecolinol and (- - homoproline (5) (picture source: angel Chem Int ed.) conclusion: Bernhard Breit group reported a method of asymmetric intramolecular hydrogen amination of rhodium catalyzed sulfonamide and terminal propadiene The method can obtain 5 and 6-n in gram scale selectivity- Heterocycles, these intermediates can also be used in the synthesis of natural products and their key intermediates after appropriate conversion.