Stereoselective Synthesis of 1,2‐trans‐Diamines Using the Three‐Component Borono‐Mannich Condensation – Reaction Scope and Mechanistic Insights

Abstract

The Petasis borono‐Mannich (PBM) process with easily accessible N‐protected α‐amino aldehydes produces 1,2‐trans‐diamines diastereoselectively with an enantiomeric excess up to 98 %. The protecting group on the nitrogen atom had a decisive influence on both the yield and the enantiomeric purity of the condensation products, and the best results were obtained with sulfonamide derivatives [nosyl (Ns), tosyl (Ts), and mesyl (Ms)]. To get a better understanding of the influence of the protecting group, we investigated the mechanism of the borono‐Mannich reaction through DFT calculations.

Reactivity and Synthetic Applications of Multicomponent Petasis Reactions

“…The PR was favored for sulfonylated substrates, such as Ts- and Ns-protected aldehydes, whereas racemization became predominant for carbamate and acetamide substrates, thereby explaining the low yields and the erosion of ee values for the carbamate and acetamide products. 35,82 It is noteworthy that in a recent first report of S N 2-type substitution using arylboronic acids as nucleophiles, α-aryl-α-mesylate acetamides were stereoselectively converted to α,α-diaryl acetamides with excellent ee values and good yield in the presence of a CONH group in the acetamide substrates. 112…”

“… The authors reported a follow-up study based on DFT calculations with a detailed mechanistic analysis of the influence of the N-protection group, which suggested an important coordination role of the protecting group to form a transient boronate intermediate and the existence of concurrent PR and racemization pathways. The PR was favored for sulfonylated substrates, such as Ts- and Ns-protected aldehydes, whereas racemization became predominant for carbamate and acetamide substrates, thereby explaining the low yields and the erosion of ee values for the carbamate and acetamide products. , It is noteworthy that in a recent first report of S N 2-type substitution using arylboronic acids as nucleophiles, α-aryl-α-mesylate acetamides were stereoselectively converted to α,α-diaryl acetamides with excellent ee values and good yield in the presence of a CONH group in the acetamide substrates …”

“…Although mechanistic understanding is still progressing, a boronate complex formed between the boronic acid and the in situ generated iminium species derived from the amine and carbonyl components is believed to be the key intermediate, which facilitates the nucleophilic addition of the boronate substituent to the electrophilic iminium carbon. This assumption has been supported by a range of mechanistic studies performed, including density functional theory (DFT) analysis − and nuclear magnetic resonance (NMR) analysis, , as well as the characterization of crystal structures for boronate intermediates . The irreversible nature of the last step involving the cis-diastereoselective transfer of the boronate substituent with the simultaneous formation of a new carbon–carbon bond classifies the PR as a type-II MCR …”

Synthesis of Enantiomerically Pure 5-Substituted Piperazine-2-Acetic Acid Esters as Intermediates for Library Production

“…Amino alcohols 15a–h were converted to their N -nosylated derivatives 16a–h , respectively, by exposure to NsCl/TEA in DCM at rt. − The crude products were treated with MsCl/TEA in DCM to give the mesylated intermediates 17a–h , respectively, as determined by LC–MS. Mesylates 17a–h were isolated in crude form by extractive workup and immediately advanced without further characterization.…”

Applications of Asymmetric Petasis Reaction in the Synthesis of Chiral Amines

“…反应 产物通过钯催化脱除烯丙基, 随后在苯硫醇作用下脱去 对硝基苯磺酰基, 可以 64%的收率制备反式手性二胺 51. 随后的研究表明手性胺基上的保护基对于反应的收 率和立体选择性有显著影响, 其中以磺酰胺类表现最佳 (Ts, Ns 及 Ms) [37] . 进一步的密度泛函理论(DFT)计算证 实反应中手性胺基醛的羰基先被活化, 而酰基或者酯类 的保护基可能会导致手性胺的烯醇消旋化, 因而反应不 能给出较高的立体选择性.…”