Application of Oxidative Ring Opening/Ring Closing by Reductive Amination Protocol for the Stereocontrolled Synthesis of Functionalized Azaheterocycles

Abstract

The current Account gives an insight into the synthesis of some N-heterocyclic β-amino acid derivatives and various functionalized saturated azaheterocycles accessed from substituted cycloalkenes via ring C=C bond oxidative cleavage followed by ring closing across double reductive amination. The ring-cleavage protocol has been accomplished according to two common approaches: a) Os-catalyzed dihydroxylation/NaIO4 vicinal diol oxidation and b) ozonolysis. A comparative study on these methodologies has been investigated. Due to the everincreasing relevance of organofluorine chemistry in drug research as well as of the high biological potential of β-amino acid derivatives several illustrative examples to the access of various fluorine-containing piperidine or azepane β-amino acid derivatives are also presented in the current Account.1 Introduction2 Olefin-Bond Transformation by Oxidative Ring Cleavage3 Synthesis of Saturated Azaheterocycles via Oxidative Ring-Opening/Ring-Closing Double Reductive Amination3.1 Importance of Fluorine-Containing Azaheterocycles in Pharmaceutical Research3.2 Synthesis of Azaheterocyclic Amino Acid Derivatives with a Piperidine or Azepane Framework through Oxidative Ring Opening/Reductive Amination3.2.1 Synthesis of Piperidine β-Amino Esters3.2.2 Synthesis of Azepane β-Amino Esters3.2.3 Synthesis of Fluorine-Containing Piperidine γ-Amino Esters3.3 Synthesis of Tetrahydroisoquinoline Derivatives through Oxidative Ring Opening/Reductive Amination Protocol3.4 Synthesis of Functionalized Benzazepines through Reductive Amination3.4.1 Synthesis of Benzo[c]azepines3.4.2 Synthesis of Benzo[d]azepines3.5 Synthesis of Various N-Heterocycles via Ozonolysis/Reductive Amination3.5.1 Synthesis of Compounds with an Azepane Ring3.5.2 Synthesis of Piperidine β-Amino Acids and Piperidine-Fused β-Lactams3.5.3 Synthesis of γ-Lactams with a Piperidine Ring3.5.4 Synthesis of other N-Heterocycles4 Summary and Outlook5 List of Abbreviations

Application of Metathesis Protocols to the Stereocontrolled Synthesis of some Functionalized β‐Amino Esters and Azaheterocycles

“…As earlier mentioned (see Section 2.1, especially Figure 2), azaheterocyclic β‐amino acids exert various biological properties, and they are present in a number of natural products, synthetic bioactive compounds, foldamers, and drugs [10–19] . As a consequence, pharmaceutical and medicinal chemistry emerged significant effort to synthetize and study azaheterocyclic β‐amino acid derivatives [10–19,26,36,97−99] . This subchapter will discuss examples in which ring‐rearrangement metathesis was utilized to obtain such compounds.…”

“…A wide variety of methods were developed during last two decades to obtain such derivatives [20–33] . Azaheterocyclic β‐amino acid derivatives were also synthesized through oxidative ring opening followed by cyclization across double reductive amination [26,30–36] …”

“…[20][21][22][23][24][25][26][27][28][29][30][31][32][33] Azaheterocyclic β-amino acid derivatives were also synthesized through oxidative ring opening followed by cyclization across double reductive amination. [26,[30][31][32][33][34][35][36] Highly functionalized azaheterocycles (including the azaheterocyclic β-amino acid derivatives) are an interesting and highly abundant compound class in pharmaceutical and medicinal chemistry. [14-15,37À 43] A number of functionalized azaheterocycles were prepared from functionalized cycloalkenes through oxidative ring opening followed by ring closing with double reductive amination.…”

Synthesis of New β‐Amino Acid Scaffolds by Means of Ring‐Rearrangement Metathesis

“…Oxidative ring opening of β‐amino esters with a cycloalkene skeleton yielded reactive dialdehydes, which were subjected to double reductive amination without isolation. The latter step involved ring closure and the overall process is ring expansion [18,19] …”

“…The latter step involved ring closure and the overall process is ring expansion. [18,19] Our earlier experiences with olefin metathesis reactions of cyclic β-amino esters [17] led us to realize that ring-rearrangement metathesis (RRM) of easily accessible N-alkenylated (or Nalkynylated) carbocyclic β-amino esters could be a feasible and stereocontrolled pathway towards novel azaheterocyclic βamino acid derivatives. Ring-rearrangement metathesis is a two-step process.…”