Stereoselective Reactions in Preparation of Chiral α-Hetera­spiro[m.n]alkanes

Abstract

The biological importance and wide occurrence of spirane systems in nature have stimulated studies in spirane chemistry. The fundamental spirane framework consists of two monocyclic rings linked in an orthogonal relationship by a common ring carbon. This review covers families of annular α-monoheteraspiranes starting with α-heteraspiro[2.4]heptanes and terminating with α-hetera[5.6]dodecanes; the annular heteroatoms are N, O, or S. The spirane systems are arranged according to the relative size of the two monocyclic rings with highest priority for the smaller ring, Often optically active spiranes are prepared for biological reasons by chemical modifications of natural products related to the spirane to be prepared. Chiral auxiliaries are useful in the introduction and control of stereochemistry in the construction of spiranes as intermediates in the preparation of novel amino acids and nucleosides. Another aspect of chiral spirane chemistry concerns modifications and conformational restrictions introduced in natural carbohydrates, nucleosides, and amino acids. 1 Introduction 2 Heteraspira[2.m]alkanes 3 Heteraspira[3.m]alkanes 4 Heteraspira[4.m]alkanes 5 Heteraspira[5.m]alkanes Key words α-heteraspiranes, chirons, stereoselective syntheses, spiroannulations, spirocyclic amino acids, spirocyclic nucleosides 2 Heteraspiro[2.m]alkanes 2.1 Heteraspiro[2.4]heptanes 2.1.1 4,6-Diazaspiro[2.4]heptane The Seebach chiron, tert-butyl (2S)-2-tert-butyl-3methyl-4-oxoimidazoline-1-carboxylate, was developed for the stereoselective construction of α-amino acids. 11 The chiron has also been used for the stereoselective synthesis of cyclic amino acids via a spirane. During lithiation of tertbutyl (2S)-2-tert-butyl-3-methyl-4-oxoimidazoline-1-carboxylate at the 5-position, the tert-butyl substituent effectively shields one face of the ylide from electrophilic attack. Thus acetate 1 (Scheme 1) is available from lithiated Seebach chiron and methyl α-bromoacetate. In a synthesis of 1-amino-2,2-dideuteriocyclopropane-1-carboxylic acid (4) via spirane 3, substrate 1 is stepwise lithiated by lithium

Facile Synthesis of Spirocyclic Lactams via [3+2] and [3+3] Aza‐Annulation Reactions

“…Spirocyclic N-heterocycles are privileged building blocks in drug discovery because of their 3D character [1,2] (escaping from aromatic flatland), conformational restriction, improved physicochemical properties, compared to their monocyclic analogs, and improved metabolic resistance (Scheme 1a). [3][4][5][6][7][8] Common methodologies for assembling spirocyclic scaffolds are mainly relaying on intramolecular S N 2 alkylation [9][10][11][12][13][14][15][16][17][18][19] and Nacylation, [11,20,21] ring closing metathesis [20,[22][23][24] of the appropriate precursors. Additionally, metal-catalyzed [25][26][27][28] and hypervalent iodine mediated [29] dearmoatization reactions, Prins reaction [30][31][32] and cycloaddition reactions [23,[33][34][35] should be mentioned.…”

“…Common methodologies for assembling spirocyclic scaffolds are mainly relaying on intramolecular S N 2 alkylation [9–19] and N‐acylation, [11,20,21] ring closing metathesis [20,22–24] of the appropriate precursors. Additionally, metal‐catalyzed [25–28] and hypervalent iodine mediated [29] dearmoatization reactions, Prins reaction [30–32] and cycloaddition reactions [23,33–35] should be mentioned.…”

Synthesis of 2,2‐Disubstituted Spirocyclic Pyrrolidines by Intramolecular Dieckmann Condensation

“…These compounds have improved physico‐chemical characteristics and better metabolic stability (Figure A) . Since then, spirocyclic building blocks have been playing an important role in medicinal chemistry . In this context, we recently developed novel spirocyclic 3,3‐disubstituted pyrrolidines for drug design (Figure B) .…”

Synthesis of 6‐Azaspiro[4.3]alkanes: Innovative Scaffolds for Drug Discovery

“…Recently, 3‐azaspiro[3.3]alkanes were introduced as surrogates for the common six‐membered aliphatic heterocycles with improved physicochemical characteristics . Since then, spirocyclic compounds have been playing an important role in medicinal chemistry (Figure ) . In this work, we have developed a synthetic approach to a new generation of spirocycles – 6‐azaspiro[4.3]alkanes (Figure ).…”