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3 Recent Advances in the Asymmetric Synthesis of Spiro Compounds Through Cycloadditions

       Alberto Vega-Peñaloza1, Suva Paria1, Luca Dell’Amico1, and Xavier Companyó1, 2

       1 Department of Chemical Sciences, University of Padova, Padova, Italy

       2 Section of Organic Chemistry, Department of Inorganic and Organic Chemistry, University of Barcelona, Barcelona, Spain

3.1 Introduction

      Spiro compounds are organic molecules that present a twisted structure where two perpendicular cycles are linked together by a single tetrasubstituted stereogenic center, known as the spiro center. Since its definition in early 1900 [1], spiro compounds have attracted the attention of the scientific community owing to their unique features. The spiranic motif is present in several natural and non‐natural compounds possessing a wide range of biological activities [2]. As a result, the introduction of spiranic scaffolds in drug candidates is gaining interest in modern drug discovery programs [3]. Their well‐defined 3D structure along with the enhanced conformational rigidity offer distinctive features for new drug candidates, such as enhanced drug–target recognition or improved physicochemical properties [3]. Hence, the increasing demand of new compounds derived from privileged scaffolds in chemistry, biology, and medicinal research has fueled the development of novel methodologies toward the synthesis of spiro compounds [4]. In addition, the construction of spiro centers in a catalytic, stereocontrolled manner represents by itself a formidable synthetic challenge. In this light, methodologies based on the catalysis by organometallic complexes offer a robust approach for the discovery of novel cycloaddition reactions [5]. The versatility of the diverse transition metals, such as Cu, Rh, or Ni, together with the development of new chiral ligands make the use of transition‐metal catalysts a very powerful approach. Recently, the advent of organocatalysis has paved the way for unprecedented activation modes and reaction pathways [6], including cyclization, cycloaddition, and cascade transformations [7], representing a complementary and straightforward approach to construct spiro compounds in asymmetric fashion.

The present chapter assesses the most relevant synthetic methodologies toward the asymmetric catalytic construction of spirocyclic compounds by means of either cycloaddition or formal cycloaddition processes published between 2015 and 2019. Therefore, the most significant transformations have been selected regardless of the concerted or stepwise nature of the reaction mechanism. For each transformation, the substrate scope, the generality, and limitations as well as the key reaction mechanism are discussed. The chapter is divided between organometallic and organocatalytic strategies, and within each section, the different methodologies are classified according to the number of atoms involved in the formation of the spiro cycle.

3.2 Organometallic Methodologies

      Over the past decades, transition‐metal catalysis has emerged as a powerful tool for the construction of complex molecules. Also, rigid and strained chiral scaffolds have been synthesized in a straightforward manner under catalytic routines. Across these molecules, spirocompounds represent an important structural family with diverse and specific biological activity. In the following pages, it will be demonstrated how transition metals have overcome the synthetic issues connected to the assembly of the rigid all‐substituted quaternary sprirocenter. Drawbacks of some transition‐metal‐based catalytic systems remain the relatively low stability under aerobic conditions, while the most recent transformations have found important applications in concert with organocatalytic approaches. The section has been divided into three subcategories according to the involved reactions: [3+2] cycloaddition, [4+2] cycloaddition, and miscellaneous reactions.

      3.2.1 Organometallic [3+2] Cycloaddition Strategies to Construct Spiro Compounds

In 2014, Franz and coworkers reported the asymmetric annulations of alkylidene oxindole 1 and allyl silane 2 for the synthesis of spirocyclic oxindole 3 (Scheme 3.1) [8]. The reaction was conducted in the presence of ScCl₃ and the chiral (R,S)‐indapybox ligand 4 and was proposed to proceed by the formation of β‐silyl carbocation 5 through a Michael/1,2‐silyl shift/cyclization sequence.

      Mechanistically, NaBArF played a dual role in the process, primarily is responsible to generating a cationic scandium complex and secondly is stabilizing the β‐silyl carbocation 5. Remarkably, this transformation represents the first example of a [3+2] annulation process involving allylsilanes and unsaturated carbonyl compounds to furnish chiral cyclopentanes in high yields (73–99%) and good to excellent stereocontrol (6 : 1–>20 : 1 dr and 64–99% ee).

Arai, Yamanaka, and coworkers presented in 2015 a [3+2] cycloaddition mediated by Cu(OTf)₂ and the chiral PyBidine ligand 13 for the synthesis of a variety of functionalized spiro[pyrrolidin‐3,3′‐oxindole]s 14 (Scheme 3.2) [9]. The catalytic system, which was previously used for the endo‐selective [3+2] cycloaddition of iminoesters with nitroalkenes [10], furnished the spiranic products in excellent yields (83%–>99%) and high stereoselectivities (5 : 1–>20 : 1 and 91%–98% ee).

Scheme 3.1 Scandium‐catalyzed enantioselective carboannulation between alkylidene oxindole and allylsilanes.

      Source: Modified from Ball‐Jones et al. [8].

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