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Spiro compound
Spiro compound
Spiro compound
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Structure of C17H20, which contains seven spiro atoms and eight cyclopropane rings[1]

In organic chemistry, spiro compounds are compounds that have at least two molecular rings sharing one common atom. Simple spiro compounds are bicyclic (having just two rings).[2]: SP-0 [3]: 653, 839  The presence of only one common atom connecting the two rings distinguishes spiro compounds from other bicyclics.[4][3]: 653ff  : 839ff  Spiro compounds may be fully carbocyclic (all carbon) or heterocyclic (having one or more non-carbon atom). One common type of spiro compound encountered in educational settings is a heterocyclic one— the acetal formed by reaction of a diol with a cyclic ketone.

The common atom that connects the two (or sometimes three) rings is called the spiro atom.[2]: SP-0  In carbocyclic spiro compounds like spiro[5.5]undecane, the spiro-atom is a quaternary carbon, and as the -ane ending implies, these are the types of molecules to which the name spirane was first applied (though it is now used general of all spiro compounds).[5]: 1138ff  The two rings sharing the spiro atom are most often different, although they can be identical [e.g., spiro[5.5]undecane and spiropentadiene, at right].[3]: 319f.846f 

Selected spiro compounds

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Carbocyclic spiro compounds

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Bicyclic ring structures in organic chemistry that have two fully carbocyclic (all carbon) rings connected through a carbon atom are the usual focus of the topic of spirocycles. Simple parent spirocycles include spiropentane, spirohexane, etc. up to spiroundecane. Several exist as isomers. Lower members of the class are strained. The symmetric isomer of spiroundecane is not.

Some spirocyclic compounds occur as natural products.[6]

Preparation

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Synthesis route to Fecht's ester, illustrating a dialkylation route to a spiroheptane.
Synthesis route to spiroundecane.[8]

The spirocyclic core is usually prepared by dialkylation of an activated carbon center. The dialkylating group is often a 1,3-, 1,4-, etc. dihalide.[9] In some cases the dialkylating group is a dilithio reagent, such as 1,5-dilithiopentane.[10] For generating spirocycles containing a cyclopropane ring, cyclopropanation with cyclic carbenoids has been demonstrated.[11]

Spiro compounds are often prepared by diverse rearrangement reactions. For example, the pinacol-pinacolone rearrangement is illustrated below.[3]: 985  is employed in the preparation of aspiro[4.5]decane.[12]].

The synthesis of a spiro-keto compound form a symmetrical diol
The synthesis of a spiro-keto compound form a symmetrical diol

Heterocyclic spiro compounds

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Preparation of a spiro ketal.[13]

Spiro compounds are considered heterocyclic if the spiro atom or any atom in either ring are not carbon atoms. Cases with a spiro heteroatom such as boron, silicon, and nitrogen (but also other Group IVA [14] are often trivial to prepare. Many borate esters derived from glycols illustrate this case.[14] Likewise, a tetravalent neutral silicon and quaternary nitrogen atom (ammonium cation) can be the spiro center. Many such compounds have been described.[5]: 1139f 

Particularly common spiro compounds are ketal (acetal) formed by condensation of cyclic ketones and diols and dithiols.[15][16][17] A simple case is the acetal 1,4-dioxaspiro[4.5]decane from cyclohexanone and glycol. Cases of such ketals and dithioketals are common.

Chirality

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Two enantiomers of a spiro diketone.

Spiranes can be chiral,[18] in various ways.[5]: 1138ff  First, while nevertheless appearing to be twisted, they yet may have a chiral center making them analogous to any simple chiral compound, and second, while again appearing twisted, the specific location of substituents, as with alkylidenecycloalkanes, may make a spiro compound display central chirality (rather than axial chirality resulting from the twist); third, the substituents of the rings of the spiro compound may be such that the only reason they are chiral arises solely from the twist of their rings, e.g., in the simplest bicyclic case, where two structurally identical rings are attached via their spiro atom, resulting in a twisted presentation of the two rings.[5]: 1138ff, 1119ff [3]: 319f.846f  Hence, in the third case, the lack of planarity described above gives rise to what is termed axial chirality in otherwise identical isomeric pair of spiro compounds, because they differ only in the right- versus left-handed "twist" of structurally identical rings (as seen in allenes, sterically hindered biaryls, and alkylidenecycloalkanes as well).[5]: 1119f  Assignment of absolute configuration of spiro compounds has been challenging, but a number of each type have been unequivocally assigned.[5]: 1139ff 

Some spiro compounds exhibit axial chirality. Spiroatoms can be the origin of chirality even when they lack the required four different substituents normally observed in chirality. When two rings are identical the priority is determined by a slight modification of the CIP system assigning a higher priority to one ring extension and a lower priority to an extension in the other ring. When rings are dissimilar the regular rules apply.[clarification needed]

Nomenclature and etymology

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Nomenclature for spiro compounds was first discussed by Adolf von Baeyer in 1900.[19] IUPAC provides advice on naming of spiro compounds.[20]

The prefix spiro denotes two rings with a spiro junction. The main method of systematic nomenclature is to follow with square brackets containing the number of atoms in the smaller ring then the number of atoms in the larger ring, separated by a period, in each case excluding the spiroatom (the atom by which the two rings are bonded) itself. Position-numbering starts with an atom of the smaller ring adjacent to the spiroatom around the atoms of that ring, then the spiroatom itself, then around the atoms of the larger ring.[21] For example, compound A in Image #4 above (Selected Spiro Compounds) is called 1-bromo-3-chlorospiro[4.5]decan-7-ol, and compound B is called 1-bromo-3-chlorospiro[3.6]decan-7-ol.

Further reading

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References

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Spiro compound

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A spiro compound is an organic featuring two or more alicyclic rings that share exactly one common atom, known as the spiro atom, which is typically a carbon atom bonded to four distinct ring segments. These structures are classified as bicyclic for the simplest monospiro variants with two rings, while polyspiro compounds involve three or more rings linked similarly. The rigid, three-dimensional architecture of spiro compounds imparts unique steric and conformational properties, distinguishing them from fused or bridged polycyclics. In IUPAC , monospiro hydrocarbons are named by prefixing "spiro" to the name of the unbranched acyclic with the same total carbon count, with the sizes of the rings indicated in square brackets in ascending order (e.g., spiro[4.5] for a five-membered and six-membered ). Numbering begins in the smaller ring adjacent to the spiro atom and proceeds to give the lowest possible locants to substituents or unsaturations. For polyspiro systems, prefixes like "dispiro" or "trispiro" are used, followed by bracketed ring size notations. can replace carbons in the rings, leading to heterocyclic spiro compounds, which follow analogous naming conventions with heteroatom prefixes. Spiro compounds occur naturally in various and sources, serving as key structural motifs in alkaloids and terpenoids with biological significance. Their synthesis has advanced through methods like double or reactions, enabling access to diverse scaffolds. Applications span , where spiro-heterocycles exhibit , anticancer, and activities as promising drug candidates. In , spiro configurations enhance , stability, and charge transport in organic optoelectronics, such as OLEDs and photodetectors. Additionally, they contribute to fragrance chemistry due to their compact, chiral frameworks and are used in agrochemicals.

Definition and Structure

Basic Definition

Spiro compounds are organic molecules characterized as bicyclic or polycyclic structures in which two or more rings share exactly one common atom, referred to as the spiro atom, typically a quaternary carbon atom. This configuration results in a unique spiro ring system where the rings are connected solely at this single point, without any additional shared atoms or bridges between them. Unlike fused ring systems, which share two adjacent atoms along a common bond, or bridged ring systems, which share two non-adjacent atoms connected by one or more bridges, spiro compounds maintain complete independence between the rings except at the spiro atom. The simplest bicyclic spiro compounds follow the general notation spiro[m.n], where m and n denote the number of carbon atoms in each chain linking back to the spiro atom (with m ≤ n), and the total carbon count determines the alkane suffix. Structurally, spiro compounds feature two or more rings intersecting at precisely one point, the spiro atom, which adopts a tetrahedral due to its four sigma bonds. This arrangement orients the ring planes nearly perpendicular to each other, imparting a distinctive three-dimensional rigidity to the molecule. For instance, spiro[4.4]nonane exemplifies this with two five-membered rings sharing the central carbon.

Structural Characteristics

Spiro compounds feature a central spiro atom, typically a tetrahedral carbon atom with sp³ hybridization, forming four sigma bonds to the carbon atoms of two or more rings, which results in the attached ring planes being nearly to each other. This orientation arises from the geometric constraints of the tetrahedral at the spiro , limiting conformational flexibility and promoting a rigid three-dimensional structure. In carbocyclic spiro compounds, the ring sizes are denoted using the notation spiro[m.n], where m and n represent the number of carbon atoms in each linking chain excluding the spiro carbon, such that the actual ring sizes are (m+1) and (n+1), and the total number of carbon atoms is m + n + 1. For example, spiro[4.4]nonane consists of two five-membered rings sharing the spiro carbon, totaling nine carbons. This notation facilitates precise description of the molecular architecture and is standardized by IUPAC guidelines. Small spiro compounds, such as spiropentane (spiro[2.2]pentane), exhibit significant angle strain due to the incorporation of three-membered rings, where the bond angles at the peripheral carbons deviate markedly from the ideal tetrahedral value of 109.5°, approaching approximately 60° as seen in units. This strain contributes to the overall instability and high reactivity of such systems, with spiropentane possessing a total strain energy of about 62.9 kcal/mol. Spiro systems can extend to polycyclic structures beyond simple bicyclic forms, including monospiro compounds with two rings sharing the spiro atom, dispiro compounds with three rings linked by two spiro atoms, and higher polyspiro variants. These extensions maintain the central tetrahedral spiro atom as the junction point, allowing for complex topologies while preserving the characteristic perpendicular ring arrangements. The sizes of the rings in a spiro compound profoundly influence its overall molecular shape; symmetric systems like spiro[4.4]nonane, with identical ring sizes, adopt a more compact and balanced conformation, whereas asymmetric examples such as spiro[4.5]decane, featuring rings of different sizes (five- and six-membered), result in elongated or irregular geometries that affect packing and interactions. This variation in shape can enhance rigidity in smaller symmetric spiro compounds or introduce flexibility in larger asymmetric ones, impacting applications in materials and pharmaceuticals.

Nomenclature and History

Naming Conventions

Spiro compounds are named using the von Baeyer system, which employs the prefix "spiro-" followed by square brackets containing numbers that indicate the number of carbon atoms in each chain linked to the spiro atom, arranged in ascending order with the smaller number first. For monospiro hydrocarbons, the name is constructed as "spiro[m.n]alkane," where m and n represent the carbon atoms in the two branches (with m ≤ n), and the alkane suffix is based on the total number of carbon atoms in the molecule, which is m + n + 1. For example, the compound with a five-membered ring and a six-membered ring sharing one carbon atom is named spiro[4.5]decane, reflecting 4 and 5 carbons in the branches (since ring size is branch carbons plus one) and a total of 10 carbons. Numbering in monospiro compounds begins at the carbon atom next to the spiro atom in the smaller ring, proceeds around the smaller ring to the spiro atom, then continues around the larger ring back to the spiro atom, ensuring the lowest possible locants for substituents or functional groups. Substituents are assigned locants according to this , with priority given to the lowest set of locants starting from the smaller ring. For polyspiro compounds, the nomenclature extends the monospiro system by using prefixes like "dispiro-" or "trispiro-" and nested or sequential bracketed numbers to describe the chains connected to multiple spiro atoms, ordered by the path of numbering that minimizes the locants of the spiro atoms. In heterocyclic spiro compounds, heteroatoms are incorporated using skeletal replacement , where prefixes such as "oxa-" for oxygen or "aza-" for replace the corresponding "a" positions in the carbon chain descriptors, with the heteroatoms receiving the lowest possible locants. For instance, a spiro compound with an oxygen atom in the smaller ring is named as 1-oxaspiro[4.5]decane, following the numbering but adjusting for heteroatom priority.

Etymology and Historical Development

The term "spiro" originates from the Latin word spira, denoting a coil or twist, which aptly describes the unique of these compounds where two or more rings share a single common atom, creating a spiraling or twisted ring arrangement. Von Baeyer originally proposed the term "spirane" for these structures. This was introduced by the German chemist in his 1900 publication, marking the first systematic discussion of naming conventions for polycyclic structures, including spiro systems, to address the growing complexity of synthetic organic compounds at the . Baeyer's early work laid the foundation for spiro chemistry. The first laboratory preparation of a spiro hydrocarbon, spiropentane, was achieved by Gustav Gustavson in 1887. Although the formal naming and structural characterization evolved subsequently through the . By the early 1900s, spiro compounds gained attention in , but nomenclature standardization advanced significantly with the International Union of Pure and Applied Chemistry (IUPAC) recommendations in 1999, which extended Baeyer's system to include polyspiro and branched structures; this was further refined in the IUPAC Blue Book for comprehensive coverage of heterocyclic and fused spiro variants. In the mid-20th century, spiro compounds received renewed interest through their identification in natural products, particularly spiroketals isolated from microbial sources in the 1960s, such as averufin from in 1965, highlighting their role in biosynthetic pathways and biological activity. This period marked a shift toward exploring spiro motifs beyond synthetic curiosities, emphasizing their prevalence in fungi and . Entering the 2020s, research on spiro compounds has intensified in , with spirocyclic scaffolds increasingly incorporated to optimize pharmacokinetic properties like metabolic stability and selectivity, as evidenced by reviews of studies from 2020 to 2024 that document their application in anticancer and candidates.

Classification

Carbocyclic Spiro Compounds

Carbocyclic spiro compounds represent a class of spiro hydrocarbons where two fully saturated carbon rings share a single quaternary carbon atom, known as the spiro atom, without any heteroatoms present in the ring structures. These compounds are bicyclic by nature, with the rings connected solely at this central carbon, leading to a distinctive three-dimensional architecture that contrasts with fused or bridged polycyclics. The nomenclature follows the von Baeyer system, denoted as spiro[m.n], where m and n (m ≤ n) indicate the number of carbon atoms in each chain linking the spiro atom, resulting in ring sizes of m+1 and n+1. For instance, spiro[4.4]nonane features two identical five-membered rings and serves as a prototypical example of this structural motif. Structural variations in carbocyclic spiro compounds arise primarily from differences in ring sizes, leading to homospiro systems with symmetric rings (e.g., spiro[4.4]nonane or spiro[5.5]undecane, the latter comprising two six-membered rings) and heterospiro systems with asymmetric rings (e.g., spiro[4.5]decane, combining a five- and six-membered ring). Spiropentane, or spiro[2.2]pentane, stands out as the smallest and most strained example, formed by two three-membered cyclopropane rings fused at the spiro carbon, which imparts unique reactivity due to its central C-C bond resembling an allene-like geometry. In contrast, spiro[5.5]undecane exemplifies a less constrained variant, often studied for its conformational flexibility resembling two interlocked cyclohexanes. These variations influence the overall molecular symmetry and potential for chirality, particularly in heterospiro cases where the rings' differing sizes can generate axial chirality. Although carbocyclic spiro compounds occur rarely in compared to their fused counterparts, they appear in select terpenoids, particularly sesquiterpenes, where the spiro motif contributes to ; notable examples include the spiro[4.5] frameworks in β-vetivone and hinesol isolated from vetiver (Vetiveria zizanioides) and related . Such natural occurrences are limited to higher and marine sources, with synthetic analogs predominantly used in model studies to probe and reactivity in polycyclic systems. Stability in these compounds increases with larger s, as smaller systems like spiropentane suffer from high angle strain—quantified at approximately 63 kcal/mol—due to compressed bond angles near 60° in the units, whereas larger homologs like spiro[5.5] exhibit minimal strain and enhanced thermal stability akin to independent cycloalkanes. This trend underscores the role of in mitigating torsional and angle distortions at the spiro junction.

Heterocyclic Spiro Compounds

Heterocyclic spiro compounds are a class of spirocyclic molecules in which two or more rings share a single spiro atom—typically a carbon—and at least one ring incorporates a heteroatom such as oxygen, , or . This structural arrangement distinguishes them from carbocyclic spiro compounds by introducing s that enhance polarity, hydrogen-bonding capabilities, and reactivity, often resulting in unique three-dimensional architectures that confer rigidity and conformational constraints. Common subtypes include spiroketals and spiroacetals, which feature oxygen atoms forming acetal-like linkages at the spiro center, exemplified by the core structure 1,6-dioxaspiro[4.4]nonane found in various natural isolates. Aza-spiro compounds, containing heteroatoms, represent another prevalent subtype, often appearing as or functionalities within the rings, such as in spiro[indole-3,3'-pyrrolidine] scaffolds. These heteroatoms typically occupy positions that stabilize the spiro junction through electronic effects, increasing the compounds' in polar environments and influencing their stereochemical preferences compared to their all-carbon analogs. Heterocyclic spiro compounds are abundantly prevalent in natural products, particularly from fungal, , and marine sources, where they contribute to diverse biosynthetic pathways and bioactivities. For instance, spiroketals are widespread in fungal metabolites like those from species, while aza-spiro motifs occur in alkaloids such as spirotryprostatin A, isolated from the fungus . These natural occurrences highlight the evolutionary advantage of spiro architectures in stabilizing complex molecular frameworks within biomolecules. Less common variations include phosphorus-containing spiro compounds, such as spirophosphoranes, where the spiro atom or adjacent positions feature pentacoordinate centers, and spiroboranes, which involve tetracoordinate in the ring systems. These variants are rarer in natural settings but have been explored for specialized applications due to their unique coordination chemistry.

Synthesis

Preparation of Carbocyclic Spiro Compounds

Carbocyclic spiro compounds, featuring two all-carbon rings sharing a single carbon atom, can be synthesized through double strategies involving dihalides or equivalent electrophiles with active methylene compounds such as malonate dianions. This approach constructs the spiro center by sequential , followed by to yield the parent framework. This method has been applied in the assembly of spirocyclic keto esters based on the spiro[3.3] scaffold for constrained analogs. Similar double alkylations using dibromo ketals as masked gem-dihalides enable the formation of carbocyclic spiro rings in spiropiperidine precursors, where the carbocyclic portion is built via reductive cyclization post-. Another key method for small-ring carbocyclic spiro systems is via the Simmons-Smith reaction, which employs a carbenoid generated from and zinc-copper couple to add across exocyclic double bonds. For instance, methylenecycloalkanes undergo stereospecific to afford spiro[2.n]nonanes, preserving the geometry of the and providing access to highly strained systems; this reaction is particularly effective at low temperatures to avoid side reactions. The intramolecular variant further enhances selectivity for fused-spiro motifs, though it is adaptable for purely carbocyclic targets by tethering appropriate alkenyl chains. Rearrangement reactions, such as the acid-catalyzed pinacol-pinacolone transformation of 1,2-diols, provide a route to spiroketones that can be reduced to hydrocarbons. In this process, cyclic diols with adjacent hydroxyl groups undergo and 1,2-migration under acidic conditions (e.g., ), forming the spiro carbon with a carbonyl; subsequent Wolff-Kishner or yields the carbocyclic spiro compound. This method is reviewed for various acid-catalyzed rearrangements leading to free carbocyclic spiro linkages, with examples including conversions to spiro[4.5]decanones. Post-2000 advancements in metal-catalyzed methods have introduced efficient spiroannulation protocols, notably palladium-catalyzed couplings of aryl halides with s. These [2+2+1] annulations proceed via alkyne-directed remote C-H arylation followed by dearomatization, constructing spirocyclic scaffolds with high using Pd(0) catalysts like Pd2(dba)3 and ligands; for carbocyclic variants, non-aromatic alkyne substrates yield all-carbon spiro rings, as demonstrated in the synthesis of spirocyclopentanes from bromoalkenes and internal s. Such reactions tolerate diverse functional groups and enable asymmetric variants with chiral ligands. The synthesis of small-ring carbocyclic spiro compounds is challenged by significant ring strain, often necessitating specialized conditions like high-pressure environments to favor cyclization or photochemical activation to generate reactive intermediates. For example, strained spiro[2.2]pentanes require photochemical [2+2] cycloadditions or high-pressure Diels-Alder variants to overcome thermodynamic barriers, as thermal methods frequently fail due to unfavorable entropy. These techniques highlight the need for tailored strategies to access highly angular systems while minimizing decomposition.

Preparation of Heterocyclic Spiro Compounds

Heterocyclic spiro compounds, which incorporate heteroatoms such as oxygen, , or into their spirocyclic frameworks, are prepared through methods that leverage the nucleophilic properties of these atoms to form the central spiro linkage. Unlike carbocyclic variants, these syntheses often involve heteroatom-specific reactions that exploit differences in and reactivity, enabling the construction of rings like oxaspiro, azaspiro, and thiaspiro systems. Common strategies include acid- or base-catalyzed cyclizations, multicomponent assemblies, and biological pathways, each tailored to incorporate one or more heteroatoms at the spiro center or adjacent positions. A primary method for synthesizing oxaspiro compounds, particularly spiroketals and spiroacetals, is the acid-catalyzed or ketal formation via cyclization of diols with ketones or aldehydes. This reaction proceeds through of the carbonyl oxygen, followed by nucleophilic attack by one hydroxyl group to form a intermediate, and subsequent cyclization with the second hydroxyl under dehydrating conditions, often using as catalyst and a Dean-Stark apparatus to remove . A representative example is the preparation of 1,4-dioxaspiro[4.5]decane from and , yielding the spirocyclic ketal in high efficiency (typically >90% yield) and serving as a model for larger scaffolds. This approach is versatile for [4.4], [4.5], and [5.5] spiro systems, with controlled by thermodynamic equilibration under acidic conditions. Heteroatom insertion methods extend this chemistry to sulfur- and nitrogen-containing spiro compounds through to carbonyls followed by intramolecular cyclization. For thiaspiro systems, add to carbonyls under (e.g., BF₃·OEt₂ or ZnCl₂) to form thioacetal intermediates, which cyclize with a second equivalent; a classic case is 1,4-dithiaspiro[4.5]decane from and 1,2-ethanedithiol, achieving spiro dithioacetal formation in 80-95% yield and providing stability under basic conditions useful for selective manipulations. Nitrogen variants involve addition to form hemiaminals or imines, followed by cyclization, often in aza-spiroketal syntheses where an attacks a carbonyl proximal to a tethered hydroxy or group, as seen in the construction of spiroaminals from amino alcohols and dialdehydes under mild acidic promotion. These insertions highlight the tunable reactivity of , with analogs offering greater resistance to than oxygen counterparts. Multicomponent reactions (MCRs) provide efficient, one-pot access to complex aza- and oxaspiro heterocycles by combining multiple building blocks around the spiro center. The Ugi four-component reaction (Ugi-4CR), involving an , , , and , generates α-aminoacyl amides that undergo post-Ugi cyclization or dearomatization to form spirocyclic piperidines or pyrrolidines; recent advances (2020-2024) include visible-light-promoted variants yielding spiro[indoline-3,4'-piperidines] in up to 85% yield with high diastereoselectivity, as demonstrated in syntheses of bioactive scaffolds. Similarly, Passerini reactions, combining , , and isocyanides to produce α-acyloxyamides, have been adapted for oxaspiro compounds through enzymatic resolution or intramolecular etherification, such as in the one-pot formation of spirooxazinones from epoxy , achieving >70% yields and enabling diversity-oriented synthesis of oxygen-embedded spiro systems. These MCRs are prized for their and ability to incorporate heteroatoms directly into the spiro junction via tandem cyclizations. Enzymatic and biosynthetic routes are crucial for natural heterocyclic spiro compounds, particularly spiroketals in families, where polyketide synthases (PKSs) assemble the carbon backbone followed by heteroatom-mediated cyclization. In rubromycin , type II PKSs elongate acetyl- and units into a poly-β-ketone chain that aromatizes to collinone; subsequent oxidative rearrangement by flavin-dependent monooxygenases like GrhO5 cleaves and cyclizes the structure into a [5,6]-spiroketal via hemiketal formation and , with GrhO1 and GrhO6 facilitating ring contractions and C-C bond cleavages to yield the in high fidelity. This pathway, reconstituted , underscores the role of PKS-associated oxygenases in generating stereospecific spiroketals found in antibiotics like griseorhodin C. Such biosynthetic insights guide chemoenzymatic syntheses, blending enzymatic precision with synthetic scalability.

Properties

Chirality and Stereochemistry

Spiro compounds derive primarily from the spiro carbon atom when the attached rings differ in size or , rendering the four chains constitutionally distinct and establishing a tetrahedral central chiral center. This central follows Cahn-Ingold-Prelog (CIP) priority rules, where ring paths are traced to assign R or S configuration, as exemplified in spiro ketals where the spiro atom lacks traditional four different substituents but achieves asymmetry through perpendicular ring planes. arises in spiro systems with twisted or perpendicular ring orientations that lack a plane of symmetry, often in conjugated or unsaturated spiro frameworks like spiro[4.5]deca-6,9-diene-8-one derivatives. In larger spiro compounds, atropisomerism can occur due to steric hindrance restricting rotation around bonds adjacent to the spiro center, leading to stable enantiomers designated as (M) or (P). For instance, 3,3'-dimethyl-3H,3'H-2,2'-spirobi[[1,3]benzothiazole] exhibits atropisomerism with a thermal barrier of 85 kJ/mol at 10°C, allowing isolation of enantiomers via chiral . Enantiomer separation and stereochemical assignment in chiral spiro compounds present challenges due to their compact, symmetric-like structures, often requiring advanced techniques like for determination. In spiro[4.4]nonane systems, such as the cis,cis-spiro[4.4]nonane-1,6-diol, analysis confirms the spiro carbon's by treating it as a chiral center in a (ab)C(ba) system, while NMR spectroscopy aids characterization but struggles with diastereomer distinction without derivatization. Separation of these s is complicated by similar physical properties, frequently necessitating or methods to isolate pure forms. Stereoselective synthesis of enantioenriched spiro compounds has advanced through asymmetric catalysis employing chiral ligands, particularly in the and continuing into the . For example, palladium-catalyzed double [2+2+2] cycloadditions using chiral spiro diphosphine ligands enable the construction of enantiopure spirodihydroquinolines with up to 99% ee. Similarly, organocatalytic approaches with derivatives facilitate asymmetric dearomatization to form chiral spirooxindoles, achieving high enantioselectivities in reactions of isatin-derived ketones. Recent advances as of include organocatalytic asymmetric synthesis of spirocyclic tetrahydroquinolines with high enantioselectivities using chiral phosphoric acids. Racemization barriers in chiral spiro compounds vary with structural ; symmetric systems with identical rings exhibit lower barriers due to easier conformational interconversion, while asymmetric ones with differing ring sizes or substituents display higher stability against . In atropisomeric spirobiindanes, the rigid spiro framework provides inherent configurational stability, preventing at ambient temperatures and enabling persistent .

Physical and Chemical Properties

Spiro compounds exhibit distinctive physical and chemical properties influenced by their unique architecture, where two rings share a single spiro atom, often leading to elevated strain and altered intermolecular interactions. Small carbocyclic spiro compounds, such as spiropentane, possess high of approximately 63 kcal/mol, exceeding twice the strain energy of (27.5 kcal/mol), primarily due to severe angle strain at the spiro carbon from the orthogonal orientation of the attached rings. This strain enhances reactivity, promoting pathways like ring opening under thermal or chemical stress. In contrast, larger spiro systems experience reduced strain, resulting in greater stability akin to unstrained cycloalkanes. Heterocyclic spiro compounds generally display increased polarity and compared to carbocyclic analogs, owing to the incorporation of heteroatoms such as oxygen or , which introduce moments and hydrogen-bonding capabilities. For instance, spiroketals and related structures often exhibit improved aqueous relative to non-spiro counterparts, facilitating applications in pharmaceuticals and materials. Boiling points of spiro hydrocarbons are typically similar to those of their acyclic isomers of comparable molecular weight, though the rigidity of the spiro framework can slightly elevate them by enhancing molecular packing efficiency. Spectroscopic characterization reveals unique signatures for spiro compounds. In ¹³C NMR spectra, the quaternary spiro carbon resonates at chemical shifts typically in the 20-40 ppm range for aliphatic systems, reflecting its tetrahedral environment with four alkyl substituents; for example, a central spiro carbon in a synthesized spirocyclopropane appears at 21.3 ppm. Spiroketals show characteristic absorption bands for C-O stretches around 1000-1200 cm⁻¹, indicative of the linkages, which aid in structural confirmation. Thermally, strained spiro compounds like those with small rings decompose via ring-opening reactions, releasing and forming acyclic or rearranged products, often at temperatures below 200°C. Larger or heterocyclic spiro systems demonstrate enhanced thermal stability, with decomposition thresholds exceeding 300°C in some cases. Chemically, spiroketals exhibit notable resistance to under neutral conditions, maintaining integrity in aqueous environments due to the stabilizing spiro linkage, though they undergo cleavage in acidic media.

Applications and Examples

Selected Spiro Compounds

Spiropentane, the smallest carbocyclic spiro compound with the formula , consists of two perpendicular rings sharing a central carbon atom, resulting in exceptional estimated at around 64 kcal/mol. First synthesized by Gustavson in 1896 by the debromination of pentaerythrityl tetrabromide using , its structure was confirmed two decades later by Zelinsky and fully characterized spectroscopically by Murray in 1944. Due to this high strain, spiropentane exhibits thermal instability, decomposing into hydrocarbons upon heating to 200 °C, which limits its practical applications but makes it a key model for studying strained hydrocarbons. Spiro[4.5]decane, a bicyclic with a five-membered and a six-membered ring connected at a spiro carbon (C₁₀H₁₈), serves as a versatile synthetic intermediate in owing to its rigid framework and conformational stability. It is frequently employed in the construction of complex polycyclic systems, such as in total syntheses of natural products like acorenone. In , derivatives of spiro[4.5]decane, including aza- and oxa-variants, have been investigated as mediators in controlled radical polymerizations of styrene, enabling the production of polymers with narrow molecular weight distributions. The 1,4-dioxaspiro[4.5]decane (C₈H₁₄O₂) is a widely used ketal derivative formed from and , functioning as a standard for ketones in multi-step syntheses. Its structure shields the carbonyl from nucleophilic attack under basic or reductive conditions while being selectively deprotected under acidic aqueous conditions, making it indispensable in and chemistry. This compound exemplifies the utility of spiro ketals in temporary manipulation, with countless applications documented in synthetic protocols since its routine adoption in the mid-20th century. Spiro[5.5]undecane (C₁₁H₂₀), featuring two six-membered rings sharing a spiro carbon atom, represents a stable model for larger carbocyclic spiro systems, exhibiting chair-chair conformations with minimal strain compared to smaller analogs. Its symmetric structure facilitates studies of stereoelectronic effects and in spiranes, as unsubstituted variants can display atropisomerism under certain substitution patterns. This compound is often utilized in computational and experimental conformational analyses to benchmark the behavior of unstrained polycyclic hydrocarbons. Recent advances in the have enabled the synthesis of polysubstituted all-carbon spiro[2.2]pentane derivatives, expanding access to these highly strained motifs beyond the parent spiropentane. A 2022 method employs regio- and diastereoselective carbometalation of sp²-disubstituted cyclopropenes followed by electrophilic trapping, yielding up to 16 examples with isolated yields of 24–81% and high stereocontrol (dr up to 20:1). These derivatives, with their rigid 3D architecture and high Fsp³ content, hold potential as bioisosteres in , though their strain (ca. 60–70 kcal/mol) necessitates careful handling.

Biological and Pharmaceutical Applications

Spiroketals represent a prominent class of natural products with significant biological roles, particularly in chemical ecology. These compounds, characterized by their rigid spirocyclic structures, serve as aggregation s in various . For instance, chalcogran, a 1,6-dioxaspiro[4.4] derivative, functions as a key component in the Douglas-fir (Dendroctonus pseudotsugae), facilitating mate attraction and host colonization. Similarly, frontalin, another aggregation , acts as an aggregation in southern pine (Dendroctonus frontalis), enhancing swarm behavior during bark infestation. In marine environments, spiroimine-containing toxins like pinnatoxin A, isolated from the bivalve Pinna muricata, exhibit potent by inhibiting nicotinic receptors, contributing to risks. This compound features a distinctive 6,6-spiroketal motif within its polyether , underscoring the structural diversity of spiro natural products. In pharmaceutical applications, spiro compounds have been exploited for their unique stereochemical properties and binding affinities. , a synthetic featuring a spiro[4.5]decan-6,7-dione ring, was approved in 1959 as a and aldosterone antagonist, effectively treating , , and by blocking receptors in the kidneys. Its spiro structure enhances metabolic stability and selectivity, reducing off-target effects compared to non-spiro analogs. Beyond diuretics, spiro-containing natural products like the spirotryprostatins, isolated from the fungus , demonstrate antibiotic and anticancer potential; spirotryprostatin A inhibits assembly, offering a lead for agents against resistant pathogens. The rigid three-dimensional architecture of spiro compounds provides advantages in , particularly for enhancing selectivity and potency in targeted therapies. In , spiroindole scaffolds, such as halogenated spirooxindoles, have emerged as promising anticancer agents in developments since the 2020s, exhibiting improved and tumor cell induction through inhibition. For example, spiro[pyrrolidine-3,3'-oxindole] derivatives show submicromolar values against and cell lines, attributed to their constrained conformation that optimizes receptor binding. Biosynthetically, these motifs arise via epoxide-mediated cyclizations; in spirotryprostatins, a flavin-dependent monooxygenase catalyzes 2,3-epoxidation, followed by nucleophilic ring opening to form the spirooxindole core, as elucidated in fungal pathway studies. Emerging applications extend spiro compounds beyond biology into materials science. Post-2020 innovations include spirofluorene-based emitters in organic light-emitting diodes (OLEDs), where their orthogonal rigidity suppresses aggregation-induced quenching, achieving external quantum efficiencies exceeding 20% in blue-emitting devices. In catalysis, spirocyclic ligands like those derived from spiro[4.4]nonanes enable asymmetric transformations, such as enantioselective spiroketal formation, with yields over 90% and ee values above 95%, facilitating scalable synthesis of chiral pharmaceuticals.

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