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Synthesis 2024; 56(01): 16-28
DOI: 10.1055/a-2124-3823
short review

Decoration on Cubane with an Awareness of Chirality: Development of Substituted Cubane Syntheses

Hiyori Takebe
,
Seijiro Matsubara  ∗

The authors were supported for their works, shown in this review, by JSPS KAKENHI Grants 23H02605, 21H05233, JST-Project JPMJMS522362 (SM), and JSPS DC1 research fellowship 23KJ1339 (HT).
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Abstract

Nearly 60 years have passed since Professor Eaton’s practical synthesis of cubane, and research using it as a unique molecular scaffold has since gained momentum. Since the early synthesis of polynitrocubane, it has been shown that up to eight substituents can be covalently assembled into a confined space. The arrangement of substituents on cubane has paved the way for the creation of unique asymmetric molecules. To put it another way, chirality is manifested by selectively introducing three or more diverse types of substituents at specific sites. Recently, there has also been a report on the synthesis of perfluorocubane, a molecule with intriguing electronic properties.

1 Introduction

2 General Information

3 Functionalization of Cubane

4 Preparation of Polysubstituted Cubanes

5 Conclusion


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Key words

cubane - HAT - DoM - chirality - cuneane
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Seijiro Matsubara (left) was educated in chemistry at Kyoto University, completing his Ph.D. in 1986 with Professors Hitosi Nozaki and Kiitiro Utimoto, and at the Université de Lausanne (1984–1985) where he was a Ph.D. course student with Prof. Manfred Schlosser. He was appointed as an Assistant Professor at Kyoto University in 1986. After postdoctoral research with Prof. Barry M. Trost at Stanford University in 1988–1989, he became an Associate Professor at Kyoto University in 1995. In 2006, he became a Full Professor at Kyoto University. Hiyori Takebe (right), she obtained B.Eng. in 2021 and M.Eng. in 2023 from Kyoto University. Now, she is a Ph.D. candidate at Kyoto University as a JSPS Research fellow (DC1).
1

Introduction

A carbon atom can form four covalent bonds. These four covalent bonds form a tetrahedral unit, which is the cornerstone of diversity in organic molecules and is also the source of chirality around the central carbon atom. Selective modification of this unit is a critical procedure in the assembly of molecules. If we understand that a regular hexahedron shape is created by fusing two regular tetrahedrons, each composed of five sp3-carbon atoms (Figure [1](a)), we can foresee that the hexahedral cubane will serve as an exceptional molecular scaffold containing two chiral centers. In other words, it can be utilized as a unique chiral molecular scaffold via the site-selective introduction of substituents. This narrative began in 1964 with Professor Eaton’s synthesis of dimethyl cubane-1,4-dicarboxylate.[1] [2] Although cubane was recognized for its unusual and intriguing molecular structure, Eaton himself also acknowledged early on the potential for this molecule to serve a practical molecular scaffold as a benzene bioisostere.[3]

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Figure 1 (a) Understanding cubane as a unique chiral molecular scaffold; (b) two strategies for the preparation of decorated dice; and (c) two examples of the preparation of substituted cubane

To construct a dice with modified vertices, we either need to prepare a geometry net with substituents and assemble it, or put substituents on to a simple dice (Figure [1] (b)). There are analogous methods for the ‘preparation of polysubstituted cubanes’. For instance, octacyclopropylcubane was prepared by de Meijere via photoinduced cycloaddition from fully cyclopropanated tricyclo[4.2.0.02,5]octa-3,7-diene,[4a] and more recently, octafluorocubane was prepared from methyl cubane-1-carboxylate via multistep fluorination.[4b] In this review, we will focus on transformations starting from cubane.


# 2

General Information

2.1

Starting Material

Since Eaton’s synthesis, dimethyl cubane-1,4-dicarboxylate (1) has emerged as the most common starting material for cubane derivatizing chemistry. Starting from cyclopentenone, cubane diester 1 can be obtained via a 7-step transformation and now is also commercially available (Scheme [1]).[1a] [c] The Barton decarboxylation after partial hydrolysis of 1 yields methyl cubanecarboxylate (2) in excellent yield and the repetitive transformations for 2 give cubane (3) also in excellent yield.[1b] [5] These three compounds 1–3 serve as starting materials for syntheses of substituted cubanes.

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Scheme 1 Most used starting materials for the synthesis of cubane derivatives

# 2.2

Chirality

It should be noted that the cubane skeleton may have chirality when three or more substituents are introduced.[6] For a synthetic organic chemist, who is accustomed to considering a 5-atom tetrahedral unit as a source of the central chirality, understanding the chirality of high symmetrical cubane (Oh ) is not straightforward. As depicted in Figure [2a, a] cubane is a regular hexahedron, and connecting every other vertex with lines results in two virtual tetrahedrons (blue and red). Chirality can be introduced into a cubane by rendering either of these tetrahedrons asymmetric. If three distinct substituents are placed at the ①-, ③-, and ⑤-positions (+ H atom on ⑦-position), one tetrahedron (blue) becomes asymmetric, resulting in a chiral cubane (Figure [2b], left). Similarly, placing three different substituents at the ①-, ②-, and ③-positions also results in a chiral cubane, as the substituent at the ③-position (R′′) renders two red carbons (i.e., ⑥ and ⑧) nonequivalent (Figure [2b], center). To make the red carbons asymmetric, it is sufficient to introduce two different substituents (i.e., R at ① and ②, Figure [2b], right). In this way, the chirality of multisubstituted cubanes can be understood by superimposing ‘virtual tetrahedron’ onto the cubane (Figure [2c]).

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Figure 2 Understanding chirality of substituted cubanes

The construction of chirality in cubane also shows that it is essential to unambiguously name the stereochemistry of the absolute structure. Indeed, the universal stereochemical notation of cubane compounds is also an interesting geometrical challenge. Fujita proposed an original nomenclature system for dealing with cubane derivatives.[7] However, while this notation is theoretically perfect, it does not match the well-known IUPAC nomenclature or the CIP system, which organic chemists invariably use. The absolute structure of the discussed chiral cubanes in this review can be determined using the CIP method, provided that the cubane backbone is numbered according to the IUPAC nomenclature system (Figure [2b]). In this scenario, it is not necessary to describe the absolute structure of all cubane vertices that have substituents inducing asymmetry. Instead, the absolute structure can be clearly determined by the R/S-descriptor of the carbon atom at just one of these vertices as shown in Figure [3].

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Figure 3 Determination of the R/S-descriptor for substituted cubanes

# 2.3

Overview of Substituent Introduction Reactions

Cubanes have been considered to be benzene bioisosteres,[3] and the synthesis of substituted cubanes can be compared schematically with substitution reactions involving benzene. Unlike benzene, it does not contain π-bonds, so the Friedel–Crafts reaction, a key method for electrophilic substitution for benzene, cannot be applied to cubane. However, the carbon atoms forming the vertices of a cubane have a larger s-character compared to normal sp3 carbons, allowing for a higher probability of using anion and radical species than typical saturated hydrocarbons.[8] In fact, substitution reactions on the vertices of cubane have been performed via C-radical or C-anion; even solvolysis has been reported.[2]

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Figure 4 Comparison of substituent introduction in benzene and cubane skeletons

For benzene, benzyne is also an important active species for introducing substituents, and there are some examples where cubene also exists as a reactive species (Figure [4]). Of course, compared to the mature techniques for introducing substituents into benzene, which have evolved over a long history, those of cubane are still developing. However, it is also true that since Eaton’s breakthrough in 1964 there have been continued enthusiastic attempts.


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# 3

Functionalization of Cubane

The absence of a reaction equivalent to the Friedel–Crafts reaction, which has been the most effective tool for site-selective functionalization of benzene, is a major drawback for the site-selective modification of cubane. However, the fact that the formation of cubyl radicals is more likely than that of phenyl radicals is a distinct advantage in the functionalization of cubane. Developing site-selectivity in radical generation reactions, though, is not an easy task. Fortunately, in cubane, ortho-metalation can be performed using amides as directing groups (Directed ortho-Metalation: DoM). This method has become the most reliable approach for site-selective functionalization in the cubane system. Cubene chemistry, which corresponds to benzyne, has long been of interest, and it is a field expected to develop further in the future.

3.1

Directed ortho-Metalation (DoM) by Base

The large pK a value of cubane (about 40) suggests the difficulty of forming carbanions through quantitative deprotonation under thermodynamic control. In other words, a directing group should be used to effectively manage the equilibrium of carbanions formed by the initial stage of deprotonation under kinetic control. In 1985, Eaton and Castaldi reported the first ortho-lithiation of cubanecarboxamide.[9] Upon treatment of N,N-diisopropylcubane-1-carboxamide with LiTMP (lithium 2,2,6,6-tetramethylpiperidide) at 0 °C followed by quenching with MeOD, a 3% yield of ortho-deuterated product was obtained. To increase the quantity of this cubyl anion equivalent produced by LiTMP, transmetalation to a more stable cubylmetal was considered. Eaton managed to achieve quantitative ortho-metalation by converting the produced cubyllithium into cubylmercury in situ (Scheme [2]).

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Scheme 2 The first example of cubanecarboxamide ortho-metalation

The low nucleophilicity of organic mercury would limit the range of applicable electrophiles. Eaton also converted the resultant cubylmercury into the corresponding lithium compound using methyllithium via a ‘reverse transmetalation’ process. It has been confirmed that this reacts with MeOD, PhSeCl, and CO2 to yield adducts in good amounts (Scheme [3]).[10]

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Scheme 3 ‘Reverse transmetalation’ to afford cubyllithium

The more practical method, however, was shown to be ‘normal transmetalation’. In 1988, Bashir-Hashemi demonstrated efficient ortho-directing metalation via transmetalation of organolithium to organomagnesium.[11a] [b] While this method required an excess amount of base, as shown in Scheme [4], it opened a path to prepare a wide range of substituted cubanes. Later, Schmitt made important observations regarding the ortho-metalation of cubanecarboxamide, emphasizing the necessity of using bulky amides, such as diisopropylamide. He noted that tert-butylethylamide was as effective as diisopropylamide, and that the choice of amide was crucial for effective DoM.[11c]

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Scheme 4 ‘Normal transmetalation’ to afford cubylmagnesium

The use of MgBr2 with two equivalents of LiTMP in Scheme [4] suggests the in situ formation of Hauser base (Mg-NR2). Eaton demonstrated regiocontrolled metalation by Hauser base by adjusting the ratio of LiTMP and MgBr2 (Scheme [5]).[12]

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Scheme 5 Regiocontrol by the Hauser base component

Knochel revisited and enhanced Hauser’s base chemistry, demonstrating TMPMgBr·LiCl and TMP2Mg·2LiCl as effective reagents for the selective metalation of various aromatic rings.[13] Recently, Takebe and Matsubara examined the use of these Knochel–Hauser bases for deprotonating N,N-diisopropylcubanecarboxamide (4) (Scheme [6]).[14]

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Scheme 6 ortho-Metalation of N,N-diisopropylcubanecarboxamide with Knochel–Hauser base

Eaton also investigated attempts to form C–C bonds through Negishi coupling.[15] Diamide 10, when treated with an excess of LiTMP in the presence of zinc chloride, may yield α,α′-dizinciocubane-1,4-dicarboxamide 16, which can undergo Pd-catalyzed cross-coupling with benzoyl chloride to afford 17 (Scheme [7]). Furthermore, as another example of transmetalation, the formation of a zincate enabled efficient cross-coupling reactions between cubane and aryl iodide. Treatment of N,N-diisopropyl-4-methyl-1-cubanecarboxamide (18) generated the corresponding zincate, which served as the Pd-catalyzed cross-coupling partner with aryl iodide.[16]

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Scheme 7 Negishi coupling via ortho-directing metalation of cubane

# 3.2

Transition-Metal-Catalyzed Directed ortho C–H Functionalization

The utilization of directing groups on the benzene ring in transition-metal-catalyzed C–H functionalization has garnered significant attention from researchers. This strategy has also been extended to the activation of alkyl–hydrogen bonds.[17] Considering cubane as an analogy to benzene, it becomes an important endeavor to explore whether a similar approach can be applied to cubane. Unlike benzene, the presence of a transition metal catalyst in cubane solution can trigger ring-opening or constitutional isomerization reactions to relieve the strain inherent in the molecule. In fact, Eaton demonstrated this phenomenon in 1970 (Scheme [8]). Treatment of dimethyl cubane-1,4-dicarboxylate (1) with Rh(I) resulted in the formation of cis,syn,cis-[3]-ladderanediene 20, while treatment with Pd(II) or Ag(I) yielded the constitutional isomer cuneane 21.[18]

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Scheme 8 Transition-metal-catalyzed isomerization of cubane

During research on C–H insertion of diazoketone-substituted cubane 22 in the presence of a Rh catalyst, Williams found ‘directing C–H functionalization on cubane’ (Scheme [9]).[19a] More recently, site-selective C–H oxidation using a quinoline directing group has also been reported. Treatment of 24 with a Pd catalyst and an oxidizing reagent produced a mixture of α-mono- and α,α′-diacetoxylated products 25a and 25b.[19b]

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Scheme 9 Transition-metal-catalyzed ortho-C–H functionalization

# 3.3

Functionalization via the Cubyl Radical

The carbanion-mediated reaction for introducing substituents into cubane was designed based on analogy with reactions on benzene. On the other hand, the use of radical species, which can be challenging with benzene, is relatively straightforward. There are two main pathways to form a cubyl radical. The first involves direct formation through C–H bond homolysis (HAT), while the second involves indirect formation via homolysis of a radical precursor such as iodocubane or cubanecarboxylic acid.

3.3.1

C–H Homolysis on the Cubane Skeleton (HAT)

The tertiary carbon radicals such as the tert-butyl radical have been considered relatively stable and useful reactive intermediates. The stability of these radicals is explained by ‘hyperconjugation,’ which is more favorable for a flat sp2-hybridized carbon. The formation of a ‘radical’ directly by C–H homolysis in highly pyramidal sp3-hybridized carbons in cubane seems to be more difficult. In 1990, however, Eaton demonstrated that treatment of cubane (3) with tert-butyl hypoiodite under tungsten-lamp irradiation resulted in a mixture of iodocubane (26) and polyiodocubane 26′ (Scheme [10]). Although this reaction is not practical use for the preparation of iodocubane, the result implied the possibility of the direct functionalization of a C–H bond via a radical-forming process.[20]

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Scheme 10 Direct C–H iodination via HAT

Controlled direct monobromination and monochlorination were achieved using a trihalomethyl radical, which is generated from tetrahalomethane and sodium hydroxide in the presence of phase-transfer catalyst (Scheme [11]). In the synthesis of iodocubane, triiodomethane, which converts into tetraiodomethane through disproportionation, was utilized with a base in the absence of a phase-transfer catalyst.[21]

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Scheme 11 Cubyl radical mediated monohalogenation

Photoinduced chloro radical formation from oxalyl chloride leads to abstraction of a hydrogen atom from cubane, resulting in the formation of chlorocarbonylated cubanes. Bashir-Hashemi demonstrated the photochemical reaction of dimethyl cubane-1,4-dicarboxylate (1) with excess oxalyl chloride, followed by treatment with methanol, leading to a mixture of regioisomers of tetrasubstituted cubanes 30 and 30′ (Scheme [12]).[22a] [b] In 2021, Linclau employed a flow reactor to enhance the efficiency of the reaction, and reduce the amount of oxalyl chloride required, enabling the mono-chlorocarbonylation of dimethyl cubane-1,4-dicarboxylate (1) to afford 30′′.[22c]

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Scheme 12 Photochemical chlorocarbonylation of dimethyl cubane-1,4-dicarboxylate

Trifluoromethylation using a stoichiometric amount of copper reagent was demonstrated by Hong,[23] although the yield was not satisfactory. Nevertheless, this method represents the only approach to introduce directly a trifluoromethyl group onto the cubane skeleton (Scheme [13]).

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Scheme 13 Direct trifluoromethylation of cubane by [Cu–CF3] reagent

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# 4

Preparation of Polysubstituted Cubanes

As discussed in Section 3, the C–H functionalization on cubane has primarily been achieved through DoM and HAT processes. The former allows for site-selectively introduction of various electrophiles adjacent to the directing group, while the latter poses challenges in terms of site-selectivity control and limited options for introducing ‘radicalphiles’. However, carboxyl groups and halogens introduced by HAT can regenerate radicals or anions, enabling further molecular transformations. Iodides, in particular, can be converted into metals to generate site-specific anions. Moreover, the transformation of the carboxyl group itself is highly valuable. By harnessing these methods, polysubstituted cubanes can be prepared (Scheme [14]).

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Scheme 14 Strategy for preparation of polysubstituted cubanes

In certain cases, DoM and HAT can be employed to introduce multiple substituents ignoring site selectivity. This allows for the incorporation of identical substituents in all eight positions of the cubane framework. Notably, a molecule with all hydrogen atoms replaced by nitro groups becomes highly explosive. Additionally, complete fluorination of cubane is expected to yield a molecule with a distinct electron state due to the high electronegativity of fluorine. The syntheses of these compounds will be described in Sections 4.1 and 4.2.

4.1

Octanitrocubane

The step-by-step strategy outlined in Scheme [14] was demonstrated in the synthesis of octanitrocubane (39) from cubanecarbonyl chloride (32) in Scheme [15].[24] It has been recognized that highly nitrated small molecule like 38 and 39 have significant explosive potential. Photoinduced chlorocarbonylation of 32 yielded tetrasubstituted cubane 33 as a major product. The formation of radicals was influenced by the electron-withdrawing effect, favoring chlorocarbonylation at the 1-,3-,5-, and 7-positions. Curtius rearrangement and oxidation of 33 produced 1,3,5,7-tetranitrocubane 37. The strong electron-withdrawing effect of the nitro groups made the remaining protons acidic. Treatment of metal amide with dinitrogen tetroxide generated a nitro adduct, ultimately leading to the formation of octanitrocubane (39).

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Scheme 15 Preparation of polynitrocubane

# 4.2

Octafluorocubane

Heptafluorocubane (42) was prepared by direct fluorination of cubanecarboxylic acid ester 40 with fluorine gas, followed by hydrolysis and decarboxylation. The acidic proton in 42 was deprotonated by a base, and the resulting carbanion was fluorinated with NFSI (N-fluorobenzenesulfonimide) to yield octafluorocubane (43) as shown in Scheme [16].[4b] This perfluorinated cubane exhibited a unique radical anion state, where the unpaired electron resides inside the cubane cage. This is due to the high electronegativity of the F-atom, which creates a large σ* orbital extending from each vertex towards the central point inside the cubane.

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Scheme 16 Preparation of polyfluorocubane

# 4.3

Site-Selective Introduction of Substituents

The syntheses of octasubstituted cubanes described above demonstrated the power of the combination of HAT and DoM methods, but they may not be sufficient for site-selective incorporation reactions. DoM allows for the synthesis of 1,2-disubstituted cubanes, (equivalent to ortho-substituted cubanes) with high selectivity but cannot be applied to the synthesis of meta-disubstituted (1,3-disubstituted) and para-disubstituted (1,4-substituted) cubanes. By repeating the DoM process, electrophiles can be sequentially introduced into the three ortho-positions adjacent to the directing group, enabling selective synthesis of 1,2-di-, 1,2,3-tri-, and 1,2,3,5-tetrasubstituted cubanes. Although the HAT method does not exhibit high site-selectivity like the DoM method, it can slow down radical generation at the vertex carbon adjacent to the carbon with an electron-withdrawing group. Sequential introduction of electron-withdrawing groups by the HAT method can be expected to generate 1,3,5-trisubstituted and 1,3,5,7-tetrasubstituted cubanes (Scheme [17]).

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Scheme 17 Site selectivity expected by DoM and HAT method
4.3.1

Site-Selective Preparation of Disubstituted Cubanes

There are three types of disubstituted cubanes, that is, 1,4-, 1,3-, and 1,2-disubstituted cubanes. Each site-selective synthesis will be described below.

4.3.1.1

1,4-Disubstituted Cubanes (Figure [5])

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Figure 5

As mentioned in Section 2.1, the most readily available cubane derivative is dimethyl cubane-1,4-dicarboxylate (1). Compound 1 can be transformed into various molecules by functional group transformations (FGT) of ester groups (Scheme [18]).[2] [19a] [25] These FGT processes have increased the value of 1,4-disubstituted cubanes as bioisosteres of para-substituted benzenes.[3] Additionally, the carboxylic acids 44 and 45 obtained by hydrolysis of the methyl ester 1 can be converted into halides through radical-mediated reactions,[6b] [26] or undergo cross-coupling reactions involving decarboxylation to yield arylated cubanes.[27] 1,4-Dihalocubanes can also be prepared using these methods.[26a]

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Scheme 18 Synthetic scheme of 1,4-disubstituted cubanes

In 1989, Eaton reported the decarboxylative iodonization of cubanecarboxylic acid using the Barton ester.[26a] In 2011, it was shown that 1,3-diiodo-5,5-dimethylhydantoin induces formation of an amide radical that forms a carboxy radical by a HAT process under irradiation by visible light, and also completes the radical chain mechanism via iodination.[26b] The method provides a convenient procedure for preparing iodocubanes. Photoinduced cubyl radical formation from carboxylic acid and lead tetraacetate utilizing Kochi-type radical formation, was used to synthesize phenylcubane derivative 47.[28] Although iodocubane was found to be a less effective transition-metal-catalyzed cross-coupling partner for several organometallic compound,[29] redox-active esters 48, prepared from carboxylic acid 44 were shown to be effective as a cross-coupling precursor in the presence of iron or nickel catalyst (Scheme [19]).[27]

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Scheme 19 Transformations starting from a cubanecarboxylic acid via cubyl radical formation

Notably, anode oxidation of carboxylic acid 44 in the presence of an alcohol yielded alkoxycubane when the reaction was performed in a flow reactor (Scheme [20]).[30] This transformation, known as the Hofer–Moest reaction, had not been successful for cubanecarboxylic acid until the use of a flow cell. As iodocubanes are also important radical precursors, they can be oxidized into cubyl cation intermediates to give alkoxycubanes.[31]

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Scheme 20 Hofer–Moest reaction of cubanecarboxylic acid

Additionally, the iodine–metal exchange reaction provided a useful synthetic route, which makes it possible to use metalated cubane as a carbanion equivalent.[29] In 1990, Eaton reported a preparation of cubyllithium from iodocubane and tBuLi, and Senge conducted a systematic study to understand the reactivity of cubyllithium (Scheme [21]). However, there are some limitations to its use as nucleophile due to its strong basicity. Eaton prepared the higher order cuprate from cubyllithium and (2-thienyl)CuCNLi, which underwent 1,4-addition with cyclohexenone.[25a]

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Scheme 21 Transformations via cubyllithium

It was demonstrated by Kato and Matsubara that treatment of 4-iodocubanecarboxamide 54 with dianionic zincate 55 yielded a cubylmetal with suitable reactivity. The adduct of 56 with an aldehyde was obtained in good yield (Scheme [22]).[32]

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Scheme 22 Iodine–metal exchange by a dianionic zincate

# 4.3.1.2

1,3-Disubstituted Cubanes (Figure [6])

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Figure 6

As discussed in Section 4.3, achieving site-selective functionalization at the meta-position is challenging. However, there is an exceptional example where radical-mediated halogenation of fluorocubane resulted in the site-selective formation of 1,3-disubstituted cubane (Scheme [23]).[21c] The highly electronegative F-atom prevents cubyl radical formation at the ortho-positions. Radical formation at the para-position is still a concern, but it may be hampered by the extensive spreading σ* orbital of the C–F bond.

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Scheme 23 Halogenation of fluorocubane via HAT

# 4.3.1.3

1,2-Disubstituted Cubanes

As discussed in Section 4.3, 1,2-disubstituted cubanes are the easiest to synthesize among the disubstituted compounds. Various electrophiles can be introduced at the 2-position of cubanecarboxamide because a reliable method using DoM has been established for introducing substituents. However, there are other challenges involved. The most commonly used cubanecarboxamide for DoM is diisopropylamide, which is known to be extremely difficult to hydrolyze. Schimitt investigated several cubanecarboxamides suitable for DoM and found that tBuMeN- is effective for DoM and can be hydrolyzed by nitric acid.[11c] Instead of hydrolysis, Eaton demonstrated a reduction-oxidation protocol to convert N,N-diisopropylcubanecarboxamide derivatives into the corresponding cubanecarboxylic acids. In Scheme [24], N,N-diisopropylcubanecarboxamide (15) was converted into 2-methylcubane-1-carboxylic acid (63) via DoM, iodine–metal exchange, reduction, and oxidation.[33]

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Scheme 24 Preparation of 2-methylcubane-1-carboxylic acid

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# 4.3.2

Site-Selective Preparation of Trisubstituted Cubanes

There are three types of trisubstituted cubanes: 1,2,4-, 1,2,3-, and 1,3,5-trisubstituted. Chirality may arise in 1,2,3- and 1,3,5-trisubstituted cubanes. The 1,2,4-substituted compound is achiral due to its plane of symmetry.

4.3.2.1

1,2,4-Trisubstituted Cubanes (Figure [7])

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Figure 7

This achiral trisubstituted cubane can be obtained through the monofunctionalization of 1,4-disubstituted cubane. Fortunately, due to the symmetry of 1,4-substituted cubanes, the remaining six C–H bonds have only two types, that is ortho- and ortho′-, which inevitably lead to site-selective reactions using DoM. For example, as shown in Schemes 3, 7, 12, and 13, various 1,2,4-trisubstituted cubanes have been synthesized since Eaton’s synthesis of dimethyl cubane-1,4-dicarboxylate was reported.


# 4.3.2.2

1,2,3-Trisubstituted Cubanes (Figure [8])

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Figure 8

It is possible to repeat the DoM process twice to synthesize 1,2,3-trisubstituted cubanes. As described in Section 2.2, 1,2,3-trisubstituted cubane can be chiral molecule (chiral cases: u ≠ v ≠ w, or u = v ≠ w). The former type of chiral cubane (u ≠ v ≠ w) was first synthesized by Eaton,[34] where the DoM process was sequentially repeated on cubanecarboxamide (Scheme [5]). Later, it was shown that a chiral cubanes 65 synthesized by a similar DoM method could be resolved by chiral high-performance liquid chromatography (cHPLC).[6b] [16] Yoshino and Matsubara showed the synthesis of the latter type of chiral cubane (Scheme [25]).[6a]

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Scheme 25 Preparation of 1,2,3-trisubstituted chiral cubanes

The sequential DoM process starting from achiral cubanecarboxamides leads to chiral 1,2,3-trisubstituted cubanes, implying the possibility of asymmetric induction. One of the most direct approaches for achieving asymmetric induction is to use a chiral amine as a chiral auxiliary. However, there are limitations on the amides that can be used in the DoM of cubanecarboxamide. Takebe and Matsubara selected bis((R)-cyclohexyl)amine, which was previously used by Anderson for the stereoselective deprotonation of a bicyclo[1.1.1]pentane derivative,[35] and performed DoM on disubstituted cubane 69 (Scheme [26]).[14] Carboxylic acids 70 and 70′ were isolated in 70% and 16% yields, respectively (63% de). This reaction represents the first example of the asymmetric synthesis of a 1,2,3-trisubstituted cubane.

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Scheme 26 Chiral auxiliary induced asymmetric synthesis of 1,2,3-trisubstituted cubane

# 4.3.2.3

1,3,5-Trisubstituted Cubanes (Figure [9])

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Figure 9

The synthesis of 1,3,5-trisubstituted cubanes is much more challenging compared to 1,2,3- and 1,2,4-trisubstituted cubanes, as the DoM method cannot be directly applied. In this trisubstituted compound, repeated introduction of substituents to the meta-position is required, and the use of the HAT method, as shown in Scheme [17], is a conceivable approach. Fokin’s halogenation method, as demonstrated in Scheme [11], was applied to chlorocubane 25 (Scheme [27]).[21c] It was expected that the HAT reaction would be controlled by the electron-withdrawing effect of the chlorine atoms, but the selectivity for the desired 1,3-isomer 71′ was somewhat excessive. The obtained 3-chloro-1-bromocubane (71′) was further iodinated through the HAT reaction to yield 1,3,5-trihalocubane 72.

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Scheme 27 Synthesis of a 1,3,5-trihalocubane using the HAT method

Kato and Matsubara succeeded in synthesizing 1,3,5-trisubstituted cubane with high selectivity[32] using bulky bromoamide 73 developed by Alexanian[36] (Scheme [28]). The HAT reaction was inhibited at the ortho-positions of amide 15-d due to steric hindrance, and the para-position was protected by a deuterium atom. As a result, selective dibromination at the 3,5-positions occurred to afford 74.

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Scheme 28 Selective bromination by Alexanian’s reagent

Yoshino and Matsubara[6b] demonstrated the preparation of chiral 1,3,5-trisubstituted cubane starting from the achiral compound 74 (Scheme [29]). Treatment of 74 with nBu4ZnLi2 led to the elimination of two bromine atoms, forming 1,3-cubene 75 with a charge-shift bond (CSB). This reactive bond can react with a carbanion equivalent to afford n-butylated cubylzinc species, which can be quenched with electrophiles. Through this process, 1,3,5-trisubstituted cubane 76 was obtained as a racemic mixture. Chiral resolution of 76 and 76′ was also performed by cHPLC. Preparative cHPLC gave both pure enantiomers that exhibited reasonable values of opposite optical rotation.

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Scheme 29 Preparation of the chiral trisubstituted cubane as a racemic mixture and their chiral resolution

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# 4.4

Tetrasubstituted Cubanes

Up to this point, various substituted cubanes have been synthesized starting from dimethyl cubane-1,4-carboxylate. Eaton demonstrated the successful use of a combination of functional group transformation (FGT), DoM, and radical reactions in the synthesis of the precursor for 1,3,5,7-tetranitrocubane, compound 86 (Scheme [30]).[37]

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Scheme 30 Designed decoration of dimethyl cubane-1,4-dicarboxylate using DoM, HAT, and FGT

Synthesis of cubanes with four or more substitutions involves repeating the DoM process for trisubstituted cubanes and applying FGT of carboxyl and iodo groups. As a chiral scaffold, the cubane skeleton is of great interest as it allows for the introduction of eight different substituents. However, a perfectly controlled protocol for achieving this has not yet been achieved.


# 4.5

Chemistry of 1,n-Dihalocubanes

As described in Section 4.3, the preparation of 1,4-dihalocubane is relatively easier compared to the synthesis of 1,2- and 1,3-dihalocubanes, as decarboxylative halogenation starting from readily available 1 is possible. Eaton suggested that 1,4-disubstituted cubanes with matching molecular widths could serve as bioisosteres for para-substituted benzenes, so it was expected that 1,4-dihalocubane would be versatile synthetic precursor for para-substituted cubanes. In recent years, there has been increased investigation into the use of bicyclo[1.1.1]pentane, despite its smaller size compared to benzene.[38] One reason for this is the facile reaction using isolatable propellanes to give 1,3-substituted bicyclo[1.1.1]pentanes.[39] It was expected that similar CSB bonds could be formed through the reductive elimination of 1,2-, 1,3-, and 1,4-dihalocubanes. Several theoretical studies have been conducted to predict the existence of these cubenes. Comparing the singlet biradical (cubene) and the triplet radical (cubanediyl), Borden implied that existence of 1,2-, and 1,3-cubene are not unreasonable (Scheme [31]).[40]

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Scheme 31 1,n-Cubenes

In 1988, Eaton demonstrated that treatment of 1,2-diiodocubane (87) with tBuLi resulted in the formation of compounds 90 and 91 through the intermediate of 1,2-cubene. Specifically, 1,2-cubene 88 was trapped by the diene 92, leading to the corresponding Diels–Alder adduct 93 in 64% yield (Scheme [32]).[41] Concerning 1,3-cubene, the reaction shown in Scheme [29] by Yoshino and Matsubara provided evidence for the existence of a charge-shift bond (CSB).[6b]

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Scheme 32 Synthesis of 1,2-cubene and its reactions

Eaton also investigated the reaction of 1,4-diiodocubane with tBuLi, which yielded similar results to the case of 1,2-diiodocubane. The reactive intermediate may be not 1,4-cubene, but rather cubane-1,4-diyl.[42] Treatment of 1,4-diiodocubane (94) with MeLi afforded 4-methyl-1-iodocubane (96) as the major product, along with the formation of 97 and 98. These compounds were formed via intermediate 95, which resulted from the reaction between cubane-1,4-diyl and MeLi. The well-tuned protocol made cubane-1,4-diyl a practical synthetic intermediate, and 96 was obtained in 70% yield (Scheme [33]).

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Scheme 33 Synthesis of 4-methyl-1-iodocubane via cubane-1,4-diyl

Another notable transformation reaction of 1,4-diiodocubane is photoinduced solvolysis. As depicted in Scheme [34, 1],4-diiodocubane (94) undergoes sequential conversion into ethers.[43]

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Scheme 34 Photoinduced solvolysis of 1,4-diiodocubane

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# 5

Conclusion

Cubane, a remarkable molecule introduced by Professor Eaton, has had a tremendous impact not only in the field of synthetic chemistry, but also in medicine, materials science, physics, theoretical chemistry, and many other fields. Cubane, with its unique structure in which the eight sp3 C–H units are tightly packed into the smallest possible space, poses a challenge to activating these C–H bonds while maintaining a cubic shape. In fact, thanks to various synthetic methods developed by Professor Eaton himself, many chemists have been trying to develop new routes to synthesize substituted cubanes. Professor Eaton has also demonstrated the metal-catalyzed structural isomerization of cubane, particularly to give the intriguing convex irregular hexahedral compound known as cuneane, which has garnered significant interest (Scheme [8]).[18] While cubane-1,4-dicarboxylic acid esters are achiral molecules, their isomerized counterparts, cuneane-2,6-dicarboxylic acid esters, exhibit chirality, making them even more fascinating as chiral scaffolds.[44] In fact, Takebe and Matsubara have already demonstrated isomerization with asymmetric induction, showcasing the potential for creating chiral cuneanes.[45] Furthermore, it has been shown that the Directed ortho-Metalation (DoM) protocol in cuneanecarboxamide can be carried out with site-selectivity (Scheme [35]).[46] As cuneanes can be regarded as ‘chiral benzene bioisosteres’, they hold promise for unlocking new avenues of chemistry in the future.

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Scheme 35 Recently developed chemistry of cuneanes

This review encompasses less than half of Prof. Eaton’s extensive body of work. It goes without saying, his groundbreaking contributions to cubane chemistry are immeasurable. Over 60 years, his research has continually incited the curiosity of other synthetic chemists, paving the way for them to explore new possibilities through unique synthetic methods. In this review, we have focused on the cubane framework as a molecule that exhibits unique chirality. With profound gratitude and the utmost respect for Professor Eaton, we conclude this review.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors acknowledged to Prof. P. E. Eaton for his warm advice. They also acknowledged Prof. C. M. Williams and Prof. M. Uchiyama for the cooperative joint-research about our cubane chemistry.


Corresponding Author

Seijiro Matsubara
Department of Material Chemistry, Graduate School of Engineering, Kyoto University
Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510
Japan   

Publication History

Received: 26 May 2023

Accepted after revision: 06 July 2023

Accepted Manuscript online:
06 July 2023

Article published online:
31 August 2023

© 2023. Thieme. All rights reserved

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Seijiro Matsubara (left) was educated in chemistry at Kyoto University, completing his Ph.D. in 1986 with Professors Hitosi Nozaki and Kiitiro Utimoto, and at the Université de Lausanne (1984–1985) where he was a Ph.D. course student with Prof. Manfred Schlosser. He was appointed as an Assistant Professor at Kyoto University in 1986. After postdoctoral research with Prof. Barry M. Trost at Stanford University in 1988–1989, he became an Associate Professor at Kyoto University in 1995. In 2006, he became a Full Professor at Kyoto University. Hiyori Takebe (right), she obtained B.Eng. in 2021 and M.Eng. in 2023 from Kyoto University. Now, she is a Ph.D. candidate at Kyoto University as a JSPS Research fellow (DC1).
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Figure 1 (a) Understanding cubane as a unique chiral molecular scaffold; (b) two strategies for the preparation of decorated dice; and (c) two examples of the preparation of substituted cubane
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Scheme 1 Most used starting materials for the synthesis of cubane derivatives
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Figure 2 Understanding chirality of substituted cubanes
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Figure 3 Determination of the R/S-descriptor for substituted cubanes
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Figure 4 Comparison of substituent introduction in benzene and cubane skeletons
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Scheme 2 The first example of cubanecarboxamide ortho-metalation
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Scheme 3 ‘Reverse transmetalation’ to afford cubyllithium
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Scheme 4 ‘Normal transmetalation’ to afford cubylmagnesium
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Scheme 5 Regiocontrol by the Hauser base component
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Scheme 6 ortho-Metalation of N,N-diisopropylcubanecarboxamide with Knochel–Hauser base
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Scheme 7 Negishi coupling via ortho-directing metalation of cubane
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Scheme 8 Transition-metal-catalyzed isomerization of cubane
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Scheme 9 Transition-metal-catalyzed ortho-C–H functionalization
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Scheme 10 Direct C–H iodination via HAT
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Scheme 11 Cubyl radical mediated monohalogenation
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Scheme 12 Photochemical chlorocarbonylation of dimethyl cubane-1,4-dicarboxylate
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Scheme 13 Direct trifluoromethylation of cubane by [Cu–CF3] reagent
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Scheme 14 Strategy for preparation of polysubstituted cubanes
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Scheme 15 Preparation of polynitrocubane
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Scheme 16 Preparation of polyfluorocubane
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Scheme 17 Site selectivity expected by DoM and HAT method
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Figure 5
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Scheme 18 Synthetic scheme of 1,4-disubstituted cubanes
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Scheme 19 Transformations starting from a cubanecarboxylic acid via cubyl radical formation
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Scheme 20 Hofer–Moest reaction of cubanecarboxylic acid
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Scheme 21 Transformations via cubyllithium
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Scheme 22 Iodine–metal exchange by a dianionic zincate
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Figure 6
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Scheme 23 Halogenation of fluorocubane via HAT
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Scheme 24 Preparation of 2-methylcubane-1-carboxylic acid
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Figure 7
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Figure 8
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Scheme 25 Preparation of 1,2,3-trisubstituted chiral cubanes
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Scheme 26 Chiral auxiliary induced asymmetric synthesis of 1,2,3-trisubstituted cubane
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Figure 9
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Scheme 27 Synthesis of a 1,3,5-trihalocubane using the HAT method
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Scheme 28 Selective bromination by Alexanian’s reagent
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Scheme 29 Preparation of the chiral trisubstituted cubane as a racemic mixture and their chiral resolution
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Scheme 30 Designed decoration of dimethyl cubane-1,4-dicarboxylate using DoM, HAT, and FGT
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Scheme 31 1,n-Cubenes
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Scheme 32 Synthesis of 1,2-cubene and its reactions
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Scheme 33 Synthesis of 4-methyl-1-iodocubane via cubane-1,4-diyl
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Scheme 34 Photoinduced solvolysis of 1,4-diiodocubane
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Scheme 35 Recently developed chemistry of cuneanes