Regioselective Aldol Reactions Directed by Charge and Orbital Effects in Cyclic Germyl Dienolates: Synthesis of Three Distinct Regio‐ and Stereoisomers

Taishi Nojima; Akihito Konishi; Makoto Yasuda

doi:10.1002/chem.71422

. 2026 Jul 17;32(38):e71422. doi: 10.1002/chem.71422

Regioselective Aldol Reactions Directed by Charge and Orbital Effects in Cyclic Germyl Dienolates: Synthesis of Three Distinct Regio‐ and Stereoisomers

Taishi Nojima ¹, Akihito Konishi ^1,^2,^3,^✉, Makoto Yasuda ^1,^2,^✉

PMCID: PMC13660488 PMID: 42467004

ABSTRACT

Regioselective aldol reactions of dienolates represent a valuable method for the construction of complex molecular scaffolds; however, controlling the reaction site of the dienolate remains a significant challenge. This study presents a method for regioselectivity switching in the aldol reactions of cyclic Ge‐dienolates, which are generated from the (4 + 1) cycloaddition of allenoates with Ge(II) salts. Through systematic tuning of the charge and orbital distributions of the Ge‐dienolates and their aldehyde reaction partners, regio‐ and stereoselective access to three distinct aldol adducts (syn‐α‐, anti‐α‐, and anti‐γ‐adducts) is achieved. The aldol reaction of Ge‐dienolates generally proceeds via an orbital‐controlled pathway to afford the anti‐γ‐adduct through a cyclic transition state. Activation of the aldehyde with a Lewis acid shifts the reaction to a charge‐controlled pathway, resulting in the syn‐α‐adduct via an acyclic transition state. Notably, coordination of a ligand or solvent to the Ge center of the cyclic Ge‐dienolates increases electron density, thereby favoring a charge‐controlled pathway, promoting selective α‐addition to yield the anti‐α‐adduct through a distinct cyclic transition state. The synthetic utility of these types of adducts is further demonstrated via gold‐catalyzed intramolecular C─H/C–Ge cross‐coupling, which enables the efficient synthesis of various fused‐ring systems.

Keywords: aldol reaction, charge‐/orbital‐controlled selectivity, dienolate, germanium, regioselectivity

Charge and orbital control represent fundamental principles in organic chemistry. In this study, these principles are applied to the aldol reactions of a cyclic Ge‐dienolate. By systematically tuning the charge and orbital distributions of the Ge‐dienolates and their aldehyde reaction partners, regio‐ and stereoselective access to three distinct aldol adducts (syn‐α‐, anti‐α‐, and anti‐γ‐adducts) is achieved. The synthetic utility of these adducts is further demonstrated through selective C─Ge bond modification.

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1. Introduction

Charge‐ and orbital‐controlled mechanisms are widely recognized as fundamental principles that govern organic reactions [1, 2, 3, 4]. According to the ‘Hard and Soft Acids and Bases’ (HSAB) theory, reactions involving highly polarized species proceed via charge‐controlled mechanisms at the sites with the highest charge density, while reactions involving less polarized species follow orbital‐controlled mechanisms at the sites with the highest orbital coefficient [5, 6, 7]. In reactions involving ambident nucleophiles, in which the distributions of electron density and orbital coefficient differ, the hardness or softness of the electrophile determines the regioselectivity. Enolates exemplify this phenomenon, that is, their negative charge is primarily localized on the oxygen atom, whereas the highest HOMO coefficient is located on the α‐carbon [8, 9]. As a result, their reactions with harder electrophiles, such as protons, alkyl tosylates [10], chlorosilanes [11, 12], or acid anhydrides [13], predominantly occur at the oxygen atom, producing enols, vinyl ethers, Si‐enolates, or enol acetates, respectively. Conversely, the use of softer electrophiles, such as alkyl iodides [10] or aldehydes [14], lead to alkylation or aldol‐type reactions at the α‐carbon atom (Figure 1a). Numerous studies have demonstrated that the regioselectivity of enolates can be rationalized in terms of charge and orbital effects.

(a) Regioselectivity switching in the nucleophilic additions of enolates depending on the hardness or softness of the reaction partner. (b) The greater complexity of regioselectivity in the nucleophilic addition reactions of dienolates compared to that of enolates. (c) Hypothesis: Controllable regioselectivity switching of Ge‐dienolate species can be achieved via inducing a charge‐ or orbital‐controlled reaction pathway.

Dienolates are valuable nucleophiles that can directly yield δ‐hydroxy ketones, a key structural motif in macrolides, via vinylogous aldol reactions [15, 16, 17]. However, the regioselectivity of these aldol reactions is more complicated than those of conventional enolates, as nucleophilic addition can occur at the oxygen, the α‐carbon, or the γ‐carbon atoms [4, 18, 19, 20, 21]. As with conventional enolates, the reactions of dienolates with hard electrophiles such as chlorosilanes typically occur at the oxygen atom to produce the corresponding Si‐dienolates [22, 23, 24]. The regioselectivity between the α‐ and γ‐positions is primarily governed by the character of the metal counterion of the dienolate. Alkylations [25, 26] and aldol reactions [27, 28] involving more polar dienolates, such as Li‐dienolates, preferentially occur at the α‐position, where electron density is high. In contrast, reactions involving less polar Si‐ [29, 30] or Cu‐dienolates [31, 32] occur selectively at the γ‐position, where the HOMO coefficient is highest (Figure 1b) [33].

Several seminal studies [34, 35, 36, 37] have achieved regioselectivity in the addition reactions of dienolates by using bulky Lewis acids [38, 39] or exploiting the reversibility of α‐adducts via a retro‐aldol process [27, 28, 40, 41, 42, 43, 44, 45]. However, the influence of charge and orbital effects on regioselectivity in dienolates remains unexplored, despite the potential as a straightforward and effective strategy to address the inherent complexity of dienolates and provide significant value to synthetic chemistry.

Two key prerequisites are necessary to achieve regioselectivity switching of a dienolate via the induction of a charge‐ or orbital‐controlled reaction mechanism (Figure 1c). The first is a suitable balance between ionic and covalent character for the metal counterion of the dienolate. The second is the ability to tune the electron density of the dienolate via a response to external additives or solvents. Based on these considerations, Ge‐dienolates emerge as suitable nucleophiles [24, 46, 47, 48]. Germanium exhibits higher ionic character than silicon while retaining covalent properties, thus endowing Ge‐dienolates with inherent duality, which can be further modulated via coordination of external ligands to the Ge center, thus enabling a precise tuning of the electronic structure of the dienolate.

Recently, we have reported a mild method for the generation of various nucleophilic species using divalent germanium salts [45, 49, 50, 51, 52, 53, 54, 55, 56, 57]. For example, Ge‐dienolates II were generated from allenones I using GeCl₂ (Figure 2a) [45]. The combination of the rigid cyclic structure of the Ge‐enolates with the moderate Lewis acidity of the Ge center [56] effectively controls the facial selectivity to achieve perfect diastereoselectivity. Furthermore, complete control of the regioselectivity could be attained via the use of a Lewis acid additive and the choice of solvent to afford either syn‐α‐IV in acetonitrile or anti‐γ‐IV in THF. However, the regioselectivity switching of II hinged on the reversible retro‐aldol nature of the α‐adducts, which constrained the practical utility of the methodology. To overcome this intrinsic limitation, we redesigned the reaction system by replacing the allenone precursors I with allenoates 1, enabling the generation of a fundamentally different Ge‐dienolate (2) with tunable electronic properties (Figure 2b). The reaction of 2 with a soft aldehyde electrophile (3) proceeds under orbital control to produce the γ‐adduct (anti‐γ‐4). In contrast, in the presence of a Lewis acid additive, aldehyde 3 becomes polarized, which induces a reaction via an ionic pathway to yield the α‐adduct (syn‐α‐4). The coordination of a ligand or solvent to the Ge center furnishes a highly coordinated dienolate [2‐Ligand] whose increased ionic character facilitates selective α‐addition, producing the anti‐α‐adduct.

(a) Our previous work: The reversibility of the α‐addition of cyclic Ge‐dienolate II enabled regioselectivity switching in the aldol reaction. (b) This work: Regioselectivity switching via charge or orbital control of the aldol reaction of cyclic Ge‐dienolate 2 provides access to three distinct isomers.

2. Results and Discussion

We first investigated the generation of dienolate 2a from ethyl allenoate 1a using GeCl₂‐dioxane (Figure 3a) based on our previously developed synthesis for dienolate IIa [45]. While ¹H NMR measurements in typical deuterated solvents did not suggest the formation of 2a, high‐resolution mass spectrometry detected the corresponding molecular ion peak (for details, see Synthetic Procedures in the Supporting Information). Quantum‐chemical calculations at the ωB97XD/6‐311G**(SMD)//ωB97XD/6‐31G* level revealed that the formation of IIa is an exergonic process (ΔG = –11.8 kcal/mol), whereas the formation of 2b from methyl allenoate 1b is an endergonic process (ΔG = 1.8 kcal/mol). These results would explain the difficulties associated with observing 2a via NMR spectroscopy (Figure S10). Stabilizing the dienolate 2a by adding external ligands was also attempted, but the generation of 2a in the presence of ligands failed, resulting in the recovery of 1a and Ge(II) salt.

(a) Attempts to observe the formation of cyclic Ge‐dienolates 2a and **IIa** [45] (b) Aldol reaction of *in situ*‐generated 2a with 3a in the presence of BF₃ ·OEt₂ in CH₃CN to give *syn*‐α‐**4aa**. (c) Aldol reaction of *in situ*‐generated 2a with 3a in THF to give a mixture of *anti*‐α‐**4aa** and *anti*‐γ‐**4aa**.

Next, we investigated the trapping of 2a using benzaldehyde 3a. The three‐component reaction of 1a, 3a, and GeCl₂‐dioxane was carried out in CH₃CN in the presence of BF₃ ·OEt₂ under our previously reported conditions (Figure 3b) [45]. Gradual crystallization from the reaction mixture furnished single crystals suitable for X‐ray analysis, which revealed that aldol adduct syn‐α‐4aa was produced selectively and was present exclusively in the form of dimers of enantiomeric pairs (Figure 4a and S1−S4). This result is consistent with the reaction of II in the presence of an external Lewis acid. S1−S4 In contrast, the three‐component reaction in THF without an external Lewis acid, in which II affords the anti‐γ‐adduct, gave not only anti‐γ‐4aa (30%) but also its regioisomer anti‐α‐4aa (16%; Figure 3c). The solid‐state structures of the three regio‐ and stereoisomers were unambiguously determined via X‐ray crystallography (Figure 4).

Molecular structures of aldol adducts (a) *syn*‐α‐**4aa**, (b) *anti*‐α‐**4aa**, and (c) *anti*‐γ‐**4aa** with thermal ellipsoids at 50% probability; some hydrogen atoms are omitted for clarity.

In the aldol reaction of II, the regioselectivity switching strongly depends on the reversibility of the α‐addition (Figure 2a), that is, only the insoluble and kinetic syn‐α‐adducts or the thermodynamically stable anti‐γ‐adducts are obtained [45]. In contrast to the previous studies [45], a retro‐aldol reaction was not observed for 2, which could potentially generate up to four isomers via regioisomerism (α‐ or γ‐adduct) and diastereomerism (syn‐ or anti‐adduct). These findings indicate that the reaction conditions can directly influence the intrinsic reactivity of the dienolate. This observation provides a strong rationale for an investigation of the regioselectivity switching in nucleophilic addition reactions of dienolates via charge‐ or orbital‐controlled reaction pathways.

The reactions of allenoate 1a, benzaldehyde 3a, and GeCl₂‐dioxane with or without additives afforded three distinct aldol adducts (syn‐α‐4aa, anti‐α‐4aa, and anti‐γ‐4aa). Three distinct reaction modes were identified, that is, (i) charge‐controlled α‐addition via activation by an external Lewis acid, (ii) charge‐controlled α‐addition via coordination to the Ge center, and (iii) orbital‐controlled γ‐addition in the absence of additives. The reaction conditions were systematically optimized to provide selective access to each of these modes (Table 1). As mentioned earlier, activation using a Lewis acid additive (BF₃·OEt₂ in CH₃CN) afforded syn‐α‐4aa exclusively (entry 2; see also Figure 3b). In contrast, simply omitting the Lewis acid shifted the selectivity to favor anti‐α‐4aa (entry 1). Anti‐α‐4aa was obtained in similarly high selectivity in other coordinating solvents, such as acetone and EtOAc (entries 3–4), whereas the use of ethereal solvents resulted in decreased regioselectivity (entries 5 and 7). Moreover, anti‐α‐4aa was generated exclusively in the presence of ⁿ Bu₄NCl in THF, albeit in low yield. This result suggests that Cl^– coordinates to the Ge center of 2a to form a highly coordinated dienolate [2a‐Cl]^–, which effectively promotes α‐addition (entry 6) [58, 59]. Conversely, non‐coordinating solvents, such as halogenated (PhCl; entry 8) and hydrocarbon (benzene or hexane; entries 9–10) solvents, primarily afforded anti‐γ‐4aa.

TABLE 1.

Optimization of the reaction conditions for the selective synthesis of syn‐α‐4aa, anti‐α‐4aa, and anti‐γ‐4aa. ^a ^.


entry	solvent	additive	yield / %	syn‐α‐4aa / anti‐α‐4aa / anti‐γ‐4aa ^b
1	CH₃CN	—	71
2 ^c	CH₃CN	BF₃·OEt₂ (2.0 eq)	75 (72) ^d
3	acetone	—	67
4	EtOAc	—	84 (63) ^d
5	THF	—	62
6	THF	ⁿ Bu₄NCl (1.0 eq)	15
7	1,4‐dioxane	—	92
8	PhCl	—	84
9	benzene	—	85
10	hexane	—	89 (100) ^d

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^{^a}

Yield and regioselectivity were determined based on ¹H NMR measurements using 1,1,2,2‐tetrachloroethane as the internal standard.

^{^b}

Bar‐chart legend: blue = syn‐α‐4aa; purple = anti‐α‐4aa; yellow = anti‐γ‐4aa. The primary values to the left and right of the bars represent the α/γ ratio; the syn‐α/anti‐α ratio is provided in parentheses.

^{^c}

1.5 equivalents of 3a were employed.

^{^d}

Reactions were conducted on 1 mmol scales. The details are summarized in the SI.

To obtain deeper insight into the reaction‐condition‐dependent regio‐ and diastereoselectivity in the aldol reactions of 2a with 3a, quantum‐chemical calculations were performed at the ωB97XD/6‐311G**(SMD)//ωB97XD/6‐31G* level. Figure 5 summarizes the energy profiles for the nucleophilic attack of dienolate 2b on 3a under each condition.

Energy profiles of the aldol reaction between 2b and 3a (a) in the presence of BF₃ ·OEt₂ in acetonitrile, (b) in n‐hexane, and (c) in the presence of chloride anions in THF. DFT calculations were performed at the ωB97XD/6‐311G**(SMD)//ωB97XD/6‐31G* level. The structure of *syn*‐α‐**4aa** in Figure 5a is depicted as a monomeric geometry. All nucleophilic attacks are assumed to occur at the Si‐face of dienolate 2b.

When the reaction is carried out in the presence of BF₃ ·OEt₂ in CH₃CN, BF₃ acts as an external Lewis acid that activates 3a to form complex 3a·BF₃ (Figure 5a). The coordination of the oxygen atoms in 2b to BF₃ may be possible, but it is an endergonic process. The subsequent aldol reaction between 2b and 3a·BF₃ proceeds via an acyclic transition state. Among the four possible transition states leading to the different regio‐ and stereoisomers, TS _linear‐syn‐α (associated with α‐addition) and TS _linear‐syn‐γ (associated with γ‐addition) are energetically favored due to substituent effects (Figure S11). The α‐addition predominantly follows a charge‐controlled pathway, whereas the γ‐addition proceeds through an orbital‐controlled mechanism [1]. Activation of 3a by the Lewis acid enhances the carbonyl polarity, thereby facilitating the charge‐controlled α‐addition (ΔΔG ^‡ = 12.5 kcal/mol; Figure 5a). A natural‐bond‐orbital (NBO) analysis indicated that BF₃ coordination increases the positive charge at the carbonyl carbon from +0.440 in 3a to +0.500 in 3a·BF₃ (Figure S15). This observation is consistent with previous findings for aldol reactions involving allenone‐derived dienolates II [45].

In the absence of additives, the Ge center of 2b itself acts as the Lewis acid, and the reaction with 3a proceeds through a cyclic transition state. Analysis of steric repulsion identifies TS _cyclic‐anti‐α (for α‐addition) and TS _cyclic‐anti‐γ (for γ‐addition) as the preferred pathways (Figure S12). Under these conditions, TS _cyclic‐anti‐γ presents a lower activation barrier of 16.1 kcal/mol compared to 18.7 kcal/mol for TS _cyclic‐anti‐α, resulting in the selective formation of anti‐γ‐4ba (Figure 5b). At the transition state of the reaction pathway, an envelope‐like 5‐membered cyclic transition state is adopted, resulting in the γ‐addition. These findings indicate that, in the absence of the external activation of aldehyde 3a, orbital‐controlled γ‐addition is favored over α‐addition. In contrast, Si‐dienolates exclusively undergo γ‐addition under all the conditions examined, highlighting the unique tunability of Ge‐dienolates.

When an external ligand or coordinating solvent is present in the reaction mixture, it binds to the Ge center of 2b to generate a highly coordinated dienolate. When a chloride anion was used as a model ligand (Table 1, entry 6), coordination of Cl^– to the Ge center of 2b was found to stabilize the system and yield [2b‐Cl]^– quantitatively. In the subsequent addition to 3a, the Ge center within [2b‐Cl]^– serves as an internal Lewis acid, facilitating the reaction through a cyclic transition state. The aldol reaction is anticipated to proceed through a boat‐like 6‐membered cyclic transition state due to the rigid cyclic structure of Ge‐enolates [60]. The moderate Lewis acidity of the highly coordinated Ge center is expected to enhance the facial selectivity of aldehydes. An analysis of substituent effects indicated that TS _cyclic‐anti‐α and TS _cyclic‐syn‐γ are the preferred pathways (Figure S13). Of the two, TS _cyclic‐anti‐α has a lower activation barrier (ΔG ^‡ = 11.7 kcal/mol) than TS _cyclic‐syn‐γ (ΔG ^‡ = 20.5 kcal/mol), resulting in the selective formation of anti‐α‐4ba (Figure 5c).

Figure 6a shows the HOMO and NBO charge at the α‐ and γ‐carbon atoms of 2b and [2b‐Cl]^–, as well as the corresponding silyl dienolate 2b′ and [2b′‐Cl]^–. The NBO‐charge values indicate a significant increase in electron density upon coordination of chloride to the Ge center (see also Figure S15). Even though the energy levels of the HOMOs are almost comparable, the NBO‐charge value at the α‐carbon atom of [2b‐Cl]^– is larger than that of [2b′‐Cl]^–. The formation of the highly coordinated dienolate also leads to a notable change in the HOMO distribution, that is, the HOMO of 2b displays diene character, while that of [2b‐Cl]^– resembles an allyl anion. The optimized bond lengths of 2b and [2b‐Cl]^– support this notion. Upon coordination of chloride to the Ge center, the O─C _ipso and C _α ─C _β bonds of 2b are compressed, resulting in an alleviation of the bond‐length alternation between the C _α ─C _β and C _β ─C _γ bonds (Figures 6b and S16). The geometric differences between 2b to [2b‐Cl]^– indicate an enhanced contribution of the allyl‐anion character in the highly coordinated enolate [2b‐Cl]^– (Figure 6c). This transformation from a diene‐like to an allyl‐anion‐like electronic structure provides a direct mechanistic basis for the observed switch from orbital‐ to charge‐controlled reactivity. Consistent with our initial hypothesis (Figure 1c), the coordination ability of the Ge center allows effective modulation of both the electron density and orbital distribution of the dienolate, enabling regioselectivity switching.

(a) Calculated orbital‐energy diagram of the HOMO and NBO charge at the α‐ and γ‐carbon atoms for 2b and [2b‐Cl]^–, as well as the corresponding silyl dienolate **2b′** and [**2b′**‐Cl]^–. (b) Optimized bond lengths in 2b and [2b‐Cl]^–. Theoretical calculations were performed at the ωB97XD/6‐311G**(SMD)//ωB97XD/6‐31G* level. (c) Estimated resonance structures of 2b and [2b‐Cl]^–.

With the optimized conditions in hand, the reactions of various carbonyl compounds with 1a were investigated (Scheme 1). A benzaldehyde bearing an electron‐withdrawing substituent (CO₂Me; 3c) gave the corresponding products syn‐α‐4ac, anti‐α‐4ac, and anti‐γ‐4ac. In contrast, electron‐donating aromatic aldehydes (3b, 3i) yielded only anti‐α‐4, and anti‐γ‐4; the absence of the syn‐α‐4 product in these cases was attributed to its inherent instability under the applied reaction conditions. Steric effects were evaluated using o‐, m‐, and p‐methylbenzaldehydes (3d–f). Regardless of the position of the methyl group, the corresponding products were obtained in good yield with high regio‐ and diastereoselectivity. Aldehydes having a naphthyl group (3 g and 3 h) were also applicable. Unfortunately, the regio‐ and diastereoselectivity is largely restricted to aromatic aldehydes. Only the anti‐γ‐adduct was obtained in the reactions with trans‐cinnamaldehyde 3j in very low yields. Notably, the high reactivity of dienolate 2a enabled a reaction with typically challenging substrates, such as the bulky alkyl aldehyde 3k and aromatic ketone 3l. However, these substrates only gave the anti‐α‐4 product under all conditions due to their distinct electrophilicity compared to benzaldehyde 3a.

Next, the scope of allenoates 1 was examined (Scheme 2). With regards to the ester moiety (CO₂R¹), benzyl ester 1c reacted efficiently, producing all three isomeric products with excellent selectivity. In contrast, phenyl ester 1d yielded only the anti‐α‐4da and anti‐γ‐4da adducts, likely due to differences in the reactivity of the dienolates derived from 1a and 1d. Allenoate esters with bearing substituents at the γ‐positions are essentially restricted to tertiary and bulky tert‐butyl ( ^t Bu) and tert‐butyldimethylsilyl (TBS) groups. The substituent at the γ‐position (R³) was found to be critical. Allenoate 1e, which features an isopropyl instead of a tert‐butyl group, produced a complex mixture of isomers that could not be identified. In contrast, allenoate 1f, which contains a tert‐BuMe₂Si group, afforded anti‐α‐4fa and anti‐γ‐4fa with excellent selectivity. Sterically demanding R³ groups promoted selective product formation under all conditions. Under conditions A, the electronic properties of R³ likely influence the preference between syn‐α‐4aa and anti‐α‐4aa.

The reaction of trisubstituted allenoates was also investigated. The γ‐disubstituted allenoate 1 g predominantly gave α‐adducts α‐4ga with almost no selectivity, indicating that the γ‐dimethyl substituents suppress the reactivity at the γ‐position. Allenoate ester bearing substituent at the α‐position is not tolerated. The introduction of an α‐substituent (1 h) severely suppressed the reaction, leading to decomposition of the dienolate.

Then, transformations of aldol adduct 4aa were investigated (Scheme 3). Initially, we attempted the direct transformation of the germanium moiety of the aldol adducts 4aa using Tamao‐Fleming oxidation, an Au‐ or Pd‐catalyst, strong acids (TFA or CF₃SO₃H), a fluoride ion, and a halogenated reagent (NBS or NIS). Unfortunately, all conditions resulted in complicated mixtures of unidentified products. Motivated by recent advances in the use of organogermanium derivatives in synthetic [61, 62, 63] and pharmaceutical chemistry [64, 65, 66, 67, 68, 69, 70] as well as materials science [71, 72, 73, 74, 75, 76, 77, 78], we aimed to synthesize multifunctionalized organogermanium compounds. Methylation of the Ge center in compounds 4 with a slight excess of MeMgBr produced anti‐α‐5 and anti‐γ‐5, both of which retained their stereocenters. The use of a large excess of MeMgBr converted the ethyl‐ester groups into tert‐alcohols (C(Me)₂OH), which can act as leaving groups in transition‐metal‐catalyzed β‐carbon elimination [79, 80, 81, 82, 83, 84]. This procedure afforded anti‐α‐6, anti‐γ‐6, and syn‐α‐6.

Subsequently, various reaction conditions were evaluated for the transformation of the GeMe₃ groups, and the gold‐catalyzed C─H/C─Ge cross‐coupling method reported by Schoenebeck and coworkers was found to be effective [85]. Anti‐α‐5 underwent intramolecular C─H/C─Ge coupling to yield methyleneindane derivative 7, wherein the stereochemistry was retained. In contrast, anti‐α‐6 produced benzofulvene derivative 8 through intramolecular coupling followed by in situ elimination of H₂O and acetone.

For anti‐γ‐5 and syn‐α‐6, Ge─Me bond cleavage was preferred over coupling, resulting in the formation of oxagermacycles 9 and 10. Protection of the hydroxyl group as a methyl ether (syn‐α‐11 and anti‐γ‐11) enabled efficient intramolecular coupling, yielding indene derivative 12 (with the concurrent elimination of methanol) and methyleneindane derivative 13. C(sp²)─Ge bonds are typically more reactive than C(sp³)─Ge bonds [61, 62, 63], the selective cleavage of the C(sp³)─Ge bond in syn‐α‐6 and anti‐γ‐5 is likely promoted by intramolecular coordination of the hydroxyl group to the Ge center [86, 87]. The differing outcomes for diastereomers anti‐α‐6 and syn‐α‐6 indicate that subtle conformational differences significantly affect the reactivity at the Ge center. Further studies on the synthesis of multi‐functionalized organogermanes, particularly the construction of stereogenic Ge centers via selective C─Ge bond functionalization [88], are currently in progress in our laboratory.

3. Conclusion

We have developed an aldol reaction of cyclic Ge‐dienolates 2, which are obtained from the by (4+1) cycloaddition of allenoates 1 with germanium(II) salts. This method provides access to three isomers via switching between charge‐ and orbital‐controlled pathways. Regiocontrol was achieved by balancing the charge density and orbital coefficients of Ge‐dienolates 2 and aldehydes 3. The use of BF₃·OEt₂ as a Lewis acid, or the addition of a coordinating ligand such as Cl^– or a coordinating solvent, promotes charge‐controlled α‐addition to yield syn‐α‐4aa or anti‐α‐4aa. Without these additives, the reaction proceeds under orbital control to give anti‐γ‐4aa. The moderate ionic character and tunable coordination number of the Ge center are essential for this selectivity.

We have furthermore demonstrated the utility of this approach via the Au‐catalyzed intramolecular C─H/C─Ge cross‐coupling of the aldol adducts, which provides access to diverse fused‐ring systems. This work thus significantly expands the scope of dienolate chemistry and provides a versatile platform for the construction of stereogenic Ge centers through selective C─Ge bond modification.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

The authors have cited additional references within the Supporting Information [89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99]. Deposition Numbers 2548107 (syn‐α‐4aa), 2548108 (syn‐α‐4ac), 2548109 (syn‐α‐4ae), 2548110 (syn‐α‐4ah), 2548111 (anti‐α‐4aa), 2548112 (anti‐γ‐4aa), 2548113 (anti‐γ‐5), 2548114 (anti‐γ‐6), and 2548115 (anti‐γ‐11) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via the joint Cambridge Crystallographic Data Centre (CCDC) and the Fachinformationszentrum Karlsruhe Access Structures service.

Supporting File 1: chem71422‐sup‐0001‐SuppMat.pdf

CHEM-32-e71422-s001.pdf^{(9.2MB, pdf)}

Acknowledgments

This work was financially supported by the Japan Society for the Promotion of Science (JSPS) via grants JP25K22182 and JP26K01501 (to M.Y.) as well as JP26K01490 (to A.K.), and by JST CREST grant JPMJCR20R3 (to M.Y.). A.K. would like to express his gratitude to MEXT for the Grant‐in‐Aid for Transformative Research Areas (A) “The Pursuit of Functionality Woven by π‐Molecular Complexity” (JP26H01349) and to the JST FOREST Program for grant JPMJFR2426. The authors would furthermore like to gratefully acknowledge the Analytical Instrumentation Facility, Graduate School of Engineering, The University of Osaka. This work was partially supported by the Asahi Glass Foundation (to A.K.).

Contributor Information

Akihito Konishi, Email: a-koni@chem.eng.osaka-u.ac.jp.

Makoto Yasuda, Email: yasuda@chem.eng.osaka-u.ac.jp.

Data Availability Statement

The data that supports the findings of this study are available in the supplementary material of this article.

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Associated Data

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Supplementary Materials

Supporting File 1: chem71422‐sup‐0001‐SuppMat.pdf

CHEM-32-e71422-s001.pdf^{(9.2MB, pdf)}

Data Availability Statement

The data that supports the findings of this study are available in the supplementary material of this article.

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PERMALINK

Regioselective Aldol Reactions Directed by Charge and Orbital Effects in Cyclic Germyl Dienolates: Synthesis of Three Distinct Regio‐ and Stereoisomers

Taishi Nojima

Akihito Konishi

Makoto Yasuda

ABSTRACT

1. Introduction

FIGURE 1.

FIGURE 2.

2. Results and Discussion

FIGURE 3.