Diastereoselective synthesis of spiro[2.n]alkanes via intramolecular carbolithiation

Abstract

Spirocycles are appealing motifs for drug design owing to their inherently rigid three-dimensional structure, but synthetic strategies to construct highly substituted spiroalkanes remain scarce. We report a highly diastereoselective protocol for the synthesis of spiro[2.n]alkanes via intramolecular carbolithiation of cyclopropenes. The methodology provides straightforward access to spiro[2.n]alkanes as single diastereomers, with up to three contiguous quaternary centres. The trapping of a generated intermediate with an electrophile provides access to functionalized spirocycles bearing halo, silyl, alcohol or carbonyl functionalities.

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Spirocycles—molecular architectures composed of two rings connected through a single atom—have attracted significant attention in medicinal chemistry.^1–6 This growing interest results from the recognition that three-dimensional, sp³-rich scaffolds enhance drug-likeness by improving solubility and oral bioavailability.^7–10 In particular, spirocyclic structures featuring adjacent quaternary carbon stereocenters¹¹ provide additional vectors for installing binding motifs in multiple spatial directions, thereby enhancing target binding affinity.^2,12 Despite these potential advantages, the broader application of spiroalkanes, especially those incorporating stereochemically defined small to medium-sized rings,^13,14 remains limited by significant synthetic challenges.^1,2,12,15 In this context, synthetic strategies have emerged to tackle the synthesis of spiro[2.n]alkanes (Scheme 1A),^16–20 mostly relying on cyclopropanation chemistry. Despite recent advances in spirocycle synthesis,^20–28 the diastereoselective synthesis of highly substituted cyclopropyl-containing spirocycles remains relatively underexplored.^17,18 As part of our ongoing efforts to develop stereoselective strategies for the construction of polysubstituted small rings via the carbometallation reaction,²⁹ we recently reported an approach to access stereodefined, highly substituted spiropentanes³⁰ and bicyclopropanes³¹ from readily available cyclopropenes (Scheme 1B). We envisaged expanding the methodology to the synthesis of spiro[2.n]alkanes beyond spiropentanes, by changing the strategy from an intermolecular to an intramolecular carbometallation pathway (Scheme 1C). To enable the synthesis of all-carbon spirocycles via this approach, we required a functional group on the cyclopropene that could be efficiently converted into an organometallic species. Alkyl iodide 1 was selected for this purpose, as it undergoes a fast and quantitative iodine–lithium exchange with tBuLi resulting in a linear alkyllithium species 2 that can eventually be transmetallated if required. The resulting organometallic species is then expected to undergo an intramolecular carbometallation into the desired spirocyclic organometallic intermediate 3. To control the diastereoselectivity of this cyclization step, a coordinating substituent on the three-membered ring was designed to direct the incoming nucleophile to the same face of the cyclopropene. Finally, the spirocyclopropyl metal species could be further functionalized by reaction with suitable electrophiles, providing various spirocyclic scaffolds 4. During the course of this study, Waser and coworkers reported an elegant palladium-catalyzed intramolecular etherification strategy,³² which provides pentasubstituted trifluoromethylated spirooxazolidines as single diastereomers. However, this approach is conceptually distinct from the carbolithiation strategy described herein and is not applicable to the synthesis of spiro[2.n]alkanes.

Scheme 1 Key precedent and proposed research.

Building on our earlier work on the enantioselective catalytic carbolithiation of cinnamyl derivatives,³³ we hypothesized that the substituent on the cyclopropenyl ring (R¹) should promote the carbometallation step, with aromatic or silyl groups expected to provide the required slight activation. However, this design also necessitates a rapid and quantitative iodine–lithium exchange, to minimize undesired intermolecular addition of alkyllithium species to the reactive double bond of the cyclopropenyl ring.³⁴ It also required to provide a configurationally stable cyclopropyl benzyl (or silyl) lithium intermediate before addition of the electrophile.³⁵ To begin our investigation, we developed a straightforward and efficient method for the preparation of the starting materials 4 (see the SI for all details). Enantiomerically enriched sp²-monosubstituted cyclopropenyl esters are readily accessible³⁶ and undergo a direct palladium-catalyzed cross-coupling reaction with a wide range of aryl iodides.³⁷

We then set out to identify reaction conditions that would promote a clean iodine–lithium exchange followed by an efficient intramolecular carbolithiation reaction on our model substrate 1a. Upon dropwise addition of tBuLi (2 equiv.)³⁸ to iodide 1a at −95 °C, the reaction mixture was gradually warmed to the desired temperature to enable carbometallation (condition A, Scheme 2). For this substrate, cyclization occurred even at −95 °C, but the transformation tolerated temperatures up to −20 °C (see the SI for all details) to provide 4a in excellent yield as a single diastereomer. However, when MeOH-d₄ was used as the electrophile, only low levels of deuterium incorporation were observed (4a_D, 20% D). This suggests that the tertiary cyclopropyllithium intermediate 3a formed during carbolithiation is more reactive than tBuLi itself towards the in situ generated t-butyl iodide under the reaction conditions. As a result, 3a reacts competitively with t-butyl iodide leading to protonated spirocycle 4a. Since this undesired side reaction could not be suppressed, we investigated the use of nBuLi for the iodine–lithium exchange, despite the likelihood of an equilibrium between linear iodide 2a and the corresponding n-alkyllithium.³⁹ Gratifyingly, the intramolecular carbolithiation provided sufficient driving force to push the reaction forward, yielding results comparable to those of tBuLi. When MeOH-d₄ was used under condition B, a significantly higher degree of deuteration (>80% D) was achieved for 4a_D (condition B). When THF was used instead of diethyl ether, the iodine–lithium exchange proceeded completely, but carbometallation was incomplete, and the major side product was the reduced linear product 5a (condition C).

Scheme 2 Conditions for intramolecular carbolithiation.

With the optimized conditions established, we next explored the substrate scope. As some of the alkyl iodides proved unstable toward chromatographic purification and prolonged storage, the crude iodides were used directly after simple filtration (see the SI for details). Consequently, the isolated yields of all spiro[2.n]alkanes in Schemes 3–5 were calculated over two steps. A series of spirocycles ranging from spiro[2,3]hexane 4b to spiro[2.5]octane 4c were obtained in high yields as single diastereomers (Scheme 3), consistent with a syn-selective carbolithiation directed by the methyl ether substituent. The formation of spiro[2.3]hexane 4b with nBuLi was also efficient, although this transformation required higher temperatures compared to the synthesis of spiro[2.4]heptane 4a. To achieve full conversion, the reaction mixture was gradually warmed to −45 °C and stirred for an additional 30 minutes at that temperature. Interestingly, in all cases, the benzyl lithium species is configurationally stable under these experimental conditions. To clarify the role of the cyclopropylcarbinol ether in directing the carbolithiation event, we designed substrate 4d as a control experiment. Introduction of the sterically demanding tert-butyldiphenylsilyl (TBDPS) protecting group led to a marked decrease in diastereoselectivity, furnishing the product in 5 : 1 dr, in contrast to the excellent selectivities observed with the corresponding methyl and benzyl ethers (>95 : 5 dr). This outcome is consistent with a directing effect exerted by the carbinol ether, which is diminished when coordination is attenuated or sterically hindered by the bulky silyl protecting group. The relative configurations of the major and minor diastereomers of 4d were assigned by NMR analysis, through detailed examination of coupling constants and NOE experiments, confirming that the minor product corresponds to the spirocycle formed through carbolithiation anti to the silyl carbinol substituent. Thus, the stereochemical outcome of substrate 4d directly supports the proposed directing role of the cyclopropylcarbinol ether. Benzyl ethers were well tolerated, providing the desired product 4e in 75% yield, whereas ester protecting groups and the shortest substrate (n = 1) (not described in Scheme 3) failed to deliver the ester-derived spirocyclic products and spiro[2.2]pentanes (see the SI for details on unsuccessful substrates). Modifying the anion-stabilizing group allowed access to TMS-substituted spiro[2.4]heptane 4f, obtained in excellent yield (79% over two steps) as a single diastereomer. Remarkably, even the bulky TBS group was tolerated on the cyclopropene, affording silylated spiro[2.4]heptane 4g in 80% yield.

Scheme 3 Substrate scope.

Scheme 4 Electrophile scope for the intramolecular carbolithiation–functionalization sequence (*contains the hydrolysis product as a side product; corrected yields reported).

Scheme 5 Towards the diastereoselective preparation of three adjacent quaternary carbon centers on the cyclopropyl ring.

We also sought to investigate the replacement of the aryl group with heteroaromatic substituents. However, access to the corresponding heteroarene-substituted cyclopropyl carbinols proved challenging, and these substrates were therefore not pursued further. Alkyl-substituted cyclopropenes were likewise not examined, as the corresponding intramolecular carbolithiation is not expected to proceed efficiently in the absence of a substituent capable of stabilizing the resulting tertiary alkyllithium species. Shorter tether lenghts that would form spiropentanes did not undergo carbolithiation under the current conditions. To further increase the complexity of the final spiroalkanes, we subsequently trapped the cyclopropyllithium intermediate with various electrophiles. As discussed previously, deuteration with MeOH-d₄ proceeded smoothly, regardless of the nature of the anion-stabilizing group, giving 69% of 4a_D with 83% of deuterium incorporation and 76% of 4g_D with 95% of deuterium incorporation (Scheme 4). Iodination of these cyclopropyl lithium intermediates furnished 4h and 4i in 44% and 66% yield, respectively, with the only detectable side products being the proton-quenched products. The higher yield of the TBS-substituted product 4i as compared to 4h is attributed to both the efficiency of the preparation and stability of the linear alkyl iodide starting material. Attempts to synthesize cyclopropyl bromides in the same manner by quenching with NBS led to decomposition (for details on unsuccessful substrates please see the SI). Despite their steric bulk, silicon electrophiles proved to be viable coupling partners, as demonstrated by the formation of TMS-functionalized spiro[2.4]heptane 4j, albeit in a low 30% yield. Carbon–carbon bond formation was also achieved using various electrophiles, affording spiro[2.4]heptanes 4k–4p, each being a pentasubstituted cyclopropane derivative, in moderate to good yield as single diastereomers. Interestingly, trapping with sterically demanding electrophiles such as TMSCl and acetone-d₆ proved more efficient for spiro[2.3]hexanes than for spiro[2.4]heptanes (compare 4j with 4q and 4l with 4r, Scheme 4). This enhanced reactivity is likely attributed to the angle strain inherent in the cyclobutyl ring, which reduces steric congestion around the cyclopropyllithium center. The steric differences between these spirocyclic systems are further reflected in their NMR spectra. For the acetone-trapped derivatives, spiro[2.4]heptane 4l exhibits restricted phenyl ring rotation at room temperature, as evidenced by six distinct aromatic signals in its ¹³C NMR spectrum. In contrast, spiro[2.3]hexane 4r and all other phenyl-substituted spirocycles examined display rapid phenyl rotation, leading to only four aromatic signals, with the ortho/ortho′ and meta/meta′ carbon atoms rendered magnetically equivalent. Alcohol 4s was easily prepared via addition of benzaldehyde, yielding a 1 : 1 mixture of alcohol diastereomers (while retaining a single diastereomer in the spirocyclic core) in 57% yield. Introduction of carbonyl groups was achieved through reactions with acetyl chloride and DMF, affording ketone 4t (44%) and aldehyde 4u (62%), respectively. Carboxylic acid 4v was obtained in 42% yield over two steps, and single X-ray crystallographic analysis⁴⁰ confirmed the relative configuration. Finally, installation of a double bond via allylation proceeded in good yield (4o, 61%), though with diminished diastereoselectivity (Scheme 4). Finally, we were interested in extending the intramolecular carbolithiation strategy to the synthesis of spiroalkanes bearing three contiguous quaternary carbon centers on the cyclopropyl ring.⁴¹ For this purpose, mesylate 6h having an additional phenyl substituent, was easily prepared.⁴²

Gratifyingly, the presence of this substituent on the cyclopropene did not reduce its reactivity toward spirocyclisation, delivering spiro[2.4]heptanes 4w–y in moderate to good yields (Scheme 5). Upon addition of electrophiles (with the exception of H and D), the reaction provides the expected corresponding spiro[2.4]heptanes possessing a fully substituted cyclopropyl core as a single diastereomer.

Conclusions

We have developed an intramolecular carbolithiation reaction of cyclopropenes that enables the efficient synthesis of spiro[2.3]hexanes, spiro[2.4]heptanes, and spiro[2.5]octanes in moderate to high yields with excellent diastereoselectivity. Electrophilic trapping of the resulting carbolithiated intermediates proceeds with complete retention of configuration and allows for the stereospecific introduction of a wide range of substituents, including the formation of C–H, C–D, C–I, C–Si, and C–C bonds, providing a rapid access to functionalized spiro[2.n]alkanes. Furthermore, fully substituted cyclopropenes were shown to undergo a similar smooth carbolithiation, granting access to spirocyclopropanes possessing fully substituted cyclopropyl rings in excellent yields as single diastereomers—a molecular pattern that remains challenging to construct using existing synthetic approaches.^{18,22–24,26,43}

Author contributions

CST: investigation, data curation, project administration, writing – initial draft, writing – review & editing; CB: methodology, investigation, data curation, writing – review & editing; MS: proof of concept; JZ: X-ray crystallography; IM: conceptualization, funding acquisition, supervision, writing – review and editing.

Conflicts of interest

There are no conflicts to declare.

Data availability

CCDC 2476391 contains the supplementary crystallographic data for this paper.⁴⁰

The data that support the findings of this study are openly available in the supplementary information (SI). Supplementary information: experimental procedures, NMR spectra, high-resolution mass spectrometry data and crystallographic data. See DOI: https://doi.org/10.1039/d6sc03169b.

Acknowledgements

This project received funding from the Israel Science Foundation administrated by the Israel Academy of Sciences and Humanities (grant 1625/22). The authors acknowledge generous support from the German research foundation (DFG, Walter-Benjamin postdoctoral fellowship to CST) and the Humboldt Foundation (postdoctoral fellowship to MS). The authors wish to thank Prof. Thorsten Bach and Tim Langschwager (both TU Munich) for laboratory access and support with HR-MS acquisition, respectively.

Notes and references

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Footnotes

† Max Planck Institute of Colloids and Interfaces, Biomolecular Systems Department, Am Muehlenberg 1, 14476 Potsdam, Germany.

‡ These authors contributed equally.

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