Access to Complex Scaffolds Through [2+2] Cycloadditions of Strained Cyclic Allenes

Abstract

We report the strain-induced [2+2] cycloadditions of strained cyclic allenes for the assembly of highly substituted cyclobutanes. By judicious choice of trapping agent, complex scaffolds bearing heteroatoms, fused rings, contiguous stereocenters, spirocycles, and quaternary centers are ultimately accessible. Moreover, we show that the resulting cycloadducts can undergo thermal isomerization. This study provides an alternative strategy to photochemical [2+2] cycloadditions for accessing highly functionalized cyclobutanes, while validating the use of underexplored strained intermediates for the assembly of complex architectures.

Graphical Abstract

INTRODUCTION

Stereochemically complex scaffolds have become increasingly desirable in the discovery of bioactive molecules.^1,2 One such motif, the cyclobutane, is present in biologically relevant compounds and many natural products.^3,4,5,6 Its rigid scaffold possesses distinct exit vectors that can be used to ultimately improve biological properties.^3,6 Three representative cyclobutane-containing compounds are shown in Figure 1A: antiviral agent Lobucavir (1),⁷ kinase inhibitor 2,⁸ cannabinoid 3,⁹ and natural products such as welwitindolinone A isonitrile (4),^10,11 arnamial (5),¹² and scopariusicide A (6).¹³

Figure 1.

(A) Cyclobutane-containing, biologically relevant molecules 1–6. (B) Strained cyclic intermediates 7a–d and 8. (C) Overview of the current study.

Cyclobutanes are commonly introduced synthetically using feedstock fragments or cycloaddition reactions. Methods to introduce cyclobutanes have been reviewed^3,14,15 and several elegant approaches have recently been reported, including those by Wilkerson–Hill,¹⁶ Yoon,^17,18 and Brown.^19,20,21 With regard to cycloadditions, photochemical [2+2] cycloadditions, which leverage in situ-generated photoexcited intermediates, are most common.^22,23 Notably, harnessing these intermediates for regio- and stereoselective syntheses intermolecularly can be difficult, necessitating specialized reagents or catalysts.²⁴ As such, new methods for the synthesis of highly functionalized cyclobutanes bearing multiple stereocenters remain coveted.

An attractive yet underutilized approach to access highly functionalized cyclobutanes relies on strain-promoted reactivity. For example, arynes (e.g., 7a and 7b)^{25,26,27,28,29,30,31} and non-aromatic cyclic alkynes (e.g., 7c and 7d)^32,33,34 are highly reactive, in situ-generated intermediates that can readily engage in [2+2] cycloadditions³⁵ due to their significant strain energies, typically ranging from 40–50 kcal/mol (Figure 1B).³⁶ A comparatively less well-studied class of compounds is strained cyclic allenes 8.^37,38,39 Like cyclic alkynes, strained cyclic allenes 8 contain a functional group that typically prefers a linear geometry, but is bent due to ring constraint, leading to significant strain energy (~30 kcal/mol).^40,41 Although historically understudied, cyclic allenes 8 are emerging building blocks in the synthetic community.^{42,43,44,45,46,47,48,49} Recent advances include cycloaddition chemistry by West,^{44,50,51,52,53,54} the synthesis of DNA-encoded libraries by Schreiber,⁵⁵ and several studies from our laboratory,^{45,56,57,58,59,60,61,62,63,64,65,66,67} including the recent use of strained cyclic allenes in total synthesis.⁶⁸ With regard to [2+2] cycloadditions of strained cyclic allenes, seminal studies by Christl and others validated reactivity.^{69,70,71,72,73} More recently, elegant studies by West have demonstrated [2+2] cycloadditions of acetoxy-substituted carbocyclic allenes,⁵³ as well as intramolecular trappings,⁵⁴ using silyl bromide precursors to cyclic allenes. Our laboratory has also reported scattered examples of [2+2] cycloadditions of cyclic allenes.^{56,57,62,66,74}

As part of a general program aimed at exploring the use of unconventional strained intermediates for the construction of complex scaffolds, we sought to investigate strain-driven [2+2] cycloadditions of cyclic allenes using the reaction design shown in Figure 1C. Cyclic allenes 8, generated via fluoride-mediated 1,2-elimination of silyl triflates 9, would engage with highly substituted alkenes 10 to afford densely functionalized cycloadducts 11. As in other [2+2] cycloadditions, two new C–C bonds would form. Moreover, through the judicious choice of trapping partner, features indicative of structural complexity,^75,76 such as heterocyclic frameworks,⁷⁷ spiro centers, contiguous stereocenters, and vicinal quaternary centers could be accessible under mild conditions. The transformation is accomplished without the need for metal-, Lewis acid-, or Brønsted acid catalysts; directing or auxiliary groups are also not required. Herein, we report the success of this approach to access highly functionalized cyclobutanes, which pushes the limits of complexity accessible from strained cyclic allene intermediates.

RESULTS AND DISCUSSION

To initiate these studies, we surveyed a range of exocyclic alkenes 14 in cyclic allene trapping experiments (Figure 2). Exocyclic alkenes are historically understudied in strained cyclic allene [2+2] cycloadditions, but if generally useful, would lead to the formation of desirable spirocyclic products.^6,78 Silyl triflate 12, a precursor to oxacyclic allene 13,^57,79 was treated with CsF in the presence of exocyclic alkenes 14 at ambient temperatures to afford cycloadducts 15. Reaction outcomes were then determined by ¹H NMR analysis. Notably, using unactivated alkene 16 afforded cycloadduct 17 in 42% yield (entry 1). Improved yields were seen when substrates containing an alkene with delocalized π-electrons were employed. For example, the electron-deficient alkene in α,β-unsaturated lactone 18 reacted to give cycloadduct 19 in high yield and moderate diastereoselectivity (entry 2). Similarly, electron-rich alkenes 20, 22, and 24 bearing heteroatoms could be employed and afforded cycloadducts 21, 23, and 25, respectively (entries 3–5).⁸⁰ Lastly, leveraging styrene 26 in the transformation provided cycloadduct 27 in 94% yield and 2.8:1 diastereomeric ratio (dr) (entry 6). Based on the synthetic efficiency observed, we elected to further pursue trappings of substrates related to dienamine 24 and styrene 26 and further push the limits of complexity in the products.⁸¹

Figure 2.

Survey of olefin partners 14 in [2+2] cycloaddition of oxacyclic allene 13. Reactions conditions are as follows: 12 (1.0 equiv, 0.050 mmol), trapping partners 14 (5.0 equiv), CsF (5.0 equiv), MeCN (0.1 M), 23 °C, 3–4 h. Yields and dr determined by ¹H NMR analysis of the crude reaction mixture using mesitylene as an external standard.

Several features of the reactions shown in Figure 2 should be noted: a) the reactions occur at ambient temperatures, b) yields and diastereomeric ratios are generally synthetically useful, although some variation in the latter was observed,⁸⁰ c) excellent regioselectivity is observed in each transformation,⁸² d) the general transformation allows for the formation of two new C–C bonds and typically two contiguous stereocenters, with access to further complexity being foreseeable based on the potential use of modified substrates, e) despite that strained cyclic allenes have historically been avoided, they can be used to readily access products containing three or more rings, including the desired spirocyclobutane and various heterocycles.

Having selected two promising classes of cycloaddition partners (i.e., 24 and 26)⁸¹ for further investigation, we assessed the scope of the methodology with respect to dienamines 28 (Figure 3). Silyl triflate 12 and dienamines 28 were combined in the presence of CsF to afford cyclobutanes 29. During early optimization efforts, it was found that substoichiometric amounts of tetrabutylammonium triflate (Bu₄NOTf) in dichloromethane as solvent was preferred when compared to acetonitrile.⁸³ Tetrabutylammonium salts are known to improve the solubility of fluoride ion in organic solvents^84,85 and have been beneficial in prior studies of cyclic allene trapping reactions.^60,62,64,68 Tosyl (Ts) and tert-butyloxycarbonyl (Boc) N-substituted substrates 24 and 30 could be employed, providing cycloadducts 25 and 31 in high yields and diastereoselectivities (entry 1). The use of tetrahydroazepine derivative 32 afforded 33 in 88% yield and 10:1 dr (entry 2). Increasingly substituted dienamines were tested as well. When 34 and 36 were utilized in the reaction, products 35 and 37 were obtained, which possess additional substitution on the cyclobutyl ring (entries 3 and 4, respectively). Notably, the trapping with 34 proceeds with moderate stereospecificity^82,86 and results in cyclobutane 35, containing three contiguous stereocenters. Substitution on the ring of the dienamine trapping partner was also tolerated. Employing iodosubstituted substrate 38 in the cycloaddition led to product 39, whereas employment of 40 bearing a gemdimethyl group furnished 41 (entries 5 and 6, respectively). The erosion in stereoselectivity when comparing the formation of 41 to 25 is attributed to the increased steric bulk from the gem-dimethyl group present in 41.⁸⁷ Of note, cycloadduct 41 contains vicinal quaternary carbons.

Figure 3.

Scope of [2+2] cycloadditions with dienamine trapping partners 28. Reaction conditions unless otherwise stated: 12 (1.0 equiv, 0.15 mmol), trapping partners 28 (3.0 equiv), CsF (5.0 equiv), Bu₄NOTf (50 mol%), CH₂Cl₂ (0.1 M), 23 °C, 24 h. Yields reflect an average of two isolation experiments; dr determined by ¹H NMR analysis. ^aThe 2.2:1 ratio reflects the ratio of the major diastereomer (2.2) to the sum of all minor diastereomers (1). ^bReaction was performed with CsF (5.0 equiv) in MeCN (0.1 M) at 23 °C for 24 h.

The use of styrenyl trapping partners (Figure 4, i.e., 42 or 43) in the methodology, including heterocyclic substrates, delivered structurally complex spiro cyclobutyl products bearing four or more interconnected rings. Using similar reaction conditions to those mentioned earlier (see Figure 3), employment of styrene 26 provided cycloadduct 27 in 80% yield and 4.0:1 dr (entry 1). Substrates 46 and 48, which possess six-membered heterocyclic rings, could be employed, thus giving rise to cycloadducts 47 and 49 (entries 2 and 3). Moreover, employment of substrate 50 furnished pentacyclic product 51 containing a spiro tetrahydrocarbazole in 86% yield and 15:1 dr (entry 4). Substitution on the exocyclic alkene was also tolerated, as demonstrated by the cycloaddition of tri- and tetra-substituted alkenes 52, 54, 56, and 58. The use of these substrates generated cycloadducts 53, 55, 57, and 59 (entries 5–8, respectively), which possess interesting features, such as three contiguous stereocenters (i.e., 53), as well as vicinal fully substituted carbons (i.e., 55, 57 and 59). Lastly, we were delighted to find that trapping of the strained cyclic allene intermediate with pyridyl-substituted alkene 60 bearing a gem-dimethyl unit afforded cycloadduct 61 in high yield and excellent diastereoselectivity (entry 9). The structure of this product, bearing vicinal quaternary carbons, was verified by X-ray crystallography.

Figure 4.

Scope of [2+2] cycloadditions with (het)aryl-substituted alkenes 42 and 43. Reaction conditions unless otherwise stated: 12 (1.0 equiv, 0.15 mmol), trapping partners 42 or 43 (3.0 equiv), CsF (5.0 equiv), Bu₄NOTf (50 mol%), CH₂Cl₂ (0.1 M), 23 °C, 24 h. Yields reflect an average of two isolation experiments; dr determined by ¹H NMR analysis. ^aTrapping partner (5.0 equiv). ^bBu₄NOTf (20 mol%). ^cSee Supporting Information, section F for details and crystallographic data.

Although our primary focus was on the use of heterocyclic allenes to build medicinally-relevant heterocycles, we also examined carbocyclic allenes (Figure 5). Treatment of silyl triflate 62 with dienamine 24 under conditions previously developed for carbocyclic allene generation,⁴⁵ delivered 64 in 75% yield and 7.1:1 dr, presumably via 1,2-cyclohexadiene (63). We were also intrigued by the possibility of using a larger, less strained cyclic allene in this methodology.⁴¹ As such, silyl tosylate 65 was subjected to conditions previously developed to generate the corresponding 1,2-cycloheptadiene (66),⁵⁹ again using dienamine 24 as the trapping partner. These conditions resulted in the formation of cycloadduct 67 in 24% yield and 5.9:1 dr. Dimerization of the presumed allene intermediate 66 occurred competitively in this case.⁵¹ 1,2-Dienes in smaller rings (i.e., 5-membered rings) are not yet accessible for use in synthesis,^88,89 but remain an opportunity for future discovery.

Figure 5.

[2+2] cycloadditions of carbocyclic allenes 63 and 66 with dienamine 24. Reaction conditions: 62 or 65 (1.0 equiv, 0.1 mmol), dienamine 24 (3.0–5.0 equiv), CsF (5.0 equiv), MeCN (0.1 M), 80 °C, 4–20 h.

Many products obtained from our studies possess strained alkylidene cyclobutanes with an adjacent π-system (i.e., alkene or aromatic ring), which could be susceptible to thermal isomerizations based on earlier studies by Christl and co-workers.⁷² Figure 6 highlights several key experimental findings, as well as computed ΔG values for each reaction shown. Cycloadduct 25, which was accessed in high diastereoselectivity (see Figure 3, entry 1) was heated at 110 °C. We observed an erosion of dr, affording epi-25 as the major isomer. This result was consistent with a computationally-determined ΔG value of −0.3 kcal/mol. Moreover, this finding suggested that comparing the ground state energetics of cycloadduct diastereomers could be used to predict the results of thermal isomerization studies. Thus, we considered cycloadducts 41 and 61 obtained in our earlier experiments. Computational analysis indicated that epi-41 and epi-61 were each thermodynamically more stable relative to the major cycloadducts obtained in our cyclic allene trapping experiments (ΔG = −3.8 and −2.7 kcal/mol, respectively). Gratifyingly, experimental results were consistent with computational predictions, allowing for the efficient conversion of 41 (1.5:1 dr) to epi-41 (>19:1 dr) and 61 (>19:1 dr) to epi-61 (>19:1 dr) under thermal conditions. Mechanistically, these isomerizations may occur by thermal homolytic cleavage of the strained bond between C6 and C4’ indicated (see substrate 25), followed by radical recombination, ultimately reaching a thermodynamic equilibrium of the two isomers. Our findings suggest that the selectivities observed in the aforementioned cyclic allene [2+2] trappings (see Figures 3 and 4) reflect kinetic distributions of products.

Figure 6.

Thermal isomerization of cycloadducts 25, 41, and 61. Yields and dr determined by ¹H NMR analysis using 1,3,5-trimethoxybenzene as an external standard. Free energies calculated using density functional theory (B3LYP/6–31G(d)).

The [2+2] cycloadditions of strained cyclic allenes with highly substituted alkenes provides a platform to quickly access exceedingly complex cyclobutane-containing structures. Figure 7 showcases several such examples via the formation of polycycles 73, 78, and 82, as well as their precursors. Ester-substituted cyclic allene precursor 68 was treated with trapping partner 38 under our usual reaction conditions to provide cycloadduct 70 in good yield and >19:1 dr. Of note, the reaction is also regioselective, favoring reaction of the alkene distal to the ester in the presumed cyclic allene intermediate 69 shown.⁹⁰ The α,β-unsaturated ester and vinyl iodide functional handles provide opportunities for further elaboration. Treatment of 70 with 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) in nitromethane delivered 71 in 51% yield and >19:1 dr, introducing a quaternary stereocenter. By cross-coupling 71 with heterocyclic boronate 72, highly decorated product 73 was obtained bearing four contiguous stereocenters, two of which are quaternary, and five rings in the core scaffold. In another example, azacyclic allene 75, generated from silyl triflate 74, was intercepted with cyclobutyl methylidene 76 to afford cycloadduct 77. Subsequent epoxidation with meta-chloroperoxybenzoic acid (m-CPBA) yielded 78, a polyspiro compound possessing four small rings and three contiguous stereocenters. Lastly, oxacyclic allene 13 was trapped with trisubstituted alkene 79⁹¹ to provide cycloadduct 80 in 84% yield, introducing vicinal quaternary carbons and three contiguous stereocenters with a high degree of stereospecificity with respect to alkene geometry of 79. Cycloadduct 80 was then subjected to nitrile oxide (3+2) cycloaddition to deliver 82. This hexacyclic product possesses five contiguous stereocenters and three fully substituted carbons, including two quaternary centers. Cyclobutane-containing compounds 73, 78, and 82 are each accessible in either one or two steps from [2+2] cycloadducts, underscoring the structural complexity now readily accessible using strained cyclic allene methodology.

Figure 7.

Synthetic elaborations of cycloadducts 70, 77, and 80 to access complex products 73, 78, and 82, respectively. ^aThe 13:1 ratio reflects the ratio of the major diastereomer (13) to the sum of all minor diastereomers (1).

CONCLUSION

Cyclobutanes are desirable motifs typically introduced using photochemical cycloadditions. As an alternative approach, we utilize the strain-driven reactivity of cyclic allenes, which are emerging synthetic building blocks, to promote [2+2] cycloadditions. We have shown that exceedingly complex structures can be accessed by intercepting cyclic allenes with highly substituted exocyclic alkenes at ambient temperature. The products obtained directly from the methodology, along with their isomers and derivatives, contain the desirable cyclobutane motif and a number of attractive features, such as heterocycles, spiro centers, contiguous stereocenters, and vicinal quaternary centers. We expect this study should not only provide a versatile tool to access highly substituted cyclobutanes but should also prompt the further strategic use of unconventional strained intermediates for the rapid assembly of complex architectures.