Construction of Complex Cyclobutane Building Blocks by Photosensitized [2+2] Cycloaddition of Vinyl Boronate Esters

Abstract

Cyclobutyl moieties in drug molecules are rare, and in general they are minimally substituted and stereochemically simple. Methods to assemble structurally complex cyclobutane building blocks suitable for rapid diversification are thus highly desirable. We report herein a photosensitized [2+2] cycloaddition with vinyl boronate esters affording straightforward access to complex, densely functionalized cyclobutane scaffolds. Mechanistic studies suggest an activation mode involving energy transfer to the styrenyl alkene rather than the vinyl boronate ester.

Graphical Abstract

Cyclobutane rings feature prominently in thousands of natural products, many of which are known to exhibit interesting biological activity (Figure 1).¹ The structures of these naturally occurring cyclobutanes can be complex: they are often embedded in polycyclic ring systems and can feature multiple stereogenic centers. In contrast, synthetic pharmaceutical agents rarely contain cyclobutanes; only nine cyclobutane-containing drug molecules have been approved by the FDA, and the structures of the cyclobutane scaffolds are generally simple, non-stereogenic, and minimally substituted.² One reason for this disparity is the challenge of synthesizing structurally complex cyclobutane rings, especially in a manner that is highly tolerant of diverse functional groups.³ The development of methods to produce complex cyclobutane building blocks amenable to rapid diversification and elaboration, therefore, is a highly desirable goal that has the potential to spur innovations in medicinal chemistry.

Figure 1.

Facile construction of cyclobutane boronate ester building blocks could bridge the complexity gap between cyclobutane-containing natural products and drug molecules.

For the past several years, our laboratory has been studying the use of visible-light-activated transition metal photocatalysts in triplet sensitization reactions.^4,5 Several important benefits have motivated the use of these photocatalysts.⁶ Ru and Ir polypyridyl complexes generally exhibit near-perfect intersystem crossing efficiencies and long excited-state triplet lifetimes. Their structures can be tuned to span a wide range of excited-state triplet energies and redox potentials. Finally, these complexes can be activated using relatively long wavelengths of visible light that are lower in energy and substantially more tolerant of structural complexity than the short-wavelength UV light required for direct photoexcitation of simple organic compounds. We have demonstrated the utility of this strategy for the intramolecular [2+2] cycloaddition of styrene and 1,3-diene substrates and have applied these methods to the synthesis of natural products including cannabiocicyclolic acid and epiraikovenal.^4a,b

Functionalized organoboron reagents are among the most versatile building blocks for medicinal chemistry.⁷ Boronate esters can be transformed into a variety of different functionalities, often in a stereospecific manner. The ability to prepare structurally complex cyclobutane cores bearing a carbon–boron bond could therefore provide a powerful tool for the discovery of new biologically active compounds with novel ring scaffolds. Relatively few methods for the preparation of cyclobutyl boronate esters have been reported, however. These have included annulations,⁸ ring expansion and contraction reactions,⁹ derivatization of preformed cyclobutenes or cyclobutanes,¹⁰ thermal cumulene cycloadditions,¹¹ and photoisomerization of 1,2–azaborines.¹² Despite these recent advances, however, there are few examples that grant access to complex, polycyclic cyclobutane scaffolds.^13,14,15

We wondered whether visible light triplet sensitization might offer a direct, alternative method for the preparation of structurally diverse cyclobutane boronate esters. There are limited examples of direct UV-initiated photocycloadditions involving vinyl boronate esters,^13, including a single example of an enantioselective photocycloaddition reported recently by Bach.¹⁴ More recently, during the course of our investigations, Grygorenko reported a benzophenone-accelerated [2+2] cycloaddition involving vinyl boronic acid derivatives.¹⁵ This study describes UV-initiated [2+2] photocycloadditions of triplet-state maleimide, which enables access to complex cyclobutane boronate ester building blocks but is limited to production of the 3-azabicyclo[3.2.0]heptane skeleton. The results also left unanswered the question of whether visible light sensitization might enable [2+2] cycloadditions of structurally varied electron-rich triplet olefins, which have very different electronic properties and reactivities than electron-deficient triplet maleimide, with vinyl boronate esters.

One initial concern was the stability of carbon–boron bonds under photocatalytic conditions. Organoboron reagents are frequently utilized as radical precursors in a wide range of photochemical transformations,¹⁶ including photoredox reactions utilizing the same class of transition metal complexes we found to be optimal for sensitization of styrenes and 1,3-dienes. Thus, it was not obvious at the outset of our investigations that boron-containing functionalities of the products would survive the conditions of photocatalytic triplet sensitization. We therefore began our investigation by testing the compatibility of several common boronic acid derivatives with the conditions previously developed for triplet sensitization and [2+2] cycloaddition of simple unfunctionalized styrenes. Gratifyingly, these vinyl boronates generally reacted smoothly to afford the corresponding boron-substituted cyclobutane products in good yield. The highest yields were observed using the B(pin) group (3a), which is advantageous considering the wealth of methods available for direct synthesis and modification of this common boronate ester. The diastereomers of the cycloadduct were also readily separated by chromatography using boric acid doped silica.¹⁷ However, an alternate boronate ester (3b) and the free boronic acid group (3c) were also well tolerated. Interestingly, a MIDA boronate also underwent [2+2] cycloaddition in good yields (3d) despite the fact that alkyl boronates are often easily oxidized and can be efficient radical precursors in a range of photoredox methods.¹⁸ Of the boronate derivatives screened, only a vinyl B(dan)-containing substrate provided an unsatisfactory yield (3e). We attribute the slow rate of conversion to competitive quenching of the photocatalyst by the electron-rich naphthalene moiety.

Studies probing the scope of this reaction are summarized in Scheme 2. While we were unable to develop effective conditions for high-yielding intermolecular cycloadditions, intramolecular reactions occurred smoothly with a variety of ether, amine, and all-carbon tethers (3a–8). This includes tethers that introduce steric bulk proximal to the reacting vinyl boronate ester and styrene (9 and 10), which did not significantly decrease the reactivity of the system. Structurally varied styrene units were tolerated well under the reaction conditions, consistent with the relative insensitivity of styrene triplet energies to perturbation. These include both substitutions on the arene (11–14) and alkene (15) moieties. Similarly, dienes, which possess triplet energies similar to those of styrenes, also react smoothly to provide vinylcyclobutanes in good yields (16 and 17). Importantly, this provides access to cyclobutanes featuring two orthogonal synthetic handles amenable to further elaboration. Finally, the relocation of the B(pin) moiety to the bridgehead position did not significant decrease the yield of the reaction (18), although the diastereoselectivity was diminished.

Scheme 2.

Reaction scope studies for the sensitized [2+2] photocycloadditions of vinyl boronate esters.

One central motivation for this investigation was the potential utility of cyclobutane boronate esters as rapidly diversifiable building blocks. As a demonstration of the versatility of the boronic ester group in this context, we explored conditions for the further conversion of compound 3a into functionalized derivatives (Scheme 3). First, we examined the scalability of this transformation and obtained an excellent yield (94%) of cycloadduct on gram scale using reduced loadings of photocatalyst 1. Protodeboronation¹⁹ of 3a yields product 19, which is similar to the fused cyclobutane core of the antipsychotic pharmaceutical candidate belaperidone.²⁰ Arylation²¹ by treatment of the boronate ester with lithiated furan affords 20. Fluorination²² (21), oxygenation (22), and bromination²³ (23) can be accomplished in good yields using known methods. Similarly, Zweifel olefination²⁴ (24) and Matteson homologation²⁵ (25) proceed in good yields and afford products bearing versatile functional group handles that enable further diversification of the cyclobutane scaffold. Likewise, the potassium trifluoroborate salt²⁶ 26 was obtained in good yield and was a suitable reactant for metallophotoredox cross-coupling to afford 27 as a single diastereomer.^18a

Scheme 3.

C–B derivatization of 3a into highly functionalized cyclobutane scaffolds.

Our design plan for this reaction was premised on the assumption that the iridium photocatalyst would sensitize the styrene moiety of the substrate, the excited state of which would initiate a typical stepwise triplet-state [2+2] photocycloaddition reaction. Gilmour and co-workers have recently disclosed the sensitization of vinyl pinacol boronate esters to enable a selective contra-thermodynamic E→Z isomerization.²⁷ With these findings in mind, we wondered whether competitive sensitization of the vinyl boronate ester might also be responsible for the formation of the observed cycloadduct. To test this possibility, we prepared vinyl boronate 28 lacking a styrene moiety. Irradiation of 28 in the presence of photosensitizer 1 or thioxanthone (64 kcal/mol)²⁸ yields no observable change to the starting material (Scheme 4A). Interestingly, irradiation at 350 nm in the presence of xanthone as a higher-energy triplet sensitizer (74 kcal/mol)²⁸ resulted in geometrical isomerization of the vinyl boronate, indicative of triplet energy transfer, without formation of the [2+2] cycloadduct.

Scheme 4.

Probing participation of the vinyl boronate ester triplet state

Steady-state Stern–Volmer luminescence quenching experiments show that the emission of photocatalyst 1 is not impacted by the addition of vinyl boronate 28 (Scheme 4B). On the other hand, the phosphorescence of the photocatalyst was quenched by 2a in a concentration-dependent fashion, from which a bimolecular quenching rate constant of k_q = 1.3 x 10⁹ M⁻¹ s⁻¹ could be determined. These studies suggest that the cycloaddition is initiated by sensitization of the styrene moiety and not the vinyl boronate. Moreover, the cyclic voltammogram of 2a features a reduction and oxidation of < −1.2 V vs. SCE and 1.73 vs. SCE, well outside of the range of photocatalyst 1 (−0.89 V vs. SCE and +1.21 V vs. SCE)²⁹ (Scheme 4C). Collectively, these data establish that the key photocatalytic step involves energy transfer to the styrenyl alkene and not the vinyl boronate ester.

In summary, we have developed a highly efficient photosensitized [2+2] cycloaddition of vinyl boronate esters. Despite the variety of photoredox methods that utilize organoboron compounds as radical precursors, we found that simple vinyl boronates readily reacted with excited-state triplet alkenes that are generated by visible light triplet sensitization. The scope of this cycloaddition proved to be broad, easily tolerating the same wide variety of functional groups as other methods for visible light triplet sensitization. More importantly, the ability to access a range of structurally complex cyclobutane boronate esters by photocatalysis coupled with the synthetic versatility of boronate ester chemistry suggests a flexible strategy to prepare novel compounds in an underexplored region of chemical space.

Scheme 1.

Examining compatibility of boron moieties with triplet sensitization using photocatalyst 1.^a

^a See Supplementary Information for experimental details. ^b Isolated as the corresponding alcohol.