Boronic Ester Enabled [2 + 2]-Cycloadditions by Temporary Coordination: Synthesis of Artochamin J and Piperarborenine B

Abstract

A strategy for the photosensitized cycloaddition of alkenylboronates and allylic alcohols by a temporary coordination is presented. The process allows for the synthesis of a diverse range of cyclobutylboronates. Key to development of these reactions is the temporary coordination of the allylic alcohol to the Bpin unit. This not only allows for the reaction to proceed in an intramolecular manner but also allows for high levels of stereo and regiocontrol. A key aspect of these studies is the utility of the cycloadducts in the synthesis of complex natural products artochamin J and piperarborenine B.

Graphical Abstract

Cycloaddition reactions are one of the most useful strategies to generate rings.¹ Among these processes, [2 + 2]-cycloaddition of alkenes is regarded as the premier approach for the synthesis of cyclobutanes.² The majority of these reactions are photochemical and therefore proceed via high-energy, and short-lived, excited-state intermediates. Consequently, to achieve reasonable reaction rates and minimize secondary photochemical reactions, researchers have extensively developed intramolecular [2 + 2]-cyclo-additions. Due to constraints with the ring forming event, stereochemical control can often be achieved (Scheme 1A). However, the substrates must be carefully designed to generate a ring and therefore this necessarily limits the scope of products that can be generated to polycycles. In addition, laborious synthetic sequences can be necessary to prepare the substrate. Intermolecular [2 + 2]-cycloadditions are also known, but to achieve reasonable reaction rates, both substrates typically need activating groups (arenes, dienes, ester, etc.) (Scheme 1A). Since these reactions are bimolecular, a range of cyclobutanes can be synthesized. However, the requirement that both coupling alkenes need activating groups remains a limitation for intermolecular [2 + 2]-cycloadditions. In addition, unlike concerted [4 + 2]-cycloadditions in which the regio- and stereochemistry can be controlled by FMOs (frontier molecular orbitals),¹ in many cases, it is difficult to control the stereo- and regiochemical outcome of intermolecular [2 + 2]-cycloaddition reactions.

Scheme 1.

Approaches Toward [2 + 2]-Cycloadditions

In this manuscript, an alternative approach is disclosed in which by virtue of a temporary association between the reactants, a biomolecular reaction can be achieved in an intramolecular fashion (Scheme 1B). In this approach, stereo and regiochemical control can be achieved while retaining the benefits of diversity from an intermolecular [2 + 2]-cycloaddition of readily available components. To implement this approach, we designed a reaction between an allylic alcohol and an alkeneylboronate (Scheme 1C). This process would allow simple unactivated alkenes to participate in [2 + 2]-cycloadditions in the form of allylic alcohols and lead to the formation of diverse borylated cyclobutanes.³

Borylated carbocycles and heterocycles are useful intermediates in the construction of complex molecules. This is primarily due to the ease with which the C–B bond can be converted to other functional groups.⁴ In recent years, an emphasis has been placed on the synthesis of rigid carbocycles and heterocycles to enable drug development. Consequently, the preparation of cyclobutylboronates is regarded as an important goal. While several strategies are known for cyclobutylboronate synthesis,^5–9 [2 + 2]-cycloadditions retain their own importance because (1) the reactions are convergent, (2) the alkene starting materials are generally widely available, and (3) products can be prepared that would be inaccessible by other approaches.^10,11 With respect to photochemical [2 + 2]-cycloaddition,^12,13 prior work has demonstrated that alkene triplet excited states can be captured with alkenylboronates. More recently, our lab has demonstrated that alkenylboronates can be photosensitized and undergo reaction with a variety of activated alkenes (e.g., styrenes, dienes).¹⁴ In the latter case, the Bpin unit acted as an activating group to allow for the cycloaddition to proceed in good yield. In this study, the Bpin unit is utilized as a coordinating group to direct the cycloaddition to occur with allylic alcohol derivatives (Scheme 1C). Cycloadditions of this type are valuable because (1) allyl alcohol derivatives are widely available yet underutilized in this field and (2) the product contains multiple functional groups for further elaboration to enable the synthesis of complex molecules, such as artochamin J and piperarborenine B.

The initial reaction optimization was conducted with allyl alcohol (1) and E-styrenylBpin (2). The choice to use E-styrenylBpin (2) stems from the fact that the sytrenyl component could be sensitized with common visible-light-activated sensitizers,^14,15 thus avoiding the use of high-energy UV light at this stage of development. Treatment of allyl alcohol (1) and E-styrenylBpin (2) in the presence of fac-Ir(ppy)₃ did not lead to product formation. It is likely that association of alcohol and the Bpin unit was minimal, and dissociation occurs before cycloaddition (Scheme 2A, entry 1). Therefore, bases were evaluated to shift the position of the equilibrium to the borate complex (Scheme 2A, entries 2–4). It was identified that use of KOt-Bu allowed for formation of 3a (Scheme 2A, entry 4). Continued optimization along this line demonstrated that use of a sensitizer with a higher triplet energy, in conjunction with a more nonpolar solvent, led to formation of [2 + 2] cycloadduct 3a in 89% yield (Scheme 2A, entry 8). The use of the higher-energy sensitizer is likely necessary to increase the rate of quenching, whereas the use of toluene likely drives the formation of the borate complex. Finally, styrenylBneop and styrenylBdmpd work in the reaction, albeit with reduced yields (see the Supporting Information for details).

Scheme 2.

Reaction Optimization

Studies were also conducted to probe the importance of the alcohol-Bpin coordination (Scheme 2B). It was found that reaction of bis-allyl boronate 4 was not productive when irradiated in the presence of 450 nm LEDs and an Ir-sensitizer. However, the addition of KOt-Bu allowed for the reaction to proceed to generate 3b. This is likely the result of the formation of tetravalent borate, which constricts the angle (compare I to II) to be like III and thus allows for cycloaddition to occur.

Under the optimized reaction conditions, the scope of the cycloaddition was investigated (Scheme 3). 1,2-Disubstituted alkenes allowed for product formation; however, a mixture of diastereomers was formed (products 6–8). With trisubstituted alkenes, the formation of penta-substituted cyclobutanes could be achieved (products 9–15). Reactions with cyclic trisubstituted alkenes allowed for the formation of bicyclic structures (products 11–15). In a similar vein to reactions of 1,2-disubstituted alkenes, reactions of unsymmetric trisubstituted alkenes gave rise to diastereomers (product 10). In one example, a tetrasubstituted alkene was tolerated to generate a highly substituted cyclobutane (product 16). At this stage of development, use of homoallylic alcohols of any substitution patterns did not result in product formation.

Scheme 3.

Substrate Scope

^aNMR yield refers to yield determined by ¹H NMR analysis of the unpurified reaction mixture of the product after functionalization of the Bpin unit. Diastereomeric ratio (dr) determined of the unpurified reaction mixture by ¹H NMR analysis. Yield is of isolated, purified product. ^bChlorobenzene was used as solvent. ^cPenn PhD Photoreactor M2 was used. ^d48 h. ^eDCM was used as solvent. ^fThe alcohol was protected using TBSCl and imidazole. ^g2.0 mol % fac-Ir(dFppy)₃. ^h1.0 mol % fac-Ir(ppy)₃ was used as catalyst.

In addition to a variety of allylic alcohols, many diverse alkenyl boronates participated in the reaction. The aryl unit could be substituted with various functional groups such as Br (product 22), unprotected amine (product 24), and CN (product 21). In addition, electron-withdrawing (product 20, 21, 23), electron-donating (product 19), and sterically demanding (product 17) substitutions were well-tolerated. Several classes of heteroaromatic compounds could be used such as furan (product 27), thiophene (product 25), indole (product 26), and pyridine (product 28). The alkenylboronate could also be substituted at the α position to form sterically congested products (29-30). Finally, dienylboronates of several substitution patterns were also tolerated (products 31–37). When substrates are 1,4-substituted dienes, a secondary photoisomerization was also observed (products 32 and 33).¹⁶ To achieve better E/Z selectivity, we envisioned using a lower-energy sensitizer that could still enable the [2 + 2]-cycloaddition to synthesize 33 efficiently (given that the substrate is highly conjugated and likely has a lower triplet energy) yet allow for a more selective photoisomerization. Indeed, fac-Ir(ppy)₃ catalyzed the reaction to form 33 with 8:1 Z/E selectivity in good yield. The synthesis of 36 is also notable as the silyl enol ether can be used as a functional handle. Notably, dienylboronates are known to undergo [4 + 2]-cycloadditions with allylic alcohols,^3e our method demonstrated an alternative reactivity. Finally, under the reaction conditions, use of alkyl-substituted alkenyl boronates did not allow for product formation.

With respect to the allylic alcohol unit, both secondary and tertiary examples were tolerated. In the case of secondary alcohols, the reactions led to the formation of single observable diastereomers (products 39 and 40) (Scheme 4A). It is likely that the high levels of stereocontrol were observed because the reaction proceeded via IV, in which the R-group was positioned in the pseudoequatorial position. In the case of tertiary alcohols, the reaction occurred smoothly and led to the synthesis of sterically congested products 42–45 (Scheme 4B). In the cases of 44 and 45, low levels of diastereoselectivity were observed due to the relatively small size difference between substituents as compared to 39 and 40.

Scheme 4.

Additional Examples

The reaction of dieneol 46 is interesting because under different sets of conditions, alternate products could be made (Scheme 5). For example, under the conditions described in this study, the alcohol directs the cycloaddition to occur at the proximal double bond to generate 47 (Scheme 5A). The reaction likely occurred by coordination of the alcohol to the Bpin unit followed by triplet energy transfer to generate VI. Radical addition allows for formation of VII, which upon intersystem crossing (ISC) and radical recombination, leads to formation of the product. On the other hand, if the conditions are modified such that the Bpin acts as an activating group and not a coordinating group (as previously described),¹⁴ product 48 is generated (Scheme 5B). Here, triplet energy transfer occurs with 2 to form VIII. The initial bond formation takes place at the terminal position of the diene. After ISC and radical recombination, product 48 is formed.

Scheme 5.

Divergent Reactivity

It is well known that organoboronates can undergo Pd-catalyzed cross coupling with aryl bromides.¹⁷ However, alkylboronates are significantly more reluctant to undergo cross coupling compared to their aryl or alkenyl counterparts.¹⁸ To overcome this issue, the Morken group developed a cross coupling of γ-hydroxyl alkylBpin.¹⁹ In these examples, the hydroxyl group facilitates the cross-coupling reaction.

As illustrated in Scheme 6A, this method can be applied to the cycloadducts to generate diverse cyclobutanes. The reactions proceed with retention of stereochemistry and function for aryl (product 49), heteroaryl (products 50–52), and alkenyl bromides/triflates (products 53 and 54).

Scheme 6.

Synthesis of Complex Molecules

Moreover, this sequence has been instrumental in the synthesis of the cyclobutane natural products artochamin J²⁰ and piperaborenine B (Scheme 6B, C).²¹ In the case of artochamin J, the synthesis commenced with cycloaddition of allylic alcohol 56 and alkenylBpin 55 (Scheme 6B). The crude material was then subjected to the cross-coupling sequence to generate 58 as a single observable diastereomer on gram scale. At this stage, cyclization of the primary alcohol with the neighboring electron-rich arene was desired. However, even after extensive investigations, the cyclization could not be achieved. Therefore, a sequence was devised that involved oxidation to the acid and Friedel–Crafts cyclization promoted by TFAA to generate 59. Clemmensen reduction²² and deprotection with TBAF allowed for the synthesis of artochamin J.

A brief synthesis of piperaborenine B was also enabled by this methodology (Scheme 6C). Starting with alkenylboronic ester 60 and allylic alcohol 61, [2 + 2]-cycloaddition and cross coupling allowed for the synthesis of 63 in 66% yield and 3.3:1 dr. Oxidative cleavage of the alkene resulted in the formation of aldehyde 64.²³ Exhaustive oxidation under Fe-catalyzed aerobic oxidation²⁴ led to formation of a dicarboxylic acid, which upon sequential treatment with oxalyl chloride and dihydropyridinone led to formation of piperaborenine B. Our method complements the reported routes, which rely on a directed C–H activation method to install the arene(s).²¹ Without additional steps to install and remove the directing group, only six steps were required to prepare piperaborenine B. Finally, it is important to note that the approaches described here are modular and thus amendable to the synthesis of derivatives.

In conclusion, a new strategy to access synthetically versatile cyclobutylboronates is presented. By taking advantage of a temporary tether between an alcohol and boronate, a region- and stereoselective reaction can be achieved. Due to the functional groups on the cyclobutane, facile diversification can be carried out to allow for the efficient synthesis of complex natural products.