From α-Bromomethylbutenolide to Fused Tri(Tetra) Cyclic Dihydrofurandiones through Barbier Reaction–Heck Arylation Sequence

A Barbier reaction–Heck arylation sequence from α-bromomethylbutenolide to fused tri and tetracyclic lactones has been developed. The first step involving a Barbier reaction enabled installing ortho-bromoaromatics in α-ylidene γ-lactones. The latter substrates were subjected to intramolecular Heck reaction conditions which selectively afforded 6,5,5 or 6,6,5 fused ring systems depending on the nature of the base employed.


Introduction
The α-ylidene γ-lactone subunit can be found in a myriad of biologically active compounds [1,2]. The conjugated exo-vinylidene fragment is believed to be essential to a wide array of biological activities and thus drove the development of numerous preparation methods [3][4][5][6][7]. The interest of the scientific community for such lactones also stems from their use as intermediates in the synthesis of complex and polycyclic molecular architectures. As examples, the synthesis of the pterocarpan [8,9] and the podophyllotoxin skeletons illustrate α-methylidene butyrolactones as key intermediates for the construction of the final ring D and central ring B, respectively ( Figure 1) [10][11][12][13].

Introduction
The α-ylidene γ-lactone subunit can be found in a myriad of biologically active compounds [1,2]. The conjugated exo-vinylidene fragment is believed to be essential to a wide array of biological activities and thus drove the development of numerous preparation methods [3][4][5][6][7]. The interest of the scientific community for such lactones also stems from their use as intermediates in the synthesis of complex and polycyclic molecular architectures. As examples, the synthesis of the pterocarpan [8,9] and the podophyllotoxin skeletons illustrate α-methylidene butyrolactones as key intermediates for the construction of the final ring D and central ring B, respectively ( Figure 1) [10][11][12][13]. Although starting from α-ylidene γ-lactone precursors provided an elegant approach to polycyclic architectures, in each of the latter cases, the preparation of α-methylidene butyrolactone intermediates bearing the mandatory ortho-halide substituent (Figure 2a, highlighted in green) required multistep sequences which somewhat hampered the overall access to polycyclic targets [10][11][12][13]. In this context, Although starting from α-ylidene γ-lactone precursors provided an elegant approach to polycyclic architectures, in each of the latter cases, the preparation of α-methylidene butyrolactone intermediates www.mdpi.com/journal/molecules bearing the mandatory ortho-halide substituent (Figure 2a, highlighted in green) required multistep sequences which somewhat hampered the overall access to polycyclic targets [10][11][12][13]. In this context, access to the podophyllotoxin derivatives was carried out mainly on two substrates which are characterized either by the absence of substituents [10,11] or by the presence of a OTIPS group [12] located at the benzylic site which connects the two fragments of the precursor (Figure 2b, highlighted in blue). Two different routes leading to podophyllotoxin derivatives have been studied involving a radical-induced cyclization, depending on the configuration of the vinylidene double bond and a Pd-mediated ring closure depending on the catalytic system used and the substitution at the benzylic site. Indeed, in the presence of a radical cyclisation agent, the Z-isomer led to a mixture of "6,6,5" and "6,5,5" architectures. In contrast, the E-isomer gave an exclusive access to the 5-membered central ring ( Figure 2a).
Molecules 2017, 22, 2171 2 of 10 access to the podophyllotoxin derivatives was carried out mainly on two substrates which are characterized either by the absence of substituents [10][11] or by the presence of a OTIPS group [12] located at the benzylic site which connects the two fragments of the precursor (Figure 2b, highlighted in blue). Two different routes leading to podophyllotoxin derivatives have been studied involving a radical-induced cyclization, depending on the configuration of the vinylidene double bond and a Pd-mediated ring closure depending on the catalytic system used and the substitution at the benzylic site. Indeed, in the presence of a radical cyclisation agent, the Z-isomer led to a mixture of "6,6,5" and "6,5,5" architectures. In contrast, the E-isomer gave an exclusive access to the 5-membered central ring (Figure 2a). Two different "6,6,5" and "6,5,5" architectures have also been obtained from Pd-catalyzed processes. Without a substituent at the benzylic site, the 6,5,5-pattern was obtained as the sole product from the Z-isomer using K2CO3 or Et3N in combination with Pd(II)/PPh3 as the catalytic system. Under these conditions, the E-isomer only led to complex mixtures. In contrast, the use of Pd(II)/PPh3, K2CO3, TlOAc and HCO2Na as the hydride source gave the 6,6,5-pattern as the exclusive product ( Figure 2a). In the presence of a OTIPS group, the issue of the Pd catalyzed cyclisation process was strongly dependant on the base used ( Figure 2b). When Hünig's base was used, the 6,5,5 pattern was isolated. Mixtures of both patterns were observed in the presence of K2CO3 and TlOAc. Finally, exclusive and high yielding access to the 6,6,5 architecture was obtained using a combination of TlOAc, dppf and pentamethylpiperidine as the base.
The development of a shortcut sequence implying a selective and rapid access to the α-ylidene γ-lactone intermediates bearing a bromine atom followed by an intramolecular Heck arylation is Two different "6,6,5" and "6,5,5" architectures have also been obtained from Pd-catalyzed processes. Without a substituent at the benzylic site, the 6,5,5-pattern was obtained as the sole product from the Z-isomer using K 2 CO 3 or Et 3 N in combination with Pd(II)/PPh 3 as the catalytic system. Under these conditions, the E-isomer only led to complex mixtures. In contrast, the use of Pd(II)/PPh 3 , K 2 CO 3 , TlOAc and HCO 2 Na as the hydride source gave the 6,6,5-pattern as the exclusive product ( Figure 2a). In the presence of a OTIPS group, the issue of the Pd catalyzed cyclisation process was strongly dependant on the base used ( Figure 2b). When Hünig's base was used, the 6,5,5 pattern was isolated. Mixtures of both patterns were observed in the presence of K 2 CO 3 and TlOAc. Finally, exclusive and high yielding access to the 6,6,5 architecture was obtained using a combination of TlOAc, dppf and pentamethylpiperidine as the base.
The development of a shortcut sequence implying a selective and rapid access to the α-ylidene γ-lactone intermediates bearing a bromine atom followed by an intramolecular Heck arylation is therefore highly desirable. In this communication, we describe a two-step strategy towards fused tricyclic architectures starting from α-bromomethylbutenolide. The key α-ylidene γ-lactone intermediate was obtained in the first step through a Barbier reaction which allowed installation of the ortho-bromoaromatics. These intermediates were subsequently subjected to intramolecular Heck reaction conditions. In our case, the presence of the OH group located at the benzylic site accounted for the selective preparation of the tricyclic 6,6,5 α-vinylidene γ-lactone or the 6,5,5 lactone motifs depending on the catalytic precursor/base combination (Figure 2c). The generation of tetracyclic analogues was then examined using the same strategy.

Results and Discussion
We first examined the Barbier reaction between α-bromomethylbutenolide 1 and orthobromobenzaldehyde 2. If such reactions are well described [3][4][5][6][7], the use of ortho-substituted benzaldehydes and further ortho-bromide derivatives remain scarcely reported [14]. In our case, 2 smoothly reacted with the starting butenolide at room temperature in THF for 16 h, in the presence of activated zinc powder (1.1 eq.) and saturated aq. NH 4 Cl as an additive. Under these conditions, homoallylic alcohol 3 was obtained at 65% with an 85:15 dr (Scheme 1).
Molecules 2017, 22, 2171 3 of 10 therefore highly desirable. In this communication, we describe a two-step strategy towards fused tricyclic architectures starting from α-bromomethylbutenolide. The key α-ylidene γ-lactone intermediate was obtained in the first step through a Barbier reaction which allowed installation of the orthobromoaromatics. These intermediates were subsequently subjected to intramolecular Heck reaction conditions. In our case, the presence of the OH group located at the benzylic site accounted for the selective preparation of the tricyclic 6,6,5 α-vinylidene γ-lactone or the 6,5,5 lactone motifs depending on the catalytic precursor/base combination (Figure 2c). The generation of tetracyclic analogues was then examined using the same strategy.

Results and Discussion
We first examined the Barbier reaction between α-bromomethylbutenolide 1 and orthobromobenzaldehyde 2. If such reactions are well described [3][4][5][6][7], the use of ortho-substituted benzaldehydes and further ortho-bromide derivatives remain scarcely reported [14]. In our case, 2 smoothly reacted with the starting butenolide at room temperature in THF for 16 h, in the presence of activated zinc powder (1.1 eq.) and saturated aq. NH4Cl as an additive. Under these conditions, homoallylic alcohol 3 was obtained at 65% with an 85:15 dr (Scheme 1). Scheme 1. Route from α-bromomethylbutenolide to fused tricyclic lactones 4 and 5.
The stereoselectivity of the major isomer is consistent with those described with other aromatic substrates [2], this was supported by our own NMR data (see ESI) and established by comparison with X-ray crystallographic analysis of the naphthalene analogue (vide infra). We next turned our attention to the intramolecular Heck cyclization under various conditions as exemplified in Table 1.
Our first attempts were based on a Pd(II) catalytic system reported in the literature for an analogous transformation [3][4][5][6][7]. Pd(PPh3)2Cl2 (5 %) in combination with K2CO3 (2 eq.) was first used as the catalytic system in refluxing THF for two hours (entry 1). Although under these conditions, the reaction did not reach completion (see ratio of compounds 3/4/5 determined by 1 H-NMR), we were able to isolate the unexpected tricyclic lactone 4 in 20% yield. The structure of 4 was unambiguously assigned by NMR experiments. Our strategy represents an alternative to the construction of fused tricyclic lactone architectures combining fused cyclopentenone and dihydrofuranone or γ-lactonefused benzopyrans [8,9,[15][16][17]. After 16 h, we noticed full conversion of the starting material and lactone 4 was isolated in a fair 60% yield together with some unidentified degradation material (entry 2). Under these conditions, no traces of the expected tricyclic 6,5,5 product was detected in the crude material. These first entries differ markedly from earlier observations within similar series [10][11][12]. Indeed, as described by Genet and Ikeda [10][11][12], the tricyclic products arising from the intramolecular Heck process is obtained either in the absence of a homoallylic hydroxyl group or in the presence of a Si-protected hydroxyl group (Figure 2a,b). In our case, the presence of an unprotected hydroxyl The stereoselectivity of the major isomer is consistent with those described with other aromatic substrates [2], this was supported by our own NMR data (see ESI) and established by comparison with X-ray crystallographic analysis of the naphthalene analogue (vide infra). We next turned our attention to the intramolecular Heck cyclization under various conditions as exemplified in Table 1.
Our first attempts were based on a Pd(II) catalytic system reported in the literature for an analogous transformation [3][4][5][6][7]. Pd(PPh 3 ) 2 Cl 2 (5 %) in combination with K 2 CO 3 (2 eq.) was first used as the catalytic system in refluxing THF for two hours (entry 1). Although under these conditions, the reaction did not reach completion (see ratio of compounds 3/4/5 determined by 1 H-NMR), we were able to isolate the unexpected tricyclic lactone 4 in 20% yield. The structure of 4 was unambiguously assigned by NMR experiments. Our strategy represents an alternative to the construction of fused tricyclic lactone architectures combining fused cyclopentenone and dihydrofuranone or γ-lactone-fused benzopyrans [8,9,[15][16][17]. After 16 h, we noticed full conversion of the starting material and lactone 4 was isolated in a fair 60% yield together with some unidentified degradation material (entry 2). Under these conditions, no traces of the expected tricyclic 6,5,5 product was detected in the crude material. These first entries differ markedly from earlier observations within similar series [10][11][12]. Indeed, as described by Genet and Ikeda [10][11][12], the tricyclic products arising from the intramolecular Heck process is obtained either in the absence of a homoallylic hydroxyl group or in the presence of a Si-protected hydroxyl group (Figure 2a,b). In our case, the presence of an unprotected hydroxyl group allowed a different pathway to take place. As shown in Scheme 2, compound 4 and two new fused O-heterocycles might arise from a ring opening-ring closure sequence starting from the potassium alcoholate, through an intramolecular trans lactonization process, followed by an intramolecular Pd-assisted C-O bond formation [18]. Attempts to modify the reaction course by using silver salts [19] proved detrimental to the transformation only affording degradation material (entry 3). Changing from THF to MeCN as the solvent or Pd(PPh 3 ) 2 Cl 2 /K 2 CO 3 to Pd(PPh 3 ) 2 Cl 2 /Cs 2 CO 3 as the catalytic combination did not improve the isolated yield or led to degradation of the starting material respectively (entries 4 and 5). A control reaction run without a palladium source (entry 6) in order to isolate the intermediate from the ring opening-ring closure sequence failed, affording tangled mixtures of polycondensation products. fused O-heterocycles might arise from a ring opening-ring closure sequence starting from the potassium alcoholate, through an intramolecular trans lactonization process, followed by an intramolecular Pdassisted C-O bond formation [18]. Attempts to modify the reaction course by using silver salts [19] proved detrimental to the transformation only affording degradation material (entry 3). Changing from THF to MeCN as the solvent or Pd(PPh3)2Cl2/K2CO3 to Pd(PPh3)2Cl2/Cs2CO3 as the catalytic combination did not improve the isolated yield or led to degradation of the starting material respectively (entries 4 and 5). A control reaction run without a palladium source (entry 6) in order to isolate the intermediate from the ring opening-ring closure sequence failed, affording tangled mixtures of polycondensation products. A combination of Pd(dppf)2Cl2/K2CO3 in MeCN or THF at reflux led to average yields of 30% and 45%, respectively, accompanied by degradation products (entries 7 and 8). Interestingly, the use of KOAc instead of K2CO3 allowed a complete switch of selectivity as tricyclic compound 4 was not detected (entry 9). Indeed, such conditions afforded a mixture of the starting material and a small amount of lactone 5. Gratifyingly, we were able to cleanly isolate lactone 5 in a 40% yield by changing from THF to MeCN as the solvent (entry 10). It is worthy to note that the intramolecular Heck cyclization afforded the carbonyl compound 5 instead of the expected corresponding benzylic alcohol. Under our conditions, the formation of lactone 5 can be explained as shown in Scheme 3. The fused O-heterocycles might arise from a ring opening-ring closure sequence starting from the potassium alcoholate, through an intramolecular trans lactonization process, followed by an intramolecular Pdassisted C-O bond formation [18]. Attempts to modify the reaction course by using silver salts [19] proved detrimental to the transformation only affording degradation material (entry 3). Changing from THF to MeCN as the solvent or Pd(PPh3)2Cl2/K2CO3 to Pd(PPh3)2Cl2/Cs2CO3 as the catalytic combination did not improve the isolated yield or led to degradation of the starting material respectively (entries 4 and 5). A control reaction run without a palladium source (entry 6) in order to isolate the intermediate from the ring opening-ring closure sequence failed, affording tangled mixtures of polycondensation products. A combination of Pd(dppf)2Cl2/K2CO3 in MeCN or THF at reflux led to average yields of 30% and 45%, respectively, accompanied by degradation products (entries 7 and 8). Interestingly, the use of KOAc instead of K2CO3 allowed a complete switch of selectivity as tricyclic compound 4 was not detected (entry 9). Indeed, such conditions afforded a mixture of the starting material and a small amount of lactone 5. Gratifyingly, we were able to cleanly isolate lactone 5 in a 40% yield by changing from THF to MeCN as the solvent (entry 10). It is worthy to note that the intramolecular Heck cyclization afforded the carbonyl compound 5 instead of the expected corresponding benzylic alcohol. Under our conditions, the formation of lactone 5 can be explained as shown in Scheme 3. The generation of a quaternary carbon center arising from oxidative addition and carbopalladation in a 5-exo process at precursor 3 precludes classical β-hydride elimination. The formation of lactone 5 could thus arise from an alternative pathway, involving an exo/endo migration of the olefin prior to A combination of Pd(dppf) 2 Cl 2 /K 2 CO 3 in MeCN or THF at reflux led to average yields of 30% and 45%, respectively, accompanied by degradation products (entries 7 and 8). Interestingly, the use of KOAc instead of K 2 CO 3 allowed a complete switch of selectivity as tricyclic compound 4 was not detected (entry 9). Indeed, such conditions afforded a mixture of the starting material and a small amount of lactone 5. Gratifyingly, we were able to cleanly isolate lactone 5 in a 40% yield by changing from THF to MeCN as the solvent (entry 10). It is worthy to note that the intramolecular Heck cyclization afforded the carbonyl compound 5 instead of the expected corresponding benzylic alcohol. Under our conditions, the formation of lactone 5 can be explained as shown in Scheme 3. The generation of a quaternary carbon center arising from oxidative addition and carbopalladation in a 5-exo process at precursor 3 precludes classical β-hydride elimination. The formation of lactone 5 could thus arise from an alternative pathway, involving an exo/endo migration of the olefin prior to Heck reaction. The α,β-unsaturated lactone thus generated would then successively undergo oxidative addition and carbopalladation in a 5-endo pattern followed by β-hydride elimination. The latter sequence would then generate an enolate and the corresponding ketone after aqueous workup. Heck reaction. The α,β-unsaturated lactone thus generated would then successively undergo oxidative addition and carbopalladation in a 5-endo pattern followed by β-hydride elimination. The latter sequence would then generate an enolate and the corresponding ketone after aqueous workup. This sequence requires an exo/endo migration of the olefin to take place prior the oxidative addition as the first key step leading to lactone 5. The formation of allylic alcohols from homoallylic alcohols including homoallylic benzylic alcohols using Pd/C and Et3N has already been reported [20]. In addition, migration of the olefin from α-methylene-γ-butyrolactone to the corresponding α,β-unsaturated lactone has been obtained using RhCl3 in EtOH [21] and observed as a side product of cross metathesis reactions [22]. Unfortunately, we have not been able to demonstrate the olefin migration on the closely related dehalogenated analogue of compound 3 under our reaction conditions. However, in good agreement with the latter reports, we have been able to acquire evidence for the olefin migration of the olefin from α-methylene-γ-butyrolactone A to the corresponding α,β-unsaturated lactone B under our reaction conditions (Pd(PPh3)2Cl2/KOAc in refluxing MeCN) as shown in Scheme 4. The presence of characteristic signals of lactone B in the 1 H-NMR of the crude material (see supplementary material) confirmed the olefin isomerization in full agreement with data reported by Jefford et al. [21]. The stereoselectivity was established by comparison with an X-ray crystallographic structure of the naphthalene analogue (vide infra). Again, the use of silver salts disappointingly afforded a sluggish reaction from which compound 5 could be isolated in 14% yield (entry 11). Finally, the use of a 1:1 mixture of K2CO3 and KOAc in refluxing THF afforded a partial conversion of the starting material 3 and formed lactone 4 as well as traces of lactone 5 in a 1/1.2/0.1 ratio (entry 12). Our results seem to indicate that both the nature of the base and the reaction conditions are essential to the selective transformation of benzylic alcohol 3. Indeed, higher temperature in MeCN combined with the use of KOAc as the base affords the tricyclic 6,5,5 lactone 5, whereas lower temperature in THF associated to K2CO3 affords the tricyclic 6,6,5 lactone 4.
The same strategy was tested on ortho-bromobenzonitrile 6 and ortho-bromobenzaldimine 7. Unfortunately, in both cases under similar Barbier conditions only the α-methylbutenolide arising from Zn-promoted reduction of the C-Br bond could be isolated ( Table 2, entries 1 and 2). In contrast, This sequence requires an exo/endo migration of the olefin to take place prior the oxidative addition as the first key step leading to lactone 5. The formation of allylic alcohols from homoallylic alcohols including homoallylic benzylic alcohols using Pd/C and Et 3 N has already been reported [20]. In addition, migration of the olefin from α-methylene-γ-butyrolactone to the corresponding α,β-unsaturated lactone has been obtained using RhCl 3 in EtOH [21] and observed as a side product of cross metathesis reactions [22]. Unfortunately, we have not been able to demonstrate the olefin migration on the closely related dehalogenated analogue of compound 3 under our reaction conditions. However, in good agreement with the latter reports, we have been able to acquire evidence for the olefin migration of the olefin from α-methylene-γ-butyrolactone A to the corresponding α,β-unsaturated lactone B under our reaction conditions (Pd(PPh 3 ) 2 Cl 2 /KOAc in refluxing MeCN) as shown in Scheme 4. The presence of characteristic signals of lactone B in the 1 H-NMR of the crude material (see supplementary material) confirmed the olefin isomerization in full agreement with data reported by Jefford et al. [21]. Heck reaction. The α,β-unsaturated lactone thus generated would then successively undergo oxidative addition and carbopalladation in a 5-endo pattern followed by β-hydride elimination. The latter sequence would then generate an enolate and the corresponding ketone after aqueous workup. This sequence requires an exo/endo migration of the olefin to take place prior the oxidative addition as the first key step leading to lactone 5. The formation of allylic alcohols from homoallylic alcohols including homoallylic benzylic alcohols using Pd/C and Et3N has already been reported [20]. In addition, migration of the olefin from α-methylene-γ-butyrolactone to the corresponding α,β-unsaturated lactone has been obtained using RhCl3 in EtOH [21] and observed as a side product of cross metathesis reactions [22]. Unfortunately, we have not been able to demonstrate the olefin migration on the closely related dehalogenated analogue of compound 3 under our reaction conditions. However, in good agreement with the latter reports, we have been able to acquire evidence for the olefin migration of the olefin from α-methylene-γ-butyrolactone A to the corresponding α,β-unsaturated lactone B under our reaction conditions (Pd(PPh3)2Cl2/KOAc in refluxing MeCN) as shown in Scheme 4. The presence of characteristic signals of lactone B in the 1 H-NMR of the crude material (see supplementary material) confirmed the olefin isomerization in full agreement with data reported by Jefford et al. [21]. The stereoselectivity was established by comparison with an X-ray crystallographic structure of the naphthalene analogue (vide infra). Again, the use of silver salts disappointingly afforded a sluggish reaction from which compound 5 could be isolated in 14% yield (entry 11). Finally, the use of a 1:1 mixture of K2CO3 and KOAc in refluxing THF afforded a partial conversion of the starting material 3 and formed lactone 4 as well as traces of lactone 5 in a 1/1.2/0.1 ratio (entry 12). Our results seem to indicate that both the nature of the base and the reaction conditions are essential to the selective transformation of benzylic alcohol 3. Indeed, higher temperature in MeCN combined with the use of KOAc as the base affords the tricyclic 6,5,5 lactone 5, whereas lower temperature in THF associated to K2CO3 affords the tricyclic 6,6,5 lactone 4.
The same strategy was tested on ortho-bromobenzonitrile 6 and ortho-bromobenzaldimine 7. Unfortunately, in both cases under similar Barbier conditions only the α-methylbutenolide arising The stereoselectivity was established by comparison with an X-ray crystallographic structure of the naphthalene analogue (vide infra). Again, the use of silver salts disappointingly afforded a sluggish reaction from which compound 5 could be isolated in 14% yield (entry 11). Finally, the use of a 1:1 mixture of K 2 CO 3 and KOAc in refluxing THF afforded a partial conversion of the starting material 3 and formed lactone 4 as well as traces of lactone 5 in a 1/1.2/0.1 ratio (entry 12). Our results seem to indicate that both the nature of the base and the reaction conditions are essential to the selective transformation of benzylic alcohol 3. Indeed, higher temperature in MeCN combined with the use of KOAc as the base affords the tricyclic 6,5,5 lactone 5, whereas lower temperature in THF associated to K 2 CO 3 affords the tricyclic 6,6,5 lactone 4.
The same strategy was tested on ortho-bromobenzonitrile 6 and ortho-bromobenzaldimine 7. Unfortunately, in both cases under similar Barbier conditions only the α-methylbutenolide arising from Zn-promoted reduction of the C-Br bond could be isolated ( Table 2, entries 1 and 2). In contrast, moving from the phenyl to the commercially available naphthyl substrate 8 led to the formation of alcohol 12 in 60% yield with an 87:13 dr (entry 3). The rigid naphthalene fragment did not affect the dr observed for compound 3. Moving towards the more flexible dihydronaphthalene platforms 9 and 10 [23] (entries 4 and 5) allowed preparation of the corresponding Barbier adducts 13 and 14 in higher yields ranging from 80 to 89% with similar drs of 87:13 and 94:6 regardless of the nature of the halide (Cl or Br) in the precursors.   X-ray crystallographic analysis undoubtedly assigned the stereoselectivity of the major isomer as shown in Figure 3. The presence of a sterically demanding naphthalene platform, as well as a bromine atom, did not affect the stereoselectivity observed for other aromatic substrates [3][4][5][6][7]. The combined presence of the lactone carbonyl and the benzyl alcohol induces the formation of hydrogen bonds associating three molecules in the solid state. Finally, (dihydro)naphthalene substrates 12, 13, and 14 were subjected to the aforementioned intramolecular Heck cyclization conditions. For the naphthyl substrate, conditions A (PdCl2(PPh3)2, KOAc, MeCN at 90 °C for 18 h) and B (PdCl2(PPh3)2, K2CO3, THF at 65 °C for 18 h) were tested. Interestingly, only the tetracyclic lactone 15 arising from a Heck cyclisation-oxidation sequence was isolated in 40% and 60% yields, respectively, under these reaction conditions. Further, no trace of the naphthyl analogue of compound 4 was observed even in the presence of K2CO3 as the base. At this stage, no satisfactory explanation for the unexpected selectivity observed towards the tetracyclic lactone 15 can be given. The reactivity of the dihydronaphthalene-based substrates 13 and 14 towards the Heck cyclization-oxidation sequence were next evaluated. Although no cyclization occurred using the less reactive chloride derivative 13, the expected product 16 could be obtained in 55 to 70%  X-ray crystallographic analysis undoubtedly assigned the stereoselectivity of the major isomer as shown in Figure 3. The presence of a sterically demanding naphthalene platform, as well as a bromine atom, did not affect the stereoselectivity observed for other aromatic substrates [3][4][5][6][7]. The combined presence of the lactone carbonyl and the benzyl alcohol induces the formation of hydrogen bonds associating three molecules in the solid state. Finally, (dihydro)naphthalene substrates 12, 13, and 14 were subjected to the aforementioned intramolecular Heck cyclization conditions. For the naphthyl substrate, conditions A (PdCl2(PPh3)2, KOAc, MeCN at 90 °C for 18 h) and B (PdCl2(PPh3)2, K2CO3, THF at 65 °C for 18 h) were tested. Interestingly, only the tetracyclic lactone 15 arising from a Heck cyclisation-oxidation sequence was isolated in 40% and 60% yields, respectively, under these reaction conditions. Further, no trace of the naphthyl analogue of compound 4 was observed even in the presence of K2CO3 as the base. At this stage, no satisfactory explanation for the unexpected selectivity observed towards the tetracyclic lactone 15 can be given. The reactivity of the dihydronaphthalene-based substrates 13 and 14 towards the Heck cyclization-oxidation sequence were next evaluated. Although no cyclization occurred using the less reactive chloride derivative 13, the expected product 16 could be obtained in 55 to 70%  X-ray crystallographic analysis undoubtedly assigned the stereoselectivity of the major isomer as shown in Figure 3. The presence of a sterically demanding naphthalene platform, as well as a bromine atom, did not affect the stereoselectivity observed for other aromatic substrates [3][4][5][6][7]. The combined presence of the lactone carbonyl and the benzyl alcohol induces the formation of hydrogen bonds associating three molecules in the solid state. Finally, (dihydro)naphthalene substrates 12, 13, and 14 were subjected to the aforementioned intramolecular Heck cyclization conditions. For the naphthyl substrate, conditions A (PdCl2(PPh3)2, KOAc, MeCN at 90 °C for 18 h) and B (PdCl2(PPh3)2, K2CO3, THF at 65 °C for 18 h) were tested. Interestingly, only the tetracyclic lactone 15 arising from a Heck cyclisation-oxidation sequence was isolated in 40% and 60% yields, respectively, under these reaction conditions. Further, no trace of the naphthyl analogue of compound 4 was observed even in the presence of K2CO3 as the base. At this stage, no satisfactory explanation for the unexpected selectivity observed towards the tetracyclic lactone 15 can be given. The reactivity of the dihydronaphthalene-based substrates 13 and 14 towards the Heck cyclization-oxidation sequence were next evaluated. Although no cyclization occurred  X-ray crystallographic analysis undoubtedly assigned the stereoselectivity of the major isomer as shown in Figure 3. The presence of a sterically demanding naphthalene platform, as well as a bromine atom, did not affect the stereoselectivity observed for other aromatic substrates [3][4][5][6][7]. The combined presence of the lactone carbonyl and the benzyl alcohol induces the formation of hydrogen bonds associating three molecules in the solid state. Finally, (dihydro)naphthalene substrates 12, 13, and 14 were subjected to the aforementioned intramolecular Heck cyclization conditions. For the naphthyl substrate, conditions A (PdCl2(PPh3)2, KOAc, MeCN at 90 °C for 18 h) and B (PdCl2(PPh3)2, K2CO3, THF at 65 °C for 18 h) were tested. Interestingly, only the tetracyclic lactone 15 arising from a Heck cyclisation-oxidation sequence was isolated in 40% and 60% yields, respectively, under these reaction conditions. Further, no trace of the naphthyl analogue of compound 4 was observed even in the presence of K2CO3 as the base. At this stage, no satisfactory explanation for the unexpected selectivity observed towards the tetracyclic lactone 15 can be given. The reactivity of the dihydronaphthalene-based substrates 13 and 14 towards the Heck cyclization-oxidation sequence were next evaluated. Although no cyclization occurred  X-ray crystallographic analysis undoubtedly assigned the stereoselectivity of the major isomer as shown in Figure 3. The presence of a sterically demanding naphthalene platform, as well as a bromine atom, did not affect the stereoselectivity observed for other aromatic substrates [3][4][5][6][7]. The combined presence of the lactone carbonyl and the benzyl alcohol induces the formation of hydrogen bonds associating three molecules in the solid state. Finally, (dihydro)naphthalene substrates 12, 13, and 14 were subjected to the aforementioned intramolecular Heck cyclization conditions. For the naphthyl substrate, conditions A (PdCl2(PPh3)2, KOAc, MeCN at 90 °C for 18 h) and B (PdCl2(PPh3)2, K2CO3, THF at 65 °C for 18 h) were tested. Interestingly, only the tetracyclic lactone 15 arising from a Heck cyclisation-oxidation sequence was isolated in 40% and 60% yields, respectively, under these reaction conditions. Further, no trace of the naphthyl analogue of compound 4 was observed even in the presence of K2CO3 as the base. At this stage, no satisfactory explanation for the unexpected selectivity observed towards the tetracyclic lactone 15 can be given. The reactivity of the dihydronaphthalene-based substrates 13 and 14 towards the Heck cyclization-oxidation sequence were next evaluated. Although no cyclization occurred  X-ray crystallographic analysis undoubtedly assigned the stereoselectivity of the major isomer as shown in Figure 3. The presence of a sterically demanding naphthalene platform, as well as a bromine atom, did not affect the stereoselectivity observed for other aromatic substrates [3][4][5][6][7]. The combined presence of the lactone carbonyl and the benzyl alcohol induces the formation of hydrogen bonds associating three molecules in the solid state.  X-ray crystallographic analysis undoubtedly assigned the stereoselectivity of the major isomer as shown in Figure 3. The presence of a sterically demanding naphthalene platform, as well as a bromine atom, did not affect the stereoselectivity observed for other aromatic substrates [3][4][5][6][7]. The combined presence of the lactone carbonyl and the benzyl alcohol induces the formation of hydrogen bonds associating three molecules in the solid state. X-ray crystallographic analysis undoubtedly assigned the stereoselectivity of the major isomer as shown in Figure 3. The presence of a sterically demanding naphthalene platform, as well as a bromine atom, did not affect the stereoselectivity observed for other aromatic substrates [3][4][5][6][7]. The combined presence of the lactone carbonyl and the benzyl alcohol induces the formation of hydrogen bonds associating three molecules in the solid state.  X-ray crystallographic analysis undoubtedly assigned the stereoselectivity of the major isomer as shown in Figure 3. The presence of a sterically demanding naphthalene platform, as well as a bromine atom, did not affect the stereoselectivity observed for other aromatic substrates [3][4][5][6][7]. The combined presence of the lactone carbonyl and the benzyl alcohol induces the formation of hydrogen bonds associating three molecules in the solid state. Finally, (dihydro)naphthalene substrates 12, 13, and 14 were subjected to the aforementioned intramolecular Heck cyclization conditions. For the naphthyl substrate, conditions A (PdCl2(PPh3)2, KOAc, MeCN at 90 °C for 18 h) and B (PdCl2(PPh3)2, K2CO3, THF at 65 °C for 18 h) were tested. Interestingly, only the tetracyclic lactone 15 arising from a Heck cyclisation-oxidation sequence was isolated in 40% and 60% yields, respectively, under these reaction conditions. Further, no trace of the naphthyl analogue of compound 4 was observed even in the presence of K2CO3 as the base. At this Finally, (dihydro)naphthalene substrates 12, 13, and 14 were subjected to the aforementioned intramolecular Heck cyclization conditions. For the naphthyl substrate, conditions A (PdCl 2 (PPh 3 ) 2, KOAc, MeCN at 90 • C for 18 h) and B (PdCl 2 (PPh 3 ) 2, K 2 CO 3 , THF at 65 • C for 18 h) were tested. Interestingly, only the tetracyclic lactone 15 arising from a Heck cyclisation-oxidation sequence was isolated in 40% and 60% yields, respectively, under these reaction conditions. Further, no trace of the naphthyl analogue of compound 4 was observed even in the presence of K 2 CO 3 as the base. At this stage, no satisfactory explanation for the unexpected selectivity observed towards the tetracyclic lactone 15 can be given. The reactivity of the dihydronaphthalene-based substrates 13 and 14 towards the Heck cyclization-oxidation sequence were next evaluated. Although no cyclization occurred using the less reactive chloride derivative 13, the expected product 16 could be obtained in 55 to 70% yields from the bromide derivative 14. Similarly, only one cyclization product was observed under both reaction conditions. Moving from the fully aromatic to the dihydro platform (compare 12 and 14) had only a minor effect on the yield. Again, single crystal X-ray diffraction analysis confirmed the tetracyclic architecture of 16 and allowed assignment of the stereochemistry of the lactone-cyclopentanone junction (Scheme 5 and Figure 4). As shown below, the crystalline lattice is formed by a pillared arrangement of tetracyclic units resulting from well-defined intermolecular π-π interactions (3.52 Å) between planar naphthalene fragments.

Materials and Methods
Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without purification. Petroleum ether was distilled under Argon. NMR spectra were recorded on 300 MHz and 200 MHz Brucker spectrometers (Bruker BioSpin GmbH, Rheinstetten, Germany).
Chemical shifts were reported in ppm relative to the residual solvent peak (7.27 ppm for CHCl3 in the 1 H-NMR and 77.0 ppm for CDCl3 13 C-NMR). High resolution mass spectroscopy data were As shown below, the crystalline lattice is formed by a pillared arrangement of tetracyclic units resulting from well-defined intermolecular π-π interactions (3.52 Å) between planar naphthalene fragments. As shown below, the crystalline lattice is formed by a pillared arrangement of tetracyclic units resulting from well-defined intermolecular π-π interactions (3.52 Å) between planar naphthalene fragments.

Materials and Methods
Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without purification. Petroleum ether was distilled under Argon. NMR spectra were recorded on 300 MHz and 200 MHz Brucker spectrometers (Bruker BioSpin GmbH, Rheinstetten, Germany).

Materials and Methods
Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without purification. Petroleum ether was distilled under Argon. NMR spectra were recorded on 300 MHz and 200 MHz Brucker spectrometers (Bruker BioSpin GmbH, Rheinstetten, Germany).

Procedure A for Intramolecular Heck Reaction
A mixture of lactone 3 (100 mg, 0.35 mmol), PdCl 2 (PPh 3 ) 2 (12.5 mg, 0.017 mmol), and K 2 CO 3 (98 mg, 0.71 mmol) in solvent (3 mL) was purged under argon atmosphere and stirred at 95 • C for 16 h. When the reaction was complete (as indicated by TLC), the mixture was diluted with water (10 mL) and extracted with CH 2 Cl 2 (3 × 10 mL). The combined organic layers were dried over anhydrous MgSO 4 , concentrated under reduced pressure, and purified by flash column chromatography on silica gel eluted with CH 2 Cl 2 /petroleum ether (8:2) to give the expected product 4.

Procedure B for Intramolecular Heck Reaction
A mixture of lactone 3 (100 mg, 0.35 mmol), PdCl 2 (PPh 3 ) 2 (12.5 mg, 0.017 mmol), and KOAc (69.6 mg, 0.71 mmol) in CH 3 CN (3 mL). The mixture was purged under argon atmosphere and stirred at 95 • C for 16 h. When the reaction was complete (as indicated by TLC), the mixture was diluted with water (10 mL) and extracted with CH 2 Cl 2 (3 × 10 mL). The combined organic layers were dried over anhydrous MgSO 4 and concentrated under reduced pressure and purified by flash column chromatography on silica gel eluting with CH 2 Cl 2 /petroleum ether (8:2), to give the expected product

Conclusions
In summary, we have developed a three-step sequence involving a Barbier reaction followed by an intramolecular Heck arylation to prepare tri-and tetracyclic lactones starting from α-bromomethylbutenolide. The Zn-promoted allylation reaction proved efficient in the benzene, naphthalene, and dihydronaphthalene series giving access to various allylic/benzylic alcohols with high stereoselectivity. In the key Heck arylation step, the nature of the base proved crucial for obtaining polycyclic architectures. In the benzene series, switching from K 2 CO 3 to KOAc selectively led to the expected tricyclic 6,5,5 pattern instead of the unexpected 6,6,5 pattern. Our strategy could be extended to tetracyclic analogues based on a naphthalene and a dihydronaphthalene platform.
Supplementary Materials: Representative synthetic procedures, characterization data of new compounds, as well as NMR and X-ray data are available online, experimental procedures as well as analytical data for new compounds.