Introduction

Synthetic approaches for constructing complex skeletons from simple starting materials via the formation of multiple bonds in a single step are very useful in organic synthesis. Sequential cycloaddition reactions are particularly effective because they facilitate the multiple formation of bonds, both regio- and stereoselectively, in one step1,2,3. In addition, no leaving groups are required, thereby intrinsically conferring excellent atom efficiency.

One carbon atom is shared by four rings in fenestrane, which is a feature that has garnered much attention because of the resultant highly frustrated and flattened quaternary carbon centers4,5,6,7,8,9. How structurally modifying fenestrane influences its flattening has been investigated both experimentally and computationally5. Experimental evidence for such an influence, however, has been hampered by difficulties encountered during fenestrane synthesis4,5. A number of biologically active natural products containing fenestrane10,11 and heteroatom-containing fenestrane12,13,14,15,16,17,18 motifs have been isolated. In addition, the rigid and nonplanar structures of heteroatom-containing fenestranes are attractive scaffolds for pharmaceutical applications. Therefore, the development of efficient synthetic approaches for (heteroatom-containing) fenestranes is an important objective.

A one-step sequential cycloaddition-based approach can effectively be used to construct (heteroatom-containing) fenestrane A (Fig. 1)4. Previously reported syntheses can be categorized into one of three approaches (Fig. 1a–c). The first approach involves the use of precursor B, which contains one or two rings present in the tetracyclic fenestrane structure (Fig. 1a). This approach employs sequential cycloaddition reactions with precursor B, resulting in the formation of fenestrane A. Denmark et al. reported the syntheses of two aza-dioxa-fenestranes via Lewis-acid-mediated sequential [4 + 2]/(3 + 2) cycloaddition reactions based on the first approach19. J. Suffert et al. reported synthesis of six fenestranes via 8p-6p electrochemical cyclization from cyclic precursors that is relevant to the first approach, although this report did not use sequential cycloadditions20. The second approach uses branched acyclic precursor C that sequentially cycloadds to afford the corresponding fenestranes (Fig. 1b). Keese et al.21,22 and Mehta et al.23 reported the syntheses of five fenestranes21,22 and one dioxa-fenestrane23, respectively, via sequential Pauson–Khand reactions (PKRs) involving branched acyclic precursors, based on the second approach. Chung et al.24 and Chen et al.25 also reported the syntheses of three24 and eight oxa-fenestranes25 using similar sequential PKR/[4 + 2] cycloaddition chemistry, while Penkett et al. reported the synthesis of a dioxa-fenestrane using unique photochemical double (3 + 2) cycloaddition chemistry26. Chung et al. reported the elegant synthesis of two fenestranes using a PKR/Tsuji–Trost-reaction/PKR sequence starting from a branched acyclic precursor C27. Koshikawa et al. reported an elegant synthesis of eleven fenestranes via sequential (3 + 2) cycloaddition/carbenoid transfer/C-H insertion that is relevant to the second approach, although this report did not use sequential cycloadditions in a strict sense28.

Fig. 1: Sequential cycloaddition-based approaches for synthesizing fenestranes.
figure 1

a Sequential cycloaddition of precursor B containing one or two rings found in the fenestrane tetracycle (the first approach). b Sequential cycloaddition involving branched acyclic precursor C (the second approach). c Sequential cycloaddition of nonbranched acyclic precursors D (the third approach). d Our developed sequential (3 + 2)/(3 + 2) cycloaddition reaction involving nonbranched acyclic nitrone precursors E (the third approach). e Our developed sequential (3 + 2)/(3 + 2) cycloaddition reaction involving nonbranched acyclic nitrile oxide precursors G (the third approach).

Full size image

The syntheses mentioned above are plagued by issues such as low yields, a limited substrate scope, or the need for a substantial number of synthetic steps to prepare the necessary precursors. Of note, no previous synthetic protocol has successfully achieved the construction of (heteroatom-containing) fenestranes with different ring sizes through a sequential cycloaddition approach. Although Chen et al. obtained both [5.5.5.5]oxafenestrane and [5.5.5.6]oxafenestrane as a mixture from the Rh-catalyzed sequential PKR/[4 + 2]cycloaddition of single trieneyne precursor, this was not selective reaction25.

The third approach involves the sequential cycloaddition of the structurally simplest nonbranched acyclic precursor D to yield fenestrane A (as depicted in Fig. 1c). While this approach is appealing due to its use of easily prepared precursors, to the best of our knowledge, there are no reports documenting the utilization of this approach in previous research.

Herein, we present the inaugural one-step synthesis of differently substituted diaza-dioxa-fenestranes labeled as F and H, featuring rings of varying sizes. This synthesis is achieved using nonbranched acyclic precursors E and G through sequential (3 + 2)/(3 + 2) cycloaddition chemistry, following the principles of the third approach (Fig. 1d, e). We designed nonbranched acyclic allene precursors E and G containing nitrones and nitrile oxides, respectively, for use in sequential cycloaddition chemistry. The two orthogonal p-orbitals of an allene were anticipated to facilitate the challenging construction of the four fenestrane rings. Our approach facilitated the creation of a broad array of structurally diverse precursors. These precursors were subsequently utilized to synthesize a total of 22 diaza-dioxa-fenestranes. A structural analysis of the synthesized fenestranes indicated that the substitution of carbon atoms in the fenestrane framework with nitrogen and oxygen atoms played a role in the flattening of the quaternary carbon center. Notably, one of the synthesized diaza-dioxa-fenestranes exhibited the flattest quaternary carbon center among all previously synthesized heteroatom-containing fenestrane derivatives.

Results

Our initial investigation focused on the one-step sequential cycloaddition reaction of nitrone-containing allene 3a that was generated in situ from bisaldehyde 1a (prepared from commercially available 4-pentyn-1-ol in 5 steps. See section 2.3 of the Supplementary Information for details.) and N-benzylhydroxylamine hydrochloride (Table 1), with solvents, including ethanol, toluene, 1,4-dioxane, and TCE, examined in the absence of a base (entries 1–3; see Supplementary Table 1 for details). The use of TCE led to the highest yield of the desired racemic [5.5.5.5]diaza-dioxa-fenestrane 2a (entry 3, 89%). We also explored the impact of different bases, including Et3N, i-Pr2NEt, pyridine, and NaHCO3 (entries 4–7). Remarkably, the use of Et3N resulted in an excellent yield (91%) for 2a (entry 4). However, when i-Pr2NEt (as a stronger base) was employed, the yield of 2a dropped significantly (19%), likely due to undesired base-mediated reactions involving bisaldehyde 1a (entry 5). As expected, nitrone-containing allene 3a underwent sequential cycloaddition to afford diaza-dioxa-fenestrane 2a in high yield.

Table 1 Investigating the one-step sequential (3 + 2)/(3 + 2) cycloaddition chemistry of a nitrone-containing allene
Full size table

We then investigated the one-step sequential cycloaddition reaction of nitrile oxide 6a, which was generated in situ from bisoxime 4a (prepared from bisaldehyde 1a in one step. See section 2.3 of the Supplementary Information for details.) (Table 2). Solvents, including CH2Cl2, ethanol, THF, and toluene, were examined in the presence of a 10% aqueous solution of NaOCl and Et3N. The use of CH2Cl2 resulted in a good yield of the desired racemic double-bond-containing [5.5.5.5]diaza-dioxa-fenestrane 5a (entry 1, 69%). The use of ethanol did not afford any of the desired product (entry 2), despite the high solubility of NaOCl in this solvent. The desired product 5a was obtained, in yields of 15% and 20% when THF and toluene was used, respectively (entries 3 and 4). Bases, including Et3N, pyridine, NaHCO3, and i-Pr2NEt were examined using CH2Cl2 as the solvent (entries 1 and 5–7); once again the use of Et3N afforded the highest yield (entry 1, 69%). The use of i-Pr2NEt afforded 5a in acceptable yield (entry 7, 59%) during the cycloaddition of bisnitrile oxide 6a, in contrast to the yield obtained using nitrone 3a. The desired product 5a was also obtained in an acceptable yield in the absence of the base (entry 8, 62%). At this point, we also examined the effect of temperature (0–100 °C) using haloalkane solvents (entries 9–13); the use of DCE at 80 °C afforded the highest yield (entry 12, 72%). Accordingly, we successfully developed a sequential cycloaddition-based approach using two types of allenes 3a and 6a containing nitrone and nitrile oxide, respectively. The structures of 2a and 5a were unambiguously determined by X-ray crystallography (see section 11 of the Supplementary Information for details); structural-analysis details are discussed below.

Table 2 Investigating the one-step sequential (3 + 2)/(3 + 2) cycloaddition chemistry of a nitrile oxide
Full size table

The substrate scope of the developed one-step sequential cycloaddition chemistry involving nitrones 3 was subsequently examined (Fig. 2a). While N-alkyl substituted fenestranes 2b–2d were obtained in good yields (64–76%), only a trace amount of N-t-butyl-substituted fenestrane 2e was obtained, while N-4-methoxybenzyl-substituted fenestrane 2f was obtained in moderate yield (48%). We next examined the functional-group tolerance of this reaction. Good yields (68–71%) were obtained in the syntheses of 2g containing Ph–Br bonds, 2h containing O–Si bonds, and 2i and 2j containing acid-labile THP and furyl groups, respectively. Fenestranes 2k and 2l containing either acid-labile Boc-carbamate or t-Bu-ester moieties, and either base-labile methyl ester or Fmoc-carbamate moieties, were also obtained in good yields (73 and 62%). On the other hand, N-phenyl substituted fenestrane 2m was only obtained in moderate yield (35%), while C,N-alkyl(oxy)-substituted fenestranes 2n–2q were obtained in acceptable-to-good yields (56–70%) as mixtures of diastereomers. Although the diastereomers of 2o were inseparable, 2n, 2p, and 2q were readily separated into their diastereomers by silica-gel column chromatography. The stereochemistry of each diastereomer was determined via 1H NMR, COSY, and NOESY spectroscopy, along with DFT calculations (see section 8 of the Supplementary Information for details). [5.5.5.6]Diaza-dioxa-fenestrane 2r and [5.6.5.6]diaza-dioxa-fenestrane 2s were obtained in yields of 65 and 12%, respectively, while [5.7.5.7]diaza-dioxa-fenestrane 2t was not obtained.

Fig. 2: Substrate scope.
figure 2

Substrate scope of our developed one-step sequential cycloaddition approach from a nitrone 3 and b nitrile oxide 6. c Derivatizing 2g using Pd-catalyzed cross-coupling reactions. d Reductive cleavage of the N–O bond in isoxazolidine 2a. e Mono- and bis-allylation of isoxazoline 5a using a Grignard reagent. aAddition of reagents at −78 °C and warmed to r.t. was repeated 5 times. Cy = cyclohexyl; TBDPS = t-butyldiphenylsilyl; THP = tetrahydropyranyl; Boc = t-butyloxy carbonyl; Fmoc = 9-fluorenylmethoxycarbonyl; Bn = benzyl; dppf = (diphenylphosphino)ferrocene; DMF = N,N-dimethylformamide.

Full size image

We next examined the substrate scope of the one-step sequential cycloaddition chemistry involving nitrile oxides 6 (Fig. 2b). C-Alkyl(oxy)-substituted fenestranes 5b and 5c were obtained in good yields (69 and 66%) as mixtures of diastereomers. While 5b was unable to be separated nor was its diastereomeric ratio able to be determined, 5c was readily separated into its diastereomers via silica-gel column chromatography. The stereochemistry of each diastereomer was determined by 1H NMR, COSY, and NOESY spectroscopy, along with DFT calculations (see section 9 of the Supplementary Information for details). To our delight, [5.5.5.6]diaza-dioxa-fenestrane 5d was obtained in moderate yield (36%), whereas [5.6.5.6]diaza-dioxa-fenestrane 5e was not obtained. While one-step sequential cycloaddition chemistry involving nitrones 3 enabled the synthesis of diaza-dioxa-fenestranes containing up to two six-membered rings, the developed chemistry involving nitrile oxides 6 enabled the synthesis of diaza-dioxa-fenestranes containing only one six-membered ring. The latter chemistry appeared to be more significantly affected by the ring size. Using the developed approach, fenestranes with different ring sizes were constructed through sequential cycloaddition.

The prepared THP-, TBDPS-, Boc-, Fmoc-, t-Bu-, and Bn-protected diaza-dioxa-fenestranes can be readily derivatized via deprotection and subsequent chemical modification. In addition, the aryl-Br bond in fenestrane 2g can be directly activated in the presence of transition-metal catalysts for further derivatization. Accordingly, 2g was subjected to Suzuki–Miyaura, Sonogashira–Hagihara, and Mizoroki–Heck coupling, which afforded the desired products 7a–7d in acceptable-to-excellent yields (Fig. 2c, 57–96%). Moreover, the reactive N–O and C=N bonds in the diaza-dioxa-fenestranes were further derivatized; reductive cleavage of the N–O bond in isoxazolidine 2a afforded spirobicycle 8 in excellent yield (Fig. 2d, 93%). Spiro[4.4]nonane 8, which was densely functionalized by two amino groups and two hydroxy groups at the neopentyl positions, was obtained as a single diastereomer. Mono- and bis-allylated isoxazolidines 9a and 9b were selectively obtained by 1,2-addition using different amounts of an allyl Grignard reagent to isoxazoline 5a; both 9a and 9b were obtained diastereoselectively in acceptable yields (Fig. 2e, 58 and 51% yield, respectively). These results clearly demonstrate that our approach facilitates the creation of structurally diverse and complex heterocyclic compounds.

As previously discussed, the flattened fenestrane quaternary carbon center, which is shared by four rings, has garnered much attention. The extent of flattening of such a quaternary carbon center can be evaluated from its two opposing angles (α and β in Fig. 3)4,5, these angles increase as the quaternary carbon center flattens. Keese et al. reported α and β values of 116.2°29 and 113.8°5 for c,c,c,c-[5.5.5.5]fenestrane (10) based on electron diffractometry and semi-empirical calculations, respectively (Fig. 3a). The flattest reported fenestranes 11 and 12 have significantly larger angles (Fig. 3b, α = 134.9°, β = 119.2°30; Fig. 3c, α = 129.2°, β = 128.3°31) than non-distorted quaternary carbon (109.5°, Fig. 3d).

Fig. 3: Fenestrane structures.
figure 3

Opposing angles: a in c,c,c,c-[5.5.5.5]fenestrane 10, b, c in the flattest previously synthesized fenestrane 11 and 12, and d for a non-distorted quaternary carbon center. e–g Experimentally determined and calculated opposing angles in c,c,c,c-[5.5.5.5]fenestrane 2a containing isoxazolidine rings, c,c,c,c-[5.5.5.6]fenestrane 2r containing isoxazolidine rings, and c,c-[5.5.5.5]fenestrane 5a containing isoxazoline rings.

Full size image

The racemic [5.5.5.5]- and [5.5.5.6]fenestranes 2a and 2r, respectively, containing isoxazolidine rings and the [5.5.5.5]fenestrane 5a containing isoxazoline rings were analyzed using X-ray crystallography, which revealed α and β values consistent with those of the most stable conformers determined by DFT at the B3LYP32/6-31 G + (d,p)33,34,35,36 level of theory (Fig. 3e–g). A comparison of the quaternary-carbon angles in fenestrane 10 with those in diaza-dioxa-fenestrane 2a (Fig. 3a, e) reveals that replacing the carbon atoms at the non-bridgehead positions in the fenestrane skeleton with nitrogen and oxygen atoms results in slight flattening of the quaternary carbon center. A comparison of the angles in [5.5.5.5]diaza-dioxa-fenestrane 2a with those in [5.5.5.6]diaza-dioxa-fenestrane 2r (Fig. 3e, f) reveals that ring expansion reduces the degree of flattening of the quaternary carbon center, which is consistent with the previously reported tendency5. In addition, a comparison of the angles in [5.5.5.5]fenestrane 2a containing isoxazolidine rings with those in [5.5.5.5]fenestrane 5a containing isoxazoline rings (Fig. 3g) reveals that the introduction of double bonds at the bridgehead positions results in flattening of the quaternary carbon center, which is also consistent with the previously reported tendency5. However, the observed angles in 5a (Fig. 3g, α = 134.7°, β = 114.9°) are very large and comparable to those of fenestrane 11 and 12, which are among the flattest fenestranes known (Fig. 3b, c). Compound 5a contains the flattest quaternary carbon center among heteroatom-containing fenestranes discovered thus far.

We performed a conformation search for fenestranes 2b and 5a. To reduce the calculation cost, fenestrane 2b with methyl groups was used instead of 2a with benzyl groups. The four most stable conformers 1–4 of 2b and the two most stable conformers 1 and 2 of 5a are shown with relative energy levels and α and β values in Supplementary Table 9 of the Supplementary Information. The chemical structure of 2a experimentally observed via X-ray crystallographic analysis (α = 117.4°, β = 117.0°) was consistent with the calculated most stable conformer 1 of 2b (α = 117.6°, β = 116.8°). Although the conformers 2–4 of 2b with more flattened quaternary carbon centers were found in the conformation search (Supplementary Table 9), they were less stable. Only two conformers with almost consistent α and β values and similar structures were found in the case of 5a. These results indicated that the compound 5a has a very rigid structure.

Discussion

In this study, all-cis-fused diastereomers (c,c,c,c-[5.5.5.5]fenestrane 2 containing isoxazolidine rings and c,c-[5.5.5.5]fenestrane 5 containing isoxazoline rings) were obtained exclusively. No generation of trans-fused fenestranes was observed in the NMR analysis of crude products, for the syntheses of both 2 and 5. DFT calculation at the B3LYP36/6-31 G + (d,p)33,34,35,36 level of theory was performed to elucidate the mechanism of the sequential (3 + 2) cycloadditions on the basis of the report of Nguyen et al.37. Alkyl substituents were replaced with methyl groups to reduce the calculation cost.

Fig. 4: DFT calculation for (3 + 2) cycloadditions.
figure 4

a DFT calculation for the first (3 + 2) cycloaddition. SME: nitrone substrate with the E-configuration, SMZ: nitrone substrate with the Z-configuration, TSE,exo: transition state of exo-cyclization of SME, TSE,endo: transition state of endo-cyclization of SME, TSZ,exo: transition state of exo-cyclization of SMZ, TSZ,endo: transition state of endo-cyclization of SMZ. IMcis: bicyclic intermediate for the all-cis-fused diastereomer of the fenestrane. IMtrans: bicyclic intermediate for the trans-fused diastereomer of the fenestrane. b DFT calculation for the second (3 + 2) cycloaddition. IME: nitrone intermediate with the E-configuration, IMZ: nitrone intermediate with the Z-configuration, TSE,exo: transition state of exo-cyclization of IME, TSE,endo: transition state of endo-cyclization of IME, TSZ,exo: transition state of exo-cyclization of IMZ, TSZ,endo: transition state of endo-cyclization of IMZ. TMtrans: trans-fused diastereomer of the fenestrane. TMcis: all-cis-fused diastereomer of the fenestrane. aNeither the energy barrier for tautomerizations between SME and SMZ nor IME and IMZ were calculated.

Full size image

We performed a DFT calculation of the sequential cycloaddition affording 2 (Fig. 4). The calculation results for the first (3 + 2) cycloaddition of the nitrone precursors with the E-configuration (SME) and Z-configuration (SMZ) affording IMcis (intermediate for the all-cis-fused diastereomer of the fenestrane) and IMtrans (intermediate for the trans-fused diastereomer of the fenestrane) are shown in Fig. 4a. The comparison of four pathways (exo- and endo-cyclizations of SME and SMZ substrates) suggested that the exo-cyclization of SME via the transition state TSE,exo is the most energetically favored pathway affording IMcis. The suggested most energetically favored pathway affording IMtrans is endo-cyclization of SME via the transition state TSE,endo. The calculated activation energy difference is 1.5 kcal/mol, and the TSE,exo leading to IMcis is energetically favored over TSE,endo leading to IMtrans. As expected, the two orthogonal p-orbitals of the allene appear to facilitate the approach of reaction sites in TSE,exo. IMcis appears to have a similar energy level to IMtrans.

The calculation results for the second (3 + 2) cycloaddition of the nitrone intermediates with the E-configuration (IME) and Z-configuration (IMZ) affording TMcis (experimentally obtained all-cis-fused diastereomer) and TMtrans (experimentally not obtained trans-fused diastereomer) are shown in Fig. 4b. The comparison of four pathways (exo- and endo-cyclizations of IME and IMZ intermediates) again suggests that the exo-cyclization of IME via the transition state TSE,exo is the most energetically favored pathway affording TMcis. In addition, the endo-cyclization of IMZ via the transition state TSZ,endo was also suggested as the energetically plausible pathway in the case of second cycloaddition because the calculated activation energy difference between TSE,exo and TSZ,endo was 0.7 kcal/mol. The most energetically favored pathway affording TMtrans was again suggested to be endo-cyclization of IME via the transition state TSE,endo. The calculated activation energy difference between TSE,exo and TSE,endo was 7.2 kcal/mol, and the TSE,exo affording TMcis was energetically favored over TSE,endo affording TMtrans. Moreover, TMcis was significantly more stable than TMtrans. These results explain the reason for obtaining only the all-cis diastereomer TMcis.

We could not calculate transition states affording a trans-fused diastereomer in the case of (3 + 2) cycloaddition of the nitrile oxide precursor, because of the highly strained structure. The calculated pathway affording the all-cis-fused diastereomer of the fenestrane 5a is presented in Supplementary Table 10 in the Supplementary Information.

We developed a one-step sequential (3 + 2) cycloaddition approach for the synthesis of diaza-dioxa-fenestranes that uses structurally simple, readily synthesizable, nonbranched acyclic allenyl precursors that facilitate sequential cycloaddition reactions. Twenty-two structurally diverse, heteroatom-containing, and variously substituted fenestranes, 2 and 5, with rings of different sizes, were successfully prepared. In addition, 2a, 2g, and 5a were further structurally modified to afford more-functionalized derivatives 7a–7d, and 9a–9b. Spiro[4.4]nonane 8, which was densely functionalized by two amino groups and two hydroxy groups at the neopentyl positions, was obtained as a single diastereomer from reductive cleavage of N-O bonds of 2a. The prepared diaza-dioxa-fenestranes 2a, 2r, and 5a were analyzed by X-ray crystallography and DFT calculations. Experimentally determined angles α and β were found to be consistent with those calculated using DFT. Our results indicate that replacing the carbon atoms at the non-bridgehead positions in the fenestrane skeleton with nitrogen and oxygen atoms slightly flattens the quaternary carbon center. In addition, we experimentally confirmed that ring expansion reduces the degree of flattening, whereas the introduction of double bonds at the bridgehead positions of a fenestrane increases the degree of flattening. Moreover, the synthesized c,c-[5.5.5.5]fenestrane 5a containing isoxazoline rings exhibited the flattest quaternary carbon center among previously synthesized heteroatom-containing fenestrane versions. This synthetic approach is expected to drive the development of structurally diverse and unique heteroatom-containing fenestranes, and the observed effects of chemical modification on the flattening of the quaternary carbon centers are expected to contribute to our further understanding of frustrated and flattened carbon centers.

Methods

General procedure for cycloaddition via nitrone

Method A: Et3N (86.6 µL, 0.625 mmol, 2.50 equiv.) and hydroxylamine hydrochloride (0.625 mmol, 2.50 equiv.) were added to a stirred solution of allene bisaldehyde 1 (0.250 mmol, 1.00 equiv.) in TCE (50.0 mL) at room temperature under argon. The mixture was stirred at 110 °C for 2 h, cooled to room temperature, and then quenched with water. The aqueous layer was extracted with CH2Cl2 (3×) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography or preparative TLC to give the corresponding fenestrane 2.

Method B: Hydroxylamine (0.625 mmol, 2.50 equiv.) was added to a stirred solution of allene bisaldehyde 1 (0.250 mmol, 1.00 equiv.) in TCE (50.0 mL) at room temperature under argon. The mixture was stirred at 110 °C for 2 h, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to afford fenestrane 2.

General procedure for cycloaddition reactions involving nitrile oxides

Aqueous NaOCl (12 wt% 1.55 mL, 2.50 mmol, 10.0 equiv.) and Et3N (347 µL, 2.50 mmol, 10.0 equiv.) were added to a stirred solution of bisoxime 4 (0.250 mmol, 1.00 equiv.) in DCE (50.0 mL) at room temperature under argon. The mixture was stirred at 80 °C for 13 h, cooled to room temperature, and subsequently diluted with water. The aqueous layer was extracted with CH2Cl2 (3×), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by using silica-gel column chromatography to afford fenestrane 5.