腿有淤青是什么原因

Introduction

Bipolarolides A and B¹ and bipoladien B^2,3 (Figure?1a), which were first isolated from Bipolaris sp. TJ403-B1 in 2019 and Bipolaris maydis in 2024, respectively, are architecturally characterized by a unique polycyclic clathrate [9.3.0.0^1,6.0^5,9.1^8,12] oxapentadecane system. Biogenetically, this class of complex, cage-like sesterterpenoids is derived from geranylfarnesyl pyrophosphate via a series of enzymatic transformations, in which a plausible biosynthetic conversion of a putative ophiobolin-related 5/8/5-fused tricyclic skeleton into a 5/6/5/6-fused tetracyclic carbon skeleton through a Prins-type cyclization (carbonyl-ene cyclization) has been proposed.¹ Stimulated by the above putative biosynthetic pathway, an elegant first synthesis of bipolarolides A and B has been reported by Jia, wherein a bioinspired vinylogous Prins cascade cyclization was utilized as a key step to install the pentacyclic core skeleton.⁴ Given the structural significance and biological potential of these caged polycyclic sesterterpenoids, developing new strategies for their chemical synthesis remains highly appealing to the synthetic community. To address this issue, bipolarolide B and bipoladien B (Figure?1a) have been selected as targets for synthetic studies in this context.

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As was known, bridgehead enones, particularly those with distortional strain, have long been a significant topic in organic chemistry,⁵ wherein the electronic density distribution and non-coplanar distortion of the π-system endow them with increased electrophilic reactivity, which might chemically differ from that of the bridgehead alkenes.^6–9 Generally, the structural types of bicyclic [m.n.1] bridgehead enones can be divided into four categories (type-1 to type-4, Figure?1c).¹⁰ Among these, type-1 bridgehead enones have garnered considerable attention due to their inherent potential for incorporating a carbon or heteroatom-quaternary center at the bridgehead position via conjugate addition and (formal) cycloaddition in organic synthesis, and early pioneering efforts in the synthesis and reactions of type-1 bridgehead enones have been made by Marchesini,^11–13 House,^14–23 Bestmann,²⁴ Kraus,^25–32 and Paquette.^33–36 Notably, despite significant focus on the methodology development and physical organic chemistry of bridgehead enones, there has been limited progress in their strategic application to the total synthesis of natural products.^5,37–43 To our knowledge, key examples include the total syntheses of kopsane indole alkaloids by Magnus in 1984,³⁷Lycopodium alkaloids by Kraus in 1985^38,39 and our group in 2017,⁴⁰ C18-norditerpenoid alkaloid by Gin in 2013,⁴¹ and ent-kaurane diterpenoids by Ma’s group in 2019⁴² and 2025.⁴³

Driven by our interest in the bridgehead enone chemistry and its application in natural product synthesis,^40,44–47 as shown in the two-dimensional view ( I) of the core skeleton of bipolarolide B and bipoladien B (Figure?1b), the structural assembly of their complex pentacyclic framework, comprising an A/B/C/D/E ring system, can be topologically inspired by the bicyclic [m.n.1] subunit featuring a bridgehead all-carbon quaternary center ( II), which might be strategically realized through the late-stage conjugate addition of type-1 bridgehead enone building blocks III. Noteworthy is that compared to the transiently existed, unstable type-1 [3.3.1] bridgehead enone IV (chair conformer) having average twisting deformation angle of 25° and strain energy of 20.8?kcal/mol (Figure?1d),²¹ the benchtop isolation of type-1 [4.3.1] bridgehead enone V with average twisting deformation angle of 14° and strain energy of 17.7?kcal/mol²¹ offers the feasibility for an intermolecular convergent late-stage multifunctionalization, especially in the case that in-situ trapping protocol could not be performed due to the incompatibility of functional groups.

Experimental Methods

Experimental procedures, Supporting Information Tables S1–3S3 and Figures S1–3S3, characterization of nuclear magnetic resonance (NMR) spectra for all synthetic compounds, comparison of the synthetic natural products with isolated samples, and copies of NMR spectra are available in the Supporting Information.

All moisture or oxygen-sensitive reactions were carried out under an argon atmosphere in oven flasks. The solvents used were purified by distillation over the drying agents indicated and were transferred under argon: tetrahydrofuran (THF) (Na), CH₂Cl₂ (CaH₂), toluene (Na), and Et₃N (CaH₂). All reactions were monitored by thin-layer chromatography on silica gel GF₂₅₄ plates using UV light as a visualizing agent (if applicable), and a solution of phosphomolybdic acid (50?g/L) in EtOH followed by heating as developing agents. The products were purified by flash column chromatography on silica gel (200–300?mesh) from the Anhui Liangchen silicon material company in China (Liuan, Anhui, China).

¹H NMR and ¹³C NMR spectra were recorded in CDCl₃ or CD₃OD solution on a Bruker AM 400?MHz instrument or Bruker AVANCE NEO 600?MHz instrument (Bruker Biospin GmbH, Rheinstetten, Germany). Chemical shifts were denoted in ppm (δ) and calibrated by using residual undeuterated solvent [CHCl₃ (7.26?ppm), CD₂HOD (3.31?ppm), and tetramethylsilane (0.00?ppm)] as an internal reference for ¹H NMR and the deuterated solvent [CDCl₃ (77.00?ppm) and CD₃OD (49.00?ppm)] as an internal standard for ¹³C NMR. The following abbreviations were used to explain the multiplicities: s?=?singlet, d?=?doublet, t?=?triplet, q?=?quartet, br?=?broad, td?=?triple doublet, dt?=?double triplet, and m?=?multiplet. The high-resolution mass spectral analysis data were measured on a Thermo Scientific Orbitrap Exploris 120 Mass Spectrometer (Thermo Fisher Scientific GmbH, Bremen, Germany) by means of the electrospray ionization technique. The infrared spectra were recorded on a Nicolet Nexus 670 FT-IR spectrometer (Bruker Optics GmbH & Co. KG, Ettlingen, Germany). The X-ray single-crystal determination was performed on an Agilent SuperNova single crystal X-ray diffractometer (Agilent Technologies Japan, Ltd., Tokyo, Japan) . The melting points were measured on an X-4 microscopic melting point apparatus without calibration (BeijingTech Instrument Co. Ltd., Beijing, China).

Results and Discussion

Based on the structural inspiration of the bridgehead enone chemistry, the retrosynthetic analysis of bipolarolide B ( 1) and bipoladien B ( 2) is presented in Scheme?1. By leveraging the potential for late-stage functionalization of type-1 [4.3.1] bridgehead enone E, which could be formed via the direct oxidative dehydrogenation (desaturation) of ketone F, functionalized building blocks D, featuring the pivotal bridgehead all-carbon quaternary center, might be strategically envisioned through a late-stage conjugate addition. Logically, the conversion of the keto moiety in D to a trisubstituted alkene unit in C could be considered through functional group transformations. Chemically, the ring contraction from the [4.3.1] ring system of C to the [3.3.1] ring system of B might be tactically enabled to forge the ring D by the oxidative cleavage of the diol moiety in C, followed by intramolecular aldol condensation. The construction of ring C in A could be considered via intramolecular hydroacylation of B having the [3.3.1] subunit. The installation of ring E via intramolecular etherification and the introduction of the side chain via conjugate addition might be envisaged in A, which could be configured from the initial disconnective transform in natural sesterterpenoids, bipolarolide B ( 1) and bipoladien B ( 2). As the precursor of type-1 bridgehead enone E, the tricyclic synthon F might be accessed via Conia-ene-type cyclization of [4.3.1]-bicyclic synthon G, which could be assembled through inter-intramolecular allylation and propargylation of cyclohexanedione monoketal 3.

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According to the abovementioned retrosynthetic consideration, the synthesis of type-1 [4.3.1]-containing bridgehead enone synthon E (Scheme?1) was first pursued. As shown in Scheme?2, commencing with readily available 1,4-cyclohexanedione mono-ethylene ketal 3, inter-intramolecular allylation⁴⁸ of the resulting enamine with cis-1,4-dichloro-2-butene at 100?°C afforded the functionalized bicyclic [4.3.1] ketone 4 in 46% yield over two steps. Propargylation of 4 with propargyl bromide and Mg in the presence of a catalytic amount of HgCl₂^49,50 at ?78?°C gave homopropargylic alcohol 5 in 85% yield, in which its diastereo-control might mostly result from the chelating assistance of ethylene ketal moiety as a directing group. Following the hydroxy-directed diastereoselective dihydroxylation of 5 with catalytic potassium osmate(VI) dihydrate (K₂[OsO₂(OH)₄]) and stoichiometric 4-methylmorpholine N-oxide (NMO), the silylation of the resulting vicinal diols and the silyl enol etherification of keto moiety in the presence of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) delivered the TBS ether intermediate Enol-TBS- 5, which was then subjected to ZnBr₂-mediated Conia-ene-type cyclization^51–55 at 0?°C to obtain tricyclic ketone 6 in 51% yield over three steps. With the precursor 6 in hand, the synthesis of type-1 bridgehead enone was initially investigated through the classic Saegusa-Ito oxidation⁵⁶ consisting of TBSOTf-mediated enol silylation and subsequent stoichiometric Pd(OAc)₂-promoted α,β-dehydrogenation (desaturation), affording the desired type-1 [4.3.1]-containing bridgehead enone 7 in 43% yield (entry 1). In addition to this two-step protocol, a one-step catalytic variant of ketone desaturation by using a catalytic amount of Pd catalyst in the presence of allyl diethyl phosphate as a stoichiometric oxidant was also considered (entries 2–4).^57,58 Among them, the preliminary optimal conditions using 0.1?equiv of Pd(CF₃CO₂)₂ as catalyst, K₃PO₄ as additive, and (CH₂Cl)₂ as solvent at 105?°C (entry 4) could lead to the desired type-1 bridgehead enone 7 in 78% yield, and pleasingly a 30 gram scale reaction under the current optimized conditions underwent smoothly to give 7 in an isolated yield of 69%. Notably, an attempt to use non-metal-mediated one-step oxidative dehydrogenation of 6 was carried through by using o-iodoxybenzoic acid (IBX) in dimethyl sulfoxide (DMSO) at 60?°C (entry 5),^59–61 but negative results with decomposition were observed.

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The stereochemistry of products 4– 7 (Cambridge Crystallographic Data Centre, CCDC 2418385–2418388) was unambiguously assigned by their X-ray crystallographic analyses. Importantly, as depicted in the X-ray crystallographic structure [chart- 7(a)] and Newman’s projection along C2=C3 [chart- 7(b)] of type-1 [4.3.1]-containing bridgehead enone 7, the apparent distortion at bridgehead C3 position was observed, in which atoms C4 and C5 are away from the C1-C2=C3 plane, leading to a pyramidal configuration at C3 via rehybridization of sp². The average twisting deformation angle τ (deviation from coplanarity of the two p-type orbitals) is about 21.6°.¹⁰ Compared with the corresponding value calculated by House in type-1 [4.3.1] bridgehead enone V (τ?=?14°, Figure?1d),^10,21 the torsional angle of this substituted type-1 [4.3.1]-containing bridgehead enone 7 (τ?=?21.6°) chemically implies its increased bridgehead strain, which is consistent to the observed tendency of pyramidalization at C3 (out of plane bending χ₁?=?20.6°).¹⁰ Interestingly, this partial deconjugation also affects the length of the double bond, and the C2=C3 bond length of 1.344?? is virtually close to that of an isolated double bond (1.346?? in 2-butene),⁶² showing the distinctive character of such a bridgehead enone system.

As shown in Scheme?3, with type-1 [4.3.1]-containing bridgehead enone 7 in hand, the elaboration of a crucial all-carbon quaternary center at the bridgehead position was then examined. Surprisingly, an unusual conjugate addition⁶³ of 7 with 3,3-dimethoxypropyl lithium as a hard organometallic nucleophile, in situ prepared from lithium-bromo exchange reaction of 3,3-dimethoxypropyl bromide with t-BuLi, was achieved to deliver the desired product 8 in 46% yield, followed by subsequent diastereoselective one-pot methylation of the lithium enolate resulting from the above conjugate addition. The relative configuration of 8 (CCDC 2418389) was clearly confirmed by its X-ray crystallographic analysis. Notably, the current unusual conjugate addition of a hard organolithium reagent to the enone system might be mostly attributed to the steric shielding of the keto carbonyl antibonding π* orbital in such a tricyclic ring-fused bridgehead enone 7 (For details, see Supporting Information page S13), offering the highly regioselective bridgehead functionalization. To introduce the trisubstituted alkene moiety in 10, a two-step protocol involving ketone reduction and hydroxyl elimination was adopted, wherein lithium tri-sec-butylborohydride (l-selectride) mediated keto-reduction of 8 in ?78?°C gave alcohol 9 (CCDC 2418390) with high diastereoselectivity in 87% yield, and then Martin’s sulfurane promoted OH-elimination⁶⁴ followed by desilylation with the tetra-n-butylammonium fluoride (TBAF) afforded alkene 10 in 89% yield. Subsequently, the ring contraction and related functional group transformations from [4.3.1] system in 10 to [3.3.1] system in 11 were realized sequentially through the vicinal diol oxidative cleavage by NaIO₄, intramolecular regioselective aldol condensation with piperidine (For details, see Supporting Information Figure S3),⁶⁵ Luche reduction by NaBH₄/CeCl₃?7H₂O, and allylic alcohol silylation with tert-butyl(chloro)diphenylsilane (TBDPS-Cl), giving functionalized 11 in 52% yield over four steps. After establishing an A/D ring system and bridgehead all-carbon quaternary center in 11, to avoid the competitive hemiacetalization of C5-OH with the aldehyde group later regenerated from C12-deacetalization, further protection of the tertiary hydroxy group in 11 by treating with lithium bis(trimethylsilyl)amide (Li-HMDS) and ClCO₂Me from ?78?°C to ?40?°C was carried out to afford the carbonate ester 12 in 97% yield.

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As shown in Scheme?4, after pyridinium p-toluenesulfonate (PPTS)-catalyzed hydrolysis of the acetal group in 12 gave aldehyde 13b in 96% yield, the hydroacylation of 13b was straightforwardly investigated in the presence of t-C₁₂H₂₅SH and 1,1′-azobis(cyanocyclohexane) (V-40) at 115?°C.^66,67 Accompanied by the formation of C11–C12 via acyl radical-mediated 5-exo-trig cyclization, to our surprise, a radical-based Wagner–Meerwein-type rearrangement^68–70 of C3 from C2 to C1 occurred smoothly through an initial C1–C3 bond forming 3-exo-trig cyclization and a subsequent C2–C3 bond cleaving fragmentation in Int-1, leading to an unexpected 6/6/6/5 tetracyclic compound 14b in 61% yield by following subsequent desilylation with TBAF and stepwise deacylation with aqueous NaOH. The structure of 14b (CCDC 2418391) was eventually determined by its X-ray crystallographic analysis. To interrupt such an undesired participation of terminal C3=C20 alkene motif after intramolecular radical-mediated hydroacylation (Scheme?4), as presented in Scheme?3, diastereoselective hydroxymercuration-demercuration⁷¹ of 12 followed by acetal hydrolysis was preferentially conducted to furnish hydroxyl aldehyde 13a in 67% yield over two steps. Gratifyingly, the construction of ring C was readily accessed through the abovementioned radical-mediated hydroacylation of 13a, providing the expected 6/6/5/5 tetracyclic product 14a in 63% yield.

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To facilitate the introduction of the side chain, α,β-dehydrogenation of 14a (Scheme?3) was first performed through seleninylation/thermal elimination with (PhSeO)₂O,⁷² followed by carbonate ester hydrolysis with aqueous NaOH, giving disubstituted enone 15 in 41% yield over two steps. Subsequently, enone 15 was subjected to conjugate addition of (6-methylhept-5-en-2-yl)magnesium bromide/CuI with LiCl as an additive in the presence of Me₃SiCl (TMSCl),^73,74 furnishing less polar 16β in 58% yield together with a separable more polar C15-epimer 16α in 36% yield. Then, Saegusa-Ito-type oxidation of TMS enol ether 16β was adopted by using stoichiometric Pd(OAc)₂ in the presence of oxygen and K₂HPO₄ in DMSO at 100?°C,⁷⁵ affording less polar trisubstituted enone 17β-1 in 43% yield and more separable polar ketone 17β-2 in 37% yield. Following the above construction of the A/D/C ring system as well as the introduction of 6-methylhept-5-en-2-yl side chain in 17β-1, further elaboration of ring E was then explored. Initially, direct reduction of enone 17β-1 with β-oriented C15-H was first examined by using Red-Al (NaAlH₂(OCH₂CH₂OCH₃)₂) at room temperature,⁷⁶ but unexpectedly, ketone 17β-2 instead of allylic alcohol 18β was isolated in 62% yield, wherein 1,4-conjugate reduction of α,β-unsaturated ketone was observed predominantly. In addition, attempts to use various reductants (e.g., NaBH₄/CeCl₃?7H₂O, LiAlH₄, AlH₃, DIBAL-H, LiBHEt₃, BH₃?THF, KBH₄, and Et₂AlCl/i-PrOH)^a were also evaluated; however, the desired 1,2-reduction resulting in the formation of 18β was not observed.

To understand this abnormal regioselectivity,^77–79 as demonstrated in Scheme?5, less separable polar enone 17α-1 with α-oriented C15-H group was additionally prepared in 40% yield through Pd(OAc)₂-mediated Saegusa-Ito-type oxidation of TMS enol ether 16α. Upon treatment of enone 17α-1 with Red-Al at 50?°C, 1,2-reduction and TBDPS-deprotection were performed to give the expected allylic alcohol 18α in 63% yield, and its stereochemistry was confirmed by the X-ray crystallographic analysis (CCDC 2418392). Importantly, further analysis of the X-ray crystallographic structure of 18α could offer valuable insights into the current Red-Al-mediated reduction. The 1,2-reduction of 17α-1 (Scheme?5) is likely primarily due to the steric shielding effect of the β-oriented C15-methyl group, which blocks the hydride delivery from Red-Al to the C14 position, directed by the C5-OH. In contrast, the 1,4-reduction of 17β-1 (Scheme?3) likely arises from the unshielded environment of the β-orientated C15-H and the directing effect of the C5-hydroxy group, which chelates with Red-Al.

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In terms of this analysis, as depicted in Scheme?3, TMSOTf-mediated silylation of the C5-OH group in 17β-1 was preferentially adopted, and pleasingly, the subsequent Red-Al reduction delivered the desired 1,2-reduction product, allylic alcohol 18β, in 78% yield over two steps. Following the silyl deprotection of 18β by utilizing TBAF, the construction of ring E was readily achieved through protonated intermediate Int-2 in the presence of PPTS, and the intramolecular etherification product 19 was obtained in 88% yield over two steps. Then, a regioselective allylic oxidation of 19 with SeO₂/t-BuO₂H furnished bipolarolide B ( 1) in 79% yield.^80,81 Divergently, Swern oxidation of 19 with (COCl)₂/DMSO accomplished bipoladien B ( 2) for the first time in 65% yield.⁸²

Conclusion

In conclusion, chemically driven by the bridgehead enone chemistry, total synthesis of caged polycyclic sesterterpenoids, bipolarolide B ( 1) and bipoladien B ( 2), has been accomplished starting from readily available 1,4-cyclohexanedione monoketal 3. Significantly, benchtop-available type-1 [4.3.1]-containing bridgehead enone 7 assigned by X-ray crystallographic analysis has been unprecedentedly accessed via Pd(II)-catalyzed ketone dehydrogenation, which was not explored previously in the bridgehead enone system. On the basis of experimental flexibility, functionalized assembly of the pivotal bridgehead all-carbon quaternary center through an unusual conjugate addition of chromatographically isolable type-1 [4.3.1]-containing bridgehead enone 7 with organolithium reagent, we have developed a new synthetic strategy mainly featuring the Conia-ene-type cyclization for forging the five-membered all-carbon ring A, the diol cleavage/regioselective intramolecular aldol condensation for forging the six-membered all-carbon ring D, the intramolecular radical-based hydroacylation for forging the five-membered all-carbon ring C, and the intramolecular acid-mediated etherification for forging the six-membered hydropyran ring E. The present study not only enriches the chemical synthesis of ophiobolin-derived sesterterpenoids but also strategically manifests the potential of bridgehead enone chemistry in natural product synthesis.

Supporting Information

Supporting Information is available and includes additional experimental details, experimental procedures, spectroscopic data, NMR spectra, and X-ray data for compounds 4-9 (CCDC 2418385-2418390), 14b (CCDC 2418391), 18α (CCDC 2418392), and 17β-3 (CCDC 2418393) (PDF).

Conflict of Interest

There is no conflict of interest to report.

Funding Information

We are grateful for the financial support from the National Key R&D Program of China (grant no. 2023YFA1506400), the National Natural Science Foundation of China (grant nos. 22071091, 21825104, 22401124, and 22371101), the Science and Technology Major Program of Gansu Province of China (grant nos. 24ZD13FA017, 23ZDFA015, and 22ZD6FA006), and the 111 Project 2.0 (grant no. BP1221004).