Recent advances in the total synthesis of cyclobutane-containing natural products

Takao K., Kai H., Yamada A., Fukushima Y., Komatsu D., Ogura A., Yoshida K.

The short, efficient total synthesis of (+)-aquatolide was achieved by a biomimetic transannular [2+2] photocycloaddition, and provides the first example of constructing a 5/5/4/8-ring system from asteriscunolides. Furthermore, the reaction leading to a 5/4/4/7-ring system, the originally proposed structure of aquatolide, was also developed. This strategy achieved syntheses of five more humulanolides, (-)-asteriscunolides A, C, D, and I, and (+)-tetradehydroasteriscanolide.

Mogi Y., Inanaga K., Tokuyama H., Ihara M., Yamaoka Y., Yamada K., Takasu K.

A multicomponent domino reaction involving three mechanistically distinct Tf2NH-catalyzed reactions was developed. The reaction cascade enables the assembly of a skewed 5/6/4 tricyclic motif with migration of the reactive site with the assistance of a catalyst. The tricyclic product was used to achieve the first total synthesis of cytotoxic paesslerin A by regioselective C-H insertion of the sulfonyl carbenoid and base-promoted olefin isomerization. Our results led to the revision of the originally proposed tricyclic structure of paesslerin A.

Zhao N., Xie S., Tian P., Tong R., Ning C., Xu J.

Here we describe the full account of the total synthesis of (+)-astellatol, as well as the first total synthesis of (−)-astellatene.

Hancock E., Wahl J.M., Brown M.K.

gem-Dimethylcyclobutanes are a common motif found in a multitude of natural products, and thus these structures have captivated synthetic chemists for years.

Hart J.D., Burchill L., Day A.J., Newton C.G., Sumby C.J., Huang D.M., George J.H.

Total syntheses of nyingchinoids A and B were achieved through successive rearrangements of a 1,2-dioxane intermediate that was assembled using a visible-light photoredox-catalysed aerobic [2+2+2] cycloaddition. Nyingchinoid D was synthesised through a competing [2+2] cycloaddition. Based on NMR data and biosynthetic speculation, a revised structure of the related natural product rasumatranin D was proposed, which was confirmed through total synthesis.

Didier D., Baumann A.N., Eisold M.

The ubiquity of strained motifs in drug discovery has recently witnessed a large regain of interest, as such scaffold can be used to modulate the properties of drug candidates. Unsaturated N-containing four-membered heterocycles present unique opportunities to access functionalized azetidines, which play an essential role in pharmacological studies. Even though those unsaturated patterns have been much less reported than the corresponding saturated versions, the consequent impact that those structures could have on molecular design with implementation of strained modules deserves to be summarized. In this review, synthetic accesses to substituted azetes, 1-azetines and 2-azetines are depicted, as well as their involvement in further transformations.

Ferrer S., Echavarren A.M.

The first total synthesis of repraesentin F has been accomplished by a highly diastereoselective gold(I)-catalyzed cyclization cascade as the key step. This cycloisomerization/Prins-type tandem transformation enabled direct access to the atypical tricyclic carbon skeleton of the natural product with the required syn/ anti/ syn ring fusion. This synthetic effort also allowed reassignment of the relative configuration of repraesentin F and determination of its absolute configuration.

Wu W., Lin Z., Jiang H.

Cyclopropanes have gained much attention by virtue of their interesting structure and unique reactivity. This review discusses the recent advances in the synthesis of cyclopropanes, and some of the related applications will be discussed.

Gao M., Wang Y., Yang K., He W., Yang X., Yao Z.

The first and enantioselective total synthesis of (+)-plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring-formation protocol was adopted to generate the characteristic tricycle[4.3.1.01,5 ]decane and trans-fused dihyrdopyran moiety. Scalable enantioselective LaIII -catalyzed Michael reaction, palladium(0)-catalyzed carbonylation and SmI2 -mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D-ring system having six continuous stereogenic centers and two all-carbon quaternary centers. The trans-fused dihyrdopyran moiety with an exo side-chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)-plumisclerin A.

Duchemin N., Skiredj A., Mansot J., Leblanc K., Vasseur J., Beniddir M.A., Evanno L., Poupon E., Smietana M., Arseniyadis S.

Biosynthetic considerations inspired us to harness the templating properties offered by DNA to promote a [2+2] photoinduced cycloaddition. The method was developed based on the dimerization of (E)-aplysinopsin, which was previously shown to be unproductive in solution. In sharp contrast, exposure of this tryptophan-derived olefin to light in the presence of salmon testes DNA (st-DNA) reproducibly afforded the corresponding homo-dimerized spiro-fused cyclobutane in excellent yields. DNA provides unique templating interactions enabling a singular mimic of the solid-state aggregation necessary for the [2+2] photocycloaddition to occur. This method was ultimately used to promote the prerequisite dimerizations leading to both dictazole B and tubastrindole B, thus constituting the first example of a DNA-mediated transformation to be applied to the total synthesis of a natural product.

Moss F.R., Shuken S.R., Mercer J.A., Cohen C.M., Weiss T.M., Boxer S.G., Burns N.Z.

Significance Ladderane lipids represent exotic natural products containing highly strained, concatenated cyclobutane rings, a motif that has not been found in any other natural products. These lipids are exclusively found in bacteria that carry out anaerobic ammonium oxidation (anammox), suggesting a biological role in the anammox process. The relationship between molecular structure and this metabolism remains unexplored due to a lack of natural lipid material to study. We use an efficient chemical synthesis to create large quantities of pure ladderane lipids for biophysical analysis. This analysis reveals some unusual properties of membranes composed of ladderane lipids. Significantly, ladderane membranes have low proton permeability, which would slow the breakdown of the proton gradient used to synthesize ATP during the slow anammox metabolism.

Huang G., Hu Z., Lei C., Wang P., Yang J., Li J., Li J., Hou A.

Eight enantiomeric pairs of new meromonoterpenoids (1a/1b-8a/8b) and four known compounds (9-12) were isolated from Rhododendron nyingchiense. Their structures were established by spectroscopic methods, quantum chemical calculations, and X-ray crystallography. The enantiomeric pairs were acquired from scalemic mixtures by chiral-phase HPLC and showed diverse heterocyclic frameworks. Compounds 1a/1b possess a rare 6/7/5/5 heterocyclic system, and 2a/2b incorporate a new 6/6/3/5 heterocyclic system featuring a quinone motif. Compounds 3a/3b represent the first meroterpenoids with a 6/6/5 ring system from the Rhododendron genus. Putative biosynthetic pathways of these compounds are proposed. Compounds 1b, 2a-4a, 8a, 8b, and 11 exhibited weak inhibitory effects on PTP1B, with IC50 values ranging from 5.7 ± 0.5 to 61.0 ± 4.8 μM.

Liu J., Wu J., Fan J., Yan X., Mei G., Li C.

The first and asymmetric total synthesis of cyclocitrinol, an unusual C25 steroid, has been accomplished in a linear sequence of 18 steps from commercially available compound 11. The synthetically challenging bicyclo[4.4.1] A/B ring system with a strained bridgehead (anti-Bredt) double bond of cyclocitrinol was constructed efficiently and diastereoselectively via a type II intramolecular [5 + 2] cycloaddition.

Zhao N., Yin S., Xie S., Yan H., Ren P., Chen G., Chen F., Xu J.

A nearly-30-year-old unanswered synthetic puzzle, astellatol, has been solved in an enantiospecific manner. The highly congested pentacyclic skeleton of this rare sesterterpenoid, which possesses a unique bicyclo[4.1.1]octane motif, ten stereocenters, a cyclobutane that contains two quaternary centers, an exo-methylene group, and a sterically encumbered isopropyl trans-hydrindane motif, makes astellatol arguably one of the most challenging targets for sesterterpenoid synthesis. An intramolecular Pauson-Khand reaction was exploited to construct the right-hand side scaffold of this sesterterpenoid. An unprecedented reductive radical 1,6-addition, mediated by SmI2 , forged the cyclobutane motif. Last, a strategic oxidation/reduction step provided not only the decisive solution for the remarkably challenging late-stage transformations, but also a highly valuable unravelling of the notorious issue of trans-hydrindane synthesis. Importantly, the synthesis of astellatol showcases a rapid, scalable strategy to access diverse complex isopropyl trans-hydrindane sesterterpenoids.

Li Q., Zhao K., Peuronen A., Rissanen K., Enders D., Tang Y.

The Plakortin polyketides represent a structurally and biologically fascinating class of marine natural products. Herein, we report a unified strategy that enables the divergent syntheses of various Plakortin polyketides with high step-economy and overall efficiency. As proof-of-concept cases, the enantioselective total syntheses of (+)-hippolachnin A, (+)-gracilioether A, (-)-gracilioether E, and (-)-gracilioether F have been accomplished based on a series of bio-inspired, rationally designed, or serendipitously discovered transformations, which include (1) an organocatalytic asymmetric 1,4-conjugate addition to assemble the common chiral γ-butenolide intermediate enroute to all of the aforementioned targets, (2) a challenging biomimetic [2+2] photocycloaddition to forge the oxacyclobutapentalene core of (+)-hippolachnin A, (3) a [2+2] photocycloaddition followed by one-pot oxidative cleavage of methyl ether/Baeyer-Villiger rearrangement to access (-)-gracilioether F, and (4) an unprecedented hydrogen-atom-transfer-triggered oxygenation of vinylcyclobutane to afford (+)-gracilioether A and (-)-gracilioether E in one pot.

Maity S., Samanta A., Debnath S., Maity S.

AbstractDifunctionalization of olefins serves as the workhorse for rapid creation of molecular complexity from simple feedstocks. However, these reactions are mostly restricted to the 1,2‐variant, with higher homologations being attempted to a much lesser extent. Radical translocation strategies serve as an escape from the traditional 1,2‐strategies, providing a means for achieving distant functionalizations that are otherwise difficult to access. Herein, we disclose visible light‐mediated strategies for the accessing of 1,3‐, 1,4‐, 1,5‐, and 1,6‐aminophosphonates via combination of various radical shifting methods. In addition, the aminophosphorylation of σ‐bonds was also achieved, leading to 1,3‐aminophosphorylated cyclobutanes.

Wei H., Zhang Y., Wang N., Fu R., Chen K., Hao W., Jiang B.

Rosca D.A., Hertwig L.E., Becker F.J.

AbstractThe [2+2]‐cycloaddition of olefins and alkynes stands out as a versatile and atom‐economical strategy for synthesizing cyclobutane and cyclobutene building blocks, which are challenging to access through other synthetic methods. While photochemical approaches have traditionally dominated this field, thermally‐driven methods employing transition metals offer distinct advantages, including decreased reliance on pre‐functionalized substrates and improved scalability. This review explores the underlying principles of metal‐catalyzed [2+2]‐cycloadditions and highlights recent advances in thermally‐driven approaches for the efficient synthesis of cyclobutane and cyclobutene frameworks. Particular attention is given to electronically unbiased substrates, which remain a significant challenge for photochemical approaches.

Xu S., Zhou Y., Zheng H., Zhu G.

AbstractThe 4‐exo‐trig radical cyclization represents a formidable challenge owing to the unfavorable thermodynamics associated with the formation of highly strained four‐membered rings. Stimulated by the explosive advancements of radical chemistry over the past decades, significant progresses have been made in this area, including the SmI2‐mediated 4‐exo‐trig carbonyl‐alkene cyclization, n‐Bu3SnH‐mediated 4‐exo cyclization of functionalized alkenes or alkynes, transition metal‐catalyzed 4‐exo‐trig ring closures, and visible light‐induced 4‐exo‐trig cyclization cascade, providing efficient protocols to overcome the inherent limitations and expand the synthetic utility of this methodology. Representative examples, reaction mechanism, scope and limitations, and synthetic applications are presented and discussed in detail. We believe that the systematic review of recent advances on 4‐exo‐trig radical cyclization will provide more insights in this field, and may enable further development of this cyclization process for the concise synthesis of four‐membered carbo‐ and heterocycles that are difficult to access via traditional methods.

Han Z., Wang L., Luo Y., Cui X.

An efficient and environmentally benign strategy for the synthesis of three-dimensional semi-saturated rings – cyclobutane-fused indolines via photocatalytic intermolecular [2 + 2] cycloaddition/dearomatization reaction.

Liu Y., Gu X., Zhao Y., Wu X.

Bai P., Hu Y., Gu Y., Zhou M., Xu X., Xie Y.

Vela Benavides F., Kirić M., Escobar-Montaño F., Macías-Sánchez A.J., Bolivar-Anillo H., Botubol-Ares J.M., Durán-Patrón R., Hernández-Galán R.

Martynova E.A., Voloshkin V.V., Villa M., Fiorentino A., Beliš M., Hecke K.V., Ceroni P., Nolan S.P.

Kim T., Jeong T., Chung E., Singh P., Rakshit A., Park J., Kim I.S.

Chen P., Dong M., Han C., Li D., Hong Y., Xue F., Liu F., Deng H.

Chen F., Duan Y., Guo Y., Liu Y., Lang M., Peng J., Peng S.

An unexpected In(OTf)3-catalyzed cascade reaction of bicyclo[1.1.0]butanes with triazinanes is reported, providing a series of butterfly-shaped biscyclobutenyl amines in good yields. This reaction features simple operation, mild reaction conditions, and...

Zhang F., Dutta S., Petti A., Rana D., Daniliuc C.G., Glorius F.

Bicyclo[1.1.0]butanes (BCBs) have recently garnered significant research interest as versatile precursors for synthesizing potential [n.1.1] bioisosteres and multi‐functionalized cyclobutanes in a straightforward and atom‐economical manner. Here, we report a solvent‐dependent divergent cyclization of BCBs that providecs highly diastereospecific decorated cyclobutanes and oxygen‐containing bicyclo[3.1.1]heptanes (BCHeps), which serve as bioisosteres of meta‐substituted arenes. This novel strategy employs precision‐oriented control to achieve the desired divergence. Additionally, an unprecedented 1,2‐difunctionalization reaction mode for BCBs was explore, expanding the available methods for efficiently exploring the chemical space of arene bioisosteres and highly functionalized cyclobutanes.

Zhang F., Dutta S., Petti A., Rana D., Daniliuc C.G., Glorius F.

Bicyclo[1.1.0]butanes (BCBs) have recently garnered significant research interest as versatile precursors for synthesizing potential [n.1.1] bioisosteres and multi‐functionalized cyclobutanes in a straightforward and atom‐economical manner. Here, we report a solvent‐dependent divergent cyclization of BCBs that providecs highly diastereospecific decorated cyclobutanes and oxygen‐containing bicyclo[3.1.1]heptanes (BCHeps), which serve as bioisosteres of meta‐substituted arenes. This novel strategy employs precision‐oriented control to achieve the desired divergence. Additionally, an unprecedented 1,2‐difunctionalization reaction mode for BCBs was explore, expanding the available methods for efficiently exploring the chemical space of arene bioisosteres and highly functionalized cyclobutanes.

Liu H., Fu Z., Li X., Yu S.

Transition-metal-free radical remote difunctionalization of bicyclo[1.1.1]butane skeletons in both two- and three-component fashions is presented.