Synthesis of Bridged Five-Membered Ring Systems by Type II [3 + 2] Annulation of Allenylsilane-ene PDF

pubs.acs.org/JACS Communication...

pubs.acs.org/JACS Communication Synthesis of Bridged Five-Membered Ring Systems by Type II [3 + 2] Annulation of Allenylsilane-ene Ling-Zi Li, Yu-Rou Huang, Zi-Xun Xu, Hong-Sen He, Hong-Wei Ran, Ke-Yu Zhu, Jing-Chun Han,* and Chuang-Chuang Li* Cite This: https://doi.org/10.1021/jacs.4c09384 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. Downloaded via INDIAN INST OF TECH ROPAR on September 7, 2024 at 20:40:44 (UTC). ABSTRACT: The first type II intramolecular [3 + 2] annulation of allenylsilane-ene has been achieved, enabling diastereoselective and efficient construction of synthetically challenging bridged five-membered ring systems such as bicyclo[3.2.1]. This mild and direct process shows a broad substrate scope and is highly stereospecific. Particularly, this work represents the first stereoselective method for the direct synthesis of bicyclo[3.2.1] ring systems from acyclic precursors. Additionally, the first asymmetric total syntheses of (+)- and (−)-strepsesquitriol, and the efficient formation of the synthetically challenging tetracyclic core of pierisjaponol D are achieved by this type II [3 + 2] annulation reaction. B ridged ring systems (Figure 1) are strained and widely found in natural products with important biological activities.1 For example, taxol contains a bridged six-membered membered ring systems directly (Scheme 1). Specifically, compound 1 with an allenylsilane linked to an enone moiety was designated as a practical cascade cyclization precursor. We ring system.2 Interestingly, camphor, longifolene, ent-kaurene, proposed that an intramolecular conjugate addition of the and ajmaline have bridged five-membered ring systems allenylsilane to the enone could occur when 1 was treated with (highlighted in red, Figure 1A). Type II intramolecular a Lewis acid (LA), giving intermediate A, in which the sp2 cycloaddition is an efficient strategy for the synthesis of carboncation is stabilized by β-silicon effect. Intermediate A bridged ring systems.3 Shea type II intramolecular Diels−Alder could go through a [1, 2]-silyl shift to generate intermediate B. cycloadditions (with a dienophile connected at the 2-position The enolate of B could undergo intramolecular SN2-type of the diene) are effective for producing bridged six-membered nucleophilic attack to afford the desired compound 2 with a ring systems4 (Figure 1B). However, no bridged five- bridged five-membered ring. However, the formation of the membered ring systems have yet been accessed by Shea’s approach or other type II intramolecular cycloadditions strained bridged five-membered ring would be energetically (including Wender-[4 + 4],5a Davies-[4 + 3],5b Li-[5 + 2],5c unfavorable. There have been no reports of the [3 + 2] and Xu-[4 + 4]5d), because it requires the formation of an annulation of allenylsilane-enes to construct bridged rings.8 unfavorable strained bridgehead double bond (Bredt’s rule).6 Conversely, intermediate A or B could undergo competitive Furthermore, there are few reactions available for the single- desilylation to give the undesired byproduct C. These factors step synthesis of bridged five-membered ring systems (such as make the desired type II intramolecular [3 + 2] annulation of 1 bicyclo[3.2.1]) from acyclic precursors.7 Therefore, it is still challenging. Furthermore, it was unclear if the chirality of the important to develop new and efficient strategies to make these allenylsilane in 1 would transfer to the final product 2. attractive bridged five-membered ring systems. We began our investigation by preparing the linear substrate Danheiser et al.8 described a notable intermolecular [3 + 2] 1a (Scheme 2), which was easily accessed in three steps from a annulation of allenylsilanes. However, this reaction provided commercially available compound (see the Supporting only a single five-membered ring or a fused five-membered ring Information (SI) for details). After optimization, treatment system (Figure 1C). Surprisingly, only one example of of 1a with TiCl4 (1.5 equiv.) in DCM at − 78 °C produced the intramolecular [3 + 2] annulation of allenylsilane-enes has desired product 2a as a single diastereomer in 79% isolated been reported since 1981.9 Additionally, no reported intra- yield. The structure of 2a was confirmed by X-ray crystallo- molecular [3 + 2] annulations of allene-enes gave bridged five- graphic analysis of its derivative 2a′ (see SI for details). membered ring systems.10 In our continuing efforts toward the Interestingly, this reaction constructed a bridged total synthesis of natural products with bridged ring systems,11 we herein present the first type II intramolecular [3 + 2] annulation of allenylsilane-ene, which enables the first Received: July 10, 2024 asymmetric total synthesis of strepsesquitriol and the efficient Revised: August 18, 2024 construction of the synthetically challenging tetracyclic core of Accepted: August 27, 2024 pierisjaponol D (Figure 1D). Initially, we anticipated that the type II intramolecular [3 + 2] annulation of allenylsilane-enes would deliver bridged five- © XXXX American Chemical Society https://doi.org/10.1021/jacs.4c09384 A J. Am. Chem. Soc. XXXX, XXX, XXX−XXX Journal of the American Chemical Society pubs.acs.org/JACS Communication Figure 1. A. Selected natural products with bridged ring systems. B. Type II intramolecular Diels−Alder cycloaddition. C. Intermolecular [3 + 2] annulation of allenylsilaness. D. Type II intramolecular [3 + 2] annulation of allenylsilane-ene and asymmetric total synthesis of strepsesquitriol. Scheme 1. Proposed Type II Intramolecular [3 + 2] the following investigation. We then turned our attention to Annulation of Allenylsilane-ene to Access Bridged Five- the substituted group of allenylsilane. The reactions proceeded Membered Ring Systems successfully with alkyl-substituted allenylsilanes, giving a series of functionalized bicyclo[3.2.1]octanes 2d−2g in good yields (even of 2g with a bulky tertiary butyl substituent). Pleasingly, the all-carbon quaternary stereocenter was constructed from α- alkyl- or α-aryl-substituted enones, giving products 2h−2k in 77%−85% yield. Of note was compound 2l with two adjacent quaternary carbons, which formed with an excellent yield of 87%. Additionally, a tetrasubstituted allenylsilane substrate gave compound 2m, which possessed an all-carbon quaternary stereocenter, in 62% yield. These results are important because the construction of an all-carbon quaternary stereocenter is very challenging.12 Interestingly, when substrate 1n with α, β- substituted enone was treated with Me2AlCl (2.5 equiv.) instead of TiCl4, it formed the more functionalized product 2n with three stereocenters diastereoselectively. The synthesis of products with an external carbonyl group on the bridged ring system was then investigated using this method (Scheme 2B). The reactions proceeded well with alkyl-substituted ketones, giving a series of functionalized products 2o−2u in moderate or good yields. The substrates with cyclic aliphatic- or aryl-substituted ketones were all tolerated and the desired products 2v−2ee were obtained in moderate yields. The reactions of substrates with conjugated or unconjugated alkenyl-substituted groups proceeded well, giving desired products 2ff−2hh. Substrate 1ii (see its bicyclo[3.2.1]octane ring system, two new C-C bonds, one structure in Scheme 3A) with a ketal group reacted in the new C-Si bond, and two stereogenic centers in a single step. presence of TiCl4 (3.0 equiv.) in DCM, giving dicarbonyl Consequently, the generality of this approach was explored product 2ii in 72% yield. The structures of 2m, 2n, 2aa, and 2ii using different substrates to construct functionalized bridged were established by X-ray crystallographic analyses of their five-membered ring systems, as shown in Scheme 2A. We corresponding derivatives (see SI for details), confirming the found that allenylsilanes with different silyl groups provided generality of this approach. products 2a−2c in good yields. Considering stability and steric Next, we sought to determine whether the chirality of the factors, TES was selected as the silyl group of allenylsilane in allenylsilane could be transferred to the final product (Scheme B https://doi.org/10.1021/jacs.4c09384 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX Journal of the American Chemical Society pubs.acs.org/JACS Communication Scheme 2. Substrate Scopea,b Scheme 3. Stereospecific Type II [3 + 2] Annulation of Chiral Allenylsilane-enes and Synthesis of the Tetracyclic Core of Pierisjaponol D a Conditions: 1 (0.1−0.6 mmol), TiCl4 (1.5 equiv.), DCM (0.05 M), annulation of optically active (−)-1ii (96% ee) and (+)-1ii 0.5 h. bIsolated yield. cMe2AlCl (2.5 equiv.) was used. (97% ee) also proceeded smoothly to give (−)-2ii (97% ee) and (+)-2ii (94% ee, 15 g scale), respectively. These results 3A). Pleasingly, optically active (−)-1j (97% ee, see SI for show that this type II intramolecular [3 + 2] annulation details) underwent a stereospecific type II [3 + 2] annulation, reaction is highly stereospecific and that the chirality of the giving (−)-2j as a single diastereomer in 77% yield and 98% ee. substrate transfers to the product. In our previous work, we did The structure of (−)-2j was confirmed by X-ray crystallog- DFT calculation to explain the chirality transfer process and raphy of its derivative. Furthermore, the desired [3 + 2] the results are consistent.9a In this work, the experiment results C https://doi.org/10.1021/jacs.4c09384 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX Journal of the American Chemical Society pubs.acs.org/JACS Communication show that the electrophile is always anti with respect to carbon- Scheme 4. Asymmetric Total Synthesis of (+)- and silicon bond as our previous work did, which determines the (−)-Strepsesquitriol chirality of the product. This result is due to steric and electronic nature of the allenylsilane (see SI for details).13 Pleasingly, the cascade DMP-oxidation/[3 + 2] annulation reaction of compound 3 (dr = 1:1) proceeded smoothly to afford (±)-2ii in 83% overall yield without using a Lewis acid (Scheme 3B). This outcome is likely due to the presence of dicarbonyl groups in intermediate 3a, which renders the double bond of the conjugate acceptor extremely electronically deficient. Additionally, optically active (+)-3 (97% ee) also underwent a stereospecific cascade oxidation/[3 + 2] annulation to give (+)-2ii (97% ee, see SI for details). With compound (±)-2ii in hand (Scheme 3C), we investigated the practical utility of our strategy by synthesizing the tetracyclic core of pierisjaponol D.14 Treatment of (±)-2ii with allenic boronate 4 and ZnEt2 followed by TBS protection provided 5 as a single diastereomer.15 Diastereoselective 1,2- addition of (4-(trimethylsilyl)but-3-yn-2-yl)lithium reagent to 5 in the presence of LaCl3·2LiCl gave 6 in 94% yield.16 The stereochemical selectivity is controlled by the steric hindrance of the substrates in the above reactions (see SI for details). Then, compound 6 underwent the desired intramolecular Pauson−Khand reaction with catalytic [RhCl(CO)2]2 under CO atomsphere to deliver 7 in 73% yield.17 Dimethylation of 7 using NaH and MeI provided 8 in 94% yield. The structure of 8 was confirmed by X-ray crystallographic analysis. Pleasingly, compound 8 contains the synthetically challenging [5−7−6− 5] tetracyclic structure of pierisjaponol D, including the desired functional groups (highlighted in red). Accordingly, this work provides a concise approach toward the total synthesis of pierisjaponol D. We then conducted the asymmetric total synthesis of (+)-strepsesquitriol (Scheme 4), which shows inhibitory activity against lipopolysaccharide-induced TNFα produc- tion.18 Structurally, (+)-strepsesquitriol is a rearranged went through ozonolysis with O3 and C-O bond cleavage with zizaane-type sesquiterpenoid19 and has a trihydroxytricyclo- SmI2 to provide (+)-12 in 64% yield over two steps. Treatment [6.2.1.01,5]undecane core including a bridged bicyclo[3.2.1]- of (+)-12 with NaH/MeI followed by diastereoselective 1,2- octane ring system. Additionally, (+)-strepsesquitriol contains four contiguous quaternary carbons, including two all-carbon addition of MeLi to the ketone group afforded (+)-13 in 55% quaternary centers at C1 and C9 and two oxygenated overall yield. Finally, hydrogenative removal of the two benzyl quaternary stereocenters at C5 and C10. Thus, (+)-strep- groups of (+)-13 provided (+)-strepsesquitriol in 95% yield, sesquitriol poses a considerable synthetic challenge and its completing the asymmetric total synthesis. Interestingly, we total synthesis has not yet been reported. also achieved the first asymmetric total synthesis of The synthesis of (+)-strepsesquitriol commenced with (−)-strepsesquitriol using (−)-2ii (97% ee) as the starting (+)-2ii. In the presence of LaCl3·2LiCl, sequential chemo- material by following a similar sequence to that shown in and diastereoselective 1,2-additions of vinylmagnesium bro- Scheme 4. The syntheses of both (+)- and (−)-strepsesquitriol mide and isopropenylmagnesium bromide to the aldehyde and will enable study of their structure−activity relationship. ketone groups of (+)-2ii, respectively, gave (+)-9 in 63% yield. In summary, the first type II intramolecular [3 + 2] Treatment of (+)-9 with Grubbs II catalyst, followed by TES annulation of allenylsilane-ene was achieved. This reaction protection of the secondary hydroxyl group and diastereose- enables diastereoselective and efficient construction of lective hydrogenation of the trisubstituted alkene with Pd/C synthetically challenging and multifunctionalized bridged five- and H2 provided (+)-10 in 73% overall yield. It is worth membered ring systems, such as bicyclo[3.2.1]. This mild and mentioning that the TES protection on C2-OH was removed direct transformation displays a broad substrate scope and is under the acidic conditions of Pd/C/H2 reaction. The absolute highly stereospecific. Notably, this work represents the first structure of (+)-10 was confirmed by X-ray crystallography. stereoselective approach for the direct synthesis of bicy- Notably, direct hydrogenation of the trisubstituted alkene with clo[3.2.1] ring systems from acyclic precursors. Furthermore, an unprotected secondary alcohol provided a mixture of the first asymmetric total synthesis of (+)- and (−)-strep- diastereomers with a 1.8:1 ratio. Removal of the silyl group of sesquitriol and the efficient construction of the synthetically (+)-10 with TFA and Bn protection of the two hydroxyl challenging tetracyclic core of pierisjaponol D were achieved groups gave (+)-11 in 68% overall yield. Compound (+)-11 by this type II [3 + 2] annulation reaction. This approach underwent SeO2-mediated allylic oxidative rearrangement to could be extended to the total synthesis of ent-kauranes and provide a product with an exocyclic double bond. This product diterpenoid alkaloids with bicyclo[3.2.1] ring systems.20 D https://doi.org/10.1021/jacs.4c09384 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX Journal of the American Chemical Society pubs.acs.org/JACS Communication * ASSOCIATED CONTENT sı Supporting Information ACKNOWLEDGMENTS This paper is in memory of Professor Li-Xin Dai. This work The Supporting Information is available free of charge at was supported by the National Natural Science Foundation of https://pubs.acs.org/doi/10.1021/jacs.4c09384. China (22225102 and 22371114), National Key R&D Detailed experimental procedure, 1H NMR and 13 C Program of China (No. 2022YFE0205500), the Guangdong NMR spectra, X-ray data information (PDF) Basic and Applied Basic Research Foundation (2022A1515011198), Shenzhen Bay Laboratory Accession Codes (SZBL2021080601005 and Shenzhen Bay Scholars), and the CCDC 2352592−2352596, 2352598, 2352644, 2352646, and Shenzhen Science and Technology Program 2364729−2364730 contain the supplementary crystallographic (JCYJ20220818100603008, JCYJ20210324104408023, and data for this paper. These data can be obtained free of charge JCYJ20210324105202006). via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cam- bridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. REFERENCES (1) Nicolaou, K. C., Montagnon, T., Eds. Molecules that Changed the World; Wiley-VCH, 2008. AUTHOR INFORMATION Corresponding Authors (2) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Chemistry and Biology of Taxol. Angew. Chem., Int. Ed. 1994, 33, 15−44. (3) Min, L.; Hu, Y.-J.; Fan, J.-H.; Zhang, W.; Li, C.-C. Synthetic Jing-Chun Han − Shenzhen Grubbs Institute, Guangming Applications of Type II Intramolecular Cycloadditions. Chem. Soc. Advanced Research Institute, Department of Chemistry, Rev. 2020, 49, 7015−7043. (4) (a) Bear, B. R.; Sparks, S. M.; Shea, K. J. The Type II Southern University of Science and Technology, Shenzhen Intramolecular Diels-Alder Reaction: Synthesis and Chemistry of 518055, China; Shenzhen Bay Laboratory, Shenzhen Bridgehead Alkenes. Angew. Chem., Int. Ed. 2001, 40, 820−849. 518132, China; Email: [email protected] (b) Shea, K. J.; Wise, S.; Burke, L. D.; Davis, P. D.; Gilman, J. W.; Chuang-Chuang Li − Shenzhen Grubbs Institute, Guangming Greeley, A. C. Applications of the Intramolecular Diels−Alder Advanced Research Institute, Department of Chemistry, Reaction to the Formation of Strained Molecules. Synthesis of Southern University of Science and Technology, Shenzhen Bridgehead Alkenes. J. Am. Chem. Soc. 1982, 104, 5708−5715. 518055, China; Shenzhen Bay Laboratory, Shenzhen (c) Shea, K. J.; Wise, S. Intramolecular Diels-Alder Reactions. A New 518132, China; orcid.org/0000-0003-4344-0498; Entry into Bridgehead Bicyclo[3.n.1]alkenes. J. Am. Chem. Soc. 1978, Email: [email protected] 100, 6519−6521. (5) (a) Wender, P. A.; Snapper, M. L. Intramolecular Nickel Authors Catalyzed Cycloadditions of Bis-Dienes: 3 Approaches to the Taxane Ling-Zi Li − Shenzhen Grubbs Institute, Guangming Advanced Skeleton. Tetrahedron Lett. 1987, 28, 2221−2224. (b) Davies, H. M. Research Institute, Department of Chemistry, Southern L.; Calvo, R.; Ahmed, G. Type II Intramolecular Annulations between Vinylcarbenoids and Furans. Tetrahedron Lett. 1997, 38, 1737−1740. University of Science and Technology, Shenzhen 518055, (c) Mei, G. J.; Liu, X.; Qiao, C.; Chen, W.; Li, C.-C. Type II China Intramolecular [5 + 2] Cycloaddition: Facile Synthesis of Highly Yu-Rou Huang − Shenzhen Grubbs Institute, Guangming Functionalized Bridged Ring Systems. Angew. Chem., Int. Ed. 2015, 54, Advanced Research Institute, Department of Chemistry, 1754−1758. (d) Zhang, J.; Wang, X.; Xu, T. Regioselective Activation Southern University of Science and Technology, Shenzhen of Benzocyclobutenones and Dienamides Lead to Anti-Bredt Bridged- 518055, China ring Systems by a [4 + 4] Cycloaddition. Nat. Commun. 2021, 12, Zi-Xun Xu − Shenzhen Grubbs Institute, Guangming 3022−3029. Advanced Research Institute, Department of Chemistry, (6) (a) Bredt, J. Steric Hindrance in the Bridge Ring (Bredt’s Rule) Southern University of Science and Technology, Shenzhen and the Meso-trans-position in Condensed Ring Systems of the 518055, China Hexamethylenes. Liebigs Ann. Chem. 1924, 437, 1−13. (b) Liu, J. Y.; Liu, X.; Wu, J. L.; Li, C.-C. Total Synthesis of Natural Products Hong-Sen He − Shenzhen Grubbs Institute, Guangming Containing a Bridgehead Double Bond. Chem 2020, 6, 579−615. Advanced Research Institute, Department of Chemistry, (7) (a) Filippini, M.-H.; Rodriguez, J. Synthesis of Functionalized Southern University of Science and Technology, Shenzhen Bicyclo[3.2.1]octanes and Their Multiple Uses in Organic Chemistry. 518055, China Chem. Rev. 1999, 99, 27−76. (b) Presset, M.; Coquerel, Y.; Hong-Wei Ran − Shenzhen Grubbs Institute, Guangming Rodriguez, J. Syntheses and Applications of Functionalized Advanced Research Institute, Department of Chemistry, Bicyclo[3.2.1]octanes: Thirteen Years of Progress. Chem. Rev. 2013, Southern University of Science and Technology, Shenzhen 113, 525−595. For the non-stereoselective construction of 518055, China bicyclo[3.2.1] ring systems from acyclic precursors, see (c) Snider, Ke-Yu Zhu − Shenzhen Grubbs Institute, Guangming B. B. Manganese(III)-Based Oxidative Free-Radical Cyclizations. Advanced Research Institute, Department of Chemistry, Chem. Rev. 1996, 96, 339−364. (8) For Danheiser original [3 + 2] annulation, see (a) Danheiser, R. Southern University of Science and Technology, Shenzhen L.; Carini, D. J.; Basak, A. (Trimethylsilyl)cyclopentene Annulation: A 518055, China Regiocontrolled Approach to the Synthesis of Five-Membered Rings. Complete contact information is available at: J. Am. Chem. Soc. 1981, 103, 1604−1606. (b) Danheiser, R. L.; Carini, https://pubs.acs.org/10.1021/jacs.4c09384 D. J.; Fink, D. M.; Basak, A. Scope and Stereochemical Course of the (Trimethylsilyl)cyclopentene Annulation. Tetrahedron 1983, 39, Author Contributions 935−947. (c) Danheiser, R. L.; Fink, D. M. The Reaction of Allenylsilanes with α,β-Unsaturated Acylsilanes: New Annulation L.-Z.L., Y.-R.H., and Z.-X.X. contributed equally. Approaches to Five and Six-Membered Carbocyclic Compounds. Notes Tetrahedron Lett. 1985, 26, 2513−2516. (d) Danheiser, R. L.; The authors declare no competing financial interest. Kwasigroch, C. A.; Tsai, Y. M. Application of Allenylsilanes in [3 + 2] E https://doi.org/10.1021/jacs.4c09384 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX Journal of the American Chemical Society pubs.acs.org/JACS Communication Annulation Approaches to Oxygen and Nitrogen Heterocycles. J. Am. Diterpenoids from the Leaves of Pieris Japonica. J. Nat. Prod. 2019, 82, Chem. Soc. 1985, 107, 7233−7235. (e) Danheiser, R. L.; Fink, D. M.; 3330−3339. Tsai, J.-M. A General [3 + 2] Annulation: cis-4-exo-Isopropenyl-1,9- (15) Fandrick, D. R.; Saha, J.; Fandrick, K. R.; Sanyal, S.; Ogikubo, dimethyl-8-(trimethylsilyl)bicyclo|4.3.0|non-8-en-2-one. Org. Synth. J.; Lee, H.; Roschangar, F.; Song, J. J.; Senanayake, C. H. Zinc- 2003, 66, 8. (f) Becker, D. A.; Danheiser, R. L. A New Synthesis of Catalyzed Allenylations of Aldehydes and Ketones. Org. Lett. 2011, Substituted Azulenes. J. Am. Chem. Soc. 1989, 111, 389−391. 13, 5616−5619. (g) Danheiser, R. L.; Stoner, E. J.; Koyama, H.; Yamashita, D. S.; (16) Li, T.; Yang, Y.; Li, B.; Bao, X.; Zhang, L. Gold-Catalyzed Silyl- Klade, C. A. A New Synthesis of Substituted Furans. J. Am. Chem. Soc. Migrative Cyclization of Homopropargylic Alcohols Enabled by 1989, 111, 4407−4413. For recent remarkable examples in total Bifunctional Biphenyl-2-ylphosphine and DFT Studies. Org. Lett. synthesis of natural products, see (h) Friese, J. C.; Krause, S.; Schafer, 2019, 21, 7791−7794. H. J. Formal Total Synthesis of the Trinorguaiane Sesquiterpenes (17) (a) Brummond, K. M.; Chen, H. F.; Fisher, K. D.; Kerekes, A. (±)-Clavukerin A and (±)-Isoclavukerin. Tetrahedron Lett. 2002, 43, D.; Rickards, B.; Sill, P. C.; Geib, S. J. An Allenic Pauson−Khand- 2683−2685. (i) Xu, B.; Xun, W.; Su, S.; Zhai, H. Total Syntheses of Type Reaction: A Reversal in p-Bond Selectivity and the Formation of (−)-Conidiogenone B, (−)-Conidiogenone, and (−)-Conidiogenol. Seven-Membered Rings. Org. Lett. 2002, 4, 1931−1934. (b) Mukai, Angew. Chem., Int. Ed. 2020, 59, 16475−16479. (j) Woo, S.; Shenvi, C.; Nomura, I.; Yamanishi, K.; Hanaoka, M. Rh(I)-Catalyzed R. A. Synthesis and Target Annotation of the Alkaloid GB18. Nature Intramolecular Allenic Pauson−Khand Reaction: Construction of a 2022, 606, 917−921. Bicyclo[5.3.0]dec-1,7-dien-9-one Skeleton. Org. Lett. 2002, 4, 1755− (9) (a) Lv, N.; Han, J.-C.; Zhang, P.; Huang, Y.-R.; Xu, Z.-X.; Xu, K.; 1758. Wang, X.-F.; Li, X.; Chung, L. W; Li, C.-C. Intramolecular [3 + 2] (18) Yang, X.-W.; Peng, K.; Liu, Z.; Zhang, G.-Y.; Li, J.; Wang, N.; Steinmetz, A.; Liu, Y. Strepsesquitriol, a Rearranged Zizaane-Type Annulation of Allenylsilane-Enes: Direct Synthesis of Highly Strained Sesquiterpenoid from the Deep-Sea-Derived Actinomycete Strepto- Trans-Fused 5/5 Ring Systems. Chem 2024, 10, 190−198. (b) Saito, myces sp. SCSIO 10355. J. Nat. Prod. 2013, 76, 2360−2363. A.; Sakamoto, W.; Yanai, H.; Taguchi, T. Intramolecular [3 + 2] (19) For a related recent total synthesis, see Zhu, Y.; Zheng, J.; Cycloaddition Reaction of α, β-Enoate Derivatives Having Allylsilane Evans, P. A. Intramolecular Rhodium-Catalyzed [(3 + 2+2)] Parts. 1,1’-Biphenyl-2,2’-di(triflyl)amide (BIPAM) + 2Me2AICI as a Carbocyclization Reactions with Dienylidenecyclopropanes: A Con- Novel Lewis Acid. Tetrahedron Lett. 2006, 47, 4181−4185. cise and Stereoselective Total Synthesis of the Sesquiterpene (10) For selected examples of intramolecular [3 + 2] annulations of (+)-Zizaene. J. Am. Chem. Soc. 2023, 145, 3833−3838. allene-enes, see (a) Wang, J.-C.; Ng, S.-S.; Krische, M. J. Catalytic (20) For selected reviews, see (a) Gao, K.; Hu, J.; Ding, H. Diastereoselective Synthesis of Diquinanes from Acyclic Precursors. J. Tetracyclic Diterpenoid Synthesis Facilitated by ODI-Cascade Am. Chem. Soc. 2003, 125, 3682−3683. (b) Wang, J.-C.; Krische, M. J. Approaches to Bicyclo[3.2.1]octane Skeletons. Acc. Chem. Res. Intramolecular Organocatalytic [3 + 2] Dipolar Cycloaddition: 2021, 54, 875−889. (b) Zhao, X.; Cacherat, B.; Hu, Q.; Ma, D. Stereospecific Cycloaddition and the Total Synthesis of (±)-Hirsu- Recent Advances in the Synthesis of ent-Kaurane Diterpenoids. Nat. tene. Angew. Chem., Int. Ed. 2003, 42, 5855−5857. (c) Long, R.; Prod. Rep. 2022, 39, 119−138. (c) Liu, X.−Y.; Ke, B.-W.; Qin, Y.; Huang, J.; Shao, W.; Liu, S.; Lan, Y.; Gong, J.; Yang, Z. Asymmetric Wang, F.-P. The Diterpenoid Alkaloids. Alkaloids Chem Biol. 2022, Total Synthesis of (−)-Lingzhiol via a Rh-Catalysed [3 + 2] 87, 1−360. Cycloaddition. Nat. Commun. 2014, 5, 5707−5716. (d) Lee, S. Y.; Fujiwara, Y.; Nishiguchi, A.; Kalek, M.; Fu, G. C. Phosphine- Catalyzed Enantioselective Intramolecular [3 + 2] Annulations to Generate Fused Ring Systems. J. Am. Chem. Soc. 2015, 137, 4587− 4591. (e) Li, S.; Zhang, P.; Li, Y.; Lu, S.; Gong, J.; Yang, Z. Diastereoselective Synthesis of Diquinanes and Triquinanes Bearing Vicinal Quaternary Carbon Stereocenters from Acyclic Allene-based Precursors via a Cascade Reaction. Org. Lett. 2017, 19, 4416−4419. For Lu’s [3 + 2] annulation, see (f) Lu, X.; Zhang, C.; Xu, Z. Reactions of Electron-Deficient Alkynes and Allenes under Phosphine Catalysis. Acc. Chem. Res. 2001, 34, 535−544. For excellent reviews on allene chemistry, see (g) Ma, S. Some Typical Advances in the Synthetic Applications of Allenes. Chem. Rev. 2005, 105, 2829−2871. (h) Yu, S.; Ma, S. Allenes in Catalytic Asymmetric Synthesis and Natural Product Syntheses. Angew. Chem., Int. Ed. 2012, 51, 3074− 3112. (11) (a) Min, L.; Liu, X.; Li, C.-C. Total Synthesis of Natural Products with Bridged Bicyclo[m.n.1] Ring Systems via Type II [5 + 2] Cycloaddition. Acc. Chem. Res. 2020, 53, 703−718. (b) Hu, Y.-J.; Gu, C.-C.; Wang, X.-F.; Min, L.; Li, C.-C. Asymmetric Total Synthesis of Taxol. J. Am. Chem. Soc. 2021, 143, 17862−17870. (12) (a) Christoffers, J., Baro, A., Eds. Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis; Wiley-VCH: Weinheim, 2005. (b) Long, R.; Huang, J.; Gong, J.; Yang, Z. Direct Construction of Vicinal All-carbon Quaternary Stereocenters in Natural Product Synthesis. Nat. Prod. Rep. 2015, 32, 1584−1601. (c) Hu, P.; Chi, H. M.; DeBacker, K. C.; Gong, X.; Keim, J. H.; Hsu, I. T; Snyder, S. A. Quaternary-Centre-Guided Synthesis of Complex Polycyclic Ter- penes. Nature 2019, 569, 703−707. (13) Neff, R. K.; Frantz, D. E. Recent Applications of Chiral Allenes in Axial-to-central Chirality Transfer Reactions. Tetrahedron 2015, 71, 7−18. (14) Zheng, G.; Zhou, J.; Huang, L.; Zhang, H.; Sun, N.; Zhang, H.; Jin, P.; Yue, M.; Meng, L.; Yao, G. Antinociceptive Grayanane F https://doi.org/10.1021/jacs.4c09384 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX