Boron-containing compounds and methods of preparation and applications thereof

Abstract

Disclosed are activation of tertiary alkylboronic esters with adamantyllithium generated in situ to enable stereoretentive boron-to-copper transmetalation and cross-coupling reaction of the resultant alkylcopper species with an array of electrophiles to furnish synthetically useful compounds bearing quaternary stereocenters. In addition, palladium-catalyzed asymmetric synthesis of nortricyclane derivatives from norbornene bis(boronate) through chiral boronate-containing nortricyclane intermediates and application of the nortricyclane derivatives as isosteres of the corresponding aromatic compounds in pharmaceutical motifs are also disclosed.

Description

[0001]Docket No.: 359006.00004 BORON-CONTAINING COMPOUNDS AND METHODS OF PREPARATION AND APPLICATIONS THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 509,173, filed on June 20, 2023, and No. 63 / 638,935, filed on April 25, 2024, the disclosures of both of which are incorporated herein by reference in their entireties. FIELD OF THE DISCLOSURE The present disclosure relates to boron-containing cyclic molecules, preparation methods, and applications thereof. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. GM127140 awarded by the National Institute of Health. The U.S. government has certain rights in the invention. BACKGROUND OF THE DISCLOSURE Catalytic construction of enantiomerically-enriched quaternary stereocenters is a challenging and yet important task in synthetic organic chemistry. (Quasdorf, K. W.; Overman, L. E.. Nature 2014, 516, 181–191.) In spite of impressive advances in stereospecific cross- coupling of configurationally stable secondary nucleophiles, transmetalation of a configurationally stable tertiary alkyl group to a transition metal is non-trivial and has hampered extension of metal-catalyzed cross-coupling to the installation of quaternary centers. (Ma, X., et al., Nat. Rev. Chem. 2020, 4, 584–599.). Most of the existing examples of transmetalation of tertiary organometallic reagents employ nucleophilic Grignard reagents ((a) Cahiez, G.; Avedissian, H., Synthesis 1998, 1998, 1199–1205. (b) Hintermann, L., et al., Angew. Chem. Int. Ed.2008, 47, 8246–8250. (c) Joshi-Pangu, A., et al., J. Am. Chem. Soc.2011, 133, 8478–8481. (d) Lohre, C., et al., Chem. Eur. J.2011, 17, 6052–6055. (e) Oi, M., et al., Chem. Sci.2019, 10, 6107–6112. (f) Tamio, H., et al., Chem. Lett.1980, 9, 767–768. (g) Terao, J., et al., Angew. Chem. Int. Ed.2007, 46, 2086–2089.), organozinc reagents ((a) Luo, X., et al. Org. Lett.2007, 9, 4571–4574. (b) Okude, R., et al., Chem. Sci.2020, 11, 7672–7675. (c) Thapa, S., et al., Angew. Chem. Int. Ed.2015, 54, 8236–8240.) and organocopper reagents, (Kondo, M., et al., Angew. Chem. Int. Ed. 2020, 59, 1970–1974.). These methods are limited by the Docket No.: 359006.00004 availability of nucleophiles, which can be difficult to prepare and are often configurationally unstable at room temperature. Compared to the above-mentioned nucleophiles, tertiary organoboronic esters exhibit higher configurational stability and may be prepared by a variety of efficient enantioselective synthesis methods. (Collins, B. S. L., et al., Angew. Chem. Int. Ed. 2017, 56, 11700–11733.). However, these reagents are less nucleophilic and thus challenging for transmetalation. Harris and coworkers utilized tertiary cyclopropyl organoboron reagents for Suzuki-Miyaura and Chan-Lam type coupling reactions, ((a) Harris, M. R., et al., Org. Lett. 2017, 19, 2450–2453. (b) Harris, M. R., et al., Org. Lett.2018, 20, 2867–2871.) and Uchiyama reported Suzuki-Miyaura cross-couplings of tert-butyllithium activated bicyclo[1.1.1]pentylboronic esters. Despite such progress, these examples are limited to strained or benzylic substrates and did not address the issue of stereospecificity. Recognizing the general challenge of coupling a tertiary nucleophile, Molander established a single-electron transmetalation process, ((a) Primer, D. N.; Molander, G. A., J. Am. Chem. Soc. 2017, 139, 9847–9850. (b) Tellis, J. C., et al., Science 2014, 345, 433–436. (c) Yuan, M., et al., J. Am. Chem. Soc.2020, 142, 7225–7234.) in which a tertiary organoboron was first converted to a free radical, which was then trapped with nickel complex; this sequence enabled catalytic cross coupling with aryl halides, but the radical nature of the reaction makes it challenging to control stereochemistry. Bioactive compounds, from natural products to clinically relevant active ingredients, often contain aromatic rings. The reasons for incorporation of this motif are multi-fold: (Salomen, L. M., et al., Angew. Chem. Int. Ed. 50, 4808–4842 (2011).) (a) the rigidity of aromatic rings often restricts available molecular conformations thereby lessening the entropic cost for the aromatic ligand to bind to a target receptor; (b) aromatic rings participate in unique non-covalent interactions that can provide enhanced attraction to receptor binding pockets; and (c) the methods used to attach substituents to aromatic rings include efficient cross-coupling reactions (Nishihara, Y., Ed. Applied cross-coupling reactions. Vol.80. (Springer, Heidelberg, Germany, 2013).) which facilitate construction and screening of diverse compound collections These significant benefits are counter-balanced by the ready oxidation of p-electron-rich aromatic rings which can severely diminish metabolic stability. (Dalvie, D., et al., in Metabolism, Pharmacokinetics and Toxicity of Functional Groups, Smith, D. A., Ed. (Royal Society of Chemistry, Cambridge, UK, 2010).) To address this limitation, bicyclic hydrocarbon frameworks have been advanced as C(sp3)-based isosteric replacements for aromatic rings. (Mykhailiuk, P. K., Org. Biomol. Chem. 17, 2839–2849 (2019).) When Docket No.: 359006.00004 appropriately designed, these molecular scaffolds retain the conformational restriction of the benzenoid ring while simultaneously providing the metabolic stability of compounds that lack oxidizable p-bonds. Aromatic rings are common elements in pharmaceutically active compounds; however, their ready oxidation can present a liability with respect to a drug's metabolic stability. (Salomen, L. M., et al., Angew. Chem. Int. Ed. 50, 4808–4842 (2011).) Replacing these aromatic rings in pharmaceutical compounds with non-aromatic isosteric motifs can enhance properties such as potency, metabolic stability, solubility, and lipophilicity. (Locke, G. M., et al., Chem. Eur. J.25, 4590–4647 (2019).) Since the binding pockets of most pharmaceutical targets are chiral, the stereochemical configuration of the isosteric replacements are expected to have an impact on the affinity of derived ligands for target receptors. A significant impediment to this approach is the lack of simple, and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. SUMMARY OF THE DISCLOSURE To address the aforementioned limitations and impediments, the present disclosure provides a novel palladium-catalyzed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes as useful isosteres for meta disubstituted aromatic rings. In one aspect, the present disclosure provides compounds of formula (X): or an isomer, or a salt thereof, wherein: T1, T2, T3, and T4are each independently selected from hydrogen, B(ORA)(ORB), B(ORX)(ORY), EA, and EB; RAand RBare same or different and are independently C1-6 alkyl, C2-6 alkenyl, or C6-10aryl; or alternatively, RAand RBtogether form an alkylene, alkenylene, or arylene, each optionally substituted; Docket No.: 359006.00004 RXand RYare same or different and are independently C1-6 alkyl, C2-6 alkenyl, or C6- 10 aryl; or alternatively, RXand RYtogether form an alkylene, alkenylene, or arylene, each optionally substituted; wherein RXand RYpair are same as or different from the RAand RBpair; EAand EBare each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, OC(O)R7, C(O)OR8, OC(O)OR8, OR15, SR15, NHR15, C(O)NRcRd, -OC(O)NHR8, C(O)NHR8, NHC(O)R7, oxo (=O), and -O-Si(Rsi)3, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OR15, SR15, NHR15, B(ORX)(ORY), NO2, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, C(O)R7, OC(O)R7, C(O)OR8, NRaRb, C(O)NRcRd, -OC(O)NHR8, and C(O)NHR8; T5is selected from hydrogen, halogen, C1-8 alkyl, C1-8 haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R15at each occurrence is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, benzyl, or C3-6cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6alkyl, or benzyl; Rsiat each occurrence is independently C1-6 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; Raand Rbare independently hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, C3-6 cycloalkyl, or -C(O)OR8, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Docket No.: 359006.00004 Rdat each occurrence is independently hydrogen or C1-6alkyl. In another aspect, the present disclosure provides a compound of formula (I-1), (I-2) or (I-3): (I-1) (I-2) (I-3) or an isomer, or a salt thereof, wherein: Rxand Ryare independently alkyl, alkenyl, or aryl; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; EAand EBare each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, OC(O)R7, C(O)OR8, OC(O)OR8, OR15, O-C1-6alkyl-R15, SR15, NHR15, C(O)NRcRd, -OC(O)NHR8, C(O)NHR8, and NHC(O)R7, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OR15, SR15, NHR15, B(ORX)(ORY), NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, C(O)R7, OC(O)R7, C(O)OR8, NRaRb, C(O)NRcRd, -OC(O)NHR8, and C(O)NHR8; R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R15at each occurrence is independently hydrogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, benzyl, , 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, or C3-6cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6alkyl, or benzyl; Docket No.: 359006.00004 Rsiat each occurrence is independently C1-6 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; Raand Rbare independently hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, C3-6 cycloalkyl, or -C(O)OR8, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl. In another aspect, the present disclosure provides a process for preparing a compound of formula (I), or an isomer or analog thereof, comprising the steps of: (a) reacting a boronate ester compound of formula (A) with adamantyl-lithium or tert-butyl lithium in the presence of a catalyst in a solvent to form an adamantyl- or tert- butyl-boronate ester adduct; (b) reacting the adamantyl-boronate ester adduct with an electrophile compound R4-X1in the presence of a copper salt in a solvent to form the compound of formula (I), wherein: X1is halide, -OS(O)2R5, -OC(O)R5, or -NRaS(O)2R5; X2is halide, CN-, BF4-, NO3-, HSO4-, or -OS(O)2R6; R1, R2, and R3are each independently alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted; or any two of R1, R2, and R3together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, each optionally substituted; or R1, R2, and R3together with the carbon atom to which they are attached form a bicycloalkyl, tricycloalkyl, bi-heterocyclyl, tri-heterocyclyl, bridged-carbocyclyl, or bridged- heterocyclyl, each optionally substituted; Docket No.: 359006.00004 wherein R4is alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, or C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted; R5is alkyl, haloalkyl, aryl, or heteroaryl, each optionally substituted; R6is alkyl, haloalkyl, or aryl, each optionally substituted; R7is alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is alkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; Rxand Ryare independently alkyl, alkenyl, or aryl; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; Raand Rbare independently hydrogen, alkyl, aryl, benzyl, or together with the nitrogen atom to which they are attached form a heterocyclyl, each optionally substituted. In another aspect, the present disclosure provides a method of preparing a compound of formula (I-2), comprising: (i) a process of preparing the compound of formula (I-1) according to any one of claims 0 to 0; and (ii) converting the compound of formula (I-1) to the compound of formula (I-2): (I-1) (I-2), wherein R4ais same as or different from R4and is independently selected from hydrogen, OH, alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, and C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted. In another aspect, the present disclosure provides a method of preparing a nortricyclane compound of formula (II) or an isomer or analog thereof, comprising reacting a Docket No.: 359006.00004 norbornene bis(boronate) ester compound of formula (B) or an analog thereof, with an electrophile compound E-X1in the presence of a palladium-catalyst and a base, optionally along with a ligand, in a solvent: , wherein: Rxand Ryat each occurrence are independently alkyl, alkenyl, or aryl, each optionally substituted; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; E is an electrophile moiety; X1is a leaving group; T5is selected from hydrogen, halogen, C1-8alkyl, C1-8haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6alkyl, or benzyl; Rsiat each occurrence is independently C1-6 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl. In another aspect, the present disclosure provides a method of preparing a nortricyclane compound of formula (III), or an isomer or analog thereof, comprising reacting a nortricyclane bis(boronate) ester compound of formula (C), or an isomer or analog thereof, Docket No.: 359006.00004 with an electrophile compound E-X1in the presence of a palladium-catalyst and a base, optionally along with a ligand, in a solvent: , wherein: Rxand Ryat each occurrence are independently alkyl, alkenyl, or aryl, each optionally substituted; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; E is an electrophile moiety; X1is a leaving group; T5is selected from hydrogen, halogen, C1-8alkyl, C1-8haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6 alkyl, or benzyl; Rsiat each occurrence is independently C1-6 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl. In another aspect, the present disclosure provides a method of preparing a nortricyclane compound of formula (IV), or an isomer or analog thereof, comprising reacting an oxo-substituted norbornane bis(boronate) ester compound of formula (D), or an isomer or analog thereof, with an amine in the presence of an acid in a solvent: Docket No.: 359006.00004 , wherein: Rxand Ryat each occurrence are independently alkyl, alkenyl, or aryl, each optionally substituted; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; Raand Rbare independently selected from hydrogen, C1-6alkyl, C6-10aryl, benzyl, and C3-6 cycloalkyl, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; T5is selected from hydrogen, halogen, C1-8alkyl, C1-8haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6 alkyl, or benzyl; Rsiat each occurrence is independently C1-6 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl. In some embodiments, in the method of the disclosure: the acid is a C1-6alkyl carboxylic acid; and the solvent is a halogenated C1-6hydrocarbon. Docket No.: 359006.00004 In another aspect, the present disclosure provides a method of preparing a nortricyclane compound of formula (V), or an isomer or analog thereof, comprising: (i) preparing a compound of formula (II), or an isomer or analog thereof, according to the method of any embodiment disclosed herein; and (ii) converting the compound of formula (II), or an isomer or analog thereof, to the compound of formula (V), or an isomer or analog thereof, under suitable conditions: , wherein E1and E are same or different, each independently selected from hydrogen, OH, alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, OR15, SR15, NHR15, C(O)NRcRd, and C(O)NHR16wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, NO2, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O- C1-4haloalkyl, C(O)OR16; NRcRd, C(O)NRcRd, and C(O)NHR16; T5is selected from hydrogen, halogen, C1-8 alkyl, C1-8 haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is alkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R15at each occurrence is independently hydrogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, benzyl, or C3-6 cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen or C1-6 alkyl; Raand Rbare independently hydrogen, C1-6alkyl, C6-10aryl, benzyl, or C3-6cycloalkyl, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein C1-6 alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Docket No.: 359006.00004 Rcat each occurrence is independently hydrogen or C1-4alkyl; and Rdat each occurrence is independently hydrogen or C1-4alkyl. In other aspects, the present disclosure provides compounds (R,S)-33 and (S,R)-33 as URB597 analogs, and compounds (S,R)-34, and (R,S)-34 as sonidegib analogs, pharmaceutical compositions thereof, use of them for treatment of diseases or conditions treatable by URB597 and sonidegib, respectively. Other aspects and advantages of the present disclosure will be better appreciated by those skilled in the art in view of the following drawing, detailed description, examples, and claims. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates the X-ray structures of compounds 42 (CD2265713) and 46 (CD2264178). FIG. 2 illustrates activity profiles of URB597, (R,S)-33 and (S,R)-33 against mouse- brain serine hydrolases. FIG.3 illustrates the structures of sonidegib, (S,R)-34, and (R,S)-34 and a presentative comparison of activity of their activity against Hedgehog (Hh) signaling. DETAILED DESCRIPTION OF THE DISCLOSURE The present disclosure provides a versatile palladium-catalyzed reaction, among other things, that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes, which are useful isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd- catalyzed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. In one aspect, the present disclosure provides compounds of formula (X): or an isomer, or a salt thereof, wherein: Docket No.: 359006.00004 T1, T2, T3, and T4are each independently selected from hydrogen, B(ORA)(ORB), B(ORX)(ORY), EA, and EB; RAand RBare same or different and are independently C1-6alkyl, C2-6alkenyl, or C6-10 aryl; or alternatively, RAand RBtogether form an alkylene, alkenylene, or arylene, each optionally substituted; RXand RYare same or different and are independently C1-6alkyl, C2-6alkenyl, or C6-10aryl; or alternatively, RXand RYtogether form an alkylene, alkenylene, or arylene, each optionally substituted; wherein RXand RYpair are same as or different from the RAand RBpair; EAand EBare each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, OC(O)R7, C(O)OR8, OC(O)OR8, OR15, SR15, NHR15, C(O)NRcRd, -OC(O)NHR8, C(O)NHR8, NHC(O)R7, oxo (=O), and -O-Si(Rsi)3, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OR15, SR15, NHR15, B(ORX)(ORY), NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, C(O)R7, OC(O)R7, C(O)OR8, NRaRb, C(O)NRcRd, -OC(O)NHR8, and C(O)NHR8; T5is selected from hydrogen, halogen, C1-8alkyl, C1-8haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R15at each occurrence is independently hydrogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, benzyl, or C3-6 cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6 alkyl, or benzyl; Rsiat each occurrence is independently C1-6alkyl, C3-6cycloalkyl, phenyl, or benzyl; Docket No.: 359006.00004 Raand Rbare independently hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, C3-6 cycloalkyl, or -C(O)OR8, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl. In some embodiments, the compounds have a structure of formula: or an isomer, or a salt thereof, wherein: RT1is selected from R15, -C(O)R7, -C(O)OR8, -C(O)NHR8, and OSi(Rsi)3; and T5, R15, R7, R8, and Rsiare as defined in formula (X). In some embodiments, in the compound structures: RAand RBare independently C1-6 alkyl, or RAand RBtogether form an alkylene; and RXand RYare independently C1-6alkyl; or RXand RYtogether form an alkylene. In some embodiments, the compound is selected from: In some embodiments, the compound has a structure of formula: Docket No.: 359006.00004 , or an isomer, tautomer, or salt thereof, wherein T2, T3, T4, T5, Ra, and Rbare as defined in formula (X). In some embodiments, in the compounds of foregoing formulas, or an isomer, or a salt thereof, RXand RYare independently C1-6 alkyl; or RXand RYtogether form an alkylene. In some embodiments, in the compounds of foregoing formulas, or an isomer, or a salt thereof, RXand RYtogether form , and RAand RBtogether form . In some embodiments, the compounds of foregoing formulas are selected from: Docket No.: 359006.00004 In some embodiments, the compounds of foregoing formulas have a structure of formula: , or an isomer, or a salt thereof, wherein: T1, T2, T3, and T4are each independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, allyl, benzyl, C3-6 cycloalkyl, C5-10 carbocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, OR15, SR15, NHR15, C(O)NRcRd, -OC(O)NHR8, -NHC(O)NHR8, and C(O)NHR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents Docket No.: 359006.00004 independently selected from halogen, CN, OR15, SR15, NHR15, B(ORX)(ORY), NO2, C1- 4alkyl, C1-4haloalkyl, C(O)R7, C(O)OR8, NRaRb, C(O)NRcRd, -OC(O)NHR8, and C(O)NHR8; T5is selected from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, CN, OH, O-C1-4alkyl, O-C1-4haloalkyl, C(O)OR9; NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl, each optionally substituted; R8is hydrogen, C1-6alkyl, C3-6cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl, each optionally substituted; R15at each occurrence is independently hydrogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, benzyl, or C3-6cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen or C1-6 alkyl; Raand Rbare independently hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, C3-6 cycloalkyl, or -C(O)OR8, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl. In some embodiments, the compounds of foregoing formulas have a structure of formula: ,or an isomer, or a salt thereof, wherein: T5is hydrogen; and T1and T2are each independently selected from: Docket No.: 359006.00004 In some embodiments, the compounds of foregoing formulas are selected from: Docket No.: 359006.00004 or an isomer, or a salt thereof. In another aspect, the present disclosure provides a compound of formula (I-1), (I-2) or (I-3): or an isomer, or a salt thereof, wherein: Rxand Ryare independently alkyl, alkenyl, or aryl; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; EAand EBare each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, OC(O)R7, C(O)OR8, OC(O)OR8, OR15, O-C1-6alkyl-R15, SR15, NHR15, C(O)NRcRd, -OC(O)NHR8, C(O)NHR8, and NHC(O)R7, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OR15, SR15, NHR15, B(ORX)(ORY), NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, C(O)R7, OC(O)R7, C(O)OR8, NRaRb, C(O)NRcRd, -OC(O)NHR8, and C(O)NHR8; R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; Docket No.: 359006.00004 R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R15at each occurrence is independently hydrogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, benzyl, , 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, or C3-6 cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6alkyl, or benzyl; Rsiat each occurrence is independently C1-6alkyl, C3-6cycloalkyl, phenyl, or benzyl; Raand Rbare independently hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, C3-6 cycloalkyl, or -C(O)OR8, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl. In some embodiments, the compounds of foregoing formulas have a structure of formula (I-1-a), (I-2-a), or (I-3): or an isomer, or a salt thereof, wherein EAand EBare independently selected from C1-8 alkyl, Docket No.: 359006.00004 wherein: p is 0, 1, or 2; q is 0, 1, 2, or 3; R7is alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is alkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R9at each occurrence is independently selected from C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, NRaRb, and oxo (=O); R10at each occurrence is independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NRaRb, halide, CN, and NO2; R11to R14at each occurrence are independently selected from hydrogen, alkyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, and C(O)OR8, wherein the alkyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted; R15at each occurrence is independently hydrogen, C1-6alkyl, benzyl, 5- or 6- membered heteroaryl, 5- or 6-membered heterocyclyl, or C3-6 cycloalkyl, each optionally substituted; and Raand Rbare independently hydrogen, C1-6alkyl, phenyl, benzyl, C3-6cycloalkyl, or - C(O)OR8, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted. In some embodiments, the compounds of foregoing formulas have a structure of formula: Docket No.: 359006.00004 or an isomer, or a salt thereof. In another aspect, the present disclosure provides a process for preparing a compound of formula (I), or an isomer or analog thereof, comprising the steps of: (A)(I)(c) reacting a boronate ester compound of formula (A) with adamantyl-lithium or tert-butyl lithium in the presence of a catalyst in a solvent to form an adamantyl- or tert- butyl-boronate ester adduct; (d) reacting the adamantyl-boronate ester adduct with an electrophile compound R4-X1in the presence of a copper salt in a solvent to form the compound of formula (I), wherein: X1is halide, -OS(O)2R5, -OC(O)R5, or -NRaS(O)2R5; X2is halide, CN-, BF4-, NO3-, HSO4-, or -OS(O)2R6; R1, R2, and R3are each independently alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted; or any two of R1, R2, and R3together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, each optionally substituted; or R1, R2, and R3together with the carbon atom to which they are attached form a bicycloalkyl, tricycloalkyl, bi-heterocyclyl, tri-heterocyclyl, bridged-carbocyclyl, or bridged- heterocyclyl, each optionally substituted; wherein R4is alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, or C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted; Docket No.: 359006.00004 R5is alkyl, haloalkyl, aryl, or heteroaryl, each optionally substituted; R6is alkyl, haloalkyl, or aryl, each optionally substituted; R7is alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is alkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; Rxand Ryare independently alkyl, alkenyl, or aryl; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; Raand Rbare independently hydrogen, alkyl, aryl, benzyl, or together with the nitrogen atom to which they are attached form a heterocyclyl, each optionally substituted. In some embodiments, in the process of the disclosure, the catalyst is 4,4'-di-tert-butyl- 1,1'-biphenyl (DBB), naphthalene, or substituted naphthalene. In some embodiments, in the process of the disclosure, the adamantyl-lithium is formed in situ by reacting an adamantyl halide compound with lithium in the presence of : Li (metal) 4,4'-di-tert-butyl-1,1'-biphenyl , wherein X is halide. In some embodiments, in the process of the disclosure, the solvent for the reaction in Step (a) is selected from tetrahydrofuran, ether-containing solvents, N,N-dimethylacetamide, and N,N-dimethylformamide. In some embodiments, in the process of the disclosure, the solvent for the reaction in Step (b) is selected from tetrahydrofuran, ether-containing solvents, N,N-dimethylacetamide, and N,N-dimethylformamide, and wherein the solvent for the reaction in Step (b) is the same or different from the solvent for the reaction in Step (a). In some embodiments, in the process of the disclosure, the copper salt is CuCN, Cu(thiophene), Cu(acetylide), or Cu(carbene). In some embodiments, in the process of the disclosure, the reaction of Step (a) is conducted at a temperature from 0 °C to room temperature. Docket No.: 359006.00004 In some embodiments, in the process of the disclosure, the reaction of Step (b) is conducted from room temperature to an elevated temperature. In some embodiments, in the process of the disclosure, the elevated temperature is in the range from about 40 °C to about 100 °C. In some embodiments, in the process of the disclosure, the elevated temperature is in the range from about 60 °C to about 80 °C. In some embodiments, in the process of the disclosure, the reaction of Step (b) is conducted in the presence of a cesium salt and triphenylphosphine (PPh3). In some embodiments, in the process of the disclosure, the compound (A) is a pinacol boronate ester, with Rxand Rytogether forming . In some embodiments, in the process of the disclosure: (i) the adamantyl-lithium is about 1.0 to about 1.5 mole equivalent to the compound (A); (ii) the catalyst is DBB in an amount in the range of about 1 mol% to 10 mol% of the compound (A); (iii) the electrophile compound R4-X1is about 1.2 to about 3.0 mole equivalent to the compound (A); (iv) the copper salt is CuCN in an amount in the range of about 5 to about 50 mol% of the compound (A); and (v) the solvent for both of the reactions in Step (a) and Step (b) comprises tetrahydrofuran. In some embodiments, in the process of the disclosure, the compound (A) is selected from: wherein: R1and R2are independently C1-12 alkyl, optionally substituted; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is an integer selected from 1-6; Docket No.: 359006.00004 i and j are independently 0, 1, 2, or 3; k is 1 or 2; h is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, 4, or 5; and R9at each occurrence is independently selected from C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, NRaRb, and oxo (=O); and R10at each occurrence is independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6haloalkoxy, NRaRb, halide, CN, and NO2. In some embodiments, in the process of the disclosure, R1, R2, and R3together with the carbon atom to which they are attached form a bicycloalkyl or bridged-carbocyclyl of formula (A-1), which optionally substituted and optionally comprises one or more C=C double bonds, and the compound (A) comprises an additional boronate ester moiety -B(ORx)(ORy): (A-1)(I-1) ,wherein i and j are independently 0, 1, 2, or 3; and k is 1 or 2. In some embodiments, in the process of the disclosure, i and j are each independently 1 or 2, and k is 1 or 2. In some embodiments, in the process of the disclosure, the electrophile compound R4- X1is selected from: wherein: Docket No.: 359006.00004 p is 0, 1, or 2; q is 0, 1, 2, or 3; X1is Cl, Br, or I; R7is alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is alkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R9at each occurrence is independently selected from C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6 haloalkoxy, NRaRb, and oxo (=O); R10at each occurrence is independently selected from C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, NRaRb, halide, CN, and NO2; and R11to R14at each occurrence are independently selected from hydrogen, alkyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, and C(O)OR8, wherein the alkyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted. In another aspect, the present disclosure provides a method of preparing a compound of formula (I-2), comprising: (i) a process of preparing the compound of formula (I-1) according to any embodiment disclosed; and (ii) converting the compound of formula (I-1) to the compound of formula (I-2): , wherein R4ais same as or different from R4and is independently selected from hydrogen, OH, alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, and C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted. In some embodiments, the method of the disclosure comprises the steps of: (i) converting the compound of formula (A-1) to the compound of formula (I-1) through a copper- Docket No.: 359006.00004 catalyzed coupling of an adamantly-boronate ester adduct with an electrophile; and (ii) converting the compound of formula (I-1) to the compound of formula (I-2) through oxidation: (I-2)In some embodiments, the method of the disclosure the oxidant is H2O2, NaBO3or a hydrate thereof, and wherein i, j, and k are each equal to 1. In another aspect, the present disclosure provides a method of preparing a nortricyclane compound of formula (II) or an isomer or analog thereof, comprising reacting a norbornene bis(boronate) ester compound of formula (B) or an analog thereof, with an electrophile compound E-X1in the presence of a palladium-catalyst and a base, optionally along with a ligand, in a solvent: , wherein: Rxand Ryat each occurrence are independently alkyl, alkenyl, or aryl, each optionally substituted; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; E is an electrophile moiety; X1is a leaving group; Docket No.: 359006.00004 T5is selected from hydrogen, halogen, C1-8 alkyl, C1-8 haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6 alkyl, or benzyl; Rsiat each occurrence is independently C1-6alkyl, C3-6cycloalkyl, phenyl, or benzyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl. In some embodiments, in the method of the disclosure: E is selected from alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, and heterocyclyl are each optionally substituted; X1is selected from halide, -OS(O)2R5, -OC(O)R5, and -NRaS(O)2R5; the palladium catalyst is Pd(0) or a Pd(II) salt, each optionally complexing with a ligand. the optional ligand is a chiral or achiral phosphine compound; the base is selected from phosphate salts, carbonate salts, and bicarbonate salts; the solvent is selected from tetrahydrofuran, water, lower alcohol, and mixtures thereof. In some embodiments, in the method of the disclosure: Rxand Rytogether form E is selected from alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, Docket No.: 359006.00004 wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted; X1is selected from halide, -OS(O)2R5, -OC(O)R5, and -NRaS(O)2R5; the palladium catalyst is Pd(OAc)2; the ligand is a chiral phosphine ligand (R)-L1 or (S)-L1, or a mixture thereof, or (R,R)-L2 or (S,S)-L2, or a mixture thereof: the base is selected from phosphate salts, carbonate salts, bicarbonate salts, metal hydroxides, metal alkoxides, and mixtures thereof; and the solvent is selected from tetrahydrofuran, water, lower alcohol, aromatic solvents, ethereal solvents, and mixtures thereof. In another aspect, the present disclosure provides a method of preparing a nortricyclane compound of formula (III), or an isomer or analog thereof, comprising reacting a nortricyclane bis(boronate) ester compound of formula (C), or an isomer or analog thereof, with an electrophile compound E-X1in the presence of a palladium-catalyst and a base, optionally along with a ligand, in a solvent: , wherein: Rxand Ryat each occurrence are independently alkyl, alkenyl, or aryl, each optionally substituted; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; E is an electrophile moiety; Docket No.: 359006.00004 X1is a leaving group; T5is selected from hydrogen, halogen, C1-8 alkyl, C1-8 haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6alkyl, or benzyl; Rsiat each occurrence is independently C1-6alkyl, C3-6cycloalkyl, phenyl, or benzyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl. In some embodiments, the method of the disclosure: E is selected from alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, and heterocyclyl are each optionally substituted; X1is selected from halide, -OS(O)2R5, -OC(O)R5, and -NRaS(O)2R5; the palladium catalyst is Pd(0) or a Pd(II) salt, each optionally complexing with a ligand. the optional ligand is a chiral or achiral phosphine compound; the base is selected from phosphate salts, carbonate salts, and bicarbonate salts; the solvent is selected from tetrahydrofuran, water, lower alcohol, and mixtures thereof. In some embodiments, in the method of the disclosure: Rxand Rytogether form E is selected from alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, Docket No.: 359006.00004 wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted; X1is selected from halide, -OS(O)2R5, -OC(O)R5, and -NRaS(O)2R5; the palladium catalyst is APhosPd (G3); the base is Cs2CO3; and the solvent is selected from tetrahydrofuran, water, lower alcohol, aromatic solvents, ethereal solvents, and mixtures thereof. In some embodiments, in the method of the disclosure, E is selected from: wherein: p is 0, 1, 2, or 3; q is 0, 1, 2, 3, or 4; R10at each occurrence is independently C1-6 alkyl, C1-6 haloalkyl, OR15, SR15, NHR15, NRaRb, halide, CN, NO2, -CO2R8, CONRaRb, -O-C(O)NRaRb, C6-10aryl, benzyl, 5- to 10- membered heteroaryl, or 5- to 10-membered heterocyclyl; R15at each occurrence is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, benzyl, or C3-6cycloalkyl, each optionally substituted; and Raand Rbare independently hydrogen, C1-6alkyl, C6-10aryl, benzyl, or C3-6cycloalkyl, or together with the nitrogen atom to which they are attached form a heterocyclyl, each optionally substituted. In some embodiments, in the method of the disclosure: (i) the palladium catalyst is about 0.5 mol% to about 5 mol% equivalent to the compound (B); Docket No.: 359006.00004 (ii) the ligand is in an amount in the range of about 1.0 to about 1.5 mole equivalent to the palladium catalyst; (iii) the electrophile compound E-X1is about 1.1 to about 1.8 mole equivalent to the compound (B); (iv) the base is about 1.1 to about 1.5 mole equivalent to the electrophile compound E-X1; and (v) the solvent is a mixture of tetrahydrofuran and water. In some embodiments, in the method of the disclosure the bis(boronate) compound (B) is prepared by reacting norbornadiene with bis(pinacolato)diboron in the presence of a cesium salt as catalyst in a solvent: In some embodiments, in the method of the disclosure, the cesium salt catalyst is Cs2CO3, and the solvent is a mixture of MeOH / THF. In some embodiments, in the method of the disclosure, the Cs-catalyst is in an amount of about 0.1 to about 0.5 equivalent to bis(pinacolato)diboron, the norbornadiene is in an amount of about 3 to about 8 equivalent to bis(pinacolato)diboron [i.e., B2(pin)2], and the reaction is conducted at an elevated temperature. In some embodiments, in the method of the disclosure, the bis(boronate) compound (C), or an analog thereof, is prepared by treating norbornene bis(boronate) compound (B), or analog thereof, with a catalytic amount of acid in a solvent: In some embodiments, in the method of the disclosure, the acid is toluene sulfonic acid, and the solvent is chloroform. Docket No.: 359006.00004 In some embodiments, in the method of the disclosure, the bis(boronate) is pinacol bis(pinacol boronate), and the reaction is conducted at an elevated temperature. In another aspect, the present disclosure provides a method of preparing a nortricyclane compound of formula (IV), or an isomer or analog thereof, comprising reacting an oxo- substituted norbornane bis(boronate) ester compound of formula (D), or an isomer or analog thereof, with an amine in the presence of an acid in a solvent: , wherein: Rxand Ryat each occurrence are independently alkyl, alkenyl, or aryl, each optionally substituted; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; Raand Rbare independently selected from hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, and C3-6cycloalkyl, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; T5is selected from hydrogen, halogen, C1-8alkyl, C1-8haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6alkyl, or benzyl; Rsiat each occurrence is independently C1-6 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl. Docket No.: 359006.00004 In some embodiments, in the method of the disclosure: the acid is a C1-6 alkyl carboxylic acid; and the solvent is a halogenated C1-6hydrocarbon. In some embodiments, in the method of the disclosure: Rxand Rytogether form and RaRbNH is a primary or secondary amine comprising a C1-6 alkyl and / or aryl group or a heterocyclyl compound comprising an NH on the ring. In another aspect, the present disclosure provides a method of preparing a nortricyclane compound of formula (V), or an isomer or analog thereof, comprising: (i) preparing a compound of formula (II), or an isomer or analog thereof, according to the method of any embodiment disclosed herein; and (ii) converting the compound of formula (II), or an isomer or analog thereof, to the compound of formula (V), or an isomer or analog thereof under suitable conditions: , wherein E1and E are same or different, each independently selected from hydrogen, OH, alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, OR15, SR15, NHR15, C(O)NRcRd, and C(O)NHR16wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, NO2, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O- C1-4haloalkyl, C(O)OR16; NRcRd, C(O)NRcRd, and C(O)NHR16; T5is selected from hydrogen, halogen, C1-8alkyl, C1-8haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is alkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; Docket No.: 359006.00004 R15at each occurrence is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, benzyl, or C3-6 cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen or C1-6alkyl; Raand Rbare independently hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, or C3-6 cycloalkyl, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein C1-6alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Rcat each occurrence is independently hydrogen or C1-4alkyl; and Rdat each occurrence is independently hydrogen or C1-4alkyl. In some embodiments, in the method of the disclosure, the step (ii) is selected from: (a) reacting with t-BuLi then Zn(OAc)2, and substituted or unsubstituted aryl bromide in the presence of G3-PdCPhos to obtain the compound of formula (V), or an analog thereof, where E1is a substituted or unsubstituted aryl group; (b) reacting with t-BuLi, then 20 mol% CuCN, 2,3-dichloropropene, to obtain the compound (V), or an analog thereof, where E1is -CH2C(Cl)=CH2; (c) reacting with t-BuLi, then 20 mol% CuCN, methyl formamide, to obtain the compound of formula (V), or an analog thereof, where E1is -CO2Me; (d) reacting with MeONH2, n-BuLi, and then Boc2O, to obtain the compound of formula (V), or an analog thereof, where E1is -NHBoc; (e) reacting with n-BuLi and CH2BrCl to obtain the compound of formula (V), or an analog thereof, where E1is -CH2B(ORx)(ORy); and (f) reacting with NaOH and H2O2to obtain a compound of formula (V), or an analog thereof, where E1is OH. The disclosure also illustrates that incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. These features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scaffold will render this platform a useful foundation for assembly of new biologically active agents. As those skilled in the art would understand, the present disclosures encompasses any reasonable combinations of any embodiments disclosed. Docket No.: 359006.00004 Solely for illustration, the compounds and methods disclosed herein are applicable to synthesis of compounds and synthetic methods partly outlined below. tricyclo[2.2.1.0]heptane= TCH(meta benzene isostere) DEFINITIONS Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The term “alkyl" refers to a branched or unbranched monovalent aliphatic hydrocarbon radical derived from an alkane by removal of one hydrogen atom. In certain embodiments, an alkyl group contains 1 to 12 carbons. In certain embodiments, an alkyl group contains 1 to 8 carbons. In certain embodiments, sometimes preferably, an alkyl group contains 1 to 6 carbons, and in certain embodiments, sometimes more preferably, an alkyl group contains 1 to 4 carbons. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, 1,2- Docket No.: 359006.00004 dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2- methylpropyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3- methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 2- ethylpentyl, 3-ethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2- dimethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, or the like. The alkyl group can be substituted or unsubstituted. The term “alkenyl” refers to any monovalent aliphatic hydrocarbon radical derived from a branched or unbranched alkene by removal of one hydrogen atom. In certain embodiments, an alkenyl group contains 2 to 12 carbons. In certain embodiments, an alkenyl group contains 2 to 8 carbons. In certain embodiments, sometimes preferably, an alkenyl group contains 2 to 6 carbons, and in certain embodiments, sometimes more preferably, an alkenyl group contains 2 to 4 carbons. Examples of alkenyl include, but are not limited to, ethenyl (or vinyl), propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, 1-buten-1-yl, 1-buten-2-yl, 2-buten-1-yl, 2-methyl-1-propen-1-yl, 4-methyl-2-penten-1-yl, or the like. An “allyl” group is a special alkenyl group, i.e., CH2=CHCH2-. The alkenyl group can be substituted or unsubstituted. The term “alkynyl" refers to a monovalent aliphatic hydrocarbon radical derived from an alkyne by removal of one hydrogen atom. In certain embodiments, an alkynyl group contains 2 to 12 carbons. In certain embodiments, an alkynyl group contains 2 to 8 carbons. In certain embodiments, sometimes preferably, an alkynyl group contains 2 to 6 carbons, and in certain embodiments, sometimes more preferably, an alkynyl group contains 2 to 4 carbons. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, or the like. The alkynyl group can be substituted or unsubstituted. The term "cycloalkyl" refers to any monovalent radical formed by removal of one hydrogen atom from a cycloalkane. In certain embodiments, cycloalkyl group contains 3 to 10 carbons. In certain embodiments, cycloalkyl group contains 3 to 8 carbons. In certain embodiments, sometimes preferably, cycloalkyl group contains 3 to 6 carbons. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. The cycloalkyl is optionally substituted or unsubstituted. Docket No.: 359006.00004 The term “carbocyclyl” refers to any monocyclic or polycyclic nonaromatic hydrocarbon group, including bicyclic, tricyclic, or policyclic hydrocarbon groups in which the adjacent rings can share an adjacent pair of carbon atoms (fused ring system) or share a single carbon atom (spiro system), wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. A “carbocyclyl” group may contain 5 to 14 ring carbon atoms, sometimes preferably more preferably 5 to 10 carbon atoms. According to the number of membered rings, fused cycloalkyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic, tricyclic or tetracyclic fused cycloalkyl, and more preferably bicyclic or tricyclic. The term “bridged cycloalkyl” or “bridged carbocyclyl” refers to any cycloalkyl or carbocycyl group, respectively, in which at least two nonadjacent ring carbon atoms are connected with each other through a hydrocarbon bridge, thus forming a bicyclic or polycyclic ring structure. A bridged cycloalkyl or carbocyclyl may contain from 5 to 14 ring carbon atoms, including the bridge carbons, and may contain one or more bridges, and may have one or more double bonds, but none of the rings has a completely conjugated pi-electron system. In some embodiments, a bridged cycloalkyl or carbocyclyl contains 6 to 12 ring carbons, sometimes preferably 7 to 10 ring carbons. According to the number of membered rings, a bridged cycloalkyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and more preferably bicyclic or tricyclic bridged cycloalkyl. Nonlimiting examples of bridged cycloalkyls include, but are not limited to: The term "heterocyclyl" refers to a cycloalkyl or carbocylcyl wherein at least one ring atom is a non-carbon atom. Examples of the non-carbon ring atom include, but are not limited to, S, O and N. Representative examples of monocyclic heterocyclyls include, but are not limited to, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, and the like. The term “alkylene” refers to a saturated linear or branched divalent aliphatic hydrocarbon group, derived by removing two hydrogen atoms the parent alkane. The straight or branched chain group containing 1 to 12 carbon atom(s) (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon atom(s)), preferably has 1 to 8 carbon atom(s), more preferably 1 to 6 carbon atom(s),and sometimes more preferably 1 to 4 carbon atom(s). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), Docket No.: 359006.00004 1,3-propylene (-CH2CH2CH2-), 1,4-butylidene (-CH2CH2CH2CH2-), etc. The alkylene group can be substituted or unsubstituted. The term “alkenylene” refers to an alkylene defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably C2-12 alkenylene, more preferably C2-8 alkenylene, sometimes more preferably C2-6 alkenylene, and sometimes even more prefereably C2-4alkenylene. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2- etc. The alkenylene group can be substituted or unsubstituted. The term “aryl” refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group, and has a completely conjugated pi- electron system. Preferably aryl is 6 to 10 membered, such as phenyl and naphthyl, sometimes more preferably phenyl. The aryl group can be substituted or unsubstituted. The term “heteroaryl” refers to an 5 to 14 membered aryl system having 1 to 4 heteroatom(s) selected from O, S and N as ring atoms. Preferably a heteroaryl is 5- to 10- membered (such as 5, 6, 7, 8, 9 and 10 membered), more preferably 5- or 6- membered, for example, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl can be fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. The heteroaryl group can be substituted or unsubstituted. In the present disclosure, “alkyl” and “alkylene,” “alkenyl” and “alkenylene,” “aryl” and “arylene,” “cycloalkyl” and “cycloalkylene,” or the like, may sometimes be used interchangeably. Thus, interpretation of these terms should be based on the context as would be understood by a person of ordinary skill in the art. The term “alkoxy” refers to both an -O-(alkyl), for example, methoxy, ethoxy, propoxy, butoxy, and the like. The term “cycloalkoxy” refers to -O-(cycloalkyl), for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The term “bond” refers to a covalent bond using a sign of “—”. The term “hydroxyl” refers to an -OH group. The term “halogen” refers to fluoro, chloro, bromo or iodo atoms. The term “amino” refers to a -NH2group. The term "alkylthio" refers to alkyl-S-. Docket No.: 359006.00004 The temr “alkylamino” refers to “alkyl-NH-”, or sometimes dialkyl amino (-NRaRb), where the two alkyl groups (Raand Rb) can be the same or different. Sometimes preferably, the alkyl group is a C1-C6alkyl, and sometimes more preferably, the alkyl is a C1-C4alkyl. Examples of alkylamino include, but are not limited to, CH3-NH-, -N(CH3)2, -N(CH2CH3)2, - NHCH2CH3, -N(CH3)(CH2CH3), -NH-But, -N(CH3)(But), or the like. The term “cyano” refers to a -CN group. The term "haloalkyl" means an alkyl group substituted by one or more halogen atoms, wherein the halogen atoms can be the same or different. The term “nitro” refers to a -NO2group. The term “oxo group” refers to a =O group. The term “carboxyl” refers to a -C(O)OH group. The term “alkoxycarbonyl” refers to a -C(O)O(alkyl) group. The term “alkylcarbonyl” refers to a -C(O)-alkyl group. The term “optional” or “optionally” means that the event or circumstance described subsequently can, but need not, occur, and the description includes the instances in which the event or circumstance may or may not occur. For example, “the heterocyclyl group optionally substituted by an alkyl” means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclyl group being substituted with an alkyl and the heterocyclyl group being not substituted with an alkyl. The term “substituted” refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atom(s), independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable. The term “covalent bonding principle”, as used herein, refers to those basic rules and principles in formation of covalent bonds in an organic compound, as generally understood by a person of ordinary skill in the art. For example, a carbon atom is tetravalent and can form only four covalent bonds (e.g., four single bonds, or a double bonds plus two single bonds, etc.), an oxygen is divalent and can only form two covalent bonds (two single bond in -O-, or a double bond in =O). In some embodiments, when an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group, or the like, or a moiety thereof, is substituted, the substituent group(s) can be substituted at any available connection point(s), and the substituents can be one or more, Docket No.: 359006.00004 sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkylthio, C1-C6alkylamino, di-(C1-C6alkyl)amino, thiol, hydroxyl, nitro, cyano, amino, C3- C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3- C6 cycloalkoxy, C1-C6 cycloalkylthio, 5- to 10-membered heterocyclylthio and oxo group. In some embodiments, sometimes preferably, the substituents are independently selected from C1-C6alkyl, halogen, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylamino, di-(C1-C6alkyl)amino, thiol, hydroxyl, nitro, cyano, amino, and oxo group. In some embodiments, sometimes more preferably, the substituents are independently selected from C1-C4alkyl, halogen, C1-C4alkoxy, C1-C4alkylthio, C1-C4alkylamino, di-(C1-C4alkyl)amino, thiol, hydroxyl, nitro, cyano, and amino. As a person of ordinary skill in the art would understand, an oxo (=O) group cannot be a substituent of an aryl or heteroaryl group, or at an unsaturated carbon in any other group. “Optional” or “optionally” means that the event or circumstance described subsequently can be, but need not be, and such descriptions include the situation in which the event or circumstance may or may not occur. For example, “the heterocyclic group optionally substituted with an alkyl” means that an alkyl group can be, but need not be, present, and such description includes the situation of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl. For any substituents alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, and carboxylic ester mentioned throughout the application, any alkyl is preferably C1-C6alkyl, sometimes more preferably C1-C4alkyl; any alkenyl is preferably C2- C6alkenyl, sometimes more preferably C1-C4alkenyl; any alkynyl is preferably C2-C6alkynyl, sometimes more preferably C1-C4 alkynyl; any cycloalkyl is preferably C3-C6 cycloalkyl; any heterocyclyl is preferably 5- to 10-membered, sometimes more preferably 5- or 6-membered heterocyclyl; any aryl is preferably C6-C10aryl, more preferably phenyl; any heteroaryl is 5- to 10-membered, sometimes more preferably 5- or 6-membered, heteroaryl; and any carboxylic ester is preferably C1-C4 alkyl ester, sometimes more preferably methyl or ethyl ester. Denotation of carbon atoms or ring atoms in a substituent group, such as alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, or the like, may take different forms but they should be understood to mean a same thing as would be understood by those skilled in the art. For example, an alkyl group containing 1 to 6 carbon atoms may be denoted as “C1-C6alkyl,” “C1-6alkyl,” “C1-6alkyl,” or the like, which may occur for other substituent groups as well. Docket No.: 359006.00004 The term “isomer,” as used herein, refers to all possible types of isomerism a compound may have, as suitable in the context. They may include stereoisomers, configurational isomers, geometrical isomers, conformational isomers, or the like. The term “stereoisomer” refers to isomers that are structurally identical but differ in the arrangement of the atoms in space, which may or may not by caused by asymmetric (chiral) centers in the structure. It includes enantiomers, diastereomers, atropisomers, or the like, and their respective mixtures. The term “atropisomers” refers to a special type of stereoisomer, i.e., conformational stereoisomers, which result from steric hindrance in a molecule such that rotation about a single bond is hindered or greatly slowed. Some atropisomers could be separated and isolated in a stable form. For example, certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal ratio mixture, a mixture enriched in one atropisomer) or a purified atropisomer under different conditions. All such stereoisomers and mixtures thereof are encompassed within the scope of the present disclosure, whether a compound is presented as a chiral form or not, whether only one single isomer or multiple isomers are presented. The present disclosure also encompasses cis- / trans- (or Z- / E-) isomers caused by the different configurations of substituents on a double bond, especially C=C, which are sometimes called geometrical isomers. The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term “tautomer” or “tautomeric form” refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form into another. Non-limiting examples include keto-enol tautomerism, imine-enamine tautomerism, or the like. The present disclosure also encompasses all suitable isotopic derivatives of the compounds disclosed. The term “isotopic derivative” refers to a compound in which at least one atom is replaced with an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, boron, nitrogen, oxygen, phosphorus, or the like, such as2H (deuterium, D),3H (deuterium, T),11C,13C,14C,8B,10B,11B,15N,17O,18O, etc. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom linked to a carbon atom may be independently replaced with a deuterium atom, as would be understood by those skilled in the art. Docket No.: 359006.00004 As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. A “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present disclosure or physiologically / pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity. The term “pharmaceutically acceptable,” as used herein, refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. “Pharmaceutically acceptable salts” refer to salts of the compounds of the disclosure, such salts being safe and effective when used in a mammal and have corresponding biological activity. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid. Pharmaceutically acceptable salts are well known in the art. See, e.g., S. M. Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids. The term “subject,” "patient,” or the like, includes both humans and other mammalian animals, including but not limited to cats, dogs, bigs, horses, sheep, goats, monkeys, chimpanzees, and so on, preferably humans. The term “therapeutically effective amount" refers to an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. A "therapeutically effective amount" can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, or other factors of the subject to be treated. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. Docket No.: 359006.00004 The term “treat”, “treating”, “treatment”, or the like, refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (ii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and / or condition. In addition, the compounds of present disclosure may be used for their prophylactic effects in preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder, and / or condition but has not yet been diagnosed as having it. The terms “a” and “an” and “the” and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one”, but it is also consistent with the meaning of “one or more”, “at least one”, and “one or more than one”. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like. The term “and / or” as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. When used in a list of two or more items, the term “and / or” means that any one of the listed items can be employed by itself, or any combination of two or more of the listed items can be employed. Throughout this application, the term “about” or “approximately” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects. In one aspect, the terms “about” or “approximately” usually mean within 10%, sometimes preferably within 5%, sometimes preferably within 3%, sometimes preferably within 2%, sometimes more preferably within 1% of a given value or range. EXAMPLES The following nonlimiting examples further illustrate certain aspects of the present disclosure. Example 1 Catalytic Stereospecific Cross-Couplings of Tertiary Boronic Esters through Group- Selective Transmetalation Docket No.: 359006.00004 Docket No.: 359006.00004 The present disclosure provides a practical catalytic method for generating adamantyllithium in situ, which then reacts with tertiary alkylboronic esters at room temperature. The resulting borate species can engage in stereospecific copper-catalyzed coupling reactions with an array of electrophiles. The examples disclosed involve stereospecific transmetalation from a tertiary boronate to another metal. In addition to providing a useful synthesis tool, these studies shed light on features that impact transmetalation efficiency. Although tert-butyllithium-activated primary and secondary organoboronic esters can undergo stereospecific transmetalation to both copper and zinc salts, thereby enabling a broad array of cross-coupling reactions (Xu, N., et al., J. Am. Chem. Soc.2022, 144, 11546–11552.), for the tertiary alkylboronic esters, a challenge would be the selectivity between transferring the activator versus the substrate alkyl group. While previous activation of secondary alkylboronic esters relied on the faster transmetalation of a secondary alkyl group relative to a tert-butyl group, effective activation of a tertiary group would require an activator that transmetalates slower than the transferring tertiary alkyl substrate. X-ray analysis of a crystal of (tert-butyl)(adamantyl)B(pin)●Li(THF)2, obtained by slow diffusion of hexane into a THF solution, hinted at selective group transfer in transmetallation: the B–(adamantyl) bond is shorter that the B–(–(tert-butyl) bond (1.673 Å vs.1.692 Å). Interestingly, the B–C bond in adamantylB(pin) (1.59 Å) is longer than the B– Docket No.: 359006.00004 C bond in acyclic tertiary pinacol boronic esters (1.57–1.58 Å) suggesting that upon conversion to dialkyl(pinacol)borates, the B–(tert-butyl) bond is weakened to a greater extent than the B– (adamantyl) bond. Aligned with these observations, DFT calculations indicated that the barrier for transmetalation of the adamantyl group from adamantyl(tert-butyl)pinacol boronate to CuCN is 2.3 kcal / mol higher in energy than for transmetalation of the tert-butyl group. Based on the results of DFT calculations and foregoing discoveries, the present inventors designed a practical method for the synthesis of the corresponding adamantyl borate complexes. Adamantyllithium has been prepared by lithiation of adamantyl halides, ((a) Molle, G.; Bauer, P. J. Am. Chem. Soc. 1982, 104, 3481–3487. (b) Molle, G., et al., J. Org. Chem. 1983, 48, 2975–2981.) however, this reaction requires low temperature and specialized lithium alloys. Additionally, the resulting adamantyllithium is a pyrophoric reagent that is unstable in many solvents and thus ill-suited for long term storage. As an alternative, a catalytic modification of a stoichiometric in situ lithiation was designed. Thus, treatment of adamantyl chloride and the tertiary boronic ester 1 with 5 mol% 4,4'-di-tert-butylbiphenyl (DBB) and excess lithium metal resulted in formation of the borate complex within one hour at room temperature as indicated by11B NMR analysis. ((a) Cohen, T.; Matz, J. R. Synth. Commun. 1980, 10, 311–317. (b) Yus, M.; Ramón, D. J. J. Chem. Soc., Chem. Commun.1991, 398–400.) Of note, DBB functions as both a catalyst and as an indicator for the reaction process: upon complete consumption of adamantyl chloride, the reaction mixture takes on the dark blue color of the residual Li–DBB adduct. With ready access to adamantyl-activated tertiary boronate complexes, their use in copper-catalyzed coupling reactions was investigated. After separation of the boronate complex from residual lithium by cannula transfer, the THF solution of the borate was added to 20 mol% copper cyanide followed by allyl electrophiles. For a variety of leaving groups, the desired allylation product 2 was obtained in 25–60% yield with only trace amounts of adamantyl coupling product being observed. Depending on the nature of the leaving group, moderate to high levels of stereospecificity (54–>98% es) were also observed in these reactions, however, the use of 2.0 equivalents of allyldiethyl phosphate resulted in yield (64%) and consistently high levels of stereospecificity. The scope of the coupling reaction was examined with a series of different allyl and propargyl electrophiles, which provided moderate to good yields of alkenes and allenes containing quaternary stereocenters. For product 2 and 12, the enantiospecificity was determined to be >98%. Of note, the Boc protecting group of product 9 survived the coupling Docket No.: 359006.00004 sequence intact. Also of note, the borate species can engage in copper-catalyzed stereospecific amination reactions. (Yang, Y., et al., Science 2015, 349, 62–66.) Thus, enantiomerically- enriched amines can be prepared in moderate to good yields and good stereospecificity. The absolute configuration of 18 was assigned based on X-ray crystallography, which indicated that the process occurs with retention of configuration at carbon. For less reactive electrophiles such as acyl chlorides (products 21–24), b-haloenones (products 26–29), 2-iodopyridine (25), sulfonylcyanamide reagent 19 (product 20) and bromoalkynes (product 30), moderate yields can be obtained. For these electrophiles, high yielding coupling reactions occurred when more reactive cyclopropylboronic esters were employed. Example 2 Coupling of Secondary Boronic Esters: Example 3 Gram-Scale Coupling and Product Derivatizations a: Gram-scale cross-coupling DBB (5 mol%) CuCN (20 mol%) 1 2 1.0 g, 93:7 er 0.37 g, 51% yield 93:7 er, >98% esb: Transformations of coupling products Docket No.: 359006.00004 B(pin) mol%) (10 mol%) B(pin) PdCl2equiv) CuCl (20 mol%) O2, DMF / H2O THF, 60 °C, 12 h rt, 12 h 60% yield 67% yield 10:1 drMePhnBu B(pin) CO2Et(equiv)G25 mol%)8 h MePh n C Et then Bu O2pinacol (2.0 equiv) (2.5 equiv)MePhNEt , rt, 30 mnBu 383in CH2Cl2, 40 °C, 12 h39 90% yield E / Z > 20:1 To examine aspects pertaining to synthesis utility, a gram-scale coupling reaction was conducted. In this process, the desired product 2 could be isolated in 51% yield and >98% enantiospecificity. With larger quantities of coupling product, transformations of the allylation adduct was also examined. It was found that the coupling product can engage in platinum- catalyzed diboration (→31), ((a) Coombs, J. R., et al., J. Am. Chem. Soc. 2013, 135, 11222– 11231. (b) Kliman, L. T., et al., J. Am. Chem. Soc. 2009, 131, 13210–13211.) palladium- catalyzed Wacker oxidation (→32), ruthenium-catalyzed olefin metathesis (→32) and hydroboration reactions (→34), which furnished synthetically-useful building blocking containing a quaternary stereocenter. Example 4 Borylated bicyclo[2.2.1]heptane as a Meta-benzene Bioisostere Precursor and Synthesis an Analog of COX-2 inhibitor Docket No.: 359006.00004 To further examine the synthetic application of the above-described coupling reactions, a general route for the synthesis of bicyclo[2.2.1]heptane derivatives 42 was designed. This framework has been suggested as a saturated bioisostere of meta disubstituted benzenes (41) due to the similar angle and distance of the two attachment points at the bridging carbon. (Mykhailiuk, P. K., Org. Biomol. Chem.2019, 17, 2839–2849.) A need for the development of this class of compounds is the selective and broad-scoped installation of functional groups at the tertiary carbons. Starting from inexpensive ketone 43, Wittig olefination followed by diboration provided 44 in good yield. Ketal deprotection followed by homologation selectively occurs at the primary boron to provide critical diboron scaffold 42. (Yang, Y., et al., Nat. Chem. 2021, 13, 950–955.) Under standard conditions for copper-catalyzed amination of tertiary boronates described above, 45 was isolated in 48% yield. Further oxidation with sodium perborate generated 46, which should serve as a useful starting point for the construction of COX-2 inhibitor analogs (i.e.47). (Pommery, N., et al., J. Med. Chem.2004, 47, 6195–6206.) The structures of compounds 42 and 46 are confirmed by X-ray crystallography (FIG.1). In conclusion, a practical and mild method for activating tertiary alkylboronic esters was developed. The adamantyllithium-activated borate complex can engage in copper- catalyzed cross-coupling reactions with an array of electrophiles. Importantly, this reaction can be used for construction of challenging quaternary stereocenters. Further studies on the utility of these processes are in progress. Docket No.: 359006.00004 Example 5 Escaping from Symmetry: Two-step Synthesis of Enantioenriched Nortricyclanes as Bioisosteres of meta-Substituted Arenes In recent years, more and more effort has been put in the development of arene bioisosteres, the replacement of flat aromatic rings with saturated, rigid polycycles. This replacement can improve pharmacokinetic properties while retaining bioactivity, and this concept is known as escaping from flatland. Though many scaffolds perform well as bioisosteres of para-substituted arenes and can be seen in FDA approved drugs, the increased complexity of ortho- and meta-substituted arene bioisosteres has rendered them less studied. Indeed, there are only a few rigid bicylic motifs that have been investigated, and they are either symmetric or they were prepared as racemates. Considering arene bioisosteres are meant to mimic arenes in pharmaceuticals whose role is to bind to chiral proteins, sugars, RNAs, etc., to achieve pharmacological functions, enantioenriched bioisosteres may be more effective. Therefore, this disclosure introduces the concept of “escaping from symmetry” and report a concise, asymmetric synthetic route to disubstituted nortricyclanes from norbornadiene powered by a new π-system assisted inventive Suzuki cross-coupling. The discovery of this research opportunity is rather serendipitous and surprising. In the research on asymmetric cross-coupling of vicinal bis(boronates), the present inventors discovered that the norbornadiene-derived bis(boronate) did not yield the desired product, but instead produced a mysterious byproduct in significant amounts. The proton and carbon NMR did not show an alkene group in the byproduct, but instead a three-membered ring appeared on the skeleton. Analysis of X-ray crystallography revealed the two exit vectors are almost coplanar with the dihedral angle being 2 degrees. Although the bond angle between the two exit vectors (127 degrees) is slightly off from that in meta-benzene, the distance between the two departure atoms is 2.4 angstroms, which matches that of meta-benzene. Docket No.: 359006.00004 More research revealed that this reaction is highly ligand dependent. Phosphine L2 shows highest enantioselectivity (96:4 er) with good yields, and surprisingly, as demethylated L2, L1 yields the opposite enantiomer as a major product (19:81 er). Following the above paradigm, an array of small bicyclic motifs have been developed that position substituents at a similar distance and with similar exit vectors compared to substituted arenes (Frank, N., et al., Nature 611, 721–726 (2022); Iida, T., et al., J. Am. Chem. Soc.144, 21848–21852 (2022); Wiesenfeldt, M. P., et al., Nature 618, 513–518 (2023); Yang, Y., et al., Nature Chem.13, 950–955 (2021); Levterov, V. V., et al., Angew. Chem. Int. Ed.59, 7161–7167 (2020); Zhao, J.-X., et al., Proc. Nat. Acad. Sci. USA 118, e2108881118 (2021); Yang, T., et al., Nature Chemistry 13950–955 (2021); Epplin, R. C., et al., Nature Comm.13, 6056 (2022); Smith, E., et. al., J. Am. Chem. Soc.145, 16365–16373 (2023); Son, J.-Y., et al., J. Am. Chem. Soc.145, 16355–16364 (2023).) A critical issue that arises when planar C(sp2)-based aromatic rings are replaced with C(sp3)-based bicyclic isosteres is that of three-dimensional shape. Even if the isostere positions its substituents in a manner that would superimpose them onto those of an aromatic nucleus, the tetrahedral nature of the saturated carbon centers in the isostere automatically results in a three-dimensionality that is absent from the flat aromatic ring system. Since the preponderance of biologically relevant receptors are chiral, the handedness of a nonsymmetric isostere may either enhance or impede binding of the derived ligand to its cognate receptor. (Nguyen, L. A., et al., Int. J. Biomed. Sci.2, 85–100 (2006).) The way MK-5108 binds to the inactive DFG- out state of the mitotic kinase Aurora A is illustrative. (de Groot, C. O., et al., Front. Oncol.5, 285 (2015). (Lake, E. W., et al., Proc. Nat. Acad. Sci. USA 115, E11894–E11903 (2018).) When bound, the meta disubstituted arene in MK-5108 is sandwiched in a hydrophobic pocket with Leu139 positioned 3.9 Å above the arene (carbon-to-carbon distance) and Gly2163.5 Å below. Thus, when a non-symmetric benzene isostere occupies this binding pocket, it would be expected to fit better if it occupies more volume in the upper region of the receptor rather than the lower. From this vantage point, it is clear that new methods are critically needed to control the absolute configuration of the overall molecular ensemble. In this respect, the present disclosure describes a modular, scalable, and enantioselective catalytic conversion of simple starting materials into chiral 3,5-disubstituted nortricyclane frameworks. Of note, comparison of the metrical parameters of the nortricyclane with those of benzene show that carbons 3 and 5 are equidistant with the meta carbons of benzene. Moreover, the exit vectors for connection to substituents at carbons 3 and 5 have an angle between them that is nearly the Docket No.: 359006.00004 same as in benzene (127° versus 120°), and the vectors are essentially co-planar as in the aromatic framework. Lastly, the process disclosed for production of 3,5-disubstituted nortricyclanes occurs by a novel catalytic reaction. This reaction occurs with low loadings of a chiral palladium complex and delivers malleable boron-containing isosteres, holding significant potential for utility. This work: ● catalytic cat. Pd / Ln● enantioselective ● scaleable E–X ● diversifiable isostere The bicyclic norbornadiene skeleton (1, see scheme above) has provided an instructive framework for studying the nature of non-classical carbocations and for probing the ability of homoconjugation to stabilize organic structures and influence the course of their chemical reactions. (Martin, H.-D. and Mayer, B., Angew. Chem. Int. Ed.22, 283–314 (1983).)(Houk, K. N., et al., J. Am. Chem. Soc.105, 5563–5569 (1983).) Due to the through-space interaction between the two p-bonds, the conversion of the bicyclo[2.2.1] framework to nortricyclanes (i.e. 2) readily occurs upon addition of suitable electrophilic reagents. (Winstein, S. and Shatavsky, M., Chem. Ind.56–57 (1956).) Similar electrophilic activation of bicyclic organometallics (i.e. 3) can result in ring-closing C–C bond formation to furnish the nortricyclane skeleton (4). (Matteson, D. S. and Waldbillig, J. O., J. Am. Chem. Soc.85, 1019–1020 (1963).) In contrast to these stoichiometric reactions, the present disclosure demonstrates that a catalytic synthesis of nortricyclanes operates when the mercury salts used in the synthesis of 2 and 4 are replaced with substoichiometric quantities of palladium complexes in conjunction with an organic electrophile. The reaction that occurs results in ring-closure with concomitant addition of the organic electrophile to the bicyclic framework. A critical finding for application of this reaction to the modular construction of enantiomerically-enriched meta benzene isosteres is that the cyclization occurs with meso diboron substrate 5, a compound that is shelf- stable and readily available on multigram scale. Reaction of 5 delivers a nortricyclane 6 that retains one boronic ester functional group, in addition to the newly appended organic substituent (E). After optimization of the reaction (conditions, ligand structure), it was found Docket No.: 359006.00004 that a wide array of enantiomerically enriched boron-containing nortricyclanes can be prepared in excellent yields and enantioselectivity. 2 mol% Pd(OAc)2 Docket No.: 359006.00004 In the presence of catalytic quantities of Pd(OAc)2 and chiral biarylmonophosphine ligand L1 (, diboron substrate 5 and organic electrophiles engage in catalytic enantioselective ring closure to nortricyclanes. (Tang, W., et al., Org. Lett.13, 1366–1369 (2011).) With simple substituted aryl bromides, the reaction occurs in high yields and enantioselectivity. It is notable that the products from both electron-deficient (11, 12) and electron-rich (13, 15) electrophiles can be readily obtained, although selectivity is diminished with a strong electron-withdrawing nitroarene electrophile (16). Also of note, heterocyclic electrophiles were found to engage in the reaction (products 20–23). With respect to practical features, it merits mention that unprotected anilines and phenols do not appear to interfere with the process and that extension to non-aromatic electrophiles (24, 25) appears promising. Example 6 2,2'-(tricyclo[2.2.1.02,6]heptane-1,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Representative Procedure A To an oven dried round bottom flask equipped with a stir bar was added (1R,4S,5S,6R)- 5,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[2.2.1]hept-2-ene (3.3 g, 9.54 mmol, 1.0 equiv.) followed by p-toluenesulfonic acid monohydrate (362 mg, 1.91 mmol, 0.2 equiv.). To the reaction mixture was then added chloroform (95 mL). The reaction mixture was then sealed with a septum under air and allowed to stir at 60 °C for 3 hours. The reaction mixture was then filtered through a plug of silica gel using diethyl ether and concentrated under reduced pressure. The crude reaction mixture was then purified with the use of silica gel chromatography. The title compound was isolated in 71% yield, 2.35 g.1H NMR (500 MHz, CDCl3) δ 2.00 (s, 1H), 1.37 (d, J = 5.1 Hz, 1H), 1.33 (dd, J = 10.3, 1.6 Hz, 1H), 1.30 – 1.25 (m, 1H), 1.24 (d, J = 6.0 Hz, 1H), 1.23 (s, 6H), 1.22 (s, 6H), 1.21 (s, 6H), 1.20 (s, 6H), 1.18 Docket No.: 359006.00004 (dd, J = 10.2, 1.5 Hz, 1H), 1.12 (d, J = 10.3 Hz, 1H), 0.93 (s, 1H).13C NMR (126 MHz, CDCl3) δ 82.8, 82.8, 36.3, 32.7, 32.3, 25.2, 25.0, 24.9, 24.5, 18.4, 17.5.11B NMR (160 MHz, CDCl3) δ 34.8. Example 7 4,4,5,5-tetramethyl-2-(7-(p-tolyl)tricyclo[2.2.1.02,6]heptan-1-yl)-1,3,2-dioxaborolane The title compound was synthesized under conditions similar to those of the representative procedure A.1H NMR (500 MHz, CDCl3) δ 7.10 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 2.89 (s, 1H), 2.33 (s, 3H), 1.89 (s, 1H), 1.62 (dq, J = 5.1, 1.2 Hz, 1H), 1.56 – 1.53 (m, 1H), 1.46 – 1.40 (m, 2H), 1.29 – 1.25 (m, 1H), 1.24 (s, 6H), 1.17 (s, 6H), 1.06 (dt, J = 10.6, 1.4 Hz, 1H). Example 8 1,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tricyclo[2.2.1.02,6]heptan-3-yl benzoate The title compound was synthesized under conditions similar to those of the representative procedure A.1H NMR (500 MHz, CDCl3) δ 8.05 – 7.98 (m, 2H), 7.56 – 7.49 (m, 1H), 7.46 – 7.37 (m, 2H), 5.12 (t, J = 1.9 Hz, 1H), 2.21 (t, J = 1.8 Hz, 1H), 2.06 (dt, J = 10.5, 1.4 Hz, 1H), 1.69 (dd, J = 4.9, 1.8 Hz, 1H), 1.53 (d, J = 4.8 Hz, 1H), 1.35 (dt, J = 10.4, 1.4 Hz, 1H), 1.31 (d, J = 3.1 Hz, 1H), 1.28 (s, 6H), 1.27 (s, 6H), 1.23 (s, 6H), 1.22 (s, 6H), 1.08 (s, 1H). Example 9 1,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tricyclo[2.2.1.02,6]heptan-3-ol Docket No.: 359006.00004 The title compound was synthesized under conditions similar to those of the representative procedure A.1H NMR (500 MHz, CDCl3) δ 3.80 (s, 1H), 1.85 (s, 1H), 1.75 (d, J = 10.8 Hz, 1H), 1.53 (d, J = 4.8 Hz, 1H), 1.44 (dd, J = 10.8, 1.4 Hz, 1H), 1.28 – 1.24 (m, 1H), 1.22 – 1.17 (m, 24H), 1.10 (s, 1H). Example 10 2-(2-(4-chlorophenyl)tricyclo[2.2.1.02,6]heptan-3-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane Representative procedure B In an Ar-filled glove box, to an oven dried 2-dram vial equipped with a stirbar was added 2,2'-(tricyclo[2.2.1.02,6]heptane-1,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (34.6 mg, 0.1 mmol, 1.0 equiv.) followed by 1-bromo-4-chloro-benzene (28.7 mg, 0.15 mmol, 1.5 equiv.) and cesium carbonate (97.8 mg, 0.3 mmol, 3.0 equiv.). To the reaction mixture was then added APhos-PdG3 (3.2 mg, 0.005mmol, 5.0 mol%), THF (0.9 mL) and water (0.3 mL). The reaction mixture was then sealed and allowed to stir at 100 °C for 20 hours. The reaction mixture was then filtered through a plug of silica gel using diethyl ether and concentrated under reduced pressure. The crude reaction mixture was then purified with the use of silica gel Docket No.: 359006.00004 chromatography. The title compound was isolated in 94% yield, 33 mg.1H NMR (500 MHz, CDCl3) δ 7.19 – 7.13 (m, 2H), 7.08 – 7.03 (m, 2H), 2.18 (s, 1H), 1.83 (dq, J = 10.3, 1.4 Hz, 1H), 1.66 (dq, J = 5.5, 1.3 Hz, 1H), 1.51 (dq, J = 10.3, 1.4 Hz, 1H), 1.45 (dt, J = 10.3, 1.5 Hz, 1H), 1.36 (s, 1H), 1.34 – 1.28 (m, 2H), 1.18 (s, 6H), 1.15 (s, 6H).13C NMR (126 MHz, CDCl3) δ 141.8, 130.3, 127.9, 127.8, 83.2, 37.3, 34.9, 33.1, 30.1, 24.9, 24.8, 24.6, 21.3.11B NMR (160 MHz, CDCl3) δ 33.8. Example 11 1-(4-methoxyphenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)tricyclo[2.2.1.02,6]heptan-3-yl benzoate The title compound was synthesized under conditions similar to those of the representative procedure B.1H NMR (500 MHz, CDCl3) δ 8.08 – 8.02 (m, 2H), 7.58 – 7.50 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.16 – 7.09 (m, 2H), 6.84 – 6.77 (m, 2H), 5.52 (t, J = 1.9 Hz, 1H), 3.78 (s, 3H), 2.40 (t, J = 1.7 Hz, 1H), 2.16 (dt, J = 10.6, 1.5 Hz, 1H), 1.98 (ddd, J = 5.1, 1.8, 1.0 Hz, 1H), 1.64 (dt, J = 10.6, 1.5 Hz, 1H), 1.54 – 1.52 (m, 1H), 1.20 (s, 6H), 1.19 (s, 6H). Example 12 tert-butyldimethyl((1-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)tricyclo[2.2.1.02,6]heptan-3-yl)oxy)silane The title compound was synthesized under conditions similar to those of the representative procedure B.1H NMR (500 MHz, CDCl3) δ 7.24 – 7.17 (m, 2H), 7.13 – 7.06 (m, 3H), 3.97 (t, J = 1.8 Hz, 1H), 1.97 (dd, J = 9.0, 1.6 Hz, 2H), 1.85 – 1.79 (m, 2H), 1.47 (s, Docket No.: 359006.00004 1H), 1.33 (dt, J = 5.2, 1.2 Hz, 1H), 1.19 (s, 6H), 1.15 (s, 6H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). Example 13 1-((1R,2S,3S,4S,7R)-7-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)tricyclo[2.2.1.02,6]heptan-1-yl)-4-phenylpiperazine Representative procedure C To an oven dried round bottom flask equipped with a stirbar was added (1R,3R,4S,6R)- 3-((tert-butyldimethylsilyl)oxy)-5,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)bicyclo[2.2.1]heptan-2-one (64.2 mg, 0.13 mmol, 1.0 equiv.) followed by 1- phenylpiperazine (21.2 mg, 0.13 mmol, 1.0 equiv.) and acetic acid (7.8 mg, 0.13 mmol, 1.0 equiv.). To the reaction mixture was then added 1,2-dichloroethane (1.3 mL). The reaction mixture was then sealed with a septum under air and allowed to stir at 23 °C for 16 hours. The reaction mixture was then filtered through a plug of silica gel using diethyl ether and concentrated under reduced pressure. The crude reaction mixture was then purified with the use of silica gel chromatography. The title compound was isolated in 83% yield, 55.0 mg.1H NMR (500 MHz, CDCl3) δ 7.23 (dd, J = 8.7, 7.2 Hz, 2H), 6.90 (dt, J = 7.9, 1.1 Hz, 2H), 6.80 (tt, J = 7.3, 1.1 Hz, 1H), 3.94 (d, J = 1.9 Hz, 1H), 3.16 – 3.05 (m, 4H), 2.96 (ddd, J = 10.6, 6.2, 3.7 Hz, 2H), 2.82 (ddd, J = 10.8, 6.3, 3.6 Hz, 2H), 1.93 (s, 1H), 1.90 (p, J = 1.6 Hz, 1H), 1.54 (d, J = 5.5 Hz, 1H), 1.40 (d, J = 10.8 Hz, 1H), 1.33 – 1.25 (m, 2H), 1.24 (s, 6H), 1.23 (s, 6H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H).13C NMR (126 MHz, CDCl3) δ 151.8, 129.1, 119.2, 116.0, 83.0, 52.3, 51.1, 49.8, 40.6, 29.0, 26.1, 24.9, 24.8, 20.7, 20.5, 18.0, -4.0, -4.5.11B NMR (160 MHz, CDCl3) δ 34.1. Example 14 Docket No.: 359006.00004 N-butyl-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)tricyclo[2.2.1.02,6]heptan-1-amine The title compound was synthesized under conditions similar to those of the representative procedure C.1H NMR (500 MHz, CDCl3) δ 2.48 (ddd, J = 9.3, 6.1, 1.4 Hz, 2H), 2.33 (s, 3H), 2.17 – 2.11 (m, J = 1.4 Hz, 1H), 1.50 – 1.41 (m, 2H), 1.37 – 1.28 (m, 6H), 1.25 (d, J = 2.1 Hz, 14H), 1.18 (d, J = 1.3 Hz, 1H), 0.92 (t, J = 7.4 Hz, 3H). Example 15 Gram-scale Preparation of Nortricyclanes as Bioisosteres of meta-Substituted Arenes and Functionalization of Remaining Boron Moiety The product from this reaction contains a secondary boronic ester moiety, which provides access to a broad array of diverse molecules with high stereospecificity. However, due to the presence of the adjacent cyclopropane, the boron moiety may be hard to functionalize or yield rearranged products. In the investigation of the reactivity of the secondary boron, the 1,2-metallate rearrangement reactions effectively yielded the corresponding alcohol and amide with moderate to high yields, and the 2-electron, copper-catalyzed coupling of the corresponding boronate complex produced allyl the coupling products in a good yield. Docket No.: 359006.00004 Practical application of the nortricyclane synthesis necessitates procedures that operate on large scale as well as functional group transformations that effectively replace the remaining boronic ester in the catalytic reaction product. With regards to the first aspect, it was found that the bis(boronate) substrate 5 could be prepared on multigram scale directly from inexpensive commercially available norbornadiene and B2(pin)2(eq.1). Reaction of 5 could be conducted on 5 mmol scale and, so long as the reaction time is extended to 24 h, could be accomplished in good yield with only 0.5 mol% of palladium complex (eq. 2). In the transformations, the boronic ester in product 7 can be replaced stereospecifically by Zn-based catalytic cross-coupling (26) (Liang, H. and Morken, J. P., J. Am. Chem. Soc.145, 9976–9981 (2023).), Cu-catalyzed allylation and carboxylation (27 and 28) (Xu, N., et al., J. Am. Chem. Soc.14411546–11552 (2022).), direct amination (29) (Mlynarski, S. N., et al., J. Am. Chem. Soc. 134, 16449–16451 (2021).), homologation 30, (Sadhu, K. M. and Matteson, D. S., Organometallics 4, 1687–1689 (1985).) or conversion to the derived alcohol (31). Example 16 Preparation of Tricyclo[2.2.1.02,6]heptane Derivatives (3S,5R)-33 and (3R,5S)-33 as Analogs of URB597 To determine whether nortricyclane frameworks are suited for use in bioactive molecules, both enantiomers of 33 were prepared as chiral isosteric analogs of the fatty acid amide hydrolase (FAAH) inhibitor URB597 and subjected to analysis. (Kathuria, S,. et al., Docket No.: 359006.00004 Nature Medicine 9, 76–81 (2003).) (Piomelli, D., et al., CNS Drug Reviews 12, 21–38 (2006).) Of note, while the isosteric analogs have similar molecular weight as URB597, they have ten- fold increased solubility in aqueous buffer while maintaining comparable lipophilicity (alog D). In addition to these positive attributes, the isosteric analogs exhibit measurably increased metabolic stability relative to URB597 as determined by mouse liver microsomal assay (Table 1). Table 1. Pharmacological data comparison of compounds (3R,5S)-33 and (3S,5R)-33 with URB597 URB597(3R,5S)-33(3S,5R)-33MW (g / mol) 338.4 354.4 354.4 kinetic 1.01 12.66 10.16 solubility (µM)aαlogDb3.69 3.57 3.56 microsomal stability 37 67 75 c (% remaining) (a) Determined in PBS buffer at pH=7.4 after 24 h. (b) Defined as logD at pH=7.4; determined by HPLC analysis. (c) Determined at 30 min in the presence of male CD-1 mouse liver microscomes with NADPH. To probe for the effect of chirality on biological activity, compounds (R,S)-33 and (S,R)-33 were compared by quantitative activity-based protein profiling (ABPP) experiments (FIG. 2). Mouse-brain homogenates were treated with varying concentrations of each compound prior to exposure to the serine hydrolase-directed activity-based probe fluorophosphonate (FP)-biotin. FP-labeled proteins were enriched on streptavidin beads and analyzed by quantitative tandem mass tagging (TMT)-based mass spectrometry. (Van Esbroeck, A. C. M., et al,. Science 356, 1084–1087 (2017).) Of note, while (R,S)-33 and (S,R)- 33 were not as potent as URB597, the isosteric analogs retained the ability to inhibit FAAH and display different potencies: at 5 mM concentrations (R,S)-33 exhibits complete FAAH inhibition, while (S,R)-33 only displays 50% inhibition. Additionally, incorporation of the isosteres did not alter the proteome-wide selectivity of URB597, as both isosteres maintained high selectivity for FAAH over the other 23 detected serine hydrolases. Thus, in another aspect, the present disclosure encompasses a pharmaceutical composition comprising a compound selected from (S,R)-33, (R,S)-33, and pharmaceutically acceptable salts thereof, or a mixture thereof, and a pharmaceutically acceptable carrier. Docket No.: 359006.00004 In another aspect, the present disclosure provides a method of treating any diseases or conditions treatable by URB597, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from (S,R)-33, (R,S)-33, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound selected from (S,R)-33 and (R,S)-33, or a mixture thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides use of the compound (S,R)-33 or (R,S)-33, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a disease or conditions treatable by URB597. Example 17 Preparation of Tricyclo[2.2.1.02,6]heptane Derivatives (3S,5R)-34 and (3R,5S)-34 as Analogs of Sonidegib In a second comparative analysis, the enantiomeric tricyclanes (S,R)-34 and (R,S)-34 were prepared as analogs of the Hedgehog (Hh) pathway inhibitor, (Chen, J. K., Nat. Prod. Rep.33, 595–601 (2016).) sonidegib (FIG.3). (Pan, S., et al., ACS Med. Chem. Lett.1, 130– 134 (2010).) Aberrant Hedgehog signaling has been implicated in certain types of cancer, and sonidegib inhibits activation of this pathway by interacting with the associated signal transducer, Smoothened (SMO). Comparison of stereoisomeric isosteres 34 was conducted by three independent IC50 determinations using a dual luciferase assay in Shh-LIGHT2 cells (Taipale, J., et al., Nature 406, 1005–1009 (2000).) and it was found that the enantiomeric sonidegib analogs inhibit Hh signaling with submicromolar potencies (IC50= 0.50 mM and 0.20 mM for the (S,R)-34 and (R,S)-34, respectively), and with a modest, at best (p=0.26), difference in activity for the two stereoisomers (Table 2). Docket No.: 359006.00004 Table 2. Pharmacological data comparison of compounds (3R,5S)-34 and (3S,5R)-34 with sonidegib sonidegib(3S,5R)-34 (3R,5S)-34MW (g / mol) 485.5 487.5 487.5 kinetic 1.0 ubility ( M)a0.02 4 0.86 solµαlogDb5.74 5.62 5.61 microsomal stability 78 31 50 0.0036 0.50 0.20(a) Determined in PBS buffer at pH=7.4 after 24 h. (b) Defined as logD at pH=7.4; determined by HPLC analysis. (c) Determined at 30 min in the presence of male CD-1 mouse liver microscomes with NADPH. (d) Inhibition of Hedgehog signalling in Shh- LIGHT2 cells. Data is an average of five replicates Overall, the preliminary analysis of the stereochemistry-dependent activity of nortricyclane isosteres (33 and 34) appears to reinforce the notion that shape matters when binding to biological targets, and it is notable that differences in activity are detected even with isosteric analogs that haven’t been reoptimized to bind their target receptors. One can anticipate that as chiral ligands are fine-tuned for affinity, the absolute stereochemistry of the isostere is likely to become increasingly important. Thus, in another aspect, the present disclosure encompasses a pharmaceutical composition comprising a compound selected from (S,R)-34, (R,S)-34, and pharmaceutically acceptable salts thereof, or a mixture thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a method of treating any diseases or conditions treatable by sonidegib, comprising administering to a subject thereof a therapeutically effective amount of a compound selected from (S,R)-34, (R,S)-34, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound selected from (S,R)-34 and (R,S)-34, or a mixture thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides use of the compound (S,R)-34 or (R,S)-34, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a disease or conditions treatable by sonidegib. Docket No.: 359006.00004 In summary, catalytic enantioselective nortricyclane synthesis provides an efficient entry into chiral meta benzene bioisosteres, and the chirality of the tricyclic motif plays a role in the shape-dependent binding of the derived ligands with their target receptors. The ease and robustness of the catalytic synthesis, combined with the biophysical properties of nortricyclanes should provide new opportunities for pharmaceutical development. While further exploration of the tricycloheptane skeleton appears warranted, further study of the unique catalytic process that leads to its formation – especially the C–C bond-forming reductive displacement of Pd(II) – may provide new strategies for reaction development. The foregoing embodiments and examples are provided for illustrative purposes only and are not intended to limit the scope of the disclosure. Many variations to those described above may be possible, and such modifications and variations are within the spirit and scope of the present disclosure. All patent or non-patent literature cited are incorporated herein by reference in their entireties without admission of them as prior art.

Claims

Docket No.: 359006.00004 CLAIMS What is claimed is:

1. A compound of formula (X):or an isomer, or a salt thereof, wherein: T1, T2, T3, and T4are each independently selected from hydrogen, B(ORA)(ORB), B(ORX)(ORY), EA, and EB; RAand RBare same or different and are independently C1-6alkyl, C2-6alkenyl, or C6-10 aryl; or alternatively, RAand RBtogether form an alkylene, alkenylene, or arylene, each optionally substituted; RXand RYare same or different and are independently C1-6alkyl, C2-6alkenyl, or C6-10 aryl; or alternatively, RXand RYtogether form an alkylene, alkenylene, or arylene, each optionally substituted; wherein RXand RYpair are same as or different from the RAand RBpair; EAand EBare each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, OC(O)R7, C(O)OR8, OC(O)OR8, OR15, SR15, NHR15, C(O)NRcRd, -OC(O)NHR8, C(O)NHR8, NHC(O)R7, oxo (=O), and -O-Si(Rsi)3, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OR15, SR15, NHR15, B(ORX)(ORY), NO2, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, C(O)R7, OC(O)R7, C(O)OR8, NRaRb, C(O)NRcRd, -OC(O)NHR8, and C(O)NHR8; T5is selected from hydrogen, halogen, C1-8alkyl, C1-8haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16,Docket No.: 359006.00004 R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R15at each occurrence is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, benzyl, or C3-6cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6alkyl, or benzyl; Rsiat each occurrence is independently C1-6 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; Raand Rbare independently hydrogen, C1-6alkyl, C6-10aryl, benzyl, C3-6cycloalkyl, or -C(O)OR8, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl.

2. The compound of claim 1, having a structure of formula:or an isomer, or a salt thereof, wherein: RT1is selected from R15, -C(O)R7, -C(O)OR8, -C(O)NHR8, and OSi(Rsi)3; and T5, R15, R7, R8, and Rsiare as defined in claim 1.

3. The compound of claim 1 or 2, wherein: RAand RBare independently C1-6alkyl, or RAand RBtogether form an alkylene; and RXand RYare independently C1-6 alkyl; or RXand RYtogether form an alkylene.

4. The compound of claim 1 or 2, selected from:Docket No.: 359006.000045. The compound of claim 1, having a structure of formula:, or an isomer, tautomer, or salt thereof, wherein T2, T3, T4, T5, Ra, and Rbare as defined in claim 1.

6. The compound of claim 5, wherein RXand RYare independently C1-6 alkyl; or RXand RYtogether form an alkylene.

7. The compound of any one of claims 1 to 6, or an isomer, or a salt thereof, wherein RXand RYtogether form, and RAand RBtogether form.Docket No.: 359006.00004, or an isomer, or a salt thereof.

9. The compound of claim 1, having the structure of formula:,Docket No.: 359006.00004 or an isomer, or a salt thereof, wherein: T1, T2, T3, and T4are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, allyl, benzyl, C3-6cycloalkyl, C5-10carbocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, OR15, SR15, NHR15, C(O)NRcRd, -OC(O)NHR8, -NHC(O)NHR8, and C(O)NHR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OR15, SR15, NHR15, B(ORX)(ORY), NO2, C1- 4alkyl, C1-4haloalkyl, C(O)R7, C(O)OR8, NRaRb, C(O)NRcRd, -OC(O)NHR8, and C(O)NHR8; T5is selected from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, CN, OH, O-C1-4alkyl, O-C1-4haloalkyl, C(O)OR9; NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl, each optionally substituted; R8is hydrogen, C1-6alkyl, C3-6cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl, each optionally substituted; R15at each occurrence is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, benzyl, or C3-6cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen or C1-6 alkyl; Raand Rbare independently hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, C3-6 cycloalkyl, or -C(O)OR8, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl.

10. The compound of claim 9, having a structure of formula:,or an isomer, or a salt thereof, wherein: T5is hydrogen; andDocket No.: 359006.00004 T1and T2are each independently selected from:

11. The compound of claim 1, selected from:Docket No.: 359006.00004or an isomer, or a salt thereof.

12. A compound of formula (I-1), (I-2) or (I-3):(I-1) (I-2) (I-3) or an isomer, or a salt thereof, wherein: Rxand Ryare independently alkyl, alkenyl, or aryl; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; EAand EBare each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, OC(O)R7, C(O)OR8, OC(O)OR8, OR15, O-C1-6alkyl-R15, SR15, NHR15, C(O)NRcRd, -OC(O)NHR8, C(O)NHR8, and NHC(O)R7, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OR15, SR15, NHR15, B(ORX)(ORY), NO2, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, 5- or 6-memberedDocket No.: 359006.00004 heteroaryl, 5- or 6-membered heterocyclyl, C(O)R7, OC(O)R7, C(O)OR8, NRaRb, C(O)NRcRd, -OC(O)NHR8, and C(O)NHR8; R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R15at each occurrence is independently hydrogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, benzyl, , 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, or C3-6 cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6alkyl, or benzyl; Rsiat each occurrence is independently C1-6 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; Raand Rbare independently hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, C3-6 cycloalkyl, or -C(O)OR8, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl.

13. The compound of claim 12, having a structure of formula (I-1-a), (I-2-a), or (I- 3):or an isomer, or a salt thereof, wherein EAand EBare independently selected from C1-8alkyl, OR15, CN, NRaRb, C(O)R7, OC(O)R7, C(O)OR8,Docket No.: 359006.00004wherein: p is 0, 1, or 2; q is 0, 1, 2, or 3; R7is alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is alkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R9at each occurrence is independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6haloalkoxy, NRaRb, and oxo (=O); R10at each occurrence is independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NRaRb, halide, CN, and NO2; R11to R14at each occurrence are independently selected from hydrogen, alkyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, andDocket No.: 359006.00004 C(O)OR8, wherein the alkyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted; R15at each occurrence is independently hydrogen, C1-6alkyl, benzyl, 5- or 6- membered heteroaryl, 5- or 6-membered heterocyclyl, or C3-6 cycloalkyl, each optionally substituted; and Raand Rbare independently hydrogen, C1-6alkyl, phenyl, benzyl, C3-6cycloalkyl, or - C(O)OR8, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted.

14. The compound of claim 12 or 13, having a structure of formula:or an isomer, or a salt thereof.

15. A process for preparing a compound of formula (I), or an isomer or analog thereof, comprising the steps of:(A)(I)(a) reacting a boronate ester compound of formula (A) with adamantyl-lithium or tert-butyl lithium in the presence of a catalyst in a solvent to form an adamantyl- or tert- butyl-boronate ester adduct; (b) reacting the adamantyl-boronate ester adduct with an electrophile compound R4-X1in the presence of a copper salt in a solvent to form the compound of formula (I), wherein: X1is halide, -OS(O)2R5, -OC(O)R5, or -NRaS(O)2R5;Docket No.: 359006.00004 X2is halide, CN-, BF4-, NO3-, HSO4-, or -OS(O)2R6; R1, R2, and R3are each independently alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted; or any two of R1, R2, and R3together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, each optionally substituted; or R1, R2, and R3together with the carbon atom to which they are attached form a bicycloalkyl, tricycloalkyl, bi-heterocyclyl, tri-heterocyclyl, bridged-carbocyclyl, or bridged- heterocyclyl, each optionally substituted; wherein R4is alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, or C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted; R5is alkyl, haloalkyl, aryl, or heteroaryl, each optionally substituted; R6is alkyl, haloalkyl, or aryl, each optionally substituted; R7is alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is alkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; Rxand Ryare independently alkyl, alkenyl, or aryl; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; Raand Rbare independently hydrogen, alkyl, aryl, benzyl, or together with the nitrogen atom to which they are attached form a heterocyclyl, each optionally substituted.

16. The process of claim 15, wherein the catalyst is 4,4'-di-tert-butyl-1,1'-biphenyl (DBB), naphthalene, or substituted naphthalene.

17. The process of claim 15 or 16, wherein the adamantyl-lithium is formed in situ by reacting an adamantyl halide compound with lithium in the presence of :,Docket No.: 359006.00004 wherein X is halide.

18. The process of any one of claims 15 to 17, wherein the solvent for the reaction in Step (a) is selected from tetrahydrofuran, ether-containing solvents, N,N- dimethylacetamide, and N,N-dimethylformamide.

19. The process of any one of claims 15 to 18, wherein the solvent for the reaction in Step (b) is selected from tetrahydrofuran, ether-containing solvents, N,N- dimethylacetamide, and N,N-dimethylformamide, and wherein the solvent for the reaction in Step (b) is the same or different from the solvent for the reaction in Step (a).

20. The process of any one of claims 15 to 19, wherein the copper salt is CuCN, Cu(thiophene), Cu(acetylide), or Cu(carbene).

21. The process of any one of claims 15 to 19, wherein the reaction of Step (a) is conducted at a temperature from 0 °C to room temperature.

22. The process of any one of claims 15 to 21, wherein the reaction of Step (b) is conducted from room temperature to an elevated temperature.

23. The process of claim 22, wherein the elevated temperature is in the range from about 40 °C to about 100 °C.

24. The process of claim 22, wherein the elevated temperature is in the range from about 60 °C to about 80 °C.

25. The process of any one of claims 15 to 24, wherein the reaction of Step (b) is conducted in the presence of a cesium salt and triphenylphosphine (PPh3).

26. The process of any one of claims 15 to 25, wherein the compound (A) is a pinacol boronate ester, with Rxand Rytogether forming.

27. The process of any one of claims 15 to 26, wherein: (i) the adamantyl-lithium is about 1.0 to about 1.5 mole equivalent to the compound (A); (ii) the catalyst is DBB in an amount in the range of about 1 mol% to 10 mol% of the compound (A); (iii) the electrophile compound R4-X1is about 1.2 to about 3.0 mole equivalent to the compound (A);Docket No.: 359006.00004 (iv) the copper salt is CuCN in an amount in the range of about 5 to about 50 mol% of the compound (A); and (v) the solvent for both of the reactions in Step (a) and Step (b) comprises tetrahydrofuran.

28. The process of any one of claims 15 to 27, wherein the compound (A) is selected from:wherein: R1and R2are independently C1-12alkyl, optionally substituted; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is an integer selected from 1-6; i and j are independently 0, 1, 2, or 3; k is 1 or 2; h is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, 4, or 5; and R9at each occurrence is independently selected from C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6 haloalkoxy, NRaRb, and oxo (=O); and R10at each occurrence is independently selected from C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, NRaRb, halide, CN, and NO2.

29. The process of ant one of claims 15 to 27, wherein R1, R2, and R3together with the carbon atom to which they are attached form a bicycloalkyl or bridged-carbocyclyl of formula (A-1), which optionally substituted and optionally comprises one or more C=C double bonds, and the compound (A) comprises an additional boronate ester moiety - B(ORx)(ORy):Docket No.: 359006.00004,wherein i and j are independently 0, 1, 2, or 3; and k is 1 or 2.

30. The process of claim 29, wherein i and j are each independently 1 or 2, and k is 1 or 2.

31. The process of any one of claims 15 to 30, wherein the electrophile compound R4-X1is selected from:wherein: p is 0, 1, or 2; q is 0, 1, 2, or 3; X1is Cl, Br, or I; R7is alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is alkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R9at each occurrence is independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6haloalkoxy, NRaRb, and oxo (=O);Docket No.: 359006.00004 R10at each occurrence is independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NRaRb, halide, CN, and NO2; and R11to R14at each occurrence are independently selected from hydrogen, alkyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, and C(O)OR8, wherein the alkyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted.

32. A method of preparing a compound of formula (I-2), comprising: (i) a process of preparing the compound of formula (I-1) according to any one of claims 29 to 31; and (ii) converting the compound of formula (I-1) to the compound of formula (I-2):(I-1) (I-2), wherein R4ais same as or different from R4and is independently selected from hydrogen, OH, alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, and C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted.

33. The method of claim 32, comprising steps of: (i) converting the compound of formula (A-1) to the compound of formula (I-1) through a copper-catalyzed coupling of an adamantly-boronate ester adduct with an electrophile; and (ii) converting the compound of formula (I-1) to the compound of formula (I-2) through oxidation:Docket No.: 359006.00004(I-2)34. The method of claim 33, wherein the oxidant is H2O2, NaBO3or a hydrate thereof, and wherein i, j, and k are each equal to 1.

35. A method of preparing a nortricyclane compound of formula (II) or an isomer or analog thereof, comprising reacting a norbornene bis(boronate) ester compound of formula (B) or an analog thereof, with an electrophile compound E-X1in the presence of a palladium- catalyst and a base, optionally along with a ligand, in a solvent:, wherein: Rxand Ryat each occurrence are independently alkyl, alkenyl, or aryl, each optionally substituted; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; E is an electrophile moiety; X1is a leaving group; T5is selected from hydrogen, halogen, C1-8 alkyl, C1-8 haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16,Docket No.: 359006.00004 R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6 alkyl, or benzyl; Rsiat each occurrence is independently C1-6alkyl, C3-6cycloalkyl, phenyl, or benzyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl.

36. The method of claim 35, wherein: E is selected from alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, and heterocyclyl are each optionally substituted; X1is selected from halide, -OS(O)2R5, -OC(O)R5, and -NRaS(O)2R5; the palladium catalyst is Pd(0) or a Pd(II) salt, each optionally complexing with a ligand. the optional ligand is a chiral or achiral phosphine compound; the base is selected from phosphate salts, carbonate salts, and bicarbonate salts; the solvent is selected from tetrahydrofuran, water, lower alcohol, and mixtures thereof.

37. The method of claim 35 or 36, wherein: Rxand Rytogether formE is selected from alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted; X1is selected from halide, -OS(O)2R5, -OC(O)R5, and -NRaS(O)2R5; the palladium catalyst is Pd(OAc)2;Docket No.: 359006.00004 the ligand is a chiral phosphine ligand (R)-L1 or (S)-L1, or a mixture thereof, or (R,R)-L2 or (S,S)-L2, or a mixture thereof:(R)-L1,(S)-L1,(R,R)-L2,(S,S)-L2;the base is selected from phosphate salts, carbonate salts, bicarbonate salts, metal hydroxides, metal alkoxides, and mixtures thereof; and the solvent is selected from tetrahydrofuran, water, lower alcohol, aromatic solvents, ethereal solvents, and mixtures thereof.

38. A method of preparing a nortricyclane compound of formula (III), or an isomer or analog thereof, comprising reacting a nortricyclane bis(boronate) ester compound of formula (C), or an isomer or analog thereof, with an electrophile compound E-X1in the presence of a palladium-catalyst and a base, optionally along with a ligand, in a solvent:, wherein: Rxand Ryat each occurrence are independently alkyl, alkenyl, or aryl, each optionally substituted; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; E is an electrophile moiety; X1is a leaving group; T5is selected from hydrogen, halogen, C1-8alkyl, C1-8haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16,Docket No.: 359006.00004 R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6 alkyl, or benzyl; Rsiat each occurrence is independently C1-6alkyl, C3-6cycloalkyl, phenyl, or benzyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; and Rdat each occurrence is independently hydrogen or C1-6alkyl.

39. The method of claim 38, wherein: E is selected from alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, and heterocyclyl are each optionally substituted; X1is selected from halide, -OS(O)2R5, -OC(O)R5, and -NRaS(O)2R5; the palladium catalyst is Pd(0) or a Pd(II) salt, each optionally complexing with a ligand. the optional ligand is a chiral or achiral phosphine compound; the base is selected from phosphate salts, carbonate salts, and bicarbonate salts; the solvent is selected from tetrahydrofuran, water, lower alcohol, and mixtures thereof.

40. The method of claim 35 or 36, wherein: Rxand Rytogether formE is selected from alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, propa-1,2-dien-1-yl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted; X1is selected from halide, -OS(O)2R5, -OC(O)R5, and -NRaS(O)2R5; the palladium catalyst is APhosPd (G3);Docket No.: 359006.00004 the base is Cs2CO3; and the solvent is selected from tetrahydrofuran, water, lower alcohol, aromatic solvents, ethereal solvents, and mixtures thereof.

41. The method of any one of claims 35 to 40, wherein E is selected from:wherein: p is 0, 1, 2, or 3; q is 0, 1, 2, 3, or 4; R10at each occurrence is independently C1-6 alkyl, C1-6 haloalkyl, OR15, SR15, NHR15, NRaRb, halide, CN, NO2, -CO2R8, CONRaRb, -O-C(O)NRaRb, C6-10aryl, benzyl, 5- to 10- membered heteroaryl, or 5- to 10-membered heterocyclyl; R15at each occurrence is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, benzyl, or C3-6 cycloalkyl, each optionally substituted; and Raand Rbare independently hydrogen, C1-6alkyl, C6-10aryl, benzyl, or C3-6cycloalkyl, or together with the nitrogen atom to which they are attached form a heterocyclyl, each optionally substituted.

42. The method of any one of claims 35 to 41, wherein: (vi) the palladium catalyst is about 0.5 mol% to about 5 mol% equivalent to the compound (B);Docket No.: 359006.00004 (vii) the ligand is in an amount in the range of about 1.0 to about 1.5 mole equivalent to the palladium catalyst; (viii) the electrophile compound E-X1is about 1.1 to about 1.8 mole equivalent to the compound (B); (ix) the base is about 1.1 to about 1.5 mole equivalent to the electrophile compound E-X1; and (x) the solvent is a mixture of tetrahydrofuran and water.

43. The method of any one of claims 35 to 42, wherein the bis(boronate) compound (B) is prepared by reacting norbornadiene with bis(pinacolato)diboron in the presence of a cesium salt as catalyst in a solvent:Norbornadiene B2(pin)244. The method of claim 34, wherein the cesium salt catalyst is Cs2CO3, and the solvent is a mixture of MeOH / THF.

45. The method of claim 43 or 44, wherein the Cs-catalyst is in an amount of about 0.1 to about 0.5 equivalent to bis(pinacolato)diboron, the norbornadiene is in an amount of about 3 to about 8 equivalent to bis(pinacolato)diboron [i.e., B2(pin)2], and the reaction is conducted at an elevated temperature.

46. The method of any one of claims 38 to 45, wherein the bis(boronate) compound (C), or an analog thereof, is prepared by treating norbornene bis(boronate) compound (B), or analog thereof, with a catalytic amount of acid in a solvent:

47. The method of claim 46, wherein the acid is toluene sulfonic acid, and the solvent is chloroform.Docket No.: 359006.00004 48. The method of claim 46 or 47, wherein the bis(boronate) is pinacol bis(pinacol boronate), and the reaction is conducted at an elevated temperature.

49. A method of preparing a nortricyclane compound of formula (IV), or an isomer or analog thereof, comprising reacting an oxo-substituted norbornane bis(boronate) ester compound of formula (D), or an isomer or analog thereof, with an amine in the presence of an acid in a solvent:, wherein: Rxand Ryat each occurrence are independently alkyl, alkenyl, or aryl, each optionally substituted; or alternatively, Rxand Rytogether form an alkylene, alkenylene, or arylene, each optionally substituted; Raand Rbare independently selected from hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, and C3-6cycloalkyl, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; T5is selected from hydrogen, halogen, C1-8alkyl, C1-8haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R8is hydrogen, alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R16at each occurrence is independently hydrogen, C1-6alkyl, or benzyl; Rsiat each occurrence is independently C1-6 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; andDocket No.: 359006.00004 Rdat each occurrence is independently hydrogen or C1-6alkyl.

50. The method of claim 49, wherein: the acid is a C1-6alkyl carboxylic acid; and the solvent is a halogenated C1-6 hydrocarbon.

51. The method of claim 49 or 50, wherein: Rxand Rytogether formand RaRbNH is a primary or secondary amine comprising a C1-6alkyl and / or aryl group or a heterocyclyl compound comprising an NH on the ring.

52. A method of preparing a nortricyclane compound of formula (V), or an isomer or analog thereof, comprising: (i) preparing a compound of formula (II), or an isomer or analog thereof, according to the method of any one of claims 35 to 45; and (ii) converting the compound of formula (II), or an isomer or analog thereof, to the compound of formula (V), or an isomer or analog thereof under suitable conditions:, wherein E1and E are same or different, each independently selected from hydrogen, OH, alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, CN, NRaRb, C(O)R7, C(O)OR8, OR15, SR15, NHR15, C(O)NRcRd, and C(O)NHR16wherein the alkyl, alkenyl, alkynyl, allyl, benzyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, NO2, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O- C1-4haloalkyl, C(O)OR16; NRcRd, C(O)NRcRd, and C(O)NHR16; T5is selected from hydrogen, halogen, C1-8alkyl, C1-8haloalkyl, CN, OH, oxo (=O), O-C1-4alkyl, O-C1-4haloalkyl, OSi(Rsi)3, C(O)R7, OC(O)R7, C(O)OR8, NRcRd, C(O)NRcRd, and C(O)NHR16, R7is alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted;Docket No.: 359006.00004 R8is alkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted; R15at each occurrence is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, benzyl, or C3-6cycloalkyl, each optionally substituted; R16at each occurrence is independently hydrogen or C1-6 alkyl; Raand Rbare independently hydrogen, C1-6 alkyl, C6-10 aryl, benzyl, or C3-6 cycloalkyl, or together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclyl, wherein C1-6alkyl, aryl, benzyl, cycloalkyl, and heterocyclyl are each optionally substituted; Rcat each occurrence is independently hydrogen or C1-4alkyl; and Rdat each occurrence is independently hydrogen or C1-4alkyl.

53. The method of claim 52, wherein the step (ii) is selected from: (a) reacting with t-BuLi then Zn(OAc)2, and substituted or unsubstituted aryl bromide in the presence of G3-PdCPhos to obtain the compound of formula (V), or an analog thereof, where E1is a substituted or unsubstituted aryl group; (b) reacting with t-BuLi, then 20 mol% CuCN, 2,3-dichloropropene, to obtain the compound (V), or an analog thereof, where E1is -CH2C(Cl)=CH2; (c) reacting with t-BuLi, then 20 mol% CuCN, methyl formamide, to obtain the compound of formula (V), or an analog thereof, where E1is -CO2Me; (d) reacting with MeONH2, n-BuLi, and then Boc2O, to obtain the compound of formula (V), or an analog thereof, where E1is -NHBoc; (e) reacting with n-BuLi and CH2BrCl to obtain the compound of formula (V), or an analog thereof, where E1is -CH2B(ORx)(ORy); and (f) reacting with NaOH and H2O2to obtain a compound of formula (V), or an analog thereof, where E1is OH.