Encoding cyclic terpenoids into isomeric modular substrates

Abstract

The present disclosure relates to methods of making cyclic terpenoids through substrate-controlled catalysis taking place in the presence of a supramolecular capsule.

Description

[0001]Attorney Docket No.: UIX-04925 ENCODING CYCLIC TERPENOIDS INTO ISOMERIC MODULAR SUBSTRATES RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 533,729, filed August 21, 2023; U.S. Provisional Application No.63 / 533,741, filed August 21, 2023; and U.S. Provisional Application No.63 / 566,618, filed March 18, 2024. STATEMENT OF GOVERNMENT SUPPORT This invention was made with government support under R35GM118185 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Terpenes are one of the most structurally diverse classes of natural products. Due to the high structural complexity of many terpenes, their preparation often requires long synthetic sequences. In nature, each subclass of terpene scaffolds derives from the enzymatic cyclization of the same linear biosynthetic precursor by a different enzyme. As a result, each such subclass represents a set of constitutional isomers corresponding to multiples of the (C5H8)nisoprene unit. In such a catalyst-controlled approach, the need for an individual fine-tuned catalyst for each desired product framework requires large investments of time and energy, thus presenting a major hindrance when access to multiple different terpene scaffolds is desired. Here we present a substrate-controlled approach to the synthesis of complex terpenoids, in which the product structure is encoded in the precursor molecule. We show that different terpene scaffolds can be formed through a cyclization reaction using a single catalyst, by the variation in the placement of structural elements in isomeric precursors. This strategy overcomes the need for individual catalysts, while allowing for the synthesis of the cyclization precursors through a predictable and high yielding modular synthesis. SUMMARY OF THE INVENTION In certain aspects, disclosed are methods of making a compound of Formula I, II, or III: 1 FH12234742.6 Attorney Docket No.: UIX-04925 (I) (II) (III) comprising combining a compound of Formula IV: A–B (IV); an acid; and a supramolecular capsule; thereby forming the compound of Formula I, II, or III; wherein the supramolecular capsule is a hexamer of calix[4]resorcinarene; is a single bond or a double bond, as valence permits; RAis selected from the group consisting of H, alkyl, and alkenyl; and when the carbon atom to which RAis attached is sp2-hybridized, RAis absent; RBis selected from the group consisting of H, alkyl, and alkenyl; and when the carbon atom to which RBis attached is sp2-hybridized, RBis absent; R1is selected from the group consisting of H, =CH2, and alkyl; provided that if the bond between the carbon atoms to which R1and R2or R1and R3are attached is a double bond, then R1is not =CH2; R2is selected from the group consisting of H, alkyl, and alkenyl; or R1and R2, taken together with the intervening atoms, form a 5-membered cycloalkyl ring, a 6-membered cycloalkyl ring, a 5-membered cycloalkenyl ring, or a 6- membered cycloalkenyl ring, each of which is optionally substituted with one or more instances of R10; R3is selected from the group consisting of H, alkyl, or alkenyl; or R2and R3, taken together with the intervening atoms, form a 6-membered cycloalkyl ring or a 6-membered cycloalkenyl ring, each of which is optionally substituted with one or more instances of R11; only one of (i) R1and R2and (ii) R2and R3forms a ring; each R4, R5, and R6is independently selected from the group consisting of H, alkyl, and alkenyl; 2 FH12234742.6 Attorney Docket No.: UIX-04925 R7is absent, H, or alkyl; R8is H or alkyl; R9is H; or R8and R9, taken together with the intervening atoms, form an optionally substituted 6-membered cycloalkyl ring or cycloalkenyl ring, each of which is optionally substituted with one or more instances of R12; R10is H, alkyl or alkenyl; R11is alkyl or alkenyl; R12is alkyl, alkenyl, or is absent; R14is H or acyl; R18is H or alkyl; A is selected from the group consisting of B is selected from the group consisting of BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 shows two approaches to controlling the THT cyclization. A. Catalyst control: the same linear substrate leads to different products in function of the enzyme operating on it. The product structure is encoded in the structure of the producing enzyme. B. Substrate control: different constitutional isomers of the same chemical formula encode different cyclization outcomes when subjected to the same artificial enzyme mimic. FIG. 2 shows encoding of sesquiterpene product structure through isomeric permutation of partially cyclized, modular precursors, and an approach for the systematic exploration of the resulting cyclization space. A. General scheme for the synthesis of 3 FH12234742.6 Attorney Docket No.: UIX-04925 cyclization precursors via Negishi coupling and their capsule-mediated cyclization. B. Major product obtained from the cyclization of each precursor (products are racemic; only one enantiomer shown). R = Ac except where noted otherwise. Yields refer to isolated product except where noted otherwise.aGC yield.b10 mol% of capsule I used, and reaction carried out at 30 ^C.cProduct isolated after preparative scale reaction of alcohol substrate (R = H); in all these cases, the same major product is observed in the reaction of the acetate substrate.dSubstrate is an equimolar mixture of diastereomers. FIG.3. A. shows synthesis of the core skeleton of the xishacorene diterpenes via the THT cyclization of compound @44. B. Methyl group positioning on a partially cyclized precursor encodes diterpene structures abietadiene (@1) and rosadiene (@2). C. Proposed mechanism for the formation of rosadiene. FIG.4 shows that an increase of capsule catalyst loading to 20 mol% and of the reaction temperature to 40 °C resulted in significantly faster reaction and a higher yield. FIG. 5 shows gas chromatography results of a reaction to form 3-isopropyl-7,7,7a- trimethyl-2,6,7,7a-tetrahydro-1H-indene in the presence of a) the supramolecular capsule, b) a blocked capsule, and c) no capsule, with 100 mol% HCl. FIG. 6 shows gas chromatography results of a reaction to form 6-ethyl-1,1,8a- trimethyl-1,2,3,7,8,8a-hexahydronaphthalene in the presence of a) the supramolecular capsule, b) a blocked capsule, and c) no capsule, with 100 mol% HCl. FIG.7 shows gas chromatography results of a reaction to form 1,1,6-trimethyl-6-vinyl- 1,2,3,4,5,6,7,8-octahydronaphthalene in the presence of a) the supramolecular capsule, b) a blocked capsule, and c) no capsule, with 100 mol% HCl. FIG. 8 shows gas chromatography results of a reaction to form 6-isopropyl-1,1- dimethyl-1,2,3,7,8,8a-hexahydronaphthalene in the presence of a) the supramolecular capsule, b) a blocked capsule, and c) no capsule, with 100 mol% HCl. FIG. 9 shows gas chromatography results of a reaction to form 6-ethyl-1,1,4a- trimethyl-1,2,3,4,4a,5-hexahydronaphthalene in the presence of a) the supramolecular capsule, b) a blocked capsule, and c) no capsule, with 100 mol% HCl. FIG. 10 shows gas chromatography results of a reaction to form(1S,5R,6R)-2,2,6- trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane and (1S,5R,6S)-2,2,6-trimethyl-9- methylene-6-vinylbicyclo[3.3.1]nonane in the presence of a) the supramolecular capsule, b) a blocked capsule, and c) no capsule, with 100 mol% HCl. 4 FH12234742.6 Attorney Docket No.: UIX-04925 FIG. 11 shows gas chromatography results of a reaction to form (1S,5S,6S)-2,2- Dimethyl-9-methylene-6-(prop-1-en-2-yl)bicyclo[3.3.1]nonane in the presence of a) the supramolecular capsule, b) a blocked capsule, and c) no capsule, with 100 mol% HCl. FIG. 12 shows gas chromatography results for the formation of 3-isopropyl-7,7,7a- trimethyl-2,6,7,7a-tetrahydro-1H-indene. FIG. 13 shows gas chromatography results for the formation of 6-ethyl-1,1,8a- trimethyl-1,2,3,7,8,8a-hexahydronaphthalene. FIG. 14 shows gas chromatography results for the formation of 1,1,6-trimethyl-6- vinyl-1,2,3,4,5,6,7,8-octahydronaphthalene. FIG. 15 shows gas chromatography results for the formation of 6-isopropyl-1,1- dimethyl-1,2,3,7,8,8a-hexahydronaphthalene. FIG. 16 shows gas chromatography results for the formation of 6-ethyl-1,1,4a- trimethyl-1,2,3,4,4a,5-hexahydronaphthalene. FIG.17 shows gas chromatography results for the formation of (±)-(1S,5R,6R)-2,2,6- trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane and (±)-(1S,5R,6S)-2,2,6-trimethyl-9- methylene-6-vinylbicyclo[3.3.1]nonane. FIG. 18 shows gas chromatography results for the formation of (±)-(1S,5S,6S)-2,2- dimethyl-9-methylene-6-(prop-1-en-2-yl)bicyclo[3.3.1]nonane. FIG. 19 shows the reaction of 3-methylene-5-(2,6,6-trimethylcyclohex-2-en-1- yl)pentan-2-yl acetate. FIG.20 shows gas chromatography results for the formation of (±)-(1R,5S,8R)-2,4,4,8- tetramethyl-8-vinylbicyclo[3.3.1]non-2-ene and (±)-(1R,5S,8S)-2,4,4,8-tetramethyl-8- vinylbicyclo[3.3.1]non-2-ene using deuterated chloroform as solvent. FIG.21 shows gas chromatography results for the formation of (±)-(1R,5S,8R)-2,4,4,8- tetramethyl-8-vinylbicyclo[3.3.1]non-2-ene and (±)-(1R,5S,8S)-2,4,4,8-tetramethyl-8- vinylbicyclo[3.3.1]non-2-ene using toluene as solvent. FIG.22 shows gas chromatography results for the formation of rosadiene (@2). FIG.23 shows gas chromatography results for the formation of abietadiene (@1). DETAILED DESCRIPTION OF THE INVENTION Terpenes represent arguably the most structurally diverse class of natural products, with many displaying important medicinal properties. Complex three-dimensional carbon frameworks such as those of many terpenes are difficult to prepare chemically, and this 5 FH12234742.6 Attorney Docket No.: UIX-04925 difficulty has been a limiting factor in utilizing this functional space in drug research which is still dominated by “flat” aromatic molecules.1,2,3,4,5. In sharp contrast to customized synthetic approaches,6,7,8,9,10the biosynthesis of most terpenes proceeds through a ‘tail-to-head’ cyclization cascade11from highly preserved linear precursors (f.i. geranylgeranyl-pp, Fig. 1C).12In this reaction, catalyzed by Class I Terpene Synthase enzymes, a single linear isoprenoid precursor gives rise to one out of many possible isomeric terpene structures. As a result, the resulting arrangement of the same chemical matter (i.e. C15H24for sesquiterpenes, C20H32for diterpenes) is encoded in the amino acid sequence of the enzyme (Fig. 1A). For example, the diterpenes abietadiene (@1) and rosadiene13(@2) both arise from the cyclization of geranylgeranyl pyrophosphate; in each case, a different amino acid sequence in each enzyme biases the cyclization towards, respectively, an abietadienyl14,15or isopimaradienyl16cyclization pattern (Fig.1C). However, the need for a unique catalyst to access each individual product structure severely hinders application of this approach to discovery-scale synthetic chemistry. Herein we present a different, substrate-controlled approach to the synthesis of sesquiterpenes. In this approach, the product structure is instead encoded in the structure of the substrate (Figure 1B). We show that variation in the arrangement of chemical matter, that is, in the positioning of methyl groups and olefins in constitutionally isomeric precursors is sufficient to meaningfully guide the cationic cyclization towards specific pathways when using a single, common catalyst. To enable this approach, the elements that compose the code need to be easily interchangeable (much like an enzyme’s amino acid sequence), and this was achieved by utilizing modular precursors. Technology that allows the generalized and even automated synthesis of modular small molecules is now becoming increasingly accessible.18,19Promising indications exist in the literature that pre-encoding of a cyclic framework into linear molecules through the presence or absence of specific functional groups is possible.20However, this consequently results in products of different chemical compositions; at the outset of our study, whether similar pre-encoding could be achieved by simple isomeric permutation was an unanswered question. Herein we demonstrate that this substrate-encoded approach to complex oligocyclic terpenes is indeed feasible. This approach requires a single catalyst that enables translation of the substrate code without influencing the course of the reaction itself. Very few such options have been developed for the THT cyclization11,21,22, and we chose a supramolecular capsule23,24catalyst that is able to mimic a terpene synthase21,22by (i) promoting the ionization of terpene allylic 6 FH12234742.6 Attorney Docket No.: UIX-04925 alcohols or allylic acetates through the use of HCl as a co-catalyst, and (ii) stabilizing carbocationic intermediates, preventing premature quenching – a reaction commonly observed in solution. Importantly, the catalyst’s highly symmetric structure does not exercise the same level of conformational control throughout the reaction as an enzyme’s complex active site, thus allowing the substrate to guide the reaction outcome and thus the efficient translation of the code. Cyclofarnesyl acetate @12 (FIG. 2) was shown to result in the selective formation of the sesquiterpene isolongifolene (@13) through THT cyclization.22This precursor was disconnected into a cyclic head group and a linear tail group, and a building-block-based synthesis via Negishi coupling was designed to access different structural permutations of this compound. A systematic investigation of the effect of isomeric structural permutation of this cyclofarnesyl precursor was carried out, using this modular approach to access all nine permutations resulting from three head and three tail groups (FIG.2A). The three cyclic head groups chosen possess a different placement of the reactive double bond. The three tail groups chosen were tail group @9 corresponding to the natural C3 placement of the methyl group on an isoprenoid; tail group @10 in which the methyl group has been shifted to the 2 position, and @11 in which the leaving group is now located on C2 instead of C1. The major products of the capsule-catalyzed cyclization conditions are shown in Figure 2. This complete 3 x 3 matrix of isomeric precursors yielded nine distinct outcomes, confirming our starting hypothesis and allowing us to draw several reactivity rules that guide the synthesis of additional terpene natural product structures through this THT cyclization methodology. The combination of a β-ionone head group @6 and C3-methylated tail group gives, as previously described,22the natural product isolongifolene in 24% yield. Shifting the methyl group to C2 through the use of tail group @10 results in formation of fused ring system @15. Employing tail group @11, where the leaving group is on the C2 position, gives rise to the formation of the unsaturated decalin system @17; a similar methyl shift to that taking place in the rearrangement towards product @15 is observed. The combination of γ-ionone head group @7 and tail group @9 gave sesquiterpene structure @19, corresponding to the carbon scaffold of the natural product nanaimoal. Presumably the quaternary center formed due to the presence of the methyl group on C3 precludes further rearrangement after the initial cyclization event. Indeed, with the methyl group placed on C2, the tertiary carbocation formed after the initial cyclization event undergoes further hydride and proton shifts to give compound @21. In contrast to the other cyclization 7 FH12234742.6 Attorney Docket No.: UIX-04925 precursors examined, the combination of head group @7 and tail group @11 in precursor @22 led to product @23 which arises not through a THT cyclization but through the initial protonation of the double bond on the head group. Presumably, the placement of the acetate group allows intramolecular delivery of a proton on the double bond, in a manner not possible with substrates @18 and @20 that are conformationally more restricted due to the E- configuration of the tail group’s double bond. Finally, α-ionone head group @8 encodes the bridged ring system of products @25 (with tail group @9, formed as an equimolar mixture of diastereomers) and @27 (with tail group @10, formed as a single diastereomer). The combination with tail group @11 in substrate @28 results in no cyclization being observed, presumably as the initial cyclization event would require formation of a bridged seven-membered ring system. Use of more forcing conditions leads to formation of product @17, likely preceded by isomerization of the substrate (@28) to substrate @16. In control reactions where the cavity of the capsule catalyst was blocked by a strongly binding guest (Bu4NBr, 1.5 equiv. with respect to the capsule catalyst), no product formation was observed, with the exception of one substrate (precursor @26). Using 1 equiv. of HCl instead of the capsule catalyst system (10-20 mol% I, 3 mol% HCl) led to product formation in only 3 cases, specifically with precursors @18, @24 and @26; these represent reactions, where no extensive rearrangement of the initially generated carbocationic species is observed, thus presumably stabilization by the internal environment of the capsule is not required. The Bronsted acid-mediated reactivity of precursor @18 is consistent with a literature report of a related cyclization employing HF.25Taken together, these results indicate that use of artificial terpene synthase mimic I is essential to fully explore the cyclization behavior of all substrates, and a simple Bronsted acid such as HCl would clearly have been insufficient. In the case of formation of a fused ring system after the initial cyclization event (through use of the γ-ionone head group, or of the β-ionone head group with tail groups @10 or @11 as described above), the methylation state of C3 acts a reactivity switch: if the position bears a hydrogen atom, a hydride shift and / or proton transfer from this position is possible and thus the carbocationic intermediate evolves towards a conjugated diene, as is the case with products @15, @17, @21 and @23. If, conversely, the C3 position is rendered quaternary and bears a methyl group, such rearrangements are precluded as an unprecedented long-range methyl-shift would be required. The reaction thus instead terminates as with product @19. Applying this simple rule to the diterpene chemical space, we designed diterpenoid substrates @3 and @4 that differ only in the positioning of the tail group’s methyl group (Figure 3B). 8 FH12234742.6 Attorney Docket No.: UIX-04925 When precursor @4 was subjected to the capsule catalyst, the diterpene rosadiene was formed in 20% yield; the initial steps towards this product reflect the formation of sesquiterpene @19, thus the observation that a methyl group placed on C3 precludes evolution towards a diene structure holds true; however, in this case a further hydride and methyl shift take place to give the rosadiene scaffold (Figure 3C). This is consistent with literature reports of a stepwise transformation of the pimaradienes (structurally analogous to @19), under prolonged acidic treatment, to the rosadiene scaffold.27Precursor @3, with the methyl group shifted to the C2 position, gives rise to the conjugated diene-bearing abietadiene in 19% yield (Figure 3B), in accordance with our hypothesis. In this case a more complex reaction mixture is encountered, including the formation of a significant amount of a polar product (@48); it is likely that the increased size of this diterpene substrate together with the decreased reactivity of the C2-Me tail group compared to the C3-Me variant lead to alternative, non-THT, acid- mediated cyclization pathways. Overall these results demonstrate that the sesquiterpene reactivity rules can be extended to diterpene substrates, although the deviation in reactivity observed in the diterpene case indicates that the possibility of further rearrangements should be taken into account. The synthesis of both rosadiene and abietadiene in this manner is significant for its demonstration of a substrate-controlled approach to the synthesis of natural terpenes: formation of either rosadiene or abietadiene is pre-programmed in the specific constitutional isomer employed, C3-Me or C2-Me correspondingly. In conclusion, we have developed a substrate-controlled approach to the synthesis of complex THT terpene products, based on encoding of the product structure in a modular precursor through isomeric structural permutation. This strategy is distinct from catalyst- control, which requires the use of an individual fine-tuned catalyst for each desired product framework. The approach reported herein not only overcomes this limitation but also features a clear advantage: it benefits from a facile preparation of the cyclization precursors via a predictable and high yielding modular synthesis. This has significant potential implications on the development of iterative automated / automatable synthetic approaches to complex terpene- like molecules.18,19,28,29To be amenable to automated synthesis such compounds must be disconnected into building blocks, and one way of achieving this is by constructing them through the cyclization of modular precursor molecules. Being able to encode the structure of the final product in the modular precursor effectively allows the desired disconnection of the final product into building blocks; this study demonstrates that this is achievable for 9 FH12234742.6 Attorney Docket No.: UIX-04925 sesquiterpenes, and represents a first step for the broader implementation of such a design strategy in small molecule synthesis. Methods of Making In certain aspects, disclosed are methods of making a compound of Formula I, II, or III: comprising combining a compound of Formula IV: A–B (IV); an acid; and a supramolecular capsule; thereby forming the compound of Formula I, II, or III; wherein the supramolecular capsule is a hexamer of calix[4]resorcinarene; is a single bond or a double bond, as valence permits; RAis selected from the group consisting of H, alkyl, and alkenyl; and when the carbon atom to which RAis attached is sp2-hybridized, RAis absent; RBis selected from the group consisting of H, alkyl, and alkenyl; and when the carbon atom to which RBis attached is sp2-hybridized, RBis absent; R1is selected from the group consisting of H, =CH2, and alkyl; provided that if the bond between the carbon atoms to which R1and R2or R1and R3are attached is a double bond, then R1is not =CH2; R2is selected from the group consisting of H, alkyl, and alkenyl; or R1and R2, taken together with the intervening atoms, form a 5-membered cycloalkyl ring, a 6-membered cycloalkyl ring, a 5-membered cycloalkenyl ring, or a 6- membered cycloalkenyl ring, each of which is optionally substituted with one or more instances of R10; 10 FH12234742.6 Attorney Docket No.: UIX-04925 R3is selected from the group consisting of H, alkyl, or alkenyl; or R2and R3, taken together with the intervening atoms, form a 6-membered cycloalkyl ring or a 6-membered cycloalkenyl ring, each of which is optionally substituted with one or more instances of R11; only one of (i) R1and R2and (ii) R2and R3forms a ring; each R4, R5, and R6is independently selected from the group consisting of H, alkyl, and alkenyl; R7is absent, H, or alkyl; R8is H or alkyl; R9is H; or R8and R9, taken together with the intervening atoms, form an optionally substituted 6-membered cycloalkyl ring or cycloalkenyl ring, each of which is optionally substituted with one or more instances of R12; R10is H, alkyl or alkenyl; R11is alkyl or alkenyl; R12is alkyl, alkenyl, or is absent; R14is H or acyl; R18is H or alkyl; A is selected from the group consisting of B is selected from the group consisting of In certain aspects, disclosed are methods of making a compound of Formula I-P, II-P, or III-P: 11 FH12234742.6 Attorney Docket No.: UIX-04925 comprising combining a compound of Formula IV-P: A–B (IV-P); an acid; and a supramolecular capsule; thereby forming the compound of Formula I-P, II-P, or III-P; wherein the supramolecular capsule is a hexamer of calix[4]resorcinarene; is a single bond or a double bond, as valence permits; R1is selected from the group consisting of H, =CH2, and alkyl; provided that if the bond between the carbon atoms to which R1and R3are attached is a double bond, then R1is not =CH2; R2is selected from the group consisting of H, alkyl, and alkenyl; or R1and R2, taken together with the intervening atoms, form a 6-membered cycloalkyl ring or a 6-membered cycloalkenyl ring, each of which is optionally substituted with one or more instances of R10; R3is selected from the group consisting of H, alkyl, or alkenyl; or R2and R3, taken together with the intervening atoms, form a 6-membered cycloalkyl ring or a 6-membered cycloalkenyl ring, each of which is optionally substituted with one or more instances of R11; one and only one of (i) R1and R2and (ii) R2and R3forms a 6-membered cycloalkyl ring or a 6-membered cycloalkenyl ring; each R4, R5, and R6is independently selected from the group consisting of H, alkyl, and alkenyl; R7is absent, H, or alkyl; R8is H or alkyl; R9is H; 12 FH12234742.6 Attorney Docket No.: UIX-04925 or R8and R9, taken together with the intervening atoms, form an optionally substituted 6-membered cycloalkyl ring or cycloalkenyl ring, each of which is optionally substituted with one or more instances of R12; R10is H, alkyl or alkenyl; R11is alkyl or alkenyl; R12is alkyl or alkenyl; R14is H or acyl; R18is H or alkyl; A is selected from the group consisting of In certain embodiments, the bond between the carbon atoms to which R1and R3are attached is a single bond, and R1is =CH2. In further embodiments, R1is methyl. In yet further embodiments, R2is H. In still further embodiments, R2is methyl. In certain embodiments, the product is represented by Formula I or Formula I-P; and R1and R2, taken together with the intervening atoms, form a 5-membered cycloalkyl ring, which is optionally substituted with one or more instances of R10. In further embodiments, the product is represented by Formula I or Formula I-P; and R1and R2, taken together with the intervening atoms, form a 5-membered cycloalkenyl ring, which is optionally substituted with one or more instances of R10. In yet further embodiments, the product is represented by Formula I or Formula I-P; and R1and R2, taken together with the intervening atoms, form a 6-membered cycloalkyl ring, which is optionally substituted with one or more instances of R10. In still further embodiments, the product is represented by Formula I or Formula I-P; and R1and R2, taken together with the 13 FH12234742.6 Attorney Docket No.: UIX-04925 intervening atoms, form a 6-membered cycloalkenyl ring, which is optionally substituted with one or more instances of R10. In certain further embodiments, R3is H. In further embodiments, R3is methyl. In certain embodiments, the product is represented by Formula I or Formula I-P; and R2and R3, taken together with the intervening atoms, form a 6-membered cycloalkyl ring, which is optionally substituted with one or more instances of R11. In further embodiments, the product is represented by Formula I or Formula I-P; and R2and R3, taken together with the intervening atoms, form a 6-membered cycloalkenyl ring, which is optionally substituted with one or more instances of R11. In yet further embodiments, R4is H. In still further embodiments, R4is methyl. In certain embodiments, R5is H. In further embodiments, R5is methyl. In yet further embodiments, R6is H. In still further embodiments, R6is methyl. In certain embodiments, R7is absent. In further embodiments, R7is H. In yet further embodiments, R7is methyl. In still further embodiments, R8is H. In certain embodiments, R8is methyl. In further embodiments, R9is H. In yet further embodiments, the product is represented by Formula III; and R8and R9, taken together with the intervening atoms, form a 6-membered cycloalkyl ring, which is optionally substituted with one or more instances of R12. In still further embodiments, the product is represented by Formula III; and R8and R9, taken together with the intervening atoms, form a 6-membered cycloalkenyl ring, which is optionally substituted with one or more instances of R12. In certain embodiments, R10is selected from the group consisting of methyl, ethyl, propyl, and butyl. In further embodiments, R10is selected from the group consisting of allyl, vinyl, and prop-1-en-2-yl. In yet further embodiments, R11is selected from the group consisting of methyl, ethyl, propyl, and butyl. In still further embodiments, R11is selected from the group consisting of allyl, vinyl, and prop-1-en-2-yl. In certain embodiments, R12is selected from the group consisting of methyl, ethyl, propyl, and butyl. In further embodiments, R12is selected from the group consisting of allyl, vinyl, and prop-1-en-2-yl. In yet further embodiments, R14is H. In still further embodiments, R14is acetyl. In certain embodiments, the compound of Formula IV is represented by Formula IVa, IVb, IVc, or IVd: 14 FH12234742.6 Attorney Docket No.: UIX-04925 (IVa) (IVb) (IVc) wherein: R15is selected from the group consisting of H, alkyl, and alkenyl; R16is selected from the group consisting of H, alkyl, and alkenyl; and R17is selected from the group consisting of H, alkyl, and alkenyl. In further embodiments, the compound of Formula IV is selected from the group consisting of: In yet further embodiments, the compound of Formula I-P is represented by Formula Ia-P, Formula Ib-P, Formula Ic-P, Formula Id-P, or Formula Ie-P: 15 FH12234742.6 Attorney Docket No.: UIX-04925 Ia-P Ib-P Ic-P Id-P In still further embodiments, the compound of Formula I is represented by Formula Ia, Formula Ib, Formula Ic, Formula Id, or Formula Ie: In certain embodiments, the compound of Formula I is selected from the group consisting of: In further embodiments, the compound of Formula II is: . In yet further embodiments, the compound of Formula III is represented by Formula IIIa-P: 16 FH12234742.6 Attorney Docket No.: UIX-04925 IIIa-P. In still further embodiments, the compound of Formula III is represented by Formula IIIa: In certainembodiments, the compound of Formula III is: In further embodiments, the acid is a Brønsted acid. In yet further embodiments, the acid is selected from the group consisting of HCl, HBr, HI, HF, H2SO4, CH3COOH, and CF3COOH. In still further embodiments, the acid is HCl. In certain embodiments, the acid is a Lewis acid. In further embodiments, the acid is selected from the group consisting of AlCl3, BF3•OEt2, BF3, Ti(OiPr)4, Al(OiPr)3, and LiCl. In yet further embodiments, the amount of the acid is from about 1 mol% to about 10 mol% relative to the compound of Formula IV. In still further embodiments, the amount of the acid is about 3 mol% relative to the compound of Formula IV. In certain embodiments, the amount of the supramolecular capsule is from about 1 mol% to about 20 mol% relative to the compound of Formula IV. In further embodiments, the amount of the supramolecular capsule is about 10 mol% or about 20 mol% relative to the compound of Formula IV. In yet further embodiments, the method further comprises combining a compound of Formula V: A-ZnCl (V); 17 FH12234742.6 Attorney Docket No.: UIX-04925 a compound of Formula VI: B-I (VI); and a palladium catalyst; thereby forming the compound of Formula IV; wherein: A is selected from the group consisting of B is selected from the group consisting of In still further embodiments, the palladium catalyst is Pd(PPh3)4. Definitions The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur. The term “alkyl” as used herein is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chain, C3-C30for branched chain), and alternatively, about 20 or fewer, or 10 or fewer. In certain embodiments, the term “alkyl” refers to a C1-C10alkyl group. In certain embodiments, the term “alkyl” refers to a C1-C6alkyl group, for 18 FH12234742.6 Attorney Docket No.: UIX-04925 example a C1-C6straight-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-C12branched-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3- C8branched-chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. The term “cycloalkyl” means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5-12 carbon atoms in their ring structure, and may have 6-10 carbons in the ring structure. Preferably, cycloalkyl is (C3-C7)cycloalkyl, which represents a monocyclic saturated carbocyclic ring, having from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form –(CH2)w-, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted. The term “(cycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more cycloalkyl groups. An example of cycloalkylalkyl is cyclohexylmethyl group. The term “heterocycloalkyl” as used herein refers to a radical of a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and having 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention, the 19 FH12234742.6 Attorney Docket No.: UIX-04925 following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, isoxazolyl, azepines, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, trithianyl, and 2- azobicyclo[3.1.0]hexane. A heterocycloalkyl group is optionally substituted by one or more substituents as described below. The term “(heterocycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups. The term “alkenyl” as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2- heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond(s) of the alkenyl group can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). The term “alkynyl” as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. The term “alkylene” is art-recognized, and as used herein pertains to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above. In one embodiment an alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. That is, in one embodiment, a “substituted alkyl” is an “alkylene”. The term “amino” is a term of art and as used herein refers to both unsubstituted and 20 FH12234742.6 Attorney Docket No.: UIX-04925 substituted amines, e.g., a moiety that may be represented by the general formulas: wherein Ra, Rb, and Rceach independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)x- Rd, or Raand Rb, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; Rdrepresents an aryl, a heteroaryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and x is zero or an integer in the range of 1 to 8. In certain embodiments, only one of Ra or Rb may be a carbonyl, e.g., Ra, Rb, and the nitrogen together do not form an imide. In other embodiments, Raand Rb(and optionally Rc) each independently represent a hydrogen, an alkyl, an alkenyl, or –(CH2)x-Rd. In certain embodiments, Raand Rbare each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, or haloalkyl, any of which may be further substituted (e.g., by halogen, alkyl, alkoxy, hydroxy, and so forth). In certain embodiments, the term “amino” refers to –NH2. In certain embodiments, the term “alkylamino” refers to -NH(alkyl). In certain embodiments, the term “dialkylamino” refers to -N(alkyl)2. The term “amido”, as used herein, means -NHC(=O)-, wherein the amido group is bound to the parent molecular moiety through the nitrogen. Examples of amido include alkylamido such as CH3C(=O)N(H)- and CH3CH2C(=O)N(H)-. The term “acyl” is a term of art and as used herein refers to any group or radical of the form RCO- where R is any organic group, e.g., alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. Representative acyl groups include acetyl, benzoyl, and malonyl. The term “aminoalkyl” as used herein refers to an alkyl group substituted with one or more one amino groups. In one embodiment, the term “aminoalkyl” refers to an aminomethyl group, i.e., -CH2NH2. The term “aminoacyl” is a term of art and as used herein refers to an acyl group substituted with one or more amino groups. The term “aminothionyl” as used herein refers to an analog of an aminoacyl in which the O of RC(O)- has been replaced by sulfur, hence is of the form RC(S)-. 21 FH12234742.6 Attorney Docket No.: UIX-04925 The term “phosphoryl” is a term of art and as used herein may in general be represented by the formula: wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl; for example, -P(O)(Ome)- or -P(O)(OH)2. When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl may be represented by the general formulas: Q50 Q50 Q51P OQ51POR59 OR59 OR59 ; wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N; for example, -O-P(O)(OH)Ome or -NH-P(O)(OH)2. When Q50 is S, the phosphoryl moiety is a “phosphorothioate.” The term “aminophosphoryl” as used herein refers to a phosphoryl group substituted with at least one amino group, as defined herein; for example, -P(O)(OH)Nme2. The term “azide” or “azido”, as used herein, means an –N3group. The term “carbonyl” as used herein refers to -C(=O)-. The term “thiocarbonyl” as used herein refers to -C(=S)-. The term “alkylphosphoryl” as used herein refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, -P(O)(OH)Me. The term “alkylthio” as used herein refers to alkyl-S-. The term “(alkylthio)alkyl” refers to an alkyl group substituted by an alkylthio group. The term “carboxy”, as used herein, means a -CO2H group. The term “aryl” is a term of art and as used herein refers to includes monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, for example, benzene, naphthalene, anthracene, and pyrene. Typically, an aryl group contains from 6-10 carbon ring atoms (i.e., (C6-C10)aryl). The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which 22 FH12234742.6 Attorney Docket No.: UIX-04925 two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic hydrocarbon, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. In certain embodiments, the term “aryl” refers to a phenyl group. The term “heteroaryl” is a term of art and as used herein refers to a monocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3- d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanyl, and the like. The “heteroaryl” may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. The term “aralkyl” or “arylalkyl” is a term of art and as used herein refers to an alkyl group substituted with an aryl group, wherein the moiety is appended to the parent molecule through the alkyl group. The term “heteroaralkyl” or “heteroarylalkyl” is a term of art and as used herein refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through the alkyl group. The term “alkoxy” as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term “alkoxyalkyl” refers to an alkyl group substituted by an alkoxy group. 23 FH12234742.6 Attorney Docket No.: UIX-04925 The term “alkoxycarbonyl” means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by -C(=O)-, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The term “alkylcarbonyl”, as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl. The term “arylcarbonyl”, as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2- pyridinyl)carbonyl. The term “alkylcarbonyloxy” and “arylcarbonyloxy”, as used herein, means an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to phenylcarbonyloxy. The term “alkenoxy” or “alkenoxyl” means an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxyl include, but are not limited to, 2-propen-1-oxyl (i.e., CH2=CH-CH2-O-) and vinyloxy (i.e., CH2=CH-O-). The term “aryloxy” as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term “heteroaryloxy” as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term “carbocyclyl” as used herein means a monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl). Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3- cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl. The term “cyano” is a term of art and as used herein refers to –CN. The term “halo” is a term of art and as used herein refers to –F, –Cl, –Br, or –I. 24 FH12234742.6 Attorney Docket No.: UIX-04925 The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, wherein some or all of the hydrogens are replaced with halogen atoms. The term “hydroxy” is a term of art and as used herein refers to –OH. The term “hydroxyalkyl”, as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl. The term “silyl”, as used herein, includes hydrocarbyl derivatives of the silyl (H3Si-) group (i.e., (hydrocarbyl)3Si–), wherein a hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert- butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2- (trimethylsilyl)ethoxy]methyl (SEM). The term “silyloxy”, as used herein, means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom. Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, compounds of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom 25 FH12234742.6 Attorney Docket No.: UIX-04925 and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction. The term “substituted” is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. In certain embodiments, the optional substituents contemplated in this invention include halogen, azide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, hydroxyl, alkoxyl, amino, aminoalkyl, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether (e.g., -alkylene-O(alkyl)), alkylthio, sulfonyl, sulfonamido, ketone (e.g., - CO(alkyl)), aldehyde (-C(O)H), ester (e.g., -COO(alkyl)), haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, and cyano. As used herein, the term “optionally substituted” or “substituted or unsubstituted” when it precedes a list of chemical moieties means that the list of chemical moieities that follow are each substituted or unsubstituted. For example, “substituted or unsubstituted aryl, heteroaryl, and cycloalkyl” or “optionally substituted aryl, heteroaryl, and cycloalkyl” means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl. The phrase “protecting group”, as used herein, means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nded.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention. 26 FH12234742.6 Attorney Docket No.: UIX-04925 For purposes of the invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67thEd., 1986-87, inside cover. Other chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco, incorporated herein by reference). Unless otherwise defined, 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 “pharmaceutically acceptable salt” as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1. For example, the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula I. As another example, the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula I per molecule of tartaric acid. The terms “carrier” and “pharmaceutically acceptable carrier” as used herein refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids, such as water, saline, and oils; and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington’s Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety. As used herein, the term “oxidizing agent” refers to a reagent that accepts one or more electrons from a substrate. Certain oxidizing agents may also induce the formation of new bonds to oxygen. Illustrative examples of oxidizing agent include, but are not limited to, oxygen, ozone, hydrogen peroxide, periodic acid, sodium periodate, Dess-Martin periodinane, peracetic acid, meta-chloroperbenzoic acid, fluorine, chlorine, bromine, iodine, nitric acid, potassium nitrate, potassium chlorate, peroxydisulfuric acid, peroxymonosulfuric acid, sodium hypochlorite, interhalogen compounds (such as ICl), chromic acids, chromium trioxide, 27 FH12234742.6 Attorney Docket No.: UIX-04925 pyridinium chlorochromate, sodium dichromate, potassium permanganate, manganese heptoxide, sodium perborate, nitrous oxide, nitrogen dioxide, dinitrogen tetroxide, ceric ammonium nitrate, and ceric sulfate. As used herein, the term “reducing agent” refers to a reagent that donates one or more electrons to a substrate. Illustrative examples of reducing agents include, but are not limited to, lithium, sodium, potassium, magnesium, aluminum, iron, tin, copper, zinc, sodium hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium tetraacetoxyborohydride, NaAlH2(OCH2CH2OCH3)2, Na(Hg), Zn(Hg), diborane, nickel boride, sodium dithionate, diisobutylaluminum hydride, and ascorbic acid. REFERENCES CITED 1 Lovering, F., Bikker, J. & Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem.52, 6752-6756 (2009). 2 Lovering, F. Escape from Flatland 2: complexity and promiscuity. MedChemComm 4, 515-519 (2013). 3 Jansen, D. J. & Shenvi, R. A. Synthesis of medicinally relevant terpenes: reducing the cost and time of drug discovery. Future Medicinal Chemistry 6, 1127-1148 (2014). 4 Talele, T. T. Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon. J. Med. 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Synthesis of highly strained terpenes by non-stop tail- to-head polycyclization. Nat. Chem.4, 915-920 (2012). 12 Christianson, D. W. Structural and Chemical Biology of Terpenoid Cyclases. Chem. Rev.117, 11570-11648 (2017). 13 Brophy, J. J., Goldsack, R. J., Wu, M. Z., Fookes, C. J. R. & Forster, P. I. The steam volatile oil of Wollemia nobilis and its comparison with other members of the Araucariaceae (Agathis and Araucaria). Biochemical Systematics and Ecology 28, 563-578 (2000). 14 Peters, R. J. & Croteau, R. B. Abietadiene synthase catalysis: Mutational analysis of a prenyl diphosphate ionization-initiated cyclization and rearrangement. Proc. Natl. Acad. Sci. U.S.A.99, 580-584 (2002). 15 Peters, R. J. & Croteau, R. B. Abietadiene Synthase Catalysis:  Conserved Residues Involved in Protonation-Initiated Cyclization of Geranylgeranyl Diphosphate to (+)- Copalyl Diphosphate. Biochemistry 41, 1836-1842 (2002). 16 Martin, D. M., Fäldt, J. & Bohlmann, J. r. Functional Characterization of Nine Norway Spruce TPS Genes and Evolution of Gymnosperm Terpene Synthases of the TPS-d Subfamily Plant Physiology 135, 1908-1927 (2004). 17 Tantillo, D. J. Importance of Inherent Substrate Reactivity in Enzyme-Promoted Carbocation Cyclization / Rearrangements. Angew. Chem. Int. Ed.56, 10040-10045 (2017). 18 Li, J. et al. Synthesis of many different types of organic small molecules using one automated process. Science 347, 1221 (2015). 19 Blair, D. J. et al. Automated iterative Csp3–C bond formation. Nature 604, 92-97 (2022). 20 Burke, M. D., Berger, E. M. & Schreiber, S. L. Generating Diverse Skeletons of Small Molecules Combinatorially. Science 302, 613-618 (2003). 21 Zhang, Q. & Tiefenbacher, K. Terpene cyclization catalysed inside a self-assembled cavity. Nat. Chem.7, 197-202 (2015). 22 Zhang, Q., Rinkel, J., Goldfuss, B., Dickschat, J. S. & Tiefenbacher, K. Sesquiterpene cyclizations catalysed inside the resorcinarene capsule and application in the short synthesis of isolongifolene and isolongifolenone. Nat. Catal.1, 609-615 (2018). 23 MacGillivray, L. R. & Atwood, J. L. A chiral spherical molecular assembly held together by 60 hydrogen bonds. Nature 389, 469-472 (1997). 29 FH12234742.6 Attorney Docket No.: UIX-04925 24 Avram, L. & Cohen, Y. Spontaneous Formation of Hexameric Resorcinarene Capsule in Chloroform Solution as Detected by Diffusion NMR. J. Am. Chem. Soc.124, 15148-15149 (2002). 25 Engler, T. A., Ali, M. H. & Takusagawa, F. Studies on the Synthesis of Acanthodoral and Nanaimoal:  Evaluation of Cationic Cyclization Routes. J. Org. Chem.61, 8456- 8463 (1996). 26 Ye, F. et al. Xishacorenes A–C, Diterpenes with Bicyclo[3.3.1]nonane Nucleus from the Xisha Soft Coral Sinularia polydactyla. Org. Lett.19, 4183-4186 (2017). 27 McCreadie, T. & Overton, K. H. The conversion of labdadienols into pimara- and rosa-dienes. Journal of the Chemical Society C: Organic, 312-316 (1971). 28 Trobe, M. & Burke, M. D. The Molecular Industrial Revolution: Automated Synthesis of Small Molecules. Angew. Chem. Int. Ed.57, 4192-4214 (2018). 29 Harwood, S. J. et al. Modular terpene synthesis enabled by mild electrochemical couplings. Science 375, 745-752 (2022). 30 Catti, L., Pöthig, A. & Tiefenbacher, K. Host-Catalyzed Cyclodehydration– Rearrangement Cascade Reaction of Unsaturated Tertiary Alcohols. Adv. Synth. Catal.359, 1331-1338 (2017). 31 Köster, J. M. & Tiefenbacher, K. Elucidating the Importance of Hydrochloric Acid as a Cocatalyst for Resorcinarene-Capsule-Catalyzed Reactions. ChemCatChem 10, 2941-2944 (2018). 32 Paradine, S. M. & White, M. C. Iron-Catalyzed Intramolecular Allylic C–H Amination. J. Am. Chem. Soc.134, 2036-2039 (2012). 33 Maier, M. E. & Bayer, A. A Formal Total Synthesis of Salvadione. Eur. J. Org. Chem.2006, 4034-4043 (2006). 34 Paquette, L. A. & Oplinger, J. A. Limitations in the application of anionic oxy-cope sigmatropy to elaboration of the forskolin nucleus. Tetrahedron 45, 107-124 (1989). 35 Mori, K. & Puapoomchareon, P. Preparative bioorganic chemistry, XV. Preparation of optically pure 2,4,4-trimethyl-2-cyclohexen-1-ol, a new and versatile chiral building block in terpene synthesis. Liebigs Ann.1991, 1053-1056 (1991). 36 Poigny, S., Nouri, S., Chiaroni, A., Guyot, M. & Samadi, M. Total Synthesis and Determination of the Absolute Configuration of Coscinosulfate. A New Selective Inhibitor of Cdc25 Protein Phosphatase. J. Org. Chem.66, 7263-7269 (2001). 30 FH12234742.6 Attorney Docket No.: UIX-04925 37 Yan, B.-C. et al. (−)-Isoscopariusin A, a Naturally Occurring Immunosuppressive Meroditerpenoid: Structure Elucidation and Scalable Chemical Synthesis. Angew. Chem. Int. Ed.60, 12859-12867 (2021). 38 Piers, E., Wong, T., Coish, P. D. & Rogers, C. A convenient procedure for the efficient preparation of alkyl (Z)-3-iodo-2-alkenoates. Can. J. Chem.72, 1816-1819 (1994). 39 Ohba, M., Kawase, N. & Fujii, T. Total Syntheses of (±)-Agelasimine-A, (±)- Agelasimine-B, and (±)-Purino-diterpene and the Structure of Diacetylagelasimine-A. J. Am. Chem. Soc.118, 8250-8257 (1996). 40 Karier, P. et al. Metathesis at an Implausible Site: A Formal Total Synthesis of Rhizoxin D. Angew. Chem. Int. Ed.58, 248-253 (2019). 41 Kumar, M., Bromhead, L., Anderson, Z., Overy, A. & Burton, J. W. Short, Tin-Free Synthesis of All Three Inthomycins. Chem. Eur. J.24, 16753-16756 (2018). 42 Ding, X.-B., Furkert, D. P. & Brimble, M. A.2-Nitropyrrole cross-coupling enables a second generation synthesis of the heronapyrrole antibiotic natural product family. Chem. Commun.52, 12638-12641 (2016). 43 Gras, J.-L., Chang, Y. Y. K. W. & Bertrand, M. Sur la réaction de l'iodure de triméthylsilyle avec les alcools acétyléniques. Tetrahedron Lett.23, 3571-3572 (1982). 44 Adam, W. & Klug, P..beta.-Stannyl Allylic Alcohols through Photooxygenation (Schenck Reaction) of Vinylstannanes and Reduction of the Resulting Allylic Hydroperoxides: Synthesis and Selected Transformations. J. Org. Chem.59, 2695- 2699 (1994). 45 Erman, W. F., Wenkert, E. & Jeffs, P. W. Base cleavage of .beta.,.gamma.- unsaturated bicyclic cyclobutanones. J. Org. Chem.34, 2196-2203 (1969). 46 Zhang, Q. & Tiefenbacher, K. Terpene cyclization catalysed inside a self-assembled cavity. Nat. Chem.7, 197-202 (2015). 47 Zhang, Q., Rinkel, J., Goldfuss, B., Dickschat, J. S. & Tiefenbacher, K. Sesquiterpene cyclizations catalysed inside the resorcinarene capsule and application in the short synthesis of isolongifolene and isolongifolenone. Nat. Catal.1, 609-615 (2018). 48 Engler, T. A., Ali, M. H. & Takusagawa, F. Studies on the Synthesis of Acanthodoral and Nanaimoal:  Evaluation of Cationic Cyclization Routes. J. Org. Chem.61, 8456- 8463 (1996). 31 FH12234742.6 Attorney Docket No.: UIX-04925 49 Blunt, J. W., Boyd, G. S., Hartshorn, M. P., Munro, M. H. G. & Pannell, L. K. The acid-catalysed dehydration of 13α-Substituted-13β-methylpodocarpan- 8β-ols. Australian Journal of Chemistry 30, 2015-2021 (1977). 50 Lee, H.-J., Ravn, M. M. & Coates, R. M. Synthesis and characterization of abietadiene, levopimaradiene, palustradiene, and neoabietadiene: hydrocarbon precursors of the abietane diterpene resin acids. Tetrahedron 57, 6155-6167 (2001). 51 Moiseenkov, A. M., Dragan, V. A., Veselovskii, V. V. & Shashkov, A. S. Synthesis of rosane diterpenes. Bulletin of the Academy of Sciences of the USSR, Division of chemical science 40, 1682-1691 (1991). 52 Zhao, Y. & Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc.120, 215-241 (2008). 53 Hehre, W. J., Ditchfield, R. & Pople, J. A. Self—Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian—Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules. J. Chem. Phys.56, 2257-2261 (1972). 54 Zev, S., Gupta, P. K., Pahima, E. & Major, D. T. A Benchmark Study of Quantum Mechanics and Quantum Mechanics-Molecular Mechanics Methods for Carbocation Chemistry. Journal of Chemical Theory and Computation 18, 167-178 (2022). 55 Schlegel, H. B. Optimization of equilibrium geometries and transition structures. Journal of Computational Chemistry 3, 214-218 (1982). 56 Marenich, A. V., Cramer, C. J. & Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. The Journal of Physical Chemistry B 113, 6378-6396 (2009). EXAMPLES The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and they are not intended to limit the invention. 32 FH12234742.6 Attorney Docket No.: UIX-04925 Example 1: General Synthetic Materials & Methods Experimental: Reactions were carried out under an atmosphere of argon in dried glassware unless otherwise indicated. For the cyclisation reactions, no precaution against air and moisture was taken. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 glass-backed plates, which were analysed after exposure to standard staining solutions (CAM: cerium ammonium molybdate, anisaldehyde or basic KMnO4). NMR experiments were performed on a Bruker Avance Neo and a Bruker Avance III HD NMR spectrometer operating at 500 MHz and 600 MHz proton frequency, respectively, equipped with a direct observe 5-mm BBFO smart probe (500 MHz) or a five-channel cryogenic 5 mm QCI probe (600 MHz) (University of Basel), or on a Varian Unity 400, Varian Unity 500, Varian Unity Inova 500NB, Bruker 500-MHz spectrometer with broad-band cryoprobe or Bruker Avance Neo 600MHz spectrometer with a Prodigy BBO-BB cryoprobe (University of Illinois at Urbana-Champaign). All probes were equipped with actively shielded z-gradients (10 A). The experiments were performed at 298 K. Chemical shifts of1H NMR and13C NMR are given in ppm. The following solvent residual signals of the deuterated solvent were used as reference: CDCl3: 7.26 ppm (δ1H), 77.00 ppm (δ13C), benzene-d6: 7.16 ppm (δ1H), 128.06 ppm (δ13C). Coupling constants (J) are reported in Hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), m (multiplet). Infrared spectra were recorded on a Perkin Elmer Spectrum Two FT- IR Spectrometer. GC analyses were carried out on two different instruments; GC conditions A: an Agilent 7890 instrument equipped with a FID detector and an HP-5 capillary column (length = 30 m). Hydrogen was used as the carrier gas and the constant- flow mode was used (flow rate = 40 mL / min) with a split ratio of 1:10. The following temperature- program was used: 60 °C for 3 min, 15 °C / min to 250 °C, and 250 °C for 5 min. GC conditions B: a Shimadzu GC- 2010 Plus instrument equipped with a FID detector and an Rtx-5 capillary column (length = 30 m). Hydrogen was used as the carrier gas and the constant- flow mode was used (flow rate = 40 mL / min) with a split ratio of 1:20. The following temperature- program was used: 60 °C for 3 min, 15 °C / min to 250 °C, and 250 °C for 5 min. High- resolution mass spectra EI and CI spectra were obtained on a VG Analytical Autospec mass spectrometer at 70 eV or a Finnigan MAT 8200; ESI spectra were obtained on either a Bruker Daltonics Apex IV, 7-Tesla FT-ICR, microTOF II or a Thermo Scientific LTQ-FT Ultra (for the last instrument, ESI source parameters for positive polarity mode were: spray voltage, 4.0 kV; capillary temperature, 275 °C; capillary voltage, 48 V; and tube lens, –120 V). Optical rotation was measured in an Anton 33 FH12234742.6 Attorney Docket No.: UIX-04925 Paar MCP 100 Circular Polarimeter operating on the sodium D-line (589 nm) and are reported as [α]DT (concentration in g / 100 mL, solvent). AgNO3-coated silica was prepared according to the literature procedure.30Sources of chemicals: Deuterated chloroform (CDCl3, 99.8%, stabilized over silver foil) was purchased from Cambridge Isotope Laboratories. Deuterated benzene was purchased from Apollo Scientific. 2-(2,6,6-Trimethylcyclohex-1-en-1-yl)acetaldehyde, 3-methyl-2- cyclohexenone, methyl bromoacetate, isobutyraldehyde, ethyl vinyl ketone, triethyl orthoacetate, (3aR)-(+)-sclareolide, propargyl alcohol, but-3-yn-2-ol, isoprene, Pd / C 5% (unreduced), triethyl phosphonoacetate, trimethylsilyl iodide, bis(cyclopentadienyl)zirconium dichloride, tetrakis(triphenylphosphine)-palladium(0), zinc chloride were purchased from Sigma-Aldrich. Ethyl but-2-ynoate, dimethyl 2-(propan-2-ylidene)malonate were purchased from Combi-Blocks. 1-(Triphenylphosphoranylidene)-2-propanone was purchased from Fluorochem. All chemicals were used as received. Transfer of liquids with a volume ranging from 1 to 10 μL or from 10 to 100 μL was performed with a microman M1 pipette (Gilson, systematic error: 1.40% - 1.60%) equipped with 10 μL or 100 μL pipette tips, respectively. Example 2: Synthesis of catalyst and cyclization substrates Synthesis of resorcinarene capsule I: Synthesis of resorcinarene capsule I was carried out as previously described.31General procedure A The alkyl bromide (3.0 equiv.) was dissolved in THF (0.4 M) and t-BuLi (1.6 M in hexanes, 6.0 equiv.) was added at −78 ºC. The solution was stirred at −78 ºC for 30 min, then cannulated to a flask containing ZnCl2(3.0 equiv.) suspended in THF (2 M), rinsing with THF (2 mL). The resulting solution was stirred at rt for 20 min, then cannulated to a flask containing the vinyl iodide (1.0 equiv.) and Pd(PPh3)4(0.1 equiv.) dissolved in THF (0.6 M with respect to the vinyl iodide), rinsing with THF (2 mL). The reaction mixture was shielded from light and stirred at rt for 18 h. Brine and EtOAc were then added, the layers separated and the aqueous layer further extracted with EtOAc. The combined organic layers were dried over Na2SO4and the solvent removed in vacuo. The crude residue was dissolved in THF (0.2 M) and TBAF was added (2.2 equiv.). The reaction mixture was stirred at rt until complete 34 FH12234742.6 Attorney Docket No.: UIX-04925 consumption of the starting material was observed by TLC (3 – 18 h). Brine and EtOAc were then added, the layers separated and the aqueous layer further extracted with EtOAc. The combined organic layers were dried over Na2SO4, the solvent removed in vacuo and the crude residue purified via flash chromatography (hexanes / EtOAc 95:5 9:1) to give the pure alcohol. General procedure B The alcohol (1.0 equiv.) was dissolved in DCM (0.2 M), and Et3N (2.5 equiv.), N,N- dimethyl 4-aminopyridine (0.4 equiv.), and acetic anhydride (2.0 equiv.) were added. The reaction mixture was stirred at rt until complete consumption of the starting material was observed by TLC (1 – 3 h). HCl 1M aqueous solution was then added, the layers separated and the aqueous layer extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via flash chromatography (hexanes / EtOAc 97:3) to give the pure acetate. Example 3: Synthesis of head groups Synthesis of 2-(2-bromoethyl)-1,3,3-trimethylcyclohex-1-ene 2-(2-Bromoethyl)-1,3,3-trimethylcyclohex-1-ene 2-(2,6,6-trimethylcyclohex-1-en-1-yl)acetaldehyde (3.20 mL, 18.0 mmol) was dissolved in MeOH (18 mL), the mixture was cooled to 0 ^C and NaBH4(2.00 g, 54.0 mmol) was added portionwise. The reaction was allowed to warm to rt and stirred overnight. H2O (20 mL) was then added, the layers separated and the aqueous layer extracted with Et2O (3 × 25 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4and the solvent removed in vacuo. The alcohol thus obtained (3.03 g, 18.0 mmol) was used in the next step with no further purification. The alcohol (3.00 g, 17.8 mmol) was dissolved in Et2O 35 FH12234742.6 Attorney Docket No.: UIX-04925 (100 mL), and CBr4(5.90 g, 17.8 mmol) was added. The mixture was cooled to 0 ^C and PPh3(6.10 g, 23.2 mmol) was added portionwise. The reaction mixture was allowed to warm to rt and stirred for 4 h; it was then diluted with n-hexane, filtered through celite, the solvent removed in vacuo and the residue purified via flash chromatography (n-hexane / EtOAc 98:2) to give the title compound as a clear oil (4.10 g, 17.7 mmol, 99% over 2 steps). The spectral data of the compound were in agreement with literature.321H NMR (500 MHz, CDCl3) 3.35 – 3.27 (m, 2H), 2.58 (t, J = 9.0 Hz, 2H), 1.90 (t, J = 6.3 Hz, 2H), 1.62 (s, 3H), 1.60 – 1.52 (m, 2H), 1.45 – 1.40 (m, 2H), 0.99 (s, 6H). Synthesis of 2-(2-bromoethyl)-1,1-dimethyl-3-methylenecyclohexane Methyl 2-(2,2-dimethyl-6-oxocyclohexyl)acetate Prepared following a literature procedure.33To CuBr (288 mg, 2.0 mmol) in THF (40 mL) was added MeMgBr (3.0 M solution in Et2O, 13.3 mL, 40.0 mmol) at 0 ^C. The mixture was stirred at the same temperature for 30 min, then 3-methyl-2-cyclohexenone (1.0 equiv., 4.40 g, 40.0 mmol) was added and the mixture stirred at 0 ^C for 2 h. Methyl bromoacetate (1.96 equiv., 7.40 mL, 78.2 mmol) was then added as a solution in DMPU (50 mL) and the mixture was allowed to warm to rt and stirred overnight. Satd. aqueous NH4Cl solution was then added (100 mL) and the mixture was extracted with Et2O (3 × 100 mL). The combined organic layers were washed with satd. aqueous NH4Cl solution (100 mL) then with brine (50 mL), dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via flash chromatography (n-hexane / Et2O = 8:2) to give the title compound as a clear oil (5.18 g, 26.4 mmol, 66%), the spectral data of which were in agreement with literature.3336 FH12234742.6 Attorney Docket No.: UIX-04925 Methyl 2-(2,2-dimethyl-6-methylenecyclohexyl)acetate Chemical Formula: C12H20O2Molecular Weight: 196.2900 At 0 ^C, n-BuLi (1.6 M solution in hexanes, 34.2 mL, 54.7 mmol) was added dropwise to methyltriphenylphosphonium bromide (20.9 g, 58.6 mmol) suspended in THF (100 mL). The reaction mixture was stirred at the 0 ^C for 30 min, then methyl 2-(2,2-dimethyl-6- oxocyclohexyl)acetate (8.30 g, 41.9 mmol) was added as a solution in THF (20 mL). The mixture was allowed to warm to rt overnight, then satd. aqueous NH4Cl solution (80 mL) was added, the layers separated and the aqueous layer extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via flash chromatography (n-hexane / EtOAc = 95:5) to give the title compound as a clear oil (4.62 g, 23.5 mmol, 56%) the spectral data of which were in agreement with literature.332-(2,2-Dimethyl-6-methylenecyclohexyl)ethan-1-ol Chemical Formula: C11H20O Molecular Weight: 168.2800 Prepared following a literature procedure.33Methyl 2-(2,2-dimethyl-6- methylenecyclohexyl)acetate (2.00 g, 10.2 mmol) was dissolved in THF (50 mL) and LiAlH4(426 mg, 11.2 mmol) was added in portions at 0 ^C. The reaction mixture was stirred at rt for 2 h, then the mixture was cooled to 0 ^C and an 1:1 mixture of THF and H2O (60 mL) was added dropwise. Et2O (100 mL) was then added, the layers separated and the aqueous layer extracted with Et2O (2 × 100 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4and the solvent removed in vacuo to give the title compound as a clear oil (1.10 g, 6.54 mmol, 64%). The spectral data obtained was in agreement with literature.332-(2-Bromoethyl)-1,1-dimethyl-3-methylenecyclohexane 37 FH12234742.6 Attorney Docket No.: UIX-04925 Chemical Formula: C11H19Br Molecular Weight: 231.1770 2-(2,2-dimethyl-6-methylenecyclohexyl)ethan-1-ol (1.10 g, 6.54 mmol) was dissolved in Et2O (30 mL) and CBr4(2.60 g, 7.85 mmol) was added. The mixture was cooled to 0 ^C and PPh3(2.40 g, 9.16 mmol) was added in portions. The reaction mixture was allowed to warm to rt and stirred for 4 h; it was then diluted with n-hexane, filtered through celite, the solvent removed in vacuo and the residue purified via flash chromatography (n-hexane / EtOAc 98:2) to give the title compound as a clear oil (1.44 g, 6.23 mmol, 95%). Rf0.79 (n-hexanes / EtOAc = 9:1)1H NMR (500 MHz, CDCl3) 4.81 (s, 1H), 4.63 (d, J = 2.2 Hz, 1H), 3.45 – 3.39 (m, 1H), 3.24 – 3.18 (m, 1H), 2.04 (app. t, J = 6.6 Hz, 2H), 2.01 – 1.91 (m, 3H), 1.59 – 1.50 (m, 2H), 1.47 – 1.39 (m, 1H), 1.26 (dt, J = 13.4, 4.7 Hz, 1H), 0.94 (s, 3H), 0.85 (s, 3H).13C NMR (125 MHz, CDCl3) 147.7, 110.0, 52.4, 36.1, 34.6, 33.1, 32.1, 30.0, 28.1, 26.4, 23.4. HRMS (EI+) m / z calculated for C11H19Br [M+]: 230.0665; found 230.0669 Synthesis of 6-(2-bromoethyl)-1,5,5-trimethylcyclohex-1-ene 2,4,4-Trimethylcyclohex-2-en-1-one Chemical Formula: C9H14O Molecular Weight: 138.2100 Prepared following a literature procedure.34To isobutyraldehyde (32.4 mL, 355.0 mmol) and ethyl vinyl ketone (23.6 mL, 238.7 mmol), in a flask equipped with a Dean-Stark 38 FH12234742.6 Attorney Docket No.: UIX-04925 apparatus (filled with isobutyraldehyde), was added H2SO4(1.80 mL, 33.8 mmol) dropwise. The mixture was heated to 120 ^C for 7 h. The crude mixture was distilled under vacuum (140 ^C at 100 mbar) to give the title compound as a clear oil (14.5 g, 104.9 mmol, 44%). The spectroscopic data of the compound matched those reported in the literature.342,4,4-Trimethylcyclohex-2-en-1-ol Me Me Me OH Chemical Formula: C9H16O Molecular Weight: 140.2260 Prepared following a literature procedure.35To 2,4,4-trimethylcyclohex-2-en-1-one (14.0 g, 101.3 mmol) dissolved in THF (280 mL) was added LiAlH4(1.28 g, 33.7 mmol) in portions at 0 ^C. The reaction mixture was allowed to warm to rt and stirred for 8 h. H2O (8.0 mL) was then added dropwise, followed by MgSO4(4.00 g). The mixture was then filtered, the filtrate washed with H2O (200 mL) then brine (200 mL), dried over MgSO4and the solvent removed in vacuo to give the title compound as a clear oil (14.0 g, 99.9 mmol, 99%). The spectroscopic data of the compound matched those reported in the literature.356-(2-bromoethyl)- trimethylcyclohex-1-ene Chemical Formula: C11H19Br Molecular Weight: 231.1770 The first two steps in this three-step sequence were carried out following literature procedures.35In a flask equipped with a Dean-Stark apparatus, 2,4,4-trimethylcyclohex-2-en- 1-ol (6.10 g, 43.5 mmol) was dissolved in triethyl orthoacetate (65 mL), then propionic acid (300 μL) was added and the solution was heated to 150 ^C. After 18 h, an additional portion of triethyl orthoacetate (15 mL) and of propionic acid (100 μL), and the mixture stirred for a further 24 h. It was then cooled to rt, H2O was added (20 mL) followed by propionic acid (100 μL), and stirred for 30 min. The mixture was then concentrated in vacuo, satd. aqueous NaHCO3solution (100 mL) was added and the mixture extracted with Et2O (3 × 100 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4and the solvent 39 FH12234742.6 Attorney Docket No.: UIX-04925 removed in vacuo to give the crude ester which was directly subjected to the next step. To LiAlH4(1.70 g, 43.6 mmol) suspended in THF (160 mL) was added the crude ester as a solution in THF (25 mL) dropwise at 0 ^C. After 18 h H2O was added (2.0 mL), followed by 15% aqueous NaOH solution (2.0 mL) and another portion of H2O (6.0 mL) and the resulting mixture was stirred for 30 min. It was then filtered through celite, eluting with Et2O (150 mL) then THF (150 mL). The filtrate was dried over Na2SO4and the solvent removed in vacuo to give the crude alcohol. This was dissolved in DCM (180 mL) and CBr4(10.2 g, 30.8 mmol) was added. The mixture was cooled to 0 ^C and PPh3(10.5 g, 40.0 mmol) was added in portions. The reaction mixture was allowed to warm to rt and stirred for 4 h; the solvent was then removed in vacuo, n-hexane was added and the mixture triturated and filtered through celite. The solvent was removed in vacuo and the residue purified via flash chromatography (n-hexane / EtOAc 98:2) to give the title compound as a clear oil (4.48 g, 19.38 mmol, 45% over 3 steps). Rf0.82 (n-hexanes / EtOAc = 9:1)1H NMR (600 MHz, CDCl3) 5.33 (s, 1H), 3.44 (t, J = 7.9 Hz, 2H), 2.10 – 2.00 (m, 1H), 2.00 – 1.93 (m, 2H), 1.92 – 1.82 (m, 1H), 1.70 (d, J = 1.9 Hz, 3H), 1.58 – 1.52 (m, 1H), 1.44 – 1.32 (m, 1H), 1.17 (dt, J = 13.2, 4.5 Hz, 1H), 0.92 (s, 3H), 0.89 (s, 3H).13C NMR (150 MHz, CDCl3) 135.2, 121.0, 48.6, 35.0, 34.0, 32.4, 31.5, 27.4, 27.1, 23.4, 22.9. HRMS (EI+) m / z calculated for C11H19Br [M+]: 230.0665; found 230.0663 Synthesis of (4S,5S,8S)-5-(2-bromoethyl)-1,1,4-trimethyl-6-methylenedecahydronaphthalene (4S,5S,8S)-5-(2-Bromoethyl)-1,1,4-trimethyl-6-methylenedecahydronaphthalene The following reduction was carried out following a literature procedure.36(3aR)-(+)- Sclareolide (5.00 g, 20.0 mmol) was dissolved in THF (70 mL), LiAlH4(758 mg, 20.0 mmol) 40 FH12234742.6 Attorney Docket No.: UIX-04925 was added in portions at 0 ^C and the reaction mixture stirred at rt overnight. EtOAc (15 mL) was then added at 0 ^C and the mixture stirred for 10 min. The solvent was then removed in vacuo, the residue redissolved in DCM (100 mL), washed with aqueous 1M HCl solution (100 mL), dried over MgSO4and the solvent removed in vacuo to give the diol (5.00 g, 19.7 mmol, 98%) which was used in the next step with no further purification. The diol (1.00 g, 3.93 mmol) was dissolved in toluene (33 mL) and NEt3(2.30 mL, 16.4 mmol) was added at 0 ^C followed by MsCl (1.07 mL, 13.8 mmol) dissolved in toluene (3 × 1 mL). The reaction mixture was stirred at 0 ^C for 1 h, then the solvent was removed in vacuo, the residue was redissolved in EtOAc (40 mL) and filtered through a plug of silica (eluting with EtOAc). The crude mesylate was used directly in the next step. The crude mesylate was dissolved in DMF (36 mL), LiBr (5.40 g, 62.0 mmol) was added and the reaction mixture stirred at 40 ^C overnight. H2O (50 mL) was then added, the mixture extracted with EtOAc (3 × 50 mL), the combined organic layers washed with brine (100 mL), dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via flash chromatography to give the title compound as a clear oil (871 mg, 2.91 mmol, 74% over 2 steps). The spectral data of the compound was consistent with literature.371H NMR (500 MHz, CDCl3) 4.84 (d, J = 1.5 Hz, 1H), 4.47 (d, J = 1.5 Hz, 1H), 3.53 (ddd, J = 9.6, 8.3, 4.3 Hz, 1H), 3.29 (ddd, J = 9.6, 8.5, 7.5 Hz, 1H), 2.40 (ddd, J = 12.8, 4.3, 2.4 Hz, 1H), 2.10 – 1.91 (m, 3H), 1.85 – 1.79 (m, 1H), 1.77 – 1.66 (m, 2H), 1.62 – 1.47 (m, 2H), 1.45 – 1.37 (m, 1H), 1.32 (qd, J = 12.9, 4.3 Hz, 1H), 1.24 – 1.00 (m, 3H), 0.88 (s, 3H), 0.80 (s, 3H), 0.69 (s, 3H). Example 4: Synthesis of tail groups Synthesis of (E)-tert-butyl((3-iodobut-2-en-1-yl)oxy)dimethylsilane Ethyl (Z)-3-iodobut-2-enoate 41 FH12234742.6 Attorney Docket No.: UIX-04925 Chemical Formula: C6H9IO2Molecular Weight: 240.0405 Prepared following a literature procedure.38A mixture of ethyl but-2-ynoate (7.00 mL, 60.1 mmol), NaI (14.4 g, 96.1 mmol) and glacial acetic acid (22.0 mL, 384.6 mmol) was heated to 115 ^C for 2.5 h. The reaction mixture was diluted with H2O (100 mL) and extracted with Et2O (3 × 100 mL). The combined organic layers were washed with satd. aqueous NaHCO3solution (80 mL), 1M aqueous Na2S2O3solution (80 mL), then brine (80 mL), dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via flash chromatography (n-hexane / EtOAc = 98:2) to give the title compound as a pale yellow oil (13.6 g, 56.7 mmol, 94%), the spectral data of which were consistent with literature.38Ethyl (E)-3-iodobut-2-enoate Me O I OEt Chemical Formula: C6H9IO2Molecular Weight: 240.0405 Prepared following a literature procedure.39Ethyl (Z)-3-iodobut-2-enoate (10.0 g, 41.7 mmol) was heated to 220 ^C in a pressure tube for 4 h. The resulting crude product was purified via flash chromatography (n-hexane / EtOAc = 95:5) to give the title compound as a pale yellow oil (5.96 g, 24.8 mmol, 60%), as well as 1.6 g of the starting Z isomer. (E)-3-Iodobut-2-en-1-ol Chemical Formula: C4H7IO Molecular Weight: 198.0035 To a solution of ethyl (E)-3-iodobut-2-enoate (5.90 g, 24.6 mmol) in THF (60 mL) at – 78 ^C was added DIBALH (1.0 M solution in hexane, 70.0 mL, 70.0 mmol) dropwise. After 3 h the mixture was warmed to rt, a satd. aqueous Rochelle salt solution was added (70 mL) and the mixture stirred for 1 h. It was then extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4and the solvent removed 42 FH12234742.6 Attorney Docket No.: UIX-04925 in vacuo to give the title compound as a clear oil (4.40 g, 22.2 mmol, 90%) the spectral data of which matched those reported in the literature.40(E)-tert-Butyl((3-iodobut-2-en-1-yl)oxy)dimethylsilane Me I OTBS Chemical Formula: C10H21IOSi Molecular Weight: 312.2665 To a solution of (E)-3-iodobut-2-en-1-ol (1.50 g, 7.58 mmol) in DCM (30 mL) was added imidazole (1.04 g, 15.2 mmol) followed by t-butyldimethylsilyl chloride (1.37 g, 9.1 mmol). After 2 h, a satd. aqueous NH4Cl solution (40 mL) was added, the layers separated and the aqueous layer extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via flash chromatography (hexanes / EtOAc = 99:1) to give the title compound as a clear oil (2.30 g, 7.36 mmol, 97%), the spectral data of which matched those reported in the literature.401H NMR (500 MHz, CDCl3) 6.29 (td, J = 6.6, 3.4 Hz, 1H), 4.12 (d, J = 6.4 Hz, 2H), 2.41 (s, 3H), 0.89 (s, 9H), 0.07 (s, 6H).13C NMR (150 MHz, CDCl3) 140.6, 96.0, 60.7, 28.1, 25.9, 18.3, -5.2. Synthesis of (E)-tert-butyl((3-iodo-2-methylallyl)oxy)dimethylsilane (E)-3-Iodo-2-methylprop-2-en-1-ol Chemical Formula: C4H7IO Molecular Weight: 198.0035 Compound prepared using a literature procedure.41To a solution of bis(cyclopentadienyl)zirconium dichloride (1.02 g, 3.49 mmol) in DCM (40 mL) at 0 °C was added Me3Al (2 M solution in toluene, 21.0 mL, 42.0 mmol) dropwise. The mixture was stirred at rt for 10 min, then propargyl alcohol (830 μL, 14.1 mmol) was added and the solution stirred 43 FH12234742.6 Attorney Docket No.: UIX-04925 at rt for 18 h. It was then cooled to –78 ^C, and iodine (4.2 g, 16.5 mmol) dissolved in THF (7 mL) was added. The resulting solution was stirred at rt for 1 h, then 1M aqueous HCl solution (50 mL) was added and the mixture extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with satd. aqueous Na2S2O3solution (100 mL) then brine (100 mL), dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via flash chromatography (n-hexane / EtOAc = 9:1 ^ 7:3) to give the title compound as a clear oil (1.86 g, 9.39 mmol, 67%) the spectral data of which were consistent with literature.41(E)-tert-Butyl((3-iodo-2-methylallyl)oxy)dimethylsilane I OTBS Me Chemical Formula: C10H21IOSi Molecular Weight: 312.2665 To a solution of (E)-3-iodo-2-methylprop-2-en-1-ol (1.86 g, 9.39 mmol) in DCM (40 mL) was added imidazole (1.28 g, 18.8 mmol) followed by t-butyldimethylsilyl chloride (1.70 g, 11.3 mmol). After 2 h, a satd. aqueous NH4Cl solution (40 mL) was added, the layers separated and the aqueous layer extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via flash chromatography (hexanes / EtOAc = 99:1) to give the title compound as a clear oil (2.87 g, 9.20 mmol, 98%). The spectral data of the compound were consistent with literature.421H NMR (600 MHz, CDCl3) 6.20 (s, 1H), 4.10 (dd, J = 1.6, 0.7 Hz, 2H), 1.78 (s, 3H), 0.91 (s, 9H), 0.07 (s, 6H).13C NMR (150 MHz, CDCl3) 146.8, 75.9, 67.1, 25.8, 21.1, 18.3, -5.5. Synthesis of tert-butyl((3-iodobut-3-en-2-yl)oxy)dimethylsilane 3-Iodobut-3-en-2-ol 44 FH12234742.6 Attorney Docket No.: UIX-04925 Chemical Formula: C4H7IO Molecular Weight: 198.0035 Prepared following a literature procedure.43To a solution of but-3-yn-2-ol (2.20 mL, 28.6 mmol) in Et2O (100 mL) was added trimethylsilyl iodide (4.20 mL, 28.6 mmol), and the reaction mixture was stirred at rt for 3. It was then washed with a satd. aqueous Na2S2O3solution (80 mL) and the aqueous layers extracted with Et2O (3 × 80 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via flash chromatography (n-hexane / EtOAc = 9:1) to give the title compound (2.38 g, 12.0 mmol, 42%) as a pale yellow oil. The spectroscopic data of the compound were consistent with literature.44tert-Butyl((3-iodobut-3-en-2-yl)oxy)dimethylsilane IMeOTBS Chemical Formula: C10H21IOSi Molecular Weight: 312.2665 To a solution of 3-iodobut-3-en-2-ol (853 mg, 4.31 mmol) in DCM (15 mL) was added imidazole (587 mg, 8.62 mmol) followed by t-butyldimethylsilyl chloride (780 mg, 5.17 mmol). After 2 h, a satd. aqueous NH4Cl solution (10 mL) was added, the layers separated and the aqueous layer extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via flash chromatography (hexanes / EtOAc = 99:1) to give the title compound as a clear oil (1.22 g, 3.91 mmol, 91%). Rf0.91 (hexanes / EtOAc = 9:1)1H NMR (600 MHz, CDCl3) 6.34 (app. t, J = 1.3 Hz, 1H), 5.75 (dd, J = 1.5, 0.7 Hz, 1H), 4.00 (q, J = 6.2 Hz, 1H), 1.27 (d, J = 6.1 Hz, 3H), 0.91 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).13C NMR (150 MHz, CDCl3) 123.2, 119.1, 74.8, 25.8, 24.2, 18.2, -4.7, -5.0 HRMS (ESI+) m / z calculated for C10H21AgIOSi [M+Ag+]: 418.9452; found 418.9456 Example 5: Synthesis of cyclization substrates (E)-2-Methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-2-en-1-ol 45 FH12234742.6 Attorney Docket No.: UIX-04925 Chemical Formula: C15H26O Molecular Weight: 222.3720 General procedure A using alkyl bromide @6 (1.27 g, 6.00 mmol) and vinyl iodide @9 (625 mg, 2.00 mmol), obtained as a clear oil (263 mg, 1.18 mmol, 59%). Rf0.21 (hexanes / EtOAc = 8:2)1H NMR (500 MHz, CDCl3) 5.45 (t, J = 6.4 Hz, 1H), 4.02 (s, 2H), 2.14 – 2.05 (m, 2H), 2.04 – 1.97 (m, 2H), 1.91 (t, J = 6.4 Hz, 2H), 1.69 (s, 3H), 1.62 (s, 3H), 1.61 – 1.54 (m, 2H), 1.45 – 1.40 (m, 2H), 1.00 (s, 6H)13C NMR (125 MHz, CDCl3) 137.0, 134.3, 127.2, 126.6, 69.0, 39.8, 34.9, 32.7, 28.6 (3 signals), 19.9, 19.5, 13.7 HRMS (EI+) m / z calculated for C15H26O [M+]: 222.1984; found 222.1991 -2-Methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-2-en-1-yl acetate Chemical Formula: C17H28O2Molecular Weight: 264.4090 General procedure B using (E)-2-Methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-2- en-1-ol (40.0 mg, 0.180 mmol), obtained as a clear oil (39.1 mg, 0.148 mmol, 82%). Rf0.51 (hexanes / EtOAc = 9:1)1H NMR (500 MHz, CDCl3) 5.50 (t, J = 6.3 Hz, 1H), 4.46 (s, 2H), 2.13 – 2.06 (m, 2H), 2.08 (s, 3H), 2.04 – 1.97 (m, 2H), 1.91 (t, J = 6.3 Hz, 2H), 1.67 (s, 3H), 1.61 (s, 3H), 1.60 – 1.53 (m, 2H), 1.44 – 1.39 (m, 2H), 1.00 (s, 6H)13C NMR (125 MHz, CDCl3) 171.0, 136.8, 130.1, 129.5, 127.3, 70.3, 39.8, 34.9, 32.7, 28.7, 28.6, 28.3, 21.1, 19.9, 19.5, 14.0 HRMS (EI+) m / z calculated for C17H28O2[M+]: 264.2089; found 264.2090 3-Methylene-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pentan-2-ol 46 FH12234742.6 Attorney Docket No.: UIX-04925 Chemical Formula: C15H26O Molecular Weight: 222.3720 General procedure A using alkyl bromide @6 (1.22 g, 5.3 mmol) and vinyl iodide @11 (550 mg, 1.76 mmol), obtained as a clear oil (254 mg, 1.14 mmol, 65%). Rf0.37 (hexanes / EtOAc = 8:2)1H NMR (500 MHz, CDCl3) 5.05 (s, 1H), 4.87 (s, 1H), 4.29 (q, J = 5.7 Hz, 1H), 2.18 – 2.11 (m, 3H), 2.11 – 2.01 (m, 1H), 1.91 (t, J = 6.3 Hz, 2H), 1.61 (s, 3H), 1.59 – 1.55 (m, 2H), 1.47 – 1.41 (m, 2H), 1.31 (d, J = 6.5 Hz, 3H), 1.00 (s, 3H), 1.00 (s, 3H)13C NMR (125 MHz, CDCl3) 154.2, 136.9, 127.4, 107.7, 71.1, 39.8, 35.0, 32.8, 32.2, 28.6 (2 signals), 27.7, 22.4, 19.8, 19.5 HRMS (EI+) m / z calculated for C15H26O [M+]: 222.1984; found 222.1981 3-Methylene-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pentan-2-yl acetate Chemical Formula: C17H28O2Molecular Weight: 264.4090 General procedure B using 3-methylene-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pentan-2-ol (40.0 mg, 0.180 mmol), obtained as a clear oil (39.9 mg, 0.151 mmol, 84%). Rf 0.55 (hexanes / EtOAc = 9:1)1H NMR (500 MHz, CDCl3) 5.33 (q, J = 6.6 Hz, 1H), 5.04 (s, 1H), 4.92 (s, 1H), 2.19 – 2.04 (m, 4H), 2.06 (s, 3H), 1.91 (t, J = 6.3 Hz, 2H), 1.60 (s, 3H), 1.59 – 1.54 (m, 2H), 1.44 – 1.41 (m, 2H), 1.34 (d, J = 6.5 Hz, 3H), 1.00 (s, 6H)13C NMR (125 MHz, CDCl3) 170.3, 149.7, 136.8, 127.4, 109.9, 72.9, 39.8, 35.0, 32.7, 32.4, 28.6, 28.5, 27.6, 21.4, 19.8, 19.5 (2 signals) HRMS (EI+) m / z calculated for C17H28O2[M+]: 264.2089; found 264.2093 (E)-5-(2,2-Dimethyl-6-methylenecyclohexyl)-3-methylpent-2-en-1-ol Chemical Formula: C15H26O Molecular Weight: 222.3720 47 FH12234742.6 Attorney Docket No.: UIX-04925 General procedure A using alkyl bromide @7 (1.30 g, 5.62 mmol) and vinyl iodide @9 (585 mg, 1.87 mmol), obtained as a clear oil (354 mg, 1.59 mmol, 85%). Rf0.15 (hexanes / EtOAc = 8:2)1H NMR (500 MHz, CDCl3) 5.40 (t, J = 7.0 Hz, 1H), 4.76 (d, J = 2.5 Hz, 1H), 4.54 (d, J = 2.5 Hz, 1H), 4.15 (d, J = 7.0 Hz, 2H), 2.11 – 1.95 (m, 3H), 1.82 – 1.74 (m, 1H), 1.72 – 1.68 (m, 1H), 1.67 (s, 3H), 1.63 – 1.41 (m, 4H), 1.34 – 1.18 (m, 2H), 0.91 (s, 3H), 0.84 (s, 3H)13C NMR (125 MHz, CDCl3) 149.2, 140.6, 122.9, 109.0, 59.5, 53.7, 38.1, 36.2, 32.4, 29.3, 28.4, 26.3, 24.5, 23.7, 16.4 HRMS (EI+) m / z calculated for C15H26O [M+]: 222.1984; found 222.2012 (E)-5-(2,2-Dimethyl-6-methylenecyclohexyl)-3-methylpent-2-en-1-yl acetate Chemical Formula: C17H28O2Molecular Weight: 264.4090 General procedure B using (E)-5-(2,2-dimethyl-6-methylenecyclohexyl)-3- methylpent-2-en-1-ol (100 mg, 0.450 mmol), obtained as a clear oil (110 mg, 0.416 mmol, 92%). Rf0.48 (hexanes / EtOAc = 9:1)1H NMR (600 MHz, CDCl3) 5.33 (t, J = 7.0 Hz, 1H), 4.76 (s, 1H), 4.59 (d, J = 7.0 Hz, 2H), 4.53 (d, J = 2.5 Hz, 1H), 2.09 – 1.97 (m, 3H), 2.06 (s, 3H), 1.85 – 1.75 (m, 1H), 1.71 – 1.67 (m, 1H), 1.69 (s, 3H), 1.62 – 1.41 (m, 4H), 1.32 – 1.18 (m, 2H), 0.91 (s, 3H), 0.84 (s, 3H)13C NMR (150 MHz, CDCl3) 171.2, 149.1, 143.0, 117.9, 109.0, 61.5, 53.7, 38.1, 36.2, 32.4, 30.7, 28.4, 26.3, 24.3, 23.7, 21.1, 16.6 HRMS (EI+) m / z calculated for C17H28O2[M+]: 264.2089; found 264.2081 (E)-5-(2,2-Dimethyl-6-methylenecyclohexyl)-2-methylpent-2-en-1-ol Chemical Formula: C15H26O Molecular Weight: 222.3720 48 FH12234742.6 Attorney Docket No.: UIX-04925 General procedure A using alkyl bromide @7 (720 mg, 3.11 mmol) and vinyl iodide @10 (483 mg, 1.56 mmol), obtained as a clear oil (109 mg, 0.490 mmol, 31%). Rf0.21 (hexanes / EtOAc = 8:2)1H NMR (500 MHz, CDCl3) 5.41 (t, J = 7.2 Hz, 1H), 4.77 (s, 1H), 4.55 (d, J = 2.4 Hz, 1H), 4.00 (s, 2H), 2.11 – 1.96 (m, 3H), 1.86 – 1.76 (m, 1H), 1.73 (dd, J = 11.3, 3.6 Hz, 1H), 1.64 (s, 3H), 1.57 – 1.37 (m, 4H), 1.31 – 1.18 (m, 2H), 0.91 (s, 3H), 0.82 (s, 3H)13C NMR (125 MHz, CDCl3) 149.3, 134.5, 126.8, 108.9, 69.1, 53.7, 36.2, 34.8, 32.4, 28.4, 26.3 (2 signals), 26.2, 23.7, 13.7 HRMS (EI+) m / z calculated for C15H26O [M+]: 222.1984; found 222.1989 (E)-5-(2,2-Dimethyl-6-methylenecyclohexyl)-2-methylpent-2-en-1-yl acetate Chemical Formula: C17H28O2Molecular Weight: 264.4090 General procedure B, using (E)-5-(2,2-dimethyl-6-methylenecyclohexyl)-2- methylpent-2-en-1-ol (20.0 mg, 0.0899 mmol), obtained as a clear oil (20.9 mg, 0.0791 mmol, 88%). Rf0.51 (hexanes / EtOAc = 9:1)1H NMR (500 MHz, CDCl3) 5.46 (t, J = 7.2 Hz, 1H), 4.77 (s, 1H), 4.54 (d, J = 2.5 Hz, 1H), 4.45 (s, 2H), 2.07 (s, 3H), 2.06 – 1.97 (m, 3H), 1.88 – 1.77 (m, 1H), 1.71 (dd, J = 11.4, 3.6 Hz, 1H), 1.62 (s, 3H), 1.56 – 1.40 (m, 5H), 1.24 – 1.18 (m, 1H), 0.91 (s, 3H), 0.82 (s, 3H)13C NMR (125 MHz, CDCl3) 171.0, 149.2, 130.3, 129.8, 109.0, 70.4, 53.7, 36.2, 34.8, 32.4, 28.4, 26.4 (2 signals), 26.1, 23.7, 21.0, 14.0 HRMS (EI+) m / z calculated for C17H28O2[M+]: 264.2089; found 264.2081 5-(2,2-Dimethyl-6-methylenecyclohexyl)-3-methylenepentan-2-ol Chemical Formula: C15H26O Molecular Weight: 222.3720 49 FH12234742.6 Attorney Docket No.: UIX-04925 General procedure A using alkyl bromide @7 (1.80 g, 7.79 mmol) and vinyl iodide @11 (810 mg, 2.60 mmol), obtained as a clear oil (equimolar mixture of diastereomers, 386 mg, 1.74 mmol, 67%). Rf0.32 (hexanes / EtOAc = 8:2)1H NMR (500 MHz, CDCl3) 5.04 (s, 2H), 4.82 (s, 2H), 4.77 (s, 2H), 4.24 (q, J = 6.9 Hz, 2H), 2.13 – 1.96 (m, 6H), 1.90 – 1.81 (m, 1H), 1.80 – 1.71 (m, 3H), 1.70 – 1.60 (m, 2H), 1.59 – 1.40 (m, 8H), 1.28 (d, J = 2.4 Hz, 3H), 1.27 (d, J = 2.4 Hz, 3H), 1.25 – 1.19 (m, 2H), 0.92 (s, 6H), 0.85 (s, 6H)13C NMR (125 MHz, CDCl3) 154.0 (2 signals), 149.2 (2 signals), 109.0 (2 signals), 107.8 (2 signals), 71.1, 71.0, 53.9, 53.8, 36.2 (2 signals), 34.9 (2 signals), 32.4 (2 signals), 30.4, 30.3, 28.4 (2 signals), 26.3 (2 signals), 24.9, 24.7, 23.7 (2 signals), 22.3 (2 signals) HRMS (EI+) m / z calculated for C15H26O [M+]: 222.1984; found 222.1992 5-(2,2-Dimethyl-6-methylenecyclohexyl)-3-methylenepentan-2-yl acetate Chemical Formula: C17H28O2Molecular Weight: 264.4090 General procedure B using 5-(2,2-dimethyl-6-methylenecyclohexyl)-3- methylenepentan-2-ol (190 mg, 0.854 mmol), obtained as a clear oil (equimolar mixture of diastereomers, 218 mg, 0.828 mmol, 97%). Rf0.52 (hexanes / EtOAc = 9:1)1H NMR (500 MHz, CDCl3) 5.28 (q, J = 6.6 Hz, 2H), 5.02 (s, 1H), 5.01 (s, 1H), 4.87 (d, J = 1.5 Hz, 1H), 4.86 (d, J = 1.5 Hz, 1H), 4.77 (s, 2H), 4.54 (s, 2H), 2.05 (s, 3H), 2.05 (s, 3H), 2.08 – 1.97 (m, 6H), 1.85 – 1.76 (m, 2H), 1.74 (app. t, J = 3.7 Hz, 1H), 1.72 (app. t, J = 3.7 Hz, 1H), 1.68 – 1.60 (m, 2H), 1.58 – 1.43 (m, 8H), 1.31 (d, J = 2.2 Hz, 3H), 1.30 (d, J = 2.2 Hz, 3H), 1.24 – 1.19 (m, 2H), 0.92 (s, 6H), 0.85 (s, 3H), 0.84 (s, 3H)13C NMR (125 MHz, CDCl3) 170.3 (2 signals), 149.5 (2 signals), 149.1 (2 signals), 110.0, 109.7, 109.1 (2 signals), 72.8 (2 signals), 53.8 (2 signals), 36.2 (2 signals), 34.9 (2 signals), 32.4 (2 signals), 30.8 (2 signals), 28.4 (2 signals), 26.3 (2 signals), 24.7, 24.6, 23.7 (2 signals), 21.3 (2 signals), 19.6, 19.4 HRMS (EI+) m / z calculated for C17H28O2[M+]: 264.2089; found 264.2092 50 FH12234742.6 Attorney Docket No.: UIX-04925 (E)-3-Methyl-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-2-en-1-ol Chemical Formula: C15H26O Molecular Weight: 222.3720 General procedure A using alkyl bromide @8 (555 mg, 2.40 mmol) and vinyl iodide @9 (824 mg, 2.64 mmol), obtained as a clear oil (253 mg, 1.14 mmol, 47%). Rf0.16 (hexanes / EtOAc = 8:2)1H NMR (600 MHz, CDCl3) 5.41 (t, J = 6.9 Hz, 1H), 5.29 (s, 1H), 4.15 (br s, 2H), 2.08 – 2.02 (m, 2H), 2.00 – 1.93 (m, 2H), 1.69 – 1.66 (m, 6H), 1.56 – 1.51 (m, 1H), 1.46 – 1.37 (m, 3H), 1.16 – 1.09 (m, 1H), 0.92 (s, 3H), 0.87 (s, 3H)13C NMR (150 MHz, CDCl3) 140.6, 136.5, 123.1, 120.1, 59.4, 49.0, 40.3, 32.6, 31.6, 29.5, 27.5, 27.4, 23.5, 23.0, 16.4 HRMS (EI+) m / z calculated for C15H26O [M+]: 222.1984; found 222.2008 (E)-3-Methyl-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-2-en-1-yl acetate Chemical Formula: C17H28O2Molecular Weight: 264.4090 General procedure B using (E)-3-methyl-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-2- en-1-ol (40.0 mg, 0.180 mmol), obtained as a clear oil (36.2 mg, 0.137 mmol, 76%) Rf0.54 (hexanes / EtOAc = 9:1)1H NMR (600 MHz, CDCl3) 5.34 (ddt, J = 7.1, 5.7, 1.3 Hz, 1H), 5.29 (br s, 1H), 4.58 (d, J = 7.1 Hz, 2H), 2.10 – 2.04 (m, 2H), 2.05 (s, 3H), 1.99 – 1.93 (m, 2H), 1.70 (s, 3H), 1.67 (app. q, J = 1.9 Hz, 3H), 1.58 – 1.51 (m, 1H), 1.44 – 1.36 (m, 3H), 1.15 – 1.09 (m, 1H), 0.92 (s, 3H), 0.86 (s, 3H)13C NMR (150 MHz, CDCl3) 171.2, 143.1, 136.5, 120.1, 118.0, 61.4, 48.9, 40.3, 32.6, 31.5, 29.3, 27.5, 27.4, 23.5, 23.0, 21.1, 16.5 HRMS (EI+) m / z calculated for C17H28O2[M+]: 264.2089; found 264.2087 51 FH12234742.6 Attorney Docket No.: UIX-04925 (E)-2-Methyl-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-2-en-1-ol Chemical Formula: C15H26O Molecular Weight: 222.3720 General procedure A using alkyl bromide @8 (1.70 g, 7.35 mmol) and vinyl iodide @10 (765 mg, 2.45 mmol), obtained as a clear oil (438 mg, 1.97 mmol, 80%). Rf0.22 (hexanes / EtOAc = 8:2)1H NMR (500 MHz, CDCl3) 5.41 (tq, J = 7.2, 1.4 Hz, 1H), 5.29 (s, 1H), 4.01 (d, J = 5.1 Hz, 2H), 2.12 – 2.04 (m, 2H), 2.01 – 1.93 (m, 2H), 1.68 (d, J = 1.4 Hz, 3H), 1.68 (s, 3H), 1.53 – 1.46 (m, 1H), 1.46 – 1.38 (m, 2H), 1.37 – 1.28 (m, 1H), 1.13 (dt, J = 12.6, 4.6 Hz, 1H), 0.93 (s, 3H), 0.87 (s, 3H)13C NMR (125 MHz, CDCl3) 136.6, 134.5, 126.9, 120.0, 69.1, 49.0, 32.5, 31.6, 30.9, 28.4, 27.5, 27.4, 23.5, 23.0, 13.7 HRMS (EI+) m / z calculated for C15H26O [M+]: 222.1984; found 222.1990 -2-Methyl-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-2-en-1-yl acetate Chemical Formula: C17H28O2Molecular Weight: 264.4090 General procedure B using (E)-2-methyl-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-2- en-1-ol (60.0 mg, 0.270 mmol), obtained as a clear oil (69.3 mg, 0.262 mmol, 97%). Rf0.52 (hexanes / EtOAc = 9:1)1H NMR (500 MHz, CDCl3) 5.47 (td, J = 7.2, 1.3 Hz, 1H), 5.29 (s, 1H), 4.46 (s, 2H), 2.12 – 2.03 (m, 2H), 2.07 (s, 3H), 2.00 – 1.93 (m, 2H), 1.68 (d, J = 1.3 Hz, 3H), 1.66 (s, 3H), 1.52 – 1.46 (m, 1H), 1.45 – 1.40 (m, 2H), 1.37 – 1.29 (m, 1H), 1.13 (dt, J = 13.2, 4.8 Hz, 1H), 0.93 (s, 3H), 0.87 (s, 3H)13C NMR (125 MHz, CDCl3) 171.0, 136.6, 130.3, 129.8, 120.1, 70.3, 49.0, 32.6, 31.6, 30.7, 28.6, 27.5, 27.4, 23.5, 23.0, 21.0, 14.0 HRMS (EI+) m / z calculated for C17H28O2Na [M+Na+]: 287.1987; found 287.1997 52 FH12234742.6 Attorney Docket No.: UIX-04925 3-Methylene-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-2-ol Chemical Formula: C15H26O Molecular Weight: 222.3720 General procedure A using alkyl bromide @8 (1.64 g, 7.09 mmol) and vinyl iodide @11 (740 mg, 2.36 mmol), obtained as a clear oil (equimolar mixture of diastereomers, 410 mg, 1.84 mmol, 78%). Rf0.35 (hexanes / EtOAc = 8:2)1H NMR (500 MHz, CDCl3) 5.31 (s, 2H), 5.03 (s, 2H), 4.82 (s, 2H), 4.26 (qd, J = 6.4, 2.8 Hz, 2H), 2.20 – 2.00 (m, 4H), 2.00 – 1.94 (m, 4H), 1.69 (d, J = 1.9 Hz, 6H), 1.66 – 1.56 (m, 2H), 1.52 – 1.40 (m, 6H), 1.30 (dd, J = 6.4, 1.0 Hz, 6H), 1.14 (dt, J = 13.4, 4.8 Hz, 2H), 0.94 (s, 6H), 0.88 (s, 6H)13C NMR (125 MHz, CDCl3) 154.2 (2 signals), 136.4 (2 signals), 120.2 (2 signals), 108.0 (2 signals), 71.0 (2 signals), 49.4 (2 signals), 32.6 (2 signals), 32.5 (2 signals), 31.7, 31.6, 30.1, 30.0, 27.6 (2 signals), 27.5, 27.4, 23.5 (2 signals), 23.0 (2 signals), 22.4, 22.3 HRMS (EI+) m / z calculated for C15H27O [M+H+]: 223.2062; found 223.2072 3-Methylene-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-2-yl acetate Chemical Formula: C17H28O2Molecular Weight: 264.4090 General procedure B using 3-methylene-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan- 2-ol (110 mg, 0.495 mmol), obtained as a clear oil (121 mg, 0.458 mmol, 93%). Rf0.56 (hexanes / EtOAc = 9:1)1H NMR (500 MHz, CDCl3) 5.33 – 5.28 (m, 4H), 5.01 (s, 2H), 4.87 (s, 2H), 2.12 – 2.06 (m, 4H), 2.05 (s, 6H), 2.01 – 1.94 (m, 4H), 1.68 (d, J = 1.9 Hz, 6H), 1.65 – 1.56 (m, 2H), 1.52 – 1.39 (m, 6H), 1.32 (d, J = 6.6 Hz, 6H), 1.14 (app. dt, J = 13.2, 4.6 Hz, 2H), 0.93 (s, 6H), 0.88 (s, 6H) 53 FH12234742.6 Attorney Docket No.: UIX-0492513C NMR (125 MHz, CDCl3) 170.3 (2 signals), 149.7 (2 signals), 136.3 (2 signals), 120.3 (2 signals), 110.1 (2 signals), 72.7 (2 signals), 49.3 (2 signals), 32.9, 32.8, 32.6 (2 signals), 31.7, 31.6, 29.9, 29.8, 27.6, 27.5, 27.4 (2 signals), 23.5, 23.4, 23.0 (2 signals), 21.3 (2 signals), 19.6, 19.5 HRMS (EI+) m / z calculated for C17H28O2Na [M+Na+]: 287.1987; found 287.1998 (E)-2-methyl-5-((1S,4aS,8aS)- trimethyl-2-methylenedecahydronaphthalen-1-yl)pent-2- en-1-ol Chemical Formula: C20H34O Molecular Weight: 290.4910 General procedure A using (4S,5S,8S)-5-(2-bromoethyl)-1,1,4-trimethyl-6- methylenedecahydronaphthalene (1.30 g, 4.35 mmol) and vinyl iodide @10 (452 mg, 1.45 mmol), obtained as a clear oil (169 mg, 0.582 mmol, 40%). Rf0.56 (cyclohexane / EtOAc = 8:2)1H NMR (500 MHz, CDCl3) 5.40 (tq, J = 7.2, 1.4 Hz, 1H), 4.83 (q, J = 1.7 Hz, 1H), 4.53 (d, J = 1.6 Hz, 1H), 4.00 (s, 2H), 2.39 (ddd, J = 12.7, 4.3, 2.4 Hz, 1H), 2.20 – 2.11 (m, 1H), 1.97 (td, J = 12.8, 5.2 Hz, 1H), 1.92 – 1.82 (m, 1H), 1.80 – 1.69 (m, 2H), 1.63 (d, J = 1.2 Hz, 3H), 1.62 – 1.35 (m, 6H), 1.32 (dd, J = 13.0, 4.3 Hz, 1H), 1.21 – 1.14 (m, 1H), 1.08 (dd, J = 12.6, 2.7 Hz, 1H), 1.00 (td, J = 12.9, 3.9 Hz, 1H), 0.87 (s, 3H), 0.80 (s, 3H), 0.67 (s, 3H)13C NMR (125 MHz, CDCl3) 148.7, 134.6, 127.0, 106.2, 69.1, 56.3, 55.5, 42.2, 39.6, 39.1, 38.4, 33.6, 33.6, 26.6, 24.5, 23.5, 21.7, 19.4, 14.4, 13.7 HRMS (ESI+) m / z calculated for C20H34ONa [M+Na+]: 313.2502; found 313.2499 (E)-2-methyl-5-((1S,4aS,8aS)- trimethyl-2-methylenedecahydronaphthalen-1-yl)pent-2- en-1-yl acetate Chemical Formula: C22H36O2Molecular Weight: 332.5280 54 FH12234742.6 Attorney Docket No.: UIX-04925 General procedure B using (E)-2-methyl-5-((1S,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)pent-2-en-1-ol (220 mg, 0.759 mmol), obtained as a clear oil (232 mg, 0.698 mmol, 92%). Rf0.50 (cyclohexane / EtOAc = 95:5)1H NMR (600 MHz, CDCl3) 5.45 (t, J = 7.2 Hz, 1H), 4.83 (s, 1H), 4.52 (s, 1H), 4.46 (s, 1H), 4.45 (s, 1H), 2.39 (ddd, J = 12.8, 4.4, 2.4 Hz, 1H), 2.20 – 2.12 (m, 1H), 2.08 (s, 3H), 1.97 (td, J = 13.1, 5.3 Hz, 1H), 1.91 – 1.82 (m, 1H), 1.77 – 1.68 (m, 2H), 1.62 (s, 3H), 1.61 – 1.36 (m, 6H), 1.31 (qd, J = 12.9, 4.3 Hz, 1H), 1.17 (td, J = 13.4, 4.1 Hz, 1H), 1.08 (dd, J = 12.6, 2.7 Hz, 1H), 0.99 (td, J = 13.0, 4.0 Hz, 1H), 0.87 (s, 3H), 0.80 (s, 3H), 0.66 (s, 3H)13C NMR (150 MHz, CDCl3) 171.1, 148.6, 130.6, 129.8, 106.2, 70.4, 56.3, 55.5, 42.1, 39.6, 39.0, 38.3, 33.6, 33.6, 26.7, 24.4, 23.3, 21.7, 21.1, 19.4, 14.4, 14.0 HRMS (ESI+) m / z calculated for C22H36O2Na [M+Na+]: 355.2608; found 355.2604 (E)-3-methyl-5-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)pent- 2-en-1-ol Chemical Formula: C20H34O Molecular Weight: 290.4910 General procedure A using (4S,5S,8S)-5-(2-Bromoethyl)-1,1,4-trimethyl-6- methylenedecahydronaphthalene (1.30 g, 4.35 mmol) and vinyl iodide @9 (452 mg, 1.45 mmol), obtained as a clear oil (385 mg, 1.33 mmol, 92%). Rf0.51 (cyclohexane / EtOAc = 8:2)1H NMR (500 MHz, CDCl3) 5.39 (tq, J = 6.9, 1.3 Hz, 1H), 4.83 (d, J = 1.7 Hz, 1H), 4.51 (d, J = 1.7 Hz, 1H), 4.15 (d, J = 7.1 Hz, 2H), 2.43 – 2.36 (m, 1H), 2.25 – 2.11 (m, 1H), 2.10 – 1.92 (m, 2H), 1.88 – 1.68 (m, 4H), 1.68 (s, 3H), 1.64 – 1.36 (m, 4H), 1.36 – 1.24 (m, 1H), 1.22 – 1.13 (m, 1H), 1.08 (dd, J = 12.6, 2.8 Hz, 1H), 1.00 (td, J = 13.0, 4.2 Hz, 1H), 0.87 (s, 3H), 0.80 (s, 3H), 0.68 (s, 3H)13C NMR (125 MHz, CDCl3) 148.6, 140.7, 123.0, 106.2, 59.5, 56.3, 55.5, 42.2, 39.7, 39.1, 38.4, 38.4, 33.6, 33.6, 24.4, 21.8, 21.7, 19.4, 16.4, 14.5 HRMS (ESI+) m / z calculated for C20H34ONa [M+Na+]: 313.2502; found 313.2500 55 FH12234742.6 Attorney Docket No.: UIX-04925 (E)-3-methyl-5-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)pent-2- en-1-yl acetate Chemical Formula: C22H36O2Molecular Weight: 332.5280 General procedure B using (E)-3-methyl-5-((1S,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)pent-2-en-1-ol (200 mg, 0.688 mmol), obtained as a clear oil (211 mg, 0.635 mmol, 92%). Rf0.60 (cyclohexane / EtOAc = 9:1)1H NMR (500 MHz, CDCl3) 5.31 (tq, J = 7.1, 1.3 Hz, 1H), 4.82 (d, J = 1.7 Hz, 1H), 4.58 (d, J = 7.1 Hz, 2H), 4.50 (d, J = 1.6 Hz, 1H), 2.42 – 2.35 (m, 1H), 2.17 (ddd, J = 14.4, 10.1, 4.2 Hz, 1H), 2.06 (s, 3H), 2.00 – 1.92 (m, 1H), 1.88 – 1.80 (m, 1H), 1.77 – 1.71 (m, 2H), 1.70 (s, 3H), 1.64 – 1.52 (m, 3H), 1.51 – 1.37 (m, 3H), 1.35 – 1.27 (m, 1H), 1.21 – 1.14 (m, 1H), 1.08 (dd, J = 12.6, 2.8 Hz, 1H), 0.99 (td, J = 13.0, 4.0 Hz, 1H), 0.87 (s, 3H), 0.80 (s, 3H), 0.68 (s, 3H)13C NMR (125 MHz, CDCl3) 171.2, 148.6, 143.2, 117.9, 106.2, 61.4, 56.2, 55.5, 42.2, 39.6, 39.1, 38.4, 38.3, 33.6, 33.6, 24.4, 21.7, 21.6, 21.1, 19.4, 16.5, 14.5 HRMS (ESI+) m / z calculated for C22H36O2Na [M+Na+]: 355.2608; found 355.2606 Example 6: Synthesis of precursor for the Xishacorene core system Methyl 4,6,6-trimethylcyclohex-3-ene-1-carboxylate Me Molecular Weight: 182.2630 56 FH12234742.6 Attorney Docket No.: UIX-04925 To dimethyl 2-(propan-2-ylidene)malonate (3.00 g, 17.4 mmol) dissolved in CHCl3(90 mL) was added isoprene (14.1 mL, 5.23 mmol) followed by AlCl3(697 mg, 5.23 mmol). The reaction mixture was stirred at 36 ºC overnight, then 1M aqueous HCl solution was added (100 mL), the layers separated and the aqueous layer extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4and the solvent removed in vacuo to give the Diels-Alder adduct as a yellow oil. This was dissolved in DMSO / H2O (40:1, 14 mL), LiCl (1.81 g, 42.4 mmol) was added and the mixture was heated to 160 ºC for 7 h. It was then diluted with water (20 mL), extracted with EtOAc (3 x 30 mL), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4and the solvent removed in vacuo. The crude residue was purified via column chromatography (cyclohexane / EtOAc = 95:5) to give the title compound as a clear oil (1.66 g, 9.11 mmol, 56% over 2 steps). The spectral data of the compound were in agreement with literature.45(E)-4-(4,6,6-Trimethylcyclohex-3-en-1-yl)but-3-en-2-one Chemical Formula: C13H20O Molecular Weight: 192.3020 Methyl 4,6,6-trimethylcyclohex-3-ene-1-carboxylate (1.66 g, 9.11 mmol) was dissolved in DCM (35 mL) and DIBAL (1M solution in toluene, 21.9 mL, 21.9 mmol) was added dropwise at –78 ºC. The reaction mixture was allowed to warm to rt and stirred overnight. Aqueous 1M HCl solution (30 mL) was then added, the layers separated, the aqueous layer extracted with DCM (2 × 30 mL), the combined organic layers washed with brine (80 mL), dried over Na2SO4and the solvent removed in vacuo to give the alcohol which was used directly in the next step. Oxalyl chloride (1.64 mL, 17.2 mmol) was dissolved in DCM (60 mL), the solution cooled to –78 ºC and DMSO (2.45 mL, 34.5 mmol) added. The reaction mixture was stirred at –78 ºC for 15 min, then the (4,6,6-trimethylcyclohex-3-en-1-yl)methanol obtained in the previous step was added as a solution in DCM (20 mL, rinsing with 5 mL) and the mixture stirred at –78 ºC for a further 30 min. NEt3(6.00 mL, 43.1 mmol) was then added, the reaction mixture stirred for a further 5 min at –78 ºC, then warmed to 0 ºC and stirred for 30 min. It was then filtered 57 FH12234742.6 Attorney Docket No.: UIX-04925 through celite and the solvent removed in vacuo, the residue redissolved in EtOAc (80 mL) and washed with satd. aqueous NaHCO3solution (50 mL), H2O (50 mL) and brine (50 mL), dried over Na2SO4and the solvent removed in vacuo to give the aldehyde which was used in the next step with no further purification. The aldehyde was then dissolved in toluene (30 mL), 1-(triphenylphosphoranylidene)-2-propanone (3.83 g, 12.0 mmol) was added and the mixture heated to 100 ºC overnight. The solvent was then removed in vacuo, the residue triturated with n-pentane (50 mL) and filtered through celite. The filtrate was concentrated in vacuo and purified via flash chromatography (pentane / EtOAc = 95:5) to give the title compound as a pale yellow oil (795 mg, 4.13 mmol, 45% over 3 steps). Rf0.56 (cyclohexane / EtOAc = 9:1)1H NMR (500 MHz, CDCl3) 6.76 (dd, J = 15.9, 9.0 Hz, 1H), 6.09 (dd, J = 15.9, 0.8 Hz, 1H), 5.37 – 5.31 (m, 1H), 2.25 (s, 3H), 2.16 – 2.07 (m, 2H), 2.00 – 1.92 (m, 1H), 1.87 – 1.79 (m, 1H), 1.74 – 1.68 (m, 1H), 1.65 (s, 3H), 0.93 (s, 3H), 0.85 (s, 3H).13C NMR (125 MHz, CDCl3) 198.7, 150.1, 133.0, 131.8, 118.0, 46.4, 44.3, 32.3, 29.0, 28.7, 27.1, 23.7, 22.9. HRMS (ESI+) m / z calculated for C13H20ONa [M+Na+]: 215.1406; found 215.1405 (E)-3-Methyl-5-(4,6,6-trimethylcyclohex-3-en-1-yl)pent-2-en-1-ol Chemical Formula: C15H26O Molecular Weight: 222.3720 (E)-4-(4,6,6-Trimethylcyclohex-3-en-1-yl)but-3-en-2-one (250 mg, 1.30 mmol) was dissolved in MeOH (12.5 mL) and Pd / C 5% (unreduced, 31.2 mg, 0.294 mmol) was added. The mixture was sparged with H2then maintained under an atmosphere of H2overnight. It was then filtered over celite and the filtrate concentrated in vacuo to give the saturated ketone which was used in the next step with no further purification. Triethyl phosphonoacetate (607 mg, 2.71 mmol) was dissolved in THF (10 mL), NaH (60% dispersion in mineral oil, 103 mg, 2.58 mmol) was added and the mixture stirred at the same temperature for 1.5 h. The ketone prepared in the previous step was then added as a solution in THF (3 mL, rinsing with 2 × 1 mL) and the 58 FH12234742.6 Attorney Docket No.: UIX-04925 mixture stirred overnight at rt. Brine (20 mL) was then added and the mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over Na2SO4and the solvent removed in vacuo. The ester thus obtained was dissolved in DCM (3 mL) and DIBAL (1M solution in toluene, 1.24 mL, 1.24 mmol) was added dropwise at –78 ºC. The reaction mixture was stirred at the same temperature for 4 h, then satd. aqueous Rochelle salt solution was added (10 mL) and the mixture stirred at rt for 30 min. The layers were then separated and the aqueous layer extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, the solvent removed in vacuo and the residue purified via flash chromatography to give the title compound as a clear oil (164 mg, 0.738 mmol, 57% over 3 steps). Rf0.28 (cyclohexane / EtOAc = 8:2)1H NMR (500 MHz, CDCl3) 5.41 (tq, J = 6.9, 1.3 Hz, 1H), 5.30 (s, 1H), 4.15 (d, J = 7.0 Hz, 1H), 2.19 – 2.07 (m, 2H), 1.92 – 1.84 (m, 1H), 1.84 – 1.77 (m, 1H), 1.70 – 1.57 (m, 3H), 1.67 (d, J = 1.3 Hz, 3H), 1.62 (s, 3H), 1.22 – 1.15 (m, 1H), 1.10 – 1.01 (m, 1H), 0.92 (s, 3H), 0.77 (s, 3H)13C NMR (125 MHz, CDCl3) 140.5, 132.7, 123.1, 119.4, 59.4, 45.7, 41.6, 37.9, 32.1, 29.0, 28.7, 27.5, 23.7, 21.3, 16.2 HRMS (ESI+) m / z calculated for C15H26ONa [M+Na+]: 245.1876; found 245.1874 Example 7: Cyclization conditions and product characterization Screening scale reactions Resorcinarene (11.1 mg, 1.67 μmol, 0.10 equiv. capsule I or 22.2 mg, 3.34 μmol, 0.20 equiv. capsule I) was dissolved in 200 μL of chloroform. To this solution was added a n-decane stock solution in chloroform (20 μL, 167 mmol l−1, 3.34 μmol, 0.2 eq). Additional chloroform was added to bring the total volume to 500 μL. The substrate was then added (16.7 μmol, 1.00 eq) followed by an HCl stock solution in chloroform (0.50 μmol, 0.03 eq), and the mixture was briefly stirred. An aliquot (approximately 10 μL) of the reaction mixture was diluted with 0.25 mL of hexane (containing 0.08% DMSO) and subjected, after centrifugation to remove the precipitate formed, to gas chromatographic analysis (initial sample). The reaction mixture was then stirred in a closed vial at the specified (internal) temperature, and further samples were taken at the indicated times and analyzed by gas chromatography. Conversions and yields were calculated as described in our previous work.46Preparation and titration of HCl stock solution in chloroform 59 FH12234742.6 Attorney Docket No.: UIX-04925 HCl stock solution in chloroform was prepared by passing HCl gas, generated by the dropwise addition of concentrated H2SO4to dry NaCl, through chloroform for approximately 30 mins. The concentration of HCl in the resulting solution was determined as follows: HCl stock solution in chloroform (100 μL) was added to a solution of phenol red in EtOH (0.002 wt%, 2.5 mL) via a Microman M1 pipette equipped with plastic tips. Upon addition the solution turned from yellow (neutral) to pink (acidic). The resulting solution was then titrated with a 0.100 M ethanolic solution of triethylamine. At the equivalence point the solution turned from pink to yellow. The HCl stock solution was kept in the fridge, and the titration was repeated immediately before each use. Choice of catalyst loading For reactions with substrates bearing tail group @9, 10 mol% of the capsule catalyst I and 3 mol% of HCl cocatalyst and a reaction temperature of 30 °C were used as previously described.47In screening scale reactions with substrate @14 bearing the less reactive tail group @10, these conditions were found to result in a sluggish reaction. An increase of capsule catalyst loading to 20 mol% and of the reaction temperature to 40 °C resulted in significantly faster reaction and a higher yield (see FIG.4), therefore these conditions were employed for preparative scale reactions of substrates bearing tail groups @10 and @11. Choice of leaving group Consistent with previous studies on the capsule-catalyzed THT cyclization of sesquiterpenes, the cyclization of precursors with an alcohol leaving group (R = H) led to the same major cyclized product as that of those with an acetate leaving group (R = Ac), with the exception of substrates bearing tail group @11. In these cases, only the acetate (R = Ac) precursors led to the formation of THT cyclization products. With the alcohol variant of precursor @16 (R = H), a ketone product was formed (see scheme below), presumably via an alternative mechanism involving protonation of the endocyclic double bond. With the alcohol variant of precursor @22 (R = H), a mixture of three products was formed, with GC retention times consistent with oxygen-containing structures; elucidation of this reaction mixture was not pursued further. 60 FH12234742.6 Attorney Docket No.: UIX-04925 Characterization data for ketone product resulting from cyclization of the alcohol variant of @16:1H NMR (500 MHz, CDCl3) 2.59 (tt, J = 12.3, 3.8 Hz, 1H), 2.11 (s, 3H), 2.01 – 1.93 (m, 1H), 1.71 – 1.57 (m, 2H), 1.49 – 1.35 (m, 4H), 1.34 – 1.23 (m, 2H), 1.23 – 1.05 (m, 3H), 0.95 (s, 3H), 0.88 (dd, J = 12.1, 2.8 Hz, 1H), 0.84 (s, 3H), 0.79 (s, 3H)13C NMR (125 MHz, CDCl3) 212.5, 53.2, 47.1, 47.0, 42.4, 41.9, 34.2, 33.0, 32.9, 29.4, 27.9, 21.2, 21.2, 19.4, 18.8 HRMS (EI+) m / z calculated for C15H26O [M+H+]: 222.1984; found 222.1988. Preparation of corresponding semicarbazone and characterization data: To a solution of semicarbazide hydrochloride (5.6 mg, 0.0502 mmol) in water (250 μL) was added sodium acetate (4.1 mg, 0.0500 mmol). After stirring at rt for 30 min, to this solution was added a solution of the ketone product (5.5 mg, 0.0247 mmol) in EtOH (150 μL, rinsing with 2×75 μL). The mixture was stirred at 50 °C for 2 h, the solvent was then removed in vacuo and the crude product subjected to flash chromatography (DCM / MeOH, 49:1) to give the title compound as a white solid (4.9 mg, 0.0175, 70%).1H NMR (500 MHz, CDCl3) 7.51 (s, 1H), 6.09 (br s, 1H), 4.77 (br s, 1H), 2.44 (t, J = 12.4 Hz, 1H), 1.96 – 1.90 (m, 1H), 1.78 (s, 3H), 1.74 – 1.57 (m, 2H), 1.53 – 1.37 (m, 4H), 1.35 – 1.31 (m, 2H), 1.26 – 1.18 (m, 1H), 1.17 – 1.08 (m, 2H), 1.00 (s, 3H), 0.95 – 0.90 (m, 1H), 0.88 (s, 3H), 0.83 (s, 3H)13C NMR (125 MHz, CDCl3) 157.5, 153.8, 53.5, 48.7, 42.5, 42.1, 41.9, 34.4, 33.0, 33.0, 31.1, 21.4, 21.2, 19.6, 18.8, 13.6. HRMS (EI+) m / z calculated for C16H30N3O [M+H+]: 280.2389; found 280.2388. General procedure C 61 FH12234742.6 Attorney Docket No.: UIX-04925 To the substrate dissolved in CHCl3was added the specified amount of resorcinarene followed by HCl stock solution in CHCl3, and the mixture was stirred at the specified temperature. Once the reaction was judged to be complete by GC analysis, the solvent was partially removed in vacuo (350 mbar at 40 ºC for short timeframes of 10-15 min – longer evaporation times could lead to significant loss of the volatile sesquiterpene products) and the mixture was passed through a column of silica (eluting with pentane) to remove the capsule catalyst and polar byproducts (for reactions utilizing 20 mol% of the capsule catalyst, two such passages may be required), followed by column chromatography as specified for each product. Example 8: Characterization of cyclization products 3-Isopropyl-7,7,7a-trimethyl-2,6,7,7a-tetrahydro-1H-indene (@15) Chemical Formula: C15H24Molecular Weight: 204.3570 General procedure C using @14-alcohol as the starting material (164 mg, 0.738 mmol), 20 mol% of capsule I (1.02 g, 0.148 mmol), 3 mol% of HCl and CDCl3as the solvent (22.5 mL). Purified by flash chromatography on AgNO3-impregnated silica (pentane) to give 43.7 mg (0.214 mmol, 29%) of the title product as a clear oil. Rf0.84 (hexanes) IR νmax(thin film) / cm−12961m, 2927m, 1467w, 1368w1H NMR (500 MHz, CDCl3) 6.25 (dd, J = 9.8, 2.9 Hz, 1H), 5.58 – 5.54 (m, 1H), 2.80 (app. p, J = 6.9 Hz, 1H), 2.42 – 2.33 (m, 1H), 2.30 – 2.20 (m, 2H), 1.80 – 1.75 (m, 1H), 1.75 – 1.69 (m, 1H), 1.41 – 1.35 (m, 1H), 1.00 (d, J = 7.2 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.75 (s, 3H)13C NMR (125 MHz, CDCl3) 141.5, 136.8, 125.9, 120.9, 51.9, 39.9, 34.5, 30.4, 28.5, 26.7, 24.7, 24.4, 21.8, 21.1, 19.9 HRMS (EI+) m / z calculated for C15H25[M+H+]: 205.1956; found 205.1955 6-Ethyl- trimethyl-1,2,3,7,8,8a-hexahydronaphthalene (@17) 62 FH12234742.6 Attorney Docket No.: UIX-04925 Chemical Formula: C15H24Molecular Weight: 204.3570 General procedure C using @16-acetate as the starting material (50.0 mg, 0.189 mmol), 20 mol% of capsule I (252 mg, 0.0378 mmol), 3 mol% of HCl and CDCl3as the solvent (6.3 mL). Purified by flash chromatography on AgNO3-impregnated silica (pentane) to give 11.0 mg (0.0538 mmol, 29%) of the title product as a clear oil. Rf0.80 (hexanes) IR νmax(thin film) / cm−12964m, 2923m, 2874m, 1457m, 1375m, 887m1H NMR (500 MHz, CDCl3) 5.73 (s, 1H), 5.33 (t, J = 3.8 Hz, 1H), 2.19 – 2.07 (m, 3H), 2.03 (q, J = 7.5 Hz, 2H), 1.97 (dd, J = 17.9, 3.8 Hz, 1H), 1.83 (ddd, J = 13.4, 11.6, 6.9 Hz, 1H), 1.53 – 1.45 (m, 2H), 1.15 (dd, J = 13.4, 6.6 Hz, 1H), 1.03 (t, J = 7.5 Hz, 3H), 0.95 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H)13C NMR (125 MHz, CDCl3) 140.3, 138.8, 123.4, 121.1, 37.7, 34.0, 33.2, 30.1, 28.1, 26.4, 24.4, 23.1, 22.8, 20.7, 12.3 HRMS (EI+) m / z calculated for C15H25[M+]: 204.1878; found 204.1874 1,1,6-trimethyl-6-vinyl-1,2,3,4,5,6,7,8-octahydronaphthalene (@19) Chemical Formula: C15H24Molecular Weight: 204.3570 General procedure C using @18-alcohol as the starting material (100 mg, 0.450 mmol), 10 mol% of capsule I (300 mg, 0.0450 mmol), 3 mol% of HCl and CDCl3as the solvent (13.9 mL). Purified by flash chromatography on AgNO3-impregnated silica (pentane) to give 22.7 mg (0.111 mmol, 25%) of the title product as a clear oil. The spectroscopic data of the compound were consistent with literature values.48Rf0.92 (hexanes)1H NMR (500 MHz, CDCl3) 5.79 (dd, J = 17.9, 10.4 Hz, 1H), 4.88 (dd, J = 17.9, 1.5 Hz, 1H), 4.88 (dd, J = 10.3, 1.6 Hz, 1H), 1.99 – 1.93 (m, 2H), 1.89 – 1.80 (m, 3H), 1.70 – 1.64 (m, 1H), 1.63 – 1.57 (m, 2H), 1.50 – 1.36 (m, 4H), 0.97 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H) 63 FH12234742.6 Attorney Docket No.: UIX-0492513C NMR (150 MHz, CDCl3) 147.8, 133.6, 125.4, 110.0, 42.3, 39.8, 35.1, 34.4, 33.5, 31.6, 27.9, 27.9, 25.6, 21.7, 19.4 6-Isopropyl-1,1-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene (@21) Chemical Formula: C15H24Molecular Weight: 204.3570 General procedure C using @20-acetate as the starting material (50.0 mg, 0.189 mmol), 20 mol% of capsule I (278 mg, 0.0417 mmol), 3 mol% of HCl and CDCl3as the solvent (6.3 mL). Purified by flash chromatography on AgNO3-impregnated silica (pentane) to give 9.5 mg (0.0465 mmol, 25%) of the title product as a clear oil. Rf0.80 (hexanes) IR νmax(thin film) / cm−12961m, 2927m, 2872w, 1464w, 1363w, 889w1H NMR (500 MHz, CDCl3) 5.81 (s, 1H), 5.40 (br s, 1H), 2.23 (app. p, J = 6.8 Hz, 1H), 2.14 – 2.01 (m, 4H), 1.94 – 1.86 (m, 2H), 1.48 – 1.36 (m, 2H), 1.22 – 1.12 (m, 1H), 1.03 (d, J = 4.2 Hz, 3H), 1.01 (d, J = 4.3 Hz, 3H), 0.99 (s, 3H), 0.76 (s, 3H)13C NMR (125 MHz, CDCl3) 145.2, 136.2, 122.7, 121.3, 45.2, 37.9, 34.9, 31.2, 29.4, 27.7, 23.7, 23.1, 21.5, 20.9, 19.4 HRMS (EI+) m / z calculated for C15H25[M+]: 204.1878; found 204.1881 6-Ethyl-1,1,4a-trimethyl-1,2,3,4,4a,5-hexahydronaphthalene (@23) Chemical Formula: C15H24Molecular Weight: 204.3570 General procedure C using @22-acetate as the starting material (100 mg, 0.378 mmol), 20 mol% of capsule I (503 mg, 0.0757 mmol), 3 mol% of HCl and CDCl3as the solvent (10.0 mL). Purified by flash chromatography on AgNO3-impregnated silica (pentane) to give 18.6 mg (0.0910 mmol, 24%) of the title product as a clear oil. Rf0.81 (hexanes) 64 FH12234742.6 Attorney Docket No.: UIX-04925 IR1H NMR (600 MHz, CDCl3) 5.80 (d, J = 5.6 Hz, 1H), 5.63 – 5.60 (m, 1H), 2.13 – 2.01 (m, 3H), 1.75 – 1.66 (m, 2H), 1.65 – 1.61 (m, 1H), 1.53 – 1.48 (m, 1H), 1.48 – 1.43 (m, 1H), 1.35 – 1.24 (m, 2H), 1.12 (s, 3H), 1.11 (s, 3H), 1.02 (t, J = 7.4 Hz, 3H), 0.98 (s, 3H)13C NMR (150 MHz, CDCl3) 150.2, 138.5, 117.1, 117.1, 46.3, 42.0, 40.5, 34.8, 34.6, 31.7, 31.5, 29.8, 23.6, 18.7, 11.8. Note: Spectra of this compound registered in CDCl3showed decomposition potentially caused by traces of acidity in the solvent; this decomposition was not observed when spectra were registered in benzene-d6(peak listing follows).1H NMR (600 MHz, benzene-d6) 5.89 (d, J = 5.6 Hz, 1H), 5.71 (s, 1H), 2.12 (d, J = 16.0 Hz, 1H), 2.07 – 1.97 (m, 2H), 1.68 (dt, J = 13.3, 3.3 Hz, 1H), 1.61 (d, J = 16.0 Hz, 1H), 1.57 (d, J = 13.1, 1H), 1.48 – 1.38 (m, 2H), 1.32 (td, J = 12.9, 3.4 Hz, 1H), 1.25 (td, J = 13.1, 3.8 Hz, 1H), 1.17 (s, 3H), 1.14 (s, 3H), 1.07 (s, 3H), 1.00 (t, J = 7.5 Hz, 3H)13C NMR (150 MHz, benzene-d6) 149.7, 138.2, 118.1, 118.1, 46.7, 42.3, 40.9, 35.0, 34.9, 31.9, 31.8, 30.3, 23.9, 19.1, 12.2 HRMS (ESI+) m / z calculated for C15H24Ag [M+Ag+]: 311.0923; found 311.0917 (±)-(1S,5R,6R)-2,2,6-Trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25a) and (±)- (1S,5R,6S)-2,2,6-trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25b) Chemical Formula: C15H24Molecular Weight: 204.3570 General procedure C using @24-alcohol as the starting material (40.0 mg, 0.180 mmol), 10 mol% of capsule I (122 mg, 0.0180 mmol), 3 mol% of HCl and CDCl3as the solvent (5.0 mL). Purified by flash chromatography on silica (pentane) to give 22.9 mg (0.113 mmol, 63%, clear oil) of the title product as a mixture of epimers (d.r. = 1:1). To obtain an analytically pure sample of each epimer the mixture was subjected to flash chromatography on AgNO3- impregnated silica (pentane pentane / Et2O = 9:1 ^ pentane / Et2O = 1:1 ^ Et2O) to give (1S,5R,6R)-2,2,6-trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (elutes in pentane 65 FH12234742.6 Attorney Docket No.: UIX-04925 fractions, 7.8 mg, 0.0382 mmol, 21%) and (1S,5R,6S)-2,2,6-trimethyl-9-methylene-6- vinylbicyclo[3.3.1]nonane (elutes in Et2O fractions, 8.4 mg, 0.0411 mmol, 23%). (±)-(1S,5R,6R)-2,2,6-Trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25a) Chemical Formula: C15H24Molecular Weight: 204.3570 Rf0.90 (hexanes)1H NMR (600 MHz, CDCl3) 5.82 (dd, J = 17.3, 11.1 Hz, 1H), 4.99 (s, 1H), 4.97 (d, J = 6.2 Hz, 1H), 4.65 (d, J = 2.6 Hz, 2H), 2.07 (td, J = 14.1, 5.9 Hz, 1H), 1.98 (dd, J = 14.0, 5.8 Hz, 1H), 1.84 (d, J = 4.9 Hz, 1H), 1.83 – 1.80 (m, 1H), 1.79 (d, J = 4.0 Hz, 1H), 1.74 – 1.64 (m, 2H), 1.63 – 1.57 (m, 1H), 1.21 (dd, J = 14.2, 6.2 Hz, 1H), 1.13 (dd, J = 14.0, 6.2 Hz, 1H), 1.00 (s, 3H), 0.97 (s, 3H), 0.90 (s, 3H).13C NMR (150 MHz, CDCl3) 152.2, 148.8, 110.4, 106.3, 49.8, 49.0, 41.6, 35.5, 34.7, 30.3, 29.2, 28.9, 27.0, 26.6, 25.6. HRMS (ESI+) m / z calculated for C15H24Ag [M + Ag+]: 311.0923; found 311.0925 (±)-(1S,5R,6S)-2,2,6-Trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25b) Chemical Formula: C15H24Molecular Weight: 204.3570 Rf0.90 (hexanes)1H NMR (600 MHz, CDCl3) 5.99 (dd, J = 17.6, 10.9 Hz, 1H), 4.91 (dd, J = 17.7, 1.4 Hz, 1H), 4.87 (dd, J = 10.9, 1.3 Hz, 1H), 4.61 (d, J = 2.6 Hz, 1H), 4.59 (d, J = 2.6 Hz, 1H), 1.96 – 1.86 (m, 3H), 1.86 – 1.74 (m, 3H), 1.72 – 1.60 (m, 2H), 1.47 (dd, J = 14.2, 6.0 Hz, 1H), 1.19 (dd, J = 13.9, 6.0 Hz, 1H), 1.04 (s, 3H), 0.98 (s, 3H), 0.92 (s, 3H). 66 FH12234742.6 Attorney Docket No.: UIX-0492513C NMR (150 MHz, CDCl3) 152.5, 148.2, 109.3, 105.9, 49.5, 48.6, 41.5, 35.5, 35.0, 32.7, 29.2, 28.9, 26.2, 26.0, 25.9. HRMS (ESI+) m / z calculated for C15H24Ag [M + Ag+]: 311.0923; found 311.0925 (±)-(1S,5S,6S)-2,2-Dimethyl-9-methylene-6-(prop-1-en-2-yl)bicyclo[3.3.1]nonane (@27) Chemical Formula: C15H24Molecular Weight: 204.3570 General procedure C using @26-alcohol as the starting material (100 mg, 0.450 mmol), 20 mol% of capsule I (599 mg, 0.090 mmol), 3 mol% of HCl and CDCl3as the solvent (13.6 mL). Purified by flash chromatography on AgNO3-impregnated silica (pentane) to give 18.7 mg (0.0915 mmol, 20%) of the title product as a clear oil. Rf0.91 (hexanes) IR νmax(thin film) / cm−12959m, 2935m, 2880w, 1456w, 1388w, 1364w, 884m1H NMR (500 MHz, CDCl3) 4.87 (s, 1H), 4.76 (s, 1H), 4.70 (d, J = 2.5 Hz, 1H), 4.57 (d, J = 2.5 Hz, 1H), 2.47 – 2.42 (m, 1H), 2.27 (app. dt, J = 12.7, 4.9 Hz, 1H), 2.15 (dd, J = 13.6, 5.7 Hz, 1H), 2.01 (app. qd, J = 13.3, 5.6 Hz, 1H), 1.87 – 1.83 (m, 1H), 1.75 (s, 3H), 1.73 – 1.61 (m, 2H), 1.61 – 1.44 (m, 3H), 1.20 – 1.13 (m, 1H), 0.99 (s, 3H), 0.91 (s, 3H)13C NMR (150 MHz, CDCl3) 155.9, 147.6, 109.5, 103.8, 50.0, 49.8, 40.8, 35.6, 35.5, 29.4, 29.4, 28.9, 25.1, 24.7, 22.7 HRMS (EI+) m / z calculated for C15H25[M+]: 204.1878; found 204.1887 (±)- -2,4,4,8-Tetramethyl-8-vinylbicyclo[3.3.1]non-2-ene (@46) and (±)- - tetramethyl-8-vinylbicyclo[3.3.1]non-2-ene (@47) core structure Chemical Formula: C15H24Molecular Weight: 204.3570 67 FH12234742.6 Attorney Docket No.: UIX-04925 General procedure C using @44-alcohol as the starting material (97.2 mg, 0.437 mmol), 10 mol% of capsule I (300 mg, 0.0450 mmol), 3 mol% of HCl and toluene as the solvent (13.5 mL). Purified by flash chromatography on AgNO3-impregnated silica (pentane) to give 40.3 mg (0.197 mmol, 45%, clear oil) of the title product as a mixture of epimers (d.r. = 1.5:1). To obtain an analytically pure sample of each epimer, the mixture was subjected to further flash chromatography on AgNO3-impregnated silica (pentane) to give (1R,5S,8R)-2,4,4,8- tetramethyl-8-vinylbicyclo[3.3.1]non-2-ene (elutes first, 8.8 mg, 0.0431 mmol, 10%) and (1S,5R,6S)-2,2,6-trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (elutes second, 11.6 mg, 0.0568 mmol, 13%). (±)-(1R,5S,8R)-2,4,4,8-Tetramethyl- non-2-ene (@46) Chemical Formula: C15H24Molecular Weight: 204.3570 Rf0.94 (cyclohexane)1H NMR (600 MHz, CDCl3) 5.91 (dd, J = 18.1, 10.5 Hz, 1H), 5.26 (s, 1H), 5.04 (s, 1H), 5.02 (d, J = 4.6 Hz, 1H), 1.80 – 1.77 (m, 1H), 1.75 (s, 3H), 1.73 – 1.69 (m, 1H), 1.67 – 1.61 (m, 2H), 1.60 – 1.55 (m, 1H), 1.48 (td, J = 13.6, 4.8 Hz, 1H), 1.44 – 1.40 (m, 1H), 1.40 – 1.33 (m, 1H), 0.98 (s, 3H), 0.91 (s, 3H), 0.88 (s, 3H)13C NMR (150 MHz, CDCl3) 147.9, 135.9, 133.3, 111.4, 44.4, 40.8, 36.4, 35.4, 31.7, 30.3, 29.6, 28.0, 26.1, 25.8, 25.2 HRMS (ESI+) m / z calculated for C15H24Ag [M+Ag+]: 311.0923; found 311.0921 (±)-(1R,5S,8S)-2,4,4,8-Tetramethyl-8-vinylbicyclo[3.3.1]non-2-ene (@47) Chemical Formula: C15H24Molecular Weight: 204.3570 Rf0.94 (cyclohexane) 68 FH12234742.6 Attorney Docket No.: UIX-049251H NMR (600 MHz, CDCl3) 5.83 (dd, J = 17.6, 10.8 Hz, 1H), 5.15 (s, 1H), 4.84 (d, J = 10.4 Hz, 1H), 4.81 (d, J = 17.6 Hz, 1H), 1.86 (dt, J = 12.3, 2.9 Hz, 1H), 1.78 – 1.71 (m, 1H), 1.71 – 1.65 (m, 3H), 1.64 (s, 3H), 1.63 – 1.60 (m, 1H), 1.44 (br s, 1H), 1.13 (s, 3H), 1.09 – 1.04 (m, 1H), 0.99 (s, 3H), 0.92 (s, 3H)13C NMR (150 MHz, CDCl3) 151.0, 135.0, 128.2, 108.9, 45.4, 39.6, 36.7, 35.3, 31.5, 27.9, 27.0, 25.9, 25.8, 24.8, 23.7 HRMS (ESI+) m / z calculated for C15H24Ag [M+Ag+]: 311.0923; found 311.0918 (2S,4aR,10aR)-2,4a,8,8-Tetramethyl-2-vinyl-1,2,3,4,4a,5,6,7,8,9,10,10a- dodecahydrophenanthrene (@2, rosadiene) Chemical Formula: C20H32Molecular Weight: 272.4760 General procedure C using @4-acetate as the starting material (50.0 mg, 0.150 mmol), 10 mol% of capsule I (100 mg, 0.0150 mmol), 3 mol% of HCl and toluene as the solvent (4.5 mL). Purified by flash chromatography on AgNO3-impregnated silica (pentane) to give 13.4 mg (0.0492 mmol, 33%) of the title product as a clear oil. The spectral data of the product matched literature values for rosadiene49. Rf0.93 (cyclohexane)1H NMR (600 MHz, CDCl3) 5.79 (dd, J = 17.7, 10.9 Hz, 1H), 5.00 (dd, J = 11.0, 1.5 Hz, 1H), 4.97 (dd, J = 17.8, 1.3 Hz, 1H), 2.09 – 1.99 (m, 1H), 1.99 – 1.89 (m, 2H), 1.89 – 1.81 (m, 1H), 1.63 – 1.56 (m, 2H), 1.53 – 1.47 (m, 2H), 1.47 – 1.37 (m, 4H), 1.37 – 1.29 (m, 2H), 1.29 – 1.19 (m, 3H), 0.96 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H)13C NMR (150 MHz, CDCl3) 147.5, 136.3, 133.0, 111.5, 41.2, 39.7, 38.5, 37.1, 37.1, 33.9, 33.0, 32.2, 31.5, 28.9, 27.8, 25.9, 25.3, 25.1, 19.9, 17.3. HRMS (ESI+) m / z calculated for C20H32Ag [M+Ag+]: 379.1549; found 379.1538 (4aS,4bR,10aS)-7-Isopropyl-1,1,4a-trimethyl-1,2,3,4,4a,4b,5,6,10,10a- decahydrophenanthrene (@1, abietadiene) 69 FH12234742.6 Attorney Docket No.: UIX-04925 General procedure C at 50 °C using @3-acetate as the starting material (70.0 mg, 0.211 mmol), 20 mol% of capsule I* (289 mg, 0.043 mmol), 3 mol% of HCl and toluene as the solvent (6.4 mL). Purified by flash chromatography on AgNO3-impregnated silica (pentane) to give 11.0 mg (0.0404 mmol, 19%) of the title product as a clear oil. The spectral data of the product matched literature values for abietadiene.50*For best results with this substrate, the capsule was dried at 50 °C for 4 h before use. Rf0.78 (cyclohexane)1H NMR (600 MHz, benzene-d6) 5.99 (s, 1H), 5.50 (s, 1H), 2.21 (p, J = 6.9 Hz, 1H), 2.10 (dt, J = 18.6, 5.5 Hz, 1H), 2.02 – 1.99 (m, 2H), 1.99 – 1.91 (m, 1H), 1.83 (d, J = 13.5 Hz, 1H), 1.77 (d, J = 12.4 Hz, 1H), 1.71 (dd, J = 12.2, 3.7 Hz, 1H), 1.59 – 1.50 (m, 1H), 1.43 – 1.39 (m, 2H), 1.32 – 1.22 (m, 2H), 1.15 (td, J = 13.7, 3.8 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 0.90 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H)13C NMR (150 MHz, benzene-d6) 144.2, 135.7, 123.8, 121.7, 51.3, 50.6, 42.8, 39.6, 35.4, 35.2, 33.5, 33.1, 27.8, 24.4, 23.1, 22.1, 21.7, 21.1, 19.3, 14.0 HRMS (ESI+) m / z calculated for C20H32Ag [M+Ag+]: 379.1549; found 379.1540 cyclopenta[a]naphthalen-3-yl)propyl acetate (@48) Isolated from the reaction towards abietadiene described above; purified by flash chromatography on AgNO3-impregnated silica (pentane / Et2O = 9:1), obtained as a clear oil (3.5 mg, 0.0105 mmol, 5%). Rf 0.70 (cyclohexane / EtOAc = 95:5)1H NMR (600 MHz, CDCl3) 4.21 (dd, J = 10.8, 4.1 Hz, 1H), 3.83 (dd, J = 10.8, 8.8 Hz, 1H), 2.24 – 2.15 (m, 1H), 2.15 – 2.07 (m, 1H), 2.05 (s, 3H), 2.00 – 1.91 (m, 1H), 1.85 – 1.70 (m, 4H), 1.67 – 1.58 (m, 2H), 1.49 – 1.38 (m, 3H), 1.33 (ddd, J = 13.0, 9.3, 5.0 Hz, 1H), 1.17 (td, 70 FH12234742.6 Attorney Docket No.: UIX-04925 J = 13.4, 4.2 Hz, 1H), 1.12 – 1.06 (m, 2H), 1.01 (s, 3H), 0.95 (s, 3H), 0.89 (s, 3H), 0.85 (s, 3H), 0.81 (d, J = 6.8 Hz, 3H).13C NMR (150 MHz, CDCl3) 171.4, 144.9, 136.8, 67.5, 52.4, 51.1, 42.1, 38.3, 37.5, 35.9, 33.4, 33.1, 31.3, 28.1, 25.2, 23.2, 21.6, 21.1, 19.4, 19.1, 18.9, 13.2. HRMS (ESI+) m / z calculated for C22H36O2Na [M+Na+]: 355.2608; found 355.2614. Example 9: Spectroscopic characterization of cyclized products 3-Isopropyl-7,7,7a-trimethyl-2,6,7,7a-tetrahydro-1H-indene Table 1: NMR Characterization of 3-Isopropyl-7,7,7a-trimethyl-2,6,7,7a-tetrahydro-1H- indene 71 FH12234742.6 Attorney Docket No.: UIX-04925 6-Ethyl-1,1,8a-trimethyl-1,2,3,7,8,8a-hexahydronaphthalene (@17) Table 2: NMR Characterization of 6-Ethyl-1,1,8a-trimethyl-1,2,3,7,8,8a- hexahydronaphthalene 72 FH12234742.6 Attorney Docket No.: UIX-04925 6-Isopropyl-1,1-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene (@21) Table 3: NMR Characterization of 6-Isopropyl-1,1-dimethyl-1,2,3,7,8,8a- hexahydronaphthalene 73 FH12234742.6 Attorney Docket No.: UIX-04925 6-Ethyl-1,1,4a-trimethyl-1,2,3,4,4a,5-hexahydronaphthalene (@23) Table 4: NMR Characterization of 6-Ethyl-1,1,4a-trimethyl-1,2,3,4,4a,5- hexahydronaphthalene 74 FH12234742.6 Attorney Docket No.: UIX-04925 75 FH12234742.6 Attorney Docket No.: UIX-04925 (±)- -2,2,6-Trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25a) Characterization of (±)-(1S,5R,6R)-2,2,6-Trimethyl-9-methylene-6- vinylbicyclo[3.3.1]nonane 76 FH12234742.6 Attorney Docket No.: UIX-04925 -2,2,6-Trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25b) Characterization of (±)-(1S,5R,6S)-2,2,6-Trimethyl-9-methylene-6- vinylbicyclo[3.3.1]nonane 77 FH12234742.6 Attorney Docket No.: UIX-04925 Note on chromatographic behavior of compounds @25a and @25b The behavior of compounds @25a and @25b on flash chromatography with AgNO3- impregnated silica is consistent with the assigned stereochemistry. Compound @25b, with both 78 FH12234742.6 Attorney Docket No.: UIX-04925 olefins positioned on the same side of the molecule, is strongly retained by AgNO3- impregnated silica (elutes with 100% Et2O) presumably due to strong bidentate interaction with Ag+. In contrast, compound @25a with the olefins positioned on opposite sides of the molecule displays far weaker interaction with AgNO3-impregnated silica (elutes with 100% pentane). (±)-(1S,5S,6S)-2,2-Dimethyl-9-methylene-6-(prop-1-en-2-yl)bicyclo[3.3.1]nonane (@27) Table 7: NMR Characterization for (±)-(1S,5S,6S)-2,2-Dimethyl-9-methylene-6-(prop-1- en-2-yl)bicyclo[3.3.1]nonane 79 FH12234742.6 Attorney Docket No.: UIX-04925 Note on determination of stereochemistry of compound @27 The coupling constants observed for proton 6 (J = 12.7, 4.9, 4.9 Hz) correspond to Karplus-derived dihedral angles that are in agreement with those calculated for the lowest energy conformer of diastereomer A (6,7: 55.7º, 6,13: 49.9 º, 6,13’: 165.8º) but not with those calculated for the lowest energy conformers of diastereomer B (6,7: 81.4º, 6,13: 86.5º, 6,13’: 27.2º for the lowest energy conformer). Higher energy conformer B’ exhibits dihedral angles that are in closer agreement with the observed coupling constants (6,7: 117.9º, 6,13: 169.7º, 6,13’: 52.5º) however this conformation is not consistent with observed NOE correlations of proton 13’ with proton 9 and with methyl group 14, which in turn are consistent with proposed structure A. -2,4,4,8-Tetramethyl-8-vinylbicyclo[3.3.1]non-2-ene 80 FH12234742.6 Attorney Docket No.: UIX-04925 Table 8: NMR Characterization for (±)-(1R,5S,8R)-2,4,4,8-Tetramethyl-8- vinylbicyclo[3.3.1]non-2-ene 81 FH12234742.6 Attorney Docket No.: UIX-04925 2,4,4,8-Tetramethyl-8-vinylbicyclo[3.3.1]non-2-ene Table 9: NMR Characterization for (±)-(1R,5S,8S)-2,4,4,8-Tetramethyl-8- vinylbicyclo[3.3.1]non-2-ene 82 FH12234742.6 Attorney Docket No.: UIX-04925 Rosadiene – Comparison with literature spectral data The spectral data obtained for rosadiene were in good agreement (<= 0.2 ppm deviation for the13C data) with literature data for isomer 1. The alternative epimeric structure 2 was ruled out based on i) comparison with literature data for that compound which presents significant deviations for multiple resonances and ii) NOE interactions which support a structure 1 with a β-Me configuration. Table 10: NMR Characterization for Rosadiene 83 FH12234742.6 Attorney Docket No.: UIX-04925 NOESY correlations 84 FH12234742.6 Attorney Docket No.: UIX-04925 Example 10: Control experiments To elucidate the role of the resorcinarene capsule I in the cyclization reactions, control experiments in which the cavity of the capsule was blocked by a strongly binding guest (1.5 equiv. of Bu4NBr per capsule, conditions otherwise identical to what is shown on Figure 2) using substrates @14-@26 were carried out. In all except one case, either no product formation or only traces of product were observed (the one exception being product @27, which was formed in 23% yield after 20d), thus providing strong evidence that the reaction takes place inside the cavity of capsule I. Furthermore, to assess the capability of a regular Brønsted acid to promote the observed cyclizations, control experiments employing 100 mol% HCl in the absence of capsule I (conditions otherwise identical to Figure 2) using the substrates in Figure 2 were carried out. In the case of substrates @18, @24 and @26, formation of respectively products @19, @25 and @27 was observed (in GC-yields of 34%, 45% and 16% respectively); these correspond to THT cyclizations in which the initial cyclization is directly followed by termination of the reaction through elimination, thus presumably the stabilizing environment of the capsule I is not essential for the cyclization reactions in these mechanistically simpler cases. Reactions with substrates @14, @16, @20 and @22, in contrast, did not lead to formation of products @15, @17, @21 and @23; formation of these products requires more extensive rearrangement cascades after the initial cyclization, and evidently in these cases the stabilizing environment of the capsule is required. Overall, these results demonstrate that the resorcinarene capsule I is crucial for the described substrate-controlled approach to the synthesis of cyclic terpenoids, and a regular Brønsted acid would be insufficient. 3-Isopropyl-7,7,7a-trimethyl-2,6,7,7a-tetrahydro-1H-indene (@15) (GC conditions A; product tR= 8.302 min, FIG.5) 85 FH12234742.6 Attorney Docket No.: UIX-04925 6-Ethyl-1,1,8a-trimethyl-1,2,3,7,8,8a-hexahydronaphthalene (@17) (GC conditions A; product tR= 9.725 min, FIG.6) 1,1,6-trimethyl-6-vinyl-1,2,3,4,5,6,7,8-octahydronaphthalene (@19) (GC conditions A; tR= 8.555 min, FIG.7) 6-Isopropyl-1,1-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene (@21) (GC conditions A; tR = 9.609 min, FIG.8) 6-Ethyl-1,1,4a-trimethyl-1,2,3,4,4a,5-hexahydronaphthalene (@23) (GC conditions B; tR= 9.627 min, FIG.9) (1S,5R,6R)-2,2,6-Trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25a) and (1S,5R,6S)-2,2,6-trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25b) 86 FH12234742.6 Attorney Docket No.: UIX-04925 (GC conditions A; tR= 8.327, 8.388 min, FIG.10) (1S,5S,6S)-2,2-Dimethyl-9-methylene-6-(prop-1-en-2-yl)bicyclo[3.3.1]nonane (@27) (GC conditions A; tR= 8.605 min, FIG.11) Example 11: Mechanistic Discussion Isolongifolene As previously described,47the mechanism for the formation of isolongifolene from substrate @12 involves an initial 1,6-cyclization after departure of the leaving group and isomerization of the double bond to the Z configuration. The spirocyclic intermediate thus formed then undergoes a concerted 3,7-ring closure / Wagner-Meerwein alkyl shift. An 1,2- alkyl shift / 1,3-hydride shift / 1,2-alkyl shift sequence (with the latter two steps being a concerted process) lead to cation @35, from which a methyl shift and elimination gives isolongifolene. 3-Isopropyl-7,7,7a-trimethyl-2,6,7,7a-tetrahydro-1H-indene (@15) 87 FH12234742.6 Attorney Docket No.: UIX-04925 In the case of substrate @14 in which the tail group is methylated in the 2 position, an initial 3,7-cyclization through an SN2’ mechanism (see next paragraph for the rationalization behind this mechanistic proposal) leads to fused ring system @42. A methyl shift followed by a proton transfer and a hydride shift lead to intermediate @43, which after elimination provides the observed product @15. 6-Ethyl-1,1,8a-trimethyl-1,2,3,7,8,8a-hexahydronaphthalene (@17) With substrate @16 (R = Ac), a 3’-7 cyclization leads to a fused ring system (top righthand structure, above). A Me-shift gives the bottom righthand intermediate, which after a proton transfer to form an allylic cation, and elimination gives product @17. In the case of this substate, different reactivity was observed between the alcohol and acetate leaving groups. While with R = Ac the THT cyclization pathway described above was observed, when the alcohol version of the substate was employed (R = H) a different product was observed, deriving from initial protonation of the head group’s double bond, followed by cyclization and elimination to give a ketone product. 88 FH12234742.6 Attorney Docket No.: UIX-04925 1,1,6-Trimethyl-6-vinyl-1,2,3,4,5,6,7,8-octahydronaphthalene (@19) With substrate @18, cyclization to the 3 position of the tail group is followed by elimination to give product @19. 6-Isopropyl-1,1-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene (@21) Cyclization to the 3 position gives the top righthand intermediate (above); a proton transfer and a methyl shift give rise to an allylic cation, which after elimination provides product @21. 6-Ethyl-1,1,4a-trimethyl-1,2,3,4,4a,5-hexahydronaphthalene (@23) 89 FH12234742.6 Attorney Docket No.: UIX-04925 A plausible mechanism for the observed cyclization of this substrate (R = Ac) involves, after ionization, a hydride shift to give the top righthand intermediate (above); deprotonation and reprotonation gives rise to the cation shown in the middle of row 2, which after cyclization and elimination gives observed product @23. (±)- -2,2,6-Trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25a) and (±)- - trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25b) Cyclization on the 3 position of the tail group gives a bridged system; elimination provides the product as a mixture of diastereomers. (±)-(1S,5S,6S)-2,2-Dimethyl-9-methylene-6-(prop-1-en-2-yl)bicyclo[3.3.1]nonane (@27) Cyclization of the 3 position of the tail group gives a bridged system, similarly to substrate @12. Elimination gives product @27, in this case as a single diastereomer. Abietadiene (@1) 90 FH12234742.6 Attorney Docket No.: UIX-04925 The mechanism for the formation of abietadiene is shown above. Cyclization on the 3 position of the tail group is followed by a proton transfer / H-shift sequence to give the allylic cation intermediate shown in the middle of the 2ndrow (above), which after elimination provides abietadiene. Polar product @48, observed in the capsule mediated cyclization of substrate @3, presumably arises from protonation of the head group’s double bond and concomitant cyclization to give the intermediate shown in the 1strow (above). A Me-shift and elimination gives product @48. Rosadiene (@2) 91 FH12234742.6 Attorney Docket No.: UIX-04925 With substrate @4, the initial cyclization gives the substrate shown in the middle of the 1strow (above); this intermediate then undergoes a H-shift and a Me-shift to give the intermediate shown in the middle of the 2ndrow (above), which after elimination gives rise to rosadiene. Example 12: GC chromatograms of reactions at full conversion Product peak(s) are highlighted. Formation of 3-isopropyl-7,7,7a-trimethyl-2,6,7,7a-tetrahydro-1H-indene (@15) (GC conditions B; product tR= 9.017 min, FIG.12) Formation of 6-ethyl- trimethyl-1,2,3,7,8,8a-hexahydronaphthalene (@17) (GC conditions A; tR= 9.725 min, FIG.13) Formation of 1,1,6-trimethyl-6-vinyl-1,2,3,4,5,6,7,8-octahydronaphthalene (@19) (GC conditions B; tR = 9.223 min, FIG.14) 92 FH12234742.6 Attorney Docket No.: UIX-04925 Formation of 6-isopropyl-1,1-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene (@21) (GC conditions A; tR = 9.609 min, FIG.15) Formation of 6-ethyl-1,1,4a-trimethyl-1,2,3,4,4a,5-hexahydronaphthalene (@23) (GC conditions B; tR= 9.626 min, FIG.16) @23 Formation of (±)-(1S,5R,6R)-2,2,6-trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25a) and (±)-(1S,5R,6S)-2,2,6-trimethyl-9-methylene-6-vinylbicyclo[3.3.1]nonane (@25b) (GC conditions A; tR= 8.327, 8.388 min, FIG.17) Formation of (±)-(1S,5S,6S)-2,2-dimethyl-9-methylene-6-(prop-1-en-2- yl)bicyclo[3.3.1]nonane (@27) (GC conditions A; tR= 8.605 min, FIG.18) 93 FH12234742.6 Attorney Docket No.: UIX-04925 Reaction of 3-methylene-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-2-yl acetate GC data are shown in FIG.19. Results of using CDCl3as the solvent are shown in FIG. 20. Results of using toluene as the solvent are shown in FIG.21. Formation of rosadiene (@2) (GC conditions B, tR= 13.118 min, FIG.22) Formation of abietadiene (@1) (GC conditions B, tR = 14.513, 15.662 min, FIG.23) 94 FH12234742.6 Attorney Docket No.: UIX-04925 INCORPORATION BY REFERENCE All US patents and US and PCT patent application publications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. 95 FH12234742.6

Claims

Attorney Docket No.: UIX-04925 CLAIMS We claim:

1. A method of making a compound of Formula I, II, or III:comprising combining a compound of Formula IV: A–B (IV); an acid; and a supramolecular capsule; thereby forming the compound of Formula I, II, or III; wherein the supramolecular capsule is a hexamer of calix[4]resorcinarene; is a single bond or a double bond, as valence permits; RAis selected from the group consisting of H, alkyl, and alkenyl; and when the carbon atom to which RAis attached is sp2-hybridized, RAis absent; RBis selected from the group consisting of H, alkyl, and alkenyl; and when the carbon atom to which RBis attached is sp2-hybridized, RBis absent; R1is selected from the group consisting of H, =CH2, and alkyl; provided that if the bond between the carbon atoms to which R1and R2or R1and R3are attached is a double bond, then R1is not =CH2; R2is selected from the group consisting of H, alkyl, and alkenyl; or R1and R2, taken together with the intervening atoms, form a 5-membered cycloalkyl ring, a 6-membered cycloalkyl ring, a 5-membered cycloalkenyl ring, or a 6- membered cycloalkenyl ring, each of which is optionally substituted with one or more instances of R10; R3is selected from the group consisting of H, alkyl, or alkenyl; 96 FH12234742.6Attorney Docket No.: UIX-04925 or R2and R3, taken together with the intervening atoms, form a 6-membered cycloalkyl ring or a 6-membered cycloalkenyl ring, each of which is optionally substituted with one or more instances of R11; only one of (i) R1and R2and (ii) R2and R3forms a ring; each R4, R5, and R6is independently selected from the group consisting of H, alkyl, and alkenyl; R7is absent, H, or alkyl; R8is H or alkyl; R9is H; or R8and R9, taken together with the intervening atoms, form an optionally substituted 6-membered cycloalkyl ring or cycloalkenyl ring, each of which is optionally substituted with one or more instances of R12; R10is H, alkyl or alkenyl; R11is alkyl or alkenyl; R12is alkyl, alkenyl, or is absent; R14is H or acyl; R18is H or alkyl; A is selected from the group consisting ofB is selected from the group consisting of2. The method of claim 1, wherein the bond between the carbon atoms to which R1and R3are attached is a single bond, and R1is =CH2. 97 FH12234742.6Attorney Docket No.: UIX-04925 3. The method of claim 1, wherein R1is methyl.

4. The method of any one of claims 1-3, wherein R2is H.

5. The method of any one of claims 1-3, wherein R2is methyl.

6. The method of claim 1, wherein the product is represented by Formula I; and R1and R2, taken together with the intervening atoms, form a 5-membered or 6-membered cycloalkyl ring, which is optionally substituted with one or more instances of R10.

7. The method of claim 1, wherein the product is represented by Formula I; and R1and R2, taken together with the intervening atoms, form a 5-membered or 6-membered cycloalkenyl ring, which is optionally substituted with one or more instances of R10.

8. The method of any one of claims 1-7, wherein R3is H.

9. The method of any one of claims 1-7, wherein R3is methyl.

10. The method of any one of claims 1-3, wherein the product is represented by Formula I; and R2and R3, taken together with the intervening atoms, form a 6-membered cycloalkyl ring, which is optionally substituted with one or more instances of R11.

11. The method of any one of claims 1-3, wherein the product is represented by Formula I; and R2and R3, taken together with the intervening atoms, form a 6-membered cycloalkenyl ring, which is optionally substituted with one or more instances of R11.

12. The method of any one of claims 1-11, wherein R4is H.

13. The method of any one of claims 1-11, wherein R4is methyl.

14. The method of any one of claims 1-13, wherein R5is H.

15. The method of any one of claims 1-13, wherein R5is methyl. 98 FH12234742.6Attorney Docket No.: UIX-04925 16. The method of any one of claims 1-15, wherein R6is H.

17. The method of any one of claims 1-15, wherein R6is methyl.

18. The method of any one of claims 1-17, wherein R7is absent.

19. The method of any one of claims 1-17, wherein R7is H.

20. The method of any one of claims 1-17, wherein R7is methyl.

21. The method of any one of claims 1-20, wherein R8is H.

22. The method of any one of claims 1-20, wherein R8is methyl.

23. The method of any one of claims 1-22, wherein R9is H.

24. The method of any one of claims 1-20, wherein the product is represented by Formula III; and R8and R9, taken together with the intervening atoms, form a 6-membered cycloalkyl ring, which is optionally substituted with one or more instances of R12.

25. The method of any one of claims 1-20, wherein the product is represented by Formula III; and R8and R9, taken together with the intervening atoms, form a 6-membered cycloalkenyl ring, which is optionally substituted with one or more instances of R12.

26. The method of any one of claims 1-25, wherein R10is selected from the group consisting of methyl, ethyl, propyl, and butyl.

27. The method of any one of claims 1-25, wherein R10is selected from the group consisting of allyl, vinyl, and prop-1-en-2-yl.

28. The method of any one of claims 1-27, wherein R11is selected from the group consisting of methyl, ethyl, propyl, and butyl. 99 FH12234742.6Attorney Docket No.: UIX-04925 29. The method of any one of claims 1-27, wherein R11is selected from the group consisting of allyl, vinyl, and prop-1-en-2-yl.

30. The method of any one of claims 1-29, wherein R12is selected from the group consisting of methyl, ethyl, propyl, and butyl.

31. The method of any one of claims 1-29, wherein R12is selected from the group consisting of allyl, vinyl, and prop-1-en-2-yl.

32. The method of any one of claims 1-31, wherein R14is H.

33. The method of any one of claims 1-31, wherein R14is acetyl.

34. The method of any one of claims 1-33, wherein the compound of Formula IV is represented by Formula IVa, IVb, IVc, or IVd:wherein: R15is selected from the group consisting of H, alkyl, and alkenyl; R16is selected from the group consisting of H, alkyl, and alkenyl; and R17is selected from the group consisting of H, alkyl, and alkenyl.

35. The method of claims 34, wherein the compound of Formula IV is selected from the group consisting of: 100 FH12234742.6Attorney Docket No.: UIX-0492536. The method of any one of claims 1-35, wherein the compound of Formula I is represented by Formula Ia, Formula Ib, Formula Ic, Formula Id, or Formula Ie:101 FH12234742.6Attorney Docket No.: UIX-04925 37. The method of claim 36, wherein the compound of Formula I is selected from the group consisting of:3 The method of claim 1, wherein the compound of Formula II is:.

39. The method of any one of claims 1-38, wherein the compound of Formula III is represented by Formula IIIa:

40. The method of claim 39, wherein the compound of Formula III is:

41. The method of any one of claims 1-40, wherein the acid is a Brønsted acid.

42. The method of any one of claims 1-40, wherein the acid is selected from the group consisting of HCl, HBr, HI, HF, H2SO4, CH3COOH, and CF3COOH. 102 FH12234742.6Attorney Docket No.: UIX-04925 43. The method of claim 42, wherein the acid is HCl.

44. The method of any one of claims 1-40, wherein the acid is a Lewis acid.

45. The method of any one of claims 1-40, wherein the acid is selected from the group consisting of AlCl3, BF3•OEt2, BF3, Ti(OiPr)4, Al(OiPr)3, and LiCl.

46. The method of any one of claims 1-45, wherein the amount of the acid is from about 1 mol% to about 10 mol% relative to the compound of Formula IV.

47. The method of any one of claims 1-46, wherein the amount of the acid is about 3 mol% relative to the compound of Formula IV.

48. The method of any one of claims 1-47, wherein the amount of the supramolecular capsule is from about 1 mol% to about 20 mol% relative to the compound of Formula IV.

49. The method of any one of claims 1-48, wherein the amount of the supramolecular capsule is about 10 mol% or about 20 mol% relative to the compound of Formula IV.

50. The method of any one of claims 1-49, further comprising combining a compound of Formula V: A-ZnCl (V); a compound of Formula VI: B-I (VI); and a palladium catalyst; thereby forming the compound of Formula IV; wherein: A is selected from the group consisting of 103 FH12234742.6Attorney Docket No.: UIX-04925B is selected from the group consisting of51. The method of claim 50, wherein the palladium catalyst is Pd(PPh3)4. 104 FH12234742.6

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