Isocampholenic Acid Derivatives as Potential Fragrances

Abstract

(+)-Isocampholenic acid, prepared in two steps from (1S)-(+)-10-camphorsulfonic acid in 60% yield (on a scale of 172 mmol), served as the starting compound for the synthesis of small libraries of isocampholenic acid derivatives, comprising a total of 60 compounds, which are of interest due to their olfactory properties. Although isocampholenic acid derivatives are thermodynamically up to 5.9 kcal/mol less stable than endocyclic alkene isomers according to DFT calculation, only minor (up to 2%) isomerization to α-campholenic acid isomers was observed in most cases. The products were fully characterized, and their odor properties were preliminarily assessed by untrained laypersons. This study represents the first systematic exploration of the chemical space of isocampholenic acid. Novel derivatives with distinct odor profiles were discovered, and promising directions for future functionalization for fragrance development were identified.

1. Introduction

Biologically, the recognition of volatile molecules plays a crucial role in communication across all species, as the environment is rich in odorous substances released by various sources. Since ancient times, humans have derived pleasure and functional uses from naturally occurring fragrances and spices. Odors consist mainly of hydrophobic volatile organic compounds with molecular weights below 300 Da. These include many chemical classes such as organic acids, alcohols, aldehydes, ethers, esters, amides, amines, hydrocarbons, halogenated hydrocarbons, ketones, nitriles, aromatics, phenols, and other nitrogen- and sulfur-containing compounds including heterocycles [1,2]. Since the 2004 Nobel Prize in Medicine was awarded to Richard Axel and Linda B. Buck “for their discoveries of odorant receptors and the organization of the olfactory system”, we have begun to understand the mechanism of odor perception in terms of the molecular receptors, which will arguably enable the rational design and synthesis of molecules with desired olfactory properties in the future [3,4,5,6,7,8,9].

Aesthetically appealing odorant substances (fragrances) are now found as ingredients in countless detergents and especially in beauty and personal care products such as cosmetics and perfumes, as well as in other formulations. The idea that only natural ingredients are used in such compositions, for example, in perfumes, is a common misconception. Chemists first synthesized naturally occurring fragrance molecules such as coumarin, vanillin and others, and then fragrances that do not occur in nature, such as the “lily of the valley” olfactory note embodied by Lilial and the synthetic musk note of Helvetolide, which enabled the development of many new sensory impressions (Figure 1, top). Nowadays, the development of perfumes and cosmetics is strongly driven by innovations in synthetic fragrances with unprecedented scents and superior physical properties, including human and environmental safety and biodegradability [10,11,12,13,14,15,16]. Furthermore, given the current production and use of fragrances of all kinds, it would be impossible to rely solely on the availability of natural sources [1,2,17,18]. In order to meet the requirements, new synthetic fragrance molecules with the desired scents and physical properties are constantly being developed.

Terpene-based fragrances, both of natural and synthetic origin, play a key role in the Flavor and Fragrance industry. Derivatives based on α- and γ-campholenic acid/aldehyde have been intensively studied and have resulted in compounds with unique odor profiles [19,20,21,22,23], such as the sandalwood character of Javanol and Pashminol (developed by Givaudan). On this basis, we expect that the compounds prepared from isomeric isocampholenic acid (Figure 1, bottom) [24,25,26], which have not yet been systematically explored, represent potentially interesting new fragrance molecules. A structure and reaction search of isocampholenic acid/aldehyde revealed no studies in the direction of a systematic investigation of isocampholenic acid/aldehyde derivatives as odorants. The availability of isocampholenic acid from camphorsulfonic acid [25] in both enantiomeric forms provides a solid platform for systematically exploring the chemical space of isocampholenic acid, the obvious points of diversification being the carboxylic acid and the exocyclic C=C bond (Figure 1, bottom). We report here on the synthesis of several small libraries of novel isocampholenic acid derivatives and the tentative evaluation of their odor properties (odor profile) by laypersons in the field.

2. Results and Discussion

Synthesis. The synthesis of the starting building blocks 3–5 began with commercially available camphorsulfonic acid, which is available in both enantiomeric forms. Starting from (1S)-(+)-10-camphorsulfonic acid (1) on a 172 mmol scale, (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetic acid ((+)-isocampholenic acid) (3) was prepared in two steps in 60% yield (Scheme 1). First, sulfonic acid 1 was converted to 10-iodocamphor (2) [27] by Appel-type transformation with PPh₃/I₂ in refluxing toluene, followed by Grob fragmentation with KOH in DMSO/H₂O to give (+)-isocampholenic acid (3) [25]. Alcohol 4 [28] was obtained in 84% yield by reduction of acid 3 with LiAlH₄ in anhydrous THF, while oxidation of alcohol 4 with freshly prepared 3-carboxypyridinium dichromate (NDC) [29,30] in anhydrous dichloromethane gave aldehyde 5 [31] in 75% yield (Scheme 1).

The scalability and repeatability of the synthesis of the starting building blocks 3–5 enabled the synthesis of the desired compound libraries. First, a library of esters was prepared from (+)-isocampholenic acid (3) (Scheme 2). Esters 6a–j were prepared either from aliphatic halides in the presence of K₂CO₃ (Method 1) or by coupling alcohols with EDCI-activated acid 3 using catalytic amounts of DMAP (Method 2). Moderate to high yields (56–89%) of the corresponding esters 6 were obtained with both methods. In all cases, the products were isolated by column chromatography. Of the synthesized esters, only methyl 6a [32], ethyl 6b [28] and allyl ester 6g [33] have been described in the literature.

In contrast, esters 7a–h were prepared in similar yields (74–96%) from alcohol 4 and the corresponding acid anhydrides or chloride in the presence of pyridine and DMAP (Scheme 3A). The EDCI-activated succinic anhydride-derived acid ester 7h was converted with methanol and ethanol to the corresponding di-esters 7i and 7j in 80% and 78% yield, respectively (Scheme 3A). A series of ethers 8a–h was then targeted and isolated in 65–96% yield, starting from alcohol 4, which was first deprotonated with NaH, followed by the S_N2 reaction with primary aliphatic halides (Scheme 3B).

(+)-Isocampholenic acid (3) was used for the synthesis of the library of ketones (Scheme 4). First, the corresponding Weinreb amide 9 was efficiently synthesized in 85% yield from the CDI-activated carboxylic acid 3. Subsequent treatment of the Weinreb amide 9 with various Grignard reagents led to the formation of the corresponding ketones 10a–k in 69–88% yield. Only ethyl ketone 10b, previously reported as prepared by thermal isomerization of the substituted isoborneol, has been described in the literature [34].

Secondary alcohols 11a–d/11a′–d′ (35–88% yield) and tertiary alcohols 12a–f/12a′–f′ (64–81% yield) were prepared from aldehyde 5 and ketones 10, respectively, by addition of selected Grignard reagents (Scheme 5). The formation of a new stereocenter of compounds 11a–d/11a′–d′ and 12a–f/12a′–f′ proceeded with low diastereoselectivity close to unity (diastereomeric ratio in the range of 60:40 to 51:49). For the secondary alcohols 11a,b,d/11a′,b′,d′, the two diastereomers could be partially separated, i.e., the first eluting diastereomer of compounds 11a,b,d, which was isolated by column chromatography, could be isolated in diastereomerically pure form in 20–27% yield. The secondary alcohol 11c/11c′ and the tertiary alcohols 12a–f/12a′–f′ could not be separated by column chromatography and were characterized as mixtures.

The concluding transformations on the carboxyl side of isocampholenic acid were olefinations using the Horner–Wadsworth–Emmons and Wittig reactions. For this purpose, the aldehyde 5 was reacted with triethyl phosphonoacetate using NaH at 0 °C, methyl(triphenylphosphoranylidene)acetate, triphenylphosphoranyliden-2-propanon and benzyltriphenylphosphonium chloride using NaH at 0 °C. In all cases, the corresponding functionalized alkenes 13–16 were obtained in 56–75% yield. Compounds 13–15 were isolated as a single (E)-diastereomers (vicinal H-C=C-H coupling ³J = 15.6–15.9 Hz), while alkene 16 was isolated as a mixture of the major (E)- and the minor (Z)-isomers in a ratio of 16:16′ = 88:12 (vicinal H-C=C-H coupling ³J(16) = 15.7 Hz, ³J(16′) = 11.7 Hz) (Scheme 6).

The functionalization of the exocyclic C=C bond of selected isocampholenic acid derivatives was subsequently explored. Alkene functionality offers numerous opportunities and challenges for both classical and modern functional group transformations [35,36,37,38], aiming to expand the diversity of compound libraries. The reasons to preferentially address the cyclopropanation of the exocyclic C=C bond are both the lability of the exocyclic C=C bond (vide infra) and the odor profile that could be favorably affected by this transformation as demonstrated in the α-campholenic acid series, i.e., Javanol [23]. The Simmons–Smith reaction with diiodomethane and a zinc-copper couple was used for cyclopropanation [39]. Ether 8a and Weinreb amide 9 were used as model substrates. Despite prolonged reaction times and excess reagents, complete conversion could not be achieved. Thus, even after repeated purification by column chromatography, the desired products 17 and 18 could not be isolated in pure form; they were isolated in 73% and 68% yield, respectively, contaminated with 8% and 5% of the starting alkene (Scheme 7). The cyclopropanated Weinreb amide 18 allowed subsequent synthesis of a series of ketones via the reactions with selected Grignard reagents. In this way, the cyclopropanated ketones 19a–d were prepared in 63–88% yield (Scheme 7). The unsaturated ketone 19c was isolated in pure form, while the products 19a,b,d contained up to 4% of byproducts derived from alkene 9. See Supplementary Materials for details.

The oxymercuration of ether 8a in anhydrous methanol gave ether 20 in 66% yield as a single stereoisomer following column chromatography (Scheme 8). The absolute configuration of the newly formed stereogenic center was not determined. Finally, treatment of the alcohol 4 with trifluoroacetic acid gave the bicyclic product 21 [40] in 38% yield. It was formed by an acid-catalyzed rearrangement followed by cyclization [25]. All attempts to prepare a similar bicyclic product 22 from the tertiary alcohol 12a did not yield the desired product (no alkene formation was observed), presumably due to steric hindrance in the product (Scheme 8).

Structure determination. The isolated products 6–20 were characterized by ¹H- and ¹³C-NMR, IR and HRMS, with the exception of the HRMS data for compounds 7e, 8a–e,g, 10i, 16/16′, 17 and 20, since these compounds did not ionize. The diastereomers of compounds 11c/11c′, 12b–f/12b′–f′ and 16/16′, which could not be separated by column chromatography, were characterized as diastereomeric mixtures. The absolute configuration of the newly formed stereogenic center of compounds 11/11′, 12b–f/12b′–f′ and 20 was not determined.

Exocyclic C=C bond isomerization. According to DFT calculations, isocampholenic acid (3), with the exocyclic C=C group, is thermodynamically up to 5.9 kcal/mol less stable than its endocyclic isomers (see Figure S1 in the Supplementary Materials for details). Consequently, the isocampholenic acid derivatives 3–16 are susceptible to isomerization of the methylene group via different mechanisms. In the presence of a strong Brønsted acid, the following transformations are expected (Scheme 9): (i) isomerization to α-campholenic derivatives via tertiary carbocation I or (ii) the 1,2-methyl shift of I and formation of tertiary carbocation II followed by ring closure in the presence of a suitably tethered nucleophile (formation of product 21) or deprotonation of II to form the tetrasubstituted alkene III, as reported in our earlier report (Scheme 9) [25]. In the present study, strongly Brønsted acidic conditions were avoided during synthesis to prevent acid-catalyzed isomerization. Another plausible mechanism for the isomerization of an exocyclic C=C bond is the pericyclic photochemical [1,3]-hydrogen shift leading to α-campholene derivatives. Similar results would be obtained in (homolytic) redox processes, i.e., formal hydrogen atom transfer reactions, that could be either organo- [41,42] and metal-catalyzed [43,44,45,46,47,48,49] or part of photoredox-catalyzed processes (Scheme 9) [50,51].

α-Campholenic acid and isocampholenic acid derivatives can be easily distinguished by their proton spectra due to the olefinic protons. Data obtained exclusively in deuterated chloroform are compared. In the isocampholenic acid derivatives 3–16, the geminal methylene protons typically appear at 4.66–4.84 ppm either as a multiplet or, if well resolved, as a separate triplet (4.79 ppm, J = 2.5 Hz) and doublet of triplet (4.81 ppm, J = 0.7; 2.2 Hz), as exemplified for aldehyde 5. In the α-campholenic acid isomers, the vinylic C(4)-proton appears as a multiplet at 5.15–5.25 ppm [52,53,54,55,56,57,58]. Type III isomers, without olefinic protons, are characterized by one C(2)-Me group appearing as a broad singlet or multiplet at 1.45–1.56 ppm and the two geminal C(3)-Me groups appearing as a singlet at 0.91–0.98 ppm [25,59,60,61], making it difficult to distinguish them from the other isomers based on the proton spectra alone (Scheme 9). See Figure S2 in the Supplementary Materials for details. A closer look at the proton spectra of the synthesized isocampholenic acid derivatives 3–16 shows that up to 2% of α-campholene isomers are formed, with the exception of esters 6e (8%), 6h (12%) and 14 (4%) and ketone 10a (3%) where up to 12% of the α-campholene isomer was observed. The starting building blocks, compounds 3–5, contain up to 1% of the α-campholene isomer (for detail, see Table S1 in the Supplementary Materials).

Olfactory properties. The odor profiles of the selected products were determined by an untrained panel of five laypersons, with the average description shown in the Supplementary Materials in Table S1. The amounts of α-campholenic acid-derived isomer impurities or, in the case of cyclopropanated products 17–19, the unreacted alkenes, are also included in Table S1, as determined by proton NMR. The samples were evaluated as neat oils. No dilution experiments or threshold determinations were performed, i.e., methods combining instrumental analysis (GC-MS) with human olfactory perception [62,63,64]. The average odor profiles determined are therefore only a rough description. Figure 2 shows the odor profile distribution (odor notes) of the synthesized isocampholenic acid derivatives according to the Michael Edwards fragrance wheel [65].

3. Materials and Methods

Solvents for extractions and chromatography were of technical grade and were distilled prior to use. Extracts were dried over technical grade anhydrous Na₂SO₄. The NMR spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for ¹H and 75.5 MHz for ¹³C nucleus, and on a Bruker UltraShield 500 plus (Bruker, Billerica, MA, USA) at 500 MHz for ¹H and 126 MHz for ¹³C nucleus, using CDCl₃ with TMS as the internal standard, as solvent. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA), and IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA, USA). Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size: 0.035–0.070 mm (Sigma-Aldrich, St. Louis, MO, USA)). All the commercially available chemicals used were purchased from Sigma-Aldrich (St. Louis, MO, USA). 3-Carboxypyridinium dichromate (NDC) was freshly prepared and used following the procedure described in the literature [29,30].

3.1. Synthesis of (1R,4R)-1-(iodomethyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one (2) [27]

Compound 2 was prepared according to the procedure described in the literature [27]. To a solution of (1S)-(+)-10-camphorsulfonic acid (1) (1.0 equiv., 172 mmol, 39.95 g) in anhydrous toluene (250 mL) under argon, PPh₃ (4.0 equiv., 688 mmol, 180.46 g) and I₂ (2.0 equiv., 344 mmol, 87.31 g) were added. The resulting reaction mixture was heated for 16 h under reflux. The volatile components were evaporated in vacuo. The residue was dissolved in EtOAc (500 mL) and washed with Na₂SO₃ (aq. sat., 5 × 100 mL or until the reaction mixture changed color from dark violet to light yellow) and NaCl (aq. sat., 3 × 50 mL). The organic phase was dried under anhydrous Na₂SO₄, filtered, and the volatile components were evaporated in vacuo. The solid residue was suspended in petroleum ether (or hexane) (500 mL) and stirred for 12 h at room temperature. The solid residue was filtered, washed with petroleum ether (or hexane) (2 × 50 mL), and the volatile components (filtrate) were evaporated in vacuo to obtain 10-iodocamphor 2. Yield: 37.77 g (ω = 0.95, 129 mmol, 75%) of yellowish solid. ¹H-NMR (500 MHz, CDCl₃): δ 0.90 (s, 3H), 1.08 (s, 3H), 1.35–1.43 (m, 1H), 1.57–1.64 (m, 1H), 1.91 (d, J = 18.4 Hz, 1H), 1.95–2.05 (m, 2H), 2.16 (t, J = 4.2 Hz, 1H), 2.40 (dd, J = 4.9, 18.4 Hz, 1H), 3.12 (d, J = 10.6 Hz, 1H), 3.31 (d, J = 10.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 0.8, 20.3, 20.5, 26.9, 30.7, 43.1, 44.2, 48.4, 59.2, 215.1.

3.2. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetic Acid (3) [25]

Compound 3 was prepared according to the procedure described in the literature [25]. To a solution of 10-iodocamphor (2) (1.0 equiv., ω = 0.95, 42.9 mmol, 12.56 g) in a mixture of DMSO (120 mL) and H₂O (40 mL) was added KOH (5.0 equiv., 214.5 mmol, 12.04 g). The resulting reaction mixture was stirred at 65 °C for 2 h. NaCl (aq. sat., 100 mL) was added to the cooled reaction mixture (room temperature), followed by extraction with Et₂O (3 × 100 mL). The organic phase was discarded, and the aqueous phase was carefully acidified with HCl (6 M in H₂O, 180 mmol, 30 mL) to pH 1–2, followed by extraction with EtOAc (3 × 100 mL). The combined organic phase was dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo to give acid 3. Product 3 was stored under argon in the absence of light. Yield: 5.85 g (34.75 mmol, 81%) of yellowish oil. ¹H-NMR (500 MHz, CDCl₃): δ 0.85 (s, 3H), 1.08 (s, 3H), 1.32–1.44 (m, 1H), 1.91–2.05 (m, 2H), 2.15 (dd, J = 10.4, 14.9 Hz, 1H), 2.28–2.39 (m, 1H), 2.40–2.52 (m, 2H), 4.78 (s, 1H), 4.80 (s, 1H), 11.34 (br s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 26.7, 28.4, 30.4, 35.2, 43.9, 46.4, 103.8, 161.0, 180.5.

3.3. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) [28]

A solution of (+)-isocampholenic acid (3) (1.0 equiv., 25.1 mmol, 4.22 g) in anhydrous THF (200 mL) was cooled to 0 °C under argon, followed by a careful addition of LiAlH₄ (1 M in THF, 2.0 equiv., 50.2 mmol, 50.2 mL). The resulting reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 20 h. The reaction mixture was cooled to 0 °C, and then cooled H₂O (0 °C, 100 mL) was carefully added dropwise to quench the excess LiAlH₄. After stirring the reaction mixture at room temperature for 15 min, most of the THF was evaporated in vacuo. The residue was extracted with Et₂O (100 mL). The organic phase was washed with NaCl (aq. sat., 3 × 100 mL), dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo to give alcohol 4. Yield: 3.255 g (21.1 mmol, 84%) of a white solid. [α]_D^r.t. = +21.0 (0.30, CH₂Cl₂). EI-HRMS: m/z = 155.1429 (MH⁺); C₁₀H₁₉O: requires m/z = 155.1430 (MH⁺); ν_max 3332, 3071, 2958, 2866, 1651, 1462, 1433, 1378, 1362, 1199, 1151, 1055, 1038, 999, 976, 921, 877, 850 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.83 (s, 3H), 1.06 (s, 3H), 1.24–1.32 (m, 1H), 1.34–1.42 (m, 1H), 1.54–1.62 (m, 1H), 1.67 (br s, 1H), 1.69–1.76 (m, 1H), 1.82–1.88 (m, 1H), 2.25–2.34 (m, 1H), 2.42–2.50 (m, 1H), 3.60–3.68 (m, 1H), 3.70–3.79 (m, 1H), 4.75–4.79 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 26.6, 28.3, 30.8, 33.2, 44.0, 46.8, 62.4, 103.1, 162.4.

3.4. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetaldehyde (5) [31]

To a solution of alcohol 4 (1.0 equiv., 5.5 mmol, 848 mg) in anhydrous CH₂Cl₂ (15 mL) was added freshly prepared 3-carboxypyridinium dichromate (NDC) [29,30] (1.857 g, 4 mmol, 0.727 equiv.). The resulting reaction mixture was stirred at room temperature for 20 h. The reaction mixture was filtered through a short plug of Silica gel 60, and the plug was washed with CH₂Cl₂ (2 × 15 mL). The volatiles were evaporated in vacuo, and the residue was purified by column chromatography (Silica gel 60, petroleum ether/EtOAc = 20:1). The fractions containing the pure product 5 were combined, and the volatile components were evaporated in vacuo. Yield: 630 mg (4.14 mmol, 75%) of a colorless oil. ¹H-NMR (500 MHz, CDCl₃): δ 0.85 (s, 3H), 1.08 (s, 3H), 1.28–1.39 (m, 1H), 1.88–1.97 (m, 1H), 2.01–2.10 (m, 1H), 2.25 (ddd, J = 2.7, 10.3, 16.0 Hz, 1H), 2.31–2.41 (m, 1H), 2.44–2.54 (m, 2H), 4.79 (t, J = 2.5 Hz, 1H), 4.81 (td, J = 0.7, 2.2 Hz, 1H), 9.81 (dd, J = 1.8, 2.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 26.4, 28.7, 30.6, 43.8, 44.2, 44.9, 103.8, 160.7, 202.7.

3.5. Synthesis of Esters 6 from (+)-Isocampholenic Acid—General Procedure 1 (GP1)

To a solution of (+)-isocampholenic acid (3) (1.0 equiv.) in anhydrous MeCN (2 mL) under argon, K₂CO₃ (2.0 equiv.) and the corresponding aliphatic halide were added. The resulting reaction mixture was stirred at room temperature for 20 h. The volatiles were evaporated in vacuo, and the residue was purified by column chromatography (Silica gel 60). The fractions containing the pure product 6 were combined, and the volatiles were evaporated in vacuo. The isolated esters 6 were fully characterized.

3.6. Synthesis of Esters 6 from (+)-Isocampholenic Acid—General Procedure 2 (GP2)

To a solution of (+)-isocampholenic acid (3) (1.0 equiv.) in anhydrous CH₂Cl₂ (7 mL) under argon, the corresponding alcohol and DMAP (0.1 equiv.) were added. The reaction mixture was cooled to −5 °C, and then EDCI (2.0 equiv.) was added. The resulting reaction mixture was stirred at −5 °C for 1 h and then at room temperature for 20 h. The volatiles were evaporated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with NaHSO₄ (aq., 1 M, 2 × 10 mL), NaHCO₃ (aq. sat., 2 × 10 mL) and NaCl (aq. sat., 3 × 10 mL). The organic phase was dried under anhydrous Na₂SO₄, filtered, and the volatile components evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60). The fractions containing the pure product 6 were combined, and the volatiles were evaporated in vacuo. The isolated esters 6 were fully characterized.

3.7. Synthesis of Methyl (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetate (6a) [32]

Following GP1. Prepared from (+)-isocampholenic acid (3) (1.0 mmol, 168 mg), K₂CO₃ (2.0 mmol, 276 mg), MeCN (2 mL) and iodomethane (1.5 mmol, 49 μL); column chromatography: EtOAc/petroleum ether = 1:10. Yield: 154 mg (0.85 mmol, 85%) of colorless oil. [α]_D^r.t. = +21.0 (0.16, CH₂Cl₂). EI-HRMS: m/z = 183.1379 (MH⁺); C₁₁H₁₉O₂: requires m/z = 183.1380 (MH⁺); ν_max 2958, 1737, 1652, 1435, 1364, 1291, 1253, 1195, 1143, 1060, 999, 880 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.84 (s, 3H), 1.07 (s, 3H), 1.29–1.41 (m, 1H), 1.87–1.94 (m, 1H), 1.96–2.04 (m, 1H), 2.12 (dd, J = 10.5, 14.7 Hz, 1H), 2.28–2.50 (m, 3H), 3.68 (s, 3H), 4.77 (t, J = 2.5 Hz, 1H), 4.80 (td, J = 0.8, 2.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 26.7, 28.4, 30.5, 35.1, 43.9, 46.7, 51.6, 103.7, 161.3, 174.2.

3.8. Synthesis of Ethyl (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetate (6b) [28]

Following GP1. Prepared from (+)-isocampholenic acid (3) (1.0 mmol, 168 mg), K₂CO₃ (2.0 mmol, 276 mg), MeCN (2 mL) and bromoethane (1.5 mmol, 114 μL); column chromatography: EtOAc/petroleum ether = 1:10. Yield: 174 mg (0.89 mmol, 89%) of colorless oil. [α]_D^r.t. = +7.0 (0.30, CH₂Cl₂). EI-HRMS: m/z = 197.1535 (MH⁺); C₁₂H₂₁O₂: requires m/z = 197.1536 (MH⁺); ν_max 2961, 1733, 1652, 1464, 1365, 1290, 1252, 1182, 1140, 1031, 879 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.84 (s, 3H), 1.07 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.30–1.41 (m, 1H), 1.87–1.94 (m, 1H), 1.96–2.04 (m, 1H), 2.11 (dd, J = 10.5, 14.6 Hz, 1H), 2.28–2.50 (m, 3H), 4.14 (q, J = 7.1 Hz, 2H), 4.77 (t, J = 2.5 Hz, 1H), 4.79 (td, J = 0.7, 2.1 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 14.4, 23.5, 26.7, 28.4, 30.5, 35.4, 43.9, 46.7, 60.4, 103.6, 161.4, 173.7.

3.9. Synthesis of Propyl (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetate (6c)

Following GP1. Prepared from (+)-isocampholenic acid (3) (1.0 mmol, 168 mg), K₂CO₃ (2.0 mmol, 276 mg), MeCN (2 mL) and 1-bromopropane (1.2 mmol, 111 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 184 mg (0.87 mmol, 87%) of colorless oil. [α]_D^r.t. = +8.0 (0.26, CH₂Cl₂). EI-HRMS: m/z = 211.1694 (MH⁺); C₁₃H₂₃O₂: requires m/z = 211.1693 (MH⁺); ν_max 2962, 1734, 1654, 1446, 1365, 1293, 1255, 1186, 1035, 879 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.84 (s, 3H), 0.95 (t, J = 7.4, 3H), 1.07 (s, 3H), 1.31–1.41 (m, 1H), 1.66 (h, J = 7.2 Hz, 2H), 1.86–1.94 (m, 1H), 1.96–2.04 (m, 1H), 2.12 (dd, J = 10.5, 14.6 Hz, 1H), 2.29–2.50 (m, 3H), 4.04 (t, J = 6.7 Hz, 2H), 4.78 (t, J = 2.5 Hz, 1H), 4.79–4.81 (m, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 10.6, 22.1, 23.6, 26.7, 28.4, 30.5, 35.4, 44.0, 46.7, 66.1, 103.7, 161.5, 174.0.

3.10. Synthesis of Butyl (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetate (6d)

Following GP1. Prepared from (+)-isocampholenic acid (3) (1.0 mmol, 168 mg), K₂CO₃ (2.0 mmol, 276 mg), MeCN (2 mL) and 1-iodobutane (1.2 mmol, 138 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 192 mg (0.85 mmol, 85%) of colorless oil. [α]_D^r.t. = +8.0 (0.29, CH₂Cl₂). EI-HRMS: m/z = 225.1847 (MH⁺); C₁₄H₂₅O₂: requires m/z = 225.1849 (MH⁺); ν_max 2959, 1734, 1652, 1464, 1364, 1289, 1249, 1179, 1141, 1063, 1020, 879 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.84 (s, 3H), 0.94 (t, J = 7.3 Hz, 3H), 1.07 (s, 3H), 1.33–1.44 (m, 3H), 1.58–1.66 (m, 2H), 1.86–1.94 (m, 1H), 1.96–2.04 (m, 1H), 2.11 (dd, J = 10.5, 14.6 Hz, 1H), 2.28–2.50 (m, 3H), 4.08 (t, J = 6.7 Hz, 2H), 4.77 (t, J = 2.3 Hz, 1H), 4.80 (t, J = 1.8 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 13.8, 19.3, 23.6, 26.7, 28.4, 30.5, 30.8, 35.4, 44.0, 46.7, 64.4, 103.7, 161.5, 173.9.

3.11. Synthesis of Isopropyl (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetate (6e)

Following GP2. Prepared from (+)-isocampholenic acid (3) (1.0 mmol, 168 mg), propan-2-ol (2.0 mmol, 121 μL), DMAP (0.1 mmol, 12.2 mg), CH₂Cl₂ (7 mL) in EDCI (2.0 mmol, ω = 98%, 391 mg); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 178 mg (0.84 mmol, 84%) of colorless oil. [α]_D^r.t. = +11.0 (0.33, CH₂Cl₂). EI-HRMS: m/z = 211.1693 (MH⁺); C₁₃H₂₃O₂: requires m/z = 211.1693 (MH⁺); ν_max 2961, 1729, 1652, 1467, 1374, 1290, 1181, 1143, 1108, 959, 879 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.83 (s, 3H), 1.07 (s, 3H), 1.24 (dd, J = 1.4, 6.3 Hz, 6H), 1.30–1.41 (m, 1H), 1.86–1.93 (m, 1H), 1.96–2.03 (m, 1H), 2.08 (dd, J = 10.5, 14.3 Hz, 1H), 2.29–2.39 (m, 2H), 2.41–2.49 (m, 1H), 4.77 (t, J = 2.5 Hz, 1H), 4.78–4.80 (m, 1H), 4.98–5.06 (m, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 22.0, 22.0, 23.6, 26.7, 28.3, 30.5, 35.8, 44.0, 46.8, 67.6, 103.6, 161.5, 173.3.

3.12. Synthesis of Isobutyl (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetate (6f)

Following GP2. Prepared from (+)-isocampholenic acid (3) (1.0 mmol, 168 mg), butan-2-ol (2.0 mmol, 187 μL), DMAP (0.1 mmol, 12.2 mg), CH₂Cl₂ (7 mL) in EDCI (2.0 mmol, ω = 98%, 391 mg); column chromatography: EtOAc/petroleum ether = 1:25. Yield: 169 mg (0.75 mmol, 75%) of colorless oil. [α]_D^r.t. = +15.0 (0.34, CH₂Cl₂). EI-HRMS: m/z = 225.1849 (MH⁺); C₁₄H₂₅O₂: requires m/z = 225.1849 (MH⁺); ν_max 2960, 1734, 1652, 1468, 1379, 1289, 1250, 1177, 1139, 1001, 879, 671 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.84 (s, 3H), 0.94 (d, J = 6.8 Hz, 6H), 1.08 (s, 3H), 1.30–1.43 (m, 1H), 1.87–2.06 (m, 3H), 2.12 (dd, J = 10.5, 14.6 Hz, 1H), 2.28–2.51 (m, 3H), 3.86 (d, J = 6.7 Hz, 2H), 4.78 (t, J = 2.5 Hz, 1H), 4.80 (td, J = 0.7, 2.3 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 19.2, 23.5, 26.7, 27.8, 28.5, 30.5, 35.4, 44.0, 46.7, 70.6, 103.7, 161.4, 173.8.

3.13. Synthesis of Allyl (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetate (6g) [33]

Following GP1. Prepared from (+)-isocampholenic acid (3) (1.0 mmol, 168 mg), K₂CO₃ (2.0 mmol, 276 mg), MeCN (2 mL) and 3-bromopropene (1.2 mmol, 107 μL); column chromatography: EtOAc/petroleum ether = 1:10. Yield: 149 mg (0.71 mmol, 71%) of colorless oil. [α]_D^r.t. = +10.0 (0.25, CH₂Cl₂). EI-HRMS: m/z = 209.1536 (MH⁺); C₁₃H₂₁O₂: requires m/z = 209.1536 (MH⁺); ν_max 2960, 1735, 1651, 1462, 1364, 1289, 1176, 1139, 1057, 987, 929, 879 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.84 (s, 3H), 1.07 (s, 3H), 1.31–1.41 (m, 1H), 1.87–1.96 (m, 1H), 1.97–2.07 (m, 1H), 2.15 (dd, J = 10.6, 14.7 Hz, 1H), 2.29–2.39 (m, 1H), 2.40–2.51 (m, 2H), 4.58 (t, J = 1.4 Hz, 1H), 4.59 (t, J = 1.4 Hz, 1H), 4.78 (t, J = 2.5 Hz, 1H), 4.80 (td, J = 0.7, 2.2 Hz, 1H), 5.24 (dq, J = 1.3, 10.4 Hz, 1H), 5.33 (dq, J = 1.5, 17.2 Hz, 1H), 5.93 (ddt, J = 5.8, 10.4, 17.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.6, 26.7, 28.4, 30.5, 35.3, 44.0, 46.7, 65.2, 103.7, 118.4, 132.4, 161.3, 173.4.

3.14. Synthesis of Benzyl (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetate (6h)

Following GP2. Prepared from (+)-isocampholenic acid (3) (1.0 mmol, 168 mg), benzyl alcohol (1.8 mmol, 189 μL), DMAP (0.1 mmol, 12.2 mg), CH₂Cl₂ (7 mL) in EDCI (2.0 mmol, ω = 98%, 391 mg); column chromatography: EtOAc/petroleum ether = 1:30. Yield: 216 mg (0.83 mmol, 83%) of colorless oil. [α]_D^r.t. = +9.0 (0.27, CH₂Cl₂). EI-HRMS: m/z = 259.1698 (MH⁺); C₁₇H₂₃O₂: requires m/z = 259.1693 (MH⁺); ν_max 2959, 1733, 1652, 1456, 1363, 1289, 1255, 1137, 971, 880, 735, 696 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.80 (s, 3H), 1.02 (s, 3H), 1.29–1.41 (m, 1H), 1.85–1.94 (m, 1H), 1.98–2.08 (m, 1H), 2.17 (dd, J = 10.6, 14.8 Hz, 1H), 2.30–2.37 (m, 1H), 2.39–2.50 (m, 2H), 4.77 (t, J = 2.3 Hz, 1H), 4.79 (t, J = 1.8 Hz, 1H), 5.12 (s, 2H), 7.30–7.40 (m, 5H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.6, 26.7, 28.4, 30.5, 35.4, 44.0, 46.7, 66.3, 103.7, 128.3, 128.4, 128.7, 136.1, 161.3, 173.6.

3.15. Synthesis of Dodecyl (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetate (6i)

Following GP1. Prepared from (+)-isocampholenic acid (3) (1.0 mmol, 168 mg), K₂CO₃ (2.0 mmol, 276 mg), MeCN (2 mL) and 1-bromododecane (1.5 mmol, ω = 0.97, 371 μL); column chromatography: EtOAc/petroleum ether = 1:30. Yield: 188 mg (0.56 mmol, 56%) of colorless oil. [α]_D^r.t. = +6.2 (0.121, CH₂Cl₂). EI-HRMS: m/z = 337.3099 (MH⁺); C₂₂H₄₁O₂: requires m/z = 337.3101 (MH⁺); ν_max 2923, 2854, 1736, 1652, 1465, 1363, 1289, 1178, 1141, 880, 722 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.84 (s, 3H), 0.88 (t, J = 6.9 Hz, 3H), 1.07 (s, 3H), 1.20–1.41 (m, 19H), 1.58–1.67 (m, 2H), 1.85–1.94 (m, 1H), 1.95–2.06 (m, 1H), 2.11 (dd, J = 10.5 Hz, 14.6, 1H), 2.28–2.51 (m, 3H), 4.07 (t, J = 6.8 Hz, 2H), 4.77 (t, J = 2.6, 1H), 4.79–4.81 (m, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 14.3, 22.8, 23.6, 26.1, 26.7, 28.5, 28.8, 29.4, 29.5, 29.7, 29.7, 29.8, 29.8, 30.5, 32.1, 35.5, 44.0, 46.8, 64.7, 103.7, 161.5, 173.9.

3.16. Synthesis of (R)-3,7-dimethyloct-6-en-1-yl 2-((R)-2,2-dimethyl-3-methylenecyclopentyl)acetate (6j)

Following GP2. Prepared from (+)-isocampholenic acid (3) (1.0 mmol, 168 mg), (R)-(+)-β-citronellol (1.1 mmol, ω = 0.95, 211 μL), DMAP (0.1 mmol, 12.2 mg), CH₂Cl₂ (7 mL) in EDCI (2.0 mmol, ω = 98%, 391 mg); column chromatography: EtOAc/petroleum ether = 1:30. Yield: 242 mg (0.79 mmol, 79%) of colorless oil. [α]_D^r.t. = +6.8 (0.272, CH₂Cl₂). EI-HRMS: m/z = 307.2635 (MH⁺); C₂₀H₃₅O₂: requires m/z = 307.2632 (MH⁺); ν_max 2959, 1735, 1652, 1460, 1378, 1290, 1178, 1140, 1058, 982, 880 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.84 (s, 3H), 0.92 (d, J = 6.6 Hz, 3H), 1.07 (s, 3H), 1.14–1.23 (m, 1H), 1.31–1.40 (m, 2H), 1.41–1.48 (m, 1H), 1.51–1.59 (m, 1H), 1.60 (s, 3H), 1.63–1.72 (m, 1H), 1.68 (s, 3H), 1.86–2.05 (m, 4H), 2.10 (dd, J = 10.5, 14.6 Hz, 1H), 2.28–2.36 (m, 1H), 2.39 (dd, J = 4.2, 14.6 Hz, 1H), 2.42–2.50 (m, 1H), 4.05–4.18 (m, 2H), 4.77 (t, J = 2.5 Hz, 1H), 4.79 (t, J = 2.2 Hz, 1H), 5.05–5.13 (m, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 17.8, 19.5, 23.6, 25.5, 25.9, 26.7, 28.4, 29.6, 30.5, 35.5, 35.6, 37.1, 44.0, 46.7, 63.0, 103.7, 124.7, 131.5, 161.4, 173.9.

3.17. Synthesis of Esters 7 from Alcohol 4—General Procedure 3 (GP3)

To a solution of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 equiv.) in anhydrous CH₂Cl₂ (2 mL) under argon, pyridine (3.0 equiv.), DMAP (0.04 equiv.) and the corresponding acid anhydride/acid chloride were added. The resulting reaction mixture was stirred at room temperature for 20 h. The volatiles were evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60). The fractions containing the pure product 7 were combined, and the volatiles were evaporated in vacuo. The isolated esters 7 were fully characterized.

3.18. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethyl Acetate (7a)

Following GP3. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), CH₂Cl₂ (2 mL), pyridine (3.0 mmol, 243 μL), DMAP (0.04 mmol, 4.9 mg) and acetic anhydride (1.5 mmol, 142 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 169 mg (0.86 mmol, 86%) of colorless oil. [α]_D^r.t. = +10.0 (0.34, CH₂Cl₂). EI-HRMS: m/z = 197.1497 (MH⁺); C₁₂H₂₁O₂: requires m/z = 197.1493 (MH⁺); ν_max 2959, 2868, 1739, 1652, 1463, 1434, 1364, 1228, 1153, 1038, 968, 878, 636, 606 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.24–1.37 (m, 1H), 1.37–1.48 (m, 1H), 1.51–1.59 (m, 1H), 1.75–1.82 (m, 1H), 1.82–1.90 (m, 1H), 2.05 (s, 3H), 2.24–2.36 (m, 1H), 2.42–2.52 (m, 1H), 4.05–4.11 (m, 1H), 4.12–4.18 (m, 1H), 4.74–4.80 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 21.2, 23.5, 26.6, 28.2, 29.0, 30.8, 44.1, 47.1, 64.2, 103.3, 162.1, 171.3.

3.19. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethyl Propionate (7b)

Following GP3. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), CH₂Cl₂ (2 mL), pyridine (3.0 mmol, 243 μL), DMAP (0.04 mmol, 4.9 mg) and propionic anhydride (1.5 mmol, 194 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 203 mg (0.96 mmol, 96%) of colorless oil. [α]_D^r.t. = +14.0 (0.35, CH₂Cl₂). EI-HRMS: m/z = 211.1689 (MH⁺); C₁₃H₂₃O₂: requires m/z = 211.1693 (MH⁺); ν_max 2959, 1736, 1652, 1463, 1384, 1362, 1348, 1274, 1179, 1082, 1022, 958, 878, 807 cm⁻¹. ¹H-NMR (300 MHz, CDCl₃): δ 0.83 (s, 3H), 1.06 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H), 1.19–1.58 (m, 3H), 1.70–1.95 (m, 2H), 2.20–2.37 (m, 3H), 2.39–2.54 (m, 1H), 4.01–4.23 (m, 2H), 4.73–4.82 (m, 2H). ¹³C-NMR (75 MHz, CDCl₃): δ 9.3, 23.4, 26.6, 27.8, 28.3, 29.1, 30.8, 44.1, 47.2, 64.1, 103.3, 162.1, 174.6.

3.20. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethyl Butyrate (7c)

Following GP3. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), CH₂Cl₂ (2 mL), pyridine (3.0 mmol, 243 μL), DMAP (0.04 mmol, 4.9 mg) and butyric anhydride (1.3 mmol, 215 μL); column chromatography: EtOAc/petroleum ether = 1:40. Yield: 198 mg (0.88 mmol, 88%) of colorless oil. [α]_D^r.t. = +12.0 (0.34, CH₂Cl₂). EI-HRMS: m/z = 225.1854 (MH⁺); C₁₄H₂₅O₂: requires m/z = 225.1849 (MH⁺); ν_max 2960, 2871, 1735, 1652, 1461, 1362, 1252, 1174, 1091, 1048, 992, 975, 933, 878 cm⁻¹. ¹H-NMR (300 MHz, CDCl₃): δ 0.82 (s, 3H), 0.95 (t, J = 7.4 Hz, 3H), 1.06 (s, 3H), 1.20–1.95 (m, 7H), 2.21–2.37 (m, 3H), 2.40–2.54 (m, 1H), 4.01–4.23 (m, 2H), 4.73–4.82 (m, 2H). ¹³C-NMR (75 MHz, CDCl₃): δ 13.8, 18.6, 23.5, 26.6, 28.2, 29.2, 30.8, 36.4, 44.1, 47.2, 63.9, 103.3, 162.2, 173.9.

3.21. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethyl Isobutyrate (7d)

Following GP3. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), CH₂Cl₂ (2 mL), pyridine (3.0 mmol, 243 μL), DMAP (0.04 mmol, 4.9 mg) and isobutyric anhydride (1.5 mmol, 249 μL); column chromatography: EtOAc/petroleum ether = 1:30. Yield: 181 mg (0.80 mmol, 80%) of colorless oil. [α]_D^r.t. = +15.0 (0.30, CH₂Cl₂). EI-HRMS: m/z = 225.1854 (MH⁺); C₁₄H₂₅O₂: requires m/z = 225.1849 (MH⁺); ν_max 2960, 1733, 1652, 1469, 1388, 1363, 1344,1258, 1190, 1153, 1075, 990, 971, 879, 754 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.17 (d, J = 7.0, 6H), 1.26–1.36 (m, 1H), 1.39–1.47 (m, 1H), 1.51–1.60 (m, 1H), 1.74–1.82 (m, 1H), 1.83–1.92 (m, 1H), 2.24–2.36 (m, 1H), 2.42–2.50 (m, 1H), 2.54 (p, J = 7.0 Hz, 1H), 4.04–4.11 (m, 1H), 4.12–4.20 (m, 1H), 4.74–4.81 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 19.2, 23.5, 26.6, 28.3, 29.1, 30.8, 34.2, 44.1, 47.2, 64.0, 103.3, 162.2, 177.4.

3.22. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethyl 3,3-dimethylbutanoate (7e)

Following GP3. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), CH₂Cl₂ (2 mL), pyridine (3.0 mmol, 243 μL), DMAP (0.04 mmol, 4.9 mg) and 3,3-dimethylbutyryl chloride (1.1 mmol, ω = 0.98, 153 μL); column chromatography: EtOAc/petroleum ether = 1:40. Yield: 187 mg (0.74 mmol, 74%) of colorless oil. [α]_D^r.t. = +10.3 (0.25, CH₂Cl₂). ν_max 3071, 2957, 2869, 1733, 1652, 1466, 1434, 1365, 1322, 1226, 1197, 1129, 1049, 1020, 996, 978, 931, 879, 795, 729, 704, 620 cm⁻¹. ¹H-NMR (300 MHz, CDCl₃): δ 0.83 (s, 3H), 1.03 (s, 9H), 1.06 (s, 3H), 1.22–1.48 (m, 2H), 1.50–1.64 (m, 1H), 1.70–1.95 (m, 2H), 2.19 (s, 2H), 2.22–2.37 (m, 1H), 2.39–2.55 (m, 1H), 3.99–4.23 (m, 2H), 4.72–4.82 (m, 2H). ¹³C-NMR (75 MHz, CDCl₃): δ 23.5, 26.6, 28.2, 29.2, 29.6, 29.8, 30.8, 44.1, 47.2, 48.2, 63.6, 103.3, 162.2, 172.6.

3.23. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethyl pent-4-enoate (7f)

Following GP3. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), CH₂Cl₂ (2 mL), pyridine (3.0 mmol, 243 μL), DMAP (0.04 mmol, 4.9 mg) and 4-pentenoic anhydride (1.5 mmol, ω = 0.98, 280 μL); column chromatography: EtOAc/petroleum ether = 1:40. Yield: 194 mg (0.82 mmol, 82%) of colorless oil. [α]_D^r.t. = +13.9 (0.28, CH₂Cl₂). EI-HRMS: m/z = 237.1849 (MH⁺); C₁₅H₂₅O₂: requires m/z = 237.1849 (MH⁺); ν_max 3073, 2959, 2868, 1735, 1651, 1463, 1435, 1362, 1235, 1167, 1102, 1050, 993, 914, 879 cm⁻¹. ¹H-NMR (300 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.20–1.65 (m, 3H), 1.70–1.94 (m, 2H), 2.20–2.54 (m, 6H), 4.02–4.24 (m, 2H), 4.72–4.82 (m, 2H), 4.95–5.13 (m, 2H), 5.73–5.92 (m, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ 23.5, 26.6, 28.2, 29.0, 29.1, 30.8, 33.8, 44.1, 47.2, 64.1, 103.3, 115.6, 136.9, 162.1, 173.2.

3.24. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethyl Benzoate (7g)

Following GP3. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), CH₂Cl₂ (2 mL), pyridine (3.0 mmol, 243 μL), DMAP (0.04 mmol, 4.9 mg) and benzoic anhydride (1.3 mmol, 297 mg); column chromatography: EtOAc/petroleum ether = 1:30. Yield: 226 mg (0.87 mmol, 87%) of colorless oil. [α]_D^r.t. = +8.0 (0.37, CH₂Cl₂). EI-HRMS: m/z = 259.1691 (MH⁺); C₁₇H₂₃O₂: requires m/z = 259.1693 (MH⁺); ν_max 2958, 1717, 1651, 1602, 1452, 1385, 1362, 1314, 1268, 1175, 1110, 1069, 1026, 958, 878, 708, 687, 675 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.86 (s, 3H), 1.10 (s, 3H), 1.31–1.44 (m, 1H), 1.52–1.61 (m, 1H), 1.62–1.70 (m, 1H), 1.88–2.00 (m, 2H), 2.26–2.38 (m, 1H), 2.44–2.54 (m, 1H), 4.30–4.44 (m, 2H), 4.76–4.82 (m, 2H), 7.40–7.48 (m, 2H), 7.52–7.59 (m, 1H), 8.01–8.08 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 26.6, 28.3, 29.2, 30.8, 44.2, 47.4, 64.8, 103.3, 128.5, 129.7, 130.6, 133.0, 162.1, 166.8.

3.25. Synthesis of (R)-4-(2-(2,2-dimethyl-3-methylenecyclopentyl)ethoxy)-4-oxobutanoic Acid (7h)

Following GP3. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), CH₂Cl₂ (2 mL), pyridine (3.0 mmol, 243 μL), DMAP (0.04 mmol, 4.9 mg) and benzoic anhydride (1.0 mmol, 100 mg). The residue (after evaporation of the volatiles) was dissolved in EtOAc (50 mL) and washed with NaHSO₄ (aq., 1 M, 2 × 5 mL) and NaCl (aq. sat., 5 mL). The organic phase was dried under anhydrous Na₂SO₄, filtered, and the volatile components evaporated in vacuo. The residue was purified by column chromatography (EtOAc). Yield: 191 mg (0.75 mmol, 75%) of colorless oil. [α]_D^r.t. = +4.8 (0.255, CH₂Cl₂). EI-HRMS: m/z = 255.1589 (MH⁺); C₁₄H₂₃O₄: requires m/z = 255.1591 (MH⁺); ν_max 2958, 1734, 1710, 1651, 1397, 1362, 1163, 1047, 993, 930, 878, 840 cm⁻¹. ¹H-NMR (300 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.20–1.64 (m, 3H), 1.71–1.93 (m, 2H), 2.21–2.37 (m, 1H), 2.39–2.55 (m, 1H), 2.56–2.74 (m, 4H), 4.04–4.26 (m, 2H), 4.72–4.82 (m, 2H), 10.33 (br s, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ 23.4, 26.6, 28.2, 29.0, 29.0, 29.1, 30.8, 44.1, 47.1, 64.6, 103.3, 162.0, 172.3, 178.3.

3.26. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethyl Methyl Succinate (7i)

Following GP2. Prepared from (R)-4-(2-(2,2-dimethyl-3-methylenecyclopentyl)ethoxy)-4-oxobutanoic acid (7h) (1.0 mmol, 254 mg), methanol (3.0 mmol, 122 μL), DMAP (0.1 mmol, 12.2 mg), and CH₂Cl₂ (7 mL) in EDCI (2.0 mmol, ω = 98%, 391 mg); column chromatography: EtOAc/petroleum ether = 1:10. Yield: 215 mg (0.80 mmol, 80%) of colorless oil. [α]_D^r.t. = +10.6 (0.23, CH₂Cl₂). EI-HRMS: m/z = 269.1751 (MH⁺); C₁₅H₂₅O₄: requires m/z = 269.1747 (MH⁺); ν_max 2957, 1733, 1651, 1436, 1362, 1317, 1155, 996, 879, 846 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.24–1.36 (m, 1H), 1.37–1.48 (m, 1H), 1.49–1.59 (m, 1H), 1.73–1.90 (m, 2H), 2.24–2.36 (m, 1H), 2.41–2.52 (m, 1H), 2.64 (s, 4H), 3.70 (s, 3H), 4.06–4.22 (m, 2H), 4.74–4.80 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 26.6, 28.2, 29.0, 29.1, 29.3, 30.8, 44.1, 47.1, 52.0, 64.5, 103.3, 162.1, 172.5, 172.9.

3.27. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethyl Succinate (7j)

Following GP2. Prepared from (R)-4-(2-(2,2-dimethyl-3-methylenecyclopentyl)ethoxy)-4-oxobutanoic acid (7h) (1.0 mmol, 254 mg), ethanol (3.0 mmol, 175 μL), DMAP (0.1 mmol, 12.2 mg), and CH₂Cl₂ (7 mL) in EDCI (2.0 mmol, ω = 98%, 391 mg); column chromatography: EtOAc/petroleum ether = 1:10. Yield: 220 mg (0.78 mmol, 78%) of colorless oil. [α]_D^r.t. = +11.6 (0.23, CH₂Cl₂). EI-HRMS: m/z = 283.1904 (MH⁺); C₁₆H₂₇O₄: requires m/z = 283.1904 (MH⁺); ν_max 2959, 1732, 1651, 1464, 1363, 1349, 1314, 1154, 1125, 967. 879 cm⁻¹. ¹H-NMR (300 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.22–1.32 (m, 1H), 1.36–1.61 (m, 2H), 1.70–1.94 (m, 2H), 2.21–2.37 (m, 1H), 2.38–2.57 (m, 1H), 2.62 (s, 4H), 4.03–4.26 (m, 4H), 4.73–4.82 (m, 2H). ¹³C-NMR (75 MHz, CDCl₃): δ 14.3, 23.5, 26.6, 28.2, 29.1, 29.4, 29.4, 30.8, 44.1, 47.2, 60.8, 64.5, 103.3, 162.1, 172.4, 172.5.

3.28. Synthesis of Ethers 8 from Alcohol 4—General Procedure 4 (GP4)

To a solution of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 equiv.) in anhydrous THF (3 mL) under argon at 0 °C was added NaH (1.2 equiv.). The resulting reaction mixture was stirred at 0 °C for 30 min, then the electrophile (aliphatic halide) was added. After stirring at room temperature for 20 h, H₂O (10 mL) was carefully added. The resulting mixture was extracted with Et₂O (30 mL). The organic phase was washed with NaCl (aq. sat., 3 × 10 mL), dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60). The fractions containing the pure product 8 were combined, and the volatiles were evaporated in vacuo. The isolated ethers 8 were fully characterized with the exception of HRMS, as the products were not ionized.

3.29. Synthesis of (R)-2-(2-methoxyethyl)-1,1-dimethyl-5-methylenecyclopentane (8a)

Following GP4. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), THF (3 mL), NaH (1.2 mmol; ω = 60%, 48.0 mg) and iodomethane (2.0 mmol, 129 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 156 mg (0.93 mmol, 93%) of colorless oil. [α]_D^r.t. = +13.0 (0.20, CH₂Cl₂). ν_max 2958, 2866, 1651, 1462, 1386, 1362, 1199, 1152, 1120, 1003, 957, 877, 836, 704 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.24–1.32 (m, 1H), 1.33–1.40 (m, 1H), 1.51–1.61 (m, 1H), 1.71–1.78 (m, 1H), 1.80–1.88 (m, 1H), 2.23–2.35 (m, 1H), 2.40–2.50 (m, 1H), 3.34 (s, 3H), 3.37–3.48 (m, 2H), 4.73–4.80 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 26.6, 28.3, 30.0, 30.9, 44.1, 47.1, 58.7, 72.4, 103.1, 162.6.

3.30. Synthesis of (R)-2-(2-ethoxyethyl)-1,1-dimethyl-5-methylenecyclopentane (8b)

Following GP4. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), THF (3 mL), NaH (1.2 mmol; ω = 60%, 48.0 mg) and bromoethane (2.0 mmol, 153 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 125 mg (0.68 mmol, 68%) of colorless oil. [α]_D^r.t. = +17.0 (0.22, CH₂Cl₂). ν_max 2959, 2863, 1651, 1463, 1377, 1362, 1111, 877, 704 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H), 1.25–1.35 (m, 1H), 1.36–1.43 (m, 1H), 1.50–1.58 (m, 1H), 1.73–1.79 (m, 1H), 1.79–1.87 (m, 1H), 2.23–2.37 (m, 1H), 2.40–2.50 (m, 1H), 3.37–3.54 (m, 4H), 4.73–4.79 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 15.4, 23.5, 26.6, 28.4, 30.2, 30.9, 44.1, 47.3, 66.2, 70.4, 103.0, 162.6.

3.31. Synthesis of (R)-1,1-dimethyl-2-methylene-5-(2-propoxyethyl)cyclopentane (8c)

Following GP4. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), THF (3 mL), NaH (1.2 mmol; ω = 60%, 48.0 mg) and 1-bromopropane (1.2 mmol, 109 μL); column chromatography: EtOAc/petroleum ether = 1:25. Yield: 154 mg (0.78 mmol, 78%) of colorless oil. [α]_D^r.t. = +13.0 (0.22, CH₂Cl₂). ν_max 3071, 2959, 2935, 2860, 1651, 1462, 1435, 1362, 1249, 1115, 981, 956, 877, 703 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 0.92 (t, J = 7.5 Hz, 3H), 1.06 (s, 3H), 1.21–1.42 (m, 2H), 1.51–1.64 (m, 3H), 1.72–1.79 (m, 1H), 1.80–1.89 (m, 1H), 2.23–2.34 (m, 1H), 2.40–2.50 (m, 1H), 3.33–3.45 (m, 3H), 3.46–3.53 (m, 1H), 4.73–4.81 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 10.8, 23.1, 23.5, 26.6, 28.4, 30.1, 30.9, 44.1, 47.3, 70.5, 72.8, 103.0, 162.6.

3.32. Synthesis of (R)-2-(2-butoxyethyl)-1,1-dimethyl-5-methylenecyclopentane (8d)

Following GP4. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), THF (3 mL), NaH (1.2 mmol; ω = 60%, 48.0 mg) and 1-iodobutane (1.0 mmol, 114 μL); column chromatography: EtOAc/petroleum ether = 1:30. Yield: 177 mg (0.84 mmol, 84%) of colorless oil. [α]_D^r.t. = +14.0 (0.20, CH₂Cl₂). ν_max 3071, 2957, 2928, 2857, 2796, 1652, 1463, 1434, 1375, 1362, 1302, 1234, 1114, 998, 962, 940, 878, 738, 704 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 0.92 (t, J = 7.4 Hz, 3H), 1.06 (s, 3H), 1.19–1.48 (m, 4H), 1.48–1.62 (m, 3H), 1.70–1.88 (m, 2H), 2.23–2.37 (m, 1H), 2.40–2.50 (m, 1H), 3.36–3.52 (m, 4H), 4.73–4.79 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 14.1, 19.6, 23.6, 26.6, 28.4, 30.1, 30.9, 32.0, 44.1, 47.3, 70.6, 70.9, 103.0, 162.6.

3.33. Synthesis of (R)-2-(2-(allyloxy)ethyl)-1,1-dimethyl-5-methylenecyclopentane (8e)

Following GP4. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), THF (3 mL), NaH (1.2 mmol; ω = 60%, 48.0 mg) and allyl bromide (1.1 mmol, ω = 0.97, 98 μL); column chromatography: EtOAc/petroleum ether = 1:15. Yield: 161 mg (0.83 mmol, 83%) of colorless oil. [α]_D^r.t. = +23.0 (0.17, CH₂Cl₂). ν_max 3071, 2958, 2934, 2865, 1651, 1463, 1433, 1362, 1145, 1106, 993, 920, 878, 704, 634 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.23–1.32 (m, 1H), 1.35–1.45 (m, 1H), 1.52–1.62 (m, 1H), 1.72–1.89 (m, 2H), 2.23–2.33 (m, 1H), 2.40–2.50 (m, 1H), 3.41–3.47 (m, 1H), 3.51 (td, J = 5.2, 8.8 Hz, 1H), 3.92–4.03 (m, 2H), 4.73–4.79 (m, 2H), 5.17 (dq, J = 1.4, 10.3 Hz, 1H), 5.28 (dq, J = 1.7, 17.2 Hz, 1H), 5.93 (ddt, J = 5.6, 10.4, 17.2, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 26.6, 28.4, 30.1, 30.9, 44.1, 47.2, 70.0, 72.0, 103.0, 116.9, 135.1, 162.6.

3.34. Synthesis of (R)-1,1-dimethyl-2-(2-((3-methylbut-2-en-1-yl)oxy)ethyl)-5-methylenecyclopentane (8f)

Following GP4. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), THF (3 mL), NaH (1.2 mmol; ω = 60%, 48.0 mg) and prenyl bromide (1.0 mmol, ω = 0.95, 121 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 171 mg (0.77 mmol, 77%) of colorless oil. [α]_D^r.t. = +2.5 (0.24, CH₂Cl₂). EI-HRMS: m/z = 223.2056 (MH⁺); C₁₅H₂₇O: requires m/z = 223.2056 (MH⁺); ν_max 2929, 2862, 1445, 1377, 1360, 1081, 1014, 799 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.81 (s, 3H), 1.06 (s, 3H), 1.24–1.34 (m, 1H), 1.34–1.43 (m, 1H), 1.49–1.61 (m, 1H), 1.68 (s, 3H), 1.75 (s, 3H), 1.76–1.87 (m, 2H), 2.23–2.34 (m, 1H), 2.40–2.50 (m, 1H), 3.42 (ddd, J = 6.9, 8.1, 9.1 Hz, 1H), 3.49 (td, J = 5.1, 8.9 Hz, 1H), 3.90–4.01 (m, 2H), 4.73–4.79 (m, 2H), 5.32–5.40 (m, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ 18.1, 23.5, 25.9, 26.7, 28.4, 30.2, 30.9, 44.1, 47.3, 67.4, 69.9, 103.0, 121.5, 136.7, 162.6.

3.35. Synthesis of (R)-1,1-dimethyl-2-methylene-5-(2-(prop-2-yn-1-yloxy)ethyl)cyclopentane (8g)

Following GP4. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), THF (3 mL), NaH (1.2 mmol; ω = 60%, 48.0 mg) and propargyl bromide (1.1 mmol, ω = 0.80, 118 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 125 mg (0.65 mmol, 65%) of colorless oil. [α]_D^r.t. = +17.9 (0.19, CH₂Cl₂). ν_max 3306, 2958, 2866, 1651, 1463, 1361, 1093, 1012, 878, 626 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.26–1.34 (m, 1H), 1.37–1.45 (m, 1H), 1.52–1.63 (m, 1H), 1.74–1.81 (m, 1H), 1.82–1.89 (m, 1H), 2.23–2.36 (m, 1H), 2.43 (t, J = 2.4 Hz, 1H), 2.43–2.51 (m, 1H), 3.53 (dt, J = 7.4, 8.9 Hz, 1H), 3.60 (ddd, J = 5.1, 8.1, 9.0 Hz, 1H), 4.10–4.21 (m, 2H), 4.73–4.81 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 26.6, 28.3, 29.9, 30.8, 44.1, 47.1, 58.2, 69.8, 74.3, 80.1, 103.1, 162.5.

3.36. Synthesis of (R)-((2-(2,2-dimethyl-3-methylenecyclopentyl)ethoxy)methyl)benzene (8h)

Following GP4. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (1.0 mmol, 154 mg), THF (3 mL), NaH (1.2 mmol; ω = 60%, 48.0 mg) and benzyl bromide (1.1 mmol, ω = 0.98, 134 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 209 mg (0.85 mmol, 85%) of colorless oil. [α]_D^r.t. = +14.0 (0.23, CH₂Cl₂). EI-HRMS: m/z = 245.1898 (MH⁺); C₁₇H₂₅O: requires m/z = 245.1900 (MH⁺); ν_max 3067, 2958, 2864, 1651, 1496, 1454, 1361, 1202, 1100, 1028, 1000, 877, 733, 696, 611 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 1.06 (s, 3H), 1.20–1.34 (m, 1H), 1.36–1.47 (m, 1H), 1.59–1.60 (m, 1H), 1.75–1.86 (m, 2H), 2.27–2.28 (m, 1H), 2.39–2.50 (m, 1H), 3.45–3.51 (m, 1H), 3.52–3.60 (m, 1H), 4.49 (d, J = 11.8 Hz, 1H), 4.53 (d, J = 11.9 Hz, 1H), 4.73–4.79 (m, 2H), 7.25–7.31 (m, 1H), 7.32–7.39 (m, 4H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.6, 26.6, 28.4, 30.1, 30.9, 44.1, 47.2, 70.1, 73.1, 103.0, 127.6, 127.8, 128.5, 138.7, 162.6.

3.37. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9)

To a solution of (+)-isocampholenic acid (3) (10 mmol, 1.68 g) in anhydrous CH₂Cl₂ (50 mL) under argon at room temperature was added CDI (12 mmol, ω = 0.95, 2.05 g). The resulting reaction mixture was stirred at room temperature for 2 h, then N,O-dimethylhydroxylamine hydrochloride (30 mmol, 2.93 g) and Et₃N (30 mmol, 4.18 mL) were added. After stirring the reaction mixture at room temperature for another 20 h, the volatile components were evaporated in vacuo. The residue was dissolved in EtOAc (150 mL) and washed with NaHSO₄ (aq., 1 M, 2 × 50 mL) and NaCl (aq. sat., 2 × 50 mL). The organic phase was dried under anhydrous Na₂SO₄, filtered, and the volatile components evaporated in vacuo. Yield: 1.80 g (8.5 mmol, 85%) of white solid. [α]_D^r.t. = +21.0 (0.30, CH₂Cl₂). EI-HRMS: m/z = 212.1606 (MH⁺); C₁₂H₂₂NO₂: requires m/z = 212.1612 (MH⁺); ν_max 2959, 1662, 1462, 1436, 1413, 1384, 1362, 1178, 1114, 1002, 935, 878, 785, 969 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.87 (s, 3H), 1.08 (s, 3H), 1.29–1.40 (m, 1H), 1.90–1.98 (m, 1H), 2.02–2.10 (m, 1H), 2.21–2.38 (m, 2H), 2.41–2.52 (m, 2H), 3.19 (s, 3H), 3.69 (s, 3H), 4.78 (t, J = 2.5 Hz, 1H), 4.79 (t, J = 2.0 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.7, 26.7, 28.6, 30.6, 32.3, 32.6, 44.0, 46.2, 61.3, 103.5, 161.8, 174.6.

3.38. Synthesis of Ketones 11 from Weinreb Amide 10—General Procedure 5 (GP5)

To a solution of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (1.0 equiv.) in anhydrous Et₂O (7 mL) under argon at 0 °C, the corresponding Grignard reagent (1.5 equiv.) was added slowly. The resulting reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 20 h. The excess Grignard reagent was quenched with NaCl (aq. sat., 3 mL), and the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic phase was washed with NaCl (aq. sat., 3 × 10 mL), dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60). The fractions containing the pure product 10 were combined, and the volatiles evaporated in vacuo. The isolated ketones 10 were fully characterized.

3.39. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)propan-2-one (10a)

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and methylmagnesium bromide (2.0 M in Et₂O, 3.0 mmol, 1.5 mL); column chromatography: EtOAc/petroleum ether = 1:10. Yield: 278 mg (1.67 mmol, 83%) of colorless oil. [α]_D^r.t. = +15.0 (0.22, CH₂Cl₂). EI-HRMS: m/z = 167.1430 (MH⁺); C₁₁H₁₉O: requires m/z = 167.1430 (MH⁺); ν_max 3071, 2960, 1712, 1651, 1463, 1434, 1362, 1285, 1241, 1170, 1148, 962, 878, 704 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.83 (s, 3H), 1.06 (s, 3H), 1.21–1.30 (m, 1H), 1.86–1.94 (m, 1H), 1.97–2.04 (m, 1H), 2.17 (s, 3H), 2.25 (dd, J = 10.5, 15.9 Hz, 1H), 2.29–2.38 (m, 1H), 2.40–2.48 (m, 1H), 2.50 (dd, J = 3.6, 15.9 Hz, 1H), 4.77 (t, J = 2.5 Hz, 1H), 4.79 (td, J = 0.8, 2.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.7, 26.6, 28.4, 30.5, 30.6, 43.9, 44.6, 45.6, 103.6, 161.3, 209.2.

3.40. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)butan-2-one (10b) [34]

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and ethylmagnesium bromide (3.0 M in Et₂O, 3.0 mmol, 1.0 mL); column chromatography: EtOAc/petroleum ether = 1:10. Yield: 314 mg (1.74 mmol, 87%) of colorless oil. [α]_D^r.t. = +14.0 (0.23, CH₂Cl₂). EI-HRMS: m/z = 181.1588 (MH⁺); C₁₂H₂₁O: requires m/z = 181.1587 (MH⁺); ν_max 3071, 2960, 1712, 1651, 1460, 1413, 1376, 1363, 1283, 1151, 1114, 1021, 986, 878, 806, 705, 635 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.83 (s, 3H), 1.02–1.10 (m, 6H), 1.19–1.30 (m, 1H), 1.83–1.91 (m, 1H), 1.97–2.05 (m, 1H), 2.24 (dd, J = 10.6, 15.7 Hz, 1H), 2.29–2.38 (m, 1H), 2.40–2.54 (m, 4H), 4.77 (t, J = 2.5 Hz, 1H), 4.79 (t, J = 2.3 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 8.0, 23.7, 26.6, 28.5, 30.6, 36.5, 43.2, 43.9, 45.7, 103.6, 161.4, 211.8.

3.41. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)pentan-2-one (10c)

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and propylmagnesium bromide (2.0 M in Et₂O, 3.0 mmol, 1.5 mL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 315 mg (1.62 mmol, 81%) of colorless oil. [α]_D^r.t. = +9.0 (0.26, CH₂Cl₂). EI-HRMS: m/z = 195.1743 (MH⁺); C₁₃H₂₃O: requires m/z = 195.1743 (MH⁺); ν_max 3071, 2960, 2873, 1711, 1651, 1462, 1409, 1363, 1285, 1198, 1125, 1026, 878, 740, 63 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 0.92 (t, J = 7.4 Hz, 3H), 1.06 (s, 3H), 1.19–1.30 (m, 1H), 1.61 (h, J = 7.3 Hz, 2H), 1.84–1.92 (m, 1H), 1.96–2.05 (m, 1H), 2.23 (dd, J = 10.6, 15.7 Hz, 1H), 2.28–2.49 (m, 5H), 4.77 (t, J = 2.5 Hz, 1H), 4.79 (t, J = 2.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 13.9, 17.4, 23.8, 26.6, 28.5, 30.6, 43.6, 43.9, 45.4, 45.6, 103.6, 161.4, 211.4.

3.42. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)hexan-2-one (10d)

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and butylmagnesium chloride (2.0 M in Et₂O, 3.0 mmol, 1.5 mL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 369 mg (1.77 mmol, 88%) of colorless oil. [α]_D^r.t. = +9.0 (0.21, CH₂Cl₂). EI-HRMS: m/z = 209.1897 (MH⁺); C₁₄H₂₅O: requires m/z = 209.1900 (MH⁺); ν_max 2958, 2871, 1712, 1651, 1463, 1435, 1409, 1377, 1363, 1285, 1198, 1126, 1035, 878, 732, 634 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (s, 3H), 0.91 (t, J = 7.4 Hz, 3H), 1.05 (s, 3H), 1.18–1.36 (m, 3H), 1.52–1.60 (m, 2H), 1.84–1.91 (m, 1H), 1.97–2.05 (m, 1H), 2.23 (dd, J = 10.6, 15.7 Hz, 1H), 2.28–2.49 (m, 5H), 4.77 (t, J = 2.6 Hz, 1H), 4.79 (t, J = 2.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 14.0, 22.5, 23.8, 26.1, 26.6, 28.5, 30.6, 43.2, 43.6, 43.9, 45.6, 103.6, 161.4, 211.5.

3.43. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)-3-methylbutan-2-one (10e)

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and isopropylmagnesium bromide (2.0 M in Et₂O, 3.0 mmol, 1.5 mL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 327 mg (1.68 mmol, 84%) of colorless oil. [α]_D^r.t. = +8.0 (0.24, CH₂Cl₂). EI-HRMS: m/z = 195.1740 (MH⁺); C₁₃H₂₃O: requires m/z = 195.1743 (MH⁺); ν_max 2961, 2871, 1710, 1652, 1464, 1382, 1363, 1286, 1198, 1152, 1089, 1028, 878, 793, 703 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.84 (s, 3H), 1.06 (s, 3H), 1.10 (d, J = 7.0 Hz, 6H), 1.17–1.27 (m, 1H), 1.83–1.91 (m, 1H), 1.99–2.07 (m, 1H), 2.26–2.38 (m, 2H), 2.39–2.45 (m, 1H), 2.48 (dd, J = 3.5, 16.1 Hz, 1H), 2.63 (hept, J = 6.9 Hz, 1H), 4.77 (d, J = 2.5 Hz, 1H), 4.79 (td, J = 0.8, 2.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 18.3, 18.4, 23.8, 26.6, 28.6, 30.6, 41.2, 41.3, 43.9, 45.4, 103.5, 161.5, 214.9.

3.44. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)pent-4-en-2-one (10f)

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and allylmagnesium bromide (1.0 M in THF, 3.0 mmol, 3.0 mL); column chromatography: EtOAc/petroleum ether = 1:30. Yield: 319 mg (1.66 mmol, 83%) of colorless oil. [α]_D^r.t. = +10.0 (0.25, CH₂Cl₂). EI-HRMS: m/z = 193.1563 (MH⁺); C₁₃H₂₁O: requires m/z = 193.1587 (MH⁺); ν_max 3073, 2960, 1714, 1651, 1463, 1434, 1363, 1332, 1290, 1198, 1113, 1039, 992, 918, 878, 706, 663 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.83 (s, 3H), 1.05 (s, 3H), 1.18–1.30 (m, 1H), 1.83–1.94 (m, 1H), 1.97–2.06 (m, 1H), 2.27 (dd, J = 10.5, 16.0 Hz, 1H), 2.31–2.39 (m, 1H), 2.40–2.48 (m, 1H), 2.51 (dd, J = 3.5, 16.0 Hz, 1H), 3.14–3.25 (m, 2H), 4.77 (t, J = 2.5 Hz, 1H), 4.79 (td, J = 0.8, 2.2 Hz, 1H), 5.11–5.23 (m, 2H), 5.93 (ddt, J = 7.0, 10.2, 17.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.7, 26.6, 28.5, 30.6, 43.2, 43.9, 45.4, 48.3, 103.6, 118.9, 130.8, 161.3, 208.8.

3.45. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)-3-phenylpropan-2-one (10g)

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and benzylmagnesium bromide (1.0 M in THF, 3.0 mmol, 3.0 mL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 378 mg (1.56 mmol, 78%) of colorless oil. [α]_D^r.t. = +4.0 (0.26, CH₂Cl₂). EI-HRMS: m/z = 243.1745 (MH⁺); C₁₇H₂₃O: requires m/z = 243.1743 (MH⁺); ν_max 3066, 3029, 2959, 1712, 1651, 1602, 1495, 1454, 1434, 1363, 1286, 1200, 1108, 1031, 879, 748, 697 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.77 (s, 3H), 1.01 (s, 3H), 1.09–1.22 (m, 1H), 1.79–1.89 (m, 1H), 1.95–2.06 (m, 1H), 2.24–2.34 (m, 2H), 2.36–2.44 (m, 1H), 2.51 (dd, J = 3.6, 16.0 Hz, 1H), 3.71 (s, 2H), 4.75 (t, J = 2.5 Hz, 1H), 4.77 (t, J = 2.2 Hz, 1H), 7.17–7.23 (m, 2H), 7.25–7.28 (m, 1H), 7.30–7.36 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.7, 26.6, 28.4, 30.6, 42.8, 43.9, 45.5, 50.6, 103.6, 127.1, 128.8, 129.6, 134.3, 161.3, 208.4.

3.46. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)but-3-en-2-one (10h)

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and vinylmagnesium bromide (1.0 M in THF, 3.0 mmol, 3.0 mL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 267 mg (1.50 mmol, 75%) of colorless oil. [α]_D^r.t. = +5.0 (0.24, CH₂Cl₂). EI-HRMS: m/z = 179.1424 (MH⁺); C₁₂H₁₉O: requires m/z = 179.1430 (MH⁺); ν_max 3071, 2959, 1681, 1651, 1614, 1463, 1434, 1399, 1363, 1332, 1292, 1194, 1149, 1112, 1068, 985, 961, 915, 878, 809, 634 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.86 (s, 3H), 1.08 (s, 3H), 1.22–1.34 (m, 1H), 1.83–1.93 (m, 1H), 1.99–2.09 (m, 1H), 2.28–2.50 (m, 3H), 2.65 (dd, J = 3.6, 15.5 Hz, 1H), 4.78 (t, J = 2.5 Hz, 1H), 4.80 (td, J = 0.8, 2.2 Hz, 1H), 5.83 (dd, J = 1.1, 10.6 Hz, 1H), 6.23 (dd, J = 1.1, 17.6 Hz, 1H), 6.38 (dd, J = 10.6, 17.6 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ 23.8, 26.7, 28.5, 30.6, 40.7, 44.1, 46.0, 103.7, 128.1, 136.9, 161.4, 201.0.

3.47. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)but-3-yn-2-one (10i)

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and ethynylmagnesium bromide (0.5 M in THF, 3.0 mmol, 6.0 mL); column chromatography: EtOAc/petroleum ether = 1:40. Yield: 282 mg (1.60 mmol, 80%) of colorless oil. [α]_D^r.t. = +12.0 (0.297, CH₂Cl₂). ν_max 3258, 2960, 2092, 1678, 1652, 1463, 1435, 1364, 1285, 1237, 1198, 1112, 1070, 880, 807, 694, 649 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.85 (s, 3H), 1.09 (s, 3H), 1.20–1.38 (m, 1H), 1.88–1.98 (m, 1H), 2.08–2.18 (m, 1H), 2.30–2.51 (m, 3H), 2.67 (dd, J = 3.9, 15.6 Hz, 1H), 3.23 (s, 1H), 4.79 (t, J = 2.5 Hz, 1H), 4.80–4.82 (m, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.7, 26.7, 28.2, 30.5, 44.0, 45.7, 46.6, 78.6, 81.8, 103.9, 160.8, 187.5.

3.48. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)pent-3-yn-2-one (10j)

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and 1-propynylmagnesium bromide (0.5 M in THF, 3.0 mmol, 6.0 mL); column chromatography: EtOAc/petroleum ether = 1:30. Yield: 263 mg (1.38 mmol, 69%) of colorless oil. [α]_D^r.t. = +6.0 (0.243, CH₂Cl₂). EI-HRMS: m/z = 191.1430 (MH⁺); C₁₃H₁₉O: requires m/z = 191.1430 (MH⁺); ν_max 2960, 2218, 1669, 1463, 1435, 1364, 1330, 1286, 1258, 1175, 1143, 1021, 972, 879, 783, 680 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.84 (s, 3H), 1.08 (s, 3H), 1.18–1.41 (m, 1H), 1.85–1.98 (m, 1H), 2.01–2.03 (m, 3H), 2.05–2.18 (m, 1H), 2.24–2.53 (m, 3H), 2.61 (dd, J = 3.7, 15.2 Hz, 1H), 4.74–4.84 (m, 2H). ¹³C-NMR (75 MHz, CDCl₃): δ 4.2, 23.7, 26.7, 28.3, 30.6, 44.0, 45.9, 46.6, 80.6, 90.0, 103.7, 161.2, 188.2.

3.49. Synthesis of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-1-phenylethan-1-one (10k)

Following GP5. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (2.0 mmol, 422 mg), Et₂O (7 mL), and phenylmagnesium bromide (3.0 M in THF, 3.0 mmol, 1.0 mL); column chromatography: EtOAc/petroleum ether = 1:30. Yield: 374 mg (1.64 mmol, 82%) of colorless oil. [α]_D^r.t. = +6.0 (0.25, CH₂Cl₂). EI-HRMS: m/z = 229.1594 (MH⁺); C₁₆H₂₁O: requires m/z = 229.1587 (MH⁺); ν_max 3068, 2959, 1682, 1651, 1597, 1580, 1462, 1448, 1363, 1333, 1286, 1205, 1180, 1147, 1075, 1001, 878, 750, 688, 646, 616 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.93 (s, 3H), 1.13 (s, 3H), 1.28–1.39 (m, 1H), 1.87–1.97 (m, 1H), 2.21–2.21 (m, 1H), 2.28–2.40 (m, 1H), 2.41–2.51 (m, 1H), 2.78 (dd, J = 10.5, 15.7 Hz, 1H), 3.06 (dd, J = 3.5, 15.7 Hz, 1H), 4.77–4.83 (m, 2H), 7.46–7.46 (m, 2H), 7.53–7.60 (m, 1H), 7.93–8.00 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.9, 26.8, 28.6, 30.6, 39.4, 44.2, 46.2, 103.6, 128.3, 128.7, 133.1, 137.4, 161.5, 200.6.

3.50. Synthesis of Secondary Alcohols 11 from Aldehyde 5—General Procedure 6 (GP6)

To a solution of aldehyde 5 (1.0 equiv.) in anhydrous Et₂O (3 mL) under argon at 0 °C, the corresponding Grignard reagent (1.4 equiv.) was added slowly. The resulting reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 20 h. The excess Grignard reagent was quenched with NaCl (aq. sat., 3 mL), and the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic phase was washed with NaCl (aq. sat., 2 × 5 mL), dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified/separated by column chromatography (Silica gel 60). The fractions containing the pure product 11 were combined, and the volatile components were evaporated in vacuo. The isolated secondary alcohols 11 were fully characterized. The two diastereomers formed could, in most cases, be partially separated by column chromatography.

3.51. Synthesis of 1-((R)-2,2-dimethyl-3-methylenecyclopentyl)propan-2-ol (11a/11a′)

Following GP6. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetaldehyde (5) (91.3 mg, 0.6 mmol), Et₂O (3 mL), and methylmagnesium bromide (3.0 M in Et₂O, 0.84 mmol, 0.28 mL); column chromatography: EtOAc/petroleum ether = 1:5. The two diastereomers formed could be partially separated by column chromatography. Diastereomeric ratio: 11a/11a′ = 54:46. Diastereomer 11a (major): Elutes first from the column. Yield: 20 mg (0.119 mmol, 20%) of colorless oil. [α]_D^r.t. = +37.1 (0.11, CH₂Cl₂). EI-HRMS: m/z = 169.1586 (MH⁺); C₁₁H₂₁O: requires m/z = 169.1587 (MH⁺); ν_max 3351, 2960, 2929, 1711, 1461, 1375, 1363, 1068, 877 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.74 (s, 3H), 0.99 (s, 3H), 1.16 (d, J = 6.2 Hz, 3H), 1.13–1.24 (m, 2H), 1.32 (br s, 1H), 1.38–1.47 (m, 1H), 1.60–1.70 (m, 1H), 1.79–1.89 (m, 1H), 2.18–2.30 (m, 1H), 2.34–2.44 (m, 1H), 3.75–3.84 (m, 1H), 4.67–4.73 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 24.9, 26.5, 28.2, 30.8, 39.7, 44.0, 46.4, 66.7, 103.0, 162.5. Diastereomer 11a′ (minor): Elutes secondly from the column. Yield: 15 mg (0.089 mmol, 15%; contains 24% of 11a) of colorless oil. ¹H-NMR (500 MHz, CDCl₃): δ 0.74 (s, 3H), 1.16 (d, J = 6.1 Hz, 3H) (the remaining signals overlap with the signals of diastereomer 11a).

3.52. Synthesis of 1-((R)-2,2-dimethyl-3-methylenecyclopentyl)pent-4-en-2-ol (11b/11b′)

Following GP6. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetaldehyde (5) (91.3 mg, 0.6 mmol), Et₂O (3 mL), and allylmagnesium bromide (1.0 M in THF, 0.84 mmol, 0.84 mL); column chromatography: EtOAc/petroleum ether = 1:10. The two diastereomers formed could be partially separated by column chromatography. Diastereomeric ratio: 11b/11b′ = 48:53. Diastereomer 11b (minor): Elutes first from the column. Yield: 32 mg (0.1647 mmol, 27%) of colorless oil. [α]_D^r.t. = +21.0 (0.215, CH₂Cl₂). EI-HRMS: m/z = 195.1745 (MH⁺); C₁₃H₂₃O: requires m/z = 195.1743 (MH⁺); ν_max 3366, 3073, 2958, 1710, 1462, 1434, 1362, 1067, 1016, 913, 877 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.74 (s, 3H), 1.00 (s, 3H), 1.13–1.26 (m, 2H), 1.39–1.53 (m, 2H), 1.67–1.77 (m, 1H), 1.80–1.89 (m, 1H), 2.07–2.17 (m, 1H), 2.19–2.31 (m, 2H), 2.34–2.44 (m, 1H), 3.60–3.68 (m, 1H), 4.67–4.73 (m, 2H), 5.04–5.12 (m, 2H), 5.72–5.84 (m, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 26.5, 28.1, 30.8, 37.2, 43.3, 44.0, 46.2, 69.2, 103.1, 118.4, 135.0, 162.6. Diastereomer 11b′ (major): Elutes secondly from the column. Yield: 30 mg (0.154 mmol, 25%; contains 19% of 11b) of colorless oil. ¹H-NMR (500 MHz, CDCl₃): δ 0.74 (s, 3H), 0.99 (s, 3H), 1.24–1.37 (m, 2H), 1.41–1.54 (m, 2H), 1.60 (s, 1H), 1.79–1.87 (m, 1H), 1.99–2.07 (m, 1H), 2.19–2.27 (m, 1H), 2.27–2.35 (m, 1H), 2.36–2.44 (m, 1H), 3.60–3.70 (m, 1H), 4.66–4.73 (m, 2H), 5.03–5.12 (m, 2H), 5.71–5.83 (m, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.4, 26.5, 29.0, 30.9, 37.2, 41.7, 44.3, 47.5, 70.4, 103.1, 118.6, 134.8, 162.2.

3.53. Synthesis of 1-((R)-2,2-dimethyl-3-methylenecyclopentyl)-3-methylbutan-2-ol (11c/11c′)

Following GP6. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetaldehyde (5) (91.3 mg, 0.6 mmol), Et₂O (3 mL), and isopropylmagnesium bromide (2.0 M in Et₂O, 1.4 mmol, 0.7 mL); column chromatography: EtOAc/petroleum ether = 1:10. The two diastereomers formed could not be separated by column chromatography. Diastereomeric ratio: 11c/11c′ = 53:47. Yield: 104 mg (0.1647 mmol, 88%) of colorless oil. [α]_D^r.t. = +25.1 (0.28, CH₂Cl₂). EI-HRMS: m/z = 197.1904 (MH⁺); C₁₃H₂₅O: requires m/z = 197.1900 (MH⁺); ν_max 3376, 2958, 2870, 1651, 1464, 1362, 1065, 994, 976, 877 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃) for both diastereomers: δ 0.82 (d, J = 3.8 Hz, 3H), 0.87–1.00 (m, 6H), 1.07 (d, J = 3.8 Hz, 3H), 1.18–1.31 (m, 2H), 1.34–1.47 (m, 1H), 1.51–1.58 (m, 1H), 1.60–1.81 (m, 2H), 1.86–1.96 (m, 1H), 2.23–2.37 (m, 1H), 2.47–2.47 (m, 1H), 3.37–3.55 (m, 1H), 4.74–4.80 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃) for both diastereomers: δ 15.8, 17.6, 18.9, 19.4, 23.5, 23.6, 26.5, 26.7, 28.0, 29.4, 30.7, 31.0, 32.8, 34.3, 34.6, 34.9, 44.0, 44.4, 46.3, 48.0, 75.1, 76.5, 103.0, 103.1, 162.5, 162.7.

3.54. Synthesis of 1-((R)-2,2-dimethyl-3-methylenecyclopentyl)but-3-yn-2-ol (11d/11d′)

Following GP6. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetaldehyde (5) (91.3 mg, 0.6 mmol), Et₂O (3 mL), and ethynylmagnesium bromide (0.5 M in THF, 0.84 mmol, 1.68 mL); column chromatography: EtOAc/petroleum ether = 1:7. The two diastereomers formed could be partially separated by column chromatography. Diastereomeric ratio: 11d/11d′ = 54:46. Diastereomer 11d (major): Elutes first from the column. Yield: 26 mg (0.146 mmol, 24%) of colorless oil. [α]_D^r.t. = +19.7 (0.14, CH₂Cl₂). EI-HRMS: m/z = 179.1432 (MH⁺); C₁₂H₁₉O: requires m/z = 179.143 (MH⁺); ν_max 3348, 3073, 2965, 1732, 1327, 1181, 1045, 892 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.76 (s, 3H), 1.01 (s, 3H), 1.21–1.33 (m, 1H), 1.45–1.56 (m, 1H), 1.68–1.83 (m, 3H), 1.84–1.94 (m, 1H), 2.19–2.31 (m, 1H), 2.35–2.46 (m, 2H), 4.33–4.39 (m, 1H), 4.68–4.74 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.57, 26.47, 28.17, 30.79, 38.57, 44.03, 45.97, 61.35, 72.92, 85.64, 103.29, 162.11. Diastereomer 11d′ (minor): Elutes secondly from the column. Yield: 46 mg (0.258 mmol, 43%; contains 17% of 11d) of colorless oil. ¹H-NMR (500 MHz, CDCl₃): δ 0.76 (s, 3H), 1.02 (s, 3H), 1.22–1.32 (m, 1H), 1.50–1.58 (m, 1H), 1.61–1.68 (m, 1H), 1.70–1.77 (m, 1H), 1.79–1.88 (m, 1H), 1.96 (s, 1H), 2.19–2.31 (m, 1H), 2.35–2.48 (m, 2H), 4.32–4.39 (m, 1H), 4.68–4.76 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.6, 26.3, 28.3, 30.8, 38.4, 44.1, 46.9, 62.4, 73.4, 84.9, 103.3, 161.9.

3.55. Synthesis of Tertiary Alcohols 12 from Ketones 10—General Procedure 7 (GP7)

To a solution of ketone 10 (1.0 equiv.) in anhydrous Et₂O (4 mL) under argon at 0 °C, Grignard reagent (2.0 equiv.) was added slowly. The resulting reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 2 h. The excess Grignard reagent was quenched with NaCl (aq. sat., 3 mL), and the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic phase was washed with NaCl (aq. sat., 3 × 10 mL), dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60). The fractions containing the pure product 12 were combined, and the volatiles evaporated in vacuo. The isolated tertiary alcohols 12 were fully characterized (as mixtures of two diastereomers).

3.56. Synthesis of (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)-2-methylpropan-2-ol (12a)

Following GP7. Prepared from (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)propan-2-one (10a) (1.0 mmol, 166 mg), Et₂O (4 mL), and methylmagnesium bromide (2.0 M in Et₂O, 2.0 mmol, 1.0 mL); column chromatography: EtOAc/petroleum ether = 1:2. Yield: 144 mg (0.79 mmol, 79%) of colorless oil. [α]_D^r.t. = +21.0 (0.13, CH₂Cl₂). EI-HRMS: m/z = 165.1637 (M-OH)H⁺; C₁₂H₂₁: requires m/z = 165.1638 (M-OH)H⁺; ν_max 3380, 3071, 2961, 1652, 1465, 1377, 1362, 1189, 1141, 1047, 955, 905, 877, 770 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.78 (s, 3H), 1.04 (s, 3H), 1.24 (s, 3H), 1.25 (s, 3H), 1.31–1.41 (m, 2H), 1.52–1.63 (m, 2H), 1.97–2.06 (m, 1H), 2.24–2.37 (m, 1H), 2.43–2.53 (m, 1H), 4.74–4.79 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.2, 25.7, 29.7, 30.4, 30.6, 31.0, 44.0, 44.7, 46.1, 71.5, 103.0, 161.9.

3.57. Synthesis of 1-((R)-2,2-dimethyl-3-methylenecyclopentyl)-2-methylbutan-2-ol (12b/12b′)

Following GP7. Prepared from (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)butan-2-one (10b) (1.0 mmol, 180 mg), Et₂O (4 mL), and methylmagnesium bromide (2.0 M in Et₂O, 2.0 mmol, 1.0 mL); column chromatography: EtOAc/petroleum ether = 1:1. The two diastereomers formed could not be separated by column chromatography. Diastereomeric ratio: 60:40. Yield: 159 mg (0.81 mmol, 81%) of colorless oil. [α]_D^r.t. = +26.0 (0.13, CH₂Cl₂). EI-HRMS: m/z = 179.1796 (M-OH)H⁺; C₁₃H₂₃: requires m/z = 179.1794 (M-OH)H⁺; ν_max 3394, 3070, 2961, 2927, 1652, 1461, 1377, 1362, 1297, 1138, 1054, 996, 920, 877, 849, 787, 756 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃) for both diastereomers: δ 0.78 (s, 3H), 0.91 (q, J = 7.6 Hz, 3H), 1.04 (s, 3H), 1.17 (d, J = 4.4 Hz, 3H), 1.30–1.45 (m, 2H), 1.50–1.62 (m, 4H), 1.96–2.06 (m, 1H), 2.24–2.35 (m, 1H), 2.43–2.53 (m, 1H), 4.74–4.80 (m, 2H) (one signal missing). ¹³C-NMR (126 MHz, CDCl₃) for both diastereomers: δ 8.3, 8.6, 23.2, 23.2, 25.8, 25.8, 26.7, 27.6, 30.3, 30.4, 31.0, 34.5, 35.5, 41.5, 41.6, 44.8, 66.8, 45.5, 45.6, 73.3, 73.4, 103.0, 161.9, 162.0.

3.58. Synthesis of 1-((R)-2,2-dimethyl-3-methylenecyclopentyl)-2-methylpentan-2-ol (12c/12c′)

Following GP7. Prepared from (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)pentan-2-one (10c) (1.0 mmol, 194 mg), Et₂O (4 mL), and methylmagnesium bromide (2.0 M in Et₂O, 2.0 mmol, 1.0 mL); column chromatography: EtOAc/petroleum ether = 1:5. The two diastereomers formed could not be separated by column chromatography. Diastereomeric ratio: 60:40. Yield: 162 mg (0.77 mmol, 77%) of colorless oil. [α]_D^r.t. = +13.0 (0.13, CH₂Cl₂). EI-HRMS: m/z = 193.1952 (M-OH)H⁺; C₁₄H₂₅: requires m/z = 193.1951 (M-OH)H⁺; ν_max 3411, 3070, 2958, 2932, 2872, 1745, 1652, 1464, 1376, 1362, 1291, 1239, 1139, 1079, 1050, 1005, 929, 877, 775, 743 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃) for both diastereomers: δ 0.78 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H), 1.03 (s, 3H), 1.15 (d, J = 5.0 Hz, 1H), 1.18 (d, J = 4.6 Hz, 3H), 1.29–1.59 (m, 8H), 1.95–2.04 (m, 1H), 2.24–2.36 (m, 1H), 2.43–2.53 (m, 1H), 4.74–4.79 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃) for both diastereomers: δ 14.8, 14.8, 17.2, 17.5, 23.2, 23.2, 25.7, 25.8, 27.3, 28.1, 30.3, 30.4, 31.0, 42.0, 42.1, 44.6, 44.8, 44.8, 45.5, 45.6, 45.6, 73.2, 73.3, 103.0, 161.9, 162.0.

3.59. Synthesis of 1-((R)-2,2-dimethyl-3-methylenecyclopentyl)-2-methylhexan-2-ol (12d/12d′)

Following GP7. Prepared from (R)-1-(2,2-Dimethyl-3-methylenecyclopentyl)hexan-2-one (10d) (1.0 mmol, 208 mg), Et₂O (4 mL), and methylmagnesium bromide (2.0 M in Et₂O, 2.0 mmol, 1.0 mL); column chromatography: EtOAc/petroleum ether = 1:5. The two diastereomers formed could not be separated by column chromatography. Diastereomeric ratio: 59:41. Yield: 153 mg (0.68 mmol, 68%) of colorless oil. [α]_D^r.t. = +20.0 (0.25, CH₂Cl₂). EI-HRMS: m/z = 207.2105 (M-OH)H⁺; C₁₅H₂₇: requires m/z = 207.2107 (M-OH)H⁺; ν_max 3404, 2958, 2931, 2869, 1652, 1462, 1376, 1362, 1297, 1139, 1085, 1025, 936, 904, 877, 776, 730 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃) for both diastereomers: δ 0.78 (s, 3H), 0.89–0.95 (m, 3H), 1.04 (s, 3H), 1.14 (d, J = 6.0 Hz, 1H), 1.18 (d, J = 4.6 Hz, 3H), 1.28–1.60 (m, 10H), 1.96–2.04 (m, 1H), 2.24–2.37 (m, 1H), 2.43–2.53 (m, 1H), 4.74–4.79 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃) for both diastereomers: δ 14.3, 23.2, 23.2, 23.4, 25.8, 25.8, 26.2, 26.4, 27.3, 28.2, 30.4, 30.4, 31.0, 41.9, 42.0, 42.0, 43.0, 44.8, 44.8, 45.5, 45.6, 73.2, 73.2, 103.0, 161.9, 162.0.

3.60. Synthesis of 1-((R)-2,2-dimethyl-3-methylenecyclopentyl)-2-methylpent-4-en-2-ol (12e/12e′)

Following GP7. Prepared from (R)-1-(2,2-dimethyl-3-methylenecyclopentyl)pent-4-en-2-one (10f) (1.0 mmol, 192 mg), Et₂O (4 mL), and methylmagnesium bromide (2.0 M in Et₂O, 2.0 mmol, 1.0 mL); column chromatography: EtOAc/petroleum ether = 1:10. The two diastereomers formed could not be separated by column chromatography. Diastereomeric ratio: 54:46. Yield: 148 mg (0.71 mmol, 71%) of colorless oil. [α]_D^r.t. = +4.5 (0.105, CH₂Cl₂). EI-HRMS: m/z = 191.1791 (M-OH)H⁺; C₁₄H₂₄O: requires m/z = 191.1794 (M-OH)H⁺; ν_max 3428, 3073, 2960, 2927, 1651, 1461, 1434, 1376, 1362, 1293, 1114, 998, 913, 877, 781, 709, 632 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃) for both diastereomers: δ 0.78 (s, 3H), 1.04 (s, 3H), 1.20 (d, J = 5.3 Hz, 3H), 1.29–1.42 (m, 3H), 1.54–1.65 (m, 2H), 1.96–2.08 (m, 1H), 2.23–2.35 (m, 3H), 2.42–2.54 (m, 1H), 4.74–4.79 (m, 2H), 5.09–5.20 (m, 2H), 5.80–5.95 (m, 1H). ¹³C-NMR (126 MHz, CDCl₃) for both diastereomers: δ 23.2, 23.2, 25.8, 25.8, 27.0, 28.0, 30.3, 30.4, 31.0, 42.1, 42.1, 44.8, 44.9, 45.5, 45.7, 46.7, 47.6, 72.5, 72.6, 103.0, 103.0, 119.0, 119.1, 134.1, 134.2, 161.8, 161.9.

3.61. Synthesis of 1-((R)-2,2-dimethyl-3-methylenecyclopentyl)-2-phenylpropan-2-ol (12f/12f′)

Following GP7. Prepared from (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-1-phenylethan-1-one (10k) (1.0 mmol, 228 mg), Et₂O (4 mL), and methylmagnesium bromide (2.0 M in Et₂O, 2.0 mmol, 1.0 mL); column chromatography: EtOAc/petroleum ether = 1:10. The two diastereomers formed could not be separated by column chromatography. Diastereomeric ratio: 57:43. Yield: 178 mg (0.73 mmol, 73%) of colorless oil. [α]_D^r.t. = +12.0 (0.11, CH₂Cl₂). EI-HRMS: m/z = 227.1798 (M-OH)H⁺; C₁₇H₂₃: requires m/z = 227.1794 (M-OH)H⁺; ν_max 3439, 3065, 2959, 1651, 1494, 1446, 1362, 1111, 1068, 1028, 936, 910, 877, 848, 765, 723, 699 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃) for both diastereomers: δ 0.75 (s, 1.5H), 0.76 (s, 1.5H), 0.88 (s, 1.5H), 0.98 (s, 1.5H), 1.02–1.13 (m, 0.5H), 1.23–1.39 (m, 1.5H), 1.48–1.55 (m, 0.5H), 1.59 (d, J = 3.5 Hz, 3H), 1.63–1.75 (m, 2.5H), 1.90 (dd, J = 1.8, 14.0 Hz, 0.5H), 1.98 (dd, J = 1.3, 14.4 Hz, 0.5H), 2.07–2.20 (m, 1H), 2.27–2.43 (m, 1H), 4.66–4.74 (m, 2H), 7.19–7.26 (m, 1H), 7.30–7.36 (m, 2H), 7.39–7.47 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃) for both diastereomers: δ 23.3, 23.3, 25.4, 25.6, 29.7, 29.9, 30.8, 30.9, 30.9, 31.6, 44.6, 44.7, 44.7, 44.9, 45.5, 45.8, 74.7, 75.4, 102.8, 102.9, 124.9, 125.0, 126.6, 126.7, 128.2, 128.2, 148.0, 148.6, 161.8, 161.9.

3.62. Synthesis of Ethyl-(R,E)-4-(2,2-dimethyl-3-methylenecyclopentyl)but-2-enoate (13)

To a suspension of NaH (0.825 mmol, ω = 0.60, 33 mg) in anhydrous THF (2 mL) under argon at 0 °C, triethyl phosphonoacetate (0.55 mmol, 110 μL) was added. The resulting reaction mixture was stirred at 0 °C for 45 min, then a solution of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetaldehyde (5) (84 mg, 0.55 mmol) in anhydrous THF (1.5 mL) was added. The reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 20 h. The excess NaH was quenched with NaCl (aq. sat., 3 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with NaCl (aq. sat., 2 × 5 mL), dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60; EtOAc/petroleum ether = 1:30). The fractions containing the pure product 13 were combined, and the volatiles were evaporated in vacuo. Yield: 80 mg (0.360 mmol, 65%) of colorless oil. [α]_D^r.t. = +8.8 (0.13, CH₂Cl₂). EI-HRMS: m/z = 223.1691 (MH⁺); C₁₄H₂₃O₂: requires m/z = 223.1693 (MH⁺); ν_max 2958, 1719, 1653, 1463, 1184, 1145, 1043, 978, 878 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.78 (s, 3H), 1.01 (s, 3H), 1.14–1.28 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H), 1.52–1.62 (m, 1H), 1.72–1.82 (m, 1H), 1.87–1.97 (m, 1H), 2.17–2.32 (m, 2H), 2.33–2.43 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.70 (t, J = 2.5 Hz, 1H), 4.72 (dt, J = 1.1, 2.1 Hz, 1H), 5.77 (dt, J = 1.5, 15.6 Hz, 1H), 6.90 (ddd, J = 6.9, 7.9, 15.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 14.4, 23.5, 27.0, 28.2, 30.6, 33.2, 44.2, 49.5, 60.3, 103.6, 122.0, 149.1, 161.9, 166.8.

3.63. Synthesis of Methyl (R,E)-4-(2,2-dimethyl-3-methylenecyclopentyl)but-2-enoate (14)

To a solution of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetaldehyde (5) (45.7 mg, 0.3 mmol) in anhydrous toluene (2 mL) under argon at room temperature, methyl (triphenylphosphoranylidene)acetate (0.45 mmol, 150 mg) was added. The resulting reaction mixture was heated under reflux for 24 h. The volatile components were evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60; EtOAc/petroleum ether = 1:20). The fractions containing the pure product 14 were combined, and the volatiles were evaporated in vacuo. Yield: 47 mg (0.2256 mmol, 75%) of colorless oil. [α]_D^r.t. = +5.8 (0.135, CH₂Cl₂). EI-HRMS: m/z = 209.1536 (MH⁺); C₁₃H₂₁O₂: requires m/z = 209.1536 (MH⁺); ν_max 2956, 1723, 1655, 1435, 1269 1194, 1041, 978, 878 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.78 (s, 3H), 1.01 (s, 3H), 1.17–1.29 (m, 1H), 1.52–1.62 (m, 1H), 1.72–1.81 (m, 1H), 1.87–1.98 (m, 1H), 2.17–2.31 (m, 2H), 2.33–2.43 (m, 1H), 3.66 (s, 3H), 4.70 (t, J = 2.5 Hz, 1H), 4.71–4.74 (m, 1H), 5.78 (dt, J = 1.5, 15.6 Hz, 1H), 6.91 (ddd, J = 7.0, 7.9, 15.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 27.0, 28.2, 30.6, 33.2, 44.2, 49.5, 51.6, 103.6, 121.6, 149.4, 161.9, 167.2.

3.64. Synthesis of (R,E)-5-(2,2-dimethyl-3-methylenecyclopentyl)pent-3-en-2-one (15)

To a solution of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetaldehyde (5) (45.7 mg, 0.3 mmol) in anhydrous CH₂Cl₂ (2 mL) under argon at room temperature, 1-triphenylphosphoranyliden-2-propanon (0.45 mmol, 143 mg) was added. The resulting reaction mixture was heated under reflux for 24 h. The volatile components were evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60; EtOAc/petroleum ether = 1:30). The fractions containing the pure product 15 were combined, and the volatiles were evaporated in vacuo. Yield: 32 mg (0.166 mmol, 56%) of colorless oil. [α]_D^r.t. = +2.2 (0.275, CH₂Cl₂). EI-HRMS: m/z = 193.1586 (MH⁺); C₁₃H₂₁O: requires m/z = 193.1587 (MH⁺); ν_max 2958, 1698, 1627, 1361, 1251, 977, 878 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.80 (s, 3H), 1.02 (s, 3H), 1.19–1.30 (m, 1H), 1.55–1.63 (m, 1H), 1.71–1.80 (m, 1H), 1.90–2.01 (m, 1H), 2.18 (s, 3H), 2.21–2.32 (m, 2H), 2.35–2.43 (m, 1H), 4.71 (t, J = 2.5 Hz, 1H), 4.73 (dt, J = 1.1, 2.2 Hz, 1H), 6.03 (dt, J = 1.4, 15.8 Hz, 1H), 6.74 (ddd, J = 6.8, 7.7, 15.9 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 23.5, 27.0, 27.0, 28.3, 30.5, 33.5, 44.2, 49.6, 103.6, 132.0, 148.2, 161.7, 198.7.

3.65. Synthesis of (R,E)-(3-(2,2-dimethyl-3-methylenecyclopentyl)prop-1-en-1-yl)benzene (16) and (R,Z)-(3-(2,2-dimethyl-3-methylenecyclopentyl)prop-1-en-1-yl)benzene (16′)

To a suspension of NaH (0.45 mmol, ω = 0.60, 18 mg) in anhydrous THF (0.5 mL) under argon at 0 °C, benzyltriphenylphosphonium chloride (0.3 mmol, 117 mg) was added. The resulting reaction mixture was stirred at 0 °C for 30 min, then a solution of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)acetaldehyde (5) (0.3 mmol, 45.6 mg) in anhydrous THF (1.0 mL) was added. The reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 20 h. The excess NaH was quenched with NaCl (aq. sat., 3 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with NaCl (aq. sat., 2 × 5 mL), dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60; petroleum ether). The fractions containing the pure products 16/16′ were combined, and the volatiles were evaporated in vacuo. Diastereomeric ratio: 16/16′ = 88:12. The two diastereomers formed could not be separated by column chromatography. Yield: 43 mg (0.190 mmol, 63%) of colorless oil. [α]_D^r.t. = +38.8 (0.22, CH₂Cl₂). EI-HRMS: the product was not ionized; ν_max 2957, 1651, 1495, 1384, 878, 742, 692 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃) for 16: δ 0.82 (s, 3H), 1.04 (s, 3H), 1.23–1.34 (m, 1H), 1.53–1.63 (m, 1H), 1.77–1.84 (m, 1H), 1.89–1.99 (m, 1H), 2.18–2.32 (m, 2H), 2.34–2.43 (m, 1H), 4.69–4.73 (m, 2H), 6.15 (ddd, J = 6.8, 7.5, 15.7 Hz, 1H), 6.33 (dt, J = 1.5, 15.7 Hz, 1H), 7.10–7.14 (m, 1H), 7.20–7.24 (m, 2H), 7.26–7.29 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃) for 16: δ 23.5, 27.1, 28.4, 30.7, 33.9, 44.2, 50.6, 103.2, 126.1, 127.0, 128.6, 130.4, 130.7, 138.0, 162.7. ¹H-NMR (500 MHz, CDCl₃) for 16′: δ 0.74 (s, 3H), 1.02 (s, 3H), 2.02–2.09 (m, 1H), 4.67–4.69 (m, 1H), 5.64 (dt, J = 7.3, 11.7 Hz, 1H) (the remaining signals overlap with the signals of diastereomer 16).

3.66. Cyclopropanation of the Methylene Group—General Procedure 8 (GP8)

Zinc dust (84.0 mg, 1.285 mmol, 2.57 equiv.) and copper(I) chloride (127 mg, 1.285 mmol, 2.57 equiv.) were introduced into a flame-dried flask under argon, followed by the addition of Et₂O (3 mL). The resulting mixture was refluxed under argon for 30 min. Diiodomethane (53 μL, 0.65 mmol, 1.3 equiv.) was then added. The reaction mixture turned dark in color, and bubbles began to form. After 5–10 min, alkene (8a or 9) (0.5 mmol) and further diiodomethane (243 μL, 3.0 mmol, 6 equiv.) were added. The resulting reaction mixture was refluxed under argon for 20 h. The cooled reaction mixture (room temperature) was filtered through a plague of Celite^® and washed with Et₂O (30 mL) to remove the solid particles. The organic phase was washed with HCl (aq., 1 M, 2 × 15 mL), H₂O (2 × 15 mL) and NaCl (aq. sat., 3 × 15 mL). The organic phase was dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60). The fractions containing the pure product were combined, and the volatile components were evaporated in vacuo. The isolated cyclopropanated products 17 and 18 were fully characterized.

3.67. Synthesis of (R)-5-(2-methoxyethyl)-4,4-dimethylspiro[2.4]heptane (17)

Following GP8. Prepared from (R)-2-(2-methoxyethyl)-1,1-dimethyl-5-methylenecyclopentane (8a) (0.5 mmol, 84 mg); column chromatography: EtOAc/petroleum ether = 1:50. Yield: 67 mg (0.367 mmol, 73%) of colorless oil. The product contains 9% of the starting alkene 8a. [α]_D^r.t. = +43.3 (0.155, CH₂Cl₂). EI-HRMS: the product was not ionized; ν_max 2935, 2867, 1468, 1386, 1117, 1070, 841 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.05–0.13 (m, 1H), 0.25–0.34 (m, 2H), 0.49–0.56 (m, 1H), 0.57 (s, 3H), 0.70 (s, 3H), 1.29–1.41 (m, 3H), 1.63–1.82 (m, 2H), 1.83–1.96 (m, 2H), 3.34 (s, 3H), 3.36–3.47 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.5, 12.3, 20.2, 22.9, 28.3, 30.7, 30.8, 34.0, 40.9, 47.3, 58.7, 72.6.

3.68. Synthesis of (R)-2-(4,4-dimethylspiro[2.4]heptan-5-yl)-N-methoxy-N-methylacetamide (18)

Following GP8. Product 18 was prepared on a 3 mmol scale. Prepared from zinc dust (504 mg, 7.71 mmol, 2.57 equiv.), copper(I) chloride (763 mg, 7.71 mmol, 2.57 equiv.), Et₂O (10 mL), diiodomethane (316 μL, 3.9 mmol, 1.3 equiv.), (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)-N-methoxy-N-methylacetamide (9) (3.0 mmol, 634 mg), and diiodomethane (1.461 mL, 18 mmol, 6 equiv.) and washed with Et₂O (60 mL); column chromatography: EtOAc/petroleum ether = 1:5. Yield: 460 mg (2.04 mmol, 68%) of colorless oil. The product contains 5% of the starting alkene 9. [α]_D^r.t. = +36.2 (0.175, CH₂Cl₂). EI-HRMS: m/z = 226.1800 (MH⁺); C₁₃H₂₄NO₂: requires m/z = 226.1802 (MH⁺); ν_max 2957, 2869, 1663, 1464, 1412, 1176, 1111, 1004 cm–1. ¹H-NMR (500 MHz, CDCl₃): δ 0.09–0.17 (m, 1H), 0.31 (dd, J = 7.0, 8.4 Hz, 2H), 0.47–0.58 (m, 1H), 0.62 (s, 3H), 0.73 (s, 3H), 1.30–1.47 (m, 2H), 1.80–1.91 (m, 1H), 1.96–2.07 (m, 1H), 2.14–2.24 (m, 1H), 2.26–2.34 (m, 1H), 2.49 (dd, J = 3.6, 14.6 Hz, 1H), 3.19 (s, 3H), 3.70 (s, 3H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.9, 12.0, 20.4, 22.9, 28.6, 30.4, 32.4, 33.4, 33.8, 40.9, 46.4, 61.3, 174.9.

3.69. Synthesis of Ketones 19 from Weinreb Amide 18—General Procedure 9 (GP9)

To a solution of (R)-2-(4,4-dimethylspiro[2.4]heptan-5-yl)-N-methoxy-N-methylacetamide (18) (1.0 equiv.; contains 5% of alkene 9) in anhydrous Et₂O (5 mL) under argon at 0 °C, the corresponding Grignard reagent (1.6 equiv.) was added slowly. The resulting reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 20 h. The excess Grignard reagent was quenched with NaCl (aq. sat., 3 mL), and the resulting mixture was extracted with Et₂O (3 × 15 mL). The combined organic phase was washed with NaCl (aq. sat., 3 × 5 mL), dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60). The fractions containing the pure product 19 were combined, and the volatiles evaporated in vacuo. The isolated ketones 19 were fully characterized.

3.70. Synthesis of (R)-1-(4,4-dimethylspiro[2.4]heptan-5-yl)propan-2-one (19a)

Following GP9. Prepared from (R)-2-(4,4-dimethylspiro[2.4]heptan-5-yl)-N-methoxy-N-methylacetamide (18) (0.5 mmol, 113 mg), Et₂O (5 mL), and methylmagnesium bromide (3 M in Et₂O, 0.8 mmol, 267 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 80 mg (0.444 mmol, 88%) of colorless oil. The product contains 4% of the alkene 9. [α]_D^r.t. = +16.2 (0.28, CH₂Cl₂). EI-HRMS: m/z = 181.1586 (MH⁺); C₁₂H₂₁O: requires m/z = 181.1587 (MH⁺); ν_max 2958, 2869, 1714, 1468, 1365, 1287, 1163, 1145, 1011 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.09–0.17 (m, 1H), 0.27–0.36 (m, 2H), 0.50–0.57 (m, 1H), 0.59 (s, 3H), 0.70 (s, 3H), 1.22–1.34 (m, 1H), 1.37–1.46 (m, 1H), 1.83–1.93 (m, 1H), 1.91–2.03 (m, 1H), 2.08–2.15 (m, 1H), 2.17 (s, 3H), 2.28 (dd, J = 10.7, 15.5 Hz, 1H), 2.51 (dd, J = 3.5, 15.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.8, 12.0, 20.4, 23.0, 28.5, 30.3, 30.4, 33.7, 40.9, 45.6, 46.0, 209.7.

3.71. Synthesis of (R)-1-(4,4-dimethylspiro[2.4]heptan-5-yl)pent-4-en-2-one (19b)

Following GP9. Prepared from (R)-2-(4,4-dimethylspiro[2.4]heptan-5-yl)-N-methoxy-N-methylacetamide (18) (0.5 mmol, 113 mg), Et₂O (5 mL), and allylmagnesium bromide (1.0 M in Et₂O, 0.8 mmol, 0.8 mL); column chromatography: EtOAc/petroleum ether = 1:50. Yield: 73 mg (0.354 mmol, 70%) of colorless oil. The product contains 3% of the alkene 9. [α]_D^r.t. = +21.1 (0.25, CH₂Cl₂). EI-HRMS: m/z = 207.1784 (MH⁺); C₁₄H₂₃O: requires m/z = 207.1785 (MH⁺); ν_max 2958, 2869, 1714, 1638, 1468, 1385, 1365, 1012, 991, 917 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.09–0.16 (m, 1H), 0.26–0.36 (m, 2H), 0.50–0.57 (m, 1H), 0.58 (s, 3H), 0.69 (s, 3H), 1.20–1.34 (m, 1H), 1.37–1.46 (m, 1H), 1.82–1.91 (m, 1H), 1.92–2.03 (m, 1H), 2.09–2.19 (m, 1H), 2.30 (dd, J = 10.7, 15.8 Hz, 1H), 2.52 (dd, J = 3.5, 15.8 Hz, 1H), 3.14–3.26 (m, 2H), 5.11–5.22 (m, 2H), 5.94 (ddt, J = 7.0, 10.2, 17.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.8, 12.0, 20.4, 23.0, 28.5, 30.3, 33.7, 40.9, 44.2, 45.8, 48.2, 118.8, 130.9, 209.2.

3.72. Synthesis of (R)-1-(4,4-dimethylspiro[2.4]heptan-5-yl)but-3-en-2-one (19c)

Following GP9. Prepared from (R)-2-(4,4-dimethylspiro[2.4]heptan-5-yl)-N-methoxy-N-methylacetamide (18) (0.5 mmol, 113 mg), Et₂O (5 mL), and vinylmagnesium bromide (1.0 M in THF, 0.8 mmol, 0.8 mL); column chromatography: EtOAc/petroleum ether = 1:40. Yield: 65 mg (0.338 mmol, 67%) of colorless oil. [α]_D^r.t. = +36.6 (0.155, CH₂Cl₂). EI-HRMS: m/z = 193.1584 (MH⁺); C₁₃H₂₁O: requires m/z = 193.1587 (MH⁺); ν_max 2958, 2869, 1680, 1615, 1400, 1365, 1011, 985, 958 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.10–0.17 (m, 1H), 0.28–0.36 (m, 2H), 0.51–0.58 (m, 1H), 0.61 (s, 3H), 0.73 (s, 3H), 1.24–1.36 (m, 1H), 1.37–1.46 (m, 1H), 1.83–1.90 (m, 1H), 1.91–2.01 (m, 1H), 2.12–2.22 (m, 1H), 2.44 (dd, J = 10.7, 15.2 Hz, 1H), 2.67 (dd, J = 3.7, 15.2 Hz, 1H), 5.81 (dd, J = 1.2, 10.6 Hz, 1H), 6.23 (dd, J = 1.2, 17.6 Hz, 1H), 6.39 (dd, J = 10.6, 17.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.9, 12.1, 20.4, 23.0, 28.5, 30.3, 33.7, 41.0, 41.5, 46.2, 129.0, 136.9, 201.4.

3.73. Synthesis of (R)-2-(4,4-dimethylspiro[2.4]heptan-5-yl)-1-phenylethan-1-one (19d)

Following GP9. Prepared from (R)-2-(4,4-dimethylspiro[2.4]heptan-5-yl)-N-methoxy-N-methylacetamide (18) (0.5 mmol, 113 mg), Et₂O (5 mL), and phenylmagnesium bromide (3.0 M in THF, 0.8 mmol, 267 μL); column chromatography: EtOAc/petroleum ether = 1:20. Yield: 76 mg (0.315 mmol, 63%) of colorless oil. The product contains 3% of the alkene 9. [α]_D^r.t. = +40.1 (0.235, CH₂Cl₂). EI-HRMS: m/z = 243.1744 (MH⁺); C₁₇H₂₃O: requires m/z = 243.1743 (MH⁺); ν_max 2957, 2868, 1682, 1448, 1365, 1286, 1213, 1045, 750, 689 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.10–0.18 (m, 1H), 0.29–0.37 (m, 2H), 0.51–0.59 (m, 1H), 0.66 (s, 3H), 0.80 (s, 3H), 1.29–1.46 (m, 2H), 1.83–1.94 (m, 1H), 2.02–2.04 (m, 1H), 2.23–2.34 (m, 1H), 2.80 (dd, J = 10.5, 15.4 Hz, 1H), 3.08 (dd, J = 3.5, 15.5 Hz, 1H), 7.41–7.51 (m, 2H), 7.52–7.62 (m, 1H), 7.93–8.00 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.9, 12.1, 20.6, 23.1, 28.6, 30.4, 33.8, 40.3, 41.2, 46.5, 128.3, 128.7, 133.0, 137.5, 200.9.

3.74. Synthesis of (3R)-1-methoxy-3-(2-methoxyethyl)-1,2,2-trimethylcyclopentane (20)

To a solution/suspension of Hg(OAc)₂ (0.65 mmol, 207 mg) in anhydrous methanol (1.5 mL) at 0 °C under argon was added (R)-2-(2-methoxyethyl)-1,1-dimethyl-5-methylenecyclopentane (8a) (0.5 mmol, 84 mg). After stirring at 0 °C for 15 min, NaOH (aq., 3 M, 0.5 mL) was added. The reaction mixture turned from colorless to yellow. Then, a solution/suspension of NaBH₄ (5.25 mmol, 199 mg) in NaOH (aq., 3 M, 0.5 mL) was added. The reaction mixture changed color from yellow to dark blue (black). The reaction mixture was stirred at room temperature under argon for 20 h. The reaction mixture was filtered through a pad of Celite^® and washed with EtOAc (20 mL). The filtrate was washed with H₂O (2 × 5 mL) and NaCl (aq. sat., 2 × 5 mL), dried under anhydrous Na₂SO₄, filtered, and the volatiles evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60, EtOAc/petroleum ether = 1:10). The fractions containing the pure product 20 were combined, and the volatile components were evaporated in vacuo. Yield: 66 mg (0.330 mmol, 66%) of colorless oil. [α]_D^r.t. = +25.2 (0.15, CH₂Cl₂). EI-HRMS: the product was not ionized; ν_max 2935, 2867, 1468, 1386, 1117, 1070, 841 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.67 (s, 3H), 0.87 (s, 3H), 1.06 (s, 3H), 1.15–1.24 (m, 1H), 1.28–1.37 (m, 1H), 1.37–1.46 (m, 1H), 1.64–1.88 (m, 2H), 1.90–2.06 (m, 2H), 3.13 (s, 3H), 3.33 (s, 3H), 3.35–3.43 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 16.0, 19.6, 19.7, 27.4, 30.0, 31.1, 43.1, 47.6, 49.4, 58.6, 73.0, 87.7.

3.75. Synthesis of (3aR,6aS)-6,6,6a-trimethylhexahydro-2H-cyclopenta[b]furan (21) [40]

To a solution of (R)-2-(2,2-dimethyl-3-methylenecyclopentyl)ethan-1-ol (4) (2.0 mmol, 308 mg) in anhydrous Et₂O (4 mL) under argon at 0 °C was added TFA (4 mL). The resulting reaction mixture was stirred at 0 °C for 1 h and at room temperature for 1 h. The volatiles were thoroughly evaporated in vacuo. The residue was purified by column chromatography (Silica gel 60, EtOAc/petroleum ether = 1:20). The fractions containing the pure product 21 were combined, and the volatile components were evaporated in vacuo. The isolated ether 21 was fully characterized with the exception of HRMS, as the product was not ionized. Yield: 118 mg (0.76 mmol, 38%) of colorless oil. [α]_D^r.t. = +5.0 (0.23, CH₂Cl₂). ν_max 2955, 2864, 1785, 1460, 1398, 1348, 1218, 1141, 943, 821, 776, 731 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.85 (s, 3H), 1.01 (s, 3H), 1.08 (s, 3H), 1.15–1.25 (m, 1H), 1.28–1.36 (m, 1H), 1.61–1.70 (m, 2H), 1.91–2.03 (m, 1H), 2.12–2.22 (m, 1H), 2.32–2.40 (m, 1H), 3.70–3.79 (m, 1H), 3.89 (td, J = 3.6, 8.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 19.1, 22.2, 25.5, 29.7, 34.9, 39.8, 46.0, 47.2, 68.0, 95.1.

3.76. DFT Calculations

Theoretical studies were carried out using AMS 2025.1, SCM, Theoretical Chemistry program [66]. Geometry optimizations of relevant equilibrium structures were performed using the M06-2X [67,68] density functional with the TZ2P basis set as implemented in ADF–AMS 2025.1. Normal mode vibrational analysis on the stationary points allowed us to confirm they are minima (zero imaginary frequencies). The M06-2X functional was chosen, as it is better suited to handling kinetics, thermodynamics, and noncovalent interactions in organic molecular systems [67,69,70,71,72,73,74]. Solvation effect (in dichloromethane) was considered using the COSMO model. An ultrafine grid was employed for all DFT calculations. Unless otherwise stated, relative Gibbs energies (ΔG) reported correspond to the M06-2X/TZ2P level at 298.13 K in dichloromethane. The 3D geometries were generated using GUI of AMS 2025.1.

4. Conclusions

The availability of (+)-isocampholenic acid from (1S)-(+)-10-camphorsulfonic acid in only two steps at a scale of 172 mmol and 60% yield enabled the first systematic exploration of its chemical space, with diversification at both the carboxylic acid and exocyclic C=C bond. Using established functional group transformations provided a total of 60 products, i.e., esters, ethers, ketones, secondary and tertiary alcohols, enones and selected cyclopropanated analogs. In most cases, a small amount of α-campholenic acid-derived isomer was detected by proton NMR (up to 2%). As shown by DFT calculations, isocampholenic acid is up to 5.9 kcal/mol less stable than its endocyclic isomers. This suggests that targeted stabilization, such as early introduction of a spirocyclopropyl group or other methylene modifications, may further improve stability. Preliminary odor evaluations by an untrained panel revealed diverse scent profiles, underscoring the untapped potential of this scaffold. The present work only begins to chart the chemical and olfactory landscape of isocampholenic acid, offering numerous opportunities for future functionalization and fragrance design.