Rhodium-Catalyzed Carbonylation of Cyclopropyl Substituted Propargyl Esters: A Tandem 1,3-Acyloxy Migration [5+1] Cycloaddition

Abstract

We have developed two different types of tandem reactions for the synthesis of highly functionalized cyclohexenones from cyclopropyl substituted propargyl esters. Both reactions were initiated by rhodium-catalyzed Saucy-Marbet 1,3-acyloxy migration. The resulting cyclopropyl substituted allenes derived from acyloxy migration then underwent [5+1] cycloaddition with CO. The acyloxy group not only eased the access to allene intermediates but also provided a handle for further selective functionalizations.

1. INTRODUCTION

Transition metal-catalyzed cycloaddition reaction is one of the most efficient ways to access ring systems.¹ Diels-Alder cycloaddition represents the most powerful method for the synthesis of cyclohexenes and has proven to be extremely valuable in the preparation of natural products and pharmaceutical agents.² However, efficient syntheses of cyclohexenes with diverse substitutions, stereochemistry, and functionalities are still challenging and continue to stimulate the development of novel cycloaddition reactions.

We previously discovered a tandem 1,3-acyloxy migration [5+1] cycloaddition reaction for the synthesis of alkylidene cyclohexenone 2 from cyclopropyl substituted propargyl ester 1 (eq 1).³ In this account, we presented the details for the development of this tandem reaction. We also disclosed our study on a related 1,3-acyloxy migration [5+1] cycloaddition cascade reaction for the synthesis of alkylidene cyclohexenone 4 from cyclopropyl substituted propargyl ester 3 for the first time (eq 2).⁴ These two new tandem reactions provided easy access to functionalized six-membered rings from readily available starting materials.

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In 2008, we reported a synthesis of cyclobutenes from cyclopropyl metal carbenes derived from transition metal catalyzed decomposition of diazo compounds (eq 3).^5,6 During our search for more stable alternative cyclopropyl carbene precursors, we were attracted by the method of metal carbene formation from propargyl esters via a transition metal-catalyzed 1,2-acyloxy migration. This convenient and atom-economical⁷ process was first described by Rautenstrauch in 1984,⁸ and has been applied in numerous cascade reactions.^9,10 We originally proposed that if cyclopropyl substituted propargyl ester 1 could undergo a Rautenstrauch 1,2-acyloxy migration via intermediate 5, we might be able to access cyclopropyl metal carbene 6 from compound 1 (Scheme 1).

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Scheme 1.

Rautenstrauch 1,2-Acyloxy Migration and Saucy-Marbet 1,3-Acyloxy Migration of Cyclopropyl Propargyl Esters

An obvious competing pathway is the 1,3-acyloxy migration of compound 1 to form allene 8 (Scheme 1).¹¹ The 1,3-acyloxy migration of propargyl esters was initially discovered by Saucy and Marbet in 1959 using a silver catalyst.¹² Other transition metal complexes including copper, platinum and gold have also been found to promote the Saucy-Marbet rearrangement.^13,14 The regioselectivity for 1,2- or 1,3-acyloxy migration of propargyl ester was often dependent on the substrates and catalysts.¹⁴

Cyclopropyl substituted propargyl ester 1 has been employed in gold catalyzed reactions. When R¹ was an alkyl group, 2-alkylidene 1,3-diketone 9 was formed and the cyclopropane ring was left untouched (Scheme 2).¹⁵ When R¹ was a vinyl or phenyl group, cyclopentene 10 was obtained.¹⁶ In the presence of Rh(I) catalyst and CO, we isolated alkylidene cyclohexenone 2.³ All three products 9, 10, and 2 were proposed to be derived from allene intermediate 8 via a transition metal-catalyzed Saucy-Marbet 1,3-acyloxy migration.

Scheme 2.

Diverse Products Derived from Transition Metal-Catalyzed Saucy-Marbet 1,3-Acyloxy Migration of Cyclopropyl Substituted Propargyl Esters

2. RESULTS AND DISCUSSION

We first prepared propargyl ester 1a and treated it with AuCl₃, (Ph₃P)AuCl, (Ph₃P)AuCl/AgSbF₆, PtCl₂, PtCl₄, AgSbF₆, Cu(MeCN)₄PF₆, PdCl₂(MeCN)₂, [CpRu(MeCN)₃]PF₆, and Rh₂(OAc)₄ catalysts. We observed either no reaction or the formation of enone 11a, presumably derived from hydrolysis of the corresponding allenyl ester intermediate 8a (eq 4).

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We then decided to examine transition metals that were not commonly used as catalysts for acyloxy migration of propargyl esters. We found that alkylidene cyclohexenone 2a (Scheme 3) was formed as a mixture of E/Z isomers (ratio = 1:1) in about 30% yield when 20 mol % of [Rh(CO)₂Cl]₂ was employed as the catalyst in toluene at rt. Product 2a was presumably generated by a Rh(I)-catalyzed [5+1] cycloaddition of allenyl ester 8a with CO via metallacycle 12a. While [5+1] cycloaddition of allenylcyclopropanes or vinylcyclopropanes with CO have been investigated by several groups, the reaction generally required stoichiometric amount of metals and the scope was often limited.¹⁷ A relatively general Rh-catalyzed [5+1] cycloaddition of vinylcyclopropanes with CO was recently reported by Yu’s group.¹⁸ Intercepting the allenyl ester intermediate derived from 1,3-acyloxy migration of propargyl ester has been realized in Ag(I), Cu(I), Pt(II), and Au(I)-catalyzed cascade reactions.^13,14 However, no cyclocarbonylation of the above allene intermediate has been reported prior to our study.³ The combination of the novel reactivity of [Rh(CO)₂Cl]₂ catalyst for facilitating Saucy-Marbet 1,3-acyloxy migration and its known reactivity for catalyzing carbonylation reaction made the cascade transformation in Scheme 3 possible.¹⁹

Scheme 3.

Proposed Mechanism for the Formation of Alkylidene Cyclohexenone 2a from Cyclopropyl Substituted Propargyl Ester 1a

The reaction condition for the synthesis of alkylidene cyclohexenone 2a was then optimized. Simply attaching a CO balloon to the reaction flask, compound 2a was isolated in 93% yield with an E/Z ratio of 1:1.3 at 60 °C after 5h (Table 1). We could run the reaction at rt without decreasing the yield of 2a when the CO pressure was lowered to 0.1–0.2 atm by diluting the balloon with nitrogen.²⁰ We also separated the two geometric isomers of 2a and resubmitted each of them back to the reaction. We did not observe any change of the configuration. This suggested that the E/Z isomers did not equilibrate under the reaction conditions. When a cationic rhodium complex (e.g. [Rh(CO)₂Cl]₂/AgOTf or [Rh(COD)₂]BF₄) was employed as the catalyst, significant amount of enone 11a (eq 4) was observed. Addition of ligands (e.g. PPh₃, P(OMe)₃, P(OPh)₃ and pyridine) either decreased the conversion of the [Rh(CO)₂Cl]₂ catalyzed reaction or completely shut it down. Slightly different E/Z ratios for product 2a were observed in other solvents, such as THF (1:1), EtOAc (1:1), or DCE (2:1). No reaction occurred in MeCN or DMF.

Table 1.

Scope of Substrates with non-Substituted Cyclopropanes^a

^a.Conditions: 5 mol % [Rh(CO)₂Cl]₂, CO (1 atm), toluene, 60 °C, 5h.

^b.Isolated yields of both isomers.

^c.2.5 mol % catalyst, 60 °C, 1h.

The scope of this tandem 1,3-acyloxy migration [5+1] cycloaddition was first examined with substrates 1b–1i (Table 1), all derived from cyclopropyl acetylene. Although the reaction worked at rt with reduced CO pressure, conducting it under 1 atm of CO at 60 °C is more convenient and provided us consistent results. No reaction occurred for secondary propargyl acetate 1b. For substrates with a tertiary ester, the tandem reaction worked well when the propargyl ester was changed from pivalate to acetate (e.g. 1h). High E/Z selectivity could be obtained for propargyl esters with sterically demanding substituents (e.g. 1f and 1i). A single product was obtained for substrate 1g. Highly functionalized product 2i could also be prepared from substrate 1i, which was derived from a steroid derivative. The structure and the configuration of the exo-cyclic olefin of product 2f were further confirmed by x-ray analysis.²¹

The cleavage of different cyclopropane C-C σ-bonds may lead to regioisomers for unsymmetrically substituted cyclopropanes. Based on studies from our lab⁵ and others,^22,23 the regioselectivity for the cleavage of C-C σ-bonds in cyclopropanes was dependent on the stereochemistry of the cyclopropane ring, the electronic and steric properties of the substituents, and the metal catalysts.

We prepared a series of trans-substituted cyclopropanes to examine the regioselectivity of the C-C σ-bond cleavage (Table 2). We found opposite regioselectivity for trans-1j and trans-1k, which had a phenyl and an alkyl substituent on the cyclopropane ring respectively. When the free alcohol in 1k was functionalized to methyl ether 1l, acetate 1m, or silyl ether 1n, the regioselectivity was increased.

Table 2.

Regioselectivity for the Cleavage of C-C σ-Bond in trans-Disubstituted Cyclopropanes^a

^a.Conditions: see Table 1, note a, unless noted otherwise.

^b.Regioisomeric ratios were determined by ¹H NMR of the crude products.

^c.Yields are isolated yields of the major isomer unless noted otherwise.

^d.Yields are combined yields of 2j and 2j’.

We also found opposite regioselectivity for cyclopropanes trans-1j and cis-1j, both of which had a phenyl substituent on the cyclopropane ring (Tables 2 and 3). High regioselectivity was observed for alkyl substituted cis-1k and cis-1n. The 1,3-acyloxy migration [5+1] cycloaddition cascade reaction worked for substrate cis-1n even at rt with 1 atm of CO. We obtained essentially one regioisomeric product at rt from this substrate, while a 16:1 ratio was observed at 60 °C. The same trend of regioselectivity was found for other substituted cyclopropanes (e.g. 1o – 1s). Cyclopropanes with a quaternary carbon, such as compounds 1p and 1q yielded only one isomer. A 16:1 regioisomeric ratio was observed for 1,2,3-trisubstituted cyclopropane 1r. The trans-aryl group and cis-PMBOCH₂ group in cyclopropane 1r should direct the cleavage of the same C-C σ-bond preferentially based on regioselectivity observed for substrates trans-1j and cis-1n. The chirality in substrate 1q was completely transferred to the corresponding cyclohexenone product. This paved the way for enantioselective synthesis of highly substituted cyclohexenones from optical pure cyclopropanes. In contrast, the chirality on the cyclopropane ring was not completely transferred in gold-catalyzed ring opening reactions.^16,24

Table 3.

Regioselectivity for the Cleavage of C-C σ-bond in cis-Disubstituted and Trisubstituted Cyclopropanes^a

^a.Conditions: see Table 1, note a, unless noted otherwise.

^b.Regioisomeric ratios were determined by ¹H NMR of the crude products.

^c.Yields are isolated yields of the major isomer unless noted otherwise.

^d.Yields are combined yields of 2j and 2j’.

^e.The reaction was run at rt.

^f.80 °C, 24h.

An E/Z ratio of 10:1 was observed for product 2s when a mixture of cyclopropane 1s (dr = 1:1) was employed. We have shown that the two E/Z isomers of alkylidene cyclohexenone product 2a do not equilibrate under the reaction conditions. As shown in Scheme 4, if the Rh-catalyzed 1,3-acyloxy migration of the propargyl ester was stereospecific and the configuration of the resulting allenes (8s-1 and 8s-2) was stable under the condition, one would predict a 1:1 E/Z ratio for product 2s. Our result indicated that either the Rh-catalyzed 1,3-acyloxy migration was not stereospecific or the two diastereomeric allenes could interconvert to each other. We propose that allenes 8s-1 and 8s-2 may interconvert to each other through ionic intermediate 8s-3 as shown in Scheme 4. Coordination of rhodium to isomer 8s-1 is favored due to steric interaction between tert-butyl group and the metal catalyst in isomer 8s-2. This may explain why (E)-2s is the major product. The proposed isomerization between 8s-1 and 8s-2 is consistent with results from gold-catalyzed 1,3-acyloxy migrations of chiral propargyl esters.¹⁶ In fact, a dynamic kinetic transformation of racemic propargyl ester was recently realized using a chiral-gold complex as the catalyst.²⁵

Scheme 4.

Proposed Mechanism for the Conversion of 1s to 2s

For all trans-substituted cyclopropanes except trans-1j in Table 2, the less hindered C-C σ-bond was selectively cleaved, presumably because of the steric interaction between the substituent R and the rhodium complex in intermediate trans-8-1 (Scheme 5). Higher regioselectivity was observed for more sterically demanding substituent (e.g. trans-1k to trans-1n). The less hindered C-C σ-bond was also selectively cleaved for all cis-disubstituted cyclopropanes in Table 3 for the same reason. Substrates with a substituent cis to the propargyl ester group generally had higher regioselectivity than the corresponding trans-substituent (e.g. trans-1k vs cis-1k and trans-1n vs cis-1n). This can be rationalized by the more significant steric interactions between the R group and rhodium complex in intermediate cis-8-1 than that in trans-8-1 (Scheme 5). For substrate trans-1j, the C-C σ-bond that was adjacent to aryl group was selectively cleaved presumably because of the electronic effect of the adjacent π-system.^5,22,23 The overall low regioselectivity observed for trans- and cis-phenyl substituted cyclopropanes 1j may be due to competing steric and electronic effects.

Scheme 5.

Proposed Mechanism for Regioselective Cleavage of C-C σ-Bond of Substituted Cyclopropanes

For bicyclic substrates 1t and 1u, the desired decalin derivatives 2t and 2u were isolated in 80% and 82% yields respectively with high regioselectivity (Scheme 6). In these two cases, the five-membered isomerization products 13 and 14 were also isolated in 19% and 11% yields respectively under the standard condition.²² The 5–6 fused bicyclic compounds 13 and 14 could be isolated in good yields by running the reaction in the absence of external CO with a lower catalyst loading. For cyclopropane 1u, the C-C σ-bond that was adjacent to alkene was selectively cleaved for the formation of both products 2u and 14. This was presumably because of the electronic effect of the adjacent π-system. It is interesting to note that no five-membered isomerization product was observed in the monocyclic system even in the absence of a CO balloon.

Scheme 6.

Rh-Catalyzed Ring Expansion of Cyclopropanes in Bicyclic Systems

We also prepared allene 8d from propargyl ester 1d using a silver catalyst.¹² Under standard conditions, product 2d was obtained in 83% yield (eq 5). The E/Z ratio of alkylidene cyclohexenone 2d was the same as products directly derived from 1d using a Rh(I) catalyst (Table 1). This result further confirmed the mechanism we proposed in Scheme 3.

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After the development of Rh-catalyzed 1,3-acyloxy migration [5+1] cycloaddition of cyclopropyl substituted propargyl esters 1 with CO to form product 2, we envisioned the acyloxy group could also be placed between the cyclopropane and the alkyne (e.g. substrate 3a, Scheme 7). Under previously optimized condition for substrate 1, we found that the reaction afforded 30% yield of the desired product 4a and 30% yield of a mixture of inseparable trienes 15a based on ¹H NMR. All of these products are presumably derived from metallacycle 16a. For substrate 3b (Table 4) without the siloxy substituent, we also obtained a mixture of [5+1] cycloaddition product and triene byproducts under the same condition.

Scheme 7.

Rh-Catalyzed 1,3-Acyloxy Migration [5+1] Cycloaddition for Substrates 3a and 3b

Table 4.

Scope of Rh-Catalyzed 1,3-Acyloxy Migration [5+1] Cycloaddition for Substrates 3a–3h^a

^a.Conditions: 5 mol % [Rh(CO)₂Cl]₂, CO (10 atm), toluene (0.05M), overnight. All E/Z ratios were determined by ¹H NMR of the crude product unless noted otherwise.

^b.70 °C.

^c.100 °C.

^d.The stereochemistry of the exo-cyclic olefin could not be determined by ¹H NMR.

^e.50 °C.

^f.Isolated yield of E-isomer.

^g.1 atm CO.

^h.The ratio was determined by ¹³C NMR.

In order to suppress the formation triene byproducts, we decided to increase the amount of [5+1] cycloaddition product by changing the pressure of CO from 1 atm to 10 atm. We found that the desired cycloaddition product 4a could be isolated in 70% yield and the triene byproduct was not formed under this condition (Table 4). The scope of this Rh-catalyzed 1,3-acyloxy migration [5+1] cycloaddition for the formation of product 4 from propargyl ester 3 was then investigated. For substrate 3b with a sterically demanding tert-butyl group, the reaction required higher temperature. For substrates with a tertiary ester (3c, 3d, 3e, 3f, and 3g), lowering the temperature to 50 °C was necessary to achieve a higher yield. We also demonstrated that substituents on the cyclopropane ring could be tolerated (e.g. 3a, 3g, and 3h). The tandem reaction worked well when the propargyl ester was changed from pivalate to acetate (e.g. 3d). Functional groups such as siloxy group and ester were tolerated (e.g. 3e and 3f). In the case of product 4g, the Z isomer decomposed during workup and we only isolated the E isomer. The two diastereomers of substrate 3h could be separated by chromatography. Each of them worked smoothly in the presence of 1 atm of CO and yielded identical result. The relative stereochemistry of the secondary ester in substrate 3h was therefore not determined. Only one regioisomeric product (4h) was obtained for either diastereomer of substrate 3h. No reaction occurred for secondary acetate 3i, which was consistent with previous observation for substrate 1b. A complex mixture was obtained for substrate 3j with a phenyl substituent.

Although the E/Z stereoselectivity for the exo-cyclic alkene in products 4a–4h is not high, it is inconsequential after hydrolysis. Diketone 17d could be obtained in good yield from the corresponding acetate 4d (eq 6).

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3. CONCLUSION

In summary, we have developed an efficient method for the synthesis of various highly functionalized monocyclic cyclohexenones from readily available cyclopropyl substituted propargyl esters. Several examples of bicyclic compounds were also prepared. The combination of the novel reactivity of Rh(I) catalyst for promoting 1,3-acyloxy migration of propargyl esters and its ability to facilitate carbonylation reaction made the tandem transformation possible. Regioselective cleavage of C-C σ-bonds could be achieved for various cis-disubstituted and tri-substituted cyclopropanes. The acyloxy group in the propargyl ester starting material not only eliminated the need for the pre-formation of allenes but also provided a useful handle for further selective functionalizations of the cyclohexenone products.

4. EXPERIMENTAL SECTION

All reactions were conducted under a positive pressure of dry argon in glassware that had been oven dried prior to use. Anhydrous solutions of reaction mixtures were transferred via an oven dried syringe or cannula. All solvents were dried prior to use unless noted otherwise. Thin layer chromatography (TLC) was performed using precoated silica gel plates. Flash column chromatography was performed with silica gel. Infrared spectra (IR) were obtained as neat oils. ¹H and ¹³C nuclear magnetic resonance spectra (NMR) were recorded in ppm (δ) downfield of TMS (δ = 0) in CDCl₃. Signal splitting patterns were described as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint),or multiplet (m), with coupling constants (J) in hertz. High resolution mass spectra (HRMS) were performed on an Electron Spray Injection (ESI) TOF mass spectrometer. Enantiomeric excess was determined by chiral HPLC analysis.

General procedures for the Rh-catalyzed 1,3-acyl migration [5+1] cycloaddition

Method for substrate 1. To an oven-dried flask attached with a CO balloon was added [Rh(CO)₂Cl]₂ (1.9 mg, 0.005 mmol), anhydrous toluene (1 mL), and cyclopropyl propargyl ester (0.1 mmol). The oil bath was heated to 60 °C. The reaction was monitored by TLC. After the reaction is complete, the solvent was evaporated and the residue was purified by flash column chromatography on silica gel.

Method for substrate 3. To an oven-dried vial was added [Rh(CO)₂Cl]₂ (1.9 mg, 0.005 mmol), anhydrous toluene (2 mL), and cyclopropyl propargyl ester (0.1 mmol). The vial was placed in a high pressure reactor which was subsequently filled with 10 atm of CO. The reaction was heated overnight. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel.

General synthetic procedures, characterization data and copies of NMR spectra for substrates in Table 1 (1a, 1c–1i), Table 2 (trans-1j and trans-1n), Table 3 (cis-1j, cis-1k, cis-1n, 1o to 1s), Scheme 6 (1t and 1u) were reported in the previous communication.³

Characterization data and copies of NMR spectra for products in Table 1 (2a–2i), Table 2 (2j, 2k, and 2n), Table 3 (2j to 2s), and Scheme 6 (2t and 2u) were reported in the previous communication.³

1-cyclopropyl-5-phenylpent-1-yn-3-yl acetate (1b)

To an oven-dried flask was added THF (50 mL), cyclopropyl acetylene (10 mmol) and the solution was cooled to −78 °C. n-BuLi (6.3 mL, 10 mmol) was added and the solution was stirred at −78 °C for 10 min. 3-Phenyl propanal (1.3 ml, 10 mmol) was added and the solution was allowed to warm to room temperature. The reaction was quenched with water, extracted with EtOAc for three times, dried over MgSO₄. The solvent was evaporated and the crude alcohol intermediate was used for next step without further purification. To an oven-dried flask was added THF (50 mL) and the above alcohol. The solution was cooled to −78 °C. n-BuLi (6.3 mL, 10 mmol) was added and the solution was stirred for 10 min. PivCl (1.2 mL, 10 mmol) was added dropwise and the solution was allowed to warm to room temperature. The reaction was quenched with water, extracted with EtOAc for three times, and dried over MgSO₄. The solvent was evaporated and the residue was purified by chromatography (EtOAc/Hexane = 1:50) to yield a colorless oil (1.92 g, 79%). ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.70 (m, 2H), δ 0.76 (m, 2H), 1.28 (m, 1H), 2.04 (m, 2H), 2.05 (s, 3H), 2.74 (d, J = 8.0 Hz, 2H), 5.33 (td, J = 6.8, 2.0 Hz, 1H), 7.16 (m, 3H), 7.30 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ −0.4. 8.5, 21.3, 31.5, 36.8, 64.2, 72.7, 89.9, 126.2, 128.55, 128.62, 141.1, 170.2. IR (film): ν 3027, 2936, 2360, 2247, 1738, 1496, 1454, 1369, 1229, 1175, 1018, 958, 909, 813, 730, 699 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₆H₁₈O₂ (M+Na)⁺ 265.1199, found 265.1190.

2,2-Dimethyl-propionic acid 3-(2-hydroxymethyl-cyclopropyl)-1,1-dimethyl-prop-2-ynyl ester (trans-1k)

To a solution of trans-1n³ (1.19 g, 3.0 mmol) in THF (45 ml) at 0 °C was added a solution of TBAF in THF (1.2 ml, 3.6 mmol, 3M). The solution was warmed to room temperature and stirred overnight. The reaction was quenched with water, extracted with EtOAc for three times, and dried over MgSO₄. The solvent was evaporated and the residue was purified by chromatography (EtOAc/Hexane = 1:4) to yield a colorless oil (661 mg, 92%). ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.73 (ddd, J = 8.8, 5.6, 4.4 Hz, 1H), 0.88 (dt, J = 8.8, 4.8 Hz, 1H), 1.16 (s, 9H), 1.20 (m, 1H), 1.42 (m, 1H), 1.59 (s, 6H), 1.75 (br, 1H), 3.49 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 5.3, 13.2, 24.4, 27.2, 29.32, 29.35, 39.3, 65.5, 72.2, 76.9, 86.2, 177.0 IR (film): ν 2981, 2241, 1733, 1288, 1176, 1128, 1062, 1028 cm⁻¹. HRMS (ESI) m/z calcd. For C₁₄H₂₂O₃ (M+Na)⁺ 261.1461, found 261.1465.

2,2-Dimethyl-propionic acid 3-(2-methoxymethyl-cyclopropyl)-1,1-dimethyl-prop-2-ynyl ester (trans-1l)

To an oven dried flask was added NaH (15mg, 0.37 mmol) and THF (1.25ml). The solution was cooled to 0 °C and trans-1k (40 mg, 0.17 mmol) was added. The solution was stirred at 0 °C for 0.5h, raised to room temperature, and stirred for 1h. MeI (52 uL, 0.84 mmol) was added and the reaction was stirred for another hour. The reaction was quenched with saturated NH₄Cl, extracted with EtOAc and dried over MgSO4. The solvent was evaporated and the residue was purified by flash chromatography (EtOAc/Hexane = 1:20) to provide 12.1 mg (29%) of product as a colorless oil. ¹H NMR (500 MHz, CDCl₃, TMS): δ 0.71 (ddd, J = 8.5, 5.5, 4.5 Hz, 1H), 0.88 (dt, J = 8.5, 4.5 Hz, 1H), 1.16 (s, 9H), 1.17 (m, 1H), 1.38 (m, 1H), 1.59 (s, 6H), 3.25 (m, 2H), 3.33 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 5.5, 13.5, 21.7, 27.3, 29.4, 39.3, 58.7, 72.3, 75.2, 77.7, 86.1, 176.9. IR (film): ν 2984, 2244, 1734, 1115 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₅H₂₄O₃ (M+Na)⁺ 275.1618, found 275.1624.

2,2-Dimethyl-propionic acid 3-(2-acetoxymethyl-cyclopropyl)-1,1-dimethyl-prop-2-ynyl ester (trans-1m)

To a solution of trans-1k (42 mg, 0.17 mmol), pyridine (0.84 ml, 10.4 mmol), DMAP (17 mg, 0.14 mmol) was added acetyl chloride (0.12 ml, 1.68 mmol) at 0 °C. The solution was allowed to room temperature and stirred for 2h. The solvent was evaporated and the residue was purified by chromatography (EtOAc/Hexane = 1:20) to yield a colorless oil (46 mg, 98%). ¹H NMR (500 MHz, CDCl₃, TMS): δ 0.80 (ddd, J = 9.0, 6.0, 5.0 Hz, 1H), 0.94 (dt, J = 9.0, 5.0 Hz, 1H), 1.20 (s, 9H), 1.27 (m, 1H), 1.48 (m, 1H), 1.62 (s, 6H), 2.10 (s, 3H), 3.91 (dd, J = 11.5, 7.0 Hz,1H), 3.99 (d, J = 11.5, 7.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 5.9, 13.8, 20.8, 21.2, 27.3, 29.4, 39.3, 67.0, 72.1, 78.0, 85.5, 171.3, 176.9. IR: ν 2976, 2243, 1733, 1231, 1116 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₆H₂₄O₄ (M+Na)⁺ 303.1566, found 303.1571.

2,2-Dimethyl-propionic acid 6-isopropylidene-3-methoxymethyl-5-oxo-cyclohex-1-enyl ester (2l)

Yield 8.0 mg, 68%; colorless oil. ¹H NMR (500 MHz, CDCl₃, TMS): δ 1.27 (s, 9H), 1.98 (s, 3H), 2.15 (s, 3H), 2.40 (dd, J = 16.5, 8.5 Hz, 1H), 2.56 (dd, J = 16.0, 5.5 Hz, 1H), 2.83 (m, 1H), 3.35 (s, 3H), 3.35 (m, 2H), 5.55 (d, J = 4.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 24.5, 25.4, 27.5, 32.9, 39.3, 41.9, 59.2, 75.3, 118.5, 128.4, 147.3, 147.8, 176.6, 200.6. IR (film): ν 2983, 1749, 1692, 1109, 916 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₆H₂₄O₄ (M+Na)⁺ 303.1567, found 303.1572.

2,2-Dimethyl-propionic acid 3-acetoxymethyl-6-isopropylidene-5-oxo-cyclohex-1-enyl ester (2m)

Yield 36.0mg, 78%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 1.27 (s, 9H), 1.99 (s, 3H), 2.05 (s, 3H), 2.16 (s, 3H), 2.42 (dd, J = 16.4, 7.6 Hz, 1H), 2.62(dd, J = 16.4, 5.6 Hz, 1H), 2.89 (m, 1H), 4.06 (d, J = 6.4 Hz, 2H), 5.52 (d, J = 6.0 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 21.0, 24.5, 25.4, 27.4, 31.9, 39.3, 41.7, 66.1, 117.0, 128.1, 148.3, 148.4, 171.1, 176.4, 199.8. IR: ν 2974, 1744, 1692, 1229, 1116 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₇H₂₄O₅ (M+Na)⁺ 331.1516, found 331.1525.

General procedures for the synthesis of compound 3

To an oven-dried flask was added THF (0.2 M), diisopropylamine (1.0 equiv) and the solution was cooled to 0 °C. A solution of n-BuLi (1.0 equiv) was added and the resulting mixture was stirred at 0 °C for 10 min and then cooled to −78 °C. The alkyne (1.0 equiv) was added dropwise and stirred for 30 min. The aldehyde or ketone (1.0 equiv) was added and the solution was allowed to warm to room temperature. The reaction was quenched with water, extracted with EtOAc for 3 times, dried over MgSO₄. The solvent was evaporated and the crude alcohol intermediate was used for next step without purification. To an oven-dried flask was added THF (0.2 M) and the above alcohol. The solution was cooled to −78 °C. A solution of n-BuLi (1.0 equiv) was added and the solution was stirred for 10 min. PivCl or acetic anhydride (1.1 equiv) was added dropwise and the solution was allowed to warm to room temperature. The reaction was quenched with water, extracted with EtOAc for three times, and dried over MgSO₄. The solvent was evaporated and the residue was purified by chromatography.

6-phenyl-1-(1-((triisopropylsilyl)oxy)cyclopropyl)hex-2-yn-1-yl pivalate (3a)

Yield 174 mg, 88%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.77–0.97 (m, 4H), 0.94 (t, J = 7.2 Hz, 3H), 1.04 (m, 21H), 1.22 (s, 9H), 1.49 (tq, J = 7.2, 7.2 Hz, 2H), 2.13 (td, J = 7.2, 2.0 Hz, 2H), 6.00 (t, J = 2.0 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 11.3, 12.8, 13.0, 13.5, 18.30, 18.32, 20.9, 22.0, 27.2, 39.0, 58.2, 69.5, 76.1, 86.0, 177.7. IR (film): ν 2964, 2868, 1723, 1462, 1279, 1216, 1145, 1044, 1015, 955, 882, 668 cm⁻¹. HRMS (ESI) m/z calcd. for C₂₃H₄₂O₃Si (M+Na)⁺ 417.2795, found 417.2791.

1-cyclopropyl-4,4-dimethylpent-2-yn-1-yl pivalate (3b)

Yield 484 mg, 62%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.38–0.55 (m, 4H), 1.19 (s, 9H), 1.19 (m, 1H), 1.21 (s, 9H), 5.30 (d, J = 6.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 1.9, 3.1, 14.4, 27.2, 27.5, 31.0, 38.9, 67.5, 74.1, 94.4, 177.7. IR (film): ν 2971, 2361, 1727, 1479, 1364, 1279, 1152, 1029, 954, 849, 667 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₅H₂₄O₂ (M+Na)⁺ 259.1668, found 259.1662.

2-cyclopropyl-7-phenylhept-3-yn-2-yl pivalate (3c)

Yield 986 mg, 79%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.50 (m, 3H), δ 0.72 (m, 1H), 1.18 (s, 9H), 1.34 (m, 1H), 1.73 (s, 3H), 1.78 (m, 2H), 2.19 (t, J = 8.5 Hz, 2H), 2.70 (t, J = 10.0 Hz, 2H), 7.18 (m, 3H), 7.27 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 2.3, 3.0, 18.2, 20.4, 27.3, 27.6, 30.6, 34.8, 39.4, 77.5, 78.7, 85.3, 126.0, 128.5, 128.8, 141.9, 176.8. IR (film): ν 2983, 2360, 1732, 1478, 1455, 1363, 1281, 1141, 1070, 1051, 927, 743, 699 cm⁻¹. HRMS (ESI) m/z calcd. for C₂₁H₂₈O₂ (M+Na)⁺ 335.1982, found 335.1994.

2-cyclopropyl-7-phenylhept-3-yn-2-yl acetate (3d)

Yield 165 mg, 60%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.50 (m, 3H), δ 0.72 (m, 1H), 1.37 (m, 1H), 1.75 (s, 3H), 1.78 (m, 2H), 2.02 (s, 3H), 2.19 (t, J = 7.2 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 7.18 (m, 3H), 7.27 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 2.5, 3.3, 18.3, 20.1, 22.4, 27.7, 30.5, 34.9, 78.0, 78.7, 85.9, 126.1, 128.5, 128.7, 141.8, 169.6. IR (film): ν 2936, 1737, 1366, 1238, 1148, 1071, 1012, 910, 699 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₈H₂₂O₂ (M+Na)⁺ 293.1512, found 293.1526.

2-cyclopropyl-6-((triisopropylsilyl)oxy)hex-3-yn-2-yl pivalate (3e)

Yield 429 mg, 47%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.48 (m, 3H), δ 0.68 (m, 1H), 1.06 (m, 21H), 1.17 (s, 9H), 1.34 (m, 1H), 1.70 (s, 3H), 2.43 (t, J = 7.2 Hz, 2H), 3.75 (t, J = 7.2 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 2.3, 2.9, 12.2, 18.2, 20.3, 23.4, 27.3, 27.5, 39.4, 62.3, 77.6, 79.0, 82.7, 176.9. IR (film): ν 2958, 2867, 1736, 1462, 1366, 1283, 1143, 1109, 1071, 917, 856, 681 cm⁻¹. HRMS (ESI) m/z calcd. for C₂₃H₄₂O₃Si (M+Na)⁺ 417.2795, found 417.2790.

5-cyclopropylhex-3-yne-1,5-diyl bis(2,2-dimethylpropanoate) (3f)

Yield 50.7 mg, 79%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.48 (m, 3H), δ 0.68 (m, 1H), 1.17 (s, 9H), 1.21 (s, 9H), 1.34 (m, 1H), 1.70 (s, 3H), 2.52 (t, J = 6.8 Hz, 2H), 4.11 (t, J = 6.8 Hz, 2H). ¹³C NMR (125 MHz, CDCl₃): δ 2.3, 3.0, 19.4, 20.3, 27.3, 27.4, 27.5, 38.9, 39.4, 62.5, 77.5, 79.5, 81.4, 176.8, 178.5. IR (film): ν 2975, 1730, 1480, 1281, 1143, 1071, 769 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₉H₃₀O₄ (M+Na)⁺ 345.2036, found 345.2032.

2-(1-methylcyclopropyl)hept-3-yn-2-yl pivalate (3g)

Yield 52.3 mg, 72%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.25(m, 1H), δ 0.33(m, 1H), δ 0.73 (m, 1H), 0.94 (t, J = 7.2 Hz, 3H), 1.02 (m, 1H), 1.12 (s, 3H), 1.16 (s, 9H), 1.48 (m, 2H), 1.67 (s, 3H), 2.13 (t, J = 6.8 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 11.0, 12.6, 13.5, 19.8, 20.8, 22.3, 22.9, 25.0, 27.3, 39.6, 78.6, 79.0, 85.3, 176.4. IR (film): ν 2965, 2361, 1738, 1284, 1158, 1065, 913, 873, 860, 658 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₆H₂₆O₂ (M+Na)⁺ 273.1825, found 273.1824.

(R)-1-((1S,2S)-2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropyl)-6-phenylhex-2-yn-1-yl pivalate (3h)

Yield 50.3mg, 38%; colorless oil. ¹H NMR (500 MHz, CDCl₃, TMS): δ 0.34 (t, J = 5.0 Hz, 1H), 0.67 (t, J = 9.0, 5.0 Hz, 1H), 1.01 (m, 1H), 1.02 (s, 3H), 1.15 (ddd, J = 10.0, 9.0, 5.0 1H), 1.23 (s, 9H), 1.40 (ddd, J = 13.5, 10.5, 7.0 Hz, 1H), 1.60 (s, 3H), 1.67 (s, 3H). 1.81 (pentet, J = 7.0 Hz, 2H), 2.03 (m, 2H), 2.21 (td, J = 7.0, 2.0 Hz, 2H), 2.71 (t, J = 7.0 Hz, 2H), 4.88 (dt, J = 10.0, 2.0 Hz, 1H), 5.10 (tt, J = 7.0, 1.5 Hz, 1H), 7.16–7.30 (m, 5H). ¹³C NMR (125 MHz, CDCl₃): δ 17.4, 17.8, 18.3, 18.7, 21.5, 25.5, 25.9, 27.3, 28.4, 30.3, 34.8, 38.8, 41.2, 66.0, 79.1, 84.5, 124.6, 126.1, 128.5, 128.8, 131.6, 141.8, 177.3. IR (film): ν 2929, 2359, 1729, 1454, 1287, 1149, 1134, 934, 745, 698 cm⁻¹. HRMS (ESI) m/z calcd. for C₂₇H₃₈O₂ (M+Na)⁺ 417.2764, found 417.2746.

1-cyclopropyl-6-phenylhex-2-yn-1-yl acetate (3i)

Yield 526 mg, 78%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.51 (m, 4H), δ 1.26 (m, 1H), 1.81 (pentet, J = 7.2 Hz, 2H), 2.10 (s, 3H), 2.21 (td, J = 7.2, 2.0 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 5.28 (dt, J = 8.0, 2.0 Hz, 1H), 7.19 (m, 3H), 7.27(m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 2.3, 3.6, 14.7, 18.3, 21.4, 30.3, 34.9, 68.1, 76.2, 86.1, 126.1, 128.6, 128.7, 141.7, 170.4. IR (film): ν 2938, 1735, 1496, 1454, 1367, 1230, 1026, 965, 894, 746, 699 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₇H₂₀O₂ (M+Na)⁺ 279.1355, found 279.1344.

1-cyclopropyl-3-phenylprop-2-yn-1-yl pivalate (3j)

Yield 494 mg, 77%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.58 (m, 4H), δ 1.24 (s, 9H), 1.36 (m, 1H), 5.43(d, J = 6.8 Hz, 1H), 7.30(m, 3H), 7.42(m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 2.4, 3.5, 14.9, 27.3, 39.0, 67.7, 85.1, 85.2, 122.6, 128.4, 128.7, 132.1, 177.8. IR (film): ν 2973, 1728, 1490, 1479, 1277, 1144, 1070, 1029, 697 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₇H₂₀O₂ (M+Na)⁺ 279.1355, found 279.1353.

1-(6-oxo-3-((triisopropylsilyl)oxy)cyclohex-2-en-1-ylidene)-4-phenylbutyl pivalate (4a, a mixture E and Z isomers)

Yield 42.8 mg, 70%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.93 (m, 3H), δ 0.93 (m, 3H), 1.09 (m, 21H), 1.09 (m, 21H), 1.30 (s, 9H), 1.30 (s, 9H), 1.50 (m, 2H), 1.50 (m, 2H), 2.21 (t, J = 7.6 Hz, 2H), 2.55 (m, 2H), 2.55 (m, 4H), 2.66 (m, 2H), 2.66 (m, 2H), 5.61 (s, 1H), 5.65 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 12.7, 12.9, 14.1, 18.10, 18.11, 20.0, 21.0, 27.3, 29.6, 29.9, 33.6, 39.2, 39.4, 39.7, 40.3, 102.7, 103.2, 121.0, 122.0, 147.9, 153.0, 153.69, 153.74, 175.7, 176.6, 197.3, 199.3. IR (film): ν 2962, 2868, 1744, 1701, 1638, 1598, 1462, 1375, 1253, 1107, 998, 881, 684, 666 cm⁻¹. HRMS (ESI) m/z calcd. for C₂₄H₄₂O₄Si (M+Na)⁺ 445.2744, found 445.2734.

2,2-dimethyl-1-(6-oxocyclohex-2-en-1-ylidene)propyl pivalate (4b, a mixture E and Z isomers)

Yield 70 mg, 72%; colorless oil. ¹H NMR (500 MHz, CDCl₃, TMS): δ 1.17 (s, 9H), δ 1.21 (s, 9H), 1.23 (s, 9H), 1.33 (s, 9H), 2.38 (m, 4H), 2.60 (m, 4H), 5.74 (m, 1H), 5.79 (dt, J = 10.0, 4.0 Hz, 1H), 5.84 (m, 1H), 6.10 (dt, J = 10.0, 1.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 23.3, 25.4, 26.9, 27.1, 27.5, 28.4, 28.8, 37.9, 39.0, 39.5, 41.5, 44.7, 122.5, 124.0, 125.1, 125.2, 125.3, 128.5, 145.8, 159.0, 175.9, 176.1, 202.4, 210.4. IR (film): ν 2970, 1746, 1694, 1478, 1122, 1096, 731, 707 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₆H₂₄O₃ (M+Na)⁺ 287.1617, found 287.1610.

(E)-1-(2-methyl-6-oxocyclohex-2-en-1-ylidene)-4-phenylbutyl pivalate (E-4c)

Yield 37.3 mg, 55%; colorless oil. ¹H NMR (500 MHz, CDCl₃, TMS): δ 1.23 (s, 9H), δ 1.86 (m, 2H), 1.89 (q, J = 1.5 Hz, 3H), 2.38(m, 2H), 2.49 (t, J = 7.5 Hz, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 8.0 Hz, 2H), 5.73 (tq, J = 4.5, 1.5 Hz, 1H), 7.16 (m, 3H), 7.26 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ 22.5, 23.9, 27.3, 29.9, 32.8, 35.8, 38.9, 39.4, 126.0, 127.5, 128.2, 128.5, 128.6, 132.5, 142.2, 155.9, 175.9, 203.1. IR (film): ν 2972, 1744, 1696, 1603, 1454, 1269, 1104, 910, 731, 699 cm⁻¹. HRMS (ESI) m/z calcd. for C₂₂H₂₈O₃ (M+Na)⁺ 363.1931, found 363.1938.

(Z)-1-(2-methyl-6-oxocyclohex-2-en-1-ylidene)-4-phenylbutyl pivalate (Z-4c)

Yield 21.3 mg, 31%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 1.18 (s, 9H), δ 1.67 (d, J = 1.2 Hz, 3H), 1.92 (pentet, J = 7.6 Hz, 2H), 2.29(m, 4H), 2.55 (t, J = 7.6 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H), 5.49 (m, 1H), 7.17 (m, 3H), 7.27 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 19.5, 23.1, 25.4, 26.1, 27.1, 35.4, 39.1, 43.9, 121.3, 126.2, 128.4, 128.59, 128.63, 129.0, 141.7, 148.0, 176.2, 205.0. IR (film): ν 2935, 1748, 1697, 1453, 1364, 1276, 1252, 1229, 1107, 909, 730, 699 cm⁻¹. HRMS (ESI) m/z calcd. for C₂₂H₂₈O₃ (M+Na)⁺ 363.1931, found 363.1945.

1-(2-methyl-6-oxocyclohex-2-en-1-ylidene)-4-phenylbutyl acetate (4d, a mixture E and Z isomers)

Yield 36.3 mg, 84%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 1.68 (q, J = 1.2 Hz, 3H), δ 1.84 (m, 2H), 1.92 (s, 3H), 1.94(m, 2H), 2.03 (s, 3H), 2.15 (s, 3H), 2.27 (m, 2H), 2.36 (m, 4H), 2.48(m, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.64 (m, 6H), 5.50 (m, 1H), 5.76 (tq, J = 4.8, 1.2 Hz, 1H), 7.18(m, 3H), 7.18(m, 3H), 7.27 (m, 2H), 7.27 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 19.6, 20.9, 21.4, 22.1, 23.1, 23.7, 25.4, 26.3, 29.5, 32.7, 35.3, 35.7, 38.7, 43.7, 121.5, 126.0, 126.2, 127.2, 128.49, 128.57, 128.58, 128.65, 128.8, 129.0, 132.2, 141.7, 142.2, 148.3, 155.5, 168.1, 168.4, 202.9, 204.7. IR (film): ν 2941, 1762, 1695, 1602, 1453, 1367, 1208, 1187, 1037, 1013, 700 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₉H₂₂O₃ (M+Na)⁺ 321.1461, found 321.1482.

1-(2-methyl-6-oxocyclohex-2-en-1-ylidene)-3-((triisopropylsilyl)oxy)propyl pivalate (4e, a mixture E and Z isomers)

Yield 39 mg, 91%; colorless oil. ¹H NMR (500 MHz, CDCl₃, TMS): δ 1.10 (m, 21H), δ 1.10 (m, 21H), 1.29 (s, 9H), 1.33 (s, 9H), 1.77(s, 3H), 1.95 (q, J = 1.5Hz, 3H), 2.33 (m, 4H), 2.42 (m, 2H), 2.53 (m, 2H), 2.84(m, 4H), 3.91 (t, J = 7.0 Hz, 2H), 4.03 (t, J = 6.5 Hz, 2H), 5.54 (m, 1H), 5.78 (m, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 12.1, 12.2, 18.16, 18.19, 19.6, 22.5, 23.1, 23.8, 26.3, 27.2, 27.3, 37.4, 38.7, 39.2, 39.4, 47.9, 59.0, 62.1, 121.2, 128.3, 128.5, 129.5, 132.4, 148.7, 153.4, 176.0, 176.1, 202.8, 203.4. IR (film): ν 2942, 2866, 1747, 1698, 1462, 1382, 1271, 1096, 1027, 935, 881, 680 cm⁻¹. HRMS (ESI) m/z calcd. for C₂₄H₄₂O₄Si (M+Na)⁺ 445.2744, found 445.2735.

(E)-1-(2-methyl-6-oxocyclohex-2-en-1-ylidene)propane-1,3-diyl bis(2,2-dimethylpropanoate) (E-4f)

Yield 41.0mg, 84% combined yield; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 1.10 (s, 9H), δ 1.29 (s, 9H), 1.91 (q, J = 1.6Hz, 3H), 2.40 (m, 2H), 2.51 (t, J = 6.8 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H), 4.22 (t, J = 7.2 Hz, 2H), 5.78 (tq, J = 4.8, 1.6 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 22.4, 23.7, 27.3, 27.4, 32.9, 38.6, 38.8, 39.4, 62.1, 128.9, 130.0, 132.2, 151.7, 176.0, 178.5, 202.6. IR (film): ν 2971, 1727, 1698, 1281, 1147, 1097, 1031 cm⁻¹. HRMS (ESI) m/z calcd. For C₂₀H₃₀O₅ (M+Na)⁺ 373.1985, found 373.1979.

(Z)-1-(2-methyl-6-oxocyclohex-2-en-1-ylidene)propane-1,3-diyl bis(2,2-dimethylpropanoate) (Z-4f)

Yield 41.0mg, 84% combined yield; colorless oil. ¹H NMR (500 MHz, CDCl₃, TMS): δ 1.17 (s, 9H), δ 1.25 (s, 9H), 1.72 (q, J = 1.5Hz, 3H), 2.31 (m, 4H), 2.89 (t, J = 6.5 Hz, 2H), 4.34 (t, J = 6.5 Hz, 2H), 5.52 (m, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 19.6, 23.1, 26.4, 27.2, 27.4, 38.9, 39.2, 43.3, 59.5, 121.6, 127.9, 129.1, 149.5, 176.1, 178.5, 201.4. IR (film): ν 2973, 1726, 1480, 1363, 1282, 1151, 1106, 133, 909, 729 cm⁻¹. HRMS (ESI) m/z calcd. for C₂₀H₃₀O₅ (M+Na)⁺ 373.1985, found 373.1979.

(E)-1-(2,3-dimethyl-6-oxocyclohex-2-en-1-ylidene)butyl pivalate (E-4g)

Yield 30.3mg, 52%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.93 (t, J = 7.6 Hz, 3H), δ 1.28 (s, 9H), 1.52 (sextet, J = 7.6 Hz, 2H), 1.78 (s, 3H), 1.79 (s, 3H), 2.31 (m, 2H), 2.39 (m, 2H), 2.55 (t, J = 7.6 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 13.9, 17.8, 19.9, 21.3, 27.4, 29.4, 33.9, 37.6, 39.3, 124.5, 129.5, 134.7, 154.2, 175.5, 204.0. IR (film): ν 2963, 1744, 1696, 1608, 1479, 1461, 1273, 1101, 1027, 914, 731 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₇H₂₆O₃ (M+Na)⁺ 301.1774, found 301.1771.

(S)-1-(4-methyl-4-(4-methylpent-3-en-1-yl)-6-oxocyclohex-2-en-1-ylidene)-4-phenylbutyl pivalate (4h, a mixture E and Z isomers)

Yield 67 mg, 62%; colorless oil. ¹H NMR (500 MHz, CDCl₃, TMS): δ 1.06 (s, 3H), 1.28 (s, 9H), 1.37 (m, 2H), 1.57 (s, 3H), 1.65 (s, 3H), 1.83 (m, 2H), 1.93 (m, 2H), 2.37 (m, 1H), 2.37 (d, J = 14.0 Hz, 1H), 2.56 (d, J = 14.0, 1H), 2.65 (t, J = 8.0 Hz, 2H), 2.80 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 5.05 (m, 1H), 5.72 (d, J = 10.0 Hz, 1H), 6.21 (d, J = 10.0 Hz, 1H), 7.16–7.30 (m, 5H). The two isomers have nearly identical ¹H NMR. ¹³C NMR (125 MHz, CDCl₃): δ 17.8, 23.3, 25.84, 25.85, 27.27, 27.34, 29.2, 31.8, 35.4, 35.8, 39.3, 39.5, 39.9, 42.4, 53.3, 120.8, 122.3, 124.2, 126.0, 126.2, 128.5, 128.58, 128.60, 132.0, 138.2, 142.2, 157.5, 175.7, 176.0, 200.0. IR (film): ν 2967, 1712, 1454, 1361, 1220, 1123, 914, 732, 700 cm⁻¹. HRMS (ESI) m/z calcd. for C₂₈H₃₈O₃ (M+Na)⁺ 445.2613, found 445.2607.

1-cyclopropyl-3-phenylpropa-1,2-dienyl pivalate (8d)

Yield 49 mg, 49%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 0.62–0.64 (m, 2H), 0.75–0.78 (m, 2H), 1.26 (s, 9H), 1.54–1.60 (m, 1H), 6.59 (d, J = 2.0 Hz, 1H), 7.24–7.26 (m, 1H), 7.31–7.35 (m, 2H), 7.41–7.43 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 5.8, 6.3, 12.3, 27.4, 39.4, 105.0, 128.1, 128.2, 128.5, 128.9, 134.2, 176.2, 196.8. HRMS (ESI) m/z calcd. for C₁₇H₂₀O₂ (M+Na)⁺ 279.1356, found 279.1360.

General Procedures for the synthesis of compound 13 and 14

To an oven-dried flask was added [Rh(CO)₂Cl]₂ (2 mol %), anhydrous toluene (0.1 M), and 1 equiv of cyclopropyl propargyl ester. The oil bath was heated to 60 °C. The reaction was monitored by TLC. After the reaction is complete, the solvent was evaporated and the residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 50:1).

2-(propan-2-ylidene)-2,4,5,6,7,7a-hexahydro-1H-inden-3-yl pivalate (13)

Yield 35 mg, 89%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 1.03–1.12 (m, 2H), 1.19–1.28 (m, 2H), 1.31 (s, 9H), 1.64 (s, 3H), 1.70–1.82 (m, 5H), 1.91–1.98 (m, 1H), 2.06 (d, br, J = 16.0 Hz, 1H), 219–2..23 (m, 1H), 2.42–2.50 (m, 1H), 2.73 (dd, J = 16.0, 8.0 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 19.3, 23.2, 25.3, 26.0, 26.2, 27.7, 35.2, 35.7, 39.3, 39.4, 119.2, 131.2, 138.0, 142.5, 176.3. IR: ν 2976, 2930, 2858, 2360, 2342, 1751, 1120. HRMS (ESI) m/z calcd. for C₁₇H₂₆O₂ (M+1) 263.2006, found 263.2017.

1-(propan-2-ylidene)-3a,4,5,7a-tetrahydro-1H-inden-2-yl pivalate (14)

Yield 44 mg, 82%; colorless oil. ¹H NMR (400 MHz, CDCl₃, TMS): δ 1.27 (s, 9H), 1.62–1.71 (m, 2H), 1.79 (s, 3H), 1.84 (s, 3H), 1.87–1.91 (m, 1H), 2.04–2.13 (m, 1H), 3.14 (s, br, 1H), 3.44 (s, br, 1H), 5.51–5.52 (m, 1H), 5.54 (s, 1H), 5.70–5.81 (m, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 20.2, 21.1, 23.0, 24.8, 27.4, 37.8, 39.4, 41.3, 123.4, 124.1, 127.6, 127.7, 134.8, 151.4, 176.4. IR: ν 2977, 2362, 2343, 1712, 1362, 1222. HRMS (ESI) m/z calcd. for C₁₇H₂₄O₂ (M+1) 261.1849, found 261.1840.

3-methyl-2-(4-phenylbutanoyl)cyclohex-2-enone (17d)

To a round bottom flask was added compound 4d (60.2 mg, 0.20 mmol), 2 mL of MeOH, and K₂CO₃ (28 mg, 0.2 mmol). The reaction was stirred for 10 min. About 5 mL of Et₂O and 5 mL of H₂O were added and the aqueous phase was extracted with 5 mL of Et₂O for 3 times. The combined organic solution was dried over MgSO₄, evaporated under vacuum and the residue was purified by flash column chromatography (EtOAc/Hexane = 1:4) to provide a colorless oil (40.2 mg, 0.144 mmol, 72% yield). ¹H NMR (400 MHz, CDCl₃, TMS): δ 1.89 (s, 3H), 1.97 (m, 4H), 2.39 (m, 4H), 2.64 (q, J = 7.2 Hz, 4H), 7.18 (m, 3H), 7.27 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 21.9, 22.0, 25.3, 32.3, 35.4, 37.6, 43.7, 126.1, 128.5, 128.7, 139.9, 142.0, 159.6, 197.2, 207.0. IR (film): ν 2931, 2360, 1698, 1661, 1378, 1181, 907, 727, 700 cm⁻¹. HRMS (ESI) m/z calcd. for C₁₇H₂₀O₂ (M+Na)⁺ 279.1356, found 279.1355.