Diastereoselective intramolecular oxidopyrylium–alkene [5 + 2]-cycloaddition of substrates with a β-chiral center on alkene tethers: synthesis of 8-oxabicyclo-[3.2.1]-octenone heterocycles

Abstract

We investigated the asymmetric intramolecular oxidopyrylium–alkene [5 + 2]-cycloaddition reaction of substrates bearing tethered alkenes containing β-chiral centers. The effect on the cycloadduct diastereoselectivity was examined for carbon chain tethered alkenes or alkoxy tethered alkenes with varying chain lengths that can form 5-, 6- and 7-membered rings. We also probed the effect of varying steric bulk on the β-chiral center substituents on cycloadduct diastereoselectivity. Various substrates with carbon chain tethered alkenes were synthesized using the Lewis acid mediated conjugate addition of an allyl group to furanyl enones. Reduction of the resulting ketones followed by the Achmatowicz reaction of furanyl alcohol provided oxidopyrylium–alkene substrates. The asymmetric [5 + 2]-cycloaddition proceeded with high diastereoselectivity for cycloadducts with five and six-membered rings. However, cycloadducts with a seven-membered ring showed no diastereoselectivity. Stereochemical models are provided to explain the high diastereoselectivity for five and six-membered products.

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Introduction

The oxidopyrylium–alkene [5 + 2]-cycloaddition provides convenient access to functionalized 8-oxabicyclo-[3.2.1]-octenone heterocycles with multiple stereogenic centers.^1,2 Over the years, the gradual development of these cycloaddition reactions led to their practical applications in organic synthesis.^3,4 In particular, these seven-membered ring systems containing an oxygen bridge have been utilized in the synthesis of natural products.^5,6 These intramolecular oxidopyrylium–alkene [5 + 2]-cycloadditions are especially attractive as the resulting cycloadducts conveniently generate a highly functionalized oxa-bridged bicyclic framework for a variety of synthetic and medicinal chemistry applications.^7–9 Despite their potential uses, the development of asymmetric intramolecular oxidopyrylium–alkene cycloaddition is relatively underexplored.^2,7,10 The early examples of asymmetric intramolecular cycloaddition reactions with chiral centers on the tether include the synthesis of (+)-phorbol by Wender and co-workers, as shown in Fig. 1.^11,12 Asymmetric [5 + 2]-cycloaddition of acetate derivative 1 containing α- and β-chiral centers on the side chain alkene tether was carried out to provide cycloadduct 2 as a single diastereomer in excellent yield.^11,12 The cycloadduct was later converted to (+)-phorbol, which is a tumor promoting agent that activates protein kinase C.¹³ Mascareñas and coworkers examined asymmetric induction of alkenesulfinyl substrate 3 to provide the product cycloadduct 4 with high diastereoselectivity (dr 97 : 3) and excellent yield.^14,15 Trivedi and co-workers reported an asymmetric [5 + 2]-cycloaddition of isopropylidene derivative 5 containing α, β, and γ-chiral centers on the side chain tether.¹⁶ This reaction proceeded with excellent diastereoselectivity (dr 97 : 3) and good yield, affording cycloadduct 6. Subsequently, other intermolecular and intramolecular asymmetric oxidopyrylium–alkene cycloaddition reactions have been reported.^17–23 We recently investigated the intramolecular asymmetric oxidopyrylium–alkene [5 + 2]-cycloaddition of substrates that contain an α-alkoxy chiral center 7, which provided cycloadduct 8 with high diastereoselectivity and isolated yield.²⁴ In a systematic study, we investigated the effect of the size of alkyl groups on the α-chiral center and the alkoxy alkene tether length on diastereoselectivity.²⁴ We now investigate the ability of substrates 9 with alkene tethers and alkoxy alkene tethers containing a β-chiral center to direct [5 + 2]-cycloaddition reactions to provide 10. The effect on the cycloadduct diastereoselectivity was examined for varying chain lengths that can form 5-, 6-, and 7-membered rings. We also examined the effect of steric bulk on the β-chiral center substituents on cycloadduct diastereoselectivity.

Fig. 1 Prior works on asymmetric intramolecular oxidopyrylium–alkene [5 + 2]-cycloaddition of substrates.

Results and discussion

In this work, we investigate intramolecular oxidopyrylium–alkene [5 + 2]-cycloaddition of substrates containing a β-alkyl or aryl substituted alkene tether that would form new five to seven membered exocyclic rings on 8-oxabicyclo-[3.2.1]-octenone heterocycles, as shown in Scheme 1. Upon exposure to a base, substrates 9 leads to oxidopyrylium ylide 11, which undergoes [5 + 2]-cycloaddition to provide cycloadduct 10. We postulate that the cycloaddition proceeds diastereoselectively through transition state 11, wherein the bulky alkyl or aryl substituent will occupy a pseudo-equatorial or equatorial position depending upon the ring size to avoid developing non-bonded interactions. We expect that the stereochemical outcome will be influenced by the size of the alkyl or aryl substituents as well. We planned to investigate the cycloadduct diastereoselectivity associated with substrates containing varying tether lengths and substituent sizes.

Scheme 1 Basic strategy for [5 + 2]-cycloadditions with alkene and alkoxy alkene tethers containing a β-chiral center.

Our synthesis of various substrates containing the β-substituent leading to the formation of a 5-membered exocyclic cyclopentane ring is shown in Scheme 2. Our synthetic plan was to carry out conjugate addition to elongate the allyl chain using readily available enones 12. However, initial attempts under Gilman conditions with enone 12a were unsuccessful, providing only trace amounts of the conjugate addition product 13a, as shown in Table 1 (entries 1–3).^25,26 The reaction of 13a with allyl magnesium bromide in the presence of the CuBr.DMS complex in THF at −78 °C to 0 °C resulted in tertiary alcohol 15 with 68% yield (entry 3). We attempted the traditional Sakurai–Hosomi reaction^27,28 using allyltrimethylsilane in the presence of TiCl₄, which resulted in the desired product 13a with 8% yield (entry 4). Other Lewis acids such as InCl₃, Sc(OTf)₃, or Bi(OTf)₃ did not lead to any improvement in the yield (entries 5–7). However, the reaction of 12a with allyltrimethylsilane in the presence of BF₃·OEt₂ resulted in a conjugate addition product 13a in 39% yield (entry 8). A significant amount of the unreacted starting material was recovered (61% recovery of the starting material). These conditions were then used for reactions with other enones. The reaction of enone 12b with allyltrimethylsilane and BF₃·OEt₂ provided addition product 13b in 29% yield. Similarly, the reaction of enone 12c provided addition product 13c in 50% isolated yield. Reduction of ketones 13a–c with NaBH₄ in MeOH at 23 °C for 2.5 h furnished furyl alcohols 14a–c as a mixture of diastereomers in very good yields. Achmatowicz reactions^29,30 of these alcohols using Oxone in the presence of KBr and NaHCO₃ in aqueous THF (4 : 1) at 0 °C furnished the corresponding lactols, which were reacted with acetyl chloride in the presence of pyridine at 0 °C for 20–30 min to provide acetoxypyranone derivatives 9a–c in good yields over 2 steps (53–67%).

Scheme 2 Syntheses of substrates 9a–c containing all carbon alkene tethers.

Table 1 Optimization of 1,4-addition reactions

Entry	Conditions	Yield 13a (%)	Yield 15 (%)
a 10–30 min reactions. b 61% recovery of the starting material. np: no product.
1	AllylBr, n-BuLi, CuCN, THF, −78 °C to 0 °C	Trace	Trace
2	AllylBr, n-BuLi, CuCN·LiCl, THF, −78 °C to 0 °C	np	np
3	AllylMgBr, CuBr·DMS, THF, −78 °C to 0 °C^a	<5	68
4	AllylTMS, TiCl4, CH2Cl2, −78 °C	8	0
5	InCl3, TMSCl, AllylTMS, CH2Cl2, 23 °C	np	np
6	Sc(OTf)3, AllylTMS, CH2Cl2, 0 °C to 23 °C	np	np
7	Bi(OTf)3, AllylTMS, CH2Cl2, 0 °C to 23 °C	np	np
8	BF3·OEt2, AllylTMS, CH2Cl2, −78 °C to 10 °C	39^b	0

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The synthesis of the β-substituted carbon tethered substrate leading to the formation of a 6-membered ring is shown in Scheme 3. The known diene 16 was prepared using the Horner–Wadsworth–Emmons reaction, as described in the literature.³¹ Exposure of diene 16 to elemental magnesium in MeOH at 65 °C for 4 h resulted in selective 1,4-reduction and ester exchange, providing methyl ester 17 in 59% yield.³² DIBAL-H reduction of 17 at −78 °C in n-pentane for 30 min provided a crude aldehyde. The reaction of the resulting aldehyde with 2-lithiofuran at −78 °C in THF for 30 min provided furanol 18 in 37% yield over 2 steps. Achmatowicz reactions of furanol 18 gave a lactol, which upon reaction with acetyl chloride in the presence of pyridine provided acetoxypyranone 9d in 59% yield over 2 steps.

Scheme 3 Synthesis of substrate 9d with carbon tethers.

The synthesis of various substrates containing alkoxy alkene tethers for the formation of a substituted tetrahydropyran ring is shown in Scheme 4. Various β-hydroxy ketone derivatives 19a–d were prepared using an aldol reaction, as described in the literature.³³ These β-hydroxy ketone derivatives were protected as tetrahydropyran (THP) ethers using 3,4-dihydro-2H-pyran (DHP) and pyridinium p-toluenesulfonate (PPTS) in CH₂Cl₂ at 23 °C for 14–72 h to provide the respective THP ethers 20a–e in good to excellent yields (76–96%). The ketone derivatives were reduced with NaBH₄ in MeOH at 23 °C with high yields. The resulting alcohols were converted to allyl ethers 21a–e with NaH and allyl bromide in THF at 23 °C for 14–22 h in 49–63% yields over two steps. Exposure of 21a–e to DOWEX-50W-X8 resin in MeOH at 23 °C provided the respective furanyl alcohols 22a–e in 34–86% yields. These alcohols were converted to acetoxypyranone derivatives 9e–i by the Achmatowicz reaction,^29,30 followed by protection of the resulting lactols as acetate derivatives in 39–58% yields over two steps.

Scheme 4 Synthesis of various substrates 9e–i containing the alkoxy alkene tethers for six-membered exocyclic rings.

We also planned to explore the stereochemical outcome for the formation of 7-membered exocyclic rings. The synthesis of various requisite substrates is shown in Scheme 5. Commercially available β-hydroxy esters 23a–c were converted to allyl ethers using O-allyl trichloroacetimidate in the presence of a catalytic amount of triflic acid in a mixture (2 : 1) of CH₂Cl₂ and pentanes at 23 °C for 15–19 h to provide allyl ethers 24a–c in 52–74% yields.^34,35 Hydroboration of alkenes with 9-BBN in THF at 23 °C for 1.5–2.5 h, followed by work up with sodium perborate tetrahydrate furnished alcohols 25a–c in 66–99% yields. DMP oxidation of these alcohols afforded the corresponding aldehydes in excellent yields. To extend the chain length, a one-carbon Wittig reaction of the resulting aldehyde from 26a was attempted; however, no alkene product was formed. However, the Peterson olefination provided reproducible results.^36–38 The reaction of aldehydes from 25a–c with TMSCH₂MgBr provided the corresponding addition products. The base-catalyzed elimination was not satisfactory. However, treatment with BF₃·OEt₂ at −78 °C for 1.5 to 3 h resulted in the respective olefins 26a–c in 8–31% yields (3-steps). DIBAL-H reduction followed by reaction of the resulting aldehyde with 2-lithiofuran provided furanols 27a–c in 23–52% yields over two steps. Achmatowicz reactions^29,30 followed by acetylation of the resulting lactols furnished the acetate derivatives 9j–l in 36–77% yields.

Scheme 5 Synthesis of alkoxy alkene substrates 9j–l for 7-membered rings.

For our investigation of [5 + 2]-cycloadditions with β-substitution, we first examined reactions in CH₃CN at low concentration in the presence of N-methylpyrrolidine (NMP) at 60 °C. These conditions were previously used for α-substituted substrates.²⁴ However, no product was formed under these reaction conditions, and the starting material was fully recovered. These reactions with β-substituted acetoxypyranones, in general, required higher temperature and a bit longer reaction time compared to substrates with α-substituted acetoxypyranones. Under the optimized reaction conditions, we carried out the reaction in a sealed tube containing the substrate (0.02 M in CH₃CN) and 1.5 equiv. of NMP at 150 °C oil bath temperature. The reaction of substrate 9a proceeded smoothly under these specified conditions within 3 h, affording the [5 + 2]-cycloadduct 10a as a major product along with its minor diastereomer in 95% yield. These diastereomers could not be separated by silica gel chromatography. Their diastereomeric ratio (dr) was determined to be 6.5 : 1 by using ¹H-NMR analysis. ¹H-NMR NOESY correlation studies of 10a were difficult due to overlapping aliphatic protons. Therefore, the relative stereochemistry was determined after the conversion of enone 10a to alcohol 28 through a three-step sequence. Catalytic hydrogenation of 10a over the Rh/Al₂O₃ catalyst afforded a mixture of (1 : 1) alcohols, which upon DMP oxidation provided the saturated ketone. Reduction of the ketone using NaBH₄ in MeOH provided alcohol 28 as a major diastereomer (dr 10 : 1 by ¹H-NMR analysis) in 37% yield over 3 steps. The relative stereochemistry of 28 was supported by 1D and 2D NMR studies. The ring junction proton H_a exhibited a NOESY correlation to H_b. In addition, NOESY correlations were observed for H_a–H_f and H_d–H_f. A W-coupling between H_b–H_d indicated that both were pseudo-equatorial. Furthermore, H_e–H_c coupling constant analysis^39,40 revealed an anti-relationship, placing the methyl group in a pseudo-equatorial position (syn-relationship to H_e) as depicted. The relative stereochemistry of the corresponding phenyl substituted derivative 10b was determined by single crystal X-ray studies. The ORTEP picture supports the assigned stereochemistry of 10b (Scheme 6).^41,42

Scheme 6 [5 + 2]-Cycloadditions of substrate 9a, NOE studies of 28, and ORTEP picture of 10b.

We examined the effect of the size and nature of the substituents on the stereochemical outcome. The results are shown in Table 2. The cycloaddition of substrate 9b containing a β-phenyl substituent proceeded very well under the above-mentioned reaction conditions. The reaction of 9b furnished [5 + 2]-cycloadduct 10b as a major product along with its minor diastereomer in a nearly quantitative yield (entry 2). The presence of the phenyl group resulted in improvement of diastereoselectivity compared to the methyl group. The cycloaddition reaction with isopropyl substituted acetoxypyranone 9c also proceeded well to provide cycloadduct 10c as a major diastereomer with excellent yield and diastereoselectivity (entry 3). We then examined the cycloaddition of methyl substituted acetoxypyranone 9d with a six-carbon tether length. The reaction resulted in cycloadduct 10d as a major product along with its minor diastereomer in 99% yield (entry 4). However, the diastereoselectivity was reduced significantly (3 : 1) compared to reactions that formed five-membered exocyclic rings (entries 1–3).

Table 2 Substrate scope and diastereoselectivity of various intramolecular [5 + 2]-cycloaddition reactions

Entry	Acetoxypyranone	Cycloadduct^a	Time (h)	Yield^b (%)	dr^c
a Reactions were carried out using N-methylpyrrolidine and NMP (1.5 equiv.) in CH3CN (0.02 M) at 150 °C. b Yield refers to the combined yield of both the major and minor diastereomers. c The diastereomeric ratios were determined by ^1H NMR. d Reaction was carried out at 150 °C with 4 equiv. of 2,2,6,6-tetramethylpiperidine as the base.
1			3	95	6.5 : 1
2			4	99	12.5 : 1
3			7	99	9.5 : 1
4			3	99	3 : 1
5			8	88	9 : 1
6			3	75	6 : 1
7			7	96	9 : 1
8			5	94	9 : 1
9			4.25	59	10 : 1
10			30	67^d	1 : 1
11			96	33^d	1 : 1
12			80	40^d	1 : 1

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We further investigated the [5 + 2]-cycloaddition of the substrate 9e with an alkenyloxy tether containing a methyl substitution. The reaction was carried out as described above in a sealed tube and afforded cycloadduct 10e as the major product along with its minor diastereomer in excellent yield with very good diastereoselectivity (dr 9 : 1, entry 5). However, the reaction took a bit longer to reach completion. The cycloadduct 10e was recrystallized from chloroform. The relative stereochemistry of 10e was determined by X-ray crystallography.^41,43 The ORTEP picture (Fig. 2) shows the relative stereochemistry of three new chiral centers that formed during the reaction. The phenyl substituted acetoxypyranone 9f provided cycloadduct 10f along with its minor diastereomer in 75% yield with a slight reduction in diastereoselectivity (entry 6). The relative stereochemistry of 10f was also determined by X-ray crystallography.^41,43 The ORTEP picture is shown in Fig. 2. The isopropyl substituted substrate 9g furnished product 10g in excellent yield with excellent diastereoselectivity (entry 7). However, the reaction time was 7 h. The allyloxy substrate 9h containing the t-butyl substitution also furnished product 10h and its minor diastereomer with excellent yield and diastereoselectivity (entry 8). The benzyl substituted substrate 9i provided product 10i with excellent diastereoselectivity. However, the reaction yield was lower (59%) compared to other alkyloxy substrates (entries 5–8).

Fig. 2 ORTEP pictures of major isomers 10e and 10f.

We then expanded the substrate scope to seven-membered rings. Acetoxypyranone 9j with a β-methyl substitution was subjected to cycloaddition conditions as described above. However, the reaction provided a 1 : 1 mixture of inseparable diastereomers with a combined low yield of 22%. The reaction of 9j with increasing equivalents of NMP did not improve the yield or diastereoselectivity. We switched the base to 2,2,6,6-tetramethylpiperidine (TMP), but with 1.5 equiv. of the base, the reaction did not provide any appreciable amount of the product.⁴⁴ However, upon increasing the equiv. of the base to 4, the cycloaddition afforded 67% yield in 30 h, but the diastereoselectivity was not improved (entry 10). When the steric bulk was increased for substrates 9k and 9f with isopropyl and phenyl substitution, the cycloaddition required much longer times, 96 h and 80 h, respectively. The product yields were significantly reduced and the diastereoselectivity did not improve (entries 11 and 12).

Overall, [5 + 2]-cycloaddition of substrates containing β-substitutions proceeded very well for the formation of five- and six-membered exocyclic rings. The carbon-tethered substrate 9a with a methyl substitution showed very good diastereoselectivity for product 10a. Increasing the steric bulk on the tether consistently improved the diastereoselectivity for products 10b and 10c. The carbon-tethered substrate 9d showed excellent yield but the diastereoselectivity was reduced. On the other hand, cycloaddition of the oxygen-tethered substrates leading to 6-membered ring systems provided products with very good diastereoselectivity and yield. The stereochemical outcome of the [5 + 2]-cycloaddition leading to 5- and 6-membered exocyclic rings can be rationalized using stereochemical models as shown in Fig. 3.

Fig. 3 Stereochemical models for [5 + 2]-cycloadditions of substrates containing β-chiral centers on the tether.

Treatment of substrate 9 with a base led to the expected aromatic oxidopyrylium zwitterion 11, which contains a β-chiral center and an all carbon or an alkoxy alkyl tether bearing a terminal alkene. The cycloaddition leading to a five-membered exocyclic ring is proposed to proceed via transition-state 11A, where the alkyl group occupies a pseudo-equatorial position on the envelope conformation of the developing five-membered ring.^45,46 The orientation of the substituent directs the approach of the terminal olefin from the bottom face, leading to the stereochemistry observed in cycloadducts 10a–c. For cycloadditions forming six-membered exocyclic rings, the reaction would likely proceed through a thermodynamically more stable chair like transition-state 11B, similar to that previously suggested by Wender and co-workers.¹¹ The alkyl or aryl β-substituents will occupy an equatorial position, leading to the approach of the alkene from the more favorable bottom face as shown. The formation of a chair-like transition-state leads to the stereochemical outcome observed in cycloadducts 10d–i. The observed diastereoselectivity ranged from 3 : 1 to 10 : 1 (dr). The lower observed diastereoselectivity for the formation of the cyclohexane ring compared to the tetrahydropyran is possibly due to further stabilization of the six-membered transition state for alkoxy derivatives where gauche interactions are significantly less or absent. However, for the β-substituted cyclohexane ring, the developing gauche interaction destabilize transition-state 11B. Interestingly, products with 7-membered rings (10j and 10k) showed no diastereoselectivity. This is possibly due to the fact that the β-positioned alkyl or aryl substituent exerts no influence on the approach of the olefin from the top or bottom face in the flexible 7-membered ring transition-state.⁴⁷

Conclusion

In summary, we investigated the diastereofacial selectivity associated with intramolecular [5 + 2]-cycloaddition reactions of substrates containing a β-chiral center on the alkene tether. The reaction generates three new chiral centers in the 8-oxabicyclo(3.2.1)-octenone core with a high degree of diastereoselectivity for 5- and 6-membered fused carbocyclic and oxacyclic rings. For the formation of five-membered rings, increasing the size of β-substituents improved the degree of diastereoselectivity. The stereochemical outcome of this oxidopyrylium–alkene cycloaddition leading to a five-membered ring was rationalized using a transition-state model, where the substituent occupies a pseudo-equatorial position in an envelope conformation. The reaction with substrates leading to six-membered fused rings was rationalized using a model with a chair-like transition state, where the β-substituent occupies an equatorial position. Cycloaddition of substrates with an all-carbon tether bearing a β-methyl substitution resulted in excellent yield of the cycloadduct; however, the diastereoselectivity was moderate. Substrates containing an allyloxy tether, affording tetrahydropyran fused products, reacted with good to excellent diastereoselectivity. However, reactions with a homoallyloxy tether leading to 7-membered ring derivatives showed no diastereoselectivity, regardless of the size of the β-substitution. The reaction generally required longer times and product yields were moderate. Further investigation, including the application of the current methods for the synthesis of bioactive compounds, is in progress in our laboratories.

Experimental section

All chemicals were purchased from commercial suppliers unless otherwise stated. All reactions were carried out under an argon atmosphere in either flame or oven-dried (120 °C) glassware. Anhydrous organic solvents were obtained as follows. Tetrahydrofuran (THF) was freshly distilled from Na/benzophenone. N,N-Diisopropylethylamine (DIPEA), diisopropylamine (DIPA), and pyridine were distilled over calcium hydride. Isobutryaldehyde, ethyl acetate, acetone, benzaldehyde, pivalaldehyde, allyl bromide, and 2-furaldehyde were fractionally distilled. All other reagents were of reaction grade. Stainless steel syringes and cannulae were used to transfer air- or moisture-sensitive liquids. Thin-layer chromatography (TLC) analysis was conducted using glass backed silica gel plates (60 Å, 250 μm thick, F-254 indicator). Flash column chromatography was performed using a 230–400 mesh and 60 Å pore diameter silica gel. Organic solvents were removed under vacuum using a rotatory evaporator at 30 °C. ¹H and ¹³C NMR spectra was obtained on a Bruker AV-III-400-HD, a Bruker AV-III-800, or an NEO500 instrument. ¹³C NMR spectra were obtained at 100 and 125 MHz. Chemical shifts are reported in parts per million (ppm) with respect to the residual solvent peak. NMR data are reported as δ (chemical shift), J-value (Hz), integration, and splitting pattern, where s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet, dd = doublet of doublets and so on. High-resolution mass spectrometry (HRMS) spectra were recorded under positive electron spray ionization (ESI+) and positive atmospheric pressure chemical ionization (APCI+) conditions using an LTQ Orbitrap Mass Spectrometer at the Purdue University Department of Chemistry Mass Spectrometry Center.

(E)-1-(Furan-2-yl)but-2-en-1-one (12a)

To a solution of known (E)-1-(furan-2-yl)but-2-en-1-ol⁴⁸ (787.3 mg, 5.78 mmol) in Et₂O (18 mL), activated MnO₂ (3.02 g, 37.4 mmol) was added and the reaction was stirred for 26 h, filtered over Celite, and concentrated in vacuo. Enone 12a (394.6 mg, 47% yield) was isolated as an amorphous white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.54 (dd, J = 1.7, 0.8 Hz, 1H), 7.16 (dd, J = 3.5, 0.8 Hz, 1H), 7.08 (dq, J = 15.4, 6.9 Hz, 1H), 6.75 (dq, J = 15.4, 1.7 Hz, 1H), 6.48 (dd, J = 3.6, 1.7 Hz, 1H), 1.90 (dd, J = 6.9, 1.7 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 177.9, 153.1, 146.4, 144.1, 126.4, 117.3, 112.2, 22.5, 18.3. Experimental data are consistent with the data reported in the literature.⁴⁹

(E)-1-(Furan-2-yl)-3-phenylprop-2-en-1-one (12b)

To a round bottom flask charged with known 1-(furan-2-yl)-3-hydroxy-3-phenylpropan-1-one⁵⁰ (3.33 g, 15.4 mmol) in CH₂Cl₂ (100 mL), MsCl (2.4 mL, 31.0 mmol) and Et₃N (8.6 mL, 61.7 mmol) were added dropwise sequentially and the reaction was stirred for 12.5 h. Upon completion, the reaction was quenched with saturated NH₄Cl solution. The organic layer was separated, and the aqueous layer was washed with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude mixture was purified via silica gel column chromatography (20% EtOAc/hexanes) to give α,β-unsaturated ketone 12b (2.09 g, 68% yield) as an amorphous solid. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 15.8 Hz, 1H), 7.65 (ddd, J = 4.5, 2.0, 0.7 Hz, 3H), 7.49–7.39 (m, 4H), 7.33 (dd, J = 3.6, 0.8 Hz, 1H), 6.60 (dd, J = 3.6, 1.7 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 146.4, 143.9, 130.5, 128.9, 128.4, 121.1, 117.4, 112.5. Experimental data are consistent with the data reported in the literature.⁵¹

(E)-1-(Furan-2-yl)-4-methylpent-2-en-1-one (12c)

The reaction was conducted according to the procedure described for 12b with known β-hydroxy ketone⁵² (475 mg, 2.61 mmol), CH₂Cl₂ (25 mL), MsCl (0.4 mL, 5.17 mmol), and Et₃N (1.4 mL, 10 mmol), and the mixture was reacted for 21 h. The crude mixture was purified via silica gel column chromatography (20% EtOAc/hexanes) to afford α,β-unsaturated ketone 12c (344.0 mg, 80% yield) as an amorphous solid. ¹H NMR (400 MHz, CDCl₃) δ 7.64–7.58 (m, 1H), 7.24–7.21 (m, 1H), 7.13 (dd, J = 15.5, 6.7 Hz, 1H), 6.74 (dd, J = 15.5, 1.5 Hz, 1H), 6.55 (dd, J = 3.6, 1.7 Hz, 1H), 2.55 (hd, J = 6.7, 1.4 Hz, 1H), 1.12 (d, J = 6.7 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 178.5, 155.2, 153.3, 146.3, 122.0, 117.3, 112.2, 31.3, 21.2. Experimental data are consistent with the data reported in the literature.⁵³

1-(Furan-2-yl)-3-methylhex-5-en-1-one (13a)

To a round bottom flask charged with 12a (20.4 mg, 0.14 mmol) in dry CH₂Cl₂ (2 mL) at −78 °C under argon, BF₃·OEt₂ (25 µL, 0.20 mmol) was added dropwise and the mixture was stirred for 15 min. Allyltrimethylsilane (0.1 mL, 0.63 mmol) was added dropwise, and the reaction was stirred for 1 h, then warmed to 0 °C slowly and stirred for 29 h. Upon completion, the reaction was quenched with saturated NaHCO₃ solution. The organic layer was separated, and the aqueous layer was washed with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude mixture was purified via silica gel column chromatography (2% EtOAc/hexanes) to give the 1,4-addition product 13a (9.6 mg, 39% yield) as a yellow oil along with the recovery of the starting material (12.5 mg, 61% recovery). ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, J = 1.7, 0.8 Hz, 1H), 7.15 (dd, J = 3.6, 0.8 Hz, 1H), 6.50 (dd, J = 3.6, 1.7 Hz, 1H), 5.84–5.70 (m, 1H), 5.02 (dtd, J = 3.3, 2.2, 1.2 Hz, 1H), 4.99 (h, J = 1.0 Hz, 1H), 2.81 (dd, J = 15.4, 5.7 Hz, 1H), 2.59 (dd, J = 15.4, 8.2 Hz, 1H), 2.31–2.17 (m, 1H), 2.15–1.97 (m, 2H), 0.95 (d, J = 6.7 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 189.2, 153.0, 146.1, 136.5, 116.8, 116.5, 112.0, 44.8, 41.2, 29.5, 19.7. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₁H₁₅O₂ 179.1067; found 179.1066.

(E)-4-(Furan-2-yl)hepta-1,5-dien-4-ol (15)

To CuBr·DMS (129.2 mg, 0.628 mmol) in THF (10 mL) at 0 °C, allylmagnesium bromide (1.25 mL, 1.0 M in hexanes, 1.25 mmol) was added dropwise, after which the suspension became black. The solution was stirred for 10 minutes and then cooled to −78 °C, and 12a (76 mg, 0.52 mmol) in THF (2 mL) was cannulated into the prepared suspension. The reaction was stirred at −78 °C for 15 min, quenched with saturated NH₄Cl solution, and diluted with EtOAc. The solids were filtered off, the organic layer was separated, and the aqueous layer was washed with EtOAc (3×). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. Purification via silica gel column chromatography (2% EtOAc/hexanes) afforded 13a in trace amounts and 15 (60.4 mg, 68% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.37 (dd, J = 1.9, 0.9 Hz, 1H), 6.31 (dd, J = 3.2, 1.8 Hz, 1H), 6.21 (dd, J = 3.2, 0.9 Hz, 1H), 5.79–5.63 (m, 3H), 5.18–5.10 (m, 2H), 2.79–2.72 (m, 1H), 2.63–2.56 (m, 1H), 1.76–1.70 (m, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 157.8, 141.8, 133.8, 133.0, 125.6, 119.5, 110.1, 105.9, 72.9, 45.0, 17.7. HRMS (APCI+) m/z: [M − OH]⁺ calcd C₁₁H₁₃O₁ 161.0961; found 161.0960.

1-(Furan-2-yl)-3-phenylhex-5-en-1-one (13b)

The reaction was conducted according to the procedure described for 13a with 12b (420.4 mg, 2.12 mmol), CH₂Cl₂ (20 mL), BF₃·OEt₂ (0.75 mL, 6.08 mmol), and allyltrimethylsilane (1.9 mL, 12.0 mmol). The reaction was stirred for 65 h. The crude mixture was purified via silica gel column chromatography (3% EtOAc/hexanes) to give the 1,4-addition product 13b (149 mg, 29% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.53 (dd, J = 1.7, 0.8 Hz, 1H), 7.30–7.25 (m, 3H), 7.25–7.20 (m, 2H), 7.20–7.14 (m, 1H), 7.10 (dd, J = 3.6, 0.8 Hz, 1H), 6.48 (dd, J = 3.6, 1.7 Hz, 1H), 5.68 (ddt, J = 17.1, 10.0, 7.0 Hz, 1H), 5.03–4.92 (m, 2H), 3.45 (p, J = 7.2 Hz, 1H), 3.14 (dd, J = 7.2, 1.5 Hz, 2H), 2.49–2.42 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 188.2, 153.0, 146.2, 144.0, 136.2, 128.4, 127.6, 126.4, 117.0, 116.8, 112.2, 44.5, 40.9, 40.6. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₆H₁₇O₂ 241.1223; found 241.1222.

1-(Furan-2-yl)-3-isopropylhex-5-en-1-one (13c)

The reaction was conducted according to the procedure described for 13a with 12c (329.6 mg, 2.01 mmol), CH₂Cl₂ (20 mL), BF₃·OEt₂ (2.5 mL, 20.3 mmol), and allyltrimethylsilane (4.8 mL, 30.2 mmol). The reaction was stirred for 14.5 h. The crude mixture was purified via silica gel column chromatography (3% EtOAc/hexanes) to give the 1,4-addition product 13c (209 mg, 50% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (dt, J = 2.0, 1.0 Hz, 1H), 6.32 (dd, J = 3.3, 1.8 Hz, 1H), 6.22 (t, J = 3.5 Hz, 1H), 5.75 (ddt, J = 17.1, 10.0, 7.1 Hz, 1H), 5.08–4.95 (m, 2H), 4.79–4.70 (m, 1H), 2.19–1.92 (m, 2H), 1.92–1.62 (m, 3H), 1.56–1.31 (m, 1H), 0.93–0.78 (m, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 157.0, 156.7, 141.8, 141.7, 137.9, 137.8, 115.8, 115.7, 110.0, 110.0, 106.0, 105.6, 66.4, 66.0, 39.7, 39.4, 36.3, 36.2, 35.5, 35.1, 29.4, 29.1, 19.2, 18.7, 18.5. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₃H₁₉O₂ 207.1385; found 207.1280.

1-(Furan-2-yl)-3-methylhex-5-en-1-ol (14a)

A round bottom flask containing 13a (37.7 mg, 0.208 mmol) in MeOH (3 mL) was charged with NaBH₄ (9 mg, 0.24 mmol) and the mixture was stirred for 2.5 h. The crude mixture was concentrated in vacuo and diluted with water and extracted with EtOAc (3×). Purification via silica gel column chromatography (5–10% EtOAc/hexanes) afforded furanol 14a (32.2 mg, 86% yield) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (td, J = 1.9, 0.8 Hz, 1H), 6.32 (dd, J = 3.2, 1.9 Hz, 1H), 6.22 (dq, J = 2.3, 0.7 Hz, 1H), 5.84–5.68 (m, 1H), 5.05–4.96 (m, 2H), 4.80–4.74 (m, 1H), 2.18–2.04 (m, 1H), 2.03–1.84 (m, 2H), 1.83–1.52 (m, 2H), 0.93 (d, J = 6.6 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 157.1, 156.7, 141.9, 141.8, 136.9, 136.8, 116.1, 116.0, 110.0, 105.9, 105.5, 65.9, 65.5, 42.0, 42.0, 41.6, 40.9, 29.2, 29.0, 19.7, 18.9. HRMS (APCI+) m/z: [M − OH]⁺ calcd C₁₁H₁₅O₂ 163.1117; found 163.1116.

1-(Furan-2-yl)-3-phenylhex-5-en-1-ol (14b)

The reaction was conducted (2.5 h) according to the procedure described for 14a with 13b (146.0 mg, 0.61 mmol) in a mixture of H₂O and THF (1 : 1) and NaBH₄ (128.5 mg, 3.40 mmol). Purification via silica gel column chromatography (5–10% EtOAc/hexanes) afforded furanol 14b (124.4 mg, 64% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.41–7.27 (m, 3H), 7.24–7.18 (m, 2H), 7.13 (dd, J = 7.5, 1.1 Hz, 1H), 6.31 (ddd, J = 20.8, 3.2, 1.8 Hz, 1H), 6.16 (ddt, J = 12.5, 3.3, 0.7 Hz, 1H), 5.76–5.54 (m, 1H), 5.04–4.89 (m, 2H), 4.44 (ddd, J = 44.3, 9.3, 4.7 Hz, 1H), 3.09–2.49 (m, 1H), 2.49–2.19 (m, 3H), 2.19–1.95 (m, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 157.0, 155.9, 144.2, 142.1, 141.7, 136.5, 136.3, 128.4, 127.8, 127.5, 126.3, 116.2, 116.2, 110.0, 106.6, 105.3, 66.0, 65.1, 42.2, 41.6, 41.4, 41.1. HRMS (ESI+) m/z: [M − OH]⁺ calcd C₁₆H₁₇O₂ 225.1274; found 225.1275.

1-(Furan-2-yl)-3-isopropylhex-5-en-1-ol (14c)

The reaction was conducted (2.3 h) according to the procedure described for 14a with 13c (166.5 mg, 0.81 mmol) in MeOH (8 mL) and 31.1 mg NaBH₄ (0.82 mmol). Purification via silica gel column chromatography (5–10% EtOAc/hexanes) afforded furanol 14c (124.4 mg, 74% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (dt, J = 2.0, 1.0 Hz, 1H), 6.32 (dd, J = 3.3, 1.8 Hz, 1H), 6.22 (t, J = 3.5 Hz, 1H), 5.75 (ddt, J = 17.1, 10.0, 7.1 Hz, 1H), 5.08–4.95 (m, 2H), 4.79–4.70 (m, 1H), 2.19–1.92 (m, 2H), 1.92–1.62 (m, 3H), 1.56–1.31 (m, 1H), 0.93–0.78 (m, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 157.0, 156.7, 141.8, 141.7, 137.9, 137.8, 115.8, 115.7, 110.0, 110.0, 106.0, 105.6, 66.4, 66.0, 39.7, 39.4, 36.3, 36.2, 35.5, 35.1, 29.4, 29.1, 19.2, 18.7, 18.5. HRMS (ESI+) m/z: [M − OH]⁺ calcd C₁₃H₁₉O₂ 191.1430; found 191.1431

Methyl 3-methylhept-6-enoate (17)

To a round bottom flask charged with argon and activated magnesium turnings (1.76 g, 72.4 mmol), known ethyl (Z)-3-methylhepta-2,6-dienoate⁵⁴ (773 mg, 4.59 mmol) in methanol (50 mL) was added and the mixture was stirred for 4 h and then brought to vigorous reflux. Upon completion, the reaction was diluted with 200 mL Et₂O and extracted twice with 1 M HCl and once with brine, dried over Na₂SO₄ and concentrated in vacuo. The crude product was passed through a silica plug to afford 17 (457 mg, 64% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.75 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 5.03–4.84 (m, 2H), 3.63 (d, J = 5.9 Hz, 3H), 2.41–1.73 (m, 4H), 1.39 (ddt, J = 15.6, 9.4, 6.1 Hz, 1H), 1.30–1.11 (m, 2H), 1.02–0.80 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ 173.4, 138.4, 114.4, 51.2, 41.4, 35.7, 31.0, 29.7, 19.4. HRMS (APCI+) m/z: [M + H]⁺ calcd C₁₀H₁₉O₂ 157.1223; found 157.1223.

1-(Furan-2-yl)-3-methylhept-6-en-1-ol (18)

To a flame dried round bottom flask with ester 17 (169.9 mg, 1.09 mmol) in dry n-pentane (10 mL) at −78 °C, DIBAL (1.0 M in hexanes, 1.15 mL, 1.15 mmol) was added dropwise over 10 min. The reaction was stirred for an additional 20 min and quenched with methanol (0.05 mL) and stirred until the evolution of hydrogen ceased. Saturated aqueous Rochelle's salt (1.1 mL) was added dropwise and the reaction was slowly brought to 23 °C and stirred until the solution became gelatinous. The mixture was filtered over a mat of Na₂SO₄ and Celite and washed twice with n-pentanes (5 mL).

A solution of 2-lithiofuran was prepared by charging a dry round bottom flask with furan (0.25 mL, 3.43 mmol) in THF (10 mL) and cooled to 0 °C; then n-BuLi (1.1 mL, 1.42 M solution in hexanes) was added dropwise. The reaction was stirred for 30 min and then cooled to −78 °C. The crude aldehyde in n-pentanes as described above was cannulated into the prepared solution of 2-lithiofuran. The reaction was stirred for 15 min, quenched with saturated NH₄Cl, and warmed to 23 °C. The solution was diluted with EtOAc and the organic layers were separated. The aqueous layer was extracted with EtOAc (3×); the combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. Purification via silica gel column chromatography afforded furanol 18 (77.5 mg, 37% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.35 (td, J = 1.7, 0.8 Hz, 1H), 6.31 (dd, J = 3.3, 1.8 Hz, 1H), 6.21 (t, J = 2.6 Hz, 1H), 5.78 (dddt, J = 16.9, 10.2, 8.9, 6.6 Hz, 1H), 4.99 (ddd, J = 17.2, 6.4, 1.8 Hz, 1H), 4.95–4.88 (m, 1H), 4.74 (dd, J = 8.8, 5.4 Hz, 1H), 2.28–1.95 (m, 2H), 1.93–1.79 (m, 1H), 1.75–1.37 (m, 3H), 1.34–1.16 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 157.2, 156.7, 141.8, 141.7, 138.9, 138.9, 114.2, 110.0, 105.8, 105.4, 65.9, 65.5, 42.6, 42.5, 36.5, 35.8, 31.0, 30.9, 28.9, 28.6, 19.8, 18.9. HRMS (APCI+) m/z: [M − OH]⁺ calcd C₁₂H₁₇O 177.1274; found 177.1276.

4-(Furan-2-yl)-4-hydroxy-1-phenylbutan-2-one (19e)

To a dried round bottom flask with dry CH₂Cl₂ (100 mL), phenyl acetone (2 mL, 14.5 mmol) was added and the mixture was cooled to −78 °C. DIPEA (3 mL, 17.2 mmol) and tert-butyl-dimethylsilyl triflate (4 mL, 17.4 mmol) were added dropwise sequentially. The reaction mixture was stirred at −78 °C for 15 min, and furfural (0.83 mL, 10 mmol) was added dropwise. Stirring of the reaction mixture was continued at −78 °C for 30 min; the mixture was then warmed to 0 °C after which it was stirred for an additional 1.5 h. The reaction mixture was poured over silica and the column was flushed with diethyl ether. The crude mixture was concentrated in vacuo and purification via silica gel column chromatography (1% EtOAc/hexanes, gravity pressure) afforded 4-((tert-butyldimethylsilyl)oxy)-4-(furan-2-yl)-1-phenylbutan-2-one in 60% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.13 (m, 7H), 6.28 (dd, J = 3.2, 1.8 Hz, 1H), 6.14 (d, J = 3.2 Hz, 1H), 5.26–5.16 (m, 1H), 3.09 (dd, J = 15.7, 8.5 Hz, 1H), 2.73 (dd, J = 15.7, 4.6 Hz, 1H), 0.82 (s, 9H), 0.03 (s, 3H), −0.10 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 205.5, 141.6, 133.6, 129.4, 128.6, 126.9, 110.0, 106.1, 64.8, 51.3, 48.6, 25.6, 25.3, 18.0, −5.2, −5.4. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₂₀H₂₈O₃SiNa 367.1705; found 367.1703.

To a dry round bottom flask charged with the above siloxane and THF (40 mL) was added TBAF (15 mL, 1.0 M in THF) and the mixture was stirred for 15 min. The reaction was quenched with sat. NH₄Cl solution and extracted with EtOAc (3×). The combined organic layers were washed with brine and dried over Na₂SO₄ and then concentrated in vacuo. Product 19e was isolated in 57% yield (16% alcohol elimination products were also isolated) via silica gel column chromatography. ¹H NMR (500 MHz, CDCl₃) δ 7.49–7.22 (m, 5H), 6.37 (dd, J = 3.2, 1.9 Hz, 1H), 6.27 (d, J = 3.3 Hz, 1H), 5.20 (dd, J = 8.7, 3.7 Hz, 1H), 3.80 (s, 2H), 3.13 (dd, J = 17.6, 8.8 Hz, 1H), 2.99 (ddd, J = 17.7, 3.4, 1.2 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 208.1, 142.2, 133.4, 129.5, 128.9, 127.4, 110.3, 106.4, 63.9, 50.8, 46.6. HRMS (ESI+) m/z: [M − OH]⁺ calcd C₁₄H₁₃O₂ 213.0910; found 213.0916.

4-(Furan-2-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-one (20a)

A round bottom flask was charged with 4-(furan-2-yl)-4-hydroxybutan-2-one⁵⁰ (2.67 g, 17.3 mmol), 3,4-dihydro-2H-pyran (3.1 mL, 34.0 mmol), and pyridinium p-toluenesulfonic acid (PPTS) (5.16 g, 20.5 mmol) in CH₂Cl₂ (170 mL) and the mixture was stirred for 19 h. The reaction was quenched with saturated NaHCO₃, the layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. Purification via silica gel column chromatography (8–10% EtOAc/hexanes) afforded 20a (3.71 g, 90% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.30–7.27 (m, 1H), 6.27–6.19 (m, 2H), 5.05 (dd, J = 8.4, 5.0 Hz, 1H), 4.77 (t, J = 3.5 Hz, 1H), 3.54 (ddd, J = 11.7, 9.0, 3.2 Hz, 1H), 3.31–3.25 (m, 1H), 3.10 (dd, J = 16.5, 8.3 Hz, 1H), 2.76 (dd, J = 16.6, 5.0 Hz, 1H), 2.09 (s, 3H), 1.73–1.32 (m, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 205.9, 154.5, 141.9, 110.2, 107.1, 98.7, 68.6, 62.0, 47.5, 30.8, 30.5, 25.3, 19.1. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₃H₁₈O₄Na 289.1416; found 289.1404.

3-(Furan-2-yl)-1-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-one (20b)

The reaction was conducted according to the procedure described for 20a with 3-(furan-2-yl)-3-hydroxy-1-phenylpropan-1-one (2.04 g, 9.42 mmol), 3,4-dihydro-2H-pyran (1 mL, 11.0 mmol), and PPTS (5.24 g, 20.9 mmol) in CH₂Cl₂ (90 mL) and stirred for 72 h. Purification via silica gel column chromatography (10% EtOAc/hexanes) afforded 20b (2.01 g, 71% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.03–7.95 (m, 2H), 7.60–7.52 (m, 1H), 7.50–7.42 (m, 2H), 7.38 (ddd, J = 5.0, 2.4, 1.3 Hz, 1H), 6.38–6.28 (m, 2H), 5.39 (ddd, J = 35.1, 7.9, 5.0 Hz, 1H), 4.74 (dt, J = 165.7, 3.2 Hz, 1H), 3.83–3.70 (m, 2H), 3.66–3.43 (m, 1H), 3.34 (ddt, J = 16.8, 8.9, 3.2 Hz, 2H), 2.19–2.02 (m, 2H), 1.72 (t, J = 8.4 Hz, 1H), 1.66–1.36 (m, 7H). ¹³C NMR (125 MHz, CDCl₃) δ 197.4, 154.8, 152.9, 142.6, 142.0, 137.3, 137.1, 133.2, 133.1, 128.6, 128.6, 128.3, 128.2, 110.2, 110.1, 109.0, 107.1, 99.1, 94.7, 69.0, 66.4, 62.1, 61.8, 43.0, 30.9, 30.5, 30.3, 25.4, 25.3, 19.2, 18.9. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₈H₂₁O₄ 301.1434; found 301.1440.

1-(Furan-2-yl)-4-methyl-1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-one (20c)

The reaction was conducted according to the procedure described for 20a with 1-(furan-2-yl)-1-hydroxy-4-methylpentan-3-one (2.63 g, 14.4 mmol), 3,4-dihydro-2H-pyran (2.6 mL, 28.5 mmol), and PPTS (3.98 g, 15.8 mmol) in CH₂Cl₂ (150 mL) and stirred for 25 h. Purification via silica gel column chromatography (8% EtOAc/hexanes) afforded 19c (3.17 g, 83% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.39–7.33 (m, 1H), 6.33–6.22 (m, 2H), 5.20 (ddd, J = 51.1, 8.4, 5.0 Hz, 1H), 4.96–4.79 (m, 1H), 4.51 (s, 0H), 3.84 (ddd, J = 21.5, 11.6, 5.4 Hz, 2H), 3.63–3.31 (m, 3H), 3.26–3.18 (m, 1H), 2.85–2.78 (m, 1H), 2.61 (dhept, J = 21.0, 7.0 Hz, 1H), 1.91–1.40 (m, 7H), 1.13–1.06 (m, 7H). ¹³C NMR (125 MHz, CDCl₃) δ 211.8, 211.5, 154.8, 152.8, 142.5, 141.9, 110.2, 110.1, 109.0, 107.0, 99.2, 94.7, 94.5, 69.0, 65.9, 63.0, 62.1, 61.7, 44.6, 44.5, 41.8, 41.6, 30.7, 30.6, 30.3, 25.5, 25.4, 25.3, 19.8, 19.2, 18.9, 17.8, 17.8, 17.7. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₃H₁₉O₄ 289.1416; found 289.1404.

1-(Furan-2-yl)-4,4-dimethyl-1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-one (20d)

The reaction was conducted according to the procedure described for 20a with 1-(furan-2-yl)-1-hydroxy-4,4-dimethylpentan-3-one (221.9 mg, 1.13 mmol), 3,4-dihydro-2H-pyran (1.0 mL, 11.0 mmol), and PPTS (309 mg, 1.23 mmol) in CH₂Cl₂ (10 mL) and stirred for 13.5 h. Purification via silica gel column chromatography (15% EtOAc/hexanes) afforded 20d (306 mg, 96% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.32 (m, 1H), 6.32–6.24 (m, 2H), 5.23 (ddd, J = 59.4, 8.2, 5.3 Hz, 1H), 4.96–4.48 (m, 1H), 3.90–3.80 (m, 1H), 3.60–3.48 (m, 1H), 3.35–3.24 (m, 1H), 2.83 (ddd, J = 32.7, 16.8, 5.3 Hz, 1H), 1.91–1.37 (m, 4H), 1.12 (d, J = 3.0 Hz, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 212.9, 212.4, 155.0, 152.8, 142.4, 141.8, 110.2, 110.0, 109.1, 107.0, 99.4, 94.7, 94.4, 69.2, 65.9, 62.9, 62.1, 61.7, 44.4, 44.3, 41.3, 41.1, 30.7, 30.6, 30.3, 26.0, 25.9, 25.5, 25.4, 25.3, 19.8, 19.2, 19.0. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₆H₂₄O₄Na 303.1572; found 303.1559.

4-(Furan-2-yl)-1-phenyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-one (20e)

The reaction was conducted (21 h) according to the procedure described for 20a with 19e (397.6 mg, 1.73 mmol), 3,4-dihydro-2H-pyran (0.19 mL, 2.08 mmol), and PPTS (435 mg, 1.73 mmol). Purification via silica gel column chromatography (15% EtOAc/hexanes) afforded 20e (416 mg, 76% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.14 (m, 7H), 6.32–6.19 (m, 2H), 5.19 (ddd, J = 53.4, 8.4, 5.2 Hz, 1H), 4.84–4.47 (m, 1H), 3.86–3.30 (m, 4H), 3.20 (ddd, J = 16.4, 8.4, 2.7 Hz, 1H), 2.84 (ddd, J = 15.9, 5.3, 2.8 Hz, 1H), 1.79–1.39 (m, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 205.5, 205.3, 154.4, 152.5, 142.6, 142.0, 133.8, 133.7, 129.6, 129.5, 128.9, 128.8, 128.7, 127.1, 127.1, 110.2, 110.1, 109.0, 107.2, 99.0, 94.8, 68.7, 66.1, 62.1, 62.0, 51.1, 51.0, 46.1, 46.1, 30.5, 30.3, 25.4, 25.3, 19.2, 19.1. HRMS (APCI+) m/z: [M + Na]⁺ calcd C₁₉H₂₂O₄Na 337.1410; found 337.1416.

2-(3-(Allyloxy)-1-(furan-2-yl)butoxy)tetrahydro-2H-pyran (21a)

A round-bottom flask was charged with 20a (67.2 mg, 0.28 mmol) and NaBH₄ (35.8 mg, 0.94 mmol) in MeOH (3 mL) and the mixture was stirred for 1 h. The reaction was quenched with sat. NH₄Cl and diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc (3×); the combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. Purification via silica gel column chromatography (25% EtOAc/hexanes) afforded 4-(furan-2-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-ol (60.1 mg, 89% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.42 (ddt, J = 3.7, 1.9, 0.9 Hz, 1H), 6.37 (tt, J = 2.1, 1.3 Hz, 1H), 6.33 (d, J = 3.3 Hz, 1H), 5.01–4.85 (m, 2H), 4.11–3.89 (m, 1H), 3.73 (dddd, J = 36.5, 11.8, 8.6, 3.3 Hz, 1H), 3.49–3.34 (m, 1H), 2.59 (s, 2H), 2.24–2.07 (m, 1H), 2.01–1.46 (m, 7H), 1.26 (ddd, J = 6.2, 3.2, 1.0 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 154.9, 142.0, 141.8, 110.1, 107.1, 106.6, 98.5, 72.6, 70.1, 66.6, 64.7, 62.6, 62.2, 42.7, 42.3, 30.8, 30.6, 25.3, 23.8, 23.6, 19.5, 19.3. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₃H₂₁O₄ 241.1434; found 241.1413.

To the above alcohol (44.7 mg, 0.19 mmol) in DMF (2 mL), TBAI (7.3 mg, 19.8 µmol), NaH (54.5 mg, 60 wt% in mineral oil, 1.36 mmol), and allyl bromide (160 µL, 1.85 mmol) were added sequentially. The reaction was warmed to 50 °C and stirred for 16 h. The solution was diluted with EtOAc and the organic layers were separated. The aqueous layer was extracted with EtOAc (3×); the combined organic layers were washed with ice and brine sequentially, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (8% EtOAc/hexanes) to give 21a (28 mg, 53% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.47–7.39 (m, 1H), 6.40–6.27 (m, 2H), 6.04–5.87 (m, 1H), 5.30 (dddd, J = 19.3, 17.3, 6.0, 1.7 Hz, 1H), 5.18 (ddd, J = 18.2, 10.3, 1.6 Hz, 1H), 5.01–4.80 (m, 2H), 4.18–3.28 (m, 5H), 2.31 (dt, J = 14.1, 7.2 Hz, 0H), 2.25–2.10 (m, 1H), 2.07–1.81 (m, 2H), 1.75–1.44 (m, 4H), 1.27–1.18 (m, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 155.9, 155.2, 154.3, 153.8, 142.4, 142.3, 141.9, 141.7, 135.5, 135.3, 116.6, 116.4, 116.3, 110.0, 109.9, 108.8, 108.2, 107.3, 106.6, 99.0, 98.0, 95.0, 72.0, 71.9, 71.7, 71.3, 69.9, 69.7, 69.6, 69.6, 69.5, 69.4, 67.4, 66.6, 62.2, 41.9, 41.7, 41.5, 41.0, 30.8, 30.7, 30.5, 25.5, 25.4, 20.0, 19.9, 19.7, 19.5, 19.4, 19.3. HRMS (ESI+) m/z: [M − OAllyl]⁺ calcd C₁₃H₁₉O₃ 223.1329; found 223.1328.

2-(3-(Allyloxy)-1-(furan-2-yl)-3-phenylpropoxy)tetrahydro-2H-pyran (21b)

The reaction was conducted according to the procedure described for 21a with 20b (2.01 g, 6.71 mmol) and NaBH₄ (508 mg, 13.4 mmol) in MeOH (70 mL), and the mixture was reacted for 30 min. Purification via silica gel column chromatography (20% EtOAc/hexanes) afforded 3-(furan-2-yl)-1-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (1.53 g, 75% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.44–7.29 (m, 5H), 7.28–7.21 (m, 1H), 6.35–6.23 (m, 2H), 5.09 (ddd, J = 17.5, 10.1, 4.0 Hz, 1H), 4.96–4.80 (m, 1H), 4.77–4.56 (m, 1H), 4.05–3.91 (m, 1H), 3.81 (d, J = 28.4 Hz, 1H), 3.73–3.27 (m, 1H), 2.50–2.30 (m, 1H), 2.22–2.05 (m, 1H), 1.89–1.41 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.6, 154.2, 153.1, 144.2, 144.1, 142.5, 142.3, 141.9, 128.4, 128.2, 127.4, 127.2, 127.0, 125.6, 125.6, 110.0, 109.9, 108.4, 107.4, 107.3, 98.7, 98.3, 95.6, 73.4, 72.4, 72.0, 70.7, 70.2, 69.5, 68.2, 64.5, 62.7, 62.1, 53.3, 43.5, 43.1, 43.0, 30.9, 30.7, 30.3, 25.1, 20.8, 19.5, 19.2.

To the above alcohol (1.53 g, 5.06 mmol) in DMF (50 mL), NaH (1.05 g, 60 wt% in mineral oil, 26.3 mmol) and allyl bromide (4.3 mL, 49.7 mmol) were added sequentially. The reaction was stirred for 18 h. The solution was diluted with EtOAc and the organic layers were separated. The aqueous layer was extracted with EtOAc (3×); the combined organic layers were washed with ice and brine sequentially, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (6% EtOAc/hexanes) to give 21b (1.56 g, 90% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.41 (ddd, J = 4.0, 1.9, 0.9 Hz, 1H), 7.37–7.23 (m, 6H), 6.36–6.21 (m, 2H), 5.98–5.77 (m, 1H), 5.31–5.00 (m, 3H), 4.95–4.72 (m, 1H), 4.65–4.47 (m, 1H), 4.13 (ddd, J = 8.9, 4.8, 1.8 Hz, 1H), 3.95–3.59 (m, 3H), 3.57–3.30 (m, 1H), 2.53–2.40 (m, 1H), 2.33–2.10 (m, 1H), 1.94–1.40 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ 153.4, 142.4, 141.9, 134.9, 128.4, 128.2, 127.4, 126.7, 126.5, 116.3, 109.8, 109.0, 95.1, 94.8, 78.2, 69.4, 67.5, 62.1, 42.7, 30.6, 30.4, 25.4, 19.2. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₂₁H₂₆O₄Na 365.1723; found 365.1728.

2-((3-(Allyloxy)-1-(furan-2-yl)-4-methylpentyl)oxy)tetrahydro-2H-pyran (21c)

The reaction was conducted according to the procedure described for 21a with 20c (3.17 g, 11.9 mmol) and NaBH₄ (692 mg, 18.3 mmol) in MeOH (100 mL) and stirred for 1.5 h. Purification via silica gel column chromatography (25% EtOAc/hexanes) afforded 1-(furan-2-yl)-4-methyl-1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol (2.32 g, 83% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.38 (ddd, J = 7.8, 1.9, 0.9 Hz, 1H), 6.37–6.24 (m, 2H), 5.00–4.82 (m, 2H), 3.75–3.56 (m, 1H), 3.43–3.30 (m, 2H), 2.82 (s, 1H), 2.48 (s, 0H), 2.14–1.94 (m, 2H), 1.87–1.42 (m, 6H), 1.00–0.86 (m, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 155.7, 155.0, 141.9, 141.6, 110.1, 107.2, 106.5, 98.7, 98.3, 74.8, 72.8, 70.3, 62.4, 62.0, 37.9, 37.7, 34.0, 33.9, 30.8, 30.6, 25.3, 25.3, 19.4, 19.2, 18.6, 18.3, 17.6, 17.5. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₅H₂₄O₄Na 291.1567; found 291.1566.

To the above alcohol (2.32 g, 8.63 mmol) in DMF (80 mL), NaH (3.51 g, 60 wt% in mineral oil, 87.8 mmol) and allyl bromide (7.5 mL, 86.7 mmol) were added sequentially, and the reaction was stirred for 22 h. The solution was diluted with EtOAc and the organic layers were separated. The aqueous layer was extracted with EtOAc (3×); the combined organic layers were washed with ice and brine sequentially, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (6% EtOAc/hexanes) to give 21c (2.2 g, 83% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.40–7.31 (m, 1H), 6.32–6.19 (m, 3H), 5.96–5.79 (m, 1H), 5.27–5.04 (m, 3H), 4.93–4.45 (m, 3H), 4.07–3.72 (m, 4H), 3.67–3.24 (m, 3H), 2.92–2.81 (m, 1H), 2.08–1.38 (m, 10H), 0.93–0.78 (m, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 156.2, 155.1, 154.7, 153.7, 142.4, 142.1, 141.9, 141.5, 135.7, 135.5, 135.4, 135.4, 116.3, 116.0, 116.0, 110.0, 110.0, 109.8, 109.2, 107.9, 107.5, 106.5, 99.1, 97.9, 95.5, 94.8, 80.7, 80.3, 80.0, 70.9, 70.8, 70.7, 70.5, 70.4, 70.2, 67.8, 67.3, 62.6, 62.1, 62.0, 62.0, 35.7, 35.2, 34.9, 34.5, 30.9, 30.8, 30.7, 30.4, 30.4, 30.4, 30.0, 25.5, 25.4, 25.4, 19.7, 19.4, 19.3, 19.2, 18.3, 18.2, 18.0, 17.3, 17.2, 17.0, 17.0. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₃H₂₀O₃Na 331.1885; found 331.1873.

2-((3-(Allyloxy)-1-(furan-2-yl)-4,4-dimethylpentyl)oxy)tetrahydro-2H-pyran (21d)

The reaction was conducted according to the procedure described for 21a with 20d (306 mg, 1.09 mmol) and NaBH₄ (96 mg, 2.54 mmol) in MeOH (10 mL) for 3 h. Purification of the product via silica gel column chromatography (25% EtOAc/hexanes) afforded 1-(furan-2-yl)-4,4-dimethyl-1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol (222.9 mg, 72% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.47–7.40 (m, 1H), 6.40–6.29 (m, 2H), 5.08–4.84 (m, 1H), 4.60–4.55 (m, 0H), 4.21–3.93 (m, 1H), 3.81–3.24 (m, 2H), 2.20–1.52 (m, 6H), 0.96 (ddd, J = 9.7, 6.5, 1.1 Hz, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 154.9, 153.5, 142.5, 142.3, 142.0, 141.7, 110.1, 110.0, 108.5, 107.3, 107.1, 106.5, 98.8, 98.6, 95.4, 79.0, 74.4, 70.9, 69.1, 64.9, 62.7, 36.0, 35.6, 34.8, 34.4, 31.0, 30.6, 30.3, 25.9, 25.8, 25.7, 25.6, 25.5, 25.3, 25.2, 21.0, 19.6. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₆H₂₆O₄ 305.1729; found 305.1714.

To the above alcohol (202 mg, 0.72 mmol) in DMF (8 mL), NaH (286 mg, 60 wt% in mineral oil, 7.16 mmol) and allyl bromide (0.6 mL, 6.93 mmol) were added sequentially and warmed to 50 °C. The reaction was stirred for 16 h. The solution was diluted with EtOAc and the organic layers were separated. The aqueous layer was extracted with EtOAc (3×); the combined organic layers were washed with ice and brine sequentially, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (6% EtOAc/hexanes) to give 21d (189 mg, 82% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.43–7.34 (m, 1H), 6.35–6.22 (m, 2H), 5.98–5.85 (m, 1H), 5.25 (ddq, J = 17.2, 6.7, 1.8 Hz, 1H), 5.14–5.07 (m, 1H), 4.93–4.71 (m, 2H), 4.53–4.23 (m, 1H), 4.08–3.86 (m, 3H), 3.70–3.16 (m, 2H), 2.65 (ddd, J = 12.0, 9.6, 2.1 Hz, 1H), 2.29–2.11 (m, 2H), 2.05–1.39 (m, 7H), 0.94–0.84 (m, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 156.1, 155.1, 154.9, 153.6, 142.5, 142.1, 142.0, 141.6, 135.8, 135.5, 135.5, 135.3, 116.0, 115.8, 115.7, 115.7, 110.1, 110.0, 109.9, 109.9, 109.5, 107.8, 106.7, 98.8, 97.9, 96.5, 94.7, 85.1, 84.6, 84.4, 74.3, 74.2, 73.9, 73.8, 71.2, 70.7, 68.6, 68.1, 63.5, 62.3, 62.1, 62.0, 37.0, 36.5, 36.1, 36.0, 35.9, 35.9, 35.8, 31.0, 30.9, 30.8, 30.4, 26.4, 26.4, 26.2, 26.2, 25.5, 25.4, 25.3, 20.3, 19.6, 19.4, 19.2.

2-(3-(Allyloxy)-1-(furan-2-yl)-4-phenylbutyl)tetrahydro-2H-pyran (21e)

The reaction was conducted according to the procedure described for 21a with 20e (700.8 mg, 2.23 mmol) and NaBH₄ (168 mg, 4.44 mmol) in MeOH (20 mL) for 1.5 h. Purification via silica gel column chromatography (25% EtOAc/hexanes) afforded 1-(furan-2-yl)-4,4-dimethyl-1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol (551.2 mg, 78% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (dtd, J = 4.6, 2.3, 1.3 Hz, 1H), 6.35–6.23 (m, 2H), 5.02–4.49 (m, 2H), 4.22–3.83 (m, 2H), 3.77–3.27 (m, 1H), 2.19–2.02 (m, 2H), 1.95–1.61 (m, 1H), 1.53 (tdd, J = 11.5, 7.8, 4.3 Hz, 4H), 1.21 (td, J = 6.4, 2.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 142.4, 110.0, 109.9, 108.1, 98.3, 95.5, 70.3, 68.3, 67.2, 64.6, 62.6, 42.6, 42.5, 30.2, 25.1, 23.3, 22.6, 19.5. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₉H₂₄O₄Na 339.1572; found 339.1571.

To the above alcohol (33.6 mg, 0.106 mmol) in DMF (2 mL), NaH (59.3 mg, 60 wt% in mineral oil, 1.48 mmol) and allyl bromide (140 µL, 1.03 mmol) were added sequentially and warmed to 50 °C. The reaction was stirred for 14 h. The solution was diluted with EtOAc and the organic layers were separated. The aqueous layer was extracted with EtOAc (3×), the combined organic layers were washed with ice and brine sequentially, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (8% EtOAc/hexanes) to give 21e (30.5 mg, 81% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.45–7.18 (m, 5H), 6.39–6.16 (m, 2H), 5.98–5.80 (m, 1H), 5.45–5.12 (m, 2H), 4.99 (td, J = 6.4, 2.9 Hz, 1H), 4.91–4.78 (m, 1H), 4.55 (dt, J = 16.9, 3.5 Hz, 1H), 4.33–3.33 (m, 5H), 2.97–2.75 (m, 2H), 2.27–2.07 (m, 2H), 2.01–1.47 (m, 5H). ¹³C NMR (100 MHz, CDCl₃) δ 153.6, 142.3, 135.0, 129.5, 128.2, 128.1, 126.0, 116.3, 109.7, 108.7, 95.0, 70.5, 70.4, 67.3, 62.1, 40.6, 38.8, 30.4, 25.4, 19.2. HRMS (ESI+) m/z: [M − OAllyl]⁺ calcd C₁₉H₂₃O₃ 299.1647; found 299.1637.

3-(Allyloxy)-1-(furan-2-yl)butan-1-ol (22a)

To a round bottom flask charged with 21a (1.82 g, 6.49 mmol) in MeOH (65 mL), DOWEX-50W-X8 (2.72 g) was added, and the reaction was stirred for 7 h. The resin was filtered off, and the crude mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (20% EtOAc/hexanes) afforded alcohol 22a (455 mg, 36% yield) as a yellow oil along with the recovery of the starting material (655 mg, 36% recovery). ¹H NMR (500 MHz, CDCl₃) δ 7.43–7.38 (m, 1H), 6.37 (td, J = 3.4, 1.8 Hz, 1H), 6.29 (t, J = 3.7 Hz, 1H), 5.97 (dddt, J = 19.3, 10.8, 5.6, 3.0 Hz, 1H), 5.37–5.27 (m, 1H), 5.26–5.20 (m, 1H), 5.00 (ddd, J = 31.4, 8.6, 3.5 Hz, 1H), 4.23–4.10 (m, 1H), 4.00–3.92 (m, 1H), 3.80 (dqd, J = 9.4, 5.9, 3.3 Hz, 1H), 2.18–1.94 (m, 2H), 1.26 (dd, J = 6.2, 2.5 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 157.1, 156.5, 141.8, 141.7, 134.9, 134.6, 117.2, 116.9, 110.1, 105.5, 75.1, 72.8, 69.6, 69.3, 67.5, 65.6, 42.6, 41.5, 19.7, 19.4. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₁H₂₁₆O₃Na 219.0997; found 219.0999.

3-(Allyloxy)-1-(furan-2-yl)-3-phenylpropan-1-ol (22b)

The reaction was conducted according to the procedure described for 22a with 21b (766 mg, 2.24 mmol) and DOWEX-50W-X8 (1.2 g) in MeOH (22 mL) for 6 h. Purification via silica gel column chromatography (8–12% EtOAc/hexanes) afforded alcohol 22b (318 mg, 36% yield) as a yellow oil along with the recovery of the starting material (318 mg, 55% recovery). ¹H NMR (500 MHz, CDCl₃) δ 7.40–7.27 (m, 6H), 6.32 (ddd, J = 11.4, 3.2, 1.8 Hz, 1H), 6.25 (t, J = 3.9 Hz, 1H), 5.90 (dddd, J = 16.8, 10.3, 6.2, 5.0 Hz, 1H), 5.25 (dq, J = 17.2, 1.6 Hz, 1H), 5.21–5.14 (m, 1H), 4.95 (ddd, J = 33.9, 8.8, 3.4 Hz, 1H), 4.59 (ddd, J = 13.7, 9.5, 3.8 Hz, 1H), 3.94 (ddt, J = 12.7, 5.1, 1.6 Hz, 1H), 3.83–3.74 (m, 1H), 2.45–2.25 (m, 1H), 2.22–2.09 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 157.0, 156.4, 141.8, 141.8, 141.7, 141.3, 134.6, 134.3, 128.7, 128.6, 128.0, 127.8, 126.6, 126.5, 117.3, 117.1, 110.2, 110.2, 105.8, 105.7, 81.1, 78.6, 69.8, 69.5, 67.1, 65.3, 43.9, 43.4. HRMS (APCI+) m/z: [M − OH]⁺ calcd C₁₆H₁₇O₂ 241.1223; found 241.1216.

3-(Allyloxy)-1-(furan-2-yl)-4-methylpentan-1-ol (22c)

The reaction was conducted according to the procedure described for 22a with 21c (61.6 mg, 0.2 mmol) and DOWEX-50W-X8 (108.8 mg) in MeOH (2 mL) for 1.5 h. Purification via silica gel column chromatography (20% EtOAc/hexanes) afforded alcohol 22c (18.5 mg, 47% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.42 (dd, J = 1.9, 0.9 Hz, 1H), 6.38 (d, J = 1.4 Hz, 1H), 6.32–6.28 (m, 1H), 6.05–5.93 (m, 1H), 5.34 (ddt, J = 17.2, 5.6, 1.6 Hz, 1H), 5.28–5.18 (m, 1H), 4.99 (ddd, J = 37.6, 8.5, 3.7 Hz, 1H), 4.21–4.10 (m, 1H), 4.05–3.94 (m, 1H), 3.47 (dddd, J = 19.1, 8.7, 4.8, 3.1 Hz, 1H), 2.15–1.92 (m, 3H), 1.03–0.90 (m, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 156.7, 141.8, 135.0, 134.6, 117.2, 116.9, 110.1, 105.6, 105.5, 84.0, 81.6, 70.9, 70.2, 67.9, 65.6, 35.0, 34.8, 30.1, 29.6, 18.8, 18.5, 17.1, 16.2. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₃H₂₀O₃Na 247.1310; found 247.1302.

3-(Allyloxy)-1-(furan-2-yl)-4,4-dimethylpentan-1-ol (22d)

The reaction was conducted according to the procedure described for 22a with 21d (188.5 mg, 0.58 mmol) and DOWEX-50W-X8 (1.02 g) in MeOH (6 mL) for 4.5 h. Purification via silica gel column chromatography (20% EtOAc/hexanes) afforded alcohol 22d (47.6 mg, 34% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.43 (ddt, J = 2.8, 1.8, 0.9 Hz, 1H), 6.39 (ddt, J = 4.9, 3.0, 1.3 Hz, 1H), 6.34–6.27 (m, 1H), 6.07–5.93 (m, 1H), 5.40–5.28 (m, 1H), 5.21 (dddd, J = 10.4, 9.0, 2.3, 1.0 Hz, 1H), 4.95 (td, J = 8.5, 4.1 Hz, 1H), 4.26–4.10 (m, 2H), 3.39–3.09 (m, 1H), 2.18–2.12 (m, 1H), 2.11–1.98 (m, 1H), 1.91 (dddd, J = 14.3, 10.4, 2.8, 0.8 Hz, 0H), 0.98 (dd, J = 10.8, 0.8 Hz, 10H). ¹³C NMR (125 MHz, CDCl₃) δ 157.4, 156.5, 141.9, 141.8, 135.4, 134.7, 116.7, 116.2, 110.2, 106.0, 105.5, 87.5, 84.5, 74.5, 74.3, 67.3, 65.2, 37.1, 36.5, 36.3, 35.9, 26.4, 26.2. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₄H₂₂O₃Na 261.1467; found 261.1459.

3-(Allyloxy)-1-(furan-2-yl)-4-phenylbutan-1-ol (22e)

The reaction was conducted according to the procedure described for 22a with 21e (375 mg, 1.05 mmol) and DOWEX-50W-X8 (567.6 mg) in MeOH (10 mL) for 24 h. Purification via silica gel column chromatography (20% EtOAc/hexanes) afforded alcohol 22e (214.6 mg, 75% yield) as a yellow oil along with the recovery of the starting material with a mixture of side products. ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.20 (m, 5H), 6.35–6.32 (m, 1H), 6.21 (dt, J = 3.2, 0.8 Hz, 1H), 5.86 (ddt, J = 17.1, 10.1, 6.8 Hz, 1H), 5.21–5.11 (m, 2H), 4.90 (dd, J = 8.8, 3.9 Hz, 1H), 3.87–3.74 (m, 2H), 3.52 (dt, J = 8.9, 6.6 Hz, 1H), 3.05 (dd, J = 13.6, 4.9 Hz, 1H), 2.78 (dd, J = 13.6, 7.5 Hz, 1H), 2.10–1.92 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 156.4, 141.8, 137.8, 134.9, 129.5, 128.5, 126.5, 117.2, 110.1, 105.6, 81.4, 68.6, 67.6, 40.5, 39.6, 34.5, 29.3. HRMS (APCI+) m/z: [M − OH]⁺ calcd C₁₇H₁₉O₂ 255.1380; found 255.1383.

Ethyl 3-(allyloxy)butanoate (24a)

A round bottom flask was charged with commercially available ethyl 3-hydroxybutanoate 23a (2 mL, 15.4 mmol) and CH₂Cl₂ (45 mL) and the mixture was cooled to 0 °C. O-Allyl 2,2,2-trichloroacetimidate (6.8 mL, 44.8 mmol) and TfOH (0.1 mL, 1.13 mmol) were added sequentially. The reaction was stirred at 0 °C for 30 min and then warmed to 23 °C and stirred for 15 h. Purification via silica gel column chromatography (2% EtOAc/hexanes) afforded allyloxy 24a (1.96 g, 74% yield) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 5.92 (ddt, J = 17.2, 10.3, 5.6 Hz, 1H), 5.33–5.13 (m, 2H), 4.17 (q, J = 7.1 Hz, 2H), 4.11–3.89 (m, 3H), 2.62 (dd, J = 15.0, 7.1 Hz, 1H), 2.40 (dd, J = 15.0, 5.9 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.24 (d, J = 6.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 171.5, 135.1, 116.7, 71.8, 69.8, 60.4, 42.1, 19.9, 14.2. Experimental data are consistent with the data reported in the literature.³³

Ethyl 3-(allyloxy)-3-phenylpropanoate (24b)

The reaction was conducted according to the procedure described for 24a with commercially available ethyl 3-hydroxy-3-phenylpropanoate 23b (1.75 mL, 10.1 mmol), O-allyl 2,2,2-trichloroacetimidate (3 mL, 19.8 mmol), and TfOH (0.1 mL, 1.13 mmol) in CH₂Cl₂ and pentanes (300 mL, 1 : 2) for 1.5 h. Purification via silica gel column chromatography (2% EtOAc/hexanes) afforded allyloxy 24b (2.24 g, 52% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.39–7.27 (m, 5H), 5.87 (dddd, J = 17.3, 10.4, 6.1, 5.1 Hz, 1H), 5.21 (dq, J = 17.2, 1.7 Hz, 1H), 5.14 (dd, J = 10.4, 1.6 Hz, 1H), 4.81 (dd, J = 9.1, 4.9 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.92 (ddt, J = 12.7, 5.2, 1.5 Hz, 1H), 3.79 (ddt, J = 12.7, 6.1, 1.4 Hz, 1H), 2.83 (dd, J = 15.3, 9.1 Hz, 1H), 2.59 (dd, J = 15.2, 4.9 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 170.9, 140.9, 134.6, 128.6, 128.0, 126.7, 116.9, 77.7, 69.7, 60.5, 43.7, 14.2. HRMS (APCI+) m/z: [M − OAllyl]⁺ calcd C₁₁H₁₃O₂ 177.0910; found 177.0913.

Ethyl 3-(allyloxy)-4-methylpentanoate (24c)

The reaction was conducted according to the procedure described for 24a with known ethyl 3-hydroxy-4-methylpenanoate 23c ³⁴ (2.4 g, 15.0 mmol), O-allyl 2,2,2-trichloroacetimidate (4.5 mL, 29.6 mmol), and TfOH (0.1 mL, 1.13 mmol) in CH₂Cl₂ and pentanes (45 mL, 1 : 2) for 19 h. Purification via silica gel column chromatography (2% EtOAc/hexanes) afforded allyloxy 24c (2.16 g 72%) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 5.94–5.83 (m, 1H), 5.24 (dd, J = 17.2, 1.7 Hz, 1H), 5.12 (dd, J = 10.4, 1.6 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 4.04–4.00 (m, 2H), 3.63 (dt, J = 8.1, 4.7 Hz, 1H), 2.51–2.38 (m, 2H), 1.88 (pd, J = 6.9, 4.8 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H), 0.92 (dd, J = 6.9, 1.9 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 172.4, 135.2, 116.4, 80.8, 71.3, 60.4, 37.0, 31.4, 18.0, 17.8, 14.2. HRMS (APCI+) m/z: [M − OAllyl]⁺ calcd C₁₀H₁₃O₂ 165.0910; found 165.0911.

Ethyl 3-(3-hydroxypropoxy)butanoate (25a)

A two-neck round-bottom flask was charged with alkene 24a (915 mg, 5.31 mmol) in THF (15 mL) and cooled to 0 °C, and 9-BBN (25 mL, 0.5 M in THF, 12.5 mmol) was added dropwise. The reaction was stirred for 30 min at 0 °C and then warmed to 23 °C and stirred for another 1.5 h. At the end of the reaction, a solution of NaBO₃·4 H₂O (4.61 g, 30 mmol) in H₂O (100 mL) was prepared. The reaction mixture was transferred using a cannula into the water and stirred for 13 h. The solution was then diluted with EtOAc and the precipitates were filtered out. The aqueous layer was extracted with EtOAc (5×), and the combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. Purification via silica gel column chromatography (20–30% EtOAc/hexanes) afforded 25a (665 mg, 66% yield) as a colourless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.10 (q, J = 7.1 Hz, 2H), 3.83 (dqd, J = 7.7, 6.2, 5.1 Hz, 1H), 3.71–3.64 (m, 3H), 3.51 (dt, J = 9.0, 6.1 Hz, 1H), 2.49 (dd, J = 15.1, 7.8 Hz, 1H), 2.35 (dd, J = 15.2, 5.1 Hz, 1H), 1.78–1.69 (m, 2H), 1.25–1.14 (m, 5H). ¹³C NMR (100 MHz, CDCl₃) δ 171.6, 72.5, 67.3, 61.2, 60.4, 41.8, 32.1, 19.4, 14.0. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₉H₁₈O₄Na 213.1103; found 213.1099.

Ethyl 3-(3-hydroxypropoxy)-3-phenylpropanoate (25b)

The reaction was conducted according to the procedure described for 24a with alkene 24b (1.24 g, 5.29 mmol) and 9-BBN (25 mL, 12.5 mmol) in THF (20 mL) and the mixture was stirred for 1.5 h; then NaBO₃·4 H₂O (5.78 g, 37.6 mmol) in H₂O (250 mL) was added and stirred for 1 h. Purification via silica gel column chromatography (20–30% EtOAc/hexanes) afforded 25b (878 mg, 66% yield) as a colourless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.31–7.19 (m, 5H), 4.67 (dd, J = 9.5, 4.3 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.63 (ddd, J = 6.3, 5.7, 2.6 Hz, 2H), 3.48–3.33 (m, 2H), 2.86 (s, 1H), 2.72 (dd, J = 15.4, 9.5 Hz, 1H), 2.50 (dd, J = 15.4, 4.3 Hz, 1H), 1.70 (p, J = 5.9 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 171.0, 140.6, 128.5, 127.9, 126.3, 78.7, 67.3, 60.7, 60.5, 43.4, 32.1, 14.0. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₄H₂₀O₄Na 275.1259; found 275.1260.

Ethyl 3-(3-hydroxypropoxy)-4-methylpentanoate (25c)

The reaction was conducted according to the procedure described for 24a with alkene 24c (2.16 g, 10.8 mmol) and 9-BBN (50 mL, 25 mmol) in THF (20 mL) and the mixture was stirred for 2.5 h; then NaBO₃·4 H₂O (11.54 g, 75.0 mmol) in H₂O (250 mL) was added and stirred for 1.75 h. Purification via silica gel column chromatography (20–30% EtOAc/hexanes) afforded 25c (2.36 g, 99% yield) as a colourless oil. ¹H NMR (500 MHz, CDCl₃) δ 4.19–4.11 (m, 2H), 3.78–3.54 (m, 3H), 2.43 (dd, J = 6.3, 2.9 Hz, 2H), 1.90 (qd, J = 6.8, 3.4 Hz, 2H), 1.81–1.71 (m, 3H), 1.27 (dd, J = 8.3, 6.4 Hz, 6H), 0.91 (dd, J = 6.9, 2.8 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 172.6, 81.6, 69.2, 61.6, 60.6, 36.6, 32.4, 31.1, 18.1, 17.6, 14.2. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₁H₁₂₂O₄Na 241.1416; found 241.1411.

Ethyl 3-(but-3-en-1-yloxy)butanoate (26a)

To a flame dried round-bottom flask charged with alcohol 25a (428.2 mg, 2.25 mmol) in CH₂Cl₂ (20 mL) at 0 °C, Dess–Martin periodinane (1.46 g, 3.45 mmol) was added; the reaction was stirred for 30 min, and then warmed to 23 °C and stirred for 15 min. The reaction was quenched with the addition of a 1 : 1 solution of 10% Na₂S₂O₃ and NaHCO₃ in water and extracted with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification via silica gel column chromatography (20% EtOAc/hexanes) afforded ethyl 3-(3-oxopropoxy)butanoate (404.1 mg, 96% yield) as a colourless oil. ¹H NMR (500 MHz, CDCl₃) δ 9.70 (s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.83 (ddt, J = 21.8, 9.7, 6.0 Hz, 2H), 3.69 (dt, J = 9.7, 6.1 Hz, 1H), 2.56 (t, J = 5.8 Hz, 1H), 2.48 (dd, J = 15.2, 7.7 Hz, 1H), 2.31 (dd, J = 15.2, 5.4 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H), 1.15 (d, J = 6.2 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 201.3, 171.3, 72.6, 62.5, 60.4, 43.9, 41.9, 19.5, 14.2. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₉H₁₆O₄Na 211.0946; found 211.0940.

The above aldehyde (384.5 mg, 2.04 mmol) was dissolved in THF (14 mL) and cooled to −78 °C. TMSMeMgCl (2.8 mL, 1.0 M in THF, 2.80 mmol) was added dropwise and the reaction was stirred for 45 min. Upon completion, the reaction was quenched with saturated NH₄Cl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification via silica gel column chromatography (10–20% EtOAc/hexanes) afforded ethyl 3-(3-hydroxy-4-(trimethylsilyl)butoxy)butanoate (206.2 mg, 37% yield) as a colourless oil along with the recovery of the starting material (119.1 mg, 31% recovery). ¹H NMR (400 MHz, CDCl₃) δ 4.18–4.09 (m, 2H), 4.00–3.82 (m, 2H), 3.79–3.50 (m, 2H), 2.54 (ddd, J = 15.4, 7.7, 6.0 Hz, 1H), 2.38 (ddd, J = 15.0, 5.2, 2.7 Hz, 1H), 1.69 (tdd, J = 5.9, 4.8, 0.9 Hz, 1H), 1.26 (td, J = 7.1, 0.9 Hz, 3H), 1.21 (dd, J = 6.2, 3.5 Hz, 3H), 0.90 (ddd, J = 14.5, 8.1, 1.1 Hz, 1H), 0.76 (ddd, J = 14.5, 6.0, 1.1 Hz, 1H), 0.03 (d, J = 0.6 Hz, 9H). HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₃H₂₈O₄SiNa 299.1655; found 299.1642.

The above alcohol (40.7 mg, 0.147 mmol) was dissolved in CH₂Cl₂ (5 mL) and cooled to −78 °C; then BF₃·OEt₂ (32 µL, 0.262 mmol) was added dropwise. The reaction mixture was stirred for 2 h, warmed to 0 °C and stirred for another 4.5 h. The reaction was quenched with H₂O and extracted with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (10% EtOAc/hexanes) to give homoallyloxy 26a (23.6 mg, 86% yield, 31% overall yield) as a colourless oil.¹²¹H NMR (400 MHz, CDCl₃) δ 5.79 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.06 (dq, J = 17.2, 1.7 Hz, 1H), 5.00 (ddt, J = 10.2, 2.1, 1.2 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.86 (dp, J = 7.4, 6.1 Hz, 1H), 3.54 (dt, J = 9.1, 6.7 Hz, 1H), 3.43 (dt, J = 9.2, 6.8 Hz, 1H), 2.56 (dd, J = 14.9, 7.4 Hz, 1H), 2.34 (dd, J = 15.0, 5.8 Hz, 1H), 2.28 (qt, J = 6.9, 1.5 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 171.5, 135.2, 116.1, 72.2, 68.1, 60.2, 42.0, 34.3, 19.7, 14.1.

Ethyl 3-(but-3-en-1-yloxy)-3-phenylpropanoate (26b)

The reaction was conducted according to the procedure described for 26a with alcohol 25b (6.66 g, 26.4 mmol) and Dess–Martin periodinane (15.72 g, 37.1 mmol) in CH₂Cl₂ (250 mL) for 1.5 h. The product was purified via silica gel column chromatography (20% EtOAc/hexanes) to give ethyl 3-(3-oxopropoxy)-3-phenylpropanoate (45.2 mg, 76%) as a colourless oil. ¹H NMR (400 MHz, CDCl₃) δ 9.72 (td, J = 2.0, 0.5 Hz, 1H), 7.39–7.27 (m, 5H), 4.76 (dd, J = 9.4, 4.5 Hz, 1H), 4.13 (qd, J = 7.1, 1.0 Hz, 2H), 3.72–3.61 (m, 2H), 2.77 (dd, J = 15.5, 9.4 Hz, 1H), 2.62–2.51 (m, 3H), 1.23 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 201.2, 170.7, 140.4, 128.6, 128.1, 126.4, 78.8, 62.8, 60.5, 43.5, 43.4, 14.1. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₄H₁₈O₄Na 273.1097; found 273.1104.

The above aldehyde (5.21 g, 20.8 mmol) was dissolved in THF (200 mL) and cooled to −78 °C. TMSMeMgCl (42 mL, 1.0 M in THF, 42 mmol) was added dropwise and the reaction mixture was stirred for 30 min. Upon completion, the reaction was quenched with saturated NH₄Cl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification via silica gel column chromatography (10–20% EtOAc/hexanes) afforded ethyl 3-(3-hydroxy-4-(trimethylsilyl)butoxy)-3-phenylpropanoate (2.2 g, 31% yield) as a colourless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.39–7.28 (m, 5H), 4.72 (dt, J = 9.6, 3.8 Hz, 1H), 4.19–4.11 (m, 2H), 4.00–3.91 (m, 1H), 3.57–3.44 (m, 2H), 2.80 (ddd, J = 15.6, 9.6, 1.5 Hz, 1H), 2.61–2.52 (m, 1H), 1.75–1.61 (m, 2H), 1.25 (td, J = 7.2, 1.9 Hz, 3H), 0.94–0.71 (m, 2H), 0.03 (d, J = 1.7 Hz, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 171.2, 171.0, 140.7, 140.5, 128.7, 128.2, 128.1, 126.6, 126.5, 79.1, 69.9, 68.6, 68.4, 67.6, 60.8, 60.7, 43.5, 43.4, 39.7, 39.6, 26.4, 26.2, 14.2, 14.2, −0.7. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₈H₃₀O₄SiNa 361.1811; found 361.1804.

The above alcohol (2.2 g, 6.48 mmol) was dissolved in CH₂Cl₂ (50 mL) and cooled to −78 °C; then BF₃·OEt₂ (0.9 mL, 7.36 mmol) was added dropwise and the reaction mixture was stirred for 1.5 h. The reaction was quenched with H₂O and extracted with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (10% EtOAc/hexanes) to give homoallyloxy 26b (1.18 g, 73% yield, 17% overall yield) as a colourless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.25 (m, 5H), 5.77 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.06–4.95 (m, 2H), 4.75 (dd, J = 9.2, 4.7 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.37 (ddt, J = 27.7, 9.3, 6.7 Hz, 2H), 2.80 (dd, J = 15.2, 9.2 Hz, 1H), 2.56 (dd, J = 15.2, 4.7 Hz, 1H), 2.35–2.23 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 171.0, 141.2, 135.3, 128.5, 127.9, 126.6, 116.2, 78.6, 68.5, 60.5, 43.8, 34.1, 14.2. HRMS (APCI+) m/z: [M + Na]⁺ calcd C₁₅H₂₀O₃Na 171.1305; found 171.1335.

Ethyl 3-(but-3-en-1-yloxy)-4-methylpentanoate (26c)

The reaction was conducted according to the procedure described for 26a with alcohol 25c (545 mg, 2.5 mmol) and Dess–Martin periodinane (1.58 g, 3.73 mmol) in CH₂Cl₂ (25 mL) for 1.5 h. The product was purified via silica gel column chromatography (20% EtOAc/hexanes) to give ethyl 4-methyl-3-(3-oxopropoxy)pentanoate (481 mg, 89%) as a colourless oil. ¹H NMR (400 MHz, CDCl₃) δ 9.75 (t, J = 2.0 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.89–3.77 (m, 2H), 3.61 (dt, J = 7.8, 4.9 Hz, 1H), 2.62–2.56 (m, 2H), 2.40 (dd, J = 6.4, 4.0 Hz, 2H), 1.87 (pd, J = 6.9, 5.0 Hz, 1H), 1.25 (d, J = 7.1 Hz, 3H), 0.89 (dd, J = 6.9, 3.2 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 201.5, 172.2, 81.3, 63.9, 60.4, 43.9, 36.5, 31.0, 17.9, 17.5, 14.1. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₁H₂₀O₄Na 239.1259; found 239.1250.

The above aldehyde (831 mg, 3.84 mmol) was dissolved in THF (200 mL) and cooled to −78 °C. TMSMeMgCl (7.7 mL, 1.0 M in THF, 7.7 mmol) was added dropwise and the reaction mixture was stirred for 25 min. Upon completion, the reaction was quenched with saturated NH₄Cl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification via silica gel column chromatography (10–20% EtOAc/hexanes) afforded ethyl 3-(3-hydroxy-4-(trimethylsilyl)butoxy)-4-methylpentanoate (181 mg, 15% yield) as a colourless oil along with the recovery of the starting material (91.5 mg, 11% recovery). ¹H NMR (500 MHz, CDCl₃) δ 4.15 (qd, J = 7.2, 2.2 Hz, 2H), 3.99–3.91 (m, 1H), 3.74–3.60 (m, 2H), 3.57 (dtd, J = 8.0, 4.7, 1.6 Hz, 1H), 2.93 (s, 1H), 2.48–2.37 (m, 2H), 1.89 (dqd, J = 11.9, 6.9, 5.1 Hz, 1H), 1.74–1.56 (m, 2H), 1.26 (td, J = 7.1, 2.5 Hz, 3H), 0.90 (ddd, J = 6.9, 3.0, 1.4 Hz, 7H), 0.03 (s, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 172.7, 172.4, 81.7, 81.6, 70.0, 69.4, 68.9, 68.6, 60.6, 40.0, 39.9, 36.6, 36.5, 31.1, 30.9, 26.4, 26.2, 18.1, 18.0, 17.6, 14.2, −0.7, −0.7. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₅H₃₂O₄SiNa 327.1968; found 327.1956.

The above alcohol (48.3 mg, 0.159 mmol) was dissolved in CH₂Cl₂ (5 mL) and cooled to −78 °C; then BF₃·OEt₂ (30 µL, 0.245 mmol) was added dropwise and the reaction mixture was stirred for 3 h. The reaction was quenched with H₂O and extracted with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (10% EtOAc/hexanes) to give homoallyloxy 26c (19.8 mg, 58% yield, 8% overall yield) as a colourless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.80 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.06 (dq, J = 17.3, 1.9 Hz, 1H), 5.00 (ddt, J = 10.3, 2.2, 1.2 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.56 (dt, J = 8.0, 4.9 Hz, 1H), 3.51 (t, J = 6.8 Hz, 2H), 2.47–2.35 (m, 2H), 2.27 (qt, J = 6.8, 1.4 Hz, 2H), 1.86 (heptd, J = 6.8, 5.0 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H), 0.90 (dd, J = 6.8, 4.1 Hz, 7H). ¹³C NMR (100 MHz, CDCl₃) δ 172.4, 135.4, 116.0, 81.1, 69.6, 60.3, 36.8, 34.5, 31.3, 18.0, 17.6, 14.1. HRMS (ESI+) m/z: [M − OCH₂CH₂CHCH₂]⁺ calcd C₈H₁₅O₂ 143.1067; found 143.1063.

3-(But-3-en-1-yloxy)-1-(furan-2-yl)butan-1-ol (27a)

To a round bottom flask charged with ester 26a (188 mg, 1.01 mmol) in CH₂Cl₂ (10 mL) at −78 °C, DIBAL (1.1 mL, 1.0 M, 1.10 mmol) was added dropwise and stirred for 30 min. The reaction was quenched with MeOH (0.12 mL, 2.96 mmol) and a saturated solution of Rochelle's salt in water (0.5 mL) was added; then the reaction was slowly warmed to 23 °C. The resulting slurry was filtered over a layer of Na₂SO₄ and a layer of Celite, and the clear solution was then concentrated under reduced pressure.

A solution of 2-lithiofuran was prepared by charging a dry round bottom flask with furan (240 µL, 3.30 mmol) in THF (4 mL) and cooled to 0 °C. n-BuLi (2 mL, 1.5 M in hexanes, 3 mmol) was added dropwise and the reaction mixture was stirred for 30 min and then cooled to −78 °C. The crude aldehyde from the above reaction was dissolved in THF (6 mL) and cannulated into the solution of 2-lithiofuran and continued to stir at −78 °C for 15 min. The reaction mixture was stirred for 15 min, quenched with saturated NH₄Cl, and warmed to 23 °C. The solution was diluted with EtOAc and the organic layers were separated. The aqueous layer was extracted with EtOAc (3×); the combined organic layers were washed with ice and brine sequentially, dried over Na₂SO₄, and concentrated under reduced pressure. Purification via silica gel column chromatography (14% EtOAc/hexanes) afforded 27a (11.5 mg, 52% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.34 (s, 1H), 6.30 (dd, J = 3.2, 1.9 Hz, 1H), 6.22 (d, J = 3.2 Hz, 1H), 5.81 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H), 5.15–5.03 (m, 2H), 4.90 (dd, J = 9.5, 3.2 Hz, 1H), 3.95 (s, 1H), 3.76–3.64 (m, 2H), 3.37 (dt, J = 9.0, 6.7 Hz, 1H), 2.37–2.28 (m, 2H), 2.18–1.96 (m, 1H), 1.89 (dt, J = 14.5, 3.2 Hz, 1H), 1.19 (d, J = 6.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 156.4, 141.5, 134.9, 116.9, 110.0, 105.3, 76.0, 67.7, 67.4, 42.4, 34.4, 19.5. HRMS (APCI+) m/z: [M − OH]⁺ calcd C₁₂H₁₇O₂ 193.1223; found 193.1224.

3-(But-3-en-1-yloxy)-1-(furan-2-yl)-3-phenylpropan-1-ol (27b)

The reaction was conducted according to the procedure described for 27a with ester 26b (64.3 mg, 0.26 mmol) and DIBAL (0.27 mL, 1.0 M, 0.27 mmol) in CH₂Cl₂ (2.6 mL). 2-Lithiofuran was prepared from furan (65 µL, 0.895 mmol) and n-BuLi (0.5 mL, 1.6 M in hexanes, 0.8 mmol) in THF (1.6 mL). The crude aldehyde obtained from DIBAL reducion, was cannulated over in THF (1 mL) and stirred for 30 min. Purification via silica gel column chromatography (14% EtOAc/hexanes) afforded 27b (16.0 mg, 23% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.42–7.25 (m, 7H), 6.36–6.21 (m, 2H), 5.81 (ddq, J = 17.0, 10.2, 6.6 Hz, 1H), 5.15–5.04 (m, 2H), 4.97 (ddd, J = 8.9, 7.0, 3.0 Hz, 1H), 4.52 (ddd, J = 21.1, 9.8, 3.5 Hz, 1H), 3.96 (s, 1H), 3.43 (dq, J = 9.2, 6.2 Hz, 1H), 3.32 (ddt, J = 22.6, 9.3, 6.6 Hz, 1H), 2.38–2.27 (m, 3H), 2.29–2.14 (m, 1H), 2.07 (dt, J = 14.7, 3.2 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 157.0, 156.3, 141.8, 141.7, 141.4, 135.3, 135.0, 128.6, 128.6, 128.0, 127.7, 126.4, 126.4, 117.1, 116.8, 110.2, 110.1, 105.8, 105.5, 82.8, 79.8, 68.2, 68.0, 67.8, 65.9, 44.0, 43.1, 34.3, 34.3. LRMS-ESI (m/z) [M + Na]⁺ 295.1.

3-(But-3-en-1-yloxy)-1-(furan-2-yl)-4-methylpentan-1-ol (27c)

The reaction was conducted according to the procedure described for 27a with ester 26c (73.9 mg, 0.35 mmol) and DIBAL (0.5 mL, 1.0 M, 0.5 mmol) in CH₂Cl₂ (3.5 mL). 2-Lithiofuran was prepared from furan (85 µL, 1.17 mmol) and n-BuLi (0.65 mL, 1.6 M in hexanes, 1.04 mmol) in THF (2.5 mL). The crude aldehyde obtained from DIBAL reduction, was cannulated over in THF (1 mL) and stirred for 15 min. Purification via silica gel column chromatography (14% EtOAc/hexanes) afforded 27c (34.0 mg, 41% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.34 (m, 1H), 6.32 (dd, J = 3.3, 1.8 Hz, 1H), 6.24 (d, J = 3.2 Hz, 1H), 5.82 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H), 5.16–5.05 (m, 2H), 4.89 (dd, J = 9.0, 3.7 Hz, 1H), 3.94 (s, 1H), 3.68 (dt, J = 9.0, 6.4 Hz, 1H), 3.46–3.37 (m, 2H), 2.39–2.29 (m, 2H), 2.06 (pd, J = 6.9, 4.1 Hz, 1H), 1.98–1.84 (m, 2H), 0.88 (dd, J = 6.9, 6.9 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 156.8, 141.7, 135.1, 117.1, 110.1, 105.4, 84.8, 68.3, 68.1, 34.7, 29.2, 18.5, 15.8. HRMS (ESI+) m/z: [M − OH]⁺ calcd C₁₄H₂₁O₂ 221.1536; found 221.1536.

2-Methyloctahydro-1H-3a,7-epoxyazulen-4-ol (28)

Cycloadduct 10a (16 mg, 98.1 µmol) was dissolved in EtOAc (3 mL), and Rh/AlO₃ (4.5 mg, 5% Rh) was added. The flask was flushed with argon and hydrogen sequentially and then stirred under a hydrogen-filled balloon for 1 h. The reaction was flushed with argon before filtering the solids out over Celite to give the alcohol as a mixture of diastereomers. The mixture of alcohols was dissolved in CH₂Cl₂ and DMP (179 mg, 0.42 mmol) and NaHCO₃ (70.3 mg, 0.84 mmol) were added in portions. The reaction mixture was stirred for 4 h and then quenched with aqueous NaHCO₃ and 10% Na₂S₂O₃. The organic layer was separated, and the aqueous layer was washed with CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The crude ketone was dissolved in dry MeOH (3 mL) and cooled to −78 °C, and NaBH₄ (7.2 mg, 0.19 mmol) was added. The reaction mixture was stirred for 15 min and then quenched with aq. sat. NH₄Cl. The reaction was diluted with EtOAc, the organic layer was separated, and the aqueous layer was washed with EtOAc (5×). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Purification via silica gel column chromatography (15% EtOAc/hexanes) gave alcohol 28 (6.6 mg, 37% in 3-step) as a clear oil. ¹H NMR (800 MHz, DMSO) δ 4.66 (d, J = 5.7 Hz, 1H), 4.29 (dd, J = 7.3, 3.8 Hz, 1H), 3.43–3.34 (m, 1H), 2.42 (ddt, J = 15.1, 10.9, 5.7 Hz, 1H), 2.11 (ddd, J = 13.0, 8.3, 1.6 Hz, 1H), 1.93–1.86 (m, 2H), 1.70 (dt, J = 12.3, 7.5 Hz, 2H), 1.60 (ddd, J = 12.1, 7.2, 4.3 Hz, 1H), 1.57–1.51 (m, 1H), 1.33–1.26 (m, 2H), 1.05 (dd, J = 13.1, 10.2 Hz, 1H), 0.93 (d, J = 6.2 Hz, 3H), 0.92–0.87 (m, 1H). ¹³C NMR (201 MHz, DMSO) δ 94.9, 77.1, 69.2, 43.4, 41.8, 41.7, 37.4, 35.9, 30.7, 27.1, 19.9. HRMS (APCI+) m/z: [M − OH]⁺ calcd C₁₁H₁₇O 165.1274; found 165.1278.

6-(2-Methylpent-4-en-1-yl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (9a)

To a round bottom flask charged with furanyl alcohol 14a (65.5 mg, 0.36 mmol) in a mixture of THF and water (4 mL, 4 : 1) at 0 °C, KBr (10 mg, 0.08 mmol), NaHCO₃ (15.6 mg, 0.18 mmol), and Oxone (364 mg, 1.19 mmol) were added at the same time and stirred for 30 min. Upon completion of the reaction, the solution was diluted with EtOAc and water, the solids were filtered out, and the organic layers were separated. The aqueous layer was extracted with EtOAc (3×); the combined organic layers were washed with ice and brine sequentially, dried over Na₂SO₄, and concentrated under reduced pressure.

To crude lactol in CH₂Cl₂ (4 mL) at 0 °C, pyridine (60 µL, 0.745 mmol) and AcCl (40 µL, 0.71 mmol) were added sequentially and stirred for 30 min. Upon completion, the reaction was quenched with saturated NaHCO₃ solution. The organic layer was separated, and the aqueous layer was washed with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. Purification via silica gel column chromatography (16% EtOAc/hexanes) afforded 9a (46 mg, 53% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.90–6.79 (m, 1H), 6.55–6.44 (m, 1H), 6.24–6.14 (m, 1H), 5.83–5.67 (m, 1H), 5.06–4.94 (m, 2H), 4.57–4.26 (m, 1H), 2.19–1.45 (m, 6H), 0.95–0.84 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 196.0, 195.8, 195.7, 195.6, 169.4, 169.2, 142.5, 142.5, 141.3, 141.1, 136.8, 136.7, 136.5, 136.4, 128.5, 128.2, 128.1, 116.3, 116.2, 116.1, 87.4, 86.9, 77.7, 77.5, 77.1, 74.2, 73.8, 41.9, 41.7, 40.1, 39.9, 39.3, 39.2, 35.6, 35.5, 28.8, 28.7, 28.5, 28.3, 20.9, 20.8, 20.0, 19.9, 18.2, 18.1. HRMS (APCI+) m/z: [M − OAc]⁺ calcd C₁₁H₁₅O₂ 179.1067; found 179.1073.

5-Oxo-6-(2-phenylpent-4-en-1-yl)-5,6-dihydro-2H-pyran-2-yl acetate (9b)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 14b (88.7 mg, 0.366 mmol), KBr (12.2 mg, 0.10 mmol), NaHCO₃ (16.6 mg, 0.2 mmol), and Oxone (325 mg, 1.06 mmol) in THF and water (4 : 1, 5 mL) for 30 min. The crude lactol was protected by treatment with pyridine (60 µL, 0.745 mmol) and AcCl (40 µL, 0.712 mmol) in CH₂Cl₂ (5 mL) for 30 min. Purification via silica gel column chromatography (16% EtOAc/hexanes) afforded 9b (73.5 mg, 67% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.35–7.13 (m, 5H), 6.84–6.73 (m, 1H), 6.51–6.43 (m, 1H), 6.21–6.06 (m, 1H), 5.72–5.57 (m, 1H), 5.03–4.90 (m, 2H), 4.44–3.76 (m, 1H), 3.08–2.88 (m, 1H), 2.50–1.90 (m, 8H). ¹³C NMR (125 MHz, CDCl₃) δ 195.9, 195.7, 195.6, 169.5, 169.4, 169.4, 169.2, 144.2, 144.0, 143.3, 142.8, 142.5, 141.3, 140.9, 136.5, 136.5, 136.1, 128.8, 128.7, 128.7, 128.5, 128.4, 128.3, 128.0, 128.0, 127.8, 126.7, 126.5, 126.4, 126.4, 116.6, 116.4, 116.3, 88.1, 87.5, 86.9, 86.4, 73.9, 73.2, 60.4, 41.5, 41.3, 41.3, 41.1, 40.8, 40.8, 40.2, 40.1, 39.2, 38.3, 35.9, 35.0, 21.1, 21.0, 20.8, 14.2. HRMS (APCI+) m/z: [M − OAc]⁺ calcd C₁₆H₁₇O₂ 241.1223; found 241.1232.

6-(2-Isopropylpent-4-en-1-yl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (9c)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 14c (82.4 mg, 0.396 mmol), KBr (12.3 mg, 0.103 mmol), NaHCO₃ (17 mg, 0.198 mmol) and Oxone (365 mg, 1.19 mmol) in THF and water (4 : 1, 5 mL) for 20 min. The crude lactol was protected by treatment with pyridine (65 µL, 0.807 mmol) and AcCl (45 µL, 0.801 mmol) in CH₂Cl₂ (5 mL) for 20 min. Purification via silica gel column chromatography (16% EtOAc/hexanes) afforded 9c (63.0 mg, 60% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.84 (ddd, J = 10.3, 4.9, 3.2 Hz, 1H), 6.54–6.43 (m, 1H), 6.25–6.13 (m, 1H), 5.84–5.64 (m, 1H), 5.07–4.91 (m, 2H), 4.57–4.24 (m, 1H), 2.19–1.49 (m, 8H), 0.96–0.75 (m, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 195.9, 169.3, 142.7, 142.6, 141.2, 141.2, 137.8, 137.7, 137.5, 128.5, 128.3, 128.2, 115.8, 115.7, 115.6, 87.8, 87.6, 87.0, 77.8, 77.6, 74.3, 74.0, 38.9, 38.4, 38.3, 35.0, 34.7, 34.5, 33.8, 33.6, 30.0, 29.8, 29.7, 28.4, 27.9, 21.0, 20.8, 19.6, 19.5, 18.3, 18.1, 17.8, 17.4. HRMS (APCI+) m/z: [M − OAc]⁺ calcd C₁₃H₁₉O₂ 207.1385; found 207.1390.

6-(2-Methylhex-5-en-1-yl)-5-oxotetrahydro-2H-pyran-2-yl acetate (9d)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 18 (52.4 mg, 0.24 mmol), KBr (6.2 mg, 0.05 mmol), NaHCO₃ (13.7 mg, 0.16 mmol) and Oxone (225.6 mg, 0.75 mmol) in THF and water (4 : 1, 5 mL) for 45 min. The crude lactol was protected by treatment with pyridine (40 µL, 0.49 mmol) and AcCl (25 µL, 0.44 mmol) in CH₂Cl₂ (5 mL) for 18.5 h. Purification via silica gel column chromatography (5–10% EtOAc/hexanes) afforded 9d (36.2 mg, 59% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.85 (dtd, J = 10.9, 6.9, 3.8 Hz, 1H), 6.51 (dd, J = 23.7, 2.4 Hz, 1H), 6.24–6.16 (m, 1H), 5.79 (ddt, J = 13.4, 10.2, 6.7 Hz, 1H), 5.05–4.87 (m, 2H), 4.56–4.12 (m, 1H), 2.19–1.91 (m, 5H), 1.84–1.12 (m, 4H), 0.90 (dd, J = 8.6, 6.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 195.9, 195.8, 169.4, 142.5, 141.2, 141.1, 138.9, 128.5, 114.2, 87.0, 86.9, 74.1, 73.9, 36.6, 36.0, 35.9, 34.8, 31.1, 30.9, 28.5, 28.0, 20.8, 19.9, 18.3. HRMS (APCI+) m/z: [M − OAc]⁺ calcd C₁₂H₁₇O₂⁺ 193.1223; found 193.1222.

6-(2-(Allyloxy)propyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (9e)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 22a (26.3 mg, 0.134 mmol), KBr (6.2 mg, 0.05 mmol), NaHCO₃ (5.5 mg, 0.0655 mmol) and Oxone (127.8 mg, 0.42 mmol) in THF and water (4 : 1, 2 mL) for 15 min. The crude lactol was protected by treatment with pyridine (20 µL, 0.25 mmol) and AcCl (20 µL, 0.28 mmol) in CH₂Cl₂ (2 mL) for 30 min. Purification via silica gel column chromatography (25% EtOAc/hexanes) afforded 9e (25 mg, 44% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.88–6.80 (m, 1H), 6.57–6.44 (m, 1H), 6.21 (ddd, J = 10.3, 4.7, 2.3 Hz, 1H), 5.99–5.76 (m, 1H), 5.30–5.06 (m, 2H), 4.79–4.34 (m, 1H), 4.13–3.61 (m, 3H), 2.12 (dd, J = 10.1, 3.2 Hz, 4H), 1.17 (dd, J = 13.0, 6.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 195.2, 169.5, 143.0, 142.8, 141.0, 140.3, 135.2, 135.1, 135.0, 128.9, 128.7, 116.5, 116.3, 116.2, 116.0, 87.7, 86.8, 73.2, 72.4, 71.3, 70.9, 69.9, 69.6, 69.3, 69.3, 39.4, 39.1, 36.7, 21.0, 20.8, 19.8, 19.2. HRMS (APCI+) m/z: [M − OAc]⁺ calcd C₁₁H₁₅O₃ 195.1016; found 195.1018.

6-(2-(Allyloxy)-2-phenylethyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (9f)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 22b (110 mg, 0.42 mmol), KBr (13.6 mg, 0.11 mmol), NaHCO₃ (19 mg, 0.22 mmol) and Oxone (404 mg, 1.32 mmol) in THF and water (4 : 1, 5 mL) for 20 min. The crude lactol was protected by treatment with pyridine (70 µL, 0.87 mmol) and AcCl (50 µL, 0.89 mmol) in CH₂Cl₂ (5 mL) for 1 h. Purification via silica gel column chromatography (16% EtOAc/hexanes) afforded 9f (97 mg, 72% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.39–7.23 (m, 6H), 6.31 (ddt, J = 8.9, 3.1, 1.5 Hz, 1H), 6.26–6.20 (m, 1H), 5.97–5.92 (m, 1H), 5.82 (dddd, J = 16.6, 10.2, 8.6, 5.0 Hz, 1H), 5.25–5.10 (m, 2H), 4.51–3.53 (m, 4H), 2.65–2.17 (m, 2H), 2.06–1.99 (m, 4H). ¹³C NMR (125 MHz, CDCl₃) δ 194.9, 169.7, 143.1, 143.0, 141.9, 140.9, 140.5, 134.9, 134.7, 134.4, 128.9, 128.8, 128.7, 128.6, 128.5, 128.3, 128.0, 127.9, 127.2, 127.1, 126.6, 126.5, 126.3, 116.7, 116.6, 116.3, 88.3, 87.9, 86.7, 73.2, 70.4, 69.7, 69.6, 69.5, 41.2, 40.3, 37.8, 21.2, 21.0. HRMS (ESI+) m/z: [M − OAc]⁺ calcd C₁₆H₁₇O₃ 257.1178; found 257.1166.

6-(2-(Allyloxy)-3-methylbutyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (9g)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 22c (231.8 mg, 1.03 mmol), KBr (27 mg, 0.22 mmol), NaHCO₃ (42 mg, 0.506 mmol) and Oxone (983 mg, 3.20 mmol) in THF and water (4 : 1, 10 mL) for 25 min. The crude lactol was protected by treatment with pyridine (160 µL, 1.99 mmol) and AcCl (112 µL, 1.99 mmol) in CH₂Cl₂ (10 mL) for 30 min. Purification via silica gel column chromatography (25% EtOAc/hexanes) afforded 9g (25.1 mg, 44% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 6.94–6.83 (m, 1H), 6.60–6.52 (m, 1H), 6.30–6.23 (m, 1H), 6.04–5.81 (m, 1H), 5.35–5.10 (m, 2H), 4.80–4.39 (m, 1H), 4.18–3.88 (m, 2H), 3.50–3.38 (m, 1H), 2.26–1.85 (m, 6H), 0.95 (ddd, J = 6.8, 4.4, 2.3 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 196.0, 195.5, 169.6, 169.2, 143.1, 143.0, 141.2, 140.2, 135.4, 135.3, 135.2, 129.0, 128.9, 128.8, 116.3, 116.2, 116.1, 115.9, 88.3, 88.0, 87.0, 80.3, 79.9, 78.9, 78.8, 73.6, 72.8, 71.8, 71.4, 70.9, 70.6, 33.7, 33.6, 31.2, 31.0, 30.9, 30.7, 30.6, 30.4, 21.1, 21.0, 18.4, 18.3, 18.0, 17.7, 17.5, 17.4, 17.1. HRMS (APCI+) m/z: [M − OAc]⁺ calcd C₁₃H₁₉O₃ 223.1329; found 223.1330.

6-(2-(Allyloxy)-3,3-dimethylbutyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (9h)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 22d (286 mg, 1.2 mmol), KBr (31 mg, 0.26 mmol), NaHCO₃ (52 mg, 0.62 mmol) and Oxone (1.12 g, 3.64 mmol) in THF and water (4 : 1, 12 mL) for 25 min. The crude lactol was protected by treatment with pyridine (0.2 mL, 2.48 mmol) and AcCl (135 µL, 2.4 mmol) in CH₂Cl₂ (12 mL) for 30 min. Purification via silica gel column chromatography (16% EtOAc/hexanes) afforded 9h (319 mg, 90% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 6.90 (dddd, J = 23.7, 10.1, 3.2, 1.8 Hz, 1H), 6.62–6.55 (m, 1H), 6.32–6.22 (m, 1H), 6.04–5.82 (m, 1H), 5.39–5.21 (m, 1H), 5.20–5.08 (m, 1H), 4.77–4.37 (m, 1H), 4.25–4.02 (m, 3H), 3.34–3.16 (m, 1H), 2.22–2.13 (m, 4H), 2.11–1.91 (m, 2H), 0.98–0.94 (m, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 196.0, 195.7, 169.6, 169.2, 143.1, 141.1, 140.3, 135.3, 135.1, 129.0, 128.8, 128.7, 115.8, 115.7, 88.3, 87.9, 87.1, 87.1, 84.3, 83.9, 82.9, 74.7, 74.5, 74.2, 73.7, 73.3, 36.1, 35.8, 34.6, 33.5, 32.0, 31.3, 26.3, 26.3, 26.2, 26.2, 21.1, 21.0, 14.2. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₆H₂₄O₅Na 319.1521; found 319.1509.

6-(2-(Allyloxy)-3-phenylpropyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (9i)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 22e (29.5 mg, 0.11 mmol), KBr (29 mg, 0.24 mmol), NaHCO₃ (46 mg, 0.54 mmol) and Oxone (101 mg, 0.33 mmol) in THF and water (4 : 1, 10 mL) for 15 min. The crude lactol was protected by treatment with pyridine (20 µL, 0.25 mmol) and AcCl (15 µL, 0.27 mmol) in CH₂Cl₂ (10 mL) for 30 min. Purification via silica gel column chromatography (20% EtOAc/hexanes) afforded 9i (21 mg, 58% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.31–7.25 (m, 6H), 7.21 (td, J = 8.8, 2.7 Hz, 5H), 6.90–6.78 (m, 1H), 6.55–6.47 (m, 1H), 6.25–6.16 (m, 2H), 5.86–5.70 (m, 1H), 5.22–5.05 (m, 2H), 4.73–4.35 (m, 1H), 4.17–3.34 (m, 5H), 2.97–2.68 (m, 3H), 2.21–1.90 (m, 7H). ¹³C NMR (125 MHz, CDCl₃) δ 195.3, 169.1, 143.1, 140.3, 134.8, 129.6, 129.5, 129.0, 128.3, 126.2, 116.6, 116.5, 88.0, 86.9, 73.1, 70.5, 70.4, 40.8, 40.7, 36.8, 34.5, 21.0. HRMS (ESI+) m/z: [M + Na]⁺ calcd C₁₉H₂₂O₅Na 353.1359; found 353.1354.

6-(2-(But-3-en-1-yloxy)propyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (9j)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 27a (96 mg, 0.46 mmol), KBr (11.0 mg, 0.09 mmol), NaHCO₃ (21.6 mg, 0.26 mmol) and Oxone (425.2 mg, 1.38 mmol) in THF and water (4 : 1, 5 mL) for 40 min. The crude lactol was protected by treatment with pyridine (75 µL, 0.93 mmol) and AcCl (50 µL, 0.89 mmol) in CH₂Cl₂ (5 mL) for 30 min. Purification via silica gel column chromatography (20% EtOAc/hexanes) afforded 9j (94 mg, 77% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 6.81 (ddt, J = 10.1, 5.4, 3.6 Hz, 1H), 6.51–6.42 (m, 1H), 6.16 (dd, J = 10.2, 7.5 Hz, 1H), 5.73 (dddd, J = 23.6, 16.9, 10.4, 6.8 Hz, 1H), 5.07–4.90 (m, 2H), 4.71–4.29 (m, 1H), 4.06 (q, J = 7.1 Hz, 1H), 3.71–3.51 (m, 1H), 3.46 (ddt, J = 15.7, 9.1, 6.8 Hz, 1H), 3.31 (ddt, J = 34.7, 9.3, 6.9 Hz, 1H), 2.30–1.86 (m, 9H), 1.23–1.17 (m, 1H), 1.14–1.08 (m, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 195.7, 195.6, 195.3, 195.2, 171.0, 169.5, 169.5, 169.1, 169.0, 143.1, 142.9, 141.2, 140.5, 135.6, 135.4, 135.3, 128.9, 128.8, 128.6, 116.3, 116.2, 116.1, 88.1, 87.8, 87.0, 86.9, 73.2, 72.6, 71.7, 71.4, 70.5, 70.4, 68.1, 67.8, 67.8, 60.3, 39.6, 39.3, 36.9, 36.7, 34.6, 34.5, 34.4, 21.0, 21.0, 20.9, 20.8, 19.9, 19.9, 19.3, 19.3, 14.2. HRMS (ESI+) m/z: [M − OAc]⁺ calcd C₁₂H₁₇O₃ 209.1172; found 209.1150.

6-(2-(But-3-en-1-yloxy)-2-phenylethyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (9k)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 27b (268 mg, 0.98 mmol), KBr (23.4 mg, 0.196 mmol), NaHCO₃ (42.5 mg, 0.51 mmol) and Oxone (926 mg, 3.02 mmol) in THF and water (4 : 1, 10 mL) for 30 min. The crude lactol was protected by treatment with pyridine (160 µL, 1.99 mmol) and AcCl (110 µL, 1.96 mmol) in CH₂Cl₂ (10 mL) for 30 min. Purification via silica gel column chromatography (20% EtOAc/hexanes) afforded 9k (116 mg, 36% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.39–7.27 (m, 5H), 6.91–6.78 (m, 1H), 6.61–6.47 (m, 1H), 6.26–6.18 (m, 1H), 5.87–5.67 (m, 1H), 5.10–4.94 (m, 2H), 4.55–4.43 (m, 1H), 4.26–4.02 (m, 1H), 3.45–3.22 (m, 2H), 2.52–2.07 (m, 10H). ¹³C NMR (125 MHz, CDCl₃) δ 195.5, 194.9, 169.6, 169.3, 143.1, 142.9, 141.2, 141.1, 140.6, 135.4, 135.3, 135.3, 128.9, 128.8, 128.6, 128.5, 128.5, 127.9, 127.9, 127.7, 127.1, 127.0, 126.5, 116.3, 116.2, 87.9, 87.1, 86.7, 78.5, 78.2, 76.5, 73.2, 72.6, 68.4, 68.3, 68.2, 41.3, 40.4, 37.9, 34.4, 34.3, 34.3, 30.9, 21.1, 21.0. HRMS (ESI+) m/z: [M − OAc]⁺ calcd C₁₇H₁₉O₃ 271.1329; found 271.1330.

6-(2-(But-3-en-1-yloxy)-3-methylbutyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (9l)

The reaction was conducted according to the procedure described for 9a with furanyl alcohol 27c (34 mg, 0.14 mmol), KBr (3.9 mg, 0.03 mmol), NaHCO₃ (6.8 mg, 0.81 mmol) and Oxone (133.3 mg, 0.434 mmol) in THF and water (4 : 1, 5 mL) for 45 min. The crude lactol was protected by treatment with pyridine (25 µL, 0.310 mmol) and AcCl (16 µL, 0.28 mmol) in CH₂Cl₂ (2 mL) for 1.5 h. Purification via silica gel column chromatography (20% EtOAc/hexanes) afforded 9l (19.5 mg, 46% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.89–6.79 (m, 1H), 6.55–6.47 (m, 1H), 6.26–6.17 (m, 1H), 5.81 (tddt, J = 17.1, 13.5, 10.3, 6.7 Hz, 1H), 5.12–4.94 (m, 2H), 4.74–4.34 (m, 1H), 3.66–3.25 (m, 3H), 2.37–1.74 (m, 9H), 0.88 (ddd, J = 7.1, 5.0, 2.7 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 196.0, 195.5, 169.5, 169.1, 142.9, 142.8, 141.0, 140.3, 135.6, 135.5, 135.4, 128.8, 128.7, 116.0, 116.0, 88.1, 87.8, 86.9, 80.3, 80.1, 78.9, 78.8, 77.1, 76.8, 73.4, 72.8, 69.9, 69.1, 68.9, 34.6, 34.5, 34.5, 33.5, 30.8, 30.3, 30.3, 29.6, 21.0, 20.8, 18.3, 18.2, 17.9, 17.5, 17.3, 17.1. HRMS (APCI+) m/z: [M − OAc]⁺ calcd C₁₄H₂₁O₃ 237.1485; found 237.1492.

2-Methyl-1,2,3,7,8,8a-hexahydro-4H-3a,7-epoxyazulen-4-one (10a)

Acetoxypyranone 9a (19 mg, 79.6 µmol) was dissolved in CH₃CN (4 mL) to 0.02 M and transferred to a dried sealed tube and then N-methylpyrrolidine (NMP) (12.5 µL, 120 µmol) was added. The reaction tube was sealed, placed in an oil bath at 150 °C, and stirred for 3 h. Upon completion, the sealed tube was cooled to 23 °C, and the crude cycloadduct was filtered over a silica plug and flushed with EtOAc (3×), and then concentrated under reduced pressure to afford 10a along with its minor diastereomer (13.5 mg, 95% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.12 (ddd, J = 29.0, 9.7, 4.4 Hz, 1H), 5.95 (dd, J = 9.7, 2.5 Hz, 1H), 4.90 (ddd, J = 57.8, 6.6, 4.4 Hz, 1H), 2.74 (ddd, J = 13.6, 7.5, 1.6 Hz, 1H), 2.38–2.09 (m, 3H), 2.04–1.96 (m, 1H), 1.91 (ddd, J = 12.0, 6.6, 5.3 Hz, 1H), 1.27–1.15 (m, 2H), 1.06 (dd, J = 10.6, 6.5 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 197.7, 152.4, 151.6, 126.3, 125.6, 98.7, 77.6, 75.5, 46.3, 43.8, 42.8, 39.8, 39.7, 38.5, 37.6, 37.1, 35.3, 33.0, 29.7, 19.4, 18.8. HRMS (APCI+) m/z: [M + H]⁺ calcd C₁₁H₁₄O₂ 179.1067; found 179.1074.

2-Phenyl-1,2,3,7,8,8a-hexahydro-4H-3a,7-epoxyazulen-4-one (10b)

The reaction was conducted according to the procedure described for 10a with acetoxypyranone 9b (24 mg, 80.0 µmol) and NMP (12.5 µL, 120 µmol) in CH₃CN (4 mL). The reaction was stirred for 4 h. Cycloadduct 10b along with its minor diastereomer (19.2 mg, 99% yield) was isolated as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.34–7.27 (m, 5H), 7.24–7.19 (m, 2H), 6.02 (d, J = 9.7 Hz, 1H), 5.03 (dd, J = 6.3, 4.5 Hz, 1H), 3.41 (tdd, J = 12.5, 7.8, 5.2 Hz, 1H), 3.07 (ddd, J = 13.7, 7.8, 1.6 Hz, 1H), 2.54–2.38 (m, 2H), 2.14–1.94 (m, 3H), 1.81–1.70 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 197.4, 152.6, 142.9, 128.5, 127.0, 126.5, 125.7, 97.9, 77.8, 49.8, 46.1, 42.1, 38.1, 35.2. HRMS (APCI+) m/z: [M + H]⁺ calcd C₁₆H₁₇O₂ 241.1223; found 241.1234.

2-Isopropyl-1,2,3,7,8,8a-hexahydro-4H-3a,7-epoxyazulen-4-one (10c)

The reaction was conducted according to the procedure described for 10a with acetoxypyranone 9c (21.3 mg, 80 µmol) and NMP (12.5 µL, 120 µmol) in CH₃CN (4 mL). The reaction was stirred for 7 h, and 10c along with its minor diastereomer (16.5 mg, 99% yield) was isolated as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.16 (dd, J = 9.7, 4.5 Hz, 1H), 5.96 (d, J = 9.7 Hz, 1H), 4.94 (dd, J = 6.6, 4.5 Hz, 1H), 2.76 (ddd, J = 13.6, 7.7, 1.6 Hz, 1H), 2.30 (dtd, J = 11.0, 7.8, 5.0 Hz, 1H), 2.23–2.15 (m, 1H), 1.99 (dd, J = 12.0, 8.3 Hz, 1H), 1.89 (dddd, J = 24.2, 12.7, 7.2, 5.2 Hz, 2H), 1.50 (dp, J = 8.3, 6.6 Hz, 1H), 1.30–1.16 (m, 2H), 0.91 (dd, J = 11.9, 6.7 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 197.8, 152.5, 125.6, 98.2, 77.4, 52.4, 45.9, 39.2, 35.4, 35.1, 33.3, 21.4, 21.4. HRMS (APCI+) m/z: [M + H]⁺ calcd C₁₃H₁₉O₂ 207.1385; found 207.1390.

3-Methyl-1,3,4,8,9,9a-hexahydro-4a,8-epoxybenzo[7]annulen-5(2H)-one (10d)

The reaction was conducted according to the procedure described for 10a with acetoxypyranone 9d (20.2 mg, 0.12 mmol) and NMP (19 µL, 0.18 mmol) in CH₃CN (6 mL). The reaction was stirred for 21 h, and 10d along with its minor diastereomer (22.6 mg, 99% yield) was isolated as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.45–7.18 (m, 2H), 5.93 (dd, J = 39.3, 9.7 Hz, 1H), 4.77–4.69 (m, 1H), 2.11–1.93 (m, 3H), 1.92–1.78 (m, 3H), 1.77–1.51 (m, 2H), 1.33–1.17 (m, 3H), 0.98 (dd, J = 29.5, 6.6 Hz, 4H). ¹³C NMR (125 MHz, CDCl₃) δ 198.8, 155.6, 153.0, 125.9, 125.5, 89.6, 72.6, 71.5, 40.1, 36.6, 35.5, 34.9, 34.2, 32.5, 32.3, 32.0, 28.1, 26.6, 26.1, 24.5, 23.0, 22.4. HRMS (APCI+) m/z: [M + H]⁺ calcd C₁₂H₁₇O₂⁺ 193.1223; found 193.1222.

3-Methyl-1,3,4,8,9,9a-hexahydro-5H-4a,8-epoxycyclohepta[c]pyran-5-one (10e)

The reaction was conducted according to the procedure described for 10a with acetoxypyranone 9e (15 mg, 59.4 µmol) and NMP (9 µL, 86.6 µmol) in CH₃CN (3 mL). The reaction was stirred for 8 h, and 10e along with its minor diastereomer (10 mg, 88% yield) was isolated as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.45–7.40 (m, 1H), 6.03 (dd, J = 9.7, 0.9 Hz, 1H), 4.79 (dd, J = 7.5, 4.8 Hz, 1H), 4.09 (dd, J = 11.6, 7.0 Hz, 1H), 3.55 (dtdd, J = 9.6, 6.0, 4.4, 2.7 Hz, 1H), 2.40 (dd, J = 15.1, 12.0 Hz, 1H), 2.11–2.03 (m, 1H), 1.93 (ddt, J = 12.6, 8.1, 1.1 Hz, 1H), 1.78–1.68 (m, 2H), 1.25–1.23 (m, 3H). ¹³C NMR (12 MHz, CDCl₃) δ 196.5, 155.1, 126.2, 87.2, 72.0, 70.4, 69.0, 34.9, 33.8, 32.1, 21.6. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₁H₁₅O₃ 195.1021; found 195.1015.

3-Phenyl-1,3,4,8,9,9a-hexahydro-5H-4a,8-epoxycyclohepta[c]pyran-5-one (10f)

The reaction was conducted according to the procedure described for 10a with acetoxypyranone 9f (15.8 mg, 50 µmol) and NMP (8 µL, 76.8 µmol) in CH₃CN (2.5 mL). The reaction was stirred for 3 h, and 10f along with its minor diastereomer (9.6 mg, 75% yield) was isolated as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (dd, J = 9.7, 4.8 Hz, 1H), 7.43–7.22 (m, 5H), 6.05 (d, J = 9.7 Hz, 1H), 5.04–4.79 (m, 1H), 4.50 (dd, J = 12.3, 2.9 Hz, 1H), 4.27 (dd, J = 11.7, 7.1 Hz, 1H), 3.42 (dd, J = 11.8, 10.5 Hz, 1H), 2.75 (dd, J = 15.2, 12.4 Hz, 1H), 2.21 (dtd, J = 10.4, 7.5, 2.9 Hz, 1H), 2.04–1.95 (m, 2H), 1.80 (ddd, J = 12.5, 7.5, 2.9 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 196.1, 154.9, 141.9, 128.4, 127.6, 126.1, 125.8, 87.2, 74.9, 72.0, 70.7, 34.9, 33.8, 32.2. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₆H₁₇O₃ 257.1172; found 257.1174.

3-Isopropyl-1,3,4,8,9,9a-hexahydro-5H-4a,8-epoxycyclohepta[c]pyran-5-one (10g)

The reaction was conducted according to the procedure described for 10a with acetoxypyranone 9g (13.5 mg, 48.0 µmol) and NMP (7.5 µL, 72.1 µmol) in CH₃CN (2.4 mL). The reaction was stirred for 5 h, and 10g along with its minor diastereomer (10.2 mg, 96% yield) was isolated as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.47 (ddd, J = 9.7, 4.8, 0.7 Hz, 1H), 7.27 (dd, J = 9.7, 4.4 Hz, 0H), 6.10–6.06 (m, 1H), 4.85 (dd, J = 7.5, 4.8 Hz, 1H), 4.16 (dd, J = 11.6, 6.9 Hz, 1H), 3.25 (dd, J = 11.7, 10.3 Hz, 1H), 3.18 (ddd, J = 12.2, 6.7, 2.8 Hz, 1H), 2.47 (dd, J = 15.0, 12.3 Hz, 1H), 2.20–2.08 (m, 1H), 1.98 (dd, J = 12.4, 8.1 Hz, 1H), 1.85–1.74 (m, 3H), 0.99 (dd, J = 26.6, 6.8 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 196.8, 154.9, 126.2, 87.3, 77.8, 72.0, 70.4, 34.9, 34.2, 33.1, 27.4, 18.6, 18.2. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₃H₁₉O₃ 223.1334; found 223.1332.

3-(tert-Butyl)-1,3,4,8,9,9a-hexahydro-5H-4a,8-epoxycyclohepta[c]pyran-5-one (10h)

The reaction was conducted according to the procedure described for 10a with acetoxypyranone 9h (12.4 mg, 41.8 µmol) and NMP (6.5 µL, 62.5 µmol) in CH₃CN (2.1 mL). The reaction was stirred for 6 h, and 10h along with its minor diastereomer (9.3 mg, 94% yield) was isolated as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.47 (ddd, J = 9.7, 4.8, 0.7 Hz, 1H), 6.08 (dd, J = 9.7, 0.7 Hz, 1H), 4.85 (dd, J = 7.5, 4.8 Hz, 1H), 4.18 (dd, J = 11.6, 7.0 Hz, 1H), 3.27 (dd, J = 11.6, 10.1 Hz, 1H), 3.15 (ddd, J = 12.5, 2.7, 0.7 Hz, 1H), 2.57–2.47 (m, 1H), 2.10 (ddd, J = 10.3, 7.5, 3.0 Hz, 1H), 1.98 (ddt, J = 12.4, 8.1, 1.0 Hz, 1H), 1.84–1.74 (m, 2H), 0.98 (d, J = 0.7 Hz, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 196.9, 154.9, 126.2, 87.6, 80.3, 72.1, 70.7, 34.8, 34.1, 25.8, 25.5, 24.8. HRMS (APCI+) m/z: [M + H]⁺ calcd C₁₄H₂₁O₃ 237.1491; found 237.1492.

3-Benzyl-1,3,4,8,9,9a-hexahydro-5H-4a,8-epoxycyclohepta[c]pyran-5-one (10i)

The reaction was conducted according to the procedure described for 10a with acetoxypyranone 9i (5.6 mg, 17.0 µmol) and NMP (2.7 µL, 26.0 µmol) in CH₃CN (0.85 mL). The reaction was stirred for 4 h, and 10i along with its minor diastereomer (2.7 mg, 59% yield) was isolated as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.40 (dd, J = 9.7, 4.8 Hz, 1H), 7.29–7.17 (m, 5H), 6.01 (d, J = 9.7 Hz, 1H), 4.80–4.74 (m, 1H), 4.09 (dd, J = 11.7, 7.0 Hz, 1H), 3.73–3.64 (m, 1H), 3.19 (dd, J = 11.7, 10.4 Hz, 1H), 2.95 (dd, J = 13.8, 7.2 Hz, 1H), 2.73 (dd, J = 13.8, 6.1 Hz, 1H), 2.46 (dd, J = 15.1, 12.0 Hz, 1H), 2.14–2.06 (m, 1H), 1.92 (ddd, J = 12.5, 8.1, 1.2 Hz, 1H), 1.78–1.69 (m, 2H), 1.52–1.41 (m, 2H), 1.26 (s, 10H), 0.90–0.86 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 196.4, 154.9, 138.1, 129.6, 129.4, 128.3, 126.3, 126.1, 87.1, 73.8, 72.0, 70.3, 54.5, 42.5, 34.8, 34.1, 31.9, 30.1, 29.7, 29.4, 22.7, 18.7, 17.4, 14.1. HRMS (APCI+) m/z: [M + H]⁺ calcd C₁₇H₁₉O₃ 271.1329; found 271.1328.

4-Methyl-1,4,5,9,10,10a-hexahydro-5a,9-epoxycyclohepta[d]oxepin-6(2H)-one (10j)

Acetoxypyranone 9j (6.7 mg, 25.0 µmol) was dissolved in CH₃CN (2.5 mL) to 0.01 M and transferred to a dried sealed tube and then 2,2,6,6-tetramethylpiperidine (TMP) (17 µL, 101 µmol) was added. The reaction tube was sealed, placed in an oil bath at 150 °C, and stirred for 18 h. Upon completion of the reaction, the sealed tube was cooled to 23 °C, and the crude cycloadduct was filtered over a silica plug and flushed with EtOAc (3×), and then concentrated in vacuo to give 10j and its diastereomer (3.5 mg, 67% yield) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.19 (dt, J = 9.6, 4.7 Hz, 1H), 5.92 (dd, J = 9.7, 8.6 Hz, 1H), 4.80 (ddd, J = 37.6, 6.9, 4.4 Hz, 1H), 4.09–3.96 (m, 1H), 3.92–3.81 (m, 1H), 3.62 (dd, J = 13.0, 10.2 Hz, 0H), 3.42 (ddd, J = 12.7, 11.0, 0.9 Hz, 1H), 2.48–2.37 (m, 1H), 2.32 (dd, J = 15.8, 9.8 Hz, 0H), 2.27–2.14 (m, 2H), 2.10–1.95 (m, 2H), 1.91–1.75 (m, 2H), 1.31–1.20 (m, 5H). ¹³C NMR (125 MHz, CDCl₃) δ 199.8, 198.4, 152.6, 152.2, 125.3, 125.2, 88.6, 88.6, 74.0, 73.8, 72.5, 70.9, 70.7, 65.2, 42.2, 39.2, 38.4, 38.3, 35.7, 35.1, 33.5, 29.7, 29.3, 23.6, 23.2. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₇H₁₉O₃ 209.1178; found 209.1168.

4-Phenyl-1,4,5,9,10,10a-hexahydro-5a,9-epoxycyclohepta[d]oxepin-6(2H)-one (10k)

The reaction was conducted according to the procedure described for 10j with acetoxypyranone 9k (10 mg, 32.9 µmol) and TMP (2.5 µL, 148 µmol) in CH₃CN (3.3 mL). The reaction was stirred for 80 h, and 10k and its diastereomer (3.1 mg, 33% yield) were isolated as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.54–7.50 (m, 1H), 7.38–7.29 (m, 4H), 7.23 (ddd, J = 9.6, 7.0, 4.4 Hz, 1H), 5.95 (dd, J = 9.7, 8.1 Hz, 1H), 5.06–4.74 (m, 2H), 4.20–3.97 (m, 1H), 3.68 (ddd, J = 109.3, 12.8, 10.6 Hz, 1H), 2.74–2.48 (m, 2H), 2.39–2.02 (m, 4H), 1.95–1.84 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 199.8, 198.1, 152.7, 152.2, 144.2, 143.6, 128.4, 128.3, 127.3, 127.1, 126.0, 125.5, 125.3, 125.3, 88.6, 79.3, 73.9, 72.6, 71.1, 65.6, 43.6, 42.3, 40.2, 38.5, 38.4, 35.7, 35.3, 33.8, 29.7. HRMS (APCI+) m/z: [M + H]⁺ calcd C₁₇H₁₉O₃ 271.1329; found 271.1329.

4-Isopropyl-1,4,5,9,10,10a-hexahydro-5a,9-epoxycyclohepta[d]oxepin-6(2H)-one (10l)

The reaction was conducted according to the procedure described for 10j with acetoxypyranone 9l (10 mg, 32.9 µmol) and TMP (2.5 µL, 2.5 µmol) in CH₃CN (3.3 mL). The reaction was stirred for 80 h, and 10l and its diastereomer (3 mg, 40% yield) were isolated as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.19 (dd, J = 9.7, 4.5 Hz, 1H), 5.92 (dd, J = 19.0, 9.7 Hz, 1H), 4.81 (ddd, J = 37.7, 6.8, 4.5 Hz, 1H), 4.09–3.85 (m, 1H), 3.70–3.33 (m, 2H), 2.49–2.35 (m, 1H), 2.33–2.12 (m, 3H), 2.08–1.94 (m, 2H), 1.90–1.68 (m, 4H), 0.99–0.89 (m, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 199.7, 198.7, 152.5, 152.0, 125.4, 89.0, 88.6, 81.6, 79.1, 73.8, 72.6, 71.0, 65.5, 42.1, 38.5, 38.2, 35.9, 34.9, 34.4, 34.1, 33.8, 33.5, 29.7, 18.8, 18.6, 17.8, 17.3. HRMS (ESI+) m/z: [M + H]⁺ calcd C₁₄H₂₁O₃ 237.1491; found 237.1479.

Conflicts of interest

There is no conflict of interest.

Data availability

The authors confirm that the data supporting these studies are available within the article and its supplementary information (SI). Supplementary information: crystallographic data collection and refinement statistics. See DOI: https://doi.org/10.1039/d5ob01429h.

CCDC 2411050 (10b), 2470759 (10e) and 2408404 (10f) contain the supplementary crystallographic data for this paper.^42,43a,b

Acknowledgements

Financial support for this work was provided by the National Institutes of Health (Grant AI150466). NMR and mass spectrometry were all performed using shared resources which are partially supported by the Purdue Center for Cancer Research through NIH grant (P30CA023168).

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