Highly Diastereoselective Intramolecular Asymmetric Oxidopyrylium-olefin [5 + 2] Cycloaddition and Synthesis of 8-Oxabicyclo[3.2.1]oct-3-enone Containing Ring Systems

Abstract

We have the investigated base mediated asymmetric intramolecular oxidopyrylium-alkene [5 + 2]-cycloaddition reaction which resulted in the synthesis of functionalized tricyclic ring systems containing an 8-oxabicyclo[3.2.1]octane core. Intramolecular cycloaddition constructed two new rings, three new stereogenic centers, and provided a tricyclic cycloadduct with high diastereoselectivity and isolated yield. We incorporated an α-chiral center and an alkoxy alkene tether on the substrates and examined the effect of the size of alkyl groups and alkene tether length on diastereoselectivity. The requisite substrates for the oxidopyrylium-alkene cycloaddition reaction were synthesized in a few steps involving alkylation of optically active α-hydroxy amide, furyllithium addition, reduction of resulting ketone, and Achmatowicz reaction followed by acylation of a lactol intermediate. We have proposed stereochemical models for the [5 + 2] cycloaddition reaction via the oxidopyrylium ylide. Interestingly, the alkoxy substituent on the stereocenter and the chain length are responsible for the degree of stereoselectivity of the cycloadduct.

Graphical Abstract

INTRODUCTION

The oxidopyrylium-alkene [5 + 2] cycloaddition reaction has emerged as an important synthetic method for the construction of complex seven-membered ring systems.^1–4 This reaction provides convenient access to a wide variety of highly functionalized seven-membered ring structures containing an oxygen bridge. Over the years, the development of new strategies and reaction protocols led this cycloaddition chemistry to become a reliable strategy for the synthesis of a diverse class of 8-oxabicyclo[3.2.1]octane heterocycles. Interestingly, these heterocyclic structural motifs are inherent to a wide variety of bioactive natural products.^4–6 Furthermore, these heterocyclic intermediates have been exploited in the design and synthesis of functionalized seven-membered ring compounds in medicinal chemistry.^7–9 Representative examples include phorbol (1, Figure 1), a tumor-promoting agent that works through activation of protein kinase C.^10,11 Resiniferatoxin (2) found in resin spurge shows extraordinary irritant properties.^12,13 Englerin B (3) and intricarene (4) possess very potent anticancer activity with medicinal potential.^14,15 Wender and co-workers elegantly utilized the intramolecular oxidopyrylium-alkene [5 + 2] cycloaddition reaction in the total synthesis of phorbol and (+)-resiniferatoxin.^16,17 Nicolaou and co-workers reported a racemic total synthesis of englerin A and englerin B utilizing the [5 + 2] cycloaddition.¹⁸ Trauner and co-workers reported a biomimetic synthesis of (+)-intricarene using an intramolecular [5 + 2] cycloaddition.¹⁹ A number of recent reviews highlighted important developments and applications of these cycloaddition reactions in organic synthesis.^4,6,20

Figure 1.

Natural products containing functionalized seven-membered and 8-oxabicyclo [3.2.1] octane core.

Among many developments, the generation of oxidopyrylium ylide through the elimination of the acetate or benzoate derivative of a 6-hydroxy-2H-pyran-3(6H)-one, which can be derived from an Achmatowicz reaction, greatly facilitated the use of oxidopyrylium-alkene [5 + 2] cycloaddition in synthesis. In 1980, Hendrickson and Farina first reported that acetoxypyranone can be used as a precursor to generate the oxidopyrylium ylide by elimination of the acetate group.^21,22 Later, Sammes and co-workers reported an intramolecular oxidopyrylium cycloaddition of 5 by using DBN as a base to provide cycloadduct 6 as shown in Figure 2.^23,24 The oxidopyrylium-alkene cycloaddition can incorporate multiple stereogenic centers in the cycloadducts. A number of reports of asymmetric catalytic oxidopyrylium cycloaddition reactions using organocatalysts have appeared in the literature.^25–28 Prior to that, a number of asymmetric intramolecular oxidopyrylium-alkene cycloadditions have been reported where the oxidopyrylium ylide possessed at least an α-chiral center. The stereochemical outcome of the cycloadduct was dictated by the substituent in the existing α-chiral center. During the synthesis of (+)-phorbol (1), Wender and co-workers carried out an asymmetric cycloaddition of acetate derivative 7 to provide cycloadduct 8 as a single diastereomer in 79% yield.¹⁶ Trivedi and co-workers reported an asymmetric cycloaddition of acetate derivative 9 to provide cycloadduct 10 with very high diastereoselectivity (dr 97%).²⁹ Several other oxidopyrylium-alkene cycloadditions have been reported with high selectivity in the literature.^30–34 We became interested in the oxidopyrylium-alkene cycloaddition reaction to provide access to structurally intriguing oxabicyclo[3.2.1]octane heterocyclic ring systems. We recently incorporated a variety of similar stereochemically defined cyclic ether-derived ligands and structural templates in the design of exceptionally potent HIV-1 protease inhibitors.^35–37 Herein, we report our studies on an asymmetric intramolecular cycloaddition reaction of the oxidopyrylium ylide bearing an α-chiral center and a number of alkoxy-alkene tethers for construction of five- to seven-membered ring systems. We have examined the effect of different alkyl groups and alkene tether lengths of the alkoxy substituents on diastereoselectivity. Various cycloaddition substrates and stereochemically defined tricyclic cycloadducts were synthesized efficiently in optically active form.

Figure 2.

Prior works on intramolecular and asymmetric oxidopyrylium-alkene [5 + 2] cycloaddition of substrates containing an α-chiral center.

RESULTS AND DISCUSSION

Our tentative plan for the asymmetric oxidopyrylium-alkene [5 + 2] cycloadditions for substrates containing an α-chiral center is shown in Scheme 1. We planned to synthesize various O-alkylated optically active Weinreb amides (12) from optically active α-hydroxy amides (11). Reaction of furyllithium is expected to provide the corresponding ketone, which, upon reduction, would provide alcohol 13 with some degree of diastereoselectivity. The stereochemistry and diastereomeric ratio are inconsequential, as the stereocenter will be destroyed during the formation of pyrylium ylide. The alcohol mixture will be converted to acetoxy dihydropyranone derivative 14, the oxidopyrylium precursors. Base catalyzed elimination of acetate from 14 would generate the oxidopyrylium ylide which would undergo intramolecular [5 + 2]-cycloaddition with a tethered alkene substituent to provide cycloadducts diaster-eoselectively. Presumably, cycloaddition would proceed through the transition states shown in 15a and 15b. Transition state 15a is preferred over 15b due to competing nonbonded interactions between the alkyl group and the alkoxy group of the pyrylium ylide in the transition-state 15b. Tricyclic diastereomer 16 with depicted stereochemistry would be expected as the major product, and diastereomer 17 would be the minor product. In this case, the new five-membered ring will place the alkyl substituent in a pseudoequatorial orientation as shown in Scheme 1. The size of the alkyl substituents is expected to influence the degree of diastereoselectivity. Also, varying the size of the alkene tethers would enable the reaction to proceed through six- and seven-membered ring systems. The stereochemical outcome is expected to be similar, as the reaction will proceed through a similar transition state as 15a. We planned to examine the effect of the R-substituents and alkoxy tether length on diastereoselectivity.

Scheme 1.

Asymmetric Oxidopyrylium-alkene [5 + 2] Cycloaddition of Substrates Containing an α-Alkoxy Stereocenter

Our synthesis of variously substituted furan derivatives 13a–d is shown in Scheme 2. Weinreb amides 11a–d were prepared from the optically active ester as described previously.³⁸ Treatment of alcohols 11a–d with NaH in THF at −20 °C for 30 min followed by reaction with allylbromide for 12–14 h provided O-alkylated products 12a (87%), 12b (87%), 12c (88%), and 12d (69%) in good yields.³⁹ Reaction of Weinreb amides 12a–d with 2-lithiofuran, generated in situ with furan and n-BuLi at −78 °C, afforded the corresponding ketone derivatives. Reduction of the resulting ketones with sodium borohydride in MeOH at −78 °C for 1 h afforded the furfuryl alcohols 13a (7:1, 84%), 13b (9:1, 85%), 13c (3:1, 83%), and 13d (1.2:1, 73%) over two steps as a mixture of diastereomers. The diastereomers were not separable by flash column chromatography and were carried forward as a mixture for the subsequent reactions. The diastereomeric ratio and stereochemistry of the new chiral center are not important, as the chiral center will eventually be destroyed during the formation of oxidopyrylium ylide. The depicted anti-stereochemistry of the major isomer is based upon the chelation control model reported for the reduction of α-alkoxy ketones.⁴⁰

Scheme 2.

Synthesis of Furan Derivatives 13a–d

Initially, the one-carbon homologue of the O-allyl tether was synthesized using the furfuryl alcohol 13a as outlined in Scheme 3. Hydroboration of alkene 13a with dicyclohexyl borane at 0 °C in THF for 2 h followed by oxidation of the resulting borane with NaBO₃·4H₂O at 23 °C for 12 h afforded the diol 18 in 88% yield.⁴¹ Diol 18 was obtained as a mixture (1:5, syn/anti) of diastereomers, which were separated by flash column chromatography over silica gel. The major isomer was carried forward for the next reaction. Selective oxidation of the primary alcohol of diol 18 was carried out by treatment with 0.1 equiv of TEMPO and 1.2 equiv of bis(acetoxy)-iodobenzene (BAIB) in THF at 0° to 23 °C for 9 h to give the aldehyde in 74% yield.⁴² Incorporation of the terminal olefin was achieved by Wittig reaction of the aldehyde with the methyltriphenylphosphonium ylide generated by treating 5 equiv of methyltriphenylphosphonium bromide with 4.5 equiv of t-BuOK to provide alkene derivative 13e in 30% yield.⁴³ Overall, this route was less than satisfactory and resulted in a poor yield of the desired O-homoallyl furfuryl alcohol 13e. Therefore, we examined an alternative and more convergent approach to synthesize O-homoallyl furfuryl alcohols via direct alkylation of the α-hydroxy esters.

Scheme 3.

Synthesis of Furan Derivative 13e

Direct O-alkylation of Weinreb amides with homoallyl bromides or iodides under various O-alkylation conditions did not provide satisfactory yield of the alkylated products. Therefore, we utilized a modified procedure using alkenyl triflates.⁴⁴ As shown in Scheme 4, reaction of α-hydroxy esters 19a–b with t-BuOK and 3-butenyl triflate in THF at −20 °C for 30 min provided O-alkylated products 20a and 20b in 47% and 54% yields, respectively. Similarly, O-alkylation of 19b with 4-pentenyl triflate afforded alkylated product 20c in 84% yield. Various alkylated ester derivatives 20a–c were converted to the corresponding Weinreb amide derivatives 12f–h by treatment with 4.0 equiv of AlMe₃ and 4.0 equiv of methoxymethylamine hydrochloride in THF at 23 °C for 24 h in good yields (12f, 75%; 12g, 65%; 12h, 80%). Reaction of these Weinreb amides 12f–h with 2-lithiofuran as described in Scheme 4 resulted in the corresponding ketones, which upon reduction with NaBH₄ in MeOH at −78 °C for 1 h as described before, furnished alcohols 13f (3:1 mixture, 84%), 13g (1:1 mixture, 80%), and 13h (1.8:1 mixture, 73%) in good yields over two steps. These diastereomeric alcohols were not separated, and the mixtures were carried forward for the subsequent reactions.

Scheme 4.

Synthesis of Furan Derivatives 13f–h

Various furfuryl alcohols 13a–h were then converted to acetoxy-pyranone derivatives 14a–h, and the results are shown in Table 1. Achmatowicz rearrangement of the furfuryl alcohols 13a–h were carried out by treatment of alcohols with a catalytic amount of KBr (0.1 equiv), NaHCO₃ (0.5 equiv), and oxone (1.5 equiv) at 0 °C in a mixture (4:1) of THF and water to provide the corresponding lactol.^45,46 Reactions of the resulting lactols with acetyl chloride in the presence of pyridine in CH₂Cl₂ at 0 °C for 30 min afforded acetoxypyranone derivatives 14a–h in good yields after silica gel chromatography (55–92%).

Table 1.

Synthesis of Cycloaddition Precursors, Acetoxypyranone^a,b

^aReactions were carried out on 0.2 to 3 mmol scale.

^bYields are calculated for two steps.

Following the synthesis of acetoxypyranone derivatives, we carried out the cycloaddition reaction with a mixture of diastereomers of (S)-phenyl acetoxypyranone 14a under various reaction conditions (Table 2). Initially, we attempted the [5 + 2]-cycloaddition reaction without any base under thermal conditions in acetonitrile at 80 °C and in toluene at 110 °C, respectively. However, no cycloadduct was formed when CH₃CN was used as a solvent (entry 1) and a complex mixture of unidentified products was obtained when acetoxypyranone 14a was heated in toluene (entry 2). We then screened different amine bases with varying equivalents in CH₃CN at 60 °C under an argon atmosphere. Treatment of acetoxypyranone 14a with 2.0 equiv of 1,4-diazabicyclo-[2.2.2]octane (DABCO) in acetonitrile at 60 °C for 12 h afforded the cycloadduct 16a (CCDC 2025567) as the major diastereomer in 56% yield (entry 3). Interestingly, increasing the equivalents of base to 4.0 improved the yield to 69%, but the diastereomeric ratio remained the same (entry 4). N-Methylpyrrolidine (NMP) afforded the best yield and diastereomeric ratio of the cycloadduct 16a (entry 5). DBN, DBU, and pyridine mediated cycloaddition reactions were inefficient (entries 6–8). To our surprise, heating the slurry of acetoxypyranone 14a in silica gel (8x wt) provided the cycloadduct in moderate yield and excellent diastereoselectivity (entry 9).

Table 2.

Initial Optimization of [5 + 2]-Cycloaddition Reaction Conditions of Acetoxypyranone 14a

Entry	Base	Equivalents	Solvent	Temp (°C)	Time (h)	Diastereomeric ratioa	Yield (%) 16a
1	No base	–	CH3CN	80	22	–	0
2	No base	–	PhMe	110	22	–	complex mix
3	DABCOb	2.0	CH3CN	60	12	9:1	56
4	DABCOb	4.0	CH3CN	60	12	9:1	69
5	NMPc	4.0	CH3CN	60	12	10:1	89
6	DBUd	4.0	CH3CN	60	11	–	complex mix
7	Pyridinee	4.0	CH3CN	60	12	–	0
8	DBNf	4.0	CH3CN	60	12	–	0
9	SiO2	–	CH3CN	80	24	10:1	44

^aDiastereomeric ratios were determined via ¹H NMR.

^bDABCO = 1,4-Diazabicyclo-[2.2.2]octane.

^cNMP = N-Methylpyrrolidine.

^dDBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene,

^eRecovered 14a (78%).

^fDBN = 1,5-Diazabicyclo[4.3.0]non-5-ene.

We then conducted cycloadditions of various other substrates using 4 equiv of NMP as shown in entry 5, Table 2, and the results are shown in Table 3. We first investigated O-allyl tethered alkenes on the acetoxypyranone derivatives to examine the scope of chirality transfer from the substrates. Cycloaddition of acetoxy-pyranone 14a provided cycloadduct 16a in 89% yield. The diastereofacial selectivity was very high, and the diastereomeric ratio (10:1) was determined using ¹H NMR analysis. Separation of the diastereomers via column chromatography proved to be difficult due to the similar R_f values of the two diastereomers in many different solvent systems.

Table 3.

Intramolecular [5 + 2] Cycloaddition with Oxidopyrylium Ion and the Terminal Alkene

^aReactions were carried out using N-methylpyrrolidine, NMP (4.0 equiv), in CH₃CN (0.02 M) at 60 °C.

^bThe diastereomeric ratios were determined by ¹H NMR.

^cReaction was carried out at 150 °C with 1.5 equiv of N-methyl pyrrolidine as base.

We have also prepared (R)-phenyl acetoxypyranone 14b from (R)-mandelic acid and subjected it to [5 + 2] cycloaddition under similar conditions. This resulted in cycloadduct 16b in 74% yield and showed a similar diastereomeric ratio (10:1). The relative stereochemistry of the major diastereomer of 16b was initially established by ¹H NMR NOESY and COSY experiments. Since the absolute stereochemistry of proton H_c comes from the chiral starting material, (R)-mandelic acid, we can assign the relative stereochemistry of protons H_f and H_i from H_c. A COSY experiment was done first to assign the protons coupled to H_f and H_i respectively. The results of the observed COSY and NOESY correlation are summarized in Figure 3. The strong NOESY correlations between H_c–H_e, H_e–H_f, and H_f–H_h provided evidence for the assigned stereochemistry of H_f. Similarly, the observed NOESY correlations between H_d–H_g and H_g–H_i supports the assigned stereochemistry of H_i. The cycloadduct 16b was later crystallized in hexanes/EtOAc (4/1) solution, and the absolute stereochemistry was unambiguously determined by X-ray crystallography (CCDC 2025568).⁴⁷ The 2-D NMR correlations are consistent with the X-ray crystal structure of 16b. More detailed NMR and X-ray studies including the ORTEP diagram of 16b and other structures are shown in the Supporting Information. This result shows that the stereochemical outcome of [5 + 2] cycloaddition reaction can be influenced by the existing chirality of the substrate.

Figure 3.

Representative ¹H NMR COSY and NOESY correlations of compound 16b.

We investigated the effect of the alkyl groups on the stereoselectivity. The cycloaddition reaction proceeded well with acetoxypyranones 14c and 14d containing the isopropyl and methyl substituents, respectively. The diastereoselectivity and yield of the cycloadduct were reduced as compared to the phenyl derivative (entries 3 and 4). Surprisingly, the presence of a methyl group on the alkene tether gave a slightly better diastereoselectivity compared to the bulkier isopropyl group. To confirm the stereochemistry of the minor isomer, we separated both isomers 16c (major) and 16c (minor) by HPLC using a chiral column (CHIRALPAK-IC). As shown in Scheme 5, Luche reduction of 16c (minor) using NaBH₄ and CeCl₃ at 0 °C for 1 h furnished allylic alcohol 21 as a single isomer in 75% yield (Scheme 5).

Scheme 5.

Synthesis of Allylic Alcohol 21

We also carried out stereochemical assignment of the alcohol 21 by 2D-NMR experiments (Figure 4). The complete assignment of all protons and carbons was achieved by proton–proton (NOESY and COSY) and proton–carbon (HMQC) correlation experiments (please see Supporting Information). Our structural assignment was not conclusive due to the lack of correlation between protons H_c–H_d. However, the X-ray crystallography of compound 21 showed that protons H_c and H_d are not in proximity and supported the correlation between proton H_c and H_e. The absolute stereochemistry of alcohol 21 was assigned by X-ray crystallography (CCDC 2064460; please see Supporting Information).⁴⁷

Figure 4.

Representative ¹H NMR COSY and NOESY correlations of alcohol 21.

We further investigated the stereochemical effect of increasing the tether length to form six- and seven-membered rings containing alkyl substituents. The reaction of O-homoallyl acetoxypyranone 14e with a phenyl substituent in the presence of 4 equiv of NMP for 4 h resulted in cycloadduct 16e in 60% yield and diastereoselectivity was excellent (>19:1 by ¹H NMR analysis of the crude reaction products). Cycloaddition reaction of homoallyl derivative 14f with an isopropyl substituent proceeded well to provide cycloadduct 16f in 84% yield and excellent diastereoselectivity (>19:1). Similarly, homoallyl derivative 14g with a methyl substituent afforded cycloadduct 16g in 79% yield with similar diastereoselectivity as the other homoallyl derivatives (entries 5–7).

We then investigated the cycloaddition of acetoxypyranone 14h with a five carbon alkenyloxy tether containing a methyl substituent. The results are shown in Table 4. Initial cycloaddition attempt with 1.5 equiv of NMP in CH₃CN at 23 °C for 24 h, resulted in no cycloaddition product (entry 1). We then carried out the cycloaddition in the presence of 4 equiv of NMP in CH₃CN at 60 °C for 4 h (entry 2). These conditions resulted in a complex mixture of products (entry 2). The reaction temperature was increased to 80 °C, and after 6 h, cycloadduct 16h was obtained in 26% yield and 10% of the starting material 14h was recovered (entry 3). The ¹H NMR analysis revealed that 16h was formed in a highly diastereoselective manner (>19:1 by ¹H NMR analysis). Intramolecular cycloaddition reactions that form seven-membered rings are in general less reactive due to unfavorable entropy. To overcome the entropic factors, we decided to carry out the cycloaddition reaction at higher temperatures (entries 4–8). Reaction of 14h at 120 °C in the presence of 1.5 equiv of NMP in CH₃CN in a sealed tube provided the cycloadduct 16h in 49% yield and excellent diastereoselectivity (>19:1 by ¹H NMR) (entry 4). The corresponding reaction in the presence of 2.0 equiv of NMP resulted in a slight decrease in the yield of the cycloadduct (entry 5). A further increase of reaction temperature to 150 °C in a sealed tube for 4 h provided cycloadduct 16h in 47% yield (entry 6). The cycloaddition proceeded a bit more efficiently in the presence of 1.5 equiv of NMP at 150 °C for 3 h which resulted in complete consumption of starting material and yielded 16h in 59% yield (entry 8). We also examined the cycloaddition reaction of 14h with 1.5 equiv of 2,2,6,6-tetramethylpiperidine in CH₃CN at 150 °C (entry 7), as reported by Mei and co-workers.⁴⁸ This condition resulted in the formation of cycloadduct 16h in 58% isolated yield.

Table 4.

Temperature Screening for [5 + 2]-Cycloaddition Reaction of Acetoxypyranone 14h

Entry	Base (equiv)	Temp (°C)	Time (h)	Yield (%)a,b 16h
1	NMP (1.5)	23	24	No product
2	NMP (4.0)	60	4	complex
3	NMP (4.0)	80	6	26
4	NMP (1.5)	120	4	49
5	NMP (2.0)	120	4	45
6	NMP (2.0)	150	4	47
7	TMP (1.5)	150	19	58
8	NMP (1.5)	150	3	59

^aProduct 16h shows excellent diastereoselectivity (>19:1 by ¹H NMR analysis). Yields refer to isolated product after chromatography.

^bCH₃CN was used as solvent. NMP, N-Methylpyrrolidine; TMP, 2,2,6,6-tetramethylpiperidine.

To explain the stereochemical outcome of the [5 + 2]-cycloaddition of chiral substrate containing an alkoxy olefin tether, we proposed stereochemical models shown in Figure 5. Treatment of acetoxyhydropyranones 14 with base will lead to the formation of the aromatic oxidopyrylium ion 15 containing an α-chiral center bearing an alkyl substituent and an alkoxy tether with a terminal alkene. The O-allyl chain with the phenyl group will adopt a transition-state 15a where the bulky phenyl group would occupy a pseudoequatorial position in the envelope conformation of the developing five-membered ring.^49,50 The alkyl groups on the tether act as a stereochemical handle to orient the pyranone ring at the bottom so that the terminal alkene can approach from the top face. As the bulkiness of the alkyl substituent (R-group) on the side chain decreases, the preference of 15a over the alternative diastereomeric transition state would also decrease and that would lead to lower diastereoselectivity for the cycloadducts. For [5 + 2] cycloaddition with a homoallyl side chain, the stereochemical outcome can be rationalized using a six-membered chair transition-state 15e similar to that suggested by Wender and co-workers.¹⁶ The phenyl group will be in the equatorial position and will block the bottom face, so that the approach of the alkene will occur from the top face as shown in transition state 15e. The formation of a six-membered transition state 15e is dominant in controlling the stereochemistry and therefore gives rise to formation of cycloadducts with high diastereoselectivity. The observed high diastereoselectivity for cycloadduct 16h with a seven-membered ring may be due to the formation of a similar dominant pseudo chairlike transition state as 15e for the six-membered ring as shown.

Figure 5.

Representations of transition states of five-membered and six-membered fused cycloadducts.

CONCLUSION

In summary, we investigated [5 + 2] intramolecular oxidopyrylium-alkene cycloaddition reactions containing an α-chiral center on the alkene tether. The presence of the α-chiral center directed the formation of three new chiral centers in the 8-oxabicyclo[3.2.1]octane core containing five- to seven-membered fused oxacyclic rings with high diastereoselectivity. These cycloadditions proceeded with good to excellent yields. The degree of diastereoselectivity for the allyloxy tether is dependent upon the size of the alkyl group for the formation of the 6–5–5 tricyclic ring systems. The phenyl substituent showed very good diastereoselectivity; however, both methyl and isopropyl groups showed lower diastereoselectivity. For cycloaddition substrates containing a homoallyloxy tether, the reaction proceeded with very good yields and excellent diastereoselectivity for methyl, isopropyl, and phenyl substituents. The stereochemical outcome of the cycloaddition reaction was rationalized using stereochemical models. The product stereochemistry was assigned by extensive ¹H NMR and X-ray crystallographic studies. For allyloxy derivatives, the cycloaddition reaction presumably proceeded through an envelope conformation with substituents oriented in a pseudoequatorial position. For the cycloaddition with homoallyloxy tethers, the reaction presumably proceeded with a chairlike transition state with the substituent on the α-chiral center oriented equatorially, avoiding competing nonbonded interactions. Various cycloaddition substrates were synthesized efficiently from optically active starting materials. Further utilization of this asymmetric cycloaddition reaction in the synthesis of bioactive compounds in medicinal chemistry is being explored.

EXPERIMENTAL SECTION

All chemicals were purchased from commercial suppliers and were used as received unless otherwise stated. Anhydrous solvents were obtained as follows: anhydrous tetrahydrofuran and diethyl ether were distilled from sodium metal under argon, anhydrous dichloromethane was dried via distillation from calcium hydride, DMF was dried overnight over barium oxide followed by vacuum distillation, and anhydrous methanol was distilled from activated magnesium under argon. All other solvents were reagent grade. All moisture-sensitive reactions were carried out under an argon atmosphere in either flame or oven-dried (120 °C) glassware. Stainless steel syringes and cannula were used to transfer airor moisture-sensitive liquids. TLC analysis was conducted using glass-backed thin-layer silica gel chromatography plates (60 Å, 250 μm thickness, F254 indicator). Column chromatography was performed using silica gel, 230–400 mesh, 60 Å pore diameter. Isolated yields and yields based on the recovered starting material (brsm) were determined following purification. Proton Nuclear Magnetic Resonance NMR (¹H NMR) spectra and carbon nuclear magnetic resonance (¹³C NMR) spectra were recorded on Bruker AV-III-400HD and Bruker AVIII-800 spectrometers. Chemical shifts for protons are reported in parts per million and are references to the NMR solvent peak (CDCl₃: δ 7.26). Chemical shifts for carbons are reported in parts per million and are referenced to the carbon resonances of the NMR solvent (CDCl₃: δ77.16). Data are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sep = septet, m = multiplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dddd = doublet of doublet of doublets of doublets, td = triplet of doublets, dq = doublet of quartets, qd = quartet of doublets, dt = doublet of triplets, brs = broad singlet. All coupling constants are measured in hertz (Hz). Optical rotations were measured on a Rudolph’sAUTOPOL-III automatic digital polarimeter with a sodium lamp and are reported as follows: [α]λ T °C (c = g/100 mL, solvent). 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 and an Agilent 6550 Q-TOF LC/MS instrument at the Purdue University Analytical Mass Spectrometry Facility.

General Procedure A: Synthesis of Weinreb Amides 11a–d.

To a solution of the indicated α-hydroxy ester (1.0 equiv) and N-methyl-O-methyl hydroxylamine hydrochloride (1.5 equiv) in THF (0.3 M) at −20 °C was added isopropylmagnesium chloride (2.0 M solution in THF, 4.0 equiv). The reaction mixture was warmed to 0 °C and stirred for 2–5 h at the same temperature. A solution of satd NH₄Cl was added, and the layers were separated. The aqueous phase was extracted with CH₂Cl₂ (3×), and the combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo. Purification by silica gel column chromatography afforded the desired Weinreb amide.

(S)-2-Hydroxy-N-methoxy-N-methyl-2-phenylacetamide (11a).

The reaction was conducted according to the general procedure A with methyl (S)-(+)-mandelate (4.86 g, 29.30 mmol), N-methyl-O-methyl hydroxylamine hydrochloride (4.30 g, 44.0 mmol), and isopropylmagnesium chloride (59.0 mL, 2.0 M solution in THF, 117.20 mmol) in THF (100 mL) for 2 h. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded the Weinreb amide 11a (4.96 g, 87% yield) as a colorless oil. Experimental data are consistent with the data reported in the literature.⁵¹

(R)-2-Hydroxy-N-methoxy-N-methyl-2-phenylacetamide (11b).

The reaction was conducted according to the general procedure A with methyl (R)-(−)-mandelate (5.30 g, 31.90 mmol), N-methyl-O-methyl hydroxylamine hydrochloride (4.60 g, 47.85 mmol), and isopropylmagnesium chloride (63.80 mL, 2.0 M solution in THF, 127.60 mmol) in THF (100 mL) for 2 h. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded the Weinreb amide 11b (5.60 g, 90% yield) as a colorless oil. Experimental data are consistent with the data reported in the literature.⁵²

(S)-2-Hydroxy-N-methoxy-3-methyl-N-methylbutanamide (11c).

The reaction was conducted according to the general procedure A with (S)-methyl 2-hydroxy-3-methylbutanoate⁵³ (1.80 g, 13.64 mmol), N-methyl-O-methyl hydroxylamine hydrochloride (2.0 g, 20.46 mmol), and isopropylmagnesium chloride (27.30 mL, 2.0 M solution in THF, 54.56 mmol) in THF (50 mL) for 4 h. Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the Weinreb amide 11c (1.47 g, 67% yield) as a yellow oil. Experimental data are consistent with the data reported in the literature.³⁹

(S)-2-Hydroxy-N-methoxy-N-methylpropanamide (11d).

The reaction was conducted according to the general procedure A with (S)-(−)-ethyl lactate (1.0 g, 8.50 mmol), N-methyl-O-methyl hydroxylamine hydrochloride (1.24 g, 12.75 mmol), and isopropylmagnesium chloride (17.0 mL, 2.0 M solution in THF, 34 mmol) in THF (28 mL) for 5 h. Purification by silica gel column chromatography (30% EtOAc/hexanes) afforded the Weinreb amide 11d (1.0 g, 89% yield) as a colorless oil. Experimental data are consistent with the data reported in the literature.⁵⁴

General Procedure B: O-Allylation of α-Hydroxy Amides 12a–d.

To a suspension of sodium hydride (60% dispersion in oil, 1.5 equiv) in dry DMF (0.6 M) at −20 °C was added a 0.3 M solution of the Weinreb amide (1.0 equiv) in dry DMF dropwise via cannula. The reaction mixture was stirred for an additional 30 min, followed by addition of allyl bromide (1.5 equiv) in one portion. The resulting yellow suspension was then warmed to −10 °C and stirred for 12–14 h. The reaction was quenched by the addition of satd NH₄Cl and allowed to warm to 23 °C. The thick white suspension was then diluted with EtOAc and washed with cold H₂O (5×). The combined aqueous layers were back extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded the O-allylated product.

(S)-2-(Allyloxy)-N-methoxy-N-methyl-2-phenylacetamide (12a).

The reaction was conducted according to the general procedure B with NaH (60% dispersion in oil, 308 mg, 7.60 mmol), Weinreb amide 11a (1.0 g, 5.10 mmol), and allyl bromide (660 μL, 7.70 mmol). Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded compound 12a (1.04 g, 87% yield) as a white amorphous solid. [α]d²⁴ +82.3 (c 1.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.44−7.37 (m, 2H), 7.33−7.23 (m, 3H), 5.91 (ddt, J = 17.3, 10.4, 5.8 Hz, 1H), 5.29−5.14 (m, 3H), 4.08−3.95 (m, 2H), 3.39 (s, 3H), 3.10 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.0, 136.6, 134.2, 128.4, 128.4, 128.0, 117.7, 77.6, 70.1, 60.9, 32.3. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₈O₃N 236.1281; found 236.1283.

(R)-2-(Allyloxy)-N-methoxy-N-methyl-2-phenylacetamide (12b).

The reaction was conducted according to the general procedure B with NaH (60% dispersion in oil, 1.60 g, 40.77 mmol), Weinreb amide 11b (5.30 g, 28.18 mmol), and allyl bromide (3.50 mL, 40.77 mmol). Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded compound 12b (5.60 g, 87% yield) as a white amorphous solid. [α]d²⁴ −83.5 (c 1.3, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.42−7.36 (m, 2H), 7.31−7.21 (m, 3H), 5.89 (ddt, J = 17.2, 10.3, 5.8 Hz, 1H), 5.28−5.11 (m, 3H), 4.07−3.92 (m, 2H), 3.37 (s, 3H), 3.08 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.0, 136.6, 134.2, 128.4, 128.3, 128.0, 117.7, 77.5, 70.1, 60.9, 32.2. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₈O₃N 236.1282; found 236.1281.

(S)-2-(Allyloxy)-N-methoxy-N,3-dimethylbutanamide (12c).

The reaction was conducted according to the general procedure B with NaH (60% dispersion in oil, 893 mg, 22.32 mmol), Weinreb amide 11c (2.40 g, 14.88 mmol), and allyl bromide (2.0 mL, 22.32 mmol). Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded compound 12c (2.62 g, 88% yield) as a colorless oil. [α]d²⁴ −30.5 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 5.94−5.75 (m, 1H), 5.20 (dq, J = 17.3, 1.7 Hz, 1H), 5.10 (dq, J = 10.4, 1.5 Hz, 1H), 4.04 (ddt, J = 12.8, 5.2, 1.6 Hz, 1H), 4.00−3.87 (m, 1H), 3.79 (ddt, J = 12.8, 6.1, 1.4 Hz, 1H), 3.62 (s, 3H), 3.15 (s, 3H), 2.08−1.89 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.2, 134.6, 116.9, 80.4, 70.8, 61.1, 32.1, 30.8, 18.8, 18.0. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₀H₂₀O₃N 202.1438; found 202.1438.

(S)-2-(Allyloxy)-N-methoxy-N-methylpropanamide (12d).

The reaction was conducted according to the general procedure B with NaH (60% dispersion in oil, 680 mg, 16.90 mmol), Weinreb amide 11d (1.50 g, 11.27 mmol), and allyl bromide (1.50 mL, 16.90 mmol). Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded compound 12d (1.33g, 69% yield) as a colorless oil. [α]d²⁴ −69.8 (c 0.8, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 6.02−5.83 (m, 1H), 5.26 (ddq, J = 17.2, 4.8, 1.6 Hz, 1H), 5.17 (ddq, J = 10.3, 4.2, 1.5 Hz, 1H), 4.38 (q, J = 6.4 Hz, 1H), 4.17−4.03 (m, 1H), 3.95−3.83 (m, 1H), 3.68 (d, J = 5.3 Hz, 3H), 3.19 (d, J = 5.2 Hz, 3H), 1.45−1.30 (m, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.7, 134.5, 117.4, 70.4, 61.3, 32.5, 17.8. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₈H₁₆O₃N 174.1125; found 174.1126.

General Procedure C: O-Alkylation of α-Hydroxy Esters 20a–c.

A flame-dried round-bottom flask was charged with 18-crown-6 (0.1 equiv) and potassium tert-butoxide (1.0 M solution in THF, 1.1 equiv) in freshly distilled THF (0.3 M) at −20 °C. To this mixture, a solution of the α-hydroxy ester (1.0 equiv) in freshly distilled THF (1.0 M) was added dropwise. The reaction mixture was stirred for 10 min followed by addition of but-3-en-1-yl trifluoromethanesulfonate or pent-4-en-1-yl trifluoromethanesulfonate (1.3–1.5 equiv) in one portion at −20 °C. After 20 min, the reaction was quenched with a satd solution of NH₄Cl and extracted with EtOAc (3×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification of crude by silica gel column chromatography afforded the O-alkylated product.

Methyl (S)-2-(But-3-en-1-yloxy)-3-methylbutanoate (20a).

The reaction was conducted according to the general procedure C with (S)-methyl 2-hydroxy-3-methylbutanoate⁵³ 19a (2.0 g, 15.15 mmol), 18-crown-6 (400 mg, 1.52 mmol), potassium tert-butoxide (1.0 M solution in THF, 23.0 mL, 22.70 mmol, 1.5 equiv), and but-3-en-1-yl trifluoromethanesulfonate⁵⁵ (4.60 g, 22.70 mmol). Purification by silica gel column chromatography (5% EtOAc/hexanes) afforded compound 20a in 47% isolated yield (1.32 g, 61% brsm) as a colorless oil. [α]d²⁴ −45.3 (c 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 5.81 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.12−4.99 (m, 2H), 3.73 (s, 3H), 3.63 (dt, J = 9.2, 6.6 Hz, 1H), 3.57 (d, J = 5.8 Hz, 1H), 3.32 (dt, J = 9.1, 6.9 Hz, 1H), 2.34 (dtd, J = 8.7, 6.8, 5.3 Hz, 2H), 2.10−1.96 (m, 1H), 0.94 (d, J = 2.0 Hz, 3H), 0.93 (d, J = 2.0 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.0, 134.8, 116.3, 84.4, 70.2, 51.5, 33.9, 31.5, 18.6, 17.7. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₀H₁₈O₃Na 209.1148; found 209.1152.

Ethyl (S)-2-(But-3-en-1-yloxy)propanoate (20b).

The reaction was conducted according to the general procedure C with (S)-(−)-ethyl lactate 19b (2.0 g, 16.94 mmol), 18-crown-6 (450 mg, 1.69 mmol), potassium tert-butoxide (1.0 M solution in THF, 18.60 mL, 18.60 mmol), and but-3-en-1-yl trifluoromethanesulfonate⁵⁵ (4.49 g, 22.02 mmol). Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded compound 20b in 54% isolated yield (1.55 g, 75% brsm) as a colorless oil. [α]d²⁴ −37.9 (c 0.9, CHCl₃). ¹H NMR (400 MHz, CDCl₃ δ 5.82 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.18−4.97 (m, 2H), 4.25−4.14 (m, 2H), 3.95 (q, J = 6.8 Hz, 1H), 3.63 (dt, J = 9.0, 6.8 Hz, 1H), 3.41 (dt, J = 8.9, 6.9 Hz, 1H), 2.44−2.27 (m, 2H), 1.39 (d, J = 6.9 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.3, 134.7, 116.4, 74.9, 69.4, 60.7, 34.0, 18.5, 14.1. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₉H₁₇O₃ 173.1172; found 173.1171.

Ethyl (S)-2-(Pent-4-en-1-yloxy)propanoate (20c).

The reaction was conducted according to the general procedure C with (S)-(−)-ethyl lactate 19b (2.50 g, 21.19 mmol), 18-crown-6 (560 mg, 2.12 mmol), potassium tert-butoxide (1.0 M solution in THF, 23.30 mL, 23.50 mmol), and pent-4-en-1-yl trifluoromethanesulfonate⁵⁶ (6.90 g, 31.77 mmol). Purification by silica gel column chromatography (5% EtOAc/hexanes) afforded compound 20c in 84% isolated yield (3.32 g, 92% brsm) as a colorless oil. [α]d²⁴ −28.7 (c 1.2, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 5.91−5.72 (m, 1H), 5.09−4.89 (m, 2H), 4.29−4.10 (m, 2H), 4.01−3.86 (m, 1H), 3.63−3.48 (m, 1H), 3.44−3.31 (m, 1H), 2.26−2.06 (m, 2H), 1.80−1.62 (m, 2H), 1.39 (dd, J = 6.8, 1.2 Hz, 3H), 1.28 (td, J = 7.1, 1.1 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.4, 138.1, 114.7, 74.9, 69.5, 60.7, 30.1, 28.8, 18.6, 14.1. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₀H₁₈O₃Na 209.1147; found 209.1149.

General Procedure D: Synthesis of Weinreb Amides 12f–h.

To a solution of N-methyl-O-methyl hydroxylamine hydrochloride (4.0 equiv mmol) in CH₂Cl₂ (0.1 M) was added trimethylaluminum (2.0 M solution in n-hexane, 4.0 equiv) at −10 °C. The resulting clear solution was stirred for 1 h at 23 °C and then cooled to −10 °C. To the reaction mixture was cannulated a solution of O-alkylated ester (1.0 equiv) in CH₂Cl₂ (1.0 M), and the reaction mixture was slowly warmed to 23 °C over 1 h. After 24 h, the reaction was quenched by adding a satd potassium sodium tartrate solution at 0 °C, and the resulting mixture was warmed to 23 °C. After 1 h, the mixture was filtered through a pad of Celite and washed with CH₂Cl₂. The filtrate was extracted with CH₂Cl₂ (2×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by silica gel column chromatography afforded the desired Weinreb amide.

(S)-2-(But-3-en-1-yloxy)-N-methoxy-N,3-dimethylbutanamide (12f).

The reaction was conducted according to the general procedure D with methyl (S)-2-(but-3-en-1-yloxy)-3-methylbutanoate 20a (500 mg, 2.69 mmol), N-methyl-O-methyl hydroxylamine hydrochloride (1.05 g, 10.76 mmol), and trimethylaluminum (2.0 M solution in n-hexane, 5.40 mL, 10.76 mmol) for 24 h. Purification by silica gel column chromatography (15% EtOAc/hexanes) afforded the Weinreb amide 12f (435 mg, 75% yield) as a colorless oil. [α]d²⁴ −25.3 (c 0.7, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 5.80 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.10−4.96 (m, 2H), 3.89 (brs, 1H), 3.68 (s, 3H), 3.61−3.53 (m, 1H), 3.34−3.26 (m, 1H), 3.20 (s, 3H), 2.42−2.25 (m, 2H), 2.11−1.97 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.4, 135.0, 116.2, 81.7, 69.4, 61.2, 34.0, 32.2, 30.9, 18.7, 18.2. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₁H₂₂O₃N 216.1594; found 216.1594.

(S)-2-(But-3-en-1-yloxy)-N-methoxy-N-methylpropanamide (12g).

The reaction was conducted according to the general procedure D with a slight modification using ethyl (S)-2-(but-3-en-1-yloxy)propanoate 20b (820 mg, 4.76 mmol), N-methyl-O-methyl hydroxylamine hydrochloride (980 mg, 10.01 mmol), and trimethylaluminum (2.0 M solution in n-hexane, 5.0 mL, 10.01 mmol) for 24 h. Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded Weinreb amide 12g (575 mg, 65% yield) as a colorless oil. [α]d²⁴ −27.9 (c 0.4, CHCl₃). ¹H NMR (400 MHz,CDCl₃) δ 5.89−5.72 (m, 1H), 5.16−4.94 (m, 2H), 4.33 (q, J = 6.8 Hz, 1H), 3.69 (s, 3H), 3.60−3.50 (m, 1H), 3.42−3.30 (m, 1H), 3.20 (s, 3H), 2.43−2.29 (m, 2H), 1.35 (dd, J = 6.7, 1.6 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.7, 134.8, 116.3, 72.5, 68.8, 61.3, 34.1, 32.2, 17.7. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₉H₁₈O₃N 188.1281; found 188.1280.

(S)-N-Methoxy-N-methyl-2-(pent-4-en-1-yloxy)propanamide (12h).

The reaction was conducted according to the general procedure D with ethyl (S)-2-(pent-4-en-1-yloxy)propanoate 20c (3.25 g, 17.47 mmol), N-methyl-O-methyl hydroxylamine hydrochloride (6.80 g, 69.89 mmol), and trimethylaluminum (2.0 M solution in n-hexane, 35.0 mL, 69.89 mmol) for 24 h. Purification by silica gel column chromatography (15% EtOAc/hexanes) afforded the Weinreb amide 12h (2.80 g, 80% yield) as a colorless oil. [α]d²⁴ −15.6 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 5.84−5.68 (m, 1H), 5.02−4.85 (m, 2H), 4.27 (q, J = 7.1, 6.7 Hz, 1H), 3.66 (t, J = 2.1 Hz, 3H), 3.52−3.40 (m, 1H), 3.35−3.23 (m, 1H), 3.16 (s, 3H), 2.13−2.01 (m, 2H), 1.73−1.59 (m, 2H), 1.35−1.27 (m, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.8, 138.1, 114.5, 72.4, 68.8, 61.3, 32.2, 30.1, 28.8, 17.7. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₀H₂₀O₃N 202.1437; found 202.1437.

General Procedure E: Synthesis of Furfuryl Alcohols 13a–h.

A flame-dried round-bottom flask was charged with furan (2.0 equiv) and dry THF (0.2 M) under argon. The reaction flask was then cooled to 0 °C, and a solution of n-BuLi (1.6 M solution in hexane, 1.8 equiv) was added dropwise. The resulting mixture was stirred at this temperature for 30 min and then cooled to −78 °C, followed by a dropwise addition of the O-alkylated Weinreb amide (1.0 equiv) solution in THF. After 1 h, the reaction was quenched with satd NH₄Cl and extracted with EtOAc (2×). The organic phase was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography.

The above furyl ketone (1.0 equiv) was dissolved in dry MeOH at −78 °C followed by portionwise addition of NaBH₄ (3.0 equiv). After 1 h, the reaction was quenched by water, the residue was diluted with CH₂Cl₂, and the aqueous layer was extracted with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography.

(2S)-2-(Allyloxy)-1-(furan-2-yl)-2-phenylethan-1-ol (13a).

The reaction was conducted according to the general procedure E with furan (2.0 mL, 27.24 mmol), n-BuLi (1.6 M solution in hexane, 15.30 mL, 24.51 mmol), and (S)-2-(allyloxy)-N-methoxy-N-methyl-2-phenylacetamide 12a (3.20 g, 13.62 mmol). Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the furyl ketone (2.90 g, 88% yield) as an amorphous white solid. [α]d²⁴ +25.3 (c 0.3, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 7.3 Hz, 2H), 7.39 (d, J = 3.6 Hz, 1H), 7.32 (dt, J = 13.8, 7.0 Hz, 3H), 6.54−6.44 (m, 1H), 5.95 (ddt, J = 16.1, 10.6, 5.7 Hz, 1H), 5.47 (s, 1H), 5.34−5.16 (m, 2H), 4.14−4.03 (m, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 186.1, 150.4, 146.8, 136.0, 133.8, 128.6, 128.4, 127.4, 119.7, 118.0, 112.2, 83.6, 70.5. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₅O₃ 243.1016; found 243.1018.

The above furyl ketone (2.80 g, 11.86 mmol) was reduced with NaBH₄ (1.35 g, 35.58 mmol) in dry MeOH (60 mL) following the general procedure E. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded the furfuryl alcohol 13a (2.82 g, 95% yield) as a colorless oil in a 7:1 diastereomeric ratio. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J = 1.8, 0.9 Hz, 1H), 7.34−7.29 (m, 3H), 7.27−7.23 (m, 2H), 6.30 (dd, J = 3.3, 1.8 Hz, 1H), 6.22−6.16 (m, 1H), 5.88−5.77 (m, 1H), 5.22−5.12 (m, 2H), 4.87 (d, J = 5.9 Hz, 1H), 4.71−4.67 (m, 1H), 4.00 (ddt, J = 13.0, 5.0, 1.6 Hz, 1H), 3.80 (ddt, J = 12.9, 6.1, 1.4 Hz, 1H), 2.32 (brs, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.3, 141.6, 137.6, 134.3, 128.2, 128.1, 127.6, 117.0, 110.2, 107.8, 82.7, 71.2, 69.9. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₅H₁₆O₃Na 267.0992; found 267.0992.

(2R)-2-(Allyloxy)-1-(furan-2-yl)-2-phenylethan-1-ol (13b).

The reaction was conducted according to the general procedure E with furan (810 μL, 11.06 mmol), n-BuLi (1.6 M solution in hexane, 6.20 mL, 9.95 mmol), and (R)-2-(allyloxy)-N-methoxy-N-methyl-2-phenylacetamide 12b (1.30 g, 5.53 mmol). Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the furyl ketone (1.16 g, 89% yield) as an amorphous white solid. [α]d²⁴ −27.0 (c 1.8, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.59−7.51 (m, 1H), 7.53−7.44 (m, 2H), 7.41−7.34 (m, 1H), 7.36−7.23 (m, 3H), 6.52−6.41 (m, 1H), 6.03−5.86 (m, 1H), 5.47 (s, 1H), 5.36−5.23 (m, 1H), 5.25−5.16 (m, 1H), 4.17−4.04 (m, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 186.0, 150.4, 146.8, 136.0, 133.8, 128.6, 128.4, 127.4, 119. 7, 118.0, 112.2, 83.6, 70.5. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₅O₃ 243.1016; found 243.1016.

The above furyl ketone (630 mg, 2.60 mmol) was reduced with NaBH₄ (300 mg, 7.80 mmol) in dry MeOH (13 mL) following the general procedure E. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded the furfuryl alcohol 13b (610 mg, 95% yield) as a colorless oil in a 9:1 diastereomeric ratio. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J = 1.8, 0.9 Hz, 1H), 7.36−7.29 (m, 3H), 7.27−7.23 (m, 2H), 6.30 (dd, J = 3.2, 1.8 Hz, 1H), 6.23−6.15 (m, 1H), 5.83 (dddd, J = 17.2, 10.4, 6.1, 5.0 Hz, 1H), 5.26−5.10 (m, 2H), 4.88 (t, J = 5.9 Hz, 1H), 4.69 (d, J = 5.9 Hz, 1H), 4.00 (ddt, J = 13.0, 5.0, 1.6 Hz, 1H), 3.80 (ddt, J = 12.9, 6.1, 1.4 Hz, 1H), 2.40−2.28 (m, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.2, 141.7, 137.6, 134.2, 128.2, 128.1, 127.6, 117.0, 110.2, 107.8, 82.7, 71.2, 69.9. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₅H₁₆O₃Na 267.0992; found 267.0993.

(2S)-2-(Allyloxy)-1-(furan-2-yl)-3-methylbutan-1-ol (13c).

The reaction was conducted according to the general procedure E with furan (1.80 mL, 24.88 mmol), n-BuLi (1.6 M solution in hexane, 14.0 mL, 22.39 mmol), and (S)-2-(allyloxy)-N-methoxy-N,3-dimethylbutanamide 12c (2.39 g, 11.89 mmol). Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the furyl ketone (2.16 g, 87% yield) as a colorless oil. [α]d²⁴ −19.4 (c 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 3.6 Hz, 1H), 6.57−6.49 (m, 1H), 5.95−5.80 (m, 1H), 5.25 (dq, J = 17.2, 1.6 Hz, 1H), 5.17 (dq, J = 10.3, 1.3 Hz, 1H), 4.09 (ddt, J = 12.7, 5.3, 1.5 Hz, 1H), 4.00 (d, J = 6.6 Hz, 1H), 3.88 (ddt, J = 12.7, 6.0, 1.3 Hz, 1H), 2.22−2.06 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.3, 151.3, 146.7, 134.1, 119.4, 117.4, 112.0, 87.9, 71.5, 32.1, 18.9, 18.2.HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₇O₃ 209.1172; found 209.1173.

The above furyl ketone(2.10 g, 10.09 mmol) was reduced with NaBH₄ (1.15 g, 30.29 mmol) in dry MeOH (50 mL) following the general procedure E. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded the furfuryl alcohol 13c (2.0 g, 95% yield) as a colorless oil in a 3:1 diastereomeric ratio. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J = 3.9 Hz, 1H), 6.33 (d, J = 2.9 Hz, 2H), 5.80 (ddt, J = 16.5, 10.8, 5.4 Hz, 1H), 5.25−5.14 (m, 1H), 5.16−5.05 (m, 1H), 4.70 (d, J = 6.3 Hz, 1H), 4.04−3.85 (m, 1H), 3.82 (dd, J = 12.5, 5.6 Hz, 1H), 3.46−3.35 (m, 1H), 2.39 (brs, 1H), 1.98−1.83 (m, 1H), 0.97 (dd, J = 6.9, 1.9 Hz, 3H), 0.96−0.89 (m, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.6, 141.6, 134.9, 116.5, 110.3, 107.6, 86.1, 73.7, 68.3, 29.6, 19.7, 17.0. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₂H₁₈O₃Na 233.1148; found 233.1149.

(2S)-2-(Allyloxy)-1-(furan-2-yl)propan-1-ol (13d).

The reaction was conducted according to the general procedure E with furan (1.10 mL, 15.03 mmol), n-BuLi (1.6 M solution in hexane, 8.50 mL, 13.52 mmol), and (S)-2-(allyloxy)-N-methoxy-N-methylpropanamide 12d (1.30 g, 7.51 mmol). Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the furyl ketone (1.20 g, 89% yield) as a colorless oil. [α]d²⁴ −68.7 (c 0.9, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.62 (dd, J = 1.7, 0.7 Hz, 1H), 7.44 (dd, J = 3.6, 0.7 Hz, 1H), 6.55 (dd, J = 3.6, 1.7 Hz, 1H), 5.91 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H), 5.27 (dq, J = 17.2, 1.6 Hz, 1H), 5.19 (dq, J = 10.4, 1.3 Hz, 1H), 4.49 (q, J = 6.9 Hz, 1H), 4.09 (ddt, J = 12.6, 5.4, 1.4 Hz, 1H), 3.96 (ddt, J = 12.6, 5.9, 1.3 Hz, 1H), 1.48 (d, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.0, 150.3, 146.8, 134.0, 119.3, 117.6, 112.1, 78.3, 70.8, 18.9. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₀H₁₃O₃ 181.0858; found 181.0859.

The above furyl ketone (1.10 g, 6.10 mmol) was reduced with NaBH₄ (700 mg, 18.30 mmol) in dry MeOH (30 mL) following the general procedure E. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded the furfuryl alcohol 13d (900 mg, 82% yield) as a colorless oil in a 1:1 diastereomeric ratio. ¹H NMR (400 MHz, CDCl₃) δ 7.40−7.37 (m, 1H), 6.35−6.32 (m, 2H), 5.93−5.86 (m, 1H), 5.33−5.22 (m, 2H), 4.81−4.72 (m, 1H), 4.48 (dd, J = 7.5, 3.1 Hz, 1H), 3.99−3.93 (m, 1H), 3.78 (d, J = 6.4 Hz, 1H), 2.57−2.49 (m, 1H), 1.14 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.7, 141.7, 134.7, 116.9, 110.1, 107.0, 76.5, 70.3, 70.1, 14.5. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₀H₁₄O₃Na 205.0835; found 205.0835.

3-((1S)-2-(Furan-2-yl)-2-hydroxy-1-phenylethoxy)propan-1-ol (18).

To a flame-dried flask flushed with argon was added cyclohexene (4.0 g, 48.77 mmol) in 35 mL of THF at 0 °C followed by the addition of borane dimethyl sulfide complex (2.30 mL, 24.37 mmol). The resulting white slurry was stirred at 0 °C for 3 h before the addition of a solution of furfuryl alcohol 13a (1.72 g, 7.17 mmol) in 8.0 mL of THF. The reaction mixture was slowly warmed to 23 °C and stirred for 2 h. Oxidation of the resulting dicyclohexylborinate was achieved by adding 0.3 M water and sodium perborate tetrahydrate (11.03 g, 71.70 mmol) at 0 °C. The resulting mixture was stirred for 12 h at 23 °C and then extracted with ethyl acetate (3×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (1% MeOH/CH₂Cl₂) afforded the diol 18 (1.60 g, 88% yield) as a white amorphous solid in a 5.4:1 diastereomeric ratio. The diastereomers were separated via column chromatography. Anti-diol: [α]d²⁴ +62.2 (c 0.9, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.43−7.37 (m, 1H), 7.39−7.28 (m, 3H), 7.25 (dt, J = 7.5, 1.4 Hz, 2H), 6.32 (dd, J = 3.3, 1.8 Hz, 1H), 6.18 (d, J = 3.2 Hz, 1H), 4.78 (d, J = 6.2 Hz, 1H), 4.61 (d, J = 6.2 Hz, 1H), 3.69 (td, J = 5.7, 2.2 Hz, 2H), 3.64−3.54 (m, 1H), 3.52−3.41 (m, 1H), 2.16 (brs, 2H), 1.83−1.72 (m, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.0, 142.0, 137.7, 128.4, 128.2, 127.3, 110.2, 108.1, 84.5, 71.1, 68.8, 61.8, 31.8. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₅H₁₈O₄Na 285.1097; found 285.1097.

(1S,2S)-2-(But-3-en-1-yloxy)-1-(furan-2-yl)-2-phenylethan-1-ol (13e).

To a solution of the above anti-diol 18 (600 mg, 2.29 mmol) in anhydrous CH₂Cl₂ (10 mL) were added TEMPO (36 mg, 0.23 mmol) and bis(acetoxy)iodobenzene (885 mg, 2.75 mmol) at 0 °C. The reaction mixture was warmed to 23 °C over 1 h and continued to stir at 23 °C. After 8 h, the reaction mixture was quenched with satd Na₂S₂O₃ and extracted with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (5% EtOAc/CH₂Cl₂) afforded the aldehyde (440 mg, 74% yield) as a yellow oil.

To a suspension of methyltriphenylphosphonium bromide (2.50 g, 6.92 mmol) in Et₂O (25 mL) was added potassium tert-butoxide (1.0 M solution in THF, 6.20 mL, 6.21 mmol) at 0 °C. The resulting yellow suspension was then warmed to 23 °C and stirred for 30 min. The reaction mixture was cooled to −20 °C followed by addition of the solution of the above aldehyde (360 mg, 1.38 mmol) in 15 mL of Et₂O. After stirring at −20 °C for 2 h, the reaction was quenched with satd NH₄Cl and extracted with Et₂O (3×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded the furfuryl alcohol 13e (105 mg, 30% yield) as a colorless oil. [α]d²⁴ +43.3 (c 0.3, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.38−7.28 (m, 4H), 7.27−7.19 (m, 2H), 6.30 (dd, J = 3.3, 1.9 Hz, 1H), 6.18 (d, J = 3.3 Hz, 1H), 5.74 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.09−4.95 (m, 2H), 4.84 (t, J = 5.6 Hz, 1H), 4.62 (d, J = 5.8 Hz, 1H), 3.50 (dt, J = 9.4, 6.6 Hz, 1H), 3.35 (dt, J = 9.4, 6.6 Hz, 1H), 2.38 (d, J = 6.0 Hz, 1H), 2.30 (qt, J = 6.6, 1.5 Hz, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.3, 141.6, 137.8, 135.0, 128.1, 128.0, 127.4, 116.3, 110.1, 107.7, 83.7, 71.2, 68.7, 34.0. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₆H₁₈O₃Na 281.1148; found 281.1147.

(2S)-2-(But-3-en-1-yloxy)-1-(furan-2-yl)-3-methylbutan-1-ol (13f).

The reaction was conducted according to the general procedure E with furan (605 μL, 8.26 mmol), n-BuLi (1.6 M solution in hexane, 7.50 mL, 7.45 mmol), and (S)-2-(but-3-en-1-yloxy)-N-methoxy-N,3-dimethylbutanamide 12f (890 mg, 4.13 mmol). Purification by silica gel column chromatography (5% EtOAc/hexanes) afforded the furyl ketone (800 mg, 87% yield) as a yellow oil. [α]d²⁴ −81.4 (c 0.6, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.61 (dd, J = 1.7, 0.8 Hz, 1H), 7.43 (dt, J = 3.6, 0.7 Hz, 1H), 6.53 (dd, J = 3.6, 1.7 Hz, 1H), 5.77 (ddt, J = 16.9, 10.0, 6.7 Hz, 1H), 5.12−4.94 (m, 2H), 3.88 (d, J = 6.9 Hz, 1H), 3.64−3.52 (m, 1H), 3.43−3.32 (m, 1H), 2.40−2.24 (m, 2H), 2.17−2.03 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.4, 151.2, 146.7, 134.8, 119.4, 116.4, 112.0, 89.2, 70.1, 34.1, 32.1, 18.8, 18.4. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₉O₃ 223.1329; found 223.1329.

The above furyl ketone (665 mg, 2.99 mmol) was reduced with NaBH₄ (500 mg, 11.98 mmol) in dry MeOH (15 mL) following the general procedure E. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded the furfuryl alcohol 13f (645 mg, 96% yield) as a yellow oil in a 3:1 diastereomeric ratio. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J = 1.8, 0.9 Hz, 1H), 6.36−6.31 (m, 2H), 5.85−5.72 (m, 1H), 5.13−4.98 (m, 2H), 4.72 (d, J = 5.9 Hz, 1H), 3.66−3.53 (m, 1H), 3.42−3.29 (m, 2H), 2.33−2.20 (m, 2H), 1.91−1.72 (m, 1H), 0.97 (dd, J = 6.9, 1.3 Hz, 3H), 0.93−0.89 (m, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.6, 141.5, 135.4, 116.5, 110.3, 107.5, 86.9, 72.3, 68.5, 34.6, 29.8, 19.6, 17.4. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₃H₂₀O₃Na 247.1304; found 247.1306.

(2S)-2-(But-3-en-1-yloxy)-1-(furan-2-yl)propan-1-ol (13g).

The reaction was conducted according to the general procedure E with furan (630 μL, 8.64 mmol), n-BuLi (1.6 M solution in hexane, 5.0 mL, 8.08 mmol), and (S)-2-(but-3-en-1-yloxy)-N-methoxy-N-methylpropanamide 12g (540 mg, 2.88 mmol). Purification by silica gel column chromatography (8% EtOAc/hexanes) afforded the furyl ketone (465 mg, 83% yield) as a yellow oil. [α]d²⁴ −20.8 (c 1.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 1.7 Hz, 1H), 7.41 (d, J = 3.6 Hz, 1H), 6.52 (dd, J = 3.6, 1.7 Hz, 1H), 5.76 (ddt, J = 17.1, 10.3, 6.7 Hz, 1H), 5.14−4.93 (m, 2H), 4.40 (q, J = 6.9 Hz, 1H), 3.54 (dt, J = 9.0, 6.8 Hz, 1H), 3.44 (dt, J = 9.0, 6.8 Hz, 1H), 2.41−2.26 (m, 2H), 1.43 (d, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.1, 150.3, 146.7, 134.7, 119.4, 116.5, 112.1, 79.3, 69.3, 34.1, 18.8. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₁H₁₅O₃ 195.1015; found 195.1016.

The above furyl ketone (400 mg, 2.0 mmol) was reduced with NaBH₄ (230 mg, 6.0 mmol) in dry MeOH (10 mL) following the general procedure E. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded the furfuryl alcohol 13g (375 mg, 96% yield) as a yellow oil in a 1:1 diastereomeric ratio. ¹H NMR (400 MHz, CDCl₃) δ 7.41−7.33 (m, 1H), 6.38−6.26 (m, 2H), 5.89−5.73 (m, 1H), 5.17−5.01 (m, 2H), 4.44 (d, J = 7.8 Hz, 1H), 3.80−3.59 (m, 2H, superimposed by peak corresponding to the minor isomer), 3.44 (dq, J = 9.2, 6.7 Hz, 1H), 3.17 (brs, 1H), 2.40−2.28 (m, 2H), 1.05 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.8, 142.1, 135.1, 116.8, 110.1, 108.0, 77.7, 71.7, 68.5, 34.3, 15.6. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₁H₁₆O₃Na 219.0992; found 219.0993.

(2S)-1-(Furan-2-yl)-2-(pent-4-en-1-yloxy)propan-1-ol (13h).

The reaction was conducted according to the general procedure E with furan (1.73 mL, 23.88 mmol), n-BuLi (1.6 M solution in hexane, 13.50 mL, 21.49 mmol), and (S)-N-methoxy-N-methyl-2-(pent-4-en-1-yloxy)propanamide 12h (2.40 g, 11.94 mmol). Purification by silica gel column chromatography (5% EtOAc/hexanes) afforded the furyl ketone (2.0 g, 81% yield) as a yellow oil. [α]d²⁴ −14.9 (c 0.6, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, J = 1.7, 0.7 Hz, 1H), 7.37 (dd, J = 3.6, 0.8 Hz, 1H), 6.50 (dd, J = 3.6, 1.7 Hz, 1H), 5.72 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.01−4.80 (m, 2H), 4.35 (q, J = 6.9 Hz, 1H), 3.46 (dt, J = 9.1, 6.5 Hz, 1H), 3.36 (dt, J = 9.1, 6.6 Hz, 1H), 2.05 (tdt, J = 8.0, 6.4, 1.4 Hz, 2H), 1.74−1.56 (m, 2H), 1.40 (d, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.1, 150.3, 146.7, 137.9, 119.2, 114.7, 112.0, 79.2, 69.3, 30.0, 28.8, 18.8. HRMS (ESI/Q-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₇O₃ 209.1171; found 209.1172.

The above furyl ketone (175 mg, 0.84 mmol) was reduced with NaBH₄ (96 mg, 2.52 mmol) in dry MeOH (4.2 mL) following the general procedure E. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded the furfuryl alcohol 13h (160 mg, 90% yield) as a yellow oil in a 2:1 diastereomeric ratio. ¹H NMR (400 MHz, CDCl₃) δ 7.35 (dd, J = 6.2, 1.7 Hz, 1H), 6.39−6.22 (m, 2H), 5.88−5.70 (m, 1H), 5.10−4.87 (m, 2H), 4.43 (d, J = 7.5 Hz, 1H), 3.77−3.47 (m, 2H), 3.38 (dt, J = 9.1, 6.5 Hz, 1H), 3.19 (brs, 1H), 2.09 (dq, J = 15.1, 6.7 Hz, 2H), 1.76−1.49 (m, 2H), 1.03 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.4, 142.0, 138.1, 114.8, 110.1, 107.8, 77.4, 71.6, 68.5, 30.3, 29.0, 15.6. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₂H₁₈O₃Na 233.1149; found 233.1148.

General Procedure F: Synthesis of Acetoxypyranone via Achmatowicz Rearrangement 14a–h.

To a stirring solution of furfuryl alcohol (1.0 equiv) in a 4:1 mixture of THF/H₂O (0.1 M) at 0 °C were added KBr (0.1 equiv), NaHCO₃ (0.5 equiv), and oxone (1.5 equiv). After the reaction mixture was stirred at 0 °C for 1–4 h, the reaction was quenched by addition of satd NaHCO₃ solution. The mixture was extracted with EtOAc (3×), washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude hydoxypyranone was used directly for the subsequent reaction without purification. To a solution of the crude hydroxypyranone (1.0 equiv) in CH₂Cl₂ at 0 °C were added pyridine (2.0 equiv) and acetyl chloride (1.5 equiv). The resulting solution was stirred for 30 min, and then the reaction was quenched by water and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded the desired acetoxypyranone.

6-((S)-(Allyloxy)(phenyl)methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl Acetate (14a).

The reaction was conducted according to the general procedure F with furfuryl alcohol 13a (300 mg, 1.23 mmol), KBr (15 mg, 0.12 mmol), NaHCO₃ (52 mg, 0.62 mmol), and oxone (1.1 g, 0.1.85 mmol) to afford the desired hydroxypyranone. The acetylation reaction was conducted according to the general procedure using the crude hydroxypyranone (320 mg, 1.23 mmol), pyridine (216 μL, 2.46 mmol), and acetyl chloride (132 μL, 1.85 mmol) in CH₂Cl₂(4 mL) for 30 min. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded an inseparable mixture of diastereomers of acetoxypyranone 14a (340 mg, 92% yield over 2 steps) as a cream color amorphous solid. ¹H NMR (400 MHz, CDCl₃) δ 7.35−7.25 (m, 5H, superimposed by peak corresponding to the minor isomer), 6.79 (dd, J = 10.3, 3.6 Hz, 1H), 6.47 (d, J = 3.7 Hz, 1H), 6.07−6.01 (m, 1H), 5.90 (dddd, J = 17.0, 10.4, 6.4, 5.1 Hz, 1H), 5.26−5.09 (m, 2H), 5.08 (d, J = 2.8 Hz, 1H), 4.95 (d, J = 2.8 Hz, 1H), 4.07−3.91 (m, 1H), 3.87−3.70 (m, 1H), 2.10 (d, J = 2.4 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃)) δ 192.6, 169.2, 141.9, 136.0, 134.2, 128.6, 128.2, 128.0, 127.8, 117.4, 87.2, 79.4, 79.3, 69.9, 20.9. HRMS (ESI/LTQ) m/z: [M + Na]⁺ calcd for C₁₇H₁₈O₅Na 325.1046; found 325.1050.

6-((R)-(Allyloxy)(phenyl)methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl Acetate (14b).

The reaction was conducted according to the general procedure F with furfuryl alcohol 13b (600 mg, 2.45 mmol), KBr (30 mg, 0.25 mmol), NaHCO₃ (103 mg, 1.23 mmol), and oxone (2.95 g, 1.8 mmol) to afford the desired hydroxypyranone. The acetylation reaction was conducted according to the general procedure using crude hydroxypyranone (637 mg, 2.45 mmol), pyridine (431 μL, 4.90 mmol), and acetyl chloride (265 μL, 3.67 mmol) in CH₂Cl₂(8 mL). Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded an inseparable mixture of diastereomers of acetoxypyranone 14b (405 mg, 55% yield over 2 steps) as a cream color amorphous solid. ¹H NMR (400 MHz, CDCl₃) δ 7.46−7.19 (m, 5H, superimposed by peak corresponding to the minor isomer), 6.78 (dd, J = 10.3, 3.7 Hz, 1H), 6.47 (d, J = 3.6 Hz, 1H), 6.03 (d, J = 10.3 Hz, 1H), 5.89 (dddd, J = 17.0, 10.3, 6.4, 5.0 Hz, 1H), 5.27−5.12 (m, 2H), 5.12−5.04 (m, 1H), 4.95 (d, J = 2.8 Hz, 1H), 4.07−3.93 (m, 1H), 3.82 (ddt, J = 12.9, 6.4, 1.3 Hz, 1H), 2.09 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 192.7, 169.3, 141.9, 135.9, 134.1, 128.6, 128.2, 128.0, 127.8, 117.5, 87.2, 79.3, 79.2, 69.9, 20.85. HRMS (ESI/LTQ) m/z: [M + Na]⁺ calcd for C₁₇H₁₈O₅Na 325.1046; found 325.1049.

6-((S)-1-(Allyloxy)-2-methylpropyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl Acetate (14c).

The reaction was conducted according to the general procedure F with furfuryl alcohol 13c (200 mg, 0.95 mmol), KBr (12 mg, 0.1 mmol), NaHCO₃ (40 mg, 0.48 mmol), and oxone (877 mg, 1.43 mmol) to afford the desired hydroxypyranone. The acetylation reaction was conducted according to the general procedure using the crude hydroxypyranone (215 mg, 0.95 mmol), pyridine (167 μL, 1.90 mmol), and acetyl chloride (102 μL, 1.43 mmol) in CH₂Cl₂ (1.5 mL) for 30 min. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded an inseparable mixture of diastereomers of acetoxypyranone 14c (198 mg, 78% over 2 steps) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.89 (dd, J = 3.6, 2.0 Hz, 1H), 6.54 (d, J = 3.8 Hz, 1H), 6.22−6.17 (m, 1H), 5.95−5.83 (m, 1H), 5.30−5.19 (m, 1H), 5.16−5.07 (m, 2H), 4.68 (d, J = 2.3 Hz, 1H), 4.16 (ddt, J = 12.7, 5.4, 1.4 Hz, 1H), 4.01 (ddt, J = 13.7, 6.8, 1.3 Hz, 1H, superimposed by peak corresponding to the minor isomer), 3.57 (dd, J = 8.5, 2.3 Hz, 1H), 2.09 (s, 3H), 1.04−0.99 (m, 1H), 0.99−0.94 (m, 3H). 13C{¹H} NMR (100 MHz, CDCl₃) δ 193.8, 169.3, 140.9, 134.8, 128.8, 116.7, 87.0, 84.4, 77.0, 72.2, 29.4, 20.8, 19.5, 19.2. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₄H₂₀O₅Na 291.1203; found 291.1202.

6-((S)-1-(Allyloxy)ethyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl Acetate (14d).

The reaction was conducted according to the general procedure F with furfuryl alcohol 13d (330 mg, 1.81 mmol), KBr (27 mg, 0.22 mmol), NaHCO₃ (76 mg, 0.90 mmol), and oxone (1.85 g, 3.01 mmol) to afford the desired hydroxypyranone. The acetylation reaction was conducted according to the general procedure using the crude hydroxypyranone (360 mg, 1.81 mmol), pyridine (318 μL, 3.62 mmol), and acetyl chloride (195 μL, 2.71 mmol) in CH₂Cl₂ (5 mL) for 30 min. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded an inseparable mixture of diastereomers of acetoxypyranone 14d (260 mg, 60% over 2 steps) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.90 (td, J = 10.1, 3.5 Hz, 1H), 6.54 (d, J = 3.5 Hz, 1H), 6.16 (d, J = 10.3 Hz, 1H), 5.93−5.81 (m, 1H), 5.16−5.03 (m, 2H), 4.66 (d, J = 2.1 Hz, 1H), 4.14−3.91 (m, 3H, superimposed by peak corresponding to the minor isomer), 2.07 (s, 3H), 1.14 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 193.7, 169.2, 142.0, 134.7, 128.7, 116.9, 87.2, 77.7, 73.9, 70.0, 20.8, 14.3. HRMS (ESI/LTQ) m/z: [M + Na]⁺ calcd for C₁₂H₁₆O₅Na 263.0890; found 263.0892.

6-((S)-(But-3-en-1-yloxy)(phenyl)methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl Acetate (14e).

The reaction was conducted according to the general procedure G with furfuryl alcohol 13e (50 mg, 0.19 mmol), KBr (2.5 mg, 0.02 mmol), NaHCO₃ (8.2 mg, 0.1 mmol), and oxone (145 mg, 0.23 mmol) to afford the desired hydroxypyranone. The acetylation reaction was conducted according to the general procedure using the crude hydroxypyranone(53 mg, 0.19 mmol), pyridine (25 μL, 0.29 mmol), and acetyl chloride (20 μL, 0.29 mmol) in CH₂Cl₂ (1.0 mL) for 3 h. Purification by silica gel column chromatography (15% EtOAc/hexanes) afforded a separable mixture of anti/syn-acetoxypyranone 14e (36 mg, 60% yield over 2 steps) as a colorless oil in 3:1 diastereomeric ratio. anti-Acetoxypyranone 14e: ¹H NMR (400 MHz, CDCl₃) δ 7.36−7.21 (m, 5H), 6.79 (dd, J = 10.3, 3.6 Hz, 1H), 6.48 (dd, J = 3.6, 0.6 Hz, 1H), 6.06 (dd, J = 10.3, 0.7 Hz, 1H), 5.79 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.10−4.97 (m, 3H), 4.92 (d, J = 2.8 Hz, 1H), 3.45 (ddt, J = 32.7, 9.3, 6.8 Hz, 2H), 2.35 (dq, J = 7.0, 1.5 Hz, 2H), 2.11 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 192.8, 169.3, 141.9, 136.3, 134.9, 128.6, 128.3, 127.9, 127.8, 116.4, 87.3, 80.5, 79.4, 68.8, 34.0, 20.9. HRMS (ESI/LTQ) m/z: [M + Na]⁺ calcd for C₁₈H₂₀O₅Na 339.1203; found 339.1208.

6-((S)-1-(But-3-en-1-yloxy)-2-methylpropyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl Acetate (14f).

The reaction was conducted according to the general procedure G with furfuryl alcohol 13f (100 mg, 0.45 mmol), KBr (5.0 mg, 0.04 mmol), NaHCO₃ (19.0 mg, 0.22 mmol), and oxone (330 mg, 0.54 mmol) to afford the desired hydroxypyranone. The acetylation reaction was conducted according to the general procedure using the crude hydroxypyranone (107 mg, 0.45 mmol), pyridine (78 μL, 0.89 mmol), and acetyl chloride (48 μL, 0.67 mmol) in CH₂Cl₂ (1.5 mL) for 30 min. Purification by silica gel column chromatography (15% EtOAc/hexanes) afforded a mixture of diastereomers of acetoxypyranone 14f (82 mg, 65% yield over 2 steps) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.91 (d, J = 3.7 Hz, 1H), 6.58−6.52 (m, 1H), 6.28−6.18 (m, 1H), 5.88−5.75 (m, 1H), 5.14−5.01 (m, 2H), 4.69 (d, J = 2.1 Hz, 1H), 3.72−3.64 (m, 1H), 3.48−3.40 (m, 2H), 2.34−2.28 (m, 2H), 2.24−2.19 (m, 1H), 2.14 (s, 3H), 1.10−0.86 (m, 6H, superimposed by peak corresponding to the minor isomer). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 193.7, 169.2, 140.9, 135.2, 128.8, 116.1, 87.7, 84.9, 79.0, 70.6, 34.3, 29.4, 20.7, 19.7, 19.2. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺ calcd for C₁₅H₂₂O₅Na 305.1360; found 305.1357.

6-((S)-1-(But-3-en-1-yloxy)ethyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl Acetate (14g).

The reaction was conducted according to the general procedure G with furfuryl alcohol 13g (55 mg, 0.28 mmol), KBr (4 mg, 0.03 mmol), NaHCO₃ (12 mg, 0.14 mmol), and oxone (210 mg, 0.34 mmol) to afford the desired hydroxypyranone. The acetylation reaction was conducted according to the general procedure using the crude hydroxypyranone (59 mg, 0.28 mmol), pyridine (50 μL, 0.55 mmol), and acetyl chloride (30 μL, 0.41 mmol) in CH₂Cl₂ (1.0 mL) for 40 min. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded a mixture of diastereomers of acetoxypyranone 14g (53 mg, 75% yield over 2 steps) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.94−6.88 (m, 1H), 6.63 (dd, J = 3.4, 0.7 Hz, 1H), 6.22−6.15 (m, 1H), 5.86−5.72 (m, 1H), 5.11−4.91 (m, 2H), 4.29−4.26 (m, 1H), 4.14−4.09 (m, 1H), 3.58−3.50 (m, 2H), 2.24−2.18 (m, 2H), 2.09 (s, 3H), 1.28 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 193.8, 169.1, 142.3, 134.9, 129.2, 116.2, 87.3, 79.8, 74.4, 69.3, 34.1, 20.8, 15.2. HRMS (ESI/LTQ) m/z: [M + Na]⁺ calcd for C₁₃H₁₈O₅Na 277.1046; found 277.1050.

5-Oxo-6-((S)-1-(pent-4-en-1-yloxy)ethyl)-5,6-dihydro-2H-pyran-2-yl Acetate (14h).

The reaction was conducted according to the general procedure G with furfuryl alcohol 13h (200 mg, 0.95 mmol), KBr (11.0 mg, 0.1 mmol), NaHCO₃ (40.0 mg, 0.48 mmol), and oxone (700 mg, 1.14 mmol) to afford the desired hydroxypyranone. The acetylation reaction was conducted according to the general procedure using the crude hydroxypyranone (215 mg, 0.95 mmol), pyridine (170 μL, 1.90 mmol), and acetyl chloride (100 μL, 1.43 mmol) in CH₂Cl₂ (3.0 mL) for 50 min. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded a mixture of diastereomers of acetoxypyranone 14h (163 mg, 64% yield over 2 steps) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.94−6.86 (m, 1H), 6.53 (d, J = 3.7 Hz, 1H), 6.21−6.13 (m, 1H), 5.83−5.65 (m, 1H), 4.94−4.85 (m, 2H), 4.29−4.23 (m, 1H), 4.08 (dd, J = 7.0, 2.8 Hz, 1H), 3.56−3.38 (m, 2H), 2.07 (d, J = 1.3 Hz, 3H), 2.03−1.93 (m, 2H), 1.66−1.58 (m, 2H), 1.24 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 193.8, 169.1, 142.3, 138.1, 129. 1, 114.6, 87.2, 79.7, 74.2, 68.4, 30.1, 28.8, 20.8, 15.2. HRMS (ESI/LTQ) m/z: [M + Na]⁺ calcd for C₁₄H₂₀O₅Na 291.0203; found 291.0207.

General Procedure G: Synthesis of the Cycloadducts 16a–h.

To a stirred solution of the acetoxypyranone (1.0 equiv) in CH₃CN (0.02 M) at 23 °C was added N-methylpyrrolidine (4.0 equiv), and the resulting mixture was heated to 60–150 °C in an oil bath. After 3–24 h, the mixture was concentrated, and the residue was purified by silica gel column chromatography afforded the desired cycloadduct.

(3S,3aS,7S,8aS)-3-Phenyl-1,7,8,8a-tetrahydro-3H,4H-3a,7-epoxycyclohepta[c]furan-4-one (16a).

The reaction was conducted according to the general procedure G with acetoxypyranone 14a (100 mg, 0.33 mmol) and N-methylpyrrolidine (138 μL, 1.32 mmol) in CH₃CN (12.7 mL) at 60 °C for 12 h. Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the cycloadduct 16a (71 mg, 89% yield, dr = 10:1) as a crystalline white solid. The purified compound was dissolved in ethyl acetate and hexanes and was allowed to crystallize at 23 °C for 5 days. ¹H NMR (800 MHz, CDCl₃) δ 7.47 (d, J = 7.4 Hz, 2H), 7.37−7.26 (m, 3H), 7.15 (dd, J = 9.7, 4.3 Hz, 1H), 6.01 (d, J = 9.7 Hz, 1H), 5.56 (s, 1H), 5.05−4.98 (m, 1H), 4.22 (t, J = 8.6 Hz, 1H), 4.08 (dd, J = 9.3, 3.4 Hz, 1H), 2.97−2.89 (m, 1H), 2.33 (dd, J = 12.1, 8.9 Hz, 1H), 2.16 (dt, J = 12.0, 6.1 Hz, 1H). ¹³C{¹H} NMR (200 MHz, CDCl₃) δ 194.9, 151.8, 135.6, 127.8, 127.8, 126.7, 126.7, 97.7, 80.0, 76.7, 71.9, 46.5, 36.4. HRMS (APCI/LTQ) m/z: [M + H]⁺ calcd for C₁₅H₁₅O₃ 243.1016; found 243.1014.

(3R,3aR,7R,8aR)-3-Phenyl-1,7,8,8a-tetrahydro-3H,4H-3a,7-epoxycyclohepta[c]furan-4-one (16b).

The reaction was conducted according to the general procedure G with acetoxypyranone 14b (170 mg, 0.56 mmol) and N-methylpyrrolidine (235 μL, 2.25 mmol) in CH₃CN (22 mL) at 60 °C for 12 h. Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the cycloadduct 16b (100 mg, 74% yield, dr = 10:1) as a crystalline white solid. The purified compound was dissolved in ethyl acetate and hexanes and was allowed to crystallize at 23 °C for 5 days. ¹H NMR (800 MHz, CDCl₃) δ 7.47 (d, J = 7.6 Hz, 2H), 7.36−7.26 (m, 3H), 7.15 (dd, J = 9.7, 4.3 Hz, 1H), 6.01 (d, J = 9.7 Hz, 1H), 5.56 (s, 1H), 5.02 (dd, J = 6.7, 4.2 Hz, 1H), 4.22 (t, J = 8.7 Hz, 1H), 4.08 (dd, J = 9.2, 3.4 Hz, 1H), 2.96−2.90 (m, 1H), 2.33 (dd, J = 12.0, 8.9 Hz, 1H), 2.16 (dt, J = 12.3, 6.3 Hz, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 194.9, 151.8, 135.6, 127.8, 127.8, 126.7, 126.7, 97.7, 80.0, 76.7, 71.9, 46.5, 36.4. HRMS (APCI/LTQ) m/z: [M + H]⁺ calcd for C₁₅H₁₅O₃ 243.1016; found 243.1018.

(3S,3aS,7S,8aS)-3-isopropyl-1,7,8,8a-tetrahydro-3H,4H-3a,7-epoxycyclohepta[c]furan-4-one (16c).

The reaction was conducted according to the general procedure G with acetoxypyranone 14c (190 mg, 0.71 mmol) and N-methylpyrrolidine (295 μL, 1.41 mmol) in CH₃CN (27 mL) at 60 °C for 12 h. Purification by silica gel column chromatography (15% EtOAc/hexanes) afforded the cycloadduct 16c (129 mg, 88% yield, dr = 2:1) as a yellow oil. 16c (major): [α]d²⁴ +38.6 (c 0.3, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.17 (dd, J = 9.8, 4.3 Hz, 1H), 5.98 (d, J = 9.8 Hz, 1H), 5.01 (dd, J = 6.6, 4.3 Hz, 1H), 4.01−3.93 (m, 2H), 3.84 (dd, J = 9.2, 3.2 Hz, 1H), 2.74−2.66 (m, 1H), 2.22 (dd, J = 12.0, 8.9 Hz, 1H), 2.05−1.90 (m, 2H), 1.06 (d, J = 6.6 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 195.4, 151.6, 126.7, 96.8, 84.6, 76.4, 71.4, 47.2, 36.2, 28.0, 20.3, 19.1. 16c (minor): [α]d²⁴ −116.4 (c 0.2, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.16 (dd, J = 9.7, 4.4 Hz, 1H), 6.00 (d, J = 9.5 Hz, 1H), 5.11 (d, J = 4.9 Hz, 1H), 4.29 (t, J = 8.2 Hz, 1H), 3.44 (t, J = 9.1 Hz, 1H), 3.28 (d, J = 10.4 Hz, 1H), 2.82 (dp, J = 9.6, 6.4 Hz, 1H), 2.66 (p, J = 7.8 Hz, 1H), 1.93 (t, J = 5.4 Hz, 2H), 1.01 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 195.7, 150.8, 128.0, 97.0, 93.1, 79.5, 72.7, 49.8, 31.9, 26.5, 20.3, 19.2.HRMS (APCI/LTQ) m/z: [M + H]⁺ calcd for C₁₂H₁₇O₃ 209.1172; found 209.1174.

(3S,3aS,7S,8aS)-3-Methyl-1,7,8,8a-tetrahydro-3H,4H-3a,7-epoxycyclohepta[c]furan-4-one (16d).

The reaction was conducted according to the general procedure G with acetoxypyranone 14d (75 mg, 0.31 mmol) and N-methylpyrrolidine (130 μL, 1.25 mmol) in CH₃CN (12 mL) at 60 °C for 12 h. Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the cycloadduct 16d (25 mg, 45% yield, dr = 4:1) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (dd, J = 9.8, 4.3 Hz, 1H), 5.97 (d, J = 9.7 Hz, 1H), 5.01 (dd, J = 6.4, 4.4 Hz, 1H), 4.43 (q, J = 6.4 Hz, 1H), 3.98 (dd, J = 9.2, 8.0 Hz, 1H), 3.84 (dd, J = 9.3, 3.0 Hz, 1H), 2.81−2.69 (m, 1H), 2.27 (dd, J = 12.0, 8.9 Hz, 1H), 2.05 (dt, J = 12.2, 6.2 Hz, 1H), 1.28 (d, J = 6.4 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 195.0, 151.9, 126.6, 96.7, 76.4, 74.9, 71.8, 46.0, 36.5, 12.8. HRMS (APCI/LTQ) m/z: [M + H]⁺ calcd for C₁₀H₁₃O₃ 181.0859; found 181.0860.

(1S,4aR,6S,9aS)-1-Phenyl-4,4a,5,6-tetrahydro-1H-6,9a-epoxycyclohepta[c]pyran-9(3H)-one (16e).

The reaction was conducted according to the general procedure G with acetoxypyranone 14e (25 mg, 0.08 mmol) and N-methylpyrrolidine (33 μL, 0.32 mmol) in CH₃CN (4.0 mL) at 60 °C for 4 h. Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the cycloadduct 16e (12 mg, 60% yield, dr >19:1) as a white amorphous solid. ¹H NMR (400 MHz, CDCl₃) δ 7.43−7.36 (m, 2H), 7.36−7.19 (m, 4H), 5.91 (dd, J = 9.8, 1.2 Hz, 1H), 5.50 (s, 1H), 4.86−4.77 (m, 1H), 4.10 (ddd, J = 11.7, 4.6, 2.3 Hz, 1H), 3.65 (td, J = 11.9, 1.7 Hz, 1H), 2.24 (qd, J = 9.0, 7.4, 5.2 Hz, 1H), 2.13 (dd, J = 12.3, 8.1 Hz, 1H), 2.00 (ddt, J = 12.3, 7.2, 4.1 Hz, 2H), 1.80−1.65 (m, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 197.1, 155.3, 138.3, 127.9, 127.7, 127.6, 126.7, 87.7, 77.2, 71.3, 66.4, 39.8, 35.1, 30.4. HRMS (APCI/LTQ) m/z: [M + H]⁺ calcd for C₁₆H₁₇O₃ 257.1172; found 257.1173.

(1S,4aR,6S,9aS)-1-Isopropyl-4,4a,5,6-tetrahydro-1H-6,9a-epoxycyclohepta[c]pyran-9(3H)-one (16f).

The reaction was conducted according to the general procedure G with acetoxypyranone 14f (50 mg, 0.18 mmol) and N-methylpyrrolidine (75 μL, 0.71 mmol) in CH₃CN (9.0 mL) at 60 °C for 24 h. The reaction mixture was concentrated, and the residue was washed with 1 N HCl. The mixture was extracted with EtOAc (3×), washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification by silica gel column chromatography (15% EtOAc/hexanes) afforded the cycloadduct 16f (33 mg, 84% yield, dr >19:1) as a white amorphous solid. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J = 9.8, 4.8 Hz, 1H), 6.02 (d, J = 9.8 Hz, 1H), 4.82 (dd, J = 7.6, 4.8 Hz, 1H), 4.01 (d, J = 7.9 Hz, 1H), 3.97−3.84 (m, 1H), 3.47−3.29 (m, 1H), 2.16−1.96 (m, 2H), 1.96−1.77 (m, 3H), 1.58−1.41 (m, 1H), 1.01 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 197.9, 154.3, 126.7, 86.8, 80.5, 71.0, 65.7, 39.5, 35.7, 30. 9, 30.6, 20.2, 19.5. HRMS (APCI/LTQ) m/z: [M + H]⁺ calcd for C₁₃H₁₉O₃ 223.1329; found 223.1331.

(1S,4aR,6S,9aS)-1-Methyl-4,4a,5,6-tetrahydro-1H-6,9a-epoxycyclohepta[c]pyran-9(3H)-one (16g).

The reaction was conducted according to the general procedure G with acetoxypyranone 14g (50 mg, 0.20 mmol) and N-methylpyrrolidine (82 μL, 0.79 mmol) in CH₃CN (10 mL) at 60 °C for 18 h. Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the cycloadduct 16g (30 mg, 79% yield, dr >19:1) as a white amorphous solid. ¹H NMR(400 MHz, CDCl₃) δ 7.43 (dd, J = 9.7, 4.8 Hz, 1H), 5.98 (d, J = 9.7 Hz, 1H), 4.87−4.79 (m, 1H), 4.40 (q, J = 6.5 Hz, 1H), 3.89 (ddd, J = 11.6, 4.6, 2.3 Hz, 1H), 3.50−3.38 (m, 1H), 2.17−2.01 (m, 2H), 1.99−1.85 (m, 2H), 1.61−1.46 (m, 1H), 1.19 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 197.4, 155.7, 126.6, 87.3, 71.3, 71.2, 65.8, 39.7, 34.1, 30.5, 16.8. HRMS (APCI/LTQ) m/z: [M + H]⁺ calcd for C₁₁H₁₅O₃ 195.1016; found 195.1017.

(1S,5aR,7S,10aS)-1-Methyl-3,4,5,5a,6,7-hexahydro-1H,10H-7,10a-epoxycyclohepta[c]oxepin −10-one (16h).

The reaction was conducted according to the general procedure G with acetoxypyranone 14h (100 mg, 0.37 mmol) and N-methylpyrrolidine (58 μL, 0.56 mmol) in CH₃CN (19 mL) in a sealed tube for 3 h at 150 °C. Purification by silica gel column chromatography (20% EtOAc/hexanes) afforded the cycloadduct 16h (46 mg, 59% yield, dr >19:1) as a white amorphous solid. ¹H NMR(400 MHz, CDCl₃) δ 7.28−7.20 (m, 1H), 5.89 (dd, J = 9.8, 0.8 Hz, 1H), 4.85 (q, J = 4.2 Hz, 1H), 4.25 (q, J = 6.5 Hz, 1H), 3.90 (dd, J = 11.5, 5.9 Hz, 1H), 3.65−3.49 (m, 1H), 2.33−2.18 (m, 1H), 2.03−1.92 (m, 3H), 1.90−1.77 (m, 2H), 1.69 (q, J = 9.1, 6.9 Hz, 1H), 1.23 (dd, J = 6.4, 0.8 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 198.4, 153.0, 125.8, 92.7, 73.7, 71.6, 40.8, 35.6, 29.0, 26.3, 18.3. HRMS (APCI/LTQ) m/z: [M + H]⁺ calcd for C₁₂H₁₇O₃ 209.1172; found 209.1174.

(3S,3aS,4S,7R,8aR)-3-Isopropyl-4,7,8,8a-tetrahydro-1H,3H-3a,7-epoxycyclohepta[c]furan-4-ol (21).

To a solution of the cycloadduct 16c (minor) (20 mg, 0.10 mmol) in a 4:1 mixture of MeOH/CH₂Cl₂ (5 mL) at 23 °C was added CeCl₃·7H₂O (54 mg, 0.14 mmol). After stirring for 30 min the reaction mixture was cooled to 0 °C and sodium borohydride (4.0 mg, 0.10 mmol) was added. After 1 h, the reaction was quenched with H₂O and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (25% EtOAc/hexanes) afforded the allylic alcohol 21 (15.0 mg, 75% yield, dr >19:1) as a white amorphous solid. [α]d²⁴ +25.3 (c 0.1, CHCl₃). ¹H NMR(400 MHz, CDCl₃) δ 5.99 (dd, J = 9.7, 3.9 Hz, 1H), 5.49 (dd, J = 9.7, 2.0 Hz, 1H), 4.86 (s, 1H), 4.74 (t, J = 5.0 Hz, 1H), 4.18 (t, J = 8.4 Hz, 1H), 3.39 (t, J = 8.7 Hz, 1H), 3.26 (p, J = 7.4 Hz, 2H), 2.10 (dq, J = 12.6, 6.4 Hz, 1H), 2.01 (dd, J = 11.6, 8.1 Hz, 1H), 1.76 (dt, J = 12.0, 6.3 Hz, 1H), 1.68 (s, 1H), 1.03 (t, J = 6.9 Hz, 6H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 133.0, 127.7, 94.2, 91.1, 80.1, 72.4, 68.2, 43.8, 36.6, 27.3, 20.1, 19.8. HRMS (APCI/LTQ) m/z: [M + H]⁺ calcd for C₁₂H₁₉O₃ 211.1329; found 211.1328.