Lewis Acid-Catalyzed Vinyl Acetal Rearrangement of 4,5-Dihydro-1,3-dioxepines: Stereoselective Synthesis of cis- and trans-2,3-Disubstituted Tetrahydrofurans

Abstract

Lewis acid-catalyzed rearrangements of 4,5-dihydro-1,3-dioxepines have been investigated. Rearrangement of vinyl acetals under a variety of conditions resulted in cis- and trans-2,3-disubstituted tetrahydrofuran derivatives in a highly stereoselective manner. Rearrangements at lower temperatures typically provided the cis-2,3-disubstituted tetrahydrofuran carbaldehydes. At higher temperatures, the corresponding trans-2,3-disubstituted tetrahydrofuran carbaldehydes are formed. The requisite substrates for the vinyl acetal rearrangement were synthesized via ring-closing olefin metathesis of bis(allyoxy)methyl derivatives using Grubbs second-generation catalyst followed by olefin isomerization using a catalytic amount of RuCl₂(PPh₃)₃. We examined the substrate scope using substituted aromatic and aliphatic derivatives. Additionally, the rearrangement was utilized in the synthesis of a stereochemically-defined bis-tetrahydrofuran (bis-THF) derivative, which is one of the key structural elements of darunavir, an FDA-approved drug for the treatment of HIV/AIDS.

Graphical Abstract

INTRODUCTION

Substituted tetrahydrofurans are important structural motifs in a variety of bioactive natural products and pharmaceutical agents.^1,2 Representative examples include anticancer agent amphidinolide T (1, Figure 1),^3,4 proliferation-promoting agent amphirionin-4 (2),⁵ antifungal agent posaconazole (3),^6,7 and anti-HIV agent darunavir (4).^8,9 Over the years, numerous methods for the synthesis of disubstituted tetrahydrofurans have been developed.^10,11 However, development of efficient methods for the synthesis of 2,3-disubstituted tetrahydrofurans has not received much attention. Synthetic methods such as halocyclization, radical cyclization, and vinyl acetal rearrangements have been utilized for the synthesis of these tetrahydrofuran derivatives.^12–14 In our continuing studies toward the protein X-ray crystal structure-based design of molecular probes, we require a range of stereochemically defined cyclic ether-derived ligands and structural templates.^15,16 Of particular interest is a general synthesis of 2-(alkoxymethyl or substituted aryl)-3-tetrahydrofuranyl-methanol derivatives. As outlined in Scheme 1, Lewis acid-catalyzed vinyl acetal rearrangement of 4,5-dihydro-1,3-dioxepines (5) provided access to substituted tetrahydrofuranyl derivatives.¹⁴ In particular, Scharf and coworkers, Frauenrath and coworkers, and Suzuki and coworkers investigated such Lewis acid-catalyzed vinyl acetal rearrangements to provide cis- and trans-2,3-tetrahydrofuran-3-carbaldehydes depending on the reaction conditions.^17–20

Figure 1.

Representative bioactive compounds containing functionalized tetrahydrofurans.

Scheme 1.

Lewis-Acid-Catalyzed Vinyl Acetal Rearrangement of 4,5-Dihydro-1,3-dioxepines to cis- and trans-Disubstituted Tetrahydrofurans

As shown, Lewis acid activation of 4,5-dihydro-1,3-dioxepines 5 with a Lewis acid of choice would provide intermediate 8, which rearranges to the kinetic zwitterionic oxocarbenium ion intermediate 9 at low temperatures. However, at higher temperatures, intermediate 9 can invert to the thermodynamically more stable oxocarbenium ion 10 to avoid steric hindrance between the bulky aromatic ring and the enolate substituent.¹⁷ Oxocarbenium ion intermediates 9 and 10 would stereoselectively provide cis- and trans-aldehydes 6 and 7, respectively.^21,22 The reaction of vinyl acetals at lower temperatures (−78 °C) under kinetically controlled conditions provided the cis-tetrahydrofuran derivatives as the major products.^14,17 Additionally, as speculated by Scharf and coworkers, there exists an equilibrium between aldehyde products 6 and 7 in which upon exposure of 6 to Lewis acid, the Lewis acid chelates to the aldehyde oxygen and the product rearranges back to intermediate 9.¹⁷ Following rearrangement, 9 then undergoes inversion to 10, ultimately resulting in the thermodynamically favored aldehyde product 7.¹⁷ Scharf and coworkers also observed that the trans-derivatives prevailed as the major isomers at higher temperatures (150 °C).¹⁷ From this work, it was concluded that at higher temperatures, the kinetic cis-aldehyde product is converted to the thermodynamically more stable trans-aldehyde. Furthermore, exposure of the aldehyde products to a deuterated acid resulted in no deuterium incorporation.¹⁷ Therefore, it can be argued that the cis-aldehyde is not converted to the trans-aldehyde via its enol form. Rather, conversion occurs via another Lewis-acid-catalyzed rearrangement. Frauenrath and coworkers observed the cis-derivatives as the major isomers at lower temperature (−78 °C), which they explain occurred through cyclization that arises from oxocarbenium ion facial bias.^18,19,21,22 Additionally, they obtained the trans-derivatives via epimerization of the cis-derivatives with 10 mol % morpholine.^18,19 In a contradicting report, Suzuki and coworkers claimed that the trans-derivatives were obtained as the major isomers at lower temperatures (−73 °C).²⁰ Additionally, Rovis and coworkers reported a stereoretentive rearrangement of vinyl acetals dictated by oxocarbenium ion facial bias and tight ion-pair binding in the solvent cage.²³

Based upon these reports, we investigated the scope and generality of these Lewis-acid-catalyzed reactions with a variety of substituted 4,5-dihydro-1,3-dioxepine derivatives under mild conditions. For efficient synthesis of 4,7-dihydro-1,3-dioxepines, we carried out ring-closing metathesis of diallyl acetals to provide the cyclic acetals in excellent yields. Subsequent double-bond isomerization using a catalytic amount of hydridic ruthenium provided the 4,5-dihydro-1,3-dioxepine substrates. We synthesized a variety of both cis- and trans-2,3-disubstituted tetrahydrofuran derivatives. Furthermore, rearrangement of the product resulting from 2-(benzyloxymethyl)-4,5-dihydro-1,3-dioxepine was converted to the bis-tetrahydrofuran derivative, a key structural component of darunavir, an FDA approved HIV-1 protease inhibitor drug for the treatment of HIV/AIDS.^15,16

RESULTS AND DISCUSSION

Our general plans for the synthesis of cis- and trans-disubstituted tetrahydrofurans using a Lewis-acid-catalyzed vinyl acetal rearrangement are shown in Scheme 2. We planned to synthesize variously substituted 4,7-dihydro-1,3-dioxepines efficiently via olefin metathesis of the corresponding diallyl acetal. As shown, our reaction sequence begins with an aldehyde of choice, which undergoes acetalization with allyl alcohol and a catalytic amount of p-toluenesulfonic acid (PTSA) to form a diallyl acetal 11. Substituted dioxepines 12 can be synthesized from diallyl acetal derivatives via olefin metathesis using Grubbs second-generation catalyst.^24,25 A ruthenium or potassium tert-butoxide catalyzed olefin isomerization of 12 would provide various 4,5-dihydro-1,3-dioxepine substrates 5 for our investigation of Lewis-acid-catalyzed rearrangements to substituted tetrahydrofurans. For accurate stereochemical analysis of our products, we planned to reduce aldehydes 6 and 7 and characterize the stereochemical outcome using alcohols 13 and 14. We initially optimized reaction conditions using the phenyl dioxepine derivative 12a (R = Ph) and utilized the conditions for other substrates. The results are shown in Table 1. The reaction of benzaldehyde with allyl alcohol in THF in the presence of a catalytic amount of PTSA and 4 Å molecular sieves at 23 °C for 24 h provided diallyl acetal 11a in 53% yield. Similarly, variously substituted aromatic aldehydes, isovaleraldehyde, and benzyloxyacetaldehyde provided the corresponding diallyl acetals 11b–11k in good to excellent yields (20–99%).

Scheme 2.

General Synthesis of 4,5-Dihydro-1,3-dioxepines and Subsequent Lewis-Acid-Catalyzed Vinyl Acetal Rearrangement

Table 1.

Synthesis of Diallyl Acetals from Aldehydes and Allyl Alcohol^a

^aReactions were carried out typically on a 7 to 8 mmol scale at 23 °C in THF (1.5 M solution) in the presence of allyl alcohol (5 equiv), PTSA·H₂O (0.2 equiv), and 4 Å MS.

^bYield taken over 2 steps.

The diallyl acetals 11a–k were then converted to dioxepine derivatives 12a–12k using ring-closing metathesis and the results are shown in Table 2. Treatment of diallyl acetal 11a with a catalytic amount (5 mol %) of Grubbs second-generation catalyst^24,25 in CH₂Cl₂ at reflux for 2 h afforded 2-phenyl-4,7-dihydro-1,3-dioxepine 12a in 81% yield. Similarly, ring closing metathesis of other diallyl acetals furnished dioxepine derivatives 12b–k in 61–95% yield.

Table 2.

Synthesis of 4,7-Dihydro-1,3-dioxepines Using Ring-Closing Metathesis^a

^aReactions were carried out typically on a 0.7 mmol scale at 40 °C in CH₂Cl₂ (0.01 M solution) in the presence of Grubbs second-generation catalyst (5 mol %).

Olefin isomerizations^20,26,27 of the 4,7-dihydro-1,3-dioxepines were then carried out using a catalytic amount of RuCl₂(PPh₃)₃ and a small amount of NaBH₄ in methanol at reflux. The results are shown in Table 3. Exposure of 12a with 2 mol % RuCl₂(PPh₃)₃ and 5 mol % NaBH₄ in methanol for 3 h provided 2-phenyl-4,5-dihydro-1,3-dioxepine 5a along with a small amount of hydrogenated product. These products were not separable by silica gel chromatography and the combined yield of both products was 67%. The ¹H NMR analysis revealed the presence of 7% hydrogenated product. Other 4,5-dihydro-1,3-dioxepines 5b–k were also prepared using the conditions below in varying yields (23–96%). Saturated product yields are shown within the parentheses. The yields of these reactions vary from substrate to substrate. The hydrogenated double-bond derivative was observed as a major side-product (typically ranging from 10 to 30%; acetals containing electron-donating groups typically had larger amounts of hydrogenated byproduct). As with the case of 5a, the hydrogenated derivatives are inseparable from the desired 4,5-dihydro-1,3-dioxepines via silica gel column chromatography. Thus, following a short column in EtOAc/hexanes spiked with triethylamine, the combined product yields were reported, and the yield of the hydrogenated products (within parentheses) are calculated by ¹H NMR integration. The saturated side-products do not affect further reactions; thus, the 4,5-dihydro-1,3-dioxepines were utilized in the next reaction without further attempts at purification. In the case of substrate 12h, the RuCl₂(PPh₃)₃ and NaBH₄-catalyzed reaction conditions provided only the corresponding saturated product in 68% yield. Therefore, we utilized alternate conditions with t-BuOK in DMSO at 23 °C for 24 h to provide 23% yield of isomerized product 5h along with 47% unreacted starting material 12h. The isomerized product 5h could not be separated from the starting material 12h by silica gel chromatography. The mixture of products was used directly in the rearrangement reaction.

Table 3.

Results and Structures from the Double Bond Isomerization Reaction^a

^aReactions were carried out at 70 °C in methanol (1 M solution) in the presence of RuCl₂(PPh₃)₃ (2 mol %) and NaBH₄ (5 mol %). See the Experimental Section for further information.

^bCombined yield of 4,5-dihydro-1,3-dioxepine and its hydrogenated derivative. Yield of hydrogenated derivative is in the parentheses.

^cAlternate conditions with t-BuOK in DMSO provided 23% yield of isomerized product 5 h (70% combined yield of product and starting material). Please see the Experimental Section for this information.

Following the synthesis of various 4,5-dihydro-1,3-dioxepines, we sought to optimize the Lewis acid-catalyzed vinyl acetal rearrangement using phenyl derivative 5. A variety of Lewis acids, along with varying reaction conditions, were examined. As mentioned previously, diastereoselectivities were determined after reduction of the aldehydes to the corresponding alcohols using NaBH₄ in MeOH from 0 to 23 °C. The results are shown in Table 4. As shown, BF₃·OEt₂-catalyzed reactions at −78 °C afforded the best ratio of cis:trans isomers and yields (entries 1–3). A lower catalyst loading of 20 mol %, as shown in entry 3, provided the optimized results with excellent cis-selectivity. Interestingly, the BF₃·OEt₂-catalyzed reaction at 23 °C afforded the trans-isomer as the major product in 22% isolated yield (entry 4). Both TMSOTf and TBSOTf catalyzed reactions showed lower selectivity and yields (entries 5 and 6). The Sc(OTf)₃-catalyzed reaction at −78 °C showed excellent cis-selectivity; however, yield was significantly lower (entry 7). The Zn(OTf)₂-catalyzed reaction at 23 °C showed marginal cis-selectivity (2:1) and at higher temperatures showed good to excellent trans-selectivity (entries 13–17).

Table 4.

Catalyst Loading and Lewis Acid Optimization of the Vinyl Acetal Rearrangement

entry	Lewis acid	equivalents of lewis acid	temperature (°C)	solvent	tme	diastereomeric ratio (cis:trans)a	yield (2 steps) (%)
1	BF3·OEt2	1	−78	CH2Cl2	10 min	20:1	77
2	BF3·OEt2	0.5	−78	CH2Cl2	10 min	20:1	77
3	BF3·OEt2	0.2	−78	CH2Cl2	10 min	20:1	77
4	BF3·OEt2	0.2	23	CH2Cl2	3 h	1:6	22
5	TMSOTf	0.2	−78	CH2Cl2	10 min	6:1	66
6	TBSOTf	0.2	−78	CH2Cl2	10 min	6:1	58
7	Sc(OTf)3	0.2	−78	CH2Cl2	6 h	14:1	52
8	Sc(OTf)3	0.2	−40	CH2Cl2	1 h	4:1	82
9	Cu(OTf)2	0.2	0	CH2Cl2	4 h	2:1	74
10	FeCl3	0.2	−20	CH2Cl2	1 h	5:1	79
11	FeCl3	0.2	0	CH2Cl2	1 h	4:1	58
12	ZnCl2	0.2	23	CH2Cl2	2 h	2:1	76
13	Zn(OTf)2	0.2	23	CH2Cl2	3 h	2:1	80
14	Zn(OTf)2	0.2	40	CH2Cl2	3 h	1:1	88
15	Zn(OTf)2	0.2	110	PhMe	3 h	1:4	69
16	Zn(OTf)2	0.2	132	PhCl	9 h	1:17	41
17	Zn(OTf)2	0.2	140	Xylenes	8.5 h	1:20	48
18	Dy(OTf)3	0.2	23	CH2Cl2	24 h	1:2	80

^aDiastereomeric ratios were determined via integration of the characteristic benzylic peak in the ¹H NMR spectra.

We then examined the vinyl acetal rearrangement with a variety of substrates using 20 mol % BF₃·OEt₂ as shown in entry 3. The results are shown in Table 5. It should be noted that the substrate in entry 10 required a slightly higher temperature for the reaction to go to completion. Introduction of p-alkyl or p-methoxy groups affected cis-diastereoselectivity (entries 2 and 3). The ortho-methoxyphenyl, however, increased the diastereomeric ratio up to greater than 20:1 (entry 4). Interestingly, electron-withdrawing substituents at the para-position of the phenyl ring also decreased the cis-diastereoselectivity drastically (entry 5). Yields and diastereomeric ratios were calculated once again after reduction of the aldehyde to the corresponding alcohol. Separation of the cis- and trans- diastereomers via column chromatography proved to be difficult due to the similar R_f values of the two diastereomers. Thus, we decided to confirm the relative stereochemistry of the cis-diastereomer of alcohol 13e by obtaining an X-ray crystal structure of the p-bromobenzoate derivative of the major diastereomer. As shown in Scheme 3, alcohol 13e was reacted with p-bromobenzoyl chloride in the presence of Et₃N and a catalytic amount of DMAP in CH₂Cl₂ at 23 °C for 12 h to provide the benzoate ester cis-16 in 80% yield. Standard recrystallization in a mixture of ethyl acetate and hexanes (23 °C, 3 days) provided crystals for X-ray analysis. The ORTEP drawing of the p-bromobenzoate ester cis-16 is shown in the Supporting Information, and the structure supported the assignment of cis-stereochemistry.^28,29

Table 5.

Substrate Scope for the Vinyl Acetal Rearrangement^a

^aReactions were carried out typically on a 0.5 mmol scale at −78 °C in CH₂O₂ (0.2 M solution) in the presence of BF₃·OEt₂ (0.2 equiv). After the consumption of starting material was observed via TLC, the reaction was cooled to 0 °C, and methanol (0.2 M with respect to the starting material) and NaBH₄ (>3 equiv) were added.

^bDiastereomeric ratios were determined via integration of the characteristic peaks in the ¹H NMR spectra.

^cToluene was utilized as a solvent for entry 8 due to the compound’s poor solubility in CH₂Cl₂.

Scheme 3.

Synthesis of p-Bromobenzoate Ester cis-16

We also investigated the Lewis-acid-catalyzed vinyl acetal rearrangement under thermal conditions in an effort to obtain trans-2,3-disubstituted tetrahydrofuran derivatives. As shown in Table 4 (entries 13–18), Zn(OTf)₂-catalyzed reactions at higher temperatures resulted in the trans-2,3-disubstituted tetrahydrofuran derivatives as major products. Thus, with a select few substrates, reactions were carried out with Zn(OTf)₂ (20 mol %) in xylenes at 140 °C. For convenient isolation and stereochemical analysis, the resulting aldehyde was reduced with NaBH₄ to provide the trans-alcohols as the major products with good diastereoselectivities. The results are shown in Table 6.

Table 6.

Lewis-Acid-Catalyzed Vinyl Acetal Rearrangements under Thermal Conditions^a

^aReactions were carried out typically on a 0.5 mmol scale at 140 °C in xylenes (0.2 M solution) in the presence of Zn(OTf)₂ (0.2 equiv). After the specified reaction time, the reaction was cooled to 0 °C, and methanol (0.2 M with respect to the starting material) and NaBH₄ (>3 equiv) were added.

^bDiastereomeric ratios were determined via integration of the characteristic benzylic peak in the ¹H NMR spectra.

Support of stereochemistry for 14e was achieved through X-ray structural analysis. As shown in Scheme 4, nitro derivative 14e was converted to p-bromobenzoyl ester derivative trans-16 in 84% yield. It was recrystallized from a mixture of ethyl acetate and hexanes (23 °C, 3 days). Subsequent single crystal X-ray crystallographic analysis supported the assignment of trans-stereochemistry.^25,26

Scheme 4.

Synthesis of p-Bromobenzoate Ester trans-16

We also carried out stereochemical assignment of compounds 13e and 14e by ¹H-NMR NOESY experiments. As shown in Figure 2, the observed NOESY between the 2,3-cis protons for compound 13e is consistent with the assigned stereochemistry. As expected, for the trans-compound 14e, a much weaker NOESY interaction was observed between the 2,3-trans protons. This interaction can be attributed to the fact that the five-membered tetrahydrofuran ring can adopt an envelope conformation, which puts the two protons at approximately a 120° angle.³⁰

Figure 2.

Representative NOESY correlation of compounds 13e and 14e. The ¹H-NOESY spectra can be found in the Supporting Information.

In an attempt to examine the equilibrium of products 6 to 7, we interrupted the reaction of substrate 5a with catalytic amount of Zn(OTf)₂ in xylenes at 140 °C at various time intervals. The product mixture was reduced as described previously. The cis/trans ratio is shown in Table 7. As shown, over time, the amount of trans-product increased. Presumably, under thermal conditions, the cis-product 6 (Scheme 1) is converted to the thermodynamically more stable trans-product via Lewis-acid-catalyzed rearrangement.

Table 7.

Study on the Diastereomeric Ratios of the Thermal Reaction of 5a to 14a at Various Time Intervals^a

entry	time (h)	diastereomeric ratio (cis:trans)b	yield (2 steps) (%)
1	1	1:7	50
2	2	1:7	50
3	4	1:14	47
4	8.5	1:20	48

^aReactions were carried out at 140 °C in xylenes (0.2 M solution) in the presence of Zn(OTf)₂ (0.2 equiv). After the specified reaction time, the reaction was cooled to 0 °C, and methanol (0.2 M with respect to the starting material) and NaBH₄ (>3 equiv) were added.

^bDiastereomeric ratios were determined via integration of the characteristic benzylic peak in the ¹H NMR spectra.

We also demonstrated the utility of the vinyl acetal rearrangement in the synthesis of bis-THF, which contains three contiguous chiral centers.¹⁶ This bis-THF ligand is an important part of the FDA approved drug darunavir.^8,9 The synthesis is shown in Scheme 5. As shown previously, vinyl acetal rearrangement of dioxepine derivative 5j afforded cis-alcohol 13j as a 5:1 mixture of cis/trans-diastereomers in 42% yield over 2 steps (Table 5, entry 10). Catalytic hydrogenation of its aldehyde precursor 6j over Pearlman’s catalyst in ethyl acetate under a hydrogen filled balloon removed the benzyl group and the resulting hemiacetal was treated with Amberlyst-15 in a mixture of MeOH and ether at 23 °C for 5 h to provide acetal 17 which was isolated as a single diastereomer. The depicted stereochemistry is based upon ¹H-NMR NOESY data.³¹ We required oxidation of tetrahydrofuran to the corresponding γ-lactone derivative. For this oxidation, we utilized ruthenium-catalyzed conditions.³² Oxidation of methyl acetal 17 with a catalytic amount of RuO₂ in the presence of NaIO₄ in a mixture of CH₂Cl₂, MeCN, and water (2:2:3) at 23 °C for 2 h afforded lactone 18 in 31% yield. Reduction of lactone 18 with LAH and treatment with a stoichiometric amount of hydrochloric acid (33% by volume in water) in ether at −10 °C for 3 h furnished the racemic alcohol 19.³³ Chiral resolution of the racemic alcohol has been previously carried out using Amano lipase PS-30.^34,35 Optically active bis-THF has been previously converted to darunavir.^8,9,36

Scheme 5.

Synthesis of Bis-THF Ligand for Darunavir

In summary, we investigated the Lewis acid-catalyzed vinyl acetal rearrangement of a wide range of substituted 4,5-dihydro-1,3-dioxepines under a variety of reaction conditions. In general, BF₃·OEt₂-catalyzed reactions afforded the best results. When the reaction was carried out at low temperatures in the presence of a catalytic amount of BF₃·OEt₂, cis-2,3-disubstituted tetrahydrofurans were obtained in a highly stereoselective manner. When the reaction was carried out at a higher temperature, around 140 °C, trans-2,3-disubstituted tetrahydrofurans were formed as major products. For the synthesis of the 4,7-dihydro-1,3-dioxepines, we developed an efficient synthesis using ring-closing metathesis of the corresponding diallyl acetal derivatives. Both aromatic and aliphatic aldehyde-derived substrates provided 4,7-dihydro-1,3-dioxepine derivatives in good to excellent yields. The syntheses of 4,5-dihydro-1,3-dioxepine substrates were carried out by a ruthenium-catalyzed olefin isomerization. The cis-tetrahydrofuran derivative obtained from benzyloxyacetaldehyde was converted to the bis-tetrahydrofuranyl alcohol, which is the P2-ligand for darunavir, a widely utilized FDA-approved drug for the treatment of HIV-1 infection and AIDS. Further applications of vinyl acetal rearrangements are in progress in our laboratories.

EXPERIMENTAL SECTION

All chemicals and reagents were purchased from commercial suppliers and used without further purification unless otherwise noted. The following reaction solvents were distilled prior to use: CH₂Cl₂ from calcium hydride, diethyl ether and tetrahydrofuran from Na/benzophenone, and methanol from activated magnesium under argon. All reactions were carried out under an argon atmosphere in either flame- or oven-dried (120 °C) glassware. TLC analysis was conducted using glass-backed thin-layer silica gel chromatography plates (60 Å, 250 μm thickness, F-254 indicator). Column chromatography was performed using 230–400 mesh, 60 Å pore diameter silica gel. ¹H and ¹³C NMR spectra were recorded at 23 °C on Varian MERCURY300, Bruker AV-400, and Bruker Avance-800 instruments. Chemical shifts (δ values) are reported in parts per million and are referenced to the deuterated residual solvent peak. NMR data are reported as δ value (chemical shift, J value (Hz), integration, where s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sep = septet, m = multiplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, td = triplet of doublets, dq = doublet of quartets, brs = broad singlet, app = apparent). LRMS and HRMS spectra were recorded at the Purdue University Department of Chemistry Mass Spectrometry Center.

Synthesis of Diallyl Acetals 11a–k: General Procedure.

To an oven-dried round-bottom flask containing activated 4 Å molecular sieves was added the aldehyde of choice (1 equiv), THF (1.5 M solution), allyl alcohol (5 equiv), and PTSA·H₂O (0.2 equiv) at 23 °C. The reaction mixture was then stirred for 24 h and filtered. The solution was concentrated under reduced pressure, and the crude material was purified by column chromatography (using specified solvent systems) over silica gel to afford 11a–k.

(Bis(allyloxy)methyl)benzene (11a).³⁷

Following the general procedure, the reaction of benzaldehyde (0.89 mL, 9.4 mmol), allyl alcohol (3.2 mL, 47 mmol), PTS·H₂O (358 mg, 1.8 mmol), and tetrahydrofuran (6.3 mL) followed by filtration and column chromatography (100% hexanes–5% EtOAc/hexanes) afforded 11a as a colorless oil (1.03 g, 5.0 mmol, 53%). ¹H NMR (400 MHz, CDCl₃, δ): 7.60–7.54 (m, 2H), 7.47–7.35 (m, 3H), 6.00 (ddt, J = 17.2, 10.7, 5.5 Hz, 2H), 5.70 (s, 1H), 5.37 (dd, J = 17.2, 1.8 Hz, 2H), 5.23 (dd, J = 10.4, 1.6 Hz, 2H), 4.12 (dt, J = 5.5, 1.6 Hz, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 138.2, 134.3 (2C), 128.2 (2C), 128.0 (2C), 126.6 (2C), 116.5 (2C), 100.2, 65.8 (2C); LRMS-ESI (m/z): 227.1 [M + Na]⁺.

1-(Bis(allyloxy)methyl)-4-isopropylbenzene (11b).

Following the general procedure, the reaction of cuminaldehyde (1.2 mL, 8.0 mmol), allyl alcohol (2.7 mL, 40 mmol), PTSA·H₂O (327 mg, 1.7 mmol), and tetrahydrofuran (5.3 mL) followed by filtration and column chromatography (100% hexanes–5% EtOAc/hexanes) afforded 11b as a light-yellow oil (1.77 g, 7.2 mmol, 89%). ¹H NMR (400 MHz, CDCl₃, δ): 7.44–7.39 (m, 1H), 7.25–7.20 (m, 1H), 5.95 (ddt, J = 17.2, 10.4, 5.5 Hz, 2H), 5.61 (s, 1H), 5.32 (dq, J = 17.2, 1.7 Hz, 2H), 5.23–5.11 (m, 2H), 4.07 (dt, J = 5.6, 1.5 Hz, 4H), 2.91 (p, J = 6.9 Hz, 1H), 1.25 (d, J = 6.9 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 149.1, 135.8, 134.6 (2C), 126.7 (2C), 126.2 (2C), 116.7 (2C), 100.5, 66.2 (2C), 33.9, 24.0 (2C). HRMS (APCI-Orbitrap) (m/z): calcd for C₁₆H₂₂O₂Na [M + Na]⁺, 269.1512; found, 269.1514.

1-(Bis(allyloxy)methyl)-4-methoxybenzene (11c).³⁸

Following the general procedure, the reaction of p-anisaldehyde (0.90 mL, 7.4 mmol), allyl alcohol (2.5 mL, 37 mmol), PTSA·H₂O (282 mg, 1.5 mmol), and tetrahydrofuran (4.9 mL) followed by column chromatography (100% hexanes–5% EtOAc/hexanes) afforded 11c as a light-yellow oil (885 mg, 3.8 mmol, 51%). ¹H NMR (400 MHz, CDCl₃, δ): 7.52–7.38 (m, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.96 (ddt, J = 17.3, 10.7, 5.5 Hz, 2H), 5.62 (s, 1H), 5.33 (dd, J = 17.2, 1.8 Hz, 2H), 5.18 (dd, J = 10.4, 1.6 Hz, 2H), 4.07 (dt, J = 5.6, 1.6 Hz, 4H), 3.80 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 159.5, 134.4 (2C), 130.5, 127.8 (2C), 116.4 (2C), 113.3 (2C), 100.1, 65.8 (2C), 55.0; LRMS-ESI (m/z): 235.1 [M + H]⁺.

1-(Bis(allyloxy)methyl)-2-methoxybenzene (11d).³⁹

Following the general procedure, the reaction of o-anisaldehyde (1.02 g, 7.5 mmol), allyl alcohol (2.5 mL, 37 mmol), PTSA·H₂O (284 mg, 1.5 mmol), and tetrahydrofuran (5.0 mL) followed by filtration and column chromatography (5–10% EtOAc/hexanes) afforded 11d as a colorless oil (1.05 g, 4.5 mmol, 60%). ¹H NMR (400 MHz, CDCl₃, δ): 7.64 (dd, J = 7.6, 1.8 Hz, 1H), 7.31 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 6.99 (td, J = 7.5, 1.0 Hz, 1H), 6.89 (dd, J = 8.3, 1.0 Hz, 1H), 6.03–5.89 (m, 3H), 5.31 (dq, J = 17.2, 1.7 Hz, 2H), 5.16 (dq, J = 10.4, 1.5 Hz, 2H), 4.11 (dt, J = 5.6, 1.5 Hz, 4H), 3.84 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 157.1, 134.8 (2C), 129.7, 127.5, 126.6, 120.3, 116.6 (2C), 110.7, 96.3, 67.0 (2C), 55.5; LRMS-ESI (m/z): 257.1 [M + Na]⁺.

1-(Bis(allyloxy)methyl)-4-nitrobenzene (11e).⁴⁰

Following the general procedure, the reaction of 4-nitrobenzaldehyde (1.07 g, 7.1 mmol), allyl alcohol (2.4 mL, 35 mmol), PTSA·H₂O (269 mg, 1.4 mmol), and tetrahydrofuran (4.7 mL) followed by filtration and column chromatography (5% EtOAc/hexanes) afforded 11e as a light-yellow oil (1.73 g, 7.0 mmol, 99%). ¹H NMR (400 MHz, CDCl₃, δ): 8.28–8.17 (m, 2H), 7.75–7.63 (m, 2H), 5.93 (ddt, J = 17.2, 10.4, 5.5 Hz, 2H), 5.70 (s, 1H), 5.32 (dq, J = 17.2, 1.6 Hz, 2H), 5.21 (dq, J = 10.4, 1.4 Hz, 2H), 4.15–3.98 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 148.0, 145.4, 133.8 (2C), 127.8 (2C), 123.4 (2C), 117.3 (2C), 99.1, 66.4 (2C); LRMS-ESI (m/z): 272.0 [M + Na]⁺.

2-(Bis(allyloxy)methyl)furan (11f).⁴¹

Following the general procedure, the reaction of furfural (0.6 mL, 7.1 mmol), allyl alcohol (2.4 mL, 36 mmol), PTSA·H₂O (271 mg, 1.4 mmol), and tetrahydrofuran (4.8 mL) followed by filtration and column chromatography (5–10% EtOAc/hexanes) afforded 11f as an amber-colored oil (1.01 g, 5.2 mmol, 73%). ¹H NMR (300 MHz, CDCl₃, δ): 7.39 (s, 1H), 6.48–6.29 (m, 2H), 5.91 (ddt, J = 16.9, 11.2, 5.7 Hz, 2H), 5.65 (s, 1H), 5.29 (dq, J = 17.2, 1.9 Hz, 2H), 5.17 (dd, J = 10.7, 2.2 Hz, 2H), 4.08 (dd, J = 5.5, 2.1 Hz, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 151.1, 142.4, 134.1 (2C), 117.0 (2C), 110.0, 108.3, 95.2, 66.3 (2C); LRMS-ESI (m/z): 217.1 [M + Na]⁺.

(1-(Bis(allyloxy)methyl)naphthalene (11g).

Following the general procedure, the reaction of naphthaldehyde (1.0 mL, 7.4 mmol), allyl alcohol (2.5 mL, 37 mmol), PTSA·H₂O (280 mg, 1.5 mmol), and tetrahydrofuran (4.9 mL) followed by filtration and column chromatography (5–10% EtOAc/hexanes) afforded 11g as a colorless oil (1.20 g, 4.7 mmol, 64%). ¹H NMR (400 MHz, CDCl₃, δ): 8.41 (dt, J = 8.7, 1.0 Hz, 1H), 7.95–7.83 (m, 1H), 7.63–7.47 (m, 4H), 6.23 (s, 1H), 6.00 (ddt, J = 17.2, 10.4, 5.6 Hz, 2H), 5.37 (dd, J = 17.2, 1.7 Hz, 2H), 5.22 (dq, J = 10.4, 1.5 Hz, 2H), 4.27–4.08 (m, 5H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 134.5 (2C), 133.7, 133.3, 130.8, 129.2, 128.4, 126.1, 125.6, 124.9, 124.8, 124.2, 116.8 (2C), 99.3, 66.4 (2C); LRMS-ESI (m/z): 197.1 [M-CH₂CHCH₂O]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₄H₁₃O [M-CH₂CHCH₂O]⁺, 197.0966; found, 197.0965.

4-(Bis(allyloxy)methyl)-1,1′-biphenyl (11h).

Following the general procedure, the reaction of biphenyl-4-carboxaldehyde (1.46 g, 8.0 mmol), allyl alcohol (2.7 mL, 40 mmol), PTSA·H₂O (304 mg, 1.6 mmol), and tetrahydrofuran (5.3 mL) followed by filtration and column chromatography (100% hexanes–10% EtOAc/hexanes) afforded 11h as a colorless oil (1.60 g, 5.7 mmol, 71%). ¹H NMR (400 MHz, CDCl₃, δ): 7.72–7.57 (m, 6H), 7.47 (dd, J = 8.3, 6.8 Hz, 2H), 7.43–7.34 (m, 1H), 6.01 (ddt, J = 17.3, 10.4, 5.5 Hz, 2H), 5.73 (s, 1H), 5.38 (dd, J = 17.2, 1.7 Hz, 2H), 5.24 (dd, J = 10.4, 1.6 Hz, 2H), 4.14 (dt, J = 5.6, 1.5 Hz, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 141.3, 140.7, 137.4, 134.5 (2C), 128.7 (2C), 127.3, 127.1 (2C), 127.1 (2C), 126.9 (2C), 116.8 (2C), 100.3, 66.1 (2C); LRMS-ESI (m/z): 303.1 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₉H₂₀O₂Na [M + Na]⁺, 303.1356; found, 303.1360.

1,1-Bis(allyloxy)-3-methylbutane (11i).

Following the general procedure, the reaction of isovaleraldehyde (0.9 mL, 7.9 mmol), allyl alcohol (2.7 mL, 40 mmol), PTSA·H₂O (302 mg, 1.6 mmol), and tetrahydrofuran (5.3 mL) followed by filtration and column chromatography (100% hexanes–10% EtOAc/hexanes) afforded 11i as a colorless oil (1.12 g, 6.1 mmol, 77%), ¹H NMR (400 MHz, CDCl₃, δ): 5.95–5.77 (m, 1H), 5.24 (dq, J = 17.2, 1.8 Hz, 2H), 5.16–5.06 (m, 2H), 4.64 (t, J = 5.9 Hz, 1H), 4.11–3.89 (m, 4H), 1.71 (dp, J = 13.5, 6.7 Hz, 1H), 1.50 (dd, J = 7.0, 5.9 Hz, 2H), 0.88 (dd, J = 6.7, 0.6 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 134.7 (2C), 116.3 (2C), 100.7, 65.8 (2C), 42.0, 24.3, 22.6 (2C).

((2,2-Bis(allyloxy)ethoxy)methyl)benzene (11j).

Following the general procedure, the reaction of benzyloxyacetaldehyde⁴² (1.33 g, 8.8 mmol), allyl alcohol (3.0 mL, 44.1 mmol), PTSA·H₂O (336 mg, 1.8 mmol), and tetrahydrofuran (6.0 mL) followed by filtration and column chromatography (5% EtOAc/hexanes–20% EtOAc/hexanes) afforded 11j as a light-yellow oil (623 mg, 2.5 mmol, 43% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ): 7.40–7.27 (m, 5H), 5.95 (ddt, J = 17.2, 10.4, 5.6 Hz, 2H), 5.32 (dd, J = 17.2, 1.7 Hz, 2H), 5.19 (dd, J = 10.4, 1.6 Hz, 2H), 4.81 (t, J = 5.2 Hz, 1H), 4.60 (s, 2H), 4.23–4.03 (m, 4H), 3.59 (d, J = 5.2 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 137.8, 134.3 (2C), 128.1 (2C), 127.5 (2C), 127.4, 116.7 (2C), 100.0, 73.2, 70.2, 67.1 (2C); LRMS-ESI (m/z): 266.1 [M+NH₄]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₅H₂₄NO₃ [M+NH₄]⁺, 266.1756; found, 266.1760.

(5-(Bis(allyloxy)methyl)benzo[d][1,3]dioxole (11k).

Following the general procedure, the reaction of piperonal (1.02 g, 6.8 mmol), allyl alcohol (2.3 mL, 34 mmol), PTSA·H₂O (259 mg, 1.4 mmol), and tetrahydrofuran (5.5 mL) followed by filtration and column chromatography (10% EtOAc/hexanes–30% EtOAc/hexanes) afforded 11k as a colorless oil (340 mg, 1.4 mmol, 20%), NMR (400 MHz, CDCl₃, δ): 7.04–6.94 (m, 2H), 6.79 (d, J = 8.0 Hz, 1H), 6.01–5.86 (m, 4H), 5.53 (s, 1H), 5.30 (dq, J = 17.2, 1.7 Hz, 2H), 5.25–5.11 (m, 2H), 4.04 (dq, J = 5.7, 1.5 Hz, 4H); ¹³C{¹H} 147.7, 134.6 (2C), 132.7, 120.5 (2C), 116.9 (2C), 108.0, 107.3, 101.2, 100.3, 66.2 (2C). HRMS (APCI-Orbitrap) (m/z): calcd for C₁₄H₁₆O₄Na [M + Na]⁺, 279.0941; found, 279.0943.

Synthesis of 4,7-Dihydro-1,3-dioxepines 12a–k: General Procedure.

To a two-necked round-bottom flask containing the diallyl acetal of choice was added CH₂Cl₂ (0.01 M solution) and Grubbs second-generation catalyst (5 mol %). The reaction mixture was then heated at reflux for 2 h, concentrated under reduced pressure and purified via silica gel column chromatography (using the specified solvent systems) to give 12a–k.

2-Phenyl-4,7-dihydro-1,3-dioxepine (12a).²⁰

Following the general procedure, the reaction of (bis(allyloxy)methyl)benzene 11a (150 mg, 0.73 mmol), Grubbs second-generation catalyst (31 mg, 0.04 mmol), and dichloromethane (73 mL) followed by column chromatography (100% hexanes–5% EtOAc/hexanes) afforded 12a as a golden-colored oil (104 mg, 0.59 mmol, 81%). ¹H NMR (400 MHz, CDCl₃, δ): 7.58–7.50 (m, 2H), 7.42–7.31 (m, 3H), 5.86 (s, 1H), 5.82–5.74 (m, 2H), 4.46–4.23 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 138.8, 129.9 (2C), 128.4, 128.2 (2C), 126.4 (2C), 102.1, 64.6 (2C).

2-(4-Isopropylphenyl)-4,7-dihydro-1,3-dioxepine (12b).

Following the general procedure, the reaction of 1-(bis(allyloxy)methyl)-4-isopropylbenzene 11b (110 mg, 0.45 mmol), Grubbs second-generation catalyst (19 mg, 0.02 mmol), and dichloromethane (45 mL) followed by column chromatography (100% hexanes–5% EtOAc/hexanes) afforded 12b as a colorless oil (88 mg, 0.40 mmol, 90%). ¹H NMR (400 MHz, CDCl₃, δ): 7.51–7.41 (m, 2H), 7.24 (dd, J = 8.9, 2.5 Hz, 2H), 5.84 (s, 1H), 5.77 (t, J = 1.8 Hz, 2H), 4.48–4.21 (m, 4H), 2.92 (p, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 149.1, 136.3, 129.9 (2C), 126.3 (2C), 126.2 (2C), 102.3, 64.6 (2C), 33.9, 24.0 (2C); LRMS-ESI (m/z): 219.1 [M + H]⁺, 241.1 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₄H₁₉O₂ [M + H]⁺, 219.1380; found, 219.1382.

2-(4-Methoxyphenyl)-4,7-dihydro-1,3-dioxepine (12c).¹⁴

Following the general procedure, the reaction of 1-(bis(allyloxy)methyl)-4-methoxybenzene 11c (194 mg, 0.83 mmol), Grubbs second-generation catalyst (35 mg, 0.04 mmol), and dichloromethane (70 mL) followed by column chromatography (100% hexanes–10% EtOAc/hexanes) afforded 12c as a brownish oil (126 mg, 0.61 mmol, 74%). ¹H NMR (400 MHz, CDCl₃, δ): 7.50–7.41 (m, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.83 (s, 1H), 5.77 (t, J = 1.8 Hz, 2H), 4.45–4.19 (m, 4H), 3.81 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 159.6, 131.1, 129.9 (2C), 127.6 (2C), 113.4 (2C), 102.0, 64.3 (2C), 55.2; LRMS-ESI (m/z): 207.1 [M + H]⁺.

2-(2-Methoxyphenyl)-4,7-dihydro-1,3-dioxepine (12d).

Following the general procedure, the reaction of 1-(bis(allyloxy)methyl)-2-methoxybenzene 11d (501 mg, 2.1 mmol), Grubbs second-generation catalyst (91 mg, 0.11 mmol), and dichloromethane (220 mL) followed by column chromatography (100% hexanes–10% EtOAc/hexanes) afforded 12d as a brownish oil (403 mg, 2.0 mmol, 91%). ¹H NMR (400 MHz, CDCl₃, δ): 7.64 (dd, J = 7.6, 1.8 Hz, 1H), 7.32 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.04–6.86 (m, 2H), 6.10 (s, 1H), 5.78 (t, J = 1.8 Hz, 2H), 4.53–4.19 (m, 4H), 3.86 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 156.9, 129.7 (2C), 129.7, 126.8, 126.7, 120.1, 110.7, 98.1, 65.2 (2C), 55.6; LRMS-ESI (m/z): 207.1 [M + H]⁺, 229.0 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₂H₁₅O₂ [M + H]⁺, 207.1016; found, 207.1018.

2-(4-Nitrophenyl)-4,7-dihydro-1,3-dioxepine (12e).

Following the general procedure, the reaction of 1-(bis(allyloxy)methyl)-4-nitrobenzene 11e (123 mg, 0.50 mmol), Grubbs second-generation catalyst (25 mg, 0.03 mmol), and dichloromethane (50 mL) followed by column chromatography (100% hexanes–10% EtOAc/hexanes) afforded 12e as a light-yellow solid (96 mg, 0.43 mmol, 88%). ¹H NMR (400 MHz, CDCl₃, δ): 8.23 (dt, J = 8.8, 1.6 Hz, 2H), 7.78–7.66 (m, 2H), 5.88 (s, 1H), 5.78 (d, J = 1.6 Hz, 1H), 4.42–4.25 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 148.0, 145.7, 129.6 (2C), 127.6 (2C), 123.4 (2C), 101.0, 64.9 (2C); HRMS (APCI-Orbitrap) (m/z): calcd for C₁₁H₁₂NO₄ [M + H]⁺, 222.0761; found, 222.0760.

2-(Furan-2-yl)-4,7-dihydro-1,3-dioxepine (12f).

Following the general procedure, the reaction of 2-(bis(allyloxy)methyl)furan 11f (266 mg, 1.4 mmol), Grubbs second-generation catalyst (58 mg, 0.07 mmol), and dichloromethane (140 mL) followed by column chromatography (100% hexanes–10% EtOAc/hexanes) afforded 12f as an amber-colored oil (139 mg, 0.84 mmol, 61%), ¹H NMR (400 MHz, CDCl₃, δ): 7.43–7.38 (m, 1H), 6.46 (dd, J = 3.3, 0.9 Hz, 1H), 6.37 (dd, J = 3.3, 1.8 Hz, 1H), 5.86 (s, 1H), 5.75 (t, J = 1.8 Hz, 2H), 4.51–4.22 (m, 5H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 151.3, 142.6, 129.8 (2C), 110.1, 107.9, 97.5, 64.8 (2C); HRMS (APCI-Orbitrap) (m/z): calcd for C₉H₁₁O₃ [M + H]⁺, 167.0703; found, 167.0702.

2-(Naphthalen-1-yl)-4,7-dihydro-1,3-dioxepine (12g).

Following the general procedure, the reaction of (1-(bis(allyloxy)methyl)-naphthalene 11g (135 mg, 0.53 mmol), Grubbs second-generation catalyst (23 mg, 0.03 mmol), and dichloromethane (53 mL) followed by column chromatography (100% hexanes–5% EtOAc/hexanes) afforded 12g as a yellowish oil (104 mg, 0.46 mmol, 87%). ¹H NMR (400 MHz, CDCl₃, δ): 8.33–8.24 (m, 1H), 7.88 (dd, J = 9.6, 7.8 Hz, 3H), 7.61–7.46 (m, 3H), 6.48 (s, 1H), 5.91–5.79 (m, 2H), 4.58–4.32 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 133.8, 133.3, 130.8, 130.0 (2C), 129.2, 128.5, 126.1, 125.5, 124.8, 124.1, 123.9, 100.4, 64.8 (2C); LRMS-ESI (m/z): 227.1 [M + H]⁺, 249.1 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₅H₁₅O₂ [M + H]⁺, 227.1067; found, 227.1070.

2-([1,1′-Biphenyl]-4-yl)-4,7-dihydro-1,3-dioxepine (12h).

Following the general procedure, the reaction of 4-(bis(allyloxy)methyl)-1,1′-biphenyl 11h (298 mg, 1.1 mmol), Grubbs second-generation catalyst (45 mg, 0.05 mmol), and dichloromethane (110 mL) followed by column chromatography (100% hexane-10% EtOAc/hexanes) afforded 12h as a white solid (165 mg, 0.66 mmol, 62%). ¹H NMR (400 MHz, CDCl₃, δ): 7.66–7.57 (m, 6H), 7.49–7.40 (m, 2H), 7.40–7.31 (m, 1H), 5.91 (s, 1H), 5.80 (t, J = 1.8 Hz, 2H), 4.44 (dt, J = 15.7, 2.0 Hz, 2H), 4.37–4.25 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 141.3, 140.8, 137.9, 129.9 (2C), 128.8 (2C), 127.4, 127.2 (2C), 127.0 (2C), 126.9 (2C), 102.1, 64.6 (2C). LRMS-ESI (m/z): 253.1 [M + H]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₇H₁₇O₂ [M + H]⁺, 253.1223; found, 253.1224.

2-Isobutyl-4,7-dihydro-1,3-dioxepine (12i).⁴³

Following the general procedure, the reaction of 1,1-bis(allyloxy)-3-methylbutane 11i (366 mg, 2.0 mmol), Grubbs second-generation catalyst (84 mg, 0.10 mmol), and dichloromethane (200 mL) followed by column chromatography (5–10% EtOAc/hexanes) afforded 12i as a colorless oil (193 mg, 1.2 mmol, 62%). ¹H NMR (400 MHz, CDCl₃, δ): 5.70 (dd, J = 2.2, 1.6 Hz, 2H), 4.82 (t, J = 5.9 Hz, 1H), 4.36 (dt, J = 16.3, 2.5 Hz, 2H), 4.21–4.06 (m, 2H), 1.73 (ddt, J = 13.3, 7.3, 6.6 Hz, 1H), 1.52 (dd, J = 7.0, 5.8 Hz, 2H), 0.91 (d, J = 6.7 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 129.8 (2C), 103.2, 64.9 (2C), 42.1, 24.5, 22.7 (2C); LRMS-ESI (m/z): 157.1 [M + H]⁺.

2-((Benzyloxy)methyl)-4,7-dihydro-1,3-dioxepine (12j).

Following the general procedure, the reaction of ((2,2-bis(allyloxy)ethoxy)-methyl)benzene 11j (588 mg, 2.4 mmol), Grubbs second-generation catalyst (101 mg, 0.12 mmol), and dichloromethane (240 mL) followed by column chromatography (100% hexanes–20% EtOAc/hexanes) afforded 12j as a yellowish oil (498 mg, 2.3 mmol, 95%). ¹H NMR (400 MHz, CDCl₃, δ): 7.42–7.26 (m, 5H), 5.71 (t, J = 1.9 Hz, 2H), 4.96 (t, J = 5.1 Hz, 1H), 4.45 (dt, J = 16.3, 2.5 Hz, 2H), 4.29–4.15 (m, 2H), 3.56 (d, J = 5.1 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 137.8, 129.4, 128.3, 127.7, 127.6, 102.1, 73.4, 69.9, 65.9; LRMS-ESI (m/z): 221.1 [M + H]⁺, 243.1 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₃H₁₇O₃ [M + H]⁺, 221.1172; found, 221.1174.

5-(4,7-Dihydro-1,3-dioxepin-2-yl)benzo[d][1,3]dioxole (12k).⁴⁴

Following the general procedure, the reaction of (5-(bis(allyloxy)-methyl)benzo[d][1,3]dioxole 11k (340 mg, 1.4 mmol), Grubbs second-generation catalyst (58 mg, 0.07 mmol), and dichloromethane (140 mL) followed by column chromatography (5% EtOAc/hexanes) afforded 12k as a light-brownish oil (271 mg, 1.2 mmol, 90%). NMR (400 MHz, CDCl₃, δ): 7.01 (tdd, J = 4.2, 1.7, 0.8 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 5.95 (s, 2H), 5.76 (dd, J = 4.3, 2.5 Hz, 3H), 4.46–4.18 (m, 4H); ¹³C{¹H} NMR 147.6, 133.1, 130.0 (2C), 120.1 (2C), 108.0, 107.2, 101.9, 101.1, 64.5 (2C); LRMS-ESI (m/z): 221.0 [M + H]⁺, 243.0 [M + Na]⁺.

Synthesis of 4,5-Dihydro-1,3-dioxepines 5a–g and 5i–k: General Procedure.

To a single-necked round-bottom flask was added the 4,7-dihydro-1,3-dioxepine of choice (1 equiv), methanol (1 M solution), RuCl₂(PPh₃)₃ (2 mol %), and NaBH₄ (0.05 equiv or 1 spatula tip). Then, a reflux condenser was attached, and the reaction was allowed to stir at reflux for 3 h. The reaction mixture was then concentrated under reduced pressure and the crude material was passed through a short silica gel column (spiked with triethylamine) to give 5a–g and 5i–k, along with their corresponding hydrogenated derivatives in most cases. Since the hydrogenated derivatives do not affect the following reactions, the quantities of the desired 4,5-dihydro-1,3-dioxepines were therefore determined by the ratios of the integrated acetal protons in the ¹H NMR spectra and used in the next steps without further purification.

Synthesis of 4,5-Dihydro-1,3-dioxepine 5h: Alternate Procedure.

To a single-necked round-bottom flask was added 4 Å molecular sieves, 2-([1,1′-biphenyl]-4-yl)-4,7-dihydro-1,3-dioxepine (1 equiv), dimethyl sulfoxide (1 M solution), and solid potassium tert-butoxide (1.2 equiv). The reaction was then allowed to stir at 23 °C for 24 h. At this point, the reaction mixture was diluted with diethyl ether and extracted once with deionized water. The aqueous layer was then extracted three times with diethyl ether. The combined organic layer was dried over sodium sulfate and the ethereal solution was concentrated under reduced pressure. After purification of the crude material over a short silica gel column (spiked with triethylamine), 5h was acquired as an inseparable mixture with its 4,7-dihydro-1,3-dioxepine starting material. Because the remaining 4,7-dihydro-1,3-dioxepine does not affect reactions later in the sequence, no further purification attempts were utilized, and the quantity of desired 4,5-dihydro-1,3-dioxepine was determined by the ratios of the integrated acetal protons in the ¹H NMR spectrum.

Synthesis of 2,3-Disubstituted Tetrahydrofurans 13a–k under Reduced Temperature Conditions: General Procedure.

To a solution of 4,5-dihydro-1,3-dioxepine 5 (1 equiv) in dichloromethane (0.2 M solution) was added BF₃·OEt₂ (0.2 equiv) at –78 °C. After consumption of the starting material was observed via TLC, the reaction mixture was immediately warmed up to 0 °C and methanol (0.2 M solution) and NaBH₄ (>3 equiv) were added. After reduction of the aldehyde was observed on TLC (about 1 h), the reaction was quenched with deionized water and the aqueous layer was extracted 3× with EtOAc. The combined organic layer was then dried over Na₂SO₄. Column chromatography using the specified solvent systems provided the 2,3-cis-disubstituted tetrahydrofuran products 13a–k as major products. Their diastereomeric ratios (cis:trans) were determined via integration of the ¹H NMR spectra.

(2-Phenyltetrahydrofuran-3-yl)methanol (13a).¹⁸

Following the general procedure, the reaction of 2-phenyl-4,5-dihydro-1,3-dioxepine 5a (1.28 g, 7.3 mmol), dichloromethane (36 mL), BF₃·OEt₂ (180 μL, 206 mg, 1.5 mmol), and methanol (36 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (30–50% EtOAc/hexanes) afforded 13a as a colorless oil (905 mg, 5.1 mmol, 70% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 20:1): 7.42–7.27 (m, 5H), 5.01 (d, J = 6.8 Hz, 1H), 4.21 (td, J = 8.3, 4.7 Hz, 1H), 3.91 (dt, J = 8.4, 7.8 Hz, 1H), 3.39–3.17 (m, 2H), 2.65 (dq, J = 7.7, 6.5 Hz, 1H), 2.18 (dtd, J = 12.5, 7.8, 4.7 Hz, 1H), 1.93 (dtd, J = 12.5, 7.9, 5.8 Hz, 1H), 1.06 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 139.5, 128.4 (2C), 127.4, 126.0 (2C), 82.0, 67.5, 62.9, 45.6, 29.0; LRMS-ESI (m/z): 179.1 [M + H]⁺.

(2-(4-Isopropylphenyl)tetrahydrofuran-3-yl)methanol (13b).

Following the general procedure, the reaction of 2-(4-isopropylphenyl)-4,5-dihydro-1,3-dioxepine 5b (263 mg, 1.2 mmol), dichloromethane (6.0 mL), BF₃·OEt₂ (30 μL, 34 mg, 0.24 mmol), and methanol (6.0 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (30–50% EtOAc/hexanes) afforded 13b as a colorless oil (181 mg, 0.82 mmol, 68% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 3:1): 7.30–7.15 (m, 4H, superimposed by peak corresponding to the minor isomer), 4.97 (d, J = 6.8 Hz, 1H), 4.18 (td, J = 8.3, 4.6 Hz, 1H), 3.88 (dt, J = 8.4, 7.8 Hz, 1H), 3.26 (ddd, J = 40.4, 11.2, 6.6 Hz, 2H), 2.89 (hept, J = 6.9 Hz, 1H, superimposed by peak corresponding to the minor isomer), 2.66–2.54 (m, 1H), 2.22–2.09 (m, 1H, superimposed by peak corresponding to the minor isomer), 1.89 (m, 1H, superimposed by peak corresponding to the minor isomer), 1.24 (d, J = 6.9 Hz, 6H, superimposed by peak corresponding to the trans isomer); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ):148.0, 136.7, 126.3 (2C), 125.8 (2C), 81.9, 67.4, 62.8, 45.5, 33.7, 28.9, 23.9 (2C); LRMS-ESI (m/z): 221.1 [M + H]⁺, 243.1 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₄H₂₁O₂ [M + H]⁺, 221.1536; found, 221.1537.

(2-(4-Methoxyphenyl)tetrahydrofuran-3-yl)methanol (13c).

Following the general procedure, the reaction of 2-(4-methoxyphenyl)-4,5-dihydro-1,3-dioxepine 5c (154 mg, 0.74 mmol), dichloromethane (3.7 mL), BF₃·OEt₂ (18 μL, 21 mg, 0.15 mmol), and methanol (3.7 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20–50% EtOAc/hexanes) afforded 13c as a light-yellow oil (76 mg, 0.36 mmol, 49% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 2:1): 7.29–7.19 (m, 2H, superimposed by peak corresponding to the minor isomer), 6.87 (dd, J = 8.9, 2.8 Hz, 2H, superimposed by the peak corresponding to the minor isomer), 4.96 (d, J = 6.8 Hz, 1H), 4.18 (td, J = 8.3, 4.5 Hz, 1H), 3.87 (q, J = 8.0 Hz, 1H), 3.79 (s, 3H, superimposed by peak corresponding to the minor isomer), 3.37–3.17 (m, 2H), 2.67–2.52 (m, 1H), 2.15 (dtd, J = 12.3, 7.8, 4.6 Hz, 1H), 1.92–1.82 (m, 1H), 1.12 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 158.9, 131.4, 127.1 (2C), 113.8 (2C), 81.7, 67.4, 62.9, 55.2, 45.5, 29.0; LRMS-ESI (m/z): 209.1 [M + H]⁺, 231.1 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₂H₁₆O₃ [M + H]⁺, 209.1172; found, 209.1176.

(2-(2-Methoxyphenyl)tetrahydrofuran-3-yl)methanol (13d).

Following the general procedure, the reaction of 2-(2-methoxyphenyl)-4,5- dihydro-1,3-dioxepine 5d (96 mg, 0.47 mmol), dichloromethane (2.4 mL), BF₃·OEt₂ (11 μL, 13 mg, 0.09 mmol), and methanol (2.4 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20–50% EtOAc/hexanes) afforded 13d as a colorless oil (57 mg, 0.27 mmol, 58% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = > 20:1): 7.47–7.35 (m, 1H), 7.26 (td, J = 8.0, 7.5, 1.8 Hz, 1H), 6.99 (td, J = 7.5, 1.0 Hz, 1H), 6.87 (dd, J = 8.1, 1.0 Hz, 1H), 5.25 (d, J = 6.7 Hz, 1H), 4.20 (td, J = 8.3, 4.3 Hz, 1H), 3.96–3.79 (m embedded in s, 4H), 3.31–3.14 (m, 2H), 2.80 (h, J = 6.7 Hz, 1H), 2.20–2.08 (m, 1H), 1.88 (dtd, J = 12.3, 8.1, 6.3 Hz, 1H), 1.64–1.55 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 155.7, 128.4, 128.3, 126.6, 121.0, 110.1, 67.2, 63.3, 55.5, 44.4, 28.7; LRMS-ESI (m/z): 209.1 [M + H]⁺, 231.1 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₂H₁₆O₃ [M + H]⁺, 209.1172; found, 209.1173.

(2-(4-Nitrophenyl)tetrahydrofuran-3-yl)methanol (13e).

Following the general procedure, the reaction of 2-(4-nitrophenyl)-4,5-dihydro-1,3-dioxepine 5e (80 mg, 0.36 mmol), dichloromethane (1.8 mL), BF₃·OEt₂ (9 μL, 10 mg, 0.07 mmol), and methanol (1.8 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (30–80% EtOAc/hexanes) afforded 13e as a brownish oil (41 mg, 0.18 mmol, 50% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 3:1): 8.22 (dd, J = 8.9, 2.3 Hz, 2H), 7.61–7.50 (m, 2H), 5.14 (d, J = 6.9 Hz, 1H), 4.28 (td, J = 8.3, 4.8 Hz, 1H), 4.00 (dt, J = 8.5, 7.7 Hz, 1H), 3.33–3.17 (m, 2H), 2.77 (h, J = 6.9 Hz, 1H), 2.24 (dtd, J = 12.5, 7.7, 4.8 Hz, 1H), 2.06–1.95 (m, 1H), 1.34 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 147.7, 147.4, 127.3 (2C), 123.7 (2C), 81.6, 68.1, 62.6, 46.0, 29.1; LRMS-ESI (m/z): 242.1 [M + H]⁺, 246.1 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₁H₁₄NO₄ [M + H]⁺, 224.0917; found, 224.0920.

(2-(Furan-2-yl)tetrahydrofuran-3-yl)methanol (13f).

Following the general procedure, the reaction of 2-(furan-2-yl)-4,5-dihydro-1,3-dioxepine 5f (111 mg, 0.67 mmol), dichloromethane (3.3 mL), BF₃·OEt₂ (16 μL, 19 mg, 0.13 mmol), and methanol (3.3 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20–80% EtOAc/hexanes) afforded 13f as a light-yellow grainy oil (61 mg, 0.36 mmol, 54% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 3:1): 7.39 (dd, J = 1.9, 0.9 Hz, 1H), 6.40–6.21 (m, 2H), 5.05 (d, J = 7.3 Hz, 1H), 4.18 (td, J = 8.3, 3.7 Hz, 1H), 3.87 (td, J = 8.4, 7.2 Hz, 1H), 3.55–3.31 (m, 2H), 2.77–2.58 (m, 1H), 2.12 (dtd, J = 12.2, 7.4, 3.7 Hz, 1H), 2.00–1.89 (m, 1H), 1.67 (s, 1H, superimposed by peak corresponding to the minor isomer); ¹³C{¹H} NMR(100 MHz, CDCl₃, δ): 153.7, 142.4, 110.4, 107.9, 76.1, 68.1, 63.1, 46.1, 28.8; LRMS-ESI (m/z): 169.1 [M + H]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₉H₁₃O₃ [M + H]⁺, 169.0859; found, 169.0858.

(2-(Naphthalen-1-yl)tetrahydrofuran-3-yl)methanol (13g).

Following the general procedure, the reaction of 2-(naphthalen-1-yl)-4,5-dihydro-1,3-dioxepine 5g (114 mg, 0.50 mmol) in dichloromethane (2.5 mL), BF₃·OEt₂ (12 μL, 14 mg, 0.10 mmol), and methanol (2.5 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20% EtOAc/hexanes–50% EtOAc/hexanes) afforded 13g as a colorless syrup (64 mg, 0.28 mmol, 55% over 2 steps), ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio= 14:1): 7.97–7.84 (m, 2H), 7.76 (ddt, J = 19.2, 7.2, 1.0 Hz, 2H), 7.57–7.40 (m, 3H), 5.61 (d, J = 6.3 Hz, 1H), 4.27 (td, J = 8.3, 5.6 Hz, 1H), 3.98 (td, J = 8.5, 6.8 Hz, 1H), 3.15–3.00 (m, 2H), 2.93 (dddd, J = 12.7, 7.9, 6.4, 3.9 Hz, 1H), 2.34 (dtd, J = 12.6, 8.2, 5.6 Hz, 1H), 2.09 (dddd, J = 12.6, 8.0, 6.8, 3.9 Hz, 1H), 1.01 (br s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 134.9, 133.5, 130.3, 129.1, 127.9, 126.3, 125.8, 125.6, 122.9, 122.8, 79.4, 67.0, 63.0, 44.4, 29.7; LRMS-ESI (m/z): 229.1 [M + H]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₅H₁₇O₂ [M + H]⁺, 229.1223; found, 223.1225.

(2-([1,1′-Biphenyl]-4-yl)tetrahydrofuran-3-yl)methanol (13h).

Following the general procedure, the reaction of 2-([1,1′-biphenyl]-4-yl)-4,5-dihydro-1,3-dioxepine 5h (46 mg, 0.18 mmol) in toluene (0.90 mL), BF₃·OEt₂ (5 μL, 6 mg, 0.04 mmol), and methanol (0.90 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20% EtOAc/hexanes–50% EtOAc/hexanes) afforded 13h as a colorless syrup (29 mg, 0.11 mmol, 63% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 11:1): 7.59 (dd, J = 7.9, 3.0 Hz, 4H), 7.47–7.38 (m, 4H), 7.37–7.31 (m, 1H), 5.07 (d, J = 6.8 Hz, 1H), 4.25 (td, J = 8.3, 4.6 Hz, 1H), 3.94 (q, J = 8.0 Hz, 1H), 3.34 (ddd, J = 35.3, 11.1, 6.5 Hz, 2H), 2.69 (h, J = 6.6 Hz, 1H), 2.21 (dtd, J = 12.5, 7.8, 4.6 Hz, 1H), 2.04–1.88 (m, 1H), 0.4 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl, δ): 140.7, 140.3, 138.6, 128.8 (2C), 127.3, 127.1 (2C), 127.0 (2C), 126.4 (2C), 81.9, 67.6, 62.9, 45.6, 29.1; LRMS-ESI (m/z): 255.1 [M + H]⁺, 277.1 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₇H₁₇O₂ [M − H]⁻, 253.1223; found, 253.1228.

(2-Isobutyltetrahydrofuran-3-yl)methanol (13i).

Following the general procedure, the reaction of 2-isobutyl-4,5-dihydro-1,3-dioxepine 5i (98 mg, 0.63 mmol), dichloromethane (3.1 mL), BF₃·OEt₂ (15 μL, 24 mg, 0.13 mmol), and methanol (3.1 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20% EtOAc/hexanes–50% EtOAc/hexanes) afforded 13i as a colorless grainy oil (54 mg, 0.34 mmol, 55% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 2:1): 3.98–3.78 (m), 3.77–3.52 (m), 2.34–2.14 (m), 2.10–1.92 (m), 1.91–1.61 (m), 1.46 (m), 1.27 (m), 0.99–0.82 (m); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 79.0, 66.3, 62.5, 43.4, 38.9, 29.0, 25.6, 23.7, 22.1; LRMS-ESI (m/z): 159.1 [M + H]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₉H₁₉O₂ [M + H]⁺, 159.1380; found, 159.1379.

(2-((Benzyloxy)methyl)tetrahydrofuran-3-yl)methanol (13j).

The reaction of 2-((benzyloxy)methyl)-4,7-dihydro-1,3-dioxepine 5j (60 mg, 0.27 mmol), dichloromethane (1.4 mL), BF₃·OEt₂ (7 μL, 11 mg, 0.05 mmol), and methanol (1.4 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20% EtOAc/hexanes–80% EtOAc/hexanes) afforded 13j as a light-brown oil (26 mg, 0.12 mmol, 42% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 5:1): 7.33 (qd, J = 7.1, 3.4 Hz, 5H, superimposed by peak corresponding to the minor isomer), 4.58 (s, 2H), 4.15 (td, J = 7.2, 4.2 Hz, 1H), 3.95 (td, J = 8.3, 3.7 Hz, 1H), 3.76–3.53 (m, 3H, superimposed by peak corresponding to the minor isomer), 2.98 (t, J = 6.4 Hz, 1H), 2.56 (pd, J = 7.8, 5.6 Hz, 1H), 1.98 (dtd, J = 12.3, 7.6, 3.7 Hz, 1H), 1.67 (dq, J = 12.4, 8.4 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 137.3, 128.7 (2C), 128.1 (2C), 128.0, 78.5, 74.1, 69.5, 67.4, 62.3, 44.0, 28.5; LRMS-ESI (m/z): 223.1 [M + H]⁺, 245.1 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₃H₁₉O₂ [M + H]⁺, 223.1329; found, 223.1328.

(2-(Benzo[d][1,3]dioxol-5-yl)tetrahydrofuran-3-yl)methanol (13k).

Following the general procedure, the reaction of 5-(4,5-dihydro-1,3-dioxepin-2-yl)benzo[d][1,3]dioxole 5k (71 mg, 0.32 mmol), dichloromethane (1.6 mL), BF₃·OEt₂ (8 μL, 13 mg, 0.06 mmol), and methanol (1.6 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20% EtOAc/hexanes–50% EtOAc/hexanes) afforded 13k as a yellowish oil (49 mg, 0.22 mmol, 68% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 4:1): 6.84–6.70 (m, 3H), 5.94 (s, 2H), 4.92 (d, J = 6.9 Hz, 1H), 4.17 (td, J = 8.3, 4.5 Hz, 1H), 3.86 (q, J = 7.9 Hz, 1H), 3.28 (ddd, J = 35.4, 11.0, 6.6 Hz, 2H), 2.68–2.53 (m, 1H), 2.14 (dtd, J = 12.3, 7.7, 4.6 Hz, 1H), 1.88 (dtd, J = 12.5, 8.0, 6.2 Hz, 1H), 1.25 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 147.9, 146.9, 133.6, 119.2, 108.3, 106.8, 101.1, 81.9, 67.6, 62.9, 45.8, 29.1; LRMS-ESI (m/z): 223.0 [M + H]⁺,245.0 [M + Na]⁺. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₂H₁₈O₄ [M + H]⁺, 223.0965; found, 223.0967.

Synthesis of Select 2,3-Disubstituted Tetrahydrofurans under Thermal Conditions: General Procedure.

To a solution of 4,5-dihydro-1,3-dioxepine 5 (1 equiv) in xylenes (0.2 M solution) was added Zn(OTf)₂ (0.2 equiv). The flask was then immediately immersed into an oil bath and heated at reflux for the time specified in Table 6. After this time, the reaction was allowed to cool to 23 °C and then to 0 °C. Then, methanol (0.2 M solution) and NaBH₄ (>3 equiv) were added. After reduction of the aldehyde was observed on TLC (about 1 h), the reaction was quenched with deionized water, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was dried over sodium sulfate. Column chromatography using the specified solvent systems provided the 2,3-trans-disubstituted tetrahydrofuran products 14a–k as major isomers. The diastereomeric ratios (cis:trans) were determined via integration of the ¹H NMR spectra.

(2-Phenyltetrahydrofuran-3-yl)methanol (14a).¹⁸

Following the general procedure, the reaction of 2-phenyl-4,5-dihydro-1,3-dioxepine 5a (56 mg, 0.32 mmol), xylenes (1.6 mL), Zn(OTf)₂ (23 mg, 0.07 mmol), and methanol (1.6 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (30–50% EtOAc/hexanes) afforded 14a as a colorless oil (27 mg, 0.15 mmol, 48% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 1:20): 7.43–7.28 (m, 5H), 4.64 (d, J = 6.7 Hz, 1H), 4.18–4.07 (m, 1H), 3.98 (td, J = 8.2, 6.0 Hz, 1H), 3.82–3.61 (m, 2H), 2.34 (dt, J = 8.0, 6.4 Hz, 1H), 2.24–2.11 (m, 2H), 1.86 (dq, J = 12.6, 7.1 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ):142.7, 128.5 (2C), 127.6, 126.1 (2C), 83.2, 68.2, 64.0, 50.3, 29.7.

(2-(4-Methoxyphenyl)tetrahydrofuran-3-yl)methanol (14c).

Following the general procedure, the reaction of 2-(4-methoxyphenyl)-4,5-dihydro-1,3-dioxepine 5c (170 mg, 0.82 mmol), xylenes (4.1 mL), Zn(OTf)₂ (60 mg, 0.16 mmol), and methanol (4.1 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20% EtOAc/hexanes–50% EtOAc/hexanes) provided 14c as a yellowish oil (56 mg, 0.27 mmol, 32% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 1:7): 7.36–7.29 (m, 2H), 6.96–6.81 (m, 2H), 4.59 (d, J = 7.0 Hz, 1H), 4.13 (ddd, J = 8.5, 7.5, 6.6 Hz, 1H), 3.98 (td, J = 8.2, 5.9 Hz, 1H), 3.83 (s, 3H), 3.79–3.65 (m, 2H), 2.43–2.31 (m, 1H), 2.21 (dtd, J = 12.5, 7.9, 5.8 Hz, 1H), 1.89 (ddt, J = 12.2, 8.0, 6.8 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 159.2, 134.5, 127.5 (2C), 114.0 (2C), 83.1, 68.0, 64.1, 55.4, 50.1, 29.8. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₂H₁₆O₃ [M + H]⁺, 209.1172; found, 209.1177.

(2-(4-Nitrophenyl)tetrahydrofuran-3-yl)methanol (14e).

Following the general procedure, the reaction of 2-(4-nitrophenyl)-4,5-dihydro-1,3-dioxepine 5e (243 mg, 1.10 mmol), xylenes (5.5 mL), Zn(OTf)₂ (80 mg, 0.22 mmol), and methanol (5.5 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (30% EtOAc/hexanes–80% EtOAc/hexanes) provided 14e as a brownish oily solid (120 mg, 0.54 mmol, 49% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 1:6) 8.14 (d, J = 8.8 Hz, 1H), 7.58–7.42 (m, 2H), 4.81 (d, J = 6.1 Hz, 1H), 4.10 (ddd, J = 8.5, 7.5, 6.3 Hz, 1H), 4.05–3.95 (m, 1H), 3.73 (d, J = 6.4 Hz, 2H), 2.29 (dp, J = 8.3, 6.4 Hz, 1H), 2.18–2.03 (m, 2H), 1.84 (ddt, J = 12.6, 7.7, 6.3 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 150.9, 147.1, 126.6 (2C), 123.6 (2C), 82.2, 68.4, 63.6, 50.4, 29.3. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₁H₁₄NO₄ [M + H]⁺, 224.0917; found, 224.0920.

2-(Naphthalen-1-yl)tetrahydrofuran-3-yl)methanol (14g).

Following the general procedure, the reaction of 2-(naphthalen-1-yl)-4,5-dihydro-1,3-dioxepine 5g (40 mg, 0.17 mmol) in xylenes (1.0 mL), Zn(OTf)₂ (13 mg, 0.04 mmol), and methanol (1.0 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20% EtOAc/hexanes–50% EtOAc/hexanes) afforded 14g as a colorless syrup (18 mg, 0.08 mmol, 45% over 2 steps), ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio= 1:5): 8.20 (dd, J = 8.3, 1.4 Hz, 1H), 7.87 (dd, J = 7.5, 2.0 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.64–7.39 (m, 4H), 5.56 (d, J = 4.7 Hz, 1H), 4.32 (qd, J = 8.3, 4.9 Hz, 1H), 4.10 (q, J = 8.1 Hz, 1H), 3.83 (ddd, J = 35.7, 10.6, 6.6 Hz, 2H), 2.62 (dtd, J = 11.4, 6.9, 4.6 Hz, 1H), 2.19 (dq, J = 12.6, 8.2 Hz, 1H), 1.94 (ddt, J = 12.3, 7.7, 4.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 138.3, 134.0, 130.8, 128.9, 128.1, 126.1, 125.7, 125.5, 123.7, 123.4, 80.6, 68.2, 64.2, 48.9, 28.4. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₅H₁₇O₂ [M + H]⁺, 229.1223; found, 229.1226.

(2-(Benzo[d][1,3]dioxol-5-yl)tetrahydrofuran-3-yl)methanol (14k).

Following the general procedure, the reaction of 5-(4,5-dihydro-1,3-dioxepin-2-yl)benzo[d][1,3]dioxole 5k (61 mg, 0.28 mmol), xylenes (1.4 mL), Zn(OTf)2 (20 mg, 0.06 mmol), and methanol (1.4 mL) and NaBH₄ (>3 equiv) followed by workup and column chromatography (20% EtOAc/hexanes-50% EtOAc/hexanes) afforded 14k as a yellowish oil (42 mg, 0.19 mmol, 67% over 2 steps). ¹H NMR (400 MHz, CDCl₃, δ) (diastereomeric ratio = 1:4): 6.86 (d, J = 1.6 Hz, 1H), 6.83–6.72 (m, 2H), 5.94 (s, 2H), 4.54 (d, J = 6.9 Hz, 1H), 4.09 (ddd, J = 8.5, 7.5, 6.5 Hz, 1H), 3.95 (td, J = 8.2, 5.8 Hz, 1H), 3.78–3.62 (m, 2H), 2.29 (dddd, J = 13.1, 8.3, 6.9, 6.2 Hz, 1H), 2.24–2.10 (m, 1H), 1.93–1.78 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 148.0, 147.1, 136.6, 119.6, 108.2, 106.7, 101.1, 83.3, 68.0, 64.0, 50.2, 29.7. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₂H₁₅O₄ [M + H]⁺, 223.0965; found, 223.0967.

Synthesis of para-Bromobenzoates cis- and trans-16e: General Procedure.

To a solution of alcohol 13e (37 mg, 0.17 mmol) or 14e (11 mg, 0.05 mmol) in dichloromethane (1.7 mL; 0.50 mL, respectively) at 23 °C was added triethylamine (46 μL, 0.33 mmol; 14 μL, 0.10 mmol, respectively) dropwise. Then, 4-bromobenzoyl chloride (72 mg, 0.33 mmol; 22 mg, 0.10 mmol, respectively) and DMAP (1 spatula tip) were added. The reactions were then allowed to stir for 12 h at 23 °C. At this point, the reactions were quenched with saturated brine solution, and the aqueous layer was extracted twice with dichloromethane. The combined organic layer was dried over sodium sulfate. Column chromatography (20% EtOAc/hexanes–50% EtOAc/hexanes) provided the para-bromo-benzoates (cis-16: 53 mg, 0.13 mmol, 80%; trans-16: 17 mg, 0.04 mmol, 84%). Recrystallization (EtOAc/hexanes, layering) provided the crystals suitable for X-ray crystallography.

cis-(2-(4-Nitrophenyl)tetrahydrofuran-3-yl)methyl-4-bromoben-zoate (cis-16).

¹H NMR (400 MHz, CDCl₃, δ) 8.14 (d, J = 8.8 Hz, 2H), 7.71–7.63 (m, 2H), 7.58–7.45 (m, 4H), 5.13 (d, J = 6.6 Hz, 1H), 4.29 (td, J = 8.3, 5.3 Hz, 1H), 4.01 (td, J = 8.3, 7.0 Hz, 1H), 3.96–3.85 (m, 2H), 3.01 (pd, J = 7.1, 5.2 Hz, 1H), 2.33 (dtd, J = 13.0, 7.9, 5.3 Hz, 1H), 2.10–1.92 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 165.4, 147.4, 146.8, 131.9 (2C), 131.0 (2C), 128.6, 128.5, 127.1 (2C), 123.7 (2C), 81.3, 67.6, 64.2, 42.7, 29.5. HRMS (APCI-Orbitrap) (m/z): calcd for C₁₈H₁₇Br⁷⁹NO₅ [M + H]⁺, 406.0285; found, 406.0276.

trans-(2-(4-Nitrophenyl)tetrahydrofuran-3-yl)methyl-4-bromobenzoate (trans-16).

¹H NMR (400 MHz, CDCl₃, δ) ¹H 8.18 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.62–7.45 (m, 4H), 4.81 (d, J = 6.8 Hz, 1H), 4.55–4.35 (m, 2H), 4.21 (ddd, J = 8.6, 7.5, 6.5 Hz, 1H), 4.09 (td, J = 8.3, 6.1 Hz, 1H), 2.61 (dqd, J = 8.3, 7.0, 5.9 Hz, 1H), 2.28 (dtd, J = 12.7, 7.8, 6.0 Hz, 1H), 2.09–1.93 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 165.7, 149.6, 147.5, 131.9 (2C), 131.1 (2C), 128.6, 128.5, 126.9 (2C), 123.8 (2C), 82.7, 68.4, 65.4, 47.4, 29.7; HRMS (APCI-Orbitrap) (m/z): calcd for C₁₈H₁₇Br⁷⁹NO₅ [M + H]⁺, 406.0285; found, 406.0276.

Synthesis of 2-((Benzyloxy)methyl)tetrahydrofuran-3-carbaldehyde 6j.

The reaction of 2-((benzyloxy)methyl)-4,7-dihydro-1,3-dioxepine 5j (1.96 g, 8.9 mmol), dichloromethane (27 mL), and BF₃·OEt₂ (220 μL, 1.8 mmol) followed by aqueous workup with saturated NaHCO₃ provided the crude tetrahydrofuran-3-carbaldehyde 6j. The crude aldehyde was utilized in the next step without further purification.

Synthesis of Hexahydrofuro[3,4-b]furan-4-ol.

To a solution of crude aldehyde 6j in ethyl acetate (45 mL) was added Pearlman’s catalyst (940 mg, 1.3 mmol). After purging the suspension three times with argon and three times once again with hydrogen gas, the reaction mixture was allowed to stir at 23 °C under a hydrogen atmosphere (balloon) for 16 h. At this point, TLC analysis indicated complete consumption of the starting material and the reaction mixture was filtered over Celite. The filtrate was concentrated under reduced pressure to provide the crude lactol. Due to suspected volatility and instability on silica gel, the crude material was utilized in the next step without further purification.

Synthesis of 4-Methoxyhexahydrofuro[3,4-b]furan 17.

To a solution of crude lactol in diethyl ether (90 mL) was added 4 Å MS, methanol (1.1 mL, 27 mmol), and Amberlyst-15 (45 g). The reaction mixture was then allowed to stir under a blanket of argon for 5 h. At this point, TLC analysis indicated complete consumption of the starting material. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. Column chromatography (10–30% EtOAc/hexanes) provided the methyl acetal 17 as a colorless oil (590 mg, 4.1 mmol, 46% over 3 steps). ¹H NMR (800 MHz, CDCl₃, δ) 4.81 (s, 1H), 4.63 (dd, J = 6.8, 4.0 Hz, 1H), 3.93 (d, J = 10.1 Hz, 1H), 3.88 (dd, J = 10.2, 4.1 Hz, 1H), 3.82 (dt, J = 8.5, 6.7 Hz, 1H), 3.71 (ddd, J = 8.5, 6.8, 5.9 Hz, 1H), 3.29 (s, 3H), 2.79 (ddd, J = 9.7, 6.7, 4.6 Hz, 1H), 2.10 (ddt, J = 12.5, 9.5, 6.9 Hz, 1H), 1.79 (dtd, J = 12.4, 6.3, 4.6 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 110.6, 82.9, 72.9, 68.9, 54.6, 50.5, 31.1. HRMS (APCI-Orbitrap) (m/z): calcd for C₇H₁₁O₃ [M − H]⁻, 143.0703; found, 143.0701.

Synthesis of 4-Methoxytetrahydrofuro[3,4-b]furan-2(3H)-one 18.

To a solution of methyl acetal 17 (590 mg, 4.1 mmol) in a mixture (2:2:3) of CH₂Cl₂:CH₃CN:H₂O (total of 39 mL) was added ruthenium oxide hydrate (217 mg) and NaIO₄ (2.62 g, 12 mmol). After 30 min of stirring under a blanket of argon at 23 °C, the reaction mixture became a greenish color. The reaction mixture was then allowed to stir for an additional 1.5 h under these same conditions. At this point, TLC analysis indicated complete consumption of the starting material. The reaction mixture was then filtered over Celite, quenched with sat. NaCl and the aqueous layer was back-extracted 3× with CH²Q². The combined organic layer was dried with Na₂SO₄. Column chromatography (10–50% EtOAc/hexanes) provided the lactone 18 as a colorless solid (200 mg, 1.3 mmol, 31%). ^lH NMR (400 MHz, CDCl₃, δ) 5.13 (dd, J = 7.1, 3.9 Hz, 1H), 4.86 (s, 1H), 4.08 (d, J = 10.9 Hz, 1H), 3.94 (dd, J = 10.9, 3.9 Hz, 1H), 3.31 (s, 3H), 3.07–2.96 (m, 1H), 2.82 (dd, J = 18.6, 11.3 Hz, 1H), 2.50 (dd, J = 18.6, 4.0 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 175.8, 110.0, 82.9, 70.6, 54.5, 45.1, 31.8; HRMS (APCI-Orbitrap) (m/z): calcd for C₇H₁₁O₄ [M + H]⁺, 159.0652; found, 159.0649.

Synthesis of Hexahydrofuro[2,3-b]furan-3-ol 19.³⁵

To a solution of lactone 18 (200 mg, 1.3 mmol) in diethyl ether (15 mL) at 0 °C was added a solution of lithium aluminum hydride (1 M in tetrahydrofuran) (1.6 mL, 1.6 mmol) dropwise. The reaction mixture was allowed to slowly warm to 23 °C and stir for 2 h. At this point, the reaction mixture was cooled to −10 °C, and an aqueous solution of HCl (33% by volume, 0.30 mL, 2.0 mmol) was added dropwise. The reaction mixture was then allowed to stir at −10 °C for 3 h. The reaction was then quenched with triethylamine (0.42 mL, 2.3 mmol), and the resulting solution was concentrated under reduced pressure over an ice bath. Column chromatography (50% Et₂O/hexanes–100% Et₂O) provided hexahydrofuro[2,3-b]furan-3-ol 19 as a colorless oil (31 mg, 0.24 mmol, 19% over 2 steps). ¹H NMR (800 MHz, CDCl₃, δ) 5.69 (d, J = 5.1 Hz, 1H), 4.53–4.37 (m, 1H), 4.06– 3.96 (m, 2H), 3.91 (ddd, J = 9.9, 8.7, 6.3 Hz, 1H), 3.64 (dd, J = 9.2, 6.9 Hz, 1H), 2.86 (ddd, J = 10.2, 7.9, 5.2 Hz, 1H), 2.31 (ddd, J = 12.9, 6.1, 2.9 Hz, 1H), 1.94–1.83 (m, 1H), 1.78 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃, δ): 109.5, 73.2, 71.1, 69.9, 46.6, 24.8.