Investigations into a Stoichiometrically Equivalent, Intermolecular Oxidopyrylium [5+2] Cycloaddition Reaction Leveraging 3-Hydroxy-4-Pyrone-Based Oxidopyrylium Dimers

Abstract

Oxidopyrylium [5+2] cycloaddition reactions are powerful strategies for constructing complex bicyclic architectures. However, intermolecular cycloadditions of oxidopyrylium ylides are limited due to competing dimerization processes, and consequently high equivalents of dipolarophiles are often used to help intercept the ylide prior to dimerization. Recent studies by our lab have revealed that oxidopyrylium dimers derived from 3-hydroxy-4-pyrones are capable of reverting back to ylides in situ, and as a result be used as a clean oxidopyrylium ylide source. The following manuscript investigates intermolecular cycloaddition reactions between 3-hydroxy-4-pyrone-derived oxidopyrylium dimers with stoichiometrically equivalent ratios of alkyne dipolarophiles under thermal conditions. With certain reactive alkynes, pure cycloadducts can be obtained following simple evaporation of solvent, which is a benefit of the completely atom economical reaction conditions. However, when less reactive alkynes are used, yields suffer due to a competing dimer rearrangement. Finally, when reactive-yet-volatile alkynes are used, such as methyl propiolate, competing 2:1 ylide-to-alkyne cycloadducts are observed. Intriguingly, these complex cycloadducts, which can be obtained in good yields from the pure cycloadducts, form with exquisitely high regio- and stereoselectivity, but both the regio-and stereoselectivity differs remarkably based upon the source of oxidopyrylium ylide.

Graphical Abstract

Introduction.

Intermolecular cycloaddition reactions are some of the most powerful reactions known to organic chemists because they can enable exceptionally convergent syntheses while building complexity, often with high regio and stereocontrol. Many of these cycloadditions, such as the widely used Diels-Alder¹ and azide-alkyne Huisgen cycloadditions,² are often highly (if not completely) atom economical as well,³ which can greatly simplify reactions and further empower their usage. Intermolecular oxidopyrylium [5+2] cycloadditions,⁴ most commonly performed by elimination of acetoxypyranose (1) in the presence of dipolarophiles (Scheme 1A),⁵ also have proven value in the synthetic chemistry community.⁶ These methods, however, lead to potentially reaction-compromising conjugate acids and/or residual base in the reaction mixtures. In addition, one major challenge associated with intermolecular oxidopyrylium cycloaddition reactions is the propensity of oxidopyrylium ylides to rapidly dimerize.⁷ Thus, a common strategy is to trap out oxidopyrylium ylides prior to dimerization, and this often requires a large excess of dipolarophile.⁸ Methods and strategies for performing oxidopyrylium cycloaddition reactions absent of byproducts and with stoichiometrically equivalent ratio of reagents would thus represent a substantial advancement to the oxidopyrylium cycloaddition literature.

Scheme 1. Oxidopyrylium cycloaddition and dimerization overview.

(A) General description of acetoxypyranose (1)-based oxidopyryilum cycloaddition reaction, along with alternative dimerization pathway. (B) Synthesis of 3-hydroxy-4-pyrone-based oxidopyrylium ylide dimer 6 from allomaltol 5, and usage in the synthesis of 3,7-dihydroxytropolone 9, which had potent antiviral activity against herpes simplex virus -1 and -2, and relatively low cytotoxicity against Vero cells.

We have recently discovered that many oxidopyrylium ylide dimers derived from 3-hydroxy-4-pyrones and methyl triflate (ie 6a, Scheme 1B)⁹ can be isolated and used as a source of ‘clean’ oxidopyrylium ylide,¹⁰ absent of the aforementioned acids and bases commonly found in oxidopyrylium cycloaddition reaction mixtures. The use of purified dimer has proven to be advantageous over in situ ylide-generating processes in reaction optimization¹¹ and total synthesis efforts¹² in our lab. While the low cost of many of the alkynes we have been working with, along with the high precedence for excess dipolarophile in oxidopyrylium cycloadditions in the literature,⁴ have admittedly biased us against driving down dipolarophile equivalences, we recently found that a stoichiometrically equivalent reaction between oxidopyrylium dimer 6a and alkyne 7a could react quantitatively at an elevated temperature of 120 °C (Scheme 1B).^12a As there were no other byproducts in the reaction mixture, following evaporation of solvent, we were able to immediately subject the resultant bicycle to methanolysis conditions and purify compound 8, which was subsequently advanced to 3,7-dihydroxytropolone 9, a potent antiviral against herpes simplex virus -1 and -2.¹³ This was the first time we had used stoichiometrically equivalent amounts of dipolarophile in the dimer-based oxidopyrylium cycloaddition reaction successfully, and it prompted us to look into the generality of the procedure in more depth. The following manuscript describes these studies, which includes isolation and characterization of key byproducts that provide added knowledge into intermolecular oxidopyrylium cycloaddition chemistry.

Research and Discussion.

Our studies began with a substrate-scope study based on the conditions previously found optimal with alkyne 7a. A solution of dimer 6a and various alkynes (ie, 7a-m) in dichloromethane stirring in a sealed microwave vial were subjected to microwave irradiation to 120 °C for 30 minutes. We began with the reaction between dimer 6a along with 7a and several other iodoalkynes to generate the corresponding iodide-containing bicycles (ie, 9b-f). The three ketone-based iodoalkynes tested gave near quantitative yields after only 30 minutes, and didn’t require any chromatography (ie, 9a-c). Yields began to drop with the less reactive iodopropiolates (ie, 9d/e), and very low yields were observed with the even less reactive iodophenylacetylene (ie, 9f). We next tested the same series without the iodides (ie, 9g-l), which revealed an advantage to the iodoalkynes. While yields of the larger ketone-containing bicycles remained high (ie, 9g/h, >90% each), cycloadduct 9i, possessing a smaller methyl ketone, was produced with substantially lower yield (50%). Cycloaddition with propiolates (ie, 9j, 26%; 9k, 38%) provided even lower yields, consistent with trends from the iodo series, while the reaction with phenylacetylene (ie, 9l, 10%) was comparable to the yield of 9f. Finally, the reaction with the highly reactive dimethyl acetylenedicarboxylate provided quantitative yields of cycloadduct 9g.

The substrate scope studies provided some indications that successful dipolarophile partners for the stoichiometrically equivalent oxidopyrylium cycloadditions with dimer 6a need to have high boiling points, and this may be the advantage of the iodide, which provides added mass to the alkynes. Specifically, reactions with the t-butylpropiolate-based alkynes (ie, 9e, 74%; 9k, 38%) are higher than those with the corresponding methylpropiolate-based alkynes (ie, 9d, 68%; 9j, 28%), and reactions with the phenyl ketone alkynes (ie, 9b, 98%; 9h, 91%) are higher than those with the corresponding methyl ketone-based alkynes (ie, 9c, 91%; 9i, 50%). This is likely due to the high temperature needed to push the reactions to completion, which may, in turn, lead more volatile alkynes to exist in the gas phase in the head space of the sealed tube. It should be noted that for these lower boiling alkynes, one could use an excess of the alkyne to facilitate quantitative cycloadditions and then evaporate off the alkyne. This approach was used recently by our lab with methyl propiolate in the chromatography-free 7-step synthesis of a carboxylic acid-appended α-hydroxytropolone.^12b High electrophilicity of the alkynes is still highly important, which is why the reaction with methyl ketone-containing alkynes (ie, 9i/9c) are more efficient than reactions with the higher boiling ester-containing alkynes (ie, 9d/e/j/k), why phenylacetylene remain poor (ie, 9f, 7%; 9i, 10%), and why the reaction with dimethyl acetylenedicarboxylate (ie, 9m, 98%) is excellent.

In the case of the cycloaddition with phenylacetylene and iodophenylacetylene (see 9f and 9l), we observed substantial amounts of rearrangement cycloadduct 6b, whose structure was unambiguously confirmed with X-ray crystallography. This appears to be the major deterrent to the reaction with less-reactive dipolarophiles, and by heating 6a to 120 °C for 30 minutes in the absence of alkyne, 6b formed in 82% yield (Scheme 3A). Meanwhile, taking 6b and heating it to 150 °C for 12 h in presence dimethyl actylenedicarboxylate only provided trace amounts of 9m. Thus, 6b appears to be a more thermally stable dimer that is accessible at higher temperatures. A similar rearrangement to an analogous symmetric dimer, 4b, was described in the seminal work by Hendrickson on the simpler Achmatowicz-derived oxidopyrylium dimer 4a (Scheme 3B).^7b It is worth noting that the rearrangement of 4a to 4b is unlikely to proceed through full cycloreversion to the monomeric oxidopyrylium ylide, but rather can arise through a formal [1,3] rearrangement process (Scheme 3B). On the other hand, 6a cannot convert to 6b through a similar process. Rather, its conversion to 6b likely proceeds through a cycloreversion-dimerization pathway, which is consistent with recent kinetic studies demonstrating full reversibility of 6a to the ylide for its cycloaddition with 7m.¹⁴ This difference in the mechanism through which these dimers rearrange to the more stable dimers could help explain why dimer 4a is not an effective source of oxidopyrylium ylide, whereas dimers such as 6a are.

Scheme 3. Oxidopyrylium Dimer Rearrangements.

(A) Rearrangement of 6a to 6b, and lack of cycloaddition between 6b and 7m at elevated temperatures.. *Based on monomeric ylide. (B) Rearrangement of 4a to 4b, which can proceed through a formal [1,3] carbon migration, avoiding the regeneration of the monomeric ylide.

We next became interested in what impact, if any, the use of pure dimer 6a had in allowing the stoichiometrically equivalent reaction. Thus, we tested this reaction by making the ylide from the salt and reacting it directly with an iodinated alkyne 7d, which provided cycloadduct 9d in moderate yields from the purified dimer (Scheme 2). The major difference in the reaction and the reaction with purified dimer would be the presence of conjugate acid and residual base (Scheme 4). When the choice of base was N,N-diisopropylaniline, the reaction provided slightly lower yield (52%) than the reaction with dimer alone. In addition, we were unable to remove the conjugate acid using an aqueous acid wash, likely due to the high lipophilicity of the base, and thus purification of this reaction would likely require chromatography or a trituration/crystallization procedure, further complicating this process. We also tried to use triethylamine, which could be washed away. However, no cycloaddition product was seen in this reaction. Thus, these examples highlight an additional advantage of using oxidopyrylium dimer as a simplified procedure for oxidopyrylium cycloaddition reactions.

Scheme 2. Oxidopyrylium Cycloaddition Using 1:1 Alkyne to Oxidopyrylium Ylide Ratio Leveraging Dimer 6a as Ylide Source.

^a Isolated yields following evaporation of solvent. ^b Isolated yields following silica gel chromatography. ^c Reaction run for 60 min.

Scheme 4. Oxidopyrylium cycloadditions generated in situ.

^aReaction yields were reported based on ¹H NMR integration based on internal standard, 1,3,5-trimethoxybenzene.

Given how well iodoalkynes worked in the stoichiometrically equivalent process, and their ease of synthesis, we decided to evaluate the further conversion of these bicycles, focusing on 9d. Previously, in our synthesis of 3,7-dihydroxytropolones, we had shown that DMAP-based methanolysis could be carried out effectively on these bicyclic structures (Scheme 1B).^12a In an effort to expand this solvolysis procedure, we evaluated the reaction with both benzyl alcohol and tert-butylthiol. Yields in both cases were comparable to those observed previously with methanol (Scheme 5A), demonstrating some new possibilities for DMAP-catalyzed solvolysis on the oxidopyrylium bicycles that could be useful in synthesis. In addition, although oxidopyrylium cycloadditions with 6a are generally highly regioselective, the reaction with phenylpropiolic ester 7n is completely non-selective, and furthermore requires three equivalents to obtain a 68% overall yield (Scheme 5B). Cross-coupling between iodobicycle 7d and tributylphenylstannane 13 is nearly quantitative, thus providing an alternative 2 step procedure that is completely regioselective (Scheme 5C). Thus, conversion of these iodide-containing bicycles into oxygen, sulfur, or carbon-containing bicycles can be done readily, demonstrating an additional advantage for the reactions with iodoalkynes.

Scheme 5. Modification of Iodoalkyne 9d.

(A) DMAP-catalyzed solvolysis with benzyl alcohol and tert-butylthiol. (B) Non-regioselective cycloaddition with phenyl methylpropiolate. (C) Cross-Coupling with tributylphenylstannane (13). * Equivalents based on monomeric ylide.

Next, we wanted to explore how these high temperature, stoichiometrically equivalent cycloadditions would behave with two alternative oxidopyrylium ylides. First we investigated chloride-containing oxidopyrylium dimer 14, which had been valuable to us in previous studies, but is more prone to side reactions. We have previously shown that bicycle 15 can be advanced to compound 16 (αHT107), which the Tavis lab found possesses potent antiviral activity against hepatitis B virus, and very little cytotoxicity.¹⁵ Previously compound 15 was synthesized in near quantitative yields from the in situ-generated 14, but in those experiments 20 equivalents of dimethyl acetylenedicarboxylate 7m were used in order to maximize yields. We were pleased to find that at elevated temperatures, the amount of alkyne could be dropped to stoichiometrically equivalent amounts and provide a yield of 83% on mmol scale, with similar yields with microwave and conventional heating (Scheme 6A). In another example, we had previously generated compound 18 through a cycloaddition reaction at 100 °C between dimer 14 and 20 equivalents of iodoalkyne 17.^12a Bicyclic product 18 was advanced to 7-hydroxystipitalide (19), a hydroxylated version of stipitalide that may be a biosynthetic precursor to the natural products puberulic and puberulonic acid.¹⁶ In this instance, elevated temperatures and stoichiometrically equivalent ratios of the reactants led to 18 with 62% yield. (Scheme 6B). Thus, stoichiometrically equivalent cycloadditions extend to reactions with dimer 14.

Scheme 6. Stoichiometrically equivalent cycloadditions with chloromethylene-containing dimer 14.

(A) Synthesis of 15, which is a precursor to the potent anti-HBV αHT107 (16), both by conventional heating and microwave heating. (B) Synthesis of 19, which had been previously advanced to 7-hydroxystipitalide (19). * Equivalents based on monomeric ylide. **Conventional heating by oil bath.

The other oxidopyrylium dimer that we wanted to assess the stoichiometrically equivalent cycloaddition with was maltol-derived dimer, 20, a regioisomeric dimer to 6a that is known to react with 7m more slowly, and unlike the reaction with 6a, has 0^th order kinetics in 7m.¹⁴ Thus, we suspected that dropping the equivalents of 7m to stoichiometric equivalent ratios would be successful, and indeed strong yields were obtained (Scheme 7B). On the other hand, we had anticipated that the reaction between 20 and 7j would be low yielding, in analogy to the 26% yield of the reaction between dimer 6a and 7j. Surprisingly, 22 was isolated in a much higher yield. Furthermore, whereas a complex array of baseline peaks accompanied the crude NMR spectrum of 9j, a significant and isolatable 2:1 ylide to alkyne byproduct, 23, whose structure was unambiguously assigned by X-ray crystal structure analysis, was observed (Scheme 8). Similar 2:1 cycloadducts arising from oxidopyrylium cycloadditions with alkynes have been described previously,¹⁷ although the complete structural assignments have been ambiguous or tentatively assigned.

Scheme 7. Stoichiometrically equivalent cycloadditions with maltol-derived dimer 20.

*Equivalents based on monomeric ylide.

Scheme 8. Synthesis of 2:1 cycloadduct 23, along with X-ray structure.

*Equivalents based upon monomeric ylides.

Aside from the insight this result gave us that may explain some of the results with more volatile alkynes, compound 23 was also interesting on account of the high stereoselectivity and surprising regioselectivity. Thus, two additional experiments were carried out to provide higher yields of 23 (Scheme 8). In one reaction, we lowered the equivalents of alkyne 7j to account for the stoichiometry of the cycloadducts. In the other experiment, we reacted 1 equivalent of 7j with cycloadduct 22. In both cases, 23 was formed as the major product in good yields.

Given the higher yields obtained, we returned our attention to the analogous reaction between 6a and 7j (9j, Scheme 2) in an attempt to see similar cycloadducts (Scheme 9). When 9j was submitted to the cycloaddition with 7j, we observed and isolated two major products, the 2:1 cycloadduct 24, as well as the thermal dimer rearrangement product 6b. On the other hand, when 6a was treated to lower amounts of 7j, we initially observed a mixture of two compounds, one of which was 24, and the other which appeared to be an alternative 2:1 cycloadduct. We were unable to characterize this other cycloadduct, as even when it was isolated it in pure form it would begin converting to 24. Thus, these 2:1 cycloadducts appear to be major side-products in our attempts at stoichiometric cycloaddition to produce 9j.

Scheme 9. Synthesis of 2:1 cycloadduct 24, along with X-ray structure.

*Equivalents based upon monomeric ylides

Aside from the knowledge this set of 2:1 cycloadducts provide regarding stoichiometric cycloadditions between 3-hydryxo-4-pyrone-derived ylides and alkynes, they also provide unique insight into stereo- and regioisomeric nuances between maltol and allomaltol-derived oxidopyrylium ylides that is worth discussing. Formation of 23 appears to be forming through endo selective cycloaddition from the more sterically accessible convex face of the alkene (left, Scheme 10A). Possibly in order to limit steric interactions between the methyl groups of the cycloaddition partners (right, Scheme 10A), the cycloaddition inverts the regiochemistry. Similar steric-based regioselectivity has been observed on 2:1 ‘Pincer’ Diels Alder cycloadducts arising from the reaction between 2-methylfuran and DMAD.¹⁸ In the case of cycloadduct 24, it forms with the expected regioselectivity, but instead provides the opposite stereochemistry. Formally, this cycloaddition would result through exo selective process from the convex face (left, Scheme 10B) or alternatively with endo selectivity from the concave face (right, Scheme 10B). While both approaches may appear sterically unfavorable, this alternative selectivity may be the result of thermodynamic control, possibly via reversibility of other competing cycloadditions, or could alternatively result through a step-wise process, similar to the dimerization pathway proposed for 6a.¹⁴ In the case of reversibility, the array of gauche interactions of ester and methyl groups that result from the regioselectivity may result in higher likelihood of such reversibility. More detailed investigations aimed at elucidating the mechanistic underpinnings that result in this differing selectivity - as well as how the selectivity differences may translate to other systems – are underway.

Scheme 10. Potential approaches Towards 2:1 Cycloadducts.

(A) Endo approach from convex face with regioselectivity that would lead to 23, along with similar approach with opposite regioselectivity to demonstrate sterics. (B) Exo-convex and endo-concave approaches that would lead to 24.

Conclusion.

Stoichiometrically equivalent cycloadditions from oxidopyrylium dimers and alkynes presents a highly simplifying procedure that, given its high atom economy, can often lead to high purity products simply following removal of solvent. The scope of cycloadditions using stoichiometrically equivalent ratios of various alkynes and oxidopyrylium ylides using oxidopyrylium dimers has been described. This procedure worked particularly well with iodoalkynes, which could be due to either increased boiling point or reactivity. These iodoalkynes provide a valuable handle for functionalization, which is illustrated by DMAP-assisted solvolysis, as well as cross-coupling reactions. We also discovered that dimers can rearrange to new, more thermodynamically stable forms at elevated temperatures, and this side-reaction is particularly problematic with less reactive dipolarophiles. On the other hand, when reactive-yet-volatile alkynes are used, 2:1 cycloadducts are formed. Interestingly, these complex cycloadducts form with high regio- and stereoselectivity, but this selectivity varies based upon the oxidopyrylium ylide source used. These studies thus provide insight into the advantages and challenges associated with oxidopyrylium dimer-as-ylide tactic for intermolecular cycloaddition chemistry.

Experimental Section

General Information.

All starting materials and reagents were purchased from commercially available sources and used without further purification, with the exception of CH₂Cl₂, which was purified on a solvent purification system prior to reactions. ¹H NMR shifts were measured using the solvent residual peak as the internal standard (CHCl₃ δ 7.26) and reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, dd = doublet of doublets, q = quartet, m = multiplet), coupling constant (Hz), integration. ¹³C{¹H} NMR shifts were measured using the solvent residual peak as the internal standard (CDCl₃ δ 77.16) and reported as chemical shifts. Infrared (IR) spectral bands are characterized as broad (br), strong (s), medium (m), and weak (w). Mass spectra were recorded on a spectrometer by the electrospray ionization (ESI) technique with a time-of-flight (TOF) mass analyzer.

The X-ray intensity data were measured on Rigaku XtaLAB Synergy-S Dualflex diffractometer equipped with a HyPix-6000 HE HPC area detector for data collection at 100.00(10) K. The structures were solved using SHELXT2 and refined using SHELXL3. Microwave reactions were performed via the Biotage Initiator EXP US (manufacturer #: 355302) (external IR temperature sensor) in a sealed vessel. Where noted, reaction products were purified via silica gel chromatography using a Biotage Isolera Prime, with Biotage SNAP 10 g, Biotage SNAP 25g, or SilaSep 12g cartridges in a solvent system of ethyl acetate in hexane.

(1S,2S,6S,7S)-4,9-dimethoxy-6,7-dimethyl-11,12-dioxatricyclo[5.3.1.12,6]dodeca-4,8-diene-3,10-dione (6b).

A solution of dimer (6a) (220 mg, 0.79 mmol) dissolved by CDCl₃ (0.5M) in a sealed vial (Biotage microwave reaction vial, 2–5 mL) was subjected to microwave irradiation at 120 °C for 30 min. The reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 10% EtOAc in hexanes (3 CV); 10-70% EtOAc in hexanes (25 CV). Product fractions were concentrated to yield 6b as a white powder (181.2 mg, 82% yield). For production of crystals for crystal structure analysis, 150 mg of 6b was dissolved in 800 μL of 10% hexane in ethyl acetate, and then crystallized in a freezer (-10 °C) overnight. Melting point (mp) = 223-225 °C. Rf = 0.20 in 30% EtOAc in hexanes. IR (thin film, KBr) 2985 (w), 2941 (w), 1708 (s), 1628 (m), 1459 (m), 1369 (m), 1277 (m), 1130 (s), 1108 (m), 1002 (m), 860 (m), 730 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 5.77 (s, 1H), 4.26 (s, 1H), 3.68 (s, 3H), 1.38 (s, 3H). ¹³C{¹H} NMR (50 MHz, CDCl₃) δ 189.1, 150.4, 116.2, 77.0, 76.3, 55.1, 24.0. HRMS (ESI-TOF) m/z: [M + Na]⁺ Calc’d for C₁₄H₁₆NaO₆⁺: 303.0839. Found: 303.0838.

4-Iodobut-3-yn-2-one (7c).

To a solution of 3-butyn-2-one (2.3 mL, 29.4 mmol) in acetone (58.0 mL) was added N-iodosuccinimide (7.9 g, 35.0 mmol). After stirring for 5 min, silver nitrate (250 mg, 1.5 mmol) was added slowly at 0 °C. The reaction was allowed to stir at rt for 2 h in the dark before being quenched by 100 mL of water. The reaction mixture was added to a separatory funnel containing 150 mL of CH₂Cl₂. The organic layer was isolated and the aqueous layer was extracted with CH₂Cl₂ (3 × 100 mL). Combined organics were extracted with 150 mL of water, 100 mL of saturated sodium bicarbonate solution, and 150 mL of aqueous sodium chloride. Organics collected and dried over Na₂SO₄, filtered, and concentrated under reduced pressure to yield crude product, which was further purified by chromatography (Biotage Isolera Prime, 25 g silica gel column, solvent gradient: 1% EtOAc in hexanes (3 CV); 1-15% EtOAc in hexanes (20 CV)). Product fractions were concentrated under reduced pressure to yield 7c as a light yellow solid (1.4 g, 25% yield). Melting point (mp) = 33-35 °C. Rf= 0.45 in 15% EtOAc in hexanes. IR (thin film, KBr) 2970 (w), 2166 (m), 1675 (s), 1523 (w), 1351 (m), 1351 (w), 1292 (s), 1189 (m), 865 (w), 836 (w), 750 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 2.35 (s, 1H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 182.9, 95.0, 32.1, 19.3. HRMS (ESI-TOF) m/z: [M + H]⁺ Calc’d for C₄H₄IO⁺: 194.9301. Found: 194.9300

tert-Butyl 3-iodopropiolate (7e).

To a solution of tert-butyl propiolate (710 mg, 5.63 mmol) in acetone (11 mL) was added N-iodosuccinimide (1.52 g, 6.75 mmol). After stirring for 5 min, silver nitrate (48 mg, 0.28 mmol) was added slowly at 0 °C. The reaction was allowed to stir at rt for 4 h in the dark before being quenched by 50 mL of water. The reaction mixture was added to a separatory funnel containing 50 mL of CH₂Cl₂. The organic layer was isolated and the aqueous layer was extracted with CH₂Cl₂ (3 x 50 mL). Combined organics were extracted with 50 mL of water, 50 mL of saturated sodium bicarbonate solution, and 50 mL of aqueous sodium chloride. Combined organics were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Product fractions were concentrated to yield 7e as a light yellow solid (910 mg, 65% yield). Melting point (mp) = 79–80 °C. Rf= 0.40 in 10% EtOAc in hexanes. IR (thin film, KBr) 3007 (w), 2980 (m), 2931 (w), 2167 (s), 1671 (s), 1471 (w), 1372 (m), 1291 (s), 1151 (s), 836 (m) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 1.48 (s, 1H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 151.5, 88.6, 84.3, 28.1, 10.7.

General Procedure for Stoichiometrically Equivalent Oxidopyrylium Cycloadditions.

To a solution of dimer (6a), (14), or (20) in CH₂Cl₂ (0.2 M) was added alkyne (2 equivalents; 1 equivalent based of monomeric ylide). The reaction was subjected to microwave irradiation at 120 °C. The reaction mixture was then either concentrated and collected or loaded directly onto silica column and purified chromatographically.

Cycloadducts 9a, 9b, 9c, 9e, 9f are characterized below. Compounds 9d, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 15, 18, 21, and 22 have been characterized previously.

Synthesis and Characterization of Oxidopyrylium Cycloadducts from Dimers (6, 14, 20).

(1R,5S)-6-([1,1′-biphenyl]-4-carbonyl)-7-iodo-3-methoxy-5-methyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one (9a).

To a solution of dimer (6a) (100 mg, 0.357 mmol) in CDCl₃ (800 μL) was added 1-([1,1′-biphenyl]-4-yl)-3-iodoprop-2-yn-1-one (237.5 mg, 0.7134 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was concentrated to yield 9a as a brown oil (315.5 mg, >98% yield). Rf = 0.23 in 15% EtOAc in hexanes. IR (thin film, KBr) 3062 (w), 2980 (w), 2934 (w), 1712 (s), 1644 (m), 1602 (s), 1449 (w), 1406 (w), 1345 (w), 1315 (w), 1300 (w), 1285 (m), 1269 (w), 1139 (w), 1125 (m), 1055, 1007, 891, 855, 751 (m), 699 (w), 677 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 7.97 – 7.94 (m, 2H), 7.77 – 7.74 (m, 2H), 7.68 – 7.65 (m, 2H), 7.51 – 7.47 (m, 2H), 7.45 – 7.40 (m, 1H), 6.25 (s, 1H), 5.17 (s, 1H), 3.63 (s, 3H), 1.68 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 192.1, 186.9, 157.6, 147.2, 145.0, 139.6, 13 3.8, 130.6, 129.2, 128.7, 127.7, 127.4, 120.3, 98.0, 93.8, 90.0, 54.9, 20.9. HRMS (ESI-TOF) m/z: [M + H]⁺ Calc’d for C₂₂H₁₈IO₄⁺: 473.0244. Found: 473.0242.

(±)-(1R,5S)-6-benzoyl-7-iodo-3-methoxy-5-methyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one (9b)

To a solution of dimer (6) (75.0 mg, 0.268 mmol) in CH₂Cl₂ (1 mL) was added 1-phenylprop-2-yn-1-one (128.5 mg, 0.535 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was concentrated to yield 9b as a light brown oil (195 mg, 98% yield). Rf = 0.24 in 15% EtOAc in hexanes. IR (thin film, KBr) 3064 (w), 2980 (w), 2935 (w), 2838 (w), 1712 (s), 1645 (m), 1610 (m), 1449 (m), 1346 (w), 1318 (m), 1286 (m), 1270 (w), 1177 (w), 1125 (m), 987 (w), 889 (w), 863 (w), 845 (w), 730 (w), 692 (w), 662 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 7.89 – 7.83 (m, 2H), 7.68 – 7.62 (m, 1H), 7.56 – 7.49 (m, 2H), 6.23 (s, 1H), 5.15 (s, 1H), 3.62 (s, 3H), 1.66 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 192.6, 186.9, 157.5, 145.0, 135.3, 134.4, 129.9, 129.1, 120.3, 98.4, 93.9, 90.0, 55.0 (s), 20.9. HRMS (ESI-TOF) m/z: [M + H]⁺ Calc’d for C₁₆H₁₄IO₄⁺: 396.9931. Found: 396.9928.

(±)-(1R,5S)-6-acetyl-7-iodo-3-methoxy-5-methyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one (9c).

To a solution of dimer (6) (222.5 mg, 0.79 mmol) in CH₂Cl₂ (3.3 mL) was added 4-Iodobut-3-yn-2-one (7c) (308.5 mg, 1.59 mmol). After subjecting microwave irradiation at 120 °C for 30 min, the reaction mixture was concentrated to yield 9c as a light yellow oil (482.0 mg, 91% yield). Rf = 0.21 in 15% EtOAc in hexanes. IR (thin film, KBr) 2990 (w), 2935 (w), 1712 (s), 1667 (s), 1609 (s), 1451 (w), 1360 (w), 1344 (w), 1285 (w), 1263 (w), 1178 (w), 1131 (m), 1116 (w), 856 (w), 694 (w) cm⁻¹. ¹H NMR (200 MHz, CDCl₃) δ 6.10 (s, 1H), 5.05 (s, 1H), 3.53 (s, 3H), 2.56 (s, 3H), 1.66 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 195.2, 186.9, 158.1, 144.7, 119.7, 100.8, 93.8, 89.1, 54.7, 29.7, 21.2. HRMS (ESI-TOF) m/z: [M + Na]⁺ Calc’d for C₁₁H₁₁INaO₄⁺: 356.9594. Found: 356.9592.

(±)-tert-Butyl (1R,5S)-7-iodo-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9e).

To a solution of dimer (6) (40.0 mg, 0.1427 mmol) in CH₂Cl₂ (713 μL) was added tert-butyl 3-iodopropiolate (72.8 mg, 0.2854 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5–10% EtOAc in hexanes (10 CV); 10–20% EtOAc in hexanes (10 CV); 20– 35% EtOAc in hexanes (8 CV)). Product fractions were concentrated to yield 9e as a light yellow oil (40.4 mg, 74% yield). Rf = 0.30 in 15% EtOAc in hexanes. IR (thin film, KBr) 2979 (w), 2936 (w), 1712 (s), 1611 (m), 1456 (m), 1370 (w), 1319 (m), 1272 (m), 1159 (m), 1133 (m), 1123 (m), 1077 (w), 1049 (w), 869 (w), 844 (w), 782 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 6.01 (s, 1H), 4.94 (s, 1H), 3.52 (s, 3H), 1.68 (s, 3H), 1.51 (s, 9H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 187.2, 161.9, 152.1, 145.1, 119.5, 101.0, 93.4, 87.9, 83.6, 54.9, 28.4, 21.6. HRMS (ESI-TOF) m/z: [M + Na]⁺ Calc’d for C₁₄H₁₉NaIO₅⁺: 415.0013. Found: 415.0011.

(±)-(1R,5S)-7-Iodo-3-methoxy-5-methyl-6-phenyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one (9f).

To a solution of dimer (6) (20.0 mg, 0.0714 mmol) in CH₂Cl₂ (357 μL) was added (Iodoethynyl)benzene (32.7 mg, 0.1428 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5–10% EtOAc in hexanes (10 CV); 10–20% EtOAc in hexanes (10 CV); 20– 35% EtOAc in hexanes (8 CV)). Product fractions were concentrated to yield 9f as a yellow oil (4.2 mg, 7% yield). Rf = 0.23 in 20% EtOAc in hexanes. IR (thin film, KBr) 3060 (w), 2982 (w), 2933 (w), 1710 (s), 1604 (m), 1490 (w), 1454 (w), 1341 (w), 1276 (w), 1160 (w), 1128 (m), 1111 (m), 863 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 7.47 – 7.37 (m, 3H), 7.32 – 7.27 (m, 2H), 6.09 (s, 1H), 5.01 (s, 1H), 3.63 (s, 3H), 1.58 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 188.0, 160.1, 145.9, 133.1, 129.1, 128.9, 126.8, 118.8, 92.1, 88.5, 87.8, 55.0, 22.3. HRMS (ESI-TOF) m/z: [M + Na]⁺ Calc’d for C₂₂H₁₉NaIO₄⁺: 368.9982. Found: 368.9980.

Synthesis of Oxidopyrylium Cycloadducts (previously characterized) from Dimers (6, 14, 20).

(±)-Methyl (1R,5S)-7-iodo-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9d).

To a solution of dimer (6) (25.0 mg, 0.089 mmol) in CH₂Cl₂ (450 μL) was added methyl 3-iodopropiolate (15.8 μl, 0.178 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5–10% EtOAc in hexanes (10 CV); 10-20% EtOAc in hexanes (10 CV); 20- 35% EtOAc in hexanes (8 CV)). Product fractions were concentrated to yield 9d as a yellow oil (29.5 mg, 68% yield). Compound 9d was consistent by ¹H NMR with previously reported data.^12a

(±)-(1S,5S)-6-([1,1′-biphenyl]-4-carbonyl)-3-methoxy-5-methyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one (9g).

To a solution of dimer (6) (25.0 mg, 0.089 mmol) in CH₂Cl₂ (450 μL) was added 1-([1,1′-biphenyl]-4-yl)prop-2-yn-1-one (15.8mg, 0.178 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was concentrated to yield 9g as a light brown oil (44.0 mg, 95% yield). Compound 9g was consistent by ¹H NMR with previously reported data.

(±)-(1S,5S)-6-benzoyl-3-methoxy-5-methyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one (9h).

To a solution of dimer (6) (40.0 mg, 0.1427 mmol) in CH₂Cl₂ (357 μL) was added 1-phenylprop-2-yn-1-one (37.2 mg, 0.2854 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 1% EtOAc in hexanes (3 CV); 5-10% EtOAc in hexanes (10 CV); 10-20% EtOAc in hexanes (10 CV); 20-35% EtOAc in hexanes (8 CV)). Product fractions were concentrated to yield 9h as a yellow oil (62.4 mg, 91% yield). Compound 9h was consistent by ¹H NMR with previously reported data.¹⁰

(±)-Methyl (1S,5S)-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9i).

To a solution of dimer (6) (20.0 mg, 0.0714 mmol) in CH₂Cl₂ (357 μL) was added 3-butyn-2-one (7i) (11.2 μL, 0.1427 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5-10% EtOAc in hexanes (10 CV); 10-20% EtOAc in hexanes (10 CV); 20-35% EtOAc in hexanes (8 CV)). Product fractions were concentrated to yield 9i as a yellow oil (14.8 mg, 50% yield). Compound 9i was consistent by ¹H NMR with previously reported data.¹⁰

(±)-Methyl (1S,5S)-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9j).

To a solution of dimer (6) (20.0 mg, 0.0714 mmol) in CH₂Cl₂ (357 μL) was added methyl propiolate (13.3 μL, 0.1427 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5-10% EtOAc in hexanes (10 CV); 10-20% EtOAc in hexanes (10 CV); 20-35% EtOAc in hexanes (8 CV)). Product fractions were concentrated to yield 9j as a yellow oil (8.9 mg, 26% yield). Compound 9j was consistent by ¹H NMR with previously reported data.²⁰

(±)-tert-Butyl (1S,5S)-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9k).

To a solution of dimer (6) (20.0 mg, 0.0714mmol) in CH₂Cl₂ (357 μL) was added tert-butyl propiolate (7k) (21.9 mg, 0.1427 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5-10% EtOAc in hexanes (8 CV); 10-20% EtOAc in hexanes (10 CV); 20-35% EtOAc in hexanes (5 CV)). Product fractions were concentrated to yield 9k as a yellow oil (14.5 mg, 38% yield). Compound 9k was consistent by ¹H NMR with previously reported data.^11b

(±)-3-methoxy-5-methyl-6-phenyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one (9l).

To a solution of dimer (6) (20.0 mg, 0.0714 mmol) in CH₂Cl₂ (357 μL) was added phenyl acetylene (7l) (15.7 μL, 0.1427 mmol). After microwave irradiation at 120 °C for 30 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5-10% EtOAc in hexanes (10 CV); 10-20% EtOAc in hexanes (10 CV); 20-35% EtOAc in hexanes (8 CV)). Product fractions were concentrated to yield 9l as a yellow oil (3.5 mg, 10% yield). Compound 9l was consistent by ¹H NMR with previously reported data.¹⁰

(±)-Dimethyl 3-methoxy-1-methyl-4-oxo-8-oxabicyclo[3.2.1]octa-2,6-diene-6,7-dicarboxylate (9m).

To a solution of dimer (6) (20.0 mg, 0.0714 mmol) in CH₂Cl₂ (357 μL) was added dimethyl acetylenedicarboxylate (17.5 μL, 0.143 mmol). After microwave irradiation at 120 °C for 30 m, the reaction mixture was concentrated to yield 9m as a yellow oil (40.4 mg, >98% yield). Compound 9m was consistent by ¹H NMR with previously reported data.¹⁰

(±)-Dimethyl 1-(chloromethyl)-3-methoxy-4-oxo-8-oxabicyclo[3.2.1]octa-2,6-diene-6,7-dicarboxylate(15).

To a solution of dimer (14) (175 mg, 0.501 mmol) in CDCl₃ (2 mL) was added dimethyl acetylenedicarboxylate (7m) (123.2 μL, 1.00 mmol). The reaction was subjected to microwave irradiation at 120 °C for 1 h, and immediately purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5-10% EtOAc in hexanes (10 CV); 10-20% EtOAc in hexanes (10 CV); 20-35% EtOAc in hexanes (8 CV)). Product fractions were concentrated en vacuo to yield 15 as a light yellow oil (235 mg, 83% yield). Compound 15 was consistent by ¹H NMR with previously reported data. ¹⁰

(Larger Scale) (±)-Dimethyl 1-(chloromethyl)-3-methoxy-4-oxo-8-oxabicyclo[3.2.1]octa-2,6-diene-6,7-dicarboxylate(15).

To a solution of dimer (14) (649.5 mg, 1.86 mmol) in CDCl₃ (7.5 mL) was added dimethyl acetylenedicarboxylate (7m) (457 μL, 3.72 mmol). The reaction was subjected to conventional heating in an oil bath at 120 °C for 1 h, and immediately purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5-10% EtOAc in hexanes (10 CV); 10-20% EtOAc in hexanes (10 CV); 20-35% EtOAc in hexanes (8 CV)). Product fractions were concentrated en vacuo to yield 15 as a light yellow oil (883.3 mg, 84% yield). Compound 15 was consistent by ¹H NMR with previously reported data. ¹⁰

(±)-Ethyl 5-(chloromethyl)-7-iodo-3-methoxy-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (18).

To a solution of dimer (14) (44 mg, 0.157 mmol) in CDCl₃ (785 μL) was added dimethyl acetylenedicarboxylate (28 μL, 0.314 mmol). The reaction was subjected to microwave irradiation at 120 °C for 2 h, and immediately purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5-10% EtOAc in hexanes (10 CV); 10-20% EtOAc in hexanes (10 CV); 20-35% EtOAc in hexanes (8 CV)). Product fractions were concentrated en vacuo to yield 15 as a clear oil (43.5 mg, 62% yield). Compound 18 was consistent by ¹H NMR with previously reported data.^12a

(±)-Dimethyl (1S,5S)-3-methoxy-5-methyl-4-oxo-8-oxabicyclo[3.2.1]octa-2,6-diene-6,7-dicarboxylate (21).

To a solution of dimer (20) (28 mg, 0.100 mmol) in CDCl₃ (500 μL, 0.2 M) was added dimethyl acetylenedicarboxylate (7m) (24.5 μL, 0.200 mmol). The reaction was subjected to microwave irradiation at 120 °C for 2 h, and immediately purified by chromatography (Biotage Isolera Prime, SNAP 12g silica gel column, 18cm x 1.8cm, solvent gradient: 0-25% EtOAc in hexanes (500 mL)). Product fractions were concentrated en vacuo to yield 21 as a clear oil (49.1 mg, 87% yield). Compound 21 was consistent by ¹H NMR with previously reported data.¹⁴

(±)-Methyl (1S,5S)-3-methoxy-1-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (22).

To a solution of dimer (20) (44 mg, 0.157 mmol) in CDCl₃ (785 μL, 0.2 M) was added methyl propiolate (7j) (28 μL, 0.314 mmol). The reaction was subjected to microwave irradiation at 120 °C for 3.5 h, and immediately purified by chromatography (Biotage Isolera Prime, SNAP 12g silica gel, 0-25% EtOAc in hexanes (500 mL)). Product fractions were concentrated en vacuo to yield 22 as a clear oil (43.5 mg, 62% yield). Compound 22 was consistent by ¹H NMR with previously reported data.¹⁴

Procedure of Oxidopyrylium Cycloaddition from Salt.

Methyl (1R,5S)-7-iodo-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9d).

To a solution of salt (30.0 mg, 0.1035 mmol) and methyl 3-iodopropiolate (21.7 mg, 0.1035 mmol) in CDCl₃ (0.2 M) was added N,N-diisopropylaniline (20.2 mL, 0.1138). After microwave irradiation at 120 °C for 30 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5-10% EtOAc in hexanes (10 CV); 10-20% EtOAc in hexanes (10 CV); 20-35% EtOAc in hexanes (8 CV)). Product fractions were concentrated to yield 9d as a yellow solid. Compound 9d was consistent by ¹H NMR with previously reported data.^12a

Synthesis of (±)-Methyl (1S,5S)-3-methoxy-5-methyl-2-oxo-7-phenyl-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9n) and (±)-Methyl (1S,5S)-3-methoxy-1-methyl-4-oxo-7-phenyl-8-oxabicyclo[3.2.1]octa-2,6-diene-6-carboxylate (9n’) by cycloaddition with methyl phenyl propiolate.

To a solution of dimer (6) (50.0 mg, 0.178 mmol) in CD₃Cl (715 μL) was added methyl phenylpropiolate (158 μL, 1.07 mmol). After microwave irradiation at 120 °C for 40 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5-10% EtOAc in hexanes (10 CV); 10-20% EtOAc in hexanes (15 CV); 20-35% EtOAc in hexanes (8 CV)). Two products were separated and product fractions were concentrated to yield 9n (18.5 mg, 35% yield) and 9n’ (18.6 mg, 35% yield), both isolated as clear oils. Methyl 3-methoxy-5-methyl-2-oxo-7-phenyl-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9n). Rf = 0.28 in 25% EtOAc in hexanes. IR (thin film, KBr) 3060 (w), 2983 (w), 2952 (w), 1720 (s), 1609 (s), 1442 (w), 1344 (m), 1277 (w), 1220 (m), 1127 (m), 987 (w), 864 (w), 700 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (dd, J = 5.1, 1.9 Hz, 3H), 7.30 – 7.26 (m, 2H), 6.06 (s, 1H), 5.32 (s, 1H), 3.66 (s, 3H), 3.64 (s, 3H), 1.50 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 188.1, 166.3, 162.9, 145.9, 131.7, 129.6, 128.4, 127.6, 127.4, 118.0, 89.1, 86.3, 55.0, 51.9, 22.0. HRMS (ESI-TOF) m/z: [M + Na]⁺ Calc’d for C₁₇H₁₆INaO₄⁺: 323.0890. Found: 323.0888. Methyl 3-methoxy-1-methyl-4-oxo-7-phenyl-8-oxabicyclo[3.2.1]octa-2,6-diene-6-carboxylate (9n’). Rf = 0.30 in 25% EtOAc in hexanes. IR (thin film, KBr) 2980 (w), 2952 (w), 2938 (w), 1709 (s), 1608 (m), 1436 (w), 1343 (m), 1284 (w), 1204 (m), 1135 (m), 1081 (w), 695 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 7.59 – 7.49 (m, 2H), 7.41 – 7.32 (m, 3H), 6.22 (s, 1H), 5.31 (s, 1H), 3.77 (s, 3H), 3.59 (s, 3H), 1.77 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 189.4, 164.9, 149.3, 145.3, 139.5, 131.0, 129.9, 129.0, 128.5, 120.8, 90.0, 88.0, 54.9, 52.0, 22.2. HRMS (ESI-TOF) m/z: [M + Na]⁺ Calc’d for C₁₇H₁₆INaO₄⁺: 323.0890. Found: 323.0890.

Synthesis of Methyl (1S,5S)-3-methoxy-5-methyl-2-oxo-7-phenyl-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9n) by cross-coupling.

To a solution of methyl (1R,5S)-7-iodo-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9d) (42.7 mg, 0.122 mmol) in THF (1.5 mL) was added phenyltributylstannane (47.8 μL, 0.146 mmol) then palladium acetate (2.74 mg, 0.012 mmol). The reaction mixture stirred covered at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure, then dissolved in 40 mL CH₂Cl₂ and extracted with 40 mL of water, 40 mL of saturated sodium bicarbonate solution, and 40 mL of aqueous sodium chloride. Organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to yield 9n (33.1 mg, 90%). Compound 9n was consistent by ¹H NMR with above reported data.

Procedures for Alcohol and Thiol Addition.

Methyl (1S,5S)-7-(benzyloxy)-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (11).

To a solution of (±)-Methyl (1R,5S)-7-iodo-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9d)(83.0 mg, 0.195 mmol) in benzyl alcohol (5.5 mL) was added 4-dimethylaminopryidine (28.6 mg, 0.234 mmol). After microwave irradiation at 80 °C for 30 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5–10% EtOAc in hexanes (10 CV); 10–20% EtOAc in hexanes (10 CV); 20–35% EtOAc in hexanes (8 CV)). Product fractions were concentrated to yield 11 as a yellow oil (41.6 mg, 65% yield). Rf = 0.18 in 15% EtOAc in hexanes. IR (thin film, KBr) 2985 (w), 2951 (w), 2864 (w), 1710 (s), 1635 (m), 1602 (m), 1455 (w), 1371 (m), 1241 (w), 1207 (m), 1164 (m), 1126 (m), 1043 (w), 783 (w), 735 (w), 697 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 7.39 – 7.31 (m, 5H), 6.18 (s, 1H), 5.31 (d, J = 12.2 Hz, 1H), 5.16 (d, J = 12.2 Hz, 1H), 5.01 (s, 1H), 3.77 (s, 3H), 3.56 (s, 3H), 1.74 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 188.9, 167.7, 164.0, 145.1, 135.4, 128.9, 128.7, 127.4, 121.8, 115.4, 85.9, 83.9, 74.6, 5, 51.7, 22.9. HRMS (ESI-TOF) [M + Na]⁺ Calc’d for C₁₈H₁₈NaO₆⁺: 353.0996. Found: 353.0995.

Methyl (1R,5S)-7-(tert-butylthiol)-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (12).

tert-butyl thiol (3.0 mL) was added to a vial of (±)-Methyl (1R,5S)-7-iodo-3-methoxy-5-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate (9d) (37.2 mg, 0.106 mmol) followed by 4-dimethylaminopryidine (15.58 mg, 0.128 mmol). After microwave irradiation at 80 °C for 50 min, the reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 5% EtOAc in hexanes (3 CV); 5–10% EtOAc in hexanes (10 CV); 10–20% EtOAc in hexanes (10 CV); 20–35% EtOAc in hexanes (8 CV)). Product fractions were concentrated to yield 12 as a yellow oil (24.1 mg, 72% yield). Rf = 0.2 in 20% EtOAc in hexanes. IR (thin film, KBr) 2930 (w), 2856 (w), 1738 (s), 1714 (s), 1611 (m), 1460 (w), 1242 (w), 1164 (w), 1126 (w), 1063 (w) 994 (w), 788 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 6.03 (s, 1H), 5.43 (s, 1H), 3.78 (s, 3H), 3.52 (s, 3H), 1.73 (s, 3H), 1.50 (s, 9H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 187.8, 164.0, 151.2, 144.7, 140.4, 119.6, 88.0, 86.4, 54.8, 51.8, 48.7, 32.5, 22.4. HRMS (ESI-TOF) m/z: [M + Na]⁺ Calc’d for C₁₅H₂₀NaO₅S⁺: 335.0924. Found: 390.0924.

Synthesis and Characterization of 2:1 Oxidopyrylium Ylide-to-Alkyne Cycloadducts.

methyl (5aR,10S,10aS)-3,8-dimethoxy-1,6-dimethyl-2,7-dioxo-2,5,6,7,10,10a-hexahydro-1,5:6,10-diepoxyheptalene-5a(1H)-carboxylate (23).

To a solution of bicycle (22) (148.5 mg, 0.6623 mmol) in CDCl₃ (3.3 μL, 0.2 M) was added dimer (20) (98.8 mg, 0.331 mmol) and was subjected to microwave irradiation at 120 °C for 3 h. The reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 20% EtOAc in hexanes (3 CV); 20–70% EtOAc in hexanes (20 CV)). Product fractions were concentrated to yield 23 as a white powder (188.9 mg, 78% yield). For production of crystals for crystal structure analysis, 120 mg of 23 was dissolved in 800 μL of 10% hexane in ethyl acetate, and then crystallized in a freezer (-10 °C) overnight. Melting point (mp) = 177–179 °C. Rf = 0.18 in 30% EtOAc in hexane. IR (thin film, KBr) 2953 (w), 2843 (w), 1736 (m), 1701 (s), 1630 (s), 1457 (w), 1367 (w), 1285 (w), 1254 (w), 1216 (w), 1128 (w), 1078 (m), 947 (w), 872 (w), 825 (w), 790 (w), 733(w), 642 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 6.03 (d, J = 5.2 Hz, 1H), 5.96 (d, J = 5.2 Hz, 1H), 5.13 (d, J = 5.2 Hz, 1H), 5.00 (d, J = 5.2 Hz, 1H), 3.61 (s, 3H), 3.57 (s, 2H), 3.56 (s, 1H), 3.06 (s, 1H), 1.65 (s, 3H), 1.55 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 192.9, 191.0, 169.4, 150.5, 150.4, 116.5, 115.6, 89.8, 88.6, 74.7, 73.9, 72.0, 55.5, 55.4, 54.9, 53.0, 16.2, 15.8. HRMS (ESI-TOF) [M + Na]⁺ Calc’d for C₁₈H₂₀NaO₈⁺: 387.1050. Found: 387.1050.

Methyl (1S,5aS,10aS)-3,8-dimethoxy-5,6-dimethyl-2,9-dioxo-2,5,6,9,10,10a-hexahydro-1,5:6,10-diepoxyheptalene-5a(1H)-carboxylate (24).

To a solution of bicycle (9j) (160.2 mg, 0.715 mmol, 1 equiv) in CDCl₃ (3.6 μL, 0.2 M) was added dimer (6a) (100.2 mg, 0.358 mmol, 1 equiv based on monomeric ylide) and was subjected to microwave irradiation at 120 °C for 3 h. The reaction mixture was purified by chromatography (Biotage Isolera Prime, 10 g silica gel column, solvent gradient: 10% EtOAc in hexanes (3 CV); 10–70% EtOAc in hexanes (25 CV); 50–70% EtOAc in hexanes (10 CV)). Product fractions were concentrated to yield 24 as a white powder (130.16 mg, 50% yield). For production crystals for crystal structure analysis, 100 mg of 24 was dissolved in 700 μL of 10% hexane in ethyl acetate, and then crystallized in a freezer (-10 °C) overnight. Melting point (mp) = 151–154 °C. Rf = 0.22 in 30% EtOAc in hexane. IR (thin film, KBr) 3072 (w), 2953 (w), 2843 (w), 1712 (s), 1623 (s), 1460 (w), 1439 (w), 1368 (w), 1263 (m), 1191 (m), 1168 (w), 1135 (w), 1057 (m), 1015 (w), 988 (w), 914 (w), 873 (w), 731 (m), 699 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 5.92 (s, 1H), 5.85 (s, 1H), 4.78 (d, J = 9.1 Hz, 1H), 4.09 (d, J = 1.2 Hz, 1H), 3.87 (dd, J = 9.1, 1.3 Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 3.54 (s, 2H), 1.75 (s, 3H), 1.53 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 190.3, 190.2, 171.3, 150.6, 147.8, 122.3, 119.5, 84.4, 82.0, 81.6, 78.7, 76.3, 55.2, 55.2, 53.7, 52.6, 24.6, 21.3. HRMS (ESI-TOF) m/z: [M + H]⁺ Calc’d for C₁₈H₂₁O₈⁺: 365.1231. Found: 365.1231.

Supplementary Data.

¹H NMR and ¹³C NMR spectra of 6b, 7c, 7e, 9a-9c, 9e, 9f, 11, 12, 23, 24 and ¹H NMR spectra of 9d, 9g-9n, 9n’ are available free of charge via the Internet at http://pubs.acs.org. X-ray structures can be obtained through Cambridge Crystallographic Data Centre, and are filed under the deposition numbers 2042050 (6b), 2042051 (23), and 2042052 (24).