Synthetic Studies on Perphoramidine and the Communesins: Construction of the Vicinal Quaternary Stereocenters

Abstract

An efficient synthetic strategy for installation of the two vicinal quaternary carbon centers of the communesins is reported. Key steps include the O-allylation/Claisen rearrangement of spirolactone systems, which are formed by tandem intramolecular Heck cyclization/carbonylation. Substituent and solvent effects on the stereochemical outcome of the Claisen rearrangements have been examined. The stereochemical assignment of the allyl spirolactone previously reported as 17 has now been revised to 32, which has the communesin relative configuration at the quaternary carbons. Key C-allyl spirolactone 59 bearing functional handles required for the communesin core has been constructed with a 9.8:1 diastereomer ratio.

Introduction and Background

About a decade ago, Numata, et al. reported two unusual natural products isolated from a Penicillium mold found growing on the marine alga Enteromorpha intestinalis.¹ The unique structures of these two compounds, communesin A (1) and communesin B (5), were established by spectroscopic analysis (Figure 1). An interesting feature of these complex, highly functionalized polycyclic compounds is the two contiguous quaternary centers at C-7,8. Communesins A and B were found to have in vitro cytotoxic activity against P-388 lymphoid leukemia cells. In 2001, Hemscheidt and coworkers described a metabolite called nomofungin, which was isolated from an unidentified fungus growing on the bark of Ficus microcarpa in Hawaii.² This material was found to have cytotoxic activity against LoVo and KB cells, which was shown to be due to the ability of the metabolite to cause microfilament disruption. The metabolite was initially proposed to have structure 9, but it was later found that this assignment was in error, and that nomofungin is actually communesin B (5). It should be noted, however, that the Hemscheidt work did serve to establish both the configuration at C-21 of 5 as well as the absolute configuration of the molecule, which were not originally determined by the Numata group. Recently, several other modified communesin derivatives have been isolated³ including communesin C (6),⁴ D (7), E (2), F (8), G (3) and H (4) (Figure 1). Some of these new compounds were found to have significant biological activity. For example, communesins D, E and F are insecticidal,^3b and communesins C and D are moderately active against various leukemia cell lines.^3a

Figure 1.

Structures of the Communesins and Perophoramidine

In 2002, Ireland reported the isolation of a congeneric compound, perophoramidine, from the marine ascidian Perophora namei collected in the Philippines.⁵ Based mainly upon NMR spectral analysis, this metabolite was assigned the hexacyclic structure 10, which contains some unique features including two amidine units, two chlorines and a bromine. Like the communesins, perphoramidine has two adjacent quaternary carbons at C-4,20, but interestingly, the natural products have the opposite relative stereochemistry at these centers. Perphoramidine has cytotoxicity against the HCT116 colon carcinoma cell line, and also induces apoptosis via PARP cleavage.

Perophoramidine and the communesins have closely related structures and presumably arise via a common biogenetic pathway.⁶ Some model studies on biogenetically-patterned synthesis of the communesin/perophoramidine ring system by the Stoltz,⁷ and Qin⁸ groups have appeared, as well as a model hetero Diels-Alder-based approach by Crawley and Funk.⁹ Moreover, Fuchs and Funk have completed an elegant, biogenetically-inspired total synthesis of racemic perophoramidine.¹⁰ In addition, Rainier and coworkers recently described a nice total synthesis of dehaloperophoramidine.¹¹

In 2003, we disclosed some preliminary results on a Heck-based strategy for total synthesis of these alkaloids.¹² In this work, it was found that acrylamides 11 and 12 underwent tandem intramolecular Heck cyclization/carbonylation¹³ to afford E/F-lactam esters 13 and 14, respectively, in good yields (Scheme 1).These compounds could then be cleanly cyclized to lactones 15 and 16 after removal of the TBS protecting groups. As part of these studies, we reported that lactone 16 could be deprotonated and alkylated with allyl bromide to afford a single product to which we assigned the perophoramidine relative stereochemistry at the quaternary centers as shown in 17 via ¹H NMR NOESY experiments. Based upon the subsequent studies discussed in this paper, we have found that the configurational assignment of this alkylation product is in fact incorrect (vide infra).

Scheme 1.

Results and Discussion

Because we believed that we had been able to efficiently access the requisite perophoramidine C-4,20 quaternary carbon stereochemistry, work was undertaken on synthesis of a Heck substrate bearing the appropriate C-ring substituents. Using a two-step procedure developed by Coe¹⁴ heating commercially available 4-bromo-2-nitrotoluene (18) in the presence of N,N-dimethylformamide dimethyl acetal and pyrrolidine in DMF generated the known enamine 19,¹⁵ which was oxidatively cleaved using NaIO₄ in THF/H₂O to afford the desired benzaldehyde 20 in 93 % yield over two steps (Scheme 2). Wittig olefination of the aldehyde 20 with readily available ylide 21¹⁶ in refluxing toluene generated the benzylidene lactone 22 in excellent yield. Ring opening of this unsaturated lactone with the aluminium amide reagent¹⁷ derived from the commercially available aniline 23 produced the nitro acrylamide 24 in quantitative yield. Subsequent protection of the primary alcohol moiety of 24 as its TBS ether and alkylation of the amide nitrogen using NaH/MOMCl resulted in the N-MOM acrylamide 25 in 84 % yield over the two steps.

Scheme 2.

To continue the synthesis, the Heck reaction/carbonylation sequence with substrate 25 was examined, leading to the desired lactam ester 28 as a mixture of diastereomers along with the reductive Heck product 27¹⁸ and ester 26 derived from uncyclized starting iodide (Scheme 3). The ratios of these products varied widely depending upon the specific reaction conditions (Pd source, ligand, solvent, base, etc) used for the Heck/carbonylation step. However, the formation of the desired cyclization products 28 was optimal under the conditions shown in the scheme. Although compounds 26-28 could be separated by chromatography and characterized spectrally (see Experimental Section), it was found best to simply expose the crude reaction mixture to TBAF, leading to lactone 29 (4:1 diastereomeric mixture) in 51% isolated overall yield from substrate 25.

Scheme 3.

This mixture of lactones was deprotonated with sodium hydride in DMF at room temperature, upon which allyl iodide was added, and the mixture was heated at in an oil bath at 90 °C. This reaction produced a single crystalline alkylation product in excellent yield whose structure was established unambiguously by X-ray analysis. We were quite surprised to find, however, that the allylated lactone has the communesin stereochemistry shown in 30 rather than the expected perophoramidine configuration at the quaternary centers.

In view of this unexpected stereochemical result, we decided to reexamine the model system shown in Scheme 1.¹² Thus, the lactone product from C-allylation of 16¹⁹ was exposed to the reagent derived from ammonium chloride and trimethylaluminum²⁰ to afford hydroxy amide 32 (Scheme 4). This material provided crystals suitable for X-ray analysis, which established that the allylation product of 16 in fact has the communesin stereochemistry shown in 31, and is not the perophoramidine diastereomer 17 which had originally been asssigned.

Scheme 4.

Since the experiments outlined above suggested that we might be able to access the quaternary carbons of the communesins stereoselectively, we turned to an investigation of systems bearing useful C and F aromatic ring substitutents for synthesis of this group of metabolites. Using methodology similar to that described above, Heck substrate 33 was prepared in a few steps. It was found, however, that under most conditions, the Heck/carbonylation sequence led to the reduced compound 35 as the major or sole product rather than the desired ester 34 (Scheme 5). After substantial experimentation, it was possible at best to produce equal amounts of 34 and 35 along with a small quantity of ester 36 using the conditions shown in the scheme. It should be noted that a similar tendency for intramolecular reductive Heck reactions has been observed by Denmark and Schnute when using nitroolefins.^18a The rationale presented for these results would also apply to our cases involving nitroarenes 25 and 33. Since the desired transformation of Heck substrate 33 to ester 34 was not synthetically useful, we turned to an alternative system lacking the nitro group which was expected to be more amenable to the requisite Heck/carbonylation process.

Scheme 5.

One solution we considered was to install the required C-ring nitrogen via a late-stage Curtius rearrangement of a system bearing a suitable carbon substituent. Thus, Heck substrate 43 was constructed via the chemistry outlined in Scheme 6. Known benzyl alcohol 37²¹ was first converted to the benzyl ether 38, and the nitro group was subsequently reduced to afford aniline 39. Conversion of this amine to the corresponding aluminum amide¹⁷ followed by reaction with benzylidene lactone 40²² then led to amide 41 in high yield. The alcohol functionality of 41 was protected as the TBS ether 42, and the amide nitrogen was methylated to yield the desired substrate 43. This compound underwent smooth tandem Heck cyclization/carbonylation to produce the desired lactam ester 44 as a single stereoisomer whose configuration was not proven, but by analogy with 13/14¹² is assumed to be as shown.

Scheme 6.

Treatment of silyl ether ester 44 with TBAF led to desilylation and in situ cyclization to lactone 45, which was produced as a 2:1 mixture of diastereomers (Scheme 7). During work with spirolactone 45 it was discovered that allylation of the corresponding enolate does not actually involve a direct C-alkylation. Thus, treatment of 45 with sodium hydride in DMF along with allyl iodide at room temperature affords the chromatographically isolable ketene acetal 46 in 57% yield (71% based on recovered lactone, formed via hydrolysis of 46 during purification). Ketene acetal 46 appears to exist as a 2:1 mixture of atropisomers, as can be seen by ¹H NMR. It was found that heating ketene acetal 46 at 130 °C in either DMF or toluene led to a Claisen rearrangement producing a separable mixture of diastereomeric C-allylation products 47 and 48, with a slightly better stereoselectivity in the former solvent. The stereochemistry of the minor isomer was established by ¹H NMR NOESY analysis to have the configuration shown in 48 (see Supporting Information). It should be noted that although we cannot isolate the ketene acetals in the two alkylations described above, we believe these processes also involve an initial O-allylation followed by a Claisen rearrangement (vide infra).

Scheme 7.

In view of the disappointing level of stereoselectivity in the alkylation of lactone 45, we decided to explore an alternative system with different substitution in the F-ring with the hope of improving this key step. Known, easily prepared phenol 49²³ was therefore first converted to the carbamate 50 and the nitro group was reduced to yield the aniline 51 (Scheme 8). Condensation of this intermediate with benzylidene lactone 40 then produced amide 52 in excellent overall yield. The alcohol functionality of 52 was protected as the MOM ether 53, and the amide nitrogen was methylated to afford 54. The tandem Heck cyclization/carbonylation of this substrate proceeded cleanly to generate the requisite lactam ester 55 as a single stereoisomer assumed to be as indicated.

Scheme 8.

The MOM protecting group of 55 was next removed with methanolic HCl to give the desired spirolactone 57 along with some of the uncyclized hydroxy ester 56 (Scheme 9). O-Allylation of the spirolactone as was done with 45 gave the ketene acetal 58, which in this case was again a 2:1 mixture of atropisomers. Heating 58 in DMF at 110°C did not show improved stereoslectivity over the system in Scheme 7, leading to a 2.3:1 mixture of stereoisomers 59 and 60 in good yield. We have been unable to definitively establish the configurations of these diastereomers, but by analogy with the three cases described above we believe the major isomer has the communesin configuration shown in 59. We were pleased to find, however, that heating ketene acetal 58 in toluene induced a Claisen rearrangement, which led to a synthetically useful 9.8:1 mixture of 59:60.

Scheme 9.

To rationalize the high stereoselectivity shown in the first two lactone allylations (cf. Schemes 3 and 4), we considered four possible half-chair transition state conformations for the Claisen rearrangement of the corresponding ketene acetal intermediates (Figure 2). The carbonyl group of the oxy-indole moiety (EF rings) could occupy either pseudo-axial (A) or pseudo-equatorial (E) positions. In addition, each transition state has two possible atropisomers (α and β) derived from the position of the substituent (R) at C(10) in the C-ring aryl moiety. It seems reasonable that the allyl group approaches the ketene acetal double bond from the face opposite to this substituent in order to avoid severe steric interactions.²⁴ Since axial attack of the allyl group is more favorable stereoelectronically,²⁵ transition states A-β and E-α are expected to be preferable to conformations A-α and E-β. In addition, it appears from inspection of models that the aryl group of the oxy-indole moiety blocks attack of the allyl substituent more effectively than does the carbonyl group, and therefore transition state E-α would seem to be favored over A-β. Steric interactions and/or electronic repulsions between the carbonyl group and the substituent R (OMe or NO₂) may additionally destabilize conformation A-β.

Figure 2.

Models for Allylation of Lactones 16 and 29

On the other hand, allylation of the lactones bearing substituents (R”) at the C-12a position of the oxy-indole moiety showed lower stereoselectivity than did the above two cases (cf. Schemes 7 and 9). As shown in Figure 3, substituent R” causes substantial steric interactions not only with substituent R in E-α but also with the allyl group in A-β. As noted above, NMR analysis shows that there is little preference for one atropisomer in ketene acetals 46 and 58 at room temperature. These steric interactions presumably slow the Claisen rearrangements of the latter two ketene acetals, making these species more easily isolable, and also lead to generally low stereoselectivities. At this point, however, we are unable to explain why we observe high stereoselectivity in the rearrangement of ketene acetal 58 in toluene.

Figure 3.

Transition State Models for Claisen Rearrangement of Ketene Acetals 46 and 58

In conclusion, we have developed a concise strategy to construct systems bearing the two quaternary centers of the communesins. Key steps in this approach involve an intramolecular tandem Heck cyclization/carbonylation, followed by a stereoselective O-allylation/Claisen rearrangement of a spirolactone enolate. We are currently attempting to utilize this methodology in a total synthesis of the communesins.

Experimental Section

3-(4-Bromo-2-nitrophenyl)-2-[2-(tert-butyldimethylsilanyloxy)ethyl]-N-(2,4-dichloro-6-iodophenyl)-N-methoxymethylacrylamide (25)

N,N-Dimethylformamide dimethyl acetal (7.25 mL, 54.6 mmol) and pyrrolidine (4.50 mL, 53.9 mmol) were added to 4-bromo-2-nitrotoluene (18, 9.66 g, 44.7 mmol, TCI) in DMF (25 mL). The reaction mixture was heated at 110 °C for 4 h to give a dark red solution. The reaction mixture was cooled to rt and the volatile organics were removed under reduced pressure resulting in the known enamine 19¹⁵ as a mass of red crystals.

The above enamine was dissolved in THF (30 mL) and added slowly to NaIO₄ (28.9 g, 135 mmol) in 50% aqueous THF (200 mL) while maintaining the temperature below 20 °C. The reaction mixture was rapidly stirred for an additional 2 h and the insoluble salts were removed by filtration and washed with EtOAc. The combined organic filtrate was washed with water, dried (MgSO₄) and concentrated. The crude product was purified by flash silica gel chromatography (1:9 EtOAc: hexanes) to afford the desired 4-bromo-2-nitrobenzaldehyde (20, 9.58 g, 93%) as a yellow solid (mp 93-95 °C; lit. mp 95 °C²⁶). IR (KBr) 3085, 2912, 2863, 1812, 1691, 1525 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 10.38 (d, J = 0.6 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 7.93 (ddd, J = 8.3, 1.8, 0.6 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H); ¹³C NMR (75 MHz, CDCl³) δ 187.2, 150.1, 137.4, 131.1, 129.9, 128.4, 127.8.

3-(Triphenyl-λ⁵-phosphanylidene)dihydrofuran-2-one (21, 4.62 g, 13.3 mmol)¹⁶ was added to nitrobenzaldehyde 20 (3.07 g, 13.3 mmol) in toluene (70 mL). The reaction mixture was heated at reflux for 2 h and cooled to rt. The volatile organics were removed under reduced pressure. The crude product was absorbed onto silica gel and purified by flash silica gel column chromatography (1:2 EtOAc: hexanes) to afford the benzylidene lactone 22 (3.96 g, 100%) as a light brown solid (mp 129-131 °C). IR (KBr) 2929, 2867, 1762, 1523 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J = 1.8 Hz, 1H), 7.82 (dd, J = 8.3, 1.8 Hz, 1H), 7.78 (t, J = 2.9 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 4.46 (t, J = 7.2 Hz, 2H), 3.07 (dd, J = 7.2, 3.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 170.8, 148.8, 136.7, 131.3, 129.3, 129.0, 128.4, 123.5, 65.7, 26.9.

2,4-Dichloro-6-iodoaniline (23, 11.1 g, 39 mmol, TCI) was dissolved in benzene (60 mL) and slowly added via syringe to AlMe₃ (2.0 M in hexanes, 21 mL, 42 mmol) in benzene (10 mL) at 0 °C. After stirring the mixture for an additional 45 min, the benzylidine lactone 22 (10.4 g, 35 mmol) dissolved in CH₂Cl₂ (60 mL) was slowly added via syringe. The reaction mixture was heated at 65 °C for 15 h then cooled to 0 °C. 1 N HCl (50 mL) was slowly added dropwise and the reaction mixture was stirred for an additional 30 min. The organic layer was removed and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO₄ and concentrated in vacuo. The crude oil was absorbed onto silica gel and purified by flash silica gel chromatography (1:2 EtOAc:hexanes) to afford the bromo dichloro acrylamide 24 (16.5 g, 81%) as a foam. ¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.80-7.83 (m, 2H), 7.67 (s, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 3.73-3.80 (br m, 2H), 2.63 (t, J = 5.8 Hz, 2H), 2.48 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 167.9, 148.2, 137.6, 137.3, 137.0, 135.1, 134.8, 133.2, 132.8, 132.4, 130.3, 128.4, 122.8, 100.2, 61.5, 31.4.

TBSCl (5.11 g, 33.9 mmol) was added in a single portion to acrylamide 24 (16.3 g, 27.8 mmol) and imidazole (4.20 g, 61.7 mmol) in DMF (30 mL) and the mixture was stirred at rt for 60 min. Water was added and the aqueous phase was extracted with ether. The combined organic extracts were dried over MgSO₄ and concentrated under reduced pressure to afford the desired TBS ether (19.5 g, 100%) as an oil, which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.74-7.77 (m, 2H), 7.70 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 3.75 (t, J = 5.6 Hz, 2H), 2.67 (t, J = 5.6 Hz, 2H), 0.82 (s, 9H), 0.02 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 167.3, 148.4, 137.9, 137.7, 136.9, 135.9, 134.7, 133.6, 133.4, 132.8, 130.7, 130.4, 128.4, 122.7, 100.8, 62.8, 31.8, 26.3, 18.7, −5.0; HRMS-APCI: [M+H]⁺ calcd for C₂₃H₂₆BrCl₂IN₂O₄Si 698.9340; found, 698.9366.

NaH (60 % dispersion in mineral oil, 1.33 g, 33.2 mmol) was added to the TBS ether (19.5 g, 27.8 mmol) in THF (140 mL) at 0 °C. The solution was stirred for an additional 20 min at this temperature before MOMCl (3.10 mL, 41.6 mmol) was introduced. The reaction solution was warmed to rt and stirred for 12 h. Saturated aqueous NaHCO₃ (100 mL) was slowly added and the organic layer was removed. The aqueous phase was extracted with EtOAc. The combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (1:4 EtOAc: hexanes) to afford the N-MOM amide 25 (17.4 g, 84%) as an oil, which solidified upon standing. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (m, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.75−7.78 (m, 2H), 7.65 (s, 1H), 7.54 (d, J = 2.1 Hz, 1H), 5.10 (AB_q, J = 67.1, 10.5 Hz, 2H), 3.81−3.85 (m, 2H), 3.28 (s, 3H), 2.71 (br. m, 2H), 0.92 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 179.4, 150.8, 137.4, 135.6, 135.1, 133.8, 130.7, 129.3, 128.9, 128.1, 123.3, 121.8, 116.9, 72.0, 59.5, 56.6, 52.8, 40.2, 39.6, 26.1, −5.4; HRMS-APCI: [M+H]⁺ calcd for C₂₅H₃₀BrCl₂IN₂O₅Si 742.9602; found, 742.9572.

(4-Bromo-2-nitrophenyl)-{3-[2-(tert-butyldimethylsilanyloxy)-ethyl]-5,7-dichloro-1-methoxymethyl-2-oxo-2,3-dihydro-1H-indol-3-yl}-acetic Acid Methyl Ester (28)

To a solution of N-MOM amide 25 (27.4 mg, 0.037 mmol) in DMA (2.0 mL) and MeOH (0.4 mL) were added Pd₂(dba)₃ (3.4 mg, 0.004 mmol), P(o-Tol)₃ (4.5 mg, 0.015 mmol), n-Bu₄NBr (23.7 mg, 0.074 mmol) and NEt₃ (26 μL, 0.187 mmol). The mixture was stirred at 85 °C under a CO atmosphere (1 atm) for 21 h. The catalyst was removed by filtration and washed with EtOAc. The filtrate was washed with water and brine, dried over Na₂SO₄ and concentrated in vacuo. The crude mixture was used for the next step without further purification. For analytical purposes the compounds were separated by preparative TLC (1:5 EtOAc:hexanes). More polar major diastereomer of 28 (pale yellow oil): IR (film) 2946, 2860, 1735, 1536, 1461, 1095 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J = 2.1 Hz, 1H), 7.70 (dd, J = 8.5, 2.1 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 5.37, 5.30 (ABq, J = 10.5 Hz, 2H), 5.09 (s, 1H), 3.65 (s, 3H), 3.42 (s, 3H), 3.24 (td, J = 6.2, 2.6 Hz, 2H), 2.25 (td, J = 6.2. 3.7 Hz, 2H), 0.72 (s, 9H), −0.17 (d, J = 2.4 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 178.4, 170.2, 151.3, 138.3, 135.6, 133.5, 133.0, 130.9, 128.5, 128.4, 126.8, 124.0, 123.2, 117.2, 72.6, 59.4, 57.1, 53.1, 52.8, 50.4, 37.2, 26.1, 18.6, −5.3, −5.4; HRMS-ES: [M+H]⁺ calcd for C₂₇H₃₄BrCl₂N₂O₇Si 675.0696; found, 675.0712. Less polar minor diastereomer of 28 (pale yellow oil): IR (film) 2946, 2860, 1735, 1536, 1461 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.5, 2.1 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 5.24, 5.19 (ABq, J = 10.5 Hz, 2H), 5.16 (s, 1H), 3.64 (s, 3H), 3.29 (t, J = 6.2 Hz, 2H), 3.22 (s, 3H), 2.22−2.12 (m, 2H), 0.72 (s, 9H), −0.17 (d, J = 2.2 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 178.6, 170.4, 151.4, 138.3, 135.7, 133.7, 133.5, 131.2, 129.0, 128.1, 127.0, 124.3, 123.0, 116.9, 72.3, 59.3, 56.8, 53.3, 53.2, 51.0, 39.3, 26.1, 18.6, −5.3, −5.4; HRMS-ES: [M+H]⁺ calcd for C₂₇H₃₄BrCl₂N₂O₇Si 675.0696; found, 675.0672.

3-(4-Bromo-2-nitrobenzyl)-3-[2-(tert-butyldimethylsilanyloxy)-ethyl]-5,7-dichloro-1-methoxymethyl-1,3-dihydroindol-2-one (27)

Pale yellow oil. IR (film) 2935, 2860, 1730, 1536, 1461, 1348 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.3, 2.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 5.19 (s, 2H), 3.80, 3.41 (ABq, J = 13.7 Hz, 2H), 3.37 (m, 2H), 3.32 (s, 3H), 2.32 (dt, J = 13.8, 6.9 Hz, 1H), 2.08 (dt, J = 13.8, 5.5 Hz, 1H), 0.75 (s, 9H), − 0.14 (d, J = 3.4 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 179.4, 150.8, 137.3, 135.7, 135.1, 133.8, 130.6, 129.3, 128.9, 128.1, 123.4, 121.8, 116.9, 72.0, 59.5, 56.5, 52.8, 40.3, 39.6, 26.1, 18.5, −5.36, −5.37; HRMSES: [M+H]⁺ calcd for C₂₅H₃₂BrCl₂N₂O₅Si 617.0641; found, 617.0659.

2-{[2-(4-Bromo-2-nitrobenzylidene)-4-(tert-butyldimethylsilanyloxy)-butyryl]-methoxymethylamino}-3,5-dichlorobenzoic Acid Methyl Ester (26)

Yellow solid (mp 125-126 °C). IR (film) 2946, 2860, 1730, 1665, 1531, 1278 cm⁻¹; ¹H NMR (360 MHz, CDCl₃, 5:1 atropisomer mixture) δ 8.30 (d, J = 1.8 Hz, 1H, major), 8.09 (d, J = 1.7 Hz, 1H, minor), 7.89 (d, J = 2.4 Hz, 1H, major), 7.85 (d, J = 2.4 Hz, 1H, minor), 7.77 (d, J = 1.8 Hz, 1H, minor), 7.75−7.69 (m, 3H, major), 7.67 (m, 1H, minor), 7.46 (s, 1H, major), 7.22 (d, J = 8.2 Hz, 1H, minor), 7.00 (s, 1H, minor), 5.23, 4.85 (ABq, J = 10.5 Hz, 2H, minor), 5.20, 4.79 (ABq, J = 10.2 Hz, 2H, major), 3.92 (s, 3H, minor), 3.89 (s, 3H, major), 3.84 (t, J = 6.0 Hz, 2H, major), 3.74 (m, 2H, minor), 3.46 (s, 3H, minor), 3.21 (s, 3H, major), 2.68 (m, 2H, major), 2.41 (m, 2H, minor), 0.90 (s, 9H, major), 0.83 (s, 9H, minor), 0.07 (s, 6H, major), -0.02 (s, 6H, minor); ¹³C NMR (75 MHz, CDCl₃) δ 171.7, 164.7, 148.5, 137.6, 136.6, 136.4, 136.2, 134.9, 134.1, 133.8, 133.1, 130.9, 130.5, 129.4, 128.2, 122.4, 83.3, 61.0, 56.8, 53.3, 33.4, 26.3, 18.7, −5.0; HRMS-ES: [M+H]⁺ calcd for C₂₇H₃₄BrCl₂N₂O₇Si 675.0696; found, 675.0665.

Synthesis of Spirolactone 29

To a stirred solution of the above crude mixture of Heck/carbonylation adducts in THF (3.0 mL) was added TBAF (0.072 mL, 1.0 M in THF, 0.072 mmol) at 0 °C. The reaction mixture was warmed to rt and stirred overnight. The mixture was diluted with EtOAc and saturated aqueous NH₄Cl. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:4 EtOAc:hexanes) to give the spiro lactone 29 (9.9 mg, 51% over 2 steps) as a pale yellow oil. IR (film) 2924, 1725, 1531, 1455, 1348 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, 4:1 diastereomeric mixture) δ 7.95 (s, 1H, minor), 7.79 (d, J = 1.9 Hz, 1H, major), 7.61 (dd, J = 8.5, 1.9 Hz, 1H, major), 7.45 (dd, J = 8.6, 1.8 Hz, 1H, minor), 7.41 (d, J = 8.5 Hz, 1H, major), 7.34 (s, 1H, minor), 7.25 (d, J = 1.8 Hz, 1H, major), 7.22 (s, 1H, minor), 7.12 (d, J = 1.7 Hz, 1H, major), 6.68 (d, J = 8.5 Hz, 1H, minor), 5.50 (br s, 1H, minor), 5.44 (s, 1H, major), 5.30 (s, 1H, minor), 5.21, 5.18 (ABq, J = 10.3 Hz, 2H, major), 5.13 (s, 1H, minor), 5.06 (dt, J = 11.5, 4.2 Hz, 1H, major), 4.85 (m, 1H, minor), 4.72 (m, 1H, minor), 4.64 (dt, J = 11.7, 4.7 Hz, 1H, major), 3.23 (s, 3H, major), 2.99 (s, 3H, minor), 2.59-2.52 (m, 1H, major and minor), 2.26 (m, 1H, minor), 2.19 (dt, J = 14.6, 4.0 Hz, 1H, major); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 168.8, 150.6, 136.3, 136.2, 134.5, 132.5, 131.8, 130.5, 127.9, 126.6, 123.1, 122.7, 117.6, 72.0, 65.2, 56.8, 52.7, 46.8, 33.2; HRMS-ES: [M+Na]⁺ calcd for C₂₀H₁₅BrCl₂N₂NaO₆ 550.9388; found, 550.9388.

Allylation of Spirolactone 29

To a stirred suspension of spiro lactone 29 (102 mg, 0.191 mmol) and NaH (9.2 mg, 60% dispersion in mineral oil, 0.230 mmol) in DMF (2.0 mL) was added allyl iodide (0.026 mL, 0.287 mmol) at 0 °C. The mixture was stirred at rt for 1 h and heated at 90 °C for 7 h. The reaction mixture was cooled to rt, diluted with saturated aqueous NH₄Cl and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:2 EtOAc:hexanes) to give the allyl lactone 30 (95 mg, 87%) as a yellow solid (mp 157-158 °C). Recrystallization from EtOAc provided X-ray quality crystals of 30. IR (film) 2924, 1725, 1536, 1461, 1359 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 8.6, 2.0 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.81 (d, J = 1.8 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 5.51-5.34 (m, 4H), 4.99 (d, J = 17.2 Hz, 1H), 4.94 (d, J = 10.4 Hz, 1H), 4.61 (dt, J = 11.6, 4.0 Hz, 1H), 3.44 (s, 3H), 3.35 (dd, J = 15.2, 6.3 Hz, 1H), 2.99 (ddd, J = 15.2, 10.9, 4.3 Hz, 1H), 2.86 (dd, J = 15.4, 7.1 Hz, 1H), 2.16 (dt, J = 14.7, 3.0 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 178.3, 168.0, 150.8, 136.1, 134.8, 134.3, 132.7, 132.6, 132.4, 131.1, 129.0, 128.0, 125.1, 122.1, 120.3, 116.9, 72.3, 65.0, 57.1, 54.4, 54.2, 44.1, 31.5; HRMS-ES: [M+Na]⁺ calcd for C₂₃H₁₉BrCl₂N₂NaO₆ 590.9701; found, 590.9697.

2-[5,7-Dichloro-3-(2-hydroxyethyl)-1-methoxymethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(2-methoxyphenyl)-pent-4-enoic Acid Amide (32)

To a stirred suspension of NH₄Cl (229 mg, 4.28 mmol) in toluene (5 mL) was slowly added Me₃Al (2.30 mL, 2.0 M in hexanes, 4.60 mmol) at 0 °C. After the addition was complete, the reaction mixture was allowed to warm to rt and was stirred for 1.5 h. To a solution of lactone 31 (291 mg, 0.61 mmol) in toluene (15 mL) was added the above aluminum amide reagent at rt, and the mixture was heated at 80 °C overnight. The reaction mixture was cooled to rt and was carefully quenched with 1N HCl. The organic layer was separated and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (10:10:1 CH₂Cl₂:EtOAc:MeOH) to give the amide 32 (286 mg, 95%) as a yellow solid (mp 179-180 °C). Recrystalization from EtOAc provided X-ray quality crystals of 32. IR (film) 3342, 1708, 1672, 1461 cm⁻¹; ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ 7.85 (br s, 1H), 7.14 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.54 (br s, 1H), 5.87 (m, 1H), 5.51 (br s, 1H), 5.17 (d, J = 16.8 Hz, 1H), 5.03 (d, J = 10.0 Hz, 1H), 4.65 (br s, 2H), 3.55-2.89 (m, 10H), 2.42 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃+CD₃OD) δ 180.2, 174.7, 156.9, 136.9, 134.6, 134.0, 131.1, 129.6, 129.1, 128.2, 127.3, 124.7, 119.4, 118.4, 114.6, 110.7, 71.3, 58.8, 58.4, 57.0, 56.3, 54.1, 37.3, 34.7; HRMS-ES: [M+H]⁺ calcd for C₂₄H₂₇Cl₂N₂O₅ 493.1297; found, 493.1285.

1-Benzyloxymethyl-2-iodo-3-nitrobenzene (38)

To a stirred solution of (2-iodo-3-nitrophenyl)-methanol (37)21 (0.86 g, 3.08 mmol) in CH₂Cl₂ (6 mL) and cyclohexane (10 mL) was added benzyl 2,2,2-trichloroacetimidate (1.14 mL, 6.13 mmol), followed by TfOH (0.03 mL, 0.34 mmol). The mixture was stirred at rt for 9 h and then diluted with saturated aqueous NaHCO₃ and EtOAc. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:15 EtOAc:hexanes) to give benzyl ether 38 (1.06 g, 93%) as a yellow oil. IR (film) 2871, 1712, 1526, 1350 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 7.6 Hz, 1H), 7.58 (dd, J = 7.9, 1.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.44−7.32 (m, 5H), 4.71 (s, 2H), 4.63 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 144.6, 137.9, 131.6, 129.4, 129.0, 128.4, 128.2, 123.9, 89.1, 76.9, 73.5; HRMS-EI: [M]⁺ calcd for C₁₄H₁₂INO₃ 368.9862; found, 368.9866.

3-Benzyloxymethyl-2-iodophenylamine (39)

To a solution of the nitrobenzene 38 (1.05 g, 2.83 mmol) in EtOH (10 mL) and glacial acetic acid (10 mL) was added iron powder (0.79 g, 14.15 mmol). The mixture was heated at 60 °C for 3 h and then cooled to rt. The mixture was diluted with iced water and carefully neutralized with solid Na₂CO₃. The resulting solution was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:5 EtOAc:hexanes) to give the aniline 39 (0.83 g, 97%) as a colorless oil. IR (film) 3447, 3357, 2859, 1610, 1463 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.45-7.29 (m, 5H), 7.14 (t, J = 7.7 Hz, 1H), 6.89 (d, J = 6.9 Hz, 1H), 6.72 (dd, J =7.9, 0.9 Hz, 1H), 4.65 (s, 2H), 4.56 (s, 2H), 4.00 (bs, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 147.4, 141.8, 138.6, 129.2, 128.9, 128.3, 128.1, 119.4, 114.5, 88.6, 77.2, 73.0; HRMS-ES: [M+H]⁺ calcd for C₁₄H₁₅INO 340.0198; found, 340.0195.

N-(3-Benzyloxymethyl-2-iodophenyl)-4-hydroxy-2-[2-(4-methoxyphenoxymethyl)-benzylidene]-butyramide (41)

To a stirred solution of the aniline 39 (0.69 g, 2.03 mmol) and lactone 40²² (0.57 g, 1.84 mmol) in CH₂Cl₂ (30 mL) was added AlMe₃ (1.80 mL, 2.0 M in hexane, 3.60 mmol) at 0 °C. The mixture was warmed to rt, stirred overnight and then poured into ice cold aqueous NH₄Cl. The aqueous layer was extracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 EtOAc:hexanes) to give the amide 41 (1.16 g, 97%) as a white solid (mp 126.5-127 °C). IR (film) 3368, 2859, 1661, 1509, 1226 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 8.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.68 (s, 1H), 7.54 (m, 1H), 7.51−7.28 (m, 10H), 6.94−6.89 (m, 2H), 6.84−6.80 (m, 2H), 5.03 (s, 2H), 4.64 (s, 2H), 4.55 (s, 2H), 3.79 (t, J = 5.8 Hz, 2H), 3.74 (s, 3H), 2.77 (t, J = 5.8 Hz, 2H), 2.70 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 168.9, 154.6, 153.1, 141.9, 138.64, 138.61, 138.3, 135.5, 135.3, 134.3, 129.9, 129.6, 129.3, 129.00, 128.95, 128.9, 128.3, 125.9, 122.5, 116.3, 115.2, 96.0, 77.1, 73.1, 69.7, 62.5, 56.2, 31.9; HRMS-ES: [M+H]⁺ calcd for C₃₃H₃₃INO₅ 650.1404; found, 650.1404.

N-(3-Benzyloxymethyl-2-iodophenyl)-4-(tert-butyldimethylsilanyloxy)-2-[2-(4-methoxyphenoxymethyl)-benzylidene]-butyramide (42)

To a solution of the amide 41 (568 mg, 0.87 mmol) and imidazole (178 mg, 2.62 mmol) in DMF (8.7 mL) was added TBSCl (316 mg, 2.09 mmol). The reaction mixture was stirred at rt overnight and then diluted with EtOAc. The solution was washed with water and brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:3 EtOAc:hexanes) to give the TBS ether 42 (641 mg, 96%) as a colorless oil. IR (film) 2950, 2848, 1678, 1509, 1226, 1090 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (s, 1H), 8.2 (dd, J = 8.0, 1.4 Hz, 1H), 7.74 (s, 1H), 7.56 (m, 1H), 7.44−7.29 (m, 9H), 6.94−6.91 (m, 2H), 6.85−6.82 (m, 2H), 5.03 (s, 2H), 4.65 (s, 2H), 4.59 (s, 2H), 3.9 (t, J = 6.1 Hz, 2H), 3.76 (s, 3H), 2.84 (t, J = 6.1 Hz, 2H), 0.87 (s, 9H), 0.03 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 167.7, 154.5, 153.3, 141.8, 139.0, 138.5, 138.3, 135.7, 135.2, 134.1, 129.9, 129.3, 129.2, 128.9, 128.8, 128.5, 128.23, 128.21, 125.6, 122.4, 116.4, 115.1, 95.9, 77.2, 73.1, 69.4, 62.5, 56.1, 31.8, 26.4, 18.8, −4.9; HRMS-ES: [M+H]⁺ calcd for C₃₉H₄₇INO₅Si 764.2268; found, 764.2271.

N-(3-Benzyloxymethyl-2-iodophenyl)-4-(tert-butyldimethylsilanyloxy)-2-[2-(4-methoxyphenoxymethyl)-benzylidene]-N-methylbutyramide (43)

To a stirred suspension of NaH (40 mg, 60% dispersion in mineral oil, 1.01 mmol) in THF (8 mL) was added a solution of the amide 42 (641 mg, 0.84 mmol) in THF (3 mL) at 0 °C. The mixture was stirred at rt for 30 min and recooled to 0 °C. To the solution was added MeI (0.08 mL, 1.29 mmol) and the reaction mixture was warmed to rt and stirred for 12 h. The reaction mixture was diluted with saturated aqueous NH₄Cl and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:3 EtOAc:hexanes) to give the N-methyl amide 43 (630 mg, 96%) as a colorless oil. IR (film) 2950, 2860, 1650, 1509, 1226, 1090 cm⁻¹; ¹H NMR (300 MHz, toluene-d₈, 90 °C) δ 7.38 (m, 1H), 7.28−7.01 (m, 12H), 6.78 (dt, J = 12.8, 3.8 Hz, 2H), 6.72 (dt, J = 12.8, 3.8 Hz, 2H), 4.59 (d, J = 5.5 Hz, 2H), 4.42 (d, J = 7.1 Hz, 2H), 4.38 (s, 2H), 3.94 (m, 2H), 3.45 (s, 3H), 3.22 (s, 3H), 2.75 (m, 1H), 2.57 (m, 1H), 0.95 (s, 9H), 0.07 (s, 6H); ¹³C NMR (75 MHz, toluene-d₈, 90 °C) δ 170.7, 155.1, 153.6, 148.3, 144.3, 137.5, 129.2, 136.3, 135.1, 131.9, 129.2, 129.1, 128.7, 128.5, 128.1, 127.84, 127.78, 127.7, 127.53, 127.48, 116.9, 115.3, 103.3, 77.1, 73.1, 69.1, 62.5, 55.4, 37.6, 34.0, 26.2, 18.5, −5.2; HRMS-ES: [M+H]⁺ calcd for C₄₀H₄₉INO₅Si 778.2425; found, 778.2397.

{4-Benzyloxymethyl-3-[2-(tert-butyldimethylsilanyloxy)-ethyl]-1-methyl-2-oxo-2,3-dihydro-1Hindol-3-yl}-[2-(4-methoxyphenoxymethyl)-phenyl]-acetic Acid Methyl Ester (44)

To a solution of N-methyl amide 43 (222 mg, 0.286 mmol) in DMA (3.0 mL) and MeOH (1.5 mL) were added Pd(OAc)₂ (6.4 mg, 0.029 mmol), biphenyldicyclohexylphosphine (30.1 mg, 0.086 mmol) and NaOAc (46.9 mg, 0.572 mmol). The mixture was stirred at 85 °C under a CO atmosphere (1 atm) for 24 h. The catalyst was removed by filtration and washed with EtOAc. The filtrate was washed with water and brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:5 EtOAc:hexanes) to give the methyl ester 44 (145 mg, 71%) as a colorless oil. IR (film) 2950, 2859, 1740, 1712, 1509, 1226 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.35−7.17 (m, 9H), 7.12 (dd, J = 14.8, 7.5 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 9.1 Hz, 2H), 6.82 (d, J = 9.2 Hz, 2H), 6.65 (d, J = 7.7 Hz, 1H), 4.93, 4.69 (ABq, J = 11.6 Hz, 2H), 4.63 (s, 1H), 4.41, 4.29 (ABq, J = 11.9 Hz, 2H), 3.89, 3.77 (ABq, J = 11.1 Hz, 2H), 3.78 (s, 3H), 3.59 (s, 3H), 3.19 (m, 2H), 3.10 (s, 3H), 2.56 (dt, J = 14.4, 7.2 Hz, 1H), 2.13 (dt, J = 13.4, 4.9 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 178.2, 171.6, 154.5, 153.1, 145.4, 138.2, 136.5, 136.0, 133.4, 130.6, 129.7, 129.0, 128.8, 128.4, 128.3, 128.2, 128.1, 126.1, 123.5, 116.2, 115.1, 107.6, 73.4, 69.2, 68.9, 60.0, 56.1, 55.1, 52.5, 38.0, 26.9, 26.4, 26.2, 18.6, −5.3, −5.4; HRMS-ES: [M+H]⁺ calcd for C₄₂H₅₂NO₇Si 710.3513; found, 710.3521.

Synthesis of Spirolactone 45

To a stirred solution of methyl ester 44 (172 mg, 0.24 mmol) in THF (10 mL) was added TBAF (0.27 mL, 1.0 M in THF, 0.27 mmol) at 0 °C. The reaction mixture was warmed to rt and stirred for 4 h. The mixture was diluted with EtOAc and saturated aqueous NH₄Cl. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 EtOAc:hexanes) to give the lactone 45 (116 mg, 85%) as a separable mixture of diastereomers (2:1). For analytical purposes the diastereomers were separated by preparative TLC (1:1 EtOAc:hexanes). More polar major diastereomer of 45 (colorless oil): IR (film) 2927, 1752, 1712, 1605, 1509, 1226 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.38−7.01 (m, 11H), 6.83−6.74 (m, 4H), 6.54 (d, J = 7.7 Hz, 1H), 5.03 (s, 1H), 4.83 (ddd, J = 11.7, 6.7, 4.9 Hz, 1H), 4.67−4.43 (m, 6H), 4.30 (ddd, J = 11.8, 7.2, 4.6 Hz, 1H), 3.77 (s, 3H), 2.96 (s, 3H), 2.61 (ddd, J = 14.7, 6.8, 4.8 Hz, 1H), 2.27 (ddd, J = 14.6, 7.4, 5.1 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 178.2, 171.1, 154.5, 153.0, 144.1, 137.3, 136.5, 134.4, 132.3, 130.8, 129.7, 129.2, 129.1, 128.79, 128.75, 128.7, 128.2, 127.8, 125.1, 116.3, 115.1, 108.6, 73.8, 70.0, 69.7, 64.8, 56.2, 52.6, 47.2, 30.3, 26.5; HRMS-ES: [M+H]⁺ calcd for C₃₅H₃₄NO₆ 564.2386; found, 564.2391. Less polar minor diastereomer of 45 (colorless oil): IR (film) 2916, 1746, 1706, 1610, 1509, 1232 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.44−7.30 (m, 5H), 7.27−7.23 (m, 3H), 7.09 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 6.88−6.84 (m, 3H), 6.63 (d, J = 7.8 Hz, 1H), 6.54 (d, J = 7.4 Hz, 1H), 5.32 (d, J = 11.7 Hz, 1H), 4.98 (s, 1H), 4.80−4.55 (m, 6H), 4.38 (dd, J = 11.7, 5.6 Hz, 1H), 3.79 (s, 3H), 2.91 (s, 3H), 2.73 (td, J = 14.5, 5.8 Hz, 1H), 2.23 (d, J = 14.9 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃), δ 179.4, 172.6, 154.6, 153.1, 144.2, 138.2, 136.7, 136.0, 131.5, 130.8, 129.8, 129.7, 129.0, 128.9, 128.6, 128.3, 128.2, 127.5, 125.4, 116.6, 115.1, 108.5, 73.6, 70.2, 69.2, 66.1, 56.1, 52.5, 47.1, 31.6, 26.8; HRMS-ES: [M+Na]⁺ calcd for C₃₅H₃₃NNaO₆ 586.2206; found, 586.2210.

O-Allylation of Spirolactone 45

To a stirred suspension of spirolactone 45 (20.6 mg, 0.037 mmol) and NaH (2.0 mg, 60% dispersion in mineral oil, 0.050 mmol) in DMF (2 mL) was added allyl iodide (0.010 mL, 0.109 mmol) at 0 °C. The mixture was stirred for 1 h at rt. The reaction mixture was diluted with saturated aqueous NH₄Cl and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:2 EtOAc:hexanes) to give the O-allyl ketene acetal 46 (12.7 mg, 57%, 71% based on recovered starting material) as a coloress oil, and unreacted spiro lactone 45 (3.9 mg). IR (film) 3470, 2927, 1706, 1509, 1226 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, 2:1 atropisomeric mixture) δ 7.44-7.22 (m, 7H, major and minor), 7.13 (t, J = 7.7 Hz, 1H, minor), 7.08−7.01 (m, 1H, major and minor), 6.98−6.96 (m, 2H, major and minor), 6.91 (d, J = 6.7 Hz, 1H, minor), 6.86−6.82 (m, 3H, major and minor), 6.77 (t, J = 7.6 Hz, 1H, major), 6.58 (d, J = 8.1 Hz, 1H, major and minor), 6.35 (d, J = 7.8 Hz, 1H, minor), 5.78 (m, 1H, major and minor), 5.27 (d, J = 13.3 Hz, 1H, major), 5.17−5.06 (m, 3H, major, 2H, minor), 5.01−4.84 (m, 2H, major and minor), 4.77−4.65 (m, 2H, major, 3H, minor), 4.44−4.24 (m, 4H, major and minor), 3.78 (s, 3H, major and minor), 3.16 (s, 3H, minor), 2.95 (s, 3H, major), 2.58 (m, 1H, major and minor), 1.98 (d, J = 14.6 Hz, 1H, major), 1.85 (d, J = 14.3 Hz, 1H, minor). ¹³C NMR (300 MHz, CDCl₃) δ 180.7, 179.4, 157.6, 156.3, 154.0, 153.9, 153.8, 153.6, 144.0, 143.6, 138.32, 138.27, 137.2, 135.2, 134.7, 134.0, 133.7, 133.4, 132.7, 130.9, 130.2, 129.8, 129.6, 129.0, 128.9, 128.81, 128.76, 128.4, 128.34, 128.26, 128.1, 127.5, 127.4, 127.1, 127.0, 126.7, 126.4, 125.2, 124.4, 118.22, 118.16, 116.2, 115.9, 115.0, 114.9, 108.0, 107.9, 87.1, 84.4, 73.8, 73.5, 69.30, 69.26, 68.33, 68.26, 65.5, 64.6, 56.1, 50.5, 50.4, 32.6, 31.4, 26.8, 26.6; HRMS-ES: [M+H]⁺ calcd for C₃₈H₃₇NO₆ 604.2699; found, 604.2684.

Thermal Claisen Rearrangement of Ketene Acetal 46

A solution of ketene acetal 46 in DMF or toluene was heated at 130 °C and stirred for 15 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (1:1 EtOAc:hexanes) to give the two allyl lactone diastereomers 47 and 48. More polar major diastereomer 47 (oil): IR (film) 2929, 1704, 1508, 1228 cm⁻¹; ¹H NMR (300 MHz, toluene-d₈, 90°C) δ 7.56 (d, J = 7.9 Hz, 1H), 7.26−6.98 (m, 9H), 6.90 (t, J = 7.2 Hz, 1H), 6.80−6.67 (m, 4H), 6.38 (d, J = 6.8 Hz, 1H), 6.10 (m, 1H), 5.21 (br. s, 1H), 5.13 (td, J = 12.1, 4.4 Hz, 1H), 4.77 (s, 1H), 4.72 (d, J = 8.8 Hz, 1H), 4.52 (br. s, 1H), 4.20, 4.13 (ABq, J = 12.1 Hz, 2H), 4.06 (dd, J = 11.0, 7.0 Hz, 1H), 3.47 (s, 3H), 3.16 (m, 1H), 3.15 (s, 2H), 2.85 (m, 1H), 2.81 (s, 3H), 2.53 (dd, J = 15.4, 6.8 Hz, 1H), 1.35 (dd, J = 14.7, 4.6 Hz, 1H); ¹³C NMR (75 MHz, toluene-d₈, 90 °C) δ 176.5, 172.4, 155.3, 154.0, 145.1, 139.6, 139.1, 138.6, 137.8, 137.3, 134.1, 132.3, 129.4, 128.7, 128.2, 127.9, 127.5, 126.7, 127.5, 126.7, 125.8, 116.1, 115.7, 107.5, 73.0, 69.6, 69.0, 64.6, 59.1, 57.0, 55.7, 41.2, 27.2, 25.7; HRMS-ES: [M+H]⁺ calcd for C₃₈H₃₈NO₆ 604.2699; found, 604.2714. Less polar minor diastereomer 48 (oil): IR (film) 2918, 1704, 1508, 1228 cm⁻¹; ¹H NMR (300 MHz, toluene-d₈, 90°C) δ 7.83 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.22−6.96 (m, 8H), 6.77 (d, J = 8.8 Hz, 2H), 6.60 (t, J = 7.8 Hz, 1H), 6.36 (br s, 1H), 5.99 (d, J = 7.7 Hz, 1H), 5.77 (m, 1H), 5.52 (td, J = 12.3, 4.1 Hz, 1H), 5.33 (d, J = 11.8 Hz, 1H), 4.98−4.85 (m, 3H), 4.60, 4.57 (ABq, J = 10.3 Hz, 2H), 4.50, 4.44 (ABq, J = 11.9 Hz, 2H), 4.0 (dd, J = 11.1, 6.9 Hz, 1H), 3.47 (s, 3H), 3.39 (dd, J = 14.7, 5.6 Hz, 1H), 2.95 (dd, J = 14.3, 6.7 Hz, 1H), 2.74 (td, J = 14.4, 6.9 Hz, 1H), 2.32 (s, 3H), 1.42 (dd, J = 14.7, 3.7 Hz, 1H); ¹³C NMR (75 MHz, toluene-d₈, 90 °C) δ 177.2, 169.9, 155.1, 154.8, 145.9, 139.7, 138.1, 137.4, 137.2, 134.5, 133.9, 129.5, 129.4, 129.3, 128.9, 128.4, 127.5, 127.3, 125.9, 125.6, 117.7, 117.1, 115.6, 107.8, 73.6, 71.2, 70.4, 64.7, 57.9, 57.8, 55.7, 42.0, 26.9, 25.4; HRMS-ES: [M+H]⁺ calcd for C₃₈H₃₈NO₆ 604.2699; found, 604.2722.

Dimethylcarbamic Acid 2-Iodo-3-nitrophenyl Ester (50)

To a stirred solution of 2-iodo-3-nitrophenol (49, 422 mg, 1.59 mmol), NEt3 (0.33 ml, 2.35 mmol)²³ and DMAP (19.4 mg, 0.16 mmol) in CH₂Cl₂ (20 mL) was added N,N-dimethylcarbamyl chloride (0.18 mL, 1.96 mmol) at 0 °C. The mixture was warmed to rt and stirred overnight. The reaction mixture was diluted with CH₂Cl₂, washed with water and brine, dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by flash column chromatography (1:1 EtOAc:hexanes) to give the carbamoyl-protected phenol 50 (505 mg, 94%) as a white solid (mp 125-126 °C). IR (film) 1713, 1531, 1386, 1359, 1246, 1165 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.75 (dd, J = 7.9, 1.4 Hz, 1H), 7.60, (t, J = 8.0 Hz, 1H), 7.53 (dd, J = 8.1, 1.4 Hz, 1H), 3.35 (s, 3H), 3.19 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 155.1, 153.9, 153.4, 130.0, 127.3, 122.4, 86.1, 37.5, 37.3; HRMS-ES: [M+Na]⁺ calcd for C₉H₉IN₂NaO₄ 358.9505; found, 358.9513.

Dimethylcarbamic Acid 3-Amino-2-iodophenyl Ester (51)

To a solution of the nitrobenzene 50 (446 mg, 1.33 mmol) in EtOH (10 mL) and glacial acetic acid (5 mL) was added iron powder (296 mg, 5.30 mmol). The mixture was heated at 60 °C for 4 h and then cooled to rt. The mixture was diluted with water and carefully neutralized with solid Na₂CO₃. The resulting solution was extracted with EtOAc. The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 EtOAc:hexanes) to give the aniline 51 (375 mg, 93%) as a white solid (mp 113-114 °C). IR (film) 3333, 1714, 1617, 1466, 1386, 1170 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.33 (t, J = 7.9 Hz, 1H), 6.80 (dd, J = 8.0, 2.9 Hz, 2H), 4.50 (br s, 2H), 3.42 (s, 3H), 3.28 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 154.3, 152.7, 149.0, 129.8, 113.0, 112.2, 82.0, 37.3, 37.2; HRMS-ES: [M+H]⁺ calcd for C₉H₁₂IN₂O₂ 306.9944; found, 306.9949.

Dimethylcarbamic Acid 3-{4-Hydroxy-2-[2-(4-methoxyphenoxymethyl)benzylidene]butyrylamino}-2-iodophenyl Ester (52)

To a stirred solution of aniline 51 (111 mg, 0.362 mmol) and lactone 40²² (107 mg, 0.345 mmol) in CH₂Cl₂ (10 mL) was added AlMe₃ (0.19 mL, 2.0 M in hexane, 0.380 mmol) at 0 °C. The mixture was warmed to rt, stirred overnight and then carefully diluted with saturated aqueous NH₄Cl at 0 °C, followed by CH₂Cl₂. The organic layer was washed with water, dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (10:1 CH₂Cl2:MeOH) to give the amide 52 (207 mg, 97%) as a white solid (mp 110-111 °C). IR (film) 3387, 2934, 1725, 1665, 1509, 1229 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1H), 8.06 (dd, J = 8.2, 1.4 Hz, 1H), 7.64 (s, 1H), 7.53−7.51 (m, 1H), 7.40−7.31 (m, 4H), 6.97 (dd, J = 8.1, 1.4 Hz, 1H), 6.92−6.79 (m, 4H), 5.01 (s, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.74 (s, 3H), 3.18 (s, 3H), 3.03 (s, 3H), 2.74 (t, J = 5.8 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 168.7, 154.6, 154.0, 153.2, 152.4, 140.0, 138.5, 135.6, 135.2, 134.5, 129.9, 129.7, 129.6, 129.0, 128.8, 119.82, 119.76, 116.4, 115.2, 89.4, 69.6, 62.3, 56.2, 37.3, 37.2, 31.8; HRMS-ES: [M+H]⁺ calcd for C₂₈H₃₀IN₂O₆ 617.1149; found, 617.1139.

Dimethylcarbamic Acid 2-Iodo-3-{4-methoxymethoxy-2-[2-(4-methoxyphenoxymethyl)benzylidene] butyrylamino}phenyl Ester (53)

To a mixture of amide 52 (961 mg, 1.56 mmol), (i-Pr)₂NEt (0.54 mL, 3.10 mmol) and NaI (467 mg, 3.12 mmol) in CH₂Cl₂ (30 mL) was added MOMCl (0.18 mL, 2.37 mmol) at 0 °C. The mixture was warmed to rt, stirred overnight and then diluted with saturated aqueous NaHCO₃ and CH₂Cl₂. The organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 EtOAc:hexanes) to give the MOM ether 53 (914 mg, 89%) as a white solid (mp 107-108 °C). IR (film) 3389, 2937, 1729, 1673, 1509, 1385, 1232 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.32 (s, 1H), 8.17 (dd, J = 8.3, 1.3 Hz, 1H), 7.67 (s, 1H), 7.57−7.54 (m, 1H), 7.43−7.34 (m, 4H), 6.98 (dd, J = 8.3, 1.3 Hz, 1H), 6.93-6.80 (m, 4H), 5.02 (s, 2H), 4.58 (s, 2H), 3.75 (s, 3H), 3.70 (t, J = 6.3 Hz, 2H), 3.29 (s, 3H), 3.19 (s, 3H), 3.05 (s, 3H), 2.84 (t, J = 6.3 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 167.6, 154.6, 153.9, 153.2, 152.3, 140.2, 138.1, 135.8, 135.1, 134.4, 130.0, 129.5, 129.3, 128.9, 128.6, 119.5, 119.4, 116.4, 115.2, 96.7, 88.8, 69.4, 66.5, 56.2, 55.8, 37.3, 37.2, 29.0; HRMS-ES: [M+H]⁺ calcd for C₃₀H₃₄IN₂O₇ 661.1411; found, 661.1397.

Dimethylcarbamic Acid 2-Iodo-3-({4-methoxymethoxy-2-[2-(4-methoxyphenoxymethyl)benzylidene]butyryl}methylamino)phenyl Ester (54)

To a stirred suspension of NaH (11.1 mg, 60% dispersion in mineral oil, 0.278 mmol) in THF (6 mL) was added a solution of lactam 53 (167 mg, 0.253 mmol) in THF (4 mL) at 0 °C. The mixture was stirred at rt for 1 h and recooled to 0 °C. To the solution was added MeI (0.019 mL, 0.305 mmol) and the reaction mixture was warmed to rt and stirred overnight. The reaction mixture was diluted with saturated aqueous NH₄Cl and water and extracted with CH₂Cl₂. The organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (10:10:1 CH₂Cl₂:EtOAc:MeOH) to give the N-methyl amide 54 (167 mg, 98%) as a colorless oil. IR (film) 2926, 1723, 1616, 1503, 1227, 1164 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.38−6.96 (m, 8H), 6.81 (br s, 4H), 4.68−4.48 (m, 4H), 3.77 (s, 3H), 3.67 (br s, 2H), 3.36 (s, 6H), 3.11 (s, 3H), 3.02 (s, 3H), 2.59 (br s, 1H), 2.43 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 171.6, 154.4, 153.8, 153.1, 148.8, 136.5, 135.9, 134.4, 133.2, 130.2, 129.1, 128.4, 127.8, 127.0, 122.8, 116.5, 114.9, 97.3, 96.6, 68.5, 66.2, 56.1, 55.7, 37.8, 37.3, 37.1, 30.3; HRMS-ES: [M+H]⁺ calcd for C₃₁H₃₆IN₂O₇ 675.1567; found, 675.1562.

[4-Dimethylcarbamoyloxy-3-(2-methoxymethoxyethyl)-1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-[2-(4-methoxyphenoxymethyl)phenyl]acetic Acid Methyl Ester (55)

To a solution of N-methyl amide 54 (280 mg, 0.415 mmol) in DMA (2.6 mL) and MeOH (1.3 mL) were added Pd(OAc)₂ (18.6 mg, 0.083 mmol), P(o-Tol)₃ (75.7 mg, 0.249 mmol) and NaOAc (68.0 mg, 0.829 mmol). The mixture was stirred at 90 °C under a CO atmosphere (1 atm) for 1 d. The reaction mixture was cooled to rt and diluted with EtOAc. The solution was washed with water and brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:2 EtOAc:hexanes) to give the ester 55 (199 mg, 79%) as a colorless oil. IR (film) 2938, 1729, 1616, 1509, 1226 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.53−7.50 (m, 1H), 7.32-7.16 (m, 4H), 6.97 (d, J = 8.4 Hz, 1H), 6.88−6.80 (m, 4H), 6.51 (d, J = 7.6 Hz, 1H), 5.08, 4.85 (ABq, J = 11.6 Hz, 2H), 4.68 (s, 1H), 4.32, 4.21 (ABq, J = 6.5 Hz, 2H), 3.78 (s, 3H), 3.61 (s, 3H), 3.19-3.03 (m, 2H), 3.12 (s, 3H), 3.09 (s, 3H), 2.88 (s, 3H), 2.64 (s, 3H), 2.63-2.55 (m, 1H), 2.47-2.40 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 177.9, 171.2, 154.5, 153.4, 153.1, 148.7, 146.3, 136.5, 133.5, 130.6, 129.9, 129.6, 128.3, 127.9, 118.6, 116.8, 116.3, 115.0, 104.9, 96.7, 69.2, 64.4, 56.2, 55.4, 54.5, 52.6, 37.2, 36.4, 34.2, 26.9; HRMS-ES: [M+H]⁺ calcd for C₃₃H₃₉N₂O₉ 607.2656; found, 607.2645.

Synthesis of Spirolactone 57

To a stirred solution of ester 55 (61.1 mg, 0.101 mmol) in MeOH (5.0 mL) was added concentrated HCl (1 drop) at rt. The mixture was warmed to 60 °C and stirred for 4 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (3:1 EtOAc:hexanes) to give spiro lactone 57 (37.5 mg, 70%) as a white solid (mp 213-215 °C) and hydroxy ester 56 (9.5 mg, 17%) as a colorless oil. Spiro lactone 57: IR (film) 1729, 1712, 1622, 1509, 1226, 1158 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.47 (dd, J = 7.5, 1.1 Hz, 1H), 7.27-7.19 (m, 2H), 7.12 (td, J = 7.6, 1.3 Hz, 1H), 7.04 (dd, J = 7.6, 1.4 Hz, 1H), 6.82 (dd, J = 8.4, 0.6 Hz, 1H), 6.78-6.70 (m, 4H), 6.42 (d, J = 7.8 Hz, 1H), 5.01 (ddd, J = 11.4, 6.8, 4.7 Hz, 1H), 4.97 (s, 1H), 4.94 (d, J = 11.9 Hz, 1H), 4.56 (ddd, J = 11.7, 7.5, 4.2 Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H), 3.75 (s, 3H), 3.00 (s, 3H), 2.95 (s, 3H), 2.94 (s, 3H), 2.55 (ddd, J = 14.8, 6.7, 4.4 Hz, 1H), 2.42 (ddd, J = 14.7, 7.7, 4.7 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5, 170.8, 154.6, 154.3, 152.9, 148.2, 144.9, 136.5, 132.2, 131.4, 130.6, 129.5, 128.3, 128.0, 121.9, 118.0, 116.7, 115.0, 106.0, 69.8, 65.0, 56.1, 52.1, 46.6, 37.6, 36.8, 30.4, 26.7; HRMS-ES: [M+Na]⁺ calcd for C₃₀H₃₀N₂NaO₇ 553.1951; found, 553.1963.

Hydroxy ester 56: IR (film) 3470, 2927, 1735, 1712, 1616, 1509, 1226, 1152 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.54−7.52 (m, 1H), 7.28−7.17 (m, 4H), 6.86−6.80 (m, 5H), 6.53 (d, J = 7.7 Hz, 1H), 5.07, 4.83 (ABq, J = 12.9 Hz, 2H), 4.70 (s, 1H), 3.78 (s, 3H), 3.64 (s, 3H), 3.34 (t, J = 6.3 Hz, 2H), 3.12 (s, 3H), 2.92 (s, 3H), 2.72 (s, 3H), 2.56 (dt, J = 13.8, 6.9 Hz, 1H), 2.34 (dt, J = 12.7, 6.4 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 177.9, 171.2, 154.5, 154.4, 153.0, 148.3, 146.2, 136.4, 133.4, 130.6, 130.0, 129.6, 128.2, 128.0, 120.3, 117.2, 116.2, 115.0, 105.5, 69.2, 59.6, 56.2, 54.6, 52.7, 37.4, 37.2, 36.6, 27.0; HRMS-ES: [M+H]⁺ calcd for C₃₁H₃₅N₂O₈ 563.2393; found, 563.2392.

O-Allylation of Spirolactone 57

To a stirred suspension of spirolactone 57 (69.1 mg, 0.130 mmol) and NaH (6.2 mg, 60% dispersion in mineral oil, 0.155 mmol) in DMF (2 mL) was added allyl iodide (0.024 mL, 0.262 mmol) at rt. The mixture was stirred at rt overnight. The reaction mixture was diluted with saturated aqueous NH₄Cl and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 EtOAc:hexanes) to give the O-allyl ketene acetal 58 (46.6 mg, 63%) as a colorless oil. IR (film) 2916, 1712, 1616, 1509, 1226 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, 2:1 atropisomeric mixture) δ 7.40 (d, J = 7.3 Hz, 1H),7.26−6.95 (m, 7.5H), 6.90−6.77 (m, 4.5 H), 6.73 (s, 2H), 6.46 (d, J = 7.7 Hz, 1H), 6.43 (d, J = 7.8 Hz, 0.5H), 5.80−5.64 (m, 1.5H), 5.24−4.86 (m, 7.5H), 4.38−4.27 (m, 4.5H), 3.78 (s, 3H), 3.76 (s, 1.5H), 3.18 (s, 3H), 3.76 (s, 1.5H), 3.18 (s, 3H), 3.073 (s, 3H), 3.067 (s, 3H), 2.99 (s, 1.5H), 2.95 (s, 3H), 2.49−2.39 (m, 1.5H), 2.08−1.99 (m, 1.5H); ¹³C NMR (75 MHz, CDCl₃) δ 180.0, 179.0, 157.1, 156.2, 154.5, 154.3, 153.9, 153.8, 153.5, 148.2, 148.0, 145.1, 145.0, 138.6, 138.1, 134.0, 133.7, 132.9, 132.5, 131.5, 131.1, 129.6, 129.5, 127.5, 127.2, 126.7, 126.4, 126.2, 123.0, 122.5, 118.3, 118.2, 117.9, 117.7, 116.3, 116.2, 115.0, 114.8, 105.5, 105.3, 88.0, 84.6, 69.5, 69.4, 68.5, 68.3, 65.1, 65.0, 56.2, 50.20, 50.15, 37.5, 37.4, 36.9, 31.6, 29.8, 26.9, 26.8; HRMSES: [M+H]⁺ calcd for C₃₃H₃₅N₂O₇ 571.2444; found, 571.2429.

Claisen Rearrangement of Ketene Acetal 58

A solution of ketene acetal 58 in DMF or toluene was heated at 110 °C and stirred overnight. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (1:1 EtOAc:hexanes) to give the allyl lacone diastereomers 59 and 60. More polar major diastereomer 59 (pale yellow oil): IR (film) 2927, 1729, 1712, 1616, 1502, 1226, 1158 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.46 (br s, 1H), 7.23 (t, J = 8.0 Hz, 2H), 7.17 (t, J = 7.0 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 6.77 (br s, 2H), 6.60−6.56 (m, 2H), 5.64 (m, 1H), 5.04−4.87 (m, 3H), 4.66 (br s, 1H), 4.47 (br s, 1H), 3.79 (s, 3H), 3.22 (br s, 1H), 3.10 (s, 3H), 2.92−2.87 (m, 4H), 2.78−2.70 (m, 4H), 2.29 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 175.8, 171.9, 154.0, 153.7, 153.0, 149.3, 145.0, 137.0, 134.9, 134.3, 131.7, 131.4, 130.1, 127.5, 126.8, 120.1, 118.3, 116.9, 115.0, 114.5, 105.2, 68.7, 65.4, 55.7, 55.4, 38.4, 36.9, 36.5, 29.7, 29.4, 24.6; HRMS-ES: [M+Na]⁺ calcd for C₃₃H₃₄N₂NaO₇ 593.2264; found, 593.2263. Less polar minor diastereomer 60 (pale yellow oil): IR (film) 2927, 1729, 1712, 1616, 1509, 1226, 1164 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.71 (br s, 1H), 7.30 (t, J = 8.1 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.02-7.00 (m, 2H), 6.90- 6.83 (m, 4H), 6.54 (br s, 1H), 6.34 (d, J = 7.7 Hz, 1H), 5.63-5.56 (m, 2H), 5.06−4.96 (m, 3H), 4.79 (br s, 1H), 4.55 (dd, J = 11.3, 6.4 Hz, 1H), 3.81 (s, 3H), 3.61 (dd, J = 15.2, 5.9 Hz, 1H), 3.23 (s, 3H), 3.18−3.02 (m, 2H), 3.11 (s, 3H), 2.58 (s, 3H), 2.01 (dd, J =14.9, 3.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 176.8, 171.1, 154.6, 154.1, 154.0, 149.4, 146.4, 138.3, 133.8, 132.4, 130.8, 129.9, 127.8, 125.9, 119.4, 118.4, 118.2, 116.4, 115.0, 113.7, 105.7, 71.1, 65.5, 56.7, 56.2 41.9, 37.5, 37.1, 30.1, 26.1, 24.9; HRMS-ES: [M+Na]⁺ calcd for C₃₃H₃₄N₂NaO₇ 593.2264; found, 593.2274.