Ring-Expansion Approaches for the Total Synthesis of Salimabromide.

We describe the evolution of a synthetic strategy for the construction of the marine polyketide salimabromide. Combining a bicyclo[3.1.0]hexan-2-one ring-expansion to build up a functionalized naphthalene and an unprecedented rearrangement/cyclization cascade, enabled synthesis of a dearomatized tricyclic subunit of the target compound. Alternatively, an intramolecular ketiminium [2+2]-cycloaddition and subsequent Baeyer-Villiger ring-expansion gave access to the sterically encumbered architecture of salimabromide. Sequential oxidation of the carbon framework finally enabled the total synthesis of this unusual natural product.


Introduction
Myxobacteria are a unique class of δ-proteobacteria with an elaborate ability for intercellular communication [1]. In an impressive process of cooperative morphogenesis, these rod-shaped gliding bacteria can aggregate and pile up on starvation conditions, forming so-called fruiting bodies. Within the maturing fruiting body, the cells differentiate into myxospores that are resistant to desiccation. Most myxobacteria also have a fascinating predatory activity on other microorganisms and can lyse a variety of bacteria and fungi to feed on the lysis products [2]. More than 100 natural product scaffolds with a broad range of biological activities were isolated from terrestrial myxobacteria since the last three decades [3]. Only in 1998, the first member of currently ten known marine myxobacterial strains was reported by Iizuka [4]. Difficulties in the cultivation of these bacteria complicate the isolation of natural products and only seven natural product classes have been identified so far ( Figure 1) [5]. These include enhygrolide A (1) and B (2) [6], enhygromic acid (3) [7], haliamide (4) [8], haliangicins (5) [9], salimyxins (6) [6] and salimabromide (7) [10].
Of those seven classes, the organobromine compound salimabromide (7) contains a unique C 20 framework that does not show any resemblance to other known natural products. Its tetrahydronaphthalene moiety features two contiguous quaternary carbon centers, one of which is asymmetric, and is annealed to a γ-butyrolactone. An enone motif connects the lactone and the saturated half of the tetrahydronaphthalene. The two bromides are located on the aromatic half, resulting in a penta-substituted arene with an uncommon ethyl side chain. First biological screens were limited as only 0.5 mg of 7 could be isolated [10]. However, they revealed a moderate antibiotic activity against Arthrobacter cristallopoedes with a MIC value of 16 μg mL -1 .
The group of Menche began first synthetic studies shortly after the isolation of 7 in 2013 [11]. In their approach, the crucial quaternary stereocenter was set via an asymmetric Denmark crotylation (95% ee) employing aldehyde 9. It is interesting to note that 9, derived from acid 8 in four steps, already contains the sterically demanding bromide substituents. The alcohol 10 was converted to the tetraline 11 within further six steps. For the introduction of the remaining carbon atoms, an additional ten steps were required to give the eightmembered lactone 12. Unfortunately, the final ring closure of the γ-butyrolactone by an intramolecular Michael-addition as well as the elimination of the neopentylic methoxy group could not be achieved at this stage.

Results and discussion
In our retrosynthetic analysis, we envisioned a complementary approach to the one developed by Menche and decided to introduce the bromide substituents of 7 at the very end of the synthesis (Scheme 2). This decision was based on the hypothesis that the biosynthesis involves a late-stage bromination and on steric arguments [10]. The enone of 7 was disconnected via a dynamic kinetic aldol reaction to provide 13 [12]. Further disconnection was accomplished by removal of the lactone and masking of the aldehyde function as an alkene to give 14. For the construction of 14, a dearomatization sequence of 15 was planned. Guided by our previously developed ring-expansion methodology, we envisioned to directly trace back 15 to 16 [13][14][15].
We therefore decided to go back to 15 and first concentrate on the installation of the gemdimethyl group (Scheme 5). For this purpose, 15 was dearomatized following an analogous procedure as above. In this way, the dearomatized product 24 was obtained in good yields (79% over two steps). Isomerization of the allylic double bond -required for the intended ozonolysis towards 13 -was accomplished by conditions developed by Skrydstrup (Pd(dba) 2 , t-Bu 3 P, i-PrCOCl, PhMe) in 84% yield [27]. With 31 in hand, we investigated introduction of the gem-dimethyl group. First, Wittig olefination proceeded smoothly to give 32 [28]. Unfortunately we were not able to cyclopropanate this alkene by employing the Simmons-Smith protocol (CH 2 I 2 , ZnEt 2 ) [29], the use of dichlorocarbene or dibromocarbene [30]. In a second approach, a Kluge-Wittig reaction/hydrolysis sequence gave aldehyde 34 which was α-methylated. Noteworthy, rigorous degassing of the solvent (THF) was mandatory to avoid competing oxidation of the enolate and diminished yields of 35. Attempts to directly reduce this aldehyde by the protocol of Wolff-Kishner [31] or the formation of a thioacetal followed by nickel catalyzed hydrogenation (Mozingo protocol) [32] failed. Therefore, 34 was reduced to the primary alcohol 36. While it was possible to tosylate this alcohol (36 to 37), 33 could not be generated by reduction with lithium aluminum hydride even under elevated temperature (60 °C). Finally, a radical Barton-McCombie deoxygenation of 38 was investigated [33]. However, the intended product was not formed but a complex product mixture was obtained. Direct dimethylation of the ketone using Reetz conditions [34] failed as the strongly Lewis acidic conditions induced a Wagner-Meerwein rearrangement (39 to 40 to 41) to give 42 as the sole product [35].

Second Generation Route
Realizing that introduction of the two quaternary carbon centers is highly problematic at this stage of the synthesis, we abandoned the indanone ring-expansion route and tried to set both centers at an earlier stage. Starting with commercially available methoxytetralone 43, addition of methylmagnesium bromide and acid-mediated elimination gave known 44 [36]. Epoxidation with concomitant Meinwald-rearrangement afforded ß-tetralone 45 in 44% yield over two steps [37]. Methylation under thermodynamic control using potassium hydride as the base set the gem-dimethyl group and afforded tetralone 46 [38]. The vicinal methyl group of 47 was introduced by Grignard addition employing Knochel's conditions (LaCl 3 • 2 LiCl, MeMgBr) [39]. Benzylic oxidation with cobalt acetylacetonate [40] gave clean 48 [41] and subsequent acid-mediated elimination afforded enone 49 [42] in good yield [43]. A three-step procedure, involving demethylation, triflation [44] and Negishi cross-coupling [21] with diethylzinc was used to replace the methoxy with an ethyl group yielding 52 (via 50 and 51, 86% over three steps). Allylation with allylmagnesium bromide (52 to 53) followed by an anionic oxy-Cope rearrangement set the quaternary stereocenter of 54 [45,46]. For the isomerization of the allyl group, Skrydrup's conditions again proved to be the method of choice affording 55 in 92% yield [27]. Surprisingly, despite extensive efforts tetralone 55 proved to be reluctant to react at its α-position. We examined several αacylation and alkylation procedures to introduce the carboxylate for the γ-butyrolactone, however, no carbon-carbon bond formation to give 56 was observed. We reasoned that steric hindrance by the adjacent quaternary stereocenter impedes nucleophilic attack of the enolate.
As steric hindrance prevented α-functionalization of the ketone, we considered an alternative [2+2]-cycloaddition strategy using the readily available 49 (Scheme 7). Conversion of 49 to 58a proceeded uneventfully via the intermediacy of 57 and involved a Wittig-Still rearrangement to construct the quaternary stereocenter (48% over three steps) [47,48]. We envisioned the primary alcohol to serve as a handle to control the facial selectivity of the ketene [2+2]-cycloaddition. First, we investigated the use of Lewis acids (AlMe 3 ; MeAlCl 2 ) to control the trajectory of the ketene derived from 59 via coordination to the alkoxide. Unfortunately, no cycloaddition product 60 was observed and only traces of the corresponding ester together with polymeric byproducts were formed. Protection of the primary alcohol (61a-d = Ac, MOM, TBS, Me) and cycloaddition with dichloroketene to give 62 was equally unproductive.
Facing the problems of ketene oligo-and polymerization we resorted to keteniminium salts, which are known to be more electrophilic and reluctant to dimerization [49,50]. Treatment of 58 with 2-chloro-N,N-diethylacetamide (63) gave 64. We were pleased to see that upon treatment with freshly distilled trifluoromethanesulfonic anhydride and sym-collidine at 80 °C, 64 underwent the intramolecular cycloaddition to the iminium salt 70. The cycloaddition product 65 was formed after hydrolysis in 70% yield and excellent regioselectivity affording exclusively the 6/4-instead of the 5/4-system. The regioselectivity finds its basis in a stepwise mechanism presumably proceeding via the benzylic cation 69 (Scheme 8). This cation should be favored over the secondary cation 67 leading to regioisomer 68.
With 65 in hand, we cleaved the ether bridge by treatment with samarium iodide to give lactol 71 (Scheme 9) [51]. Reduction with lithium aluminum hydride afforded diol 72 and oxidation under Swern conditions provided cyclobutanone 73 in 95% yield. All efforts to functionalize the cyclobutanone ring and to convert 73 to 74a-d failed. Under basic conditions formation of 77 was observed in minor amounts. We believe that 77 is formed via ring-opening of the enolate 75 (stepwise or electrocyclic) and subsequent aldol condensation of 76.
At this point, we realized that synthesis of 13, the key-substrate for the intended kinetic dynamic aldol condensation, might not be possible via the investigated routes. Therefore, we reassessed our strategy once again. Encouraged by the high selectivity of the keteniminium mediated cycloaddition of 64 we decided to investigate an [2+2]-cycloaddition approach using a carbon chain tether (Scheme 10) [52]. For this purpose, we resorted to alcohol 58a. Since synthesis of 58a was rather low-yielding so far, we considered other synthetic options to get rapid access to the tetraline core. Inspired by the work of El-Fouty [53] and our desire to rapidly introduce both quaternary carbon centers, we envisioned the synthesis of 80 by a Wagner-Meerwein cyclization sequence of epoxide 79. [54] When conducting this reaction wet benzene, followed by DMP oxidation in dichloromethane gives reproducible yields of both 94b and 95b even on gram scale (see Experimental for details).
Introduction of the remaining bromine substituents was accomplished by treatment of 94b with bromine and silver trifluoroacetate to give 296 mg of salimabromide (7) in a single batch (Scheme 12). The use of silver trifluoroacetate to form highly reactive trifluoroacetyl hypobromite was essential [66,67]. Other bromination reagents (NBS; n-Bu 4 NBr 3 /ZnCl 2 ; Br 2 /FeBr 3 ) only lead to monobromination or decomposition of 94b [54]. The analytical data for synthetic salimabromide matched those reported in the literature [10].

Conclusion
We presented two complementary strategies for the total synthesis of salimabromide. In our initial route we targeted a highly-substituted keto-aldehyde that was thought to be synthesized via ring-expansion of a cyclopropanated indanone and subsequent dearomatization. Although both key-transformations were realized, efforts to introduce the gem-dimethyl group as well as the stereocenters connecting the lactone and the tetrahydronaphthalene core failed. In our second approach, we relied on a [2+2]cycloaddition to construct the carbon skeleton. While intermolecular cycloaddition reactions were unsuccessful, an intramolecular ketiminium [2+2]-cycloaddition showed to be highyielding and proceeded with excellent regioselectivity. Three regioselective oxidations (allylic, Baeyer-Villiger, late-stage bromination) enabled completion of the total synthesis in 18 steps (longest linear sequence). The developed route allowed production of 296 mg of salimabromide in a single batch.

Experimental
All reactions were performed in flame-dried glassware fitted with rubber septa under a positive pressure of argon, unless otherwise noted. Air-and moisture-sensitive liquids were transferred via syringe or stainless-steel cannula through rubber septa. Solids were added under inert gas counter flow or were dissolved in appropriate solvents. Low temperaturereactions were carried out in a Dewar vessel filled with a cooling agent: acetone/dry ice (-78 °C), water/ice (0 °C). Reaction temperatures above room temperature were conducted in a heated oil bath. The reactions were magnetically stirred and monitored by NMR spectroscopy or analytical thin-layer chromatography (TLC), using aluminum plates precoated with silica gel (0.25 mm, 60-Å pore size, Merck) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light (UV), were stained by submersion in aqueous potassium permanganate solution (KMnO 4 ), ceric ammonium molybdate solution (CAM) or p-anisaldehyde solution (Anis), and were developed by heating with a heat gun. Flash-column chromatography was performed as described by Still [68] employing silica gel (60 Å, 40-63 μm, Merck KGaA). The yields refer to chromatographically and spectroscopically ( 1 H and 13 C NMR) pure material. Tetrahydrofuran (THF) and diethyl ether (Et 2 O) were distilled under nitrogen atmosphere from sodium and benzophenone or sodium/potassium alloy prior to use. Dichloromethane (CH 2 Cl 2 ), Acetonitrile (MeCN), acetone and methanol (MeOH) were purchased from Acros Organics as 'extra dry' reagents and used as received. All other reagents and solvents were Schmid (Hz), integration intensity, assigned proton). The multiplicities are abbreviated with s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). In case of combined multiplicities, the multiplicity with the larger coupling constant is stated first. Except for multiplets, the chemical shift of all signals, as well for centrosymmetric multiplets, is reported as the center of the resonance range. Additionally to 1 H and 13 C NMR measurements, 2D NMR techniques such as homonuclear correlation spectroscopy (COSY), total correlation spectroscopy (TOCSY), heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond coherence (HMBC) were used to assist signal assignment. For further elucidation of 3D structures of the products, nuclear Overhauser enhancement spectroscopy (NOESY) was conducted. Coupling constants J are reported in Hz. All raw fid files were processed and the spectra analyzed using the program MestReNOVA 9.0 from Mestrelab Research S. L. All mass spectra were measured by the analytic section of the Department of Chemistry, Ludwig-Maximilians-Universität München and the group of Thomas Müller at the Department of Chemisty, Leopold-Franzens Universität Innsbruck. Mass spectra were recorded on the following spectrometers (ionization mode in brackets): MAT 95 (EI), MAT 90 (ESI) from Thermo Finnigan GmbH and Q Exactive Orbitrap (ESI) from Thermo Fisher Scientific. Mass spectra were recorded in high-resolution. The method used is reported at the relevant section of the experimental section. IR spectra were recorded on a PerkinElmer Spectrum BX II FT-IR system. If required, substances were dissolved in CH 2 Cl 2 or CDCl 3 prior to direct application on the ATR unit. Data are represented as follows: frequency of absorption (cm −1 ) and intensity of absorption (vs = very strong, s = strong, m = medium, w = weak, br = broad).

Methyl 5-bromo-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (18)
To a suspension of sodium hydride (60% dispersion in mineral oil, 19.9 g, 497 mmol, 2.00 equiv) and dimethyl carbonate (39.9 mL, 474 mmol, 2.00 equiv) in tetrahydrofuran (470 mL) in a 3-necked 1-liter round bottom flask fitted with a reflux condenser, dropping funnel and thermometer was added 5-bromo-1-indanone (17) (50.0 g, 237 mmol, 1 equiv) in tetrahydrofuran (680 mL) at 0 °C over 45 min. The dark brown reaction mixture was stirred at 0 °C for 30 min, warmed very slowly to 23 °C and carefully heated to 70 °C for 15 h. The solution was cooled to 0 °C and diluted with saturated aqueous ammonium chloride solution (200 mL), aqueous hydrogen chloride solution (2 M; 200 mL) and diethyl ether (300 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3 × 400 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (300 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered through a short pad of Celite® and the filtrate was concentrated. The crude product S1 was afforded as a dark brown solid and was used without additional purification for the next step. To crude I.71 in dry dimethyl sulfoxide (240 mL) was added potassium carbonate (65.5 g, 474 mmol, 2.00 equiv) portionwise at 0 °C. After dropwise addition of methyl iodide (29.5 mL, 474 mmol, 2.00 equiv) the dark green slurry was stirred at 23 °C for 2 h. The excess methyl iodide was removed by distillation (23 °C, 50 mbar). The reaction mixture was cooled to 0 °C, diluted with saturated aqueous ammonium chloride solution (100 mL), water (100 mL) and ethyl acetate (250 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 × 400 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (300 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered through a short pad of Celite® and the filtrate was concentrated. The crude product 18 was afforded as a dark brown solid and was used without additional purification for the next step.

5-bromo-2-methyl-2,3-dihydro-1H-inden-1-one (19)
Crude 18 was dissolved in water (82 mL), glacial acetic acid (400 mL) and aqueous hydrogen chloride solution (37%, 125 mL, 924 mmol, 3.90 equiv). The reaction mixture was heated to 100 °C for 16 h. After cooling to 23 °C, the solution was diluted with dichloromethane (300 mL) and water (300 mL) and was carefully neutralized by portionwise addition of sodium bicarbonate (250 g) and aqueous sodium hydroxide solution (10%, 300 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3 × 400 mL). The combined organic layers were dried over sodium sulfate. The dried solution was filtered through a short pad of Celite® and the filtrate was concentrated. The crude product 19 was afforded as a dark brown solid and was used without additional purification for the next step.

2,5-Dibromo-2-methyl-2,3-dihydro-1H-inden-1-one (20)
To a solution of crude indanone 19 in ethyl acetate (1 L) and chloroform (1 L), was added copper(II) bromide (106 g, 474 mmol, 2.00 equiv). The green suspension was heated to 70 °C and while stirring with a KPG stirrer. After 22 h, the mixture was allowed to cool to 23 °C, filtered through a short pad of Celite® and the filtrate was concentrated. The crude product 20 was used without additional purification for the next step. An analytical pure sample of 20 was obtained by flash column chromatography on silica gel (2% ethyl acetate in hexanes

Methyl 3-bromo-1-chloro-6a-methyl-6-oxo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1carboxylate (21)
To crude indanone 20 in benzene (474 mL) was added 1,8-diazabicyclo [5.4.0]undec-7-ene (106 mL, 711 mmol, 3.00 equiv) at 0 °C. After 5 min, the solution was warmed to 23 °C and was stirred for 45 min. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (100 mL) and diethyl ether (200 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3 × 300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (200 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered through a short pad of Celite® and the filtrate was concentrated (>200 mbar). The crude indenone S2 was afforded as a yellow-brown oil and was used immediately without additional purification for the next step. Note: Indenones undergo facile polymerizations and should therefore be used immediately after preparation. For safety reasons the cyclopropanation was carried out in two parallel batches. The crude material of both batches was subsequently combined and purified together. To a stirred solution of lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 137 mL, 137 mmol, 1.15 equiv) in tetrahydrofuran (119 mL) in a 3-necked 2 liter round bottom flask fitted with a reflux condenser, dropping funnel and thermometer, was added methyl dichloroacetate (12.9 mL, 125 mmol, 1.05 equiv) over 30 min at −78 °C.
After stirring for 105 min, a solution of crude indenone S2 in tetrahydrofuran (238 mL) was added over 1.5 h and after the addition, the reaction mixture was allowed to warm slowly to 23 °C. After 16 h, the mixture was cooled to 0 °C and diluted with saturated aqueous ammonium chloride solution (200 mL) and ethyl acetate (300 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3 × 300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (200 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (2 to 3% ethyl acetate in hexanes) to obtain 21 (38.9 g, 50% over 6 steps, inconsequential mixture of diastereomers) as a yellow solid.

4-Allyl-8-ethyl-4-methyl-1-vinyl-1,4-dihydronaphtho[1,2-c]furan-3,5-dione (28)
Tetrakis(triphenylphosphine)palladium(0) (32.8 mg, 0.0284 mmol, 0.100 equiv) was added to a Schlenk flask and the flask was purged with argon. Carbonate 27 (100 mg, 0.284 mmol, 1 equiv) was added and the flask was purged with argon. The reactants were dissolved in degassed toluene (7.5 mL) and degassed n-hexanes (0.75 mL) and stirred at 45 °C for 45 min. The reaction mixture was filtered through a plug of silica gel and rinsed thoroughly with diethyl ether (100 mL). The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (5% ethyl acetate in hexanes) to obtain 28 (60 mg, 69%, mixture of diastereomers) as a yellow oil. Note: A small sample of the diastereomeric mixture was used to separate the diastereomers by flash column chromatography on silica gel (5% ethyl acetate in hexanes). Analytical data for the major
After stirring for 20 min, saturated aqueous sodium bicarbonate solution (200 mL) and dichloromethane (200 mL) were added, the layers were separated and the aqueous layer was extracted with dichloromethane (3 × 200 mL). The combined organic layers were dried over sodium sulfate, the dried solution was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (6% ethyl acetate in hexanes) to obtain 45 (

6-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (46)
To a suspension of freshly washed potassium hydride (4.55 g, 114 mmol, 1.20 equiv) in degassed tetrahydrofuran (40 mL) was added a degassed solution of 45 (18.0 g, 94.6 mmol, 1 equiv) in tetrahydrofuran (500 mL) over 25 min at 0 °C. After 20 min, the ice bath was removed and the reaction mixture was stirred at 23 °C. After 1 h, the mixture was cooled to 0 °C, methyl iodide (11.8 mL, 189 mmol, 2.00 equiv) was added and the ice bath was removed after the addition. After 25 min at 23 °C, the mixture was again cooled to 0 °C, saturated aqueous ammonium chloride solution (200 mL) and ethyl acetate (100 mL) were added, the layers were separated and the aqueous layer was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over sodium sulfate, the dried solution was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (6% ethyl acetate in hexanes) to afford 46 (

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7-methoxy-3,4,4-trimethylnaphthalen-1(4H)-one (49)
A mixture of 48 (270 mg, 1.15 mmol, 1 equiv) in acetic acid (11.5 mL) and sulfuric acid (97%, 30 μL) was heated to 100 °C for 10 min. After cooling to 23 °C, the reaction mixture was diluted with water (30 mL) and dichloromethane (50 mL). Sodium bicarbonate was slowly added until pH=7. The layers were separated and the aqueous layer was extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (25% ethyl acetate in hexanes) to obtain 49 (220 mg, 88%) as a yellow solid. Analytical data for 49

5,5,6-trimethyl-8-oxo-5,8-dihydronaphthalen-2-yl trifluoromethanesulfonate (51)
To a solution of 49 (200 mg, 0.925 mmol, 1 equiv) in dichloromethane (4.6 mL) was added dropwise boron tribromide (1 M, in dichloromethane, 4.62 mL, 4.62 mmol, 5 equiv) at −78 °C. The reaction mixture was allowed to warm to 0 °C over 2 h and methanol (3 mL) was added dropwise. Water (40 mL) was added, the layers were separated and the aqueous layer was extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The crude product 50 was used in the next step without further purification. To a solution of crude 50 in dichloromethane (4.6 mL) was added triethylamine at −78 °C and the mixture was stirred for 5 min before trifluoromethanesulfonic anhydride (0.230 mL, 1.39 mmol, 1.50 equiv) was added over 10 min. The reaction was allowed to warm to 23 °C over 3 h and saturated aqueous sodium bicarbonate solution (15 mL) and dichloromethane (20 mL) were added. The layers were separated and the aqueous layer was extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (14% ethyl acetate in hexanes) to afford 51 (302 mg, 98% over 2 steps) as a yellow solid.

methoxy)dimethylsilane (61c)
To a solution of 58a (20.0 mg, 0.0861 mmol, 1 equiv) in dimethylformamide (0.21 mL) were added imidazole (11.7 mg, 0.172 mmol, 2.00 equiv) and tert-butyldimethylsilyl chloride (19.5 mg, 0.129 mmol, 1.50 equiv) at 0 °C and the reaction was allowed to warm to 23 °C. After 20 h, saturated aqueous ammonium chloride solution (10 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (3 × 10 mL) and the combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL). The washed solution was dried over sodium sulfate, the dried solution was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (5% ethyl acetate in hexanes) to obtain 61c (20.

tert-butyl((6-ethyl-1,1,2-trimethyl-1,2-dihydronaphthalen-2-yl)methoxy)diphenylsilane (84)
To a solution of triflate 83 ( (20 mL), water (100 mL) and saturated aqueous ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL) and the washed solution was dried over sodium sulfate. The filtrate was concentrated under reduced pressure, passed through a plug of silica (5% ethyl acetate in cyclohexane) and used without further purification in the next step. Analytical Data for 84: The physical data were identical in all respects to those previously reported [54].
3.51 (6-ethyl-1,1,2-trimethyl-1,2-dihydronaphthalen-2-yl)methanol (58b) To a stirred solution of protected alcohol 84 (ca. 25.5 mmol, 1 equiv) in tetrahydrofuran (130 mL) was added a solution of tetrabutylammonium fluoride (1 M in THF, 35 mL, 35 mmol, 1.4 equiv) at 0 °C. The ice bath was removed after 15 min and the reaction was stirred at 23 °C for 18 h. Excess fluoride was quenched by addition of water (50 mL). The reaction was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL) and the washed solution was dried over sodium sulfate. The filtrate was concentrated under reduced pressure. Purification by flash column chromatography (1% ethyl acetate in cyclohexane initially, grading to 5% ethyl acetate in cyclohexane) afforded the title compound 58b (5.9 g, 99%) as a colorless viscous oil. Analytical Data for 58b: The physical data were identical in all respects to those previously reported [54].

6-ethyl-1,1,2-trimethyl-1,2-dihydronaphthalene-2-carbaldehyde (85b)
To a solution of oxalyl chloride (4.4 mL, 50 mmol, 2.0 equiv) in dichloromethane (250 mL) was added a solution of dimethyl sulfoxide (4.4 mL, 63 mmol, 2.5 equiv) in dichloromethane dropwise at -78 °C. The mixture was stirred for 30 min before a solution of alcohol 58b (5.8 g, 25 mmol, 1 equiv) in dichloromethane (25 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h before triethylamine (17 mL, 0.13 mol, 5.0 equiv) was added. The reaction was stirred for 30 min at -78 °C and 4 h at 23 °C. Excess base was quenched by the addition of saturated aqueous ammonium chloride solution (100 mL). The biphasic mixture was extracted with diethyl ether (3 × 200 mL). The combined organic layers were washed with concentrated aqueous sodium chloride solution (200 mL) and dried over sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (5% ethyl acetate in cyclohexane) afforded aldehyde 85b as colorless oil (5.7 g, 99%). Analytical Data for 85b: The physical data were identical in all respects to those previously reported [54].

Salimabromide (7)
A flask charged with lactone 94b (438 mg, 1.41 mmol, 1 equiv) and silver trifluoroacetate (935 mg, 4.23 mmol, 3.00 equiv) was sparged with nitrogen. Trifluoroacetic acid (10 mL) was added and the mixture was stirred at 0 °C until a clear solution was formed. Bromine (0.22 mL, 4.2 mmol, 3.0 equiv) was added dropwise under rigorous stirring. The whiteorange suspension was stirred for 10 min at 0 °C. Excess bromine and trifluoroacetic acid were quenched by the addition of saturated aqueous sodium thiosulfate solution (10 mL) and