Bis-enolates with extended π-conjugation are powerful nucleophiles. Study of their alkylation reactions with very hindered C-electrophiles

Bis-enolates with extended π-conjugation are powerful nucleophiles. Study of their alkylation reactions with very hindered C-electrophiles Mariña Castroagudín, Rubén Lobato,† Lucas Martínez-García, F. Javier Sardina* and M. Rita Paleo* Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain † Present address Mestrelab Research S. L., Feliciano Barrera 9, 15706 Santiago de Compostela, Spain Email: [email protected] [email protected] Abstract: Bis-enolates with extended π-conjugation, prepared by alkali metal mediated reduction of several aromatic and unsaturated diesters, can be efficiently and regioselectively alkylated with very hindered C-electrophiles, such as neopentyl, secondary and tertiary alkyl 1. Na/C10H8, THF Na/C10H8 THF CO2iPr CO2iPr OiPr ONa OiPr ONa α γCO2iPr CO2iPr R1 R2R3 CO2iPr CO2iPr CO2Me CO2Me CO2Me CO2Me t-Bu 2. t-BuI a: 1. Hindered R-X, 2. O2 b: 1. Ad-I, DMF, 2. Br(CH2)nBr, 3. DBU a b halides and tosylates. A one-step synthesis of 4-alkyl phthalates was derived from the reductive-alkylation of a phthalate diester with hindered halides followed by rearomatization with oxygen. Additionally, synthetic protocols have been developed to efficiently prepare complex fusedor spiro-bicycles from diisopropyl phthalate in just one or two steps. Introduction Reductive alkylation reactions are useful tools to build complex structures from simple aromatic compounds.1 In this particular topic we have been studying the reductive alkylation of aromatic diesters, e.g. dialkyl phthalates, promoted by alkali metals under ammonia free conditions2 or mediated by tin-lithium reagents through a nucleophilic stanna-Brook rearrangement,3 to gain access to complex polycyclic systems. We have proposed that the key intermediates of these reactions are relatively stable bis-enolates with extended πconjugation that can be trapped with primary α,ω-bis-electrophiles to give fused bicyclic compounds.2 These alkylations occur regioselectively, with the C-C bond formation taking place at both the α positions of the enolate moieties, resulting in two adjacent quaternary centers being formed in the process. Reductive alkylation with different primary biselectrophiles was achieved starting from anthracene4 and naphthalene5 diesters as well, to give a variety of fused and bridged polycycles. Although two possible nucleophilic sites are available in these dianionic species, αor γto each enolate group, exclusive α-alkylation was always observed when primary halides or tosylates were used as electrophiles (Scheme 1). There are countless examples in the literature of C-C bond-forming reactions between a carbon dianion and primary electrophiles.6 In stark contrast, reports of alkylations of carbon dianions with more hindered (secondary) alkyl halides are scarce and there are no reports of alkylations with tertiary or neopentylic electrophiles, probably due to the fact that elimination or rearrangement processes become the predominant reaction pathways for these highly basic nucleophiles when the C-electrophiles used are somewhat hindered.7 We now report the unexpected finding that bis-enolates with extended π-conjugation, such as 2, undergo efficient, regioselective alkylation reactions with very hindered electrophiles such as secondary, neopentylic, and even tertiary alkyl halides. As a direct application of this transformation, from its simplest case, namely the alkylation of phthalate diester 1, a regioselective one-step synthesis of 4-alkyl phthalates has been developed. As relevant precedents of our work we should mention that the synthesis of alkylsubstituted arenes via reductive alkylation-rearomatization of aromatic carboxylic acids has been reported. The procedure employed involves performing a Birch reaction8 on benzoic acids followed by an alkylation of the intermediate enolate formed and then carrying out a decarbonylative rearomatization on the resulting cyclohexadiene carboxylic acid.9 In the same vein, different dearomatization/rearomatization approaches have also been successfully developed for the regioselective introduction of up to three alkyl groups onto an aromatic ring.10, 11, 12 However only primary alkyl halides or the relatively unhindered iPrBr have been used successfully as electrophiles in all the aforementioned synthetic sequences. Thus, the attachment of hindered (bulky) alkyl groups to aromatic rings via the alkylation of anionic species remains a challenge which has remained unaddressed to date. Scheme 1. Dearomatization/Alkylation of Phthalate 1 Results and Discussion We have previously shown that the generation of bis-enolates, such as 2 (Scheme 1, more on the characterization of the nature of this dianionic intermediate below), from CO2iPr CO2iPr CO2iPr CO2iPr R ONa OiPr OiPr ONa α γ 1 CO2iPr CO2iPr R + 24 3 aromatic diesters can be easily accomplished by reaction of phthalates with alkali metals in the presence of naphthalene as an electron carrier in THF as solvent.13 To test the feasibility of alkylating dianion 2 with hindered halides we initially chose 1-iodoadamantane as the electrophile.14 In a typical reaction, diisopropyl phthalate (1) was treated with excess sodium naphthalene in THF for 6 h at –78 ºC, 1-iodoadamantane in DMF was then added and the reaction mixture was stirred for 16 h while letting it warm up to –30 ºC. Examination of the crude reaction product showed that adamantylation had indeed taken place to give the γalkyl-cyclohexadienes 4 (R = 1-adamantyl, as a mixture of diastereoisomers), along with an alkylated and rearomatized product 5 (see Scheme 2). Cyclohexadienes 4 (a mixture of cis and trans isomers) showed a remarkable tendency to rearomatize under attempted chromatographic purification, or simply upon standing, so we decided to directly oxidize the crude reaction mixture before performing the aqueous work-up, to obtain directly the adamantyl-substituted phthalate 5a (see Scheme 2). For this purpose we tested DDQ, air and oxygen as oxidants, and found that the latter provided a higher yield of a cleaner rearomatized product. Thus, the optimized alkylation-rearomatization procedure involved the treatment of the sodium bis-enolate derived from phthalate 1 with 1-iodoadamantane for 16 h at –30 ºC, followed by bubbling oxygen through the reaction mixture for 1 hour. The desired product 5a was isolated in 62% yield and its structure was confirmed by X-ray crystallography. Attempted reductive alkylation with lithium/naphthalene at -30 ºC followed by treatment with 1-iodoadamantane was unsuccessful and only led to reduced (nonalkylated) products. Scheme 2. γ-Alkylation with Hindered Halides followed by Rearomatization When t-butyl iodide was used as electrophile, the t-butylated phthalate 5b was isolated in 53% yield. In this case, reductive/alkylation with lithium/naphthalene and t-butyl iodide was also effective to give 5b in a slightly lower yield (46%). Analogous results were obtained with the t-alkyl halides methylcyclohexyl iodide and 6-iodo-2,6-dimethyloctane, which gave diesters 5c (42% yield) and 5d (49% yield), respectively (see Scheme 2). Tertiary alkyl bromides were also successfully used as electrophiles in this transformation and alkylation of 2 with t-butyl bromide gave 5-t-butylphthalate 5b, although in a slightly lower yield (47%) than the reaction with the corresponding iodide. In the same vein, the use of t-pentyl bromide as electrophile afforded 5e in 59% yield. In contrast, the CC bond forming reactivity decreased dramatically when 1-bromoadamantane was reacted with bis-enolate 2, as no alkylated product was observed in the crude reaction mixture. CO2iPr CO2iPr CO2iPr CO2iPr CO2iPr CO2iPr CO2iPr CO2iPr CO2iPr CO2iPrCO2iPr CO2iPr 2. R-X, –78 ºC to –30 ºC, 16 h 1. Na/C10H8, –78 ºC, 6 h 3. O2, –78 ºC, 1 h CO2iPr CO2iPr CO2iPr CO2iPr R 5 1 5a (X = I, 62%; Br, 0%) 5b (X = I, 53%; Br, 47%) 5e (X = Br, 59%) 5d (X = I, 49%) 5c (X = I, 42%) 5f (X = I, 75%) iPrO2C HH H CO2iPr CO2iPr CO2iPr CO2iPr 5h (X = I, 64%) 5i (X = I, 64%) 3 5g (X = I, 53%, 1.5:1) iPrO2C The behavior of other types of very sterically hindered electrophiles was next examined. Efficient, exclusive γ-alkylation was also observed upon reaction of bis-enolate 2 with 3-iodo-2,4-dimethylpentane, a very hindered secondary electrophile, which gave a 75% yield of the desired alkylated product 5f. A chiral hindered secondary substrate, 3-β-iodocholest-5-ene, also led to the expected γ-alkylated product 5g in 53% yield, but as a 1.5:1 mixture of epimers at C3 (more on the lack of stereospecificity in this reaction later). In the same vein, we decided to study the behavior of bis-enolate 2 towards neopentyl halides, notorious very poor electrophiles.14b,15 In our case, efficient alkylation of 2, without rearrangement of the neopentyl moiety, was achieved with neopentyl iodide (to give 5h in 64% yield) and with 3-iodo-2,2-dimethylbutane (to give 5i in 64% yield). The fact that bis-enolate 2 is exclusively alkylated at the γ position with very hindered electrophiles, while it reacts with complete regioselectivity through the α position with primary electrophiles2,3a prompted us to examine in more detail the alkylation of our workhorse dianionic nucleophile with electrophiles of varying steric demands (Table 1). We initially examined its reaction with isopropyl iodide and we observed that the alkylation took place solely at the bis-enolate α-carbon. By quenching this reaction with HOAc at –30 ºC, the unconjugated diene 3a was obtained as the main product (72% isolated yield). The effect of the leaving group was next examined and we found that isopropyl bromide also performs well in the alkylation reaction, the desired 3a being isolated in 80% yield. Unsurprisingly, no alkylation was observed when the much poorer electrophile isopropyl chloride was used (Table 1). Table 1. Alkylations of 1 with Secondary Halides. Effect of the Leaving Group We then surveyed the behavior of the family of 4to 8-membered cycloalkyl halides as electrophiles, so the effects of ring size and leaving group could be evaluated. As shown in Table 1, the best results (in terms of regioselectivity) were obtained when bromide was used as the leaving group, the corresponding α-alkylated products 3 being isolated in good yields (3b: 86%, 3c: 84%, 3d: 79%, 3e: 83%, 3f: 80%, respectively). Cycloalkyl tosylates reacted more sluggishly and the desired α-alkylated products were obtained only in low to moderate yields (3d: 22%, 3e: 56%, 3f: 47%). In contrast, alkylation of bis-enolate 2 with cycloalkyl iodides led to mixtures of regioisomers 3 and 4. The regioselectivity of the alkylation decreased in the series cyclohexane (10:1) > cycloheptane (~5:2) > cyclooctane (~3:2). As CO2iPr CO2iPr 1. Na/C10H8, –78 ºC, 6 h 3. HOAc, –30 ºC, 1 min 1 CO2iPr 3 CO2iPr CO2iPr R CO2iPr 4 + R R iPr iPr iPr Cyclobutyl Cyclopentyl Cyclopentyl Cyclohexyl Cyclohexyl Cyclohexyl Cycloheptyl Cycloheptyl Cycloheptyl Cyclooctyl Cyclooctyl Cyclooctyl 4-Tetrahydropyranyl N-Boc-4-piperidinyl entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 α-alkylation 3a, 72% 3a, 80% 3a, 0% 3b, 86% 3c, 67% 3c, 84% 3d, 74% 3d, 79% 3d, 22% 3e, 51% 3e, 83% 3e, 56% 3f, 34% 3f, 80% 3f, 47% 3g, 43% 3h, 76% γ-alkylationa - - - - - - 4d, 7% tr - 4e, 21% tr - 4f, 21% 4f, 3% - - - 2. R-X, –78 to –30 ºC, 16 h X I Br Cl Br I Br I Br OTs I Br OTs I Br OTs Br Br 6 (R = COC6H4-4-Br) OR OR 1. LiAlH4, THF 2. 4-Br-C6H4-COCl 3d a The product of γ-alkylation 4 was isolated as the corresponding rearomatized phthalate 5 examples of the use of heteroatom containing electrophiles, we treated bis-enolate 2 with 4bromotetrahydropyran and with 1-Boc-4-bromopiperidine to obtain the α-alkylated products 3g and 3h in 43% and 76% yield, respectively, thus indicating that the reaction conditions tolerate the presence of heteroatoms and a Boc-protecting group in the electrophile. NOE experiments to establish the stereochemistry of 3 were inconclusive, but the relative trans configuration of the ester groups of 3 was unambiguously determined by X–ray crystallography of a crystalline derivative of 3d, obtained by LiAlH4 reduction to the corresponding diol and subsequent derivatization with p-bromobenzoyl chloride to the diester 6. Cyclohexadienes 3 tend to slowly equilibrate to the conjugated isomer 7 on standing (Scheme 3). We took advantage of this behavior by quenching the reaction mixture with iPrOH instead of HOAc, and subsequent stirring of the reaction mixture for 3 h at rt so as to equilibrate isomers 3 towards the more stable, fully conjugated regioisomer 7. Under these conditions, compounds 7 were prepared in yields comparable to those obtained for their kinetic regioisomers 3 (see Scheme 3). Scheme 3. Reductive-Alkylation with Secondary Bromides 1. Na, C10H8 3. iPrOH 1 CO2iPr 7 R CO2iPr 2. R-Br CO2iPr CO2iPr 7a, 76% 7b, 85% 7c, 78% 7d, 75% 7e, 83% 7f, 76% R = R = R = R = R = R = 7g, 45% O R = 7h, 56% NBoc R = The ease of the alkylation of bis-enolate 2 with very hindered electrophiles, including tertiary and neopentyl halides, is exceptional and prompts questions about what could be the origin of the high nucleophilicity of this species. We speculated that the dianionic nature of bis-enolate 2 could contribute to its nucleophilic strength, due to the high negative charge of this type of intermediate. However, the most thoroughly studied bis-enolate in the literature, the dianion derived from methyl acetoacetate, has been efficiently alkylated only with primary alkyl halides and with isopropyl iodide. The only published attempt at alkylating this dianion with a tertiary electrophile, namely t-butyl bromide, was unsuccessful.16 In our hands, and following the reaction conditions described by Weiler et al., treatment of the dianion of methyl acetoacetate with t-butyl iodide or with 1-adamantyl iodide failed to produce any alkylated products. Scheme 4. Scope of Reductive Alkylation of Aromatic Diesters with t-Butyl Iodide CO2Me CO2Me Na, C10H8 THF 8 MeO2CH CO2Me 10 (46%) CO2R CO2R 11a, R = iPr 11b, R = Me tBu CO2Me CO2Me 15 (53%) CO2iPr tBu CO2iPr CO2iPr CO2iPr tBu + 13 (52%) 14 (29%) Na, C10H8 9 OMeNaO OMeNaO –78 ºC to rt 18 h –78 ºC, 3 h t-BuI NaO OR ORNaO –50 ºC, 6 h 12 1.t-BuI, –30 ºC, 16 h 2. MeOH, 3 h 1.t-BuI, –30 ºC 2. HOAc C bond forming transformation we treated bis-enolate 2 first with 1-iodoadamantane and then with 1,3-dibromopropane. Under the usual reaction conditions, bis-enolate 2 was alkylated with 1-iodoadamantane at the γ-position, then 1,3-dibromopropane was added at – 30 ºC and the reaction mixture was stirred for 10 h while warming to rt. At this point we expected that doubly alkylated diester 23 should have formed in the reaction mixture and further reasoned that the removal of the remaining acidic hydrogen of 23 with a suitable base could lead to a cyclization via a third enolate alkylation reaction. In fact, when DBU was added to the reaction mixture obtained as described previously (before quenching) at 0 ºC, the desired adamantyl hydrindadiene 24 was obtained in 57% isolated yield (Scheme 7). The relative configuration of the diester was confirmed to be cis by X-Ray crystallography of crystalline diol 25 obtained by LiAlH4 reduction of diester 24. Scheme 7. One Pot Sequential Alkylations from Phthalate 1 In the same vein of trying to make the most of the versatile, multiple nucleophilic nature of bis-enolate 2, we decided to explore the further alkylation reactions of monoenolate 26, resulting from the α-selective alkylation of 2 with less sterically demanding electrophiles. We hypothesized that, due to the steric hindrance exerted by the newly introduced α-alkyl group, a second electrophile would react at the γ-carbon of the πCO2iPr CO2iPr CO2iPr CO2iPr 1 1. Na/C10H8, –78 ºC, 6 h 2. Ad-I,DMF, –78 to –30 ºC, 16 h 3. Br(CH2)3Br, –30 ºC to rt, 10 h 4. DBU, 0 ºC to rt, on 24 (57%) CO2iPr CO2iPr 23 Br 22 OiPr ONa CO2iPr 25 (91%)OH OH Ad LiAlH4 extended monoenolate. Furthermore, the use of a bis-electrophile for the second alkylation process could open a way for a two-step, or maybe even a one-pot, preparation of spirocycles25 from phthalate 1 (see Scheme 8). In practice, reductive alkylation of phthalate 1 with 1-iodopropane afforded 27 in 80% yield. Deprotonation of 27 with NaOiPr in THF at –30 ºC generates a dienolate that reacts at the γ-position with 1,4-dibromobutane or with 1,5-dibromopentane to give the fiveand sixmembered spirocyclic compounds 28a (90%) and 28b (87%), respectively. The sevenmembered ring homologue could not be obtained from an analogous reaction of 27 with 1,6dibromohexane.26 Increasing the rigidity of the electrophile to restrict rotation in the chain proved to be instrumental for the cyclization to occur, and the unsaturated 7-membered spirocycle 28c was isolated in 67% yield when 2,2′-bis(chloromethyl)-1,1′-biphenyl was used as the electrophile. Excellent results were also obtained when o-dichloroxylene and 1,8bis(bromomethyl)naphthalene were used, yielding 28d (91%) and 28e (88%), respectively. Spirocyclic compounds were also prepared in just one pot from phthalate 1 (see Scheme 8). Sequential alkylation of the bis-enolate derived from 1 with 1-iodopropane at -78 ºC for 6 h afforded a monoenolate that was trapped with 1,4-dibromobutane. After stirring at –78 ºC for 18 h, LDA was added at –30 ºC and the reaction mixture was stirred for an additional 6 h while warming to rt. Spiro compound 28a was isolated after column chromatography in 62% yield, slightly lower than the yield of the two-step procedure (72%). The addition of base is necessary for the dialkylated compound to evolve to the cyclized product.27 Scheme 8. Synthesis of Spirocycles Conclusion In summary, we have established that bis-enolates with extended conjugation prepared by alkaline metal mediated reduction of several aromatic and unsaturated diesters can be regioselectively alkylated with very sterically encumbered electrophiles, including tertiary and neopentyl alkyl halides, in good yields. Additionally, we have, to an extent, delineated (i) the dianionic nature of the nucleophile, (ii) the structural parameters responsible for this nucleophilic behavior, observing that the dianionic nature of these species in conjugation with the extended π-conjugated systems are required for the success of the substitution reactions at extremely sterically hindered electrophilic centers, and (iii) the alkylation mechanism. The regioselectivity displayed by the studied bis-enolates in their reaction with a variety of electrophiles ranged from complete or almost complete α-alkylation in crossconjugated systems, to complete γ-alkylation in linearly conjugated bis-enolate 2 (with CO2iPr Pr CO2iPr CO2iPr Pr CO2iPr CO2iPr Pr CO2iPr 28d (91%) 28e (88%) 28c (67%) CO2iPr CO2iPr CO2iPr Pr CO2iPr R2 R3 128 (67-91%) CO2iPr Pr CO2iPr 28a One pot: 62% Two steps: 72% CO2iPr Pr CO2iPr 28b (87%) 1. Na/C10H8 –78 ºC 2. Pr-I CO2iPr Pr CO2iPr 27 (80%) NaOiPr Bis-electrophile 1. Na/C10H8, –78 ºC, 6 h 2. Pr-I, 6 h Pr CO2iPr 26 ONa OiPr 3. Br(CH2)4Br, 18 h 4. LDA, —30 ºC to rt, 6h tertiary, hindered secondary and neopentyl halides), or complete α-alkylation with primary, isopropyl and cycloalkyl bromides and tosylates. As a synthetic application of this reactivity study, we have developed a simple protocol for the direct, one-pot regioselective functionalization of diisopropyl phthalate with bulky substituents, based on the reductive alkylation of phthalate 1 with very hindered tertiary, neopentylic and secondary alkyl halides and the subsequent oxidation of the monoenolate intermediates with oxygen to give 4-alkylphthalates 5. Additionally, the reactivity of the monoenolate intermediates resulting from these alkylations was put to good synthetic use in developing a protocol for consecutive reductive-alkylation-alkylation protocols which allowed the building of complex fused and spiro-structures from phthalate esters in one-pot or two steps operations. Experimental Section General Experimental Methods. All reactions were performed under an inert atmosphere of Argon in flame-dried glassware. Reaction temperatures are reported as the temperature of the bath surrounding the vessel. Solvents were distilled immediately before use: Tetrahydrofuran (THF) from sodium/benzophenone and DMF from CaH2. Flash column chromatography was performed using Merck silica gel (230-400 mesh) or using a CombiFlash Rf-200 (Teledyne-Isco) with RediSep packed columns. NMR spectra were recorded on a Varian Mercury 300 or a Varian Inova 500 instrument. Chemical shifts are reported in parts per million (ppm) and referenced to the residual solvent resonance. Melting points (Mp) were determined using a Büchi B-540 apparatus. Infrared spectra were measured using an Agilent Technologies Cary 630 FTIR spectrometer. High-resolution mass spectra were carried out on a Bruker Microtof spectrometer. 1and 2-Bromoadamantane (Aldrich) were used as received. 1-Iodoadamantene was purified by column chromatography (SiO2, hexanes). The other commercial alkyl halides were distilled immediately prior to use. 1-Iodo-1-methylcyclohexane,28 6-iodo-2,6-dimethyloctane,29 3-iodo-2,2-dimethylbutane30 and 3-β-iodo-cholestene31 were prepared by literature procedures. General Procedure A for the One-Pot Reductive Alkylation of Diisopropyl Phthalate (1) and Rearomatization. A –78 ºC suspension of small pieces of sodium (245 mg, 10.6 mmol) and naphthalene (150 mg, 1.17 mmol) in THF (4 mL) was treated with a solution of 1 (250 µL, 1.06 mmol) in THF (1 mL) and stirred for 6 h. The resulting solution was transferred via cannula to a –78 ºC flask, washed with THF (5 mL) and treated with a solution of the corresponding halide (1.17 mmol, 110 mol%) in DMF (1 mL). The reaction mixture was stirred for 16 h at –30 ºC, cooled down to –78 ºC and oxygen gas was bubbled through the solution for 1h. The reaction mixture was then partitioned between EtOAc (20 mL) and pH 7 buffer solution (15 mL). The aqueous layer was extracted with EtOAc (2 x 5 mL), and the combined organic layer was washed with 10% aqueous Na2S2O3 solution (20 mL) and brine (10 mL), dried (anhydrous Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (SiO2, 2-5% EtOAc/hexane). Diisopropyl 4-(adamantan-1-yl)phthalate (5a). Column chromatography afforded 5a (253 mg, 62% yield) as a white solid when 1-iodoadamantane was used as the electrophile. Mp 130-132 ºC (EtOAc/hexane); 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 8.2, 2.0 Hz, 1H), 5.23 (m, 2H), 2.11 (m, 3H), 1.91 (d, J = 3.0 Hz, 6H), 1.78 (m, 6H), 1.37 (d, J = 6.3 Hz, 6H), 1.35 (d, J = 6.3 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 168.1, 166.9, 154.9, 133.3, 129.3, 129.0, 127.3, 125.4, 69.3, 69.0, 43.0, 36.7, 36.7, 28.9, 21.9, 21.9; IR (neat): 1715 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C24H33O4 385.2373, found 385.2374. Diisopropyl 4-(t-butyl)phthalate (5b). Column chromatography (2-5% EtOAc/hexane) afforded 5b (172 mg, 53% yield) as pale yellow oil when t-butyl iodide was used as the electrophile. 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.2, 2.0 Hz, 1H), 5.23 (m, 2H), 1.38 (d, J = 6.3 Hz, 6H), 1.36 (d, J = 6.3 Hz, 6H), 1.33 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 168.0, 166.9, 154.8, 133.2, 129.4, 129.0, 127.6, 125.6, 69.3, 69.0, 35.1, 31.1, 21.9, 21.9; IR (neat): 1718 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C18H27O4 307.1904, found 307.1905. Diisopropyl 4-(1-methylcyclohexyl)phthalate (5c). Column chromatography (2-5% EtOAc/hexane) afforded 5c (155 mg, 42% yield) as a pale yellow oil when 1-iodo-1methylcyclohexane was used as the electrophile. 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 8.2, 2.1 Hz, 1H), 5.23 (dhept, J = 10.0, 6.3 Hz, 2H), 1.98 (m, 2H), 1.64-1.50 (m, 4H), 1.46-1.30 (m, 16H), 1.18 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 168.0, 166.9, 153.8, 133.3, 129.3, 129.1, 128.3, 126.4, 69.2, 69.0, 38.4, 37.8, 30.3, 26.3, 22.6, 21.9, 21.9; IR (neat): 1718 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C21H31O4 347.2217, found 347.2217. Diisopropyl 4-(3,7-dimethyloctan-3-yl)phthalate (5d). Column chromatography (25% EtOAc/hexane) afforded 5d (204 mg, 49% yield) as a colorless oil when 6-iodo-2,6dimethyloctane was used as the electrophile. 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.2, 2.0 Hz, 1H), 5.22 (dhept, J = 8.8, 6.3 Hz, 2H), 1.81-1.62 (m, 2H), 1.56 (dq, J = 14.5, 7.4 Hz, 1H), 1.52-1.39 (m, 2H), 1.36 (d, J = 6.2 Hz, 6H), 1.35 (d, J = 6.2 Hz, 6H), 1.26 (s, 3H), 1.18-1.03 (m, 3H), 0.91 (m, 1H), 0.78 (dd, J = 6.1, 1.4 Hz, 6H), 0.64 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 168.0, 167.0, 152.0, 133.0, 129.3, 128.8, 128.7, 126.8, 69.2, 68.9, 42.8, 41.6, 39.7, 35.6, 27.8, 23.4, 22.8, 22.6, 21.9, 21.9, 21.8, 8.7; IR (neat): 1722 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C24H39O4 391.2843, found 391.2845. Diisopropyl 4-(t-pentyl)phthalate (5e). Column chromatography (2-5% EtOAc/hexane) afforded 5e (200 mg, 59% yield) as colorless oil when 2-bromo-2- methylbutane was used as the electrophile. 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.2, 2.0 Hz, 1H), 5.23 (dhept, J = 10.9, 6.3 Hz, 2H), 1.66 (q, J = 7.4 Hz, 2H), 1.37 (d, J = 6.3 Hz, 6H), 1.35 (d, J = 6.3 Hz, 6H), 1.29 (s, 6H), 0.67 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 168.0, 167.0, 153.3, 133.1, 129.3, 128.9, 128.3, 126.3, 69.3, 69.0, 38.4, 36.7, 28.3, 21.9, 21.9, 9.2; IR (neat): 1718 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C19H29O4 321.2060, found 321.2063. Diisopropyl 4-(2,4-dimethylpentan-3-yl)phthalate (5f). Column chromatography (25% EtOAc/hexane) afforded 5f (279 mg, 75% yield) as colorless oil when 3-iodo-2,4dimethylpentane was used as the electrophile. 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 1H), 7.36 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 5.23 (hept, J = 6.3 Hz, 2H), 2.23-2.08 (m, 3H), 1.36 (d, J = 6.2 Hz, 12H), 0.86 (d, J = 6.4 Hz, 6H), 0.72 (d, J = 6.4 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 167.8, 167.2, 145.8, 132.5, 131.9, 130.1, 130.0, 128.3, 69.2, 69.1, 59.4, 28.8, 21.9, 21.9, 21.7, 19.3; IR (neat): 1718 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C21H33O4 349.2373, found 349.2377. 3-Iodo-2,4-dimethylpentane. To a 0 ºC solution of PPh3 (6.74 g, 25.7 mmol), imidazole (1.75 g, 25.7 mmol), and 2,4-dimethylpentan-3-ol (3 mL, 21.4 mmol) in CH2Cl2 (107 mL) was added I2 (6.5 g, 25.6 mmol) and the resulting mixture was stirred at rt for 16 h. H2O (25 mL) was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (20 mL), and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 100% hexane) to yield 3-iodo-2,4-dimethylpentane (2.27 g, 47%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 3.96 (t, J = 6.1 Hz, 1H), 1.55 (h, J = 6.5 Hz, 2H), 1.02 (d, J = 6.4 Hz, 1H), 0.98 (d, J = 6.6 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 64.4, 33.3, 23.1, 22.7. Diisopropyl 4-((8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-4-methylpentan2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren- 3-yl)phthalate (5g). Column chromatography afforded 5g (349 mg, 53% yield) as pale yellow oil and as 1.5:1 mixture of epimers when 3-β-iodocholest-5-ene was used as the electrophile. 1H NMR (500 MHz, CDCl3) δ (minor + major) 7.69 and 7.47 (d, J = 1.8 Hz, 1H), 7.60 and 7.66 (d, J = 8.0 Hz, 1H), 7.51 and 7.35 (dd, J = 8.0, 1.8 Hz, 1H), 5.46 and 5.36 (m, 1H), 5.23 (m, 2H), 3.13 and 2.58 (m, 1H), 2.42 (m, 1H), 2.80 and 2.17 (m, 1H), 2.061.94 (m, 3H), 1.89-1.69 (m 3H), 1.62-0.84 (m, 35H), 0.93 and 0.90 (d, J = 6.5 Hz, 3H), 0.87 (m, 6H), 0.70 and 0.68 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (minor + major) 167.9, 167.7, 167.2, 166.8, 150.7, 150.2, 142.3, 140.9, 133.6, 132.6, 130.6, 129.8, 129.5, 129.3, 128.9, 128.8, 128.6, 127.1, 122.3, 120.8, 69.3, 69.0, 69.0, 68.9, 57.0, 56.9, 56.3, 56.3, 50.6, 49.9, 45.8, 42.4, 40.3, 39.9, 39.8, 39.8, 39.7, 39.6, 38.5, 37.4, 37.0, 36.3, 36.0, 35.9, 35.4, 32.9, 32.1, 32.0, 32.0, 31.9, 29.8, 28.4, 28.4, 28.1, 28.1, 24.4, 24.4, 24.0, 24.0, 23.0, 22.7, 22.0, 21.9, 21.9, 21.1, 20.8, 19.8, 19.7, 18.9, 18.8, 12.0, 12.0; IR (neat): 1722 cm-1 (C=O); HRMS (ESI) m/z [M + Na]+ calcd for C41H62O4Na 641.4540, found 641.4544. Diisopropyl 4-neopentylphthalate (5h). Column chromatography afforded 5h (217 mg, 64% yield) as colorless oil when 1-iodo-2,2-dimethylpropane was used as the electrophile. 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.23 (dd, J = 8.0, 1.8 Hz, 1H), 5.22 (m, 2H), 2.53 (s, 2H), 1.34 (dd, J = 6.4, 2.5 Hz, 12H), 0.89 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 167.7, 167.0, 143.4, 132.7, 132.5, 130.4, 129.8, 128.5, 69.1, 69.0, 49.9, 32.0, 29.3, 21.9, 21.8; IR (neat): 1718 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C19H29O4 321.2060, found 321.2061. Diisopropyl 4-(3,3-dimethylbutan-2-yl)phthalate (5i). Column chromatography afforded 5i (227 mg, 64% yield) as colorless oil when 3-iodo-2,2-dimethylbutane was used as the electrophile. 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.28 (dd, J = 8.0, 1.7 Hz, 1H), 5.23 (dhept, J = 12.9, 6.5 Hz, 2H), 2.62 (q, J = 7.1 Hz, 1H), 1.36 (dd, J = 6.3, 4.2 Hz, 12H), 1.25 (d, J = 7.2 Hz, 3H), 0.86 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 167.7, 166.9, 148.9, 132.5, 131.0, 129.8, 129.2, 128.3, 69.1, 68.9, 49.9, 33.8, 27.7, 21.8, 21.8, 21.8, 15.6; IR (neat): 1718 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C20H31O4 335.2217, found 335.2219. General Procedure B for the Reductive Alkylation of Diisopropyl Phthalate (1) with Secondary Halides. Preparation of Kinetic Isomer 3. A –78 ºC suspension of small pieces of sodium (245 mg, 10.6 mmol) and naphthalene (150 mg, 1.17 mmol) in THF (4 mL) was treated with a solution of 1 (250 µL, 1.06 mmol) in THF (1 mL) and stirred for 6 h. The resulting solution was transferred via cannula to a –78 ºC flask, washed with THF (5 mL) and treated with a solution of the corresponding secondary halide (1.17 mmol) in DMF (1 mL). The reaction mixture was slowly warmed to –30 ºC and stirred for 16 h, quenched by addition of deoxygenated HOAc (150 µL, 2.62 mmol) and stirred for 1 min. The reaction mixture was partitioned between EtOAc (20 mL) and pH 7 buffer solution (15 mL). The aqueous layer was extracted with EtOAc (2 x 5 mL), and the combined organic layer was washed with 10% aqueous Na2S2O3 solution (20 mL) and brine (10 mL), dried (anhydrous Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (SiO2, 2-5% EtOAc/hexane). Diisopropyl trans-1-isopropylcyclohexa-3,5-diene-1,2-dicarboxylate (3a). Colorless oil, 80% yield (250 mg) using 2-bromopropane as the electrophile. 1H NMR (500 MHz, CDCl3) δ 6.00 (dd, J = 9.7, 5.1 Hz, 1H), 5.91 (m, 1H), 5.81 (dd, J = 9.4, 4.8 Hz, 1H), 5.73 (d, J = 9.6 Hz, 1H), 5.01 (m, 2H), 3.97 (dd, J = 4.8, 2.0 Hz, 1H), 2.37 (hept, J = 6.9 Hz, 1H), 1.23 (d, J = 6.4 Hz, 6H), 1.21 (d, J = 6.3 Hz, 6H), 0.98 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 173.6, 170.9, 128.1, 124.7, 124.4, 123.6, 68.4, 68.0, 52.2, 46.0, 32.0, 22.0, 21.8, 21.8, 21.7, 18.8, 17.9; IR (neat): 1722 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C17H27O4 295.1904, found 295.1902. Diisopropyl trans-1-cyclobutylcyclohexa-3,5-diene-1,2-dicarboxylate (3b). Colorless oil, 86% yield (279 mg) using bromocyclobutane as the electrophile. 1H NMR (500 MHz, C6D6) δ 5.99 (dd, J = 9.7, 3.2 Hz, 1H), 5.92 (dd, J = 9.7, 5.2 Hz, 1H), 5.69 (m, 1H), 5.58 (dd, J = 9.7, 1.1 Hz, 1H), 5.00 (dhept, J = 25.1, 6.3 Hz, 2H), 4.36 (t, J = 3.2 Hz, 1H), 3.09 (tt, J = 10.4, 7.7 Hz, 1H), 2.11 (m, 3H), 1.95 (m, 1H), 1.73 (qt, J = 10.4, 8.1 Hz, 1H), 1.61 (m, 1H), 1.07 (m, 9H), 1.01 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (126 MHz, C6D6) δ 174.0, 170.9, 126.4, 125.0, 124.7, 123.6, 68.2, 68.1, 50.6, 47.0, 39.2, 25.5, 25.3, 21.9, 21.8, 21.7, 21.7, 19.2; IR (neat): 1718 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C18H27O4 307.1904, found 307.1905. Diisopropyl trans-1-cyclopentylcyclohexa-3,5-diene-1,2-dicarboxylate (3c). Colorless oil, 84% yield (285 mg) using bromocyclopentane as the electrophile. 1H NMR (500 MHz, CDCl3) δ 6.02 (dd, J = 9.7, 5.1 Hz, 1H), 5.92 (ddd, J = 9.7, 5.1, 2.2 Hz, 1H), 5.85 (dd, J = 9.6, 4.1 Hz, 1H), 5.71 (d, J = 9.7 Hz, 1H), 5.02 (dhept, J = 16.3, 6.3 Hz, 2H), 4.05 (dd, J = 4.1, 2.3 Hz, 1H), 2.36 (tt, J = 9.6, 7.4 Hz, 1H), 1.72 (m, 2H), 1.58-1.34 (m, 6H), 1.23 (dt, J = 8.4, 6.2 Hz, 12H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.3, 171.3, 127.6, 124.4, 123.9, 68.5, 68.2, 51.3, 47.3, 43.7, 28.5, 27.2, 25.3, 25.0, 22.0, 21.9, 21.8, 21.8; IR (neat): 1715 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C19H29O4 321.2060, found 321.2060. Diisopropyl trans-[1,1'-bi(cyclohexane)]-3,5-diene-1,2-dicarboxylate (3d). Colorless oil, 79% yield (279 mg) using bromocyclohexane as the electrophile. 1H NMR (500 MHz, CDCl3) δ 5.98 (dd, J = 9.7, 5.1 Hz, 1H), 5.90 (ddd, J = 9.7, 5.1, 1.9 Hz, 1H), 5.80 (dd, J = 9.5, 4.8 Hz, 1H), 5.76 (d, J = 9.7 Hz, 1H), 5.01 (dhept, J = 12.5, 6.3 Hz, 2H), 3.96 (dd, J = 4.8, 2.0 Hz, 1H), 1.98 (m, 2H), 1.75-1.56 (m, 4H), 1.28-1.14 (m, 15H), 1.13-0.98 (m, 2H); 13C{1H} NMR (126 MHz, 60 ºC, CDCl3) δ 173.8, 170.9, 128.4, 124.7, 124.6, 2.58 (tt, J = 12.2, 3.4 Hz, 1H), 2.13 (dt, J = 13.0, 2.7 Hz, 1H), 1.47 (qd, J = 12.3, 4.2 Hz, 1H), 1.32 (m, 1H), 1.26 (dd, J = 6.2, 3.5 Hz, 6H), 1.18 (m, 1H), 1.18 (d, J = 6.2 Hz, 3H), 1.15 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 173.0, 165.7, 138.1, 130.5, 126.5, 124.8, 68.6, 68.5, 68.2, 51.6, 41.3, 29.2, 29.0, 27.4, 22.0, 21.9, 21.8, 21.6; IR (neat): 1729, 1707 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C19H29O5 337.2010, found 337.2010. Diisopropyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)cyclohexa-2,4-diene-1,2dicarboxylate (7h). Colorless oil (252 mg, 56% yield). 1H NMR (500 MHz, CDCl3) δ 7.09 (t, J = 3.7 Hz, 1H), 5.87 (d, J = 9.9 Hz, 1H), 5.55 (d, J = 10.1 Hz, 1H), 5.01 (hept, J = 6.3 Hz, 1H), 4.93 (hept, J = 6.3 Hz, 1H), 4.06 (m, 2H), 2.93-2.53 (m, 4H), 2.42 (m, 1H), 2.18 (br d, J = 12.9 Hz, 1H), 1.40 (s, 9H), 1.29-1.08 (m, 14H), 0.96 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 172.9, 165.7, 154.8, 138.0, 130.6, 126.3, 124.7, 79.2, 68.1, 68.1, 51.5, 44.3, 42.2, 28.5, 28.2, 28.0, 27.2, 21.9, 21.9, 21.7, 21.5; IR (neat): 1730, 1692 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C24H38NO6 436.2694, found 436.2695. Dimethyl 9-(t-butyl)-9,10-dihydroanthracene-9,10-dicarboxylate (10). A suspension of small and thin pieces of sodium (156 mg, 6.8 mmol) and naphthalene (192 mg, 1.5 mmol) in THF (5 mL) was sonicated for 45 min to rt. The dark purple solution was transferred via cannula to a flask under Ar, and the excess sodium was washed with THF (0.8 mL). The vessel was cooled to –78 ºC and a solution of anthracene 8 (200 mg, 0.68 mmol) in THF (1 mL) was added. After 3 h, t-butyl iodide (90 µL, 0.75 mmol) was added, and the resulting mixture was stirred for 16 h while slowly warming to rt. The reaction was quenched with deoxygenated HOAc (100 µL, 1.75 mmol), pH 7 phosphate buffer was added (10 mL), and the mixture extracted with EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2 x 5 mL) and the combined organic phase was washed with 10% aqueous Na2S2O3 solution (10 mL) and brine (10 mL), dried, filtered and evaporated. The residue was purified by flash column chromatography (SiO2, 2-5% EtOAc/hexane) to give 110 mg of 10 as a white solid (46% yield). Mp 166-169 ºC (EtOAc-Hex); 1H NMR (500 MHz, CD2Cl2) δ 7.54 (dd, J = 7.8, 1.5 Hz, 2H), 7.34 (td, J = 7.5, 1.4 Hz, 2H), 7.27 (td, J = 7.6, 1.5 Hz, 2H), 7.10 (dd, J = 8.0, 1.4 Hz, 2H), 5.08 (s, 1H), 3.64 (s, 3H), 3.45 (s, 3H), 0.94 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.0, 172.1, 136.3, 132.4, 131.6, 130.1, 126.6, 126.1, 62.9, 52.7, 51.9, 50.6, 39.9, 27.4; IR (neat): 1726 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C22H25O4 353.1747, found 353.1745. Alkylation of Diisopropyl Naphthalene-1,4-dicarboxylate (11a) with t-Butyl Iodide. A suspension of small pieces of sodium (190 mg, 8.3 mmol) and naphthalene (235 mg, 1.83 mmol) in THF (5 mL) was sonicated for 45 min at rt. The dark purple solution was transferred via cannula to a flask under Ar, and the excess sodium was washed with THF (3 mL). The vessel was cooled to –50 ºC and a solution of naphthalene 11a (250 mg, 0.83 mmol) in THF (1 mL) was added, stirred for 6 h, and treated with t-butyl iodide (110 µL, 0.92 mmol). The reaction mixture was slowly warmed to –30 ºC and stirred for 16 h, quenched by addition of deoxygenated HOAc (120 µL, 2.1 mmol). The reaction mixture was partitioned between EtOAc (10 mL) and pH 7 buffer solution (10 mL). The aqueous layer was extracted with EtOAc (2 x 5 mL), and the combined organic layer was washed with 10% aqueous Na2S2O3 solution (20 mL) and brine (10 mL), dried (anhydrous Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (15-42 µm SiO2, 50-70% CH2Cl2/hexane) to give 13 (155 mg, 52%) and 14 (86 mg, 29%) as colorless oils. Diisopropyl 1-(t-butyl)-1,4-dihydronaphthalene-1,4-dicarboxylate (13). 1H NMR (500 MHz, CDCl3) δ 7.56 (dd, J = 7.9, 1.5 Hz, 1H), 7.34 (dd, J = 7.6, 1.6 Hz, 1H), 7.25 (td, J = 7.4, 1.4 Hz, 1H), 7.21 (td, J = 7.6, 1.7 Hz, 1H), 6.17 (m, 2H), 5.02 (dhept, J = 9.6, 6.3 Hz, 2H), 4.37 (d, J = 3.5 Hz, 1H), 1.22 (m, 9H), 1.11 (d, J = 6.3 Hz, 3H), 1.01 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 173.0, 171.3, 134.0, 132.5, 130.5, 129.9, 129.9, 126.5, 125.8, 122.8, 68.8, 68.3, 57.2, 46.4, 39.5, 27.6, 21.8, 21.8, 21.8, 21.5; IR (neat): 1722 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C22H31O4 359.2217, found 359.2211. Diisopropyl 2-(t-butyl)-1,2-dihydronaphthalene-1,4-dicarboxylate (14). Mixture of cis-trans isomers (1.0: 1.4), 1H NMR (500 MHz, CDCl3) δ (minor + major) 7.83 and 7.81 (2d, J = 7.8 Hz, 1H), 7.30-7.15 (m, 3H), 7.09 (dd, J = 3.2, 1.3 Hz, 0.6H) and 6.99 (dd, J = 6.5, 1.1 Hz, 0.4H), 5.22 (hept, J = 6.2 Hz, 0.6H) and 5.19 (hept, J = 6.2 Hz, 0.4H) , 4.88 (hept, J = 6.2 Hz, 0.4H) and 4.81 (hept, J = 6.2 Hz, 0.6H), 3.81 (s, 0.4H) and 3.77 (dd, J = 6.2, 1.3 Hz, 0.6H), 2.77 (dd, J = 6.5, 1.3 Hz, 0.4H) and 2.61 (dd, J = 6.1, 3.1 Hz, 0.6H), 1.35 (m, 6H), 1.07 (m, 12H), 0.85 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (major + minor) 172.9, 171.7, 166.2, 166.0, 139.6, 139.0, 135.4, 133.2, 131.7, 131.3, 130.9, 130.3, 129.4, 127.9, 127.7, 127.7, 127.5, 127.2, 126.1, 68.5, 68.2, 68.1, 68.0, 49.0, 46.9, 46.3, 45.7, 36.2, 32.7, 28.4, 27.7, 22.1, 22.1, 22.0, 21.8, 21.7, 21.6, 21.5; IR (neat): 1715 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C22H31O4 359.2217, found 359.2214. Dimethyl 1-(t-butyl)-1,2-dihydronaphthalene-1,4-dicarboxylate (15). A suspension of small pieces of sodium (235 mg, 10.2 mmol) and naphthalene (289 mg, 2.25 mmol) in THF (5 mL) was sonicated for 45 min at rt. The dark purple solution was transferred via cannula to a flask under Ar, and the excess sodium was washed with THF (3 mL). The vessel was cooled to –50 ºC and a solution of dimethyl naphthalene-1,4-dicarboxylate 11b (250 mg, 1.02 mmol) in THF (1 mL) was added, stirred for 6 h, and treated with t-butyl iodide (135 µL, 1.13 mmol). The reaction mixture was slowly warmed to –30 ºC and stirred for 16 h, deoxygenated MeOH (105 µL, 2.56 mmol) was added and stirred for 3h at –30 ºC. Work-up as above gave a residue that was purified by flash column chromatography (15-42 µm SiO2, 50-70% CH2Cl2/hexane) to give 15 (165 mg, 53%) as a colorless oil. 1H NMR (500 MHz, CD2Cl2) δ 7.81 (dd, J = 7.8, 1.6 Hz, 1H), 7.47 (dd, J = 7.8, 1.5 Hz, 1H), 7.27 (td, J = 7.6, 1.5 Hz, 1H), 7.22 (td, J = 7.6, 1.6 Hz, 1H), 6.99 (dd, J = 6.5, 3.2 Hz, 1H), 3.81 (s, 3H), 3.66 (s, 3H), 3.31 (dd, J = 18.9, 3.2 Hz, 1H), 2.85 (dd, J = 18.9, 6.6 Hz, 1H), 1.02 (s, 9H); 13C{1H} NMR (126 MHz, CD2Cl2) δ 175.5, 167.3, 138.8, 134.0, 131.6, 130.3, 130.1, 127.6, 127.5, 126.7, 56.4, 52.5, 52.2, 39.3, 30.3, 27.8; IR (neat): 1715 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C18H23O4 303.1591, found 303.1588. Ring-Opening and Alkylation Reactions from Bicycle 16. A suspension of Li (36 mg, 5.18 mmol) and naphthalene (290 mg, 2.26 mmol) in THF (5 mL) was sonicated at room temperature for 45 min. The solution was transferred via cannula to another roundbottomed flask, washed with THF (5 mL), cooled to –30 ºC, and treated with a solution of 16 (300 mg, 1.02 mmol) in THF (1 mL). After 1 h, the reaction mixture was treated with tbutyl iodide (490 µL, 4.11 mmol). The reaction was stirred for an additional 20 h while slowly warming to rt, quenched with pH 7 buffer solution (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried, filtered, and evaporated under reduced pressure. Purification by column chromatography (15-42 µm SiO2, 50-70% CH2Cl2/Hexane) afforded 18a (63 mg, 21%) and 19 (133 mg, 37%) as clear oils. Isopropyl 6-(t-butyl)-10-oxobicyclo[4.3.1]deca-2,4-diene-1-carboxylate (18a). 1H NMR (500 MHz, DMSO-D6, 100 ºC) δ 5.93 (m, 2H), 5.85 (m, 1H), 5.61 (m, 1H), 4.98 (hept, J = 6.2 Hz, 1H), 2.34 (td, J = 12.9, 4.1 Hz, 1H), 2.00 (ddd, J = 13.3, 12.0, 4.4 Hz, 1H), 1.93-1.69 (m, 4H), 1.23 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.06 (s, 9H); 13C{1H} NMR (126 MHz, DMSO-D6) δ 205.0, 170.2, 130.4, 128.1, 123.6, 122.9, 67.6, 65.9, 60.6, 36.0, 35.7, 34.0, 26.1, 20.9, 20.7, 17.0; IR (neat): 1733 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C18H27O3 291.1955, found 291.1957. Diisopropyl 1-(t-butyl)-1,4,5,6,7,7a-hexahydro-3aH-indene-3a,7-dicarboxylate (19). Compound 19 was isolated as a 2:3 mixture of isomers in 37% combined yield. Minor isomer (51 mg, 14%): 1H NMR (500 MHz, CDCl3) δ 5.77 (dd, J = 5.8, 2.6 Hz, 1H), 5.59 (dd, J = 5.8, 1.8 Hz, 1H), 4.98 (hept, J = 6.3 Hz, 1H), 4.90 (hept, J = 6.3 Hz, 1H), 2.91 (dd, J = 4.8, 2.9 Hz, 1H), 2.81 (dt, J = 13.0, 4.1 Hz, 1H), 2.56 (q, J = 2.5 Hz, 1H), 1.80 (m, 1H), 1.71-1.44 (m, 5H), 1.28-1.16 (m, 12H), 0.75 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 176.6, 175.1, 134.1, 133.1, 67.9, 67.7, 60.2, 56.8, 41.0, 40.6, 33.2, 27.7, 27.5, 22.2, 21.9, 21.8, 17.5, 15.8; IR (neat): 1718 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C21H35O4 351.2530, found 351.2532. Major isomer (82 mg, 23%): 1H NMR (500 MHz, CDCl3) δ 5.69 (dd, J = 5.8, 2.3 Hz, 1H), 5.59 (dd, J = 5.8, 1.9 Hz, 1H), 4.97 (dhept, J = 8.6, 6.2 Hz, 2H), 2.97 (dd, J = 6.2, 4.8 Hz, 1H), 2.42 (q, J = 6.2 Hz, 1H), 2.29 (dt, J = 4.5, 2.1 Hz, 1H), 1.87 (m, 2H), 1.63 (m, 2H), 1.44 (m, 2H), 1.24 (d, J = 6.2 Hz, 3H), 1.22 (d, J = 6.3 Hz, 3H), 1.20 (dd, J = 6.2, 1.4 Hz, 6H), 0.86 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 176.0, 175.5, 134.8, 132.4, 67.7, 67.7, 62.4, 58.5, 44.1, 41.5, 33.6, 30.6, 28.1, 22.8, 22.0, 21.9, 21.9, 21.8, 17.4; IR (neat): 1711 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C21H35O4 351.2530, found 351.2532. Isopropyl 6-isopropyl-10-oxobicyclo[4.3.1]deca-2,4-diene-1-carboxylate (18b). Following the same procedure as for 18a, starting from 16 (143 mg, 0.49 mmol) and using 2-bromopropane as the electrophile (182 µL, 1.94 mmol), 18b was isolated as a colorless oil in 74% yield (100 mg) after column chromatography purification (SiO2, 2-5% EtOAc/Hex). 1H NMR (500 MHz, CDCl3) δ 5.96-5.78 (m, 3H), 5.38 (d, J = 11.6 Hz, 1H), 5.08 (hept, J = 6.3 Hz, 1H), 2.40 (m, 1H), 2.15 (quint, J = 6.9 Hz, 1H), 1.99-1.83 (m, 3H), 1.82-1.66 (m, 2H), 1.25 (dd, J = 6.5, 2.8 Hz, 6H), 0.94 (t, J = 6.5 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 206.1, 171.6, 131.7, 128.2, 124.6, 123.9, 69.0, 66.4, 59.3, 37.5, 35.7, 32.8, 21.8, 21.6, 18.5, 17.9; IR (neat): 1711 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C17H25O3 277.1798, found 277.1799. Diisopropyl 5-(adamantan-1-yl)-2,3-dihydro-1H-indene-3a,7a-dicarboxylate (24). A –78 ºC suspension of small pieces of sodium (245 mg, 10.6 mmol) and naphthalene (150 mg, 1.17 mmol) in THF (4 mL) was treated with a solution of 1 (250 µL, 1.06 mmol) in THF (1 mL) and stirred for 6 h. The resulting solution was transferred via cannula to a –78 ºC flask, washed with THF (5 mL) and treated with a solution of 1-iodoadamantane (305 mg, 1.17 mmol) in DMF (1 mL). The reaction mixture was slowly warmed to –30 ºC and stirred for 16 h, treated with 1,3-dibromopropane (120 µL, 1.17 mmol) and stirred for 8 h at rt. The reaction mixture was cooled to 0 ºC, DBU (175 µL, 1.17 mmol) was added, and stirring was continued for an additional 16 h at rt. The reaction mixture was partitioned between EtOAc (10 mL) and pH 7 buffer solution (10 mL). The aqueous layer was extracted with EtOAc (2 x 5 mL), and the combined organic layer was washed with 10% aqueous Na2S2O3 solution (10 mL) and brine (10 mL), dried, filtered and evaporated. The residue was purified by flash column chromatography (SiO2, 2-5% EtOAc/hexane) to yield 24 as a pale yellow oil (261 mg, 57%). 1H NMR (500 MHz, CDCl3) δ 6.01 (d, J = 10.0 Hz, 1H), 5.91 (d, J = 9.9 Hz, 1H), 5.40 (s, 1H), 4.93 (hept, J = 6.3 Hz, 2H), 2.48 (m, 1H), 2.38 (ddd, J = 13.9, 9.2, 5.4 Hz, 1H), 2.04-1.89 (m, 5H), 1.77-1.48 (m, 14H), 1.17 (m, 12H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.1, 174.0, 141.7, 130.4, 121.8, 121.1, 67.8, 67.7, 56.5, 55.6, 40.7, 40.1, 39.9, 37.0, 35.5, 28.6, 21.8, 21.7, 21.7, 21.3; IR (neat): 1722 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C27H39O4 427.2843, found 427.2840. Synthesis of Diol 25. A solution of 24 (60 mg, 0.14 mmol) in THF (1 mL) was slowly added to a 0 ºC suspension of LiAlH4 (12.5 mg, 0.31 mmol, 95%) in THF (1 mL). The reaction mixture was stirred at room temperature for 3 h. After cooling to 0 ºC, EtOAc (0.5 mL) was slowly added, followed by CHCl3 (2 mL), sat. Na2CO3 (1 mL), KH2PO4, and Na2SO4. The resulting mixture was stirred at room temperature for 1 h, filtered over celite, and washed with CHCl3 (10 mL). The combined clear filtrate and washings were evaporated to give a colorless residue. Column chromatography purification (SiO2, 20% EtOAc/Hex) afforded 25 as a white solid (40.3 mg, 91%). Mp 140-141 ºC (EtOAc/hexane); 1H NMR (500 MHz, CDCl3) δ 6.12 (d, J = 9.9 Hz, 1H), 5.53 (d, J = 9.9 Hz, 1H), 5.10 (s, 1H), 3.69 (d, J = 11.5 Hz, 2H), 3.44 (dd, J = 11.6, 6.2 Hz, 2H), 3.23 (br s, 1H), 3.04 (br s, 1H), 2.01 (s, 3H), 1.82-1.50 (m, 17H), 1.44 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 143.8, 133.8, 124.2, 123.0, 67.1, 66.7, 50.3, 50.1, 40.9, 38.3, 37.9, 37.0, 35.5, 28.6, 21.8; HRMS (ESI) m/z [M + H]+ calcd for C21H31O2 315.2319, found 315.2318. General Procedure C for the Synthesis of Spirocycles 28. A –78 ºC suspension of small pieces of sodium (245 mg, 10.65 mmol) and naphthalene (150 mg, 1.17 mmol) in THF (4 mL) was treated with a solution of 1 (250 µL, 1.06 mmol) in THF (1 mL) and stirred for 6 h. The resulting solution was transferred via cannula to a –78 ºC flask, and treated with 1iodopropane (109 µL, 1.12 mmol). The reaction mixture was stirred for 16 h at -78 ºC, quenched by addition of deoxygenated HOAc (150 µL, 2.6 mmol) and then partitioned between EtOAc (10 mL) and pH 7 phosphate buffer (10 mL). The aqueous layer was extracted with EtOAc (2 x 5 mL), and the combined organic extracts were washed with aqueous saturated Na2S2O3 (10 mL) and brine (10 mL), dried and concentrated. The residue was purified by flash column chromatography (SiO2, 2-5% EtOAc/hexane) to yield 27 (250 mg, 80%) as a colorless oil. A –30 ºC suspension of NaH (40 mg, 1.69 mmol) and iPrOH (catalytic amount) in THF (9 mL) was treated with a solution of 27 (100 mg, 0.34 mmol) in THF (1 mL). The reaction mixture was stirred for 2 h at –30 ºC, then cooled down to –78 ºC and the corresponding bis-electrophile was added (0.39 mmol). The reaction mixture was stirred for 20 h while slowly warming to rt, then quenched by addition of a solution of HOAc (1 mL) in H2O (5 mL), and extracted with CH2Cl2 (3 x 10 mL). The combined organic layer was washed with H2O (2 x 10 mL) and brine (10 mL), dried (anhydrous Na2SO4), filtered and concentrated to a residue that was purified by column chromatography (SiO2, 9% EtOAc:Hexane). Diisopropyl 8-propylspiro[4.5]deca-6,9-diene-7,8-dicarboxylate (28a). Following general procedure C, and using 1,4-dibromobutane (45 µL, 0.39 mmol) as the electrophile, 28a was isolated as a colorless oil (105 mg, 90%). 1H NMR (500 MHz, CDCl3) δ 6.93 (d, J = 2.0 Hz, 1H), 5.69 (dd, J = 9.8, 2.0 Hz, 1H), 5.29 (d, J = 9.9 Hz, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 4.93 (hept, J = 6.3 Hz, 1H), 2.16 (m, 1H), 1.88-1.50 (m, 9H), 1.25 (dd, J = 9.7, 6.3 Hz, 6H), 1.16 (d, J = 6.3 Hz, 6H), 1.07 (m, 1H), 0.86 (m, 4H); 13C{1H} NMR (75 MHz, CDCl3) δ 173.6, 166.1, 146.5, 133.9, 127.5, 126.0, 68.0, 68.0, 50.2, 45.3, 41.2, 40.8, 37.0, 25.0, 24.9, 21.9, 21.7, 21.7, 18.0, 14.5; IR (KBr): 1732 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C21H33O4 349.2373, found 349.2376; Anal. Calcd for C21H32O4: C, 72.38; H, 9.26. Found: C, 72.67; H, 9.03. Diisopropyl 3-propylspiro[5.5]undeca-1,4-diene-2,3-dicarboxylate (28b). Following general procedure C, and using 1,5-dibromopentane (50 µL, 0.39 mmol) as the electrophile, 28b was isolated as a colorless oil (107 mg, 87%). 1H NMR (500 MHz, CDCl3) δ 7.05 (d, J = 1.9 Hz, 1H), 5.88 (dd, J = 10.1, 2.0 Hz, 1H), 5.32 (d, J = 10.0 Hz, 1H), 5.06 (hept, J = 6.2 Hz, 1H), 4.93 (hept, J = 6.2 Hz, 1H), 2.15 (td, J = 13.4, 4.1 Hz, 1H), 1.72 (m, 1H), 1.65-1.35 (m, 10H), 1.25 (dd, J = 9.6, 6.3 Hz, 6H), 1.16 (d, J = 6.2 Hz, 6H), 1.07 (m, 1H), 0.86 (m, 4H); 13C{1H} NMR (75 MHz, CDCl3) δ 173.5, 166.1, 146.5, 133.4, 128.1, 126.9, 68.0, 50.9, 38.1, 37.7, 37.5, 36.9, 31.7, 26.0, 22.8, 21.9, 21.7, 21.7, 21.3, 18.3, 14.5, 14.3; IR (KBr): 1732 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C22H35O4 363.2530, found 363.2527; Anal. Calcd for C22H34O4: C, 72.89; H, 9.45. Found: C, 73.07; H, 9.77. Diisopropyl 4-propyl-5',7'-dihydrospiro[cyclohexane-1,6'- dibenzo[a,c][7]annulene]-2,5-diene-3,4-dicarboxylate (28c). Following general procedure C, and using 2,2’-bis(cloromethyl)-1,1’-biphenyl (100 mg, 0.39 mmol) as the electrophile, 28c was isolated as a colorless oil (107 mg, 67%). 1H NMR (500 MHz, CD2Cl2) δ 7.46 (m, 2H), 7.41 (td, J = 7.5, 1.3 Hz, 2H), 7.34 (tt, J = 7.6, 2.2 Hz, 2H), 7.23 (dd, J = 13.2, 7.4 Hz, 2H), 6.99 (d, J = 2.0 Hz, 1H), 5.82 (dd, J = 9.9, 2.0 Hz, 1H), 5.42 (d, J = 9.9 Hz, 1H), 5.04 (hept, J = 6.2 Hz, 1H), 4.93 (hept, J = 6.3 Hz, 1H), 2.45 (br s, 4H), 2.19 (td, J = 13.1, 4.2 Hz, 1H), 1.78 (td, J = 13.4, 4.3 Hz, 1H), 1.31-1.09 (m, 13H), 0.97 (m, 1H), 0.91 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 173.1, 165.9, 144.3, 141.0, 140.9, 135.7, 132.6, 130.0, 129.9, 129.0, 128.5, 128.4, 127.7, 127.5, 127.4, 68.2, 50.9, 49.1, 44.1, 43.7, 36.9, 21.9, 21.8, 21.7, 18.3, 14.6; IR (KBr): 1730 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C31H37O4 473.2686, found 473.2687. Diisopropyl 4-propyl-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-2,5-diene-3,4dicarboxylate (28d). Following general procedure C, and using o-dichloroxylene (70 mg, 0.39 mmol) as the electrophile, 28d was isolated as a colorless oil (122 mg, 91%). 1H NMR (500 MHz, CDCl3) δ 7.19 (m, 4H), 7.04 (d, J = 2.1 Hz, 1H), 5.84 (dd, J = 9.9, 2.0 Hz, 1H), 5.39 (d, J = 9.8 Hz, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 4.96 (hept, J = 6.2 Hz, 1H), 3.00 (m, 4H), 2.20 (ddd, J = 13.8, 12.0, 4.0 Hz, 1H), 1.77 (m, 1H), 1.25 (d, J = 6.2 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.20 (d, J = 6.3 Hz, 3H), 1.18 (d, J = 6.2 Hz, 3H), 1.12 (m, 1H), 0.98-0.84 (m, 4H); 13C{1H} NMR (75 MHz, CDCl3) δ 173.3, 165.9, 145.0, 141.4, 141.3, 133.0, 128.8, 127.3, 126.9, 126.9, 124.8, 124.8, 68.2, 68.2, 50.4, 47.1, 46.8, 46.1, 36.9, 21.9, 21.8, 21.7, 18.1, 14.5; IR (KBr): 1730 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for for C25H33O4 397.2373, found 397.2369. Anal. Calcd for C25H32O4: C, 75.73; H, 8.13. Found: C, 75.39; H, 8.51. Diisopropyl 4-propyl-1'H,3'H-spiro[cyclohexane-1,2'-phenalene]-2,5-diene-3,4dicarboxylate (28e). Following general procedure C, and using 1,8-bis- (chloromethyl)naphthalene (90 mg, 0.39 mmol) as the electrophile, 28e was isolated as a colorless oil (133 mg, 88%). 1H NMR (500 MHz, CD2Cl2) δ 7.73 (dt, J = 8.5, 1.5 Hz, 2H), 7.42 (ddd, J = 8.2, 7.0, 4.3 Hz, 2H), 7. 24 (ddd, J = 13.1, 7.0, 1.2 Hz, 2H), 6.88 (d, J = 2.1 Hz, 1H), 5.61 (dd, J = 10.0, 2.1 Hz, 1H), 5.37 (d, J = 10.0 Hz, 1H), 5.01 (hept, J = 6.2 Hz, 1H), 4.93 (hept, J = 6.2 Hz, 1H), 3.22 (dd, J = 15.8, 4.0 Hz, 2H), 3.05 (t, J = 15.6 Hz, 2H), 2.18 (ddd, J = 13.7, 12.5, 4.7 Hz, 1H), 1.75 (ddd, J = 13.7, 12.3, 4.4 Hz, 1H), 1.26-1.13 (m, 13H), 0.98 (m, 1H), 0.91 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 173.1, 165.9, 145.0, 133.3, 132.4, 132.2, 131.7, 129.9, 129.2, 128.3, 126.6, 126.5, 125.9, 125.3, 125.2, 68.3, 68.3, 50.9, 43.0, 42.6, 37.6, 36.9, 21.9, 21.9, 21.8, 21.8, 18.3, 14.5; IR (KBr): 1730 cm-1 (C=O); HRMS (ESI) m/z [M + H]+ calcd for C29H35O4 447.2530, found 447.2524. Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H NMR spectra of bis-enolate 2 (with sodium and lithium counterions), EPR spectra of sodium bis-enolate 2 (containing Na/naphthalene) and Na/naphthalene, 1H NMR of monoenolate 22 obtained by quenching bis-enolate 2 with excess adamantyl iodide and 1H NMR of monoenolate 29 obtained by quenching bis-enolate 2 with excess isopropyl bromide, X-ray crystallographic data and ORTEP of 5a, 6, 10, and 25; 1H and 13C NMR spectra for all new compounds. Acknowledgements Financial support from Ministerio de Economía y Competitividad of Spain (CTQ201784354-P), Xunta de Galicia (GRC 2014/029 and Centro singular de investigación de Galicia accreditation 2016-2019, ED431G/09) and the European Union (European Regional Development Fund-ERDF) is gratefully acknowledged. References (1) (a) Schultz, A. G. The asymmetric Birch reduction and reduction–alkylation strategies for synthesis of natural products. Chem. Commun. 1999, 1263-1271. (b) Hook, J. M.; Mander, L. N. Recent Developments in the Birch Reduction of Aromatic Compounds: