Discusión y conclusiones – Una mirada hacia la inestabilidad de la economía basada en teorías de desarrollo territorial.

Based on the viability of the alkylidene cyclopropane to vinyl cyclopropane in mediating Cope rearrangements, this group was chosen for our first experiments. Compound 1.1a, synthesized from 2–cyclopropylideneethanol and 1,3–Me2–2–naphthol under Mitsunobu conditions, was thus used for exploratory studies.

Combining 1.1a with 10 mol% Ph3PAuNTf252 _{in CD2Cl2 at room temperature provided the} dearomatized product 1.1b in a sluggish reaction as assessed by in situ 1_{H NMR spectroscopy.} Under these conditions significant catalyst decomposition to inactive (Ph3P)2AuNTf2 occurs. A change in solvent to 1,2– DCE slowed this decomposition and provided 1.1b in 75% isolated yield (Table 1.1). The successful migration of this group installs a synthetically versatile vinyl cyclopropane,22,53–55 _{adjacent to an all–carbon quaternary center.}

We rationalized that other allyl–type motifs might be susceptible to electrophilic activation/migration. The O–allenyl methyl naphthol 1.2a is well behaved and migrates to forge an all carbon quaternary 1,3–butadienyl–containing center in good yield (1.2b). With 5 mol% catalyst, the O–propargyl substrate (1.3a) was considerably more reactive, and while satisfactory yields could be achieved at −78 °C, it was more convenient to carry out reactions in toluene at room temperature where product decomposition was inhibited (71% isolated yield). The

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substituted allene 1.4a smoothly provides 1.4b as a 1:1 mixture of diastereomers. Allyl naphthyl ether 1.5a was also a suitable Claisen substrate, yielding the rearrangement product in 67% yield. The baseline naphthol to phenyl enone rearrangement itself is therefore sufficiently favorable to proceed without the extra driving force that results from a strain–releasing type O– to C–migration. As shown in Table 1.2, 1–naphthol–based substrates also yield the expected products.

12 Table 1.2. C−C Migrations for Allyl 1–Naphthyl Ethers

Vinylcyclopropanes,22,53–55 _{1,3–dienes, and allenes}56,57 _{have well–developed reaction} chemistry that can be brought to bear further modification these structures. Since these groups would not be expected to survive the strongly oxidizing conditions of a typical dearomatization procedure, the catalyzed Claisen route is particularly efficacious at yielding products that facilitate rapid gains in complexity.

In an analogy to oxidative dearomatization of 1– and 2–naphthol derivatives, a single regioisomer of the ene−one product was obtained in each case. Hypothesizing that the 2–naphthol regioselectivities were caused by the avoidance of an ortho–benzoquinodimethane intermediate (i.e., 1.12), we tested whether 1.10 might yield a dearomatized product despite having a potential keto−enol tautomerization route to the most preferred naphthol 1.13 (Scheme 1.6A). In the event, Ph3PAuNTf2 (10 mol%) exclusively provides the kinetic product 1.11 in 53% yield (14% 1.10 recovered), confirming that allenyl methyl group migration to C3 (to form 1.12) is highly disfavored. Thermolysis of 1.10 (75% conv., 48 h, 120 °C) similarly provided 1.11 indicating the observed selectivity is generic and not necessarily due to the role of the metal catalyst. In the case

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of 1–(allyloxy)–2–methylnaphthalene, 4–allyl–2–methyl–1–naphthol was isolated in 30% yield which arises through a tandem Claisen/Cope rearrangement followed by a net [1, 5] H–shift. This undesired reactivity was not observed in any other case tested (Scheme 1.6B).

Scheme 1.6 Selectivity for monosubstituted naphthyl ethers

The feasibility of a diverse collection of migrating groups generates multiple options for modifying the dearomatized structures (Scheme 1.6). As expected, styrenone 1.2b is a suitable diene for Diels−Alder cycloadditions with, for example, dimethylacetylene dicarboxylate (DMAD). Partial auto–oxidation of the resulting 1,4–cyclohexadiene was avoided by treating the Claisen solution with DDQ to give the net–arylated styrenone 1.14 in 93% yield (Scheme 1.6A). The hydration of allene 1.8b is also well behaved and provides a good yield of the methyl ketone (70%) using 5 mol% (IPr)AuOTf (Scheme 1.6C). Interestingly, the hydration regioselectivity was opposite that found by Weidenhoefer et al., where allylic alcohols were preferred.56,58 _{The resulting} 1,4–dione also has many avenues available for product diversification.

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Scheme 1.7 Example styrenone derivatizations

The presence of an all carbon quaternary center adjacent to enones in 1.3b prompted us to explore the possibility of a diastereoselective carbonyl reduction which would generate two contiguous stereocenters. The use of L–selectride resulted in decomposition of starting material, but the reduction of 1.3b with DIBAL–H or LiEt3BH at –78 °C in THF gave 1.15 in 4:1 and 5:1 d.r. respectively. Lowering the temperature to –95 °C (liq. N2, toluene bath) using LiEt3BH gave the highest diastereoselectivity (13:1) in excellent yield (92%).

Determination of the relative stereochemistry of the reduction proved to be challenging. 1D–NOESY experiments selectively irradiating the carbinol proton were inconclusive as correlations to both the methyl and allenyl group were observed (Figure 1.8). Cyclization of 1.15 to the tetrahydrofuran or dihydropyran could potentially aid in this type of analysis, however Au(I) and Pt(II) catalysts were ineffective at catalyzing this hydroalkoxylation. Benzoylation with 4– nitrobenzoyl chloride and 4–bromobenzoyl were successful. All attempts to crystallize and characterize these esters via X–ray crystallography were unsuccessful.

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Figure 1.5. 1D–NOSEY of 1.15 in CDCl3 at 25 °C

To assign the relative stereochemistry of the reduction we utilized a computational approach in combination with the 1D–NOESY correlations. A–values (Me = 1.9 kcal/mol, allene = 1.5 kcal/mol)59,60 _{suggest that hydride should be delivered to the allenyl face of the styrenone.} In similar reductions, where the allenyl group is replaced by a phenyl61 _{ring (Ph = 2.9 kcal/mol),}62 the reduction occurs with >20:1 d.r with the hydride being delivered from the methyl face of the styrenone.

Conformational searching by molecular mechanics followed by DFT energy minimization (Figure 1.9) reveals that the lowest energy conformer for the diastereomer predicted by considering A values has short interatomic distances between the carbinol C–H and the allenyl methine (2.40 Å) and methyl group (2.48 Å). A similar computational analysis of the lowest energy conformers

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of the opposite diastereomer, lacks the short contacts between the carbinol and the allenyl methine (3.25 Å). Only in a relatively high energy conformation (Erel = +2.23 kcal/mol) is this distance short (2.83 Å). This data in conjunction with A–value arguments leads us to assign the relative stereochemistry as depicted, where the hydride attacks the ketone from the face containing the slightly smaller allenyl group.

Figure 1.6 Conformational analysis of 1.15