MIRC reactions using sulfoxides and synthesis of dictyopterene A

Michael initiated ring closure reactions, using alkyl imidazolyl sulfoxides as nucleophiles, provided a 2-substituted cyclopropanecarboxylate 2 and cyclohexanecarboxylate 5 , with high yields and excellent diastereoselectivity. Thermal elimination of the imidazolylsulfinyl group gave an alkene 3 . This method was used to carry out a short synthesis of dictyopterene A. A 2-hexenylcyclopropanecarboxylate 13 was prepared using a MIRC reaction of hexyl 1-methyl-2-imidazolyl sulfoxide with 4-bromocrotonate, followed by pyrolytic elimination of the imidazolylsulfinyl group. Straightforward conversion of the ester group into a vinyl group furnished dictyopterene A.


Introduction
The term MIRC (Michael Initiated Ring Closure) was first used by Little and Dawson to describe the reactions which involve (i) nucleophilic conjugate addition to a Michael acceptor, and (ii) ring closure of the resulting enolate. 1 Many interesting and synthetically useful examples have been reported. 2We now describe the use of sulfoxide-stabilised carbanions as nucleophiles in MIRC reactions, along with an application to stereoselective natural product synthesis.The use of sulfoxide-stabilised carbanions as chiral carbon nucleophiles is a very useful strategy for stereoselective synthesis. 3he first ever report of a diastereoselective conjugate addition reaction of a sulfoxidestabilised carbanion involved a MIRC reaction using a benzyl sulfoxide. 4Recently, Toru and coworkers showed that enantiopure p-tolyl 2-trimethylsilylethyl sulfoxide could be used to prepare several cyclic products via highly diastereoselective MIRC reactions. 5However, the scope of their method is somewhat restricted by the requirement that the trimethylsilyl group be present.We have conducted an extensive study of conjugate reactions of sulfoxide-stabilised carbanions and have shown that high diastereoselectivity can be achieved using appropriate nonacidic "spectator" groups on the sulfoxides. 6In an extension of that work, we now report the results of a preliminary study of MIRC reactions of alkyl imidazolyl sulfoxides

MIRC Reactions
We first carried out some model studies to determine the scope of the process, beginning with "Type I" MIRC reactions, in which the alkylating agent is attached to the Michael acceptor.We had earlier found that conjugate additions of alkyl sulfoxides gave high yields when 2-pyridyl or 1-methyl-2-imidazolyl spectator groups were used.6c Excellent diastereoselectivity was obtained provided that hexamethyldisilazide bases were used.Hence, the MIRC reactions were carried out using1-methyl-2-imidazolyl sulfoxides.The imidazolyl phenethyl sulfoxide 1 was deprotonated using LiHMDS and reacted with methyl 4-bromocrotonate at -78 °C over 20 min.Work-up and chromatography afforded the desired cyclopropane 2 in 86% yield, as a single diastereomer (Scheme 1).The relative stereochemistry at the new centres α and β to the sulfur was assigned by analogy with earlier conjugate addition results.6c The trans stereochemistry of the disubstituted cyclopropane ring was assigned by interpretation of the 1 H coupling constants (each ring hydrogen had one cis coupling constant of ca. 8 Hz and two trans/geminal coupling constants of 4-6 Hz), and by analogy with numerous precedents for trans-cyclopropane formation in MIRC reactions. 2An attractive feature of the use of sulfoxides is the availability of several useful transformations of the products.6d,7 For example, product 2 underwent smooth thermal elimination at 61 °C over 5 hours to afford the (E)-alkene 3 in high yield.The use of the electron-withdrawing heteroaryl spectator group significantly reduces the temperature required for the elimination reaction.Preparation of a six-membered ring was also studied.This required the synthesis of methyl 7iodoheptenoate 4, 8 which was obtained from dihydropyran in excellent overall yield using straightforward transformations (Scheme 2).Addition of the imidazolyl sulfoxide 1 to the iodide 4 proceeded very smoothly to afford the cyclohexane 5 in 68% isolated yield as a single diastereomer).Thus, MIRC reactions using alkyl imidazolyl sulfoxides as nucleophiles provide three-and six-membered rings, with high yields, and excellent diastereoselectivity, and further extension of the scope will, no doubt, be possible.The stereochemistry of the cyclohexanecarboxylate 5 was assigned on the basis of the diaxial coupling of the proton αto the ester (δ 2.50, 1H, dt, J = 3.5, 11.5 Hz).The same product could, in principle, be obtained via conjugate addition to a cyclohenecarboxylate ester, but earlier work had shown that the conjugate addition of a tert-butyl sulfoxide to methyl tiglate proceeded in very low yield, 6a so the MIRC reaction is the only viable route to products of this kind.A brief study of "Type II" MIRC reactions, in which the alkylating agent is attached to the nucleophile, was also carried out.Deprotonation of the 3-chloropropyl sulfoxide 6 using LiHMDS, in the presence of methyl crotonate, rapidly gave a new product, but the spectroscopic data showed that it was the cyclopropane 7 (Scheme 3).There was no trace of 1,4-adduct, or of the desired cyclopentane, indicating that the cyclisation of the sulfoxide-stabilised anion was much faster than reaction with the crotonate.As expected, treatment of the sulfoxide 6 with LiHMDS the absence of crotonate gave the cyclopropane in high yield.The analogous 4-chlorobutyl sulfoxide 8 was then prepared, in the expectation that cyclobutane formation would be much slower (Scheme 4).Deprotonation and addition to methyl crotonate did give the conjugate adduct 9, rather than the cyclobutyl sulfoxide, but all efforts to bring about cyclisation to the desired cyclohexanecarboxylate 10 were unsuccessful.For example, warming of the reaction mixture to 0 °C, use of KHMDS rather than LiHMDS, addition of HMPA or KOBu t to the reaction mixture, and attempting the cyclisation of isolated conjugate adduct 9, all failed to bring about intramolecular enolate alkylation by the alkyl chloride.Efforts were then directed toward the preparation of the analogous 4-bromobutyl sulfoxide, but these were stymied by the formation of polar materials, presumably cyclic sulfonium salts formed by intramolecular S-alkylation of the desired sulfoxide and the sulfide precursor.Although we did not succeed in effecting Type II MIRC reactions, they are of interest because they may yet provide useful new annulation strategies.Synthesis of dictyopterene A. The preliminary study showed that alkyl imidazolyl sulfoxides undergo efficient diastereoselective Type I MIRC reactions, which show considerable promise as a synthetic tool.To demonstrate this synthetic potential, a synthesis of (±)-dictyopterene A was undertaken.The dictyopterenes are sexual pheromones for several species of seaweed, and dictyopterene A, trans-1-(1-hexenyl)-2-vinylcyclcopropane, 16 is responsible for the characteristic "ocean" smell of these algae. 9Several syntheses of dictyopterene A have been reported. 10It was decided to prepare an hexenylcyclopropanecarboxylate using a Type I MIRC reaction, followed by pyrolytic elimination of the imidazolylsulfinyl group.Straightforward modification of the ester was then expected to provide dictyopterene A. The required sulfoxide 11 was prepared using the conventional method in 87% yield (Scheme 5).The MIRC reaction with (E)-methyl 4-bromocrotonate furnished the desired transdisubstituted cyclopropane 12 in 71% yield as a single diastereomer.Thermal elimination of the sulfinyl moiety was found to require relatively harsh conditions.Thus, refluxing the sulfoxide 12 and K 2 CO 3 in toluene for 30 hours afforded an inseparable geometric mixture of alkenes 13 (E/Z ca.5/1 by 1 H NMR) in 90% yield (Scheme 5).Addition of K 2 CO 3 to the reaction mixture was found to be essential for clean alkene formation.Presumably, its role is to scavenge the sulfenic acid byproduct.The poor geometric purity may reflect the high temperature required to effect the elimination at a synthetically useful rate and the relatively small size of the cyclopropyl group.
Reduction of the ester 13 using LiAlH 4 gave the alcohol 14 in quantitative yield.The synthesis was completed by following literature precedents.Oxidation with PCC gave the known aldehyde 15 10i,k in 94% yield.A Wittig reaction using methylene-triphenylphosphorane, followed by careful distillation of the crude product afforded (±)-dictyopterene A 16, as a very odourous volatile oil in poor yield (25%).The 1 H NMR spectrum showed that the sample was contaminated with hexamethyldisilazane (LiHMDS was used to generate the phosphorane), but the data for the major product were in excellent agreement with those reported for dictyopterene A. 9,10 The product was obtained as a ca.5:1 mixture of E and Z isomers.The yield of final step was disappointing, due principally to the difficulty of isolating the volatile product on a small scale.However, good yields for this step have been recorded by others, 10i,k so, having proven the structure of our product, we did not attempt to optimise the procedure.

Conclusions
The results described above indicate that MIRC reactions of alkyl imidazolyl sulfoxides, followed by further transformations of the sulfoxide products, provide an efficient, versatile, and highly diastereoselective route to substituted cycloalkanecarboxylates.This total synthesis of dictyopterene A is a demonstration of the synthetic potential of this chemistry, and it compares favourably with earlier syntheses of this natural product.The power of this methodology will only be fully realised when enantiopure sulfoxides are used.In that context, it is noteworthy that highly enantioselective methods for the oxidation of imidazolyl 11,12 and benzimidazolyl 12 sulfides have been developed.A solution of dihydropyran (10.00 g, 119 mmol) and 1N HCl (30 mL) in THF (120 mL) was stirred at room temperature for 16 h.The mixture was poured into water (30 mL) and extracted with CH 2 Cl 2 (5 x 30 mL).The combined organic layers were washed with brine, dried, and concentrated in vacuo to give the title compound as a mobile oil (12.00 g, 118 mmol, 100%).

4-Chlorobutyl 1-methyl-2-imidazolyl (RS)-sulfoxide (8a).
The crude sulfide was dissolved in a 1:1 mixture of methanol and water (210 mL), and cooled to 0 °C.NaIO 4 (4.95 g, 23 mmol) was added in one portion and the suspension was stirred for 48 h.It was filtered and the filtrate was concentrated in vacuo to remove as much methanol as possible.The crude oil was dissolved in water (100 mL), and extracted with CHCl 3 (400 mL).The combined organic layers were dried and concentrated in vacuo, and the crude product was subjected to flash chromatography (EtOAc) to yield the title compound 8a as an oil, which was dried over several days under vacuum (3.00 g, 13.42 mmol, 60%).