A new synthesis of pleraplysillin-1, a sponge metabolite, using Wittig olefination

A new synthesis of pleraplysillin-1, a sponge metabolite, has been accomplished using Wittig olefination of 2-bromo-1-formyl-4,4-dimethylcyclohex-1-ene with an appropriate ylide. A generalized study on the Wittig olefination of several 2-bromo-1-formyl-1-cycloalkenes with the ylides generated in situ from 2-(3/2-furyl)ethyltriphenylphosphonium bromides was also undertaken as a prerequisite. The described methodology is not the most efficient route to the desired isomer. However, it does offer a new route to molecules of type 1


Introduction
In the recent past, we have been using β-halo-α,β-unsaturated aldehydes as building blocks for the synthesis of various heterocycles, [1][2][3][4][5] including furophenanthraquinones. 6 In this context, our attention was recently drawn to pleraplysillin-1 (1), a cytotoxic furosesquiterpenoid isolated from Pleraplysilla spinifera, a marine sponge, by Cimino et al. 7 It possesses a unique ochtodane, i.e., 3,3-dimethyl-1-ethylcyclohexane skeleton (2), [8][9][10] (Figure 1) which is attached to a 3-furylmethyl group, and its 1,3-diene system is separated from the furan ring by a one-carbon unit.A decade later, its unique structure expectedly triggered its syntheses by Masaki et al. 11,12 In the first synthesis that they reported, 11 they synthesized 1 from an ochtodane monoterpenol using Sharpless regioselective epoxide ring-opening reaction as the crucial step.The final step was a reductive elimination of the β-acetoxy-sulfone which furnished a diastereomeric mixture of 1 with its Z-isomer in ca.5:1 ratio (Scheme 1).Scheme 1.First synthesis of pleraplysillin-1 (1) by Masaki et al. 11 In their second report, 12 they constructed the carbon skeleton of 1 by the coupling of a sulfone, derived from the same ochtodane monoterpenol, with 3-furylmethyl bromide, followed by successive detosylation, phenylthionation and elimination of thiophenol (Scheme 2).However, it furnished a regioisomeric mixture of 1 (major) and its ∆ 8,13 -isomer (minor) in 3:2 ratio.In both reported syntheses, the overall yields were poor.© ARKAT USA, Inc Scheme 2. Second synthesis of pleraplysillin-1(1) by Masaki et al. 12 Scott et al. later reported an efficient synthesis of pure pleraplysillin-1 using Pd(0)-catalyzed cross coupling of an (E)-furan-3-allyltin with 5,5-dimethylcyclohex-1-en-1-triflate. 13,14However, since in both of Masaki's attempts, the product was a mixture of regio-or stereo-isomers, we planned to utilize our ongoing strategy, viz. the employment of a suitable β-halo-α,β-unsaturated aldehyde as a starting material for the development of a new synthesis of pleraplysillin-1 and its analogues via a new route using Wittig olefination as the crucial step.Our planned retro-synthesis of pleraplysillin-1 is depicted in Scheme 3.
The in situ generation of ylides from 4 and 6 and their reaction with 5a,e and 5a-e, respectively, was carried out in the presence of n-BuLi in THF at -78 °C under argon atmosphere, which furnished diastereomeric (E-+Z-) mixtures of the bromo analogues of the dienyl-3/2-furyl derivatives (7a,e/8a-e) in good overall yields (77-84 %) (Scheme 4).Clearly, the desired diastereoselectivity was not achieved, and the E-/Z-ratios were found to be 1:1.6 to 1:2.3 (Table 1), as calculated from the relative intensities of the vinylic and the allylic proton signals in their 1 H NMR spectra.All of the products, with the exception of most of the bromo derivatives, were duly identified by 1 H and 13 C (PND) NMR spectra, supported by MS/analytical data.
Though lacking diastereoselectivity, the method offers a new route to the synthesis of molecules of type 1. We, therefore, applied this methodology to the synthesis of the bromo derivative of pleraplysillin-1.Thus, the ylide, generated in situ from 4, was allowed to react with the required bromo-formylcyclohexene (5c) under similar conditions.It furnished an inseparable (following silica-gel column chromatography) mixture of the desired (E)-isomer (3) and its (Z)-isomer in 88% overall yield (Scheme 5).The E-/Z-ratio, calculated as before, exhibited a greater lack of diastereoselectivity. Since the target molecule was formed, albeit as a diastereomeric mixture, its proto-debromination was accomplished by treating the mixture with n-BuLi/THF at -78°C in THF under argon atmosphere for about 2 h, followed by quenching with water.This reaction furnished a mixture of 1 and its Z-isomer in 77% overall yield (Scheme 5).

Conclusions
The present methodology to pleraplysillin-1 is certainly not the best of the available methods.It does, however, offer a new route to molecules of type 1.Of course, conditions need to be developed to improve upon the diastereoselectivity at the crucial Wittig olefination stage.Our method has the additional advantages that (i) it is relatively simple, (ii) it does not involve expensive and toxic organometallic reagents and (iii) the overall yields of the bromo analogues and the final diastereomeric mixtures are much better than reported earlier.

Experimental Section
General.All the melting points were recorded in open glass capillaries in a sulfuric acid bath.The column chromatographies (CC) were carried out in either silica gel (SiO2) or neutral alumina (Al2O3).For CC, SiO2 and Al2O3 were purchased from E. Merck India and SRL, India.All of the reagents were of analytical grade and purchased from either Merck India or Sigma-Aldrich Chemicals.The β-bromo-α,β-unsaturated aldehydes (5ae) were prepared from the respective cycloalkanones, procured commercially, using modified Vilsmeier-Haack reaction as was reported earlier from our laboratory. 13,14All the solvents were conventionally dried before use in reactions.Unless otherwise stated, the 1 H and Br 81 ] + Synthesis of 2-bromo-1-formyl-5,5-dimethylcyclohex-1-ene (5c).PBr3 (0.6 mL) was added dropwise to a solution of DMF (0.9 mL) and CHCl3 (2 mL) at 0-5 °C.The ice bath was removed and the mixture stirred at rt for about 30 min.It was again cooled to 0-5 °C, a solution of 4,4-dimethylcyclohexanone (0.25 g, 2 mmol) in CHCl3 (1 mL) was added dropwise to it, and the mixture was stirred at rt for another 8 h under anhydrous condition.
The solution was poured into cold, saturated aq.NaOAc so that the pH was adjusted to ~ 6 and extracted with CHCl3 (3 x 10 mL).The extracted organic layer was washed successively with water, aq.NaHCO3, again with water, dried and the solvent removed.The crude product was then purified by CC using PE as eluent, which furnished 5c as light yellow oil.Yield 0.33 g (76%).IR (νmax, cm -1 ): 1695.