Synthesis of platencin core structures via twist-brendane

The formation of a twist-brendane via intramolecular enolate alkylation is described. Conversion of bicyclo[2.2.1]heptane scaffold present in this twist-brendane through a Grob-type fragmentation to unravel a functionalized bicyclo[2.2.2] system which contains all the necessary carbon atoms of the lipophilic core structure of nor -platencin, a platencin analogue is presented. Synthesis of core structure of platencin was also accomplished by extending this strategy to a starting material possessing a surrogate for the exocyclic methylene group.


Introduction
][11][12][13]  As a novel potent antibiotic, platencin 14,15 inhibits two proteins essential for bacterial fatty acid biosynthesis, β-ketoacyl carrier protein synthase II (FabF) and III (FabH) with similar potency.Owing to their interesting novel chemical scaffold and biological activity as antibacterial agents platencin and its congeners 16 have attracted widespread attention amongst synthetic chemists since their discovery with prospect that these would be used as lead compounds for the development of a valuable class of antibiotics.Although platencin shows the potent antibacterial activity it suffers from the poor in vivo efficacy that is attributed to its rapid clearance from tissues. 16,17So the synthesis of new potent analogues of platencin with improved potency and pharmacokinetic properties suitable for clinical trials is in high demand. 17latencin core structure constitutes tricyclic system with a bicyclic octane ring having exomethylene group, fused with a cyclohexenone ring.Many synthetic strategies have been developed for the construction of platencin core structure involving key steps like homoallyl radical rearrangement of bicyclo[3.2.1]octane to bicyclo[2.2.2]octane, [18][19][20][21][22] intramolecular Diels-Alder reaction, [22][23][24] intramolecular Michael addition, 25 Michael addition followed by aldol condensation, 26 ring closing metathesis reaction, 27,28 pinacol coupling reaction, 29 radical cyclization reactions [30][31][32][33] and intramolecular aldol reaction. 34lthough nor-platencin is less potent than its parent molecule, but serves as a convenient target as it lacks the acid-sensitive exo-methylene group present in platencin which is also responsible for the decrease in the metabolic stability of platencin. 35In this paper we report synthesis of platencin core structures which features the construction of tricyclic core via a twistbrendane derivative, followed by Grob-type fragmentation and Robinson annulation.

Results and Discussion
During the course of our studies on base mediated bridgehead elimination and substitution reactions, 36 we observed the formation of a twist-brendane derivative 5 through intramolecular enolate alkylation in 70% yield along with the originally intended product 6 (yield 17%) from 4 (Scheme 1).Synthesis of the parent twist-brendane 5 has been described in the literature by intramolecular enolate alkylation using NaH in DMF at 60 °C followed by deoxygenation.We have also adopted the same protocol, but with slight modification wherein THF was used instead of DMF, to avoid the side product 6 and observed smooth formation of twist-brendane 5 without any side products.The complete sequence involved Michael addition of acetone to the enone 3 to give intermediate 4 which on exposure to NaH in THF at 60 °C provided the twist-brendane 5 in 89% yield (Scheme 1).The structure of twist-brendane was unequivocally proved by single crystal Xray analysis (Scheme 1).Compared to the parent twist-brendane, compound 5 is equipped with maneuverable functional groups such as a ketal moiety at C-7 and a suitably positioned keto group for the execution of Grob-type fragmentation 12,13 to unravel a useful bicyclo[2.2.2]octane derivative.
As anticipated, the Grob-type fragmentation of 5 with pTSA in toluene afforded a separable mixture of bicyclo[2.2.2]octane derivative 7 (Scheme 2).A closely related compound to 7, having exo-methylene group sans the chloro and ester substitutions has been reported for the synthesis of platencin core. 33Our attempts to cyclize 7 via Robinson annulation using NaOH/EtOH (or MeOH) even at reflux conditions failed, yielding complex mixtures.The presence of chlorine substituents might be responsible for the observed complications.In this context, we initially carried out the hydrodehalogenation reaction of the mixture 7 using nBuSnH/AIBN which yielded a complex mixture.However, treatment of 7 with zinc dust in acetic acid at room temperature furnished the diketone 8 as a single diastereomer (Scheme 2).

Scheme 2. Synthesis of nor-platencin skeleton.
Having the diketo ester 8 in hand, our next task was to convert it to tricyclic enone 9.This was achieved by refluxing 8 in NaOH/MeOH for 12 h followed by diazomethane workup which provided a separable mixture of diastereomers 9a/9b in 1:1 exo/endo ratio of methyl ester (Scheme 2).Reduction enone 9a was carried out using Raney nickel 33,37 in THF to obtain the keto ester 10 as a single diastereomer in 83% yield.Several two-step protocols are available in the literature for the conversion of ketone to enone moiety.Silylation followed by 2iodoxybenzoic acid (IBX) 38 oxidation is a well practiced method in the synthesis of platencin. 22,23,30However, in our case Nicolaou's 39 one-step protocol furnished the desired compound 11 when ketoester 10 was treated with IBX in toluene/DMSO at 65 °C along with a minor product 9a (Scheme 2).Structure of 11 was confirmed by single crystal structure X-ray analysis (Scheme 2).
Next, we planned for the synthesis of the core structure of platencin incorporating a keto functionality and adopted similar reaction sequences of the synthesis of core structure of norplatencin.Synthesis commenced with bromination (Scheme 3).Our initial attempts for bromination at the α-methyl group of ketone 18 with NBS in THF, 40 NBS/TMSOTf in CH 3 CN, 41 NBS/DBU in CH 3 CN, 42  The conversion of twist-brendane to bicyclo[2.2.2]octane 21 was easily achieved through a smooth Grob-type fragmentation by treatment of 15 with pTSA in toluene at 80 °C (Scheme 3).Hydrodechlorination with zinc dust in AcOH gave diketone 14. Robinson annulation of 14 using NaOH in MeOH at reflux temperature afforded tricyclic enone 22 in 4:1 exo/endo ratio, as determined from 1 H NMR. Deprotection of ketal group with 6N HCl at room temperature gave 13 in good yield.Regioselective Wittig reaction of unconjugated ketone group in 13 to exomethylene proceeded smoothly at -78 °C to give dienone 12 in 72% yield (Scheme 3).As Wittig reaction was carried out under strong basic condition one can expect the abstraction of proton adjacent to the ester group.Once the carbanion is formed the bulky ester group would prefer relatively free room exo position and hence the conversion of endo isomer to exo occurs, which can be accounted for the high diastereoselectivity (exo:endo 10:1) in the Wittig reaction.The stereochemistry of the major component in 13 was arrived at from 2D NMR data analysis of the mixture.Based on the correlations of proton signals at δ 2.44 (m, 1H) and 2.36 (m, 1H) (CH 2 group adjacent to CO in the bicyclooctane ring) with carbon at δ 210.9 in HMBC, these were assigned to methylene group attached to ketone.Similarly, methine group attached to methyl ester was deduced by correlation between proton at δ 2.87-2.79(m, 1H) and carbon at δ 174.3, which also shows correlation with methoxy group at δ 3.72.The absence of correlation between the protons at δ 2.52-2.34 and δ 2.87-2.79 in NOESY confirms that the methine proton is endo and the ester group is exo in compound 13 and also 12.As expected, during the strongly basic Witting reaction conditions, further isomerization of 13 resulted in substantial enhancement in exo/endo ratio from 4:1 in 13 to 10:1 in 12.

Conclusions
In conclusion, we have synthesized functionalized twist-brendane derivatives through intramolecular enolate alkylation.We have demonstrated a strategy for the conversion of bicyclo[2.2.1]heptane to bicyclo[2.2.2]octane derivative through the formation twist-brendane followed by Grob-type fragmentation.The fragmented products were carried forward for the synthesis of the core structures of both nor-platencin and platencin.Structures and stereochemistry of some of the intermediates were confirmed by single crystal X-ray analysis and 2D NMR analysis.

Experimental Section
General.Unless otherwise specified, all reactions were carried out in oven dried glassware, under argon atmosphere.Melting points were determined on an electrothermal melting point apparatus and are uncorrected.THF was dried by refluxing over sodium metal.Sodium methoxide was prepared from sodium and methanol.Zinc was activated by 10% HCl before use.DMSO was distilled from anhydrous CaSO 4 /calcium hydride.Potassium tert-butoxide was sublimed before use. 1 H and proton decoupled 13 C NMR spectra were recorded in 400 and 100 MHz, respectively.The NMR samples were prepared by dissolving in CDCl 3 , chemical shifts (δ ppm) are reported with reference to either internal standard tetramethylsilane, TMS (δ H = 0.00 ppm) or CHCl 3 (δ H = 7.27 ppm) for 1 H NMR and CHCl 3 [δ C =77.00 ppm (central line of the triplet)] chemical shifts (δ ppm) for 13 C NMR.The multiplicity are reported as follows s = singlet, d = doublet, dd = double doublet, t = triplet, dt = double triplet, td = triple doublet, q = quartet, br = broad m = multiplet and the coupling constants were in Hz.HRMS was performed using a Q-TOF multimode source.

intermediate 19 provided diketone 17 in excellent
yield.Subjecting this to Wittig reaction gave enone 16 in 97% yield.Michael addition of enone 16 with acetone using NaOH (aq) gave intermediate 20 in near quantitative yield (Scheme 3).NaH mediated intramolecular enolate alkylation proceeded as expected to provide twist-brendane 15.