Synthetic studies towards pteridanone, a novel protoilludane-type tricyclic sesquiterpenoid

A synthetic approach directed towards the total synthesis of the novel protoilludane sesquiterpene pteridanone, the aglycon of the glucoside pteridanoside from a bioactive hot-water extract of the neotropical braken fern Pteridium aquilinum var. caudatum (Dennstaedtiaceae), has been delineated. This endeavour has delivered an advanced pre-target having the complete protoilludane skeleton with strategic placement of the functionalities and set the stage for the total synthesis of the natural product. The key features of our approach are the ready availability of the starting material (1,5-cyclooctadiene), an interesting photochemical [2+2]-cycloaddition and a thallium(III) mediated ring expansion reaction.

hardly surprising that the protoilludyl cation 2, itself is captured in nature and many oxygenated derivatives based on this system have been isolated and characterized. 1 Recently, a protoilludane-type sesquiterpene glucoside, pteridanoside 7, from a bioactive hot-water extract of the neotropical braken fern Pteridium aquilinum var.caudatum (Dennstaedtiaceae) has been isolated. 3The enzymatic hydrolysis of 7 led to its aglycon, pteridanone 8, bearing an interesting oxygen functionalisation and to our knowledge this is the first protoilludane with a cyclopentanone moiety. 3In view of our ongoing interest in the synthesis of cyclobutane fused polycyclic sesquiterpenoids, 4 structure of 8 aroused our interest and herein we report our synthetic studies in pursuit of this natural product.Our efforts have led to the acquisition of the complete protoilludyl framework with functionality in the five-membered ring, necessary for the synthesis of the natural product.
Our synthetic approach to pteridanone 8 was delineated through the retrosynthetic analysis depicted in the Scheme 1, which identified the key steps as well as the main starting material.Thus, tricyclic ketone A, embodying the entire skeleton of the natural product 8 and bearing functionalities in the five and the six-membered rings emerged as the advanced pre-target, which in turn could be accessed through the ring expansion of the tricyclic ketone B. The tricyclic ketone B could be derived from the diquinane enone C through stereoselective [2+2]photocycloaddition.The diquinane enone C was sought to emanate from the bicyclic cis-diol 9 of C 2 -symmetry, which is available from the commercially available 1,5-cyclooctadiene.4a,5 In delineating this synthetic plan, we were influenced by the ongoing efforts in our research group 4 and promising leads in the literature along similar lines. 6

Scheme 1
Readily available cis-diol 9, prepared from commercial 1,5-cyclooctadiene via Pd(II) catalysed transannular cyclization, 5 was oxidised with PCC to the dione 10, Scheme 2. 4b At this stage, it was important to differentiate between the two carbonyl groups of 10.Selective monocarbonyl protection in 10 with 2,2-dimethylpropanediol furnished the mono-ketal 11.Protected ketone 11 was now subjected to α−gem-dimethylation to furnish 12 and further reduced with lithium metal in liq.NH 3 to furnish the thermodynamically more stable exohydroxy compound 13 in a stereoselective manner.Deprotection of the ketal moiety in 13 was smooth and led to the hydroxy ketone 14.

Scheme 2
Stage was now set to elaborate the bicyclic ketone 14 for the projected [2+2]photocycloaddition protocol (Scheme 1).Towards this end, the hydroxy group in 14 was protected and the derived acetate was treated with IBX to effect one step dehydrogenation as described recently by Nicolaou et al. 7 to furnish the enone 15 in excellent yield, Scheme 3. Copper(I) mediated addition of methylmagnesium iodide to 15 delivered 16 as a mixture of diastereomers through 1, 4-conjugate addition.The trimethylated ketone 16 was again subjected to IBX oxidation 7 to deliver the bicyclic enone 17, corresponding to the intermediate C identified in the retrosynthetic theme shown in Scheme 1.
Irradiation of 17 from a 450W medium pressure Hg-lamp, in the presence of an excess of trans-1,2-dichloroethylene, furnished tricyclic ketones 18 in excellent yield, as a mixture of diastereomers, Scheme 4. 4 The halogen functionality in 18 now needed to be dispensed with.Attempts towards direct reductive dehalogenation in 18 were not productive and therefore a more circuitous approach involving protective group manoeuvre was resorted to.Thus, the carbonyl group in the tricyclic ketones 18 was protected as the 2,2-dimethyl-1,3-propylene ketal 19 and further eliminative dehalogenation 8 furnished the cyclobutene compound 20 in good yield.Deprotection of the ketal moiety in 20 delivered the unsaturated ketone 21 and was hydrogenated to furnish the saturated tricyclic ketone 22, corresponding to the advanced intermediate B identified in the retrosynthetic formulation.

Scheme 3 Scheme 4
The next target was to transform the central five-membered ring in the tricyclic ketone 22 to a six-membered ring through one carbon ring expansion methodology.In this regard, several efforts using conventional protocols with diazomethane or diazoesters in the presence of various catalysts proved to be singularly unsuccessful.An alternate approach was thus devised in which one carbon ring expansion was sought to be effected through thallium(III) oxidation of the terminal olefin derived from 22. 9 To implement this protocol, tricyclic ketone 22 was subjected to Wittig olefination to furnish the exocyclic olefin 23, Scheme 5. On exposing 23 to oxidation with thallium trinitrate (TTN) 9 in aqueous DME, two regioisomeric ketones 24 and 25 in a 2:1 ratio were obtained.While the structures of 24 and 25 were revealed through the incisive analysis of their spectroscopic data (vide experimental), a distinction between them beyond the realm of ambiguity was not possible.Therefore, the crystalline tricyclic cyclohexanone 24 was subjected to X-ray crystal structure determination and an ORTEP projection is shown in the Figure .The regioselectivity observed in the preferential formation of 24 during the ring expansion is interesting.If one considers the mechanism of the thallium(III) mediated ring expansion, as depicted in Scheme 6, it reveals that the regiochemistry emerges through the preferential migration of the cyclobutylcarbinyl C-C (bond 'a') vs cyclopentylcarbinyl C-C bond ('b') migration.The product ratio of 24 and 25 observed here indicates the dominance of the former process.

Scheme 5 Scheme 6
With the arrival of 24 and 25, we had reached the pre-target stage A indicated in Scheme 1.What remained to be done en route was to effect strategic functional group adjustments in these substrates to reach the target.Our initial efforts in this direction employing the limited amounts of tricyclic ketones 24 and 25 available to us have not been successful.In particular, αcarbomethoxylation and α-hydroxymethylation on 24 proved to be quite capricious.We therefore decided to first accomplish the synthesis of the full framework of the protoilludane system with appropriate functionalisation in the five-membered ring.This was accomplished simply by subjecting 25 to a Wittig olefination to furnish the C 15 -tricycle 26 having the complete protoilludane framework, Scheme 7. Access to 26 was a satisfying accomplishment and sets the stage for further evolution towards the target structure 8.

Scheme 7
In summary, a new synthetic approach to the protoilludane system has been executed, from the commercially available 1,5-cyclooctadiene, en route the newly isolated sesquiterpene natural product pteridanone 8.

Experimental Section
General Procedures.All compounds reported here are racemic and the relative configuration shown here is for convenience only.All reactions were monitored by employing tlc technique using appropriate solvent systems for development.Moisture sensitive reactions were carried out using standard syringe-septa techniques under nitrogen or argon atmosphere.Dichloromethane and chloroform were distilled over P 2 O 5 .Benzene and DME were distilled over sodium and stored over pressed sodium wire.Dry tetrahydrofuran was distilled freshly over sodiumbenzophenone ketyl prior to use.DMSO and TMSCl were dried over calcium hydride.All solvent extracts were washed with water, brine and dried over anhydrous sodium sulphate, and then concentrated under reduced pressure.Yields reported are of isolated material and the homogeneity was judged by tlc and NMR.
To the ketone 16 (450 mg, 2 mmol) in dry toluene and DMSO (2:1, 10 ml) was added IBX (1 g, 3.57 mmol) and stirred for 4 h at 75 o C. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate.The organic extract was washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate.Evaporation of the solvent gave the crude product, which was charged on a silica gel column.Elution with 20% ethyl acetate-hexane furnished the enone 17 (370 mg, 83%) as oil.IR: 1738, 1700, 1620 cm -1 ;
To a solution of 19 (580 mg, 1.43 mmol) in dry DME (10 ml) at rt, sodium naphthalenide reagent (prepared from 0.313 g, 13.6 mmol of sodium and 3.84 g, 30 mmol of naphthalene in DME, 25 ml at rt for about 12 h) was added until the deep bluish-green color persisted.After 0.5 h, the reaction was quenched with dry methanol (1 ml) and saturated NH 4 Cl solution and extracted with ether (30 ml).The organic phase was washed with saturated NH 4 Cl solution, brine and dried over anhydrous sodium sulfate.Removal of the solvent gave a crude product, which was charged on a silica gel column and elution with hexane removed naphthalene and less polar impurities.Further elution with 5% ethyl acetate-hexane furnished the cis, anti, cis tricyclic ketal 20 as a clear liquid (460 mg, 96%).

Figure 1
Figure 1 Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre.The CCDC depository number is CCDC 199848.This data can be obtained by free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html.An ORTEP diagram of 24 with 50% ellipsoidal probability is shown in the Figure (excluding 2 nd molecule for clarity).