Synthesis of a tricyclic lactone embodying the ABC-ring system of stephaoxocanidine, by tin(IV) chloride-assisted sulfonamidoacetal cyclization and an aromatization promoted by triethylamine

The synthesis of the polysubstituted 8-oxa-1-azaphenalene lactone 4 , which embodies the ABC-ring system of stephaoxocanidine, a tetracyclic isoquinoline alkaloid recently isolated from the tubers of Stephania cepharantha Hayata, is reported. Elaboration of 4 was carried out by means of the camphorsulfonic acid-assisted lactonization of 9 , coupled to a titanium(IV) chloride-mediated acetal cyclization of the resulting lactone 10 to form the tricyclic intermediate 12 , followed by the base-promoted aromatization of the latter to 13 and final benzylic bromination. Lactone 4 constitutes an advanced key intermediate for the total synthesis of stephaoxocanidine, the simplest stephaoxocane.


Introduction
The stephaoxocanes constitute a new, small family of isoquinoline alkaloids sharing the tetracyclic stephaoxocane 1 skeleton (1a).This family, which was independently uncovered during the past decade by Japanese, 1 Chinese 2 and Brazilian 3 research groups, has only five members (1b-1f), all of which have been isolated from Menispermaceae employed in folk medicine. 4The structurally simplest stephaoxocane is stephaoxocanidine (1b), a Stephania cepharantha Hayata alkaloid which contains a fully unsaturated isoquinoline ring system like eletefine (1c), isolated from Cissampelos glaberrima (also known as Cissampelos pareira).

OMe
We have demonstrated that the cyclization of sulfonamido acetals originally reported by Jackson and coworkers 6 is a versatile protocol, capable of providing useful intermediates towards polysubstituted isoquinolines, tetrahydroisoquinolines and tetahydroprotoberberines. 7In addition, we have recently reported 8 the synthesis of a tricyclic oxazaphenalene derivative related to the stephaoxocanes, employing a reaction sequence entailing a Friedel-Crafts acylation in association with a benzylic functionalization strategy and a Jackson-type toluenesulfonamide acetal cyclization. 6s part of our ongoing project aimed to the synthesis of stephaoxocanes, we describe here the elaboration of polysubstituted 8-oxa-1-azaphenalen-9-one 4 from the previously reported tricarbonylic compound 5, in turn easily accessible from commercially available 2,3dimethoxytoluene. 8 Tricyclic lactone 4 embodies the ABC-ring system of stephaoxocanidine (1b) and constitutes a convenient advanced key intermediate for its total synthesis.The 8-oxa-1azaphenalene structure is a new and unprecedented heterocyclic ring system, being this unit unique to the stephaoxocanes.

Results and Discussion
As shown in Scheme 1, the synthesis commenced with the selective reduction of tricarbonylic compound 5 to mandelate 6. Sodium cyanoborohydride proved to be a more appropriate reducing agent than sodium borohydride, which caused partial removal of the acetate, furnishing the benzylic alcohol in 91% yield.Next, alcohol 6 was smoothly and efficiently transformed into the related chloride 7 in 82% yield by reaction with methanesulfonyl chloride, employing triethylamine as base. 9By analogy with similar processes, this transformation most probably proceeded through chloride ion displacement 10 of a transient mesylate, 11 which was not isolated.
Benzylic chloride 7 was aminated with aminoacetaldehyde dimethyl acetal in a DMSOtoluene (1:4) solvent mixture, 12 to which N-ethyl diisopropylamine was added as HCl scavenger, furnishing secondary amine 8 in almost quantitative yield.In turn, this was uneventfully converted into the related sulfonamide (9) with tosyl chloride under forcing conditions, 8 required to overcome the steric crowding surrounding the nitrogen atom.
We have previously reported that submission of 9 to Jackson's protocol for 1,2dihydroisoquinoline formation (6 N HCl, dioxane, reflux) resulted only in moderate yields of tetrahydroisoquinoline derivative 10.We have also recently disclosed that N-sulfonyl tetrahydroisoquinolines bearing a carbonyl substituent at C-1 are capable of undergoing aromatization of the heterocyclic ring on exposure to KF supported on alumina under microwave irradiation. 13With these precedents in mind, attempts were made to cyclize 9 under more efficient, alternative conditions; however, cyclization with HCl in dioxane to which EtOH was added 14 did not yield improved results and reaction of sulfonamido acetal 9 with SnCl 4 at -40ºC produced only scarce amounts of 10, together with a complex mixture of decomposition products.
Thus, a stepwise approach towards the desired tricyclic compound was explored, consisting in the elaboration of lactone 11 as a first step, followed by its subsequent submission to an acetal cyclization protocol and a final B-ring aromatization.Not unexpectedly, however, initial attempts to lactonize 9 either by basic hydrolysis (LiOH, THF/H 2 O and K 2 CO 3 , MeOH/H 2 O) followed by acidic work-up or by transesterification under basic conditions (K 2 CO 3 in MeOH) 15 met with failure, probably due to the acidity of the tertiary benzylic proton, which resulted in oxidative desulfonylation of 9, with loss of para-toluenesulfinic acid and subsequent hydrolysis of the resulting imine, to yield 5. This side reaction is analogous to one previously reported in a similar environment. 16herefore, we turned our attention to an acid catalyzed lactonization process, 17 which to our delight provided lactone 11 in 94% yield, when performed with catalytic amounts of camphorsulfonic acid (CSA) in dry methanol.With isochroman-3-one 11 in our hands, exploration of the Lewis acid promoted acetal cyclization was undertaken.However, exposure of 11 to BF 3 .Et 2 O during 4 h at -78ºC or 15 h at -20ºC gave no reaction, while running the transformation at 0ºC resulted in a series of products which decomposed on contact with the silica gel during the chromatographic purification step.

Scheme 1
On the other hand, when the reaction was carried out with 2 equivalents of SnCl 4 for 2 h at -65ºC or during 20 min at -30ºC, smooth and complete cyclization of 11 to a slightly less polar compound was observed.Interestingly, only one diastereomer was obtained, to which structure 12 was assigned by analogy with previous work 8 and taking into account the results of differential NOE experiments, showing a 2% enhancement of the H-9a signal upon irradiation of H-3, and the coupling constant values J H2ax-H3 = 10.1 Hz and J H2eq-H3 = 4.8 Hz.Formation of a single diastereomer is probably due to severe steric restrictions imposed by the isochroman-3-one system to the nucleophilic attack of the activated acetal by the aromatic moiety during the cyclization. 8n spite that tricyclic compound 12 tolerated basic work-up, it proved to be unstable and readily decomposed upon contact with silica gel; however, pretreatment of the chromatographic medium with 2% triethylamine in hexane caused efficient in situ transformation of 12 into oxazaphenalene 13, 18 this becoming the preferred method for accessing the isoquinoline.
Aromatization of the nitrogen containing heterocyclic ring may be the driving force of this transformation which, as shown in Scheme 2, could probably take place through an initial baseassisted oxidative desulfonylation of 12 entailing loss of para-toluenesulfinic acid to give intermediate 14, a process favored by the acidity of H-9a.In turn, and after elimination of methanol, 14 would readily provide compound 13, carrying a fully unsaturated AB ring system.The overall transformation is somehow reminiscent of the scarcely employed Pictet-Gams modification of the classical Bischler-Napieralski synthesis, capable of converting β-hydroxyor β−methoxyphenethylamine derivatives into isoquinolines. 19

Scheme 2
The proposal that oxidative desulfonylation precedes the loss of methanol during the aromatization is supported by the relatively harsh conditions required to transform N-tosyl-1,2dihydroisoquinolines into isoquinolines, 13 compared to the observed ease with which the basepromoted desulfonylation reaction takes place.
Finally, benzylic bromination of 13 with NBS in refluxing CCl 4 , under the assistance of AIBN, furnished brominated derivative 4 in moderate but satisfactory yield. 20Interestingly, in spite that the benzylic bromination of benzyl ethers has been studied in some detail, 21 there are only scarce references to the bromination of lactones carrying a benzylic methylene attached to oxygen. 22Compound 4 has different C-7 and C-9 functionalities, suitable for the elaboration of the remaining oxocane-type D-ring of stephaoxocanidine.

Conclusions
The synthesis of polysubstituted 8-oxa-1-azaphenalene derivative 4 was successfully and efficiently achieved in 8 steps and 21% overall yield from tricarbonylic compound 5. Efficient synthesis and amination of chloride 7, coupled to lactonization of acetate 9 prior to acetal cyclization and use of tin(IV) chloride as cyclization promoter proved to be crucial for attaining good yields of tricyclic product 12, while the unusual base-promoted aromatization of 12 was fundamental for accessing oxazaphenalene derivative 13 in good yields.Studies employing 4 as key intermediate for the total synthesis of stephaoxocanidine are under way and will be reported in due time.

Experimental Section
General Procedures.Melting points were taken on an Ernst Leitz Wetzlar model 350 hot-stage microscope apparatus and are informed uncorrected.FT-IR spectra were determined with Bruker IFS 25 or Beckman Acculab 8 spectrophotometers as thin films held between NaCl cells or as dispersions in KBr disks.The 1 H and 13 C-NMR spectra were acquired in CDCl 3 employing TMS as internal standard, with a Bruker AC200-E spectrometer operating at 200.13 and 50.33 MHz, respectively.DEPT 135 and DEPT 90 experiments aided the interpretation of the fully decoupled 13 C NMR spectra.HRMS and microanalytical data were obtained from Kent Electronics (UK), Atlantic Microlab (USA) and UMyMFOR (Argentina).Reactions were carried out under dry Nitrogen or Ar atmospheres, employing oven-dried glassware.Commercially obtained reagents were used without further purification.Dry THF and toluene were prepared by distillation from Na-benzophenone ketyl; anhydrous DMSO, N-ethyl diisopropylamine and Et 3 N were accessed by reflux and distillation from CaH 2 ; CHCl 3 and CH 2 Cl 2 were distilled from P 2 O 5 and pyridine was dried over KOH pellets and then distilled; anhydrous solvents were stored in dry Schlenk bottles.All new compounds gave single spots on TLC plates run in different solvent systems.Spots were visualized by exposure to UV light (254 and 365 nm), followed by spraying with ethanolic p-anisaldehyde/sulfuric acid reagent and careful heating.Standard work-up procedures consisted in diluting the reaction with brine (5 -20 mL) and extracting the products with EtOAc (3 x 20 -40 mL); the combined organic extracts were washed once with brine, dried over Na 2 SO 4 , concentrated under reduced pressure and the respective residues were chromatographed.Flash column chromatographies were carried out with silica gel 60 H, eluting with hexane-EtOAc mixtures under positive pressure and employing gradient techniques.Mixtures of EtOAcacetone and EtOAc-EtOH were used for the separation of 4 and 13, respectively.