Stereocontrolled total synthesis of ( ± )-tochuinyl acetate and facile total synthesis of ( ± )- α -cuparenone and ( ± )-cuparene

A stereocontrolled total synthesis of (±)-tochuinyl acetate has been successfully accomplished involving intramolecular cyclisation of methyl 3-methyl-3-p -tolyl-6-bromohexanoate and in situ methylation of the resulting cyclopentanecarboxylate as the key reaction. A total synthesis of (±)- α -cuparenone has been achieved using α , α -dimethylation of methyl 3-methyl-3-p -tolyl-6,6-ethylenedioxyhexanoate as a key step.


Introduction
Cuparane and isocuparane sesquiterpenes possessing sterically crowded cyclopentane moieties belong to an expanding family of sesquiterpenes and have become popular synthetic targets in recent years, as some members exhibit interesting biological activities.Tochuinyl acetate 1, a cuparene-type sesquiterpene, was isolated 1 by Andersen and Williams, along with dihydrotochuinyl acetate 4, from the skin extracts of the dendronotid nudibranch Tochuina tetraquetra, collected from Port Hardy, British Columbia.Subsequently, the acetates 1 and 4 were also isolated 1 from the extracts of the soft coral Gersemia rubiformis, which was found to be a feed for T. tetraquetra.The presence of a sterically congested cyclopentane ring with stereogenic quaternary centres at C-1 and C-2 makes the acetate 1 an interesting synthetic target.The related sesquiterpene ketone α -cuparenone 5 was first isolated 2 by Dev et al. from the essential oil of Thuja orientalis.Subsequently, 5 was also isolated 3 from the liverwort Mannia fragrans and its presence was detected in a number of essential oils.The total synthesis of naturally occurring sesquiterpenes containing 1,1,2-trisubstituted-2-arylcyclopentane ring system Figure 1 has been an active area of research in recent times and current interest in sesquiterpenes 1 4 and 5 5 (Figure 1) is reflected in a number of diverse synthetic approaches to these compounds.The synthesis of these sesquiterpenes is associated with the difficulty in the generation of two adjacent quaternary carbon atoms at C-1 and C-2 on a cyclopentane ring and a substitued aromatic ring at C-2.The first synthesis of (±)-1 was accomplished by Ishibashi et al. 6 using a thiochromane approach, and later Taber and coworkers 7 synthesised (±)-1 involving rhodium catalysed intramolecular C-H insertion of a diazo ketone as a key step.Srikrishna et al. 8 reported the total syntheses of (±)-1 and (±)-4 involving cyclopentenone annulation of pmethoxyacetophenone via a Claisen rearrangement-Wacker oxidation sequence to generate 5methyl-5-p-tolylcyclopent-2-en-1-one as a key intermediate to 1. Very recently, Srikrishna and co-workers achieved 4 the synthesis of (±)-1 employing a ring-closing metathesis reaction based methodology.In order to generate 1,1,2,2-tetrasubstitutedcyclopentane ring system related to the sesquiterpene 1, we envisaged that an intramolecular cyclisation of methyl 3-methyl-3-p-tolyl-6bromohexanoate 6 in the presence of base and in situ methylation of the resulting cyclopentanecarboxylate from the less hindered side would stereoselectively generate, in one step, cis-1,2-dimethyl-1-methoxycarbonyl-2-p-tolylcyclopentane 7 as a key intermediate to 1, as shown in Scheme 1.Based on this approach, we have successfully accomplished a highly stereoselective total synthesis of (±)-1.The present method may be easily adapted for the synthesis of several other bicyclic sesquiterpenes of the cuparane and isocuparane (herbertane) family.Since Birch reduction of the alcohol 2 and subsequent acetylation provides 8 (±)-dihydrotochuinyl acetate 4 in high yield, the present work also constitues a formal total synthesis of (±)-4.We have also achieved facile total synthesis of (±)-α -cuparenone 5 and (±)-cuparene 3 involving one pot α, α -dimethylation of methyl 3-methyl-3-p-tolyl-6,6-ethylenedioxyhexanoate 10 as a key step (Scheme 3).

Results and Discussion
Our synthesis of (±)-tochuinyl acetate 1 is outlined in Scheme 2. The first quaternary carbon atom was created through conjugate addition to the unsaturated cyanoester 8. 9 Thus, conjugate addition of 3,3-ethylenedioxypropylmagnesium bromide 10 to the unsaturated cyanoester 8 in the presence of CuBr.S(CH 3 ) 2 provided 9 which was contaminated with 8 (ca.33%).Separation of 9 from 8 was effected by a simple procedure.The mixture was treated with calculated quantity of the sodium salt of cyanoacetamide in EtOH at room tmperature for several hours.On dilution with water, 8 was removed completely as a water soluble salt 11 and the desired conjugate addition product 9 was recovered in a pure state in 58% overall yield.Hydrolysis of 9 with KOH in refluxing ethylene glycol : water (4:1) followed by decarboxylation and esterification afforded the ester 10 in 75% yield.Deacetalisation of 10 followed by reduction of the resulting aldehyde 11 with NaBH 4 afforded the primary alcohol 12 (83%) which was treated with PBr 3 to give the bromoester 6 in 74% yield.The bromoester 6 was converted into the cyclopentanecarboxylate 7 (85%) in a one pot process involving an intramolecular cyclisation of 6 by treatment with LDA (1.2 equiv.) in THF and HMPA at -70°C followed by alkylation with MeI at 0°C in the presence of LDA (1.6 equiv.)and HMPA (2 equiv.),without isolating the initial cyclised product 7a.The second quaternary carbon atom was thus generated very efficiently and in a stereoselective manner, highlighting the potential of the present method.High stereoselectivity observed in the transformation of 6 into 7 is due to methylation taking place from the less hindered side of the intermediate enolate of the ester 7a.In the 1 H NMR spectrum of 7, the ester methyl signal appeared at δ 3.25 ppm indicating shielding of the methoxycarbonyl group by the vicinal cis aryl group.The stereostructure 7 of the ester, as shown in Scheme 2, was further confirmed by conversion of 7, which is suitably functionalised, into (±)-tochuinyl acetate 1.Thus, reduction of 7 with LiAlH 4 followed by acetylation of the resulting alcohol 2 furnished (±)-1 in 74% overall yield.The spectral data of synthetic 1 were identical with those of the natural product.
For the synthesis of α-cuparenone 5, the acetal-ester 10 was used as an internediate.This was converted in high yield into the corresponding α,α -dimethylated ester 13 (Scheme 3) in a single step employing a sequential methylation of 10.Thus, alkylation of 10 with MeI at -78 °C in the presence of LDA (1 equiv.)as the base yielded the corresponding monomethyl ester which without isolation was again alkylated with MeI at 0 °C in the presence of LDA (1.7 equiv.)and HMPA (2 equiv.) to give the α,α-dimethylated ester 13 in 88% yield.The second quaternary carbon atom of α-cuparenone 5 was thus generated in an extremely facile manner.Deacetalisation of 13 followed by oxidation of the resulting aldehyde 14 with Jones reagent and esterification with CH 2 N 2 furnished the diester 15 in 74 % overall yield.The spectral characteristics of the compounds 13 -15 as revealed through their 1 H and 13 C NMR spectra were fully in accord with their structures.Dieckmann cyclisation of the diester 15 in the presence of t-BuOK followed by decarbomethoxylation of the resulting crude в-ketoester furnished (±)-α-cuparenone 5 in 75% yield.Huang-Minlon reduction of 5 yielded the parent hydrocarbon (±)-cuparene 3 (82%).The identities of our synthetic compounds 5 and 3 were secured through comparison of 1 H NMR and 13 C NMR data with those of authentic compounds.

Experimental Section
General Procedures.The compounds described here are all racemates.IR spectra were recorded in thin film on Perkin-Elmer model PE 298 and Shimadzu FTIR-8300 spectrophotometers.Unless otherwise stated, 1 H and 13 C NMR spectra were recorded in CDCl 3 solution at 300 MHz and 75 MHz respectively on a Bruker DPX-300 spectrometer with SiMe 4 as internal standard.Moisture sensitive reactions were carried out using standard syringe-septum technique.Anhydrous solvents were obtained by standard procedures.All solvent extracts were dried over anhydrous Na 2 SO 4 .Product purities were routinely checked by TLC.Ether refers to diethyl ether and light petroleum refers to the fraction of petroleum ether in the boiling point range 60 -80 0 C.

Ethyl 2-cyano-3-methyl-3-(4-methylphenyl)-6,6-ethylenedioxyhexanoate (9).
Copper bromidedimethyl sulfide complex (0.8 g, 3.9 mmol) was added to a solution of the unsaturated cyanoester 8 9 (3.5 g, 15 mmol) in anhydrous ether (15 mL) containing dry tetrahydrofuran (8 mL).The mixture was stirred at 0 °C for 10 min and then a solution of 3,3ethylenedioxypropylmagnesium bromide 10 in tetrahydrofuran (15 mL) [prepared from magnesium (0.51 g, 0.021 g-at.) and 3,3-ethylenedioxypropyl bromide (3.3 g, 18 mmol)] was added under nitrogen during 30 min with vigorous stirring.The mixture was further sitrred at 0 °C for 2 h and then allowed to stand at room temperature for 6 h.It was then cooled in an icebath, decomposed with saturated solution of ammonium chloride (50 mL) and extracted with ether (3x60 mL).The combined ethereal extract was washed with water (2x50 mL), dried and concentrated.The residue was evaporatively distilled at 174-176 °C (bath temperature)/0.2mmHg to afford a colourless oil (4.5 g).From integration of the 1 H NMR signals, the oil was estimated to contain 9 and 8 in a ratio of 2:1.A solution of the oil (4.5 g) in EtOH (5 mL) was added under nitrogen to a stirred suspension of sodium salt of cyanoacetamide [prepared from EtONa (0.4 g, 5.88 mmol) and cyanoacetamide (0.5 g, 5.95 mmol)] in EtOH (8 mL).After 16 h at 25 °C, the reaction mixture was diluted with water (30 mL) and extracted with ether (3x50 mL).The combined ethereal extract was washed with water (2x30 mL), dried and concentrated.The residue was chromatographed over silica gel using ether: light petroleum (1:3) as eluent to afford the cyano-ester 9 (2.93 g, 58%) as a colourless oil (diastereomeric mixture), IR: 2240, 1736 cm -1 : 1 H NMR δ 0.95, 1.15(2t, J = 7 Hz each, total 3H),  (10).The cyano-ester 9 (2.7 g, 8.15 mmol) was hydrolysed by refluxing under nitrogen for 24 h with a solution of potassium hydroxide (10 g) in ethylene glycol (32 mL) and water (8 mL).The mixture was cooled to room temperature, diluted with water (35 mL) and the neutral material was extracted with ether.The alkaline solution was then acidified at 0 °C with cold dilute acetic acid (1:1) and extracted with ether (3x60 mL).The organic extract was washed with water (2x30 mL), dried and concentrated.The crude product was decarboxylated by heating it at 190 °C for 20 min.and the resulting acid (1.8 g) was esterified by treatment with an excess of ethereal solution of diazomethane at 0 °C.Usual work-up of the reaction mixture followed by chromatography of the crude product over neutral alumina and elution with benzene : light petroleum (1:4) afforded the methyl ester 10 (1.79 g, 75% ) as a colourless oil; IR: 1735 cm -1 : 1