Synthesis of herbertenediol and mastigophorenes A-D

Formal total synthesis of (±)-herbertenediol and mastigophorenes A-D, starting from vanillin, has been described. A combination of alkylation, Wacker oxidation and intramolecular aldol condensation was employed for the generation of the cyclopentenone with two vicinal quaternary carbon atoms.


Introduction
Liverworts from the genus Herbertus contain herbertane sesquiterpenoids which are considered as chemical markers of the genus. 1 The herbertane group is a class of aromatic sesquiterpenes, containing sterically crowded 1-aryl-1,2,2-trimethylcyclopentane carbon framework incorporating two vicinal quaternary carbon atoms on a cyclopentane ring.The first member of this class of sesquiterpenes, herbertene 1, was isolated in 1981 by Matsuo and coworkers from the ethyl acetate extract of the liverwort Herberta adunca (Dicks.)S. Gray belonging to the family Herbertaceae.In 1982, research groups of Matsuo and Asakawa have reported isolation of three phenolic herbertanes, α-herbertenol 2, α-formylherbertenol 3 and β-herbertenol 4 along with herbertene 1 and cuparene sesquiterpenes from the species H. aduncus, H. sakuraii and H. subdetatus. 3solation of two more herbertenoids herbertenediol 5 and herbertenolide 6 was reported in 1983 by Matsuo and coworkers. 4In 1988 and 1991 Asakawa and coworkers reported the isolation of the dimeric herbertanes, mastigophorenes A-D 7-10, dimers of herbertenediol 5, from the liverwort Mastigophora diclados (Mastigophoraceae). 5The mastigophorenes A-D 7-10 are presumably formed by one electron oxidative phenolic coupling of herbertenediol 5. Subsequently, isolation of several herbertenoids 11-21 from various liverworts was reported. 1,6tructures of the herbertanes and mastigophorenes known so far are depicted in Chart 1.The herbertane sesquiterpenes, mainly the phenolic herbertanes have been shown to possess interesting biological properties such as growth inhibiting activity, antilipid peroxidation activity. 3,4,6The growth inhibiting activity of a few herbertenoids was tested on some plant pathogenic fungi.Some of the phenolic herbertanes were found to be strong inhibitors of the plant pathogenic fungi, Botrytis cinerea, Rhizoctonia solani and Pythium debaryanum.Mastigophorenes A-D 7-10 were found to exhibit intriguing neurotropic properties i.e. promote neuronal out growth and enhance choline acetyl transferase activity in the primary cultures of fetal rat cerebral hemisphere.
Presence of an interesting carbon framework, sterically crowded 1-aryl-1,2,2trimethylcyclopentane, the difficulty associated with the construction of vicinal quaternary carbon atoms on a cyclopentane ring, and the novel biological properties associated with the phenolic herbertanes made the herbertenoids and mastigophorenes challenging synthetic targets.Even though, herbertanes were known since 1981, very little synthetic effort was reported in the literature on the synthesis of phenolic herbertanes prior to 1999.][9] During the same time, three approaches have been reported for the synthesis of mastigophorenes A and B 7 and 8, and one of which has been extended to the synthesis of mastigophorenes C and D 9 and 10. 8 Herein, we report the details of the formal total synthesis of (±)-herbertenediol and mastigophorenes A-D. 9

Results and Discussion
For the formal total synthesis of herbertenediol and mastigophorenes cyclopentanone 22 was chosen as the target molecule, since its conversion to herbertenediol 5 and mastigophorenes A-D 7-10 has already been reported in the literature.7h,8a,d An intramolecular aldol condensation based strategy was contemplated for the construction of the cyclopentanone 22 as depicted in the retrosynthetic scheme 1. Presence of two ortho oriented oxygen substituents prompted us to choose 2-methoxy-4-methylphenol 26, which could be readily obtained from vanillin 27, as the starting material.A Claisen rearrangement was considered as an ideal methodology for the introduction of a side chain at the C-6 position, which could be elaborated into cyclopentanone 22.

Scheme 1
The synthetic sequence is depicted in schemes 2 and 3. To begin with, vanillin 27 was converted into the phenol 26 via Clemmensen's reduction. 10Treatment of the phenol 26 with anhydrous potassium carbonate and allyl bromide in refluxing acetone generated the allyl aryl ether 28 in 92% yield, which on thermal activation at 180 o C furnished the ortho Claisen product 29 in 67% yield.The phenol 29 on etherification with dimethyl sulfate and 10% aqueous sodium hydroxide generated the dimethoxy compound 30 in 87% yield.Ozonolytic cleavage of the allyl group in the compound 30 in methanol and methylene chloride followed by reductive workup with dimethyl sulfide gave the aldehyde 31 in 88% yield.Oxidation of the aldehyde 31 with 2.5 M Jones reagent in acetone at 0 o C furnished the acid 8a 32 in 93% yield, which on esterification with methanol in the presence of sulfuric acid generated the ester 25 in 94% yield.

Scheme 2
For creating the first quaternary center, sequential alkylation of the ester 25 was explored.Thus, generation of the lithium enolate of the ester 25 with lithium diisopropylamide (LDA) in THF at -70 o C followed by alkylation with methyl iodide furnished the ester 33 in 88% yield, whose structure rests secured from the spectral data.For the projected intramolecular aldol condensation for the generation of cyclopentenone 23, an allyl group was chosen as the acetone equivalent.Generation of the lithium enolate of the ester 33 with LDA in THF and HMPA at -70 o C followed by alkylation with allyl bromide generated the ester 34 in 74% yield.To avoid regiochemical problems at a later stage, the ester moiety in 34 was converted into an aldehyde.Consequently, reduction of the ester 34 using lithium aluminum hydride (LAH) in ether gave the primary alcohol 35 in 94% yield, which on oxidation with pyridinium chlorochromate (PCC) and silica gel in methylene chloride furnished the aldehyde 36 in 91% yield.For the conversion of the terminal vinyl group in the pentenal 36 into an acetyl moiety, Wacker oxidation was chosen. 11Thus, treatment of the pentenal 36 with 0.2 equivalent of palladium chloride and 3 equivalents of cupric chloride in N,N-dimethylformamide (DMF) and water in oxygen atmosphere (balloon), produced the keto-aldehyde 24 in 77% yield.Intramolecular aldol condensation of the ketoaldehyde 24 with 2 M methanolic potassium hydroxide in THF at room temperature generated the cyclopentenone 23 in 92% yield.Presence of the molecular ion peak at m/z 246 (C 15 H 18 O 3 ) in the mass spectrum and in the IR spectrum presence of an absorption band at 1715 cm -1 due to the cyclopentenone carbonyl group suggested the formation of the aldol product 23.In the 1 H NMR spectrum, presence of two typical doublets at δ 7.80 and 6.15 due to the β and α protons, respectively, of a cyclopentenone, and an AB quartet at 2.66 and 2.55 ppm due to the methylene α to the ketone, established the structure of the cyclopentenone 23.The 13 C NMR spectrum with characteristic resonances, a quaternary carbon at δ 208.8 due to the ketone, two methines at 170.7 and 130.7 due to the β and α olefinic carbons, respectively, of a cyclopentenone and a methylene at 51.0 ppm due to the C-5 carbon, in addition to other resonances confirmed the structure of the cyclopentenone 23.Dialkylation of the cyclopentenone 23 using sodium hydride and methyl iodide in dry THF and DMF at room temperature, created the second quaternary centre and generated the enone 37 in 75% yield, whose structure was established from its spectral data, in particular the resonance at 0.65 ppm in the 1 H NMR spectrum due to the C-5 methyl group, which is cis to the aromatic ring and experiencing the shielding effect of the aromatic π-cloud.Finally, hydrogenation of the enone 37 using 10% palladium over carbon as the catalyst at one atmospheric pressure (balloon) of hydrogen in ethanol, furnished the cyclopentanone 22 in 95% yield, which exhibited 1 H and 13 C NMR spectra identical to those of the sample obtained by Mukherjee and coworkers.7h Since the cyclopentanone 22 has already been converted 7h,8a,d into herbertenediol 5 and mastigophorenes A-D 7-10, the present sequence constitutes a formal synthesis of these terpenoids.

Experimental Section
General Procedures.IR spectra were recorded on Jasco FTIR 410 spectrophotometer. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on JNM λ-300 spectrometer.The chemical shifts (δ ppm) and coupling constants (Hz) are reported in the standard fashion with reference to either internal tetramethylsilane (for 1 H) or the central line (77.0 ppm) of CDCl 3 (for 13 C).In the 13 C NMR spectra, the nature of the carbons (C, CH, CH 2 or CH 3 ) was determined by recording DEPT-135 spectra, and are given in parentheses.Low-resolution mass spectra were recorded using Jeol JMS-DX 303 and Shimadzu QP-5050A GCMS instruments using direct inlet mode.Relative intensities are given in parentheses.High resolution mass spectra were recorded on a Micromass Q-TOF micro mass spectrometer using electron spray ionization mode.Ozonolysis experiments were carried out using Fischer 502 ozone generator.The oxygen flow was adjusted and calibrated to generate one mmole of ozone per four minutes.Hydrogenation reactions at one atmospheric pressure were carried out using a balloon filled with hydrogen.Acme's silica gel (100-200 mesh) was used for column chromatography.All small-scale dry reactions were carried out using standard syringe-septum technique.Low temperature reactions were conducted in a bath made of alcohol and liquid nitrogen.

2-(2,3-Dimethoxy-5-methylphenyl)-2-methylpent-4-enal (36).
To a cold (-20 o C) magnetically stirred solution of the ester 34 (250 mg, 0.90 mmol) in dry ether (4 ml) was added LAH (17 mg, 0.45 mmol) in one portion.The reaction mixture was stirred at the same temperature for 2 h and allowed to warm to 0 o C over a period of 30 min.Ethyl acetate (2 ml) was carefully introduced to consume the excess reagent and the reaction was quenched with ice-cold water (5 ml).The solution was filtered through a sintered funnel and the residue thoroughly washed with ether (3 x 5 ml).The ether layer was separated, washed with brine and dried (Na 2 SO 4 ).Evaporation of the solvent and purification of the residue over a silica gel column using ethyl acetate-hexane (1:5) as eluent furnished the primary alcohol 35 (210 mg, 94%) as oil.IR (neat):

2-(2,3-Dimethoxy-5-methylphenyl)-2-methyl-4-oxovaleraldehyde (24).
A suspension of palladium chloride (23 mg, 0.13 mmol) and cuprous chloride (257 mg, 1.92 mmol) in DMF (2 ml) and water (1 ml) was magnetically stirred in an oxygen atmosphere, created via evacuative displacement of air using an oxygen balloon, for 1 h at RT.A solution of the enal 36 (160 mg, 0.64 mmol) in DMF (2 ml) was added to the reaction mixture and stirred for 16 h at RT in the oxygen atmosphere.Then 3 N aq.HCl (5 ml) was added to the reaction mixture and extracted with ether (3 x 4 ml).The combined ether extract was washed with saturated aq.NaHCO 3 solution and brine, and dried (Na 2 SO 4 ).Evaporation of the solvent and purification of the residue over a silica gel column using ethyl acetate-hexane (1:10)
tert-CH 3 ), 21.6 (CH 3 , ArCH 3 ).To a magnetically stirred suspension of PCC (344 mg, 1.6 mmol) and silica gel (344 mg) in dry CH 2 Cl 2 (4 ml) was added a solution of the alcohol 35 (200 mg, 0.80 mmol) in CH 2 Cl 2 (2 ml) and stirred vigorously for 1 h at RT.The reaction mixture was then filtered through a small silica gel column, and the column eluted with more CH 2 Cl 2 .