From Labdanes to Drimanes. Degradation of the Side Chain of Dihydrozamoranic Acid

A new route for the degradation of the saturated side chain of dihydrozamoranic acid has been devised, giving an advanced intermediate, compound 14, useful for the synthesis of insect antifeedants such as warburganal and polygodial.


Introduction
One of the main problems of our civilization is the shortage of food, especially in Third World countries.The intensity of the problem will increase as the global caloric demand is likely to double over the next ten years.This may be addressed in two ways; by better distribution of existing resources and by increasing total food supplies.With a rising productive area the number of pests has also increased considerably and thus the use of herbicides and insecticides [1].Several insect species have developed resistance against agrochemicals causing not only a significant increase in the amount of chemicals used but also in the environmental pollutant level.The strategy used by plants to protect themselves from insect attack is the biosynthesis of secondary metabolites with antifeedant activity.These natural products are highly specific to some insect species and are completely inactive against other species useful to human beings [2].Moreover, these compounds are biodegradable and there is no danger of accumulation or environmental pollution [3].Among the natural antifeedants, azadirachtin isolated from Azadirachta indica [4], some clerodane diterpenoids such as jodrellin A and B isolated from Schutellaria woronowii Juss [5] and some drimanes such as warburganal (2b) isolated from Warburgia ugandensis [6] and polygodial (2a) isolated from Polygonum hydropiper [7] should be highlighted because their specific and high antifeedant activity against Spodoptera species [8], which causes more than 30% crop losses in India [9].In our lab several bioactive drimanes (Figure 1) have been synthetised starting from zamoranic acid [10].

Results and Discussion
Dihydrozamoranic [11] acid (1), is a diterpene isolated from Halimium verticillatum and Halimium viscosum, being a main component in the first case.This compound's only difference with zamoranic acid is the saturation of the side chain.The transformation of this compound into an intermediate readily transformed in turn into natural compounds with biological activity would be of interest.Some of these intermediates are diene 4, the diacetylderivative 5 [12] and epoxide 6.The last compound has been transformed by us into poligodial (2a), warburganal (2b) and pereniporin A (3).
Starting from dihydrozamoranic acid methyl ester (1a), the retrosynthetic analysis as indicated below (Scheme 1), could be accomplished by two routes.In both cases the main degradation reaction is an elimination of the terminal carbon of the side chain, either by transformation into a double bond or by oxidative decarboxylation of an acid.Route A The first route followed for the degradation of the side chain is shown in Scheme 2. Treatment of 1a with o-nitrophenylselenocyanate (nBu 3 P/THF) [13] gave an 87% yield of the nitrophenylselenyl derivative 7, which with H 2 O 2 [14], produced a minor derivative 8 (4%) and compound 9 in 92% yield.Treatment of 9 under Wacker conditions [15] with CuCl/PdCl 2 /O 2 , lead to ketone 10 in 80% yield.Baeyer-Villiger oxidation [16] of 10 with m-CPBA gives 11, a 1:2 mixture of α and β epoxides, in 95% yield.This compound shows a degradation of the side chain by two carbons.
The hydrolysis of 11 with K 2 CO 3 /MeOH gives 12 (85% yield), a mixture of epoxy alcohols that by oxidation with CrO 3 /Py [17] gave the epoxyketones 13 (82%).As in previous studies, the degradation of the nor-derivatives to the drimane skeleton was done by Norrish II type reaction [18].Photochemical treatment (hυ; λ = 366 nm) of 13 lead to olefins 14 (9.5%) and 15 (22.5%), while a (39%) of 13 was recovered, so the global yield is quite good when the recovery of the starting material is taken into account.Compound 13 can also be obtained in a different manner, starting from 20, a natural compound isolated from H. verticillatum and H. viscosum [19] (Scheme 4), which in a similar manner as described before was transformed into compound 24.Hydrolysis of 24 under basic conditions gave 25, the epoxide of Payne rearrangement [20] 26 and 27 that were separated by CC.Compound 25 was oxidized to give 13, previously transformed into drimanes 14/15 (Scheme 2).

Route B
A second approach is based on the degradation of the side chain by an oxidative decarboxylation process (Scheme 5).The synthesis of the acid group on C-15 and epoxide C-7 can be acheived in two different ways.Oxidation of 1a with CrO 3 /AcOH gives acid 28 in 60% yield, which by treatment with m-CPBA lead to the 3:2 mixture of α and β epoxides 29 in 60% yield.Alternatively, treatment of 1a with m-CPBA gives the 3:2 mixture of α and β epoxides 16, then oxidation with PDC/DMF [21] or CrO 3 /AcOH lead to the same 3:2 mixture of α and β epoxides 29, (in 74% and 56% yields) respectively.Oxidative decarboxylation of 28 gave 30 and 31 in 40% and 8% yield, respectively.The major component was hydrolysed to give alcohols 32 and 33.It is very interesting to note that the decarboxylation takes place giving mainly an isobutyl group in the parent compound 30.

Scheme 5.
The minor compound 31 was transformed by ozonolysis and Norrish II type reaction into diene 4, already transformed into active drimanes [12].As the yield was very poor it was decided to do the same reaction with compound 29, leading again, to a major component 34 (62%) and a terminal olefin 35 (12%) which was transformed into epoxides 13.
As we have seen with m-CPBA, a mixture of epoxides at C-7 was always obtained.In order to obtain only one epoxide, dihydrozamoranic acid methyl ester (1a) was treated with dimethyldioxirane [23], giving selectively only compound 29α in 45% yield and producing the oxidation of the primary alcohol into the acid at C-15; following the same sequence as in Scheme 6 only compound 14 was obtained.

Conclusions
We have developed a new procedure to obtain drimane 14 from dihydrozamoranic acid, making use of methodology developed in our laboratory [24] that could be useful for further transformations.

General
Unless otherwise stated, all chemicals were purchased as the highest purity commercially available and were used without further purification.IR spectra (thin film) were recorded on a MATTSON-GENESIS II FT-IR spectrophotometer. 1 H-and 13 C-NMR spectra were recorded in deuterochloroform and referenced to the residual peak of CHCl 3 at δ 7.26 ppm and δ 77.0 ppm, for 1 H-and 13 C-, respectively, on a Bruker WP-200 SY or a Bruker DRX 400 MHz instrument.Chemical shifts are reported in δ ppm and coupling constants (J) are given in Hz.MS were performed at a VG-TS 250 spectrometer at 70 eV ionising voltage.Mass spectra are represented at m/z (% rel.int.).HRMS were recorded on a VG Platform (Fisons) spectrometer using chemical ionisation (ammonia as gas).Optical rotations were determined at a digital ADP 220 polarimeter in 1 dm cells.Diethyl ether, THF and benzene were distilled from sodium, and pyridine and dichloromethane were distilled from calcium hydride under an Ar atmosphere.The raw material 1 was isolated from a hexane extract of Halimium verticillatum as reported in reference [11].
To a solution of 10 (334.5 mg, 1.0 mmol) in dry CH 2 Cl 2 (5 mL), m-CPBA (345.0 mg, 2.0 mmol) was added and the mixture stirred at room temperature.After 12 h, the solvent was removed and ether was added.The organic phase was washed with 40% Na 2 S 2 O 3 , 10% Na 2 CO 3 and water until neutrality, dried over Na 2 SO 4 , filtered and evaporated to give 11 (317.8mg, 95%). 1  To a solution of 11 (250 mg, 0.68 mmol) in methanol (12 mL) was added K 2 CO 3 (150 mg).The reaction mixture was stirred at room temperature for 1 h, water was added and the mixture extracted with ether, washed with 2N HCl and H 2 O, dried, filtered and evaporated yielding 212 mg (85%) of 12.
A solution of 13 (250.0mg, 0.77 mmol) in dry hexane (250 mL) was placed in a quartz flask and a stream of dry N 2 was bubbled through.The solution was irradiated with UV light (Hanau TQ-150, high pressure) for 90 min.Removal of solvent afforded a yellow oil which was purified by chromatography on silica-gel eluting with 98:2 hexane-EtOAc to yield 23.3 mg (9.3%) of 14, 56.3 mg (22.5%) of 15 and 97.5 mg (39%) of the starting material 13.
Compound 17α: 1  Compound 19 (300 mg, 0.86 mmol) was dissolved in anhydrous CH 2 Cl 2 (10 mL) and m-CPBA (276 mg, 1.6 mmol) was added.The mixture was stirred at 30º C and monitored by TLC.After 5 h the reaction was complete and the solvent evaporated.Work-up afforded 290 mg of crude product that after chromatography on silica-gel gave in the 9:1 hexane/EtOAc fractions 264 mg (88%) of 11 as an epoxide mixture.
Method A: To a solution of 24 (98.5 mg, 0.26 mmol) in methanol (4 mL) was added K 2 CO 3 (120 mg).The reaction mixture was stirred at room temperature for 10 h, water was added and the mixture extracted with ether washed with 2N HCl and H 2 O, dried, filtered, evaporated and chromatographed yielding 59.1 mg of 25+26 (60%), and 29.6 mg of 27 (30%).
Method B: To a solution of 24 (110 mg, 0.29 mmol) was added a solution of 4% NaOH in methanol (6 mL).The reaction mixture was stirred at room temperature for 5 h, water was added and the mixture extracted with ether, washed with 2N HCl and H 2 O, dried, filtered, evaporated and chromatographed yielding 33 mg (30%) of 25, 16.5 mg (15%) of 26 and 36.3 mg (33%) of 27.
Method A: CrO 3 (235 mg, 2.3 mmol) was added to 90% acetic acid (5.0 mL).After stirring for 15 min, 16 (330 mg, 0.9 mmol) in CH 2 Cl 2 (5 mL) and glacial acetic acid (2 mL) were added and stirring was continued at room temperature for 8 h.MeOH was added and the solvent removed in vacuo.Work-up afforded 320 mg of crude product that after chromatography on silica-gel gave 181.5 mg (55%) of 29 in the EtOAc fractions.
Method B: To a stirred solution of PDC (1.2 mg, 3.3 mmol) in DMF (12.0 mL) was added 16 (340 mg, 1.0 mmol).After 40 h at room temperature the solvent is evaporated, extracted with ether, washed with 7-10 vol of water and dried over Na 2 SO 4 .The residue was chromatographed on silica-gel affording 889 mg (74%) of 29 in the EtOAc fractions.To a solution of 28 (343 mg, 0.98 mmol) in dry C 6 H 6 (10 mL) was added dry pyridine (0.1 mL) under a N 2 atmosphere and the mixture was stirred at room temperature.After 15 min, dry (AcO) 2 Cu (60 mg, 0.33 mmol) was added and the reaction mixture was heated at 80º C. (AcO) 4 Pb (1.280 g, 2.9 mmol) was added in six portions over the next 6 h.The solvent was removed and extracted with ether.The ethereal solution of neutral products was washed with water and dried over Na 2 SO 4 , filtered and evaporated to give 273 mg of crude mixture that by CC afforded 103.2 mg of 30 and 21.8 mg of 31.
Compound 30: 1   A solution of 31 (100 mg, 0.3 mmol), in CH 2 Cl 2 (4 mL) was cooled to -78º C with acetone/Dry Ice.Ozone (about 5.2 g of O 3 /h) was bubbled through this solution for 1.5 min.To the cooled reaction mixture Ph 3 P (164.5 mg, 0.6 mmol) in CH 2 Cl 2 (3 mL) was added and then it was gradually allowed to reach room temperature.The solvent was removed under reduced pressure and the residue chromatographed on silica-gel to give 75 mg (75%) of product.A solution of the reaction product (75 mg, 0.24 mmol) in dry hexane (250 mL) was placed in a quartz flask and a stream of dry N 2 was bubbled through it.The solution was irradiated with UV light (Hanau TQ-150, high pressure) for 2 h.Removal of solvent afforded a yellow oil which was purified by chromatography on silica-gel eluting with 95:5 hexane/EtOAc to yield 37.5 mg (50%) of 5 and 34.2 mg (45%) of the starting material.
Compound 32: 1    A solution of 35 (220 mg, 0.69 mmol) in CH 2 Cl 2 (6 mL), was cooled to -78º C with acetone/dry ice.Ozone (about 5.2 g of O 3 /h) was bubbled through this solution for 8 min.To the cooled reaction mixture Ph 3 P (230 mg, 0.90 mmol) in CH 2 Cl 2 (6 mL) was added and the mixture was gradually allowed to reach room temperature.The solvent was then removed under reduced pressure and the residue chromatographed on silica-gel affording 16.7 mg (7.6%) of 35 and 158.4 mg (72%) of 13.

Norrish type II reaction of 13α: Synthesis of 14.
A solution of 13α (100 mg, 0.31 mmol) in dry hexane (250 mL) was placed in a quartz flask and a stream of dry N 2 was bubbled through.The solution was irradiated with UV light (Hanau TQ-150, high pressure) for 90 min.Removal of the solvent afforded a yellow oil which was purified by chromatography on silica-gel eluting with 98:2 hexane/EtOAc, to yield 28.5 mg (28%) of 14 and 40.0 mg (40%) of the starting material 13α.