The chemistry of the himachalenes and atlantones from Cedrus

Synthesis and functionalization of natural products are useful procedures to access and develop new and interesting molecules with biological properties. In this review we discuss the major sesquiterpenes isolated from the essential oil of cedar, which represents a family of abundant and inexpensive natural materials. Some total synthesis and chemical transformations described in the literature have been included


Introduction
Plants have always been a vital source of medicines.Today the majority of the world's populations, particularly in developing countries, are treated only with traditional herbal remedies.The modern pharmaceutical industry is largely based on the diversity of secondary metabolites to find new molecules with new biological properties. 1 The study of plants represents a huge potential for discovery of new substances or new "lead compounds" if we consider that each of these plants can contain hundreds or thousands of secondary metabolites. 2The largest pharmaceutical companies know that tropical forests and fields can become a potential sources of valuable drugs.They invest significant capital to find new substances to make drug candidates that can be commercialized.Research in this field becomes automated and pharmaceutical companies will soon have the opportunity to study millions of chemical substances per week. 3he genus Cedar belongs to the family Pinaceae.This kind of tree has existed since the tertiary era.In this review, the term "Cedar" refers to four species: Cedrus brevifolia, Cedrus deodara, Cedrus libani and Cedrus atlantica.The Atlas cedar (Cedrus atlantica) is endemic to North Africa, especially Morocco and Algeria.It is exposed to a bright and dry climate in summer.The Himalayan cedar (Cedrus deodara) remains the species most represented, with an estimated area of 500,000 hectares.It occurs in the regions of the Himalayas from Afghanistan to western Nepal where there is a sub-Mediterranean temperate and subtropical climate.Cedrus libani, the emblem of Lebanon, occupies large areas in the mountains of northern and central Lebanon.
This review covers the chemical composition of the essential oil of cedar, different routes to synthesis of major constituents of this oil and its chemical transformation.Evans et al. 32 used the same approach to synthesize cis-α-himachalene starting from a chiral dienimide 51 (Scheme 5).Reaction of this chiral compound with acrolein leads stereoselectively to allylic alcohol 52. 33The latter undergoes Parikh-Doering oxidation to give the trienone 53. 34Intramolecular [4+2] cycloaddition of the trienone 53 in presence of ZnBr 2 provides the product 54, which was converted into an S-ethyl β-ketothioester by action of LiSEt.Decarboxylation of the latter provides the ketone 41 and the synthesis is completed by treating with Tebbe reagent. 35sing an intermolecular Diels-Alder reaction, Brown and Liu achieved the synthesis of α-cis-and βhimachalenes in eleven steps and in an effective overall yield of 21% from 4,4-dimethyl-2-cyclohexenone. 36heme 5. Synthesis of α-cis -himachalene from N-acyloxazolidinone 51.
Another synthesis in seven steps was carried out by Mehta and Kapoor starting from the tricyclic sesquiterpene longifolene. 37This strategy allowed synthesis of (+)-himachalene dihydrochloride which is an intermediate that gave access to trans-himachalene derivatives and (+)-ar-himachalene (Scheme 6).Scheme 6. Synthesis of (+)-trans-himachalenes.
The key step is the preparation of a bifunctional longibornane derivative 58 as the initial target.This was obtained from ω-bromolongifolene 55 via an acid-catalyzed rearrangement involving an intramolecular 1,5hydride shift.The bicyclic ketone 59 was prepared from 58 using Corey reaction. 38Thus, Wolff-Kishner reduction of 59 and purification (AgNO 3 -silica gel) gave the himachalene isomer 60.A stream of HCl gas through an acetic acid solution of 60 gave (+)-himachalene dihydrochloride 37. 39 The latter has already been converted into β-himachalene.Thus, the ar-himachalene was obtained from 60 by dehydrogenation with chloranil followed by aromatization with Pd/C.
In a similar way, a study of Dev and Shastri 40 showed that α-and β-himachalene can be obtained by Wagner-Meerwein rearrangement of longipinene with a variety of acids (BF 3 .Et 2 0, HClO 4 in aqueous dioxane, H 2 NS0 2 0H in acetone, and H 2 S0 4 in glacial acetic acid).© ARKAT USA, Inc Piers and Ruediger 41 have described a total synthesis of β-himachalene 10 using cuprate 67 prepared from 5,5-dimethyl-2-vinyl-1,3-dioxane 61.The latter reacted with bromoform and sodium hydroxide in presence of a phase-transfer catalyst to give dibromocyclopropane 62. Treatment of the latter with n-butyllithium and methyl iodide gave a mixture of two epimers 63 (87-93%) and 64 (7-13%).The hydrolysis of product 63 with formic acid followed by Wittig reaction with isopropylidene triphenylphosphorane provided a brominated cyclopropane 66 which was converted into cuprate 67 by treatment with nBuLi/PhSCu.The interaction of 3iodocyclohex-2-enone 68 with a cuprate 67 followed by thermolysis (xylene reflux) provided dienone 70 in quantitative yield.Methylation of the latter gave the compound 71, which was converted into ketone 72 by hydrolysis in the presence of tris-triphenylphosphine rhodium chloride.The transformation of the ketone to the corresponding enol phosphate was followed by reduction to give β-himachalene 10 (Scheme 7).
α-cis-Himachalene has also been prepared starting from tropone 73 as described by Rigby and McGuire. 42his strategy is based on a 1,8-addition-intramolecular cycloaddition protocol for construction of the bicyclo[5.4.0]undecane motif.The reaction of Grignard reagent 74 with tropone led to the formation of compound 75.Then, the oxidation and protection of the corresponding alcohol provided compound 76.The latter was then reacted with hydroxylamine hydrochloride under standard conditions.Conversion of the resultant oxime to the nitrile oxide by oxidation with sodium hypochlorite proceeded without incident and cycloaddition ensued to give the cis-fused bicyclic product 77.Reductive cleavage of the isoxazoline ring furnished amino alcohol 78 which was converted into α-himachalene 9. 30,36,43,44 Scheme 8. Synthesis of α-cis-himachalene from tropone.
The first step involves opening of the epoxide 79 followed by protection of the resulting alcohol 80 with isobutyric anhydride to obtain the product 81.Acid 82 was obtained by Ireland-Claisen rearrangement of 81.Then compound 82 was converted into 84 by a sequence of reactions involving LiAlH 4 reduction to 83 followed by oxidation with pyridinium chlorochromate (PCC), 46 and treatment with TsOH in benzene.Products 85a and 85b were obtained by treatment of 84 with ethylene glycol and trifluoroacetic acid respectively.The 85b was transformed to the bicyclic product 86b with expansion of the six-membered ring with Me 2 SiCHN 2 and BF 3 -OEt 2 . 47The study showed that the last step was regioselective, providing only one product from the migration of the methylene group.Finally, treatment of the mixture 86a/86b with Bu 4 NF in MeCN provided 86a.(+)-β-Himachalene was obtained by a reduction of 86a, the first time with NaBH 4 and then with Li in liquid ammonia.
Recently, enantiospecific synthesis of (+)-trans-α-himachalene was performed by Srikrishna and Kumar via an intramolecular type II carbonyl-ene reaction. 49Indeed, the (+)-trans-α-himachalene was obtained from (R)carvone 89.First step involves the preparation of compound 94.The latter was obtained from carvone 89 in five steps.Indeed, alkylation of carvone with methyl bromoacetate followed by reduction of keto ester 90, produce hydroxy ester 91, which was transformed into methoxyester 92 in the presence of sodium hydride and methyl iodide.Double alkylation of ester 92 using LDA and methyl iodide gave a compound 94 in 25% yield based on carvone.Accordingly, reduction with LiAlH 4 followed by a mild oxidation with PCC/NaOAc furnished aldehyde 96.Wittig reaction with methoxymethylenetriphenylphosphorane provided enol ether 97 in a mixture of two isomers Z and E (1:1).Treatment with hydrochloric acid gave the aldehyde intermediate 98, which undergoes spontaneous intramolecular hetero-ene reaction to give a mixture of bicyclic alcohol 100 and diol 99 with high stereoselectivity.Thereafter, the alcohol 100 was mesylated with MsCl.Thus, OMe and OMs groups are removed with lithium in liquid ammonia to obtain directly trans-α-himachalene 38 with 12% yield based on 98 (Scheme 10).Scheme 9. Enantioselective synthesis of (+)-β-himachalene.
Finally, it should be noted that the trans-himachalene isomer can be obtained from its isomer cishimachalene by hydrochlorination reaction with gaseous HCl followed by dehydrochloration/isomerization in pyridine or filtering on alumina. 6,29,39,50,51cheme 10.Enantiospecific synthesis of (+)-trans-α-himachalene. Dufour et al. 52 have also reported the synthesis of α-himachalene 9 starting from a commercially available mixture of ethyl chrysanthemate ester isomers 103 (Scheme 11).Reduction of 103 with LiAlH 4 followed by catalytic TPAP (tetrapropylammonium Perruthenate) oxidation in presence of NMO (N-methylmorpholine-N-Oxide) gave aldehyde 104 (92% two steps).Acid catalysed rearrangement with p-TsOH generated an aldehyde with the artemesyl carbon skeleton, 53  The Dielse Alder cyclization catalyzed by differents Lewis acids (SnCl 4 .5H 2 O, ZnCl 2 or ZnBr 2 ), which all gave only one regioisomer and good diastereoselectivity.The best results were obtained with ZnCl 2 as catalyst, which gave 95% yield and an endo/exo ratio of 16/1.Then, the endo isomer 106 was reacted with vinylmagnesium bromide followed by ring-closing metathesis using Grubbs' catalyst to give a bicyclic compound 108.The latter underwent an oxidation with TPAP and NMO followed by reduction of the double bond with L-Selectride to produce a compound 110 (Scheme 11).The last steps was methylenation with Tebbe reagent to obtain a disered product α-himachalene 9 (in 12% overall).

Synthesis of ar-himachalene
Different approaches to synthesis the ar-himachalene were reported in the literature such as that by Kapoor and Mehta mentioned previously. 37The first total synthesis of ar-himachalene was reported by Dev's group in 1968. 54It involved a synthesis in nine steps starting from m-methylacetophenone 111 according to scheme 12. Interaction of m-methylacetophenone with ethyl cyanoacetate furnished unsaturated ester 112, and then the addition of MeMgI to 112 gave a saturated cyano-ester 113.The latter was hydrolysed and decarboxylated to give 114 which was reduced to the corresponding alcohol 115.The chain extension by two carbon atoms was achieved with malonic ester to give 117, which readily underwent intramolecular acylation in polyphosphoric acid to obtain 5,5,7-trimethylbenzosubarone 118.Simple hydrogenation under H 2 provided the required product 12.A shorter and more efficient method was described by Sonawane et al. 55 (Scheme 13).The key step of this method is based on the insertion of a carbenoid into an aromatic ring catalyzed by a rhodium complex. 56,57The resulting product undergoes an acid-catalyzed rearrangement to give the ketone 125.The latter was demethylated and then reduced by a Wolff-Kishner reaction to achieve the arhimachalene 12 (Scheme 13).
A total synthesis performed by Momany et al. 58 provides a series of sesquiterpenes including arhimachalene.The route involved ten steps from cycloheptanone 128.Firstly, the latter was dimethylated with MeI and t-BuOK in t-BuOH under Ireland-Marshall conditions. 59Bromination of the resulting product 129 followed by HBr elimination using LiBr-Li 2 CO 3 in DMF, provided enone 131. 60Interaction of the latter with Me 2 CuLi followed by Michael addition in the presence of silyl ketone 132 gave silyl diketone 133. 61The silyl group was removed by treatment with ethanolic KOH and the resulting compound 133 was cyclized to the bicyclic products 135 and 136 in a 97/3 ratio.The predominant compound 135 reacted with MeLi to give a mixture of two diastereoisomers 137 and 138 (19:81).Both alcohols were converted into the corresponding olefin products 139 and 140 by the action of Dowex 50W-X4.Finally, aromatization with chloranil provided the desired product 12 (Scheme 14 Another method was reported by Mori et al. 62 This provided an enantioselective synthesis of (R) and (S) ar-himachalene starting from (S)-and (R)-citronellal 141 respectively.Treatment of (S)-citronellal (141) with pyridinium dichromate (PDC) provides (S)-citronellic acid (142).The latter was esterified and the resulting ester 143 was converted into the corresponding aldehyde 144 by ozonolysis.The mixture of E and Z diethyl ester 145 (87:13) was obtained from aldehyde 144 by Horner-Wadsworth-Emmons olefination.Catalytic hydrogenation of the double bond with Adams platinum oxide catalyst furnished diesters 146.The β-oxo ester 147 was obtained by treatment of 146 with t-BuOK. 63,64Hydrolysis and decarboxylation by heating to reflux in the presence of sodium hydroxide in aqueous methanol furnished ketone (S)-148 which was methylated with potassium tert-butoxide and methyl iodide in tert-butyl alcohol to give trimethyl ketone (S)-149.The bicyclic ketone (1R,2S)-150 was obtained by Robinson annulation of (S)-151 with 3-(trimethylsilyl)-3-buten-2-one under Stork's conditions. 65,66Finally, a Wittig reaction followed by aromatization with chloranil T provided (S)ar-himachalene 12.The same procedure was followed to prepare the other enantiomer (R) starting from (R)citronellal (Scheme 15).

Scheme 15. Total synthesis of (S) ar-himachalene starting from (S)-citronellal.
One year later, Mori studied a synthesis of (R)-ar-turmerone and its conversion to (R)-ar-himachalene. 67he first step started from (4-methylphenyl)acetic acid (152).Acyl chloride 153 was obtained using thionyl chloride, followed by Evans asymmetric alkylation via (S)-4-benzyl-3-(4-methylphenylacetyl)-2-oxazolidinone (155) as the key step to introduce the stereogenic center. 68Methylation of 154 proceeded with methyl iodide and sodium hexamethyldisilazanide (NaHMDS), followed by reduction of the resulting compound with lithium aluminum hydride furnished alcohol (S)-156 (89% ee).Activation with tosyl chloride, then chain-elongation via the carbonitrile followed by hydrolysis with hot aqueous potassium hydroxide, gave acid (R)-160.The next step was conversion of acid (R)-160 to Weinreb amide 69  Recently, an enantioselective synthesis of both isomers of ar-himachalene was carried out by Chavan et al. 72 starting from α,4-dimethylstyrene.The key reactions include Sharpless asymmetric dihydroxylation to introduce the stereogenic center and ring expansion by hypervalent iodine reagent or trimethylsilyldiazomethane (TMSCHN 2 ) (Scheme 18).Indeed, Sharpless asymmetric dihydroxylation of the dimethylstyrene 169 using AD-mix-β, furnished diol (R)-170.The latter was converted into primary alcohol (R)-171 by hydrogenolysis.This step was studied with various reagents under different condition to remove the tertiary hydroxyl group and to introduce the chirality at the benzylic position.The best result was obtained with Pd/C in ethanol under pressure of H 2 (60 psi) at room temperature.The iodo derivative (R)-172 was obtained by treatment of the alcohol with iodine in the presence of PPh 3 and imidazole.The latter was treated with diethyl malonate in presence of sodium hydride, with tetrabutylammonium iodide (TBAI) as a phase transfer catalyst, to obtain the diester (S)-173, which was decarboxylated to furnish acid (S)-174.Intramolecular acylation 73 of (S)-174 using trifluoroacetic acid and trifluoroacetic anhydride gave (S)-175.Ketone (S)-126 with seven membered ring can be prepared by two routes: directly from (S)-175 with TMSCHN 2 and BF 3 OEt 2 .However, this reaction gave a low yield.To improve the yield, the authors have chosen to obtain it in two steps: Wittig reaction of ketone (S)-175 followed by ring expansion of the six-to a seven-membered ring using Koser's reagent [hydroxy(tosyloxy)iodo]benzene (HTIB). 74,75Finally, dimethylation of (S)-126 with excess of methyl iodide and potassium t-butoxide furnished compound (S)-127 which after Wolff-Kishner reduction of the carbonyl group gave the (S)-ar-himachalene 12. 76 Scheme 18. Enantioselective synthesis of ar-himachalene starting from α,4-dimethylstyrene.
Campagne et al. 77 have reported a straightforward strategy for the syntheses (R) ar-himachalene.Synthesis includes a catalytic and asymmetric vinylogous Mukaiyama reaction and a stereospecific hydrogenolysis of a tertiary benzylic center using Pd/C or Ni/Raney catalysts (Scheme 19).The first step was the synthesis of the lactone starting from silyldienolate 178 and methylacetophenone 179 .The reaction was carried out with a copper base catalyst associated with a various chiral ligands in the presence of 20% of TBAT (Tetrabutylammonium difluorotriphenylsilicate).The best results (93% yield and 87% ee) were observed with Several studies have shown that ar-himachalene can also be obtained directly from α-, β-and γ-cis himachalene.The reaction can be performed either on the mixture of three himachalenes or each taken separately (Scheme 18).Various dehydrogenating agents were used: selenium, 79,80 chloranil, 54 palladium, 81 Raney nickel, 82 bromine, 83 DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone). 84The selectivity and yield of this transformation is dependent on the reagent employed and the operating conditions. 85,86heme 20.Synthesis of ar-himachalene from α-, β-and γ-himachalenes.

Hydrochlorination of himachalenes
Hydrochlorination is a well studied reaction of himachalenes since it provides a pathway to synthesize transhimachalenes. 39In fact, treatment of the mixture of himachalenes with hydrochloric acid gave 3,7dichlorohimachalane 37; then its crystallization from methanol led to the formation of 3-chloro-7-methylene himachalane 215 by loss of an HCl molecule.The authors showed that the ring junction changes configuration during formation of the product 37, becoming trans (Scheme 27). 50,51cheme 27.Hydrochlorination and dehydrochlorination of himachalene.

Epoxidation of himachalenes.
Epoxidation of himachalenes is one of the most studied reactions since it provides new enantiomerically pure oxygenated compounds that could be used for perfumery or agrochemicals, or in pharmacology.The reactivity of two double bonds present in himachalenes with different systems has a particular interest.Thus, Dev et al. prepared the product 6α,7α-epoxyhimachalene 5 by action of m-chloroperbenzoic acid on β-himachalene (10) (Scheme 30). 101The same epoxide 5 was prepared chemoand stereo-selectively by Benharref et al. 102,103 The stereochemistry of the α-oxiran bridge in 6,7-position has been confirmed by X-ray diffraction carried out on the product 222. 104,105Both diepoxides 222 and 223 was obtained by treating the monoepoxide 5 with a stoichiometric amount of m-CPBA, as well starting from compound 10 using an excess of peracid (m-CPBA).
In contrast, oxidation of cis-γ-himachalene 11 provided two diepoxides 227 and 228 regardless of the amount of the peracid used (Scheme 32).This was explained by the equivalence of the two double bonds of the structure. 108,109cheme 32.Epoxidation of γ-himachalene.
Recent studies have shown that the epoxides 224 and 5 described previously can be obtained from a mixture of two isomeric α-and β-himachalenes.Indeed, the mixture of α-and β-himachalene on reaction with stochiometric amount of peracid gave two monoepoxides 224 and 5 in 28/72 ratio. 110 catalytic oxidation of the himachalene mixture was carried out at 80 °C using the complex [MoO 2 (SAP)] 2 shown in Scheme 31.Using a catalytic amount (1%) of the catalyst in the presence of TBHP as the oxygen source, both products 224 and 5 could be obtained in 80% and 90% yields after 90 min in a ratio of 33/67.and the greener conditions of the solvent-free catalyzed method claimed to be a significant improvement.110 Scheme 33.[MoO 2 (SAP)] 2 complex.
Concerning the metal-catalyzed olefin epoxidation by TBHP, mostly realized with molybdenum-or vanadium-based catalysts.Poli et al. have proposed relevant mechanisms in organic solvents that involve the addition of TBHP to the catalyst in the activation phase.They have recently shown that the olefin epoxidation with the [MoO 2 (SAP)] fragment as a catalyst and TBHP as an oxidant follows a mechanism relatively similar to that operating in the presence of peracids.On this basis, the slight difference in selectivity observed between m-CPBA and [MoO 2 (SAP)]/TBHP system can be attributed to the slight differences in steric interaction between the oxygen atom delivering species and the substrate in the transition state. 111he reaction of the exocyclic double bond of 7-chlorohimachal-7,13-ene 215, which is obtained from α-, βand γ-himachalene by hydrochlorination, with one equivalent of m-chloroperbenzoic acid under the same conditions as above, provided two diastereoisomers 229 and 230 in 85/15 ratio (Scheme 34).Treatment of (1S,3R,8R)-2,2-dichloro-3,7,7,10-tetramethyltricyclo[6,4,0,0 1,3 ]dodec-9-ene 231 with a stoichiometric amount of m-CPBA gave two products 232 and 233 in a 70:30 ratio with 80% yield (Scheme 33). 110poxidation of 231 has been also monitored under the conditions previously described for the Mo-catalyzed epoxidation of 7-chlorohimachal-7,13-ene 215.The epoxides were isolated as a mixture of two diastereoisomers in 50:50 ratio with 80% conversion after 5 h. 110heme 35.Epoxidation of compound 231.

Gem-dihalogenocyclopropanation of β-himachalene
Several products containing a cyclopropane ring were prepared from β-himachalene.Treatment of βhimachalene 10 with a stoichiometric amount of dichlorocarbene, generated in situ from chloroform using NaOH as a base at 0 °C in the presence of tetrabutylammonium chloride (TBA-Cl) as a catalyst, gave the dihalogenated products 231 and 234.Similar products were obtained using bromoform (Scheme 36). 112heme 36.Synthesis of di-and tetra-halo-cyclopropahimachalenes.
Ourhriss et al. 113,114 founded that the tetrachloro-dicyclopropa-himachalenes 235 was obtained in 60% yield as two diastereoisomers in 85/15 ratio.However when they used an excess of bromoform, only the dibromated product 234 was obtained (Scheme 36).The mixed tetrahalogenated products were prepared by treatment of the dichlorocyclopropa-himachalene 231 with 1.5 equivalents of bromoform, or treatment of dibromocyclopropa-himachalene 234 under the same conditions with 1.5 equivalents of chloroform. 115,116In order to prepare other cyclopropahimachalene derivatives they reduced the product 231 with metallic sodium in a mixture of MeOH/H 2 O which gave 237 with a cyclopropane motif. 117The gem-dihalocyclopropanation reaction of compound 238 was performed in the same condition described above and gave the products 239 and 240 with 40% and 25% yield respectively as two diastereoisomers in each case (Scheme 37).Scheme 37. Dihalogenocyclopropanation of 5 and 238.
][120] The reaction led to the tetracyclic products 241 and 242 in 80% and 85% yields respectively.The products were obtained in the form of two diastereoisomers in 75/25 and 80/20 ratios respectively (Scheme 35).

Rearrangements of epoxy-himachalenes
Epoxides constitute a class of compound with high interest.They are known as important synthons in organic synthesis.These have the advantage of generating a wide variety of functions including several different polyfunctional compounds.The ring-opening of β-diepoxy-himachalene 223 was performed by bubbling HCl gas for one minute in chloroform (Scheme 38). 121The formation of the tricyclic derivative 245 can be explained by double S N 2 type reactions.After the protonation of epoxide at position 6-7, anti nucleophilic attack of Cl -at position C3 opened the 2,3-epoxide and then the oxygen at C2 in an intramolecular nucleophilic attack on the carbon C7 forms the bridging tetrahydrofuran ring.

Scheme 38. Rearrangement of diepoxy-himachalene by HCl gas.
Rearrangement of α-epoxyhimachalene 224 was studied by El Haib et al. 122 The rearrangement of epoxide 224 in presence of a catalytic amount of Lewis acid in dichloromethane led mainly to the formation of two tricyclic products, ketone 246 and alcohol 247 (Scheme 39).
The ketone was the product formed predominantly, using (BF 3 Et 2 O, BF 3 MeOH, InCl 3 , FeCl 3 ) except in the case of Bi(OTf) 3 since the alcohol was the main product produced.The comparisons of the various results obtained showed the effect of the Lewis acid on the kinetic and the selectivity of the reaction.With BF 3 Et 2 O and BF 3 MeOH, a rapid and complete conversion of the epoxide was observed while the reaction time must be increased to 6 hours or 9h 30min to achieve complete conversion of substrate with FeCl 3 and InCl 3 respectively.Rearrangement of β-epoxyhimachalene 5 in the presence of BF 3 Et 2 O in dichloromethane, gave ketone 248 and ar-himachalene 12, the two products can be isolated in 62% and 16% yield respectively (Scheme 39).However, the compound 249 with cyclobutane motif could be isolated using BF 3 MeOH as catalyst. 123heme 39.Rearrangement of epoxy-himachalene by Lewis acid.
Brønsted acids have also been used as catalysts in order to compare their activity and selectivity to those of Lewis acids.Rearrangement of α-epoxyhimachalene 224 was studied in the presence of a catalytic amount of methanesulfonic acid (MSA) or p-toluenesulfonic acid (PTSA).It led to the formation of alcohol 247 and/or 250 and/or 251.In the same way, the β-epoxy-himachalene 5 gave ketone 248 and/or ar-himachalene 12 and/or compound 252 (Scheme 40).

Scheme 40. Rearrangement of epoxy-himachalene by Brønsted acid.
Several experiments were conducted using different solvents and temperatures.The results showed that the total conversion of epoxide requires larger amount of Brønsted acids (1%) and longer reaction times.Unidentifiable by-products in small quantities were observed by gas chromatography as with Lewis acids.The chemoselectivity of the reaction depends on the solvent, temperature, and catalyst used.In methanol, MSA and PTSA catalysts promoted the rearrangement of α-epoxyhimachalene 224 into alcohol 247 and methoxy derivative 250 as a new product.However, in the case of epoxyhimachalene 5, a compound 252 was isolated besides the ketone 248 and ar-himachalene 12.In addition, the selectivity in favor of alcohol 247 at room temperature was switched and in favor of methoxy compound 250 by heating at 60°C.With PTSA, compound 250 could be obtained in 63% yield.However, using MSA, the epoxide rearrangement afforded a mixture of three products, 247, 250 and 251 in 35%, 44%, and 10% respectively.

Amination of himachalenes
Benzocycloheptene and their derivatives are a biologically potent class of bicyclic frameworks and are attractive synthetic targets for organic and medicinal chemistry.A new series of benzocycloheptene amino vinyl bromide derivatives were synthesized from the mixture of α, β and γ-himachalenes through two steps: The mixture of three isomers α, β and γ-himachalenes was treated with DDQ in dry benzene under nitrogen at reflux.In these conditions, the reaction gave α-dehydro-ar-himachalene 253 as major product (Scheme 41).Optimization of the bromination of α-dehydro-ar-himachalene 253 with Br 2 /DCM, Br 2 /AcOH and NBS all led to the formation of mixture of dibrominated products.Finally, bromination using KBr (4 equiv) and ceric ammonium nitrate (CAN, 3 equiv) in DCM/H 2 O (1:1, v/v) for 5 h at room temperature provided a compound 254 as a major product, which was founded to be unstable during its purification by column chromatography.
Mechanistically, the alkene reacted with bromide radicals to form a dibromo intermediate 254 which rearranged to product 255.The intermediate 255 was further treated with 1.5 equiv of amine in the presence of 2 equiv of K 2 CO 3 in DMF at 90 °C for 15 h to produce benzocycloheptenamino derivative 256 as major product.This reaction was investigated using different aromatic and aliphatic amines.Several secondary amines such as morpholine, piperidine, piperazine, pyrrolidine, and diethylamine were used giving satisfactory yields ranging from 62% to 76%.Different primary amines such as cyclohexyl-, benzyl-, iso-butyl-, t-butylamine, and phenylethyl-amines were also tested in the same reaction.Good yields were founded, ranging from 50 to 72% according to the amine used.The structures of the various products were confirmed by NMR and X-ray crystallographic analyses.The new products were further evaluated for their antidepressant activities and it was observed that the piperazine substituted derivative showed good activity.Thus, the piperazine derivative was considered as a lead entity selected for further modifications to obtain more efficacious and potent antidepressant drugs. 124ecently, five new 2,9,9-trimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-ylidene imine derivatives were synthesized by Chaudhary et al. 84 Starting from the same substrate α-dehydro-ar-himachalene 253.Oxidation of the exocyclic double bond with NaIO 4 and OsO 4 in a mixture of water/THF (1:1, v/v) for 20 h at room temperature produced a corresponding benzocycloheptenone 118 in 73 % yield.Finally, using dry silica gel (H) as a Lewis acid and an appropriate amine gave good conversions to the corresponding imines.Different imines 257 were obtained with good yields up to 79% according to the amine used (Scheme 41).The prepared compounds were tested against a group of sixteen organisms including gram positive and gram negative bacterial and fungal strains.The imine containing an isobutyl group showed the highest activity amongst tested compounds.Scheme 41.Synthesis of amino-dehydro-ar-himachalenes.
Ourhriss et al. 127 have described the synthesis of tricyclic thiosemicarbazone derivative of β-himachalene.Dichlorocyclopropanation of β-himachalene, from essential oil of Atlas cedar, followed by allylic oxidation using N-bromosuccinimide and condensation with thiosemicarbazide, gave a compound 269 (Scheme 43).The structure was elucidated by 1 H and 13 C NMR spectroscopy and its absolute configuration established by singlecrystal X ray diffraction analysis.

Synthesis of ar-Himachalene Derivatives
The Friedel Craft acylation of ar-himachalene obtained by dehydrogenation of a mixture of the three isomers α-,β-and γ-himachalene was carried out with acetyl chloride and AlCl 3 at room temperature. 128Under these conditions the reaction produced one product: 1-(3,5,5,9-tetramethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)ethanone 270.The study also showed that with increasing the temperature from 25 to 100 °C the reaction gave a mixture of the acylated compound 270 as major product (69%) and 1-(8-ethyl-8-hydroperoxy-3,5,5-trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone 271 (21%) (Scheme 46).The formation of the acyl hydroperoxide 271 could be explained by oxyfunctionalization of the acyl-ar-himachalene with molecular oxygen when exposed to air.Its structure was confirmed by X-ray diffraction.Nitration of ar-himachalene with nitric acid in a mixture of acetic anhydride and acetic acid produced two products, 275 and 276.When the reaction was performed in sulfuric acid medium, only the dinitrate compound was obtained. 129ecently, similar results were obtained by a catalytic route.Catalytic nitration of ar-himachalene was studied with complexes based on transition metals. 130In fact, a practical system of metal (2,4-pentanedionate) (M(acac) n (M = Fe, Zn, Co and V)) with phosphorus pentoxide (P 2 O 5 ) in the presence of nitric acid, catalyzed regioselective nitration of ar-himachalene to the mononitro-ar-himachalene in moderate to good yields under mild conditions.It was founded that the reaction selectivity was excellent if the mononitrate was required, compared with the classical method using HNO 3 /H 2 SO 4 .Scheme 47. Aromatization of atlantones followed by condensation with thiosemicarbazone.

Cyclocarbonylation of atlantone derivatives
Cyclocarbonylation is an alkoxycarbonylation reaction of a substrate containing both olefin and -ZH function (Z = O, N) which will react with the acyl intermediate formed during the catalytic cycle.Cyclocarbonylation of allylic alcohols 280 and 281 obtained from Z and E-α-atlantones after aromatization with Pd/C followed by Grignard reaction was studied in the presence of catalyst [PdCl 2 L 2 /SnCl 2 .2H 2 O] with L = monophosphine or diphosphine ligand (Scheme 48). 134cheme 48.Cyclocarbonylation of homoallylic alcohols derived from (E)-and (Z)-α-atlantones.
Alcohol 280 was transformed into lactones 282a and 282b with a selectivity ranging from 78 to 82%.This study showed that the regioselectivity depends heavily on the nature of the ligand used.Indeed, using monophosphine ligand mainly promoted the formation of the lactone five-membered ring 282b, whereas in the case of diphosphines, the regioselectivity was reversed in favor of the six-membered lactone 282a.Similarly, cyclocarbonylation of alcohol 281 was performed under the same catalytic and experimental conditions.Introduction of a methyl group in position γ resulted in a lower conversion but the regioselectivity to form the six-membered lactone 283a was excellent since the latter was formed exclusively.This result showed that this reaction does not depend only on the nature of the ligand used, but also on the nature of the substrate.

Acylation of atlantone derivatives
The acylation of 2-methyl-6-(4-methylphenyl)hept-2-en-4-one 167 was performed in the presence of acetyl chloride and AlCl 3 in dichloromethane. 135The reaction led to the formation of two acylated compounds 284 and 285 with an overall yield of 90%, in a ratio 284/285 of 55/35 (Scheme 47).Formation of product 285 can be explained by activation of the double bond in the presence of AlCl 3 which generates a positive partial charge on the C2 carbon, leading to an intramolecular Friedel-Crafts reaction.Scheme 49.Acylation of atlantone derivative 167.

Conclusions
Chemists have a compelling curiosity to discover what compounds nature provides, but to obtain this information it is necessary to isolate compounds from their natural source and to determine their structures.This is seldom an easy task, especially when the compound of interest is present at low concentrations.In this circumstance a high degree of skill and technology is required in both the isolation procedures and the subsequent investigations to establish the chemical structure.A second objective is the total synthesis of the compound from smaller molecules.Indeed, in the classical approach to structure determination, a structure was assigned to a natural product through chemical degradation studies to smaller, identifiable molecules.However, the assigned structure was not regarded as fully confirmed until the compound was synthesized and shown to be identical in all respects (composition, configuration, conformation) with the natural compound.This approach persists, although the enormous impact of modern methods of separation and spectroscopic analysis has made it possible to determine structure beyond a reasonable doubt in almost all cases without recourse to synthesis.Nevertheless, despite the problems of stereoselectivity and the high number of steps, the synthesis of natural products continues to be important.It provides new methodology, new reactions and techniques.It also provides alternative sources of natural compounds and offers routes to related but unnatural analogs.In the case of a useful drug, the synthetic objective is to find a related structure that is more potent at lower dosages with fewer side effects than the natural compound.This review provides an overview of research concerning the upgrading of essential oil of cedar.Firstly we showed the different work cited in the literature on the chemical constituents of these essences and the different methods that allow synthesis of the main constituents from commercial products.We have also reviewed the significant contributions of various research groups on the chemical transformation of the main sesquiterpenes in order to increase the biological activity of the molecule or to discover new activities.This inexhaustible source allows the identification of several products to achieve a range of activities of growing potential and targeted to cover a broad spectrum of diseases.