**2.4. Total synthesis of (+)-cymbodiacetal**

In 2010, Hayes and his co-workers reported [7] a total synthesis of (+)-Cymbodiacetal **12** by a biomimetic route proposed earlier [8, 9] using (R)-(+)-limonene **13**, the key step involves hetero Diels-Alder cycloaddition which proceeds with an *endo* selectivity (2:1) in a quantitative Recent Developments in Selected Sesquiterpenes: Molecular Rearrangements, Biosynthesis… http://dx.doi.org/10.5772/intechopen.74998 91

**Scheme 4.** Molecular rearrangement of (−)-modhephene **9** to (−)-isocomene **10** and (−)-triquinane **11**.

yield. Exploitation of *exo*-isomer with *m*-CPBA followed by acid catalyzed opening afforded (+)-cymbodiacetal **12** (**Scheme 5**). The uncertainty in absolute stereochemistry was independently established by X-ray crystallography. These studies also clarified discrepancies in the previously published work [8, 9].

**Scheme 5.** Total synthesis of (+)-cymbodiacetal **12**.

**2.3. Synthesis of (−)-isocomene and (−)-triquinane by acid catalyzed rearrangement** 

**Scheme 3.** Acid catalyzed rearrangement of triketone **5** to 1–11 seco-moreliane derivative **6**.

Triquinanes have received considerable attention by their unique structure as well as their reported biological activities. (−)-Modhephene **9** of established absolute stereochemistry was subjected to acid catalyzed carbocation rearrangements which led to an interesting synthesis of (−)-isocomene **10** and (−)-triquinane **11**[6]. This study was extended further by preparation of (−)-modhephene **9d** stereospecifically at 14β geminal methyl group. Under same experimental conditions, deuterium labeled (−)-triquinane **11d** a stereospecific 1,2-migration of 7/4β

In 2010, Hayes and his co-workers reported [7] a total synthesis of (+)-Cymbodiacetal **12** by a biomimetic route proposed earlier [8, 9] using (R)-(+)-limonene **13**, the key step involves hetero Diels-Alder cycloaddition which proceeds with an *endo* selectivity (2:1) in a quantitative

**of (−)-modhephene**

90 Terpenes and Terpenoids

methyl group was observed (**Scheme 4**).

**Figure 1.** Skeletons of longipinane, moreliane and 1–11 seco-moreliane.

**2.4. Total synthesis of (+)-cymbodiacetal**

#### **2.5. BF3 catalyzed molecular rearrangements of mono epoxides of α- and β-himachalenes**

Previous examples of acid catalyzed rearrangements of sesquiterpenes have shown that the opening of the epoxide triggers the reaction and directs the subsequent molecular rearrangements. In practically, among all the cases the aim is to valorize the naturally occurring sesquiterpene hydrocarbons.

Manoury and co-workers [10] observed that on treatment of α-himachalene monoepoxide **14** with BF3 -Et<sup>2</sup> O in CH<sup>2</sup> Cl<sup>2</sup> at room temperature afforded a tricyclic ketone **16** (71% isolated yield) product along with an unsaturated alcohol **17** (18%). The structure **16** was unambiguously assigned to ketone based on 1 H, <sup>13</sup>C, <sup>1</sup> H-2D NMR experiments. The proposed mechanism (**Scheme 6**) involves ring opening of epoxide followed by participation of terminal methylene group to generate a tricyclic bridgehead carbocation **18** by ring contraction of seven membered ring to generate intermediate **19**. A stereospecific 1,4-hydride transfer is proposed in the last step to the formation of **16**.

Inspection of molecular models of intermediate **19** shows that the proposed stereospecific 1,4-hydride shift is unlikely and therefore a different process is responsible for the formation of ketone **16**.

Compounds **16**, **17** and **20** are all optically active and since the absolute stereochemistry of himachalenes are known, it is observed that C7 α-H of α-himachalenes remains intact throughout the rearrangement. The absolute stereochemistry of **16**, **17** and **20** is shown in

catalyzed transformation of β-himachalenes monoepoxide **15** to ketone **20**.

Recent Developments in Selected Sesquiterpenes: Molecular Rearrangements, Biosynthesis…

http://dx.doi.org/10.5772/intechopen.74998

93

Santonic acid **21** (the diketocarboxylic acid obtained from santonin on digestion with aq. alkali) was subjected to reduction with the Zn-HCl-ether system [12] with an aim to obtain the previously prepared pinacol **22** *via* intramolecular pinacolisation primarily because of conformational structure of santonic acid with close proximity of the 1,4-diketone system. Under these conditions santonic acid **21** did not afford the pinacol **22**, but yielded a 60:40 mix-

proceeds *via* pinacol **22**, which, under strong acidic conditions, undergoes further rearrange-

H NMR) of succinic anhydride derivatives **23** and **24**. It is clear that the reaction

**Figure 2**.

**Scheme 7.** Mechanism for BF3

ture (GCMS, <sup>1</sup>

**2.6. Santonic acid: Zn-HCl-ether reduction**

**Figure 2.** Absolute stereochemistries of ketone **16** alcohol **17** and ketone **20**.

ment to give anhydrides **23** and **24** (**Scheme 8**).

**Scheme 6.** Proposed mechanism for the formation of unsaturated alcohol **17** and tricyclic ketone **16**.

The structure assignment **17** to the minor product, a tricyclic unsaturated alcohol is based on spectral analysis and confirmed by single crystal X-ray data. The characteristic feature of **17** is the presence of a double bond involving a bridgehead carbon.

β-Himachalene monoepoxide **15** under identical experimental conditions gave two products major product (62%) and aryl-himachalene (10%). The major product was assigned structure **20**. The proposed mechanism explains formation of **20** (**Scheme 7**). The gross structure of this compound an allo-himachalol, a natural product isolated from *Cedrus deodara* [11].

Recent Developments in Selected Sesquiterpenes: Molecular Rearrangements, Biosynthesis… http://dx.doi.org/10.5772/intechopen.74998 93

**Scheme 7.** Mechanism for BF3 catalyzed transformation of β-himachalenes monoepoxide **15** to ketone **20**.

Compounds **16**, **17** and **20** are all optically active and since the absolute stereochemistry of himachalenes are known, it is observed that C7 α-H of α-himachalenes remains intact throughout the rearrangement. The absolute stereochemistry of **16**, **17** and **20** is shown in **Figure 2**.

**Figure 2.** Absolute stereochemistries of ketone **16** alcohol **17** and ketone **20**.

#### **2.6. Santonic acid: Zn-HCl-ether reduction**

**2.5. BF3**

**β-himachalenes**

92 Terpenes and Terpenoids

**14** with BF3

of ketone **16**.

terpene hydrocarbons.


O in CH<sup>2</sup>

ously assigned to ketone based on 1

the last step to the formation of **16**.

Cl<sup>2</sup>

 **catalyzed molecular rearrangements of mono epoxides of α- and** 

Previous examples of acid catalyzed rearrangements of sesquiterpenes have shown that the opening of the epoxide triggers the reaction and directs the subsequent molecular rearrangements. In practically, among all the cases the aim is to valorize the naturally occurring sesqui-

Manoury and co-workers [10] observed that on treatment of α-himachalene monoepoxide

yield) product along with an unsaturated alcohol **17** (18%). The structure **16** was unambigu-

(**Scheme 6**) involves ring opening of epoxide followed by participation of terminal methylene group to generate a tricyclic bridgehead carbocation **18** by ring contraction of seven membered ring to generate intermediate **19**. A stereospecific 1,4-hydride transfer is proposed in

Inspection of molecular models of intermediate **19** shows that the proposed stereospecific 1,4-hydride shift is unlikely and therefore a different process is responsible for the formation

The structure assignment **17** to the minor product, a tricyclic unsaturated alcohol is based on spectral analysis and confirmed by single crystal X-ray data. The characteristic feature of **17** is

β-Himachalene monoepoxide **15** under identical experimental conditions gave two products major product (62%) and aryl-himachalene (10%). The major product was assigned structure **20**. The proposed mechanism explains formation of **20** (**Scheme 7**). The gross structure of this

compound an allo-himachalol, a natural product isolated from *Cedrus deodara* [11].

**Scheme 6.** Proposed mechanism for the formation of unsaturated alcohol **17** and tricyclic ketone **16**.

the presence of a double bond involving a bridgehead carbon.

H, <sup>13</sup>C, <sup>1</sup>

at room temperature afforded a tricyclic ketone **16** (71% isolated

H-2D NMR experiments. The proposed mechanism

Santonic acid **21** (the diketocarboxylic acid obtained from santonin on digestion with aq. alkali) was subjected to reduction with the Zn-HCl-ether system [12] with an aim to obtain the previously prepared pinacol **22** *via* intramolecular pinacolisation primarily because of conformational structure of santonic acid with close proximity of the 1,4-diketone system. Under these conditions santonic acid **21** did not afford the pinacol **22**, but yielded a 60:40 mixture (GCMS, <sup>1</sup> H NMR) of succinic anhydride derivatives **23** and **24**. It is clear that the reaction proceeds *via* pinacol **22**, which, under strong acidic conditions, undergoes further rearrangement to give anhydrides **23** and **24** (**Scheme 8**).

**Scheme 8.** Mechanistic pathway for the conversion of santonic acid **21** to bicyclo[3.3.0] octanes **23** and **24**.
