**2.8. The biosynthesis of caryol-1(11)-ene-10-ol: on the mechanism of the formation of caryolene: a putative biosynthetic precursor to caryol-1(11)-ene-10-ol**

In 2013, Nguyen and Tantillo [17] investigated the mechanism of the formation of caryolene **30**, a putative biosynthetic precursor to caryol-1(11)-ene-10-ol **31** by DFT calculations (**Figure 3**).

**Figure 3.** Structures of caryolene **30** and caryol-1(11)-en-10-ol **31**.

**2.7. Biosynthesis of albaflavenone**

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albaflavenol **28** intermediates (**Scheme 9**) [14].

**Scheme 9.** Biosynthetic pathway of albaflavenone **25**.

The tricyclic sesquiterpene antibiotic albaflavenone **25** isolated from the gram positive soil bacteria *Streptomyces coelicolor* A3 and *Streptomyces albidoflavus* is biosynthesized by enzymes encoded in a two-gene operm [13]. Initially, the sesquiterpene epi-isozizaene synthase catalyzes the cyclization of *2E*, *6E*-farnesyl diphosphate (FPP) to (+)-epi-isozizaene **26**. A two-step allylic oxidation of **26** catalyzed by a single cytochrome P450170A1 (crP170A1) results in the formation of (+)-albaflavenone **25** *via* an epimeric mixture of (*5S*)-albaflavenol **27** and (*5R*)-

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

The mechanism and stereochemistry of FPP to epi-isozizaene **26** *via* (*3R*)-nerolidyl diphosphate **29** has been conclusively established by labeling studies [15]. The entire biosynthetic process from FPP to epi-isozizaene is shown (**Scheme 10**). A two-step chemical synthesis of

albaflavenone **25** from epi-isozizaene **26** was reported in this study.

Quantum chemical calculations indicated the mechanism involving a secondary carbocation intermediate **32** is not energetically viable. They proposed two mechanisms for caryolene **30** formation (pathway a and b). The pathway involves a base catalyzed deprotonation/reprotonation sequence and a tertiary carbocation minima (more likely) whereas pathway b involves intramolecular proton transfer and the generation of a secondary carbocation minima. Both mechanisms are predicted to involve concerted suprafacial/suprafacial [2 + 2] cycloaddition, whose asynchomicity allows them to avoid the constrains of orbital symmetry (**Scheme 11**).

9-epi-*E*-Caryophyllene **32**, caryophyllene **33** and (+)-koraiol **31** were identified by Dickschat and co-workers [18, 19] who carried out investigation on the volatiles of *Fusarium fujikuroi* by the use of CLSA-GCMS. The sesquiterpenoids were divided in to two groups based on their proposed biosynthetic pathways. Volatile sesquiterpenoids produced by sesquiterpene cyclase Ffsc4 were characterized as β-caryophyllene and an optically active alcohol (+)-koraiol **31**. The structure **31** was assigned by extensive spectral analysis. The relative configuration of (+)-koraiol was elucidated by NOESY experiments. The *cis* fusion of rings A and B was deduced from the NOESY couplings of the bridge head hydrogen atoms 1H and 9H with each other with methyl protons 15-H and the pro-5-methylene protons 3-H. Interestingly, Khan et al. isolated (+)-koraiol, [α]D + 31.7° from the oleoresin of Korean pine (*Pinus koraiensis* Sieb.). The relative stereochemistry as shown in **31** has been established by X-ray analysis [20]. The absolute stereostructure of the rare sesquiterpene (+)-9-epi-*E*-caryophyllene, an enantiomer of **32** was isolated from *Dacrydium cupressinum* by Weavers and co-workers [21] (**Figure 4**). It is tempting to speculate (+)-koraiol **31** is biosynthesized from 9-epi-*E*-caryophyllene **32**.

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**Figure 4.** Structures of 9-epi-*E*-Caryophyllene **32**, caryophyllene **33** and (+)-koraiol **31**.

**Scheme 12.** Biosynthesis of (+)-koraiol **31**.

**Scheme 11.** Proposed mechanisms for the formation of 1,10-caryolene **30**.

#### **2.9. Biosynthesis of (+)-koraiol**

As an outcome of Tantillo's mechanism for caryolene **30** [17], biosynthetic pathway for koraiol **31** becomes evident (**Scheme 12**).

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**Scheme 12.** Biosynthesis of (+)-koraiol **31**.

pathway b involves intramolecular proton transfer and the generation of a secondary carbocation minima. Both mechanisms are predicted to involve concerted suprafacial/suprafacial [2 + 2] cycloaddition, whose asynchomicity allows them to avoid the constrains of

As an outcome of Tantillo's mechanism for caryolene **30** [17], biosynthetic pathway for koraiol

orbital symmetry (**Scheme 11**).

96 Terpenes and Terpenoids

**2.9. Biosynthesis of (+)-koraiol**

**Scheme 11.** Proposed mechanisms for the formation of 1,10-caryolene **30**.

**31** becomes evident (**Scheme 12**).

9-epi-*E*-Caryophyllene **32**, caryophyllene **33** and (+)-koraiol **31** were identified by Dickschat and co-workers [18, 19] who carried out investigation on the volatiles of *Fusarium fujikuroi* by the use of CLSA-GCMS. The sesquiterpenoids were divided in to two groups based on their proposed biosynthetic pathways. Volatile sesquiterpenoids produced by sesquiterpene cyclase Ffsc4 were characterized as β-caryophyllene and an optically active alcohol (+)-koraiol **31**. The structure **31** was assigned by extensive spectral analysis. The relative configuration of (+)-koraiol was elucidated by NOESY experiments. The *cis* fusion of rings A and B was deduced from the NOESY couplings of the bridge head hydrogen atoms 1H and 9H with each other with methyl protons 15-H and the pro-5-methylene protons 3-H. Interestingly, Khan et al. isolated (+)-koraiol, [α]D + 31.7° from the oleoresin of Korean pine (*Pinus koraiensis* Sieb.). The relative stereochemistry as shown in **31** has been established by X-ray analysis [20]. The absolute stereostructure of the rare sesquiterpene (+)-9-epi-*E*-caryophyllene, an enantiomer of **32** was isolated from *Dacrydium cupressinum* by Weavers and co-workers [21] (**Figure 4**).

It is tempting to speculate (+)-koraiol **31** is biosynthesized from 9-epi-*E*-caryophyllene **32**.

**Figure 4.** Structures of 9-epi-*E*-Caryophyllene **32**, caryophyllene **33** and (+)-koraiol **31**.
