**2.7. Biosynthesis of albaflavenone**

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

Ito and co-workers [16] reported a concise nine step total synthesis of albaflavenone without use of any protecting groups. Moreover, the absolute configuration of naturally occurring

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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**).

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

**2.8. The biosynthesis of caryol-1(11)-ene-10-ol: on the mechanism of the formation** 

**Scheme 10.** Mechanism of the cyclization of *E,E*-FPP to epi-isozizaene **26** *via* (*3R*)-nerodilyl diphosphate **29**.

(+)-albaflavenone has been unambiguously established as *1S*, *7S* and *8R*.

**of caryolene: a putative biosynthetic precursor to caryol-1(11)-ene-10-ol**

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

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

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.

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**Scheme 10.** Mechanism of the cyclization of *E,E*-FPP to epi-isozizaene **26** *via* (*3R*)-nerodilyl diphosphate **29**.

Ito and co-workers [16] reported a concise nine step total synthesis of albaflavenone without use of any protecting groups. Moreover, the absolute configuration of naturally occurring (+)-albaflavenone has been unambiguously established as *1S*, *7S* and *8R*.
