Synthetic terpenoids in the world of fragrances: Iso E Super® is the showcase

Abstract

The history of fragrances is closely associated with the chemistry of terpenes and terpenoids. For thousands of years mankind mainly used plant extracts to collect ingredients for the creation of perfumes. Many of these extracts contain complex mixtures of terpenes, that show distinct olfactoric properties as pure compounds. When organic synthesis appeared on the scene, the portfolio of new scents increased either in order to substitute natural fragrances without change of olfactoric properties or to broaden the scope of scents. This short review describes the story of the most successful synthetic fragrance ever which is called Iso E Super^® as it is an ingredient in a large number of perfumes with varying percentages and is the first example being used as a pure fragrance. Structurally, it is related to natural terpenes like many other synthetic fragrances. And indeed, the story began with a classic in the field of fragrances, the natural product ionone.

Keywords: asymmetric synthesis; fragrances; odorants; sandalwood; scents; terpenes; terpenoids.

Figure 1

Terpene constituents 1–9 found in geranium and bergamot oils and specified odours of individual components. Perfumes are composed of compounds that are perceived immediately (top notes), that form the principal bouquet (heart notes) and compounds that are mainly perceived in the dry-out (bottom notes) [6]. Classification of 1. top notes: a) citrus, b) aldehydic, c) fruity, d) green and e) herbaceous/herbal, 2. heart notes: a) floral light, b) floral green, c) floral fresh, d), floral fruity, e) floral heavy and f) floral woody and 3. bottom notes: a) aromatic, b) balsamic, c) moss/leather/animalic, d) musk, e) amber and f) wood.

Figure 2

Other selected mono- and sesquiterpenes (10–26) as fragrance materials [6].

Figure 3

Main constituents of natural iris oil: irone (27).

Scheme 1

First synthesis of ionone (30) [11].

Scheme 2

First synthesis of Ambrelux (32) [14].

Scheme 3

Industrial synthesis of myrcene (1) by pyrolysis of β-pinene (8).

Scheme 4

First synthesis of Iso E Super^® (33), Iso E Super Plus^® (34) and Georgywood^® (35) as a mixture of isomers [15].

Figure 4

Iso E Super^® region of GC spectra of Molecule 01 (left, 75 €–100 € per 100 mL; march 2019), a low-priced counterpart from TOP2BASE (middle, 20 € per 100 mL) and product produced in our laboratories under flow conditions. Note, although both samples provide a similar smell, the olfactory effects slightly vary because of different proportions of products and isomers produced in very small amounts that impact the nuances of a scent significantly (GC analyses were conducted in the author´s laboratories on a Zebron™ phenomenex ZB-1MS F&F (20 m, 0.18 mm, 0.18 µm) column).

Scheme 5

First synthetic route to (−)-Georgywood^® (35) by Corey and Hong [33].

Scheme 6

First synthetic route to the odour-active (+)-enantiomer of Iso E Super Plus^® (+)-34 [33].

Scheme 7

Analysis of the isomerisation process and formation of products. Most importantly, Iso E Super^® (33), Iso E Super Plus^® (34) and Iso Gamma (55) are formed [1]. All compounds are obtained as racemates [25].

Scheme 8

Isomerisation using additives such as alcohols or carboxylic acids. The product with the γ-positioned double bond is the desired Iso E Super Plus^® (34). Products 58 (α double bond) and product 53 (β double bond) are not desired [26].

Scheme 9

Iso E Super Plus^® (34) can undergo a third cyclisation to tetrahydrofuran 59 through compound rac-53 [22].

Figure 5

(Adapted from ref. [8]) Ionone (30, 1893, odour threshold: 0.8 ng L⁻¹), koavone (1982, odour threshold: 75 ng L⁻¹), Iso E Super^® (33) (1972, odour threshold: 500 ng L⁻¹), timberole (1982, odour threshold: 26 ng L⁻¹) Iso E Super Plus^® (34) (1990, odour threshold: 5 pg L⁻¹) and Georgywood^® (35, 1996, odour threshold: 15 pg L⁻¹–30 pg L⁻¹) [,,,–38].

Figure 6

Branched, terpene-like cyclohexene derivatives, that are synthetic fragrance components: 60: Iso damascone, 61: Precyclemone B, 62: Lyral^®, 63: Cashmeran^®, 64: Kephalis, and 65, 66: Givescone^®.

Scheme 10

New unnatural terpenoid 70 from unnatural farnesyl pyrophosphate derivative 69 and comparison with natural biotransformation (67→68) and olfactory property of tetrahydrofuran 70 [39].