Present and Future of Cyclopropanations in Fragrance Chemistry

Abstract

The elaboration of new cyclopropanation methods is expected to make selectively new Δ-compounds available, either as precursors or as new ingredients with superior olfactory impacts. The improvement of cyclopropanation processes through understanding of reaction mechanisms reduces costs and environmental impact. Givaudan is the leading 'Flavor & Frangrance' company which successfully brings Δ-molecules to the market. Javanol(®) , for example, with its unique performance exemplifies the product of an efficient industrial cyclopropanation of a dienol precursor. Serenolide(®) , Toscanol(®) , and Pashminol(®) are other high-impact Δ-fragrance ingredients manufactured at Givaudan. This review describes our journey from advanced SimmonsSmith methodology using Zn carbenoids, to Al- and Mg-mediated cyclopropanation techniques in the context of related alternative cyclopropanation methods for the transfer of the CH2 group onto CC bonds. The resulting cyclopropane products are themselves interesting substrates for further transformation to other flavor and fragrance compounds. Throughout this Review, the notation Δ refers to the presence of a cyclopropane ring, i.e., a 'Δ-compound' is defined as a compound that contains a cyclopropyl substituent or a 'fused cyclopropa' component, or a 'spiro-cyclopropane' moiety.

Oxygen-Tethered 1,6-Enynes and [4.1.0]-Bicyclic Ether Skeletons as Hedonic Materials for the Fragrance Industry

“…The crude product was purified over silica gel flash chromatography (petroleum benzine/Et2O, 90/10) to afford S-(3-phenylprop-2-yn-1-yl) ethanethioate 18d (1.50g, 78%) as an orange oil. 2H,11,15),3H,12,13,14),1H,5),3.43 (s,2H,2),3.36 (d,J = 7.8 Hz,2H,6), 1.77 (s, 3H, 8), 1.74 (s, 3H, 9). = 12.8,9.4,7.5 Hz,1H,8'),4H,8'',11,12), 1.14 (s, 3H, 10), 1.03 (s, 3H, 9), 0.90 (t, J = 7.2 Hz, 4H, 13), 0.75 -0.69 (m, 1H, 3).…”

Diastereo‐ and Enantioselective Iridium Catalyzed Carbonyl (α‐Cyclopropyl)allylation via Transfer Hydrogenation

“…Due to its relatively high metabolic stability with respect to oxidation and unique geometrical features, the cyclopropane ring has emerged as an important structural motif in human medicines, agrochemicals and fragrance ingredients (Figure 1). 1, 2 Cyclopropanes are ubiquitous in nature3 and owing to the energetic driving force associated with the release of ring strain they also serve as important functional groups in chemical synthesis, including enantioselective processes 4. Consequently, efforts toward the development of asymmetric methods that create or introduce the cyclopropane ring are longstanding, and encompass some of the earliest examples of enantioselective catalysis 5.…”

“…[4] Consequently,e fforts towardt he development of asymmetricm ethods that create or introduce the cyclopropane ring are longstanding, and encompass some of the earliest examples of enantioselective catalysis. [5,6] Despite increasing interest in cyclopropanec hemistry [1][2][3][4][5] and expandingc apabilities vis-à-vis carbonyla llylation [7] there are no examples of catalytic enantioselective allylative methodsf or the delivery of cyclopropanes rings. [8] Studies in our laboratory on the catalytic redox-triggered CÀCc oupling of primarya lcohols [9] and allylic carboxylates suggestt hat a-cyclopropyl allyl acetate might serve as ar eagent for diastereo-and enantioselective carbonyl (a-cyclopropyl)allylation, [9][10][11] however,t he feasibility of such ap rocess was uncertain due to the potentiall abilityo f( a-cyclopropyl)allyliridium intermediates with respect to fragmentation of the cyclopropanesr ing.…”

Cyclopropyl- and Cyclobutylboronates and -silanes: A Stereo­selective Approach

“…Cyclopropanes 1 and cyclobutanes 2 have always fascinated organic chemists due to the challenge involved in their synthesis as well as their unusual reactivity. They are not only extremely useful synthetic intermediates, but are also found in a broad number of natural products, 3 pharmaceuticals, 4 and cosmetics 5 (Figure 1). In particular, stereodefined small rings with multiple stereocenters are gaining increasing attention because they provide rigidity and at the same time three dimensionality, both valuable attributes in drug discovery.…”