Brief introduction. Epoxides (also known as oxiranes) are three membered ring cyclic ethers. The epoxide moiety is present in a large variety of natural products and synthetic compounds. Simple epoxides like epichlorhydrin or ethyenoxide find many industrial applications in the manufacturing of polymeric materials, resins and detergents.
Epoxidic functional groups are also present in many fragrances (epoxides of carvone, alpha-cedrene, beta-ionone), pheromones ((+)-disparlure), alkaloids (scopolamine), antibiotics such as fosfomycin, macrolide antibiotics (mycinamicin), polyphenol antibiotics (griseorhodin).
(-)-Scopolamine (W-105903) Fosfomycin (W-107422)
Important anti-tumor agents (epothilones, hedamycin) also contain an epoxide ring. Endogenous epoxides are also fundamental metabolic intermediates: Squalene-2,3-epoxide is a precursor of cholesterol (and consequently of all steroids) and vitamin K epoxide is an important co-factor in blood coagulation.
The electrophilic oxidation of alkenes with peracids (1) (Prilezhaev reaction) and the nucleophylic epoxydation of α,β unsaturated carbonyl compounds (2) (Weitz–Scheffer) are probably among the most widely employed general epoxidation methods. Alternatively, epoxides can also be obtained by reaction of ketones with sulphur ylides (Corey-Chaykovsky Reaction). Oxiranes can also be obtained sterospecifically by ring-closing of chiral halohydrines (which in turn can be prepared by stereoselective reduction of apha halo-ketones).
General Epoxidation examples.
High levels of enantioselectivity can be obtained using modern and well established methodologies. Some of the most powerful methods are: the Jacobsen-Katsuki expoxidation using chiral Mn-Salen catalysts and sodium hypochlorite as the oxidant; the Sharpless epoxidation using titanium tetraisopropylate, t-butyl peroxide and diethyltartrate as a chiral auxiliary; or the Shi epoxidation based on the oxidation of chiral ketones with potassium peroxymonosulfate (MPS, Oxone, Caroat) to chiral dioxiranes which in turn efficiently oxidize alkenes enantioselectively to epoxides.
Asymmetric epoxidation methods.
(1) J. Am Chem. Soc. 2001,123,11308.
(2) J. Am. Chem. Soc. 2005, 127, 6284
Recommended reading: Aziridines and Epoxides in organic Sysnthesis , Edited by Adrei K. Yudin, Wiley-VCH, 2006
Due to their nature of small constrained rings, epoxides can react with electrophiles and nucleophiles. Often the oxirane ring can be opened under mild conditions and in a regioselective fashion. These characteristics make epoxides highly versatile building blocks for an infinite number of synthetic transformations.
Typical oxirane ring reactivity.
Synthetic application examples:
1) Design of novel NRIs using (2R,3R)-3 Phenylglycidol
CAS No. [98819-68-2], Cat. No. J-800391
New norepinephrine reuptake inhibitors (NRIs) for multiple indications have been generated using (2R,3R)-3-Phenylglycidol and indole. This way a series of 1-(indolin-1-yl)-1-phenyl-3-propan 2-olamines was created which proved efficient in certain rat and mouse models. These compounds exhibit efficacy in treatments of induced acute visceral pain, thermoregulatory dysfunction and neuropathic pain (2).
(1) J. Org. Chem. 1978, 10, 1975
(2) J. Med. Chem. 2010, 53, 2051
2) Obtaining valuable pharmaceutical building blocks from (R)-1,2-epoxyhex-5-ene.
The process for the preparation of cannabinoid receptor agonist APD 371 (Arena pharmaceuticals) relies on a chiral epoxide to generate enantiomerically pure cyclopropanols (1). Literature (2) suggests that the lithiation of terminal epoxiedes has a relatively wide scope using different epoxides.
The cyclopropanation reaction, followed by alcohol oxidation proved alsoto be scalable on multikilogram quantities according to a recent process chemistry publication (3).
(1) US8778950 B2J.
(2) J. Am. Chem. Soc. 2004, 8664.
(3) Org. Proc. Res. Dev. 2007, 637.
3) Access to advanced synthetic intermediates.
The following are a few examples of Biosynth's chiral epoxides. Click here to see all of our oxiranes and chiral epoxides.
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