Highly enantioselective ylide-mediated synthesis of terminal epoxides

Abstract

The highly efficient asymmetric epoxidation of aldehydes by methylene transfer is now possible using new sulfonium salts.The importance of chiral epoxides as synthetic building blocks in asymmetric synthesis is extremely difficult to overstate. While the highly enantioselective Sharpless, 1,2 and JacobsenKatsuki, [3][4][5] protocols for the epoxidation of internal alkenes are now mature technologies of inestimable value, the conversion of terminal alkenes to enantioenriched 1-oxiranes has proven a considerably more difficult process to control. 5,6 Arguably the current method of choice (in terms of product ee) for the catalytic synthesis of these molecules is the Co-salen complexcatalysed kinetic resolution of racemic epoxides. 6a,7,8 While progress towards the efficient asymmetric oxidation of terminal alkenes has been made -e.g. Fe/Mn-porphyrin complexes, 9 chiral Ti 10 and Pt-complexes 11 and chiral dioxiranes (styrene substrates only), 12 the difficulties in preparing terminal epoxides in 490% ee via alkene oxidation has fostered interest in alternative protocols. 13 One methodology which holds promise is catalytic methylene transfer to aldehydes mediated by sulfonium ylides.14 Since it is often from the aldehyde that the alkene substrate for oxidation processes is prepared, a methylene transfer reaction would represent a more direct synthesis of the product, which could potentially be performed in an operationally simple manner, in a transition metal-ion free environment. The stabilised-and semi-stabilised sulfonium ylide-mediated asymmetric epoxidation of aldehydes catalysed by chiral sulfides has proven a highly useful process for the formation of 1,2-disubstituted epoxides with excellent product diastereo-and enantioselectivity. 15,16 In an unfortunate parallel to the alkene oxidation methodologies, the corresponding sulfonium ylide-mediated aldehyde oxidation to form terminal epoxides (nearly 40 years after the first disclosed asymmetric attempt) 17 is characterised by moderate yields and low-moderate levels of product enantiomeric excess.18-22 For instance, both benchmark methodologies (A and B, developed by Goodman 19 and Aggarwal 20 respectively, Scheme 1) for the conversion of the archetypal substrate benzaldehyde (1) to styrene oxide (2) involve the employment of (super)stoichiometric loadings of a chiral sulfide and a Simmons-Smith type Zn-carbenoid, and furnish the product in o60% yield and ee. In an attempt to develop a more atom-economic process, we have shown that the ylide can be generated via an alkylation and subsequent deprotonation route (C, Scheme 1).23,24b Sulfide 6 could be utilised at 20 mol% loading if the alkylating agent and base were added portion-wise, however no progress was made towards improving upon the mediocre enantioselectivity which bedevils this (otherwise) potentially very useful reaction.With the goal of solving this problem, we reflected upon the likely causes of the low enantioselectivity. The first major difficulty -as Aggarwal 14b has pointed out -associated with...

Synthesis of enantiopure 1,2-azido and 1,2-amino alcohols via regio- and stereoselective ring-opening of enantiopure epoxides by sodium azide in hot water

“…Oxirane 4i was obtained as a clear unstable liquid (1.44 g, 99%); [α] D 22 = − 13.0 ( c 3.3, CHCl 3 ), Lit. 12b [α] D 20 = − 26 ( c 1, CHCl 3 ) for 72% ee. 1 H NMR (400 MHz, CDCl 3 ): δ 2.85 (dd, J 1 = 2.6 Hz, J 2 = 5.6 Hz, 2H), 3.17 (dd, J 1 = 4.0 Hz, J 2 = 5.6 Hz, 2H), 3.85 (s, 3H), 3.87 (m, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 51.0, 52.2, 55.3, 114.0, 126.9, 129.5, 159.7; MS m/z (relative intensity): 150 M •+ (20%), 121 (100%), 91 (18%), 77 (14%).…”

“…Due to the recent availability of well-established synthetic routes for the asymmetric syntheses of monosubstituted epoxides, 8–12 the development of practical and environmentally friendly methods for the synthesis of highly enantiopure 1,2-amino ethanols is an area of great relevance. Aminolysis and azidolysis reactions of oxiranes have been extensively studied for the synthesis of racemic vicinal amino alcohols with a diversity of results.…”

“…18 As illustrated in Scheme 2, we recently reported a useful protocol for the borane-mediated reduction of 2-haloketones 2 catalyzed by the spiroaminoborate 1a to obtain enantiopure aryl and aliphatic ( S )-halohydrines 3 , which upon subsequent cyclization with NaOH, gave the corresponding chiral oxiranes 4 . 12 Preliminary studies of the ring–opening of ( S )-styryl and ( S )-4-chlorostyryl epoxides with sodium azide in water at 60 °C indicated the preferential formation of ( R )-2-azido-2-arylethanols 5 , with almost complete inversion of configuration at the benzylic position. Thus, it was of great interest to examine the regio- and stereoselective ring–opening of representative aryl, pyridyl and adamantyl ( S )-oxiranes (Scheme 2) by sodium azide under neutral hydrolytic conditions.…”

Organokatalytische asymmetrische Epoxidierungen – Reaktionen, Mechanismen und Anwendungen

“…[116] Unter Verwendung des Katalysators 135 und der Phosphazen-Base 136 wurde das terminale Epoxid 137 in 70 % Ausbeute und mit 43 % ee erhalten (Schema 44). [117] Obwohl sich sulfidkatalysierte Epoxidierungen, die über den Weg der Alkylierung/Deprotonierung ablaufen, als einfache und wirksame Methode zur Herstellung der trans-Epoxide 124 erwiesen haben, ist der Anwendungsbereich dieser Reaktionen eher begrenzt. Um den Nutzen von Sulfidkatalysatoren zu erhçhen, wurde ein neues Verfahren eingeführt, das die Umsetzung der Carben-Zwischenstufe 139 mit dem Sulfid 118 unter Bildung des Ylids 120 umfasst (Schema 45).…”

The Use of Sulfides Derived from Carane, P-Menthane, Pinane, and Bornane in the Synthesis of Optically Active Epoxides

“…2,3 Although the first successful example of using chiral sulfonium ylides for the synthesis of optically active epoxides was reported by Furukawa searching for new reagents for the synthesis of asymmetric epoxides is still the current direction of modern developments. 5,6 The aim of our investigation was to develop a synthesis of optically active sulfides derived from commercially available monoterpenes [(+)-3-carene, (-)-menthol, (-)-β-pinene, and (-)-borneol] and test them as auxiliaries for the stereoselective synthesis of epoxides. Previous studies on the use of sulfur ylides containing a monoterpene substructure in the sulfide structures were presented for camphor, 4,[7][8][9][10][11][12][13] pulegone, 14 α-pinene, 15 limonene, 16 and carvone 17 derivatives.…”