Catalytic Z-selective olefin cross-metathesis for natural product synthesis

Abstract

Alkenes are found in many biologically active molecules, and there are a large number of chemical transformations in which alkenes act as the reactants or products (or both) of the reaction. Many alkenes exist as either the E or the higher-energy Z stereoisomer. Catalytic procedures for the stereoselective formation of alkenes are valuable, yet methods enabling the synthesis of 1,2-disubstituted Z alkenes are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and of allylic amides, used until now only in E-selective processes. The corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. These transformations, promoted by catalysts that contain the highly abundant and inexpensive metal molybdenum, are amenable to gram-scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. The utility of this method is demonstrated by its use in syntheses of an anti-oxidant plasmalogen phospholipid, found in electrically active tissues and implicated in Alzheimer's disease, and the potent immunostimulant KRN7000.

Figure 1. A catalytic cross-metathesis (CM) reaction involves two different types of alkenes and can afford as many as six products; the challenge is to design an efficient process that favors formation of the cross products

Particularly difficult is the development of a process that affords the higher energy Z alkene predominantly. To accomplish a Z-selective CM, a variety of catalysts was considered, such as stereogenic-at-Mo complexes (1–2) or other previously reported Mo- and Ru-based complexes (3–5). The structural flexibility of the stereogenic-at-metal complexes 1–2 can give rise to exceptional reactivity and free rotation around the Mo–O bond of these alkylidenes might serve as the basis for development of highly Z-selective olefin metathesis reactions of terminal olefins. The sphere represents an appropriate size imido substituent.

Figure 2. Z-selective cross-metathesis (CM) reactions of enol ethers with terminal alkenes and application to stereoselective synthesis of C18 (plasm)-16:0 (PC)

Various Z enol ethers are synthesized with 1.2–5.0 mol % of Mo complex 1a and typically require 2.0 (in the case of p-methoxyphenylvinyl ether) or 10.0 (with butylvinyl ether) equivalents of the terminal enol ether; excess butyl vinyl ether (6) is easily removed in vacuo. The desired Z-olefins are obtained in 51–77% yield and in 94% to >98% Z selectivity. Application to synthesis of C18 (plasm)-16:0 (PC) demonstrates utility of the Z-selective Mo-catalyzed CM, which is used in conjunction with a site- and enantioselective Cu-catalyzed dihydroboration of the terminal alkyne in 14 (see the Supplementary Information for details). *The reactions were performed under N₂ atm; catalysts we prepared and used in situ.Conversions and Z selectivities determined by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures; yields of isolated products (±5%). Conversion and Z:E ratios measured by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures; the variance of values are estimated to be <±2%. ^§ Performed with 2.5 mol % 1a and 10 equiv 6 (see the Supplementary Information for experimental details). † Performed with 1.2 mol % 1a and 2.0 equiv 9 (see the Supplementary Information for experimental details). ‡ Performed with 5.0 mol % 1a and 10 (10b) or 2.0 equiv 9 (10d) (see the Supplementary Information for experimental details). **Conditions for synthesis of 16: (a) 1. 2.5 mol % 1a, C₆H₆, 22 °C, 2.0 h, decalin, 1.0 torr. 2. 5.0 equiv (n-Bu)₄NF, thf, 22 °C, 2 h. (b) 2.5 mol % 15, 2.5 mol % CuCl, 20 mol % NaOt-Bu, 2.1 equiv bis(pinacolato)diboron, 3.0 equiv MeOH, thf, 0 °C, 24 h; 30% H₂O₂, NaOH in aqueous thf, 1.0 h.

Figure 3. Z-selective cross-metathesis (CM) reactions of allylic amides with terminal alkenes and application to stereoselective synthesis of KRN7000

A range of Z-1,2-Disubstituted alllylic amides can be synthesized; in most cases use of reduced pressure leads to substantially improved yield and stereoselectivity. Application to the stereoselective synthesis of KRN7000, involving catalytic diastereoselective dihydroxylation of the Z alkene obtained by Mo-catalyzed CM, leads to an expeditious route for preparation of this biologically significant natural product (see the Supplementary Information for details). *The reactions were performed under N₂ atm with 3.0 mol % 2, 3.0 equiv of the non-N-containing alkenes (19b-c) or 5.0 mol % 2 and 10.0 equivalents of cross partner, 7.0 torr, 5.0 hours, 22 °C; catalysts were prepared and used in situ. Conversions and Z selectivities determined by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures; yields of isolated products after purification (±5%). Conversion and Z:E ratios measured by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures; the variance of values are estimated to be <±2%. § Reduced pressure was not used; reaction performed at 50 °C for 12 h (see the Supplementary Information for experimental details). † Reaction time was one hour (see the Supplementary Information for experimental details). **Conditions for synthesis of 24: (a) 8.0 mol % 2 (in situ-generated), C₆H₆, 22 °C, 5.0 h, 1.0 torr. (b) 5 mol % OsO₄, 2.5 equiv N-Me-morpholine oxide, CH₂Cl₂, 0 °C, 24 h. (c) 10% trifluoroacetic acid, CH₂Cl₂, 22 °C, 30 min. (d) 1.2 equiv 23, Et₃N, thf, 50 °C, 12 h.