Double activation

Nu = malonate anion, amines, thiolate anion, enamines, cuprates (usually requires double activation of cyclopropane)... 

Erythronolide B, the biosynthetic progenitor of the erythromycin antibiotics, was synthesized for the first time, using as a key step a new method for macrolactone ring closure (double activation) which had been devised specifically for this problem. Retrosynthetic simplification included the clearance of the stereocenters at carbons 10 and 11 and the disconnection of the 9,10-bond, leading to precursors A and B. Cyclic stereocontrol and especially the Baeyer-Villiger and halolactonization transforms played a major role in the retrosynthetic simplification of B which was synthesized starting from 2,4,6-trimethylphenol. 

The first synthesis of enterobactin, a microbial chelator and transporter of environmental iron, was accomplished by the coupling of three protected L-serine units and macrocyclization by the double activation method. 

The l ,J -DBFOX/Ph-transition metal aqua complex catalysts should be suitable for the further applications to conjugate addition reactions of carbon nucleophiles [90-92]. What we challenged is the double activation method as a new methodology of catalyzed asymmetric reactions. Therein donor and acceptor molecules are both activated by achiral Lewis amines and chiral Lewis acids, respectively the chiral Lewis acid catalysts used in this reaction are J ,J -DBFOX/Ph-transition metal aqua complexes. 

We employed malononitrile and l-crotonoyl-3,5-dimethylpyrazole as donor and acceptor molecules, respectively. We have found that this reaction at room temperature in chloroform can be effectively catalyzed by the J ,J -DBFOX/Ph-nick-el(II) and -zinc(II) complexes in the absence of Lewis bases leading to l-(4,4-dicya-no-3-methylbutanoyl)-3,5-dimethylpyrazole in a good chemical yield and enantio-selectivity (Scheme 7.47). However, copper(II), iron(II), and titanium complexes were not effective at all, either the catalytic activity or the enantioselectivity being not sufficient. With the J ,J -DBFOX/Ph-nickel(II) aqua complex in hand as the most reactive catalyst, we then investigated the double activation method by using this catalyst. 

Natural product total syntheses are particularly valuable when they are attended by the development of general utility methods of synthesis. In some instances, the successful completion of a natural product total synthesis requires the development and application of a new synthetic method. The total synthesis of erythronolide B by Corey et al. is one of these instances. The double activation macro-lactonization method was a fruitful innovation that was introduced in response to the challenge presented by the macrocyclic structures of the erythromycins. Several other methods to achieve the same objective, and numerous applications followed. 

Feringa-butenolide 114, in the presence of Dess-Martin periodinane reagent and 2,6-lutidine, gave the bis-ketone 115 which underwent intramolecular cycloaddition to afford endo-selectively the desired decalin-based lactone 116 (Equation 2.32) [114]. Double activation of butenolidic double bond strongly increases the reactivity of dienophile 115. 

The LPDE system is applied to several reactions in which the metal ions coordinate to the lone pairs of heteroatoms, thereby activating the substrate. Initially, the effectiveness was shown in Diels Alder reactions (Scheme 1). In a highly concentrated (5.0 M) LPDE solution, Diels- Alder reactions proceeded smoothly.6-7 Generally, a catalytic amount of LiC104 is not effective in this reaction. In some cases, a catalytic amount of an additional Bronsted acid, such as camphorsulphonic acid (CSA), gives better results.8 An interesting double activation of carbonyl moieties by using dilithium compounds has been reported (compound... 

Anthracenecarbonitrile oxide, prepared directly from 9-anthracenecarbald-oxime and N-chlorosuccinimide, reacts with dimethyl acetylenedicarboxylate to afford dimethyl 3-(9/-anthracenyl)isoxazole-4,5-dicarboxylate in good yield. Double activation reactions between this diester and hydrogenated lexitropsin 430, in a 1 2 molar ratio, produce a novel intercalating isoxazolyl bis-lexitropsin conjugate 431 as the major product (43). 

TaCl593 reacted with metallic sodium in neat trimethylphosphine to give the phosphinocarbene tantalum complexes 100 and 101, respectively. These reactions are the first examples of double activation of coordinated trimethylphosphine via oxidative cleavage of a substituent methyl C-H bond. A similar process was also observed in the reduction of tantalum pentabrom-ide with magnesium turnings in the presence of dimethylphenylphosphine.94... 

Macrolactonization of CD-hydroxyl-acid using 2,2 -dipyridyl disulfide. Also known as Corey-Nicolaou double activation method. 

With the success in asymmetric C—C bond formations based on the addition of sp C—H bonds to double bonds, an even bigger challenge is to achieve enantioselective C—C bond formation based on the double activation of the sp C—H bonds of alkynes and the sp C—H bonds of prochiral CH2 groups (Scheme 5.3), designated as... 

Scheme 15 Double activation of reaction components by an enamine/iminium mechanism [81]...

In the phosphonium iodide and chloride salt catalyzed TMSCN addition on aldehydes and ketones, a double activation should exist. Not only the activation of the ketones or aldehydes with the phosphonium cation is necessary, but also the activation of the TMSCN by the soft Lewis base [I] or the harder Lewis base [Cl], which can form a pentavalent silicon intermediate [121]. 

Figure 8.4 Proposed transition state to explain the double activation of the carbonyl group and the nucleophile by the gold catalyst.

One cyclization procedure that depends on this approach has been described in an earlier section. A further method that affords double activation of a methylene group at C-6 of aldose derivatives, and simultaneous release of an aldehydic group, leads to C-6- to C-l-bonding under extremely mild conditions and is compatible with the presence of most O-protecting groups (Scheme 11). For this reason, and because the cyclization step is normally very efficient and stereoselective, this strategy has been used extensively, ft... 

Thermolysis of the complexes R2M[N(SiMe3)2]2 (M = Zr, Hf) was found to proceed with double activation of the y-CH bonds leading to a dimeric complex containing a bridging alkylidene function (equation 98).252... 

Abe, N. Hanawa, H. Maruoka, K. Sasaki, M. Miyashita, M. Highly effident alkylation of epoxides with R3A1/H20 systems based on the double activation of epoxy oxygens. Tetrahedron Lett. 1999, 40, 5369-5372. 

Maruoka has reported that chiral bimetallic Lewis acid catalysts 9-11, prepared from (S)-BINOL, M(0-i -Pr)4 (M=Ti, Zr, Hf), and the corresponding spacer, strongly enhance the reactivity of aldehydes or ketones toward allyl transfer from allylstannanes [18-20]. For example, treatment of acetophenone (42) with tetraallyltin (41) in the presence of 30 mol% of the chiral bidentate Ti(IV) catalyst 10 provided the (S)-enriched homoallylic alcohol 43 in 95% yield with 90% ee (Scheme 2) [19]. A suggested reaction mechanism involves double activation of carbonyls owing to the simultaneous coordination of two Ti atoms to a carbonyl oxygen atom. 

All these mechanisms are non-redox in nature, as is easily found by consideration of the oxidation states of the carbon centers involved. They are furthermore chain reactions, initiated by electron transfer, and the term electron-transfer chain catalysis (ETC catalysis) is therefore appropriate (Alder, 1980). Another term is the DAISET (Double Activation Induced by Single Electron Transfer) concept, recently introduced by Chanon and Tobe (1981). The DAISET (ETC) concept is applicable to inorganic mechanisms too. 

Corey s double activation procedure (Method 2) does not use an external reagent to activate the functional group, but effects cyclization by heating a solution of the 2-pyridinethiol ester of a hydroxy acid for a prolonged period. Several pieces of evidence point to the intermediacy of 2 in this lactonization.10 If one accepts this intermediate, it follows that a hydroxy(2-pyridinethiolJ ester, heavily substituted near the reaction centers (i.e., near the hydroxyl and acyl groups), would encounter a high... 

Method 2. Corey s double activation method for lactone formation is patterned after Mukaiyama s procedure for peptide formation and involves refluxing a solution of the 2-pyridinethiol ester of a hydroxy acid in a high-boiling solvent for a prolonged period of time.6... 

Treatment of cyclic or acyclic a-haloenones with various carbon nucleophiles that possess a double activated methylene group under basic phase-transfer conditions affords 2,3-dihydrofurans in a stereoselective manner with good to high yields. This reaction system provides a general method for the construction of [. ]-fused dihydrofuran rings (Equation 60) <1998TL9739>. 

This double activation method has been successfully used in numerous syntheses of complex natural products [7]. Plata and Kallmerten [16] claimed that this procedure was the most reliable one examined for effecting macrocyclization in the synthesis of the naturally occuring antibiotic ( + )-18-deoxynargenicin (18). 

Thioxanthenes are not only valuable synthetic intermediates [1], they also find considerable interest in pharmaceutical research [2] and as dyes for numerous applications [3]. Only few methods are known for the stereoselective synthesis of S-heterocycles [4], Sequential transformations are a powerful strategy in organic synthesis frequently allowing the synthesis of complex molecules in a single synthetic operation [5]. It was anticipated that 4-silyloxy-l-benzothiopyrylium-salts 1 [6], which represent double-activated 4-thiochromanones, can be used for the stereoselective synthesis of aimulated thiochromanones 3 by reaction with 2-silyloxy-l,3-butadienes 2 [7]. 

As expected, the reaction of the 4-silyloxyquinolinium-salt 1, which can be regarded as a double activated 4-quinolone, with the unsubstituted 2-silyloxy-l,3-butadiene 2 diastereoselectively gives the cis-flised acridone 5 with 86 % yield. 

A great advantage of the new method is that both reactants, the double activated 4-silyloxyquinolinium-salt 1 and the 2-silyloxy-l,3-butadiene 2 [6], are obtained in situ from the corresponding 4-quinolone 6 and methyl vinyl ketone 7 by reaction with triisopropylsilyltrifluoro-methanesulfonate (TIPSOTf) and TIPSOTfy2,6-lutidine, respectively. 

The object of the present work is to show that the double activation energy or EE model is a suitable approximation to the decomposition rate equation for propane, n-butane, and n-hexane and, by extension, other paraffins and isoparaffins. Ethane is a somewhat special case and is excluded for the present. 

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