Electrophiles, chiral

The asymmetric Baylis-Hillman reaction of sugar-derived aldehydes as chiral electrophiles with an activated olefin in dioxane water (1 1) proceeded with 36-86% de and in good yields of the corresponding glycosides (Eq. 10.47).104 The use of chiral /V-mcthylprolinol as a chiral base catalyst for the Baylis-Hillman reaction of aromatic aldehydes with ethyl acrylate or methyl vinyl ketone gave the adducts in good yields with moderate-to-good enantioselectivities in l,4-dioxane water (1 1, vol/vol) under ambient conditions.105... 

In addition to the reactions discussed above, a,//-unsaturated oxazolines can also act as chiral electrophiles to undergo conjugated addition of organolithium reagent to give optically active / ,/ -disubstituted carboxylic acids.52 The vinyl oxazolines 48 are prepared using the two methods outlined in Scheme 2-27. 

The synthesis of optically active compounds by the diastereoselective reaction of allyltitanium reagents with chiral electrophiles has also been reported. The reaction of allyltitanium reagents with chiral imines proceeds with excellent diastereoselectivity, as shown in Eq. 9.28, thus providing a new method for synthesizing optically active homoallylic amines with or without a P-substituent [51,52],... 

Since the first experiments with chiral copper complexes reported by Nozaki [650] and Aratani [1027] many different catalysts have been examined, both for intermolecular and intramolecular cyclopropanations (for a review, see [1369]). Syntheses of natural products [955,1370] and drugs [1371] using asymmetric cyclopropanation with chiral electrophilic carbene complexes have been reported. A selection of useful catalysts is given in Figure 4.20 (see also Experimental Procedure 4.1.1). 

The conjugate addition of organometallic reagents R M to an electron-deficient alkene under, for instance, copper catalysis conditions results in a stabilized car-banion that, upon protonation, affords the chiral yS-substituted product (Scheme 7.1, path a). Quenching of the anionic intermediate with an electrophile creates a disubstituted product with two new stereocenters (Scheme 1, path b). With a pro-chiral electrophile, such as an aldehyde, three new stereocenters can be formed in a tandem 1,4-addition-aldol process (Scheme 1, path c). 

Recently, the semi-synthesis of Vancomycin (48) on solid supports was accomplished using an allylic linker (Scheme 3.2) [123, 124]. Polymer-bound chiral electrophilic selenium reagents have been developed and applied to stereoselective se-lenylation reactions of various alkenes (Tab. 3.9) [125]. 

Regiospeciflc, uncatalysed hydrophosphination of typical Michael acceptors, such as methyl acrylate, has been reported to proceed readily with alkenyl- an alkynyl-phosphine oxides, e.g. R(l )P(H)0. Good stereoselectivity was observed when a chiral electrophile was used. The reaction is believed to proceed owing to the strong... 

Besides the interesting possibility of connecting a chiral electrophile to a chiral nucleophile, which is created from the same precursor in a completely stereoselective manner, this sequence seems to open a general route to enantiomerically pure ot-Iithiated ethers29,32. 

Enantioselectivity may be achieved by reaction of an enolate with a chiral electrophile. However, there are no systematic investigations on this topic. 

The phase-transfer-catalyzed asymmetric alkylation of 1 has usually been performed with achiral alkyl halides, and hence the stereochemistry of the reaction with chiral electrophiles has scarcely been addressed. Nevertheless, several groups have tackled this problem. Zhu and coworkers examined the alkylation of 1 with stereo-chemically defined (5S)-N-benzyloxycarbonyl-5-iodomethyl oxazolidine using 4d to prepare (2S,4R)-4-hydroxyornithine for the total synthesis of Biphenomycin. Unexpectedly, however, product 7 with a 2 R absolute configuration was formed as a major isomer, and the diastereomeric ratio was not affected by switching the catalyst to pseudoenantiomeric 2d and even to achiral tetrabutylammonium bromide (TBAB), indicating that the asymmetric induction was dictated by the substrate (Scheme 2.3) [21]. 

Despite numerous efforts to develop the asymmetric phase-transfer-catalyzed alkylation of 2 into a powerful method for the synthesis of natural and unnatural a-amino adds, the stereochemistry of the alkylation of 2 with chiral electrophiles has scarcely been addressed. 

In the metal-free epoxidation of enones and enoates, practically useful yields and enantioselectivity have been achieved by using catalysts based on chiral electrophilic ketones, peptides, and chiral phase-transfer agents. (E)-configured acyclic enones are comparatively easy substrates that can be converted to enantiomeri-cally highly enriched epoxides by all three methods. Currently, chiral ketones/ dioxiranes constitute the only catalyst system that enables asymmetric and metal-free epoxidation of (E)-enoates. There seems to be no metal-free method for efficient asymmetric epoxidation of achiral (Z)-enones. Exocyclic (E)-enones have been epoxidized with excellent ee using either phase-transfer catalysis or polyamino acids. In contrast, generation of enantiopure epoxides from normal endocyclic... 

However, because the transition states for reactions of the two enantiomeric organolithiums with the chiral electrophile are diastereoisomeric, one product must be formed faster than the other. If the organolithium is configurationally stable on the timescale of addition to the aldehyde, this rate difference will be of no consequence eventually both enantiomers will... 

Barbier reactions can be highly regioselective depending on the conditions of allylation, they could proceed via Sg2 - or SEZ-pathway.256 270 272 Good diastereoselectivity can also be obtained by using a chiral electrophile (Equations (158)-( 160)).258 273-275... 

These reactions have also been performed using enantiomerically pure selenium electrophiles to access heterocyclic compounds with stereogenic centers. The yields and selectivities obtained using some selected chiral electrophiles generated from the diselenides are given in Table 2. 

Asymmetric synthesis via enolate intermediates has been extensively studied. Asymmetric induction can be divided into five main categories (1) a chiral auxiliary covalently linked to an enolate moiety,2,3 (2) a chiral ligand of a countercation of an enolate,4-6 (3) a chiral electrophile,7,8 (4) a chiral Lewis acid,9,10 and (5) a chiral phase-transfer catalyst.11,12 Rather than reviewing these examples, we introduce here the principle of asymmetric induction for... 

Enantiofacial discrimination of achiral enolates by chiral electrophiles is also possible. Duhamel and co-workers reported that the reaction of the... 

Mukaiyama and co-workers developed a chiral Lewis acid complex 15 consisting of tin (II) triflate and a chiral diamine. An aldol reaction of enol silyl ether 16 and octanal is promoted by 15 to give 17 in a highly diastereo-and enantioselective manner. The enantioface of the aldehyde is selectively activated by coordination with 15. This method is similar to method 3, in that an aldehyde-chiral Lewis acid complex can be regarded as a chiral electrophile. An advantage of method 4 over method 3 is the possible catalytic use of a chiral Lewis acid. In the reaction of Scheme 3.6, 20 mol% of 15 effects the aldol reaction in 76% yield with excellent selectivity.9... 

There have been many studies on the use of chiral electrophilic selenium reagents for stereoselective additions to alkenes <1998JA3376, B-1999MI35, 1999T1, 2000AGE3740> with notable diastereoselectivity in some cases. 

Related Reagent. For the complementary synthesis of a-substituted a-amino acids via a chiral electrophilic glycine equivalent, see 3-Bmmo-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazin-2-one. 

Related Reagents. The synthesis of chiral diazenedicarboxylates as potential chiral electrophilic aminating agents has received little attention. A series of chiral bomyl, isobomyl and menthyl diazenedicarboxylates has been reported and their reaction with achiral enolates of esters and N,N-dimethyl amides afforded a-hydrazino acid derivatives with little or no selectivity. Incorporation of a chiral azodicarboxamide unit into a chiral bridging binaphthyl moiety afforded a-hydrazino acid derivatives with high stereoselectivity in reactions with achiral oxazolidinone anions. ... 

Chiral electrophilic cyclopropanes (63) are prepared in high enantiomeric excess starting from butadiene-iron tricarbonyl complexes (60) containing a non-complexed double bond. Reaction with diazomethane and decomposition of the resulting pyrazolines (61) in the presence of Ce" gave the corresponding chiral cyclopropanes (62). Breakdown of the dienic substituent of electrophilic cyclopropane (62) by means of ozonization resulted in the formation of formyl-substituted electrophilic cyclopropane (63) still carrying the asymmetric centre (equation 10) " . ... 

Scheme 2.92 Uncharged chiral electrophilic fluorination reagents of the first generation N-fluoro camphorsultams 7a-7d [181a] and N-fluorosultam 8 [205].

There are numerous reactions in which enamines and enamine derivatives, such as metalloenamines, are used for the synthesis of enantiomerically pure compounds (EPC synthesis) In principle, such EPC synthesis could involve a chiral amine component of the enamine reacting with an achiral electrophile or an achiral enamine reacting with a chiral electrophile. The cyclohexenamines seem to be the preferred test objects for this kind of reaction enamines of open-chain ketones and aldehydes have been investigated only rarely. Examples are chiral enamines from substituted pyrrolidine 104i -i (R = CHjOMe,CHiOSiMe3,COOMeX = Me,CH20Me),... 

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