Steric control

Many studies of the Wittig reaction were and still are directed towards developing techniques for controlling the ( /Z)-selectivity. Essentially two strategies are followed in these studies  

Reactive ylides, in apolar solvents under salt-free conditions, preferentially form olefins with the (Z)-configuration (see Section C.l). To optimize this effect, various techniques have been developed for preparing salt-free ylide solutions [21-25]. The phosphonium salt is deprotonated, for example with sodium amide in THF or liquid ammonia [23], with sodium hexamethyldisilazane in an ether solvent such as THF [21], or with potassium r-butoxide in THF or toluene [22], with the addition of crown ether if appropriate [24]. A particularly elegant application of the salt-free Wittig reaction is the instant-ylide technique [25]. 

The highly stereoselective conversion of the a-haloylides 6 into the 1-alkenyl halides 7 is a remarkable and rare example of the specific synthesis of (Zj-olefms from semi-stabilized ylides. 

Instead of protonation, the P-oxidoylide can be scavenged by other electrophiles such as aldehydes or methyl iodide to give a-substituted betaines. Trisubstituted olefins are obtained directly in this manner. The designation substitution + carbonyl olefination via p-oxido phosphonium ylides (SCOOPY) has been proposed for this reaction [19,33]. 

In the case of Wittig reactions between alkenyl-substituted, i.e. semi-stabilized, ylides and aliphatic aldehydes, the f j-content could be substantially increased under salt-free conditions when a stationary phenyl group on the phosphorus was replaced by a methyl or alkenyl group [37]. 

Stereoregular polymerization requires that the faces of the prochiral monomer must have a different reactivity toward one given chiral reactive site. By using 3g nmR to examine the stereochemical sequences of the configurations of the monomer units of polypropyl- 

Figiire 1, C ISIMR spectxa (22,63 MHz) of sanples 1-4 ) (methyl region). Iteproduced. with permission of the authors from Ref. 8. 

The stereospecific polymerization of ot-olefins is one of the best examples which illustrate the possible applications of high resolution NMR to the determination of reaction mechanisms. As a matter of fact, the stereoregular structure of the reaction products and the sensitivity of chemical shifts to stereochemical environments make it possible to obtain considerable and important information about very subtle details of the reaction mechanism. This is especially true when NMR is used in conjunction with isotopic substitution. 

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E. Vedejs (1978) developed a general method for the sterically controlled electrophilic or-hydroxylation of enolates. This uses a bulky molybdenum(VI) peroxide complex, MoO(02)2(HMPTA)(Py), which is rather stable and can be stored below 0 °C. If this peroxide is added to the enolate in THF solution (base e.g. LDA) at low temperatures, oneO—O bond is broken, and a molybdyl ester is formed. Excess peroxide is quenched with sodium sulfite after the reaction has occurred, and the molybdyl ester is cleaved to give the a-hydroxy car-... 

These reactions can be cataly2ed by bases, eg, pyridine, or by Lewis acids, eg, 2inc chloride. In the case of asymmetric alcohols, steric control, ie, inversion, racemi2ation, or retention of configuration at the reaction site, can be achieved by the choice of reaction conditions (173,174). Some alcohols dehydrate to olefins when treated with thionyl chloride and pyridine. 

N-Unsubstituted 1,2,3-triazoles are methylated mainly in the 1-position with methyl iodide and silver or thallium salts, but mainly in the 2-position by diazomethane. There is also some steric control. For example, 4-phenyl-l,2,3-triazole with dimethyl sulfate gives the 2-methyl-4-phenyl (38%) and l-methyl-4-phenyl isomers (62%), but none of the more hindered 1-methyl-5-phenyltriazole (74AHC(16)33). JV-Unsubstituted 1,2,4-triazoles are generally alkylated at N-1. 

Reactions demonstrating steric control have been reported. Cyclization of the dimethyl acetal 103 led to a 9 1 ratio of 104 105 instead of a 1 1 ratio using unsubstituted dioxolane lOl. " Yet others reported sterics did not control the selectivity of cyclization. 

Stereoselective reactions of this type known at present only deal with four- or five-membered cyclic iV-acyliminium ions. The reactions with carbon nucleophiles usually lead to rra/u-substi-tuted compounds with very high stereoselectivity due to steric control by the substituent already present in the ring. 

The elimination is of course syn, so the product is sterically controlled. Alkenes that are not sterically favored can be made this way in high yield (e.g., cis-PhCH2CH=CHCH2Ph). Certain other five-membered cyclic derivatives of 1,2-diols can also be converted to alkenes. ... 

Fig. 3.31 Steric control in alternating ROMP Tendencies of norbomene and cyclooctene to give productive olefin metathesis upon coordination are illustrated by a thick arrow (preferred monomer) or a thin arrow (less favoured monomer) (a) only minor steric hindrance SlMes greatly favours the polymerisation of the strained norbomene (b) the rotating phenylethyl-group induces a steiically more congested active site, leading to preferred incorporation of the smaller cyclooctene (c) the flexible and small cyclooctene derived polymer fragment permits the incorporation of the bulky norbomene...

The oxidation results in mixtures of cis- and trans-isomers, the ratio of which is primarily sterically controlled. The oxidant appears to approach the sulfur atom preferentially from the least-sterically hindered direction, so that the thermodynamically least stable isomers may occasionally predominate " ... 

This research was carried ont in two parts. The first one explored the relationships between alloy structnre, alloy activation and the resulting catalyst, and the second one looked at the nse of sterically controlled Ni ensembles for improved reaction... 

The situation encounters another factor with enolates having a C(2) substituent. The case of steric control has been examined carefully. The stereoselectivity depends on the orientation of the stereocenter relative to the remainder of the TS. The Felkin TS is A. TS B represents a non-Felkin conformer, but with the same facial approach as A. The preferred TS for the Z-enolate is believed to be structure C. This TS is preferred to A because of the interaction between the RM group and the R2 group of the enolate... 

Entry 2 shows an E-enolate of a hindered ester reacting with an aldehyde having both an a-methyl and (3-methoxy group. The reaction shows a 13 1 preference for the Felkin approach product (3,4-syn) and is controlled by the steric effect of the a-methyl substituent. Another example of steric control with an ester enolate is found in a step in the synthesis of (-t-)-discodermolide.99 The E-enolate of a hindered aryl ester was generated using LiTMP and LiBr. Reaction through a Felkin TS resulted in syn diastereoselectivity for the hydroxy and ester groups at the new bond. 

Entries 4 and 9 are closely related structures that illustrate the ability to control stereochemistry by choice of the Lewis acid. In Entry 4, the Lewis acid is BF3 and the (3-oxygen is protected as a f-butyldiphenylsilyl derivative. This leads to reaction through an open TS, and the reaction is under steric control, resulting in the 3,4-syn product. In Entry 9, the enolate is formed using di-n-butylboron triflate (1.2 equiv.), which permits the aldehyde to form a chelate. The chelated aldehyde then reacts via an open TS with respect to the silyl ketene acetal, and the 3,4-anti isomer dominates by more than 20 1. 

Entry 15 involves a benzyloxy group at C(2) and is consistent with control by a (3-oxy substituent, which in this instance is part of a ring. The anti relationship between the C(2) and the C(3) groups results from steric control by the branched substituent in the silyl enol ether. The stereogenic center in the ring has only a modest effect. 

Scheme 2.4 provides some specific examples of facial selectivity of enolates. Entry 1 is a case of steric control with Felkin-like TS with approach anti to the cyclohexyl group. 

Enantioselective Reactions of Organocopper Reagents. Several methods have been developed for achieving enantioselectivity with organocopper reagents. Chiral auxiliaries can be used for example, oxazolidinone auxiliaries have been utilized in conjugate additions. The outcome of these reactions can be predicted on the basis of steric control of reactant approach, as for other applications of the oxazolidinone auxiliaries. 

In a recent study, we showed that the more flexible pyrido[l,2-a]indole-based cyclopropyl quinone methide is not subject to the stereoelectronic effect.47 Scheme 7.17 shows an electrostatic potential map of the protonated cyclopropyl quinone methide with arrows indicating the two possible nucleophilic attack sites on the electron-deficient (blue-colored) cyclopropyl ring. The 13C label allows both nucleophile attack products, the pyrido[l,2-a]indole and azepino [l,2-a]indole, to be distinguished without isolation. The site of nucleophilic is under steric control with pyrido [1,2-a]indole ring formation favored by large nucleophiles. 

The redox interaction with a co-reductant permits the formation of a reversible redox cycle for one-electron reduction as shown in Scheme 2. Furthermore, the function of transition metals is potentially and sterically controlled by ligands. A more efficient interaction between the orbitals of metals and substrates leads to facile electron transfer. Another interaction with an additive as a Lewis acid towards a substrate also contributes to such electron transfer. 

The nature of intermolecular force is essentially no different from that which participates in the chemical bond or chemical reaction. The factor which determines the stable shape of a molecule, the influence on the reaction of an atom or group which does not take any direct part in the reaction, and various other sterically controlling factors might also be comprehended by a consideration based on the same theoretical foundation. 

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