Chelation Control Mechanism

With a-substituted cyclohexanones, the transition state 25a giving -isomers suffers from severe steric repulsion, and hence Z-isomers such as (Z)-26 are 

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The high diastereoselectivity which is found in the nucleophilic addition of Grignard reagents to chiral 2-0x0 acetals can be explained by a chelation-controlled mechanism. Thus, coordination of the magnesium metal with the carbonyl oxygen and the acetal moiety leads to a rigid structure 3A in the transition state with preferred attack of the nucleophile occurring from the S/-side. 

These results may be explained by a chelation-controlled mechanism A with M representing a complex of JVtg(ll), Ce( 111) or of both cations. The highly stereoselective addition of the organocop-per reagent can be rationalized either by the dipolar model B or the Felkin-Anh model C (see also ref 12). 

Murakami and Taguchi utilized a diastereoselective Grignard addition to a substituted-chiral oxazoline aldehyde 524 (Scheme 8.170) in an improved stereoselective synthesis of D-n7 o-phytosphingosine. The good stereoselectivity observed for 525 can be rationalized by a Felkin-Ahn transition state model although a chelation control mechanism could not be mled out. 

The effect of ionic liquid solvents on the stereochemical selectivity of allylation of 2-methoxycyclohexanone has been investigated, and found a higher selectivity (axial alcohol 34/equatorial alcohol 35) toward the chelation-controlled mechanism in ionic liquid than in conventional solvents such as water and THF. The use of 0.1 equiv. of indium, combined with Mn and TMSC1 (2 equiv. of each), results in the isolation of the desired products in good purity, with an overall conversion of 81% (Scheme 39).168... 

Giignard addition to the BOC-protected phenylalaninal (27 equation 11) occurs mainly through a cyclic chelation controlled mechanism to yield (28) and (29) in a ratio of 70 30. Conditions which favor coordination of the nitrogen and magnesium atoms (high temperature) are essential for the selectivity observed. 

A chelation-controlled mechanism was discussed in the asymmetric hetero-Diels-Alder reaction of a-alkoxy aldehydes and A-protected amino aldehydes with Brassard s diene mediated by Eu(hfc)3 (eq. (9) BOC = r-butoxycarbonyl) [107]. 

Keck [99] first disclosed the Lewis acid-promoted reaction of a y-siloxy or al-koxyallylstannane with either a- or / -alkoxy aldehydes (Scheme 10-61). Reaction of the a-alkoxy aldehyde 141 with the allylstannane 142 affords the homoallylic alcohol 143 as the only product. Reaction of the / -alkoxy aldehyde 52 with the allylstannane 142 also proceeds in high diastereoselectivity ( 50/l) to produce the homoallylic alcohol 144. The stereochemical outcome of these reactions is consistent with a chelation-control mechanism. 

The lithium aluminum hydride reduction of /i-chirar / -alkyl dialkylamino ketones has also been investigated776. Although some of the reactions were effectively unselective, others showed a modest syn selectivity, for example, the reduction of 3-dimethylamino-l-phenylbu-tanone. The sense of the asymmetric induction is consistent with a chelation-controlled mechanism analogous to that of the. svn-selective reductions of /1-hydroxv ketones (see Section 2.3.3.1.1.2.3.). 

As can perhaps be appreciated from this account, the sulfoxide moiety can be an efficient and highly selective stereocontrol element for a wide variety of synthetic transformations. The sulfoxide group is readily incorporated into the substrate structure, using established methods. In most cases, the sulfinyl group can be removed after its contribution to the synthetic scheme without loss of enantiomeric purity in the desired product. In most cases the sense of stereoselection observed can be predicted and rationalized on the basis of steric, stereoelectronic and/or chelation control mechanisms. 

On the other hand, high Z-selectivity is seen in the olefination reactions of the carbanion 19 derived from 3,3-diethoxybutylphosphonate with aldehydes (Scheme 2.16) [41, 42]. Similarly, Z-selective Peterson reactions of the in situ generated a-phosphoryl-a-(trimethylsilyl)allyl anion 104 with aldehydes or alkyl formates to afford the 2-dienylphosphonates 105 have been reported (Scheme 2.63) [168, 169]. These methods allow access to (Z)-alkenylphosphonates, whereas Wittig-Horner reactions give the thermodynamic ( )-alkenes almost exclusively. These excellent Z-selectivities can be rationalized in terms of the chelation control mechanism (see Section 2.2.2.3). 

Even though the model shown above is consistent with the stereochemical outcome, Flowers has shown that changing the reaction conditions or the substituents in the (3-hydroxy ketone substrates can have an impact on the stereochemical outcome of the chelation-controlled reaction.23,24 A more detailed discussion of the mechanism of this reduction can be found in Chapter 4, Section 4.3. 

The mechanism of olefination can be deduced by consideration of orbital interactions to proceed via torquoselective olefination, rather than chelation control, for the following reasons (1) the sterically hindered siloxy and phenoxy groups are also effective for high -induction (2) in the presence of a crown ether, the selectivity still remains high and (3) an axially oriented siloxy group induces a high Z-selectivity. Theoretical calculations indicate that the transition state of inward rotation is stabilized by an orbital interaction between a(C-O) and ct (C-OR) (157) . 

LiC104 was shown to be a more compatible Lewis acid for chelation in an ethereal solvent—when TiCU, a typical chelation agent for a-alkoxyaldehydes, was used in EtaO for alkylation of 79, moderate diastereoselectivity (68 32) was obtained. Rapid injection NMR studies of the TiCU-promoted chelation-controlled Mukaiyama aldol reaction and the Sakurai reaction show that an acyclic transition state must be involved in which the silyl groups never reach the carbonyl oxygen atom. In LPDE-mediated enolsilane additions silylated products predominate. Obviously, the mechanism is different—it is a group-transfer aldol reaction [107]. 

In addition to the aforementioned X-ray analysis to disclose the structure of a few crystalline titanium chelates, and NMR studies have been performed to provide evidence for the chelation structure of a- and /1-oxycarbonyl compounds in solution [33-35]. Approximate solution structures for -alkoxyaldehydes are as shown in Fig. 7 [34]. The mechanism of chelation-controlled reactions of organotitanium reagents has been investigated experimentally [5] and theoretically [36], and the subject has been reviewed [10]. The formation of a chelate structure with titanium metal at the center plays a pivotal role in determining the reactivity and selectivity [37] in many synthetic reactions as shown in the following discussion. 

The basic concept, although most likely not the detailed mechanism, of the Enders asymmetric induction follows from the chelation-controlled asymmetric alkylation of imine anions introduced by Meyers and Whitesell. The hydrazones derived from either the (5)- or the (/ )-enantiomer of iV-amino-2-methoxymethylpyrrolidine (SAMP and RAMP, derived from the amino acid proline) can be converted to anions that undergo reaction with a variety of electrophiles. After hydrolysis of the product hydrazones, the alkylated ketones can be obtained with good to excellent levels of optical purity (Scheme 19). 

Lewis acid breaks up the closed transition state normally found in thermal reactions. Contrary to the Hiyama-Nozaki reaction the induced stereoselections for allylstannanes-i-Lewis acids are extremely high, due to chelate-Cram controlled mechanisms [reaction (91), Scheme 30] [76]. Reagent controlled diastereoselec-tivity may be exerted in terms of 1,3- [reaction (92)] [77] and 1,5-inductions [reaction (93)] [78]. 

Figure 4.14. Applications of oxathianes linalool [53], dimethyl acetylcitramalate [54], mevalolactone [56], malyngolide [55], and the mosquito oviposition attractant [39]. For the latter, the C-5 stereocenter was formed by a chelate-controlled reduction while the C-6 position could be produced as either epimer by a chelate or acyclic mechanism, depending on the reducing agent.

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