Cyclic transition state, aldol reaction

It is noteworthy that reaction diastereoselectivity closely parallels the isomeric purity of the allyiboronates, thus underscoring the requirement that the method of reagent synthesis be highly stereoselective. The data presented in Table 1 also provide strong evidence for the involvement of chair-like, cyclic transition states, analogous to the transition states previously invoked for aldol reactions46. 

Boron Enolates. Another important version of the aldol reaction involves the use of boron enolates. A cyclic transition state is believed to be involved, and, in general, the stereoselectivity is higher than for lithium enolates. The O—B bond distances are shorter than the O—Li bond in the lithium enolates, and this leads to a more compact transition state, which magnifies the steric interactions that control stereoselectivity. 

The synthesis in Scheme 13.30 uses stereoselective aldol condensation methodology. Both the lithium enolate and the boron enolate method were employed. The enol derivatives were used in enantiomerically pure form, so the condensations are examples of double stereodifferentiation (Section 2.1.3). The stereoselectivity observed in the reactions is that predicted for a cyclic transition state for the aldol condensations. 

Aldol reactions of magnesium enolates are frequently more diastereoselective than the corresponding reactions of lithium enolates. The aldol condensation proceeds via a cyclic transition state in agreement with the Zimmerman-Traxler chelated model . 

The approach for the enantioselective aldol reaction based on oxazolidinones like 22 and 23 is called Evans asymmetric aldol reaction.14 Conversion of an oxazolidinone amide into the corresponding lithium or boron enolates yields the Z-stereoisomers exclusively. Reaction of the Z-enolate 24 and the carbonyl compound 6 proceeds via the cyclic transition state 25, in which the oxazolidinone carbonyl oxygen and both ring oxygens have an anti conformation because of dipole interactions. The back of the enolate is shielded by the benzyl group thus the aldehyde forms the six-membered transition state 25 by approaching from the front with the larger carbonyl substituent in pseudoequatorial position. The... 

Boron enolates react with aldehydes and ketones under neutral conditions to give intermediates which hydrolyze to aldol products. The reaction proceeds via a cyclic transition state (Equation B5.2) and is analogous to the allylborane reactions discussed above. 

Independently, Yamamoto, Yanagisawa, and others reported the asymmetric aldol reaction using trimethoxysilyl enol ethers.19 The reaction was conducted with aldehydes and trimethoxysilyl enol ethers in the presence of Tol-BINAP-AgF to give the corresponding adducts with high enantioselectivities and diastereoselectiv-ities. They obtained vyra-aldol adducts as major products even when silyl enol ethers derived from cyclic ketones were used. Moreover, when a,(3-unsaturated aldehydes were employed as substrates, 1,2 adducts were obtained exclusively (Table 9.10). From an NMR study and correlation between the E Z ratio of the enol ethers and diastereoselectiviy, they proposed a cyclic transition state (Fig. 9.5). Thus, the reaction of E enol ethers proceeded via a boat form, whereas the reaction of Z enol ethers took place via a chair form. 

Enantioselective aldol reaction of tin enolates with aldehydes catalyzed by BINAP-AgOTf complex has been accomplished. This reaction proceeds through a cyclic transition state with the aid of chiral silver complex (Equation (67)).221... 

The aldol step itself is now a very favourable intramolecular reaction with a six-membered cyclic transition state. The product is initially the lithium alkoxide of the aldol, which gives the aldol on work-up. 

These are the experimental facts how can we explain them Aldol reactions are another class of stereoselective process with a cyclic transition state. During the reaction, the lithium is transferred from the enolate oxygen to the oxygen of the carbonyl electrophile. This is represented in the margin both in curly arrow terms and as a transition state structure. 

The cyclic transition state explains how enolate geometry controls the stereochemical outcome of the aldol reaction. But what controls the geometry of the enolate For lithium enolates of ketones the most important factor is the size of the group that is not enolized. Large groups force the enolate to adopt the cis geometry small groups allow the fram-enolate to form. Because we can t separate the lithium enolates, we just have to accept that the reactions of ketones with small R will be less dias ter eoselective. 

The six-member ed transition state for the reaction of an allylic borane or boron ate is very reminiscent of the cyclic transition state for the aldol reaction you met in Chapter 34. In this case the only change is to replace the oxygen of the enolate with a carbon to make the allyl nucleophile. The transition state for the aldol reaction was a chair and the reaction was stereospecific so that the geometry of the enolate determined the stereochemistry of the product aldol. The same is true in these reactions. -Crotyl boranes (or boronates) give anti homoallylic alcohols and Z-crotyl boranes (or boronates)... 

If the metal-binaphthyl complex is not fitted directly into the cyclic transition state, it becomes difficult to explain the asymmetric inductions observed. The following rule seems to be generally valid for both BINOL and BINAP complexes The complexation of carbonyl or imine moieties by (R)-binaphthyl-metal complexes results in a shielding of the si face, the reaction proceeds from the re face. Correspondingly, the opposite principle applies when (STbinaphthyl complexes are used. All aldol reactions and carbonyl-ene reactions which are catalyzed by binaphthyl complexes abide by this rule [18], and the scheme can also be applied to the addition of ketene-silyl-acetals to imines with boron-BINOL catalysts [19]. 

There is a dichotomy in the sense of syn-anti diastereofacial preference, dictated by the bulkiness of the migrating group [94]. The sterically demanding silyl group results in syn diastereofacial preference but the less demanding proton leads to anti preference (Sch. 35). The anti diastereoselectivity in carbonyl-ene reactions can be explained by the Felkin-Anh-like cyclic transition-state model (Ti) (Sch. 36). In the aldol reaction, by contrast, the now inside-crowded transition state (Ti ) is less favorable than Tg, because of steric repulsion between the trimethylsilyl group and the inside methyl group of aldehyde (Ti ). The syn-diastereofacial selectivity is, therefore, visualized in terms of the anti-Felkin-like cyclic transition-state model (T2 )-... 

Recently the isolation arid structure determination of the aldol product of the chiral iron enolate (161) with benzaldehyde was obtained as (162). Hiis structure is presumed to mimic closely the structure of the cyclic transition state for the aldol reaction. 

The use of these auxiliaries in anti aldol reactions has been described, though not by generation of the anticipated ( )-enolate. Instead, the typical (Z)-enolate is formed, and then precomplexation of a Lewis acid with the reacting aldehyde diverts the reaction away from a cyclic transition state [23]. The contrasting stereochemical trends of the catalyzed and non-catalyzed reactions are evident in an early approach to muamvatin (Scheme 9-13) [24]. Alternatively, Oppolzer has reported the Lewis acid catalyzed anti aldol reaction of a silyl enol ether derived from sultam 38 [25]. In general, however, this methodology has seen limited use in the synthesis of complex natural products. 

Aldol condensation of the tin enolates with aldehydes often takes place spontaneously at room temperature, but Lewis acids (e.g. TiCL, BF3.OEt2, ZnCl2, CuCl2) or PdCl2[(o-C6H4)3P]2 can be used as catalysts, and enantioselective addition can be achieved with an (/ )-BINAP-AgOTf catalyst.101 The stereoselectivity is dependent on the reaction conditions, and the high threo selectivity at low temperature is ascribed to the presence of a cyclic transition state 14-20.104... 

More impressive and more important is the performance of these lithium enolates in aldol reactions. Ester enolates are awkward things to use in reactions with enolisable aldehydes and ketones because of the very efficient self-condensation of the aldehydes and ketones. The traditional solutions involve such devices as Knoevenagel-style reactions with malonates.11 Lithium enolates of esters, e.g. 76, react cleanly with enolisable aldehydes and ketones to give high yields of aldols,12 e.g. 79 in a single step also involving a six-membered cyclic transition state 77. 

The relationship between enolate geometry and aldol stereochemistry has now been well established for many aldol reactions. The geometry of lithium enolates expresses itself through the so-called Zimmerman-Traxler5 transition state which is nothing more than the six-membered cyclic transition state that we met in the last chapter. When a lithium enolate reacts with an aldehyde, both the enolate and aldehyde oxygen atoms coordinate to the lithium atom 10 so that the transition state 11 is a partly unsaturated six-membered ring. 

Lithium enolates 279 do give a-hydroxy-carbonyl compounds but there is a significant side reaction that is a kind of aldol reaction on the imine product 272 through a six-membered cyclic transition state 280 like those we used to explain the stereoselectivity of aldol reactions in chapter 4. Hence the Na or K disilazide bases NaHMDS or KHMDS are usually used. 

Simple stereoselective aldol reactions (chapter 3) can also be controlled by tandem conjugate addition. Addition of Me2CuLi to the simple unsaturated ketone 27 gives the lithium enolate 28. It would be very difficult to produce this enolate from the parent ketone MhiCO.Me with regio- or stereoselectivity. The cyclic transition state 29 with zinc replacing lithium then shows the way to the anti-aldol7 30. 

The first step is of course the aza-Diels-Alder reaction 218 with no regioselectivity but lots of stereochemistry. The cis ring junction in 217 comes from the cis alkene in maleimide and the endo transition state gives the remaining centre. The next step is an allyl boronate reaction 219 with the aldehyde. Coordination of the aldehyde oxygen with the boron ensures that the aldehyde is delivered to the top face and the aldol stereochemistry comes from the six-membered cyclic transition state. Snieckus comments that the reaction works well as a tandem process because the 4 + 2 cycloaddition is slower than the allyl boronate reaction so the unstable intermediate does not accumulate. This comment has more general application. 

---