Conformation aldol reactions

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

Acyclic stereocontrol has been a striking concern in modern organic chemistry, and a number of useful methods have been developed for stereoregulated synthesis of conformationally nonrigid complex molecules such as macrolide and polyether antibiotics. Special attention has therefore been paid to the aldol reaction because it constitutes one of the fundamental bond constructions in biosynthesis. 

Detailed analysis of the rate and equilibrium constants determined for both phases of intramolecular aldol condensation reactions (13 —>15, 16—>18, and 19—>21) in terns of Marcus theory, has established that the intrinsic barriers for die intramolecular reactions are the same as those determined previously for the intermolecular counterparts.31 Consequently, rate constants for intramolecular aldol reactions are predictable from the energetics of the reactions and the effective molarity can be calculated. An associated discussion of Baldwin s rales suggests that they are a consequence of the need to achieve a conformation from which reaction can take place... 

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... 

A few theoretical studies of oxetanes and oxetanones have been reported since CHEC-II(1996). Building upon a study of the oxetane- -HCl complex studied by rotational spectroscopy, MP2 calculations were used to investigate the axial and equatorial HCl arrangement, and to try and explain why for oxetane- -HCl only one conformer was observed <2001CPL250, 2002CPL123>. The amine-catalyzed aldol reaction via enamine intermediates has been explored using density functional theory (DFT) (B3LYP/6-31G ) and conductor-like polarizable continuum model... 

Whereas the (S)-proline- and 13-catalyzed Mannich reactions afforded (2S,3S)-syn-products and (2S,3R)-anh-products, respectively, as shown in Scheme 2.15, with high diastereo- and enantioselectivities, the (S)-pipecolic acid (14)-catalyzed reaction afforded (2S,3S)-syn- and (2S,3.R)-anh-products with moderate diastereo-selectivities but high enantioselectivities for both the syn- and anti-products [74] (Scheme 2.16). This was explained by computational analyses indicating that (S)-pipecolic acid uses both the s-trans and s-cis conformations of the enamine similarly (the energy differences 0.2 kcal mol-1 for pipecolic acid versus 1.0 lccal mol-1 for proline) in the C-C bond-forming transition state [74]. Note that (S)-pipecolic acid was not a catalyst for the aldol reaction of acetone and... 

After mercury(II)-assisted hydrolysis of the thioenol ether, aldehyde 3 was obtained. This was then subjected to the critical vinylogous aldol reaction needed to complete the carbon backbone of the natural product. The latter process furnished a 3.5 1 mixture of the y to ot addition products. The stereoselectivity observed in the installation of the C(5)-hydroxyl (natural product numbering) was only 2 1. Fortunately, the predominant isomer was the desired product 2. In retrospect, it can be seen that the level of selectivity attained conformed to the predictions of the Still model.4... 

The aldol reactions of the titanium Z-enolates proceeded smoothly with various aldehydes precomplexed with titanium chloride at -78° C. The diastereose-lectivity is high to excellent, with the single exception of benzaldehyde. The high degree of diastereoselection associated with this current asymmetric anti-aldol process can be rationalized by a Zimmerman-Traxler type of six-membered chairlike transition state Al9fl (Scheme 2.2r). The model is based on the assumptions that the titanium enolate is a seven-membered metallocycle with a chairlike conformation, and a second titanium metal is involved in the transition state, where it is chelated to indanolyloxy oxygen as well as to the aldehyde carbonyl in a six-membered chairlike transition-state structure. 

The resulting ketone can be enolized on the phosphate side and added to the free aldehyde group to form the cyclohexane ring. We can draw the mechanism for the aldol reaction easily if we first change the conformation. 

The enolate must prefer to attack the aldehyde in the same way as in the biological reaction to give the all-equatorial product as the conformational drawing shows. The arrangement of the enolate in the aldol reaction itself will be the same as in the cyclization of the phosphate above. 

Interestingly, Ab72D4 also catalyzes a (45)-selective retro aldol reaction and a complementary (4A (-selective p-climination reaction (Scheme 5.62). Chemoselectivity in this system appears to be a consequence of the conformational control imposed by the antibody pocket, although the nature of this interaction is not understood.116... 

To examine the syn/anti selectivity, Houk examined the aldol reaction of acetaldehyde and propanal with methanamine as catalyst. Reaction 6.19. The E or Z enamine can react to give syn or anti product. They located four TSs 52a-d, shown in Figure 6.22. Again, these TSs are in a half-chair conformation with internal proton transfer. The TSs involving the E isomer are lower than those with the Z isomer. The E isomer prefers to give the anti isomer (52a is 0.7 kcal mol" below 52b), while the Z isomer favors the syn product (52c is 1.4 kcal mol" below 52d) These results are consistent with experiments that show preference... 

Houk has further explored conformational factors that may play a role in determining selectivity. The proline ring can be puckered in two orientations, up 57 or down 58. Consideration of the four TSs with the up orientation and the four with the down orientation for the aldol reaction of acetone with p-nitrobenzaldehyde is necessary. The up TSs predict an ee that is too low, while the down TSs predict an... 

On the basis of Kiyooka s working hypothesis for the aldol reaction mechanism, the reduction proceeds via by an intramolecular hydride transfer this is accelerated by matching between the chirality of the promoter and that of the newly formed aldol (Eq. 50). An alternative mechanism without chelation is also possible, and involves hydride delivery to the preferred O-silyl oxocarbenium ion conformer (Eq. 51). 

Zirconium enolates are prepared by the reaction of lithium enolates with Cp2ZrCl2. Aldol reactions mediated by zirconium enolates are characterized by high syn selectivity and good yields as a result of stereo control of the ligands on the metal (Eq. 1) [2]. Even at -78 °C zirconium enolates are reactive in addition to aldehydes because of the high Lewis acidity of the metal. The reaction of (Z)-enolates with aldehydes proceeds via chair-like conformation the conformation is boat-like for (E)-eno-lates [2a]. Thus both ( )- and (Z)-enolates (2) prepared from ketone 1 give predominantly syn aldols syn- i. 

The syn selectivity of the aldol reaction comes from the chair conformation of the eye (Zimmerman-Traxler) transition state. Ignoring the stereochemistry of the aldehyde we have thc--simplified explanation. 

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