Substrate directed stereoselectivity

This section deals with substrate-controUed stereoselective hydroformylation, since asymmetric hydroformylation is covered in chapter 5. The stereoselectivity of the hydroformylation reaction is the result of the cis addition of the proton and the formyl group to the less hindered face of the double bond [41]. The presence of heteroatoms in the substrate causes chelation, so the stereoselectivity can be controlled, (see section 6.5). 

There are various ways of generating stereocenters by hydroformylation. In monosubstimted terminal alkenes, a steieocenter is generated when the 

The reaction is highly stereoselective and only the syn isomer 54 is observed. The process is kinetically controlled, and the olefin insertion is apparently the rate-determining step. 

In these exocyclic alkenes the chemo- and regioselectivity of the process depends heavily on the conformation [46]. Thus, compound 55, which in chair conformation has an axial methyl close to the coordinating point, led to the anti isomer 59 after hydroformylation, together with significant amounts of the isomerization compound 63. Elevated catalyst loading and drastic conditions were required, and the results were best when PCys was the auxiliary ligand. 

Both hydroformylation and isomerization were foimd to occur from the same diastereoface of enol ether 55. The fact that isomerization must take place through a tertiary rhodium-alkyl which has a 1,3-diaxial interaction in chair conformation seems to indicate that the intermediate has a boat conformation. 

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This chapter will concentrate on examples of templated synthesis where the template takes the form of a temporary, covalent tether. The intermediate molecule containing both reacting species is in all cases isolable (or potentially so). This distinguishes this intra molecularization approach from substrate-directed stereoselective synthesis. In this case, the template, most frequently a metal, is used in a much more transient sense allowing the potential for developing catalytic systems, which is obviously not possible using a covalently bound template. 

Kim H, Yen C, Preston P, Chin J. Substrate-directed stereoselectivity in vicinal diamine-catalyzed synthesis of warfarin. Org. Lett. 2006 8(23) 5239-5242. 

Modern synthetic chemistry has taken up the challenge of acyclic substrate-induced stereoselection302, including auxiliary-directed stereoselectivity. The main principles are 1,2-in-duction, the formation of cyclic intermediates, and intramolecular reactions. Many aspects, rules , and examples of diastereoface-differentiating reactions, both in cyclic and in acyclic systems, are summarized in Section 2.3.5.2. 

The phenyl ring of styrene substrates directs a syn selectivity in their ene reactions with singlet oxygen [71], This effect was demonstrated by the photo-oxygenation of (3,(3-dimethyl styrene. This substrate, a part of the ene product, produces the 1,2-dioxetane and two diastereomeric diendoperoxides [72,73], as shown in Scheme 12. The stereospecific labeling of the anti methyl by deuterium in compound 24 to produce substrate 25 was required in order to study the syn/anti stereoselectivity of the ene products. 

Most reports on diastereoselective oxidation of sulfides are substrate-directed. Diastereoselectivity has been achieved by either steric- or neighboring-group participation.21 Incipient hydrogen bonding between the substrate hydroxyl group and the incoming percarboxylic acid has been evoked to explain the high diastereoselectivity observed in the oxidation of 10-exo-hydroxy-bornyl- derivatives 7 and 9 (Scheme 1). The oxidation of 9 with m-CPBA in MeOH occurs without stereoselectivity. 

In the following epoxidation step, m /a-chlorobenzoic acid (w-CPBA) has the choice to attack the 10,11-double bond or the 13,14-double bond. Because a hydrogen bond between the alcohol at C-9 and the peracid stabilizes the transition state 80, only the 10,11-double bond is epoxidized. In addition, this hydrogen bond also directs the attack to come from the same side as the alcohol and thus leads to a high substrate-controlled stereoselectivity. 

Stereoselective allylation of secondary radicals is possible when a suitable steric bias is present. For example, the thiocarbonyl compound 41 reacts to give exclusively the exo allylated product 42, in which allyl tributylstannane approaches from the less-hindered convex face of the cyclic radical (4.40). In acyclic substrates high stereoselectivity can be achieved by chelation with a Lewis acid. For example, allylation of the selenide 43 is much more stereoselective in the presence of trimethylaluminium, in which the aluminium alkoxide chelates to the carbonyl group to give the species 44, such that the approach of the allyl stannane is directed to the less hindered face (4.41). 

Once we realized that the substrate-directed arylation strategy could promote a rapid increase in the structural complexity of the allylic acetates, we decided to apply it in the total synthesis of biologically active kavalactones, represented by compound 18 in Scheme 7. The key step would be the stereoselective arylation of the substrate 19, which would lead us directly to the core skeleton of these natural products. 

In summary, the stereoselective arylation of allylamine derivatives was accomplished by a substrate-directed Heck-Matsuda strategy. The data we obtained from these studies suggest that the origin for the regiocontrol in favor... 

This methodology was also applied to the stereoselective arylation of substituted cyclic compounds to provide highly complex aryl-substituted cyclo-pentene scaffolds with total control of the double bond position. This unique substrate-directed Heck-Matsuda reaction was applied in the total synthesis of the SlPi agonist VPC01091 (130). 

Based on the results of coupling reaction of tosylhydrazones and aryl halides, Barluenga et al. further achieved a one-pot process directly from linear or cyclic carbonyl compounds in the presence of 1.1 equiv. of tosyUiydrazide with catalyst Pd2(dba)3-Xphos (Fig. 7) [89], In this reactimi, tosyUiydrazone is produced in situ and subjected to the subsequent reaction without separation. Compared with the reaction starting from pre-formed tosylhydrazones, the scope of ketone substrates and stereoselectivity of products do not exhibit any obvious difference. Moreover,... 

The direct goal of stereochemical strategies is the reduction of stereochemical complexity by the retrosynthetic elimination of the stereocenters in a target molecule. The greater the number and density of stereocenters in a TGT, the more influential such strategies will be. The selective removal of stereocenters depends on the availability of stereosimplifying transforms, the establishment of the required retrons (complete with defined stereocenter relationships), and the presence of a favorable spatial environment in the precursor generated by application of such a transform. The last factor, which is of crucial importance to stereoselectivity, mandates a bidirectional approach to stereosimplification which takes into account not only the TGT but also the retrosynthetic precursor, or reaction substrate. Thus both retrosynthetic and synthetic analyses are considered in the discussion which follows. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

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