Group-selective reactions

Compounds with asymmetric centers can be obtained from prochiral starting molecules by either face-selective reactions [1] (stereoheterotopic facial addition) or group-selective reactions (stereoheterotopic ligand substitution). The transition states of these selective stereodivergent reactions must be diastereomeric, and the kinetics are the same as those of parallel reactions with different products (enantiomers or diastereo-mers). The selectivity in the stereoselective event leading to the different transition states can never be exceeded by the final yield of the major stereoisomer. 

Interligand asymmetric induction. Group-selective reactions are ones in which heterotopic ligands (as opposed to heterotopic faces) are distinguished. Recall from the discussion at the beginning of this chapter that secondary amines form complexes with lithium enolates (pp 76-77) and that lithium amides form complexes with carbonyl compounds (Section 3.1.1). So if the ligands on a carbonyl are enantiotopic, they become diastereotopic on complexation with chiral lithium amides. Thus, deprotonation of certain ketones can be rendered enantioselective by using a chiral lithium amide base [122], as shown in Scheme 3.23 for the deprotonation of cyclohexanones [123-128]. 2,6-Dimethyl cyclohexanone (Scheme 3.23a) is meso, whereas 4-tertbutylcyclohexanone (Scheme 3.23b) has no stereocenters. Nevertheless, the enolates of these ketones are chiral. Alkylation of the enolates affords nonracemic products and O-silylation affords a chiral enol ether which can... 

Group selective reactions of divinyl carbinols. It is important to remember that the reagent control strategy is inapplicable to situations where the resident chirality is on the allylic position bearing the hydroxyl handle for the catalyst. However, the pref-... 

The first example of an enantioselective intramolecular cascade Mizoroki-Heck-cyanation sequence was recently reported which included the reaction of amide 104 (Scheme 12.24) [33], The cyanide source employed was potassium ferro(II)cyanide, which has been utilized for the palladium-catalysed cyanation of aryl halides. The proposed reaction pathway for the Mizoroki-Heck-cyanation involves capture of a a-alkylpalladium intermediate. Previous examples of enantioselective Mizoroki-Heck cyclization-anion capture most often involve trapping of the 7r-allylpalladium complexes in group-selective reactions. Reaction conditions were surveyed for the Mizoroki-Heck cyanation sequence. It was found that Pd(dba)2 afforded better enantioselectivities than Pd(OAc)2 with Ag3P04 as the additive. Using PMP under neutral conditions led to racemic product. To improve the enantioselectivity, several bidentate ligands were screened, and the ligand DIFLUORPHOS 54a was found to give the best enantioselectivity. 

As was the case for kinetic resolution of enantiomers, enzymes typically exhibit a high degree of selectivity toward enantiotopic functional groups. Selective reactions of enantiotopic groups provide enantiomerically enriched products. Thus, the treatment of a racemic material containing two enantiotopic functional groups is a means of effecting resolution. Most successful examples reported to date have involved hydrolysis. Several examples are outlined in Scheme 2.10. 

Another interesting feature of Bowden s system is its ability to act as an active membrane to carry out functional group-selective reactions. The PDMS matrix is hydrophobic, which allows organic molecules to diffuse in, but prevents ionic substances from doing so. In two separate experiments shown in Scheme 5.11, incorporated catalyst 4 was added to a mixture of methanol and water (90 10) containing two different diene substrates (135-136) that readily undergo RCM. In the first reaction, sodium hydroxide was added to deprotonate substrate 135, while in the second, /)-toluenesulfonic acid (PTSA) was added to help facilitate the diffusion of 135 into the PDMS matrix. Under the basic conditions of the first reaction, no formation of 137 was observed, whereas substrate 136 reacted to... 

Asymmetric intramolecular carbopalladation is an effective reaction for producing enantioenriched polycycles. Most examples are intramolecular Heck reactions. One seminal example from natural product synthesis is the 5-exo carbopalladation of eneamide 201 to oxindole 202 (after acid treatment) from a total synthesis of ( )-physostigmine 203 (Scheme 31).The reaction occurs in 84% yield with 95% ee, which is remarkably efficient for the construction of a quaternary center. Reaction conditions that favor the neutral manifold of the Heck reaction are employed. Examination of the scope of the oxindole synthesis and mechanistic analysis have appeared. " Group selective reactions are also powerful reactions in carbopalladation asymmetric synthesis.From a synthesis of (+)-vemolepin 206, alkenyl triflate 204 is... 

Wang Z, Deschenes D. Enantiospecific synthesis via sequential diastereofacial and diastereotopic group selective reactions enantiodivergent synthesis of syn-l,3-polyols. J. Am. Chem. Soc. 1992 114 1090-1091. 

Inoue T, Kitagawa O, Saito A, Taguchi T. Catalytic asymmetric iodocarbocyclization reaction of 4-alkenylmalonates and its application to enantiotopic group selective reaction. J. Org. Chem. 1997 62(21) 7384-7389. 

CFIDF end group, no selective reaction would occur on time scales above 10 s. Figure B2.5.18. In contrast to IVR processes, which can be very fast, the miennolecular energy transfer processes, which may reduce intennolecular selectivity, are generally much slower, since they proceed via bimolecular energy exchange, which is limited by the collision frequency (see chapter A3.13). 

Application of class reactions. The apphcation of selected reactions that indicate the presence or absence of certain functional groups, with due regard to the indications provided by tests 1, 2 and 3, will locate the class (or classes) to which the compound belongs or wUl, at least, serve to eliminate all but a few classes to which the compound can be assigned. 

Functional group selectivity is often easy to achieve in reduction and condensation reactions since several highly selective reagents for reduction and for protection offunctional groups are available. 

Aminophenols. Reaction of chloroformate with aminophenols (qv) also takes place at the more reactive amino group selectively. Thus (9-aminophenol [95-55-6] gives benzoxazolone [59-49-4] by cyclization of the intermediate carbamate (31). 

Many other examples are known of non-selective reactions of halo groups in pyridopyridazines with amines, alkoxides, sulfur nucleophiles such as hydrosulfide and thiolate ions, or thiourea, hydrazine(s), cyanide ion and dimethyl sulfoxide, or on catalytic reduction. 

In the following example the acetonide protective group is selectively converted to one of two t-butyl groups. The reaction appears to be general, but the alcohol bearing the t-butyl group varies with structure.Benzyli-dene ketals are also cleaved. 

The sulfhydiyl group in cysteine can be selectively protected in the presence of the amino group by reaction with 2,4-dinitrophenol at pH 5-6. ... 

Substitution, addition, and group transfer reactions can occur intramolecularly. Intramolecular substitution reactions that involve hydrogen abstraction have some important synthetic applications, since they permit functionalization of carbon atoms relatively remote from the initial reaction site. ° The preference for a six-membered cyclic transition state in the hydrogen abstraction step imparts position selectivity to the process ... 

However, treatment of cortisone 3,20-bissemicarbazone with acetic anhydride and pyridine removes the 20-semicarbazone group preferentially. Selective removal of a protecting group can be also achieved by a selective reaction to give a new intermediate which can be converted into the desired product ketone. Thus progesterone 20-monoenol acetate (42) is prepared from the 3,20-bisenol acetate (40) via selective electrophilic attack of iodine at C-6 followed by reductive dehalogenation of (41). ... 

This approach to carbonyl protection uses the relative differences in basicity and the differences in steric effects to protect selectively either the more basic carbonyl group or the less hindered carbonyl group from reactions with nucleophiles such as DIB AH and MeLi. ... 

In comparing the reactivity at different positions in a heterocycle, a poly-substituted derivative is sometimes used with the idea that selective reaction of the same leaving group at different positions in a single molecule gives the most clear-cut answer. However, in a polychloroazine, the mutual activation of the chlorines by one another is not identical (unless the molecule is symmetrical, in which case the... 

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