Desymmetrization bonds

Among recently described new Pd-catalysed enantioselective reactions, the ring opening of meso oxabicyclic alkenes with dialkyl zinc reagents in the presence of chiral P/P and P/N ligands reported by Tautens el al. constitutes a synthetically outstanding C-C bond-forming desymmetrization reaction. 

Formal hydration of the double bond appeared by the hydroboration-oxidation sequence. Desymmetrization reactions with catalytic asymmetric hydroboration are not restricted to norbornene or nonfunctionalized substrates and can be successfully applied to meso bicyclic hydrazines. In the case of 157, hydroxy derivative 158 is formed with only moderate enantioselectivity both using Rh or Ir precatalysts. Interestingly, a reversal of enantioselectivity is observed for the catalytic desymmetrization reaction by exchanging these two transition metals. Rh-catalyzed hydroboration involves a metal-H insertion, and a boryl migration is involved when using an Ir precatalyst (Equation 17) <2002JA12098, 2002JOC3522>. 

Recently, Krische and co-workers developed an effective protocol for the catalytic desymmetrization and parallel kinetic resolution of enone-diones via tandem conjugate addition-aldol cyclization (Scheme 66).150 This transformation, involving enantioselective rhodium-catalyzed conjugate addition methodology, enabled the formation of two C-G bonds and four contiguous stereogenic centers from simple precursors with high diastereo- and enantiocontrol. 

Desymmetrization, which refers to a process of efficiently desymmetrizing maw-molecules or achiral molecules to produce chiral ones, is a versatile method for preparing chiral nonracemic molecules.90 Desymmetrization of meso-compounds generally leads to the formation of a C-C or a C-X (X is a hetero atom) bond. The reaction normally uses a functional group residing on the symmetric element (in most cases the C2 axis or a plane) to differentiate two (or more) symmetrically equivalent functionalities elsewhere within the substrate molecule. This work was first reported by Hoye et al.91 and Mislow and Siegel92 in 1984. 

In addition to its utility in the enantioselective formation of C-0 bonds (cf. Scheme 15), Trost s chiral ligand 102 has been used in the catalytic asymmetric synthesis of C-N bonds. An impressive application of this protocol is in the enantioselective total synthesis of pancrastatin by Trost (Scheme 17) H9i Thus, Pd-catalyzed desymmetrization of 112 leads to the formation of 113 efficiently and in > 95 % ee. The follow-up use of the N3 group to fabricate the requisite cyclic amide via isocyanate 117 demonstrates the impressive versatility of this asymmetric technology. 

Catalytic asymmetric desymmetrization as a field is still growing, with new applications appearing weekly. It is evident that advances in this subfield have kept in step with advances in catalysis as a whole. Some spectacular successes have been reported in recent years, and this strategy has been applied to many new reactions. Willis mentions in conclusion to his 1999 review of this field that desymmetrization reactions involving catalytic enantioselective construction of C—C bonds are... 

The addition of large linear blocks to dendrons with opposite polarity creates a desymmetrized structure predisposed to sequester insoluble components by aggregation rather than intramolecular hydrogen-bonding. Amphiphilic, linear-dendritic diblock (AB) and triblock (ABA) copolymers self-assemble into multimolecular micelles with CMC values that are well below those of low molecular weight surfactants. Typically, a hydrophilic linear block such as PEG is attached to the focal point... 

Azacycles can also be constructed by C-C bond construction. The enantiomerically-pure amide 8 is easily prepared by photolysis of pyridine followed by acetylation and enzymatic desymmetrization. 

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

SE.3.1.2. Desymmetrization of gem-Dwarboxylates An equivalent of asymmetric carbonyl addition can be achieved by the alkylation of gem-dicarboxylates (Scheme 8E.17). The alkylation of gem-dicarboxylates, which are easily prepared by the Lewis acid-catalyzed addition of acid anhydrides to an aldehyde, converts the problem of differentiating the two enantiotopic 7t-faces of a carbonyl group into that of asymmetric substitution of either enantiotopic C-O bond of the gem-dicarboxylate. Although asymmetric induction may be derived from enantio-discrimination in the ionization step or in the alkene coordination step, the fast and reversible nature of alkene coordination suggests that the ionization step is more likely to be the source of enantio-discrimination. 

Asymmetric epoxidation, dihydroxylation, aminohydroxylation, and aziridination reactions have been reviewed.62 The use of the Sharpless asymmetric epoxidation method for the desymmetrization of mesa compounds has been reviewed.63 The conformational flexibility of nine-membered ring allylic alcohols results in transepoxide stereochemistry from syn epoxidation using VO(acac)2-hydroperoxide systems in which the hydroxyl group still controls the facial stereoselectivity.64 The stereoselectivity of side-chain epoxidation of a series of 22-hydroxy-A23-sterols with C(19) side-chains incorporating allylic alcohols has been investigated, using m-CPBA or /-BuOOH in the presence of VO(acac)2 or Mo(CO)6-65 The erythro-threo distributions of the products were determined and the effect of substituents on the three positions of the double bond (gem to the OH or cis or trans at the remote carbon) partially rationalized by molecular modelling. 

The desymmetrization of dicarbonate 206 was initiated by the addition of one equivalent of N-(3-butenyl) nosylamide 207 under palladium catalysis in the presence of Trost s chiral diphosphine ligand 205. When the first allylic substitution was completed, the reaction was warmed and the resulting intermediate 208 was treated in situ with one equivalent of a second nosylamide 209. Product 210 resulting from this double substitution reaction was submitted to a tandem intramolecular ROM/RCM to furnish key precursor 211, which was engaged in the final cyc-lization step by the reduction of the double bonds, followed by the HCl-promoted domino deprotection of the acetal and aminal formation. 

Olefin metathesis does not generate stereogenic centers, however, the reaction may be employed in the desymmetrization of prochiral (poly)olefins of the kinetic resolution of racemates. In the example depicted in Scheme 17, a trialkene is desymmetrized, and the preference for the cyclization reaction with one of the two symmetry-equivalent C = C double bonds leads to the enantioselective formation of the reaction product, a chiral dihydrofuran. The following principal conclusions can be drawn from this study ... 

Most of the inherently chiral calix[5]arenes described up to now, owe their chirality, however, to the asymmetric substitution pattern at the narrow rim, and due to the lack of other general, selective derivatization reactions are derived from 1,2-or 1,3-crown ethers. Both compounds possess a symmetry plane and can be desymmetrized by a single O-alkyl or O-acyl residue in position 3 (=5) or 4 (=5).151,152,153 In practice, 1,2-crown ethers 79 were prepared from mono-O-alkyl derivatives by reaction with the appropriate ditosylates, while 80 was obtained from the 1,3-crown-ether by subsequent O-alkylation or O-acylation using a weak base to benefit from the fact, that the first deprotonation leads to a hydrogen-bonded (4/5)monoanion. The picolyl derivatives 79 (n = 2) were resolved by HPLC... 

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