1,4-addition auxiliary-controlled

An interesting approach to zr n.v-2,3-disubstituted cyeloalkanones is offered by auxiliary controlled intramolecular Michael additions. The diastereoselectivity depends on the chiral alcohol used193> l94. When the borneol derivative 7 was used as substrate, a single diastereomer of 8 resulted when the reaction was performed at 25 "C under thermodynamic control with a catalytic amount of sodium hydride in benzene. 

The application of auxiliary control in the asymmetric Michael addition of chiral enolates derived from ketones is rare the only example known is the use of (27 ,37 )-2,3-butancdiol as an auxiliary. The ketal of (27 ,37 )-2,3-butanediol with 3-methyl-l,2-cyclohexanedione reacts with 3-buten-2-one using as base a catalytic amount of sodium ethoxide in ethanol195. 

To minimize damage due to power outage, the Celanese Corporation in their plant at Newark, N.J., instituted a policy of always generating half its own power. Merck Company installed additional auxiliary steam power to insure constant refrigeration for its biochemicals at its West Point, Pa., plant. At Allied Chemical s phenol plant in Frankfort, Pa., electric devices on air compressors and pumps were replaced by steam-operated controls, and diesel generators were installed to maintain cooling water circulation. 19... 

Normally where it is necessary, fireproofing is preferred over water spray for several reasons. The fireproofing is a passive inherent safety feature, while the water spray is a vulnerable active system that requires auxiliary control to be activated. Additionally the water spray relies on supplemental support systems that may be vulnerable to failures, i.e., pumps, distribution network, etc. The integrity of fireproofing systems is generally considered superior to explosion incidents compared to water spray piping systems. The typical application of water sprays in place of fireproofing is for vessel protection. 

The major disadvantage of the classical auxiliary-controlled 3,3-sigmatropic rearrangements is still the requirement of two additional chemical transformations the attachment and the removal of the auxiliary had always to be considered. The efficiency of these steps influences the usability of the whole sequence. 

Tab. 6.5. A selection of auxiliary controlled diastereoselective conjugate additions with organocopper reagents. (TMEDA = N,N,N, N -tetramethylethylenediamine, Piv = pivaloyl)... 

Selective labelling of the two diastereotopic methyl groups of i-leucine (144) has enabled their fates during secondary metabolic reactions to be elucidated [66]. Moreover, in the context of protein interactions, differentiation of the leucine pro-R and pro-S methyl groups in protein NMR spectra allows molecular recognition phenomena to be studied [67]. Recently, efficient routes to both forms of Relabeled leucine, based on application of an auxiliary-controlled stereoselective conjugate addition reaction (Scheme 6.27) have been described [68]. Thus, starting... 

Scheme 6.27. Auxiliary-controlled stereoselective cuprate addition as the key step for the construction of both diastereomeric forms of [5-"q-leucine 144.

The focus in this section is the electrophilic a-functionalization of 2,2-dimethyl-l,3-dioxan-5-one. Various reactions have been carried out, such as alkylations, aldol additions, Mannich reactions, and transition metal-catalyzed reactions. Conditions were described for diastereoselective transformations, or auxiliary controlled diastereoselective transformations, providing enantiomerically pure products, and enantioselectively catalyzed reactions using organo-catalysts. 

Apart from cyclic or acyclic transition state geometry further distinctions of diastereoselec-tion have to be made with respect to the way in which the chiral center is attached to the reactive site. The term auxiliary control is used if a chiral subunit, e.g., an alcohol or an amine, is fixed covalently to the unsaturated substrate and then removed by bond cleavage after the addition. In contrast, if the stereogenic center remains part of the molecule after the addition, the term substrate control is applied (these definitions are given in Section A. 1.). 

Until recently only a few examples of stereoselective alkylation reactions of localized carban-ions which proceed under auxiliary control have been reported. The reason is obviously to be found in the difficulty of generating such carbanions having no additional stabilization and, if generated, in the low nucleophilicity of these strongly basic reagents. 

Formulations are optimized with additives to control granule strength, dissolution, chemical stability, viscosity, stability on storage, or fungal growth. They can also contain toning dyes and auxiliaries to improve their efficiency in a given application. 

The osmylation of l-[Af-methylphenylsulfoximinomethyl]-l-hydroxy-2-cyclopentenols and -2-cyclohexenols, obtained in turn from the corresponding 2-cycloalkenones by the addition of lithiated, V,.S -dimethyl-5-phenylsulfoximine, occurs from the same side as the sulfoximino functionality with complete Ik topicity. Subsequent thermal elimination of the sulfoximine group allows the synthesis of optically pure 2,3-dihydroxycycloalkanones. This method can, therefore, be regarded as proceeding via an auxiliary-controlled osmylation92-93. 

The majority of the reported examples are diastereoselective conjugate additions (Section 7.3.1.). This section has been organized into reactions where the chiral information is located on the nucleophile (Section 7.3.1.1.), on the electrophile (Section 7.3.1.2.), or on both the nucleophile and the electrophile (Section 7.3.1.3.). Further division has then been made, i.e., substrate-controlled vs. auxiliary-controlled diastereoselective reactions, and subdivision according to whether the reactions are inter- or intramolecular in nature. 

Auxiliary-Controlled Intermolecular Diastereoselective Conjugate Addition... 

Auxiliary-Controlled Intramolecular Diastereoselective Conjugate Addition of /V-Nucleophiles... 

Auxiliary-Controlled Diastereoselective Conjugate Addition to Chiral a,/ -Unsaturated Compounds... 

Several enantioselective approaches to vitamin E (1), based on resolution of the products, the use of enantiopure natural building blocks, auxiliary controlled reactions and asymmetric oxidations have been described. In addition, a palladium-catalyzed asymmetric allylic alkylation reaction to build up the chiral chroman framework has been employed by Trost. Tietze and coworkers have developed asymmetric syntheses of the chiral chroman moiety using either the selective ally-lation of an alkyl methyl ketone or a Sharpless dihydroxylation as the key step. However, none of these methods is efficient enough for an industrial approach. ... 

The synthesis of the C1-C9 fragment 120 began with an auxiliary controlled aldol reaction of the chloroacetimide 121, where chlorine is present as a removable group to ensure high diastereoselectivity in what would otherwise have been a non-selective addition (Scheme 9-39). The Lewis acid-catalyzed, Mukaiyama aldol reaction of dienyl silyl ether 122 with / -chiral aldehyde 123 proceeded with 94%ds, giving the 3-anti product 124, as predicted by the opposed dipoles model [3]. Anti reduction of the aldol product and further manipulation then provided the C1-C9 fragment 120 of the bryostatins. 

Other approaches to the bryostatins have also used enantio- or diastereoselective aldol reactions. An interesting iterative strategy for the synthesis of the Cj-Cg polyacetate region 134 has been disclosed where each aldol addition proceeds with excellent stereocontrol (99 1) under the catalytic influence of oxazaborolidine 135 (Scheme 9-42) [60J. Finally, a moderately selective, auxiliary controlled, acetate aldol reaction has been used for the introduction of the C3 stereocenter of the bryostatins giving adduct 136 (84% d.s) [61]. 

Diastereoselective conjugate radical additions to control stereochemistry at the P center has been approached in a number of ways. Chiral auxiliaries have been exploited on the radical trap as well as the radical itself, producing products with high diastereoselectivities in both cases. 1,2-Selectivity has been induced by the... 

The most intensely studied aldol addition mechanisms are those beUeved to proceed through closed transition structures, which are best understood within the Zimmerman-Traxler paradigm (Fig. 5) [Id]. Superposition of this construct on the Felkin-Ahn model for carbonyl addition reactions allows for the construction of transition-state models impressive in their abiUty to account for many of the stereochemical features of aldol additions [50a, 50b, 50c, 51]. Moreover, consideration of dipole effects along with remote non-bonding interactions in the transition-state have imparted additional sophistication to the analysis of this reaction and provide a bedrock of information that may be integrated into the further development and refinement of the corresponding catalytic processes [52a, 52b]. One of the most powerful features of the Zimmerman-Traxler model in its application to diastereoselective additions of chiral enolates to aldehydes is the correlation of enolate geometry (Z- versus E-) with simple di-astereoselectivity in the products syn versus anti). Consequently, the analyses of catalytic, enantioselective variants that display such stereospecificity often invoke closed, cyclic structures. Further studies of these systems are warranted, since it is not clear to what extent such models, which have evolved in the context of diastereoselective aldol additions via chiral auxiliary control, are applicable in the Lewis acid-catalyzed addition of enol silanes and aldehydes. 

---