Auxiliaries, chiral amino alcohols

One of the early syntheses of orlistat (1) by Hoffmann-La Roche utilized the Mukaiyama aldol reaction as the key convergent step. Therefore, in the presence of TiCU, aldehyde 7 was condensed with ketene silyl acetal 8 containing a chiral auxiliary to assemble ester 9 as the major diastereomer in a 3 1 ratio. After removal of the amino alcohol chiral auxiliary via hydrolysis, the a-hydroxyl acid 10 was converted to P-lactone 11 through the intermediacy of the mixed anhydride. The benzyl ether on 11 was unmasked via hydrogenation and the (5)-7V-formylleucine side-chain was installed using the Mitsunobu conditions to fashion orlistat (1). 

Although some reactions of electrophilic animation of phosphorus-stabilized anions had already been reported in the literature [5a,d], the first example of such a stereoselective reaction opening access to optically active a-amino phosphonic acids was described in 1992 by Denmark and co-workers [45] and by Jommi and co-workers [46]. Both of these groups used chiral amino alcohols as auxiliaries for diastereo-selective induction in the animating process. Denmark and co-workers chose trisyl azide (2,4,6-triisopropylbenzenesulfonyl azide) as equivalent of NHJ , whereas Jommi and co-workers performed the reaction with DTBAD. 

Another chiral auxiliary used in diastereoselective addition reactions is the 1,3-oxazine derivative 4a which shows a close structural resemblance to the 1,3-oxathiane 16 (vide supra). However, in contrast to the oxathiane, 4a cannot be readily acylatcd in the 2-position. Therefore, the benzoyl derivative 4b was prepared by condensing amino alcohol 3 with phenylglyoxal. 

A number of chiral alcohols and amino alcohols have been applied as auxiliaries to enolates. The induction may be explained by the shielding of one of the faces of the cnolate by a bulky alkoxy or aryl substituent. Representative examples, together with the results in diastereoselec-tive 1,4-additions with different Michael acceptors, are given in the following. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

In some cases the yields were poor due to competing deprotonation of the substrate by the organolithium reagent. Deprotonation was the predominant reaction with methyllithium or when (Z)-2-(l-alkenyl)-4,5-dihydrooxazoles were employed. The stereochemical outcome has been rationalized as occurring from a chelated transition state. The starting chiral amino alcohol auxiliary can also be recovered without racemization for reuse. 

A new chiral auxiliary based on a camphor-derived 8-lactol has been developed for the stereoselective alkylation of glycine enolate in order to give enantiomerically pure a-amino acid derivatives. As a key step for the synthesis of this useful auxiliary has served the rc-selective hydroformylation of a homoallylic alcohol employing the rhodium(I)/XANTPHOS catalyst (Scheme 11) [56]. 

Hydride reductions of C = N groups are well known in organic chemistry. It was therefore obvious to try to use chiral auxiliaries in order to render the reducing agent enantioselective [88]. The chiral catalyst is prepared by addition of a chiral diol or amino alcohol, and the active species is formed by reaction of OH or NH groups of the chiral auxiliary with the metal hydride. A major drawback of most hydride reduction methods is the fact that stoichiometric or higher amounts of chiral material are needed and that the hydrolyzed borates and aluminates must be disposed of, which leads to increased costs for the reduction step. 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

The reduction of phenyl mesityl ketone was studied with LAH modified with amino alcohols 65 to 72 in ether (the ratio LAH alcohol ketone = 1.1 1.1 1) (83). Optical yields were modest, with the highest 39%, obtained with 65 as the chiral auxiliary reagent. It was observed that there is a relationship between the preferred enantiomeric product and the structure and absolute configuration of the carbons carrying the hydroxy and amino groups. Thus the threo... 

Ager, D. J. Prakash, L Schaad, D. R. (1996) 1,2-Amino Alcohols and Their Heterocyclic Derivatives as Chiral Auxiliaries in Asymmetric Synthesis., Chem. Rev., 96, 835-876... 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

The phenylalanine-derived oxazolidinone featured here enjoys three practical advantages over the valine-derived oxazolidinone developed earlier in this laboratory. First, both the intermediate g-amino alcohol and the derived oxazolidinone are crystalline solids which can be purified conveniently by direct crystallization. Second, the oxazolidinone contains a UV chromophore which greatly facilitates TLC or HPLC analysis when it is employed as a chiral auxiliary. Finally, both enantiomers of phenylalanine are readily available, enabling stereocontrol in either sense simply by using the oxazolidinone derived from the appropriate enantiomer. 

Chiral (3-amino alcohols are important building blocks for the preparation of chiral auxiliaries, ligands, and natural products (for reviews on the asymmetric synthesis and use of vicinal amino alcohols, see [44-47]). Catalytic enantioselective... 

To recover the chiral auxiliary, the aqueous phases are made basic with 2 M sodium hydroxide. After extraction with dielhyl ether, the amino alcohol is recycled in >80% yield. 

It has been shown that the S-amino alcohol (—)-3-exo-(dimethylamino)isobomeol (DAIB) serves as an excellent chiral auxiliary in the enantioselective addition of Ft2Zn to aldehydes. As a model compound for the anticipated intermediate, the structure of MeZn(DAIB) (142) in the solid state was determined by X-ray crystallography. In the... 

The (R)-enantiomer of (242) has also been prepared and used as a chiral auxiliary in an enantioselective aldol synthesis of (+)-(S )-gingerol (79CB3703). (R )-Glutamic acid (246) was thus converted into (i )-pyroglutamic acid by simply heating in water. Conversion of (247) to its methyl ester and LAH reduction delivered alcohol (248). Ethyl nitrite treatment of (248) gave nitrosoamine (249), which was methylated to furnish (250). Exposure of (250) to LAH completed the synthesis of the required chiral auxiliary RAMP [(R)- l-amino-2-(methoxymethyl)pyrrolidine]. The hydrazone (252), derived from RAMP and acetone, was... 

Organometallic compounds asymmetric catalysis, 11, 255 chiral auxiliaries, 266 enantioselectivity, 255 see also specific compounds Organozinc chemistry, 260 amino alcohols, 261, 355 chirality amplification, 273 efficiency origins, 273 ligand acceleration, 260 molecular structures, 276 reaction mechanism, 269 transition state models, 264 turnover-limiting step, 271 Orthohydroxylation, naphthol, 230 Osmium, olefin dihydroxylation, 150 Oxametallacycle intermediates, 150, 152 Oxazaborolidines, 134 Oxazoline, 356 Oxidation amines, 155 olefins, 137, 150 reduction, 5 sulfides, 155 Oxidative addition, 5 amine isomerization, 111 hydrogen molecule, 16 Oxidative dimerization, chiral phenols, 287 Oximes, borane reduction, 135 Oxindole alkylation, 338 Oxiranes, enantioselective synthesis, 137, 289, 326, 333, 349, 361 Oxonium polymerization, 332 Oxo process, 162 Oxovanadium complexes, 220 Oxygenation, C—H bonds, 149... 

The amino alcohol-catalyzed enantioselective addition of dialkylzincs to aldehydes, detailed in Chapter 5 (27), is accomplished with polymer catalysts containing DAIB, a camphor-derived auxiliary, and other chiral amino alcohols (28). Reactions that involve matrix isolation of the catalyst not only result in operational simplicity but also greatly facilitate understanding of the reaction mechanism. In solution, the catalytic chiral alkylzinc alkoxide derived from a dialkylzinc and DAIB exists primarily as dimer (27) however, when immobilized, its monomeric structure can be maintained. 

Imines with an adjacent chiral auxiliary undergo diastereoselective addition of organometallic reagents in a similar fashion, as discussed above (equation 122)487. The products are readily converted into enantiomeric /J-amino alcohols, which are useful in further synthetic sequences or the target moiety in some natural products. Other such syntheses have been performed via additions to both imines488-490 and the related hydrazone moiety491-493. 

While f -amino alcohols have been widely studied as chiral auxiliaries, a series of (S)-amino alcohols - built into norbornane frameworks - have been examined as catalysts of enantioselective addition of dialkylzincs to benzaldehydes.236... 

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