Auxiliary Groups

The frequent use of chiral controller or auxiliary groups in enantioselective synthesis (or diastereoselective processes) obviously requires the addition of such units retrosynthetically, as illustrated by the antithetic conversion 34 =i> 35. 

In the synthesis of polymers it is very important to control the configuration of the multiple stereogenic centers but free radical methods generally fail to give significant stereochemical control (96T(52)4181). To compare the effects of several chiral and achiral auxiliary groups, acrylamides of type 110 were studied. 

The chiral auxiliary group is removed in an immolative" way by Bacycr-Villiger oxidation of the major product, which is available as the pure diastereomer by HPLC in a 36% yield41. 

In addition to ketone enolates, azaenolatcs with chiral auxiliary groups attached to the nitrogen atom are suitable for the introduction of an a-unsubstituted enolate of the keto-type into an aldehyde in a stereoselective manner (see Section D.1.3.5.). 

R)- and (,S )-1.1,2-Triphenyl-l,2-ethancdiol which are reliable and useful chiral auxiliary groups (see Section 1.3.4.2.2.3.) also perform ami-sclcctive aldol additions with remarkable induced stereoselectivity72. The (/7)-diastercomer, readily available from (7 )-methyl mandelate (2-hy-droxy-2-phcnylaeetate) and phenylmagnesium bromide in a 71 % yield, is esterified to give the chiral propanoate which is converted into the O-silyl protected ester by deprotonation, silylation, and subsequent hydrolysis. When the protected ester is deprotonated with lithium cyclohexyliso-propylamide, transmetalated by the addition of dichloro(dicyclopentadienyl)zirconium, and finally reacted with aldehydes, predominantly twm -diastereomers 15 result. For different aldehydes, the ratio of 15 to the total amount of the syn-diastereomers is between 88 12 and 98 2 while the chemical yields are 71 -90%. Furthermore, high induced stereoselectivity is obtained the diastereomeric ratios of ami-15/anti-16 arc between 95 5 and >98 2. 

The removal of the carbohydrate auxiliary group and the hydrolysis of the amino nitriles is achieved by acidolytic cleavage of the hemiaminal /V-glycosidic bond and the concomitant acid-catalyzed solvolysis of the nitrile using either hydrogen chloride in formic acid or hydrogen bromide in acetic acid56 57. 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

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. 

Successful applications of these stereocontrolled conjugate additions have led to asymmetric syntheses of several natural products such as (+ )-cuparenone (39) which involves formation of a quaternary carbon center81, (- )-/ -vetivone (40)8° and steroidal equilenin 4182 the wavy lines in these structures indicate that C—C bond formed stereoselectively under the influence of a temporarily-attached stereogenic sulfoxide auxiliary group. 

Waldmann H. Amino Add Esters Versatile Chiral Auxiliary Groups for the Asymmetric Synthesis of Nitrogen Heterocycles Synlett 1995 133-141... 

In continuing efforts toward the development of other nontoxic insecticides, many new products are being synthesized and tested. The direction of the synthetic work is guided by the theory that the insecticidal activity of a given substance is due to the combined influence of a toxic nucleus and modifying auxiliary groups. To illustrate the theory, this paper presents information on six materials related to piperonyl butoxide, when tested in combination with pyrethrins. 

The classical method, which was followed to prepare the first example of an optically pure chiral organotin compound, is characterized by the use of a auxiliary chiral group necessary to convert the racemic mixture of enantiomers into a mixture of diastereomers which are then separated by a suitable physical method and converted back into the separated enantiomers by splitting off the chiral auxiliary group. This last step is sometimes difficult to achieve 34 ). 

The problems associated with the use of this classical method in organotin chemistry are essentially due to the fact that the carbon-tin bond can sometimes very easily be cleaved by electrophiles or by nucleophiles. The crucial step is therefore the elimination of the auxiliary group without the cleavage of any of the carbon-tin bonds. This cleavage could for instance not be achieved successfully in the case of /7-(z -propylmethylphenylstannyl)-N,N-dimethylaniline [formula (60) in... 

The cyclo-adducts were removed from the auxiliaries by reductive cleavage. The auxiliary group was readily re-functionalized and reused in subsequent... 

Synthesis of acid 129 starts from the commercially available 6-heptenoic acid (122), which upon reaction with (4S)-benzyloxazolidin-2-one (123) as the chiral auxiliary group yields the intermediate 124, hydroxymethylation of which affords compound 125. Hydrolysis of compound 125 followed by condensation with O-benzylhydroxylamine gives rise to the hydroxamate (126), which is then converted into (Claclam 127 via an intramolecular Mitsunobu reaction. Hydrolysis of the (Claclam 127 affords acid 128, which is subsequently formylated at the benzyloxyamine moiety to give the required intermediate acid (129) in quantitative yield, as depicted in Scheme 26. 

The addition of a-lithiomethoxyallene 144 [55] to benzaldehyde dimethylhydra-zone 145 (Eq. 13.48) leads to a mixture of pyrroline 146 and dihydroazete 147 [56]. The cydization in this case, which takes place in the same operation as the addition to the hydrazone, follows two distinct pathways, with attack of the nitrogen atom taking place at the inner, in addition to the terminal, carbon atom of the allene. A similar reaction of 144 with SAMP-hydrazone 148 (Eq. 13.49) leads to 3-pyrroline 149 in 88% yield and excellent diastereoselectivity [57]. Cleavage of the chiral auxiliary group from 149 takes place in two steps (1, methyl chloroformate 2, Raney nickel, 50 bar, 50 °C) in 74% overall yield. When the addition of 144 to 148 is conducted in diethyl ether, cydization of the adduct does not take place. Surprisingly, the hydrazones of aliphatic aldehydes react with 144 in poor yield in THF, but react quantitatively and diastereoselectively in diethyl ether to give the (uncyclized) allenyl hydrazone products. 

In 1988 Kunz and Pfrengle introduced the preparation of chiral amino acid derivatives by the U-4CR in the presence of 2,3,4,6-tetra-6)-pivaloyl- 3-D-galacto-pyranosylamine, 57, in the presence of ZnCl2-etherate as catalyst. They obtained excellent stereoselectivity and high yields of their products. One of the disadvantages of such U-4CRs is that only formic acid can be used as the acid component, and the auxiliary group of the products can only be removed by half-concentrated hot methanolic HCl. 

A few years later Goebel and Ugi formed a-aminoacid derivatives by the U-4CR with tetra-6)-aIkyl-l-glucopyranosylamines, 58, where any carboxylic acid component can participate. Lehnhoff and Ugi used the U-4CR with 1-amino-2-deoxy-2-Al-acetylamino-3,4,6-tri-6)-acetyl- 3-D-glucopyranose, 59, whose large variety of products could be formed stereoselectively in excellent yields. The desired selective cleavage of the auxiliary groups of these products was equally unefficient. 

Ross and Ugi" prepared l-amino-5-deoxy-5-thio-2,3,4-tri-6)-isobutanoyl-P-D-xylopyranose 61a from xylose via the 5-desoxy-5-thio-D-xylopyranose. The U-4CRs of this amine form a-aminoacid derivatives stereoselectively and in excellent yields. These products have the advantage that their products are stable and their auxiliary group 5-desoxy-5-thio-D-xylopyranose can be cleaved off selectively by mercury(II) acetate and trifluoroacetic acid. The expected steric structure of the corresponding U-4CR product was confirmed by X-ray measurement. 

Since Ugi is now an emeritus and he and his co-workers cannot continue their experimental studies, we propose that the analog l-amino-5-desoxy-5-thio-D-xylopyranose 61b should be prepared and be used as a reagent of U-4CRs. It has a good chance to form stereoselectively high yields of products whose auxiliary group can be selectively removed. 

The first diastereoselective synthesis of a tetrahydrothiophene derivative was reported by Karlsson and Hdgberg (32,95). The parent ylide la was added to a variety of C,C-dipolarophiles (79) bearing (—)-(15)-2,10-camphorsultam as the chiral auxiliary group to exclusively give trans-cycloadducts 80a,b with high diastereoselectivity [diastereomeric ratio (dr) 9 1], (Scheme 5.28). 

In this context, a logical inconsistency in relation to auxiliaries must be pointed out. Frequently the configuration of the auxiliary group, i.e., after attachment of the auxiliary compound, is given by the optical rotation of the auxiliary (compound), e.g., (—)-menlhyl group instead of (17 )-menthyl group. This practice can lead to serious errors and must be avoided. 

The carbocupration of (5./ ,77 )-l-cthyl-5,7-dimcthyl-4,8-dioxaspiro[2.5]oct-l-ene, a cyclo-propene carrying an auxiliary group, gave a 96 4-mixture of two diastereomeric addition products for which the relative configuration at the newly formed stereogenic centers had to be determined (see p 479)123. 

Removal of the Auxiliary Group and Determination of the Absolute Configuration... 

Removal of the auxiliary group from 12 (see p413) to give 13 followed by several steps yields (-)-(65)-tetrahydro-6-undecyl-2//-pyran-2-one (14), a pheromone of the wasp Vespa orientalis. Comparison of the optical rotation of the synthetic product with that of the natural product served to confirm the stereochemistry of the initial reduction to 12. 

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