Ester Auxiliaries

Several studies have focussed on the use of chiral esters as auxiliary groups in radical transformations. Perhaps the most comprehensive survey of auxiliary groups was reported by Snider and collaborators in their pioneering examination of Mn(llI)-promoted radical cyclization reactions of fi keto amides and esters [34]. The selectivities obtained in cyclization generally mirror those observed in inter-molecular addition reactions. These examples again illustrate that the models developed for intermolecular radical reactions can apparently be applied successfully to intramolecular additions (cyclizations). Selectivity for the conversion of 34 to 35 

A recently reported synthesis of (-l-)-triptophenolide illustrates the utility of this auxiliary in radical reactions [37]. The key step in the synthesis, outlined in Fig. 6, is a lanthanide triflate-promoted oxidative radical cyclization of an 8-phenylmenthyl keto ester mediated by Mn(OAc)3. The product of the radical cyclization is formed in excellent yield and selectivity in the presence of ytterbium triflate. The Lewis acid presumably locks the p keto ester in a syn orientation. The configuration of the transformation can be understood based upon a transition state arrangement as shown in 36. 

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The most commonly applied ot,p-unsaturated ester auxiliary is the menthol group. It is inexpensive and easy to handle. Several different menthyl 2-alkenoates (157), in particular acrylates, have been applied in 1,3-dipolar cycloaddition reactions (Scheme 12.51). The major drawback of the menthyl ester auxiliary in 1,3-dipolar cycloadditions are the poor selectivities often associated with these reactions, except for reactions with azomethine ylides. 

Heathcook et al. have performed a diastereoselective aza-ene reaction using chiral di-(+)-menthyl diazenedicarboxylate 91 as the nitrogen source [54]. Compound 91 was found to react with various alkenes in the presence of 2 equiv. SnCl4, and the corresponding allylic aminated product was obtained in good yield and with de up to 42 %. The problem with this approach was the removal of the chiral menthyl ester auxiliary, which was found to be rather difficult. 

The concept of using an ester auxiliary which also contains a handle suitable for chelation was first disclosed in 1984/1985. Thus TiCU-promoted addition of cyclopentadiene to the acrylate of ethyl (S)-lactate (379) proceeded readily at -63 C to give (with a 39 1 endolexo preference) a 93 7 mixture of norbomenes (381a) and (382a), from which the major product (381a) was isolated by MPLC (Scheme 93, Table 23, entry 1). Mild saponification of adduct (381a) with LiOH in aqueous THF and purification via iodolactonization/elimination provided pure (l/ ,2/ )-5-norbomene-2-carboxylic acid. 

Pietruszka, J., and With A., Enantiomerically pure cyclopropylboronic esters. Auxiliary- versus substrate-control, J. Chem. Soc., Perkin Trans. 1, 4293, 2000. 

Comparison of Schemes 77 and 79 reveals that the topological interaction of the two menthyl ester groups is fundamentally different in [4 + 2] additions of fumarates (308) compared with those of methylenemalonates (318). In the latter, both ester auxiliaries cooperate in terms of activating the dienophiile through formation of a stable chelate (319) but their individual stereoface biases in (319) are reversed. However, the observed ir-face discrimination can be rationalized by assuming that the C-2,C-3 moiety of cyclopentadiene is more bulky than the 5-CH2 group so that orientations c and d are favored over orientations a and b. Consistent with this hypothesis, no asymmetric induction could be achieved on addition of (318 R = H) to cyclohexadiene, which has comparably bulky C-2.C-3 and C-5.C-6 moieties. 

The f.Z-diene of the seco acid 2 would result from Horner-Emmons and Wittig reactions from aldehyde 3 (Scheme 2). The trimethoxyaniline functionality is carried along as a stable nitrobenzene that would be unmasked at a late stage prior to macrolactam formation. The syn methoxy-hydroxy functionality at C6-7 in 3 is installed using the newly developed glycolate aldol reaction with enal 4 and norephedrine glycolate ester auxiliary 5. This new method is an application of Masamune s recent work with propionate norephedrine aldol reactions.The CIO methyl is installed using the aforementioned hydroboration reaction,... 

Diastereoselective complexation of the latter cases (144a) proceeded with only modest selectivity for the former cases (144b) selectivity varied with solvent and temperature. The best case (dr, 97 3) utilized a matched enantiopure allyl tosylate with a menthyl ester auxiliary. Finally, in a few cases the addition of HFe(CO)3(NO) across diene has also proved successful in the synthesis of (143). ... 

One of the most common auxiliaries is menthyl, where an acrylic acid derivative is attached to menthol to form a menthyl ester, 255. Morrison and Mosher22l showed that asymmetric induction is possible with 255 when it reacts with cyclopentadiene to give diastereomers 256 and 257, 22 as shown in Table 11.13.221 in the absence of a Lewis acid, however, the % ee is rather poor. Similarly, (-)-dimenthyl fumarate (258) reacted with butadiene to give 259 and 260, after reduction of the ester products with lithium aluminum hydride. Hydride reduction of esters (sec. 4.2.B) is a common method for removing ester auxiliaries. The work of... 

The (S)-amino acid methyl ester auxiliary results in the (li ,45) configuration of the fused bicyclic products the (i )-configured auxiliary produces the (15,47 ) bridgehead stereochemistry. The observed stereochemistries are explained by assuming a compact dienophile conformation where the ester carbonyl is proximal to the imine group. The subsequent approach of the diene is governed by secondary orbital interactions with the ester carbonyl and steric interactions from the amino acid side-chain (see Scheme 2.1). 

Another approach to conduct asymmetric conjugate addition reactions has been the use of ester auxiliaries derived from chiral alcohols [81]. Oppolzer [82, 83] reported a notable example using unsaturated esters such as 68 derived from (-)-8-phenylmenthol [84] (Equation 14) [82]. The addition of phenylcopper to 68 was catalyzed by BF3-OEt2 [70] and afforded the acid 70 in > 99 % ee after saponification. Analysis of the stereochemical outcome led to the suggestion that the observed induction results from addition to the exposed olefin face in conformer 69 [82], which is favored because of stabilizing orbital overlap between the enone and aromatic groups [85]. 

Czamik et al." studied the auxiliary-assisted copper(II)-ion catalysed hydrolysis of acrylate esters... 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

Aziridination remains less well developed than epoxidation. Nevertheless, high selectivity in inline aziridination has been achieved through the use of chiral sulfi-nimines as auxiliaries. Highly successful catalytic asymmetric aziridination reactions employing either sulfur ylides or diazo esters and chiral Lewis acids have been developed, although their scope and potential applications in synthesis have yet to be established. 

There has been some investigation of auxiliary-controlled cycloadditions of azir-ines. Thus, camphor-derived azirine esters undergo cycloaddition with dienes, with poor diastereoselectivity [70]. The same azirines were also observed to react unselectively with phenylmagnesium bromide. Better selectivities were obtained when Lewis acids were used in the corresponding cycloaddition reactions of 8-phe-nylmenthyl esters of azirine 2-carboxylates (Scheme 4.48) [71]. The same report also describes the use of asymmetric Lewis acids in similar cycloadditions, but mediocre ees were observed. 

One of the first examples of this type of reaction, using a chiral alcohol as an auxiliary, was the asymmetric synthesis of 2-hydroxy-2-phenylpropanoic acid (atrolactic acid, 3, R1 =C6H5 R3 = CH3) by diastereoselective addition of methyl magnesium iodide to the men-thyl ester of phcnylglyoxylie acid4,5 (Table 22). 

The tartramide-based reagents, 10-allyl-3,6-dibenzyl-9,ll-dioxa-3,6-diaza-10-borabicyclo[6.3.0]-undecane-2,7-diones, are significantly more enantioselective than the parent tartrate ester derivatives7lb 73. Unfortunately, they have poor solubility at — 78 =C and consequently reactions times are long and conversions are often poor. The full scope of this tartramide reagent system awaits the development of a more soluble auxiliary. 

Compared to the lithium enolates of l and 5, the higher stereoselectivity obtained by the Mukaiyama variation is, in general, accompanied by reduced chemical yields. The chiral alcoholic moieties of the esters 3 and 7 can be removed either by reduction with lithium aluminum hydride (after protection of the earbinol group) or by aqueous alkaline hydrolysis with lithium hydroxide to afford the corresponding carboxylic acid. In both cases, the chiral auxiliary reagent can be recovered. 

Corey s auxiliary reagent 10 is also applied in order to obtain a f/-2-bromo-3-hydroxy-carboxylic esters in enantiomeric purities of 91-98%. The a-bromo esters thus obtained are useful intermediates for the preparation of a-unsubstituted /Miydroxy esters as well as for 2-amino-3-hydroxy- and 3-amino-2-hydroxycarboxylates64a b. 

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. 

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