Chiral auxiliaries diastereoselective reactions

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with (-)-8-phenylmenthyl a-chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8-29). When this (-)-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided dia-stereomers of (2J ,3J )-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%. 

By use of a chiral auxiliary, diastereoselective aziridination could also be achieved [69]. Reaction of chiral N-enoylbornane[10,2]sultams with N-aminophthalimide in the presence of lead tetraacetate in CH2CI2 proceeded smoothly and afforded excellent yields of the corresponding N-phthalimidoaziridines with high diastereomeric excess (Scheme 13.48) [69a]. 

The [4 + 2] cycloaddition of 1-methoxy-l,3-butadiene (8) to (2/ )-/V-glyoxyloylbornane-10,2-sultam (7) leads to crystalline, easily separable adducts 9-12. In a noncatalyzed reaction (room temperature and high pressure) the diastereoselectivity obtained is moderate, but higher than that obtained when (-)-(/ )-menthol and (-)-(/ )-8-phenylmenthol arc used as chiral auxiliaries. The reaction is already catalyzed by very mild Lewis acids Eu(fod), yields adduct 9 with an excellent selectivity exceeding a d.r. 96 433. 

Copper(II) salts are efficient one-electron oxidants for the generation of radicals from lithium enolates [1]. This concept was successfully applied for the oxidative coupling of ketones or amides 36 to afford the corresponding 1,4-dicarbonyl compounds 37 in good yield [17]. If an optically active imidazolidinone is used as chiral auxiliary, the reaction exhibits an excellent simple and induced diastereoselectivity (Scheme 12). 

Lewis acid-mediated asymmetric Diels-Alder reactions between 2H-azirines 59, bearing chiral auxiliaries, with enophiles such as 60 afforded mixtures of bicyclic aziridine-2-carboxylates 61 (Scheme 3.20) [68]. 8-Phenylmenthol appeared to be the auxiliary of choice in this reaction in terms of yield and diastereoselectivity. 

With chiral auxiliaries1,41 a remote chiral moiety is temporarily introduced into the substrate in order to direct the nucleophilic addition diastereoselectively. The chiral auxiliary can be removed from the initial addition product with complete conservation of the chirality of the desired product and also of the chiral auxiliary. The recovered chiral auxiliary can then be reused in further reactions. Therefore, chiral auxiliaries are used to chiralize an a priori achiral carbonyl substrate by the introduction of a covalently bound, but nevertheless easily removable, chiral source. 

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. 

Besides high effectiveness in the diastereoselective control of nucleophilic addition reactions, another major goal in the design of chiral auxiliaries is the use of readily available, chiral starting materials. The hexahydro-l//-pyrrolo[l,2-c]imidazole derivatives 9a-e are examples which use the inexpensive amino acid L-proline (7) as starting material. 

The reaction of methyl 4-formyl-2-mcthylpentanoate and the chiral (Z)-2-butenylboronate clearly shows 52b-103, however, that the chiral auxiliary is not sufficiently enantioselective to increase the diastereoselectivity to >90% in either the matched [( + )-auxiliary] or mismatched [(—)-auxiliary] case. This underscores the requirement that highly enantioselective chiral reagents be utilized in double asymmetric reactions. 

A decisive improvement in the stereoselective performance of the Ugi reaction was achieved by the use of 1-ferrocenylalkylamines, in particular, l-ferrocenyl-2-methylpropylamine. as the inducing chiral auxiliary 18, S7. The iminc formed from the (/ )-enantiomer and isobutyralde-hyde reacts at — 78 °C with tm-butyl isocyanidc and benzoic acid to give the (S )-valine derivative with a diastereoselectivity of about 100 1. 

The addition reactions of alkyllithium-lithium bromide complexes to a-trimethylsilyl vinyl sulfones that have as a chiral auxiliary a y-mono-thioacetal moiety derived from ( + )-camphor are highly diastereoselective. A transition state that involves chelation of the organolithium reagent to the oxygen of the thioacetal moiety has been invoked. The adducts are readily converted via hydrolysis, to chiral a-substituted aldehydes22. 

The use of additives such as germanium can lead to highly diastereoselective reactions." Using chiral auxiliaries or chiral additives, good enantioselec-tivity can be achieved. 

The extent of diastereoselectivity observed in the reaction of l-(l-phenylalkoxy)buta-1,3-dienes with indantrione and alloxane is associated with the steric requirements of the alkoxy function in the chiral auxiliary <96SYN105>. 

McKervey and Ye have developed chiral sulfur-containing dirhodium car-boxylates that have been subsequently employed as catalysts for asymmetric intramolecular C-H insertion reactions of y-alkoxy-ot-diazo-p-keto esters. These reactions produced the corresponding ci -2,5-disubstituted-3(2H)-furanones with diastereoselectivities of up to 47% de. Moreover, when a chiral y-alkoxy-a-diazo-p-keto ester containing the menthyl group as a chiral auxiliary was combined with rhodium(II) benzenesulfoneprolinate catalyst, a considerable diastereoselectivity enhancement was achieved with the de value being more than 60% (Scheme 10.74). 

The stereogenic centers may be integral parts of the reactants, but chiral auxiliaries can also be used to impart facial diastereoselectivity and permit eventual isolation of enantiomerically enriched product. Alternatively, use of chiral Lewis acids as catalysts can also achieve facial selectivity. Although the general principles of control of the stereochemistry of aldol addition reactions have been well developed for simple molecules, the application of the principles to more complex molecules and the... 

Derivatives with various substituted sulfonamides have been developed and used to form enolates from esters and thioesters.137 An additional feature of this chiral auxiliary is the ability to select for syn or anti products, depending upon choice of reagents and reaction conditions. The reactions proceed through an acyclic TS, and diastereoselectivity is determined by whether the E- or Z-enolate is formed.138 /-Butyl esters give A-enolates and anti adducts, whereas phenylthiol esters give syn adducts.136... 

Scheme 2.6 shows some examples of the use of chiral auxiliaries in the aldol and Mukaiyama reactions. The reaction in Entry 1 involves an achiral aldehyde and the chiral auxiliary is the only influence on the reaction diastereoselectivity, which is very high. The Z-boron enolate results in syn diastereoselectivity. Entry 2 has both an a-methyl and a (3-benzyloxy substituent in the aldehyde reactant. The 2,3-syn relationship arises from the Z-configuration of the enolate, and the 3,4-anti stereochemistry is determined by the stereocenters in the aldehyde. The product was isolated as an ester after methanolysis. Entry 3, which is very similar to Entry 2, was done on a 60-kg scale in a process development investigation for the potential antitumor agent (+)-discodermolide (see page 1244). 

The highly ordered cyclic TS of the D-A reaction permits design of diastereo-or enantioselective reactions. (See Section 2.4 of Part A to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.80 The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best diastereoselectivity is observed in catalyzed reactions. Several chiral auxiliaries that are capable of high levels of diastereoselectivity have been developed. Chiral esters and amides of acrylic acid are particularly useful because the auxiliary can be recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. Early examples involved acryloyl esters of chiral alcohols, including lactates and mandelates. Esters of the lactone of 2,4-dihydroxy-3,3-dimethylbutanoic acid (pantolactone) have also proven useful. 

The following cycloaddition reactions involve chiral auxiliaries and proceed with a good degree of diastereoselectivity. Provide a rationalization of the formation of the preferred product on the basis of a TS. 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

The Davies group has described several examples of a rhodium-catalyzed decomposition of a diazo-compound followed by a [2+1] cycloaddition to give divinyl cyclopropanes, which then can undergo a Cope rearrangement. Reaction of the pyrrol derivative 6/2-51 and the diazo compound 6/2-52 led to the tropane nucleus 6/2-54 via the cyclopropane derivative 6/2-53 (Scheme 6/2.11) [201]. Using (S)-lactate and (R)-pari lolaclorie as chiral auxiliaries at the diazo compound, a diastereoselectivity of around 90 10 could be achieved in both cases. 

Dienes with Chiral Auxiliaries The use of dienes with the chiral auxiliary attached to the C-l position of the dienes is the most popular in asymmetric Diels-Alder reactions.59 In 1980, Trost reported high asymmetric induction in the Diels-Alder reaction using l-(S)-0-methylmandeloxy-l,4-butadiene59a However, the result obtained by Trost et al. has remained unique for more than a decade, at least in terms of enantioselectivity. The asymmetric Diels-Alder reaction of chiral diene-amines with nitroalkenes gives aminocyclohexenes with good diastereoselectivity (Eq. 8.37).60 The development in the area of chiral dienes is slow it may be due to the difficulty of preparing these compounds. 

At atmospheric pressure the Diels-Alder adducts of 1,4-benzoquinones are often not stable under the conditions of reaction and undergo an isomerization leading to the corresponding hydroquinones (Scheme 4). Due to the acceleration at high pressure the temperature of reaction can be lowered so that the secondary isomerization does not proceed and the primary Diels-Alder adduct can be isolated in good yields. The diastereoselectivity at high pressure induced by a chiral auxiliary, however, is with a diastereomeric excess of d.e. = 36%, only moderate. 

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