Diastereoselective Diels-Alder Reactions Using Chiral Auxiliaries

4 Diastereoselective Diels-Alder Reactions Using Chiral Auxiliaries 

Other optically active alcohols have been employed as auxiliaries in diastereoselective, auxiliary-controlled Diels-Alder cycloaddition reactions. Helm-chen has pioneered the use of pantolactone as a chiral auxiliary that has the ability to form chelates with appropriate Lewis acids [64, 65]. Thus, treatment of 106 with isoprene and TiCl4 furnished 108 as a 97 3 mixture of dia-stereomers (Equation 8) [65]. The Ti chelate 107 was proposed as a key intermediate, leading to superb levels of asymmetric induction in the cycloaddition. 

Esters have also been investigated as chiral controlling groups on the diene partner. Trost documented the use of dienes such as 110, incorporating a mandelic acid ester as the chiral auxiliary (Equation 9) [66]. Excellent face selectivity was observed in the Diels-Alder reaction between 110 and ju-glone (109), giving the product 111 with high diastereoinduction ( 97 3) and in 98 % yield. 

The most successful and widely employed auxiliaries are without question those of Evans, namely, chiral oxazolidinones, such as 119 (Equation 11) [5, 70]. In studies involving their application in diastereoselective Diels-Alder cycloaddition reactions, Et2AlCl was identified as the optimal Lewis acid. Interestingly, it was noted that the use of more than one equivalent of Et2AlCl had a profound positive effect both on the reaction rate and the stereoselectivity. Evans has proposed that the presence of excess Et2AlCl leads to a dis- 

17 Diels-Alder and Hetero-Diels-Alder Reactions 

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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. 

The 3-acyl-2(3F/)-oxazolones function as good dienophiles in cycloaddition reactions with cyclic 2,4-dienes such as cyclopentadienes and anthracenes. Thus, the thermal reaction of 3-acetyl-2(37/)-oxazolone with cyclopentadiene and the hexachloro and hexamethyl derivatives gives endo-cycloadducts exclusively. In particular, the chiral cycloadducts 221 and 223 derived from the diastereoselective Diels-Alder reactions of 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazo-lones with hexamethylcyclopentadiene and 9,10-dimethylanthracene, respectively, are highly useful as chiral 2-oxazolidinone auxiliaries. The conformationally rigid roofed structures play a crucial role in affording excellent chiral induction (Fig. 5.54). 

Both enantiomers of lactic acid (2-hydroxypropanoic acid) are natural products and easily obtained by biotechnological methods, so there is no need for their synthesis in the laboratory. Even their esters with alkanols, e.g.. 1, are comparatively inexpensive and, therefore, convenient starting materials for derivatization to chiral reagents and auxiliaries. If necessary, such esters can be obtained by any convenient esterification technique. O-Acylated derivatives of lactic esters have been used very successfully as chiral auxiliaries in diastereoselective Diels-Alder reactions (Section D.1.6.1.1.1.1.2.). The acrylate 2 and methacrylate 31-3 and the fu-marate 43 give very high enantiomeric excesses. These are obtained from the lactic ester by treatment with an acid chloride. 

The recent explosion in the development of asymmetric strategies for organic synthesis has fostered investigations into the discovery of methods for enantioselective and diastereoselective Diels-Alder reactions. Some early forays into this field focused on the use of chiral auxiliaries covalently attached to one of the reaction partners however, nearly all recent investigations have centered on developing chiral catalysts. The multitude of new catalysts spans the range of Lewis acids and Bronsted acids and bases as well as metal-based and organic molecules. 

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... 

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... 

Asymmetric Diels-Alder reactions. Unlike methyl crotonate, which is a weak dienophile, chiral (E)-crotonyl oxazolidinones when activated by a dialkylaluminum chloride (1 equiv.) are highly reactive and diastereoselective dienophiles. For this purpose, the unsaturated imides formed from oxazolidinones (Xp) derived from (S)-phenylalanol show consistently higher diastereoselectivity than those derived from (S)-valinol or (IS, 2R)-norephedrine. The effect of the phenyl group is attributed in part at least to an electronic interaction of the aromatic ring. The reactions of the unsaturated imide 1 shown in equation (I) are typical of reactions of unsaturated N-acyloxazolidinones with cyclic and acyclic dienes. All the Diels-Alder reactions show almost complete endo-selectivity and high diastereoselectivity. Oxazolidinones are useful chiral auxiliaries for intramolecular Diels-Alder... 

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

At Tokyo College of Pharmacy [284], esters of 2-(trifluoromethyl)propenoic acid were used to synthesise 16,16,16-trifluororetinal (Eq. 101). Intermolecular Lewis acid-catalysed Diels-Alder reaction with a pantolactone chiral auxiliary allowed the diastereoselective construction of the core cyclohexenone portion with the quaternary centre set in the desired absolute configuration. 

The chiral boron complex prepared in situ from chiral binaphthol and B(OPh)3 is utilized for the asymmetric aza-Diels-Alder reaction of Danishefsky s diene and imines [67] (Eq. 8A.43). Although the asymmetric reaction of prochiral imine affords products with up to 90% ee, the double asymmetric induction with chiral imine by using oc-benzylamine as a chiral auxiliary has achieved almost complete diastereoselectivity for both aliphatic and aromatic aldimines. This method has been successfully applied to the efficient asymmetric synthesis of anabasine and coniine of piperidine alkaloides. 

Ghosh has also shown that cis- l-(arylsulfonamido)-2-indanols could be used as excellent chiral auxiliaries in Diels-Alder reaction.85 Reaction of 80 with cyclopentadiene using a variety of Lewis acids led to 81 in good yield, with endo. exo ratios superior to 99 1 and diastereoselectivities ranging from 72% to 92%. The best selectivities were observed using titanium tetrachloride as the Lewis acid. The high degree of diastereoselection was presumed to result from effective metal chelation (Scheme 24.17). 

Saigo and co-workers reasoned that, by analogy, high levels of diastereofacial discrimination could be achieved in the Lewis acid-mediated Diels-Alder reaction of dienes with oxazolidinone 108-derived dienophiles. Indeed, excellent regioselectivities (endo. exo) and diastereoselectivities were reached in the Diels-Alder reaction of 109 with cyclic and acyclic dienes using Et2AlCl as the activator (Scheme 24.28).107 The selectivities obtained actually surpassed those reported with cis-1 -amino-2-indanol 1 as the chiral auxiliary (93% de) (see Scheme 24.16).82 The additional bulk... 

For the diastereoselective hetero Diels-Alder reaction of carbonyl compounds using removable chiral auxiliaries, intensive studies of the uncatalyzed... 

Numerous further chiral imines activated by electron-withdrawing substituents have been investigated in order to carry out stereoselective aza Diels-Alder reactions. In these studies, Bailey et al. have recently introduced the use of two inducing stereocenters in the imine. This approach proved to yield excellent diastereoselectivities thus, imine 3-12 bearing a (,R)-8-phenylmenthyl auxiliary gave the essentially pure cycloadduct 3-13 upon hetero Diels-Alder reaction with cyclopentadiene (Fig. 3-4) [194-196]. 

After having developed a reliable route to the enantiopure carboxylic acid 4a, we next turned our attention to gain access to the enantiopure decalin fragment. One of the most efficient approaches to this structural motif is the intramolecular Diels-Alder reaction. The first systematic studies in the racemic series were performed by Roush and co-workers in 1981 (Roush and Hall 1981). Evans (Evans et al. 1984, 1988) and Oppolzer (Oppolzer and Dupuis 1985) showed that chiral auxiliaries in combination with strong Lewis acids allowed the generation of the endo adducts with excellent diastereoselectivities (Scheme 5). Recently, chiral Lewis acid catalysts were successfully used by Evans (Evans et al. 1999) and Corey (Zhou et al. 2003). 

Diels-Alder Reactions. Chiral a,p-unsaturated imides participate in Lewis acid-promoted Diels-Alder cycloaddition reactions to afford products in uniformly excellent endo/exo and endo diastereoselectivities (eq 50 and 51). Unfortunately, this reaction does not extend to certain dienophiles, including methacryloyl imides, p,3-dimethylacryloyl imides, or alkynic imides. Cycloadditions also occur with less reactive acyclic dienes with high diastereoselectivity (eq 52). Of the auxiliaries surveyed, the phenylalanine-derived oxazolidinones provided the highest diastereoselectivities. This methodology has been recently extended to complex intramolecular processes (eq 53). In this case, use of the unsubstituted achiral oxazolidinone favored the undesired diastereomer. 

Cycloadditions. Oppolzer first used this chiral acrylate derivative as an auxiliary in the Diels-Alder reaction with cyclopen-tadiene. Promotion by Lewis acids such as TiCU SnCU, and Et2AlCl provides the adduct in greater than 90% de (eq 1). Lithium perchlorate-promoted [4 + 2] reaction between 1 and 1-acetoxybutadiene was similarly effective." More recently, an exo-selective Diels-Alder addition of 1 with 2-acylamino dienes provided a single diastereomer in 80% yield. Cyclopentane formation is possible through exposure of 1 to methylenecyclo-propane and Ni(0) (eq 2). An example of a higher-order cycloaddition with 1 gave only low diastereoselection (78 22) for the endo product. 

Diastereoselective acylnitroso Diels-Alder reactions were performed using enantiopure hydroxamic acids derived from camphor and a-amino acids as chiral auxiliaries (Equation 90) <1997JOC3806, 1998T10537, 2003TL4571>. 

In order to obtain an insight into the diastereoselectivity in the Diels-Alder reaction of acetylenic sulfinates, chiral (+)-trans-2-phenylcyclohexanol [35] was used in place of cyclohexanol in the synthesis of the dienophile. A 1 1 dia-stereoisomeric mixture of acetylenic sulfinates 69 and 70 was obtained. After separation, each diastereoisomer was subjected to a Diels-Alder reaction with cyclopentadiene. Although the reaction once again occurred readily at room temperature, to our disappointment an inseparable mixture of diastereomeric adducts (3 2 by NMR) was obtained for each sulfinate. Apparently, a more spatially demanding chiral auxiliary needs to be incorporated into the dienophile in order to generate chiral sulfinates which cycloadd with prominent diastereoselectivity. 

The studies reported last year on the stereoisomeric control of the photo-induced Diels Alder reaction of maleic anhydride with homo-chiral anthracene derivatives such as (46) have been extended using 320-400 nm radiation, and this gives the head-to-tail anthracene dimer as well as the previously reported adduct (47) with excellent diastereoselectivity. The thermal and photochemical retroaddition process has been examined and the results suggest that this facile process may promote the anthracene as a new chiral auxiliary. 

Chiral Auxiliaries for Diels-Alder Reactions The highly ordered cyclic TS of the Diels-Alder reaction permits design of reactants and catalysts that lead to a preference between diastereomeric or enantiomeric adducts. (See Section 2.4) to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve diastereoselectivity is to install a chiral auxiliary. The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature and the greater stereoselectivity, the best diastereoselectivity is often observed in Lewis acid-catalyzed reactions. Chiral esters and amides of acrylic acid are particularly useful because the chiral auxiliary can be easily recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. 

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