Chiral dienophiles cycloaddition

Furanones are a class of chiral dienophiles very reactive in thermal cycloadditions. For example, (5R)-5-(/-menthyloxy)-2-(5H)-furanone (28) underwent Diels Alder reaction with cyclopentadiene (21) with complete re-face-selectivity (Equation 2.10), affording a cycloadduct which was used as a key intermediate in the synthesis of dehydro aspidospermidine [27]. 

Keywords carbonyl compounds, chiral dienophiles, chiral dienes, chiral catalysts, intramolecular cycloadditions, chiral Lewis acids... 

Cycloaddition. Recently )V-vinyloxazol id i nones were presented as new potential chiral dienophiles in inverse hetero-Diels-Alder reactions to activated 1-oxabutadienes, leading with high diastereocontrol to heteroadducts under Eu(fod)3-catalyzed conditions (Scheme 49).17... 

Chiral dienes or chiral dienophiles or chiral Lewis acid catalysts may be involved in cycloaddition reactions. When any two of these are combined double asymmetric induction operates111. Thus the chiral diene 223 and the optically active dienophile 224 (from D-mandelic acid) gave 225 in high de values, whereas the same diene and the enantiomeric dienophile 226 (from L-mandelic acid) — a mismatched pair—formed the diastereomeric cycloadduct 227 in only 4% de (equation 121)112. 

The 3-nitro analog was also synthesized by Isobe laboratory with the intention of using it a chiral dienophile in synthetic approaches to heterocyclic systems of natural products, based on highly stereoselective cycloaddition reactions. 

Chiral dienes have proved to be less popular in asymmetric Diels-Alder reactions than their chiral dienophile counterparts. This is primarily a result of the problem of designing a molecule that incorporates a chiral moiety, such as the formation of a chiral isoprenyl ether or vinyl ketene acetal.187-190 In addition, diastereoselectivities often are not high,54 191-199 as illustrated by the cycloaddition of the chiral butadiene 5 with acrolein (Scheme 26.4). Improved stereoselection is observed through the use of double asymmetric induction, although this is a somewhat wasteful protocol.35,54 177 200... 

In recent years several highly efficient asymmetric cycloadditions employing chiral oxabutadienes have been developed. The use of chiral dienophiles was less satisfying as shown for the cycloaddition of 2-162 to 2-120 to give the dihydro-pyran 2-163 (Fig. 2-46) [161c]. 

A recent study performed by Ghosez et al. deals with the use of unsaturated SAMP hydrazones as chiral 1-aza-1,3-butadienes for asymmetric cycloadditions [226]. In this investigation, the reaction of the chiral heterodiene 3-21 with N-methylmaleimide afforded the cycloadduct 3-22 in excellent induced diastereoselectivity (Fig. 3-7). Thus, the selectivities obtained are very promising, but the application of this method is restricted to highly reactive electron-deficient dienophiles. The complementary approach, an aza Diels-Alder reaction of an 1-aza-l,3-butadiene with a chiral dienophile.has been investigated by Waldner [227]. 

Basing on this investigation, 5-17 has been cycloadded to numerous chiral dienophiles in order to increase the asymmetric induction [430]. The use of chiral oxazolidinones allowed to obtain induced diastereoselectivities up to 92 % de. On the other hand, the complementary application of enantiopure, chiral thia- 1,3-butadienes introduced by Fishwick et al. has yielded very promising results [431]. Upon in situ generation of the chiral heterodiene 5-22 from 5-21, a completely exo-selective cycloaddition occurred in the presence of cyclopente-ne leading to the fused thiopyran 5-23 as a single diastereomer (Fig. 5-7). 

Cationic ansa metallocenes can be utilized as chiral catalysts in Diels-Alder reactions. For example, in the presence of the cationic zirconocene complex [(ebthi)Zr(Ot-Bu) thf]+, the [4 + 2] cycloaddition of acrolein and cyclopentadiene proceeds efficiently to afford endo and exo cycloadducts (equation 71). In reactions in which methyl acrylate is used as the dienophile, cycloadditions occur with lower levels of enan-tioselection (23% ee), but with significantly higher degrees of diastereoselectivity (17 1 endo, exo). In these processes, recent studies demonstrated the great influence of chiral metallocene structure and the dramatic solvent effect. ... 

Chiral Auxiliary for Cycloaddition Reactions. Cam-phanate ester (11) has been used as a chiral dienophile in cycloaddition reactions with substituted furans to produce 7-oxabicyclo[2.2.1]heptene derivatives (eq ). ... 

Diek-Alder Cycloadditions (Athene Six-Membered Cycloadduct) A-Enoylsultam derivatives were originally devised as activated chiral dienophiles for stereoselective Diels-Alder reactions. ... 

Asymmetric [4 + 2] cycloadditions of an optically active diene, or dienophile with chiral sulfinyl groups, with a quaternary sulfur center have succeeded in the LiC104-CH2CI2 medium. When chiral dienophile 66 and CP were subjected to cyclization, neither the endotexo ratio nor the enantiofacial selectivity of endo adducts was high [83], In the reaction of chiral diene 67 with MA, the best catalyst was LiC104-CH2CI2 this gave only endo isomers endo-6Sa and endo-6Sb in 70 % yield in the ratio of 96 4, presumably via TS-2 (Sch. 35) [84]. 

The application of cyclic carbohydrate derivatives as chiral dienophiles has been investigated by several groups. 2,3-Dideoxy-DL-pent-2-enopyranose-4-ulose (17) in the thermal [4+2] cycloaddition to the acyclic dienes 18a-c is reported to produce mixtures of cycloadducts 19a-c epimeric on the hemiacetal center with an all-as-configuration of the other newly formed bonds. The reaction with cyclopentadiene (10) and 1,3-cyclohexadiene (11) yields adducts 20 as the sole products31. It should be emphasized that epimerization may occur on the anomeric center during the protection step (as an equilibrium process), thus leading to a mixture of adducts, while the endolexo ratio remains the same. 

Nonauxiliary-Controlled Dienophiles Cycloaddition to Chiral Aldehydes... 

Figure 6.15. Natural products synthesized using asymmetric cycloadditions to chiral dienophiles as the key stereodifferentiating step sarkomycin [167,195] brefeldin A [168] (of the 3 stereocenters formed in the asymmetric acrylate/cyclopentadiene cycloaddition, the indicated stereocenter is the only one retained) 0-methyl loganin aglycone [196] bilabolide [197] yohimbine [198].

Asymmetric Diels-Alder reactions. Single-sited coordination of chiral dienophiles (e.g., the acrylate of ti-pantolactone) confers diastereoselectivity to the cycloaddition. 

The Diels-Alder reaction of 2-azadienes also benefits from the presence of an electron-donating substituent, to enhance the reactivity with electron-deficient dienophiles. Cycloaddition with alkynyl dienophiles and aromatization leads to substituted pyridines (3.54). Silyloxy-substituted 2-azadienes such as 68 are effective dienes and have been used to prepare substituted 2-pyridones and piperidones after methanolysis (3.55). Asymmetric hetero Diels-Alder reactions with the chiral Lewis acid catalyst 66 provide access to the piperidone products with very high enantioselectivity. ... 

Reactions of dienes containing optically active auxiliary groups have not been so widely studied as those of chiral dienophiles. There are, however, examples of the use of various chiral auxiliaries attached to either C-1 or C-2 of the diene. The 1-substituted diene 130, derived from mandelic acid, undergoes cycloaddition with dienophiles in the presence of boron trifluoride or boron triacetate (3.94). With the dienophile juglone, the adduct 131 was formed with virtually complete asymmetric induction. The absolute configuration of the product corresponds to reaction of the diene in the conformation in which one face of the diene is shielded by the phenyl substituent. 

This type of reaction has been explored in detail as the chemical character of the conjugated system and reactivity of levoglucosenone is highly suitable for functionalization though cycloaddition reactions. Horton s laboratory (43,44) was the first to explore the potential of levoglucosenone as a chiral dienophile in Diels-Alder cycioadditions. 

Nonracemic a,P-unsaturated p-tolylsulfoxide dienophiles bearing an electron-withdrawing group in the a-position have been employed successfully in Diels-Alder cycloadditions [28,29,94,133], although less frequently than their 3-substituted counterparts. Koizumi and coworkers have reported the use of optically active 2-p-tolylsulfinylacrylate (188) as a chiral dienophile which exhibits high reactivity and diastereoselectivity in cycloaddition reactions with anthracene and cyclopentadiene (Scheme 5.62), affording cycloadducts (189) and (190),... 

Direct Wittig reaction of Ph PCHCOn,Me with the four unsubstituted D-aldopentoses followed by acetylation provides convenient preparative access to acyclic seven-carbon trans-2.3-unsaturated sugar derivatives. These products served as dienophiles for a detailed comparative study in Diels—Alder cycloaddition with cyclopentadiene. Related syntheses afforded analogous cis-dienophiles. Cycloaddition under uncatalyzed thermal conditions gave mixtures of the four possible stereoisomeric norbornene adducts. The endo, exo ratios, and diastereofacial selectivities of the adducts were determined by NMR spectroscopy and by chemical transformations, supplemented by selected X-ray crystallographic analyses. Different distributions of isomers were encountered when a Lewis acid was used to catalyze the cycloaddition. The reaction can be controlled to provide preparative access to selected isomers and thus constitutes a versatile method for chirality transfer from the precursor sugar to four new asymmetric centers in a carbocyclic framework. 

Chiral substituents in dienophiles can be used to make Diels-Alder reactions enantioselective. Some examples of chiral dienophiles that have been used successfully are collected in Scheme 6.2. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid catalyzed reactions, the best enantioselectivity is often observed in the catalyzed reactions. Chiral esters and amides of acrylic acid are particularly useful because the chiral auxiliary can be easily recovered by hydrolysis of the adduct. The cycloaddition proceeds to give two diastereomeric products, which can be separated and purified. Hydrolysis then gives enantiomerically pure carboxylic acid. 

As one of the pioneering works on asymmetric synthesis, Evans and coworkers reported diastereoselective Diels-Alder reaction of acryloyl oxazolidinones mediated by Et2AlCl [140]. Intramolecular version of this cycloaddition was also reported, in which interesting stereochemical difference depending on substituents at oxazo-lidinone ring was found. As an another excellent example, Oppolzer and coworkers reported diastereoselective Diels-Alder reaction of chiral dienophiles equipped with camphorsultam auxiliary [141]. Recently, these diastereoselective reactions were applied to enantioselective synthesis of ceralure Bl, known as Mediterranean fruit fly attr actant (Scheme 6.118) [142]. 

In a similar fashion, chiral dienophile 59 underwent cycloaddition with 2-methoxyfuran under high-pressure conditions [49]. The resulting mixture of endolexo adducts (dr for both > 98 2) was dihydroxylated and subsequently transformed into acetonide 61. Conversion of 61 into crotonate ester 62 followed by acid hydrolysis gave the antibiotic (-)-COTC 63 (Scheme 13.19) [49]. 

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