Chiral dienophiles, diastereoselective

FIGURE 4.35 Some diastereoselective examples using chiral dienophiles. 

Chiral dienophiles, prepared from an aldehyde and asparagine in water followed by reacting with acryloyl chloride, reacted with cyclopentadiene at room temperature in water or ethanol-water to provide cycloadducts diastereoselectively and chiral products upon separation and hydrolysis (47-64% ee for the endo isomers endo/exo 82 18) (Eq. 12.18).61... 

As mentioned in the previous section, chiral dienophile 17 is highly enantiose-lective and meets the criteria for double asymmetric induction. A set of asymmetric reactions have been performed by Masamune s group using 49 as an achiral diene and (S)/(R -methyl mendelates (S)/(R)-51 as chiral dienes.2a The Diels-Alder reaction between (,S)-17 and 49 exhibits the high diastereoselective potential of 17. As shown in Scheme 5-17, in the presence of a catalytic amount of BF3 Et20, the reaction of (.S )-17 and 49 gives compound 50 as the major product with a diastereoselectivity of over 100 1. The reaction of (S )-17 with... 

When comparing these results with those previously obtained using carbohydrate-based vinyl ethers as chiral dienophiles, this improved facial diastereoselectivity to heterodienes under similar conditions is noteworthy.81 The efficient chiral transfer in the second example might mostly be attributed to the specific architecture of the l,2 5,6-di-0-isopropylidene-a-D-glucofuranose moiety.Those findings open the way to develop well-defined spiro-carbohydrate templates towards improved auxiliaries for chirality transfer in a wide range of syntheses. 

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... 

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). 

A more readily available Fe-complex for asymmetric Diels-Alder reaction is from chiral hydrobenzoin.Dienophiles derived from f7/ ,61 )-l-pivaloyloxyspiro[4.4]nonan-6-ol 5 give chiral adducts on reaction with dienes. A representative of axially chiral dienophiles is 65 which gives Diels-Alder reactions with high endo- and diastereoselectivity. An access to dihydropyranyl ethers by the hetero-Diels-Alder reaction, C2-syiiunetric Cu(II) complexes such as and yttrium tri[(7 )-l,l -binaphth-2,2 -diyl]phosphonate are... 

Fukuzawa and coworkers reported the rare earth (III) salt-catalyzed asymmetric Diels-Alder reaction of cyclopentadiene with a chiral dienophile in SCCO2 [112]. The Diels-Alder reaction in SCCO2 proceeded rapidly to give the corresponding adducts with higher diastereoselectivities than those in CH2CI2 (Scheme 7.41). 

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

The chiral alcohols are mainly employed as esters or enol ethers. Esters with carboxylic acids can be obtained by any convenient esterification technique. Dienol ethers were obtained by transetherification with the ethyl enol ether of a 1,3-diketone, followed by Wittig reaction8 silyldienol ethers were obtained by the method of Danishefsky11-12 and simple enol ethers by mercury-catalyzed transetherification13. Esters and enol ethers have been used as chiral dienophiles or dienes in diastereoselective Diels-Alder reactions (Section D. 1.6.1.1.1.1.). (R)-l-Phenylethanol [(R)-4] has been used for enantioselective protonation (Section C.) and the (S)-enantiomer as chiral leaving group in phenol ethers for the synthesis of binaphthols (Section B.2.) the phenol ethers are prepared as described for menthol in the preceding section. (S)-2-Octanol [(S)-2] has found applications in the synthesis of chiral allenes (Section B.I.). 

Unlike lactic acid, mandelic acid (7) occurs in nature only in small amounts and is therefore more expensive. Formerly, it was obtained by resolution of the racemate with a chiral base, such as l-phenylethylamines or ephedrine6, but enantioselective reductions of a-oxo-a-phenylacetic acid by chemical or biochemical methods have become feasible (Section D.2.3.I.). Esters of mandelic acid, e.g.. 8. can be prepared by any convenient esterification technique (see. for example, refs 7 and 46) and have been used for enantioselective protonation reactions (Sections C. and D.2.I.). Similar to the corresponding lactic esters, fumaric acid derivatives 9 are obtained from the mandelic esters and used as chiral dienophiles in diastereoselective Diels Alder reactions (Section D. 1.6.1.1.1.2.2.1.). 

Chiral sulfoxides with a pyridine substituent 16 are useful chiral dienophiles (Section D. 1.6.1.1.1.1.2.2.). The synthesis starts with the (—)-menthyl ester of propynoic acid which undergoes addition of 2-pyridinethiol to the triple bond. The oxidation of the sulfur occurs with some diastereoselectivity and the isomers are separated by crystallization from hexane16. 

A diastereoselective Diels-Alder reaction of cyclopentadiene with a chiral dienophile, iV,iV -fumaroyldi[(2/ )-bornane-10,2-sultam], was carried out in scC02. The highest diastereoselectivity (65% conversion and 93% de) is obtained around the critical point (74 bar) at 33 C. Lanthanide triflate catalyzes the reaction of cyclopentadiene and 3-acryloyl-(4S)-isopropyloxazolidin-2-one 21 in SCCO2 to give the endo adduct endo exo = 10 30) with a higher diastereoselectivity (59% de) than in CH2CI2 (38-42% de) (Scheme 36). ... 

Asymmetric Diels-Alder reactions of the chiral dienophile 5-(alkyloxy)-5 /-2-furanone (D), derived fi om the chiral auxiliary 10, with a variety of dienes have been studied in toluene at 120°C. Thereby, diastereoselectivities up to 96% de were determined. From cyclic dienes with exocyclic or vinylic double bonds, such as (3), substituted decalins were obtained as optically pure cycloadducts. 

More recently, chiral Br0nsted bases have been employed along with chiral dienophiles in the Diels-Alder reaction of 3-hydroxy-2-pyrone and give good levels of diastereoselectivity (vide infra). ... 

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),... 

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]. 

Scheme 65 Highly diastereoselective Cr(III)-catalyzed HDA reaction with chiral dienophile to access A ring fragment of bryostatins [119]...

Chiral 3-alkenoyl-l,3-oxazolidin-2-ones have been developed and used in highly diastereoselective Diels-Alder reactions by Evans et al. [26] (Scheme 1.34). In this reaction these dienophiles are highly reactive compared with the corresponding... 

Base-catalyzed Diels-Alder reactions are rare (Section 1.4). A recent example is the reaction of 3-hydroxy-2-pyrone (145) with chiral N-acryloyl oxazolidones 146 that uses cinchona alkaloid as an optically active base catalyst [97] (Table 4.25). Only endo adducts were obtained with the more reactive dienophile 146 (R = H), the best diastereoselectivity and yields being obtained with an i-Pr0H/H20 ratio of 95 5. The reaction of 146 (R = Me) is very slow, and a good adduct yield was only obtained when the reaction was carried out in bulky alcohols such as t-amyl alcohol and t-butanol. 

Diastereoselective Diels-Alder reactions with chiral sulfinyl derivatives as dienophiles under high pressure [88]... 

The alkenyl oxonium ion dienophiles generated from dioxolanes can be made diastereoselective by use of chiral diols. For example, acetals derived from anti-pentane-2,4-diol react under the influence of TiCl4/Ti(/-OPr)4 with stereoselectivity ranging from 3 1 to 15 1. 

Note Added in Proof. The stereochemistry of the Diels-Alder addition reactions shown in Scheme 1 to give products 20-22 has been examined by 400 MHz lH-NMR. These data indicate that the cycloadditions occur with a high degree of stereoselectivity (having diastereoselectivities of greater than 94 6). The chiral Fe environment of the dienophile 17 strongly influences the direction of the facial attack of the diene reactants. 

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... 

Oppolzer sultam-like chiral auxiliary (e.g., Xc in 304) has been studied in Diels-Alder cycloaddition reactions (Scheme 43) <2003JP0700>. The TiCU-promoted reaction of dienophile 304 and 1,3-cyclopentadiene 305 in DCM is complete within 18h and excellent diastereoselectivity of product 306 is observed. The same reaction in the absence of Lewis acid provides product 306 in very low yield. However, switching to trifluoroethanol as the solvent, the cycloaddition reaction proceeds to completion, albeit with slightly diminished levels of diastereoselectivity for Diels-Alder adduct 306. Surprisingly, the use of hexane as the solvent affords the opposite (23, J 31-diastereomer of 306 as the major product. 

The diastereoselective cycloaddition of 2-phenyl-4-dimethylamino-l-thia-3-azabuta-l,3-diene with a choice of dienophiles and in the presence of a Lewis acid provides a convenient route to 5,6-dihydro-4//-l,3-thiazines <2002TL6067, 2004T1827>. The more stable /ra r-adducts are produced exclusively. The approach using (4A)-3-acryloyl-4-benzyloxazolidin-2-one 198 provides access to the chiral 5,6-dihydro-4//-l,3-thiazine 199 <2004T1827>. The exceptional level of selectivity is only achieved when magnesium bromide is used. The chiral auxiliary was removed by reaction with lithium benzoxide to give the benzyl ester 200, and reaction with catalytic amount of samarium triflate and methanol provides the methyl ester 201 (Scheme 21). 2-Substituted-5,6-dihydro-l,3-thiazines are conveniently synthesized from nitriles or thiocyanates and 4-mercapto-2-methylbutan-2-ol to produce... 

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