Chiral dienophiles derivatives

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

Entry 9 uses the oxaborazolidine catalysts discussed on p. 505 with 2-bromopropenal as the dienophile. The aldehyde adopts the exo position in each case, which is consistent with the proposed TS model. Entry 10 illustrates the use of a cationic oxaborazolidine catalyst. The chirality is derived from trans-1,2-diaminocyclohcxanc. Entry 12 shows the use of a TADDOL catalyst in the construction of the steroid skeleton. Entry 13 is an intramolecular D-A reaction catalyzed by a Cu-Ws-oxazoline. Entries 14 and 15 show the use of the oxazaborolidinone catalyst with more complex dienes. 

Cadogan and coworkers160 developed a fructose-derived l,3-oxazin-2-one chiral auxiliary which they applied in the Diels-Alder reactions of its iV-enoyl derivatives 246 with cyclopentadiene using diethylaluminum chloride as the Lewis acid catalyst. The reactions afforded mixtures of endo 247 and exo 248 (equation 68). The catalyst binds to the chiral dienophile in a bidentate fashion (co-ordination to both carbonyl groups). As a consequence, the dienophile is constrained to a rigid conformation which accounts for the almost complete diastereofacial selectivities observed. 

Vogel185 used 3-aza-6,8-dioxabicyclo[3.2.1]octane based chiral dienophiles to prepare anthracyclines and anthracycline derivatives. 

Prior to the advent of chiral catalysts, the most widely used approach to chiral adducts has involved the use of chiral dienophiles and, of these, acrylates, derived from a chiral alcohol or amine and acryloyl chloride, are the most common (Table 26.2).3 4... 

Although a large number of chiral dienophiles have been developed (Table 26.2), their ability to provide high asymmetric induction appears to be limited to specific dienes. However, there are some dienophiles that tolerate a wider variety of dienes including menthol derivatives,117 118 camphor derivatives,6 39 40 105 107-113 181 182 and oxazolidinones.120 165 183 184 It should be noted that even these auxiliaries would require an efficient recycle protocol for economic scale up. One exception is the use of sacrificial chiral oxazolidinones, which are relatively inexpensive. This approach has been used in the large-scale preparation of the base cyclohexane unit of Ceralure Bj.168 A procedure has been developed for the preparation of (75,25)-5-norbomene-2-carboxylic acid where the D-panta-lactone auxiliary can be recycled efficiently.185186... 

Diels-Alder Reaction. The Diels-Alder reaction of methacrolein with 1,3-dienol derivatives can also be catalyzed by the chiral BINOL-derived titanium complex BINOL-T1CI2. The endo adduct was obtained in high enantioselectivity (eq 15). The sense of asymmetric induction is exactly the same as observed for the asymmetric catalytic reactions shown above. Asymmetric catalytic Diels-Alder reactions with naphthoquinone derivatives as a dienophile provide an efficient entry to the asymmetric synthesis of anthracyclinone aglycones (eq 16). ... 

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. ... 

Carbamoyl nitroso dienophiles, derived from chiral pyrrolidines, have been generated and their reactivity with cyclohexa-diene investigated. Using (—)-fra/w-2,5-dimethylpyirolidine as the auxiliary, the [4 + 2] cycloadduct is isolated in 82% yield and with 98% diastereomeric excess (eq 10). Similarly, chiral ynamine dienophiles have been utilized in asymmetric [4 + 2] cycloadditions with a,p-unsaturated nitroalkenes to afford cyclic nitronic esters. The resulting esters subsequently undergo a rapid [1,31-rearrangement to afford chiral cyclic nitrones in moderate yield and high diastereoselectivity (eq 11)-... 

The crucial role of chelation in terms of increasing rigidity and reactivity of chiral dienophiles was first demonstrated (1983) with a-hydroxy ketone derivatives (Scheme 83, Table 18). Conjugated a-hy-droxy ketones (340) and their enantiomers were prepared via separation of acid (338) from its enantiomer, followed by successive treatment with Bu"Li and the appropriate vinyllithium reagent (339). 

In close relation to the work on acrylates derived from lactate, pantolactone and 2,5-disubstituted pyrrolidines (vide infra), A -acryloylproline benzyl ester (391) has t n studied as a chiral dienophile... 

This is a Diels-Alder reaction in which 25 as the dienophile and 26 as the diene form a new cyclohexene ring. In terms of the electron demand this is a normal Diels-Alder reaction with an electron-rich diene 26 and an electron-poor dienophile 25. The use of a chiral camphor-derived auxiliary means that only one diastereomer is obtained in 70 % yield. The reaction proceeds via the endo transition state 38 with the auxiliary blocking one side of the dienophile. 

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... 

Davies and coworkers , for example, used iV-enoyl derivatives of a cw-l-aminoindan-2-ol based L3-oxazolidin-2-one (222) as chiral dienophiles in the Diels-Alder reactions with isoprene (91a) and piperylene (91b) which give 223 (equation 62). Their results have been summarized in Table 6. The reactions proceeded with high endo/exo and regioselectivities. Bidentate co-ordination of the catalyst to both carbonyl groups kept the dienophile in a rigid conformation, which gave rise to the high de values observed. 

While copper and iron Lewis acids are the most prominent late transition metal Diels-Alder catalysts, there are reports on the use of other chiral complexes derived from ruthenium [97,98],rhodium [99],andzinc [100] in enantioselective cycloaddition reactions, with variable levels of success. As a comparison study, the reactions of a zinc(II)-bis(oxazoline) catalyst 41 and zinc(II)-pyridylbis(ox-azoline) catalyst 42 were evaluated side-by-side with their copper(II) counterparts (Scheme 34) [101]. The study concluded that zinc(II) Lewis acids catalyzed a few cycloadditions selectively, but, in contrast to the [Cu(f-Bubox)](SbFg)2 complex 31b (Sect. 3.2.1), enantioselectivity was not maintained over a range of temperatures or substitution patterns on the dienophile. An X-ray crystal structure of [Zn(Ph-box)] (01)2 revealed a tetrahedral metal center the absolute stereochemistry of the adduct was consistent with the reaction from that geometry and opposite that obtained with Cu(II) complex 31. 

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. 

Dienophiles derived from sugars are ideal chiral auxiliaries. The diethylaluminum chloride (2.2 equiv) catalyzed double addition of cyclopen tadiene (2) to the D-mannitol derivative 1 was performed, affording a 2 1 mixture of 3 and 4 in 96% yield. Although degradation of 4 leads to a racemic compound, the adduct 3 (crystalline 60 %) was further transformed to an optically pure precursor of loganin (5)1. 

The easy accessibility of the chiral dienophiles obtained from carbohydrates resulted in several interesting results. Thus, the diethylaluminum chloride catalyzed addition of D-mannitol derivatives 1 to cyclopentadiene (2) has been studiedThe later revised results2 are summarized in the following table. 

The [4 + 2] cycloaddition of chiral dienes to carbonyl dienophiles has been studied extensively. 1-Alkoxydienes l23 were chosen as model compounds, and as the chiral auxiliaries derivatives of D-hexoses D-glucose and D-galactose. Adducts thus obtained are, in fact, disaccharide precursors and can be converted into naturally occurring disaccharides24. 

In more recent studies, Kresze has found that by using more effective chiral auxiliaries, high enantiomeric excesses can be achieved.29 Thus, the a-chloronitroso dienophile derived from epiandrosterone [Eq. (16)]... 

A variety of solid Lewis and Br0nsted acids has been shown to catalyze Diels-Alder reactions. In several instances the results obtained with heterogeneous catalysts were better than those with homogeneous Lewis acid catalysts. Most of the reported reactions of interest in the synthesis of fine chemicals were catalyzed by (modified) zeolites, clays, alumina, or silica. Catalysts with interesting properties were obtained when support materials such as zeolites, alumina, or silica were treated with Lewis acids. These catalysts were moderately selective in diastereo-selective Diels-Alder reactions with chiral dienophiles and induced enantioselec-tivity (up to 31 % e. e.) in the reaction of cyclopentadiene with methacrolein after treatment with chiral derivatives. Excellent enantioselectivity in this reaction (up to 95 % e. e.) was observed with a polymer-supported chiral oxazaborolidinone. Because of their facile recovery and recycling, we expect that solid-acid catalysts will find increasing use in Diels-Alder reactions in the future. 

Proline benzyl ester 3 is the starting material for a variety of A -substituted derivatives formed by A-acylation with unsaturated acids, which are useful chiral dienophiles for enantioselective Diels-Alder reactions (Section D. 1.6.1.1.1.). The synthesis of these derivatives, e.g., (S)-6 or (S)-7 is conveniently achieved by A-acylation of the hydrochloride or tosylate of the benzyl ester (the allyl ester may also be used) of proline with triethylamine/4-(dimethyl-amino)pyridine5. 

Many chiral dihydrooxazoles and oxazolidines are derived from amino alcohols, such as valinol (Section 2.3.1.). Thus, (5>)-4-isopropyIoxazolidine (15) was obtained from (S)-valinol by reaction with formaldehyde 7 and used for the formation of chiral amides in [2,3] sigmatropic rearrangements (Section D.1.6.3.2.). A bicyclic derivative of valinol 16 was obtained by reaction with 4-oxopentanoic acid8 and used as a chiral dienophile (Section D.1.6.1.1.2.1.2.). A detailed procedure for an analogous derivative from (S,S)-2-amino-l-phenyl-1.3-propanediol has been published9. 

Cyclic sulfonamides are Lermed sultams. From the enantiomeric 10-camphorsulfonic acids, both enantiomers of camphorsultam (49) are readily available by reduction of the intermediate sulfon-imide 484fi 50 and are commercially available. They have been used for the formation of amides with unsaturated acids, which are useful chiral dienophiles and dipolarophiles (Sections D. 1.6,1.1.1- and D. 1.6.1.2.1.) or undergo osmium tetroxide catalyzed dihydroxylations (Section D.4.4.). Other amides may be used for enolate reactions (Sections D.1.1.1.3.1., D.l.5.2.1. and D.4.3.). The. V-fluorinated derivative was obtained by direct fluorination of the sultam with 10% fluorine in nitrogen at low temperature5 , and has been used for the enantioselective formation of C —F bonds (Section D.3.). 

The intermediate sulfonimide derived from saccharin by addition of an alkyllithium compound is also the starting material for sultams mimicking the behavior of camphorsultams. The sultams arc readily obtained from, e.g., 3-methylbenzisothiazole 1,1-dioxide, by ruthenium-catalyzed enantioselective reduction, using BINAP as a chiral ligand, in enantiomerically pure form 79. Thus, both enantiomers can be obtained by using the appropriate enantiomer of the control ligand. Like the camphorsultams, the saccharin derivatives readily form amides with carboxylic acids which can be alkylated via the carbanion (Section D.1.1.1.3.1.) or, if unsaturated carboxylic acids are used, may react as chiral dienophiles in Diels—Alder reactions (Section D.l.6.1.1.1.). 

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