Cycloaddition titanium -catalyzed

As mentioned in the introduction, the chiral titanium-catalyzed asymmetric [2-1-2] cycloaddition reaction proceeds between methyl ( )-4-oxo-4-(2-oxo-l,3-... 

The interest in chiral titanium(IV) complexes as catalysts for reactions of carbonyl compounds has, e.g., been the application of BINOL-titanium(IV) complexes for ene reactions [8, 19]. In the field of catalytic enantioselective cycloaddition reactions, methyl glyoxylate 4b reacts with isoprene 5b catalyzed by BINOL-TiX2 20 to give the cycloaddition product 6c and the ene product 7b in 1 4 ratio enantio-selectivity is excellent - 97% ee for the cycloaddition product (Scheme 4.19) [28]. 

The inverse electron-demand catalytic enantioselective cycloaddition reaction has not been investigated to any great extent. Tietze et al. published the first example of this class of reaction in 1992 - an intramolecular cycloaddition of heterodiene 42 catalyzed by a diacetone glucose derived-titanium(IV) Lewis acid 44 to give the cis product 43 in good yield and up to 88% ee (Scheme 4.31) [46]. 

Several titanium(IV) complexes are efficient and reliable Lewis acid catalysts and they have been applied to numerous reactions, especially in combination with the so-called TADDOL (a, a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol) (22) ligands [53-55]. In the first study on normal electron-demand 1,3-dipolar cycloaddition reactions between nitrones and alkenes, which appeared in 1994, the catalytic reaction of a series of chiral TiCl2-TADDOLates on the reaction of nitrones 1 with al-kenoyloxazolidinones 19 was developed (Scheme 6.18) [56]. These substrates have turned out be the model system of choice for most studies on metal-catalyzed normal electron-demand 1,3-dipolar cycloaddition reactions of nitrones as it will appear from this chapter. When 10 mol% of the catalyst 23a was applied in the reaction depicted in Scheme 6.18 the reaction proceeded to give a yield of up to 94% ee after 20 h. The reaction led primarily to exo-21 and in the best case an endo/ exo ratio of 10 90 was obtained. The chiral information of the catalyst was transferred with a fair efficiency to the substrates as up to 60% ee of one of the isomers of exo3 was obtained [56]. 

The reactions of nitrones constitute the absolute majority of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions. Boron, aluminum, titanium, copper and palladium catalysts have been tested for the inverse electron-demand 1,3-dipolar cycloaddition reaction of nitrones with electron-rich alkenes. Fair enantioselectivities of up to 79% ee were obtained with oxazaborolidinone catalysts. However, the AlMe-3,3 -Ar-BINOL complexes proved to be superior for reactions of both acyclic and cyclic nitrones and more than >99% ee was obtained in some reactions. The Cu(OTf)2-BOX catalyst was efficient for reactions of the glyoxylate-derived nitrones with vinyl ethers and enantioselectivities of up to 93% ee were obtained. 

Several aluminum- and titanium-based compounds have been supported on silica and alumina [53]. Although silica and alumina themselves catalyze cycloaddition reactions, their catalytic activity is greatly increased when they complex a Lewis acid. Some of these catalysts are among the most active described to date for heterogeneous catalysis of the Diels-Alder reactions of carbonyl-containing dienophiles. The Si02-Et2AlCl catalyst is the most efficient and can be... 

Inverse electron-demand Diels-Alder reaction of (E)-2-oxo-l-phenylsulfo-nyl-3-alkenes 81 with enolethers, catalyzed by a chiral titanium-based catalyst, afforded substituted dihydro pyranes (Equation 3.27) in excellent yields and with moderate to high levels of enantioselection [81]. The enantioselectivity is dependent on the bulkiness of the Ri group of the dienophile, and the best result was obtained when Ri was an isopropyl group. Better reaction yields and enantioselectivity [82, 83] were attained in the synthesis of substituted chiral pyranes by cycloaddition of heterodienes 82 with cyclic and acyclic enolethers, catalyzed by C2-symmetric chiral Cu(II) complexes 83 (Scheme 3.16). 

The Lewis acid catalyst 53 is now referred to as the Narasaka catalyst. This catalyst can be generated in situ from the reaction of dichlorodiisopropoxy-titanium and a diol chiral ligand derived from tartaric acid. This compound can also catalyze [2+2] cycloaddition reactions with high enantioselectivity. For example, as depicted in Scheme 5-20, in the reaction of alkenes bearing al-kylthio groups (ketene dithioacetals, alkenyl sulfides, and alkynyl sulfides) with electron-deficient olefins, the corresponding cyclobutane or methylenecyclobu-tene derivatives can be obtained in high enantiomeric excess.18... 

In contrast to the limited success with vinyl sulfides as components of [2 + 2] cycloadditions, allenyl sulfides show wide applicability. As illustrated in Scheme 8.91, Lewis acid-catalyzed [2 + 2] cycloadditions of l-trimethylsilyl-l-methylthio-1,2-propadiene (333) with a variety of electron-deficient olefins 336 provide cycloadducts 337 with excellent regioselectivity but with moderate stereoselectivity [175c], Nara-saka and co-workers reported the first Lewis acid-catalyzed asymmetric [2 + 2] cycloaddition of C-l-substituted allenyl sulfides 319 with a,/3-unsaturated compounds 338 using a chiral TADDOL-titanium catalyst. The corresponding cycloadducts 339 were obtained with 88-98% ee, but a low level of trans/cis selectivity (Scheme 8.92) [169,175d[. 

Monochlorotitanium complex 418, prepared from (l/J,25 )-Af-(2,4,6-trimethylbenze-nesulfonyl)-2-amino-l-indanol and titanium tetraisopropoxide followed by treatment with titanium tetrachloride effectively catalyzed the cycloaddition of a-bromoacrolein to cyclo-pentadiene, affording 366 with 93% ee (equation 125)259. Catalyst 418 induced an ee of 90% in the reaction of isoprene with a-bromoacrolein. 

Scheme 11.45 shows a proposal for the transition state involved in a related Lewis acid catalyzed cycloaddition where a disubstituted dipolarophile is used and endo/exo issues are examined. By coordination of the bulky titanium Lewis acid catalyst, the a-carbon of the acceptor becomes sterically more hindered, disfavoring exo-approach, which involves a serious steric interaction of the benzylidene phenyl moiety with the ligands on the titanium ion. Accordingly, the endo-cycloadduct is the only product observed. 

An important catalyst-substrate intermediate that applies to both the TiCl2-TADDOLate catalyzed 1,3-dipolar cycloadditions and Diels-Alder reactions has been isolated and characterized (353). The crystalline compound 248 has been characterized by X-ray analysis, showing that the oxazolidinone is coordinated to the titanium center in a bidentate fashion (Scheme 12.75). The four oxygen atoms. 

An attractive synthesis of cyclobutanones involves the titanium(IV) chloride catalyzed cycloaddition of mixed ketene acetals 46 with divinylsulfone (49) used as an ethene equivalent, The primary 2-vinylsulfonylcyclobutanones 50 formed can be desulfonylated to the corresponding cyclobutanones 51 in the presence of an aluminum amalgam.20... 

The use of chiral catalysts in [2 + 2] cycloadditions can result in significant asymmetric induction. The chiral titanium(IV) catalyst prepared from chiral 1,4-diol 13 catalyzes the cycloaddition of l.I-bis(methylsulfanyl)ethene with electron-deficient alkenes giving cyclobutanes with > 90% enantiomeric excess.19-21 These derivatives can be readily converted to chiral cyclobu-tanones. 

The chiral titanium reagent (6) also catalyzes the [2 + 2] cycloaddition reaction of 1,3-oxazolidin-2-one derivatives of a,(3-unsaturated carboxylic acids and ketene dithioacetals in the presence of MS 4A to give cyclobutanone dithioacetal derivatives with high optical purity (eq 10). Vinyl sulfides, alkynyl sulfides, and 1,2-propadienyl sulfides can also be employed in this reaction to give the corresponding cyclobutanes, cyclobutenes and methylenecyclobutane derivatives with high optical purity (eqs 11 and 12). ... 

Cycloadditions. The asymmetric Diels-Alder reaction of phenylmenthyl acrylate with 5-benzyloxymethyl-cyclopentadiene in the presence of Aluminum Chloride produces an 89% yield of the endo cycloadduct (eq 1), accompanied by 7% of the exo adduct. This provides a useful intermediate for the preparation of various prostaglandins. The Tin(IV) Chloride and Titanium(IV) Chloride catalyzed reactions with Cyclopenta-diene deliver a mixture of endo and exo adducts in 89% de, and 90% de, respectively (eq 2). The TiCU reaction gives an 89 11 endo. exo ratio, while the SnCU reaction gives an 84 16 endoiexo ratio. From a practical point of view, the titanium and tin catalysts are the best of the various Lewis acids surveyed. The use of TiCl4 is also the most effective for the reaction of the acrylate... 

The following transformations demonstrate the characteristie feature of titanium alk-oxide-catalyzed transesterification. The isolated double bond does not enter into conjugation with the active methylene moiety (Eq. 218) [515]. Removal of a sterically demanding chiral auxiliary was possible without affecting the ketoester moiety (Eq. 219) [516,517]. Preparation of an allyl ester was achieved in good yield with retention of the nitrone moiety essential for subsequent cycloaddition (Eq. 220) [518]. 

Asymmetric [2 + 2] cycloaddition reaction affords a practical means of synthesis of optically active cyclobutanes, which can be used as useful intermediates in organic synthesis [138]. Narasaka reported that asymmetric [2 -i- 2] cycloaddition between acryloyl oxazolidinone derivatives and bis(methylthio)ethylene proceeded with high enantios-electivity when catalyzed by TADDOL-derived titanium complex (Sch. 58) [139]. The cyclobutane product was transformed into carbocyclic oxetanocin analogs or (-n)-grand-isol [140]... 

Chiral titanium complexes are also employed as effective asymmetric catalysts for other carbon-carbon bond-forming reactions, for example addition of diketene (Sch. 66) [154c,162], Friedel-Crafts reaction (Sch. 67) [163] (Sch. 68) [164], iodocar-bocyclization (Sch. 69) [165], Torgov cyclization (Sch. 70) [166], and [2 -i- 1] cycloaddition (Sch. 71) [167]. Asymmetric functional group transformations can also be catalyzed by chiral titanium complexes. These transformations, for example the Sharpless oxidation [168] or hydride reduction [169] are, however, beyond the scope of this review because of space limitations. Representative results are, therefore, covered by the reference list. 

Introduction of an alkylthio group on the allene system increased the reactivity of the allene moiety in [2 + 2] cycloaddition reactions. It proved possible to conduct reactions of this allene at much lower temperatures. By adding Lewis acids, the reaction temperature could be decreased even more, as was illustrated by the Lewis acid catalyzed [2-1-2] cycioadditions of l-trimethylsilyl-l-methylthio-l,2-propadiene with a variety of electron-poor alkenes, including cyclic and non-cyclic enones, acrylates, methyl fumarate and acrylonitrile. When a chiral diol 21 based titanium catalyst was employed, the [2-1-2] cycloaddition reactions of /-acryloyl-l,3-oxazolidin-2-ones 17a and 17b with allenyl sulfides 18 yielded methylenecyclobutanes 19 and 20 with high optical purities (equation The highest yields were obtained with electron-poor allenophile 17b. 

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