Titanium stereochemistry

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

Table 21.2 Oxidation states and stereochemistries of titanium, zirconium and hafnium...

On the other hand, in the presence of Lewis acids such as titanium(lV) chloride or eerium(TIT) chloride, the (S)-e s-conformer predominates via chelation of the two carbonyl groups and a reversed stereochemistry of the addition reaction is observed1 °. 

The syn selectivity in the titanium(IV) chloride mediated reactions can be explained by an intermolecular chelation, with transition state 21A being sterically favored over 21B. On the other hand, nonchelation control governs the stereochemistry of the boron trifluoride mediated reactions. Thus, the sterically favored transition state 21 C leads to the observed anf/ -diastereo-mer12. 

Complete control of stereochemistry was also obtained in a total synthesis of ptilocaulin. As the key step, addition of trimethyl(2-propenyI)silane to an enantiomerically pure 5,6-di-aikylcyclohexenone in the presence of titanium(IV) chloride was used to establish a new stereocenter at C-5 with appropriate configuration31. 

Titanium, tetrakis(trimethysilyl)oxy-, 3, 334 Titanium, tetranitrato-stereochemistry, 1,94 Titanium, triaquabis(oxalato)-structure, I, 78 Titanium, tris(acetylacetone)-structurc, 1,65 Titanium alkoxides oligomeric structure, 2,346 synthesis ammonia, 2, 338 Titanium chloride photographic developer, 6,99 Titanium complexes acetylacetone dinuclear, 2, 372 alkyl... 

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

Titanium enolates can be prepared from lithium enolates by reaction withatrialkoxy-titanium(IV)chloride,suchasfra-(isopropoxy)titaniumchloride.21 Titanium enolates are usually prepared directly from ketones by reaction with TiCl4 and a tertiary amine.22 Under these conditions, the Z-enolate is formed and the aldol adducts have syn stereochemistry. The addition step proceeds through a cyclic TS assembled around titanium. 

A 3 -benzyloxy ketone gives preferential 2,2 -syn stereochemistry through a chelated TS for several titanium enolates. The best results were obtained using isopropoxytitanium trichloride.112 The corresponding /(-boron enolate gives the 2,2 -anti-2,3-anti isomer as the main product through a nonchelated TS.110... 

Entry 6 involves a titanium enolate of an ethyl ketone. The aldehyde has no nearby stereocenters. Systems with this substitution pattern have been shown to lead to a 2,2 syn relationship between the methyl groups flanking the ketone, and in this case, the (3-siloxy substituent has little effect on the stereoselectivity. The configuration (Z) and conformation of the enolate determines the 2,3-vyn stereochemistry.113... 

Entries 4 and 5 are cases in which the oxazolidinone substituent is a 3-ketoacyl group. The a-hydrogen (between the carbonyls) does not react as rapidly as the y-hydrogen, evidently owing to steric restrictions to optimal alignment. The all -syn stereochemistry is consistent with a TS in which the exocyclic carbonyl is chelated to titanium. 

The stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

In the envisaged titanium oxo complex, the Ti atom is side-bound to the peroxy moiety (02H), consistent with all the spectroscopic results mentioned in Section III in Scheme 27, between the two O atoms that are side-bound to Ti4+, the O atom attached to both the Ti and H atoms is expected to be more electrophilic than the O atom attached to only the Ti atom and is likely to be the site of nucleophilic attack by the alkene double bond. The formation of the Ti-OH group (and not the titanyl, Ti=0, as proposed by Khouw et al. (221)) after the epoxidation and its subsequent condensation with Si-OH to regenerate the Ti-O-Si links had been observed (Section III.B) by FTIR spectroscopy by Lin and Frei (133). Because this is a concerted heterolytic cleavage of the 0-0 bond, high epoxide selectivity and retention of stereochemistry may be expected, as indeed has been observed experimentally (204). 

Although the reaction of a titanium carbene complex with an olefin generally affords the olefin metathesis product, in certain cases the intermediate titanacyclobutane may decompose through reductive elimination to give a cyclopropane. A small amount of the cyclopropane derivative is produced by the reaction of titanocene-methylidene with isobutene or ethene in the presence of triethylamine or THF [8], In order to accelerate the reductive elimination from titanacyclobutane to form the cyclopropane, oxidation with iodine is required (Scheme 14.21) [36], The stereochemistry obtained indicates that this reaction proceeds through the formation of y-iodoalkyltitanium species 46 and 47. A subsequent intramolecular SN2 reaction produces the cyclopropane. 

Rothwell and colleagues352 studied the titanium mediated [2 + 2 + 2] cycloaddition of alkenes with monoynes and diynes. Among the reactions studied, the reaction between styrene (29) and diyne 609 in the presence of titanium catalyst 610 proved cleanest (equation 175). The reaction yielded 614 via a [2 + 2 + 2] cycloaddition followed by a titanium mediated suprafacial [1,5] H-shift involving 611-613. The cis relationship between the trimethylsilyl group and the phenyl group indicated that the initially formed titananorbornene 611 had an endo stereochemistry. 

Transmetalations with first row transition metal elements such as titanium or manganese have produced useful synthetic applications. Organotitanate species of type 123 show the advantage of high Sn2 selectivity in the anti stereochemistry of the resulting copper(I) intermediates (Scheme 2.56) [119, 120],... 

The hypothesis of stereochemical control linked to catalyst chirality was recently confirmed by Ewen (410) who used a soluble chiral catalyst of known configuration. Ethylenebis(l-indenyl)titanium dichloride exists in two diaste-reoisomeric forms with (meso, 103) and C2 (104) symmetry, both active as catalysts in the presence of methylalumoxanes and trimethylaluminum. Polymerization was carried out with a mixture of the two isomers in a 44/56 ratio. The polymer consists of two fractions, their formation being ascribed to the two catalysts a pentane-soluble fraction, which is atactic and derives from the meso catalyst, and an insoluble crystalline fraction, obtained from the racemic catalyst, which is isotactic and contains a defect distribution analogous to that observed in conventional polypropylenes obtained with heterogeneous catalysts. The failure of the meso catalyst in controlling the polymer stereochemistry was attributed to its mirror symmetry in its turn, the racemic compound is able to exert an asymmetric induction on the growing chains due to its intrinsic chirality. 

Under these conditions, the Z-enolate is formed and the aldol adducts have syn stereochemistry. The addition can proceed through a cyclic transition state assembled around titanium. 

Further process optimization by Thiruvengadam and co-workers (Thimvengadam et al., 1999), led to a novel, stereoselective, scalable two-step process devoid of chromatography for chiral 2-azetidinone construction (Scheme 13.4). As above, the titanium-enolate of chiral oxazolidinone 11a was preformed, but now when reacted with well behaved imines of type 16, affords the unexpected anti-addition product. This surprising result was further supported by careful comparison to minor antiproducts obtained in the earlier aldol-addition methodology and determination that the major product was indeed 17a (undesired RSR series). Adjustment of the oxazolidinone absolute stereochemistry to the fortuitously less expensive 2S-series afforded the desired diastereo-mer 17b in 95% de and in 50-70% yield. Recrystallization improved the stereochemical purity to >99% de. 

The most common coordination number of titanium is six (recognized for all oxidation states of the metal), although compounds are known in which the coordination number is four, five, seven or eight. The common oxidation states of titanium with the associated coordination numbers and stereochemistries are summarized in Table 3. The properties of these molecules will be discussed in the appropriate sections. In brief, however, titanium compounds in the +III or lower oxidation states are readily oxidized to the +IV state. Furthermore, titanium compounds can usually be hydrolyzed to compounds containing Ti—O linkages. 

The overall course of reaction depends on the relative rate constants for the various secondary radical processes. Aliphatic ketones are often photoreduced to secondary alcohols (4.121, but although there are interesting features in the stereochemistry of the reduction, the method is not a worthwhile alternative to thermal reduction using hydride reagents, except in cases where the substrate is sensitive to basic conditions. Photoaddition of methanol is promoted in the presence of titaniurnfiv) chloride, both for acyclic and cyclic (4.33) ketones the titanium involvement probably starts in the early steps of the reaction, but the detailed mechanism is not known. Addition may also be a major pathway when cyclohexene is used as hydrogen source (4.341 unlike many other simple alkenes, cydohexene does not readily give oxetanes by photocycloaddition (see p. 126). 

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