Titanium mediated coupling

In addition, other carboxylic acid derivatives, such as tertiary carboxamides and cyclic carbonates, readily undergo cyclopropanation reactions under similar conditions to provide cyclopropylamines ° and cyclopropanone hemiacetals," respectively. The cognate titanium-mediated coupling of imides has been shown to afford synthetically useful N-acylhemiaminals. ... 

Vinylogous porphyrins are formally built up of odd-numbered carbon spacers separating four pyrrole rings. There are, however, several expanded porphyrins that contain four pyrrolic or pyrrole-like subunits that contain only even-numbered carbon spacers. These macrocycles will be grouped under the general heading stretched porphycenes , since they are typically prepared via the low-valent titanium mediated coupling of pyrrolic aldehydes just as are the porphycenes (cf. Chapter 3). 

A mechanistic scheme for the titanium-mediated coupling of two carbonyl groups involves an initial one-electron transfer from titanium metal to the aldehyde or ketone carbonyl group to produce radical anions (ketyl species), which then dimerize to a Ti-pinacolate. Hydrolysis of the pinacolate generates the vicinal diol. 

Mukaiyama has described a total synthesis of taxol wherein pinacol cyclization of a diketone was employed to construct the A ring in good yield (Eq. 3.13) [31J. In this work, partially reduced alcohols and rearranged compounds were the major side products of the titanium-mediated coupling process. 

Ring-expansions have been used in two syntheses of the monoterpene kara-hanaenone (12). In the first, the interest lies in the regioselectivity of the addition of thiophenol to the allene (13) and the rapid Cope rearrangement of the cis-product (Scheme 20), whilst in the second the availability of the pinacolic intermediate relies on the success of the titanium-mediated coupling of acetone with the requisite cyclohexanone [equation (17)]. ... 

Formation o( oleltns by coupling or cross coupling of ketones, mediated by low valent titanium Also coupling ol enol ethers of 1,3-dicarbonyl compounds. 

Titanium-mediated pinacol coupling reactions have been reviewed until 2000.80 81 Since then, various intermole-cular pinacol couplings have been reported with aldehydes, - ketones, a-ketoesters, and imines, as well as asymmetric versions thereof.101-104 Scheme 29 shows one example of an asymmetric pinacol coupling of aromatic aldehydes, promoted and catalyzed by the new chiral titanium complex (A)-75, that has been developed by Riant and co-workers.101 Yields for pinacol products 76 are generally high. Under catalytic conditions, ee is moderate (up to 63%), while stoichiometric conditions allow to obtain up to 91% ee. 

By choosing an appropriate titanium complex, a /ra r-isomer of 1,2-cyclohexanols can be prepared selectively. Because intramolecular pinacol coupling of hexanedials with Sml2 usually produces t-isomers of cyclohexane-1,2-diols, the titanium-mediated reaction complements the samarium-mediated cyclization (Equation (17)). In addition, when a /-butyl group fixes the conformation of the substrate, one of the diastereomers is produced selectively (Equation (18)). ... 

The following combinations have also been reported of titanium-mediated reductive coupling of imines TiCU-Mg in DME (or THF), TiCU-Li in DME (or THF), TiCU-EtjN in Catalytic use of... 

In 1977, an article from the authors laboratories [9] reported an TiCV mediated coupling reaction of 1-alkoxy-l-siloxy-cyclopropane with aldehydes (Scheme 1), in which the intermediate formation of a titanium homoenolate (path b) was postulated instead of a then-more-likely Friedel-Crafts-like mechanism (path a). This finding some years later led to the isolation of the first stable metal homoenolate [10] that exhibits considerable nucleophilic reactivity toward (external) electrophiles. Although the metal-carbon bond in this titanium complex is essentially covalent, such titanium species underwent ready nucleophilic addition onto carbonyl compounds to give 4-hydroxy esters in good yield. Since then a number of characterizable metal homoenolates have been prepared from siloxycyclopropanes [11], The repertoire of metal homoenolate reactions now covers most of the standard reaction types ranging from simple... 

Titanium alkoxide-mediated coupling of functionalized allenes and acetylenes afforded various types of products the first propargyltitanation of acetylenes was achieved by the appropriate choice of allenes.74... 

The first total synthesis of ( )-sarcophytol B (5) from S./i-famesal (92), which was reported by McMurry et al. in 1989, used a low-temperature titanium-induced pinacol coupling reaction of 1,14-dialdehyde as the key step. They concluded that the natural sarcophytol B has the stereochemistry of a trans diol (Scheme 6-5). Li et al. reported on a concise total synthesis of ( )-sarcophytol B (5) from /i./i-famesol (91) by a low-valent titanium-mediated intramolecular McMurry... 

The first enantioselective total synthesis of (- -)-l 1,12-epoxycembrene C (28) has been accomplished via a macro-olefination strategy by employing titanium-mediated McMurry coupling as a key step and the Sharpless asymmetric epoxidation for the introduction of chiral epoxide. Based on the enantioselective Sharpless asymmetric epoxidation, Li et al. assumed the configuration of natural 28 to be (115,125) (Scheme 6-21). ... 

Furstner et al. synthesized lamellarin O dimethyl ether following their previous research on carbon-carbon double bond formation from carbonyl compounds by catalytic titanium coupling reactions <94JOC5215, 95JA4468>. A new titanium-mediated approach to pyrrole synthesis, based on the cyclization of a 3-acylamino-enone, was reported <95JOC6637>. 

The electron-rich nature of silyl ketene acetals enables their facile coupling with imines in the presence of a titanium salt [101,102]. Interesting results are obtained from comparison of the efficiency of a titanium salts of the type 71X4. Switching the halogen X from F to Cl to Br to I, uniformly increases the product yield and diaster-eoselectivity of the TiX4-catalyzed reaction between a ketene silyl acetal and an imine (Eq. 28) [103]. The finding illustrated by Eq. (28) was further applied to diastereose-lective carbon-carbon bond formation as shown in Eq. (29) [103]. More examples of the titanium-mediated reaction of ketene silyl acetals and imines or their derivatives, for example (N,6>)-acetals, are summarized in Table 3. 

Vogel and coworkers have also explored an alternative approach to the synthesis of isocorroles. This more rational approach involves the low-valent titanium-mediated intramolecular reductive coupling of an a,co-formyl-substituted linear tetrapyrrolic species. Specifically, ring closure of the linear species 2.272, carried out under these McMurry-type conditions, afforded the etioisocorrole 2.270 in 10% yield (Scheme 2.2.4). The putative corrologen , thought to occur as an intermediate in this reaction, was not isolated. Rather, oxidation by molecular oxygen or FeCls during workup was presumed to occur spontaneously. 

In addition to the above, two air-stable, crystalline 20-Tt-electron dithia-A, A -dihydroporphycene derivatives, specifically 3.51 and 3.52, have been prepared recently by Neidlein and coworkers (Scheme 3.1.8). As could perhaps be imagined, these species were also prepared via a low-valent titanium-mediated reductive coupling procedure, involving the diformyl thiophene-pyrrole 3.50, carried out in the presence of TiCU and Zn. Interestingly, it is not only 3.51 but also 3.52 that is isolated under these conditions. This stands in direct contrast to what is observed in the case of the mixed furan-pyrrole coupling discussed above (Scheme 3.1.7) there, only one of the two possible isomers was isolated. 

Methylene cyclopentenones can be made with allenes - instead of alkenes - as precursor compounds. Thus, iron-, molybdenum-, cobalt- and titanium-mediated PK-type C-C coupling reactions lead preferentially to the j0-methylene cyclopentenones [25, 26]. A side reaction is the polymerization of allenes in the presence of Co2(CO)g if the allenes are not at least disubstituted. An example using Co2(CO)g/ A-methylmorpholine A-oxide (6 equiv.) in THF/CH2CI2 at -80/-I-20 °C is shown in eq. (9) (cf. [25]). 

McMurry has developed a titanium-mediated keto ester coupling (cf, acyloin condensation see R. Brettle, in Comprehensive Organic Synthesis , ed. B. M. Trost, Pergamon Press, Oxford, 1991, vol. 3, chap. 2.7) J. E. McMurry and D. D. Miller, J. Am. Chem. Soc., 1983,105, 1660. 

Periplanone C. McMurry has reported an enantioselective synthesis of (-)-periplanone C, a sesquiteipene that serves as a sex pheromone for cockroaches, through a route involving a pinacol cyclization of a 1,10-keto aldehyde (Eq. 3.7) [24]. MM2 calculations based on a model for predicting the stereoselection of titanium-mediated pinacol coupling reactions were in qualitative, but not quantitative, agreement with the experimental results. 

Palominol. Corey has reported the application of an intramolecular titanium-mediated pinacol coupling reaction to the synthesis of a 15-membered ring, en route to palominol, a marine diterpenoid that displays cytotoxicity toward the human colon cell line (Eq. 3.10) [28]. Slow addition of the keto aldehyde (32 h) to the titanium reagent furnished the cyclized product in 53% yield as a mixture of diastereomers (2.1 1). 

In the Evans synthesis of the polypropionate region (Scheme 9-45), the boron-mediated anti aldol reaction of -ketoimide ent-25 with a-chiral aldehyde 145 afforded 146 with 97% ds in what is expected to be a matched addition. Adduct 146 was then converted into aldehyde 147 in readiness for union with the C -Cs ketone. This coupling was achieved using the titanium-mediated syn aldol reaction of enolate 148 leading to the formation of 149 with 97% ds. 

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