Nazarov torquoselectivity

Smith, D. A., Ulmer, C. W., II. Theoretical studies of the Nazarov cyclization 3. Torquoselectivity and hyperconjugation in the Nazarov cyclization. The effects of inner versus outer 3-methyl and 3-silyl groups. J. Org. Chem. 1993, 58, 4118-4121. 

The Nazarov reaction, in which the key electrocyclic step is the conrotatory process 6.505, has one more atom in the ring but the same number of electrons. The question with respect to torquoselectivity now, since this reaction is taking place in the opposite direction, namely ring-closing, is which reacts faster, a dienone... 

Another silicon-assisted kind of torquoselectivity is in the allylsilane-type of Nazarov cyclisation. Now there is chirality, and there is a high level of torquoselectivity in the sense shown by the allylsilane 6.507, determined by the chirality.957... 

With two more electrons, and rather more complicated structures, the Nazarov-like reactions of the carbamates 6.536 and 6.538 are conrotatory, with the torquoselectivity determined, as in the Favorskii reactions, by which side of the conjugated system the nucleofugal group departs from, clockwise as drawn for the carbamate 6.536 and anticlockwise for its diastereoisomer 6.538.964 The topological sense of the event in the left-hand ally lie system corresponds to an anti Sn2 reaction in both cases. 

Denmark and co-workers reported a good example of torquoselection in the silicon-directed Nazarov cyclization (see Section 3.4.5.1). They demonstrated that cyclohexenyl-derived divinyl ketones 26 cyclize to give the relative stereoisomer 27 as the major product (see Section 3.4.5.1 for the mechanism of the silicon-directed reaction). The use of bulky alkyl groups (such as /-butyl) and/or bulky silicon substituents gave the best selectivity, at the expense of the chemical yield. It is interesting that the corresponding cyclopentenyl-derived systems gave only poor torque-selectivity. 

As with many asymmetric processes, there are three ways to control absolute stereochemistry in the Nazarov cyclization Asymmetry transfer, the use of chiral auxiliaries, or asymmetric catalysis. It is important to realize, however, that there are two distinct processes operating that determine the stereochemistry of the product. To control the absolute stereochemistry of the p-carbon atom(s), it is necessary to control the sense of conrotation, clockwise or counterclockwise (torquoselectivity, see Section 3.4.3). To control the absolute stereochemistry of the a-carbon atom however, it is necessary to control the facial selectivity for enol protonation. 

It is important to note that silyl-appended substrates have also demonstrated applicability in the control of torquoselectivity (see Section 3.4.3), and asymmetric transfer (see Section 3.4.4.4) in the Nazarov cyclization. 

Several reports gave account of the successful employment of chiral oxazolidinones as chiral auxiliaries. For example, they were used to direct, with a proper stereocontrol, the synthesis of modified amino acids (13BJ02009) and iso-fatty acids (13BJO1807) in one case, they were used to control a torquoselective Nazarov cyclization that yielded a precursor of the natural compound (+)-pauci lorol F (130L4118). 

Computational studies of oxazolidinone-directed Nazarov cyclization show that the chiral oxazolidinone auxiliaries provide control over the torquoselectivity of 4n electrocyclic ring closure and the regioselectivity of subsequent deprotonation (Scheme 177). °... 

Synthetic applications of the Nazarov reaction require substrates other than an unsubstituted l,4-pentadien-3-one. Indeed, substituents on the divinyl ketone moiety have a significant impact on reactivity. Steric and electronic effects of substituents play a major role regarding both substrate reactivity and the torquoselectivity (see Section 3.3.3) of the cyclization. 

In the Nazarov reaction, silyl substituents are frequently employed as traceless intermediates to enable stereocontrol. Denmark and coworkers [15] demonstrated that a P-silyl substituent can be used in combination with a substituent on a six-membered ring to induce torquoselectivity (Scheme 3.12). The substituent is assumed to adopt an equatorial or pseudoequatorial orientation in the transition state of the reaction. There are two conrotatory pathways, each of which gives rise to one of two diastereomeric products. Owing to better orbital overlap, the new bond is created on the less-hindered face of the six-membered ring favoring one diastereomer over the other. The desilylation process removes all trace of the... 

Scheme 3.12 Torquoselective induction via the use of silyl groups in the Nazarov reaction.

Scheme 3.13 Torquoselectivity in allenyl vinyl ketones during the Nazarov reaction.

Another way to induce torquoselectivity involves the use of chiral catalysts. In 2003, Aggarwal and Belfield disclosed the first asymmetric Nazarov reaction catalyzed by a chiral LA complex (Scheme 3.16) [19]. It was found that a complex formed between copper bromide and tridentate ligand 71 was capable of controlling the conrotation of the cyclization of precursor 70 in good enantioselectivity and yield. With substrate attached, the resulting complex 73... 

The ( )-p-alkoxy divinyl ketones 129, potential Nazarov reaction precursors, are prepared according to the torquoselective olefination methodology with ynolates (Fig. 45). For example, ethyl 3-phenylpropionate (127) is olefinated by the ynolate to afford the p-alkoxy-ot,p-unsaturated acid 128 with high -selectivity. The acid 128 is converted into the Weinreb amide, which is subjected to alkenylation to provide the p-alkoxy divinyl ketone 129 in good overall yield. 

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