Quaternary carbon, Claisen rearrangements

As shown earlier in many examples, the Claisen rearrangement of allyl vinyl ethers also provides a very powerful method for carbon-carbon bond formation in domino processes. Usually, the necessary ethers are formed in a separate step. However, both steps can be combined in a novel domino reaction developed by Buchwald and Nordmann [306]. This starts from an allylic alcohol 6/4-102 and a vinyl iodide 6/4-103, using copper iodide in the presence of the ligand 6/4-104 at 120 °C to give 6/4-105 (Scheme 6/4.25). The reaction even allows the stereoselective formation of two adjacent quaternary stereogenic centers in high yield. 

Silylene transfer to a -unsaturated esters produces oxasilacyclopentenes and provides a new method for regio- and stereo-selective formation of enolate that can undergo facile and selective Ireland-Claisen rearrangements and aldol addition reactions to provide products with multiple contiguous stereocenters and quaternary carbon centers (Scheme 37). 

Several factors contribute to the versatility of the ester enolate Claisen rearrangement. Among these are the ability to use a stoichiometric combination of the alcohol and the acid components, the relatively low temperature - of the pericyclic process that allows for the assembly of complex, highly functionalized structures, and the transformation of a carbon-oxygen into a carbon-carbon bond that lends itself easily to the assembly of contiguous quaternary centers. - ... 

The Ireland variant of the Claisen rearrangement relies on the generation of the vinyl moiety of the double unsaturated system by enolization of an ester. The principle of this technique is given in Scheme 11.42 and it allows the transformation of allylic alcohol 177 into 180 via ester 178 and the ketene acetal 179. Application of this chemistry to the construction of the chiral quaternary carbon atom of the zaragozic acid core is shown in Scheme 11.47 [142]. Additional examples of this rearrangement are found in Section 11.5.2.2. 

Scheme 24 Cascade Claisen rearrangement installing the vicinal tertiary and quaternary carbons...

The synthesis of (-) and ( )-mesembranol (413) has been described in two reports construction of the quaternary carbon center in the former involved Claisen rearrangement (79S) (Scheme 48), whereas that in the latter case was performed by radical-mediated cyclization (74S) (Scheme 49). 

The chiral auxiliary mediated aza-Claisen rearrangement of /V-allylketcnc. V.O-acetals also allows the diastereoselective construction of quaternary carbon centers642. Butyllithium proved to be an unsuitable base for the neutralization step in this case because the increased steric hindrance at C-l causes C-2 nucleophilic addition to become competitive with C-l deprotonation. However, this problem can be overcome by the use of lithium tov-butoxide or lithium isopropoxide. This is shown for the achiral. V-allylketene A. O-aceta] precursor 8. 

Tetraethynylmethane (39), a potential monomer for a three-dimensional superdiamonoid carbon network [1], was elusive for many years [51, 52], until its synthesis was accomplished in 1993 by Feldman and co-workers [53]. The key step in the synthesis was the acid-mediated Johnson orthoester variant of the Claisen rearrangement, which provided the central quaternary methane C-atom with suitable functional groups for the ultimate transformation into 39 [Scheme 13-9(b)]. Solid 39, like tetraethynylethene (20), decomposes rapidly at room temperature in either the presence or absence of oxygen. The earlier efforts to prepare tetraethynylmethane had yielded the peralkynylated derivatives 40-42 [Scheme 13-9(c, d)] [51, 52]. Tetraethy-nylallene represents another potential precursor for a three-dimensional carbon network [1], but remains elusive of the perethynylated [K]cumulenes, so far only the silyl-protected [3]cumulenes 43a and 43b [Scheme 13-9 (e)] have been prepared [54]. With 44 [Scheme 13-9 (f)], the first transition metal complex of a perethynylated ligand is now available [55]. 

With the preparation of racemic drhydroisocodeine (79), Chida reported a formal synthesis of morphine [52], The synthesis is based on a cascade of sequential Claisen rearrangements of an allylic vicinal diol derivative as key steps. The Claisen rearrangement protocol, as an efficient strategy for the installation of the C13 quaternary carbon, was successfully employed in the preparation of the Amaryllidaceae alkaloid galanthamine, published 1 year before the synthesis of dihydroisocodeinone [64],... 

The Kobayashi group has observed the intramolecular diastereoselective spirocyclization of racemic 2-haloindoles bearing a C3-tethered allylic alcohol [71, 72]. For example, CuCl-catalyzed intramolecular Ullmann coupling of 117 followed by spontaneous Claisen rearrangement of the intermediate pyranoindole 118 afforded, in a one-pot synthesis, the all-carbon quaternary center of spiro-oxindole 119 in 95% de (Scheme 31). The methodology has been extended to the synthesis of hexahydropyrroloindoles, e.g., ( )-debromoflustramine B and E. 

The next and particularly crucial phase of the synthesis was the construction of the quaternary carbon center associated with galanthamine as well as the formation of the furan or B-ring. While it took some time to establish the right sequence of reactions to realize such an outcome, this was eventually achieved in just three steps (Scheme 4). The first was the engagement of the allylic alcohol moiety within compound 15 in an Eschenmoser-Claisen (EC) rearrangement by treating it with the dimethyl acetal of... 

Starting from the a-methyl-D-mannopyranoside (295). Vittatine (42) has been prepared from D-glucose. The sequence involved a Perrier carbocyclization to yield a cyclohexenone derivative that, after functionalization and a Claisen rearrangement, gave an intermediate with the quaternary carbon atom and the required stereochemistry for the closure of the aryloctahydroindole ring system to provide the desired product (296). 

Scheme 12.38 Construction of a quaternary carbon hy the Claisen rearrangement. Scheme 12.39 Total synthesis of galanthamine.

Apart from its practicahty, the synthetic value of the Meerwein-Eschenmoser-Claisen rearrangement Ues in its abihty to overcome considerable sterical hindrance, for instance the establishment of quaternary stereocenters (Fig. 7.1). The reaction allows for chirahty transfer starting from readily accessible enantiomeri-caUy pure allyhc and propargyhc alcohols to afford amides with carbon-based... 

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