Contiguous quaternary

A major difficulty with the Diels-Alder reaction is its sensitivity to sterical hindrance. Tri- and tetrasubstituted olefins or dienes with bulky substituents at the terminal carbons react only very slowly. Therefore bicyclic compounds with polar reactions are more suitable for such target molecules, e.g. steroids. There exist, however, several exceptions, e. g. a reaction of a tetrasubstituted alkene with a 1,1-disubstituted diene to produce a cyclohexene intermediate containing three contiguous quaternary carbon atoms (S. Danishefsky, 1979). This reaction was assisted by large polarity differences between the electron rich diene and the electron deficient ene component. 

Two closely related methods for the diastereoselective preparation of <5-oxo esters have been developed. The first method uses the chelated lithio enamine 2. These Michael donors are readily available from the tert-butyl ester of L-valine and jS-oxo esters. The Michael addition of this lithio enamine 2 to 2-(arylmethylene)propanedioates, followed by hydrolytic removal of the auxiliary, provides d-oxo esters with contiguous quaternary and tertiary carbon centers with high diastereoselectivity59 60. 

Oxo esters are accessible via the diastereoselective 1,4-addition of chiral lithium enamine 11 as Michael donor. The terr-butyl ester of L-valine reacts with a / -oxo ester to form a chiral enamine which on deprotonation with lithium diisopropylamide results in the highly chelated enolate 11. Subsequent 1,4-addition to 2-(arylmethylene) or 2-alkylidene-l,3-propanedioates at — 78 °C, followed by removal of the auxiliary by hydrolysis and decarboxylation of the Michael adducts, affords optically active -substituted <5-oxo esters232 (for a related synthesis of 1,5-diesters, see Section 1.5.2.4.2.2.1.). In the same manner, <5-oxo esters with contiguous quaternary and tertiary carbon centers with virtually complete induced (> 99%) and excellent simple diastereoselectivities (d.r. 93 7 to 99.5 0.5) may be obtained 233 234. 

Among Michael acceptors that have been shown to react with ketone and ester enolates under kinetic conditions are methyl a-trimethylsilylvinyl ketone,295 methyl a-methylthioacrylate,296 methyl methylthiovinyl sulfoxide,297 and ethyl a-cyanoacrylate.298 Each of these acceptors benefits from a second anion-stabilizing substituent. The latter class of acceptors has been found to be capable of generating contiguous quaternary carbon centers. 

While the yields are generally good for the cyclization of diimines derived from aldehydes, the process does not work satisfactorily using diketoimines such as 20. This is not too surprising, given the need to form two contiguous quaternary centers in 21. 

Nitrogen heterocycles with contiguous quaternary and tertiary stereocentres (118) have been prepared in high enantiomeric purity (<95% ee) by intramolecular conju- gate addition of enolates generated from a-amino acid derivatives (117) via memory of chirality.160... 

As shown in Equation (179), a tandem Claisen rearrangement-lactonization involving the C-3 side chain of furan 292 was employed for a concise synthesis of hyperolactone C <2003JNP1039>. Although the product yield was low, the reaction created two contiguous quaternary carhon centers in one step. 

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 total synthesis of the complex bioactive indole alkaloid ditryptophenaline, having two contiguous quaternary stereocenters related by C2 symmetry, was accomplished in the laboratory of L.E Overman.In the late stages of the synthetic effort the complex diol substrate was oxidized to the dicarboxylic acid using a two-step procedure first, a Dess-Martin oxidation to the dialdehyde followed by the Pinnick oxidation. The mild reaction condition ensured that the integrity of the stereocenters at the a-positions was preserved. 

Gilbert, J. C., Kelly, T. A. Diastereoselective formation of contiguous quaternary centers. The modified Carroll rearrangement. Tetrahedron 1988,44, 7587-7600. 

Lewis acid-promoted allylation of imines [30] and allylative substitution of selenides have been reported [31]. Displacement of selenide results in formation of a contiguous quaternary C-C bond with retention of configuration (Scheme 12.10). 

Radical cyclization of 4-[(bromomethyl)dimethylsiloxy]-2-methyl-l-undecen-5-yne in the presence of acrylonitrile leads stereoselectively by a radical cascade to the diquinane system71. This one-pot reaction allows the consecutive formation of four C-C bonds with two contiguous quaternary centers, and controls the stereoselective construction of four stereogenic centers. 

Scheme 5.43 illustrates three applications of this methodology to total synthesis. The first exeunple is taken from Posner s synthesis of estrone and estradiol [211], the second from Posner s synthesis of methyl jasmonate [212], and the third from Holton s synthesis of aphidicolin [213]. The latter is particularly noteworthy in that two contiguous quaternary centers are created in the asymmetric addition with excellent selectivity. In the estrone synthesis, the chirality sense of the product is consistent with the nonchelate model, but the other two examples adhere to a chelate model. Note that the difference is the degree of substitution at the a-position of the enolate. 

Other attempts to promote radical DA reactions were pursued, notably to open an entry into steroidal structures. An interesting case is the radical cyclization of ynone 153 in order to prepare tetracyclic ketone 155 through a 13-e rfo-dig macrocyclization-radical tandem transannular DA cascade. The unique resulting tetracyclic compound 158, displays a completely different structure with two contiguous quaternary sp carbons and two conjugated enone moieties (Scheme 42),... 

Asymmetric intramolecular conjugate addition of chiral enolates to form pyrrolidine, piperidine, indoline, and tetrahydroisoquinoline derivatives with contiguous quaternary and tertiary stereocenters 06YZ617. 

In the case of 1,1,2,2-tetramethylenecyclobutane made optically active by virtue of labeling frani-methyls with deuterium, pyrolytic retro 2 + 2 cycloaddition is much faster than either double or single rotation. This must represent the difficulty of reclosure of any biradical to generate two contiguous quaternary centers relative to cleavage. 

Overman, L.E. and Watson, D.A. (2006) Diastereoselection in the formation of contiguous quaternary carbon stereocenters by the intramolecular Heck reaction. J. Org. Chem., 71, 2600-8. 

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