Dearomatizing cyclization

Recently, some examples of the dearomatizing cyclization of unstabilized a-amino-organolithium compounds have been reported. For example, Clayden and Kenworthy showed that cyclization onto an oxazoline-activated naphthalene ring gives a lithium azaenolate. Note the high diastereoselectivity of the subsequent electrophilic quench, which places the electrophile cis to the carbon-carbon bond formed in the cyclization step (Scheme 25). "... 

Scheme 88 Synthesis of spirocyclic P-lactams by dearomatizing cyclization reaction...

The extended cyclic enolate derived from a simple pyrrol-3-en-2-one (butenolac-tam) has been deuterated at the 5-position with very high diastereoselectivity if the (g) nitrogen atom carries a a-methyl-p-methoxybenzyl group (de > 99 l).27 A similar diastereoselective protonation has been observed in a pyrrol-3-en-2-one formed by dearomatizing cyclization of a pyrrole. 

Cyclizations of organolithiums onto pyrrole or aromatic rings leading to a fused heterocycle activation of the cyclizations by oxazolinyl substitutents use of dearomatization cyclization in the synthesis of cainoids, pyrrolidine-2,3-dicarboxylic acid derivatives capable of interaction with receptors of neurotransmitters 04S1721. 

Recently, Clayden et al. reported a dearomatizing cyclization reaction of Uthi-ated 1 -naphthamides with a phenylglycinol-derived chiral auxiUary (Scheme 25) [74]. Amides 88 were dilithiated with t-BuLi which readily cyclized to afford 89 in moderate yields with diastereoselectivities up to 10 1. 

Treatment of 3-allyloxyphenyl oxazolines with organolithium gives allyllithiums that undergo dearomatizing cyclization. The resulting anions react with electrophiles to form benzopyrans (Scheme 188). ... 

The mechanism of the dearomatization-cyclization of aromatic amides takes place by initial lithiation at the ortho position of the aromatic ring. This species is in equilibrium with the more stable a-amide lithiated compound, which forms the final product by means of a 6n electrocyclic ring closure. 

Scheme 1-133. Dearomatizing cyclization of lithiated TV -benzyl- or 7V-allyl-iV-tert-butyl-1 -naphthamides.

Dipolar addition of mesitylene nitrile oxide with 4,7-phenanthroline 159 gave a 2 1 adduct 160 with a very low yield (Equation 19), the dearomatization of the pyridine ring giving rise to a more reactive double bond which, in turn, underwent cyclization <1998T9187>. 

TOTAL SYNTHESIS OF KAINOIDS BY DEAROMATIZING ANIONIC CYCLIZATION... 

As shown in other sections of this chapter, overall attention has shifted from diazonium salts as aryl radical sources to bromo- or iodobenzenes. One of the few recent attempts to improve the classical Pschorr cyclization using diazonium ions as starting materials led to the discovery of new catalysts [119]. Results from a first samarium-mediated Pschorr type show the variety of products that can be expected from intramolecular biaryl syntheses under reductive conditions (Scheme 22). Depending on the substitution pattern of the target aromatic core and the reaction conditions, either the spirocycle 60, the biphenyl 61, or the dearomatized biphenyl 62 were formed as major product from 63 [120]. 

Anisole and its derivatives have thus far demonstrated the widest variety of [Os]-mediated dearomatization reactions. These transformations have included substitutions, asymmetric tandem addition sequences, and a variety of cyclizations. 

Quinazolin-4(3//)-one undergoes dearomatization with 2,2 -iminodi(benzoyl chloride) to yield the cyclization product 9/7,10.ff,14c/7,15//-4b,9a,14b-triazanaphtho[l,2,3-/g]naphtacene-9,10,15-trione directly, without isolation of the bis-amide. " ... 

Schmalz has reported on the intramolecular radical cyclization of (arene)Cr(CO)3 complexes (Scheme 10). Whilst most of the products from these reactions were transformed into aromatics, dearomatized products can potentially be accessed via this new and appealing approach [32-34]. 

Our first specific Wessely oxidation approach is outlined in Scheme 2. Following an aldol-type reaction between an appropriately protected resorcinol fragment and an aldehyde, we expected the Wessely oxidation to selectively dearomatize at the ortho position of both phenols. The intramolecular Diels-Alder cycloaddition reaction was then expected to form the tricyclic core, which could then be converted to the critical tetracyclic cage via a samarium diiodide(II)-type 6-exo-trig ketyl radical cyclization reaction. 

With the exciting validation of our expedient strategy to form the tetracyclic cage structure using the oxidative dearomatization/Diels-Alder approach followed by consecutive cyclizations, we were now in position to modify each component to best serve the needs to realize a successful total synthesis of vinigrol. 

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