Annulation intramolecular

Lansbury, P.T., and Vacca, J.P, Superior methodology for y-lactone annulation. Intramolecular alkoxyhydride reduction of conjugated nitriles. Tetrahedron Lett., 23, 2623. 1982. 

Besides the intermolecular versions of this [3+2] annulation, intramolecular reactions are also possible. The first example of this transformation was reported by Oshima as early as 1988 in a synthesis of vinyl cylopentenes [8]. More recently this methodology was applied to the preparation of bicyclo[3.3.0]lactams and lactones... 

Heck Annulation. Intramolecular Heck reactions are useful for annulation in heterocychc structures. A-(2-Iodobenzoyl)indoles or -pyrrole undergo Pd-catalyzed annulation to furnish... 

Pd(II)-catalyzed cyclization of the siloxyhexatriene 34 offers a cyclohexe-none annulation method. The Pd enolate 35, formed by transraetallation of the silyl enol ether with Pd(II), is an intermediate which undergoes intramolecular eWo-alkene insertion. Then Pd(II) is regenerated to give 36, and finally cyclohexenone is formed[38]. 

Robinson annulation (Section 18.13) A combination of conjugate addition of an enolate anion to an a,p-unsaturated ketone with subsequent intramolecular aldol condensation. 

Robinson annulation (Section 18.13) The combination of a Michael addition and an intramolecular aldol condensation used as a synthetic method for ring formation. 

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

Robinson annulation reaction (Section 23.12) A synthesis of cyclohexenones by sequential Michael reaction and intramolecular aldol reaction. 

Scheme 36. Piers s annulation strategy based on the intramolecular Stille reaction.

Intramolecular coupling of the easily prepared 12-membered bis(imine) 1 can be used to synthesize the highly annulated 1,4-diazocine 2.12... 

For 10 years, attention has been focused on the intramolecular additions ofallylic and alkynyl-silanes to enones. In early studies, a variety of Lewis acids were tested and reaction conditions were optimized to make this reaction a powerful tool in the synthesis of spiro-annulated, and 1,2-fused ring systems, which can be utilized in the total synthesis of natural products34,35. 

Stereoselective Ring Annulations by Intramolecular 1,6-Addition of an Allylsilane Function... 

Helquist and coworkers60 have developed a six-membered ring annulation via a conjugate addition of aryllithium generated by metal-halogen exchange and subsequent intramolecular alkylation. This is illustrated in equation 71. 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

A particularly important example of the intramolecular aldol reaction is the Robinson annulation, a procedure that constructs a new six-membered ring from a ketone.171 The reaction sequence starts with conjugate addition of the enolate to methyl... 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Oshima et al. explored a cationic rhodium-catalyzed intramolecular [4+2] annulation of l,3-dien-8-ynes in water in the presence of sodium dodecyl sulfate (SDS), an anionic surfactant.132 When the substrate l,3-dien-8-yne was a terminal alkyne, the reaction provided an inter-molecular [2+2+2] product (Eq. 4.68). In water, a reactive cationic rhodium species was formed by the dissociation of the Rh-Cl bond in the presence of SDS. The SDS forms negatively charged micelles, which would concentrate the cationic rhodium species (Scheme 4.15). 

The 1,5- and 1,6-dialdehydes 22 and 24 undergo the annulative pinacol coupling to give the cyclic vzc-diols 23 and 25, respectively (Scheme 13) [29]. The vanadium-catalyzed intramolecular coupling reaction of 1,5-diketone 26 also proceeds with excellent selectivity (Scheme 14) although the intermolecular coupling of ketones such as acetophenone results in low diastereoselectivity under these conditions [21]. 

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