Annulation Methodology

The construction of carbocydic compounds by ring-annulation procedures frequently plays a prominent role in total synthesis. The tolerance of various functional groups in the zinc reagents employed in copper-catalyzed asymmetric 1,4-additions forms the basis for three novel catalytic enantioselective annulation methods discussed here. 

Very recently, a catalytic enantioselective route to prostaglandin i methyl ester was developed based on a tandem 1,4-addition-aldol reaction [84]. 

The use of copper catalysts based on chiral phosphorus ligands to assist 1,4-additions of dialkylzinc reagents has in recent years produced major breakthroughs, with excellent enantioselectivities. A number of monodentate and bidentate phos-phoramidites, phosphites, phosphonites, and phosphines are now available as chiral ligands for alkyl transfer to a variety of cyclic and acyclic enones. So far. 

A few catalysts display activity and selectivity levels sufficiently high for application in organic synthesis. Their utilization in the synthesis of a number of chiral building blocks and target molecules is emerging as summarized in the second part of this chapter. 

In the first method a dialkylzinc reagent bearing an acetal moiety at the -position is used (Sdieme 7.25(b)). The catalytic 1 4-addition is follov/ed by acetal hydrolysis and aldol cydization of the 4-substituted cydoalkanone, affording 6 6- (92) 6j7-j (93) and 6 8- (94) annulated ring systems with high enantioselectivities ( 96% ees) [80]. In addition, dimethyl-substituted decalone 95, with a structure frequently found in natural products, is readily obtained in enantiomerically pure form. 

Comparison with the Hajos-Parrish asymmetric version of the Robinson annulation [81] (Sdieme 7.25(a)) shows the following distinct differences between the two methods. Firstly, the cydoalkenone in the Cu(OTf)2/ligand IS-catalyzed procedure is the Michael acceptor, whereas the cydoalkanone is the Midi ad donor in the proline-mediated annulation. Secondly, the asymmetric induction occurs in the 1,4-addition step in the new method, in contrast to the asymmetric aldol-cydization in the Hajos-Parrish procedure. 

Catalytic erartioselective arrulatiors of five-membered rings. 

254 I 7 Copper-catalyzed Enantioselecth/e Conjugate Addition Reactions of Organozinc Reagents 

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The asymmetric Michael addition of chiral nonracemic ketone enolates has most frequently been used as part of the Robinson annulation methodology in the synthesis of natural products171-172. The enolates are then derived from carbocyclic chiral ketones such as (+)-nopinone, (-)-dihydrocarvone, or (-)-3-methylsabinaketone. 

The a-oxoketene dithioacetals 6 (6.1-6.43) employed in this work as three carbon 1,3-biselectrophilic components have been drawn from various active methylene ketones and are described in the Table-1. The corresponding a-oxoketene N,S- and 0,S-acetals (17.1- 17.15) which are usually derived from a-oxoketene dithioacetals are described in Table-2. These examples are only a representative groups to demonstrate the general application of the new Jl-heteroaromatic annulation methodology... 

In a projected synthesis of verrucarol in which the tetrahydropyranone 175 is envisioned to play a role, the lactone 176 can serve as a viable intermediate (Scheme 6)7S>. Using cyclobutanone annulation methodology, 177 becomes the required intermediate. The geminal substitution of 177 can also be recognized to derive from a spiroannulation approach as previously analyzed. 

Scheme 7.25. Annulation methodology a) Hajosh-Parrish version of the Robinson annulation, b) catalytic enantioselective annulation with functionalised organozinc reagents.

Bicyclo[4.3.0]nonenes, thanks to their frequent appearance in natural products, are other important targets for novel annulation methodology. A six-membered ring-annulation to cyclopentenones has yet to be developed, the main reason for this being that, until very recently, the levels of enantioselectivity in catalytic 1,4-additions to 2-cyclopentenone were too low for a synthetically useful procedure. However, a highly enantioselective annulation of a five-membered ring to 2-cyclo-hexenone has been developed (Scheme 7.26) [80]. 

The Sceletium alkaloid ( )-A4 (36) has been synthesized as shown in Scheme 5, using previously developed enamine-vinyl ketone ring annulation methodology (see Vol. 7 of these Reports).12 Treatment of the hydrochloride of the 2-pyrroline (32) with the acetal enone (33) gave a mixture of epimeric keto-acetals (34) in 85%... 

Thiophenes are also readily available by treatment of 3-halocinnamonitriles with a-haloacetic acid derivatives in the presence of sodium sulfide and a base. In a stepwise route, the precursor 4 was converted to the intermediate 5, which was finally subjected to base induced cyclization giving the thiophene 6 <07SC1133>. Related annulation methodology has been used for construction of a series of 3-amino-5-arylthiophene-2-carbonitriles <07S1027>, and thieno[3,2-Z>]pyridine-5(477)-ones <07S2153>. 

The synthetic utility of this annulation methodology is significantly enhanced by the fact that the cy-clopentenylmethyl sulfone anions generated in the rearrangement step can be tnq> in situ with a variety of organic electr hiles, and that desulfonylation can then be conveniently achieved in the same flask under mild conditions. The transformations outlined in Scheme 14 illustrate this strategy. Thus, re-... 

A [2 + 3] dihydrofuran annulation methodology was recently developed based on this rearrangement. Divinyloxiranes (142) were generated by the stereospecific addition of the lithium dienolate of ethyl a-bromocrotonate to al hydes, and the subsequent pyrolysis to dihydrofurans (143 Scheme 30) occurred in excellent isolated yields (except for R = Bu", Pr ). ... 

Six-membered nitrogen heterocycles are found in a wide variety of naturally occurring alkaloids, and are often incorporated into the design of biologically active pharmaceutical products. Of the many ways to construct these heterocycles, the aza-annulation of enamine substrates with a,(J-unsaturated carboxylic acid derivatives has been a versatile and efficient method for the formation of dihydropyridone and pyridone products. The synthetic utility of this approach has led to incorporation of aza-annulation methodology as a key step in the synthesis of a number of interesting heterocyclic molecules. 

Aza-annulation methodology that involved 269 was applied to the synthesis of ( )-camptothecin (125, Scheme 21).80 Combination of 205 and 273 generated 274, which was transformed to 275 under mild conditions by aza-annulation with 269. Intermediate 275 was then converted to 276, which was carried on to ( )-camptothecin (125). 

The present [3 + 4] annulation methodology for the synthesis of seven-membered carbocycles involves a straightforward procedure that also provides the product functionalities (e.g., masked and unmasked ketone carbonyl and trimethylsilyl groups) that can be transformed to hitherto inaccessible or difficult-to-prepare cycloheptane structures. The prior approach,7-9 based on Cope rearrangement of cis-1,2-divinylcyclopropane, bears an intrinsic drawback in that there exist a limited number of methods for stereoselective preparation of the substrate. 

A number of heteroatom-substituted indoles have been prepared by this annulation methodology. For example, starting with various substituted pyri-dines, 5- [99-101], 6- [99,100,102,103], and 7-azaindoles [100,101,103,104] can be readily prepared (Eq. 46). 

Cyclopentanoids constitute one of the most common stmctural features of many natural and synthetic products. Many research efforts have been devoted to their formation. An annulation methodology was developed in our group based on the indium-mediated allylation reaction in water (eq. 11) (20). Various compounds have been transformed into bicyclic, spiral, or simple cyclopentanoids. 

An Overview of the Total Synthesis of Pytrolizidine Alkaloids via [4+1] Azide-Diene Annulation Methodology"... 

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