Dieckmann cyclization sequence

Cyclizations. Cyclization of hydroxylated propargyl sulfones may involve isomerization to the corresponding allenyl sulfones which should behave as Michael acceptors. Access to the indolizidine skeleton by an intramolecular Michael reaction of 5-tosyl-4-pentenamide and subsequent alkylation at nitrogen and carbon is quite efficient. A synthesis of resorcinols from dimethyl acetonedicarboxylate and alkyl alkynoates involves a Michael reaction-Dieckmann cyclization sequence. 

The cyclic /3-keto ester produced in a Dieckmann cyclization can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis (Section 22.7). For example, alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate yields a 2-alkylcvclohexanone. The overall sequence of (1) Dieckmann cyclization, (2) /3-keto ester alkylation, and (3) decarboxylation is a powerful method for preparing 2-substituted cyclohexanones and cyclopentanones. 

Reaction sequence E removed an extraneous oxygen by Sml2 reduction and installed an oxygen at C(15) by enolate oxidation. The C(l) and C(15) hydroxy groups were protected as a carbonate in Step E-5. After oxidation of the terminal vinyl group, the C-ring was constructed by a Dieckmann cyclization in Step F-4. After temporary protection of the C(7) hydroxy as the MOP derivative, the (1-ketoestcr was subjected to nucleophilic decarboxylation by phenylthiolate and reprotected as the BOM ether (Steps F-5, F- 6, and F-7). 

To obtain sufficient quantities of benzazepinone 10 for large-scale synthesis of 1, the Yamanouchi process group subsequently turned to the preparation of 10 in a five-step sequence commencing with anthranilic acid 16.33 Acid-mediated esterification of 16 followed by aniline tosylation provided sulfonamide 17, which was subsequently alkylated with 4-chlorobutyronitrile to furnish the jV-(3-cyanopropyl)anthranilate 18. Dieckmann cyclization of 18 with sodium hydride in DMF then established the... 

The importance of stereochemistry is illustrated by Corey s disconnection sequence 10.=> 11 => 12 => 13. The second transform involves a Dieckmann cyclization (see sec. 9.4.B.ii), and several steps are required to prepared 12 from 13. Focus your attention on the stereochemical relationship of the various groups and of the ring juncture. We must not only consider methods that make bonds, but also those that form the bond with control of the relative and absolute stereochemistry. 

The starting material in this reaction is the P-keto ester product formed by the Dieckmann cyclization seen in part (a) of Problem 20.14. The P-keto esters formed by Claisen condensations (Sections 20.5 and 20.7) and the acylation of ketones with esters (Section 20.8) can also be employed as reactants in analogous alkylation-saponification-decarboxylation sequences. 

The product of a Dieckmann cyclization can undergo alkylation, hydrolysis, and decarboxylation. This sequence represents an efficient method for preparing 2-substituted cyclopentanones and cyclohexanones (below). Using this information, propose an efficient synthesis of 2-propylcyclohexanone using 1,7-heptanediol and propyl iodide. 

Szantay and coworkers were able to improve the efficiency of the yohimbine synthetic sequence by utilizing the nitrile 265, derived from the ketone 260 (Scheme 3.42) (48,49). Dieckmann cyclization of 265 afforded regioselec-tively the a-cyano ketone 267 which on treatment with sodium borohydride provided the epimeric j5-cyano alcohols 268, 269, and 270. Nitriles 268 and 269 were then independently converted to yohimbine (4) and ) -yohimbine (5), respectively. 

Modem synthetic practice frequently requires the use of methods mote specific than those outlined above. Much attention has been focused on the mixed Claisen or Dieckmann reaction, i.e. the acylation of one ester by another, or its intramolecular equivalent, the regioselective cyclization of an unsymmetri-cal diester. A similar problem arises with the acylation of unsymmetrical ketones. This chapter thus describes the inter- and intra-molecular carbon-carbon bond-forming reactions in which a delocalized enolate anion (or close equivalent) reacts at an sp carbon atom in an addition-elimination sequence, as well as the acid-catalyzed equivalent employing an enol. In Table 1 we list the potential nucleophiles and the electrophiles that have been employed in these reactions, although not every possible combination has been reduced to synthetic practice. Table 2 gives details of acid-catalyzed acylations (see Section 3.6.4.3). 

The cyclization reactions described in this chapter and, occasionally, even the acyclic condensation reactions, can often be prefaced by a different type of process such as a Michael reaction. We shall term such a sequence a tandem reaction and a number of these have already been described. Others will be collected here to illustrate the types of processes that have been observed. The cycloenones (198), when treated with a nucleophile (199) under basic conditions, react in a Michael fashion to give the intermediates (200), which then undergo the Dieckmann reaction to give the bicyclic dione (201). Similarly, methyl cinnamate (202) reacts with the nucleophile (203) in the same tandem sequence to give the cyclopentanone (204) as a diastereomeric mixture (Scheme 89). ... 

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