The case for noncompetitive cyclizative options during attempted expedient construction of the core ring system of CP-263,114

The C-6 alkylation of 2-cyclohexenone with methyl bromoacetate was followed by bromination-dehydrobromination of the double bond. Palladium-catalyzed coupling of 8 to dimethyl ( E )-2- hexenedioate provided the key triester 4. All attempts to bring about intramolecular oxidative cyclization of the dienolate of 4 was found to result in preferred formation of the Dieckmann product 9 instead.


Introduction
Recently, a research team at Pfizer discovered two structurally remarkable new compounds currently known as CP-225,197 (1) and CP-263,114 (2). 1 These substances were identified in a fermentation broth generated from a Texas juniper fungus that co-produces zaragozic acid A (squalestatin 1). 2,3The high medicinal promise of 1 and 2 derives from their impressive inhibitory activity against protein farnesyl transferase, these compounds exhibiting an IC50 in rat brain of 6-20 µM.This enzyme is widely recognized to be responsible for catalyzing the addition of farnesyl pyrophosphate to a cysteine residue at the carboxy terminus of protein p21, a product of the ras oncogene.Under normal circumstances, a carcinogenic condition develops because of a one-amino acid mutation of p21 whose effect is to leave the protein in a permanently active state.Cell division and growth subsequently proceed in an uncontrolled manner.Should the initial addition step be impeded, the expectation is that the carcinogenic process will not be turned on.In a different context, 1 is also active against squalene synthase in rat liver microsomes (IC50 43 µM), the enzyme that catalyzes the co-condensation of farnesyl pyrophosphate to presqualene pyrophosphate on the way to squalene.Since this process is central to cholesterol biosynthesis, this agent or analogues thereof are expected to be serviceable cholesterol-lowering drugs. 5

O O
The intriguing structural features defined by these nonadrides have prompted the design of a divergent collection of routes to these systems, 6-14 one of which has eventuated in a successful total synthesis. 15In connection with an attempt to achieve a short preparative route to the core ring system of 1 and 2, we have considered a pathway that would eventuate in the delivery of 3 in only five steps from 2-cyclohexenone (Scheme 1).However, the success of this potentially powerful strategy rests directly on our ability to effect proper intramolecular oxidative coupling of the dienolate of 4 without competitive operation of a Dieckmann cyclization. 16This brief report details the series of observations made in the context of this investigation.

Scheme 1
The first transformation involved alkylation of the kinetic enolate of 5 with methyl bromoacetate 17

Scheme 2
The bromo enone 7 generated in this manner was conveniently responsive to acetalization under the Noyori conditions. 18Introduction of the diester-containing side chain was accomplished at this stage by stirring 8 with dimethyl (E)-hexenedioate under conventional Heck conditions. 19Application of this difunctional reagent, directly available from the palladiumcatalyzed dimerization of methyl acrylate, 20 provided the key triester 4.
The ability of cupric and ferric ions to bring about the oxidative coupling of ester enolates, recognized more than 20 years ago, 21 has serviced several synthetic objectives in both its intermolecular [22][23][24] and intramolecular variants. 25,26Comparable success has been realized with elemental iodine as the oxidant. 27,28A variety of possibilities for effecting the conversion of 4 into 3 by these methods failed to achieve the desired carbon-carbon bond formation (Table I).
In those examples where consumption of starting material was evident, keto diester 9 could be isolated in yields up to 60%.Alternative recourse to copper(II) bromide 22 or silver(I) oxide (DMSO, 80 o C, 8 days) 29,30 fared no better.When 4 failed to respond to the combined action of potassium tert-butoxide and iodine, 28 the decision was made to determine the readiness with which 4 entered into the Dieckmann condensation.Quite evidently, the rate of five-ring closure associated with the Dieckmann pathway cannot be overridden by the kinetics associated with formation of the larger ring resident in 3. Beyond that, the conversion of 4 into 9 does not require dienolate generation.In addition, 9 does not find it possible to return to 4 since deprotonation of the acidic hydrogen positioned in the 1,3dicarbonyl subunit guarantees irreversibility.Had 3 been produced, we had every expectation that chemoselective oxidation to 10 could have been accomplished by the Wilkening-Mundy protocol.