Synthetic Studies on Palau’amine. Construction of the Cyclopentane Core via an Asymmetric 1,3-Dipolar Cycloaddition

Abstract

The cyclopentane core of palau’amine has been constructed in optically pure form through the use of an asymmetric azomethine ylid [1,3]-dipolar cycloaddition reaction.

Palau’amine is a dauntingly complex hexacyclic bis-guanidine antibiotic obtained from the sponge Stylotella agminata that displays potent cytotoxic and immunosuppressive activities (Figure 1).1a,b This substance has attracted considerable attention from the synthetic community2 and a recent, brilliant total synthesis of racemic palau’amine by the Baran laboratory is particularly noteworthy.3 The relative stereochemistry of palau’amine was recently revised independently by Quinn4 and Köck5 to the stereostructure depicted in Figure 1 and turned out to be a fortuitous stereochemical array for the approach described herein. The related alkaloids, the styloguanidines were isolated from the marine sponge Stylotella aurantium and have been shown to be inhibitors of chitinase, an important enzyme in the molting of crustaceans.6 The axinellamines, isolated from the marine sponge Axinella sp., display moderate bactericidal activity against Helicobacter pylori.7

Figure 1.

Structures of palau’amine and congeners.

All of these substances share a structurally related cyclopentane core and thus far, only the Baran laboratory has been successful in total synthesis efforts in this family of alkaloids.8,9 The relative stereochemistry of the cyclopentane core of palau’amine and the styloguanidines is the same while the axinellamines dispose the aminomethyl substituent adjacent to the chlorine atom in an anti-relationship.

It should be noted that the absolute stereochemistry of these natural products has not been rigorously assigned, although based on CD similarities with monobromophakellin hydrochloride, Scheuer, et al., have postulated the absolute stereostructure shown.1 All of these agents represent an unusually challenging density of functionality and stereochemistry and provides a perhaps extreme test of suitable synthetic methodologies. While the landmark accomplishment by Baran and co-workers on the first total synthesis of palau’amine represents an important milestone in the chemistry of this fascinating family of alkaloids, the asymmetric synthesis of palau’amine remains an important synthetic objective.

We have devised an efficient, stereocontrolled entry to the highly functionalized cyclopentane core of palau’amine by an asymmetric intramolecular azomethine ylide dipolar cycloaddition10, 11 as the key step and report these preliminary studies herein (Scheme 1).

Scheme 1.

Asymmetric synthesis of cyclopentane 11.

Our synthesis commences with the enolate acylation of commercially available oxazinone 111 to provide 2 (relative stereochemistry unassigned and inconsequential). Removal of the t-Boc group furnishes aminoketone 3 which was condensed with formaldehyde to generate the incipient azomethine ylid (A) that produced tricyclic intramolecular cycloaddition product 4 as a single diastereomer in 63% overall yield for the three steps. The intrinsic facial bias of this intramolecular cycloaddition remain unclear and constitute the subject of ongoing studies.

This substance was reduced with LiAlH₄ to triol 5, followed by catalytic hydrogenation and t-Boc-protection to give 6 in 61% overall yield from 4. Ruthenium-mediated oxidation cleanly afforded ketoamide 7 in 81% yield that was converted into the unsaturated ketone by exposure to IBX and N-methylmorpholine N-oxide in DMSO delivering enone 8 in 80% yield.12

Stereoselective installation of the two one-carbon arms to enone 8 was accomplished in two stages beginning with a Morita-Baylis-Hillman type of hydroxymethylation that deployed aqueous formaldehyde and tri-N-butyl phosphine providing 9 in good yield.13 Methanolic lithium hydroxide treatment of 9 gave the monocyclic methyl ester 10 in 75% overall yield from 9. For the second stage, enone 10 was then treated with nitromethane and tetramethyl guanidine in acetonitrile at room temperature to give exclusively, the 1,2-anti product. Reduction of the ketone gave diol 11 which was subjected to extensive ¹H NMR nOe experiments to secure the relative stereochemistry of this substance. The relative stereochemistry of the vicinal hydroxymethyl and nitromethyl substituents in 11 are set with the correct relative stereochemistry as per the newly reassigned stereochemistry of palau’amine.

Cyclopentane 11 embodies the stereochemistry and relevant functionality to constitute a viable intermediate for the asymmetric synthesis of palau’amine and congeners. Efforts to complete an asymmetric total synthesis of palau’amine from cyclopentane 11 are currently under investigation in these laboratories.