An Aldol-Based Synthesis of (+)-Peloruside A, A Potent Microtubule Stabilizing Agent

Abstract

A convergent synthesis of the marine natural product (+)-peloruside has been reported. This target has been assembled through the successive application of two methyl ketone boron aldol addition reactions to the latent C 7 -C 11 dialdehyde synthon. This approach afforded a 22-step synthesis of this natural product. The influence of resident stereocenters on aldol reaction diastereoselection has been examined in detail.Peloruside A (1) is a secondary metabolite of a marine sponge (Mycale genus) collected from Pelorus Sound, New Zealand. In addition to its structure elucidation, the initial disclosure by Northcote 1 also demonstrated peloruside A to be cytotoxic to P388 murine leukemia cells at nanomolar concentrations. Subsequent investigations 2 revealed peloruside's anti-proliferation potency is similar to that exhibited by paclitaxel. The first synthesis of 1, reported by De Brabander, established the absolute stereochemistry of this natural product. 3 In the interim, two additional syntheses have been published. 4,5 The purpose of this communication is to report a convergent approach to this natural product suitable for analogue synthesis.The deconstruction of 1 relies on the two highlighted aldol disconnections illustrated in Scheme 1. Based on prior art, 6 we anticipated that the C 3 and C 15 stereocenters would favorably influence the stereochemical outcome of these two bond constructions. In the following discussion, the syntheses of subunits 3 and 4 will be described along with their elaboration to (+)-peloruside A (1). The synthesis of 5 is included in the Supplementary Information.The synthesis of C 1 -C 6 synthon 3 requires six steps from commercially available (S)-4-benzyl-2-oxazolidinone 7a and is summarized in Scheme 2. Notably, the illustrated imideevans@chemistry.harvard.edu. Supporting Information Available: Experimental details and analytical data including copies of 1 H and 13 C NMR spectra for all new compounds (xx pages) (PDF). The synthesis of methyl ketone 5 is also included. This material is available free of charge via the Internet at http://pubs.acs.org. The synthesis of synthon 4, based on the use of (S)-pantolactone, is summarized in Scheme 3. The chelate-controlled borohydride reduction was quite diastereoselective (95:5); however, competing conjugate reduction was noted as a minor side reaction. NIH Public AccessSelection of the illustrated C 9 hydroxyl configuration in subunit 4 bears comment. On the basis of previous model studies probing the influence of β-oxygen stereocenters on aldehyde face selectivity, 8 we concluded that the (R)-C 3 , (S)-C 8 and (R)-C 9 stereocenters in fragments 3 and 4 would be mutually reinforcing in this double stereodifferentiating aldol addition. A recent study by Paterson documents the diminished selectivities if the other C 9 epimer is employed in a similar aldol addition.9The aldol union of methyl ketone 3 and aldehyde 4 is summarized in Scheme 4. In developing this reaction, we noted a surprising diastereoselectivity dependence on the par...

A Chemoenzymatic Approach to the Stereocontrolled Synthesis of the C1–C11 fragment of (+)‐Peloruside A

“…The C1-C11 fragment 4 of (+)-peloruside A prepared as described above closely resembles a building block which Evans successfully converted into the natural product in his synthesis of (+)-peloruside A. [20] …”

“…[17] Thus far, three more total syntheses have been published by Taylor, Ghosh, and Evans and their respective co-workers. [18][19][20] Whereas in the Brabander and Taylor syntheses the pyran was assembled in the form of a [a] Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany Fax: +49-341-9736599 E-mail: schneider@chemie.uni-leipzig.de dihydropyranone ring ahead of the macrolactonization, the Ghosh and Evans syntheses featured a macrolactonization of the seco acid of the natural product followed by an acidcatalyzed lactol formation in the final step. Our retrosynthetic analysis of peloruside A is based upon an aldol coupling of methyl ketone 3 (C12-C19 fragment) and aldehyde 4 (C1-C11 fragment) similar to what Evans reported in his synthesis.…”

Hypervalent iodine reagents in the total synthesis of natural products

“…This was exemplified in the oxidation of a diol to the corresponding dicarbonylic derivative in the synthesis of (+)-peloruside A (Scheme 8). 212 Another example was reported by Dai and co-workers, who formed a ketone bearing stereocenters on both α-carbonyl positions in the synthesis of amphidinolide T2 (Scheme 9). 147 Analogous examples have been reported in the synthesis of (─)-callystatin A 102 and nakiterpiosin.…”

Eine hoch konvergente Synthese von Pelurosid A

“…[2] Pelorusid A wurde von Northcote und Mitarbeitern aus Schwämmen der Gattung Mycale in Neuseeland isoliert. [3] Seine Konstitution und die relative Konfiguration wurden durch umfangreiche NMR-spektroskopische Untersuchungen ermittelt.…”