A synthesis-enabled relative stereochemical assignment of the C1–C28 region of hemicalide

Abstract

Through synthesising both candidate diastereomers of a model C1-C28 fragment of the potent cytotoxic marine polyketide hemicalide, an assignment of the relative configuration between the C1-C15 and C16-C26 regions has been achieved. By detailed NMR comparisons with the natural product, the relative stereochemistry between these two 1,6-related stereoclusters is elucidated as 13,18-syn rather than the previously proposed 13,18-anti relationship. A flexible and modular strategy using an advanced C1-C28 ketone fragment 22 is outlined to elucidate the remaining stereochemical features and achieve a total synthesis.

Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide

“…Considering that the relative stereochemistry of the C8–C13, C18–C24 and C36–C42 subunits had only been assigned independently, the absolute configuration of the stereocenters in these latter clusters and that of the remaining unassigned five asymmetric carbons (C27, C29, C31, C32 and C45) were selected randomly in our target hemicalide stereoisomer 1 . While this work was ongoing, Paterson and co‐workers reported the synthesis of two diastereomeric C1–C28 subunits with NMR data comparisons indicating a 13,18‐ syn relationship rather than the 13,18‐ anti already selected in compound 1 . However, a different relative configuration between the C8–C13 and C18–C24 stereoclusters does not question the synthetic plan reported herein.…”

“…Comparison of the NMR spectra data of 19 with those of hemicalide indicated some variations of chemical shifts in the C1-C7 triene segment( likelyd ependent on the protonation state of the carboxyl group) that do not impact the proximate nuclei, as previously noted. [7,13] Ag ood agreement was observedf or clusters in which the relative stereochemistryw as already assigned, but deviations were apparent within the C26-C33s ubunit, in which configurations were selected randomly. [29] In conclusion, we have reported synthetic studies towards the marinen atural product hemicalide and the assembly of the entire carbon backboneo fo ne stereoisomer by ac onvergent approach relying on Horner-Wadsworth-Emmons and Julia-Kocienski olefination reactions for the construction of the C6=C7 and C34=C35 bonds, respectively,a na ldol reaction to create the C27ÀC28 bond,a nd aS uzuki-Miyaura cross-coupling as the endgame for the formation of the C15ÀC16 bond.…”

“…Considering that the relative stereochemistry of the C8-C13, C18-C24 and C36-C42 subunits had only been assigned independently,t he absolute configurationo ft he stereocenters in these latter clustersa nd that of the remaining unassigned five asymmetricc arbons (C27, C29, C31, C32 and C45) were selected randomly in our target hemicalide stereoisomer 1.W hile this work was ongoing, Paterson and co-workers reportedt he synthesis of two diastereomericC 1-C28 subunitsw ith NMR data comparisons indicating a1 3,18-syn relationship rather than the 13,18-anti already selected in compound 1. [13] However,adifferent relative configuration between the C8-C13 and C18-C24s tereoclusters does not question the synthetic plan reportedh erein. Our retrosynthetic analysiso fh emicalide stereoisomer 1 relies on four main disconnections and the synthesis was planned from the five subunits A-E.E laboration of the C1-C15 segment would be achieved by formation of the C6= C7 bond using aH orner-Wadsworth-Emmons (HWE) olefination between phosphonate A and aldehyde B.T he C34=C35 bond would be constructed by aJ ulia-Kocienski olefination [14] between sulfone D (C28-C34 subunit) and aldehyde E (C35-C46 subunit).…”

DP4-AI automated NMR data analysis: straight from spectrometer to structure

“…7). [50][51][52][53][54][55] This test set has been designed to include natural Fig. 7 Figure illustrating the 47 molecules utilized to evaluate the performance of DP4-AI.…”

Stereocontrolled Synthesis as an Enabling Tool for the Configurational Assignment of Marine Polyketide Natural Products

“…From intermediate ent‐ 69 , the completion of the C16–C28 fragment 71 required five steps (Scheme ), and this was planned to undergo an analogous Stille coupling with a suitable C1–C15 stannane 72 . The construction of the C1–C15 stannane 72 commenced with an Evans syn aldol with aldehyde 73 and 74 to generate adduct 75 . Subsequent manipulations revealed aldehyde 76 , which engaged with ketone ent‐ 32 via a 1,4‐ syn boron‐mediated aldol reaction to give 77 .…”