A Chiral Building Block for the ­Stereocontrolled Installation of the 1,3‐Diol Motif

Abstract

A new chiral building block for the direct installation of the 1,3‐diol motif is presented. Aldehyde olefination followed by directed reduction allows for the synthesis of both the syn‐ and the anti‐configured diol in a fully stereocontrolled way. The building block was used for the total synthesis of naturally occurring 1,2,4‐trihydroxynonadecanes starting from pentadecanal.

Versatile process for the stereodiverse construction of 1,3-polyols: iterative chain elongation with chiral building blocks

“…The natural product was accessed through universal deprotection and cyclization under acidic conditions; while the conversion of 21 with TFA effectively cleaved the acetonide protecting groups, further treatment with p-TSA was necessary to complete the final cyclization step. Thus, sufficient amounts of cryptocaryol A were obtained to positively match NMR spectroscopic data ( 1 H, 13 C) with those previously reported, 25,[28][29][30] which gave us verification that the desired hexaol 19 was indeed synthesised as planned. Comparison with the previous strategies for the synthesis of cryptocaryol A shows that our method with 22 linear steps (16 from aldehyde 18) is competitive regarding the step count (O'Doherty: 23, Cossy: 20, Dias: 17 linear steps for 22); [28][29][30] however, our building block approach ensures full flexibility with respect to stereochemical variants of the target molecule.…”

“…12 We recently disclosed the application of chiral phosphine oxides 1 as building blocks for the stereospecific introduction of 1,3-diols in the synthesis of polyketidic structures; (R)-1 and (S)-1 were accessible on a multigram scale through a facile and high-yielding sequence of six and seven linear steps, respectively. 13 In this work, we expanded on that principle by using these four-carbon building blocks, which already carry preinstalled stereo-chemical information, in a repetitive chain elongation process as shown in Scheme 1. While, for example, Paterson et al used boron-mediated aldol reactions for the synthesis of polyketide-type sequences, 14 our strategy focused on the use of olefination reactions to attach the chiral building block 1 at the terminal aldehyde functionality A 1 -A n in an iterative way.…”

“…We were pleased to find that the synthesis via three iterations of the elongation cycle (the last of which was shortened by the ozonolysis step to stop at the terminal olefin) proceeded as smoothly and efficiently as hoped: a stereospecific elongation by thirteen carbon atoms and six stereogenic centres was achieved in eleven steps, with an average yield of 84% per step for all three iterations, to furnish hexaol 19 under full stereocontrol. Including the six-step synthesis of building block (R)-1, 13 the longest linear sequence toward hexaol 19 consists of 17 steps. Regarding reaction conditions of the iteration steps, minor changes (specifically of solvents and reaction temperature) were required here in some instances due to solubility issues arising from the long aliphatic chain (see ESI †).…”

Stereocontrolled Synthesis of Harzialactone A and Its Three Stereoisomers by Use of Standardized Polyketide Building Blocks

“…In order to become effective as a standardized polyketide building block, its defining feature shall be that it possesses a pre‐installed stereogenic secondary alcohol prone for stereocontrolled follow‐up chemistry, and no challenging enantioselective reaction will be involved in the build‐up of the polyketidic chain. To this end, we developed the acetonide 5 shown in Scheme , a reagent that is readily available in both enantiomeric forms and thus became the ideal building block, in our hands: we already demonstrated its simple use in a short four step iteration sequence (consisting of Horner–Wittig reaction, reduction, protection and ozonolysis) . We now present the total synthesis of the polyketidic Harzialactone A and its three diastereomers using this standardized 1,3‐diol precursor.…”

“…We began the synthesis with the connection between building block 5 , the manufacturing of which was described elsewhere, and inexpensive benzaldehyde ( 6 ), thus installing the first of the two stereogenic centers (Scheme ). The Horner–Wittig reaction proceeded in good yields without loss of enantiomeric excess: β‐hydroxy ketone 7 having the R ‐configuration was obtained with the R ‐configured building block 5 in 71 % yield, upon acidic work‐up.…”