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

Abstract

In this paper, we present a short and convenient synthesis of the natural product Harzialactone A and its three stereoisomers. In a three‐step synthesis starting from cheap and commercially available benzaldehyde, we created the small polyketidic compound with full control over its two stereogenic centers. To this end, we employed a chiral building block previously described by us, introducing the first stereogenic center through a Horner–Wittig reaction. The second stereogenic center was installed via stereocontrolled syn‐ or anti‐reduction with the corresponding β‐hydroxy ketone intermediates. Upon ozonolysis followed by oxidation the natural product and its stereovariants were produced with excellent enantio‐ and diastereopurities.

Low‐Impact Synthesis of γ‐Lactones through Photoinduced Baeyer‐Villiger Oxidation of Cyclic Ketones

“…[1] It is possible to identify γ-lactones in the aroma components of Whiskey and Cognac (whiskey and Cognac lactone), [2] in plants extract, (eg., rubrynolide and paeonylactone-A), [3] in microorganisms, as in the case of mupircocin H (mupH), [4] and in marine fungi (harzialactone A). [5] Furthermore, a certain number of γ-lactones endowed with pheromonal activity have been isolated from insects, including muricatacin and Japolnilure. [6] On the other hand, several synthetic derivatives have been developed over the years for the treatment of various pathologies such as the diuretic spironolactone (Aldactone™), [7] aldosterone antagonists for the treatment of primary or secondary hyperaldosteronism, and arterial hypertension, or mycophenolat-mofetil (Cellcept™), a drug employed to prevent rejection in kidney, heart, or liver transplants.…”

“…Five‐membered cyclic esters, better known as γ‐lactones, are recurring motifs contained in a wide range of biomolecules [1] . It is possible to identify γ‐lactones in the aroma components of Whiskey and Cognac (whiskey and Cognac lactone), [2] in plants extract, (eg., rubrynolide and paeonylactone‐A), [3] in microorganisms, as in the case of mupircocin H (mupH), [4] and in marine fungi (harzialactone A) [5] . Furthermore, a certain number of γ‐lactones endowed with pheromonal activity have been isolated from insects, including muricatacin and Japolnilure [6] .…”

Total synthesis of both enantiomers of the biosurfactant aureosurfactin via bidirectional synthesis with a chiral Horner–Wittig building block

“…For the synthesis of both enantiomers 2a and 2b we selected our recently developed modular strategy for the diastereoselective synthesis of syn - and anti -1,3-polyol units based on the chiral diphenylphosphane oxide (6 S )- 3 (Scheme 1), 19,20 which can be easily prepared from readily available and inexpensive 2-deoxy- d -ribose in seven steps. 21 A Horner–Wittig reaction with aldehydes 4a (R = n Pr) and 4b (R = OPMB), respectively, and a subsequent syn -reduction should provide the 1,3-diols 5a and 5b .…”

Total Synthesis of Cryptoconcatone D via Construction of 1,3-Diol Units Using Chiral Horner–Wittig Reagents

“…Polyketides represent one of the largest groups of bioactive natural products and are characterized by having extraordinarily diverse structures. − The 1,3-diol motif is one of the most abundant structural features of polyketidic natural products. Consequently, it is of utmost interest for synthetic chemists to possess efficient tools for the stereocontrolled construction of enantiomerically pure syn - and anti -1,3-diol moieties. − Several examples for the modular assembly of 1,3-polyols via iterative sequences were developed. , In 2016, we reported a modular strategy for the stereoselective 1,3-polyol synthesis based on the chiral diphenylphosphane oxide building block 1 , a four-carbon building block that already carries preinstalled stereochemical information (Scheme ). , Module connection and fixation of the stereogenic centers that were part of the building blocks was realized through a classical and highly reliable Horner–Wittig reaction; substrate-controlled directed reduction allowed for the creation of the desired syn - and anti -1,3-diol entities.…”

“…This should allow for the required extensions through olefination strategies. As shown in Scheme , we began the synthesis of fragment 5 using the Horner–Wittig reaction of building block 1 with aldehyde 13 , mediated by LDA and potassium tert -butoxide . Upon acidic workup, the resulting β-hydroxy-ketone 14 was obtained in 89% yield.…”