Polyketide framework

Bis(allyl)homoallyloxysilanes 56a and 56b are designed for a tandem intramolecular silylformylation-allylsUylation reaction, which has turned out to be an efficient approach to construct polyol and polyketide frameworks [21], For example, heating a solution of 56 in benzene at 60 °C in the presence of Rh(acac)(CO)2 under CO atmosphere followed by the Tamao oxidation gives syn,syn-triols 59 stereoselectively via oxasilacyclopentanes 57 and 58 (Scheme 5.14). Bis(ds-cro-tyl)silane 56b is readily prepared by double Pd-catalyzed 1,4-hydrosilylation of 1,3-butadiene with dichlorosilane followed by reduction with UAIH4 and alcoholysis with the corresponding homoallylic alcohol. 

The framework of coccinelline-type alkaloids may be generated by linear combination of seven acetate units, as illustrated in Scheme 57 (330,336). An intermediate such as 456 would explain the existence of the different ladybug alkaloids. Support for the polyketide origin has been provided by feeding experiments ( " CHjCOONa and CHg COONa) with Coccinella septempunctata (330). 

Aromatic polyketides are structurally diverse, often polycyclic molecules that are derived from unreduced polyketone chains. This group of compounds is produced with the help of type II polyketide synthase (PKS), a complex of enzymes that catalyzes the iterative decarboxylative condensation of malonyl-CoA extender units with an acyl starter unit [70], The carbon framework of aromatic polyketides is further decorated with different functionalities, and carbohydrates are often one of them. Their presence has profound effects on physico-chemical and biological properties of aromatic polyketides. For example, anthracycline aglycones are stable and unpolar, while polyglycosylated anthracyclines are quite polar and often... 

A multifunctional biosynthetic machinery mediates the synthesis of these complex natural products from acetyl- and propionyl-coenzyme A [3). In the case of type I polyketide-synthases, the )8-oxo-esters made by polycondcnsa-tion steps are modified for example by reduction or dehydration after the chain elongation. Additional specific enzymatic transformations, e.g. oxidations and glycosylations, usually take place after the decoupling at the completed macrocyclic ring framework [1,3],... 

Actinoplanic acids A and B (Figure 15) are structurally complex polyketide-derived polycarboxylic acids isolated from the unicellular organism Actinoplanes sp. These compounds were efficiently isolated [86,87] by two-step processes employing gel filtration and reverse phase HPLC. The structure elucidation of these complex molecules required the use of a battery of 2D NMR methods. The HMBC correlations of the methyl groups to the respective carbons were most helpful in delineation of the carbon framework. 

A variety of monoterpenes take part in a hetero Diels-Alder reaction with the oxabutadiene derivative formed from 1,3-cyclohexanedione and formaldehyde, giving polyketide terpene frameworks by a one-pot regio-, chemo- and stereoselective reaction. Amongst the products accessible by this route is the oxapropellane (4) (94H661). 

Floss and Hu in 2004 reported studies on feeding experiments conducted S. nodosus ssp. asukaensis ATCC 29757 that shed light on the biosynthesis of asukamycin 221. Thus, because 221 is assembled from three components, namely an upper polyketide chain initiated by cyclohexanecarboxylic acid, a lower polyketide chain initiated by the mC-j starter unit, and a cyclized 5-aminolevulinic acid moiety, 2-amino-3-hydroxycyclopent-2-enone (C5N unit) 232, it was logical to expect that these are synthesized separately from their respective precursors and are then assembled into the complete molecular framework. To try to elucidate in which order these building blocks are assembled, the various components and partial assemblies of components were synthesized in labeled form, reported in Figure 3.73, and the ones that are incorporated into the final product asukamycin 221 were determined [259]. 

Electrocyclizations often produce six-membered dienes or four-membered strained enes which can be part of a cydoaddition if appropriate reaction partners such as enes or dienes are available. Such cascades are able to quickly generate highly complex obgocydic frameworks with excellent stereocontrol [41], The Trauner group has made remarkable contributions to this field and has exploited this field for elegant and efficient natural product syntheses. An example yielding the tricycUc core structure of the fungal polyketide (—)-PF-1018 is presented in Scheme 6.25. 

The condensation, reduction, cyclisation and methylation steps shown above result in an a-methoxy-y-pyrone unit appended to a linear polyketide-derived side-chain of varying degrees of reduction. However, the majority of y-pyrone-containing natural products isolated from sacoglossan molluscs do not possess linear side-chains, instead exhibiting complex carbon frameworks commonly characterised by cyclic motifs. For example, 9,10-deoxytridachione (2) [13] possesses a 1,3-cyclohexadiene unit, whilst ocellapyrone A (5) is endowed with a bicyclo[4.2.0]octadiene appendage (Fig. 1.1). 

Terpene polyethers have also been proposed to arise through epoxide-opening cascade reactions. These structures are distinct from the other compound classes in this chapter because their carbon frameworks are not derived from polyketide synthase pathways. However, epoxide hydrolases are commonly encountered in terpene biosynthetic pathways [18], indicating that epoxides are viable intermediates in the construction of these compounds. 

This groundbreaking experiment initiated a period of frenetic activity in the natural products community, which established that non-aromatic compounds can likewise be biosynthesized by condensation of esters according to what became known as the Collie-Birch polyketide hypothesis [27, 28). In this regard, impressive radiolabeling studies by Cane established the propionate origin of the carbon framework in erythronolide A, one of the classic macrolide antibiotics (Figure 4.1) [29]. 

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