Polypropionate natural products

Aldol reactions using chiral auxiliaries are popular as the stereochemical outcome is usually highly predictable and, as such, they provide a reliable method for the incorporation of adjacent stereocenters. The oxazolidinone-based imides 36 and (ent)-36 are the most commonly employed, and these lead to syn aldol products with high levels of stereocontrol [20]. The reaction can be extended to include a variety of a-heteroatom functionality as in 37 (Scheme 9-13) [21]. Numerous examples of the use of these auxiliaries in the synthesis of polypropionate natural products have been reported. Many related auxiliaries are also available and the camphor-based sultam 38 is notable [22]. 

Panek and co-workers have demonstrated that crotylsilanes 217 and 343 react with a variety of electrophiles including aldehydes, a, ff-unsaturated ketones, acetals and imines under appropriate activation conditions (usually Lewis acidic) to form homoallylic ethers [149, 261], homoallylic alcohols [58, 150, 151], tetrahy-drofurans [262, 263], cyclopentanes [264], pyrrolidines and homoallylic amines [265] with high levels of enantio- and diastereoselectivity [12]. This review will focus on the reactions of crotylsilanes 217 with Lewis acid-activated acetals and aldehydes, and the application of these reactions to the synthesis of polypropionate natural products [266-271]. 

Marshall s chiral allenylmetal reagents have been utilized in double asymmetric reactions with chiral aldehydes for the synthesis of polypropionate natural products. All four dipropionate diastereomers are accessible from the reactions of chiral allenylmetal reagents with a-chiraI-y5-alkoxy aldehydes 97 (153, 158, 276, 277]. The BF3-OEt2-catalyzed addition of allylstannane (l )-218a to aldehyde 97a occurs in high yield and diastereoselectivity to give the xyn.syn-dipropionate 395, presumably through either the synclinal or antiperiplanar Felkin transition states 396 and 397 (Eq. (11.31)). 

Stereoselective anti-aldol reactions. As part of a synthesis of polypropionate natural products, Evans et al. have studied the stereoselectivity of the reaction of isobutyraldehyde with the chiral /3-kctoimide la, which has been shown to undergo syn-sclectivc aldol reactions.4 Surprisingly, the (E)-boron cnolatc, generated in ether from dicyclohexylchloroborane and ethyldimcthylaminc, reacts with isobutyraldehyde to give the anti, am/-aldol 2 and the syn, anri-aldol 2 in the ratio 84 16. Similar diastereoselectivity obtains with the reaction of the isomeric /3-kctoimide lb. 

Examples of the exploitation of furan Diels-Alder cycloadditions for the construction of complex systems are many two delightful examples are shown below. In the first, the residual dienophilie double bond of the Diels-Alder adduct between one of the two furan rings and dimethyl acetylenedicarboxylate then enters into cycloaddition with the second furan ring. In the second example, a pentacyclic array related to the skeletons and oxygenation pattern of polypropionate natural products, was assembled from another molecule containing two furan rings and a reaction partner with two dienophilie double bonds. ... 

In recent years, a number of structurally diverse y-pyrone-containing polypropionate natural products have been isolated from opisthobranch molluscs of the order Sacoglossa (Fig. 1.1) [1 ]. 

Biosynthesis of y-Pyrone-Containing Polypropionate Natural Products... 

Moses and co-workers took this hypothesis one step further, speculating that the original biosynthetic polyene precursor was not the ( ,Z,Z, )-telraene 35 but the all E isomer 40 [17], Furthermore, they postulated that this polyene was the precursor to a number of y-pyrone polypropionate natural products, diversification occurring via selective double bond isomerisations followed by varying electro-cyclisations or cycloadditions. Thus the polyene 40 was synthesised by a Suzuki... 

Scheme 1.7 Moses synthesis of y-pyrone polypropionate natural products from the common precursor 40. Reagents and conditions a Pd(PPh3)4, aq. KOH, THF, 80 °C b xylenes, 150 °C, dark c hv, cyclohexane...

Much tvork in the field of aldol reactions of ketones tvas performed by Evans to enable the synthesis of polypropionate natural products. They demonstrated that j5-ketoimides like 159 vere selectively and completely enolized at the C4 position rather than the potentially labile methyl-bearing C2 position, most probably because steric factors prohibited alignment of the carbonyl groups necessary to activate the C2 proton. As sho vn in Table 2.29, it vas demonstrated that these compounds vould react vith aldehydes to provide syn-syn product 161, via titanium enolates, vith good yield and excellent selectivity, and the corresponding syn-anti product 162 could be favored by use of a tin enolate reaction [58]. They invoked the chelated transition state assembly 160 to explain the product stereochemistry observed, in vhich the C2-methyl group directs diastereofacial selectivity. Interestingly, reduction vith Zn(BH4)2 provided the syn diol diastereoselec-tively. 

The erythromycins are examples of polypropionates , natural products biosynthetically derived largely from propionic acid units via a series of condensation reactions. Many natural products, broadly called polyketides, share this biosynthetic origin. These compounds are decorated with multiple stere-ogenic centers, and acyclic diastereoselection problems that are much more complex than the terpenoid sidechain stereochemistry problem will surface with erythromycin, including the problem of asymmetric synthesis. 

Note that oxidative cleavage of the olefins in 110 and 116 would provide or-methyl-j8-hydroxy carbonyl compounds. This is the repeating unit found in polypropionate natural products. This methodology has been widely used in syntheses of such natural products. The same unit can be produced by aldol methodology (for example see 19 to 20 on Lasonolide-4). This methodology has also been widely used. 

Evans DA, Ng HP, Clark JS, Rieger DL. Diastereoselective anti aldol reactions of cbiral etbyl ketones. Enantioselective processes for the synthesis of polypropionate natural products. Tetrahedron 1992 48(11) 2127-2142. 

SELECTED TOTAL SYNTHESIS OF POLYPROPIONATE NATURAL PRODUCTS... 

The work on total syntheses of polypropionate natural products has resulted in many effective C—C and C-Q (Q = heteroatom) bond-forming reactions that already are or should be included in textbooks devoted to organic synthesis. Nevertheless, on some occasions, the area of total synthesis of natural products is considered an academic exercise that illustrates the power of new methodologies but does not always produce reasonable amounts of... 

SELECTED TOTAL SYNTHESIS OE POLYPROPIONATE NATURAL PRODUCTS 309... 

---