Homoallylic derivatives natural products synthesis

Direct carbonylation of organomercurials is a low yielding process that reqnires high temperatures and pressures. However, it can be performed efficiently under milder conditions in the presence of transition metal catalysts, particnlarly, rhodium and palladium. Two important applications of this protocol have recently been reported. The Rh -catalyzed formylation of organomercurials has been applied to the synthesis of a polyol-derived natural product. The organomercury chloride substrate is synthesized by oxymercuration of the corresponding homoallylic alcohol with Hg(OAc)Cl (Scheme 5). 

The addition of 2-butenyltrifluorosilane 68 to chiral aldehydes has been examined by Roush in the synthesis of the a fi,ant/-dipropionate stereotriad, a common but difficult-to-synthesize subunit in polyketide-derived natural products [54], The synthetic approach involves the 2-butenylation reaction of a-methyl-)9-hydroxy aldehydes 72 with (Z)-68 (Scheme 10-30). Using this approach, the anti,anti-dipro-pionate 73 could be obtained in excellent selectivity. The best selectivity is observed when anti-/]-hydroxy aldehydes are used. When the syn aldehyde is used, a mixture of homoallylic alcohols is produced which may arise from a nonche-lated Zimmenuan-Traxler transition structure. 

A final example of the use of tartrate-derived crotylboronates in natural product synthesis is illustrated in the formal total synthesis of ikarugamicin (Scheme II-11) [179]. Here, Roush and Wada used the asymmetric crotylboration of meso-(t/" -2,4-hexadien-1,6-dial)iron tricarbonyl 266 with (S,S)-(E)-219 to set three stereocenters in their synthesis of the a,s-indacene unit of ikarugamycin. This key reaction provided 267 in 90% yield and >98% ee. Homoallylic alcohol 267 was converted to the allylic acetate 268, which underwent stereoselective ethylation with EtsAl with retention of stereochemistry. The resulting adduct 269 was subsequently elaborated to as -indacene unit 271 through a 15-step synthetic sequence, including the intramolecular Diels-Alder reaction of 270. 

There are numerous reports of hydrofonnylation reactions where an amine substituent in the substrate condenses with the aldehyde product to form a heterocyclic ring (Fig. 6). Intramolecular hydroaminomethylation reactions are often referred to as cyclohydrocarbonylation reactimis. A Cbz-protected homoallylic amine underwent cyclohydrocarbonylatiOTi with Rh-biphephos to form the natural product, ( )-coniine (Fig. 6, 13) [25]. Alper recently reported the formation the seven-membered ring of 2-benzazepines (Fig. 6, 14) by hydroformylation of 2-isopropenylbenzaldehydes in the presence of anilines [26]. Intramolecular hydroaminomethylation of 2-isopropenylanilines produces 1,2,3,4-tetrahydroquinolines (Fig. 6, 15) [27]. In some instances, the enamine derived from intramolecular condensation of the resulting aldehyde is desired. For example, the synthesis of a key intermediate (Fig. 6,16) in the synthesis of a series of ACE inhibitors was... 

Recently we undertook the preparation of chiral lactones of different ring sizes utilizing chiral homoallylic alchols derived from the asymmetric allylboration of appropriate aldehydes as the starting materials (6-S). Our procedures are reviewed here. The application of our allylboration-esterification-ring closing metathesis reaction sequence for the synthesis of biologically active natural products (S-/i) are also summarized. 

Allylation of carbonyl compounds is another very useful carbon-carbon bond forming asymmetric transformation in organic synthesis. This transformation yields the homoallylic alcohols that have proven to be valuable reagents and intermediates that have found numerous applications in natural product total synthesis. In particular, asymmetric allyl-boration of aldehydes employing tartrate- and pinane-derived reagents has been widely exploited. Although the asymmetric allylation reaction is well documented and widely used in solution phase, the asymmetric variant of the allylation of carbonyl compounds on the solid support has remained largely unexplored. ... 

Hydroformylation of substrates incorporating O- or N-nudeophilic moieties leads to cyclic hemiacetals, acetals, 0,N-acetals, or enamines depending on the reaction conditions and the functional groups of the substrates. In the total synthesis of the anticancer agent, natural product leucascandroUde A (24), three different carbonyla-tion steps were incorporated (Scheme 12.1). Alkene 20 underwent a cyclohydrocar-bonylation reaction under hydroformylation conditions, resulting in the formation of hemiacetal 21. The other two carbonylation steps involved formylation of 18 and intramolecular alkoxycarbonylation of alkene 22 [28]. Various tryptamine derivatives [29] and the framework of piperidine alkaloids [30] were also synthesized via cyclohydrocarbonylation starting from functionalized homoallylic amines or aniline derivatives, respectively. 

A further application of the carbonylation strategy for construction of 2,3-cis substituted tetrahydrofuran derivatives is shown in Scheme 15.23. Nesbitt and McErlean reported on the synthesis of C19 lipid diols, the enantiomers of the anthelmintic marine natural products. Key steps in the divergent synthesis include a syn selective epoxidation of a homoallylic alcohol, a one-pot alkoxypalladation-lactonization reaction sequence, and diethyl azodicarboxy-late promoted Mitsunobu inversion. 

In the context of the development of enzymatic methods for the synthesis of higher-carbon sugars we recently developed a new strategy by which dodeca-2,11-diuloses — formally derived from ketohexoses by C-coupling tail to tail — become accessible with deliberately addressable substitution patterns by the twofold aldolase-catalyzed chain elongation ( tandem aldolization) of simple, readily available dialdehydes [207]. The choice of furanoid (179) or pyranoid (180) nature of the products can be determined by a suitable placement of hydroxyl substituents in the allylic (181) or homoallylic ( 182) positions of a corresponding cycloolefinic precursor. 

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