Subject natural product synthesis

The addition of an enolsilane to an aldehyde, commonly referred to as the Mukaiyama aldol reaction, is readily promoted by Lewis acids and has been the subject of intense interest in the field of chiral Lewis acid catalysis. Copper-based Lewis acids have been applied to this process in an attempt to generate polyacetate and polypropionate synthons for natural product synthesis. Although the considerable Lewis acidity of many of these complexes is more than sufficient to activate a broad range of aldehydes, high selectivities have been observed predominantly with substrates capable of two-point coordination to the metal. Of these, benzy-loxyacetaldehyde and pyruvate esters have been most successful. 

A relevant reductive process, which has found wide application in organic synthesis, is the deoxygenation of alcohols introduced in 1975 by Barton and McCombie [58]. Reaction (4.28) shows that the thiocarbonyl derivatives, easily obtained from the corresponding alcohol, can be reduced in the presence of BusSnH under free radical conditions. The reactivity of xanthates and thiocarbonyl imidazolides [58] was successfully extended to 0-arylthiocarbonates [59] and (9-thioxocarbamates [60]. Several reviews have appeared on this subject, thus providing an exhaustive view of this methodology and its application in natural product synthesis [61-64]. 

N-Boc-N-(but-2-enoyl)amine is an excellent pronucleophile for the Ir-catalyzed allylic amination under salt-free conditions (cf. Table 9.3, entries 15-18). The products were subjected to RCM with good results, even upon application of the Grubbs I catalyst (Scheme 9.29) [27bj. The resultant N-Boc protected a,P-unsaturated y-lactams are valuable chiral intermediates with appUcations in natural products synthesis and medicinal chemistry. 

Metal enolates have played a Umited role in the metal-catalyzed isomerization of al-kenes . As illustrated in a comprehensive review by Bouwman and coworkers, ruthenium complex Ru(acac)3 (51) has been used to isomerize a wide range of substituted double bonds, including aUylic alcohols (131), to the corresponding ketones (132) (equation 38) . The isomerization of aUylic alcohols affords products that have useful applications in natural product synthesis and in bulk chemical processes. An elegant review by Fogg and dos Santos shows how these complexes can be used in tandem catalysis, where an alkene is subjected to an initial isomerization followed by a hydroformylation reaction ... 

Numerous applications of the latter methods to stereoselective20 25- 94 105 and asymmet-ric26-33,io6-r is organic ancj natural product synthesis have been described however, those methods which use a stoichiometric amount of the metal are not the subject of this section. Few examples of transition metal catalyzed cyclopentenone and cyclopentadienone syntheses starting from alkenes and alkynes have been reported 34. It should be noted, however, that considerable efforts (and the first positive results) towards the catalytic use of zirconium13 and cobalt (in the Pauson-Khand reaction)35 36- U6l 117 have been reported. 

Other complex, chiral oxazolidines of this type have proved to be useful in natural product synthesis (Scheme 76). The epimeric esters 218 were separately converted to their respective O-benzylcarbinols 219. These were subjected to a desaturation-oxidation sequence to give 220. Lactam reduction followed by N- and 0-hydrogenolysis gave the azasugars 221 <04TL4903>. 

Eight-membered rings can be obtained by [4+4]-cycloadditions of 1,3-dienes [1] via diradicals or other intermediates. Synthesis of such compounds has been achieved by thermal, [2] photochemical, [3] and by metal-catalyzed [4] processes these reactions have been the subject of extensive mechanistic [5] and theoretical [5c] studies. Their strategic applications in natural product synthesis have been reviewed. [5d] The thermal version has generated little interest, except in orthoquino-dimethane dimerizations and in cycloreversions the Cope rearrangement of 1,2-divinyl-cyclobutanes [3] is more commonly used. [4+4]-Cycloadditions are also used with 1,3-dipoles or mesoionic heterocycles for the synthesis of six- and seven-membered rings. Sometimes also [6+4]-cycloadditions are... 

This chapter is divided according to a number of subject areas. First and foremost will come information on new catalyst systems that have served to increase the applicability of this chemistry. Second, some examples for the use of the Stille chemistry in natural product synthesis will be given this area is increasing explosively in importance. Applications in organic chemistry wiU then be presented, followed by selected examples dealing with the synthesis of polymeric and inorganic target molecules. 

Another recent and outstanding achievement of Canesi s group is their version of a synthesis of rac-isostrychnine in only nine steps starting from the readily available phenol 166, which was first converted into the phenohc amide 167 (Fig. 42) [106]. This compound was subjected to a DIB-mediated methoxylative phenol dearomatization to afford the para-quinol ether 168, the amide function of which was then engaged in an intramolecular aza-Michael addition (Mito its cyclohexa-2,5-dienone moiety to forge the fused bicyclic system 169 en route to isostrychnine, which was obtained after six additional steps (Fig. 42) [106]. Canesi s group also reported several elegant applications of the phenol dearomatization-induced processes of their own invention in natural product synthesis, such as in... 

The first successful natural product synthesis incorporating a DTDA reaction sequence was published by Sherburn and coworkers in 2008, and constitutes a formal synthesis of triptolide (165) (Scheme 12.34) [46]. The carbon framework of this natural product was rapidly assembled from silyl protected [3]dendralene 161, beginning with a DA reaction between the free alcohol and methyl acrylate. In situ lactonization provided semicyclic diene 162, which was subjected to a high-pressure DA reaction with quinone 163. Tetracycle 164 was functionalized further to intercept an intermediate from Berchtold s 1982 total synthesis of triptolide [47]. 

In 2007, Hoveyda and Gillingham disclosed the total synthesis of (+)-baconipyrone C (143), which represents the first, and a rare example of, application of a Ru-catalyzed alkene ROM/RCM to complex natural product synthesis (Fig. 38) [90]. By treatment of oxabicycle (144) with 2 mol% chiral Ru carbene catalyst, the key highly functionahzed pyran intermediate (145) was prepared in 63% yield and 88% ee. Notably, the chiral catalyst was generated in situ by subjection of... 

The total synthesis of fluvirucinine A1 127 provides a powerful illustration of the utility of Fu s methodology in natural product synthesis (Scheme 13.34). The asymmetric Negishi reaction of racemic allylic chloride 122 with alkylzinc bromide 123 in the presence of Ni/Pybox catalyst system provided ester 124 in 93% yield and 96% ee. After few steps, the organozinc reagent of bromide 125 was subjected to a second Negishi reaction with chloride 122 under identical coupling conditions to furnish derivative 126 in 80% yield and excellent enantioselectivity. 

Diels-Alder reaction to give 226 as an intennediate. When 226 was subjected to healing, an aza-Prins reaction followed by loss of a proton afforded 228 in 77 % overall yield for the entire sequence commencing with diol 224. This late-stage intermediate was readily utilized to complete the total synthesis of the squalene-derived natural product methyl homosecodaphniphyllate (229) [114]. This masterful synthesis qualifies, without doubt, as one of the all-time triumphs in natural products synthesis [116],... 

Total synthesis of baconipyrone C, summarized in Scheme 12.5 [10], is the first and only application of Ru-catalyzed enantioselective olefin metathesis to natural product synthesis. Treatment of oxabicycle 11 with styrene and 2mol% chiral Ru complex [Ru]-XV [11] leads to the formation of pyran 12 in 62% yield and with an enantiomeric ratio of 94 6. Ru-carbene [Ru]-XV is generated in situ by subjecting the corresponding Ag-based N-heterocyclic carbene (NHC) to an achiral Ru-PCys complex and Nal. It is also worthy of note that the diketone fragment of baconipyrone C was synthesized through a tandem double-allylic alkylation process promoted by a chiral NHC-Cu complex that is structurally related to carbene [Ru]-XV. 

The synthesis of natural products containing the quinonoid stmcture has led to intensive and extensive study of the classic diene synthesis (77). The Diels-Alder cycloaddition of quinonoid dienophiles has been reported for a wide range of dienes (78—80). Reaction of (2) with cyclopentadiene yields (79) [1200-89-1] and (80) [5439-22-5]. The analogous 1,3-cyclohexadiene adducts have been the subject of C-nmr and x-ray studies, which indicate the endo—anti—endo stereostmcture (81). 

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