Macrolide Natural Products

Titanium enolate aldol reactions have been used in the syntheses of several of important antitumor macrolides and of the immunosuppressive macrolide rapamycin. Duthaler s titanium enolate acetate aldol reaction svas used in the synthesis of epothilone 490. A variety of titanium enolate-based syn aldol reactions highlight the scope and utility of this technique. 

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Migrastatin (192) (Scheme 37) is a novel macrolide natural product that displays an inhibitory effect on the migration of human tumor cells. After an RCM-based synthesis of the 14-membered macrolide core of 192 [94], Danishefsky also achieved the first total synthesis of the natural compound [95], using the fully functionalized tetraene 191 as the metathesis precursor. Under the conditions shown in Scheme 37, the ring-closing step proceeded (E)-selectively with exclusive participation of the two terminal double bonds in 191, delivering only the ( , ,Z)-trienyl arrangement present in 192. 

A large number of macrolide natural products contain long, stereodefined polyol fragments. In their original report on the linchpin three-component coupling... 

Masamune s norephedrine-based anti -aldol methodology was again employed successfully in the total synthesis of the antitumor macrolide natural product rhizoxin D (17)7 (Scheme 2.2g). The synthesis began with an anti-aldol addition of boron enolate of 3-ent to the aldehyde 18. The addition proceeded with... 

Bryostatin 1 (Figure 8.15) is a complex macrolide natural product originally discovered by Pettit and his collaborators under an early NCI program. It has excellent anticancer activity which is due, at least in part, to its ability to interact with protein kinase C (PKC) isozymes. Compound supply as usual proved to be a major problem, but enough cGMP-grade material could be isolated from wild collections to supply material for clinical trials. ... 

White, J.D., Tiller, T., Ohba, Y, Porter, W.J., Jackson, R.W., Wang, S., and Hanselmann, R., Total synthesis of rutamycin B via Suzuki macrocyclization, J. Chem. Soc., Chem. Commun., 19, 1998. Lafontaine, J.A., Provencal, D.P., Gardelli, C., and Leahy, J.W., The enantioselective total synthesis of the antitumor macrolide natural product rhizoxin D, Tetrahedron Lett., 40, 4145, 1999. 

Due to the prevalence of many macrolide natural products, Yamaguchi s esterification has been used extensively in the total syntheses of such compounds. Increasingly, Yamaguchi s method has succeeded where other notable esterification conditions have failed. A recent example involves the coupling of two monomers to form the clavosolide A dimer.17 The Corey-Nicolaou protocol mentioned previously gave only a 30% conversion whereas the Yamaguchi esterification resulted in a clean reaction with a 66% yield. 

Salomon, A. R., Zhang, Y, Seto, H., and Khosla, C. (2001). Structure-activity relationships within a family of selectively cytotoxic macrolide natural products. Org. Lett. 3, 57-59. 

We begin these case studies with a total synthesis of the macrolide natural product... 

Tam and Fraser-Reid have also prepared the geometric isomers of compound (7) as analogues of the furenone moieties found in many germacranolide sesquiterpenes (see outline in Scheme I), and compound (8) is a further branched-chain furanoid product obtained from a carbohydrate (Scheme 3). It is a synthon for the macrolide natural product maytansine. ... 

Since 2007, our group has been working on the total synthesis and biochemical mode of action of marine macrolide natural products. We have already published total syntheses of neopeltolide (first generation, 2008 " second generation, 2010 ) and aspergillides A and B (2010). On the basis of these successful experiences, we initiated our own studies on the total synthesis of lyngbyaloside B, which will be detailed in the following sections. 

The synthesis of macrolide natural products has captured the attention and inspired significant research effort over many decades. Compounds in this class frequently display potent biological activity. Often, completion of the target requires a late stage macrocyclization event between an activated carboxylic acid derivative and... 

In 2003, Theodorakis et al. described the asymmetric synthesis of a key fragment corresponding to borrelidin (267, Figure 7.7). This macrolide natural product was isolated from Streptomyces rochei in 1949 and exhibits a broad antiviral and antibacterial prolile. Structurally, it contains an atypical 18-membered ring distinguished by a 1,3,5,7-skipped methylene chain, cyclopentane carboxylic acid, and conjugate cyanodiene unit. 

The use of directed reductions has proven to be a versatile and reliable tool in complex molecule synthesis, in particular in the synthesis of macrolide natural products. An example that highlights this strategy is the synthesis of the antifungal polyene macrolide roxaticin (137), which incorporates both 1,3-syn and 1,3-anti dioxygenated structural motifs (Scheme 2.16). In their impressive total syntheses, Mori [83] and Evans [84] took advantage of both syn- and anti-selective reductions. In all cases, these proceeded in excellent yield and diastereoselectivity. 

Natural Products. Naturally occurring 14-membered macrolides are given in Table 3. 

Use of DMF as a solvent for the oxidation of l-o1efins has been reported by Clement and Selwitz. The method requires only a catalytic amount of PdCl2 and gives satisfactory yields under mild conditions. A small amount of olefin migration product is the only noticeable contaminant in the cases reported. The procedure can be applied satisfactorily to various 1-olefins with other functional groups. This useful synthetic method for the preparation of methyl ketones has been applied extensively in the syntheses of natural products such as steroids,macrolides, dihydrojasmone, and muscone. " A comprehensive review article on the palladium-catalyzed oxidation of olefins has... 

Many natural products are lactones, and it is not unusual to find examples in which the ring size is rather large. A few naturally occuning lactones are shown in Figure 19.8. The macrolide antibiotics, of which erythromycin is one example, are macrocyclic (large-ring) lactones. The lactone ring of erythromycin is 14-membered. 

This highly convergent synthesis amply demonstrates the utility of Evans s asymmetric aldol and alkylation methodology for the synthesis of polypropionate-derived natural products. By virtue of the molecular complexity and pronounced lability of cytovaricin, this synthesis ranks among the most outstanding synthetic achievements in the macrolide field. 

The hydroxy groups in natural products like, for example, the macrolide antibiotics erythromycin, 1"1 and desmycosin, 2001 2011 as well as the 3-(hydroxymethyl)-2- or 3-cephems 2021 and derivatives of the amino sugar garamin 2031 have been converted into the carbamate function with CDI and amines. In the case of aminoglycoside antibiotics of the sisomicin series, thiocarbamates or dithiocarbamates have been prepared from alcohols or thiols using ImCSIm and amines.12041... 

The described procedure has been widely used by Smith III and coworkers [250] in the efficient total synthesis of natural products containing extended 1,3-hydroxylated chains. This architecture is often found as a structural element in polyene macrolide antibiotics [251] such as mycotoxin A and B, dermostatin, and roxaticin. The Smith group used the above-mentioned approach (e. g., as five-component coupling) for the synthesis of the pseudo-C2-symmetric trisacetonide (+)-2-471 [252], which was employed by Schreiber and coworkers [253] within the synthesis of (+)-mycotoxin A (2-470a) (Scheme 2.108). Thus, lithiation of 2.5 equiv. dithiane 2-462b followed by treat-... 

The thermally and Lewis acid-promoted transannular Diels-Alder reactions have proven to be a powerful tool for the synthesis of steroids and other natural products [24]. A research team led by Takamura, Arimoto, and Uemura utilized this reaction to assemble the polycyclic skeleton of nakiterpiosin (1) [25]. Heating macrolide 39 at 160 °C gave 40 and 41 as a mixture of diastereomers in good yields. 

Steroid chemistry, the glamor area of natural product research in the years following World War II, was replaced by macrolides, alkaloids, and prostanoids. Sterol chemistry again became exciting when an unanticipated rich diversity of marine invertebrate sterols were isolated, notably from sponges. After pioneering research in Italy, the field was reborn in Carl Djerassi s laboratory at Stanford. As a result, we now have a better and more detailed knowledge of sterol biosynthesis than of any other class of marine natural products. The authors of Chapter 1 are Stanford alumni. 

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