Total Synthesis of Natural Products

Thus, radical denitradon has developed as a reliable tool in organic synthesis and has been mainly carried out using dn hydnde in total syntheses of natural products. There is one report in which NaTeH was used for removing the nitro group. Norslanadione, a biologically acdve... 

Figure 2. Selected landmark total syntheses of natural products from 1828 to 1944.

Saito N., Grieco P. A. Development of Cationic Diels-Alder Reaction in Highly Polar Media and Total Syntheses of Natural Products Yuki Gosei Kagaku Kyo-kaishi 2000 58 39-49... 

Scheme 9.17 Baeyer—Villiger biooxidation of a prochiral hetero-bicycloketone and subsequent synthetic elaboration in formal total syntheses of natural products.

Several synthetic transformations that are parts of total syntheses of natural products are summarized by retrosynthetic outlines. For each retrosynthetic transform suggest a reagent or short reaction sequence that could accomplish the forward synthetic conversion. The proposed route should be diastereoselective but need not be enantioselective. 

The intramolecular insertion reactions of nitrenoids into G-H bonds as described above provide an attractive alternative to conventional methods of amine formation. Both carbamate and sulfamate C-H insertions have been applied successfully to the total syntheses of natural products. - The first application of carbamate G-H insertion was reported by Trost in the total synthesis of methyl-L-callipeltose 118 (Equation (92)).230 Intermolecular G-H insertion of carbamate 117 using 10mol% Rh2(OAc)4, PhI(OAc)4, and DTBMP (2,6-di-/ / -butyl-4-methylpyridine) in dichloromethane (40 °C) furnished methyl-L-callipeltose 118 in 63% yield. In an another independent total synthesis of 118, Panek performed this step in refluxing benzene and improved the yield to 93%.231... 

TABLE 7-1. Comparison of Some Total Syntheses of Natural Products... 

An impressive example of a multi-step biomi-metic domino process is the synthesis of codaphni-phyllin by Heathcock et al. (see scheme 14). Another example is the highly efficient biomimetic synthesis of (+)-hirsutine by my group (see scheme 13). In addition several other total syntheses of natural products have been developed using domino processes these are described in the different sections of this chapter. 

Rhodium-catalyzed [5 + 2]-cycloaddition of an allene and a vinylcyclopropane proceeds with complete chemo-, endo/exo- and diastereoselectivity, representing an effective general route to bicyclo[5.3.0]decane derivatives (Scheme 16.75) [81]. This cydoaddition protocol has been applied successfully to asymmetric total syntheses of natural products [82, 83]. 

The application of chiral auxiliaries is an alternative route to obtain enantiomerically pure compounds. This approach has been frequently used in the total syntheses of natural products like hirsutene [53] and (+)-15-norpentalene [61]. 

Allyl alcohols readily react with trichloroacetonitrile to give the corresponding trichloroacetimidates 145. Activation of the double bond with electrophilic reagents results in ring closure to yield oxazolines 146. The most commonly employed electrophiles include iodine, iodine monochloride, phenylselenyl chloride, and mercuric trifluoroacetate. Other nitriles including cyanogen bromide and N,N-dimethylcyanamide can also be used. Since oxazolines readily hydrolyze to amides, the net effect of this reaction sequence is to produce p-amino alcohols 147 from an allyl alcohol. This strategy has been employed in numerous total syntheses of natural products. Examples are listed in Table 8.18 (Fig. 8.7 Scheme 8.43). ° ... 

Obtaining the correct stereochemistry at an asymmetric centre is crucial in the total syntheses of natural products. Moreover, pharmacological properties are closely related to the correct stereochemistry. Thus, the epimerization reaction, which enables equilibration of C-3 epimers,... 

Thereafter, these methodologies were extended to the preparation of o-quinone monoacatals (2b) [32-34] [Eq. (2)], and have been utilized widely for total syntheses of natural products such as miroestrol (4),thielocin Al (5),dyne-micin A (6), manumycin (7), nisamycin (8), xestoquinone (9), calicheamicinone (10), and asatone (11). 

These reactions were applied to total syntheses of natural products such as 6, ventiloquinone E (12), KW-2170 (13), and E09 (14). 

These related reactions have been utilized for total syntheses of natural products such as makaluvamine D (54), makaluvamine I (55), makaluvamine M (56), makaluvamine F (57), and michellamine A (58). Furthermore, synthetic studies on ellagitannin (59),benzo[c]phenanthridines (60), and rebeccamycin (61) have also been carried out. 

Total syntheses of natural products bearing a quinone structure have been accomplished efficiently by PIFA oxidation. That is, in the syntheses of antitu-... 

Ring-closing alkyne metathesis (RCAM) leads to alkyne macrocydes in excellent yields [36]. When combined with hydrogenation using a Lindlar-type catalyst, it is a convenient pathway to macrocydic Z-cydoalkenes. Fiirstner and coworkers utilized this strategy for numerous total syntheses of natural products [37], epothilone A being one of them [38]. 

As the reaction becomes more selective, CM steps are ever more frequently finding their way into total syntheses of natural products and their derivatives... 

Evans and others used this methodology to complete numerous total syntheses of natural products. For example, they built the spiroketal subunit 29 in the asymmetric synthesis of the macrolide antibiotic rutamycin B13 (Scheme 2.11). The... 

Boger et al. have worked out numerous total syntheses of natural products basing on aza Diels-Alder reactions of electron-deficient N-heterocycles which act as diaza-1,3-butadienes [11]. The key steps of these reactions have been highlighted in Sect. 3.5. 

The transient intervention of a carbonyl ylids has culminated in numerous elegant approaches to total syntheses of natural products, such as the synthesis of the tigliane ring system (61-63) by Dauben [53] (Scheme 28). 

Efficient and elegant syntheses of complex organic molecules with multiple stereogenic centers continue to be important in both academic and industrial laboratories (Nicolaou et al. 2003, 2006). In particular, catalytic asymmetric multicomponent domino reactions, used in the course total syntheses of natural products and synthetic building blocks, are highly desirable (Nicolaou et al. 2003, 2006 Tietze and Beifuss 1993 Tietze 1996 Tietze and Haunert 2000 Wasilke et al. 2005 Ramon and Yus 2005 Guo and Ma 2006 Pellissier 2006 Pellisier 2006 Tietze... 

Mori, M (2005) Development of a Novel Synthetic Method for Ring Construction Using Organometallic Complexes and Its Application to the Total Syntheses of Natural Products. Chem Pharm Bull 53 457 especially pp. 457 59... 

Several nucleophilic epoxidations have only been performed as one of several steps during the total syntheses of natural products. 

General Considerations. In addition to its use in peptide chemistry, (S)-proline is often applied as a chiral precursor in the total syntheses of natural products, e.g. odorin, pumiliotoxin, petasinecine," or threonine. Some highly effective pharmaceuticals, such as optically pure ACE inhibitors, are prepared from L-proline. In the last two decades, (S)-proline has attracted much attention as an optically active auxiliary in asymmetric synthesis. 

This transformation has found extensive use in converting cyclopentenone and cyclohexenone ring systems to the rearranged allylic alcohols during the course of the total syntheses of natural products. In the preparation of ( )-quadrone (Scheme 12), the tricyclic enone was epoxidized and the resulting a,P-epoxy ketone treated with hydrazine to afford the allylic alcohol. The cyclopropane-directed epoxidation shown in Scheme 13 gives an allylic alcohol that is taken on to (-)- and (+)-carenones. In the total syn-... 

Vinyl V,V,V, V -tetramethylphosphorodiamidates have also been of value in the total syntheses of natural products, such as ( )-castelanolide (Scheme 28) and ( )-albene (Scheme 29). Acetals survive the reduction, but benzyl ethers are cleaved. 

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