Totally disconnected

Formylrifamycin was then attached to the solid support through hydra-zone formation. Under several cleavage conditions, it proved possible to obtain either 3-formylrifamycin or rifampicin in good to excellent yield. For example, in case of cleavage with acetone/1% HCl, the product is obtained in 80% overall yield over linker synthesis and connection/ disconnection (total six steps) [98]. 

Disconnection of non-building-block rings which are embedded in a skeleton and also centrally located, either by breaking one bond or a pair of bonds. The one-bond disconnections which are of value are (a) bonds between C and N, O or S and (b) bonds leading to a totally symmetrical, locally symmetrical, or linear skeleton. The bond-pair disconnections which are most effective in simplification are those which generate two structures of roughly equal complexity. 

If B— [bij] is an N xN matrix in which bu equals the degree of vertex i, bij = —1 if vertices i and j are adjacent and bij = 0 otherwise, then the number of spanning tree of G is equal to the determinant of any principal minor of B [hararybO]. The extremes occur for totally disconnected graphs that have no spanning trees and thus a complexity of zero, and for complete graphs of order N that contain the maximum possible number of distinct trees on N vertices. ... 

The synthesis of an epothilone model system via an alternative C9-C10 disconnection was first examined by Danishefsky in 1997. However, extension of this C9-C10 strategy to a fully functionalized epothilone intermediate was not successful, demonstrating the limitations of RCM with the early catalysts A and B [116]. In 2002, Sinha and Sun disclosed the stereoselective total syntheses of epoA (238a) and epoB (238b) by the RCM of epoxy compounds 242 in the presence of catalyst C (Scheme 50) [117]. The reaction furnished an inconsequential mixture of isomers 243 (E/Z 1 1) in high yield. Subsequent selective hydrogenation of the newly formed double bond followed by deprotection led to epothilones A and B. 

The overall yield was about 12% over a longest linear sequence of 23 steps and about 40 steps total. The major disconnections are illustrated below. 

In determining the total amount of depreciation an estimate must be made of the value of the asset when it is taken out of service. This is called the salvage value. Usually before an item can be sold it must be disconnected and removed from the system. When the cost of these operations is subtracted from the salvage value, the net salvage value is obtained. The total amount to be depreciated is then the original cost minus net salvage value. 

An unusual cationic domino transformation has been observed by Nicolaou and coworkers during their studies on the total synthesis of the natural product azadirachtin (1-105) [30]. Thus, exposure of the substrate 1-106 to sulfuric acid in CHjClj at 0°C led to the smooth production of diketone 1-109 in 80% yield (Scheme 1.27). The reaction is initiated by proto nation of the olefinic bond in 1-106, affording the tertiary carbocation 1-107, which undergoes a 1,5-hydride shift with concomitant disconnection of the oxygen bridge between the two domains of the molecule. Subsequent hydrolysis of the formed oxenium ion 1-108 yielded the diketone 1-109. 

An alternative disconnection of homopropargylic alcohols substrates for intramolecular hydrosilylation is the opening of an epoxide with an alkynyl anion. This strategy was employed in a total synthesis of the macrolide RK-397 (Scheme 20). Epoxide ring opening serves to establish homopropargylic alcohol C with the appropriate stereochemistry. A hydrosilylation/oxidation protocol affords the diol E after liberation of the terminal alkyne. The... 

The C12,C13 disconnection strategy has been employed by several groups to complete total syntheses of epothilone A (4). Nicolaou et al. were the first to report the successful application of this strategy to the construction of a naturally occurring epothilone [13,15] (Scheme 5). 

Using a similar C12,C 13 disconnection approach, Schinzer et al. also achieved a total synthesis of epothilone A (4) [16]. The key step involved a highly selective aldol reaction between ketone 27 and aldehyde 10 to afford exclusively alcohol 28 with the correct C6,C7 stereochemistry (Scheme 6). Further elaboration led to triene 29, which underwent RCM using ruthenium initiator 3 in dichloromethane at 25°C, to afford macrocyles 30 in high yield (94%). Although no selectivity was observed (Z E=1 1), deprotection and epoxidation of the desired Z-isomer (30a) completed the total synthesis [16]. 

An application of this variation was put forward in the total synthesis of oc-talactin (Scheme 14). In retrosynthetic disconnection the macrolactone sim-... 

The obvious disconnection in cyclopeptide alkaloids and indeed the strategy employed in most total syntheses of this type of compound is the formation of the aryl ether bond. Many groups chose to form the macrocyclic aryl ether by S Ar reaction. We decided to follow the inverse strategy, i.e., displacement of an allylic leaving group by a phenolate. In case of the natural cyclopeptide alkaloids, this would involve activation of yS-hydroxy-a-amino acids, which is likely to be accompanied by extensive elimination. Elimination is not possible when a-methylene- -hydroxy acids are used. Additionally, the double bond activates the leaving group and provides a handle for a possible later side chain attachment. 

Synthetic transformations which are parts of total syntheses of natural products are outlined by a general retrosynthetic outline. For each retrosynthetic disconnection, suggest a reagent or short sequence of reactions which could accomplish the forward synthetic reaction. The proposed route should be diastereoselective but need not be enantioselective. 

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