Disconnection strategies

Figure 10.3-40. The rating for the disconnection strategy carbon-heteroatom bonds is illustrated, Please focus on the nitrogen atom of the tertiary amino group. It is surrounded by three strategic bonds with different values. The low value of 9 for one ofthese bonds arises because this bond leads to a chiral center. Since its formation requires a stereospecific reaction the strategic weight of this bond has been devalued. In contrast to that, the value of the bond connecting the exocyclic rest has been increased to 85, which may be compared with its basic value as an amine bond.

The disconnection strategy Carbon-Heteroatom Bonds gives only one strategic bond, which is rated with a value of 100. 

In order to continue the design of a synthesis, 2 is now analysed further by the disconnection strategy for aliphatic bonds. WODCA detects two strategic bonds which are rated 100 and 67, respectively. The disconnection of the bond with the highest rating forms two precursor compounds, 3 and 4 (Figure 10,3-52),... 

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). 

The cyclopropane moiety is a fundamental class of functional group present in both natural products and numerous therapeutic agents. It has provided the impetus for significant breakthroughs in the use of metal carbenoids [151] and organocatalytic ylide intermediates [152, 153] such that rehable methods exist for most disconnective strategies on this ring system. 

Target molecules which contain a carbon-carbon double bond, in the presence of other functionality or not, may be treated as in a one- or two-group disconnection strategy, as noted above. However, disconnection at the double bond may be a valuable retrosynthetic transform, since the synthons may then be related to reagent equivalents for a Wittig-type (Section 5.2.3, p.495 and Section 5.18) or aldol-type (Section 5.18) synthesis. 

The disconnection strategies summarised on p. 586 reveal that the nucleophilic organometallic reagents derived from alkyl halides (e.g. R MgX, RLi) require... 

An alternative representation of the disconnection strategy shown on p. 606 for these methods of synthesis of ketones is formulated below. 

The disconnection strategies shown in Tables 5.2 and 5.3 suggest the acylation of a ketone, in either the a-carbanion (7) or enol (8) [or specific enol equivalent (9)] forms, as a route to a 1,3-diketone. 

When the alkylidenesuccinic ester is derived from an aldehyde [e.g. (26)], functional group modification provides a route to y-keto acids and the overall process relates to the disconnection strategy outlined above. The required modifications are hydrolysis of the diester to the diacid and photocatalysed... 

Three target molecules, namely, cyclopropyl methyl ketone (1), cyclobutane-carboxylic acid (2) and 3-benzylcyclobutanone (3), are used to illustrate appropriate retrosynthetic disconnection strategies that may be applied to devise suitable synthetic procedures for these compounds. 

In 2007, Betzer, Ardisson and co-workers reported their synthesis of discodermo-lide [64] following the Marshall disconnection strategy of C7-C8 acetylide addition and Suzuki cross-coupling at C14-05 (Scheme 32) [53, 54], The synthesis of the key subunits 160 (C1-C7), 161 (C8-C14) and 162 (C15-C24) demonstrated the versatility of the Hoppe crotyltitanation reaction [166-169] in the synthesis of polypropionate motifs, using the incorporated (Z)-0-enecarbamate to configure the requisite alkene substitution patterns [170, 171],... 

A similar disconnection strategy was adopted by Dixon et al. in the United Kingdom in the synthesis of muricatetrocin The retro-synthesis disconnected the... 

Asperlicin (115), a potent cholecystoki-nin-A antagonist, was subjected to two different bond disconnection strategies, as indicated (72). 

WODCA offers four different disconnection strategies to identify strategic bonds in the target (1) aliphatic bonds (2) aromatic substitution (3) carbon-heteroatom bonds and (4) polycyclic compounds. Each strategy provides its own rules and results in a ranking factor for a bond between 0 and 100. The ranking is relative to the current chemical environment of the bond. This is due to the physicochemical properties that are calculated dynamically for each chemical environment rather than relying on static bond properties. 

After the disconnection strategy is defined, the systems indicate the strategic bond together with their ranks. The user can now analyze the precursor or can verify the disconnection by performing a reaction substructure search in any of the interfaced reaction databases. To perform a search in the reaction database, the user can define the bond sphere to be considered as identity criterion. The first sphere, for instance, includes bonds attached to the atoms of the strategic bond. A hit is presented as a reaction with additional information from the reaction database, such as reaction condition, yield, and references. 

The C-C disconnection strategy is more general (44) and has been used to make many pharmaceuticals. ... 

Disconnections that are based on powerful reactions will, therefore, greatly decrease the molecular complexity of the target, which is, of course, a major goal of a disconnection strategy. Corey listed several examples of such reactions.These reactions and synthetic examples are shown in Table 10.1. ... 

Scheme 1.13 Functionalization of C—H bonds a to a heteroatom as alternative disconnection strategies.

More recent contributions take advantage of hydroamination disconnection strategies in the assembly of more comphcated natural products. In these examples, simple hydroamination was not required, but an exploration of known hydroamination catalyst systems resulted in the identification of suitable reaction conditions for catalytic hydroguanidination reactions for the assembly of complex alkaloid targets. 

These final examples illustrate the power of hydroamination as a disconnection strategy in the assembly of complex natural products. Most importantly, these examples show that efforts in catalyst development have realized catalytic protocols that can be compatible with heavily functionalized substrates and can also be transferred to more specialized hydroguanidation reactions. 

In another report, the selection of a suitable point for the cydization of linear precursors was considered important for the disconnection strategy by Xia and Smith [156]. In their report, they determined the lowest energy conformation of each of the three possible hnear precursors using semiempirical calculations... 

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