Retrosynthetic analysis bond disconnections

A generalised retrosynthetic analysis involving disconnection of the carbon-heteroatom bond may be depicted as follows. 

An example of the Knorr pyrrole synthesis is provided by the formation of 3,5-diethoxycarbonyl-2,4-dimethylpyrrole (55). Overall ring construction in this case may be related to (46) above. A retrosynthetic analysis involving disconnection of the N—C2 bond, appropriate prototropic shifts, and finally a retro-aldol reaction to effect disconnection of the C3—C4 bond, reveals ethyl acetoacetate and ethyl a-aminoacetoacetate (ethyl 2-amino-3-oxo-butanoate) (56) as reagents. An FGI transform on this latter compound generates the corresponding nitroso (oximino) compound which may also be derived from ethyl acetoacetate. 

Topological Strategy. The use of a particular bond, pair of bonds, set of bonds, or subunit as eligible for disconnection to guide retrosynthetic analysis conversely the designation of bonds or cyclic subunits as ineligible for disconnection (i.e. to be preserved). 

Proceeding with the retrosynthetic analysis, it is now timely to address the issue of the rather sensitive oxetane ring. Disconnection of the C5-0 bond as indicated in structure 5 and engagement of... 

Scheme 1. Strategic bond disconnections and retrosynthetic analysis of taxol (1).

The initial step in creating a synthetic plan involves a retrosynthetic analysis. The structure of the molecule is dissected step by step along reasonable pathways to successively simpler compounds until molecules that are acceptable as starting materials are identified. Several factors enter into this process, and all are closely interrelated. The recognition of bond disconnections allows the molecule to be broken down into key intermediates. Such disconnections must be made in such a way that it is feasible to form the bonds by some synthetic process. The relative placement of potential functionality strongly influences which bond disconnections are preferred. To emphasize that these disconnections must correspond to transformations that can be conducted in the synthetic sense, they are sometimes called antisynthetic transforms, i.e., the reverse of synthetic steps. An open arrow symbol, = , is used to indicate an antisynthetic transform. 

In considering the retrosynthetic analysis of juvabione, two factors draw special attention to the bond between C(4) and C(7). First, this bond establishes the stereochemistry of the molecule. The C(4) and C(7) carbons are stereogenic centers and their relative configuration determines the diastereomeric structure. In a stereocontrolled synthesis, it is necessary to establish the desired stereochemistry at C(4) and C(7). The C(4)-C(7) bond also connects the side chain to the cyclohexene ring. As a cyclohexane derivative is a logical candidate for one key intermediate, the C(4)-C(7) bond is a potential bond disconnection. 

The initial retrosynthetic analysis of 1 resulted in the cleavage of the two amide bonds and a C-N bond leading to the four components oxadiazole carbonyl chloride 2, methyl iodide, 4-fluorobenzylamine (4-FBA) and the densely functionalized hydroxypyrimidinone 3 (Scheme 6.1). These synthetic disconnections were reasonable and should be applicable for long term route development. 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

Since in the synthesis of heterocyclic compounds the ring closure usually involves the formation of the carbon-heteroatom bond, in the retrosynthetic analysis the first bond to be disconnected is the carbon-heteroatom bond (Cf. heuristic principle HP-8), either directly or after the pertinent (FGI or FGA) functional group manipulation. For instance, compound 17 -which is the starting material for Stork s synthesis of Aspidosperma alkaloids [30]- may be disconnected as shown in Scheme 6.11. 

Since in the systems containing two adjacent heteroatoms it is not usual that the ring clorure involves the formation of the bond between them (exceptions may be found in the cases of functional groups such as nitro, nitroso or diazonium), in the retrosynthetic analysis the bond between the two adjacent heteroatoms should not be disconnected. 

The retrosynthetic analysis also involves disconnection of the "strategic bond" C(2)-C(3) and the sequence is very similar to that described above by Szychowski and MacLean Heading 75.2.5). The actual synthesis, however, rather than the intermediate 48b shown in Scheme 13.2.13 -whose hydrogenation leads to the wrong stereochemistry (51)- requires the tetrahydro derivative 52 from which ester 47b can be obtained stereoselectively by catalytic hydrogenation with Adam s... 

The retrosynthetic analysis proceeds according to Scheme 13.4.1 and starts with the application of the heuristic principle number 8 (HP-8) i.e., performing the systematic disconnection of the nucleophilic heteroatom attached to the carbon backbone. Of the three bonds connecting the nitrogen atom, bond a is the most... 

In contrast to Nicolaou s synthetic plan, the retrosynthetic analysis of Holton s approach preserves the non-synthetically significant B ring and proceeds through disconnection of bonds which are involved in the D and C rings, to arrive finally to the bicyclo[5.3.1]undecane derivative 32, as the starting material. 

Systematic bond disconnection of porantherine [151] with recognition of the double bond-carbonyl equivalence for synthesis generated a synthetic pathway which is based on two intramolecular Mannich reactions. The symmetrical nature of the amino diketone precursor identified by the retrosynthetic analysis facilitates its preparation and subsequent transformations. Moreover, all the hetero atoms (donors) are separated by odd-numbered carbon chains and such arrangements are most amenable to normal modes of assembly. 

While the carbonyl group is a very common starting point for bond disconnections in retrosynthetic analysis, an olefinic or acetylenic unit is also a useful reference point in many instances. This is because a terminal acetylene can be used as an... 

A retrosynthetic analysis applied to each of these carboxylic acid derivatives suggests a fission of the carbon-heteroatom bond (C—O, C—X, C—N), i.e. disconnection processes. Such logic can be useful in the recognition of the reagents that could be used in the synthesis of these functional types, when these are present in more complex molecules, as illustrated below. 

This time-honoured view of ring construction preceded the retrosynthetic approach it is still of value since it provides an indication of which bonds could be selected for disconnection. The more rigorous application of the principles of retrosynthetic analysis leads of course to the formulation of synthons and their reagent equivalents. 

A retrosynthetic analysis of (50) and (52) involving disconnection at both carbon-heteroatom bonds reveals hexane-2,5-dione as the four-carbon fragment needed for ring assembly ring construction is thus of type (45). The most convenient reagents for the appropriate heteroatom synthons are ammonium carbonate and phosphorus pentasulphide (Expts 8.11 and 8.13). 

The retrosynthetic analysis of 2,4,6-triphenylpyrylium tetrafluoroborate (86), involving an initial reduction followed by a disconnection of one carbon-oxygen bond (cf. disconnection of 2,5-dimethylfuran, Section 8.3.1, p. 1146), reveals the substituted 1,5-dicarbonyl compound (89). Further rational disconnection then reveals acetophenone and l,3-diphenylprop-2-en-l-one (chalcone) clearly the latter may originate from acetophenone and benzaldehyde (cf. Section 6.12.2, p. 1032). 

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