Retrosynthetic analysis disconnections

Figure 1.3 Retrosynthetic analysis disconnection of A to give two synthons (d) and (e)...

Scheme 3. Typical oligosaccharide structures found as complex-type t -glycans. Retrosynthetic analysis —> disconnections 1-4.

There are three key mles to be followed in retrosynthetic analysis disconnection should follow the correct mechanism, allow maximal simplification of the TM and lead to available starting materials. The fexofenadine molecule can be maximally simplified by discormections made at critical bonds (Scheme 10.3). These are disconnections at the CH2-aryl bond (a) and an alternative disconnection of the CH2-CH2Ar bond (b). In addition, disconnection of the N-CH2 bond, after FGI of the amine to an amide group, represents another possibility (c), which can be completed to create a pathway to the sila-bioisostere of fexofenadine, as described in Sect. 10.4.3. 

Here it is important to note the principle difference between the retrosynthetic steps in Schemes 1.3 and 1.4. In the first one we anticipate interconversion of the functional group (FGI), in the second one the disconnection of the C-C bond (DIS). They reflect the difference between two basic types of reactions in synthetic organic chemistry the transformation of one functional group and formation of a new C-C bond. By far more synthetically important are C-C bond-forming reactions, which enhance the complexity of the carbon skeleton. A rather sharp difference between these two types of reactions in synthetic organic chemistry is reflected in retrosynthetic analysis. Disconnection of the C-C bond in TM la is presented in some detail (Scheme 1.5). 

To recognize the different levels of representation of biochemical reactions To understand metabolic reaction networks To know the principles of retrosynthetic analysis To understand the disconnection approach To become familiar with synthesis design systems... 

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). 

Methoxatin, now known as coenzyme PQQ, was originally obtained from methylotrophic bacteria but is now known to be a mammalian cofactor, for example, for lysyl oxidase and dopamine p-hydroxylase. The first synthesis of this rare compound was accomplished by the route outlined below. In the retrosynthetic analysis both of the heterocyclic rings were disconnected using directly keyed transforms. 

The co-occurring marine allomones 2- and 9-isocyanopupukeanane have been synthesized from a common intermediate. This condition along with topologically based strategic disconnection had a major impact on the retrosynthetic analysis. 

Venustatriol, a marine-derived antiviral agent, as with many polyether structures, is a straightforward problem for retrosynthetic analysis. The major issues, clearance of stereocenters and topologically strategic disconnection, were readily resolved to generate the pathway of synthesis described below. 

The retrosynthetic analysis presented in Scheme 6 (for 1, 2, and 16-19) focuses on these symmetry elements, and leads to the design of a strategy that utilizes the readily available enantiomers of xylose and tartaric acid as starting materials and/or chiral auxiliaries to secure optically active materials.14 Thus by following the indicated disconnections in Scheme 6, the initially generated key intermediates 16-19 can be traced to epoxide 23 (16,19 =>23),... 

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. 

Scheme 13.3. Retrosynthetic Analysis of Juvabione with Disconnection to... 

A retrosynthetic analysis corresponding to the synthesis in Scheme 13.28 is given in Scheme 13.27. The striking feature of this synthesis is the structural simplicity of the key intermediate 27-IV. A synthesis according to this scheme generates the tricyclic skeleton in a single step from a monocyclic intermediate. The disconnection 27-III-27-IV corresponds to a cationic cyclization of the highly symmetric allylic cation 27-IVa. 

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. 

The natural product panepophenanthrin (6/1-170), isolated in 2002 from the fermented broth of the mushroom strain Panus radus IFO 8994 [90], is the first example of an inhibitor of the ubiquitin-activating enzyme [91]. Retrosynthetic analysis based on a biomimetic analysis led to the conjugated diene 6/1-172 by a retro-Diels-Alder reaction via the hemiacetal 6/1-171. Further disconnections of 6/1-172 produces the vinyl stannane 6/1-173 and the vinyl bromide 6/1-174 [92]. 

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. 

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