Disconnection of Bridged-Ring Systems

The individual bonds of a bridged ring system which are eligible for inclusion in the set of strategic bond disconnections are those which meet the following criteria. 

A strategic bond must be an exendo bond within a primary (i.e. non-peripheral, or non-perimeter) ring of 4-7 members and exo to a primary ring larger than 3-membered. 

A disconnection is not strategic if it involves a bond common to two bridged primary rings and generates a new ring having more than 7 members. Thus the disconnections shown for 128 and 129 are allowed by rules 1 and 2, whereas those shown for 130 and 131 are not. 

If the disconnection of a bond found to be strategic by criteria 1-3 produces a new ring appendage bearing stereocenters, those centers should be removed if possible (by stereocontrolled transforms) before the disconnection is made. 

Bonds within aromatic and heteroaromatic rings are not strategic. 

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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. 

Two possible intramolecular disconnections are available for the [2.2.2] bicyclo-octane ring system (path A and path B, Scheme 1.4). The choice between the initial [4+2] disconnections A and B at first appears inconsequential leading to idealized intermediates of comparable complexity (54 and 57). However, when the [4+2] and [3+2] disconnections are considered in sequence, the difference becomes clear. For path A, retrosynthetic [3+2] disconnection of intermediate 54 leads to the conceptual precursor 56, which embodies a considerable simplification. In contrast, path B reveals a retrosynthetic [3+2] disconnection of intermediate 57 to provide the precursor 59, a considerably less simplified medium-ring bridged macrocycle. Thus, unification of the [3+2]/[4+2] dual cycloaddition strategy, using the staging... 

As in the case of acyclic compounds, the level of difficulty of the synthesis of a cyclic compound depends upon whether the molecule is a consonant or a dissonant system. However, some additional difficulties may be encountered in molecules with medium-sized rings as well as in polycyclic bridged compounds, which are treated in the next Chapter. On the other hand, as we have seen in Heading 4.3, even simple monofunctionalised cyclic molecules may require a FGA operation before bond disconnection of the cyclic network at the ipso-, a- or 13-positions can be effected. 

Enyne cycloisomerizations can also be exploited to annulate a cyclopentane onto an existing ring system. An example drawn from Trost and co-workers asymmetric total synthesis of picrotoxinin (119) is the conversion of bridged bicyclic intermediate 117 into tricycle 118 (Scheme 6-20) [46]. The optimal cyclization conditions in this case were unusual, requiring an internal proton delivery and a bidentate phosphine. A related example is the conversion of 120 to 121, which was the pivotal step in Trost s synthesis of (—)-dendrobine (122) [47]. An all-carbon tether is not required, as is exemplified by the conversion of 123 to 124 in the total synthesis of ( )-phyllanthocin (125) [48]. Note that in-situ reduction of the o-palladium species prior to /5-hydride elimination has occuined in this latter-example. The enyne disconnection in the synthesis of ( )-phyllanthocin was... 

In fact, the overall perspective and conception of a synthesis commences with a careful logical dissection of the tai et-drug-molecular skeleton into S3mthons. However, the disconnection of a bond within a monocyclic system shall be a retro-synthetic ring-opening phenomenon, otherwise termed as the retro-synthetic approach. Likewise, the disconnection of a bond caused in a bridged-structure would ultimately produce either a mono- or a di- substituted monocyclic structure. Sometimes, it may also be possible to accomplish two-bond disconnections taking place almost simultaneously. 

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