Anellated bicycles

During the last 10-15 years, more emphasis has been on the development of new synthetic routes for obtaining variously substituted less common representatives and new varieties of CC- or C/V-anellated bicyclic diazaphosphole systems. CC-Anellation is possible in A, B, and D, out of which benzo anellated representative of only D has been reported. But, C7V-fused derivative of D is not reported, though... 

Retrosynthetic analysis of anellated bicycles in this manner does not consider the endoendo bond, which is also called a fusion bond (Scheme 6.20). 

Similarly, tandem hydroformylation/aldol sequences can be applied to the formation of bicyclic and spirocyclic compounds. Thus silyl enol ethers of 3-vinyl and 3-allyl cycloalkanones give ring anellated products (Scheme 33) [86,87]. 

Our approach was to use the unsaturated bromodeoxylactones in an intramolecular radical reaction, since these compounds possess both the radical precursor and the radical trap within the same molecule. Thus, reacting the unsaturated bromodeoxyheptonolactone 20 (Scheme 14) with tributyltin hydride and a radical initiator, the bicyclic lactone 65 a was obtained in a quantitative yield within 1 h. The stereocontrol in the reaction was determined by the structure of the product, since the compound obtained has two fused cyclopentane rings which can only be cis anellated. The radical A, which is the intermediate, was trapped by the tin hydride. The stereochemistry of the newly formed chiral center is determined by the configuration at C-4 in the educt 20 [45]. 

Today the family of 1,3-heterophospholes contains monocyclic 1,3-azaphospholes (5), 1,3-oxaphospholes (6), 1,3-thiaphospholes (7) and 1,3-selenaphospholes (8), as well as the benzo derivatives (1), (2), (9) of (5)-(7) and a naphtho derivative (10). While the benzo derivatives (1) result formally from the 4,5-anellation to (5), 1,5- and 1,2-aneUation leads to two isomeric bicyclic systems such as (11) and (12) with a bridgehead nitrogen atom. Strictly speaking they therefore belong in Volume 8. However, they are also described here as they are closely related to the monocyclic... 

Scheme 6.21 Bond-sets for anellation schemes to obtain functionalized bicycles...

Annelation schemes provide a viable route to obtain bicycles. A much more rapid increase in complexity is achieved in bicyclization reactions. Here, bicycles arise directly from open chain precursors. Scheme 6.22 shows that again exendo bonds are considered in this two-bond disconnection, but it is a different pair of the exendo bonds than in anellation schemes ... 

When the target bicycle lacks a suitably placed double bond in a six-membered ring, retrosynthesis starts with FGA (= add double bond) [95, 96, 97, 98]. In bicyclization reactions forming an endoendo bond, the stereochemistry of the reaction has to be monitored (formation of a cis or of a trans fusion of the two rings). With anellated systems of a five- to a six-membered ring the cis juncture is thermodynamically favored. This renders it possible to reach a cis fused bicyclo[4.3.0]nonane system by an epimerization process following the bicyclization reaction [99] (Scheme 6.25). 

To judge the relative merits of an anellation versus a bicyclization strategy, it is instructive to look at the many syntheses [101] of compactin and mevinolin, which represented a popular synthesis target in the early 1980s (Scheme 6.27). 

Scheme 6.27 Anellation versus bicyclization during syntheses of compactin and mevinolin...

When considering the synthesis of anellated bi- and polycycles, the rapid increase in complexity associated with bicyclization reactions suggests that an evaluation of this possibility should be considered first. Therefore, determine whether the target contains a centrally located six-membered ring that can be constructed using an intramolecular Diels-Alder cycloaddition. 

There is a peculiarity in the examples in Scheme 6.53. The bond that is cleaved in reversal of the add bond operation is not the one that was made in the preceding bicyclization. Rather, it is one which has been intentionally introduced with one of the partners of the bicyclization. For the generation of eight-membered rings via an overbred skeleton, not only do bicyclo[4.2.0]octane systems serve well (Scheme 6.53), but so too do bicy-clo[3.3.0]octane systems, i.e., anellated 5/5-ring systems (Scheme 6.54). 

Cheng et al. have demonstrated the [2+2+2] cocyclization of two arynes with bicyclic alkenes giving the corresponding norbomane anellated 9,10-dihydrophenanthrene derivatives 105. The reaction probably proceeds by initial formation of a palladacycle from one aryne molecule and the... 

Although a solution seemed to be close by with these thiophenes, a technical breakthrough was achieved not until the Bayer researchers Friedrich Jonas and Gerhard Heywang decided to extend the thiophene structures to bicyclic ring systems. In other words, ring closure of two alkoxy substituents had to be accomplished to form dioxolane-, dioxane-, or dioxepane 3,4-anellated thiophenes (see Figure 4.3). 

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