Bicyclization reactions

Scheme 4.9 Some bicyclization reactions relevant to our desired transformation...

In the course of our successful synthesis, we identified several limitations of our new method and associated strategy (1) the harsh conditions of the bicyclization reaction do not tolerate base-sensitive functionality such as vinyl halides (2) post-cyclization manipulations such as iododesilylation reactions are complicated by the sensitive/ reactive functionality of the products (a,p-unsaturated aldehyde, indoline, etc.) and (3) the incorporation of the required functionality into the Zincke aldehyde requires the synthesis of a complex tryptamine derivative, resulting in a lengthy, non-convergent route. In order to develop a concise route to strychnine, we would have to address each of these issues, and a straightforward solution to obviate all of these is described below. 

SCHEME 8. Available bicycle reaction mechanisms. Main route heavy arrows minor pathways light arrows R1 or R2 = Ph, R3 = Ph... 

These allylpalladation-acylpalladation cascade bicyclization reactions have been applied mainly by Oppolzer to the synthesis of various natural products including (zb)-pentalenolactone E methyl ester [152], 3-isorauniti-cine [153], ( )-coriolin [154], and ( )-hirsutene [155]. Their application to the syntheses of [5.5.5.5]fenestrane derivatives by Keese [156,157] (Scheme 63) is also noteworthy. 

Consideration of molecular orbital interactions suggests that it would be ideal to use a transition metal complex having at least two empty and one filled nonbonding metal valence shell orbital, i.e. a 14-elec-tion species, for observing facile bicyclization reactions shown in equations (2)-(4). This is based on assumptions that effective ir-complexation of an alkyne or an alkene with a metal complex requires the... 

Prior to the development of enyne bicyclization reactions promoted by Zr and other Group IV metals, the Co-catalyzed enyne bicyclization-carbonylation reaction (the Pauson-Khand reaction ) was known. This reaction is discussed in Volume 5, Chapter 9.1. In the Pauson-Khand reaction, the overall transformation is the conversion of enynes into bicyclic enones, and the organometallic bicyclic intermediates are usually neither readily available nor isolated. The use of Co2(CO)s, an 18-electron species, necessitates relatively high reaction temperatures. These and other limitations suggested the desirability of developing alternative enyne bicyclization reactions. 

Fifthly, the bicyclization reaction of nitrogen-containing enynes, i.e. (16)-(18), not only proceeds satisfactorily but also reveals an intriguing and beneficial heteroatom effect. 

In more demanding cases, however, the Ti-promoted bicyclization reaction appears to be far inferior to the Zr-promoted reaction. For example, the reported yields of (28) for the Ti- and Zr-promoted reactions... 

The results presented above indicate that the Zr-promoted bicyclization reactions of enynes and diynes constitute novel and attractive synthetic methods. The corresponding reaction of dienes remains to be developed. Somewhat unexpectedly, the reactions of monoalkynes and monoalkenes can, in many cases, be highly pair selective and regioselective. Many aspects of these reactions also need to be further developed. Besides being attractive from the viewpoint of organic synthesis, the chemistry of ZrCp2 provides a number of novel structural and mechanistic features that broaden the horizon of organometallic chemistry. 

An intramolecular bicyclization reaction of the Robinson annelation-type has been reported as an extension of the aldol-type reaction (Eq. 12) [10]. The success of this multi-step reaction might be attributable to both the basicity and acidity of zirconium alkoxide. 

Zimmerman, H. E., Sebek, P., Photochemistry in a Crystalline Cage. Control of the Type B Bicyclic Reaction Course Mechanistic and Exploratory Organic Photochemistry, J. Am. Chem. Soc. 1997, 119, 3677 3690. 

Bicyclization reactions are used to form aromatic steroidal or homosteroidal (six-membered D-ring) skeletons. 

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). 

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