Bicyclo ring systems synthesis

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. 

The [4+ 4]-cycloaddition reaction of tethered bis-dienes has been used by Wender and co-workers in total synthesis as exemplified in syntheses of ( )-salsolene oxide and (-l-)-asteriscanolide (Scheme 28). In the synthesis of ( )-salsolene oxide, a nickel(0)-catalyst cleanly effects the cycloaddition of the two conjugated dienes in compound 93 to afford the bicyclo[5.3.1]undecadiene in a good yield and with moderate selectivity.99 The first synthesis of (-l-)-asteriscanolide was accomplished in only 13 steps. The key [4+ 4]-cycloaddition reaction efficiently set the requisite eight-membered ring of (-l-)-asteriscanolide in good yield and with excellent diastereoselectivity.100 The diastereoselective [4 + 4]-cycloaddition has also been applied to the synthesis of the core ring system found in several sesterterpenes such as the ophiobolins (Scheme 28).101... 

Previous work by Holton [15] on the synthesis of taxane ring systems, indicated that the preparation of the bicyclo[5.3.1]undecane skeleton lies basically on the work of Biichi on patchouli alcohol [16], which led him to the development of the so-called "epoxy alcohol fragmentation" [15a]. 

Due to the plethora of bicyclo[5.3.0]ring systems in natural products and the limited number of efficient methods that facilitate the construction of seven-membered rings the synthesis of bicyclo[5.3.0]compounds based on a PK reaction has recently been a subject of intense interest. Generally, the preparation of larger ring systems [n.3.0] (n>4) has proven challenging with traditional PK reaction catalysts. One of the few examples reported is the Co2(CO)g catalyzed formation of the azabicyclo[5.3.0j-decenonone derivative 15 (X = OTBS) from the conformationally restricted substrate 14... 

As part of on going efforts of Williams and his coworkers [46] to elucidate the biosynthesis of the core bicyclo[2.2.2] ring system of the related alkaloids the brevianamides [51], they have applied methodology originally developed for the stereocontrolled total synthesis of (-)-brevianamide B [52] to complete the first stereocontrolled total synthesis of (+)-PHB. 

The application of this reaction to other ring systems has shown that the yield of the bicyclic hydrocarbon decreases as the strain involved in the product increases. For example, the mercury sensitized decomposition of bicyclo [3.2.0] heptanone-3 (XXIII) leads to very little of bicyclo [2.2.0] hexane and gives more of bicyclo [2.1.1] hexane than of bicyclo [2.2.0] hexane. The reaction has been successfully applied to the synthesis of a substituted bicyclo [2.1.0] pentane (XXVIII) from a sub-... 

The sesquiterpene (+)-asteriscanolide 1 was first isolated from Asteriscus aquaticus L and characterized by San Feliciano in 1985.1 It has captured the attention of organic chemists mainly because of its uncommon bicyclo[6.3.0]undecane ring system bridged by a butyrolactone fragment. The only prior enantioselective synthesis of 1 has been described by Wender in 1988 featuring an Ni(0)-promoted [4 + 4]-cycloaddition.2 Booker-Milburn and co-workers described the sequential application of intramolecular [2 + 2]-photocycloaddition, Curtius rearrangement, and oxidative fragmentation to produce the 7-desmethyl derivative in 1997.3... 

A good deal of effort has been devoted to the preparation of derivatives of the cyclohepta[cd]indole and bicyclo[4.3.1]decane ring systems, that can be considered related to the ABC and CD ring systems of welwistatin, respectively, but much of this work cannot be translated easily to methods relevant to welwistatin synthesis. For instance, many successful approaches to the cyclohepta[cd] indole system are based on intramolecular radical cycliza-tions [12] or Heck reactions [13]. In many published examples, a substituent at the indole C-2 avoids the competing reaction at this position, but this device renders the reaction products inadequate to achieve the oxindole struc-... 

Intramolecular alkylation reactions employing allylsilanes have been developed. A taxoid bicyclo[9.3. l]pentadecane ring system was prepared via intramolecular alkylation of (150). It is interesting to note that the alkylation occurred in the y-position relative to the alkyne (Scheme 218). A Nicholas reaction was used in the synthesis of (+)-epoxydictymene (Scheme 219). 

The key intennediate for the synthesis of ( )-sinulaiene (159), a structurally unusual marine natural product, was the bicyclic divinylcyclopropane (160). Successful Cope rearrangement of this substance would be expected to proceed via the endo isomer (161) to produce the bicyclo[3.2.1]octa-2,6-diene (162), possessing the correct stereochemistry at C-4 (exo-isopropyl group) and fimctionality (exo-vinyl group at C-8, enol ether associated with C-6 and C-7) that would allow the straightforward preparation of the tricyclic ring system of ( )-(159). 

Transannulation of the mesylate (33), derived from 4,8-dimethylcycloocta-4-en-l-ol, using sodium carbonate in aqueous dioxane has provided the bicyclo[3.3.0]octanol (34), a central precursor to the monoterpene iridomyrmecin (35 equation 13). In studies of the biomimetic synthesis of the natural tri-quinanes capnellene (37 equation 14) and pentalenene (40 equation IS) Pattenden et al. have shown that both molecules can be produced from appropriate cycloocta-l,S-diene precursors, i.e. (36) and (39) [or indeed their corresponding positional isomers (38) and (41), respectively] by treatment with boron trifluoride. Mehta et al. have described an alternative transannulation approach to the triquinane unit found in pentalenene, i.e. (42) - (43 equation 16), and also to the ring system (44 equation 17) found... 

Kuroda, C.. Sumiya, II.. Murase, A., and Koito, A., Iron(ni)-induced tandem Nazarov cyclization-rearrangement of a-(triincLhylsilylmethyl)divinyl ketone. Synthesis of the bicyclo[4.3.0]nonane ring system via spiro[4.4]nonanc, J. Chem. Soc., Chem. Commun.. 1177. 1997. 

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