Triquinane

Figure 1. Representative linear, angular, and propellane triquinane natural products.

Hirsutene (1) and A9(,2,-capnellcnc (2), the parent members of the hirsutane and capnellane families of triquinane natural products, respectively, are isomeric molecules that possess four contiguous stereogenic centers, one of which is quaternary. The linearly fused tricyclopentanoid frameworks of compounds 1 and 2 are obviously very similar, differing only with respect to the positions of the three methyl groups. An asset of Curran s tandem radical cyclization strategy is that it provides a unified entry into a wide variety of linear condensed cyclopentanoid natural products. As a result, it is possible to devise nearly identical retrosynthetic pathways for these structurally related molecules. 

Analogous deoxygenations were carried out with antibiotics such as nargenicin,[42] fortimicin,[43] seldomycin,[44 erythromycin,[45H47] with baccatin (taxol group),[48] the triquinane hirsuten,[49] the tuberculosis inhibitor a-C-mannobioside,[49a] and the steroids alisol,[50] and progesterone.[51]... 

It should be noted that this strategy could also be utilized to build up the linear triquinane framework 3-257 in 45% yield, employing the 11-membered ring system 3-256 in which the BMDMS group is simply moved from one to the other side of alkyne moiety as compared to 3-252 (Scheme 3.66) [105],... 

The Balme group [82] also used the anion capture approach to develop a short entry to triquinanes as 6/1-150 forming a transient Pdn-complex in a Heck reaction of the vinyl iodide 6/1-149 (Scheme 6/1.39). The latter reacts with the carbanion ofa malonate moiety in the substrate however, the products of the normal Heck reaction are also formed. 

Kaliappan and coworkers [249] prepared dioxa-triquinanes 6/3-68 together with the spiro compound 6/3-67 by a domino enyne RCM of the ene-yne 6/3-66 (Scheme 6/3.19). 

Chung and coworkers [280] combined a [2+2+1] with a [2+2+2] cycloaddihon for the synthesis of multi-ring skeletons, angular triquinanes, and fenestranes. For the preparation of tetracyclic compounds such a 6/4-17, these authors used diynes as 6/4-16 and CO as substrates (Scheme 6/4.5). Fully substituted alkynes gave low yields, and 1,5- as well as 1,7-dialkynes, did not react... 

Scheme 6/4.15. Nickel-mediated formation of the triquinane skeletons.

An additional prerequisite in this reaction, however, is inhibition of a premature P-hydrogen elimination. Reaction of 6/4-56 and 6/4-57 led to 6/4-58 with 41 % yield. Again, one can assume that first a Ni-complex 6/4-59 is formed, which gives the bicyclic 6/4-60 followed by formation of the triquinane skeleton 6/4-58 via 6/4-61 with a P-hydride elimination being the last step (Scheme 6/4.15). 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

The synthesis of other angularly fused triquinanes as well as linearly fused sesquiterpenes such as hirsutene and capnellene quickly followed. Many general methods for the synthesis of cyclopentanoid natural products emerged as a result of the target-oriented effort [6]. These accomplishments have been reviewed extensively on numerous occasions [7]. This chapter reviews the history of retigeranic acid from its isolation and structure determination to published approaches to its synthesis and the four total syntheses accomplished to date. 

Scheme 10.2 Hudlicky s synthesis of the triquinane portion of retigeranic acid...

The synthesis of triquinane acids, initiated by the preparation of isocomenic acid [22], thus provided a general method for control of the stereochemistry of secondary methyl groups in these terpenes. The [4+1] annulation based on the dienes of type 23 then laid the groundwork for the first-generation design and a model study for the approach to retigeranic acid [23]. 

Although Wender s synthesis was completed prior to Hudlicky s, it was published later [65]. It utilized the technique of mefa-photocycloaddition of arenes that Wender developed into a general method of synthesis for both angular and linear triquinanes. The overall strategy was centered around an intramolecular Diels-Alder cycloaddition for construction of the internal six-membered ring of the target. 

Scheme 10.14 Wender s synthesis of triquinane part of retigeranic acid by meta-photocycloadditon...

In order to gain more insight into this proposed mechanism, Montgomery and co-workers tried to isolate the intermediate metallacycle. This effort has also led to the development of a new [2 + 2 + 2]-reaction.226 It has been found that the presence of bipyridine (bpy) or tetramethylethylenediamine (TMEDA) makes the isolation of the desired metallacycles possible, and these metallacycles are characterized by X-ray analysis (Scheme 56).227 Besides important mechanistic implications for enyne isomerizations or intramolecular [4 + 2]-cycloadditions,228 the TMEDA-stabilized seven-membered nickel enolates 224 have been further trapped in aldol reactions, opening an access to complex polycyclic compounds and notably triquinanes. Thus, up to three rings can be generated in the intramolecular version of the reaction, for example, spirocycle 223 was obtained in 49% yield as a single diastereomer from dialdehyde 222 (Scheme 56).229... 

Iterative trapping of the alkylpalladium species with tethered olefins is also possible, which allows tandem cycloisomerizations and zipper reactions to take place. Thus, depending upon the juxtaposition of the unsaturated bonds, Trost achieved highly atom-economical syntheses of triquinanes, propellanes (264) from the ynediene 263, and polyspiranes (Scheme 67).261... 

Si-directed Nazarov cyclization (13, 133-134). Denmark2 has extended the Si-directed cyclization of (i-silyl divinyl ketones to preparation of linear tricycles (triquinanes). These cyclizations proceed very readily even at low temperatures, and the position of the double bond is controlled by the silyl group. The reactions... 

Just one reaction has been described where lithiated methoxyallene 42 reacted with bicyclo[3.2.0]heptenone 175 to form the triquinane derivative 176 via a tandem oxy-Cope-transannular ring closure sequence (Eq. 8.31) [111]. However, cycloocta-none 177 was isolated as a major product, which is unusual since other alkenyl-lithium compounds and 175 provide only triquinanes. The authors assumed that the additional sp2-hybridized C-atom in the eight-membered ring intermediate (eno-late of 177) induces a conformation which is less susceptible to transannular ring closure. 

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