Retigeranic acids

The multistrategic retrosynthetic analysis of retigeranic acid, which led to the synthesis outlined below, has been described in Section 6.6 of Part One. 

Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada e-mail thudlicky brocku.ca 

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. 

In 1965 Seshardri et al. described the isolation of an unknown terpenoid acid B obtained from the lichens of Lobaria retigera in the western Himalayas [8]. (Note that this annotation bears no relation to the subsequent nomenclature later defined by Corey and Shibata.) Four collections had been made in the summer of 1962 from under the Rutba plants in the Valley of Flowers (12,500 feet) and on the way to Hemkund Lokpal (13,500 feet) and from underneath rocks and from pine trees in Ganghariya (10,000 feet). The samples were subjected to a series of increasingly polar extractions (petroleum ether, diethyl ether, acetone). The unknown terpenoid acid B was present in all petroleum ether extracts, except that of the sample obtained from the Valley of Flowers, in compositions ranging from 0.47 % to 

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Scheme 5.23. Synthesis of retigeranic acid (5-116) by photochemical mefa-cycloaddition.

The seminal publication [ 12] on the isolation of retigeranic acid proposed a possible biosynthetic pathway by means of cyclization from geranyl famesyl pyrophosphate (12) (Fig. 10.2) to tertiary carbocationic cyclopentane 13. A series of [1, 5] and [1, 2] hydride shifts were proposed to establish the skeletal core of the sesterterpene, whose subsequent oxidation would yield retigeranic acid. 

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]. 

Scheme 10.3 Initial convergent designs for retigeranic acid by Hudlicky...

Scheme 10.4 Fallis s synthesis of hydrindanone in the approach to retigeranic acid...

Scheme 10.5 Fraser-Reid s approach to retigeranic acid from carvone...

Trauner and coworkers released a report on a unified approach to isopropyl containing frans-hydrindane sesterterpenes via a common intermediate [38]. Their effort provided compounds that lend themselves to the substitution patterns embedded in retigeranic acids A (1) and B (2) as well as oxygenated precursors providing access to other sesterterpenes such as nitidasin (6), astellatol (3), and YW3699 (89). 

Scheme 10.7 Trauner s synthesis of ent-hydrindanone as intermediate for ent-retigeranic acid...

It was envisioned that hydrindanone 83 and cyclopentene 85 could be used as intermediates in the synthesis of e f-retigeranic acid A (1) and e f-retigeranic acid B (2), respectively. To prepare the building block 90, cyclopentene 85 was reduced with diimide (93 %) in order to prevent isomerization and subsequently deprotected with PPTS to yield hydrindanone 90 (quant.), which could provide access to <77/-retigeranic acid B (2) (Scheme 10.7). Hydrindanone 83 was reduced via an enol triflate and then subjected to Pd-catalyzed reduction to provide cyclopentene 91 (87 % from 83). Upon hydrogenation of 91 with Pd/C and cleavage of the acetal with iodine, protected hydrindanone 92 (95 % from 91) was obtained. The deprotection of 92 provided ent-60, whose enantiomer was used in previous syntheses of retigeranic acid A (1) by Corey [14] and Hudlicky [46, 47]. 

Completion of total synthesis of retigeranic acid by Corey... 

Scheme 10.11 Paquette s synthesis of left half precursor for retigeranic acid...

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