Of retigeranic acid

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

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

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. 

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...

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 10.12 Completion of synthesis of retigeranic acid and its isomers by Paquette...

The synthesis reported by Paquette was plagued by several steps of very low stereoselectivity and is, at 26 steps, the longest of the four approaches. However, the analysis of the various stereoisomers related to retigeranic acid helped to finally end the confusion regarding the mixture of stereoisomers in the original isolate of retigeranic acid. 

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

Scheme 10.16 Completion of retigeranic acid synthesis by Wender...

The strategy explored in the syntheses of the siphipeifolenes has more recently proven effective in the asymmetric total synthesis of (-)-retigeranic acid 22), as illustrated in Scheme IS. 

T. Hudlicky et al. achieved the short enantioselective total synthesis of (-)-retigeranic acid. " The C ring of the natural product was assembled via the thermai vinyicyciopropane-cyciopentene rearrangement for which the precursor was prepared by the vinyicyciopropanation of a bicyclic enone with a dienolate. The vinylcyclopropane was evaporated at 585 °C in high vacuum through a Vycor tube conditioned with PbCOs (flash vacuum pyrolysis) to afford the annulated product in good yield. 

P. A. Wender and S. K. Singh, Synthetic studies on arene-olefin cycloadditions. 11. Total synthesis of (-)-retigeranic acid. Tetrahedron Lett. 31,2517-2520 (1990). 

---