Retigeranic acid synthesis

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

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. 

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

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...

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...

The last two chapters by Hoffmann and Ramamurthy deal with a collection of photochemical reactions with arenes, the ortho-, meta- and para photocycloadditions and with a conceptually exciting concept in organic photochemistry, the use of contrained media. Retigeranic acid (16, by formal asymmetric synthesis) was synthesized via a fabulous reaction sequence involving an intramolecular meta photocycloaddition as key step [16]. 

H-silphiperfol-5-ene 93 (R = 11, R2 = Me) [70], subergorgic acid 94 [71], crinipellin B 95 (formal synthesis) [72], (—)-retigeranic acid 96 (formal asymmetric synthesis) [73] were synthesized via intramolecular meta cycloaddition as key step (Sch. 18). In the same way, linear triquinane... 

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