Isocomene synthesis

Isobutylene, as alkylating agent 941 Isocomene, synthesis of 1252 Isodihydrofutoquinol A,... 

A new approach to isocomene synthesis involving a transannular reaction has been described 2i. Rcgioselective oxirane ring opening after protonation initiates a stereoselective reaction to give the hydroxy ketone 15, w hich can be transformed into the natural product in several steps. 

The key features of Pirrung s synthesis of isocomene are outlined retrosynthetically in Scheme 1. Working one step back from 1 gives the tertiary carbocation intermediate 2. The intermediacy of 2 should be brief, for it should readily participate in an Ei-type reaction, in the forward sense, to give isocomene (1). Inspired by the observation that bicyclo[3.3.0] frameworks can be accessed from bicyclo[4.2.0] frameworks through cyclobutyl carbinyl cation rear-... 

In this synthesis, we have witnessed the dramatic productivity of the intramolecular enone-olefin [2+2] photocycloaddition reaction. This single reaction creates three contiguous and fully substituted stereocenters and a strained four-membered ring that eventually provides the driving force for a skeletal rearrangement to give isocomene. 

Scheme 10.1 Hudlicky s synthesis of isocomene, and epi-isocomene. Validation of Chatterjee s ketone fraud...

Chatterjee synthesis of isocomene constituted fraud because of the low probability of hydrogenation occurring from the concave surface of ester 24. The final direct proof was obtained by the synthesis of Chatterjee ketone 30, its hydrogenation to 29, and further conversion to epiisocomene [21],... 

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]. 

Such reactions have also often been used in the synthesis of sesquiterpenes as (+)-epiprecapnelladiene4m) (4.49), ( )-isocomene 462) (4.50) or of hir-sutane derivatives (4.51) 463). 

The synthesis of (+ )-isocomene is another good example showing the versatility of the cyclobutylcarbinyl cation — cyclopentyl cation rearrangement. A high yield of isocomene (286) was obtained when the olefin (285) was treated with pTsOH in benzene97 . 

The Pirrung synthesis is notable for its brevity and clever amalgamation of [2 + 2] photocycloaddition and Wagner-Meerwein rearrangement chemistry Enol ether 757 was reacted with the Grignard rea nt from 5-bromo-2-methyl-l-pentene, subjected to acid hydrolysis, and irradiated to generate the tricycle 738. Wittig olefination of this ketone and treatment with p-toluenesulfonic acid provided racemic isocomene. 

A purportedly expedient synthesis of isocomene outlined by Chatterjee is unquestionably bogus However, success in arriving at 731 has been enjoyed by... 

All the above examples share high stereofacial selectivity defined by the configuration of the stereogenic center that connects the enone chromophore with the alkenyl side chain. However, chiral induction at the enone and/or the alkenyl tethered must be introduced to achieve stereofacial selectivity in the more general systems in which the alkene is connected at the a-carbon or /1-carbon of the enone. One of the successful early examples is found in Pirrung s120 synthesis of ( )-isocomene 263. Irradiation of 261 afforded the single product 262, which was transformed to isocomene in a two-step sequence. 

These intramolecular meta-addition processes were utilized in the key steps for the total synthesis of a-cedrene [245], isocomene [246], hirsutene [247], coriolin [248], silphinene [249], rudmollin [250], laurenene [251], and fenestranes [252-254], which were synthesized by Wender s and Keese s groups (Scheme 58). 

The cyclization provides a route to the angularly fused triquinanc system of 3, which lacks two of the methyl groups present in the natural sesquiterpene isocomene (4). Cyclization of a suitably substituted enyne for synthesis of 4, however, proceeds in minute yield. ... 

Paquette and Han used these conditions in the final step in a synthesis of ( )-isocomene (3). 

The syndesis of cedrene served to establish a firm foundation for the implementation of the meta cycloaddition in complex molecule synthesis and allowed also for a comparison of the effectiveness of an arene-alkene based strategy with the many impressive approaches to this well-known target. On the other hand, the next application of the meta cycloaddition was directed at isocomene (90 Scheme 10), a relatively new structural motif but one which has been found with increasing frequency in new natural... 

An improved version of the Carroll reaction, the ester enolate Carroll rearrangement, was reported in 1984 by Wilson and Ptice. Dianions of allylic acetoacetates, generated by treatment with 2 equiv. of LDA at -78 °C in THF, were rearranged at room temperature or 65 C to yield >keto acids in 40-80% yield (equation 12). In the course of a synthesis of the sesquiterpene isocomene, Snider and Beal used this method for the rearrangement of acetoacetate (73), prepared in 83% yield from reaction of cyclopen-tene (72) with diketene and a catalytic amount of DMAP (Scheme 11). The ( )-isomer of ketone (74) is obtained stereospecifically, since there is a severe steric interaction between the methyl groups in the Carroll rearrangement transition state leading to the (Z)-isomer. 

A intramolecular version of this potential process was conducted with equal success. In addition, a formal synthesis of the angular triquinane isocomene was highlighted (Sch. 42) [92],... 

The Hudlicky route making vinylcyclopropanes by intramolecular car bene additions to dienes has led to a variety of polycyclic cyclopentanoic terpenes. The crucial step in a synthesis of isocomenic acid is illustrated by equation 157. ... 

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