A new route to the cis–anti–cis triquinane ring system. The synthesis of 4,4-dimethyltricyclo[6.3.0.0^2,6]undecan-3-one via β-enolate rearrangement

Abstract

A synthesis of cis, anti, cis-4,4-dimethyltricyclo[6.3.0.0'6]undecan-3-one is described in which the key step is p-enolate rearrangement of 9,9-dimethyltricyclo[5.3.1 The discovery and characterization of several naturally occurring compounds having the linearly fused tricyclopentanoid ring system of cis, anti, cis-tricyclo[6.3.0.02~6]undecane, such as hirsutene ( I ) and coriolin ( 2 ) , have attracted considerable interest since many of these materials exhibit anti-tumor and (or) antibiotic activity (1). An array of synthetic routes to 1, 2 , and congeners has been described (2) including, from this laboratory (3), a sequence leading to 1 which utilizes a stereocontrolled p-enolate rearrangement for the generation of the ring system. The key step is the conversion of 3 -+ 42 via proton abstraction from C-11 in 3 with the stereochemistry of the subsequent rearrangement constrained to give the correct con-'part 110 in the series ' "mr studies; for Part 109 see ref.8. The required tricyclic ketone 6 was prepared from the known epoxide 7 (4) as outlined in Scheme 1. After heating 7 under reflux with lithium triethyl borohydride ("Super Hydride") in THF ( 3 , the product was oxidized with alkaline peroxide to furnish a 85 : 15 mixture of alcohols 8 and 9 which were separable by flash chromatography (6). Pyridine -chromic acid oxidation (7) of 8 furnished the corresponding ketone 10a in high yield. The generation of the homologous ketone 12 via cyclopropanation of the silyl en01 ether of 1Oa followed by homoketonization failed, in sharp contrast to the behavior of the isomeric l l a which is readily transformed to 14 by this route (8). Each of several attempts, under a variety of conditions, gave a complex mixture of unidentified products. As an alternative, the Tiffeneau -Demjanov ring expansion (9) was examined and found to be satisfactory although less efficient because of the concomitant formation of the unwanted isomer 13. Treatment of 10a with trimethylsilyl cyanide (10) gave the trimethylsilyl cyanohydrin ether l o b , which was reduced to the p-aminoalcohol 10c with lithium aluminium hydride. Reaction of 1Oc with nitrous acid furnished a 2: 1 mixture of ketones 12 and 13 which were separated by flash chromatography. The overall yield for the ring expansion of IOU -+ 12 and 13 was 80%. Ketones 12 and 13 were easily distinguished by their I3Cmr spectra since the quaternary carbon signals appeared at 66.1 and 52.6 ppm, respectively. The 13.5 ppm downfield shift of this signal in 12 is readily attributed to the a-carbonyl group. The identity of these ketones was confirmed by carrying alcohol 9 through the same series of reactions to a 64: 36 mixture of two ketones in 74% yield. These two ketones were separated 'With the skeletal rearrangement. a different numbering scheme is required as indicated in the formulas. Can. J. Chem. Downloaded from www.nrcresearchpress.com by 54.202.233.140 on 05/12/18For personal use only.

13C nuclear magnetic resonance studies. 114. An examination of the [3.3.1.0] → [4.3.0.0] rearrangement via β-enolization and H/D exchange in tricyclic ketones

“…The factors governing the regioselectivity and relative reactivity of such proton abstractions are of considerable interest since, in principle, the rearrangements (isomerizations) can provide a means of generating carbon skeletons which are not readily accessible through other routes. Some examples of the use of p-enolization in the syntheses of some naturally occurring carbon skeletons from more readily available systems have been described (3)(4)(5). With a better understanding of both the regioselectivity and stereoselectivity of P-and y-enolization the scope of their synthetic applications could be enhanced.…”

Stereoselective Synthesis of gem‐Difluoromethylenated Linear Azatriquinanes

“…[1a], Owing to their significant and wide‐ranging biological activities, the development of synthetic methods to access linear triquinanes and their structural modifications are of interest to many research groups. [1a], [2a], Notably, the synthesis of linear and other azatriquinanes has recently been reported. Because of the unique properties of the fluorine atom, the presence of a fluorine atom or a fluorine‐containing motif in organic frameworks has been found to enhance their physical and biological properties .…”