Synthesis of DEFG ring system of cneorins

The cneorins have been isolated from the xerophytic shrub Cneorum pulverulentum , which is native to the Canary Islands. They are natural products containing a [4.3.1]propellane ring system (DEFG rings) as the northern part of the molecule and a 5,5-spiroketal unit and a butenolide moiety (A ring) as the southern part. The synthesis of the DEFG ring system of the cneorins is described. The key steps include: intramolecular cyclopropanation of a diazomalonate providing the EFG ring fragment and an anionic cyclization of a sulfone yielding the [4.3.1]propellane ring system.


Introduction
The cneorins (1, 2) (Figure 1) were originally isolated from the xerophytic shrub Cneorum pulverulentum, native to the Canary Islands, in the late 1970's. 1 This shrub hosts a variety of bitter principles, all of which contain the [4.3.1]propellanering system. 2 These oxidized pentanortriterpenes (C 25 compounds) also have other interesting structural features in common, such as a 5,5-spiroketal unit and a butenolide moiety.The relative stereochemistry of the parent natural products were initially reported based on degradation studies, and later confirmed by Xray diffraction structures.The absolute stereochemistry has been indirectly determined for only one derivative of cneorin C, and must be considered with caution for the other structural members of these natural products.Biogenetically these compounds are thought to be related to the limonoid triterpenes. 3Due to lack of material from natural sources, these compounds have not received proper pharmacological screening.In addition to Cneorum pulverulentum, the Cneoraceae plant family consists of two other species, Cneorum tricoccon, which is native to coastal areas of the western Mediterranean, and Cneorum trimerum, which belongs to the flora of Cuba.The tricoccins (3, Figure 1) were isolated from the former, but the latter has not been adequately studied due to lack of access to the required plant materials.Recently, some close structural relatives of the cneorins, the cedkathryns (4), were isolated from Cedrelopsis gracilis from Madagascar (Figure 1). 4 In addition, some compounds that could result from rearrangements of the cneorins or the tricoccins, for example cedmilinol (5), have been isolated from Cedrelopsis grevei.Despite the intriguing structures of the cneorins, these molecules have not attracted synthetic attention except from our group. 6Retrosynthetically (Scheme 1), the structure of cneorin C can be divided into two advanced substructures, namely hydroxyketone 6, which consists of the DEFG rings of the molecule, and the A ring butenolide fragment 7.The DEFG ring system of cneorin B ( 6) is an ideal candidate for the intramolecular cyclopropanation [7][8][9][10][11] of diazomalonate 8, which can be conveniently prepared from the furyl substituted allylic alcohol (S)-9.

Scheme 1. Retrosynthetic analysis of cneorin B.
We have previously described the enantioselective synthesis of allylic alcohol (S)-9 by enzymatic kinetic resolution. 6In this paper we disclose our results on the cyclopropanation to yield the EFG ring fragment and closing the D ring to obtain the [4.3.1]propellanestructure of cneorin related natural products.
The catalyst complexes (Figure 2) and reaction conditions used in this study were chosen in accordance with earlier results, [9][10][11] according to which the best results were obtained with catalyst complex 10c. 15The air stability and ease of handling of Cu(MeCN) 4 PF 6 16 was reported to make the PF 6 salts superior to CuOTf. 17We therefore decided to investigate also complexes 10a and 10b 18 the latter of which was expected to exhibit reduced Lewis acidity of copper thus making it less reactive and more selective towards the targeted double bond.The diazomalonates for the cyclopropanation reaction were synthesized as follows (Scheme 3 and Table 1).Alcohols 11-14 were treated with the monoester of malonic acid 15a-b in the presence of dicyclohexylcarbodiimide and DMAP 19 to provide the corresponding malonates 16-21.Diazo transfer 20 of the malonates with tosyl azide 21 gave the cyclopropanation precursors 22-27.
Scheme 3. Synthesis of diazomalonates.For substrates and yields, see Table 1.The ability of the furan ring to participate in carbenoid insertion reactions is well known, 22,23 and indeed, the model studies confirmed this.Whereas in a model study, the phenyl substituted diazomalonate 22 upon treatment with catalyst 10c produced the corresponding cyclopropanolactone in 67% yield, the 3-furyl substituted diazomalonates were extensively decomposed with this catalyst.We soon learned that for the alcohol protection, TBS was too labile, and the ethyl allyl malonates also led to extensive decomposition.Finally, of the examined Cu catalyst complexes, 10a gave reproducible cyclopropanation of 27 to give 28 in 30% yield as a separable 1:1 mixture of diastereomers.
Thus, we embarked on the synthesis of both the antiand syn-diastereomers of ketosulfone 32 with the t-butyl ester.The TBDPS protected anti-cyclopropanolactone 28a was deprotected with tetrabutylammonium fluoride 24 to yield alcohol 29a in modest yield (Scheme 4), which was then transformed into sulfide 30a under the Hata conditions 25,26 and the sulfide was oxidized with m-CPBA to sulfone 31a in excellent yield.Exposure of sulfone 31a to n-BuLi in THF at -100 °C gave the [4.3.1]propellane32a in 55% yield as a 1:0.8 mixture of two diastereomers at the sulfur bearing carbon.In the diastereomeric series towards cneorin B and the other natural products shown in Figure 1, the synthesis proceeded similarly, except for the closure of ring D. With the syn-phenylsulfone 31b, n-BuLi did not only affect the D ring cyclization but the n-butyl anion attacked the lactone as well.Fortunately, subjecting sulfone 31b to KHMDS provided the cyclized product.Having secured access to the DEFG ring system, we considered different options for removing the sulfone from 32. Single electron reductants such as Raney Ni, Na/Hg and Al/Hg have traditionally been used to reduce the sulfur -carbon bond.][29][30] Results of the sulfone removal of the anti-diastereomer are presented in Scheme 6. Raney nickel caused slow decomposition of the starting sulfone 32a and the other single electron reductants, aluminum amalgam 31 and sodium amalgam, 32 effected a reductive opening of the cyclopropyl ring and ketone 33 was obtained in addition to decomposed starting material.

Summary
In this work, the synthetic efforts towards the DEFG ring system of cneorin B and C have been reported.Synthesis of cneorin C was hampered by difficulties in removing the sulfone from antiketosulfone 32a.Fortunately, this step was successful for the syn-diastereomer 32b.
The enantiomer of the DEFG ring fragment of cneorin B 34 was synthesized for the first time in 14 steps from commercially available starting materials.This is the first time that a cyclopropane containing [n.n.1]propellane structure of a natural product has been prepared by means of a cyclopropanation reaction.

Figure 1 .
Figure 1.Selected structures of natural products related to cneorins.