Synthetic approaches to the daucane sesquiterpene derivatives employing the intramolecular Buchner cyclisation of α-diazoketones
Graphical abstract
The use of the intramolecular Buchner cyclisation of an α-diazoketone as an approach to the synthesis of daucane sesquiterpenes is described; in particular the synthesis of the cis-fused analogue of dihydro CAF-603.
Introduction
CAF-603 1 (Fig. 1), a carotane or daucane sesquiterpenoid, was first isolated from the culture broth of a strain of Trichoderma virens (Gliocladium virens IFO 9166), by Watanabe and co-workers in 1990.1 The structure was elucidated by spectroscopic methods. It was also discovered separately by researchers at Merck in 1995.2 On this occasion it was isolated from a fungal source, Arthrinium phaeospermum, and was found to have almost identical spectroscopic data to a compound discovered some five years earlier. The structure was further verified by X-ray crystallography.
As part of this work, it was revealed that CAF-603 1 possessed antifungal activity against Candida albicans strains. The biological activity of this sesquiterpenoid was further exhibited by the later study, where the compound was reported as a potent modulator of the large conductance, calcium-activated potassium (Maxi-K) channel, a member of a large group of proteins present in neuronal and smooth muscle tissue.3 These channels play an important role in controlling a number of cellular processes, such as neurotransmitter release, neuroendocrine secretion and smooth muscle contraction. As a result of this, agonists of Maxi-K may be useful in the treatment of neurological disorders and airway smooth muscle disorders, such as asthma. Compounds 2 and 3, derivatised from 14-hydroxy CAF-603 4,4 and L-735,334 5 (Fig. 1), which has been isolated from natural sources, displayed distinct biological activity on the Maxi-K channels.5, 6 To date, no total synthesis of CAF-603 or its derivatives has been published.
Over the last four decades, a number of synthetic methodologies towards the formation of the bicyclo[5.3.0]decane skeleton have been described, including ring closing metathesis, solvolysis, cycloaddition and transition metal catalysed chemistry.7, 8, 9 The use of α-diazocarbonyl chemistry in total synthesis has also been well documented.10, 11, 12 The intramolecular Buchner aromatic addition reaction of α-diazoketones is one such method that has been exploited in the area of bicyclic sesquiterpenoid natural product synthesis, namely the synthesis of the pseudoguaianolide (+)-confertin.13, 14 The intramolecular Buchner reaction, one of the mildest methods for transforming aromatic compounds to more reactive systems, has been studied for many years in our team.15, 16, 17, 18, 19, 20 Areas that have been investigated include the stereo-, regio- and enantiocontrol of this chemical transformation. A large number of azulenones have been synthesised using this methodology, some of which include products bearing the core skeleton of the daucane (carotane) group of sesquiterpene natural products. We describe here the extension of this methodology to the synthesis of the cis-fused derivative of dihydro CAF-603 6.
Section snippets
Results and discussion
The synthetic strategy devised to generate the required bicyclo[5.3.0]decane skeleton possessed by CAF-603 1 and its analogues, emanated from the intramolecular Buchner cyclisation of α-diazoketone 7 to generate the azulenone 8, as outlined in Scheme 1. This transformation provides the required carbon skeleton, while also controlling the stereochemistry at the key quaternary bridgehead centre. This compound was generated in three steps from the commercially available para-methylcinnamic acid 9,
Conclusion
The racemic synthesis of the cis-derivative of dihydro CAF-603 6 was achieved in 13 synthetic steps from commercially available starting material. The bicyclic skeleton was established in excellent yield in only four steps, using the rhodium catalysed intramolecular Buchner cyclisation. This was the key step in the synthesis, providing access to the bicyclo[5.3.0]decane framework of the daucane sesquiterpenes and establishing the stereochemistry at the quaternary bridgehead centre. This
General
All solvents were distilled prior to use by the following methods: dichloromethane was distilled from phosphorus pentoxide and when used for diazoketone decompositions was further distilled from calcium hydride, ethyl acetate was distilled from potassium carbonate or phosphorous pentoxide, acetone was distilled from potassium permanganate followed by potassium carbonate, toluene was distilled from sodium benzophenone ketyl, hexane was distilled prior to use, ethanol and methanol were distilled
Acknowledgements
The authors wish to thank Pfizer (studentships to D.F. and P.O'L.), National University of Ireland (Postdoctoral Fellowship to P.O'L.), Cork Corporation (grant to N.R.B.), Science Foundation Ireland (Grant No. 05/PICA/B802/EC07) and Enterprise Ireland for funding.
References and notes (54)
- et al.
Bioorg. Med. Chem. Lett.
(1995) - et al.
Eur. J. Pharmacol.
(1997) - et al.
Tetrahedron
(2010) - et al.
Tetrahedron
(2011) - et al.
Tetrahedron Lett.
(1983) - et al.
Tetrahedron
(1997) - et al.
Tetrahedron Lett.
(1996) - et al.
Tetrahedron: Asymmetry
(1997) - et al.
J. Nat. Prod.
(1990) - et al.
J. Nat. Prod.
(2000)
J. Nat. Prod.
Curr. Pharm. Design
J. Org. Chem.
J. Am. Chem. Soc.
Chem. Rev.
Curr. Org. Synth.
J. Org. Chem.
J. Chem. Soc., Chem. Commun.
J. Chem. Soc., Perkin Trans. 1
Chem. Commun.
J. Chem. Soc., Perkin Trans. 1
J. Org. Chem.
Synlett
Synlett
Synlett
Ber. Dtsch. Chem. Ges.
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Current address: School of Chemistry, National University of Ireland, Galway, University Road, Galway, Ireland.