Stereoselective Synthesis of Bioactive Compounds
(Track)
Novel synthetic methodologies to prepare unnatural acids, aminoacids and peptidomimetics
Mauro F. A. Adamo
Centre for Synthesis and Chemical Biology (CSCB), Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, Ireland
Abstract:
We have developed an original synthon, 3-methyl-4-nitro-5-styrylisoxazole 1 (Scheme 1),1 and novel organocatalyses (Schemes 1 and 2). Compounds 1 are stable crystalline compounds which could be generated in multigram scale from isoxazole 2 and aldehyde 3. Compounds 1 contain two electrophilic centres: (i) soft E1 which reacted selectively with stabilised nucleophiles; (ii) hard E2 which reacted selectively with hard nucleophiles such as -OH.
The addition of -OH to E2 is the bases of a synthetically useful reaction which transformed the 4-nitroisoxazol-5-yl core into a carboxylate, demonstrating compounds 1 as synthetic equivalent to cinnamates 4. The 4 nitroisoxazole-5-yl core also activated the alkene as the resulting anion, delocalised across a large number of conjugated atoms, was more stable: compared to cinnamic esters and aldehydes, isoxazoles 1 reacted faster and more efficiently. Compounds 1 were intermediate in multi component processes (over 20 peer-reviewed papers published 2005-2010) and more recently substrates for enantioselective phase transfer catalyses (Scheme 1). γ-Aminoacids 8,2 derived from 5, α-aminoacids 6 and their derivatives 9, heavily substituted cyclopropanes 10, and chiral isonitriles 11 were obtained from 1 in high yields and ees. My group has also developed a unique sulfonylation process which allowed obtaining multigram amounts of enantiopure sulfonic acids 13 (Scheme 2).3 Sulfonic acids are extensively employed as resolving agent and possess several interesting biological properties, exerting key metabolic roles in the central nervous system (CNS). The sulfonic acid functionality is also present in natural products, for example in 6-gingesulfonic acid, extracted from ginger (Zingiberis Rhizoma) and used as an anti-ulcer drug in Chinese and Japanese medicine. My independent work resulted in 40 peer reviewed publications, 5 patents and 3 application pending. The paper describing the synthesis of 5 was selected as Hot paper in Angewandte Chemie Int. Ed., and was highlighted twice in Synfacts for the novelty of 1 being synthetic equivalent to cinnamates and for the use of 5 in the preparation of Baclophen. The synthesis of compounds 6-7 is still unpublished. The patent describing the sulfonylation of alkenes (Scheme 2) won the IDEA price 2009 hosted by Enterprise-Ireland.
References:
1. M. F. A. Adamo, V. R. Konda, Org. Lett., 2007, 9, 303-305
2. A. Baschieri, L. Bernardi, A. Ricci, S. Suresh, M. F. A. Adamo, Angew. Chem. Int. Ed. 2009, 9342-9345.
3. M. F. A. Adamo, M. Nagabelli, F. Fini, Adv. Synth. Catalysis, 2010, adsc.201000543; M. F. A. Adamo, F.
Fini, M. Moccia, M. Scagnetti Angew. Chem. Int. Ed. 2010, in press.
