Nicolaou studies

Scheme 21. The Sonogashira coupling reaction in Nicolaou s dynemicin A model study.

K. C. Nicolaou was bom in 1946 in Cyprus. He studied chemistry at the University of London (B.Sc., 1969 Ph.D., 1972), Columbia University (postdoctoral research) and Harvard University (postdoctoral research). Between 1976 and 1989 he was a faculty member at the University of Pennsylvania. He currently holds joint appointments at The Scripps Research Institute, where he is the Darlene Shiley Professor of Chemistry and Chairman of the Department of Chemistry, and at the University of California, San Diego, where he is Professor of Chemistry. His research interests span the areas of synthetic organic chemistry, bioorganic chemistiy, molecular design, and the chemistry and biology of natural products. 

An unusual cationic domino transformation has been observed by Nicolaou and coworkers during their studies on the total synthesis of the natural product azadirachtin (1-105) [30]. Thus, exposure of the substrate 1-106 to sulfuric acid in CHjClj at 0°C led to the smooth production of diketone 1-109 in 80% yield (Scheme 1.27). The reaction is initiated by proto nation of the olefinic bond in 1-106, affording the tertiary carbocation 1-107, which undergoes a 1,5-hydride shift with concomitant disconnection of the oxygen bridge between the two domains of the molecule. Subsequent hydrolysis of the formed oxenium ion 1-108 yielded the diketone 1-109. 

With the synthesis of epothilones A and B secured, subsequent studies concentrated on the preparation of analogs of the natural molecules. In addition to providing structure-activity relationships, it was anticipated that these studies would provide a further test for the generality of the RCM process. In this context, a general strategy was developed by Nicolaou et al. [20] to investigate the... 

Nicolaou, K.C. Hughes, R. Pfefferkom, J.A. Barluenga, S, (2001) Optimization and mechanistic studies of psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus. Angew. Chem. Int. Ed. Engl., 40,4296-310. 

In the regioselective total synthesis of edulane and its analogues, the acid-catalyzed reaction of the chroman 93 was studied, giving rise to a mixture of chromenes (Scheme 5) <1997J(P1)1875>. Nicolaou ef a/, showed that it is possible to constmct benzopyrans via an intramolectular 67t-electrocyclization, although a mixture of products was observed (Equation 31) <2004JA5493>. 

Fused ring 7-lactones may also be formed by cyclizations of l-cycloalkeneacetic acids under equilibrating conditions. Nicolaou obtained evidence for the presence of an unstable -lactone in the phenyl-selenolactonization of 1-cyclohexeneacetic acid, but rearrangement occured readily at room temperature to the more stable 7-lactone (equation 12).32 An example of a one-step conversion of a 2-methyl-1-cyclohexeneacetic acid to a fused butenolide by use of diphenyldiselenide and electrochemical oxidation has been reported.47 Recent studies by Rutledge showed that simultaneous addition of bromine and thallium carbonate to 1-cyclohexeneacetic acid gave the 7-lactone as the exclusive product (compare to Table 2) however, the mechanism of this reaction may differ from other cyclofunctionalizations.21... 

Iodine(V) reagents such as Dess-Martin periodinane (DMP) and o-iodoxyben-zoic acid (IBX) are known as general reagents for oxidation of alcohols and have been utilized widely for natural product syntheses. Besides their general use for alcoholic oxidation, recently, the active studies on novel utilization of iodine( V) reagents such as DMP and IBX have been pursued mainly by Nicolaou and coworkers [26]. In particular, the versatile reactivities of anilides (62) with IBX or DMP are interesting and involve unprecedented features as follows. o-Imido-quinones (63) are prepared from 62 by the action of DMP and water. This reaction has been investigated extensively and was found to lead to p-quinones (64)... 

A mere 4 months after the discovery of platensimycin 17, Nicolaou et al. achieved the first total synthesis of the molecule in racemic form <2006AGE7086>. Although the racemic platensimycin obtained would have to be resolved to render the active version of the natural product, the synthesis established an approach for synthesizing nonnatural analogs to be used in structure-activity relationship studies in search of characteristics better than the native compound. 

An impressive application of an aldehyde-oxime coupling was reported by Nicolaou in their studies on the total synthesis of the complex natural product diazonamide A (see Chapter 7, Section 7.4).29,30 Naito31 and Skrydstrup32 have reported impressive applications of the heteropinacol cyclisation for the stereoselective synthesis of the azepine ring of the PKC-inhibitor balanol (see Chapter 7, Section 7.4). 

In the synthetic studies of the marine natural products brevetoxins A and B, Nicolaou and coworkers [157] developed a highly efficient cyclization reaction of hydroxy dithioketals leading to oxocenes. As shown in Scheme 88, exposure of the hydroxy dithioketal 261 to 1.1 equiv of AT-chlorosuccinimide (NCS) in CH3CN in the presence of 2 equiv of 2,6-lutidine, 1.1 equiv of AgNOj, molecular sieves and silica gel at 25 °C for 5 min led to the oxocene 262 in 95% yield. 

Nicolaou, K. C. ZuccaieUo, G. Rianer, C. Estevez, V. A. Dai, W. M. Design, synthesis, and study of simple monocyclic conjugated enediynes. The 10-manbered ring enediyne moiety of the enediyne anticanca antibiotics, 7. Am. Chem. Soc. 1992,114, 7360-7371. 

Vilarino, N. Nicolaou, K.C., Frederick, M.O., Cagide, E., Ares, I.R., Louzao, M.C., Vieytes, M.R., and Botana, L.M. 2006. Cell growth inhibition and actin cytoskeleton disorganisation induced by azaspiracid-A. Structure-activities studies. Chem. Res. Toxicol 19, 1459-1466. 

Nicolaou [47] has applied this methodology in synthetic studies towards the antibiotic everinomicin 13,384-1. Glycosylation of immobilized fluoride donors such as 258 (Scheme 65) with sugar acceptors allowed the synthesis of disaccharides such as 259, attached to solid support through a selenium fink-... 

Hadjivassilis, 1., L. Tebai, and M. Nicolaou (1994). Joint treatment of industrial effluent Case study of limassol industrial estate. Water Science Technol. Proc. lAWQ Int. Specialized Conf. Pretreatment of Industrial Wastewaters, Oct. 13-15, 1993, Athens, Greece, 29, 9, 99-104, Pergamon Press, Tarrytown, NY. 

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