Natural Products Synthesis REVIEWS cortisone( ychnine(1954) 271 M reserpine(1958) 28 6-demethyl-6-deoxytetracycline(1962)285 cephalosporin C(1966)30 isolongistrobine(1973) 2871 penems(1978) 2901 vitamin B12(1973)/32 HOOo with A Eschenmoser illudalic acid(1977)/289 illudinine(1977)/ 289 illudacetalic acid (1977)/289 erythromycin A(1981)33 Figure 3. Selected syntheses by the Woodward Group(1944-1981). throughout his career. He clearly influenced the careers of not Urbana-Champaign. His dynamism and brilliance were to only his students, but also of his peers and colleagues, for make him the natural recipient of the total synthesis baton Blo nple, J. wilkinson(sandwich structure of ferrocene), K. from R.B. Woodward, even though the two men overlapped Block(steroid biosynthesis), R. Hoffmann(Woodward and for two decades at Harvard. Corey's pursuit of total synthesis Hoffmann rules), all of whom won the Nobel Prize for was marked by two distinctive elements, retrosynthetic analysis and the development of new synthetic methods lis brilliant use of rings to install and control stereo- an integral part of the endeavor, even though Woodward hemical centers and to unravel functionality by rupturing (consciously or unconsciously) must have been engaged in them is an unmistakable feature of his syntheses. This theme such practices. It was Corey's 1961 synthesis of longifolene/ 34 ppears in his first total synthesis, that of quinine, 12 and that marked the official introduction of the principles of appears over and over again as in the total synthesis of retrosynthetic analysis 4I He practiced and spread this concept reserpine, /28 vitamin B2, B32 and, remarkably, in his last throughout the world of total synthesis, which became a much ynthesis, that of erythromycin. 33 Woodwards mark was that more rational and systematic endeavor. Students could now of an artist, treating each target individually with total be taught the"logic"of chemical synthesis I by learning how mastery as he moved from one structural type to another. to analyze complex target molecules and devise possibl He exercised an amazing intuition in devising strategies synthetic strategies for their construction. New synthetic toward his targets, magically connecting them to suitable methods are often incorporated into the synthetic schemes starting materials through elegant, almost balletlike, maneu- towards the target and the exercise of the total synthesis becomes an opportunity for the invention and discovery of However, the avalanche of new natural products appearing new chemistry. Combining his systematic and brilliant ap- on the scene as a consequence of the advent and development proaches to total synthesis with the new tools of organic of new analytical techniques demanded a new and more synthesis and analytical chemistry, Corey synthesized hun systematic approach to strategy design. A new school of dreds of natural and designed products within the thirty year thought was appearing on the horizon which promised to take period stretching between 1960 and 1990 (Figure 4)the year the field of total synthesis, and that of organic synthesis in of his Nobel Prize general, to its next level of sophistication Corey brought a highly organized and systematic approach to the field of total synthesis by identifying unsolved and important structural types and pursuing them until they fell. 3.3. The Corey Era The benefits and spin-offs from his endeavors were even more impressive: the theory of retrosynthetic analysis, new syn In 1959 and at the age of 31 E J. Corey arrived at Harvard thetic methods, asymmetric synthesis, mechanistic proposals, as a full professor of chemistry from the University of Illinois, and important contributions to biology and medicine. Some of Angew. Chem. Int Ed 2000, 39, 44-122Natural Products Synthesis REVIEWS throughout his career. He clearly influenced the careers of not only his students, but also of his peers and colleagues, for example, J. Wilkinson (sandwich structure of ferrocene), K. Block (steroid biosynthesis), R. Hoffmann (Woodward and Hoffmann rules), all of whom won the Nobel Prize for chemistry. [13] His brilliant use of rings to install and control stereo￾chemical centers and to unravel functionality by rupturing them is an unmistakable feature of his syntheses. This theme appears in his first total synthesis, that of quinine, [22] and appears over and over again as in the total synthesis of reserpine, [28] vitamin B12 , [3, 32] and, remarkably, in his last synthesis, that of erythromycin. [33] Woodwards mark was that of an artist, treating each target individually with total mastery as he moved from one structural type to another. He exercised an amazing intuition in devising strategies toward his targets, magically connecting them to suitable starting materials through elegant, almost balletlike, maneu￾vers. However, the avalanche of new natural products appearing on the scene as a consequence of the advent and development of new analytical techniques demanded a new and more systematic approach to strategy design. A new school of thought was appearing on the horizon which promised to take the field of total synthesis, and that of organic synthesis in general, to its next level of sophistication. 3.3. The Corey Era In 1959 and at the age of 31 E. J. Corey arrived at Harvard as a full professor of chemistry from the University of Illinois, Urbana-Champaign. His dynamism and brilliance were to make him the natural recipient of the total synthesis baton from R. B. Woodward, even though the two men overlapped for two decades at Harvard. Coreys pursuit of total synthesis was marked by two distinctive elements, retrosynthetic analysis and the development of new synthetic methods as an integral part of the endeavor, even though Woodward (consciously or unconsciously) must have been engaged in such practices. It was Coreys 1961 synthesis of longifolene[34] that marked the official introduction of the principles of retrosynthetic analysis. [4] He practiced and spread this concept throughout the world of total synthesis, which became a much more rational and systematic endeavor. Students could now be taught the ªlogicº of chemical synthesis[4] by learning how to analyze complex target molecules and devise possible synthetic strategies for their construction. New synthetic methods are often incorporated into the synthetic schemes towards the target and the exercise of the total synthesis becomes an opportunity for the invention and discovery of new chemistry. Combining his systematic and brilliant ap￾proaches to total synthesis with the new tools of organic synthesis and analytical chemistry, Corey synthesized hun￾dreds of natural and designed products within the thirty year period stretching between 1960 and 1990 (Figure 4)Ðthe year of his Nobel Prize. Corey brought a highly organized and systematic approach to the field of total synthesis by identifying unsolved and important structural types and pursuing them until they fell. The benefits and spin-offs from his endeavors were even more impressive: the theory of retrosynthetic analysis, new syn￾thetic methods, asymmetric synthesis, mechanistic proposals, and important contributions to biology and medicine. Some of Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 49 N H N H H H MeO2C H OMe O O MeO OMe OMe H N N N N Me Me H2N H2N H2N Me Me NH2 Me H H H H Me Me H O O O NH2 O O Co CN Me NH O O P O Me O O O OH HO H N N Me Me H H H NH2 O H Me Me Me HO Me H Me O OH Me O Me O Me O Me HO Me OH O Me Me O Me OMe MeOH O HO NMe2 Me NMe H CO2H HO HO CO2H H OH OH OH O OH O NH2 NMe2 H OHO N O O H H H H N N S H H3N N O OAc CO2H H H CO2 O MeO O NHAc MeO MeO OMe O Me Me O O OH OH H H H N N N N Mg MeO O 2C O O HN H O H H OHC O HO N S O CO2H R' H N H O R O N N Me N O OH O O O OH N MeO HO N H H N O O OMe CO2H OH OHC HO O OMe MeO OMe HO O reserpine (1958)[28] vitamin B12 (1973)[32] [with A. Eschenmoser] marasmic acid (1976)[288] lanosterol (1954)[25] penems (1978)[290] erythromycin A (1981)[33] lysergic acid (1954)[26] PGF2α (1973)[31] 6-demethyl-6-deoxytetracycline (1962)[285] strychnine (1954)[27] cephalosporin C (1966)[30] colchicine (1965)[286] isolongistrobine (1973)[287] patulin (1950)[23] quinine (1944)[22] cortisone (1951)[24] chlorophyll a (1960)[29] illudinine (1977)[289] illudalic acid (1977)[289] illudacetalic acid (1977)[289] Figure 3. Selected syntheses by the Woodward Group (1944 ± 1981)