Editorial: In celebration of Professor Barry M. Trost's 75th birthday

This special issue is dedicated to Barry M. Trost, Tamaki Professor of Humanities and Sciences, on the occasion of his 75th birthday. First of all, I would like to thank all those who contributed to this special issue. Most of them are members of the large Trost family of chemistry and many of them are leaders in organic chemistry in today's academia and industry. The academic training and education of more than 500 PhD students and postdocs from all over the world by Professor Trost is in itself a remarkable achievement, and in addition to his purely scientific achievements, his students have certainly been a major factor for the extraordinary impact Barry Trost has had in science in general and academia and chemistry in particular.

Barry Trost started his career in chemistry with a bachelor degree from the University of Pennsylvania. He moved to MIT for doctoral studies with H. O. House, where he worked on fundamental aspects of enolate chemistry. In 1965, at a remarkably young age of 24, he was appointed as an Assistant Professor at the University of Wisconsin. There, his scientific success led to rapid promotion and he became a Full Professor just four years later at the age of 28! After more than twenty years at Madison, a major change occurred when he accepted an offer from Stanford University, where he moved in 1987. In 1990, he was appointed Tamaki Professor of Humanities and Sciences.

In the course of his long academic career, he has received the highest level of recognition from the scientific community. Of his large number of awards I would like to mention just a personal selection, including the Roger Adams Award (ACS), the H. C. Brown Award for Creative Research in Synthetic Methods (ACS), the Presidential Green Chemistry Challenge Award, the Yamada Prize (Japan), the Arthur C. Cope Award (ACS), the Ryoji Noyori Prize (Japan), the August-Wilhelm-von-Hofmann Medal (GdCH, Germany) and, most recently, the prestigious Linus Pauling Medal Award (ACS). He is a member of the National Academy of Sciences and holds two honorary doctoral degrees (Technion in Haifa, Israel, and the University of Lyon, France).

Barry Trost's remarkable career in organic chemistry, uniting synthesis and catalysis, has made him one of the world's leading organic chemists and one of the most cited chemists in the world. His enormous scientific achievements are documented in nearly 1000 original publications and patents.

The ability to construct matter on a molecular, defined level requires the necessary chemical reactions and transformations. Barry Trost has proven to be a master in designing new reactions, new reagents and new catalysts for this purpose. He generated a large network of powerful molecular transformations and impressively demonstrated their utility in more than 200 total syntheses of complex molecular targets. In two seminal papers, he defined what today characterizes efficient organic synthesis. In the first paper, he outlined how important all aspects of selectivity (chemo-, regio- and stereoselectivity) are in order to achieve efficient chemical synthesis.¹ The second paper may be viewed as the very foundation of the field of Green Chemistry.² It has become known as atom economy and defines the optimal use of raw material with simultaneous minimization of waste. Both concepts have been a major stimulus and driving force for generations of chemists in the development of ever more efficient chemical reactions and processes mostly relying on catalysis.

An early project allowed Professor Trost to identify the structure of the juvenile hormone, which became the basis for a new way of insect growth regulation.³ In another early program, electronically destabilized antiaromatic 4nπ systems were prepared, such as pyracyclene.⁴ Although theoretically predicted, some of these compounds displayed unusual NMR paramagnetic ring currents. Today, such systems may become of interest as organic conductors.

A huge program on organosulfur chemistry was developed allowing for adjustment of oxidation levels and creating “chemical chameleons” in which carbon neighboring a sulfur function can act both as a nucleophile and electrophile.⁵ The release of ring strain as a driving force for new chemical reactions in combination with sulfur-containing functions (e.g. sulfur ylides) became a paradigm for a wide range of reactions, such as spiroannulation, lactone annulation, cyclopentanone annulation, geminal alkylation, etc.⁶

At a time when the areas of organic synthesis and organometallic chemistry were very much separated, Barry Trost recognized the enormous potential of transition metals in organic synthesis. His program on palladium catalysis was of major impact, and his pioneering contributions on allylic alkylation (today known as the Tsuji–Trost reaction) in particular have resulted in a plethora of new ways for carbon/carbon and carbon/heteroatom bond construction.⁷ While classic nucleophilic displacement reactions following the S_N2 mechanism proceed with inversion of configuration, the new palladium-catalyzed allylic substitutions displayed a net retention of configuration, highlighting how the participation of transition metal catalysts can expand the toolbox of organic synthesis. Other metal catalysts such as molybdenum and tungsten were explored and performed with complementary regiochemistry to palladium catalysts.

Since the early days of palladium catalysis, Barry Trost's vision was to achieve catalyst control of the enantioselectivity of the allylic alkylation reaction. After a basic understanding of the underlying mechanism of the allylic alkylation reaction, it became clear that this would be a major challenge. Difficulties arise from the fact that the stereochemistry-determining step is an external attack of a nucleophile to a palladium-bound allyl electrophile, which is at maximum distance from the chiral information of a chiral ligand coordinated to the palladium center. Trost's vision was to create an enzyme-inspired chiral space that reaches around the palladium to efficiently create chiral space around the allyl electrophile.^8,9 Today, such systems are known as the Trost Ligands and their development in the early 90s provided a boost to a new area of palladium-catalyzed allylic alkylation chemistry. The broad applicability of these ligands triggered the asymmetric synthesis of many natural and unnatural bioactive target molecules and to this day, there are ongoing developments for commercial applications.¹⁰

Further work on palladium-catalyzed alkylation led to the development of palladium-catalyzed TMM (trimethylenemethane) chemistry, which enabled a new fundamental set of cycloaddition reactions that complement the Diels–Alder reaction. Remarkably, in recent years, an asymmetric catalytic version of this process has been established.¹¹

The notion that the reaction of a Brönsted acid and a low-valent palladium species generates a palladium-hydride intermediate paved the way for the development of novel ene/yne-cyclization reactions to furnish either 1,4- or 1,3-dienes. Such isomerization reactions are completely atom economic and can be regarded as complementary to the classic Alder-ene reaction.¹² These discoveries certainly inspired the first ideas of the concept of atom economy, which later led to the development of a more atom economic variant of the allylic alkylation, the addition of pronucleophiles to allenes. This reaction showed remarkable efficiency for the formation of macrocyclic and medium-membered ring systems.

Professor Trost opened new chapters for the use of ruthenium catalysts in organic synthesis. He has developed the first examples of catalytic processes involving vinylidene and allenylidene ruthenium intermediates.¹³ This led to the implementation of a wide range of unprecedented reactions, such as

• a simple one-step synthesis of important 1,5-dicarbonyl compounds

• a three-component coupling of alkyne, water and a vinylketone to form 2-alkyl-1,5-dicarbonyl compounds

• an unprecedented type of [2 + 2 + 2] cycloaddition of alkynes to 1,5-cyclooctadiene

• the addition of allenes and vinyl ketones to furnish 1,3-dienes, and

• a [5 + 2] cycloaddition to form seven-membered rings, among many others.

A more recent research area has been the design and application of new binuclear chiral zinc-catalysts.¹⁴ These catalysts allowed for the asymmetric catalysis of a number of fundamental transformations, such as the direct aldol reaction, the Mannich reaction, the nitroaldol (Henry) reaction, conjugate addition (Michael reaction) as well as the asymmetric alkinylation of carbonyls. These catalysts show inspiring enzyme-like behavior with Lewis-basic and Lewis-acidic reaction sites orchestrating the bond-forming event between nucleophile and electrophile within the chiral environment of the catalyst.

This enormous range of new chemical transformations relying on both transition metal catalysis and main group elements has been probed in the context of the total synthesis of more than 200 complex molecular targets, many of which possess important biological functions. Certainly a highlight is Barry Trost's approach to the anticancer polyketide natural product Bryostatin. Employing novel disconnections based on novel ruthenium-catalyzed C–C and C–O bond formations developed in his laboratory, Barry Trost could cut short the so far best-known synthesis by nearly half.¹⁵ Similarly impressive is his synthesis of the alkaloid morphine, which has been a yardstick for probing synthetic efficiency for over half a century. Barry Trost prepared this complex structure in the least number of steps to date, using his palladium-catalyzed allylic alkylation.¹⁶

The fundamental and wide-ranging research contributions in more than 50 years of his independent academic career have enriched and changed the way we perform and think about organic synthesis. His unique way of merging synthesis and catalysis has shown us which direction organic synthesis must take to become ever more efficient and sustainable in the future. His outstanding achievements have made Barry Trost one of the most prominent organic chemists worldwide. Those who know Barry personally are well aware that these achievements are the result of a highly talented individual with a unique dedication, creativity and enthusiasm for chemistry. He has been an inspiration and a role model for generations of chemists. Today, we want to celebrate his special day and wish him all the best for the coming years.

References

1. B. M. Trost, Science, 1983, 219, 245.
2. B. M. Trost, Science, 1991, 254, 1471.
3. B. M. Trost, Acc. Chem. Res., 1970, 3, 120.
4. B. M. Trost, G. M. Bright, C. Frihart and D. Brittelli, J. Am. Chem. Soc., 1971, 93, 737.
5. B. M. Trost and M. R. Chadiri, J. Am. Chem. Soc., 1984, 106, 7260.
6. B. M. Trost and L. S. Melvin, Sulfur Ylides – Emerging Synthetic Intermediates, Academic Press, 1975.
7. For a personal review, see B. M. Trost, Tetrahedron, 2015, 71, 5708.
8. B. M. Trost, D. L. van Vranken and C. Bingel, J. Am. Chem. Soc., 1992, 114, 9327.
9. B. M. Trost, B. Breit, S. Peukert, J. Zambrano and J. W. Ziller, Angew. Chem., Int. Ed. Engl., 1995, 34, 2386.
10. B. M. Trost, J. Org. Chem., 2004, 69, 5813.
11. B. M. Trost, S. M. Silverman and J. P. Stambuli, J. Am. Chem. Soc., 2007, 129, 12398.
12. B. M. Trost and M. J. Krische, Synlett, 1998, 1.
13. B. M. Trost, M. U. Frederiksen and M. T. Rudd, Angew. Chem., Int. Ed., 2005, 44, 6630.
14. B. M. Trost and C. S. Brindle, Chem. Soc. Rev., 2010, 39, 1600.
15. B. M. Trost and G. Dong, Nature, 2008, 456, 485.
16. B. M. Trost, W. Tang and F. D. Toste, J. Am. Chem. Soc., 2005, 127, 14785.

---