40TH ANNIVERSARY ARTICLE www.rsc.org/chemcomm | ChemComm Sir Jack Baldwin, FRS: Biomimetic studies at Oxford{ John E. Moses*a and Robert M. Adlington*b DOI: 10.1039/b512961c Professor Sir Jack Baldwin, FRS, has recently stepped down as the Wayneflete Professor of Organic Chemistry at the University of Oxford. This article is intended to overview some aspects of Professor Baldwin’s spectacular career, with an emphasis on his contributions towards the field of biomimetic synthesis. Introduction Continuing a tradition of great scientific London, where he gained a PhD in achievement, and building upon stan- organic chemistry working for the October 2005 has brought about the end dards set by his predecessors, Sir Jack, or Nobel laureate, Professor Sir Derek of an era in organic chemistry at the ‘‘The Prof’’, as known by many past and Barton, FRS. He remained at Imperial University of Oxford. Almost two years present students, has been at the fore- for a short period where he was since the doors of the Dyson Perrins front of scientific achievement through- appointed lecturer, before moving over- (DP) Laboratory were closed to organic out his tenure at Oxford. seas to pursue a career in the USA. The chemistry, the last Head of this Born in London in 1938, Jack Baldwin move proved very successful, and it renowned department has retired his studied chemistry at Imperial College, wasn’t too long before Professor chair. Professor Sir Jack Baldwin, FRS Baldwin had built an international repu- (Fig. 1), Wayneflete Professor of Organic tation for pioneering work in organic Chemistry, joined Oxford in 1978, chemistry. Beginning his career at succeeding Sir Ewart Jones, FRS. Pennsylvania State University, and then later moving to MIT, Sir Jack quickly moved up the ranks, gaining ever- aThe School of Pharmacy, University of London, UK. E-mail: [email protected]; increasing attention from the chemistry Fax: +44 (0)20 7753 5804; community. As a result of his success, he Tel: +44 (0)20 7753 5800 was elected as Fellow of the Royal bThe Chemistry Research Laboratory, University of Oxford, UK. Society (FRS) in 1978, and made a E-mail: [email protected]; Foreign Honorary member of the Fax: +44 (0)1865 275 626; American Academy of Arts and Tel: +44 (0)1865 275 626 Science. His varied scientific achieve- { Dedicated to Professor Sir Jack Baldwin, Fig. 1 Professor Sir Jack Baldwin, FRS. FRS on the occasion of his 67th birthday. ments at that time include the landmark John Moses graduated from Robert Adlington graduated the University of Bath in 2001 from Imperial College, with a 1st class M.Chem. London in 1980 with a degree, having spent a year in PhD in organic chemistry, Purdue University, USA, supervised by Professor A. undertaking research with G. M. Barrett, FRS. Professor Ian P. Rothwell. Robert then joined the He then moved on to the Dyson Perrins Laboratory, University of Oxford to pursue University of Oxford to a D.Phil. in synthetic organic work as a postdoctoral chemistry, working under the research associate of supervision of Professor Sir Professor Sir Jack Jack Baldwin, FRS. John then Baldwin, FRS. In 1990 he spent a short spell at The became a full University Scripps Research Institute, Lecturer and Collegiate La Jolla, working with Professor K. B. Sharpless, before returning Fellow of Lady Margaret Hall. Over the years Robert has to the UK to take up an EPSRC academic fellowship at The School formed a productive partnership with Sir Jack (over 200 co- of Pharmacy. His research interests include natural product authored publications), especially in the areas of synthesis synthesis, biomimetic synthesis and chemical biology. and mechanistic evaluation. This journal is ß The Royal Society of Chemistry 2005 Chem. Commun., 2005, 5945–5952 | 5945 elucidating the mechanistic details on, The biomimetic approach the biosynthesis of the b-lactam anti- biotics. This pioneering study, which was Biomimetic synthesis—from the Greek initially undertaken in collaboration with word ‘‘bios’’, meaning life, and mimetic – Sir Edward Abraham, FRS, led to the the adjective for ‘‘mimesis’’ – imitation or isolation, cloning and ultimately the mimicry—is the application of methods structure of the enzyme isopenicillin N and systems found in Nature to the study synthase which catalyzes the formation and design of synthetic systems. This of the penam nucleus from its tripep- technology transfer is desirable because tide precursor d-(L-a-aminoadipoyl)-L- evolutionary pressure typically forces cysteinyl-D-valine (Scheme 1) and natural systems to become highly opti- molecular oxygen.4 The elegant and mised and efficient. When applied to Fig. 2 Baldwin’s capped porphyrin. insightful work carried out by the natural product syntheses, biomimetic Baldwin group placed Oxford at the approaches can often facilitate rapid synthesis of an artificial capped porphyrin, centre of biosynthetic b-lactam access to complex structures that may capable of reversibly binding oxygen when antibiotic research, building upon the otherwise require inconceivable conven- 1 complexed with ferrous iron, thus laying legacy established by Chain, Florey and tional synthetic pathways. In general, the foundations for a potential source of Abraham.5 biomimetic approaches mimic a key step synthetic blood (Fig. 2). In recognition of Professor Baldwin’s in the proposed (or known) biosynthetic Sir Jack can also lay claim to the pioneering work in the sciences, he was pathway, and are mostly applicable to recognition of the general class of [2,3]- knighted in 1997 for his contributions to those systems that are not under strict 2 sigmatropic rearrangements, further organic chemistry. enzymatic control. Instead the structure emphasising his many and diverse research Trained as a synthetic organic chemist, itself is predisposed to the biomimetic interests. However, it was his ‘‘Rules for Sir Jack never lost his appetite for chemical change. Heathcock has written 3 Ring Closures’’ published in 1976 that the challenge of natural product of the biomimetic strategy that ‘‘The cast Sir Jack into the chemistry limelight synthesis. However, unlike conventional basic assumption of this approach is that and made him a textbook name in organic approaches towards total synthesis, the Nature is the quintessential process chemistry. The rules, which distinguish Prof’s keen interest in biological pro- development chemist. We think that the between two types of ring closure, Exo and cesses influenced his style, and led him to molecular frameworks of most natural Endo, have proved to be an extremely establish an ongoing programme dedi- products arise by intrinsically favourable valuable tool for organic chemists ever cated to the biomimetic synthesis of chemical pathways – favourable enough since. The scientific importance of Sir complex natural products. that the skeleton could have arisen by a Jack’s 1976 paper is reflected in the fact It would be impossible to comprehen- non-enzymatic reaction in the primitive that it has recently been identified as the sively review the lifetime work of Sir Jack organism. If a molecule produced in this most cited article in the history of in an article of this size, a career that has purely chemical manner was beneficial to Chemical Communications,withmore borne over 600 scientific publications, the organism, enzymes would have than 1500 citations.3 and trained scores of doctoral students. evolved to facilitate the production of 6 Upon appointment at Oxford, However, it is highlights of his contribu- this useful material’’. Professor Baldwin’s research interests tion to the field of biomimetic synthesis Biomimetic syntheses, by their nature, became increasingly focused towards that will be briefly discussed, since are often elegant and efficient processes, the interface of organic chemistry and this body of work presents significant providing novel pathways to some of biology, with a particular emphasis upon progress in the field of organic synthesis Nature’s most complex structures. The achieving an understanding of, and and has not been previously reviewed. origin of the field of biomimetic synthesis can be traced back to 1917, when Sir Robert Robinson, FRS, reported a one pot synthesis of the bicyclic alkaloid, tropinone.7 Since those pioneering early days there have been significant advances in the field, with ever increasingly com- plex molecular structures being synthe- sised using biomimetic approaches.8 In more recent times the powerful ‘‘retro-synthetic analysis’’ approach developed by Corey has dictated the thinking and learning processes of the new generation of synthetic organic chemists.9 In this approach the sub- Scheme 1 Biosynthesis of the b-lactam antibiotics. skeletal functionalisation generally occurs early on in the synthetic plan, 5946 | Chem. Commun., 2005, 5945–5952 This journal is ß The Royal Society of Chemistry 2005 and problems sometimes arise in assem- The same criteria towards target selec- could be reduced into four building bling together such highly functionalised tion, coupled with a desire to understand blocks: ammonia, a C10 dialdehyde, sub-units into structures resembling the how such strange entities are created in tryptophan, and a C3 acrolein equivalent, targeted natural products. In contrast, Nature are the driving force behind much shown in Scheme 2 for manzamine B Nature generally assembles the molecular of Jack Baldwin’s biomimetic work. In (2).16 The key step in the proposal is scaffolding firstly with relatively few, but particular, if no obvious biosynthetic an intramolecular endo-Diels–Alder key, functional groups in place, and then pathways can explain the formation of cycloaddition of the enamine form and such structures are functionalised in a certain compounds, this makes them all iminium form of the macrocyclic bis- highly specific manner, by the process of the more attractive targets, and this has dihydropyridiene (4). Of his manzamine secondary metabolism etc. Biomimetic led Baldwin to describe such metabolites proposal Baldwin later said, ‘‘If I was chemistry in the Baldwin group is as ‘‘Molecules from Mars’’.13 God, I would have made it [manzamines] directed towards developing a deeper this way’’.