Structural Dna Nanotechnology State of the Art and Future Perspective
Proc Math Phys Eng Sci. 2014 Mar 8; 470(2163): 20130690.
Organic synthesis: the art and science of replicating the molecules of living nature and creating others like them in the laboratory
Received 2013 Oct 15; Accepted 2013 November 18.
Abstruse
Constructed organic chemists have the power to replicate some of the nearly intriguing molecules of living nature in the laboratory and apply their adult constructed strategies and technologies to construct variations of them. Such molecules facilitate biology and medicine, equally they often find uses equally biological tools and drug candidates for clinical development. In improver, past employing sophisticated catalytic reactions and appropriately designed constructed processes, they can synthesize not only the molecules of nature and their analogues, but too myriad other organic molecules for potential applications in many areas of science, technology and everyday life. Later on a brusque historical introduction, this commodity focuses on recent advances in the field of organic synthesis with demonstrative examples of total synthesis of complex bioactive molecules, natural or designed, from the author's laboratories, and their bear upon on chemistry, biology and medicine.
Keywords: chemistry, biology, medicine, natural products, anti-cancer agents, neurotoxins
ane. Introduction
Among what matters the most is matter itself. It is, therefore, non a surprise that chemistry, the scientific discipline of matter, is considered past many as the central science lying between physics and biology. Its power derives from its ability to analyse and synthesize molecules from atoms and other, more than or less complex, molecules. The latter practice, synthesis, is of paramount importance to our well-beingness, for through it nosotros create new chemical entities (i.due east. molecules) from which we derive our nearly precious textile items. A subdiscipline of synthesis is organic synthesis, the art and science of constructing substances, natural or designed, whose master element is carbon. The flagship of organic synthesis is total synthesis, the effort of synthesizing the molecules of living nature in the laboratory. The ability of man to replicate the molecules of living creatures, and create other molecules similar them, is a remarkable development in human history. Its birth goes dorsum to 1828, when High german chemist Friedrich Wöhler, a Strange Fellow member of the Regal Social club (ForMemRS), synthesized urea, an example of a naturally occurring substance from the living world [1]. Such molecules are commonly known every bit natural products, a term commonly referring to secondary metabolites. The creative nature of full synthesis earned this discipline the privilege of beingness called a fine art and a precise scientific discipline. Technologies derived from it, and organic synthesis in general, have led to an impressive host of benefits to gild, including useful products ranging from pharmaceuticals, dyes, cosmetics and agronomical chemicals to diagnostics and loftier-technology materials used in computers, mobile phones and spaceships [two].
2. Organic synthesis in perspective
The world has changed dramatically in the last two centuries every bit a effect of scientific discoveries and their applications. 1 of the most profound of these discoveries is the appearance of organic synthesis equally marked past Wöhler's synthesis of urea. And although its foundations go back before that era, this initial effect, together with developments in structural theory and analytical techniques, gave momentum to its advancement and application in several fields. But what were the conditions and foundations that allowed this science to emerge? And from where did they come? To answer these questions, we must get dorsum to aboriginal times, when humans were practising transformations of affair as a ways to prepare nutrient, medicines, dyes, tools and weapons. The artefacts left behind from ancient civilizations like those of the Egyptians, Babylonians, Greeks, Romans and Chinese provide prove for such endeavours, although there was no pregnant understanding of the nature of these transformations. The curiosity well-nigh nature, yet, drove the Aboriginal Greeks to retrieve and speculate most matter, a practise that led to Democritus' atomic theory.
The latter served every bit the basis from which the more precise diminutive theory of the English language pharmacist and physicist John Dalton, a Fellow of the Royal Guild (FRS), emerged at the dawn of the nineteenth century. Dalton's theory was one of the most influential theoretical developments in science of all fourth dimension and gave enormous momentum to further the advancement of chemistry [3]. Merely earlier we movement forward in fourth dimension, we must mention the alchemists and their practices that tin be traced back to thousands of years ago in the Middle East and the Orient, and prevailed later during the Middle Ages in Europe. From these endeavours, modern chemistry emerged slowly in the eighteenth century. Among the main protagonists responsible for the transition to modern chemical science from alchemy was Irish-born Robert Boyle (FRS), who was both an alchemist and a modern pharmacist. He exposed his philosophies in his volume The Sceptical Chymist, which was published in 1661, one year later on the Royal Society was founded. Boyle promoted experimentation based on purity, precision and data.
Experimentation and quantitative analysis were moved to a higher level by French pharmacist Antoine-Laurent de Lavoisier (ForMemRS), who many consider as the father of modern chemical science, with Boyle viewed equally the grandfather. Lavoisier described his chemic philosophy and methods in his Traité Élémentaire de Chimie that provided the foundation for the emergence of modernistic chemistry. His chemistry was primarily inorganic and was based on combustion and elemental analysis. Lavoisier published a list of chemical elements but had no ways to distinguish between them and atoms; the latter had to look Dalton's atomic theory and subsequent developments that took hold in the nineteenth century. Among these developments was the emergence of organic chemical science, the branch of chemistry dealing with organic compounds, those fabricated of carbon and a few other elements, most commonly hydrogen, oxygen, nitrogen, sulfur, phosphorus and halogens.
The chemistry of natural products was born in the eighteenth century, primarily from the work of the apothecaries, the pharmacists of the fourth dimension, amongst whom Swedish Carl Wilhelm Scheele was the well-nigh prominent. He, as well existence credited with the identification of oxygen, discovered several naturally occurring organic acids, including citric, gallic, malic, lactic, oxalic and uric acids. Scheele too developed important applied laboratory techniques such every bit distillation and crystallization.
By the dawn of the nineteenth century, the stage was fix for the arrival of organic chemical science in general and organic synthesis in detail. Thus, in add-on to the advancement of Dalton's atomic theory, a number of other important discoveries and ideas emerged and eventually gave rise to the understanding of the structure of the molecule and the art of its synthesis. Included among the initial prominent contributions to the establishment of the foundations of modern chemistry are those of English language pharmacist Humphry Davy (FRS and President of the Majestic Guild), Swedish chemist Jöns Jakob Berzelius (ForMemRS), English chemists Alexander Williamson (FRS) and William Odling (FRS), and French pharmacist and physicist Joseph Gay-Lussac (ForMemRS). Their theories and discoveries served as the foundation from which farther advancements occurred, including the distinction between atomic and equivalent weights, the structural theory and the tetrahedral nature of carbon. Among the protagonists of these developments were French chemists Jean-Baptiste André Dumas (ForMemRS), Auguste Laurent, Charles Gerhardt, Joseph Le Bel and C. Adolphe Wurtz (ForMemRS), German chemist Friedrich August Kekulé (ForMemRS), Italian chemists Amedeo Avogadro and Stanislao Cannizzaro (ForMemRS), Russian chemist Dmitri I. Mendeléev (ForMemRS), French physicist, pharmacist and mathematician Jean-Baptiste Biot (ForMemRS), French chemist and microbiologist Louis Pasteur (ForMemRS) and Dutch chemist Jacobus van't Hoff (ForMemRS) [ane,3].
iii. Emergence and development of organic synthesis and total synthesis
The development of experimental methods for practical chemistry and the discoveries of naturally occurring substances such as urea, quinine, morphine and strychnine in the belatedly eighteenth and early nineteenth centuries laid the foundations and provided the impetus for the emergence of organic synthesis [1].
Equally mentioned higher up, the outset natural product to be synthesized in the laboratory was urea (for the molecular structure of urea and of the other milestone molecules mentioned in this article, see effigy one). This momentous effect, albeit a serendipitous discovery, meant that man could construct organic compounds, the molecules of living nature, in the laboratory and without the help of living creatures or their organs. This important singularity led to the downfall of vitalism, the agreement of the phenomenon of isomerism, and to a revolution in scientific discipline that came to be known every bit organic synthesis. Equally urea was a naturally occurring organic compound, the milestone of its synthesis as well marks the birth of total synthesis, the subdiscipline of organic synthesis dealing with the construction of nature's organic molecules. The accomplishment of the synthesis of urea by Wöhler was followed by the total synthesis of acerb acrid, a natural production containing ii carbon atoms (as opposed to urea'southward one), past German chemist Hermann Kolbe (ForMemRS) in 1845.
Select historical milestone accomplishments in total synthesis (* formal full synthesis).
Shortly after its occurrence, the advent of organic synthesis gave nascency first to the dye industry and and then to the pharmaceutical industry with the synthesis and commercialization of mauve (or mauveine) and acetylsalicylic acid (aspirin), respectively, triggering these industrial revolutions. The get-go discovery was fabricated, likewise serendipitously, past English chemist William Henry Perkin (FRS) during his attempts to synthesize quinine (the miracle natural product used as medication to treat malaria), employing an erroneous recipe. At the fourth dimension, Perkin was a student of High german chemist August Wilhelm von Hofmann (FRS), who founded and directed the Royal College of Chemistry in London upon invitation past Queen Victoria. The second discovery was made by German chemist Felix Hoffmann at the Bayer company and was based on the isolation and structural elucidation of salicin, the active pain-relieving ingredient of the willow bawl, whose medicinal properties were known from ancient times [two].
Indeed, natural products played a crucial role in the emergence and advocacy of organic synthesis from its nascency to the present twenty-four hours. Thus, from the early days of elemental assay of natural products, these substances fascinated and challenged organic chemists, kickoff with their structural elucidation and and so with their total synthesis. Past the dawn of the twentieth century, chemists had synthesized, besides urea and acetic acid, numerous natural and designed molecules, including indigo, alizarin, glucose, coniine and salicylic acid, the precursor of acetylsalicylic acid. They had also discovered several new reactions and practical them to the synthesis of a wide range of organic compounds, including many derivatives of benzene, collectively known as effluvious compounds [1–3].
The major achievements in organic synthesis and total synthesis of the concluding decades of the nineteenth century were widely recognized and appropriately hailed, as acknowledged by two Nobel Prizes in Chemical science awarded during the beginning 5 years of the Prize's existence [iv]. The commencement went to German chemist Emil Fischer (ForMemRS) in 1902 'in recognition of the extraordinary services he has rendered by his work on sugar and purine syntheses', and the second to German pharmacist Adolf von Baeyer (ForMemRS) in 1905 'in recognition of his services in the advancement of organic chemistry and the chemic industry, through his work on organic dyes and hydroaromatic compounds'. Many more Nobel Prizes would follow with notable frequency and regularity, reflecting the impressive advances made continuously in these fields throughout the twentieth century, underscoring their importance to science and guild. These advances were fabricated possible not simply by discoveries and inventions within the field of organic synthesis in terms of new synthetic reactions, methods and strategies, but also by the improvement of analytical techniques and instrumentation, also equally theories that led to improve understanding of the nature of the chemical bond [v] and chemical reactivity. The isolation and structural elucidation of novel molecular architectures from natural sources provided fuel and inspiration to the practitioners of total synthesis. Amid the nigh of import new reactions to be discovered in the first part of the twentieth century were the catalytic hydrogenation reaction of unsaturated carbon–carbon bonds past French chemist Paul Sabatier (ForMemRS) and the Grignard reaction for the formation of carbon–carbon bonds by French chemist Victor Grignard. Sabatier and Grignard shared the 1912 Nobel Prize in Chemistry for their pioneering and influential discoveries. Another highly influential discovery of that era was the Diels–Alder reaction (four+2 cycloaddition for constructing six-membered band compounds) made past German chemists Otto Diels and Kurt Alder in 1928. Their work was recognized in 1950 with the Nobel Prize in Chemistry. A number of relatively complex alkaloid natural products were synthesized, including tropinone, quinine, morphine and strychnine. The total synthesis of strychnine was accomplished past American pharmacist Robert Burns Woodward (ForMemRS), a major effigy who led a revolutionary movement in the field in the 1950s and 1960s that culminated in his recognition by the Royal Swedish Academy of Sciences with the 1965 Nobel Prize in Chemistry 'for his achievements in the art of organic synthesis' [half-dozen]. By then, in addition to strychnine, he had synthesized quinine (formal total synthesis), reserpine, chlorophyll and cephalosporine, so went on to consummate the total synthesis of vitamin B12, the almost complex natural product to be replicated in the laboratory at the time, in collaboration with Swiss chemist Albert Eschenmoser (ForMemRS) [7]. Woodward'south contributions likewise included the adoption of modern instrumentation for structural purification and elucidation purposes, every bit well as theoretical aspects of organic chemical science, for example the Woodward–Hoffmann rules.
In the meantime, the spectacular success of penicillin as a life-saving antibiotic generated impetus for the discovery of a broad range of new biologically active natural products from microorganisms, a surge at the captain of which were initially the pharmaceutical companies, presently to be joined by bookish institutions. Many of these compounds became clinical agents to care for disease and some are in utilize even today. Their attraction attracted the attention of synthetic organic chemists of the 2d half of the twentieth century and resulted in major achievements in the field of total synthesis. Human hormones such every bit the steroids and the eicosanoids (east.g. prostaglandins, thromboxanes and leukotrienes) played similar roles to those natural products derived from plants and microbes in challenging and inspiring young practitioners inbound the field. Ane of these practitioners was American chemist Elias J. Corey (ForMemRS), whose legendary contributions helped shape organic synthesis in decisive means during the second half of the twentieth century. His achievements included the introduction of the theory of retrosynthetic analysis, the development of several new synthetic methods, reagents and catalysts and the total synthesis of numerous bioactive naturally occurring substances, including several members of the prostaglandins, leukotriene and macrolide classes, ginkgolide B, maytansine and ecteinascidin 743. Corey was awarded the Nobel Prize in Chemistry in 1990 'for his development of the theory and methodology of organic synthesis' [8–10].
The latter part of the twentieth century witnessed impressive advances in the expanse of new synthetic methodology, which propelled the art of organic synthesis to higher levels of elegance, practicality and efficiency. These new methods facilitated discovery research, production development and manufacturing of pharmaceuticals and other fine chemicals that benefited lodge. Amidst the well-nigh powerful of these useful reactions are the Wittig reaction for constructing carbon–carbon double bonds, adult by High german chemist Georg Wittig, and the hydroboration reaction, adult by American chemist Herbert C. Brown. Dark-brown and Wittig shared the 1979 Nobel Prize in Chemistry 'for their development of the use of boron- and phosphorus-containing compounds, respectively, into of import reagents in organic synthesis'. The contributions of English chemist Sir Derek H. R. Barton (FRS) and Norwegian chemist Odd Hassel to conformational analysis played a major role in shaping our understanding of molecular structure that facilitated chemic reactivity and selectivity. Barton's discoveries extended well beyond stereochemistry and into other domains of organic synthesis such every bit biomimetic oxidative coupling reactions and radical chemistry. His pioneering studies in the latter field included deoxygenation and oxygenation methods (C−H activation/functionalization) that proved highly useful and inspiring to synthetic organic chemists of his and later generations. Barton and Hassel shared the 1969 Nobel Prize in Chemistry 'for their contributions to the development of the concept of conformation and its application in chemistry'. American chemist Gilbert Stork (ForMemRS) and Albert Eschenmoser made pioneering contributions to organic synthesis of theoretical and practical importance. Thus in 1955, they independently proposed the so-called Stork–Eschenmoser hypothesis stating that polyunsaturated molecules possessing all trans olefinic bonds (e.grand. squalene oxide, the biosynthetic precursor of steroid hormones) should undergo stereospecific cyclization to furnish a polycyclic system with all trans ring fusion stereochemistry (e.g. trans, trans, trans for dammaratienol, the production of squalene cyclization). This hypothesis was later verified experimentally by W. S. Johnson, who achieved the kickoff biomimetic total synthesis of progesterone in 1971. Stork made several other seminal contributions to organic synthesis, including stereocontrol, pour radical reactions and full synthesis. Eschenmoser's contributions to organic synthesis are equally impressive and include regio- and stereocontrol reactions, method development, corrin chemistry and the aforementioned landmark total synthesis of vitamin B12. Other of import reactions include phosphate and amide bond forming processes, discovered by Indian-born American biochemist H. Gobind Khorana (ForMemRS; 1968 Nobel Prize in Physiology or Medicine, shared with American biochemists Robert Due west. Holley and Marshall Westward. Nirenberg) and American biochemist R. Bruce Merrifield (1984 Nobel Prize in Chemistry), for the synthesis of oligonucleotides and peptides, respectively. In the concurrently, catalytic asymmetric reactions for oxidation, reduction and a variety of other important processes (2001 Nobel Prize in Chemical science awarded to American chemist K. Barry Sharpless, Japanese chemist Ryoji Noyori (ForMemRS) and American chemist William S. Knowles), metathesis reactions (2005 Nobel Prize in Chemistry awarded to American chemists Robert H. Grubbs and Richard R. Schrock (ForMemRS) and French chemist Yves Chauvin) for the structure of olefinic bonds and cyclic structural motifs and polymers, and palladium-catalysed cantankerous-coupling carbon–carbon bond-forming reactions (2010 Nobel Prize in Chemistry awarded to American chemist Richard F. Heck and Japanese chemists Ei-ichi Negishi and Akira Suzuki) changed the mode synthetic chemists were thinking almost and practising their scientific discipline.
The impact of organic synthesis on science and technology does not finish with biology and medicine. It encompasses many other scientific and technological endeavours and facilitates their improvement, scope and reach. Amongst the nearly prominent fields that benefited enormously from applications of organic synthesis are those of molecular recognition and supramolecular chemistry, materials science and nanotechnology and chemic biology. Indeed, the universe of compounds synthesized by organic synthesis, natural and designed, is very large and could exist almost space. Reflective of the progress made in organic synthesis in recent years are the numerous elegant total syntheses of biologically and medically important molecules achieved in laboratories around the earth [xi–fifteen].
4. Endeavours in full synthesis
The selection of the target molecule from the myriad natural products for full synthesis by the practitioner of the art depends on the novelty of its molecular construction, biological action and natural scarcity, among other criteria. Thus, some synthetic chemists may wish to use the structure of the molecule as an opportunity to detect and develop new reactions for unmet needs in organic synthesis in order to construct its unusual or sensitive structural motifs. Others may be interested to investigate and develop a deficient biologically active natural product, or a variation of it, every bit a biological tool or a pharmaceutical drug candidate for development as a clinical agent to utilise against illness. And still others may wish to undertake a full synthesis campaign for the intellectual claiming and sheer excitement that it provides. To these reasons must be added the educational activity and training of young students and the problem-solving skills they acquire during such endeavours, too as the value of the cardinal discoveries that are often fabricated whether through logical reasoning or serendipity.
Endeavours in total synthesis tin can be more or less challenging depending on the complexity of the molecular construction targeted. Simple and chemically stable molecules yield to synthesis more than hands than those possessing complex and labile architectures. Even so, complication does not ever equate with size when it comes to molecules and their structure. Thus, a smaller molecule with unusual atom connectivities and structural motifs is ever more challenging to synthetic organic chemists than one possessing a larger, just repetitive structure such every bit a polymer, a polypeptide or a polynucleotide.
The more challenging the total synthesis appears to exist, the more chances it has to offering opportunities to discover and invent new synthetic strategies and technologies. And the higher the importance of the biological science and medicine of the target molecule, the richer the harvest of the benefits and rewards of the try is likely to be. Such campaigns oft plow into interesting chemical biology studies and drug discovery programmes through molecular blueprint and synthesis of analogues of the natural product. The select target molecules shown in figure ii are just a few of those completed in our laboratories over the years [xvi]. The cases of calicheamicin 
(ane), Taxol (two) and brevetoxin B (3) are exemplary of the total synthesis endeavours we have been conducting, and volition exist highlighted below.
Select molecules synthesized in the author's laboratories.
v. The total synthesis of calicheamicin 
Calicheamicin 
(1, effigy three) is a fascinating molecule whose intrigue stems from not only its phenomenal cytotoxic properties and potential as an anti-cancer agent merely also its stunning molecular compages and fascinating mechanism of activity. At the time of its isolation from Micromonospora echinospora ssp. calichensis in the 1980s, neither its structure nor its machinery of action was precedented. Particularly striking were the 10-membered enediyne, oligosaccharide and trisulfide structural motifs of the molecule of calicheamicin 
, all three of which are involved in its mode of action that leads to lethal double-strand cuts of the genetic material (double-helix DNA). This mechanism can be compared to that of a guided missile in which the enediyne moiety acts as the explosive payload (generating reactive benzenoid diradicals through Bergman cycloaromatization), the oligosaccharide domain as the commitment arrangement (binding to the pocket-sized groove of DNA) and the trisulfide unit every bit the triggering device (initiating, upon activation, the Bergman cycloaromatization reaction). With all these exquisite features in place, the phase was set for what nosotros expected to exist an exciting gamble ahead as we embarked on the journey to the total synthesis of calicheamicin 
in the late 1980s. Indeed, we had no thought at the outset whether nosotros could ever go far at our destination, for the challenges facing us were formidable and unpredictable, owing to the demonic complexity of the molecule and its potential chemical instability.
Highlights of the total synthesis of calicheamicin 
: (a) in retrosynthetic format and (b) in forward synthetic format.
Arduous and difficult every bit the sail was, it led us, v years later, triumphantly to calicheamicin 
, our molecular 'Ithaca'. Almost chiefly, we arrived there much wiser and quite content with the compensation of discoveries and inventions we collected on the way. These rewards came in the course of new constructed methods and strategies, designed analogues of calicheamicin 
that exhibit like biological backdrop despite their simpler structures, and a final confirmation of the originally assigned structure of the natural production. The details of our full synthesis of calicheamicin 
have been published and reviewed in other forums [17–19] and, therefore, volition non be dealt with here beyond the highlights depicted in effigy 3. As shown in effigy 3 a in retrosynthetic format, a number of strategic bail disconnections allowed the definition of a gear up of building blocks (i.e. 4, 11–16, figure 3 b), which were constructed, coupled and elaborated appropriately to two larger intermediates, enediyne fragment ten and oligosaccharide fragment17. These two domains were then coupled through a glycosidation reaction to afford the entire framework of the molecule in the required atomic spatial arrangements. This advanced intermediate was so transformed to synthetic calicheamicin 
(1), identical in all respects (enantiomeric, chromatographic, spectroscopic and mass spectrometric) to the natural substance. A second synthesis of calicheamicin 
has been reported by the Danishefsky group [20].
The calicheamicin 
total synthesis endeavour proved delightfully rich in fundamental and practical knowledge. Thus, new synthetic strategies and technologies for the construction of the molecule's unprecedented structural motifs were developed, and a serial of analogues were designed, synthesized and tested for their ability to carve double-stranded Deoxyribonucleic acid and impale neoplasm cells. All in all, our constructed studies with calicheamicin 
created the foundations that shaped the enediyne surface area of anti-neoplasm antibiotics [21]. This field continues to be of great interest to scientists and clinicians alike, with new enediynes, natural and designed, emerging from nature and the laboratory.
One of the most promising new leads from nature is uncialamycin, a scarce enediyne anti-neoplasm antibody recently isolated from a marine brute. Our first full syntheses of uncialamycin [22,23] that led to its full structural consignment are currently being optimized and exploited as a means to produce this natural product and its analogues in large quantities and as potential payloads for conjugation to antibodies. Such antibody drug conjugates (ADCs) have recently been hailed every bit potential 'magic bullets' for targeted cancer chemotherapy [24]. The outset ADC drug to receive approval in the early 1990s for clinical utilise was gemtuzumab ozogamicin (Mylotarg; Wyeth/Pfizer), an antibody-linker–calicheamicin 
conjugate directed confronting acute myeloid leukaemia. Although withdrawn later owing to efficacy/safety concerns, Mylotarg proved inspirational and pathpointing. Today there are at least two ADC drugs on the market place for cancer chemotherapy, brentuximab vedotin (Adcetris; Seattle Genetics and Millennium/Takeda; confronting advanced Hodgkin's lymphoma) and trastuzumab emtansine (Kadcyla; Genentech/Roche; against late-stage HER2-positive chest cancer). Many other ADC drug candidates are currently in various stages of development [24].
6. The full synthesis of Taxol
The legendary cancer curative properties of Taxol (paclitaxel) are matched by the intrigue of its discovery and development as an anti-cancer drug in the latter part of the twentieth century. Originally isolated from Taxus brevifolia (Pacific yew tree) and structurally characterized in the early on 1970s, Taxol remained a scientific marvel until its antimitotic mechanism of action equally an anti-tumour agent was recognized in the early on 1980s. The latter discovery gave momentum to its clinical development, and information technology became an approved drug in the early on 1990s. Taxol is currently one of the most effective and widely used anti-cancer drugs for a variety of cancers, administered to patients either alone or in combination with other drugs. The natural scarcity of the molecule in its original source, coupled with the anticipated demand for the drug, created an urgency for its laboratory synthesis in the 1980s, one that was frustrated past the formidable challenge of the task attributable to its molecular complexity. Indeed, numerous groups around the world embarked on its full synthesis at the fourth dimension, and others continue to exist intrigued to this twenty-four hours by its structure as a synthetic target. The importance and lure of Taxol did non escape united states, and, in the early 1990s, nosotros initiated a campaign to synthesize it, an attempt that ended with the first published full synthesis of Taxol in 1994 [25].
The strategy adult for the synthesis of Taxol was based on the principle of convergency, pregnant that a number of primal building blocks had to be defined, constructed and coupled sequentially, and the resulting intermediates grown and elaborated towards the terminal target molecule. Depicted in retrosynthetic format in figure 4 a, this strategy defined, through the strategic bond disconnections indicated, building blocks 22, 27 and 32 (figure 4 b). These intermediates were constructed, coupled and elaborated, as outlined in figure iv b, through a series of key reactions as designated past the arrows. Thus, two [4+2] cycloadditions (Diels–Alder reactions) were employed to catechumen starting materials 18 and 19 and 23 and 24 to cyclohexene systems 21 and 26 through transition states 20 and 25, respectively. Each of these processes was notable for dissimilar reasons. The first led to the expected (from the rules of the Diels–Alder reaction) regioisomer, ring A (21), despite the severe steric congestion effectually the 2 adjacent tetrasubstituted (quaternary) carbon centres inside this compound. The second [4+ii] cycloaddition, leading, upon farther rearrangement, to band C (26), was impressive for the regiochemical exclusivity by which information technology proceeded, a consequence of the temporary boron tethering which oriented the two reactant partners properly in infinite, as shown in 25. Subsequent elaboration of 21 and 26 furnished required building blocks 22 and 27, respectively. Coupling of these key building blocks through a Shapiro reaction led to product 28, stereoselectively. Farther elaboration of the latter compound gave bis-aldehyde 29, whose ring closure in the presence of freshly generated titanium metal afforded the desired ABC ring system of the growing molecule thirty through a process known equally the McMurry reaction. This advanced intermediate was then subjected to further elaboration, leading to compound 31, which was coupled selectively to β-lactam 32 to give, afterwards appropriate deprotections, synthetic Taxol (1), identical in all respects to the natural product. In the latter coupling reaction, the β-lactam served as a surrogate to the side concatenation of Taxol, as expected from the well-known chemistry of this structural motif. Indeed, the same kind of reactivity is manifested in the antibacterial machinery of action of penicillin and other β-lactam antibiotics. Farther strategic and experimental details of our total synthesis of Taxol tin can exist found in the original publications and several reviews [19,25,26].
Highlights of the total synthesis of Taxol: (a) in retrosynthetic format and (b) in forrad constructed format.
Besides our total synthesis, a number of other elegant total syntheses of Taxol accept been reported by Holton et al. [27], Danishefsky et al. [28], Wender et al. [29], Mukaiyama et al. [30] and Kuwajima and co-workers [31]. Collectively, these accomplishments advanced the art and science of organic synthesis, enabled the design and synthesis of numerous analogues of Taxol, and facilitated biological investigations and drug discovery efforts in the area, including identification of biological tools and drug candidates. In addition to the methodological developments and facilitation of biology and medicine, the Taxol total syntheses served to demonstrate the sharp state of the art of full synthesis at the time and provided inspiration for farther advancements to occur in the field.
vii. The full synthesis of brevetoxin B
The long known 'red tide' phenomena, the first instance of which is perhaps noted in the Bible, are frequently responsible for major catastrophes involving environmental impairment, massive fish kills and poisoning of humans and other living creatures through seafood consumption. Two of the almost notorious poisons associated with these menacing occurrences are the highly stiff neurotoxin brevetoxin B (iii, figure five) and its sis molecule brevetoxin A.
Highlights of the full synthesis of brevetoxin B: (a) in retrosynthetic format and (b) in forward synthetic format.
Produced by the dinoflagellate Karenia brevis, brevetoxin B (iii) was isolated and structurally elucidated in 1981. Its molecular construction is a stunningly beautiful associates of carbon, oxygen and hydrogen atoms arranged precisely in space in a ladder-like array of 11 rings, ranging in size from six- to eight-membered. Such structures were unprecedented at the time, and, equally such, they provided challenge and inspiration to synthetic organic chemists whose drive to advance their science to college levels of sophistication is frequently fuelled by discoveries of new structural motifs from nature. Indeed, this was our main motivation in entering the campaign of the total synthesis of brevetoxin B [32–34] and, later on, its related congener brevetoxin A [19,35].
The stunning molecular structure of brevetoxin B meant the lack of suitable methods for its structure, specifically its circadian ether structural units of varying sizes. This state of affairs necessitated a search for such methods as a prerequisite before any serious effort to develop a strategy for the synthesis of the molecule could be launched. This search was fruitful and led to a rich compensation of new synthetic methods for the construction of cyclic ethers, common structural motifs in natural and designed molecules of biological and medical importance. These synthetic technologies and strategies have been amply described in previous manufactures and will non be further commented on here, except for two that played pivotal roles in the synthesis of brevetoxin B and other ladder-similar marine biotoxins. These are the regio- and stereospecific intramolecular opening of hydroxy epoxides conveying an olefinic bond side by side to the epoxide carbon–oxygen bond that undergoes the initial nucleophilic set on to form tetrahydropyran systems (six-membered cyclic ether structural motifs), and the hydroxy dithioketal cyclization leading to oxocene systems (eight-membered cyclic ether structural motifs).
Armed with our newly adult synthetic technologies, we were able to devise a successful strategy towards our target molecule brevetoxin B [32,33], but non before an arduous odyssey of 12 years' duration, full of unimaginable adventures and excitement [34]. Figure 5 summarizes the devised constructed strategy both in retrosynthetic format (figure 5 a), which defined the starting materials and key building blocks, and in the forward constructed direction (figure 5 b), which allowed the coupling and elaboration of the constructed building blocks to the terminal target molecule.
Thus, equally shown in effigy 5 b, the total synthesis of brevetoxin B began with d-mannose (34), a readily available starting material that provided the appropriate chirality for reaching the target molecule in its naturally occurring enantiomeric class. This material was elaborated to hydroxy epoxide 35, which served admirably as a forerunner to the side by side desired intermediate, tricyclic organisation 36, through an acid-catalysed regio- and stereoselective hydroxy epoxide opening co-ordinate to our specifically developed weather condition for tetrahydrofuran formation every bit mentioned above. The latter was so avant-garde to the IJK ring system aldehyde dithioketal 37 in waiting to be coupled to the larger ABCDEFG fragment (41), whose construction began with 2-deoxy-d-ribose (38), another readily bachelor starting material possessing the correct chirality for our purposes, and proceeded through intermediates 39 and forty. Advanced key intermediates 37 and 41 were then coupled through a Wittig reaction, forming hydroxy dithioketal 42, whose band closure under the action of argent perchlorate led commencement to ethylthio oxocene organization 43 and thence, through appropriate chemical transformations, to the ABCDEFGHIJK ring system 44 containing the unabridged undecacyclic ring framework of brevetoxin B. Further elaboration of the latter precursor generated constructed brevetoxin B (3), identical in all respects to the naturally occurring substance. Reported in 1995, the total synthesis of brevetoxin B [33,34] was followed by our total synthesis of brevetoxin A [35]. Subsequent to our work, the Nakata and Yamamoto groups accomplished a 2nd and third total synthesis, respectively, of brevetoxin B [36,37], while the Crimmins group achieved a 2d full synthesis of brevetoxin A [38].
The brevetoxin B project proved delightfully enriching in knowledge and supply of this deficient biotoxin. Virtually chiefly, it set the stage for more than advances to occur in the field of ladder-like marine neurotoxins, whose family unit currently boasts over 50 members and continues to grow. Besides brevetoxins B and A, several other members of the class accept been reached by a number of groups through total synthesis, including hemibrevetoxin, ciguatoxin 3C, gambierol, gymnosin A, breveral and the azaspiracids. These works have been reviewed by Nicolaou et al. [39]. Furthermore, big fragments of maitotoxin (see figure half dozen for molecular construction), the largest fellow member of the ladder-similar family unit of marine biotoxins, have been synthesized [40].
Molecular structures of maitotoxin and urea.
viii. Future perspectives
Always since its inception in 1828, organic synthesis has been on the march, advancing to new levels of performance and accomplish in terms of molecular complication and diverseness [16,41]. Its applications have been equally impressive and continue to expand into new domains, thereby increasing its affect on scientific discipline and order. Thus, from the tiny molecule of urea (CHivN2O, run across figure 6) containing a single carbon cantlet and no stereogenic site, constructed organic chemists of our fourth dimension cartel to try the synthesis of giant molecules such equally that of maitotoxin (C164H256O68SouthtwoNa2, meet effigy half dozen), the largest secondary metabolite discovered thus far from nature, boasting 164 carbon atoms and 99 sites of stereoisomerism [xl]. And from dyes and pharmaceuticals, organic synthesis came to provide the foundation of a whole new generation of scientific endeavours and industries, including polymers and plastics. Endeavours in total synthesis provided numerous, more or less, complex biologically agile molecules (natural or designed) for biological and pharmaceutical studies. Other synthetic efforts rendered available biomolecules such as nucleic acids, proteins and polysaccharides, and their smaller cousins oligonucleotides, peptides and carbohydrates. Fine chemicals used as fuels, pesticides and herbicides, diagnostics and medical devices, vitamins, perfumes, cosmetics, fabrics and all sorts of high-technology materials used in televisions, computers and other information technologies, and transportation and space machines are also the products of organic synthesis.
The latter applications became possible only considering of the advances fabricated in the field of organic synthesis. Information technology is, therefore, of paramount importance to go along to advance this subject field for its own sake and to constantly imagine new areas for its application. The former objective is in the minds and hands of the practitioners of organic synthesis, those who devote their efforts to the discovery and invention of new synthetic reactions, methods and strategies. Indeed, their inventiveness and imagination is already aiming at new directions and ambitious goals. Among them are pour reactions, C−H activation/functionalization, biomimetic synthetic strategies, new metal- and organocatalytic reactions and green chemistry. Ideally, the ultimate goal of organic synthesis practitioners should be to strive to elevate their art and science to the standards of nature and across in terms of efficiency, practicality and elegance.
The latter objective, that of applying wisely the power of organic synthesis to the benefit of other disciplines and society, can exist best achieved through the ingenuity and imagination by those same practitioners of the art of synthesis or past other scientists and engineers whose needs may be met through the enabling ways of organic synthesis. The virtually constructive way, however, for achieving novel applications and products is through multi- and transdisciplinary research programmes involving scientists from different disciplines and with overlapping and complementary expertise. A perfect case of such collaborations is that currently practised among chemists, biologists and clinicians during the drug discovery and evolution procedure. As more than academicians are attracted to this process, it is expected that new paradigms will emerge that will involve, in addition to chemists, biologists and clinicians, other specialists such as computational experts, bioinformaticians, engineers and logicians, amongst others. Their combined and integrated efforts should result in improved drug discovery and development practices with higher productivity, lower toll and higher odds of success in the clinic for drug candidates. In the meantime, other similar transdisciplinary programmes are being intensified, including collaborative research among chemists, physicists and materials scientists in the field of nanotechnology. In improver, i can also imagine several other yard challenges that can benefit from solutions provided through contributions of organic synthesis. These challenges include nutrient production, free energy sources and environmental protection through light-green chemical science and other means.
Information technology is my sincere hope that with this short perspective I succeeded, at least partly, in explaining the essence, purpose and societal bear on of organic synthesis to the broader readership of this journal of the Royal Society. The progress made in the field in its nearly two-century history is impressive, but considering the bewildering molecular complexity and diversity of molecules that nature can synthesize with such beauteous elegance and efficiency, nosotros must admit that our prowess and proficiency in this art is profoundly inadequate. Nosotros tin only wonder what the founder of organic synthesis, Friedrich Wöhler, would think of its progress, the present land of the art and its prospects for the future. My suspicion is that, while he would be happy and content, he would urge us to keep reaching for higher levels of composure and into new pastures in search of further discoveries and applications of the new and the one-time.
Acknowledgements
My sincere thank you and deep appreciation go to my many students whose collaborative efforts led to the accomplishments described in this article and whose names are found in the references below and the papers cited therein. I too wish to express my gratitude to the diverse agencies, companies and benefactors, whose names are found in the original publications, for supporting our research programmes over the years. Last but not to the lowest degree, I am indebted to my teachers and mentors for their constant guidance and inspiration, and to my wife, Georgette, my daughter, Colette, my sons, Alex, Christopher and P. J., and my grandson, Nicolas, for their continuous support and unconditional love.
Funding statement
This piece of work was partially supported by the US National Institutes of Health, The Skaggs Institute for Chemical Biology and the Cancer Prevention Research Establish of Texas (CPRIT).
Writer contour
K. C. Nicolaou obtained his BSc degree at Bedford College and his PhD degree from University Higher, University of London, under the supervision of Peter Garratt and Franz Sondheimer (FRS). He after carried out research as a postdoctoral fellow at Columbia and Harvard Universities, nether the mentorship of Thomas J. Katz and E. J. Corey, respectively. During his independent career, he worked at the University of Pennsylvania, The Scripps Research Institute, the Academy of California, San Diego, and currently at Rice University, where he is the Harry C. and Olga K. Wiess Professor of Chemical science. Between 2004 and 2010, he served as the Director of the Chemical Synthesis Laboratory, of which he was the founder, at A*STAR, Singapore. His enquiry activities focus on the discovery and evolution of new synthetic strategies and technologies, and their applications to the full synthesis of natural and designed molecules of biological and medical importance. K. C. Nicolaou was elected equally a Foreign Fellow member of the Royal Society in 2013.
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