Ja 201762

The Journal of Antibiotics (2018) 71, 153–184
& 2018 Japan Antibiotics Research Association All rights reserved 0021-8820/18
www.nature.com/ja
REVIEW ARTICLE
A brief history of antibiotics and select advances in

their synthesis
Kyriacos C Nicolaou and Stephan Rigol
The advent of modern antibiotics contributed enormously to the dramatic extension of human lifespan since their discovery by
virtue of their lethal and selective action against pathogenic microbes. And yet despite our powerful arsenal of weapons against
these pathogens, the war against them has not been won. And it may never be. Drug resistance is still menacing the society with
many lives being lost due to deadly infections caused by continuously evolving strains spread beyond our means to eradicate
them or prevent their spreading. Herein, the emergence and evolution of antibiotics is briefly reviewed, and a select number of
total syntheses of naturally occurring antibiotics from the authors’ laboratories are highlighted. The article concludes with a
strong endorsement of the current efforts to intensify our fight against these dangerous pathogens with the hope that, this time,
these initiatives will be sufficiently focused and serious enough so as to achieve our set goals of, at least, being prepared and
ahead of them as part of our drive to improve humanity’s healthcare and wellbeing.
The Journal of Antibiotics (2018) 71, 153–184; doi:10.1038/ja.2017.62; published online 5 July 2017
HISTORICAL PERSPECTIVE second half of the nineteenth century that the French chemist and
The origin of the term ‘antibiotic’ can be traced back to the bacteriologist Louis Pasteur contributed decisively to our understand-
word antibiose first used as an antonym to symbiosis by ing of the underlying causes of infectious diseases through his
Paul Vuillemin1 in his 1890 publication to describe the antagonistic experimental studies with bacteria that culminated in his germ theory
action between different microorganisms (for example, fungi vs of disease. The subsequent contributions of the German physician
bacteria; bacteria vs protozoa).2,3 Later, the word antibiotic was used Robert Koch also proved transformative. His discoveries, including the
to describe naturally occurring secondary metabolites produced by so-called four ‘Koch postulates’ establishing a causative relationship
bacteria and fungi possessing either growth inhibitory (bacteriostatic) between microbes and disease (predicated on work of Jakob Henle,5
or killing (bactericidal) activities against bacteria or fungi. Today the and together with Friedrich Loeffler), propelled bacteriology toward its
term has a broader meaning, in one sense to include designed modern era.6–8 In 1882 Koch, together with Bernhard Fischer and
molecules and a narrower definition, in another and with the terms Georg Gaffky, isolated the Mycobacterium tuberculosis and in 1884 the
antibacterial or antifungal, to designate their specific actions against Vibrio cholerae (a species first described in 1854 by Italian anatomist
bacteria and fungi, respectively, but not viruses.2 The term antiviral is and pathologist Filippo Pacini),9 the causative strains that lead to the
reserved for the latter. In the Middle Ages, the miasma (or miasmatic, corresponding diseases. These milestone discoveries earned Koch one
from the Greek μίασμα, meaning pollution, fowl air or contaminated of the first Nobel Prizes in Physiology or Medicine (1905).
vapors) theory was used to explain the causes of various diseases. In The first antibiotic to be discovered from nature was mycophenolic
1546 the Italian scholar Girolamo Fracastoro (Hieronymus Fracastor- acid (1, Figure 1). Reported by the Italian physician and microbiologist
ius) proposed transmittable, imperceptible seed-like particles (semi- Bartolomeo Gosio in 1893, this antibiotic was isolated from Penicil-
naria morbi) as causative agents for the outbreak of certain diseases.4 lium glaucum (P. brevicompactum) as a crystalline solid while he was
It took several centuries to prove that bacteria are one example of such studying pellagra.10,11 At that time it was shown that mycophenolic
‘particles’. In the meantime, the Hungarian physician Ignaz Semmel- acid inhibits the growth of Bacillus anthracis, and later that it also
weis, also known as the ‘savior of mothers’, recognizing the impor- possess antiviral, antifungal, antitumor and anti-psoriasis properties.12
tance of hygiene in hospitals suggested and enforced hand washing This seminal discovery remained unnoticed (probably due to its
with chlorinated lime solutions before patient examinations, while the publication in Italian) until mycophenolic acid was rediscovered in
Scottish surgeon Sir Joseph Lister treated surgery wounds with phenol 1913 in the United States.13 Its structure, however, remained unknown
(carbolic acid) solutions to avoid infections. In the 1860s the French until 1952,14 while its total synthesis was achieved in 1969.15,16 It was
physician Casimir Davaine demonstrated that blood injections from not until 1995 that the 2-(morpholin-4-yl)ethyl ester of mycophenolic
animals infected with anthrax to healthy animals caused infection, acid (a prodrug of 1) was approved by the US Food and Drug
providing further clues for the cause of disease. It was also in the Administration, although not as an antibacterial drug but rather as an
Department of Chemistry, BioScience Research Collaborative, Rice University, Houston, TX, USA
Correspondence: Professor KC Nicolaou, Department of Chemistry, BioScience Research Collaborative, Rice University, 6100 Main Street, MS-602, Houston, TX 77005, USA.
E-mail: [email protected]
Received 6 March 2017; revised 17 April 2017; accepted 23 April 2017; published online 5 July 2017
Advances in the synthesis of antibiotics
KC Nicolaou and S Rigol
154
Figure 1 Historic discoveries and developments of antibiotics as drugs.
immunosuppressant to prevent transplant rejection (through a of Paul Ehrlich and approved in 1910 as a drug,18 the story of
mechanism involving the inhibition of DNA biosynthesis).17 Salvarsan began when the immunologist Ehrlich was introduced to cell
The first decade of the twentieth century witnessed the emergence staining by his cousin Carl Weigert, who demonstrated that aniline
of the first man-made antibacterial agent, arsphenamine (Salvarsan, 2, dyes can be used for this purpose in histology.19–22 Ehrlich was
Figure 1). Synthesized by chemist Alfred Bertheim in the laboratories fascinated by the fact that selective staining of different cell types,
The Journal of Antibiotics

155
including bacteria, was possible, and this led him to contemplate the the structure of penicillin was elucidated through X-ray crystal-
idea of chemotherapia specifica and to propose his famous concept of lographic analysis by Dorothy Crowfoot Hodgkin,29 allowing it to be
the Zauberkugel (magic bullet) that continues to inspire biologists and classified as the first member of the β-lactam family of naturally
chemists alike today. Starting in 1906, Ehrlich and his group started to occurring antibiotics. Later that year, Alexander Fleming, Ernst Boris
synthesize and test compounds derived from arsanilic acid (atoxyl) Chain and Howard Walter Florey were jointly awarded the Nobel
against bacterial strains. In 1909, a year after Ehrlich shared the Nobel Prize in Physiology or Medicine for the discovery of penicillin and its
Prize in Physiology or Medicine with Ilya Mechnikov for their work curative effect in various infectious diseases. The first total synthesis of
on immunology, he and his assistant Sahachirō Hata found that a member of the penicillin family (that is, penicillin V) was reported in
compound 606 was effective against bacterial strains of Spirochaetes, 1957 by John Sheehan.30,31 It featured five linear steps and resulted in
and against protozoa Trypanosoma, findings that led to clinical trials, 1.4% overall yield of the product. Even though not useful for
and eventual marketing of the drug for the treatment of syphilis, industrial production, the synthesis provided the first opportunity to
a disease caused by bacterium Treponema pallidum. For nearly 40 years prepare analogs of penicillin from 6-aminopenicillanic acid, an
Salvarsan was the standard therapy for this disease, with new versions intermediate that emerged from the endeavor. In contrast to the
(Neosalvarsan and Solu-Salvarsan) being introduced later as improved mode of action of the sulfonamides, penicillin and its other β-lactam
drugs,23–26 allowing for easier application and causing less side effects. siblings act bactericidally and, through a mechanism that involves
Interestingly, the precise molecular structure of arsphenamine inhibition of serine-type D-alanyl-D-alanine carboxypeptidase, an
remained vague, with Ehrlich assuming it was dimeric in nature with enzyme crucial to the peptidoglycan layer of the bacterial cell wall.
the two As-atoms doubly bonded. A recent mass spectrometric Exerting its antibiotic activities (bactericidal) through the same
investigation, however, revealed both trimeric (see 2, Figure 1) and mode of action as penicillin, cephalosporin C (3a, Figure 1),
pentameric species.27 the first member of the cephalosporins (a sub-class of β-lactams),
Staphylococci, a summer sojourn, and the serendipitous scrutiny was originally discovered in 1945 by Giuseppe Brotsu32,33
of a Scottish scientist are the three ingredients that led to one of the from Cephalosporium acremonium (now Acremonium chrysogenum).
most impactful discoveries in the history of medicine: penicillin Cephalosporin C was rediscovered in 195534 and structurally
(3, Figure 1). After returning from his vacation in September 1928, elucidated by chemical degradation studies35 and X-ray crystallo-
Alexander Fleming, a bacteriologist at St Mary’s Hospital, went back to graphic analysis in 1961.36 Its first total synthesis was achieved by
his laboratory in Paddington (Westminster, London) and found a Robert B. Woodward in 1965 and reported in his Nobel lecture before
Staphylococcus aureus colony he had left on his bench contaminated it was published in 1966.37 Although cephalosporin C did not become
with a fungus (Penicillium notatum, now P. chrysogenum) in an a clinical agent, its structure inspired numerous synthetic efforts that
intriguing pattern. This finding had occurred already to other scientists led to designed analogs from which emerged powerful antibacterial
before him, but Fleming did not dispose of the contaminated petri drugs, with cefalotin being the first clinically approved cephalosporin
dish without further examination. He realized that in proximity to the antibacterial agent.
mold, the Staphylococci underwent lysis while colonies further away The next advance in the antibiotics area was marked by the
appeared to be normal and unaffected. Fleming went on to grow the discovery and deployment of the sulfonamide drugs. First synthesized
fungus as a pure culture and to treat several pathogenic bacterial as a dye by Fritz Mietzsch and Josef Klarer at Bayer in December 1932,
strains with its extract to descry similar effects as previously observed sulfamidochrysoidin (4, Prontosil, Figure 1) was recognized as an
with the Staphylococci, especially for Gram-positive ones. He con- antibacterial agent by Gerhard Domagk,38 a fortunate event that led to
cluded that the fungus must have excreted a substance that killed the its marketing as a drug in 1935, and a Nobel Prize in Physiology or
bacteria, and named it penicillin in March 1929.28 Fleming attempted Medicine to him in 1939. Before the Nobel Prize and the approval of
early on to collaborate with a number of researchers in an effort to the drug, Domagk and his family were rewarded with the saving of
isolate and purify the unknown substance, hoping to demystify the the life of his 6-year-old daughter who was suffering from a life-
puzzle of penicillin, but without success. In 1939, pathologist Howard threatening sepsis. He decided to use the then still experimental drug,
Walter Florey and biochemists Ernst Boris Chain and Norman Heatley code named D 4145 (Streptozon), to treat her, a decision that must
at Oxford University started to work on the isolation of the mystery have given him the most happiness of all his prizes. In the same year
substance, and within a year managed to test the isolated compound in that Prontosil was approved, Jacques and Thérèse Tréfouël, Federico
a mouse model, revealing phenomenal results. In early 1941, the first Nitti, and Daniel Bovet at the Pasteur Institute determined that
human, policeman Albert Alexander who was suffering from a severe sulfamidochrysoidin acts as a prodrug, releasing in vivo the active
face infection causing a sepsis, was treated with penicillin. His antibacterial agent p-aminophenylsulfonamide (through reductive
condition improved significantly during the first five days of therapy, cleavage of the diazo linkage).39 The latter compound, however, had
but unfortunately the limited drug supply run out and the patient died already been synthesized by the Austrian chemist Paul Gelmo in
from the prevailing sepsis. However, it became clear to the clinicians 1908,40 and hence this molecular entity and compounds releasing it
that penicillin was a powerful drug with auspicious properties. Later, were not patentable. This predicament led to a surge of activities in the
and after painfully securing adequate supplies of the drug, several 1930s and 1940s, primarily in Europe and the USA, that resulted in
other patients were treated successfully and with full recovery. Out of the discovery and development of several new and patentable drugs.
necessity, and motivated by the outbreak of the Second World War, The sulfonamides are bacteriostatic agents, acting through a mechan-
the collaborative Anglo-American penicillin project was launched. ism that involves inhibition of folic acid biosynthesis in bacteria,
Its aim was to produce sufficient amounts of the new antibiotic for the leaving normal human cells unharmed since the latter have no folic
needs of the allied forces fighting and dying from infections in the acid biosynthesis machinery.41
battle fields of Europe, Africa and Asia. In 1945, penicillin became A new chapter on antibiotics was opened in 193942–44 when French
available to the public and was no longer an exclusive medication for microbiologist René Dubos isolated tyrothricin45–47 from Bacillus
the military, consummating in the transformation of an allegedly brevis. It was later shown that tyrothricin was a mixture consisting
failed experiment to a life-saving drug for millions. The same year, of gramicidin D (itself a mixture of gramicidins A1/2–C1/2, all linear

156
pentadecapeptides differing at positions one and/or eleven of the thereafter, several other members of the tetracycline family were
amino acid sequence) and tyrocidine (a mixture consisting of isolated at Pfizer (New York, NY, USA) by a group headed by
tyrocidines A–D). In 1942, Soviet biologist Georgyi Frantsevich Gause Alexander C. Finlay, including oxytetracyclin (from Strep. rimosus)
and his wife Maria Brazhnikova discovered another gramicidin from and tetracycline (from Strep. aureofaciens).75 The gross structure of
the same bacterial strain (Bacillus brevis) and named it gramicidin S (5, chlortetracycline was first determined by Woodward through chemical
Figure 1).48 A symmetrical macrocyclic homodetic decapeptide [cyclo derivatization methods in 1954.76 This was followed by X-ray crystal-
(D-Phe-Pro-Val-Orn-Leu-)2], gramicidin S is also classified as a lographic studies in 195977,78 and 196379, which led to the elucidation
member of the polypeptide antibiotics mentioned above but differs of the relative stereochemical structure of chlortetracycline. Although a
from the polymyxins, another family of cyclic decapeptides, in that it total synthesis of chlortetracycline (7), oddly enough, has not been
lacks the characteristic extended lipophilic side chain of the latter. reported as yet, a formal total synthesis was reported in 1973 by Hans
Gramicidin S was found to be active against Gram-positive and some Muxfeldt et al.80,81 The formal total synthesis of tetracycline (7-
Gram-negative bacteria. It was used for the first time in the year of its dechloro-7) itself was achieved by Mikhail M. Shemyakin in 196782–85
discovery (1942) in military hospitals, and starting in 1943 in the while Woodward had already succeeded in synthesizing the first
eastern front during the Second World War, making it the biologically active tetracycline derivative in 1962.86,87 Furthermore,
Soviet counterpart of penicillin.49 And, interestingly just like penicillin, several other tetracyclines have been synthesized over the years.88–98
the structure of gramicidin S was solved in Great Britain, this Like streptomycin, the tetracyclines exert their bacteriostatic properties
time by Richard Synge who employed classical derivatization/degrada- through a mechanism involving inhibition of bacterial protein
tion methods,50–52 and Hodgkin who used X-ray crystallography to biosynthesis by binding to the ribosome at the 30S site.74 Numerous
decipher the structure,53 after the Red Cross brought a sample from tetracycline derivatives have been synthesized in efforts to overcome
Moscow.49 In 1964, Hodgkin was awarded the Nobel Prize in the emergence of resistance to the original drugs, including tigecycline
Chemistry for her determinations by X-ray techniques of the (7a, Figure 2a), which was approved by the US Food and Drug
structures of important biochemical substances. The total synthesis Administration in 2005.99
of gramicidin S was reported in 1957 by Robert Schwyzer54,55 Before the end of the decade of the 1940s, yet another original
following previously published methods.56 The clinical application of antibiotic made its entrance, chloramphenicol (8, Figure 1), a member
gramicidin S is limited to topical infections (for example, eye, ear) due of the phenylpropanoids. Discovered initially by John Ehrlich in 1947
to its undesired hemolytic properties originating from membrane (from Strep. venezuelae),100 and shortly thereafter and independently
lysis.57 Its mechanism of action as a bactericidal antibiotic relies on its by David Gottlieb et al.101,102 and Umezawa et al.,103 chloramphenicol
ability to form ion channels in the bacterial cell wall upon dimeriza- proved to be a broad spectrum antibiotic and was used clinically for
tion, causing collapse of the electrochemical gradient.58,59 the first time, and with remarkable success during the 1947 typhus
Another important milestone in the history of antibiotics was the epidemic in Bolivia.75 Its chemistry was investigated in 1948104 and its
discovery of streptomycin (6, Figure 1) from Actinomyces griseus (now structure was proposed105 and confirmed by total synthesis106 in 1949.
Streptomyces griseus), the first aminoglycoside antibiotic, in 1943 by Chloramphenicol was approved for clinical use as an antibacterial
Albert Schatz and Selman Waksman.60,61 Significantly, it was shown agent in the same year and became one of the best-selling drugs at the
that, in addition to being active against Gram-positive strains, the time. Its mechanism of action (bacteriostatic) involves binding to the
newly isolated antibiotic was also potent against multiple Gram- 50S subunit of the bacterial ribosome, resulting in protein biosynthesis
negative bacteria as well as against Mycobacterium tuberculosis.62 Since inhibition.107,108 It is notable that chloramphenicol became the first
the latter strain was not affected by penicillin, streptomycin was naturally occurring antibiotic produced by chemical synthesis, rather
meeting an unmet medical need, offering physicians and patients than fermentation. This may be a reflection of a combination of
suffering from tuberculosis hope for a potential cure for the first factors, including its relative structural simplicity and the increasing
time.63 The development of streptomycin as a powerful drug against capabilities of organic synthesis at the time.
this dreaded disease eventually led to the Nobel Prize in Physiology or Besides the rush for the discovery of antibiotics from nature
Medicine to Waksman in 1952, but not without creating a bitter triggered by penicillin’s spectacular success, the 1950s saw the
dispute between Waksman and Schatz over their individual contribu- re-emergence of interest in synthetic designed antibacterial agents
tions and the wealth of royalties from the streptomycin patent.64,65 such as Salvarsan and Prontosil, two of the very first antibacterial
The first human cure of an infection by streptomycin was reported in agents to be introduced for clinical use. The opportunity arose when a
1944, and was followed by the successful treatment of a patient rather simple natural antibiotic, azomycin (2-nitroimidazole) was
suffering from tuberculosis 2 months later.65 Upon completion of originally discovered (1953)109 and structurally elucidated (1954).110
successful clinical trials, the drug was approved for broad clinical use Azomycin proved too toxic for clinical use, but nevertheless inspired
in 1946. After full structural elucidation of streptomycin,66–68 the first scientists at Rhône-Poulenc in France as a lead compound to design
total synthesis of the natural product was achieved in 1974 by Sumio and synthesize analogs of it, from which metronidazole (9, Figure 1)
Umezawa et al.,69 the group having first completed the synthesis of was selected as a drug candidate for further development due to its
dihydrostreptomycin.70 The mode of action of streptomycin (bacter- high potency and low toxicity.111–113 Metronidazole was approved as a
icidal) involves inhibition of bacterial protein biosynthesis71 through clinical agent in France in 1960 and in the United States in 1963.113
binding to the 30S subunit of the prokaryotic ribosome.72 It exerts its antibacterial properties through a distinctively different
The first member of one of the most important classes of mechanism than the other antibiotics discussed above in that it
antibiotics, that of the tetracyclines, was unearthed in 1945, being damages directly the genetic material of the bacteria through
isolated from Strep. aureofaciens by American plant physiologist intracellular generation of nitroso radicals.114 These reactive nitroso
Benjamin M. Duggar. It was originally named aureomycin due to its radicals are produced reductively through a single-electron transfer to
golden color, but is known today as chlortetracycline (7, Figure 1).73 the nitro group. This mechanism is expected to operate especially in
In 1948, it was approved for clinical use as a broad spectrum antibiotic anaerobic bacteria such as Bacteroides, Clostridium, Helicobacter or
against both Gram-positive and Gram-negative bacteria.74 Soon Campylobacter, but hardly in human cells, endowing the drug with the

157
desired bactericidal properties against bacteria without side effects to a soil sample imported to the USA from the Philippines. Erythromy-
the patient.114 cins A and B were marketed in the same year under the name
Another inspirational antibiotic that did not actually make it to Ilotycin128,129 as a mixture of compounds. This mixture was later
the clinic is pleuromutilin (10, Figure 1).115 Isolated in 1951 by separated and the main components were renamed as erythromycins
Frederick Kavanagh from basidiomycetes Pleurotus passeckerianus A–D, with A being the most abundant. The molecular structure of
(now Clitopilus passeckerianus) and Pleurotus mutilus (Fr.) Sacc erythromycin A (11, Figure 1) was first determined in 1957130–138 with
(now Clitopilus scyphoides).116,117 Found active predominantly against the X-ray crystallographic analysis of the dihydrate reported in
Gram-positive bacteria, but also against a number of Gram-negative, 1997.139 The total synthesis of erythromycin A was accomplished
pleuromutilin was structurally elucidated in 1962 after extensive and published by the Woodward group (posthumously for Wood-
chemical studies118 conducted independently at Manchester ward) in 1981.140–142 It was preceded by the total synthesis of
(UK)119,120 and Zürich (Switzerland).121,122 Its structure was con- erythronolide B (the aglycon of erythromycin B) which was accom-
firmed by X-ray crystallographic analysis and ORD studies in 1968.123 plished by the Corey group in 1978.143,144 The mechanism of action of
Pleuromutilin was synthesized first, in racemic form (1982),124,125 the erythromycins (bacteriostatic or bactericidal, depending on
and thence enantioselectively (2013) by David J. Procter.126 Numerous medicated strain and concentration) involves binding to the 50S
semisynthetic analogs of pleuromutilin have been synthesized and subunit of the ribosome and inhibition of bacterial protein
tested, one of which, retapamulin (carrying a thiotropine moiety at the biosynthesis.145,146
glycolic acid side chain), was approved as a clinical antibacterial drug Soon after the discovery of the erythromycins, another family of
in 2007 in the United States. The mechanism of (bacteriostatic) action powerful antibiotics, that of the glycopeptides, was discovered. The
of the pleuromutilin family of antibiotics is based on their ability to first member of the class was isolated in 1953 from Strep. orientalis
bind the 50S subunit of the bacterial ribosome.127 (now Amycolatopsis orientalis) found in a soil sample originating from
The 1950s would usher in a new crop of novel antibiotics, among Borneo.147 Later named vancomycin (from its ability to vanish
the most prominent of which were the erythromycins. Endowed with bacteria) (12, Figure 1), this legendary antibiotic was found to be
complex 14-membered macrolide structures, erythromycins A and B especially active against Gram-positive bacteria, and most significantly
were isolated by Eli Lilly (Indianapolis, IN, USA) scientists led by against penicillin-resistant Staphylococci. Vancomycin was approved as
James M. McGuire in 1952 from Saccharopolyspora erythraea, found in a clinical agent for the treatment of bacterial infections in 1958. Its use
Figure 2 Select widely used (a) and last resort (b) antibiotics.

158
was later decreased in favor of other antibiotics for toxicity reasons,148 consisting of one part trimethoprim to five parts sulfamethoxazole,
although it continues to be employed in severe cases against and later also as a single molecular entity drug.189 Trimethoprim acts
drug-resistant bacteria. The quest for the structural elucidation of bacteriostatically through inhibition of dihydrofolate reductase, an
vancomycin involved chemical studies (1977)149–151 and X-ray crystal- enzyme involved in the bacterial folic acid biosynthesis. It has the
lographic analysis, first of its degradation product CDP-1 (1978)152 distinction of being the first member of the dihydrofolate reductase
and thence the natural product itself (1996).153 The first total synthesis inhibitors.190
of the aglycon of vancomycin was accomplished in 1998 by the Evans Nalidixic acid (16, Figure 1) was also synthesized in 1962 and found
group154,155 and our group.156–158 The total synthesis of vancomycin to be highly potent in vitro and in vivo,191 its activity being most
itself was achieved in 1999 by our group.159 The mechanism of pronounced against Gram-negative bacteria such as Escherichia coli,
bacteriostatic action of vancomycin resembles that of the β-lactams in Proteus mirabilis and Shigella flexneri, while exhibiting low toxicity.191
that it interferes with the construction of the bacterial cell wall. This discovery turned out to be highly significant in that it led to the
It exerts its disruptive activity by binding to the D-Ala-D-Ala unit of a emergence of quinolones, an important family of synthetic antibiotics
pentapeptide moiety essential for the knitting of the peptidoglycan whose structures are related to quinoline.192 Depending on the
network of the cell wall, thereby hindering its proper formation.160 concentration, nalidixic acid can act as a bacteriostatic or bactericidal
In the same year that vancomycin was discovered, another new agent.193 Its biological target is topoisomerase II,194,195 an enzyme
antibiotic was isolated, ushering in the family of streptogramins. The catalyzing the ATP-dependent negative supercoiling of double-
eponymous compound, streptogramin was isolated as a secondary stranded closed-circular DNA,196 thus causing interruption of bacterial
metabolite from a then unknown Streptomyces spp. (later named DNA biosynthesis.197 Nalidixic acid was launched as a clinical
Strep. graminofaciens) and found to be especially active against antibacterial agent in 1967,192 but was later replaced by fluoroquino-
Gram-positive bacterial strains.161,162 It was subsequently found that lones like ciprofloxacin (16a, Figure 2a) which proved superior
streptogramin is a mixture of two distinct components, streptogramin as drugs.
A (also named pristinamycin IIA, virginiamycin M1, ostreogrycin A, The ansamycins198 are a group of macrolactam antibiotics whose
mikamycin A, 13, Figure 1) and streptogramin B (also named first members were reported in 1959 by Piero Sensi, Maria T. Timbal
pristinamycin IA, virginiamycin S1, mikamycin B, vernamycin Bα, and Pinhas Margalith.199 Named rifamycins, these early ansamycins
14, Figure 1).163 The structures of both components were elucidated were isolated from Strep. mediterranei (now Amycolatopsis rifamyci-
during the mid-1960s164–166 and confirmed by X-ray crystallographic nica). The structures of a number of them were elucidated through
analysis in 1974167 (streptogramin A) and in 1990168 (streptogramin chemical degradation studies in 1964,200 while that of rifamycin B was
B). Being comprised of two structurally unrelated, but concurrently determined in the same year by X-ray crystallographic analysis.201,202
produced compounds by a single species and classified as groups A Naturally occurring rifamycin B failed to become a drug, but one of its
and B, this paradigm represents a special case characteristic of the slightly modified semisynthetic versions (that is, rifamycin SV) was
streptogramins. Substances of group A feature a 23-membered approved as a clinical antibacterial agent especially effective against
polyunsaturated macrolactone framework while members of group tuberculosis,203 albeit intravenously delivered. Further studies led to
B possess a cyclic hexa- or hepta depsipeptide scaffold. Remarkably, improved and orally active drugs,204 one of them being rifaximin (17,
the streptogramins demonstrated strong synergistic effects when Figure 1).205 The latter is specifically used to treat colon-related
administered in combination.163,169 The mechanism of their anti- infections without significant systemic side effects due to its poor
bacterial action relies on sequential binding of first streptogramin A, absorption properties upon oral administration,204 and thus only
and then B to the 50S subunit of the bacterial ribosome, thus effective in the intestinal lumen. The bactericidal action of the
inhibiting protein biosynthesis. When applied as single substances, rifamycins originates from their ability to inhibit bacterial DNA-
each compound acts bacteriostatically, but when used together they dependent RNA biosynthesis, which in turn inhibits protein
develop bactericidal activities.170,171 For a long period of time, the biosynthesis.206,207
streptogramins were mostly used in the agricultural sector as growth After the introduction of the quinolones in the 1960s, it took,
promoters. They were first launched in 1973 (as a 1:1 mixture of 13 surprisingly, more than two decades for the next class of antibiotics to
and 14) as pristinamycin in Europe for the treatment of infections be ushered into the clinic. The story of linezolid (18, Figure 1) goes
caused by Streptococci and Staphylococci. Later, studies at Rhône- back to at least the 1970s when certain oxazolidinones were recognized
Poulenc Rorer directed toward improving the water solubility of by DuPont scientists as possessing antibacterial properties.208,209
streptogramins A and B led to the semisynthesis of quinupristin and It was, however, a group at the Upjohn pharmaceutical
dalfopristin, respectively, two analogs that were successfully developed company (Kalamazoo, MI, USA)210,211 that discovered and developed
in a 3:7 combination as an antibacterial drug172 and approved by the linezolid as a clinically used antibacterial agent,212 approved in the
US Food and Drug Administration in 1999. This combination United States in 2000.210 Linezolid is particularly effective in treating
medication is used especially in severe cases of infections associated infections caused by Gram-positive bacterial strains such as Strepto-
with vancomycin-resistant Enterococcus faecium. Since their discovery cocci and Enterococci, especially in cases where other antibiotics failed.
several synthetic approaches toward the total synthesis of select The mechanism of action of this bacteriostatic last resort antibiotic213
members of the streptogramin family have been reported,173–179 with involves binding to the 50S subunit of the ribosome and inhibition of
some successfully reaching their targets.180–185 bacterial protein biosynthesis.214
Trimethoprim (15, Figure 1) is another early unnatural antibiotic. The so-called ketolide family of antibacterial agents arose from the
Synthesized in 1962, this compound was found to exhibit strong erythromycin class through semisynthetic studies. It was scientists at
antibacterial activities against both Gram-positive and Gram-negative Roussel-UCLAF in France who prepared compound RU-66647 from
strains.186 In the same year, the first successful clinical data were erythromycin A (11, Figure 1) in 1997 and showed it to be active
reported,187 and included synergistic effects when the drug was against bacteria, especially Gram-positive strains.215 Later named
administered to patients together with sulfonamides.188 Trimethoprim telithromycin (11a, Figure 1), this first member of the ketolide family
was marketed in 1974 as co-trimoxazole, a combination medication was successfully developed and launched as an antibacterial drug,

159
first in Europe (2001) and thence in the United States (2004).216 mutations involving genetic changes that result in inactivation of the
Although derived from erythromycin A, telithromycin and its siblings drug (for example, β-lactamases), modification of previously essential
structurally differ, significantly, from the latter in that they lack the biosynthetic pathways, or alteration of the target site (cell wall
L-cladinose sugar moiety at C3, exhibiting instead a keto group at that construction, folic acid biosynthesis, protein biosynthesis). Expulsion
position and, thereby, improving the drug stability toward acidic of the drug from the cell (efflux) is another mechanism bacteria can
conditions. In addition, the ketolides include in their structures a use to evade the action of antibiotics. These genetic changes can later
cyclic carbamate moiety fused onto the macrolide ring at C11 and spread through lateral gene transfer via transformation, transduction
C12, with the N-atom originating from replacement of the O-atom of or conjugation.226–229 It was as early as the 1940s when the problem of
the erythromycin precursor of the molecule. Telithromycin specifically resistance development and the problems of self-medication were
includes an alkyl side chain on the carbamate nitrogen ending with discussed in public,230 but even today in many countries antibiotics
two N-heterocyclic rings.217 Its mechanism of action resembles its are available over the counter without prescription and are extensively
precursor compound, erythromycin A, namely inhibition of bacterial used in veterinary context worldwide. Particularly dangerous are the
protein biosynthesis through binding to domain II of the 23S rRNA drug-resistant bacterial strains collectively known as ESKAPE patho-
site of the ribosome.218 Telithromycin generally acts bacteriostatically, gens (vancomycin-resistant Enterococci, MRSA, Klebsiella pneumoniae,
but also shows bactericidal properties at higher dosings.219 Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.),
Just like telithromycin, telavancin (12a, Figure 1) was derived which can cause difficult to treat nosocomial infections.231 Although
semisynthetically from an abundant naturally occurring antibiotic, in the development of resistance is inevitable, its spreading is not and
this case vancomycin (12, Figure 1).220 It is a newer antibacterial drug that is where we can make a difference.
belonging to the family of lipoglycopeptides, the name being derived Bacteria surpass us massively in numbers, total mass, replication
from the lipid chain attached on the glycopeptide domain. In addition time, and time of existence on earth.232 Our inability to eradicate their
to the lipophilic decylaminoethyl side chain attached onto the terminal pathogenic strains is, therefore, not surprising. All we can do at
carbohydrate moiety, telavancin also features a hydrophilic phospho- present is to be vigilant and alert to stay ahead of them in our efforts
nomethyl aminomethyl substituent on the biphenyl domain of to avoid catastrophic epidemics and deaths by them. Antibiotic
vancomycin.221 Its bactericidal properties toward several Gram- resistance is a continuous threat to society as proven before and after
positive strains, including methicillin-resistant Staph. aureus penicillin’s discovery, whose action on certain bacteria became
(MRSA),222 derive from a dual mechanism of action. On one hand, obsolete even before its development as a drug during the Second
it hinders the peptidoglycan construction by binding to its D-Ala-D-Ala World War. Certain dangerous bacterial strains developed resistance
dipeptide terminus, thus weakening the bacterial cell wall, and on the to almost all approved antibacterial drugs since (such as tetracyclines,
other it interferes with the cell wall precursor lipid II, thereby causing erythromycins, methicillin, gentamicin, vancomycin, imipenem,
membrane depolarization.223 Telavancin was approved for clinical use ceftazidime, levofloxacin, linezolid, daptomycin and ceftaroline), either
in the United States in 2009.223 immediately or shortly after their approval.233 And to exacerbate the
Today, more or less severe infections caused by microbes are situation, the number of new antibacterial drugs approved after the
alleviated with a variety of antibiotics, albeit not always successfully, golden age of antibiotics (1940s to 1960s) has been steadily declining.
from the large arsenal we have come to discover and develop from It was only until recently, and after a lean time period of more than 30
nature and the laboratory. Among the most prevalent of these drugs years, that a new antibiotic, teixobactin (26, Figure 3), was discovered
are amoxicillin (3b), ciprofloxacin (16a), azithromycin (11b), cepha- in 2015 and found to be impressively active against Gram-positive
lexin (3c), levofloxacin (16b), tobramycin (19), tigecycline (7a), bacteria. Affecting the bacterial cell wall biosynthesis234 and showing
fosfomycin (20), moxifloxacin (16c), trimethoprim/sulfamethoxazole promising properties against resistance development, this new anti-
(21) and amoxicillin/clavulanic acid (22), all shown in Figure 2a. As a biotic was also accessed by total synthesis in 2016.235 Even more
last line of defense, humanity has vancomycin (12, Figure 2b) and its recently, another new antibiotic, lugdunin (27, Figure 3), was isolated
analog telavancin (12a, Figure 1), amikacin (23, Figure 2b), linezolid from Staph. lugdunensis and structurally elucidated,236 revealing its
(18, Figure 2b), colistin (polymyxin E, 24, Figure 2b), and amphoter- macrocyclic peptide nature. Its total synthesis confirmed its
icin B (25, an antifungal agent, Figure 2b). Isolation and synthetic thiazolidine-containing constitution. The prevailing doctrine of using
organic chemists have played a major role in the discovery and overwhelming force of antibiotics (larger doses and prolonged times)
development of these life-saving antibiotics. To be sure they will to eradicate all pathogenic bacteria in the patent first introduced by
continue to be protagonists in our seemingly never ending fight Fleming has recently being challenged. The new theory suggests that
against pathogenic microbes. just the opposite might by the right strategy, as lower doses may be a
wiser tactic based on the competition of non-resistant bacteria and
ANTIBIOTIC RESISTANCE drug-resistant bacteria allowing the patient’s immune system to finish
Antibiotic resistance is apparently an inevitable consequence of the use the job of killing them both.233 This may depend on the drug used,
of antibiotics against bacteria, a war waged against them by us but also, however, and the final verdict is not in yet as further research is on
and for a much longer time, by bacteria against each other, ironically the way.
using the same weapons in both cases. That means that bacteria had According to a recent review on resistance to antimicrobial drugs by
the chance to develop resistance through various mechanisms to evade O’Neil,237 on behalf of the British government and the Wellcome
the action of these antibiotics which we isolated from them in the first Trust, 700 000 people die every year from infections caused by
place.224 This explains the so-termed primary resistance of certain drug-resistant pathogens, and the number can reach 10 million by
bacterial strains that are often unaffected by some antibiotics, whereas 2050 if nothing is done to stop the trend. According to a survey
they are susceptible to others (for example, Gram-negative vs Gram- published in 2013238 approximately one-fourth of the 40 million
positive).225 More dangerous is secondary resistance, the acquired people with respiratory diseases were prescribed antibiotics between
ability of bacteria to withstand the action of antibiotics that were once 2007 and 2009 in the United States, albeit only rarely indicated for
effective against them. Such resistance may be developed through their specific condition and in 78% of these cases broad spectrum

160
versions were recommended, despite the risk for more severe side antibiotic BE-43472B (41), hirsutellone B (42), epicoccin G,
effects.239 Here lies the paradox: a chance to be healed or to heal 8,8′-epi-ent-rostratin B and emethallicin E (43, 44 and 45),
compels the patient or the doctor to ask or prescribe an antibiotic to viridicatumtoxin B (46), and antibiotic CJ-16,264 (47)].
an individual for the possibility of a cure without concern of spreading
drug resistance. Antibiotic X-14547A (indanomycin)
Improvements in this regard can be achieved with rapid testing first, Isolated from Strep. antibioticus NRRL 8167,241,242 antibiotic
and then deciding whether an antibiotic will help the patient or not. X-14547A (28, Figure 5a) belongs to the ionophore class of antibiotics
And it will be even more helpful if the on-the-spot testing could reveal and forms, interestingly, a 2:1 (acid:base) salt with (R)-(+)-1-amino-1-
the type of antibiotic to be used effectively. There is no question that (4-bromophenyl)ethane. The latter yielded suitable crystals for X-ray
we are in a saddle war with pathogenic bacteria, although we are crystallographic analysis that led to the complete structural elucidation
cognizant that we need bacteria around us as essential symbiotic of the molecule.242 Its properties include antibacterial activities against
partners. A response is necessary in order to avoid major catastrophes Gram-positive bacteria, antihypertensive and antitumor activities
from occurring in the future as multiple indicators predict they will. and growth promotion in ruminants.241–244 Its enantioselective
Remedies to stop the antibiotic resistance problem include: (a) stop total synthesis was achieved in our laboratories in 1981.245–247
the use of antibiotics as growth hormones in animals; (b) develop and The employed retrosynthetic analysis is shown in Figure 5a, whereas
use vaccines where appropriate for prophylaxis as opposed to highlights of the devised total synthesis are summarized in Figure 5b.
treatment; (c) enforce better hygiene practices in clinics and hospitals; The initial synthetic maneuvers were the conversion of (−)-diethyl
(d) stop the prescribing of antibiotics for viral diseases before proper tartrate (48) to (S,S)-epoxide 49 (chiral pool) and the asymmetric
diagnosis; and (e) encourage innovation to develop new antibiotics alkylation of SAMP-hydrazone 54 to afford aldehyde 55 (asymmetric
through incentives to academia and industry. Suggestions to achieve synthesis). These two intermediates were converted to the required
the latter initiative have been made not only for increased funding for tetrahydropyran fragment 53 (through intermediates 50–52) and
research and development but also for ‘entry rewards’ that will tetrahydroindan 58 (through intermediates 56–57), respectively.
guarantee to the investors substantial initial financial rewards in These intermediates were coupled to afford advanced precursor 59,
addition to sales. which was converted to carboxylic acid 60. The latter was transformed
to antibiotic X-14547A (28) through a sequence involving
HIGHLIGHTS OF SELECTED TOTAL SYNTHESES OF conversion to the corresponding 2-pyridinylthioester, its reaction with
ANTIBIOTICS pyrrolylmagnesium chloride to install the 2-ketopyrrole system, and
The importance of natural products and their derivatives in medicine methyl ester hydrolysis. Several other synthetic approaches248–250 and
has been amply demonstrated through their direct clinical use, but total syntheses251–255 of antibiotic X-14547A have been subsequently
also as biological probes that unravel biological pathways and targets reported.
for pharmacological intervention. The success of penicillin intensified
the search for new antibiotics and other bioactive molecules from Efrotomycin
nature as evidenced from the postwar World War II surge in the Efrotomycin (29, Figure 6a) (isolated from Nocardia lactamdurans)256
discovery of such agents of which many became drugs to treat and its aglycon (aurodox or goldinomycin) are members of the
bacterial infections and cancer,240 among other diseases. Many became elfamycin family of antibiotics. Their biological actions include
challenging targets for synthetic organic chemists because of their activities against bacilli and dysentery, as well as growth promoting
unusual molecular architectures and the opportunities they presented properties in ruminants.257–259 The structure of efrotomycin contains
for discovery and invention of new synthetic strategies and two glycoside bonds, one amide linkage, a number of olefinic units,
technologies for broader use. Figure 4 depicts a number of selected and several other interesting structural motifs. The devised total
naturally occurring antibiotics synthesized in our laboratories synthesis of this antibiotic was based on the retrosynthetic
during the last few decades. Herein, we highlight the total disconnections indicated in Figure 6a. It proceeded from key building
syntheses of some of these antibiotics [that is, antibiotic X-14547A blocks 61, 62, 64, 68 and 73 and through advanced intermediates
(indanomycin, 28), efrotomycin (29), amphotericin B (25), vanco- 63, 66, 72, 74 and 75 as summarized in Figure 6b. Key steps in this
mycin (12), everninomicin 13,384-1 (ziracin, 30), coleophomones synthesis260–262 are the stereoselective glycosylation reactions of 61 and
B and C (31 and 32), thiostrepton (33), abyssomicin C and atrop- 62 to afford disaccharide 63, the cascade sequence involved in the
abyssomicin C (34 and 34′), marinomycins A, B and C (35, 36, 37), conversion of diepoxide 69 to the tetrahydrofuran intermediate 70, the
platensimycin (38), platencin (39), the alleged rugulin structure (40), stereoselective coupling of aldehyde 72 with the phosphorane derived
Figure 3 Recently discovered antibiotics.

161
from 74 to form the conjugated triene precursor of advanced final comparison with the acetate of the natural product), upon global
intermediate 75, and the final coupling of the latter with γ-lactone deprotection and selective acetylation, respectively. This endeavor
fragment 67, which generated efrotomycin (29) and its acetate (76, for demonstrated the use of glycosyl fluorides and arylthioglycosides as
Figure 4 Select antibiotics synthesized in the authors’ laboratories.

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Figure 5 Retrosynthetic analysis (a) and highlights of the total synthesis (b)
of X-14547A (indanomycin, 28).
glycosyl donors in complex molecule construction, pushed the

frontiers of total synthesis to new levels of molecular complexity
and diversity at the time, and provided opportunities for analog
construction within the efrotomycin family of antibiotics.
Amphotericin B
A powerful antifungal263,264 and antiprotozoal265 drug, initially
isolated in 1954 from Strep. nodosus Trejo,266 amphotericin B (25,
Figure 7a) possesses an imposing structure featuring a 38-membered
macrolide ring, a conjugated heptaene system, an aminosugar, a host
of hydroxyl groups and a carboxyl group. Its 19 stereogenic centers,
β-glycoside bond and macrocyclic ring were the primary challenges
from the synthetic point of view. Figure 7a presents the strategic bond of efrotomycin (29).
disconnections that led to the definition of building blocks 77, ent-77,
78, ent-49 and 92 as starting materials for its total synthesis.267–270 As
outlined in Figure 7b, the enantiomeric building blocks 77 and ent-77 building blocks were also synthesized from the prochiral allyl
[(+)- and (−)-xylose, chiral pool approach] were selectively converted alcohol 78 through the then newly discovered catalytic asymmetric
to key intermediates aldehyde 79 and ketophosphonate 80. The same epoxidation reaction, furnishing epoxides 81 and ent-81 in high

163
Figure 7 Retrosynthetic analysis (a) and highlights of the total synthesis (b) of amphotericin (25).
chemical yield and enantiomeric excess. Horner–Wadsworth– presumed explanation for its antifungal action was that amphotericin
Emmons coupling of ketophosphonate 80 with aldehyde 79, followed B creates pores in the pathogen’s outer membrane causing leakage of
by reduction of the resulting enone led to ketone 82. Further monovalent ions. The newly acquired information suggested a
elaboration of the latter furnished methylthiophosphonate 83, whose different mode of action, including the formation of extramembra-
reaction with aldehyde 84 (obtained from tartaric acid-derived epoxide nous aggregates that extract ergosterol from the lipid bilayers in a
ent-49; as shown in Figure 5b) afforded methylthioenol ether 85. This sponge-like fashion.274 Several other synthetic approaches to frag-
key intermediate was converted to ketophosphonate 86. Coupling of ments and derivatives of amphotericin B have also been reported by
the latter with conjugated aldehyde 89 (also obtained from epoxide other groups.275–295
ent-49 through a different route through intermediates 87 and 88)
furnished ketophosphonate aldehyde 90ab, which proved a worthy Vancomycin
precursor to the coveted macrocyclic polyene 91ab under carefully Vancomycin (12, Figure 8a), known once as the last line of defense of
defined conditions (K2CO3, 18-crown-6). Impressively, polyenone humanity against bacteria, was not only a vanquishing agent for them,
91ab was selectively reduced and glycosylated with carbohydrate but also a demonic challenge to synthetic chemists for a long time,
donor 92 to afford, selectively, the desired β-glycoside, whose further the latter designation being due to its unusual macrocyclic motifs and
elaboration led to amphotericin B (25). Featuring both the chiral pool 20 stereogenic elements. The flagship of glycopeptide antibiotics,
(auxiliary based) and catalysis approaches to asymmetric synthesis and vancomycin was isolated from Strep. orientalis (later renamed, first
highlighting the power of the ketophosphonate/aldehyde macrolacto- to Nocardia orientalis and then to Amycolatopsis orientalis).296–298 Its
nization, this total synthesis served as facilitator to further research on mechanism of action as mentioned in the previous section involves
amphotericin B and related compounds that led to new insights into interference with the bacterial cell wall biosynthesis through binding to
the mechanism of action of this important antifungal agent, and novel D-Ala-D-Ala structural motifs. Its total synthesis was reported from
drug candidates for clinical development.271–274 For decades the our laboratories in 1999.159 Figure 8a indicates the strategic bond

164
disconnections of vancomycin that led to the devised synthetic strategy fragments and elaboration of the growing intermediates (100–111)
and defined key building blocks 93–99 as shown in Figure 8b. into the final target. Among them are the palladium-catalyzed
Figure 8c highlights the reactions employed for the assembly of these coupling of building block 93 and 94 to afford, upon further
Figure 8 Retrosynthetic analysis (a), key building blocks (b), and highlights of the total synthesis (c) of vancomycin (12).

165
elaboration, azidobiaryl carboxylic acid 100. The latter was coupled Coleophomone B and C
with aminoester fragment 95, leading to the corresponding amide Coleophomones B (31) and C (32) were originally isolated from the
whose Boc group was removed to afford amine 101 in preparation for fungus Stachybothys cylindrospora RF-5900 by a Shionogi group,319 and
the next coupling. That step involved amide bond formation between subsequently from a Coleophoma sp. (MF6338) fungi by a
carboxylic acid 99 and amino building block 101, which furnished the Merck Sharp & Dohme group (Rahway, NJ, USA).320 Their
desired precursor for the first macrocyclization reaction, phenolic antibacterial action is partly based on their ability to inhibit the
dibromotriazine 102. Intramolecular displacement of one of the two bacterial cell wall transglycosylase activity, thus disrupting peptidogly-
bromide residues by the phenolic hydroxyl group under the influence can biosynthesis. Furthermore, the coleophomones inhibit RNA-,
of CuBr·Me2S led to the macrocyclic bis-aryl ether 103, together with DNA- and protein biosynthesis.320 Their antifungal, antibacterial and
its atropisomer. The stage was then set for the next macrocyclization inhibitory activities against human heart chymase,319,321 coupled with
(103 → 104 → 106), and then the next (106 → 107 → 108), leading their novel molecular architectures were enticing, inspiring us to
to complete vancomycin aglycon framework 109 upon further undertake their total synthesis.322,323 The highly strained and compact
manipulation of the triazine moiety of 108 to the required phenolic nature of their 11-membered ring characterized by an (E)-olefinic
group as summarized in Figure 8c. Vancomycin aglycon 110 was then bond (coleophomone B) or (Z)-olefinic bond (coleophomone C) and
generated from 109 via a seven-step sequence. Vancomycin itself their unique polyoxygenated framework presented an intriguing
was synthesized from its aglycon (110) via intermediate 111 by synthetic challenge. Having attempted and failed to construct their
sequential glycosylations with glycosyl donors 98 and 97, followed unusual macrocycle structural motifs through traditional methods, the
by deprotections and functional group adjustments as highlighted in olefin metathesis reaction came to the rescue. As seen in Figure 10a, the
Figure 8c. The vancomycin endeavor provided opportunities for new retrosynthetic analysis improvised for a ring-closing metathesis reaction
methodological advances, including the triazine-driven macrocyclic turned out to be pleasantly stereoselective in forming either the (E)- or
arylether forming reaction to cast the two bis-arylether domains of the (Z)-olefin within the macrocycle, depending on the exact structure of
molecule, as well as new solid phase combinatorial chemistry the precursor. Figure 10b highlights the total synthesis of both
for analog construction. Significantly, a number of the analogs coleophomones B and C through an initially convergent strategy that
that emerged from these studies proved to be more potent than led to advanced key intermediate 142 (from building blocks 137 and
vancomycin against drug-resistant bacterial strains.299–301 140 and intermediates 138, 139 and 141), and which subsequently
diverged to generate precursors 144 and 145 (in addition to compound
Everninomicin 13,384-1 (ziracin) 143). The structural constitution of each substrate, 144 (exocyclic
Isolated from Micromonospora carbonacea var. africana, everninomicin methoxy enone) and 145 (endocyclic methoxy enone), proved
13,384-1 (30, Figure 9a)302–306 is a member of the orthosomicin class decisively influential in forming selectively, through the indented olefin
of antibiotics.307 It exhibited promising antibacterial properties against metathesis reaction (cat. 146), each desired product, 147 [(E)-olefin]
drug-resistant bacteria, including methicillin-resistant Staphylococci and 148 [(Z)-olefin], respectively. From these precursors, the targeted
and vancomycin-resistant Streptococci and Enterococci.308,309 Its natural products [coleophomones B (31) and C (32)] emerged through
bactericidal action310 is based on its ability to inhibit protein a short synthetic sequence as shown in Figure 10b. This achievement
biosynthesis by binding to the 50S subunit of the bacterial was a triumph for the metathesis reaction in that it demonstrated its
ribosome.311 Contained within its structure are a number of unique power where other alternatives failed.322,323
novel and puzzling structural motifs, including two sensitive and
synthetically challenging orthoesters, a 1,1′-disaccharide bridge Thiostrepton
(an oxygen bonded to two anomeric positions), a nitrosugar, and As the flagship of the thiopeptide class of antibiotics due to its
two aromatic esters situated at the two terminal loci of the molecule. magnificent structure,324 and because of its diverse and important
In total, everninomicin 13,384-1 possesses 13 rings and 35 stereogenic biological properties325,326 that include antibacterial, antimalarial,
centers, making its total synthesis a formidable task. Its total synthesis, immunosuppressive and cytotoxic activities, and veterinary medical
featuring an array of new synthetic methods and tactics, was reported use, thiostrepton (33, Figure 11a) served as a challenge and inspiration
from our laboratories in 1999.312–318 Figure 9a indicates the strategic to us in the early 2000s.327–333 Thiostrepton was isolated from three
bonds and their disconnections, defining key building blocks 112–121 different species of Streptomyces (azureus ATCC 14921, hawaiiensis
(Figure 9b) that were used for the devised synthesis. Starting ATCC 12236 and laurentii ATCC 31255).334 Its mechanism of action
with commercially available and other readily prepared starting is based on the inhibition of elongation factor G (translocase), a
materials, these key intermediates were assembled orderly and the prokaryotic enzyme responsible for the translocation of the tRNA and
resulting products elaborated to advanced intermediates 126 (through mRNA down the ribosome.335–337 We reasoned that although its total
compounds 122–125), 130 (through compounds 127–129) and 135 synthesis might not be of urgent need due to its natural abundance it
(through compounds 132–134) as summarized in Figure 9c. Advanced would certainly be a playground for advancing the art of organic
intermediates 126 and 130 were then joint through a glycosylation synthesis and a means to produce otherwise unavailable designed
reaction to afford polycycle 131, after further elaboration (Figure 9c). analogs for biological investigations. Besides, there were the elements
Finally, the two penultimate advanced key building blocks, glycosyl of excitement, in breaking another glass ceiling of molecular complex-
fluoride 135 and hydroxyl octacycle 131, were coupled through a ity and diversity for total synthesis, and serendipity for discovering
SnCl2-promoted α-selective glycosylation furnishing precursor 136, new chemistry and gathering useful intelligence for future explorations
whose conversion to everninomicin 13,384-1 (30) was achieved in and applications. The most intriguing structural motif of thiostrepton
four steps as summarized in Figure 9c. This total synthesis was is undoubtedly its dihydropiperidine structural moiety with its
notable, not only for the complexity of the target molecule but also surrounding substituents, including the three thiazole rings and its
because of its featuring of new synthetic strategies and tactics as well as tetrasubstituted carbon atom, not to mention that the entire structure
new synthetic methods. The latter included a series of glycosylation is loaded with reactive and unpredictable functionalities in terms of
reactions and 1,2-phenylthio- and -phenylseleno migrations.318 their installment and chemical behavior. Figure 11a presents the

166
Figure 9 Retrosynthetic analysis (a), key building blocks (b), and highlights of the total synthesis (c) of everninomicin 13,384-1 (ziracin, 30).

167
150 and 152, see Figure 11b). Azadiene 154 reacted spontaneously
upon generation via endo transition stage 155 and through inter-
mediate 156, the latter collapsing under the reaction conditions to the
desired product (158) through intermediate 157. The crucial forma-
tion of the sterically challenging amide bond in the next advanced
intermediate (160) was achieved through the use of azidoacid chloride
building block 159. The latter advanced intermediate was then grown
to thiostrepton by crafting on it (that is, building block 160) fragments
161, 164 and 166 through a sequence of reactions involving inter-
mediates 162, 163, 165 and 167, as summarized in Figure 11b. It is of
note that the three phenylseleno groups, introduced on the growing
molecule as masking devices for the two reactive dehydroalanine
structural motifs, had a crucial role in ensuring the survival and
eventual emergence of these moieties in the final stages of the
synthesis. Another worthy feature of the synthesis was the generation,
in the final step and under the desilylation conditions (HF·py), of the
olefinic bond conjugated to the thiazoline ring in its correct
geometrical form. We would be remiss if we did not mention that
it was during this endeavor that we discovered and developed the now
popular method for selective hydrolysis of methyl esters using
trimethyltin hydroxide.339,340
Abyssomicins
Abyssomicin C (34, Figure 12a) was originally isolated from the
marine-derived actinomycete strain Verrucosispora AB-18-032 in
2004.341,342 Its sibling, atrop-abyssomicin C (34′, Figure 12a) was
subsequently discovered from the same species,343 but not before
it was synthesized in our laboratories.344–346 Exhibiting potent anti-
bacterial properties against drug-resistant strains due to its ability
to inhibit the conversion of chorismate into p-aminobenzoic acid
(thus blocking the tetrahydrofolate biosynthesis)342 and because of its
novel molecular architecture, abyssomicin C presented an irresistible
challenge as a synthetic target. Our devised strategy for its total
synthesis was based on the retrosynthetic analysis depicted in
Figure 12a and featured a Diels–Alder reaction and a ring-closing
metathesis as highlighted in Figure 12b. The synthetic sequence
employed building blocks 168, 171 and 175, and ligand 170 needed
for the success of the stereoselective Diels–Alder reaction of 169 with
171, to afford product 173 via transition state 172. Elaboration of
bicyclic product 173 then furnished tricycle 174, which was coupled
under basic conditions with δ-lactone 175 to afford, upon dithioketal
formation, intermediate 176. Oxidation followed by vinyl Grignard
addition to the resulting aldehyde then gave metathesis precursor 177.
The coveted ring-closing metathesis of precursor 177 was achieved
through the use of ruthenium catalyst 178, leading, after oxidation,
exclusively to macrocycle 179, from which atrop-abyssomicin
C (34′, Figure 12b) was generated by exposure to phenyliodo
bistrifluoroacetate. Finally, atrop-abyssomicin C was converted under
acidic conditions into a separable mixture of abyssomicin C (34) and
Figure 10 Retrosynthetic analyses (a) and highlights of the total syntheses atrop-abyssomicin C (34′; 34:34′ ca. 2:1). Interestingly, in addition
(b) of coleophomone B (31) and C (32). to being discovered in nature, atrop-abyssomicin C exhibited even
higher potencies against bacteria than its sibling, abyssomicin C.343
employed retrosynthetic disconnections based on which the final This endeavor demonstrated and expanded further the power of the
strategy was devised for its total synthesis. Although details of the Diels–Alder and metathesis reactions in total synthesis, provided useful
synthesis of thiostrepton can be found in our publications on the insights and understanding of atropisomerism, especially as it pertains
subject,327–333 including a review,338 its highlights can be seen in to naturally occurring molecules, and resulted in a number of
Figure 11b. Among them are the biomimetic aza-Diels–Alder-based structure-activity relationships within the abyssomicin family. It also
construction of the tetrasubstituted dihydropiperidine structural motif led to the total synthesis of a natural product in the laboratory before
from azadiene 154 (generated from precursor 153 whose preparation its discovery from nature, a rare, but noteworthy contribution of the
from building blocks 149 and 151 proceeded through intermediates art and science of total synthesis. Besides our own work, other groups

168
Figure 11 Retrosynthetic analysis (a) and highlights of the total synthesis (b) of thiostrepton (33).

169
have also attempted347–351 or completed the formal352 and total

synthesis of the abyssomicins.353–355
Marinomycins
Marinomycin A (35, Figure 13a) is the most prominent member of
the marinomycin family of marine-derived natural products isolated
from the actinomycete ‘Marinispora’ CNQ-140.356 Featuring a
44-membered dimeric macrolide ring and endowed with potent
antibacterial and cytotoxic properties, these scarce molecules
became synthetic targets in our group not only because of their
biological properties but also due to their novel and synthetically
challenging architectures. Our total synthesis of marinomycin A357,358
is summarized in Figure 13a (retrosynthetic disconnections) and 13b
(highlights). The sequence employed building blocks 180, 181, 185
and 189 and proceeded through intermediates 182–184 and 186–193
as outlined in Figure 13b. The key macrocyclization reaction
involved conversion of acetylenic vinyl bromide 193 to afford the
corresponding vinyl borane, which underwent intramolecular Suzuki
coupling furnishing, upon global desilylation, the target molecule
marinomycin A (35). Interestingly, the Heck, Stille and metathesis
reactions failed to produce the corresponding macrocyclic products.
of marinomycin A (35).
Figure 12 Retrosynthetic analysis (a) and highlights of the total syntheses

(b) of abyssomicin C (34) and atrop-abyssomicin C (34').

170
of platencin (39).
Two other total syntheses of marinomycin A were more recently

reported, one by the Evans group361 and the other by the Hatakeyama
group.362
Platensimycin
Aided by a new screening technique,363,364 scientists at Merck Sharp
& Dohme were able to isolate and characterize platensimycin
Figure 14 Retrosynthetic analysis (a) and highlights of the total synthesis (b) (38, Figure 14a), a novel secondary metabolite from Strep. platensis
of platensimycin (38), and select designed analogues and their biological
activities (c).
that exhibited inhibitory activity against the FabH and FabF
condensing enzymes of the fatty acid biosynthetic pathway crucial to
bacteria.365–367 Its unique mechanism of action, coupled with its
Another interesting outcome of this project was the preparation unprecedented molecular architecture, propelled platensimycin to a
of the 22-membered monomeric counterpart of marinomycin A, priority status as a synthetic target and a potential new antibiotic
which proved inactive as compared to the natural product against the for investigation and further development. From the several total
same bacterial strains. Furthermore, marinomycin A was transformed, syntheses we developed,368–372 we present in Figure 14a (retrosynthetic
upon photo-irradiation, to its geometrical isomers, marinomycins B disconnections) and 14b (highlights) an asymmetric version373 that
and C (as a mixture with A), which were separated as individual involved an enantioselective rhodium-catalyzed cyclization of a
compounds.357,358 In 2007, the Cossy group published their work on prochiral eneyne bis-enone (that is, 196, obtained from building
the synthesis of the monomeric counterpart of marinomycin A.359,360 block 194 via 195) to afford bicyclic aldehyde 197. A samarium-

171
induced ring closure within the latter then led to tricyclic alcohol 198,
from which pentacycle 199 was formed through acid-catalyzed
etherification, as shown in Figure 14b. Sequential bis-alkylation of
ketone 199 then led to olefinic substrate 200, whose cross metathesis
reaction with vinyl boronate 201 under the influence of ruthenium
catalyst 202 furnished advanced intermediate 203, from which the
coveted carboxylic acid 204 emerged in two steps. The required
benzenoid domain (206) of the target molecule was secured from
building block 205 through a high-yielding five-step sequence.
Coupling of carboxylic acid 204 with aniline derivative 206 under
the influence of HATU and Et3N led to the corresponding amide,
from which platensimycin (38) was derived upon deprotection,
as shown in Figure 14b. This and the other synthetic strategies
and technologies we developed during this program facilitated the
design, synthesis and biological evaluation of numerous analogs of
platensimycin. Among them, carbaplatensimycin (207)374 and
adamantaplatensimycin (208)375 are notable for their comparable
potencies against drug-resistant bacteria (see Figure 14c). Besides our
initial total synthesis,368 numerous other strategic approaches376–380
and formal and total syntheses have been reported.381–400
Platencin
Isolated from Strep. platensis MA7339,401,402 platencin (39, Figure 15a)
is a relative of platensimycin (38) discussed above. Its antibacterial
properties and mechanism of action are similar to those of platensi-
mycin (38) and so is its molecular structure, except from its tricyclic
domain. The latter structural site of platencin differs from that of
platensimycin in that it includes a completely carbocyclic framework
consisting of only three rings, instead of the tetracyclic cyclic ether-
featuring framework of platensimycin. From the several strategies we
developed toward platencin,403–406 the one depicted in Figure 15a
(retrosynthetic disconnections) and 15b (highlights) is distinguished
for its enantioselectivity and novel carbocyclization to forge one of the
rings of the molecule.406 Starting with building blocks 209, 211, 222
and 224, and using catalyst 214 and proceeding through intermediates
210, 213, 215–221 and 223 as shown in Figure 15b, this total synthesis
of platencin delivered the natural product in its natural enantiomeric
form. One of its most notable steps was the asymmetric,
cobalt-catalyzed Diels–Alder reaction between diene 210 and
dienophile 213 in the presence of catalyst 214 to afford cyclohexene
215, whose one-pot conversion to hydroxyenone 216 proceeded in
92% yield and 98% ee (after recrystallization). Another pleasing step Figure 16 Retrosynthetic analysis (a) and highlights of the total synthesis (b)
was the high-yielding (95%) gold-catalyzed cyclization of acetylenic of the alleged structure of rugulin (40).
enol ether substrate 217 to afford bicyclic system 218. Several other
elegant (formal) total syntheses of platencin and its analogs have been
reported.394,398,407–427 with cytoskyrin A433 and 2,2′-epi-cytoskyrin A.432,434 The developed
synthetic strategy toward this novel structure involved two of the
Rugulin simplest reagents (that is, MnO2 and CF3COOH) and proceeded
There is a mystery surrounding the structure of rugulin, an alleged smoothly under thermal conditions (25–45 °C). Starting from
natural product isolated from Penicillium rugulosum in 1978 and dihydroanthracenone building block 225, this rather stunning cascade
claimed to possess structure 40 (Figure 16a)428 and to exhibit
sequence gave precursor 230. It involved initial oxidation of the
antibacterial properties.429 Its intriguing molecular architecture is
dihydroanthracenone 225 to the corresponding quinone (that is,
characterized by a central core in the shape of a twisted cylinder
226), which served as a substrate for the next step involving
defined by four five-membered carbocyclic rings, the latter in its naked
hydrocarbon form termed ‘skyrane’.430–432 Its unusual and challenging enolization/dimerization to afford bis-enol 227. The latter underwent
structure, coupled with its reported biological properties, motivated us rapture of the oxygen bridge triggered by further MnO2-induced
to undertake its laboratory synthesis. We achieved the total synthesis oxidation to furnish the corresponding bis-anthraquinone system
of the alleged structure of rugulin432 following the novel strategy 228, which entered an intramolecular Michael reaction to form the
shown in Figure 16b, which employs the so-called ‘cytoskyrin cascade’ second required C–C bond of the skyrane cage, leading to inter-
developed in our laboratories430,431 for the purposes of synthesizing mediate 229. Upon treatment with Et3N in the same pot, this
other members of the class, to which this structure belongs, along intermediate suffered a second intramolecular Michael reaction to

172
Figure 17 Retrosynthetic analysis (a) and highlights of the total synthesis (b) of antibiotic BE-43472B (41).
generate advanced intermediate 230, missing only one of the four biological evaluation of designed analogs. Figure 17 displays the
required C–C bonds to close the skyrane cage. This remaining retrosynthetic analysis that guided the development of the devised
objective was achieved by the addition of further amounts of strategy (panel a) and the highlights of the successful total synthesis of
MnO2 in the same pot forming, upon exposure to CF3COOH, the antibiotic BE-43472B (panel b) featuring two esthetically pleasing
targeted rugulin structure 40. As elegant as the synthesis was, it only cascades. The first cascade sequence began with the Diels–Alder fusion
proved that the originally assigned structure of rugulin was wrongly of diene 232 and dienophile 233 (see transition state 234) and
assigned, leaving the true structure of the natural product in a shroud proceeded through intermediates 235–237 [involving an ipso aromatic
of mystery and a continuing structural puzzle. This unfortunate substitution reaction (SNAr) and expulsion of a molecule of MeOH] to
mystery remains to this day, due to the fact that we were not able afford octacycle 238. The second cascade sequence involved the photo-
to obtain either a sample of the natural product or its full set of induced rapture of epoxide 240 (prepared from 238 in six steps via
spectral data. intermediate 239) to form diradical 241, whose rearrangement led to
isomeric radical 242, from which antibiotic BE-43472B emerged after
Antibiotic BE-43472B
an intramolecular H-atom shift and tautomerization of the resulting
The bis-anthraquinone antibiotic BE-43472B (41, Figure 17a) was
keto-enol as indicated in Figure 17b. The developed synthetic strategy
isolated from Streptomyces sp. A43472 found in a blue-green
algae associated with the ascidian Ecteinascidia turbinate.435,436 allowed the total synthesis of both enantiomeric forms [(+)-41 and
This structurally novel antibiotic possesses, in addition to its two ent-(−)-41] of antibiotic BE-43472B, allowing its absolute configura-
anthraquinone-type structural motifs, an unusual bicyclic core tion to be assigned as that depicted by 41 in Figure 17b. Interestingly,
featuring an internal ketal functionality and a highly sterically hindered synthetic antibiotic BE-43472B (41) and its enantiomer (ent-41)
carbon-carbon bond. Its potent activities against drug-resistant exhibited essentially the same potencies against drug-resistant bacteria
bacteria such as MRSA and tetracycline-resistant Staph. aureus [that is, 41: MIC = 0.083–0.166 μg ml −1 (methicillin-resistant Staph.
and vancomycin-resistant Enterococcus faecium,437 coupled with its aureus), 0.33–0.83 (vancomycin-resistant Enterococcus faecalis); ent-41:
challenging molecular architecture prompted us to pursue its total MIC = 0.055–0.11 μg ml−1 (MRSA), 0.17–1.1 (vancomycin-resistant
synthesis.438–440 Our motivation was to develop novel chemistry, Enterococci)].439 In 2013, Keisuke Suzuki and his group reported a
determine its then unknown absolute configuration, and apply the racemic total synthesis of antibiotic BE-43472B featuring an isoxazole-
developed synthetic strategies and technologies to the synthesis and directed pinacol 1,2-shift.441

173
aryl ether bridge and five out of the ten stereogenic centers of the
molecule. Its biological properties as a potential antituberculosis agent
and novel molecular architecture elevated it to an opportunistic target
molecule. Figure 18a indicates the disconnections of the identified
strategic bonds onto which the devised synthetic strategy was based.
A summary of the total synthesis of hirsutellone B, achieved in our
laboratories in 2009,443 is depicted in Figure 18b. Thus, starting from
(R)-(+)-citronellal (243), polyunsaturated epoxide 244 was prepared
and subjected to the influence of Et2AlCl in CH2Cl2 at −78 → 25 °C,
conditions that allowed its stereoselective transformation to tricyclic
system 247 through a cascade sequence featuring activation of the
epoxide, a chloride-induced desilylation/ring closure/epoxide opening,
and an intramolecular Diels–Alder reaction. Proceeding through
transition states/intermediates 245 and 246, this cascade sequence
delivered its product in 50% yield and with all eight stereocenters in
their desired configurations. Product 247 was then converted to
dihydroxyaryl ether 248, which, on exposure to ZnI2 and AcSH,
furnished in one step iodothioacetate 251 through presumed oxonium
species 249 and 250. The latter intermediate was elaborated to
macrocyclic sulfone 252 by sequential cyclization and oxidation.
A Ramberg–Bäcklund rearrangement then led to olefin 253, from
which hirsutellone B (42) was generated through intermediates 254
and 255 as shown in Figure 18b. This synthesis is marked by the
elegance of its cascade reactions and its flexibility to deliver other
members of the hirsutellone class444 and analogs thereof. Besides our
presented synthesis, a number of other conceptual studies445–448 were
pursued with two culminating in formal449 and total syntheses.450
Epicoccin G, 8,8′-epi-ent-rostratin B and emethallicin E

Epidithiodiketopiperazines and bis-(methylthio)diketopiperazines are
naturally occurring molecules whose biological properties include
antiviral, antibacterial, antimalarial and cytotoxic activities.451–463
Because of their biological actions, these natural products hold
potential as drug candidates or lead compounds for drug discovery,
but they are often scarce for thorough biological evaluation. Their
synthesis and analogs are, therefore, of crucial importance for
biological investigations and drug discovery initiatives. In an effort
to improve the methods for their synthesis, often suffering from the
key sulfenylation step (the installment of the two required sulfur
atoms onto appropriate diketopiperazine scaffolds), and in order to
render them readily available for further explorations, we initiated a
program directed toward their total synthesis. Attracted by the
molecular architectures and biological properties of certain members
of this class, and aiming to develop a new sulfenylation method, we
targeted for total synthesis464 epicoccin G [43, Figure 19a, originally
isolated from Epicoccum nigrum (XZC04-CS-302)],465–467 8,80 -epi-ent-
rostratin B (44, Figure 19a; rostratin B was isolated from Exserohilum
rostratum)468 and emethallicin E (45, Figure 19c, isolated from
Emericella heterothallica ATCC 16824).469 Figure 19a shows the
retrosynthetic disconnections that led to the development of the
synthetic strategy toward these target molecules. Crucial to the success
of hirsutellone B (42).
of these total syntheses, whose highlights are summarized in
Figure 19b, were the bis-photo-oxygenation/Kornblum–DeLaMare
rearrangement and the discovery of an improved method for the
Hirsutellone B sulfenylation of diketopiperazines (Figure 19d, method developing
A member of a large class of fungal metabolites, hirsutellone B box). The asymmetric synthesis of epicoccin G (43) started with the
(42, Figure 18a) rose to prominence due to its potent activity against readily available building block 256 (from N-Boc-L-tyrosine), which
Mycobacterium tuberculosis, the causative pathogen of tuberculosis. was converted to diketopiperazine 261 through a series of synthetic
Isolated from fungus Hirsutella nivea BCC 2594,442 hirsutellone B steps involving intermediates 257–260 (Figure 19b). Having failed in
includes in its structure a 6,5,6-fused tricyclic core, a hydroxy our attempts to introduce the required sulfur atoms in the next step,
γ-lactam, and a 13-membered p-cyclophane ring encompassing an we were motivated to improve existing methods previously employed

174
Figure 19 Retrosynthetic analyses (a) and highlights of the total syntheses of epicoccin G (43) and 8,80 -epi-ent-rostratin B (44) (b), and emethallicin E (45)
(c) as well as the mechanistic rationale for the developed sulfenylation method (d), and select synthesized designed analogues and their biological activities (e).
in such operations.470–483 We soon discovered that treating sulfur Figure 19. Applying the newly developed method to diketopiperazine
with NaHMDS in THF at ambient temperature for a few minutes 261 gave epidithiodiketopiperazine intermediate 262, formed together
produced a solution that contained reactive sulfur species capable with its 2,2′-epimer (2,2′-epi-262, see Figure 19b). The former was
of sulfenylating enolates generated from diketopiperazines (see smoothly transformed to epicoccin G (43), whereas the latter was
270 → 271, Figure 19d, box) under the same basic conditions and in employed to synthesize 8,8′-epi-ent-rostratin B (44) as summarized in
the same pot.484 Consisting mainly of tetrasulfides, the generated Figure 19b. The same key building block 256 was converted by similar
products (for example, 272, formed via 271, Figure 19d, box) were chemistry to emethallicin E (45) through intermediates 276–281 as
easily converted to either epidithiodiketopiperazines (274) or bis- highlighted in Figure 19c. In addition to the benefit of developing the
methylthio diketopiperazines (275) via dithiolate species 273 (formed improved and valuable sulfenylation reaction, this project revealed,
by NaBH4 reduction of 272, see Figure 19d, box), as shown in through biological testing, potent activities against the poliovirus of the

175
encountered intermediates 262 and 282 (see Figure 19e, box).

In addition to our own efforts several other laboratories reported
on their progress toward or total syntheses of epicoccin G,485,486
8,8′-epi-ent-rostratin B,487–490 and emethallicin E.491
Viridicatumtoxin B
Resembling but being more structurally complex than its siblings,
viridicatumtoxin B (46, Figure 20a)492 is loosely classified as a member
of the tetracycline class of antibiotics due to its linear tetracyclic
structural domain. Isolated from Penicillium sp. FR11 and possessing
of viridicatumtoxin B (±-46), and select designed analogues and their
biological activities (c). Figure 21 Retrosynthetic analysis (a) and highlights of the total synthesis (b)
of antibiotic CJ-16,264 (47), and select designed analogues and their
biological activities (c).

176
two additional rings than the traditional tetracyclines weaved in a antibiotic readily available (unpublished results), whose synthesis and
spirocyclic structural motif, viridicatumtoxin B exhibits impressive biological evaluation will be reported in due course.
antibacterial activities against drug-resistant bacteria, including Staph.
aureus (MRSA).492 The antibacterial properties of this impressive CONCLUSION
molecule presumably arise from its ability to inhibit UPP synthase, Microbes have been menacing society ever since the beginning of our
a key enzyme for bacterial peptidoglycan biosynthesis.493,494 It became existence. Empowering us to create new molecules in the laboratory,
a synthetic target in our laboratories for its complexity and challenge, the advent of organic synthesis in the nineteenth century led to the
the appeal of its biological properties, and its potential as a lead introduction of the first antibacterial drugs. But it was not until we
compound for drug discovery. Figure 20a shows the strategic bond learned more about the pathogenesis of infectious diseases and the
disconnections that guided the design of our synthetic strategy, which nature of microbes that we began to strategize against them in rational
included two Michael–Dieckmann reactions, an SN2-type alkylation, ways. Indeed, it was bacteria and fungi themselves that taught us how
and a Lewis acid-catalyzed spirocyclization. Requiring building blocks to fight them in the most effective ways: with the same weapons by
283, 285, 287 and 292 as starting materials, the synthesis proceeded which they have been waging war against each other and continue to
along the pathway depicted in Figure 20b and through intermediates do so today. Chemists were able to isolate an avalanche of powerful
284, 286, 288–291, 293–297. Noteworthy steps in this route, which in antibiotics from natural sources in a surge that climaxed into the
its original form delivered racemic viridicatumtoxin B,97 included the antibiotic rush in the 1950s after the success of penicillin. And for a
alkylation of anthrone 286 under mild conditions, a step at which while it was perceived that the war against bacteria had been won. This
asymmetry could be introduced, in principle, in the growing molecule. is not so, as we came to know shortly thereafter. And we might not
Another remarkable step of this total synthesis is the final demasking ever win it completely as we attempt to control the continuously
of the distinguishing tetracyclic enolamide structural motif from its emerging bacterial resistance, a phenomenon based on natural
surrogate oxazoline functionality by hydrogenolysis, conditions that evolution. Ironically, it is human behavior and weakness that
also led to the rapture of the two benzyl ethers of the ultimate accelerate and spread bacterial resistance, whether it is through our
precursor (297, Figure 20b). The total synthesis of viridicatumtoxin medical, agricultural or psychological practices. Thankfully, the ever
B not only rendered the racemic natural product readily available increasing power of our abilities to isolate new antibiotics from nature
but also resulted in its structural revision.97 Furthermore, an enantio- and to design and synthesize others like them in the laboratory
selective total synthesis of viridicatumtoxin B (and decipherment of its provide us with the means to catch up with them, at least temporarily,
absolute configuration) has been achieved in these laboratories by discovering and enlisting new weapons against them. The new
employing phase-transfer catalysis.495 Another important outcome antibiotics included in the last section and the synthetic work
of this total synthesis endeavor was the synthesis and biological associated with them, for example, may hold the secrets to one or
evaluation of a series of simpler analogs of viridicatumtoxin B,98 from more new weapons to add to our arsenal—if only the funds were
which compounds ( ± )-298 and ( ± )-299 were notable for their available to advance these investigations beyond the ‘valley of death’
potencies as compared to those of the racemic natural product where, unfortunately, so many academic discoveries remain buried.
[( ± )-46] against drug-resistant bacteria (see Figure 20c). The importance of continuous research and development for new
antibiotics was furthermore highlighted by a press release from the
Antibiotic CJ-16,264 World Health Organization (WHO) in February 2017.499 It contains a
A member of the pyrrolizidinone family of natural products, antibiotic list of the following 12 families of bacteria representing the greatest
CJ-16,264 (47, Figure 21a) was isolated from fungus CL39457.496 risk to human health.
It possesses a highly substituted decalin system and exhibits potent
antibacterial properties against drug-resistant bacteria.496 Its total WHO priority pathogens list for R&D of new antibiotics
synthesis from our laboratories rendered the natural product in its Priority 1: (critical)499
naturally occurring enantiomeric form readily available and led to its
structural revision (configurations at C1 and C7′).497 Figure 21a Acinetobacter baumannii, carbapenem-resistant
summarizes our synthetic strategy, in retrosynthetic format, toward Pseudomonas aeruginosa, carbapenem-resistant
this target molecule which included a Reformatsky-type coupling Enterobacteriaceae, carbapenem-resistant, ESBL-producing
and an intramolecular Diels–Alder reaction. The forward synthesis
proceeded from citronellal (ent-243, also available in the other Priority 2: (high)
enantiomeric form) and racemic building block ( ± )-305498 through
intermediates 300 or 302 and 301, 303, 304 and 307 (Figure 21b). The Enterococcus faecium, vancomycin-resistant
availability of both enantiomers of these two building blocks was Staph. aureus, methicillin-resistant, vancomycin-intermediate and
crucial for the final structural elucidation of antibiotic CJ-16,264. resistant
It provided several isomeric forms of the targeted molecule, allowing Helicobacter pylori, clarithromycin-resistant
its structural identification as that depicted by structure 47. The Campylobacter spp., fluoroquinolone-resistant
most striking feature of this synthesis was the exclusive formation of Salmonellae, fluoroquinolone-resistant
diolide 303 incorporating two units of the desired decalin system from Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-
macrodiolide 301 through two consecutive, thermally induced, resistant
intramolecular Diels–Alder reactions. From the six isomers synthe-
sized, the ones shown in Figure 21c proved the most active against Priority 3: (medium)
methicillin-resistant Staph. aureus, Enterococcus faecalis S613 and
Enterococcus faecium 105 (see Figure 21c). In addition to these Streptococcus pneumoniae, penicillin-non-susceptible
CJ-16,264 isomers, the developed synthetic strategies and technologies Haemophilus influenzae, ampicillin-resistant
made a number of structurally simpler analogs of this rather complex Shigella spp., fluoroquinolone-resistant

177
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The Journal of Antibiotics (2018) 71, 153–184

A brief history of antibiotics and select advances in

Figure 1 Historic discoveries and developments of antibiotics as drugs.

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Figure 3 Recently discovered antibiotics.

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Figure 4 Select antibiotics synthesized in the authors’ laboratories.

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glycosyl donors in complex molecule construction, pushed the

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have also attempted347–351 or completed the formal352 and total

Figure 12 Retrosynthetic analysis (a) and highlights of the total syntheses

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Two other total syntheses of marinomycin A were more recently

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Epicoccin G, 8,8′-epi-ent-rostratin B and emethallicin E

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encountered intermediates 262 and 282 (see Figure 19e, box).

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