Review pubs.acs.org/CR

Discovery of Novel Synthetic Methodologies and Reagents during Natural Product Synthesis in the Post-Palytoxin Era Ahlam M. Armaly, Yvonne C. DePorre, Emilia J. Groso, Paul S. Riehl, and Corinna S. Schindler* Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States 2.12. Quinoline Alkaloids: Discovery of an Intramolecular ipso-Halocyclization Reaction 2.13. Daphmanidin E: Cobalt-Catalyzed HeckType Coupling Reactions 2.14. Oasomycin A: Ceric Ammonium NitratePromoted Oxidation of Oxazoles 3. Discovery of New Reagents 3.1. Panduratin A: Silver Nanoparticle-Catalyzed Diels−Alder Cycloaddition of 2′-Hydroxychalcones 3.2. Axinellamines A and B: Discovery of a Practical and Reactive Chlorinating Reagent 4. Discovery of New Reactivities 4.1. Solanoeclepin A: Discovery of an Anomalous Heck Reaction 4.2. Celogentin C: Proline Esters as Electrophilic Chlorine Scavengers in Oxidative Coupling Reactions 4.3. FR182877: Intramolecular Allenolate Acylations 4.4. Zoanthenol: Discovery of a Cyclization− Decarbonylation Cascade Reaction 4.5. Chlorosulfolipids: Chloronium Ions as Intermediates in Epoxide Opening Reactions 4.6. Norhalichondrin A: Highly Stereoselective Reductions of Planar Oxocarbenium Ions 5. Conclusion Author Information Corresponding Author Author Contributions Notes Biography Acknowledgments References

CONTENTS 1. Introduction 2. Discovery of New Reactions 2.1. Phomoidrides or CP Molecules 2.1.1. Discovery of DMP- and IBX-Mediated Cascade Reactions 2.1.2. Dynamic Kinetic Resolution in an OxyCope/Dieckmann Cascade Cyclization 2.1.3. Discovery of a Stereoconvergent Palladium-Catalyzed Carbonylation Reaction 2.1.4. Deoxygenation of Alcohols Employing Water as the Hydrogen Atom Source 2.2. Streptorubin B and Metacycloprodigiosin: Discovery of Platinum- and Acid-Catalyzed Enyne Metathesis Reactions 2.3. Stephacidin A: Chemoselective N-tert-Prenylation by C−H Functionalization 2.4. Strychnine: Stereocontrolled Synthesis of ZDienes Based on Zincke Aldehydes 2.5. Banyaside B 2.5.1. Facile Formation of N-Acyloxazolidinone Derivatives by Use of Acid Fluorides 2.5.2. Nucleophilic Opening of Oxabicyclic Ring Systems 2.6. Gambieric Acid A: Discovery of an Olefinic Ester Ring-Closing Metathesis Reaction 2.7. Haouamines A and B 2.7.1. Discovery of a Friedel−Crafts Triflation Reaction 2.7.2. Discovery of a Novel Chichibabin Pyridine Synthesis 2.8. Tetrapetalones A−D: Stereoselective Reduction of Substituted Pyrroles 2.9. Karahanaenone: Titanium-Mediated CrossCouplings to Access γ-Lactols 2.10. Diazonamide A: Deoxygenations of Sulfoxides, N-Oxides, and Selenoxides 2.11. Actinophyllic Acid: Electron-Transfer Photoredox Catalysis

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1. INTRODUCTION The synthesis of naturally occurring substances has been a central part of synthetic organic chemistry since the late 19th century. Looking back on 150 years of history, the primary focus and importance of the total synthesis of natural products has changed dramatically over time. Initially, natural product synthesis mainly pursued the structural determination of naturally occurring compounds.1 In the classical approach to structure determination, a structure was assigned to a natural product, and through chemical degradation the molecule was

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structural elucidation of strychnine was in fact accompanied by the discovery of a vast number of new transformations of the Strychnos skeleton. Woodward defended the shifted focus of natural product synthesis, stating that there is no “reason to suppose that the challenge for the hand and intellect must be less, or the fruits less tantalizing, when chemistry begins at the advanced vantage point of an established structure ... [T]he lure of unknown structures has in the past yielded a huge dividend of unsought fact, which has been of major importance in building organic chemistry as a science. Should a surrogate now be needed, we do not hesitate to advocate the case for synthesis.” In other words, Woodward suggested the total synthesis of established complex structures as a new challenge for organic chemists and marked the beginning of the golden era of natural product synthesis. Indeed, R. B. Woodward was able to complete the total synthesis of strychnine only 6 years after its structural elucidation, based on a landmark synthetic strategy.18 Albert Eschenmoser agreed with Woodward and would later describe this turning point in natural product history as a unique opportunity. He realized that the “demise of the classical function of structure proof means freedom from the restrictive, although once valid, principle that the synthetic route must consist of structure proving steps of known reaction type.”1 Synthetic organic chemists were now able to explore new transformations to access complex structures without being limited to familiar reactions or tied to the restrictions that structural degradation had previously imposed upon them. In this new era, scientists could freely explore and invent new reactions to access complex molecules that were previously considered impossible to make. In the words of Eschenmoser, there was enormous “potential for stimulation and discovery that natural product research holds for the whole of organic chemistry.”1 An early example of the discovery of new reactivity in the course of natural product synthesis is the total synthesis of colchicine (4) reported by Woodward in 1963.19 Colchicine was first isolated in 1820 by Pelletier and Caventou,20 but it was not until 1949 that its structural elucidation was completed.21 The tropolone moiety was one of the main reasons why the structure of colchicine attracted widespread interest as a synthetic target. Three research groups successfully reported synthetic strategies toward its completion, prior to Woodward’s contribution.22−24 Woodward’s approach relied on an isothiazole heterocycle to mask the nitrogen atom of the carbamate present in colchicine, which he expected to be inherently reactive. The strategy required a late-stage introduction of the C-ring tropolone system that Woodward planned to construct from the diketone 5 (Scheme 2). Woodward and co-workers expected to convert diketone 5 to the corresponding enol derivative 6 upon treatment with

broken down into smaller, identifiable components. Definitive confirmation of the structure involved a detailed analysis of the composition, configuration, and conformation of the synthesized product and its associated synthetic fragments, which were then compared to the isolated natural product and its associated degradation fragments. The development of novel and more powerful spectroscopic methods and their wide availability to a range of academic institutions in the 1950s changed the classical approach to structure determination. Work in the area of synthetic structural elucidation nearly became obsolete when modern methods of spectroscopic analysis enabled the determination of a natural product within hours or daysan effort that would have taken decades relying on traditional synthetic degradative methods. This revolution in the field was exemplified by the structural elucidation of strychnine, an alkaloid isolated by Pelletier and Caventou in 1818 from the beans of Strychnos ignatii (Figure 1).2,3

Figure 1. Strychnine (1) isolated from Strychnos ignatii by Pelletier and Caventou in 1818.2

Due to its molecular size, strychnine was considered the most complex substance known in the 1950s, and its structural determination proved to be a major challenge. The structural elucidation of strychnine was completed in 1949 after four decades of work based on degradative investigations and UV spectroscopy. The successful structural determination of strychnine was made possible by contributions from several groups: primarily from the work of Prelog and co-workers,4−6 Robinson and co-workers,7−10 Leuchs,11 and finally Woodward and Brehm and co-workers12,13 (Scheme 1). Soon after the structural elucidation, two separate X-ray crystallographic reports published in 1951 succeeded in providing the stereochemical correlations observed in strychnine that could otherwise not be obtained from degradative investigations.14−16 The impressive impact of modern spectroscopic analysis made it possible to determine a structure without recourse to chemical degradation and synthesis. Natural product synthesis was facing its first turning point, and for many scientists at the time it had lost its main justification as a method of structure determination. In their famous article “The Total Synthesis of Strychnine” published in 1963,17 R. B. Woodward and co-workers responded to the criticism of natural product chemistry and pointed out that the

Scheme 1. Reactivity of Strychnine (1) Discovered during Degradative Studies

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Scheme 2. An “Amiable Accident” Discovered during the Total Synthesis of Colchicine (4)a

a

As reported by Woodward in 1963.19.

Figure 2. Structure of the vasoconstrictor palytoxin (10) isolated in 1971 from a Hawaiian soft coral.35

During the 1970s, the spotlight shined upon natural product synthesis as impressively complex target structures were being synthesized. Larry Overman25 captured the excitement of the time when he described the impressive “accomplishments of R.B. Woodward, E.J. Corey, Gilbert Stork, W.S. Johnson, Albert Eschenmoser, Yoshito Kishi and many others” in this new era of natural product synthesis. The main question of this period was whether it would be possible to develop a viable synthetic strategy for any complex structure found in nature. An additional justification for the immense research efforts was that investigations of the inherent reactivity of many target structures often led to fundamental insights and the discovery of novel synthetic transformations. For many scientists working in the field, the “surprises encountered on the journey” were as important as the actual destination or the completion of the target structure itself.26 The total synthesis of vitamin B12 represents one of the biggest accomplishments of this golden era of total synthesis. Through the combined efforts and close collaboration between R. B. Woodward at Harvard and Albert Eschenmoser at ETH

pyridine and acetic anhydride. They planned a dehydrogenative sequence from enol 6 to form the tropolone aromatic system found in colchicine 4. According to Woodward, he “could not envision any direct process, having its origin in the diketone, in which the transition state for dehydrogenation could be stabilized by its tropoloid character.” The sole product isolated upon reaction of 5 with pyridine and acetic acid was the corresponding dienol acetate 7, which presumably formed via the intermediate enol 6. Upon “routine physical examination” of the dienol acetate 7, which included the treatment of 7 with a “drop of alkali in alcohol solution,” the authors were surprised to isolate a new compound that showed two new, longwavelength bands in the UV absorption spectrum. The novel product was later identified as the desired tropolone 9. In his initial report of the total synthesis of colchicine (4), Woodward19 described this cascade reaction as an “amiable accident” that proceeded via an intermediate enediol dianion 8 with subsequent loss of two electrons to molecular oxygen to generate the new aromatic C-ring in 9. C

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Scheme 3. Discovery of the Nozaki−Hiyama−Kishi Reaction in 1986 during Studies toward Total Synthesis of 10

difficulty.” The yield of the reaction was highly dependent on the source and batch of the CrCl2 reagent used to initiate this coupling reaction. Kishi and co-workers hypothesized that the varying CrCl2 source might actually contain an unidentified contaminant that is essential for the success of the desired transformation. To identify this potential additive, various metal salts were evaluated for their ability to catalyze the coupling reaction between iodoalkenes and their respective aldehydes. As such, NiCl2 and Pd(OAc)2 were identified as highly effective catalysts. These studies led to a robust reaction protocol for the Cr(II)-mediated coupling reaction that is known today as the Nozaki−Hiyama−Kishi reaction, and it achieves the desired transformation “using CrCl2 from any source with excellent reproducibility.” The Nozaki−Hiyama−Kishi reaction was found to be highly selective with regard to the electrophilic aldehyde, and it also tolerated numerous nucleophiles for formation of the respective organochromium intermediates.44 In their initial report, Kishi and co-workers postulated that the reduction of a Ni(II) species to Ni(I) or Ni(0) by Cr(II) occurs, followed by an oxidative addition of the alkenyl iodide 17 (Scheme 4) to Ni(I) or Ni(0).

Zürich, the synthesis of vitamin B12 further illustrates the potential that natural products hold for new discoveries.27−31 While exploring a problem in the context of the synthesis of vitamin B12, Woodward hypothesized that the role of orbital symmetry was important in certain chemical reactions, an insight that would later lead to establishment of the Woodward−Hoffmann rules for orbital symmetry.32 As a result of the intensified research focus in the field, many successful synthetic strategies for important biologically active natural products were reported in the following decades. The golden era of total synthesis of natural products faced its second turning point in the mid-1990s with the completion of the synthesis of palytoxin (Figure 2) by Yoshito Kishi and coworkers at Harvard University.33,34 Palytoxin (10) was first isolated in 1971 from a Hawaiian soft coral, limu-make-ohana.35 However, it was not until 1982 that its full chemical structure was elucidated, based on the work of Uemura and coworkers.36−38 Palytoxin is a vasoconstrictor that targets the sodium−potassium pump protein, effectively destroying the ion gradient essential for most cells.39 Aside from the appealing biological properties associated with 10, what really caught the attention of the synthetic scientific community at the time was its sheer size and complexity. The structure contains more than 100 stereocenters, which made it one of the most complex molecules ever isolated. The total synthesis of 10 by Yoshito Kishi was completed only 12 years after its structural elucidation. In hindsight, the synthesis was described as “the Mount Everest of organic synthesis, the largest molecule that anyone has ever even thought about making” and was based on extensive conformational studies led by the Kishi group.40,41 During studies toward the synthesis of 10, Kishi and coworkers42 were faced with the challenge to transform aldehyde 14 into trans-allylic alcohol 16 (Scheme 3). They explored several synthetic procedures known at the time but failed to obtain the desired product 16. Allylic alcohol 16 was finally formed in sufficient quantities when Kishi and co-workers turned to a reaction protocol published in 1983 by Takai and Hiyama and co-workers43 (Scheme 3). This transformation forms alkenylchromium compounds from vinyl halides (12) and anhydrous CrCl2. The selective subsequent addition of the resulting alkenylchromium compound to aldehydes (11) produces the corresponding allylic alcohols (13). This Cr(II)mediated coupling reaction provided a viable synthetic strategy to access the desired trans-allylic alcohol 16, but one additional challenge remained, which Kishi referred to as a “technical

Scheme 4. Reaction Mechanism of the Nozaki−Hiyama− Kishi Reaction, Catalytic in Nickel

A subsequent metal exchange with Cr(II) or Cr(III) generates the reactive intermediate, which is then capable of undergoing the desired C−C bond-forming reaction with the aldehyde electrophile 18. The total synthesis of 10 was reported eight years later by Kishi and co-workers, based on this novel C−C bond-forming reaction. There is no doubt that completion of the synthesis of palytoxin marked a “defining moment” in the field of natural product synthesis. It unequivocally answered the question “whether it will be possible to make any molecule that nature makes” with a resounding “yes.”26 After this milestone was achieved, it was unclear for many scientists working in the field D

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discoveries made in the course of complex molecule syntheses conducted in the post-palytoxin era. Without a doubt, many more exciting new transformations have been discovered during recent studies toward the synthesis of natural products and subsequently developed into novel methodologies of general synthetic utility. However, the unforeseen origins of a specific new design idea or initial synthetic evidence resulting in the development of a novel synthetic transformation are rarely exalted in scientific reports to date. If at all, short statements along the lines of “in studies that were driven by our total synthesis program, we recently discovered ...”50 or “... our initial results were obtained serendipitously in the course of a program aimed at ...”,51 indicate that the new synthetic methodology or novel reagent developed was indeed enabled by an initial discovery encountered during complex molecule syntheses. As a result, these scientific communications are difficult to find and often impossible to identify without further insight. The examples presented herein have been collected over the past years on the basis of lectures, literature reports, and personal communications but most definitely represent only the “tip of the iceberg” of novel discoveries during complex molecule synthesis in the post-palytoxin era. This review aims to demonstrate the key role that total synthesis plays in the advancement of reaction and reagent discovery today and encourages synthetic chemists not to shy away from highlighting future discoveries made in the context of natural product synthesis to further demonstrate the importance of the field.

what direction synthesis in the post-palytoxin era would take. In 1999, an article published in Science entitled “Race for Molecular Summits” refers to this time as a “period of soulsearching” for total synthesis, as it encountered its epoch of “greatest uncertainty.”26 Many scientists agreed that natural product synthesis would continue to be valued as a way to test novel synthetic methodologies in a complex setting. However, the discoveries of novel unexpected transformationswhich used to be a key justification for the synthesis of natural productswould become rarer as the field progressed. A common opinion of the post-palytoxin era was that “[o]rganic chemists can work on discovering fundamental principles of organic chemistry, or they can make something, such as a natural product.”26 The discovery of novel synthetic transformations and the synthesis of natural products were now seen as two distinct fields of research. In response to this divide, synthetic chemists have altered their focus, and the field of natural product synthesis has advanced in the past decade with regard to development of more concise and scalable strategies. These approaches now rely on the novel ideas of atom,45 step,46 and redox economy47 to access complex molecules of biological importance. Impressive contributions have already been made in the beginning stages of this new era of natural product synthesis. More creative solutions to long-standing problems in total synthesis will undoubtedly be reported in the years to come. Paul Wender brought the changes in the field to attention when he refers to the new challenge in synthesis which is “increasingly not whether a molecule can be made, but whether it can be made in a practical fashion, in sufficient quantities for the needs of research and society, and in a way that is environmentally friendly if not ideal.”48 There is no doubt that striving for new reactions will succeed in the development of increasingly shorter synthetic sequences to complex targets. Additionally, the application of these new synthetic methods in complex settings will eventually lead to more robust reaction protocols. Scott Denmark appropriately argues that “the fundamental fact remains that the ability to rapidly, efficiently, selectively, and inexpensively synthesize compounds defines the horizon for the success of all of these enterprises.”49 The question is whether one of the key justifications for natural products synthesis in its golden era, the discovery of novel synthetic reactions, has indeed become extinct. Are the discovery of novel synthetic transformations and the synthesis of complex molecules indeed mutually exclusive fields of research today? Or has this new period that strives for the “ideal” and elegant synthesis of complex target structures inspired chemists to develop creative synthetic solutions that once again enable the discovery of novel unexpected transformations? In other words, are there still discoveries to be made during the synthesis of natural products? To follow up on this question, this review aims to highlight key serendipitous discoveries made in the course of recent endeavors toward the total synthesis of natural products in the post-palytoxin era. In some cases, the discovery of novel unprecedented reactivity still awaits further investigation toward broadly applicable general synthetic utility. However, in other cases key discoveries have already led to fundamental new insights as well as the development of novel general synthetic transformations in the field of organic chemistry, which would have not been possible without an initial invested interest in the synthesis of complex target structures. It is important to note that the following examples do not represent a complete list of all unexpected

2. DISCOVERY OF NEW REACTIONS 2.1. Phomoidrides or CP Molecules

The structural elucidation of two novel natural products, CP225,917 or phomoidride A (19) and CP-263,114 or phomoidride B (20), was reported by Kaneko and co-workers at Pfizer Central Research in 199752 (Figure 3). The compounds, which are related to the nonadrides, were isolated from the fermentation broth of a fungus from a juniper twig in Texas. The CP molecules originally attracted attention when Kaneko and co-workers showed that they inhibited squalene synthase (SQS) as well as Ras farnesyltransferase, which have the potential to control abnormal growths of cells transformed

Figure 3. Phomoidrides A (19) and B (20) reported by Kaneko and co-workers.52 E

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Scheme 5. Discovery of a Novel Hetero-Diels−Alder Reaction during CP Molecule Synthesis

Scheme 6. Reactivity of Carbamate Substrates 30 with DMP (21) and IBX (33)

by mutated ras. Both phomoidrides 19 and 20 incorporate an unprecedented cagelike core structure based on a bicyclo[4.3.1]deca-1,6-diene system in the presence of a sterically hindered bridgehead alkene moiety. Additionally, unique structural features include a C14 quaternary stereocenter, a lactone ring system, and a fused maleic anhydride subunit. To date, more than 20 research groups have been inspired by this structural complexity and contributed synthetic studies toward the total syntheses of the CP molecules.53−98 2.1.1. Discovery of DMP- and IBX-Mediated Cascade Reactions. The approach of Nicolaou and co-workers99 toward the CP molecules 19 and 20 relied on a Diels−Alder cycloaddition100 to access the densely functionalized CP ring core system common to the phomoidrides. Extensive model

studies showed that a cascade oxidation sequence mediated by Dess−Martin periodinane (DMP, 21) was viable, and subsequent oxidation with 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) gave rise to the desired γ-hydroxylactone functionality. Application of these reaction conditions to the highly functionalized diol 22 (Scheme 5) proceeded as expected and resulted in the formation of γ-hydroxylactone 23. Unfortunately, γ-hydroxylactone 23 proved to be inert to amide hydrolysis, and the desired free carboxylic acid 24 could not be obtained.101−103 Nicolaou et al.104 decided to switch protecting groups and synthesized anilide 25 (Scheme 5). Upon the subjection of 25 to the previously established oxidation sequence, they were surprised to observe the selective formation of a novel F

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Scheme 7. Mechanism for Periodinane-Mediated Hetero-Diels−Alder Reactiona

a

Proposed by Nicolaou et al.106

polycyclic compound 29 instead of the desired γ-hydroxylactone 27. The scope of this transformation was subsequently explored on a selection of simple carbamates such as 30 (Scheme 6). Tricyclic ring systems (31) were generated as the sole products upon treatment of 30 with DMP in refluxing benzene in up to 96% yield. During the studies aimed at the optimization of the DMP-mediated reaction with anilides, Nicolaou et al.105 found that the corresponding carbamate substrates 30 also underwent a selective cyclization reaction with 2-iodoxybenzoic acid (IBX, 33) to the corresponding Nphenyl-γ-lactams 32 (Scheme 6) instead of tricycles 31. Subsequent mechanistic studies of periodinane-mediated reactions of anilides such as 30 were undertaken to gain further understanding of the individual reaction sequences involved in this novel series of synthetic transformations.106 Nicolaou et al. proposed the initial formation of an intermediate 35 upon reaction of anilide 34 with DMP. They suggested that two species, 21 and acetylated 36, are required for the formation of 37. This hypothesis is based on the observation that no reaction is observed in the presence of 21 alone under strictly anhydrous conditions nor with only acetylated 36. Upon reaction with 1 equiv of base, 37 reacts to form the substrate for an intramolecular hetero-Diels−Alder reaction, which gives rise to the observed tricycle 39 (Scheme 7). This mechanistic hypothesis triggered further modifications of the reaction conditions, leading to an optimal reaction protocol that used dichloromethane as solvent, a minimum of 2 equiv of DMP, 1 equiv of water, and 1 equiv of pyridine at ambient temperature. The initial serendipitous discovery of DMP-mediated formation of polycyclic 29 from anilide 25 inspired the development and investigation of numerous novel synthetic transformations (Scheme 8),107−110 such as the IBX-mediated dehydrogenation of carbonyl compounds,111 the synthesis of nitrogen-containing quinones,112 the synthesis of amino sugars,113 IBX-mediated benzylic oxidations, the synthesis of α-tosylketones from epoxides, and the IBX-mediated oxidation of various nitrogen- and sulfur-containing compounds.114 Additionally, iodic acid (HIO3) and iodine pentoxide (I2O5) were established as mild alternatives to IBX for the desaturation of ketones.115 2.1.2. Dynamic Kinetic Resolution in an Oxy-Cope/ Dieckmann Cascade Cyclization. Shair and co-workers116

devised a unique synthetic strategy for the rapid assembly of the CP core 44c (Scheme 9A), based on an initial addition of a vinyl organometallic reagent 41 to racemic β-keto ester 40. The resulting alkoxide 42 can subsequently undergo an anionaccelerated oxy-Cope rearrangement to afford the ninemembered ring enolate 43a. The final step toward the completion of the CP core 44c involves a transannular Dieckmann-like cyclization, which was inspired by the biosynthetic hypothesis.52,117 Shair and co-workers were successful in turning this retrosynthetic strategy into a viable synthetic route, forming the desired bicyclic carbon core common to the CP molecules in up to 64% yield, starting from the simple β-keto ester 40. This later enabled completion of the total synthesis of (+)-CP-263,114 (20).118 During their studies toward the synthesis of the core structure, Shair and co-workers119 made a series of unique observations when enantioenriched β-keto ester 40b was converted under previously established cascade reaction conditions (Scheme 9B). Conversion of 40b (99% enantiomeric excess, ee) with vinyl Grignard 41 for 12 h led to a racemic mixture of the bicyclic ring system 44a/44b. However, when the same reaction was stopped after 15 min and subsequently treated with acetic acid, the corresponding alcohol 42b was isolated in enantioenriched form (99% ee) in 82% yield. Shair and co-workers postulated that a retro-aldol/aldol equilibrium between the two enantiomeric alkoxides 42a and 42b (Scheme 10) could account for this unexpected observation. The results support the hypothesis that rate of equilibration between the two alkoxides is significantly higher than the rates for the respective anion-accelerated oxy-Cope rearrangements (kE > kOC). In the course of this cascade transformation, epimerization of the quaternary stereocenter present in 40b occurs only after addition of the Grignard reagent in the course of the retro-aldol/aldol equilibrium between 42a and 42b.119 Shair and co-workers119 realized the potential of this retroaldol/aldol equilibrium to give rise to a dynamic kinetic resolution methodology. They hypothesized that a single enantiomer of an enantioenriched chiral vinyl Grignard reagent added to a racemic β-keto ester could result in the formation of two possible diastereomeric products. The rapid equilibration between diastereomeric enolates at a higher rate than the anion-accelerated oxy-Cope rearrangement, and the subsequent G

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introduction of the tetracyclic carbon core based on an anionic oxy-Cope strategy of alcohol 48 to the corresponding sigmatropic rearrangement product 49 (Scheme 12). Bio and Leighton hypothesized that incorporating the unsaturated lactone spiroketal system into the oxy-Cope substrate 50 would lead to significant buildup of ring strain in the transition state and allow the desired rearrangement to 51 to proceed under milder reaction conditions. The desired spiro ketal 53 was synthesized from hydroxyenol triflate 52 in only 19% yield upon treatment with 10 mol % Pd(PPh3)4 and Et3N under CO (600 psi) at 60 °C. Compound 53 was then converted to the desired oxy-Cope product 54 in 95% yield. However, simply raising the reaction temperature to 110 °C upon conversion of enol triflate 52 with Pd(PPh3)4 under otherwise identical reaction conditions led to exclusive formation of the desired product 54 in 46% yield. The initial studies to establish the feasibility of the anionic oxy-Cope strategy by Bio and Leighton had not included the C14 stereocenter present in the natural products 19 and 20 (Figure 3). In further attempts to extend the sigmatropic rearrangement approach to incorporate a C14 substituent, Bio and Leighton121 envisioned a vinyl C14 substituent attached to 52 that was expected to be inert under the respective oxy-Cope rearrangement sequence. The desired sigmatropic rearrangement was first tested on vinyl enol triflate (Z)-55, and this resulted in formation of the desired CP carbocyclic core 60 in 46% yield (Scheme 13). In additional studies, the corresponding enol triflate (E)-55 was also subjected to the reaction conditions to form the same CP core 60 in 56% yield. This serendipitous discovery rendered the tedious stereoselective synthesis of the enol triflate (Z)-55 redundant and provided a significant strategic advantage for synthesis of the CP molecules. A mechanistic hypothesis for this unexpected transformation relies on initial insertion of Pd(0) into the enol triflate (E)-55 and subsequent CO migratory insertion (Scheme 13). Unlike its isomer formed upon reaction of (Z)-55, the resulting (E)vinylpalladium complex cannot react in an intramolecular reaction with the pendant primary hydroxyl group and instead isomerizes via the π-allyl palladium complex 56 to the corresponding (Z)-vinylpalladium species 57. Migratory insertion of CO and trapping of the intermediate palladium acyl complex 58 results in the formation of spiro ketal 59, which then undergoes the desired sigmatropic rearrangement to form the CP core structure 60 that includes the C14 quaternary stereocenter. This serendipitous discovery reported by Bio and Leighton represents the first example of an isomerization sequence of a 2-substituted 1,3-butadiene motif and enabled the selective synthesis of 60 from a mixture of enol triflate isomers (Z)-55 and (E)-55, which tremendously facilitated the overall synthetic approach. Although this method has not yet been explored in regard to its generality beyond the synthesis of the CP molecules, it does represent a unique approach to the synthesis of unsaturated lactones via palladiumcatalyzed carbonylation of 2-substituted 1,3-butadienes that may find further applications in future studies. 2.1.4. Deoxygenation of Alcohols Employing Water as the Hydrogen Atom Source. In 2001, Njardson and Wood122 reported a synthetic strategy toward the phomoidrides 19 and 20 that relied on a late-stage fragmentation reaction to form the desired unsaturated bicyclic carbon core present in 19 from S-methyl dithiocarbonate 61 (Figure 4). To evaluate the viability of their anticipated approach, Wood and

Scheme 8. Hypervalent Iodine Reactions Inspired by the DMP-Mediated Cyclization Reaction

reactivity of these two diastereomers at different rates, could lead to a dynamic kinetic resolution. Shair and co-workers119 were able to prove this hypothesis, which enabled the synthesis of the respective cascade reaction products such as 47 with high diastereoselectivity in up to 75% yield (Scheme 11) from 45 and 46. This reaction, reported in the course of synthetic studies aimed toward the CP molecules, represents a rare example of a dynamic kinetic resolution involving substrates with chiral all-carbon quaternary centers that necessitates a reversible C−C bond forming reaction as an intermediate step in the reaction cascade (Scheme 10). 2.1.3. Discovery of a Stereoconvergent PalladiumCatalyzed Carbonylation Reaction. The approach of Bio and Leighton75,120 to the CP molecules relied on a late-stage H

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Scheme 9. (A) Rapid Assembly of CP-263,114 Core Structure via Tandem Oxy-Cope Rearrangement and Dieckmann Cyclization. (B) Racemic 44a/44b from Enantiopure 40b as Evidence for a Retro-Aldol/Aldol Equilibrium

Scheme 10. Retro-Aldol/Aldol Equilibrium Leading to Racemization in the Oxy-Cope-Dieckmann Cascade Reaction

co-workers assumed that the rate of hydrogen transfer from Bu3 SnH itself was too fast compared to the desired fragmentation reaction. As a result, alternative reaction conditions for formation of the radical 64 were investigated that excluded the addition of a direct hydrogen-atom source. A promising reaction protocol, also reported by Barton and coworkers,125,126 relied on the use of trialkylboranes to slowly reduce secondary xanthate esters, presumably via intermediate alkyl radicals. When Wood and co-workers127 subjected xanthate 63 to a modified reaction protocol using Me3B in benzene, they were surprised to find that the only compound isolated in the course of this transformation was the corresponding reduction product 66. Intrigued by the potential of this tin-free reduction protocol, the authors investigated the potential hydrogen-atom source. Initial deuterium-labeling studies pointed toward water; however, based upon comparison of the respective bonddissociation energies (O−H bond with 117.6 kcal/mol versus C−H bond with 113.5 kcal/mol),128,129 the simple explanation of water as the hydrogen-atom source seemed unlikely. Wood

Scheme 11. Dynamic Kinetic Resolution by Use of Chiral Grignard Reagents with Racemic β-Keto Esters

co-workers123 designed the model system 62, which was easily converted to the desired xanthate 63 upon reaction with carbon disulfide, potassium hydride, and methyl iodide (Scheme 14). Wood and co-workers envisioned an intermediate radical 64, formed under traditional Barton−McCombie dehalogenation conditions,124 to initiate the desired fragmentation reaction leading to the unsatured bicyclic carbon core 65 common to the phomoidrides. Following this initial hypothesis, 63 was treated with Bu3SnH and AIBN, and this resulted predominantly in the formation of the reduced product 66. Wood and I

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Scheme 12. Development of Anionic Oxy-Cope Strategy toward Synthesis of the Tetracyclic Carbon Core of CP Molecules

Figure 4. Retrosynthetic approach of Njardson and Wood122 to 19 from S-methyl dithiocarbonate 61.

initial aerobic oxidation of the trialkylborane to liberate a methyl radical, which subsequently reacts with the xanthate substrate 70 to form radical 71. Decomposition of this radical leads to the formation of dithiocarbonate 72 and the alkyl radical R•, which is reduced by the borane−water complex 73 to form the observed product 74. On the basis of their detailed mechanistic investigations, the authors were able to optimize and generalize this reaction protocol. As a result, it represented one of the first generally applicable tin-free reduction protocols for xanthate esters (Scheme 16). Two years later, Wood and co-workers130 reported the successful extension of this methodology to the tin-free dehalogenation of alkyl iodides using trialkylborane reagents and water. 2.2. Streptorubin B and Metacycloprodigiosin: Discovery of Platinum- and Acid-Catalyzed Enyne Metathesis Reactions

and co-workers127 postulated that complexation of the trialkylboron as a Lewis acidic reagent to water might form a complex sufficiently activated for O−H bond homolysis, thus giving rise to a hydrogen-atom source. Ab initio calculations pointed toward a decrease in the O−H bond dissociation energy for the trialkylboron−water complex 67 to 86 kcal/mol (Scheme 15A). The radical 68 formed upon O−H bond homolysis could then undergo dissociation into a methyl radical and Me2BOH (69). On the basis of their experimental and theoretical investigations, Wood and co-workers127 proposed a mechanism for the tin-free xanthate reduction reaction using water as the hydrogen-atom source (Scheme 15B). The process relies on

The “prodiginine” alkaloids are a group of structurally related natural products produced by a restricted group of eubacteria and actinomycetes of the Serratia and Streptomyces genera (Figure 5).131,132 These unique compounds have been reported to have antimicrobial, cytotoxic, and antimalarial activity. Clinical applications of prodiginine alkaloids have so far been hampered by their high toxicity; however, recent reports on undecylprodigiosin (76) as a potent inhibitor of T-cell proliferation at low, nontoxic doses have generated novel interest in designing viable strategies toward the synthetic access of these natural products.133−136

Scheme 13. Proposed Mechanism for the Stereoconvergent Palladium-Catalyzed Carbonylation Reaction

J

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Scheme 14. Treatment of Xanthate Ester 63 with Me3B in Benzene, Resulting Predominantly in Formation of Reduced Product 66 Instead of Fragmentation Product 65

Scheme 15. (A) Ab Initio Calculations for Formation of Trialkylboron−Water Complex 67. (B) Mechanism for Tin-free Reduction of Xanthatesa

a

Proposed by Wood and co-workers.127

Fürstner132 became particularly interested in metacycloprodigiosin (77) as well as streptorubin B (78) when these cyclic analogues of prodigiosin were reported to be similarly potent immunomodulators. The initial synthetic approach relied on a cycloisomerization protocol inspired by work reported by Trost et al.133−136 (Scheme 17). Fürstner et al.137 attempted to perform the cycloisomerization by reacting an electrondeficient alkyne such as 79 with palladacycle 80, tris(O-tolyl phosphite), and dimethyl acetylenedicarboxylate. Under these conditions, the desired bicyclic product 81 was isolated in only 18% overall yield. Fürstner et al.137 subsequently evaluated additional cycloisomerization protocols before they focused their attention on platinum salts (PtCl2, PtCl4, PtBr2, and PtBr4) as Lewis acid catalysts.138 They were surprised to discover that enynes bearing electron-withdrawing substituents, such as 79 and 83, afforded the desired bicyclic products 82 and 84 in good to

Scheme 16. General Reaction Protocol for Tin-free Dehalogenation, Inspired by the Trialkylboron−Water Xanthate Ester Reduction Methodology

Figure 5. “Prodiginine” alkaloids produced by eubacteria and actinomycetes of the Serratia and Streptomyces genera. K

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Scheme 17. Initial Attempts To Obtain the Bicyclic Core of Streptorubin B (78)

excellent yields upon reaction with catalytic quantities of platinum salts (Scheme 18).

Scheme 19. Novel PtCl2-Catalyzed Cycloisomerizations Developed from the Initial Discovery of a PtCl2-Catalyzed Enyne Metathesis Reaction138

Scheme 18. Discovery of Platinum-Catalyzed Enyne Metathesis Reaction

Overall, this serendipitous discovery represents a new pyrrole synthesis based on a PtCl2-catalyzed enyne metathesis. The transformation is formally a cycloisomerization and converts an enyne 85 into a bicyclic diene 86. Subsequent aromatization affords the desired bicyclic pyrroles 87 (Scheme 18). Fürstner et al.139−141 hypothesize that this reaction proceeds via πcomplexation of the alkyne entity onto the platinum salt. They hypothesize that this formal “enyne metathesis” reaction most likely involves “non-classical” carbocations as the reactive intermediates and is best described as a Wagner−Meerwein rearrangement. In additional mechanistic investigations, several strong Lewis acids (SnCl4, AlCl3, TiCl4, ZnCl2, and BF3·Et2O) and Brønsted acids were also found to promote the desired transformation. The mechanistic insights obtained by Fürstner et al. further enabled this concept of PtCl2-catalyzed cycloisomerizations to be extended to other previously unexplored transformations (Scheme 19).

Figure 6. (+)-Stephacidin A (88) and (+)-avrainvillamide (89): novel antitumor alkaloids isolated from marine mitosporic fungi.

ent prostate LNCaP cell line. These biologically active natural products were found to be structurally related to the cytotoxic marine natural product avrainvillamide (89), which was first isolated from a marine fungal strain of Aspergillus sp. by Fenical et al. in 2000.143 In the course of their synthetic investigations toward the stephacidin family of natural products, Baran and co-workers144 worked toward a one-pot sequence to convert N-Boctryptophan methyl ester 90 directly into the C2-prenylated tryptophan 91, using 2-methyl-2-butene in an electrophilic palladation protocol (Scheme 20). Although they were not able to detect any of the desired product 91, they isolated the

2.3. Stephacidin A: Chemoselective N-tert-Prenylation by C−H Functionalization

Two novel antitumor alkaloids, (+)-stephacidin A (88) and its dimeric isomer (−)-stephacidin B, were isolated by QianCutrone et al.142 at the Bristol-Myers Squibb Pharmaceutical Research Institute in 2002 from the mitosporic fungus Aspergillus ochraceus WC76466 (Figure 6). Both stephacidins A and B demonstrated in vitro cytotoxicity against various human tumor cell lines, especially against testosterone-dependL

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Scheme 20. Discovery and Optimization of Direct, Chemoselective N-tert-Prenylation of Indoles by C−H Functionalization

corresponding N-tert-prenylated indole 92 in 10% overall yield. Baran and co-workers realized the potential of this transformation, which represented the first direct N-tert-prenylation of indoles. Prenylated indoles are incorporated in a wide array of structurally diverse fungal, plant, and bacterial natural products that exhibit an array of important biological activities.145 The authors decided to improve on this initial observation and developed the first generally applicable direct N-tert-prenylation protocol for indoles. Optimized reaction conditions were identified in the course of these studies and include the use of acetonitrile as solvent, substoichiometric palladium (40 mol % Pd(OAc)2 or 20 mol % [Pd2(dba)3]· CHCl3), 30 equiv of 2-methyl-2-butene, stoichiometric Cu(OAc)2, and an appropriate Ag(I) source (AgOTf or AgTFA) as a co-oxidant (Scheme 20).144 Under these optimized N-tert-prenylation reaction conditions, the substituted indole derivatives are now accessible in a single transformation in up to 87% yield.

Scheme 21. Discovery of Stereocontrolled Synthesis of ZDienes (98 and 100) Based on Zincke Aldehydes

2.4. Strychnine: Stereocontrolled Synthesis of Z-Dienes Based on Zincke Aldehydes

The indole alkaloid strychnine (1) has been a source of inspiration for synthetic organic chemists for the past 60 years since Woodward’s first successful synthetic approach in 1963.17 Vanderwal and co-workers146 became particularly interested in developing a novel, concise approach toward strychnine based on an intramolecular Diels−Alder cycloaddition of a tryptamine-derived aminodiene 93 (Scheme 21). In the course of model studies aimed at the intramolecular Diels−Alder reaction of 94 and also tetrahydro-β-carboline-derived Zincke-aldehyde 97, they unexpectedly observed the formation of the unsaturated amides 95 and 98 as the major products. In a subsequent experiment, the simpler aldehyde 99 was similarly converted at 160 °C to the corresponding (Z)-dienamide 100 as the sole product (Scheme 21). Vanderwal and co-workers recognized the potential of their discovery and focused on the identification of a general set of reaction conditions for the synthesis of substituted (Z)-dienamides. The required Zincke aldehyde substrates (102) were easily obtained according to a literature protocol from activated pyridinium salts (101) upon treatment with secondary amines.147,148 To elucidate a general reaction protocol, mechanistic investigations were initiated starting from C2-substituted

Zincke aldehyde 103 (Scheme 22). Upon heating to 200 °C for prolonged periods of time, the only product observed was the dienamide 104, bearing the methyl substituent in the αposition to the amide carbonyl. On the basis of these results, M

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Scheme 23. Extension of Z-Selective Formation of Dienamides to the Synthesis of Polycyclic Lactams

Scheme 22. Mechanistic Hypothesis for Pericyclic Cascade Reactiona

a

Discovered during studies towards the synthesis of strychnine by Kearny and Vanderwal.148.

Vanderwal and co-workers proposed a mechanistic sequence starting with an E to Z isomerization in 103 to form 105, which could subsequently undergo a 6π-electrocyclization to intermediate 106. A [1,5]-hydrogen shift leads to the formation of intermediate 107, which then undergoes a 6π-electrocyclic ring opening to form Z-dienamide 104, the product of a formal transposition of the amino functional group. Subsequent studies undertaken by Vanderwal and co-workers proved the generality of this rearrangement with respect to the amine and substitution patterns on Zincke aldehyde substrates (Scheme 23). Microwave irradiation between 200 and 220 °C in odichlorobenzene proved superior compared to the initial reaction conditions and afforded the desired products with excellent Z-selectivity and up to 87% yield.148 In 2009, Steinhardt and Vanderwal149 were able to extend their initial report of the stereocontrolled synthesis of Zdienamides to the synthesis of polycyclic lactams as single diastereomers (Scheme 23, reactions 3 and 4). The reaction follows the same mechanistic hypothesis, relying on an alkene isomerization, 6π-electrocyclization, [1,5]-sigmatropic hydrogen shift, 6π-electrocyclic ring opening, and a final Diels−Alder cycloaddition reaction.

azabicyclononane core 109 common to banyasides A and B (108) and subsequent functionalization of the N2 secondary amine (Figure 7B), C9 hydroxyl, and C3 ester fragments to install the peptide as well as glycosyl side chains. Initial efforts to functionalize the N2 amine functionality in 109 proved remarkably challenging. No formation of the desired peptide coupling product was observed when 109 was reacted with carboxylic acid 110 and derivatives thereof together with coupling reagents such as EDC, BOPCl, BOP, HATU, or HBTU. 2.5.1. Facile Formation of N-Acyloxazolidinone Derivatives by Use of Acid Fluorides. Carreira and co-workers postulated that the steric environment of the N2-secondary amine in 109 was too congested to allow formation of the tetrahedral intermediate required for peptide bond formation. As a result, the strategy was revised to incorporate tricyclic iodide 111 as a substrate since 111 was postulated to possess a sterically more accessible secondary amine (Scheme 24). However, standard peptide coupling reagents repeatedly failed to provide the desired amide product, and a direct acylation protocol for amine 111 seemed more promising. Reaction of amine 111 with the acyl chloride of L-Cbz-leucine, Hünig’s base, and catalytic 4-dimethylaminopyridine (DMAP) in N,Ndimethylformamide (DMF) also led to the exclusive reisolation of starting material. Alternatively, acylation with the more reactive acyl fluoride 112 under otherwise identical reaction conditions formed a new product (114), which was obtained in 89% yield.156

2.5. Banyaside B

The natural products generally known as aeruginosins represent one of the seven main classes of cyanobacterial peptides.150,151 These structurally unique secondary metabolites, also referred to as microcin or spumigin, have been isolated from the planktonic cyanobacterial species Microcystis aeruginosa and genera Planktothrix (Oscillatoria) and Nodularia. Today, more than 35 compounds are considered to be known congeners of the aeruginosin family (Figure 7). Despite their diverse origins, these members of the aeruginosin family all contain a distinctive cis-fused-2-carboxyperhydroindole core structure (Choi). A structural analogue of this Choi moiety is the azabicyclononane fragment (Abn), which is found in four highly functionalized peptides, one of them being banyaside B (108).152,153 The biological activity mainly associated with members of the aeruginosin family of natural products is the in vivo inhibition of serine proteases such as thrombin and trypsin, along with other enzymatic targets such as plasmin. The total synthesis of banyaside B (108), as envisioned by Carreira and coworkers,154,155 focused on an initial formation of the N

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Figure 7. (A) Microcin SF608. (B) Retrosynthetic strategy toward banyaside B (108). Both microcin SF608 and banyaside B are members of the aeruginosin family of natural products, and 108 contains an azabicyclononane core.

Scheme 24. Reaction of Core Structure 111 with Acyl Fluoride 112, Resulting in Exclusive Formation of NAcylated Oxazolidinone 114

Scheme 25. Evaluation of Newly Discovered Method for NAcylation of Oxazolidinones

Subsequent 2D NMR studies revealed that the newly formed product was in fact the N-acylated oxazolidinone 114 and not the expected peptide 113. Compared to previous conditions for N-acylation of oxazolidinone derivatives that relied on the use of superstoichiometric strong bases, the reaction conditions identified serendipitously represented a much milder alternative. Carreira and co-workers157 subsequently investigated the scope and generality of this transformation with regard to various amino acid-derived acid fluorides and a variety of commercially available oxazolidinones. The reaction conditions for N-acylation of oxazolidinones identified serendipitously toward the synthesis of banyaside B (108) proved to be applicable to a wide range of substrates (Scheme 25). Organic synthesis makes use of substituted oxazolidin-2-ones158 primarily as chiral auxiliaries, first employed by Evans et al. in 1981,159 in an overwhelming variety of synthetic asymmetric transformations. Application of oxazolidinones such as 115 and 117 (Scheme 25) as chiral auxiliaries in asymmetric transformations requires attachment of the substrate, which is generally accomplished through the use of strong bases to deprotonate the oxazolidinone N−H (i.e., nBuLi, NaH, Scheme 25).160 A common problem associated with these reaction conditions is the potential for epimerization161 or polymerization162 when acryloyl substrates are being used.

The new reaction conditions for N-acylation of oxazolidinones using acid fluorides, identified en route to banyaside B (108), represent a mild alternative to previously established protocols. For oxazolidinones that proved to be poorly soluble in dichloromethane, special reaction conditions relying upon in situ formation of the corresponding O-silyloxazolidinone have been demonstrated to provide access to the desired products in high yields. Overall, no epimerization of the oxazolidinone or the amino acid-derived acid fluorides was observed in the newly established reaction protocol. 2.5.2. Nucleophilic Opening of Oxabicyclic Ring Systems. As a result of failed attempts to functionalize the secondary amine in endo-iodide 111 as the corresponding amide, Carreira and co-workers envisioned preparation of the amide prior to the iodoamination step in order to avoid the difficulties associated with formation of a hindered peptide bond. When amide 122 was initially subjected to previously O

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Scheme 26. Unexpected Formation of 125 via Ring Opening of Ketene Aminal 123

Scheme 27. Investigation of Cyclization of Unsaturated and Saturated Oxabicyclic Substrates

Figure 8. Structure of gambieric acid A (126), a marine ladder toxin isolated from Gambierdiscus toxicus by Yasumoto and co-workers in 1992.167,168

established cyclization conditions with N-iodosuccinimide, no transformation of the starting material was observed. A possible explanation for the observed lack of reactivity was that amide 122 was significantly less nucleophilic than the corresponding primary amine, which had previously been applied under otherwise identical transformation conditions. To increase the nucleophilicity of 122, Carreira and co-workers decided to form O-silyl imidate 123 in situ by use of trimethylsilyl trifluoromethanesulfonate (TMSOTf). Ketene aminal 123 would then be converted by use of N-iododsuccinimide to an intermediate N-iodinated peptide, which could subsequently cyclize as previously reported to form the desired peptide 124 (Scheme 26). However, the exclusive product, isolated in 89% yield, turned out to be the [4.3.0] bicyclic octahydroindole 125, formed upon ring opening of the oxabicyclic precursor 122.163,164

Although the reactivity described above was unprecedented, Carreira and co-workers rationalized their observation as a consequence of an allylic leaving group undergoing electrophilic activation. Subsequent examinations focused on elucidating the extent to which ring opening was indeed facilitated by virtue of the embedded 5,6-olefin in 122. This led to investigation of the newly discovered transformation by use of unactivated oxabicyclic substrates wherein the 5,6-olefin moiety of the oxabicyclic building blocks (Scheme 27, reactions 3 and 4) is saturated. The analogous cyclization was found to proceed quite readily in the absence of the olefin functionality in a remarkably facile transformation to afford [4.3.0] and [4.4.0] bicyclic products (Scheme 27). Carreira and co-workers speculated that the energetic driving force for this unprecedented transformation stems from the estimated 6.5 kcal/mol strain energy of the oxabicycloheptanes. The reaction is proposed to proceed under P

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Scheme 28. Development of an Olefinic Ester Ring-Closing Metathesis Cascade Reaction Using the Tebbe Reagent

Scheme 29. Direction of Reactivity in Olefinic Ester Ring-Closing Reactionsa

a

Based on the titanium alkylidene reagent.

Takai−Utimoto reduced alkylidene reagent,172 cyclic ether 127 was successfully converted to a mixture of acyclic and cyclic enol ethers 128 and 129 in 69% overall yield. The observed cyclic ether was proposed to result from an initial olefin metathesis reaction to form intermediate 130 followed by a carbonyl olefination sequence to yield 129.172 In comparison to the established reactivity of the Takai−Utimoto reduced alkylidene reagent, Majumder and Rainier173 discovered a direct dependence of the product distribution upon the respective alkylidene reagent used in the actual transformation (Scheme 29). Specifically, Rainier and co-workers found that the titanium methylidene reagent derived from dibromomethane as the corresponding alkylidene led to exclusive formation of the acyclic enol ether 132 starting from terminal alkene 131. However, conversion of the cis-alkene 133 with the corresponding ethylidene reagent CH3CHBr2 resulted in sole formation of cyclic enol ether 134. The ability to tune the reactivity of olefinic esters based on the substitution of the titanium alkylidene reagent itself was unprecedented, and the generality as well as scope of this novel transformation was investigated in subsequent studies. Rainier and co-workers suggested that, for titanium ethylidene reagents, cross-metathesis with the olefin precedes cyclization. In contrast, titanium methylidene reagents appear to prefer direct carbonyl olefination. The discovery that titanium ethylidene reagents are capable of inducing olefinic ester cyclizations was subsequently further

Lewis acidic activation of the oxybridge and silylation of the amide functionality in 122 (Scheme 26). This renders the latter more reactive for nucleophilic attack onto the oxybridge carbon atom, leading to the observed formation of the 6,5-membered tricycle 125. This serendipitous discovery represents a novel and unprecedented approach to highly functionalized [4.3.0] and [4.4.0] bicyclic ring systems, which also enabled the synthesis of microcin SF608 and thus enabled the design of a unifying strategy toward the aeruginosin family of natural products, which was exemplified in the synthesis of microcin SF608.165,166 2.6. Gambieric Acid A: Discovery of an Olefinic Ester Ring-Closing Metathesis Reaction

Gambieric acid A (126, Figure 8) belongs to the marine ladder toxin family of natural products and was isolated from the marine dinoflagellate Gambierdiscus toxicus in 1992 by Yasumoto and co-workers.167,168 Gambieric acid A (126) has been shown to inhibit the binding of brevetoxin B (PbTx-3) to site 5 of voltage-gated sodium channels.169 A general investigation and understanding of the biological acitivity of the gambieric acids has been hampered by the fact that these compounds are not generated in sufficient quantities by the producing organisms to enable biological studies.170 Prior to the development of a synthetic strategy toward the gambieric acids, Rainier et al.171 had successfully established an enol ether-olefin ring-closing metathesis cascade reaction to effect olefinic ester cyclizations for the construction of polycyclic ether fragments (Scheme 28). Based on a modified Q

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Scheme 31. Intramolecular Friedel−Crafts Reactiona

explored by Rainier and co-workers and extended (Scheme 30) to diene ring-closing metathesis reactions,174 two-directional olefinic ester ring-closing metathesis reactions,50 and olefinic amide as well as olefinic lactam cyclizations.175 Scheme 30. Extension of Olefinic Ester Reactions by Titanium Ethylidine Reagents to Other Types of Cyclization Reactions

a

Developed by Grundl and Trauner177 to obtain the quaternary stereocenter of the haouamine alkaloids.

cation 139, which could subsequently be trapped with the nucleophilic pendant aryl system to form the indenotetrahydropyridine 138 upon rearomatization from cation 140. Further development of these reaction conditions established a general reaction protocol for both inter- and intramolecular Friedel−Crafts triflation of electron-rich arenes to access polycyclic ring systems with “region-defined”178 double bonds (Scheme 32). The reaction conditions were found to be optimal with highly polar solvents (such as MeCN or MeNO2), with MeCN providing superior yields compared to MeNO2 in the intermolecular reactions (Scheme 32). This Friedel−Crafts triflation reaction represents an operationally simple alternative to cuprate conjugate additions followed by interception of the resulting metal enolate with Comins’ reagent or phenyl triflimide while forming triflic acid as the sole byproduct.178 In their initial scientific communication, the authors highlight the potential of this transformation in cases where the actual organometallic species proves difficult to generate in the presence of an enone moiety, which is often found in intramolecular reaction settings. 2.7.2. Discovery of a Novel Chichibabin Pyridine Synthesis. Baran and co-workers postulated that the unprecedented core structure common to the haouamines could potentially arise from a 2,3,5-trisubstituted pyridinium salt such as 141 as a biosynthetic precursor (Scheme 33) to 135 and 136.179,180 To test the viability of this biosynthetic hypothesis, the synthesis of pyridinium salt 141 was sought

2.7. Haouamines A and B

The alkaloids haouamines A (135) and B (136) were isolated in 2003 by Salvá and co-workers176 from the marine tunicate Aplidium haouarianum (Figure 9). In initial cytotoxicity tests against five cancer cell lines, 135 was found to inhibit growth of human colon carcinoma cells HT-29 (IC50 = 0.1 μg/mL), and 136 displayed activity against murine endothelial MS-1 cells. The haouamine core was found to exist as an inseparable mixture of two interconverting isomers that incorporate a highly strained aza-paracyclophane with a bent aromatic subunit. 2.7.1. Discovery of a Friedel−Crafts Triflation Reaction. The synthetic approach toward the haouamines developed by Grundl and Trauner177 relies on an intramolecular Friedel−Crafts reaction to establish the diaryl quaternary alkaloid stereocenter present in 135 and 136. Upon treatment of enone 137 (Scheme 31) with triflic anhydride and a sterically hindered base, the selective formation of the indeno-tetrahydropyridine core (138), common to the haouamines, was observed in up to 63% yield.101 The reaction was proposed to proceed upon activation of the electron-rich enone 137 with triflic anhydride to form an allylic

Figure 9. Haouamines A (135) and B (136) isolated from Aplidium haouarianum by Salvá and co-workers in 2003.176 R

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Scheme 32. Expansion of Triedel−Crafts Triflation Methodology to Inter- and Intramolecular Reactions

Scheme 33. Proposed Biosynthesis and Possible Retrosynthetic Strategy of Haouamine Alkaloids

Scheme 34. Suggested Reaction Mechanism for the Unexpected Synthesis of 3,5-Diphenylpyridinium Salt (145) via a Novel Chichibabin Pyridine Synthesis

after, based on the pyridine synthesis of Chichibabin181 starting from hydroxylated phenylacetaldeyde 142 and ammonia. As a model substrate for pyridinium salt 141, Burns and Baran183 focused their attention on a literature protocol182 to access pyridinium triflate 143 from phenylacetaldehyde 144 and benzylammonium chloride upon reaction with ytterbium triflate in water. However, the single product observed in the course of this reaction was not the predicted 2-benzyl-3,5diphenylpyridinium salt 143 but the corresponding 3,5diphenylpyridinium salt 145 (Scheme 34). In subsequent efforts, Baran and co-workers established the generality of this novel “abnormal” Chichibabin reaction

protocol that proceeded under remarkably mild conditions using ytterbium triflate in water. They propose a reaction mechanism that relies on initial formation of an imine 146 (Scheme 34) upon reaction of phenylacetaldehyde and benzylammonium chloride. This intermediate can subsequently undergo a 6π-electrocyclization to form dihydropyridine 147, which in the final step undergoes an oxidative dealkylation with molecular oxygen184 to form pyridinium triflate 145 upon the loss of benzaldehyde. Previously reported conditions for reactions to form pyridinium salts such as 145 relied on high temperatures and elevated pressures (235 °C at 1150 psi in ethanol for 6 h, resulting in 13% yield)185 and thus proved S

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Figure 10. Tetrapetalone family of natural products: tetrapetalones A (148), C (149), and A-Me aglycon (150), isolated from Streptomyces sp. USF4727 by Hirota and co-workers in 2003.186,187

incompatible with a wide variety of functional groups and complex substrates. This novel set of reaction conditions represented a mild alternative and was applicable to a wide variety of substrates. The desired pyridinium salts such as 145 were acquired in yields of up to 68% regardless of the electronic nature of the respective aldehyde component

Scheme 35. Stereocontrolled Reduction of 2-KetoSubstituted Pyrroles by Use of 5 Mol % Rh/Al2O3

2.8. Tetrapetalones A−D: Stereoselective Reduction of Substituted Pyrroles

The tetrapetalone family of natural products (Figure 10) was first isolated from a strain of bacteria, Streptomyces sp. USF4727, by Hirota and co-workers in 2003.186,187 The tetrapetalones were found to display moderate activity against soybean lipoxygenase (SLO). This is of particular interest because human lipoxygenase and cyclooxygenase are known to catalyze the first step in the arachidonic acid pathway. This metabolic network forms signaling molecules such as leukotrienes, lipoxins, and prostaglandins, which have been shown to be involved in the development of a variety of human diseases.188 During studies toward the synthesis of tetrapetalone A-Me aglycon (150), Frontier and co-workers189,190 found that hydrogenation of substituted pyrroles such as 151 (Scheme 35), which incorporate an α-keto ester substituent at the 2position, led to the reduction of both the ketone and the pyrrole ring with high diastereoselectivity to form the corresponding amine 152 [diastereomeric ratio (dr) > 20:1]. This impressive transformation was achieved with 5 mol % Rh/ Al2O3 as the active catalyst at elevated pressures with hydrogen gas. Frontier and co-workers subsequently decided to study the scope of this heterogeneous catalytic transformation and found that a wide variety of bicyclic pyrroles and substituted pyrroles such as 153 were efficiently reduced in a stereocontrolled manner to access the desired bicyclic amines 152 or pyrrolidines 154 in high diastereomeric ratios. This novel synthetic transformation represents a general protocol for the efficient and diastereoselective catalytic hydrogenation of highly substituted pyrrole heterocycles to access the corresponding pyrrolidines from simple, readily accessible starting materials.191 A series of interesting observations was made during the initial optimization studies conducted by Jiang and Frontier.190 Use of either Rh/Al2O3 or Pt/Al2O3 in the hydrogenation of 151 (Scheme 36A) led to initial hydrogenation of the ketone, resulting in the formation of alcohol 155. Subsequent reduction of 155 by use of Rh/Al2O3 then led to pyrrolidine 152. Although the orientation of the side chain during reduction is unknown, Jiang and Frontier suggest that hydrogen is delivered to the face anti to the hydroxyl group, as the side chain may hinder approach to one face of the pyrrole over the other. Moreover, the unselective reduction observed upon hydrogenation of 156 solely with Rh/Al2O3 provided additional insight. Partial reduction of 156 had previously been achieved with Pt/Al2O3 in 99% yield resulting in the formation of 157,

which could subsequently be hydrogenated with Rh/Al2O3 to form 158 in a two-step sequence that overall resulted in higher diastereoselectivities (3:1 ratio, Scheme 36B) than the direct hydrogenation of 156 with Rh/Al2O3 (1:1 ratio, Scheme 36B). On the basis of these preliminary experiments, Jiang and Frontier suggested that the pyrrole alcohol stereocenter is indeed essential in order to observe diastereoselectivity in this transformation. However, the diastereoselectivity is not solely controlled by this stereocenter. Additionally, the authors hypothesized that the electron-donating nature of the methoxy substituent present in 151 results in an overall lower reduction rate of the pyrrole subunit itself relative to the ketone functionality. 2.9. Karahanaenone: Titanium-Mediated Cross-Couplings to Access γ-Lactols

Seven-membered carbocyclic subunits are present in a wide variety of biologically important natural products, such as the monoterpene karahanaenone (159), the sesquiterpene daucadiene (160), and the diterpene barekoxide (161) (Figure T

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Scheme 36. Observations Made during Initial Optimization Studies toward General Reaction Conditions for Stereoselective Reduction of Substituted Pyrroles

Figure 11. Natural products incorporating 7-membered carbocyclic subunits.

Scheme 37. Treatment of Alkenes 162 and 165 with Cp2TiCl/H2O, Resulting in the Unexpected Formation of Lactols 163 and 166

carbon bond-forming reaction to form γ-lactols in a 7-endo-dig cyclization. When aldehyde 162 was treated with stoichiometric amounts of Cp2TiCl in the precence of water, the isolated product was not the anticipated products of a pinacol coupling. However, the only product isolated in the course of this transformation was the 4R*,5S*-γ-lactol 163, obtained in 86% yield (5:1 mixture of C2 epimers).196 It is known that under anhydrous conditions, Cp2TiCl can be employed in the pinacol coupling of both aromatic aldehydes and conjugated alkenals.197−201 Alternatively, aromatic aldehydes react with Cp2TiCl in the presence of water to form a mixture of

11).191−194 Oltra and co-workers195 devised a research program aimed at the direct synthesis of seven-membered carbocycles via free-radical titanocene(III)-catalyzed 7-endo-dig and 7-endotrig cyclizations (Figure 11), which was successfully extended to the synthesis of a variety of naturally occurring carbon skeletons containing cycloheptane ring systems, including barekoxide (161). In the course of their studies involving titanocene(III) complexes for the construction of seven-membered carbocycles, Oltra and co-workers195 discovered that the same complexes also have the ability to promote a stereoselective carbon− U

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Scheme 38. Proposed Reaction Mechanism for Titanium-Catalyzed 7-endo Cyclization Involving a Key Inner-Sphere Single Electron Transfer to Carbonyl 167

reduction and pinacol coupling products.202 The homocoupling product 163, obtained upon reaction of aldehyde 162 and Cp2TiCl, was confirmed spectroscopically and further reacted via PCC oxidation to give lactone 164. In subsequent studies, Oltra and co-workers probed the stereoselectivity of this crosscoupling reaction, which provided the 4R*,5R*-γ-lactol 166 seletively from the corresponding isomer 165 under otherwise identical reaction conditions (Scheme 37). The stereoselectivity of this radical-mediated coupling reaction prompted Oltra and co-workers to suggest that titanium played a key role in what is best described as a 7endo cyclization. The proposed mechanism relies on an innersphere single-electron transfer from TiIII to the carbonyl of the α,β-unsaturated aldehyde to give a titanoxy-allyl radical 168 (Scheme 38). The resulting TiIV complex can subsequently coordinate the aldehyde to form intermediate 169. TiIV complex 169 has the proper π-orbital overlap of the aldehyde carbonyl and the delocalized allylic radical to allow for the 7endo radical cyclization to give intermediate 170. Reduction by excess Zn facilitates formation of 171, which can subsequently be hydrolyzed to 172.203 This novel TiIII/H2O-induced coupling mechanistically differs from SmI2-induced cross-coupling reactions of aldehydes and ketones to form α,β-unsaturated esters and nitriles.204 In subsequent studies, Oltra and co-workers196 extended the susbtrate scope of this carbon−carbon bond-forming reaction to the intramolecular titanocene-mediated coupling of unsaturated aldehydes such as 174 (Scheme 39). The reaction of

aldehyde 174 with Cp2TiCl enables stereoselective access to fused γ-lactol or γ-lactone ring systems such as 175 found in a variety of trans-fused menthane lactones. 2.10. Diazonamide A: Deoxygenations of Sulfoxides, N-Oxides, and Selenoxides

Diazonamide A is a secondary metabolite that was first isolated by Fenical and co-workers in 1991 from Diazona angulata, a marine ascidian found on the Siquijor Islands.205 Initial biological evaluation against human colon carcinoma and murine melanoma cell lines showed potent levels of cytotoxicity.206 Fenical and co-workers proposed the structure of diazonamide A (177) based on X-ray crystallographic studies. This unique structure, combined with the biological activity, posed an exciting challenge for synthetic chemists (Figure 12). However, upon completion of the total synthesis of 177 by Harran and co-workers in 2001,207,208 it became clear that the structural assignment originally proposed by Fenical and co-workers was incorrect. Not only did the spectroscopic data of the synthesized compound 177 not match that of natural diazonamide A, but 177 also exhibited low levels of cytoxicity and was highly unstable.209 This prompted Harran and co-workers to propose a revised structure of diazonamide A (176),207 and shortly thereafter, Nicolaou et al.210,211 became the first to synthesize the revised structure and confirm compound 176 as diazonamide A. While working toward the synthesis of diazonamide A, Nicolaou et al.212 planned to generate an alkene via a Tebbe olefination of aldehyde 178 (Scheme 40). However, upon treatment of 178 with Tebbe reagent 179, they observed not only generation of the alkene but also deoxygenation of the sulfoxide to the corresponding sulfide 180. This was particularly exciting, as it eliminated the need to perform the reduction later in the synthetic sequence. It also was performed under mild conditions with a shorter reaction time compared to previous methods. Recognizing the utility of this method, Nicolaou et al. explored this newly discovered methodology and found that the Tebbe reagent could rapidly reduce a variety of diaryl, aryl, alkyl, and dialkyl sulfoxides in good yields at low temperatures (Scheme 41). The only difficulty encountered with this method was with sterically hindered di-tert-butyl sulfoxide. After 18 h, this reaction only generated the sulfide in 25% yield. This method was further expanded to the reduction of N-oxides, which resulted in the formation of 2-methylpyridines, as well as diphenylselenoxides. All of these substrates underwent rapid deoxygenation. Nicolaou et al. hypothesized that the mechanism of deoxygenation proceeded via a carbene-initiated process by a titanocene methylidene complex generated from the Tebbe

Scheme 39. Investigation of Substrate Scope: Stereoselective Synthesis of γ-Lactols by Use of Cp2TiCl in both Inter- and Intramolecular Settings

V

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Figure 12. Revised structure of diazonamide A (176) and its originally proposed structure (177).

Scheme 42. Proposed Deoxygenation Mechanism of NOxides via a Titanocene Methylidine Complex

Scheme 40. Discovery of Concomitant Tebbe Olefination and Sulfoxide Reduction of 178

Scheme 41. Reduction of Sulfoxides, N-Oxides, and Selenoxides by Use of the Tebbe Reagent

by Nicolaou et al. provides a mild method for the effective deoxygenation of a variety of sulfoxides and selenoxides. 2.11. Actinophyllic Acid: Electron-Transfer Photoredox Catalysis

The indole alkaloid actinophyllic acid (186) was isolated by Carroll et al. in 2005213 upon fractionation of the aqueous extract of the leaves of Alstonia actinophylla (Figure 13). These

Figure 13. Actinophyllic acid (186), isolated in 2005 by Carroll et al.213

efforts of Carroll et al. were specifically directed at the identification of novel natural products as potential lead structures for treating cardiovascular disorders. Actinophyllic acid (186) was found to inhibit carboxypeptidase U (CPU), which catalyzes the cleavage of C-terminal arginine and lysine residues from fibrin and fibrin degradation products and thus acts as an endogenous inhibitor of the fibrinolysis process.214,215 Stephenson and co-workers developed a synthetic strategy toward actinophyllic acid (186), which relied on the formation of diethyl malonate 190 upon treatment of indole 187 and bromomalonate 188 with tris(2,2′-bipyridyl)ruthenium(II) chloride (189), 2,6-lutidine and visible light.216 The direct transformation of indole 187 and bromomalonate 188, inspired by reductive radical generation by Fukuzumi et al.,217 resulted

reagent (Scheme 42). Coordination of the oxygen of the Noxide 181 to the titanium generates intermediate 182. The carbanion subsequently adds to the ortho position of the pyridine ring, resulting in the formation of a five-membered metallacycle 183 via a formal [3 + 2] cycloaddition. Fragmentation of 183 eliminates Cp2TiO and generates 184, which upon protonation gives the final 2-methylpyridine product 185. Sulfoxides are proposed to react via a similar reaction mechanism. However, after coordination of the oxygen, the carbanion adds to the sulfur to form a fourmembered metallacycle. Fragmentation of this metallocycle leads to an unstable ylide that decomposes to generate the deoxygenated sulfide. The development of this novel method W

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Scheme 43. Discovery of Tin-free Reductive Dehalogenation Reaction Using Photoredox Electron-Transfer Catalysisa

a

By Stephenson and co-workers.

in formation of the desired diethyl malonate 190, albeit in only 30% yield (Scheme 43). Subsequent efforts directed at optimization of the reaction resulting in 190 focused on the evaluation of various tertiary amine bases. When the reaction of indole 187 and bromomalonate 188 was conducted with Hünig’s base under otherwise identical reaction conditions, exclusive formation of diethylmalonate (191) was observed. The reaction represents a direct reductive dehalogenation of the bromomalonate starting material and as such a tin-free alternative to the well-established dehalogenation conditions using Bu3SnH and a radical initiator, such as AIBN.125 Preliminary studies aimed to optimize this novel photoredoxcatalyzed reductive dehalogenation reaction. When bromopyrroloindoline 192 (Scheme 44) was subjected to irradiation by a 14 W fluorescent lamp with Ru(bpy)3Cl2 (5 mol %) using Hünig’s base in DMF, the desired reduced product 193 was obtained in 25% yield. Subsequent optimization efforts established a general reaction protocol for this reductive debromination reaction using catalytic Ru(bpy)3Cl2, resulting in yields greater than 90%. Further studies aimed at elucidating the scope of this transformation showed that both C−Br and C−Cl were reduced efficiently under these novel reaction conditions.218 Subsequent investigations directed at establishing a mechanistic hypothesis for the photoredox-catalyzed tin-free reductive dehalogenation reactions gave rise to the hypothesis that Hünig’s base is likely the major hydrogen-atom source in this transformation. On the basis of the experimental results obtained, Stephenson and co-workers propose a mechanism that relies on initial single electron-transfer from an ammonium formate complex to the excited Ru(II)*, which results in the formation of Ru(I) and the radical cation complex 195 (Scheme 44). Subsequent reduction of the carbon−halogen bond by Ru(I) forms the alkyl radical 196, which is reduced upon abstraction of a hydrogen atom (Ha or Hb) from one of the methine carbons of the radical cation 195 to result in formation of the desired reduction product (197 or 200, Scheme 44). This novel process for the photoredox-catalyzed reductive dehalogenation of carbon−halogen bonds, discovered toward the synthesis of actinophyllic acid, represents a mild and environmentally benign alternative to currently available dehalogenation procedures, which rely on the generation of intermediate alkyl radicals by use of trialkyltin hydrides (Scheme 45). This novel transformation enabled an alternate means of accessing radicals as reactive intermediates for

Scheme 44. Plausible Mechanism for Reductive Dehalogenation Reaction Using Photoredox ElectronTransfer Catalysis

subsequent reduction reactions or carbon−carbon bondforming reactions. This initial discovery led to the establishment of a wide range of generally applicable reaction protocols for photocatalytic cascade radical cyclizations,219 oxidative Henry reactions,220 atom transfer radical additions,221 photocatalytic C−O bond halogenation reactions,222 oxidative coupling reactions of trialkylamines to electron-deficient arenes,223 and redox neutral fragmentation reactions (Scheme 46).224 X

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2.13. Daphmanidin E: Cobalt-Catalyzed Heck-Type Coupling Reactions

Scheme 45. Tin-free Photoredox-Catalyzed Reductive Halogenation Reactions as a Novel, Environmentally Benign Alternative to Currently Available Dehalogenation Procedures

In 2006, two new alkaloids, daphmanidins E (210a) and F (210b), were isolated from the leaves of the flowering tree Daphniphyllum teijsmannii (Figure 15).229 Both natural products represent novel hexacyclic structures that incorporate a central bicyclo[2.2.2]octane core in addition to deca- or octahydrocyclopentazulene moieties. These fused dihydropyrrole natural products were found to show moderate vasorelaxant activity on rat aorta in a vasodilator assay.229 In 2011, Weiss and Carreira230 reported the total synthesis of (+)-daphmanidin E (210a). During the course of this synthesis, Weiss and Carreira faced the challenge of forming the fused seven- and five-membered ring system. Beginning with alkyl iodide 211, they conducted extensive experimental investigations in order to establish a viable cyclization protocol for the formation of octahydroazulene 213. However, several established literature procedures such as free radical cyclizations, Barbier conditions, and many transition metal-mediated cyclizations proved futile. In the course of these studies, a novel intramolecular cobalt-catalyzed Heck-type reaction of alkyl iodides to olefins was established, which proceeds under mild reaction conditions with irradiation of visible light, both stoichiometrically and catalytically (Scheme 49). The cobalt catalyst 212 has structural similarities to coenzyme B12, and its mechanism was hypothesized to proceed in a similar radical fashion. Because of the weak nature of the Co−Sn bond, Carreira and Weiss and coworkers231 proposed that, when subjected to visible light, catalyst 212 and an alkyl iodide 214 would produce Ph3SnI and the cobalt−alkyl species 215. This alkyl−cobalt would then add to the olefin to produce adduct 216. After disproportionation, the newly formed olefin would be released, giving hydridocobalt 217. When this reaction is performed catalytically, the hydridocobalt 217 could be deprotonated by a suitable amine base, leading to the anionic cobalt species 218, which could then attack the alkyl iodide to regenerate 215 and complete the catalytic cycle (Scheme 50). This new reaction, discovered during the synthesis of daphmanidin E, was then further tested for its general synthetic utility and applied to a wider variety of substrates.231 This novel cobalt-catalyzed intramolecular Heck-type coupling reaction of alkyl iodides and olefins was subsequently found to be broadly applicable and compatible with many functional groups such as amides, esters, and ethers (Scheme 51).231

2.12. Quinoline Alkaloids: Discovery of an Intramolecular ipso-Halocyclization Reaction

The quinoline alkaloids are a class of natural products that were isolated from the cinchona plant.225 Notable quinoline alkaloids include quinine (201a), quinidine (202a), cinchonidine (201b), and cinchonine (202b). These complex structures (Figure 14) are biosynthetically derived from L-tryptophan upon rearrangement of the indole core into the quinoline system. Quinolines have found widespread applications as fungicides, antibiotics, dyes, and flavoring agents. Several quinolines isolated from natural sources or derivatives thereof are significant with respect to their use as antimalarials.226 Chloroquine (203) and hydroxychloroquine (204) are among the most famous antimalarials containing the quinoline scaffold and have additionally been used to suppress the disease process in rheumatoid arthritis. As a result of their important biological activities, the development of novel strategies to access substituted quinolines has been an important focus of synthetic method development. Larock and co-workers227,228 envisioned a novel synthetic strategy to obtain iodinated quinoline scaffolds based on a cyclization strategy of propargylic anilines with appropriate electrophiles, such as I2, ICl, and PhSeBr. They aimed to develop mild reaction conditions that could convert Npropargylic anilines to a variety of 3-haloquinolines in good yields. During the course of their studies, Zhang and Larock227 attempted to use this new method to convert 205 to dihydroquinoline 207 (Scheme 47). However, instead of forming the dihydroquinoline, the reaction resulted in the formation of the 1-azaspirotrienone 206 in 88% yield. Zhang and Larock227 proposed the following mechanism to explain the transformation (Scheme 48). Electrophilic addition of iodine to the alkyne of 205 generates an iodonium intermediate 208 that is then activated toward a 5-endo-dig ipsoiodocyclization to generate 209. Finally, nucleophilic attack on 209 cleaves the methyl group, yielding 206. When the reaction was conducted at room temperature, the yield of spiro[4.5]trienone decreased to 46%, but dihydroquinoline 207 was obtained in 48% yield. This suggests that the spiro[4.5]trienone is the kinetically favored product. This new method represents a novel iodonium-induced intramolecular cyclization of alkynes onto an arene moiety, which is uncommon under such mild conditions. Additionally, this method provides access to the spiro[4.5]decane structural feature that is common to a variety of natural products.227

2.14. Oasomycin A: Ceric Ammonium Nitrate-Promoted Oxidation of Oxazoles

In 1993, two new 42-membered ring macrolactones, oasomycins A (219) and B, were isolated from a culture broth of Streptoverticillium baldacii that was obtained from a soil sample from a botanical garden in Bombay, India (Figure 16).232 Oasomycin A (219) was found to be an inhibitor of de novo cholesterol biosynthesis. With 22 chiral centers, including 13 alcohols, 219 represents a unique synthetic challenge, especially with regard to the high density of hydroxyl functional groups. In 2007, Evans et al.233−235 developed a synthetic strategy toward oasomycin A (219) to validate the structural assignment. Kishi and co-workers had previously proposed the absolute stereochemistry of oasomycin A (219),236 relying on their “universal NMR database.”233 A particularly challenging transformation toward the synthesis of oasomycin A (219) Y

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Scheme 46. Novel Synthetic Reactionsa Based on the Initial Discovery of a Photoredox-Catalyzed Tin-free Dehalogenation Reaction

a

Developed by Stephenson and co-workers.

included installing the exocyclic five-membered lactone fragment on the “eastern-fragment” of the molecule while maintaining overall integrity of configuration.237 The associated alcohol and carboxylic acid of the lactone were carried through the synthesis with a PMP (p-methoxyphenyl) acetal and oxazole protecting groups, respectively. The initial synthetic plan called for the oxazole to be deprotected with singlet oxygen, which was successfully implemented in the final strategy toward the synthesis of oasomycin A (219). However,

during the course of these studies, Evans et al. discovered that the oxazole masking group was also sensitive to one-electron oxidants. The synthetic intermediate 220 was exposed to ceric ammonium nitrate (CAN), which resulted in cleavage of the oxazole to form the proposed imide intermediate 221. The resulting imide is subsequently cleaved to result in the corresponding carboxylic acid, which upon deprotection of the 1,3-diol yields the five-membered lactone 222 (Scheme 52). Z

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Figure 14. Biologically active substituted quinolines, both naturally occurring and synthetic.

Scheme 47. Discovery of ipso-Halocyclization Reaction from 205, Resulting in Formation of the Substituted Spiro[4.5]trienone 206

Scheme 49. Intramolecular Cobaloxime-Catalyzed Hecktype Reaction of Alkyl Iodide with Alkenea

Scheme 48. Proposed Mechanism of Intramolecular ipsoIodocyclization Resulting in Selective Formation of Spiro[4.5]trienone 206 a

Developed by Weiss and Carreira230 toward total synthesis of (+)-daphmanidin E (210a).

Wasserman singlet oxygen conditions for complex substrates bearing functionalities sensitive toward singlet oxygen.

3. DISCOVERY OF NEW REAGENTS 3.1. Panduratin A: Silver Nanoparticle-Catalyzed Diels−Alder Cycloaddition of 2′-Hydroxychalcones

Panduratin A (225) and nicolaidesin C (226) belong to the class of prenylated flavonoids, which have promising anticancer, anti-HIV, and anti-inflammatory activities (Figure 17).238 In their approach toward this class of biologically active natural products, Porco and co-workers were inspired by the proposed biosynthesis of these compounds, which are postulated to be formed through an enzymatic Diels−Alder cycloaddition of 2′-hydroxychalcones as dienophiles (227) and trans-β-ocimene (228) as the corresponding diene (Scheme 54).239 Although this process has been proposed as a biosynthetic pathway,239 a synthetically equivalent Diels− Alder reaction is faced with several challenges, primarily with the electron-rich dienophile 227, which displays only low levels of reactivity even under Lewis acid-promoted conditions. The corresponding diene component (228) further complicated the synthetic approach, as it was susceptible to isomerization and polymerization reactions under acidic conditions.240 To develop a unifying strategy toward this class of prenylated flavonoids, Porco and co-workers241 established a general reaction protocol for the [4 + 2] cycloaddition employing electron-rich 2′-hydroxychalcone dienophiles such as 227 (Scheme 54) and a catalyst system composed of Bu4NBH4 as an electron donor and ZnI2 as a Lewis acid. The reaction conditions proved uniquely effective in promoting the cycloaddition of model chalcone 229 and diene 230 to the desired Diels−Alder product 231 in 98% yield. Unfortunately, subsequent attempts undertaken by Porco and co-workers242

Figure 15. Daphmanidin E (210a) and daphmanidin F (210b) were isolated from Daphniphyllum teijsmannii leaves in 2006 by Morita et al.229

Since this mechanism is proposed to proceed through an imide intermediate 221, Evans et al. hypothesized that imides such as 224 could be formed from oxazoles (223) under similar reaction conditions for a general set of substrates (Scheme 53). In subsequent studies aimed at establishing the general utility of this new methodology for the CAN-promoted oxidation of oxazoles, Evans et al.237 developed a viable alternative to the AA

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Scheme 50. Proposed Mechanistic Hypothesis for Cobalt-Catalyzed Alkyl Heck Coupling Reaction Using an Amine Base for Catalytic Turnover

Scheme 51. Cobalt-Catalyzed Heck-type Reactiona Applied as a General Methodology toward a Variety of Substratesb

Scheme 52. CAN-Promoted Reaction of Oxazoles Discovereda during the Course of Oasomycin A (219) Synthesis

a

a

Developed during the synthesis of daphmanidin E (210a).230 bBy Carreira and co-workers in 2011.231

By Evans et al.237

Scheme 53. Synthesis of Imides from Oxazoles by CANa

a

Discovered accidentally by Evans et al. while synthesizing the lactone fragment of oasomycin A.

Figure 16. Macrolactone oasomycin A (219) isolated from a Streptoverticillium baldacii culture broth by Zeeck and co-workers in 1993.232

(Scheme 54). These studies revealed a combination of 30 mol % AgBF4 and 10 mol % Bu4NBH4 to be uniquely effective in promoting the desired transformation to form cycloadduct 231 in 98% yield as a single regioisomer. Evaluation of additional silver salts revealed a significant and undesirable counterion effect with AgPF6, AgSbF6, Ag2CO3, and Ag2O that resulted in low yields of the desired product 231. The Ag(I) salts alone, Bu4NBH4, or commercially available Ag powder were also found to display no reactivity in the desired

to extend this reported methodology to the synthesis of panduratin A (225) via a cycloaddition between 227 and 228 proved unsuccessful. They decided to evaluate additional metal salts in combination with Bu4NBH4 for the desired [4 + 2] cycloaddition of 2′-hydroxychalcone 229 and diene 230 AB

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catalytic conditions (Scheme 56), the desired cycloadduct was isolated in 85% yield, which upon cleavage of the aryl acetate completed the synthesis of panduratin A (225). This report by Porco and co-workers represented the first example of a metal nanoparticle-catalyzed Diels−Alder reaction and identified a novel catalytic system that has the potential to find widespread applications as a novel heterogeneous catalytic system for additional synthetic transformations.

Figure 17. Biologically active prenylated flavonoids panduratin A (225) and nicolaidesin C (226).

3.2. Axinellamines A and B: Discovery of a Practical and Reactive Chlorinating Reagent

Quinn and co-workers243 first isolated and characterized axinellamines A (239) and B (240) from multiple members of the Axinella genus of Australian marine sponges in 1999 (Figure 18). These alkaloids incorporate a highly functionalized tetracyclic bisguanidine core structure with eight contiguous stereocenters and are often referred to as the “most complex marine natural products isolated to date.”244 Initial biological investigations showed that axinellamine B (240) had moderate antibacterial activity against Helicobacter pylori, a microbe that is found in patients with stomach ulcers. Subsequent biological studies enabled by the development of a scalable synthesis of axinellamines A (239) and B (240) identified these marine alkaloids as broad-spectrum antibacterial agents, with promising activity against Gram-positive and Gram-negative bacteria.245 The synthetic strategy toward the axinellamines envisioned by Baran and co-workers244 relied on the highly functionalized bicyclic guanidine 245 (Scheme 57) as the key intermediate.246 In pursuit of an efficient and stereoselective route to spiro amino alcohol 245, allylic guanidine 243 was synthesized from homoallylic alcohol 241 upon Boc deprotection and guanidinylation with Goodman’s reagent 242. Treatment of this reaction mixture containing crude allylic guanidine 243 with tBuOCl yielded the desired chlorospirocyclization product 245 in 55% yield over three steps. Further optimizations of this reaction sequence were aimed at conducting the reaction under otherwise identical conditions, however, with purified allylic guanidine 243. Surprisingly, varying results were obtained with purified 243, resulting in overall lower isolated yields. Additional investigations aimed at elucidating a plausible

transformation. The success of the AgBF4/Bu4NBH4 reagent combination prompted Porco and co-workers to focus subsequent studies on identifying the actual catalytic system. These studies revealed the presence of silver nanoparticles (AgNP) that accounted for the observed uniquely potent catalytic activity and selectivity. Additional investigations with silica-supported AgNPs showed higher catalytic activity compared to the in situ prepared AgNPs. Furthermore, the corresponding endo Diels− Alder cycloadducts were favored with a single regioisomer using unsymmetrical dienes. Following their experimental results, Porco and co-workers242 propose a general reaction mechanism (Scheme 55). A single electron transfer (SET) from the adsorbed chalcone 229 to the silver nanoparticle would occur upon removal of a proton, forming the stabilized phenoxyl radical 232, which is in resonance with radical 233. Subsequent cycloaddition between diene 234 and AgNP-bound dienophile 232/233 provides the cycloadduct 235. A back electron transfer (BET) and protonation event then form 236. Desorption from the AgNP releases the product 237 and turns over the catalytic cycle. The newly identified catalytic system was next evaluated on its ability to promote the desired cycloaddition to build up the carbon core structure of panduratin A (225). Initial attempts employing the unprotected 2,4,6-trisubstituted chalcone analogue 227 proved unsuccessful. Porco and co-workers242 postulated that a less electron-rich chalcone analogue 238 with fewer free hydroxyl groups would be a more suitable dienophile. Upon conversion of 238 with 228 under AgNP

Scheme 54. Biosynthetically Inspired [4 + 2] Cycloaddition Catalyzed by AgNPsa

a

Reported by Porco and co-workers.242 AC

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Scheme 55. Proposed Catalytic Cycle of AgNP-Catalyzed Cycloadditions

Scheme 56. Conditions for AgNP-Catalyzed [4 + 2] Cycloaddition of Panduratin A

Scheme 57. Synthesis of Highly Functionalized Bicyclic Guanidine 245 toward the Synthesis of Axinellamines

Figure 18. Axinellamines A and B, isolated from members of genus Axinella.

reaction mechanism of this chlorocyclization process proved that formation of an intermediate N-chloroguanidine 244 upon treatment with tBuOCl was crucial for the success of this transformation. Residual TfNH2, formed during the reaction of 243 and present in the crude reaction mixture, was eventually discovered to be beneficial for the formation of spirocycle 245 as a single diastereomer. However, in the absence of TfNH2 or with an excess of TfNH2, the spirocyclization reaction resulted in the formation of complex product mixtures. The discovery of N-chloroguanidine 244 as the functioning chlorinating agent of the chlorospirocyclization and success in the synthesis of 245 inspired Baran and co-workers247 to initiate investigations into reagents of similar structure to develop a guanidine-based chlorinating reagent of general

utility. Subsequent studies on N-chloroguanidines with a focus on heteroaromatic chlorination succeeded in identifying chlorobis(methoxycarbonyl)guanidine (CBMG or palau’chlor, 247) as a new guanidine-based chlorinating reagent. Palau’chlor (247) was found to be highly effective for the chlorination of aromatic heterocycles, such as 248, providing the corresponding chlorinated indole derivative 249 in 70% AD

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Scheme 58. Synthesis and Utility of Newly Invented Chlorinating Agent Palau’chlor 247

isolated by Mulder and co-workers in 1986. 248 The extermination of PCN based on existing agricultural chemicals as well as nematicides is extremely difficult, and PCNs cause serious damage to crop plants. Within recent years, the increased focus on the extermination of PCNs has been aimed at application of the hatch stimulus solanoeclepin A, which has subsequently attracted significant attention in the synthetic community.249 During their studies aimed at construction of the sevenmembered ring system (Scheme 59), Sarpong and coworkers250 envisioned synthetic access to tricycle 256 starting from ditriflate 254 and divinyl carbinol 255. Under standard Heck reaction conditions, PdCl2(PPh3)2 and Hünig’s base at 80 °C in DMF, a mixture of two unexpected compounds, enal 257 and bisenal 258, were isolated as the main products of this transformation. The reaction of divinyl carbinol 255 and a variety of simple aryl halides and triflates under otherwise identical reaction conditions was found to result predominantly in the formation of the standard Heck reaction products. Ensuing studies aimed at the elucidation of reaction conditions that disfavor β-hydride elimination, resulted in optimized reaction conditions using PdCl2(PPh3)2, Et4NCl, and Hünig’s base in N,N-dimethylacetamide (DMA) as solvent. Sarpong and co-workers250 suggested a mechanism that initially relies on oxidative addition of an in situ generated Pd(0) active catalyst to aryl bromide 259 to generate organopalladium intermediate 260, which can subsequently undergo migratory insertion of the divinyl carbinol 255 to form intermediate 261 (Scheme 60). Subsequent β-hydride elimination in 261 is hypothesized to be prevented by coordination to either the hydroxyl or,

yield (Scheme 58). The general reaction protocol leads to formation of the desired products in good yields at ambient temperature under mild reaction conditions. Nonheteroaromatic substrates have been shown to undergo chlorination with 247, which often proved superior to established chlorinating reagents, such as N-chlorosuccinimide. Treatment of methoxybenzene (250) with palau’chlor (247) and HCl in dioxane at elevated temperatures results in the quantitative chlorination with high selectivity in favor of the para position (Scheme 58). Palau’chlor has recently been commercialized by Sigma−Aldrich and is an effective tool for both C−H and N−H chlorinations for a wide range of substrates.

4. DISCOVERY OF NEW REACTIVITIES 4.1. Solanoeclepin A: Discovery of an Anomalous Heck Reaction

Solanoeclepin A (253, Figure 19) is the key hatch-stimulating substance for potato cyst nematode (PCN), and was first

Figure 19. Solanoeclepin A (253), isolated by Mulder and co-workers in 1986.

Scheme 59. Discovery of a New Method for Synthesis of Tri- and Tetrasubstituted Olefinsa

a

By Sarpong and co-workers.250. AE

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Scheme 60. Proposed Mechanistic Routes Leading to β,γ-Unsaturated Aldehyde 265

Scheme 61. Skeletal Rearrangements of Divinyl and Enyne Carbinols

Figure 20. Antimitotic compounds celogentin A (268), B (269), and C (270) isolated from Celosia argentea.

4.2. Celogentin C: Proline Esters as Electrophilic Chlorine Scavengers in Oxidative Coupling Reactions

alternatively, excess halide or the alkene moiety itself. Later migratory insertion results in the formation of cyclopropanol 263, which could potentially react in one of two ways. One possible route is initiated by a decarbopalladative rearrangement of 263 to form organopalladium intermediate 264 (Scheme 60, path A). The β-hydride elimination from 264 results in the formation of the β,γ-unsaturated aldehyde 265, which upon isomerization yields the observed aldehyde 266. Alternatively, deprotonation of 263 and concomitant fragmentation of the cyclopropanol 267 leads to formation of 265 (Scheme 60, path B). The optimized reaction conditions developed by Sarpong and co-workers250 enabled the synthesis of a series of enals, enones, and dienones that are otherwise difficult to access from simple divinyl and enyne carbinols in a palladium-mediated anomalous Heck reaction (Scheme 61).

In 2001, Kobayashi et al.251 reported the isolation and structural elucidation of three new bicyclic peptides from the seeds of the tropical herbaceous plant Celosia argentea (Figure 20). Celogentins A (268), B (269), and C (270) were shown to inhibit the polymerization of tubulin, giving them antimitotic properties.252 Investigations by Kobayashi and co-workers253 identified the right-hand subunit of the natural products to have a crucial effect on the observed antimitotic activities. Specifically, 270 displayed the strongest inhibitory activity in a microtubule assembly assay compared to other known bicyclic peptides and their derivatives. In their original “right-to-left” route toward the synthesis of the bicyclic peptide,254 Castle and co-workers planned on using a previously developed strategy for synthesis of the right-hand ring of 270 via an indole−imidazole oxidative coupling/ macrolactonization.255,256 The method afforded indole−imidazole-linked tetrapeptide 274 via oxidative coupling of 271 with AF

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Scheme 62. Synthesis of Tetrapeptide 274 via Oxidative Coupling of Dipeptides 271 and 273

Scheme 63. Synthesis of Octapeptide 278 via Oxidative Coupling of 275 and 273 with Pro-OBn 276 Acting as a Chlorine Scavenger

Figure 21. Cytotoxic natural product FR182877 isolated from Streptomyces culture broth by Sato et al. in 2000172 and retrosynthetic strategy envisioned by Sorensen and co-workers.258

(Scheme 63). Spectroscopic analysis suggested that an inactive dichlorinated species was being formed and 276 was essential for preventing deactivation. Subsequent studies suggested that 276 reacts directly with NCS to form an N-chloroamine that in the presence of base collapses to an imine upon elimination of HCl. This process moderates the concentration of NCS and favors the chloroindolenine over the inactive dichlorinated species. As such, Castle and co-workers discovered the synthetically useful role of proline esters to scavenge and sequester electrophilic chlorine. Although this methodology has not yet been generally explored, this discovery highlights the potential of proline ester

dipeptide 273 in 92% yield. The reaction proceeds by formation of a highly reactive chloroindoline 272, which upon treatment with the dipeptide coupling partner results in tetrapeptide 274 (Scheme 62). Unable to access celogentin C (270) with their original route, Castle and co-workers developed a new “left-to-right” strategy that incorporated this oxidative coupling. When hexapeptide 275 was exposed to the same reaction with Nchlorosuccinimide (NCS) and 1,4-dimethylpiperazine, no reaction with dipeptide 273 was observed. Interestingly, when a sample of 275 that was contaminated with Pro-OBn (276) was exposed to the reaction conditions, the desired octapeptide 278 was produced, suggesting that 276 was crucial for reactivity AG

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Scheme 64. Evaluation of the Allenolate Cyclization Strategy on a Model System as an Alternative to the Knoevenagel Condensation

Scheme 65. Application of Sorensen’s Method for Constructing Alkylidine Dicarbonyls toward Synthesis of 281

single product in 90% yield, which turned out to be αalkylidene β-keto-δ-lactone, albeit of unexpected geometry. When the isomeric α-bromoenoate 285 was converted under otherwise identical reaction conditions, the same product 284 was again isolated in almost quantitative yield. The fact that this reaction was found to be stereoselective but not stereospecific prompted Sorensen and co-workers to postulate a transitory allenolate ion that subsequently attacks the Weinreb amide to yield a single product 284. The fact that both isomers 283 and 285 yield the same product, 284, was considered evidence for a stereoablative260 allenolate ion intermediate. Sorensen and co-workers further developed this methodology to apply it toward the synthesis of FR182877 (281). In the course of these studies, intermediate 286, which was synthesized via a Horner−Wadsworth−Emmons reaction, was subjected to identical reaction conditions to generate the desired allenolate ion intermediate 287, which was subsequently confirmed by X-ray crystallography (Scheme 65). Unfortunately, the allenolate intermediate 287 cyclized to form the undesired product 289, which represents the geometrical isomer of the desired product 288. Although this intermediate could not be utilized toward the synthesis of FR182877 (281), this reaction represents a novel reductive ring forming methodology as a stereocontrolled alternative to the traditional Knoevenagel condensation.

derivatives to function as general electrophilic chlorine scavengers in oxidative coupling reactions. 4.3. FR182877: Intramolecular Allenolate Acylations

In 2000, Sato et al.257 reported the isolation of the natural product FR182877 (281) from the culture broth of a strain of Streptomyces obtained from a soil sample in Tokushima Prefecture, Japan. FR182877 (281) showed potent antitumor properties against several cancer cell lines in vitro. Moreover, it exhibited cytotoxicity comparable to that of paclitaxel (Taxol), a drug for the treatment of ovarian and breast cancers.258 Upon retrosynthetic analysis of 281, Sorensen and coworkers258 proposed that the hexacyclic core could be constructed in a trans-annular hetero Diels−Alder reaction from an intermediate such as 282 (Figure 21). Because of structural similarities between this macrocyclic intermediate 282 and other cytotoxic natural products, Sorensen and coworkers hypothesized that several natural products, such as macquarimicin A and cochleamycin A, might be linked biogenetically via this type of transannular cyclization reaction.258 To test this biogenic proposal, they sought to synthesize intermediate 282 and subsequently subject it to transannular hetero Diels−Alder conditions for construction of the core of FR182877. However, a Knoevenagel condensation required for the construction of fragment 282 proved futile for the synthesis of their desired alkylidine dicarbonyl. In the search for an alternative method, a novel allenoate acylation reaction was discovered, which enables the synthesis of geometrically defined alkylidene dicarbonyl derivatives (Scheme 64).259 Upon treatment of 283 with tBuLi at −78 °C in THF, Sorensen and co-workers were able to isolate a

4.4. Zoanthenol: Discovery of a Cyclization−Decarbonylation Cascade Reaction

As part of an initiative to study new biologically active compounds, samples of the zoanthid Zoanthus sp. were obtained from an intertidal zone at the Canary Islands in AH

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1996.261,262 Along with several previously known compounds, five new alkaloids were isolated from the zoanthid extract and identified by Norte and co-workers in 1999261 (Figure 22). One

Scheme 66. Proposed Mechanism for the Novel Decarbonylation Reaction of 293 into the TetrahydrofuranContaining Product 295a

Figure 22. Structures of the alkaloids zoanthenol (290), zoanthamine (291), and norzoanthamine (292) isolated from the zoanthid Zoanthus sp.

of these alkaloids, zoanthenol (290), differed from all previously isolated zoanthamine alkaloids, such as zoanthamine (291) and norzoanthamine (292), by the presence of an aromatic ring rather than a cyclohexene moiety. In 2003, these molecules were evaluated for their antiplatelet activities, and zoanthenol showed selective inhibition of platelet aggregation induced by collagen.263 During their synthesis of the zoanthenol core, Stoltz and coworkers264 treated intermediate 293 with trifluoroacetic acid (TFA), followed by tetrabutylammonium fluoride (TBAF), with the intention of performing a sequence of cascade reactions, including phenol desilylation, acetal deprotection, acetonide elimination, 6-endo cyclization, and lactonization reactions all in one pot, to result in the formation of lactone 294. However, only the tetrahydrofuran-containing molecule 295 was isolated, resulting from an unexpected decarbonylation during the course of this reaction (Scheme 66). Stoltz and coworkers264 proposed that this acid-catalyzed decarbonylation reaction proceeds through either acylium intermediate 296 or the mixed anhydride intermediate 297, both resulting in the loss of CO to form ether product 295 rather than dehydration to yield the desired lactone 294. Although the synthetic intermediate 295 was not utilized for the total synthesis of zoanthenol, a new methodology for forming five-membered ethers was discovered serendipitously while working toward the synthesis of this natural product. The generality of this cyclization−decarbonylation cascade reaction has not yet been explored; however, it has the potential to find widespread use as a novel synthetic method to directly form cyclic ethers from carboxylic acid substrates.

a

Discovered by Stoltz and co-workers264 while working toward the synthesis of zoanthenol (290).

Figure 23. Hexachlorosulfolipid (298) and the nominal undecachlorosulfolipid A (299), illustrating the structural complexity of molecules from the chlorosulfolipid family.

formation of the 4,5-syn-allylic chloride 301 upon treatment with trimethylsilyl chloride (TMSCl) in ethyl acetate (Scheme 67).266 The major product isolated in the course of this transformation was initially assumed to represent the desired 4,5-syn relative configuration, and it was not until completion of the synthesis of hexachlorosulfolipid 298 and comparison to the spectral data obtained from natural samples that a significant mismatch was revealed. Subsequent detailed investigations proved that the C4 and C5 centers in 302 indeed possessed the anti configuration and not the expected syn arrangement, which requires the preceding epoxide opening to occur with retention rather than inversion of configuration. On the basis of these outcomes, it was proposed that anchimeric assistance of one of the chlorides at the C2 and C3 position via chloronium ions 303 or 304, respectively, could explain this unexpected result (Scheme 67) with the fivemembered chloronium ion resulting in the formation of the

4.5. Chlorosulfolipids: Chloronium Ions as Intermediates in Epoxide Opening Reactions

Chlorosulfolipids represent a class of marine toxins that consist of polychlorinated acyclic carbon chains with O-sulfate esters and were first isolated in 1968 from Ochromonas danica by Elovson and Vagelos265 (Figure 23). Since their discovery, assignment of the stereochemistry of the chlorosulfolipids proved to be a significant challenge, and total synthesis was an effective way to confirm the relative and absolute stereochemistry. In 2009, Carreira and co-workers266,267 reported the first total synthesis of a member of this class, racemic hexachlorosulfolipid (298). The strategy initially envisioned by Carreira and co-workers for the synthesis of chlorosulfolipid 298 relied on epoxide 300, which was expected to result in the AI

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Scheme 67. Anchimeric Participation of an Alkyl Halide Moiety Resulting in a Five-Membered Chloronium Ion

Treatment of allylic epoxide 305 with TiCl4 and LiCl resulted in the formation of chlorohydrins 306 and 307 via intermediate 308 and showed significant preference for attack at C3 (Scheme 68).268 In comparison, conversion of allylic epoxide 309 with ZrCl4 yielded a mixture of two isomeric chlorohydrins, 310 and 311 (ratio 1.3:1). This reaction proceeded with concomitant inversion at C4, presumably via anchimeric assistance by the chloride at this carbon atom during the opening of the trans-substituted chloronium ion 312.268 The initial serendipitous discovery of anchimeric assistance in the epoxide-opening reaction enabled synthetic access to all four diastereomeric 4,5-dichloro-2,3-epoxyhexanediols from ethyl sorbate (Scheme 69).

major product 302. In subsequent studies, Nilewski and Carreira268 prepared a collection of trichlorohexanediols bearing stereochemical permutations at the 1,2,3- and 1,2,4positions based on reported conditions as well as the serendipitously discovered anchimeric assistance in epoxide openings using ZrCl4 (Scheme 68), which enabled correlation of the specific NMR spectral data with data obtained by X-ray crystallographic analysis. Scheme 68. (A) Expected Nucleophilic Epoxide Opening with Chloride Anion Favoring 306.268 (B) Inversion at C4 during Epoxide Opening with ZrCl4 Is Hypothesized to Proceed via Trans-Substituted Chloronium Ion 312.268

4.6. Norhalichondrin A: Highly Stereoselective Reductions of Planar Oxocarbenium Ions

Norhalichondrin A (313, Figure 24) and other halichondrins were first isolated in 1985 by Uemura et al.269 from Halichondria okadai, a marine sponge commonly found off the coast of Japan. Halichondrins are an exciting class of molecules that have been shown to have remarkable antitumor properties. Norhalichondrin A shares this bioactivity, and it is also a key structural component in many of the known halichondrins. Due to its potent antitumor properties as well as its complex structure (Figure 24), norhalichondrin A (313) and its diastereomer, norhalichondrin B, presented a daunting task for synthetic chemists. The first total synthesis of norhalichondrin B was completed by Kishi and co-workers in 1992270 and utilized a Nozaki− Hiyama−Kishi coupling procedure previously discovered during the synthesis of palytoxin (10). While working toward the synthesis of the C27−C38 fragment of norhalichondrin A (313), Phillips and co-workers271 synthesized the pyranone hemiacetal 314 (Scheme 70) by performing an Achmatowicz oxidation of 314 in the presence of VO(acac)2. The crude hemiacetal 315 was directly subjected to Kishi reduction conditions to selectively generate the target 2,6-syn-pyranone 316 with over 20:1 diastereoselectivity.272 This high diastereoselectivity was unexpected, as 315 does not have any apparent directing groups to allow for anchimeric assistance.272 This striking result prompted Phillips and co-workers to conduct computational investigations in collaboration with the Houk group.272 Evidence suggested that the Kishi reaction of 315 proceeds through an oxocarbenium intermediate 317 that is generated upon the loss of water when 315 is subjected to acidic conditions. Transition-state analysis was performed by utilizing density functional theory, B3LYP with the 6-31G(d) basis set, and the initial results obtained from these studies suggested oxocarbenium intermediate 317 to be almost AJ

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Scheme 69. Four Different Trichloride Fragments of Chlorosulfolipids Can Be Accessed from Two Epoxides as a Result of Significant Anchimeric Assistance in Epoxide Opening

5. CONCLUSION Over the past 150 years, the primary focus of the field of natural product synthesis has changed dramatically. What started out as the classical approach to structure determination of complex molecules found a new justification in the 1950s, when the actual total synthesis of naturally derived compounds from readily available starting materials became the prime motivation. The golden era of natural product synthesis began when organic chemists were able to invent and explore new transformations to access complex structures without the limitations and restrictions that structural degradation had previously imposed upon them. The main question at the time was whether it would be possible to devise a viable synthetic strategy to any complex target structure previously isolated from natural sources. Additional justification for the fortified research efforts were the “surprises encountered on the journey”,26 as the inherent reactivity of many complex structures often led to the discovery of new transformations and fundamental new insights. The question whether it would be possible to synthesize “any molecule that nature makes”26 was answered for many in the mid-1990s with completion of the synthesis of palytoxin (10), a molecule that had been described as the “Mount Everest of organic synthesis”26 and “the largest molecule that anyone has ever even thought about making.”26 After this milestone was achieved, some were convinced that natural product synthesis had served its purpose and had entered a “period of [...] greatest uncertainty.”26 Many scientists agreed that the discovery of novel unexpected transformationsa former key validation for natural product synthesiswould become rarer as the field progressed. In fact, the discovery of novel synthetic methods and the total synthesis

Figure 24. Norhalichondrin A, isolated from Halichondria okadai.

completely planar. However, the calculations showed that the molecule loses its planarity and becomes staggered in the transition state during the actual hydride attack (Scheme 70). The syn attack by the hydride is disfavored (318) due to the transition state being destabilized by 1,3-diaxial strain between the hydride and the allyl side chain. In the case of anti attack on 317 (319 in Scheme 70), the allyl side chain is placed in an equatorial position that avoids unfavorable steric interactions. This unforeseen discovery represents the first example of a diastereoselective reduction of an oxocarbenium ion intermediate without anchimeric assistance. Although the scope of this method has not yet been explored, it proves that high levels of diastereoselectivity can be achieved in reductions of oxocarbenium ions without the presence of a directing group.

Scheme 70. Diastereoselective Synthesis of 316 Resulting from Favored Anti Attack of Oxacarbenium Intermediate

AK

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Author Contributions

of natural products were no longer considered concurrent endeavors but two distinct fields of research. A common opinion voiced in the post-palytoxin era was that “[o]rganic chemists can work on discovering fundamental principles of organic chemistry, or they can make something, such as a natural product.”15 In response to this divide, synthetic chemists have altered their focus. In fact, the new challenge in this era of total synthesis is particularly ambitious. The question is “increasingly not whether a molecule can be made, but whether it can be made in a practical fashion, in sufficient quantities for the needs of research and society, and in a way that is environmentally friendly if not ideal.”48 In other words, particular focus is placed on the synthetic strategy itself. The new challenge in complex molecule synthesis that strives for the “ideal” and elegant synthetic strategy does undoubtedly require novel creative solutions that once again have the potential to engender the discovery of novel reactions, reagents, and previously unprecedented reactivity. This review follows up on the question whether the discovery of novel synthetic transformations and the synthesis of complex molecules have indeed become mutually exclusive fields of research today. The examples presented throughout this review most definitely represent only the “tip of the iceberg” of novel discoveries made during the course of natural product syntheses within recent years. As a matter of fact, many discoveries and surprises encountered in the course of natural product syntheses, which ultimately lead to the development of novel synthetic transformations, are usually not specifically identified as such in scientific communications. However, the examples that are reported demonstrate the continuing importance of the field of natural product synthesis for the development of novel synthetic methodologies. In fact, the discovery of new principles and novel reactivities and the synthesis of natural products are not mutually exclusive practices but can in fact go hand-in-hand. The examples discussed in this review show that valuable serendipitous discoveries have been made not only regardless of the size and complexity of the initial target structure but also independent of the novelty of the natural product. It has previously been postulated that “relying on safe, well-established reactions ... makes fewer fundamental discoveries along the way.”26 However, amidst the highly functionalized intermediates of a natural product synthesis, it often remains unclear what exactly is a “safe” reaction to apply. There is no question that the field of complex molecule synthesis is ambitiously challenging and continuously improving itself. However, it is doubtful that the development of synthetic strategies toward natural products in this new era will proceed without any surprises and discoveries made along the way, which are of course impossible to predict but will most certainly not be made otherwise. The examples presented above suggest that Albert Eschenmoser’s assertion that natural product synthesis holds the “potential for stimulation and discovery for the whole of organic chemistry”1 still rings true in this particularly ambitious era of natural product synthesis.

The manuscript was written through equal contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest. Biography

Ahlam M. Armaly (center in photo) received her B.S. in chemistry in 2013 from Furman University in Greenville, SC. During her time at Furman, she worked under the guidance of Professor Brian C. Goess on the synthesis and elucidation of biological activity of several members of the furanosteroid family of natural products and their derivatives. She is currently pursuing her Ph.D. in chemistry at the University of Michigan under the guidance of Professor Corinna S. Schindler with the support of a National Science Foundation graduate research fellowship. Her research interests include total synthesis of natural products and methods development. Yvonne C. DePorre (second from right in photo) earned her B.S. in chemistry from Michigan State University in East Lansing, MI, in 2013, followed by a summer internship at Dow Agrosciences in Indianapolis, IN. In Dr. Kevin Walker’s lab, she studied the mechanism of TcPAM enzyme-catalyzed intermolecular transamination reactions and also participated in the Plant Genomics REU at Michigan State University during the summer of 2011. In Dr. Aaron Odom’s lab, she synthesized novel chromium(VI) nitrido complexes with selenium and tellurium ligands for measurement of ligand donor parameters. During the summer of 2012, she participated in the Lando-NSF REU program at the University of MinnesotaTwin Cities in the lab of Dr. William Tolman, synthesizing aluminum−salen catalysts with differing electronic substituents for cyclic ester polymerization mechanistic studies. Currently, she is a Ph.D. candidate at the University of Michigan under the guidance of Dr. Corinna Schindler. Her research interests include total synthesis of natural products and mechanistic studies. Emilia J. Groso (far right in photo) earned her B.S. in professional chemistry from the University of Nevada, Reno in 2013. In 2010 she started in Professor Jason Shearer’s lab and focused on synthesizing human prion proteins in order to understand how the proteins behave during metal coordination. In 2011 she joined Professor Robert S. Sheridan’s research group and completed a thesis on the elaboration of pyridyl-based diazirines and their corresponding carbenes in order to explore their electronic properties. She is currently pursuing her Ph.D. in organic chemistry at the University of Michigan in Professor

AUTHOR INFORMATION Corresponding Author

*E-mail [email protected] AL

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(13) Woodward, R. B.; Brehm, W. J. The Structure of Strychnine. Formulation of the Neo Bases. J. Am. Chem. Soc. 1948, 70, 2107− 2115. (14) Robertson, J. H.; Beevers, C. A. The Crystal Structure of Strychnine Hydrogen Bromide. Acta Crystallogr. 1951, 4, 270−275. (15) Bokhoven, C.; Schoone, J. C.; Bijvoet, J. M. The Fourier Synthesis of the Crystal Structure of Strychnine Sulfate Pentahydrate. Acta Crystallogr. 1951, 4, 275−280. (16) Peerdeman, A. F. The Absolute Configuration of Natural Strychnine. Acta Crystallogr. 1956, 9, 824. (17) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Dafniker, H. U.; Schenker, K. The Total Synthesis of Strychnine. Tetrahedron 1963, 19, 247−288. (18) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. The Total Synthesis of Strychnine. J. Am. Chem. Soc. 1954, 76, 4749−4751. (19) Woodward, R. B. Harvey Lect. 1963, 59, 31−47. (20) Pelletier, P. J.; Caventou, J. B. Examen chimique de plusieurs végétaux de la famille des colchicées, et du principe actif qu’ils renferment. Ann. Chim. Phys. 1820, 14, 69−81. (21) Dewar, M. J. S. Structure of Colchicine. Nature 1945, 141−142. (22) Schreiber, J.; Leimgruber, W.; Pesaro, M.; Schudel, P.; Eschenmoser, A. Synthese des Colchicins. Angew. Chem. 1959, 71, 637−640. (23) Van Tamelen, E. E.; Spencer, T. A., Jr.; Allen, D. S., Jr.; Orvis, R. L. The Total Synthesis of Colchicine. J. Am. Chem. Soc. 1959, 81, 6341. (24) Sunagawa, G.; Nakamura, T.; Nakazawa, J. Studies on the Total Synthesis of dl-Colchiceine. II. Synthesis of dl-Demethoxydeoxyhexahydrocolchiceine. Chem. Pharm. Bull. 1962, 10, 291−299. (25) Overman, L. E. Molecular Rearrangements in the Construction of Complex Molecules. Tetrahedron 2009, 65, 6432−6446. (26) Service, R. F. Race for Molecular Summits. Science 1999, 285, 184−187. (27) Woodward, R. B. Recent advances in the chemistry of natural products. Pure Appl. Chem. 1968, 17, 519−547. (28) Woodward, R. B. Recent advances in the chemistry of natural products. Pure Appl. Chem. 1971, 25, 283−304. (29) Woodward, R. B. The total synthesis of vitamin B12. Pure Appl. Chem. 1973, 33, 145−178. (30) Eschenmoser, A. Studies on the synthesis of corrins. Pure Appl. Chem. 1963, 7, 297−316. (31) Eschenmoser, A. Organische Naturstoffsynthese heute. Vitamin B12 als Beispiel. Naturwissenschaften 1974, 61, 513−525. (32) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry. Angew. Chem., Int. Ed. Engl. 1969, 8, 781−853. (33) Armstrong, R. W.; Beau, J.-M.; Cheon, S. H.; Christ, W. J.; Fujioka, H.; Ham, W.-H.; Hawkins, L. D.; Jin, H.; Kang, S. H.; Kishi, Y.; Martinelli, M. J.; McWhorter, W. W., Jr.; Mizuno, M.; Nakata, M.; Stutz, A. E.; Talamas, F. X.; Taniguchi, M.; Tino, J. A.; Ueda, K.; Uenishi, J.; White, J. B.; Yonaga, M. Total Synthesis of Palytoxin Carboxylic Acid and Palytoxin Amide. J. Am. Chem. Soc. 1989, 111, 7530−7533. (34) Suh, E. M.; Kishi, Y. Synthesis of Palytoxin from Palytoxin Carboxylic Acid. J. Am. Chem. Soc. 1994, 116, 11205−11206. (35) Moore, R. E.; Scheuer, P. J. Palytoxin: A New Marine Toxin from a Coelenterate. Science 1971, 172, 495−498. (36) Uemura, D.; Ueda, K.; Hirata, Y.; Naoki, H.; Iwashita, T. Further Studies on Palytoxin. II. Structure of Palytoxin. Tetrahedron Lett. 1981, 22, 2781−2784. (37) Moore, R. E.; Bartolini, G. Structure of Palytoxin. J. Am. Chem. Soc. 1981, 103, 2491−2494. (38) Cha, J. K.; Christ, W. J.; Finan, J. M.; Fujioka, H.; Kishi, Y.; Klein, L. L.; Ko, S. S.; Leder, J.; McWhorter, W. W., Jr.; Pfaff, K.-P.; Yonaga, M.; Uemura, D.; Hirata, Y. Stereochemistry of Palytoxin. Part 4. Complete Structure. J. Am. Chem. Soc. 1982, 104, 7369−7371. (39) Wu, C. H. Palytoxin: Membrane Mechanisms of Action. Toxicon 2009, 54, 1183−1189. (40) Crawford, M. H. Harvard Synthesizes Palytoxin Molecule. Science 1989, 246, 34.

Corinna S. Schindler’s research group with the support of a National Science Foundation graduate student research fellowship. Her research is focused on catalyst design and methods development. Paul S. Riehl (second from left in photo) received his B.Sc. degree in chemistry from the University of Virginia in 2013. His research under Professor James P. Landers was focused on the design and fabrication of microfluidic devices for more efficient and cost-effective biochemical analyses. His projects included the development of new burst valve technology for polymer-based microdevices and design of a microfluidic device for DNA amplification by polymerase chain reaction (PCR). He is currently pursuing his Ph.D. in organic synthesis under Professor Corinna Schindler at the University of Michigan. His current research interests are focused on total synthesis of biologically active diterpene natural products and development of new [2 + 2] cycloaddition methods. Corinna S. Schindler (far left in photo) has been an assistant professor at the University of Michigan since the summer of 2013. She obtained her diploma in chemistry from the Technical University of Munich, Germany, after working with Professor K. C. Nicolaou at the Scripps Research Institute. She then joined the group of Professor Erick M. Carreira at ETH Zurich, Switzerland, for her Ph.D. studies and the group of Professor Eric N. Jacobsen for her postdoctoral research. Her independent work focuses on the development of novel synthetic methodologies for the synthesis of biologically active target structures, often derived from natural products.

ACKNOWLEDGMENTS A.M.A and E.J.G. thank the National Science Foundation for graduate research fellowships. C.S.S. is the William R. Roush assistant professor at the University of Michigan. REFERENCES (1) Eschenmoser, A.; Wintner, C. E. Natural Product Synthesis and Vitamin B12. Science 1977, 196, 1410−1420. (2) Pelletier, P. J.; Caventou, J. B. Note sur un nouvel Alcali. Ann. Chim. Phys. 1818, 8, 323. (3) Pelletier, P. J.; Caventou, J. B. Sur un nouvel Alcali végétal (la Strychnine) trouve dans la fève de Saint-Ignace, la noix vomique, etc. Ann. Chim. Phys. 1819, 10, 142. (4) Prelog, V.; Szpilfogel, S. Strychnos-Alkaloide. (2. Mitteilung). Abbauversuche im ringe E des Strychnins. Helv. Chim. Acta 1945, 28, 1669−1677. (5) Prelog, V.; Kocór, M. Strychnos-Alkaloide. (4. Mitteilung). Ü ber die Lage der Oxy-Gruppe in Pseudostrychnin. Helv. Chim. Acta 1947, 30, 359−366. (6) Prelog, V.; Kocór, M. Strychnos-Alkaloide. 6. Mitteilung. Abbau des Strychnis zu einer Amino-dicarbonsäure C13H18O5N2. Helv. Chim. Acta 1948, 31, 237−241. (7) Briggs, L. H.; Openshaw, T. H.; Robinson, R. Strychnine and brucine. Part XLII. Constitution of the neo-series of bases and their oxidation products. J. Chem. Soc. 1946, 903−908. (8) Robinson, R. The Constitution of Strychnine. Experientia 1946, 2, 28−29. (9) Anet, F. A. L.; Robinson, R. Conversion of the Wieland-Gumlich aldehyde into strychnine. Chem. Ind. 1953, 245. (10) Anet, F. A. L.; Robinson, R. Alkaloids of Australian Strychnos species. Part II. The constitution of strychnospermine and spermostrychnine. J. Chem. Soc. 1955, 2253−2262. (11) Leuchs, H. Ü ber Strychnon und Pseudo-strychnon als Nebenproduckte der Darstellung des Pseudo-strychnins und über weitere Versuche in dessen Reihe. (Teilweise mit Fritz Räck.) (über Strychnos-Alkaloide, 110. Mitteil.). Chem. Ber. 1940, 73, 731−739. (12) Woodward, R. B.; Brehm, W. J.; Nelson, A. L. The Structure of Strychnine. J. Am. Chem. Soc. 1947, 69, 2250. AM

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DOI: 10.1021/acs.chemrev.5b00034 Chem. Rev. XXXX, XXX, XXX−XXX

Discovery of Novel Synthetic Methodologies and Reagents during Natural Product Synthesis in the Post-Palytoxin Era.

Discovery of Novel Synthetic Methodologies and Reagents during Natural Product Synthesis in the Post-Palytoxin Era. - PDF Download Free
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