SYNFORM ISSUE 2020/10

Phytoalexins have attracted much attention due to their health-promoting effects and their vital role in plant health during the last years. Especially the 6a-hydroxypterocarpans glyceollin I and glyceollin II, which may be isolated from stressed soy plants, possess a broad spectrum of bioactivities such as anticancer activity and beneficial contributions against western diseases by anti-oxidative and anti-cholesterolemic effects. Aiming for a catalytic asymmetric access to these natural products, we establish the asymmetric syntheses of the natural isoflavonoids (−)-variabilin, (−)-homopterocarpin, (−)-medicarpin, (−)-3,9-dihydroxypterocarpan, and (−)-vestitol by means of an asymmetric transfer hydrogenation (ATH) reaction. We successfully adapt this pathway to the first catalytic asymmetric total synthesis of (−)-glyceollin I and (−)-glyceollin II. This eight-step synthesis features an efficient one-pot transformation of a 2′-hydroxyl-substituted isoflavone to a virtually enantiopure pterocarpan by means of an ATH and a regioselective benzylic oxidation under aerobic conditions to afford the susceptible 6a-hydroxypterocarpan skeleton. Concise total syntheses of 6a-hydroxypterocarpans are sought after due to their broad spectrum of bioactivities. Here, the authors report the asymmetric syntheses of several natural isoflavonoids, including (−)-glyceollin I and (−)-glyceollin II, by means of an asymmetric transfer hydrogenation (ATH) reaction.

Sulfones are well-known chemical chameleons, namely building blocks that can behave as either nucleophiles or electrophiles depending on how they are activated and reacted. For example, a sulfone can stabilize an adjacent carbanion or alternatively can be displaced by a carbon nucleophile, upon suitable activation. For this reason, some sulfones can be considered as 1,1-dipole synthons. This peculiar reactivity of sulfones continues to attract the interest of organic chemists and represents an invaluable source of new reactions. The story of this SYNTHESIS paper started with a discovery by Professor Kojima's and Professor Matsunaga's group at Hokkaido University (Japan) in 2018: at that time, they were studying the dual cobalt-photoredox catalysis for allylic alkylation. "The system can be considered as a new type of metallaphotoredox catal ysis 1 and worked very well for branch-selective substitutions of allyl carbonates and allyl carboxylates," said Professor Kojima. He continued: "However, we were moti vated to identify a unique feature of cobalt catalysis compared to the estab lished rhodium or iridium catalysis." Gratifyingly, Professor Kojima discovered that the cobalt-photoredox sy stem was uniquely effective for substitution of allyl sulfones, which proceeded via challenging C-S bond cleavage and was not feas ible using the known noble-metal-based catalysis (Scheme 1). 2 Professor Kojima said: "Koji Takizawa and I also discovered that the 4-chlorophenylsulfonyl leaving group facilitated the allylic substitution, presumably due to greater leaving-group ability of 4-chlorophenylsulfinate compared to phenyl sulfinate." In 1990, Trost and Merlic proposed the potential of allyl sulfone as an ambiphilic 1,1-synthon. 3 "Its application in multistep synthesis remained a challenge, however, partly because the regioselectivity in the molybdenum-catalyzed substitution of allyl sulfones remained modest," remarked Professor Kojima. He continued: "We envisioned that sequential base-mediated α-alkylation and cobalt-photoredox-catalyzed allylic substitution might provide a solution to this problem." Graduate student Tomoyuki Sekino took over the study and explored the potential of allyl 4-chlorophenyl sulfone as a 1,1-synthon (Scheme 2). Professor Kojima said: "An unexpected problem came up in base-mediated α-alkylation. Initial trials using butyllithium and an alkyl iodide, followed by acidic workup using aqueous NH 4 Cl, afforded an inseparable mixture of allyl sulfone and vinyl sulfone." This "isomeriza tion problem" was solved by Professor Tatsuhiko Yoshino's and Professor Shigeki Matsunaga's suggestion that quenching the reaction under milder protonation conditions might circumvent the undesired isomerization. Professor Kojima said: "Following their advice, Tomoyuki identified the optimal workup method (addition of 1 M AcOH in THF at -78 °C) which finally enabled the practical use of the allyl 4-chlorophenylsulfone as a 1,1-synthon."

SYNTHESIS Highlight Synform A141
With support from undergraduate students Shunta Sato and Kazuki Kuwabara, Tomoyuki Sekino revealed the broad scope of the sequential α-alkylation/cobalt-catalyzed allylic substitution of allyl sulfones (Scheme 2). "In general, group 9 metal catalysis (rhodium 4 or iridium 5 ) affords branched products in high regioselectivity in allylic substitution," explained Professor Kojima. He continued: "Cobalt catalysis was no exception, and the photoredox-enabled cobalt catalysis allowed access to synthetically valuable branched products in >20:1 regioselectivity in most cases. Notably, functional groups including ester and Weinreb amide were tolerated under the two-step transformations. We anticipate that such functional group compatibility will be beneficial for future applications in the synthesis of complex molecules." "Compared to rhodium-or iridium-catalyzed methods, the study of cobalt-catalyzed allylic substitution has just begun 6 ," said Professor Kojima. He concluded: "Furthermore, the merger of photoredox and cobalt catalysis 7 is also a new and untapped research area compared to nickel-photoredox 8 or copper-photoredox 9 systems. With these two promising directions in sight, we would like to unlock more potential and demonstrate the unique utility of photoredox-enabled cobalt catalysis for organic synthesis."

K. Takizawa
Solid-phase peptide synthesis (SPPS) -pioneered by the 1984 Nobel Prize winner Robert Bruce Merrifield -is the method of choice for the preparation of polypeptides. This highly versatile technology is used worldwide for the manual as well as automated synthesis of a wide range of peptides. Despite its success, direct monitoring of reactions on resin is not as straightforward as for reactions in solution where samples can be easily collected and directly analysed through a variety of analytical and spectroscopic methods, such TLC, HPLC and NMR. The Kaiser test -based on the reaction between primary amino groups and ninhydrin which develops an intense blue color -is destructive and can easily lead to false positives (for example when Fmoc protecting groups are la bile to the pyridine contained in the test cocktail) or negatives (secondary amines such as proline give rise to a rather ambiguous redbrownish color). Besides, the Kaiser test is time consuming and the test cocktail contains highly toxic reagents such as KCN.
The group of Professor Hiroyuki Konno at Yamagata University (Japan) recently reported a new test protocol to detect Nterminal amino groups during FmocSPPS using a revers ible and non-destructive reaction. Professor Konno explained: "This is a novel approach attempted for the first time by our research group, since for a hundred years ninhydrin has been used as a detecting reagent for primary amino groups. The Kaiser test with ninhydrin results in blue staining and is defin itely useful, but it sacrifices the small amount of resin used for the test and cannot detect most secondary and tertiary amino groups." He continued: "Interestingly, our methodology can detect most primary, secondary and tertiary amino groups, using a reversible process and coloration. Therefore, we do not need to lose any resin."

Literature Coverage Synform A145
The group tested all 20 proteogenic amino acids, some Nmethyl amino acids, and Aib to ensure that all of them could be detected by their new approach. Professor Konno remarked: "Fortunately, no byproducts have ever been shown in HPLC analysis." The new protocol for staining free amino groups and protected amino groups is shown in Figure 1. "This is a unique method that makes it very easy to check the presence of amino groups," explained Professor Konno. He continued: "In addition, only cheap reagents and no expensive analytical equipment are required. As I saw the red crystal of the complex with Nhydroxyphthalimide and dimethylamine, I had a "Eureka moment" concerning this amino group staining. Since the red color disappears as the complex is dissociated, I immediately felt that this phenomenon was valuable." Professor Konno then paid tribute to Rio Suzuki, the sole coworker, who performed all the experiments and analyzed the data. Professor Konno remarked: "She is an outstanding student and the success of this research is due to her deep insight and sharp observant eye." Professor Konno concluded by speaking about potential or actual applications for their work, saying: "In the future, one of our most important aims is to reduce the stoichiometric proportions of reagents used by this system in peptide synthesis, not only to reduce costs but also the environmental impact of the protocol." Dr. C. Wang One of our ongoing research projects is to establish conceptually new and practically useful protocols that enable cleavage of inert C-O/C-N bonds in a selective and mild manner by means of transition-metal catalysis, photocatalysis, and/or other reaction patterns. We are also focusing on exploring novel and efficient reactions and reagents for synthetic transformations of group 14 elements that are of versatile applicability in organic synthesis and functional materials, as well as medicinal chemistry.

SYNFORM When did you get interested in synthesis?
Dr. C. Wang In the second semester of my first year at Peking University, we began to be taught organic chemistry. The textbook we used was named Basic Organic Chemistry (基礎有機化学), 2 nd Edition, edited by a group of professors led by Prof. Qi-Yi Xing (邢 其毅 教授: 1911-2002), a great Chinese chemist and educator. This textbook deeply impressed many generations of chemists in China, who give it a hearty nickname in Chinese: 邢大本 (Xing's Great Book). It is not only a friendly, accessible, and engaging primer to organic chemistry, but also a comprehensive and in-depth account that provides a panoramic view of organic chemistry. This book is fantastic to me. It is fertile soil where my interest in organic chemistry sprouted. It was also fortunate that I met several fantastic lecturers in the organic chemistry courses, Prof. Weiwei Pei and

SYNFORM What do you think about the modern role and prospects of organic synthesis?
Dr. C. Wang This is a big question. Just in view of my research areas, I think that synthetic chemistry has demonstrated great ability to create products of high value to provide an impressive range of useful and necessary substances and materials for human use. However, current chemical synthesis is highly dependent on the utilization of non-renewable fossil fuels and noble metals. Fossil fuels contain highly reduced molecules (with many C-H bonds), which must be oxidized during most chemical processes, leading to large emissions of CO 2 . In the future, we need to replace fossil-fuel-based traditional synthetic protocols with novel strategies based on biomass feedstocks, renewable resources and clean energy. We also need to utilize non-precious elements more efficiently, to break the dependence on expensive, rare noble metals. I believe that future innovations of synthetic chemistry will make great contributions to the transformation of our lifestyle to one with reduced natural and social costs and for achieving a sustainable society.

Young Career Focus Synform
the 'smallest catalyst'; 3) mild, rapid, and quantitative procedures for introducing functional elements such as Si, Ge, or Sn; and 4) clarification of complex reaction mechanisms as well as biosynthetic routes by means of computational chemistry (Scheme 1).
SYNFORM What is your most important scientific achieve ment to date and why?
Dr. C. Wang In 2015, we described our computational study on the mechanism of Ni-catalysed inert C-O bond cleavage reaction (Chem. Eur. J. 2015, 21, 13904-13908). As early as in 1979, Wenkert reported the first Ni-catalysed cross-coupling through etheric Ar-OR bond cleavage. This was very 'abnormal', because the OR group 'normally' acted as an electrondonating 'stand-by' in most reactions of arenes. This breakthrough was overlooked for decades, but now substantial experimental efforts have been made toward the development of improved conditions since 2004. Even so, the mechanism of this type of reaction remained unclear. By DFT calculations, we successfully established a reasonable reaction pathway involving the anionic Ni(0)-ate complex. This study not only explained the experimental facts well, but also provided a new type of reaction mechanism for cross-coupling, distinct from the conventional catalytic cycle of oxidative addition, transmetalation, and reductive elimination.
In the same year, we also reported a facile, rapid and quantitative protocol for the preparation of stannyl or germyl lithiums that facilitated diverse transformations (J. Am. Chem. Soc. 2015, 137, 10488-10491; Patent JP6452500; highlighted in Synform 2016, A38-A39). Most synthetic methods for stannyl or germyl lithium species (E-Li, E = Sn or Ge) have suffered from poor yield, low atom-efficiency, less stability, and generation of toxic by-products. By catalytic use of poly cyclic aromatic hydrocarbons (e.g. naphthalene, DBB) as simple and efficient accelerators of electron transfer, we have, for the first time, established a fast and quantitative preparative method of E-Li since the discovery of such reagents in the 1950s. This straightforward protocol can be achieved with 100% Snatom economy without formation of any (toxic) by-products, and E-Li obtained by this method is highly stable and can be stored for months at ambient temperature. Further, the E-Li reagent prepared by our method shows excellent reactivity in a variety of transformations with high tolerance of di verse functional groups, indicating a great potential for efficient preparation of Sn-or Ge-contained functional molecules.
More recently, we demonstrated a new method to generate silyl radicals (R 3 Si•) through visible-light-induced decarboxylation reaction of silyl carboxylic acids (R 3 SiCOOH) (Angew. Chem. Int. Ed. 2020, 59, 10639-10644). R 3 SiCOOH can be prepared in high yield by reaction of CO 2 with the corresponding R 3 Si-Li or R 3 Si-Na reagents. It was first synthesized in the 1950s, as a 'heavy' analogue of carboxylic acid. However, despite the easy accessibility and high stability, the reactivity and synthetic utility of R 3 SiCOOH have been largely ignored until now. We found that irradiation of R 3 SiCOOH with blue LEDs in the presence of a commercially available photocatalyst could release silyl radicals, which can further react with various alkenes to give the corresponding hydrosilylation products in good to high yields with broad functional group compatibility. Meanwhile, germyl radicals (R 3 Ge•) were similarly obtained from germyl carboxylic acids (R 3 GeCOOH).
While I believe that my most important achievements lie ahead of me, I am indeed delighted with the progress that we have made in these fields, overlooked so long.

Literature Coverage Synform
Phytoalexins are structurally diverse, low-molecular-weight secondary metabolites that are produced ex novo in appreciable amounts by plants following a pathogenic attack. These antimicrobials may be isolated from stressed soy plants and, owing to their interesting biological properties, have attracted the attention of many research groups in recent years. Some phytoalexins have shown capacity for selectively modulating the activity of the oestrogen receptor, which plays an important role in the growth of oestrogen-related cancers, e.g. mammary carcinoma or ovarian cancer. Furthermore, their anti-inflammatory and anti-cholesterolemic activity, as well as further health-promoting effects, are under investigation all over the world.
However, the isolation of the pure phytoalexins from natural sources is generally challenging. The development of a concise catalytic access to structurally defined phytoalexins, such as the enantiopure pterocarpans glyceollin I and glyceollin II, is an important entry to these compounds and was the driving force of the research described in a paper recently published by Professor Peter Metz and Dr. Philipp Ciesielski (Technische Universität Dresden, Germany). Professor Metz commented: "With our work we wanted to make these phytoalexins and further isoflavonoids more readily available, especially for detailed studies on their bioactivity." Professor Metz noted that a common pathway for the enantioselective construction of the 6a-hydroxypterocarpan skeleton of several phytoalexins is the Sharpless asymmetric dihydroxylation (SAD) of a suitable isoflav-3-ene. But as the SAD of isoflav-3-enes requires stoichiometric amounts of the toxic and expensive osmium tetroxide and of chiral ligand as well -as demonstrated in the first asymmetric synthesis of glyceollin I by the Erhardt group (University of Toledo, USA)a novel catalytic access was desirable (for references, see the original paper).
"Some years ago, we found that a ruthenium-catalysed asymmetric transfer hydrogenation (ATH) of racemic isoflavanones succeeds with a highly selective dynamic kinetic resolution to give the corresponding enantiomerically pure isoflavan-4-ols in yields exceeding 90%," said Professor Metz. He continued: "Now, for the first time, we were also able to use an isoflavone as a substrate for ruthenium-catalysed ATH. In this process a conjugate reduction to a racemic isoflavanone is car-ried out first, which is then reduced with dynamic kinetic resolution. Aiming for the pterocarpan skeleton, the ATH can be quenched with hydrochloric acid after dilution with ethanol to achieve a smooth cyclisation." Searching for suit able conditions for the regioselective installation of the benzylic hydroxyl group at C-6a, the authors found an adapted protocol from the group of Ishii (Kansai University, Japan), which was superior to the other methods tested. "Indeed, we believe we are the first to apply this aerobic oxidation to a complex molecule," explained Professor Metz. He concluded: "Using this biomimetic strategy, only eight steps were necessary to secure glyceollin I in good overall yield from the commercially available (2,4-dimethoxyphenyl)acetic acid. Furthermore, our approachillustrated in Scheme 1 -gave access to several other naturally occurring phytoalexins in an efficient manner and high enantiomeric purity."  Trost (1983Trost ( -1984; University of Wisconsin-Madison, USA), he returned to Münster and completed his Habilitation in 1991. Following temporary full professorships at the University of Hamburg (Germany, 1992(Germany, -1993, the University of Kiel (Germany, 1994) and the Technische Universität Dresden (Germany, 1996), he became a full professor at the TU Dresden (1997). His research inter est covers the total synthesis of biologically active natural products and their analogues, as well as the development of novel methods and strategies for stereoselective synthesis.

Synfact of the Month in category "Peptide Chemistry": Coupling of Amino Acids and α-Branched Aldehydes
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