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Studies on Efficient Strategies for Constructing Complex Organic Molecules
Prof. Keisuke Suzuki has studied organic synthesis, centering particular focus on the development of new strategies and tactics for the selective synthesis of complex natural products. Based on the deep insights into various organic reactions as well as the unique ideas to the logic of multi-step synthesis, various enabling methodologies have been developed and applied to the total syntheses.
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Prof. Keisuke Suzuki
Tokyo Institute of Technology
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1. Acyclic stereocontrol via stereospecific pinacol-type 1,2-rearrangement
Around 1980, it was a common belief that such an anionotropic 1,2-shift is not a suitable reaction for asymmetric synthesis of acyclic molecules, because of the seemingly inevitable racemization as demonstrated by Collins (1957). By choosing a suitable set of conditions, however, Suzuki showed that such class of reactions proceeds without any racemization or epimerization, providing a powerful means of acyclic stereocontrol. 1,2-Rearrangements of mesyloxy alcohol as well as epoxy alcohols are effectively promoted by hard Lewis acids with Al, B, Si, Ti metal centers. By exploiting vinylsilane as a stereo-controlling element, an enantio- and diastereo-controlled approach was developed to acyclic molecules with multiple stereogenic centers, which was applied to the synthesis of optically active pheromenes, antibiotics including the mycinamicin-class macrolide aglycons. The viable construction of quaternary stereogenic centers is worth noting, as demonstrated in the first asymmetric total synthesis of furaquinocin-class antitumor antibiotics. The 1,2-shift of heteroaromatics, like furan and indole, opened a novel entry to heterocyclic compounds with stereogenicity at adjacent positions.
2. Synthetic studies on glycoconjugates
Recognizing the significance of glycosylation in various natural products, he developed novel methods for O- and C-glycoside synthesis. Through the effort to the total synthesis of the mycinamicin-class macrolide antibiotics, remarkably high abilities of cationic zirconocene- or hafnocene species were disclosed as the strong activators of glycosyl fluoride, allowing rapid O-glycosylation of various alcohols with high steric hindrance and/or delicate functionalities. This finding not only allowed himself to complete the projected macrolide synthesis, but also has been extensively utilized for constructing large oligosaccharide synthesis, posing strong impact in the related fields of biological research.
Aryl C-glycoside antibiotics have been his synthetic targets, which a new class of natural products featured by a common structure: polyaromatic nucleus connected to a sugar through a C-C bond. For the key connection of a sugar to polycyclic aromatic cores, he devised a biogenesis-inspired reaction what he calls O¨C-glycoside rearrangement, constructing a C-glycoside structure at the ortho position to a phenol. This reaction has showed its potency for construction of ortho-Cglycoside structure, serving as the key steps toward the total synthesis of antitumor antibiotics, vineomycinone B2 and aquayamycin. Furthermore, a trick what he calls the gresorcinol trickh allowed the reaction to be applied to the selective construction of the para-C-glycosides, as featured by the first total synthesis of antitumor antibiotics, the gilvocarcins.
Through these studies, he recognized the challenges and opportunities presented by hybrid natural products, i.e., composites of two or more moieties of distinct biogenesis. Such hybridization offers, by definition, an enhancement in the molecular diversity. A good example is the polyketide-derived polycycles, which have already a high level of molecular diversity within itself, but the hybridization with other structure classes such as sugars and terpenoids generates a great array of attractive structures, presenting a rich source of pharmaceutical candidates. From the synthetic points of view, such hybridized molecular architectures pose various challenging problems, presenting good starting points to learn and devise new synthetic strategies and tactics. He centered attention to copuple the O- and C-glycosylation methods and the assembly of polycyclic structures so as to synthesize glycoconjugates or hybrid natural products in a more general sense.
3. Efficient construction of polyketide-derived polycyclic structures
Charmed by the structural beauties, his recent research has focused to the polycyclic compounds derived from the type-II polyketide biosynthesis, in particular the ones with partial aromatization. As potential approaches for assembling such densely functionalized polycycles and controlling multiple stereogenic centers, he developed several innovative synthetic transformations, including annulations and stereoselective cyclizations. For construction of the densely functionalized polycycles, he paid attention to two reactive intermediates, benzyne and nitrile oxide. As for the former species, alpha-haloaryl triflates were that undergo rapid, quantitative halogen?lithium exchange to allow generation of benzyne species at low temperature. The high to perfect regioselectivities of alpha-alkoxybenxynes in the [2+2]- (to ketene silyl acetals), [2+3]- (to nitrones) and [2+4]- (to alpha-alkoxyfuran) cycloadditions were discovered. Among others, the [2+2] cycloaddition opened a general route to various highly oxidized benzocyclobutene derivatives, which in turn serve as the starting materials for the [2+2+2] approach that is comprised of two consecutive pericyclic processes, en route to the phenylnaphthalene structural motif embedded in various natural products. As an enabling strategy to polycyclic structures, the SmI2-mediated pinacol cyclization served for total syntheses of the benanomicin?pradimicin antibiotics (anti-HIV) and TAN-1085 (anticancer).
More recently, a new approach to the polyketide-derived polycyclic assembly was developed, starting with the cyclocondensation of nitrile oxides and active methylene compounds followed by the enantioselective benzoin-forming reaction. The approach was applied to the total synthesis of cassialoin, a sugar?xanthone hybrid natural product.
4. Synthesis of intriguing natural/unnatural aromatic products
His research interests have recently expanded to the total synthesis of other class of natural products as well as to unnatural organic molecules. As for the natural product area, one of the current targets is the catechin / epicatechin-derived molecules that have been left aside during the long history in organic synthesis. The synthesis is often challenging, at the levels of both monomers and oligomers, mainly due to the labile nature of the molecules. Some effective approaches have been developed en route to this intriguing, potentially useful class of natural products. In particular, selective oligomer synthesis was realized by sugar-catechin analogy adopting various ideas of oligosaccharide synthesis to analyze the flavan reactivities.
Also the synthesis of structurally intriguing unnatural products has been carried out, including dicyclo- and tricyclobutabenzenes with long-standing curiosity in structural organic chemistry in view of the high molecular strain and bond alternation, which was realized by repeated use of [2+2]-cycloaddition of benzyne to ketene silyl acetals.
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