Total synthesis of (+)-davidiin

Quite strained: The total synthesis of (+)-davidiin, an ellagitannin with more substituents in axial than in equatorial positions, requires a conformational lock of the glucose, induced by steric repulsion between adjacent bulky silyloxy groups. This conformational lock played a pivotal role in 1)?the β-selective formation of the glycosyl ester at the anomeric position, 2)?the formation of the 1,6-HHDP bridge, and 3)?the complete control of axial chirality in the aryl-aryl coupling.     

Microwave-assisted transition-metal-catalyzed synthesis of N-shifted and ring-expanded buflavine analogues

Two novel and efficient strategies for the synthesis of hitherto unknown N-shifted and ring-expanded buflavine analogues are presented. Construction of the medium-sized ring system of the title molecules, a difficult task due to the high activation energy needed for the ring-closure with the additional rigidity imposed by the biaryl skeleton, was achieved by using Suzuki-Miyaura biaryl coupling and a ring-closing metathesis reaction as the key steps. The combination of a second-generation Grubbs catalyst and microwave irradiation proved to be highly useful in generating the otherwise difficult to obtain medium-sized ring system of the buflavine analogues.     

Asymmetric Synthesis of Densely Functionalized Medium‐Ring Carbocycles and Lactones through Modular Assembly and Ring‐Closing Metathesis of Sulfoximine‐Substituted Trienes and Dienynes

An asymmetric synthesis of densely functionalized 7–11‐membered carbocycles and 9–11‐membered lactones has been developed. Its key steps are a modular assembly of sulfoximine‐substituted C‐ and O‐tethered trienes and C‐tethered dienynes and their Ru‐catalyzed ring‐closing diene and enyne metathesis (RCDEM and RCEYM). The synthesis of the C‐tethered trienes and dienynes includes the following steps: 1) hydroxyalkylation of enantiomerically pure titanated allylic sulfoximines with unsaturated aldehydes, 2) α‐lithiation of alkenylsulfoximines, 3) alkylation, hydroxy‐alkylation, formylation, and acylation of α‐lithioalkenylsulfoximines, and 4) addition of Grignard reagents to α‐formyl(acyl)alkenylsulfoximines. The sulfoximine group provided for high asymmetric induction in steps 1) and 4). RCDEM of the sulfoximine‐substituted trienes with the second‐generation Ru catalyst stereoselectively afforded the corresponding functionalized 7–11‐membered carbocyles. RCDEM of diastereomeric silyloxy‐substituted 1,6,12‐trienes revealed an interesting difference in reactivity. While the (R)‐diastereomer gave the 11‐membered carbocyle, the (S)‐diastereomer delivered in a cascade of cross metathesis and RCDEM 22‐membered macrocycles. RCDEM of cyclic trienes furnished bicyclic carbocycles with a bicyclo[7.4.0]tridecane and bicyclo[9.4.0]pentadecane skeleton. Selective transformations of the sulfoximine‐ and bissilyloxy‐substituted carbocycles were performed including deprotection, cross‐coupling reaction and reduction of the sulfoximine moiety. Esterification of a sulfoximine‐substituted homoallylic alcohol with unsaturated carboxylic acids gave the O‐tethered trienes, RCDEM of which yielded the sulfoximine‐substituted 9–11‐membered lactones. RCEYM of a sulfoximine‐substituted 1,7‐dien‐10‐yne showed an unprecedented dichotomy in ring formation depending on the Ru catalyst. While the second‐generation Ru catalyst gave the 9‐membered exo 1,3‐dienyl carbocycle, the first‐generation Ru catalyst furnished a truncated 9‐membered 1,3‐dieny carbocycle having one CH₂ unit less than the dienyne.     

Total synthesis and biological assessment of (-)-exiguolide and analogues

We describe herein an enantioselective total synthesis of (-)-exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross-metathesis for the assembly of readily available acyclic segments and intramolecular oxa-conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20-membered macrocyclic framework was constructed in an efficient manner by means of Julia-Kocienski coupling and Yamaguchi macrolactonization. Finally, the (E,Z,E)-triene side chain was introduced stereoselectively via Suzuki-Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (-)-exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI-H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure-activity relationships of (-)-exiguolide, which elucidated that the C5-methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity.     

Lewis acid catalyzed intramolecular [3+2] cross-cycloaddition of donor-acceptor cyclopropanes with carbonyls: a general strategy for the construction of acetal[n.2.1] skeletons

Build a bridge: The first catalytic intramolecular [3+2] cycloaddition of monodonor-monoacceptor cyclopropanes (see scheme) provides a general and efficient strategy for construction of structurally diverse acetal[n.2.1] and 1,4-dioxygen-substituted cyclic skeletons, which are widely distributed in biologically important natural products.     

A Highly Efficient Macrolactonization Method via Ethoxyvinyl Ester

Facile and efficient macrolactonization of hydroxycarboxylic acid via ethoxyvinyl esters (EVEs), which can give 9‐ to 14‐membered macrolactones in good yields, has been developed (see scheme; DCE = 1,2‐dichloroethane). The method is useful for acid‐/base‐sensitive substrates and applicable to the compound with many functional groups.

     

Total synthesis and biological evaluation of marinopyrrole A and analogues

A five-step total synthesis of the antibiotic marinopyrrole A (1) is described. The developed synthetic technology enabled the synthesis of several marinopyrrole A analogs whose antibacterial properties against methicillin-resistant Staphylococcus aureus TCH1516 were evaluated.     

Enantioselective synthesis of paraconic acids

The development of a new method for the enantioselective synthesis of disubstituted gamma-butyrolactones is reported. Based on this strategy, the total synthesis of three paraconic acids, that is (-)-roccellaric acid, (-)-nephrosteranic acid and (-)-protopraesorediosic acid, and the formal total synthesis of (-)-methylenolactocin and (-)-protolichesterinic acid is described, which are important because of their antibiotic and antitumor properties. Key steps of the synthesis are copper(I)-catalyzed asymmetric cyclopropanations of furans, highly diastereoselective Sakurai allylations, Lewis acid or Lewis base catalyzed retroaldol/lactonization cascades, and ruthenium(II)-catalyzed, intermolecular cross metathesis reactions.     

Total synthesis of myxovirescin A1

A convergent total synthesis of the antibiotic macrolide myxovirescin A1 (1) is described that is largely based on reagent- and catalyst-controlled transformations. This includes a highly regioselective Negishi reaction of dibromo-alkene 48 with an alkynylzinc reagent, and a palladium catalyzed alkyl-Suzuki coupling of the resulting enyne derivative 12 with the 9-BBN-adduct derived from alkene 61. The latter was obtained via an asymmetric hydrogenation of the chlorinated beta-ketoester 49 and an anti-selective oxyallylation of the functionalized aldehyde 53 as the key steps. The preparation of the bis-borylated allyl-donor 57 used in the oxyallylation step, however, required careful optimization and led to important insights into the nature of the classical hydroborating agent "di(isopinocampheyl)borane (Ipc2BH)". It was unambiguously shown by X-ray crystallography that in the solid state this compound is dimeric, but it is prone to undergo an essentially quantitative mono-deborylation when dissolved in CH2Cl2 or benzene; its composition in ethereal solvents is even more complex as evident from 11B NMR data. Product 71 derived from 12 and 61 was elaborated into the enyne-yne derivative 75, which served as the substrate for an exquisitely selective ring closing alkyne metathesis reaction (RCAM) catalyzed by the molybdenum tris-amido complex 20 activated in situ with CH2Cl2. The resulting cyclic enyne 76 was subjected to a ruthenium catalyzed trans-hydrosilylation/proto-desilylation tandem. Although [Cp*Ru(MeCN)3]PF6 had previously been recommended as catalyst of choice for trans-hydrosilylation reactions of internal alkynes, this complex failed to afford the desired product, whereas its sterically less hindered congener [CpRu(MeCN)3]PF6 permitted the reaction to be performed in appreciable yield, but at the expense of a lower stereoselectivity. AgF-mediated proto-desilylation of the isomeric silanes 79 and 80 followed by cleavage of the remaining acetal protecting groups afforded myxovirescin A1 and its hitherto unknown 14Z-isomer 81, respectively.