Total synthesis of (+)-allocyathin B2

The first enantioselective synthesis of (+)-allocyathin was achieved. The synthesis features a Pd-catalyzed asymmetric allylic alkylation to install the first quaternary center, a Ru-catalyzed diastereoselective cycloisomerization to construct the six-membered ring, and a diastereoselective hydroxylative Knoevenagel reaction to introduce the final hydroxyl group. The unusual olefin isomerization of the Ru-catalyzed cycloisomerization was discussed and exploited for the synthesis.     

Total synthesis of echinopines A and B: exploiting a bioinspired late-stage intramolecular cyclopropanation

Total synthesis of echinopine A and B have been accomplished, based on a strategy that involved two transition-metal-mediated ene-yne cycloisomerizations. A modified Pd-catalyzed enyne cycloisomerization/intramolecular Diels-Alder cascade rendered a more streamlined synthesis of tricyclic ketone 15, and a Ru-catalyzed ene-yne cycloisomerization/cyclopropanation resembled the late-stage [5/7] → [3/5/5/7] ring-forming sequence in the proposed biosynthetic pathway.     

Total synthesis of (+)-frondosin A. Application of the Ru-catalyzed [5+2] cycloaddition

The first total synthesis of (+)-frondosin A was accomplished in 19 longest linear and 21 total steps from commercially available materials. The key features of the synthesis include a Ru-catalyzed [5+2] cycloaddition, a Claisen rearrangement, and a ring expansion to construct the core of the frondosin A in a diastereoselective and regioselective fashion. This is the first application of a Ru-catalyzed [5+2] cycloaddition in the total synthesis of a natural product. Through this synthesis, the absolute configuration of (+)-frondosin A was established.     

Migratory hydroamination: a facile enantioselective synthesis of benzomorphans

We describe a highly efficient, general strategy for the enantioselective synthesis of benzomorphans (45-46% overall yield from commercially available material). The new synthesis demonstrates the effectiveness of an unprecedented diastereoselective cycloisomerization via migratory hydroamination and the power of palladium-catalyzed asymmetric allylic alkylation (AAA) of simple ketone enolates in the context of complex synthesis. The strategy outlined here for the enantioselective synthesis of three contiguous stereogenic centers and the novel cycloisomerization should have many applications in alkaloid synthesis.     

Double cycloisomerization as a novel and expeditious route to tricyclic heteroaromatic compounds: short and highly diastereoselective synthesis of (+/-)-tetraponerine T6

[reaction: see text] Cu-Assisted double cycloisomerization of bis-alkynylpyrimidines afforded the 5-6-5 tricyclic heteroaromatic skeleton. This transformation was used as a key step in the highly diastereoselective total synthesis of (+/-)-tetraponerine T6.     

A flexible approach toward trans-fused polycyclic tetrahydropyrans. A synthesis of prymnesin and yessotoxin units

Ru-catalyzed cycloisomerization and oxidative cyclization of bis-homopropargylic alcohols provide a rapid iterative approach to structural units of the ladder toxins.     

Total Synthesis of Cryptotrione

The total synthesis of cryptotrione ( 1 ) was enabled by substrate-controlled diastereoselective construction of the bicyclo[3.1.0]hexene framework through platinum-catalyzed enyne cycloisomerization and Lewis acid induced polyene cyclization to construct the abietane-type tricyclic diterpene skeleton. The stereogenic tertiary carbon center in the side chain was installed in a diastereodivergent manner by conjugate addition reactions.     

On the diastereoselectivity of ru-catalyzed [5 + 2] cycloadditions

[reaction: see text]. Ru-catalyzed cycloisomerization of cyclopropylenynes proceeds with good to high diastereoselectivities to form hexahydroazulenes.     

Ring-closing metathesis of sulfoximine-substituted N-tethered trienes: modular asymmetric synthesis of medium-ring nitrogen heterocycles

A synthesis of sulfoximine-substituted medium-ring nitrogen heterocycles (MRNHs) having a high degree of substitution has been developed. Its key steps are the modular asymmetric synthesis of sulfoximine-substituted N-tethered trienes and their Ru-catalyzed ring-closing metathesis (RCM) reaction. The highly substituted N-tethered trienes were obtained enantio- and diastereopure through 1) the diastereoselective aminoalkylation of sulfoximine-substituted allyltitanium complexes with N-tert-butylsulfonyliminoester, 2) N-allylation of homoallylic N-sulfonyl amines, 3) allylation, hydroxylalkylation, and formylation of α-lithioalkenylsulfoximines, and 4) allylation of α-formylalkenylsulfoximines. The Ru-catalyzed RCM reaction of the sulfoximine-substituted 1,7,10- and 1,7,12-trienes stereoselectively afforded the corresponding nine-, ten-, and eleven-membered MRNHs in good yields. An interesting difference in reactivity was noted in the case of a sulfoximine-substituted 1,7,10-triene and its corresponding 1,10-diene. While the triene readily underwent a RCM reaction, the diene reacted only in the presence of Ti(OiPr)(4) under formation of the corresponding MRNH. The feasibility of a removal of the sulfoximine auxiliary and the N-sulfonyl protecting group from the MRNHs were demonstrated through reduction and cleavage, respectively, of a nine-membered heterocycle, both of which proceeded readily and gave the corresponding cyclic alkene and amine, respectively.     

Enantioselective synthesis of GNE-6688, a potent and selective inhibitor of interleukin-2 inducible T-cell kinase (ITK)

An enantioselective synthesis of the previously-disclosed ITK inhibitor GNE-6688 is described. Synthesis of the nitropyrazole fragment is highlighted by a Ru-catalyzed transfer hydrogenation using the Wills tethered ligand system. Synthesis of the pyrazole carboxylic acid fragment features an allylboration catalyzed by a chiral diol-SnCl₄ complex, followed by a highly diastereoselective directed cyclopropanation.     

A formal synthesis of (-)-mycalamide A

Novel strategies are developed for an efficient formal synthesis of (-)-mycalamide A. The left-hand side (-)-7-benzoylpederic acid is synthesized from (2S,3S)-2,3-epoxybutane. The key features include a highly regioselective Ru-catalyzed alkene-alkyne coupling reaction and a novel way to control the challenging C(7) stereocenter. The right-hand side was synthesized from (R)-pantolactone. The complex trioxodecalin core is constructed with two Pd(0)-catalyzed O-pi-allyl cyclizations. The first one is chemoselective, while the second one is highly diastereoselective. Three additional steps would be required to complete a total synthesis of (-)-mycalamide A.     

Thionium ion initiated medium-sized ring formation: the total synthesis of asteriscunolide D

The first synthesis of the biologically active humulene natural product asteriscunolide D has been accomplished in nine steps without the use of protecting groups. The challenging 11-membered ring was forged via a diastereoselective thionium ion initiated cyclization, which constitutes a formal aldol disconnection to form a strained macrocycle. A stereospecific thioether activation-elimination protocol was developed for selective E-olefin formation, thus providing access to the most biologically active asteriscunolide. The absolute stereochemical configuration was established by the Zn-ProPhenol catalyzed enantioselective addition of methyl propiolate to an aliphatic aldehyde to afford a γ-hydroxy propiolate as a handle for butenolide formation via Ru-catalyzed alkene-alkyne coupling.     

Highly Diastereoselective Hydrosilane-Assisted Rhodium-Catalyzed Spiro-Type Cycloisomerization of Succinimide and Pyrazolone-Based Functional 1,6-Dienes

Organosilicon compounds are important reagents and synthetic intermediates that play a key role in the construction of new materials and complex products. Here we show a highly diastereoselective rhodium-catalyzed cycloisomerization of 1,6-dienes, in which the use of (EtO)₃SiH accelerates the intramolecular cyclization reaction to afford a novel spiro-fused succinimide and pyrazolone derivatives in moderate to excellent yields as a single diastereoisomer. The proposed mechanism involves an active Rh−H species from the hydrosilane that is the H-donor in this spiro-type cycloisomerization reaction.     

A synthesis of L-vancosamine derivatives from non-carbohydrate precursors by a short sequence based on the Marshall, McDonald, and Du Bois reactions

[reaction: see text] The carbamate-protected l-vancosamine glycal, viewed as a universal precursor for vancosamine derivatives, was prepared by a short scheme based on diastereoselective addition of an allenyl stannane to a lactaldehyde ether, the tungsten-catalyzed alkynol cycloisomerization, and the rhodium-catalyzed C-H insertion of a carbamate nitrogen. This sequence is a prototype for a new and efficient strategy for the synthesis of 3-amino sugar derivatives. The key intermediate was elaborated to the silyl ether of N,N-dimethyl vancosamine glycal.     

Effective synthesis of bicyclodienes via palladium-catalyzed asymmetric allylic alkylation and ruthenium-catalyzed cycloisomerization

[n.3.0]Bicycles (n = 3–6) can be synthesized using palladium-catalyzed asymmetric allylic alkylation followed by ruthenium-catalyzed cycloisomerization. New types of triarylphosphino-1,2-diaminooxazoline ligands show the same high levels of enantioselectivity observed with Trost ligand when employed in Pd-catalyzed allylic alkylation reactions. The enyne products of these allylic alkylation reactions were further elaborated using a Ru-catalyzed redox isomerization process, for which a mechanism is proposed.     

A modular approach to aryl-C-ribonucleosides via the allylic substitution and ring-closing metathesis sequence. a stereocontrolled synthesis of all four α-/β- and D-/L-C-nucleoside stereoisomers

Iridium(I)-catalyzed allylation of the enantiopure monoprotected copper(I) alkoxide, generated from (S)-5a, with the enantiopure allylic carbonates (R)-9a,b has been developed as the key step in a new approach to C-nucleoside analogues. The anomeric center was thus constructed via a stereocontrolled formation of the C-O rather than C-C bond with retention of configuration. The resulting bisallyl ethers 15a,b (≥90% de and >99% ee) were converted into C-ribosides 29a,b via the Ru-catalyzed ring-closing metathesis, followed by a diastereoselective dihydroxylation catalyzed by OsO(4) or RuO(4) and deprotection. Variation of the absolute configuration of the starting segments 5a and 9a,b allowed a stereocontrolled synthesis of all four α/β-D/L-combinations.     

Total synthesis of laulimalide: synthesis of the northern and southern fragments

The first stage in the development of a synthetic route for the total synthesis of laulimalide (1) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product by using a Ru-catalyzed alkene-alkyne coupling. This would be preceded by an esterification of the C19 hydroxyl group, joining together two equally sized synthons, the northern fragment 7 and the southern fragment 8. Our first generation approach to the northern fragment entailed a key sequential Ru/Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, but the inability to achieve a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn-catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct 66 with excellent syn/anti selectivity (10:1), and allowed for the successful completion of the northern fragment 7. The key step for the synthesis of the southern fragment was a chemoselective Rh-catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six-membered ring, over a seven. The use of an electron-deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading.     

Diastereoselective intramolecular temporary silicon-tethered rhodium-catalyzed [4+2+2] cycloisomerization reactions: regiospecific incorporation of substituted 1,3-butadienes

Transition metal-catalyzed carbocyclization reactions represent powerful methods for the construction of complex polycyclic systems. We have developed a regiospecific and diastereoselective intramolecular temporary silicon-tethered rhodium-catalyzed [4+2+2] cycloisomerization reaction of a tethered enyne for the construction of tricyclic eight-membered heterocycles and carbocycles. This methodology also allows (E)- and (Z)-olefins to be utilized in a stereospecific manner. The incorporation of either alkene geometry is particularly significant, since related carbocyclization reactions are often limited in this respect. Finally, the ability to utilize carbon-tethered 1,6-enynes and to regiospecifically incorporate substituted 1,3-butadiene derivatives provides exciting opportunities for future applications toward the total synthesis of cyclooctanoid containing diterpenes.     

Collective Total Syntheses of Atisane‐Type Diterpenes and Atisine‐Type Diterpenoid Alkaloids: (±)‐Spiramilactone B, (±)‐Spiraminol, (±)‐Dihydroajaconine,and (±)‐Spiramines C and D

The first total syntheses of the architecturally complex atisane‐type diterpenes and biogenetically related atisine‐type diterpenoid alkaloids (±)‐spiramilactone B, (±)‐spiraminol, (±)‐dihydroajaconine, and (±)‐spiramines C and D are reported. Highlights of the synthesis include a late‐stage biomimetic transformation of spiramilactone B, a facile formal lactone migration from the pentacyclic skeleton of spiramilactone E, a highly efficient and diastereoselective 1,7‐enyne cycloisomerization to construct the functionalized tetracyclic atisane skeleton, and a tandem retro‐Diels–Alder/intramolecular Diels–Alder sequence to achieve the tricyclo[6.2.2.0] ring system.     

Collective Total Syntheses of Atisane‐Type Diterpenes and Atisine‐Type Diterpenoid Alkaloids: (±)‐Spiramilactone B, (±)‐Spiraminol, (±)‐Dihydroajaconine,and (±)‐Spiramines C and D

The first total syntheses of the architecturally complex atisane‐type diterpenes and biogenetically related atisine‐type diterpenoid alkaloids (±)‐spiramilactone B, (±)‐spiraminol, (±)‐dihydroajaconine, and (±)‐spiramines C and D are reported. Highlights of the synthesis include a late‐stage biomimetic transformation of spiramilactone B, a facile formal lactone migration from the pentacyclic skeleton of spiramilactone E, a highly efficient and diastereoselective 1,7‐enyne cycloisomerization to construct the functionalized tetracyclic atisane skeleton, and a tandem retro‐Diels–Alder/intramolecular Diels–Alder sequence to achieve the tricyclo[6.2.2.0] ring system.