A Biomimetic Synthesis of (±)‐Basiliolide B

A highly diastereoselective and practical biomimetic total synthesis of (±)‐basiliolide B has been achieved through the study of the two proposed biosynthetic pathways (O‐methylation and O‐acylation) for the unprecedented 7‐methoxy‐4,5‐dihydro‐3H‐oxepin‐2‐one (C ring). The synthesis featured a cyclopropanation/ring opening strategy for establishing the stereogenic centers at C8 and C9, a biomimetic 2‐pyrone Diels–Alder cycloaddition for the synthesis of the ABD ring system, and finally a highly efficient biomimetic intramolecular O‐acylation for the C ring formation. This result provides an important perspective on the biosynthetic origin of the unprecedented 7‐membered acyl ketene acetal moiety of the C ring.     

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.     

A facile synthesis of substituted 3‐amino‐1H‐quinazoline‐2,4‐diones

A new synthesis of a series of 3‐amino‐1H‐quinazoline‐2,4‐diones is described. The 1H‐quinazoline‐2,4‐dione 10 was made starting with fluorobenzoic acid in three high yielding steps. The key step of this synthesis involved the generation of the dianion of urea 7 and the subsequent intramolecular nucleophilic displacement of the 2‐fluoro to form the quinazolinedione ring. The 3‐amino moiety was incorporated using (2,4‐dinitro‐phenyl)‐hydroxylamine as the aminating reagent.     

A Synthetic Route to Chiral Dihydrobenzothiazines through Ring Opening of Activated Aziridines with 2‐Halothiophenols/Copper‐Powder‐Mediated C−N Cyclization

A simple protocol for the synthesis of dihydrobenzothiazines through regio‐ and stereoselective S_N2‐type ring opening of N‐tosylaziridines with sulfur nucleophiles followed by copper‐powder‐mediated intramolecular C?N cyclization in excellent yields (up to 95 %) with high diastereo‐ and enantioselectivity (up to >99 %) is reported.     

Asymmetric Total Synthesis of (−)‐Stenine and 9a‐epi‐Stenine

A route for the asymmetric synthesis of (?)‐stenine, a member of the Stemona alkaloid family used as folk medicine in Asian countries, is described. The key features of the sequence employed include stereoselective transformations on a cyclohexane ring controlled by a chiral auxiliary unit and an intramolecular Mitsunobu reaction to construct the perhydroindole ring system. By using an intermediate in the route to (?)‐stenine, an asymmetric synthesis of 9a‐epi‐stenine was also executed. The C(9a) stereocenter in 9a‐epi‐stenine was installed by using a Staudinger/aza‐Wittig reaction of a keto–azide precursor followed by reduction of the resulting imine. The results of this effort demonstrate the applicability of the chiral auxiliary based strategy to the preparation of naturally occurring alkaloids that contain highly functionalized cyclohexane cores.     

Total Synthesis of Diterpenoid Steenkrotin A

A concise and diastereoselective total synthesis of the diterpenoid (±)‐steenkrotin A is described for the first time. The strategy mainly features three key ring formations: 1) a rhodium‐catalyzed O? H bond insertion followed by an intramolecular carbonyl‐ene reaction to build up the tetrahydrofuran subunit; 2) sequential SmI₂‐mediated Ueno–Stork and ketyl–olefin cyclizations to construct the [5,7] spirobicyclic skeleton; and 3) an intramolecular aldol condensation/vinylogous retro‐aldol/aldol sequence to form the final six‐membered ring with inversion of the relative configuration at the C7 position.     

Novel π2s+π2a Electrocyclization of Triethylenic‐Malonic Acids Exemplified for a One‐Pot Synthesis of New γ‐Dilactones cis‐Fused with a Cyclopentene

A new, easy and rapid synthesis of γ‐dilactones is cis‐fused with a cyclopentenic ring via cyclization of 7‐chlorotriethylenic‐malonic acids. The key step implicates an intramolecular cyclization to a cyclopentenyl cation, according to an electrocyclic π_2s + π_2a conrotatory process. This cyclopentenyl cation led to unstable γ‐lactones intermediates that are rearrange to more stable isomers. δ‐lactones (6Z and 6E‐(3‐chlorobut‐2‐en‐2‐yl)‐5‐methyl‐3,6‐dihydro‐2H‐pyran‐2‐one) were obtained as secondary products. Mechanistic pathways were considered. The structures of the newly synthesized compounds were established by elemental and spectral data.     

Two‐step Synthesis of New γ‐Lactones via Cyclization of 7‐Chloro‐2‐(methoxycarbonyl)‐4‐6‐dimethylocta‐(2E,4E,6E)‐trienoic acid

A new rapid synthesis of γ‐lactones, cis fused with a cyclopentenic ring by thermal cyclization of 7‐chloro‐2‐(methoxycarbonyl)‐4‐6‐dimethylocta‐7‐phenyl (or methyl) (2E,4E,6E)‐trienoic acids was reported. The key step implicates an intramolecular cyclization to a cyclopentenyl cation, according to an electrocyclic π_2s + π_2a conrotatory process, published in a recent paper (from the corresponding diacids). We have investigated the thermal behavior of the corresponding half‐esters since; if the cyclization obeys to the proposed mechanism, the diacids, half‐esters must also cyclize in a similar manner. Saponification of these led to γ‐dilactones via intermediary cyclopropanes. Mechanistic pathways were investigated.     

Convergent Synthesis of (−)‐Quinocarcin Based on the Combination of Sonogashira Coupling and Gold(I)‐Catalyzed 6‐endo‐dig Hydroamination

The total synthesis of the pentacyclic tetrahydroisoquinoline alkaloid quinocarcin, which possesses intriguing structural and biological features, has been achieved through a gold(I)‐catalyzed regioselective hydroamination reaction. It is noteworthy that the regioselectivity of the intramolecular hydroamination of an unsymmetrical alkyne could be completely switched through substrate control. Other key features of this synthesis include the highly stereoselective synthesis of 2,5‐cis‐pyrrolidine through the intramolecular amination of the bromoallene and the Lewis acid mediated ring opening of dihydrobenzofuran.     

Asymmetric Total Synthesis of (−)‐Kravanhin B

The first asymmetric total synthesis of kravanhin B has been accomplished with a linear reaction sequence of 13 steps starting from (R)‐(?)‐carvone. The synthesis features an intramolecular aldol cyclization to construct the desired cis‐fused decalin skeleton and an acid‐catalyzed dehydration and olefin isomerization to install the γ‐butenolide ring.     

Expedient Synthesis of (+)‐Lycopalhine A

Two amino acids play a key role in the first total synthesis of lycopalhine A. l ‐glutamic acid serves as a convenient chiral starting material for the 13‐step synthesis, and l ‐proline promotes an unusual 5‐endo‐trig Mannich cyclization that generates the central pyrrolidine ring of the Lycopodium alkaloid. The bicyclo[3.3.0]octanol moiety of the molecule is formed through an intramolecular aldol addition that may occur spontaneously in nature.     

Short Chemoenzymatic Total Synthesis of ent‐Hydromorphone: An Oxidative Dearomatization/Intramolecular [4+2] Cycloaddition/Amination Sequence

A short synthesis of ent‐hydromorphone has been achieved in twelve steps from β‐bromoethylbenzene. The key transformations involved the enzymatic dihydroxylation of the arene to the corresponding cis‐dihydrodiol, Mitsunobu coupling with the ring A fragment, oxidative dearomatization of the C3 phenol, and the subsequent [4+2] cycloaddition to form ring B of the morphinan. The synthesis was completed by intramolecular amination at C9.     

A Catalytic Diastereoselective Formal [5+2] Cycloaddition Approach to Azepino[1,2‐a]indoles: Putative Donor–Acceptor Cyclobutanes as Reactive Intermediates

A catalytic formal [5+2] cycloaddition approach to the diastereoselective synthesis of azepino[1,2‐a]indoles is reported. The reaction presumably proceeds through a Lewis acid catalyzed formal [2+2] cycloaddition of an alkene with an N‐indolyl alkylidene β‐amide ester to form a donor–acceptor cyclobutane intermediate, which subsequently undergoes an intramolecular ring‐opening cyclization. Azepine products are formed in up to 92 % yield with high degrees of diastereoselectivity (up to 34:1 d.r.).     

Total Synthesis of (+)‐MPC1001B

The first total synthesis of an epidithiodiketopiperazine alkaloid, (+)‐MPC1001B, was accomplished. This synthesis features a tetra‐n‐butylammonium fluoride mediated intramolecular aldol reaction for forming the 15‐membered macrolactone ring, and the construction of an epidithiodiketopiperazine substructure through a stepwise sulfenylation reaction involving a novel trityl trisulfide (TrSSS)‐group transfer.     

Ligand‐Controlled Regiodivergent Nickel‐Catalyzed Annulation of Pyridones

The 1,6‐annulated 2‐pyridone motif is found in many biologically active compounds and its close relation to the indolizidine and quinolizidine alkaloid core makes it an attractive building block. A nickel‐catalyzed C? H functionalization of 2‐pyridones and subsequent cyclization affords 1,6‐annulated 2‐pyridones by selective intramolecular olefin hydroarylation. The switch between the exo‐ and endo‐cyclization modes is controlled by two complementary sets of ligands. Irrespective of the ring size, the regioselectivity during the cyclization is under full catalyst control. Simple cyclooctadiene promotes an exo‐selective cyclization, whereas a bulky N‐heterocyclic carbene ligand results in an endo‐selective mode. The method was further applied in the synthesis of the lupin alkaloid cytisine.     

Multi‐Gram Scale Synthesis of Chiral 3‐Methyl‐2,5‐trans‐tetrahydrofurans

In this article, we report the rapid and facile synthesis of chiral 3‐methyl‐2,5‐trans‐tetrahydrofurans. This reaction utilizes cheap and easily available starting materials. A domino hydrolysis and intramolecular Michael‐type ring closure reaction was the key step. As a result, synthesis of the desired 3‐methyl‐2,5‐trans‐tetrahydrofurans could be achieved in gram‐scale over seven linear steps with high chemical yield and high diastereoselectivity.     

Enantioselective Synthesis of (−)‐(R)‐Cordiachromene and (−)‐(R)‐Dictyochromenol Utilizing Intramolecular SNAr Reaction

A simple and efficient enantioselective synthesis of chromene, (?)‐(R)‐cordiachromene ( 1 ), and (?)‐(R)‐dictyochromenol ( 2 ) has been accomplished. This convergent synthesis utilizes intramolecular S_NAr reaction for the formation of chroman ring, and Seebach's method of ‘self‐reproduction of chirality’ should establish the (R)‐configuration of the C(2) side chain as key steps.     

Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)‐Myrioneurinol

The first total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid (±)‐myrioneurinol has been accomplished using three highly diastereoselective reactions as pivotal steps: 1) an intramolecular Michael addition of a benzyloxycarbonyl‐protected lactam titanium enolate to an α,β‐unsaturated ester for construction of the spirocyclic C5 quaternary center and the a/d rings, 2) a malonate anion conjugate addition to a transient nitrosoalkene to install the requisite functionality and configuration at the C7 position, and 3) an intramolecular sulfonyliminium aza‐Sakurai reaction to form the b ring and the attendant C9/C10 configuration of the natural product.     

The Cobalt Way to Angucyclinones: Asymmetric Total Synthesis of the Antibiotics (+)‐Rubiginone B2, (−)‐Tetrangomycin,and (−)‐8‐O‐Methyltetrangomycin

A cobalt(I)‐mediated convergent and asymmetric total synthesis of angucyclinones with an aromatic B ring has been developed. In the course of our research, we synthesized three naturally occurring anguclinone derivatives, namely, (+)‐rubiginone B₂ ( 1 ), (?)‐8‐O‐methyltetrangomycin ( 2 ), and (?)‐tetrangomycin ( 3 ). By combining 3‐hydroxybenzoic acid, 3‐methoxybenzoic acid, citronellal, and geraniol as starting materials in a convergent way, we were able to synthesize chiral triyne chains, which were cyclized with [CpCo(C₂H₄)₂] (Cp=cyclopentadienyl) by means of an intramolecular [2+2+2] cycloaddition to their corresponding tetrahydrobenzo[a]anthracenes. Successive oxidation and deprotection steps led to the above‐mentioned natural products 1 – 3 .     

Asymmetric Total Synthesis of Propindilactone G,Part 2: Enantioselective Construction of the Fully Functionalized BCDE Ring System

The enantioselective synthesis of the fully functionalized BCDE tetracyclic ring system of propindilactone G ( A ) is reported. Several synthetic methods were developed and applied to achieve this goal, including: 1) an asymmetric Diels–Alder reaction in the presence of Hayashi′s catalyst for the synthesis of optically pure key intermediate 3 ; 2) an intramolecular Pauson–Khand reaction (PKR) for the stereoselective synthesis of the BCDE ring with an all‐carbon chiral quaternary center at the C13 position by using the TMS‐substituted acetylene as the substrate; and 3) Pd‐catalyzed reductive hydrogenolysis for the stereoselective synthesis of the fully functionalized BCDE tetracyclic ring system. The chemistry developed herein provided a greater understanding of the total synthesis propindilactone G ( A ) and its analogues.