Asymmetric Total Synthesis of Propindilactone G,Part 1: Initial Attempts towards the Synthesis of Schiartanes

Our first‐generation synthetic study towards the total synthesis of propindilactone G ( 1 ) and its analogues is reported. The key synthetic steps were an intramolecular Pauson–Khand reaction (PKR) and a vinylogous Mukaiyama reaction (VMAR). The stereoselective synthesis of the CDE ring moiety with an all‐carbon quaternary center through a PKR was difficult, whilst a VMAR afforded a product with the opposite stereochemistry at the C20 position on the side chain. These results led us to redesign our synthetic strategy for the total synthesis of compound 1 .     

Asymmetric Total Synthesis of Propindilactone G,Part 3: The Final Phase and Completion of the Synthesis

Two independent synthetic approaches were evaluated for the final phase of the asymmetric total synthesis of propindilactone G ( 1 ). The key steps that led to the completion of the asymmetric total synthesis included: 1) an intermolecular oxidative heterocoupling reaction of enolsilanes to link the core structure to the side chain; 2) an intermolecular Wittig reaction for the formation of the α,β,γ,δ‐unsaturated ester; and 3) a regio‐ and stereoselective OsO₄‐catalyzed dihydroxylation of an α,β,γ,δ‐unsaturated enone, followed by an intramolecular lactonization reaction to afford the final product. These reactions enabled the synthesis of (+)‐propindilactone G in only 20 steps. As a consequence of our synthetic studies, the structure of (+)‐propindilactone G has been revised. Furthermore, the direct oxidative coupling strategy for ligation of the core of propindilactone G with its side chain may find application in the syntheses of other natural products and complex molecules.     

Formal Synthesis of Sarain A: Intramolecular Cycloaddition of an Eight‐Membered Cyclic Nitrone to Construct the 2‐Azabicyclo[3.3.1]nonane Framework

An enantioselective route to the tetracyclic skeleton of sarain A has been developed. Asymmetric reduction of an ynone introduced a chiral center which was transferred to the contiguous tertiary stereogenic centers through an Ireland–Claisen rearrangement. The 2‐azabicyclo[3.3.1]nonane framework was constructed by an unprecedented intramolecular cycloaddition of an eight‐membered cyclic nitrone. Using the steric bias of the bicyclic system, the quaternary carbon atom was constructed by a stereoselective aldol reaction. Further ring formations were performed by ring‐closing metathesis for the 13‐membered ring and an iodoamidation reaction for the pyrrolidine ring. The present synthesis has successfully provided an alternative route to the late‐stage intermediate of Overman’s synthesis.     

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.     

Total Synthesis of (−)‐Nakadomarin A

A highly efficient 12‐step synthesis of the marine alkaloid (?)‐nakadomarin A has been accomplished. The key advanced intermediate, a tetracyclic ketone derivative, was constructed in just seven steps using a sequence that includes an asymmetric Pauson–Khand reaction, an Overman rearrangement reaction, a ring‐closing metathesis reaction, and an amination reaction. Late introduction of the furan ring during the synthesis of (?)‐nakadomarin A means that the key tetracyclic ketone derivative has the potential to serve as an advanced intermediate for the synthesis of related marine alkaloids.     

Enantioselective Total Synthesis of (+)‐Ophiobolin A

The enantioselective total synthesis of (+)‐ophiobolin A is described. This total synthesis features the construction of the spiro CD ring of (+)‐ophiobolin A through a stereoselective intramolecular Hosomi–Sakurai cyclization reaction, the joining of the A ring to the CD ring by using a reaction reported by Utimoto, and the construction of the ophiobolin eight‐membered carbocyclic ring through ring‐closing metathesis (RCM), which was performed for the first time in this study. This successful RCM reaction required the use of a substrate that contained either a benzyloxy or a methoxymethoxy group at the C5 position and either an isopropenyl group or its hydroxylated form at the C6 position.     

Diastereoselective Total Synthesis of (±)‐Schindilactone A,Part 3: The Final Phase and Completion

The final phase for the total synthesis of (±)‐schindilactone A ( 1 ) is described herein. Two independent synthetic approaches were developed that featured Pd–thiourea‐catalyzed cascade carbonylative annulation reactions to construct intermediate 3 and a RCM reaction to make intermediate 4 . Other important steps that enabled the completion of the synthesis included: 1) A Ag‐mediated ring‐expansion reaction to form vinyl bromide 17 from dibromocyclopropane 30 ; 2) a Pd‐catalyzed coupling reaction of vinyl bromide 17 with a copper enolate to synthesize ketoester 16 ; 3) a RCM reaction to generate oxabicyclononenol 10 from diene 11 ; 4) a cyclopentenone fragment in substrate 8 was constructed through a Co–thiourea‐catalyzed Pauson–Khand reaction (PKR); 5) a Dieckmann‐type condensation to successfully form the A ring of schindilactone A ( 1 ). The chemistry developed for the total synthesis of schindilactone A ( 1 ) will shed light on the synthesis of other family members of schindilactone A.     

Total Synthesis of (±)‐Aspidophylline A

A total synthesis of aspidophylline A, a pentacyclic akuammiline‐type monoterpene indole alkaloid, is described. The synthesis features: 1) rapid access to a fully functionalized dihydrocarbazole through the desymmetrization of readily available 2‐allyl‐2‐(o‐nitrophenyl)cyclohexane‐1,3‐dione; 2) an intramolecular azidoalkoxylation of an enecarbamate to install both the furoindoline ring and the azido functionality; and 3) an intramolecular Michael addition for the construction of the 2‐azabicyclo[3.3.1]nonane ring system.     

A Photoredox‐Induced Stereoselective Dearomative Radical (4+2)‐Cyclization/1,4‐Addition Cascade for the Synthesis of Highly Functionalized Hexahydro‐1H‐carbazoles

A stereoselective synthesis of functionalized hexahydrocarbazoles was developed based on an unprecedented photoredox‐induced dearomative radical (4+2)‐cyclization/1,4‐addition cascade between 3‐(2‐iodoethyl)indoles and acceptor‐substituted alkenes. The title reaction simultaneously generates three C−C bonds and one C−H bond, along with three contiguous stereogenic centers. The hexahydro‐1H ‐carbazole products are highly valuable intermediates for the synthesis of novel antibiotics, as well as unnatural ring homologues of polycyclic indoline alkaloids.     

A Flexible Approach to Grandisine Alkaloids: Total Synthesis of Grandisines B,D, and F

This article describes in detail the first total synthesis of grandisine alkaloids, grandisines B, D, and F, which show affinity for the human δ‐opioid receptor. The key steps in this synthesis are construction of the isoquinuclidinone moiety of 2 by intramolecular imine formation and the tetracyclic ring system of 4 by stereoselective ring closure of the enolate of amine 8 generated by 1,4‐addition of ammonia to 9 . Synthesis of key intermediate 9 featured a highly stereoselective Brønsted acid mediated Morita–Baylis–Hillman (MBH) reaction via the N‐acyl iminium ion.     

Total Syntheses of Norrisolide‐Type Spongian Diterpenes Cheloviolene C,Seconorrisolide B,and Seconorrisolide C

The first total syntheses of three unusual norrisolide‐type rearranged spongian diterpenes, cheloviolene C, seconorrisolide B, and seconorrisolide C, have been accomplished via a common intermediate through late‐stage ring‐scissoring. The synthesis features a Wolff ring contraction for the synthesis of the trans‐hydrindane system, and a crucial retro Diels–Alder reaction/intramolecular ene cyclization for the rapid stereoselective construction of the furo[2,3‐b]furan system, which is commonly seen in rearranged spongian 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.     

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 the Tiacumicin B (Lipiarmycin A3/Fidaxomicin) Aglycone

Tiacumicin B (lipiarmycin A3, fidaxomicin) is an atypical macrolide antibiotic which is used for the treatment of Clostridium difficile infections. Tiacumicin B is also a potent inhibitor of Mycobacterium tuberculosis, but due to its limited oral bioavailability is unsuitable for systemic therapy. To provide a basis for structure–activity studies that might eventually lead to improved variants of tiacumicin B, we have developed an efficient approach to the synthesis of the tiacumicin B aglycone. The synthesis features a high‐yielding intramolecular Suzuki cross‐coupling reaction to effect macrocyclic ring closure. Key steps in the synthesis of the macrocyclization precursor were a highly selective, one‐pot Corey–Peterson olefination and an ene–diene cross‐metathesis reaction. Depending on the reaction conditions, the final deprotection delivered either the fully deprotected tiacumicin B aglycone or partially protected versions thereof.     

Total Synthesis of (−)‐Glaucocalyxin A

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃‐mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (?)‐glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.     

Total Synthesis of (−)‐Salvinorin A

Salvinorin A ( 1 ) is natural hallucinogen that binds the human κ‐opioid receptor. A total synthesis has been developed that parlays the stereochemistry of l ‐(+)‐tartaric acid into that of (?)‐ 1 via an unprecedented allylic dithiane intramolecular Diels–Alder reaction to obtain the trans‐decalin scaffold. Tsuji allylation set the C9 quaternary center and a late‐stage stereoselective chiral ligand‐assisted addition of a 3‐titanium furan upon a C12 aldehyde/C17 methyl ester established the furanyl lactone moiety. The tartrate diol was finally converted into the C1,C2 keto‐acetate.     

A convergent coupling strategy for the formation of polycyclic ethers: stereoselective synthesis of the BCDE fragment of brevetoxin A

A stereoselective synthesis of the BCDE fragment of brevetoxin A has been completed. anti-Glycolate aldol, glycolate alkylation, and ring-closing metathesis reactions were employed as key bond-forming events. A convergent assembly strategy was employed that relied on a Horner-Wadsworth-Emmons union of two complex fragments. Subsequent cyclization and dehydration led to efficient generation of an intermediate endocyclic enol ether, which was advanced to a tetracyclic fragment. [reaction: see text]     

Applications of Dainshefsky's Dienes in the Asymmetric synthesis of Aza‐Diels‐Alder Reaction

Asymmetric hetero‐Diels‐Alder (AHDA) reactions provide a multitude of opportunities for the highly efficient, regio‐ and stereoselective construction of various heterocycles in enantiomerically pure form. The asymmetric aza‐Diels‐Alder (A‐aza‐DA) reaction using diversely hetero‐dienophiles and hetero‐dienes have been increasingly developed as a valuable method for the synthesis of functionalized nitrogen ring systems. The purpose of this review is to give a detailed discussion of the A‐aza‐DA reaction particularly, the stereoselective reactions of imines as dienophiles with Dainshefsky dienes to obtain optically pure aza‐Diels‐Alder products. The development of stereoselective variants of the reaction make use of imines as the dienophile and Dainshefsky dienes is at the forefront of these studies. This review updates the A‐aza‐DA reactions covering the literature from 1972 till date     

Diastereoselective Total Synthesis of (±)‐Schindilactone A,Part 2: Construction of the Fully Functionalized CDEFGH Ring System

The successful synthesis of the highly complex model compound ( 2 ) of the CEFGH ring system of schindilactone A ( 1 ) is described. Several synthetic methodologies were developed and applied to achieve this goal, including ring‐closing metathesis (RCM) and Co–thiourea‐catalyzed Pauson–Khand reactions. Furthermore, two independent approaches were developed for the construction of the GH ring of model compound 2 , the key steps of which included Pd–thiourea‐catalyzed carbonylative annulation, methylation, and sequential RCM/oxa‐Michael‐addition reactions. The chemistry developed herein has provided a greater understanding of the synthesis of schindilactone A ( 1 ) and its analogous compounds of the same family.