Enantioselective Total Synthesis of Terreumols A and C from the Mushroom Tricholoma terreum

The cytotoxic meroterpenoids terreumol A and C from the grey knight mushroom Tricholoma terreum were synthesized for the first time. The key step of the enantioselective total synthesis of terreumol C is a ring‐closing metathesis to form a trisubstituted Z double bond embedded in the 10‐membered ring of the [8.4.0] bicycle. Interestingly, the presence of a free hydroxy group in the metathesis precursor prevents cyclization and favors cross metathesis. (?)‐Terreumol C was converted into (?)‐terreumol A by diastereoselective epoxidation. Starting from 2‐bromo‐3,5‐dimethoxybenzaldehyde, 14 steps with an overall yield of 23 % are needed for the synthesis of (?)‐terreumol A. X‐ray analysis of the benzoquinone analogue of terreumol A provides independent proof of the absolute configuration.     

Synthesis of 8‐Desmethoxy Psymberin: A Putative Biosynthetic Intermediate Towards the Marine Polyketide Psymberin

The synthesis of a putative biosynthetic precursor of psymberin including a formal synthesis of the natural product is described. The key step towards the densely functionalized tetrahydropyran core was an enantioselective catalytic Mukaiyama aldol reaction using a titanium(IV)–BINOL catalyst system. syn‐Selective reduction followed by ozonolysis led to a rapid assembly of the tetrahydropyran ring. This flexible approach also allows the synthesis of similar fragments of other complex molecules such as bryostatins and pederins. The syn‐selective coupling between the tetrahydropyran and the aromatic aldehyde was achieved using a boron‐mediated aldol reaction which was followed by further transformations to complete the synthesis of the precursor as well as the formal synthesis of the natural product.     

Formal Total Synthesis of (−)‐Taxol through Pd‐Catalyzed Eight‐Membered Carbocyclic Ring Formation

A formal total synthesis of (?)‐taxol by a convergent approach utilizing Pd‐catalyzed intramolecular alkenylation is described. Formation of the eight‐membered carbocyclic ring has been a problem in the convergent total synthesis of taxol but it was solved by the Pd‐catalyzed intramolecular alkenylation of a methyl ketone affording the cyclized product in excellent yield (97 %), indicating the high efficiency of the Pd‐catalyzed intramolecular alkenylation. Rearrangement of the epoxy benzyl ether through a 1,5‐hydride shift, generating the C3 stereogenic center and subsequently forming the C1–C2 benzylidene, was discovered and utilized in the preparation of a substrate for the Pd‐catalyzed reaction.     

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.     

Total Synthesis of Potent Antitumor Agent (−)‐Lasonolide A: A Cycloaddition‐Based Strategy

A detailed account of the enantioselective total synthesis of (?)‐lasonolide A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an α‐alkoxyacetimide derivative containing an α′ stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3‐dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero‐Diels–Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively.     

A Bioinspired Synthesis of (±)‐Rubrobramide, (±)‐Flavipucine,and (±)‐Isoflavipucine

A biomimetic synthesis of naturally occurring lactams rubrobramide, flavipucine, and isoflavipucine is described. The key step is a regioselective Darzens reaction between isobutyl glyoxal and an α‐bromo‐β‐ketoamide. The construction of the core tricyclic ring system of rubrobramide was achieved by a cascade reaction in a single step from an α,β‐epoxy‐γ‐lactam. Furthermore, the absolute configuration of naturally occurring (+)‐rubrobramide was determined by vibrational circular dichroism. (±)‐Flavipucine and (±)‐isoflavipucine were synthesized from an epoxyimide, which was prepared by reaction of isobutyl glyoxal with a protected α‐bromo‐β‐ketoamide. Deprotection of the epoxyimide and formation of the pyridone ring gave (±)‐flavipucine, which was converted into (±)‐isoflavipucine by thermal isomerization.     

A Cascade Strategy Enables a Total Synthesis of (−)‐Gephyrotoxin

A concise and efficient synthesis of (?)‐gephyrotoxin from L ‐pyroglutaminol has been realized. The key step in this approach is a diastereoselective intramolecular enamine/Michael cascade reaction that forms two rings and two stereocenters and generates a stable tricyclic iminium cation. A hydroxy‐directed reduction of this intermediate plays a key role in establishing the required cis‐decahydroquinoline ring system, enabling the total synthesis of (?)‐gephyrotoxin in nine steps and 14 % overall yield. The absolute configuration of the synthetic material was confirmed by single‐crystal X‐ray diffraction and is consistent with the structure originally proposed for material isolated from the natural source.     

Concise and Enantioselective Total Synthesis of (−)‐Mehranine, (−)‐Methylenebismehranine,and Related Aspidosperma Alkaloids

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (?)‐mehranine and (+)‐(6S,7S)‐dihydroxy‐N‐methylaspidospermidine. A late‐stage dimerization of (?)‐mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (?)‐methylenebismehranine.     

Enantioselective,Protecting‐Group‐Free Total Synthesis of Sarpagine Alkaloids—A Generalized Approach

A generalized synthetic access to sarpagine alkaloids through a joint synthetic sequence has been accomplished. Its applicability is showcased by the enantioselective total syntheses of vellosimine ( 1 ), N‐methylvellosimine ( 3 ), and 10‐methoxyvellosimine ( 8 ). The synthetic sequence is concise (eight steps) from known compound 13 , and requires no protecting groups. The indole heterocycle was introduced in the last step. This strategy allows access to sarpagine alkaloids through a shared synthetic route leading to precursor 10 , which we term “privileged intermediate”. Starting from this intermediate, all sarpagine alkaloids can be synthesized using phenylhydrazines with different substitution patterns ( 15 – 17 ). Our approach brings about the advantage, that synthesis optimization only needs to be performed once for many natural products. The key features of the synthesis are a [5+2]‐cycloaddition and a ring enlargement.     

A Unified Strategy Targeting the Thiodiketopiperazine Mycotoxins Exserohilone,Gliotoxin, the Epicoccins,the Epicorazines,Rostratin A and Aranotin

A unified synthetic strategy directed towards mycotoxins belonging to the thiodiketopiperazine family is reported. The building blocks for a number of natural products—including exserohilone, gliotoxin, the epicoccins, the epicorazines, rostratin A and aranotin—have been synthesised stereoselectively from a common precursor. This key intermediate was constructed through an efficient and highly diastereoselective [2+2] cycloaddition between a ketene and an enecarbamate derived from L ‐pyroglutamic acid. The annelation of the second ring was accomplished through ring‐closing metathesis and enol ether–olefin ring‐closing metathesis to provide both cis‐ and trans‐annelated azabicyclic cyclohexenones, as well as an annelated seven‐membered cyclic enol ether. A Pd‐catalysed elimination of allyl acetate gave rise to the cyclohexadienol structure of gliotoxin. Dimerisation of one building block to afford the diketopiperazine core was demonstrated.     

Stereoselective total synthesis of (-)-spirofungin A by utilising hydrogen-bond controlled spiroketalisation

The stereoselective total synthesis of the spiroketal containing Streptomyces metabolite (?)‐spirofungin A ( 1 ) is described. A key step involved a spiroketalisation controlled by an intramolecular H‐bond which favoured the desired spiroketal 4 (13:1 ratio). The presence of the intramolecular H‐bond in 4 is possibly due to a 1,5‐alkyne–oxygen interaction. Other key steps include an efficient cross‐metathesis to form the spiroketal precursor, a tin mediated syn‐aldol reaction and a Stille cross‐coupling reaction to create the C22? C23 bond. A final Wittig extension followed by deprotection gave (?)‐spirofungin A ( 1 ).     

Gram‐Scale Enantioselective Formal Synthesis of Morphine through an ortho–para Oxidative Phenolic Coupling Strategy

A gram‐scale catalytic enantioselective formal synthesis of morphine is described. The key steps of the synthesis involve an ortho–para oxidative phenolic coupling and a highly diastereoselective “desymmetrization” of the resulting cyclohexadienone that generates three of the four morphinan ring junction stereocenters in one step. The stereochemistry is controlled from a single carbinol center installed through catalytic enantioselective hydrogenation. These transformations enabled the preparation of large quantities of key intermediates and could support a practical and scalable synthesis of morphine and related derivatives.     

Preparation,Modification, and Evaluation of Cruentaren A and Analogues

An expeditious total synthesis of the highly cytotoxic F‐ATPase inhibitor cruentaren A ( 1 ) is described based on a ring‐closing alkyne metathesis (RCAM) reaction for the formation of the macrocylic ring. Other key transformations comprise a C‐acylation of the benzyl lithium reagent derived from orsellinic acid ester 9 with Weinreb amide 7 , a CBS reduction of the resulting ketone 10 , and a Soderquist propargylation of aldehyde 21 with allenylborane (S)‐ 27 to set the C‐15 chiral center of the required alcohol fragment 25 . The RCAM precursor 33 was assembled by acylation of 25 with acid fluoride 32 , since more conventional methods for ester bond formation were unproductive. Moreover, the choice of the protecting groups, in particular for the secondary alcohol at C‐9, which is prone to engage in translactonization, turned out to be critical; a relatively stable TBDPS ether had to be chosen for this site, which was removed in the final step of the synthesis with aqueous HF since other fluoride sources met with failure. The successful synthetic route was then expanded beyond the natural product, bringing a series of analogues into reach that feature incremental but deep‐seated structural modifications. Three of these fully synthetic compounds turned out to be as or even more cytotoxic than cruentaren A itself against L‐929 mouse fibroblast cells, reaching IC₅₀ values as low as 0.7 ng mL^?1.     

Enantio‐ and Diastereoselective Total Synthesis of (+)‐Panepophenanthrin,a Ubiquitin‐Activating Enzyme Inhibitor,and Biological Properties of Its New Derivatives

The asymmetric total synthesis of (+)‐panepophenanthrin, an inhibitor of ubiquitin‐activating enzyme (E1), has been accomplished using catalytic asymmetric α aminoxylation of 1,4‐cyclohexanedione monoethylene ketal as a key step, followed by several diastereoselective reactions. The biomimetic Diels–Alder reaction of a monomer precursor was found to proceed efficiently in water. The investigation of the biological properties of new derivatives of (+)‐panepophenanthrin enabled us to develop new cell‐permeable E1 inhibitors, RKTS‐80, ‐81, and ‐82.     

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.     

Enantioselective Total Synthesis of Brevetoxin A: Unified Strategy for the B,E, G,and J Subunits

Brevetoxin A is a decacyclic ladder toxin that possesses 5‐, 6‐, 7‐, 8‐, and 9‐membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings based upon a ring‐closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium‐ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the completion of a convergent synthesis of brevetoxin A.     

Synthesis of Isagarin,a Tetracyclic Naphthoquinone via a Palladium‐Catalyzed Cyclization

Total synthesis of isagarin (2) has been accomplished in five steps with 24.1% overall yield from 2‐bromonaphthoquinone (6). The key step is a palladium‐catalyzed cyclization to form a bicyclic ketal ring.     

Total Syntheses of the Tetracyclic Cyclopiane Diterpenes Conidiogenone,Conidiogenol, and Conidiogenone B

Total syntheses of the biologically important and structurally unique tetracyclic diterpenes conidiogenone, conidiogenol, and conidiogenone B of the cyclopiane class are reported. The absolute configuration of naturally occurring conidiogenone B was also corrected. The key step of our strategy involved the highly efficient construction of both ring C and the quaternary carbon center shared by rings A and C through a one‐step regioselective and diastereoselective cycloenlargement in the form of a semipinacol‐type rearrangement. In particular, the desired regioselectivity was made possible by properly adjusting the migratory aptitude of the migrating carbon atom through the introduction of an electron‐donating phenylthio group at this position.     

Total Synthesis of the Monoterpenoid Indole Alkaloid (±)‐Aspidophylline A

Aspidophylline A belongs to the akuammiline alkaloid family, the members of which possess intriguing cagelike structures and diverse biological activities. Herein we report a 15‐step synthesis of this alkaloid from conveniently available starting materials. The key elements of the synthesis include an intramolecular oxidative coupling to create the tetracyclic furoindoline motif of the natural product and a [Ni(cod)₂]‐mediated cyclization to install its piperidine ring.     

Intramolecular (4+3) Cycloadditions of Pyrroles and Application to the Synthesis of the Core of Class II Galbulimima Alkaloids

The first intramolecular (4+3) cycloaddition of pyrroles with epoxy enolsilanes as the electrophiles was developed and used to generate optically‐enriched cycloadducts containing the nortropane substructure in good yields. Using this pyrrole cycloaddition as the key step, we achieved the asymmetric synthesis of a nortropane compound bearing the BCDEF ring structure common to the Class II galbulimima alkaloids.