Total Synthesis of (+)‐Neomarinone

The first total synthesis of (+)‐neomarinone has been achieved by following a concise and convergent route using methyl (R)‐lactate and (R)‐3‐methylcyclohexanone as chiral building blocks. Key steps of the synthesis are the stereocontrolled formation of the two quaternary stereocenters by diastereoselective 1,4‐conjugate addition and enolate alkylation reactions, and the construction of the furanonaphthoquinone skeleton by regioselective Diels–Alder reaction between a 1,3‐bis(trimethylsilyloxy)‐1,3‐diene and a bromoquinone. The synthesis proves the relative and absolute stereochemistry of natural neomarinone.     

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.     

Enantioselective and Regioselective Pyrone Diels–Alder Reactions of Vinyl Sulfones: Total Synthesis of (+)‐Cavicularin

The total synthesis of (+)‐cavicularin is described. The synthesis features an enantio‐ and regioselective pyrone Diels–Alder reaction of a vinyl sulfone to construct the cyclophane architecture of the natural product. The Diels–Alder substrate was prepared by a regioselective one‐pot three‐component Suzuki reaction of a non‐symmetric dibromoarene.     

An Unexpected Transannular [4+2] Cycloaddition during the Total Synthesis of (+)‐Norcembrene 5

We report a concise and versatile total synthesis of the diterpenoid (+)‐norcembrene 5 from simple building blocks. Ring‐closing metathesis and an auxiliary‐directed 1,4‐addition are the key steps of our synthetic route. During the synthesis, an unprecedented, highly oxidized pentacyclic structural motif was established from a furanocembranoid through transannular [4+2] cycloaddition.     

Total Synthesis and Structural Revision of Antibiotic CJ‐16,264

The total synthesis and structural revision of antibiotic CJ‐16,264 is described. Starting with citronellal, the quest for the target molecule featured a novel bis‐transannular Diels–Alder reaction that casted stereoselectively the decalin system and included the synthesis of six isomers before demystification of its true structure.     

Total Synthesis of Tetrodotoxin

A total synthesis of tetrodotoxin was accomplished. A Diels–Alder reaction between a known enone and a siloxy diene gave a tricyclic product, the steric bias of which was used to construct the remaining stereogenic centers. A nitrogen atom was introduced either by a four‐step sequence involving a Curtius rearrangement, or a three‐step sequence featuring a newly developed transformation of a terminal alkyne into a nitrile. Introduction of the guanidine moiety followed by the formation of the heterocyclic system by cascade reactions led to tetrodotoxin.     

Quinones as Dienophiles in the Diels–Alder Reaction: History and Applications in Total Synthesis

In the canon of reactions available to the organic chemist engaged in total synthesis, the Diels–Alder reaction is among the most powerful and well understood. Its ability to rapidly generate molecular complexity through the simultaneous formation of two carbon? carbon bonds is almost unrivalled, and this is reflected in the great number of reported applications of this reaction. Historically, the use of quinones as dienophiles is highly significant, being the very first example investigated by Diels and Alder. Herein, we review the application of the Diels–Alder reaction of quinones in the total synthesis of natural products. The highlighted examples span some 60 years from the landmark syntheses of morphine (1952) and reserpine (1956) by Gates and Woodward, respectively, through to the present day examples, such as the tetracyclines.     

The Diels–Alder Reaction in Total Synthesis

The Diels–Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule construction, the Diels–Alder cycloaddition has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alder's birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized.     

Total Synthesis of (+)‐Dibromophakellin

Two members of a family of pyrrole–imidazole marine alkaloids, (+)‐dibromophakellin and the nonnatural congener (+)‐phakellin, were synthesized enantioselectively from 4‐hydroxy‐L ‐proline. The chiral aminal at C10 was constructed efficiently by means of an Overman‐type [3,3] sigmatropic rearrangement of an enamide (see scheme).

     

Pyrone Diels–Alder Routes to Indolines and Hydroindolines: Syntheses of Gracilamine,Mesembrine, and Δ7‐Mesembrenone

Although the Diels–Alder reaction has long been utilized for the preparation of numerous heterocycles, opportunities to extend its power remain. Herein, we detail a simple, modular, and robust approach that combines various amines regioselectively with 4,6‐dichloropyrone to create substrates which, under appropriate conditions, can directly deliver varied indolines and hydroindolines through [4+2] cycloadditions with substitution patterns difficult to access otherwise. As an initial demonstration of the power of the strategy, several different natural products have been obtained either formally or by direct total synthesis, with efforts toward one of these—the complex amaryllidaceae alkaloid gracilamine—affording the shortest route to date in terms of linear step count.     

Bioinspired Synthesis of (−)‐PF‐1018

The combination of electrocyclizations and cycloadditions accounts for the formation of a range of fascinating natural products. Cascades consisting of 8π electrocyclizations followed by a 6π electrocyclization and a cycloaddition are relatively common. We now report the synthesis of the tetramic acid PF‐1018 through an 8π electrocyclization, the product of which is immediately intercepted by a Diels–Alder cycloaddition. The success of this pericyclic cascade was critically dependent on the substitution pattern of the starting polyene and could be rationalized through DFT calculations. The completion of the synthesis required the instalment of a trisubstituted double bond by radical deoxygenation. An unexpected side product formed through 4‐exo‐trig radical cyclization could be recycled through an unprecedented triflation/fragmentation.     

Synthesis and Characterization of New 7‐Substituted 6,14‐Ethenomorphinane Derivatives: N‐{5‐[(5α,7α)‐4,5‐Epoxy‐3,6‐dimethoxy‐17‐methyl‐6,14‐ethenomorphinan‐7‐yl]‐1,3,4‐oxadiazol‐2‐yl}arenamines

In this study, (5α,7α)‐4,5‐epoxy‐3,6‐dimethoxy‐17‐methyl‐6,14‐ethenomorphinan‐7‐carboxylic acid hydrazide ( 5 ) was synthesized by the condensation of methyl (5α,7α)‐4,5‐epoxy‐3,6‐dimethoxy‐17‐methyl‐6,14‐ethenomorphinan‐7‐carboxylate ( 4 ) with NH₂NH₂⋅H₂O. The (5α,7α)‐4,5‐epoxy‐3,6‐dimethoxy‐17‐methyl‐6,14‐ethenomorphinan‐7‐carboxylic acid 2‐[(arylamino)carbonyl]hydrazides 6a – 6q were prepared by the reaction of 5 with corresponding substituted aryl isocyanates, and the N‐{5‐[(5α,7α)‐4,5‐epoxy‐3,6‐dimethoxy‐17‐methyl‐6,14‐ethenomorphinan‐7‐yl]‐1,3,4‐oxadiazol‐2‐yl}arenamines 7a – 7q were obtained via the cyclization reaction of 6a – 6q in the presence of POCl₃. The synthesized compounds have a rigid morphine structure, including the 6,14‐endo‐etheno bridge and the 5‐(arylamino)‐1,3,4‐oxadiazol‐2‐yl residue at C(7) adopting the (S)‐configuration (7α). The structures of the compounds were confirmed by high‐resolution mass spectrometry (HR‐MS) and various spectroscopic methods such as FT‐IR, ¹H‐NMR, ¹³C‐NMR, APT, and 2D‐NMR (HETCOR, COSY, INADEQUATE).     

Total Synthesis of (+)‐Machaeriols B and C and of Their Enantiomers with a Cannabinoid Structure

An efficient and concise synthesis of the biologically interesting (+)‐machaeriol B ( 2 ) and its enantiomer 5 was accomplished from O‐phenylhydroxylamine ( 7 ) in four steps (Scheme 2). In addition, the first total synthesis of natural (+)‐machaeriol C ( 3 ) and its enantiomer 6 was achieved from the readily available ester 15 in eight steps (Scheme 4). The key strategies in the syntheses of 2 and 5 involved benzofuran formation through a [3,3]‐sigmatropic rearrangement and trans‐hexahydrodibenzopyran formation by a domino aldol‐type/hetero‐Diels–Alder reaction. In the case of 3 and 6 , the key steps were stilbene formation by a Horner–Wadsworth–Emmons reaction and trans‐hexahydrodibenzopyran formation by domino reactions.     

Total Synthesis of Ramonanins A–D

The first total synthesis of the ramonanin family of lignan natural products is described. The short synthesis involves a 2,5‐diaryl‐3,4‐dimethylene tetrahydrofuran intermediate, which participates in an unexpectedly facile Diels–Alder dimerization, generating all four natural products. Insights into the reactivity and stereoselectivity of the key dimerization are provided through computational studies employing B3LYP/6‐31G(d) and M06‐2X/6‐31G(d) model chemistries.     

Total Synthesis of Sporolide B

An ocean of discovery : The first total synthesis of the highly oxygenated, marine‐derived, natural product sporolide B has been achieved through a convergent strategy. The key steps involve a ruthenium‐catalyzed [2+2+2] cycloaddition to assemble the indene structural motif and a thermally induced Diels–Alder‐type reaction to forge the macrocycle (see scheme).

     

Synthetic Study of (−)‐Norzoanthamine: Construction of the ABC Ring Moiety

Throw your hat in the ring : A highly diastereoselective synthesis of the ABC rings of (?)‐norzoanthamine has been achieved starting from the (?)‐Hajos–Parrish ketone (see scheme). Three asymmetric quaternary carbon centers on the C ring were constructed by a 1,4‐addition, and an intramolecular Diels–Alder reaction provided a trans‐decalin scaffold on the AB rings.

     

First Stereoselective Total Synthesis of a Dimeric Naphthoquinonopyrano‐γ‐lactone: (+)‐γ‐Actinorhodin

We have accomplished the first total synthesis of an isomerically pure naphthoquinonopyrano‐γ‐lactone dimer, γ‐actinorhodin, in eleven steps. Two steps exploit pairs of peri‐MeO groups as unusual selectivity controls. The respective MeO groups convey the steric bulk of a bromo or iodo substituent located ortho to one MeO group as steric hindrance into the vicinity of the second MeO group. This relay effect was indispensable for exerting regiocontrol in an aromatic bromination and diastereocontrol in an oxa‐Pictet–Spengler cyclization. The absolute configuration of our target compound was established in an asymmetric Sharpless dihydroxylation of a β,γ‐unsaturated ester, which was synthesized in a Heck coupling of a bromoiodonaphthalene with ethyl vinylacetate. The dihydroxylation provided the γ‐hydroxylactone moiety of the bromonaphthalene that was used as the substrate in the oxa‐Pictet–Spengler cyclization. Dimerization to the core of γ‐actinorhodin occurred by two Suzuki couplings.