Total Synthesis of Marine Eicosanoid (−)‐Hybridalactone

(?)‐Hybridalactone ( 1 ) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13‐membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid‐labile skipped Z,Z‐diene motif. In this paper, we report on the total synthesis of (?)‐hybridalactone ( 1 ). The unique eicosanoid (?)‐hybridalactone ( 1 ) was synthesized starting from optically active γ‐butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9 %. A key step in the synthesis of (?)‐hybridalactone ( 1 ) is the methyl phenylsulfonylacetate‐mediated one‐pot synthesis of the cis‐cyclopropane‐γ‐lactone derivative. This reaction provided an efficient and stereoselective access to cis‐cyclopropane‐γ‐lactone 12 . Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (?)‐hybridalactone.     

Asymmetric Total Syntheses of (−)‐α‐Lycorane, (−)‐Zephyranthine,and Formal Synthesis of (+)‐Clivonine

An asymmetric route to (−)‐α‐lycorane and (−)‐zephyranthine, and a formal total synthesis of (+)‐clivonine were achieved. A pivotal intermediate, which serves as a potent precursor for the divergent syntheses of these natural products, was accessed by a diastereoselective Pd‐catalyzed cinnamylation of an N ‐tert ‐butanesulfinyl imine.     

First Total Synthesis of N‐(3‐Guanidinopropyl)‐2‐(4‐hydroxyphenyl)‐2‐oxoacetamide

The first total synthesis of the α‐oxo amide‐based natural product, N‐(3‐guanidinopropyl)‐2‐(4‐hydroxyphenyl)‐2‐oxoacetamide ( 3 ), isolated from aqueous extracts of hydroid Campanularia sp., has been achieved. The α‐oxo amide 12 , prepared via the oxidative amidation of 1‐[4‐(benzyloxy)phenyl]‐2,2‐dibromoethanone ( 9a ) with 4‐{[(tert‐butyl)(dimethyl)silyl]oxy}butan‐1‐amine ( 10a ), has been used as the key intermediate in the total synthesis of 3 as HBr salt. On the way, an expeditious total synthesis of polyandrocarpamide C ( 2c ), isolated from marine ascidian Polyandrocarpa sp., was carried out in four steps.     

Configurational Assignment of ‘Cryptochiral’ 10‐Hydroxystearic Acid Through an Asymmetric Catalytic Synthesis

An asymmetric catalytic total synthesis of (S)‐10‐hydroxystearic acid ( 1 ) for comparison of its absolute configuration to that of samples obtained by fermentative hydration of oleic acid is reported. The synthesis involves two catalytic key‐steps, namely Ru‐catalyzed anti‐Markovnikov hydration of 9‐decynoic acid ( 7 ) to 10‐oxodecanoic acid ( 5 ), followed by titanium‐mediated asymmetric catalytic addition of dioctylzinc ( 25 ) to 5 in presence of the chiral ligand N,N’‐((1R,2R)‐cyclohexane‐1,2‐diyl)bis(1,1,1‐trifluoromethanesulfonamide) ( 6 ). The synthesis is short and efficient and avoids use of protecting groups. Ozonolysis of 10‐undecynoic acid ( 9 ) to 5 provides an alternative entry point into the synthetic route. The double dehydrobromination of (ω,ω‐1)‐dibromoalkanoic acids to ω‐alkynoic acids under a variety of conditions was investigated with 10,11‐dibromoundecanoic acid ( 11 ) as model substrate and using qNMR to quantify all reaction products. The synthetic approaches presented here have the potential to be generalized to the asymmetric catalytic synthesis of a variety of n‐hydroxy‐fatty acids.     

10‐Step Asymmetric Total Synthesis and Stereochemical Elucidation of (+)‐Dragmacidin D

The asymmetric synthesis of dragmacidin D ( 1 ) was completed in 10 steps. Its sole stereocenter was set by using direct asymmetric alkylation enabled by a C₂‐symmetric tetramine and lithium N‐(trimethylsilyl)‐tert‐butylamide as the enolization reagent. A central Larock indole synthesis was employed in a convergent assembly of the heterocyclic subunits. The stereochemical evidence from this work strongly supports the predicted S configuration at the 6′′′ position, which is consistent with other members of the dragmacidin family of natural products.     

Catalytic Enantioselective Synthesis of a 3‐Aryl‐3‐benzyloxindole (=3‐Aryl‐3‐benzyl‐1,3‐dihydro‐2H‐indol‐2‐one) Exhibiting Antitumor Activity

A palladium‐catalyzed intramolecular α‐arylation of an amide in the presence of a bulky chiral N‐heterocyclic carbene ligand is the key step in the first catalytic synthesis of (3R)‐6‐chloro‐3‐(3‐chlorobenzyl)‐1,3‐dihydro‐3‐(3‐methoxyphenyl)‐2H‐indol‐2‐one ((R)‐ 5 ). This oxindole, in racemic form, had been shown previously to be an anticancer agent. (R)‐ 5 was obtained with an overall yield of 45% and with 96% enantioselectivity.     

Synthesis of Epigoitrin from (R)‐(+)‐4‐Hydroxy‐γ‐butyrolactone

Epigoitrin is one of the major components of several natural species, including Isatis indigotica Fort, turnip, and cabbage. It presents antithyroid and antivirus activities. Here, we report an efficient and practical method for the chemical synthesis of epigoitrin from commercially available (R)‐(+)‐4‐hydroxy‐γ‐butyrolactone.     

Stereoselective Synthesis of α‐3‐Deoxy‐D‐manno‐oct‐2‐ulosonic Acid (α‐Kdo) Glycosides Using 5,7‐O‐Di‐tert‐butylsilylene‐Protected Kdo Ethyl Thioglycoside Donors

An efficient methodology for the synthesis of α‐Kdo glycosidic bonds has been developed with 5,7‐O‐di‐tert‐butylsilylene (DTBS) protected Kdo ethyl thioglycosides as glycosyl donors. The approach permits a wide scope of acceptors to be used, thus affording biologically significant Kdo glycosides in good to excellent chemical yields with complete α‐selectivity. The synthetic utility of an orthogonally protected Kdo donor has been demonstrated by concise preparation of two α‐Kdo‐containing oligosaccharides.     

Enantioselective Total Synthesis of (+)‐Plumisclerin A

The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective La^III‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI₂‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A.     

Short and Divergent Total Synthesis of (+)‐Machaeriol B, (+)‐Machaeriol D, (+)‐Δ8‐THC,and Analogues

Short and highly efficient stereoselective syntheses provide machaeriols and cannabinoids in a divergent approach starting from a common precursor, commercially available (S)‐perillic acid. Key features of the novel strategy are a stereospecific palladium‐catalyzed decarboxylative arylation and a one‐pot sequence comprising a stereoselective hydroboration followed by oxidation or reduction of the corresponding intermediary boranes. The divergent approach is convincingly demonstrated by the five‐step syntheses of (+)‐machaeriol B, (+)‐machaeriol D, and related analogues, and the four‐step synthesis of (+)‐Δ⁸‐THC and an analogue.     

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.     

Efficient Total Synthesis of (S)‐14‐Azacamptothecin

An efficient total synthesis of (S)‐14‐azacamptothecin has been accomplished in 10 steps and 56 % overall yield from 5H‐pyrano[4,3‐d]pyrimidine 8 . A mild Hendrickson reagent‐triggered intramolecular cascade cyclization, a highly enantioselective dihydroxylation, and an efficient palladium‐catalyzed transformation of an O‐allyl into N‐allyl group are the key steps in the synthesis. This work provides a much higher overall yield than the previous achievement and shows sound flexibility for the further applications that will lead to new bioactive analogues.     

A Concise and Highly Enantioselective Total Synthesis of (+)‐anti‐ and (−)‐syn‐Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines

A concise asymmetric (>99:1 e.r.) total synthesis of (+)‐anti‐ and (?)‐syn‐mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless‐derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)‐anti‐ and (?)‐syn‐mefloquine, respectively. The synthetic (+)‐anti‐ and (?)‐syn‐mefloquine samples were derivatized with (S)‐(+)‐mandelic acid tert‐butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X‐ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)‐anti‐ as well as (?)‐syn‐mefloquine.     

Practical Synthesis of (20S)‐10‐(3‐Aminopropyloxy)‐7‐ethylcamptothecin,a Water‐Soluble Analogue of Camptothecin

A robust, practical synthesis of (20S)‐10‐(3‐aminopropyloxy)‐7‐ethylcamptothecin (T‐2513, 5 ), which is a water‐soluble analogue of camptothecin, has been developed. The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N‐arylsulfonyl‐(R)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl‐(S)‐2‐acyloxy‐2‐(6‐cyano‐5‐oxo‐1,2,3,5‐tetrahydroindolizin‐7‐yl)butanoate ( 8 k ) in 93 % yield and 87 % de. Optically pure compound 8 k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5 . This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi‐gram scale in 6.3 % overall yield (16 steps).     

A Flexible Approach to Azasugars: Asymmetric Total Syntheses of (+)‐Castanospermine, (+)‐7‐Deoxy‐6‐epi‐castanospermine,and (+)‐1‐epi‐Castanospermine

The asymmetric total synthesis of natural azasugars (+)‐castanospermine, (+)‐7‐deoxy‐6‐epi‐castanospermine, and synthetic (+)‐1‐epi‐castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)‐ 8 . The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama‐type reaction with either chiral or achiral aldehydes (≥95 % de; de=diastereomeric excess) and a diastereodivergent reduction of tetramic acids, which allows formation of three continuous stereogenic centers with high diastereoselectivities. The method also provides a flexible access to structural arrays of 5‐(α‐hydroxyalkyl)tetramic acids, such as 17/34 , and 5‐(α‐hydroxyalkyl)‐4‐hydroxyl‐2‐pyrrolidinones, such as 18 and 25/35 a . The method constitutes the first realization of the challenging chiral synthons A and D and thus of the conceptually attractive retrosynthetic analysis shown in Scheme 1 in a highly enantioselective manner.     

Enantioselective Total Synthesis of (−)‐Diversonol

For the synthesis of (?)‐diversonol (ent‐ 1 ), an enantioselective domino‐Wacker/carbonylation/methoxylation reaction and an enantioselective Wacker oxidation were used to give the chroman in high yield and 96 % and 93 % ee, respectively. Dihydroxylation at the vinyl moiety using the Sharpless procedure and a Wittig–Horner reaction followed by hydrogenation, benzylic oxidation, and an intramolecular acylation provided the tetrahydroxanthenone, from which ent‐ 1 is accessible in a few steps. Furthermore, the synthesis of the diastereomeric diversonol rac‐1,9 a‐epi‐diversonol (rac‐ 41 ) is also described.     

From‐Core and From‐End Direct CH Arylations: A Step‐Saving New Synthetic Route to Thieno[3,4‐c]pyrrole‐4,6‐dione (TPD)‐Incorporated D‐‐π–A–π–D Functional Oligoaryls

In contrast to the traditional multistep synthesis, herein an efficient and fewer‐steps new synthetic strategy is demonstrated for the facile preparation of organic‐electronically important D–π–A–π–D‐type oligoaryls through sequential direct C?H arylations. This methodology has shown that the synthesis of thieno[3,4‐c]pyrrole‐4,6‐dione (TPD)‐ or furano[3,4‐c]pyrrole‐4,6‐dione (FPD)‐centred target molecules could be accessed step‐economically either from the core structure (acceptor) or from the end structure (donor), which supplied a more flexible and succinct new synthetic alternative to the preparation of the π‐functional small‐molecule semiconducting materials. In addition, optical and electrochemical properties of the synthesized oligoaryls were examined.     

The ‘Azirine/Oxazolone Method’ on Solid Phase: Introduction of Various α,α‐Disubstituted α‐Amino Acids

Peptides containing various α,α‐disubstituted α‐amino acids, such as α‐aminoisobutyric acid (Aib), 1‐aminocyclopentane‐1‐carboxylic acid, α‐methylphenylalanine, and 3‐amino‐3,4,5,6‐tetrahydro‐2H‐pyran‐3‐carboxylic acid have been synthesized from the N‐ to the C‐terminus by the ‘azirine/oxazolone method’ under solid‐phase conditions. In this convenient method for the synthesis of sterically demanding peptides on solid‐phase, 2H‐azirin‐3‐amines are used to introduce the α,α‐disubstituted α‐amino acids without the need for additional reagents. Furthermore, the synthesis of poly(Aib) sequences has been explored.     

Synthetic Studies toward C‐Glucosidic Ellagitannins: A Biomimetic Total Synthesis of 5‐O‐Desgalloylepipunicacortein A

C‐glucosidic ellagitannins constitute a subclass of bioactive polyphenolic natural products with strong antioxidant properties, as well as promising antitumoral and antiviral activities that are related to their capacity to interact with both functional and structural proteins. To date, most synthetic efforts toward ellagitannins have concerned glucopyranosic species. The development of a synthetic strategy to access C‐glucosidic ellagitannins, whose characteristic structural feature includes an atropoisomeric hexahydroxydiphenoyl (HHDP) or a nonahydroxyterphenoyl (NHTP) unit that is linked to an open‐chain glucose core by a C‐aryl glucosidic bond, is described herein. The total synthesis of the biarylic HHDP‐containing 5‐O‐desgalloylepipunicacortein A ( 1 β ) was achieved by either using the natural ellagic acid bis‐lactone as a precursor of the requested HHDP unit or by implementing an atroposelective intramolecular oxidative biarylic coupling to forge this HHDP unit. Both routes converged in the penultimate step of this synthesis to enable a biomimetic formation of the key C‐aryl glucosidic bond in the title compound.     

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.