Highly stereoselective total synthesis of fully hydroxy-protected mycolactones A and B and their stereoisomerization upon deprotection

Unprecedentedly efficient and highly (≥98 %) stereoselective syntheses of mycolactones A and B side chains relied heavily on Pd‐catalyzed alkenylation (Negishi version) and were completed in 11 longest linear steps from ethyl (S)‐3‐hydroxybutyrate in 12 % and 11 % overall yield, respectively, roughly corresponding to an average of 82 % yield per step. The synthesis of mycolactone core was realized by using Pd‐catalyzed alkenyl? allyl coupling and an epoxide‐opening reaction with a trialkylalkenylaluminate as key steps. Fully hydroxy‐protected mycolactones A and B of ≥98 % isomeric purity were synthesized successfully for the first time. However, unexpected 4:3–5:4 inseparable mixtures of mycolactones A and B were obtained upon deprotection.     

Total Synthesis of Mycolactones A and B

First and second generation total syntheses of mycolactones A and B are reported. The first generation total synthesis unambiguously confirmed our earlier assignment of the relative and absolute stereochemistry of mycolactones A and B. Knowledge of the chemical properties of the mycolactones accumulated through the first generation total synthesis allowed us to implement several major improvements to the original synthesis, including: (1) optimizing the choice of protecting groups, (2) eliminating the unnecessary adjustment of protecting groups, and (3) improving the overall stereoselectivity and synthetic efficiency. The second generation total synthesis consists of 21 longest linear steps, with 6.3% overall yield.     

First total synthesis of rhuscholide A,glabralide B and denudalide

The first total synthesis of rhuscholide A, a benzofuran lactone possessing anti-HIV-1 activity, had been accomplished in 14 linear steps with 10.6% overall yield. In this synthesis, base-mediated phenol ortho-alkylation and piperidine promoted aldol condensation were exploited as key steps. The synthesis was flexible and allowed for the convenient preparation of two analogous natural products glabralide B and denudalide.     

A one-pot chemoenzymatic synthesis of (2S, 4R)-4-methylproline enables the first total synthesis of antiviral lipopeptide cavinafungin B

We report an efficient ten-step (longest linear sequence) synthesis of antiviral natural product cavinafungin B in 37% overall yield. By leveraging a one-pot chemoenzymatic synthesis of (2S,4R)-4-methylproline and oxazolidine-tethered (AT (Boc)G-Rink resin) SPPS methodology, the assembly of our molecular target could be conducted in an efficient manner. This general strategy could prove amenable to the construction of other natural and unnatural linear lipopeptides. The value of incorporating biocatalytic steps in complex molecule synthesis is highlighted by this work.     

Diastereoselective reactions at enantiomerically pure, sterically congested cyclohexanes as an entry to wailupemycins A and B: total synthesis of (+)-wailupemycin B

Wailupemycin A (1) and B (2) are polyketide natural products with a highly substituted cyclohexanone core. Three different routes for the syntheses of these compounds were pursued, which commenced from either (R)-(-)-carvone (ent-5) or (S)-(+)-carvone (5). In the first approach it was attempted to construct the skeleton of wailupemycin A from triol 19 (nine steps from ent-5; 19 % yield) by a sequence of diastereoselective epoxidation, nucleophilic ring opening at C-13 and carbonyl addition at C-5. The synthetic plan failed at the stage of the carbonyl addition to aldehyde 27, which had been obtained in seven steps (18 % yield) from triol 19. The second route included an epoxide ring opening at C-13 and a carbonyl addition at C-7 as key steps. It could have led to either wailupemycin A or B depending on the diastereoselectivity of the addition step. Starting from allylic alcohol 30 (six steps from ent-5; 59 % yield) the cyclohexanone 28 was obtained in five steps (54 % yield). Unfortunately, the carbonyl addition failed also in this instance. In the eventually successful third attempt the skeleton of wailupemycin B was built from cyclohexanone 43 (eight steps from 5; 53 % yield) by highly diastereoselective carbonyl addition reactions at C-7 and C-12. The phenyl group at C-14 was introduced at a late stage of the synthetic sequence. Careful protecting group manipulation finally allowed for the total synthesis of (+)-wailupemycin B. The absolute and relative configuration of the natural product was unambiguously confirmed. The total yield of wailupemycin B amounted to 6 % over 23 steps starting from (S)-(+)-carvone (5).     

Organocatalytic Highly Enantioselective Substitution of 3‐(1‐Tosylalkyl)indoles with Oxindoles Enables the First Total Synthesis of (+)‐Trigolutes B

A highly enantioselective organocatalytic substitution of 3‐(1‐tosylalkyl)indoles with oxindoles has been established by using chiral bifunctional organocatalysts, providing an efficient entry to multiply functionalized 3,3′‐disubstituted oxindoles, and was exploited as the key step to enable the first asymmetric total synthesis of optically pure (+)‐trigolutes B to be accomplished in a concise manner, within seven steps with an 18 % overall yield.     

Protecting-group-free total synthesis of 4-epi-phomonol

A concise first total synthesis of 4-epi-phomonol has been accomplished in 6 steps and 33% overall yield from (R)-1,2-epoxypentane. The key features of the synthesis include an application of protecting-group-free strategy, a prins cyclization to install the tetrahydropyran ring, and a substrate-controlled dihydroxylation to fix the stereocenters at the C3 and C4 positions.     

Novel Total Synthesis of Mansouramycin B

A novel total synthesis of Mansouramycin B ( 1 ) was performed via 10 steps in 28% overall yield starting from the readily available and cheap salicylaldehyde. Two key steps of this total synthesis are noteworthy. The first one is base‐promoted one‐pot aerobic aromatization of N‐tosyltetrahydroisoquinoline 6 , the second one is oxidation of 5‐hydroxy‐3‐methyl‐isoquinoline 8 with iodobenzene diacetate [PhI(OAc)₂].     

Racemic synthesis of an intermediate for the formal synthesis of madindoline A and B

On the basis of the application of the Darzens/ring-expansion process of cyclobutenedione developed previously by our group, a new strategy for the multisubstituted cyclopentene units of madindoline A and madindoline B has been reported in this paper. In light of the strategy, the synthesis of racemic Omura’s intermediate was finished in four steps and 34% overall yield, which furnished a new formal synthetic route to madindolines A and B.     

Synthetic studies on neomarinone: practical and efficient stereoselective synthesis of the side chain

A practical and efficient stereoselective synthesis of the side chain of neomarinone is reported. The synthesis was achieved in six steps (41% overall yield) from 2-methyl-2-cyclohexenone. The key step is a novel stereoselective 1,4-conjugate addition/enolate alkylation by an epoxide-opening reaction.     

Total synthesis of Tasimelteon

A simple and efficient approach has been accomplished for the total synthesis of active pharmaceutical ingredient (API) of Tasimelteon which is effective for treatment of non-24-h sleep-wake disorder. Starting from 4-vinyl-2, 3-dihydrobenzofuran, the synthesis involves asymmetric epoxidation, Wittig reaction, reduction of the nitrile group and propionation of the amine. The synthesis was accomplished in four steps in overall 48% yield.     

First stereoselective total synthesis of Neocosmosin A: a facile approach

First stereoselective concise synthesis of Neocosmosin A, with in vitro binding affinity for human opioid and cannabinoid receptors, has been reported using readily available starting materials such as methylacetoacetate, cyclohexanone, and homoallyl alcohol involved in the key transformations. There are three fragments involved in the synthesis of target molecule, bearing acid functionality, (R)-pent-4-en-2-ol, and Weinreb amide which are synthesized in four, eight, and three steps, respectively. Then the fragments were coupled in four steps to yield the target molecule in an overall yield of 28.6%.     

Toward the synthesis of norzoanthamine: complete fragment assembly

The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C1-C5 fragment A, the C6-C10 fragment B, and the C11-C24 fragment C. The synthesis of fragment A was achieved in 14 steps and 33% overall yield from (R)-gamma-hydroxymethyl-gamma-butyrolactone. Fragment B was made in two steps from PMB-protected 4-pentynol in 76% yield. The C11-C24 fragment C was made from (S)-carvone via (R)-isocarvone in 18 steps (6% overall yield). The convergent stereoselective synthesis of the entire carbon framework (C1-C24) of the target molecule was achieved via the following assemblage. Alkenyl iodide 20 derived from the C11-C24 fragment C was coupled to fragment B (C6-C10) through a high-yielding Stille coupling reaction of these two sterically very demanding coupling partners, affording the key Diels-Alder precursor 24. The intramolecular Diels-Alder reaction proceeded smoothly in excellent yield and diastereoselectivity, generating the tricyclic trans-anti-trans perhydrophenanthrene motif of norzoanthamine (C6-C24). The final fragment coupling between lithiated fragment A (C1-C5) and aldehyde 40 (C6-C24) has also been successfully accomplished affording the entire carbon framework of the natural product.     

Total synthesis of (±)-cyclooroidin

The first total synthesis of (±)-cyclooroidin, a member of the pyrrole-imidazole alkaloid family recently isolated from the sponge Agelas oroides in optically pure form, is described. The synthesis was achieved in nine linear steps, with an overall yield of 10%. Key step was a Wolff bromoketone synthesis performed on the intermediate longamide B.     

The first synthesis of the pentacyclic pyridoacridine marine alkaloids: arnoamines A and B

The synthesis of the marine pyridoacridine alkaloids arnoamines A and B has been accomplished in six and seven steps from 4-chloro-8-methoxy-5-nitroquinoline in 13% and 4% overall yield, respectively.     

An Efficient Synthesis of Selective Human NR2A Antagonist NVP-AAM077

A short and efficient synthesis of the selective human N-methyl-D-aspartate （NMDA） receptor 2A （NR2A） antagonist NVP-AAM077 is described. The target was achieved in 8 steps and in 54% overall yield from the commercially available chemical 3-methylbenzene-1,2-diamine. A NaIO4/DMF-based oxidation of the bromide to corresponding aldehyde and an addition of phosphinic acid ester to the aldimine successfully served as the key steps.     

Total synthesis of (+)-blasticidin s

The first total synthesis of the peptidyl nucleoside antibiotic, blasticidin S (1), has been achieved by the coupling reaction of cytosinine (3) and blastidic acid (2). A key step in the synthesis of cytosinine (3) is the sigmatropic rearrangement of allyl cyanate 24; this reaction provided efficient and stereoselective access to 2,3-dideoxy-4-amino-D-hex-2-enopyranose (26 a). Further elaboration of 26 a gave methyl hex-2-enopyranouronate 29, and cytosine N-glycosylation of 31 using the Vorbrüggen conditions for the silyl Hilbert-Johnson reaction furnished the differentially protected cytosinine (32) in 11 steps from 2-acetoxy-D-glucal (14) (4.0 % overall yield). Synthesis of the Boc-protected blastidic acid 47 in nine steps starting from chiral carboxylic acid 35 (23 % overall yield) utilized Weinreb's protocol for the preparation of benzyl amide 38 and Fukuyama's protocol for the synthesis of the secondary amine 40. Assembly of the protected cytosinine (32) and blastidic acid (47) by the BOP method in the presence of HOBt, and finally elaboration to 1 by deprotection of the fully protected 54 established the total synthesis of blasticidin S (1).     

Improved synthesis of UDP-2-(2-ketopropyl)galactose and a first synthesis of UDP-2-(2-ketopropyl)glucose for the site-specific linking of biomolecules via modified glycan residues using glycosyltransferases

The potential of wild-type and mutant glycosyltransferases to produce glycoconjugates carrying sugar moieties with chemical handles has made it possible to conjugate biomolecules with orthogonal reacting groups at specific sites. The synthesis of UDP-2-(2-ketopropyl)galactose has been previously carried out, albeit with difficulty and low efficiency. A modified approach has been developed for the synthesis of UDP-2-(2-ketopropyl)glucose and UDP-2-(2-ketopropyl)galactose, allowing better access to the desired test compounds, the UDP-2-(2-ketopropyl)glucose and UDP-2-(2-ketopropyl)galactose analogs were synthesized in eight steps and 4.8% and 5.3% overall yield, respectively, an improvement over the first generation synthesis involving eight steps and an overall yield of 0.7%.     

Stereoselective Synthesis of (6R)-6-(5-Methyl-2-furyl)-2-oxocyclohexanecarboxyl-10', 2'-Sultam

PseudolaricacidA(l)whichexhibitsantifungalandantifertilityactivitieswasisolatedfromPeudolarl-xKaenlpjbriGord'.Theabsoluteconfigurationsofthesechiralcenterswereassignedtobe3S,4S,10RandIIRrespectively'.Accordingtotheretrosyfltheticanalysis.theskeletonofIcouldbeconstructedbyintramolecular[4- 31cycloadditiontyomaseven-memberedlactone2(Schemel)whichcouldbeobtainedfrom(6S)-6-Thesynthesisbeganwithbetalprotected0-ketoacid4,tbllowedbyamidationwith(-)-camphorsultamandDCCtoobtainapairofdiastereomer…     

Total Synthesis of Echinoside A,a Representative Triterpene Glycoside of Sea Cucumbers

Echinoside A, a sulfonylated holostane tetrasaccharide with potent anticancer and antifungal activity, was synthesized in a longest linear sequence of 35 steps and 0.6 % overall yield. The synthetic approach is adaptable to the synthesis of congeners and analogues, as exemplified by the ready synthesis of ds-echinoside A and echinoside B, and thus will facilitate in-depth studies on the promising biological effects of echinoside A. Moreover, the present synthesis demonstrates the feasibility of synthetic access to the characteristic complex triterpene glycosides that occur ubiquitously in sea cucumbers.