Total synthesis of dysiherbaine

An efficient total synthesis of dysiherbaine, a potent and subtype-selective agonist for ionotropic glutamate receptors, has been achieved. An advanced key intermediate in the previous synthesis of neodysiherbaine A and its analogues was selected as the starting point, and cis-oriented amino alcohol functionality on the tetrahydropyran ring was installed by using an intramolecular S_N2 cyclization of N-Boc-protected amino alcohol. The amino acid appendage was constructed by catalytic asymmetric hydrogenation of enamide ester.     

Total synthesis and biological evaluation of neodysiherbaine A and analogues

Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the total synthesis of 2 and its structural analogues 3-8. Advanced key intermediate 16 was employed as a branching point to assemble a series of these analogues 3-8 with respect to the C8 and C9 functionalities, which would not have been accessible through manipulations of the natural product itself. The synthesis of key intermediate 16 features (i) stereocontrolled C-glycosylation to set the C6 stereocenter, (ii) concise synthesis of the bicyclic ether skeleton through chemo- and stereoselective dihydroxylation of the exo-olefin and stereoselective epoxidation of the endo-olefin, followed by epoxide ring opening/5-exo ring closure, and (iii) catalytic asymmetric hydrogenation of enamide ester to construct the amino acid appendage. A preliminary biological evaluation of analogues for their in vivo toxicity against mice and binding affinity for glutamate receptors showed that both the type and stereochemistry of the C8 and C9 functional groups affected the subtype selectivity of dysiherbaine analogues for members of the kainic acid receptor family.     

Synthesis of the dysiherbaine tetrahydropyran core employing a tethered aminohydroxylation reaction

A stereocontrolled and scalable synthesis of an advanced intermediate of the dysiherbaine tetrahydropyran core has been achieved in 11 steps and 27% overall yield. The key feature of this synthetic approach is the application of the Donohoe tethered aminohydroxylation reaction to install the amino diol and establish the four contiguous syn stereocenters on the tetrahydropyran ring.     

A highly stereocontrolled total synthesis of dysiherbaine

A total synthesis of dysiherbaine, a potent agonist of AMPA-KA type glutamate receptors, has been accomplished in completely stereocontrolled manner starting from tri-O-acetyl-D-galactal in 25 steps and in 3% overall yield.     

6-Oxodendrolasinolide的全合成

以香叶醇(2)和异戊烯醇(5)为起始原料, 经过12步反应, 以5.6%的总收率完成了倍半萜内酯6-Oxodendrolasinolide (1)的全合成. 其关键步骤包括乙烯基二噻烷(7)的负离子与烯丙基氯(4a)的区域选择性烷基化反应和Corey's氧化内酯化反应.     

Total synthesis of (+)-batzelladine A and (-)-batzelladine D, and identification of their target protein

Asymmetric total synthesis of batzelladine A (1) and batzelladine D (2) has been achieved. Our synthesis of batzelladines features 1) stereoselective construction of the cyclic guanidine system by means of successive 1,3-dipolar cycloaddition reaction and subsequent cyclization, 2) direct esterification of the bicyclic carboxylic acid 35 with the guanidine alcohol 8 or 59 to construct the whole carbon skeleton of batzelladines, and 3) one-step formation of the alpha,beta-unsaturated aldehyde 53 from the primary alcohol 47 with tetra-n-propylammoniumperruthenate (TPAP), providing an efficient route to the left-hand bicyclic guanidine alcohol of batzelladine A (1). With the synthetic compounds 1 and 2 in hand, their target protein was examined by using immobilized CD4 and gp120 affinity gels. The results indicated that batzelladines A (1) and D (2) bind specifically to CD4.     

Total synthesis of dysiherbaine

A convergent total synthesis of the marine natural product dysiherbaine was accomplished. The key steps of the synthesis are an alkylation at the gamma-carbon of a protected glutamate with a highly substituted pyran derived from mannose, which was followed by a ring-contraction cascade reaction, which simultaneously gave the tetrasubstituted carbon and the hexahydrofuro[3,2-b]pyran ring system of the natural product.     

Synthesis of the dysiherbaine tetrahydropyran core utilizing improved tethered aminohydroxylation conditions

A concise stereoselective route to the dysiherbaine tetrahydropyran core was achieved in nine steps and 39% overall yield. Donohoe’s improved tethered aminohydroxylation conditions were employed to concurrently install the amino and alcohol groups and construct the tetrahydropyran ring, which features four contiguous cis-stereocenters.     

First total synthesis of (+)-pentandranoic acid A

The first total synthesis of (+)-pentandranoic acid A (1) was accomplished in 14 steps, starting from alcohol 3. Our synthesis features several key transformations, such as an ozonolysis-aldol cyclization-dehydration ring contraction sequence and a selective 1,4-diol oxidation, and provides an efficient synthetic route to this rare clerodane diterpenoid.     

Stereoselective synthesis of uridine-derived nucleosyl amino acids

Novel hybrid structures of 5'-deoxyuridine and glycine were conceived and synthesized. Such nucleosyl amino acids (NAAs) represent simplified analogues of the core structure of muraymycin nucleoside antibiotics, making them useful synthetic building blocks for structure-activity relationship (SAR) studies. The key step of the developed synthetic route was the efficient and highly diastereoselective asymmetric hydrogenation of didehydro amino acid precursors toward protected NAAs. It was anticipated that the synthesis of unprotected muraymycin derivatives via this route would require a suitable intermediate protecting group at the N-3 of the uracil base. After initial attempts using PMB- and BOM-N-3 protection, both of which resulted in problematic deprotection steps, an N-3 protecting group-free route was envisaged. In spite of the pronounced acidity of the uracil-3-NH, this route worked equally efficient and with identical stereoselectivities as the initial strategies involving N-3 protection. The obtained NAA building blocks were employed for the synthesis of truncated 5'-deoxymuraymycin analogues.     

Efficient synthesis of [3H]-sanglifehrin A via selective oxidation/reduction of alcohols at C31 and C35

[Reaction: see text]. Sanglifehrin A is a novel complex natural product showing strong immunosuppressive activity and remarkably high affinity for cyclophilin A. To assess its pharmacokinetic properties in vivo, an efficient synthetic route was developed to introduce a tritium label in position C35 of sangliferin A via an oxidation/reduction strategy. The synthetic approach is particularly attractive, because the C35-oxo intermediate 7 is available in good yield on large scale and the reducing agent, lithium tri-sec-butylborotritide, is readily available. An attempt to apply a similar strategy to the alcohol in position C31 led primarily to C31-epi-hydroxy sanglifehrin A under a variety of conditions.     

The intramolecular asymmetric Pauson-Khand cyclization as a novel and general stereoselective route to benzindene prostacyclins: synthesis of UT-15 (treprostinil)

A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI(2), namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C(3a), C(9a), and C(1)).     

Total syntheses of bupleurynol and its analog

An efficient route to the natural products bupleurynol and its analog (RB-2), isolated from Bupleuri Radix, was established based on versatile intermediate (15). In this synthetic route, Sonogashira and Cadiot-Chodkiewicz coupling as well as Julia-Kocienski olefination are utilized as key steps. The highly efficient synthetic route provides opportunities to explore the biological behavior of bupleurynol and RB-2.     

Mimicry of peptide backbone geometry and heteroatomic side-chain functionality: synthesis of enantiopure indolizidin-2-one amino acids possessing alcohol, acid, and azide functional groups

Indolizidinone amino acids possessing various heteroatomic side chains at their 5- and 7-positions have been synthesized through modification of hydroxymethyl indolizidinone amino acids 5 and 6. Displacements of the methanesulfonates from alcohols 5 and 6 with sodium azide, as well as oxidation of alcohol 5, have been used to furnish orthogonally protected indolizidin-2-one diamino carboxylates 7 and 8, and indolizidin-2-one amino dicarboxylate 9. Both 5- and 7-hydroxymethylindolizidinone amino acids 5 and 6 were obtained from sequences commencing with the Claisen condensation of alpha-tert-butyl gamma-methyl l-N-(PhF)-L-glutamate to furnish di-tert-butyl 4-carbomethoxy-5-oxo-2,8-di-[N-(PhF)amino]azelate 10 (PhF = 9-(9-phenylfluorenyl)). Subsequent hydride reduction of 10 to an isomeric mixture of diols 12, selective protection of the primary alcohol as tert-butyldimethylsilyl ether 14 and oxidation of the secondary alcohol gave di-tert-butyl 4-tert-butyldimethylsilyloxymethyl-5-oxo-2,8-di-[N-(PhF)amino]azelate 15 as a separable diastereomeric mixture. Linear ketone 15 and alcohol 14 were then converted to the indolizidinone heterocycles by routes featuring reductive aminations, methanesulfonate displacements, and lactam cyclizations. A series of rigid scaffolds designed to mimic the conformations of dipeptides possessing serine, lysine, and glutamate residues has thus been synthesized by this new route for installing heteroatomic side-chain functional groups onto the indolizidin-2-one system.     

Total Synthesis of the Polyoxygenated Sesquiterpenes Guignarderemophilanes C and D

The total syntheses of the neural anti‐inflammatory agents guignarderemophilanes C and D have been accomplished for the first time starting from γ‐hydroxy carvone in 15 and 14 steps, respectively. The presented synthetic route proceeds via a known intermediate, whose synthesis has been elaborated in our group in the course of the total synthesis of the sesquiterpenoid periconianone A. Key for the successful conversion of this intermediate into both targets was finding a suitable strategy to install the 1,2,3‐trihydroxylated A‐ring scaffold. For this purpose, we effectively employed a Mitsunobu inversion, epoxidation, and regioselective epoxide opening sequence, before the bicyclic ring system was constructed by an aldol condensation reaction on a sterically demanding substrate. Our reported synthesis set the stage for SAR studies to prepare even more potent compounds by modification and derivatization of the natural product's scaffold.     

Second-generation, highly abbreviated route for elaboration of the oxetane D-ring in a fully functionalized taxane

A six-step conversion of oxirane 3 to oxetane 9 is reported. The synthetic route takes particular advantage of the acid-catalyzed ring opening of 3 to allyl alcohol 4 in a polar reaction medium and of the heightened capability of the OsO4.TMEDA complex to effect the efficient stereocontrolled dihydroxylation of this intermediate. The overall yield of the new sequence is 33%.     

Total synthesis of (-)-herbindoles A, B, and C via transition-metal-catalyzed intramolecular [2 + 2 + 2] cyclization between ynamide and diynes

The total syntheses of (-)-herbindoles A, B, and C as naturally occurring forms were accomplished for the first time through transition-metal-catalyzed intramolecular [2 + 2 + 2] cyclization between ynamide and diynes. This strategy provided a highly efficient synthetic route to all three herbindoles from an identical indoline derivative as a common intermediate.     

Synthesis of the 3-(3,4,5-Trimethoxyphenyl)-pyrrolidine: A New Conformationally Constrained Mescaline Analogue

The total synthesis of the 3‐(3,4,5-trimethoxyphenyl)-pyrrolidine, a new and conformationally constrained mescaline analogue, was accomplished in a concise and efficient manner. The synthetic route encompassed only 4 steps from the starting N-Cbz-3-pyrrolidine, in 46% overall yield. The route features a highly effective Heck arylation of the non-activated olefin N-Cbz-3-pyrrolidine with the 3,4,5-trimethoxybenzene diazonium tetrafluoroborate. The hemiaminal (lactamol) Heck adduct was converted to the mescaline analogue in a sequence of reactions: (a) dehydration of the intermediate hemiaminal 3 with trifluoroacetic acid anhydride, (b) hydrogenation/hydrogenolysis of the endocyclic enecarbamate 6 with H2-Pd/C, and (c) formation of the rather stable mescaline analogue in the form of a hydrochloride salt. The target molecule constitutes a new mescaline analogue with potential activity towards 5‐HT2 dopamine receptors.     

A second-generation synthesis of the C1-C28 portion of the altohyrtins (spongistatins)

A practical second-generation synthesis of an advanced intermediate in our total synthesis of altohyrtin C (spongistatin 2) has been developed. A new approach to the C1-C15 (AB) portion features a vinyllithium addition to an aldehyde followed by a palladium-catalyzed allylic reduction to install the troublesome C13-C15 segment. Our general approach to the C16-C28 (CD) spiroketal has been retained, but some improvements have been made. Most notably, the kinetically controlled CD-spiroketalization reaction now proceeds in high yield with excellent diastereoselection. This new strategy uses the anti-aldol coupling used in our first-generation synthesis to join AB and CD fragments. A total of 9.6 g of intermediate 57 has been produced using this improved route.     

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.