Total syntheses of (+/-)-montanin A and (+/-)-teuscorolide

The first total syntheses of (+/-)-montanin A and (+/-)-teuscorolide have been achieved from an advanced precursor previously developed via a Diels-Alder strategy; in the synthetic sequence, the synthesis of montanin A was first accomplished in 8 steps, from which teuscorolide was readily achieved in 2 steps by using a novel furan oxidative cyclization-retro-cyclization process as a key operation.     

Enantioselective total synthesis of isishippuric acid B via intramolecular Michael reaction

The first enantioselective total synthesis of isishippuric acid B bearing a novel 4,5-seco-6-norquadrane skeleton was accomplished from (R)-citronellal with use of a Diels-Alder cycloaddition and an intramolecular Michael addition as the ring-forming steps. Comparison of the optical rotation of the synthetic material with that of the natural product confirmed the absolute configuration of isishippuric acid B to be 1R, 2R, 8R, and 11R.     

Synthesis of saramycetic acid

The first reported synthesis of saramycetic acid, a degradation product of the complex thiopeptide antibiotic cyclothiazomycin, is achieved in nine steps and 11% overall yield from diethoxyacetonitrile by a strategy, which incorporates two Hantzsch thiazole syntheses using thioamides prepared from the corresponding nitriles without the use of gaseous H₂S. The synthetic material was transformed to methyl saramycetate, which had spectroscopic properties in excellent agreement with the literature data.     

Strychnine as Target,Samarium Diiodide as Tool: A Personal Story

Strychnine stands out from the group of classical natural products as one of the first complex compounds to be isolated in pure form and an extreme challenge to be structurally characterized. It has played a central role in natural product total syntheses and the surge in the development of innovative synthetic methods for many decades. Recently, we have accomplished one of the shortest formal total syntheses of strychnine (in ten steps and 14% overall yield or even shorter in eight steps and 10% overall yield). The evolution of a productive synthetic strategy, as well as the synthetic challenges tackled, are described here in detail, including examples of related transformations. The successful synthetic strategy was inspired by the premise that the core structure could be derived from simple aromatic indole precursors by a reductive SmI₂‐induced ketyl–aryl coupling. Other key reactions included a diastereoselective reduction and a regioselective elimination protocol. Altogether one of the shortest syntheses of iso‐strychnine and hence of strychnine was established.     

Total synthesis of (+/-)-goniomitine via a formal nitrile/donor-acceptor cyclopropane [3 + 2] cyclization

The total synthesis of (+/-)-goniomitine has been accomplished in 17 linear steps with 5.2% overall yield starting from commercially available delta-valerolactam. A synthetic highlight includes the first application of a formal [3 + 2] cycloaddition between a highly functionalized nitrile and a donor-acceptor cyclopropane to prepare an indole nucleus. The use of a microwave reactor is shown to greatly improve the reaction times for two steps.     

Enantioselective synthesis of a key "A-ring" intermediate for the preparation of 1alpha-fluoro vitamin D3 analogues

1Alpha-fluoro A-ring dienol 2, a useful building block for the preparation of fluorinated vitamin D3 analogues, was synthesized in eight steps from 4-{[tert-butyldimethylsilyl]oxy}cyclohexanone. The most distinctive synthetic development to emerge from this new synthesis is an unprecedented substrate-controlled diastereoselective fluorodesilylation of an advanced dienylsilane intermediate. This is the first enantioselective route to compound 2 relying on the use of an electrophilic fluorinating reagent.     

Synthesis of the marine bromotyrosine psammaplin F and crystal structure of a psammaplin A analogue

Psammaplin F, an unsymmetrical disulfide bromotyrosine, was isolated from the sponge Pseudoceratina purpurea in 2003. We reported here the first total synthesis of psammaplin F in 12% overall yield by employing Cleland's reagent reduction as key step. The longest linear synthetic sequence starting from 3-bromo-4-hydroxybenzaldehyde and hydantoin was seven steps. In addition, a detailed X-ray crystal structure analysis of psammaplin A analogue 8b is given for the first time.     

A Short,Efficient Synthesis of the Octamannan Residue of High Mannose Type Sugar Chains

Abstract

An efficient route for the synthesis of octamannan 1, found in high mannose type sugar chains, is described. to construct octasaccharide 1 by as few synthetic steps as possible, we employed a chemoenzymatic strategy: the enzymatic synthesis of oligosaccharide blocks using glycosidases followed by chemical coupling to form a branched structure. By use of this methodology, many synthetic steps were eliminated and 1 was easily synthesized.     

Convergent stereoselective and efficient synthesis of furanic-steroid derivatives

The stereoselective synthesis of furanic-steroid derivatives involving ring-closing metathesis and catalytic hydrogenation as key steps is described. The synthetic strategy was first illustrated by the synthesis of the furanic-estrane derivative 1 in seven steps starting from estrone and 2-methylene-propane-1,3-diol. This compound initially targeted as a potential inhibitor of 17β-hydroxysteroid dehydrogenase type 1 by a docking experiment was found to inhibit the enzyme. The scope of this new strategy was also extended to furanic-androstane derivatives by synthesizing compound 20.     

Synthesis of Arcyriarubin A and Arcyriaflavin A via Cross-Coupling of Indolylboronic Acid with Dibromomaleimides

Arcyriarubin A was first isolated by Steglich in 1980; it is also the key intermediate in the synthesis of indolocarbazole compounds. A new synthetic approach to the natural products arcyriaflavin A and arcyriarubin A is described. The key step is a Suzuki cross-coupling reaction using indolylboronic acid as the starting material. The preparation of arcyriaflavin A was accomplished in eight steps from indole for a total yield of 21%.     

Solid-phase synthesis of multiple classes of peptidomimetics from versatile resin-bound aldehyde intermediates

A wide variety of highly substituted lactam containing peptidomimetic scaffolds are prepared by solid-phase synthesis from a single, versatile class of resin-bound aldehyde intermediates (1). These include monocyclics 3, bicyclics 4, tricyclics 5, and tetracyclics 6. The key intermediate 1 is readily synthesized from resin-bound natural or unnatural alpha-amino acids. The synthetic procedures permit the construction of a large diversity of substitution patterns for ready use in combinatorial chemistry. In every case, the release of final products from resin is by a cyclitive cleavage process. Since this depends on successful completion of multiple intermediate synthetic steps, the products are often quite pure, even though previous steps involve only a filtration workup. The mild conditions for many of these synthetic procedures offer the promise of using this chemistry in peptide fragment condensations to produce modified peptides, at either the N-terminus or C-terminus, or as individually assembled peptide segments with a wide variety of conformationally restricted peptidomimetic linkers at the point of juncture.     

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).     

De novo asymmetric synthesis of all-D-, all-L-, and D-/L-oligosaccharides using atom-less protecting groups

Oligosaccharide synthesis is hindered by the need for multiple steps as well as numerous selective protections and deprotections. Herein we report a highly efficient de novo route to various oligosaccharide motifs, of use for biological and medicinal structure activity studies. The key to the overall efficiency is the judicious use of asymmetric catalysis and synthetic design. These green principles include the bidirectional use of highly stereoselective catalysis (Pd(0)-catalyzed glycosylation/post-glycosylation). In addition, the chemoselective use of C-C and C-O π-bond functionality, as atom-less protecting groups as well as an anomeric directing group (via a Pd-π-allyl), highlights the atom-economical aspects of the route to a divergent set of natural and unnatural oligosaccharides (i.e., various d-/l-diastereomers of oligosaccharides as well as deoxysugars which lack C-2 anomeric directing groups). For example, in only 12 steps, the construction of a highly branched heptasaccharide with 35 stereocenters was accomplished from an achiral acylfuran.     

A new synthesis of (−)-epipyriculol: a phytotoxic metabolite

A convenient synthesis of the phytotoxic natural product epipyriculol has been accomplished in 17 steps from methyl l-tartrate. The synthetic strategy is based upon the use of a butanediacetal-protected scaffold as central core from which the alkenyl side chains were assembled.     

Asymmetric total synthesis of (-)-saframycin A from L-tyrosine

The asymmetric total synthesis of (-)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing L-tyrosine as the starting chiral building block in 24 steps for the longest linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular Pictet-Spengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protection-deprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in the first two steps resulted in both high selectivity and efficiency of the synthetic route.     

First Synthesis of 3''''- Geranyl-2'''', 3,4,4''''-tetrahydroxychalcone with 5 α- Reductase Inhibitory Properties

The geranylated chalcone 1,3′-geranyl-2′, 3,4,4′-tetvahydroxychalcone with high 5α-reductase inhibitory prop erties, was isolated from Artocarpus incisus by Shimizu in 2000. [1] Herein, we describe the first synthesis of the natural product 1 by four steps starting from compounds 2 and 7. The synthetic route was shown in Scheme 1:     

Convenient Synthetic Route to (±)-Frontaliu

Frontalin, the pheromone of Dendroctonus Bark Beetles, was first isolated by Kinzer^[1] from hindgut extracts of male western pine beetles. Its structure was determined as 1,5-dimethyl-6,8-dioxabicyclo[3.2.1] octane (1) by spectral analysis and was confirmed by the synthesis of its racemate^[1,2]. On account of its structural novelty and economic value, this compound has been studied extensively ^[3-5]. But most of its synthetic methods required relatively longer steps or suffered from the inaccessibility of starting materials or reagents. Now, we report a convenient synthetic method for (±)-frontalin starting from easily available material, natural unsaturated aliphatic aicd, oleic acid. The synthesis is shown in scheme.     

Asymmetric total synthesis of (+)-isocryptotanshinone and formal synthesis of (−)-cryptotanshinone

The first asymmetric total synthesis of (+)-isocryptotanshinone was achieved in 12 linear steps with 12% overall yield from commercially available dihydrobenzopyrone. The key step was a base-mediated cyclization reaction. In addition, the synthetic strategy included the formal synthesis of (−)-cryptotanshinone.     

Diastereoselective synthesis of allosecurinine and viroallosecurinine from menisdaurilide

A new and versatile synthetic route to Securinega alkaloids is reported. The first synthesis of allosecurinine has been accomplished in seven steps and 40% yield, starting from (+)-menisdaurilide, using a vinylogous Mannich reaction as the key transformation. Similarly, viroallosecurinine has been synthesized from (-)-menisdaurilide.     

Enantioselective synthesis of stephacidin B

We describe an enantioselective synthetic route to the antiproliferative alkaloid stephacidin B (1) proceeding in 18 steps and 4.0% yield from 4,4-(ethylenedioxy)-2,2-dimethylcyclohexanone (3). Key features of the synthetic sequence include the use of the Corey-Bakshi-Shibata (CBS) reduction to introduce asymmetry early in the synthetic route, use of the novel electrophile N-(tert-butoxycarbonyl)-5-(isopropylsulfonyloxymethyl)-2,3-dihydropyrrole in a stereoselective enolate alkylation, a diastereoselective Strecker-type addition of hydrogen cyanide to an N-Boc enamine substrate in the solvent hexafluoroisopropanol, platinum-catalyzed nitrile hydrolysis under neutral conditions, cyclization of an acylamino radical intermediate to form the diketopiperazine core of stephacidin B, and implementation of a convergent procedure for introduction of the key 3-alkylidene-3H-indole 1-oxide functional group in the final stage of the route to prepare the structure 2, previously proposed to be the fungal metabolite avrainvillamide (17 steps, 4.2% yield). We observed that synthetic (-)-2 dimerized in the presence of triethylamine to form (+)-stephacidin B (>95%). We also obtained evidence that 2 can form 1 under mild conditions, and that 2 reacts with nucleophiles, such as methanol, by conjugate addition.