Total synthesis of (+)-asperazine

The first total synthesis of the structurally novel cyclotryptophan alkaloid asperazine is reported. The central step in the synthetic sequence is a diastereoselective intramolecular Heck reaction in which the substituent controlling stereoselection is external to the ring being formed. This synthesis confirmed the structure of (+)-asperazine (1) proposed by Crews and co-workers and provided material for additional biological studies. The in vitro cytotoxicity originally reported for the marine isolate was not confirmed with synthetic (+)-asperazine.     

Asymmetric total syntheses of (+)-mycoepoxydiene and related natural product (-)-1893A: application of one-pot ring-opening/cross/ring-closing metathesis to construct their 9-oxabicyclo[4.2.1]nona-2,4-diene skeleton

The total syntheses of (+)-mycoepoxydiene and (-)-1893A have been completed. The present synthetic strategy features the use of one-pot ring-opening/cross metathesis (ROM/CM) followed by a ring-closing metathesis (RCM) reaction, allowing for the concise construction of the 9-oxabicyclo[4.2.1]nona-2,4-diene framework from a 7-oxabicyclo[2.2.1]hept-2-ene derivative and 1,3-butadiene. The sequential metathesis product was converted into (+)-mycoepoxydiene through the oxidative rearrangement of a furfuryl alcohol to a pyranone, thereby establishing its absolute stereochemistry. From the common intermediate, a structurally related natural product (-)-1893A was also synthesized via the vinylogous aldol reaction.     

The Preparation and Evaluation of Electron Poor Benzylidene Fischer Carbene Complexes: Studies Toward the Total Synthesis of (+)-Olivin

The continued exploration into the fate of the benzannulation reaction is put forth using the electronic nature of substituents on the aryl ring of benzylidene Fischer carbene complexes as a handle to predict, using σ-para values as a guide, the outcome of the reaction based on the accepted mechanism. The design of this work focuses on evaluation of the synthetic utility of the benzannulation reaction and the means by which this reaction may be improved to be a better synthetic tool in the preparation of complex natural products as this is illustrated in our ongoing total synthesis of (+)-olivin which uses the benzannulation reaction as the key convergent synthetic step. To accomplish these tasks, the preparation of several electron poor benzylidene Fischer carbene complexes was carried out and their reaction with simple alkyne substrates studied. While much is known about the preparation of electron rich benzylidene Fischer carbene complexes, little is known about the preparation of their electron poor counterparts. Thus efforts toward developing useful preparative methods of these elusive targets has also been studied. While the use of both carbon and oxygen based aryl substituents has been explored, to date the preparation of benzylidene carbene complexes containing oxygen based aryl substituents has been exploited to a greater degree since these systems carry more immediate synthetic importance. This is so because the skeletal core of many of the natural products that have been targeted with the benzannulation reaction including (+)-olivin contain a highly oxygenated polycyclic aromatic core. The enhancement in efficiency of the benzannulation reaction using this synthetic methodology is demonstrated by the successful completion of the convergent synthetic step in the total synthesis of (+)-olivin.     

Scope of the organocatalysed asymmetric reductive amination of ketones with trichlorosilane

A highly active organocatalyst has been shown to affect the asymmetric reductive amination of ketones producing both aromatic and aliphatic amines. At 1 mol% catalyst loading, a series of structurally diverse chiral amines were quickly and economically prepared with good enantioselectivity and generally useful yield. The efficient synthesis of the calcimimetic (+)-NPS R-568 (67%, 89% ee) demonstrated the synthetic applicability of this methodology.     

Synthesis and biological evaluation of 6-oxa-nor-tropane glycomimetics as glycosidase inhibitors

The preparation of polyhydroxylated 6-oxa-nor-tropane glycomimetics structurally related to the glycosidase inhibitor family of the calystegines is reported. The synthetic strategy involves the furanose→piperidine rearrangement of 5-deoxy-5-ureido-l-idose precursors, followed by intramolecular glycosylation involving the primary hydroxyl group. Inversion of the configuration at C-3 in the resulting 6-oxa-(+)-calystegine B₂ analogue allows accessing the elusive 3-epi-6-oxa-(+)-calystegine B₂ skeleton. Acid-catalyzed opening of the nor-tropane bicycle was observed, however, which could be avoided by careful neutralization of the reaction mixture. The inhibition results suggest that (+)-calystegine B₂ derivatives and the corresponding C-3 epimers can be seen as glucomimetics and galactomimetics, respectively, pointing to a 1-azasugar mode of action for this family of alkaloids.     

Identification of an Unexpected 2-Oxonia[3,3]sigmatropic Rearrangement/Aldol Pathway in the Formation of Oxacyclic Rings. Total Synthesis of (+)-Aspergillin PZ

This paper reports the first unambiguous evidence that the cascade synthesis of tetrahydrofuran-containing oxacyclic molecules depicted in Scheme 12 can take place by a 2-oxonia[3,3]sigmatropic/aldol mechanism rather than by a Prins cyclization/pinacol rearrangement sequence. The 8-oxabicyclo[3.2.1]octyl aldehyde products of this reaction, 20 and 29, were employed to complete the first total synthesis of the structurally remarkable isoindolone alkaloid (+)-aspergillin PZ (1). The lack of activity seen in two tumor cell lines for synthetic (+)-aspergillin PZ calls into question the suggestion that aspergillin PZ, like many aspochalasin diterpenes, might exhibit useful antitumor properties.     

Transannular Diels-Alder studies on the asymmetric total synthesis of chatancin: the pyranophane approach

[reaction: see text] A pathway is proposed for the biosynthesis of (+)-chatancin and (+)-sarcophytin linking these tetracycles to cembranoids by a pyranophane transannular Diels-Alder reaction. Preliminary synthetic results in this direction to reach macrocyclic dienedione 28 from farnesol are reported. Major synthetic steps include a Prins reaction, two enantioselective hydrogenations, and a macrocyclization via a beta-ketosulfoxide Michael-addition on an enone.     

Formal enantioselective synthesis of (+)-compactin

[reaction: see text] The challenging structural features and important biological activity of (+)-compactin (1) explain the substantial synthetic interest that it has generated. We report a novel enantioselective approach to the advanced intermediate 2a, which constitutes a formal synthesis of (+)-1. The sequence utilizes MacMillan's organocatalytic Mukaiyama-Michael reaction, which stereoselectively adds the silyloxyfuran 6 to alpha,beta-unsaturated aldehyde 7. The chirality generated in this reaction guides the formation of the other three consecutive stereocenters found in 2a.     

Asymmetric total synthesis of (+)-gabosine C and (+)-4-epi-gabosine J using acetate migration and RCM reaction

A concise, unified and stereoselective total synthesis of (+)-gabosine C and (+)-4-epi-gabosine J from a common polyhydroxylated cyclohexenol intermediate which was synthesized from readily available D-ribose has been described. The synthetic avenue includes stereoselective Grignard reaction, silyl ether deprotection followed by acetate migration, RCM reaction, oxidative diol cleavage, hydroxymethylation and oxidative rearrangement as key steps.     

I2/K2CO3-promoted ring-opening/cyclization/rearrangement/aromatization sequence: A powerful strategy for the synthesis of polysubstituted furans

An efficient and straightforward synthetic method has been developed for the preparation of 4-cyanofuran-3-carboxylate derivatives via iodine/potassium carbonate-promoted ring-opening/cyclization/rearrangement domino reaction of 1-cyanocyclopropane-1-carboxylates, which are a wide range of structurally interesting and pharmacologically significant compounds.     

Synthetic approach to seco-tetracenomycin natural products saccharothrixone A–C

Design and development of first synthetic approach to the functionalized tetracyclic framework of structurally novel seco-tetracenomycin natural products saccharothrixones A–C has been reported. A thermal dehydro Diels-Alder reaction of an arenyne-alkyne unit has been utilized as the key synthetic step. This strategy has been extended for the generation of a small library of diversely functionalized tetracyclic systems of seco-tetracenomycins. An approach for the synthesis of poly-hydroxyl tetracyclic system has also been described. This report represents the first synthetic approach to the tetracenomycin natural products saccharothrixones A–C.     

A six-step synthetic approach to marine natural product (+)-aureol

A concise synthetic approach to the marine natural product (+)-aureol has been achieved from readily available starting materials using obviously fewer steps in comparison to the related report in literature (6 steps versus 12 steps from (+)-sclareolide). Key steps of this protocol include a boron trifluoride-catalyzed domino 1,2-H and 1,2-methyl shifts and a nickel(II)-catalyzed cross-coupling reaction between an alkyl iodide and an aryl Grignard reagent.     

Total synthesis of (+)-macquarimicin A

The first total synthesis of (+)-macquarimicin A (1), a novel inhibitor of neutral sphingomyelinase (N-SMase) with antiinflammatory activity, has been accomplished. The present work determined the absolute configuration of (+)-1 and revised the C(2)-C(3) geometry to be Z. The synthesis features a transannular Diels-Alder reaction, which constructed the tetracyclic framework stereoselectively, and a convergent and efficient synthetic pathway, which afforded (+)-macquarimicin A (1) in 27 steps (longest linear sequence) with 9.9% overall yield.     

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.     

Diastereo‐ and Enantioselective Access to Stereotriads through a Flexible Coupling of Substituted Aldehydes and Alkenes

A flexible redox‐neutral coupling of aldehydes and alkenes enables rapid access to stereotriads starting from a single stereocenter with perfect levels of enantio‐ and diastereoselectivity under mild conditions. The versatility of the method is highlighted by the installation of heteroatoms along the tether, which enables a route to structurally diverse building blocks. The formal synthesis of (+)‐neopeltolide further demonstrates the synthetic utility of this approach.     

钯催化二溴代化合物自偶联环化合成二苯并[a,e]环辛四烯

由于独特的结构和广泛的应用,多取代环辛四烯及其苯并稠环衍生物的合成方法研究具有重要意义.本文报道了一种钯催化烯基溴化物与芳基溴化物的偶联反应.利用此钯催化的环化自偶联反应,以中等至较好的收率高选择性地从双溴代芳基或烯基化合物合成了多种二苯并[a,e]环辛四烯衍生物.     

Formal synthesis of (+)-brefeldin A: application of a zinc-mediated ring expansion reaction

An efficient formal synthesis of (+)-brefeldin A was accomplished through a synthetic approach that relied upon three keys steps. The five-membered ring was generated in a stereocontrolled fashion through application of a tandem conjugate addition-intramolecular cyclization method developed by Toru. Ring-closing metathesis provided access to a twelve-membered beta-keto lactone, which was ring-expanded to the alpha,beta-unsaturated-gamma-keto lactone through a zinc carbenoid-mediated reaction. Conversion of this lactone to (+)-brefeldin A has been reported previously.     

Basic instinct: design, synthesis and evaluation of (+)-sparteine surrogates for asymmetric synthesis

(-)-Sparteine, a naturally occurring lupin alkaloid, is widely used as a chiral ligand for asymmetric synthesis. To address the limitation that sparteine is only available as its (-)-antipode, our group introduced a family of (+)-sparteine surrogates that are structurally similar to (+)-sparteine but lack the D-ring. After briefly summarising the design aspect, this feature article provides an overview of synthetic routes to the sparteine surrogates and a detailed comparison with (-)-sparteine in a range of asymmetric reactions. The main conclusions are: (i) the (+)-sparteine surrogates are most easily prepared starting from (-)-cytisine extracted from Laburnum anagyroides seeds; (ii) in nearly all examples, use of the (+)-sparteine surrogates produced essentially equal but opposite enantioselectivity compared to (-)-sparteine and (iii) the N-Me-substituted (+)-sparteine surrogate is the most useful and versatile of those investigated.     

Synthesis of (+)-salvianolic acid A from sodium Danshensu

(+)-Salvianolic acid A, one of the most active components in the traditional Chinese medicine Danshen, has been synthesized over 10 steps in 6.5% overall yield. Starting from inexpensive ortho-vanillin and sodium Danshensu (synthesized via asymmetric catalysis in our group), the process consists of the following: A Wittig reaction that gives the desire product with absolute E-configuration, a demethylation reaction with AlCl₃ in a satisfactory yield, and a practical deprotection of allylic groups to afford the terminal product (+)-salvianolic acid A. The current synthetic technology possesses the advantages of using inexpensive starting materials, mild reaction conditions and has the potential for use in large scale synthesis.     

Concise enantioselective total syntheses of (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine and (+)-norchelidonine by a Pd II-catalyzed ring-opening strategy

New enantioselective syntheses of the B/C hexahydrobenzo[c]phenanthridine alkaloids (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine, and (+)-norchelidonine are described. Our rapid and convergent route to this class of natural products involved the development and application of a Pd II-catalyzed asymmetric ring-opening reaction of a meso-azabicyclic alkene with an aryl boronic acid as the key step. By screening a variety of functionalized ortho-substituted aryl boronic acids, chiral ligands and reaction conditions we were able to prepare the requisite cis-1-amino-2-aryldihydronaphthalenes in high yield and in up to 90 % ee. Early attempts to complete the synthesis of (+)-homochelidonine using an N-Boc azabicyclic alkene are described in full. The successful route required a protecting group alteration followed by B ring formation and then stereoselective installation of the C-11 syn-hydroxy group by regioselective epoxide ring-opening using a hydride source. Ring-opening of the same epoxide intermediate with water ultimately led to the synthesis of (+)-chelamidine. The same strategy was then used to synthesize the other structurally similar B/C hexahydrobenzo[c]phenanthridine alkaloids, (+)-chelidonine, (+)-chelamidine, and (+)-norchelidonine.