Oxocarbenium ion cyclizations for C-branched cyclitols: synthesis of a relay intermediate for fumagillin analogues

A highly stereoselective oxocarbenium ion-alkene cyclization for synthesis of C-branched cylitols is described. This methodology was applied to 10S, a potentially versatile intermediate for side-chain analogues of the antiangiogenic agent fumagillin. Compound 10S was subsequently converted to diene 5. Because racemic 5 has been converted to racemic fumagillin, this synthesis of 5 constitutes a formal synthesis of the natural product.     

Oxidative synthesis of azacyclic derivatives through the nitrenium ion: application of a hypervalent iodine species electrochemically generated from iodobenzene

Oxidation of the methoxyamide derivatives 1, 4, and 7 has been examined to elaborate efficient synthetic methodology of the azacyclic derivatives 2, 3, 5, 6, and 8, which would be applicable as synthetic intermediates of complicated bioactive substances. In addition to direct anodic and PIFA [phenyliodine(III) bis(trifluoroacetate)] oxidations, an active species derived from iodobenzene generated under electrolytic conditions was examined as an oxidant, and its synthetic efficacy was demonstrated in comparison of the reaction outcomes with other oxidation methods. In the oxidation, the methoxy substitution of substrates modulated the cyclization mode to provide the azaspiro- (2, 8) or quinolinone-type (3, 5, 6) products.     

Stereoselective synthesis of α-glucosides by neighbouring group participation via an intermediate thiophenium ion

The use of a 2-O-(thiophen-2-yl)methyl protecting group allows highly stereoselective α-glucosylation of a trichloroacetimidate donor; increased stereoselectivity, presumably arising from the intramolecular formation of a transient intermediate thiophenium ion, correlates with increased bulk of the glycosyl acceptor.     

Oxidative cyclizations: the asymmetric synthesis of (-)-alliacol A

A tandem anodic coupling-Friedel-Crafts alkylation strategy has been used to rapidly complete the asymmetric synthesis of alliacol A. The anodic oxidation reaction allowed for the generation of a new bond between two nucleophiles. In the synthesis, the absolute stereochemistry of the final natural product is set relative to a methyl group that is incorporated early in the sequence using an asymmetric Michael reaction.     

Stereoselective synthesis of the naturally occurring styryllactones (+)-goniofufurone and (+)-cardiobutanolide

The naturally occurring gamma-lactones (+)-goniofufurone 1 and (+)-cardiobutanolide 2, two pharmacologically active products from Goniothalamus species (Annonaceae), have been synthesized in enantiopure form using l-erythrulose as the chiral starting material. Key steps of these syntheses were a stereoselective anti boron aldol reaction and an asymmetric allylboration.     

Furanophane transannular Diels-Alder approach to (+)-chatancin: an asymmetric total synthesis of (+)-anhydrochatancin

(+)-anhydrochatancin was synthesized while attempting an enantioselective total synthesis of (+)-chatancin. The presented route constitutes the furanophane approach, one of the two ways of proposed biosynthesis which may involve transannular Diels-Alder (TADA) reaction to link this diterpene biogenetically to the furanocembranoids. Highlights of the synthetic work include the assembly of chiral, acyclic, trisubstituted furan 28 via a coupling of aldehyde 10 and dilithiofuroic acid 11, a macrocyclization to furanophane 29E via ring-closing metathesis, a TADA reaction to reach tetracyclic intermediate 4, and a hydride shift mediated oxygen transposition as a final rearrangement to the target. Unfortunately, the strongly acidic condition required for the last step allows only the isolation of anhydrochatancin 30 due to the acid sensitivity of chatancin 1.     

Versatile asymmetric synthesis of the kavalactones: first synthesis of (+)-kavain

[reaction: see text] Three asymmetric pathways to the kavalactones have been developed. The first method is chiral auxiliary-based and utilizes aldol reactions of N-acetyl thiazolidinethiones followed by a malonate displacement/decarboxylation reaction. The second approach uses the asymmetric catalytic Mukaiyama additions of dienolate nucleophile equivalents developed by Carreira and Sato. Finally, tin-substituted intermediates, prepared by either of these routes, can serve as advanced general precursors of kavalactone derivatives via Pd(0)-catalyzed Stille couplings with aryl halides.     

Stereoselective strategy for the synthesis of (+)-polyoxamic acid and some polyhydroxylated pyrrolidines

An efficient strategy for the synthesis of dihydroxy chiral amino moiety which can be utilized for the synthesis of polyoxamic acid, 1,4-dideoxy-1,4-imino-d-xylitol, and dihydroxy pyrrolidine by using highly diastereoselective nucleophilic addition on chiral imine has been reported.     

Two remarkable epimerizations imperative for the success of an asymmetric total synthesis of (+)-aigialospirol

Two remarkable epimerization processes were uncovered during our pursuit of an enantioselective synthesis of(+)-aigialospirol featuring a cyclic acetal tethered ring-closing metathesis.Through modeling,we were able to turn these two unexpected epimerizations to our advantage via modeling to ensure a successful and concise total synthesis,thereby firmly establishing cyclic acetal tethered RCM as a powerful strategy in natural product synthesis.Most importantly,calculations allowed us to fully understand the ...     

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.     

Convergent asymmetric synthesis of (+)-aureothin employing an oxygenase-mediated resolution step

Need an enzymatic push? The desymmetrization of α,α'-dimethoxy-γ-pyrone allows the convergent and rapid preparation of the complete carbon skeleton of (+)-aureothin. The final step in the synthesis of the target molecule is the regiodivergent parallel kinetic resolution promoted by cytochrome P450 monooxygenase AurH to deliver the enantiopure natural product.     

Facile and efficient synthesis of lactols by a domino reaction of 2,3-epoxy alcohols with a hypervalent iodine(III) reagent and its application to the synthesis of lactones and the asymmetric synthesis of (+)-tanikolide

The domino reaction of 2,3-epoxy-1-alcohol derivatives, namely tetrasubstituted 2,3-epoxy-1-alcohols and 2- or 3-alkyl trisubstituted 2,3-epoxy-1-alcohols, with PhI(OCOCF(3))(2) in the presence of H(2)O is described in detail. In this reaction, several types of lactol derivatives can be directly obtained from the 2,3-epoxy-1-alcohol derivatives in a single operation. The obtained lactols were successively converted into the corresponding lactones. This reaction is applicable to the construction of optically active lactone compounds. The asymmetric total synthesis of (+)-tanikolide, an antifungal marine natural product, has been effectively achieved by using this reaction.     

Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

In the presence of (R)-SEGPHOS-Pd(OAc)₂ catalyst, the intramolecular N-arylation of ortho-tert-butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89-98% ee) to give optically active atropisomeric lactams having an N-C chiral axis. MPLC purification of the enantio-enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric lactam with various alkyl halides gave α-substituted and α,α-disubstituted lactam products with high diastereoselectivity. α-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.     

Stereoselective synthesis of (+)-cryptocarya diacetate by an iterative Prins cyclisation and reductive cleavage sequence

A highly stereoselective synthesis of (+)-cryptocarya diacetate is achieved through our recently developed strategy for the construction of 1,3-diols via Prins cyclisation. The route relies mainly on the reductive cleavage of allylic ethers, ozonolysis and Wittig olefination along with Prins cyclisation.     

Stereoselective synthesis of an advanced taxusin intermediate: an application of the type 2 intramolecular Diels–Alder reaction

Stereoselective synthesis of an advanced taxusin intermediate is described. The key step is the successful application of the type 2 intramolecular Diels–Alder (IMDA) reaction for the assembly of the tricyclic core of this natural product.     

Studies in macrolide synthesis: A concise asymmetric synthesis of a macrolide intermediate for the erythronolides.

The enantiomerically-pure 14-membered ring macrolide 1 is prepared in 14 steps from the racemic aldehyde 4, Z=SPh. The C₂-C₄ and C₈-C₁₀ stereorelationships in 1 are controlled in a single step by an Evans aldol condensation with (±)-4. Macrolactonisation, 23 → 1, takes place in high yield (91%).     

A strategy for the asymmetric synthesis of medium ring oxygen heterocycles: Enantioselective total synthesis of (+)-octahydrodeacetyldebromolaurencin

The asymmetric synthesis of the laurencin degradation product (2) by methylenation of the chiral heptanolide (5), conformationally controlled hydroboration of the enol ether (6), to give exclusively the cis-alcohol (7), and introduction of the pentyl side chain, demonstrates a new approach to the enantioselective synthesis of 2,8-disubstituted oxocanes, and confirms the absolute configuration of laurencin (1).