A tether controlled exo-selective trans-annular Diels-Alder (TADA) reaction

[reaction: see text] A fully substrate controlled stereoselective route to construct cis-hexahydronaphthalene 4 is described starting from nonracemic butenolide 6. The key step is an exo-selective transannular Diels-Alder reaction (TADA) of tetraene 5, whose intrinsic constraint allows selective formation of one stereodefined product. Compound 4 is a key intermediate in the synthesis of the novel antibiotic branimycin (1).     

Enantioselective synthesis of antiinfluenza compound A-315675

Drug discovery efforts at Abbott Laboratories have led to the identification of influenza neuraminidase inhibitor A-315675 (1) as a candidate for development as an antiinfluenza drug. A convergent, stereoselective synthesis of this highly functionalized pyrrolidine is reported that utilizes pyrrolinone 2 as the key intermediate. The C5, C6 stereochemistry was established through a diastereoselective condensation of chiral imine compound 3 with silyloxypyrrole 4 to give pyrrolinone 2. The stereochemical outcome of this reaction depended critically on the choice of the imine functional group (FG), with tritylsulfenyl and (R)-toluenesulfinyl providing the desired products in good yields as crystalline intermediates. Conversion of pyrrolinone 2 into 1 was accomplished in seven subsequent steps, including Michael addition of cis-1-propenylcuprate at C4 and introduction of a cyano group as a carboxylic acid equivalent at C2.     

New approach to aphidicolin and total asymmetric synthesis of unnatural (11R)-(-)-8-epi-11-hydroxyaphidicolin by tandem transannular Diels-Alder/aldol reactions

The 8-epiaphidicolane skeleton (3) was formed in one key reaction by highly diastereoselective tandem transannular Diels-Alder (TADA)-aldol reactions from the trans-trans-cis trienic macrocycle (4). The unnatural derivative (11R)-(-)-8-epi-11-hydroxyaphidicolin (2) was thus constructed, and an original solution to the C16 functionalization problem of many aphidicolin (1) syntheses is presented.     

Formal total synthesis of (+/-)-gamma-lycorane and (+/-)-1-deoxylycorine using the [4+2]-cycloaddition/rearrangement cascade of furanyl carbamates

The total syntheses of gamma-lycorane and (+/-)-1-deoxylycorine were accomplished using an intramolecular Diels-Alder cycloaddition of a furanyl carbamate as the key step. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. The key intermediate used in both syntheses corresponds to hexahydroindolinone 20. Removal of the t-Boc group in 20 followed by reaction with 6-iodobenzo[1,3]dioxole-5-carbonyl chloride afforded enamide 22. Treatment of this compound with Pd(OAc)(2) employing the Jeffrey modification of the Heck reaction provided the galanthan tetracycle 24 in good yield. Compound 24 was subsequently converted into (+/-)-gamma-lycorane using a four-step procedure to establish the cis-B,C-ring junction. A radical-based cyclization of the related enamide 33 was used for the synthesis of 1-deoxylycorine. Heating a benzene solution of 33 with AIBN and n-Bu(3)SnH at reflux gave the tetracyclic compound 38 possessing the requisite trans fusion between rings B and C in good yield. After hydrolysis and oxidation of 38 to 40, an oxidative decarboxylation reaction was used to provide the C(2)(-)C(3)(-)C(12) allylic alcohol unit characteristic of the lycorine alkaloids. The resulting enone was eventually transformed into (+/-)-1-deoxylycorine via known synthetic intermediates.     

Synthesis of griseolic acid analogues: regioselective alpha-facial [1,2]-migration in the rhodium acetate catalyzed reaction of D-glucose derived alpha-diazo-beta-keto ester

This paper describes an efficient route for the synthesis of known and novel griseolic acid analogues 1d and 1e, respectively. The key intermediate dioxabicyclo derivative 6, with the required stereochemical orientation at C6, was obtained by rhodium acetate catalyzed reaction of d-glucose derived alpha-diazo-beta-keto ester 5 in a novel high-yielding methodology.     

Total syntheses of amphidinolide T1, T3, T4, and T5

A concise, flexible, and high yielding entry into the family of amphidinolide T macrolides, a series of cytotoxic natural products of marine origin, has been developed. All individual members, except amphidinolide T3 (3), derive from compound 39 as a common synthetic intermediate which is formed from three building blocks of similar size and complexity. The fragment coupling steps involve a highly diastereoselective SnCl(4) mediated reaction of the furanosyl sulfone derivative 11 with the silyl enol ether 18 and a palladium-catalyzed Negishi type coupling reaction between the polyfunctional organozinc reagent derived from iodide 32a and the enantiopure acid chloride 24b. The 19-membered macrocyclic ring is then formed by a high yielding ring closing metathesis (RCM) reaction of diene 33 catalyzed by the "second generation" ruthenium carbene complex 34. The efficiency of the RCM transformation stems, to a large extent, from the conformational bias introduced by the syn-syn-configured stereotriad at C12-C14 of the substrate which constitutes a key design element of the synthesis plan. The use of Nysted's reagent 38 in combination with TiCl(4) was required for the olefination of the sterically hindered ketone group in 36, whereas more conventional alkene formations were unsuccessful for this elaboration. Finally, it is shown that the inversion of a single and seemingly remote stereocenter (C12) in one of the building blocks not only affects the efficiency and stereochemical outcome of the RCM step but also exerts a significant influence on the course of the acyl-Negishi reaction, allowing a radical manifold to compete with productive cross coupling.     

Studies toward the total synthesis of nakiterpiosin: construction of the CDE ring system by a transannular Diels-Alder strategy

The transannular Diels-Alder (TADA) reaction was applied to the synthesis of the CDE ring system of nakiterpiosin (1). Tetracyclic compound 25 may be a key intermediate in the total synthesis of 1.     

Total synthesis of (-)-stemoamide

A stereocontrolled total synthesis of (-)-stemoamide (1) is presented. The synthesis starts from commercially available (S)-pyroglutaminol (4). A chemoselective iodoboration of 5 was used to access key intermediate 3. The beta,gamma-unsaturated azepine derivative 2 was obtained via a Pd(0)-catalyzed sp(2)-sp(3) Negishi cross-coupling using a Reformatsky nucleophile followed by a ring-closing metathesis reaction. The required C8-C9 trans-stereochemistry of 1 was accessed through a stereoselective bromolactonization/1,4-reduction sequence.     

Memory of chirality in diastereoselective alpha-alkylation of isoleucine and allo-isoleucine derivatives

[reaction: see text] alpha-Methylation of 3 gave 5 as a major product whereas 4 gave 6 predominantly, although both 3 and 4 have an (S)-chiral center at C(3). This indicates that chirality at C(2) in 3 and 4 was memorized in the corresponding intermediate enolates and the induced chirality made a major contribution in the stereochemical course of the reaction, while chirality at the adjacent chiral center C(3) had little effect.     

A new mode of stereochemical control revealed by analysis of the biosynthesis of dihydrogranaticin in Streptomyces violaceoruber Tü22.

A class of Streptomyces aromatic polyketide antibiotics, the benzoisochromanequinones, all shows trans stereochemistry at C-3 and C-15 in the pyran ring. The opposite stereochemical control found in actinorhodin (3S, 15R, ACT) from S. coelicolor A3(2) and dihydrogranaticin (3R, 15S, DHGRA) from S. violaceoruber Tü22 was studied by functional expression of the potentially relevant ketoreductase genes, actIII, actVI-ORF1, gra-ORF5, and gra-ORF6. A common bicyclic intermediate was postulated to undergo stereospecific reduction to provide either the 3-(S) or the 3-(R) configuration of an advanced intermediate, 4-dihydro-9-hydroxy-1-methyl-10-oxo-3-H-naphtho[2,3-c]pyran-3-acetic acid (DNPA). Combinations of the four ketoreductase genes were coexpressed with the early biosynthetic genes encoding a type II minimal polyketide synthase, aromatase, and cyclase. gra-ORF6 was essential to produce (R)-DNPA in DHGRA biosynthesis. Out of the various recombinants carrying the relevant ketoreductases, the set of gra-ORF5 and -ORF6 under translational coupling (on pIK191) led to the most efficient production of (R)-DNPA as a single product, implying a possible unique cooperative function whereby gra-ORF6 might encode a "guiding" protein to control the regio- and stereochemical course of reduction at C-3 catalyzed by the gra-ORF5 protein. Updated BLAST-based database analysis suggested that the gra-ORF6 product, a putative short-chain dehydrogenase, has virtually no sequence homology with the actVI-ORF1 protein, which was previously shown to determine the 3-(S) configuration of DNPA in ACT biosynthesis. This demonstrates an example of opposite stereochemical control in antibiotic biosynthesis, providing a key branch point to afford diverse chiral metabolic pools.     

Neighboring group participation of the indole nucleus: An unusual DAST-mediated rearrangement reaction

A rearrangement reaction involving the indole nucleus was investigated using stereochemical markers and low-temperature NMR experiments. Treatment of (3S, 4S)-3-hydroxy-4-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with diethylaminosulfur trifluoride gave stereospecifically (3S, 4S)-4-fluoro-3-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with complete regioselectivity. The initial formation of a reactive spirocyclopropyl-3H-indole intermediate is believed to be responsible for the stereo- and regiochemical outcome of the reaction.     

Pyranophane transannular diels-alder approach to (+)-chatancin: a biomimetic asymmetric total synthesis

An asymmetric total synthesis of (+)-chatancin was achieved via a transannular Diels-Alder (TADA) reaction of an in situ generated macrocyclic pyranophane pseudobase. The presented route constitutes the second of two proposed biosynthetic pathways that involves a TADA reaction. It links this diterpene biogenetically to the cembranoids. A set of TADA selection rules that rationalize the formation of (+)-chatancin from a dynamic equilibrium of four 2-hydroxy-2H-pyrane bicycles and their 16 potential TADA transition states are also outlined. Beyond the TADA reaction, highlights of the synthetic work include the assembly of a chiral acyclic macrocyclization substrate from (S)-citronellol and an efficient macrocyclization via a beta-ketosulfoxyde/enone Michael addition.     

Stereochemical control in the reduction of 2-chromanols

[reaction: see text] Reduction of C5-substituted 2-hydroxychromans selectively provides 2,4-cis-chromans using large silane reductants and 2,4-trans-chromans using the smaller silane PhSiH(3). The stereochemical outcome has been rationalized on the basis of a Curtin-Hammett kinetic situation arising from hydride delivery to two different conformations of an intermediate oxocarbenium ion. This method provides a powerful way to control the relative stereochemistry of these substructures which are prevalent in bioactive natural products.     

Transannular Diels-Alder reactivities of 14-membered macrocylic trienes and their relationship with the conformational preferences of the reactants: a combined quantum chemical and molecular dynamics study

Transannular Diels-Alder (TADA) reactions that occur between the diene and dienophile moieties located on a single macrocyclic triene molecule have been recognized as effective synthetic routes toward realizing complex tricyclic molecules in a single step. In this paper, we report a comprehensive study on the TADA reactions of 14-membered cyclic triene macrocycles to yield A.B.C[6.6.6] tricycles using quantum chemical methods and using classical molecular dynamics simulations. A benchmark study has been performed to examine the reliability of the commonly used ab initio methods and hybrid density functional levels of theory in comparison with results from CCSD(T) calculations to accurately model TADA reactions. The energy barriers obtained using the M06-2X functional were found to be in quantitative agreement with the CCSD(T) level of theory using a reasonably large basis set. Conformational properties of the reactants have been systematically studied using extensive molecular dynamics (MD) simulations. For this purpose, model systems were conceived, and force field parameters corresponding to the dihedral terms in the potential energy function were obtained. Linear relationship between the activation energies corresponding to the TADA reactions and the probability of finding the reactant in certain conformational states was obtained. A clustering method along with optimizations at the molecular mechanics and density functional M06-2X levels has been used to locate the most stable conformation of each of the trienes.     

Biomimetic entry to the sarpagan family of indole alkaloids: total synthesis of +-geissoschizine and +-N-methylvellosimine

A concise synthesis of (+)-geissoschizine (1), a biosynthetic precursor of a variety of monoterpenoid indole alkaloids, from d-tryptophan (19) was performed as a critical prelude to achieving the first biomimetic, enantioselective synthesis of the sarpagine alkaloid (+)-N(a)-methylvellosimine (5). The approach to (+)-geissoschizine was designed to address the dual problems of stereocontrolled formation of the E-ethylidene moiety and the correct relative configuration at C(3) and C(15). Key steps in the synthesis involve a vinylogous Mannich reaction to prepare the carboline 22, which has the absolute stereochemistry at C(3) corresponding to that in 1 and 5, and an intramolecular Michael addition that leads to the tetracyclic corynantheane derivative 24, which possesses the correct stereochemical relationship between C(3) and C(15). Compound 24 was then transformed into 27, the pivotal intermediate in the syntheses of 1 and 5, by a sequence that allowed the stereospecific introduction of the E-ethylidene moiety. Selective reduction of the lactam in 27 followed by removal of the C(5) carboxyl group by radical decarbonylation gave deformylgeissoschizine (2) that was converted into (+)-geissoschizine (1) by formylation. The common intermediate 27 was then converted via a straightforward sequence of reactions into the alpha-amino nitrile 39. The derived silyl enol ether 40 underwent ionization upon exposure to BF(3).OEt(2) to give the intermediate iminium ion 41 that then cyclized in a biomimetically inspired intramolecular Mannich reaction to deliver (+)-N(a)-methylvellosimine (5). This transformation provides experimental support for the involvement of such a cyclization as one of the key steps in the biosynthesis of the sarpagine and ajmaline alkaloids.     

Assay for the enantiomeric analysis of [2H1]-fluoroacetic acid: insight into the stereochemical course of fluorination during fluorometabolite biosynthesis in streptomyces cattleya

A sensitive method for the configurational analysis of (R)- and (S)-[2H1]-fluoroacetate has been developed using 2H[1H]-NMR in a chiral liquid crystalline solvent. This has enabled biosynthetic experiments to be conducted which reveal stereochemical details on biological fluorination occurring during the biosynthesis of fluoroacetate and 4-fluorothreonine in the bacterium Streptomyces cattleya. In particular, feeding experiments to S. cattleya with isotopically labeled (1R, 2R)- and (1S, 2R)-[1-2H1]-glycerol 3d and 3e and [2,3-2H(4)]-succinate 4a gave rise to samples of enantiomerically enriched [2-2H1]-fluoroacetates 1a. The predominant enantiomer resulting from each experiment suggests that the stereochemical course of biological fluorination takes place with an overall retention of configuration between a glycolytic intermediate and fluoroacetate 1. Consequently, this outcome suggests that the stereochemical course of the recently identified fluorinase enzyme which mediates a reaction between fluoride ion and S-adenosyl-l-methionine (SAM), occurs with an inversion of configuration.     

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.     

Preparation of perhydroisoquinolines via the intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates: a formal synthesis of (+/-)-reserpine

The intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates provides an efficient method for the synthesis of cis-fused hexahydroisoquinolones. As a demonstration of the stereochemical control offered by this cycloaddition, two approaches to the construction of the DE rings of reserpine are reported. In the second entry, N-((4-(trimethylsilyl)ethoxymethoxy)methyl-6-benzyloxy-3Z,5E-hexadienoyl)-1-aza-2-ethoxy-1,3-butadiene (40) undergoes cycloaddition to produce as the major product (4aS,7R,8aS)-7-benzyloxy-5-((2-trimethylsilyl)ethoxymethoxy)methyl-3,4,4a,7,8,8a-hexahydroisoquinol-3-one (41). Cycloadduct 41 is then stereospecifically elaborated to (4aS,5S,6R,7R,8aR)-6-methoxy-5-methoxycarbonyl-7-(3,4,5-trimethoxy)benzoyldecahydroisoquinoline-2-carboxylic acid methyl ester (3), a key intermediate previously transformed to reserpine.     

Total synthesis of himandravine

[reaction: see text] The first total synthesis of (+)-himandravine (1) is described, starting from (2S,6S)-cis-2-formyl-6-methyl-N-Boc-piperidine (8) in 11 linear steps and 17% overall yield. The key step involves a highly diastereoselective intramolecular Diels-Alder reaction of the key intermediate 5 that contains the entire latent carbon framework and functional group substitution of himandravine.