Central-to-axial chirality transfer in the benzannulation reaction of optically pure Fischer carbene complexes in the synthesis of allocolchicinoids

A method for the synthesis of allocolchicinoids is explored that involves the benzannulation reaction of Fischer chromium carbene complexes with alkynes. The benzannulation reaction is employed to install the aromatic C-ring via the reaction of an α,β-unsaturated carbene complex in which the carbene complex is attached to a seven-membered ring that is to become the B-ring of the allocolchicinoids. Two different regioisomeric series can be accessed depending on which position the carbene complex is on the seven-membered ring. A key issue that is addressed is the stereochemistry of the newly formed axis of chirality that results from a stereo-relay from an existing chiral center on the seven-membered ring at the position destined to be C(7) in the allocolchicinoids. The level of stereochemistry is dependent on the position of the carbene complex on the seven-membered ring. A mechanism is proposed to account for this stereochemical dependence and to account for the observed effects of temperature and solvent on the stereoselectivity. Finally, the benzannulation reactions of optically pure complexes are examined and quite surprisingly one, but not both, of the diastereomeric products is racemized. The racemization can be prevented with the proper choice of solvent and temperature. A mechanism is proposed to account for the racemization of only one of the diastereomers of the product that involves the intermediacy of an o-quinone methide chromium tricarbonyl complex.     

Total synthesis of the polyenoyltetramic acid polycephalin C

The total synthesis of the polyenoyltetramic acid polycephalin C is described. Key steps of the synthesis include a double Swern oxidation, double Takai reaction and a double Stille reaction. In addition, the absolute stereochemistry of the ring junction has been determined by synthesis of both isomers and comparison of their CD spectra with natural polycephalin C.     

Enantioselective synthesis of the antiinflammatory agent (-)-acanthoic acid.

An enantioselective synthesis of the potent antiinflammatory agent (-)-acanthoic acid (1) is described. The successful strategy departs from (-)-Wieland-Miescher ketone (10), which is readily available in both enantiomeric forms and constitutes the starting point toward a fully functionalized AB ring system of 1. Conditions were developed for a regioselective double alkylation at the C4 center of the A ring, which produced compound 32 as a single stereoisomer. Construction of the C ring of 1 was accomplished via a Diels-Alder reaction between sulfur-containing diene 43 and methacrolein (36), which after desulfurization and further functionalization yielded synthetic acanthoic acid. The described synthesis confirms the proposed stereochemistry of the natural product and represents a fully stereocontrolled entry into an underexplored class of biologically active diterpenes.     

Synthesis and Stereochemistry of Some New Spiro-1,3-perhydrooxazines

 The synthesis and the stereochemistry of new spiro-1,3-perhydrooxazines are reported. The stereoisomerism of these compounds is discussed considering the data of conformational analysis, the helical chirality of the spiro[5.5]undecane skeleton, and the triligand virtual chiral center belonging to the 1,3-perhydrooxazine ring.     

Theoretical studies on the mechanism and stereoselectivity of Rh(Phebox)-catalyzed asymmetric reductive aldol reaction

Density functional theory calculations (B3LYP) have been carried out to understand the mechanism and stereochemistry of an asymmetric reductive aldol reaction of benzaldehyde and tert-butyl acrylate with hydrosilanes catalyzed by Rh(Phebox-ip)(OAc)(2)(OH(2)). According to the calculations, the reaction proceeds via five steps: (1) oxidative addition of hydrosilane, (2) hydride migration to carbon-carbon double bond of tert-butyl acrylate, which determines the chirality at C2, (3) tautomerization from rhodium bound C-enolate to rhodium bound O-enolate, (4) intramolecular aldol reaction, which determines the chirality at C3 and consequently the anti/syn-selectivity, and (5) reductive elimination to release aldol product. The hydride migration is the rate-determining step with a calculated activation energy of 23.3 kcal mol(-1). In good agreement with experimental results, the formation of anti-aldolates is found to be the most favorable pathway. The observed Si-facial selectivity in both hydride migration and aldol reaction are well-rationalized by analyzing crucial transition structures. The Re-facial attack transition state is disfavored because of steric hindrance between the isopropyl group of the catalyst and the tert-butyl acrylate.     

Synthesis and Stereochemistry of Some New Spiro-1,3-perhydrooxazines

Summary.  The synthesis and the stereochemistry of new spiro-1,3-perhydrooxazines are reported. The stereoisomerism of these compounds is discussed considering the data of conformational analysis, the helical chirality of the spiro[5.5]undecane skeleton, and the triligand virtual chiral center belonging to the 1,3-perhydrooxazine ring. Received February 21, 2000. Accepted (revised) April 18, 2000     

Enantioselective total synthesis of (+)-lysergic acid, (+)-lysergol, and (+)-isolysergol by palladium-catalyzed domino cyclization of allenes bearing amino and bromoindolyl groups

Enantioselective total synthesis of the biologically important indole alkaloids (+)-lysergol, (+)-isolysergol, and (+)-lysergic acid is described. Key features of these total synthesis include (1) a facile synthesis of a chiral 1,3-amino alcohol via the Pd(0)- and In(I)-mediated reductive coupling reaction between L-serine-derived 2-ethynylaziridine and formaldehyde; (2) the Cr(II)/Ni(0)-mediated Nozaki-Hiyama-Kishi (NHK) reaction of an indole-3-acetaldehyde with iodoalkyne; and (3) Pd(0)-catalyzed domino cyclization of an allene bearing amino and bromoindolyl groups. This domino cyclization enabled direct construction of the C/D ring system of the ergot alkaloids skeleton, as well as the creation of the C5 stereogenic center with transfer of the allenic axial chirality to the central chirality.     

Asymmetric Total Synthesis of Propindilactone G,Part 1: Initial Attempts towards the Synthesis of Schiartanes

Our first‐generation synthetic study towards the total synthesis of propindilactone G ( 1 ) and its analogues is reported. The key synthetic steps were an intramolecular Pauson–Khand reaction (PKR) and a vinylogous Mukaiyama reaction (VMAR). The stereoselective synthesis of the CDE ring moiety with an all‐carbon quaternary center through a PKR was difficult, whilst a VMAR afforded a product with the opposite stereochemistry at the C20 position on the side chain. These results led us to redesign our synthetic strategy for the total synthesis of compound 1 .     

Stereochemical elucidation and total synthesis of dihydropacidamycin D, a semisynthetic pacidamycin.

Hydrogenation of the C(4') exocyclic olefin of the pacidamycins has been shown to produce a series of semisynthetic compounds, the dihydropacidamycins, with antimicrobial activity similar to that of the natural products. Elucidation of stereochemistry in the pacidamycins has been completed through a campaign of natural product degradation experiments in combination with the total synthesis of the lowest-molecular weight dihydropacidamycin, dihydropacidamycin D. The stereochemical identities of the tryptophan and two alanine residues contained in pacidamycin D have been shown to be of the natural (S) configuration, and the unique 3-methylamino-2-aminobutyric acid contained in this series of antibiotics has been shown to be of the (2S,3S) configuration. Finally, the stereochemistry obtained by hydrogenation of the C(4')-C(5') exocyclic olefin has been shown to be (R) at the C(4') nucleoside site.     

Synthesis of the naphthalene portion of the rubromycins

[reaction: see text]. A synthesis of a reduced version of the naphthazarin found in the rubromycin class of natural products is reported. The naphthalene ring system is formed via a D?tz reaction with a symmetrical alkyne. Differentiation between the C1' and C3' groups of the D?tz adduct is achieved by selective oxidation since the two methylene groups possess different oxidation potentials.     

Stereoselective synthesis of the eastern quinolizidine portion of himeradine A

The synthesis of the C(15)-C(17)/N(1')-C(11') quinolizidine portion of himeradine A is disclosed. An intramolecular, heteroatom Michael addition was employed to establish the C(6') stereogenic center with high diastereoselectivity. The quinolizidine ring was constructed using microwave-induced cyclization at the N(1')-C(2') position. The C(17) stereogenic center was introduced through a diastereoselective Overman rearrangement.     

Synthesis and pairing properties of oligodeoxynucleotides containing bicyclo-RNA and bicyclo-ANA modifications

The synthesis of the ribo(bc-rT)- and arabino(bc-araT)-version of bicyclothymidine (bc-dT) has been achieved. A conformational analysis by X-ray and/or (1)H NMR spectroscopy on the corresponding 3',5'-benzyl-protected nucleosides featured a rigid C(2')-endo conformation for the furanose ring, irrespective of the configuration of the OH group at C(2'). The conformation of the carbocyclic ring in these nucleosides was found to be less defined and thus more flexible. Both nucleosides were converted into the corresponding phosphoramidites and incorporated into oligodeoxynucleotides by standard DNA chemistry. T(m)-data of duplexes with cDNA and RNA revealed that a bc-rT unit strongly destabilized duplexes with cDNA and RNA by 6-8 °C/mod, while bc-araT was almost T(m) neutral. A rationale based on a previous structure of a bc-DNA mini duplex suggests that the strong destabilization caused by a bc-rT unit arises from unfavorable steric interactions of the equatorial 2'-OH group with the sugar residue of the 3'-neighboring nucleotide unit.     

Asymmetric total synthesis of ent-(-)-roseophilin: assignment of absolute configuration

An asymmetric total synthesis of ent-(-)-roseophilin (1), the unnatural enantiomer of a novel naturally occurring antitumor antibiotic, is described. The approach enlists a room temperature heterocyclic azadiene inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7) with the optically active enol ether 6 bearing the C23 chiral center followed by a reductive ring contraction reaction for formation of an appropriately functionalized pyrrole ring in a key 1,2,4,5-tetrazine --> 1,2-diazine --> pyrrole reaction sequence. A Grubbs' ring closing metathesis reaction was utilized to close the unusual 13-membered macrocycle prior to a subsequent 5-exo-trig acyl radical-alkene cyclization that was used to introduce the fused cyclopentanone and complete the preparation of the tricylic ansa-bridged azafulvene core 32. Condensation of 32 with 33 under the modified conditions of Tius and Harrington followed by final deprotection provided (22S,23S)-1. Comparison of synthetic (22S,23S)-1 ([alpha](25)(D), CD) with natural 1 established that they were enantiomers and enabled the assignment of the absolute stereochemistry of the natural product as 22R,23R. Surprisingly, ent-(-)-1 was found to be 2-10-fold more potent than natural (+)-1 in cytotoxic assays, providing an unusually rewarding culmination to synthetic efforts that provided the unnatural enantiomer.     

Influence of Proline Chirality on Neighbouring Azaproline Residue Stereodynamic Nitrogen Preorganization

We report herein the first systematic crystal structural investigation of azaproline incorporated in homo- and heterochiral diprolyl peptides. The X-ray crystallography data of peptides 1 – 5 illustrates that stereodynamic nitrogen in azaproline adopted the stereochemistry of neighbouring proline residue without depending on its position in the peptide sequence. Natural bond orbital analysis of crystal structures indicates O_azPro−C′_Pro of peptides 4 and 5 participating in n→π* interaction with stabilization energy about 1.21–1.33 kcal/mol. Density functional theory calculations suggested that the endo-proline ring puckering favoured over exo-conformation by 6.72–7.64 kcal/mol. NBO and DFT data reveals that the n→π* interactions and proline ring puckering stabilize azaproline chirality with the neighbouring proline stereochemistry. The CD, solvent titration, variable-temperature and 2D NMR experimental results further supported the crystal structures conformation.     

Control of oxygen atom chirality and chelate ring conformation by protected/free sugar hydroxyl groups in glucose-pendant dipicolylamine-copper(II) complexes

A pair of copper(II) complexes 1 and 2 exhibit an enantiomeric chiral center at the oxygen atom that coordinates to the metal center. The configurations of the oxygen atom chirality and the chelate ring conformation are simply controlled by protected/free hydroxyl groups of the sugar moiety, yielding mirror image CD spectra. In this system, repulsive and attractive forces are used to regulate chirality on the copper-coordinated oxygen atom both in the solid state and in solution.     

Conversion of the enantiomers of spiro[4.4]nonane-1,6-diol into both epimeric carbaspironucleosides having natural C1' absolute configuration

[reaction: see text] The enantiomers of spiro[4.4]nonane-1,6-diol have been transformed by different reaction pathways into the two possible carbaspironucleoside epimers with natural C1' absolute stereochemistry.     

The products of 5-fluorouridine by the action of the pseudouridine synthase TruB disfavor one mechanism and suggest another

The pseudouridine synthase TruB handles 5-fluorouridine in RNA as a substrate, converting it into two isomeric hydrated products. Unexpectedly, the two products differ not in the hydrated pyrimidine ring but in the pentose ring, which is epimerized to arabinose in the minor product. This inversion of stereochemistry at C2' suggests that pseudouridine generation may proceed by a mechanism involving a glycal intermediate or that the previously proposed mechanism involving an acylal intermediate operates but with an added reaction manifold for 5-fluorouridine versus uridine. The arabino product strongly disfavors a mechanism involving a Michael addition to the pyrimidine ring.     

Structure Determination and Total Synthesis of (+)‐16‐Hydroxy‐16,22‐dihydroapparicine

Herein, we describe the first asymmetric total synthesis and determination of the relative and absolute stereochemistry of naturally occurring 16‐hydroxy‐16,22‐dihydroapparicine. The key steps include 1) a novel phosphinimine‐mediated cascade reaction to construct the unique 1‐azabicyclo[4.2.2]decane core, including a pseudo‐aminal‐type moiety; 2) a highly stereospecific 1,2‐addition of 2‐acylindole or a methylketone through a Felkin–Anh transition state for the construction of a tetrasubstituted carbon center; and 3) an intramolecular chirality‐transferring Michael reaction of the ketoester, with neighboring‐group participation, to introduce a chiral center at C15 in the target molecule. In addition, we evaluated the antimalarial activity of synthetic (+)‐(15S,16R)‐16‐hydroxy‐16,22‐dihydroapparicine and its intermediate against chloroquine‐resistant Plasmodium falciparum (K1 strain) parasites.     

An efficient one-pot asymmetric synthesis of biaryl compounds via Diels-Alder/retro-Diels-Alder cascade reactions

[reaction: see text] A single-step chirality transfer method for the synthesis of axially chiral biaryl compounds by construction of the second aromatic ring via a Diels-Alder/retro-Diels-Alder cascade reaction is reported. This methodology should find broad application in the synthesis of natural products and asymmetric catalysts.     

Programming the supramolecular helical polymerization of dendritic dipeptides via the stereochemical information of the dipeptide

Many natural biomacromolecules are homochiral and are built from constituents possessing identical handedness. The construction of synthetic molecules, macromolecules, and supramolecular structures with tailored stereochemical sequences can detail the relationship between chirality and function and provide insight into the process that leads to the selection of handedness and amplification of chirality. Dendritic dipeptides, previously reported from our laboratory, self-assemble into helical porous columns and serve as fundamental mimics of natural porous helix-forming proteins and supramolecular polymers. Herein, the synthesis of all stereochemical permutations of a self-assembling dendritic dipeptide including homochiral, heterochiral, and differentially racemized variants is reported. A combination of CD/UV-vis spectroscopy in solution and in film, X-ray diffraction, and differential scanning calorimetry studies in solid state established the role of the stereochemistry of the dipeptide on the thermodynamics and mechanism of self-assembly. It was found that the highest degree of stereochemical purity, enantiopure homochiral dendritic dipeptides, exhibits the most thermodynamically favorable self-assembly process in solution corresponding to the greatest degree of helical order and intracolumnar crystallization in solid state. Reducing the stereochemical purity of the dendritic dipeptide through heterochirality or by partially or fully racemizing the dendritic dipeptide destructively interferes with the self-assembly process. All dendritic dipeptides were shown to coassemble into single columns regardless of their stereochemistry. Because these columns exhibit no deracemization, the thermodynamic advantage of enantiopurity and homochirality suggests a mechanism for stereochemical selection and chiral amplification.