A total synthesis of guanacastepene C

A total synthesis of the structure corresponding to the novel tricyclic diterpene guanacastepene C has been realized in which a Knoevenagel cyclization serves as a key step to annulate the six-membered C-ring on a stereochemically secured bicyclic hydroazulene precursor.     

Total synthesis of guanacastepene a: a route to enantiomeric control

[reaction: see text] The goal of the total synthesis of guanacastepene A served as a focus to bring together several chemical inquiries. One involved the synthesis of fused 5,7-hydrazulenones (see structure 20). Another issue had to do with the mechanistic intermediates in reductive cyclizations (see 17 to 18 and 19). The total synthesis required a mastery of an intramolecular Knoevenagel condensation of a beta,gamma-unsaturated ketone (see compound 41). Actually, cyclization was best accomplished when the terminal double bond of 41 was first converted to an epoxide. Further issues related to the stereochemistry at C5 and, rather surprisingly, the propensity for beta-face acetoxylation at C13. Crystallographic verification of the assigned beta-stereochemistry at C13 is provided. Finally, a route to optically active material is provided (see compound 20). A key element in this construction was an enantioselective addition of isopropenyl cuprate to 2-methylcyclopentenone (see compound 99).     

Development of a catalytic enantioselective synthesis of the guanacastepene and heptemerone tricyclic core

For nearly two decades, synthetic chemists have been fascinated by the structural complexity and synthetic challenges afforded by the guanacastepene and heptemerone diterpenoids. Numerous synthetic approaches to these compounds have been reported, but to date the application of enantioselective catalysis to this problem has not been realized. Herein we report an enantioselective synthesis of an advanced intermediate corresponding to the tricyclic core common to the guanacastepenes and heptemerones. Highlights of this work include sequential Pd-catalyzed decarboxylative allylic alkylation reactions to generate the two all carbon quaternary stereocenters, the use of ring-closing metathesis to close the A ring in the presence of a distal allyl sidechain, and a regio- and diastereoselective oxidation of a trienol ether to introduce oxygenation on the A ring.     

Study of the stereoselectivity of the nucleophilic epoxidation of 3-hydroxy-2-methylene esters

The diastereoselectivity of the nucleophilic epoxidation of 3-hydroxy-2-methylene esters has been studied. The 3-hydroxy-2-methylene esters were obtained through a Morita–Baylis–Hillman reaction. The resulting epoxyesters were treated with thiophenol for transformation into 2,3-dihydroxy-2-((phenylthio)methyl), which upon treatment with triphosgene afforded the corresponding cyclic carbonates.     

Surprising stereoselectivity in the Payne epoxidation of terpinen-4-ol with acetonitrile/hydrogen peroxide

A surprisingly high level of cis-stereoselectivity in the Payne epoxidation has been identified with the homoallylic alcohol, terpinen-4-ol. Very high efficiencies for hydrogen peroxide are realized under mild conditions. The necessity for peroxyimidic acid stabilization by solvent is replaced by coordination to the directing hydroxyl function, resulting in dramatically improved space yields at up to the one kilogram scale.     

Substrate-directed stereoselectivity in vicinal diamine-catalyzed synthesis of warfarin

[Structure: see text] A new mechanism involving a diimine intermediate is proposed for vicinal diamine-catalyzed synthesis of warfarin. Decreasing the NCCN dihedral angle by varying the diamine results in an increase in the enantioselectivity of warfarin synthesis.     

The pH of the reaction controls the stereoselectivity of organocatalyzed direct aldol reactions in water

The direct aldol reaction of 4-nitrobenzaldehyde and cyclohexanone, catalyzed by a protonated prolinamide catalyst in water, proceeds with the formation of aldol product that has high diastereoselectivity and enantioselectivity in an optimal pH range of 4–5.     

Studies toward the total synthesis of diterpene antibiotic guanacastepene A: construction of the hydroazulenic core

[reaction: see text] As a part of studies aimed toward the total synthesis of biologically important natural product guanacastepene A of contemporary interest, a new and concise route to a fully functionally endowed hydroazulenic core is delineated. The strategy involves the building of the requisite stereochemical features on a endo-tricyclo[5.2.1.0(2,6)]decane matrix and excision of the five-membered ring through a retro-Diels-Alder reaction. Generation of the seven-membered ring to access the hydroazulenic framework was achieved employing ring closure metathesis (RCM) reaction as the key step.     

Modeling the stereoselectivity of the Johnson-Claisen rearrangements in the Danishefsky synthesis of gelsemine

[reaction: see text] The stereochemistries of [3,3] sigmatropic Johnson-Claisen (J-C) rearrangements of six intermediates studied in the synthesis of gelsemine were modeled using DFT methodology. The possible origins of the rearrangement stereoselectivity are explored and compared with the experimentally suggested rationalizations by Danishefsky et al. (J. Am. Chem. Soc. 2002, 124, 9812-9824). In the intermediate used for the J-C rearrangement in the Danishefsky synthesis (3), the closure is inhibited by the repulsive interactions between the enolate terminus and the carbon atoms of the double bond as well as with the hydrogen on C7. The closure is favored by stabilizing interactions between the enolate terminus and the H's of the oxetane ring.     

Enantioselective total synthesis of guanacastepene N using an uncommon 7-endo Heck cyclization as a pivotal step

A convergent, enantioselective total synthesis of (+)-guanacastepene N was developed that features a 7-endo Heck cyclization as the key step. In the course of this synthesis, short syntheses of the enantiomerically pure cyclopentenone and cyclohexene building blocks 5 and 6, which constitute A and C ring fragments of guanacastepene N, were developed. These fragments were linked by a challenging conjugate addition reaction that also generated the C11 quaternary carbon stereocenter. Regioselective 7-endo Heck cyclization gave rise to a tricyclic intermediate, which was elaborated to complete the first total synthesis of guanacastepene N and the second enantioselective total synthesis of a guanacastepene natural product.     

Remarkable stereoselectivity in intramolecular Borono-Mannich reactions: synthesis of conduramines

An unprecedented intramolecular Petasis condensation provides a novel approach to biologically important conduramines. The compounds are produced with an exclusive anti stereoselectivity for the newly created β-amino alcohol motif. The stereochemical outcome of the reaction is opposite to the one usually observed in the intermolecular reaction.     

An improved synthesis of a ketone catalyst for asymmetric epoxidation of olefins

An efficient synthesis of a ketone catalyst for asymmetric epoxidation of olefins from D-glucose in six steps is described.     

Docking and molecular dynamics studies on the stereoselectivity in the enzymatic synthesis of carbohydrates

Glycosidases constitute a vast family of enzymes that catalyze the breaking and formation of glycosidic bonds. The synthesized oligosaccharides, being crucial to life, are involved in many biochemical processes, particularly in the pharmaceutical and food industries. The proposed catalytic mechanism of retaining glycoside hydrolases (glycosidases) occurs via a double displacement mechanism involving a covalent glycosyl enzyme intermediate. During the transglycosylation reactions, the control of the stereoselectivity for the formation of the new bond remains a complicated problem in the chemical synthesis of oligosaccharides. In this paper, docking and molecular dynamics methods were used to study the second step of the mechanism of transglycosylation in retaining glycosidases from six microorganisms with known stereoselectivity. Using the natural substrates as donor and acceptor molecules, we were able to corroborate and provide structural information about the active site, the trapped monosaccharide acceptor and the bound intermediates during the step that precedes transglycosylation, as well as identify and understand the commonly displayed stereoselectivity by these glycosidases in nature. The information obtained with this procedure helps to recognize, explain and predict the stereoselectivity of the sugars studied. These kind of procedures can be used to improve the efficiency of large-scale industrial synthesis of a specific sugar.     

Enantioselective synthesis of 3-demethoxyaranciamycinone via asymmetric epoxidation

The tetracyclic olefin 1 was enantioselectively epoxidized using a molybdenum(VI)- oxodiperoxo complex containing a chiral lactamide. Conversion to the glycosides 8 and 9 showed the epoxide 2 to be the predominant (3 : 1) enantiomer.     

Synthesis of the hydroazulene ring system of guanacastepene

[reaction: see text] A 12-step synthesis of 26, the functionalized hydroazulenone ring of guanacastepene (1), has been completed using the EtAlCl(2)-initiated cyclization of gamma,delta-unsaturated ketone 13 to construct 2,2,3-trisubstituted cyclopentanone 14, the palladium-catalyzed coupling of vinylmagnesium bromide with enol triflate 17 to prepare triene 21, and olefin metathesis of triene 21 to form the key hydroazulene 20.     

Total synthesis of epothilone a through stereospecific epoxidation of the p-methoxybenzyl ether of epothilone C

The total synthesis of epothilone A is described by the coupling four segments 4-7 a. Three of the segments, 4, 5 and 7 a, have only one chiral center; all other chiral centers were introduced by simple asymmetric catalytic reactions. The key steps are the ring opening of epoxide 5 with acetylide 8 for the construction of the C12-C13 cis double bond and a practical hydrolytic kinetic resolution (HKR) developed by Jacobsen group for the introduction the chiral center at C3. Especially, the stereospecific epoxidation of 3-O-PMB epothilone C 3 b through long-range effect of 3-O-PMB protecting group gave high yields of the C12-C13 alpha-epoxide for the synthesis of target molecule.     

Inversion of stereoselectivity in a metallocene catalyst

Inversion of stereoselectivity of a particular metallocene (Me₂Si(Flu) (N-t-Bu)ZrCl₂) (Me: methyl, Flu: fluorenyl, t-Bu: tert-butyl) from syndiospecific into isospecific was observed by changing the cocatalyst from methylaluminoxane (MAO) to [Ph₃C]⁺ [B(C₆F₅)₄]⁻/AliBu₃ (iBu:isobutyl). The change of the solvent-separated ion pair (in case of MAO as cocatalyst) into the contact ion pair (in case of the more polar and less bulky borate anion) was proposed as the plausible explanation of this phenomenon.