Showing papers by "Leo A. Paquette published in 1993"

Enantioselective total synthesis of (-)-subergorgic acid

Abstract: A completely stereocontrolled total synthesis of (-)-subergorgic acid (1) has been accomplished. The starting β-hydroxy ketone was prepared in optically pure condition by lipase-promoted hydrolysis of the racemic chloroacetate.Ring A was introduced by a reaction sequence that included a Mukaiyama-type aldol condensation and subsequent photochemical oxidation with (diacetoxyiodo)benzene and iodine. To permit proper functionalization within ring C, a carbonyl group was transformed into an internal double bond by Pd(II)-promoted reduction of the derived enol triflate with formate ion

Synthetic equivalents of the taxol C,D ring system. Examination of nucleophilic bicyclic oxetanes and less-strained acetonide equivalents

Abstract: A procedure is described for the conversion of 3-bromo-2-cyclohexenone into the functionalised bicyclic oxetanes 13a and 13b, 7-oxabicyclo[4.2.0]octene derivatives. These heterocycles undergo halogen-metal exchange readily in the presence of tert-butyllithium at -78 o C, and the resulting vinyl anions are capable of nucleophilic addition to ketones either directly or via cerate intermediates without complication. Whereas 2-(7-oxabicyclo[4.2.0]oct-2-en-3-yl)-5-norbornen-2-ol 20 smoothly undergoes anionic oxy-Cope rearrangement at 0 o C when transformed into its potassium salt, alcohols 23 and 24, 2-(7-oxabicyclo[4.2.0]oct-2-en-3-yl)-1-vinyl-norbornan-2-ol are especially prone to aromatisation with loss of the oxetane subunit under the same conditions. In order to skirt these complications, attention was directed to bromo acetonides 1,3-benzodioxan derivatives 36 and 37. Sequential treatment of 36 with tert-butyllithium and anhydrous cerium trichloride gave the corresponding organocerate that added stereoselectively to the endo surface of the carbonyl group in optically pure ketone 7,7-dimethyl-1-vinyl-norbornan-2 -one 22. The individual diastereomers thus produced were subjected to anionic oxy-Cope rearrangement in the presence of hexamethyldisilazide and air to give methanocyclodeca[f]-1,3-benzodioxine derivative

A means for stereocontrolled introduction of the C-2 oxygen substituent in functionalized cis-tricyclo[9.3.1.03,8]pentadecanones related to taxol

Abstract: Several optically pure cis-tricyclo[9.3.1.0 3,8 ]pentadecanones have been prepared via anionic oxy-Cope rearrangement of exo-norbornanol precursors that have been obtained by convergent coupling of two functionalized reaction partners. The sigmatropic rearrangement is shown to proceed with exceptionally good stereochemical transmission because of universal adherence to the same endochair transition state. The atropisomeric aspects of this pivotal transformation are addressed. Also investigated was the proclivity of the products to undergo transannular hemiketal formation following osmylation of the bridgehead double bond. As matters turn out, the operation or nonoperation of this intramolecular addition to the C-9 carbonyl group is amenable to control merely by adjusting properly the stereochemistry of a single pendant substituent

A-ring oxygenation studies in bridgehead hydroxyl-substituted trans-tricyclo[9.3.1.03,8]pentadecan-14-one congeners of taxol

Abstract: The ready availability of 4-t-butyldimethylsiloxy-perhydro-12a,13,13-trimethyl-6,10-methanobenzocyclodecene-7,12-dione(5) has prompted examination of a convenient means for carbonyl transposition in its A-ring. Attempts to implement such chemistry directly on 5 and its silyl-protected derivative suffer from a kinetic proclivity for transannular capture of the enolate anion. This undesirable process was circumvented by reduction of the C9 carbonyl following conversion to a silyl enol ether 8. Once the resulting 9a-alcohol was protected as its MOM ether, the enolates of 10a and 10b could be efficiently oxygenated at C13 by treatment with the Davis sulfonyl oxaziridine despite severe steric congestion in that locale. The resultant α-alcohol 11a could be epimerized to the 13β-isomer by exposure to potassium hexamethyldisilazide

An intramolecular cyclization approach to optically active cyclopentenyl bromides

Abstract: The two antipodes of 1-bromo-3,3-dimethyl-4-[(tert-butyldimethylsilyl)oxy] cyclopentene, the dextrorotatory form of which (1) is regarded as a potential synthetic precursor to kalmanol, have been prepared in a state of high enantiomeric purity from propargyl alcohol. The key steps in the abbreviated synthetic pathway involve the bromination-dehydrobromination of 3-(trimethylsilyl)propenal 12 to give 2-bromo-3-(trimethylsilyl)propenal 7, the conversion of 2-bromo-3-(trimethylsilyl)propen-1-ol 13 to the 1-bromo-3,3-dimethylcyclopenten-4-ol 18 by a novel tandem Claisen-Sakurai reaction sequence, and efficient enzymatic resolution of 18 via its chloroacetate ester. The absolute configurational assignments are based on 1 H NMR analyses of the (R)- and (S)-MTPA esters of (-)-20

A unified synthetic strategy for elaboration of the DEF tricyclic subunit common to the austalide mycotoxins

Abstract: Furo[3,4-g]-1-benzopyrane derivative (19), representing the DEF subunit common to all known austalide mycotoxins, has been economically synthesized from 2,3-dihydropyran in 8 steps via several highly stereo- and regioselective transformations

Enantioselective Total Synthesis of (‐)‐Subergorgic Acid.

Abstract: A completely stereocontrolled total synthesis of (-)-subergorgic acid (1) has been accomplished. The starting β-hydroxy ketone was prepared in optically pure condition by lipase-promoted hydrolysis of the racemic chloroacetate.Ring A was introduced by a reaction sequence that included a Mukaiyama-type aldol condensation and subsequent photochemical oxidation with (diacetoxyiodo)benzene and iodine. To permit proper functionalization within ring C, a carbonyl group was transformed into an internal double bond by Pd(II)-promoted reduction of the derived enol triflate with formate ion

Ring Expansion by Tandem Double Tebbe‐Claisen Technology.

Abstract: 2-Cyclohexenone rings that form part of a larger structural assembly are amenable to peracid oxidation with formation of an epoxy lactone. These intermediates are readily transformed under acidic, basic, or neutral conditions to ring-contracted aldehydo lactones, which are then subjected to condensation with a slight excess of Tebbe reagent. These conditions result in methylenation of carbonyl groups and set the stage for operation of a Claisen rearrangement. When the latter is catalyzed by Tribal, the sigmatropic process occurs at room temperature. With systems typified by 17 and 24, the isomerization is complete within 15 min. The presence of a proximate angular methyl group as in 9b, 29, and 37 exerts a retarding kinetic effect. In such examples, a period of 6 h is required to achieve completion. Swern oxidation completes the conversion to the 4-cyclooctenones, where the two carbons stemming from the Tebbe reagent are inserted between the original carbonyl and α-olefinic carbons. The overall process is...

Stereocontrolled Access to the Most Highly Condensed Pentalenolactone Antibiotic. From Cycloheptatriene to Pentalenolactone P Methyl Ester.

Abstract: The first total synthesis of the title compound has been accomplished. Besides the immediate establishment of the trans cyclopropane-lactone relationship by an appropriate Diels-Alder reaction, other notable transformations include a regioselective chain-lengthening, oxadi-π-methane rearrangement, lactone ring construction by an intramolecular Michael reaction-oxidation sequence, and use of monomeric formaldehyde to introduce the final carbon atom. The chemistry outlined defines a strategy that is highly stereocontrolled and completely tolerant of a sterically congested cyclopropane ring that is carried through to the target from the very first step

A Unified Synthetic Strategy for Elaboration of the DEF Tricyclic Subunit Common to the Austalide Mycotoxins.

Abstract: Furo[3,4-g]-1-benzopyrane derivative (19), representing the DEF subunit common to all known austalide mycotoxins, has been economically synthesized from 2,3-dihydropyran in 8 steps via several highly stereo- and regioselective transformations

An Intramolecular Cyclization Approach to Optically Active Cyclopentenyl Bromides.

Abstract: The two antipodes of 1-bromo-3,3-dimethyl-4-[(tert-butyldimethylsilyl)oxy] cyclopentene, the dextrorotatory form of which (1) is regarded as a potential synthetic precursor to kalmanol, have been prepared in a state of high enantiomeric purity from propargyl alcohol. The key steps in the abbreviated synthetic pathway involve the bromination-dehydrobromination of 3-(trimethylsilyl)propenal 12 to give 2-bromo-3-(trimethylsilyl)propenal 7, the conversion of 2-bromo-3-(trimethylsilyl)propen-1-ol 13 to the 1-bromo-3,3-dimethylcyclopenten-4-ol 18 by a novel tandem Claisen-Sakurai reaction sequence, and efficient enzymatic resolution of 18 via its chloroacetate ester. The absolute configurational assignments are based on 1 H NMR analyses of the (R)- and (S)-MTPA esters of (-)-20

Setting the Bridgehead Oxidation Level in trans-Tricyclo(9.3.1.03,8) pentadecanes as a Prelude to the Dual Synthesis of Taxol and Taxusin.

Abstract: The key elements associated with the synthetic elaboration of functionalized trans-tricyclo-[9.3.1.03,8]pentadecanes carrying either a bridgehead H or OH substituent are detailed. Starting with 12, a ketone available in two steps from (R)-2-oxo-7,7-dimethyl-l-vinylbicyclo[2.2.1]heptane, it proved possible to introduce trans-B/C ring juncture configuration as in 16 in five steps. This advanced intermediate constitutes the point of bifurcation. The pathway to taxusin precursor 23 was attained by stereospecific osmylation, reduction, and pinacol-like 1,2-Wagner-Meerwein rearrangement within acetoxy mesylate 22c. Still more abbreviated is the route to 32, which again takes advantage of the osmylation step but proceeds, forward without reduction of the rear carbonyl group. Once hydroxy diketone 31 is produced, equilibration in the presence of (t-BuO)3Al results in complete conversion to 32. The many stereoselective transformations developed in the course of this study, in combination with the several thermodynamic questions that have been clarified, are expected to be highly serviceable as more advanced thrusts toward taxusin and taxol are mounted.

Asymmetric Functionalization of Conformationally Distinctive Cs- Symmetric cis-(n.3.1)Bicyclic Ketones. Definition of the Absolute Course of Enantio- and Diastereodifferentiation.

Abstract: The four C s -symmetric cis[n.3.1] bicyclic ketones where n=3,5,7, and 9 were acetalized with (R,R)-2,4-pentanediol, and the resulting derivatives were cleaved with triisobutylaluminum (TRIBAL). The first three examples, all of which have their polymethylene chain rigidly fixed in a diaxial orientation, undergo ring opening with very high diastereoselectivity. In the fourth case (n=9), the chain is sufficiently long to be attached in a diequatorial manner

Electrostatic Modulation of Hydroxyl Group Ionization in Acidic Media. Evidence for the Competitive Operation of Intramolecular SN2 Reactions.

Abstract: The acid-catalyzed cyclodehydration of the cis and trans isomers of 2-substituted 1-(3-hydroxypropyl)cyclohexanols results in the formation of spirocyclic tetrahydrofurans. The stereochemical course of these reactions is highly varied, ranging from a dominant preference for retention when R=OCH 3 to modestly favored inversion when R=CH 3 . Experiments with 18 O-labeled diols show that in the methoxyl series most of the isotope is retained irrespective of relative stereochemistry. On the other hand, the pair of phenyl-substituted isomers responds by losing approximately 50% of the label

A Carbenoid Ring Expansion Route to the First Member of a Newly Discovered Diterpene Class. Total Synthesis of 18-Oxo-3-virgene.

Abstract: Virginia 115 tobacco cultivars produce the structurally unusual diterpene 2 , which has presently been synthesized from bicyclic ketone 3 .

Alkoxy and Cyclic Ether Oxygens Exhibit Disparate Capabilities for Directing ortho-Lithiation.

Abstract: Metalation of 4a and 4b with n-butyllithium under kinetically controlled conditions (C6H6, 20 °C or Et2O, TMEDA (2 equiv), 20 °C) leads to preferred deprotonation α to the heterocyclic ring.

Enantioselective Synthesis of Natural (+)‐Dactyloxene‐B and ‐C by Actuation of Oxonium Ion‐Initiated Pinacol Rearrangement.

Abstract: A direct route is described for assembling the spirocyclic framework of two sesquiterpene ethers derived biogenetically from the cyclization of farnesol with rearrangement of a methyl group.