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David Crich

Publications and source records attributed to David Crich.

At least 37 records · Page 2Linked to original sources
PubMed2005

Stereochemical memory effects in alkene radical cation/anion contact ion pairs: effect of substituents, and models for diastereoselectivity.

A series of 12 stereochemically defined 2,m-dimethyl- and 2,m,n-trimethyl-6-benzylamino-2-nitro-3-(diphenylphosphatoxy)hexanes have been synthesized and their cyclization reactions leading to di- and trisubstituted N-benzyl pyrrolidines examined in the presence of tributyltin hydride and azoisobutyronitrile in benzene at reflux. The cyclizations are interpreted in terms of generation of an alkyl radical by abstraction of the nitro group with a stannyl radical. The phosphate leaving group is then expelled in a heterolytic cleavage to give a contact alkene radical cation/phosphate anion pair. For the majority of the examples studied, the cyclizations are best understood in terms of nucleophilic attack by the amine on the opposite face of the alkene radical cation to the one shielded by the leaving group, within the confines of the initial contact ion pair, resulting in overall cyclization with inversion of configuration. Dependent on the relative stereochemistry of the substituents, the cyclization is envisaged as taking place through either chair-like or twist-boat-like transition states with the maximum number of substituents pseudo-equatorial. The model breaks down when cyclization on the initial contact ion pair would engender significant destabilizing steric interactions, especially (1,3)A strain in the alkene radical cation. In these cases a fully equilibrated Beckwith-Houk-type transition state provides a satisfactory model. Interesting examples of matching and mismatching in the Corey-type oxazaborolidine-mediated reduction of alkyl (methyl-1-nitroethyl) ketones by a beta-methyl group in the alkyl chain are reported, and the mismatching is attributed to a developing syn-pentane interaction in the transition state.

Journal Article↗
PubMed2005

2-O-propargyl ethers: readily cleavable, minimally intrusive protecting groups for beta-mannosyl donors.

[reaction: see text]. The use of 2-O-propargyl ethers as protecting groups in 4,6-O-benzylidene-protected mannopyranosyl donors bearing either bulky silyl groups or glycosidic linkages on O3 overcomes the poor stereoselectivity achieved with the corresponding 2-O-benzyl ethers, due to a reduction of steric buttressing. Deprotection is conducted by treatment with potassium tert-butoxide followed by catalytic osmium tetroxide and N-methylmorpholine N-oxide.

Benzylidene Compounds↗
PubMed2005

Synthesis and stereoselective glycosylation of D- and L-glycero-beta-D-manno-heptopyranoses.

[reaction: see text] A method for the direct stereocontrolled synthesis of D- and L-glycero-beta-D-manno-heptopyranosides such as those found in the repeating unit of the O-specific polysaccharide from the CNCTC 113/92 LPS (serotype 54) is described. The method relies on the presence of a 4,6-O-benzylidene acetal to effect stereocontrol at the anomeric center; the configuration at C6 (L- or D-glycero) is of minimal importance.

Carbohydrate Sequence↗
PubMed2005

Synthesis of a 4,6-disubstituted dibenzofuran beta-sheet initiator by reductive radical arylation of benzene.

[reaction: see text] Tributyltin hydride mediated addition of 3-iodosalicylaldehyde to benzene in the presence of catalytic benzeneselenol affords (1,4-cyclohexadien-3-yl)salicylaldehyde. Homologation of the aldehyde group is followed by cycloetherification with dimethyl dioxirane to give a 4,6-disubstituted tetrahydrodibenzofuran. Adjustment of oxidation states and introduction of a second chain by Wittig olefination affords the beta-sheet initiator, ethyl 4-(2-tert-butoxycarbonylaminoethyl)-6-dibenzofuranpropanoate.

Alkylation↗
PubMed2005

6-O-Benzyl- and 6-O-silyl-N-acetyl-2-amino-2-N,3-O-carbonyl-2-deoxyglucosides: effective glycosyl acceptors in the glucosamine 4-OH Series. effect of anomeric stereochemistry on the removal of the oxazolidinone group.

[reaction: see text] The 4-OH groups of both alpha- and beta-methyl glycosides of N-acetylglucosamine, protected with an oxazolidinone spanning the nitrogen and O-3, and bearing benzyl or silyl protection on O-6, show excellent reactivity as acceptors in couplings to a range of glycosyl donors. The enhanced reactivity of these acceptors is attributed in part to the tied back nature of the oxazolidinone, which reduces hindrance around the nucleophilic oxygen. The N-acetyloxazolidinone function also reduces the tendency seen in simple N-acetylglucosamines toward amide glycosylation, and removes the possibility of problematic hydrogen bonding networks. In the beta-, but not the alpha-, series selective hydrolysis of the N-acetyloxazolidinone directly to the N-acetylglucosamine was possible with barium hydroxide, a feature attributed to chelate formation between the acetamide carbonyl group and the glycosidic oxygen in the beta-series.

Acetylation↗
PubMed2004

Direct chemical synthesis of the beta-mannans: linear and block syntheses of the alternating beta-(1-->3)-beta-(1-->4)-mannan common to Rhodotorula glutinis, Rhodotorula mucilaginosa, and Leptospira biflexa.

Two stereocontrolled syntheses of a methyl glycoside of an alternating beta-(1-->4)-beta-(1-->3)-mannohexaose, representative of the mannan from Rhodotorula glutinis, Rhodotorula mucilaginosa, and Leptospira biflexa, are described. Both syntheses employ a combination of 4,6-O-benzylidene- and 4,6-O-p-methoxybenzylidene acetal-protected donors to achieve stereocontrolled formation of the beta-mannoside linkage. The first synthesis is a linear one and proceeds with a high degree of stereocontrol throughout and an overall yield of 1.9%. The second synthesis, a block synthesis, makes use of the coupling of two trisaccharides, resulting in a shorter sequence and an overall yield of 4.4%, despite the poor selectivity in the key step.

Benzylidene Compounds↗
PubMed2004

Direct chemical synthesis of the beta-D-mannans: the beta-(1-->2) and beta-(1-->4) series.

The direct syntheses of a beta-(1-->2)-mannooctaose and of a beta-(1-->4)-mannohexaose are reported by means of 4,6-O-benzylidene-protected beta-mannosyl donors. The synthesis of the (1-->2)-mannan was achieved by means of the sulfoxide coupling protocol, whereas the (1-->4)-mannan was prepared using the analogous thioglycoside/sulfinamide methodology. In the synthesis of the (1-->4)-mannan, the glycosylation yields and stereoselectivities remain approximately constant with increasing chain length, whereas those for the (1-->2)-mannan consist of two groups with the formation of the tetra- and higher saccharides giving yields and selectivities consistently lower than those of the lower homologues. The decrease in yield after the trisaccharide in the (1-->2)-mannan synthesis is attributed to steric interference by the n-3 residue and is consistent with the collapsed, disordered structure predicted by early computational work. The consistently high yields and selectivities seen in the synthesis of the (1-->4)-mannan are congruent with the more open, ordered structure originally predicted for this polymer. The lack of order in the structure of the (1-->2)-mannan, as compared to the high degree of order in the (1-->4)-mannan, is also evident from a comparison of the NMR spectra of the two polymers and even from their physical nature: the (1-->2)-mannan is a gum and the (1-->4)-mannan is a high melting solid.

Carbohydrate Conformation↗
PubMed2004

Design, synthesis, and evaluation of oxyanion-hole selective inhibitor substituents for the S1 subsite of factor Xa.

We have designed, synthesized, and evaluated the factor Xa inhibitory activities of p-amidinophenyl-sulfones, amines, and alcohols intended to take advantage of the polarity and hydrogen-bonding potential of the oxyanion hole region of the S1 specificity pocket. We demonstrate that placement of an anionic group within the oxyanion hole region of the catalytic site substantially enhances activity, with small flexible groups favored over bulkier ones. Ab initio pKa calculations suggest that the hydroxyl substituent frequently used for benzamidine moieties may be ionized to form an anionic group, consistent with the general trend. One nonamidine based substituent also shows promising activity.

Alcohols↗
PubMed2004

Benzylidene acetal fragmentation route to 6-deoxy sugars: direct reductive cleavage in the presence of ether protecting groups, permitting the efficient, highly stereocontrolled synthesis of beta-D-rhamnosides from D-mannosyl glycosyl donors. Total synthesis of alpha-D-Gal-(1-->3)-alpha-D-Rha-(1-->3)- beta-D-Rha-(1-->4)-beta-D-Glu-OMe, the repeating unit of the antigenic lipopolysaccharide from Escherichia hermannii ATCC 33650 and 33652.

An approach to the stereocontrolled synthesis of beta-d-rhamnopyranosides is described in which 2,3-O-benzyl or related 4,6-O-[alpha-(2-(2-iodophenyl)ethylthiocarbonyl)benzylidene]-mannosyl thioglycosides are first used to introduce the beta-d-mannopyranoside linkage in high yield and stereoselectivity. Following glycosylation, treatment with tributyltin hydride in toluene at reflux brings about reductive radical fragmentation directly to the 6-deoxy sugar in high yield. A variation of these donors bearing a carboxylated donor on O3 is a highly alpha-selective mannosyl and, after radical fragmentation, alpha-d-rhamnosyl donor. Using this stereoselective glycosylation/radical-fragmentation approach, a concise synthesis of the title tetrasaccharide is realized in which both the beta-d- and alpha-d-rhamnopyranosyl units are obtained in a single step by a double radical fragmentation of the modified benzylidene acetals.

Benzylidene Compounds↗
PubMed2004

Endo-selective quenching of hexahydropyrrolo[2,3-b]indole-based N-acyliminium ions.

Radical decarboxylation of L-tryptophan-derived (2S,3aR,8aS)-8-arylsulfonyl-1,2-di(methoxycarbonyl)-1,2,3,3a,8,8a-hexahydro-2H-pyrrolo[2,3-b]indoles 8 and 9 in the presence of diphenyl diselenide results in the endo-selective formation of (2R,3aR,8aS)-8-arylsulfonyl-1-methoxycarbonyl-2-phenylselenyl-1,2,3,3a,8,8a-hexahydro-2H-pyrrolo[2,3-b]indoles 10 and 11. These selenides, in conjunction with Lewis acids, serves as precursors to the corresponding N-acyl iminium ions, which undergo selective endo-face quenching by allyltributylstannane, allyltrimethylsilane, propargyltrimethylsilane, and trimethylsilylcyanide. Stereochemical assignments rest on NMR data and crystallographic studies. The endo-selective nature of these reactions is interpreted in terms of minimization of allylic strain at the transition state for nucleophilic attack on the N-acyl iminum ion.

Journal Article↗
PubMed2004

The intramolecular asymmetric Pauson-Khand cyclization as a novel and general stereoselective route to benzindene prostacyclins: synthesis of UT-15 (treprostinil).

A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI(2), namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C(3a), C(9a), and C(1)).

Alkanes↗
PubMed2004

Catalytic allylic oxidation with a recyclable, fluorous seleninic acid.

In conjunction with iodoxybenzene as reoxidant perfluorooctylseleninic acid catalyzes the allylic oxidation of alkenes to enones in trifluoromethylbenzene at reflux in moderate to good yield. After a reductive workup with sodium metabisulfite, the catalyst is recovered by fluorous extraction in the form of bis(perfluorooctyl) diselenide, which, itself, serves as a convenient catalyst precursor. [reaction: see text]

Journal Article↗
PubMed2003

The 3,4-O-carbonate protecting group as a beta-directing group in rhamnopyranosylation in both homogeneous and heterogeneous glycosylations as compared to the chameleon-like 2,3-O-carbonates.

It is demonstrated that the beta-selectivity observed in the insoluble silver salt mediated couplings of 2,3-O-carbonate-protected rhamnosyl bromides is uniquely due to the heterogeneous nature of the reaction. In homogeneous solution these same donors are alpha-selective, a fact that is attributed to the half-chair conformation of these substances which reduces the energy barrier to oxacarbenium ion formation. It is suggested that the 2,3-O-carbonate group be dubbed torsionally arming in the manno- and rhamnopyranose series. When the carbonate group is removed to the 3,4-O-position a beta-selective system is formed, in both homogeneous and heterogeneous conditions, and it is demonstrated that this selectivity arises from the combination of the electron-withdrawing nature of the carbonate and its inability to take part in neighboring participation.

Alkenes↗
PubMed2003

Influence of the 4,6-O-benzylidene, 4,6-O-phenylboronate, and 4,6-O-polystyrylboronate protecting groups on the stereochemical outcome of thioglycoside-based glycosylations mediated by 1-benzenesulfinyl piperidine/triflic anhydride and N-iodosuccinimide/trimethylsilyl triflate.

The effect of 4,6-O-benzylidene acetals, 4,6-O-phenylboronate esters, and 4,6-O-polystyrylboronate esters on the stereoselectivity of couplings to galacto-, gluco-, and mannopyranosyl thioglycosides, otherwise protected with benzyl ethers, has been investigated by the benzenesulfinyl piperidine/trifluoromethanesulfonic anhydride (BSP), diphenyl sulfoxide/trifluoromethanesulfonic anhydride (Ph(2)SO), and N-iodosuccinimide/trimethylsilyl trifluoromethanesulfonate (NIS/TMSOTf) methods. The BSP and Ph(2)SO methods give comparable results in all three systems whereas the NIS method affords significantly different stereoselectivities in both the gluco and manno, but not the galacto series. The benzylidene acetal and boronate esters influence the stereochemistry in a similar manner in the beta-selective manno series and the alpha-selective galacto series but show significant differences with the glucose donors. The differences between the glucose, galactose, and mannose series reflect the established differences in reactivity and, especially for mannose, those in the anomeric effect and are best interpreted in terms of changes in the relative energetics between the alpha- and beta-covalent triflate intermediates and the various contact ion pairs with which they are necessarily in equilibrium.

Carbohydrate Conformation↗
PubMed2003

Branched aliphatic alkanes with quaternary substituted carbon atoms in modern and ancient geologic samples.

A pseudohomologous series of branched aliphatic alkanes with a quaternary substituted carbon atom (BAQCs, specifically 2,2-dimethylalkanes and 3,3- and 5,5-diethylalkanes) were identified in warm (65 degrees C) deep-sea hydrothermal waters and Late Cretaceous black shales. 5,5-Diethylalkanes were also observed in modern and Holocene marine shelf sediments and in shales spanning the last 800 million years of the geological record. The carbon number distribution of BAQCs indicates a biological origin. These compounds were observed but not identified in previous studies of 2.0 billion- to 2.2 billion-year-old metasediments and were commonly misidentified in other sediment samples, indicating that BAQCs are widespread in the geological record. The source organisms of BAQCs are unknown, but their paleobiogeographic distribution suggests that they have an affinity for sulfides and might be nonphotosynthetic sulfide oxidizers.

Alkanes↗
PubMed2003

Enantioselective cyclization of alkene radical cations.

[reaction: see text] Enantiomerically enriched beta-(diphenylphosphatoxy)nitroalkanes undergo radical ionic fragmentation, induced by tributyltin hydride and AIBN in benzene at reflux, to give alkene radical cations in contact radical ion pairs. These contact ion pairs are trapped intramolecularly by amines to give pyrrolidines and piperidines with significant enantioselectivity ( approximately 60% ee), indicative of cyclization competing effectively with equilibration within the ion pairs. Use of an intramolecular N-propargylamine as a nucleophile provides an enantiomerically enriched pyrrolizidine skeleton via a tandem polar/radical crossover sequence.

Journal Article↗