Stereochemical Sense Research Articles

Probing the helical integrity of multivicinal all-syn-fluoro alkanes.

This study extends our interest in the synthesis and conformational behaviour of all-syn multivicinal fluoro alkane motifs. Specifically an all-syn 1,2,3,6,7,8-hexafluorooctane chain was assembled with a run of three fluorines, of the same stereochemical sense (syn) to the direction of the chain, on each side of an ethylene (-CH2CH2-) spacer to explore if the helical sense of the chain crosses the ethylene bridge. The solid state (X-ray) structure indicated a continuous helix however in solution (NMR) and by DFT computation, although the individual all-syn 1,2,3-trifluoro motifs maintain good helical integrity, the molecule is much more dynamic across the ethylene bridge. It was notable however that a low energy, non-helical conformer has a high molecular dipole (μ = 7.15 D) indicating a role for this skipped motif in soft materials such as liquid crystals or polar polymers.

Understanding Silica from the Viewpoint of Asymmetry.

Silica is abundant in the Earth's crust, and silicate materials are used on the global scale, from industrial products for architecture, vehicles, electronics, and optics to consumption as foods, medicines, supplements, and cosmetics. Silica has become increasingly important in current science and technology, as seen in the components of advanced materials. The characteristic formula of silica is very simply often expressed as SiO2 . However, it is difficult to draw silica precisely owing to its intricate chemical structures. We need to make a greater effort in understanding silica, even though silica chemistry has existed for over 200 years. Similar to the homochirality observed in natural amino acids, natural silica of quartz is chiral, and in some sense, the origin of life with chirality might be partly related to quartz-like silica chirality. This review focuses on the asymmetry of silica from the view of the formation of irregular tetrahedron structures of SiO4 . Silica is composed of several repeated tetrahedron units of SiO4 , leading to the formation of inorganic polymers with divergently expanded 3D structures. In this large polymeric skeleton, not every unit of SiO4 can maintain an ideal tetrahedron, and thus, it becomes twisted. The twisting results in an asymmetric point on the Si atom, leading silica to become racemic in the stereochemical sense. Therefore, enantioselective preparation of silica should endow silica with chirality through the silica skeleton. Some recent achievements exhibit that silica is an effective chiral material and has great potential for transferring chirality from silica to other matter.

Highly Enantioselective Hydrogenation of β‐Acyloxy and β‐Acylamino α,β‐Unsaturated Phosphonates Catalyzed by Rhodium Phosphane‐Phosphite Complexes

AbstractThe enantioselective hydrogenation of β‐(acyloxy)‐ and β‐(acylamino)vinylphosphonates with rhodium catalysts based on chiral phosphane‐phosphite ligands has been studied. In the case of the β‐(acyloxy)vinylphosphonates, the reaction also produces an achiral phosphonate resulting from the elimination of the benzoate group. High ligand modularity has led to a highly chemo‐ and enantioselective catalyst for both types of substrates, which afford a good range of β‐acyloxy‐ and β‐acylaminophosphonates with enantioselectivities between 90 and 99% ee. Most interestingly, the configuration of the hydrogenation products indicates the same stereochemical sense for the reduction of both types of substrates, which is opposite to that observed before for α‐(acyloxy)vinylphosphonates. This observation has been rationalized by assuming the formation of a β‐alkyl intermediate during the catalytic cycle, which also explains the formation of the elimination product in the hydrogenation of the β‐(acyloxy)‐vinylphosphonates.

Enantioselective addition of alkynylzinc to arylaldehydes catalyzed by azetidino amino alcohols bearing an additional stereogenic center

Chiral azetidino amino alcohol ligands bearing an additional stereogenic center were readily prepared and used as catalysts for the asymmetric addition of alkynylzinc to aromatic aldehydes with enantioselectivities of up to 87% ee. The relationship between the reaction enantioselectivity and the structure of the chiral ligands was also evaluated in this reaction. The experimental results showed that the enantioselectivity level of the reaction was greatly influenced by the second stereogenic center attached to azetidine ring, but the stereochemical sense was only determined by the configuration of the azetidine ring. A possible transition structure for the catalytic asymmetric addition was also proposed.

Understanding the catalytic role of flexible chiral δ-amino alcohols: the 1-(2-aminoethyl)norbornan-2-ol model

An empiric first approach to the knowledge about the structural factors influencing the catalytic behavior of conformationally flexible δ-amino-alcohol-based ligands, for the enantioselective addition of dialkylzincs to prochiral carbonyl groups, has been applied using the 1-(2-aminoethyl)norbornan-2-ol moiety as the model chiral system, and the asymmetrically catalyzed addition of diethylzinc to benzaldehyde as the test reaction. For this purpose, a selected small library of seven norbornane-based chiral ligands, bearing well-defined structural variations to allow a comparative study, that is, variation of the relative configuration and steric hindrance at the C(2), C(3) and/or C(7) norbornane positions, has been synthesized and probed in the mentioned test reaction. The experimental results obtained have been rationalized empirically using diastereomeric Noyori-like transition states, demonstrating that the conformational flexibility of the δ-amino-alcohol ligands, contrary to the more studied and rigid β-amino-alcohols, plays a crucial role on the catalytic behavior of such ligands (stereochemical sense and degree of the stereodifferentiation in the asymmetric process), which makes such structural factors, important for the improved design of new related chiral catalysts. In this sense, a robust crude empirical model for the prediction of the catalytic behavior of such δ-amino-alcohol-based ligands is proposed.

Highly Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by Isoindolinyl Alcohol as a Chiral Ligand.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by Isoindolinyl Alcohol as a Chiral Ligand

Enantioselective alkylation of carbonyl compounds is a challenged domain of asymmetric C-C bond formation. Particularly, asymmetric addition of diethylzinc to aldehydes is one of the important synthetic methods for the preparation of optically active secondary alcohols, and numerious efforts have been made to find effective chiral ligands. To date, most of the successful results were obtained by using sterically constrained β-amino alcohols such as N,Ndialkylated norephedrine derivatives. Extensive studies by Soai on the effect of ligand structure on enantioselectivity indicated that the chain length of the N-alkyl substituent is very imporant. Thus, the catalyst with N-alkyl substituents of a chain length of four carbons, 1 (DBNE), gave the best results in dialkylzinc addition to various aliphatic (87-93% ee) and aromatic (90-95% ee) aldehydes. It has been recently reported that some azacyclo β-amino alcohols (2 and 3) are among the most efficient chiral ligand in catalytic asymmetric reaction. Employment of conformationally rigid rings such as pyrrolidine and piperidine would provide beneficial on controlling precisely the stereochemical sense in asymmetric catalysis. Here we wish to report a new-type of amino alcohol (4) bearing isoindolinyl moiety as a face blocker and its catalytic efficiency in asymmetric addition of diethylzinc to various aldehydes. The isoindolinyl moiety may possess similar steric and electronic properties with substituted groups at nitrogen of the DBNE, but conformationally more rigid. Hence, compare to DBNE or pyrrolidine ligand 2, it may block effectively the approach of the attacking species to one of the enantiotopic faces of aldehydes. The (1S,2R)-1-phenyl-2-(2-isoindolinyl)-1-propanol[(1S,2R)4] was easily prepared in 95% yield by the reaction of (1S,2R)-norephedrine with α,α'-dibromoxylene in ethanol in the presence of potassium carbonate (Scheme 1). In order to examine the catalytic ability of the ligand 4, the enantioselective addition of diethylzinc to aldehydes was Figure 1. β-Aminoalcohols for diethylzinc addition.

Stereocontrolled conversion of some optically active (4 S,5 R)-dihydroisoxazoles into acyclic 3-acetamido-1,2-diols

Optically active (4 S,5 R)-dihydroisoxazoles 5a– c (90–91% ee) have been prepared by reaction of the epoxyketones 4a– c with hydroxylamine. Reduction of compounds 5a and 5b using lithium aluminium hydride took place exclusively from the Re face to give (1 R,2 S,3 S)-1,3-disubstituted-3-aminopropane-1,2-diols 6a and 6b . These amino-diols were characterised by N-acetylation and the stereochemical sense of the hydride reduction was confirmed by conversion of amides 7a and 7b into α-amino acid derivatives 10a and 10b .

The Ireland-Claisen rearrangement as a probe for the diastereoselectivity of nucleophilic attack on a double bond adjacent to a stereogenic centre carrying a silyl group.

The E- and Z-silyl enol ethers 4 derived from allyl 3-R-3-dimethyl(phenyl)silylpropanoate (R = Me, Pr(i) and Ph) and the Z-silyl enol ethers 7 derived from 4-R-4-dimethyl(phenyl)silylbut-2-enyl acetate (R = Me and Pr(i)) undergo Ireland-Claisen rearrangements largely in the same stereochemical sense, with C-C bond formation taking place anti to the silyl group in the conformations 22, 23 and 24 in which the hydrogen atom on the stereogenic centre is inside, more or less eclipsing the double bond. The E-silyl enol ether E-7a derived from 4-methyl-4-dimethyl(phenyl)silylbut-2-enyl acetate shows low diastereoselectivity in the alternative sense, probably because C-C bond formation takes place anti to the silyl group in the conformation 26 with the methyl group inside, but the silyl enol ether E-7b derived from 4-isopropyl-4-dimethyl(phenyl)silylbut-2-enyl acetate shows low diastereoselectivity in the normal sense. The E- and Z-silyl enol ethers 33 derived from cis-crotyl 3-phenyl-3-dimethyl(phenyl)silylpropanoate and the E-silyl enol ether 39 derived from trans-crotyl 3-phenyl-3-dimethyl(phenyl)silylpropanoate undergo Ireland-Claisen rearrangements largely in the same stereochemical sense as their allyl counterparts, but with moderately high levels of diastereocontrol in setting up the third stereogenic centre following from chair-like transition structures.

Configurational stability and transfer of stereochemical information in the reactions of enantioenriched organolithium reagents.

The conversion of a prochiral methylene group into a stereogenic center by means of a lithiation/substitution sequence has emerged as a powerful synthetic transformation over the past 15 years. This reaction proceeds via a chiral organolithium intermediate, and the stereochemical fidelity of the overall reaction sequence is intimately dependent on the stereochemical behavior of the chiral organolithium as well as on the rate and stereochemical sense of the electrophilic substitution step. Chiral organolithium reagents were first reported by Letsinger, Curtin, and Applequist half a century ago. The lithiated intermediates in these early studies were not highly configurationally stable, and applications in stereoselective synthesis were not immediately forthcoming. The two decades that followed the 1980 report by Still and Sreekumar of a configurationally stable alpha-oxyorganolithium were marked by an increased interest in these reagents. As the synthetic applications of chiral organolithium reagents have grown, so have accompanying mechanistic studies of these intermediates which serve as the basis for this review.

Chlorophyll Breakdown – On a Nonfluorescent Chlorophyll Catabolite from Spinach

In extracts of senescent leaves of spinach (Spinacia oleracea) that had degreened naturally after the onset of flowering, four colorless compounds, which had characteristic UV/VIS properties of nonfluorescent chlorophyll catabolites (NCCs), were detected by HPLC. From the extracts of 58.7 g of senescent leaves of Sp. oleracea, a two-stage HPLC purification procedure provided ca. 15 μmol of So-NCC-2, the most abundant polar NCC in the leaves of this vegetable. So-NCC-2 was isolated as a slightly yellow powder and analyzed by spectroscopic means. The high-resolution mass spectra indicated that So-NCC-2 has the same molecular formula as Hv-NCC-1 from barley (Hordeum vulgare), the first non-green chlorophyll catabolite from a higher plant to be structurally analyzed. Homo- and hetero-nuclear NMR spectroscopy indicated So-NCC-2 to have the same constitution as its epimer Hv-NCC-1, and to differ from the latter by the configuration at C(1). The catabolite from spinach could be identified with one of the products from OsO4 dihydroxylation at the vinyl group of the main NCC from Cercidiphyllum japonicum. Chlorophyll breakdown in spinach and in C. japonicum apparently involves an enzyme-catalyzed reduction that occurs with the same stereochemical sense at C(1), but opposite to that in barley.

Active Site Residues of Glutamate Racemase

Glutamate racemase, MurI, catalyzes the interconversion of glutamate enantiomers in a cofactor-independent fashion and provides bacteria with a source of D-Glu for use in peptidoglycan biosynthesis. The enzyme uses a "two-base" mechanism involving a deprotonation of the substrate at the alpha-position to form an anionic intermediate, followed by a reprotonation in the opposite stereochemical sense. In the Lactobacillus fermenti enzyme, Cys73 is responsible for the deprotonation of D-glutamate, and Cys184 is responsible for the deprotonation of L-glutamate; however, very little is known about the roles of other active site residues. This work describes the preparation of four mutants in which strictly conserved residues containing ionizable side chains were modified (D10N, D36N, E152Q, and H186N). During the course of this research, the structural analysis of a crystallized glutamate racemase indicated that three of these residues (D10, E152, and H186) are in the active site of the enzyme [Hwang, K. Y., Cho, C.-S., Kim, S. S., Sung, H.-C., Yu, Y. G., and Cho, Y. (1999) Nat. Struct. Biol. 6, 422-426]. Two of the mutants, D10N and H186N, displayed a marked decrease in the values of k(cat), but not K(M), and are therefore implicated as important catalytic residues. Further analysis of the primary kinetic isotope effects observed with alpha-deuterated substrates showed that a significant asymmetry was introduced into the free energy profile by these two mutations. This is interpreted as evidence that the mutated residues normally assist the catalytic thiols in acting as bases (D10 with C73 and H186 with C184). An alternate possibility is that the residues may serve to stabilize the carbanionic intermediate in the racemization reaction.

Synthesis of (±)-Calicheamicinone by Two Methods

Ketene acetal 25 was converted into silyl enol ether 20, which underwent a Diels−Alder reaction with methyl (E)-3-nitropropenoate to afford ketone 27. This was converted by two routes into (±)-calicheamicinone (1). In the first, modification of the nitro, ester, and allyl substituents gave ketone 38, which reacted stereoselectively with cerium trimethylsilylacetylide to place the acetylene unit syn to the nitrogen function (38 → 39). Further elaboration took the route as far as aldehyde 42. A slightly different series of reactions served to convert ketone 27 into tricyclic ketone 43. This also reacted with cerium trimethylsilylacetylide, but in the opposite stereochemical sense to 38, so as to place the acetylene unit anti to the nitrogen function (43 → 50). Further elaboration took this second route as far as lactone 44. Both 42 and 44 serve as advanced intermediates for the synthesis of (±)-calicheamicinone. The monoacetylenic aldehyde 42 reacted stereoselectively with cerium trimethylsilylacetylide to ...

Facile asymmetric syntheses of 1-deoxycastanospermine and 1-deoxy-8a-epi-castanospermine

The asymmetric syntheses of 1-deoxycastanospermine (6) and 1-deoxy-8a-epi-castanospermine (7) have been completed. A key step in these syntheses was the stereoselective addition of 2-furyllithium to the 4-O-tert-butyldiphenylsilyl-protected threose derivative 13 to give the C(7)-C(8) syn-adduct 14 as the major product. The diastereoselectivity of this reaction is particularly noteworthy since the related addition of 2-furyllithium to the corresponding 4-O-benzyl-protected aldehyde 8 proceeded in the opposite stereochemical sense to give primarily the C(7)-C(8) anti-adduct 10. Oxidation of the furan ring in 14 followed by refunctionalization led to the azido ketone 20, followed by reductive amination gave 6 or 7

Rearrangements of cyclobutenones. Conversion of selected 4-allylcyclobutenones to bicyclo[3.2.0]heptenones

J . Org. Chem. 1989,54, 6018-6021 Scheme I11 TEST H --Co2Et v OAc c K-PH1 5 HI 1 x=o .c-- fi OAc X =aOAc;PH (i) DiBAH c (ii) Ph3P = CH (CH& QK from 12. The overall yield of 1 from 3 is 27%. As pre- viously described, 35J2 is readily available in enantiomer- ically homogeneous form from cis-l,4-diacetoxycyclo- pentene. The stereochemical outcome a t C13 arising from the coupling of similar substrates under the same conditions is amazing. In the previously described aldols5 leading to 5 and 6 no other stereoisomers were observed. Yet when the ynal 7 is employed 8 is the only product observed! Instead of offering ad hoc interpretations that do not flow from sound experimental observations, we prefer to outline an agenda of questions that must be addressed. Why does a particular substitution type on the aldehyde favor or disfavor silyl transfer? Is silyl transfer fundamental or accessory to the stereochemical outcome? Do the sharply differing results arise from a common transition-state (12) Cf: (a) Deardorff, D. R.; Myles, D. C.; MacFerrin, K . D. Tetra- hedron Lett. 1985, 5615. (b) Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Ibid. 1986, 1255. alignment differing in the placement of the R and H group of the aldehyde or do the reaction types differ in overall topography (chair vs boat, synclinal vs antiperiplanar)? Answers to these sorts of questions are not readily obtained but are crucial to illuminating this interesting stereo- chemical finding and extending it to new domains. I n the meantime, we note that the chemistry disclosed here and previously5 provides straightforward access to optically pure prostaglandins with complete control of the con- figuration at either C13 or C15 in any stereochemical sense. Acknowledgment. This research was supported by PHS Grant HL25848. NMR Spectra were obtained through the auspices of the Northeast Regional NSF/ NMR facility at Yale University, which was supported by NSF Chemistry Division Grant CHE 7916210. Supplementary Material Available: Experimental proce- dures and characterization data for all compounds (5 pages). Ordering information is given on any current masthead page. Rearrangements of Cyclobutenones. Conversion of Selected 4-Allylcyclobutenones to Bicycle[ 3.2.0lheptenones Simon L. Xu and Harold W . Moore* Department of Chemistry, University of California, Iruine, California 9271 7 Received October 9. 1989 Summary: 4-Allyl-4-alkoxy(or hydroxy or (trimethyl- sily1)oxy)cyclobutenones are reported to rearrange to bi- cyclo[3.2.0] hept-2-en-7-ones upon thermolysis in refluxing toluene. The synthetic scope and mechanism of this un- usual transformation are discussed. The products are envisaged to arise from an electrocyclic ring opening of the cyclobutenones to the corresponding vinylketenes which then undergo an intramolecular [ 2 21 cycloaddition of the ketene moiety to the nonconjugated allylic double bond. Sir: Selected 4-alkynyl, 4-alkenyl-, and 4-arylcyclo- butenones have recently been shown to undergo facile ring expansion to respectively benzoquinones, hydroquinones, 0 1989 American Chemical Society

Total synthesis of 13-oxygenated prostanoids derived from arachidonate: an instance of extraordinary variability in the stereochemical sense of a Mukaiyama aldol reaction

Total synthesis of 13-oxygenated prostanoids derived from arachidonate: an instance of extraordinary variability in the stereochemical sense of a Mukaiyama aldol reaction

An epoxidation cis to two allylic benzoyloxy-groups

Direct epoxidation of tri-O-benzoylcyclopentene-3,5/4-triol proceeds in the same stereochemical sense as that of the parent triol, which yields 1,2-anhydrocyclopentane-1,2,3,5/4-pentol.

Studies on Isopentenyl Pryophosphate Isomerase with Artificial Substrates

Two isopentenyl pyrophosphate homologs, 3-ethylbut-3-enyl pyrophosphate (I), and trans-3-methylpent-3-enyl pyrophosphate (II)have been found to act as substrates for isopentenyl pyrophosphate isomerase from pig live. The compound (I) is converted much faster into II than into cis-3-methylpent-2-enyl pyrophosphate (III), whereas II gives exclusively trans-3-methylpent-2-enyl pyrophosphate (IV). The isomerization between II and IV is reversible and similar in stereochemical sense to that between isopentenyl pyrophosphate and dimethylallyl pyrophosphate. However, the unusual isomerization of I to II is irreversible. The mechanism for these isomerizations is proposed.

Studies on the biosynthesis of cholesterol XIX. Steric course of hydrogen eliminations and of C-C bond formations in squalene biosynthesis.

1. Three molecules of isopentenyl pyrophosphate are used in the biosynthesis of one molecule of farnesyl pyrophosphate. In this process, one hydrogen atom is added and three are eliminated : these three were all originally attached to C-4 of an earlier precursor, mevalonate. It is demonstrated that these eliminations are stereospecific and that all three occur in the same stereochemical sense. The absolute configuration of the eliminated hydrogen is defined. 2. In the association of three isopentenyl pyrophosphate molecules to form farnesyl pyrophosphate, two new C—C bonds are formed with expulsion of two pyrophosphate ions. It is demonstrated that both these processes occur with inversion of configuration at the pyrophosphate-bearing carbon atom. 3. In the biosynthesis of squalene from two molecules of farnesyl pyrophosphate, one farnesyl residue suffers exchange of one hydrogen atom and one new C—C bond is formed. It is demonstrated that this bond is formed with inversion of configuration at that farnesyl residue which does not exchange hydrogen.