Stereospecific Reaction Research Articles

Z‐Selective or Stereospecific Alkenylation Reaction: A Novel Synthetic Method for α‐Fluoro‐α,β‐unsaturated Esters.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Copper-Catalyzed γ-Selective and Stereospecific Substitution Reaction of Allylic Carbonates with Diboron: Efficient Route to Chiral Allylboron Compounds

A copper-catalyzed gamma-selective and stereospecific substitution reaction of allylic carbonates with a diboron reagent affording allylboron compounds is described. Boryl group was selectively introduced at the gamma-position of the leaving carbonate group. Functionalized allylboronates that have an acetal, ester, or isolated alkene were prepared. The reaction of optically active allylic carbonates underwent complete alpha-to-gamma chirality transfer with anti-stereochemistry to produce optically active allylboronates having a boron-substituted stereogenic center.

Palladium mediated spiroketal synthesis: application to pheromone synthesis

Stereospecific Stille coupling reactions of 2-metallo-dihydropyrans with Z-vinyl iodo alcohols and subsequent cyclisation provides rapid access to 1,7-dioxaspiro[5.5]undecane family of spiroketals.

Stereoselective 4‐Benzyloxybut‐2‐enylation of Aldehydes via an Allyl‐Transfer Reaction Using a Chiral Allyl Donor.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Sequential Cross‐Coupling of 1,4‐Bissilylbutadienes: Synthesis of Unsymmetrical 1,4‐Disubstituted 1,3‐Butadienes.

A mild and general and stereospecific cross-coupling reaction of unsymmetrical 1,4-bissilyl-1,3-butadienes has been accomplished. By the use of either a benzyldimethylsilyl or 2-thienyldimethylsilyl unit at one end of the dienylsilanol, a selective cross-coupling could be effected under mildly basic conditions (KOTMS) to afford 4-aryl-1,3-dienylsilanes in excellent yield for a wide range of aryl and alkenyl coupling partners. The second cross-coupling could be effected cleanly by the action of TBAF with electron-rich or electron-poor halides. The sequential process could be telescoped into a “one pot” procedure with overall excellent yields of the unsymmetrical 1,4-diaryl-1,3-butadienes.

A Stereospecific Synthesis of Imidazolidin-2-ones from Aziridine-2-carboxylates and Isocyanates

A mild, Lewis acid (MgBr2 or TMSCl)­ catalyzed regiospecific and stereospecific reaction of aziridine-2-carboxylates with isocyanates to afford imidazolidin-2-ones is reported. Although aziridine ring expansion reactions are common, stereospecific processes are relatively rare (J.-O. Baeg, C. Bensimon, H. Alper J. Am. Chem. Soc. 1995, 117, 4700-4701). The reaction proceeds with retention of configuration controlled by the α-benzylamine chiral auxiliary in good to excellent yields.

Z-Selective or Stereospecific Alkenylation Reaction: A Novel Synthetic Method for α-Fluoro-α,β-unsaturated Esters

Abstract The Z-selective formation of α-fluoro-α,β-unsaturated esters was achieved using the deselenenic acid of the syn- and/or anti-3-aryl-2-fluoro-3-hydroxy-2-organoselanylacetates 3 and 4 with trifluoromethanesulfonic acid. In contrast, the 3-alkyl-substituted propanoates 3f and 4b stereospecifically underwent alkenylation to give the (E)- or (Z)-α-fluoro-α,β-unstaurated esters 5f. We were also successful in the one-pot alkenylation reactions.

Stereoselective 4-Benzyloxybut-2-enylation of Aldehydes via an Allyl-Transfer Reaction Using a Chiral Allyl Donor

[reaction: see text] A direct and highly stereoselective (E)-4-benzyloxybut-2-enylation of aldehydes was successfully carried out to give 5-benzyloxyhomoallylic alcohol (11) via an allyl-transfer reaction using a chiral allyl donor (10). The chiral allyl donor (10) was prepared by catalytic Sharpless asymmetric epoxidation of 3-methylbut-2-en-1-ol, followed by a stereospecific vinyl Grignard reaction of the epoxide in the presence of CuBr and selective benzylation of the primary alcohol of diol.

Cover Picture: Elemental Fluorine and HOF·CH3CN in Service of General Organic Chemistry (Eur. J. Org. Chem. 12/2005)

AbstractThe cover picture shows part of the synthetic possibilities opened now by using elemental fluorine as a starting material. Mixtures of F2 with inert gases such as N2 are commercially available or easily prepared from commercial 95% fluorine. During the last 15 years, chemists started to accept the notion that F2 could be used for fluorination purposes. More recently, they slowly started to get acquainted with yet another side of this element − its ability to perform difficult reactions leading to fluorine‐free derivatives. Thus, the most reactive element of the periodic table is an excellent tool for versatile regio‐ and stereospecific reactions which can not be performed without its “help”. Representative examples are presented in the Microreview by S. Rozen on p. 2433 ff.

Sequential Cross-Coupling of 1,4-Bissilylbutadienes: Synthesis of Unsymmetrical 1,4-Disubstituted 1,3-Butadienes

A mild and general and stereospecific cross-coupling reaction of unsymmetrical 1,4-bissilyl-1,3-butadienes has been accomplished. By the use of either a benzyldimethylsilyl or 2-thienyldimethylsilyl unit at one end of the dienylsilanol, a selective cross-coupling could be effected under mildly basic conditions (KOTMS) to afford 4-aryl-1,3-dienylsilanes in excellent yield for a wide range of aryl and alkenyl coupling partners. The second cross-coupling could be effected cleanly by the action of TBAF with electron-rich or electron-poor halides. The sequential process could be telescoped into a "one pot" procedure with overall excellent yields of the unsymmetrical 1,4-diaryl-1,3-butadienes.

A General Strategy for the Synthesis of Vincamajine-Related Indole Alkaloids: Stereocontrolled Total Synthesis of (+)-Dehydrovoachalotine, (−)-Vincamajinine, and (−)-11-Methoxy-17-epivincamajine as Well as the Related Quebrachidine Diol, Vincamajine Diol, and Vincarinol1

[structures: see text] The highly convergent stereocontrolled total synthesis of (-)-vincamajinine (7), (-)-11-methoxy-17-epivincamajine (9), and the oxygen-bridged (+)-dehydrovoachalotine (22) are described. Key steps in the synthesis of 7 and 9 involved the stereospecific enolate-driven palladium-catalyzed cross-coupling reaction, a Tollens reaction, an acid-assisted intramolecular cyclization to form the C(7)-C(17) quaternary center, and two stereospecific reductions. The efficiency of this strategy is illustrated by the completion of the synthesis of 7 and 9 in 16 [from d-(+)-tryptophan methyl ester 17] and 17 (from the Schöllkopf chiral auxiliary 27) reaction vessels, respectively. This constitutes the first total synthesis of these indole alkaloids and provides the first regiospecific route to 11-methoxy-substituted ajmaline/vincamajine-related alkaloids. The synthesis of 22 required a novel DDQ-mediated cyclization to furnish the C(6)-O(17) bond, executed in stereospecific fashion. Completion of these syntheses illustrates a concise and versatile strategy for the synthesis of vincamajine-related alkaloids, which has also been employed to prepare the related compounds quebrachidine diol (53), vincamajine diol (56), and vincarinol (59).

Stereospecific Reaction of α‐Carbamoyloxy‐2‐alkenylboronates and α‐Carbamoyloxy‐alkylboronates with Grignard Reagents — Synthesis of Highly Enantioenriched Secondary Alcohols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Nitrile Biotransformations for Highly Enantioselective Synthesis of Oxiranecarboxamides with Tertiary and Quaternary Stereocenters; Efficient Chemoenzymatic Approaches to Enantiopure α-Methylated Serine and Isoserine Derivatives

[reaction: see text] Biotransformations of a number of differently substituted and configured oxiranecarbonitriles using Rhodococcus sp. AJ270, a microbial whole-cell catalyst that contains nitrile hydratase/amidase, were studied. While almost all trans-configured 3-aryl-2-methyloxiranecarbonitriles and 2,3-dimethyl-3-phenyloxiranecarbonitrile were efficiently hydrated by the action of the less enantioselective nitrile hydratase, the amidase exhibited excellent 2S,3R-enantioselectivity against 2-methyl-3-(para-substituted-phenyl)oxiranecarboxamides. Under very mild conditions, biotransformations of nitriles provided an efficient and practical synthesis of 2R,3S-(-)-3-aryl-2-methyloxiranecarboxamides, electrophilic epoxides with tertiary and quaternary stereocenters, in excellent yield with enantiomeric excess greater than 99.5%. The synthetic applications of the resulting enantiomerically pure epoxides were demonstrated by convenient and straightforward syntheses of polyfunctionalized chiral molecules possessing a quaternary stereocenter such as R-(+)-2-hydroxy-2-methyl-3-phenylpropionic acid, 2R,3R-(-)-3-amino-2-hydroxy-2-methyl-3-phenylpropionic acid, and 2S,3S-(+)-2-amino-3-hydroxy-2-methyl-3-phenylpropionic acid, employing the regio- and stereospecific epoxide ring opening reactions of 2R,3S-(-)-2-methyl-3-phenyloxiranecarboxamide as the key steps.

Total synthesis of (−)-physovenine from (−)-3a-hydroxyfuroindoline

Total synthesis of calabar bean alkaloid (−)-physovenine (−)- 3 has been achieved in a concise manner starting from optically active (−)-3a-hydroxyfuroindoline (−)- 2 , synthesized via modified Sharpless epoxidation of tryptophol 1 . Our strategy involved a stereospecific radical substitution reaction and regioselective oxidation at the C5 position.

Short communication: An alternative and effective catalyst in the stereo-specific reaction ofZ-1-aryl-1-stannyl-2-silylethenes with allyl bromide

The Pd(dba)2-catalyzed reaction of Z-1-aryl-1-(tributylstannyl)-2-(trimethylsilyl)ethenes with allyl bromide in the presence of copper(I) iodide is reported for the first time. The reaction in the presence of 0.5 mol% Pd(dba)2 and 8 mol% CuI in dimethylformamide takes place at room temperature to give E-2-aryl-1-(trimethylsilyl)penta-1,4-dienes exclusively in isolated yields of 62–99%. A putative reaction mechanism is proposed. Copyright © 2005 John Wiley & Sons, Ltd.

Asymmetric cyclopropane synthesis via phosphine oxide mediated cascade reactions

A silyloxy-THF has been converted into a cyclopropane containing three stereocentres as mixture of diastereoisomers. The mechanism of the reaction has been established and the source of stereochemical leakage proposed. An alternative stereospecific cascade reaction has been discovered.

Stereoselective Synthesis of Highly Enantioenriched (E)‐Allylsilanes by Palladium‐Catalyzed Intramolecular Bis‐Silylation: 1,3‐Chirality Transfer and Enantioenrichment via Dimer Formation

Highly enantioenriched (E)-allylsilanes have been synthesized from optically active allylic alcohols on the basis of Pd-catalyzed intramolecular bis-silylation followed by highly stereospecific Si-O elimination reactions. The method involves three steps: 1) O-disilanylation of the allylic alcohols with chlorodisilanes, 2) intramolecular bis-silylation in the presence of a 1,1,3,3-tetramethylbutyl isocyanide/[Pd(acac)2] (acac = acetylacetonate) catalyst at 110 degrees C, and 3) treatment of the reaction mixture with organolithium reagents. The overall transformation proceeds with nearly complete conservation of the enantiopurity of the starting allyl alcohols by transposition of the C=C bond. For instance, (R)-(E)-3-decen-2-ol (99.6-99.7 % ee) produced (S)-(E)-4-(organosilyl)-2-decene of 98.8-99.4 % ee for a variety of silyl groups, including Me3Si, Me2PhSi, tBuMe2Si, Et3Si, and iPr3Si. In the bis-silylation step, the initially formed trans-1,2-oxasiletanes immediately dimerize to stereoselectively give 1,5-dioxa-2,6-disilacyclooctanes, which are isolated in high yield by carrying out the reaction at 70 degrees C. The eight-membered ring compounds undergo thermal extrusion of (E)-allylsilanes in high yield at 110 degrees C, along with formation of 1,3-dioxa-2,5-disilacyclohexane derivatives. These in turn undergo a Peterson-type elimination by treatment with nucleophiles such as BuLi and PhLi to give the (E)-allylsilanes. All of the steps involved in the sequence proceed with extremely high stereoselectivity and stereospecificity, leading to almost complete 1,3-chirality transfer through the overall transformation. The dimerization step, which forms diastereomeric intermediates, allows the synthesis of a highly enantioenriched allylsilane (99.4 % ee) from an optically active allylic alcohol with lower enantiopurity (79.2 % ee) by enrichment of enantiopurity. A general method for the determination of the enantiomeric excesses of (E)-allylsilanes is also described in detail.

Total Synthesis of Absinthin

(+)-Absinthin, a structurally unique triterpene, has been efficiently constructed in nine reaction steps and in 18.6% overall yield from O-acetylisophotosantonic lactone. The synthesis features Mitsunobu arylselenylation, oxidative elimination of allylic arylselenides, biomimetic dimerization via regio- and stereospecific Diels-Alder reaction, and a four-step stereochemical inversion of a highly sterically congested tertiary alcohol. This approach has not only tackled the formidable synthetic challenges in assembling structurally complex (+)-absinthin but also paved an efficient synthetic route to a series of medicinally attractive absinthin analogues.

Facile, Efficient, and Enantiospecific Syntheses of 1,1‘-N-Linked Pseudodisaccharides as a New Class of Glycosidase Inhibitors

This article describes an efficient synthesis of a potent trehalase inhibitor, 1,1'-N-linked pseudodisaccharide 1 (consisting of two valienamines), in 14 steps with an overall yield of 12% and a first synthesis of 2 (consisting of two 2-epi-valienamines) in 15 steps with an overall yield of 24% from (-)-quinic acid. The synthesis involves a stereospecific palladium-catalyzed coupling reaction between an allylic amine and an allylic chloride as the crucial step. The acetonide blocking groups were shown to be the best hydroxyl protecting groups, compatible with the palladium-catalyzed allylic amination reaction that afforded high yields of the 1,1'-N-linked pseudodisaccharides with a minimum amount of an elimination diene side product.

Direct Observation of Aβ Amyloid Fibril Growth and Inhibition

Amyloid fibril formation is a phenomenon common to many proteins and peptides, including amyloid beta (Abeta) peptide associated with Alzheimer's disease. To clarify the mechanism of fibril formation and to create inhibitors, real-time monitoring of fibril growth is essential. Here, seed-dependent amyloid fibril growth of Abeta(1-40) was visualized in real-time at the single fibril level using total internal reflection fluorescence microscopy (TIRFM) combined with the binding of thioflavin T, an amyloid-specific fluorescence dye. The clear image and remarkable length of the fibrils enabled an exact analysis of the rate of growth of individual fibrils, indicating that the fibril growth was a highly cooperative process extending the fibril ends at a constant rate. It has been known that Abeta amyloid formation is a stereospecific reaction and the stability is affected by l/d-amino acid replacement. Focusing on these aspects, we designed several analogues of Abeta(25-35), a cytotoxic fragment of Abeta(1-40), consisting of l and d-amino acid residues, and examined their inhibitory effects by TIRFM. Some chimeric Abeta(25-35) peptides inhibited the fibril growth of Abeta(25-35) strongly, although they could not inhibit the growth of Abeta(1-40). The results suggest that a more rational design of stereospecific inhibitors, combined with real-time monitoring of fibril growth, will be useful to invent a potent inhibitor preventing the amyloid fibril growth of Abeta(1-40) and other proteins.