Oxazolidinone Chiral Auxiliary Research Articles

The Reaction of Singlet Oxygen with Enecarbamates: A Mechanistic Playground for Investigating Chemoselectivity, Stereoselectivity, and Vibratioselectivity of Photooxidations

Photochirogenesis, the control of chirality in photoreactions, is one of the most challenging problems in stereocontrolled photochemistry, in which the stereodifferentiation has to be imprinted within the short lifetime of the electronically excited state. Singlet oxygen (1O2), an electronically excited molecule that is known to be sensitive to vibrational deactivation, has been selected as a model case for testing stereoselective control by vibrational deactivation. The stereoselectivity in the reaction of 1O2 with E/Z enecarbamates 1, equipped with the oxazolidinone chiral auxiliary, has been examined for the mode selectivity ([2 + 2]-cycloaddition versus ene-reaction) and the stereoselectivity in the oxidative cleavage of the alkenyl functionality to the methyldesoxybenzoin (MDB) product. Through the appropriate choice of substituents in the enecarbamate, the mode selectivity (ene versus [2 + 2]), which depends on the alkene geometry (E or Z), the steric bulk of the oxazolidinone substituent at the C-4 position, and the C-3' configuration on the side chain, may be manipulated. Phenethyl substitution gives exclusively the [2 + 2]-cycloaddition product, irrespective of the alkene geometry. The stereoselection in the resulting methyldesoxybenzoin (MDB) product is examined in a variety of solvents as a function of temperature by using chiral GC analysis. The extent (% ee) as well as the sense (R versus S) of the stereoselectivity in the MDB formation for the E isomer depends significantly on solvent and temperature, whereas the corresponding Z isomers are not affected by such variations. The complex temperature and solvent effects are scrutinized in terms of the differential activation parameters (DeltaDeltaS++, DeltaDeltaH++) for the photooxygenation of E/Z-enecarbamates in various solvents at different temperatures. The enthalpy-entropy compensations provide a mechanistic understanding of the temperature dependence of the ee values for the MDB product and the difference in the behavior between the Z and E enecarbamates. The E enecarbamates show a relatively high contribution from the entropy term and an appreciable contribution from the enthalpy term; both terms possess the same sign. In contrast, the corresponding relative insensitivity of Z enecarbamates to temperature and solvent variation is convincingly explained by the near-zero DeltaDelta S++ and DeltaDelta H++. Such effects, associated with temperature- and solvent-dependent conformational factors, are most likely dictated by the stereogenic center at the C-3' phenethyl substituent. The high stereocontrol during the photooxygenation of the chiral enecarbamates is shown to be independent of the steric demand of the oxazolidinone substituent at the C-4 position. In view of the reduced stereocontrol on deuteration of the oxazolidinone substituent at the C-4 position, we propose that the unusual stereoselective vibrational quenching of the attacking singlet oxygen (excited-state reactivity), a novel mechanistic concept, works in concert with the usual steric impositions (ground-state reactivity) exercised by the substituents to afford the high stereoselectivity observed in the dioxetane product during the [2 + 2] cycloaddition. Such synergistic interplay is held responsible for the highly stereoselective photooxidative cleavage of the chiral enecarbamates. The efficacy of stereocontrol in this photooxidation is demonstrated by kinetically resolving the epimers of the enecarbamate cleavage product (MDB) in essentially perfect stereoselectivity, a new methodology that we coin "photo-Pasteur-type kinetic resolution".

Michael Addition Reactions to 3-(4-Chloro-4,4-difluorobut-2-enoyl)oxazolidin-2-one

1,4-Addition reactions to chlorodifluorinated Michael acceptor 1b containing a chiral oxazolidinone auxiliary were found to proceed smoothly either with alkyllithium or Grignard reagents in the presence of CuY (Y = I or CN) or ZnCl2. In contrast to the corresponding cuprates, R2Zn or R3ZnMgBr species (prepared from 2 or 3 equiv. of RMgX and ZnCl2, respectively) were quite effective in suppression of the unfavorable β-elimination mechanism leading to the terminally difluorinated byproduct 3.

Synthesis of Non-cross-linked Polystyrene Supported 5,5-dimethyl Oxazolidinone Chiral Auxiliary

A new chiral auxiliary, non-cross-linked polystyrene supported 5,5-dimethyl oxazolidinone was synthesised in 25.1% yield using L-tyrosine as the starting material using a six-step method.

Stereoselective Diels–Alder reactions of 3-phosphonopropenoyl derivatives of 1,3-oxazolidin-2-ones

Dienophiles of the general structure (EtO) 2P(O)CH CHCOX have been prepared, where X represents an oxazolidinone chiral auxiliary. Use of the ( S)-4-isopropyl-5,5-diphenyl-1,3-oxazolidin-2-one auxiliary gave Diels–Alder adducts with several cyclic and acyclic dienes. The crystal structures of the main cyclohexa-1,3-diene and 2,3-dimethylbutadiene adducts formed during reactions in the presence of dialkylaluminium halides are consistent with a reaction, which is stereoselectively endo with respect to the carbonyl group and occurs on the less hindered face of the dienophile when aluminium is chelated between the two carbonyl groups.

A comparative mechanistic analysis of the stereoselectivity trends observed in the oxidation of chiral oxazolidinone-functionalized enecarbamates by singlet oxygen, ozone, and triazolinedione

The stereoselectivity in the reactions of the E/ Z enecarbamates 1, equipped with the oxazolidinone chiral auxiliary, has been examined for singlet oxygen ( 1O 2), ozone (O 3), and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) in a variety of solvents as a function of temperature. The oxidative cleavage of the alkenyl functionality by 1O 2 and O 3 releases the enantiomerically enriched methyldesoxybenzoin (MDB) product. The extent (% ee) as well as the sense ( R vs S) of the stereoselectivity in the MDB formation depends on the electronic nature of the oxidant. A high stereoselectivity, substantially dependent on solvent and temperature, is displayed for the reactions with 1O 2, whereas the ground-state reactants O 3 and PTAD are rather unaffected by solvent and temperature variations. The present comparative analysis clearly substantiates our hypothesis of stereoselective vibrational quenching of the attacking 1O 2, whereas O 3 and PTAD are only subject to steric impositions. The electronically excited 1O 2 is sensitive to all three stereochemically relevant structural characteristics embodied in the chiral enecarbamates, namely the R/ S configuration at the C 4 position of the oxazolidinone chiral auxiliary, the Z/ E geometry of the ‘ alkene’ functionality, and R/ S configuration at the C 3′ position of the enecarbamate side chain.

Conformationally controlled (entropy effects), stereoselective vibrational quenching of singlet oxygen in the oxidative cleavage of oxazolidinone-functionalized enecarbamates through solvent and temperature variations

On photooxygenation (methylene blue as sensitizer) of E/Z enecarbamates, equipped with the oxazolidinone chiral auxiliary, the oxidative cleavage of the alkenyl functionality releases the enantiomerically enriched methyldesoxybenzoin (MDB) product. The extent (% ee) as well as the sense (R vs S) of the stereoselectivity in the MDB formation depends on the choice of the alkene configuration; the efficacy of stereocontrol may be tuned by appropriate solvent and temperature conditions. Highlighted is the finding that the formation of the preferred MDB enantiomer (R or S) depends for the E isomer on the chosen solvent and temperature, but not for the corresponding Z isomer. The activation parameters for the various solvents disclose that differential entropy effects (ΔΔS‡) dominate the conformationally more flexible E diastereomers. As mechanistic rationale for this unprecedented conformationally imposed stereochemical behavior, we propose the competitive action of stereoselective vibrational quenching of the attacking singlet oxygen by the enecarbamate versus sterically controlled stereoselective oxidative cleavage of its double bond.

Asymmetric Reformatsky Reaction with a Chiral Oxazolidinone Auxiliary

Asymmetric Reformatsky Reaction with a Chiral Oxazolidinone Auxiliary

Improved Synthesis of Triketide δ-Lactones from the Pikromycin Biosynthetic Pathway

In connection with the generation of hybrid polyketide synthases (PKSs) derived from the pikromycin PKS system, we have been interested in δ-lactones 1 and 2. We reported a synthesis of both lactones by the routes based on the asymmetric aldol and the Reformatsky reaction as key steps. Although the desired δ-lactones 1 and 2 were prepared successfully, the synthesis did have limitations. While the δ-lactone 2 was efficiently synthesized by the reported route, the lactone 1 having an epimeric stereochemistry on C-3 could not be prepared efficiently due to the low diastereomeric selectivity in the asymmetric Reformatsky reaction step. Also, the origin of the stereoselectivity was based on the Evans chiral oxazolidinone auxiliary. It is, therefore, desirable to eliminate the use of rather expensive Evans chiral auxiliary to prepare the lactone 1 more practically. Herein, we wish to report modified synthetic routes to the δ-lactones, focusing especially on more efficient and more practical synthesis of the lactone 1.

Control of Chirality by Cations in Confined Spaces: Photooxidation of Enecarbamates Inside Zeolite Supercages†

On photooxygenation of the optically active Z/E enecarbamates 1 (X = i-Pr) and 2 (X = Me) equipped with the oxazolidinone chiral auxiliary in methylene-blue (MB)-incorporated, alkali-metal (M = Li, Na, K, Cs, Rb), exchanged Y-type zeolites (MY-MB), oxidative cleavage of the alkenyl functionality releases the enantiomerically enriched methyldesoxybenzoin (MDB) product. The extent (%ee) and/or the sense (R or S) of the stereoselectivity in the formation of the MDB product depends on the choice of the alkyl substiuent (i-Pr or Me) at the C-4 position of the oxazolidinone chiral auxiliary, the Z/E configuration of the alkene functionality in the enecarbamates, and the type of alkali metal in the zeolite. Most significantly-the highlight of this study-is the reversed sense (R or S) in the stereoselection when the photooxygenation is run in CDCl3 solution versus inside the MY-MB zeolite. As a mechanistic rationale for this novel stereochemical behavior, we propose the combined action of spatial confinement and metal-ion coordination (assessed by density-functional calculations) of the substrate within the zeolite supercage, both of which greatly reduce the freedom of the substrate and entropically manipulate the stereochemical outcome.

Recyclable supports for stereoselective 1,3-dipolar cycloadditions: application of a fluorous oxazolidinone chiral auxiliary

The utility of a new fluorous-supported chiral auxiliary was tested using a series of catalyzed and uncatalyzed 1,3-dipolar cycloaddition reactions with diphenylnitrone. The yields and selectivities of the cycloadducts compare favourably with those obtained using the conventional Evans-type auxiliaries, while purification was greatly assisted by using fluorous solid phase extraction. Following characterization, the cycloadducts were released from the auxiliaries by reductive cleavage. The auxiliary was readily refunctionalized and reused in subsequent cycloaddition reactions, with no deterioration of the observed yields or selectivities.

Stereoselective Conjugate Radical Additions: Application of a Fluorous Oxazolidinone Chiral Auxiliary for Efficient Tin Removal

[reaction: see text] A series of asymmetric free-radical-mediated intermolecular conjugate additions using a fluorous oxazolidinone chiral auxiliary has been completed. The fluorous auxiliary facilitated product isolation using fluorous solid phase extractions (FSPE), effectively removing excess organic and organometallic reagents. Parallel reactions carried out with a similar but nonfluorous norephedrine-derived oxazolidinone demonstrated the superior stereoselectivity and purification obtainable with the fluorous chiral auxiliary.

Stereoselective synthesis of an anti-HIV drug candidate

The asymmetric synthesis of a Merck anti-HIV drug candidate is described. The target molecule contains four stereogenic centers, three of which are located in a highly functionalized cyclopentane unit. The convergent synthesis involves the preparation of two key advanced intermediates: the cyclopentane unit and a substituted pyrazole unit. The cyclopentane unit was prepared via two different procedures; a highly diastereoselective Diels-Alder reaction with a chiral oxazolidinone auxiliary and a sequence that incorporated a molybdenum-catalyzed asymmetric allylic alkylation reaction to set the stereocenters. The other key step was a highly diastereoselective hydroxyl-directed reductive amination. The overall yield for the 16-step synthesis was 10%.

Diastereoselective Atom Transfer Radical Cyclization Reactions of Unsaturated α‐Bromo Oxazolidinone Imides Catalyzed by Lewis Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Diastereoselective atom transfer radical cyclization reactions of unsaturated α-bromo oxazolidinone imides catalyzed by Lewis acids

A new Lewis acid-catalyzed atom transfer radical cyclization reaction of unsaturated α-bromo oxazolidinone imides is reported. In the presence of Lewis acids such as Mg(ClO 4) 2 and Yb(OTf) 3, a series of trans cyclic products was obtained in high yield (up to 87%) between 0°C and room temperature. The loading of strong Lewis acids, such as Yb(OTf) 3, can be reduced to 0.1 equiv. without significantly compromising the yield. Excellent diastereoselectivity could be achieved by using 1,2-stereocontrol or a chiral oxazolidinone auxiliary. For substrates 1e and 1f bearing a β-methyl substituent and the chiral auxiliary, ( S)-(−)-4-benzyl-5,5-dimethyl-2-oxazolidinone, respectively, the diastereomeric ratio of the products was greater than 50:1.

Asymmetric Aldol Reactions Using a Fluorous Oxazolidinone Chiral Auxiliary.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Concise stereocontrolled routes to fumagillol, fumagillin, and TNP-470.

A concise, diastereoselective synthesis of (+/-)-fumagillol (3) and formal, enantioselective syntheses of the potent angiogenesis inhibitors fumagillin (1) and TNP-470 (2) are reported. The origin of asymmetry is a highly diastereoselective Diels-Alder reaction using a diene with a chiral oxazolidinone auxiliary. The stereochemical course of a key conjugate addition reaction is controlled by the cup-shaped architecture of a cis-fused bicyclic enal. Other key steps include a facile hetero-Claisen rearrangement and a site-selective Sharpless epoxidation.

Asymmetric Aldol ReactionsUsing a Fluorous Oxazolidinone Chiral Auxiliary

A new class of supported oxazolidinone chiral auxiliary has been synthesized from l-phenylalanine. The use of a perfluorooctyl chain as a support facilitates enolate reactions under standard solution conditions, with reaction products rapidly isolated by solid-phase extraction on fluorous silica. Reactions employing a syn-oxazolidinone afforded yields and stereoselectivities in titanium-mediated aldol reactions that were comparable to those reported in the literature using the standard Evans-type auxiliaries under similar conditions. These results are the first demonstration of asymmetric enolate chemistry using fluorous compounds.

Highly Diastereoselective Dioxetane Formation in the Photooxygenation of Enecarbamates with an Oxazolidinone Chiral Auxiliary: Steric Control in the [2 + 2] Cycloaddition of Singlet Oxygen Through Conformational Alignment.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly diastereoselective dioxetane formation in the photooxygenation of enecarbamates with an oxazolidinone chiral auxiliary: steric control in the [2 + 2] cycloaddition of singlet oxygen through conformational alignment.

The photooxygenation of oxazolidinone-substituted enecarbamates leads to diastereomerically pure dioxetanes. The high diastereoselectivity is rationalized in terms of effective pi-facial control achieved by shielding one side of the double bond with the chiral auxiliary. The absolute configuration of the dioxetanes is assigned by derivatization to diols.

Synthesis of Natural Fragrant Molecules cis-3-Methyl-4-decanolide and Aerangis Lactone. General Enantioselective Routes to β,γ-cis-Disubstituted γ-Lactones and γ,δ-cis-Disubstituted δ-Lactones

General enantioselective routes to 3,4-cis-dialkyl substituted gamma-lactones and 4,5-cis-dialkyl substituted delta-lactones using TiCl(4)-mediated Evans asymmetric aldolization as the key step are reported. The syntheses are exemplified with two natural fragrant molecules, cis-3-methyl-4-decanolide (1) and aerangis lactone (2). The (R,R) steroegenic centers were established using (S)-phenylalanine-derived 2-oxazolidinone or thiazolidinethione as chiral auxiliary, whereas the (S,S) ones were constructed with auxiliary prepared from (R)-phenylglycine. NaBH(4)/CaCl(2)/THF in the presence of a small amount of EtOH was introduced as a new effective method for reductive cleavage of chiral oxazolidinone auxiliaries. Previously unknown, tricky concentration effects were observed during the monotosylation of diol 7 and BOM protection of Evans aldol 23.