Stereoselectivity of intramolecular SN' cyclizations of alkyllithium reagents on methoxy alkenes

The cyclization of alkyllithium reagents onto methoxy alkenes has been investigated. The alkyllithium reagent was generated by reductive lithiation of an alkyl nitrile. In an unbiased substrate, a methoxy leaving group attached to a stereogenic secondary carbon atom led to the cyclization product with high optical purity. The configuration of the product demonstrated that the cyclization had proceeded with high syn-S(N)' selectivity. Previously we have shown that 2-lithiotetrahydropyran reagents cyclize to form spirocycles with the alkene cis to the pyran oxygen. Substrates were prepared to evaluate the importance of the configuration of the secondary allyl methyl ether against the alpha-alkoxy alkyllithium configuration. In the matched case (cyano acetal 38), a very selective cyclization ensued. In the mismatched case (cyano acetal 39), the spiro ether selectivity dominated. The syn-S(N)' selectivity overcame the normal E selectivity in the cyclization and accounted for the major product, Z-alkene 45. Thus the stereochemical preference in these alkyllithium cyclizations is dominated by the spiroether effect, followed by the syn-S(N)' selectivity and finally the preference for E-alkene formation.     

Comprehensive study of okaspirodiol: characterization, total synthesis, and biosynthesis of a new metabolite from Streptomyces

The new spiro[4.5]acetal okaspirodiol (4) was isolated from Streptomyces sp. G? TS 19 as a secondary metabolite in yields up to 380 mg/L. The structure of this cryptic ketotetrol was elucidated by different methods including X-ray analysis, and its equilibration under mildly acidic conditions furnishing three additional isomers was thoroughly studied. Although metabolite 4 is not the thermodynamically favored isomer, a high-yielding total synthesis was accomplished comprising a stereoselective spiroacetalization under equilibrium conditions. This approach benefits from the important influence of an intramolecular hydrogen bond on the stabilization of the spiro[4.5]acetal moiety. The biosynthesis of 4 was investigated by feeding experiments with 13C-labeled precursors proving its origin from a new type of the rare mixed acetate-glycerol biosynthetic pathway. All results are discussed on the basis of the structural diversity of spiroacetals in nature and their chemical properties.     

A Stereoselective Approach to β-l-Arabino Nucleoside Analogues: Synthesis and Cyclization of Acyclic 1',2'-synN,O-Acetals

Reported herein is a novel and versatile strategy for the stereoselective synthesis of unnatural β-l-arabinofuranosyl nucleoside analogues from acyclic N,OTMS-acetals bearing pyrimidine and purine bases. These unusual acetals undergo a C1' to C4' cyclization where the OTMS of the acetal serves as the nucleophile to generate 2'-oxynucleosides with complete retention of configuration at the C1' acetal center. N,OTMS-acetals are obtained diastereoselectively from additions of silylated nucleobases onto acyclic polyalkoxyaldehydes in the presence of MgBr(2)·OEt(2). The strategy reported is addressing important synthetic challenges by providing stereoselective access to unnatural l-nucleosides starting from easily accessible pools of d-sugars and, as importantly, by allowing the formation of the sterically challenging 1',2'-cis nucleosides. A wide variety of nucleoside analogues were synthesized in 7-8 steps from easily accessible d-xylose.     

Synthesis of the spirofungin B core by a reductive cyclization strategy

[reaction: see text] A reductive decyanation approach to the synthesis of the core of spirofungin B has been developed. Spirofungin B has only one anomeric stabilization in the spiroacetal and was isolated along with its spiroacetal epimer, spirofungin A. The cyclization precursor was constructed from readily available starting materials. The reductive cyclization reaction was both efficient and stereoselective. The reductive cyclization strategy to spiroacetals is convergent and effective.     

Controlling chemoselectivity—application of DMF di-t-butyl acetal in the regioselective synthesis of 3-monosubstituted indolizines

Among a number of DMF dialkyl acetals investigated for the regioselective synthesis of 3-acylindolizines, the di-t-butyl acetal, via its iminium intermediate readily formed in situ, provides the highest chemoselectivity for the intermolecular cyclization of picolinium salts. DMF di-t-butyl acetal was applied to the syntheses of a variety of 3-acylated indolizines including alkyl, aryl, and heteroaryl substituents.     

Synthesis of 2,3-disubstituted benzofurans by platinum-olefin-catalyzed carboalkoxylation of o-alkynylphenyl acetals

The PtCl2-catalyzed cyclization reaction of o-alkynylphenyl acetals 1 in the presence of 1,5-cyclooctadiene produces 3-(alpha-alkoxyalkyl)benzofurans 2 in good to high yields. For example, the reaction of acetaldehyde ethyl 2-(1-octynyl)phenyl acetal (1a), acetaldehyde ethyl 2-(cyclohexylethynyl)phenyl acetal (1c), and acetaldehyde ethyl 2-(phenylethynyl)phenyl acetal (1f) in the presence of 2 mol % of platinum(II) chloride and 8 mol % of 1,5-cyclooctadiene in toluene at 30 degrees C gave the corresponding 2,3-disubstituted benzofurans 2a, 2c, and 2f in 91, 94, and 88% yields, respectively.     

Catalytic cyclization of o-alkynylbenzaldehyde acetals and thioacetals. Unprecedented activation of the platinum catalyst by olefins. Scope and mechanism of the reaction

A general protocol for the synthesis of functionalized indenes from o-alkynylbenzaldehyde acetals and thioacetals has been elaborated. Acetals uniformly give cyclization products having the alkyl group from the starting acetylene migrated to the alpha-position, whereas the cyclization of the corresponding thioacetals proceeds without alkyl migration. Optimization of the catalytic system for the cyclization of o-alkynylbenzaldehyde acetals revealed an unknown activation effect: PtCl(2) was found to be a better catalyst for the cyclization of acetals in the presence of olefins than without. A similar catalytic system (PtCl(2)/benzoquinone) has been found to be appropriate for the cyclization of cyclic acetals, whereas the optimal catalyst for the reaction of thioacetals is PdI(2). NMR monitoring of two reactions, acetal 3a + Pd(CH(3)CN)Cl(2) in CD(3)CN and thioacetal 5j + PdI(2) in CD(2)Cl(2), revealed that in both reactions similar cationic species are formed at the early stage of the transformation. Computational data (B3LYP/SDD level of theory) suggest that the difference in the reaction pathways for acetals and thioacetals can be rationalized by taking into account the relative stabilities of the corresponding vinylpalladium intermediates (22 vs 20 and 19 vs 21), which suggests a reversible thermodynamically controlled alkyl migration in the intermediate vinylcationic species.     

Recognition of cyclic, acyclic, exocyclic, and spiro acetals via structurally diagnostic ion/molecule reactions with the (CH3)2N-C(+)=O acylium ion

Reactions of the model acylium ion (CH3)2N-C(+)=O with acyclic, exocyclic, and spiro acetals of the general formula R(1)O-CR(3)R(4)-OR(2) were systematically evaluated via pentaquadrupole mass spectrometry. Characteristic intrinsic reactivities were observed for each of these classes of acetals. The two most common reactions observed were hydride and alkoxy anion [R(1)O(-) and R(2)O(-)] abstraction. Other specific reactions were also observed: (a) a secondary polar [4(+) + 2] cycloaddition for acetals bearing alpha,beta-unsaturated R(3) or R(4) substituents and (b) OH(-) abstraction for exocyclic and spiro acetals. These structurally diagnostic reactions, in conjunction with others observed previously for cyclic acetals, are shown to reveal the class of the acetal molecule and its ring type and substituents and to permit their recognition and distinction from other classes of isomeric molecules.     

Catalytic,Cascade Ring‐Opening Benzannulations of 2,3‐Dihydrofuran O,O‐ and N,O‐Acetals

An Al(OTf)₃‐catalyzed intramolecular cascade ring‐opening benzannulation of 2,3‐dihydrofuran O,O‐ and N,O‐acetals is described. The cascade sequence involves the dihydrofuran ring‐opening by acetal hydrolysis, an intramolecular Prins‐type cyclization, and aromatization to generate an array of benzo‐fused (hetero)aromatic systems in up to 95 % yield. This method represents the first example of dihydrofuran acetal usage in benzannulation reactions. The approach provides excellent regiocontrol based on the choice of alkenes used to form the requisite dihydrofuran acetals.     

Enantioselective Synthesis of Piperidines through the Formation of Chiral Mixed Phosphoric Acid Acetals: Experimental and Theoretical Studies

An enantioselective intramolecular chiral phosphoric acid‐catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two‐step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous S_N2′‐like displacement to yield the product with stereoselectivity in agreement with experimental observations.     

Synthesis of [5'-13C]ribonucleosides and 2'-deoxy[5'-13C]ribonucleosides

The present efficient synthesis of [5'-13C]ribonucleosides and 2'-deoxy[5'-13C]ribonucleosides is characterized by the synthesis of the D-[5-13C]ribose derivative as an intermediate via the Wittig reaction of 4-aldehydo-D-erythrose dialkyl acetals with Ph3P13CH3I-BuLi to introduce the 13C label at the 5-position of a pentose. This was followed by the highly diastereoselective osmium dihydroxylation for the preparation of 2,3-di-O-benzyl-D-[5-13C]ribose dialkyl acetal and the cyclization from D-[5-13C]ribose dialkyl acetal derivatives to the alkyl D-[5-13C]ribofuranoside derivative by the use of LiBF(4). The obtained D-[5-13C]ribose derivative was converted into [5'-13C]ribonucleosides and subsequently into the corresponding 2'-deoxynucleosides.     

A reductive cyclization approach to attenol A

A reductive cyclization strategy was applied to the synthesis of attenol A. This nontraditional approach to the spiroacetal structure illustrated several advantages of the reductive cyclization methodology. The attenol A core was formed in a carbon-carbon bond coupling that gave rise to a previously inaccessible spiroacetal epimer, a new method to synthesize thioketene acetals from a phenyl sulfone was realized, and the configurational stability of a nonanomeric spiroacetal was evaluated. A minor byproduct in the reductive cyclization reaction was identified that for the first time allowed direct evaluation of the stereoselectivity in a reductive cyclization of a dialkyloxy alkyllithium reagent.     

Toward the development of a general chiral auxiliary. A total synthesis of (+)-tetronolide via a tandem ketene-trapping [4 + 2] cycloaddition strategy

A highly convergent, enantioselective total synthesis of the aglycone of the tetrocarcins, (+)-tetronolide, is described. The synthesis highlights the use of several new methods, including camphor auxiliary-directed asymmetric alkylation and the enantioselective preparation of acyclic mixed acetals bearing chirality at the acetal center, and the highly efficient connection of the two major precursors via a ketene-trapping/intramolecular [4 + 2] cycloaddition strategy.     

TFAA‐Catalyzed Annulation Synthesis of Spiro Pyrrolo[1,2‐a]quinoxaline Derivatives from 1‐(2‐Aminophenyl)pyrroles and Benzoquinones/Ketones

A metal‐free trifluorosulfonate anhydride (TFAA)‐catalyzed strategy for the synthesis of spiro pyrrolo[1,2‐a]quinoxalines from 1‐(2‐aminophenyl)pyrroles and benzoquinones/ketones has been developed. With this general method, spiro pyrrolo[1,2‐a]quinoxalines have been accessed via nucleophilic addition and cyclization. This reaction exhibits good functional group tolerance, and a wide range of products are obtained in moderate to good yields.     

Radical cyclization–fragmentation of ω-haloalkyl cyclobutanones: a modular approach to medium-sized carbocycles

A facile radical cyclization–fragmentation sequence of ω-haloalkyl-tethered spirocyclobutanones, which are readily available by the Kulinkovich cyclopropanation of cycloalkene carboxylates and subsequent electrophilic addition to haloalkyl acetals, provides a convenient method for appending seven- and eight-membered rings onto cycloalkene carboxylates. An enantioselective preparation of a medium-sized carbocycle is possible by the use of a non-racemic, C₂-symmetric acetal.     

A synthesis of 2-alkyl-3-furoic acids

An efficient synthesis of 2-alkyl-3-furoic acids has been developed. Addition of the lithium dianion of 4-oxo-2-phenylthiobutanoic acid ethylene acetal to aldehydes followed by acid-catalyzed cyclization produces furan products in high yield.     

Inter- and intramolecular differentiation of enantiotopic dioxane acetals through oxazaborolidinone-mediated enantioselective ring-cleavage reaction: kinetic resolution of racemic 1,3-alkanediols and asymmetric desymmetrization of meso-1,3-polyols

Acetals derived from racemic 1,3-alkanediols undergo kinetic resolution in chiral oxazaborolidinone-mediated ring-cleavage reaction with nucleophiles such as enol silanes and allylic silanes. Enantioselectivity of the reaction is affected by nucleophiles, the N-sulfonyl groups of oxazaborolidinones, and the substituents attached to the acetal carbon. For disubstituted acetals rac-1 and for trisubstituted acetal rac-2, derived from syn-2,4-dimethyl-1,3-pentanediol, satisfactory enantioselectivity is obtained by using methallylsilane 7b,c as a nucleophile in combination with N-mesyloxazaborolidinone 4a. On the other hand, enantioselective reaction of trisubstituted acetal rac-3b, derived from anti-2,4-dimethyl-1,3-pentanediol, is realized by using silyl ketene acetal 5e in combination with N-tosyloxazaborolidinone 4b. The reaction conditions optimized for the kinetic resolution, or enantiomer differentiating reaction, of the racemic acetals are successfully applied to asymmetric desymmetrization of meso-1,3-polyols through intramolecular differentiation of the enantiotopic acetal moieties of the bis-acetal derivatives. The utility of the ring-cleavage reaction as a method for enantioselective terminal differentiation of prochiral polyols is demonstrated in convergent asymmetric synthesis of pentol derivative 35 corresponding to the C(19)[bond]C(27) ansa-chain of rifamycin S.     

Ketene acetal monomers: Synthesis and characterization

A new, facile, and high-yield synthesis of ketene acetals derived from readily available and inexpensive starting materials has been developed. For example, an α,β-unsaturated aldehyde can be condensed with an alkane diol to afford a 2-vinyl substituted cyclic acetal. This latter compound can be converted to the desired cyclic ketene acetal by isomerization of the double bond in the presence of tris(triphenylphosphine)ruthenium(II) dichloride. Good to excellent yields of cyclic ketene acetals were obtained employing this method. The novel monomers were fully characterized by IR, NMR, and by elemental analysis. © 1996 John Wiley & Sons, Inc.     

Rearrangement of N-tert-butanesulfinyl α-halo imines with alkoxides to N-tert-butanesulfinyl 2-amino acetals as precursors of N-protected and N-unprotected α-amino carbonyl compounds

Reaction of N-tert-butanesulfinyl α-halo imines with alkoxides afforded new N-tert-butanesulfinyl 2-amino acetals in good to excellent yield. These N-tert-butanesulfinyl 2-amino acetals are convenient precursors for the TMSOTf-promoted synthesis of the corresponding N-protected α-amino aldehydes and ketones, as well as for the HCl-promoted synthesis of 2-amino acetal hydrochlorides and α-amino ketone and α-amino aldehyde hydrochlorides in high yield. Via this method, an asymmetric synthesis of (S)-cathinone hydrochloride (er 94:6) was achieved.     

Radical oxidative cyclization of spiroacetals to bis-spiroacetals: an overview

The use of iodobenzene diacetate and iodine under photolytic conditions provides and efficient method for the oxidative cyclization of spiroacetals bearing an hydroxyalkyl side chain to bis-spiroacetals. An overview is provided of the use of this reaction for the synthesis of several bis-spiroacetal containing natural products such as the polyether antibiotics salinomycin and CP44,161 and the shellfish toxins, the spirolides.