Concerning the selective protection of (Z)-1,5-syn-ene-diols and (E)-1,5-anti-ene-diols as allylic triethylsilyl ethers

Treatment of unsaturated 1,5-diols 2 with TES-Cl (1.1 equiv), imidazole, and catalytic DMAP in 1:1 CH2Cl2-DMF at -78 degrees C effects selective silylation of the allylic alcohol with >95:5 chemoselectivity when the allylic and homoallylic alcohols are in similar steric environments.     

Stereoselective synthesis of optically active alpha-hydroxy ketones and anti-1,2-diols via asymmetric transfer hydrogenation of unsymmetrically substituted 1,2-diketones

[reaction: see text] A well-defined chiral Ru catalyst RuCl(N-(p-toluenesulfonyl)-1, 2-diphenylethylenediamine)(eta(6)-arene) effectively promotes asymmetric transfer hydrogenation of 1-aryl-1,2-propanedione with HCOOH/N(C(2)H(5))(3), leading preferentially to optically active 1-aryl-2-hydroxy-1-propanone with up to 99% ee and 89% yield at 10 degrees C. The reaction at 40 degrees C gives anti-1-aryl-1, 2-propanediol with up to 95% ee and 78% yield. This is a highly efficient procedure for the synthesis of optically active anti-diols.     

Asymmetric sulfur ylide reactions with boranes: scope and limitations, mechanism and understanding

The reactions of aryl-stabilized sulfur ylides with organoboranes has been studied under a variety of conditions. At 5 or -78 degrees C, the reaction with Et3B gave a mixture of the first and second homologation products, but at -100 degrees C, only the first homologation product was obtained even with just 1.1 equiv of Et3B. Under these optimized conditions, the chiral sulfur ylides (derived from camphor sulfonic acid) with different aryl groups were reacted with Et3B to give the corresponding alcohols (95-98% yield, 96-98% ee) and amines (74-77% yield, >98% ee). The origin of the high enantioselectivity is discussed. The use of nonsymmetrical 9-BBN derivatives was also explored. It was found that whereas primary alkyl substituents gave mixtures of products derived from competing migration of the boron substituent and the boracycle, all other groups resulted in either exclusive migration of the boron substituent (Ph, hexenyl, i-Pr) or exclusive migration of the boracycle (hexynyl, cyclopropyl). The factors responsible for the outcome of the reactions involving a hindered (i-Pr) and an unhindered (propynyl) substituent were studied by DFT calculations. This revealed that, in the case of an unhindered substituent, the conformation of the ate complex is the dominant factor whereas, in the case of a hindered substituent, the barriers to interconversion between the conformers of the ate complex and subsequent migration control the outcome of the reaction.     

Asymmetric allyl- and crotylboration with the robust, versatile, and recyclable 10-TMS-9-borabicyclo[3.3.2]decanes

The remarkable versatility and selectivity of the 10-(trimethylsilyl)-9-borabicyclo[3.3.2]decanes (10-TMS-9-BBDs) in the allyl- and crotylboration of representative aldehydes are reported. The new reagents are prepared through air-stable crystalline pseudoephedrine borinic ester complexes of the 10-TMS-9-BBDs (4), which are available in 63% overall yield from B-MeO-9-BBN through a simple two-step procedure. These complexes 4 are directly converted to the corresponding B-allyl-10-TMS-9-BBDs (1) with allylmagnesium bromide, which either can be isolated (98%) or used in situ for the allylations. The remarkable enantioselectivity (96 to > or =99% ee) of these reagents in the rapid (<3 h), asymmetric allylboration process at -78 degrees C is only slightly diminished when it is conducted at 25 degrees C, a phenomenon attributable to its rigid bicyclic structure. In addition to providing the homoallylic alcohols 6 efficiently (68-80%), the procedure also permits the efficient recovery of 4 (68-84%) for the direct regeneration of 1. Alternatively, an oxidative workup procedure can be used for the preparation of 6. The reagent gives predictable stereochemistry and exhibits an extremely high level of reagent control in the allylboration of d-glyceraldehyde acetonide. A simple and efficient procedure has been developed for the preparation of all four geometric and enantiomeric isomers of the B-crotyl-10-TMS-9-BBDs (10) from optically pure enantiomers of B-MeO-10-TMS-9-BBD (3). These reagents 10 also add rapidly (<3 h) and efficiently to representative aldehydes at -78 degrees C, providing ready access to all four of the possible stereoisomers of the beta-methyl homoallylic alcohols 12-15 (69-92%) in high dr (> or =98:2) and ee (94-99%).     

Highly stereoselective syntheses of syn- and anti-1,2-amino alcohols

The reduction of N-protected amino ketones can be carried stereoselectively to produce either the syn- or anti-amino alcohol diastereomer. Carbamate-protected amino ketones can be reduced predictably and selectively to anti-amino alcohols with LiAlH(O-t-Bu)3 in ethanol at -78 degrees C. N-Trityl-protected amino ketones can be reduced selectively to syn-amino alcohols with LiAlH(O-t-Bu)3 in THF at -5 degrees C.     

Intramolecular Pauson-Khand reactions of methylenecyclopropane and bicyclopropylidene derivatives as an approach to spiro(cyclopropanebicyclo[n.3.0]alkenones)

The trimethylsilyl-protected enynes 9a-c and 14a,b with alkynyl substituents on the three-membered ring or on the double bond of a methylenecyclopropane or a bicyclopropylidene moiety were prepared in two steps from the alcohols 6a-c and 12a,b, respectively, by conversion to the iodides and their coupling with lithium (trimethylsilyl)acetylide (8) in 38-73% overall yields. The bicyclopropylidene derivative 9d was synthesized in 49% yield directly from bicyclopropylidene (3) by lithiation followed by coupling with (5-iodopent-1-ynyl)trimethylsilane (11). Enynes 9b-d were protiodesilylated by treatment with K2CO3 in methanol to give the corresponding unprotected enynes 10b-d in 53, 74 and 94% yield, respectively. Enynes 17a-c with a carbonyl group adjacent to the acetylenic moiety were synthesized from oxo derivatives 15a-c by Wittig olefination followed by coupling with 8 in 47, 18 and 12% overall yield, respectively. Pauson-Khand reactions of the methylenecyclopropane derivatives with a substituent on the ring (9a,b and 10a) as well as on the double bond (14a,b and their in situ prepared protiodesilylated analogues) proceeded smoothly by stirring of the corresponding enyne with [Co2(CO)8] in dichloromethane at ambient temperature followed by treatment of the formed complexes with trimethylamine N-oxide under an oxygen atmosphere at -78 degrees C to give tricyclic or spirocyclopropanated bicyclic enones 18a,b, 19a, 20a,b, 21a,b in good yields. Alkynylbicyclopropylidene derivatives 9c,d and 10c,d formed the corresponding cobalt complexes at -78 to -20 degrees C. Treatment of the latter with N-methylmorpholine N-oxide under an argon atmosphere at -20 degrees C gave the spirocyclopropanated tricyclic enones 18c, 19c and 18d in 31-45% yields. The structure of 19c was proved by X-ray crystal structure analysis. The cyclization of enynones 17a-c in MeCN at 80 degrees C gave the spirocyclopropanated bicyclic diketones 22a-c in 38-65% yields. Intramolecular PKRs of the enynes 25a,d with a chiral auxiliary adjacent to the triple bond gave the corresponding products 26a,d in 70 and 79% yield, respectively, as 5:1 and 8:1 mixtures of diastereomers, respectively. Addition of lithium dimethylcuprate or higher order cuprates to the double bond of the former furnished bridgehead-substituted bicyclo[3.3.0]octanones 27a-c in 57-86% yields. Protiodesilylation of 27a followed by acetal cleavage gave the enantiomerically pure spirocyclopropanated bicyclo[3.3.0]octanedione (1R,5R)- 29a with [alpha]D(20)=-148 (c=1.0 in CHCl3) in 55% overall yield.     

Asymmetric skeletal rearrangement of symmetrically alpha,alpha-disubstituted alpha-amino aldehydes: a new entry to optically active alpha-hydroxy ketones

A unique asymmetric skeletal rearrangement of symmetrically alpha,alpha-disubstituted alpha-amino aldehydes has been accomplished for the first time using a chiral organoaluminum Lewis acid 1. For instance, treatment of (S)-2,2'-bis(trifluoromethanesulfonylamino)-1,1'-binaphthyl with Me3Al (1.0 equiv) in toluene at room temperature for 15 min and at 110 degrees C for an additional 15 min produced (S)-1, and a subsequent reaction with alpha -amino aldehyde 2a (R = CH2Ph) at -78 degrees C for 4 h and at -40 degrees C for 12 h resulted in the smooth rearrangement to the zwitterionic iminium intermediate A, which furnished the alpha-hydroxy ketone 3a (R = CH2Ph) in 93% isolated yield with 95% ee (S) after acidic hydrolysis. This result, together with other representative examples, clearly demonstrates the effectiveness of the present method for the hitherto difficult asymmetric synthesis of acyloins. Furthermore, we found that the treatment of the in situ generated A with DIBAH afforded the corresponding anti amino alcohol exclusively without loss of enantiomeric excess. Our approach casts light on the previously unexplored yet potential utility of alpha-amino aldehydes as synthetic building blocks and also provides a new entry to optically active alpha-hydroxy ketones and 1,2-amino alcohols.     

Practical Oppenauer (OPP) oxidation of alcohols with a modified aluminum catalyst

[reaction: see text] Modified aluminum catalyst 2 was found to be highly effective for Oppenauer (OPP) oxidation of alcohols under mild conditions. For example, oxidation of carveol in toluene with t-BuCHO (1.2 equiv) as a hydride acceptor in the presence of 2 (1 mol %) proceeded smoothly at 21 degrees C to give carvone in 94% yield after 1 h. A practical aspect of this system was highlighted by the facile OPP oxidation of terpenoids and steroids with 1.2-3.0 equiv of acetone and 2 (3-5 mol %).     

Synthesis and applications of chiral organoboranes generated from sulfonium ylides

The reactions of aryl-stabilized sulfonium ylides with trialkyl/triarylboranes have been investigated. Clean monohomologation of the boranes with only a small amount of the higher homologation products (<10%) was observed. The homologation products were isolated as the alcohols (treatment with H2O2/NaOH) and amines (treatment with NH2OSO3H). Although the reactions were conveniently conducted at 5 degrees C, the ylide reaction with tributylborane was very fast even at -78 degrees C (complete after 15 min). Use of chiral sulfides rendered the reactions asymmetric, and high enantioselectivity (>95% ee) was observed in all cases. The ylide-borane reaction was applied to short syntheses of the anti-inflammatory agents neobenodine and cetirizine, both of which contain a chiral diarylmethylalkoxy and diarylmethylamino moiety, respectively.     

Acceleration effect of Lewis acid in allylboration of aldehydes: catalytic,regiospecific, diastereospecific,and enantioselective synthesis of homoallyl alcohols

The addition of pinacol allylboronic esters to aromatic and aliphatic aldehydes smoothly occurred at -78 degrees C in toluene in the presence of a catalytic amount of AlCl3 or Sc(OTf)3 (10 mol %) to give the corresponding homoallyl alcohols in high yields. The reactions proceeded regio- and diastereospecifically, yielding the isomerically pure syn- and anti-homoallyl alcohols from (Z)- and (E)-allylboronic esters, respectively. The protocol was also applied to enantioselective reactions by using a chiral Lewis acid catalyst.     

Phase-transfer-catalyzed asymmetric glycolate alkylation

[reaction: see text] Asymmetric surrogate glycolate alkylation has been performed under phase-transfer conditions. Diphenylmethyloxy-2,5-dimethoxyacetophenone with trifluorobenzyl cinchonidinium catalyst and cesium hydroxide provided alkylation products at -35 degrees C in high yield (80-99%) and with excellent enantioselectivities (90:10 to 95:5). Useful alpha-hydroxy products were obtained using bis-TMS peroxide Baeyer-Villiger conditions and selective transesterification. The intermediate aryl ester can be obtained with >99% ee after a single recrystallization. A tight ion-pair model for the observed (S)-stereoinduction is proposed.     

Reactions of zirconacyclopentadienes with C [double bond] ), C [double bond] N, and N [double bond] N moieties with electron-withdrawing groups: formation of six-membered heterocycles

Reactions of zirconacyclopentadienes with diethyl ketomalonate gave alpha-pyrans in excellent yields in the presence of BiCl3. In the absence of BiCl3, zirconacyclopentadienes did not react with diethyl ketomalonate. Tetraphenylzirconacyclopentadiene reacted with diethyl ketomalonate in the presence of BiCl3 to give a ring-opening product, dienolic ether, in 53% yield. The structures of the alpha-pyran prepared from diethyldiphenylzirconacyclopentadiene and the ring-opening product were determined by X-ray analysis. When oximinosulfonate was added to tetraethylzirconacyclopentadiene in THF at -78 degrees C, 3,4,5,6-tetraethylpyridine-2-carbonitrile was obtained in 95% yield within 10 min. The structure of the product was confirmed by X-ray analysis. When tetraethylzirconacyclopentadiene was treated with azodicarboxylate in the presence of 2 equiv of CuCl at -78 degrees C, 1,2-dialkoxycarbonyl-3,4,5,6-tetraethyl-1,2-dihydropyridazine derivatives were obtained. The structure of one of dihydropyridazine was also confirmed by X-ray analysis.     

Highly concentrated catalytic asymmetric allylation of ketones

[reaction: see text] We report the catalytic asymmetric allylation of ketones under highly concentrated reaction conditions with a catalyst generated from titanium tetraisopropoxide and BINOL (1:2 ratio) in the presence of isopropanol. This catalyst promotes the addition of tetraallylstannane to a variety of ketones to produce tertiary homoallylic alcohols in excellent yield (80-99%) with high enantioselectivities (79-95%). The resulting homoallylic alcohols can also be epoxidized in situ using tert-butyl hydroperoxide (TBHP) to afford cyclic epoxy alcohols in high yield (84-87%).     

Determination of bisphenol-A in water by semi-micro column high-performance liquid chromatography using 2-methoxy-4-(2-phthalimidinyl)phenylsulfonyl chloride as a fluorescent labeling reagent.

A highly sensitive method for the determination of bisphenol-A in water with semi-micro column high-performance liquid chromatography using 2-methoxy-4-(2-phthalimidinyl)phenylsulfonyl chloride as a fluorescent labeling reagent has been developed. The labeling reaction was carried out at 70 degrees C for 20 min in borate buffer (pH 9.5). The derivative eluted at 11.6 min on a reversed-phase column with methanol-water (78:22, v/v) at a flow-rate of 0.2 ml/min. The fluorescence was monitored at 308 nm for excitation and 410 nm for emission. The detection limit (S/N = 3) was 10 fmol per injection. The labeling yield was about 95%.     

A thermal cascade route to pyrroloisoindolone and pyrroloimidazolones

Flash vacuum pyrolysis (FVP) of indol-1-ylacrylate derivatives 11 and 15 or the isomeric indol-3-ylacrylates 21, 22, and 24 at 925 degrees C (0.05 Torr) provides pyrrolo[1,2-a]indol-3-ones 2, 18, 28, and 29 in 53-90% yield by a cascade mechanism that involves a sigmatropic migration, elimination, electrocyclization sequence. Pyrrolo[1,2-a]imidazol-5-ones 3 and pyrrolo[1,2-c]imidazol-5-ones 4 were similarly obtained by FVP of corresponding 2,5-unsubstituted imidazol-1-ylacrylates (e.g., 33), with the former isomer predominating in ca. 80:20 ratio. Migration to the 2-position is therefore favored in the initial sigmatropic shift. FVP of 2-substituted imidazol-1-ylacrylates 35, 37, and 51 (825-875 degrees C) instead give pyrrolo[1,2-c]imidazol-5-ones 56-58 only (88-91%), and that of 4,5-disubstituted imidazol-1-ylacrylates 39 and 41 (825-850 degrees C) provide pyrrolo[1,2-a]imidazol-5-ones 59 and 60 exclusively (93-95%), and thus the selectivity of the initial shift can be controlled by the presence of substituents on the imidazole 2- and 5-positions. FVP of the benzimidazole analogues 61 and 62 at 950 degrees C gave the pyrrolo[1,2-a]benzimidazol-1-ones 6 (71%) and 63 (36%), respectively.     

Synthesis of 3-trifluoroethylfurans by palladium-catalyzed cyclization-isomerization of (Z)-2-alkynyl-3-trifluoromethyl allylic alcohols

Hydroiodonation of trifluoromethyl propargylic alcohols 1 regio- and stereoselectively produce (Z)-2-iodo-3-trifluoromethyl allylic alcohols 2. (Z)-2-Alkynyl-3-trifluoromethyl allylic alcohols 5, available through Pd(PPh3)4-mediated coupling of 2 and terminal alkynes 4, cyclize and subsequently isomerize to 3-trifluoroethylfurans 6 upon catalysis under PdCl2(CH3CN)2 in THF at 5-10 degrees C.     

Asymmetric synthesis of primary amines via the spiroborate-catalyzed borane reduction of oxime ethers

[reaction: see text] The enantioselective borane reduction of O-benzyloxime ethers to primary amines was studied under catalytic conditions using the spiroborate esters 5-10 derived from nonracemic 1,2-amino alcohols and ethylene glycol. Effective catalytic conditions were achieved using only 10% of catalyst 5 derived from diphenylvalinol in dioxane at 0 degrees C resulting in complete conversion to the corresponding primary amine in up to 99% ee.     

Enantioselective diene Cyclization/Hydrosilylation catalyzed by optically active palladium bisoxazoline and pyridine-oxazoline complexes

A 1:1 mixture of (N-N)Pd(Me)Cl ?N-N = (S,S)-4,4'-dibenzyl-4,5,4', 5'-tetrahydro-2,2'-bisoxazoline (S,S-4a) and NaBAr(4) ?Ar = 3, 5-C(6)H(3)(CF(3))(2) (5 mol %) catalyzed the asymmetric cyclization/hydrosilylation of dimethyl diallylmalonate (2) and triethylsilane at -30 degrees C for 48 h to form an 8.1:1 mixture of the silylated carbocycle (S,S)-trans-1, 1-dicarbomethoxy-4-methyl-3-?(triethylsilyl)methylcyclop ent ane (S, S-3) (95% de, 72% ee) and dimethyl 3,4-dimethylcyclopentane-1, 1-dicarboxylate (S,S-6) in 64% combined yield. In comparison, a 1:1 mixture of the palladium pyridine-oxazoline complex (N-N)Pd(Me)Cl ?N-N = (R)-(+)-4-isopropyl-2-(2-pyridinyl)-2-oxazoline (R-5b) and NaBAr(4) (5 mol %) catalyzed the asymmetric cyclization/hydrosilylation of 2 and triethylsilane at -32 degrees C for 24 h to form carbocycle S,S-3 in 82% yield (>95% de, 87% ee) as the exclusive product. Asymmetric diene cyclization catalyzed by complex R-5b was compatible with a range of functional groups and produced carbocycles with up to 91% ee. The procedure also tolerated substitution at a terminal olefinic position and at the allylic position of the diene.     

First Exclusive Regioselective Fragmentation of Primary Ozonides Controlled by Remote Carbonyl Groups and a New Method for Determining the Regiochemistry of Carbonyl Oxide Formation

The first exclusive regioselective fragmentation of primary ozonides controlled by remote carbonyl groups on ozonolysis of norbornene derivatives and reaction of final ozonides with triethylamine as a new probe for determining the regiochemistry of carbonyl oxide formation from primary ozonide fragmentation are reported. Ozonolysis of the endo adducts 3a-d and the deuterated compounds 8a and 8b in CDCl(3) at -78 degrees C gave the final ozonides 4a-d, 9a, and 9b as the sole products (>95%), respectively. No detectable amount of the isomeric final ozonides 5, 10, 11, and 12 was obtained. A mechanism is proposed to account for the exclusive regioselective fragmentation of the primary ozonides. Ozonolysis of 3a-d, 8a, and 8b in CH(2)Cl(2) at -78 degrees C followed by treatment with triethylamine exclusively gave the convex tetraquinane oxa cage compounds 16a-d, 19a, and 19b in 85-90% yields, respectively. No detectable amount of the other regioisomers 17a-d, 20a, and 20b was obtained. Ozonolysis of 3a-d, 8a, and 8b in CH(2)Cl(2) at -78 degrees C followed by reduction with dimethyl sulfide gave the tetraacetal tetraoxa cage compounds 21a-d, 23a, and 23b in 85% yields, respectively. The difference in function between triethylamine and dimethyl sulfide in reaction with final ozonide is demonstrated. Ozonolysis of the endo adducts 24a and 24b in CDCl(3) at -78 degrees C exclusively gave the final ozonides 27a and 27b, respectively. The order of the preference of various remote carbonyl groups to control the fragmentation of the primary ozonides formed by ozonolysis of norbornene derivatives is investigated. Ozonolysis of the endo esters 32a-c in CH(2)Cl(2) at -78 degrees C followed by reduction with dimethyl sulfide gave the new tetraacetal oxa cages 35a-c, with an alkoxyl group directly on the skeleton, and the novel triacetal oxa cages 36b and 36c, respectively. The structures of triacetal oxa cages are proven for the first time by X-ray analysis of the crystalline compound 36c.     

Highly diastereoselective addition of cinnamylzinc derivatives to alpha-chiral carbonyl compounds

Cinnamylzinc reagents react with cyclic and acyclic alpha-chiral ketones under very mild conditions (-78 degrees C, 1 h), yielding the corresponding homoallylic alcohols bearing three adjacent stereocenters with high diastereoselectivity. An extension of this reaction to enantioenriched alpha-chiral ketones is also described.