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A simplified effective synthetic process is described for the diastereoselective synthesis of the chiral C2-symmetric CF3-ureas (R,R)-15 and (S,S)-15 from (S)-α-phenylethylamine, glyoxal and CF3I.

Bromolactamization of the N-Boc derivatives of unsaturated amides using N-bromosuccinimide and lithium t-butoxide in tetrahydrofuran occurs smoothly to give excellent yields of bromo N-Boc α-lactams, which are valuable as synthetic intermediates.

This letter describes a combined photochemical and X-ray crystallographic study of routes for the synthesis of cyclobutane or ladderane structures by a [2+2]-cycloaddition pathway and leads to a clearer definition of the 3-D structural requirements for such processes in the solid state.

The ouabain isomers 1, 6, 20, 21, and 22 have been synthesized and shown to be readily separable by HPLC, which indicates that they do not correspond to a putative endogenous ouabain-like cardioregulator. 11-epi-Ouabain (1) is of interest as a safer alternative to ouabain.

Methods have been developed for the regioselective formation of both aldol condensation products from a non-symmetrical dialdehyde derived from 5α-cholestan-3-one. The findings disclosed herein, as well as their mechanistic implications, should assist in achieving selective intramolecular aldol closures in other contexts.

Lithium N-trityl-N-(R)-1-phenylethylamide (6) is a readily available and useful reagent for the enantioselective (20:1) conversion of 4-t-butylcyclohexanone to the corresponding (S)-enolate. This reaction provides access to numerous useful chiral compounds.

t-Butyltritylamine (1) and lithium t-butyltritylamide (2) are introduced as readily available and useful superhindered bases.

Methodology is described for the enantioselective conversion of achiral aldehydes by anti-selective aldol reaction to chiral β-hydroxy-α-phenylthio esters and aldehydes.

The chiral diazaborolidine 1 has been applied to the enantioselective syntheses of chloramphenicol (2) and ( d )-threo-N-acetylsphingosine (3), a synthetic precursor of the diastereomeric ( d )-sphingosines.

As a result of steric repulsion between the equatorial substituents of the trans-(2-thiacyclohexyl)sulfone 3, the preferred molecular geometry in solution and in the solid state is the diaxial conformer.

Selective reactions at the C(18) angular methyl group of ouabain derivatives employing rhodium- and photochemically-mediated CC bond formation allow the synthesis of annulation products 4 and 13 .

Suspensions of powdered glassy solids prepared by fusion of 1:1 mixtures of CsF-CsOH and CsF-CsCl effectively catalyze the generation of enolates, acetylide and other anions from trimethylsilylated precursors.

A general process is reported for the highly enantioselective 1,4-addition of isopropenyl trifluoroborate to cyclic enones under catalysis by a chiral Rh(I) complex and triethylamine at room temperature.

Catalytic enantioselective Diels–Alder reactions of furans and 1,1,1-trifluoroethyl acrylate in the presence of oxazaborolidium catalysts 2 or 3 provide 7-oxabicyclo[2.2.1]hept-5-enes with high endo -selectivity and excellent enantioselectivity.

The synthesis of two diastereomers of lactacystin β-lactone (2), the β-lactones 3 and 4, is described.

An expeditious total synthesis of the stable and potent proteasome inhibitor 3 is described.

The chiral quaternary ammonium salt 1 serves as phase transfer catalyst for the enantioselective conversion of the glycine derivative 2 to a variety of cyclic and acyclic chiral α-amino acids with enantioselectivities as high as 200:1 in alkylation and Michael addition reactions.

A short synthesis of (±)-palominol (1) and (±)-dolabellatrienone (2) starting from farnesol is reported. Noteworthy steps include an intramolecular pinacol coupling to form a 15-membered carbocyclic diol and subsequent dianion-accelerated oxy-Cope rearrangement to form the 11,5-trans-fused ring system of the dolabellanes.

A remarkably simple process for the synthesis of a series of rigid bicyclic diethers and diamines is described.

Lewis-acid catalyzed reactions of unsaturated epoxides 1 and 2 afford the unprecedented products 3 and 5, respectively. Mechanistic pathways for these reactions are presented (Schemes 2 and 4) along with a more fundamental analysis.

A new pathway for the simple, stereocontrolled and economical synthesis of (±)-1 from benzaldehyde is described. The structures of two intermediates (Scheme 1) have been revised to those shown in Scheme 2.

A method is described for the rapid and stereoselective assembly of E-trisubstituted olefins by a convergent process from three components

Three new sequences are described for the synthesis of the bicyclo[3.2.1]octane core of diterpenoids such as the kaurenes ( Schemes 1–3 ) . © 1997 Elsevie Science Ltd.

An expeditious and stereoselective synthesis of a key chiral intermediate (2) for the synthesis of the therapeutically useful PGI2 analog CicaprostTM is described. © 1997 Elsevier Science Ltd.

A logically derived mechanistic model is presented for the Mikami enantioselective ene reaction which correctly describes the absolute and relative stereochemistry resulting from transition-state structures such as 3 and 5.

The coupling of an acylsilane, 2-propenyllithium and an alkyl halide produces tetrasubstituted Z-enol silyl ether in good yields, and provides the first route to these isomerically pure compounds.

The asymmetric dihydroxylation of several enantiomerically pure 4-substituted allylic 4′-methoxybenzoates proceeds with excellent reagent-controlled diastereoselectivities. This observation, coupled with the high enantio- and regioselectivity provided by the Sharpless asymmetric dihydroxylation of suitably protected dienes, has been used to accomplish the stereocontrolled total syntheses of several vic-polyols.

The first examples of catalytic enantioselective Diels-Alder reactions of cyclopentadiene and α,β-acetylenic aldehydes such as Bu3SnCCCHO are described.

Formyl CH--O hydrogen bonding provides a rational explanation of several diverse catalytic enantioselective addition reactions of aldehydes, as outlined in Figures 1–5.

Two selective and mild aromatic annulation procedures are described for the synthesis of chiral substituted tetrahydronaphthalene derivatives from ( − )-menthone and ( + )-dihydrocarvone . © 1997 Elsevier Science Ltd.

The occurrence of formyl CH--O hydrogen bonding in enantioselective allylation, aldol and Diels-Alder reactions of aldehydes with chiral Lewis acid catalysts is a key to the understanding of absolute stereochemistry.

A system for in situ regeneration of SmI2 from SmI3 is described which allows the annulation of ketones to γ-lactones, the deoxygenation of oxiranes to olefins and radical π-cyclization to be conducted with 10 mole % SmI2.

A number of noteworthy enantioselective reactions involving a variety of chiral boron Lewis acids and aldehydes can be rationalized in terms of the occurrence of formyl CH--O hydrogen bonds in the transition states and the additional three-dimensional organization which they provide.

X-ray crystallographic analysis of six complexes of formyl compounds with BF or BO containing boron Lewis acids reveals in every case a geometric preference for a conformation in which the formyl group and the BF or BO bond are coplanar, or nearly so.

The COX-2 inhibitor rofecoxib (Vioxx ™ , 1 ) ionizes under physiological conditions to an anion that reacts readily with dioxygen to form inter alia the reactive maleic anhydride derivative 6 , a potentially toxic compound.

An efficient enantioselective synthesis of the spiro tetrahydroisoquinoline unit in ecteinascidin 743 is described, employing (+)-tetrahydrocarvone as a readily available and recoverable chiral auxiliary. The synthetic sequence involves a triply-convergent stereoselective bisannulation to construct the tetrahydroisoquinoline framework within 2 .

A new process has been developed for the highly enantioselective catalytic reduction of 2-aroylpyridines and successfully applied to the synthesis of (S)-carbinoxamine ( 1 ), a therapeutically important histamine H 1 antagonist. Related enantioselective reductions of 4-aroylpyridines and ortho-substituted benzophenones are also described.

The 12 C 13 C kinetic isotope effects for the bis-cinchona-OsO4 catalyzed dihydroxylation of 4-nitrostyrene, 4-methoxystyrene and allyl 4-methoxybenzoate have been measured at the olefinic carbons by the method of Singleton. For each olefin, the 12 C 13 C kinetic isotope values are substantial and similar at the two olefinic carbons. These results accord well with prediction based on a [3+2] cycloaddition pathway but not with expectations for a [2+2] cycloaddition process.

The first enantioselective synthesis of cetirizine hydrochloride ( 1 ) has been developed using the highly stereospecific chiral oxazaborolidine (CBS) reduction of 4[ η 6 -chromium tricarbonylbenzoyl]chlorobenzene to establish the benzhydryl stereocenter. The chromium tricarbonyl unit also served as stereocontroller to allow the stereospecific displacement of hydroxyl by amino at the benzylic stereocenter, as outlined in Scheme 1.

The relatively modest potency of inhibition of lanosterol synthase by the tetracyclic ammonium ion 10, a structural analog of the protosterol cation 4, IC50 = 22 μM, indicates that the protosterol cation is not strongly bound by the enzyme.

Lanosterol synthase converts the truncated analog 6 of 2,3-oxidosqualene ( 1 ) into three tricyclic products, 7 , 8 and 9 , each of which contains a five-membered C-ring. The results are in accord with expectations based on previous work indicating that the six-membered C-ring of sterols is formed via a five-membered predecessor.

The asymmetric dihydroxylation of p-methoxybenzoate esters of p-methoxyphenyl ethers of 2-hydroxymethyl-1,3-butadienes or 2-hydroxyethyl-1,3-butadienes proceeds with excellent position and enantioselectivity using bis-cinchona alkaloid catalysts. The regioselectivity of these reactions is strongly influenced by binding interactions between the aromatic ether or ester group and the catalyst as predicted from a previously proposed transition state model.

The catalytic dihydroxylation of p-methoxybenzoate esters of various bishomoallylic alcohols proceeds with excellent enantioselectivity and, in the case of diolefins, with imporved regioselectivity using a designed catalyst that incorporates an N-anthracenylmethyl group to enhance catalyst-substrate binding interactions.

Summary A new class of highly enantiotelective oxazaborohdine-catalyzed reductions of achiral ketones is reported which depends on stereoelectronic effects involving p-substituted non-planar aromatic ketones, or π-coordinated transition-metal containing ketones, or strained ring ketones, as exemplified in Table 1. The discovery of these reactions was guided by the transition-state model 1, for which they provide experimental support. Because high enantioselectivities (> 30 :1) are achievable, these reductions define an excellent method for the synthesis of, for example, chiral benzhydrols, chiral propargylic, or chiral allylic alcohols. Lower enantioselectivities observed with CH2Cl2 as solvent, relative to toluene as solvent, are consistent with the transition-state model 1 and indicate that CH2Cl2 hydrogen bonds to the donor groups in the π-electron-rich carbonyl substituent (rl in 1 therein-diminishing electron supply.

Summary The mechanistically designed bis-cinchona alkaloid derivative 3 serves as an excellent catalytic ligand in the OsO4-promoted catalytic enantioselective dihydroxylation of the terminal isopropylidene group infamesyl, geranylgeranyl, and solanesyl esters and also squalene, with selectivity as high as 120: 1 with E,E-farnesyl acetate. 1H NMR and X-ray studies support the conformation described by 3 in which the V-shaped catalytic binding pocket is composed of the two 6-(4-heptyloxy)-quinoline units (sides and rear) and the naphthopyridazine linker (bottom).

Summary A simple, highly enantioselective synthesis of sirenin ( 1 ) (bioactive form) has been developed which depends on the intramolecular [2 +1] cycloaddition reaction of diazo ester 5 to form bicyclic ester 6 (95 : 5 enantioselectivity) using a new and remarkably stable monomeric chiral Cu(I) complex ( 2 ) whose structure was proven by X-ray diffraction analysis.

Summary The selective oxidation of 1,4-diols to γ-lactols by o-iodoxybenzoic acid occurs by a rate-limiting carbonyl-forming elimination pathway in which the carbinol proton is abstracted internally via a six-atom cyclic arrangement, which explains the observed selectivity.

Lanosterol synthase [(S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), EC 5.4.99.7] catalyzes the cyclization of (S)-2,3-oxidosqualene to lanosterol in the reaction that forms the sterol nucleus. We report herein the cloning and characterization of the human gene (OSC) encoding lanosterol synthase, a predicted 83 kDa protein of 732 amino acids. The deduced amino acid sequence is 36-40% identical to known yeast and plant homologues and 83% identical to Rattus norvegicus lanosterol synthase. The new gene was shown to encode lanosterol synthase. The yeast lanosterol synthase deficient mutant SMY8 was complemented by the human gene, and a cell-free homogenate of SMY8 expressing the human gene was shown to convert 2,3-oxidosqualene to lanosterol.

A simple and efficient synthesis of the biologically important vitamin A-derived retinoid (14R)-14-hydroxy-4,14-retro-retinol ( 1 ) from retinyl acetate in four steps is described.

The catalytic dihydroxylation of p-methoxyphenyl ethers of various homoallylic alcohols proceeds with excellent enantioselectivity and in the case of diolefins with regioselectivity due to the favorable influence of the aryl ether moiety, as predicted from a previously proposed transition-state model.