Enantiomerically pure rhodium complexes bearing 1,5-diphenyl-1,5-cyclooctadiene as a chiral diene ligand. Their use as catalysts for asymmetric 1,4-addition of phenylzinc chloride

[reaction and structures: see text] A rhodium complex coordinated with 1,5-diphenyl-1,5-cyclooctadiene (Ph-cod), [RhCl((R)-Ph-cod)]2, was obtained enantiomerically pure through optical resolution of diastereomeric isomers [Rh(Ph-cod)((R)-1,1'-binaphthyl-2,2'-diamine)]BF4. The enantiomerically pure rhodium complexes showed high catalytic activity and enantioselectivity (up to 98% ee) in the asymmetric 1,4-addition of phenylzinc chloride to alpha,beta-unsaturated ketones and esters in the presence of chlorotrimethylsilane.     

Flexible synthesis of enantiomerically pure 2,8-dialkyl-1,7-dioxaspiro[5.5]undecanes and 2,7-dialkyl-1,6-dioxaspiro[4.5]decanes from propargylic and homopropargylic alcohols

A new approach to enantiomerically pure 2,8-dialkyl-1,7-dioxaspiro[5.5]undecanes and 2,7-dialkyl-1,6-dioxaspiro[4.5]decanes is described and utilizes enantiomerically pure homopropargylic alcohols obtained from lithium acetylide opening of enantiomerically pure epoxides, which are, in turn, acquired by hydrolytic kinetic resolution of the corresponding racemic epoxides. Alkyne carboxylation and conversion to the Weinreb amide may be followed by triple-bond manipulation prior to reaction with a second alkynyllithium derived from a homo- or propargylic alcohol. In this way, the two ring components of the spiroacetal are individually constructed, with deprotection and cyclization affording the spiroacetal. The procedure is illustrated by acquisition of (2S,5R,7S) and (2R,5R,7S)-2-n-butyl-7-methyl-1,6-dioxaspiro[4.5]-decanes (1), (2S,6R,8S)-2-methyl-8-n-pentyl-1,7-dioxaspiro[5.5]undecane (2), and (2S,6R,8S)-2-methyl-8-n-propyl-1,7-dioxaspiro[5.5]undecane (3). The widely distributed insect component, (2S,6R,8S)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane (4), was acquired by linking two identical alkyne precursors via ethyl formate. In addition, [(2)H(4)]-regioisomers, 10,10,11,11-[(2)H(4)] and 4,4,5,5-[(2)H(4)] of 3 and 4,4,5,5-[(2)H(4)]-4, were acquired by triple-bond deuteration, using deuterium gas and Wilkinson's catalyst. This alkyne-based approach is, in principle, applicable to more complex spiroacetal systems not only by use of more elaborate alkynes but also by triple-bond functionalization during the general sequence.     

Synthesis of Enantiomerically Pure Bis(hydroxymethyl)-Branched Cyclohexenyl and Cyclohexyl Purines as Potential Inhibitors of HIV

The synthesis of the enantiomerically pure bis(hydroxymethyl)-branched cyclohexenyl and cyclohexyl purines is described. Racemic trans-4,5-bis(methoxycarbonyl)cyclohexene [(+/-)-6] was reduced with lithium aluminum hydride to give the racemic diol (+/-)-7. Resolution of (+/-)-7 via a transesterification process using lipase from Pseudomonas sp. (SAM-II) gave both diols in enantiomerically pure form. The enantiomerically pure diol (S,S)-7was benzoylated and epoxidized to give the epoxide 9. Treatment of the epoxide 9 with trimethylsilyl trifluoromethanesulfonate and 1,5-diazabicyclo[5.4.0]undec-5-ene followed by dilute hydrochloric acid gave (1R,4S,5R)-4,5-bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10). Acetylation of 10 gave (1R,4S,5R)-1-acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11). (1R,4S,5R)-1-Acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11) was converted to the adenine derivative 12 and guanine derivative 13 via palladium(0)-catalyzed coupling with adenine and 2-amino-6-chloropurine, respectively. Hydrogenation of 12 and 13 gave the correspondning saturated adenine derivative 14 and guanine derivative 15. (1R,4S,5R)-4,5-Bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10) was converted to the adenine derivative 16 and guanine derivative 17 via coupling with 6-chloropurine and 2-amino-6-chloropurine, respectively, using a modified Mitsunobu procedure. Hydrogenation of 16 and 17 gave the corresponding saturated adenine derivative 18 and guanine derivative 19. Compounds 12-19 were evaluated for activity against human immunodeficiency virus (HIV), but were found to be inactive. Further biological testings are underway.     

Diastereoselective Hartwig-Buchwald reaction of chiral amines with rac-[2.2]paracyclophane derivatives

A Hartwig-Buchwald addition of a variety of chiral amines to rac-4-bromo-[2.2]paracyclophane and rac-trifluoromethanesulfonic acid (4-[2.2]paracyclophane) ester was performed with high diastereoselectivities. Kinetic racemic resolution of the starting materials was achieved, providing a rapid access to enantiomerically enriched 4-bromo-[2.2]paracyclophane and the corresponding enantiomerically pure [2.2]paracyclophane amines. Additionally, the first reaction of a secondary amine with a [2.2]paracyclophane halide was achieved.     

Non-destructive Cleavage of N-Acylsultams Under Neutral Conditions: Preparation of Enantiomerically,Pure Fmoc-Protected α-Amino Acids

Heating diastereoisomerically pure N-acylsultams 3 or 4 with allyl alcohol/Ti(OR)₄ efficiently yields sultams 1 or 2 and allyl esters 5 . Esters 5 are hydrolyzed under nonbasic conditions in the presence of Wilkinson's catalyst to give enantiomerically and diastereoisomerically pure carboxylic acids 7 . A series of [(fluoren-9-yl)methoxy]-carbonyl-(Fmoc)-protected amino acids 14 were thus prepared from N-[N'-(Fmoc)amino]acylsultams 12 .     

Novel multichiral diols and diamines by highly stereoselective pinacol coupling of planar chiral [2.2]paracyclophane derivatives

The TiCl4/Zn-mediated intermolecular pinacol coupling of the planar chiral carbonyl compounds [2.2]paracyclophane-4-carbaldehyde, 4-acetyl[2.2]paracyclophane (ketone) and the four regioisomeric 5-, 7-, 12- and 13-methoxy[2.2]paracyclophane-4-carbaldehydes as well as the pTosOH-Zn/Cu-promoted coupling of their N-substituted imines is described. Coupling of the enantiomerically pure substrates (most of carbonyl compounds and all imines) occurs stereoselectively giving rise to diastereomerically pure 1,2-diols and 1,2-diamines. Racemic aldehydes and ketone react with different degrees of stereoselectivity (depending on the substituents in certain positions) and produce one to three diastereomers. 7-methoxy[2.2]paracyclophane-4-carbaldehyde undergoes a tandem pinacol coupling-pinacol rearrangement to yield bis-(7-methoxy[2.2]paracyclophane-4-yl)acetaldehyde. Coupling of the racemic imines produces a mixture of single racemic D,L-diamine and single meso-diamine in each case. The stereoselective formation of the asymmetric centres is governed by the planar chiral [2.2]paracyclophanyl moiety. The techniques elaborated are extended to the intramolecular coupling of [2.2]paracyclophane-4,13-dicarbaldehyde and its bis-N-phenylimine, resulting in stereoselective formation of the chiral triply-bridged diol and exclusive formation of the meso-diamine. X-Ray investigations of several diols and diamines have been carried out and the structural features of these derivatives are discussed.     

A convergent approach to the synthesis of aprepitant: a potent human NK-1 receptor antagonist

A simple and convergent approach to enantiomerically pure 5-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)morpholin-4-yl]methyl]-1,2-dihydro-1,2,4-triazol-3-one 1, a potent orally active antagonist of the human neurokinin-1 (NK-1) receptor, is described. The synthetic procedure starts from p-fluorobenzaldehyde to access the racemic morpholinone 2 via a modified Strecker synthesis and utilizes a diastereomeric salt resolution technique to accomplish the synthesis of 1 in enantiomerically pure form and good yield.     

Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans

The N-phenethyl analogues of (1R*,4aR*,9aS*)-2-phenethyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol and 8-ol and (1R*,4aR*,9aR*)-2-phenethyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2.3-c]pyridin-6-ol and 8-ol, the ortho- (43) and para-hydroxy e- (20), and f-oxide-bridged 5-phenylmorphans (53 and 26) were prepared in racemic and enantiomerically pure forms from a common precursor, the quaternary salt 12. Optical resolutions were accomplished by salt formation with suitable enantiomerically pure chiral acids or by preparative HPLC on a chiral support. The N-phenethyl (-)- para-e enantiomer (1S,4aS,9aR-(-)-20) was found to be a mu-opioid agonist with morphine-like antinociceptive activity in a mouse assay. In contrast, the N-phenethyl (-)-ortho-f enantiomer (1R,4aR,9aR-(-)-53) had good affinity for the mu-opioid receptor (K(i) = 7 nM) and was found to be a mu-antagonist both in the [(35)S]GTP-gamma-S assay and in vivo. The molecular structures of these rigid enantiomers were energy minimized with density functional theory at the level B3LYP/6-31G* level, and then overlaid on a known potent mu-agonist. This superposition study suggests that the agonist activity of the oxide-bridged 5-phenylmorphans can be attributed to formation of a seven membered ring that is hypothesized to facilitate a proton transfer from the protonated nitrogen to a proton acceptor in the mu-opioid receptor.     

Ab initio calculation of optical rotation in (P)-(+)-[4]triangulane

Optical rotation, the angle through which plane-polarized light rotates when passed through an enantiomerically pure medium, plays a vital role in the determination of the absolute configurations of chiral molecules such as natural products. We describe new quantum mechanical methodology designed to assist in this endeavor by providing high-accuracy computational optical rotatory dispersion data for matching to experimental results. Comparison between theory and experiment for the rigid, helical molecule trispiro[2.0.0.2.1.1]nonane [also known as (P)-(+)-[4]triangulane], recently synthesized with enantiomeric purity, shows that the coupled cluster quantum chemical model provides superb agreement for optical rotation across a wide range of wavelengths (589-365 nm), with errors averaging only 1%.     

Carbocyclic ribosylamines: synthesis of 5-substituted carbocyclic beta-ribofuranosylamines

A synthesis of 5-substituted cyclopentylamine precursors for 5'-substituted carbocyclic nucleoside analogues was developed. We show that the stereochemistry of the OsO4-catalyzed hydroxylation of an apically brominated lactam, 7-bromo-2-azabicyclo[2.2.1]hept-5-en-3-one, can be controlled through the appropriate selection of the lactam N-H protecting group. Sterically large groups direct the hydroxylation to the exo-face of the olefin, yielding hydroxylation products that can be converted into analogues of carbocyclic ribosides. Conversely, a sterically small protecting group permits OsO4 approach from the endo-face, yielding hydroxylation products analogous to carbocyclic lyxosides. A key intermediate for carbocyclic sugar production, (1S,2S,3R, 4R,5S)-1-(tert-butyloxycarbonyl)amino-5-bromo-2,3-(dimethylmethylene)dioxy-4-hydroxymethylcyclopentane, was synthesized starting from a commercially available enantiomerically pure lactam, (1S)-(+)-2-azabicyclo[2.2.1]hept-5-en-3-one, in seven steps in an overall yield of 21%.     

Asymmetric diels - alder reactions with α-chloronitroso compounds - I. Application of α-chloronitroso epiandrosterone in synthesis

The Diels - Alder reaction of 1,3-cyclohexadiene (9) with the enantiomerically pure α-chloronitroso compound 8, synthesized from epiandrosterone (7a), gives the adduct 10a with 1-(R),4-(S) configuration in 69 % chemical yield and ?95 % enantiomeric excess.     

Facile Synthesis of Enantiomerically Pure 1-（5-Bromo-2-chlorophenyl）-1-（4-ethoxyphenyl）ethane

A facile 7-step procedure for the synthesis of enantiomerically pure 1-（5-bromo-2-chlorophenyl）-1-（4-ethoxyphenyl）ethanes[（R）-2 and（S）-2] that started from （5-bromo-2-chlorophenyl）（4-ethoxyphenyl）methanone 3 was developed.The key step was the resolution of 2-（5-bromo-2-chlorophenyl）-2-（4-ethoxyphenyl）acetic acid 6 by crystallizations of its L-and D-menthyl esters 7 and 8 from petroleum ether to give optically pure enantiomers 9 and 10,respectively.The absolute configurations of the products were unambiguously determined by single-crystal X-ray diffractions of four key intermediates,9,10,13 and 14.This procedure is characterized by inexpensiveness,scalability and ability to produce two individual enantiomers of a diarylethane with unambiguously determined absolute configurations and high enantiomeric purities.     

The first enantiomerically pure [n]triangulanes and analogues: sigma-[n]helicenes with remarkable features

(M)-(-)- and (P)-(+)-Trispiro[2.0.0.2.1.1]nonanes [(M)- and (P)-3] as well as (M)-(-)- and (P)-(+)-tetraspiro[2.0.0.0.2.1.1.1]undecanes [(M)- and (P)-4]-enantiomerically pure unbranched [4]- and [5]triangulanes-have been prepared starting from racemic bicyclopropylidenecarboxylic [(1RS)-12] and exo-dispiro[2.0.2.1]heptane-1-carboxylic [(1RS,3SR)-13] acids. The optical resolutions of rac-12 and rac-13 furnished enantiomerically pure acids (S)-(+)-12, (R)-(-)-12, (1R,3S)-(-)-13, and (1S,3R)-(+)-13. The ethyl ester (R)-25 of the acid (R)-(-)-12 was cyclopropanated to give carboxylates (1R,3R)-26 and (1R,3S)-26. The ester (1R,3S)-26 and acids (1R,3S)-13 and (1S,3R)-13 were converted into enantiomerically pure methylene[3]triangulanes (S)-(-)- and (R)-(+)-28. An alternative approach consisted of an enzymatic deracemization of endo-[(1SR,3SR)-dispiro[2.0.2.1]heptyl]methanol (rac-20) or anti-[(1SR,3RS)-4-methylenespiropentyl]methanol (rac-18). This afforded (S)-(-)- and (R)-(+)-28 (starting from rac-20), as well as enantiomerically pure (M)-(-)- and (P)-(+)-1,4-dimethylenespiropentanes [(M)- and (P)-23] starting from rac-18. The methylenetriangulanes (S)-(-)- and (R)-(+)-28 were cyclopropanated furnishing (M)- and (P)-3. The rhodium-catalyzed cycloaddition of ethyl diazoacetate onto (S)-(-)- and (R)-(+)-28 yielded four diastereomeric ethyl trispiro[2.0.0.2.1.1]nonane-1-carboxylates in approximately equal proportions. The enantiomerically pure esters (1R,3S,4S)- and (1S,3R,4R)-30 were isolated by careful distillation and then transformed into [5]triangulanes (M)- and (P)-4 using the same sequence of reactions as applied for (M)- and (P)-3. The structures of the key intermediates (R)-12 and rac-31 were confirmed by X-ray analyses. Although [4]- and [5]triangulanes have no chromophore which would lead to any significant absorption above 200 nm, they have remarkably high specific rotations even at 589 nm with [alpha](20)D=-192.7 [(M)-3, c=1.18, CHCl(3))] or +373.0 [(P)-4, c=1.18, CHCl(3))]. This remarkable optical rotatation is in line with their helical arrangement of sigma bonds, as confirmed by a full valence space single excitation configuration interaction treatment (SCI) in conjunction with DFT computations at the B3LYP/TZVP//B3LYP/6-31+G(d,p) level of theory which reproduce the ORD very well. Thus, it is appropriate to call the helically shaped unbranched [n]triangulanes the "sigma-[n]helicenes", representing the sigma-bond analogues of the aromatic [n]helicenes.     

Generation of chiral boron enolates by rhodium-catalyzed asymmetric 1,4-addition of 9-aryl-9-borabicyclo[3.3.1]nonanes (B-Ar-9BBN) to alpha,beta-unsaturated ketones

Asymmetric 1,4-addition of 9-phenyl-9-borabicyclo[3.3.1]nonane (2m) to 2-cyclohexenone (1a) proceeded with high enantioselectivity in toluene at 80 degrees C in the presence of 3 mol % of a rhodium catalyst generated from [Rh(OMe)(cod)]2 and (S)-binap to give a high yield of boron enolate (S)-3am, which is 98% enantiomerically pure. Reaction of the boron enolate 3am with electrophiles, methanol-d, propanal, and allyl bromide, gave the corresponding 2-substituted (3S)-3-phenylcyclohexanones with perfect regio- and diastereoselectivity.     

Asymmetric synthesis of conformationally constrained 4-hydroxyprolines and their applications to the formal synthesis of (+)-epibatidine

This report describes the synthesis of enantiomerically pure (1S,3S,4R)- and (1S,3R,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acids, two new conformationally constrained 4-hydroxyprolines, using a straightforward synthetic route and starting from (−)-8-phenylmenthyl 2-acetamidoacrylate. The easy transformation of the pure (1S,3S,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acid into (1R,4S)-N-Boc-7-azabicyclo[2.2.1]heptan-2-one constitutes a new formal synthesis of (+)-epibatidine.     

Syntheses and properties of enantiomerically pure higher (n > or = 7) [n-2]triangulanedimethanols and sigma-[n]helicenes

(P)-(+)-Hexaspiro[2.0.0.0. 0.0.2.1.1.1.1.1]pentadecane [(P)-17] as well as (M)-(-)- and (P)-(+)-octaspiro[2.0.0.0.0.0.0.0.2.1.1.1.1.1.1.1]nonadecanes [(M)- and (P)-25]-enantiomerically pure unbranched [7]- and [9]triangulanes-have been prepared starting from racemic THP-protected (methylenecyclopropyl)methanol 6. The relative configurations of all important intermediates as well as the absolute configurations of the key intermediates were established by X-ray crystal structure analyses. This new convergent approach to enantiomerically pure linear [n]triangulanes for n=7, 9 was also tested in two variants towards [15]triangulane. Some of the most prominent and unexpected features of the newly prepared compounds are the remarkable modes of self-assembly of the diols (P)-14, (E)-(3S,3'S,4S,4'S,5R,5'R)-21, (P)-(+)-22, and (E)-31 in the solid state through frameworks of intermolecular hydrogen bonds leading to, depending on the respective structure, nanotube- [(P)-14, (P)-(+)-22, and (E)-31], honeycomb-like structures [(E)-(3S,3'S,4S,4'S,5R,5'R)-21] or a supramolecular double helix [(P)-(+)- and (M)-(-)-22]. Liquid crystalline properties of the esters and ethers of the diols (P)-14, (P)-, and (M)-22 have also been tested. Although all of these [n]triangulanes have no chromophore which would lead to significant absorptions above 200 nm, they exhibit surprisingly high specific rotations even at 589 nm with [alpha](20)(D)=+672.9 (c=0.814 in CHCl(3)) for (P)-(+)-17, +909.9 (c=0.96 in CHCl(3)) for (P)-(+)-25, -890.5 (c=1.01 in CHCl(3)) for (M)-(-)-25, and -1302.5 (c=0.36 in CHCl(3)) for (M)-(-)-39, and the specific rotations increase drastically on going to shorter wavelengths. This outstanding rotatory power is in line with their rather rigid helical arrangement of sigma bonds, and accordingly these helically shaped unbranched [n]triangulanes may be termed "sigma-[n]helicenes", as they represent the sigma-bond analogues of the aromatic pi-[n]helicenes. Density functional theory (DFT) computations at the B3 LYP/6-31+G(d,p) level of theory for the geometry optimization and time-dependent DFT for determining optical rotations with a triplet-zeta basis set (B3 LYP/TZVP) reproduce the optical rotatory dispersions (ORD) very well for the lower members (n=4, 5) of the sigma-[n]helicenes. For the higher ones (n=7, 9, 15) the computed specific rotations turn out increasingly larger than the experimental values. The remarkable increase of the specific rotation with an increasing number of three-membered rings is proportional neither to the molecular weight nor to the number of cyclopropane rings in these sigma-[n]helicenes.     

Diastereoselective synthesis of 3,4-disubstituted 5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones: chirality transfer in the enantioselective synthesis of ethyl (+)-(3S,4aS,7aS)-1-oxo-octahydro-1H-cyclopenta[c]pyridine-3-carboxylate

The base-mediated reaction of enantiomerically pure -sulfinylketimine (+)-1 with (E)-,β-disubstituted propenoate esters afforded 3,4-disubstituted-5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones 9-13 and 14 with high or complete diastereoselectivity. A sole diastereomer of the four possible ones, with regard to the nature of ester, was isolated, which revealed the stereocontrol of the chiral sulfinyl group in the Michael reaction and transenolization steps. In addition, the enantioselective synthesis of ethyl (+)-(3S,4aS,7aS)-1-oxo-octahydro-1H-cyclopenta[c]pyridine-3-carboxylates (+)-17 is described (five steps; 47% yield; ee 97%). The absolute configuration of stereocentres introduced in (+)-17 was assigned on the basis of ¹H NMR data.     

Organoselenium mediated asymmetric cyclizations. Synthesis of enantiomerically pure 1,6-dioxaspiro[4.4]nonanes

The asymmetric cyclization of 1-hydroxyoct-7-en-4-one, promoted by camphorselenenyl tetrafluoroborate, generated from camphor diselenide and silver tetrafluoroborate in dichloromethane at room temperature, afforded a mixture of two diastereoisomeric E- and two diastereoisomeric Z-2-[(camphorseleno)methyl]-1,6-dioxaspiro[4.4]nonanes. These were separated by medium pressure liquid chromatography and then deselenenylated with triphenyltin hydride and AIBN to give enantiomerically pure 2-methyl-1,6-dioxaspiro[4.4]nonanes. The camphorseleno group was also substituted by an allyl function using allyltributyltin in the presence of AIBN.     

An access to 3,4-(aminomethano)proline in racemic and enantiomerically pure form

Protected racemic and enantiomerically pure 3,4-(aminomethano)prolines rac-9 and (2S,2'R,3R,4R)-9 have been prepared applying a titanium-mediated reductive cyclopropanation as a key step. Thus, cyclopropanations of N,N-dibenzylformamide with titanacyclopropanes generated in situ from racemic or enantiomerically pure tert-butyl N-Boc-3,4-dehydroprolinates rac-8 or (S)-8 proceed diastereoselectively, and furnish the protected racemic and enantiomerically pure diamino acid 9. The latter was incorporated into three tripeptides containing glycyl, alanyl and phenylalanyl moieties.     

Chiral macrocyclic aliphatic oligoimines derived from trans-1,2-diaminocyclohexane

Aliphatic dialdehydes of rigid structures having a cyclohexane, a bicyclo[2.2.2]octane or a [7]triangulane skeleton, have been condensed with enantiomerically pure trans-1,2-diaminocyclohexane to give [3+3] or [2+2] macrocyclization products. Unlike acyclic aliphatic imines, these macrocyclic oligoimines show enhanced stabilities and their structures in the crystals could be determined by X-ray diffraction analyses. The enantiomerically pure [7]triangulane dialdehyde showed remarkable diastereoselectivity in the condensation with the two enantiomers of trans-1,2-diaminocyclohexane: only one of the enantiomers gave a [2+2] macrocyclization product. Circular dichroism measurements combined with computational analysis show that the lowest energy electronic transition in these cyclic oligoimines is of n-pi* type.