Synthesis of enantiopure 4-hydroxypipecolate and 4-hydroxylysine derivatives from a common 4,6-dioxopiperidinecarboxylate precursor

tert-Butyl 2-substituted 4,6-dioxo-1-piperidinecarboxylates 4 have been prepared in good yield starting from Boc-Asp-O(t)Bu and other beta-amino acids. By analogy with chiral tetramic acids, their reduction by NaBH(4) in CH(2)Cl(2)/AcOH afforded the corresponding cis-4-hydroxy delta-lactams in good yield and stereoselectivity (68-98% de). In the absence of the A(1,3) strain (reduction of 6-substituted 2,4-dioxo-1-piperidines 7), the cis-4-hydroxy isomer was still obtained as the major product but the de values were consistently lower. 4-Hydroxy-6-oxo-1,2-piperidinedicarboxylate 2a, readily accessible from Boc-Asp-O(t)Bu (three steps, 63% overall yield), has proven to be an excellent building block for the synthesis of cis- and trans-4-hydroxypipecolates 17 and 24 (52 and 36% overall yield, respectively) and for the synthesis of a protected 4-hydroxylysine derivative 29 (41% overall yield).     

Hetero-Diels-Alder reactions of alpha-aryl-beta-monohalo-alpha-nitrosoethylenes: diastereoselective synthesis of 6-substituted 3-aryl-4-halo-5,6-dihydro-4H-1,2-oxazines.

Treatment of alpha-aryl-beta-bromo(or chloro)-alpha-nitrosoethylene, prepared in situ from alpha-monobromo(or chloro)ketoximes and sodium carbonate in ether at rt, with allytrimethylsilane afforded exclusively trans-(4S,6S)- and trans-(4R,6R)-3-aryl-4-halo-6-[(trimethylsilyl)methyl]-5,6-dihydro-4H-1,2-oxazines 10 albeit in low yields. Similar treatment of beta-halo-alpha-nitrosoethylenes with ethyl vinyl ether, however, gave single stereoisomers, i.e., cis-(4S,6S)- and cis-(4R,6R)-6-ethoxy-4-halo-5,6-dihydro-4H-1,2-oxazines 11, in moderate to good yields. The result is in contrast to the reported predominant formation of trans-11a by a radical reaction. On the other hand, similar reactions with tert-butyl vinyl ether at 30 degrees C gave diastereomeric mixtures of cis-(4S,6S)-, cis-(4R,6R)-, trans-(4S,6R)-, and trans-(4R,6S)-6-(tert-butoxy)-4-halo-5,6-dihydro-4H-1,2-oxazines 12. In contrast to compounds 11, the major isomers have (4S,6R) and (4R,6S) configurations. The tendency of a [4 + 2] cycloaddition reaction is consistent with that observed in the Diels-Alder reaction with inverse-electron demand. The stereochemistries of compounds 10-12 were assigned on the basis of the (1)H NMR coupling constants, which were unambiguously determined by the decoupling experiments. All reactions leading to compounds 10-12 proceed with very high regioselectivity. Diastereoselectivity and high regioselectivity are understood in terms of the frontier orbital method. It has been found that cis-12g is isomerized to a mixture of stereoisomers in favor of the trans-isomer in the presence of HClO(4) (72%) in CHCl(3) at rt.     

Stereoselective preparation of six diastereomeric quatercyclopropanes from bicyclopropylidene and some derivatives

Diastereomeric meso- and d,l-bis(bicyclopropylidenyl) (5) were obtained upon oxidation with oxygen of a higher-order cuprate generated from lithiobicyclopropylidene (4) in 50 and 31 % yield, respectively. Their perdeuterated analogues meso-[D(14)]- and d,l-[D(14)]-5 were obtained along the same route from perdeuterated bicyclopropylidene [D(8)]-3 (synthesized in six steps in 7.4 % overall yield from [D(8)]-THF) in 20.5 % yield each. Dehalogenative coupling of 1,1-dibromo-2-cyclopropylcyclopropane (6) gave a mixture of all possible stereoisomers of 1,5-dicyclopropylbicyclopropylidene 16 in 69 % yield, from which (Z)-cis-16 was separated by preparative gas chromatography (26 % yield). The crystal structure of meso-5 looks like a superposition of the crystal structures of two outer bicyclopropylidene units (3) and one inner s-trans-bicyclopropyl unit, whereas the two outer cyclopropyl moieties adopt a gauche orientation with respect to the cyclopropane rings at the inner bicyclopropylidene units in (Z)-cis-16. Birch reduction with lithium in liquid ammonia of meso-5 and d,l-5 gave two pairs of diastereomeric quatercyclopropanes trans,trans-(R*,S*,R*, S*)-17/cis,trans-(R*,S*,R*,R*)-18 and trans,trans-(R*,S*,S*,R*)-19/cis,trans-(R*,S*,S*,S*)-20 in 97 and 76 % yield, respectively, in a ratio 9:1 for every pair. The latter diastereomer was also obtained as the sole product by Birch reduction of (Z)-cis-16 in 96 % yield. Under the same conditions, tetradecadeuterio analogues trans,trans-[D(14)]-(R*,S*,R*,S*)-17/cis,trans-[D(14)]-(R*, S*,R*,R*)-18 (8:1) and trans,trans-[D(14)]-(R*,S*,S*,R*)-19/cis,trans-[D(14)]-(R*,S*,S*,S*)-20 (12:1) were prepared from meso-[D(14)]-5 and d,l-[D(14)]-5 in 37 and 63 % yield, respectively. Reduction of meso-5 with diimine gave the cis,cis-quatercyclopropane (S*,S*,R*,R*)-21 as the main product (58 % yield) along with the cis,trans-diastereomer (S*,S*,R*,S*)-18 (29 % yield). Thus, five of the six possible diastereomeric quatercyclopropanes were obtained from meso-5, d,l-5, and (Z)-cis-16. The X-ray crystal structure analyses of trans,trans-(R*,S*,R*,S*)-17 and cis,cis-(S*,S*,R*,R*)-21 revealed for the both an unusual conformation in which the central bicyclopropyl unit adopts an s-trans-(antiperiplanar) orientation with phi=180.0 degrees , and the two terminal bicyclopropyl moieties adopt a synclinal conformation with phi=49.8 and 72.0 degrees , respectively. In solution the vicinal coupling constants (3)J(H,H) in trans,trans-(R*,S*,R*,S*)-[D(14)]-17, trans,trans-(R*,S*,S*,R*)-[D(14)]-19, trans,cis-(R*,S*,R*,R*)-[D(14)]-18 and trans,cis-(R*,S*,S*,S*)-[D(14)]-20 were found to be 4.1, 4.7, 5.9 and 5.9 Hz, respectively. This indicates a predominance of the all-gauche conformer in (R*,S*,R*,S*)-17 and a decreasing fraction of it in this sequence of the other diastereomers.     

Practical enantioselective synthesis of endothelin antagonist S-1255 by dynamic resolution of 4-methoxychromene-3-carboxylic acid intermediate

A practical multikilogram-scale synthesis of enantiomerically pure S-1255 (1), a potent and orally active ET(A) receptor antagonist, is described. Utilizing readily available starting materials and reagents, the entire sequence of reactions starting from 2,5-dihydroxyacetophenone 8 proceeded under mild conditions to give 1 in an excellent chemical yield (8 steps, 41% overall yield) and in a high enantiopurity (98% ee). The crucial step of the synthesis is a dynamic resolution of key intermediate 16. (R)-Methoxy acid (R)-16 having 97-99% ee was obtained in 83-84% yield from racemic 16 as a crystalline (1S,2R)-(+)-norephedrine or (+)-cinchonine salt by the dynamic resolution comprising concurrent crystallization and in situ racemization. A mechanism of the dynamic resolution through a ring-opened zwitterionic intermediate is discussed. In the final synthetic step, an effective carbon-carbon bond formation between the C4 carbon and the p-anisyl group was accomplished by a conjugate addition-elimination reaction of Grignard reagent 3 to (R)-16 to give 1 having 98% ee. Owing to high efficiencies of functional group transformations, carbon-carbon bond formations, and the dynamic resolution, the synthesis required no chromatographic purification and was amenable to a multikilogram-scale preparation. Several kilograms of 1 for clinical trials were successfully prepared by this process.     

Enantioselective nitrile anion cyclization to substituted pyrrolidines. A highly efficient synthesis of (3S,4R)-N-tert-butyl-4-arylpyrrolidine-3-carboxylic acid

[reaction: see text] A practical asymmetric synthesis of N-tert-butyl disubstituted pyrrolidines via a nitrile anion cyclization strategy is described. The five-step chromatography-free synthesis of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (2) from 2-chloro-1-(2,4-difluorophenyl)-ethanone achieved a 71% overall yield. The cyclization substrate was prepared via a catalytic CBS asymmetric reduction, t-butylamine displacement of the chlorohydrin, and a conjugate addition of the hindered secondary amine to acrylonitrile. The key nitrile anion 5-exo-tet cyclization concomitantly formed the pyrrolidine ring with clean inversion of the C-4 center to afford 1,3,4-trisubstituted chiral pyrrolidine in >95% yield and 94-99% ee. Diethyl chlorophosphate and lithium hexamethyldisilazide were shown to be the respective optimum activating group and base in this cyclization. The trans-cis mixture of the pyrrolidine nitrile undergoes a kinetically controlled epimerization/ saponification to afford the pure trans-pyrrolidine carboxylic acid target compound in >99.9% chemical and optical purity. This chemistry was also shown to be applicable to both electronically neutral and rich substituted phenyl substrates.     

Asymmetric synthesis and absolute configuration of 1-α-phenylethyl-2,5-dimethyl-4-piperidone isomers

Reaction of the methyl iodide of trans-1,2,5-trimethyl-4-piperidone with S--phenylethylamine proceeds asymmetrically and leads in 66% optical yield to the formation of the cis- and trans-diastereomeric pair of 1-(-phenylethyl)-2,5-dimethyl-4-piperidone, in which the new asymmetric centers possess the 2S,5S- and 2S,5R-configurations, respectively. According to x-ray structural analysis, the minor trans-1-(-phenylethyl)-2,5-dimethyl-4-piperidone component possesses the 2R,5S-configuration. The occurrence of asymmetric synthesis accompanying transamination was confirmed via the preparation of enantiomers of trans-2,5- and trans-1,2,5-trimethyl-4-piperidones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1641–1648, December, 1986.     

Asymmetric synthesis of substituted 1-aminocyclopropane-1-carboxylic acids via diketopiperazine methodology

Diketopiperazinespirocyclopropane 12 is prepared in > 98% d.e. via the conjugate addition of a phosphorus ylide to (6S)-N,N'-bis(p-methoxybenzyl)-3-methylenepiperazine-2,5-dione 2. Deprotection and hydrolysis of adduct 12 and subsequent peptide coupling demonstrate the applicability of this methodology to the asymmetric synthesis of 1-aminocyclopropane-1-carboxylic acids for incorporation into novel peptides. A model for the high level of diastereofacial selectivity observed in the cyclopropanation reaction is presented. A highly selective asymmetric approach (> 98% d.e.) to (S)-[2,2-(2)H2]-1-aminocyclopropane-1-carboxylic acid 29 is also reported via a deuterated sulfur ylide addition to acceptor 2.     

An efficient enantioselective synthesis of (S)-(-)-acromelobic acid

[reaction: see text] A highly efficient enantioselective synthesis of (S)-(-)-acromelobic acid (1) was achieved via asymmetric hydrogenation of dehydroamino acid derivative (3) using (R,R)-[Rh(DIPAMP)(COD)]BF(4) catalyst followed by removal of protective groups in >98% ee and good over all yield. The key intermediate (3) was prepared from the commercially available citrazinic acid (4) in six steps.     

Bis(acetylacetonato)ruthenium(II) complexes containing alkynyldiphenylphosphines. Formation and redox behaviour of [Ru(acac)2(Ph2PC triple bond CR)2] (R=H, Me, Ph) complexes and the binuclear complex cis-[{Ru(acac)2}2(micro-Ph2PC triple bond CPPh2)}2

Two equivalents of Ph(2)PC triple bond CR (R=H, Me, Ph) react with thf solutions of cis-[Ru(acac)(2)(eta(2)-alkene)(2)] (acac=acetylacetonato; alkene=C(2)H(4), 1; C(8)H(14), 2) at room temperature to yield the orange, air-stable compounds trans-[Ru(acac)(2)(Ph(2)PC triple bond CR)(2)] (R=H, trans-3; Me=trans-4; Ph, trans-5) in isolated yields of 60-98%. In refluxing chlorobenzene, trans-4 and trans-5 are converted into the yellow, air-stable compounds cis-[Ru(acac)(2)(Ph(2)PC triple bond CR)(2)] (R=Me, cis-4; Ph, cis-5), isolated in yields of ca. 65%. From the reaction of two equivalents of Ph(2)PC triple bond CPPh(2) with a thf solution of 2 an almost insoluble orange solid is formed, which is believed to be trans-[Ru(acac)(2)(micro-Ph(2)PC triple bond CPPh(2))](n) (trans-6). In refluxing chlorobenzene, the latter forms the air-stable, yellow, binuclear compound cis-[{Ru(acac)(2)(micro-Ph(2)PC triple bond CPPh(2))}(2)] (cis-6). Electrochemical studies indicate that cis-4 and cis-5 are harder to oxidise by ca. 300 mV than the corresponding trans-isomers and harder to oxidise by 80-120 mV than cis-[Ru(acac)(2)L(2)] (L=PPh(3), PPh(2)Me). Electrochemical studies of cis-6 show two reversible Ru(II/III) oxidation processes separated by 300 mV, the estimated comproportionation constant (K(c)) for the equilibrium cis-6(2+) + cis6 <=> 2(cis-6(+)) being ca. 10(5). However, UV-Vis spectra of cis-6(+) and cis-6(2+), generated electrochemically at -50 degrees C, indicate that cis-6(+) is a Robin-Day Class II mixed-valence system. Addition of one equivalent of AgPF(6) to trans-3 and trans-4 forms the green air-stable complexes trans-3 x PF(6) and trans-4 x PF(6), respectively, almost quantitatively. The structures of trans-4, cis-4, trans-4 x PF(6) and cis-6 have been confirmed by X-ray crystallography.     

Asymmetric synthesis of (4R,5R)-cytoxazone and (4R,5S)-epi-cytoxazone

(4R,5R)-Cytoxazone has been prepared in four steps and in 61% overall yield and >98% ee. Conjugate addition of lithium (R)-N-benzyl-N-[small alpha]-methylbenzylamide to tert-butyl (E)-3-(p-methoxyphenyl)prop-2-enoate and subsequent in situ diastereoselective enolate oxidation with (+)-(camphorsulfonyl)oxaziridine gave tert-butyl (2R,3R,[small alpha]R)-2-hydroxy-3-(p-methoxyphenyl)-3-(N-benzyl-N-[small alpha]-methylbenzylamino)propanoate in >98% de. Subsequent N-benzyl deprotection to the primary [small beta]-amino ester via hydrogenolysis, oxazolidinone formation with C(2)-retention by treatment with diphosgene and chemoselective ester reduction furnishes (4R,5R)-cytoxazone. The synthesis of the C(5)-epimer, (4R,5S)-epi-cytoxazone in 44% overall yield, has also been completed via a protocol involving N-Boc protection of the primary [small beta]-amino ester, utilization of the N-Boc group to facilitate simultaneous C(2)-inversion and oxazolidinone formation, and subsequent reduction.     

Efficient and selective synthesis of (S,R,R,S,R,S)-4,6,8,10,16,18-hexamethyl-docosane via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction)

(S,R,R,S,R,S)-4,6,8,10,16,18-Hexamethyldocosane (1) was synthesized in 11% yield in 11 steps in the longest linear sequence from > or =98% pure (S)-beta-citronellal and 6 additional steps for the preparation of 11 in 23% yield from propene. Five of the six asymmetric carbon centers were generated catalytically and stereoselectively by the ZACA reaction (5 times), one lipase-catalyzed acetylation, and two chromatographic operations.     

Stereoselective synthesis of (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile

(S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966, (1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford β-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S(N)2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1'-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.     

Concurrent induction of two chiral centers from symmetrical 3, 4-disubstituted and 3,3,4-trisubstituted 4-pentenals using Rh-catalyzed asymmetric cyclizations

Asymmetric cyclization of symmetrical 3,4-disubstituted and 3,3, 4-trisubstituted 4-pentenals was studied using Rh-complexes with chiral ligands. The cyclization of symmetrical 4-pentenals 4a,b by a neutral Rh[(R)-BINAP]Cl afforded cis-3,4-disubstituted (4R)-cyclopentanones 9a,b of >95% ee in 25-31% yields; on the other hand, the cyclization of 4a-c by a cationic Rh[(R)-BINAP]ClO(4) afforded trans-3,4-disubstituted (4S)-cyclopentanones 10a-c of >95% ee in 70-81% yields. All stereoisomers could be stereoselectively made by the selection of a neutral or cationic Rh-complex, and (R)- or (S)-BINAP ligand. The Rh-catalyzed cyclization could be applied to the construction of cyclopentanones 17 and 18 bearing a chiral quaternary carbon. The cyclization by the cationic Rh[(R)-BINAP]ClO(4) afforded the optically active trans-3,3, 4-trisubstituted cyclopentanones 18a-c of 92-95% ee in 75-83% yields. The catalytic cycle was also studied by using deuterium aldehyde, and the tentative mechanisms of the enantio- and diastereoselection were proposed.     

A concise synthesis of a very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via reductive etherification

This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.     

Substitution of the terminal chloride ligands of [Re(6)S(8)Cl(6)](4-) with triethylphosphine: photophysical and electrochemical properties of a new series of [Re(6)S(8)](2+) based clusters

A systematic substitution of the terminal chlorides coordinated to the hexanuclear cluster [Re(6)S(8)Cl(6)](4-) has been conducted. The following complexes: [Re(6)S(8)(PEt(3))Cl(5)](3-) (1), cis- (cis-2) and trans-[Re(6)S(8)(PEt(3))(2)Cl(4)](2-) (trans-2), mer- (mer-3) and fac-[Re(6)S(8)(PEt(3))(3)Cl(3)](-) (fac-3), and cis- (cis-4) and trans-[Re(6)S(8)(PEt(3))(4)Cl(2)] (trans-4) were synthesized and fully characterized. Compared to the substitution of the halide ligands of the related [Re(6)S(8)Br(6)](4-) and [Re(6)Se(8)I(6)](3-) clusters, the chloride ligands are slower to substitute which allowed us to prepare the first monophosphine cluster (1). In addition, the synthesis of fac-3 was optimized by using cis-2 as the starting material, which led to a significant increase in the overall yield of this isomer. Notably, we observed evidence of phosphine isomerization taking place during the preparation of the facial isomer; this was unexpected based on the relatively inert nature of the Re-P bond. The structures of Bu(4)N(+) salts of trans-2, mer-3, and fac-3 were determined using X-ray crystallography. All compounds display luminescent behavior. A study of the photophysical properties of these complexes includes measurement of the excited state lifetimes (which ranged from 4.1-7.1 μs), the emission quantum yields, the rates of radiative and non-radiative decay, and the rate of quenching with O(2). Quenching studies verify the triplet state nature of the excited state.     

Formation of cyclic ethers via the palladium-catalyzed cycloaddition of activated olefins with allylic carbonates having a hydroxy group at the terminus of the carbon chain

The reaction of the activated olefins 1 with the allylic carbonate 2, having a hydroxy group at the terminus of the carbon chain, in the presence of catalytic amounts of Pd(2)dba(3).CHCl(3) and dppe in THF at room temperature gave the corresponding cycloaddition products, tetrahydrofuran derivatives 5, in good to very high yields. The diastereoselectivities (trans/cis ratios) of the products were in the range of ca. 60-70/40-30. The reaction of 1 with the hydroxy allylic carbonate 3 in the presence of catalytic amounts of Pd(2)dba(3).CHCl(3) and (o-tolyl)(3)P in THF at 50 degrees C afforded the corresponding cycloaddition products, tetrahydropyran derivatives 6, in good to high yields. The trans/cis ratios of the products were in the range of ca. 0-40/99-80. The reaction of 1a with the hydroxy allylic carbonate 4 needed higher reaction temperatures (approximately 100 degrees C) to give the cycloaddition product, the oxepane 7a, in 31% yield with low diastereoselectivity. Next, catalytic asymmetric syntheses of tetrahydrofuran and -pyran derivatives were carried out. With the Trost ligand 15, good to high ees were accomplished in the cycloaddition, although the diastereoselectivities were of low level. With the Hayashi ligand 16, good to high ees were also achieved in the cycloaddition. The absolute stereochemistries of the major enantiomers of 5l, 5m, and 6d were determined unambiguously by X-ray crystallographic analysis: trans-(2R,4R)-5l, cis-(2S,4R)-5l, 4R-5m, trans-(2S,4S)-6d, and cis-(2R,4S)-6d were major enantiomers. Based upon the absolute stereochemistries of the major enantiomers, the mechanism of catalytic asymmetric induction in the cycloaddition reaction is discussed.     

Stereocontrolled synthesis of (-)-kainic acid from trans-4-hydroxy-L-proline

[reaction: see text] A highly stereoselective synthesis of (-)-kainic acid has been achieved in 14 steps and >7% overall yield starting from inexpensive trans-4-hydroxy-L-proline. The key steps are diastereoselective enolate alkylation and cuprate substitution reactions.     

Enzymatic resolution, desymmetrization, and dynamic kinetic asymmetric transformation of 1,3-cycloalkanediols

An efficient desymmetrization of cis-1,3-cyclohexanediol to (1S,3R)-3-(acetoxy)-1-cyclohexanol ((R,S)-2a) was performed via Candida antarctica lipase B (CALB)-catalyzed transesterification, in high yield (up to 93%) and excellent enantioselectivity (ee's up to >99.5%). (R,R)-Diacetate ((R,R)-3a) was obtained in a DYKAT process at room temperature from (1S,3R)-3-acetoxy-1-cyclohexanol ((R,S)-2a), in a high trans/cis ratio (91:9) and in excellent enantioselectivity of >99%. Metal- and enzyme-catalyzed dynamic transformation of cis/trans-1,3-cyclohexanediol using PS-C gave a high diastereoselectivity for cis-diacetate (cis/trans = 97:3). The (1R,3S)-3-acetoxy-1-cyclohexanol (ent-(R,S)-2a) was obtained from cis-diacetate by CALB-catalyzed hydrolysis in an excellent yield (97%) and selectivity (>99% ee). By deuterium labeling it was shown that intramolecular acyl migration does not occur in the transformation of cis-monoacetate to the cis-diacetate.     

Synthesis and characterization of some new C2 symmetric chiral bisamide ligands derived from chiral Feist's acid

The hemilabile chiral C2 symmetrical bidentate substituted amide ligands (1R,2R)-5(a-d) and (1S,2S)-6(a-d) were synthesized in quantitative yield from (1R,2R)-(+)-3-methylenecyclo-propane-1,2-dicarboxylic acid (1R,2R)-3 and (1S,2S)-(-)-3-methylene-cyclopropane-1,2-dicarboxylic acid (1S,2S)-3, in two steps, respectively. The chiral Feist's acids (1R,2R)-3 and (1S,2S)-3 were obtained in good isomeric purity by resolution of trans-(±)-3-methylene-cyclopropane-1,2-dicarboxylic acid from an 8:2 mixture of tert-butanol and water, using (R)-(+)-α-methylbenzyl amine as a chiral reagent. This process is reproducible on a large scale. All these new synthesized chiral ligands were characterized by 1H-NMR, 13C-NMR, IR, and mass spectrometry, as well as elemental analysis and their specific rotations were measured. These new classes of C2 symmetric chiral bisamide ligands could be of special interest in asymmetric transformations.     

Stereoselective synthesis of protected (2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid: a novel amino acid of callipeltins A and D

An orthogonally protected derivative 1 of (2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid, the unusual amino acid residue of the biologically active marine peptides such as callipeltins A and D and neamphamide A, was efficiently prepared in 10 steps and 30% overall yield from a commercially available L-ornithine derivative 2. The key step includes the N-diphenylmethylene-controlled diastereoselective dihydroxylation of (Z)-ester 3 with >13:1 selectivity for the desired isomer.