A Carbohydrate Approach to the Enantioselective Synthesis of 1,3-Polyols

Treatment of per-O-benzoyl-D-glycero-D-gulo-heptono-1,4-lactone (2) with tertiary amines afforded selectively and with good yields the (5H)-furan-2-one derivatives 3, 4, and 5, formed by controlled elimination of one, two, or three molecules of benzoic acid, respectively. The stereochemistry for the exocyclic double bonds of 4 and 5 was determined by means of NMR techniques. Particularly, the furanone 4 was obtained from 2 ( approximately 90% yield) as a mixture of the E and Z diastereoisomers, which were separated by column chromatography or, more efficiently, by HPLC. The catalytic hydrogenation of compounds 4-E and 4-Z took place diastereoselectively, due to the chiral induction of the stereocenter located in the lateral chain. Thus, hydrogenation of 4-E led to a mixture of the 4,5-dihydro-(3H)-furan-2-ones having 3R,5S,2'S (D-xylo, 6) and 3S,5R,2'S (D-arabino, 7) configurations, with 6 as the major product; whereas the 4-Z isomer gave the same mixture, but being 7 preponderant. On hydrogenation of the original 4-E/Z mixture, compound 6 was obtained pure after recrystallization. O-Debenzoylation of 6gave 9, which was reduced with NaBH(4) to the 3,5-dideoxy-meso-xylo-heptitol (11). The peracetate (12) and perbenzoate (13) of the latter were prepared, and the 1-(tert-butyldiphenylsilyl)oxy derivative (16) was also synthesized via the 3'-(silyloxy)-4,5-dihydro-(3H)-furan-2-one 14. Chemoselective reduction of the lactone function of 6 with diisoamylborane gave the 2,5,6-tri-O-benzoyl-3,6-dideoxy-D-xylo-heptofuranose (17). The 3,5-dideoxy-D-arabino-heptitol (18), a diastereoisomer of 11, was also isolated and characterized.     

Enantioselective trans dihydroxylation of nonactivated C-C double bonds of aliphatic heterocycles with Sphingomonas sp. HXN-200

The bacterial strain Sphingomonas sp. HXN-200 was used to catalyze the trans dihydroxylation ofN-substituted 1,2,5,6-tetrahydropyridines 1 and 3-pyrrolines 4 giving the corresponding 3,4-dihydroxypiperidines 3 and 3,4-dihydroxypyrrolidines 6, respectively, with high enantioselectivity and high activity. The trans dihydroxylation was sequentially catalyzed by a monooxygenase and an epoxide hydrolase in the strain with epoxide as intermediate. While both epoxidation and hydrolysis steps contributed to the overall enantioselectivity in trans dihydroxylation of 1, the enantioselectivity in trans dihydroxylation of the symmetric substrate 4 was generated only in the hydrolysis of meso-epoxide 5. The absolute configuration for the bioproducts (+)-3 and (+)-6 was established as (3R,4R) by chemical correlations. Preparative trans dihydroxylation of 1a and 4b with frozen/thawed cells of Sphingomonas sp. HXN-200 afforded the corresponding (+)-(3R,4R)-3,4-dihydroxypiperidine 3a and (+)-(3R,4R)-3,4-dihydroxy pyrrolidine 6b in 96% ee both and in 60% and 80% yield, respectively. These results represent first examples of enantioselective trans dihydroxylation with nonterpene substrates and with bacterial catalyst, thus significantly extending this methodology in practical synthesis of valuable and useful trans diols. Enantioselective hydrolysis of racemic epoxide 2a with Sphingomonas sp. HXN-200 gave 34% of (-)-2a in >99% ee, which is a versatile chiral building block. Further hydrolysis of (-)-2a with the same strain afforded (-)-(3S,4S)-3a in 96% ee and 92% yield. Thus, both enantiomers of 3a can be prepared by biotransformation with Sphingomonas sp. HXN-200.     

Stereoselective hydrocoupling of cinnamic acid esters by electroreduction: application to asymmetric synthesis of hydrodimers

The electroreduction of Ar-substituted methyl cinnamates in acetonitrile gave all-trans cyclized hydrodimers stereoselectively (58 approximately 90% de). In all cases, small amounts (<10% yield) of meso hydrodimers were also formed. The electrolysis was performed conveniently using an undivided cell at a constant current. The transition states for the hydrocoupling were calculated with semiempirical methods. The all-trans cyclized hydrodimers were transformed to C(2)-symmetric dl-3,4-diaryladipic acids and trans-3,4-diarylcyclopentanones. The chiral auxiliary [(1R)-exo]-3-exo-(diphenylmethyl)borneol, prepared from (1R)-(+)-camphor, was highly effective for the stereoselective hydrocoupling of its cinnamates by electroreduction. From the resulting hydrodimers, (3R,4R)-3,4-diaryladipic acid esters and (3R,4R)-3,4-diarylhexane-1,6-diols were synthesized in 87-95% ee.     

Synthesis of (R)-curcumene and (R)-xanthorrizol based on 1,2-Aryl migration via phenonium ion

Solvolysis reaction of methyl (4S,5S)-4-(4'-methoxyphenyl)-5-tosyloxy-2(E)-hexenoate 5 in water-saturated MeNO(2) gave the 1,2-migration product, (4S,5S)-5-hydroxy-4-(4'-methoxyphenyl)-2-(E)-hexenoate 6 (55% yield), which was converted to methyl (R)-(4'-methylphenyl)hexanoate 11 in 25% overall yield (5 steps). Treatment of (R)-11 with MeLi gave tertiary alcohol congener 12, which was subjected to dehydration to afford (R)-(-)-curcumene 1. An introduction of hydroxyl group at meta-position of the aromatic ring in (R)-11 was achieved based on consecutive treatment [1) selective iodination, 2) conversion of aryl iodide to aryl boronate, 3) conversion of aryl boronate to phenol]. Thus obtained phenol (R)-16 was treated with MeLi to give tertiary alcohol congener 17, which was subjected to dehydration to afford (R)-(-)-xanthorrizol 2.     

A New Sphingolipid and Furanocoumarins with Antimicrobial Activity from <i>Ficus exasperata</i>

From the methanol extract of the stem bark of Ficus exasperata, a new sphingolipid named Ficusamide, (2S,3S,4R,11E)-2-[(2',3'-dihydroxyhexacosanoylamino)]-11-octadecene-1,3,4-triol (1), along with three known furanocoumarins, (S)-(－) oxypeucedanin hydrate (2), (R)-(+) oxypeucedanin hydrate (3), bergapten (5-methoxypsoralen) and six other known compounds, were isolated. Their structures were characterized basing on spectroscopic methods and chemical evidence. Compounds (1-3) were analyzed for their antimicrobial activity. Ficusamide (1) showed wick activity (minimal inhibitory concentration (MIC)=312.5?μg/mL) against Escherichia coli, while the furanocoumarins (2) and (3) showed significant activity (MIC=9.76?μg/mL) against Bacillus cereus, Candida albicans and Microsporum audouinii.     

Total synthesis of (+)-hatomarubigin B.

The first total synthesis of (+)-hatomarubigin 3 is described. The tetra-O-acetyl diborate promoted Diels-Alder reaction of 5-hydroxy-8-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyloxy)-1,4-naphthoquinone 8 and (E, 1R*,5R*)-3-(2'-methoxyvinyl)cyclohex-2-enol (+/-)-7 gave a mixture of four cycloadducts from which (1S,3S,6S,6aR,12aR,12bS)-1,8-dihydroxy-6-dimethoxy-1-hydroxy-3-methyl-11-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyloxy)-1,2,3,4,6,6a,12a,12b-octahydrobenz[a]anthracene-7,12-dione 12 was isolated in 51% yield. Selective methylation and acetylation of 12 gave (1S,3S,6S,6aR,12aR,12bS)-1-acetoxy-6,8-dimethoxy-3-methyl-11-(2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyloxy)-1,2,3,4,6,6a,12a,12b-octahydrobenz[a]anthracene-7,12-dione 10a. Sequential aromatization, photooxidation and hydrolysis of the glucosyl unit gave (+)-3 (98% ee) in an 8% overall yield from 8.     

Formal total synthesis of (+)-macrosphelide A based on regioselective hydrolysis using lipase

Three kinds of seco-macrosphelide A congeners, (4R,5S,10R,11S,15S)-6, (4R,5S,9S,14R,15S)-7 and (3S,8R,9S,14R,15S)-8 were chemically synthesized, and they were exposed to the lipase OF-360 from Candida rugosa to give three hydroxy carboxylic acids, respectively. Macrolactonization of the hydroxy acid (4R,5S,10R,11S)-18 derived from (4R,5S,10R,11S,15S)-6 gave 12-membered lactone (19) in 47% overall yield from 6, while that of the seco-acid (4) derived from (4R,5S,9S,14R,15S)-7 afforded (-)-dibenzyl macrosphelide A (25) in 27% overall yield from 7. Macrolactonization of the hydrolysis product, seco-acid (5) derived from (3S,8R,9S,14R,15S)-8, provided (-)-dibenzyl macrosphelide A (25) (5% overall yield from 8) and 12-membered lactone (19) (20% overall yield from 8) concurrently.     

Synthesis of (+)-Cladospolide C

(+)-Cladospolide C was synthesized in eight steps with 5% total yield, using methyl acrylate, (3R,4R)-1,5-hexadiene-3,4-diol, and (6R)-6-hepten-2-ol as the starting materials. Two cross-metathesis reactions and Yamaguchi esterification were applied to assemble the three units into (+)-Cladospolide C. Unsuccessful routes using ring-closing metathesis are also discussed.     

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.     

Asymmetric synthesis of (+)-negamycin

An asymmetric synthesis of the antibiotic (+)-negamycin (1) has been achieved, starting from commercially available (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (2). The synthesis involved the stabilized Wittig olefination of the lactone carbonyl group of 2 and subsequent asymmetric hydrogenation to generate the corresponding all-syn oxazine 4 with excellent diastereoselectivity. Conversion of 4 into beta-alkoxy imine 7 and subsequent CeCl3-promoted chelation-controlled allylation of 7 generated the corresponding homoallylamine 8 with good diatereoselectivity, which was readily converted into (+)-negamycin (1) in 25% overall yield over 11 steps.     

Stereoselective Synthesis of (5R, 65)-(-) Erythro-6-Acetoxy-5-Dodecanolide,A Lower Homologue of a Mosquito Oviposition Attractant Pheromone,from Argentilactone

Starting from argentilactone [(5R)-(-)- δ -lactone of 5-hydroxydodeca-Z,Z-2,6-dienoic acid] and via the hydrobromic acid opening of the 65, 75-epoxide followed by acetylation and catalytic hydrogenation of the corresponding bromohydrin, (5R, 65)-(-)-erythro-6-acetoxy-5-dodecanolide was obtained. Through the 6R, 7R-epoxide and following the same sequence, the stereoisomer (5R, 6R)-(+)-threo-6-acetoxy-5-dodecanolide, was also synthesized.     

Structural requirements in chiral diphosphine-rhodium complexes—XI: Asymmetric homogeneous hydrogenation of z-α-acylaminocinnamic acids and esters with (1s, 2s)-trans-1,2-bis(diphenylphosphinomethyl) cyclohexane/rhodium(i) complexes

Z-α-acylaminocinnamate esters were hydrogenated with neutral rhodium(I) complexes containing (1S, 2S)-trans-1,2-bis(diphenylphosphinomethyl)cyclohexane. Increasing the steric bulk of the alcohol moiety of the ester function results in increased enantioface differentiation in favor of the re-si prochiral face to yield an excess of the S-amino acid derivatives. In the series of N-acetylphenylalanine ester products (resulting from hydrogenation of Z-α-acetamidocinnamate esters) the optical purity increased from 1% ee-(R) [Me]; 20% ee-(S) [Et]; 47% ee-(S) [i-Pr]; to 58% ee-(S) [t-Bu]. Increasing the steric bulk of the acyl function (NHCOR, where R is an alkyl moiety) favors the reduction of the si-re prochiral face [in the methyl ester substrates] to yield an excess of the R-amino acid derivatives. In the series of N-acylphenylalanine methyl ester products (resulting from hydrogenation of Z-methyl α-acylaminocinnamates) the optical purity increased from 1% ee-(R) [Me]; 13% ee-(R) [i-Pr]; to 15% ee-(R) [t-Bu and 1-adamantyl]. The α-formamido and α-benzamido substrates gave hydrogenation products having 22% ee-(R) [H] and 35% ee-(R) [Ph]. In the corresponding free acids, increasing the steric bulk of the acyl function (NHCOR, where R is an alkyl moiety) results in almost no change in the optical purity of the reduction products. In the series of N-acylphenyl-alanine products (resulting from hydrogenation of Z-α-acylaminocinnamic acids) the optical purity was 35% ee-(S) [Me]; 31% ee-(S) [i-Pr]; 33% ee-(S) [t-Bu]; and 35% ee-(S) [1-adamantyl]. The α-benzamido substrate gave a hydrogenation product having 8% ee-(S).     

Chiral Cyclopentane-Based Mimics of D-myo-Inositol 1,4,5-Trisphosphate from D-Glucose

Two routes from D-glucose to chiral, ring-contracted analogs of the second messenger D-myo-inositol 1,4,5-trisphosphate are described. Methyl alpha-D-glucopyranoside was converted by an improved procedure into methyl 4,6-O-(p-methoxybenzylidene)-alpha-D-glucopyranoside (6) and thence into methyl 2-O-benzyl-3,4-bis-O-(p-methoxybenzyl)-alpha-D-gluco-hexodialdopyranoside (1,5) (14) in four steps. In the first ring-contraction method 14 was converted into methyl 2-O-benzyl-6,7-dideoxy-3,4-bis-O-(p-methoxybenzyl)-alpha-D-gluco-hept-6-enopyranoside (1,5) (15), which on sequential treatment with Cp(2)Zr(n-Bu)(2) followed by BF(3).Et(2)O afforded a mixture of (1R,2S,3S,4R,5S)-3-(benzyloxy)-4-hydroxy-1,2-bis[(p-methoxybenzyl)oxy]-5-vinylcyclopentane (16) and its 4S,5R diastereoisomer 17. Removal of the p-methoxybenzyl groups of 16 and subsequent phosphorylation and deprotection afforded the first target compound, (1R,2R,3S,4R,5S)-3-hydroxy-1,2,4-tris(phosphonooxy)-5-vinylcyclopentane (3). In the second route, intermediate 14 was subjected to SmI(2)-mediated ring contraction to give (1R,2S,3S,4R,5S)-3-(benzyloxy)-4-hydroxy-5-(hydroxymethyl)-1,2-bis[(p-methoxybenzyl)oxy]cyclopentane (20). Benzylation of 20 provided (1R,2S,3S,4R,5S)-3-(benzyloxy)-6-[(benzyloxy)methyl]-4-hydroxy-1,2-bis[(p-methoxybenzyl)oxy]cyclopentane (22) and (1R,2S,3S,4R,5S)-3,4-bis(benzyloxy)-5-(hydroxymethyl)-1,2-bis[(p-methoxybenzyl)oxy]cyclopentane (21), which were elaborated to the target trisphosphates (1R,2R,3S,4R,5S)-3-hydroxy-5-(hydroxymethyl)-1,2,4-tris(phosphonooxy)cyclopentane (4) and (1R,2S,3R,4R,5S)-1,2-dihydroxy-3,4-bis(phosphonooxy)-5-[(phosphonooxy)methyl]cyclopentane (5), respectively. Both 3 and 4 mobilized intracellular Ca(2+), but 4 was only a few fold less potent than D-myo-inositol 1,4,5-trisphosphate, demonstrating that effective mimics can be designed that do not bear a six-membered ring.     

Catalytic hydrogenation of methyl 3,4-diazatricyclo-[5.2.1.0<Superscript>2,6</Superscript>]dec-4-ene-5-carboxylate

The hydrogenation at Raney nickel of the pyrazoline ring in methyl exo-3,4-diazatricyclo-[5.2.1.0^2,6]dec-4-ene-5-carboxylate takes place quantitatively with the preferential formation of the trans isomer of 5-amino-exo-3-azatricyclo[5.2.1.0^2,6]decan-4-one. The 3-methoxycarbonylmethyl-, 3-acetyl-, and 3-nitroso-substituted esters are not hydrogenated under these conditions.     

一种新型噁唑烷酮类抗生素的合成

以2,4-二溴吡啶为原料,经Weinreb酰胺酰化、Noyori不对称氢转移反应、脱Boc保护基、环化、Suzuki偶联、磷酸单酯化及成盐共七步反应制得一种新型噁唑烷酮类抗生素【【(3R,3aS)-7-{6-［(S)3-甲基-2-噁唑烷酮-5-基］吡啶-3-基}-1-氧-1,3,3a,4-四氢苯并［b］噁唑［3,4-d］［1,4］噁嗪-3-基】甲基】磷酸单酯二钠盐,其结构经¹H NMR, ¹³C NMR和HR-MS（ESI）确征,总收率7%,纯度99.7%。     

Process‐Scale Total Synthesis of Nature‐Identical (−)‐(S,S)‐7‐Hydroxycalamenal in High Enantiomeric Purity through Catalytic Enantioselective Hydrogenation

A process‐scale stereoselective synthesis of nature‐identical (−)‐(S,S)‐7‐hydroxycalamenal (=(−)‐(5S,8S)‐5,6,7,8‐tetrahydro‐3‐hydroxy‐5‐methyl‐8‐(1‐methylethyl)naphthalene‐2‐carbaldehyde; (−)‐ 1a ) in 96% enantiomeric excess (ee) with the aid of chiral Ru complexes has been developed. The key step was the enantioselective hydrogenation of easily accessible 2‐(4‐methoxyphenyl)‐3‐methylbut‐2‐enoic acid ( 10 ) to (+)‐ 11 in a 86% ee (Scheme 5 and Table 1). A substantial increase in optical purity (96% ee) was achieved by induced crystallization of the intermediate (+)‐3,4‐dihydro‐4‐(1‐methylethyl)‐7‐methoxy‐2H‐naphthalen‐1‐one ((+)‐ 3 ). Computational conformation analysis carried out on the analog (−)‐ 9 rationalized the high diastereoselectivity achieved in the catalytic hydrogenation of the CC bond.     

Concise enantiospecific, stereoselective syntheses of (+)-crispine A and its (-)-antipode

An enantiospecific and stereoselective total synthesis of the natural product (+)-crispine A has been demonstrated employing a Pictet-Spengler bis-cyclization reaction between commercially available (R)-(-)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate and 4-chloro-1,1-dimethoxybutane to preferentially provide the cis tricyclic adduct. Decarboxylation by a convenient two-step protocol provided the enantiopure natural product in three steps with an overall isolated yield of 32% from the amino acid. The unnatural antipode (-)-crispine A was similarly prepared in three steps from the commercially available (S)-(+)-amino acid.     

Synthesis of d- and l-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-5-hydroxymethylproline and tripeptides containing them

Enantiomerically pure (-)-(1R,4R,5R,6S)- and (+)-(1S,4S,5S,6R)-7-(tert-butoxycarbonyl)-5,6-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]hept-2-one ((-)-3 and (+)-3) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrrole and 2-bromo-1-(p-toluenesulfonyl)acetylene, including the Alexakis optical resolution of ketone (+/-)-3 via formation of cyclic aminals with (1R,2R)-diphenylethylenediamine. Compounds (-)-3 and (+)-3 were converted into d- and l-2,3-trans-3,4-cis-4,5-trans-N-(tert-butoxycarbonyl)-5-hydroxymethyl-3,4-isopropylidenedioxyprolines (-)-4 and (+)-4, respectively. Applying the Boc and Fmoc strategies of peptide synthesis, these compounds were used to construct two tripeptides containing the d- or l-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-5-hydroxymethylproline.     

Catalytic asymmetric hydrogenation of 2,3,5-trisubstituted pyrroles

Catalytic asymmetric hydrogenation of N-Boc-protected pyrroles proceeded with high enantioselectivity by using a ruthenium catalyst modified with a trans-chelating chiral bisphosphine PhTRAP. The ruthenium catalyst prepared from Ru(eta3-methallyl)2(cod) and (S,S)-(R,R)-PhTRAP in the presence of triethylamine was the most enantioselective for the asymmetric hydrogenation of methyl pyrrole-2-carboxylate, giving the desired (S)-proline derivative with 79% ee in 92% yield. Moreover, 2,3,5-trisubstituted pyrroles bearing a large substituent at the 5-position were hydrogenated with 93-99.7% ee. The asymmetric reduction of 4,5-dimethylpyrrole-2-carboxylate gave only all-cis isomer and created three chiral centers with high degree of stereocontrol in a single process. This is the first highly enantioselective reduction of pyrroles.     

erythro-1-Naphthyl-1-(2-piperidyl)methanol: synthesis,resolution, NMR relative configuration,and VCD absolute configuration

The erythro isomer of 1-naphthyl-1-(2-piperidyl)methanol 4, an efficient chiral modifier for asymmetric heterogeneous hydrogenation, was obtained as the major isomer (95%) in two steps while the threo isomer can be obtained as the major isomer (67%) in three steps. erythro-4 and threo-4 were resolved on a CHIRALCEL OD-RH column. It has been shown by VCD that the diastereomer determined as the erythro by NMR was indeed the erythro and that the first eluted (-)-enantiomer on CHIRALCEL OD-R or -RH columns has the (1R,2S) configuration. The VCD studies identify the presence of at least five conformers in CDCl(3) solution. Moreover, this (-)-(1R,2S) absolute configuration found by VCD is consistent with the expected stereo-outcome of catalytic hydrogenation of pyruvate into lactate, which supported the (+)-(1S,2R) assignment.