Organocatalytic, Asymmetric Total Synthesis of (-)-Haliclonin A.

The first total synthesis of the alkaloid (-)-haliclonin A is reported. The asymmetric synthesis relied on a novel organocatalytic asymmetric conjugate addition of nitromethane with 3-alkenyl cyclohex-2-enone to set the stereochemistry of the all-carbon quaternary stereogenic center. The synthesis also features a Pd-promoted cyclization to form the 3-azabicyclo[3,3,1]nonane core, a SmI2 -mediated intermolecular reductive coupling of enone with aldehyde to form the requisite secondary chiral alcohol, ring-closing alkene and alkyne metathesis reactions to build the two aza-macrocyclic ring systems, and an unprecedented direct transformation of enol into enone.

Modular enantioselective synthesis of 8-aza-prostaglandin E1.

We report herein for the first time the enantioselective synthesis of 8-aza-PGE1. The synthesis used the cross olefin metathesis reaction to connect the 5-vinyl-γ-lactam subunit, prepared from (R)-malic acid via the Ley's sulfone-based α-amidalkylation protocol (dr = 6.8:1), with the chiral pre-ω-chain.

Total synthesis of (-)-sessilifoliamide J.

An efficient synthesis of the Stemona alkaloid (-)-sessilifoliamide J (1) in 12 steps and 7.7% overall yield from the known building block 8 is presented. The synthesis features the Corey lactonization reaction and a highly diastereoselective α-methylation reaction to build the spiro-lactone moiety.

Highly enantioselective Henry reactions of aromatic aldehydes catalyzed by an amino alcohol-copper(II) complex.

Amino alcohol-Cu(II) catalyst: Highly enantioselective Henry reactions between aromatic aldehydes and nitromethane have been developed. The reactions were catalyzed by an easily available and operationally simple amino alcohol-copper(II) catalyst. In total, 38 substrates were tested and the R-configured products were obtained in good yields with excellent enantioselectivities.

One-pot reductive coupling of N-acylcarbamates with activated alkenes: application to the asymmetric synthesis of pyrrolo[1,2-a]azepin-5-one ring system and (-)-xenovenine.

The one-pot reductive coupling of N-acylcarbamates with activated alkenes is described. The method is based on partial reduction of N-acylcarbamates with DIBAL-H, followed by N-acyliminium ion formation and SmI(2)-mediated radical coupling with activated alkenes. Both acyclic and cyclic N-acylcarbamates can be used as stable substrates, and a range of activated alkenes serve as effective radical receptors.

Diastereoselective synthesis and bioactivity of long-chain anti-2-amino-3-alkanols.

An improved four-step approach for the stereoselective synthesis of long-chain anti-2-amino-3-alkanols is described. Using this method, the syntheses of antiproliferative (antitumoral) compounds, spisulosine (ES-285, 2), clavaminols A and B (3 and 4), the deacetylated products of clavaminols H and N (7 and 8), as well as (2S,3R)-2-aminododecan-3-ol (9) and xestoaminol C (10), have been achieved in excellent diastereoselectivities. In vitro study showed that these compounds induced cell death and dose-dependently inhibited cell proliferation in human glioblastoma cell line SHG-44, indicating the anti-tumor property of this series of compounds.

SmI2-mediated radical cross-couplings of α-hydroxylated aza-hemiacetals and N,S-acetals with α,β-unsaturated compounds: asymmetric synthesis of (+)-hyacinthacine A2, (-)-uniflorine A, and (+)-7-epi-casuarine.

The SmI(2)-mediated radical coupling reactions of β-hydroxylated pyrrolidine/piperidine aza-hemiacetals 8 and 9 and N,S-acetals 6 and 33 with α,β-unsaturated compounds are described. This method allows a rapid access to β-hydroxylated pyrrolidines, piperidines, pyrrolizidinones, and indolizidinones. Starting from N,S-acetal 33 and via a common intermediate 27, the alkaloids hyacinthacine A(2) (2), uniflorine A (3, 6-epi-casuarine), and the unnatural epimer 7-epi-casuarine (37) have been synthesized in four and five steps with overall yields of 34%, 16%, and 13%, respectively.

A flexible asymmetric approach to methyl 5-alkyltetramates and its application in the synthesis of cytotoxic marine natural product belamide A.

By using a methyl tetramate derivative (R)- or (S)-9 as a novel chiral building block, a direct, flexible, and highly enantioselective approach to methyl (R)- or (S)-5-alkyltetramates (2) is disclosed. Among the synthesized methyl 5-alkyltetramates 2, methyl 5-methyltetramate (2 a) is found in cytotoxic mirabimide E (4) and dysideapyrrolidone (5), and methyl 5-benzyltetramate (2 g) is a substructure in the potent antineoplastic dolastatin 15 (3). On the basis of this method, the first asymmetric synthesis of the antimitotic tetrapeptide belamide A (7) has been achieved in seven steps from (S)-9, with an overall yield of 23.

The first enantioselective synthesis of cytotoxic marine natural product palau'imide and assignment of its C-20 stereochemistry.

Methyl tetramate derivative 6 has been developed as a new building block for the flexible and racemization-free synthesis of methyl 5-benzyl-3-methyltetramate via alkylation, and used in the first asymmetric synthesis of palau'imide (1). This allowed the establishment of the hitherto unknown stereochemistry at the C-20 of palau'imide as S.

[Enantioseparation of 1,1'-bi-2-naphthol benzoates using high performance liquid chromatography].

The enantioseparations of 2'-hydroxy-1,1'-binaphthyl-2-yl benzoate (HBNB), 1,1'-binaphthyl-2,2'-diyl dibenzoate (BNDB) and 2'-methoxy-1,1'-binaphthyl-2-yl benzoate (MBNB) were studied on Chirex (S)-LEU & (S)-NEA, cellulose tris (3,5-dimethylphenylcarbamate) (Chiralcel OD-H) and amylose tris (3,5-dimethylphenyl-carbamate) (Chiralpak AD-H) columns, respectively, using high performance liquid chromatography. The effects of mobile phase, column temperature and compound structures on the enantioseparations were discussed. The Chiralpak AD-H exhibited stronger capability of enantioseparation in comparison with those of Chirex (S)-LEU & (S)-NEA and Chiralcel OD-H for 1,1'-bi-2-naphthol benzoates.

A concise, protection-free and divergent approach for the enantioselective syntheses of two pheromonal epoxide components of the fall webworm moth and other species.

On the basis of Zhou's modified Sharpless asymmetric epoxidation, sequential coupling reactions, and a divergent strategy, the protection-free syntheses of two main pheromonal components 1 and 5, found in the fall webworm moth, Hyphantria cunea, and other species have been accomplished in 10 steps (for two compounds). The overall yields are 31% for 1, 28% for 5, and 25% for both 1 and 5, respectively. The ee values of the final products 1 and 5 are at least 99%.

Asymmetric synthesis of the cytotoxic marine natural product (+)-awajanomycin and its C-11 epimer.

Full details of the convergent synthetic approach to awajanomycin, and the first total syntheses of the marine natural product (+)-awajanomycin (1) and its C-11 epimer 38 by an improved 13-step approach, are described. The key elements of the synthetic strategy resided in the use of (R)-18 as the chiral building block to construct the gamma-lactone-delta-lactam core 3 and cross-olefin metathesis as the key reaction to couple the latter with the allylic alcohol segment (R- or S-4). The efficient construction of the core 3 was realized by taking advantage of the inherent multiple reactivities of the chiral building block (R)-18.

A flexible approach to azasugars: asymmetric total syntheses of (+)-castanospermine, (+)-7-deoxy-6-epi-castanospermine, and (+)-1-epi-castanospermine.

The asymmetric total synthesis of natural azasugars (+)-castanospermine, (+)-7-deoxy-6-epi-castanospermine, and synthetic (+)-1-epi-castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)-8. The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama-type reaction with either chiral or achiral aldehydes (> or = 95% de; de=diastereomeric excess) and a diastereodivergent reduction of tetramic acids, which allows formation of three continuous stereogenic centers with high diastereoselectivities. The method also provides a flexible access to structural arrays of 5-(alpha-hydroxyalkyl)tetramic acids, such as 17/34, and 5-(alpha-hydroxyalkyl)-4-hydroxyl-2-pyrrolidinones, such as 18 and 25/35 a.

One-pot cross-coupling of N-acyl N,O-acetals with alpha,beta-unsaturated compounds.

The synergistic action of BF(3).OEt(2) and SmI(2) allowed a series of intermolecular cross-couplings of readily available N-acyl N,O-acetals with alpha,beta-unsaturated compounds to be performed in high yields, which was applied to the stereoselective synthesis of pyrrolizidine alkaloid (+)-xenovenine.

Asymmetric total synthesis of (-)-awajanomycin.

The first asymmetric total synthesis of the unnatural enantiomer of cytotoxic awajanomycin (1) is reported. The synthetic approach features first a convergent strategy using the cross-olefin metathesis reaction to link the lipid side chain 2 and the piperidinone core structure 3. The second feature of the synthesis resides on the construction of segment 3 from the building block 5 via a three-component tandem reaction on the mixed imide 12.

A new approach to 3-hydroxyprolinol derivatives by samarium diiodide-mediated reductive coupling of chiral nitrone with carbonyl compounds.

A flexible diastereoselective approach to trans-(3S)-hydroxyprolinol derivatives is described, which is based on the samarium diiodide-mediated reductive coupling of the chiral 1-pyrroline N-oxide (nitrone)(S)-10 with carbonyl compounds. The reductive hydroxyalkylation of nitrone 10 with ketones and aromatic aldehydes is highly diastereoselective in establishing the C-2 chiral center of the pyrrolidine ring.

Diversity-oriented asymmetric synthesis of hapalosin: construction of three small C9/C4/C3-modified hapalosin analogue libraries.

A flexible approach to the beta-hydroxy gamma-amino acid residue (fragment C) of hapalosin has been developed on the basis of the the regio- and diastereoselective Grignard reaction. The method allows the introduction of different side chains at the C9 of hapalosin. Asymmetric syntheses of hapalosin (1a), 9-homohapalosin (1b), 9-i-butyl-hapalosin (1c), 8-epi-hapalosin (epi-1a), and three small libraries diversified at C9 (3-member, 1L3), C9/ C4 (9-member, 1L9), or C9/C4/C3 (27-member, 1L27) have been produced using this method.

A versatile approach for the asymmetric syntheses of (1R,9aR)-epiquinamide and (1R,9aR)-homopumiliotoxin 223G.

[reaction: see text] Using 5b as a common intermediate, the first asymmetric synthesis of (-)-epiquinamide (4) and a formal asymmetric synthesis of (-)-homopumiliotoxin 223G (2) is described. A key feature of our approach is the flexible introduction of a functionalized C(4) side chain to (S)-3-benzyloxyglutarimide 7 in a regio- and diastereoselective manner. Utilization of a tandem Swern oxidation-Grignard addition strategy efficiently prevented racemization.

Detailed studies on the enantioselective synthesis and HPLC enantioseparation of N-protected 3-hydroxyglutarimides.

An analytical HPLC method using CHIREX (S)-LEU/(S)-alpha-NEA column was developed for the determination of the enantiomeric excesses of N-protected (S)-3-hydroxyglutarimides. Using this method, detailed studies on the base-promoted ring-expansion reaction of the amidolactones, derived from l-glutamic acid, were undertaken.

[Enantiomeric separation of mandelic acid and its analogues by high performance liquid chromatography with 2,6-di-O-pentyl-beta-cyclodextrin coated symmetry C8 column].

2,6-Di-O-pentyl-beta-cyclodextrin, synthesized from beta-CD in dimethyl sulfoxide (DM-SO), was dynamically coated on a Symmetry C8 column through hydrophobic interaction. Using the coated column, the resolution of six racemic mixtures of mandelic acid and its analogues by reversed-phase high performance liquid chromatography was achieved: (+/-)-mandelic acid, (+/-)-mandelic acid methyl ester, (+/-)-mandelic acid ethyl ester, (+/-)-2-phenylglycine, (+/-)-phenylsuccinic acid and (+/-)-benzoin. The enantiomeric separation mechanism is discussed.

A general approach to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidinones: application to the asymmetric syntheses of neurokinin substance P receptor antagonist (-)-L-733,061 and (-)-deoxocassine.

A general approach to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidinones based on the regio- and diastereoselective reductive alkylation of (S)-3-benzyloxyglutarimide 7 is described. This method opens an entrance to chiral nonracemic substituted 3-piperidinols. The versatility of the method is illustrated by the asymmetric syntheses of neurokinin substance P receptor antagonist L-733,061 (ent-1), (-)-deoxocassine (4), and an inhibitor of HIV proteases (5a).

A concise asymmetric synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-yl Acetate and propionate, the sex pheromones of pine sawflies.

(2S,3S,7S)-3,7-Dimethylpentadecan-2-yl acetate (2) and its propionate analogue (3) are the main sex pheromones of all Neodiprion species and Diprion similes, respectively. Starting from (S)-malic acid and employing a highly chemo-, regio-, and stereoselective tandem ester reduction-epoxide formation-reductive epoxide-opening reaction protocol, an efficient total synthesis of (2S,3S,7S)-2 and -3 is reported herein.