Acros Organics

acta
Toac

A Novel Nitroxide Spin-Labeled C-Tetrasubstituted -Amino Acid

A versatile Family of Polypyrazolylborate Ligands

1 5

Scorpionates
Doyle dirhodium catalysts

Asymmetric Catalysis with Chiral Dirhodium(II) Carboxamidates

Acros Organics journal for chemists

Phenylselenocyanate Chemoselective Reactions with prim- and sec-Alcohols;

September 1998

Efficient Syntheses of Alkanes, Alkenes and Stereoselective Synthesis of Alkylbromides with Retention of Configuration.
(R)-(-)-2-(2-Iso-indolinyl)butan-1-ol

A Novel Chiral -Aminoalcohol for Asymmetric Reduction of Prochiral Ketones

13

cts u d o r p w e n r o See inside f

Fine

research and industry

Editors note
Acros Organics is proud to present in this edition of our Acros Organics ACTA again some very different articles on recent developments and applications of reagents available from our new catalog. The wide variety of research interests from our customers also inspired us to extend our product range in complementary chemistry directions. Next to the many new building blocks, chiral reagents, catalysts, macromolecules, organometallics being introduced, we also recenlty added quality ranges of specialty chemicals. Our company will continue to expand the Acros Organics product line to help you meet your chemical requirements in todays multi-disciplinary research projects. We although need your input to guide us define what the next catalog should contain. Any suggestion, whether from customers in search of new reagents, or from chemists who developed new reagents and are ready to share these with others through the Acros Organics catalog, is most welcome. We therefor invite you, if you have not got a subscription to your copy, to claim your free-of-charge catalog on CD-ROM. The catalog on CD-ROM is a semestrially updated complete survey of our offer. Also the above new product families are included in todays release ! If you use or need structure-search in your lab, you will find also our recent CD edition most helpful: it comes with a run-time net-version of ChemFinder. In this issue of our Acros Organics ACTA you will find a summary of this handsome PC-tool that should make your life as a researcher much easier and more fun. Acros Organics operates also a bulk-department, dedicated to provide you a special offer and customized delivery schedules on larger quantities of most reagents from our vaccatalog. If you have succesfully completed a research project, and are ready to scale up your procedures, please call upon us. You will find Acros Organics bulk department a most professional partner for development and industrial quantities. If you want to know more about this part of our offer, ask for our special bulk brochure. Thanks for your interest and confidence in Acros Organics. We hope you will enjoy this edition and promise you many more novelties in next issues.

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More product documentation for your research

Poly-L-leucine, reagent for a simple, quick and reproducible route to chiral epoxides New nickel on silica and alumina catalysts for hydrogenations and reductions Chiracamphox, a practical and highly versatile reagent for use in assymetric transformations Chiral diamines in asymmetric synthesis Asymmetric, catalytic, inverse electron-demand Dield-Alders reactions of 3-carboalkoxy2-pyrone derivatives (S)-(+)-Camptothecin, an alkaloid with antileukemic and antitumor activity 10-Deacetylbaccatin III, a starting material in semisynthetic production of Taxol and analogues Calix(8(arene, a tool for recognition and purification of fullerenes Aminomalonaldehyde, a versatile intermediate to build many unusual heterocyclic molecules.

N 43 N 44 N 45 N 46

Chemistry review reprints

N 01 on Combinatorial Chemistry: Solid phase synthesis of compound libraries and their applications in drug discovery, by Mark A. Gallop, Affimax Research Institute, USA N 02 on Asymmetric Catalysis: From homogeneous to heterogeneous catalysis, recent advantages in asymmetric synthesis with nitrogen containing ligands, by F.Fache, P.Gamez, B.Dunjic and M.Lemaire, Institut de Recherches sur la Catalyse, UCBL-CPE, Villeurbanne, France

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Biopolymer Research Centre, CNR, Department of Organic Chemistry, University of Padova, Via Marzolo 1, 35131 Padova, Italy

Claudio Toniolo, Fernando Formaggio and Marco Crisma

Toac
A Novel Nitroxide Spin-Labeled C-Tetrasubstituted -Amino Acid
The 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino4-carboxylic acid (TOAC) is a nitroxide spin-labeled, achiral, C-tetrasubstituted -amino acid that has recently been shown to be a strong turn- and helixinducer in peptides and an excellent and relatively rigid ESR-probe and fluorescence-quencher. TOAC is a member of the family of C-tetrasubstituted -amino acids, the prototype of which is 2-aminoisobutyric acid (Aib) (Scheme 1). Aib and all the achiral, cyclic -amino acids of this family, like TOAC and Ac6c (1-amino-1-cyclohexanecarboxylic acid), the cycloaliphatic analogue of TOAC, have been shown to strongly stabilize -turns and 310/-helical conformations in peptide molecules (1-7). TOAC is characterized by a saturated heterocyclic structure containing a stable paramagnetic probe (a nitroxide group). A favourable property of TOAC over other spin-labeled -amino acids is that rotation about side-chain bonds is hampered by incorporation of the nitroxide nitrogen and C, C, and C atoms into a cyclic moiety. Using ESR
Scheme 1 O

In addition, TOAC was shown: (i) to induce a dramatic quenching of the Trp fluorescence (at about 330 nm) in suitably designed TOAC/Trp-containing peptides (4); (ii) to possess a weak ( = 5-20) band in the VIS spectral range ( = 420-430 nm), assigned to the n* transition of the nitroxide chromophore, which may become optically active in a chiral peptide and be detected by CD (2,3); (iii) to undergo a reversible, nitroxide-based oxidation in cyclic voltammetry investigations (3). Introduction of a TOAC residue at an internal position and subsequent elongation of the peptide chain are conveniently performed using Fmoc N-protection. The Fmoc derivative was obtained by reacting TOAC with Fmoc-OSu, N-(9H-fluoren-2-ylmethoxycarbonyloxy)succinimide (2,3,7,12) (Scheme 2). The Fmoc group is cleaved under mild conditions with a secondary amine in an organic solvent. The acidic and reducing conditions required to remove the Boc- and Z-groups are not compatible with the full chemical integrity of the nitroxide moiety. Finally, the extremely high crystallinity induced by TOAC in its derivatives and peptides allowed the X-ray diffraction structures of a number of compounds to be solved (2-5,19). As an example, Figure 1 shows the structure of Fmoc-TOAC-OH.
Figure 1: X-ray diffraction structures of Fmoc-TOAC-OH

N H3 C HN Aib C H3 CO HN Ac 6c CO HN CO

T O AC

technique, the reactivity in the coupling reaction and the self-aggregation tendency of TOAC mono-labeled peptides were assessed (8-13). Side-chain (Lys) TOAC mono- and doubly-modified calmodulin derivatives were prepared and the motion of the protein at those sites was monitored (14,15). Model peptides, including homo-oligomers, were synthesized and shown to possess intriguing magnetic properties (16-18). TOAC doubly-labeled synthetic peptides proved to be extremely useful in the discrimination of (310 vs ) helical conformations (6,7).
Scheme 2

O N F moc-O S u dioxane , NaHC O 3, H2O H3 N H2-T O AC -O C OO C H2-O -C O -NH F moc-T O AC -O H

O N

C OOH

Acros Organics Acta 5 - 1998

TOAC - A Novel Nitroxide Spin-Labeled Ca-Tetrasubstituted a-Amino Acid

Claudio Toniolo, Fernando Formaggio and Marco Crisma Biopolymer Research Centre, CNR, Department of Organic Chemistry, University of Padova, Via Marzolo 1, 35131 Padova, Italy

References
(1) Toniolo, C. Janssen Chim. Acta 1993, 11, 2, 10. (2) Valente, E. Chemistry Degree Thesis, University of Padova, Italy, 1994. (3) Toniolo, C.; Valente, E.; Formaggio, F.; Crisma, M.; Pilloni, G.; Corvaja, C.; Toffoletti, A.; Martinez, G.V.; Hanson, M.P.; Millhauser, G.L.; George, C.; Flippen-Anderson, J.L. J. Pept. Sci. 1995, 1, 45. (4) Crisma, M.; Bianco, A.; Formaggio, F.; Toniolo, C.; Kamphuis, J. Lett. Pept. Sci. 1995, 2, 187. (5) Flippen-Anderson, J.; George, C.; Valle, G.; Valente, E.; Bianco, A.; Formaggio, F.; Crisma, M.; Toniolo, C. Int. J. Pept. Protein Res., in press (6) Hanson, P.; Martinez, G.; Millhauser, G.; Formaggio, F.; Crisma, M.; Toniolo, C.; Vita, C. J. Am. Chem. Soc. 1996, 118, 271. (7) Smythe, M.L.; Nakaie, C.R.; Marshall, G.R. J. Am. Chem. Soc. 1995, 117, 10555. (8) Nakaie, C.R.; Goissis, G.; Schreier, S.; Paiva, A.C.M. 0Brazil. J. Med. Biol. Res. 1981, 14, 173.

` (9) Nakaie, C.R.; Schreier, S.; Paiva, A.C.M. Biochim. Biophys. Acta 1983, 742, 63. (10) Nakaie, C.R.; Marchetto, R.; Schreier, S.; Paiva, A.C.M. in Peptides: Chemistry and Biology, Ed. G.R. Marshall, ESCOM, Leiden, The Netherlands, 1988, p.249. (11) Nakaie, C.R.; Marchetto, R.; Schreier, S.; Paiva, A.C.M. in Peptides: Chemistry, Structure and Biology, Ed. J.E. Rivier, G.R. Marshall, ESCOM, Leiden, The Netherlands, 1990, p.1022. (12) Marchetto, R.; Schreier, S.; Nakaie, C.R. J. Am. Chem. Soc. 1993, 115, 11042. (13) Cilli, E.M.; Marchetto, R.; Oliveira, E.; Jubilut, G.N.; Schreier, S.; Nakaie, C.R. in Peptides 1994, Ed. H.L.S. Maia, ESCOM, Leiden, The Netherlands, 1995, p.258. (14) Jackson, A.E.; Puett, D. J. Biol. Chem. 1984, 259, 14985. (15) Jackson, A.E.; Harris, T.M.; Puett, D. J. Protein Chem. 1987, 6, 497. (16) Seidemann, R.; Dulog, L. Makromol. Chem. 1986, 187, 2545. (17) Seidemann, R. Makromol. Chem. 1989, 190, 1891. (18) Dulog, L.; Wang, W. Liebigs Ann. Chem. 1992, 301. (19) Crisma, M.; Formaggio, F.; Valle, G.; Toniolo, C. in preparation

PRODUCTS AVAILABLE AT ACROS ORGANICS

2,2,6,6-Tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid Synonym: TOAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .250 mg 1-Amino-1-cyclohexanecarboxylic acid, 98% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 g . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .100 g 1-Amino-1-cyclohexanecarboxylic acid hydrochloride, 98% . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 g . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .250 g 2-Aminoisobutyric acid, 99+% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 g Synonym: 2-methylalanine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .100 g N-(9H-Fluoren-2-ylmethoxycarbonyloxy)succinimide, 98% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 g Synonyms: Fmoc-OSu, Fmoc-ONSu

. . . . . . . .

. . . . . . . .

. . . . . . . .

.30145-2500 .20395-0250 .20395-1000 .24034-0250 .24034-2500 .22576-0250 .22576-1000 .24310-0050

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3,4-Diaminothiophene
recently introduced by Acros Organics, can supply you both the hydrochloride as hydrobromide salt that provide you the starting material for many new synthetic pathways.
S

anti ul cer a gent s

S N (1 ) (8 ) SH

N N S N

NH B r

NH B r (7)

H 2N

NH2 ( 2)

H S O S (5 ,6 ) (4 ) HO HO S N O H N R S N R N S N R H R N N R S O (3 ) N

angio t ensinII nta a gonis ts

th i enodia zepi nes

3,4-DIAMINOTHIOPHENE IS READILY AVAILABLE FROM ACROS ORGANICS:

3,4-Diaminothiophene dihydrobromide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 g . . . . 27947-0010

3,4-Diaminothiophene dihydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 g . . . . 32589-0010 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 g . . . . 32589-0050

Tips and hints Tips and hints Tips and hint

The recently launched substructure searchable CD from Acros Organics is a nice piece of software,that allows you to screen rapidly the Acros Organics catalogue. Queries can be made by combinations of entries and of course by drawing a structure as shown by the following example where we are looking for pyrazoleborates available from Acros Organics.

1 After installing the software, following screen will show up, left-click the search menu and select enter Query. 2 Searchable fields become blank, to query by a chemical structure right-click in the structure field and select edit structure.
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3 In the Chemdraw window, left-click the cyclopentadiene icon and left-click the edit screen. 4 Left-click solid bond, left-click the C of the cyclopentadiene to attach the solid bond.

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5 To change the cyclopentadiene into a pyridazole,

left-click the text icon ( A symbol ), left-click the Carbon in the cyclopentadiene, type N in the box. Repeat this with the next Carbon atom. Repeat this operation on the solid bond, type B to make it a pyrazoleborate. You finished drawing your sub-structure!Left-click in the structure field.
6 To query the database left-click

6
7

the find icon, or left-click the search menu and select Find. After a few seconds the first hit shows up.

To get an overview of the hits left-click View and select Data Table. You can hide and unhide, change the order of appearance of the columns by clicking and dragging. Congratulations, ask for your free copy available from ACROS ORGANICS.

ob applications Job applications Job applic

The following young chemists call upon readers of the Acros Organics Acta to offer job opportunities. If youve finished your studies, and are ready to start your career in chemistry, send us your application summary. Details of entries are shown below.
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Something new from Acros Organics: this is your chance to find a job Advertise yourself in the next issue of the Acros Organics Acta. Your future employer may see your details
RULES: 1. Adverts are limited to 35 words maximum. 2. Advertisers must include their name, address, daytime telephone number, (E-mail address), details of their skills, experience and job requirements. 3. This offer is open to unemployed people or students who are seeking a job. 4. These ads are free of charge. 5. Space is strictly limited. Acros Organics reserve the right to select advertisers. 6. Acros Organics do not accept any responsibility concerning the advertisements. Replys to these ads should be sent directly to the advertiser, and not via Acros Organics.

DuPont Central Research and Development Department, Wilmington, DE 19880-0302, USA

S. Trofimenko

Scorpionates
A versatile Family of Polypyrazolylborate Ligands
The coordination chemistry of homoscorpionate (trispyrazolylborate) ligands can be modified or dramatically altered through the facile introduction of appropriate substituents at the 3-positions, leading to unusual or unique complexes. The user-friendly polypyrazolylborate class of ligands, nicknamed "scorpionates", exemplified by the general trispyrazolylborate structure, and denoted according to the "Tp" abbreviation systems (1) , has been employed ever more frequently in recent years. These ligands find use in various areas of transitionand main-group metal coordination chemistry, and in the construction of diverse enzyme analogs. The publication of a major general review (1), and of two large specialized reviews (2,3), bears witness to the expanding interest and activity in this area. The scorpionates are air-stable, and have excellent shelf-life. They are powerful ligands, displacing not only the usual leaving groups, such as halides, sulfonates and carboxylates, but also phosphines and, in some cases, even the cyclopentadienide ion or metal-bonded alkyl groups. The 3-alkylsubstituted ligands are insoluble in water, but are soluble in polar solvents (acetone, THF, DMF), and in halocarbons. Their Tl salts have good solubility in aromatic hydrocarbons. Typical preparation of derivatives consists of stirring the ligand salt in a polar organic solvent with an appropriate organometallic species containing a suitable leaving group, filtering off the KCl or TlCl formed, and concentrating the filtrate. The products may be purified by recrystallization, sublimation, or by chromatography. Most of the earlier work was done using the parent ligand, [HB(pyrazol-1-yl)3]- (=Tp) and the 3,5-dimethyl analog, [HB(2,5-dimethylpyrazol-1yl)3]- (=TpMe2 or Tp*), the chemistry of the latter being governed by a modest degree of steric hindrance due to the 3-methyl groups. However, the fuller potential of scorpionate ligands became more evident after the introduction of their "second generation" (4), containing a larger variety of bulky substituents in the 3-position of the pyrazole ring. For instance, using the very sterically restricted ligand with R= Tbu (= TptBu), the first monomeric magnesium (5) and zinc (6) alkyls were prepared, as was beryllium hydride (7), and the first mononuclear Cu-NO complex (8). Ligands with somewhat lesser hindrance, where R=isopropyl (sometimes with additional substituents on the pyrazolyl ring), led to interesting species such as dioxygen complexes of copper (9), cobalt (10), to their carbonate derivatives, and to T piPr, 4Br RuH(COD) (11). The ligand with R=phenyl, TpPh, permitted the isolation of the air-stable indium(I) complex, TpPhIn (12). The ZnOH derivative of a TpPh analog containing additional substituents was used to cleave, in enzyme fashion, a variety of esters, amides, and phosphates (13). The 3-(2-thienyl) sustituent is unusual, in that its steric hindrance appears to fall between that of H and Me. Thus, the ligand TpTh can be used to fine-tune the steric range between the parent Tp and Tp* (14). Another interesting ligand, Tppy; contains a 3-(2-pyridyl) substituent and it was shown to be capable of hexadentate coordination, yielding icosahedral, 12-coordinate complexes with lanthanides and actinides, as was demonstrated in the case of Sm(II) and U(III) (15). Because the coordination chemistry of polypyrazolylborates is so dependent on the steric environment around the coordinated metal, precise adjustment of the ligand dimensions is of major importance. Therefore, initial experiments generally include scouting several types of scorpionate ligands to find those with the best fit for the particular metal ion (which may also contain other co-ligands). The typical hierarchy of scorpionate ligands based on increased steric hindrance around the coordinated metal is: HB(pz)3 = Tp; < HB[3-(2-thenyl)pz]3 = TpTh; < HB (3,5Me2pz)3 = Tp* or TpMe2; < HB(3-phenylpz)3 = TpPh; < HB(3-iPrt-4-Brpz)3 = TpiPr,4Br; < HB(3-tBupz)3 = TptBu. Within this range researchers can establish quickly which particular ligand is most suitable for their purposes, and then to proceed further with the optimal one or two candidates. Some of the ligands are used as potassium salts, other as the thallium(I) salts. The latter are usually easier to purify, and are definitely preferred when working in non-aqueous solvents, although they can also be used in a two-phase aquo-organic system, under phase transfer conditions.
Acros Organics Acta 5 - 1998

A versatile Family of Polypyrazolylborate Ligands - Scorpionates

S. Trofimenko DuPont Central Research and Development Department, Wilmington, DE 19880-0302, USA

References
(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) Trofimenko, S., Chem. Revs, 1993, 93, 943-980 Parkin, G., Advances in Inorganic chemistry, 1995, 42, 291-393 Kitajima, N., Tolman, W. Progress in Inorganic Chemistry, 1995, 43, 419-531 Trofimenko, S., Calabres, J., Thromspon, J., Inorg.Chem. 1987, 26, 1507-1514 Han, R., Looney, A., Parkin, G., J. Am.Chem.Soc., 1989, 111, 7276-8 Gorrell, I., Looney, A., Parkin, G., J.Chem.Soc., Chem.Commun, 1990, 220-2 Han, R., Parkin, G., Inorg.Chem, 1992, 31, 983-8 Carrier, S., Ruggiero, C., Tolman, W., J. Am.Chem.Soc., 1992, 114, 4407-8 Kitajima, N., Morooka, Y., Chem.Rev., 1994, 94, 737-757 Reinaud, O., Thopold, K., J.Am.Chem.Soc., 1994, 116, 6979-80

(11) Moreno, B., Sabo-Etienne, S., Chaudret, B., Rodriguez-Fernandez, A., Jalon, F., Trofimenko, S., J.Am.Chem.Soc., 1994, 116,2635-6 (12) Frazer, A., Piggott, B., Hursthouse, M., Mazid, M. , J.Am.Chem.Ssoc., 1994, 116, 4127-8 (13) Ruf, M., Weis, K., Vahrenkamp, H., J.Chem.Soc., Chem.commun., 1994, 135-6 (14) Calabrese, J., Domaille, P., Trofimenko, S., Long, G., Journ.Inorg.Chem. 1991, 30, 2975-81 (15) Amoroso, A., Jeffery, C., Jones, P., McCleverty, J., Rees, L., Rheingold, A., Sun, Y., Tkats, J., Trofimenko, S., Ward, M., Yarp, G., J.Chem.Soc., Chem.Commun., 1995, 1881(16) The HB(3iPr-4-Brpz)3 ligand is the easiest to purify among those containing the 3-iPr substituent, and its yield most readily crystalline derivatives.

PRODUCTS AVAILABLE AT ACROS ORGANICS

Hydrotris(pyrazol-1-yl)borate, potassium salt (TpK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 g. Hydrotris(3-(2-thienyl)pyrazol-1-yl)borate, potassium salt (TpThK) . . . . . . . . . . . . . . . . . . . . .500 mg. Hydrotris(3-(2-thienyl)pyrazol-1-yl)borate, thallium salt (TpThTl) . . . . . . . . . . . . . . . . . . . . . . . . . .1 g. Hydrotris(3,5-dimethylpyrazol-1-yl)borate, potassium salt (TpMe2K,Tp*K) . . . . . . . . . . . . . . . . . . .5 g. Hydrotris(3-phenylpyrazol-1-yl)borate, potassium salt (TpPhK) . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 g. Hydrotris(3-phenylpyrazol-1-yl)borate, thallium salt (TpPhTl) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 g. Hydrotris(pyrazol-1-yl)borate, potassium salt (TpiPr,4BrK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 g. Hydrotris(3-tert.-butylpyrazol-1-yl)borate, thallium salt (TptBuTl) . . . . . . . . . . . . . . . . . . . . . . . . . .1 g. Tetrakis(pyrazol-1-yl)borate, potassium salt (pzTpK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 g. Hydrotris(3-p-tolylpyrazol-1-yl)borate, thallium salt (TpTolTl) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 g. Hydrotris(3-anisylpyrazol-1-yl)borate, potassium salt (TpAnK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 g. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29601-0050 30014-5000 30015-0010 29602-0050 30011-0010 30012-0010 29601-0050 30010-0010 30016-0010 30017-0010 30018-0010

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Samples Carbohydrates . . . . . . . . . . Carboxylic Acids . . . . . . . . . Amino acids, Peptides . . . . Amino Acids (also Amines) . Steroids, (Phospho)Lipids, Subst. Phenols . . . . . . . . . . Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recommended Spray Aniline phthalate . . . . . . . . . . Bromocresol green . . . . . . . . Dimethylamino-benzaldehyde Ninhydrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Packsize . . . . .240 .240 .240 .240 ml ml ml ml . . . . . . . . Productcode . . . . .326992400 .327002400 .327012400 .327022400

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Trinity University, San Antonio, Texas Regis Technologies, Morton Grove, Illinois

Michael P. Doyle, Marina N. Protopopova,

Doyle dirhodium catalysts

Asymmetric Catalysis with Chiral Dirhodium(II) Carboxamidates
Dirhodium(II) carboxamidates with chiral 2-oxopyrrolidine, oxozolidinone, or N-acylimidazolidine ligands have been designed and developed for asymmetric carbon-carbon bond forming reactions via highly enantioselective metal carbene transformations of diazoesters and diazoamides). Their reported uses include intramolecular cyclopropanation (1-5) and intramolecular carbon-hydrogen insertion reactions (6-11) leading to chiral lactones and lactams, as well as intermolecular cyclopropenation (12) leading to the formation of chiral cyclopropenecarboxylates and cyclopropenecarboxamides.
Scheme 1
Me Me Rh2(5R-MEPY)4 O O (1 S ,5 R ), 98% ee 4 0 C, CH2Cl2 84%
o

design features of the catalysts that effect high enantiocontrol along with high turnover numbers. Starting diazoesters and diazoamides are readily prepared from corresponding alcohols or amines (2,5) and are generally stable at temperatures below 100oC (13).

References

Me Me

O O

(1) (a) Martin, S. F.; Spaller, M. R.; Liras, S.; Hartmann, B. J. Am. Chem. Soc. 1994, 116, 4493; (b) Dwyer, M. P.; Hartman, B.; Knight, K. S.; Martin, S. F. 211 ACS National Meeting, New Orleans, 1996, ORGN, 167. (2) (a) Doyle, M. P.; Kalinin, A. V.; J. Org. Chem. 1996, 61, 2179; (b) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C. Me Me J.; Pieters, R. J. Protopopova, M. N.; Raab, Rh2(5S-MEPY)4 C. E.; Roos, G. H. P.; CHN 2 o 40 C, CH2Cl2 Zhou, Q.-L.; Martin, S. O 89% O F. J. Am. Chem. Soc. (1R,5S), 98% ee 1995, 117, 5763.

The unique advantages of this catalytic methodology are associated with the variety of transformations that can be achieved with characteristic chemo-, regio-, and diastereoselectivity and with the
Scheme 2
COOH O HC Synthesi s of (-)-heliotridane , R = Me H N HO O OH O (1 0 ) R ( Et O ) 2C H 98% ee (1 2) (1 1) H O (1 ) H COOMe O H O 99% ee R1 Synthesis of GABA anal ogs (2 ) X O N 97% ee H O O (8 ) (4 ) R 98% ee OH (7 ) OH H (6) O O O O H 97% ee c/ t = 99:1 X COOH cis-chrysanthemic acid cis-permethrenic acid O > 94% ee O R R1 (5 ) R R 94-95% ee Synthesis of - renin and collagenase inhibitors - (+)-presqualene diphosphate Me Synthesis of pyrethroid insecticides O O (9 ) O Rh Rh N N R O 92-98% ee H C OO M e (3 ) R 1O R 2O R3 O R2 NH H H O OH Synthesi s of enkephalin mi mics H N

deoxyxylolact one Synthesis of AZT

H

(-)-enterolactone
Synthesis of lignan lact ones 91-96% ee

Me

(3) Doyle, M. P., unpublished data. (4) Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D. A.; Martin, S. F.; Spaller, M. R.; Liras, S. J. Am. Chem Soc. 1995, 117, 11021. (5) (a) Doyle, M. P.; Pieters, R. J.; Martin, S. F.; Austin, R. E.; Oalmann, C. J.; Muller, P. J. Am. Chem. Soc. 1991, 113, 1423; (b) 2b; (c) Doyle, M. P.; Winchester, W. R.; Protopopova, M. N.; Kazala, A. P.; Westrum, L. J. Organic Synthesis 1996, 73, 13; (d) Martin, S. F.; Austin, R. E.; Oalmann, C. J.; Baker, W. R.; Condon, S. L.; Delara, E.; Rosenberg, S. H.; Spina, K. P.; Stein, H. H.; Cohen, J.; Kleinert, H. D. J. Med. Chem.. 1992, 35, 1710; (e) Martin, S. F.; Oalmann, C. J.; Liras, S. Tetrahedron 1993, 49, 3521; (e) Rogers, D. H.; Yi, E. C.; Poulter, D. J. Org. Chem. 1995, 60, 941. (6) Doyle, M. P.; Dyatkin, A. B.; Roos, G. H. P.; Canas, F.; Pierson, D. A.; van Basten, A.; Muller, P.; Polleux, P. J. Am. Chem. Soc. 1994, 116, 4507. (7) (a) Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L.; Bode, J. W.; Simonsen, S. H.; Lynch, V. J. Org. Chem. 1995, 60, 6654; (b) Bode, J. W.; Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L. J. Org. Chem. 1996, 61. (8) Doyle, M. P.; Dyatkin, A. B.; Protopopova, M. N.; Yang, C. I.; Miertschin, C. S.; Winchester, W. R.; Simonsen, S. H.; Lynch, V.; Ghosh, R. Recl. Trav. Chim. Pays-Bas 1995, 114, 163. (9) Doyle, M. P.; Kalinin, A. V. Synlett 1995, 1075. (10) Doyle, A. B.; Dyatkin, A. B.; Tedrow, J. S. Tetrahedron Lett. 1994, 35, 3853. (11) Doyle, M. P.; Kalinin, A. V. Tetrahedron Lett. 1996, 37, 1371. (12) (a) Protopopova, M. N.; Doyle, M. P.; Muller, P.; Ene, D. J. Am. Chem. Soc. 1992, 114, 2755; (b) Doyle, M. P.; Protopopova, M. N.; Muller, P.; Ene, D.; Shapiro, E. A. J. Am. Chem. Soc. 1994, 116, 8492. (13) Regitz, M.; Maas, G. Diazo Compounds, Academic Press: New York, 1986.

Acros Organics Acta 5 - 1998

Doyle dirhodium catalysts - Asymmetric Catalysis with Chiral Dirhodium(II) Carboxamidates

Michael P. Doyle, Marina N. Protopopova, Trinity University, San Antonio, Texas Regis Technologies, Morton Grove, Illinois

PRODUCTS AVAILABLE AT ACROS ORGANICS (AS DOYLE CATALYSTS)

Doyle Doyle Doyle Doyle Doyle dirhodium dirhodium dirhodium dirhodium dirhodium catalyst catalyst catalyst catalyst catalyst Rh2(5R-MEPY)4* . Rh2(5S-MEPY)4* . Rh2(4R-MEOX)4* . Rh2(4S-MPPIM)4* Rh2(CAPY)4* . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
X

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

50 50 50 50 50

mg mg mg mg mg

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

30252-0500 30253-0500 30254-0500 30255-0500 30256-0500

* sold under license from Regis Technologies Inc

O MeOOC X MeOOC N Rh O N X N O Rh O

COOMe X COOMe N

Rh2(5S -MEPY)4 Rh2(4S -MEOX)4 Rh2(4S -MPPIM) 4

X = CH2 X=O X = NC(O)CH2CH2 Ph

ymposia Symposia Symposia Symposia

Below is a selection of symposia where Acros Organics will have a booth. Come and visit us, register yourself at our stand and win a nice prize.

when
Oct 19th & 20th Oct 19th & 21st Nov 9th - 11th

what
Chiral Europe 98 LabExpo ChiraTech 98 Conference CPHI 98

where
Nice France Stockholm, Sweden Barcelona Hilton Barcelona, Spain Netherlands, Adam

topic
Chiral Technology General Chemical & Laboratory Equipment Show The Dynamics of Superior Product & Process Innovation Bulk Intermediates

Dec 2nd - 4th

Please feel free to contact us (Acros Organics, Attn Karin Vercauteren, fax + 32 14 59 34 34, E-mail: k.vercauteren@acros.be ) if you think we have forgotten an important congress/ symposia/ fair. Thanks for your cooperation and help.

Acros Organics Acta 5 - 1998

Department of Chemistry, Facults Universitaires N.D. de la Paix and Acros R&D unit, 61 rue de Bruxelles, 5000 Namur, Belgium

Alain Krief

Phenylselenocyanate
Chemoselective Reactions with prim- and sec-Alcohols; Efficient Syntheses of Alkanes, Alkenes and Stereoselective Synthesis of Alkylbromides with Retention of Configuration.
Phenylselenocyanate allows the insertion, under mild conditions, of the phenylseleno moiety into organic molecules. It reacts in the presence of tributylphosphine with alcohols, aldehydes, enones and carboxylic acids and produces selenides, including functionalized ones and selenol esters. The selenides have proved to be valuable precursors of selenium-free compounds (2-9) (Scheme 1).
Scheme 1
H R3SnH, 120C, 0.5h PhSe PhSeCN, PBu 3, THF, 20C R2 R1 Br2-NEt3, CH2Cl2, 20C, 0.5h H R2 R1 HO R1 R2 H
HO

Scheme 3
OH CONMe2 PhSeCN PBu3, 80 C 78% PhSe CONMe2 Ph 3SnH AIBN CONMe2

96%

CONMe2

Scheme 4
O N N PhSeCN PBu3,20C PhSe 64% N-Ph O PhSe 89% N N-Ph N O 77% O Ph 3SnH AIBN N N-Ph N O O

[Oxydant]

R2 R1 Br R1 R2 H

1. Synthesis of phenylselenides involving phenylselenocyanate

Phenylselenocyanate (PhSeCN, [2179-79-5], MW 182.083, Bp 115116C / 12 mBar) is inert, in neutral media, towards several functional groups but reacts : with alcohols, aldehydes, enones and carboxylic acids, in the presence of tributylphoshine (1.2 eq. PhSeCN, 1.2 eq. PBu3, THF or pyridine, 0-60C), to produce selenides (10) (Schemes 2-4),
Scheme 2
5.3 Ph3SnH, 120 C, 0.5h 84% 1.5 PhSeCN, 1.5 PBu 3, THF, 20 C, 100h PhSe 76 %

The most useful among the above-mentioned reactions is, without contest, the selenenylation of alcohols, which has been successfully achieved on a large variety of compounds including primary-, secondary- and benzylic alcohols (Schemes 2,4) as well as on cyclopropyl carbinols (14), (Scheme 3) which have usually a very high propensity to rearrange. It proceeds stereospecifically with net inversion of the configuration at the substituted carbon from secondary alcohols (15) (Scheme 2).
Scheme 5
O Bu PhSeCN, Bu3P Bu THF, 20 C high yield CN (i) LDA SePh (ii) MeI 78 % Bu CN Me SePh

Scheme 6
O OH ArSeCN, 2 eq. Bu 3P CH2Cl2., 20 C, 2h 88% O SePh Pyrrolyl-MgBr-CuI, THF, 20C, 1h 80% O NH

HO

Br2-NEt3, CH2 Cl2, 20 C, 0.5h Br 93%

-phenylselenonitriles (11) (Scheme 5), -phenylseleno-,-unsaturated nitriles (11) and selenol esters (12) (Scheme 6) respectively in reasonably good yields. Ketones however do not undergo cyanoselenenylation (11). with sodium borohydride (NaBH4, ethanol or DMF) or with potassium hydroxide and produces phenylselenolates (2,3,13). This reaction, however offers no advantages over conventional methods that use instead diphenyldiselenide (2,3,13).

The reaction has proved to be much less efficient with rigid cyclohexanols bearing axial hydroxyl groups, such as cis-4-t-butylcyclohexanol and 3-cholestanol (43-47% yields), than with their equatorial stereoisomers (74-80%), because of competing elimination on the intermediate oxophosphonium salt, which is favored by the trans-antiperiplanar arrangement between this group and a -hydrogen (15) (Scheme 2).

Acros Organics Acta 5 - 1998

11

Phenylselenocyanate - Chemoselective Reactions with prim- and sec-Alcohols.

Alain Krief Department of Chemistry, Facults Universitaires N.D. de la Paix and Acros R&D unit, 61 rue de Bruxelles, 5000 Namur, Belgium

2. Transformation of phenylselenides to alkanes, alkenes and alkyl bromides

The resulting selenides and functionalized selenides have, in turn been, transformed into a large variety of selenium-free molecules, by taking advantage of the unique properties of selenides. They allow thus the synthesis from alcohols of :
alkanes. This involves the very mild reduction with tin hydrides of

References
(1) Toshimitsu, A.; Uemura, S. The Chemistry of Organic Selenium and Tellurium Compounds, Patai, S.; Rappoport, Z. Eds, John Wiley and Sons, Chichester, 1987, 2, 541. (2) Rheinboldt, H. in Schwefel-, Selen-, Tellur- Verbindungen, Methoden Org. Chem. (Houben-Weyl) Mller, E. Ed., Georg Thieme Verlag, Stuttgart, 1967, 9, 917. (3) The Chemistry of Organic Selenium and Tellurium Compounds, Vol. 2, Patai, S.; Rappoport, Z. Eds, John Wiley and Sons, Chichester, 1987. (4) Nicolaou, K.C.; Petasis, N.A. Selenium in Natural Products Synthesis, Cis Inc, Philadelphia, 1984. (5) Clive, D. L. J. Tetrahedron 1978, 34, 1049. (6) Reich, H.J. in Oxidation in Organic Chemistry: Organoselenium Oxidations, Trahanovsky, W.S.; Wasserman, H.H. Ed., Academic Press, New York, 1978, pp 1. (7) Paulmier, C. in Selenium Reagents and Intermediates in Organic Synthesis, Baldwin, J.E. Ed., Pergamon Press, Oxford, 1986, 5, pp 1. (8) Krief, A. Tetrahedron 1980, 36, 2531. (9) Krief, A. in Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I. Eds, Pergamon Press, Oxford, 1991, 1,629. (10) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485. (11) Grieco, P. A.; Yokoyama, Y. J. Am. Chem. Soc. 1977, 99, 5210. (12) Grieco, P. A.; Yokoyama, Y.; Williams, E. J. Org. Chem. 1978, 43, 1283. (13) Gnther, W. H. H. in Organic Selenium Compounds: Their Chemistry and Biology, Klayman, D.L.; Gnther, W.H.H. Ed., John Wiley and Sons, Chichester, 1973. (14) Clive, D. L. J.; Daigneault, S. J. Org. Chem. 1991, 56, 3801. (15) Sevrin, M.; Krief, A. J. Chem. Soc. Chem. Commun. 1980, 656. (16) Clive, D. L. J.; Chittattu, G. J.; Farina, V.; Kiel, W. A.; Menchen, S. M.; Russell, C. G.; Singh, A.; Wong, C. K.; Curtis, N. J. J. Am. Chem. Soc. 1980, 102, 4438. (17) Clive, D. L. J.; Bergstra, R. J. J. Org. Chem. 1990, 55, 1786. (18) Sharpless, K. B.; Gordon, K. M.; Lauer, R. F.; Patrick, D. W.; Singer, S. P.; Young, M. W. Chem. Scr. 1975, 8, 9. (19) Nakahara, Y.; Fujita, A.; Ogawa, T. Agric. Biol. Chem. 1985, 49, 1491.

the corresponding phenylselenides (R3SnH R = Bu or Ph, toluene, 120C, 0.5h) (16) (Schemes 1, 2), which occurs via a radical intermediate. In some cases, however, in which the strain can be released, as with cyclopropyl methyl radicals, ring opening takes place instead (14) (Scheme 3). In other cases, in which a C,C double bond is located in a suitable position, a five- or six- membered cycle is formed (17) (Scheme 4). These different types of reactions have been used purposely in organic synthesis.
alkenes. This transformation takes advantage of the particularly

facile elimination of the corresponding selenoxides (on reaction of the selenide with hydrogen peroxide, sodium periodide, m-chloroperbenzoic acid or ozone, 20C, 1-4h) (2-9,18) (Scheme 1). This transformation, especially the one that involves primary alcohols, is usually best achieved with o-nitrophenylselenocyanate (10).
alkyl bromides with retention of configuration at the substituted

carbon (15) (Schemes 1, 2). This transformation takes advantage of the reaction of secondary alcohols with phenylselenocyanate, which delivers the corresponding phenyl selenides, and their further reaction with bromine (Br2-NEt3, CH2Cl2, 20C). Both reactions occur stereospecifically with inversion of configuration at the substituted carbon. Phenylselenocyanate reacts in the presence of tributyl phosphine (2 eq.) with alkyl and aryl carboxylic acids and produces selenol esters (12) (Scheme 6). The reaction is best carried out at room temperature with equimolar amounts of phenylselenocyanate in methylene dichloride for 0.5-3 h and delivers the selenol esters in reasonably good yields (70-85 %) except with p-chloro benzoic acid (36 %). Chemoselective reactions are performed in the presence of a C,C double bond or a secondary alkyl bromide (12). Selenol esters are activated esters that are valuable intermediates in organic synthesis and have proved particularly useful for the synthesis of 2-acylpyrroles (19) (Scheme 6).

PRODUCTS AVAILABLE AT ACROS ORGANICS

Phenylselenocyanate, tech., 90+% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 ml Tri-n-butylphosphine, 95% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .100 ml . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .500 ml Tri-n-butyltin hydride, 97% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 g . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50 g Triphenyltin hydride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 g . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 g . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29368-0050 13934-1000 13934-5000 21573-0100 21573-0500 22378-0050 22378-0250

10

Acros Organics Acta 5 - 1998

Aqualine non-pyridine based reagents for moisture determination

! W E N
Since the 1930's when it was first introduced Karl Fischer analysis has become the most popular technique for moisture determination, mainly due to its high reliability. However, traditional reagents which contain pyridine have an unpleasant odour and are subject to a limited shelf life. Fisher Chemicals have just launched Aqualine, a new range of reagents for the volumetric determination of moisture in a wide variety of substances. Their special formulation offers a number of advantages over traditional reagents in that they are i) pyridine free ii) they have low odour iii) they have an extended shelf life and iv) they titrate rapidly with a resulting stable end-point. The range includes single component reagents, branded Complete 1, Complete 2 and Complete 5 which contain all the reactants (ie: sulfur dioxide, iodine and the base) necessary for the Karl Fischer reaction. The naming of the Complete reagents reflects their water equivalency, with Complete 5, the most widely used reagent offering 5mg H2O/ml. The lower water equivalencies offered by Complete 2 and Complete 1 have been developed where decreasingly lower amounts of water are to be titrated.

In general the single component reagent is usually chosen where convenience is the users main criteria. Where rapid titration is the important factor a two component system is normally the method of choice and for this we have developed Aqualine Solvent and Aqualine Titrants 2 and 5. Aqualine Solvent is a methanolic solution of sulfur dioxide and a base, with the Titrants essentially being methanolic iodine solutions. Similar to Complete reagents, water equivalence Titrants should be selected where small amounts of water are to be titrated. The analysis of ketones and aldehydes has often been a problem area within Karl Fischer analysis due to side reactions which can form or consume water resulting in spurious results. Aqualine Complete 5K is a single component reagent which is used for Ketone and aldehyde analysis but has been carefully formulated for to avoid these problems. Complete 5K is used with Aqualine Matrix K which acts as the working medium and solvent for the sample under test.

For any technical questions regarding Aqualine we have set up user hotlines on
e-mail:aqualine.fisher.co.uk fax +44 (0)1509 616121
Aqualine reagents are available through all Fisher Scientific companies and selected distributors throughout Europe.

For further details, including the address of your local distribution point please contact
Rob Brinklow on fax +44 (0) 1509 616121

Bishop Meadow Road Loughborough Leicester LE11 5RG United Kingdom

ew products New products New products

Chiral Diamines in Asymmetric Synthesis
R COOEt R'O CHO N H N H CHO R' O Ph N N N Ph N N R R Ph CH 2OH H COOEt R' N Me MeOOC N Ts Ph N N Me COOMe R Ph MeO H CHO MeO R

*
R

COOEt

Ph R

N N

*
R'O

CHO O

Chiral and cyclic Aminals, nitrogen equivalents of acetals, are stable imidazoline ring reagents, readily formed with a chiral 1,2-diamine without a catalyst in aqueous media. The illustrated applications have excellent stereocontrol (de or ee > 95%). The following chiral 1,2-diamines are available from stock at Acros Organics:

Ph OHC

PRODUCTS AVAILABLE AT ACROS ORGANICS

(1R,2R)-(+)-N,N-Dimethyl-1,2-bis[3-(trifluoromethyl)phenyl]-1,2-ethanediamine (1S,2S)-(-)-N,N-Dimethyl-1,2-bis[3-(trifluoromethyl)phenyl]-1,2-ethanediamine . (1R,2R)-(+)-N,N-Dimethyl-N,N-Dimethyl-1,2-diphenyl-1,2-ethanediamine . . . . . (1S,2S)-(-)-N,N-Dimethyl-N,N-Dimethyl-1,2-diphenyl-1,2-ethanediamine . . . . . 3-(1,3-Dimethyl-4(S),5(S)-diphenylimidazolidin-2-yl)piperidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .250 .250 .250 .250 .250 mg mg mg mg mg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29464 29465 29466 29467 29569

Ask for your copy of Acros Organics special Technical Information Sheet n 41 with more information and references.

Announcement Acros Organics

Announce

awards 97-98
We are pleased to announce the winners of the first Acros Organics Award. The Scientific Committee was most pleased with the quality of entries, so much so that they found it by no means an easy task to identify the prize winning entries! Participants shared with us many most innovative PhD dissertations, including very creative organic chemistry approaches and documenting us on a number of novel synthetic pathways which hopefully could lead to the entrants and our Product Management team working together to develop and promote new chemical developments for Acros Organics.

We are very pleased to award the following participants each with the Acros Organics Award of $2,000 GREAT BRITAIN: Dr Nathalie Guillo, Imperial College of Science, London for her work on : Synthesis and Use of Constrained Analogues of Phenylalanine NETHERLANDS: Dr Pablo Steenwinkel, Universiteit van Utrecht, Utrecht for his work on : Multinuclear organometallics based on anionic chelating arylamine ligands ITALY: Dr Luca Arista, Universita degli Studi, Palermo for his work on: Asymmetric Synthesis of oxygenated heterocycles and their open chain precursors BELGIUM: Dr Frdric Laduron, Universit Catholique de Louvain, Louvain-la-Neuve for his work on: New trifluoromethylated reagents: trifluorothioamidium salts and trifluoromethyl epoxysulfones We congratulate Dr Guillo, Dr Steenwinkel, Dr Arista and Dr Laduron, as well as all other participants who have participated in this first Award competition. We wish you every success in your most promising future careers. Acros Organics also invites the new generation of young chemists, preparing now for a PhD, to participate in the next 98-99 Acros Organics Award. Watch this space for details

Laboratoire de Synthse Organique (ERA N 482), Facult des Sciences, Avenue Olivier Messiaen, BP 535 - 72017 Le Mans, France

E. Brown,

(R)-(-)-2-(2-Iso-indolinyl)butan-1-ol
A Novel Chiral -Aminoalcohol for Asymmetric Reduction of Prochiral Ketones Scheme 3
HO H X X= X= X= X= X= Me Cl Br I CF3

Lithium aluminium hydride previously treated with 2.5 equivalents of (R)-(-)-2-(2-iso-indolinyl)butan-1-ol (Figure 1) in ether solution, can reduce ortho-substituted prochiral benzophenones into the corresponding (R)-benzhydrols in high yields and with nearly 100% enantiomeric excesses. The asymmetric reduction of prochiral ketones using ethereal solutions of lithium aluminium OH hydride partially decomposed N with 1, 2 or 3 molar amounts of an appropriate, enantiomerically (R*-OH) pure, b-aminoalcohol provides a general method for the enantioselective synthesis of chiral secondary alcohols. In practice, the enantiomeric excess of the final alcohol is strongly dependent upon the structures of both the b-aminoalcohol and the starting ketone.
Et
Scheme 1

HO

H Me Cl

HO

Br

Me

From a more general standpoint, (R)-(-)-2-(2-iso-indolinyl)butan-1-ol can be recommended for the preparative, asymmetric reduction of prochiral ketones substituted by bulky groups.

Preparation of (R)-(+)-2-trifluoromethylbenzhydrol
Approximately molar ethereal solutions of LiAlH4 were used. Their reducing hydride content was estimated by fluorenone as described (4). To an ethereal solution of LiAlH4 (60.0 mL ; 59.40 mmol), a solution of (R)-(-)-2-(2-iso-indolinyl)butan-1-ol (28.40 g ; 148.5 mmol) in dry ether (500 mL) was added with stirring under argon for 1 h at room temperature. After stirring for a further 30 min, the mixture was cooled to -15C and a solution of 2-trifluoromethyl benzophenone (13,9 g ; 55.67 mmol) in dry ether (75 mL) was added dropwise in 1h 15 min. After stirring for another 10 h (TLC), the mixture was hydrolyzed with aqueous 1N NaOH (56 mL). The resulting crude (R)(+)-2-trifluoromethyl benzhydrol (14.04 g; 100%) was isolated and molecularly distilled, Eb0.07 100C, thus affording a colourless oil (13.7 g ; 97.5% yield), [a]D+68.0 (c 1.31, Me2CO). The 1H NMR spectrum of this benzhydrol, run in the presence of Eu(hfc)3 revealed that the enantiomeric excess was higher than 95%. When working on a smaller scale (5 mmol) the reaction time was shorter (30 min) and the ee of the distilled (R)-(+)-trifluoromethylbenzhydrol was >99% (1H NMR), having [a]D +71.6 (c 0.80, Me2CO).

Enantiomerically pure benzhydrols were obtained upon treatment of the corresponding ortho-substituted benzophenones with an ethereal solution of lithium aluminium hydride previously treated with 2.5 equivalents of (R)-(-)-2-(2-iso-indolinyl)butan-1-ol which corresponds to the gross formula LiAl (OR*)2.5H1.5 for the asymmetric reducing species in solution. The enantiomerically pure benzhydrols shown in figure 3 were thus obtained in excellent yields and on a multigram scale (1). Using Horeau's method (2), the absolute configuration of these benzhydrols was found to be R in all cases.
Scheme 2
ArCOAr' 1) LiAl(OR*)2.5H1.5 2) H3O+ HO C Ar Ar' H

References
(1) Brown, E.; Lz, A.; Touet, J. Tetrahedron : Asymmetry 1992, 3, 841. (2) a) Horeau, A. Tetrahedron Lett. 1961, 506. b) Horeau, A. Tetrahedron Lett. 1962, 965. c) Barnekow, D.E.; Cardellina, J.H. Tetrahedron Lett. 1989, 30, 3629. (3) Brown, E.; Chevalier, C.; Huet, F.; Le Grumelec, C.; Lz, A.; Touet, J. Tetrahedron : Asymmetry 1994, 5, 1191. (4) Brown, E.; Lz, A.; Touet, J. Tetrahedron Lett. 1991, 32, 4309.

As a typical procedure, the preparation is given below of (R)-(+)-2trifluoromethyl benzhydrol (Figure 3). The enantiomeric excess of chiral acids can be determined by 19F NMR studies of their esters deriving from (R)-(+)-2-trifluoromethyl benzhydrol (3).

PRODUCTS AVAILABLE AT ACROS ORGANICS

(R)-(-)-2-(2-Iso-indolinyl)butan-1-ol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Lithium aluminum hydride, tablets, 98% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .100 g. g. g. g. . . . . . . . . . . . . . . . . 30008-0010 27127-0100 27127-0250 27127-1000

Acros Organics Acta 5 - 1998

15

Novelties Novelties Novelties Novelties

Extra dry solvents from Acros Organics, This packaging garantuees you a virtual infinite not just dry... shelflife of your dry solvent.
If you are tired of preparing decent dry solvents, ACROS ORGANICS now comes with the solution you only could dream about. These solvents are not only dry (down to 10 ppm), but also the packaging eliminates indefinetely any risk of water contamination. Packaged under inert gas,septum sealed quality bottles are supplied in double sealed double layer aluminium bags. Open the bag only just before use! Our own QC lab completed extensive tests for you that: After 4 punctures over a period of 3 weeks the water contents of the remaining solvent stayed below specifications. All solvents are offered in a convenient 250 ml personal use format, so no need to buy 1 liter. Choosing the ACROS ORGANICS solvent, you will achieve considerable waste reduction, improve lab safety and realise substantial costsavings.

PRODUCTS AVAILABLE AT ACROS ORGANICS

Acetone, extra dry, water <50 ppm . . . . . . . . . . . Acetonitrile, extra dry, water <10 ppm . . . . . . . . . Chloroform, extra dry, water <10 ppm . . . . . . . . . Cyclohexane, extra dry, water <10 ppm . . . . . . . . 1,2-Dichloroethane, extra dry, water <30 ppm . . . Dichloromethane, extra dry, water <30 ppm . . . . Dimethylformamide, extra dry, water <50 ppm . . 1,4-Dioxane, extra dry, water <30 ppm . . . . . . . . Ether, extra dry, water <50 ppm . . . . . . . . . . . . . . Ethyl acetate, extra dry, water <50 ppm . . . . . . . n-Heptane, extra dry, water <20 ppm . . . . . . . . . n-Hexane, extra dry, water <20 ppm . . . . . . . . . . Isopropanol, extra dry, water <50 ppm . . . . . . . . . Methyl alcohol, extra dry, water <50 ppm . . . . . . N-Methylpyrrolidinone, extra dry, water <50 ppm Methyl sulfoxide, extra dry, water <50 ppm . . . . . Tetrahydrofuran, extra dry, water <50 ppm . . . . . Toluene, extra dry, water <10 ppm . . . . . . . . . . . . 2,2,4-Trimethylpentane, extra dry, water <30 ppm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .250 .250 .250 .250 .250 .250 .250 .250 .250 .250 .250 .250 .250 .250 .250 .250 .250 .250 .250 ml ml ml ml ml ml ml ml ml ml ml ml ml ml ml ml ml ml ml . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326802500 326812500 326822500 326832500 326842500 326852500 326872500 326892500 326862500 326902500 326912500 326922500 326962500 326952500 326932500 326882500 326972500 326982500 326942500

Synthetic D-erythro ceramides

Recently an increasing number of products containing ceramides or ceramides analogs have come into the market. These ceramides were untill now prepared from natural sources. As the use of animal tissues such as brains was recently banned due to safety problems, products originated of milk may induce allergy and plant and yeast sources lack the most relevant sphingosine base in humans, the solution is large scale production of fully synthetically prepared material. Synthetic ceramides offered by ACROS ORGANICS contain the very special D-erythro structure and the trans double bond of the natural mammalian ceramide and show the biological activity of naturally occuring ceramides.

New products New products New product

New reagents for chiral Synthesis Meyers Bicyclic Lactams from Acros Organics
Acros Organics is proud to offer you a new set of most useful reagents for the Synthesis of optically active

QUATERNARY CENTERS, CYCLOPENTENONES, CYCLOPROPANES, PIPERIDINES

R COOEt R'O CHO N H N H CHO R' O Ph N N N Ph N N R R Ph CH 2OH H COOEt R' N Me MeOOC N Ts Ph N N Me COOMe R Ph MeO H CHO MeO R

*
R

COOEt

Ph R

N N

*
R'O

CHO O

Ph OHC

above applications are documented in:

D. Romo and A.I. Meyers, Tetrahedron, 1991, 47, 9503-9569 A.I. Meyers in Stereocontrolled Organic Synthesis, B.M. Trost, Ed Blackwell, 1994, 145-175 C.J. Andres, P.H. Lee, T.H. Nguyen and A.I. Meyers, J.Org.Chem., 1995, 60, 3189-3193 A.I. Meyers and L. Snyder, J.Org.Chem., 1993, 58, 36-42 A.I. Meyers and G.P. Bregnel, J.Chem.Soc.Chem.Comm., 1997, 1

THE FOLLOWING MEYERS BICYCLIC LACTAMS ARE AVAILABLE FROM STOCK AT ACROS ORGANICS
Catalog n R1 R2 Saturated bicyclic lactams . . . . . . . . . . . . . . . . . . . . . . . . . . .i -Pr . . . . . . . . . .Me . . . . . . . . . . .(+) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .i -Pr . . . . . . . . . .Me . . . . . . . . . . .(-) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Ph . . . . . . . . . .Me . . . . . . . . . . .(+) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Ph . . . . . . . . . .Me . . . . . . . . . . .(-) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Ph . . . . . . . . . . .Ph . . . . . . . . . . .(+) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Ph . . . . . . . . . . .Ph . . . . . . . . . . . .(-) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Ph . . . . . . . . . . .H . . . . . . . . . . . .(+) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Ph . . . . . . . . . . .H . . . . . . . . . . . .(-) Unsaturated bicyclic lactams . . . . . . . . . . . . . . . . . . . . . . . . .i -Pr . . . . . . . . . .Me . . . . . . . . . . .(+) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .i -Pr . . . . . . . . . .Me . . . . . . . . . . .(-) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Ph . . . . . . . . . .Me . . . . . . . . . . .(+) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Ph . . . . . . . . . .Me . . . . . . . . . . .(-) (+) or (-) . . .32646 . . .32649 . . .32650 . . .32651 . . .32645 . . .32652 . . .32653 . . .32654 . . .32655 . . .32656 . . .32647 . . .32648

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Are you more interested in optically active EPOXIDES ?

Ask for your free copy of Acros Organics special Technical Information Sheet n 38 on our product 32758 Poly-L-Leucine, the best reagent for a simple, quick and reproducible way to chiral epoxides.

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