Chemical synthesis in microreactors is a novel way of conducting chemistry in a highly controlled way with improved yields at impressive selectivities and with reduced overall effort. This paper describes recent technological progress with the potential as well as the application of the technology to chemical synthesis, discusses novel chemical optimization technology and reports on the transfer of the technology into production.

Continuous processing of liquid/liquid synthesis and microreaction technology are shown to reduce the cost of process development and manufacturing of active pharmaceutical ingredients and other functional molecules on a commercial scale. Combinatorial synthesis systems for continuous chemistry are introduced, and their applications are described. Reactions within these systems scale seamlessly in standardized commercial continuous synthesis equipment allowing rapid access to kilogram quantities of advanced intermediates. Chemical and process development within such systems are illustrated by a case study of a continuous multistep process. Additionally, another case study shows the benefit of microreaction technology in the manufacture of high value added functional chemicals.

Photolactonization: a Novel Synthetic Entry to Macrolides 0-Quinol acetates, hydroxyalkylated at C(6), are easily accessible from simple phenols by Wessely acetoxylation (preferentially catalyzed by BF,). On UV irradiation (in the presence of an appropriate tertiary amine), they are smoothly converted to macrocyclic lactones. Subtle conditions have been elaborated to lead to high overall yields, and the scope of the conversion of phenols to macrolides has been elucidated 1. Einleitung. -Der Begriff 'Photolactonisierung' kennzeichnet ein photochemisches Verfahren zur Herstellung von Makromonoliden C und/oder Makrodioliden D (s.

After having established the absolute configuration of the title compound ['] and having opened up a new synthetic route to large ring sized lactones, we now report the total synthesis of the first isolated lichen macrolide.[21 The core of our total synthesis of (+)-aspidin 8 is the photolactonization of the diastereomeric o-quinol acetates 1 and 3 (via the seco-isomeric diene ketene 213]) to the diastereomeric macrolides 4 and 6 (69%, ratio 2.5 : 1;[41 see Scheme 1). The mixture of the photolactones 4 and 6 is converted, without the lactone ring ever being opened again, into the enantiomerically pure target compound 8 via the dienone lactone 5 and the dienol lactone 7 a .Chemoselective azidolysisf6' of the enol acetate group of 4 and 6 and subsequent elimination of the benzenesulfinate anion, furnishes a 1 : 1 :2 mixture of 5 and its (E,E)and (Z,E)-stereoisomers. The (E,Z)-diastereomer 5 has been isolated in 72% overall yield (referred to the mixture of lactones 4 and 6): 22% immediately after azidolytic elimination, the rest after photoisomerization of the (E,E)and (2,E)-stereoisomers of 5 with light of the wavelength region > 340 nm.l']Reduction of the keto group, at -90°C in toluene, with Yamamoto's reagent"! converts the dienone lactone 5 with exceedingly high stereoselection almost exclusively into the dienol lactone 7a (96Y0).[~~ The relative and (as the (S)chirality at C(17) is already known by use of 12; see Scheme 2) absolute configuration of 7a have been established by single-crystal X-ray analysis of rac-7b.'Io1 The center of chirality at C(17) already present prior to reduction, by the tendency of the CH3 group to take up the pseudo equatorial position, determines the dominating conformation of the dienone lactone 5. Due to the preferred approach of the reducing agent from the less occupied half spacef"] C( 17) finally controls the configuration 3 t-"$6, 6 7a: R-H b: R=OAC t "5'6. Scheme 1. a) hv, d>340 nm, N-methylirnidazole (1.3 equiv.), CCI,, 30 min; flash chromatography 151. b) NaN, (I I equiv.), benzene/water (6 + I), methyltrialkyl(C,-C,o)arnmoniurn chloride (ADOGEN 464@, Janssen), RT, 120 h; separation of 5 by flash chromatography; hv, d > 340 nm, hexane, 90 min; flash chromatography and threefold repetition of the irradiation-chromatography cycle [7J.c) Diisobutylaluminum hydride in toluene (14 equiv.), 2,6-di-tert-butyl-4methylphenol (28 equiv.), 1 h, 0-4°C; addition of 5 in toluene at -90"C, 2 h at -9O"C, 2 h at -4OOC; 0 . 1~ HCI (aq.); Flash chromatography, crystallization. d) OsO, (1.25 equiv.) in CH2C12 at RT to 7a (I equiv.), pyridine (5 equiv.) in CH2C12, 30 rnin; rnethanol (15-fold amount), 15 min passage of H2S, evaporation, dissolution of residue in ethyl acetate, filtration over Celite, semipreparative HPLC.

Bei Verwendung von Isopropylisocyanat und methanolischer HCI bilden sich unter den angegebenen Bedingungen neben Isopropylcarbamoyl-aminosaure-methylestern auch N-Isopropylhydantoine, die zwar ebenfalls gaschromatographisch getrennt werden konnen, jedoch nicht vo1-lig konfigurationsstabil sind. In einigen Fallen erwies es sich als vorteilhaft, das Peptid vor der Umsetzung rnit Isocyanat rnit HCI/Isopropylalkohol (1.0 N) zu verestern, denn die Loslichkeit in Pyridin und der Umsatz zum Carbamoylderivat werden dadurch haufig verbessert.Ein vollstandiger Abbau von Peptiden in der Grii13en-ordnung von 8-10 Aminosiiuren gelang rnit 0.5-1 mg Ausgangsmaterial.Die Methode wurde unter anderem bei der Untersuchung eines synthetischen Octapeptids der Sequenz H-Val- Der Vergleich der nach Totalhydrolyse und der nach sequentiellem Abbau bestimmten Racemisierungsanteile (Tabelle 1) 1aBt erkennen, da13 auch die Hydrolyse des Peptids in 6 N HCI zur Racemisierung beitragt. Ala