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Herein, we report the formal synthesis of (+)-discodermolide (1), a promising anticancer agent of sponge origin, in 24 linear steps, with 35 steps in total. The route proceeds from lactone 2, a building block containing the common 1,2-anti-2,3-syn stereotriad found in each of the three subunits, methyl ketone 4 (C1−C6), vinyl iodide 7 (C9−C14), and iodide 8 (C15−C24) utilized for the construction of 1. The key fragment union was achieved by a Suzuki cross-coupling between 7 and 8.

Various new N-aryl oxindoles were synthesized as intermediates for the preparation of pharmacologically active 2-(N-arylamino)-phenylacetic acids. Two novel approaches were explored for the construction of diarylamine and N-aryl oxindole core structures, in addition to Buchwald-arylamination and Smiles rearrangement. Condensation of anilines with 2-oxo-cyclohexylidene-acetic acid derivatives and subsequent dehydrogenation is a new and viable method for the preparation of N-aryl oxindoles.

Coupling of C9-14 (4) and C15-21 (5a) fragments to produce the cis-trisubstituted olefin was achieved using Suzuki-type coupling conditions employed by Marshall (5a/tert-BuLi/B-OMe-9-BBN added to 4/Cs2CO3/Pd(dppf)2). The terminal (Z)-diene moiety was attached to aldehyde 10 by using a sequential Nozaki−Hiyama allylation and Peterson olefination sequence; careful monitoring of the disappearance of both diastereomeric β-hydroxysilanes was found to be essential for achieving a high yield. In the oxidation of alcohols 12 and 16 to 13 and 7, respectively, using iodobenzene diacetate and TEMPO, addition of a trace of water was found to be crucial for complete conversion. The C8-9 (Z)-olefin functionality was introduced on to aldehyde 13 using a Still−Gennari HWE reaction. Subsequent carbamate installation at C-19 followed by a reduction/oxidation sequence gave the title fragment C7-24 (7) ready to be coupled with the C1-6 fragment, which is described in Part 2 of this series.

The decahydroisoquinoline derivative NVP-ACQ090 is a potent and selective antagonist at the somatostatin sst3 receptor. The original research synthesis of NVP-ACQ090 comprises a main chain of nine linear steps and two side chains of three and steps, respectively. This synthesis is highly convergent, but very complex and expensive, and involves several reagents that are not acceptable for a large scale synthesis. In chemical development, all the unacceptables could be replaced, and the overall efficiency of the synthesis was much improved.

3- Substituted octahydrobenzo[g]quinolines are important intermediates for pharmaceutically active compounds. A short, efficient synthesis, which is feasible for large-scale manufacturing of rac-(3S,4aR,10aR)-6-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylic acid methyl ester is presented. As starting materials the cheap and readily available 1,6-dimethoxynaphthalene and ethoxymethylenecyanoacetic acid ethyl ester were chosen. All atoms of the skeleton were introduced in the first step, by the reaction of 7-lithiated 1,6-dimethoxynaphthalene with ethoxymethylenecyanoacetic acid ethyl ester. Subsequent hydrogenation, followed by Birch reduction and acidic cyclization gave the 6-methoxy-2,3,4,4a,5,10-hexahydrobenzo[g]quinoline-3-carboxylic acid·hydrochloride in high yield. The trans fusion of the two six-membered rings was established after NaBH4 reduction. After esterification, n-propylation, and kinetic protonation of an intermittantly formed trimethylsilylketene acetal, the d...

cis-4,5,7a,8,9,10,11,11a-Octahydro-7H-10-methylindolo[1,7-bc][2,6]naphthyridine (rac-4) (SDZ SER-082) is a selective and potent 5-HT2C/2B receptor antagonist, exerting weak affinity towards the 5-HT2A receptor site. The compound 4 was found to be a potential development candidate in several CNS indications. The key step in the initial synthesis was the photocyclization of the indolyl tetrahydropyridino-carbamic acid ethyl ester 1 to afford the cis/trans-naphthyridine 2/3. This process turned out to be inefficient for a scale-up. Three alternative synthetic routes A, B and C are discussed: The 'Imino-Diels-Alder' reaction applying indoline/formaldehyde/cyclopentadiene (route A) and the intramolecular Heck cyclization of 7-bromo-2,3-dihydro-1-[(1,2,5,6-tetrahydro-1-methyl-4-pyridyl)-carbonyl]-1H -indole (10) (route B) were surpassed in their synthetic efficiency by the Friedel-Crafts cyclization of 4-(2,3-dihydroindole-1-carbonyl)-1-methylpiperidin-3-one (16) (route C), followed by reduction to give rise to the racemic naphthyridine rac-4. It was subjected to resolution by applying a kg scale repetitive chromatography on a chiral stationary phase to give (+)-(7aS,11aR)-4 in over 90% yield and 99.9% enantiomeric purity.

Diastereo- and Enantioselective Reduction of beta;-Keto Esters Derived from Cyclopentanone, Cyclohexanone, Piperidone and Tetralone by ‘Non-fermenting’ Baker's Yeast Under ‘non-fermenting’ conditions, i.e. in tap water, in the absence of nutrients baker's yeast (25–380 g/g of substrate, aerobic) reduces β-keto esters such as those mentioned in the title with better selectivity than under the normally employed ‘fermenting’ conditions (sugar and nutrients, CO2 development). With the β- keto esters containing the tetralone substructure, large amount of yeast are required (250–380 g/g); the substrate disappears in the biomass, and the desired reduction product can be extracted after reaction times of up to a week at 30°. The configuration of most products(16–24) is established. Generally, the (R)-β-keto ester is reduced faster than the (S)-enantiomer (the two esters are in equilibrium under the reactio conditions), and the hydride transfer takes place preferentially from the diastereotopic Re-face. The β-hydroxy esters thus available are useful starting materials for syntheses of enantiomerically pure compounds (EPC).