Synthesis of P-Blockers

The introduction of MA -diethylurea is carried out at a fairly early stage of the process with an expensive reagent, diethylcarbamoyl chloride (DECC). Being labile, this unit 

2 Ring-Closing Metatheses as a Pathway to Chiral Compounds  

We were dehghted by the radical ring-opening reaction described above and envisaged that quenching of in situ-generated homoallyl radical (Fig. 30.1) with allyl tri-n-butyltin should lead to the formation of gem-diallyl derivative.  

Our next task was to perform ring-closing metathesis reactions to secure novel spiro-cyclopentyl derivatives. Compound 90 was treated with Grubbs catalyst in CH2CI2 at 

Radical-induced diallylation of xanthate gave 111 RCM reaction and catalytic hydrogenation produced the bis-spiro derivative (113). Similarly the other isomer 

---

Both saturated (50) and unsaturated derivatives (51) are easily accepted by lipases and esterases. Lipase P from Amano resolves azide (52) or naphthyl (53) derivatives with good yields and excellent selectivity. PPL-catalyzed resolution of glycidyl esters (54) is of great synthetic utiUty because it provides an alternative to the Sharpless epoxidation route for the synthesis of P-blockers. The optical purity of glycidyl esters strongly depends on the stmcture of the acyl moiety the hydrolysis of propyl and butyl derivatives of epoxy alcohols results ia esters with ee > 95% (30). 

Lipase-catalyzed enantioselective transesterification of 0-substituted-l,2-diols is another practical route for the synthesis of P-blockers. Lipase PS suspended in toluene catalyzes the transesterification of (63) with vinyl acetate to give the (5)-ester in 43% yield and >98% ee (78). The desired product, optically pure (R)-ttitylglycidol, is then easily obtained by treating the ester with alcohoHc alkaU. Moreover, Pseudomonas Hpase catalyzes the acylation of oxazohdinone (64) with acetic anhydride in very good yield and selectivity (74). PPL-catalyzed transesterification of a number of /n j -norbomene derivatives proceeds in about 30% yield and 92% ee (79,80). 

Scheme 6. Catalytic asymmetric synthesis of P-blockers using (k)-LLB as a catalyst...

The synthetic utihty of the above transformations stems from the fact that many monoesters obtained as a result of hydrolysis may be converted to pharmaceutically important intermediates. For example, the optically active glycerol derivative (27) is a key intermediate in the production of P-blockers. Akyl derivative (25) may be converted into (5)-paraconic acid [4694-66-0] ((5)-5-oxo-3-tetrahydrofurancarboxyhc acid) that is a starting material for the synthesis of (3R)-A-factor. The unsaturated chiral cycHc monoacetate (31) is an optically active synthon for prostaglandins, and the monoester (29) is used for the synthesis of platelet activating factor (PAF) antagonists. 

The alkane hydroxylase from Pseudomonas oleovorans is particularly suitable for the epoxidation of terminal aliphatic double bonds and enables rapid access to the (3-blocker metoprolol (Scheme 9.14) [113,116]. Complementing this regioselectivity, chloroperoxidases are particularly suitable biocatalysts for the epoxidation of (ds substituted) subterminal olefins [112,117]. This enzyme also accepts terminal olefins and is utilized for the effident synthesis of P-mevalono-ladone [118]. 

Chiral polymers can be obtained in two different ways. The use of a chiral catalyst during polymerization can lead to helical structures, as observed in polysaccharides. The other synthesis path uses chiral monomers, which are polymerized to give a chiral polymer capable of folding to a supramolecular stmcture [20]. For application in HPLC, all of these polymers must be coated onto silica, since they are imable to withstand the high pressures encountered in HPLC. Currently, chiral stationary phases based on polyacrylates or polymethacrylates play only a minor role. Chirasphere (Merck) is derived from a silica material coated with poly(N-acryloyl-(S)-phenylalanine ethyl ester) and can be used for the separation of P-blockers in the normal-phase mode. The chiral polymethacrylates Chiralpak OP and Chiralpak OT (Daicel) are able to separate aromatic compounds into their enantiomers. 

Peukert S, Brendel J, Pirard B, Briiggemann A, Below P, Kleemann HW, Hem-merle H, Schmidt W. Identification, synthesis, and activity of novel blockers of the voltage-gated potassium channel Kvl.5. J Med Chem 2003 46 486-98. 

The synthesis of benzo[Z>]furan derivatives has become a very active field because these molecules have been recently identified as having a variety of biological activities. For example, they can function as inhibitors of protein tyrosine phosphatase IB with antihyperglycemic properties <00JMC1293>, as well as potent and short-acting p-blockers in the treatment of various cardiovascular diseases . An inexpensive, reusable clay has been utilized to catalyze a facile cyclodehydration under microwave without solvent to form 3-substituted benzo[2>]furans from substituted a-phenoxy acetophenones 104. One of the important features of this procedure is that all the selected cyclodehydration reactions are complete in less than 10 minutes <00SL1273>. 

The synthesis of a typical p-blocker starts with the mono-alkylation of catechol to give the ether (19-1). Application of the standard side chain budding sequence leads to the nonselective (3-blocker oxprenolol (19-2) [16] (the olol ending is approved USAN nomenclature for (3-blockers). Atenolol (19-5) is one of the most widely used (3i selective agents. The requisite phenol (19-4) can be obtained by ester interchange of methyl 4-hydroxyphenylacetate (19-3) with ammonia. Elaboration of the thus obtained intermediate (19-4) via the customary scheme then affords atenolol (19-5) [17]. 

Diols obtained from the catalytic AD of aryloxyallyl ethers, such as those of entries 8,9, and 12, are useful as precursors for the synthesis of the pharmacologically important P-blockers [49],... 

Yang W, Xu J-H et al (2006) Asymmetric reduction of ketones by employing Rhodotorula sp. AS2.2241 and synthesis of the P-blocker (R)-nifenalol. Tetrahedron Asymmetry 17 1769-1774... 

Di Nunno, L. Franchini, C. Scilimati, A. Sinicropi, M. S. Tortorella, P. Chemical and hemoenzymatic routes to l-(benzothiazol-2-yl-sulfanyl)-3-chloropropan-2-ol, a precursor of drugs with potential /-blocker activity. Tetrahedron Asymmetry 2000, 11, 1571-1583. Cavelier, F. First synthesis of the enantiomerically pure a-hydroxy analogue of S-tert-butyl cysteine. Tetrahedron Asymmetry 1997, 8, 41-43. 

The (—) isomer of the L-type calcium channel blocker (+)-niguldipine is dexniguldipine. This agent binds to an intracellular domain of P-gp with a K, of 10 nm. In addition, this compound can block RNA synthesis at 5 pM and possesses some anticancer activity (302). Currently, only a few studies have been conducted to evaluate the use of this compound as a P-gp modulator. Definitive results are yet to be reported. 

Scientists at Merck have reported a number of biocatalytic routes derived from screening various microorganisms targeted to produce key intermediates that are then combined with chemical reactions to prepare the target molecule. The biocatalytic step was often carried out by necessity as a result of poor chemical yield, low optical purity, or both. 6-Bromo-P-tetralone (2) was reduced to (S)-6-bromo-P-tetralol (3) by the yeast Trichosporon capitatum MY 1890 (Scheme 19.6).79 The tetralol 3 is a key intermediate for the synthesis of MK-0499 (4), a potassium channel blocker. The (S)-P-tetralol 3 was produced in gram quantities with an ee of >99% to support further development of MK-0499. Baker s yeast was tested for its ability to carry out this reduction but showed insignificant product formation. 

Because thioamides inhibit the synthesis of new thyroid hormone and do little to inhibit the activity of circulating thyroid hormone, p blockers are needed to control the hypertension and tachycardia of hyperthyroidism in the first few weeks of therapy. In addition, adrenergic receptors are upregulated (there is a higher population in the vasculature) in the hyperthyroid patient, this it is important to block these P receptors and thereby reduce the blood pressure. With return to euthryroid condition, the receptor number decreases. 

Prostaglandin synthesis. Nonsteroidal anti-inflammatory drugs (NSAIDs), e.g. indomethacin, attenuate the antihypertensive effect of p-adrenoceptor blockers and of diuretics, perhaps by inhibiting the synthesis of vasodilator renal prostaglandins. This effect can also be important when a diuretic is used for severe left ventricular failure. 

In Chapter 43 we also gave the structure of timolol, a thiadiazole-based p-blocker drug for reduction of high blood pressure. This compoimd has an aromatic 1,2,5-thiadiazole ring system and a saturated morpholine as well as an aliphatic side chain. Its synthesis relies on ring formation by rather a curious method followed by selective nucleophilic substitution, rather in the style of the last synthesis. The aromatic ring is made by the action of S2CI2 on cyanamide . 

---