Open synthesis

Nicolaou, KC, Prasad, C VC, Somers, PK, Hwang, CK, Activation of 7-emio over 6-exo epoxide openings. Synthesis of oxepane and tetrahydropyran systems, J. Am. Chem. Soc., Ill, 5335-5340, 1989. 

Oxidative ring opening Synthesis of ketocarboxylic acids... 

An efficient diketene ring-opening synthesis of dihydropyridine derivatives using SBA-15 sulfonic acid-modified mesoporous substrate as a green and reusable... 

Orthoester Claisen rearrangement, -, Replacement, -, Ring opening, - Synthesis, -, Transetherification, --, effect of bases on - of j8-elimination 28,944 Germanes... 

Proudfoot, J.R. and Djerassi, C. (1984) Stereochemical eflfects in cyclopropane ring openings synthesis and isomerisation of petrosterol and all three of its trans cyclopropane diastereoisomers. ). Am, Chem, Soc 106, 5613-5622. 

Interest in AIN, GaN, InN and their alloys for device applications as blue light-emitting diodes and blue lasers has recently opened up new areas of high-pressure synthesis. Near atmospheric pressure, GaN and InN are nnstable with respect to decomposition to the elements far below the temperatures where they might melt. Thus, large boules of these materials typically used to make semiconductor devices caimot be grown from the... 

Substructure searches provide another method of searching for available starting materials. They arc used primarily for planning the synthesis of combinatorial libraries. After the target compound has been dissected into a set of suitable precursors, substructure searches can provide for each of them a series of representatives of a certain class of compounds, Siibsti ucturc searches enable the user to specify attributes such as open sites or atom lists at certain positions of the structure. Figure 10.3-38 shows the possible specification elements for the query in a substructure search. 

Figure 10.3-39. A substructure search in a catalog of fine chemicals. The precursor illustrated may be needed for the synthesis of a library, A substructure is defi ned by setting an open site at the position of the R group. Some representative examples of the 69 compounds in the Acros catalog which were obtained are shown.

The strategic bond is disconnected by just clicking with the mouse on it. A suitable synthesis precursor is then generated automatically by WODCA by adding appropriate atoms or groups to the open valences. 

If an open-chain organic molecule contains an electron acceptor and an electron donor site, two carbon atoms may be combined intramolecularly. This corresponds to the synthesis of a monocyclic compound. 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

The last group of reactions uses ring opening of carbonyl or 1-hydroxyalkyl substituted cyclopropanes, which operate as a -synthons. d -Synthons, e.g. hydroxide or halides, yield 1,4-disubstituted products (E. Wenkert, 1970 A). (1-Hydroxyalkyl)- and (1-haloalkyl)-cyclopropanes are rearranged to homoallylic halides, e.g. in Julia s method of terpene synthesis (M. Julia, 1961, 1974 S.F. Brady, I968 J.P. McCormick, 1975). 

Cyclopentene-l-carboxaldehydes are obtained from cyclohexene precursors by the sequence cyclohexene - cyclohexane-1,2-diol -> open-chain dialdehyde - cyclopentane aldol. The main advantage of this ring contraction procedure is, that the regio-and stereoselectivity of the Diels-Alder synthesis of cyclohexene derivatives can be transferred to cyclopentane synthesis (G. Stork, 1953 G. BUchi, 1968). 

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from add derivatives by alkylation (see p. 45ff,), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethyicyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial ds-trans mixture, e.g. by distillation or chromatography. 

The benzylidene derivative above is used, if both hydroxyl groups on C-2 and C-3 are needed in synthesis. This r/vzns-2,3-diol can be converted to the sterically more hindered a-cpoxide by tosylation of both hydroxy groups and subsequent treatment with base (N.R. Williams, 1970 J.G. Buchanan, 1976). An oxide anion is formed and displaces the sulfonyloxy group by a rearside attack. The oxirane may then be re-opened with nucleophiles, e.g. methyl lithium, and the less hindered carbon atom will react selectively. In the following sequence starting with an a-glucoside only the 2-methyl-2-deoxyaltrose is obtained (S. Hanessian, 1977). 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

Two approaches to convergent steroid syntheses are based on the thermal opening of benzocyclobutenes to the o-quinodimethane derivatives (see p. 80 W. Oppolzer, 1978 A) and their stereoselective intramolecular Diels-Alder cyclizations. T, Kametani (1977 B, 1978) obtained (+ )-estradiol in a six-step synthesis. The final Diels-Alder reaction occurred regio- and stereoselectively in almost quantitative yield, presumably because the exo transition state given below is highly favored over the endo state in which rings A and D would stcrically inter-... 

Other aromatic best-sellers in the pharmacy are given below. Syntheses of these compounds are simple and may be outlined by the interested reader himself. The only common open-chain synthetic drug is meprobamate. Its conventional synthesis is given. 

The mechanism of the Hantzsch s synthesis was studied at a very early stage by several authors. The intermediates were generally assumed to be open-chain a-thioketones, but in a series of papers by Murav eva and Schukina (470, 490) the isolation of hydroxythiazolines from the reaction between a-haloketones and a variety of thioureas was reported. 

Alkene synthesis via alcohol dehydration is complicated by carbocation rearrangements A less stable carbocation can rearrange to a more sta ble one by an alkyl group migration or by a hydride shift opening the possibility for alkene formation from two different carbocations... 

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