Stereochemistry of cyclization

Stereochemistry of Cyclization. Until now, we have been dealing with the formation of centers of asymmetry in compounds with an already-formed carbon skeleton. We must also consider the stereochemistry of the formation of such centers in the very process of the formation of the steroid skeleton, i.e., in cyclization reactions. In the majority of known methods of cyclization (see Table 4), adjacent to the newly formed ring there is a pre-existing or newly formed double bond, which raises the question of the stereochemistry of the reaction. Only comparatively rarely in the total synthesis of steroids does cyclization lead directly to the production of new centers of asymmetry. As an example we may mention the cyclization of 13,17-seco-16-carboxy-A -steroids of the type of 

Methods of Res olving Racemates. The chemical reactions used in the total synthesis of steroids lead in all cases to racemic dl compounds. Nevertheless, for practical use as biologically active substances and also for direct comparison with the natural steroids we must have the individual optical antipodes. For this purpose it is necessary to resolve the racemates. This is achieved by two groups of methods, chemical and enzymatic. 

The chemical method of resolving racemates consists of a sequence of reactions which is general in organic chemistry the formation of dias-tereo-isomers by the reaction of the racemate with some optically active compound, subsequent separation of these by crystallization or chromatography and, finally, the removal from each of the diastereoisomers separated of the optically active residue initially introduced, with the formation of the individual enantiomers. In the resolution of racemic steroids 

For resolving racemates, it has also been proposed to use the microbiological reduction and oxidation of oxygen functions in positions 3, 17, and 20, the formation of A -bonds, and the introduction of hydroxy groups in positions 6, 7, 9, 11, 14, 15, 16, 17, or 21 [106-111]. 

It is rather difficult to make a generalizing comparison of chemical and enzymatic methods of resolving racemates. In the majority of cases, both 

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Internal nucleophilic capture of seleniranium ion is governed by general principles similar to those of other electrophilic cyclizations.96 The stereochemistry of cyclization can usually be predicted on the basis of a cyclic TS with favored pseudoequatorial orientation of the substituents. 

It has been found that when 8,e-enolates bearing (3-siloxy substiments are subject to iodolactonization, the substituent directs the stereochemistry of cyclization in a manner opposite to an alkyl substituent. Suggest a TS structure that would account for this difference. 

Biosynthesis and Metabolism.—Pathways and Reactions. Two reviews of carotenoid biosynthesis discuss, respectively, the early steps and the later reactions." The former paper deals with the mechanism of formation of phytoene and the series of desaturation reactions by which phytoene is converted into lycopene, and also describes in detail the biosynthesis of bacterial C30 carotenoids. The second paper" presents details of the mechanism and stereochemistry of cyclization and the other reactions that involve the carotenoid C-1 —C-2 double bond and the later modifications, especially the introduction of oxygen functions. 

Cyclization of nitrile oxides with a four-atom intervening chain to the alkene always leads to 5,6-fused bicylic isoxazolines possessing a bridgehead C—N double bond. This is in contrast to nitrone cycliza-tions where competition to form bridged bicyclic isoxazolidines is observed. The alkenyl oximes (73) and (74) cyclize in typical fashion via nitrile oxide intermediates (Scheme 21).33a>36 The stereochemistry of cyclization here was studied both experimentally and by calculation. The higher stereoselectivity observed with the (Z)-alkene is typical. (Z)-Alkenes cycloadd much slower than ( >alkenes in intermole-cular reactions this is attributed to greater crowding in the transition state. Thus, intramolecular cycloaddition of (Z)-alkenes depends on a transition state that is heavily controlled by steric factors. 

Stereoselective radical cyclization of 1,5-cyclooctadienes. Winkler and Sridar14 have noted transannular effects on the stereochemistry of cyclization of these octadienes (equation I). Thus radical cyclization of cis-1 and of the corresponding ketone (3) is highly frans-selective and is more rrans-selective than that of the monosubstituted diene 5. Cyclization of a 3,8-disubstituted cyclooctene is... 

Two pinene cyclases have been isolated from sage (19,35). Electrophoretically pure pinene cyclase I converts geranyl pyrophosphate to (+)-a-pinene and to lesser quantities of (+)-camphene and (+)-limonene, whereas pinene cyclase II, of lower molecular weight, converts the acyclic precursor to (-)-B-pinene and to lesser quantities of (-)-a-pinene, (-)-camphene and (-)-limonene. Both purified enzymes also utilize neryl and linalyl pyrophosphate as alternate substrates for olefin synthesis. The availability of enzyme systems catalyzing formation of enantiomeric products from a common, achiral substrate has provided an unusual opportunity to examine the stereochemistry of cyclization. 

Quinolizidine derivatives formed by hydrogenation of the dicyano ketone 4 to catalyst loading affects the stereochemistry of cyclization, probably by isomerization. 

Intramolecular cyclizations offer a versatile method for the preparation of bicyclic and polycyclic ketones. Indeed, in favorable cases, reaction can ensue on simply heating the acyl halide " as well as on treatment with a Lewis acid, offering control of the product isolated (Scheme 3). However, the structural constraints imposed in detailed examination of specific ring systems in which the stereochemistry of cyclization can be determined may well preclude the deduction of more general conclusions about stereochemical control. 

Generally the oxygen atom of the nitrone moiety attacks the olefinic carbon atom which lies farther from the nitrone. The stereochemistry of cyclization is not specific sometimes cis-ring fusion takes place exclusively, while in other cases trans-ring fusion accompanies cis-fusion. For instance, the reaction of vV-methylhydroxylamine with trans- or cis-5-heptenal is stereospecific thus from the former the c/s-isoxazolidine... 

Scheme 4.58 Stereochemistry of cyclization of substituted 5-hexenyl radicals.

These cyclizations are usually highly stereoselective, with the stereochemical outcome being predictable on the basis of reactant conformation. " The stereochemistry of cyclization products in the decalin family can be predicted by assuming that cyclizations will occur through conformations which resemble chair cyclohexane rings. The stereochemistry at ring junctures is that expected for anti attack at the participating double bonds ... 

The stereochemistry of the carbinol was also shown not to affect the stereochemistry of cyclization. This was reported during the synthesis of estrone by Johnson and co-workers.Whether 50 or 51 was taken into the cyclization, a similar ratio of isomeric products was obtained. 

Carbohydrate alkenes derived by Wittig reaction of aldohexoses undergo radical cyclization to cyclopentane analogues, e.g., (46)— (47)(Scheme 11). The stereochemistry of cyclization was found to depend mainly on the substituent at C-2 of the original sugar... 

For research of synthetic opportunities of the developed approach, regio- and stereochemistry of cyclization as model substrates we used alkenes 2-7. It is necessary to note that recently in reaction of 2-pyridineselenenyl bromide analogous selenenyl chloride la with styrene 2 in methanol is received only solvoadduct - l-methoxy-l-phenyl-2-(2-pyridylselanyl)ethane - in quantitative yield [18]. 

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