Ring stereoselectivity

When Ireland wanted to introduce a cyclopropane ring stereoselectively into a pentacyclic system containing an enone, he first reduced the ketone to an alcohol (DIBAL gave only the equatorial alcohol) that controlled the stereochemistry of the Simmons-Smith reaction. Oxidation with Cr(VI) put back the ketone. 

Iodocyclization of carbamates involving electron-deficient alkenes such as a,/l-unsaturated esters is greatly facilitated by the use of silver triflate and proceeds with excellent trans ring stereoselectivity. It is worth mentioning, however, that the resultant iodides can undergo epimerization, whose rate depends on the solvent used in the process21. 

Oxygenation of ( )- and (Z)-4-phenyl-l-(2-phenylcyclopropyl)but-l-ene (32) also proceeded in high yield, with syn ring stereoselectivity, to give a mixture of (E)- and (Z)-l-dioxolanyl-4-phenylbut-l-enes 33. Best stereoselectivity was obtained with diphenyl disulfide catalysis. ... 

Chiral olefins (racemic or enantiomerically pure) can provide two diastcreomers when carbene (carbenoid) CX2 is added, or four diastereomers when carbene (carbenoid) CXY is employed. Cyclic alkenes (on-ring stereoselection) are considered before acyclic olefins (acyclic stcrcosclcction) are discussed. 

Chemoselectivity competition between different functional groups in a molecule. Regioselectivity e.g. ortAo versus para substitution in aromatic rings. Stereoselectivity enantioselectivity and diastereoselectivily. 

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 early Escherunoser-Stork results indicated, that stereoselective cyclizations may be achieved, if monocyclic olefins with 1,5-polyene side chains are used as substrates in acid treatment. This assumption has now been justified by many syntheses of polycyclic systems. A typical example synthesis is given with the last reaction. The cyclization of a trideca-3,7-dien-11-ynyl cyclopentenol leads in 70% yield to a 17-acetyl A-norsteroid with correct stereochemistry at all ring junctions. Ozonolysis of ring A and aldol condensation gave dl-progesterone (M.B. Gravestock, 1978 see p. 279f.). 

Synthetically useful stereoselective reductions have been possible with cyclic carbonyl compounds of rigid conformation. Reduction of substituted cyclohexanone and cyclopentan-one rings by hydrides of moderate activity, e.g. NaBH (J.-L. Luche, 1978), leads to alcohols via hydride addition to the less hindered side of the carbonyl group. Hydrides with bulky substituents 3IQ especially useful for such regio- and stereoselective reductions, e.g. lithium hydrotri-t-butoxyaluminate (C.H. Kuo, 1968) and lithium or potassium tri-sec-butylhydro-borates or hydrotri-sec-isoamylborates (=L-, K-, LS- and KS-Selectrides ) (H.C. Brown, 1972 B C.A. Brown, 1973 S. Krishnamurthy, 1976). 

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

Oxidation of olefins and dienes provides the classic means for syntheses of 1,2- and 1,4-difunctional carbon compounds. The related cleavage of cyclohexene rings to produce 1,6-dioxo compounds has already been discussed in section 1.14. Many regio- and stereoselective oxidations have been developed within the enormously productive field of steroid syntheses. Our examples for regio- and stereoselective C C double bond oxidations as well as the examples for C C double bond cleavages (see p. 87f.) are largely selected from this area. 

The most common stereoselective syntheses involve the formation and cleavage of cyclopentane and cyclohexane derivatives or their unsaturated analogues. The target molecule (aff-cts)-2-methyl-l,4-cyclohexanediol has all of its substituents on the same side of the ring. Such a compound can be obtained by catalytic hydrogenation of a planar cyclic precursor. Methyl-l,4-benzoquinone is an ideal choice (p-toluquinone M. Nakazaki, 1966). 

The C—C double bond in the cyclopentene ring can be cleaved by the osmium tetroxide-periodate procedure or by photooxygenation. The methoxalyl group on C-17 can, as a typical a-dicarbonyl system, be split off with strong base and is replaced by a proton. Since this elimination occurs with retention of the most stable configuration of the cyclization equi-hbrium, the substituents at C-17 and C-18 are located trans to one another. The critical introduction of both hydrogens was thus achieved regio- and stereoselectively. 

Cyclopentene derivatives with carboxylic acid side-chains can be stereoselectively hydroxy-lated by the iodolactonization procedure (E.J. Corey, 1969, 1970). To the trisubstituted cyclopentene described on p. 210 a large iodine cation is added stereoselectively to the less hindered -side of the 9,10 double bond. Lactone formation occurs on the intermediate iod-onium ion specifically at C-9ot. Later the iodine is reductively removed with tri-n-butyltin hydride. The cyclopentane ring now bears all oxygen and carbon substituents in the right stereochemistry, and the carbon chains can be built starting from the C-8 and C-12 substit""" ... 

Proton-catalyzed olefin cyclizations of open-chain educts may give tri- or tetracyclic products but low yields are typical (E.E. van Tamelen, 1968, 1977 see p. 91). More useful are cyclizations of monocyclic educts with appropriate side-chains. The chiral centre to which the chain is attached may direct the steric course of the cyclization, and several asymmetric centres may be formed stereoselectively since the cyclizations usually lead to traas-fused rings. 

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-... 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

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