Stereoselectivity iodolactonization

Fig. 3.47. Stereoselective iodolactonization (top) and stereoselective bromoetherifi-cation (bottom). See Figure 1.39 for the dehalo-genations of the iodolactone and of the bromoether shown.

Stereoselective iodolactonization of small achiral molecules is a very useful methodology to create a tetrahydrofuran framework leading to 3, 5 -C-branched carbohydrates [82]. Starting... 

Stereoselective iodolactonization stereoselective epoxidation. lodolactoniza-tion of 7,8- and 8,c-unsaturated acids with iodine in the presence of NaHCOs exhibits only slight stereoselectivity (kinetic control). In the absence of base, equilibration occurs to ive the more stable rrans-isomers. Epoxides are formed in quantitative yield on methanolysis (CH3OH + NazCOs) of the iodolactones. Examples ... 

Haas J, Piguel S, Wirth T. Reagent-controlled stereoselective iodolactonizations. Org. Lett. 2002 4 2) 297 300. 

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""" ... 

Because the Corey synthesis has been extensively used in prostaglandin research, improvements on the various steps in the procedure have been made. These variations include improved procedures for the preparation of norbomenone (24), alternative methods for the resolution of acid (26), stereoselective preparations of (26), improved procedures for the deiodination of iodolactone (27), alternative methods for the synthesis of Corey aldehyde (29) or its equivalent, and improved procedures for the stereoselective reduction of enone (30) (108—168). For example, a catalytic enantioselective Diels-Alder reaction has been used in a highly efficient synthesis of key intermediate (24) in 92% ee (169). 

Under kinetic conditions, iodolactonization reflects reactant conformation. Several cases illustrate how the stereoselectivity of iodolactonization can be related to reactant conformation. For example, the high stereoselectivity of 1 corresponds to proximity of the carboxylate group to one of the two double bonds in the preferred reactant... 

On page 313, the effect of methyl substitution on the stereoselectivity of a,a-diallylcarboxylic acids under iodolactonization conditions was discussed. Consider the two compounds shown and construct a reaction energy profile for... 

SCHEME 2. The stereoselective Diels-Alder reaction leading to an important iodolactone prosta-glandine precursor... 

Birch reduction-alkylation of 5 with 2-bromoethyl acetate was carried out with complete facial selectivity to give 57. This tetrafunctional intermediate was converted to the bicyclic iodolactone 58 ( > 99% ee) from which the radical cyclization substrate 59 was prepared. The key radical cyclization occurred with complete regio- and facial-selectivity and subsequent stereoselective reduction of the resulting tertiary radical gave 60 with the required trans BC ring fusion.The allylic alcohol rmit of (+)-lycorine was obtained by a photochemical radical decarboxylation, 62 63. 

Few applications of cyclizations to form fused ring 8-lactones or tetrahydropyrans are found. Two consecutive bromolactonizations were used to effect stereoselective dihydroxylation of a cyclohexadi-enone system in a total synthesis of erythronolide B (Scheme S).64 Iodolactonization of an NJV-di-ethylbenzamide derivative to form a ds-fused benzolactone was a key step in a recent synthesis of pancratistatin.641 A di-fused tetrahydropyran was produced in good yield by intramolecular oxymercura-tion as shown in equation (17),59 although attempts to cyclize a more highly functionalized system have been reported to fail.65 Formation of a fused ring tetrahydropyran via an anti-Markovnikov 6-endo sel-enoetherification has been reported in cases where steric and stereoelectronic factors disfavor a 5-exo cyclization to a spirocyclic structure.38... 

Examples of 1,3-asymmetric induction in cyclizations to 8-lactones have been observed. Iodolactonization of 3-methyl-5-hexenoic acid to a 8-lactone under equilibrating conditions showed reasonable stereoselectivity (6 1 cis trans).l20b Recent studies have examined the formation of 8-lactones from cyclization of 5-hexenoic acids with a homoallylic oxygen substituent at C-3.135 Selenolactonization of 3-hydroxy-5-hexenoic acid under conditions of kinetic control provided the trans lactone in modest yield (40%) and high stereoselectivity.13515 Equilibrating conditions led to a slight preponderance of the cis... 

The stereoselectivity of iodolactonization of 2-substituted 4-pentenoic acids (with OH, NHTs or CH2OH group at C-2) by NIS or I2 can be increased in the presence of (PriO)4Ti223. In contrast, the stereochemistry of analogous haloetherification of 2-hydroxymethyl-4-penten-l-ol is reversed by the addition of (Pr O Ti223. 

The following cyclic example illustrates the stereoselective aspect of iodolactonization. 

We have said little in this chapter about the stereospecific transformation of one ring into another but we now have an opportunity to remedy that defect. Iodolactonization of a terminal alkene with a stereogenic centre next to it is as stereoselective as (if not more than) the example we have just seen. The two side chains on the ring end up trans to one another as we should expect. This is a purely stereoselective process as the alkene has no geometry. 

The more obvious way to make this epoxide would be by epoxidation of the ester of the original unsaturated acid. However, the stereoselectivity in that reaction is nowhere near as good as in the iodolactonization. We shall return to this subject when we discuss reactions in acyclic systems in the next chapter. 

Iodolactonization of yfi-unsaturated amides. Halolactonization (I2 or NBS) of a-substituted "y,8-unsaturated amides in DME/H,0 at room temperature gives predominantly fra/w-2,4-disubstituted y-butyrolactones (equation I). This 1,3-stereoselectivity is in sharp contrast to the moderate 1,3-cw-selectivity observed with a-substituted y,8-unsaturated acids (8,257 9,248). Both diastereomers of a, 3-disubstituted y.S-unsaturated amides are converted into 2.4-rram-2,3,4-trisub tituted lactones (equation II). 

The stereochemistry of cyelization is induced by the presence of a substituent near the double bond of alkenoic acids. The stereoselectivity towards cis- or mms-iodolactones may be achieved under either kinetic or thermodynamic conditions. 

When performed with iodine in acetonitrile in the absence of base18a 18b under thermodynamic conditions, the iodolactonization of 3-substituted 4-pentenoic acids proceeds with high 1,2-asymmetric induction. The equilibration of the protonated iodolactone intermediate leads to the more stable rnms-isomer which is obtained in good yield and very high stereoselectivity. Thus, treatment of 3-methyl-4-pentenoic acid (1) with iodine in acetonitrile at 0°C for 2 hours gives the corresponding iodolactone 2 in 84% yield with a d.r. (tram/cis) of 91 918a. 

The stereoselectivity observed in the cyclization of 4-unsaturated amides is dependent on the electrophilic halogen species. With /V-chlorosuccinimide the trans/cis ratio is reduced to 3 2, while with A -bromosuccinimide the fra .v-isomer is obtained in >98% purity. The structures of the iodolactones 4 were confirmed by reduction with tributyltin hydride to the trans- and rw-2.4-dimethy]-y-lactones. The high 1,3-trans selectivity strongly contrasts with the results obtained when 2-methyl-4-pentenoic acid is cyclized under thermodynamic conditions with iodine in acetonitrile. In this case a 92% yield and a 32 68 mixture of the f/ww/m-com pounds was obtained. 

A number of chiral y,<5-unsaturated amides (e.g., 7) have been prepared utilizing ( + )-(2R,6R)-2,6-bis-(benzyloxymethyl)piperidine37 as chiral auxiliary with stereoselective alkylation in the a-position. The subsequent iodolactonization affords the 3,5-/tw ,v-ci substituted 2(3/7)-furail ones in diastcreoselectivities >90 10. 

Low asymmetric induction is observed when (R)-3-benzyloxycarbonylamino-5-hexenoic acid (1, R = H) is iodolactonized under kinetic conditions (iodine/potassium iodide/sodium hydrogen carbonate). A mixture of the cis- and trww-iodo-5-lactones (60 40) in 94% yield is obtained. Better stereoselectivity can be obtained when the. V-benzyl derivative 1 (R = Bn) is cyclized under the same conditions. In fact, an 86 14 cisjtram) ratio is observed, showing that halolactonization is kinetically favored over halocarbamation, with the bulky substituent at nitrogen inducing high selectivity7. n n... 

Low yields are observed when substrate 9 is iodolactonized under kinetically controlled conditions. However, yields increase when the cyclization is carried out on the corresponding silyl ethers, and the stereoselection increases in favor of the rra/w-isomer with an increase in the bulk of the silyloxy group8 9. 

Stereoselective Cyclizations. Sultams have been demonstrated to be superior sources of chirality in selected cases of iodolactonizations, oxidative 1,5-diene cyclizations, and Claisen-type rearrangements of p-acetoxyl substrates. ... 

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