Michael addition diastereoselectivity

Dramatic rate accelerations of [4 + 2]cycloadditions were observed in an inert, extremely polar solvent, namely in5 M solutions oflithium perchlorate in diethyl ether(s 532 g LiC104 per litre ). Diels-Alder additions requiring several days, 10—20 kbar of pressure, and/ or elevated temperatures in apolar solvents are achieved in high yields in some hours at ambient pressure and temperature in this solvent (P.A. Grieco, 1990). Also several other reactions, e.g, allylic rearrangements and Michael additions, can be drastically accelerated by this magic solvent. The diastereoselectivities of the reactions in apolar solvents and in LiClO EtjO are often different or even complementary and become thus steerable. 

The stereochemical outcome of the Michael addition reaction with substituted starting materials depends on the geometry of the a ,/3-unsaturated carbonyl compound as well as the enolate geometry a stereoselective synthesis is possible. " Diastereoselectivity can be achieved if both reactants contain a stereogenic center. The relations are similar to the aldol reaction, and for... 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

In contrast, the diastereoselectivity of the conjugate addition of a chiral alkenylcoppcr-phosphinc complex to 2-mcthyl-2-cyclopentenone was dictated by the chirality of the reagent63. The double Michael addition using the cyclopentenone and 3-(trimethylsilyl)-3-buten-2-one and subsequent aldol condensation gave 4 in 58 % overall yield. The first Michael addition took place from the less hindered face of the m-vinylcopper, in which chelation between copper and the oxygen atom fixed the conformation of the reagent. 

In the Michael addition of achiral enolates and achiral Michael acceptors the basic general problem of simple diastereoselection (see Section D.1.5.1.3.2.), as described in Section 1.5.2.3.2. is applicable. Thus, the intermolecular 1,4-addition of achiral metal enolates to enones, a.jS-unsat-urated esters, and thioamides, results in the formation of racemic syn-1,2 and/or anti-3,4 adducts. 

When chiral enolates or chiral Michael acceptors are used, for instance, when stereogenic centers are present in the substrate or when X or Y are chiral auxiliaries, both simple and induced diastereoselectivity is observed. This results, in principle, in the formation of four diastereomers 1 -4. The diastereoselectivity in the Michael addition of lithium enolates to enones can be rationalized by consideration of chelated transition states A-D372. 

For amide enolates (X = NR2), with Z geometry, model transition state D is intrinsically favored, but, again, large X substituents favor the formation of nt/-adducts via C. Factors that influence the diastereoselectivity include the solvent, the enolate counterion and the substituent pattern of enolate and enonc. In some cases either syn- or unh-products are obtained preferentially by varying the nature of the solvent, donor atom (enolate versus thioeno-late), or counterion. Most Michael additions listed in this section have not been examined systematically in terms of diastereoselectivity and coherent transition stale models are currently not available. Similar models to those shown in A-D can be used, however all the previously mentioned factors (among others) may be critical to the stereochemical outcome of the reaction. 

The intramolecular Michael addition of an achiral metal enolate is similarly subject to simple diastereoselection. 

Two closely related methods for the diastereoselective preparation of <5-oxo esters have been developed. The first method uses the chelated lithio enamine 2. These Michael donors are readily available from the tert-butyl ester of L-valine and jS-oxo esters. The Michael addition of this lithio enamine 2 to 2-(arylmethylene)propanedioates, followed by hydrolytic removal of the auxiliary, provides d-oxo esters with contiguous quaternary and tertiary carbon centers with high diastereoselectivity59 60. 

In general, the Michael addition of a-substituted amide dienolates to a,/j-unsaturated esters is a method with great future potential for the diastereoselective construction of adjacent tertiary and quaternary stereogenic centers80. 

Lactones have been ultilized as donors, as well as acceptors, in Michael additions giving products with excellent diastereoselectivity. Once the 7>faces of the enolate or the oi,/ -unsatu-rated lactone are effectively shielded by an appropriate substituent at a stereogenic center a to the olefin moiety, this results in the exclusive formation of the Irons-adduct. 

The diastereoselective intramolecular Michael addition of /(-substituted cyclohexcnoncs results in an attractive route to ra-octahydro-6//-indcn-6-ones. The stereogenic center in the -/-position of the enone dictates the face selectivity, whereas the trans selectivity at Cl, C7a is the result of an 6-exo-trig cyclization. c7.v-Octahydro-5//-inden-5-ones are formed as the sole product regardless of which base is used, e.g., potassium carbonate in ethanol or sodium hydride in THF, under thermodynamically controlled conditions139 14°. An application is found in the synthesis of gibberellic acid141. 

Successful methodology for diastereoselective Michael additions with chirality in the donor is so far limited to chiral cyclic enolates. The stereocontrol is mainly due to shielding of one of the jr-faces of the enolate by the ring substituent that resides at the stereogenic center. The (nmv-diastereoselective Michael addition of (5)-2-methyl-3-vinylcyclopentanonc illustrates this principle154-157. 

A very efficient method for annulations158 is based on the addition of lithium or silyl enolates to a-silylated enones as a key step. The diastereoselective 1,4-addition is followed by an aldol condensation. This procedure allows Michael additions under aprotic conditions, whereby the silyl substituent stabilizes the enolate of the Michael adduct preventing polymerization of the enone, 59 l63. 

Using 3-substituted cyclohexanones the /rans-diastereoselective synthesis of decalones and octahydro-1 //-indenones may be achieved 164 169. This method has been applied, for instance, in the synthesis of 19-norsteroids. In a related Michael addition the lithium enolate of (R)-5-trimethylsilyl-2-cyclohexenone reacts with methyl 2-propenoate selectively tram to the trimethylsilyl substituent. Subsequent intramolecular ring closure provides a single enantiomer of the bicyclo[2.2.2]octane170 (see also Section 1.5.2.4.4.). 

An interesting approach to zr n.v-2,3-disubstituted cyeloalkanones is offered by auxiliary controlled intramolecular Michael additions. The diastereoselectivity depends on the chiral alcohol used193> l94. When the borneol derivative 7 was used as substrate, a single diastereomer of 8 resulted when the reaction was performed at 25 "C under thermodynamic control with a catalytic amount of sodium hydride in benzene. 

Optically active y-alkoxycyclopentenones have become popular in the diastereoselective synthesis of hms-3,4-disubstituted cyclopentanones. The Michael addition to these cyclic enones catalyzed by sodium ethoxide in ethanol277 or by potassium tm-butoxide278 279 proceeds under kinetic control trans with respect to the y-substituent. 

The enolate of the 1,4-adduct, obtained after the stereoselective Michael addition step, as discussed in the previous sections, may be quenched in situ with various electrophiles. The fact that additional stereogenic centers may be formed via such tandem Michael addition/quench-ing procedures, giving products with high diastereoselectivity in many cases, extends the scope of these methods substantially. Furthermore these procedures occasionally offer the possibility of reversing the syn/anti diastereoselection. In the next sections pertinent examples of diastereoselective inter- and intramolecular quenching reactions will be discussed. 

When the cyclic enone is unsubstituted, but the resulting enolate is quenched with an electrophile under conditions of kinetic control the irons adduct is formed exclusively303. Particularly successful is the sequential Michael addition/enolate alkylation in diastereoselective routes to frans-a,/j-difunctionalized cycloalkanones and lactones304-308. The key steps in the synthesis of methyl ( + )-jasmonate (3)309-310 (syn/anti diastereoselection) and (-)-khushimone (4) (syn/anti and induced diastereoselection) illustrate this sequence311 (see also Section D. 1.1.1.3.). 

The use of enantiomerically pure (R)-5-menthyloxy-2(5.//)-furanone results in lactone enolates, after the initial Michael addition, which can be quenched diastereoselectively trans with respect to the /J-substituent. With aldehydes as electrophiles adducts with four new stereogenic centers arc formed with full stereocontrol and the products are enantiomerically pure. Various optically active lactones, and after hydrolysis, amino acids and hydroxy acids can be synthesized in this way317. 

This modification was used in the synthesis of (-)-avenaciolide. The key step is the trans-diastereoselective Michael addition of the lithium enolate of tert-butyl 2-(phenylse-leno)propionate (THF, — 78 CC) to (R)-5-octyl-2(5//)-furanone and subsequent trans-diastereoselective iodonation318. u e... 

A complete diastereoselective triple Michael addition to form a bicyclic ring structure is also known. In this reaction the new ring is formed by a M1MIRC reaction (see also Sec-... 

Consecutive Michael additions and alkylations can also be used for the diastereoselective synthesis of 5- and 6-membered ring systems. For instance when 6-iodo-2-hexenoates or 7-iodo-2-heptenoates are employed the enolate of the Michael adduct is stereoselectively quenched in situ to provide the cyclic compound with trans stereochemistry (>94 6 diastereomeric ratio). As the enolate geometry of the Michael donor can be controlled, high stereoselectivity can also be reached towards either the syn or anti configuration at the exocyclic... 

When the cnolate of an enone is brought into reaction with an enone, usually a carbocyclic system is prepared by two consecutive Michael additions (M1MIRC reactions). Due to the lower temperatures employed and the absence of diene polymerization these reactions are useful alternatives for Diels-Alder reactions and proceed in general with high diastereoselectivities. When neither enolate nor enone is cyclic a monocyclic system is formed 338 which can be converted into a bicyclic system when the Michael addition is followed by an aldol reaction339. When, however, the enolate is cyclic a bicyclic or a tricyclic system is formed340 341. 

The reactions of the lithium enolates of substituted 2-cyclohexenones and 2-cyclopentenones with ( )-l-nitropropene give a mixture of syn- and ami-products3. The lithium enolate of 3,5,5-trimethyl-2-cyclohexenone gives a mixture of the syn- and //-3.5,5-trimethyl-6-(l-methyl-2-nitroethyl)-2-cyclohexcnoncs in modest diastereoselection when the reaction mixture is quenched with acetic acid after. 30 minutes at —78 =C. When the reaction mixture is heated to reflux, tricyclic products are obtained resulting from intramolecular Michael addition of the intermediate nitronate ion to the enone moiety. 

Modest diastereoselectivity was observed for the Michael addition reaction of rac-14 to 13 and these diasteromers 28-a/28-b could be separated and individually identified. The minor isomer 28-b was found to readily undergo conversion to benzoxathiin 30 when treated with BF3 etherate, presumably through the transient intermediate 29-b. The major isomer 28-a was converted by BF3 etherate to intermediate 29-a. Conversion to 30 required the use of the stronger Lewis acid TMSOTf, presumably due to the cis-stereochemistry between the methoxy and the neighboring hydrogen, making it more difficult to eliminate/aromatize. 

Diastereoselective domino Michael addition/Friedel-Crafts/SN-type cyclizations which allow the synthesis of bridged tetrahydroquinolines such as 2-405 have been observed by Yadav and coworkers when a mixture of anilines 2-403 and 6-hydroxy-a, 3-unsaturated aldehydes 2-404 were treated with catalytic amounts of Bi(OTf)3 or InClj in MeCN at 80 °C (Scheme 2.96) [222],... 

The Michael addition of phosphine nucleophiles to nitroalkenes provides novel P-nitro phosphonates, as in Eq. 4.32.38 Yamashita and coworkers have shown that the nucleophilic addition of Ph2POH to chiral nitroalkenes derived from sugars proceeds stereoselectively to the S- -isomer (Eq. 4.32) in high diastereoselectivity (ds 11 1). 

The Michael addition of enamines to nitroalkenes proceeds with high syn selectivity. The syn selectivity is explained by an acyclic synclinal model, in which there is some favorable interaction between the nitro group and the nitrogen lone pair of the enamine group (Eq. 4.67). 86a-b Both Z- and E-nitrostyrenes afford the same product in over 90% diastereoselectivity. 

The Michael addition of nitromethane to vinylogous esters of / -protected amino acids proceeds with good yields and with good diastereoselectivity (Eq. 4.135).195... 

The (//(-configured center is formed by a diastereoselective Michael addition of piperidazine to the (4 )-cster 400, easily available from mannitol, and a subsequent cyclization gives the corresponding lactam 401. Small amounts of by-products 402 and 403 are also formed (Equation 56) <1996HCA1995>. 

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