Michael addition stereochemistry

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

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... 

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. 

Herein, the stereogenic center in 2-12 controls the stereochemistry in the way that the Michael addition occurs from the less-hindered a-face of the enolate to the si-side of the crotonate 2-13 according to transition structure 2-16. The second Michael addition occurs from the same face, again under chelation control, followed by an axial protonahon of the formed enolate to give the cis-compound 2-14a. It should be noted that after the usual aqueous work-up procedure an inseparable... 

Oare, D. A., Stereochemistry of the Base-Promoted Michael Addition Reaction, 19, 227 Acyclic Stereocontrol in Michael Addition Reactions of Enamines and Enol Ethers, 20, 87 Okamoto, Yoshio, Optically Active Polymers with Chiral Recognition Ability, 24, 157. 

Michael additions of ketone enolates. The stereochemistry of Michael additions of lithium enolates of ketones to a,(3-enones is controlled by the geometry of the enolate. Addition of (Z)-enolates results in anti-products with high diaster-eoselectivity, which is not changed by addition of HMPT. Reaction of (E)-enolates is less stereoselective but tends to favor syn-selectivity, which can be enhanced by addition of HMPT. 

However, use of a less reactive reagent where [R = R =(CH2)4, (CH2)s, (CH2)20(CH2)2] led to the isolation of products 61 and 62, with a reduction in the yields of the desired cycloadducts. The product 62 arises from Michael addition of the liberated methanethiol to A-methylmaleimide. The protocol was further extended to olefinic dipolarophiles with dimethyl fiimurate, dimethyl maleate, fumaronitrile, and 2-chloroacrylonitrile leading to the corresponding adducts, although these dipolarophiles proved somewhat less reactive with reduced yields being observed. Where applicable, the alkene configuration was reflected in the relative stereochemistry of the cycloadducts (Fig. 3.5). 

Nitrooxazoles 271a-C also react with electron-rich ynamines to yield isoxazo-lines. °° The proposed reaction mechanism involves the Michael addition of the ynamine to give 275, followed by rearrangement to a nitrile oxide 277. Intramolecular 1,3-dipolar cycloaddition of 277 accounts for the exclusive cis stereochemistry observed in the products 278a-c (Scheme 8.78). 

In a closely related asymmetric reaction, the required absolute stereochemistry at C-4 was established via a Michael addition of a cuprate reagent to a dihydropiperidinone (Scheme 12). The stereochemistry at C-3 was introduced in the form of piperidinone 61, a compound readily available from (5)-glutamic acid. Protection of both the amino and alcohol functionalities was achieved using standard reaction conditions to give 62. Introduction of the A -double bond was accomplished via phenylselenation of the lithium... 

Stereoselective Michael additions. In the absence of strong steric effects, the stereochemistry of Michael addition of amide enolates depends on the enolate geometry, with (Z)-enolates giving mainly antf-adducts and (E)-enolates giving mainly syn-adducts.1 Ester enolates show higher stereoselectivity than amide enolates, as shown by the (E)- and (Z)-enolates of r-butyl propionate (1). The (E)-... 

Finally, a discussion of the relative stereochemistry of such reactions completes this section on inter-molecular Michael additions. It should be pointed out that Chapter 1.5, this volume, is devoted wholly to asymmetric induction in Michael reactions and thus this topic is not covered here. 

Carbocyclization of m-alkcnyl-z-methoxybcnzy I lithiums to form five- or six-membered rings has been studied 101 the five-membered ring is formed with a cis-stereochemical relationship between the methoxy substituent and the adjacent methyl group. Intramolecular carbolithiation of vinyl sulfides at — 105°C in THF has been found to occur non-stereospecifically with regard to the newly formed C—Li centre.102. The stereochemistry of selective tandem Michael addition alkylation reactions of vinylphosphonates has been explored.103... 

We have found that the Michael addition of w-hexyl cuprate to levoglucosenone (2) gives the exo adduct 7 (stereochemistry determined by NOE lH NMR spectroscopy) as the major product in 70-80% yield less than... 

Fig. 13.68. Michael addition to an tt,/kunsaturated ketone. A sequence of reactions is shown that effects the 1,4-addition of acetic acid to the unsaturated ketone. See Figure 17.51 regarding step 2 and Figure 13.37 for the mechanism of step 3. The stereochemistry of reaction steps 1 and 2 has not been discussed in the literature. The third step consists of a decarboxylation as well as an acid-catalyzed epimerization of the carbon in the position a to the carbonyl group. This epimerization allows for an equilibration between the cis,trans-isomeric cyclohexanones and causes the trans-configuration of the major product.

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