Crotylzincation

The carbonyl substrate 3 to be reacted with the organozinc compound 2 can be an aldehyde or ketone that may contain additional functional groups. With a vinylogous halo ester—i.e. a y-halocrotyl ester—the corresponding y-crotylzinc derivative is formed. 

When the pure (E) isomer of the vinyl lithium 75 is used as starting material, syn-77 is obtained in 81% yield and with 95/5 dr. This diastereoselection can be accounted for by a kinetically favoured (Z) configuration of the crotylzinc species in a chair-like transition state 76 (cf. path c, Scheme 6). However, the metallo ene pathway cannot be ruled out completely and was used sometimes to rationalize the experimental results44. This methodology can also be applied to more functionalized molecules as shown in equation 34.42... 

Computational results were also able to account for the observed selectivity in reactions of crotylzinc reagents, which were found to react preferentially in a cisoid form (see previous examples). This could be accounted for by the energetic difference of the respective transition states 106 and 107 (equation 50). 

As shown in Scheme 6, the addition forms two stereogenic centers via the favorable chair-like transition state. The diastereoselective construction of stereogenic centers has been studied extensively by Marek and Normantla. For the control of stereochemistry, one should think about the configuration of allylzinc compounds and the alkenyl metal. Interestingly, a comparison of four possible transition states (Scheme 7) by calculation concludes that Z-crotylzinc bromide is the most favorable transition state. This means that it is not necessary to think about the stereochemistry of crotylzinc bromide as its configuration changes via 1,3-transposition of the zinc atom (Scheme 6)12. 

Based on these investigations, stereochemically defined alkenyllithium is treated with stereochemically undefined crotylzinc to give the adduct diastereoselectively (equation 16)26. Many types of stereoselective reactions will be shown in Section . 

Indeed, as shown in Scheme 31, highly diastereoselective crotylzincation of t-butoxy-substituted Z-alkenyl lithium affords. sy 3-geminated organodimetal compound with high diastereoselectivity41. Once the alkenyllithium has a secondary allylic substituent, three... 

Interestingly, the Zr-promoted crotylzincation of 5-decyne occurred without allylic transposition (equation 75), presumably via a four-centered transition state, unlike the uncatalyzed addition of crotylzinc bromide to alkynylsilanes which proceeded with complete S 2 regioselectivity108. 

Thus, the alkenyllithium reagent derived from the (X)-y-iodo allylic ether 205 underwent addition of crotylzinc bromide in ether at — 50 °C and, after hydrolysis of the resulting dimetallic reagent, compound 206 was obtained with high diastereoselectivity (anti/syn = 93/7) (equation 101)146. 

It is worth mentioning that the crotylzincation is a reversible reaction as, after addition, prolonged stirring at room temperature or heating at reflux for a few hours resulted in the formation of an equilibrium mixture of diastereomers and regioisomers (equation )128,139. 

Combining substrate-induced diastereoselection and mutual diastereoselectivity, as illustrated for the crotylzincation of the alkenyllithium derived from 209, led to excellent results as the gewt-dimetallic species 217 was obtained in a highly stereoselective fashion. The stereochemical outcome was explained by the addition of the kinetically reactive cisoid metallotropic form of the crotylzinc reagent anti to the propyl group in the chelated allyl alkenylzinc intermediate. After hydrolysis, compound 218 was obtained as a single diastereomer (equation 106)148,149. 

The mutual diastereoselection between the alkenyllithium and the zincated allylic ether turned out to be the same as for a crotylzinc species, and could be rationalized by kinetic addition of a cisoid -alkoxyallylic organozinc compound. 

Although substrate-induced diastereoselection can be conveniently achieved when the alkenylmetal was coordinated by an oxygen atom, other heteroatoms such as sulfur and nitrogen resulted in high inductions as illustrated by the crotylzincation of the organolithium reagents derived from the allylic sulfide 238 or the tertiary amine 239 (equation 117)154. 

Substrate-induced diastereoselective allylzincations essentially rely on coordination of the alkenylmetal by an appropriately located heteroatom, but a zinc-alkene -interaction23 27 can also exert a remarkable stereodirecting effect. Indeed, the alkenyllithium derived from 248, bearing an appropriately located carbon—carbon double bond, underwent highly diastereoselective allyl- and crotylzincations which led after hydrolysis to the corresponding 1,6-dienes 249 and 250. The stereochemical outcome... 

Crotylzinc bromide can also add twice to alkynyl Grignard reagents and the resulting bis-adducts exclusively incorporate two 2-butenyl groups (equation 141)169,170. 

It is also possible to achieve the formation of five-membered rings by coupling the allylzincation of a metallated alkyne with an intramolecular nucleophilic substitution. Thus, allylzincation of the ethylzinc alkynylide generated from 5-iodo-l-pentyne (66)45, or direct treatment of the latter with excess crotylzinc chloride177, led to the alkenyl... 

Nevertheless, chiral propargylic amines remain interesting substrates for achieving the diastereoselective addition of substituted allylic organozinc compounds to metallated alkynes. Besides crotylzincation, one example of diastereoselective addition of zincated allyl ethyl ether to 328 has also been reported183. 

Several papers are concerned with the threo-erythro stereoselectivity of the reaction of allylic organozinc reagents with carbonyl compounds. The addition (involving allylic rearrangement) of crotylzinc derivatives to various aldehydes occurs stereoselectively, and the relative amount of tAreo-alcohol increases with increasing steric demand of the group R tert-Bu, S4% f-Pr, 707o n-Bt, 46%) and in the sequence of metals Mg < Zn < Cd 3, 7). The temperature or the polarity of the solvent... 

In the reaction of crotylzinc reagents with substituted cyclohexanone, the stereoselectivity decreases with increasing distance of the substituent from the carbonyl group, e.g., the percentage of equatorial attack decreases from 88.5% in 2-methyl- to 75% in 3-methyl-, and to 65% in 4-methylcyclohexanone (6). In a comparative study of this type of reaction, the highest stereoselectivity was observed for diallylzinc and the following sequence has been observed Mg < Cd < Zn (6, 7). 

Tliis methodology has been generalized to various functionalized molecules y-amino and -arylthio vinylmetals react diastereoselectively with crotylzinc bromide [107] (Scheme 7-93). 

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