Acyclic substrates

Relative Stability of Zwitterion and Cyclopropanone A. Acyclic Substrates 

Fort was the first to obtain evidence for the zwitterion by studying the behavior of chlorodibenzylketone 29c under Favorskii rearrangement conditions. In the presence of a weak base such as 2,6-lutidine in MeOH 29c yields the methoxydibenzylketone 30. With a stronger base such as EtONa in EtOH, the rearranged derivative 31 is obtained. On the other hand, in the presence of lutidine and furan in DMF, Fort isolated the adduct 33. The reactivity of compound 29c is similar to that of 2-chlorocyclohexanone (27) (Table 4), which forms a symmetrical intermediate. The similarity in reactivity is confirmed by the isolation of adduct 33, which provides evidence for the intervention of a symmetrical delocalized intermediate which is most likely to be the zwitterion 32, stabilized by two phenyl groups. 

As in lutidine-methanol, l-chloro-2-propanone undergoes methanolysis much more slowly than does 29c this difference in reactivity is due to the effect of the two phenyl groups in zwitterion 32.  

It is of interest to note that the reduction of aa -disubstituted and -dihalogenated ketones by sodium iodide, zinc-copper, or iron nonacarbonyl involves a zwitterionic intermediate. The capture of the latter by a diene is possible only when the zwitterion is stabilized by phenyl or alkyl substituents. A typical example of the formation of this kind of zwitterion is 

TABLE 5. Theoretical Calculations of the Difference in Energy Between Zwitterion and Cyclopropanone 

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Table 6.8. Stereochemistry of E2 Eliminations for Some Acyclic Substrates...

The thermolysis of xanthates derived from primary alcohols yields one olefin only. With xanthates from secondary alcohols (acyclic or alicyclic) regioisomeric products as well as fi/Z-isomers may be obtained see below. While acyclic substrates may give rise to a mixture of olefins, the formation of products from alicyclic substrates often is determined by the stereochemical requirements the /3-hydrogen and the xanthate moiety must be syn to each other in order to eliminate via a cyclic transition state. 

Conjugated dienes can be epoxidized to provide vinylepoxides. Cyclic substrates react with Katsuki s catalyst to give vinylepoxides with high ees and moderate yields [17], whereas Jacobsen s catalyst gives good yields but moderate enantiose-lectivities [18]. Acyclic substrates were found to isomerize upon epoxidation (Z, )-conjugated dienes reacted selectively at the (Z)-alkene to give trans-vinylepoxides (Scheme 9.4a) [19]. This feature was utilized in the formal synthesis of leuko-triene A4 methyl ester (Scheme 9.4b) [19]. 

Experimentally, there are two approaches to the elucidation of the structure of vinyl cations first, preparation and solvolysis of systems where because of geometric restrictions the intermediate vinyl cation by necessity is bent and second, by a careful examination of the stereochemistry of solvolysis of appropriate acyclic substrates. 

In 2006, these workers successfully expanded the previous study to several acyclic and cyclic allylic substrates (Scheme 1.17)." In all cases, the best enantioselectivity (up to 91% ee) was obtained by using the ligand that contained the more bulky sulfur substituent (t-Bu). The methodology was also applied to monosubstituted acyclic substrates but, however, this ligand proved to be inadequate in terms of regioselectivities, whereas a good enantioselectivity of up to 89% ee was obtained. 

For clarification, individual transformations of independent functionalities in one molecule - also forming several bonds under the same reaction conditions -are not classified as domino reactions. The enantioselective total synthesis of (-)-chlorothricolide 0-4, as performed by Roush and coworkers [8], is a good example of tandem and domino processes (Scheme 0.1). I n the reaction of the acyclic substrate 0-1 in the presence of the chiral dienophile 0-2, intra- and intermolecular Diels-Alder reactions take place to give 0-3 as the main product. Unfortunately, the two reaction sites are independent from each other and the transformation cannot therefore be classified as a domino process. Nonetheless, it is a beautiful tandem reaction that allows the establishment of seven asymmetric centers in a single operation. 

The reaction of aryldiazoacetates with cyclohexene is a good example of the influence of steric effects on the chemistry of the donor/acceptor-substituted rhodium carbenoids. The Rh2(reaction with cyclohexene resulted in the formation of a mixture of the cyclopropane and the G-H insertion products. The enantios-electivity of the C-H insertion was high but the diastereoselectivity was very low (Equation (31)). 0 In contrast, the introduction of a silyl group on the cyclohexene, as in 15, totally blocked the cyclopropanation, and, furthermore, added sufficient size differentiation between the two substituents at the methylene site to make the reaction to form 16 proceed with high diastereoselectivity (Equation (32)).90 The allylic C-H insertion is applicable to a wide array of cyclic and acyclic substrates, and even systems capable of achieving high levels of kinetic resolution are known.90... 

The kinetic resolution by etherification has also been conducted through the cyclization of epoxy aliphatic alcohols.274 In these reactions catalyzed by monomeric complex 51, the ring closure of acyclic substrates occurred with exclusive / -selectivity (Equation (74)), whereas m -openings were observed in the desymmetrization of... 

Replacing hex-3-ene with trans-1,4-dimethoxybut-2-ene resulted in slightly slower reactions, but gave comparable yields of cross-metathesis products. The desired reactions did not take place, however, when ris-but-2-ene-l,4-diol was used as the acyclic substrate. 

Approach (control) Acyclic (reagent) Cyclic (substrate) Acyclic (substrate) Acyclic (reagent) Acyclic... 

The efficient rearrangement of these cyclic ethers may stem from the favorable juxtaposition of the reactive centers. Rearrangement of related acyclic substrates is notably less efficient. 

The numerous studies prior to 1996 on Cu-catalyzed additions of Grignard reagents to cydohexenone as a model substrate revealed that, with a few exceptions, enantioselectivity was exclusively found with either cyclic substrates (Grignard reagents) or acyclic substrates (dialkylzinc reagents) (Scheme 7.2). 

Cycloisomerization represents another approach for the construction of cyclic compounds from acyclic substrates, with iridium complexes functioning as efficient catalysts. The reaction of enynes has been widely studied for example, Chatani et al. reported the transformation of 1,6-enynes into 1-vinylcyclopentenes using [lrCl(CO)3]n (Scheme 11.26) [39]. In contrast, when 1,6-enynes were submitted in the presence of [lrCl(cod)]2 and AcOH, cyclopentanes with two exo-olefin moieties were obtained (Scheme 11.27) [39]. Interestingly, however, when the Ir-DPPF complex was used, the geometry of olefinic moiety in the product was opposite (Scheme 11.28) [17]. The Ir-catalyzed cycloisomerization was efficiently utilized in a tandem reaction along with a Cu(l)-catalyzed three-component coupling, Diels-Alder reaction, and dehydrogenation for the synthesis of polycyclic pyrroles [40]. 

Aryldichlorotellurolactones (general procedure). A solution of the 7,5-unsaturated acid (5 mmol) and/7-methoxyphenyltellurium trichloride (2.0 g, 5.8 mmol) in CHCI3 (80 ml.) is heated under reflux (acyclic substrates, 1 h cyclic substrates, 2.5-7 h). The solution is evaporated and the residue filtered through SiOj with the aid of CHCI3. The solution is dried (MgS04) and evaporated. The residue is recrystallized from CHCl3/petroleum ether at 30-60°C, giving the pure product. 

The scope of Michael additions with catalysts containing cyclohexane-diamine scaffolds was broadened by Li and co-workers [95]. When screening for a catalyst for the addition of phenylthiol to a,p-nnsatnrated imides, the anthors fonnd that thiourea catalyst 170 provided optimal enantioselectivities when compared to Cinchon alkaloids derivatives (Scheme 41). Electrophile scope inclnded both cyclic and acyclic substrates. Li attributed the enantioselectivity to activation of the diketone electrophiles via hydrogen-bonding to the thiourea, with simultaneous deprotonation of the thiol by the tertiary amine moiety of the diamine (170a and 170b). Based on the observed selectivity, the anthors hypothesized that the snbstrate-catalyst... 

However, a similar rearrangement of the related 9- and 17-membered substrates 67 and 69 with amide 63 provided lower ee values (25 and 33% ee in the products 68 and 70, respectively) (equations 35 and 36) . Accordingly, the level of enantioselection appears to depend critically upon the chiral environment provided by the cyclic framework of the substrate. In fact, no appreciable level of enantioselectivity was observed in the rearrangement of acyclic substrate 71 to 72 with amide 63 (equation 37). 

Cyclic allylic alcohols have different steric requirements than the acyclic substrates discussed above. Sarzi-Amade and coworkers addressed the mechanism of epoxida-tion of 2-cyclohexen-l-ol by locating all the transition structures (TSs) for the reaction of peroxyformic acid (PFA) with both pseudoequatorial and pseudoaxial cyclohexenol con-formers. Geometry optimizations were performed at the B3LYP/6-31G level, and the total energies were refined with single-point B3LYP/6-311- -G //B3LYP/6-31G calculations. 

The chelate Cram model 6, p 125 has already shown how acyclic induction may be improved by forming a temporary cyclic species with a frozen conformation. This concept has been generalized in different ways. One is the incorporation of the acyclic substrate in a macrocyclic template. 

Modern synthetic chemistry has taken up the challenge of acyclic substrate-induced stereoselection302, including auxiliary-directed stereoselectivity. The main principles are 1,2-in-duction, the formation of cyclic intermediates, and intramolecular reactions. Many aspects, rules , and examples of diastereoface-differentiating reactions, both in cyclic and in acyclic systems, are summarized in Section 2.3.5.2. 

The scope of the reaction is reasonably general in terms of the cyclic ketones that could be used, but an acyclic substrate such as 3-pentanone led to a lower enantioselectivity. Besides ethylene, other olefinic partners such as propene and styrene also took part in the reaction. Addition to propene occurred with a lower yield and the adduct incorporating an isopropyl group was obtained, indicating that the addition took place regioselectively... 

With acyclic substrates such as (45), simple steric arguments are a suitable rationale for the observed stereoselectivity.851 For example, in the reaction of PI1CU-BF3 with enoate (45), acid (46) was obtained, after hydrolysis, in 99.5% ee. This preference is consistent with an attack of the reagent from the least sterically encumbered side of the carbon-carbon double bond (shown by the arrow equation 49). 

The activity and enantioselectivity of chiral Ir catalysts have been tested by using 2,3,3-trimethylindolenine as a model substrate. Hydrogenation of the cyclic imine with [Ir(bdpp)Hl2 2 gives the corresponding chiral amine with 80% ce (Scheme 1.99) [350]. The stereoselectivity is somewhat better than that with acyclic substrates (see Scheme 1.94). A neutral BCPM-Ir complex with Bil3 effects asymmetric hydrogenation in 91% optical yield [354], A complex of MCCPM shows similar enantioselection [354], These complexes are not applicable to the reaction of other acyclic and six-membered cyclic imines. An MOD-DIOP-Ir complex is also usable with the aid of ( -C4H9)4NI [355], An Ir complex of BICP with phthalimide effectively... 

E.3.2.1. Deracemization of Acyclic Substrates When chiral allylic substrates generate meso 71-allyl intermediates, the two allylic termini of such intermediates are enantiotopic. Thus, enantioselectivity is derived from the regiochemistry of the nucleophilic addition (a vs. b), and the alkylation process corresponds to a deracemization event (Eq. 8E,2). One of the prototypical reactions, which has been studied in extensive detail, is the 1,3-diphenylallyl system. Since its introduction as a different mechanistic motif in contrast with the 1,1,3-triphenylallyl system, this reaction has become a benchmark for design and comparison of a variety of different ligands in recent years [73]. 

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