Allylic asymmetric

Ci-TunePhos-modified Pd catalysts have found applications in allylic asymmetric alkylations, asymmetric hydrogenations of a- and /3-ketoesters <2006SL1169, 2000JOC6223>, allylphthalimides <2005AGE4933>, enol acetates <2002OL4495>, and asymmetric cycloadditions <2005TL8213>. 

A very useful extension of the de Mayo reaction has been recently introduced by Blechert et al. (Scheme 6.26) [78]. The retro-aldol fragmentation was combined with an intramolecular enantioselective allylation (asymmetric ring-expanding allylation) catalyzed by a chiral Pd complex. Bicycloheptane 68, for example, was accessible by intermolecular [2 + 2]-photocycloaddition of cyclopentenone 67 with allene. Further transformation in the presence of Pd2(dba)3 (dba = dibenzylideneacetone) and the chiral oxazoline ligand 69 (tBu-phox) resulted in the enantioselective formation of cycloheptadione 70. 

The effect of an internal allylic asymmetric center on the course of the intramolecular cycloaddition reaction has been studied (82TL2081). Subjection of the (Z)-nitroalkene (238) to phenyl isocyanate-triethylamine led to the desired cycloaddition product (240) in high yield (>98% purity), whereas the corresponding (E)-nitroalkene gave a 3 1 mixture of two cycloadducts. These results are understandable in terms of A1,3 strain present in the transition state for cycloaddition (68CRV375). For the cis- alkene (238), one mode of cycloaddition (241) would involve a severe Me-Me interaction whereas the other (239) contains a less serious Me-H interaction (82TL2081). 

When the (Z)-alkene 5 was subjected to the reaction conditions, the diastereomers (ctS,2R)- and (y.R.2S)-() were obtained in an 11 1 ratio. A related study dealt with the effect of allylic asymmetric induction in the cyclization of the enoate 742. Under optimum conditions, the diastereomer-ic products 8 were obtained in 76% yield and again in a (otR,2R)j(aS,2S) ratio of 11 1. 

Nitroalkanes are smoothly allylated. Asymmetric allylation of nitromethane with the carbonate 169b at room temperature afforded 170 in 90 % yield with 98.5 % ee. PHOX derivative VII-3 was used as a chiral ligand [64],... 

Labelle M, Guindon Y (1989) Diastereoselective synthesis of 2, 3-disubstituted tetrahydrofuran synthons via the iodoetherification reaction. A transition state model based rationaU-zation of the allylic asymmetric induction. J Am Chem Soc 111 2204—2210... 

The same catalyst system works well in hetero-allylic asymmetric alkylations (h-AAA Scheme 1-16). Substrates such as enol esters 163 provide entry to nonracemic esters of allylic alcohols. Remarkably, competing 1,2-addition and/or acyl transfer were not issues yields are good (80-99%). In these cases, catalyst loading can go as low as 0.8%, and ee s are mostly >95%. Additional chemoselectivity has been noted in the case of cinnamyl ester 163, where the desired Sn2 AAA takes place without competing Cu-catalyzed 1,4-addition to the enoate. This sets the stage for a subsequent metathesis (GH-2 = Grubbs-Hoveyda second-generation catalyst) en route to butenolide 164. 

In the case of isomerization which proceeds according to the 7c-allyl mechanism, 1,3-hydrogen transfer takes place. These reactions are catalyzed by palladium(II) complexes which easily form 7r-allyl complexes from 7r-olefin compounds. Also, compounds of nickel, rhodium, iron, etc., are utilized as catalysts. Effective isomerization is possible if the hydrogen addition to both terminal carbon atoms of the 7r-allyl asymmetric grouping takes place. 

We begin by considering a three-atom system, the allyl radical. A two anchor loop applies in this case as illush ated in Figure 12 The phase change takes place at the allyl anchor, and the phase-inverting coordinate is the asymmetric stretch C3 mode of the allyl radical. Quantum chemical calculations confiiin this qualitative view [24,56]. In this particular case only one photochemical product is expected. 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

In all cases examined the ( )-isomers of the allylic alcohols reacted satisfactorily in the asymmetric epoxidation step, whereas the epoxidations of the (Z)-isomers were intolerably slow or nonstereoselective. The eryfhro-isomers obtained from the ( )-allylic alcohols may, however, be epimerized in 95% yield to the more stable tlireo-isomers by treatment of the acetonides with potassium carbonate (6a). The competitive -elimination is suppressed by the acetonide protecting group because it maintains orthogonality between the enolate 7i-system and the 8-alkoxy group (cf the Baldwin rules, p. 316). 

Simple esters cannot be allylated with allyl acetates, but the Schiff base 109 derived from o -amino acid esters such as glycine or alanine is allylated with allyl acetate. In this way. the o-allyl-a-amino acid 110 can be prepared after hydrolysis[34]. The Q-allyl-o-aminophosphonate 112 is prepared by allylation of the Schiff base 111 of diethyl aminomethylphosphonates. [35,36]. Asymmetric synthesis in this reaction using the (+ )-A, jV-dicyclohex-ylsulfamoylisobornyl alcohol ester of glycine and DIOP as a chiral ligand achieved 99% ec[72]. 

Enamines derived from ketones are allylated[79]. The intramolecular asymmetric allylation (chirality transfer) of cyclohexanone via its 5-proline ally ester enamine 120 proceeds to give o-allylcyclohexanone (121) with 98% ee[80,8l]. Low ee was observed in intermolecular allylation. Similarly, the asymmetric allylation of imines and hydrazones of aldehydes and ketones has been carried out[82]. 

Asymmetric allylation of carbon nucleophiles has been carried out extensively using Pd catalysts coordinated by various chiral phosphine ligands and even with nitrogen ligands, and ee > 90% has been achieved in several cases. However, in most cases, a high ee has been achieved only with the l,3-diaryl-substitiitcd allylic compounds 217, and the synthetic usefulness of the reaction is limited. Therefore, only references are cited[24,133]. 

Asymmetric hydrogenolysis of allylic esters with formic acid with satisfactory ee was observed[387], Geranyl methyl carbonate (594) was reduced to 570 with formic acid using l,8-bis(dimethylamino)naphthalene as a base and MOP-Phen as the best chiral ligand, achieving 85% ee. 

Enzymatic hydrolysis of A/-acylamino acids by amino acylase and amino acid esters by Hpase or carboxy esterase (70) is one kind of kinetic resolution. Kinetic resolution is found in chemical synthesis such as by epoxidation of racemic allyl alcohol and asymmetric hydrogenation (71). New routes for amino acid manufacturing are anticipated. 

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). 

The Sharpless-Katsuki asymmetric epoxidation reaction (most commonly referred by the discovering scientists as the AE reaction) is an efficient and highly selective method for the preparation of a wide variety of chiral epoxy alcohols. The AE reaction is comprised of four key components the substrate allylic alcohol, the titanium isopropoxide precatalyst, the chiral ligand diethyl tartrate, and the terminal oxidant tert-butyl hydroperoxide. The reaction protocol is straightforward and does not require any special handling techniques. The only requirement is that the reacting olefin contains an allylic alcohol. 

In 1980, Katsuki and Sharpless communicated that the epoxidation of a variety of allylic alcohols was achieved in exceptionally high enantioselectivity with a catalyst derived from titanium(IV) isopropoxide and chiral diethyl tartrate. This seminal contribution described an asymmetric catalytic system that not only provided the product epoxide in remarkable enantioselectivity, but showed the immediate generality of the reaction by examining 5 of the 8 possible substitution patterns of allylic alcohols all of which were epoxidized in >90% ee. Shortly thereafter. Sharpless and others began to illustrate the... 

Asymmetric catalytic epoxidation of allylic alcohols 93MI2. 

The landmark report by Winstein et al. (Scheme 3.6) on the powerful accelerating and directing effect of a proximal hydroxyl group would become one of the most critical in the development of the Simmons-Smith cyclopropanation reactions [11]. A clear syw directing effect is observed, implying coordination of the reagent to the alcohol before methylene transfer. This characteristic served as the basis of subsequent developments for stereocontrolled reactions with many classes of chiral allylic cycloalkenols and indirectly for chiral auxiliaries and catalysts. A full understanding of this phenomenon would not only be informative, but it would have practical applications in the rationalization of asymmetric catalytic reactions. 

The ethers clearly do not interfere with the selective reaction by providing an alternative site for reagent coordination, a problem that will be addressed again later in the section on asymmetric catalysis. Cyclic allylic alcohols are cyclopropa-nated with high selectivity as well (Table 3.8, entry 8). 

---