Dienolates extended

Enolates may be derived from a,/l-unsaturated ketones 16 by base-catalyzed proton abstraction. Under kinetic control the a -proton is abstracted and a cross-conjugated metal dienolate is formed, whereas under thermodynamic conditions the extended dienolate is the major product3,, l. Successful alkylations of dienolates derived from cyclic a,/l-unsaturated ketones have been performed (see Section 1.1.1.3.1.1.2.1.). The related a,/ -unsaturated ester systems have also been investigated22-24. Open-chain structures 16 pose a rather complicated... 

As an interesting challenge we examined an extension of this procedure to its vinylogous analogue [71]. Commonly, reactions between extended dienolates such as 90 and carbonyl compounds have focused on the use of aldehydes as an acceptor component. In contrast, we decided to investigate catalytic asymmetric... 

Significant efforts have extended the scope of catalytic enantioselective Mukaiyama aldol addition reactions beyond the acetate and propionate enoxysilanes and have been used traditionally. Recent reports describe novel addition reactions of silyl dienolates along with isobutyrate-derived enol silanes. 

Catalytic, enantioselective addition of silyl ketene acetals to aldehydes has been carried out using a variant of bifunctional catalysis Lewis base activation of Lewis acids.145 The weakly acidic SiCU has been activated with a strongly basic phor-phoramide (the latter chiral), to form a chiral Lewis acid in situ. It has also been extended to vinylogous aldol reactions of silyl dienol ethers derived from esters. 

Silyl dienol ethers.2 The isomerization of 1,3-dienes by (naphthalene)chro-mium(CO)3 (14, 25) has been extended to (silyloxy)methylbutadienes. Thus (1Z)-1-(silyloxymethyl)-butadienes such as 1 are isomerized exclusively to silyl dienol... 

Controlled alkylation at the more reactive site in dianions has been accomplished algo108,504-516 in anions with extended conjugation, alkylation may occur at different sites and this may be controlled in some cases. For example, with dienolates, zinc bromide catalyzed alkylation usually leads to predominant a-alkylation while use of titanium tetrachloride gives mostly y-alkylation products502,517. 

An elegant synthesis of ( )-hirsutene (32) was developed by Cohen and coworkers . The key step of the synthesis is the one pot, completely stereoselective, oxidative cyclopen-tannulation of dienolate 31 with two equivalents of FeCls in dmf (equation 17). CuCl2 was also tested, but proved inferior. The formation of a single diastereoisomer of the triquinane intermediate (31 ) is useful and suggests that stereochemical equilibration may occur at some stage. This annulation procedure can also be extended to cyclohexanone enolates. 

Fuchs has used this reaction type for the construction of an 11-membered ring in the course of model studies for the [ll]cytochalasin synthesis. These cytostatic compounds, e.g. cytochalasin C (109), are metabolites of microorganisms. Reductive fragmentation of the benzenesulfonates (110 Scheme 37) produces the dienols (111). In contrast, both the sulfonates (112) on treatment with LDA afford the tricyclic ketones (113), the products of internal alkylation. Less than 1% of (111) is formed. In conclusion, the author points out that the enolate conformation (Scheme 37, in parentheses) appears to be all important in determining the reaction products of the four diastereoisomers (110) and (112). Whenever the enolate can easily assume a folded conformation, the tricyclic cyclobutane (113) will result. Models of the enolates of (110), where the intraannular fragmentation successfully occurs, show that the folded conformations are more strained than are the extended conformations. 

A variety of lithium dialkylamide bases can be used to produce cross-conjugated lithium dienolates, which may then be alkylated with even less reactive alkylating agents, e.g. propyl iodide, in good to excellent yields without equilibration to the corresponding extended dienolates. a -Alkylations of cyclo-hex-2-enones, certain cyclopent-2-enones, l(9)-octalin-2-ones and steroidal 4-en-3-ones have been accomplished by this procedure. ... 

In general, the thermodynamically stable extended dienolates (M) have been prepared by deprotonation of enones (62) with sodium or potassium alkoxides in protic solvents or with sodium or potassium hydride in aprotic solvents.Kinetically formed cross-conjugated lithium enolates may be converted into the corresponding extended systems in the presence of excess ketone but in certain cases equilibration is quite slow. Presumably, because the Tr-electron density is higher at the a-carbon than the y-carbon, extended dienolates normally react with alkylating agents to produce a-alkyl-f3,y-unsaturated ketones. 

The stereochemistry of alkylations of extended dienolates of enones such as (70) has been extensively investigated (Scheme 33).In general, the results are similar to those found for the related decalone enolates (43a) and (44), i.e. steric factors within the anion play a dominant role. Thus, axial attack is preferred with (70 R = H), but equatorial attack is strongly favored when an angular methyl group is present (70 R = Me). There is a modest preference for axial alkylation when an angular ethoxycarbonyl... 

Stoik et al. have shown that heteroannular extended dienolates such as (73), which contain substituents at both the a- and y-positions, undergo predominantly equatorial alkylation (Scheme 35). The dienolate (73) was product by lithium-ammonia reduction of the tricyclic dienone (72) and the product of its alkylation wiA I-bromo-3-chloro-2-butene and hydrolysis of the resulting enol ether, i.e. (74), was a key intermediate in a short, highly stereoselective synthesis of ( )-adrenosterone. It was pointed out that equatorial alkylation is obtained with dienolates such as (73) and related compounds brcause a peri interaction (Me OMe) of the a- and y-substituents forces the ring a to adopt a half-boat conformation in which the a-face of the ir-system is accessible to attack. 

As shown in Scheme 36,2,2-disubstituted-5-alkyl-3(2//)-furanones also undergo -y-alkylation via their extended dienolate intermediates (75). Similarly, 4-isopropyl-6-methyl-(2H)-pyran-2-one, which may be regarded as a vinylogous S-alkyl-3(2//)-furanone, was deprotonated and alkylated at the methyl group. ... 

As shown in Scheme 49, the cyclohexylimine of 10-methyl-l(9)-octalin-2-one has been methylated at C-3 via the kinetically formed cross-conjugated dienamine anion (95) or monomethylated at C-1 via the thermodynamically more stable extended anion (96). Steroidal and simpler enones have also been monoalkylated at the a-position via their corresponding hetero- or homo-annular extended dienamine anions. Likewise, a-alkylations are the rule for liAiated a,3-unsaturated aldimines. The thermodynamically controlled procedure for the synthesis of a-methyl a,3-unsaturated ketones is a vast improvement over conventional methodology using extended metal dienolates where a,a-dimethylation is a severe... 

Other efforts have been focused on a conceptually new, directed aldol condensation [54]. Mixed aldol condensations between two different carbonyl compounds with several possible sites for enolization are extremely difficult and there is a variety of undesired pathways involving proton transfer and over-alkylation. The aldol reaction of an a,/ -unsaturated carbonyl compound with an aldehyde was investigated in the presence of ATPH. The reaction first involves fhe demand for control of reactivity and selectivity of the a, -unsaturated carbonyl compound, which upon deprotonation leads to the corresponding extended dienolate of ATPH. A second carbonyl compound aldehyde which serves as an electrophile is activated electronically (but sterically deactivated) by complexation with ATPH. This activation would enable rapid in-situ capture of fhe extended dienolate. ATPH was the reagent of choice, because it could effectively make a strong coordination bond upon encapsulating a number of a, -unsaturated carbonyl compounds. 

ATPH-carbonyl complexes resemble the corresponding extended dienolates... 

The asymmetric Mannich reaction of an enolate and an imine furnishing valuable p amino carbonyls is a fundamental C C bond forming process in organic chemistry that has broad utility in organic synthesis particularly for P amino acid synthesis [1]. Extending the enolate component into a dienolate offers the opportunity for a bond forming event with an electrophile both at the a and the y positions of this ambident nucleophile (Scheme 5.1). 

A similar phenomenon has been reported by Sugiyama and coworkers, who found that the vinylogous amide (23) reacts with benzaldehyde to give (24) as the sole product (equation 90). When (23) is treated with two equivalents of sodium amide in ammonia, followed by treatment with benzaldehyde, aldol (25) is formed in 25% yield. Although the authors invoke a dianion in the latter reaction, it is unlikely that one could be formed under the reaction conditions used. Instead, it is likely that deprotonation at the endocyclic a-position is preferred kinetically, and that this leads to the product observed with NaNH2/NH3 (irreversible enolate formation). Reaction of this enolate must be slow, for steric reasons, as witnessed by the low yield in the aldol reaction. Under conditions of enolate equilibration, the more stable extended dienolate is produced. 

---