Dioxolanones enolates

The stereoselective introduction of both benzyl groups simultaneously in one step seemed to be particularly attractive for a short synthesis of a- hy-droxylated lactone lignans from malic acid (99). Such a simultaneous double alkylation requires the formation of a chiral l,3-diene-l,4-diolate, which was not known. On the other hand, achiral 1,3-diene-1,4-diolates (di-enolates) have been previously prepared by Garrett et al. [58] and subsequently employed for the synthesis of racemic lignans by Snieckus [59] and Pohmakotr [60]. With knowledge of the synthesis and reactivity of di-enolates, we planned to prepare chiral di-enolates from dioxolanones and to alkylate these di-enolates in a stereocontrolled manner (Scheme 22). For the development of the described double deprotonation/alkylation strategy, tert-hutyl... 

Since the formation of optically active, dioxolanone-based di-enolates was not successful, a consecutive alkylation strategy was developed for a short synthesis of (-)-wikstromol (ent-3) from (-)-malic acid (99) (Scheme 25). The first alkylation reaction was analogous to that reported for the enantioselective total synthesis of (-)-meridinol (97). In order to avoid a reduction/re-oxidation sequence and an almost unselective second alkylation, two disadvantages of the synthesis of meridinol (97) [55], we planned to use a different strategy for the second alkylation. Therefore, we have focused our strategy on two stereoselective alkylation reactions, one of dialkyl malates and one of a dioxolanone prepared thereof. Both alkylation reactions were previously described by Seebach and coworker [56, 63, 64]. The... 

Reactions of the Enolate of (1) with Electrophiles. Addition of the dioxolanones (1) to solutions of Lithium Diiso-propylamide or Lithium Hexamethyldisilazide in THF at dry-ice temperature generates the corresponding enolates which react with alkyl halides, - carbonyl compounds, and nitroalkenes almost exclusively from the face remote from the t-Bu group to give products of type (2). These can be hydrolyzed to simple ot-hydroxy-ot-methyl carboxylic acids or further elaborated. Four examples are shown in (3)-(6) in which the part of the molecule originating from lactic acid is indicated in bold. 

The enolates of dioxolanones (107) react with aldehydes to give aldols (108) and (109) with, at most, a 3 1 preference for the former (equation 81). This modest preference is of the same magnitude, and in... 

Aldol reactions of chiral dioxolanones (113) and (114) are summarized in Scheme 6 and Table 9. ° With both (113) and (114), essentially perfect diasterofacial selectivity is observed. The simple dia-stereoselection is modest to good, and is dependent on the enolate counterion. For the lithium and magnesium enolates, the sense of simple diastereoselection is the same as is observed with the achiral dioxolanone (107) and the chiral dioxolanone (110). Use of the zirconium enolate generally reverses the sense of simple diastereoselection, although the isomer ratios are not very high in some cases. 

A milder preparation of these 1,3-dioxolanones is illustrated in Scheme 10, this time utilizing 2. Rhodium triflate, [Rh(CH3CN)3(triphos)] (CF3S03 )3, catalyzed acetalization of pivaldehyde with 2 followed by a single crystallization from ether/pentane furnishes pure cis 50 in high yield (80—90%). Diastereoselective alkylation of the lithium enolate of 50 with... 

Dixneuf reported using the ruthenium catalyst 25 in the synthesis of enol ethersfrom alkynes and carboxylic acids. Both formation of enol esters by Markovnikov addition of a carboxylic acid to a terminal alkyne (Eq. 9) and formation of dioxolanones (Eq. 10) was successful. In both cases the reactions were carried out homogeneously at 100 °C and the catalyst was recovered by cooling. Filtration led to recovery of the catalyst which was successfully recycled multiple times, as shown by experiments where a single 0.1 mmol sample of catalyst was used to prepare over 50 mmol of a mixture of enol esters using different carboxylic acids and different alkynes in a series of sequential reactions with different substrates and the same catalyst sample. 

The effect of reaction conditions on the enantioselective protonation of enolates derived from dioxolanones and oxathiolanones (15) has been studied... 

Ramage and coworkers (537) have developed a biomimetic synthesis of pulvinic acids which relies for its success on the facility with which dioxolanones of type (110) undergo nucleophilic attack at the lactone carbonyl group with subsequent extrusion of cyclohexanone. In the synthesis of xerocomic acid (Scheme 15) the dioxolanone (110), obtained as the predominant isomer from reaction between the phos-phorane (109) and methyl (3,4-dibenzyloxyphenyl)glyoxalate, was cleaved with the lithium enolate of /-butyl (4-benzyloxyphenyl)acetate. The intermediate dianion (111) probably exists at first as the chelate (112) which is then broken down on aqueous work up and subsequently cyclised specifically at the less hindered carbonyl group to produce the ester (113). The dianion (111) is analogous to the hypothetical... 

The unambiguous synthesis of 3, 4, 4-trihydroxypulvinone (115) has more recently been reported by Ramage and coworkers (Scheme 17) 536). By cleavage of the dioxolanone (117) with the lithium enolate of methyl (4-benzyloxyphenyl)acetate at —78° C the bright yellow carboxylic acid (118) was obtained in hydrated form after work up. Attempts to purify (118) brought about efficient lactone formation. Final-... 

The lithium enolate of R,R-tartrate acetonide (11) is another easily accessible chiral molecule and has been alkylated by reactive electrophiles (allyl and benzyl halides) with excellent stereospecificity (>80%). This approach has been used in the synthesis of piscidic acid (12). Similarly, the dioxolanones (13) (from pivalaldehyde and 5-lactic acid) and (14) (from mandelic acid), and the... 

Scheme 4.22 Alkylation of dioxolanone 115 via the lithium enolate and application in a...

The immolative character was overcome by pursuing the principle of selfregeneration of chirality and using lithium enolates like 111 (Scheme 4.21) of dioxolanones, a method, which is not only suitable for enolate alkylations but also... 

Another class of hard nucleophiles is the hthium enolates of lactones. Although an early single result in the aUylic alkylation of dioxolanones was not very encouraging because of very moderate enantioselectivity [30], Braun and Meletis undertook a more general study of the Tsuji-Trost reaction of hthium... 

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