Malic acid alkylation

Alkyl hahdes in the presence of silver oxide react with alkyl malates to yield alkoxy derivatives of succinic acid, eg, 2-ethoxysuccinic acid, H00CCH2CH(0C2H )C00H (12,13). A synthetic approach to produce ethers of malic acid is the reaction of malic esters and sodium alkoxides which affords 2-alkoxysuccinic esters (14). 

Scheme 9). Although cyanohydrin acetonide 64 could conceivably have been used, the silyl ether 75 was chosen. This compound is readily available from (l)-malic acid, and can undergo electrophilic activation under far more mild conditions than compound 64. Alkylation of the 1,3-diol synthon 75 with bromide 76 created the C11-C26 framework of roflamycoin, in 85% yield. A two-step conversion of the terminal siloxy group to the primary iodide (78) proceeded in 80% overall yield. 

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... 

The best compromise with respect to reactivity and availability of the starting material was the use of diisopropyl malate 107. This malic acid ester is easy to prepare and its alkylation with various benzyl bromides can be achieved with good yields (53-67%, not optimized) and high stereoselectivities (dr 95 5 for 120 and 121). An exception with respect to the stereoselectivity was the 2,4,6-trimethylbenzyl substituted succinate 122, which was obtained in a dr of only 83 17 (Fig. 6) [71]. 

S )-3-Hydroxy-4-butanolide (1), which is readily available from (—)-(S)-malic acid, can be converted into the dianion and the latter alkylated with alkyl halides or mesylates with moderate yields but with high diastereoselectivity (d.r. >98 2)39. 

Similarly, alkylation of ent-l from ( + )-(/ )-malic acid with homogeranyl iodide under analogous conditions furnished 3 in 35% yield. Above — 45 °C elimination of hydrogen iodide from homogeranyl iodide to give the conjugated diene occurred more rapidly than alkylation of the dianion of en -l41. 

Some approaches to the stereoselective synthesis of a-hydroxylated lactone lignans have been reported [59,60]. As a short and efficient example, the synthesis of a dibenzylbutyrolactone lignan wikstromol from two diastereo-selective alkylations of malic acid (+) has recently been reported [61]. In order to get high stereoselectivity, isoPr malate was chosen for the synthesis of (+)-wikstromol its formation in six steps with a 20% overall yield is shown in Fig. 10. 

Cyclocondensation of pipecolinic acid and malic acid anhydride in pyridine afforded 3-hydroxy-2,3-dimethylperhydropyrido[l,2-a]pyrazine-l, 4-dione (74CB2804). Cyclocondensation of bis(2,4,6-trichlorophenyl) mal-onates with 2-methyl-, 2-benzyl- and 2-ethoxycarbonylmethylquinoxalines and -3-ones at 250°C afforded 8-hydroxy-10//-pyrido[l,2-a]quinoxalin-10-ones and their 5,6-dihydro-6,10-dione derivatives (77M103). Under Horner-Wittig reaction conditions, the reactions of 2-formylquinoxaline and dialkyl phosphonosuccinates (314) also involved cyclization to give alkyl 10-oxo-10//-pyrido[l,2-a]quinoxahne-8-carboxylate (80LA542). 

As an alternative to the alkylation of 113 for the preparation of compounds of type 103-105, 110, and 111, Meyers et al. developed a variant of the Com-forth oxazole synthesis. This had been used previously to prepare 113-115 (67, 70). In this scheme, the imino ether 128, the adduct of methanol, HC1, and acetonitrile, is condensed with methyl glycinate (129) to yield 130, which is for-mylated to 131. Deprotonation of the formyl anion 131 at the incipient 2-methyl position of the oxazole followed by alkylation with the electrophile of choice [in this case the acetonide 132 derived from (S)-malic acid] and Lewis acid-... 

Examples of alkylation of malic esters are listed in Table I, together with those of double alkylation, which can also be achieved, see 2 4 in Scheme 1. Since the (S) and the (R) forms of malic acid are both readily available,18 the enantiomers of all structures shown in Table I can be... 

In Table II, a series of useful chiral building blocks is shown, which are accessible through alkylations of malic acid derivatives the table also contains some natural products which were synthesized from such building blocks. 

CHIRAL, NON-RACEMIC BUILDING BLOCKS AND NATURAL PRODUCTS SYNTHESIZED THROUGH ALKYLATION OF MALIC ACID DERIVATIVES. THE FOUR-CARBON UNIT OF THE STRUCTURE WHICH IS DERIVED FROM MALIC ACID IS INDICATED BY HEAVY LINES. 

Two equivalents of LiHMDS (HMDS = hexamethyldisilazide) have been used to deprotonate a 1,3-dioxoIan-lone derived from malic acid having an acetic acid group at C-5 alkylation and acid work-up then gave the substituted dioxolanone (Equation 23) <2005TL3815>. 

The (/ )-(+) -isomer of malic acid 72 must be used and the lactone 73 is the enantiomer of 65. The alkylating agent is the terpene derivative homogeranyl iodide and the selectivity is anti as expected. The yields in this synthesis are not wonderful but it is short and biomimetic. 

Synthesis of Bacillariolides I-III. Marine oxylipin bacillariolides I-III are synthesized from (ft1)-malic acid, using a common chiral cyclopentane derivative prepared as depicted in Eq. 145.252 Two consecutive alkylation reactions of lithioallyl sulfone are responsible for the generation of the cyclopentane intermediate. The synthetic route also includes a reductive desulfonylation with Na/Hg in MeOH/THF (Eq. 145). 

CJ-15,183 (44) has been isolated from the fermentation culture of the fungus, Aspergillus aculeatus CL38916 as a squalene synthase inhibitor. The compound potently inhibited rat liver and human squalene synthases. In addition, it showed antifungal activities against filamentous fungi and yeast. The structure was elucidated to be an aliphatic tetracarboxylic acid compound consisting of an alkyl y-lactone, malic acid and isocitric acid moieties by spectroscopic analyses [69]. 

An equilibrium constant of 8.8 1.1 was obtained at 0.88-0.264 M H+. Oxy species of malic acid, ZrO(CH2CHOH(COO)2) and K2ZrO(CH2-CH0H(C00)2)2 406), and citric acid also are reported SOO). Polymeric lactate complexes have been reported by workers at Takeda Industries 551). Although a complete analysis was not given, the isolation of a polymer formulated as M4[Zr(O0HRCO2) ], where M is sodium or potassium and R is methyl or another alkyl, was reported. Blumenthal 63) has questioned whether the normal lactate will ever be formed. 

Quinidine [3, (9S)-6 -methoxy-9-cinchonanol] is mostly applied for the same purposes as quinine, such as the addition of zinc alkyls to carbonyl compounds (Section D 1.3.1.4.), or addition of thiophenol to acrylic derivatives (Section D.2.I.). An important technical synthesis of malic acid is based on the quinidine catalyzed enantioselective [2 + 2] cycloaddition of ketene to chloral (see Section D. 1.6.1.3.). Esters and ethers of dihydroquinidine (4) (just like the corresponding derivatives of dihydroquinine) have been used as chiral ligands in osmium tetroxide catalyzed dihydroxylations of alkenes (Section D.4.4.). 

The designation chiral pool was introduced to denote an available source of enantiomerically pure natural products. These include the (5)-amino acids, as well as (iS)-lactic acid, (5)-malic acid, (RJl)-tartaric acid and / -D-glucose. How the knowledge of their chirality can be utilized for asymmetric syntheses is demonstrated by an example of the chiral auxiliaries S) and (i )-l-amino-2-(methoxymethyl)pyrrolidine developed by Enders and abbreviated as SAMP (2) and RAMP [61]. They are synthesized from (5)- or (R)-proline in several steps [62]. The enantioselective synthesis of the insect pheromone (5)-4-methylheptan-3-one 8 by alkylation of pentan-3-one 1 serves as an example for the use of these chiral auxiliaries ... 

A 13-step synthesis of benzoylpedamide (140), a key building block for the construction of pederin, has been reported starting with (5)-malic acid via diol ester 45a, as shown in Scheme 17 [43]. In the initial 0-methylation step, 45a 131, alkylation must be accomplished under mild conditions (diazomethane-silica gel) in order to obtain high yield. Under standard basic conditions the product 131 tends to undergo elimination. 

The introduction of alkyl groups into the malic acid framework further expands its synthetic utility as an important and inexpensive source of chirality for the construction of asymmetric molecules. Consequently, methods for alkylating the C-2 or C-3 carbons of malic acid both chemoselectively and diastereoselectively are highly desirable. 

As in the case of lactic acid, incorporation of the 1-carboxyl and 2-hydroxyl groups into a dioxolanone ring increases the susceptibility of the hydroxyl-bearing carbon to substitution reactions. With malic acid, dioxolanone 170 can be readily alkylated in a highly stereoselective fashion to furnish alkylated dioxolanones 206 with diastereoselectivity surpassing 95% (Scheme 27) [59]. 

In the enolate-forming step, the chiral center inherent to the malic acid is destroyed (205), but in the alkylation step the bulky cr butyl group directs the approach of the incoming electrophile to the opposite face of the enolate, thereby furnishing alkylated derivatives 206 with the same hydroxyl configuration as in the starting malic acid. This process is called selfreproduction of chirality . Acidic hydrolysis of 206 (R=CH3) furnishes (5)-(-h )-citramalic acid (207). For further uses of citramalic acid see Section 3.5. 

Substitution at the C-3 carbon of malic acid primarily involves alkylation reactions. In contrast to alkylations at the C-2 carbon (Section 3.2.2.2), which require prior manipulation of the 1-carboxyl and hydroxyl groups, alkylation at the C-3 carbon c be performed directly on malic acid esters. ... 

The (5)-epoxy alcohol 388, previously synthesized from EE- protected malic acid, can also be prepared from THP-protected malic acid via diol 417 (Scheme 59) [107]. When the anion of acetone A, A-dimethylhydrazone is sequentially alkylated with (.S)-1,2-epoxypropane followed by 389 and the resulting product is hydrolyzed under acidic conditions, the result is a mixture of exogonols 430 in 47% yield. 

Both enantiomers of 3-hydroxy-l,7-dioxaspiro[5.5]undecane (471), the minor component of the olive fly pheromone, can be synthesized from (5)-malic acid via acetonide 454b (Scheme 66) [120]. The initial carbon skeleton is constructed by sequential alkylation of 341 with 454b and then EE-protected 4-iodobutanol. Copper-mediated hydrolysis of the dithiepin ring affords a complex mixture of products, two of which, (3aS, 65)-471 and 472, are isolated in 33% and 18% yields respectively. 

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