Dimenthyl fumarates

Fig. 30. Complexation of dimenthyl maleate and dimenthyl fumarate with iron tetracarbonyl...

The use of a chiral fumarate ester allows for asymmetric induction irrespective to the approach of the dienophile to the diene. In particular, dimenthyl fumarate (6) has been advocated for large scale because of its ready availability, low cost, excellent yields, and high asymmetric induction.35128129 203-208 Although other more exotic chiral auxiliaries may be used,32 the use of 5 coupled with a homogeneous Lewis acid catalyst at low temperatures allows for remarkably high diastereo-selectivity with a number of dienes (Scheme 26.5).125 164-209... 

In search for control of absolute stereochemistry, the reaction of thio-chalcones was investigated with unsaturated amides bearing an Evans chiral oxazolidinone [223] and dimenthyl fumarate [224, 225]. For the first time with thiocarbonyl compounds, the efficiency of Lewis acid addition was demonstrated, and reactions could be conducted at room temperature. With EtAlCl2 (Table 4, entry 2) or A1C13 (entry 3), levels of induction up to 92% were attained for the endo isomer. Yb(OTf)3 in DMSO also caused the acceleration of the reaction with chiral acrylamides with p-facial selectivity [226]. This group has also reported [227] an intramolecular hetero Diels-Alder reaction with divinyl thioketones and the double bond of an allyloxy group (Table 4, entry 4). 

Enantioselective cyclopropanation. The reaction of dimenthyl fumarates (2) with isopropylidene(triphenyl)phosphorane proceeds in 74% de in THF at -78 — 20°. (1S,3S)-3 is obtained when the /-menthyl group is used inductor (lR,3R)-3 is obtained in the same optical yield when the unnatural //-menthyl group is used. The concentration plays an important role enantioselectivity is increased by dilution and decreased by concentration. 

Cydoadditions of dienes with menthyl acrylates are usually poorly selective unless the cooperative effect ( 1.6) is used with diesters. As early as 1963, Wal-borsky and coworkers observed an interesting selectivity in TiCl4 catalyzed reaction of 1,3-butadiene with dimenthyl fumarate 1.22. This reaction has been generalized by Yamamoto and coworkers, who performed it at low temperature (-78° to -40°C) in the presence of Et2AlCl (Figure 9.23). 

In 196146 the initial work on ( —)-(/t)-dimenthyl fumarate (l)47 was revised and a diastereomeric ratio of 78.5 21.5 (15,25) for the aluminum chloride promoted addition to 1,3-butadiene (2) was reported. The absolute configuration was established by degradation of the major cycloadduct 3 to threo-2>,4-dimethyl adipic acid (5). Absence of Lewis acids reverses the sense of chiral induction [d.r. 51.2 48.8 (l/ ,27 )]. These observations are rationalized by means of a modified Prelog model. 

Fumarates. Asymmetric cycloaddition to fumarates has been accomplished by modification of either one or both ends of the diacid. In fact, addition of butadiene to dimenthyl fumarate, reported by Walborsky in 1961, was the first highly selective (89% ds) asymmetric Diels-Alder reaction ever recorded [186,187]. Scheme 6.45 shows examples of cycloadditions of several dienes to dimenthyl fumarate [186-189]. Scheme 6.45a illustrates the presumed reactive conformation of dimenthyl fumarate This conformation features (c/. Figure 6.13a) an trans conformation at C1-C2, cis orientation of the ester ligand relative to the carbonyl oxygen, and orientation of the menthyl moiety to relieve Af3 strain. In this conformation, preferred approach of the diene is from the (rear) C2 Si face. In addition to menthol (Figure 6.12a) 1-mesityl trifluoroethanol (Figure 6.12d) has beep used as a Z w-auxiliary [169]. 

One of the most common auxiliaries is menthyl, where an acrylic acid derivative is attached to menthol to form a menthyl ester, 255. Morrison and Mosher22l showed that asymmetric induction is possible with 255 when it reacts with cyclopentadiene to give diastereomers 256 and 257, 22 as shown in Table 11.13.221 in the absence of a Lewis acid, however, the % ee is rather poor. Similarly, (-)-dimenthyl fumarate (258) reacted with butadiene to give 259 and 260, after reduction of the ester products with lithium aluminum hydride. Hydride reduction of esters (sec. 4.2.B) is a common method for removing ester auxiliaries. The work of... 

Table 11.14. Selectivity in the Diels-Alder Reaction of (-)-Dimenthyl Fumarate and 1,3-Butadiene...

Michael addition-condensation sequence of menthyl chloroacetate and menthyl acrylate, and cobalt(O) or nickel(0) complex-catalyzed cyclopropanation of dimenthyl fumarate with dibromomethane. The present method is characterized by good chemical and high optical yields, simple operation, preparation of both enantiomers with equal ease, and the ready availability of the starting materials. 

The preparation of 35 started from the chiral, non-racemic Diels-Alder adduct 36a, obtainable by treatment of butadiene with dimenthyl fumarate, followed by hydrolysis or by resolution of rac-36a with quinine as a resolving agent. Subsequent reduction afforded 36b. From there, the further route via 36c, 37a, and 37b led to 35 (Scheme 13). 

A soln. of (—)-dimenthyl fumarate and butadiene in benzene added rapidly at — 80° to a mixture of AIGI3 and benzene, stirred 1 hr. at the same temp., filtered, the solvent removed, and the residue reduced by LiAlH4 -> ( + )-4-cyclohexene-fra/25-l,2-dimethanol. Y 71% 57% asym. synthesis.—Under different conditions, without AIGI3, a product of opposite sign and configuration is obtained. H. M. Walborsky, L. Barash, and T. G. Davis, J. Org. Ghem. 26, 4778 (1961). 

Further support for this suggestion is provided by induced circular dichroism in copolymers of NVC and (—)-dimenthyl fumarate, in which case the natural tendency to alternation ensures that an optimum sequence distribution has not yet been reached even at 75% incorporation of NVC ... 

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