Reduction chelation-controlled stereoselectivity

Zinc borohydride has some interesting properties it is less basic than NaBH4 and thus it is especially suitable for the reduction of base-sensitive compounds. Also, the zinc cation has a better coordinating ability than either Na or Li , making Zn(BH4)2 often the reagent of choice for chelation-controlled, stereoselective reductions of acyclic ketones (see Section 4.12). 

The Li—F chelation is also useful for stereoselective reactions. In particular, chelation between lithium of enolates and a fluorine of a trifluoromethyl group results in conformational fixation of substrates, leading to markedly enhanced stereoselection. This concept has often been employed to achieve stereocontrol in fluorinated enolate chemistry. Morisawa reported Li—F chelation-controlled stereoselective a-hydroxylation of enolate of 40 [22]. The oxidant approaches from the less hindered side of the Li—F chelated enolate intermediate (41), affording anti-alcohol (42) exclusively (Scheme 3.11). The syn-alcohol (45) was prepared by NaBlrh reduction of ketoester (43) via a reaction course predicted by Felkin-Anh s model (44). 

Chelation Control. The stereoselectivity of reduction of carbonyl groups can be controlled by chelation when there is a nearby donor substituent. In the presence of such a group, specific complexation among the substituent, the carbonyl oxygen, and the Lewis acid can establish a preferred conformation for the reactant. Usually hydride is then delivered from the less sterically hindered face of the chelate so the hydroxy group is anti to the chelating substituent. 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

In addition to accelerating the rate of carbonyl reduction, chelation can be used to control the diastereoselectivity of reductions and carbon-carbon bondforming reactions through highly organised transition states. Keck showed that appropriately subsituted p-hydroxy ketones are stereoselectively reduced by... 

Zinc borohydride has found many synthetic applications in the context of a chelation-controlled reduction.17 In the synthesis of the antibiotic tirandamycin 30, DeShong et al. prepared a key intermediate (32) via stereoselective reduction of a P-silyloxy ketone18 (Scheme 4.11). Reduction of 31 with Zn(BH4)2 gave the mono-TBS-protected 1,2-syn -2,3-anti -diol 32 stereoselectively. Oxidation of... 

Transition states for reduction according to our usual model of chelation-controlled 2-acyl 1,3-dithiane 1-oxide reactivity, together with steric approach control were proposed to rationalize the high levels of observed stereoselectivity. Previous work by Solladie suggests that ketone reduction by the DIBAL/ZnCl2 system does indeed involve such chelated transition states.15... 

The reduction of aminoketones by LAH, LTBA, and borohydrides has been well studied [N5, T2]. Highly stereoselective reductions have been observed in certain cases [BLl, El, KL5, T2]. As early as 1972, it was shown that the reduction of a-aminoketones by LAH in Et20 could be highly stereoselective. According to the size of the nitrogen substituent of 3.95, the reduction takes place either with or without chelation control [DD3] (Figure 3.31). Similar results were observed with a-aminocyclanones [T2]. 

Acylation of an oxygen would also be expected to lower its ability to coordinate to a metal ion, and thus to form chelates. Results from the reduction of (5)-4,5-dihydro-5-(l -oxopropyl)furan-2(3//)-one, available in optically active form from glutamic acid, support this notion24. Thus, zinc borohydride gives the chelation-controlled other hand, excellent syn selectivity in the Felkin-Anh sense can be achieved with L-Selectride. The latter method was extended to several other substrates and was uniformly successful24. 

The reaction is not chelation-controlled and does not involve hydride transfer to the Lewis acid since BF3 OEt2, which can only be four-coordinate, also gives excellent anti stereoselectivity. Tethering the reagent and intramolecularizing the process is also important for the rate of reaction - the analogous intermolecular process was found to be sluggish, even at 0 °C. Rhodium(I) complexes also catalyze the reduction reaction. Burk... 

MEM-Protected butyrolactone 282 is instrumental in the stereoselective synthesis of the C-12 to C-17 fragment of the antibiotic aplasmomycin (Scheme 39) [90]. The key steps are those that result in the formation of new asymmetric centers. Reduction of 283 with zinc borohy-dride gives the a /-alcohol 284a with 15 1 diastereoselectivity as the result of chelation-controlled addition of hydride to the carbonyl group. The isomers are separable at the stage of intermediate 285. A second hydride reduction of 286 at —78 °C affords the yw-alcohol 287... 

The reduction of a diastereomeric mixture of enantiomerically pure /3-keto sulfoxides (7) furnished one of the four possible isomers with good overall stereoselectivity (90%), when carried out under conditions which favor epimerization of the a chiral center (eq 16). This outcome derives from a chelation-controlled reduction (involving the sulfoxide oxygen) coupled with a kinetic resolution of the two diastereoisomers of (7). ... 

Guindon Y, Lavallee J-F, Llinas-Brunet M, Homer G, Rancourt J (1991) Stereoselective chelation-controlled reduction of a-iodo-p-alkoxy esters under radical conditions. J Am Chem Soc 113 9701-9702... 

---