Reduction chelation control

With an oxygen-bearing stereocenter in proximity to the C-16 ketone carbonyl in 155, the prospects for achieving a diastereose-lective ketone reduction seemed favorable. From the work of Mori and Suzuki, it was known that similarly constituted ketones are amenable to /i-chelation-controlled reductions with lithium alumi-... 

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. 

The effect of the steric bulk of the hydride reducing agent has been examined in the case of 3-benzyloxy-2-butanone.135 The ratio of chelation-controlled product increased with the steric bulk of the reductant. This is presumably due to amplification of the steric effect of the methyl group in the chelated TS as the reductant becomes more sterically demanding. In these reactions, the degree of chelation control was also enhanced by use of CH2C12 as a cosolvent. 

A survey of several of alkylborohydrides found that LiBu3BH in ether-pentane gave the best ratio of chelation-controlled reduction products from a- and (3-alkoxy ketones.134 In this case, the Li+ cation acts as the Lewis acid. The alkylborohydrides provide an added increment of steric discrimination. 

A unique approach to the requisite C-ring fragment 51 is achieved through reductive cyclization of olefinic ester 55 by way of the titanium alkylidene, as described by Rainer and Nicolaou [59]. The olefinic ester 55 is prepared in ten steps from (R)-isobutyl lactate using consecutive chelation-controlled... 

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. 

The construction of the heterocycle 3 started with enantiomerically-pure ethyl lactate. Protection, reduction and oxidation led to the known aldehyde 6. Chelation-controlled allylation gave the monoprotected-diol 7. Formation of the mixed acetal with methacrolein followed by intramolecular Grubbs condensation then gave 3. The dihydropyran 3 so prepared was a 1 1 mixture at the anomeric center. 

A similar cyclization of a ketyl anion (produced via reaction with SmE) onto an allene was reported by Gillmann in 1993 (equation 29)85 The regiochemistry and high diasterose-lectivity associated with this process was explained on the basis of a chelation-controlled cyclization (e.g. TS 48). The same reduction carried out with n-Bu3SnH resulted in only a 37% yield and a 5 1 ratio of diastereomers. 

Step 2 Chelation-controlled reduction of the ketone produces the anti-alcohol diastereoselectively. 

Reductive removal of the amide carbonyl with borane and Mannich closure of the middle ring give P-lycorane 72. A feature of this synthesis is that by changing the order of events and by adding ArLi with chelation control, all three lycoranes can be made selectively. 

Further alkylation of the lithium (Z)-enolate of 25 with methyl iodide gave 26, introducing the C16 stereocentre (3 1 dr) and completing the carbon backbone. Oxidation at Cl and carbamate formation gave 27 which underwent a chelation-controlled reduction at C17 (30 1 dr). Finally, global deprotection completed the synthesis of discodermolide (1), with an overall yield of 4.3% achieved over 24 steps in the longest linear sequence. 

Fig. 11.11. Wittig-Horner synthesis of stereouniform alkenes via ketophosphine oxide B. The reaction proceeds via its Felkin-Anh-selective or chelate-controlled reduction to form the syn-configured hydroxyphosphine oxides D and the anti-configured hydroxyphosphine oxides E. D and E continue to react—after deprotonation with KO-tert-Bu—via a syn-elimination to give the trans- and cis-alkene, respectively. R1 in the formula A-C corresponds to a primary (prim-alkyl) or a secondary alkyl residue (sec-altyl).

Dichloroindium hydride (Cl2InH), generated by the reaction of InCl3 with tributyltin hydride, is also successfully used for the reduction of carbonyl compounds and for the debromination of alkyl bromides.366 This reductant has features such as the chemoselective reduction of functionalized benzaldehydes, chelation-controlled reduction of benzoin methyl ether, and 1,4-reduction of chalcone. The stable carbene and tertiary phosphine adducts of indium trihydride, InH3 CN(Mes)CH=CHN(Mes) and InH3 P(c-G6H11)3, reduce ketones to alcohols (Equation (90)).367... 

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... 

Even though the model shown above is consistent with the stereochemical outcome, Flowers has shown that changing the reaction conditions or the substituents in the (3-hydroxy ketone substrates can have an impact on the stereochemical outcome of the chelation-controlled reaction.23,24 A more detailed discussion of the mechanism of this reduction can be found in Chapter 4, Section 4.3. 

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