Diastereoselectivity reagents with chiral ketone

The reactions of 2-propenyltitanium reagents with chiral aldehydes (0) or ketones ( and ) usually exhibit enhanced induced diastereoselectivities compared to allyl Grignard reagents. This enhanced diastereoselection is mainly attributed to the greater bulk and lower reactivity of the reagent. Some examples are collected ( )52. 

When the achiral or chiral reagent approaches chiral ketone 10 from preferred diastereoface one, diastereomer is the prevailing product. Double asymmetric induction takes place when chiral ketone 10 is reduced by the chiral reagent or catalyst. As a result we can expect enhanced or lowered diastereoselectivity in comparison to the reaction with the achiral reagent. This is a consequence of the match or mismatch between the two chiral effects. 

Very high levels of induced diastereoselectivity are also achieved in the reaction of aldehydes with the titanium enolate of (5)-l-rerr-butyldimethylsiloxy-1-cyclohexyl-2-butanone47. This chiral ketone reagent is deprotonated with lithium diisopropylamide, transmetalated by the addition of triisopropyloxytitunium chloride, and finally added to an aldehyde. High diastereoselectivities are obtained when excess of the titanium reagent (> 2 mol equiv) is used which prevents interference by the lithium salt formed in the transmetalation procedure. Under carefully optimized conditions, diastereomeric ratios of the adducts range from 70 1 to >100 1. 

Buynak et al. reported the synthesis of representative 7-vinylidenecephalosporine derivatives bearing an axial allene chirality (Scheme 4.5) [9]. A chiral allene 24 was prepared stereoselectively utilizing the reaction of an organocopper reagent with propargyl triflate 23, obtained by a diastereoselective ethynylation of the ketone 22 with ethynylmagnesium bromide. Terminally unsubstituted allene 26 was synthesized via bromination of the triflate 23 followed by reduction of the bromide 25 with a zinc-copper couple. 

Complete details are available concerning stereoselective addition of these reagents to chiral aldehydes or ketones and of crotyltitanium compounds to carbonyl groups (12, 354).2 The most diastereoselective additions to cyclohexanones known to date are effected with organotitanium reagents. 

These reagents add to the chiral ketones 3 with high 1,5-asymmetric induction. Grignard and organolithium reagents show slight diastereoselectivity.3 Example ... 

Diastereospecific aldol condensations,u The titanium enolate of the chiral ketone 1 reacts with aldehydes to give mainly the syn-aldol (—90 10). However, use of excess titanium reagent or addition of 12-crown-4 (which complexes Li+) results in >99 1 diastereoselectivity. 

Asymmetric reduction of ketones. Chiral ketals 2, obtained by reaction of 1 with prochiral ketones, are reduced diastereoselectively to 3 by several aluminum hydride reagents, the most selective of which is dibromoalane (LiAIHj-AIBr, 1 3). Oxidation and cleavage of the chiral auxiliary furnishes optically active alcohols (4) in optical yields of 78-96% ee (equation 1). 

Reaction with chiral acetals. The chiral ketals derived from (2R,4R)-( - )-2,4-pentanediol (1) can be cleaved with high diastereoselectivity by aluminum hydride reagents, in particular DIB AH, C12A1H, and Br2AlH. Oxidative removal of the chiral auxiliary affords optically active alcohols. This process provides a useful method for highly asymmetric reduction of dialkyl ketones.3... 

Chiral acetals can be used as auxiliaries in the diastereoselective reactions of Grignard reagents with acyclic as well as cyclic a-keto acetals. Nucleophilic addition to the monoprotected diketone (69 equation 18) occurs with excellent stereoselectivity to generate the corresponding tertiary alcohol (70) as the major product, usually with greater than 95 5 selectivity. Removal of the ketal yields a-hydroxy ketones of high optical purity. In most examples, enantiomeric excesses of 95% and higher are observed in the resultant keto alcohols. Table 17 represents the results of additions to cyclic and acyclic substrates. 

There are few reports which deal with questions of chemo- and stereo-selectivity of Kdbrich reagents. Lithiobromomethane reacted preferentially with a saturated ketone in the presence of an a,3-unsaturated ketone in a steroidal substrate, although the reaction was not stereoselective. However, addition of a related reagent to an acyclic chiral ketone was reported to occur with complete diastereoselectivity (equation 29). ° ... 

An appreciation of the ability of 48 to attain appreciable levels of double diastereoselection when reacted with chiral (racemic) vinyl organocerium reagents had earlier been gained in this laboratory [32]. Consequently, it occasioned no surprise to observe that 49 [33] adds to this bicyclic ketone with customary endo stereoselectivity to deliver 50 and 51 in a relative ratio of 92 8. The major product, easily purified by chromatographic means, was smoothly isomerized to 52 under anionic conditions at room temperature. For structural reasons, this sigmatropic change is required to proceed via a boat-like transition state. The all-... 

For general reviews on aUylations, see (a) S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763-2793. Catalytic enantioselective addition of aUylic organometaUic reagents to aldehydes and ketones, (b) C. E. Masse, J. S. Panek, Chem. Rev. 1995, 95, 1293-1316. Diastereoselective reactions of chiral allyl-and aUenylsilanes with activated C=X n bonds, (c) Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207-2293. Selective reactions using aUylic metals. 

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