Stereoselective additions to aldehydes

Stereoselective addition to aldehydes is another powerful tool in organic chemistry. Two very specihc types of this reaction include allylation of aldehydes and cyanohydrin formation. These are both reactions that can beneht from the use of chiral bis(oxazoline) ligands.Two examples are summarized in Figure 9.53. 

As already shown in Section B.I, certain organotitanium reagents readily form isolable, octahedral 1 2 adducts with such donor molecules as THF, glyme, thio-ethers, amines and diamines1,19) (Equation 47). In case of methyltitanium trichloride 17, structural data show the methyl group to occupy the equatorial position 96). In order to test whether such molecules undergo stereoselective addition to aldehydes (Equation 47), we reacted 134, 135 and 136 (prepared from TMEDA, glyme and THF, respectively) with 2-phenylpropanal 12491. The 125 126 ratios of 80 20, 82 18 und 85 15 show that the Cram product is preferred in all cases... 

Alkyl titanium reagents in stereoselective addition to aldehydes and dialkylamino titanium compounds as protecting groups of aldehydes in the presence of ketones (see 1st edition). 

FIGURE 3 General structure of allylboronates and their stereoselective addition to aldehydes. 

The development of methods that involve in situ enolization and stereoselective addition to aldehydes has been considerably expanded with the introduction of new catalyst systems. Shibasaki has developed a class of aldol ad-... 

The foregoing examples do not represent useful chiral formyl anion equivalents in a direct sense since the stereoselectivity of the initial addition to aldehydes is poor, although as has been explained, the situation is salvaged by oxidation and re-reduction. On the other hand, by lithiation at the 2 position of the achiral oxazo-lidine 53 in the presence of (-)-sparteine followed by addition of benzaldehyde, useful levels of d.e. and e.e. are achieved directly (98TA3125). For example, by adding MgBr2 before the benzaldehyde, the major product obtained is 54 in 80% d.e. and 86% e.e. 

In contrast, highly stereoselective aldol reactions are feasible when the boron etiolates of the mandelic acid derived ketones (/ )- and (5,)-l- t,r -butyldimethylsiloxy-l-cyclohexyl-2-butanone react with aldehydes33. When these ketones are treated with dialkylboryl triflate, there is exclusive formation of the (Z)-enolates. Subsequent addition to aldehydes leads to the formation of the iyn-adducts whose ratio is 100 1 in optimized cases. 

S)-Tricarbonyl(2-methoxyacetophenone)chromium is a starting material which provides remarkable substrate-induced stereoselectivity. Thus, its conversion into a boron enolate and subsequent addition to aldehydes delivers the chromium complexes 7 and 8 with diastereomeric ratios of 92 8 to 95 559. 

The C j-symnietric A, A"-bis(4-tnethylphenylsulfonyl)-l,2-diphcnyl-l,2-cthanediamine (see Sections 1.3.4.2.2.1. and 1.3.4.2.2.2.) also provides remarkable induced stereoselectivity in thioac-etatc aldol additions51. For example, (5)-phenyl thioacetate reacts with the bromoborolane available from the reaction of the diamine with tribromoborane to give the enolate. Subsequent addition to aldehydes affords the /5-hydroxy thioestcrs in good yield and enantiomeric excess51. 

Acetylsultam 15 is also used for stereoselective syntheses of a-unsubstituted /1-hydroxy-carboxylic acids. Thus, conversion of 15 into the silyl-A/O-ketene acetal 16 and subsequent titanium(IV) chloride mediated addition to aldehydes lead to the predominant formation of the diastereomers 17. After separation of the minor diastereomer by flash chromatography, alkaline hydrolysis delivers /f-hydroxycarboxylic acids 18, with liberation of the chiral auxiliary reagent 1919. 

Thus we see that steric effects, chelation, and the polar effects of a- and (3-substituents can influence the facial selectivity in aldol additions to aldehydes. These relationships provide a starting point for prediction and analysis of stereoselectivity... 

The stereoselectivity of addition to aldehydes has been of considerable interest.160 With benzaldehyde the addition of 2-butenylstannanes catalyzed by BF3 gives the syn isomer, irrespective of the stereochemistry of the butenyl group.161... 

Pentadienyltrimethylstannanes undergo regioselective conjugate additions to aldehydes, catalysed by Lewis acids. The dominant product obtained depends on the catalyst used, as shown in reaction 46. In the case of titanium tetrachloride catalysis the reaction is also stereoselective and only one diasteroisomer is obtained297. Reaction with chiral aldehydes leads to asymmetric induction with similar organotin compounds298. 

Not only acyclic but also cyclic dienes can be employed to form t]3-aiiyititanium complexes. The complexes derived from 1,3-cyclopenta- and 1,3-cyclohexadiene undergo highly stereoselective addition with aldehydes (Scheme 13.11) [23]. 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

One of the main reasons for the popularity of allylic boron reagents in stereo-controlled synthesis is that their additions to aldehydes are reliably highly stereoselective and the ontcome is predictable. The diastereospecificify of the reaction was first recognized by Hoffmann and Zeiss using both E- and Z-crofylboronates... 

Ooi has recently reported application of chiral P-spiro tetraaminophosphonium salt 37 as a catalyst for the highly enantio- and diasterioselective direct Henry reaction of a variety of aliphatic and aromatic aldehydes with nitroalkanes (Scheme 5.51) [92]. Addihon of the strong base KO Bu generates in situ the corresponding catalyhcally active triaminoiminophosphorane base A. Ensuing formation of a doubly hydrogen-bonded ion pair B positions the nitronate for stereoselective addition to the aldehyde. This catalyst system bears many similarities to guanidine base catalysis. 

Stereoselective addition to an a-alkoxy aldehyde.3 The addition of organo-metallic reagents to acrolein dimer 1 can be controlled to a remarkable extent by the metal, evidently as a result of chelation, with R2Zn being more stereoselective than RLi or RMgBr. 

C-NMR spectroscopy proves that titanoxycyclopropane 182 is the crucial species, which is formed at ca. —30 °C and reacts with the aldehyde at lower temperature without chlorination. Scheme 8 illustrates generation of 182 and its stereoselective addition to the aldehyde with a transition state TS locating the phenyl group in the sterically favourable ann -position with respect to the large tert-butyl group. 

Stereoselective additions to chiral a- and -alkoxy aldehydes. Lewis-acid-catalyzed additions of enol silyl ethers to chiral ct-alkoxy or (3-alkoxy aldehydes can proceed with high 1,2- and 1,3-asymmetric induction. Moreover, the sense of induction can be controlled by the Lewis acid. Thus BF, which is nonchelating, can induce diastereo-... 

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