Stereoselectivity with carbonyl compounds

The stereoselectivity of organometallic additions with carbonyl compounds fits into the general pattern for nucleophilic attack discussed in Chapter 3. With 4-r-butylcyclohex-anone, there is a preference for equatorial approach but the selectivity is low. Enhanced steric factors promote stereoselective addition. 

Stereoselectivity in the condensation reaction of 2-arylethylamines with carbonyl compounds to give 1,2,3,4-tetrahydroisoquinoline derivatives was somewhat dependent on whether acid catalysis or superacid catalysis was invoked. Particularly in the cases of 2-alkyl-N-benzylidene-2-phenethylamines, an enhanced stereoselectivity was observed with trifluorosulfonic acid (TFSA) as compared with the weaker acid, trifluoroacetic acid (TFA). Compound 43 was cyclized in the presence of TFA to give modest to good transicis product ratios. The analogous compound 44 was cyclized in the presence of TFSA to give slightly improved transicis product ratios. 

Allyl anion synthons A and C, bearing one or two electronegative hetero-substituents in the y-position are widely used for the combination of the homoenolate (or / -enolate) moiety B or D with carbonyl compounds by means of allylmetal reagents 1 or 4, since hydrolysis of the addition products 2 or 5 leads to 4-hydroxy-substituted aldehydes or ketones 3, or carboxylic acids, respectively. At present, 1-hetero-substituted allylmetal reagents of type 1, rather than 4, offer the widest opportunity for the variation of the substitution pattern and for the control of the different levels of stereoselectivity. The resulting aldehydes of type 3 (R1 = H) are easily oxidized to form carboxylic acids 6 (or their derivatives). 

Allylboron compounds have proven to be an exceedingly useful class of allylmetal reagents for the stereoselective synthesis of homoallylic alcohols via reactions with carbonyl compounds, especially aldehydes1. The reactions of allylboron compounds and aldehydes proceed by way of cyclic transition states with predictable transmission of olefinic stereochemistry to anti (from L-alkene precursors) or syn (from Z-alkene precursors) relationships about the newly formed carbon-carbon bond. This stereochemical feature, classified as simple diastereoselection, is general for Type I allylorganometallicslb. 

Thus unsubstituted (R=H) and substituted (R = alkyl) non-stabilized diyiides 1 react with phenylisocyanate and dicyclohexylcarbodiimide (R NCX), leading to the formation of new monoylide type intermediates. These last ones react in situ with carbonyl compounds through a Wittig type reaction leading respectively to a,)8-unsaturated amides 2 and amidines 3, with a high E stereoselectivity, the double bond being di- or tri-substituted [48,49]. By a similar reactional pathway, diyiides also react with carbonic acid derivatives, with the synthesis as final products of -a,/l-unsaturated esters 4 and acids 5 [50]. 

The existence of ketenes was established over a hundred years ago, and, in recent years, asymmetric synthesis based on [2 + 2] cycloadditions of ketenes with carbonyl compounds to form chiral p-lactones has been achieved with high yields and high stereoselectivities. In 1994, Miyano et al. reported the use of Ca-symmetric bis(sulfonamides) as ligands of trialkylaluminum complexes to promote the asymmetric [2 + 2] cycloaddition of ketenes with aldehydes. The corresponding oxetanones were obtained in good yields and enantioselectivities... 

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],... 

The mode of reaction of titanacydobutenes with carbonyl compounds is largely dependent on steric factors (Scheme 14.31) [72]. Ketones and aldehydes tend to insert into the titanium—alkyl bond of 2,3-diphenyltitanacydobutene, and homoallylic alcohols 70 are obtained by hydrolysis of the adducts 71 [65a,73]. On the contrary, when dialkyl-substi-tuted titanacydobutenes are employed, the reaction with aldehydes preferentially proceeds through insertion into the titanium—vinyl bond. Thermal decomposition of the adducts 72 affords conjugated dienes 73 with E-stereoselectivity as a result of a concerted retro [4+2] cycloaddition [72]. 

In recent years, Hoppe s group has considerably extended the isomerization-addition methodology, especially for the highly regio- and stereoselective synthesis of 1,2-alkadienyl carbamates. It involves deprotonation of alkynyl carbamates, transme-talation into a titanium species and subsequent reaction with carbonyl compounds [26-30]. This group recently described the preparation of enantiomerically enriched 4-hydroxyallenyl carbamates 22 by sparteine-mediated lithiation of alkynyl carbamates 20 [29]. Impressive examples of these transformations are summarized in Scheme 8.8. 

Hydrozirconation of monosubstituted allenes offers easy access to allylzircono-cene chlorides, which react with carbonyl compounds to afford homoallylic alcohols in a highly regio- and stereoselective manner (Scheme 16.68) [73-75],... 

NR = nonreactive toward hydrocarbons PO = oxidation of phosphines to phosphine oxides MF — peroxometallacyclic adduct formation with cyanoalkenes NSE — nonstereoselective epoxidation SE=stereoselective epoxidation AE = asymmetric epoxidation HA- hydroxylation of alkanes HB=hydroxylation of arenes OA = oxidation of alcohols to carbonyl compounds K = ketonization of Lermina 1 alkenes SO oxidation of S02 to coordinated S04 MO = metallaozonide formation with carbonyl compounds I = oxidation of isocyanides to isocyanates. 

Hirashita, T. Kamei, T. Horie, T. Yamamura, H. Kawai, M. Araki, S. Preparation of y-het-erosubstituted allylindium and diindium reagents and their reactions with carbonyl compounds./. Org. Chem. 1999, 64,172-177. Yamaguchi, M. Mukaiyama, T. The stereoselective synthesis of d- and L-ribose. Chem. Lett. 1981, 1005-1008. 

Normant, J. F. Preparation of propargylic carbenoids and reactions with carbonyl compounds. A stereoselective synthesis of propargylic halohydrins and oxiranes. Eur. J. Org. Chem. 2001, 3295-3300. 

Allyl boronates react very slowly with carbonyl compounds as compared to the corresponding allyldialkylboranes, due to the presence of two oxygen atoms on boron which diminish the Lewis acidity of boron. However, the activity of the allyl boronates can be enhanced by the addition of Lewis acid catalysts. There have been two complementary approaches described for the stereoselective allylation with allyl boronates, one involving the use of chiral Lewis acid, and the other involving chiral allyl boronates in conjunction with achiral Lewis acid catalyst. Several chiral fVsymmetric-based 1,2-diols 197 have been employed in combination with SnCLj as a Lewis acid and excellent level of enantioselectivity has been observed for the allylation to furnish homoallylic alcohols 198 with high ee (Equation 8) <2006AGE2426>. 

In reaction (28) y-elimination of LiCl with the formation of an epoxide is obviously faster than P-elimination of Me3SiOLi (Peterson-olefination). Seyferth and his collaborators34) found that this reaction takes place when bis(trimethylsilyl)bromo-methyllithium is reacted with carbonyl compounds, albeit not stereoselectively (Eq. (30)). In contrast, thermal dehydrohalogenation of 1,1-dichloro-l-phenyl-dimethylsilyl-alkanes furnishes Z-olefins only (Eq. (31)) according to the results of Larson et al. 35) ... 

The amino acid synthesis from Strecker has been known since 1850 [25]. Stereoselective versions of this synthesis start with chiral amines, which are condensed with carbonyl compounds to form imines. Addition of hydrogen cyanide and subsequent hydrolysis of the amino nitriles yields the amino acids. When ketones are used for the condensation, a-alkylated amino acids are obtained in high yields and optical purities... 

Several papers are concerned with the threo-erythro stereoselectivity of the reaction of allylic organozinc reagents with carbonyl compounds. The addition (involving allylic rearrangement) of crotylzinc derivatives to various aldehydes occurs stereoselectively, and the relative amount of tAreo-alcohol increases with increasing steric demand of the group R tert-Bu, S4% f-Pr, 707o n-Bt, 46%) and in the sequence of metals Mg < Zn < Cd 3, 7). The temperature or the polarity of the solvent... 

Aldol reaction. Quantitative yields of 1,2-adducts of alkyllithiums to ketones can be obtained at -65° in the presence of Cel,. Cerium enolates, formed by reaction of CeCl, with lithium enolates, also show enhanced reactivity in reactions with carbonyl compounds, particularly ketones. Yields of aldols are increased, but the stereoselectivity remains moderate. ... 

Zinc and zirconium 1,1-bimetallic reagents 4.104, prepared by the hydrozirconation of alkenylzinc halides 4.103, react with carbonyl compounds to produce alkenes with high R-stereoselectivity (Scheme 4.51). Ketones give an E/Z mixture of stereoisomers . 

The olefination based upon the reaction of benzothiazolyl- and phenyltetra-zolyl sulfones with carbonyl compounds is widely used in the target-oriented synthesis. In order to illustrate the reaction scope, yields and stereoselectivities, in this section we present selected examples of these reactions. The examples include reactions of saturated sulfones with saturated aldehydes, saturated sulfones with o, j6-unsaturated carbonyl compounds, -unsaturated sulfones with saturated aldehydes, and /l,y-imsaturated sulfones with a, -unsaturated aldehydes. The emphasis is given to recent work. A complete account of earlier applications of the modified Julia reaction has been given in the Blakemore review [98]. 

Reaction of alkenes with carbonyl compounds or carbonyl derivatives in the presence of Lewis acids, the ene reaction, enables the stereoselective preparation of highly functionalized compounds. Copper Lewis acids activate both aldehydes and imines in ene reactions. Evans has reported that Cu(II) Lewis acids catalyze glyoxylates in reactions with alkenes (Sch. 56) [103]. The homoallylic alcohols 257 and 259 are produced in high yield and enantioselectivity. The bis aquo complex 260 is a readily prepared and air-stable catalyst and gave high chemical yield and excellent selectivity in the ene reactions. Another point of note is that catalysts 260 and 261 furnish enantiomeric products even though they differ from each other only by the substituent at the 4-posi-tion of the oxazoline. 

The triethylaluminum or triethylborane ate complexes (12) of the (isopropylthio)allyl carbanion react with carbonyl compounds at the a-position (equation 10). In the reactions with carbonyl compounds, very high regioselectivity (for example, butanal 95 5, 3-methylbutanal 99 1, cyclohexanone 92 8 and acetophenone 95 5) was achieved by using the aluminum ate complex. On the other hand, the a-regio-selectivity with ketones decreases if the boron ate complex is used (cyclohexanone 72 28, acetophenone 45 55). It is noteworthy that the stereoselectivity of the a-adduct from an aldehyde is low. Ihesumably the geometry of the double bond in the ate complex (12) is not homogeneous. ... 

When chloromethyl p-tolyl sulfoxide (102 R = p-tolyl) is treated with carbonyl compounds (103) and potassium t-butoxide in t-butyl alcohol ether, (p-tolylsulfmyl)oxiranes (104) are directly formed. Chloromethyl methyl sulfoxide (102 R = Me) exhibits the same behavior (Scheme 29). These reactions proceed with high stereoselection at the position a to the sulfmyl group. The stereochemical course proposed for the attack of the carbanion of an a-halo sulfoxide on a carbonyl compound is shown in Figure 4. ... 

In the P-ketosilane approach, the condensation of a-silyl carbanions with carbonyl compounds produces mixtures of diastereomeric P-hydroxysilanes. Therefore, the preparation of stereodefined alkenes via the Peterson reaction hinges on the availability of just one diastereomer. To overcome this shortcoming, procedures have been developed to prepare stereoselectively P-hydroxyalkylsilanes via the P-ketosilane or the epoxysilane routes, as exemplilRed below. 

The reactions of substituted arsonium ylides with carbonyl compounds can be carried out with high stereoselectivity in favor of tra/w-disubstituted epoxides (equation 14). Equatorial attack is observed for addition to 4-t-butylcyclohexanone. Good stereoselectivity (S9 l) was observed for the addition of triphenylarsonium methylide to some (N,)V-dibenzyl)amino aldehydes at -78 C in THF. Interestingly, the initial hydroxy tetraalkylarsonium adducts were isolated under these conditions, and had to be cyclized under the action of sodium hydride in a separate step. 

Brown, M. J., Harrison, T., Herrinton, P. M., Hopkins, M. H., Hutchinson, K. D., Overman, L. E., Mishra, P. Acid-promoted reaction of cyclic allylic diols with carbonyl compounds. Stereoselective ring-enlarging tetrahydrofuran annulations. J. Am. Chem. Soc. 1991,113, 5365-5378. 

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