Stereoselective carbonylation

Alcohols can be synthesized by the addition of carbanions to carbonyl compounds (W.C. Still, 1976) or epoxides. Both types of reactions often produce chiral centres, and stereoselectivity is an important aspect of these reactions. 

A classical reaction leading to 1,4-difunctional compounds is the nucleophilic substitution of the bromine of cf-bromo carbonyl compounds (a -synthons) with enolate type anions (d -synthons). Regio- and stereoselectivities, which can be achieved by an appropiate choice of the enol component, are similar to those described in the previous section. Just one example of a highly functionalized product (W.L. Meyer, 1963) is given. 

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

Synthetically useful stereoselective reductions have been possible with cyclic carbonyl compounds of rigid conformation. Reduction of substituted cyclohexanone and cyclopentan-one rings by hydrides of moderate activity, e.g. NaBH (J.-L. Luche, 1978), leads to alcohols via hydride addition to the less hindered side of the carbonyl group. Hydrides with bulky substituents 3IQ especially useful for such regio- and stereoselective reductions, e.g. lithium hydrotri-t-butoxyaluminate (C.H. Kuo, 1968) and lithium or potassium tri-sec-butylhydro-borates or hydrotri-sec-isoamylborates (=L-, K-, LS- and KS-Selectrides ) (H.C. Brown, 1972 B C.A. Brown, 1973 S. Krishnamurthy, 1976). 

Allylic phosphates are used for carbonylation in the presence of amines under pressure. Carbonylation of diethyl neryl phosphate (389) affords ethyl homonerate (390), maintaining the geometric integrity of the double bond[244]. The carbonylation of allyl phosphate in the presence of the imine 392 affords the /3-lactam 393. The reaction may be explained by the formation of the ketene 391 from the acyl phosphate, and its stereoselective (2 + 2] cycloaddition to the imine 392 to give the /3-lactam 393(247],... 

In the carbonylation of trans,trans,cis-CDT, the trans double bond is attacked preferentially to give the monoester 10, and then the diester 11. Attack of the cis double bond to give the triester is slow[15]. Only the C-16 alkene was carbonylated regio- and stereoselectively to give the Ibo-carboxy-late 12 by carbonylation of the C-5 and C-16 unsaturaied steroid[]6]. 

Enzyme catalyzed reductions of carbonyl groups are more often than not com pletely stereoselective Pyruvic acid for example is converted exclusively to (5) (+) lactic acid by the lactate dehydrogenase NADH system (Section 15 11) The enantiomer... 

Section 17 14 Nucleophilic addition to the carbonyl group is stereoselective When one direction of approach to the carbonyl group is less hindered than the other the nucleophile normally attacks at the less hindered face... 

Stereoselective All lations. Ben2ene is stereoselectively alkylated with chiral 4-valerolactone in the presence of aluminum chloride with 50% net inversion of configuration (32). The stereoselectivity is explained by the coordination of the Lewis acid with the carbonyl oxygen of the lactone, resulting in the typ displacement at the C—O bond. Partial racemi2ation of the substrate (incomplete inversion of configuration) results by internal... 

Conjugated dienes, upon complexation with metal carbonyl complexes, are activated for Friedel-Crafts acylation reaction at the akyhc position. Such reactions are increasingly being used in the stereoselective synthesis of acylated dienes. Friedel-Crafts acetylation of... 

The unstable CH TiCl [12747-38-8] from (CH3 )2 2n + TiCl forms stable complexes with such donors as (CH2)2NCH2CH2N(CH2)2, THF, and sparteine, which methylate carbonyl groups stereoselectively. They give 80% of the isomer shown and 20% of the diastereomer this is considerably more selective than the mote active CH MgBt (201). Such complexes or CH2Ti(OC2H2 methylate tertiary halides or ethers (202) as follows ... 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

A very important relationship between stereochemistry and reactivity arises in the case of reaction at an 5 carbon adjacent to a chiral center. Using nucleophilic addition to the carbonyl group as an example, it can be seen that two diastereomeric products are possible. The stereoselectivity and predictability of such reactions are important in controlling stereochemistry in synthesis. 

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. 

Analyze the factors which would determine stereoselectivity in the addition of organometallic compoimds to the following carbonyl compounds. Predict the major product. 

The well-known reduction of carbonyl groups to alcohols has been refined in recent studies to render the reaction more regioselective and more stereoselective Per-fluorodiketones are reduced by lithium aluminum hydride to the corresponding diols, but the use of potassium or sodium borohydride allows isolation of the ketoalcohol Similarly, a perfluoroketo acid fluonde yields diol with lithium aluminum hydnde, but the related hydroxy acid is obtainable with potassium borohydnde [i f] (equations 46 and 47)... 

Triflates of titanium and tin are effective catalysts for various condensations of carbonyl compounds [I2I, 122, 123, 124, 125] Claisen and Dieckmann type condensations between ester functions proceed under mild conditions in the presence of dichlorobis(trifluoromethanesulfonyloxy)titaiiiuin(rV) and a tertiary amine (equations 59 and 60) These highly regio- and stereoselective condensations were used successfully m the synthesis of carbohydrates [122]... 

The chemical reduction of enamines by hydride again depends upon the prior generation of an imonium salt (111,225). Thus an equivalent of acid, such as perchloric acid, must be added to the enamine in reductions with lithium aluminum hydride. Studies of the steric course (537) of lithium aluminum hydride reductions of imonium salts indicate less stereoselectivity in comparison with the analogous carbonyl compounds, where an equatorial alcohol usually predominates in the reduction products of six-membered ring ketones. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

In transforming bis-ketone 45 to keto-epoxide 46, the elevated stereoselectivity was believed to be a consequence of tbe molecular shape — tbe sulfur ylide attacked preferentially from tbe convex face of the strongly puckered molecule of 45. Moreover, the pronounced chemoselectivity was attributed to tbe increased electropbilicity of the furanone versus the pyranone carbonyl, as a result of an inductive effect generated by tbe pair of spiroacetal oxygen substituents at tbe furanone a-position. ... 

An explanation for the stereoselectivity of the reaction involves optimal overlap of the 7t-orbital of the carbonyl with the developing electron rich p-orbital on C2 during the Sj,j2 displacement of the chloride by the alkoxide (24). Thus, orbital overlap imposes conformational constraints in the transition state that leads to nonbonding interactions disfavoring transition state 15P... 

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. 

There has been recent interest in naphtho-fused dithiepines as chiral acyl anion equivalents, particularly since the starting dithiol 128 can be obtained in enan-tiomerically pure form (89TL2575). This is transformed using standard methods into the dithiepine 129, but showed only moderate diastereoselectivity in its addition to carbonyl compounds. On the other hand, as we have seen previously for other systems, formation of the 2-acyl compound 130 and reduction or addition of a Grignard reagent gave the products 131 with much better stereoselectivity (91JOC4467). 

H )-Euranones are useful building blocks in the synthesis of a variety of organic compounds. In addition, they often serve as valuable synthetic intermediates in the stereoselective construction of substituted y-butyrolactones via conjugated addition to the Q ,/3-unsaturated carbonyl moiety or catalytic hydrogenation of the double bond (88JOC1560). 

---