Cram selectivity

Chelation Control Model- "Anti-Cram" selectivity... 

Formation of C-C Bonds by Addition to Chiral Acyclic Carbonyl Compounds 1.3.1.3.1. Addition to Acyclic a-Alkyl-Substituted Carbonyl Compounds Cram-Selective 1,2-Asymmetric Induction... 

In addition to the boron trifluoride-diethyl ether complex, chlorotrimcthylsilanc also shows a rate accelerating effect on cuprate addition reactions this effect emerges only if tetrahydrofuran is used as the reaction solvent. No significant difference in rate and diastereoselectivity is observed in diethyl ether as reaction solvent when addition of the cuprate, prepared from butyllithium and copper(I) bromide-dimethylsulfide complex, is performed in the presence or absence of chlorotrimethylsilane17. If, however, the reaction is performed in tetrahydrofuran, the reaction rate is accelerated in the presence of chlorotrimethylsilane and the diastereofacial selectivity increases to a ratio of 88 12 17. In contrast to the reaction in diethyl ether, the O-silylated product is predominantly formed in tetrahydrofuran. The alcohol product is only formed to a low extent and showed a diastereomeric ratio of 55 45, which is similar to the result obtained in the absence of chlorotrimethylsilane. This discrepancy indicates that the selective pathway leading to the O-silylated product is totally different and several times faster than the unselective pathway" which leads to the unsilylated alcohol adduct. A slight further increase in the Cram selectivity was achieved when 18-crown-6 was used in order to increase the steric bulk of the reagent. 

Addition of 15-crown-5 to the higher-order cuprate led to a reagent that is totally unrcac-tive towards 2-phenylpropanal even at room temperature18. If, however, boron trifluoride-diethyl ether complex was added as additional ingredient, the reactivity was restored and, furthermore, the Cram selectivity increased to 90 10 (Table 4). Analogous results could be obtained by placing the crown-ether effect within the cuprate itself, as in reagent 10. 

In accord with the Felkin-Anh model, a-chiral ketones react more diastereoselectively than the corresponding aldehydes. Increasing steric demand of the acyl substituent increases the Cram selectivity. Due to the size of the acyl substituent, the incoming nucleophile is pushed towards the stereogenic center and therefore the diastereoface selection becomes more effective (see also Section 1.3.1.1.). Thus, addition of methyllithium to 4-methyl-4-phenyl-3-hexanonc (15) proceeds with higher diastercoselectivity than the addition of ethyllithium to 3-methyl-3-phenyl-2-pen-tanone (14)32. 

In fact, the highest anti-Cram selectivity reported to date (96% de) was observed with the MAT-mediated addition of methylmagnesium bromide to 2-(l-cyclohexenyl)propanal3 i 36. The stereochemical outcome of this addition reaction can be explained as follows on treatment of the carbonyl compound with the large aluminum reagent, the sterically least hindered complex 9 is formed. Subsequent addition of the nucleophile from the side opposite to the bulky aluminum reagent produces the anti-Cram diastereomer preferentially. 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

In contrast to the results obtained with the jS-alkoxy-a-alkyl-y-lactol 16 (vide supra), a chelation-directed, anti-Cram selective nucleophilic addition to the a-methyl-y-lactol 1 was not only observed with methyllithium and methylmagnesium bromide but also with (triisopropoxy)methyl-titanium72. In fact, the highest diastereoselectivity (> 98 % de) was observed with the titanium reagent in dichloromethane as reaction solvent. A seven-membered chelate 3 with the a-methyl substituent in a pscudoequatorial position has been postulated in order to explain the stereochemical outcome. 

Methylmagnesium chloride has been added to various d-(4-substituted-phenyl) <5-oxo esters 15 (X = H, Cl 13, F, Cl, Br, OC11,) which provides the diastereomeric -lactones 1642. The electronic properties of the phenyl 4-substituent have no significant influence on the diastereoselectivity. Except for the 4-methoxyphenyl compound, which is unreactive even at 60 °C, a ratio of ca. 40 60 in favor of the anti-Cram product is observed at 60 "C in tetrahydrofuran as reaction solvent. Lowering the reaction temperature to 0 °C slightly increases the anti-Cram selectivity in the case of the 4-fluoro-, 4-chloro-, and 4-bromo-substituted compounds. On the other hand, a complete loss of reactivity is observed with the <5-phenyl- and <5-(4-methylphenyl)-substituted h-oxo esters. 

Some special features arise from pericyclic reactions. In the reaction of an a-methyl-branched aldehyde with ( )-crotylboronates, Cram selectivity is enhanced, whereas the Z-isomers show moderate anti-Cram selectivity23 - 25 (see Section D.1.3.3.3.3.1.3.). These findings can most likely be applied generally. 

Good Cram selectivity is observed for Lewis acid induced reactions between allylstannanes and aldehydes with alkyl-substituted a-chiral centers66,87. This enhanced Cram selectivity may be due to the effect of the Lewis acid on the trajectory of nucleophilic attack on the aldehyde66. 

With 2-butenyl- and 3-phenyl-2-propenylstannanes coupling of this Cram selectivity with the intrinsic stereoselectivity of the Lewis acid induced allylstannane-aldehyde reaction gives useful stereocontrol at three contiguous stereogenic centers66,81. 

Excellent chelation control was observed using tributyl(2-propenyl)stannane and a-benzyloxy-cyclohexaneacetaldehyde with magnesium bromide or titanium(IV) chloride, whereas useful Cram selectivity was observed for boron trifluoride-diethyl ether complex induced reactions of the corresponding ferr-butyldimethylsilyl ether89. 

Useful Cram selectivity is observed for Lewis acid induced reactions between 3-alkoxyallylstan-nanes and aldehydes with alkyl substituted a-stereogenic centers116. 

An allylcadmium reagent was reported to add to D-glyceraldehyde acetonide with high Cram selectivity and moderate regioselectivity58. 

Extraordinarily high Cram selectivity was reported for the reaction of 2-propenyltriisopro-poxytitanium with a-siloxy ketones88. 

In its reaction with a twofold excess of racemic 2-phenylpropanal, a moderate Cram selectivity of reagent 8 was found35. 

In contrast to ordinary chiral aldehydes (having no ability to be chelated), the reaction of 9-allyl-9-borabicyclo[3.3.1]nonane(allyl-9-BBN) with the corresponding chiral imines 4 produces the isomer syn-6 either exclusively or predominantly (Cram selectivity Table 8)5,6. The very high 1,2-asymmetric induction is explained by a six-membered. chair-like transition state, in which the inline R group occupies an axial position due to the stereoelectronic effect of imines (R CH = NR). 

Table 8. 1,2-Asymmetric Induction in the Addition of Organometallics to N-Alkylimines 4, Cram Selectivity 6...

The combination of metal tuning and double stereodifferentiation helps to prepare chelation and nonchelation products in the imine series7. In the case of an alkoxy substituent adjacent to the aldimino, the chelation product 10 is predominantly obtained with allylmagnesium chloride, chloromagnesium allyltriethylaluminate or allylzinc bromide, while the use of allyl-boronates or allyltitanium triisopropoxide, which lack the requisite Lewis acidity for chelation, gives 11 with good Cram selectivity. 

Normally, the addition of C-nucleophiles to chiral a-alkoxyaldehydes in organic solvents is opposite to Cram s rule (Scheme 8.15). The anti-Cram selectivity has been rationalized on the basis of chelation control.142 The same anti preference was observed in the reactions of a-alkoxyaldehydes with allyl bromide/indium in water.143 However, for the allylation of a-hydroxyaldehydes with allyl bromide/indium, the syn isomer is the major product. The syn selectivity can be as high as 10 1 syn anti) in the reaction of arabinose. It is argued that in this case, the allylindium intermediate coordinates with both the hydroxy and the carbonyl function leading to the syn adduct. 

The observation that aldehyde diastereoface selection is interrelated with allylborane geometry has important implications for the related aldol processes. The reactions of (-)-180a and (-)-180b with both enantiomers of aldehyde 181 revealed both consonant and dissonant double stereodifferentiation. For the Cram-selective ( )-crotyl... 

A Mukaiyama-type aldol reaction of silyl ketene thioacetal (48) with an aldehyde with large and small a-substituents (e.g. Ph and Me), catalysed by boron trifluoride etherate, gives mainly the iyn-isomer (49), i.e. Cram selectivity. For the example given, changing R from SiBu Me2 to Si(Pr )3 raises the syn preference considerably, which the authors refer to as the triisopropylsilyl effect. Even when the and R groups are as similar as ethyl and methyl, a syn. anti ratio of 5.4 was achieved using the triisopropylsilyl ketene thioacetal. 

Application of this condensation to aldehydes with an a-chiral center gives rise to two chiral centers, the relative stereochemistry of which can be related to the Prelog-Cram selectivity rule. Such a reaction was used for a short stereoselective synthesis of... 

Fig. 10.14. Examples and structural requirements for the occurrence of Cram-selective additions of hydride donors to tt-chiral carbonyl compounds. In the three compounds at the bottom RUrge refers to the large...

The Reason for Cram and Anti-Cram Selectivity and for Felkin-Anh and Cram Chelate Selectivity Transition State Models... 

In additions of hydride donors to a-chiral carbonyl compounds, whether Cram or anti-Cram selectivity, or Felkin-Anh or Cram chelate selectivity occurs is the result of kinetic control. The rate-determining step in either of these additions is the formation of a tetrahedral intermediate. It takes place irreversibly. The tetrahedral intermediate that is accessible via the most stable transition state is produced most rapidly. However, in contrast to what is found in many other considerations in this book, this intermediate does not represent a good transition state model for its formation reaction. The reason for this deviation is that it is produced in an... 

Today, it is known that Cram was wrong about this preferred conformation (he assumed that the bulkiest Ca carbon bond was oriented anti to the C=0 double bond actually this Ca carbon bond prefers a syn-orientation). If Cram had known this conformation at that time, he would certainly not have based his explanation of Cram selectivity upon a reaction with the most stable conformer of the aldehyde. This is because, in order to establish the experimentally found product geometry, the nucleophile would have been required to approach the C=0 double bond of the truly favored conformer from the sterically more hindered side. However, even at that time this error could have been avoided (see below). 

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