Selectivity, diastereofacial

In light of the pivotal role that asymmetric cycloadditions have played in many notable synthetic endeavors over the years, it is not surprising that this important aspect of aqueous Diels-Alder chemistry is of interest. Diastereofacial selectivity can be achieved by incorporating stereochemistry into either the diene 4.1 (chiral R ) or dienophile 4.2 (chiral R ) [47]. 

The degree of (kinetic) stereocontrol or asymmetric induction will then depend on the differential energies of the diastereomeric transition states 

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The solvent effect on the diastereofacial selectivity in the reactions between cyclopentadiene and (lR,2S,5R)-mentyl acrylate is dominated by the hydrogen bond donor characteristics of the solvent... 

The Lewis acid-catalyzed addition of silyl kelene acetals occurred m high yield, and when the ketene acetal bore a substituent, the reactions occurred with modest diastereofacial selectivity [d] (equation 7) (Table 3)... 

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. 

Nucleophilic addition reactions to A -monoprotected a-amino aldehydes 1 (Table 20) represent the beginning of the worldwide interest in peptide isosteres for the preparation of certain specific enzyme inhibitors (e.g., aspartylproteinase inhibition). Some examples of this reaction type show a relatively low diastereofacial selectivity, especially when the reactions are per-... 

Several detailed studies of reactions of achiral aiiylboronates and chiral aldehydes have been reported4,52 - 57. Diastereofacial selectivity in the reactions of 2-(2-propenyl)- or 2-(2-butenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolanes with x-methyl branched chiral aldehydes are summarized in Table 252, 53, while results of reactions with a-heteroatom-substituted aldehydes are summarized in Table 34,52d 54- 57. 

This point is also strikingly demonstrated in the enantiotopic group and diastereofacial selective allylboration of the me so complex 5 that provides the (45,65)-diastereomer with 45 1 diastereoselectivity and >98%ee85b. 

Evidently, the intrinsic diastereofacial selectivity preference of 13 is too great for the chiral 2-butenylboronate to dominate the stereochemical course of this reaction. A second unsuccessful attempt at a demanding case of mismatched double diastereoselection has been reported by Burgess87. 

By way of comparison, the mismatched double asymmetric reaction of (5)-2-methylbu-tanal and E)- -methoxy-2-butenylboronate (5)-4 exhibits much greater selectivity. Dia-stereomers 9 (ca. 95%) and 7 (ca. 5%) are the only observed products, indicating that the diastereofacial selectivity of the 9/10 pair is >95 5. Here again, the small amount of 7 that was obtained (5 %) probably derives from the reaction of (S)-2-methylbutanal and the enantiomeric reagent (/ )-4, since (S)-4 is not enantiomerically pure (ca. 90% ee). 

The greater diastereofacial selectivity of 4 is also evident in the attempted mismatched double asymmetric reactions of 3 and 4 with aldehydes 11 and 15. which have greater intrinsic diastereofacial preferences than (S)-2-methylbutanal. 

The diastereofacial selectivity of Lewis acid promoted reactions of allylsilancs with chiral aldehydes has been thoroughly investigated58. Aldehydes with alkyl substituted a-stereogenic centers react with a mild preference for the formation of Cram products, this preference being enhanced by the use of boron trifluoride-diethyl ether complex as catalyst58. 

Allyl(trimethyl)silanes react efficiently with Lewis acids to give the corresponding tertiary alcohols67. Although only modest diastereofacial selectivity was observed for reaction with menthyl esters67, improved selectivity was found for chiral a-oxo imides68 and a-oxo amides derived from proline69. 

The diastereofacial selectivity of addition of achiral allylchromium to chiral aldehydes is mainly determined by steric approach control even a- and /5-alkoxy-subsliluents apparently do not give rise to a rate-determining chelation9. 

All four possible diastereomers are formed from the addition of the same Z-azaenolate to a series of aldehydes. Both the ratio of topside (major)/bottomside (minor) attack (4 1, controlled by the dihydroisoxazole substituents) and the diastereofacial selectivity (syn/anti ratio) are nearly independent of the structure of the aldehyde used26. 

As demonstrated, the organozinc reagent provides exclusively the Cram product, while the organomagnesium reagent shows poor diastereofacial selectivity in the addition to 1 and even reverses the selectivity in the addition to 4. 

In the course of investigations on the synthesis of ( + )-biotin (7) the addition of isothiocyana-toacetate enolates 8 to 1,3-thiazolines 9 has been studied16 17. The diastereofacial selectivity of these reactions is controlled by attack of the enolate on the imine face opposite the 5-pentyl group and correctly establishes the relative stereochemistry at C-l and C-2 of biotin. 

The. tytt-selective process [d.r. (syn/anti) >90 10] is rationalized by a C(E,E) type of transition state 5. The diastereofacial selectivity, determined by converting /1-amino esters 3 to /1-lactams 4 and measuring their optical purity, is satisfying (70% ee)29. 

Interestingly, the diastereofacial selectivity can be reversed in the Strecker reaction of aldimines derived from galactosylamine 1 by simply changing the solvent. When the reaction of trimethylsilyl cyanide with the Schiff bases 2 catalyzed by zinc chloride, is carried out in chloroform instead of 2-propanol, there is a preferred formation of the (.S)-amino nitrile diastereomers63. 

The principle discussed in the previous section can be used in asymmetric synthesis, utilizing a chiral auxiliary in the 2-position of the cyclopentenone in order to achieve diastereofacial selectivity. Three types of chiral auxiliaries, the 4-methylphenylsulfinyl (E), menthyloxycar-bonyl (C), and 8-phenylmenthyloxycarbonyl groups (D), have been studied32. 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

Ail extremely useful method for the asymmetric synthesis of substituted amino acids, in particular glutamic acids, is based on optically active bislactim ethers of cyclodipeptides. The lithium etiolates of bislactim ethers (which are prepared easily from amino acids) undergo 1,4-addition to various a,/ -unsaturated esters to give -substituted 2,5-dihydropyrazine-propanoates203-205 with high diastereofacial selectivity, ratio (R/S) > 140-200 1. 

As an example the enolatc of (5,)-2,5-dihydro-5-isopiopyl-3,6-diinethoxypyrazine, prepared from (S>valine and glycine, reacts with methyl (2s)-3-phenylpropenoate and the (2/ ,/ S)-iso-mer is obtained as the major diastereomer. The diastereofacial selectivity is reflected by a 2R/2S ratio of 99.6 0.4, whereas the high simple diastereoselectivity is shown by the diastereomeric ratio (syn/ami) of 91 9. Using methyl (Z)-3-phenylpropenoate the (2R, R)-isomer is formed... 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

Addition to Chiral Enimines I.5.3.I.I. Diastereofacial Selectivity Enimines Bearing a Chiral Auxiliary... 

I.5.3.2.2. Diastereofacial Selectivity Chiral Enolates and Related Anions... 

I.5.3.3. Addition to 2-Vinyl or 2-Aryl-4,5-dihydrooxazoles I.5.3.3.I. Diastereofacial Selectivity Chiral 4,5-Dihydrooxazoles... 

I.5.3.4.2. Diastereofacial Selectivity I.5.3.4.2.I. Chiral a,/i-Unsaturated Sulfones Addition of Enolates and Related Anions... 

The diastereofacial selectivity of this asymmetric [3C+2S] process is explained following a model similar to that described in Sect. 2.6.4.4 for the reaction of chiral alkenylcarbene complexes and 1,3-dienes. Thus, the proposed mechanism that explains the stereochemistry observed assumes a [4+2] cycloaddition reaction between the chromadiene system and the C=N double bond of the imine. The necessary s-cis conformation of the complex makes the imine... 

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