Anti-syn ratios

In ( )-[2-(l-propenyl)-l, 3-dithian-2-yl]lithium, no problem of EjZ selectivity arises. It is easily prepared by deprotonation of the allylic dithiane87,88 with butyllithium in THF, whereas deprotonation of the 2-propylidene-l, 3-dithiane requires the assistance of HMPA. The addition to saturated aldehydes proceeds with excellent y-regioseleetivity and anti selectivity88,89. As often observed in similar cases, aldehydes which bear an, p2-carbon atom adjacent to the carbonyl group give lower selectivities. The stereoselectivity decreases with ketones (2-bu-tanone y/a 84 16, antiisyn 77 23)88. The reaction with ethyl 2-oxopropanoate is merely nonstereoselective90, but addition of zinc chloride improved the syn/anti ratio to 96 4, leading to an efficient synthesis of ( )-crobarbatic acid. 

The lithium enolate of the following (1 /C2.S )-2-phenyl-1-cyclohexylpropionate turns out to provide syn selectivity when reacted with benzaldehyde at —100 °C. However, the syn/anti ratio is only 86 14, and the induced stereoselectivity 92.5 7.522. 

The aldol addition of deprotonated (3-isopropyl-6-methyl-2-oxo-2-propionyl)-l,3.2-oxazaphos-phorinane 36 to benzaldehyde delivers (2f ,3/ )-3-hydroxy-2-methyl-3-phenylpropanoic acid in 47% ee via the /1-lactone 37, with syn/anti ratio of 94 6106c. 

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. 

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. 

In 1980 and 1982, Callot and co-workers reported that Rh(Por)l catalyzed the reaction between alkenes and ethyl diazoacetate to give syn cyclopropoanes as the major products (Eq. 25). " This was unusual as most transition metal catalysts for this reaction give the anti isomers as the predominant products. Kodadek and co-workers followed up this early report and put considerable effort into trying to improve the syn/anti ratios and enantioselectivity using porphyrins with chiral substituents. 

The stereoselectivity can be enhanced by addition of Ti(0-i-Pr)4. The active nucleophile under these conditions is expected to be an ate complex in which a much larger Ti(0- -Pr)4 group replaces Li+ as the Lewis acid.313 Under these conditions, the syn anti ratio is dependent on the stereochemistry of the enolate. 

In a similar way, carbocycles having a quaternary center could be obtained from acyclic unsaturated 1,3-dicarbonyl compounds [206]. Other combinations are the domino hydroformylation/Wittig olefmation/hydrogenation described by Breit and coworkers [207]. The same group also developed the useful domino hydroformyla-tion/Knoevenagel/hydrogenation/decarboxylation process (Scheme 6/2.14) [208] a typical example is the reaction of 6/2-66 in the presence of a monoester of malonic acid to give 6/2-67 in 41 % yield in a syn anti-ratio of 96 4. Compounds 6/2-68 and 6/2-69 can be assumed as intermediates. 

For many catalytic cyclopropanations, the stereoselectivity describing the stereochemical relation between substituents at the carbenoid and those at the double bond is not very pronounced. EjZ or syn/anti ratios of ca. 1-3 in favor of the less congested isomer may be considered normal (for examples see Tables 6 and 7). The stereochemical outcome can be expected to be governed by the nature of the olefin, the diazo compound and the catalyst. 

A related catalyst 20 was used in the diastereoselective carbonyl-ene reaction between ethylidenecyclohexane, ethylidenecycloheptane, or 2-methyl-2-butene and trifluoroacetaldehyde (21, R = CF3, Equation (ll))19 or methyl glyoxylate (R = C02Me).20 The best results were obtained when X = Br 63-85% yields are obtained with syn/anti ratios of 95 5 or better, and ee s of the. qw-isomer of 74-89%. 

The general synthetic equation can be expressed by Eq. 3-1. M represents various metals. These conversions generate two new stereocenters and four possible diastereomeric products. The product syn/anti ratio reflects the ratio in the crotyl moiety, which may include B-, A1-, Sn-, Si-, or Ti-based reagents. 

Aldol reactions of 1 and 2 can be used to obtain any one of the four possible stereoisomers of a,3-dihydroxy esters.3 Thus 1 reacts with aldehydes to provide (2S)-aldols, and 2 reacts to provide (2R)-aldols. The syn/anti ratio of the aldols can be controlled by the choice of the enolate counterion. Thus lithium or magnesium enolates provide mainly an/i-aldols, whereas 5yn-aldols predominate with zirconium enolates. Ethanolysis of the purified adducts yields the optically pure a,p-dihydroxy esters without epimerization with recovery of 8-phenylmenthol. 

A formal synthesis of y-lycorane was accomplished by Vollhardt and colleagues by employing a [2 + 2 + 2] cycloaddition between enyne 589 and 568h (equation 169)344. The reaction afforded a mixture of syn and anti adducts 590 and 591 in a 80 20 ratio when the reaction was conducted at room temperature. When the reaction was conducted in refluxing 568h/THF (1 1, v/v), a syn anti ratio of 60 40 was obtained. A small amount of [2 + 2] adduct 592 was also isolated. This product became the dominant product when the enamide double bond was substituted. The additional steric hindrance probably prevented the enamide double bond from participating in the cycloaddition reaction. 

If the substituents are all hydrogen, the syn conformer is present to the extent of 100%, but the syn-anti ratio is 13 87 when the 3-position is substituted by two methyl groups. 

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. 

Tin(IV) halide-catalysed reactions of 4-, 5-, and 6-alkoxy(alk-2-enyl)stannanes exhibit 1,5-, 1,6-, and 1,7-asymmetric induction, respectively. For example, 4-substituted (pent-2-enyl)stannanes (56) give e-hydroxy derivatives (57) with a syn anti ratio of >30 for hydroxy and benzyloxy substrates (i.e. R = OH, OCH2Ph). A key allyltin trichloride intermediate has now been identified, and the transition states for its reaction with aldehyde have been calculated as being over lOkcalmol" apart for the alternative product stereochemistries. ... 

Organic Reaction Mechanisms 1998 Table 1. Syn/anti ratio in electrophilic additional to (1)... 

The construction of an indolizidine skeleton has been successfully obtained by radical cyclizations mediated by (TMS)3SiH. Reaction (7.44) represented a key step in the total synthesis of (—)-slaframine. The two pairs of diastereomers were first separated and then hydrolysed to the corresponding alcohols in a 76% overall yield [55]. On the other hand the cyclization of the A-iodopropyl pyridinones in Reaction (7.45) occurs smoothly at room temperature using Et3B/02 as initiator, to give the desired products with a trifluoromethyl group at the bridgehead position in a syn/anti ratio of 7 3 [56]. 

C——C— (where X was an atom having an unshared pair of electrons) there was no evidence of the formation of any but the syn isomer, while in the absence of any 5,6-chain the syn anti ratio was approximately 60 40. 

In a pair of papers last year, Scott Nelson of the University of Pittsburgh expanded the range of the ketene aldol . In the first paper (J. Am. Chem. Soc. 2004,126, 14), he employed a chiral Al-based catalyst 3. This catalyst mediated additions such as propionyl bromide 1 to 2 to give 4 in 98 2 syn/anti ratio and 95% . 

The idea that the stereochemical outcome of an intramolecular enolate alkylation is determined by chelation in the transition state was recently demonstrated by Denmark and Henke, who observed a marked preference for a "closed transition state (coordination of the cationic counterion to an enolate and the developing alcohol) resulting in a syn product. For example, the highest syn anti ratio (89 11) was obtained in toluene and the lowest syn.anti ratio (2 98) was obtained with a crown ether. These observations parallel the facial selectivities described herein and in ref 11 on the intramolecular SN2 reaction see (a) Denmark, S. A. Henke, B. R. J. Am. Chem. Soc. 1991, 113, 2177. (b) Denmark, S. A. Henke, B. R. J. Am. Chem. Soc. 1989, 111, 8022. 

The freshly ground lithium enolate 1 (1.2 equiv.) was mixed with o-anisaldehyde 2a (1 equiv.) in argon atmosphere at room temperature. The reaction was allowed to continue at room temperature under vacuum for three days, quenched with aqueous NH4CI and the mixture extracted with three portions of diethyl ether. The combined organic extract was washed with water and dried with anhydrous Na2S()4- The solvent was removed using a rotary evaporator at reduced pressure to yield the crude product. The crude product was found to contain mainly anti aldol product (syn/anti ratio 8 92). Further purification was earned out using preparative TLC with methanol-benzene (5 95 in volume) as eluent. The purified product thus isolated was a colorless solid (mp 64-65 °C, yield 70%) with the same syn/anti ratio as that of the crude product. 

Table 7 shows syn/anti ratios obtained for a variety of styrylsilanes, together with group electronegativities. 

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