Erythro selectivity

An interesting example from carbohydrate chemistry is the boron trifluoride-diethyl ether complex catalyzed nucleophilic addition of silyl enol ethers to chiral imines (from n-glyceralde-hyde or D-serinal)22. This reaction yields unsaturated y-butyrolactones with predominantly the D-arabino configuration (and almost complete Cram-type erythro selectivity). 

Whereas SHMT in vivo has a biosynthetic function, threonine aldolase catalyzes the degradation of threonine both l- and D-spedfic ThrA enzymes are known [16,192]. Typically, ThrA enzymes show complete enantiopreference for their natural a-D- or a-t-amino configuration but, with few exceptions, have only low specificity for the relative threo/erythro-configuration (e.g. (122)/(123)) [193]. Likewise, SHMT is highly selective for the L-configuration, but has poor threo/erythro selectivity [194]. For biocatalytic applications, the knovm SHMT, d- and t-ThrA show broad substrate tolerance for various acceptor aldehydes, notably induding aromatic aldehydes [193-196] however, a,P-unsaturated aldehydes are not accepted [197]. For preparative reactions, excess of (120) must compensate for the unfavorable equilibrium constant [34] to achieve economical yields. 

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

Related reactions, catalyzed by tetra-n-butylammonium fluoride (TBAF), have been reported (74). Under the influence of 5 to 10 mol % of TBAF (THF, -78°C), enolsilane 75 afforded the erythro and threo adducts 76E and 76T whose ratios were time dependent (5 min, E T =1 2 10.5 hr, E T =1 3) (74). The reaction of enolsilane 77 at various temperatures has also been reported (2). At -78 C (1 hr) complete kinetic erythro diastereoselection was observed under the conditions reported by Noyori (74), but at higher temperatures product equilibration was noted (2). It is significant that the kinetic aldol condensation of this tetraalkylammonium enolate exhibits complete erythro selection as noted for the analogous lithium derivative. 

For purposes of illustration, consider the erythro selective reaction illustrated in eq. [69]. For aldehydes containing an adjacent asymmetric center (R, Rl = medium and large alkyl substituents), the bias for nucleophilic addition from a given diastereotopic face of the aldehyde is predicted empirically by Cram s rule (the open-chain... 

Other related chiral erythro selective ketone enolates (iS -139 and (i )-139, readily prepared from (5)- and (i )-atrolactic acid, also exhibit good aldol diastereoface selection (3). From the data summarized in Table 34a, the influence of asymmetry in both condensation partners (entries C-F) has been amply demonstrated. The... 

Erythro diastereoselection has also been examined in these addition reactions. The addition of the (Z)-2-butenylboronate ester 179 [>95% (Z)-isomer] to representative aldehydes (Me, CjHj, i-CsH, Ph) was found to exhibit excellent erythro selection (eq. [117]) (132c), in direct analogy with the similar stereoselection observed with boryl enolates (6). 

The diastereoselectivity in the ene reaction of O2 with chiral alkenes bearing a stereogenic centre at the a-position with respect to the double bond has been extensively studied. Chiral alkenes which bear a substituent on the asymmetric carbon atom other than the hydroxy or amine functionality afford predominately erythro allylic hydroperoxides. The erythro selectivity was attributed to steric and electronic repulsions between... 

Deprotonation of the A -acyl substituent of benzothiazines gives a nucleophile that reacts by deacylation with a second molecule of starting material (Equation 46) < 1980TL3001 >. Such anions also react with ketones in an erythro-selective aldol condensation (Equation 47) <1983TL3883>. The selectivity is due to the formation of a Z-enolate and the reaction was also extended to A -acylphenothiazines. 

Enantioselective condensation of aldehydes and enol silyl ethers is promoted by addition of chiral Lewis acids. Through coordination of aldehyde oxygen to the Lewis acids containing an Al, Eu, or Rh atom (286), the prochiral substrates are endowed with high electrophilicity and chiral environments. Although the optical yields in the early works remained poor to moderate, the use of a chiral (acyloxy)borane complex as catalyst allowed the erythro-selective condensation with high enan-tioselectivity (Scheme 119) (287). This aldol-type reaction may proceed via an extended acyclic transition state rather than a six-membered pericyclic structure (288). Not only ketone enolates but ester enolates... 

Stereoselective routes to the lactone precursors of the 1-hydroxyethylene isosteres using a titanium-mediated condensation has been reported by both Shibuya and co-workers1 and DeCamp et al. 19 The former method (Scheme 9) features the reaction between (2S)-2-dibenzylamino aldehydes and optically active dichloroisopropoxytitanium ester homo-enolates to provide the desired lactone with high erythro selectivity. Then, the lactone is opened by treatment with an amine and trimethylaluminum to give the 1-hydroxyethylene isostere. The experimental details of DeCamp et al. s high yielding and stereoselective synthesis 19 of lactone 8 (Scheme 10) is discussed in Section 10.6.2.2. 

ERYTHRO-SELECTIVE REDUCTION OF a-SUBSTITUTED J-KETO ACID DERIVATIVES WITH PhMe2SiH/H+ REAGENTa... 

Aldol condensation.2 Theenolateofl reacts with aldehydes to form preferentially cn7hm-f/-methyl-a,/f-di hydroxy carboxylic esters (equation I). The O-MEM ether of methyl lactate shows similar erythro-selectivity (ca. 6 1). In contrast, the anion of... 

Evans DA, Bartroli J et al (1981) Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates. J Am Chem Soc 103 2127-2129... 

A completely different product class, a-amido, (3-hydroxy carboxylic acids, can be obtained from the [2+2]-photocycloaddition of aldehydes to 5-methoxyoxazoles and subsequent hydrolysis of the bicyclic oxetanes [3]. Compound 3 is available from the triplet benzaldehyde addition to dimethyl 5-methoxyoxazole in diastereomerically pure (erythro-selective) form. 

A number of other acyclic Z and E lithium enolates were quenched similarly. In all cases the stereochemistry at the enol double bond was retained, as shown by subsequent conversion into the corresponding silyl enol ether. Upon reacting the titanium enolates with aldehydes, very clean aldol addition occured (>90% conversion at —78 °C). Generally, erythro-selectivity was observed irrespective of the geometry of the enolate. Equations 64 and 65 are typical25). 

Variation of the ligands at titanium can lead to improvements. For example, enolates 197a b react with benzaldehyde to afford 92 8 and 97 3 mixtures of 195 a and 196a, respectively 25). Enolates 199-202, derived from ketones, lactones and lactams, add erythro-selectively to benzaldehyde to yield the corresponding aldols (erythro threo as 85 15, 91 9, 92 8, 58 42 and 88 12, respectively) 25,77). 

Reactions of titanated hydrazones with aldehydes occur cleanly at —20 °C (Equation 69). It is not clear whether the observed erythro-selectivity (Table 8) depends upon the geometry of the double bond, since attempts to prepare Z configurated analogs were not rewarding115). The lithiated precursors themselves are unsuitable for selective additions. Titanation not only increases stereo-differentiation, but also chemoselectivity 115). The assumption of a pericyclic transition state means that chair orientations 213 and 214 must be considered, the latter being of higher energy. However, boat transition states also explain the results U5). 

Table 8. Erythro-selective Addition of Titanated Hydrazones 209 to Aldehydes...

FDP A was employed in a study of pancratistatin analogs to catalyze the formation of the D-threo stereochemistry (Scheme 5.24). When rhamnulose 1-phosphate aldolase (Rha 1-PA) was used the L-threo stereoisomer was obtained with excellent selectivity. Thus these two enzymes allow the stereoselective synthesis of the two threo-stereoisomers [44]. They were also utilised successfully for the synthesis of different diastereoisomers of sialyl Lewis X mimetics as se-lectin inhibitors. Not only the two threo-selective aldolases RAMA and Rha 1-PA, but also the D-erythro-selective Fuc 1-PA was employed. In this way it was possible to synthesise three of the four diastereoisomers enantioselectively (Scheme 5.25). The L-erythro stereochemistry as the only remaining diastereo-isomer was not prepared [45]. This is because the aldolase that might catalyze its formation, TDP A, is not very stereoselective and therefore often yields mixtures of diastereoisomers. 

Allylic alcohols with R3 + H lb are epoxidized with high anti (erythro) selectivity by /err-butyl hydroperoxide catalyzed by vanadium (or titanium12), due to the strong steric interaction of R4 with R3 in the syn (threo) transition state (see Houben-Weyl, Vol, E13/2, p 1185 and reference 13) (A1,2 strain). 

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