Diastereoselective Aldol-Type Additions

Nucleophiles such as enolates or substituted allylmetal compounds are known to react with prochiral aldehydes and ketones to form mixtures of threo or erythro adducts. In case of aldehydes, high degrees of diastereoselection have been achieved 48 91,108). In the following three Sections, reactions of titanium and zirconium enolates as well as allyl derivatives are presented. 

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The alkylation of doubly deprotonated 6-hydroxy esters, an example of which 1s described 1n the procedure above, 1s not just a useful alternative to the diastereoselective aldol-type addition, but can supply enantiomerically pure products from appropriate precursors, and it can be used for the preparation of a/x-disubstituted derivatives (see 4 in Scheme 1). These were hitherto not available stereoselectively from enolates of a-branched esters and aldehydes. 

Chiral silyl ketene acetals (Il)-(20) were recently introduced for diastereoselective aldol-type additions. Camphor derivatives (11)-(16) are conformationally rigid with one diastereotopic face of the enol silane sterically shielded. - A -Methylephedrine derivatives (17)-(20) are likely to bind to TiCU through the NMe2 group with consequent dramatic conformational constraint.As a result the Lewis acid mediated additions to C=X occur in a highly stereoselective way. The chiral auxiliaries can then be removed (and recycled) by reduction, saponification or displacement with various nucleophiles to give useful synthetic intermediates. 

Chiral silvl ketene acetals (camphor derivatives and N-methylephedrine derivatives ) were recently introduced for diastereoselective aldol-type additions. N-methylephedrine derivatives 16-19 are likely to bind to TiCl4 through the NMe2 group with consequent dramatic conformational constraint. ... 

Other reports deal with a pyrrolidine-catalysed homo-aldol condensation of aliphatic aldehydes (further accelerated by benzoic acid), a diastereoselective aldol-type addition of chiral boron azaenolates to ketones,the use of TMS chloride as a catalyst for TiCU-mediated aldol and Claisen condensations, a boron-mediated double aldol reaction of carboxylic esters, gas-phase condensation of acetone and formaldehyde to give methyl vinyl ketone, and ab initio calculations on the borane-catalysed reaction between formaldehyde and silyl ketene acetal [H2C=C(OH)OSiH3]. ... 

The major difference, when compared with simple diastereoselection in aldol-type additions, is the E- and Z-geometrical isomers of the Michael acceptor. Model transition state G shows one of the orientations of the enantiofaces of an (A)-enolate with a (Z)-enone. These additions, again, result in the same. vyn/an/i-adducts, as in the case of an (A)-enone, but the substituent interactions will be different. 

Early examples of successful, highly diastereoselective alkylations of bicyclic /1-lactams include reactions of the enolates from penicillin and cephalosporin derivatives (e.g., 1 and 4). These enolates have also been used in aldol-type additions, acylations and in the preparation of hetero-substituted penicillins and cephalosporins1. 

Substituted 3-phenylsulfonyl-5-hydroxymethyl-THFs (e.g. 44) have been prepared chemo-, regio-, and diastereo-selectively via reaction of a y,5-cpoxycarbanion with aldehydes, RCHO.156 The initial aldol-type addition is non-diastereoselective, but reversible. The subsequent cyclization is selective, and exerts overall thermodynamic control. 

Aldol-Type Addition. Aldol-type addition of the magnesium enolate of (R)-(+)-7-butyl 2-(p-tolylsulfinyl)acetate, prepared with 7-butylmagnesium bromide, with aldehydes and ketones afforded, after desulfurization with Aluminum Amalgam, p-hydroxy esters in very high diastereoselectivity (eq Two chiral centers are created in the first step with very high diastereoselectivity (mainly one diastereomer is formed). A model M based on the structure of the sulfinyl ester enolate (determined by C NMR) and on electrophilic assistance of magnesium to the carbonyl approach, was proposed to explain and predict the absolute configuration of the two created chiral centers. ... 

Scheme 10.129 Diastereoselective formation of aldol surrogates by sequential carbocupra-tion of chiral ynamides/zinc carbenoid homologation/aldol-type addition [110].

Trimethylsilyloxyfuran 338 has shown promise as a masked butenolide fragment To fuUy exploit these qualities, the threo versus erythro (339 vs 340) diastereoselectivity in aldol-type additions has to be controlled. In fact it has been shown that this is easily achieved by appropriate reaction conditions. Applying Mukaiyama conditions (i.e., using the silyl enol ether as the donor in the presence of a Lewis acid such as TESOTf to generate oxonium species) leads to threo preference for 339, presumably via an open transition state, whereas desilylation with TBAF generates the erythro-diastereomer 340, this time via a closed Diels-Alder (or Zimmerman-Traxler)-like transition state. In both cases, chelating effects can be ruled out... 

Due to the high a-C,H acidity in the alkoxyethylidene complexes 6 (e.g.,piCa=8 (R=Me)) [ 16], transformations via an enolate analog are possible and have been used to introduce additional functionality into the carbene side chain to access various Fischer carbene complexes [3]. The a,/J-unsaturated complex 8 could be obtained from 6 (R=Et) by an aldol-type condensation with benzaldehyde 7 in the presence of triethylamine and trimethylsilyl chloride (Scheme 2) [17]. This reaction proceeds completely diastereoselectively to yield only the trans-isomer. Analogously, binuclear complexes have been prepared from 6 and 1,3-and 1,4-phthaldialdehyde in good yields [17]. This type of condensation has... 

Recent developments of aldol-type reactions with titanium enolates include the a- and /3-C-glycosidation of glycals73 and the diastereoselective addition to 2-acetoxytetrahydrofurans.74 Mukaiyama and co-workers have developed a one-pot procedure for the preparation of unsymmetrical double aldols.75... 

This enantioselective preparation of allylic alcohols has been applied to the synthesis of the side chain of prostaglandins . The addition to functionalized aldehydes, such as 483, allows the synthesis of C2-symmetrical 1,4-diols, such as 484, with excellent diastereoselectivity and enantioselectivity . An extension of this method allows the synthesis of C3-symmetrical dioF . Aldol-type products result from the catalytic enantioselective addition of functionalized dialkylzincs to 3-TIPSO-substituted aldehydes, such as 485, followed by a protection-deprotection and oxidation sequence affording 486 in 70% yield and 91% ee (Scheme 118) . The addition to a-alkoxyaldehydes provides a... 

The Mukaiyama aldol reaction of carbonyl substrates with silyl enol ethers is the most widely accepted of Lewis acid-promoted reactions. Many Lewis acids for the reaction have been developed and used enantioselectively and diastereoselectively. In 1980, catalytic amounts of la were found by Noyori et al. to effect aldol-type condensation between acetals and a variety of silyl enol ethers with high stereoselectivity [2c,20]. Unfortunately, la has poor Lewis acidity for activation of aldehydes in Mukaiyama s original aldol reaction [21]. Hanaoka et al. showed the scope and limitation of 11-cat-alyzed Mukaiyama aldol reaction, by varying the alkyl groups on the silicon atom of silyl enol ethers [22]. Several efforts have been since been made to increase the reactivity and/or the Lewis acidity of silicon. One way to enhance the catalyst activity is to use an additional Lewis acid. 

Scheme 23 shows how four possible diastereomers can arise from the combination of two sp -carbon centers C-1 and C-2 in a donor component 23-1 and an acceptor component 23-2. Species 23-3 and 23-4 are two diastereomers and 23-5 and 23-6 are their enantiomers.The problem of simple diastereoselection is the control of the diastereomer ratio 23-3-1-23-5/23-4-1-23-6. The enantiocontrol of 23-3 vs 23-5 or of 23-4 vs 23-6 cannot be achieved by simple diastereoselection in this case an external source of chirality has to be applied, for instance a chiral catalyst or the incorporation of stereogenic units in one of the components. Simple diastereoselection can be exerted in terms of closed and open transition states, depending on the mutual interaction of the termini X and Do, respectively. If these termini are linked via a six-membered chelate, a closed ( Zimmerman-Traxler ) transition state 23-7 with synperiplanar olefinic units is formed. On the other hand, if the termini have a repulsive interaction an open transition state 23-8 with an antiperiplanar arrangement of the olefinic units is adopted. Efficient stereocontrol via Zimmerman-Traxler transition states 24-1 to 24-4 is observed in aldol-type and allylborane carbonyl additions (Scheme 24). The crucial stereo differentiating interaction is the diaxial repulsion between Rax and R, which must be kept as low as possible. Only small substituents (nor-...

The influence of Lewis acids on the diastereoselectivity of the cycloaddition of /f-alkoxyalde-hydes has also been studied35. Magnesium bromide, highly effective for a-alkoxyaldehydes, fails in the case of the cycloaddition of aldehyde 10 to diene 2 and the reaction does not exhibit any selectivity, probably due to a change of mechanism to Mukaiyama s aldol type. One reason may be the change of solvent from tetrahydrofuran to a mixture of benzene and diethyl ether. The additions of aldehyde 10 to other dienes are more selective but diastereoselectivity is still much lower than for the a-alkoxy aldehydes. Boron trifluoride-diethyl etherate complex also leads to a mixture of four possible products. Excellent selectivity is achieved for the titanium(IV) chloride catalyzed addition of aldehyde 10a to diene 2b, 11c is obtained as the only product. 

This reaction was first reported by Schollkopf in 1979. It is a synthesis of an unnatural nonproteinogenic amino acid from the lithiated enolate equivalent of a simple amino acid (e.g., glycine, alanine and valine), which involves the diastereoselective alkylation of the lithiated bis-lactim ether of an amino acid with an electrophile or an Aldol Reaction or Michael Addition to an o ,jS-unsaturated molecule and subsequent acidic hydrolysis. Therefore, the intermediate of the bis-lactim ether prepared from corresponding amino acids is generally referred to as the Schollkopf bis-lactim ether, " Schollkopf chiral auxiliary, Schollkopf reagent, or Schollkopf bis-lactim ether chiral auxiliary. Likewise, the Schollkopf bis-lactim ether mediated synthesis of chiral nonproteinogenic amino acid is known as the Schollkopf bis-lactim ether method, Schollkopf bis-lactim method, or Schollkopf methodology. In addition, the reaction between a lithiated Schollkopf bis-lactim ether and an electrophile is termed as the Schollkopf alkylation, while the addition of such lithiated intermediate to an Q ,j8-unsaturated compound is referred to as the Schollkopf-type addition. ... 

Sulfinylenamine (36) was reduced in a diastereoselective fashion to yield 81% of diastereoisomers (37a), (37b), (38a) and (38b) in 4 4 1 1 ratio, as indicated in Scheme 4.20. The diastereoisomers were separable by flash column chromatography. As in previous transition state models, approach of the hydride nucleophile from the least hindered face of the enEunine is preferred. Since the stereochemistry of the p-position chiral centre is controlled by hydride addition, both (37a) and (37b) are equally useful in later synthetic steps. Aldol-type butyrylation of (37a) or (37b) was found to be stereoselective, yielding 76% of a 2 1 mixture of alcohols (39a) and (39b), irrespective of the isomer of (37) used (Scheme 4.21). 

With this new methodology in hands, Hu et al. [166] explored the trapping of the 1,4-addition intermediate with a different electrophile for the development of a new MCR. RhjCOAc) was again the most active catalyst in the 1,4-addition/aldol-type intramolecular cascade reaction. Under the optimized reaction conditions, this three-component reaction worked well with a broad family of bifunctional substrates 135 bearing different substituents on the aryl group next to the enone moiety and a variety of alcohols 136 (Scheme 3.63). In all cases, 1-indanols 137 were obtained in 60-83% yield and with complete diastereoselectivity. Enantiopure 1-indanol was obtained employing a L-menthol-derived diazo compound. The intermolecular four-component version was also attempted, but the formation of the desired product was not observed. 

Sibi et al. demonstrated for the first time that intermolecular radical addition to a,P-disubstituted substrates (12) followed by hydrogen atom transfer proceeded with high diastereo- and enantioselectivities (Scheme 4.6) [4]. In particular, a chiral bis(oxazoline)s-Mgl2 catalytic system was applied to the enantioselective and highly diastereoselective antijsyn = 99/1) synthesis of anti-aldol-type adducts (13). This is noteworthy because there have been few examples of highly selective methods for preparing anti aldol despite the array of solutions for the synthesis of syn aldol. The key to increasing the reactivity for a,P-disubstituted substrate (12) was N-H imide templates that relieve problems, and the promotion of Lewis acid catalysis via... 

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