Syn-aldol adducts

It was anticipated that two of the three stereochemical relationships required for intermediate 12 could be created through reaction of the boron enolate derived from imide 21 with a-(benzyloxy)ace-taldehyde 24. After conversion of the syn aldol adduct into enone 23, a substrate-stereocontrolled 1,2-reduction of the C-5 ketone car-... 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

Scheme 6a presents the synthesis of fragment 15. Intermediate 15 harbors two vicinal stereogenic centers, and is assembled in a very straightforward manner through the use of asymmetric aldol methodology. Treatment of the boron enolate derived from 21 with 3-[(p-methoxybenzyl)oxy]propanal (22) affords crystalline syn aldol adduct 34 in 87 % yield as a single diastereomer. Transamination to the A-methoxy-A-methylamide,20 followed by silylation of the secondary hydroxyl group at C-19 with triethylsilyl chloride, provides intermediate 15 in 91 % yield. 

A jy -diastereoselective aldol reaction based on titanium enolates from (A)-l-benzyloxy-2-methyl-3-pentanone was developed by Solsona et al. (Equation (12)).64 The titanium enolate of this chiral ketone afforded the corresponding syn-syn aldol adducts in high yields and diastereomeric ratios with a broad range of aldehydes. 

Aldol addition of aliphatic aldehydes to 105 [50] yielded the expected syn-aldol adducts 106, which spontaneously lactonized upon warming to 0 °C to give the y-butyrolactones 107 in good yields and excellent optical purities. The chemoselective deprotonation of 105 in a-position to the im-... 

Diastereoselective aldol condensations.1 The reaction of (S)-( - )-2-benzyl-oxyhexanal (2) complexed with TiCl4 with the bistrimethylsilyl enol ether (1) of methyl acetoacetate gives almost exclusively the syn-aldol adduct (3). This reaction... 

Recently, Yamamoto et al. have shown that the chiral acyloxyborane complex 31 is an excellent catalyst for the asymmetric Mukaiyama condensation of simple silyl enol ethers (Scheme 8B1.19 Table 8B1.11 entries 1-7) [43], The syn-aldol adducts are formed preferentially with high enantiomeric excess regardless of the stereochemistry (EI7) of the silyl enol ethers, suggesting an extended transition state (entries 4, 7). This methodology has been... 

Recently, a conceptually different synthesis of MeBmt using an asymmetric glycine aldol reaction was reported by Evans and Weber [29]. The key step consists in the stereochemically controlled condensation of the chiral glycine enolate synthon (23) with the (R)-aldehyde (24) mediated by stannous triflate (tin salt of trifluoromethanesulphonic acid). The desired syn-aldol adduct (25) was isolated in form of the heterocyclic compound (26). The sense of asymmetric induction in the aldol reaction was established by conversion of (26) over three steps into uniform MeBmt (3). 

For satisfactory diemo- and stereoselectivity, most catalytic, direct cross-aldol methods are limited to the use of non enolizable (aromatic, a-tert-alkyl) or kineti-cally non enolizable (highly branched, ,/funsaturated) aldehydes as acceptor carbonyls. With aromatic aldehydes, however, enantioselectivity is sometimes moderate, and the dehydration side-product may be important. With regard to the donor counterpart, the best suited pronucleophile substrates for these reactions are symmetric ketones (acetone) and ketones with only one site amenable for enolization (acetophenones). With symmetric cyclic or acyclic ketones superior to acetone, syn/anti mixtures of variable composition are obtained [8b, 11, 19a]. Of particularly broad scope is the reaction of N-propionylthiazolidinethiones with aldehydes, which regularly gives high enantioselectivity of the syn aldol adduct of aromatic, a,fi-unsaturated, branched, and unbranched aldehydes [13]. 

Aldol Reactions. The dibutyl boryl enolates of chiral acylox-azolidinones react to afford the syn-aldol adducts with virtually complete stereocontrol (eq 32). 14,43.61-64 Notably, the sense of induction in these reactions is opposite to that predicted from the analogous alkylation reactions. This reaction is general for a wide range of aldehydes and imide enolates. - Enolate control overrides induction inherent to the aldehyde reaction partner. 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

In recent pioneering studies, Crimmins has reported the use of acyloxazolidine-thione auxiliaries (18) and TiCl4 for the preparation of either syn aldol adducts as a function of the stoichiometry of the amine base and metal (Eq. (8.6)) [11]. The use of 1 2 TiCl4 and TMEDA or sparteine yielded the normal 1,2-syn Evans aldol adduct 21 however, the use of 2 1 TiCU Pr2NEt leads to dramatic reversal to give the non-Evans , 2-syn diastereomer 20 in remarkable diastereoselectiv-ity (>99 1). 

In most cases, the relative stereochemistry of an aldol product is determined by the geometry of the enolate component, where (Z)-enolates give syn aldol adducts and ( )-enolates afford anti products. Asymmetric induction in the aldol reaction... 

The complex (A,A)-(ebthi)TiCl(OMe) has been synthesized from the corresponding titanium dichloride. This compound catalyzes the asymmetric aldol reaction of enol trichloroacetate of cyclohexanone with aromatic aldehydes with the result that the optically active syn-aldol adduct is obtained with up to 91% ee.1664... 

A-Acylaziridines can be deprotonated to yield enolates, which can participate in alkylations and aldol condensations <91TL2533, 94AG(E)599>. The aziridine ring was used as a chiral auxiliary, and good to excellent diastereoselectivity was obtained. Equation (47) shows an example of such an enolate alkylation. Quenching the enolate with an aldehyde produced a single syn aldol adduct. 

The biologically active monosaccharide 3-deoxy-D-ura6//io-heptulosonic acid 7-phosphate (8 DAMP) is an important intermediate in the biosynthesis of aromatic amino acids in plants (the shikimate pathway). As shown in Scheme 2, this compound has been produced in a combined chemical and enzymatic synthesis from racemic V-acetylaspartate 3-semialdehyde (4) and DHAP (1). The four-step synthesis proceeds in an overall yield of 13% (37% for the aldolase reaction). The enzymatic step generates the required, enantiomerically pure, syn aldol adduct compound (5). In view of the broad range of substrates tolerated by FDP aldolase, this method may be applicable to the production of analogs of DAMP. 

In practice, aldehydes bearing an adjacent stereogenic center, particularly one devoid of a bulky group, typically provide only modest aldol stereoselectivity. For example, consider the reaction of aldehyde 28 with Z boron enolate 27 as shown in Scheme 3a. According to the models just discussed, one would expect this reaction to provide only 1,2-syn products with anti-Felkin- Ahn stereoselectivity. Indeed, that conjecture proved to be true for the most part as exclusively 1,2-syn aldol adducts resulted with 29, a compound whose stereotriad reflected anti-Felkin—Ahn selectivity, constituting the predominant product. However, a fair amount of the alternate 1,2-syn Felkin- Ahn adduct (30) was also observed, such that the final ratio of 29 to 30 was a disappointing 1.75 1. 

In addition to the preceding methods that involve functionalization of an enone or enoate p-carbon with an alkyl or aryl functionality, methods for the nickel-catalyzed reductive aldol functionalization of enoates have also been developed (Scheme 3-81). Using triethylborane as the terminal reductant with Ni(cod)2 as catalyst, reductive aldol reactions proceed to give syn aldol adducts. An unusual role of phenyl iodide as a promoter for the process was found in this study. Intramolecular reductive aldol additions utilizing Ni(acac)2 as catalyst and diethylzinc as the terminal reduetant were also described. ... 

Tin enolates of the g-alanine derivatives (504), generated using stannous triflate and N-ethylpiperidine, condense with aldehydes to give high yields of virtually pure syn-aldol adducts,... 

In the reaction of the tin(II) enolate derived from (1) with aldehydes, enantioselectivities are disappointingly low, while good diastereoselectivities are observed. Highly diastereo- and enan-tioselective aldol reactions of propionate derivatives with aldehydes have been achieved by using the ketene silyl thioacetal (7) instead of the tin(II) enolate. The complex (8) produced by mixing tin(n) triflate and the chiral diamine (6) works as an efficient chiral Lewis acid. The reaction of (7) with various aldehydes proceeds smoothly in the presence of (8) and dibutyltin diacetate in dichloromethane to afford the syn aldol adducts in high yields with almost perfect stereochemical control (eq 9). ... 

The boron-mediated aldol reaction of an Evans s acyl oxazolidinone with an aldehyde affords the Evans-syn aldol adduct 9. The process proceeds via formation of the Z enolate that reacts with the aldehyde, presumably through a well ordered six-membered, chair-shaped Zimmerman-Traxler model... 

The boron-mediated aldol reaction of 24 (or 26) with aldehydes to give the syn aldol adduct 25 (or 27) is one of the most reliable aldol bond formations. ... 

The enolates derived from TV-a-alkoxvacetyloxazolidinones provide syn aldol adducts in good yield and selectivity. ... 

A Haloacetyl oxazolidinones form suitable enolate partners in aldol reactions, although complete aldehyde conversion requires the use of a slight excess of imide. Nucleophilic azide displacement of a-halo-P-hydroxy syn aldol adducts affords the corresponding anti a-amino- 3-hydroxy compounds. ... 

In the synthesis of the C1-C12 fragment of amphidinolide Tl, syn aldol adduct 77 was prepared in 92% yield as a single diastereomer by the Crimmins modified Evan s strategy (TiCU with (-)-sparteine). This protocol was also used to install the stereocenters at the C4 and C5 in 80 with excellent diastereoselectivity (96% de) in the total synthesis of (-)-bitungolide F. In the total synthesis of cruentaren B, the Crimmins modified condition was used in the Evans syn aldol reaction, giving adduct 82 in excellent yield and diastereoselectivity (92%, 98% de). ... 

TiCU and (-)-sparteine the reaction of the enolate of 91 with chiral aldehyde gave the syn-aldol adduct 92 with an excellent selectivity (96% de). Execution of the second asymmetric aldol, under the same condition, yielded the syn-aldol adduct 94 (96% de) ... 

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