Acetates, aldol stereochemistry

In addition to the acetate aldol problem, stereoselective aldol additions of substituted enolates to yield 1,2-anti- or f/treo-selective adducts has remained as a persistent gap in asymmetric aldol methodology. A number of innovative solutions have been documented recently that provide ready access to such products. The different successful approaches to anri-selective propionate aldol adducts stem from the design of novel auxiliaries coupled to the study of metal and base effects on the reaction stereochemistry. The newest class of auxiliaries are derived from A-arylsulfonyl amides prepared from readily available optically active vicinal amino alcohols, such as cw-l-aminoindan-2-ol and norephedrine. 

The key asymmetric acetate aldol reaction was carried out using Carreira s conditions (Scheme 12-1) to give 4 in nearly quantitative yields and perfect enantioselectivity, followed by hydrolysis to acid ent-5. This is the enantiomer of the fragment present in the natural products. Because of later difficulties with the macrolactonization, that step was carried out under Mitsunobu conditions with inversion of the alcohol, hence necessitating the opposite stereochemistry in precursor ent-5. 

Titanium enolate aldol reactions have been shown to be very effective for control of relative and absolute stereochemistry in acetate aldol and both syn and anti aldol reactions. The use of readily available and inexpensive titanium reagents make these methods convenient for large-scale synthesis. The synthetic potential of a variety of aldol reactions has been demonstrated by highlighting the synthesis of numerous bioactive complex natural products. The significance of enantio- and diastereoselection in synthesis, particularly in this pharmaceutical age, ensures that titanium enolate aldol reactions will remain an important part of organic synthesis for years to come. There is no doubt that unprecedented success has been achieved in the development of a variety of titanium enolate aldol reactions in the past decade. Much new potential and other exciting possibilities remain to be... 

In addition to the advances in auxiliary-controlled acetate aldol addition reactions, a number of innovative solutions for the preparation of propionate-derived 1,2-anti products have also appeared using auxiliaries other than Evans oxazolidinone. The various successful approaches to anti aldol adducts stem from the design of novel auxiliaries coupled with the study of metal and base effects on the reaction stereochemistry. Masamune documented that the addition of optically active ester enolate 112 to aldehydes afforded anti aldol adduct 113 in superb yield and diastereoselectivity (Equation 10) [70]. After careful selection of the reaction conditions for the enolization of the ester [71], the aldol addition was successfully carried out with a broad range of substrates including aliphatic, aromatic, unsaturated, and functionalized aldehydes. An attractive feature of this process is the subsequent facile removal of the auxiliary (LiOH, THF/H2O) to afford the corresponding acid without concomitant deterioration of the configurational integrity of the products [70]. 

A similar case of enolatc-controlled stereochemistry is found in aldol additions of the chiral acetate 2-hydroxy-2.2-triphenylethyl acetate (HYTRA) when both enantiomers of double deprotonated (R)- and (S)-HYTRA are combined with an enantiomerically pure aldehyde, e.g., (7 )-3-benzyloxybutanal. As in the case of achiral aldehydes, the deprotonated (tf)-HYTRA also attacks (independent of the chirality of the substrate) mainly from the /te-side to give predominantly the t/nii-carboxylic acid after hydrolysis. On the other hand, the (S)-reagcnt attacks the (/ )-aldebyde preferably from the. S7-side to give. s wz-carboxylic acids with comparable selectivity 6... 

The synthesis of Baccatin HI shown in Scheme 13.57, which was completed by a group led by the Japanese chemist Teruaki Mukaiyama, takes a different approach for the previous syntheses. Much of the stereochemistry was built into the B-ring by a series of acyclic aldol additions in Steps A through D. A silyl ketene acetal derivative... 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Note that harsher conditions may lead to further changes, e.g. epimerization at C-3 in fmctose, plus isomerization, or even reverse aldol reactions (see Section 10.3). In general, basic conditions must be employed with care if isomerizations are to be avoided. To preserve stereochemistry, it is usual to ensure that free carbonyl groups are converted to acetals or ketals (glycosides, see Section 12.4) before basic reagents are used. Isomerization of sugars via enediol intermediates features prominently in the glycolytic pathway of intermediary metabolism (see Box 10.1). 

The present procedures illustrate general methods for the use of preformed lithium enolates5 as reactants in the aldol condensation6 and for the quenching of alkali metal enolates in acetic anhydride to form enol acetates with the same structure and stereochemistry as the starting metal enolate.7 The aldol product, [Pg.55]

A diastereoselective Mukaiyama aldol lactonization between thiopyridylsilylketene acetals and aldehydes was used to form the /3-lactone ring in the total synthesis of (-)-panclicin D <1997T16471>. Noyori asymmetric hydrogenation was a key step in a total synthesis of panclicins A-E and was used to establish the stereocenter in aldehyde 140, which in turn directed the stereochemistry of subsequent reactions <1998J(P1)1373>. The /3-lactone ring was then formed by a [2+2] cycloaddition reaction of 140 with alkyl(trimethylsilyl)ketenes and a Lewis acid catalyst. 

The syntheses of the Cl -C6 aldol fragment (C) and similar building blocks with defined stereochemistry at C3 reveal several general problems. On one hand, it is difficult to transfer an acetate unit to an aldehyde with good ) -induc-tion, this usually is referred to as the aeetate-problem [44]. On the other hand the CI-C5... 

Mukaiyama Aldol Condensation. The BINOL-derived titanium complex BINOL-T1CI2 is an efficient catalyst for the Mukaiyama-type aldol reaction. Not only ketone silyl enol ether (eq 25), but also ketene silyl acetals (eq 26) can be used to give the aldol-type products with control of absolute and relative stereochemistry. 

Kiyooka et al. reported that the 3i-catalyzed aldol reaction of a silyl ketene acetal involving a dithiolane moiety with y3-siloxy aldehyde resulted in the production of syn and anti 1,3-diols with complete stereoselectivity depending on the stereochemistry of the catalyst used [45b]. This methodology was applied to the enantioselective synthesis of the optically pure lactone involving a syn-l,3-diol unit, known to be a mevinic acid lactone derivative of the HMG-CoA reductase inhibitors mevinolin and compac-tin (Sch. 2). 

The absolute stereochemistries observed are best explained in terms of the acyclic extended transition-state mechanism which Noyori postulated in the TMSOTf-cata-lyzed aldol reactions of dimethyl acetals (Fig. 6) [144]. In the reaction of aromatic silyl enol ethers, the left transition state, which is stabilized by the jr-attractive interaction between the phenyl and naphthyl groups, is favored over the right. In the reaction of... 

Azaborolyl complex (- -)-218 has been used in a stereoselective Mukaiyama aldol reaction as illustrated in Scheme 32 <2005JA15352>. Complex (- -)-218 reacts with electron rich aromatic aldehydes and silyl ketene acetals to generate adduct 220. X-ray structures indicate the stereochemistry is as illustrated. This stereochemistry is... 

The first enantioselective total synthesis of tetracyclic sesquiterpenoid (+)-cyclomyltaylan-5a-ol, isolated from a Taiwanese liverwort, was accomplished by H. Hagiwara and co-workers. They started out from Hajos-Parrish ketone analogue, (S)-(+)-4,7a-dimethyl-2,3,7,7a-tetrahydro-6/-/-indene-1,5-dione, that could be synthesized from 2-methylcyclopentane-1,3-dione and ethyl vinyl ketone in an acetic acid-catalyzed Michael addition followed by an intramolecular aldol reaction. The intramolecular aldol reaction was carried out in the presence of one equivalent (S)-(-)-phenylalanine and 0.5 equivalent D-camphorsulfonic acid. The resulting enone was recrystallized from hexane-diethyl ether to yield the product in 43% yield and 98% ee. Since the absolute stereochemistry of the natural product was unknown, the total synthesis also served to establish the absolute stereochemistry. 

In order to confirm the structures of solanapyrones, chemical synthesis of these phytotoxins were attempted based on biogenetic consideration [55], The retro synthesis envisaged intramolecular Diels-Alder reaction of the achiral polyketide triene (a), a key intermediate, which is further divided into a pyrone moiety (b) and a diene moiety (c). The moieties a and b were prepared from dehydroacetic acid and hexadienyl acetate, respectively. Aldol condensation of the aldehyde (72) with the dithioacetal (73) gave a dienol, which was further converted to a triene (74). The intramolecular Diels-Alder reaction of 74 in toluene at 170-190 °C for 1 hr in a sealed tube yielded a mixture of the adducts (75) and (76) in a ratio of 1 2. This product ratio depends on the solvents, i.e. in water (1 7), and should be useful in differentiating between artificial and enzymatic reactions in biosynthetic studies. Removal of the thioacetal groups in 75 and 76 yielded solanapyrone A (67) and D (70) in a ratio of 3 5. Though solanapyrone D (70) had not been isolated from the natural resources at this stage, the structure and stereochemistry were confirmed by H NMR spectrum. 

There are also stereochemical considerations here and Holmes used the Evans asymmetric aldol reaction (chapter 27) to make the starting material 174 R=Bn. The formation of any allyl vinyl ether reagent involves no change in the stereochemistry of the allyl alcohol - this is acetal exchange at the vinyl ether or acetal centre. The enol ether was added in masked form as a selenium compound 175 (chapter 32) as selenoxides eliminate at room temperature. The stereochemistry is developed directly from that in 177 as it transforms during the [3,3] shift. 

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