Chiral auxiliaries acetals

Efficient acetalization of alkenes bearing various EWG with an optically active 1.3-diol 72 proceeds smoothly utilizing PdCN, CuCI. and O2 in DME to give the 1,3-dioxane 73[113], Methacrylamide bearing 4-t-butyloxazolidin-2-one 74 as a chiral auxiliary reacts with MeOH in the presence of PdCE catalyst... 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

Acetylsultam 15 is also used for stereoselective syntheses of a-unsubstituted /1-hydroxy-carboxylic acids. Thus, conversion of 15 into the silyl-A/O-ketene acetal 16 and subsequent titanium(IV) chloride mediated addition to aldehydes lead to the predominant formation of the diastereomers 17. After separation of the minor diastereomer by flash chromatography, alkaline hydrolysis delivers /f-hydroxycarboxylic acids 18, with liberation of the chiral auxiliary reagent 1919. 

In another approach to the meso problem , utilization of a chiral auxiliary attached at nitrogen appears to induce very high stereoselectivity. Reduction of the optically active imide 10a (see Appendix) with tetramethylammonium triacetoxyborohydridc in acetone/ acetic acid at 25 "C gives a 4 96 mixture of the diastcreomers 11a and 12a in 87% yield44. On changing the solvent to acetonitrile/acetic acid the diastereomeric ratio is improved to < 1 99, but the yield is lower (63%). 

Only one example, showing high stereoselectivity, is known in this class of reactions. On treatment of the acyclic glycine cation equivalent 1 (see Appendix), containing the ( + )-cam-phor-10-sulfonamide ester as a chiral auxiliary, with boron trifluoridc and anisole at 0"C a mixture of aromatic substitution products is obtained in essentially quantitative yield 55. Besides 11 % of cuV/io-substitution product, the mixture contains (R,S)-2 and its (/ ,/ )-epimer in a ratio >96 4 (NMR). The same stereoisomer 2 predominates when the reaction is conducted in sulfuric acid/acetic acid 1 9, although the selectivity is slightly lower (91 9 besides 25% of ortho substitution). 

In y-alkoxyfuranones the acetal functionality is ideally suited for the introduction of a chiral auxiliary simultaneously high 71-face selectivity may be obtained due to the relatively rigid structure that is present. With ( + )- or (—(-menthol as auxiliaries it is possible to obtain both (5S)- or (5/ )-y-menthyloxy-2(5//)-furanones in an enantiomerically pure form293. When the auxiliary acts as a bulky substituent, as in the case with the 1-menthyloxy group, the addition of enolates occurs trans to the y-alkoxy substituent. The chiral auxiliary is readily removed by hydrolysis and various optically active lactones, protected amino acids and hydroxy acids are accessible in this way294-29s-400. 

Cyclic dithioketals and acetals represent another important class of sulfur containing chiral auxiliaries, which are available in chiral form by biooxidation. Biotransformations were performed on a preparative scale using whole-cells (wild type and recombinant) and isolated enzyme. Again, enantiocomplementary oxidation of unsubstituted dithianes (linear and cyclic, R = H) was observed when using and CPMOcomo (Scheme 9.28) [211,212]. Oxygenation of functionalized substrates (R = substituted alkyl) with gave preferably trans... 

Kinetic resolution of racemic allylic acetates has been accomplished via asymmetric dihydroxylation (p. 1051), and 2-oxoimidazolidine-4-carboxy-lates have been developed as new chiral auxiliaries for the kinetic resolution of amines. Reactions catalyzed by enzymes can be utilized for this kind of resolution. ... 

Mukaiyama aldol reactions have been reported, usually using chiral additives although chiral auxiliaries have also been used. This reaction can also be run with the aldehyde or ketone in the form of its acetal R R C(OR )2> in which case the product is the ether R COCHR2CR R OR instead of 27. Enol acetates and enol ethers also give this product when treated with acetals and TiCLi or a similar catalyst. When the catalyst is dibutyltin bis(triflate), Bu2Sn(OTf)2, aldehydes react, but not their acetals, while acetals of ketones react, but not the ketones themselves. 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

DHQD-CL or DHQ-CL) was used as the chiral auxiliary.175,176 However, the enantioselectivity observed under catalytic conditions was inferior to that observed under stoichiometric conditions. The addition of triethylammonium acetate, which increases the rate of hydrolysis of the Osvm-glycolate intermediate, improved enantioselectivity. A further improvement in enantioselectivity was brought about by the slow addition of substrates (Scheme 44).177 These results indicated that the hydrolysis of the Osvm-glycolate intermediate (57) was slow under those conditions and (57) underwent low enantioselective dihydroxylation (second cycle). Thus, Sharpless et al. proposed a mechanism of the dihydroxylation including a second cycle (Scheme 45).177 Slow addition reduces the amount of unreacted olefin in the reaction medium and suppresses the... 

Nagao, Y., Hagiwara, Y., Kumagai, T., Ochiai, M., Inoue, T., Hashimoto, K., and Fujita, E. (1986). New C4-chiral l,2-thiazolidine-2-thiones Excellent chiral auxiliaries for highly diastereocontrolled aldol-type reactions of acetic acid and a,b-unsaturated aldehydes. J. Org. Chem. 51, 2391-2393. 

One example of the use of 2D-NMR experiments in conformational analysis is the study of molecular interactions between cinchonidine and acetic acid [26]. These alkaloids are used as chiral auxiliaries in enantioselective hydrogenations, and the enantiomeric excess is dependent on solvent polarity, acetic acid being a good solvent This suggests that protonation and a preferred conformation play a role in achieving high enantioselectivities. With a combination of COSY-experiments, 3J coupling constants and NOESY experiments, it was shown that one conformer is preferred in acidic solutions. 

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... 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

Novel bicyclic imidazo-oxazaphosphinines have been synthesized in high diastereoselectivity by Marsault and Just <1996TL977>. In the first step, iV-tritylimidazole 209 was lithiated and, subsequently, treated with (.S )-propylcnc oxide as a chiral auxiliary and acetic acid to give the intermediate 210, which was reacted with alkyl dichlorophos-phite to yield the ring-closed product 211 as a single diastereomer (Scheme 33). Extension of these approaches for further derivatives 212 has also been published <1998NN939>. 

The third group4 used (1R,2S)-N methylephedrine as the chiral auxiliary. Thus the derived silylketene acetal (6) reacts with 1 in the presence of TiCl4 to give 7 in 45-70% yield with —90% stereoselectivity. The products are converted by TFA and LiOH to (R)-a-hydrazino acids (8), which are obtained in 5=98% ee after one crystallization. 

Moreover, this two-step equivalent of an aldol condensation can proceed with high enantioselectivity in the presence of a chiral auxiliary. Thus reaction of the enolate of chiral silyl ketene acetal (5) with isobutyryl chloride gives 6 in 89% yield and 94% ee after reduction of the intermediate. 

Very recently the tandem hydroformylation/acetalization has been used for the synthesis of new synthetically valuable chiral auxiliary derived from camphor. Stereoselective allylation of camphor and subsequent terminal hydroformylation of the resulting homoallylic alcohol affords the 5-lactol auxiliary (camTHP OH) in multigram scale (Scheme 8) [41]. 

The addition of doubly deprotonated HYTRA to achiral4 5 as well as to enantiomerically pure aldehydes enables one to obtain non-racemic (3-hydroxycarboxylic acids. Thus, the method provides a practical solution for the stereoselective aldoi addition of a-unsubstituted enolates, a long-standing synthetic problem.7 As opposed to some other chiral acetate reagents,7 both enantiomers of HYTRA are readily available. Furthermore, the chiral auxiliary reagent, 1,1,2-triphenyl-1,2-ethanediol, can be recovered easily. Aldol additions of HYTRA have been used in syntheses of natural products and biological active compounds, and some of those applications are given in Table I. (The chiral center, introduced by a stereoselective aldol addition with HYTRA, is marked by an asterisk.)... 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

Optically active cyanohydrins are obtained in good selectivity by the nucleophilic attack of cyanating reagents to chiral acetals.(21) However, the chiral auxiliaries are destroyed, and not recovered. In catalytic processes with chiral boryl compounds,(22) D-oxynitrilase,(23) and synthetic peptides,(24) the optical purities of the resulting cyanohydrins are generally not sufficient. 

Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by the use of various C-functionalized chiral nitrones in order to enforce enantioselec-tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as in the work of Merino et al. (40), that asymmetric induction is at best partial with dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot completely direct the addition to the nitrone. After poor results with menthol ester-and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-lidine 8a and its diastereomer 8b in near quantitative yield using the A-glycosyl... 

Diastereoselective cleavage of propynyl acetals of enantiomeric pure diols with organocopper(I) reagents leads to alkoxyallenes with high diastereomeric purity, in which the chiral auxiliary is included... 

A mixture of 1.5-3.5 mmol of the a-alkylated benzylimino product and 10-25 mL of0.5 M hydroxylamine acetate in anhyd ethanol is stirred at 25 C for 4-10 h. concentrated, the residue is dissolved in 30-50 mL of benzene, the solution is washed with sat. aq NaHC03 and then NaCI, concentrated, acidified with 10-20 mL of 5% aq hydrochloric acid, the mixture is stirred for 0.5 h and extracted with six 10-mL portions of diethyl ether. Concentration of the ethereal layer gives the oxime. The aqueous layer is basified with Na2C03, extracted with six 10-mL portions of diethyl ether, dried over potassium carbonate. Concentration and distillation (bulb-lo-bulb) gives the product. The chiral auxiliary can be recovered and recycled39. 

A special case of asymmetric induction using chiral auxiliaries has been reported for the alkylation of /1-keto esters94,106. In this approach the reaction proceeds in a diastereoselective manner via a base-catalyzed opening of the corresponding chiral 1.2-cyclohexanedioxy or 1,2-cyclohep-tanedioxy acetal, e g., acetal 50. 

Palladium(0)-catalyzed a-allylation of silyl ethers is a reaction which can be carried out with ketones as well as with aldehydes91. It is highly regiospecific when applied to ketones. a-Allylations can also be performed with enol acetates using allyl carbonates in the presence of catalytic amounts of palladium(O) complexes and (tributyl)methoxytin92,93. The steric course of the reaction has not been studied systematically but a high level of diastereoselectivity is expected and possibilities for asymmetric induction by the use of chiral auxiliaries are envisaged. 

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