1.3- diols, asymmetric aldol reactions

Stereoselective Synthesis of 1,3-Diols Asymmetric Aldol Reactions... 

Ligands for catalytic Mukaiyama aldol addition have primarily included bidentate chelates derived from optically active diols,26 diamines,27 amino acid derivatives,28 and tartrates.29 Enantioselective reactions induced by chiral Ti(IY) complex have proved to be one of the most powerful stereoselective transformations for synthetic chemists. The catalytic asymmetric aldol reaction introduced by Mukaiyama is discussed in Section 3.4.1. 

In the total synthesis of (+)-trienomycins A and F, Smith et al. used an Evans aldol reaction technology to construct a 1,3-diol functional group8 (Scheme 2.1i). Asymmetric aldol reaction of the boron enolate of 14 with methacrolein afforded exclusively the desired xyn-diastereomer (17) in high yield. Silylation, hydrolysis using the lithium hydroperoxide protocol, preparation of Weinreb amide mediated by carbonyldiimidazole (CDI), and DIBAL-H reduction cleanly gave the aldehyde 18. Allylboration via the Brown protocol9 (see Chapter 3) then yielded a 12.5 1 mixture of diastereomers, which was purified to provide the alcohol desired (19) in 88% yield. Desilylation and acetonide formation furnished the diene 20, which contained a C9-C14 subunit of the TBS ether of (+)-trienomycinol. 

Optically active 1,2-diol units are often observed in nature as carbohydrates, macrolides or polyethers, etc. Several excellent asymmetric dihydroxylation reactions of olefins using osmium tetroxide with chiral ligands have been developed to give the optically active 1,2-diol units with high enantioselectivities. However, there still remain some problems, for example, preparation of the optically active anti-1,2-diols and so on. The asymmetric aldol reaction of an enol silyl ether derived from a-benzyloxy thioester with aldehydes was developed in order to introduce two hydroxyl groups simultaneously with stereoselective carbon-carbon bond formation by using the chiral tin(II) Lewis acid. For example, various optically active anti-a,p-dihydroxy thioester derivatives are obtained in good yields with excellent diastereo-... 

A stoichiometric amount of 3f catalyzed the asymmetric aldol reaction of aldehydes with enol silyl ethers and subsequent asymmetric reduction, in one pot, to afford syn 1,3-diols with high enantioselectivity (Eq. 49) [43b]. With a variety of aldehydes, 1,3-diols were obtained in moderate yields (53-70 %) with high syn diastereoselectivity. The syn 1,3-diols prepared from aliphatic aldehydes in the reaction (in EtCN as sol-... 

Asymmetric synthesis of 1,2-diol derivatives based on asymmetric aldol reactions of a-alkoxy silyl enol ethers with aldehydes has been developed. The reaction of (Z)-2-benzyloxy-l-(5)-ethyl-l-trimethylsiloxyethene with benzaldehyde was conducted in dichloromethane at -78 °C with a chiral promoter consisting of Sn(OTf)2, (5)-l-ethyl-2-[(piperidin-l-yl)methyl]pyrrolidine, and Bu2Sn(OAc)2, to afford the corresponding aldol adduct in 83 % yield with 99 % anti preference. The enantiomeric excess of anti aldol is 96 % [38a]. In the aldol reaction of several kinds of aldehydes, e.g. aromatic,... 

Bahmanyar, S., Houk, K. N. Proline-catalyzed direct asymmetric aldol reactions. Catalytic asymmetric synthesis of anti-1,2-diols. Chemtracts 2000,13, 904-911. 

In sharp contrast to the utility of chiral boron Lewis acids, chiral aluminum Lewis acids have been little used for asymmetric aldol reactions of silyl enolates since the first example reported by Reetz et al. [115]. Fujisawa et al. have reported that an equimolar amount of a chiral Lewis acid prepared from Et2AlCl and a bor-nane-2,3-diol promotes the aldol reaction of 48 in moderate yields with good enantioselectivity [127]. 

A few secondary/tertiary diols have been used as chiral auxiliaries. The monoacetates of (R)- and (SJ-1.32 (R = Ph) [204] are interesting precursors for asymmetric aldol reactions [205-210], (S)-1 -Phenyl-3,3-bis(trifluoromethji)pro-... 

The 1,3-diol systems are often found in the polyoxomacrolide ring. Thus, two major synthetic transformations for the construction of 1,3-diols are described in this section (1) asymmetric aldol reaction and (2) asymmetric epoxidation and epoxide ring-opening. 

Aldolization and related reactions. Tartaric acid-derived acyloxyborane complexes are shown to be useful catalysts for asymmetric aldol reactions. (5)-4-Isopropyl-3-tosyl-l,3,2-oxazaborolidin-5-one is an excellent cataly.st, not only for the aldolization " between a silyl enol ether and an aldehyde it also reduces the products to afford syn-l,3-diols. ... 

The air stable and storable zirconium catalyst, formed from Zr(0 Bu)4, 3,3 -diiodo-l,l -binaphthalene-2,2 -diol (3,3 -l2-BINOL), -propanol and water, with the putative dimeric structure (7.33) also catalyses auft -selective asymmetric aldol reactions. While this process is beheved to proceed through an acyclic transition state, as depicted in Figure 7.2, it is postulated that the greatest steric interaction is now between the silyl enol ether substituent R3 and the bulky Lewis acid resulting in the formation of the fluft -diastereomer predominantly. 

Floreancig completed the total synthesis of (+)-dactylohde via a sequential Peterson olefination and an intramolecular Hosomi-Sakurai-Prins cycli-zation of the acetal-linked substrate (Scheme 32). Macrocychzation was performed by Horner-Emmons olefination as Smith did (Sect. 3.2.1). The key element of 2,6-cfs-tetrahydropyran in 155 was constructed via the sequential cyclization starting from acetal 156, which involved aldehyde 157 and 1,3-diol 158, synthesized via Denmark s asymmetric aldol reaction and Stille coupling. 

Reports of the use of chiral aluminum Lewis acids in the asymmetric aldol reaction are quite limited. The first enantioselective aluminum-catalyzed Mukaiyama aldol reaction was reported about 10 years ago (158). In this asymmetric version, /5-hydroxy ester was formed in high enantiomeric excess by the ketene silyl acetal with aldehyde in the presence of a chiral Lewis acid prepared from diethylaluminum chloride (Et2AlCl) and chiral diol derived from... 

Optically active syn and anti diol units can be easily prepared by the asymmetric aldol reaction of aldehydes with silyl enolates (4) and (5), respectively, under the influence of chiral tin(II) Lewis acid (6). Diastereofacial selectivities are controlled simply by choosing the protective group of the ct-alkoxy part of ketene silyl acetals (eqs 2 and 3). 

Table 2 A chiral diol-calcium complex-catalyzed asymmetric aldol reaction...

Because optically active molecules containing 1,2-diol units are often observed in nature (e.g. carbohydrates, macrolides, polyethers), asymmetric aldol reaction of the silyl enolate of a-benzyloxythioacetate 82 with aldehydes has been investigated for simultaneous introduction of two vicinal hydroxy groups with stereoselective carbon-carbon bond-formation. It has, interestingly, been found that the anti-a,fd-dihydroxy thioester derivatives 83 are... 

As an early example of asymmetric aldol reaction mediated by chiral aluminum Lewis acids, Fujisawa and Shimizu reported the use of several catalysts generated from a series of chiral bornane type diols or the related amino alcohols (Scheme 6.22)... 

L-Threonine-derived catalysts were demonstrated to be remarkably effective for the direct aldol reaction. Lu et al. investigated the potential of serine and threonine analogs in the direct asymmetric aldol reaction in aqueous medium [28]. While L-serine and L-threonine were found to be ineffective, sUylated threonine and serine derivatives were wonderful catalysts for the direct aldol reaction of cyclohexanone and aromatic aldehydes in the presence of water, affording the aldol adducts in excellent yields and with nearly perfect enantioselectivities. L-Serine-derived 9a was inferior to the corresponding threonine-based catalysts. The reaction could be extended to hydroxyacetone, and sy -diols were obtained with very good enantioselectivities (Scheme 3.6). Subsequently, Teo and coworkers also employed silylated serine catalysts for the same reaction [29]. Very recently, Cordova et al. [30] reported a co-catalyst system consisting of 8a and l,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea, and applied such catalytic pairs to the direct aldol reaction between ketones and aromatic aldehydes both cyclic and acycUc ketones were found to be suitable substrates. 

Di[3,5-(trifluoromethyl)phenyl]prolinol has been used to effect enantioselective formation of y-oxo- -hydroxy-a-substituted aldehydes with anti selectivity.Homoboro-proline bifunctional catalysts have been fine-tuned for asymmetric aldol reactions in DMF by adjusting the Lewis acidity of boron through in situ esterification with mildly sigma-electron-withdrawing diols. NMR study of the more stable five-ring boronate esters has shed light on their mode of action (17) was particularly effective. 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

The first basic asymmetric catalysts of type A were prepared from LnCl3 (Ln = Y or La) and enantiopure bidentate diol derivatives such as 164 under the conditions outlined in Figure 3. Although the structures of the type A catalytic species were still open to conjecture, they nonetheless proved effective for catalytic asymmetric reactions. Thus treatment of 14 with the yttrium catalyst of type A in THF at -52 °C for 6 days gave a 60% yield of 15a with 52% ee.5 However, it was shown that the enantiomeric purity of isolated 15a decreased when further exposed to the type A catalyst at -30 °C, suggesting that the product had a tendency to undergo a retro aldol reaction. 

Precursor of Useful Chiral Ligands. OPEN is widely used for the preparation of chiral ligands. Organometallic compounds with these ligands act as useful reagents or catalysts in asymmetric induction reactions such as dihydroxylation of olefins, transfer hydrogenation of ketones and imines, Diels-Alder and aldol reactions, desymmetrization of meso-diols to produce chiral oxazolidinones, epoxidation of simple olefins, benzylic hydroxylation, and borohydride reduction of ketones, imines, and a,p-unsaturated carboxylates. ... 

Sato/Kaneko [104] and Carreira [105] have independently employed acetoacetate-derived O-silyl dienolates as Si-substituted nucleophiles in asymmetric catalytic aldol reactions. The aldol products, d-hydroxy-/3-ketoesters, and the derived syn- and anti-yS,d-diol esters are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotics. These structural subunits are also found in chemotherapeutics, most notably compactin analogs [106] that have been studied as... 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

Chiral borane catalyst 47g, prepared from N-losyl-(a.S, /j R)-/i-melhyltryptophari and (p-chlorophenyl)dibromoborane, is fairly effective in asymmetric aldol-type reaction of 1,3-dioxolanes bearing an aryl or vinyl group at fhe 2-position (Scheme 10.45) [125]. The ring-cleavage products can be converted into free aldols without epimerization by iodination and subsequent reduction. The chiral borane-promoted reaction wifh 48 is very valuable for asymmetric desymmetrization of symmetric 1,3-dioxolanes and 1,3-dioxanes leading to mono protected 1,2- and 1,3-diols, respectively [126]. 

The asymmetric carbonyl-ene reaction has been developed by using chiral aryloxy complexes, i.e, 64 [197,198] and 65 [199]. Titanium complexes bearing chiral diols such as 66 and 67 have been used as catalysts for various enantioselective reactions such as synthesis of cyanohydrin, aldol reactions [200], [2 + 2] cycloaddition reactions [201], the reaction of diketene with aldehyde [202], hydroboration [203], allylation of aldehydes [204], and Diels-Alder reactions [205]. 

A new phase-transfer catalyzed asymmetric glycolate aldol reaction was reported that provides diols in low to good yields, high de, and moderate to good ee as illustrated in Scheme 37. The recystalhzation of diol products could enrich the ee to 95%, additionally, the authors used 128 (R = Ph) to synthesize a known (S TJydiol methyl ester to show utility of this new method <05OL3861>. 

It turns out that one of the best ketones for these asymmetric crossed aldol reactions is hydroxy-acetone 96. Combination with isobutyraldehyde 89 gives an aldol that is also an anti-diol 97 with almost perfect selectivity.21 The proline enamine of hydroxyacetone is evidently formed preferentially on the hydroxy side. You will recall from chapter 25 that asymmetric synthesis of anti-diols is not as easy as that of syn diols. 

Asymmetric syrc-selective aldol reaction of four carbons enolates (with attached chiral auxiliary) 290 and acrolein equivalent 291 was the key step in the Pettus synthesis of KDO [153]. Condensation adduct 292 was converted into the hydroxy lactone 293, which in turn after silyl deprotection and diol side chain installation gave lactone 204. Final addition of a carboxylic acid to the lactone carbonyl group of 204 was done with a-ethoxy vinyllithium. Reductive ozonolysis of the surrogate provided the ethyl ester 138 (Scheme 62). 

The Evans asymmetric alkylation [127] and aldol reactions were also effectively applied to the synthesis of the C10-C19 top segment 230 (Scheme 33). The starting chiral unit 223 was synthesized via the Evans asymmetric alkylation of 218a. The subsequent Evans aldol reaction of 223 with 224 followed by trans-amidation yielded 2,3-sy -diol derivative 225 with complete stereoselectivity. Addition of alkyl lithium 226 to the Weinreb amide 225 produced ketone 227, which was stereoselectively reduced and methylated to give dimethyl ether 228. The standard functional group manipulation afforded thioacetal 229, which was converted into phosphine oxide 230. 

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