Chiral 1,3-dioxane

As shown in racemic series [220], the stereoselectivity of the allylation of chiral 1,3-dioxanes 6.20 depends upon the reaction conditions and upon the nature of the reagent (silane or stannane). The most selective reagent is CH2=CHCH2SnBu3. Most of the reactions have been carried out with trimethyl-allylsilane in the presence of TiC1.4/Ti(0/-Pr)4 under the conditions recommended by Johnson and coworkers [213], After oxidation of the products and treatment with a base, nonracemic homoallylic alcohols are obtained with excellent enantiomeric excesses (Figure 6.58). From CH2=C=CHCH2SiMe3, dienyl alcohols are similarly obtained [1228, 1229] (Figure 6.58). The TiC -catalyzed reactions of dioxanes 6.20 with alkynylsilanes also lead to nonracemic a-alkynyl alcohols [223],... 

A further application of chiral 1,3-dioxanes of type 21 is the stereoselective fission of the 1,3-dioxane ring, e.g. of 25, by silyl nucleophiles in the presence of TiCl4 or other titanium compounds ... 

Thus, the chiral 1,3-dioxane system mediates the enantioselective addition of nucleophiles to an aldehyde [132], since the resulting P-alkoxycarboxylic acids 27 can be cleaved by lithium diisopropylamide to give the chiral alcohols 28 with elimination of crotonic acid. 

The chiral 1,3-dioxanes 21 and 25 are obtained from the biopolymer poly[(i )-3-hydroxybutyric acid] (PHB) by hydrolysis providing the chiral P-hydroxy acid 26 which is condensed with aldehydes. 

Similar to the a-alkylbenzylamine auxiliaries, the chiral dioxane is destroyed during removal. 

Denmark SE, Almstead NG (1991) Stereoselective opening of chiral dioxane acetals. Nucleophile dependence J Org Chem 55 6485-6487... 

Denmark studied fhe reactivity and stereoselectivity of group 14 allylic organo-metaUic compounds toward chiral dioxane acetals [16]. Allylation with allyltributylstannane was significantly more selective than that with allyltrimethylsilane for several chiral dioxane acetals examined (Tab. 11.1). 

Allylation of dioxane acetals (cf. 12, 375-378). Allylation of chiral dioxane acetals such as 2 has been shown to proceed with marked stereoselectivity with al-lyltrimethylsilanc promoted by TiCl4/Ti(0-i -Pr)4. A more recent study, indicates that... 

Shi Asymmetric epoxidation of alkenes catalyzed by chiral dioxanes... 

When the ester group is (+)-menthyl, chiral induction is complete. The principle of asymmetric steric shielding has been used to control hydrocyanation of Schiff s bases formed between thienylcarboxaldehydes and a chiral dioxan hydrolysis of the... 

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... 

By statbng with eaanbonietically enriched ot pure /J-allenylcatboxylales, il is possible lo carry out several of the transformabons menboned above steteoselectively. With regard lo tlie requited substtales, chiral 5-alky nylidene-l,3-dioxan-4-ones of... 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

Cyclopenta[fc]dioxanes (44) are accessible from the reaction of the dioxenylmolybdenum carbene complex (43) with enynes <96JOC159>, whilst an intramolecular and stereoselective cyclisation of (Ti5-dienyl)tricarbonyliron(l+) cations affords chiral frans-2,3-disubstituted 1,4-dioxanes <96JOC1914>. 2,3-Dimethylidene-2,3-dihydro-1,4-benzodioxin is a precursor of the 3,8-dioxa-lff-cyclopropa[i]anthracene, which readily dimerises to dihydrotetraoxaheptacene (45) and the analogous heptaphene <96AJC533>. 

The C(9)-C(14) segment VI was prepared by Steps D-l to D-3. The formation of the vinyl iodide in Step D-3 was difficult and proceeded in only 25-30% yield. The C(15)-C(21) segment VII was synthesized from the common intermediate 17 by Steps E-l to E-6. A DDQ oxidation led to formation of a 1,3-dioxane ring in Step E-l. The A-methoxy amide was converted to an aldehyde by LiAlH4 reduction and the chain was extended to include C(14) and C(15) using a boron enolate of an oxazo-lidinone chiral auxiliary. After reductive removal of the chiral auxiliary, the primary alcohol group was converted to a primary iodide. The overall yield for these steps was about 25%. 

The asymmetric Baylis-Hillman reaction of sugar-derived aldehydes as chiral electrophiles with an activated olefin in dioxane water (1 1) proceeded with 36-86% de and in good yields of the corresponding glycosides (Eq. 10.47).104 The use of chiral /V-mcthylprolinol as a chiral base catalyst for the Baylis-Hillman reaction of aromatic aldehydes with ethyl acrylate or methyl vinyl ketone gave the adducts in good yields with moderate-to-good enantioselectivities in l,4-dioxane water (1 1, vol/vol) under ambient conditions.105... 

An enantioselective synthesis of 2-alkylidene-l,4-dioxanes is based on the Pd-catalysed heteroannulation of alkynyl carbonates to benzene-1,2-diol in the presence of chiral diphosphine ligands (Scheme 63) . 

Hydrogenation of a series of /Z-isomeric mixtures of a-arylenamides with a MOM-protected /3-hydroxyl group catalyzed by a BICP-Rh complex or an Me-DuPhos complex leads to the formation of chiral /3-amino alcohol derivatives with excellent enantioselectivities.70b A 1,4-diphosphane 26 with a rigid 1,4-dioxane backbone is also very effective for this transformation (Equation (28)).76 DIOP -Rh72a and Me-DuPhos-Rh219 catalysts are also effective for this transformation. 

Using a stoichiometric amount of (i ,i )-DIPT as the chiral auxiliary, optically active 2-isoxazolines can be obtained via asymmetric 1,3-dipolar addition of achiral allylic alcohols with nitrile oxides or nitrones bearing an electron-withdrawing group (Scheme 5-53).86a Furthermore, the catalytic 1,3-dipolar cycloaddition of nitrile oxide has been achieved by adding a small amount of 1,4-dioxane (Scheme 5-53, Eq. 3).86b The presence of ethereal compounds such as 1,4-dioxane is crucial for the reproducibly higher stereoselectivity. 

Bicyclic lactams 189 are uniquely suited as precursors for the synthesis of chiral substituted 4,5-dihydro-277-pyridazinones 190 by hydrolysis with NH2NH2 and HC1 in dioxane at 85 °C. The reaction gave, as a side product, the ketoacid 191 in some cases (Equation 32) <2003TL7997>. 

Scheme 2.29 Diastereoselective 1,6-cuprate addition to chiral 5-alkynylidene-l, 3-dioxan-4-one 82.

Dioxo-l,3-dioxanes ring-open under basic conditions. Cleavage of the 5,5-disubstituted derivatives in the presence of quininium or quinidinium alkoxides produces chiral malonic hemi-esters (ee 30-40%) in high yield [11]. The addition of cetyltrimethylammonium bromide promotes the base-catalysed cleavage of p-keto esters to form ketones under sonication [12]. 

C-alkylated Meldrum s acid derivatives are cleaved asymmetrically by alkoxide anions in the presence of quininium salts to yield chiral half esters (9.2.2) [11]. Thus, benzylquininium and cinchonidinium salts produce fl-hemi-esters and the cincho-nium and quinidinium salts produce the S-hemi-esters from, for example, 2,2,5-trimethyl-5-pheny 1-1,3-dioxane-4,6-dione. 

The stereoselective epoxidation of chalcones, followed by acid-catalysed ring closure and concomitant cleavage of the epoxide ring, provides a very efficient route to chiral flavon-3-ols and, subsequently, by borohydride reduction to produce flavan-3,4-diols [13, 14], It has been shown that diastereoselective reduction of the chiral flavon-3-ols by sodium borohydride in methanol yields the trans-2,3-dihydroxy compounds, whereas borohydride reduction in dioxan produces the cis-isomers [14] the synthetic procedure confirms the cis configuration of the 2,3-hydroxy groups of naturally occurring leucodelphinidins [14]. 

Typical NP conditions involve mixtures of n-hexane or -heptane with alcohols (EtOH and 2-propanol). In many cases, the addition of small amounts (<0.1%) of acid and/or base is necessary to improve peak efficiency and selectivity. Usually, the concentration of alcohols tunes the retention and selectivity the highest values are reached when the mobile phase consists mainly of the nonpolar component (i.e., n-hexane). Consequently, optimization in NP mode simply consists of finding the ratio n-hexane/alcohol that gives an adequate separation with the shortest possible analysis time [30]. Normally, 20% EtOH gives a reasonable retention factor for most analytes on vancomycin and TE CSPs, while 40% is more appropriate for ristocetin A-based CSPs. Ethanol normally gives the best efficiency and resolution with reasonable backpressures. Other combinations of organic solvents (ACN, dioxane, methyl tert-butyl ether) have successfully been used in the separation of chiral sulfoxides on five differenf glycopepfide CSPs, namely, ristocetin A, teicoplanin, TAG, vancomycin, and VAG CSPs [46]. 

The inclusion of enantiomers into the chiral cavities of the network is supposed to be the main chiral recognition mechanism. Moreover, hydrogen bonding between polar groups of the solutes and the amide groups of the polymers are also assumed to participate in the chiral recognition process. Apolar mobile phases such as hexane-dioxane and toluene-dioxane mixtures are therefore commonly used with this type of CSPs. 

By starting with enantiomerically enriched or pure j8-allenylcarboxylates, it is possible to carry out several of the transformations mentioned above stereoselectively. With regard to the required substrates, chiral 5-alkynylidene-l,3-dioxan-4-ones of... 

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