Carbonyl compounds chiral acyclic

Formation of C-C Bonds by Addition to Chiral Acyclic Carbonyl Compounds 1.3.1.3.1. Addition to Acyclic a-Alkyl-Substituted Carbonyl Compounds Cram-Selective 1,2-Asymmetric Induction... 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

Saito et al. (32,121) developed a variety of tartaric acid derivatives, including Ci-symmetric chiral alkenes such as 76. The 1,3-dipolar cycloaddition between 76 and 77 gave primarily endo-1%. (Scheme 12.26) The diastereofacial selectivity of the reaction is excellent, as endo-1% is obtained with >98% de. Other cyclic and acyclic nitrones have been employed in reactions with 76, and in all cases, moderate to excellent endo/exo-selectivities and excellent diastereofacial selectiv-ities were obtained (32,121). Three other research groups have applied various y-hydroxylated ot,p-unsaturated carbonyl compounds in related reactions with nitrones (122-124). However, the selectivities were somewhat lower than those obtained by Saito and et al. (32,121). 

For many years acyclic stereoselection has been one of the main interests in organic chemistry35. The most studied case is 1,2-induction, usually with a-chiral carbonyl compounds or olefins. 

Enantlomerically pure B-suhstituted carbonyl compounds serve as useful intermediates in the synthesis of many chiral organic compounds. The enantloselective synthesis of acyclic 0-substituted carboxylic acids has been reported by Meyers, Mukaiyama, and Koga. However, no effective, general method for the enantio-controlled preparation of P-substituted cycloalkanones was available prior to the investigations by the submitters. For example, poor enantloselectivity was observed in conjugate additions of organometallic... 

Cheap and readily available L-proline has been used numerous times for the intermediate and reversible generation of chiral iminium ions from a,/ -unsaturated carbonyl compounds. For example, Yamaguchi et al. reported in 1993 that the rubidium salt of L-proline catalyzes the addition of di-iso-propyl malonate to the acyclic Michael acceptors 40a-c (Scheme 4.13), with enantiomeric excesses as high as 77% [22], With 2-cycloheptenone and 2-cyclohexenone as substrates ca 90% yield and ee of 59% and 49% were obtained. Later the enantioselectivity of this process was increased to a maximum of 88% ee in the addition of di-tert-butyl malonate to the E-pentenone 40a in the presence of 20 mol% Rb-L-prolinate and 20 mol% CsF [23], Taguchi and Kawara employed the L-proline-derived ammonium salts 41a and... 

When the plane of the double bond of a carbonyl compound is flanked by diastereotopic halfspaces, a stereogenic addition of a hydride can take place diastereoselectively (cf. Section 3.4.1). In Section 10.3.1, we will investigate which diastereomer is preferentially produced in such additions to the C=0 double bond of cyclic ketones. In Sections 10.3.2 and 10.3.3, we will discuss which diastereomer is preferentially formed in stereogenic additions of hydride donors and acyclic chiral ketones or acyclic chiral aldehydes. 

Diastereoselectivity of the Addition of Hydride Donors to a-Chiral Acyclic Carbonyl Compounds... 

Cyclic and acyclic enol derivatives 480 can be asymmetrically aziridinated with (A -tosylimino)iodobenzene 481 using a chiral copper catalyst prepared in situ from [Cu(MeCN)4]PF6 and the optically active ligand 479. Collapse of the aminal (i.e., 482) leads to the formation of enantiomerically enriched Q-amino carbonyl compounds 483, although ee s to date are modest <2000EJ0557>. Similarly, dienes can be selectively aziridinated using the chiral Mn-salen complex 484 to give vinyl aziridines 486 in scalemic form (Scheme 124) <2000TL7089>. 

The addition of HCN to aldehydes has been a well-known reaction since the 19th century, especially in the context of the Kiliani-Fischer synthesis of sugars. Even older is the Strecker synthesis of amino acids by simultaneous reaction of aldehydes with ammonia and HCN followed by hydrolysis. The challenge in recent years has been to achieve face-selectivity in the addition to chiral aldehydes. These face-selective additions, known as nonchelation-controlled processes, refer to the original formulation of Cram s for the reaction of nucleophiles with acyclic chi carbonyl compounds. The chelation-controlled reactions refer also to a formulaticxi of Cram s, but whose stereochemical consequences sometimes differ. 2... 

Carbonyl functions often are protected as thioacetals, because these derivatives are stable to acids and bases. Dithio-acetals and -ketals generally are prepared by reaction of the carbonyl compound with a thiol in the presence of an acid catalyst. This transformation has been used in carbohydrate chemistry for a long time to lock aldoses in their acyclic forms (see equation 26). In recent years, this blocking principle for carbohydrates has been exploited in several chiral pool syntheses. Several other methods for... 

As pointed out in an earlier section, the ees for the asymmetric hydroxylation of acyclic enolates derived from a-branched carbonyl compounds is often low because of the difficulty in generating a specific enolate geometric isomer as well as poor enantiofacial discrimination between the re and si faces of the enolate (Scheme 25). In one example of a double stereodifferentiation process, the asymmetric oxidation of a chiral enolate, was successfully employed to circumvent these difficulties <87JOC5288>. For the matched pair, (—)-(179) and oxaziridine (—)-(114), the de was 88-91% (Equation (43)) whereas with the mismatched pair, (—)-(179) and (+)-(114), the de dropped to 48.4%. The pyrrolidine methanol chiral auxiliary in (180) was removed without racemization by basic hydrolysis affording nonracemic atrolactic acid in 70-89% yield. 

Acyclic monothio acetals and ketals can be prepared directly from a carbonyl compound or by fra .v-ketalization, a reaction that does not involve a free carbonyl group, from a 1,3-dithiane or 1,3-dithiolane. They are cleaved by acidic hydrolysis or Hg(II) salts. One of their primary liabilities is that with ketones a new chiral center is introduced which may complicate product analysis. 

Br, or I) (equation 1). Another method relies on alkylation of a-hydroxy or a-alkoxy carbonyl compounds. The induction of diastereoselectivty, in these cases, is achieved through the use of chiral auxiliaries and other stereodirecting groups (equation 2). The third method frequently utilizes the nucleophilic addition of hydride or other carbanions to a-dicarbonyl compounds (equation 3). In addition to being laborious, nonoxidative methods are limited to the synthesis of acyclic compounds, which greatly reduces the magnitude of their synthetic practicality. 

Despite high yield, the Rubottom oxidation is limited by the necessity for synthesis of the requisite silane ethers. The direct oxidation of enolates has thus emerged as the preferred method for the stereoselective formation of a-hydroxy carbonyl compounds because of the method s effectiveness for both acyclic and cyclic substrates. Davis s oxaziridine reagents have proved to be ideally suited for the one-step enolate hydroxylation process. The following chiral oxaziridine reagents have been utilized effectively in this protocol and will be showcased throughout the chapter. 

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