Heterosubstituted alcohols

The semipinacol rearrangement is not restricted to 2-heterosubstituted alcohols. Thus, the addition of diazoalkanes to ketones yields homologated ketones (equation 4), via rearrangement of the adduct (3). This process is closely related to the rearrangement of 2-amino alcohols on treatment with nitrous acid (equation 5). Similarly, 2-hydroxyimines undergo rearrangement to 2-amino ketones in a related process (equation 6). 

Similar yields of p-heterosubstituted alcohols have been observed 35) with deoxybenzoin and 2,2,6-trimethylcyclohexanone for all three heterosubstituted lithio derivatives if the reactions are performed at — 78 °C in THF (Scheme 34 g, i), whereas the best results are obtained when (methylseIeno)eyclopropyllithium is reacted at the same temperature but in ether instead of THF (Scheme 34 h, j)). This is probably due to a reduction of the degree of enolisation of the starting ketone when ether is used 87). This is a tendency which proved to be general for other a-selenoalkyl-lithiums 7 8-9-12)... 

An interesting variation of this reaction that made use of a three-component, one-pot solventless procedure with the corresponding trialkyl phosphites gave dramatically improved yields of many heterosubstituted glyphosate phosphonate diesters (37). When exactly one equivalent of water, 25, and tris-p-chloroethyl phosphite were mixed and heated under neat conditions for a few hours, nearly quantitative yields of displaced p-chloroethanol and the desired triester product 27 were obtained. If desired, the displaced alcohol was first removed by vacuum distillation, or the mixture could be hydrolyzed directly to GLYH3. Various oxygen, sulfur, nitrogen, cyano, and carboxylate functionalities were similarly accommodated in the trialkyl phosphite. 

The second type of weak bases for imine ligations are 1,2- or 1,3-heterosubstituted amines of amino thiols and amino alcohols. Of the two, the amino thiols appear to be the more suitable choice because they form stable thiazolidine derivatives under very mild reaction condi-tions 84"89,114 121 140 Furthermore, the 1,2-and 1,3-aminothiol moieties are found in cysteines and homocysteines that form a stable heterocyclic ring with an aldehyde within ten minutes at pH 4-5. Thiazolidine ring formation has been successfully used to ligate both linear and constrained peptides to K2K dendron types of cores and proteins containing a-oxoacyl groups. 

Heterosubstituted cyclopropanes can be synthesized from appropriate olefins and car-benes. Since cyclopropane resembles olefins in its reactivity and is thus an electron-rich car bo-cycle (p. 76ft). it forms complexes with Lewis acids, e.g. TiCL, and is thereby destabilized This effect is even more pronounced in cydopropanone ketals. If one of the alcohols forming the ketal is a silanol, the ketal is stable and distillable. The O—Si-bond is cleaved by TiCl4 and a d3-reagent is formed. This reacts with a -reagents, e.g. aldehydes or ketals. Various 4-substituted carboxylic esters are available from 1-alkoxy-l-siloxycyclopropanes in this way (E. Nakamura, 1977). If one starts with l-bromo-2-methoxycyclopropanes, the bromine can be selectively substituted by lithium. Subsequent treatment of this reagent with carbonyl compounds yields (2-methoxycyclopropyl)methanols, which can be transformed to /7,y-unsaturated aldehydes (E.J. Corey, 1975B). 

Heterosubstitutions.—One of the most useful processes for conversion of alcohols into halides (mostly chlorides) is the Appel reaction.247 Treatment of free sucrose with Ph3P and CC14 in pyridine affords tiA -dichloro-b/i -dideoxysucrose in 91% yield.248,249 Surprisingly, a similar procedure performed on a penta-D-benzylsucrose was much less selective.250 Other dihalosucroses (bromides, iodides) are also accessible by reaction with modified Appel or related reagents.251,252... 

Stereoselectivity also arises in additions to cinnamyl alcohol 32 when the product organolithium is quenched with an electrophile. Single diastereoisomers of both 38 and 39 are obtained.27 29 Since non-heterosubstituted benzyllithiums are typically configurationally unstable, the selectivity presumably arises from the preferred direction of attack on a more or less planar or rapidly epimerising organolithium 37. Represented as shown below, attack from the top face yields the observed stereoselectivity. 

J-Heterosubstituted organoboranes, which are highly sensitive to elimination, can be derived from heterocyclic alkenes and are cleanly transformed into the corresponding chiral alcohols of high optical purity (Table 2). 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

One of the interesting features of functionalized cyclopropyl and cyclobutyl derivatives is, without doubt, their ability to release the strain and to produce larger rings or straight-chain derivatives. This has been demonstrated by the pioneering work of Julia on cyclopropyl carbinols, which in acidic media lead to homoallyl alcohols and bv the well-known propensity of p-heterosubstituted (RO ... 

Alternatively, a,a-diaryl prolinol catalysts 22 (5 mol%) in combination with /1-nitrobenzoic acid or catalyst 15a (20 mol%) could be used to promote the a-selenenylation of aldehydes using A-(phenylseleno)phtalimides as electrophile [113]. For this reaction, toluene was the solvent of choice and the in situ reduction of the obtained product to the corresponding alcohol was needed in order to preserve the achieved levels of enantioselectivities (Scheme 4.15). A wide range of aldehydes, including alkyl, alkenyl and heterosubstituted aldehydes were suitable substrates, affording the expected products 79 with excellent enantioselectivities. 

---