Cyclic Amino Alcohols

The ligands were prepared by phosphitylation of diphenols with 53 and its analogue obtained from (S)-(- -)-indolinemethanol. Compounds 57-60 were obtained in 81-86% yields in high optical purity ( 90% de) except for 59, which was unexpectedly racemic. These compounds were successfully employed to form palladium cyclometallated complexes. 

Alcohol 61 is easily prepared from a chemical found in industrial waste and was used to prepare the tricyclic oxazaphospholidine borane 62 in 64% combined yield. The X-ray structure revealed that in this case the phosphorus atom had S absolute configuration. In the same paper they described the preparation of 64 in 40% yield and in optically pure form, starting from the azetidinic alcohol 63. The same authors prepared the phosphine oxide version of 62 via oxidation of the P(III) precursor and by direct reaction of 61 with PhP(0)Cl2/NEt3. 

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Jager and coworkers have used the TBAF catalyzed-stereoselective niho-aldol reaction for the synthesis of cyclic amino alcohols such as iminopolyols, imino sugars, and cyclic amino acids. They are important classes of compounds and have the potential utility as anh-diabetic. 

The aminoglycosides are a closely related family of antibiotics produced almost exclusively by members of the genus Streptomyces and Micromonospora (Table 1.19). Most are polycationic compounds, composed of a cyclic amino alcohol to which amino sugars are attached. They all induce their bacteriocidal effect by inhibiting protein synthesis (apparently by binding to the 30 S and, to some extent, the 50 S, ribosomal subunits). Most are orally inactive, generally necessitating their parenteral administration. 

Cyclic amino alcohols have been used in a Mitsunobu alkylation of 4-substituted phthalazin-l(2//)-ones <1996LA1477>. Mitsunobu alkylation has also been used to graft 6-chloropyridazin-3(2//)-one on a Wang resin. In this case competitive N- and O-alkylation is observed <2005JC0414>. 

The second altogether different strategy does not involve a cyclic amino alcohol but an acyclic one, and its reaction with a cyclic epoxide or dielectrophile. The reactions have been shown in Scheme 28 for both ds- or trans-iuscA tetrahydrooxazines (263 to 109 and 264 to 110) <1978CB1164>, in Scheme 38 for r-fused tetrahydrooxazines of the type 344 <1990AP43>, and in Equation (50) for a /ra r-fused tetrahydrooxazine 349 <1987AP625>. 

Optically active namral and unnamral amino acids as well as various cyclic amino alcohols have been utilized in the synthesis of a wide variety of bis(oxazo-line) ligands. As previously mentioned, the first bis(oxazoline) ligands, py-box la-d, were synthesized by Nishiyama and co-workers in 1989. The common material for their syntheses was pyridine 2,6-dicarboxylic acid 19. Conversion of 19 to the acid chloride was achieved by treatment with thionyl chloride, as illustrated in Figure 9.4. This was followed by condensation with (5)-valinol in the presence of triethylamine. Conversion of the resulting bis(amidodiol) 20 to py-box-ip lb was achieved by sequential treatment of 20 with thionyl chloride at 50 °C followed by cyclization with aqueous sodium hydroxide in methanol to afford py-box-/p lb in 60% overall yield. The same synthetic scheme can be used to obtain the other... 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

Asymmetric hydrogen transfer from 2-propanol to aromatic ketones such as acetophenone (99) has been achieved by using the same chiral Ru complex in 2-propanol containing KOH at room temperature, and (S)-1 -phenylethanol (100) with 98% ee was obtained [68,69]. Similarly, efficient Ru-catalysed transfer hydrogenation of aromatic ketones using the cyclic amino alcohol [(I. S, 3R,4i )-2-azanorbomylmetha-nol] (110) [70] and bis(oxazolinylmethyl) amine (111) [71] was reported. 

In the case of acetophenone reduction, it appears that amino alcohols that are sterically hindered at the carbon adjacent to the alcohol lead to much better results. A dramatic effect has been found in the case of prolinol and diphenylprolinol the enantiomeric excess increases from 50% to 97%. Cyclic amino alcohols where the nitrogen is in a 4- or 5-membered ring have exceptional catalytic properties and lead to very good enantiomeric excesses (Tables 16.1 and 16.2). Diphenylprolinol (4) is a very good choice because of its availability and performance. 

Since the discoveries of Itsuno32 and Corey,33 remarkable advances have been made in the enantio-selective reduction of prochiral ketones using amino alcohol-derived oxazaborolidines (see Chapter 16).34 35 In most cases, these amino alcohols were obtained from chiral pool sources. Consequently, extensive synthetic manipulations were often necessary to access their unnatural antipode. Didier and co-workers were first to examine the potential of m-aminoindanol as a ligand for the asymmetric oxazaborolidine reduction of ketones.36 Several acyclic and cyclic amino alcohols were screened for the reduction of acetophenone (Scheme 17.2), and m-aminoindanol led to the highest enantioselectivity (87% ee). 

In the case of cyclic amino alcohols where nitrogen enters into the composition of the cycle, the optimal anticholinergic effect is produced not by the N-ethyl, iV-isopropyl, or N-allyl, but by N-methyl radical, as is apparent from a comparison of the esters of tropine (Tables 4-6). It may be that the elements of the cyclic structure occupy a sufficiently large space besides the nitrogen atom. 

In the so called pinacol(ine)(one)-rearrangement water is eliminated from 1,2-diols 57). If it is run under acid-catalysis, it will undoubtedly proceed via a more or less free solvated carbocation, in which a migration ( Wagner-Meerwein-rearrange-ment ) of the substituent occurs from relative position 2 to 3. Therefore, it should be classified as a [l,2,3]-elimination (Scheme 5). The same is true for the Tiffenau-reaction (Scheme 6), which also succeeds in the poly- and acyclic families. By deamination of cyclic -amino-alcohols [oxidative [l,2,3]-elimination of (formally) ammonia via a possibly not fully free carbocation] the same ring enlarged ketones... 

Many other phosphorinane oxides have been prepared due to their pharmacological applications. Of particular importance are those containing fused bicyclic and tricyclic systems. They can be readily prepared by reaction of the chiral cyclic amino alcohol and the appropriate phosphonic dichloride and they are usually obtained as mixtures of epimers, often separable by column chromatography. A few examples are displayed in Figure 3.11. 

In this case, there will be perfect stereospecificity with the configuration of the ether bond (see circle) determining the configurations of the sp -center generated. When this procedure is applied to cyclic amino alcohols, it opens the road to non-natural amino acids [141]. 

Liu S, Xie J-H, Li W, Kong W-L, Wang L-X, Zhou Q-L. Highly enantioselective synthesis of chiral cyclic amino alcohols and conhydrine hy ruthenium-catalyzed asymmetric hydrogenation. Org. Lett. 2009 ll(21) 4994-4997. 

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