Amino alcohols, formation

Most remarkably, catalytic aminohydroxylation of cinnamate amides with sulfonamides in the absence of cinchona alkaloid ligands showed a remarkable chemoselectivity in favor of amino alcohol formation [75]. 

Deprotonation of enols of P-diketones, not considered unusual at moderate pH because of their acidity, is faciUtated at lower pH by chelate formation. Chelation can lead to the dissociation of a proton from as weak an acid as an aUphatic amino alcohol in aqueous alkaU. Coordination of the O atom of triethanolamine to Fe(III) is an example of this effect and results in the sequestration of iron in 1 to 18% sodium hydroxide solution (Fig. 7). Even more striking is the loss of a proton from the amino group of a gold chelate of ethylenediamine in aqueous solution (17). 

Cyanohydrin Synthesis. Another synthetically useful enzyme that catalyzes carbon—carbon bond formation is oxynitnlase (EC 4.1.2.10). This enzyme catalyzes the addition of cyanides to various aldehydes that may come either in the form of hydrogen cyanide or acetone cyanohydrin (152—158) (Fig. 7). The reaction constitutes a convenient route for the preparation of a-hydroxy acids and P-amino alcohols. Acetone cyanohydrin [75-86-5] can also be used as the cyanide carrier, and is considered to be superior since it does not involve hazardous gaseous HCN and also virtually eliminates the spontaneous nonenzymatic reaction. (R)-oxynitrilase accepts aromatic (97a,b), straight- (97c,e), and branched-chain aUphatic aldehydes, converting them to (R)-cyanohydrins in very good yields and high enantiomeric purity (Table 10). 

Vicinal effects can also play a part in the course of the reaction utilizing Oppenauer conditions. 1,3-Diols or j5-amino alcohols may not react, presumably on account of format on of an aluminum complex. If oxida-... 

Pentafluorophenyl acetate is a highly selective acetylating reagent, useful for acetylations at hydroxyl and amino groups under mild conditions When applied to the acetylation of amino alcohols, it gives selective formation of H acetyl derivatives at room temperature and M,0 diacetylated products under moderate heating in the presence of triethylamine [149]... 

Step from general acid-catalyzed formation of immonium ions to general base-catalyzed hydration of these ions to the amino alcohol [Eq. (6)]. 

Dehydrogenation of amino alcohols of type 40 affords even bicyclic compounds 41, the formation of which can be explained by nucleophilic attack of the hydroxyl group on the formed enamine salt (133,134). 

During attempted acetonide formation of an amino alcohol derivative, smooth tosyl cleavage was observed. The reaction is general for those cases having a carboxyl group, as in the following example, but fails for simple amino alcohol derivatives that lack this functionality. ... 

The reaction of nitrous acid with the amino group of the /3-amino alcohol—e.g. 1-aminomethyl-cyclopentanol 1—leads to formation of the nitrosamine 4, from which, through protonation and subsequent loss of water, a diazonium ion species 5 is formed " —similar to a diazotization reaction ... 

Ring-opening of diastereomerically pure vinylaziridine 131, prepared by azir-idination of butadiene with 3-acetoxyaminoquinazolinone 130 [52], yielded acetate 132 with inversion of configuration, together with amino alcohol 133 with retention (Scheme 2.34) [53]. The formation of 133 can be explained by assuming participation by the quinazolinone carbonyl oxygen, which produces an intramolecular reaction with the aziridine carbon with retention of configuration. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

Nitrile oxides are usually prepared via halogenation and dehydrohalogenation of aldoximes [11] or via dehydration of primary nitro alkanes (Scheme 1) [12]. However, it is important to note that nitrile oxides are relatively unstable and are prone to dimerization or polymerization, especially upon heating. 1,3-Dipolar cycioaddition of a nitrile oxide with a suitable olefin generates an isoxazoline ring which is a versatile synthetic intermediate in that it provides easy access to y-amino alcohols, )5-hydroxy ketones, -hydroxy nitriles, unsaturated oximes, and a host of other multifunctional molecules (Scheme 1) [5a]. Particularly for the formation of )5-hydroxy ketones, nitrile oxide-olefin cycioaddition serve as an alternative to the Aldol reaction. 

It was also of interest to apply such lOOC reactions to formation of carbocyclic rings. Oxime olefins 230 a-e, formed in good yield via reaction of 229 with 0-silyl-a-bromoaldoximes 228 in the presence of F ions, cyclized in a sealed tube at 190 °C to provide 231 a-e (Eq. 24, Table 22) [63]. Reduction of 231a provided amino alcohol 232 a in 68% yield. Amino alcohol 232 e was converted stereo-specifically to the fused -lactam 233. 

Certain alkylated ammonium, phosphonium, or sulfonium compounds are effective, in relatively low concentrations, in interfering with the growth of gas hydrate crystals [972] and therefore are useful in inhibiting plugging by gas hydrates in conduits containing low-boiling hydrocarbons and water. For example, tetrabutylammonium bromide will be active. Gas hydrate or ice formation is further inhibited in lines by adding amino acids or amino alcohols [523]. 

The reactions of chlorocyclophosphazenes with difunctional reagents such as diamines, diols, or amino alcohols can in principle lead to the formation of several products. These are shown in Fig. 19. The reactions of these reagents with the chlorocyclophosphazenes are discussed below. 

Obviously, there are two ways to prepare Efavirenz from the pMB protected chiral amino alcohol 50 (i) creation of the benzoxazinone first then removal of the pMB group or (ii) removal of the pMB first then formation of benzoxazinone. Preparation of the benzoxazinone was demonstrated by Medicinal Chemistry from the amino-alcohol with CDI. 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

A classical approach to driving the unfavorable equilibrium of an enzymatic process is to couple it to another, irreversible enzymatic process. Griengl and coworkers have applied this concept to asymmetric synthesis of 1,2-amino alcohols with a threonine aldolase [24] (Figure 6.7). While the equilibrium in threonine aldolase reactions typically does not favor the synthetic direction, and the bond formation leads to nearly equal amounts of two diastereomers, coupling the aldolase reaction with a selective tyrosine decarboxylase leads to irreversible formation of aryl amino alcohols in reasonable enantiomeric excess via a dynamic kinetic asymmetric transformation. A one-pot, two-enzyme asymmetric synthesis of amino alcohols, including noradrenaline and octopamine, from readily available starting materials was developed [25]. 

Reaction of the (S)-amino alcohol 171 with A-(2-bromoethyl)phosphoramidic dichloride or aryl phosphonodichloridates 154 in the presence of triethylamine led to the formation of a single diastereomer in each case of 1,3,2 oxazaphospholidine-2-ones 172a-e (taking into consideration that in the 31P-NMR spectra only one singlet in the range 6.49-2.45 ppm was observed) (Scheme 48) [79],... 

The diastereoselectivity of the reduction of a-substiluted ketones has been the subject of much investigation. The reagent combination of trifluoroacetic acid and dimethylphenylsilane is an effective method for the synthesis of erythro isomers of 2-amino alcohols, 1,2-diols, and 3-hydroxyalkanoic acid derivatives.86,87,276,375 Quite often the selectivity for formation of the erythro isomer over the threo isomer of a given pair is >99 1. Examples where high erythro preference is found in the products are shown below (Eqs. 218-220).276 Similar but complementary results are obtained with R3SiH/TBAF, where the threo isomer product... 

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. 

When sulfamate esters 114 are used as substrates, six-membered-ring formation is favored, and results in the selective formation of 1,2,3-oxathiazinane-2,2-dioxide heterocycles 115.251 Nevertheless, five-membered cyclic sulfamidates could be obtained when no alternative cyclization was possible. 1,3-Amino alcohols and related /2-amino acids are thus readily accessible from the same simple alcohols 113 by converting them into sulfamates 114 (Equation (90)). Furthermore, in comparison to the carbamate reaction (Scheme 9), the sulfamate substrates have... 

---