Aminohydroxylation of Olefins

Details Aminohydroxylation of Olefins Aminohydroxylation of Olefins

1999-08-20

2002-02-26

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C549S076000, C560S012000, C560S027000, C560S029000, C560S115000, C560S160000, C562S553000, C562S590000

Reexamination Certificate

active

06350905

ABSTRACT:

TECHNICAL FIELD
The present invention relates to the aminohydroxylation of olefins. More particularly, the present invention relates to an acceleration of the aminohydroxylation reaction by the use of olefinic substrates having ionic groups and to an expansion of the reaction to include the aminohydroxylation of olefins having a site of unsaturation at the &agr;,&bgr;, &bgr;,&ggr;, or &ggr;,&dgr; positions with respect to such ionic groups.
SUMMARY
Aminohydroxylation of ionic olefinic substrates is disclosed herein to be accelerated and/or have an expanded range as compared to nonionic olefinic substrates. Both anionic and cationic olefinic substrates are disclosed to be excellent substrates for the aminohydroxylation reaction. Also, it is disclosed herein, that, with the use of ionic olefinic substrates, the range of the reaction is expanded to include the aminohydroxylation of olefins having a site of unsaturation at the &agr;,&bgr;, &bgr;,&ggr;, or &ggr;,&dgr; positions with respect to polar ionic groups.
In the case of olefinic carboxylic acids, the aminohydroxylation reaction is disclosed to be rapid and nearly quantitative with very low catalyst loading in the absence of cinchona alkaloid ligands and with only one equivalent of the haloamine salt. The reactions can be conducted at molar concentrations in substrate, whereas the asymmetric aminohydroxylation (AA) process is best performed at 0.1 molar or less. A consequence of this “ligand-independent” reactivity is that the aminohydroxylation is not enantioselective, even in the presence of excess (e.g. 10 mol %) of the chiral ligand. This type of reactivity is referred to herein as “special A” below (“A” for “Aminohydroxylation”).
The ready availability of the unsaturated acids from natural sources, the outstanding synthetic methods which lead to this functionality, and the importance of the &agr;,&bgr;-hydroxyaminoacid derivatives obtained, make them one of the most attractive olefin classes yet found for the “special A” reaction. These substrates require the addition of base to neutralize the acid before the “special A” reactivity is observed. The base of choice is sodium bicarbonate, as it can be used in slight excess without impeding the rate of reaction, thus even further simplifying the experimental procedure. Of course, other bases can be successfully employed, provided that pH of the reaction mixture does not exceed ca. 11. A range of solvents can be employed for this reaction (water/acetonitrile, water/tert-butanol), but very importantly, the reaction often proceeds just as well in water without organic cosolvent. Exactly one equivalent of haloamine salt can be employed without compromising in aminohydroxylation of other substrates), and osmium catalyst loading is among the lowest known for the catalytic aminohydroxylations (0.1-1.0%, as opposed to the usual 4-5%). The only byproduct of the reaction is sodium chloride. Upon acidification, most products precipitate in pure form making chromatography or recrystallization unnecessary. In cases where regioisomers are possible, their separation is usually quite easy. For example, the &agr;-toluenesulfonamido-&bgr;-hydroxy derivative of cinnamic acid is water soluble, whereas its regioisomer is not (Scheme 1).
This newly discovered transformation is of wide scope and has been performed on large scale with fumaric acid, producing the aminohydroxylated product in almost quantitative yield (Scheme 2).
Another notable feature is that unlike other substrate classes, the reaction does not strictly require the “activating group” to be directly attached to the olefin for the enhanced reactivity effect. Thus, &bgr;,&ggr;-unsaturated acids have also been found to aminohydroxylate readily (Scheme 3).
Thus, a class of olefins has been discovered which exhibits extraordinary reactivity in the catalytic aminohydroxylation process. The products are racemic, since tertiary amine ligands appear to play no role in the catalytic cycle. Nevertheless, the outstanding yields and practicality make these racemic variants important alternatives to the related AA transformations. The mechanistic implications of these observations are described in the next section.
Mechanistic Considerations.
An overall mechanistic pathway for aminohydroxylation is outlined below (Scheme 4). Osmium(VIII) trioxoimido species 1 can add to olefin to give the Os(VI) azaglycolate complex 2. This step is presumably strongly accelerated by the chiral ligand L, accounting for asymmetric induction in the process. Complex 2 can be hydrolyzed (not shown) or reoxidized to the central OS(VIII) azaglycolate 3. This species completes the “first cycle” by hydrolysis, or enters the “second cycle” by oxidizing another olefin to give bis(azaglycolate) complex 4. It is disclosed that the five-coordinate nature of 3 (in contrast to the four-coordinate 1) provides sufficient electron density at the metal center to allow olefin oxidation to proceed without external ligand. Indeed, chiral ligands such as those derived from DHQ and DHQD, even in five-fold excess relative to osmium, have no effect on the rate, yield, chemo-, regio- or stereochemical outcome of the reaction. In principle, the azaglycolate ligand resident on 3 can contribute to selectivity in this second olefin oxidation event.
Hydrolysis of 4 restores 2, completing the second cycle. The second cycle in dihydroxylation (in which the oxidant is an Os(VII) trioxo glycolate species) leads to low enantiomeric excess in the Upjohn process. This does not mean that a second cycle is necessarily deleterious to aminohydroxylation; indeed, we believe it to be the dominant catalytic mechanism for “special A” reactions, for the reasons outlined below. An important insight is that for aminohydroxylation reactions, hydrolysis is the turnover-limiting event in either catalytic cycle. This has been demonstrated in several ways, one example being the general observation that aminohydroxylation of a mixture of two olefins invariably proceeds at the same rate as the slower substrate alone. In these cases, the resting state of the osmium catalyst is the azaglycolate complex of the slowest substrate, with the overall reaction rate determined by the rate of its hydrolysis.
A structure representing the bis complex within the Second Cycle for the osmium catalysis of &agr;,&bgr; unsaturated carboxylic acids is illustrated in FIG.
5
. The complex has the expected square-pyramidal structure that is consistent with solution-phase NMR data. Note that, in comparison to the Os(VI) bis(glycolate) species that occupies the same position in the AD second cycle, complex 5 has much greater steric hindrance along the path by which water must approach the only open coordination site of osmium to initiate hydrolysis. The approach of water may also be slowed by the hydrophobic pocket created by the two tosyl groups that point “down” and around the vacant coordination site. These features are consistent with the observation that catalytic aminohydroxylation is generally slower than dihydroxylation, and with the hypothesis that hydrolysis is turnover-limiting.
Unsaturated carboxylic acids that exhibit “special A” reactivity (very high yields, no diol contamination, very low catalyst loadings, stoichiometric amounts of oxidant) seem to have overcome many of the problems that hindered the use of AA (Asymmetric Aminohydroxylation) except, of course, for enantioselectivity. The key feature among these olefins is that they all contain highly polar group(s) (e.g., carboxylates) near the double bond, thus providing a more hydrophilic environment in the vicinity of the open coordination site under the square pyramid of the Os(VI) bis(azaglycolate) complex, and/or near the apical oxo group on the other side. These are the two sites whose environment is disclosed herein to have the largest effect on the rates of the initial steps in ligand exchange/hydrolysis. A proximal carboxylate, for example, can directly facilitate hydrolysis of the complex as shown in Scheme 5 (a general structure of Os(VI) bis-azaglycolate com

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