Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
1999-04-05
2003-01-21
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S424000, C564S080000, C564S123000
Reexamination Certificate
active
06509506
ABSTRACT:
FIELD OF INVENTION
The invention relates to the synthesis of D- and AL- &agr;-amino acids and D- and L- &agr;-amino aldehydes from olefins and other unsaturated substrates. More particularly, the invention relates to a two step synthesis in which the first step is an asymmetric &bgr;-aminohydroxylation of the olefin or unsaturated substrate and the second step is an oxidation of the deprotected product of the first step to form a D- or L- &agr;-amino acid or a D- or L- &agr;-amino aldehyde.
BACKGROUND
D- and L- &agr;-amino acids are key building blocks for peptides, proteins, pharmaceuticals, and other important biomolecules. Naturally occurring L- &agr;-amino acids are readily available from biological sources. However, enantiomerically pure D- &agr;-amino acids and unnatural L- &agr;-amino acids are more difficult to obtain. Due to their chirality, these compounds can be difficult to synthesize in an enantiomerically pure form. Several compounds within this class have significant economic value. Similarly, and D- and L- &agr;-amino aldehydes are a re-occurring motif in biologically and pharmaceutically important molecules but are difficult to obtain in enantiomerically pure form.
Over the past 20 years, separate and distinct synthetic methodologies have been developed by Sharpless et al. for the vicinal hydroxyamination of olefins. There are three major groups of oxyamination procedures which produce aminoalcohols (Sharpless et al.
J. Am. Chem. Soc
. 1975, 97, 2305; Sharpless et al.
J. Org. Chem
. 1978, 43, 2628; Sharpless et al.
J. Org. Chem
. 1980, 45, 2257), hydroxysulfonamides (Sharpless et al.
J. Org. Chem
. 1976, 41, 177; Sharpless et al.
J. Org. Chem
. 1978, 43, 2544; Sharpless et al.
J. Org. Chem
. 1979, 44, 1953; Sharpless et al.
Org. Syn
. 1980, 61, 85) or hydroxycarbamates (Sharpless et al.
J. Am. Chem. Soc
. 1978, 100, 3596; Sharpless et al.
J. Org. Chem
. 1980, 45, 2710; Sharpless et al. U.S. Pat. No.'s 4,871,855; 4,965,364; 5,126,494; EP 0 395 729). Each oxyamination procedure has unique reaction conditions and includes variations in solvents, auxiliary salts, nucleophiles, temperature, stoichiometric v. catalytic amounts of osmium species and stoichiometric v. catalytic amounts of ligand. Each procedure is highly dependant on the nature of the substrate and possesses unique properties which afford different yields, chemoselectivities, stereoselectivities, regioselectivities and enantioselectivitive outcomes.
1. Aminoalcohols
The first reported oxyamination procedure (Sharpless et al.
J. Am. Chem. Soc
. 1975, 97, 2305) generated aminoalcohols from mono and di substituted olefins, using stoichiometric quantities of a tri-oxo(tert-butylimido)osmium species. The procedure required reductive cleavage of the osmate ester which was performed with lithium aluminum hydride and afforded tertiary vicinal aminoalcohols. Yields were good to excellent, but in some cases, the side product vicinal diol was formed as an undesired by-product. The stereochemistry of addition, in methylene chloride or pyridine, was exclusively cis (Sharpless et al.
J. Org. Chem
. 1978, 43, 2628). In addition, the carbon-nitrogen bond formed was, in every case, at the least substituted olefinic carbon atom. Di and tri-substituted olefins reacted much slower with the generated imido reagent than with monosubstituted alkenes; tetrasubstituted alkenes yielded only the corresponding diol. However, by using a coordinating solvent such as pyridine, higher yields and higher ratios of aminoalcohol to diol were reported. Sharpless et al.
J. Org. Chem
. 1980, 45, 2257; Sharpless et al.
J. Org. Chem
. 1976, 41, 177; Sharpless et al.
J. Org. Chem
. 1978, 43, 2544.
2. Hydroxysulfonamides
Sharpless et al. first demonstrated that hydroxysulfonamides could be obtained using either stoichiometric or catalytic amounts of 1% osmium tetraoxide in the presence of 1.5-5 equivalents of Chloramine-T trihydrate (TsSO
2
NClNa.3H
2
O, Ts=tosylate; commercially obtained) to effect cis addition of a hydroxyl (OH) and an arylsulfonamide moiety (Ar—SO
2
NH) across a mono or disubstituted olefinic linkages (Sharpless et. al.
J. Org. Chemistry
1976, 41, 177).
Two procedures were developed to effect hydroxyamination of olefins using sulfonamides. (Sharpless et al.
Org. Syn
. 1980, 61, 85). The first procedure used phase transfer catalysis conditions at 55-60° C. With 1% OsO
4
, 1:1 v/v, 0.20 Molar CHCl
3
/H
2
O, and benzyltriethylammonium chloride as the phase transfer catalyst. The chloramine T-trihydrate (TsSO
2
NClNa.3H
2
O) was either added directly or formed in situ in water; this solution was then directly used in the phase transfer mixture. The in situ procedure, for generating the chloramine salts, involved stirring a suspension of the arylsulfonamide with an equivalent of sodium hypochlorite (Clorox) until a homogenous solution was obtained. The yields were comparable with those obtained with isolated chloramine salts and the procedure was found most effective for monosubstituted and 1,2 disubstituted olefins. The phase transfer method, however, gave poor results with trisubstituted and 1,1-disubstituted olefins and the procedure did not succeed with diethyl fumarate and 2-cyclohexen-1-one. Sharpless et al.
J. Org. Chem
. 1978, 43, 2544.
A second procedure was carried out in tert-butyl alcohol at 55-60° C. with 1% OsO
4
, silver nitrate (with or without) and commercially obtained chloramine T-trihydrate (TsSO
2
NClNa.3H
2
O) which provided the only source (of water. The procedure did not succeed with tetramethylethylene and cholesterol, and negative results were found with most hindered tri- and tetrasuostituted olefins. Sharpless et. al.
J. Org. Chemistry
1976, 41, 177; Sharpless et al.
Org. Syn
. 1980, 61, 85. The addition of divalent metal salts such as AgNO
3
and Hg(NO
3
)
2
improved some reactions, however, other reactions suffered deleterious effects from the addition of the metal salts. Sharpless et al.
J. Org Chem
. 1978, 43, 2544; Sharpless et. al.
J. Org. Chemistry
1976, 41, 177.
Further elaboration on either procedure showed that other sulfonamide derivatives (ArSO
2
NClNa) could be successfully employed in addition to chloramine T, where Ar=phenyl, o-tolyl, p-chlorophenyl, p-nitrophenyl, and o-carboalkoxyphenyl. Sharpless et al.
J. Org. Chem
.1978, 43, 2546.
Neither the phase transfer catalyst or tert-butyl alcohol procedures succeeded with tetramethyl ethylene, 2,3-dimethyl-2-octene, diethyl fumarate, or 2-cyclohexen-1-one. Negative results were also obtained with most hindered tri- and tetrasubstituted olefins. Herranz E., MIT Ph.D. Thesis, 1979, 33.
Solvent conditions for the synthesis of the hydroxysulfonamides included organic solvents such as acetonitrile, tert-butyl alcohol, isopropyl alcohol and chloroform which was in contact with the aqueous phase in the phase transfer catalyst procedure.
The tert-butyl alcohol procedure (including other solvents used) was not run with added water; the phase transfer catalyst (PTC) procedure required a biphasic mixture of 1:1 v/v chloroform/water. Recently, however, an improvement was reported which used a 1:1 ratio of organic solvent to water in a homogeneous, rather than a biphasic solution or organic solvent with small amounts of water. These conditions were found to provide optimum enantioselectivity, regioselectivity and improved yields from either the previously described t-butyl alcohol or PTC conditions. Sharpless et al.
Angew. Chemie Intl Ed
. 1996, 35, 451.
The use of chiral ligands with sulfonamides provides enantioselectivity and has been observed to both accelerate and decelerate the rate of catalysis. The hydroxysulfonamide process is a stereoselective cis process. The presence of ligands also has a dramatic effect on the regioselectivity. In a study with no ligand present with methyl cinnamate, the two regioisomers were present in a 2:1 ratio. With the addition of ligand, the ratio was improved to 5:1 or greater. Another positive effect of the ligand was its ability to suppress formation of diol by-produc
Li Guigen
Sharpless K. Barry
Fitting Thomas
Lewis Donald G.
Price Elvis O.
Richter Johann
The Scripps Research Institute
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