Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-05
2002-09-10
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C502S158000, C540S604000, C544S264000, C548S965000, C548S969000, C549S513000, C549S518000, C562S064000
Reexamination Certificate
active
06448414
ABSTRACT:
BACKGROUND OF THE INVENTION
The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages (reviewed in, e.g., Stinson, S. C.,
Chem Eng News,
Sep. 28, 1992, pp. 46-79) include fewer side effects and greater potency of enantiomerically pure compounds.
Traditional methods of organic synthesis have often been optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: use of enantiomerically pure starting materials derived from natural sources (the so-called “chiral pool”), or resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available. Resolution of racemates, which requires the use of resolving agents, may be inconvenient and time-consuming. Furthermore, resolution often means that the undesired enantiomer is discarded, thus wasting half of the material.
Epoxides are valuable intermediates for the stereocontrolled synthesis of complex organic compounds due to the variety of compounds which can be obtained by epoxide-opening reactions. For example, &agr;-amino alcohols can be obtained simply by opening of an epoxide with azide ion, and reduction of the resulting &agr;-azido alcohol (for example, by hydrogenation). The reaction of epoxides with other nucleophiles similarly yields functionalized compounds which can be converted to useful materials. A Lewis acid may be added to act as an epoxide-activating reagent.
The utility of epoxides has expanded dramatically with the advent of practical asymmetric catalytic methods for their synthesis (Johnson, R. A.; Sharpless, K. B. In
Catalytic Asymmetric Synthesis.
Ojima, I., Ed.: VCH: New York, 1993; Chapter 4.1. Jacobsen, E. N.
Ibid.
Chapter 4.2). In addition to epoxidation of prochiral and chiral olefins, approaches to the use of epoxides in the synthesis of enantiomerically enriched compounds include kinetic resolutions of racemic epoxides (Maruoka, K.; Nagahara, S.; Ooi, T.; Yamamoto, H.
Tetrahedron Lett
1989, 30, 5607. Chen, X. -J.; Archelas, A.; Rurstoss, R.
J Org Chem
1993, 58, 5528. Barili, P. L.; Berti, G.; Mastrorilli, E.
Tetrahedron
1993, 49, 6263.)
A particularly desirable reaction is the asymmetric ring-opening of symmetrical epoxides, a technique which utilizes easily made achiral starting materials and can simultaneously set two stereogenic centers in the functionalized product. Although the asymmetric ring-opening of epoxides with a chiral reagent has been reported, in most previously known cases the enantiomeric purity of the products has been poor. Furthermore, many previously reported methods have required stoichiometric amounts of the chiral reagent, which is likely to be expensive on a large scale. A catalytic asymmetric ring-opening of epoxides has been reported (Nugent, W. A.,
J Am Chem Soc
1992, 114, 2768); however, the catalyst is expensive to make. Furthermore, good asymmetric induction (>90% e.e.) was observed only for a few substrates and required the use of a Lewis acid additive. Moreover, the catalytic species is not well characterized, making rational mechanism-based modifications to the catalyst difficult.
SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided a process for stereoselective chemical synthesis which generally comprises reacting a nucleophile and a chiral or prochiral cyclic substrate in the presence of a non-racemic chiral catalyst to produce a stereoisomerically enriched product. The cyclic substrate comprises a carbocycle or heterocycle having a reactive center susceptible to nucleophilic attack by the nucleophile, and the chiral catalyst comprises an asymmetric tetradentate or tridentate ligand complexed with a metal atom. In the instance of the tetradentate ligand, the catalyst complex has a rectangular planar or rectangular pyramidal geometry. The tridentate ligand-metal complex assumes a planar or trigonal pyramidal geometry. In a preferred embodiment, the ligand has at least one Schiff base nitrogen complexed with the metal core of the catalyst. In another preferred embodiment, the ligand provides at least one stereogenic center within two bonds of a ligand atom which coordinates the metal.
In general, the metal atom is a transition metal from Groups 3-12 or from the lanthanide series, and is preferably not in its highest state of oxidation. For example, the metal can be a late transition metal, such as selected from Group 5-12 transition metals. In preferred embodiments, the metal atom is selected from the group consisting of Cr, Mn, V, Fe, Co, Mo, W, Ru and Ni.
In preferred embodiments, the substrate which is acted on by the nucleophile and catalyst is represented by the general formula 118:
in which
Y represents O, S, N(R
50
), C(R
52
)(R
54
), or has the formula A-B-C; wherein R
50
is selected from the set comprising hydrogen, alkyls, acyls, carbonyl-substituted alkyls, carbonyl-substituted aryls, and sulfonyls; R
52
and R
54
each independently represent an electron-withdrawing group; A and C are independently absent, or represent a C
1
-C
5
alkyl, O, S, carbonyl, or N(R
50
); and B is a carbonyl, a thiocarbonyl, a phosphoryl, or a sulfonyl; and
R
30
, R
31
, R
32
, and R
33
independently represent an organic or inorganic substituent which forms a covalent bond with the C1 or C2 carbon atoms of 118, and which permit formation of a stable ring structure including Y. For instance, the substituents R
30
, R
31
, R
32
, and R
33
each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH
2
)
m
—R
7
; or any two or more of the substituents R
30
, R
31
, R
32
, and R
33
taken together form a carbocylic or heterocyclic ring having from 4 to 8 atoms in the ring structure. In this formula, R
7
represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is an integer in the range of 0 to 8 inclusive. In certain embodiments, R
30
, R
31
, R
32
, and R
33
are chosen such that the substrate has a plane of symmetry.
Exemplary cyclic substrates for the subject reactions include epoxides, aziridines, episulfides, cyclopropanes, lactones, thiolactones, lactams, thiolactams, cyclic carbonates, cyclic thiocarbonates, cyclic sulfates, cyclic anhydrides, cyclic phosphates, cyclic ureas, cyclic thioureas, and sultones.
In a preferred embodiment, the method includes combining a nucleophilic reactant, a prochiral or chiral cyclic substrate, and a non-racemic chiral catalyst as described herein, and maintaining the combination under conditions appropriate for the chiral catalyst to catalyze stereoselective opening of the cyclic substrate at the electrophilic atom by reaction with the nucleophilic reactant.
In preferred embodiments, the chiral catalyst which is employed in the subject reaction is represented by the general formula:
in which
Z
1
, Z
2
, Z
3
and Z
4
each represent a Lewis base;
the C
1
moiety, taken with Z
1
, Z
3
and M, and the C
2
moiety, taken with Z
2
, Z
4
and M, each, independently, form a heterocycle;
R
1
, R
2
, R′
1
and R′
2
each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached,
R
40
and R
41
each independently are absent, or represent one or more covalent substitutions of C
1
and C
2
with an organic or inorganic substituent permitted by valence requirements of the ring atom to
Jacobsen Eric N.
Larrow Jay F.
Tokunaga Makoto
Foley & Hoag LLP
Gerstl Robert
Gordon Dana M.
President and Fellows of Harvard College
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