Chemical methods

Details Chemical methods Chemical methods

2001-07-27

2004-02-24

Shippen, Michael L. (Department: 1621)

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

Organic compounds

Oxygen containing

C560S101000, C560S105000, C562S553000, C562S559000, C562S562000, C562S563000, C562S570000, C562S573000, C562S575000, C562S576000, C568S331000

Reexamination Certificate

active

06696611

ABSTRACT:

BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates generally to reductive methods useful in chemical synthesis. In particular, the present invention provides enantioselective reductive methods using chiral organostannanes and Lewis acids.
The scientific literature contains numerous reports of free-radical reactions proceeding with distereocontrol (see for example, reviews such as Curran et al.,
Stereochemistry of Radical Reactions
, VCH, Weinheim, 1995; Smadja et al.,
Synlett.,
1, 1994; Porter et al.,
Acc. Chem. Res.,
24:296, 1991; and Sibi et al.,
Acc. Chem. Res.,
32:163, 1999). However, there are relatively very few examples of free-radical reactions which proceed with genuine enantiocontrol. The majority of the examples that demonstrate enantioselective outcomes involve the use of chiral auxiliaries and, as a result, are actually further examples of diastereo-selectivity in free-radical chemistry.
Of the remaining few reports, the introduction of asymmetry in the substrate has been achieved through the use of chiral Lewis acid mediation (see, for example, Guindon et al.,
Tetrahedron Lett.,
31:2845, 1990; Guindon et al.,
J. Am. Chem. Soc.,
113:9701, 1991; and Renaud et al.,
Angew. Chem. Int. Ed.,
37:2563, 1998), or by a chiral reagent through the use of chiral ligands on the tin atoms in suitably constructed stannanes (Schumann et al.,
J. Organomet. Chem.,
265:145, 1984; Curran et al.,
Tetrahedron. Asymmetry,
7:2417, 1996; Blumstein et al.,
Angew. Chem. Int. Ed.,
36:235, 1997; and Schartzkopfetal.,
Eur. J. Chem.,
177, 1998).
It has now been found that the enantioselectivity of free radical reductions using chiral non-racemic stannanes can be enhanced by the use of an appropriate Lewis Acid.
SUMMARY OF THE INVENTION
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Improved methods for the enantioselective reduction of prochiral carbon radicals using chiral and achiral Lewis acids in conjunction with chiral non-racemic stannanes have now been developed which result in an enhanced enantioselectivity when compared to the use of the chiral non-racemic stannane alone.
Accordingly, the present invention provides a method for enantioselectively reducing a prochiral carbon centred radical having one or more electron donator groups attached directly to the central prochiral carbon atom of the radical, and/or attached to a carbon atom within 1 to 4 atoms of the central prochiral carbon atom, comprising treating said radical with a chiral non-racemic organotin hydride in the presence of a Lewis acid.
Preferably, the electron donator group is attached directly to the central prochiral carbon atom or to a carbon atom within 1 or 2 atoms of the central prochiral carbon atom.
In a particular embodiment, the invention is directed towards a method of producing optically enhanced &agr; or &bgr;-amino acids, by treatment of a prochiral amino acid carbon centred radical with a chiral non-racemic organotin hydride in the presence of a Lewis acid, wherein the central prochiral carbon atom is an &agr;-carbon atom of an &agr;-amino acid.or a &bgr;-carbon atom of a &bgr;-amino acid.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “prochiral carbon centred radical” is a radical of formula R
1
R
2
R
3
C., wherein each R residue is different and is not hydrogen. Accordingly, the central prochiral carbon atom is the carbon atom to which the R residues are attached. Reduction of the prochiral carbon centred radical with a hydrogen atom donor affords the chiral compound R
1
R
2
R
3
CH. The present invention thus relates to the preparation of enantioselectively enhanced chiral compounds.
The prochiral carbon centred radical can be generated from any suitable radical precursor using methods known in the art. Exemplary radical precursors include aryl, e.g., phenyl, selenides; aryl, e.g., phenyl, sulfides; aryl, e.g., phenyl, tellurides; xanthates; thionoformates and Barton esters (see, for example, Giese,
Radicals in Organic Synthesis—Formation of C—C Bonds
, Pergamon Press, Oxford, 1986, the contents of which are incorporated herein by reference). Particularly suitable radical precursors for generating the prochiral carbon centred radicals for use in the invention are tertiary chiral halosubstrates, i.e., R
1
R
2
R
3
C-halogen, where R
1
-R
3
are different and not hydrogen and halogen is chlorine, bromine or iodine, preferably bromine.
The prochiral carbon centred radicals which can be reduced by the methods of the invention include radicals which bear one or more electron donator groups directly on the prochiral central carbon atom and/or attached to a carbon atom or to the centralprochiral carbon atom, i.e., within 1, 2, 3 or 4 atoms, preferably within 1 or 2 atoms. Suitable electron donator groups include those containing an electron donator atom such as oxygen, nitrogen, and/or sulfur and which will not be affected by the organotin hydride. One example of an electron donator group is a carbonyl group C(═O), present, as, for example, in aldehydes, ketones, carboxy acid, carboxy esters, carboxy amides, anhydrides, lactones, lactams, carbonates, carbamates and thioesters, etc. Other electron donator groups include, thioalkyl groups, amines (unsubstituted or substituted once or twice by, for example, a group selected from alkyl, acyl and aryl), hydroxy groups and ethers (e.g., alkyl and aryl). A preferred electron donator is a carbonyl group. Preferably the carbonyl group is adjacent to, i.e.,—to the chiral carbon to be reduced. Expressed in another way, the prochiral carbon centred radical has at least one electron donator atom within 5 atoms (i.e., 1, 2, 3, 4, or 5) of the central prochiral carbon atom. It will be recognized that some electron donator groups may contain one or more electron donating atoms, e.g., carboxy acid, carboxy ester, thioester, carboxy amide. A prochiral carbon centred radical may also contain more than one electron donating group attached to the central prochiral atom.
Exemplary prochiral carbon centred radicals include those of the formula R
1
R
2
R
3
C., wherein R
1
-R
3
are different (and not hydrogen) and are independently selected from alkyl, alkenyl, alkynyl, aryl, heterocyclyl, acyl, amino, substituted amino, carboxy, anhydride, carboxy ester, carboxy amide, lactone, lactam, thioester, formyl, optionally protected hydroxy, thioalkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heterocyclyloxy; or alternatively, any two of R
1
-R
3
can together, with the central prochiral carbon atom, form a mono- or poly-cyclic group or fused polycyclic group including as cycloalkyl, cycloalkenyl, cycloalkynyl, a lactone, a lactam, cyclic anhydride, or heterocyclyl and bi-, tri- and tetracyclic fused combinations thererof. At least one of R
1
-R
3
, or a cyclic group formed by any two of R
1
-R
3
, contains an electron donator atom within 1 to 5 atoms of the prochiral central carbon atom to be reduced. It will be understood that a radical precursor may contain more than one prochiral radical precursor sites and that reduction may therefore occur at one or more of these sites.
In one preferred embodiment, at least one of R
1
-R
3
is an optionally substituted aryl or heteroaryl group. In another preferred embodiment at least one of R
1
-R
3
is an optionally substituted alkyl, alkenyl, or alkynyl group. In another embodiment, at least one of R
1
-R
3
is a ketone, aldehyde, carboxy acid, carboxy ester, carboxy amide, anhydride, lactone, lactam or thioester, or two of R
1
-R
3
together with the central prochiral carbon atom form a cyclic anhydride, lactam or lactone.
Preferred “ketones” have the formula —C(O)—R wherein R can be any residue, having a carbon atom covalently bonded to the carbonyl group, such as alkyl, alken

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