Asymmetric hydrogenation of vinyl sulfones

Details Asymmetric hydrogenation of vinyl sulfones Asymmetric hydrogenation of vinyl sulfones

1998-09-24

2001-08-14

Vollano, Jean F (Department: 1621)

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

Organic compounds

Carboxylic acid esters

C562S512000, C568S028000, C568S030000, C568S031000, C564S123000

Reexamination Certificate

active

06274758

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the preparation of enantiomerically enriched sulfones via asymmetric hydrogenation of vinyl sulfones.
BACKGROUND OF THE INVENTION
Enantiopure sulfones, e.g. of the formula R
1
—CHX—CHR
3
—SO
2
R
2
(1), are of interest as synthetic building blocks, for example, as intermediates in the preparation of enantiopure hydroxamic acids which are under investigation as MMP inhibitors, as described in, inter alia, WO-A-9805635. The enantiopure hydroxamic acids may be prepared by resolution of an intermediate; however, resolution processes are inefficient, with a maximum yield 50% of the correct enantiomer being obtainable. For drug manufacture, an asymmetric synthesis which provides a single enantiomer is often more attractive.
3-Substituted 2-sulfonylmethylpropionic acids have been prepared in moderate e.e. (enantiomeric excess), i.e. up to around 80% e.e. in two steps, from the corresponding allyl sulfides, by sequential asymmetric hydrogenation and oxidation at sulfur (DE-A-4233100; Jendralla, Tetrahedron: Asymmetry (1994) 5:1183-1186; Beck et al, Tetrahedron (1994) 50:4691-4698; Jendrella, Proceedings of Chira Tech '97 (The Catalyst Group). The requisite allyl sulfides are normally prepared as E/Z mixtures by a Wittig olefination reaction; subsequent separation of geometric isomers is required to give optimum results in the asymmetric hydrogenation process. For example, (E)-2-tert-butylthiomethyl-3-(1-naphthyl)acrylic acid was hydrogenated in methanol using a catalyst prepared from (S)-(−)-BINAP, benzeneruthenium (II) chloride dimer and NaOAc at 150° C. and 13800 kPa (2000 psi), followed by peracid oxidation to give (S)-3-tert-butylsulfonyl-2-(1-naphthylmethyl)propionic acid. Similar results were achieved via hydrogenation of the corresponding cyclohexylamine salt form. To access (S)-3-tert-butylsulfonyl-2-(1-naphthylmethyl)propionic acid in >99% e.e. required additional processing, with concomitant loss of yield, by crystallisation of diastereomeric salts formed with (R)-1-phenylethylamine.
Homogeneous diastereoselective hydrogenation of (&agr;-hydroxyalkyl)vinyl sulfones of formula 3
with an achiral Rh catalyst is known (Ando el al, J. Chem. Soc., Chem. Commun. (1992) 592), giving hydrogenated material in high d.e. This reaction was elaborated by carrying out a kinetic resolution of an (&agr;-hydroxalkyl)vinyl sulfone using (S,S)-dipamp Rh. The starting (&agr;-hydroxyalkyl)vinyl sulfone was recovered in 76% e.e. at 50% substrate conversion and 89% e.e. at 57% conversion. The authors indicated that diasteroselectivity is controlled predominantly by coordination of the catalyst to the &agr;-OH group at the chiral center of the substrated. However, the products have limited utility as synthetic intermediates.
This directing group effect may be akin to that required in asymmetric hydrogenation of other substrate classes. For example, the preparation of &agr;-amino acids by asymmetric hydrogenation of enamides requires a group such as acetyl (Ac) on the nitrogen, which then has to be removed carefully under conditions giving minimal racemisation at the newly created chiral centre.
SUMMARY OF THE INVENTION
This invention is based on the surprising discovery that prochiral vinyl sulphones of formula (2) can be hydrogenated with high enantioselectivity, in the presence of a chiral catalyst, to give enantioenriched or enantiopure sulfones of formula (1)
By contrast to the disclosure of Ando et al, no OH group is required as a directing group in the &bgr;-position with respect to the sulfone (i.e. as in compound (3) above); the vinyl sulfones (2) are prochiral. The reaction does not require elevated temperature or pressure to achieve good chemical conversion and high enanthioselectivity. Typically, this hydrogenation can be carried out at low to moderate pressure, e.g. 7-4140 kPa (1-600 psi) and low temperatures, e.g. 0 to 60° C.
The desired sulfone product (1) is produced directly, without the need for subsequent oxidation at sulfur. In addition, the coordinating group X present in (1) provides versatile functionality for further synthetic transformations, e.g. to prepare biologically active compounds such as those described in WO-A-9805635. The sulfone group itself also facilitates a wide range of reactions, such as those reviewed by Simpkins “Sulfones in Organic Synthesis”, pub. Pergamon (1993). The process of the subject invention may additionally comprise converting the group X to give an enantiopure compound having therapeutic utility as an inhibitior of matrix metalloproteinases.
DESCRIPTION OF THE INVENTION
In formulae (1) and (2): R
1
, R
2
and R
3
are each any hydrocarbon group of less than 20 carbon atoms, optionally substituted at any position; in addition, either of R
1
and R
3
may be H. The nature of any substituent is not critical to the generality of the procedure.
X will not normally be removable; it is a co-ordinating group including, but not restricted to, CO
2
H or a salt form thereof, CO
2
R, CONHOH, CONH
2
, CONHR, CONR
2
etc. The substrate (1) for hydrogenation may be in the form of a single geometric isomer, e.g. E, wherein R
2
SO
2
and X groups are trans. However, this is not always necessary, since certain hydrogenation catalysts allow the enantioconvergent reaction of E/Z mixtures.
The complex which comprises the hydrogenation catalyst is made up of a transition metal, preferably rhodium, ruthenium or iridium, and a chiral ligand, preferably mono or diphosphines. Rhodium is especially preferred as the metal. Cyclic phosphines are preferred, especially those incorporating a trans-2,5-disubstituted phospholane moiety (4)
or its antipode, wherein R
4
is a hydrocarbon substituent of up to 20 C atoms, typically C
1-10
linear or branched alkyl. Known examples of such phosphines are those in the DuPHOS (U.S. Pat. No. 5,171,892) and BPE (U.S. Pat. No. 5,008,457) series. Known examples of the catalysts include [(S,S)-EtDuPHOS Rh (COD)]BF
4
, [(R,R)-MeDuPHOS Rh (COD)]BF
4
, [(S,S)-iPrDuPHOS Rh (COD)]BF
4
, and [(R,R)-MeBPE Rh (COD)]BF
4
. Both enantiomers of these catalysts are available with equal facility, and therefore either enantiomer of the sulphone (2) can be obtained by the asymmetric hydrogenation.
Alternative catalyst complexes, of the phosphetane type, are described in WO-A-9802445.
In a preferred embodiment of the present invention, vinyl sulfone (2a) [2: R
1
is Pr, R
2
is 4-o-methoxybenzyl, R
3
is H and X is CO
2
H] was hydrogenated using [(S,S)-EtDuPHOS Rh (COD)]BF
4
in methanol at 1035 kPa (150 psi) hydrogen at room temperature for 2 hours, after which time complete substrate conversion was observed. Chiral HPLC showed that the hydrogenated sulfone (1a) [variable defined as for 2a] had an e.e. of 96%. Asymmetric hydrogenation of analogues of (2a), bearing additional functionality in the R
1
substituent, was similarly successful.
The vinyl sulfones (starting materials) for the process of the invention may be conveniently prepared using a modified version of the procedure described by Najera et al (J. Chem. Soc., Perkin Trans. I (1988) 1029-1032) and in EP-A-0644176. The following reaction scheme applies:
A compound of formula (5) where R
1
and R
3
are defined as for formula (2) is reacted with sulfonyl iodide of formula R
2
SO
2
I where R
2
defined as for formula (2), in a solvent such as DCM, and then the reaction mixture is treated with a base such as triethylamine to eliminate hydrogen iodide and yield a vinyl sulfone of formula (2). When X is electron-withdrawing, e.g. CO
2
H, and R
3
is H, the reaction is stereoselective and the stereochemistry of the resultant vinyl sulfones is E (trans) (Najera et al, supra). Formation of a single geometric isomer, rather than an E/Z mixture, facilitates straightforward purification by crystallisation.
The sulfonyl iodide may be prepared from the respective sodium sulfinic acid sodium salt (R
2
SO
2
Na) by shaking an aqueous solution of the latter with a solution of io

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