An Efficient Synthesis of Chiral Cyclic β-Amino Acids via Asymmetric Hydrogenation

Abstract

Cyclic b-amino acids, homoproline, homopipecolic acid and 3-carboxy-methylmorpholine were obtained in high enantiomeric excesses by transition metal-catalyzed asymmetric hydrogenation of cyclic b-acylamino-alkenoates. These compounds were synthesized by a thio-Wittig reaction on N-protected thiolactames.The synthesis of conformationally constrained amino acid derivatives has recently received much attention due to their ability to act as conformational probes when incorporated into peptides and peptidomimetics. 1 Among them, optically active b-amino acids, although of less importance than the parent a-amino acids, are crucial structural units of numerous biologically active and natural products. 2 Various methods are available for the synthesis of linear compounds of this series by both asymmetric synthesis and enzymatic resolutions. 3In contrast, there are few methods available for the asymmetric synthesis of cyclic b-amino acids. Some methods are known for the b 2,3 -acids. 4 For the b 3 -acids, ArndtEistert homologation of (S)-proline has been used to access to homoproline 5 and homopipecolic acid. 6 More recently, two general approaches to five-and six-membered cyclic b 3 -amino acids have been disclosed using diastereo-controlled Michael additions of chiral amides to a,b-unsaturated esters followed by intramolecular ringclosure 7 and diastereoselective reduction of the resulting chiral b-enamino esters. 8Although linear b-amino acids may be obtained in high enantiomeric excesses by asymmetric hydrogenation of b-(acylamino)acrylates, 9 to the best of our knowledge, only the synthesis of homoproline by enantioselective hydrogenation has been reported until now. 10In this paper, we wish to describe a novel and efficient synthesis of N-protected homoproline, homopipecolic acid and 3-carboxymethylmorpholine by transition metalcatalyzed hydrogenation of cyclic enamido esters.It is well known that the use of bidentate substrates is generally required to achieve highly enantioselective metal-catalyzed hydrogenations. Compounds 1-4 fit well with such requirement; they were then considered as substrates for enantioselective hydrogenations (Scheme 1). Scheme 1In contrast with the linear b-acylamido acrylates the preparation of which is well known, the cyclic analogs are of a more difficult access. The synthesis of non-protected Zenamino esters by addition of a Meldrum acid salt to a lactime ether was previously described by Lhommet et al. 11 However, such a method is not general. Only the fivemembered cyclic derivative 1 may be obtained by direct acylation of the nitrogen atom with acetyl chloride. The six-and seven-membered ring enamino esters are always acylated in position a to the ester function. Consequently, we have then developed an alternative method based on a thio-Wittig condensation 12 to access to the required compounds. The N-protected thiolactames prepared by thiolation of the corresponding lactones followed by protection of the nitrogen atom were reacted with a Wittig reagent to give mainly the E-isom...

Asymmetric Hydrogenation of Nonaromatic Cyclic Substrates

“…Ruthenium complexes of axially chiral diphosphine ligands ( S )-BINAP ( L1 S ) and ( S )-MeO-BIPHEP ( L2 S ) (Scheme ) were able to successfully hydrogenate structurally related ( E )-2-(pyrrolidin-2-ylidene)­acetate S4 with 94% and 97% ee, respectively …”

“…Ruthenium complexes of axially chiral diphosphine ligands (S)-BINAP (L1S) and (S)-MeO-BIPHEP (L2S) (Scheme 1) were able to successfully hydrogenate structurally related (E)-2-(pyrrolidin-2-ylidene)acetate S4 with 94% and 97% ee, respectively. 16 The asymmetric hydrogenation of a 6-membered cyclic βenamidoester S5 was also examined using a [RuCl 2 (p-cymene)] 2 and (R)-BINAP (L1R) complex to give the corresponding product with 90% ee (Figure 6). 17 2.1.2.…”

Industrial Catalysts for Regio‐ or Stereo‐Selective Oxidations and Reductions. A Review of Key Technologies and Targets

“…b-Homophenylalanine has been a widely reported as an example from this family of compounds. Other structures that use members of this family as their components are exemplified by the 'fiban' compounds (shown in Figure 1.5) which display various b-amino acid residues, including a cyclic constrained structure that forms an important sub-group of the b-amino acids family [6] . The enantioselective synthesis of the b-amino acid ester shown in Figure 1.6 has recently been reported by Kubryk and Hansen [7] (Merck) where good ees were obtained by asymmetric hydrogenation.…”

Stereocontrolled synthesis and alkylation of cyclic β-amino esters: asymmetric synthesis of a (–)-sparteine surrogate

“…Scheme 1 pipecolic esters, 9 conjugate addition of chiral amine derivatives to ab-unsaturated esters and subsequent cyclisation, 2,10,11 S N 2 displacement-cyclisation of ab-unsaturated esters using a chiral amine, 3,12 stereoselective allylation of a chiral iminium ion 6 and hydrogenation of enamide esters using a chiral auxiliary 13, 14 or chiral catalyst. 15 Previous research in our group has led to the development of two different approaches for the asymmetric synthesis of cyclic b-amino esters: (i) conjugate addition of chiral lithium amides to ab-unsaturated esters followed by N-deprotection and cyclisation 2 and (ii) S N 2 displacement of an iodo-substituted ab-unsaturated ester using a chiral amine and concomitant cyclisation. 3 Of these two methods for synthesising cyclic b-amino esters 1, our preferred approach, which we have now optimised, is the diastereoselective Bunce-style 16 S N 2 substitution-cyclisation of iodo-ab-unsaturated ester 3 and (S)-a-methylbenzylamine to amino esters (R,S)-4 and (S,S)-4 (Scheme 2).…”