Ring Closing Metathesis for the Asymmetric Synthesis of (S)-Homopipecolic Acid, (S)-Homoproline and (S)-Coniine

Abstract

Diastereoselective conjugate addition of lithium (S)-Nallyl-N-a-methylbenzylamide to a,b-unsaturated esters or Weinreb amides, followed by ring closing metathesis is used to afford the cyclic b-amino acids (S)-homopipecolic acid and (S)-homoproline and the amine (S)-coniine in high ee.The synthesis of conformationally constrained amino acid derivatives has received much recent attention due to their ability to act as conformational probes when incorporated into peptides and peptidomimetics. 1 Asymmetric approaches toward these targets have largely focused upon the production of novel a-amino acid derivatives, 2 with the preparation of homochiral cyclic b-amino acids relatively less studied, although these attractive synthetic targets have previously been constructed by homologation of a-amino acids, 3 intramolecular ring closure 4 and stereoselective hydrogenation. 5 Previous investigations from our laboratory have shown that the highly diastereoselective conjugate addition of homochiral lithium N-alkyl-N-amethylbenzylamides to a range of a,b-unsaturated esters and subsequent N-deprotection offers an efficient route to the asymmetric synthesis of b-amino acid derivatives. 6 In order to extend the utility of this methodology, a protocol involving functionalisation, rather than deprotection, of the N-alkyl groups of the chiral lithium amide used in the conjugate addition reaction was desired. The N-allyl functionality contained within (S)-N-allyl-N-a-methylbenzylamide 1 was selected for this purpose and we describe herein the use of ring closing olefin metathesis 7 for the synthesis of cyclic b-amino acids and amines (Figure). 8The initial target for this methodology was the synthesis of (S)-homopipecolic acid 6. 9 Thus, conjugate addition of lithium (S)-N-allyl-N-a-methylbenzylamide 1 to (E,E)-methyl heptan-2,5-dieneoate 2 gave (3S,aS)-methyl 3-(Nallyl-N-a-methylbenzylamino)hept-5-enoate 3 in 69% yield and >95% de. 10 Treatment of b-amino ester 3 with Grubbs' ruthenium alkylidene catalyst 11 furnished cyclic N-protected b-amino ester 4 in 49% yield and in >95% de, indicating that no epimerisation had taken place during the ring closing metathesis protocol. N-deprotection via catalytic hydrogenation afforded b-amino ester 5 in 93% yield and >95% ee, 12 with subsequent ester hydrolysis giving (S)-homopipecolic acid 6 {[a] D 26 +24.0 (c 0.87, H 2 O); lit. 13 [a] D +22.

Olefin Metathesis of Amine‐Containing Systems: Beyond the Current Consensus

“…[37] RCM reactions of more crowded amines bearing an N-a-methylbenzyl, an N-diphenylmethyl or an N-triphenylmethyl (trityl) protecting group are depicted in Scheme 4, Scheme 5, Scheme 6, Scheme 7, Scheme 8 and Scheme 9. [38][39][40][41][42] Comparisons of yields obtained under similar conditions from dienes 14, 16 and 18 indicated clearly that the efficiency of the RCM increases with the steric hindrance around the amino group (see also Scheme 30).…”

Asymmetric total synthesis of sperabillins B and D via lithium amide conjugate addition

“…The ninhydrin positive fractions were combined and the solvent removed in vacuo to afford a white solid, which was dissolved in warm MeOH (250 mL). The solvent was removed in vacuo to afford the title compound 55 as a white powder (1.74 g, 99%); mp 222 °C; [] 24 D +20.9 (c = 0. (14), 164 (22), 114 (14).…”

“…5 : 1 mixture of its hydrobromide and HOBT salts. This mixture was dissolved in DCM/MeOH (10 : 1, 10 mL), MP carbonate resin (Argotech ® , 120 mg, 2.55 mmol g −1 , 0.31 mmol) added and the mixture stirred for 2 h. After removal of the resin by filtration, and washing with DCM (2 × 10 mL), the sol-vent was removed from the combined filtrate and washings in vacuo to afford the title compound 77 as a pale yellow oil (28 mg, 99%); [] 24 D +47.7 (c = 0.59, CHCl 3 );  max (film) 3298 (N-H), 2934 (C-H), 1691, 1654 (CO, CN), 1626 (CC), 1597 (CC), 1527 (amide II);  H (500 MHz, CDCl 3 ) 1.25 (2H, br s, CH 2 CN), 1.32 (3H, d, J = 5.9, CH 3 CHN), 1.43 (9H, s, C(CH 3 ) 3 ), 1.58 (3H, s, CH 3 CCH 3 ), 1.66 (3H, s, CH (2E,4Z )-Hexa-2,4-dienoyl chloride 80. To a stirred solution of (2E,4Z )-hex-2,4-dienoic acid 79 (500 mg, 4.46 mmol, 94 : 6 dr) in DCM (10 mL) was added oxalyl chloride (0.58 mL, 6.70 mmol) drop-wise, followed by 2 drops of DMF.…”

“…23 Subsequent studies showed that conjugate addition of lithium amide (R)-21 to methyl ester acceptor 18 afforded (3R,R)--amino ester 25 in 73% isolated yield in >96% d.e., which could be readily purified to homogeneity by chromatography (Scheme 5). 24 Synthesis of the core amino acid fragment: (3R,5R,6R)-3,6diamino-5-hydroxyheptanoic acid Investigations were next concerned with the conversion of N-allyl -amino esters 23 and 25 into the desired core diamino hydroxy acid. The N-allyl protecting groups within 23 and 25 could be removed smoothly using either palladium 25 or rhodium catalysis, 26 giving amino esters 26 and 27 in 91% and >96% d.e.…”

Expedient Pathway into Optically Active 2‐Oxopiperidines

“…[14] Among various applications of the metathesis reaction, ring-closing metathesis (RCM) has emerged as one of the most powerful tools for construction cyclic compounds. [15,16] Following up on recent research developed in our own group demonstrating the opportunities of RCM of a,β-unsaturated dehydroamino esters, [17] we now wish to report further exploration of this methodology leading to optically active heterocyclic systems of type 1. Synthesis of these compounds was anticipated to proceed via initial condensation of unsaturated amides with ethyl pyruvate to yield enamides 2.…”