Asymmetric Formation of Allylic Amines with N‐Substituted Quaternary Stereocenters by Pd^II‐Catalyzed Aza‐Claisen Rearrangements

Abstract

Dedicated to Professor Dieter Seebach on the occasion of his 70th birthdayEnantiomerically pure allylic amines are valuable building blocks, as they possess two highly versatile functional groups. Two widely used methods for their preparation are the transition-metal-catalyzed allylic substitution [1] and the azaClaisen rearrangement of trihaloacetimidates (Overman rearrangement).[2] A longstanding problem is the catalytic enantioselective formation of quaternary stereocenters by either of these methodologies. Since quaternary carbon atoms bearing a nitrogen substituent are a widespread structural motif for bioactive natural and non-natural compounds, [3] the asymmetric construction of those stereocenters by means of asymmetric catalysis is an important challenge. Enantiopure allylic amines possessing a quaternary N-substituted stereocenter are particularly attractive for the synthesis of quaternary amino acids, [4] which are important targets owing to their ability to induce helical peptide structures [5] and owing to the fact that peptides incorporating quaternary amino acid residues possess enhanced stability toward proteases. [6] Recently, we have developed a planar-chiral ferrocenyl imidazoline palladacycle catalyst 1-X (FIP-X), which displays unprecedented levels of activity for the highly enantioselective aza-Claisen rearrangement of Econfigured allylic PMP-trifluoroacetimidates (PMP = p-methoxyphenyl).[2h]Compound 1-X is in fact about 50-100 times more active for the rearrangement of this class of substrates than the best previously reported catalysts. The exceptionally high catalytic activity is attributed to the pentaphenylcyclopentadienyl (Cp F ) ligand and can be explained at least in part by the electron-withdrawing nature of the five phenyl substituents, which enhance the Lewis acidity of the Pd center in 1-X.This excellent catalytic activity has prompted us to investigate the formation of quaternary stereocenters by the rearrangement of 3,3-disubstituted allylic trifluoroacetimidates 4, which were prepared from the corresponding allylic alcohols 2 [Eq. (1)]. [7] The isomerically almost pure 3,3-disubstituted allylic alcohols 2 were formed by CuI-mediated 1,4-additions to methyl-or ethyl-2-ynoates 6 and subsequent reduction with DIBAL [Eq. (2)].Functionalized derivatives were prepared starting from geranyl acetate (7) by regioselective epoxidation and subsequent treatment with periodic acid, leading to the corresponding aldehyde, which was reduced to alcohol 8 (Scheme 1).[8] The alcohol was then used to synthesize a silylether, carbonate, and BOC-protected amine derivative (2 d-f). Alternatively, ester 2 g (R = Me, R' = (CH 2 ) 2 CO 2 Et) was prepared by Johnson-Claisen rearrangement (see the Supporting Information). The allylic alcohols were then condensed with iminochloride 3 [Eq. (1)].2.0 mol % of the catalyst precursor FIP-Cl (1-Cl, X = Cl), activated in situ with 3.75 equivalents AgTFA (relative to 1-Cl, TFA = trifluoroacetate), [2h] was generally sufficient to give high conversion after 2.5 ...

Stereospecific Overman Rearrangement of Substituted Cyclic Vinyl Bromides: Access to Fully Substituted α-Amino Ketones

“…Supporting Information for Alexy,Yoritate,Wright and Stoltz SI11 128.3,116.2 (q,J = 289.7 Hz),115.3,115.1,113.8,113.3,68.0,55.5,41.4,32.2,30.5,27.1,20.7;19 F NMR (282 MHz,; IR (Neat film, NaCl) 3443,2936,1698,1509,1252,1201,1179,1154,1032,970,834 4,132.8,132.6,129.2,128.4,125.4,116.2 (q,J = 289.8 Hz),113.8,113.3,68.0,55.5,41.5,30.4,20.8;19 5,132.7,132.4,131.5,128.2,127.8,124.5,123.5,116.2 (q,J = 289.7 Hz),113.9,113.5,88.9,80.8,…”

“…= 15.9, 4.5, 1.8 Hz, 1H), 2.51 -2.34 (m, 2H), 2.33 -1.85 (m, 8H), 1.85 -1.58 (m, 3H);13 C NMR (100 MHz, Chloroform-d) δ 205.0, 160.4, 157.3 (q, J = 35.1 Hz), 140.9, 132 4,. 131.8, 128.5, 128.1, 127.7, 126.2, 122.3, 116.3 (q, J = 288.3 Hz), 114.0, 113.9, 72.0, 55.6, 40.1, 36.5, …”

Metallocyclic Ferrocenyl Ligands

“…Included in the range of substrates transformed were Z-configured trifluoroacetimidates containing an a-branched substituent (Z)-117, (R ¼ i-Pr), and the methodology has been successfully extended to a give a range of highly scalemic functionalized allylic amine building blocks [35b]. The use of trifluoroacetimidate substrates has been extended to the asymmetric synthesis of quaternary stereogenic centers with the monopalladocyclic FIP-catalyst precursor (S p ) 2 -119 (Scheme 12.34) [77]. The addition of 3 equiv (with respect to (S p ) 2 -119) of 1,8-bis(dimethylamino)naphthylene as an acid scavenger largely suppresses the acid-catalyzed elimination of trifluoroacetamide which is otherwise a significant problem with the 3,3-disubstituted substrates 122.…”

Preparation of ferrocenyl imidazolines using bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate

“…Cui, Wu and their coworkers showed that the ferrocenylimidazoline palladacycles were efficient catalysts for the Suzuki-Miyaura cross-coupling reaction, even allowing the use of aryl chlorides [12,13] . In addition, chiral ferrocenyl imidazolines have also been synthesized by Peters and coworkers [14][15][16][17][18][19][20][21] . They found the planar chiral palladacycles derived from the above chiral ferrocenyl imidazolines were able to catalyze the aza-Claisen rearrangements with up to excellent enantioselectivities [21][22][23][24][25][26][27][28] .…”