Asymmetric synthesis of 2-arylpyrrolidines starting from γ-chloro N-(tert-butanesulfinyl)ketimines

Abstract

The enantioselective reductive cyclization of gamma-chloro N-(tert-butanesulfinyl)ketimines towards the short and efficient synthesis of (S)- and (R)-2-arylpyrrolidines (ee >99%) is described for the first time by treatment with LiBEt(3)H and subsequent acid deprotection.

Stereoselective Synthesis of Dipeptidyl Peptidase‐4 (DPP‐4) Inhibitor, (R)‐Sitagliptin

“…The stereochemistry of 5 was established by converting it into a known b-amino acid 7. [15] Accordingly, the removal of the sulfinyl group [16] using dioxane-HCl followed by Boc protection of the free amine using Boc 2 O and triethyl amine gave the N-Boc derivative 6 in 86 % yield (over two steps). [17] Cleavage of the olefin using KMnO 4 in the presence of NaIO 4 in water afforded the corresponding carboxylic acid 7 in 80 % yield (Scheme 2).…”

tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon–Nitrogen Bond Forming Reactions

“…By contrast, five-membered ring formation by displacement of a halide leaving group is far more usual and has been implemented in several ways (Scheme 2). It has been accomplished either at 50°C by treatment with KOH in H 2 O/THF [17] or tBuOK in iPrOH, [13] or at room temperature in THF using LiHMDS [18] (see the formation of 6), KHMDS, [19] or a combination of NaH and a crown ether additive (15-Crown-5). [20] As illustrated with 7, the latter conditions are tolerant of functionalized substrates.…”

A general, enantioselective synthesis of 1-azabicyclo[m.n.0]alkane ring systems

“…1) are limited. 1–8 In general, the existing strategies for the construction of azabicyclic ring systems rely on Staudinger-aza-Wittig approaches, 9 7-exo- tet -cyclizations, 10,11 cycloadditions ([5+2], [4+2] and [2+2+2]), 12 ring-closing metathesis (RCM) strategies, 13 Mitsunobu approaches 14 and rearrangements (nitrone and intramolecular Schmidt rearrangements) 15,16 For the larger azabicyclic ring systems, routes are very rare, and those reported lack stereocontrol. 8,17 …”

“…De Kimpe and co-workers recently demonstrated the asymmetric synthesis of 2-arylpyrrolidines 15 from γ-chloro N -( te rt-butanesulfinyl)ketimines 13 , 11 and Brown and co-workers employed a related strategy for the total synthesis of (−)-tashiromine 17 and (−)-epilupinine 18 (Scheme 2, eq. 1).…”

“…18,22,23 After column chromatography, single diasteromers of analogs 20 resulted, which were carried forward. Following modification of the known protocols, 11,21 acid-mediated deprotection and base-induced, microwave-assisted cyclization and alkyation with the required allyl, butenyl and pentenyl bromides smoothly afforded the chiral N -alkyl azocines 21 in 63–83% yields for the three step, one-pot reaction sequence (Scheme 4). 27 To enable the one-pot sequence, a number of bases, solvents and temperatures were evaluated; however, K 2 CO 3 , NaI in DMF under microwave irradiation (120 °C, 15 min) proved to be general for all substrates, even the larger 7-azocine rings.…”