Investigation of bispidines as the stoichiometric ligand in the two-ligand catalytic asymmetric deprotonation of N -Boc pyrrolidine

A range of achiral bispidines have been synthesized and evaluated as the stoichiometric ligand in the two-ligand catalytic asymmetric deprotonation of N -Boc pyrrolidine.


Introduction
Organolithium/chiral diamine complexes are now established as versatile and useful reagents for the asymmetric synthesis of chiral molecules. 1,2In this context, (-)-sparteine is the most widelyinvestigated diamine 3 following the pioneering work by Hoppe 4 and Beak. 5 Indeed, reagents comprising organolithium reagents (e.g.s-BuLi or n-BuLi) and (-)-sparteine have been used for the asymmetric synthesis of a diverse range of compounds including amines, 6 alcohols, 7 phosphines, 8 ferrocenes 9 and paracyclophanes. 10An example from Bailey and Mealy 11,12 is representative of the synthetic potential afforded by organolithium/(-)-sparteine reagents.Treatment of di-allylated bromoaniline 1 with t-BuLi/(-)-sparteine 3 followed by incubation at -40 °C and quenching with MeOH delivered chiral indoline (R)-2 in 69% yield and 93:7 er (Scheme 1).The reaction proceeds via bromine-lithium exchange and subsequent intramolecular carbolithiation in which the facial attack onto the alkene is controlled by coordination of (-)sparteine to the aryllithium intermediate.

Scheme 2
In both of the examples shown in Scheme 2, success was achieved using a designed recycling diamine, bis-i-Pr-bispidine 6.The idea was that the steric hindrance in s-BuLi/bispidine 6 would lead to slow lithiation of N-Boc pyrrolidine 4.However, despite the steric hindrance of bispidine 6, we hoped that it would participate in ligand exchange and thus recycle the chiral diamine.The successful examples of two-ligand catalysis supported our conjecture.Unfortunately, as disclosed in our original report, bispidine 6 was prepared in a disappointing 26% yield via a known 23 two-step route.As a result, we screened several other diamines in an attempt to find a recycling diamine that was easier to synthesise 19 and ultimately concluded that the bispidine framework exemplified by 6 was optimum.Hence, in this paper, we present our efforts at identifying an alternative recycling bispidine ligand to bispidine 6.

Results and Discussion
To start with, a range of different bispidines was prepared as outlined in Scheme 3. A double Mannich reaction using freshly distilled N-i-Pr-piperidone 8, i-propylamine and formaldehyde gave bispidone 10 in 67% yield (~21 g scale of product, purified by fractional distillation).In the same way, the n-Pr analogue 11 was prepared in 44% yield from N-n-Pr-piperidone 9 and npropylamine.Our plan was to investigate different methodology for removing or masking the carbonyl functionality in bispidone 10.A Wittig reaction using the ylid from Ph3PMe + Br - required some optimisation.Eventually, it was found that use of KHMDS as the base and refluxing for 16 hours delivered alkene 12 in 65% yield.Subequent hydrogenation of alkene 12 using NH4 + HCO2 -and Pd(OH)2/C gave bispidine 13 in 65% yield.The ketone in bispidone 10 was readily reduced using NaBH4 to give alcohol 14 (69% yield).

Scheme 3
Finally, as part of this study, we re-evaluated the Wolff-Kishner reduction of bispidone 10 to bis-i-Pr-bispidine 6.In our reported method, reaction with hydrazine/KOH was carried out at 180 °C for 4 hours. 17It transpired that the reaction was incomplete after 4 hours and a simple change to a reaction time of 16 hours led to a significant improvement in yield (88% compared to 38%).In addition, during the work-up, it was necessary to cool the reaction mixture to ~60 °C and transfer it to a separating funnel and then add water.If the diethylene glycol solution was cooled to room temperature before addition of water then the reaction mixture became very viscous and difficult to work with.The bis-n-Pr-bispidine 15 was prepared in 84% yield in the same way.

Conclusion
In conclusion, we have optimised the two-step synthesis of bis-i-Pr-bispidine 6 and carried out the synthesis of other bispidines for use in the two-ligand catalytic asymmetric deprotonation of N-Boc pyrrolidine 4.Although alkene bispidine 12 worked well, we believe that bis-i-Prbispidine 6 remains the best stoichiometric recycling diamine for such catalytic asymmetric deprotonation reactions.

Experimental Section
General.H2O is distilled water.Brine refers to a saturated aqueous solution of NaCl.Et2O, THF or Methyl-THF were freshly distilled from sodium and benzophenone ketyl.All diamines and N-Boc pyrrolidine were distilled over CaH2 before use.Petrol refers to the fraction of petroleum ether boiling in the range 40-60 C.All reactions were carried out under O2-free Ar using ovendried and/or flame-dried glassware.n-Butyllithium and s-butyllithium were titrated against Nbenzylbenzamide before use. 25lash column chromatography was carried out using Fluka Chemie GmbH silica (220-440 mesh).Thin layer chromatography was carried out using Merck F254 aluminium-backed silica plates. 1 H (400 MHz) and 13 C (100.6 MHz) NMR spectra were recorded on a Jeol ECX-400 instrument with an internal deuterium lock.Chemical shifts are quoted as parts per million and referenced to CHCl3 (H 7.27) and or CDCl3 (C 77.0, central line of triplet). 13C NMR spectra were recorded with broadband proton decoupling. 13C NMR spectra were assigned using DEPT experiments.Coupling constants (J) are quoted in Hertz.IR spectra were recorded on an ATI Matteson Genesis FT-IR spectrometer.Boiling points given for compounds purified by Kügelrohr distillation correspond to the oven temperature during distillation.Electrospray high and low resolution mass spectra were recorded on a Bruker Daltronics microOTOF spectrometer.Optical rotations were recorded at room temperature on a Jasco DIP-370 polarimeter (using sodium D line; 259 nm) and [α]D given in units of 10 -1 deg cm 3 g -1 .Chiral stationary phase (CSP)-HPLC was performed on an Agilent 1200 series instrument and a multiple wavelength, UV/Vis diode array detector; integration was normally performed at 230 nm.